WO2013039202A1 - Novel acrylic acid derivative - Google Patents

Novel acrylic acid derivative Download PDF

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Publication number
WO2013039202A1
WO2013039202A1 PCT/JP2012/073632 JP2012073632W WO2013039202A1 WO 2013039202 A1 WO2013039202 A1 WO 2013039202A1 JP 2012073632 W JP2012073632 W JP 2012073632W WO 2013039202 A1 WO2013039202 A1 WO 2013039202A1
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group
compound
acceptable salt
pharmacologically acceptable
alkyl group
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PCT/JP2012/073632
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French (fr)
Japanese (ja)
Inventor
勉 永田
小林 順
昌倫 岸田
崇 石山
洋成 清水
研吾 野口
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第一三共株式会社
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Publication of WO2013039202A1 publication Critical patent/WO2013039202A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a novel acrylic acid derivative having excellent TAFIa inhibitory activity.
  • thrombus In vivo, when a failure occurs in a blood vessel, platelets and / or a coagulation cascade are activated to prevent blood leakage, and a thrombus is formed to suppress bleeding.
  • Thrombin generated by the activation of the coagulation cascade cleaves fibrinogen to form insoluble fibrin. Fibrin exists in a mesh form in the thrombus and has a function of strengthening the thrombus. This reaction is called coagulation.
  • the formed fibrin is then degraded by an in vivo reaction. This reaction is fibrinolysis. Under normal conditions, the balance between coagulation and fibrinolysis is regulated and no abnormal amount of thrombus accumulates in the blood vessel.
  • Thrombus formation occurs due to three factors (Virchow's three principles: changes in blood vessel wall properties, changes in blood components, changes in blood flow). Diseases resulting from thrombus formation are one of the most common causes of death among developed countries.
  • TAFI is a carboxypeptidase that is produced in the liver and secreted into the blood.
  • the N-terminal 92-amino acid complex is cleaved by thrombin or thrombin / thrombomodulin residues. Activated.
  • TAFI is also called carboxypeptidase U, carboxypeptidase R, or plasma carboxypeptidase B.
  • TAFIa Activated TAFI is called TAFIa.
  • TAFIa inhibits fibrinolysis by removing the C-terminal Lys or Arg residue of fibrin, which is a major component of thrombus, and fibrin partial degradation products (FDP, Fibrin Degradation Products).
  • FDP Fibrin Degradation Products
  • Two enzymes that induce and promote fibrinolysis, tPA (tissue-type plasminogen activator) and plasminogen bind to fibrin and Lys residues of FDP via their Lys binding sites To do. Subsequently, tPA activates plasminogen on the surface of the fibrin molecule to convert it into plasmin, and initiates fibrinolysis.
  • a Lys or Arg residue appears at the C-terminus of FDP generated by plasmin cleaving fibrin.
  • new plasminogen and tPA bind to the Lys residue of FDP, and further plasmin is generated, so that fibrinolysis proceeds efficiently (positive feedback mechanism of fibrinolysis).
  • TAFIa removes the C-terminal Lys residue of FDP, activation of plasminogen by tPA on the fibrin molecule is inhibited, and an efficient fibrinolytic reaction does not occur.
  • TAFIa suppresses the positive feedback mechanism of fibrinolysis.
  • coagulation As described above, a delicate balance between coagulation and fibrinolysis is established in vivo.
  • coagulation is enhanced due to a disease or the like, blood clots are easily formed, and various diseases develop.
  • diseases include myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation syndrome and pulmonary fibrosis. is there.
  • enzymes in the coagulation cascade are often targeted for the treatment of thrombosis. These include activated coagulation factor X (Xa) and thrombin. Inhibitors to these enzymes are at risk for potential side effects such as bleeding. Heparin and low molecular weight heparin cannot be expected to have a medicinal effect when administered orally and must be administered in hospitals. Warfarin can be administered orally, but regular blood tests are necessary for reasons such as interactions with other drugs. Aspirin is an orally administrable drug that inhibits platelet activation and inhibits thrombus formation, but has side effects such as gastric bleeding. One of the goals for further improving the current treatment methods is not to prolong bleeding time while maintaining a high therapeutic effect by drug administration. TAFIa inhibitors are thought to have a low risk for bleeding because they do not affect the process of coagulation and hemostasis by platelets.
  • the fibrinolysis reaction can be made efficient by inhibiting TAFIa and the blood clot can be removed more quickly.
  • it can be expected to exhibit excellent effects in the treatment and prevention of diseases caused by blood clots. So far, several examples of animal experiments that have shown antithrombotic effects by inhibiting TAFIa have been reported.
  • Non-patent Document 2 There is a report that an anti-thrombotic effect was shown in an iron chloride-induced thrombus model by intravenously administering a 39-amino acid polypeptide potatocarboxypeptidase inhibitor (PCI) that inhibits TAFIa to mice.
  • PCI 39-amino acid polypeptide potatocarboxypeptidase inhibitor
  • Non-patent Document 3 In the rabbit venous thrombosis model, the low molecular weight TAFIa inhibitor decreased the thrombus amount by about 35% by intravenous administration (Non-patent Document 3).
  • the low molecular weight TAFIa inhibitor compound is the equivalent of a rat thromboembolism model that reduces the amount of thrombus deposited on the kidney, increases the fibrinolytic marker D-dimer, and reduces the dose of tPA in combination with tPA.
  • the antithrombotic effect was shown (nonpatent literature 4 and 5).
  • Patent Documents 1 to 5 disclose compounds exhibiting TAFIa inhibitory activity.
  • the present inventors have excellent TAFIa inhibitory activity, myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation Various synthetic studies were conducted with the aim of acquiring therapeutic agents for syndrome or pulmonary fibrosis. As a result, the inventors have found that an acrylic acid derivative having a specific structure or a pharmacologically acceptable salt thereof exhibits excellent TAFIa inhibitory activity, and has completed the present invention.
  • the present invention provides an acrylic acid derivative exhibiting excellent TAFIa inhibitory activity or a pharmacologically acceptable salt thereof, and a pharmaceutical containing these.
  • R a is a C 1 -C 6 alkyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group A; A C 2 -C 6 alkenyl group optionally substituted by 3 groups; a C 3 -C 10 cycloalkyl group optionally substituted by 1 to 3 identical or different groups selected from Substituent Group B An aryl group which may be substituted with the same or different 1 to 3 groups selected from Substituent Group B; which may be substituted with the same or different 1 to 3 groups selected from Substituent Group B; A saturated heterocyclyl group; or an unsaturated heterocyclyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group B (the substituent group A is a hydroxyl group, a halogen atom, a cyano group, Nitro group, amino group, carboxy group, 3 ⁇ C 8 cycloalkyl group, C 1 ⁇ C 3 alkoxy group, a
  • R a is a C 1 -C 6 alkyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group A; A C 2 -C 6 alkenyl group optionally substituted by 3 groups; a C 3 -C 10 cycloalkyl group optionally substituted by 1 to 3 identical or different groups selected from Substituent Group B An aryl group which may be substituted with the same or different 1 to 3 groups selected from Substituent Group B; which may be substituted with the same or different 1 to 3 groups selected from Substituent Group B; A saturated heterocyclyl group; or an unsaturated heterocyclyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group B (the substituent group A is a hydroxyl group, a halogen atom, a cyano group, Nitro group, amino group, carboxy group, 3 ⁇ C 8 cycloalkyl group, C 1 ⁇ C 3 alkoxy group, a
  • R a is the same or different 1 to 3 groups selected from a hydroxyl group, a halogen atom, an amino group, a C 1 to C 3 alkyl group, a C 3 to C 6 cycloalkyl group, a phenyl group and a phenoxy group.
  • An optionally substituted C 1 -C 6 alkyl group substituted with the same or different 1 to 3 groups selected from a hydroxyl group, a halogen atom, an amino group, a C 1 -C 3 alkyl group, a phenyl group and a phenoxy group; which may be C 2 ⁇ C 6 alkenyl group; a hydroxyl group, a halogen atom, an amino group and a C 1 ⁇ C 3 may be substituted by the same or different 1 to 3 groups selected from alkyl radicals C 3 ⁇ C 8 cycloalkyl group; a hydroxyl group, a halogen atom, a cyano group, an amino group, C 1 ⁇ C 3 alkyl group, a halogeno C 1 ⁇ C 3 alkyl group (said substituents may indicate the same 1 to 3 halogen atoms .), C 1 ⁇ C 3 alkoxy group, C 1 ⁇ C 3 alkylsulfonyl group,
  • R a is a C 3 -C 6 alkyl group; a C 3 -C 6 cycloalkyl group or a C 1 -C 2 alkyl group substituted with a phenyl group; a C 3 -C 7 cycloalkyl
  • R a is a group
  • the compound according to item 1, or a pharmacologically acceptable salt thereof (12) The compound according to any one of (1) to (10) above, wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and R 8 are all hydrogen atoms, or Its pharmacologically acceptable salts, (13) The compound according to any one of (1) to (12), wherein R 3 and R 9 are both hydrogen atoms, or a pharmacologically acceptable salt thereof, (14) R 9 is a prodrug group, and the prodrug group is the same selected from an amino group, a halogen atom, a hydroxyl group, a carboxy group, a carbamoyl group, a C 1 -C 6 alkoxy group, an aryl group, and a heterocyclyl group.
  • R 9 is a prodrug group, and the prodrug group includes a phenylalanyl group, an L-norleucyl group, [(5-methyl-2-oxo-1,3-dioxol-4-yl
  • a C 1 -C 6 alkyl group which may be substituted with three groups; or may be substituted with the same or different 1 to 3 groups selected from an oxo group and a C 1 -C 6 alkyl group
  • R 3 is a prodrug group, and the prodrug group is a benzyl group or a [(isopropoxycarbonyl) oxy] ethyl group, according to any one of (1) to (12) above
  • a compound, or a pharmacologically acceptable salt thereof (18)
  • the compound according to (1) or a pharmacologically acceptable salt thereof selected from the group consisting of: (19) A medicament comprising the compound according to any one of (1) to (18) above or a pharmacologically acceptable salt thereof as an active ingredient, (20) A TAFIa inhibitor comprising the compound according to any one of (1) to (18) above or a pharmacologically acceptable salt thereof as an active ingredient, (21) A fibrinolysis promoter containing the compound according to any one of (1) to (18) or a pharmacologically acceptable salt thereof as an active ingredient, (22) A prophylactic agent for a disease caused by inhibition of fibrinolysis comprising the compound according to any one of (1) to (18) or a pharmacologically acceptable salt thereof as an active ingredient, or Therapeutic drugs, (23) Myocardial infarction, angina pectoris (stable angina, unstable angina) containing the compound according to any one of (1) to (18) or a pharmacologically acceptable salt thereof as an active ingredient Acute coronary syndromes such as cardiomyopathy; venous
  • thrombosis / embolism such as disease (25)
  • Lung diseases such as embolic pulmonary hypertension; glomerulonephritis (acute glomerulonephritis, chronic glomerulonephritis, nephrotic nephritis, acute progressive glomerulonephritis, etc.), kidney diseases such as renal infarction, diabetic nephritis; Liver disease such as liver fibrosis, hepatitis, cirrhosis; eye disease associated with ocular fibrin deposition; organ
  • the acrylic acid derivative represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has excellent TAFIa inhibitory activity, and exhibits high oral absorption, plasma concentration and retention in blood. Showed excellent pharmacological action.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is excellent in pharmacokinetics such as distribution in the body, retention in blood, etc., has no prolonged bleeding time, and is highly safe. .
  • the acrylic acid derivative represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is preferably used as a medicine (especially a prophylactic or therapeutic drug for diseases caused by inhibition of fibrinolysis, Are useful as therapeutic agents), especially acute coronary syndromes such as myocardial infarction and angina (stable angina, unstable angina); venous thromboembolism such as deep vein thrombosis and pulmonary embolism; blood vessels Thrombosis or embolism in the cardiovascular system after surgical operations such as reopening surgery, angioplasty, stent placement, bypass surgery, etc .; Thrombus after artificial joint replacement surgery such as knee replacement surgery and hip replacement surgery Inflammation-related intravascular diseases such as sepsis, disseminated intravascular coagulation syndrome (DIC); Originated / related to peripheral vascular disorders such as peripheral arterial embolism (PAO), arteriosclerosis, diabetes disease; Diseases related to tumors such as shape cancer and blood cancer; or prophylactic drugs
  • the compound of the present invention is a disease caused by contact with a foreign body such as a medical device such as an artificial joint, a vascular catheter, an artificial blood vessel, a vascular stent, or an artificial valve at the time of joint replacement; It is useful as a prophylactic or therapeutic agent (preferably a therapeutic agent) for thrombosis / embolism such as a disease caused by contact of blood with an external medical device such as a cardiopulmonary device or a medical device during hemodialysis.
  • a medical device such as an artificial joint, a vascular catheter, an artificial blood vessel, a vascular stent, or an artificial valve at the time of joint replacement
  • a prophylactic or therapeutic agent preferably a therapeutic agent for thrombosis / embolism
  • an external medical device such as a cardiopulmonary device or a medical device during hemodialysis.
  • the compound of the present invention is used for pulmonary hypertension, adult respiratory urgency syndrome, pulmonary fibrosis, chronic thromboembolic pulmonary hypertension and the like; glomerulonephritis (acute glomerulonephritis, chronic glomerulonephritis, nephrotic nephritis) , Acute progressive glomerulonephritis), kidney diseases such as renal infarction, diabetic nephritis; liver diseases such as liver fibrosis, hepatitis, cirrhosis; eye diseases associated with ocular fibrin deposition; organ transplantation or resection Postoperative organ dysfunction; microcirculatory disturbance due to microthrombosis including thrombotic microangiopathy; or preventive or therapeutic (preferably, therapeutic) for diseases / symptoms associated with cancer cell migration / metastasis It is useful as a prophylactic or therapeutic agent (preferably a therapeutic agent) for diseases associated with thrombosis / embolism or associated with fibrin deposition or the like
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • C 1 -C 6 alkyl group means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group.
  • halogeno C 1 -C 3 alkyl group is the above “C 1 -C 3 alkyl group” substituted with 1 to 3 of the above “halogen atoms”, preferably 1 to 3 A C 1 -C 3 alkyl group substituted with a fluorine atom, and more preferably a trifluoromethyl group.
  • C 3 -C 10 cycloalkyl group means a saturated hydrocarbon ring having 3 to 10 carbon atoms, and is exemplified by a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like.
  • a polycycloalkyl group such as a bicycloalkyl group or a tricycloalkyl group is also included.
  • bicycloalkyl group examples include a norbornyl group such as an exo-2-norbornyl group, an endo- Such as 2-norbornyl group, 3-pinanyl group, bicyclo [3.1.0] hexyl group, bicyclo [2.2.1] heptyl group, bicyclo [2.2.2] oct-2-yl group, tricyclo
  • the alkyl group examples include an adamantyl group such as a 1-adamantyl group and a 2-adamantyl group.
  • Number 3 is a saturated hydrocarbon ring of ⁇ 8 (C 3 ⁇ C 8 cycloalkyl group), more preferably a saturated hydrocarbon ring having 3 to 7 carbon atoms (C 3 ⁇ C 7 cycloalkyl group), further More preferred is a cyclohexyl group.
  • the “C 1 -C 6 alkoxy group” means a linear or branched alkyloxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a tert- Examples thereof include a butoxy group, preferably a linear or branched alkyloxy group having 1 to 3 carbon atoms (C 1 -C 3 alkoxy group), and more preferably a methoxy group.
  • halogeno C 1 -C 3 alkoxy group is the above-mentioned “C 1 -C 3 alkoxy group” substituted with the same or different 1 to 3 “halogen atoms”, preferably 1 to 3 A C 1 -C 3 alkoxy group substituted with a fluorine atom, and more preferably a trifluoromethoxy group.
  • C 1 -C 3 alkylsulfonyl group means a linear or branched alkylsulfonyl group having 1 to 3 carbon atoms, and includes a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, and an isopropylsulfonyl group. Can be mentioned.
  • Aryl group means an aryl group having 6 to 14 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, an anthryl group, and a phenanthryl group.
  • heterocyclyl group is a monocyclic or bicyclic 3 to 10-membered saturated or unsaturated heterocyclic ring containing 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom Group, for example, aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isothiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl Group, pyrazinyl group, benzimidazolyl group, benzoxazolyl group, quinolyl group, pyrrolinyl group, imidazolinyl group, pyrazolinyl group, dihydropyridyl group, tetrahydropyridyl group, etc., and
  • Aryloxy group means a group composed of the aryl group and an oxy group, and examples thereof include a phenoxy group and a naphthoxy group.
  • C 2 -C 6 alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, butenyl, 1-propenyl, isopropenyl. Groups and the like.
  • halogenoaryl group is the above “aryl group” substituted with 1 to 3 “halogen atoms” which are the same or different, and examples thereof include a chlorophenyl group and a bromophenyl group.
  • Halogeno unsaturated heterocyclyl group means the above “unsaturated heterocyclyl group” substituted with 1 to 3 of the above “halogen atoms”, and examples thereof include a chlorothienyl group “C 1 -C
  • the “ 6 alkanoyl group” means a linear or branched alkanoyl group having 1 to 6 carbon atoms, such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, An isovaleryl group, a pivaloyl group, a hexanoyl group, etc. are mentioned.
  • C 2 -C 6 alkanoyloxy group means a group consisting of a linear or branched alkanoyl group having 2 to 6 carbon atoms and an oxy group, such as an acetyloxy group, propionyloxy group. Group, hexanoyloxy group and the like.
  • (C 3 -C 6 cycloalkyl) carbonyloxy group means a group consisting of a saturated hydrocarbon ring having 3 to 6 carbon atoms and a carbonyloxy group, such as a cyclopropylcarbonyloxy group, a cyclohexylcarbonyloxy group. Etc.
  • the “(C 1 -C 6 alkoxy) carbonyl group” means a group composed of the C 1 -C 6 alkoxy group and a carbonyl group, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and an isopropoxycarbonyl group.
  • Heterocyclyloxy group means a group composed of the heterocyclyl group and an oxy group, and examples thereof include a pyrrolidin-3-yloxy group and a pyridin-4-yloxy group.
  • heterocyclylalkyl group means a group consisting of the heterocyclyl group and the C 1 -C 6 alkyl group, and examples thereof include a 1,3-dioxol-4-ylmethyl group.
  • heterocyclylalkyloxycarbonyl group means a group consisting of the heterocyclyl group, the C 1 -C 6 alkoxy group and a carbonyl group, and examples thereof include a 1,3-dioxol-4-ylmethoxycarbonyl group. .
  • the “prodrug group” is a group that can be converted into the compound (I) that is an active ingredient of the pharmaceutical composition of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized or reduced.
  • the prodrug group in R 3 is a prodrug group with respect to a carboxy group, and is preferably the same or selected from a C 2 to C 6 alkanoyloxy group, a (C 3 to C 6 cycloalkyl) carbonyloxy group and an aryl group.
  • C 1 -C 6 alkyl group optionally substituted with 1 to 3 different groups, or 1 to 3 groups selected from the same or different groups selected from oxo group and C 1 -C 6 alkyl group
  • a heterocyclylalkyl group which may be a benzyl group or a [(isopropoxycarbonyl) oxy] ethyl group.
  • the prodrug group in R 9 is a prodrug group with respect to an amino group, and preferably from an amino group, a halogeno group, a hydroxyl group, a carboxy group, a carbamoyl group, a C 1 -C 6 alkoxy group, an aryl group, and a heterocyclyl group.
  • a heterocyclylalkyloxycarbonyl group which may be substituted with the same or different 1 to 3 groups selected from An aenylalanyl group, an L-norleucyl group, a [(5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy] carbonyl group, a [1- (isobutyryloxy) ethoxy] carbonyl group, [1- A (2,2-di
  • the compound represented by the general formula (I) is preferably a compound represented by the general formula (Ia).
  • R a is preferably selected from (a) a hydroxyl group, a halogen atom, an amino group, a C 1 -C 3 alkyl group, a C 3 -C 6 cycloalkyl group, a phenyl group and a phenoxy group.
  • C 1 -C 6 alkyl group which may be substituted with the same or different 1 to 3 groups; the same or selected from hydroxyl group, halogen atom, amino group, C 1 -C 3 alkyl group, phenyl group and phenoxy group
  • a C 2 -C 6 alkenyl group optionally substituted with 1 to 3 different groups; the same or different 1 to 3 groups selected from a hydroxyl group, a halogen atom, an amino group and a C 1 -C 3 alkyl group;
  • * indicates a bonding position
  • R b is preferably (a) a hydrogen atom or a methyl group, and more preferably (b) a hydrogen atom.
  • R 1 , R 2 , R 4 , R 6 , R 7 and R 8 are each preferably a hydrogen atom (a).
  • R 5 is preferably (a) a hydrogen atom or a methyl group, and more preferably (b) a hydrogen atom.
  • R 3 is preferably (a) a hydrogen atom.
  • R 3 is a prodrug group
  • a prodrug group bonded to the oxygen atom of the carboxyl group preferably (c) a C 2 -C 6 alkanoyloxy group, (C 3 -C 6 cyclo An alkyl) carbonyloxy group and an aryl group, and a C 1 to C 6 alkyl group which may be substituted with the same or different 1 to 3 groups selected from an aryl group; or an oxo group and a C 1 to C 6 alkyl group Heterocyclylalkyl group which may be substituted with the same or different 1 to 3 groups, more preferably (d) benzyl group or [(isopropoxycarbonyl) oxy] ethyl group.
  • R 9 is preferably (a) a hydrogen atom.
  • R 9 is a prodrug group
  • a prodrug group bonded to the nitrogen atom of the amino group preferably (c) an amino group, a halogen atom, a hydroxyl group, a carboxy group, a carbamoyl group, C 1 ⁇ C 6 alkoxy group, the same or different 1 to 3 is substituted with a group optionally C 1 even if ⁇ C 6 alkanoyl group selected from heterocyclyl, an aryl group, and to; C 1 ⁇ C 6 alkyl radical; C 2 ⁇ (C 1 -C 6 alkoxy) carbonyl group optionally substituted by the same or different 1 to 3 groups selected from C 6 alkanoyloxy group, (C 3 -C 6 cycloalkyl) carbonyloxy group and aryl group Or a heterocyclylalkyloxycarbonyl optionally substituted by the same or different 1 to 3 groups
  • R a is a hydroxyl group, a halogen atom, an amino group, a C 1 -C 3 alkyl group, a C 3 -C 6 cycloalkyl group, a phenyl group, and C 1 -C 6 alkyl group which may be substituted with the same or different 1 to 3 groups selected from phenoxy group; hydroxyl group, halogen atom, amino group, C 1 -C 3 alkyl group, phenyl group and phenoxy group A C 2 -C 6 alkenyl group which may be substituted with the same or different 1 to 3 groups selected from: a hydroxyl group, a halogen atom, an amino group and a C 1
  • R a is a cyclohexyl group substituted with 1 to 2 methyl groups
  • R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are both hydrogen atoms
  • R a is a group
  • R a is a group
  • R b R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are all hydrogen atoms. It is.
  • R 3 is a prodrug group
  • R a is preferably a cyclohexyl group substituted with 1 to 2 methyl groups
  • R b , R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are all hydrogen atoms
  • R 3 is a prodrug group bonded to the oxygen atom of the carboxyl group
  • R a is a cyclohexyl group substituted with 1 to 2 methyl groups
  • R b , R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is a hydrogen atom
  • R 3 is the same or different 1 to 3 groups selected from a C 2 -C 6 alkanoyloxy group, a (C 3 -C 6 cycloalkyl) carbonyloxy group and an aryl group
  • a C 1 -C 6 alkyl group which may be substituted by: or a heterocycly
  • R 9 is a prodrug group
  • R a is preferably a cyclohexyl group substituted with 1 to 2 methyl groups
  • R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are all hydrogen atoms
  • R 9 is a prodrug group bonded to the nitrogen atom of the amino group
  • R a is a cyclohexyl group substituted with 1 to 2 methyl groups
  • R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is a hydrogen atom
  • R 9 is the same or different one selected from an amino group, a halogen atom, a hydroxyl group, a carboxy group, a carbamoyl group, a C 1 -C 6 alkoxy group, an aryl group and a heterocyclyl group.
  • C 1 -C 6 alkanoyl group optionally substituted with three groups; C 1 -C 6 alkyl group; C 2 -C 6 alkanoyloxy group, (C 3 -C 6 cycloalkyl) carbonyloxy group and aryl the same or different 1 to 3 may be substituted by a group (C 1 ⁇ C 6 alkoxy) carbonyl group selected from the group; or, the same or different selected from oxo group and C 1 ⁇ C 6 alkyl group 1 to 3 substituents which may be heterocyclylalkyl alkyloxycarbonyl group with a group that, More preferably, R a is a cyclohexyl group substituted with 1 to 2 methyl groups, and R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is a hydrogen atom, and R 9 is a phenylalanyl group, an L-norleucyl group,
  • Preferred specific examples of the compound represented by the general formula (I) or (Ia) include the following.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a and R b are the same as described above, and R 10 is substituted with a fluorine atom.
  • An optionally substituted C 1 -C 3 alkyl group or a phenyl group PG 1 represents an amino protecting group, PG 2 represents a hydrogen atom or an amino protecting group, and PG 3 represents a carboxy protecting group. Show.
  • Compound (IV) can be produced by subjecting compound (IIa) and compound (III) to an aldol reaction to produce compound (IV), and the resulting compound (IV) can be subjected to a dehydration reaction.
  • compound (V) can be produced by performing a wittig reaction between compound (IIb) and compound (III).
  • Compound (Ib) can be produced by removing the protecting group of the obtained compound (V).
  • the aldol reaction is a reaction in which compound (IIa) as a CH active compound and compound (III) containing a carbonyl group are combined in the presence of a strong base to form compound (IV).
  • the strong base include carbonates of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride; Metal alkoxide, alkali metal hydroxide or hydride; alkyllithium such as n-butyllithium, organometallic base represented by dialkylaminolithium such as lithium diisopropylamide; or such as lithium hexamethyldisilazide An organometallic base of bissilylamine can be used.
  • reaction solvent examples include acyclic, cyclic or aromatic hydrocarbons, alcohols, or polar aprotic solvents such as tetrahydrofuran, N, N-dimethylformamide or diethoxyethane, and mixed solvents thereof. Can be used.
  • the reaction temperature is usually about ⁇ 78 ° C. to room temperature.
  • the hydroxyl group of compound (IV) is treated with a sulfonyl halide such as methanesulfonyl chloride or benzenesulfonyl chloride in an inert solvent at ⁇ 78 ° C. to 50 ° C. in the presence of triethylamine to form a sulfonate ester.
  • a sulfonyl halide such as methanesulfonyl chloride or benzenesulfonyl chloride in an inert solvent at ⁇ 78 ° C. to 50 ° C. in the presence of triethylamine to form a sulfonate ester.
  • the inert solvent examples include alkyl halide solvents such as methylene chloride, chloroform and carbon tetrachloride; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane; aromatic solvents such as benzene and toluene; Alternatively, amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one and the like, and in addition to these, sulfoxide solvents such as dimethyl sulfoxide and sulfolane may be mentioned; It is also possible to use ketone solvents such as acetone and methyl ethyl ketone; or acetonitrile.
  • alkyl halide solvents such as methylene chloride, chloroform and carbon tetrachloride
  • ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and di
  • pyridine 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU) is used. be able to. In some cases, the dehydration reaction may proceed during the aldol reaction.
  • DBU diazabicyclo [5.4.0] undec-7-ene
  • the Wittig reaction is a reaction in which a compound (IIb) having a phosphoryl group and a compound (III) having a carbonyl group are reacted in the presence of a base to produce a compound (V) which is an ⁇ , ⁇ -unsaturated ester.
  • a base sodium hydride, sodium methoxide, potassium carbonate, potassium hexamethylsilazide and the like can be used.
  • a base such as diazabicyclo [5.4.0] undec-7-ene (DBU) or triethylamine and lithium chloride can be used in combination.
  • cyclic ethers such as 18-crown 6-ether can be added as additives.
  • reaction temperature may be selected depending on the substrate, and the reaction can be carried out from ⁇ 78 ° C. under reflux conditions. It can be produced with reference to the following document. 1) Blanchette, M .; A. , Et al. Tetrahedron Lett. 1984, 25, 2183. 2) Still, W .; C. , Et al. Tetrahedron Lett. 1983, 24, 4405.
  • a protecting group usually used as an amino-protecting group in the synthesis of organic compounds, particularly in peptide synthesis may be used.
  • a tert-butoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group may be used.
  • Alkoxycarbonyl groups such as benzyl groups; arylmethoxycarbonyl groups such as benzyloxycarbonyl groups, paramethoxybenzyloxycarbonyl groups, para (or ortho) nitrobenzyloxycarbonyl groups; benzyl groups, 4-methoxybenzyl groups, triphenylmethyl groups, etc.
  • alkanoyl group such as a formyl group or an acetyl group; an aroyl group such as a benzoyl group; or an arylsulfonyl group such as a 2,4-dinitrobenzenesulfonyl group or an orthonitrobenzenesulfonyl group.
  • These amino-protecting groups may be selected according to the properties of the compound protecting the amino group, and the reagents and conditions corresponding to the protecting groups may be selected when removing these protecting groups.
  • protecting group for the carboxy group examples include an alkyl group, an aryl group, and an arylalkyl ester group. These protecting groups for the carboxy group may be selected according to the properties of the compound protecting the carboxy group, and the reagents and conditions corresponding to the protecting group may be selected when removing these protecting groups.
  • Compound (I) of the present invention can also be produced by the following method.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b , PG 1 , PG 2 and PG 3 are the same as described above, and PG 4 represents a protecting group for an amide group.
  • the cyclization reaction proceeds by keeping the reaction solution neutral to basic, whereby the lactam body (VI) can be produced.
  • the obtained lactam body (VI) is converted to compound (VII) by a dehydration reaction to protect the amide group, and then subjected to a ring-opening reaction to produce compound (IX).
  • Compound (Ic) can be produced by removing the protecting group of compound (IX).
  • the amino group of compound (IV) for example, when PG 1 is a benzyloxycarbonyl group, PG 2 is a hydrogen atom, and PG 3 is a methyl group, the amino group is protected by hydrogenation with a heterogeneous catalyst. It is possible to selectively remove groups. Further, in this case, the subsequent intramolecular cyclization reaction proceeds to produce compound (VI).
  • the solvent for example, water, methanol, ethanol, ethyl acetate, acetic acid and the like can be used.
  • the catalyst palladium-carbon (Pd / C), Pearlman's catalyst (Pd (OH) 2 ), or the like can be used.
  • the reaction temperature can be from room temperature to reflux conditions.
  • the amino group can be selectively deprotected by selecting reagents and conditions according to the protecting group.
  • References include Greene, T .; W. Wuts, P .; G. M.M. , Protective Groups in Organic Synthesis (1999), 3rd Ed. , Wiley-Interscience and the like.
  • acid hydrolysis is used as the amino group deprotection reaction, an amine salt is formed and the cyclization reaction does not proceed sufficiently, so the reaction system must be neutralized.
  • the hydroxyl group of compound (VI) is treated with a sulfonyl halide such as methanesulfonyl chloride or benzenesulfonyl chloride at ⁇ 78 ° C. to 50 ° C. in the presence of a base in an inert solvent, and then further treated with a base.
  • a sulfonyl halide such as methanesulfonyl chloride or benzenesulfonyl chloride
  • the protection of the amide group is a reaction in which compound (VIII) is formed by protecting amide NH on the lactam ring of compound (VII).
  • the protecting group PG 4 is preferably a tert-butoxycarbonyl group. It is possible to protect the amide group by reacting di-tert-butyl dicarbonate under conditions of 0 ° C. to reflux using 4-dimethylaminopyridine as a base in an inert solvent such as dichloromethane or acetonitrile. .
  • an inert solvent such as dichloromethane or acetonitrile.
  • protecting groups for other amide groups for example, Greene, T. et al. W. Wuts, P .; G. M.M. , Protective Groups in Organic Synthesis (1999), 3rd Ed. , Wiley-Interscience and the like.
  • the ring-opening reaction is a reaction for obtaining compound (IX) by hydrolyzing the lactam ring of compound (VIII).
  • PG 4 is a tert-butoxycarbonyl group
  • lithium hydroxide or the like is allowed to act as a base in a mixed solvent of water and tetrahydrofuran at room temperature.
  • Compound (I) of the present invention can also be produced by the following method.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b , PG 1 , PG 2 , PG 3 and PG 4 are the same as above.
  • PG 5 represents an imidazole protecting group.
  • Compound (X) can be produced by a method similar to Production Method 1 and Production Method 2 using Compound (IIc) in which a protecting group is introduced into the nitrogen atom of imidazole as a starting material. After protecting the carboxyl group of compound (X) to obtain compound (XI), only the protecting group for the nitrogen atom of imidazole can be removed to produce compound (XII).
  • Compound (XIII) is produced by alkylating, alkenylating, cycloalkylating, saturated heterocyclylating, arylating or unsaturated heterocyclylating the nitrogen atom of the imidazole moiety of compound (XII) and removing the protecting group Thus, compound (Ic) can be produced.
  • Examples of the protecting group for the nitrogen atom of imidazole include sulfonyl groups such as benzenesulfonyl group and tosyl group; alkoxycarbonyl groups such as t-butoxycarbonyl group and benzyloxycarbonyl group; or trityl group, methoxymethyl group, benzyloxy Examples thereof include alkyl groups such as a methyl group and [2- (trimethylsilyl) ethoxy] methyl group. Among these, a trityl group is preferable.
  • the protecting group for the nitrogen atom of these imidazoles may be selected according to the properties of the compound, and reagents and conditions corresponding to the protecting group may be selected when removing these protecting groups.
  • Protecting / deprotecting amino groups, amide groups, and carboxyl groups is the same as in manufacturing method 1 and manufacturing method 2.
  • Alkylation reaction, cycloalkylation reaction and saturated heterocyclylation reaction are carried out in the presence of a base, for example, elimination of R a -I, R a -Br, R a -OSO 2 CH 3 , R a -OSO 2 CF 3, etc.
  • a compound having a group is reacted with compound (XII) to produce compound (XIII).
  • the reaction solvent an acyclic, cyclic or aromatic hydrocarbon or a polar aprotic solvent can be used.
  • tetrahydrofuran, N, N-dimethylformamide, diethoxyethane, or a mixed solvent thereof can be used. it can.
  • the base for example, cesium carbonate, sodium hydride and the like can be used.
  • the alkenylation reaction, unsaturated heterocyclylation reaction and arylation reaction can be performed by reacting, for example, unsaturated heterocyclylboronic acid or arylboronic acid compound R a -B (OH) 2 with compound (XII). This reaction generates (XIII).
  • a known reaction ((PYS.Lam et al., Tetrahedron Lett., 39, 2941, 1998) can be referred to.
  • the unsaturated heterocyclylation reaction may alternatively be carried out by reacting R a —Br (or R a —I, R a —F, R a —Cl, etc.) with compound (XII) in the presence of copper oxide.
  • XIII can be obtained.
  • WO2003 / 061652 can be referred to.
  • the intermediate (II) of the compound of the present invention can be produced, for example, by the following method.
  • R ⁇ a> , R ⁇ b> , R ⁇ 10 > and PG ⁇ 3 > show the same thing as the above.
  • the nitrogen atom of the imidazole moiety of compound (XVI) that is commercially available or synthesized using well-known methods is alkylated, alkenylated, cycloalkylated, saturated heterocyclylated, arylated, or unsaturated heterocyclyl. It is possible to produce the compound (XVII) by preparing the compound (XVII) by a wittig reaction using the compound (XVIII).
  • Alkylation, alkenylation, cycloalkylation, saturated heterocyclylation, arylation, or unsaturated heterocyclylation is a reaction for synthesizing compound (XV) from compound (XIV) in the same manner as in Production Method 3. .
  • the Wittig reaction in production method 4 is carried out by reacting a compound (XVIII) having a phosphoryl group with a compound (XVII) having a carbonyl group in the presence of a base to produce a compound (XV) which is an ⁇ , ⁇ -unsaturated ester. It is a reaction.
  • a base sodium hydride, sodium methoxide, potassium carbonate and the like can be used.
  • a base such as diazabicyclo [5.4.0] undec-7-ene (DBU) or triethylamine and lithium chloride can be used in combination.
  • reaction temperature may be selected depending on the substrate, and the reaction can be carried out under a condition of ⁇ 78 ° C. to reflux.
  • the reduction reaction is a reaction in which compound (XV) is hydrogenated to compound (IId) by hydrogenation with a heterogeneous catalyst.
  • a heterogeneous catalyst for example, water, methanol, ethanol, ethyl acetate, acetic acid and the like can be used.
  • the catalyst palladium-carbon (Pd / C), Perlman catalyst (Pearlman's catalyst: Pd (OH) 2 ), Raney nickel, Adams catalyst (Adams' catalyst: PtO 2 ), or the like can be used.
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R a and R b are the same as described above, R 9a represents a prodrug group, and LG 1 represents desorption. Indicates a leaving group.
  • Compound (Ic) can produce a prodrug (Id) by converting an amino group into a prodrug.
  • a prodrug formation of an amino group is a reaction for obtaining a compound (Id) from a compound (Ic) and a compound R 9a —OH by using a condensation reaction.
  • a condensation reaction for example, N, N'- dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, Hydrochloride (EDC.HCl), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride hydrate (DMT-MM), (1H-benzo Triazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (BOP), 1- [bis (dimethylamino) methylene] -1H-benzotriazolium-3-oxide hexafluorophosphate (HBTU), etc
  • compound (Id) can be obtained by condensing compound (Ic) with compound R 9a -LG 1 which is an active ester.
  • LG 1 includes a p-nitrophenyloxy group, a pentafluorophenyloxy group, a chlorine atom, and the like.
  • a method according to a condensation reaction between a carboxylic acid and an active ester used in usual peptide synthesis can be used.
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b and PG 4 are the same as described above, and LG 2 is a leaving group.
  • R 3a represents a prodrug group of a carboxyl group.
  • Compound (Ie) which is a prodrug, can be produced by converting the carboxyl group of compound (IX) into a prodrug and then removing the amino protecting group.
  • a prodrug of a carboxy group is a reaction in which compound (IX) and compound R 3a —OH that is an alcohol are condensed to obtain compound (XIX).
  • the condensing agent N, N′-dicyclohexylcarbodiimide (DCC), N, N′-diisopropylcarbodiimide (DIC), or the like can be used.
  • DCC N, N′-dicyclohexylcarbodiimide
  • DIC N, N′-diisopropylcarbodiimide
  • the reactivity is improved by adding a catalytic amount of 4-dimethylaminopyridine (DMAP).
  • compound (XIX) can be obtained by reacting compound (IX) with compound R 4a -LG 2 which is an alkylating agent under basic conditions.
  • LG 2 includes an iodo group, a bromine atom and the like.
  • an alcohol sulfonate ester eg, R 3a —OSO 2 CH 3 , R 3a —OSO 2 CF 3, etc.
  • R 4a -LG 2 As the reaction solvent, water, tetrahydrofuran, N, N-dimethylformamide, diethoxyethane, or a mixed solvent thereof can be used.
  • the base include alkali metal or alkaline earth metal carbonates such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, and potassium hydrogen carbonate.
  • the acrylic acid derivative of the present invention has an excellent TAFIa inhibitory activity, is excellent in pharmacokinetics such as high oral absorption, blood retention and metabolic stability, and is also useful as a pharmaceutical.
  • Particularly useful as a therapeutic agent for myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation syndrome, pulmonary fibrosis, etc. is there.
  • it is useful as a therapeutic agent for diseases derived from thromboembolism. It is also useful as a medicine for improving organ function after transplantation.
  • thrombus formation and promotion of thrombus dissolution by filling a blood vessel catheter (indwelling catheter for dialysis), extracorporeal blood circulation device and artificial blood vessel, and filling a TAFIa inhibitor solution in the tube. It is also useful as a therapeutic agent for atherothrombosis, fibrosis (pulmonary fibrosis such as chronic obstructive pulmonary disease, fibrosis after ophthalmic surgery, etc.). It is also useful for improving dysfunction associated with the acute phase of ischemic cerebrovascular disorder.
  • the compound represented by the general formula (I) of the present invention has a basic group such as an amino group, it can be converted to an acid addition salt with a pharmacologically acceptable acid.
  • a pharmacologically acceptable acid examples include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide; nitrates, perchlorates, sulfates, phosphates and the like.
  • Inorganic acid salts lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; aryl sulfonates such as benzene sulfonate and p-toluene sulfonate; acetic acid, malic acid, Organic acid salts such as fumarate, succinate, citrate, tartrate, oxalate, maleate; and amino acid salts such as ornithate, glutamate, aspartate, and halogenated Hydronate or aryl sulfonate is preferred, and hydrochloride, benzene sulfonate, or p-toluene sulfonate is more preferred, and benzene sulfonate or p-toluene is preferred.
  • Nsuruhon salt is even more Preferably, p- toluenesulfonic
  • the compound represented by the general formula (I) since the compound represented by the general formula (I) has an acidic group such as a carboxy group, it is generally possible to form a base addition salt.
  • pharmacologically acceptable salts include alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; inorganic salts such as ammonium salt; dibenzylamine salt and morpholine.
  • phenylglycine alkyl ester salt ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, diethanolamine salt, N-benzyl-N -Organic amine salts such as-(2-phenylethoxy) amine salt, piperazine salt, tetramethylammonium salt and tris (hydroxymethyl) aminomethane salt; amino acid salts such as arginine salt; and the like.
  • the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may exist as a free form or a solvate, and these solvates are also included in the scope of the present invention.
  • the solvate is not particularly limited as long as it is pharmacologically acceptable. Specifically, a hydrate, an ethanol solvate, and the like are preferable, and a hydrate is more preferable.
  • a nitrogen atom exists in the compound of the present invention represented by the general formula (I), and the nitrogen atom may be an N-oxide, and these solvates and N-oxides are also present. It is included in the scope of the invention.
  • the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof and a production intermediate of the compound of the present invention may be a geometric isomer such as a cis isomer, a trans isomer, etc.
  • various isomers such as optical isomers such as R isomer and S isomer may exist, but the compound of the present invention is not particularly limited, all isomers, stereoisomers and any ratio of these isomers. It also includes isomers and stereoisomer mixtures.
  • the compound of the present invention or a pharmacologically acceptable salt thereof may also contain an unnatural proportion of atomic isotopes at one or more of atoms constituting such a compound.
  • the atomic isotopes such as deuterium (2 H), tritium (3 H), carbon -13 (13 C), carbon -14 (14 C), nitrogen -15 (15 N), chlorine -37 (37 Cl) or iodine-125 ( 125 I).
  • the compound may also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
  • Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • the present invention relates to a compound that is converted into compound (I) which is an active ingredient of the pharmaceutical composition of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized, reduced, Also included in the present invention is a compound that undergoes hydrolysis or the like and is converted to compound (I), or a “pharmaceutically acceptable prodrug compound” that undergoes hydrolysis or the like by gastric acid or the like and is changed to compound (I). .
  • composition containing the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof an appropriate preparation is selected according to the administration method, and methods for preparing various commonly used preparations Can be prepared.
  • a pharmaceutical composition mainly comprising the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof is administered to a mammal (particularly a human), it can be administered systemically or locally, orally or It can be administered parenterally.
  • oral pharmaceutical forms include tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, syrups, elixirs and the like.
  • These forms of drugs are usually based on the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof, and a diluent, excipient or carrier as a pharmaceutically acceptable additive.
  • the preparation of the pharmaceutical composition comprises any suitable pharmaceutically acceptable binder, disintegrant, lubricant, swelling agent, as or in addition to a pharmaceutically acceptable diluent, excipient or carrier.
  • coating agents plasticizers, stabilizers, preservatives, antioxidants, colorants, solubilizers, suspending agents, emulsifiers, sweeteners, preservatives, buffering agents, wetting agents, etc.
  • coating agents plasticizers, stabilizers, preservatives, antioxidants, colorants, solubilizers, suspending agents, emulsifiers, sweeteners, preservatives, buffering agents, wetting agents, etc.
  • parenteral pharmaceutical forms include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, and the like.
  • These forms of drugs are usually based on the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof, and a diluent, excipient or carrier as a pharmaceutically acceptable additive.
  • the preparation of the pharmaceutical composition may be performed as any suitable pharmaceutically acceptable stabilizer, preservative, solubilizer, humectant, as or in addition to a pharmaceutically acceptable diluent, excipient or carrier.
  • Preservatives antioxidants, flavoring agents, gelling agents, neutralizing agents, buffering agents, isotonic agents, surfactants, coloring agents, buffering agents, thickeners, wetting agents, fillers, absorption enhancement It can carry out according to a conventional method using what was suitably selected from an agent, a suspending agent, a binder, etc. as needed.
  • references regarding the above-mentioned pharmaceutically acceptable excipients include, for example, “Handbook of Pharmaceutical Excipients, 2nd Edition, (1994), Edited by A. Wade and PJ Weller”.
  • the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof can be used in combination with other drugs.
  • Anticoagulant drugs warfarin, heparin, low molecular weight heparin, antithrombin drug, anti-Xa drug, etc.
  • antiplatelet drugs aspirin, ticlopidine, clopidogrel, prasugrel, phosphodiesterase inhibitor, etc.
  • fibrinolysis Enzyme tPA, genetically modified tPA, plasminogen activator such as urokinase, streptokinase, plasmin
  • anticancer drug anti-inflammatory drug, antifibrotic drug, antihypertensive drug, antipulmonary hypertension drug, immunosuppressant drug and so on.
  • the dose of the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof varies depending on symptoms, age, body weight, the kind and dose of drugs administered in combination, etc.
  • the compound (I) equivalent amount is in the range of 0.01 mg to 5000 mg, preferably in the range of 0.1 mg to 1000 mg, more preferably in the range of 1 mg to 200 mg per adult.
  • compound (I) is contained in the range of 0.001 mg / kg to 100 mg / kg, preferably in the range of 0.005 mg / kg to 20 mg / kg, more preferably 0.01 mg / kg to 5 mg. / Kg range.
  • This daily dose may be administered systemically or locally, once a few days to once to several times a day, orally or parenterally, or intravenously in the range of 1-24 hours per day Administer continuously. The daily dose may exceed the above amount if necessary.
  • Triethylamine (9.50 mL) was added dropwise at ⁇ 78 ° C., and the mixture was stirred for 20 minutes, and further stirred at 0 ° C. for 40 minutes.
  • Water was added to the reaction solution, which was diluted with methylene chloride and separated. The aqueous layer was extracted with methylene chloride, and the resulting organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the organic solvent was evaporated under reduced pressure to give the title compound (3.05 g).
  • the aqueous layer was extracted with methylene chloride, and the resulting organic layers were combined and washed with saturated brine.
  • the organic layer was dried over anhydrous sodium sulfate.
  • Step 2 3-O-acetyl-5-[(tert-butoxycarbonyl) amino] -2,4,5-trideoxy-2-[(1-trityl-1H-imidazol-4-yl) methyl] pentonic acid
  • methylene chloride 2.0 mL
  • triethylamine 0.0326 mL
  • acetic anhydride 0.100 mL in methylene chloride: 0 0.192 mL was used as a solution dissolved in 900 mL
  • 4-dimethylaminopyridine in methylene chloride (4-dimethylaminopyridine: 4.0 mg dissolved in 0.500 mL of methylene chloride: 0.080 mL was used) and stirred for 7.5 hours.
  • 1,8-diazabicyclo [5.4.0] undec-7-ene (0.0221 mL) was added to the reaction solution, and the mixture was further stirred for 15 hours.
  • Water and methylene chloride were added to the reaction solution to separate it.
  • the aqueous layer was extracted with methylene chloride, and the resulting organic layers were combined and washed with saturated brine.
  • the organic layer was dried over anhydrous sodium sulfate.
  • reaction solution was air-cooled, and a methylene chloride-methanol solution (20 v / v) and water were added for liquid separation.
  • a methylene chloride-methanol solution (20 v / v) and water were added for liquid separation.
  • the aqueous layer was extracted with methylene chloride, and the resulting organic layers were combined and washed with saturated brine.
  • the organic layer was dried over anhydrous sodium sulfate.
  • Step 4 (2E) -5-amino-2- (imidazol-4-ylmethyl) pent-2-enoic acid dihydrochloride
  • the compound obtained in Step 3 (59.0 mg) was suspended in 5N hydrochloric acid, Stir at 85 ° C. for 3 hours. The reaction solution was air-cooled and insoluble matters were filtered off. The filtrate was concentrated under reduced pressure to obtain the title compound (27.8 mg).
  • 1 H NMR (CD 3 OD) ⁇ : 2.67-2.76 (2H, m), 3.05-3.13 (2H, m), 3.79 (2H, s), 6.96 (1H, t, J 7.0 Hz), 7.28 (1H , s), 8.77 (1H, s).
  • reaction solution was cooled to ⁇ 78 ° C., potassium hexamethyldisilazide (0.5 mol / L toluene solution, 0.42 mL) was added dropwise, and the mixture was stirred at the same temperature for 40 minutes.
  • a solution of the compound (18 mg) obtained in Reference Example 1 in tetrahydrofuran (0.5 mL) was added to the reaction solution and stirred for 30 minutes, and then stirred at 0 ° C. for 40 minutes and further at room temperature for 1.5 hours.
  • Aqueous ammonium chloride solution was added to the reaction solution, diluted with methylene chloride, and separated. The aqueous layer was extracted with methylene chloride, and the resulting organic layers were combined and washed with saturated brine.
  • Step 2 (2Z) -5-amino-2- (1H-imidazol-4-ylmethyl) pent-2-enoic acid dihydrochloride
  • the compound obtained in Step 1 (39.3 mg) was suspended in 5N hydrochloric acid. And stirred at 85 degrees for 4 hours.
  • the reaction solution was cooled to 0 ° C., and insoluble matters were filtered off.
  • the residue obtained by concentrating the filtrate under reduced pressure was purified by reverse phase HPLC (column: GL sciences Prep-ODS; size: 250 ⁇ 30 mm; flow rate: 15 mL / min; elution solvent: H 2 O), and then lyophilized. This gave the title compound (7.9 mg).
  • 18-Crown-6 (825 mg) was added and cooled to -78 ° C.
  • potassium hexamethyldisilazide 0.5 mol / L toluene solution, 1.72 mL
  • an anhydrous tetrahydrofuran solution (30 mL) of the compound obtained in Reference Example 1 (149 mg) was added dropwise over 40 minutes.
  • Saturated aqueous ammonium chloride solution was added, and the mixture was extracted 3 times with methylene chloride.
  • Step 3 (2E) -5-[(tert-butoxycarbonyl) amino] -2-[(1-propyl-1H-imidazol-4-yl) methyl] penta-2-enoic acid methyl obtained in Step 2
  • the compound (65 mg) was dissolved in N, N-dimethylformamide, 1-bromopropane (21 ⁇ L) and triethylamine (43 ⁇ L) were added to this solution, and the mixture was stirred at 60 to 70 ° C. for 4 days. Furthermore, 1-bromopropane (58 ⁇ L) and triethylamine (173 ⁇ L) were added and stirred for 10 hours.
  • Step 2 (2Z) -5-[(tert-butoxycarbonyl) amino] -2-[(1-propyl-1H-imidazol-5-yl) methyl] pent-2-enoic acid methyl obtained in Step 1
  • the compound (127 mg) was dissolved in N, N-dimethylformamide (1.0 mL), triethylamine (84 ⁇ L) and 1-iodopropane (44 ⁇ L) were added to the solution, and the mixture was stirred overnight at room temperature. The mixture was further stirred at 40 ° C. for several hours. Dilute with water and extract several times with ethyl acetate. The organic layer was washed again with water.
  • Step 3 (2Z) -5-amino-2-[(1-propyl-1H-imidazol-5-yl) methyl] pent-2-enoic acid dihydrochloride
  • 5N hydrochloric acid aqueous solution (3.0 mL) was added, and the mixture was stirred at 85 ° C. for about 4 hours. After allowing to cool, the operation of adding a small amount of toluene to the residue obtained by concentrating the reaction solution under reduced pressure and azeotroping was repeated several times. The title compound (12.4 mg) was obtained by drying under reduced pressure.
  • Step 2 3-[(1-Propyl-1H-imidazol-4-yl) methyl] -5,6-dihydropyridin-2 (1H) -one
  • the compound obtained in Step 1 (4.0 g) was converted into methylene chloride. (20 mL) and triethylamine (4.7 mL), methanes and sulfonyl chloride (2.0 mL) were added under ice cooling. The reaction solution was stirred for 10 minutes under ice cooling, and then stirred at room temperature for 2 hours. 1,8-diazabicyclo [5.4.0] undec-7-ene (10.1 mL) was added at room temperature, and the mixture was stirred for about 40 hours.
  • Step 3 6-Oxo-5-[(1-propyl-1H-imidazol-4-yl) methyl] -3,6-dihydropyridine-1 (2H) -tert-butyl carboxylate
  • Compound obtained in Step 2 (1.8 g) was dissolved in methylene chloride (50 mL), and di-tert-butyl dicarbonate (2.0 g) and 4-dimethylaminopyridine (1.0 g) were added to the solution, and the mixture was stirred at room temperature under a nitrogen atmosphere. Stir all day and night. Di-tert-butyl dicarbonate (3.4 g) was further added, and the mixture was stirred for 32 hours.
  • Step 4 (2Z) -5-amino-2-[(1-propyl-1H-imidazol-4-yl) methyl] pent-2-enoic acid
  • the compound (1.6 g) obtained in Step 3 was converted to tetrahydrofuran. / Water mixed solvent (2/1, 20 mL), lithium hydroxide monohydrate (630 mg) was added to this solution, and the mixture was stirred at room temperature for 4 hours. After concentration under reduced pressure, 5N aqueous hydrochloric acid solution (10 mL) was added to the obtained residue under ice cooling, and the mixture was stirred at the same temperature for 10 min and further at room temperature for 1 hr.
  • the obtained residue was dissolved in a small amount of water and adsorbed on a column containing an ion exchange resin (DOWEX® 50Wx8 / 100-200 Mesh / H form, 20 g).
  • the resin was sufficiently washed with ion-exchanged water until the eluate from the lower part of the column became neutral with pH test paper, and then eluted with a solution obtained by diluting 28% ammonia water 10-fold with ion-exchanged water.
  • the eluate was washed with methylene chloride, and the aqueous layer was concentrated under reduced pressure. Acetone was added to the obtained residue to solidify, and the powder was collected by filtration and dried to obtain the title compound (0.9 g).
  • Step 2 3-[(1-Trityl-1H-imidazol-4-yl) methyl] -5,6-dihydropyridin-2 (1H) -one
  • the title compound (2.43 g) was obtained from the compound (4.22 g) obtained in Step 1.
  • Step 3 6-oxo-5-[(1-trityl-1H-imidazol-4-yl) methyl] -3,6-dihydropyridine-1 (2H) -tert-butyl carboxylate Step 3 of Example 5 and Similarly, the title compound (2.82 g) was obtained from the compound (2.43 g) obtained in Step 2 of this example.
  • Step 5 (2Z) -5-[(tert-Butoxycarbonyl) amino] -2- (1H-imidazol-4-ylmethyl) pent-2-enoic acid tert-butyl
  • Step 4 After stirring in 90% acetic acid at 60 ° C. for 2 hours, the reaction solution was neutralized by adding an aqueous sodium hydrogen carbonate solution. Extraction with methylene chloride was performed, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography to obtain the title compound (80.0 mg).
  • Step 6 (2Z) -5-[(tert-butoxycarbonyl) amino] -2- ⁇ [1- (3,3-dimethylbutyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-ene
  • Sodium hydride (63%, 9.5 mg) was added to a solution of the compound obtained in Step 5 (80.0 mg) in N, N-dimethylformamide (3 mL) with stirring at 0 ° C., followed by reference.
  • a solution of the compound obtained in Example 7 (53.1 mg) in N, N-dimethylformamide (0.5 mL) was added, and the mixture was warmed to room temperature and stirred overnight.
  • Step 7 (2Z) -5-amino-2- ⁇ [1- (3,3-dimethylbutyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid
  • 5 M hydrochloric acid 3 mL
  • the reaction mixture was concentrated, and the residue was purified by cation exchange resin (DOWEX 50WX8-200, elution solvent: 3% aqueous ammonia) to give the title compound (26.1 mg).
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (3,3-dimethylbutyl) -1H-imidazol-4-yl] methyl ⁇ -4-methylpent-2-enoic acid of Example 5
  • the target product was obtained as a pale yellow solid from the compound obtained in Step 1 of this example (129 mg).
  • Example 9 (2Z) -5-amino-2-[(1-cyclohexyl-1H-imidazol-4-yl) methyl] pent-2-enoic acid Obtained in Reference Example 12 in the same manner as in Example 5. The title compound (343 mg) was obtained from the obtained compound.
  • Example 10 (2Z) -5-amino-2-[(1- ⁇ [5- (5-chloro-2-thienyl) isoxazol-3-yl] methyl ⁇ -1H-imidazol-4-yl) [Methyl] pent-2-enoic acid [Step 1] (2Z) -5-[(tert-butoxycarbonyl) amino] -2-[(1-trityl-1H-imidazol-4-yl) methyl] pent-2- Methyl enoate The compound (3.72 g) obtained in Step 3 of Example 6 was dissolved in tetrahydrofuran (37 mL), and water (20 mL) containing lithium hydroxide monohydrate (0.90 g) was added with stirring at room temperature.
  • Step 3 (2Z) -5-amino-2-[(1- ⁇ [5- (5-chloro-2-thienyl) isoxazol-3-yl] methyl ⁇ -1H-imidazol-4-yl) methyl ] Penta-2-enoic acid hydrochloride
  • the compound obtained in Step 2 of this example (247 mg) and 3- (bromomethyl) -5- (5-chloro-2-thienyl) isoxazole (Journal of Medicinal Chemistry, 2005) 48, 4511) (223 mg)
  • the alkylation reaction was carried out in the same manner as in Step 6 of Example 6.
  • 5M hydrochloric acid 5 mL was added and heated to reflux for 4 hours.
  • Example 11 (2Z) -5-amino-2- ⁇ [1- (3-methylphenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Reference Example 8, Reference Example 6 and In the same manner as in Example 5, the title compound (250 mg) was obtained from methyl (2E) -3- (1H-imidazol-4-yl) acrylate and (3-methylphenyl) boronic acid.
  • Example 12 (2Z) -5-amino-2- ⁇ [1- (3-methoxyphenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Reference Example 8, Reference Example 6 and In the same manner as in Example 5, the title compound (379 mg) was obtained from methyl (2E) -3- (1H-imidazol-4-yl) acrylate and (3-methoxyphenyl) boronic acid.
  • Example 13 (2Z) -5-amino-2-( ⁇ 1- [3- (trifluoromethyl) phenyl] -1H-imidazol-4-yl ⁇ methyl) pent-2-enoic acid
  • Reference Example 8 In the same manner as in Reference Example 6 and Example 5, the target product was obtained from methyl (2E) -3- (1H-imidazol-4-yl) acrylate and [3- (trifluoromethyl) phenyl] boronic acid. Obtained as a white solid (366 mg).
  • Example 15 (2Z) -5-amino-2- ⁇ [1- (2-cyclohexylethyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Same as Step 3 in Example 10 The title compound (2.0 mg) was obtained using the compound (100 mg) obtained in Step 2 of Example 10 and (2-bromoethyl) cyclohexane (0.056 mL).
  • Example 16 (2Z) -5-amino-2- ⁇ [1- (2-phenylethyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid
  • the title compound (3.0 mg) was obtained using the compound (100 mg) obtained in Step 2 of Example 10 and (2-bromoethyl) benzene (0.048 mL).
  • Example 17 (2Z) -5-amino-2- ⁇ [1- (2-cyclopropylethyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Reference Example 6 and Example 5 In the same manner as in the above, the title compound (182 mg) was obtained from the compound obtained in Reference Example 15.
  • Example 19 (2Z) -5-Amino-2- ⁇ [1- (tetrahydro-2H-pyran-4-yl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Reference Example 6 In the same manner as in Example 5, the title compound (184 mg) was obtained from the compound obtained in Reference Example 17.
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (4-methylphenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid As in Step 7 of Example 6.
  • the title compound (81.3 mg) was obtained from the compound (161 mg) obtained in Step 1 of this example.
  • Example 24 (2Z) -5-amino-2- ⁇ [1- (cyclohexylmethyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Step 6 and Step 7 of Example 6 Similarly, the title compound (56 mg) was obtained using the compound (200 mg) obtained in Step 5 of Example 6 and (bromomethyl) cyclohexane.
  • Example 25 (2Z) -5-amino-2- ⁇ [1- (3,3-dimethylbutyl) -5-methyl-1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Reference Example 6 In the same manner as in Example 6 and Example 5, the title compound (121 mg) was obtained from the compound obtained in Reference Example 22.
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (4,4-dimethylcyclohexyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Step 7 of Example 6 and Similarly, the title compound (38 mg) was obtained from the compound (84 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (4-chlorophenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid
  • the title compound (166 mg) was obtained from the compound (378 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (2-methylphenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid As in Step 7 of Example 6.
  • the title compound (178 mg) was obtained from the compound (336 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (4-fluorophenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid As in Step 7 of Example 6.
  • the title compound (144 mg) was obtained from the compound (265 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (4-methoxyphenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid As in Step 7 of Example 6.
  • the title compound (205 mg) was obtained from the compound (370 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (3-thienyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid As in Step 7 of Example 6.
  • the title compound (64.0 mg) was obtained from the compound (113 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (4-ethylphenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid As in Step 7 of Example 6.
  • the title compound (214 mg) was obtained from the compound (419 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-amino-2-( ⁇ 1- [4- (trifluoromethyl) phenyl] -1H-imidazol-4-yl ⁇ methyl) pent-2-enoic acid
  • Step 6 (2Z) -5-amino-2-( ⁇ 1- [4- (trifluoromethyl) phenyl] -1H-imidazol-4-yl ⁇ methyl) pent-2-enoic acid
  • Example 34 (2Z) -5-amino-2- ⁇ [1- (4-tert-butylphenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid [Step 1] (2Z ) -5-[(tert-Butoxycarbonyl) amino] -2- ⁇ [1- (4-tert-butylphenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid tert-butyl Reference Example In the same manner as in Example 8, the title compound (337 mg) was obtained from the compound obtained in Step 5 of Example 6 (500 mg) and 4-tert-butylphenylboronic acid (507 mg).
  • Step 2 (2Z) -5-amino-2- ⁇ [1- (4-tert-butylphenyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Step 7 of Example 6 and Similarly, the title compound (113 mg) was obtained from the compound (337 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-amino-2-[(1-pyridin-3-yl-1H-imidazol-4-yl) methyl] pent-2-enoic acid
  • the title compound (103 mg) was obtained from the compound (179 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-amino-2-[(1-biphenyl-4-yl-1H-imidazol-4-yl) methyl] pent-2-enoic acid As in Step 7 of Example 6.
  • the title compound (258 mg) was obtained from the compound (458 mg) obtained in Step 1 of this example.
  • Step 2 (2Z) -5-[(tert-butoxycarbonyl) amino] -2- ⁇ [1- (cis-4-hydroxycyclohexyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-ene Acid tert-butyl
  • tetrahydrofuran 5 mL
  • TBAF tetrabutylammonium fluoride
  • Step 3 (2Z) -5-amino-2- ⁇ [1- (cis-4-hydroxycyclohexyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Step 7 of Example 6 and Similarly, the title compound (22 mg) was obtained from the compound (65.8 mg) obtained in Step 2 of this example.
  • Example 40 (2Z) -5-amino-2- ⁇ [1- (4,4-difluorocyclohexyl) -1H-imidazol-4-yl] methyl ⁇ pent-2-enoic acid Step 1 of Example 39 In the same manner as in Step 7 of Example 6, the title compound (20 mg) was obtained.
  • Example 41 (2Z) -5-( ⁇ [1- (isobutyryloxy) ethoxy] carbonyl ⁇ amino) -2- ⁇ [1- (trans-4-methylcyclohexyl) -1H-imidazole-4- Yl] methyl ⁇ pent-2-enoic acid sodium salt
  • the compound obtained in Example 21 (600 mg) and sodium hydrogen carbonate (346 mg) were dissolved in water (10 mL), and stirred at room temperature, isobutyric acid 1-( ⁇ [ A solution of (2,5-dioxopyrrolidin-1-yl) oxy] carbonyl ⁇ oxy) ethyl (WO2005 / 66122) in acetonitrile (5 mL) was added and stirred overnight.
  • TAFI HEPES buffered saline (20 mM HEPES, 150 mM NaCl, pH 7.4, hereinafter HBS) was used for the preparation of the reaction solution.
  • HBS buffered saline
  • TAFIa Ten minutes later, 10 ⁇ L of 100 ⁇ M PPACK (thrombin inhibitor) was added to neutralize thrombin to terminate the activation of TAFI.
  • the produced TAFIa was stored in ice and diluted with 2050 ⁇ L of an HBS solution containing BSA (bovine serum albumin) prepared to a final concentration of 0.1% immediately before use in measurement.
  • BSA bovine serum albumin
  • the compound of the present invention exhibits excellent TAFIa inhibitory activity, and includes myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation. It is useful as a medicament for the treatment of syndrome or pulmonary fibrosis.
  • reaction solution A (13.8 U / mL human thrombin, 170 mM CaCl 2 and 0.9 U / mL thrombomodulin) was added and stirred again, and the absorbance at 405 nm was measured with a plate reader. The temperature was measured every 30 seconds while keeping at 37 ° C., and the degree of coagulation was measured. Of the changes in absorbance, the average value (ABS-ave: [(ABS-max)-(ABS-min)] / 2) of the maximum absorbance (ABS-max) and the minimum absorbance (ABS-min) in the fibrinolysis process is the highest.
  • the time point indicating the near absorbance was set to 1/2 lysis time (1/2 LT), which was used as an index of the fibrinolytic activity of each well. From the relationship between the concentration and 1/2 LT of the test substance, the concentration was calculated for the 1/2 LT 50% as EC 50.
  • compound A the compound of Example 7 in WO 2002/014285 pamphlet was used. The results are shown in Table 2.
  • the compound of the present invention exhibits excellent fibrinolysis promoting activity, myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular It is useful as a medicament for the treatment of coagulation syndrome or pulmonary fibrosis.
  • Test Example 3 Evaluation of fibrinolysis-promoting activity in rat thromboembolism model Wistar rats (supplier: Japan SLC) were used. A test substance prepared with a 0.5% methylcellulose solution is orally administered at an arbitrary time point, or a test substance prepared with physiological saline is intravenously administered. After 40 minutes or 4 hours, the jugular vein under thiopental anesthesia Further, PT reagent (Thromboplastin C plus, Sysmex) prepared to 2.25 U / mL with physiological saline was continuously injected (16.8 mL / kg / hr x 20 min). As a positive control group, an overdose TAFIa inhibitor administration group was set.
  • citrate blood was collected from the jugular vein to obtain plasma.
  • the amount of D-dimer contained in plasma is measured using a fully automatic coagulation analyzer ACL-9000 or ACL-TOP500CTS, the ratio to the mean value of the positive control group is calculated, and ED 50 is used as a dose to increase D-dimer by 50 %.
  • ACL-9000 or ACL-TOP500CTS the ratio to the mean value of the positive control group
  • ED 50 is used as a dose to increase D-dimer by 50 %.
  • the compound of the present invention exhibits excellent fibrinolysis promoting activity in vivo, myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, dissemination It is useful as a medicine for the treatment of vascular coagulation syndrome or pulmonary fibrosis.
  • Formulation Example 1 Hard Capsule Each standard bipartite hard gelatin capsule contains 100 mg of the powdered compound of Example 1, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate. The unit capsule is manufactured by filling, and after washing, dried.
  • Formulation Example 3 Tablet According to conventional methods, 100 mg of the compound of Example 3, 0.2 mg colloidal silicon dioxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg Manufactured using lactose.
  • Formulation Example 5 Cream 40% white petrolatum, 3% microcrystalline wax, 10% lanolin, 5% span 20, 0.3% Tween 20 and 41.7% water Prepared by mixing 100 mg of the finely divided compound of Example 5 in 5 g of cream.
  • the acrylic acid derivative represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent TAFIa enzyme inhibitory activity, and includes myocardial infarction, angina pectoris, acute coronary insufficiency syndrome, cerebral infarction, It is useful as a therapeutic agent for deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation syndrome, pulmonary fibrosis and the like, and as a therapeutic agent for diseases derived from thromboembolism.

Abstract

A compound represented by general formula (I) (in the formula, Ra represents an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted saturated heterocyclyl group, or an optionally substituted unsaturated heterocyclyl group; Rb represents a hydrogen atom or an alkyl group; R1, R2, R5, and R6 represent a hydrogen atom, fluorine atom, or alkyl group; R4, R7, and R8 represent a hydrogen atom or alkyl group; and R3 and R9 represent a hydrogen atom or a prodrug group.), which has TAFIa enzyme inhibitory activity and is useful as a therapeutic drug for myocardial infarction, angina pectoris, acute coronary syndrome, stroke, deep vein thrombosis, pulmonary embolism, or the like; or a pharmacologically acceptable salt thereof.

Description

新規アクリル酸誘導体New acrylic acid derivatives
 本発明は、優れたTAFIa阻害活性を有する新規なアクリル酸誘導体に関する。 The present invention relates to a novel acrylic acid derivative having excellent TAFIa inhibitory activity.
 生体内では、血管内での障害が起こると、血液の漏出を防ぐために血小板及び/又は凝固カスケードが活性化され、血栓が形成されて出血が抑えられる。凝固カスケードが活性化されて生成されたトロンビン(thrombin)がフィブリノーゲン(fibrinogen)を切断し、不溶性のフィブリン(fibrin)が形成される。フィブリンは血栓中に網目状に存在し、血栓を強固にする働きがある。この反応が凝固(coagulation)と呼ばれる。形成されたフィブリンはその後、生体内の反応により分解される。この反応が線溶(fibrinolysis)である。正常な条件下では凝固と線溶のバランスが調節され、異常量の血栓が血管内に蓄積することは無い。しかし、一旦そのバランスが崩れ凝固が亢進すると、血管内で血栓が形成されやすい状態になり、血栓症に起因する様々な疾患へと移行する場合がある。血栓形成は3つの要因(Virchowの3原則:血管壁の性状変化、血液成分の変化、血流の変化)により起こる。血栓形成に起因する疾患は先進諸国の間で最も一般的な死因のひとつである。 In vivo, when a failure occurs in a blood vessel, platelets and / or a coagulation cascade are activated to prevent blood leakage, and a thrombus is formed to suppress bleeding. Thrombin generated by the activation of the coagulation cascade cleaves fibrinogen to form insoluble fibrin. Fibrin exists in a mesh form in the thrombus and has a function of strengthening the thrombus. This reaction is called coagulation. The formed fibrin is then degraded by an in vivo reaction. This reaction is fibrinolysis. Under normal conditions, the balance between coagulation and fibrinolysis is regulated and no abnormal amount of thrombus accumulates in the blood vessel. However, once the balance is lost and coagulation is enhanced, a blood clot is likely to be formed in the blood vessel, and there are cases in which it shifts to various diseases caused by thrombosis. Thrombus formation occurs due to three factors (Virchow's three principles: changes in blood vessel wall properties, changes in blood components, changes in blood flow). Diseases resulting from thrombus formation are one of the most common causes of death among developed countries.
 TAFI(thrombin-activatable fibrinolysis inhibitor)は肝臓で生産され血液中に分泌されるカルボキシペプチダーゼ(carboxypeptidase)のひとつで、トロンビンやトロンビン/トロンボモジュリン(thrombomodulin)の複合体によってN末端92アミノ酸残基が切断されて活性化される。TAFIはprocarboxypeptidase U、procarboxypeptidase R又はplasma procarboxypeptidase Bとも呼ばれている。 TAFI is a carboxypeptidase that is produced in the liver and secreted into the blood. The N-terminal 92-amino acid complex is cleaved by thrombin or thrombin / thrombomodulin residues. Activated. TAFI is also called carboxypeptidase U, carboxypeptidase R, or plasma carboxypeptidase B.
 活性化されたTAFIはTAFIaと呼ばれる。TAFIaは血栓の主要成分であるフィブリン(fibrin)やフィブリン部分分解物(FDP、Fibrin Degradation Products)のC末端のLys又はArg残基を除去することで線溶を阻害する。線溶を誘導し促進する2つの酵素、tPA(tissue-type plasminogen activator:組織プラスミノーゲンアクチベータ)及びプラスミノーゲン(plasminogen)は自身のLys結合部位を介してフィブリン及びFDPのLys残基に結合する。続いて、フィブリン分子表面でtPAがプラスミノーゲンを活性化してプラスミン(plasmin)に変換し、線溶を開始する。プラスミンがフィブリンを切断し生成されたFDPのC末端にLys又はArg残基が現れる。線溶が続くことで、FDPのLys残基に新たなプラスミノーゲンとtPAが結合して、さらにプラスミンが生成され、線溶が効率的に進むようになる(線溶のポジティブフィードバック機構)。TAFIaがFDPのC末端Lys残基を除去することによってフィブリン分子上でのtPAによるプラスミノーゲンの活性化が阻害され、効率的な線溶反応が起こらなくなる。TAFIaは線溶のポジティブフィードバック機構を抑制する。これらの知見はTAFI及びその阻害薬に関する総説(非特許文献1)に詳細が記載されている。 Activated TAFI is called TAFIa. TAFIa inhibits fibrinolysis by removing the C-terminal Lys or Arg residue of fibrin, which is a major component of thrombus, and fibrin partial degradation products (FDP, Fibrin Degradation Products). Two enzymes that induce and promote fibrinolysis, tPA (tissue-type plasminogen activator) and plasminogen bind to fibrin and Lys residues of FDP via their Lys binding sites To do. Subsequently, tPA activates plasminogen on the surface of the fibrin molecule to convert it into plasmin, and initiates fibrinolysis. A Lys or Arg residue appears at the C-terminus of FDP generated by plasmin cleaving fibrin. As fibrinolysis continues, new plasminogen and tPA bind to the Lys residue of FDP, and further plasmin is generated, so that fibrinolysis proceeds efficiently (positive feedback mechanism of fibrinolysis). When TAFIa removes the C-terminal Lys residue of FDP, activation of plasminogen by tPA on the fibrin molecule is inhibited, and an efficient fibrinolytic reaction does not occur. TAFIa suppresses the positive feedback mechanism of fibrinolysis. These findings are described in detail in a review on non-patent literature 1 regarding TAFI and its inhibitors.
 上述のように生体内では凝固と線溶の精妙なバランスが成り立っている。疾患等により凝固が亢進した場合、血栓が形成されやすくなり、種々の疾患が発症する。そのような疾患には、心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群及び肺線維症などがある。 As described above, a delicate balance between coagulation and fibrinolysis is established in vivo. When coagulation is enhanced due to a disease or the like, blood clots are easily formed, and various diseases develop. Such diseases include myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation syndrome and pulmonary fibrosis. is there.
 これまでの血栓症の治療には凝固カスケード中の酵素が標的となることが多かった。それらには、活性化凝固第X因子(Xa)やトロンビンなどがある。これらの酵素に対する阻害薬には、出血などの潜在的副作用のリスクが存在する。ヘパリンや低分子ヘパリンは経口投与での薬効は期待できず、病院内での投与が必要になる。ワーファリンは経口投与が可能であるが、他の薬物との相互作用等の理由によって、定期的な血液検査が必要である。アスピリンは血小板の活性化を抑制して血栓形成を阻害する経口投与可能な薬剤であるが、胃出血などの副作用がある。現状の治療法をさらに向上させるための目標のひとつは、薬剤投与によって高い治療効果を保ったまま出血時間を延長させないことである。TAFIa阻害薬は、凝固及び血小板による止血のプロセスに影響を与えないことから出血に対するリスクは小さいと考えられている。 [To date, enzymes in the coagulation cascade are often targeted for the treatment of thrombosis. These include activated coagulation factor X (Xa) and thrombin. Inhibitors to these enzymes are at risk for potential side effects such as bleeding. Heparin and low molecular weight heparin cannot be expected to have a medicinal effect when administered orally and must be administered in hospitals. Warfarin can be administered orally, but regular blood tests are necessary for reasons such as interactions with other drugs. Aspirin is an orally administrable drug that inhibits platelet activation and inhibits thrombus formation, but has side effects such as gastric bleeding. One of the goals for further improving the current treatment methods is not to prolong bleeding time while maintaining a high therapeutic effect by drug administration. TAFIa inhibitors are thought to have a low risk for bleeding because they do not affect the process of coagulation and hemostasis by platelets.
 凝固反応が亢進し血栓が出来やすい状態になっている病態では、TAFIaを阻害することで線溶反応を効率化して、より早く血栓を除去することができる。このことで、血栓に起因する疾患の治療・予防に優れた効果を発揮することが期待できる。これまでに、TAFIaを阻害することで抗血栓効果を示した動物実験の例がいくつか報告されている。 In the pathological condition where the coagulation reaction is enhanced and the blood clot is likely to be formed, the fibrinolysis reaction can be made efficient by inhibiting TAFIa and the blood clot can be removed more quickly. Thus, it can be expected to exhibit excellent effects in the treatment and prevention of diseases caused by blood clots. So far, several examples of animal experiments that have shown antithrombotic effects by inhibiting TAFIa have been reported.
 TAFIaを阻害する39アミノ酸からなるポリペプチドpotato carboxypeptidase inhibitor(PCI)をマウスに静脈内投与することで塩化鉄誘導血栓モデルにて抗血栓効果を示したという報告がある(非特許文献2)。 There is a report that an anti-thrombotic effect was shown in an iron chloride-induced thrombus model by intravenously administering a 39-amino acid polypeptide potatocarboxypeptidase inhibitor (PCI) that inhibits TAFIa to mice (Non-patent Document 2).
 低分子量TAFIa阻害薬はウサギ静脈血栓症モデルにおいて、静脈投与で血栓量を約35%低下させた(非特許文献3)。 In the rabbit venous thrombosis model, the low molecular weight TAFIa inhibitor decreased the thrombus amount by about 35% by intravenous administration (Non-patent Document 3).
 低分子量TAFIa阻害化合物はラットの血栓塞栓症モデルで腎臓への血栓の沈着量の低下、線溶マーカーD-dimerの増加効果、tPAとの併用で、tPAの用量を低減したうえで、同等の抗血栓効果を示した(非特許文献4及び5)。 The low molecular weight TAFIa inhibitor compound is the equivalent of a rat thromboembolism model that reduces the amount of thrombus deposited on the kidney, increases the fibrinolytic marker D-dimer, and reduces the dose of tPA in combination with tPA. The antithrombotic effect was shown (nonpatent literature 4 and 5).
 特許文献1~5には、TAFIa阻害活性を示す化合物が開示されている。 Patent Documents 1 to 5 disclose compounds exhibiting TAFIa inhibitory activity.
国際公開第2002/014285号パンフレットInternational Publication No. 2002/014285 Pamphlet 国際公開第2003/061652号パンフレットInternational Publication No. 2003/061652 Pamphlet 国際公開第2003/061653号パンフレットInternational Publication No. 2003/061653 Pamphlet 国際公開第2005/105781号パンフレットInternational Publication No. 2005/105781 Pamphlet 国際公開第2003/013526号パンフレットInternational Publication No. 2003/013526 Pamphlet
 現在知られているTAFIa阻害活性を有する化合物は、有効性又は出血リスクなどの安全性の面で満足できるものではなく、安全性及び有効性に優れたTAFIa阻害薬が切望されている。 Currently known compounds having TAFIa inhibitory activity are not satisfactory in terms of safety such as efficacy or bleeding risk, and TAFIa inhibitors excellent in safety and effectiveness are eagerly desired.
 本発明者らは、優れたTAFIa阻害活性を有する、心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の治療薬の獲得を目指して種々の合成検討を行った。その結果、特定の構造を有するアクリル酸誘導体又はその薬理上許容される塩が、優れたTAFIa阻害活性を示すことを見出し、本発明を完成するに至った。 The present inventors have excellent TAFIa inhibitory activity, myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation Various synthetic studies were conducted with the aim of acquiring therapeutic agents for syndrome or pulmonary fibrosis. As a result, the inventors have found that an acrylic acid derivative having a specific structure or a pharmacologically acceptable salt thereof exhibits excellent TAFIa inhibitory activity, and has completed the present invention.
 本発明は、優れたTAFIa阻害活性を示すアクリル酸誘導体又はその薬理上許容される塩及びこれらを含有する医薬を提供する。 The present invention provides an acrylic acid derivative exhibiting excellent TAFIa inhibitory activity or a pharmacologically acceptable salt thereof, and a pharmaceutical containing these.
 すなわち、本発明は、
(1) 一般式(I)
That is, the present invention
(1) General formula (I)
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
[式中、Raは置換基群Aから選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルキル基;置換基群Aから選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルケニル基;置換基群Bから選ばれる同一又は異なる1~3個の基で置換されていてもよいC~C10シクロアルキル基;置換基群Bから選ばれる同一又は異なる1~3個の基で置換されていてもよいアリール基;置換基群Bから選ばれる同一又は異なる1~3個の基で置換されていてもよい飽和ヘテロシクリル基;又は、置換基群Bから選ばれる同一又は異なる1~3個の基で置換されていてもよい不飽和ヘテロシクリル基を示し(置換基群Aは、水酸基、ハロゲン原子、シアノ基、ニトロ基、アミノ基、カルボキシ基、C~Cシクロアルキル基、C~Cアルコキシ基、ハロゲノC~Cアルコキシ基、C~Cアルキルスルホニル基、アリール基、飽和ヘテロシクリル基、不飽和ヘテロシクリル基、及び、アリールオキシ基からなる。置換基群Bは、置換基群Aの各置換基、C~Cアルキル基及びハロゲノC~Cアルキル基からなる。)、Rは水素原子又はC~Cアルキル基を示し、R、R、R5及びRは各々独立して水素原子、フッ素原子又はC~Cアルキル基を示し、R、R及びRは各々独立して水素原子又はC~Cアルキル基を示し、R及びRは各々独立して水素原子又はプロドラッグ基を示す。]で表される化合物、又はその薬理上許容される塩、
(2) 一般式(Ia)
[Wherein, R a is a C 1 -C 6 alkyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group A; A C 2 -C 6 alkenyl group optionally substituted by 3 groups; a C 3 -C 10 cycloalkyl group optionally substituted by 1 to 3 identical or different groups selected from Substituent Group B An aryl group which may be substituted with the same or different 1 to 3 groups selected from Substituent Group B; which may be substituted with the same or different 1 to 3 groups selected from Substituent Group B; A saturated heterocyclyl group; or an unsaturated heterocyclyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group B (the substituent group A is a hydroxyl group, a halogen atom, a cyano group, Nitro group, amino group, carboxy group, 3 ~ C 8 cycloalkyl group, C 1 ~ C 3 alkoxy group, a halogeno C 1 ~ C 3 alkoxy group, C 1 ~ C 3 alkylsulfonyl group, an aryl group, a saturated heterocyclyl group, unsaturated heterocyclyl group, and, aryloxy Substituent group B consists of each substituent of substituent group A, a C 1 -C 3 alkyl group and a halogeno C 1 -C 3 alkyl group.), R b is a hydrogen atom or C 1 -C 3 6 alkyl group, R 1 , R 2 , R 5 and R 6 each independently represents a hydrogen atom, a fluorine atom or a C 1 -C 6 alkyl group, and R 4 , R 7 and R 8 are each independently Each represents a hydrogen atom or a C 1 -C 6 alkyl group, and R 3 and R 9 each independently represent a hydrogen atom or a prodrug group. Or a pharmacologically acceptable salt thereof,
(2) General formula (Ia)
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
[式中、Raは置換基群Aから選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルキル基;置換基群Aから選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルケニル基;置換基群Bから選ばれる同一又は異なる1~3個の基で置換されていてもよいC~C10シクロアルキル基;置換基群Bから選ばれる同一又は異なる1~3個の基で置換されていてもよいアリール基;置換基群Bから選ばれる同一又は異なる1~3個の基で置換されていてもよい飽和ヘテロシクリル基;又は、置換基群Bから選ばれる同一又は異なる1~3個の基で置換されていてもよい不飽和ヘテロシクリル基を示し(置換基群Aは、水酸基、ハロゲン原子、シアノ基、ニトロ基、アミノ基、カルボキシ基、C~Cシクロアルキル基、C~Cアルコキシ基、ハロゲノC~Cアルコキシ基、C~Cアルキルスルホニル基、アリール基、飽和ヘテロシクリル基、不飽和ヘテロシクリル基、及び、アリールオキシ基からなる。置換基群Bは、置換基群Aの各置換基、C~Cアルキル基及びハロゲノC~Cアルキル基からなる。)、Rは水素原子又はC~Cアルキル基を示し、R、R、R5及びRは各々独立して水素原子、フッ素原子又はC~Cアルキル基を示し、R、R及びRは各々独立して水素原子又はC~Cアルキル基を示し、R及びRは各々独立して水素原子又はプロドラッグ基を示す。]で表される(1)の化合物、又はその薬理上許容される塩、
(3) Raが、水酸基、ハロゲン原子、アミノ基、C~Cアルキル基、C~Cシクロアルキル基、フェニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルキル基;水酸基、ハロゲン原子、アミノ基、C~Cアルキル基、フェニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルケニル基;水酸基、ハロゲン原子、アミノ基及びC~Cアルキル基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cシクロアルキル基;水酸基、ハロゲン原子、シアノ基、アミノ基、C~Cアルキル基、ハロゲノC~Cアルキル基(当該置換基は同一の1~3個のハロゲン原子を示す。)、C~Cアルコキシ基、C~Cアルキルスルホニル基、フェニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいフェニル基;水酸基、ハロゲン原子、シアノ基、アミノ基、C~Cアルキル基、ハロゲノC~Cアルキル基、C~Cアルコキシ基、C~Cアルキルスルホニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいチエニル基;水酸基、ハロゲン原子、アミノ基、C~Cアルキル基、ハロゲノC~Cアルキル基、C~Cアルコキシ基、C~Cアルキルスルホニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいピリジル基;又は、水酸基、ハロゲノ基、アミノ基、C~Cアルキル基、ハロゲノC~Cアルキル基、C~Cアルコキシ基、C~Cアルキルスルホニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいテトラヒドロピラニル基である、(1)又は(2)の化合物、又はその薬理上許容される塩、
(4) Raが、C~Cシクロアルキル基又はフェニル基で置換されていてもよいC~Cアルキル基;水酸基、若しくは同一の1~2個のC~Cアルキル基で置換されていてもよいC~Cシクロアルキル基;ハロゲン原子、C~Cアルキル基、ハロゲノC~Cアルキル基(当該置換基は1~3個のフッ素原子を示す。)、C~Cアルコキシ基又はフェニル基で置換されていてもよいフェニル基;ハロゲン原子、C~Cアルキル基及びC~Cアルコキシ基から選ばれる同一又は異なる1~2個の基で置換されていてもよいチエニル基;ハロゲン原子、C~Cアルキル基及びC~Cアルコキシ基から選ばれる同一又は異なる1~2個の基で置換されていてもよいピリジル基;又は、テトラヒドロピラニル基である、前記(1)又は(2)の化合物、又はその薬理上許容される塩、
(5) Raが、C~Cアルキル基;C~Cシクロアルキル基若しくはフェニル基で置換されているC~Cアルキル基;C~Cシクロアルキル基;水酸基若しくは1~2個のメチル基で置換されているシクロヘキシル基;フェニル基;塩素原子、フッ素原子、C~Cアルキル基、トリフルオロメチル基若しくはフェニル基で置換されているフェニル基又は、チエニル基、ピリジル基、又は、テトラヒドロチエニル基である、前記(1)又は(2)の化合物、又はその薬理上許容される塩、
(6) Raが、1~2個のメチル基で置換されたシクロヘキシル基である、前記(1)又は(2)の化合物、又はその薬理上許容される塩、
(7) Raが、基
[Wherein, R a is a C 1 -C 6 alkyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group A; A C 2 -C 6 alkenyl group optionally substituted by 3 groups; a C 3 -C 10 cycloalkyl group optionally substituted by 1 to 3 identical or different groups selected from Substituent Group B An aryl group which may be substituted with the same or different 1 to 3 groups selected from Substituent Group B; which may be substituted with the same or different 1 to 3 groups selected from Substituent Group B; A saturated heterocyclyl group; or an unsaturated heterocyclyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group B (the substituent group A is a hydroxyl group, a halogen atom, a cyano group, Nitro group, amino group, carboxy group, 3 ~ C 8 cycloalkyl group, C 1 ~ C 3 alkoxy group, a halogeno C 1 ~ C 3 alkoxy group, C 1 ~ C 3 alkylsulfonyl group, an aryl group, a saturated heterocyclyl group, unsaturated heterocyclyl group, and, aryloxy Substituent group B consists of each substituent of substituent group A, a C 1 -C 3 alkyl group and a halogeno C 1 -C 3 alkyl group.), R b is a hydrogen atom or C 1 -C 3 6 alkyl group, R 1 , R 2 , R 5 and R 6 each independently represents a hydrogen atom, a fluorine atom or a C 1 -C 6 alkyl group, and R 4 , R 7 and R 8 are each independently Each represents a hydrogen atom or a C 1 -C 6 alkyl group, and R 3 and R 9 each independently represent a hydrogen atom or a prodrug group. Or a pharmacologically acceptable salt thereof,
(3) R a is the same or different 1 to 3 groups selected from a hydroxyl group, a halogen atom, an amino group, a C 1 to C 3 alkyl group, a C 3 to C 6 cycloalkyl group, a phenyl group and a phenoxy group. An optionally substituted C 1 -C 6 alkyl group; substituted with the same or different 1 to 3 groups selected from a hydroxyl group, a halogen atom, an amino group, a C 1 -C 3 alkyl group, a phenyl group and a phenoxy group; which may be C 2 ~ C 6 alkenyl group; a hydroxyl group, a halogen atom, an amino group and a C 1 ~ C 3 may be substituted by the same or different 1 to 3 groups selected from alkyl radicals C 3 ~ C 8 cycloalkyl group; a hydroxyl group, a halogen atom, a cyano group, an amino group, C 1 ~ C 3 alkyl group, a halogeno C 1 ~ C 3 alkyl group (said substituents may indicate the same 1 to 3 halogen atoms .), C 1 ~ C 3 alkoxy group, C 1 ~ C 3 alkylsulfonyl group, the same or different 1 to 3 phenyl group which may be substituted with a group selected from phenyl group and phenoxy group; a hydroxyl group, a halogen The same or different selected from atoms, cyano groups, amino groups, C 1 -C 3 alkyl groups, halogeno C 1 -C 3 alkyl groups, C 1 -C 3 alkoxy groups, C 1 -C 3 alkylsulfonyl groups and phenoxy groups A thienyl group optionally substituted by 1 to 3 groups; a hydroxyl group, a halogen atom, an amino group, a C 1 -C 3 alkyl group, a halogeno C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, C 1 ~ C 3 alkylsulfonyl group and the same or different 1 to 3 pyridyl group which may be substituted with a group selected from phenoxy group; or a hydroxyl group, halogeno , Amino group, C 1 ~ C 3 alkyl group, a halogeno C 1 ~ C 3 alkyl group, the same or different 1 to 3 selected from C 1 ~ C 3 alkoxy group, C 1 ~ C 3 alkylsulfonyl group and a phenoxy group A compound of (1) or (2), or a pharmacologically acceptable salt thereof, which is a tetrahydropyranyl group optionally substituted by a group of
(4) R a is a C 1 -C 6 alkyl group optionally substituted with a C 3 -C 6 cycloalkyl group or a phenyl group; a hydroxyl group or the same 1-2 C 1 -C 3 alkyl groups A C 3 -C 8 cycloalkyl group which may be substituted with a halogen atom, a C 1 -C 3 alkyl group, or a halogeno C 1 -C 3 alkyl group (the substituent represents 1 to 3 fluorine atoms). ), A C 1 -C 3 alkoxy group or a phenyl group optionally substituted by a phenyl group; one or two identical or different groups selected from a halogen atom, a C 1 -C 3 alkyl group and a C 1 -C 3 alkoxy group A thienyl group which may be substituted with a group of: pyridyl which may be substituted with the same or different one or two groups selected from a halogen atom, a C 1 -C 3 alkyl group and a C 1 -C 3 alkoxy group Group; Salt, tetrahydropyranyl group, the compound of the above (1) or (2), or its pharmacologically acceptable,
(5) R a is a C 3 -C 6 alkyl group; a C 3 -C 6 cycloalkyl group or a C 1 -C 2 alkyl group substituted with a phenyl group; a C 3 -C 7 cycloalkyl group; a hydroxyl group or A cyclohexyl group substituted with 1 to 2 methyl groups; a phenyl group; a phenyl group substituted with a chlorine atom, a fluorine atom, a C 1 -C 4 alkyl group, a trifluoromethyl group or a phenyl group, or a thienyl group , A pyridyl group or a tetrahydrothienyl group, the compound of the above (1) or (2), or a pharmacologically acceptable salt thereof,
(6) The compound of (1) or (2), or a pharmacologically acceptable salt thereof, wherein R a is a cyclohexyl group substituted with 1 to 2 methyl groups,
(7) R a is a group
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
(ここで、*は結合位置を示す。)である、前記(1)又は(2)の化合物、又はその薬理上許容される塩、
(8) Raが、基
(Wherein, * represents a bonding position), the compound of (1) or (2), or a pharmacologically acceptable salt thereof,
(8) R a is a group
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
(ここで、*は結合位置を示す。)である、前記(1)又は(2)の化合物、又はその薬理上許容される塩、
(9) Rが水素原子又はメチル基である、前記(1)~(8)のいずれか1項に記載の化合物、又はその薬理上許容される塩、
(10) Rが水素原子である、前記(1)~(8)のいずれか1項に記載の化合物、又はその薬理上許容される塩、
(11) R、R、R、R、R及びRがいずれも水素原子であり、R5が水素原子又はメチル基である、前記(1)~(10)のいずれか1項に記載の化合物、又はその薬理上許容される塩、
(12) R、R、R、R5、R、R及びRがいずれも水素原子である、前記(1)~(10)のいずれか1項に記載の化合物、又はその薬理上許容される塩、
(13) R及びRがいずれも水素原子である、(1)~(12)のいずれか1項に記載の化合物、又はその薬理上許容される塩、
(14) Rがプロドラッグ基であり、当該プロドラッグ基が、アミノ基、ハロゲン原子、水酸基、カルボキシ基、カルバモイル基、C~Cアルコキシ基、アリール基及びへテロシクリル基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルカノイル基;C~Cアルキル基;C~Cアルカノイルオキシ基、(C~Cシクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1~3個の基で置換されていてもよい(C~Cアルコキシ)カルボニル基;又は、オキソ基及びC~Cアルキル基から選ばれる同一又は異なる1~3個の基で置換されていてもよいヘテロシクリルアルキルオキシカルボニル基である、前記(1)~(12)のいずれか1項に記載の化合物、又はその薬理上許容される塩、
(15) Rがプロドラッグ基であり、当該プロドラッグ基が、フェニルアラニル基、L-ノルロイシル基、[(5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メトキシ]カルボニル基、[1-(イソブチリルオキシ)エトキシ]カルボニル基、[1-(2,2-ジメチルプロパノイルオキシ)エトキシ]カルボニル基、({1-[(シクロヘキシルカルボニル)オキシ]エトキシ}カルボニル)基、又は、(1-アセトキシエトキシ)カルボニル基である、前記(1)~(12)のいずれか1項に記載の化合物、又はその薬理上許容される塩、
(16) Rがプロドラッグ基であり、当該プロドラッグ基が、C~Cアルカノイルオキシ基、(C~Cシクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルキル基;又は、オキソ基及びC~Cアルキル基から選ばれる同一又は異なる1~3個の基で置換されていてもよいヘテロシクリルアルキル基である、前記(1)~(12)のいずれか1項に記載の化合物、又はその薬理上許容される塩、
(17) Rがプロドラッグ基であり、当該プロドラッグ基が、ベンジル基又は[(イソプロポキシカルボニル)オキシ]エチル基である、前記(1)~(12)のいずれか1項に記載の化合物、又はその薬理上許容される塩、
(18) 下記式
(Wherein, * represents a bonding position), the compound of (1) or (2), or a pharmacologically acceptable salt thereof,
(9) The compound according to any one of (1) to (8), wherein R b is a hydrogen atom or a methyl group, or a pharmacologically acceptable salt thereof,
(10) The compound according to any one of (1) to (8), wherein R b is a hydrogen atom, or a pharmacologically acceptable salt thereof,
(11) Any of (1) to (10) above, wherein R 1 , R 2 , R 4 , R 6 , R 7 and R 8 are all hydrogen atoms, and R 5 is a hydrogen atom or a methyl group. 1. The compound according to item 1, or a pharmacologically acceptable salt thereof,
(12) The compound according to any one of (1) to (10) above, wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and R 8 are all hydrogen atoms, or Its pharmacologically acceptable salts,
(13) The compound according to any one of (1) to (12), wherein R 3 and R 9 are both hydrogen atoms, or a pharmacologically acceptable salt thereof,
(14) R 9 is a prodrug group, and the prodrug group is the same selected from an amino group, a halogen atom, a hydroxyl group, a carboxy group, a carbamoyl group, a C 1 -C 6 alkoxy group, an aryl group, and a heterocyclyl group. Or a C 1 -C 6 alkanoyl group optionally substituted with 1 to 3 different groups; a C 1 -C 6 alkyl group; a C 2 -C 6 alkanoyloxy group, (C 3 -C 6 cycloalkyl) carbonyl (C 1 -C 6 alkoxy) carbonyl group optionally substituted by the same or different 1 to 3 groups selected from an oxy group and an aryl group; or an oxo group and a C 1 -C 6 alkyl group Any one of the above (1) to (12), which is a heterocyclylalkyloxycarbonyl group which may be substituted with the same or different 1 to 3 groups Compound, or a pharmacologically acceptable salt thereof according to,
(15) R 9 is a prodrug group, and the prodrug group includes a phenylalanyl group, an L-norleucyl group, [(5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy] Carbonyl group, [1- (isobutyryloxy) ethoxy] carbonyl group, [1- (2,2-dimethylpropanoyloxy) ethoxy] carbonyl group, ({1-[(cyclohexylcarbonyl) oxy] ethoxy} carbonyl) Or a pharmacologically acceptable salt thereof according to any one of (1) to (12) above, which is a group or a (1-acetoxyethoxy) carbonyl group,
(16) R 3 is a prodrug group, and the prodrug group is the same or different from 1 to 6 selected from a C 2 to C 6 alkanoyloxy group, a (C 3 to C 6 cycloalkyl) carbonyloxy group and an aryl group. A C 1 -C 6 alkyl group which may be substituted with three groups; or may be substituted with the same or different 1 to 3 groups selected from an oxo group and a C 1 -C 6 alkyl group The compound according to any one of (1) to (12) above, which is a heterocyclylalkyl group, or a pharmaceutically acceptable salt thereof,
(17) R 3 is a prodrug group, and the prodrug group is a benzyl group or a [(isopropoxycarbonyl) oxy] ethyl group, according to any one of (1) to (12) above A compound, or a pharmacologically acceptable salt thereof,
(18) The following formula
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
からなる群より選ばれる前記(1)に記載の化合物、又はその薬理上許容される塩、
(19)前記(1)~(18)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬、
(20)前記(1)~(18)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有するTAFIa阻害薬、
(21)前記(1)~(18)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する線溶促進剤、
(22)前記(1)~(18)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、線溶が阻害されることにより引き起こされる疾患の予防薬若しくは治療薬、
(23)前記(1)~(18)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、心筋梗塞、狭心症(安定狭心症、不安定狭心症)などの急性冠症候群;深部静脈血栓症、肺塞栓症などの静脈血栓塞栓症;血管再開通術、血管形成術、ステント留置術、バイパス出術などの外科的手術後の心臓血管系に起こる血栓症若しくは塞栓症;膝関節置換手術、股関節置換手術などの人工関節置換手術後の血栓症若しくは塞栓症;敗血症、播種性血管内凝固症候群(DIC)のような炎症に関連する血管内の疾患;末梢動脈塞栓症(PAO)、動脈硬化、糖尿病などの末梢血管障害に由来・関連する疾患;固形癌、血液癌などの腫瘍に関連する疾患;又は、肺塞栓、脳梗塞、腎梗塞などの血栓・塞栓に起因する臓器の障害のような血栓症・塞栓症及びそれらの後遺症の予防薬若しくは治療薬、
(24)前記(1)~(18)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、関節置換術時の人工関節、血管カテーテル、人工血管、血管ステント、人工弁などの医療機器のような体内の異物との接触によって起こる疾患;又は、心臓手術時の人工心肺装置、血液透析時の医療器具などの体外の医療器具と血液が接触することによって起こる疾患のような血栓症・塞栓症の予防薬若しくは治療薬、
(25)前記(1)~(18)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、肺高血圧症、成人呼吸切迫症候群、肺線維症、慢性血栓塞栓性肺高血圧症などの肺の疾患;糸球体腎炎(急性糸球体腎炎、慢性糸球体腎炎、ネフローゼ性腎炎、急性進行性糸球体腎炎など)、腎臓梗塞、糖尿病性腎炎などの腎臓の疾患;肝線維症、肝炎、肝硬変などの肝臓の疾患;眼部フィブリン沈着に伴う眼部の疾患;臓器移植又は切除術後の臓器機能障害;血栓性微小血管症を始めとする微小血栓による微小循環障害;又は、癌細胞の遊走・転移に伴う疾患・症状のような血栓・塞栓症に関連する又はフィブリン沈着若しくは線維化を伴う疾患の予防薬若しくは治療薬、
(26)前記(1)~(18)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の治療薬、
(27)前記(1)~(18)のいずれか1項に記載の化合物又はその薬理上許容される塩及び薬理上許容される担体を含有する医薬組成物、
(28)前記(1)~(18)のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物を投与することによる、心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の治療方法、並びに、
(29)心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の治療における使用のための前記(1)~(18)のいずれか1項に記載の化合物又はその薬理上許容される塩を提供するものである。
The compound according to (1) or a pharmacologically acceptable salt thereof selected from the group consisting of:
(19) A medicament comprising the compound according to any one of (1) to (18) above or a pharmacologically acceptable salt thereof as an active ingredient,
(20) A TAFIa inhibitor comprising the compound according to any one of (1) to (18) above or a pharmacologically acceptable salt thereof as an active ingredient,
(21) A fibrinolysis promoter containing the compound according to any one of (1) to (18) or a pharmacologically acceptable salt thereof as an active ingredient,
(22) A prophylactic agent for a disease caused by inhibition of fibrinolysis comprising the compound according to any one of (1) to (18) or a pharmacologically acceptable salt thereof as an active ingredient, or Therapeutic drugs,
(23) Myocardial infarction, angina pectoris (stable angina, unstable angina) containing the compound according to any one of (1) to (18) or a pharmacologically acceptable salt thereof as an active ingredient Acute coronary syndromes such as cardiomyopathy; venous thromboembolism such as deep vein thrombosis and pulmonary embolism; cardiovascular system after surgical operations such as revascularization, angioplasty, stent placement, bypass surgery Thrombosis or embolism occurring after surgery: Thrombosis or embolism after joint replacement surgery such as knee replacement surgery or hip replacement surgery; Intravascular related to inflammation such as sepsis, disseminated intravascular coagulation syndrome (DIC) Diseases related to or related to peripheral vascular disorders such as peripheral arterial embolism (PAO), arteriosclerosis, diabetes; diseases related to tumors such as solid cancer, blood cancer; or pulmonary embolism, cerebral infarction, renal infarction Organs caused by thrombus / emboli Thrombosis-embolism and prophylactic or therapeutic agent for their sequelae such as failure,
(24) An artificial joint, vascular catheter, artificial blood vessel, blood vessel at the time of joint replacement, comprising as an active ingredient the compound according to any one of (1) to (18) or a pharmacologically acceptable salt thereof. Diseases caused by contact with foreign bodies in the body such as stents, prosthetic valves, etc .; or by contact of blood with extracorporeal medical devices such as heart-lung machines during cardiac surgery and medical devices during hemodialysis Preventive or therapeutic agent for thrombosis / embolism such as disease
(25) Pulmonary hypertension, adult respiratory urgency syndrome, pulmonary fibrosis, chronic thrombus, comprising as an active ingredient the compound according to any one of (1) to (18) or a pharmacologically acceptable salt thereof Lung diseases such as embolic pulmonary hypertension; glomerulonephritis (acute glomerulonephritis, chronic glomerulonephritis, nephrotic nephritis, acute progressive glomerulonephritis, etc.), kidney diseases such as renal infarction, diabetic nephritis; Liver disease such as liver fibrosis, hepatitis, cirrhosis; eye disease associated with ocular fibrin deposition; organ dysfunction after organ transplantation or resection; microcirculatory disturbance due to microthrombosis including thrombotic microangiopathy Or preventive or therapeutic agent for diseases associated with thrombosis / embolism such as diseases / symptoms associated with cancer cell migration / metastasis, or with fibrin deposition or fibrosis,
(26) Myocardial infarction, angina pectoris, acute coronary insufficiency syndrome, cerebral infarction, comprising as an active ingredient the compound according to any one of (1) to (18) or a pharmacologically acceptable salt thereof, Drugs for deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation syndrome or pulmonary fibrosis,
(27) A pharmaceutical composition comprising the compound according to any one of (1) to (18) or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier,
(28) Myocardial infarction, angina pectoris by administering a pharmaceutical composition containing the compound according to any one of (1) to (18) or a pharmacologically acceptable salt thereof as an active ingredient, A method for treating acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation syndrome or pulmonary fibrosis, and
(29) For use in the treatment of myocardial infarction, angina pectoris, acute coronary insufficiency syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation syndrome or pulmonary fibrosis The compound or the pharmacologically acceptable salt thereof according to any one of the above (1) to (18).
 本発明の一般式(I)で表されるアクリル酸誘導体又はその薬理上許容される塩は、優れたTAFIa阻害活性を有し、かつ高い経口吸収性、血漿中濃度及び血中滞留性を示し、優れた薬理作用を示した。また、本発明の一般式(I)で表される化合物又はその薬理上許容される塩は、体内分布、血中滞留性等の体内動態に優れ、出血時間の延長がなく、安全性も高い。 The acrylic acid derivative represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has excellent TAFIa inhibitory activity, and exhibits high oral absorption, plasma concentration and retention in blood. Showed excellent pharmacological action. In addition, the compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is excellent in pharmacokinetics such as distribution in the body, retention in blood, etc., has no prolonged bleeding time, and is highly safe. .
 したがって、本発明の一般式(I)で表されるアクリル酸誘導体又はその薬理上許容される塩は医薬(特に、線溶が阻害されることにより引き起こされる疾患の予防薬若しくは治療薬、好適には治療薬)として有用であり、特に心筋梗塞、狭心症(安定狭心症、不安定狭心症)などの急性冠症候群;深部静脈血栓症、肺塞栓症などの静脈血栓塞栓症;血管再開通術、血管形成術、ステント留置術、バイパス出術などの外科的手術後の心臓血管系に起こる血栓症若しくは塞栓症;膝関節置換手術、股関節置換手術などの人工関節置換手術後の血栓症若しくは塞栓症;敗血症、播種性血管内凝固症候群(DIC)のような炎症に関連する血管内の疾患;末梢動脈塞栓症(PAO)、動脈硬化、糖尿病などの末梢血管障害に由来・関連する疾患;固形癌、血液癌などの腫瘍に関連する疾患;又は、肺塞栓、脳梗塞、腎梗塞などの血栓・塞栓に起因する臓器の障害のような血栓症・塞栓症及びそれらの後遺症の予防薬又は治療薬(好ましくは、治療薬)として有用である。また、本発明化合物は、関節置換術時の人工関節、血管カテーテル、人工血管、血管ステント、人工弁などの医療機器のような体内の異物との接触によって起こる疾患;又は、心臓手術時の人工心肺装置、血液透析時の医療器具などの体外の医療器具と血液が接触することによって起こる疾患のような血栓症・塞栓症の予防薬又は治療薬(好ましくは、治療薬)として有用である。更に、本発明化合物は、肺高血圧症、成人呼吸切迫症候群、肺線維症、慢性血栓塞栓性肺高血圧症などの肺の疾患;糸球体腎炎(急性糸球体腎炎、慢性糸球体腎炎、ネフローゼ性腎炎、急性進行性糸球体腎炎など)、腎臓梗塞、糖尿病性腎炎などの腎臓の疾患;肝線維症、肝炎、肝硬変などの肝臓の疾患;眼部フィブリン沈着に伴う眼部の疾患;臓器移植又は切除術後の臓器機能障害;血栓性微小血管症を始めとする微小血栓による微小循環障害;又は、癌細胞の遊走・転移に伴う疾患・症状の予防薬又は治療薬(好ましくは、治療薬)のような血栓・塞栓症に関連する又はフィブリン沈着若しくは線維化を伴う疾患の予防薬又は治療薬(好ましくは、治療薬)として有用である。 Therefore, the acrylic acid derivative represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof is preferably used as a medicine (especially a prophylactic or therapeutic drug for diseases caused by inhibition of fibrinolysis, Are useful as therapeutic agents), especially acute coronary syndromes such as myocardial infarction and angina (stable angina, unstable angina); venous thromboembolism such as deep vein thrombosis and pulmonary embolism; blood vessels Thrombosis or embolism in the cardiovascular system after surgical operations such as reopening surgery, angioplasty, stent placement, bypass surgery, etc .; Thrombus after artificial joint replacement surgery such as knee replacement surgery and hip replacement surgery Inflammation-related intravascular diseases such as sepsis, disseminated intravascular coagulation syndrome (DIC); Originated / related to peripheral vascular disorders such as peripheral arterial embolism (PAO), arteriosclerosis, diabetes disease; Diseases related to tumors such as shape cancer and blood cancer; or prophylactic drugs for thrombosis / embolism such as pulmonary embolism, cerebral infarction, renal infarction, etc. It is useful as a therapeutic agent (preferably a therapeutic agent). In addition, the compound of the present invention is a disease caused by contact with a foreign body such as a medical device such as an artificial joint, a vascular catheter, an artificial blood vessel, a vascular stent, or an artificial valve at the time of joint replacement; It is useful as a prophylactic or therapeutic agent (preferably a therapeutic agent) for thrombosis / embolism such as a disease caused by contact of blood with an external medical device such as a cardiopulmonary device or a medical device during hemodialysis. Further, the compound of the present invention is used for pulmonary hypertension, adult respiratory urgency syndrome, pulmonary fibrosis, chronic thromboembolic pulmonary hypertension and the like; glomerulonephritis (acute glomerulonephritis, chronic glomerulonephritis, nephrotic nephritis) , Acute progressive glomerulonephritis), kidney diseases such as renal infarction, diabetic nephritis; liver diseases such as liver fibrosis, hepatitis, cirrhosis; eye diseases associated with ocular fibrin deposition; organ transplantation or resection Postoperative organ dysfunction; microcirculatory disturbance due to microthrombosis including thrombotic microangiopathy; or preventive or therapeutic (preferably, therapeutic) for diseases / symptoms associated with cancer cell migration / metastasis It is useful as a prophylactic or therapeutic agent (preferably a therapeutic agent) for diseases associated with thrombosis / embolism or associated with fibrin deposition or fibrosis.
 以下に、本明細書中における置換基について説明する。 Hereinafter, the substituents in this specification will be described.
 「ハロゲン原子」は、フッ素原子、塩素原子、臭素原子、又はヨウ素原子を意味する。 “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
 「C~Cアルキル基」とは、炭素数1~6の直鎖又は分岐鎖の飽和炭化水素基を意味し、例えば、メチル基、エチル基、プロピル基、イソプロピル基、n-ブチル基、sec-ブチル基、tert-ブチル基、イソブチル基、n-ペンチル基、n-ヘキシル基、1-エチルプロピル基、2,2-ジメチルプロピル基などが挙げられ、好適には炭素数1~3の直鎖又は分岐鎖の飽和炭化水素基(C~Cアルキル基)であり、より好適には炭素数1~2の飽和炭化水素基(C~Cアルキル基)であり、更により好適にはメチル基である。 “C 1 -C 6 alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group. , Sec-butyl group, tert-butyl group, isobutyl group, n-pentyl group, n-hexyl group, 1-ethylpropyl group, 2,2-dimethylpropyl group, etc., preferably having 1 to 3 carbon atoms A straight-chain or branched-chain saturated hydrocarbon group (C 1 -C 3 alkyl group), more preferably a saturated hydrocarbon group having 1 to 2 carbon atoms (C 1 -C 2 alkyl group), More preferably, it is a methyl group.
 「ハロゲノC~Cアルキル基」とは、同一又は異なる1~3個の前記「ハロゲン原子」で置換された前記「C~Cアルキル基」であり、好適には1~3個のフッ素原子で置換されたC~Cアルキル基であり、より好適にはトリフルオロメチル基である。 The “halogeno C 1 -C 3 alkyl group” is the above “C 1 -C 3 alkyl group” substituted with 1 to 3 of the above “halogen atoms”, preferably 1 to 3 A C 1 -C 3 alkyl group substituted with a fluorine atom, and more preferably a trifluoromethyl group.
 「C~C10シクロアルキル基」とは、炭素数3~10の飽和炭化水素環を意味し、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、シクロオクチル基等で例示されるモノシクロアルキル基の他に、ポリシクロアルキル基、例えば、ビシクロアルキル基、トリシクロアルキル基等も包含され、ビシクロアルキル基としては、ノルボルニル基、例えば、exo-2-ノルボルニル基、endo-2-ノルボルニル基、3-ピナニル基、ビシクロ〔3.1.0〕ヘキシル基、ビシクロ〔2.2.1〕ヘプチル基、ビシクロ〔2.2.2〕オクト-2-イル基等、トリシクロアルキル基としては、アダマンチル基、例えば、1-アダマンチル基、2-アダマンチル基などが挙げられ、好適には炭素数3~8の飽和炭化水素環(C~Cシクロアルキル基)であり、より好適には炭素数3~7の飽和炭化水素環(C~Cシクロアルキル基)であり、更により好適にはシクロヘキシル基である。 “C 3 -C 10 cycloalkyl group” means a saturated hydrocarbon ring having 3 to 10 carbon atoms, and is exemplified by a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like. In addition to a monocycloalkyl group, a polycycloalkyl group such as a bicycloalkyl group or a tricycloalkyl group is also included. Examples of the bicycloalkyl group include a norbornyl group such as an exo-2-norbornyl group, an endo- Such as 2-norbornyl group, 3-pinanyl group, bicyclo [3.1.0] hexyl group, bicyclo [2.2.1] heptyl group, bicyclo [2.2.2] oct-2-yl group, tricyclo Examples of the alkyl group include an adamantyl group such as a 1-adamantyl group and a 2-adamantyl group. Number 3 is a saturated hydrocarbon ring of ~ 8 (C 3 ~ C 8 cycloalkyl group), more preferably a saturated hydrocarbon ring having 3 to 7 carbon atoms (C 3 ~ C 7 cycloalkyl group), further More preferred is a cyclohexyl group.
 「C~Cアルコキシ基」とは、炭素数1~6の直鎖状又は分岐鎖状のアルキルオキシ基を意味し、例えば、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、tert-ブトキシ基などが挙げられ、好適には炭素数1~3の直鎖状又は分岐鎖状のアルキルオキシ基(C~Cアルコキシ基)であり、より好適にはメトキシ基である。 The “C 1 -C 6 alkoxy group” means a linear or branched alkyloxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a tert- Examples thereof include a butoxy group, preferably a linear or branched alkyloxy group having 1 to 3 carbon atoms (C 1 -C 3 alkoxy group), and more preferably a methoxy group.
 「ハロゲノC~Cアルコキシ基」とは、同一又は異なる1~3個の前記「ハロゲン原子」で置換された前記「C~Cアルコキシ基」であり、好適には1~3個のフッ素原子で置換されたC~Cアルコキシ基であり、より好適にはトリフルオロメトキシ基である。 The “halogeno C 1 -C 3 alkoxy group” is the above-mentioned “C 1 -C 3 alkoxy group” substituted with the same or different 1 to 3 “halogen atoms”, preferably 1 to 3 A C 1 -C 3 alkoxy group substituted with a fluorine atom, and more preferably a trifluoromethoxy group.
 「C~Cアルキルスルホニル基」とは、炭素数1~3の直鎖状又は分岐鎖状のアルキルスルホニル基を意味し、メチルスルホニル基、エチルスルホニル基、プロピルスルホニル基及びイソプロピルスルホニル基が挙げられる。 The “C 1 -C 3 alkylsulfonyl group” means a linear or branched alkylsulfonyl group having 1 to 3 carbon atoms, and includes a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, and an isopropylsulfonyl group. Can be mentioned.
 「アリール基」とは、炭素数6~14のアリール基を意味し、例えばフェニル基、ナフチル基、アントリル基、フェナントリル基が挙げられる。 “Aryl group” means an aryl group having 6 to 14 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, an anthryl group, and a phenanthryl group.
 「ヘテロシクリル基」とは、窒素原子、酸素原子及び硫黄原子からなる群より選択される1~3個の原子を含有する単環若しくは二環性の3~10員の飽和若しくは不飽和の複素環基を意味し、例えば、アジリジニル基、アゼチジニル基、ピロリジニル基、モルホリニル基、ピロリル基、フリル基、チエニル基、ピラゾリル基、イミダゾリル基、オキサゾリル基、イソチアゾリル基、ピラニル基、ピリジル基、ピリダジニル基、ピリミジニル基、ピラジニル基、ベンゾイミダゾリル基、ベンゾオキサゾリル基、キノリル基、ピロリニル基、イミダゾリニル基、ピラゾリニル基、ジヒドロピリジル基、テトラヒドロピリジル基などが挙げられ、「飽和ヘテロシクリル基」及び「不飽和ヘテロシクリル基」に分類でき、好適にはチエニル基、ピリジル基、テトラヒドロピラニル基、イソオキサゾリル基である。 The “heterocyclyl group” is a monocyclic or bicyclic 3 to 10-membered saturated or unsaturated heterocyclic ring containing 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom Group, for example, aziridinyl, azetidinyl, pyrrolidinyl, morpholinyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isothiazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl Group, pyrazinyl group, benzimidazolyl group, benzoxazolyl group, quinolyl group, pyrrolinyl group, imidazolinyl group, pyrazolinyl group, dihydropyridyl group, tetrahydropyridyl group, etc., and "saturated heterocyclyl group" and "unsaturated heterocyclyl group" Preferably, thienyl group, pi Jill group, tetrahydropyranyl group, isoxazolyl group.
 「アリールオキシ基」とは、前記アリール基とオキシ基からなる基を意味し、例えば、フェノキシ基、ナフトキシ基などが挙げられる。 “Aryloxy group” means a group composed of the aryl group and an oxy group, and examples thereof include a phenoxy group and a naphthoxy group.
 「C~Cアルケニル基」とは、炭素数2~6の直鎖状又は分岐鎖状のアルケニル基を意味し、例えば、ビニル基、アリル基、ブテニル基、1-プロペニル基、イソプロペニル基などが挙げられる。 “C 2 -C 6 alkenyl group” means a linear or branched alkenyl group having 2 to 6 carbon atoms, such as vinyl, allyl, butenyl, 1-propenyl, isopropenyl. Groups and the like.
 「ハロゲノアリール基」とは、同一又は異なる1~3個の前記「ハロゲン原子」で置換された前記「アリール基」であり、例えば、クロロフェニル基、ブロモフェニル基などが挙げられる。 The “halogenoaryl group” is the above “aryl group” substituted with 1 to 3 “halogen atoms” which are the same or different, and examples thereof include a chlorophenyl group and a bromophenyl group.
 「ハロゲノ不飽和ヘテロシクリル基」とは、同一又は異なる1~3個の前記「ハロゲン原子」で置換された前記「不飽和ヘテロシクリル基」であり、例えばクロロチエニル基などが挙げられる
 「C~Cアルカノイル基」とは、1~6個の炭素原子を有する直鎖状又は分岐鎖状のアルカノイル基を意味し、例えば、ホルミル基、アセチル基、プロピオニル基、ブチリル基、イソブチリル基、バレリル基、イソバレリル基、ピバロイル基、ヘキサノイル基などが挙げられる。
“Halogeno unsaturated heterocyclyl group” means the above “unsaturated heterocyclyl group” substituted with 1 to 3 of the above “halogen atoms”, and examples thereof include a chlorothienyl group “C 1 -C The6 alkanoyl group” means a linear or branched alkanoyl group having 1 to 6 carbon atoms, such as formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, An isovaleryl group, a pivaloyl group, a hexanoyl group, etc. are mentioned.
 「C~Cアルカノイルオキシ基」とは、2~6個の炭素原子を有する直鎖状又は分岐鎖状のアルカノイル基とオキシ基からなる基を意味し、例えば、アセチルオキシ基、プロピオニルオキシ基、ヘキサノイルオキシ基などが挙げられる。 The “C 2 -C 6 alkanoyloxy group” means a group consisting of a linear or branched alkanoyl group having 2 to 6 carbon atoms and an oxy group, such as an acetyloxy group, propionyloxy group. Group, hexanoyloxy group and the like.
 「(C~Cシクロアルキル)カルボニルオキシ基」とは、炭素数3~6の飽和炭化水素環とカルボニルオキシ基からなる基を意味し、例えば、シクロプロピルカルボニルオキシ基、シクロヘキシルカルボニルオキシ基などが挙げられる。 “(C 3 -C 6 cycloalkyl) carbonyloxy group” means a group consisting of a saturated hydrocarbon ring having 3 to 6 carbon atoms and a carbonyloxy group, such as a cyclopropylcarbonyloxy group, a cyclohexylcarbonyloxy group. Etc.
 「(C~Cアルコキシ)カルボニル基」とは、前記C~Cアルコキシ基とカルボニル基からなる基を意味し、メトキシカルボニル基、エトキシカルボニル基、イソプロポキシカルボニル基などが挙げられる。 The “(C 1 -C 6 alkoxy) carbonyl group” means a group composed of the C 1 -C 6 alkoxy group and a carbonyl group, and examples thereof include a methoxycarbonyl group, an ethoxycarbonyl group, and an isopropoxycarbonyl group.
 「ヘテロシクリルオキシ基」とは、前記ヘテロシクリル基とオキシ基からなる基を意味し、例えば、ピロリジン-3-イルオキシ基、ピリジン-4-イルオキシ基などが挙げられる。 “Heterocyclyloxy group” means a group composed of the heterocyclyl group and an oxy group, and examples thereof include a pyrrolidin-3-yloxy group and a pyridin-4-yloxy group.
 「ヘテロシクリルアルキル基」とは、前記ヘテロシクリル基及び前記C~Cアルキル基からなる基を意味し、例えば、1,3-ジオキソール-4-イルメチル基などが挙げられる。 The “heterocyclylalkyl group” means a group consisting of the heterocyclyl group and the C 1 -C 6 alkyl group, and examples thereof include a 1,3-dioxol-4-ylmethyl group.
 「ヘテロシクリルアルキルオキシカルボニル基」とは、前記ヘテロシクリル基、前記C~Cアルコキシ基及びカルボニル基からなる基を意味し、例えば、1,3-ジオキソール-4-イルメトキシカルボニル基などが挙げられる。 The “heterocyclylalkyloxycarbonyl group” means a group consisting of the heterocyclyl group, the C 1 -C 6 alkoxy group and a carbonyl group, and examples thereof include a 1,3-dioxol-4-ylmethoxycarbonyl group. .
 「プロドラッグ基」とは、生体内における生理条件下で酵素や胃酸等による反応により本発明の医薬組成物の有効成分である化合物(I)に変換せしめる基、すなわち、酵素的に酸化、還元、加水分解等を起こして化合物(I)に変化せしめる基、又は胃酸等により加水分解等を起こして化合物(I)変化せしめる基を意味し、例えば、フェニルアラニル基、L-ノルロイシル基、[(5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メトキシ]カルボニル基、[1-(イソブチリルオキシ)エトキシ]カルボニル基、[1-(2,2-ジメチルプロパノイルオキシ)エトキシ]カルボニル基、{1-[(シクロヘキシルカルボニル)オキシ]エトキシ}カルボニル基、(1-アセトキシエトキシ)カルボニル基、ベンジル基、[(イソプロポキシカルボニル)オキシ]エチル基などが挙げられる。Rにおけるプロドラッグ基は、カルボキシ基に対するプロドラッグ基であり、好適には、C~Cアルカノイルオキシ基、(C~Cシクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルキル基、又は、オキソ基及びC~Cアルキル基から選ばれる同一又は異なる1~3個の基で置換されていてもよいヘテロシクリルアルキル基であり、より好適には、ベンジル基又は[(イソプロポキシカルボニル)オキシ]エチル基である。Rにおけるプロドラッグ基は、アミノ基に対するプロドラッグ基であり、好適には、アミノ基、ハロゲノ基、水酸基、カルボキシ基、カルバモイル基、C~Cアルコキシ基、アリール基及びへテロシクリル基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルカノイル基、C~Cアルキル基、C~Cアルカノイルオキシ基、(C~Cシクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1~3個の基で置換されていてもよい(C~Cアルコキシ)カルボニル基、又は、オキソ基及びC~Cアルキル基から選ばれる同一又は異なる1~3個の基で置換されていてもよいヘテロシクリルアルキルオキシカルボニル基であり、より好適には、フェニルアラニル基、L-ノルロイシル基、[(5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メトキシ]カルボニル基、[1-(イソブチリルオキシ)エトキシ]カルボニル基、[1-(2,2-ジメチルプロパノイルオキシ)エトキシ]カルボニル基、({1-[(シクロヘキシルカルボニル)オキシ]エトキシ}カルボニル)基、又は、(1-アセトキシエトキシ)カルボニル基である。 The “prodrug group” is a group that can be converted into the compound (I) that is an active ingredient of the pharmaceutical composition of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized or reduced. , Means a group that undergoes hydrolysis or the like to change into compound (I), or a group that undergoes hydrolysis or the like by gastric acid or the like to alter compound (I), and includes, for example, a phenylalanyl group, an L-norleucyl group, [ (5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy] carbonyl group, [1- (isobutyryloxy) ethoxy] carbonyl group, [1- (2,2-dimethylpropanoyloxy) ) Ethoxy] carbonyl group, {1-[(cyclohexylcarbonyl) oxy] ethoxy} carbonyl group, (1-acetoxyethoxy) carbonyl group, benzyl group, Etc. (isopropoxycarbonyl) oxy] ethyl groups. The prodrug group in R 3 is a prodrug group with respect to a carboxy group, and is preferably the same or selected from a C 2 to C 6 alkanoyloxy group, a (C 3 to C 6 cycloalkyl) carbonyloxy group and an aryl group. C 1 -C 6 alkyl group optionally substituted with 1 to 3 different groups, or 1 to 3 groups selected from the same or different groups selected from oxo group and C 1 -C 6 alkyl group A heterocyclylalkyl group, which may be a benzyl group or a [(isopropoxycarbonyl) oxy] ethyl group. The prodrug group in R 9 is a prodrug group with respect to an amino group, and preferably from an amino group, a halogeno group, a hydroxyl group, a carboxy group, a carbamoyl group, a C 1 -C 6 alkoxy group, an aryl group, and a heterocyclyl group. C 1 -C 6 alkanoyl group, C 1 -C 6 alkyl group, C 2 -C 6 alkanoyloxy group, (C 3 -C 6 cyclo) optionally substituted with the same or different 1 to 3 groups selected An alkyl) carbonyloxy group and an aryl group, which may be substituted with the same or different 1 to 3 groups selected from (C 1 -C 6 alkoxy) carbonyl group, or an oxo group and a C 1 -C 6 alkyl group A heterocyclylalkyloxycarbonyl group which may be substituted with the same or different 1 to 3 groups selected from An aenylalanyl group, an L-norleucyl group, a [(5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy] carbonyl group, a [1- (isobutyryloxy) ethoxy] carbonyl group, [1- A (2,2-dimethylpropanoyloxy) ethoxy] carbonyl group, a ({1-[(cyclohexylcarbonyl) oxy] ethoxy} carbonyl) group, or a (1-acetoxyethoxy) carbonyl group.
 本発明において、一般式(I)で表される化合物は、好適には、一般式(Ia)で表される化合物である。 In the present invention, the compound represented by the general formula (I) is preferably a compound represented by the general formula (Ia).
 以下に、一般式(I)又は(Ia)で表される化合物(特に、一般式(Ia)で表される化合物)について詳細に説明する。 Hereinafter, the compound represented by the general formula (I) or (Ia) (particularly, the compound represented by the general formula (Ia)) will be described in detail.
 (1)式中、Rは、好適には、(a)水酸基、ハロゲン原子、アミノ基、C~Cアルキル基、C~Cシクロアルキル基、フェニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルキル基;水酸基、ハロゲン原子、アミノ基、C~Cアルキル基、フェニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルケニル基;水酸基、ハロゲン原子、アミノ基及びC~Cアルキル基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cシクロアルキル基;水酸基、ハロゲン原子、シアノ基、アミノ基、C~Cアルキル基、ハロゲノC~Cアルキル基(当該置換基は同一の1~3個のハロゲン原子を示す。)、C~Cアルコキシ基、C~Cアルキルスルホニル基、フェニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいフェニル基;水酸基、ハロゲン原子、シアノ基、アミノ基、C~Cアルキル基、ハロゲノC~Cアルキル基、C~Cアルコキシ基、C~Cアルキルスルホニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいチエニル基;水酸基、ハロゲン原子、アミノ基、C~Cアルキル基、ハロゲノC~Cアルキル基、C~Cアルコキシ基、C~Cアルキルスルホニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいピリジル基;又は、水酸基、ハロゲノ基、アミノ基、C~Cアルキル基、ハロゲノC~Cアルキル基、C~Cアルコキシ基、C~Cアルキルスルホニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいテトラヒドロピラニル基であり、より好適には、(b)C~Cシクロアルキル基又はフェニル基で置換されていてもよいC~Cアルキル基;水酸基、若しくは同一の1~2個のC~Cアルキル基で置換されていてもよいC~Cシクロアルキル基;ハロゲン原子、C~Cアルキル基、ハロゲノC~Cアルキル基(当該置換基は1~3個のフッ素原子を示す。)、C~Cアルコキシ基又はフェニル基で置換されていてもよいフェニル基;ハロゲン原子、C~Cアルキル基及びC~Cアルコキシ基から選ばれる同一又は異なる1~2個の基で置換されていてもよいチエニル基;ハロゲン原子、C~Cアルキル基及びC~Cアルコキシ基から選ばれる同一又は異なる1~2個の基で置換されていてもよいピリジル基;又は、テトラヒドロピラニル基であり、更により好適には、(c)C~Cアルキル基;C~Cシクロアルキル基若しくはフェニル基で置換されているC~Cアルキル基;C~Cシクロアルキル基;水酸基若しくは1~2個のメチル基で置換されているシクロヘキシル基;フェニル基;塩素原子、フッ素原子、C~Cアルキル基、トリフルオロメチル基若しくはフェニル基で置換されているフェニル基又は、チエニル基、ピリジル基、又は、テトラヒドロチエニル基であり、更により好適には、(d)1~2個のメチル基で置換されたシクロヘキシル基であり、特に好適には、(e)基 In the formula (1), R a is preferably selected from (a) a hydroxyl group, a halogen atom, an amino group, a C 1 -C 3 alkyl group, a C 3 -C 6 cycloalkyl group, a phenyl group and a phenoxy group. C 1 -C 6 alkyl group which may be substituted with the same or different 1 to 3 groups; the same or selected from hydroxyl group, halogen atom, amino group, C 1 -C 3 alkyl group, phenyl group and phenoxy group A C 2 -C 6 alkenyl group optionally substituted with 1 to 3 different groups; the same or different 1 to 3 groups selected from a hydroxyl group, a halogen atom, an amino group and a C 1 -C 3 alkyl group; An optionally substituted C 3 -C 8 cycloalkyl group; a hydroxyl group, a halogen atom, a cyano group, an amino group, a C 1 -C 3 alkyl group, a halogeno C 1 -C 3 alkyl group (the substituents are the same 1 ~ 3 halogen atoms.), A C 1 -C 3 alkoxy group, a C 1 -C 3 alkylsulfonyl group, a phenyl group and a phenoxy group may be substituted with the same or different 1 to 3 groups Good phenyl group; hydroxyl group, halogen atom, cyano group, amino group, C 1 -C 3 alkyl group, halogeno C 1 -C 3 alkyl group, C 1 -C 3 alkoxy group, C 1 -C 3 alkylsulfonyl group and phenoxy A thienyl group optionally substituted by the same or different 1 to 3 groups selected from a group; a hydroxyl group, a halogen atom, an amino group, a C 1 -C 3 alkyl group, a halogeno C 1 -C 3 alkyl group, C 1 ~ C 3 alkoxy group, C 1 ~ C 3 alkylsulfonyl group and the same or different 1 to 3 pyridyl group which may be substituted with a group selected from a phenoxy group; It is the same selected hydroxyl, halogeno group, an amino group, C 1 ~ C 3 alkyl group, a halogeno C 1 ~ C 3 alkyl group, C 1 ~ C 3 alkoxy group, a C 1 ~ C 3 alkylsulfonyl group and a phenoxy group Or a tetrahydropyranyl group which may be substituted with 1 to 3 different groups, and more preferably (b) C 1 which may be substituted with a C 3 -C 6 cycloalkyl group or a phenyl group. A C 6 -alkyl group; a hydroxyl group or a C 3 -C 8 cycloalkyl group optionally substituted with 1 to 2 identical C 1 -C 3 alkyl groups; a halogen atom, a C 1 -C 3 alkyl group, Halogeno C 1 -C 3 alkyl group (the substituent represents 1 to 3 fluorine atoms). ), A C 1 -C 3 alkoxy group or a phenyl group optionally substituted by a phenyl group; one or two identical or different groups selected from a halogen atom, a C 1 -C 3 alkyl group and a C 1 -C 3 alkoxy group A thienyl group which may be substituted with a group of: pyridyl which may be substituted with the same or different one or two groups selected from a halogen atom, a C 1 -C 3 alkyl group and a C 1 -C 3 alkoxy group A tetrahydropyranyl group, and even more preferably, (c) a C 3 -C 6 alkyl group; a C 1 -C 2 alkyl substituted by a C 3 -C 6 cycloalkyl group or a phenyl group group; C 3 ~ C 7 cycloalkyl group; a cyclohexyl group substituted with a hydroxy or 1-2 methyl groups; a phenyl group; a chlorine atom, a fluorine atom, C 1 ~ C 4 alkyl Group, a trifluoromethyl group or a phenyl group substituted by a phenyl group, a thienyl group, a pyridyl group, or a tetrahydrothienyl group, and even more preferably (d) substituted by 1 to 2 methyl groups Cyclohexyl group, particularly preferably (e) group
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
(ここで、*は結合位置を示す。)であり、最も好適には、(f)基 (Wherein * represents a bonding position), and most preferably (f) group
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
(ここで、*は結合位置を示す。)である。 Here, * indicates a bonding position.
 (2)式中、Rは、好適には、(a)水素原子又はメチル基であり、より好適には、(b)水素原子である。 In the formula (2), R b is preferably (a) a hydrogen atom or a methyl group, and more preferably (b) a hydrogen atom.
 (3)式中、R、R、R、R、R及びRは、好適には、(a)いずれも水素原子である。 (3) In the formula, R 1 , R 2 , R 4 , R 6 , R 7 and R 8 are each preferably a hydrogen atom (a).
 (4)式中、Rは、好適には、(a)水素原子又はメチル基であり、より好適には、(b)水素原子である。 In the formula (4), R 5 is preferably (a) a hydrogen atom or a methyl group, and more preferably (b) a hydrogen atom.
 (5)式中、Rは、好適には、(a)水素原子である。Rがプロドラッグ基であるとき、(b)カルボキシル基の酸素原子に結合するプロドラッグ基であり、好適には、(c)C~Cアルカノイルオキシ基、(C~Cシクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルキル基;又は、オキソ基及びC~Cアルキル基から選ばれる同一又は異なる1~3個の基で置換されていてもよいヘテロシクリルアルキル基であり、より好適には、(d)ベンジル基又は[(イソプロポキシカルボニル)オキシ]エチル基である。 (5) In the formula, R 3 is preferably (a) a hydrogen atom. When R 3 is a prodrug group, (b) a prodrug group bonded to the oxygen atom of the carboxyl group, preferably (c) a C 2 -C 6 alkanoyloxy group, (C 3 -C 6 cyclo An alkyl) carbonyloxy group and an aryl group, and a C 1 to C 6 alkyl group which may be substituted with the same or different 1 to 3 groups selected from an aryl group; or an oxo group and a C 1 to C 6 alkyl group Heterocyclylalkyl group which may be substituted with the same or different 1 to 3 groups, more preferably (d) benzyl group or [(isopropoxycarbonyl) oxy] ethyl group.
 (6)式中、Rは、好適には、(a)水素原子である。Rがプロドラッグ基であるとき、(b)アミノ基の窒素原子に結合するプロドラッグ基であり、好適には、(c)アミノ基、ハロゲン原子、水酸基、カルボキシ基、カルバモイル基、C~Cアルコキシ基、アリール基及びへテロシクリル基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルカノイル基;C~Cアルキル基;C~Cアルカノイルオキシ基、(C~Cシクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1~3個の基で置換されていてもよい(C~Cアルコキシ)カルボニル基;又は、オキソ基及びC~Cアルキル基から選ばれる同一又は異なる1~3個の基で置換されていてもよいヘテロシクリルアルキルオキシカルボニル基であり、より好適には、(d)フェニルアラニル基、L-ノルロイシル基、[(5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メトキシ]カルボニル基、[1-(イソブチリルオキシ)エトキシ]カルボニル基、[1-(2,2-ジメチルプロパノイルオキシ)エトキシ]カルボニル基、({1-[(シクロヘキシルカルボニル)オキシ]エトキシ}カルボニル)基、又は、(1-アセトキシエトキシ)カルボニル基である。 (6) In the formula, R 9 is preferably (a) a hydrogen atom. When R 9 is a prodrug group, (b) a prodrug group bonded to the nitrogen atom of the amino group, preferably (c) an amino group, a halogen atom, a hydroxyl group, a carboxy group, a carbamoyl group, C 1 ~ C 6 alkoxy group, the same or different 1 to 3 is substituted with a group optionally C 1 even if ~ C 6 alkanoyl group selected from heterocyclyl, an aryl group, and to; C 1 ~ C 6 alkyl radical; C 2 ~ (C 1 -C 6 alkoxy) carbonyl group optionally substituted by the same or different 1 to 3 groups selected from C 6 alkanoyloxy group, (C 3 -C 6 cycloalkyl) carbonyloxy group and aryl group Or a heterocyclylalkyloxycarbonyl optionally substituted by the same or different 1 to 3 groups selected from an oxo group and a C 1 -C 6 alkyl group; And more preferably (d) phenylalanyl group, L-norleucyl group, [(5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy] carbonyl group, [1 -(Isobutyryloxy) ethoxy] carbonyl group, [1- (2,2-dimethylpropanoyloxy) ethoxy] carbonyl group, ({1-[(cyclohexylcarbonyl) oxy] ethoxy} carbonyl) group, or ( 1-acetoxyethoxy) carbonyl group.
 上記(1)の(a)~(f)、(2)の(a)~(b)、(3)の(a)、(4)の(a)~(b)、(5)の(a)~(d)、及び、(6)の(a)~(d)は、それぞれ任意の組合せを選ぶことができる。例えば、一般式(Ia)で表される化合物において、好適には、Rが、水酸基、ハロゲン原子、アミノ基、C~Cアルキル基、C~Cシクロアルキル基、フェニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルキル基;水酸基、ハロゲン原子、アミノ基、C~Cアルキル基、フェニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルケニル基;水酸基、ハロゲン原子、アミノ基及びC~Cアルキル基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cシクロアルキル基;水酸基、ハロゲン原子、シアノ基、アミノ基、C~Cアルキル基、ハロゲノC~Cアルキル基(当該置換基は同一の1~3個のハロゲン原子を示す。)、C~Cアルコキシ基、C~Cアルキルスルホニル基、フェニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいフェニル基;水酸基、ハロゲン原子、シアノ基、アミノ基、C~Cアルキル基、ハロゲノC~Cアルキル基、C~Cアルコキシ基、C~Cアルキルスルホニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいチエニル基;水酸基、ハロゲン原子、アミノ基、C~Cアルキル基、ハロゲノC~Cアルキル基、C~Cアルコキシ基、C~Cアルキルスルホニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいピリジル基;又は、水酸基、ハロゲノ基、アミノ基、C~Cアルキル基、ハロゲノC~Cアルキル基、C~Cアルコキシ基、C~Cアルキルスルホニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいテトラヒドロピラニル基であり、Rが、水素原子又はメチル基であり、R、R、R、R、R、R、R及びRが、いずれも水素原子であり、Rが、水素原子又はメチル基であり、
より好適には、Rが、C~Cシクロアルキル基又はフェニル基で置換されていてもよいC~Cアルキル基;水酸基、若しくは同一の1~2個のC~Cアルキル基で置換されていてもよいC~Cシクロアルキル基;ハロゲン原子、C~Cアルキル基、ハロゲノC~Cアルキル基(当該置換基は1~3個のフッ素原子を示す。)、C~Cアルコキシ基又はフェニル基で置換されていてもよいフェニル基;ハロゲン原子、C~Cアルキル基及びC~Cアルコキシ基から選ばれる同一又は異なる1~2個の基で置換されていてもよいチエニル基;ハロゲン原子、C~Cアルキル基及びC~Cアルコキシ基から選ばれる同一又は異なる1~2個の基で置換されていてもよいピリジル基;又は、テトラヒドロピラニル基であり、R、R、R、R、R、R、R、R、R及びRが、いずれも水素原子であり、
更により好適には、Rが、C~Cアルキル基;C~Cシクロアルキル基若しくはフェニル基で置換されているC~Cアルキル基;C~Cシクロアルキル基;水酸基若しくは1~2個のメチル基で置換されているシクロヘキシル基;フェニル基;塩素原子、フッ素原子、C~Cアルキル基、トリフルオロメチル基若しくはフェニル基で置換されているフェニル基又は、チエニル基、ピリジル基、又は、テトラヒドロチエニル基であり、R、R、R、R、R、R、R、R、R及びRが、いずれも水素原子であり、
更により好適には、Rが、1~2個のメチル基で置換されたシクロヘキシル基であり、R、R、R、R、R、R、R、R、R及びRが、いずれも水素原子であり、
特に好適には、Rが、基
(1) (a) to (f), (2) (a) to (b), (3) (a), (4) (a) to (b), (5) ( Arbitrary combinations can be selected for (a) to (d) and (a) to (d) in (6). For example, in the compound represented by the general formula (Ia), preferably, R a is a hydroxyl group, a halogen atom, an amino group, a C 1 -C 3 alkyl group, a C 3 -C 6 cycloalkyl group, a phenyl group, and C 1 -C 6 alkyl group which may be substituted with the same or different 1 to 3 groups selected from phenoxy group; hydroxyl group, halogen atom, amino group, C 1 -C 3 alkyl group, phenyl group and phenoxy group A C 2 -C 6 alkenyl group which may be substituted with the same or different 1 to 3 groups selected from: a hydroxyl group, a halogen atom, an amino group and a C 1 -C 3 alkyl group C 3 -C 8 cycloalkyl group optionally substituted with 3 groups; hydroxyl group, halogen atom, cyano group, amino group, C 1 -C 3 alkyl group, halogeno C 1 -C 3 ar A same or different 1 selected from a kill group (the substituents are the same 1 to 3 halogen atoms), a C 1 to C 3 alkoxy group, a C 1 to C 3 alkylsulfonyl group, a phenyl group and a phenoxy group; A phenyl group optionally substituted by 3 groups; a hydroxyl group, a halogen atom, a cyano group, an amino group, a C 1 -C 3 alkyl group, a halogeno C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group A thienyl group which may be substituted with the same or different 1 to 3 groups selected from a C 1 to C 3 alkylsulfonyl group and a phenoxy group; a hydroxyl group, a halogen atom, an amino group, a C 1 to C 3 alkyl group, halogeno C 1 ~ C 3 alkyl group, C 1 ~ C 3 alkoxy group, still at the same or different one to three groups selected from C 1 ~ C 3 alkylsulfonyl group and a phenoxy group Which may be a pyridyl group; or a hydroxyl group, a halogeno group, an amino group, C 1 ~ C 3 alkyl group, a halogeno C 1 ~ C 3 alkyl group, C 1 ~ C 3 alkoxy group, C 1 ~ C 3 alkylsulfonyl A tetrahydropyranyl group which may be substituted with the same or different 1 to 3 groups selected from a group and a phenoxy group, R b is a hydrogen atom or a methyl group, and R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 and R 9 are all hydrogen atoms, R 5 is a hydrogen atom or a methyl group,
More preferably, R a is a C 1 -C 6 alkyl group optionally substituted with a C 3 -C 6 cycloalkyl group or a phenyl group; a hydroxyl group or the same 1-2 C 1 -C 3 A C 3 -C 8 cycloalkyl group optionally substituted with an alkyl group; a halogen atom, a C 1 -C 3 alkyl group, a halogeno C 1 -C 3 alkyl group (the substituent contains 1 to 3 fluorine atoms) A C 1 -C 3 alkoxy group or a phenyl group optionally substituted with a phenyl group; the same or different 1 to 3 selected from a halogen atom, a C 1 -C 3 alkyl group and a C 1 -C 3 alkoxy group; A thienyl group which may be substituted with two groups; may be substituted with one or two same or different groups selected from a halogen atom, a C 1 -C 3 alkyl group and a C 1 -C 3 alkoxy group Good piri Or a tetrahydropyranyl group, and R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are all hydrogen atoms,
Even more preferably, R a is a C 3 -C 6 alkyl group; a C 3 -C 6 cycloalkyl group or a C 1 -C 2 alkyl group substituted with a phenyl group; a C 3 -C 7 cycloalkyl group A cyclohexyl group substituted with a hydroxyl group or 1 to 2 methyl groups; a phenyl group; a phenyl group substituted with a chlorine atom, a fluorine atom, a C 1 -C 4 alkyl group, a trifluoromethyl group or a phenyl group, or , Thienyl group, pyridyl group or tetrahydrothienyl group, and R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are all hydrogen atoms. And
Even more preferably, R a is a cyclohexyl group substituted with 1 to 2 methyl groups, and R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are both hydrogen atoms,
Particularly preferably, R a is a group
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
(ここで、*は結合位置を示す。)であり、R、R、R、R、R、R、R、R、R及びRが、いずれも水素原子であり、
最も好適には、Rが、基
(Wherein * represents a bonding position), and R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are all hydrogen atoms. And
Most preferably, R a is a group
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
(ここで、*は結合位置を示す。)であり、R、R、R、R、R、R、R、R、R及びRが、いずれも水素原子である。 (Wherein * represents a bonding position), and R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are all hydrogen atoms. It is.
 また、Rがプロドラッグ基である場合、好適には、Rが、1~2個のメチル基で置換されたシクロヘキシル基であり、R、R、R、R、R、R、R、R及びRが、いずれも水素原子であり、Rが、カルボキシル基の酸素原子に結合するプロドラッグ基であり、
より好適には、Rが、1~2個のメチル基で置換されたシクロヘキシル基であり、R、R、R、R、R、R、R、R及びRが、いずれも水素原子であり、Rが、C~Cアルカノイルオキシ基、(C~Cシクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルキル基;又は、オキソ基及びC~Cアルキル基から選ばれる同一又は異なる1~3個の基で置換されていてもよいヘテロシクリルアルキル基であり、
更により好適には、Rが、1~2個のメチル基で置換されたシクロヘキシル基であり、R、R、R、R、R、R、R、R及びRが、いずれも水素原子であり、Rが、ベンジル基又は[(イソプロポキシカルボニル)オキシ]エチル基である。
In addition, when R 3 is a prodrug group, R a is preferably a cyclohexyl group substituted with 1 to 2 methyl groups, and R b , R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are all hydrogen atoms, R 3 is a prodrug group bonded to the oxygen atom of the carboxyl group,
More preferably, R a is a cyclohexyl group substituted with 1 to 2 methyl groups, R b , R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is a hydrogen atom, and R 3 is the same or different 1 to 3 groups selected from a C 2 -C 6 alkanoyloxy group, a (C 3 -C 6 cycloalkyl) carbonyloxy group and an aryl group A C 1 -C 6 alkyl group which may be substituted by: or a heterocyclylalkyl group which may be substituted by the same or different 1 to 3 groups selected from an oxo group and a C 1 -C 6 alkyl group Yes,
Even more preferably, R a is a cyclohexyl group substituted with 1 to 2 methyl groups, R b , R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is a hydrogen atom, and R 3 is a benzyl group or a [(isopropoxycarbonyl) oxy] ethyl group.
 また、Rがプロドラッグ基である場合、好適には、Rが、1~2個のメチル基で置換されたシクロヘキシル基であり、R、R、R、R、R、R、R、R及びRが、いずれも水素原子であり、Rが、アミノ基の窒素原子に結合するプロドラッグ基であり、
より好適には、Rが、1~2個のメチル基で置換されたシクロヘキシル基であり、R、R、R、R、R、R、R、R及びRは、いずれも水素原子であり、Rが、アミノ基、ハロゲン原子、水酸基、カルボキシ基、カルバモイル基、C~Cアルコキシ基、アリール基及びへテロシクリル基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルカノイル基;C~Cアルキル基;C~Cアルカノイルオキシ基、(C~Cシクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1~3個の基で置換されていてもよい(C~Cアルコキシ)カルボニル基;又は、オキソ基及びC~Cアルキル基から選ばれる同一又は異なる1~3個の基で置換されていてもよいヘテロシクリルアルキルオキシカルボニル基であり、
より好適には、Rが、1~2個のメチル基で置換されたシクロヘキシル基であり、R、R、R、R、R、R、R、R及びRは、いずれも水素原子であり、Rが、フェニルアラニル基、L-ノルロイシル基、[(5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メトキシ]カルボニル基、[1-(イソブチリルオキシ)エトキシ]カルボニル基、[1-(2,2-ジメチルプロパノイルオキシ)エトキシ]カルボニル基、({1-[(シクロヘキシルカルボニル)オキシ]エトキシ}カルボニル)基、又は、(1-アセトキシエトキシ)カルボニル基である。
Also, when R 9 is a prodrug group, R a is preferably a cyclohexyl group substituted with 1 to 2 methyl groups, and R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are all hydrogen atoms, R 9 is a prodrug group bonded to the nitrogen atom of the amino group,
More preferably, R a is a cyclohexyl group substituted with 1 to 2 methyl groups, and R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is a hydrogen atom, and R 9 is the same or different one selected from an amino group, a halogen atom, a hydroxyl group, a carboxy group, a carbamoyl group, a C 1 -C 6 alkoxy group, an aryl group and a heterocyclyl group. C 1 -C 6 alkanoyl group optionally substituted with three groups; C 1 -C 6 alkyl group; C 2 -C 6 alkanoyloxy group, (C 3 -C 6 cycloalkyl) carbonyloxy group and aryl the same or different 1 to 3 may be substituted by a group (C 1 ~ C 6 alkoxy) carbonyl group selected from the group; or, the same or different selected from oxo group and C 1 ~ C 6 alkyl group 1 to 3 substituents which may be heterocyclylalkyl alkyloxycarbonyl group with a group that,
More preferably, R a is a cyclohexyl group substituted with 1 to 2 methyl groups, and R b , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 is a hydrogen atom, and R 9 is a phenylalanyl group, an L-norleucyl group, a [(5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy] carbonyl group, [ 1- (isobutyryloxy) ethoxy] carbonyl group, [1- (2,2-dimethylpropanoyloxy) ethoxy] carbonyl group, ({1-[(cyclohexylcarbonyl) oxy] ethoxy} carbonyl) group, or (1-acetoxyethoxy) carbonyl group.
 一般式(I)又は(Ia)で表される化合物の好ましい具体例としては、以下のものが挙げられる。 Preferred specific examples of the compound represented by the general formula (I) or (Ia) include the following.
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
 以下に、本発明の化合物の代表的な製造方法について説明するが、この方法に何ら限定されるものではない。 Hereinafter, a typical method for producing the compound of the present invention will be described, but the present invention is not limited to this method.
 [製造方法1]
 一般式(I)で表される化合物、その塩、それらの溶媒和物は、例えば下記の方法で製造することができる。
[Production Method 1]
The compound represented by the general formula (I), a salt thereof, and a solvate thereof can be produced, for example, by the following method.
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
 式中、R、R、R、R、R、R、R、R、R及びRは前記と同じものを示し、R10は、フッ素原子で置換されていてもよいC~Cアルキル基又はフェニル基を示し、PGはアミノ基の保護基を示し、PGは水素原子又はアミノ基の保護基を示し、PGはカルボキシ基の保護基を示す。 In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a and R b are the same as described above, and R 10 is substituted with a fluorine atom. An optionally substituted C 1 -C 3 alkyl group or a phenyl group, PG 1 represents an amino protecting group, PG 2 represents a hydrogen atom or an amino protecting group, and PG 3 represents a carboxy protecting group. Show.
 化合物(IIa)及び化合物(III)をアルドール反応させることにより、化合物(IV)を製造し、得られた化合物(IV)を脱水反応させることで化合物(V)を製造することができる。あるいは、化合物(IIb)及び化合物(III)をwittig反応させることにより、化合物(V)を製造することができる。得られた化合物(V)の保護基を除去することで、化合物(Ib)を製造することができる。 Compound (IV) can be produced by subjecting compound (IIa) and compound (III) to an aldol reaction to produce compound (IV), and the resulting compound (IV) can be subjected to a dehydration reaction. Alternatively, compound (V) can be produced by performing a wittig reaction between compound (IIb) and compound (III). Compound (Ib) can be produced by removing the protecting group of the obtained compound (V).
 アルドール反応とは、この場合、CH活性化合物としての化合物(IIa)と、カルボニル基を含む化合物(III)を、強塩基の存在下で結合させ化合物(IV)を生成する反応である。強塩基としては、例えば、炭酸ナトリウム、炭酸カリウム、ナトリウムエトキシド、カリウムブトキシド、水酸化ナトリウム、水酸化カリウム、水素化ナトリウム、水素化カリウムのようなアルカリ金属もしくはアルカリ土類金属の炭酸塩;アルカリ金属アルコキシド、アルカリ金属水酸化物もしくは水素化物;n-ブチルリチウムのようなアルキルリチウム、リチウムジイソプロピルアミドのようなジアルキルアミノリチウムに代表される有機金属塩基;又は、リチウムヘキサメチルジシラジドのようなビスシリルアミンの有機金属塩基などを使用することができる。反応溶媒としては、例えば、非環状、環状若しくは芳香族炭化水素、アルコール類、又は極性非プロトン性溶媒が挙げられ、例えばテトラヒドロフラン、N,N-ジメチルホルムアミド又はジエトキシエタンなどや、これらの混合溶媒を用いることができる。反応温度としては、通常、約-78℃~室温である。 In this case, the aldol reaction is a reaction in which compound (IIa) as a CH active compound and compound (III) containing a carbonyl group are combined in the presence of a strong base to form compound (IV). Examples of the strong base include carbonates of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride; Metal alkoxide, alkali metal hydroxide or hydride; alkyllithium such as n-butyllithium, organometallic base represented by dialkylaminolithium such as lithium diisopropylamide; or such as lithium hexamethyldisilazide An organometallic base of bissilylamine can be used. Examples of the reaction solvent include acyclic, cyclic or aromatic hydrocarbons, alcohols, or polar aprotic solvents such as tetrahydrofuran, N, N-dimethylformamide or diethoxyethane, and mixed solvents thereof. Can be used. The reaction temperature is usually about −78 ° C. to room temperature.
 脱水反応は、化合物(IV)の水酸基を不活性溶媒中、トリエチルアミン存在下に-78℃~50℃で、例えば、メタンスルホニルクロリド又はベンゼンスルホニルクロライドなどのスルホニルハライドで処理することでスルホン酸エステルに変換後、さらに塩基で処理することにより、化合物(V)を生成する反応である。不活性溶媒としては、例えば、塩化メチレン、クロロホルム、四塩化炭素などのハロゲン化アルキル系溶媒;テトラヒドロフラン、1,2-ジメトキシエタン、ジオキサンなどのエーテル系溶媒;ベンゼン、トルエンなどの芳香族系溶媒;又は、N,N-ジメチルホルムアミド、N,N-ジメチルアセトアミド、N-メチルピロリジン-2-オンなどのアミド系溶媒が挙げられ、これらに加えて場合によってはジメチルスルホキシド、スルホランなどのスルホキシド系溶媒;アセトン、メチルエチルケトンなどのケトン系溶媒;又は、アセトニトリルなどを使用することも可能である。塩基としては、例えば、ピリジン、2,6-ルチジン、コリジン、4-ジメチルアミノピリジン、トリエチルアミン、N-メチルモルホリン、ジイソプロピルエチルアミン、ジアザビシクロ[5.4.0]ウンデカ-7-エン(DBU)を用いることができる。尚、場合によっては、上記アルドール反応の際に脱水反応が進行することもある。 In the dehydration reaction, the hydroxyl group of compound (IV) is treated with a sulfonyl halide such as methanesulfonyl chloride or benzenesulfonyl chloride in an inert solvent at −78 ° C. to 50 ° C. in the presence of triethylamine to form a sulfonate ester. After the conversion, it is a reaction that produces a compound (V) by further treatment with a base. Examples of the inert solvent include alkyl halide solvents such as methylene chloride, chloroform and carbon tetrachloride; ether solvents such as tetrahydrofuran, 1,2-dimethoxyethane and dioxane; aromatic solvents such as benzene and toluene; Alternatively, amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one and the like, and in addition to these, sulfoxide solvents such as dimethyl sulfoxide and sulfolane may be mentioned; It is also possible to use ketone solvents such as acetone and methyl ethyl ketone; or acetonitrile. As the base, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, N-methylmorpholine, diisopropylethylamine, diazabicyclo [5.4.0] undec-7-ene (DBU) is used. be able to. In some cases, the dehydration reaction may proceed during the aldol reaction.
 Wittig反応は、この場合、塩基の存在下でホスホリル基を有する化合物(IIb)とカルボニル基を有する化合物(III)と反応させ、α,β-不飽和エステルである化合物(V)を生成する反応である。塩基としては、水素化ナトリウム、ナトリウムメトキシド、炭酸カリウム、カリウムヘキサメチルシラジドなどが使用できる。あるいは、ジアザビシクロ[5.4.0]ウンデカ-7-エン(DBU)又はトリエチルアミンなどの塩基と塩化リチウムを併用することも可能である。また、添加剤として、18-クラウン6-エーテルなどの環状エーテルなどを加えることも可能である。溶媒としては、アルコール類、テトラヒドロフラン、1,2-ジメトキシエタン、ジメチルスルホキシド、アセトニトリルなどを用いることができる。反応温度は基質により、適切な温度を選択すればよく、-78℃から還流条件下で反応を行うことができる。以下の文献を参考に製造することが可能である。1)Blanchette,M.A.,et al.Tetrahedron Lett.,1984年,25巻,2183頁。2)Still,W.C.,et al.Tetrahedron Lett.,1983年,24巻,4405頁。 In this case, the Wittig reaction is a reaction in which a compound (IIb) having a phosphoryl group and a compound (III) having a carbonyl group are reacted in the presence of a base to produce a compound (V) which is an α, β-unsaturated ester. It is. As the base, sodium hydride, sodium methoxide, potassium carbonate, potassium hexamethylsilazide and the like can be used. Alternatively, a base such as diazabicyclo [5.4.0] undec-7-ene (DBU) or triethylamine and lithium chloride can be used in combination. In addition, cyclic ethers such as 18-crown 6-ether can be added as additives. As the solvent, alcohols, tetrahydrofuran, 1,2-dimethoxyethane, dimethyl sulfoxide, acetonitrile and the like can be used. An appropriate reaction temperature may be selected depending on the substrate, and the reaction can be carried out from −78 ° C. under reflux conditions. It can be produced with reference to the following document. 1) Blanchette, M .; A. , Et al. Tetrahedron Lett. 1984, 25, 2183. 2) Still, W .; C. , Et al. Tetrahedron Lett. 1983, 24, 4405.
 アミノ基の保護基としては、有機化合物の合成、中でもペプチド合成においてアミノ基の保護基として通常用いられる保護基を使用すればよく、具体的にはtert-ブトキシカルボニル基、メトキシカルボニル基、エトキシカルボニル基等のアルコキシカルボニル基;ベンジルオキシカルボニル基、パラメトキシベンジルオキシカルボニル基、パラ(またはオルト)ニトロベンジルオキシカルボニル基等のアリールメトキシカルボニル基;ベンジル基、4-メトキシベンジル基、トリフェニルメチル基等のアリールメチル基;ホルミル基、アセチル基等のアルカノイル基;ベンゾイル基等のアロイル基;又は、2,4-ジニトロベンゼンスルホニル基、オルトニトロベンゼンスルホニル基等のアリールスルホニル基等を挙げることができる。これらのアミノ基の保護基は、アミノ基を保護する化合物の性質などに応じて取捨選択すればよく、それらの保護基の除去に際してもその保護基に応じた試薬や条件を選択すればよい。 As the amino-protecting group, a protecting group usually used as an amino-protecting group in the synthesis of organic compounds, particularly in peptide synthesis may be used. Specifically, a tert-butoxycarbonyl group, a methoxycarbonyl group, an ethoxycarbonyl group may be used. Alkoxycarbonyl groups such as benzyl groups; arylmethoxycarbonyl groups such as benzyloxycarbonyl groups, paramethoxybenzyloxycarbonyl groups, para (or ortho) nitrobenzyloxycarbonyl groups; benzyl groups, 4-methoxybenzyl groups, triphenylmethyl groups, etc. An alkanoyl group such as a formyl group or an acetyl group; an aroyl group such as a benzoyl group; or an arylsulfonyl group such as a 2,4-dinitrobenzenesulfonyl group or an orthonitrobenzenesulfonyl group. . These amino-protecting groups may be selected according to the properties of the compound protecting the amino group, and the reagents and conditions corresponding to the protecting groups may be selected when removing these protecting groups.
 カルボキシ基の保護基としては、例えば、アルキル基、アリール基またはアリールアルキルエステル基が挙げられる。これらのカルボキシ基の保護基は、カルボキシ基を保護する化合物の性質などに応じて取捨選択すればよく、それらの保護基の除去に際してもその保護基に応じた試薬や条件を選択すればよい。 Examples of the protecting group for the carboxy group include an alkyl group, an aryl group, and an arylalkyl ester group. These protecting groups for the carboxy group may be selected according to the properties of the compound protecting the carboxy group, and the reagents and conditions corresponding to the protecting group may be selected when removing these protecting groups.
 アミノ基およびカルボキシ基の保護・脱保護に関しては、参考文献として例えば、Greene,T.W.,Wuts,P.G.M.,Protective Groups in Organic Synthesis(1999),3rd Ed.,Wiley-Interscienceなどを挙げることができる。 Regarding the protection and deprotection of amino groups and carboxy groups, for example, Greene, T. et al. W. Wuts, P .; G. M.M. , Protective Groups in Organic Synthesis (1999), 3rd Ed. , Wiley-Interscience and the like.
 [製造方法2]
 本発明の化合物(I)は、下記の方法でも製造することができる。
[Production Method 2]
Compound (I) of the present invention can also be produced by the following method.
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
 式中、R、R、R、R、R、R、R、R、R、R、PG、PG及びPGは前記と同じものを示し、PGはアミド基の保護基を示す。 In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b , PG 1 , PG 2 and PG 3 are the same as described above, and PG 4 represents a protecting group for an amide group.
 化合物(IV)のアミノ基の保護基のみを選択的除去後、反応液を中性~塩基性に保つことで環化反応が進行しラクタム体(VI)が製造できる。得られたラクタム体(VI)を脱水反応により化合物(VII)に変換し、アミド基を保護した後、開環反応に付すことで化合物(IX)が製造できる。化合物(IX)の保護基を除去することにより、化合物(Ic)が製造できる。 After selectively removing only the protecting group of the amino group of the compound (IV), the cyclization reaction proceeds by keeping the reaction solution neutral to basic, whereby the lactam body (VI) can be produced. The obtained lactam body (VI) is converted to compound (VII) by a dehydration reaction to protect the amide group, and then subjected to a ring-opening reaction to produce compound (IX). Compound (Ic) can be produced by removing the protecting group of compound (IX).
 化合物(IV)のアミノ基の脱保護反応に関しては、例えば、PGがベンジルオキシカルボニル基、PGが水素原子、PGがメチル基の場合、不均一系触媒による水素化によってアミノ基の保護基を選択的に除去することが可能である。さらに、この場合、続く分子内環化反応が進行し、化合物(VI)が製造できる。溶媒としては例えば、水、メタノール、エタノール、酢酸エチル、酢酸などが使用できる。触媒としては、パラジウム-炭素(Pd/C)、パールマン触媒(Pearlman’s catalyst:Pd(OH))などを使用することが可能である。反応温度は室温~還流条件下で行うことが可能である。 Regarding the deprotection reaction of the amino group of compound (IV), for example, when PG 1 is a benzyloxycarbonyl group, PG 2 is a hydrogen atom, and PG 3 is a methyl group, the amino group is protected by hydrogenation with a heterogeneous catalyst. It is possible to selectively remove groups. Further, in this case, the subsequent intramolecular cyclization reaction proceeds to produce compound (VI). As the solvent, for example, water, methanol, ethanol, ethyl acetate, acetic acid and the like can be used. As the catalyst, palladium-carbon (Pd / C), Pearlman's catalyst (Pd (OH) 2 ), or the like can be used. The reaction temperature can be from room temperature to reflux conditions.
 また、上記以外の保護基を用いた場合においても、その保護基に応じた試薬や条件を選択することで、アミノ基の選択的な脱保護が可能である。参考文献としてはGreene,T.W.,Wuts,P.G.M.,Protective Groups in Organic Synthesis(1999),3rd Ed.,Wiley-Interscienceなどを挙げることができる。なお、アミノ基の脱保護反応として酸加水分解を用いた場合には、アミンの塩が生成し環化反応が十分に進行しないことから、反応系を中和する必要がある。 In addition, even when a protecting group other than the above is used, the amino group can be selectively deprotected by selecting reagents and conditions according to the protecting group. References include Greene, T .; W. Wuts, P .; G. M.M. , Protective Groups in Organic Synthesis (1999), 3rd Ed. , Wiley-Interscience and the like. When acid hydrolysis is used as the amino group deprotection reaction, an amine salt is formed and the cyclization reaction does not proceed sufficiently, so the reaction system must be neutralized.
 脱水反応は、化合物(VI)の水酸基を、不活性溶媒中、塩基存在下に-78℃~50℃でメタンスルホニルクロリド又はベンゼンスルホニルクロライドなどのスルホニルハライドで処理後、さらに塩基で処理することにより化合物(VII)を生成する反応である。製造方法1と同様の方法にて製造することが可能である。 In the dehydration reaction, the hydroxyl group of compound (VI) is treated with a sulfonyl halide such as methanesulfonyl chloride or benzenesulfonyl chloride at −78 ° C. to 50 ° C. in the presence of a base in an inert solvent, and then further treated with a base. This is a reaction for producing compound (VII). It can be manufactured by the same method as manufacturing method 1.
 アミド基の保護は、化合物(VII)のラクタム環のアミドNHを保護することによって化合物(VIII)を生成する反応である。保護基PGとしては、tert-ブトキシカルボニル基が好ましい。ジクロロメタン又はアセトニトリルなどの不活性溶媒中、塩基として4-ジメチルアミノピリジンを用い、ジ-tert-ブチルジカーボネートを0℃~還流条件下で反応させることで、アミド基を保護することが可能である。その他のアミド基の保護基導入に関しては、参考文献として例えば、Greene,T.W.,Wuts,P.G.M.,Protective Groups in Organic Synthesis(1999),3rd Ed.,Wiley-Interscienceなどを挙げることができる。 The protection of the amide group is a reaction in which compound (VIII) is formed by protecting amide NH on the lactam ring of compound (VII). The protecting group PG 4 is preferably a tert-butoxycarbonyl group. It is possible to protect the amide group by reacting di-tert-butyl dicarbonate under conditions of 0 ° C. to reflux using 4-dimethylaminopyridine as a base in an inert solvent such as dichloromethane or acetonitrile. . Regarding the introduction of protecting groups for other amide groups, for example, Greene, T. et al. W. Wuts, P .; G. M.M. , Protective Groups in Organic Synthesis (1999), 3rd Ed. , Wiley-Interscience and the like.
 開環反応は、化合物(VIII)のラクタム環を、加水分解することで化合物(IX)を得る反応である。具体的な反応条件としては、PGがtert-ブトキシカルボニル基の場合、水及びテトラヒドロフランの混合溶媒中、室温条件下、塩基として水酸化リチウムなどを作用させることが挙げられる。 The ring-opening reaction is a reaction for obtaining compound (IX) by hydrolyzing the lactam ring of compound (VIII). As specific reaction conditions, when PG 4 is a tert-butoxycarbonyl group, lithium hydroxide or the like is allowed to act as a base in a mixed solvent of water and tetrahydrofuran at room temperature.
 化合物(IX)の脱保護反応に関しては、製造方法1で挙げたアミノ基の保護基と同様である。 The deprotection reaction of compound (IX) is the same as the amino-protecting group mentioned in Production Method 1.
 [製造方法3]
 本発明の化合物(I)は、下記の方法でも製造することができる。
[Production Method 3]
Compound (I) of the present invention can also be produced by the following method.
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
 式中、R、R、R、R、R、R、R、R、R、R、PG、PG、PG及びPGは前記と同じものを示し、PGはイミダゾールの保護基を示す。 In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b , PG 1 , PG 2 , PG 3 and PG 4 are the same as above. PG 5 represents an imidazole protecting group.
 イミダゾールの窒素原子に保護基を導入した化合物(IIc)を出発物質とし、製造方法1及び製造方法2と同様の方法にて、化合物(X)を製造することができる。化合物(X)のカルボキシル基を保護して化合物(XI)を得た後、イミダゾールの窒素原子の保護基のみを除去し化合物(XII)を製造することができる。化合物(XII)のイミダゾール部分の窒素原子を、アルキル化、アルケニル化、シクロアルキル化、飽和へテロシクリル化、アリール化又は不飽和へテロシクリル化することによって化合物(XIII)を製造し、保護基を除去することで化合物(Ic)を製造することができる。 Compound (X) can be produced by a method similar to Production Method 1 and Production Method 2 using Compound (IIc) in which a protecting group is introduced into the nitrogen atom of imidazole as a starting material. After protecting the carboxyl group of compound (X) to obtain compound (XI), only the protecting group for the nitrogen atom of imidazole can be removed to produce compound (XII). Compound (XIII) is produced by alkylating, alkenylating, cycloalkylating, saturated heterocyclylating, arylating or unsaturated heterocyclylating the nitrogen atom of the imidazole moiety of compound (XII) and removing the protecting group Thus, compound (Ic) can be produced.
 イミダゾールの窒素原子の保護基としては、例えば、ベンゼンスルホニル基、トシル基などのスルホニル基;t-ブトキシカルボニル基、ベンジルオキシカルボニル基などのアルコキシカルボニル基;又は、トリチル基、メトキシメチル基、ベンジルオキシメチル基、[2-(トリメチルシリル)エトキシ]メチル基などのアルキル基が挙げられる。この中でもトリチル基が好ましい。これらのイミダゾールの窒素原子の保護基は、化合物の性質などに応じて取捨選択すればよく、それらの保護基の除去に際してもその保護基に応じた試薬や条件を選択すればよい。その他のイミダゾールの窒素原子の保護基導入・脱保護に関しては、参考文献として例えば、Greene,T.W.,Wuts,P.G.M.,Protective Groups in Organic Synthesis(1999),3rd Ed.,Wiley-Interscienceなどを挙げることができる。 Examples of the protecting group for the nitrogen atom of imidazole include sulfonyl groups such as benzenesulfonyl group and tosyl group; alkoxycarbonyl groups such as t-butoxycarbonyl group and benzyloxycarbonyl group; or trityl group, methoxymethyl group, benzyloxy Examples thereof include alkyl groups such as a methyl group and [2- (trimethylsilyl) ethoxy] methyl group. Among these, a trityl group is preferable. The protecting group for the nitrogen atom of these imidazoles may be selected according to the properties of the compound, and reagents and conditions corresponding to the protecting group may be selected when removing these protecting groups. Regarding the introduction and deprotection of the protecting group of the nitrogen atom of other imidazoles, for example, Greene, T. et al. W. Wuts, P .; G. M.M. , Protective Groups in Organic Synthesis (1999), 3rd Ed. , Wiley-Interscience and the like.
 アミノ基、アミド基、カルボキシル基の保護・脱保護に関しては、製造方法1及び製造方法2と同様である。 Protecting / deprotecting amino groups, amide groups, and carboxyl groups is the same as in manufacturing method 1 and manufacturing method 2.
 アルキル化反応、シクロアルキル化反応及び飽和へテロシクリル化反応は、例えば塩基存在下、R-I、R-Br、R-OSOCH、R-OSOCFなどの脱離基を有する化合物を、化合物(XII)と反応させることで化合物(XIII)を生成する反応である。反応溶媒としては、非環状、環状若しくは芳香族炭化水素又は極性非プロトン性溶媒を用いることができ、例えばテトラヒドロフラン、N,N-ジメチルホルムアミド又はジエトキシエタンなどや、これらの混合溶媒を用いることができる。塩基としては、例えば炭酸セシウム、水素化ナトリウムなどを用いることができる。 Alkylation reaction, cycloalkylation reaction and saturated heterocyclylation reaction are carried out in the presence of a base, for example, elimination of R a -I, R a -Br, R a -OSO 2 CH 3 , R a -OSO 2 CF 3, etc. In this reaction, a compound having a group is reacted with compound (XII) to produce compound (XIII). As the reaction solvent, an acyclic, cyclic or aromatic hydrocarbon or a polar aprotic solvent can be used. For example, tetrahydrofuran, N, N-dimethylformamide, diethoxyethane, or a mixed solvent thereof can be used. it can. As the base, for example, cesium carbonate, sodium hydride and the like can be used.
 アルケニル化反応、不飽和へテロシクリル化反応及びアリール化反応は、例えば、不飽和へテロシクリルボロン酸、アリールボロン酸化合物R-B(OH)を、化合物(XII)と反応させることで化合物(XIII)を生成する反応である。公知の反応((P.Y.S.Lam他、Tetrahedron Lett.、第39巻、2941ページ、1998年)を参考にすることができる。 The alkenylation reaction, unsaturated heterocyclylation reaction and arylation reaction can be performed by reacting, for example, unsaturated heterocyclylboronic acid or arylboronic acid compound R a -B (OH) 2 with compound (XII). This reaction generates (XIII). A known reaction ((PYS.Lam et al., Tetrahedron Lett., 39, 2941, 1998) can be referred to.
 不飽和へテロシクリル化反応は、別法として酸化銅存在下、R-Br(又はR-I、R-F、R-Clなど)と化合物(XII)と反応させることで化合物(XIII)を得ることができる。例えば、WO2003/061652を参考にすることができる。 The unsaturated heterocyclylation reaction may alternatively be carried out by reacting R a —Br (or R a —I, R a —F, R a —Cl, etc.) with compound (XII) in the presence of copper oxide. XIII) can be obtained. For example, WO2003 / 061652 can be referred to.
 [製造方法4]
 本発明の化合物の中間体(II)は、例えば下記の方法で製造することができる。
[Production Method 4]
The intermediate (II) of the compound of the present invention can be produced, for example, by the following method.
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
 式中、R、R、R10及びPGは前記と同じものを示す。 In formula, R <a> , R <b> , R < 10 > and PG < 3 > show the same thing as the above.
 市販、又は周知の方法を利用して合成される化合物(XIV)のイミダゾール部分の窒素原子を、アルキル化、アルケニル化、シクロアルキル化、飽和へテロシクリル化、アリール化又は不飽和へテロシクリル化することによって化合物(XV)を製造することが可能である。 Alkylating, alkenylating, cycloalkylating, saturated heterocyclylating, arylating or unsaturated heterocyclylating the nitrogen atom of the imidazole moiety of compound (XIV) that is commercially available or synthesized using well-known methods It is possible to produce compound (XV).
 あるいは、市販、又は周知の方法を利用して合成される化合物(XVI)のイミダゾール部分の窒素原子を、アルキル化、アルケニル化、シクロアルキル化、飽和へテロシクリル化、アリール化、又は不飽和へテロシクリル化することによって化合物(XVII)を製造し、化合物(XVIII)を用いたwittig反応により化合物(XV)を製造することが可能である。 Alternatively, the nitrogen atom of the imidazole moiety of compound (XVI) that is commercially available or synthesized using well-known methods is alkylated, alkenylated, cycloalkylated, saturated heterocyclylated, arylated, or unsaturated heterocyclyl. It is possible to produce the compound (XVII) by preparing the compound (XVII) by a wittig reaction using the compound (XVIII).
 得られた化合物(XV)のオレフィン部分を還元することで中間体(IId)を製造することが可能である。 It is possible to produce intermediate (IId) by reducing the olefin part of the obtained compound (XV).
 アルキル化、アルケニル化、シクロアルキル化、飽和へテロシクリル化、アリール化、又は不飽和へテロシクリル化は、製造方法3と同様の方法で、化合物(XIV)から化合物(XV)を合成する反応である。 Alkylation, alkenylation, cycloalkylation, saturated heterocyclylation, arylation, or unsaturated heterocyclylation is a reaction for synthesizing compound (XV) from compound (XIV) in the same manner as in Production Method 3. .
 製造方法4におけるWittig反応は、塩基の存在下でホスホリル基を有する化合物(XVIII)とカルボニル基を有する化合物(XVII)と反応させ、α,β-不飽和エステルである化合物(XV)を生成する反応である。塩基としては、水素化ナトリウム、ナトリウムメトキシド、炭酸カリウムなどが使用できる。あるいは、ジアザビシクロ[5.4.0]ウンデク-7-エン(DBU)又はトリエチルアミンなどの塩基と塩化リチウムを併用することも可能である。溶媒としてはアルコール類、テトラヒドロフラン、1,2-ジメトキシエタン,ジメチルスルホキシド、アセトニトリルなどを用いることができる。反応温度は基質により、適切な温度を選択すればよく、-78℃~還流条件下で反応を行うことができる。 The Wittig reaction in production method 4 is carried out by reacting a compound (XVIII) having a phosphoryl group with a compound (XVII) having a carbonyl group in the presence of a base to produce a compound (XV) which is an α, β-unsaturated ester. It is a reaction. As the base, sodium hydride, sodium methoxide, potassium carbonate and the like can be used. Alternatively, a base such as diazabicyclo [5.4.0] undec-7-ene (DBU) or triethylamine and lithium chloride can be used in combination. As the solvent, alcohols, tetrahydrofuran, 1,2-dimethoxyethane, dimethyl sulfoxide, acetonitrile and the like can be used. An appropriate reaction temperature may be selected depending on the substrate, and the reaction can be carried out under a condition of −78 ° C. to reflux.
 還元反応は、不均一系触媒による水素化によって化合物(XV)を化合物(IId)に水素化する反応である。溶媒としては、例えば、水、メタノール、エタノール、酢酸エチル、酢酸などが使用できる。触媒としては、パラジウム-炭素(Pd/C)、パールマン触媒(Pearlman’s catalyst:Pd(OH))、ラネーニッケル、アダムス触媒(Adams’ catalyst:PtO)などを使用することが可能である。 The reduction reaction is a reaction in which compound (XV) is hydrogenated to compound (IId) by hydrogenation with a heterogeneous catalyst. As the solvent, for example, water, methanol, ethanol, ethyl acetate, acetic acid and the like can be used. As the catalyst, palladium-carbon (Pd / C), Perlman catalyst (Pearlman's catalyst: Pd (OH) 2 ), Raney nickel, Adams catalyst (Adams' catalyst: PtO 2 ), or the like can be used.
 [製造方法5]
 本発明の化合物(I)のうち、プロドラッグ基を導入した化合物は、下記の方法で製造することができる。
[Production Method 5]
Among the compounds (I) of the present invention, a compound into which a prodrug group has been introduced can be produced by the following method.
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
 式中、R、R、R、R、R、R、R、R及びRは前記と同じものを示し、R9aはプロドラッグ基を示し、LGは脱離基を示す。 In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R a and R b are the same as described above, R 9a represents a prodrug group, and LG 1 represents desorption. Indicates a leaving group.
 化合物(Ic)は、アミノ基をプロドラッグ化することでプロドラッグ体(Id)を製造することが可能である。 Compound (Ic) can produce a prodrug (Id) by converting an amino group into a prodrug.
 アミノ基のプロドラッグ化は、化合物(Ic)と化合物R9a-OHから、縮合反応を用いて化合物(Id)を得る反応である。縮合反応は通常のペプチド合成で使用されているものを用いればよく、縮合剤としては、例えばN,N’-ジシクロヘキシルカルボジイミド(DCC)、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド・塩酸塩(EDC・HCl)、4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド水和物(DMT-MM)、(1H-ベンゾトリアゾール-1-イルオキシ)トリス(ジメチルアミノ)ホスホニウムヘキサフルオロホスファート(BOP)、1-[ビス(ジメチルアミノ)メチレン]-1H-ベンゾトリアゾリウム-3-オキシドヘキサフルオロホスファート(HBTU)などが挙げられる。例えばTetrahedron、2004年、60巻、2447頁を参考に製造することが可能である。 A prodrug formation of an amino group is a reaction for obtaining a compound (Id) from a compound (Ic) and a compound R 9a —OH by using a condensation reaction. What is necessary is just to use what is used by the usual peptide synthesis for a condensation reaction, for example, N, N'- dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, Hydrochloride (EDC.HCl), 4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride hydrate (DMT-MM), (1H-benzo Triazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (BOP), 1- [bis (dimethylamino) methylene] -1H-benzotriazolium-3-oxide hexafluorophosphate (HBTU), etc. Can be mentioned. For example, it can be produced with reference to Tetrahedron, 2004, 60, 2447.
 アミノ基のプロドラッグ化の別法として、化合物(Ic)と活性エステルである化合物R9a-LGを縮合させることで化合物(Id)を得ることも可能である。LGとしてはp-ニトロフェニルオキシ基、ペンタフルオロフェニルオキシ基、塩素原子などが挙げられる。通常のペプチド合成で用いられるカルボン酸と活性エステルとの縮合反応に従った方法が利用できる。 As another method for converting an amino group into a prodrug, compound (Id) can be obtained by condensing compound (Ic) with compound R 9a -LG 1 which is an active ester. LG 1 includes a p-nitrophenyloxy group, a pentafluorophenyloxy group, a chlorine atom, and the like. A method according to a condensation reaction between a carboxylic acid and an active ester used in usual peptide synthesis can be used.
 [製造方法6]
 本発明の化合物(I)のうち、プロドラッグ基を導入した化合物は、下記の方法で製造することも可能である。
[Production Method 6]
Among the compounds (I) of the present invention, compounds into which a prodrug group is introduced can also be produced by the following method.
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
 式中、R、R、R、R、R、R、R、R、RおよびPGは前記と同じものを示し、LGは脱離基を示す。R3aはカルボキシル基のプロドラッグ基を示す。 In the formula, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 , R a , R b and PG 4 are the same as described above, and LG 2 is a leaving group. R 3a represents a prodrug group of a carboxyl group.
 化合物(IX)のカルボキシル基をプロドラッグ化した後、アミノ基の保護基を除去することでプロドラッグ体である化合物(Ie)を製造することが可能である。 Compound (Ie), which is a prodrug, can be produced by converting the carboxyl group of compound (IX) into a prodrug and then removing the amino protecting group.
 カルボキシ基のプロドラッグ化は、化合物(IX)とアルコールである化合物R3a-OHを縮合させることで化合物(XIX)を得る反応である。縮合剤としてはN,N’-ジシクロヘキシルカルボジイミド(DCC)、N,N’-ジイソプロピルカルボジイミド(DIC)などを用いることができる。尚、触媒量の4-ジメチルアミノピリジン(DMAP)を加えておくことで反応性が向上する。 The formation of a prodrug of a carboxy group is a reaction in which compound (IX) and compound R 3a —OH that is an alcohol are condensed to obtain compound (XIX). As the condensing agent, N, N′-dicyclohexylcarbodiimide (DCC), N, N′-diisopropylcarbodiimide (DIC), or the like can be used. The reactivity is improved by adding a catalytic amount of 4-dimethylaminopyridine (DMAP).
 カルボキシ基のプロドラッグ化の別法として、化合物(IX)とアルキル化剤である化合物R4a-LGを塩基性条件化で反応させて化合物(XIX)を得ることができる。この場合、LGとしてはヨード基、臭素原子などが挙げられる。あるいは、R4a-LGとしてアルコールのスルホン酸エステル(例えば、R3a-OSOCH、R3a-OSOCFなど)を使用することも可能である。反応溶媒としては、水や、テトラヒドロフラン、N,N-ジメチルホルムアミド又はジエトキシエタンなどや、これらの混合溶媒を用いることができる。塩基としては、例えば炭酸ナトリウム、炭酸水素ナトリウム、炭酸カリウム、炭酸水素カリウムのようなアルカリ金属もしくはアルカリ土類金属の炭酸塩などを用いることができる。 As another method for forming a carboxy group as a prodrug, compound (XIX) can be obtained by reacting compound (IX) with compound R 4a -LG 2 which is an alkylating agent under basic conditions. In this case, LG 2 includes an iodo group, a bromine atom and the like. Alternatively, an alcohol sulfonate ester (eg, R 3a —OSO 2 CH 3 , R 3a —OSO 2 CF 3, etc.) can be used as R 4a -LG 2 . As the reaction solvent, water, tetrahydrofuran, N, N-dimethylformamide, diethoxyethane, or a mixed solvent thereof can be used. Examples of the base include alkali metal or alkaline earth metal carbonates such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, and potassium hydrogen carbonate.
 アミノ基の脱保護に関しては、製造方法1と同様である。 The deprotection of the amino group is the same as in Production Method 1.
 本発明のアクリル酸誘導体は、優れたTAFIa阻害活性を有し、かつ高い経口吸収性、血中滞留性及び代謝安定性等の体内動態に優れ、安全性も高いことから、医薬として有用であり、特に心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群、肺線維症などの治療薬として有用である。また、血栓塞栓症に由来する疾患の治療薬として有用である。また、移植後の臓器の機能改善のための医薬として有用である。外科手術後の冠状動脈疾患(経皮的経管的冠状動脈血管形成)、代用血管(自家血管、人工血管)の移植又は置換、ステントの設置での再狭窄再閉塞の治療薬として有用である。また、血管カテーテル(透析のための留置カテーテル)、体外血液循環装置ならびに人工血管へのコーティング及び管内へのTAFIa阻害薬溶液の充満による血栓形成の予防、血栓の溶解促進として有用である。アテローム性動脈血栓症、線維症(慢性閉塞性肺疾患のような肺線維症、眼科手術後の線維症など)の治療薬としても有用である。虚血性脳血管障害急性期に伴う機能障害の改善にも有用である。 The acrylic acid derivative of the present invention has an excellent TAFIa inhibitory activity, is excellent in pharmacokinetics such as high oral absorption, blood retention and metabolic stability, and is also useful as a pharmaceutical. Particularly useful as a therapeutic agent for myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation syndrome, pulmonary fibrosis, etc. is there. Moreover, it is useful as a therapeutic agent for diseases derived from thromboembolism. It is also useful as a medicine for improving organ function after transplantation. Useful for the treatment of post-surgical coronary artery disease (percutaneous transluminal coronary angioplasty), transplantation or replacement of blood vessels (autologous blood vessels, artificial blood vessels), and restenosis / reocclusion with stent placement . Further, it is useful for prevention of thrombus formation and promotion of thrombus dissolution by filling a blood vessel catheter (indwelling catheter for dialysis), extracorporeal blood circulation device and artificial blood vessel, and filling a TAFIa inhibitor solution in the tube. It is also useful as a therapeutic agent for atherothrombosis, fibrosis (pulmonary fibrosis such as chronic obstructive pulmonary disease, fibrosis after ophthalmic surgery, etc.). It is also useful for improving dysfunction associated with the acute phase of ischemic cerebrovascular disorder.
 本発明の一般式(I)で表される化合物は、アミノ基等の塩基性基を有するため、薬理上許容される酸との酸付加塩とすることができる。そのような塩としては、例えばフッ化水素酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩等のハロゲン化水素酸塩;硝酸塩、過塩素酸塩、硫酸塩、燐酸塩等の無機酸塩;メタンスルホン酸塩、トリフルオロメタンスルホン酸塩、エタンスルホン酸塩等の低級アルカンスルホン酸塩;ベンゼンスルホン酸塩、p-トルエンスルホン酸塩等のアリールスルホン酸塩;酢酸、りんご酸、フマル酸塩、コハク酸塩、クエン酸塩、酒石酸塩、蓚酸塩、マレイン酸塩等の有機酸塩;及びオルニチン酸塩、グルタミン酸塩、アスパラギン酸塩等のアミノ酸塩を挙げることができ、ハロゲン化水素酸塩又はアリールスルホン酸塩がこのましく、塩酸塩、ベンゼンスルホン酸塩又はp-トルエンスルホン酸塩がより好ましく、ベンゼンスルホン酸塩又はp-トルエンスルホン酸塩が更によりこのましく、p-トルエンスルホン酸塩が特に好ましい。 Since the compound represented by the general formula (I) of the present invention has a basic group such as an amino group, it can be converted to an acid addition salt with a pharmacologically acceptable acid. Examples of such salts include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide; nitrates, perchlorates, sulfates, phosphates and the like. Inorganic acid salts; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; aryl sulfonates such as benzene sulfonate and p-toluene sulfonate; acetic acid, malic acid, Organic acid salts such as fumarate, succinate, citrate, tartrate, oxalate, maleate; and amino acid salts such as ornithate, glutamate, aspartate, and halogenated Hydronate or aryl sulfonate is preferred, and hydrochloride, benzene sulfonate, or p-toluene sulfonate is more preferred, and benzene sulfonate or p-toluene is preferred. Nsuruhon salt is even more Preferably, p- toluenesulfonic acid salts are particularly preferred.
 また、一般式(I)で表される化合物は、カルボキシ基等の酸性基を有するため、一般的に塩基付加塩を形成することが可能である。薬理上許容される塩としては、例えばナトリウム塩、カリウム塩、リチウム塩等のアルカリ金属塩;カルシウム塩、マグネシウム塩等のアルカリ土類金属塩;アンモニウム塩等の無機塩;ジベンジルアミン塩、モルホリン塩、フェニルグリシンアルキルエステル塩、エチレンジアミン塩、N-メチルグルカミン塩、ジエチルアミン塩、トリエチルアミン塩、シクロヘキシルアミン塩、ジシクロヘキシルアミン塩、N,N’-ジベンジルエチレンジアミン塩、ジエタノールアミン塩、N-ベンジル-N-(2-フェニルエトキシ)アミン塩、ピペラジン塩、テトラメチルアンモニウム塩、トリス(ヒドロキシメチル)アミノメタン塩等の有機アミン塩;アルギニン塩等のアミノ酸塩;等を挙げることができる。 In addition, since the compound represented by the general formula (I) has an acidic group such as a carboxy group, it is generally possible to form a base addition salt. Examples of pharmacologically acceptable salts include alkali metal salts such as sodium salt, potassium salt and lithium salt; alkaline earth metal salts such as calcium salt and magnesium salt; inorganic salts such as ammonium salt; dibenzylamine salt and morpholine. Salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, diethylamine salt, triethylamine salt, cyclohexylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, diethanolamine salt, N-benzyl-N -Organic amine salts such as-(2-phenylethoxy) amine salt, piperazine salt, tetramethylammonium salt and tris (hydroxymethyl) aminomethane salt; amino acid salts such as arginine salt; and the like.
 本発明の一般式(I)で表される化合物又はその薬理上許容される塩は、遊離体若しくは溶媒和物として存在することもあり、これらの溶媒和物も本発明の範囲に包含される。溶媒和物としては、薬理上許容され得るものであれば特に限定されないが、具体的には、水和物、エタノール和物等が好ましく、水和物がより好ましい。また、一般式(I)で表される本発明化合物中には窒素原子が存在するが、当該窒素原子はN-オキシド体となっていてもよく、これら溶媒和物及びN-オキシド体も本発明の範囲に含まれる。 The compound represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof may exist as a free form or a solvate, and these solvates are also included in the scope of the present invention. . The solvate is not particularly limited as long as it is pharmacologically acceptable. Specifically, a hydrate, an ethanol solvate, and the like are preferable, and a hydrate is more preferable. In addition, a nitrogen atom exists in the compound of the present invention represented by the general formula (I), and the nitrogen atom may be an N-oxide, and these solvates and N-oxides are also present. It is included in the scope of the invention.
 一般式(I)で表される本発明化合物又はその薬理上許容される塩及び本発明の化合物の製造中間体は、置換基の種類や組み合わせによって、シス体、トランス体等の幾何異性体、又はR体、S体等の光学異性体等の各種異性体が存在し得るが、本発明の化合物は、特に限定していない場合はそれら全ての異性体、立体異性体及びいずれの比率のこれら異性体及び立体異性体混合物をも包含するものである。 The compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof and a production intermediate of the compound of the present invention may be a geometric isomer such as a cis isomer, a trans isomer, etc. Alternatively, various isomers such as optical isomers such as R isomer and S isomer may exist, but the compound of the present invention is not particularly limited, all isomers, stereoisomers and any ratio of these isomers. It also includes isomers and stereoisomer mixtures.
 また、本発明の化合物又はその薬理上許容される塩は、このような化合物を構成する原子の1以上に、原子同位体の非天然割合も含有し得る。原子同位体としては、例えば、重水素(H)、トリチウム(H)、炭素-13(13C)、炭素-14(14C)、窒素-15(15N)、塩素-37(37Cl)又はヨウ素-125(125I)などが挙げられる。また、前記化合物は、例えば、トリチウム(H)、ヨウ素-125(125I)又は炭素-14(14C)などの放射性同位体で放射性標識され得る。放射性標識された化合物は、治療又は予防剤、研究試薬、例えば、アッセイ試薬、及び診断剤、例えば、インビボ画像診断剤として有用である。本発明の化合物の全ての同位体変異種は、放射性であると否とを問わず、本発明の範囲に包含されるものとする。 In addition, the compound of the present invention or a pharmacologically acceptable salt thereof may also contain an unnatural proportion of atomic isotopes at one or more of atoms constituting such a compound. The atomic isotopes such as deuterium (2 H), tritium (3 H), carbon -13 (13 C), carbon -14 (14 C), nitrogen -15 (15 N), chlorine -37 (37 Cl) or iodine-125 ( 125 I). The compound may also be radiolabeled with a radioisotope such as, for example, tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents, and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
 さらに、本発明は、生体内における生理条件下で酵素や胃酸等による反応により本発明の医薬組成物の有効成分である化合物(I)に変換される化合物、すなわち、酵素的に酸化、還元、加水分解等を起こして化合物(I)に変化される化合物又は胃酸等により加水分解等を起こして化合物(I)に変化される「医薬的に許容されるプロドラッグ化合物」も本発明に包含する。 Furthermore, the present invention relates to a compound that is converted into compound (I) which is an active ingredient of the pharmaceutical composition of the present invention by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo, that is, enzymatically oxidized, reduced, Also included in the present invention is a compound that undergoes hydrolysis or the like and is converted to compound (I), or a “pharmaceutically acceptable prodrug compound” that undergoes hydrolysis or the like by gastric acid or the like and is changed to compound (I). .
 一般式(I)で表される本発明の化合物又はその薬理上許容される塩を含有する医薬組成物は、投与法に応じ適当な製剤を選択し、通常用いられている各種製剤の調製法で調製することができる。 For the pharmaceutical composition containing the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof, an appropriate preparation is selected according to the administration method, and methods for preparing various commonly used preparations Can be prepared.
 一般式(I)で表される本発明化合物又はその薬理上許容される塩を主剤とする医薬組成物を哺乳動物(特にヒト)に投与する場合には、全身的又は局所的に、経口又は非経口で投与することができる。 When a pharmaceutical composition mainly comprising the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof is administered to a mammal (particularly a human), it can be administered systemically or locally, orally or It can be administered parenterally.
 経口用の医薬の形態としては、錠剤、丸剤、散剤、顆粒剤、カプセル剤、水剤、懸濁剤、乳剤、シロップ剤、エリキシル剤等が挙げられる。これら形態の医薬は、通常、一般式(I)で表される本発明化合物又はその薬理上許容される塩を主剤とし、薬学上許容される添加物としての希釈剤、賦形剤又は担体と混合された医薬組成物として調製される。医薬組成物の調製は、薬学上許容される希釈剤、賦形剤又は担体として、又はそれらに加えて、任意の適切な薬学上許容される結合剤、崩壊剤、滑沢剤、膨潤剤、膨潤補助剤、コーティング剤、可塑剤、安定剤、防腐剤、抗酸化剤、着色剤、溶解補助剤、懸濁化剤、乳化剤、甘味剤、保存剤、緩衝剤、湿潤剤等から必要に応じて適宜選択したものを用いて、常法に従って行うことができる。 Examples of oral pharmaceutical forms include tablets, pills, powders, granules, capsules, solutions, suspensions, emulsions, syrups, elixirs and the like. These forms of drugs are usually based on the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof, and a diluent, excipient or carrier as a pharmaceutically acceptable additive. Prepared as a mixed pharmaceutical composition. The preparation of the pharmaceutical composition comprises any suitable pharmaceutically acceptable binder, disintegrant, lubricant, swelling agent, as or in addition to a pharmaceutically acceptable diluent, excipient or carrier. As needed from swelling aids, coating agents, plasticizers, stabilizers, preservatives, antioxidants, colorants, solubilizers, suspending agents, emulsifiers, sweeteners, preservatives, buffering agents, wetting agents, etc. Can be carried out in accordance with a conventional method using an appropriately selected one.
 非経口用の医薬の形態としては、注射剤、軟膏剤、ゲル剤、クリーム剤、湿布剤、貼付剤、噴霧剤、吸入剤、スプレー剤、点眼剤、点鼻剤、座剤等が挙げられる。これら形態の医薬は、通常、一般式(I)で表される本発明化合物又はその薬理上許容される塩を主剤とし、薬学上許容される添加物としての希釈剤、賦形剤又は担体と混合された医薬組成物として調製される。医薬組成物の調製は、薬学上許容される希釈剤、賦形剤又は担体として、又はそれらに加えて、任意の適切な薬学上許容される安定化剤、防腐剤、溶解補助剤、保湿剤、保存剤、抗酸化剤、着香剤、ゲル化剤、中和剤、緩衝剤、等張剤、界面活性剤、着色剤、緩衝化剤、増粘剤、湿潤剤、充填剤、吸収促進剤、懸濁化剤、結合剤等から必要に応じて適宜選択したものを用いて、常法に従って行うことができる。 Examples of parenteral pharmaceutical forms include injections, ointments, gels, creams, poultices, patches, sprays, inhalants, sprays, eye drops, nasal drops, suppositories, and the like. . These forms of drugs are usually based on the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof, and a diluent, excipient or carrier as a pharmaceutically acceptable additive. Prepared as a mixed pharmaceutical composition. The preparation of the pharmaceutical composition may be performed as any suitable pharmaceutically acceptable stabilizer, preservative, solubilizer, humectant, as or in addition to a pharmaceutically acceptable diluent, excipient or carrier. , Preservatives, antioxidants, flavoring agents, gelling agents, neutralizing agents, buffering agents, isotonic agents, surfactants, coloring agents, buffering agents, thickeners, wetting agents, fillers, absorption enhancement It can carry out according to a conventional method using what was suitably selected from an agent, a suspending agent, a binder, etc. as needed.
 上記の薬学的に許容される賦形剤に関する参考文献としては、例えば「Handbook of Pharmaceutical Excipients,2nd Edition,(1994),Edited by A.Wade and P.J.Weller」を挙げることができる。 References regarding the above-mentioned pharmaceutically acceptable excipients include, for example, “Handbook of Pharmaceutical Excipients, 2nd Edition, (1994), Edited by A. Wade and PJ Weller”.
 また、上記の薬学上許容される担体又は希釈剤に関する参考文献としては、例えば、「Remington’s Pharmaceutical Sciences,Mack Publishing Co.(A.R.Gennaro edit.1985)」を挙げることができる。 In addition, as a reference for the pharmaceutically acceptable carrier or diluent, for example, “Remington's Pharmaceutical Sciences, Mack Publishing Co. (AR Gennaro edit. 1985)” can be cited.
 一般式(I)で表される本発明の化合物又はその薬理上許容される塩は、他の薬剤との併用が可能である。併用可能な薬剤には抗凝固薬(ワーファリン、ヘパリン、低分子ヘパリン、抗トロンビン薬、抗Xa薬など)、抗血小板薬(アスピリン、チクロピジン、クロピドグレル、プラスグレル、ホスホジエステラーゼ阻害剤など)、線溶に関わる酵素(tPA、遺伝子改変型tPA、ウロキナーゼなどのプラスミノーゲン活性化因子、ストレプトキナーゼ、プラスミンなど)、抗癌薬、抗炎症薬、抗線維化薬、降圧薬、抗肺高血圧薬、免疫抑制薬などがある。 The compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof can be used in combination with other drugs. Anticoagulant drugs (warfarin, heparin, low molecular weight heparin, antithrombin drug, anti-Xa drug, etc.), antiplatelet drugs (aspirin, ticlopidine, clopidogrel, prasugrel, phosphodiesterase inhibitor, etc.), fibrinolysis Enzyme (tPA, genetically modified tPA, plasminogen activator such as urokinase, streptokinase, plasmin), anticancer drug, anti-inflammatory drug, antifibrotic drug, antihypertensive drug, antipulmonary hypertension drug, immunosuppressant drug and so on.
 一般式(I)で表される本発明の化合物又はその薬理上許容される塩の投与量は、症状、年齢、体重、組み合わせて投与する薬剤の種類や投与量等によって異なるが、ヒト人体用の医薬として使用する場合、化合物(I)換算量で、成人一人一回につき0.01mg~5000mgの範囲で、好ましくは0.1mg~1000mgの範囲で、より好ましくは1mg~200mgの範囲であり、体重換算量では、化合物(I)を、0.001mg/kg~100mg/kgの範囲で、好ましくは0.005mg/kg~20mg/kgの範囲で、より好ましくは0.01mg/kg~5mg/kgの範囲である。この一日量を、全身的又は局所的に、数日に1回ないし一日1回から数回、経口又は非経口投与されるか、或いは一日1時間~24時間の範囲で静脈内に持続投与する。また一日量は必要によっては上記の量を超えてもよい。 The dose of the compound of the present invention represented by the general formula (I) or a pharmacologically acceptable salt thereof varies depending on symptoms, age, body weight, the kind and dose of drugs administered in combination, etc. When used as a pharmaceutical, the compound (I) equivalent amount is in the range of 0.01 mg to 5000 mg, preferably in the range of 0.1 mg to 1000 mg, more preferably in the range of 1 mg to 200 mg per adult. In terms of body weight, compound (I) is contained in the range of 0.001 mg / kg to 100 mg / kg, preferably in the range of 0.005 mg / kg to 20 mg / kg, more preferably 0.01 mg / kg to 5 mg. / Kg range. This daily dose may be administered systemically or locally, once a few days to once to several times a day, orally or parenterally, or intravenously in the range of 1-24 hours per day Administer continuously. The daily dose may exceed the above amount if necessary.
 以下、参考例、実施例、試験例及び製剤例により本発明を具体的に説明するが、この方法に何ら限定されるものではない。 Hereinafter, the present invention will be specifically described with reference examples, examples, test examples and formulation examples, but the present invention is not limited to these methods.
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
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Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000028
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Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
 [参考例1](3-オキソプロピル)カルバミン酸tert-ブチル
 シュウ酸クロリド(2.20mL)の塩化メチレン(75mL)溶液を-78℃に冷却し、ジメチルスルホキシド(3.6mL)の塩化メチレン(15mL)溶液を同温度で滴下した。20分後、同温度で3-(tert-ブトキシカルボニルアミノ)-1-プロパノール(3.08g)の塩化メチレン(75mL)溶液を滴下し、1時間攪拌した。-78℃でトリエチルアミン(9.50mL)を滴下し、20分間攪拌した後、0℃でさらに40分間攪拌した。反応液に水を加えて塩化メチレンで希釈し、分液した。水層を塩化メチレンで抽出し、得られた有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥させた。不溶物を濾別後、有機溶媒を減圧留去することにより、標題化合物(3.05g)を得た。
1H NMR (CDCl3) δ: 1.40 (9H, s), 2.68 (2H, t, J = 5.7 Hz), 3.39 (2H, q, J = 5.7 Hz), 4.87 (1H, br s), 9.78 (1H, s)。
[Reference Example 1] A solution of tert-butyl (3-oxopropyl) carbamate oxalate chloride (2.20 mL) in methylene chloride (75 mL) was cooled to −78 ° C., and dimethyl sulfoxide (3.6 mL) in methylene chloride (3.6 mL) 15 mL) solution was added dropwise at the same temperature. After 20 minutes, a solution of 3- (tert-butoxycarbonylamino) -1-propanol (3.08 g) in methylene chloride (75 mL) was added dropwise at the same temperature, and the mixture was stirred for 1 hour. Triethylamine (9.50 mL) was added dropwise at −78 ° C., and the mixture was stirred for 20 minutes, and further stirred at 0 ° C. for 40 minutes. Water was added to the reaction solution, which was diluted with methylene chloride and separated. The aqueous layer was extracted with methylene chloride, and the resulting organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the organic solvent was evaporated under reduced pressure to give the title compound (3.05 g).
1 H NMR (CDCl 3 ) δ: 1.40 (9H, s), 2.68 (2H, t, J = 5.7 Hz), 3.39 (2H, q, J = 5.7 Hz), 4.87 (1H, br s), 9.78 ( 1H, s).
 [参考例2]4-(クロロメチル)-1-トリチル-1H-イミダゾール
 (1-トリチル-1H-イミダゾール-4-イル)メタノール(1.24g)のトルエン(25mL)懸濁液に、室温でトリエチルアミン(0.607mL)を添加し、0℃で塩化チオニル(0.278mL)を滴下した。反応液を室温で10分間攪拌後、反応液に塩化メチレン(10mL)を添加し、さらに1時間攪拌した。不溶物を濾別し、濾物をトルエンで洗浄した。濾液と洗浄液を合わせ、溶媒を減圧下留去した。得られた残渣に塩化メチレン及びヘキサンを添加し、不溶物を濾別した。濾液を減圧下留去し、得られた残渣にヘキサンを添加して析出した固体を濾取し、乾燥させることにより標題化合物(0.957g)を得た。
1H NMR (CDCl3) δ: 4.53 (2H, s), 6.82 (1H, s), 7.06 - 7.12 (6H, m), 7.28 - 7.33 (9H, m), 7.38 (1H, d, J = 1.7 Hz)。
Reference Example 2 4- (Chloromethyl) -1-trityl-1H-imidazole (1-trityl-1H-imidazol-4-yl) methanol (1.24 g) in a toluene (25 mL) suspension at room temperature Triethylamine (0.607 mL) was added, and thionyl chloride (0.278 mL) was added dropwise at 0 ° C. The reaction solution was stirred at room temperature for 10 minutes, methylene chloride (10 mL) was added to the reaction solution, and the mixture was further stirred for 1 hour. Insoluble matter was filtered off, and the residue was washed with toluene. The filtrate and washings were combined and the solvent was removed under reduced pressure. Methylene chloride and hexane were added to the resulting residue, and the insoluble material was filtered off. The filtrate was evaporated under reduced pressure, hexane was added to the resulting residue, and the precipitated solid was collected by filtration and dried to give the title compound (0.957 g).
1 H NMR (CDCl 3 ) δ: 4.53 (2H, s), 6.82 (1H, s), 7.06-7.12 (6H, m), 7.28-7.33 (9H, m), 7.38 (1H, d, J = 1.7 Hz).
 [参考例3]2-(ジメトキシホスホリル)-3-(1-トリチル-1H-イミダゾール-4-イル)プロピオン酸メチル
 参考例2で得られた化合物(0.102g)のテトラヒドロフラン(3.0mL)溶液に、室温でヨウ化ナトリウム(0.122g)を添加し、1.5時間攪拌した。反応液にホスホノ酢酸トリメチル(0.0452mL)を添加し、0℃に冷却後、水素化ナトリウム(10.2mg)を添加し、同温度で1時間攪拌した。反応液に水及び塩化メチレンを加えて分液した。水層を塩化メチレンで抽出し、得られた有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥させた。不溶物を濾別後、有機溶媒を減圧留去して得られた残渣をシリカゲル薄層クロマトグラフィー(溶出溶媒:塩化メチレン/メタノール=20/1)で精製することにより、標題化合物(53.0mg)を得た。
1H NMR (CDCl3) δ: 2.99 3.08 (1H, m), 3.10 - 3.22 (1H, m), 3.39 - 3.53 (1H, m), 3.59 (3H, s), 3.72 - 3.78 (6H, m), 5.26 (1H, s), 6.52 (1H, s), 7.04-7.12 (6H, m), 7.25 - 7.35 (10H, m).
LRMS (FAB) m/z 505 [M + H]+
[Reference Example 3] Methyl 2- (dimethoxyphosphoryl) -3- (1-trityl-1H-imidazol-4-yl) propionate Tetrahydrofuran (3.0 mL) of the compound (0.102 g) obtained in Reference Example 2 To the solution, sodium iodide (0.122 g) was added at room temperature and stirred for 1.5 hours. Trimethylphosphonoacetate (0.0452 mL) was added to the reaction solution, and after cooling to 0 ° C., sodium hydride (10.2 mg) was added, and the mixture was stirred at the same temperature for 1 hour. Water and methylene chloride were added to the reaction solution for liquid separation. The aqueous layer was extracted with methylene chloride, and the resulting organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The insoluble material was filtered off, the organic solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (elution solvent: methylene chloride / methanol = 20/1) to give the title compound (53.0 mg )
1 H NMR (CDCl 3 ) δ: 2.99 3.08 (1H, m), 3.10-3.22 (1H, m), 3.39-3.53 (1H, m), 3.59 (3H, s), 3.72-3.78 (6H, m) , 5.26 (1H, s), 6.52 (1H, s), 7.04-7.12 (6H, m), 7.25-7.35 (10H, m).
LRMS (FAB) m / z 505 [M + H] + .
 [参考例4]2-[ビス(2,2,2-トリフルオロエトキシ)ホスホリル]-3-(1-トリチル-1H-イミダゾール-4-イル)プロピオン酸メチル
 無水テトラヒドロフランに溶解した参考例2で得た化合物(3.8g)にヨウ化ナトリウム(3.2g)を加え、室温下で1時間攪拌した(溶液A)。これとは別に、無水テトラヒドロフランに懸濁した水素化ナトリウム(0.5g)に、ビス(2,2,2-トリフルオロエチル)(メトキシカルボニルメチル)ホスホネート(2.5mL)を氷冷下40分間で滴下し、室温下で40分間攪拌した。さらに、氷冷下で溶液Aを滴下し、室温下で7時間攪拌した。反応溶液に水を加え、酢酸エチルで3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムを加えて乾燥し、減圧下で溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:塩化メチレン/メタノール=100/0→97/3)にて精製した。さらに、分取薄層クロマトグラフィー(溶出溶媒:塩化メチレン/メタノール=20/1で6回展開)にて精製し、標題化合物(1.2g)を得た。
1H-NMR (CDCl3) δ: 3.10-3.24 (2H, m), 3.62-3.73 (4H, m), 4.31-4.49 (4H, m), 6.59 (1H, s), 7.08-7.12 (6H, m), 7.32-7.34 (9H, m), 7.36 (1H, s).
LRMS (ESI) m/z 663 [M + Na]+
[Reference Example 4] Methyl 2- [bis (2,2,2-trifluoroethoxy) phosphoryl] -3- (1-trityl-1H-imidazol-4-yl) propionate Reference Example 2 dissolved in anhydrous tetrahydrofuran Sodium iodide (3.2 g) was added to the obtained compound (3.8 g), and the mixture was stirred at room temperature for 1 hour (solution A). Separately, bis (2,2,2-trifluoroethyl) (methoxycarbonylmethyl) phosphonate (2.5 mL) was added to sodium hydride (0.5 g) suspended in anhydrous tetrahydrofuran for 40 minutes under ice-cooling. And stirred at room temperature for 40 minutes. Furthermore, the solution A was dripped under ice-cooling, and it stirred at room temperature for 7 hours. Water was added to the reaction solution, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 100/0 → 97/3). Further purification by preparative thin layer chromatography (elution solvent: methylene chloride / methanol = developed 6 times with 20/1) gave the title compound (1.2 g).
1 H-NMR (CDCl 3 ) δ: 3.10-3.24 (2H, m), 3.62-3.73 (4H, m), 4.31-4.49 (4H, m), 6.59 (1H, s), 7.08-7.12 (6H, m), 7.32-7.34 (9H, m), 7.36 (1H, s).
LRMS (ESI) m / z 663 [M + Na] + .
 [参考例5](2E)-3-(1-プロピル-1H-イミダゾール-4-イル)プロパ-2-エン酸メチル
 無水テトラヒドロフラン(200mL)に懸濁した水素化ナトリウム(63%油性、5.6g)に、(ジメトキシホスホリル)酢酸メチル(25.0g)の無水テトラヒドロフラン(100mL)溶液を氷冷下50分間で滴下した。同温で10分間攪拌した後、室温で約1時間攪拌した。さらに、氷冷下で1-プロピル-1H-イミダゾール-4-カルボアルデヒド(18.6g)の無水テトラヒドロフラン(100mL)溶液を40分間で滴下した。同温で10分間攪拌した後、室温で約3.5時間攪拌した。水を加え、酢酸エチルで3回抽出した。有機層を飽和重曹水及び飽和食塩水で洗浄し、無水硫酸マグネシウムを加えて乾燥した後、減圧下で溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:ヘキサン/酢酸エチル=30/70→100/0)にて精製し、標題化合物(24.8g)を得た。
1H-NMR (CDCl3) δ: 0.94 (3H, t, J = 7.4 Hz), 1.79-1.85 (2H, m), 3.77 (3H, s), 3.89 (2H, t, J = 7.0 Hz), 6.55 (1H, d, J = 15.6 Hz), 7.09 (1H, s), 7.48 (1H, s), 7.56 (1H, d, J = 15.6 Hz)。
[Reference Example 5] Methyl (2E) -3- (1-propyl-1H-imidazol-4-yl) prop-2-enoate Sodium hydride suspended in anhydrous tetrahydrofuran (200 mL) (63% oily, 5. 6 g), a solution of methyl (dimethoxyphosphoryl) acetate (25.0 g) in anhydrous tetrahydrofuran (100 mL) was added dropwise over 50 minutes under ice cooling. After stirring at the same temperature for 10 minutes, the mixture was stirred at room temperature for about 1 hour. Further, a solution of 1-propyl-1H-imidazole-4-carbaldehyde (18.6 g) in anhydrous tetrahydrofuran (100 mL) was added dropwise over 40 minutes under ice cooling. After stirring at the same temperature for 10 minutes, the mixture was stirred at room temperature for about 3.5 hours. Water was added and extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 30/70 → 100/0) to give the title compound (24.8 g).
1 H-NMR (CDCl 3 ) δ: 0.94 (3H, t, J = 7.4 Hz), 1.79-1.85 (2H, m), 3.77 (3H, s), 3.89 (2H, t, J = 7.0 Hz), 6.55 (1H, d, J = 15.6 Hz), 7.09 (1H, s), 7.48 (1H, s), 7.56 (1H, d, J = 15.6 Hz).
 [参考例6]3-(1-プロピル-1H-イミダゾール-4-イル)プロパン酸メチル
 参考例5で得た化合物(24.3g)をメタノール(250mL)に溶解し、この溶液に含水10%パラジウム-炭素(8.0g)を加え、水素雰囲気下(1気圧)にて室温で5時間攪拌した。反応溶液をセライトろ過した。減圧下で溶媒を留去し、乾燥して、標題化合物(23.6g)を得た。
1H-NMR (CDCl3) δ: 0.91 (3H, t, J = 7.8 Hz), 1.73-1.82 (2H, m), 2.69 (2H, t, J = 7.4 Hz), 2.89 (2H, t, J = 7.4 Hz), 3.67 (3H, s), 3.81 (2H, t, J = 7.0 Hz), 6.65 (1H, s), 7.35 (1H, s).
LRMS (ESI) m/z 197 [M + H]+
[Reference Example 6] Methyl 3- (1-propyl-1H-imidazol-4-yl) propanoate The compound (24.3 g) obtained in Reference Example 5 was dissolved in methanol (250 mL). Palladium-carbon (8.0 g) was added, and the mixture was stirred at room temperature for 5 hours under a hydrogen atmosphere (1 atm). The reaction solution was filtered through celite. The solvent was distilled off under reduced pressure and dried to obtain the title compound (23.6 g).
1 H-NMR (CDCl 3 ) δ: 0.91 (3H, t, J = 7.8 Hz), 1.73-1.82 (2H, m), 2.69 (2H, t, J = 7.4 Hz), 2.89 (2H, t, J = 7.4 Hz), 3.67 (3H, s), 3.81 (2H, t, J = 7.0 Hz), 6.65 (1H, s), 7.35 (1H, s).
LRMS (ESI) m / z 197 [M + H] + .
 [参考例7]1-ヨード-3,3-ジメチルブタン
 3,3-ジメチルブタン-1-オール(20.4g)、トリフェニルホスフィン(62.7g)及びイミダゾール(16.3g)の塩化メチレン溶液(400mL)に、0℃攪拌下、ヨウ素(60.7g)を少しずつ加えた後、室温に昇温して終夜攪拌した。反応液を濃縮後、残渣にヘキサンを加えて希釈した。シリカゲルを通して不溶物を除去し、ろ液を濃縮することにより、標題化合物(28.6g)を得た。
1H NMR (CDCl3) δ: 0.91 (9H, s), 1.88-1.93 (2H, m), 3.14-3.19 (2H, m)。
[Reference Example 7] Methylene chloride solution of 1-iodo-3,3-dimethylbutane 3,3-dimethylbutan-1-ol (20.4 g), triphenylphosphine (62.7 g) and imidazole (16.3 g) To (400 mL), iodine (60.7 g) was added little by little with stirring at 0 ° C., and then the mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated, and the residue was diluted with hexane. The insoluble material was removed through silica gel, and the filtrate was concentrated to give the titled compound (28.6 g).
1 H NMR (CDCl 3 ) δ: 0.91 (9H, s), 1.88-1.93 (2H, m), 3.14-3.19 (2H, m).
 [参考例8](2E)-3-(1-フェニル-1H-イミダゾール-4-イル)アクリル酸メチル
 (2E)-3-(1H-イミダゾール-4-イル)アクリル酸メチル(J.Org.Chem.2010年、75巻、4604頁)(3.10g)の塩化メチレン溶液(110mL)に、室温攪拌下、モレキュラーシーブス4A(1.30g)、酢酸銅(II)(3.84g)、ピリジン(3.30mL)及びフェニルボロン酸(3.77g)を加えた。そのまま空気下で終夜攪拌した後、反応液に炭酸水素ナトリウム水溶液を加え、室温にてしばらく攪拌した。不溶物をセライトろ過で除去した後、ろ液を分液し、水層から塩化メチレンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより、標題化合物(2.09g)を得た。
1H NMR (CDCl3) δ: 3.80 (3H, s), 6.65 (1H, d, J = 15.6 Hz), 7.38-7.45 (4H, m), 7.49-7.53 (2H, m), 7.63 (1H, d, J = 15.6 Hz), 7.87 (1H, s)。
[Reference Example 8] Methyl (2E) -3- (1-phenyl-1H-imidazol-4-yl) acrylate (2E) -3- (1H-imidazol-4-yl) methyl acrylate (J. Org. Chem. 2010, 75, 4604) (3.10 g) in a methylene chloride solution (110 mL) with stirring at room temperature, molecular sieves 4A (1.30 g), copper (II) acetate (3.84 g), pyridine (3.30 mL) and phenylboronic acid (3.77 g) were added. After stirring overnight under air, an aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was stirred at room temperature for a while. Insoluble material was removed by Celite filtration, and the filtrate was separated and extracted from the aqueous layer with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography to obtain the title compound (2.09 g).
1 H NMR (CDCl 3 ) δ: 3.80 (3H, s), 6.65 (1H, d, J = 15.6 Hz), 7.38-7.45 (4H, m), 7.49-7.53 (2H, m), 7.63 (1H, d, J = 15.6 Hz), 7.87 (1H, s).
 [参考例9](2E)-3-[1-(3,3-ジメチルブチル)-1H-イミダゾール-4-イル]アクリル酸メチル
 水素化ナトリウム(63%、1.13g)のN,N-ジメチルホルムアミド懸濁液(40mL)に、0℃攪拌下、(2E)-3-(1H-イミダゾール-4-イル)アクリル酸メチル(4.12g)のN,N-ジメチルホルムアミド溶液(30mL)を加えた。そのままの温度で1時間攪拌した後、参考例7で得た化合物(6.32g)のN,N-ジメチルホルムアミド溶液(30mL)を加えた。室温に昇温して終夜攪拌した後、反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより、標題化合物(4.43g)を得た。
1H NMR (CDCl3) δ: 0.99 (9H, s), 1.70-1.74 (2H, m), 3.77 (3H, s), 3.91-3.95 (2H, m), 6.54 (1H, d, J = 15.6 Hz), 7.10 (1H, br s), 7.49 (1H, br s), 7.55 (1H, d, J = 15.6 Hz)。
Reference Example 9 (2E) -3- [1- (3,3-Dimethylbutyl) -1H-imidazol-4-yl] methyl acrylate Sodium hydride (63%, 1.13 g) N, N— To a dimethylformamide suspension (40 mL), a solution of methyl (2E) -3- (1H-imidazol-4-yl) acrylate (4.12 g) in N, N-dimethylformamide (30 mL) was stirred at 0 ° C. added. After stirring at the same temperature for 1 hour, an N, N-dimethylformamide solution (30 mL) of the compound obtained in Reference Example 7 (6.32 g) was added. After warming to room temperature and stirring overnight, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography to obtain the title compound (4.43 g).
1 H NMR (CDCl 3 ) δ: 0.99 (9H, s), 1.70-1.74 (2H, m), 3.77 (3H, s), 3.91-3.95 (2H, m), 6.54 (1H, d, J = 15.6 Hz), 7.10 (1H, br s), 7.49 (1H, br s), 7.55 (1H, d, J = 15.6 Hz).
 [参考例10]3-[1-(3,3-ジメチルブチル)-1H-イミダゾール-4-イル]プロピオン酸メチル
 参考例9で得た化合物(4.43g)の酢酸エチル溶液(80mL)に10%パラジウム炭素(wet)(1.50g)を加え、水素雰囲気下、室温にて終夜攪拌した。セライトろ過し、減圧濃縮することにより、標題化合物(4.45g)を得た。
1H NMR (CDCl3) δ: 0.96 (9H, s), 1.66-1.71 (2H, m), 2.68 (2H, t, J = 7.4 Hz), 2.88 (2H, t, J = 7.4 Hz), 3.67 (3H, s), 3.83-3.88 (2H, m), 6.66 (1H, s), 7.36 (1H, s)。
[Reference Example 10] Methyl 3- [1- (3,3-dimethylbutyl) -1H-imidazol-4-yl] propionate Into an ethyl acetate solution (80 mL) of the compound (4.43 g) obtained in Reference Example 9 10% palladium carbon (wet) (1.50 g) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The title compound (4.45 g) was obtained by filtration through celite and concentration under reduced pressure.
1 H NMR (CDCl 3 ) δ: 0.96 (9H, s), 1.66-1.71 (2H, m), 2.68 (2H, t, J = 7.4 Hz), 2.88 (2H, t, J = 7.4 Hz), 3.67 (3H, s), 3.83-3.88 (2H, m), 6.66 (1H, s), 7.36 (1H, s).
 [参考例11](2E)-3-(1-シクロヘキサ-2-エン-1-イル-1H-イミダゾール-4-イル)アクリル酸メチル
 水素化ナトリウム(63%,0.83g)のN,N-ジメチルホルムアミド懸濁液(40mL)に、0℃攪拌下、(2E)-3-(1H-イミダゾール-4-イル)アクリル酸メチル(3.00g)のN,N-ジメチルホルムアミド溶液(15mL)を加えた。室温に昇温して1時間攪拌した後、再度0℃に冷却し、3-ブロモシクロヘキセン(3.49g)を加えた。室温に昇温して終夜攪拌した後、反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより、標題化合物(2.85g)を得た。
1H NMR (CDCl3) δ: 1.63-1.82 (3H, m), 2.03-2.18 (3H, m), 3.74 (3H, s), 4.64-4.68 (1H, m), 5.68-5.71 (1H, m), 6.07-6.11 (1H, m), 6.51 (1H, d, J = 15.6 Hz), 7.11 (1H, s), 7.52 (1H, s), 7.52 (1H, d, J = 15.6 Hz)。
Reference Example 11 (2E) -3- (1-Cyclohex-2-en-1-yl-1H-imidazol-4-yl) methyl acrylate Sodium hydride (63%, 0.83 g) N, N A solution of methyl (2E) -3- (1H-imidazol-4-yl) acrylate (3.00 g) in N, N-dimethylformamide (15 mL) with stirring at 0 ° C. in a dimethylformamide suspension (40 mL) Was added. The mixture was warmed to room temperature and stirred for 1 hour, then cooled again to 0 ° C., and 3-bromocyclohexene (3.49 g) was added. After warming to room temperature and stirring overnight, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography to obtain the title compound (2.85 g).
1 H NMR (CDCl 3 ) δ: 1.63-1.82 (3H, m), 2.03-2.18 (3H, m), 3.74 (3H, s), 4.64-4.68 (1H, m), 5.68-5.71 (1H, m ), 6.07-6.11 (1H, m), 6.51 (1H, d, J = 15.6 Hz), 7.11 (1H, s), 7.52 (1H, s), 7.52 (1H, d, J = 15.6 Hz).
 [参考例12]3-(1-シクロヘキシル-1H-イミダゾール-4-イル)プロピオン酸メチル
 参考例11で得た化合物(2.85g)を酢酸エチル(30mL)とメタノール(10mL)の混合溶媒に溶解させ、10%パラジウム炭素(wet)(0.70g)を加え、水素雰囲気下、室温にて終夜攪拌した。セライトろ過し、減圧濃縮することにより、標題化合物(2.89g)を得た。
1H NMR (CDCl3) δ: 1.18-1.28 (1H, m), 1.34-1.45 (2H, m), 1.54-1.64 (2H, m), 1.71-1.76 (1H, m), 1.86-1.91 (2H, m), 2.05-2.10 (2H, m), 2.68 (2H, t, J = 7.6 Hz), 2.89 (2H, t, J = 7.6 Hz), 3.67 (3H, s), 3.78-3.85 (1H, m), 6.70 (1H, s), 7.42 (1H, s)。
[Reference Example 12] Methyl 3- (1-cyclohexyl-1H-imidazol-4-yl) propionate The compound (2.85 g) obtained in Reference Example 11 was mixed into a mixed solvent of ethyl acetate (30 mL) and methanol (10 mL). After dissolution, 10% palladium carbon (wet) (0.70 g) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. The title compound (2.89 g) was obtained by filtration through Celite and concentration under reduced pressure.
1 H NMR (CDCl 3 ) δ: 1.18-1.28 (1H, m), 1.34-1.45 (2H, m), 1.54-1.64 (2H, m), 1.71-1.76 (1H, m), 1.86-1.91 (2H , m), 2.05-2.10 (2H, m), 2.68 (2H, t, J = 7.6 Hz), 2.89 (2H, t, J = 7.6 Hz), 3.67 (3H, s), 3.78-3.85 (1H, m), 6.70 (1H, s), 7.42 (1H, s).
 [参考例13]2-シクロプロピルエタノール
 水素化リチウムアルミニウム(5.58g)のジエチルエーテル懸濁液(200mL)に、0℃攪拌下、シクロプロピル酢酸(9.82g)のジエチルエーテル溶液(50mL)を加え、室温に昇温して終夜攪拌した。反応液を0℃に冷却し、水(5.6mL)、15%水酸化ナトリウム水溶液(5.6mL)及び水(16.8mL)を順次加え、室温に昇温してしばらく攪拌した。セライトろ過し、減圧濃縮することにより、標題化合物(8.45g)を得た。
1H NMR (CDCl3) δ: 0.06-0.10 (2H, m), 0.44-0.49 (2H, m), 0.68-0.78 (1H, m), 1.48 (2H, dt, J = 6.6, 6.6 Hz), 3.73 (2H, t, J = 6.6 Hz)。
Reference Example 13 2-Cyclopropylethanol To a diethyl ether suspension (200 mL) of lithium aluminum hydride (5.58 g) under stirring at 0 ° C., a solution of cyclopropylacetic acid (9.82 g) in diethyl ether (50 mL) The mixture was warmed to room temperature and stirred overnight. The reaction solution was cooled to 0 ° C., water (5.6 mL), 15% aqueous sodium hydroxide solution (5.6 mL) and water (16.8 mL) were sequentially added, and the mixture was warmed to room temperature and stirred for a while. The title compound (8.45 g) was obtained by filtration through Celite and concentration under reduced pressure.
1 H NMR (CDCl 3 ) δ: 0.06-0.10 (2H, m), 0.44-0.49 (2H, m), 0.68-0.78 (1H, m), 1.48 (2H, dt, J = 6.6, 6.6 Hz), 3.73 (2H, t, J = 6.6 Hz).
 [参考例14](2-ヨードエチル)シクロプロパン
 参考例7と同様にして、2-シクロプロピルエタノール(4.23g)から、標題化合物(5.84g)を得た。
1H NMR (CDCl3) δ: 0.09-0.13 (2H, m), 0.47-0.52 (2H, m), 0.76-0.85 (1H, m), 1.76 (2H, dt, J = 7.0, 7.0 Hz), 3.23 (2H, t, J = 7.0 Hz)。
[Reference Example 14] (2-Iodoethyl) cyclopropane In the same manner as in Reference Example 7, the title compound (5.84 g) was obtained from 2-cyclopropylethanol (4.23 g).
1 H NMR (CDCl 3 ) δ: 0.09-0.13 (2H, m), 0.47-0.52 (2H, m), 0.76-0.85 (1H, m), 1.76 (2H, dt, J = 7.0, 7.0 Hz), 3.23 (2H, t, J = 7.0 Hz).
 [参考例15](2E)-3-[1-(2-シクロプロピルエチル)-1H-イミダゾール-4-イル]アクリル酸メチル
 水素化ナトリウム(63%、0.41g)のN,N-ジメチルホルムアミド懸濁液(15mL)に、0℃攪拌下、(2E)-3-(1H-イミダゾール-4-イル)アクリル酸メチル(1.50g)のN,N-ジメチルホルムアミド溶液(10mL)を加えた。そのままの温度で1時間攪拌した後、参考例14で得た化合物(2.12g)を加えた。室温に昇温して終夜攪拌した後、反応液に水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより、標題化合物(1.30g)を得た。
1H NMR (CDCl3) δ: 0.03-0.07 (2H, m), 0.46-0.51 (2H, m), 0.57-0.65 (1H, m), 1.66 (2H, dt, J = 7.0, 7.0 Hz), 3.77 (3H, s), 4.00 (2H, t, J = 7.0 Hz), 6.55 (1H, d, J = 15.6 Hz), 7.11 (1H, s), 7.50 (1H, s), 7.56 (1H, d, J = 15.6 Hz)。
Reference Example 15 (2E) -3- [1- (2-Cyclopropylethyl) -1H-imidazol-4-yl] methyl acrylate Sodium hydride (63%, 0.41 g) in N, N-dimethyl To a formamide suspension (15 mL), a solution of methyl (2E) -3- (1H-imidazol-4-yl) acrylate (1.50 g) in N, N-dimethylformamide (10 mL) was added with stirring at 0 ° C. It was. After stirring at the same temperature for 1 hour, the compound (2.12 g) obtained in Reference Example 14 was added. After warming to room temperature and stirring overnight, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography to obtain the title compound (1.30 g).
1 H NMR (CDCl 3 ) δ: 0.03-0.07 (2H, m), 0.46-0.51 (2H, m), 0.57-0.65 (1H, m), 1.66 (2H, dt, J = 7.0, 7.0 Hz), 3.77 (3H, s), 4.00 (2H, t, J = 7.0 Hz), 6.55 (1H, d, J = 15.6 Hz), 7.11 (1H, s), 7.50 (1H, s), 7.56 (1H, d , J = 15.6 Hz).
 [参考例16](2E)-3-(1-シクロペンチル-1H-イミダゾール-4-イル)アクリル酸メチル
 (2E)-3-(1H-イミダゾール-4-イル)アクリル酸メチル(2.65g)、ヨウ化シクロペンチル(4.16mL)及び炭酸セシウム(17.0g)をN,N-ジメチルホルムアミド(55mL)中で110℃にて9時間攪拌した。反応液に水を加え、酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより、標題化合物(1.48g)を得た。
1H NMR (CDCl3) δ: 1.72-1.90 (6H, m), 2.18-2.25 (2H, m), 3.77 (3H, s), 4.41-4.48 (1H, m), 6.54 (1H, d, J = 15.6 Hz), 7.13 (1H, br s), 7.54 (1H, br s), 7.56 (1H, d, J = 15.6 Hz)。
[Reference Example 16] Methyl (2E) -3- (1-cyclopentyl-1H-imidazol-4-yl) acrylate (2E) -3- (1H-imidazol-4-yl) methyl acrylate (2.65 g) , Cyclopentyl iodide (4.16 mL) and cesium carbonate (17.0 g) were stirred in N, N-dimethylformamide (55 mL) at 110 ° C. for 9 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography to obtain the title compound (1.48 g).
1 H NMR (CDCl 3 ) δ: 1.72-1.90 (6H, m), 2.18-2.25 (2H, m), 3.77 (3H, s), 4.41-4.48 (1H, m), 6.54 (1H, d, J = 15.6 Hz), 7.13 (1H, br s), 7.54 (1H, br s), 7.56 (1H, d, J = 15.6 Hz).
 [参考例17](2E)-3-[1-(テトラヒドロ-2H-ピラン-4-イル)-1H-イミダゾール-4-イル]アクリル酸メチル
 テトラヒドロ-2H-ピラン-4-オール(3.00g)及びトリエチルアミン(8.14mL)の塩化メチレン溶液(70mL)に、0℃攪拌下、メタンスルホニルクロリド(4.55mL)を加え、そのままの温度で終夜攪拌した。反応液に水を加えた後、有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮することにより、メタンスルホン酸テトラヒドロ-2H-ピラン-4-イルの粗生成物(5.50g)を得た。
Reference Example 17 (2E) -3- [1- (Tetrahydro-2H-pyran-4-yl) -1H-imidazol-4-yl] methyl acrylate tetrahydro-2H-pyran-4-ol (3.00 g ) And triethylamine (8.14 mL) in methylene chloride (70 mL), methanesulfonyl chloride (4.55 mL) was added with stirring at 0 ° C., and the mixture was stirred at the same temperature overnight. After adding water to the reaction solution, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave a crude product (5.50 g) of tetrahydro-2H-pyran-4-yl methanesulfonate.
 水素化ナトリウム(63%,0.69g)のN,N-ジメチルホルムアミド懸濁液(30mL)に、0℃攪拌下、(2E)-3-(1H-イミダゾール-4-イル)アクリル酸メチル(2.50g)のN,N-ジメチルホルムアミド溶液(10mL)を加えた。室温に昇温して1時間攪拌した後,メタンスルホン酸テトラヒドロ-2H-ピラン-4-イルの粗生成物(3.55g)を加え、100℃にて4時間攪拌した。反応液に水を加え、酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより、標題化合物(850mg)を得た。
1H NMR (CDCl3) δ: 1.95-2.08 (4H, m), 3.52 (2H, td, J = 11.7, 2.6 Hz), 3.78 (3H, s), 4.10-4.20 (3H, m), 6.56 (1H, d, J = 15.2 Hz), 7.16 (1H, br s), 7.56 (1H, d, J = 15.2 Hz), 7.58 (1H, br s)。
To a suspension of sodium hydride (63%, 0.69 g) in N, N-dimethylformamide (30 mL) with stirring at 0 ° C., (2E) -3- (1H-imidazol-4-yl) methyl acrylate ( 2.50 g) of N, N-dimethylformamide solution (10 mL) was added. After warming to room temperature and stirring for 1 hour, a crude product (3.55 g) of tetrahydro-2H-pyran-4-yl methanesulfonate was added and stirred at 100 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography to obtain the title compound (850 mg).
1 H NMR (CDCl 3 ) δ: 1.95-2.08 (4H, m), 3.52 (2H, td, J = 11.7, 2.6 Hz), 3.78 (3H, s), 4.10-4.20 (3H, m), 6.56 ( 1H, d, J = 15.2 Hz), 7.16 (1H, br s), 7.56 (1H, d, J = 15.2 Hz), 7.58 (1H, br s).
 [参考例18](2E)-3-(1-シクロブチル-1H-イミダゾール-4-イル)アクリル酸メチル
 (2E)-3-(1H-イミダゾール-4-イル)アクリル酸メチル(1.50g)、臭化シクロブチル(1.94mL)及び炭酸セシウム(9.64g)をN,N-ジメチルホルムアミド(20mL)中で100℃にて4時間攪拌した。反応液に水を加え、酢酸エチルで抽出した後、有機層を無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮した後,得られた粗生成物をヘキサンで洗浄することにより、標題化合物(1.69g)を得た。
1H NMR (CDCl3) δ: 1.84-1.98 (2H, m), 2.30-2.40 (2H, m), 2.49-2.57 (2H, m), 3.77 (3H, s), 4.54-4.62 (1H, m), 6.55 (1H, d, J = 15.6 Hz), 7.17 (1H, br s), 7.53 (1H, br s), 7.56 (1H, d, J = 15.6 Hz)。
[Reference Example 18] Methyl (2E) -3- (1-cyclobutyl-1H-imidazol-4-yl) acrylate (2E) -3- (1H-imidazol-4-yl) methylacrylate (1.50 g) , Cyclobutyl bromide (1.94 mL) and cesium carbonate (9.64 g) were stirred in N, N-dimethylformamide (20 mL) at 100 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was washed with hexane to obtain the title compound (1.69 g).
1 H NMR (CDCl 3 ) δ: 1.84-1.98 (2H, m), 2.30-2.40 (2H, m), 2.49-2.57 (2H, m), 3.77 (3H, s), 4.54-4.62 (1H, m ), 6.55 (1H, d, J = 15.6 Hz), 7.17 (1H, br s), 7.53 (1H, br s), 7.56 (1H, d, J = 15.6 Hz).
 [参考例19](2E)-3-[1-(trans-4-メチルシクロヘキシル)-1H-イミダゾール-4-イル]アクリル酸メチル
 cis-4-メチルシクロヘキサノール(4.24g)及びトリエチルアミン(10.3mL)の塩化メチレン溶液(100mL)に、0℃攪拌下、メタンスルホニルクロリド(5.75mL)を加え、そのままの温度で終夜攪拌した。反応液に水を加えた後、有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮することにより、メタンスルホン酸cis-4-メチルシクロヘキシルの粗生成物(7.96g)を得た。
[Reference Example 19] (2E) -3- [1- (trans-4-methylcyclohexyl) -1H-imidazol-4-yl] methyl acrylate cis-4-methylcyclohexanol (4.24 g) and triethylamine (10 .3 mL) in methylene chloride (100 mL) was added methanesulfonyl chloride (5.75 mL) with stirring at 0 ° C., and the mixture was stirred at that temperature overnight. After adding water to the reaction solution, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave a crude product (7.96 g) of cis-4-methylcyclohexyl methanesulfonate.
 (2E)-3-(1H-イミダゾール-4-イル)アクリル酸メチル(2.50g)、メタンスルホン酸cis-4-メチルシクロヘキシルの粗生成物(6.32g)及び炭酸セシウム(16.1g)をN,N-ジメチルホルムアミド(40mL)中で110℃にて3時間攪拌した。反応液に水を加え、酢酸エチルで抽出した後、有機層を無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより、標題化合物(600mg)を得た。
1H NMR (CDCl3) δ: 0.96 (3H, d, J = 6.6 Hz), 1.07-1.17 (2H, m), 1.42-1.52 (1H, m), 1.62-1.72 (2H, m), 1.85-1.90 (2H, m), 2.09-2.13 (2H, m), 3.77 (3H, s), 3.87 (1H, tt, J = 11.9, 3.8 Hz), 6.54 (1H, d, J = 15.6 Hz), 7.14 (1H, s), 7.55 (1H, s), 7.56 (1H, d, J = 15.6 Hz)。
(2E) -3- (1H-imidazol-4-yl) methyl acrylate (2.50 g), crude product of cis-4-methylcyclohexyl methanesulfonate (6.32 g) and cesium carbonate (16.1 g) Was stirred in N, N-dimethylformamide (40 mL) at 110 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography to obtain the title compound (600 mg).
1 H NMR (CDCl 3 ) δ: 0.96 (3H, d, J = 6.6 Hz), 1.07-1.17 (2H, m), 1.42-1.52 (1H, m), 1.62-1.72 (2H, m), 1.85- 1.90 (2H, m), 2.09-2.13 (2H, m), 3.77 (3H, s), 3.87 (1H, tt, J = 11.9, 3.8 Hz), 6.54 (1H, d, J = 15.6 Hz), 7.14 (1H, s), 7.55 (1H, s), 7.56 (1H, d, J = 15.6 Hz).
 [参考例20](2E)-3-[1-(cis-4-メチルシクロヘキシル)-1H-イミダゾール-4-イル]アクリル酸メチル
 trans-4-メチルシクロヘキサノール(3.81g)及びトリエチルアミン(9.25mL)の塩化メチレン溶液(80mL)に、0℃攪拌下、メタンスルホニルクロリド(5.16mL)を加え、そのままの温度で終夜攪拌した。反応液に水を加えた後、有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮することにより、メタンスルホン酸trans-4-メチルシクロヘキシルの粗生成物(7.16g)を得た。
[Reference Example 20] (2E) -3- [1- (cis-4-methylcyclohexyl) -1H-imidazol-4-yl] methyl acrylate trans-4-methylcyclohexanol (3.81 g) and triethylamine (9 To a methylene chloride solution (80 mL) of .25 mL), methanesulfonyl chloride (5.16 mL) was added with stirring at 0 ° C., and the mixture was stirred at the same temperature overnight. After adding water to the reaction solution, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. Filtration and concentration under reduced pressure gave a crude product of trans-4-methylcyclohexyl methanesulfonate (7.16 g).
 (2E)-3-(1H-イミダゾール-4-イル)アクリル酸メチル(2.50g)、メタンスルホン酸cis-4-メチルシクロヘキシルの粗生成物(6.32g)及び炭酸セシウム(16.1g)をN,N-ジメチルホルムアミド(40mL)中で110℃にて3時間攪拌した。反応液に水を加え、酢酸エチルで抽出した後、有機層を無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製した。得られた固体をヘキサンで洗浄することにより、標題化合物(1.66g)を得た。
1H NMR (CDCl3) δ: 1.00 (3H, d, J = 7.0 Hz), 1.44-1.51 (2H, m), 1.63-1.71 (2H, m), 1.83-1.92 (3H, m), 1.95-2.04 (2H, m), 3.77 (3H, s), 3.97-4.04 (1H, m), 6.55 (1H, d, J = 15.6 Hz), 7.18 (1H, s), 7.57 (1H, d, J = 15.6 Hz), 7.59 (1H, s)。
(2E) -3- (1H-imidazol-4-yl) methyl acrylate (2.50 g), crude product of cis-4-methylcyclohexyl methanesulfonate (6.32 g) and cesium carbonate (16.1 g) Was stirred in N, N-dimethylformamide (40 mL) at 110 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography. The obtained solid was washed with hexane to give the title compound (1.66 g).
1 H NMR (CDCl 3 ) δ: 1.00 (3H, d, J = 7.0 Hz), 1.44-1.51 (2H, m), 1.63-1.71 (2H, m), 1.83-1.92 (3H, m), 1.95- 2.04 (2H, m), 3.77 (3H, s), 3.97-4.04 (1H, m), 6.55 (1H, d, J = 15.6 Hz), 7.18 (1H, s), 7.57 (1H, d, J = 15.6 Hz), 7.59 (1H, s).
 [参考例21]1-(3,3-ジメチルブチル)-5-メチル-1H-イミダゾール-4-カルバルデヒド及び1-(3,3-ジメチルブチル)-4-メチル-1H-イミダゾール-5-カルバルデヒド
 4-メチル-5-イミダゾールカルバルデヒド(1.50g)のジメチルホルムアルデヒド溶液(35mL)に、室温攪拌下、参考例7で得た化合物(3.47g)及び炭酸セシウム(13.3g)を加えた。室温にて終夜攪拌した後、反応液に水を加えて酢酸エチルで抽出し、有機層を無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより、標題化合物の混合物(2.62g)を得た。
1H NMR (CDCl3) δ: 1.00 (9H, s), 1.02 (9H, s), 1.62-1.69 (4H, m), 2.50 (3H, s), 2.54 (3H, s), 3.86-3.90 (2H, m), 4.23-4.27 (2H, m), 7.46 (1H, s), 7.53 (1H, s), 9.84 (1H, s), 9.93 (1H, s)。
Reference Example 21 1- (3,3-Dimethylbutyl) -5-methyl-1H-imidazole-4-carbaldehyde and 1- (3,3-dimethylbutyl) -4-methyl-1H-imidazole-5 To a dimethylformaldehyde solution (35 mL) of carbaldehyde 4-methyl-5-imidazole carbaldehyde (1.50 g), the compound (3.47 g) obtained in Reference Example 7 and cesium carbonate (13.3 g) were stirred at room temperature. added. After stirring overnight at room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography to obtain a mixture of title compounds (2.62 g).
1 H NMR (CDCl 3 ) δ: 1.00 (9H, s), 1.02 (9H, s), 1.62-1.69 (4H, m), 2.50 (3H, s), 2.54 (3H, s), 3.86-3.90 ( 2H, m), 4.23-4.27 (2H, m), 7.46 (1H, s), 7.53 (1H, s), 9.84 (1H, s), 9.93 (1H, s).
 [参考例22](2E)-3-[1-(3,3-ジメチルブチル)-5-メチル-1H-イミダゾール-4-イル]アクリル酸メチル
 ジメチルホスホノ酢酸メチル(3.32g)及び塩化リチウム(0.77g)のアセトニトリル溶液(20mL)に、0℃攪拌下、1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン(2.73mL)を加えた。そのまま0℃にて10分間攪拌した後、参考例21で得た化合物(3.22g)のアセトニトリル溶液(20mL)を加えた。室温に昇温して終夜攪拌した後、反応液に水を加え、少量のメタノールを含む塩化メチレンで抽出し、有機層を無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより、標題化合物(1.57g)及び異性体である(2E)-3-[1-(3,3-ジメチルブチル)-4-メチル-1H-イミダゾール-5-イル]アクリル酸メチル(1.31g)をそれぞれ得た。
標題化合物:1H NMR (CDCl3) δ: 1.00 (9H, s), 1.61-1.65 (2H, m), 2.30 (3H, s), 3.77 (3H, s), 3.81-3.85 (2H, m), 6.53 (1H, d, J = 15.2 Hz), 7.44 (1H, s), 7.60 (1H, d, J = 15.2 Hz).
異性体:1H NMR (CDCl3) δ: 1.01 (9H, s), 1.65-1.70 (2H, m), 2.40 (3H, s), 3.81 (3H, s), 3.96-4.00 (2H, m), 6.09 (1H, d, J = 16.0 Hz), 7.46 (1H, s), 7.60 (1H, d, J = 16.0 Hz)。
Reference Example 22 (2E) -3- [1- (3,3-Dimethylbutyl) -5-methyl-1H-imidazol-4-yl] methyl acrylate Methyl dimethylphosphonoacetate (3.32 g) and chloride 1,8-diazabicyclo [5.4.0] undec-7-ene (2.73 mL) was added to an acetonitrile solution (20 mL) of lithium (0.77 g) with stirring at 0 ° C. After stirring at 0 ° C. for 10 minutes as it was, an acetonitrile solution (20 mL) of the compound obtained in Reference Example 21 (3.22 g) was added. After warming to room temperature and stirring overnight, water was added to the reaction solution, extracted with methylene chloride containing a small amount of methanol, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography to give the title compound (1.57 g) and the isomer (2E) -3- [1- (3, 3-dimethylbutyl) -4-methyl-1H-imidazol-5-yl] methyl acrylate (1.31 g) was obtained.
Title compound: 1 H NMR (CDCl 3 ) δ: 1.00 (9H, s), 1.61-1.65 (2H, m), 2.30 (3H, s), 3.77 (3H, s), 3.81-3.85 (2H, m) , 6.53 (1H, d, J = 15.2 Hz), 7.44 (1H, s), 7.60 (1H, d, J = 15.2 Hz).
Isomers: 1 H NMR (CDCl 3 ) δ: 1.01 (9H, s), 1.65-1.70 (2H, m), 2.40 (3H, s), 3.81 (3H, s), 3.96-4.00 (2H, m) , 6.09 (1H, d, J = 16.0 Hz), 7.46 (1H, s), 7.60 (1H, d, J = 16.0 Hz).
 [参考例23](2E)-3-(1-シクロヘプチル-1H-イミダゾール-4-イル)アクリル酸メチル
 (2E)-3-(1H-イミダゾール-4-イル)アクリル酸メチル(2.00g)、臭化シクロヘプチル(4.44mL)及び炭酸セシウム(12.9g)をN,N-ジメチルホルムアミド(20mL)中で110℃にて4時間攪拌した。反応液に水を加え、酢酸エチルで抽出した後、有機層を無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮した後、得られた粗生成物をヘキサンで洗浄することにより、標題化合物(2.72g)を得た。
1H NMR (CDCl3) δ: 1.50-1.72 (6H, m), 1.77-1.91 (4H, m), 2.08-2.15 (2H, m), 3.77 (3H, s), 4.06-4.13 (1H, m), 6.53 (1H, d, J = 15.2 Hz), 7.13 (1H, br s), 7.53 (1H, s), 7.56 (1H, d, J = 15.2 Hz)。
Reference Example 23 (2E) -3- (1-Cycloheptyl-1H-imidazol-4-yl) methyl acrylate (2E) -3- (1H-imidazol-4-yl) methyl acrylate (2.00 g ), Cycloheptyl bromide (4.44 mL) and cesium carbonate (12.9 g) were stirred in N, N-dimethylformamide (20 mL) at 110 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was washed with hexane to obtain the title compound (2.72 g).
1 H NMR (CDCl 3 ) δ: 1.50-1.72 (6H, m), 1.77-1.91 (4H, m), 2.08-2.15 (2H, m), 3.77 (3H, s), 4.06-4.13 (1H, m ), 6.53 (1H, d, J = 15.2 Hz), 7.13 (1H, br s), 7.53 (1H, s), 7.56 (1H, d, J = 15.2 Hz).
 [参考例24](2E)-3-(1-シクロプロピル-1H-イミダゾール-4-イル)アクリル酸メチル
 酢酸銅(II)(2.44)及び2,2-ビピリジル(2.05g)を1,2-ジクロロエタン(60mL)中で混合し,70℃にて5分間攪拌した懸濁液を、(2E)-3-(1H-イミダゾール-4-イル)アクリル酸メチル(2.00g)、シクロプロピルボロン酸(2.26g)及び炭酸ナトリウム(2.79g)の1,2-ジクロロエタン懸濁液(30mL)に加え、空気下70℃にて終夜攪拌した。反応液に飽和塩化アンモニウム水溶液(50mL)及びエチレンジアミン四酢酸二水素二ナトリウム二水和物(4.89g)を加え、室温でしばらく攪拌した後、塩化メチレンで抽出し、有機層を無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより、標題化合物(1.96g)を得た。
1H NMR (CDCl3) δ: 0.92-1.03 (4H, m), 3.28-3.34 (1H, m), 3.73 (3H, s), 6.50 (1H, d, J = 15.6 Hz), 7.12 (1H, d, J = 1.2 Hz), 7.49 (1H, d, J = 15.6 Hz), 7.53 (1H, d, J = 1.2 Hz)。
[Reference Example 24] (2E) -3- (1-Cyclopropyl-1H-imidazol-4-yl) methyl acrylate Copper acetate (II) (2.44) and 2,2-bipyridyl (2.05 g) A suspension which was mixed in 1,2-dichloroethane (60 mL) and stirred at 70 ° C. for 5 minutes was used as methyl (2E) -3- (1H-imidazol-4-yl) acrylate (2.00 g), To a suspension of cyclopropylboronic acid (2.26 g) and sodium carbonate (2.79 g) in 1,2-dichloroethane (30 mL), the mixture was stirred at 70 ° C. overnight under air. Saturated aqueous ammonium chloride solution (50 mL) and disodium ethylenediaminetetraacetate dihydrate (4.89 g) were added to the reaction mixture, and the mixture was stirred for a while at room temperature, extracted with methylene chloride, and the organic layer was washed with anhydrous sodium sulfate. Dried. After filtration and concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography to obtain the title compound (1.96 g).
1 H NMR (CDCl 3 ) δ: 0.92-1.03 (4H, m), 3.28-3.34 (1H, m), 3.73 (3H, s), 6.50 (1H, d, J = 15.6 Hz), 7.12 (1H, d, J = 1.2 Hz), 7.49 (1H, d, J = 15.6 Hz), 7.53 (1H, d, J = 1.2 Hz).
 [実施例1](2E)-5-アミノ-2-(イミダゾール-4-イルメチル)ペンタ-2-エン酸 2塩酸塩
 [工程1]5-[(tert-ブトキシカルボニル)アミノ]-2,4,5-トリデオキシ-2-[(1-トリチル-1H-イミダゾール-4-イル)メチル]ペントン酸メチル
 3-[1-(トリフェニル)メチル-1H-イミダゾール-4-イル]プロピオン酸メチルエステル(Helvetica Chimica Acta、2004年、第87巻、3131頁)(0.360g)のテトラヒドロフラン(7.6mL)溶液に、-78℃でリチウムヘキサメチルジシラジド(1.0規定テトラヒドロフラン溶液、0.91mL)を滴下し、同温度で1時間攪拌した。反応液に、参考例1で得た化合物(87.0mg)のテトラヒドロフラン(1.5mL)溶液を添加し、30分間攪拌し、さらに0℃で5分間攪拌した。0℃で塩化アンモニウム水溶液を加え、塩化メチレンで希釈し、分液した。水層を塩化メチレンで抽出し、得られた有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した。不溶物を濾別後、有機溶媒を減圧留去して得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:塩化メチレン/メタノール=20/1)で精製し、さらに、シリカゲル薄層クロマトグラフィー(溶出溶媒:塩化メチレン/メタノール=15/1)で再度精製することにより、標題化合物(0.187g)を得た。
1H NMR (CDCl3) δ: 1.41 (9H×1/2, each s), 1.42 (9H×1/2, each s), 1.53 - 1.82 (2H, m), 2.69 - 3.06 (3H, m), 3.12 - 3.23 (1H, m), 3.38 - 3.49 (1H, m), 3.56 (3H×1/2, s), 3.59 (3H×1/2, s), 6.51 (1H×1/2, d, J = 1.3 Hz), 6.55 (1H×1/2, d, J = 1.5 Hz), 7.08 - 7.14 (6H, m), 7.29 - 7.36 (10H, m).
MS (FAB) m/z 570 [M + H]+
[Example 1] (2E) -5-amino-2- (imidazol-4-ylmethyl) pent-2-enoic acid dihydrochloride [Step 1] 5-[(tert-butoxycarbonyl) amino] -2,4 , 5-Trideoxy-2-[(1-trityl-1H-imidazol-4-yl) methyl] pentonic acid methyl 3- [1- (triphenyl) methyl-1H-imidazol-4-yl] propionic acid methyl ester ( To a solution of Helvetica Chimica Acta, 2004, Vol. 87, 3131) (0.360 g) in tetrahydrofuran (7.6 mL) at −78 ° C., lithium hexamethyldisilazide (1.0 N tetrahydrofuran solution, 0.91 mL). ) Was added dropwise and stirred at the same temperature for 1 hour. A solution of the compound (87.0 mg) obtained in Reference Example 1 in tetrahydrofuran (1.5 mL) was added to the reaction solution, and the mixture was stirred for 30 minutes and further stirred at 0 ° C. for 5 minutes. Aqueous ammonium chloride solution was added at 0 ° C., diluted with methylene chloride, and separated. The aqueous layer was extracted with methylene chloride, and the resulting organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The insoluble material was filtered off, the organic solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 20/1), and further silica gel thin layer chromatography (elution). The title compound (0.187 g) was obtained by purification again with a solvent: methylene chloride / methanol = 15/1).
1 H NMR (CDCl 3 ) δ: 1.41 (9H × 1/2, each s), 1.42 (9H × 1/2, each s), 1.53-1.82 (2H, m), 2.69-3.06 (3H, m) , 3.12-3.23 (1H, m), 3.38-3.49 (1H, m), 3.56 (3H × 1/2, s), 3.59 (3H × 1/2, s), 6.51 (1H × 1/2, d , J = 1.3 Hz), 6.55 (1H × 1/2, d, J = 1.5 Hz), 7.08-7.14 (6H, m), 7.29-7.36 (10H, m).
MS (FAB) m / z 570 [M + H] + .
 [工程2]3-O-アセチル-5-[(tert-ブトキシカルボニル)アミノ]-2,4,5-トリデオキシ-2-[(1-トリチル-1H-イミダゾール-4-イル)メチル]ペントン酸メチル
 工程1で得た化合物(44.6mg)の塩化メチレン(2.0mL)溶液に、室温でトリエチルアミン(0.0326mL)、無水酢酸の塩化メチレン溶液(無水酢酸:0.100mLを塩化メチレン:0.900mLに溶解させた溶液として、0.192mLを用いた)及び4-ジメチルアミノピリジンの塩化メチレン溶液(4-ジメチルアミノピリジン:4.0mgを塩化メチレン:0.500mLに溶解させた溶液として、0.080mLを用いた)を添加し、7.5時間攪拌した。反応液に1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン(0.0221mL)を添加し、さらに15時間攪拌した。反応液に水と塩化メチレンを加えて分液した。水層を塩化メチレンで抽出し、得られた有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥した。不溶物を濾別後、有機溶媒を減圧留去して得られた残渣をシリカゲル薄層クロマトグラフィー(塩化メチレン/メタノール=20/1)で精製することにより、標題化合物(44.8mg)を得た。
1H NMR (CDCl3) δ: 1.39 (9H×1/2, each s), 1.40 (9H×1/2, each s), 1.69 - 1.96 (2H, m), 2.02 (3H×1/2, each s), 2.05 (3H×1/2, each s), 2.72 - 2.99 (3H, m), 3.03-3.13 (1H, m), 3.25 - 3.38 (1H, m), 3.54 (3H×1/2, each s), 3.55 (3H×1/2, each s), 5.06 - 5.23 (2H, m), 6.51 - 6.56 (1H, m), 7.07 - 7.15 (6H, m), 7.29 - 7.36 (10H, m).
MS (FAB) m/z 612 [M + H]+
[Step 2] 3-O-acetyl-5-[(tert-butoxycarbonyl) amino] -2,4,5-trideoxy-2-[(1-trityl-1H-imidazol-4-yl) methyl] pentonic acid To a solution of the compound obtained in Step 1 (44.6 mg) in methylene chloride (2.0 mL) at room temperature was added triethylamine (0.0326 mL) and acetic anhydride in methylene chloride (acetic anhydride: 0.100 mL in methylene chloride: 0 0.192 mL was used as a solution dissolved in 900 mL) and a solution of 4-dimethylaminopyridine in methylene chloride (4-dimethylaminopyridine: 4.0 mg dissolved in 0.500 mL of methylene chloride: 0.080 mL was used) and stirred for 7.5 hours. 1,8-diazabicyclo [5.4.0] undec-7-ene (0.0221 mL) was added to the reaction solution, and the mixture was further stirred for 15 hours. Water and methylene chloride were added to the reaction solution to separate it. The aqueous layer was extracted with methylene chloride, and the resulting organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The insoluble material was filtered off, the organic solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (methylene chloride / methanol = 20/1) to give the title compound (44.8 mg). It was.
1 H NMR (CDCl 3 ) δ: 1.39 (9H × 1/2, each s), 1.40 (9H × 1/2, each s), 1.69-1.96 (2H, m), 2.02 (3H × 1/2, each s), 2.05 (3H × 1/2, each s), 2.72-2.99 (3H, m), 3.03-3.13 (1H, m), 3.25-3.38 (1H, m), 3.54 (3H × 1/2 , each s), 3.55 (3H × 1/2, each s), 5.06-5.23 (2H, m), 6.51-6.56 (1H, m), 7.07-7.15 (6H, m), 7.29-7.36 (10H, m).
MS (FAB) m / z 612 [M + H] + .
 [工程3](2E)-5-[(tert-ブトキシカルボニル)アミノ]-2-[(1-トリチル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸メチル
 工程2で得た化合物(41.1mg)の1,4-ジオキサン(3.0mL)溶液に、室温で1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン(0.0201mL)を添加し、55℃で3時間攪拌後、室温に14時間放置した。反応液を80℃で9時間攪拌し、室温に16時間放置した後、1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン(0.100mL)を添加し、80℃で6時間攪拌した。反応液を空冷し、塩化メチレン-メタノール溶液(20v/v)と水を加えて分液した。水層を塩化メチレンで抽出し、得られた有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥させた。不溶物を濾別後、有機溶媒を減圧留去して得られた残渣をシリカゲル薄層クロマトグラフィー(溶出溶媒:塩化メチレン/メタノール=20/1)で精製し、標題化合物(13.8mg)を得た。
1H NMR (CDCl3) δ: 1.27 (9H, s), 2.54 - 2.63 (2H, m), 3.28 - 3.34 (2H, m), 3.46 - 3.53 (2H, m), 3.64 (3H, s), 6.61 (1H, s), 6.85 (1H, t, J = 8.1 Hz), 7.05 - 7.13 (6H, m), 7.25 - 7.34 (10H, m), 8.07 (1H, s).
LC-MS m/z 552 (M + H)+.
なお、COSY及びNOE差スペクトルにより二重結合の幾何をEと決定した。
[Step 3] (2E) -5-[(tert-butoxycarbonyl) amino] -2-[(1-trityl-1H-imidazol-4-yl) methyl] pent-2-enoic acid methyl obtained in Step 2 1,8-diazabicyclo [5.4.0] undec-7-ene (0.0201 mL) was added to a solution of the compound (41.1 mg) in 1,4-dioxane (3.0 mL) at room temperature, And stirred at room temperature for 14 hours. The reaction solution was stirred at 80 ° C. for 9 hours and allowed to stand at room temperature for 16 hours. Stir. The reaction solution was air-cooled, and a methylene chloride-methanol solution (20 v / v) and water were added for liquid separation. The aqueous layer was extracted with methylene chloride, and the resulting organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The insoluble material was filtered off, the organic solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel thin layer chromatography (elution solvent: methylene chloride / methanol = 20/1) to give the title compound (13.8 mg). Obtained.
1 H NMR (CDCl 3 ) δ: 1.27 (9H, s), 2.54-2.63 (2H, m), 3.28-3.34 (2H, m), 3.46-3.53 (2H, m), 3.64 (3H, s), 6.61 (1H, s), 6.85 (1H, t, J = 8.1 Hz), 7.05-7.13 (6H, m), 7.25-7.34 (10H, m), 8.07 (1H, s).
LC-MS m / z 552 (M + H) + .
The double bond geometry was determined to be E based on the COZY and NOE difference spectra.
 [工程4](2E)-5-アミノ-2-(イミダゾール-4-イルメチル)ペンタ-2-エン酸 2塩酸塩
 工程3で得た化合物(59.0mg)を5規定塩酸に懸濁させ、85℃で3時間攪拌した。反応液を空冷し、不溶物を濾別した。濾液を減圧下濃縮することにより、標題化合物(27.8mg)を得た。
1H NMR (CD3OD) δ: 2.67 - 2.76 (2H, m), 3.05 - 3.13 (2H, m), 3.79 (2H, s), 6.96 (1H, t, J = 7.0 Hz), 7.28 (1H, s), 8.77 (1H, s).
MS (ESI) m/z 196 [M + H]+.
HRMS (ESI) m/z 196.10861 [M + H]+. (Calcd. C9H14N3O2: 196.10860)。
[Step 4] (2E) -5-amino-2- (imidazol-4-ylmethyl) pent-2-enoic acid dihydrochloride The compound obtained in Step 3 (59.0 mg) was suspended in 5N hydrochloric acid, Stir at 85 ° C. for 3 hours. The reaction solution was air-cooled and insoluble matters were filtered off. The filtrate was concentrated under reduced pressure to obtain the title compound (27.8 mg).
1 H NMR (CD 3 OD) δ: 2.67-2.76 (2H, m), 3.05-3.13 (2H, m), 3.79 (2H, s), 6.96 (1H, t, J = 7.0 Hz), 7.28 (1H , s), 8.77 (1H, s).
MS (ESI) m / z 196 [M + H] + .
HRMS (ESI) m / z 196.10861 [M + H] + . (Calcd. C 9 H 14 N 3 O 2 : 196.10860).
 [実施例2](2Z)-5-アミノ-2-(1H-イミダゾール-4-イルメチル)ペンタ-2-エン酸 2塩酸塩
 [工程1](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-[(1-トリチル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸メチル
 参考例3で得た化合物(0.101g)のテトラヒドロフラン(2.0mL)溶液に、室温で18-クラウン-6-エーテル(0.211g)のテトラヒドロフラン(1.3mL)溶液を添加した。反応液を-78℃に冷却し、カリウムヘキサメチルジシラジド(0.5mol/Lトルエン溶液、0.42mL)を滴下し、同温度で40分間攪拌した。反応液に参考例1で得た化合物(18mg)のテトラヒドロフラン(0.5mL)溶液を添加して30分間攪拌した後、0℃で40分間、さらに室温で1.5時間攪拌した。反応液に塩化アンモニウム水溶液を加えて塩化メチレンで希釈し、分液した。水層を塩化メチレンで抽出し、得られた有機層を合わせ、飽和食塩水で洗浄した。有機層を無水硫酸ナトリウムで乾燥させた。不溶物を濾別後、有機溶媒を減圧留去して得られた残渣をシリカゲル薄層クロマトグラフィー(溶出溶媒:塩化メチレン/メタノール=20/1)で精製することにより、標題化合物(10.7mg)を得た。また、別の画分より異性体であるE-体(6.6mg)を得た。
1H NMR (CDCl3) δ: 1.36 (9H, s), 2.55 - 2.63 (2H, m), 3.10 - 3.20 (2H, m), 3.48 (2H, br), 3.58 (3H, s), 4.86 (1H, br), 5.92 (1H, t, J = 7.0 Hz), 6.50 (1H, s), 7.05 - 7.12 (6H, m), 7.25 - 7.35 (10H, m).
MS (FAB) m/z 552 [M + H]+
[Example 2] (2Z) -5-amino-2- (1H-imidazol-4-ylmethyl) pent-2-enoic acid dihydrochloride [Step 1] (2Z) -5-[(tert-butoxycarbonyl) Amino] -2-[(1-trityl-1H-imidazol-4-yl) methyl] pent-2-enoic acid methyl ester To a solution of the compound (0.101 g) obtained in Reference Example 3 in tetrahydrofuran (2.0 mL), A solution of 18-crown-6-ether (0.211 g) in tetrahydrofuran (1.3 mL) was added at room temperature. The reaction solution was cooled to −78 ° C., potassium hexamethyldisilazide (0.5 mol / L toluene solution, 0.42 mL) was added dropwise, and the mixture was stirred at the same temperature for 40 minutes. A solution of the compound (18 mg) obtained in Reference Example 1 in tetrahydrofuran (0.5 mL) was added to the reaction solution and stirred for 30 minutes, and then stirred at 0 ° C. for 40 minutes and further at room temperature for 1.5 hours. Aqueous ammonium chloride solution was added to the reaction solution, diluted with methylene chloride, and separated. The aqueous layer was extracted with methylene chloride, and the resulting organic layers were combined and washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate. The insoluble material was filtered off, the organic solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel thin layer chromatography (elution solvent: methylene chloride / methanol = 20/1) to give the title compound (10.7 mg ) Further, an E-isomer (6.6 mg) as an isomer was obtained from another fraction.
1 H NMR (CDCl 3 ) δ: 1.36 (9H, s), 2.55-2.63 (2H, m), 3.10-3.20 (2H, m), 3.48 (2H, br), 3.58 (3H, s), 4.86 ( 1H, br), 5.92 (1H, t, J = 7.0 Hz), 6.50 (1H, s), 7.05-7.12 (6H, m), 7.25-7.35 (10H, m).
MS (FAB) m / z 552 [M + H] + .
 [工程2](2Z)-5-アミノ-2-(1H-イミダゾール-4-イルメチル)ペンタ-2-エン酸 2塩酸塩
 工程1で得た化合物(39.3mg)を5規定塩酸に懸濁させ、85度で4時間攪拌した。反応液を0℃に冷却し、不溶物を濾別した。濾液を減圧下濃縮して得られた残渣を逆相HPLC(カラム:GL sciences Prep-ODS;サイズ:250×30mm;流量:15mL/min;溶出溶媒:HO)で精製した後、凍結乾燥することにより標題化合物(7.9mg)を得た。
1H NMR (CD3OD) δ: 2.40 - 2.50 (2H, m), 2.87 - 2.94 (2H, m), 3.51 (2H, br), 5.33 (1H, t, J = 8.3 Hz), 6.80 (1H, s), 7.53 (1H, s).
MS (ESI) m/z 196 [M + H]+.
HRMS (ESI) m/z 196.10985 [M + H]+. (Calcd. C9H14N3O2: 196.10860)。
[Step 2] (2Z) -5-amino-2- (1H-imidazol-4-ylmethyl) pent-2-enoic acid dihydrochloride The compound obtained in Step 1 (39.3 mg) was suspended in 5N hydrochloric acid. And stirred at 85 degrees for 4 hours. The reaction solution was cooled to 0 ° C., and insoluble matters were filtered off. The residue obtained by concentrating the filtrate under reduced pressure was purified by reverse phase HPLC (column: GL sciences Prep-ODS; size: 250 × 30 mm; flow rate: 15 mL / min; elution solvent: H 2 O), and then lyophilized. This gave the title compound (7.9 mg).
1 H NMR (CD 3 OD) δ: 2.40-2.50 (2H, m), 2.87-2.94 (2H, m), 3.51 (2H, br), 5.33 (1H, t, J = 8.3 Hz), 6.80 (1H , s), 7.53 (1H, s).
MS (ESI) m / z 196 [M + H] + .
HRMS (ESI) m / z 196.10985 [M + H] + . (Calcd. C 9 H 14 N 3 O 2 : 196.10860).
 [実施例3](2E)-5-アミノ-2-[(1-プロピル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸 二塩酸塩
 [工程1](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-[(1-トリチル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸メチル及び(2E)-5-[(tert-ブトキシカルボニル)アミノ]-2-[(1-トリチル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸メチル
 参考例4で得た化合物(500mg)を無水テトラヒドロフラン(20mL)に溶解し、この溶液に18-クラウン-6(825mg)を加え、-78℃に冷却した。これにカリウムヘキサメチルジシラジド(0.5mol/Lトルエン溶液,1.72mL)を10分間で滴下した。同温で1時間攪拌した後、参考例1で得た化合物(149mg)の無水テトラヒドロフラン溶液(30mL)を40分間で滴下した。約6時間かけて徐々に室温まで昇温した後、同温で一昼夜攪拌した。飽和塩化アンモニウム水溶液を加え、塩化メチレンで3回抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムを加えて乾燥し、減圧下で溶媒を留去した。得られた残渣を分取薄層クロマトグラフィー(溶出溶媒:塩化メチレン/メタノール=30/1で3回、20/1で2回展開)にて精製し、標題化合物のZ-体(88mg)及びE-体(116mg)をそれぞれ得た。
Z-体:1H-NMR (CDCl3) δ: 1.40 (9H, s), 2.61-2.65 (2H, m), 3.18-3.22 (2H, m), 3.52 (2H, s), 3.62 (3H, s), 4.85 (1H, br s), 5.95 (1H, t, J = 7.6 Hz), 6.53 (1H, s), 7.12-7.14 (6H, m), 7.32-7.33 (9H, m), 7.35 (1H, s).
E-体:1H-NMR (CDCl3) δ: 1.27 (9H, s), 2.61-2.65 (2H, m), 3.34-3.37 (2H, m), 3.54 (2H, s), 3.64 (3H, s), 6.62 (1H, s), 6.86 (1H, t, J = 8.1 Hz), 7.11-7.13 (6H, m), 7.30-7.33 (9H, m), 8.15 (1H, s)。
[Example 3] (2E) -5-amino-2-[(1-propyl-1H-imidazol-4-yl) methyl] pent-2-enoic acid dihydrochloride [Step 1] (2Z) -5 [(Tert-Butoxycarbonyl) amino] -2-[(1-trityl-1H-imidazol-4-yl) methyl] pent-2-enoic acid methyl and (2E) -5-[(tert-butoxycarbonyl) amino ] -2-[(1-Trityl-1H-imidazol-4-yl) methyl] pent-2-enoic acid methyl compound The compound obtained in Reference Example 4 (500 mg) was dissolved in anhydrous tetrahydrofuran (20 mL). 18-Crown-6 (825 mg) was added and cooled to -78 ° C. To this, potassium hexamethyldisilazide (0.5 mol / L toluene solution, 1.72 mL) was added dropwise over 10 minutes. After stirring at the same temperature for 1 hour, an anhydrous tetrahydrofuran solution (30 mL) of the compound obtained in Reference Example 1 (149 mg) was added dropwise over 40 minutes. After gradually raising the temperature to room temperature over about 6 hours, the mixture was stirred at the same temperature all day and night. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted 3 times with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (elution solvent: methylene chloride / methanol = 30/1, developed 3 × 20/1 twice) to obtain the Z-form (88 mg) of the title compound and E-isomer (116 mg) was obtained.
Z-isomer: 1 H-NMR (CDCl 3 ) δ: 1.40 (9H, s), 2.61-2.65 (2H, m), 3.18-3.22 (2H, m), 3.52 (2H, s), 3.62 (3H, s), 4.85 (1H, br s), 5.95 (1H, t, J = 7.6 Hz), 6.53 (1H, s), 7.12-7.14 (6H, m), 7.32-7.33 (9H, m), 7.35 ( 1H, s).
E-isomer: 1 H-NMR (CDCl 3 ) δ: 1.27 (9H, s), 2.61-2.65 (2H, m), 3.34-3.37 (2H, m), 3.54 (2H, s), 3.64 (3H, s), 6.62 (1H, s), 6.86 (1H, t, J = 8.1 Hz), 7.11-7.13 (6H, m), 7.30-7.33 (9H, m), 8.15 (1H, s).
 [工程2](2E)-5-[(tert-ブトキシカルボニル)アミノ]-2-(1H-イミダゾール-4-イルメチル)ペンタ-2-エン酸メチル
 工程1で得られた(2E)-5-[(tert-ブトキシカルボニル)アミノ]-2-[(1-トリチル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸メチル(115mg)に90%酢酸水溶液(1.0mL)を加え、60℃で4時間攪拌した。放冷後、水で希釈し、塩化メチレンで3回洗浄した。飽和重曹水を加えて塩基性とし、塩化メチレン/メタノールの混合溶媒(10/1)で3回抽出した。無水硫酸マグネシウムを加えて乾燥した後、減圧下で溶媒を留去した。これをそのまま次反応に用いた。
1H-NMR (CDCl3) δ: 1.44 (9H, s), 2.56-2.61 (2H, m), 3.26-3.31 (2H, m), 3.62 (2H, s), 3.71 (3H, s), 6.80-6.84 (2H, m), 7.49 (1H, s).
LRMS (ESI) m/z 310 [M + H]+
[Step 2] (2E) -5-[(tert-Butoxycarbonyl) amino] -2- (1H-imidazol-4-ylmethyl) pent-2-enoic acid methyl ester (2E) -5 obtained in Step 1 90% acetic acid aqueous solution (1.0 mL) was added to [[tert-butoxycarbonyl) amino] -2-[(1-trityl-1H-imidazol-4-yl) methyl] pent-2-enoate (115 mg). , And stirred at 60 ° C. for 4 hours. After standing to cool, it was diluted with water and washed 3 times with methylene chloride. Saturated aqueous sodium bicarbonate was added to make the mixture basic, and the mixture was extracted 3 times with a mixed solvent of methylene chloride / methanol (10/1). After adding anhydrous magnesium sulfate and drying, the solvent was distilled off under reduced pressure. This was directly used in the next reaction.
1 H-NMR (CDCl 3 ) δ: 1.44 (9H, s), 2.56-2.61 (2H, m), 3.26-3.31 (2H, m), 3.62 (2H, s), 3.71 (3H, s), 6.80 -6.84 (2H, m), 7.49 (1H, s).
LRMS (ESI) m / z 310 [M + H] + .
 [工程3](2E)-5-[(tert-ブトキシカルボニル)アミノ]-2-[(1-プロピル-1H-イミダゾール-4-イル)メチル] ペンタ-2-エン酸メチル
 工程2で得られた化合物(65mg)をN,N-ジメチルホルムアミドに溶解し、この溶液に1-ブロモプロパン(21μL)及びトリエチルアミン(43μL)を加え、60~70℃で4日間攪拌した。さらに、1-ブロモプロパン(58μL)及びトリエチルアミン(173μL)を加えて、10時間攪拌した。反応溶液に水を加え、酢酸エチルで数回抽出した。有機層を水で洗浄し、無水硫酸マグネシウムを加えて乾燥後、減圧下で溶媒を留去した。得られた残渣を分取薄層クロマトグラフィー(溶出溶媒:塩化メチレン/メタノール=10/1)にて精製し、標記化合物(18.7mg)を得た。
1H-NMR (CDCl3) δ: 0.91 (3H, t, J = 7.3 Hz), 1.44 (9H, s), 1.75-1.79 (2H, m), 2.62-2.66 (2H, m), 3.34-3.37 (2H, m), 3.58 (2H, s), 3.69 (3H, s), 3.80 (2H, t, J = 6.8 Hz), 6.70 (1H, s), 6.85 (1H, t, J = 8.3 Hz), 7.31 (1H, s), 7.40 (1H, br s).
LRMS (ESI) m/z 352 [M + H]+
[Step 3] (2E) -5-[(tert-butoxycarbonyl) amino] -2-[(1-propyl-1H-imidazol-4-yl) methyl] penta-2-enoic acid methyl obtained in Step 2 The compound (65 mg) was dissolved in N, N-dimethylformamide, 1-bromopropane (21 μL) and triethylamine (43 μL) were added to this solution, and the mixture was stirred at 60 to 70 ° C. for 4 days. Furthermore, 1-bromopropane (58 μL) and triethylamine (173 μL) were added and stirred for 10 hours. Water was added to the reaction solution, and extracted several times with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (elution solvent: methylene chloride / methanol = 10/1) to obtain the title compound (18.7 mg).
1 H-NMR (CDCl 3 ) δ: 0.91 (3H, t, J = 7.3 Hz), 1.44 (9H, s), 1.75-1.79 (2H, m), 2.62-2.66 (2H, m), 3.34-3.37 (2H, m), 3.58 (2H, s), 3.69 (3H, s), 3.80 (2H, t, J = 6.8 Hz), 6.70 (1H, s), 6.85 (1H, t, J = 8.3 Hz) , 7.31 (1H, s), 7.40 (1H, br s).
LRMS (ESI) m / z 352 [M + H] + .
 [工程4](2E)-5-アミノ-2-[(1-プロピル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸 二塩酸塩
 工程3で得られた化合物(17mg)に5規定塩酸水溶液(2.0mL)を加え、85℃で約6時間攪拌した。放冷後、減圧下で反応溶液を濃縮した残渣に少量のトルエンを加えて共沸する操作を数回繰り返した。減圧下で乾燥することによって、標記化合物(14.4mg)を得た。
1H-NMR (CD3OD) δ: 0.94 (3H, t, J = 7.3 Hz), 1.88-1.91 (2H, m), 2.73 (2H, td, J = 7.8, 7.3 Hz), 3.13 (2H, t, J = 7.3 Hz), 3.79 (2H, s), 4.14 (2H, t, J = 7.1 Hz), 7.00 (1H, t, J = 7.3 Hz), 7.41 (1H, s), 8.85 (1H, s).
LRMS (ESI) m/z 238 [M + H]+.
HRMS (ESI) Calcd for C12H20N3O2: 238.15555. Found: 238.15510。
[Step 4] (2E) -5-Amino-2-[(1-propyl-1H-imidazol-4-yl) methyl] pent-2-enoic acid dihydrochloride To the compound (17 mg) obtained in Step 3 5N hydrochloric acid aqueous solution (2.0 mL) was added, and the mixture was stirred at 85 ° C. for about 6 hours. After allowing to cool, the operation of adding a small amount of toluene to the residue obtained by concentrating the reaction solution under reduced pressure and azeotroping was repeated several times. The title compound (14.4 mg) was obtained by drying under reduced pressure.
1 H-NMR (CD 3 OD) δ: 0.94 (3H, t, J = 7.3 Hz), 1.88-1.91 (2H, m), 2.73 (2H, td, J = 7.8, 7.3 Hz), 3.13 (2H, t, J = 7.3 Hz), 3.79 (2H, s), 4.14 (2H, t, J = 7.1 Hz), 7.00 (1H, t, J = 7.3 Hz), 7.41 (1H, s), 8.85 (1H, s).
LRMS (ESI) m / z 238 [M + H] + .
HRMS (ESI) Calcd for C 12 H 20 N 3 O 2 : 238.15555. Found: 238.15510.
 [実施例4](2Z)-5-アミノ-2-[(1-プロピル-1H-イミダゾール-5-イル)メチル]ペンタ-2-エン酸 二塩酸塩
 [工程1](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-(1H-イミダゾール-4-イルメチル)ペンタ-2-エン酸メチル
 実施例3の工程1で得られた(2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-[(1-トリチル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸メチル(290mg)に90%酢酸水溶液(2.0mL)を加え、60℃で2時間攪拌した。放冷後、水で希釈し、塩化メチレンで3回洗浄した。水層に飽和重曹水を加えて塩基性とし、塩化メチレン/メタノールの混合溶媒(10/1)で3回抽出した。無水硫酸マグネシウムを加えて乾燥した後、減圧下で溶媒を留去し、乾燥した。これをそのまま次反応に用いた。
1H-NMR (CDCl3) δ: 1.44 (9H, s), 2.62-2.66 (2H, m), 3.27-3.30 (2H, m), 3.58 (2H, s), 3.73 (3H, s), 4.83 (1H, br s), 6.06 (1H, t, J = 7.8 Hz), 6.81 (1H, s), 7.56 (1H, s)。
[Example 4] (2Z) -5-amino-2-[(1-propyl-1H-imidazol-5-yl) methyl] pent-2-enoic acid dihydrochloride [Step 1] (2Z) -5 [(Tert-Butoxycarbonyl) amino] -2- (1H-imidazol-4-ylmethyl) pent-2-enoic acid methyl (2Z) -5-[(tert-butoxycarbonyl) obtained in Step 1 of Example 3 ) Amino] -2-[(1-trityl-1H-imidazol-4-yl) methyl] pent-2-enoate (290 mg) was added with 90% aqueous acetic acid (2.0 mL), and the mixture was stirred at 60 ° C. for 2 hours. Stir. After standing to cool, it was diluted with water and washed 3 times with methylene chloride. Saturated aqueous sodium hydrogen carbonate was added to the aqueous layer to make it basic, and the mixture was extracted 3 times with a mixed solvent of methylene chloride / methanol (10/1). After anhydrous magnesium sulfate was added and dried, the solvent was distilled off under reduced pressure and dried. This was directly used in the next reaction.
1 H-NMR (CDCl 3 ) δ: 1.44 (9H, s), 2.62-2.66 (2H, m), 3.27-3.30 (2H, m), 3.58 (2H, s), 3.73 (3H, s), 4.83 (1H, br s), 6.06 (1H, t, J = 7.8 Hz), 6.81 (1H, s), 7.56 (1H, s).
 [工程2](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-[(1-プロピル-1H-イミダゾール-5-イル)メチル]ペンタ-2-エン酸メチル
 工程1で得られた化合物(127mg)をN,N-ジメチルホルムアミド(1.0mL)に溶解し、この溶液にトリエチルアミン(84μL)と1-ヨードプロパン(44μL)を加え、室温下で1昼夜攪拌した。さらに40℃で数時間攪拌した。水で希釈し、酢酸エチルで数回抽出した。有機層を再度、水で洗浄した。無水硫酸マグネシウムを加えて乾燥した後、減圧下で溶媒を留去した。得られた残渣を分取薄層クロマトグラフィー(溶出溶媒:塩化メチレン/メタノール=10/1)にて精製し、標題化合物の異性体(4-イル体)(38mg)及び標題化合物(14mg)をそれぞれ得た。
標題化合物の異性体(イミダゾール-4-イル体):1H-NMR (CDCl3) δ: 0.89 (3H, t, J = 7.4 Hz), 1.42 (9H, s), 1.71-1.80 (3H, m), 2.61-2.66 (2H, m), 3.19-3.24 (2H, m), 3.54 (2H, s), 3.69 (3H, s), 3.80 (2H, t, J = 7.0 Hz), 4.87 (1H, br s), 5.98 (1H, t, J = 7.8 Hz), 6.60 (1H, s), 7.34 (1H, s).
LRMS (ESI) m/z 352 [M + H]+.
標題化合物(イミダゾール-5-イル体):1H-NMR (CDCl3) δ: 0.93 (3H, t, J = 7.4 Hz), 1.44 (9H, s), 1.70-1.79 (2H, m), 2.62-2.67 (2H, m), 3.19-3.24 (2H, m), 3.54 (2H, s), 3.73 (3H, s), 3.76 (2H, t, J = 7.2 Hz), 4.77 (1H, br s), 5.84 (1H, t, J = 7.4 Hz), 6.76 (1H, s), 7.43 (1H, s).
LRMS (ESI) m/z 352 [M + H]+
[Step 2] (2Z) -5-[(tert-butoxycarbonyl) amino] -2-[(1-propyl-1H-imidazol-5-yl) methyl] pent-2-enoic acid methyl obtained in Step 1 The compound (127 mg) was dissolved in N, N-dimethylformamide (1.0 mL), triethylamine (84 μL) and 1-iodopropane (44 μL) were added to the solution, and the mixture was stirred overnight at room temperature. The mixture was further stirred at 40 ° C. for several hours. Dilute with water and extract several times with ethyl acetate. The organic layer was washed again with water. After adding anhydrous magnesium sulfate and drying, the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin layer chromatography (elution solvent: methylene chloride / methanol = 10/1) to give the isomer of the title compound (4-yl) (38 mg) and the title compound (14 mg). I got each.
Isomers of the title compound (imidazol-4-yl): 1 H-NMR (CDCl 3 ) δ: 0.89 (3H, t, J = 7.4 Hz), 1.42 (9H, s), 1.71-1.80 (3H, m ), 2.61-2.66 (2H, m), 3.19-3.24 (2H, m), 3.54 (2H, s), 3.69 (3H, s), 3.80 (2H, t, J = 7.0 Hz), 4.87 (1H, br s), 5.98 (1H, t, J = 7.8 Hz), 6.60 (1H, s), 7.34 (1H, s).
LRMS (ESI) m / z 352 [M + H] +.
Title compound (imidazol-5-yl): 1 H-NMR (CDCl 3 ) δ: 0.93 (3H, t, J = 7.4 Hz), 1.44 (9H, s), 1.70-1.79 (2H, m), 2.62 -2.67 (2H, m), 3.19-3.24 (2H, m), 3.54 (2H, s), 3.73 (3H, s), 3.76 (2H, t, J = 7.2 Hz), 4.77 (1H, br s) , 5.84 (1H, t, J = 7.4 Hz), 6.76 (1H, s), 7.43 (1H, s).
LRMS (ESI) m / z 352 [M + H] + .
 [工程3](2Z)-5-アミノ-2-[(1-プロピル-1H-イミダゾール-5-イル)メチル]ペンタ-2-エン酸 二塩酸塩
 工程2で得られた化合物(14mg)に、5規定塩酸水溶液(3.0mL)を加え、85℃で約4時間攪拌した。放冷後、減圧下で反応溶液を濃縮した残渣に少量のトルエンを加えて共沸する操作を数回繰り返した。減圧下で乾燥することによって、標記化合物(12.4mg)を得た。
1H-NMR (CD3OD) δ: 1.00 (3H, t, J = 7.1 Hz), 1.90-1.92 (2H, m), 2.94-2.95 (2H, m), 3.10 (2H, t, J = 6.8 Hz), 3.76 (2H, s), 4.19 (2H, t, J = 6.8 Hz), 6.27 (1H, t, J = 6.3 Hz), 7.34 (1H, s), 8.94 (1H, s).
LRMS (ESI) m/z 238 [M + H]+
[Step 3] (2Z) -5-amino-2-[(1-propyl-1H-imidazol-5-yl) methyl] pent-2-enoic acid dihydrochloride To the compound (14 mg) obtained in Step 2 5N hydrochloric acid aqueous solution (3.0 mL) was added, and the mixture was stirred at 85 ° C. for about 4 hours. After allowing to cool, the operation of adding a small amount of toluene to the residue obtained by concentrating the reaction solution under reduced pressure and azeotroping was repeated several times. The title compound (12.4 mg) was obtained by drying under reduced pressure.
1 H-NMR (CD 3 OD) δ: 1.00 (3H, t, J = 7.1 Hz), 1.90-1.92 (2H, m), 2.94-2.95 (2H, m), 3.10 (2H, t, J = 6.8 Hz), 3.76 (2H, s), 4.19 (2H, t, J = 6.8 Hz), 6.27 (1H, t, J = 6.3 Hz), 7.34 (1H, s), 8.94 (1H, s).
LRMS (ESI) m / z 238 [M + H] + .
 [実施例5](2Z)-5-アミノ-2-[(1-プロピル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸
 [工程1]4-ヒドロキシ-3-[(1-プロピル-1H-イミダゾール-4-イル)メチル]ピペリジン-2-オン
 参考例6で得た化合物(20.8g)を無水テトラヒドロフラン(200mL)に溶解し、窒素雰囲気下で-78℃に冷却した。リチウムビス(トリメチルシリル)アミド(1.0Mテトラヒドロフラン溶液、106mL)を1時間で滴下し、同温で1時間攪拌した。この溶液に、(3-オキソプロピル)カルバミン酸ベンジル(Tetrahedron、1997年、53巻、12391頁)(11.0g)を含む無水テトラヒドロフラン(100mL)溶液を40分かけて滴下し、同温で1時間攪拌し、さらに氷浴に代えて30分間攪拌した。飽和塩化アンモニウム水溶液を加え、酢酸エチルで2回抽出した。併せた有機層に無水硫酸マグネシウムを加えて乾燥した後、減圧下で溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:塩化メチレン/メタノール=100/0→96/4)にて精製し、アルドール付加体(10.0g)を得た。これをエタノール(120mL)に溶解後、含水5%パラジウム-炭素(6.0g)を加えて、水素雰囲気下(1気圧)にて室温で一昼夜攪拌した。反応溶液をセライトろ過し、減圧下で溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:塩化メチレン/メタノール=100/0→85/15)にて精製し、標題化合物(4.3g)を得た。
1H-NMR (CDCl3) δ: 0.90-0.94 (3.0H, m), 1.74-1.91 (3.0H, m), 2.00-2.07 (0.5H, m), 2.14-2.20 (0.5H, m), 2.44 (0.5H, td, J = 8.8, 2.6 Hz), 2.52 (0.5H, dt, J = 10.6, 4.7 Hz), 2.84 (0.5H, dd, J = 15.1, 8.4 Hz), 2.97 (0.5H, dd, J = 14.9, 10.6 Hz), 3.20 (1.0H, dd, J = 14.5, 4.7 Hz), 3.29 (1.0H, dd, J = 10.8, 4.1 Hz), 3.55 (0.5H, dd, J = 15.2, 2.7 Hz), 3.70 (0.5H, td, J = 11.5, 4.2 Hz), 3.83 (2.0H, td, J = 7.1, 3.8 Hz), 3.92-3.98 (0.5H, m), 4.08-4.10 (0.5H, m), 5.79 (0.5H, br s), 5.86 (0.5H, br s), 6.75 (1.0H, s), 7.36 (1.0H, s).
LRMS (ESI) m/z 238 [M + H]+
[Example 5] (2Z) -5-amino-2-[(1-propyl-1H-imidazol-4-yl) methyl] pent-2-enoic acid [Step 1] 4-hydroxy-3-[(1 -Propyl-1H-imidazol-4-yl) methyl] piperidin-2-one The compound (20.8 g) obtained in Reference Example 6 was dissolved in anhydrous tetrahydrofuran (200 mL) and cooled to -78 ° C. under a nitrogen atmosphere. . Lithium bis (trimethylsilyl) amide (1.0 M tetrahydrofuran solution, 106 mL) was added dropwise over 1 hour, and the mixture was stirred at the same temperature for 1 hour. To this solution, a solution of anhydrous tetrahydrofuran (100 mL) containing benzyl (3-oxopropyl) carbamate (Tetrahedron, 1997, 53, 12391) (11.0 g) was added dropwise over 40 minutes. The mixture was stirred for an hour, and further stirred for 30 minutes instead of the ice bath. Saturated aqueous ammonium chloride solution was added, and the mixture was extracted twice with ethyl acetate. After adding anhydrous magnesium sulfate to the combined organic layer and drying, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 100/0 → 96/4) to obtain an aldol adduct (10.0 g). This was dissolved in ethanol (120 mL), water-containing 5% palladium-carbon (6.0 g) was added, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere (1 atm). The reaction solution was filtered through celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 100/0 → 85/15) to give the title compound (4.3 g).
1 H-NMR (CDCl 3 ) δ: 0.90-0.94 (3.0H, m), 1.74-1.91 (3.0H, m), 2.00-2.07 (0.5H, m), 2.14-2.20 (0.5H, m), 2.44 (0.5H, td, J = 8.8, 2.6 Hz), 2.52 (0.5H, dt, J = 10.6, 4.7 Hz), 2.84 (0.5H, dd, J = 15.1, 8.4 Hz), 2.97 (0.5H, dd, J = 14.9, 10.6 Hz), 3.20 (1.0H, dd, J = 14.5, 4.7 Hz), 3.29 (1.0H, dd, J = 10.8, 4.1 Hz), 3.55 (0.5H, dd, J = 15.2 , 2.7 Hz), 3.70 (0.5H, td, J = 11.5, 4.2 Hz), 3.83 (2.0H, td, J = 7.1, 3.8 Hz), 3.92-3.98 (0.5H, m), 4.08-4.10 (0.5 H, m), 5.79 (0.5H, br s), 5.86 (0.5H, br s), 6.75 (1.0H, s), 7.36 (1.0H, s).
LRMS (ESI) m / z 238 [M + H] + .
 [工程2]3-[(1-プロピル-1H-イミダゾール-4-イル)メチル]-5,6-ジヒドロピリジン-2(1H)-オン
 工程1で得られた化合物(4.0g)を塩化メチレン(20mL)に溶解し、氷冷下でトリエチルアミン(4.7mL),メタンス及びルホニルクロライド(2.0mL)を加えた。この反応液を氷冷下で10分間攪拌した後、室温で2時間攪拌した。室温下で1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン(10.1mL)を加え、約40時間攪拌した。減圧下で溶媒を留去して得られた残渣をシリカゲルカラムクロマトグラフィー(溶出溶媒:塩化メチレン/メタノール=100/0→97/3)にて精製し、標題化合物(1.8g)を得た。
1H-NMR (CDCl3) δ: 0.92 (3H, t, J = 7.4 Hz), 1.74-1.83 (2H, m), 2.32-2.36 (2H, m), 3.38 (2H, td, J = 7.1, 2.5 Hz), 3.55 (2H, s), 3.82 (2H, t, J = 7.2 Hz), 5.57 (1H, br s), 6.41-6.43 (1H, m), 6.75 (1H, s), 7.37 (1H, s).
LRMS (ESI) m/z 220 [M + H]+
[Step 2] 3-[(1-Propyl-1H-imidazol-4-yl) methyl] -5,6-dihydropyridin-2 (1H) -one The compound obtained in Step 1 (4.0 g) was converted into methylene chloride. (20 mL) and triethylamine (4.7 mL), methanes and sulfonyl chloride (2.0 mL) were added under ice cooling. The reaction solution was stirred for 10 minutes under ice cooling, and then stirred at room temperature for 2 hours. 1,8-diazabicyclo [5.4.0] undec-7-ene (10.1 mL) was added at room temperature, and the mixture was stirred for about 40 hours. The residue obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 100/0 → 97/3) to obtain the title compound (1.8 g). .
1 H-NMR (CDCl 3 ) δ: 0.92 (3H, t, J = 7.4 Hz), 1.74-1.83 (2H, m), 2.32-2.36 (2H, m), 3.38 (2H, td, J = 7.1, 2.5 Hz), 3.55 (2H, s), 3.82 (2H, t, J = 7.2 Hz), 5.57 (1H, br s), 6.41-6.43 (1H, m), 6.75 (1H, s), 7.37 (1H , s).
LRMS (ESI) m / z 220 [M + H] + .
 [工程3]6-オキソ-5-[(1-プロピル-1H-イミダゾール-4-イル)メチル]-3,6-ジヒドロピリジン-1(2H)-カルボン酸tert-ブチル
 工程2で得られた化合物(1.8g)を塩化メチレン(50mL)に溶解し、この溶液にジ-tert-ブチルジカーボネート(2.0g)及び4-ジメチルアミノピリジン(1.0g)を加え、窒素雰囲気下、室温で一昼夜攪拌した。さらにジ-tert-ブチルジカーボネート(3.4g)を追加して、32時間攪拌した。減圧下で溶媒を留去して得られた残渣をそのままシリカゲルカラムクロマトグラフィー(溶出溶媒:塩化メチレン/メタノール=100/0→96/4)にて精製し、標記化合物(2.0g)を得た。
1H-NMR (CDCl3) δ: 0.92 (3H, t, J = 7.3 Hz), 1.54 (9H, s), 1.75-1.82 (2H, m), 2.34-2.37 (2H, m), 3.56 (2H, s), 3.80-3.83 (4H, m), 6.60 (1H, t, J = 4.2 Hz), 6.75 (1H, s), 7.35 (1H, s).
LRMS (ESI) m/z 320 [M + H]+
[Step 3] 6-Oxo-5-[(1-propyl-1H-imidazol-4-yl) methyl] -3,6-dihydropyridine-1 (2H) -tert-butyl carboxylate Compound obtained in Step 2 (1.8 g) was dissolved in methylene chloride (50 mL), and di-tert-butyl dicarbonate (2.0 g) and 4-dimethylaminopyridine (1.0 g) were added to the solution, and the mixture was stirred at room temperature under a nitrogen atmosphere. Stir all day and night. Di-tert-butyl dicarbonate (3.4 g) was further added, and the mixture was stirred for 32 hours. The residue obtained by distilling off the solvent under reduced pressure was directly purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 100/0 → 96/4) to obtain the title compound (2.0 g). It was.
1 H-NMR (CDCl 3 ) δ: 0.92 (3H, t, J = 7.3 Hz), 1.54 (9H, s), 1.75-1.82 (2H, m), 2.34-2.37 (2H, m), 3.56 (2H , s), 3.80-3.83 (4H, m), 6.60 (1H, t, J = 4.2 Hz), 6.75 (1H, s), 7.35 (1H, s).
LRMS (ESI) m / z 320 [M + H] + .
 [工程4](2Z)-5-アミノ-2-[(1-プロピル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸
 工程3で得られた化合物(1.6g)をテトラヒドロフラン/水の混合溶媒(2/1,20mL)に溶解し、この溶液に水酸化リチウム一水和物(630mg)を加えて室温下で4時間攪拌した。減圧下で濃縮後、得られた残渣に氷冷下で5規定塩酸水溶液(10mL)を加え、同温で10分間、さらに室温下で1時間攪拌した。反応溶液を減圧下で濃縮後、得られた残渣を少量の水に溶解し、イオン交換樹脂(DOWEX(登録商標)50Wx8/100-200Mesh/H form、20g)を入れたカラムに吸着させた。カラム下部からの溶出液がpH試験紙にて中性となるまでイオン交換水で樹脂を十分洗浄した後、28%アンモニア水をイオン交換水で10倍希釈した溶液で溶出した。溶出液を塩化メチレンで洗浄し、水層を減圧下で濃縮した。得られた残渣にアセトンを加えて固化させ、粉末を濾取し、乾燥して標題化合物(0.9g)を得た。
1H-NMR (CD3OD) δ: 0.90 (3H, t, J = 7.2 Hz), 1.73-1.83 (2H, m), 2.46-2.53 (2H, m), 2.97-3.00 (2H, m), 3.50 (2H, s), 3.90 (2H, t, J = 7.0 Hz), 5.36-5.41 (1H, m), 6.89 (1H, s), 7.54 (1H, s).
LRMS (ESI) m/z 238 [M + H]+.
HRMS (ESI) Calcd for C12H20N3O2: 238.15555. Found: 238.15492. 
Anal. Calcd for C12H19N3O2・3/5H2O: C, 58.14; H, 8.26; N, 17.08. Found: C, 58.09; H, 8.21; N, 16.94。
[Step 4] (2Z) -5-amino-2-[(1-propyl-1H-imidazol-4-yl) methyl] pent-2-enoic acid The compound (1.6 g) obtained in Step 3 was converted to tetrahydrofuran. / Water mixed solvent (2/1, 20 mL), lithium hydroxide monohydrate (630 mg) was added to this solution, and the mixture was stirred at room temperature for 4 hours. After concentration under reduced pressure, 5N aqueous hydrochloric acid solution (10 mL) was added to the obtained residue under ice cooling, and the mixture was stirred at the same temperature for 10 min and further at room temperature for 1 hr. After the reaction solution was concentrated under reduced pressure, the obtained residue was dissolved in a small amount of water and adsorbed on a column containing an ion exchange resin (DOWEX® 50Wx8 / 100-200 Mesh / H form, 20 g). The resin was sufficiently washed with ion-exchanged water until the eluate from the lower part of the column became neutral with pH test paper, and then eluted with a solution obtained by diluting 28% ammonia water 10-fold with ion-exchanged water. The eluate was washed with methylene chloride, and the aqueous layer was concentrated under reduced pressure. Acetone was added to the obtained residue to solidify, and the powder was collected by filtration and dried to obtain the title compound (0.9 g).
1 H-NMR (CD 3 OD) δ: 0.90 (3H, t, J = 7.2 Hz), 1.73-1.83 (2H, m), 2.46-2.53 (2H, m), 2.97-3.00 (2H, m), 3.50 (2H, s), 3.90 (2H, t, J = 7.0 Hz), 5.36-5.41 (1H, m), 6.89 (1H, s), 7.54 (1H, s).
LRMS (ESI) m / z 238 [M + H] +.
HRMS (ESI) Calcd for C 12 H 20 N 3 O 2 : 238.15555. Found: 238.15492.
Anal. Calcd for C12H19N3O2 · 3 / 5H 2 O: C, 58.14; H, 8.26; N, 17.08. Found: C, 58.09; H, 8.21; N, 16.94.
 [実施例6](2Z)-5-アミノ-2-{[1-(3,3-ジメチルブチル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 [工程1]4-ヒドロキシ-3-[(1-トリチル-1H-イミダゾール-4-イル)メチル]ピペリジン-2-オン
 実施例5の工程1と同様にして、3-(1-トリチル-1H-イミダゾール-4-イル)プロピオン酸メチル(Bioorg.Med.Chem.2005年,13巻,6309頁)(8.90g)及び(3-オキソプロピル)カルバミン酸ベンジル(9.30g)から、標題化合物(1.77g)を得た。
1H NMR (CDCl3) δ: 1.80-1.90 (1H, m), 2.00-2.06 (0.5H, m), 2.15-2.20 (0.5H, m), 2.43-2.53 (1H, m), 2.77 (0.5H, dd, J = 15.4, 8.8 Hz), 2.92 (0.5H, dd, J = 14.9, 10.6 Hz), 3.18 (0.5H, dd, J = 14.9, 4.7 Hz), 3.18-3.25 (0.5H, m), 3.27-3.32 (1H, m), 3.56-3.60 (0.5H, m), 3.65-3.72 (0.5H, m), 3.93-3.99 (0.5H, m), 4.07-4.10 (0.5H, m), 5.69 (0.5H, s), 5.75 (0.5H, s), 7.10-7.13 (6H, m), 7.31-7.36 (10H, m)。
[Example 6] (2Z) -5-amino-2-{[1- (3,3-dimethylbutyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid [Step 1] 4- Hydroxy-3-[(1-trityl-1H-imidazol-4-yl) methyl] piperidin-2-one In the same manner as in Step 1 of Example 5, 3- (1-trityl-1H-imidazol-4-yl) ) From methyl propionate (Bioorg. Med. Chem. 2005, 13, 6309) (8.90 g) and benzyl (3-oxopropyl) carbamate (9.30 g), the title compound (1.77 g) was obtained. Obtained.
1 H NMR (CDCl 3 ) δ: 1.80-1.90 (1H, m), 2.00-2.06 (0.5H, m), 2.15-2.20 (0.5H, m), 2.43-2.53 (1H, m), 2.77 (0.5 H, dd, J = 15.4, 8.8 Hz), 2.92 (0.5H, dd, J = 14.9, 10.6 Hz), 3.18 (0.5H, dd, J = 14.9, 4.7 Hz), 3.18-3.25 (0.5H, m ), 3.27-3.32 (1H, m), 3.56-3.60 (0.5H, m), 3.65-3.72 (0.5H, m), 3.93-3.99 (0.5H, m), 4.07-4.10 (0.5H, m) , 5.69 (0.5H, s), 5.75 (0.5H, s), 7.10-7.13 (6H, m), 7.31-7.36 (10H, m).
 [工程2]3-[(1-トリチル-1H-イミダゾール-4-イル)メチル]-5,6-ジヒドロピリジン-2(1H)-オン
 実施例5の工程2と同様にして、本実施例の工程1で得られた化合物(4.22g)から、標題化合物(2.43g)を得た。
1H NMR (CDCl3) δ: 2.30-2.35 (2H, m), 3.37 (2H, td, J = 7.0, 2.7 Hz), 3.53 (2H, s), 5.45 (1H, br s), 6.32 (1H, t, J = 4.3 Hz), 6.66 (1H, d, J = 1.2 Hz), 7.13-7.15 (6H, m), 7.31-7.33 (9H, m), 7.37 (1H, d, J = 1.2 Hz)。
[Step 2] 3-[(1-Trityl-1H-imidazol-4-yl) methyl] -5,6-dihydropyridin-2 (1H) -one In the same manner as in Step 2 of Example 5, The title compound (2.43 g) was obtained from the compound (4.22 g) obtained in Step 1.
1 H NMR (CDCl 3 ) δ: 2.30-2.35 (2H, m), 3.37 (2H, td, J = 7.0, 2.7 Hz), 3.53 (2H, s), 5.45 (1H, br s), 6.32 (1H , t, J = 4.3 Hz), 6.66 (1H, d, J = 1.2 Hz), 7.13-7.15 (6H, m), 7.31-7.33 (9H, m), 7.37 (1H, d, J = 1.2 Hz) .
 [工程3]6-オキソ-5-[(1-トリチル-1H-イミダゾール-4-イル)メチル]-3,6-ジヒドロピリジン-1(2H)-カルボン酸tert-ブチル
 実施例5の工程3と同様にして、本実施例の工程2で得た化合物(2.43g)から、標題化合物(2.82g)を得た。
1H NMR (CDCl3) δ: 1.53 (9H, s), 2.33-2.37 (2H, m), 3.54 (2H, s), 3.80 (2H, t, J = 6.5 Hz), 6.50 (1H, t, J = 4.3 Hz), 6.66 (1H, d, J = 1.6 Hz), 7.12-7.15 (6H, m), 7.31-7.34 (9H, m), 7.36 (1H, d, J = 1.6 Hz)。
[Step 3] 6-oxo-5-[(1-trityl-1H-imidazol-4-yl) methyl] -3,6-dihydropyridine-1 (2H) -tert-butyl carboxylate Step 3 of Example 5 and Similarly, the title compound (2.82 g) was obtained from the compound (2.43 g) obtained in Step 2 of this example.
1 H NMR (CDCl 3 ) δ: 1.53 (9H, s), 2.33-2.37 (2H, m), 3.54 (2H, s), 3.80 (2H, t, J = 6.5 Hz), 6.50 (1H, t, J = 4.3 Hz), 6.66 (1H, d, J = 1.6 Hz), 7.12-7.15 (6H, m), 7.31-7.34 (9H, m), 7.36 (1H, d, J = 1.6 Hz).
 [工程4](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-[(1-トリチル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸tert-ブチル
 工程3で得た化合物(500mg)をテトラヒドロフラン(6mL)及び水(3L)の混合溶媒に溶解させ、室温攪拌下、水酸化リチウム一水和物(121mg)を加えた。3時間攪拌した後さらに水酸化リチウム一水和物(121mg)を加えて終夜攪拌した。反応液を濃縮後、水を加え、ジエチルエーテルで洗浄し、水層を1M塩酸で中和した。塩化メチレンで抽出した後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮した後、得られた残渣をベンゼン(8mL)に溶解させ、80℃加熱攪拌下,N,N-ジメチルホルムアミドジ-tert-ブチルアセタール(1.15mL)をゆっくり滴下した。そのままの温度で2時間攪拌した後、N,N-ジメチルホルムアミドジ-tert-ブチルアセタール(1.15mL)を追加で加え、さらに3時間攪拌した。放冷後、反応液を水、1M水酸化ナトリウム水溶液、飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより、標題化合物(205mg)を得た。
1H NMR (CDCl3) δ: 1.38 (9H, s), 1.40 (9H, s), 2.57-2.62 (2H, m), 3.17-3.22 (2H, m), 3.48 (2H, s), 4.92 (1H, br s), 5.83-5.88 (1H, m), 6.58 (1H, s), 7.11-7.14 (6H, m), 7.31-7.33 (9H, m), 7.36 (1H, s)。
[Step 4] (2Z) -5-[(tert-Butoxycarbonyl) amino] -2-[(1-trityl-1H-imidazol-4-yl) methyl] pent-2-enoic acid tert-butyl The obtained compound (500 mg) was dissolved in a mixed solvent of tetrahydrofuran (6 mL) and water (3 L), and lithium hydroxide monohydrate (121 mg) was added with stirring at room temperature. After stirring for 3 hours, lithium hydroxide monohydrate (121 mg) was further added and stirred overnight. The reaction mixture was concentrated, water was added, washed with diethyl ether, and the aqueous layer was neutralized with 1M hydrochloric acid. After extraction with methylene chloride, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting residue was dissolved in benzene (8 mL), and N, N-dimethylformamide di-tert-butylacetal (1.15 mL) was slowly added dropwise with stirring at 80 ° C. After stirring at the same temperature for 2 hours, N, N-dimethylformamide di-tert-butylacetal (1.15 mL) was further added, and the mixture was further stirred for 3 hours. After allowing to cool, the reaction mixture was washed with water, 1M aqueous sodium hydroxide solution, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography to obtain the title compound (205 mg).
1 H NMR (CDCl 3 ) δ: 1.38 (9H, s), 1.40 (9H, s), 2.57-2.62 (2H, m), 3.17-3.22 (2H, m), 3.48 (2H, s), 4.92 ( 1H, br s), 5.83-5.88 (1H, m), 6.58 (1H, s), 7.11-7.14 (6H, m), 7.31-7.33 (9H, m), 7.36 (1H, s).
 [工程5](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-(1H-イミダゾール-4-イルメチル)ペンタ-2-エン酸tert-ブチル
 工程4で得た化合物(205mg)を90%酢酸中で60℃にて2時間攪拌した後、反応液に炭酸水素ナトリウム水溶液を加えて中和した。塩化メチレンで抽出し、有機層を無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより、標題化合物(80.0mg)を得た。
1H NMR (CDCl3) δ: 1.44 (18H, s), 2.56-2.62 (2H, m), 3.27-3.32 (2H, m), 3.53 (2H, s), 4.85 (1H, br s), 5.97 (1H, t, J = 8.0 Hz), 6.83 (1H, s), 7.60 (1H, s)。
[Step 5] (2Z) -5-[(tert-Butoxycarbonyl) amino] -2- (1H-imidazol-4-ylmethyl) pent-2-enoic acid tert-butyl Compound (205 mg) obtained in Step 4 was obtained. After stirring in 90% acetic acid at 60 ° C. for 2 hours, the reaction solution was neutralized by adding an aqueous sodium hydrogen carbonate solution. Extraction with methylene chloride was performed, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography to obtain the title compound (80.0 mg).
1 H NMR (CDCl 3 ) δ: 1.44 (18H, s), 2.56-2.62 (2H, m), 3.27-3.32 (2H, m), 3.53 (2H, s), 4.85 (1H, br s), 5.97 (1H, t, J = 8.0 Hz), 6.83 (1H, s), 7.60 (1H, s).
 [工程6](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-{[1-(3,3-ジメチルブチル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸tert-ブチル
 工程5で得た化合物(80.0mg)のN,N-ジメチルホルムアミド溶液(3mL)に、0℃攪拌下、水素化ナトリウム(63%,9.5mg)を加え、続いて参考例7で得た化合物(53.1mg)のN,N-ジメチルホルムアミド溶液(0.5mL)を加えた後、室温に昇温して終夜攪拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄した。ろ過し、減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより、標題化合物(50.5mg)を得た。
1H NMR (CDCl3) δ: 0.96 (9H, s), 1.43 (9H, s), 1.44 (9H, s), 1.65-1.69 (2H, m), 2.57-2.62 (2H, m), 3.20-3.25 (2H, m), 3.51 (2H, s), 3.84-3.88 (2H, m), 4.98 (1H, br s), 5.88 (1H, t, J = 7.8 Hz), 6.65 (1H, s), 7.40 (1H, s)。
[Step 6] (2Z) -5-[(tert-butoxycarbonyl) amino] -2-{[1- (3,3-dimethylbutyl) -1H-imidazol-4-yl] methyl} pent-2-ene Tert-Butyl acid Sodium hydride (63%, 9.5 mg) was added to a solution of the compound obtained in Step 5 (80.0 mg) in N, N-dimethylformamide (3 mL) with stirring at 0 ° C., followed by reference. A solution of the compound obtained in Example 7 (53.1 mg) in N, N-dimethylformamide (0.5 mL) was added, and the mixture was warmed to room temperature and stirred overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine. After filtration and concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography to obtain the title compound (50.5 mg).
1 H NMR (CDCl 3 ) δ: 0.96 (9H, s), 1.43 (9H, s), 1.44 (9H, s), 1.65-1.69 (2H, m), 2.57-2.62 (2H, m), 3.20- 3.25 (2H, m), 3.51 (2H, s), 3.84-3.88 (2H, m), 4.98 (1H, br s), 5.88 (1H, t, J = 7.8 Hz), 6.65 (1H, s), 7.40 (1H, s).
 [工程7](2Z)-5-アミノ-2-{[1-(3,3-ジメチルブチル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 工程6で得た化合物(50.5mg)を5M塩酸(3mL)中で室温にて2時間、40℃にて30分間攪拌した。反応液を濃縮後、残渣を陽イオン交換樹脂(DOWEX 50WX8-200、溶出溶媒:3%アンモニア水)にて精製することにより、標題化合物(26.1mg)を得た。
1H NMR (CD3OD) δ: 0.97 (9H, s), 1.68-1.72 (2H, m), 2.48-2.51 (2H, m), 2.98-2.99 (2H, m), 3.49 (2H, s), 3.94-3.99 (2H, m), 5.39 (1H, t, J = 8.6 Hz), 6.90 (1H, s), 7.58 (1H, s).
LRMS (ESI): m/z 280 [M + H]+, 302 [M + Na]+.
HRMS (ESI) m/z calcd for C15H26N3O2: 280.20250 [M + H]+; found: 280.20165。
[Step 7] (2Z) -5-amino-2-{[1- (3,3-dimethylbutyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid Compound obtained in Step 6 ( 50.5 mg) was stirred in 5 M hydrochloric acid (3 mL) at room temperature for 2 hours and at 40 ° C. for 30 minutes. The reaction mixture was concentrated, and the residue was purified by cation exchange resin (DOWEX 50WX8-200, elution solvent: 3% aqueous ammonia) to give the title compound (26.1 mg).
1 H NMR (CD 3 OD) δ: 0.97 (9H, s), 1.68-1.72 (2H, m), 2.48-2.51 (2H, m), 2.98-2.99 (2H, m), 3.49 (2H, s) , 3.94-3.99 (2H, m), 5.39 (1H, t, J = 8.6 Hz), 6.90 (1H, s), 7.58 (1H, s).
LRMS (ESI): m / z 280 [M + H] + , 302 [M + Na] + .
HRMS (ESI) m / z calcd for C 15 H 26 N 3 O 2 : 280.20250 [M + H] + ; found: 280.20165.
 [実施例7](2Z)-5-アミノ-2-[(1-フェニル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸
 参考例6及び実施例5の方法と同様にして、参考例8で得た化合物から標題化合物(175mg)を得た。
1H NMR (CD3OD) δ: 2.51-2.55 (2H, m), 3.01 (2H, t, J = 6.3 Hz), 3.60 (2H, s), 5.49 (1H, t, J = 8.3 Hz), 7.35-7.39 (2H, m), 7.48-7.54 (4H, m), 8.06 (1H, d, J = 1.5 Hz).
LRMS (ESI): m/z 272 [M + H]+, 294 [M + Na]+.
HRMS (ESI) m/z calcd for C15H18N3O2: 272.13990 [M + H]+; found: 272.13922。
[Example 7] (2Z) -5-amino-2-[(1-phenyl-1H-imidazol-4-yl) methyl] pent-2-enoic acid In the same manner as in Reference Example 6 and Example 5. The title compound (175 mg) was obtained from the compound obtained in Reference Example 8.
1 H NMR (CD 3 OD) δ: 2.51-2.55 (2H, m), 3.01 (2H, t, J = 6.3 Hz), 3.60 (2H, s), 5.49 (1H, t, J = 8.3 Hz), 7.35-7.39 (2H, m), 7.48-7.54 (4H, m), 8.06 (1H, d, J = 1.5 Hz).
LRMS (ESI): m / z 272 [M + H] + , 294 [M + Na] + .
HRMS (ESI) m / z calcd for C 15 H 18 N 3 O 2 : 272.13990 [M + H] + ; found: 272.13922.
 [実施例8](2Z)-5-アミノ-2-{[1-(3,3-ジメチルブチル)-1H-イミダゾール-4-イル]メチル}-4-メチルペンタ-2-エン酸
 [工程1]3-{[1-(3,3-ジメチルブチル)-1H-イミダゾール-4-イル]メチル}-5-メチル-5,6-ジヒドロピリジン-2(1H)-オン
 テトラヒドロフラン(40mL)にリチウムビス(トリメチルシリル)アミドのテトラヒドロフラン溶液(1M、7.87mL)を加えた後、-78℃攪拌下、参考例10で得た化合物(1.25g)のテトラヒドロフラン溶液(20mL)を加えた。そのままの温度にて50分間攪拌した後、(2-メチル-3-オキソプロピル)カルバミン酸tert-ブチル(Org.Lett.2010年、12巻、3192頁)(1.67g)のテトラヒドロフラン溶液(20mL)を加えた。そのままの温度にて30分間攪拌した後、0℃に昇温して1時間攪拌した。反応液に塩化アンモニウム水溶液を加えて分液し、酢酸エチルで抽出した後、有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮することにより得られた残渣を塩化メチレン(15mL)に溶解させ、トリフルオロ酢酸(15mL)を加えて室温にて3時間攪拌した。反応液を減圧濃縮することにより得られた残渣をトルエン(25mL)に溶解させ、0℃攪拌下、トリエチルアミン(15mL)を加え、室温にて3時間、45℃にて1時間攪拌した。反応液を減圧濃縮することにより得られた残渣を塩化メチレン(30mL)に溶解させ、0℃攪拌下、トリエチルアミン(1.45mL)及びメタンスルホニルクロリド(0.81mL)を加え、室温に昇温して5時間攪拌した。さらにトリエチルアミン(0.73mL)及びメタンスルホニルクロリド(0.41mL)を加えて終夜攪拌した。反応液を減圧濃縮した後、酢酸エチルを加え、有機層を飽和炭酸水素ナトリウム水溶液、飽和塩化アンモニウム水溶液及び飽和食塩水で洗浄した。洗浄後の各水層からそれぞれさらに塩化メチレンで抽出した後,有機層を全て合わせて無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより、目的物を茶色固体として得た(800mg)。
1H NMR (CDCl3) δ: 0.96 (9H, s), 1.07 (3H, d, J = 7.0 Hz), 1.68-1.72 (2H, m), 2.58-2.64 (1H, m), 3.08 (1H, ddd, J = 11.7, 9.4, 2.3 Hz), 3.39 (1H, ddd, J = 11.7, 5.9, 3.1 Hz), 3.49 (1H, d, J = 16.0 Hz), 3.56 (1H, d, J = 16.0 Hz), 3.84-3.88 (2H, m), 5.45 (1H, br s), 6.28 (1H, d, J = 2.7 Hz), 6.75 (1H, s), 7.38 (1H, s)。
[Example 8] (2Z) -5-amino-2-{[1- (3,3-dimethylbutyl) -1H-imidazol-4-yl] methyl} -4-methylpent-2-enoic acid [Step 1 ] 3-{[1- (3,3-Dimethylbutyl) -1H-imidazol-4-yl] methyl} -5-methyl-5,6-dihydropyridin-2 (1H) -one Lithium bis in tetrahydrofuran (40 mL) A tetrahydrofuran solution (1M, 7.87 mL) of (trimethylsilyl) amide was added, and then a tetrahydrofuran solution (20 mL) of the compound (1.25 g) obtained in Reference Example 10 was added with stirring at −78 ° C. After stirring at the same temperature for 50 minutes, a solution of tert-butyl (2-methyl-3-oxopropyl) carbamate (Org. Lett. 2010, 12, 3192) (1.67 g) in tetrahydrofuran (20 mL) ) Was added. After stirring for 30 minutes at the same temperature, the temperature was raised to 0 ° C. and stirring was performed for 1 hour. Aqueous ammonium chloride solution was added to the reaction solution, and the mixture was separated and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by filtration and concentration under reduced pressure was dissolved in methylene chloride (15 mL), trifluoroacetic acid (15 mL) was added, and the mixture was stirred at room temperature for 3 hr. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in toluene (25 mL), triethylamine (15 mL) was added with stirring at 0 ° C., and the mixture was stirred at room temperature for 3 hours and at 45 ° C. for 1 hour. The residue obtained by concentrating the reaction solution under reduced pressure was dissolved in methylene chloride (30 mL), triethylamine (1.45 mL) and methanesulfonyl chloride (0.81 mL) were added with stirring at 0 ° C., and the mixture was warmed to room temperature. And stirred for 5 hours. Further triethylamine (0.73 mL) and methanesulfonyl chloride (0.41 mL) were added and stirred overnight. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, saturated aqueous ammonium chloride solution and saturated brine. Each aqueous layer after washing was further extracted with methylene chloride, and all the organic layers were combined and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the obtained crude product was purified by silica gel column chromatography to obtain the desired product as a brown solid (800 mg).
1 H NMR (CDCl 3 ) δ: 0.96 (9H, s), 1.07 (3H, d, J = 7.0 Hz), 1.68-1.72 (2H, m), 2.58-2.64 (1H, m), 3.08 (1H, ddd, J = 11.7, 9.4, 2.3 Hz), 3.39 (1H, ddd, J = 11.7, 5.9, 3.1 Hz), 3.49 (1H, d, J = 16.0 Hz), 3.56 (1H, d, J = 16.0 Hz ), 3.84-3.88 (2H, m), 5.45 (1H, br s), 6.28 (1H, d, J = 2.7 Hz), 6.75 (1H, s), 7.38 (1H, s).
 [工程2](2Z)-5-アミノ-2-{[1-(3,3-ジメチルブチル)-1H-イミダゾール-4-イル]メチル}-4-メチルペンタ-2-エン酸
 実施例5の工程3及び工程4と同様にして、本実施例の工程1で得た化合物から、目的物を薄黄色固体として得た(129mg)。
1H NMR (CD3OD) δ: 0.97 (9H, s), 0.99 (3H, d, J = 6.6 Hz), 1.68-1.72 (2H, m), 2.56 (1H, dd, J = 12.1, 11.7 Hz), 3.00 (1H, dd, J = 11.7, 4.7 Hz), 3.00-3.11 (1H, m), 3.33 (1H, d, J = 15.6 Hz), 3.64 (1H, d, J = 15.6 Hz), 3.95-3.99 (2H, m), 5.09 (1H, d, J = 9.8 Hz), 6.91 (1H, br s), 7.59 (1H, br s).
LRMS (ESI): m/z 294 [M + H]+, 316 [M + Na]+.
HRMS (ESI) m/z calcd for C16H27N3O2: 294.21815 [M + H]+; found: 294.21560。
[Step 2] (2Z) -5-amino-2-{[1- (3,3-dimethylbutyl) -1H-imidazol-4-yl] methyl} -4-methylpent-2-enoic acid of Example 5 In the same manner as in Step 3 and Step 4, the target product was obtained as a pale yellow solid from the compound obtained in Step 1 of this example (129 mg).
1 H NMR (CD 3 OD) δ: 0.97 (9H, s), 0.99 (3H, d, J = 6.6 Hz), 1.68-1.72 (2H, m), 2.56 (1H, dd, J = 12.1, 11.7 Hz ), 3.00 (1H, dd, J = 11.7, 4.7 Hz), 3.00-3.11 (1H, m), 3.33 (1H, d, J = 15.6 Hz), 3.64 (1H, d, J = 15.6 Hz), 3.95 -3.99 (2H, m), 5.09 (1H, d, J = 9.8 Hz), 6.91 (1H, br s), 7.59 (1H, br s).
LRMS (ESI): m / z 294 [M + H] + , 316 [M + Na] + .
HRMS (ESI) m / z calcd for C 16 H 27 N 3 O 2 : 294.21815 [M + H] + ; found: 294.21560.
 [実施例9](2Z)-5-アミノ-2-[(1-シクロヘキシル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸
 実施例5と同様にして、参考例12で得た化合物から、標題化合物(343mg)を得た。
1H NMR (CD3OD) δ: 1.23-1.33 (1H, m), 1.39-1.50 (2H, m), 1.61-1.75 (3H, m), 1.85-1.91 (2H, m), 2.01-2.06 (2H, m), 2.47-2.52 (2H, m), 2.98 (2H, t, J = 6.3 Hz), 3.49 (2H, s), 3.96 (1H, tt, J = 11.7, 3.8 Hz), 5.37-5.42 (1H, m), 6.95 (1H, d, J = 1.6 Hz), 7.62 (1H, d, J = 1.6 Hz).
LRMS (ESI): m/z 278 [M + H]+, 300 [M + Na]+.
HRMS (ESI) m/z calcd for C15H24N3O2: 278.18685 [M + H]+; found: 278.18589。
Example 9 (2Z) -5-amino-2-[(1-cyclohexyl-1H-imidazol-4-yl) methyl] pent-2-enoic acid Obtained in Reference Example 12 in the same manner as in Example 5. The title compound (343 mg) was obtained from the obtained compound.
1 H NMR (CD 3 OD) δ: 1.23-1.33 (1H, m), 1.39-1.50 (2H, m), 1.61-1.75 (3H, m), 1.85-1.91 (2H, m), 2.01-2.06 ( 2H, m), 2.47-2.52 (2H, m), 2.98 (2H, t, J = 6.3 Hz), 3.49 (2H, s), 3.96 (1H, tt, J = 11.7, 3.8 Hz), 5.37-5.42 (1H, m), 6.95 (1H, d, J = 1.6 Hz), 7.62 (1H, d, J = 1.6 Hz).
LRMS (ESI): m / z 278 [M + H] + , 300 [M + Na] + .
HRMS (ESI) m / z calcd for C 15 H 24 N 3 O 2 : 278.18685 [M + H] + ; found: 278.18589.
 [実施例10](2Z)-5-アミノ-2-[(1-{[5-(5-クロロ-2-チエニル)イソオキサゾール-3-イル]メチル}-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸
 [工程1](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-[(1-トリチル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸メチル
 実施例6の工程3で得た化合物(3.72g)をテトラヒドロフラン(37mL)に溶解させ、室温攪拌下、水酸化リチウム一水和物(0.90g)を含む水(20mL)を加えた。室温で三日間攪拌した後、塩化メチレン及び10%クエン酸水溶液を加えて分液し、水層を塩化メチレンで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧下溶媒留去した。得られた残渣をテトラヒドロフラン(10mL)及びメタノール(10mL)の混合溶媒に溶解し、トリメチルシリルジアゾメタン(2Mへキサン溶液、5.37mL)を加えて室温で1時間撹拌した。減圧下溶媒留去し、シリカゲルクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=2/92)で精製して標題化合物(2.56g)を得た。
1H-NMR (CDCl3) δ: 1.38 (9H, s), 2.61 (2H, q, J = 6.9 Hz), 3.18 (2H, dt, J = 7.6, 6.9 Hz), 3.50 (2H, s), 3.60 (3H, s), 4.84 (1H, br s), 5.93 (1H, t, J = 7.6 Hz), 6.51 (1H, d, J = 1.2 Hz), 7.08-7.13 (6H, m), 7.28-7.33 (10H, m).
LRMS (ESI): m/z 552 [M + H]+, 574 [M + Na]+
Example 10 (2Z) -5-amino-2-[(1-{[5- (5-chloro-2-thienyl) isoxazol-3-yl] methyl} -1H-imidazol-4-yl) [Methyl] pent-2-enoic acid [Step 1] (2Z) -5-[(tert-butoxycarbonyl) amino] -2-[(1-trityl-1H-imidazol-4-yl) methyl] pent-2- Methyl enoate The compound (3.72 g) obtained in Step 3 of Example 6 was dissolved in tetrahydrofuran (37 mL), and water (20 mL) containing lithium hydroxide monohydrate (0.90 g) was added with stirring at room temperature. added. After stirring at room temperature for 3 days, methylene chloride and a 10% aqueous citric acid solution were added for liquid separation, and the aqueous layer was extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and methanol (10 mL), trimethylsilyldiazomethane (2M hexane solution, 5.37 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent: methanol / methylene chloride = 2/92) to obtain the title compound (2.56 g).
1 H-NMR (CDCl 3 ) δ: 1.38 (9H, s), 2.61 (2H, q, J = 6.9 Hz), 3.18 (2H, dt, J = 7.6, 6.9 Hz), 3.50 (2H, s), 3.60 (3H, s), 4.84 (1H, br s), 5.93 (1H, t, J = 7.6 Hz), 6.51 (1H, d, J = 1.2 Hz), 7.08-7.13 (6H, m), 7.28- 7.33 (10H, m).
LRMS (ESI): m / z 552 [M + H] + , 574 [M + Na] + .
 [工程2](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-(1H-イミダゾール-4-イルメチル)ペンタ-2-エン酸メチル
 実施例6の工程5と同様にして、本実施例の工程1で得た化合物(2.56g)から標題化合物(1.26g)を得た。
1H-NMR (CDCl3) δ: 1.42 (9H, s), 2.62 (2H, q, J = 6.8 Hz), 3.21-3.28 (2H, m), 3.56 (2H, s), 3.70 (3H, s), 4.86 (1H, br s), 6.02 (1H, t, J = 7.8 Hz), 6.78 (1H, d, J = 0.8 Hz), 7.53 (1H, d, J = 0.8 Hz).
LRMS (ESI): m/z 310 [M + H]+, 332 [M + Na]+
[Step 2] Methyl (2Z) -5-[(tert-butoxycarbonyl) amino] -2- (1H-imidazol-4-ylmethyl) pent-2-enoate In the same manner as in Step 5 of Example 6, The title compound (1.26 g) was obtained from the compound (2.56 g) obtained in Step 1 of the Example.
1 H-NMR (CDCl 3 ) δ: 1.42 (9H, s), 2.62 (2H, q, J = 6.8 Hz), 3.21-3.28 (2H, m), 3.56 (2H, s), 3.70 (3H, s ), 4.86 (1H, br s), 6.02 (1H, t, J = 7.8 Hz), 6.78 (1H, d, J = 0.8 Hz), 7.53 (1H, d, J = 0.8 Hz).
LRMS (ESI): m / z 310 [M + H] + , 332 [M + Na] + .
 [工程3](2Z)-5-アミノ-2-[(1-{[5-(5-クロロ-2-チエニル)イソオキサゾール-3-イル]メチル}-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸 塩酸塩
 本実施例の工程2で得た化合物(247mg)及び3-(ブロモメチル)-5-(5-クロロ-2-チエニル)イソオキサゾール(Journal of Medicinal Chemistry、2005年、48巻、4511頁)(223mg)を用いて、実施例6の工程6と同様の方法でアルキル化反応を行った。得られた粗生成物に5M塩酸(5mL)を加えて4時間過熱還流した。反応液を濃縮後,残渣を陽イオン交換樹脂(DOWEX 50WX8-200、溶出溶媒:3%アンモニア水)にて精製し、得られた化合物に塩酸を加えて濃縮することにより、標題化合物(124mg)を得た。
1H-NMR (CD3OD) δ: 2.89-2.97 (2H, m), 3.05-3.11 (2H, m), 3.72 (2H, s), 5.58 (2H, s), 6.28 (1H, t, J = 7.4 Hz), 6.77 (1H, s), 7.11 (1H, d, J = 3.9 Hz), 7.46 (1H, d, J = 3.9 Hz), 7.50 (1H, br s), 9.02 (1H, br s).
LRMS (ESI): m/z 393 [M + H]+, 415 [M + Na]+.
Anal. calcd for C17H17ClN4O3S・2.1HCl・1H2O: C, 41.89; H, 4.36; Cl, 22.55; N, 11.49; S, 6.58. Found: C, 41.85; H, 4.00; Cl, 22.67; N, 11.61; S, 6.71。
[Step 3] (2Z) -5-amino-2-[(1-{[5- (5-chloro-2-thienyl) isoxazol-3-yl] methyl} -1H-imidazol-4-yl) methyl ] Penta-2-enoic acid hydrochloride The compound obtained in Step 2 of this example (247 mg) and 3- (bromomethyl) -5- (5-chloro-2-thienyl) isoxazole (Journal of Medicinal Chemistry, 2005) 48, 4511) (223 mg), the alkylation reaction was carried out in the same manner as in Step 6 of Example 6. To the obtained crude product, 5M hydrochloric acid (5 mL) was added and heated to reflux for 4 hours. After concentrating the reaction solution, the residue was purified with a cation exchange resin (DOWEX 50WX8-200, elution solvent: 3% aqueous ammonia), and the resulting compound was concentrated by adding hydrochloric acid to give the title compound (124 mg). Got.
1 H-NMR (CD 3 OD) δ: 2.89-2.97 (2H, m), 3.05-3.11 (2H, m), 3.72 (2H, s), 5.58 (2H, s), 6.28 (1H, t, J = 7.4 Hz), 6.77 (1H, s), 7.11 (1H, d, J = 3.9 Hz), 7.46 (1H, d, J = 3.9 Hz), 7.50 (1H, br s), 9.02 (1H, br s ).
LRMS (ESI): m / z 393 [M + H] + , 415 [M + Na] + .
Anal.calcd for C 17 H 17 ClN 4 O 3 S ・ 2.1HCl ・ 1H 2 O: C, 41.89; H, 4.36; Cl, 22.55; N, 11.49; S, 6.58. Found: C, 41.85; H, 4.00 Cl, 22.67; N, 11.61; S, 6.71.
 [実施例11](2Z)-5-アミノ-2-{[1-(3-メチルフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 参考例8、参考例6及び実施例5の方法と同様にして、(2E)-3-(1H-イミダゾール-4-イル)アクリル酸メチル及び(3-メチルフェニル)ボロン酸から,標題化合物(250mg)を得た。
1H NMR (CD3OD) δ: 2.41 (3H, s), 2.50-2.57 (2H, m), 3.01 (2H, t, J = 6.3 Hz), 3.59 (2H, s), 5.49 (1H, t, J = 9.0 Hz), 7.18-7.21 (1H, m), 7.29-7.39 (4H, m), 8.04 (1H, d, J = 1.6 Hz).
LRMS (ESI): m/z 286 [M + H]+, 308 [M + Na]+.
HRMS (ESI) m/z calcd for C16H20N3O2: 286.15555 [M + H]+; found: 286.15738。
[Example 11] (2Z) -5-amino-2-{[1- (3-methylphenyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid Reference Example 8, Reference Example 6 and In the same manner as in Example 5, the title compound (250 mg) was obtained from methyl (2E) -3- (1H-imidazol-4-yl) acrylate and (3-methylphenyl) boronic acid.
1 H NMR (CD 3 OD) δ: 2.41 (3H, s), 2.50-2.57 (2H, m), 3.01 (2H, t, J = 6.3 Hz), 3.59 (2H, s), 5.49 (1H, t , J = 9.0 Hz), 7.18-7.21 (1H, m), 7.29-7.39 (4H, m), 8.04 (1H, d, J = 1.6 Hz).
LRMS (ESI): m / z 286 [M + H] + , 308 [M + Na] + .
HRMS (ESI) m / z calcd for C 16 H 20 N 3 O 2 : 286.15555 [M + H] + ; found: 286.15738.
 [実施例12](2Z)-5-アミノ-2-{[1-(3-メトキシフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 参考例8、参考例6及び実施例5の方法と同様にして、(2E)-3-(1H-イミダゾール-4-イル)アクリル酸メチル及び(3-メトキシフェニル)ボロン酸から、標題化合物(379mg)を得た。
1H NMR (CD3OD) δ: 2.51-2.55 (2H, m), 3.01 (2H, t, J = 6.3 Hz), 3.59 (2H, s), 3.85 (3H, s), 5.49 (1H, t, J = 8.3 Hz), 6.92-6.94 (1H, m), 7.07-7.10 (2H, m), 7.34-7.41 (2H, m), 8.06 (1H, d, J = 1.5 Hz).
LRMS (ESI): m/z 302 [M + H]+, 324 [M + Na]+.
HRMS (ESI) m/z calcd for C16H19N3O3Na: 324.13241 [M + Na]+; found: 324.13436。
[Example 12] (2Z) -5-amino-2-{[1- (3-methoxyphenyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid Reference Example 8, Reference Example 6 and In the same manner as in Example 5, the title compound (379 mg) was obtained from methyl (2E) -3- (1H-imidazol-4-yl) acrylate and (3-methoxyphenyl) boronic acid.
1 H NMR (CD 3 OD) δ: 2.51-2.55 (2H, m), 3.01 (2H, t, J = 6.3 Hz), 3.59 (2H, s), 3.85 (3H, s), 5.49 (1H, t , J = 8.3 Hz), 6.92-6.94 (1H, m), 7.07-7.10 (2H, m), 7.34-7.41 (2H, m), 8.06 (1H, d, J = 1.5 Hz).
LRMS (ESI): m / z 302 [M + H] + , 324 [M + Na] + .
HRMS (ESI) m / z calcd for C 16 H 19 N 3 O 3 Na: 324.13241 [M + Na] + ; found: 324.13436.
 [実施例13](2Z)-5-アミノ-2-({1-[3-(トリフルオロメチル)フェニル]-1H-イミダゾール-4-イル}メチル)ペンタ-2-エン酸
 参考例8、参考例6及び実施例5の方法と同様にして、(2E)-3-(1H-イミダゾール-4-イル)アクリル酸メチル及び[3-(トリフルオロメチル)フェニル]ボロン酸から,目的物を白色固体として得た(366mg)。
1H NMR (CD3OD) δ: 2.51-2.55 (2H, m), 2.99 (2H, t, J = 6.1 Hz), 3.60 (2H, s), 5.50 (1H, t, J = 8.1 Hz), 7.45 (1H, s), 7.67-7.73 (2H, m), 7.84 (1H, d, J = 7.8 Hz), 7.89 (1H, s), 8.19 (1H, s).
LRMS (ESI): m/z 340 [M + H]+.
HRMS (ESI) m/z calcd for C16H17F3N3O2: 340.12729 [M + H]+; found: 340.12745。
[Example 13] (2Z) -5-amino-2-({1- [3- (trifluoromethyl) phenyl] -1H-imidazol-4-yl} methyl) pent-2-enoic acid Reference Example 8, In the same manner as in Reference Example 6 and Example 5, the target product was obtained from methyl (2E) -3- (1H-imidazol-4-yl) acrylate and [3- (trifluoromethyl) phenyl] boronic acid. Obtained as a white solid (366 mg).
1 H NMR (CD 3 OD) δ: 2.51-2.55 (2H, m), 2.99 (2H, t, J = 6.1 Hz), 3.60 (2H, s), 5.50 (1H, t, J = 8.1 Hz), 7.45 (1H, s), 7.67-7.73 (2H, m), 7.84 (1H, d, J = 7.8 Hz), 7.89 (1H, s), 8.19 (1H, s).
LRMS (ESI): m / z 340 [M + H] + .
HRMS (ESI) m / z calcd for C 16 H 17 F 3 N 3 O 2 : 340.12729 [M + H] + ; found: 340.12745.
 [実施例14](2Z)-5-アミノ-2-[(1-ベンジル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸
 実施例10の工程3と同様にして、実施例10の工程2で得た化合物(150mg)及び塩化ベンジル(0.061mL)を用いて標題化合物(16.2mg)を得た。
1H-NMR (CD3OD) δ: 2.44-2.51 (2H, m), 2.97 (2H, t, J = 6.1 Hz), 3.49 (2H, s), 5.13 (2H, s), 5.39 (1H, t, J = 8.2 Hz), 6.89 (1H, s), 7.20-7.38 (5H, m), 7.64 (1H, s).
LRMS (ESI): m/z 286 [M + H]+.
HRMS (ESI) m/z calcd for C16H20N3O2: 286.15555 [M + H]+; found: 286.15587。
[Example 14] (2Z) -5-amino-2-[(1-benzyl-1H-imidazol-4-yl) methyl] pent-2-enoic acid In the same manner as in Step 3 of Example 10, The title compound (16.2 mg) was obtained using the compound obtained in Step 2 of 10 (150 mg) and benzyl chloride (0.061 mL).
1 H-NMR (CD 3 OD) δ: 2.44-2.51 (2H, m), 2.97 (2H, t, J = 6.1 Hz), 3.49 (2H, s), 5.13 (2H, s), 5.39 (1H, t, J = 8.2 Hz), 6.89 (1H, s), 7.20-7.38 (5H, m), 7.64 (1H, s).
LRMS (ESI): m / z 286 [M + H] + .
HRMS (ESI) m / z calcd for C 16 H 20 N 3 O 2 : 286.15555 [M + H] + ; found: 286.15587.
 [実施例15](2Z)-5-アミノ-2-{[1-(2-シクロヘキシルエチル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 実施例10の工程3と同様にして、実施例10の工程2で得た化合物(100mg)及び(2-ブロモエチル)シクロヘキサン(0.056mL)を用いて標題化合物(2.0mg)を得た。
1H-NMR (CD3OD) δ: 0.91-1.03 (2H, m), 1.14-1.32 (4H, m), 1.61-1.78 (7H, m), 2.46-2.53 (2H, m), 2.98 (2H, t, J = 6.3 Hz), 3.50 (2H, s), 3.93-4.00 (2H, m), 5.36-5.42 (1H, m), 6.90 (1H, s), 7.56 (1H, s).
LRMS (ESI): m/z 306 [M + H]+.
HRMS (ESI) m/z calcd for C17H27N3NaO2: 328.20010 [M + Na]+; found: 328.19939。
[Example 15] (2Z) -5-amino-2-{[1- (2-cyclohexylethyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid Same as Step 3 in Example 10 The title compound (2.0 mg) was obtained using the compound (100 mg) obtained in Step 2 of Example 10 and (2-bromoethyl) cyclohexane (0.056 mL).
1 H-NMR (CD 3 OD) δ: 0.91-1.03 (2H, m), 1.14-1.32 (4H, m), 1.61-1.78 (7H, m), 2.46-2.53 (2H, m), 2.98 (2H , t, J = 6.3 Hz), 3.50 (2H, s), 3.93-4.00 (2H, m), 5.36-5.42 (1H, m), 6.90 (1H, s), 7.56 (1H, s).
LRMS (ESI): m / z 306 [M + H] + .
HRMS (ESI) m / z calcd for C 17 H 27 N 3 NaO 2 : 328.20010 [M + Na] + ; found: 328.19939.
 [実施例16](2Z)-5-アミノ-2-{[1-(2-フェニルエチル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 実施例10の工程3と同様にして、実施例10の工程2で得た化合物(100mg)及び(2-ブロモエチル)ベンゼン(0.048mL)を用いて標題化合物(3.0mg)を得た。
1H-NMR (CD3OD) δ: 2.45-2.52 (2H, m), 2.97 (2H, t, J = 6.1 Hz), 3.03 (2H, t, J = 7.0 Hz), 3.47 (2H, s), 4.17 (2H, t, J = 7.0 Hz), 5.32 (1H, t, J = 8.0 Hz), 6.89 (1H, s), 7.09 (2H, d, J = 7.0 Hz), 7.15-7.30 (4H, m).
LRMS (ESI): m/z 300 [M + H]+.
HRMS (ESI) m/z calcd for C17H22N3O2: 300.17120 [M + Na]+; found: 300.17019。
[Example 16] (2Z) -5-amino-2-{[1- (2-phenylethyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid As in Step 3 of Example 10 The title compound (3.0 mg) was obtained using the compound (100 mg) obtained in Step 2 of Example 10 and (2-bromoethyl) benzene (0.048 mL).
1 H-NMR (CD 3 OD) δ: 2.45-2.52 (2H, m), 2.97 (2H, t, J = 6.1 Hz), 3.03 (2H, t, J = 7.0 Hz), 3.47 (2H, s) , 4.17 (2H, t, J = 7.0 Hz), 5.32 (1H, t, J = 8.0 Hz), 6.89 (1H, s), 7.09 (2H, d, J = 7.0 Hz), 7.15-7.30 (4H, m).
LRMS (ESI): m / z 300 [M + H] + .
HRMS (ESI) m / z calcd for C 17 H 22 N 3 O 2 : 300.17120 [M + Na] + ; found: 300.17019.
 [実施例17](2Z)-5-アミノ-2-{[1-(2-シクロプロピルエチル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 参考例6及び実施例5の方法と同様にして、参考例15で得られた化合物から、標題化合物(182mg)を得た。
1H NMR (CD3OD) δ: 0.00-0.04 (2H, m), 0.41-0.45 (2H, m), 0.58-0.66 (1H, m), 1.63 (2H, dt, J = 7.0, 6.6 Hz), 2.46-2.51 (2H, m), 2.95 (2H, t, J = 6.6 Hz), 3.50 (2H, s), 4.01 (2H, t, J = 7.0 Hz), 5.38 (1H, t, J = 8.2 Hz), 6.90 (1H, br s), 7.56 (1H, br s).
LRMS (ESI): m/z 264 [M + H]+, 286 [M + Na]+.
HRMS (ESI) m/z calcd for C14H22N3O2: 264.17120 [M + H]+; found: 264.17060。
Example 17 (2Z) -5-amino-2-{[1- (2-cyclopropylethyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid Reference Example 6 and Example 5 In the same manner as in the above, the title compound (182 mg) was obtained from the compound obtained in Reference Example 15.
1 H NMR (CD 3 OD) δ: 0.00-0.04 (2H, m), 0.41-0.45 (2H, m), 0.58-0.66 (1H, m), 1.63 (2H, dt, J = 7.0, 6.6 Hz) , 2.46-2.51 (2H, m), 2.95 (2H, t, J = 6.6 Hz), 3.50 (2H, s), 4.01 (2H, t, J = 7.0 Hz), 5.38 (1H, t, J = 8.2 Hz), 6.90 (1H, br s), 7.56 (1H, br s).
LRMS (ESI): m / z 264 [M + H] + , 286 [M + Na] + .
HRMS (ESI) m / z calcd for C 14 H 22 N 3 O 2 : 264.17120 [M + H] + ; found: 264.17060.
 [実施例18](2Z)-5-アミノ-2-[(1-シクロペンチル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸
 参考例6及び実施例5の方法と同様にして、参考例16で得られた化合物から、標題化合物(147mg)を得た。
1H NMR (CD3OD) δ: 1.68-1.88 (6H, m), 2.12-2.20 (2H, m), 2.47-2.52 (2H, m), 2.99 (2H, t, J = 6.3 Hz), 3.49 (2H, s), 4.46-4.53 (1H, m), 5.40 (1H, t, J = 8.2 Hz), 6.94 (1H, br s), 7.60 (1H, br s).
LRMS (ESI): m/z 264 [M + H]+, 286 [M + Na]+.
HRMS (ESI) m/z calcd for C14H22N3O2: 264.17120 [M + H]+; found: 264.17066。
[Example 18] (2Z) -5-amino-2-[(1-cyclopentyl-1H-imidazol-4-yl) methyl] pent-2-enoic acid In the same manner as in Reference Example 6 and Example 5. The title compound (147 mg) was obtained from the compound obtained in Reference Example 16.
1 H NMR (CD 3 OD) δ: 1.68-1.88 (6H, m), 2.12-2.20 (2H, m), 2.47-2.52 (2H, m), 2.99 (2H, t, J = 6.3 Hz), 3.49 (2H, s), 4.46-4.53 (1H, m), 5.40 (1H, t, J = 8.2 Hz), 6.94 (1H, br s), 7.60 (1H, br s).
LRMS (ESI): m / z 264 [M + H] + , 286 [M + Na] + .
HRMS (ESI) m / z calcd for C 14 H 22 N 3 O 2 : 264.17120 [M + H] + ; found: 264.17066.
 [実施例19](2Z)-5-アミノ-2-{[1-(テトラヒドロ-2H-ピラン-4-イル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 参考例6及び実施例5の方法と同様にして、参考例17で得られた化合物から、標題化合物(184mg)を得た。
1H NMR (CD3OD) δ: 1.91-2.00 (4H, m), 2.46-2.51 (2H, m), 2.93 (2H, t, J = 6.3 Hz), 3.50 (2H, s), 3.50-3.56 (2H, m), 4.01-4.05 (2H, m), 4.20-4.28 (1H, m), 5.39 (1H, t, J = 8.2 Hz), 7.00 (1H, br s), 7.65 (1H, br s).
LRMS (ESI): m/z 280 [M + H]+, 302 [M + Na]+.
HRMS (ESI) m/z calcd for C14H21N3O3Na: 302.14806 [M + H]+; found: 302.14888。
Example 19 (2Z) -5-Amino-2-{[1- (tetrahydro-2H-pyran-4-yl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid Reference Example 6 In the same manner as in Example 5, the title compound (184 mg) was obtained from the compound obtained in Reference Example 17.
1 H NMR (CD 3 OD) δ: 1.91-2.00 (4H, m), 2.46-2.51 (2H, m), 2.93 (2H, t, J = 6.3 Hz), 3.50 (2H, s), 3.50-3.56 (2H, m), 4.01-4.05 (2H, m), 4.20-4.28 (1H, m), 5.39 (1H, t, J = 8.2 Hz), 7.00 (1H, br s), 7.65 (1H, br s ).
LRMS (ESI): m / z 280 [M + H] + , 302 [M + Na] + .
HRMS (ESI) m / z calcd for C 14 H 21 N 3 O 3 Na: 302.14806 [M + H] + ; found: 302.14888.
 [実施例20](2Z)-5-アミノ-2-[(1-シクロブチル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸
 参考例6及び実施例5の方法と同様にして、参考例18で得られた化合物から、標題化合物(204mg)を得た。
1H NMR (CD3OD) δ: 1.81-1.89 (2H, m), 2.32-2.50 (6H, m), 2.91 (2H, t, J = 6.5 Hz), 3.50 (2H, s), 4.60-4.68 (1H, m), 5.38 (1H, t, J = 8.8 Hz), 7.02 (1H, d, J = 1.6 Hz), 7.59 (1H, d, J = 1.6 Hz).
LRMS (ESI): m/z 250 [M + H]+, 272 [M + Na]+.
HRMS (ESI) m/z calcd for C13H20N3O2: 250.15555 [M + H]+; found: 250.15465。
[Example 20] (2Z) -5-amino-2-[(1-cyclobutyl-1H-imidazol-4-yl) methyl] pent-2-enoic acid In the same manner as in Reference Example 6 and Example 5. The title compound (204 mg) was obtained from the compound obtained in Reference Example 18.
1 H NMR (CD 3 OD) δ: 1.81-1.89 (2H, m), 2.32-2.50 (6H, m), 2.91 (2H, t, J = 6.5 Hz), 3.50 (2H, s), 4.60-4.68 (1H, m), 5.38 (1H, t, J = 8.8 Hz), 7.02 (1H, d, J = 1.6 Hz), 7.59 (1H, d, J = 1.6 Hz).
LRMS (ESI): m / z 250 [M + H] + , 272 [M + Na] + .
HRMS (ESI) m / z calcd for C 13 H 20 N 3 O 2 : 250.15555 [M + H] + ; found: 250.15465.
 [実施例21](2Z)-5-アミノ-2-{[1-(trans-4-メチルシクロヘキシル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 参考例6及び実施例5の方法と同様にして、参考例19で得られた化合物から、標題化合物(164mg)を得た。
1H NMR (CD3OD) δ: 0.95 (3H, d, J = 6.3 Hz), 1.10-1.19 (2H, m), 1.44-1.49 (1H, m), 1.68-1.76 (2H, m), 1.82-1.86 (2H, m), 2.01-2.05 (2H, m), 2.46-2.50 (2H, m), 2.94 (2H, t, J = 6.1 Hz), 3.49 (2H, s), 3.93 (1H, tt, J = 12.0, 3.8 Hz), 5.38 (1H, t, J = 8.1 Hz), 6.95 (1H, s), 7.59 (1H, s).
LRMS (ESI): m/z 292 [M + H]+, 314 [M + Na]+.
HRMS (ESI) m/z calcd for C16H26N3O2: 292.20250 [M + H]+; found: 292.20223。
[Example 21] (2Z) -5-amino-2-{[1- (trans-4-methylcyclohexyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid Reference Example 6 and Examples In the same manner as in Method 5, the title compound (164 mg) was obtained from the compound obtained in Reference Example 19.
1 H NMR (CD 3 OD) δ: 0.95 (3H, d, J = 6.3 Hz), 1.10-1.19 (2H, m), 1.44-1.49 (1H, m), 1.68-1.76 (2H, m), 1.82 -1.86 (2H, m), 2.01-2.05 (2H, m), 2.46-2.50 (2H, m), 2.94 (2H, t, J = 6.1 Hz), 3.49 (2H, s), 3.93 (1H, tt , J = 12.0, 3.8 Hz), 5.38 (1H, t, J = 8.1 Hz), 6.95 (1H, s), 7.59 (1H, s).
LRMS (ESI): m / z 292 [M + H] + , 314 [M + Na] + .
HRMS (ESI) m / z calcd for C 16 H 26 N 3 O 2 : 292.20250 [M + H] + ; found: 292.20223.
 [実施例22](2Z)-5-アミノ-2-{[1-(cis-4-メチルシクロヘキシル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 参考例6及び実施例5の方法と同様にして、参考例20で得られた化合物から、標題化合物(211mg)を得た。
1H NMR (CD3OD) δ: 1.02 (3H, d, J = 7.3 Hz), 1.45-1.51 (2H, m), 1.66-1.72 (2H, m), 1.81-1.88 (3H, m), 1.98-2.06 (2H, m), 2.46-2.51 (2H, m), 2.94 (2H, t, J = 6.3 Hz), 3.50 (2H, s), 4.00-4.05 (1H, m), 5.38 (1H, t, J = 8.3 Hz), 6.99 (1H, s), 7.62 (1H, d, J = 1.0 Hz).
LRMS (ESI): m/z 292 [M + H]+, 314 [M + Na]+.
HRMS (ESI) m/z calcd for C16H26N3O2: 292.20250 [M + H]+; found: 292.20266。
[Example 22] (2Z) -5-amino-2-{[1- (cis-4-methylcyclohexyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid Reference Example 6 and Examples In the same manner as in Method 5, the title compound (211 mg) was obtained from the compound obtained in Reference Example 20.
1 H NMR (CD 3 OD) δ: 1.02 (3H, d, J = 7.3 Hz), 1.45-1.51 (2H, m), 1.66-1.72 (2H, m), 1.81-1.88 (3H, m), 1.98 -2.06 (2H, m), 2.46-2.51 (2H, m), 2.94 (2H, t, J = 6.3 Hz), 3.50 (2H, s), 4.00-4.05 (1H, m), 5.38 (1H, t , J = 8.3 Hz), 6.99 (1H, s), 7.62 (1H, d, J = 1.0 Hz).
LRMS (ESI): m / z 292 [M + H] + , 314 [M + Na] + .
HRMS (ESI) m / z calcd for C 16 H 26 N 3 O 2 : 292.20250 [M + H] + ; found: 292.20266.
 [実施例23](2Z)-5-アミノ-2-{[1-(4-メチルフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 [工程1](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-{[1-(4-メチルフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸tert-ブチル
 参考例8と同様の方法にて、実施例6の工程5で得られた化合物(200mg)及び4-メチルフェニルボロン酸(155mg)から、標題化合物(161mg)を得た。
1H NMR (CDCl3) δ: 1.41 (9H, s), 1.44 (9H, s), 2.39 (3H, s), 2.60-2.65 (2H, m), 3.22-3.27 (2H, m), 3.59 (2H, s), 4.94 (1H, br s), 5.94 (1H, t, J = 7.6 Hz), 6.99 (1H, br s), 7.24-7.26 (4H, m), 7.72 (1H, br s)。
[Example 23] (2Z) -5-amino-2-{[1- (4-methylphenyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid [Step 1] (2Z)- Tert-Butyl 5-[(tert-butoxycarbonyl) amino] -2-{[1- (4-methylphenyl) -1H-imidazol-4-yl] methyl} pent-2-enoate Similar to Reference Example 8 By the method, the title compound (161 mg) was obtained from the compound (200 mg) obtained in Step 5 of Example 6 and 4-methylphenylboronic acid (155 mg).
1 H NMR (CDCl 3 ) δ: 1.41 (9H, s), 1.44 (9H, s), 2.39 (3H, s), 2.60-2.65 (2H, m), 3.22-3.27 (2H, m), 3.59 ( 2H, s), 4.94 (1H, br s), 5.94 (1H, t, J = 7.6 Hz), 6.99 (1H, br s), 7.24-7.26 (4H, m), 7.72 (1H, br s).
 [工程2](2Z)-5-アミノ-2-{[1-(4-メチルフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 実施例6の工程7と同様にして、本実施例の工程1で得られた化合物(161mg)から、標題化合物(81.3mg)を得た。
1H NMR (CD3OD) δ: 2.38 (3H, s), 2.50-2.56 (2H, m), 3.01 (2H, t, J = 6.3 Hz), 3.59 (2H, s), 5.50 (1H, t, J = 8.4 Hz), 7.29-7.32 (3H, m), 7.38-7.41 (2H, m), 8.01 (1H, br s).
LRMS (ESI): m/z 286 [M + H]+, 308 [M + Na]+.
HRMS (ESI) m/z calcd for C16H20N3O2: 286.15555 [M + H]+; found: 286.15270。
[Step 2] (2Z) -5-amino-2-{[1- (4-methylphenyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid As in Step 7 of Example 6. The title compound (81.3 mg) was obtained from the compound (161 mg) obtained in Step 1 of this example.
1 H NMR (CD 3 OD) δ: 2.38 (3H, s), 2.50-2.56 (2H, m), 3.01 (2H, t, J = 6.3 Hz), 3.59 (2H, s), 5.50 (1H, t , J = 8.4 Hz), 7.29-7.32 (3H, m), 7.38-7.41 (2H, m), 8.01 (1H, br s).
LRMS (ESI): m / z 286 [M + H] + , 308 [M + Na] + .
HRMS (ESI) m / z calcd for C 16 H 20 N 3 O 2 : 286.15555 [M + H] + ; found: 286.15270.
 [実施例24](2Z)-5-アミノ-2-{[1-(シクロヘキシルメチル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 実施例6の工程6及び工程7と同様にして、実施例6の工程5で得られた化合物(200mg)及び(ブロモメチル)シクロヘキサンを用いて、標題化合物(56mg)を得た。
1H-NMR (DMSO-d6) δ: 0.80-1.71 (11H, m), 2.25-2.32 (2H, m), 2.74-2.80 (2H, m), 3.18-3.43 (2H, m), 3.67-3.73 (2H, m), 5.22 (1H, t, J = 8.2 Hz), 6.75 (1H, s), 7.40 (1H, s).
LRMS (ESI): m/z 292 [M + H]+, 314 [M + Na]+.
HRMS (ESI) m/z calcd for C16H26N3O2: 292.20250 [M + H]+; found: 292.20180。
Example 24 (2Z) -5-amino-2-{[1- (cyclohexylmethyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid Step 6 and Step 7 of Example 6 Similarly, the title compound (56 mg) was obtained using the compound (200 mg) obtained in Step 5 of Example 6 and (bromomethyl) cyclohexane.
1 H-NMR (DMSO-d 6 ) δ: 0.80-1.71 (11H, m), 2.25-2.32 (2H, m), 2.74-2.80 (2H, m), 3.18-3.43 (2H, m), 3.67- 3.73 (2H, m), 5.22 (1H, t, J = 8.2 Hz), 6.75 (1H, s), 7.40 (1H, s).
LRMS (ESI): m / z 292 [M + H] + , 314 [M + Na] + .
HRMS (ESI) m / z calcd for C 16 H 26 N 3 O 2 : 292.20250 [M + H] + ; found: 292.20180.
 [実施例25](2Z)-5-アミノ-2-{[1-(3,3-ジメチルブチル)-5-メチル-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 参考例6及び実施例5の方法と同様にして、参考例22で得た化合物から、標題化合物(121mg)を得た。
1H NMR (CD3OD) δ: 1.00 (9H, s), 1.59-1.62 (2H, m), 2.18 (3H, s), 2.43-2.47 (2H, m), 2.91 (2H, t, J = 6.3 Hz), 3.45 (2H, s), 3.88-3.92 (2H, m), 5.26 (1H, t, J = 8.3 Hz), 7.51 (1H, s).
LRMS (ESI): m/z 294 [M + H]+, 316 [M + Na]+.
HRMS (ESI) m/z calcd for C16H28N3O2: 294.21815 [M + H]+; found: 294.21720。
Example 25 (2Z) -5-amino-2-{[1- (3,3-dimethylbutyl) -5-methyl-1H-imidazol-4-yl] methyl} pent-2-enoic acid Reference Example 6 In the same manner as in Example 6 and Example 5, the title compound (121 mg) was obtained from the compound obtained in Reference Example 22.
1 H NMR (CD 3 OD) δ: 1.00 (9H, s), 1.59-1.62 (2H, m), 2.18 (3H, s), 2.43-2.47 (2H, m), 2.91 (2H, t, J = 6.3 Hz), 3.45 (2H, s), 3.88-3.92 (2H, m), 5.26 (1H, t, J = 8.3 Hz), 7.51 (1H, s).
LRMS (ESI): m / z 294 [M + H] + , 316 [M + Na] + .
HRMS (ESI) m / z calcd for C 16 H 28 N 3 O 2 : 294.21815 [M + H] + ; found: 294.21720.
 [実施例26](2Z)-5-アミノ-2-{[1-(4,4-ジメチルシクロヘキシル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 [工程1](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-{[1-(4,4-ジメチルシクロヘキシル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸tert-ブチル
 4,4-ジメチルシクロヘキサノール(80mg)をトルエン(10mL)に溶解し、実施例6の工程5で得られた化合物(200mg)及びシアノメチレントリブチルホスホラン(CMBP、151mg)を加えて100℃で1時間加熱した。さらに、4,4-ジメチルシクロヘキサノール(219mg)及びCMBP(412mg)を加えて100℃で8時間撹拌した。反応液に酢酸エチル、水及び飽和食塩水を加えて分液し、無水硫酸マグネシウムで乾燥した。減圧下溶媒留去し、シリカゲルカラムクロマトグラフィー(溶出溶媒:酢酸エチル)で精製した。さらに分取用薄層クロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=5/95)で精製して標題化合物(84mg)を得た。
1H-NMR (CDCl3) δ: 0.97 (3H, s), 0.98 (3H, s), 1.29-1.41 (2H, m), 1.42 (9H, s), 1.43 (9H, s), 1.49-1.59 (2H, m), 1.75-1.85 (2H, m), 1.85-1.93 (2H, m), 2.57-2.63 (2H, m), 3.19-3.25 (2H, m), 3.51 (2H, s), 3.77 (1H, tt, J = 11.7, 4.2 Hz), 4.93 (1H, br s), 5.86 (1H, t, J = 7.6 Hz), 6.69 (1H, s), 7.44 (1H, br s).
LRMS (ESI): m/z 462 [M + H]+, 484 [M + Na]+
[Example 26] (2Z) -5-amino-2-{[1- (4,4-dimethylcyclohexyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid [Step 1] (2Z ) -5-[(tert-Butoxycarbonyl) amino] -2-{[1- (4,4-dimethylcyclohexyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid tert-butyl 4, 4-Dimethylcyclohexanol (80 mg) was dissolved in toluene (10 mL), the compound (200 mg) obtained in Step 5 of Example 6 and cyanomethylenetributylphosphorane (CMBP, 151 mg) were added, and the mixture was added at 100 ° C. for 1 hour. Heated. Furthermore, 4,4-dimethylcyclohexanol (219 mg) and CMBP (412 mg) were added and stirred at 100 ° C. for 8 hours. Ethyl acetate, water and saturated brine were added to the reaction solution, and the mixture was separated, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate). Further purification by preparative thin layer chromatography (elution solvent: methanol / methylene chloride = 5/95) gave the title compound (84 mg).
1 H-NMR (CDCl 3 ) δ: 0.97 (3H, s), 0.98 (3H, s), 1.29-1.41 (2H, m), 1.42 (9H, s), 1.43 (9H, s), 1.49-1.59 (2H, m), 1.75-1.85 (2H, m), 1.85-1.93 (2H, m), 2.57-2.63 (2H, m), 3.19-3.25 (2H, m), 3.51 (2H, s), 3.77 (1H, tt, J = 11.7, 4.2 Hz), 4.93 (1H, br s), 5.86 (1H, t, J = 7.6 Hz), 6.69 (1H, s), 7.44 (1H, br s).
LRMS (ESI): m / z 462 [M + H] + , 484 [M + Na] + .
 [工程2](2Z)-5-アミノ-2-{[1-(4,4-ジメチルシクロヘキシル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 実施例6の工程7と同様にして、本実施例の工程1で得られた化合物(84mg)から、標題化合物(38mg)を得た。
1H-NMR (CD3OD) δ: 0.97 (3H, s), 1.03 (3H, s), 1.36-1.47 (2H, m), 1.50-1.57 (2H, m), 1.84-1.94 (4H, m), 2.46-2.54 (2H, m), 2.96-3.02 (2H, m), 3.50 (2H, s), 3.88-3.97 (1H, m), 5.41 (1H, t, J = 7.8 Hz), 6.99 (1H, s), 7.66 (1H, s).
LRMS (ESI): m/z 306 [M + H]+, 328 [M + Na]+.
HRMS (ESI) m/z calcd for C17H28N3O2: 306.21815 [M + H]+; found: 306.21789。
[Step 2] (2Z) -5-amino-2-{[1- (4,4-dimethylcyclohexyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid Step 7 of Example 6 and Similarly, the title compound (38 mg) was obtained from the compound (84 mg) obtained in Step 1 of this example.
1 H-NMR (CD 3 OD) δ: 0.97 (3H, s), 1.03 (3H, s), 1.36-1.47 (2H, m), 1.50-1.57 (2H, m), 1.84-1.94 (4H, m ), 2.46-2.54 (2H, m), 2.96-3.02 (2H, m), 3.50 (2H, s), 3.88-3.97 (1H, m), 5.41 (1H, t, J = 7.8 Hz), 6.99 ( 1H, s), 7.66 (1H, s).
LRMS (ESI): m / z 306 [M + H] + , 328 [M + Na] + .
HRMS (ESI) m / z calcd for C 17 H 28 N 3 O 2 : 306.21815 [M + H] + ; found: 306.21789.
 [実施例27](2Z)-5-アミノ-2-{[1-(4-クロロフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 [工程1](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-{[1-(4-クロロフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸tert-ブチル
 参考例8と同様の方法にて、実施例6の工程5で得られた化合物(500mg)及び4-クロロフェニルボロン酸(468mg)から,標題化合物(378mg)を得た。
1H NMR (CDCl3) δ: 1.41 (9H, s), 1.44 (9H, s), 2.60-2.65 (2H, m), 3.22-3.27 (2H, m), 3.58 (2H, s), 4.90 (1H, br s), 5.94 (1H, t, J = 7.8 Hz), 7.00 (1H, br s), 7.30 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6 Hz), 7.73 (1H, br s)。
[Example 27] (2Z) -5-amino-2-{[1- (4-chlorophenyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid [Step 1] (2Z) -5 -[(Tert-Butoxycarbonyl) amino] -2-{[1- (4-chlorophenyl) -1H-imidazol-4-yl] methyl} pent-2-butylate tert-butyl In the same manner as in Reference Example 8 The title compound (378 mg) was obtained from the compound (500 mg) obtained in Step 5 of Example 6 and 4-chlorophenylboronic acid (468 mg).
1 H NMR (CDCl 3 ) δ: 1.41 (9H, s), 1.44 (9H, s), 2.60-2.65 (2H, m), 3.22-3.27 (2H, m), 3.58 (2H, s), 4.90 ( 1H, br s), 5.94 (1H, t, J = 7.8 Hz), 7.00 (1H, br s), 7.30 (2H, d, J = 8.6 Hz), 7.43 (2H, d, J = 8.6 Hz), 7.73 (1H, br s).
 [工程2](2Z)-5-アミノ-2-{[1-(4-クロロフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 実施例6の工程7と同様にして、本実施例の工程1で得られた化合物(378mg)から、標題化合物(166mg)を得た。
1H NMR (CD3OD) δ: 2.50-2.55 (2H, m), 3.01 (2H, t, J = 6.3 Hz), 3.59 (2H, s), 5.50 (1H, t, J = 8.4 Hz), 7.35 (1H, d, J = 1.6 Hz), 7.50 (2H, d, J = 9.0 Hz), 7.55 (2H, d, J = 9.0 Hz), 8.08 (1H, d, J = 1.6 Hz).
LRMS (ESI): m/z 306 [M + H]+, 328 [M + Na]+.
HRMS (ESI) m/z calcd for C15H17ClN3O2: 306.10093 [M + H]+; found: 306.09952。
[Step 2] (2Z) -5-amino-2-{[1- (4-chlorophenyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid In the same manner as in Step 7 of Example 6. The title compound (166 mg) was obtained from the compound (378 mg) obtained in Step 1 of this example.
1 H NMR (CD 3 OD) δ: 2.50-2.55 (2H, m), 3.01 (2H, t, J = 6.3 Hz), 3.59 (2H, s), 5.50 (1H, t, J = 8.4 Hz), 7.35 (1H, d, J = 1.6 Hz), 7.50 (2H, d, J = 9.0 Hz), 7.55 (2H, d, J = 9.0 Hz), 8.08 (1H, d, J = 1.6 Hz).
LRMS (ESI): m / z 306 [M + H] + , 328 [M + Na] + .
HRMS (ESI) m / z calcd for C 15 H 17 ClN 3 O 2 : 306.10093 [M + H] + ; found: 306.09952.
 [実施例28](2Z)-5-アミノ-2-{[1-(2-メチルフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン
 [工程1](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-{[1-(2-メチルフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸tert-ブチル
 参考例8と同様の方法にて、実施例6の工程5で得られた化合物(500mg)及び2-メチルフェニルボロン酸(387mg)から、標題化合物(336mg)を得た。
1H NMR (CDCl3) δ: 1.37 (9H, s), 1.44 (9H, s), 2.17 (3H, s), 2.59-2.65 (2H, m), 3.22-3.27 (2H, m), 3.61 (2H, s), 5.00 (1H, br s), 5.93 (1H, t, J = 7.8 Hz), 6.78 (1H, br s), 7.17-7.19 (1H, m), 7.25-7.33 (3H, m), 7.48 (1H, br s)。
[Example 28] (2Z) -5-amino-2-{[1- (2-methylphenyl) -1H-imidazol-4-yl] methyl} pent-2-ene [Step 1] (2Z) -5 -[(Tert-Butoxycarbonyl) amino] -2-{[1- (2-methylphenyl) -1H-imidazol-4-yl] methyl} pent-2-butylate Similar method as in Reference Example 8 The title compound (336 mg) was obtained from the compound (500 mg) obtained in Step 5 of Example 6 and 2-methylphenylboronic acid (387 mg).
1 H NMR (CDCl 3 ) δ: 1.37 (9H, s), 1.44 (9H, s), 2.17 (3H, s), 2.59-2.65 (2H, m), 3.22-3.27 (2H, m), 3.61 ( 2H, s), 5.00 (1H, br s), 5.93 (1H, t, J = 7.8 Hz), 6.78 (1H, br s), 7.17-7.19 (1H, m), 7.25-7.33 (3H, m) , 7.48 (1H, br s).
 [工程2](2Z)-5-アミノ-2-{[1-(2-メチルフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 実施例6の工程7と同様にして,本実施例の工程1で得られた化合物(336mg)から、標題化合物(178mg)を得た。
1H NMR (CD3OD) δ: 2.19 (3H, s), 2.51-2.56 (2H, m), 3.02 (2H, t, J = 6.3 Hz), 3.60 (2H, s), 5.49 (1H, t, J = 8.6 Hz), 7.05 (1H, d, J = 1.2 Hz), 7.25-7.27 (1H, m), 7.29-7.35 (1H, m), 7.36-7.39 (2H, m), 7.70 (1H, d, J = 1.2 Hz).
LRMS (ESI): m/z 286 [M + H]+, 308 [M + Na]+.
HRMS (ESI) m/z calcd for C16H20N3O2: 286.15555 [M + H]+; found: 286.15487。
[Step 2] (2Z) -5-amino-2-{[1- (2-methylphenyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid As in Step 7 of Example 6. The title compound (178 mg) was obtained from the compound (336 mg) obtained in Step 1 of this example.
1 H NMR (CD 3 OD) δ: 2.19 (3H, s), 2.51-2.56 (2H, m), 3.02 (2H, t, J = 6.3 Hz), 3.60 (2H, s), 5.49 (1H, t , J = 8.6 Hz), 7.05 (1H, d, J = 1.2 Hz), 7.25-7.27 (1H, m), 7.29-7.35 (1H, m), 7.36-7.39 (2H, m), 7.70 (1H, d, J = 1.2 Hz).
LRMS (ESI): m / z 286 [M + H] + , 308 [M + Na] + .
HRMS (ESI) m / z calcd for C 16 H 20 N 3 O 2 : 286.15555 [M + H] + ; found: 286.15487.
 [実施例29](2Z)-5-アミノ-2-{[1-(4-フルオロフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 [工程1](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-{[1-(4-フルオロフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸tert-ブチル
 参考例8と同様の方法にて、実施例6の工程5で得られた化合物(500mg)及び4-フルオロフェニルボロン酸(398mg)から、標題化合物(265mg)を得た。
1H NMR (CDCl3) δ: 1.41 (9H, s), 1.44 (9H, s), 2.60-2.65 (2H, m), 3.22-3.27 (2H, m), 3.59 (2H, s), 4.92 (1H, br s), 5.95 (1H, t, J = 7.6 Hz), 6.97 (1H, br s), 7.13-7.18 (2H, m), 7.31-7.34 (2H, m), 7.70 (1H, br s)。
[Example 29] (2Z) -5-amino-2-{[1- (4-fluorophenyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid [Step 1] (2Z)- Tert-Butyl 5-[(tert-butoxycarbonyl) amino] -2-{[1- (4-fluorophenyl) -1H-imidazol-4-yl] methyl} pent-2-enoate Similar to Reference Example 8 By the method, the title compound (265 mg) was obtained from the compound (500 mg) obtained in Step 5 of Example 6 and 4-fluorophenylboronic acid (398 mg).
1 H NMR (CDCl 3 ) δ: 1.41 (9H, s), 1.44 (9H, s), 2.60-2.65 (2H, m), 3.22-3.27 (2H, m), 3.59 (2H, s), 4.92 ( 1H, br s), 5.95 (1H, t, J = 7.6 Hz), 6.97 (1H, br s), 7.13-7.18 (2H, m), 7.31-7.34 (2H, m), 7.70 (1H, br s ).
 [工程2](2Z)-5-アミノ-2-{[1-(4-フルオロフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 実施例6の工程7と同様にして、本実施例の工程1で得られた化合物(265mg)から、標題化合物(144mg)を得た。
1H NMR (CD3OD) δ: 2.50-2.55 (2H, m), 3.00-3.03 (2H, m), 3.59 (2H, s), 5.50 (1H, t, J = 8.2 Hz), 7.22-7.28 (2H, m), 7.31 (1H, d, J = 1.6 Hz), 7.54-7.57 (2H, m), 8.02 (1H, d, J = 1.6 Hz).
LRMS (ESI): m/z 290 [M + H]+, 312 [M + Na]+.
HRMS (ESI) m/z calcd for C15H17FN3O2: 290.13048 [M + H]+; found: 290.13064。
[Step 2] (2Z) -5-amino-2-{[1- (4-fluorophenyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid As in Step 7 of Example 6. The title compound (144 mg) was obtained from the compound (265 mg) obtained in Step 1 of this example.
1 H NMR (CD 3 OD) δ: 2.50-2.55 (2H, m), 3.00-3.03 (2H, m), 3.59 (2H, s), 5.50 (1H, t, J = 8.2 Hz), 7.22-7.28 (2H, m), 7.31 (1H, d, J = 1.6 Hz), 7.54-7.57 (2H, m), 8.02 (1H, d, J = 1.6 Hz).
LRMS (ESI): m / z 290 [M + H] + , 312 [M + Na] + .
HRMS (ESI) m / z calcd for C 15 H 17 FN 3 O 2 : 290.13048 [M + H] + ; found: 290.13064.
 [実施例30](2Z)-5-アミノ-2-{[1-(4-メトキシフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 [工程1](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-{[1-(4-メトキシフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸tert-ブチル
 参考例8と同様の方法にて、実施例6の工程5で得られた化合物(500mg)及び4-メトキシフェニルボロン酸(432mg)から、標題化合物(370mg)を得た。
1H NMR (CDCl3) δ: 1.41 (9H, s), 1.44 (9H, s), 2.60-2.65 (2H, m), 3.22-3.27 (2H, m), 3.58 (2H, s), 3.84 (3H, s), 4.93 (1H, br s), 5.94 (1H, t, J = 7.6 Hz), 6.94 (1H, br s), 6.95-6.98 (2H, m), 7.25-7.27 (2H, m), 7.67 (1H, br s)。
[Example 30] (2Z) -5-amino-2-{[1- (4-methoxyphenyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid [Step 1] (2Z)- Tert-Butyl 5-[(tert-butoxycarbonyl) amino] -2-{[1- (4-methoxyphenyl) -1H-imidazol-4-yl] methyl} pent-2-enoate Similar to Reference Example 8 By the method, the title compound (370 mg) was obtained from the compound (500 mg) obtained in Step 5 of Example 6 and 4-methoxyphenylboronic acid (432 mg).
1 H NMR (CDCl 3 ) δ: 1.41 (9H, s), 1.44 (9H, s), 2.60-2.65 (2H, m), 3.22-3.27 (2H, m), 3.58 (2H, s), 3.84 ( 3H, s), 4.93 (1H, br s), 5.94 (1H, t, J = 7.6 Hz), 6.94 (1H, br s), 6.95-6.98 (2H, m), 7.25-7.27 (2H, m) , 7.67 (1H, br s).
 [工程2](2Z)-5-アミノ-2-{[1-(4-メトキシフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 実施例6の工程7と同様にして、本実施例の工程1で得られた化合物(370mg)から、標題化合物(205mg)を得た。
1H NMR (CD3OD) δ: 2.50-2.55 (2H, m), 3.01 (2H, t, J = 6.1 Hz), 3.58 (2H, s), 3.83 (3H, s), 5.49 (1H, t, J = 8.4 Hz), 7.03 (2H, d, J = 9.0 Hz), 7.25 (1H, d, J = 1.6 Hz), 7.42 (2H, d, J = 9.0 Hz), 7.93 (1H, d, J = 1.6 Hz).
LRMS (ESI): m/z 302 [M + H]+, 324 [M + Na]+.
HRMS (ESI) m/z calcd for C16H20N3O3: 302.15047 [M + H]+; found: 302.15123。
[Step 2] (2Z) -5-amino-2-{[1- (4-methoxyphenyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid As in Step 7 of Example 6. The title compound (205 mg) was obtained from the compound (370 mg) obtained in Step 1 of this example.
1 H NMR (CD 3 OD) δ: 2.50-2.55 (2H, m), 3.01 (2H, t, J = 6.1 Hz), 3.58 (2H, s), 3.83 (3H, s), 5.49 (1H, t , J = 8.4 Hz), 7.03 (2H, d, J = 9.0 Hz), 7.25 (1H, d, J = 1.6 Hz), 7.42 (2H, d, J = 9.0 Hz), 7.93 (1H, d, J = 1.6 Hz).
LRMS (ESI): m / z 302 [M + H] + , 324 [M + Na] + .
HRMS (ESI) m / z calcd for C 16 H 20 N 3 O 3 : 302.15047 [M + H] + ; found: 302.15123.
 [実施例31](2Z)-5-アミノ-2-{[1-(3-チエニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 [工程1](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-{[1-(3-チエニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸tert-ブチル
 参考例8と同様の方法にて、実施例6の工程5で得られた化合物(500mg)及び3-チオフェンボロン酸(372mg)から、標題化合物(113mg)を得た。
1H NMR (CDCl3) δ: 1.42 (9H, s), 1.44 (9H, s), 2.60-2.65 (2H, m), 3.23-3.27 (2H, m), 3.58 (2H, s), 4.93 (1H, br s), 5.94 (1H, t, J = 7.6 Hz), 6.98 (1H, br s), 7.13-7.16 (2H, m), 7.39-7.41 (1H, m), 7.73 (1H, br s)。
[Example 31] (2Z) -5-amino-2-{[1- (3-thienyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid [Step 1] (2Z) -5 -[(Tert-Butoxycarbonyl) amino] -2-{[1- (3-thienyl) -1H-imidazol-4-yl] methyl} pent-2-butylate tert-butyl Then, the title compound (113 mg) was obtained from the compound (500 mg) obtained in Step 5 of Example 6 and 3-thiopheneboronic acid (372 mg).
1 H NMR (CDCl 3 ) δ: 1.42 (9H, s), 1.44 (9H, s), 2.60-2.65 (2H, m), 3.23-3.27 (2H, m), 3.58 (2H, s), 4.93 ( 1H, br s), 5.94 (1H, t, J = 7.6 Hz), 6.98 (1H, br s), 7.13-7.16 (2H, m), 7.39-7.41 (1H, m), 7.73 (1H, br s ).
 [工程2](2Z)-5-アミノ-2-{[1-(3-チエニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 実施例6の工程7と同様にして、本実施例の工程1で得られた化合物(113mg)から、標題化合物(64.0mg)を得た。
1H NMR (CD3OD) δ: 2.51-2.54 (2H, m), 3.01 (2H, t, J = 6.3 Hz), 3.57 (2H, s), 5.48 (1H, t, J = 8.4 Hz), 7.32 (1H, d, J = 1.6 Hz), 7.35 (1H, dd, J = 5.1, 1.6 Hz), 7.51 (1H, dd, J = 3.1, 1.6 Hz), 7.56 (1H, dd, J = 5.1, 3.1 Hz), 8.04 (1H, d, J = 1.6 Hz).
LRMS (ESI): m/z 278 [M + H]+, 300 [M + Na]+.
HRMS (ESI) m/z calcd for C13H16N3O2S: 278.09632 [M + H]+; found: 278.09674。
[Step 2] (2Z) -5-amino-2-{[1- (3-thienyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid As in Step 7 of Example 6. The title compound (64.0 mg) was obtained from the compound (113 mg) obtained in Step 1 of this example.
1 H NMR (CD 3 OD) δ: 2.51-2.54 (2H, m), 3.01 (2H, t, J = 6.3 Hz), 3.57 (2H, s), 5.48 (1H, t, J = 8.4 Hz), 7.32 (1H, dd, J = 1.6 Hz), 7.35 (1H, dd, J = 5.1, 1.6 Hz), 7.51 (1H, dd, J = 3.1, 1.6 Hz), 7.56 (1H, dd, J = 5.1, 3.1 Hz), 8.04 (1H, d, J = 1.6 Hz).
LRMS (ESI): m / z 278 [M + H] +, 300 [M + Na] +.
HRMS (ESI) m / z calcd for C13H16N3O2S: 278.09632 [M + H] +; found: 278.09674.
 [実施例32](2Z)-5-アミノ-2-{[1-(4-エチルフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 [工程1](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-{[1-(4-エチルフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸tert-ブチル
 参考例8と同様の方法にて、実施例6の工程5で得られた化合物(500mg)及び4-エチルフェニルボロン酸(427mg)から、標題化合物(419mg)を得た。
1H NMR (CDCl3) δ: 1.26 (3H, t, J = 7.6 Hz), 1.41 (9H, s), 1.44 (9H, s), 2.60-2.65 (2H, m), 2.69 (2H, q, J = 7.7 Hz), 3.22-3.27 (2H, m), 3.59 (2H, s), 4.95 (1H, br s), 5.94 (1H, t, J = 7.6 Hz), 6.99 (1H, br s), 7.26-7.27 (4H, m), 7.73 (1H, br s)。
[Example 32] (2Z) -5-amino-2-{[1- (4-ethylphenyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid [Step 1] (2Z)- Tert-Butyl 5-[(tert-butoxycarbonyl) amino] -2-{[1- (4-ethylphenyl) -1H-imidazol-4-yl] methyl} pent-2-enoate Similar to Reference Example 8 By the method, the title compound (419 mg) was obtained from the compound (500 mg) obtained in Step 5 of Example 6 and 4-ethylphenylboronic acid (427 mg).
1 H NMR (CDCl 3 ) δ: 1.26 (3H, t, J = 7.6 Hz), 1.41 (9H, s), 1.44 (9H, s), 2.60-2.65 (2H, m), 2.69 (2H, q, J = 7.7 Hz), 3.22-3.27 (2H, m), 3.59 (2H, s), 4.95 (1H, br s), 5.94 (1H, t, J = 7.6 Hz), 6.99 (1H, br s), 7.26-7.27 (4H, m), 7.73 (1H, br s).
 [工程2](2Z)-5-アミノ-2-{[1-(4-エチルフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 実施例6の工程7と同様にして、本実施例の工程1で得られた化合物(419mg)から、標題化合物(214mg)を得た。
1H NMR (CD3OD) δ: 1.25 (3H, t, J = 7.6 Hz), 2.50-2.55 (2H, m), 2.69 (2H, q, J = 7.6 Hz), 3.01 (2H, t, J = 6.3 Hz), 3.59 (2H, s), 5.49 (1H, t, J = 8.4 Hz), 7.35-7.31 (3H, m), 7.41-7.43 (2H, m), 8.01 (1H, d, J = 1.6 Hz).
LRMS (ESI): m/z 300 [M + H]+, 322 [M + Na]+.
HRMS (ESI) m/z calcd for C17H22N3O2: 300.17120 [M + H]+; found: 300.17017。
[Step 2] (2Z) -5-amino-2-{[1- (4-ethylphenyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid As in Step 7 of Example 6. The title compound (214 mg) was obtained from the compound (419 mg) obtained in Step 1 of this example.
1 H NMR (CD 3 OD) δ: 1.25 (3H, t, J = 7.6 Hz), 2.50-2.55 (2H, m), 2.69 (2H, q, J = 7.6 Hz), 3.01 (2H, t, J = 6.3 Hz), 3.59 (2H, s), 5.49 (1H, t, J = 8.4 Hz), 7.35-7.31 (3H, m), 7.41-7.43 (2H, m), 8.01 (1H, d, J = 1.6 Hz).
LRMS (ESI): m / z 300 [M + H] + , 322 [M + Na] + .
HRMS (ESI) m / z calcd for C 17 H 22 N 3 O 2 : 300.17120 [M + H] + ; found: 300.17017.
 [実施例33](2Z)-5-アミノ-2-({1-[4-(トリフルオロメチル)フェニル]-1H-イミダゾール-4-イル}メチル)ペンタ-2-エン酸
 [工程1](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-({1-[4-(トリフルオロメチル)フェニル]-1H-イミダゾール-4-イル}メチル)ペンタ-2-エン酸tert-ブチル
 参考例8と同様の方法にて、実施例6の工程5で得られた化合物(500mg)及び4-(トリフルオロメチル)フェニルボロン酸(551mg)から、標題化合物(403mg)を得た。
1H NMR (CDCl3) δ: 1.41 (9H, s), 1.45 (9H, s), 2.62-2.66 (2H, m), 3.23-3.27 (2H, m), 3.60 (2H, s), 4.89 (1H, br s), 5.97 (1H, t, J = 7.6 Hz), 7.09 (1H, br s), 7.49 (2H, d, J = 8.6 Hz), 7.73 (2H, d, J = 8.6 Hz), 7.84 (1H, br s)。
[Example 33] (2Z) -5-amino-2-({1- [4- (trifluoromethyl) phenyl] -1H-imidazol-4-yl} methyl) pent-2-enoic acid [Step 1] (2Z) -5-[(tert-Butoxycarbonyl) amino] -2-({1- [4- (trifluoromethyl) phenyl] -1H-imidazol-4-yl} methyl) pent-2-enoic acid tert -Butyl In the same manner as in Reference Example 8, the title compound (403 mg) was obtained from the compound (500 mg) obtained in Step 5 of Example 6 and 4- (trifluoromethyl) phenylboronic acid (551 mg). .
1 H NMR (CDCl 3 ) δ: 1.41 (9H, s), 1.45 (9H, s), 2.62-2.66 (2H, m), 3.23-3.27 (2H, m), 3.60 (2H, s), 4.89 ( 1H, br s), 5.97 (1H, t, J = 7.6 Hz), 7.09 (1H, br s), 7.49 (2H, d, J = 8.6 Hz), 7.73 (2H, d, J = 8.6 Hz), 7.84 (1H, br s).
 [工程2](2Z)-5-アミノ-2-({1-[4-(トリフルオロメチル)フェニル]-1H-イミダゾール-4-イル}メチル)ペンタ-2-エン酸
 実施例6の工程7と同様にして、本実施例の工程1で得られた化合物(403mg)から、標題化合物(240mg)を得た。
1H NMR (CD3OD) δ: 2.51-2.56 (2H, m), 3.02 (2H, t, J = 6.3 Hz), 3.60 (2H, s), 5.51 (1H, t, J = 8.2 Hz), 7.47 (1H, d, J = 1.6 Hz), 7.77 (2H, d, J = 8.6 Hz), 7.82 (2H, d, J = 8.6 Hz), 8.22 (1H, d, J = 1.6 Hz).
LRMS (ESI): m/z 340 [M + H]+, 362 [M + Na]+.
HRMS (ESI) m/z calcd for C16H17F3N3O2: 340.12729 [M + H]+; found: 340.12684。
[Step 2] (2Z) -5-amino-2-({1- [4- (trifluoromethyl) phenyl] -1H-imidazol-4-yl} methyl) pent-2-enoic acid Step of Example 6 In the same manner as in Example 7, the title compound (240 mg) was obtained from the compound (403 mg) obtained in Step 1 of this example.
1 H NMR (CD 3 OD) δ: 2.51-2.56 (2H, m), 3.02 (2H, t, J = 6.3 Hz), 3.60 (2H, s), 5.51 (1H, t, J = 8.2 Hz), 7.47 (1H, d, J = 1.6 Hz), 7.77 (2H, d, J = 8.6 Hz), 7.82 (2H, d, J = 8.6 Hz), 8.22 (1H, d, J = 1.6 Hz).
LRMS (ESI): m / z 340 [M + H] + , 362 [M + Na] + .
HRMS (ESI) m / z calcd for C 16 H 17 F 3 N 3 O 2 : 340.12729 [M + H] + ; found: 340.12684.
 [実施例34](2Z)-5-アミノ-2-{[1-(4-tert-ブチルフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 [工程1](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-{[1-(4-tert-ブチルフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸tert-ブチル
 参考例8と同様の方法にて、実施例6の工程5で得られた化合物(500mg)及び4-tert-ブチルフェニルボロン酸(507mg)から、標題化合物(337mg)を得た。
1H NMR (CDCl3) δ: 1.35 (9H, s), 1.40 (9H, s), 1.44 (9H, s), 2.60-2.65 (2H, m), 3.23-3.27 (2H, m), 3.59 (2H, s), 4.98 (1H, br s), 5.94 (1H, t, J = 7.8 Hz), 7.00 (1H, br s), 7.27 (2H, d, J = 9.0 Hz), 7.46 (2H, d, J = 9.0 Hz), 7.74 (1H, br s)。
[Example 34] (2Z) -5-amino-2-{[1- (4-tert-butylphenyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid [Step 1] (2Z ) -5-[(tert-Butoxycarbonyl) amino] -2-{[1- (4-tert-butylphenyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid tert-butyl Reference Example In the same manner as in Example 8, the title compound (337 mg) was obtained from the compound obtained in Step 5 of Example 6 (500 mg) and 4-tert-butylphenylboronic acid (507 mg).
1 H NMR (CDCl 3 ) δ: 1.35 (9H, s), 1.40 (9H, s), 1.44 (9H, s), 2.60-2.65 (2H, m), 3.23-3.27 (2H, m), 3.59 ( 2H, s), 4.98 (1H, br s), 5.94 (1H, t, J = 7.8 Hz), 7.00 (1H, br s), 7.27 (2H, d, J = 9.0 Hz), 7.46 (2H, d , J = 9.0 Hz), 7.74 (1H, br s).
 [工程2](2Z)-5-アミノ-2-{[1-(4-tert-ブチルフェニル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 実施例6の工程7と同様にして、本実施例の工程1で得られた化合物(337mg)から、標題化合物(113mg)を得た。
1H NMR (CD3OD) δ: 1.35 (9H, s), 2.50-2.56 (2H, m), 3.01 (2H, t, J = 6.3 Hz), 3.59 (2H, s), 5.49 (1H, t, J = 8.4 Hz), 7.32 (1H, d, J = 1.6 Hz), 7.44 (2H, d, J = 8.6 Hz), 7.54 (2H, d, J = 8.6 Hz), 8.02 (1H, d, J = 1.6 Hz).
LRMS (ESI): m/z 328 [M + H]+, 350 [M + Na]+.
HRMS (ESI) m/z calcd for C19H26N3O2: 328.20250 [M + H]+; found: 328.20215。
[Step 2] (2Z) -5-amino-2-{[1- (4-tert-butylphenyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid Step 7 of Example 6 and Similarly, the title compound (113 mg) was obtained from the compound (337 mg) obtained in Step 1 of this example.
1 H NMR (CD 3 OD) δ: 1.35 (9H, s), 2.50-2.56 (2H, m), 3.01 (2H, t, J = 6.3 Hz), 3.59 (2H, s), 5.49 (1H, t , J = 8.4 Hz), 7.32 (1H, d, J = 1.6 Hz), 7.44 (2H, d, J = 8.6 Hz), 7.54 (2H, d, J = 8.6 Hz), 8.02 (1H, d, J = 1.6 Hz).
LRMS (ESI): m / z 328 [M + H] + , 350 [M + Na] + .
HRMS (ESI) m / z calcd for C 19 H 26 N 3 O 2 : 328.20250 [M + H] + ; found: 328.20215.
 [実施例35](2Z)-5-アミノ-2-[(1-ピリジン-3-イル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸
 [工程1](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-[(1-ピリジン-3-イル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸tert-ブチル
 参考例8と同様の方法にて、実施例6の工程5で得られた化合物(500mg)及び3-ピリジンボロン酸(402mg)から、標題化合物(179mg)を得た。
1H NMR (CDCl3) δ: 1.41 (9H, s), 1.45 (9H, s), 2.61-2.66 (2H, m), 3.23-3.27 (2H, m), 3.60 (2H, s), 4.91 (1H, br s), 5.97 (1H, t, J = 7.6 Hz), 7.06 (1H, br s), 7.41-7.44 (1H, m), 7.68-7.70 (1H, m), 7.79 (1H, br s), 8.61-8.62 (1H, m), 8.72-8.72 (1H, m)。
[Example 35] (2Z) -5-amino-2-[(1-pyridin-3-yl-1H-imidazol-4-yl) methyl] pent-2-enoic acid [Step 1] (2Z) -5 -[(Tert-Butoxycarbonyl) amino] -2-[(1-pyridin-3-yl-1H-imidazol-4-yl) methyl] pent-2-butylate The title compound (179 mg) was obtained from the compound (500 mg) obtained in Step 5 of Example 6 and 3-pyridineboronic acid (402 mg).
1 H NMR (CDCl 3 ) δ: 1.41 (9H, s), 1.45 (9H, s), 2.61-2.66 (2H, m), 3.23-3.27 (2H, m), 3.60 (2H, s), 4.91 ( 1H, br s), 5.97 (1H, t, J = 7.6 Hz), 7.06 (1H, br s), 7.41-7.44 (1H, m), 7.68-7.70 (1H, m), 7.79 (1H, br s ), 8.61-8.62 (1H, m), 8.72-8.72 (1H, m).
 [工程2](2Z)-5-アミノ-2-[(1-ピリジン-3-イル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸
 実施例6の工程7と同様にして、本実施例の工程1で得られた化合物(179mg)から、標題化合物(103mg)を得た。
1H NMR (CD3OD) δ: 2.51-2.56 (2H, m), 3.02 (2H, t, J = 6.3 Hz), 3.61 (2H, s), 5.51 (1H, t, J = 8.4 Hz), 7.44 (1H, d, J = 1.2 Hz), 7.56-7.60 (1H, m), 8.04-8.07 (1H, m), 8.19 (1H, d, J = 1.2 Hz), 8.55-8.56 (1H, m), 8.83-8.84 (1H, m).
LRMS (ESI): m/z 328 [M + H]+, 350 [M + Na]+.
HRMS (ESI) m/z calcd for C19H26N3O2: 328.20250 [M + H]+; found: 328.20215。
[Step 2] (2Z) -5-amino-2-[(1-pyridin-3-yl-1H-imidazol-4-yl) methyl] pent-2-enoic acid In the same manner as in Step 7 of Example 6. The title compound (103 mg) was obtained from the compound (179 mg) obtained in Step 1 of this example.
1 H NMR (CD 3 OD) δ: 2.51-2.56 (2H, m), 3.02 (2H, t, J = 6.3 Hz), 3.61 (2H, s), 5.51 (1H, t, J = 8.4 Hz), 7.44 (1H, d, J = 1.2 Hz), 7.56-7.60 (1H, m), 8.04-8.07 (1H, m), 8.19 (1H, d, J = 1.2 Hz), 8.55-8.56 (1H, m) , 8.83-8.84 (1H, m).
LRMS (ESI): m / z 328 [M + H] + , 350 [M + Na] + .
HRMS (ESI) m / z calcd for C 19 H 26 N 3 O 2 : 328.20250 [M + H] + ; found: 328.20215.
 [実施例36](2Z)-5-アミノ-2-[(1-ビフェニル-4-イル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸
 [工程1](2Z)-2-[(1-ビフェニル-4-イル-1H-イミダゾール-4-イル)メチル]-5-[(tert-ブトキシカルボニル)アミノ]ペンタ-2-エン酸tert-ブチル
 参考例8と同様の方法にて、実施例6の工程5で得られた化合物(500mg)及び4-ビフェニルボロン酸(563mg)から、標題化合物(458mg)を得た。
1H NMR (CDCl3) δ: 1.42 (9H, s), 1.45 (9H, s), 2.61-2.66 (2H, m), 3.24-3.28 (2H, m), 3.61 (2H, s), 4.99 (1H, br s), 5.97 (1H, t, J = 7.6 Hz), 7.08 (1H, d, J = 1.2 Hz), 7.39-7.49 (5H, m), 7.59-7.61 (2H, m), 7.68 (2H, d, J = 8.6 Hz), 7.83 (1H, d, J = 1.2 Hz)。
[Example 36] (2Z) -5-amino-2-[(1-biphenyl-4-yl-1H-imidazol-4-yl) methyl] pent-2-enoic acid [Step 1] (2Z) -2 -[(1-Biphenyl-4-yl-1H-imidazol-4-yl) methyl] -5-[(tert-butoxycarbonyl) amino] pent-2-butylate The title compound (458 mg) was obtained from the compound (500 mg) obtained in Step 5 of Example 6 and 4-biphenylboronic acid (563 mg).
1 H NMR (CDCl 3 ) δ: 1.42 (9H, s), 1.45 (9H, s), 2.61-2.66 (2H, m), 3.24-3.28 (2H, m), 3.61 (2H, s), 4.99 ( 1H, br s), 5.97 (1H, t, J = 7.6 Hz), 7.08 (1H, d, J = 1.2 Hz), 7.39-7.49 (5H, m), 7.59-7.61 (2H, m), 7.68 ( 2H, d, J = 8.6 Hz), 7.83 (1H, d, J = 1.2 Hz).
 [工程2](2Z)-5-アミノ-2-[(1-ビフェニル-4-イル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸
 実施例6の工程7と同様にして、本実施例の工程1で得られた化合物(458mg)から、標題化合物(258mg)を得た。
1H NMR (CD3OD) δ: 2.51-2.57 (2H, m), 3.02 (2H, t, J = 6.1 Hz), 3.61 (2H, s), 5.51 (1H, t, J = 8.4 Hz), 7.34-7.38 (1H, m), 7.41 (1H, d, J = 1.6 Hz), 7.44-7.48 (2H, m), 7.62 (2H, d, J = 8.6 Hz), 7.64-7.66 (2H, m), 7.76 (2H, d, J = 8.6 Hz), 8.12 (1H, d, J = 1.6 Hz).
LRMS (ESI): m/z 348 [M + H]+, 370 [M + Na]+.
HRMS (ESI) m/z calcd for C21H22N3O2: 348.17120 [M + H]+; found: 348.17122。
[Step 2] (2Z) -5-amino-2-[(1-biphenyl-4-yl-1H-imidazol-4-yl) methyl] pent-2-enoic acid As in Step 7 of Example 6. The title compound (258 mg) was obtained from the compound (458 mg) obtained in Step 1 of this example.
1 H NMR (CD 3 OD) δ: 2.51-2.57 (2H, m), 3.02 (2H, t, J = 6.1 Hz), 3.61 (2H, s), 5.51 (1H, t, J = 8.4 Hz), 7.34-7.38 (1H, m), 7.41 (1H, d, J = 1.6 Hz), 7.44-7.48 (2H, m), 7.62 (2H, d, J = 8.6 Hz), 7.64-7.66 (2H, m) , 7.76 (2H, d, J = 8.6 Hz), 8.12 (1H, d, J = 1.6 Hz).
LRMS (ESI): m / z 348 [M + H] + , 370 [M + Na] + .
HRMS (ESI) m / z calcd for C 21 H 22 N 3 O 2 : 348.17120 [M + H] + ; found: 348.17122.
 [実施例37](2Z)-5-アミノ-2-[(1-シクロヘプチル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸
 参考例6及び実施例5の方法と同様にして、参考例23で得られた化合物から、標題化合物(239mg)を得た。
1H NMR (CD3OD) δ: 1.52-1.72 (6H, m), 1.74-1.83 (2H, m), 1.85-1.94 (2H, m), 2.00-2.08 (2H, m), 2.46-2.51 (2H, m), 2.94 (2H, t, J = 6.3 Hz), 3.49 (2H, s), 4.16 (1H, tt, J = 10.4, 4.3 Hz), 5.37 (1H, t, J = 8.2 Hz), 6.94 (1H, br s), 7.58 (1H, br s).
LRMS (ESI): m/z 292 [M + H]+, 314 [M + Na]+.
HRMS (ESI) m/z calcd for C16H26N3O2: 292.20250 [M + H]+; found: 292.20325。
[Example 37] (2Z) -5-amino-2-[(1-cycloheptyl-1H-imidazol-4-yl) methyl] pent-2-enoic acid In the same manner as in Reference Example 6 and Example 5. The title compound (239 mg) was obtained from the compound obtained in Reference Example 23.
1 H NMR (CD 3 OD) δ: 1.52-1.72 (6H, m), 1.74-1.83 (2H, m), 1.85-1.94 (2H, m), 2.00-2.08 (2H, m), 2.46-2.51 ( 2H, m), 2.94 (2H, t, J = 6.3 Hz), 3.49 (2H, s), 4.16 (1H, tt, J = 10.4, 4.3 Hz), 5.37 (1H, t, J = 8.2 Hz), 6.94 (1H, br s), 7.58 (1H, br s).
LRMS (ESI): m / z 292 [M + H] + , 314 [M + Na] + .
HRMS (ESI) m / z calcd for C 16 H 26 N 3 O 2 : 292.20250 [M + H] + ; found: 292.20325.
 [実施例38](2Z)-5-アミノ-2-[(1-シクロプロピル-1H-イミダゾール-4-イル)メチル]ペンタ-2-エン酸
 参考例6及び実施例5の方法と同様にして、参考例24で得られた化合物から、標題化合物(303mg)を得た。
1H NMR (CD3OD) δ: 0.94-0.98 (4H, m), 2.50-2.45 (2H, m), 2.92 (2H, t, J = 6.3 Hz), 3.36-3.42 (1H, m), 3.47 (2H, s), 5.38 (1H, t, J = 8.2 Hz), 6.92 (1H, d, J = 1.2 Hz), 7.59 (1H, d, J = 1.2 Hz).
LRMS (ESI): m/z 236 [M + H]+, 258 [M + Na]+.
HRMS (ESI) m/z calcd for C12H18N3O2: 236.13990 [M + H]+; found: 236.13809。
[Example 38] (2Z) -5-amino-2-[(1-cyclopropyl-1H-imidazol-4-yl) methyl] pent-2-enoic acid In the same manner as in Reference Example 6 and Example 5. Then, the title compound (303 mg) was obtained from the compound obtained in Reference Example 24.
1 H NMR (CD 3 OD) δ: 0.94-0.98 (4H, m), 2.50-2.45 (2H, m), 2.92 (2H, t, J = 6.3 Hz), 3.36-3.42 (1H, m), 3.47 (2H, s), 5.38 (1H, t, J = 8.2 Hz), 6.92 (1H, d, J = 1.2 Hz), 7.59 (1H, d, J = 1.2 Hz).
LRMS (ESI): m / z 236 [M + H] + , 258 [M + Na] + .
HRMS (ESI) m / z calcd for C 12 H 18 N 3 O 2 : 236.13990 [M + H] + ; found: 236.13809.
 [実施例39](2Z)-5-アミノ-2-{[1-(cis-4-ヒドロキシシクロヘキシル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 [工程1](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-{[1-(cis-4-{[tert-ブチル(ジフェニル)シリル]オキシ}シクロヘキシル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸tert-ブチル
 実施例26の工程1と同様にして、実施例6の工程5で得られた化合物(500mg)とtrans-4-{[tert-ブチル(ジフェニル)シリル]オキシ}シクロヘキサノール(1.51g)から、標題化合物(132mg)を得た。
1H-NMR (CDCl3) δ: 1.10 (9H, s), 1.37-1.47 (20H, m), 1.74-1.89 (4H, m), 2.16-2.29 (2H, m), 2.57-2.66 (2H, m), 3.19-3.27 (2H, m), 3.53 (2H, s), 3.78-3.88 (1H, m), 4.06 (1H, br s), 4.94 (1H, br s), 5.90 (1H, t, J = 7.4 Hz), 6.74 (1H, s), 7.35-7.50 (7H, m), 7.63-7.69 (4H, m)。
[Example 39] (2Z) -5-amino-2-{[1- (cis-4-hydroxycyclohexyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid [Step 1] (2Z ) -5-[(tert-butoxycarbonyl) amino] -2-{[1- (cis-4-{[tert-butyl (diphenyl) silyl] oxy} cyclohexyl) -1H-imidazol-4-yl] methyl} Tert-butyl penta-2-enoate In the same manner as in Step 1 of Example 26, the compound obtained in Step 5 of Example 6 (500 mg) and trans-4-{[tert-butyl (diphenyl) silyl] oxy } The title compound (132 mg) was obtained from cyclohexanol (1.51 g).
1 H-NMR (CDCl 3 ) δ: 1.10 (9H, s), 1.37-1.47 (20H, m), 1.74-1.89 (4H, m), 2.16-2.29 (2H, m), 2.57-2.66 (2H, m), 3.19-3.27 (2H, m), 3.53 (2H, s), 3.78-3.88 (1H, m), 4.06 (1H, br s), 4.94 (1H, br s), 5.90 (1H, t, J = 7.4 Hz), 6.74 (1H, s), 7.35-7.50 (7H, m), 7.63-7.69 (4H, m).
 [工程2](2Z)-5-[(tert-ブトキシカルボニル)アミノ]-2-{[1-(cis-4-ヒドロキシシクロヘキシル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸tert-ブチル
 工程1で得た化合物(132mg)をテトラヒドロフラン(5mL)に溶解し、テトラブチルアンモニウムフルオリド(TBAF、1mol/Lテトラヒドロフラン溶液、0.5mL)を加えて室温で終夜撹拌した。さらに、TBAF(1mL)を加えて室温で終夜攪拌後、TBAF(3mL)を加えて終夜撹拌した。減圧下溶媒を留去して、酢酸エチル及び水を加えて分液した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。濃縮後、シリカゲルクロマトグラフィー(溶出溶媒:メタノール/塩化メチレン=5/95)で精製し、標題化合物(65.8mg)を得た。
1H-NMR (CDCl3) δ: 1.39-1.47 (18H, m), 1.54-1.71 (2H, m), 1.80-1.96 (4H, m), 2.03-2.17 (2H, m), 2.53-2.64 (2H, m), 3.19-3.26 (2H, m), 3.52 (2H, br s), 3.81-3.92 (1H, m), 4.11 (1H, br s), 4.95 (1H, br s), 5.87 (1H, t, J = 7.8 Hz), 6.72 (1H, s), 7.47 (1H, s)。
[Step 2] (2Z) -5-[(tert-butoxycarbonyl) amino] -2-{[1- (cis-4-hydroxycyclohexyl) -1H-imidazol-4-yl] methyl} pent-2-ene Acid tert-butyl The compound (132 mg) obtained in Step 1 was dissolved in tetrahydrofuran (5 mL), tetrabutylammonium fluoride (TBAF, 1 mol / L tetrahydrofuran solution, 0.5 mL) was added, and the mixture was stirred overnight at room temperature. Further, TBAF (1 mL) was added and stirred overnight at room temperature, and then TBAF (3 mL) was added and stirred overnight. The solvent was distilled off under reduced pressure, and ethyl acetate and water were added for liquid separation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration, the residue was purified by silica gel chromatography (eluent: methanol / methylene chloride = 5/95) to give the title compound (65.8 mg).
1 H-NMR (CDCl 3 ) δ: 1.39-1.47 (18H, m), 1.54-1.71 (2H, m), 1.80-1.96 (4H, m), 2.03-2.17 (2H, m), 2.53-2.64 ( 2H, m), 3.19-3.26 (2H, m), 3.52 (2H, br s), 3.81-3.92 (1H, m), 4.11 (1H, br s), 4.95 (1H, br s), 5.87 (1H , t, J = 7.8 Hz), 6.72 (1H, s), 7.47 (1H, s).
 [工程3](2Z)-5-アミノ-2-{[1-(cis-4-ヒドロキシシクロヘキシル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 実施例6の工程7と同様にして、本実施例の工程2で得られた化合物(65.8mg)から、標題化合物(22mg)を得た。
1H-NMR (CD3OD) δ: 1.64-1.73 (2H, m), 1.78-1.91 (4H, m), 2.03-2.14 (2H, m), 2.46-2.53 (2H, m), 2.99 (2H, t, J = 6.1 Hz), 3.50 (2H, s), 3.96-4.06 (2H, m), 5.39 (1H, t, J = 8.5 Hz), 6.97 (1H, s), 7.63 (1H, s).
LRMS (ESI): m/z 294 [M + H]+, 316 [M + Na]+.
HRMS (ESI) m/z calcd for C15H24N3O3: 294.18177 [M + H]+; found: 294.18207。
[Step 3] (2Z) -5-amino-2-{[1- (cis-4-hydroxycyclohexyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid Step 7 of Example 6 and Similarly, the title compound (22 mg) was obtained from the compound (65.8 mg) obtained in Step 2 of this example.
1 H-NMR (CD 3 OD) δ: 1.64-1.73 (2H, m), 1.78-1.91 (4H, m), 2.03-2.14 (2H, m), 2.46-2.53 (2H, m), 2.99 (2H , t, J = 6.1 Hz), 3.50 (2H, s), 3.96-4.06 (2H, m), 5.39 (1H, t, J = 8.5 Hz), 6.97 (1H, s), 7.63 (1H, s) .
LRMS (ESI): m / z 294 [M + H] + , 316 [M + Na] + .
HRMS (ESI) m / z calcd for C 15 H 24 N 3 O 3: 294.18177 [M + H] +; found: 294.18207.
 [実施例40](2Z)-5-アミノ-2-{[1-(4,4-ジフルオロシクロヘキシル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸
 実施例39の工程1及び実施例6の工程7と同様にして、標題化合物(20mg)を得た。
1H-NMR (CD3OD) δ: 1.62-2.29 (8H, m), 2.46-2.56 (2H, m), 2.91-3.01 (2H, m), 3.62 (2H, s), 4.17-4.27 (1H, m), 5.21-5.28 (1H, m), 6.79 (1H, s), 7.75 (1H, s).
LRMS (ESI): m/z 314 [M + H]+, 336 [M + Na]+.
HRMS (ESI) m/z calcd for C15H22F2N3O2: 314.16801 [M + H]+; found: 314.16771。
Example 40 (2Z) -5-amino-2-{[1- (4,4-difluorocyclohexyl) -1H-imidazol-4-yl] methyl} pent-2-enoic acid Step 1 of Example 39 In the same manner as in Step 7 of Example 6, the title compound (20 mg) was obtained.
1 H-NMR (CD 3 OD) δ: 1.62-2.29 (8H, m), 2.46-2.56 (2H, m), 2.91-3.01 (2H, m), 3.62 (2H, s), 4.17-4.27 (1H , m), 5.21-5.28 (1H, m), 6.79 (1H, s), 7.75 (1H, s).
LRMS (ESI): m / z 314 [M + H] + , 336 [M + Na] + .
HRMS (ESI) m / z calcd for C 15 H 22 F 2 N 3 O 2 : 314.16801 [M + H] + ; found: 314.16771.
 [実施例41](2Z)-5-({[1-(イソブチリルオキシ)エトキシ]カルボニル}アミノ)-2-{[1-(trans-4-メチルシクロヘキシル)-1H-イミダゾール-4-イル]メチル}ペンタ-2-エン酸 ナトリウム塩
 実施例21で得られた化合物(600mg)及び炭酸水素ナトリウム(346mg)を水(10mL)に溶解させ、室温攪拌下、イソ酪酸1-({[(2,5-ジオキソピロリジン-1-イル)オキシ]カルボニル}オキシ)エチル(WO2005/66122)のアセトニトリル溶液(5mL)を加え、終夜攪拌した。反応液を濃縮した後、残渣に飽和食塩水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。ろ過し、減圧濃縮した後、得られた粗生成物をシリカゲルカラムクロマトグラフィーにて精製することにより、標題化合物のフリー体を得た(339mg)。これをアセトン(6mL)及びイオン交換水(6mL)の混合溶媒に溶解させ、室温攪拌下、炭酸ナトリウム(40.0mg)を加えた。室温にて2時間攪拌した後、反応液を濃縮し、残渣を凍結乾燥することにより標題化合物(351mg)を得た。
1H NMR (CD3OD) δ: 0.94 (3H, d, J = 6.6 Hz), 1.11-1.19 (2H, m), 1.12 (6H, d, J = 7.0 Hz), 1.41 (3H, d, J = 5.5 Hz), 1.43-1.52 (1H, m), 1.67-1.77 (2H, m), 1.81-1.85 (2H, m), 2.01-2.05 (2H, m), 2.42-2.48 (2H, m), 2.46-2.53 (1H, m), 3.12-3.16 (2H, m), 3.50 (2H, s), 3.92 (1H, tt, J = 11.9, 3.8 Hz), 5.32 (1H, t, J = 7.4 Hz), 6.73 (1H, q, J = 5.5 Hz), 6.93 (1H, d, J = 1.6 Hz), 7.53 (1H, d, J = 1.6 Hz).
LRMS (ESI): m/z 448 [M - Na]-.
HRMS (ESI) m/z calcd for C23H34N3O6: 448.24476 [M - H]-; found: 448.24477。
Example 41 (2Z) -5-({[1- (isobutyryloxy) ethoxy] carbonyl} amino) -2-{[1- (trans-4-methylcyclohexyl) -1H-imidazole-4- Yl] methyl} pent-2-enoic acid sodium salt The compound obtained in Example 21 (600 mg) and sodium hydrogen carbonate (346 mg) were dissolved in water (10 mL), and stirred at room temperature, isobutyric acid 1-({[ A solution of (2,5-dioxopyrrolidin-1-yl) oxy] carbonyl} oxy) ethyl (WO2005 / 66122) in acetonitrile (5 mL) was added and stirred overnight. The reaction mixture was concentrated, saturated brine was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography to obtain a free form of the title compound (339 mg). This was dissolved in a mixed solvent of acetone (6 mL) and ion-exchanged water (6 mL), and sodium carbonate (40.0 mg) was added with stirring at room temperature. After stirring at room temperature for 2 hours, the reaction mixture was concentrated, and the residue was lyophilized to give the title compound (351 mg).
1 H NMR (CD 3 OD) δ: 0.94 (3H, d, J = 6.6 Hz), 1.11-1.19 (2H, m), 1.12 (6H, d, J = 7.0 Hz), 1.41 (3H, d, J = 5.5 Hz), 1.43-1.52 (1H, m), 1.67-1.77 (2H, m), 1.81-1.85 (2H, m), 2.01-2.05 (2H, m), 2.42-2.48 (2H, m), 2.46-2.53 (1H, m), 3.12-3.16 (2H, m), 3.50 (2H, s), 3.92 (1H, tt, J = 11.9, 3.8 Hz), 5.32 (1H, t, J = 7.4 Hz) , 6.73 (1H, q, J = 5.5 Hz), 6.93 (1H, d, J = 1.6 Hz), 7.53 (1H, d, J = 1.6 Hz).
LRMS (ESI): m / z 448 [M-Na] - .
HRMS (ESI) m / z calcd for C 23 H 34 N 3 O 6: 448.24476 [M - H] -; found: 448.24477.
 [試験例1]TAFIa酵素阻害活性の測定
 (1) TAFIの活性化
 反応液の調製にはHEPES buffered saline(20mM HEPES,150mM NaCl、pH7.4、以下HBS)を用いた。250μg/mLのTAFI溶液12μLに、4U/mLヒトトロンビン、12U/mLウサギ肺トロンボモジュリン、及び12mM CaClを含むHBS溶液を30μL添加し、穏やかに撹拌した後、室温でTAFIを活性化させた。10分後に100μM PPACK(トロンビン阻害剤)を10μL加え、トロンビンを中和することによりTAFIの活性化を終了させた。生成したTAFIaは氷中保存し、測定に用いる直前に終濃度0.1%となるように調製したBSA(ウシ血清アルブミン)を含むHBS溶液2050μLで希釈した。
[Test Example 1] Measurement of TAFIa enzyme inhibitory activity (1) Activation of TAFI HEPES buffered saline (20 mM HEPES, 150 mM NaCl, pH 7.4, hereinafter HBS) was used for the preparation of the reaction solution. To 12 μL of 250 μg / mL TAFI solution, 30 μL of HBS solution containing 4 U / mL human thrombin, 12 U / mL rabbit lung thrombomodulin, and 12 mM CaCl 2 was added, and after gently stirring, TAFI was activated at room temperature. Ten minutes later, 10 μL of 100 μM PPACK (thrombin inhibitor) was added to neutralize thrombin to terminate the activation of TAFI. The produced TAFIa was stored in ice and diluted with 2050 μL of an HBS solution containing BSA (bovine serum albumin) prepared to a final concentration of 0.1% immediately before use in measurement.
 (2)TAFIa阻害活性の測定
 被検物質はHBSで溶解し、評価濃度の10倍濃度からなる希釈系列を調製した。96wellプレートの各wellに80μLのTAFIa溶液及び10μLの被検物質を添加し、10分間振盪して混和させた。各wellに5mg/mLに調製したフリルアクリロイル-アラニル-リジン(FAAK)を10μLずつ添加し、この混合液の330nmにおける吸光度の推移を30分間読み取り、基質の分解速度を測定した。
(2) Measurement of TAFIa inhibitory activity The test substance was dissolved in HBS, and a dilution series consisting of 10 times the evaluation concentration was prepared. To each well of a 96-well plate, 80 μL of TAFIa solution and 10 μL of a test substance were added and mixed by shaking for 10 minutes. 10 μL of furylacryloyl-alanyl-lysine (FAAK) adjusted to 5 mg / mL was added to each well, and the change in absorbance at 330 nm of this mixture was read for 30 minutes, and the degradation rate of the substrate was measured.
 (3)阻害活性IC50の算出
 各wellにおける基質の分解速度をTAFIa溶液の希釈系列よりなる標準曲線に当てはめ、TAFIa活性を算出した。被検化合物の濃度とTAFIa活性の相関より、50%阻害濃度(IC50)を算出した。なお、対照として、化合物A(国際公開第2002/014285号パンフレット中の実施例7の化合物)を用いた。結果を表1に示す。
(3) Calculation of inhibitory activity IC 50 The degradation rate of the substrate in each well was applied to a standard curve consisting of a dilution series of TAFIa solution to calculate TAFIa activity. A 50% inhibitory concentration (IC 50 ) was calculated from the correlation between the concentration of the test compound and the TAFIa activity. As a control, compound A (the compound of Example 7 in WO 2002/014285 pamphlet) was used. The results are shown in Table 1.
 [表1]TAFIa酵素阻害活性
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実施例番号     TAFIa IC50(μM)
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実施例21        0.0062
化合物A         0.034
―――――――――――――――――――――――――――――――――。
[Table 1] TAFIa enzyme inhibitory activity ――――――――――――――――――――――――――――――――――
Example No. TAFIa IC 50 (μM)
――――――――――――――――――――――――――――――――――
Example 21 0.0062
Compound A 0.034
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 本発明の化合物は、優れたTAFIa阻害活性を示し、心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の治療のための医薬として有用である。 The compound of the present invention exhibits excellent TAFIa inhibitory activity, and includes myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation. It is useful as a medicament for the treatment of syndrome or pulmonary fibrosis.
 [試験例2]血漿塊溶解時間の測定による線溶促進活性の評価
 96穴プレートに20μL/wellのHBS、50μL/wellのヒト正常血漿、10μL/wellの化合物溶液(HBSにより溶解し、同バッファーにて段階希釈して化合物溶液を調製した)、10μL/wellのtPA(アクチバシン(協和発酵キリン)を添付の溶解液により60万U/mLになるように調製し、HBSにより希釈)を添加して撹拌後、10μL/wellの反応液A(13.8U/mLのヒトトロンビン、170mMのCaCl及び0.9U/mLのトロンボモジュリン)を添加して再び撹拌してプレートリーダーにて405nmの吸光度を、37℃で保温しながら30秒ごとに測定し、凝固の程度を測定した。吸光度の推移のうち線溶過程における最大吸光度(ABS-max)と最小吸光度(ABS-min)の平均値(ABS-ave:[(ABS-max)-(ABS-min)]/2)に最も近い吸光度を示す時点を1/2 lysis time(1/2 LT)として各ウェルの線溶活性の指標とした。被験物質の濃度と1/2 LTの関係から、1/2 LTを50%とする濃度をEC50として算出した。なお、対照として、化合物A(国際公開第2002/014285号パンフレット中の実施例7の化合物)を用いた。結果を表2に示す。
[Test Example 2] Evaluation of fibrinolysis-promoting activity by measuring plasma clot dissolution time 20 μL / well HBS, 50 μL / well human normal plasma, 10 μL / well compound solution (dissolved in HBS and buffered in a 96-well plate) 10 μL / well tPA (activacin (Kyowa Hakko Kirin) was prepared to 600,000 U / mL with the attached solution and diluted with HBS) was added. After stirring, 10 μL / well of reaction solution A (13.8 U / mL human thrombin, 170 mM CaCl 2 and 0.9 U / mL thrombomodulin) was added and stirred again, and the absorbance at 405 nm was measured with a plate reader. The temperature was measured every 30 seconds while keeping at 37 ° C., and the degree of coagulation was measured. Of the changes in absorbance, the average value (ABS-ave: [(ABS-max)-(ABS-min)] / 2) of the maximum absorbance (ABS-max) and the minimum absorbance (ABS-min) in the fibrinolysis process is the highest. The time point indicating the near absorbance was set to 1/2 lysis time (1/2 LT), which was used as an index of the fibrinolytic activity of each well. From the relationship between the concentration and 1/2 LT of the test substance, the concentration was calculated for the 1/2 LT 50% as EC 50. As a control, compound A (the compound of Example 7 in WO 2002/014285 pamphlet) was used. The results are shown in Table 2.
 [表2]線溶促進活性
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実施例       血漿塊溶解 EC50(nM)
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実施例21        11
化合物A         65
―――――――――――――――――――――――――――――――――。
[Table 2] Fibrinolysis promoting activity ――――――――――――――――――――――――――――――――――
Example Plasma Clot Lysis EC 50 (nM)
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Example 21 11
Compound A 65
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 本発明の化合物は、優れた線溶促進活性を示し、心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の治療のための医薬として有用である。 The compound of the present invention exhibits excellent fibrinolysis promoting activity, myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular It is useful as a medicament for the treatment of coagulation syndrome or pulmonary fibrosis.
 [試験例3]ラット血栓塞栓症モデルでの線溶促進活性の評価
 Wistarラット(購入先:日本SLC社)を使用した。任意の時点において0.5%メチルセルロース溶液で調製した被検物質を経口投与し、又は生理食塩水で調製した被験物質を静脈内投与し、40分後又は4時間後にチオペンタール麻酔下にて頸静脈より生理食塩水で2.25U/mLに調製したPT試薬(Thromboplastin C plus、Sysmex)を持続注入(16.8mL/kg/hr x 20min)した。陽性対照群として、過剰用量のTAFIa阻害薬投与群を設定した。PT試薬の注入開始から45分後に頚静脈よりクエン酸採血し、血漿を獲得した。全自動凝固測定装置ACL-9000又はACL-TOP500CTSを用いて血漿中に含まれるD-dimer量を測定し、陽性対照群の平均値に対する比率を算出し、D-dimer50%上昇させる用量としてED50を算出した。
[Test Example 3] Evaluation of fibrinolysis-promoting activity in rat thromboembolism model Wistar rats (supplier: Japan SLC) were used. A test substance prepared with a 0.5% methylcellulose solution is orally administered at an arbitrary time point, or a test substance prepared with physiological saline is intravenously administered. After 40 minutes or 4 hours, the jugular vein under thiopental anesthesia Further, PT reagent (Thromboplastin C plus, Sysmex) prepared to 2.25 U / mL with physiological saline was continuously injected (16.8 mL / kg / hr x 20 min). As a positive control group, an overdose TAFIa inhibitor administration group was set. 45 minutes after the start of PT reagent injection, citrate blood was collected from the jugular vein to obtain plasma. The amount of D-dimer contained in plasma is measured using a fully automatic coagulation analyzer ACL-9000 or ACL-TOP500CTS, the ratio to the mean value of the positive control group is calculated, and ED 50 is used as a dose to increase D-dimer by 50 %. Was calculated.
 本発明の化合物は、生体内で優れた線溶促進活性を示し、心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の治療のための医薬として有用である。

 (製剤例1)ハ-ドカプセル剤
 標準二分式ハ-ドゼラチンカプセルの各々に、100mgの粉末状の実施例1の化合物、150mgのラクト-ス、50mgのセルロ-ス及び6mgのステアリン酸マグネシウムを充填することにより、単位カプセルを製造し、洗浄後、乾燥する。
The compound of the present invention exhibits excellent fibrinolysis promoting activity in vivo, myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, dissemination It is useful as a medicine for the treatment of vascular coagulation syndrome or pulmonary fibrosis.

Formulation Example 1 Hard Capsule Each standard bipartite hard gelatin capsule contains 100 mg of the powdered compound of Example 1, 150 mg lactose, 50 mg cellulose and 6 mg magnesium stearate. The unit capsule is manufactured by filling, and after washing, dried.
 (製剤例2)ソフトカプセル剤
 消化性油状物、例えば、大豆油、綿実油又はオリ-ブ油中に入れた、実施例2の化合物の混合物を調製し、正置換ポンプでゼラチン中に注入して、100mgの活性成分を含有するソフトカプセルを得、洗浄後、乾燥する。
Formulation Example 2 Soft Capsules A mixture of the compound of Example 2 in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected into gelatin with a positive displacement pump, Soft capsules containing 100 mg of active ingredient are obtained, washed and dried.
 (製剤例3)錠剤
 常法に従って、100mgの実施例3の化合物、0.2mgのコロイド性二酸化珪素、5mgのステアリン酸マグネシウム、275mgの微結晶性セルロ-ス、11mgのデンプン及び98.8mgのラクト-スを用いて製造する。
Formulation Example 3 Tablet According to conventional methods, 100 mg of the compound of Example 3, 0.2 mg colloidal silicon dioxide, 5 mg magnesium stearate, 275 mg microcrystalline cellulose, 11 mg starch and 98.8 mg Manufactured using lactose.
 なお、所望により、剤皮を塗布する。 In addition, if desired, apply a coating.
 (製剤例4)懸濁剤
 5mL中に、100mgの微粉化した実施例4の化合物、100mgのナトリウムカルボキシ基メチルセルロ-ス、5mgの安息香酸ナトリウム、1.0gのソルビト-ル溶液(日本薬局方)及び0.025mLのバニリンを含有するように製造する。
(Formulation example 4) Suspension agent In 5 mL, 100 mg of the compound of Example 4 finely divided, 100 mg sodium carboxy group methylcellulose, 5 mg sodium benzoate, 1.0 g sorbitol solution (Japanese Pharmacopoeia ) And 0.025 mL of vanillin.
 (製剤例5)クリ-ム
 40%のホワイトペトロラトム、3%の微結晶性ワックス、10%のラノリン、5%のスパン20、0.3%のトゥイ-ン20及び41.7%の水からなる5gのクリ-ム中に100mgの微粉化した実施例5の化合物を混入することにより製造する。
Formulation Example 5 Cream 40% white petrolatum, 3% microcrystalline wax, 10% lanolin, 5% span 20, 0.3% Tween 20 and 41.7% water Prepared by mixing 100 mg of the finely divided compound of Example 5 in 5 g of cream.
 (製剤例6)注射剤 1.5重量%の実施例6の化合物を、10重量%のプロピレングリコール中で撹拌し、次いで、注射用水で一定容量に調整した後、滅菌して注射剤とする。 (Formulation example 6) Injection: 1.5% by weight of the compound of Example 6 is stirred in 10% by weight of propylene glycol, adjusted to a certain volume with water for injection, and then sterilized to give an injection. .
 本発明の一般式(I)で表されるアクリル酸誘導体又はその薬理上許容される塩は、優れたTAFIa酵素阻害活性を有し、心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群、肺線維症などの治療薬として、また、血栓塞栓症に由来する疾患の治療薬として有用である。
 
The acrylic acid derivative represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has an excellent TAFIa enzyme inhibitory activity, and includes myocardial infarction, angina pectoris, acute coronary insufficiency syndrome, cerebral infarction, It is useful as a therapeutic agent for deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation syndrome, pulmonary fibrosis and the like, and as a therapeutic agent for diseases derived from thromboembolism.

Claims (29)

  1.  一般式(I)
    Figure JPOXMLDOC01-appb-C000001
    [式中、Raは水素原子、置換基群Aから選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルキル基;置換基群Aから選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルケニル基;置換基群Bから選ばれる同一又は異なる1~3個の基で置換されていてもよいC~C10シクロアルキル基;置換基群Bから選ばれる同一又は異なる1~3個の基で置換されていてもよいアリール基;置換基群Bから選ばれる同一又は異なる1~3個の基で置換されていてもよい飽和ヘテロシクリル基;又は、置換基群Bから選ばれる同一又は異なる1~3個の基で置換されていてもよい不飽和ヘテロシクリル基を示し(置換基群Aは、水酸基、ハロゲン原子、シアノ基、ニトロ基、アミノ基、カルボキシ基、C~Cシクロアルキル基、C~Cアルコキシ基、ハロゲノC~Cアルコキシ基、C~Cアルキルスルホニル基、アリール基、飽和ヘテロシクリル基、不飽和ヘテロシクリル基、及び、アリールオキシ基からなる。置換基群Bは、置換基群Aの各置換基、C~Cアルキル基及びハロゲノC~Cアルキル基からなる。)、Rは水素原子又はC~Cアルキル基を示し、R、R、R5及びRは各々独立して水素原子、フッ素原子又はC~Cアルキル基を示し、R、R及びRは各々独立して水素原子又はC~Cアルキル基を示し、R及びRは各々独立して水素原子又はプロドラッグ基を示す。]で表される化合物、又はその薬理上許容される塩。
    Formula (I)
    Figure JPOXMLDOC01-appb-C000001
    [Wherein, R a is a hydrogen atom, a C 1 to C 6 alkyl group optionally substituted with the same or different 1 to 3 groups selected from the substituent group A; C 2 -C 6 alkenyl group optionally substituted with 1 to 3 different groups; C 3 -C 10 optionally substituted with 1 to 3 same or different groups selected from Substituent Group B A cycloalkyl group; an aryl group optionally substituted with the same or different 1 to 3 groups selected from Substituent Group B; substituted with the same or different 1 to 3 groups selected from Substituent Group B A saturated heterocyclyl group which may be substituted; or an unsaturated heterocyclyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group B (the substituent group A is a hydroxyl group, a halogen atom, Cyano group, nitro group, amino group, cal Alkoxy group, C 3 ~ C 8 cycloalkyl group, C 1 ~ C 3 alkoxy group, a halogeno C 1 ~ C 3 alkoxy group, C 1 ~ C 3 alkylsulfonyl group, an aryl group, a saturated heterocyclyl group, unsaturated heterocyclyl group, The substituent group B consists of each substituent of the substituent group A, a C 1 -C 3 alkyl group and a halogeno C 1 -C 3 alkyl group), and R b is a hydrogen atom or A C 1 -C 6 alkyl group, R 1 , R 2 , R 5 and R 6 each independently represent a hydrogen atom, a fluorine atom or a C 1 -C 6 alkyl group; and R 4 , R 7 and R 8 Each independently represents a hydrogen atom or a C 1 -C 6 alkyl group, and R 3 and R 9 each independently represents a hydrogen atom or a prodrug group. Or a pharmacologically acceptable salt thereof.
  2.  一般式(Ia)
    Figure JPOXMLDOC01-appb-C000002
    [式中、Raは置換基群Aから選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルキル基;置換基群Aから選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルケニル基;置換基群Bから選ばれる同一又は異なる1~3個の基で置換されていてもよいC~C10シクロアルキル基;置換基群Bから選ばれる同一又は異なる1~3個の基で置換されていてもよいアリール基;置換基群Bから選ばれる同一又は異なる1~3個の基で置換されていてもよい飽和ヘテロシクリル基;又は、置換基群Bから選ばれる同一又は異なる1~3個の基で置換されていてもよい不飽和ヘテロシクリル基を示し(置換基群Aは、水酸基、ハロゲン原子、シアノ基、ニトロ基、アミノ基、カルボキシ基、C~Cシクロアルキル基、C~Cアルコキシ基、ハロゲノC~Cアルコキシ基、C~Cアルキルスルホニル基、アリール基、飽和ヘテロシクリル基、不飽和ヘテロシクリル基、及び、アリールオキシ基からなる。置換基群Bは、置換基群Aの各置換基、C~Cアルキル基及びハロゲノC~Cアルキル基からなる。)、Rは水素原子又はC~Cアルキル基を示し、R、R、R5及びRは各々独立して水素原子、フッ素原子又はC~Cアルキル基を示し、R、R及びRは各々独立して水素原子又はC~Cアルキル基を示し、R及びRは各々独立して水素原子又はプロドラッグ基を示す。]で表される、請求項1に記載の化合物、又はその薬理上許容される塩。
    Formula (Ia)
    Figure JPOXMLDOC01-appb-C000002
    [Wherein, R a is a C 1 -C 6 alkyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group A; A C 2 -C 6 alkenyl group optionally substituted by 3 groups; a C 3 -C 10 cycloalkyl group optionally substituted by 1 to 3 identical or different groups selected from Substituent Group B An aryl group which may be substituted with the same or different 1 to 3 groups selected from Substituent Group B; which may be substituted with the same or different 1 to 3 groups selected from Substituent Group B; A saturated heterocyclyl group; or an unsaturated heterocyclyl group which may be substituted with the same or different 1 to 3 groups selected from the substituent group B (the substituent group A is a hydroxyl group, a halogen atom, a cyano group, Nitro group, amino group, carboxy group, 3 ~ C 8 cycloalkyl group, C 1 ~ C 3 alkoxy group, a halogeno C 1 ~ C 3 alkoxy group, C 1 ~ C 3 alkylsulfonyl group, an aryl group, a saturated heterocyclyl group, unsaturated heterocyclyl group, and, aryloxy Substituent group B consists of each substituent of substituent group A, a C 1 -C 3 alkyl group and a halogeno C 1 -C 3 alkyl group.), R b is a hydrogen atom or C 1 -C 3 6 alkyl group, R 1 , R 2 , R 5 and R 6 each independently represents a hydrogen atom, a fluorine atom or a C 1 -C 6 alkyl group, and R 4 , R 7 and R 8 are each independently Each represents a hydrogen atom or a C 1 -C 6 alkyl group, and R 3 and R 9 each independently represent a hydrogen atom or a prodrug group. The compound of Claim 1 represented by these, or its pharmacologically acceptable salt.
  3.  Raが、水酸基、ハロゲン原子、アミノ基、C~Cアルキル基、C~Cシクロアルキル基、フェニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルキル基;水酸基、ハロゲン原子、アミノ基、C~Cアルキル基、フェニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルケニル基;水酸基、ハロゲン原子、アミノ基及びC~Cアルキル基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cシクロアルキル基;水酸基、ハロゲン原子、シアノ基、アミノ基、C~Cアルキル基、ハロゲノC~Cアルキル基(当該置換基は同一の1~3個のハロゲン原子を示す。)、C~Cアルコキシ基、C~Cアルキルスルホニル基、フェニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいフェニル基;水酸基、ハロゲン原子、シアノ基、アミノ基、C~Cアルキル基、ハロゲノC~Cアルキル基、C~Cアルコキシ基、C~Cアルキルスルホニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいチエニル基;水酸基、ハロゲン原子、アミノ基、C~Cアルキル基、ハロゲノC~Cアルキル基、C~Cアルコキシ基、C~Cアルキルスルホニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいピリジル基;又は、水酸基、ハロゲノ基、アミノ基、C~Cアルキル基、ハロゲノC~Cアルキル基、C~Cアルコキシ基、C~Cアルキルスルホニル基及びフェノキシ基から選ばれる同一又は異なる1~3個の基で置換されていてもよいテトラヒドロピラニル基である、請求項1又は2に記載の化合物、又はその薬理上許容される塩。 R a is substituted with 1 to 3 identical or different groups selected from a hydroxyl group, a halogen atom, an amino group, a C 1 -C 3 alkyl group, a C 3 -C 6 cycloalkyl group, a phenyl group and a phenoxy group. C 1 -C 6 alkyl group which may be substituted with 1 to 3 same or different groups selected from hydroxyl group, halogen atom, amino group, C 1 -C 3 alkyl group, phenyl group and phenoxy group A good C 2 -C 6 alkenyl group; a C 3 -C 8 cycloalkyl optionally substituted by the same or different 1 to 3 groups selected from a hydroxyl group, a halogen atom, an amino group and a C 1 -C 3 alkyl group group; a hydroxyl group, a halogen atom, a cyano group, an amino group, C 1 ~ C 3 alkyl group, a halogeno C 1 ~ C 3 alkyl group (shown said substitution the same 1 to 3 halogen atoms.) C 1 ~ C 3 alkoxy group, C 1 ~ C 3 alkylsulfonyl group, the same or different 1 to 3 phenyl group which may be substituted with a group selected from phenyl group and phenoxy group; a hydroxyl group, a halogen atom, a cyano 1 to 3 identical or different selected from a group, an amino group, a C 1 -C 3 alkyl group, a halogeno C 1 -C 3 alkyl group, a C 1 -C 3 alkoxy group, a C 1 -C 3 alkylsulfonyl group and a phenoxy group Thienyl group optionally substituted by one group; hydroxyl group, halogen atom, amino group, C 1 -C 3 alkyl group, halogeno C 1 -C 3 alkyl group, C 1 -C 3 alkoxy group, C 1 -C A pyridyl group optionally substituted by the same or different 1 to 3 groups selected from a 3- alkylsulfonyl group and a phenoxy group; or a hydroxyl group, a halogeno group, an amino group 1 to 3 identical or different groups selected from the following groups: C 1 -C 3 alkyl group, halogeno C 1 -C 3 alkyl group, C 1 -C 3 alkoxy group, C 1 -C 3 alkylsulfonyl group and phenoxy group The compound according to claim 1 or 2, or a pharmacologically acceptable salt thereof, which is a tetrahydropyranyl group optionally substituted with a group.
  4.  Raが、C~Cシクロアルキル基又はフェニル基で置換されていてもよいC~Cアルキル基;水酸基、若しくは同一の1~2個のC~Cアルキル基で置換されていてもよいC~Cシクロアルキル基;ハロゲン原子、C~Cアルキル基、ハロゲノC~Cアルキル基(当該置換基は1~3個のフッ素原子を示す。)、C~Cアルコキシ基又はフェニル基で置換されていてもよいフェニル基;ハロゲン原子、C~Cアルキル基及びC~Cアルコキシ基から選ばれる同一又は異なる1~2個の基で置換されていてもよいチエニル基;ハロゲン原子、C~Cアルキル基及びC~Cアルコキシ基から選ばれる同一又は異なる1~2個の基で置換されていてもよいピリジル基;又は、テトラヒドロピラニル基である、請求項1又は2に記載の化合物、又はその薬理上許容される塩。 R a is a C 1 -C 6 alkyl group optionally substituted with a C 3 -C 6 cycloalkyl group or a phenyl group; a hydroxyl group or one or two identical C 1 -C 3 alkyl groups An optionally substituted C 3 -C 8 cycloalkyl group; a halogen atom, a C 1 -C 3 alkyl group, a halogeno C 1 -C 3 alkyl group (the substituent represents 1 to 3 fluorine atoms), C A 1 to C 3 alkoxy group or a phenyl group optionally substituted by a phenyl group; one or two groups selected from the same or different groups selected from a halogen atom, a C 1 to C 3 alkyl group and a C 1 to C 3 alkoxy group; A thienyl group which may be substituted; a pyridyl group which may be substituted with one or two identical or different groups selected from a halogen atom, a C 1 -C 3 alkyl group and a C 1 -C 3 alkoxy group; or , A tiger tetrahydropyranyl group, compound, or a pharmacologically acceptable salt thereof according to claim 1 or 2.
  5.  Raが、C~Cアルキル基;C~Cシクロアルキル基若しくはフェニル基で置換されているC~Cアルキル基;C~Cシクロアルキル基;水酸基若しくは1~2個のメチル基で置換されているシクロヘキシル基;フェニル基;塩素原子、フッ素原子、C~Cアルキル基、トリフルオロメチル基若しくはフェニル基で置換されているフェニル基又は、チエニル基、ピリジル基、又は、テトラヒドロチエニル基である、請求項1又は2に記載の化合物、又はその薬理上許容される塩。 R a is a C 3 to C 6 alkyl group; a C 3 to C 6 cycloalkyl group or a C 1 to C 2 alkyl group substituted with a phenyl group; a C 3 to C 7 cycloalkyl group; a hydroxyl group or 1 to 2 A cyclohexyl group substituted with one methyl group; a phenyl group; a phenyl group substituted with a chlorine atom, a fluorine atom, a C 1 -C 4 alkyl group, a trifluoromethyl group or a phenyl group, or a thienyl group or a pyridyl group Or the compound of Claim 1 or 2 which is a tetrahydrothienyl group, or its pharmacologically acceptable salt.
  6.  Raが、1~2個のメチル基で置換されたシクロヘキシル基である、請求項1又は2に記載の化合物、又はその薬理上許容される塩。 The compound according to claim 1 or 2, or a pharmacologically acceptable salt thereof, wherein R a is a cyclohexyl group substituted with 1 to 2 methyl groups.
  7.  Raが、基
    Figure JPOXMLDOC01-appb-C000003
    (ここで、*は結合位置を示す。)である、請求項1又は2に記載の化合物、又はその薬理上許容される塩。
    R a is a group
    Figure JPOXMLDOC01-appb-C000003
    (Wherein * represents a binding position), or the pharmacologically acceptable salt thereof according to claim 1 or 2.
  8.  Raが、基
    Figure JPOXMLDOC01-appb-C000004
    (ここで、*は結合位置を示す。)である、請求項1又は2に記載の化合物、又はその薬理上許容される塩。
    R a is a group
    Figure JPOXMLDOC01-appb-C000004
    (Wherein * represents a binding position), or the pharmacologically acceptable salt thereof according to claim 1 or 2.
  9.  Rが水素原子又はメチル基である、請求項1~8のいずれか1項に記載の化合物、又はその薬理上許容される塩。 The compound according to any one of claims 1 to 8, or a pharmacologically acceptable salt thereof, wherein R b is a hydrogen atom or a methyl group.
  10.  Rが水素原子である、請求項1~8のいずれか1項に記載の化合物、又はその薬理上許容される塩。 The compound according to any one of claims 1 to 8, or a pharmacologically acceptable salt thereof, wherein R b is a hydrogen atom.
  11.  R、R、R、R、R及びRがいずれも水素原子であり、R5が水素原子又はメチル基である、請求項1~10のいずれか1項に記載の化合物、又はその薬理上許容される塩。 The compound according to any one of claims 1 to 10, wherein R 1 , R 2 , R 4 , R 6 , R 7 and R 8 are all hydrogen atoms, and R 5 is a hydrogen atom or a methyl group. Or a pharmacologically acceptable salt thereof.
  12.  R、R、R、R5、R、R及びRがいずれも水素原子である、請求項1~10のいずれか1項に記載の化合物、又はその薬理上許容される塩。 The compound according to any one of claims 1 to 10, wherein R 1 , R 2 , R 4 , R 5 , R 6 , R 7 and R 8 are all hydrogen atoms, or a pharmaceutically acceptable salt thereof. salt.
  13.  R及びRがいずれも水素原子である、請求項1~12のいずれか1項に記載の化合物、又はその薬理上許容される塩。 The compound according to any one of claims 1 to 12, or a pharmacologically acceptable salt thereof, wherein both R 3 and R 9 are hydrogen atoms.
  14.  Rがプロドラッグ基であり、当該プロドラッグ基が、アミノ基、ハロゲン原子、水酸基、カルボキシ基、カルバモイル基、C~Cアルコキシ基、アリール基及びへテロシクリル基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルカノイル基;C~Cアルキル基;C~Cアルカノイルオキシ基、(C~Cシクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1~3個の基で置換されていてもよい(C~Cアルコキシ)カルボニル基;又は、オキソ基及びC~Cアルキル基から選ばれる同一又は異なる1~3個の基で置換されていてもよいヘテロシクリルアルキルオキシカルボニル基である、請求項1~12のいずれか1項に記載の化合物、又はその薬理上許容される塩。 R 9 is a prodrug group, and the prodrug group is the same or different 1 selected from an amino group, a halogen atom, a hydroxyl group, a carboxy group, a carbamoyl group, a C 1 -C 6 alkoxy group, an aryl group and a heterocyclyl group. A C 1 -C 6 alkanoyl group optionally substituted with 3 groups; a C 1 -C 6 alkyl group; a C 2 -C 6 alkanoyloxy group, a (C 3 -C 6 cycloalkyl) carbonyloxy group and (C 1 -C 6 alkoxy) carbonyl group optionally substituted by the same or different 1 to 3 groups selected from an aryl group; or the same or different selected from an oxo group and a C 1 -C 6 alkyl group The compound according to any one of claims 1 to 12, which is a heterocyclylalkyloxycarbonyl group optionally substituted with 1 to 3 groups. Or a pharmacologically acceptable salt thereof.
  15.  Rがプロドラッグ基であり、当該プロドラッグ基が、フェニルアラニル基、L-ノルロイシル基、[(5-メチル-2-オキソ-1,3-ジオキソール-4-イル)メトキシ]カルボニル基、[1-(イソブチリルオキシ)エトキシ]カルボニル基、[1-(2,2-ジメチルプロパノイルオキシ)エトキシ]カルボニル基、({1-[(シクロヘキシルカルボニル)オキシ]エトキシ}カルボニル)基、又は、(1-アセトキシエトキシ)カルボニル基である、請求項1~12のいずれか1項に記載の化合物、又はその薬理上許容される塩。 R 9 is a prodrug group, and the prodrug group includes a phenylalanyl group, an L-norleucyl group, a [(5-methyl-2-oxo-1,3-dioxol-4-yl) methoxy] carbonyl group, [1- (isobutyryloxy) ethoxy] carbonyl group, [1- (2,2-dimethylpropanoyloxy) ethoxy] carbonyl group, ({1-[(cyclohexylcarbonyl) oxy] ethoxy} carbonyl) group, or The compound according to any one of claims 1 to 12, which is a (1-acetoxyethoxy) carbonyl group, or a pharmacologically acceptable salt thereof.
  16.  Rがプロドラッグ基であり、当該プロドラッグ基が、C~Cアルカノイルオキシ基、(C~Cシクロアルキル)カルボニルオキシ基及びアリール基から選ばれる同一又は異なる1~3個の基で置換されていてもよいC~Cアルキル基;又は、オキソ基及びC~Cアルキル基から選ばれる同一又は異なる1~3個の基で置換されていてもよいヘテロシクリルアルキル基である、請求項1~12のいずれか1項に記載の化合物、又はその薬理上許容される塩。 R 3 is a prodrug group, and the prodrug group is the same or different 1 to 3 selected from a C 2 to C 6 alkanoyloxy group, a (C 3 to C 6 cycloalkyl) carbonyloxy group and an aryl group A C 1 -C 6 alkyl group optionally substituted with a group; or a heterocyclylalkyl group optionally substituted with 1 to 3 identical or different groups selected from an oxo group and a C 1 -C 6 alkyl group The compound according to any one of claims 1 to 12, or a pharmacologically acceptable salt thereof.
  17.  Rがプロドラッグ基であり、当該プロドラッグ基が、ベンジル基又は[(イソプロポキシカルボニル)オキシ]エチル基である、請求項1~12のいずれか1項に記載の化合物、又はその薬理上許容される塩。 The compound according to any one of claims 1 to 12, wherein R 3 is a prodrug group, and the prodrug group is a benzyl group or [(isopropoxycarbonyl) oxy] ethyl group, or pharmacologically Acceptable salt.
  18.  下記式
    Figure JPOXMLDOC01-appb-C000005
    からなる群より選ばれる前記(1)に記載の化合物、又はその薬理上許容される塩。
    Following formula
    Figure JPOXMLDOC01-appb-C000005
    The compound according to (1) or a pharmacologically acceptable salt thereof selected from the group consisting of:
  19.  請求項1~18のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬。 A medicament comprising the compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt thereof as an active ingredient.
  20.  請求項1~18のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有するTAFIa阻害薬。 A TAFIa inhibitor containing the compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt thereof as an active ingredient.
  21.  請求項1~18のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する線溶促進剤。 A fibrinolysis accelerator comprising the compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt thereof as an active ingredient.
  22.  請求項1~18のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、線溶が阻害されることにより引き起こされる疾患の予防薬若しくは治療薬。 A preventive or therapeutic agent for diseases caused by inhibition of fibrinolysis, comprising the compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt thereof as an active ingredient.
  23.  請求項1~18のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、心筋梗塞、狭心症(安定狭心症、不安定狭心症)などの急性冠症候群;深部静脈血栓症、肺塞栓症などの静脈血栓塞栓症;血管再開通術、血管形成術、ステント留置術、バイパス出術などの外科的手術後の心臓血管系に起こる血栓症若しくは塞栓症;膝関節置換手術、股関節置換手術などの人工関節置換手術後の血栓症若しくは塞栓症;敗血症、播種性血管内凝固症候群(DIC)のような炎症に関連する血管内の疾患;末梢動脈塞栓症(PAO)、動脈硬化、糖尿病などの末梢血管障害に由来・関連する疾患;固形癌、血液癌などの腫瘍に関連する疾患;又は、肺塞栓、脳梗塞、腎梗塞などの血栓・塞栓に起因する臓器の障害のような血栓症・塞栓症及びそれらの後遺症の予防薬若しくは治療薬。 Acute myocardial infarction, angina pectoris (stable angina pectoris, unstable angina pectoris), etc. containing the compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt thereof as an active ingredient Coronary syndrome: Venous thromboembolism such as deep vein thrombosis and pulmonary embolism; Thrombosis or embolism occurring in the cardiovascular system after surgical operation such as revascularization, angioplasty, stent placement, bypass surgery, etc. Thrombosis or embolism after artificial joint replacement surgery such as knee replacement surgery, hip replacement surgery; intravascular disease related to inflammation such as sepsis, disseminated intravascular coagulation syndrome (DIC); peripheral artery embolism Diseases related to or related to peripheral vascular disorders such as PAO, arteriosclerosis and diabetes; diseases related to tumors such as solid cancer and blood cancer; or thrombosis and embolism such as pulmonary embolism, cerebral infarction and renal infarction Like organ damage caused Thrombosis, embolism and prophylactic or therapeutic agent of their sequelae.
  24.  請求項1~18のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、関節置換術時の人工関節、血管カテーテル、人工血管、血管ステント、人工弁などの医療機器のような体内の異物との接触によって起こる疾患;又は、心臓手術時の人工心肺装置、血液透析時の医療器具などの体外の医療器具と血液が接触することによって起こる疾患のような血栓症・塞栓症の予防薬若しくは治療薬。 An artificial joint, vascular catheter, artificial blood vessel, vascular stent, artificial valve, etc. at the time of joint replacement, comprising as an active ingredient the compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt thereof. Diseases caused by contact with foreign bodies in the body such as medical devices; or thrombi such as diseases caused by blood contact with extracorporeal medical devices such as heart-lung machines during cardiac surgery and medical devices during hemodialysis Preventive or therapeutic agent for cerebral embolism.
  25.  請求項1~18のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、肺高血圧症、成人呼吸切迫症候群、肺線維症、慢性血栓塞栓性肺高血圧症などの肺の疾患;糸球体腎炎(急性糸球体腎炎、慢性糸球体腎炎、ネフローゼ性腎炎、急性進行性糸球体腎炎など)、腎臓梗塞、糖尿病性腎炎などの腎臓の疾患;肝線維症、肝炎、肝硬変などの肝臓の疾患;眼部フィブリン沈着に伴う眼部の疾患;臓器移植又は切除術後の臓器機能障害;血栓性微小血管症を始めとする微小血栓による微小循環障害;又は、癌細胞の遊走・転移に伴う疾患・症状のような血栓・塞栓症に関連する又はフィブリン沈着若しくは線維化を伴う疾患の予防薬若しくは治療薬。 A pulmonary hypertension, adult respiratory urgency syndrome, pulmonary fibrosis, chronic thromboembolic pulmonary hypertension, etc. containing the compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt thereof as an active ingredient Diseases of the lungs; glomerulonephritis (acute glomerulonephritis, chronic glomerulonephritis, nephrotic nephritis, acute progressive glomerulonephritis, etc.), kidney diseases such as renal infarction, diabetic nephritis; liver fibrosis, hepatitis, Liver diseases such as cirrhosis; ocular diseases associated with ocular fibrin deposition; organ dysfunction after organ transplantation or resection; microcirculatory disturbances due to microthrombosis including thrombotic microangiopathy; or cancer cells A prophylactic or therapeutic agent for diseases associated with thrombosis / embolism such as diseases / symptoms associated with migration / metastasis, or with fibrin deposition or fibrosis.
  26.  請求項1~18のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する、心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の治療薬。 A myocardial infarction, angina pectoris, acute coronary insufficiency syndrome, cerebral infarction, deep vein thrombosis, lung containing the compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt thereof as an active ingredient Drugs for embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation syndrome or pulmonary fibrosis.
  27.  請求項1~18のいずれか1項に記載の化合物又はその薬理上許容される塩及び薬理上許容される担体を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier.
  28.  請求項1~18のいずれか1項に記載の化合物又はその薬理上許容される塩を有効成分として含有する医薬組成物を投与することによる、心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の治療方法。 A myocardial infarction, angina pectoris, acute coronary insufficiency syndrome, brain by administering a pharmaceutical composition containing the compound according to any one of claims 1 to 18 or a pharmacologically acceptable salt thereof as an active ingredient A method for treating infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation syndrome or pulmonary fibrosis.
  29.  心筋梗塞、狭心症、急性冠不全症候群、脳梗塞、深部静脈血栓症、肺塞栓症、末梢動脈塞栓症、敗血症、播種性血管内凝固症候群又は肺線維症の治療における使用のための請求項1~18のいずれか1項に記載の化合物又はその薬理上許容される塩。
     
    Claims for use in treating myocardial infarction, angina pectoris, acute coronary syndrome, cerebral infarction, deep vein thrombosis, pulmonary embolism, peripheral arterial embolism, sepsis, disseminated intravascular coagulation syndrome or pulmonary fibrosis The compound according to any one of 1 to 18 or a pharmacologically acceptable salt thereof.
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