CN102146066A - C-glucoside derivatives containing saturated six-membered ring as well as preparation method and application thereof - Google Patents

C-glucoside derivatives containing saturated six-membered ring as well as preparation method and application thereof Download PDF

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CN102146066A
CN102146066A CN2010105333012A CN201010533301A CN102146066A CN 102146066 A CN102146066 A CN 102146066A CN 2010105333012 A CN2010105333012 A CN 2010105333012A CN 201010533301 A CN201010533301 A CN 201010533301A CN 102146066 A CN102146066 A CN 102146066A
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atoms
nitrogen
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alkyl
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赵桂龙
邵华
刘巍
王玉丽
汤立达
徐为人
龚珉
谭初兵
张士俊
刘冰妮
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Tianjin Institute of Pharmaceutical Research Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4433—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Abstract

The invention relates to the field of medicines related to diabetes. More specifically, the invention relates to a sodium galactose transporter type 2 (SGLT2) inhibitor having a structure of C-glucoside derivatives containing saturated six-membered ring, a preparation method thereof, a pharmaceutical composition containing the derivatives and application of the derivatives in preparing diabetes medicines, wherein X and Y are defined as the followings: (1) X = Y = carbon atom; (2) X = Y = nitrogen atom; (3) X = nitrogen atom and Y = oxide atom; and (4) X = nitrogen atom and Y = carbon atom. Other groups are defined as specification.

Description

One class contains C-glucoside derivative, the Preparation Method And The Use of saturated six-ring
Technical field
The present invention relates to the pharmaceutical field relevant with diabetes.Particularly, the present invention relates to the medicative 2 type sodium glucose that contain the C-glucoside structure of saturated six-ring of diabetes cotransport son (SGLT2) inhibitor and preparation method thereof and the pharmaceutical composition that contains them.
Background technology
Whole world diabetic subject is at present nearly about 1.7 hundred million, wherein about most II type (being non-insulin-depending type) diabetic subjects that are.Antidiabetic medicine in clinical use mainly contains N1,N1-Dimethylbiguanide class, sulfonylurea, insulin type, thiazolidinediones, alpha-glucosidase inhibitor class and dipeptidyl peptidase-iv inhibitor class medicine at present, these medicines have good therapeutic action, but there is safety issue in long-term treatment, as: liver toxicity, the part medicine still has problems such as weight increase.
2 type sodium glucose (SGLT2) that cotransports is the novel targets of the treatment diabetes of discovered in recent years.SGLT2 mainly is distributed in the kidney proximal tubule, and its effect is the glucose that absorbs in the urine, and it is turned back in the blood, and that therefore suppresses SGLT2 just can reduce glucose concn in the blood, and this method has reduced glucose level from different in the past approach.When the SGLT2 function is obstructed, will secrete more glucose in the urine, this will help the diabetic subject to keep correct glucose level.Because the SGLT2 inhibitor stays out of glucose metabolism, it can be used as the means of supplementing out economy of glycemic control main stream approach.
The compound that Chinese patent CN200610093189.9 discloses time array structure is as the SGLT2 inhibitor:
Wherein, A is O, S, NH, (CH 2) n, n=0-3.
The compound that Chinese patent CN200380110040.1 discloses time array structure is as the SGLT2 inhibitor:
Figure BDA0000031006190000021
Wherein, A is a covalent linkage, O, S, NH, (CH 2) n, n=1-3.
The compound that Chinese patent CN200480006761.2 discloses time array structure is as the SGLT2 inhibitor:
Figure BDA0000031006190000022
Wherein, X is covalent linkage or low-grade alkylidene.
The compound that WO2005/012326 discloses time array structure is as the SGLT2 inhibitor:
Figure BDA0000031006190000023
The invention provides C-glucoside analog derivative that a class contains saturated six-ring as novel SGLT2 inhibitor, these inhibitor lay the foundation for the medicine that further can be used for the treatment of diabetes, particularly non insulin dependent diabetes.
Summary of the invention
An object of the present invention is to overcome the shortcoming and defect of prior art, a kind of excellent activity that has is provided, have the compound of general formula I and pharmaceutically acceptable salt and prodrug ester.
Another object of the present invention provides preparation and has the compound of general formula I and the method for acceptable salt and prodrug ester pharmaceutically thereof.
A further object of the present invention provide the compound that contains general formula I and pharmaceutically acceptable salt and prodrug ester as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carriers, vehicle or thinner, and the application aspect the treatment diabetes.
Now content of the present invention is specifically described in conjunction with purpose of the present invention.
The compound that the present invention has general formula I has following structural formula:
Figure BDA0000031006190000031
Wherein,
R 1, R 2Independently be selected from H, F, Cl, Br, I, OR 3, SR 4, OCF 3, CF 3, CHF 2, CH 2F, C 1-C 3Alkyl, contain the cycloalkyl of 3-5 carbon atom, wherein R 3And R 4Independently be selected from C 1-C 3Alkyl, abovementioned alkyl or cycloalkyl all can be replaced by one or more F, Cl atom;
The definition of X and Y is selected from following several situation:
(1) X=Y=carbon atom;
(2) X=Y=nitrogen-atoms;
(3) X=nitrogen-atoms, the Y=Sauerstoffatom;
(4) X=nitrogen-atoms, the Y=carbon atom.
Preferred following compound of Formula I,
Wherein,
R 1, R 2Independently be selected from H, F, Cl, OR 3, SR 4, OCF 3, CF 3, CHF 2, CH 2F, C 1-C 3Alkyl, contain the cycloalkyl of 3-5 carbon atom, wherein R 3And R 4Independently be selected from C 1-C 3Alkyl, abovementioned alkyl or cycloalkyl all can be replaced R by one or more F atoms 1Be in the contraposition of phenyl ring, R with sugared loop section 2Under possible situation, be connected with atom Y, wherein when the Y=nitrogen-atoms, R 2Link to each other with Y.
The definition of X and Y is selected from following several situation:
(1) X=Y=carbon atom;
(2) X=Y=nitrogen-atoms;
(3) X=nitrogen-atoms, the Y=Sauerstoffatom;
(4) X=nitrogen-atoms, the Y=carbon atom.
The compound that has general formula I more preferably,
Figure BDA0000031006190000041
Compound of Formula I of the present invention is synthetic by following steps:
Figure BDA0000031006190000051
Compound I I handles with trimethylsilyl reagent in the presence of alkali, obtains compound III, used alkali such as N-methylmorpholine, triethylamine, pyridine, 4-Dimethylamino pyridine etc., trimethylsilyl reagent such as trimethylchlorosilane etc.
Compound IV is handled with alkyl lithium reagents such as n-Butyl Lithium, obtains compound V, and compound V does not add to be separated in the reaction system directly and reacts with Compound I I, obtains compound VI.Compound VI acid as catalysis such as methylsulfonic acid, trifluoromethanesulfonic acid, tosic acid under with methyl alcohol processing, obtain compound VI I.Compound VI I is at Lewis acid such as BF 3Et 2O, BF 3Existence such as MeCN or trifluoroacetic acid obtains compound VIII with reduction such as reductive agent such as triethyl silicane, tri isopropyl silanes down.Compound VIII is used in existence such as alkali such as sodium acetate, anhydrous, pyridine, 4-Dimethylamino pyridine and obtains IX with reagent acetylizes such as acetic anhydride, Acetyl Chloride 98Min.s down.Compound I X handles with methods such as column chromatography or recrystallizations, obtains compounds X.Compounds X usefulness alkali such as sodium methylate, processing such as NaOH, KOH are taken off ethanoyl and are obtained Compound I.
Compound IV can adopt following method preparation because of the different of X and Y.
(1) X=Y=carbon atom,
This moment, compound IV became IV-1:
Figure BDA0000031006190000061
Compound IV-1 can adopt following route synthetic:
Compounds X I and Mg reaction obtain compounds X II, and wherein Hal is selected from Cl, Br, I.Compounds X II and compounds X III reaction obtain compounds X IV.Compounds X IV halogenating agent such as PBr 3, POCl 3Deng processing, obtain compounds X V, wherein Hal is selected from Cl, Br, I.Compounds X V reductive agent such as LiAlH 4Deng reduction, obtain compound IV-1.Perhaps, compounds X IV reduces in the presence of as boron trifluoride diethyl etherate, trifluoroacetic acid etc. in acid with reductive agent such as triethyl silicane, tri isopropyl silane etc., can obtain compound IV-1.
(2) X=Y=nitrogen-atoms,
This moment, compound IV became IV-2:
Figure BDA0000031006190000063
Compound IV-2 can adopt following route synthetic:
Figure BDA0000031006190000071
Compounds X VI and compounds X VII reaction obtain compound IV-2, and wherein Hal is selected from Cl, Br, I.
(3) X=nitrogen-atoms, the Y=Sauerstoffatom,
This moment, compound IV became IV-3:
Figure BDA0000031006190000072
Compound IV-3 can adopt following route synthetic:
Figure BDA0000031006190000073
Compounds X VI and compounds X VIII reaction obtain compound IV-3, and wherein Hal is selected from Cl, Br, I.
(4) X=nitrogen-atoms, the Y=carbon atom,
This moment, compound IV became IV-4:
Figure BDA0000031006190000074
Compound IV-4 can adopt following route synthetic:
Figure BDA0000031006190000075
Compounds X VI and compounds X IV reaction obtain compound IV-4, and wherein Hal is selected from Cl, Br, I.
The pharmaceutically acceptable prodrug ester of formula I compound of the present invention comprises the ester that any one or a plurality of hydroxyl in the molecule and ethanoyl, pivaloyl group, various phosphoryl, formamyl, alkoxyl formyl etc. form.
Formula I compound of the present invention can be made pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be made formulations such as solid orally ingestible, liquid oral medicine, injection.Described solid and liquid oral medicine comprise: tablet, dispersible tablet, sugar-coat agent, granule, dry powder doses, capsule and solution.Described injection comprises: little pin, infusion solutions, freeze-dried powder etc.
Composition of the present invention can be accepted auxiliary material and be selected from: weighting agent, disintegrating agent, lubricant, glidant, effervescent, correctives, sanitas, coating material or other vehicle on described pharmacy or the bromatology.
Composition of the present invention can be accepted auxiliary material on described pharmacy or the bromatology.Weighting agent is one or more the composition that weighting agent comprises lactose, sucrose, dextrin, starch, pregelatinized Starch, N.F,USP MANNITOL, sorbyl alcohol, secondary calcium phosphate, calcium sulfate, lime carbonate, Microcrystalline Cellulose; Described tackiness agent comprises one or more composition of sucrose, starch, polyvidone, Xylo-Mucine, hypromellose, hydroxypropylcellulose, methylcellulose gum, polyoxyethylene glycol, medicinal alcohol, water; Described disintegrating agent comprises one or more composition of starch, crosslinked polyvidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmethose, gas-producing disintegrant.
Compound of Formula I of the present invention has the restraining effect of SGLT2 enzyme, can be used as the medicine that effective constituent is used to prepare the diabetes aspect.The activity of compound of Formula I of the present invention is by hypoglycemic modelling verification in the body.
Compound of Formula I of the present invention is effective in quite wide dosage range.For example the dosage of taking every day is divided into once or administration for several times in 1mg-1000mg/ people's scope.The actual dosage of taking compound of Formula I of the present invention can be decided according to relevant situation by the doctor.These situations comprise: by curer's physical state, route of administration, age, body weight, to the individual reaction of medicine, the severity of symptom etc.
Embodiment
The present invention is further illustrated below in conjunction with embodiment.Need to prove that following embodiment is used for explanation, and is not to be used to limit the present invention.The various variations that those skilled in the art's training centre according to the present invention is made all should be within the desired protection domain of the application's claim.
Embodiment 1
1-[4-chloro-3-(cyclohexyl methyl) phenyl]-1-deoxidation-β-D-Glucopyranose
Figure BDA0000031006190000091
A.4-bromo-1-chloro-2-(cyclohexyl methyl) benzene
Add 2.19g (10mmol) 2-chloro-5-bromobenzaldehyde and 10mL anhydrous tetrahydro furan in the round-bottomed flask of a 100mL, gained solution cools off induction stirring with ice-water bath, drips 11mL (11mmol with constant pressure funnel; 1.0M) the THF solution of cyclohexyl bromination magnesium, after dropwising, reaction mixture at room temperature stirs after one hour and carefully pours in the 200mL frozen water, regulates pH=3-4 with concentrated hydrochloric acid.The gained acid system extracts at twice with the 100mL methylene dichloride, the water washing of combining extraction liquid body and function saturated common salt once, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators obtains a colorless oil, is (5-bromo-2-chloro-phenyl-) (cyclohexyl) methyl alcohol.2.88g, productive rate 95%, ESI-MS, m/z=303.1 ([M ( 79Br)+1]), 305.2 ([M ( 81Br)+1]).
Above-mentioned (5-bromo-2-chloro-phenyl-) (cyclohexyl) methyl alcohol oily matter 2.88g (9.5mmol) that obtains is dissolved in the 3mL dry methylene chloride, and the ice-water bath cooling is stirred down, successively adds triethyl silicane 2mL and boron trifluoride diethyl etherate 1mL.The gained reaction system at room temperature stirs spends the night, and carefully is poured in the 100mL frozen water, is adjusted to pH=8 with saturated sodium bicarbonate solution, extract at twice with the 100mL methylene dichloride, the water washing of combining extraction liquid body and function saturated common salt once, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, obtain a colorless oil, be 4-bromo-1-chloro-2-(cyclohexyl methyl) benzene, 2.46g, productive rate 90%, ESI-MS, m/z=287.3 ([M ( 79Br)+1]), 289.2 ([M ( 81Br)+1]).
B.2,3,4, the trimethyl silicon based Gluconolactone of 6-four-O-
Add 1.78g (10mmol) Gluconolactone, 8.09g (80mmol) N-methylmorpholine and dry tetrahydrofuran 20mL in the round-bottomed flask of a 250mL, system is induction stirring under the ice-water bath cooling, and the trimethylchlorosilane that slowly drips 6.52g (60mmol) is dissolved into the solution that obtains in the 10mL dry THF.After dropwising, system at room temperature stirs spends the night, and uses the 100mL dilution with toluene, the frozen water cooling is then transferred to the gained mixture in the separating funnel down toward wherein slowly dripping 10mL water, uses saturated sodium dihydrogen phosphate of 100mL and saturated common salt water washing successively, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators obtains a colorless oil, be 2,3,4, the trimethyl silicon based Gluconolactone of 6-four-O-, drying is two hours under room temperature on the vacuum oil pump, and is standby.4.68g, productive rate 100%.
C.1-[4-chloro-3-(cyclohexyl methyl) phenyl]-1-deoxidation-β-D-Glucopyranose
Add 2.46g (8.55mmol) 4-bromo-1-chloro-2-(cyclohexyl methyl) benzene of above-mentioned preparation in the round-bottomed flask of a 100mL, 10mL exsiccant tetrahydrofuran (THF) and a magneton then seal with the TR thin rubber plug, place acetone-dry ice system to be cooled to-78 ℃.Stir down, in this reaction vessel, slowly add 8mL (8mmol with syringe; 1.0M) hexane solution of n-BuLi, add the back system-78 ℃ of following restir one hour, then in this reaction vessel, slowly add 2,3 of above-mentioned preparation again with syringe, 4, the trimethyl silicon based Gluconolactone of 6-four-O-is dissolved into the solution that forms in the 10mL dry toluene.After adding, system restir one hour then is dissolved into the solution that forms in the 10mL anhydrous methanol with the methylsulfonic acid that syringe adds 1.92g (20mmol), and then system slowly is warmed up to room temperature, stirs under the room temperature and spends the night.Reaction mixture is poured in the saturated aqueous common salt, extract at twice with the 100mL methylene dichloride, the water washing of combining extraction liquid body and function saturated common salt once, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, obtain a colorless oil, be 1-{4-chloro-3-(cyclohexyl methyl) phenyl }-α/β-D-methyl glucopyranoside, 2.98g, productive rate 87%, ESI-MS, m/z=401.3 ([M+1]).
Above-mentioned 1-{4-chloro-3-(cyclohexyl methyl) phenyl that obtains }-α/β-D-methyl glucopyranoside oily matter 2.98g (7.4mmol) is dissolved in the 3mL dry methylene chloride, the ice-water bath cooling is stirred down, successively adds triethyl silicane 2mL and boron trifluoride diethyl etherate 1mL.The gained reaction system at room temperature stirs spends the night, and carefully is poured in the 100mL frozen water, is adjusted to pH=8 with saturated sodium bicarbonate solution, extract at twice with the 100mL methylene dichloride, the water washing of combining extraction liquid body and function saturated common salt once, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, obtain a colorless oil, be 1-{4-chloro-3-(cyclohexyl methyl) phenyl }-α/β-D-Glucopyranose, 2.44g, productive rate 89%, ESI-MS, m/z=3712 ([M+1]).
Above-mentioned 1-{4-chloro-3-(cyclohexyl methyl) phenyl that obtains }-α/β-D-Glucopyranose colorless oil 2.44g (6.6mmol) is dissolved in the 20mL acetic anhydride, adds the 0.5g sodium acetate, anhydrous, induction stirring temperature rising reflux 1 hour.After the cooling, system is poured in the 100mL water, stirs under the room temperature and spends the night; extract at twice with the 100mL methylene dichloride, the water washing of combining extraction liquid body and function saturated common salt once, anhydrous sodium sulfate drying; evaporate to dryness on Rotary Evaporators obtains the off-white color solid, obtains a clear crystal through purification by silica gel column chromatography; 2,3,4; 6-four-O-ethanoyl-1-{4-chloro-3-(cyclohexyl methyl) phenyl }-1-deoxidation-β-D-Glucopyranose, 3.45g, productive rate 97%; ESI-MS, m/z=539.4 ([M+1]).
Above-mentioned 2; 3; 4; 6-four-O-ethanoyl-1-{4-chloro-3-(cyclohexyl methyl) phenyl }-1-deoxidation-β-D-Glucopyranose 3.45g (6.4mmol) is dissolved in the 7mL anhydrous methanol that contains 0.11g (2mmol) sodium methylate; stirred 5 hours under the room temperature; then add 1g exsiccant storng-acid cation exchange resin, stir under the room temperature and spend the night.Remove by filter resin, gained filtrate evaporate to dryness on Rotary Evaporators obtains a white solid, is 1-[4-chloro-3-(cyclohexyl methyl) phenyl]-1-deoxidation-β-D-Glucopyranose, 2.37g, productive rate 100%, ESI-MS, m/z=371.2 ([M+1]).
Embodiment 2-10
Be understandable that, use method and the flow process of embodiment 1, change R 1, R 2Can obtain the listed compound of following table.
Figure BDA0000031006190000111
Figure BDA0000031006190000112
Figure BDA0000031006190000121
Embodiment 14
1-{4-chloro-3-[(4-ethyl piperazidine-1-yl) methyl] phenyl }-1-deoxidation-β-D-Glucopyranose
Figure BDA0000031006190000122
A.4-methyl bromo-1-chloro-2-[(4-ethyl piperazidine-1-yl)] benzene
Add 2.84g (10mmol) 5-bromo-2-chlorine bromotoluene in the round-bottomed flask of a 100mL, 1.14g (10mmol) 1-ethyl piperazidine, 1.01g (10mmol) triethylamine and 20mL anhydrous tetrahydro furan, after at room temperature stirring and spend the night, the gained reaction mixture is poured in the 200mL water, extract at twice with the 100mL methylene dichloride, the water washing of combining extraction liquid body and function saturated common salt once, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, obtain the off-white color solid, be 4-bromo-1-chloro-2-[(4-ethyl piperazidine-1-yl) methyl] benzene.3.11g, productive rate 98%, ESI-MS, m/z=317.2 ([M ( 79Br)+1]), 319.3 ([M ( 81Br)+1]).
B.1-{4-methyl chloro-3-[(4-ethyl piperazidine-1-yl)] phenyl }-1-deoxidation-β-D-Glucopyranose
3.11g (9.8mmol) the 4-bromo-1-chloro-2-[(4-ethyl piperazidine-1-yl that adds above-mentioned preparation in the round-bottomed flask of a 100mL) methyl] benzene, 10mL exsiccant tetrahydrofuran (THF) and a magneton, then seal, place acetone-dry ice system to be cooled to-78 ℃ with the TR thin rubber plug.Stir down, in this reaction vessel, slowly add 10mL (10mmol with syringe; 1.0M) hexane solution of n-BuLi, add the back system-78 ℃ of following restir one hour, then in this reaction vessel, slowly add again according to 2 of the preparation of the method among the embodiment 1 with syringe, 3,4, the trimethyl silicon based Gluconolactone of 6-four-O-is dissolved into the solution that forms in the 10mL dry toluene.After adding, system restir one hour then is dissolved into the solution that forms in the 10mL anhydrous methanol with the methylsulfonic acid that syringe adds 1.92g (20mmol), and then system slowly is warmed up to room temperature, stirs under the room temperature and spends the night.Reaction mixture is poured in the saturated aqueous common salt, be adjusted to pH=8 with saturated sodium bicarbonate solution, extract at twice with the 100mL methylene dichloride, the water washing of combining extraction liquid body and function saturated common salt once, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators obtains a colorless oil, is 1-{4-chloro-3-[(4-ethyl piperazidine-1-yl) methyl] phenyl }-α/β-D-methyl glucopyranoside, 3.64g, productive rate 86%, ESI-MS, m/z=431.3 ([M+1]).
The above-mentioned 1-{4-chloro-3-[(4-ethyl piperazidine-1-yl that obtains) methyl] phenyl }-α/β-D-methyl glucopyranoside oily matter 3.64g (8.4mmol) is dissolved in the 3mL dry methylene chloride, the ice-water bath cooling is stirred down, successively adds triethyl silicane 2mL and boron trifluoride diethyl etherate 1mL.The gained reaction system at room temperature stirs spends the night, and carefully is poured in the 100mL frozen water, is adjusted to pH=8 with saturated sodium bicarbonate solution, extract at twice with the 100mL methylene dichloride, the water washing of combining extraction liquid body and function saturated common salt once, anhydrous sodium sulfate drying, evaporate to dryness on Rotary Evaporators, obtain a colorless oil, be 1-{4-chloro-3-[(4-ethyl piperazidine-1-yl) methyl] phenyl }-α/β-D-Glucopyranose, 3.06g, productive rate 91%, ESI-MS, m/z=4012 ([M+1]).
The above-mentioned 1-{4-chloro-3-[(4-ethyl piperazidine-1-yl that obtains) methyl] phenyl }-α/β-D-Glucopyranose colorless oil 3.06g (7.6mmol) is dissolved in the 20mL acetic anhydride, adds the 0.5g sodium acetate, anhydrous, induction stirring temperature rising reflux 1 hour.After the cooling; system is poured in the 100mL water; stir under the room temperature and spend the night; be adjusted to pH=8 with saturated sodium bicarbonate solution, extract at twice with the 100mL methylene dichloride, the water washing of combining extraction liquid body and function saturated common salt once; anhydrous sodium sulfate drying; evaporate to dryness on Rotary Evaporators obtains the off-white color solid, obtains a clear crystal through purification by silica gel column chromatography; 2; 3,4,6-four-O-ethanoyl-1-{4-chloro-3-[(4-ethyl piperazidine-1-yl) methyl] phenyl }-1-deoxidation-β-D-Glucopyranose; 4.07g; productive rate 94%, ESI-MS, m/z=569.3 ([M+1]).
Above-mentioned 2; 3; 4; 6-four-O-ethanoyl-1-{4-chloro-3-[(4-ethyl piperazidine-1-yl) methyl] phenyl }-1-deoxidation-β-D-Glucopyranose 4.07g (7.1mmol) is dissolved in the 7mL anhydrous methanol that contains 0.11g (2mmol) sodium methylate; stirred 5 hours under the room temperature; then add 1g exsiccant storng-acid cation exchange resin, stir under the room temperature and spend the night.Remove by filter resin, gained filtrate evaporate to dryness on Rotary Evaporators obtains a white solid, be 1-{4-chloro-3-[(4-ethyl piperazidine-1-yl) methyl] phenyl }-1-deoxidation-β-D-Glucopyranose, 2.85g, productive rate 100%, ESI-MS, m/z=401.4 ([M+1]).
Embodiment 15-26
Be understandable that, use method and the flow process of embodiment 14, change R 1, R 2And Y, can obtain the listed compound of following table.
Figure BDA0000031006190000141
Figure BDA0000031006190000151
Embodiment 27
Consumption/sheet
Embodiment 1 sample 10mg
Microcrystalline Cellulose 80mg
Pregelatinized Starch 70mg
Polyvinylpyrrolidone 6mg
Carboxymethyl starch sodium salt 5mg
Magnesium Stearate 2mg
Talcum powder 2mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, thorough mixing, add polyvinylpyrrolidonesolution solution, mix, the system softwood, sieve, the system wet granular is in 50-60 ℃ of drying, with the carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, join compressing tablet in the above-mentioned particle then.
Embodiment 28
Consumption/sheet
Embodiment 2 sample 10mg
Microcrystalline Cellulose 80mg
Pregelatinized Starch 70mg
Polyvinylpyrrolidone 6mg
Carboxymethyl starch sodium salt 5mg
Magnesium Stearate 2mg
Talcum powder 2mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, thorough mixing, add polyvinylpyrrolidonesolution solution, mix, the system softwood, sieve, the system wet granular is in 50-60 ℃ of drying, with the carboxymethyl starch sodium salt, Magnesium Stearate and talcum powder sieve in advance, join compressing tablet in the above-mentioned particle then.
Embodiment 29
Consumption/grain
Embodiment 3 sample 10mg
Microcrystalline Cellulose 30mg
Pregelatinized Starch 20mg
Polyvinylpyrrolidone 3mg
Magnesium Stearate 2mg
Talcum powder 1mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, and thorough mixing adds polyvinylpyrrolidonesolution solution, mixes, the system softwood sieves, and the system wet granular is in 50-60 ℃ of drying, Magnesium Stearate and talcum powder are sieved in advance, join then in the above-mentioned particle, encapsulated, promptly.
Embodiment 30
Consumption/grain
Embodiment 4 sample 10mg
Microcrystalline Cellulose 30mg
Pregelatinized Starch 20mg
Polyvinylpyrrolidone 3mg
Magnesium Stearate 2mg
Talcum powder 1mg
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, and thorough mixing adds polyvinylpyrrolidonesolution solution, mixes, the system softwood sieves, and the system wet granular is in 50-60 ℃ of drying, Magnesium Stearate and talcum powder are sieved in advance, join then in the above-mentioned particle, encapsulated, promptly.
Embodiment 31
Consumption/50mL
Embodiment 14 sample 10mg
Citric acid 100mg
NaOH an amount of (transferring pH 4.0-5.0)
Distilled water 50mL
In distilled water, add earlier distilled water and citric acid, stirring and dissolving and after, add sample again, low-grade fever makes dissolving, and adjust pH is 4.0-5.0, add 0.2 gram activated carbon, stirred 20 minutes under the room temperature, filter filtrate, strength of solution is decided in middle detection, by 5 milliliters of packing of every peace bottle, high-temperature sterilization 30 minutes promptly gets injection liquid.
Embodiment 32
Consumption/50mL
Embodiment 18 sample 10mg
Citric acid 100mg
NaOH an amount of (transferring pH 4.0-5.0)
Distilled water 50mL
In distilled water, add earlier distilled water and citric acid, stirring and dissolving and after, add sample again, low-grade fever makes dissolving, and adjust pH is 4.0-5.0, add 0.2 gram activated carbon, stirred 20 minutes under the room temperature, filter filtrate, strength of solution is decided in middle detection, by 5 milliliters of packing of every peace bottle, high-temperature sterilization 30 minutes promptly gets injection liquid.
Embodiment 33
Embodiment 21 sample 3.0g
Poloxamer 1.0g
Sodium hydroxide 0.2g
Citric Acid QS
N.F,USP MANNITOL 26.0g
Lactose 23.0g
Water for injection 100ml
Preparation technology: get water for injection 80ml, add main ingredient, N.F,USP MANNITOL, lactose, poloxamer stir make dissolving after, the Citric Acid that adds 1mol/L is regulated PH to 7.0-9.0, mends and adds water to 100ml.Add the 0.5g gac, stirred 20 minutes down, take off charcoal, adopt the filtering with microporous membrane degerming at 30 ℃, filtrate is carried out packing by every 1ml, and pre-freeze is after 2 hours, freezing drying under reduced pressure down 12 hours, to sample temperature after room temperature, dry 5 hours again, make the white loose block, seal promptly.
Embodiment 34
100 bags of granules
Embodiment 24 sample 30.0g
Lactose 55.0g
N.F,USP MANNITOL 14.0g
The sweet 0.05g of A Siba
Essence 0.05g
2% hypromellose (pure water preparation) QS
Preparation technology: main ingredient and auxiliary material are crossed 100 mesh sieves respectively, and thorough mixing takes by weighing recipe quantity auxiliary material and main ingredient thorough mixing then.Add tackiness agent system softwood again, 14 mesh sieves are granulated, 55 ℃ of dryings, and the whole grain of 12 mesh sieves is measured heavily packing of bag.
Embodiment 35
Sample is mixed with the suspension of 5mg/mL concentration with 1% Xylo-Mucine, and the administration capacity is the 0.2mL/20g body weight, is equivalent to 10mg/kg dosage.
Healthy ICR mouse, male and female half and half, body weight 20-24g meets primary standard.Animal fasting 16 hours, the dextrose in saline solution of 2h abdominal injection 2g/kg behind the medicine (1.5h injectable dextrose monohydrate behind the Dapagliflozin medicine), 0.5h, 1h, 2h, 3h and 4h regularly take kapillary and get blood from mouse ball rear vein beard after modeling, centrifugation serum is with each time point serum glucose level of determination of glucose oxidase.The results are shown in the form of nextpage:
Figure BDA0000031006190000201
Above result shows that each administration all can significantly reduce the mouse blood sugar dosis tolerata that glucose causes.

Claims (8)

1. have the compound of general formula I structure and pharmaceutically acceptable salt and prodrug ester,
Figure FDA0000031006180000011
Wherein,
R 1, R 2Independently be selected from H, F, Cl, Br, I, OR 3, SR 4, OCF 3, CF 3, CHF 2, CH 2F, C 1-C 3Alkyl, contain the cycloalkyl of 3-5 carbon atom, wherein R 3And R 4Independently be selected from C 1-C 3Alkyl, abovementioned alkyl or cycloalkyl all can be replaced by one or more F, Cl atom;
The definition of X and Y is selected from following several situation:
(1) X=Y=carbon atom;
(2) X=Y=nitrogen-atoms;
(3) X=nitrogen-atoms, the Y=Sauerstoffatom;
(4) X=nitrogen-atoms, the Y=carbon atom.
2. claim 1 is defined has the compound of general formula I and pharmaceutically acceptable salt and a prodrug ester, wherein,
R 1, R 2Independently be selected from H, F, Cl, OR 3, SR 4, OCF 3, CF 3, CHF 2, CH 2F, C 1-C 3Alkyl, contain the cycloalkyl of 3-5 carbon atom, wherein R 3And R 4Independently be selected from C 1-C 3Alkyl, abovementioned alkyl or cycloalkyl all can be replaced R by one or more F atoms 1Be in the contraposition of phenyl ring, R with sugared loop section 2Under possible situation, be connected with atom Y, wherein when the Y=nitrogen-atoms, R 2Link to each other with Y.
The definition of X and Y is selected from following several situation:
(1) X=Y=carbon atom;
(2) X=Y=nitrogen-atoms;
(3) X=nitrogen-atoms, the Y=Sauerstoffatom;
(4) X=nitrogen-atoms, the Y=carbon atom.
3. the defined compound of Formula I of claim 2 is selected from following compounds:
Figure FDA0000031006180000021
4. defined compound of Formula I of claim 1-3 and pharmaceutically acceptable salt and the prodrug ester application of transporting sub-inhibitor thereof as 2 type sodium semi-lactosis.
5. the defined compound of Formula I of claim 4 and pharmaceutically acceptable salt and the application of prodrug ester aspect preparation treatment diabetes medicament.
6. pharmaceutical composition contains the compound of Formula I of one of claim 1-3 and pharmaceutically acceptable salt and prodrug ester, and appropriate carriers or vehicle.
7. the described pharmaceutical composition of claim 6, wherein, described composition is solid orally ingestible, liquid oral medicine or injection.
8. comprise according to described solid of claim 7 and liquid oral medicine: tablet, dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, granule, oral solution, described injection preparation comprises injection liquid drugs injection, injection freeze-dried powder, infusion solutions, primary infusion.
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