WO2010018438A2 - Tetrazole glycosides - Google Patents

Tetrazole glycosides Download PDF

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Publication number
WO2010018438A2
WO2010018438A2 PCT/IB2009/006497 IB2009006497W WO2010018438A2 WO 2010018438 A2 WO2010018438 A2 WO 2010018438A2 IB 2009006497 W IB2009006497 W IB 2009006497W WO 2010018438 A2 WO2010018438 A2 WO 2010018438A2
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Prior art keywords
compound
tetrazol
pyran
tetrahydro
isomer
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PCT/IB2009/006497
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French (fr)
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WO2010018438A3 (en
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Vedula Manohar Sharma
Musku Madhanmohan Reddy
Poshala Ramesh
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Hetero Research Foundation
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Publication of WO2010018438A3 publication Critical patent/WO2010018438A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/056—Triazole or tetrazole radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings

Definitions

  • the invention relates to tetrazole glycoside derivatives, which are inhibitors of Sodium dependent glucose co transporter (SGLT), particularly SGLT2.
  • SGLT Sodium dependent glucose co transporter
  • Type 2 diabetes mellitus T2DM
  • T2DM Type 2 diabetes mellitus
  • T2DM Type 2 diabetes mellitus
  • T2DM is a heterogeneous disorder characterized by impaired insulin secretion in response to glucose, increased hepatic glucose production, and decreased insulin-dependent glucose uptake in the peripheral tissues or insulin resistance.
  • Sodium dependent glucose transporter-2 (SGLT2) is present in the S 1 segment of the kidney's proximal tubule, participates mainly in reabsorption of glucose filtrated through glomerular (J. Clin. Invest, Vol. 93, pp. 397-404
  • SGLT2 inhibitors may be relevant with respect to diabetes, diabetic complications or obesity.
  • X can be H, lower alkyl group, lower perfluoro alkyl group, aralkyl group, phenyl group, O- ⁇ or ⁇ -D-glucopyranosyl group, ⁇ or ⁇ -D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or ⁇ -D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxylgroup may be esterified);
  • Ring A and B are independently can be selected from phenyl, naphthyl, heteroaryl, cycloalkyl or heterocyclyl which may contain 5 to 7 membered ring, which may contain 1 to 4 hetero atoms like N, O, S, SO or SO 2 in the ring;
  • a compound of formula (1) wherein X is substituted or unsubstituted alkyl.
  • alkyl is methyl or ethyl.
  • Y is substituted or unsubstituted aryl.
  • aryl is phenyl.
  • Y is substituted or unsubstituted aryl-C(O)-, substituted or unsubstituted aryl-CH2-, or substituted or unsubstituted aryloxy-CH 2 - .
  • aryl is phenyl.
  • Rj and R 2 are selected from O- ⁇ or ⁇ -D-glucopyranosyl group, ⁇ or ⁇ -D- glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or ⁇ -D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxylgroup may be esterified).
  • prodrugs of the compounds of the formula (IA), including ester prodrugs are also contemplated.
  • Another preferred embodiment of the present invention is a compound of Formula (IB),
  • XB can be H, lower alkyl group, O- ⁇ or ⁇ -D-glucopyranosyl group, ⁇ or ⁇ -D- glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or ⁇ -D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified);
  • Y B can be
  • Z A can be (CH 2 )n; n can be an integer 0-1;
  • Ring A B and B B are independently can be a phenyl;
  • R IB and R 2B independently can be selected from H, -Cl, -Br, -OMe, or CF 3 ;
  • R 3B and R 4B are independently can be selected from H, alkyl, or O- alkyl;
  • R 5 B can be alkyl.
  • Pharmaceutically acceptable salts of the compounds of the formula (IB) are also contemplated.
  • pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (IB) are contemplated.
  • prodrugs of the compounds of the formula (IB), including ester prodrugs are also contemplated.
  • a pharmaceutical preparation which comprises any one of the above tetrazole glycoside compounds or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.
  • such a pharmaceutical preparation which is an inhibitor of sodium-dependent glucose transporter 2 activity.
  • such a pharmaceutical preparation which is a prophylactic or therapeutic agent for diabetes, diabetes- related diseases or diabetic complications.
  • the compounds and pharmaceutical compositions described herein are useful in the treatment of diseases, conditions and/or disorders mediated by SGLT2 inhibitors.
  • the invention further provides a method of treating a disease, condition and/or disorder mediated by SGLT2 inhibitors in a subject in need thereof by administering to the subject one or more compounds described herein in the amount effective to cause inhibition of such receptor.
  • the invention provides a method of treating type II diabetes in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to the invention.
  • Ring A and B are independently can be selected from phenyl, naphthyl, heteroaryl, cycloalkyl or heterocyclyl which may contain 5 to 7 membered ring, which may contain 1 to 4 hetero atoms like N, O, S, SO or
  • Z can be oxygen, methylene, (CH 2 ) n , dimethylmethylene, difluoromethylene, carbonyl, O-alkyl, S-alkyl, SO 2 alkyl, -C(O)-NH-R 1 R 2 or Z may represent a bond between rings A and B; n can be an integer 0-3;
  • Y also can be , substituted or unsubstituted aryl group more particularly substituted or unsubstituted phenyl group, substituted or unsubstituted aryl-C(O)-, substituted or unsubstituted aryl- CH 2 -, or substituted or unsubstituted aryloxy-CH2-, where in substituents are Ri and R 2 ; Ri and R 2 are independently can be selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, Ci- ⁇ -alkyl, C 2-6 alkynyl, C 3- 6 cycloalkyl, C 1 -C 4 alkylcarbonyl, aryl carbonyl, heteroarylcarbonyl, amino carbonyl, Ci- 4 -alkylaminocarbonyl, hydroxyl, cyano, Ci -4 alkyl sulphonylamino, arylsulphonylamino, Ci- ⁇ alkoxy, C 3-7 cycloalk
  • R 5 can be alkyl or perfluoroalkyl; an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N- oxide thereof, a tautomer thereof, a regeoisomers thereof, a stereoisomer thereof, a prodrug thereof or a polymorph thereof, the process comprising the steps of: (a) reacting the cyano compounds of formula (1)
  • X can be H, lower alkyl group, lower perfluoro alkyl group, aralkyl group, phenyl group, O- ⁇ or ⁇ -D-glucopyranosyl group, ⁇ or ⁇ -D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or ⁇ -D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxylgroup may be esterified);
  • Ring A and B are independently can be selected from phenyl, naphthyl, heteroaryl, cycloalkyl or heterocyclyl which may contain 5 to 7 membered ring, which may contain 1 to 4 hetero atoms like N, O, S, SO or SO 2 in the ring;
  • Z may represent a bond between rings A and B; n can be an integer 0-3;
  • Y also can be , substituted or unsubstituted aryl group more particularly substituted or unsubstituted phenyl group, substituted or unsubstituted aryl-C(O)-, substituted or unsubstituted aryl-
  • R] and R 2 are independently can be selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, d-e-alkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, Ci-C 4 alkylcarbonyl, aryl carbonyl, heteroarylcarbonyl, amino carbonyl, C 1-4 -alkylaminocarbonyl, hydroxyl, cyano, C 1-4 alkyl sulphonylamino, arylsulphonylamino, C 1 .
  • R 3 and R 4 are independently can be selected from hydrogen, alkyl, halo, perfluoroalkyl, CN, OH, O-alkyl, O-cycloalkyl, phenyl,
  • R 5 can be alkyl or perfluoroalkyl; an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N- oxide thereof, a tautomer thereof, a regeoisomers thereof, a stereoisomer thereof, a prodrug thereof or a polymorph thereof, the process comprising the steps of:
  • the invention provides one more process for the preparation of a compound of formula (I):
  • 15 X can be H, lower allcyl group, lower perfluoro alkyl group, aralkyl group, phenyl group, O- ⁇ or ⁇ -D-glucopyranosyl group, ⁇ or ⁇ -D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or ⁇ -D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxylgroup may be esterified);
  • Ring A and B are independently can be selected from phenyl, naphthyl, heteroaryl, cycloalkyl or heterocyclyl which may contain 5 to 7 membered ring, which may contain 1 to 4 hetero atoms like N, O, S, SO or SO 2 in the ring;
  • Z can be oxygen, methylene, (CH 2 ) n , dimethylmethylene, difluoromethylene, carbonyl, O-alkyl, S-alkyl, SO 2 alkyl, -C(O)-NH-RiR 2 or
  • Z may represent a bond between rings A and B; n can be an integer 0-3;
  • Y also can be , substituted or unsubstituted aryl group more particularly substituted or unsubstituted phenyl group, substituted or unsubstituted aryl-C(O)-, substituted or unsubstituted aryl-
  • Ri and R 2 are independently can be selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, Ci- 6 -alkyl, C 2-6 alkynyl, C3-6 cycloalkyl, Ci-C 4 alkylcarbonyl, aryl carbonyl, heteroarylcarbonyl, amino carbonyl, Ci- 4 -alkylaminocarbonyl, hydroxyl, cyano, Ci -4 alkyl sulphonylamino, arylsulphonylamino, Ci- 6 alkoxy, C3 -7 cycloalkoxy, aryloxy, aralkyloxy, aryloxyalkyl, O- ⁇ or ⁇ -D-glucopyranosyl group, ⁇ or ⁇ -D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or ⁇ -D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group
  • the invention further provides for the use wherein the SGLT2 mediated disease, disorder or syndrome is diabetes, especially type I and type II diabetes, including complications of diabetes such as retinopathy, neuropathy, nephropathy and delayed wound healing, and related diseases such as insulin resistance and impaired glucose homeostasis (IGH), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hyperlipidemia including hypertriglyceridemia, Syndrome X, hypertension, atherosclerosis and related diseases, and for increasing high density lipid levels, and the conditions, diseases, and maladies collectively referred to as IGH), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hyperlipidemia including hypertriglyceridemia, Syndrome X, hypertension, atherosclerosis and related diseases, and for increasing high density lipid levels, and the conditions, diseases, and maladies collectively referred to as IGH), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty
  • the invention provides tetrazole glycoside derivatives, which may be used as SGLT2 inhibitors and processes for the synthesis of these compounds.
  • Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, positional isomers, enantiomers, diastereomers, polymorphs of these compounds that may have the same type of activity are also provided.
  • Pharmaceutical compositions containing the described compounds together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of diseases, condition and/or disorders mediated by SGLT2 inhibitors are further provided.
  • the following definitions apply to the terms as used herein:
  • alkenyl refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched chain having from 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso- propenyl, 2-methyl- 1-propenyl, 1-butenyl, and 2-butenyl.
  • haloalkyl is used to denote a group comprised of an alkyl group substituted with halogen atom, where alkyl group is as defined above and halogen is used to denote fluorine, chlorine, bromine or iodine, an example of such group is trifluoromethyl, difluoromethyl.
  • alkoxy group is used to denote a linear or branched alkoxy group containing 1 to 6 carbon atoms. Preferred are C 1-4 alkoxy groups including a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group and a tert-butoxy group.
  • cycloalkyl denotes a non-aromatic mono or multicyclic ring system of from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • cycloalkenyl refers to a cyclic ring-containing radical having from 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl.
  • aryl refers to an aromatic radical having from 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
  • heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxinyl benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-o
  • heteroarylalkyl refers to a heteroaryl ring radical directly bonded to an alkyl group.
  • the heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
  • chronic complications includes, for example, microangiopathy (e.g., nephropathy, retinopathy), arteriosclerosis (e.g., atherosclerosis, heart infarction, brain infarction, or lower extremity arterial occlusion), neuropathy (e.g., sensory nerves, motor nerves, or autonomic nerves), foot gangrene, etc.
  • microangiopathy e.g., nephropathy, retinopathy
  • arteriosclerosis e.g., atherosclerosis, heart infarction, brain infarction, or lower extremity arterial occlusion
  • neuropathy e.g., sensory nerves, motor nerves, or autonomic nerves
  • foot gangrene e.g., foot gangrene, etc.
  • Major complications are diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.
  • the phannaceutical compositions provided in the invention include at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
  • the contemplated pharmaceutical compositions include a compound(s) described herein in an amount sufficient to inhibit SGLT2 in a subject.
  • the carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical compositions described herein may be prepared, e.g., as described in Remington: The Science and Practice of Pharmacy. 20 th Ed., 2003 (Lippincott Williams & Wilkins).
  • the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container, for example, in a sachet.
  • compositions may be, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
  • the present invention further provides a method of treating a disease, condition and/or disorder mediated by SGLT2 inhibitors in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
  • Diseases, conditions, and/or disorders that are mediated by SGLT2 inhibitors include, but are not limited to, diabetes, especially type I and type 11 diabetes, including complications of diabetes such as retinopathy, neuropathy, nephropathy and delayed wound healing, and related diseases such as insulin resistance and impaired glucose homeostasis (IGH), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hyperlipidemia including hypertriglyceridemia, Syndrome X, hypertension, atherosclerosis and related diseases, and for increasing high density lipid levels.
  • IGH insulin resistance and impaired glucose homeostasis
  • hyperglycemia hyperinsulinemia
  • hyperinsulinemia hyperinsulinemia
  • elevated blood levels of fatty acids or glycerol obesity
  • hyperlipidemia including hypertriglyceridemia
  • Syndrome X hypertension
  • atherosclerosis and related diseases and for increasing high density lipid levels.
  • the conditions, diseases, and maladies collectively referred to as "Syndrome
  • the compounds of the present invention can obtain more advantageous effects than additive effects in the prevention or treatment of the above diseases when using suitably in combination with the above drugs. Also, the administration dose can be decreased in comparison with administration of either drug alone, or adverse effects of co administrated drugs other than SGLT2 inhibitors can be avoided or declined.
  • the compounds of Formula (1) (wherein, X and Y are same as defined above) can be prepared by the above procedure as described in Scheme 1.
  • the nitrile compounds of formula 1 can be treated with sodium azide compounds of formula 2 to give the tetrazole compounds of formula 3 (as described in J. Organic chemistry, 2001, 66, 7945-7950) in presence of metal halides such as, zinc bromide or the like in the solvents for example, isopropyl alcohol in water, or the like.
  • the tetrazole compounds of formula 3 can be reacted with the acylated-bromo sugar compounds of formula 4 (as described in Organic Synthesis Collective volume 3, page 11, 1955) to give the acylated sugar compounds of formula 5 in presence of a base such as, potassium or cesium carbonate or the like in the solvents such as, for example, acetonitrile, chloroform or the like.
  • the acylated sugar compounds of formula 5 can be hydrolyzed to give the sugar compounds of formula 6 in the presence of hydrolyzing agents such as, for example methanolic ammonia, or the like.
  • Produgs of compounds of formula 1 can be prepared by reacting the haloformates in the presence of a base like triethyl amines.
  • Formula 1 when X is Formula 1, when X is glucopyranosyl acylated glucopyranosyl
  • the compounds of Formula (1) also can be prepared by the above procedure as described in Scheme 2.
  • the nitrile amine compounds of formula 7 can be treated with the acidic-nitrile compounds of formula 8 to give the amide-nitrile compounds of fo ⁇ nula 9 in presence of coupling agents such as l-(3-dimethyl aminopropyl)-3 -ethyl carbodiimide hydrochloride, 1-hydroxy-benzotriazole or the like in the solvents such as dimethyl formamide or the like.
  • the amide-nitrile compounds of formula 9 can be treated with sodium azide compounds of formula 2 to give the tetrazole compounds of formula 10 (as described in J. Organic chemistry, 2001, 66, 7945-7950) in presence of metal halides such as, zinc bromide or the like in the solvents for example, isopropyl alcohol in water, or the like.
  • metal halides such as, zinc bromide or the like in the solvents for example, isopropyl alcohol in water, or the like.
  • acylated-bromo sugar compounds of formula 4 (as described in Organic Synthesis Collective volume 3, page 11, 1955) to give the acylated sugar compounds of formula 11 in presence of a base such as, potassium or cesium carbonate or the like in the solvents such as, for example, acetonitrile, chloroform or the like.
  • the acylated sugar compounds of formula 11 can be hydro lyzed to give the sugar compounds of formula 12 in the presence of hydrolyzing agents such as, for example methanolic ammonia, or the like.
  • Produgs of compounds of formula 1 can be prepared by reacting the haloformates in the presence of a base like triethyl amines.
  • the compounds of Formula (1) (wherein, P is protecting group (benzyl or tertiary butyl), X, and Y are same as defined above) also can be prepared by the above procedure as described in Scheme 3.
  • the nitrile compounds of formula 13 can be reacted with sodium azide compounds of formula 2 to give the tetrazole compounds of formula 14 (as described in J. Organic chemistry, 2001, 66, 7945- 7950) in presence of metal halides such as, zinc bromide or the like in the solvents for example, isopropyl alcohol in water, or the like.
  • the tetrazole compounds of formula 14 can be reacted with the bromo compounds of formula 15 to give the compounds of formula 16 in presence of base such as, potassium or cesium carbonate or the like in the solvents such as, for example, acetonitrile, chloroform or the like.
  • the compounds of formula 16 can be deprotected in presence of deprotecting agents such as palladium on carbon or the like to give the hydroxy compounds of formula 17.
  • the hydroxy compounds of formula 17 can be reacted with the acylated-bromo sugar compounds of formula 4 (as described in Organic Synthesis Collective volume 3, page 11, 1955) to give the acylated sugar compounds of formula 18 in presence of a base such as, potassium or cesium carbonate or the like in the solvents such as, for example, acetonitrile, chloroform or the like.
  • the acylated sugar compounds of formula 18 can be hydrolyzed to give the sugar compounds of formula 19 in presence oh hydrolyzing agents such as, for example methanolic ammonia, or the like.
  • Produgs of compounds of formula 1 can be prepared by reacting the haloformates in the presence of a base like triethyl amines.
  • Step 2 Preparation of 2-(acetoxymethyl)-6-(5-benzyl-2H-tetrazol-2-yl)tetrahydro- 2H-pyran-3, 4, 5-triyl triacetate:
  • Example 35 ethyl f3.4,5-trihydroxy-6-(5-(4-isopropoxybenzyl)-2H-tetrazol-2- yl)tetrahvdro-2H-pyran-2-yl)methyl carbonate:
  • Example 36 2-(acetoxymethyl ' )-6-(5-f4-benzylbenzyl)-2H-tetrazol-2-yl)tetrahvdro- 2H-t)yran-3 A5-triyl triacetate:
  • step 1 5-(4-(benzyloxy)benzyl)-2-ethyl-2H-tetrazole (step 1, about 2 g) in ethanol, 10% Pd/C ( about Ig) was added at room temperature and stirred for overnight under H 2 pressure and completion of the reaction monitored by TLC. The reaction mixture was filtered through celite pad and washed with ethanol. The organic layer was allowed for concentration to afford the title compound.
  • Step 3 Preparation of 2-(acetoxymethyl)-6-(4-((2-ethyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahydro-2H-pyran-3 ,4,5-triyl triacetate:
  • step 2 To 4-((2-ethyl-2H-tetrazol-5-yl)methyl)phenol (step 2, about 1 g, 1 equivalent) in acetonitrile, terra acetyl glucopyranosyl bromide (about 2.6 g, 1.3 equivalent) and anhydride K 2 CO 3 (about 2.02 g, 3 equivalents) were added. Contents were stirred at reflux temperature for about 16 hours. Completion of the reaction was monitored by TLC. The reaction mixture was filtered, washed with acetonitrile and filtrate was poured into ice water while stirring then pH was adjusted to 6-7. Extracted with ethyl acetate and washed with 12% brine solution, dried and evaporated. The residue was purified by DIP then again purified by column chromatography to afford the title compound.
  • Example 40 2-(acetoxymethyl)-6-f4-(Y2-methyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahvdro-2H-pyran-3 ,4,5-triyl triacetate:
  • reaction was terminated after ten seconds by diluting the 60 ⁇ L reaction mixture with 1 mL of ice-cold stop solution (300 mmol mannitol, 80 mmol Na2SO4, 10 mmol Tris H2SO4 and 0.3 mmol phlorizin pH 7.4), which was then filtered through wet Millipore filters (0.45 ⁇ m pore size) and kept under suction.
  • the filters were washed twice with 1 mL of ice-cold stop solution and dissolved in 5 niL of scintillation fluid, and the experiments were performed in triplicate.
  • the radioactivity on the membrane was measured with a liquid scintillation counter (Tricarb).
  • Example 47 Screening the activity of SGLT inhibitor in the rat cell based assay:

Abstract

The invention relates to the tetrazole glycosides derivatives, which are inhibitors of Sodium dependent glucose co transporter (SGLT), particularly SGLT2 and method of treating diseases, conditions and/or disorders inhibited by SGLT2 with them, and processes for preparing them.

Description

TETRAZOLE GLYCOSIDES
This application claims the benefit of Indian Provisional Patent Application No. 1934/CHE/2008, filed August 11, 2008, which is herein incorporated by reference. Field of the Invention
The invention relates to tetrazole glycoside derivatives, which are inhibitors of Sodium dependent glucose co transporter (SGLT), particularly SGLT2.
Background of the Invention Diabetes is one of lifestyle-related diseases with the background of change of eating habit and lack of exercise. Hence, diet and exercise therapies are performed in patients with diabetes. Approximately 200 million people worldwide suffer from Type 2 diabetes mellitus (T2DM), which is characterized by hyperglycemia due to excessive hepatic glucose production and peripheral insulin resistance, the root causes of which are as yet not clearly understood. Type 2 diabetes mellitus (T2DM) is a heterogeneous disorder characterized by impaired insulin secretion in response to glucose, increased hepatic glucose production, and decreased insulin-dependent glucose uptake in the peripheral tissues or insulin resistance. The prevalence of T2DM is reaching epidemic proportion with more than 194 million cases reported in 2003, expected to increase to 333 million by 2025 (Pharmacother.; 118(2): 181- 191; 2008). The prolonged hyperglycemia in combination with insulin resistance, causes microvascular and macrovascular damage, which is a cause of considerable morbidity and mortality. Although, diet and exercise are the cornerstones of treatment in order to correct obesity and hyperglycemia, about 40 to 60 % of newly treated patients do not respond adequately or fail to comply with diet. In recent years, development of new type antidiabetic agents has been progressing, which promote urinary glucose excretion and lower blood glucose level by preventing excess glucose reabsorption at the kidney (J. Clin. Invest., Vol. 79, pp. 1510-1515 (1987)). Sodium dependent glucose transporter-2 (SGLT2) is present in the S 1 segment of the kidney's proximal tubule, participates mainly in reabsorption of glucose filtrated through glomerular (J. Clin. Invest, Vol. 93, pp. 397-404
(1994)). Accordingly, inhibiting a human SGLT2 activity prevents reabsorption of excess glucose at the kidney, subsequently promotes excreting excess glucose though the urine, and normalizes blood glucose level. Therefore, fast development of antidiabetic agents, which have a potent inhibitory activity in human SGLT2 is desired. In addition, since such agents promote the excretion of excess glucose though the urine and consequently the glucose accumulation in the body is decreased, they are also expected to have a preventing or alleviating effect on obesity and a urinating effect. Furthermore, the agents are considered to be useful for various related diseases which occur accompanying the progress of diabetes or obesity due to hyperglycemia. Since SGLT-2 inhibitors do not stimulate insulin secretion; therefore, they would be expected to have a low hypoglycemia risk {Intl journal of clinical practice; 62 (8), 1279-1284, 2008).
In the recent past, many articles were published in various journals on SGLT inhibitors {Diabetes, 2008, 57, 1723-24; Diabetes, obesity and metabolism, 11,
2009, 79-88; and Diabetes, 1999, 48, 1794-1800). European journal of Pharmacology, 391 (2000), 183-192, Nature protocols, 2007, 2(6), 1356-59 described some preliminary assay methods to evaluate the compounds potential such as inhibition of Na+-glucose co transporter activity in brush border membrane vesicles (BBMVs) and Isolation of renal proximal tubular brush-border membranes.
It is thus believed SGLT2 inhibitors may be relevant with respect to diabetes, diabetic complications or obesity. PCT Publications Nos. WO 01//016147, WO
01/074835, WO 02/068439, WO 02/083066, WO 03/020737, WO 03/080635, WO
04/063209, WO 04/089967, WO 06//034489, WO 08/072726, WO 08/116195, WO 08/122014, WO 08/101939 and WO 08/144346; US patent application/patent Nos.
US 7,476,671, US 7,439,232, US 2006/0194809 and US 2008/0132563; EP patent application/patent Nos. EP 150621 IBl, EP 1224195B1, EP 1268502B1, EP 1268503A1, EP 1581543A4 and EP 1685147A4 disclose SGLT2 inhibitors, for treatment of various diseases mediated by SGLT2 inhibitors. Also some disclosures and publications on various aspects of SGLT are as follows: Biochem.Biophys Acta 1975 ,554,259-263; Diabetes, vol.48, (1999), 1794- 1800; IntJ.Med Sci.2007, (3)131-139; Biol. & Pharma.Bulletin, 2000, 23, 1434; British J.of pharmacology 2001, 32,578-586;
AmJ.Physiol.Endocrinol.Metab.2000.280, 535; Clin. & Experi. Pharmacology & physiology 2002, 9, 86; J.Med.cheml999, 42(26) 5311-5324; J.Med.chem2008, 51,
145-1149; Nature protocols 2007, 2(5), 356-1359; US 6,555,519; Bioorganic & Medicinal chemistry Letters 2003, 3, 269 - 2272; US 6,414,126 Bl; US 6,683,056 B2; International Journal of medical Sciences 2006, 3(3), 84-91; J.Clin.Invest.1994, 93,397-404; The Journal of Pharmacology and Experimental Therapeutics 2007, 320(1), 323-330; The Journal of Biological Chemistry 1995, 270 (49), 29365-29371; Life Sciences 2005; 76, 2655-2668; Bioorganic & Medicinal chemistry Letters 2005, 15, 2655 - 2668; The Journal of Biological Chemistry 1993, 268 (3), 1509- 1512; Tetrahedron Letters 2000; 41, 9213-9217; Life Sciences 2005, 76, 1039-1050; Biol. Pharm. Bull 2006, 29(1), 114-118; Bioorganic & Medicinal chemistry Letters
2003, 13, 2269 - 2272; Drugs of the future 2001, 26(8), 750; Drugs of the future
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Summary of the Invention The present invention relates to tetrazole glycoside compounds of the formula (1):
Figure imgf000004_0001
wherein,
X can be H, lower alkyl group, lower perfluoro alkyl group, aralkyl group, phenyl group, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxylgroup may be esterified);
Y can be
Figure imgf000005_0001
Ring A and B are independently can be selected from phenyl, naphthyl, heteroaryl, cycloalkyl or heterocyclyl which may contain 5 to 7 membered ring, which may contain 1 to 4 hetero atoms like N, O, S, SO or SO2 in the ring;
Z can be oxygen, methylene, (CH2)n, dimethylmethylene, difluoromethylene, carbonyl, O-alkyl, S-alkyl, SO2 alkyl, -C(O)-NH-R1R2 or Z may represent a bond between rings A and B; n can be an integer 0-3 ;
Y also can be
Figure imgf000005_0002
s substituted or unsubstituted aryl group more particularly substituted or unsubstituted phenyl group, substituted or unsubstituted aryl-C(O)-, substituted or unsubstituted aryl- CH2-, or substituted or unsubstituted aryloxy-CH2-, where in substituents are Ri and R2; Ri and R2 are independently can be selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, Ci-6-alkyl, C2-β alkynyl, C3-6 cycloalkyl, Ci-C4alkylcarbonyl, aryl carbonyl, heteroarylcarbonyl, amino carbonyl, Ci-4-alkylaminocarbonyl, hydroxyl, cyano, Ci-4 alkyl sulphonylamino, arylsulphonylamino, Ci- β alkoxy, C3-7 cycloalkoxy, aryloxy, aralkyloxy, aryloxyalkyl, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified); R3 and R4 are independently can be selected from hydrogen, alkyl, halo, perfluoroalkyl, CN, OH, O-alkyl, O-cycloalkyl, phenyl, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D- glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified);
R5 can be alkyl, or perfluoroalkyl.
Pharmaceutically acceptable salts of the compounds of the formula (1) are also contemplated. Likewise, pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (1) are contemplated.
It should be understood that the formula (1) structurally encompasses all positional isomers, stereo isomers, including enatiomers and diastereomers that may be contemplated from the chemical structure of the genus described herein. Also contemplated are prodrugs of the compounds of the formula (1), including ester prodrugs.
According to one embodiment, there is provided a compound of formula (1), wherein X is O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxylgroup may be esterified).
According to one embodiment, there is provided a compound of formula (1), wherein X is substituted or unsubstituted alkyl. In this embodiment, preferably alkyl is methyl or ethyl. According to one embodiment, there is provided a compound of formula (1), wherein Y is substituted or unsubstituted aryl. In this embodiment, preferably aryl is phenyl.
According to one embodiment, there is provided a compound of formula (1), wherein Y is substituted or unsubstituted aryl-C(O)-, substituted or unsubstituted aryl-CH2-, or substituted or unsubstituted aryloxy-CH2- . In this embodiment, preferably aryl is phenyl.
According to one embodiment, there is provided a compound of formula (1),
wherein Y is
Figure imgf000006_0001
In this embodiment, preferably A is phenyl, B is phenyl, and
Z is CH2. According to one embodiment, there is provided a compound of formula (1),
wherein Y
Figure imgf000007_0001
In this embodiment, preferably R3 and R4 are selected from H or O-alkyl, and R5 is methyl.
According to one embodiment, there is provided a compound of formula (1), wherein Ri and R2 are selected from H, fluorine, chlorine, bromine, trifluoromethyUCi-β-allcyl, hydroxyl, Q-6 alkoxy, or aralkyloxy.
According to one embodiment, there is provided a compound of formula (1), wherein Rj and R2 are selected from O-α or β-D-glucopyranosyl group, α or β-D- glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxylgroup may be esterified).
According to one embodiment, there is provided a compound of formula (IA):
Figure imgf000007_0002
wherein,
XA can be H, lower alkyl group, lower perfluoro alkyl group, O-α or β-D- glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxylgroup may be esterified); RiA and R2A are independently can be selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, Ci-6-alkyl, hydroxyl, cyano, Ci-6 alkoxy, C3-7 cycloalkoxy, aryloxy, aralkyloxy, aryloxyalkyl, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified).
Pharmaceutically acceptable salts of the compounds of the formula (IA) are also contemplated. Likewise, pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (IA) are contemplated. It should be understood that the formula (IA) structurally encompasses all positional isomers, stereoisomers, including enantiomers and diastereomers that may be contemplated from the chemical structure of the genus described herein.
Also contemplated are prodrugs of the compounds of the formula (IA), including ester prodrugs.
Another preferred embodiment of the present invention is a compound of Formula (IB),
Figure imgf000008_0001
Formula (IB) wherein, XB can be H, lower alkyl group, O-α or β-D-glucopyranosyl group, α or β-D- glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified); YB can be
Figure imgf000008_0002
wherein,
ZA can be (CH2)n; n can be an integer 0-1;
Ring AB and BB are independently can be a phenyl; RIB and R2B independently can be selected from H, -Cl, -Br, -OMe, or CF3;
R3B and R4B are independently can be selected from H, alkyl, or O- alkyl;
R5B can be alkyl. Pharmaceutically acceptable salts of the compounds of the formula (IB) are also contemplated. Likewise, pharmaceutically acceptable solvates, including hydrates, of the compounds of the formula (IB) are contemplated.
It should be understood that the formula (IB) structurally encompasses all positional isomers, stereoisomers, including enantiomers and diastereomers that may be contemplated from the chemical structure of the genus described herein.
Also contemplated are prodrugs of the compounds of the formula (IB), including ester prodrugs.
According to another embodiment, there is provided a pharmaceutical preparation, which comprises any one of the above tetrazole glycoside compounds or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient.
According to another embodiment, there is provided such a pharmaceutical preparation which is an inhibitor of sodium-dependent glucose transporter 2 activity. According to another embodiment, there is provided such a pharmaceutical preparation which is a prophylactic or therapeutic agent for diabetes, diabetes- related diseases or diabetic complications.
Below are the representative compounds which are illustrative in nature only and are not intended to limit to the scope of the invention. 2-(acetoxymethyl)-6-(5-benzyl-2H-tetrazol-2-yl)tetrahydro-2H-pyran-3,4,5- triyl triacetate (Compound No. 1),
2-(5-benzyl-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5- triol (Compound No. 2),
2-(acetoxymethyl)-6-(5-(4-bromobenzyl)-2H-terrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. 3),
2-(5-(4-bromobenzyl)-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol (Compound No. 4),
2-(acetoxymethyl)-6-(5-(2,4-dichlorobenzyl)-2H-tetrazol-2-yl)tetrahydro- 2H-pyran-3,4,5-triyl triacetate (Compound No. 5), 2-(5-(2,4-dichlorobenzyl)-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3,4,5-triol (Compound No. 6),
2-(acetoxymethyl)-6-(5-(4-methoxybenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. 7), 2-(hydroxymethyl)-6-(5-(4-methoxybenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- ρyran-3 ,4,5-triol (Compound No. 8),
2-(acetoxymethyl)-6-(5-(3,4-dichlorobenzyl)-2H-tetrazol-2-yl)tetrahydro- 2H-pyran-3,4,5-triyl triacetate (Compound No. 9), 2-(5-(3,4-dichlorobenzyl)-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3,4,5-triol (Compound No. 10),
2-(acetoxymethyl)-6-(5-(4-(trifluoromethyl)benzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 11),
2-(hydroxymethyl)-6-(5-(4-(trifluoromethyl)benzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3 ,4,5-triol (Compound No. 12),
2-(acetoxymethyl)-6-(5-(4-(benzyloxy)benzyl)-2H-tetrazol-2-yl)tetrahydro- 2H-pyran-3,4,5-triyl triacetate (Compound No. 13),
2-(5-(4-(benzyloxy)benzyl)-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3,4,5-triol (Compound No. 14), 2-(acetoxymethyl)-6-(5-(4-hydroxybenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. 15),
2-(5-(4-hydroxybenzyl)-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro-2H- pyran-3 ,4,5-triol (Compound No. 16),
2-(acetoxymethyl)-6-(5-phenethyl-2H-tetrazol-2-yl)tetrahydro-2H-pyran- 3,4,5-triyl triacetate (Compound No. 17),
2-(hydroxymethyl)-6-(5-phenethyl-2H-tetrazol-2-yl)tetrahydro-2H-pyran- 3,4,5-triol (Compound No. 18),
2-(acetoxymethyl)-6-(5-(2-oxo-2-phenylethyl)-2H-tetrazol-2-yl)tetrahydro- 2H-pyran-3,4,5-triyl triacetate (Compound No. 19), l-phenyl-2-(2-(3,4J5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)-2H-tetrazol-5-yl)ethanone (Compound No. 20),
2-(acetoxymethyl)-6-(5-(2-(4-chlorophenoxy)ethyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 21),
2-(5-(2-(4-chlorophenoxy)ethyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 22),
2-(acetoxymethyl)-6-(5-(4-methylbenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. 23),
2-(hydroxymethyl)-6-(5-(4-metliylbenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triol (Compound No. 24), 2-(acetoxymethyl)-6-(5-(4-ethylbenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. 25),
2-(5-(4-ethylbenzyl)-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol (Compound No. 26), 2-(acetoxymethyl)-6-(5-(2-methoxybenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. 27),
2-(hydroxymethyl)-6-(5-(2-methoxybenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triol (Compound No. 28),
2-(acetoxymethyl)-6-(5-(3-methoxybenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. 29),
2-(hydroxymethyl)-6-(5-(3-methoxybenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triol (Compound No. 30),
2-(acetoxymethyl)-6-(5-(4-ethoxybenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. 31), 2-(5-(4-ethoxybenzyl)-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol (Compound No. 32),
2-(acetoxymethyl)-4-hydroxy-6-(5-(4-isopropoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,5-diyl diacetate (Compound No. 33),
2-(hydroxymethyl)-6-(5-(4-isopropoxybenzyl)-2H-tetrazol-2-yl)tetrahydro- 2H-pyran-3,4,5-triol (Compound No. 34), ethyl (3,4,5-trihydroxy-6-(5-(4-isopropoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-2-yl)methyl carbonate (Compound No. 35),
2-(acetoxymethyl)-6-(5-(4-benzylbenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. 36), 2-(5-(4-benzylbenzyl)-2H-tetrazol-2-yl)-6-(hydroxymetriyl)tetrahydro-2H- pyran-3,4,5-triol (Compound No. 37),
2-(acetoxymethyl)-6-(4-((2-ethyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 38),
2-(4-((2-ethyl-2H-tetrazol-5-yl)methyl)phenoxy)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 39),
2-(acetoxymethyl)-6-(4-((2-metliyl-2H-tetrazol-5- yl)methyl)phenoxy)tetraliydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 40),
2-(hydroxymethyl)-6-(4-((2-methyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahydiO-2H-pyran-3,4,5-triol (Compound No. 41), 2-(acetoxymethyl)-6-(5-(2-oxo-2-(l-phenylethylamino)ethyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 42),
N-(l-phenylethyl)-2-(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H- pyran-2-yl)-2H-tetrazol-5-yl)acetamide (Compound No. 43), 2-(acetoxymethyl)-6-(5-(2-(l-(4-methoxyphenyl)ethylamino)-2-oxoetliyl)-
2H-tetrazol-2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 44),
N-(l-(4-methoxyphenyl)ethyl)-2-(2-(3,4,5-trihydroxy-6-
(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-2H-tetrazol-5-yl)acetamide (Compound No. 45), or pharmaceutically acceptable salts, solvates, isomers, including hydrates and prodrugs of compounds 1-45 are also contemplated.
Also below are representative isomeric compounds which are exemplary in nature only and are not intended to limit to the scope of the invention.
/corner .4 o/2-(acetoxymethyl)-6-(5-benzyl-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. IA),
Isomer B o/2-(acetoxymethyl)-6-(5-benzyl-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. IB),
Isomer A o/2-(5-benzyl-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol (Compound No. 2A), Isomer B o/2-(5-benzyl-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol (Compound No. 2B),
Isomer A ø/2-(acetoxymethyl)-6-(5-(4-bromobenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 3A),
Isomer B o/2-(acetoxymethyl)-6-(5-(4-bromobenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 3B),
Isomer A o/2-(5-(4-bromobenzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 4A),
Isomer B o/2-(5-(4-bromobenzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 4B), Isomer A o/2-(acetoxymethyl)-6-(5-(2,4-dichlorobenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 5A),
J^ome7-5 o/2-(acetoxymethyl)-6-(5-(2,4-dichlorobenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 5B), Isomer A ø/2-(5-(2,4-dichlorobenzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3J4,5-triol (Compound No. 6A),
Isomer B o/2-(5-(2,4-dichlorobenzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 6B), Isomer A o/"2-(acetoxymethyl)-6-(5-(4-methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 7A),
Isomer B o/2-(acetoxymethyl)-6-(5-(4-methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 7B),
Isomer A o/2~(hydroxymethyl)-6-(5-(4-methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 8A),
Isomer B o/"2-(hydroxymethyl)-6-(5-(4-methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 8B),
Isomer A <9/"2-(acetoxymethyl)-6-(5-(3,4-dichlorobenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 9A), Isomer B o/2-(acetoxymethyl)-6-(5-(3,4-dichlorobenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 9B),
Isomer A o/2-(5-(3,4~dichlorobenzyl)-2H-tetrazol~2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 10A),
Isomer B o/2-(5-(3,4-dichlorobenzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 10B),
Isomer A o/2-(acetoxymethyl)-6-(5-(4-(trifluoromethyl)benzyl)-2H-tetrazol- 2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. HA),
Isomer B o/2-(acetoxymethyl)-6-(5-(4-(trifluoromethyl)benzyl)-2H-tetrazol- 2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 11B), Isomer A o/2-(hydroxymethyl)-6-(5-(4-(trifluoromethyl)benzyl)-2H-tetrazol-
2-yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 12A),
/5O7wer 5 o/2-(hydroxymethyl)-6-(5-(4-(trifluoromethyl)benzyl)-2H-tetrazol- 2-yl)tetrahydro-2H-pyran-3,4,5-triol (Compound Net. 12B),
/5θ7κer^ o/2-(acetoxymethyl)-6-(5-(4-(benzyloxy)benzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 13A),
Λθ7«er5 o/2-(acetoxymethyl)-6-(5-(4-(benzyloxy)benzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 13B),
Isomer A o/2-(5-(4-(benzyloxy)benzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-ρyran-3,4,5-triol (Compound No. 14A), Isomer B ø/2-(5-(4-(benzyloxy)benzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 14B),
Isomer A o/2-(acetoxymethyl)-6-(5-(4-hydroxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 15A), Isomer B o/"2-(acetoxymethyl)-6-(5-(4-hydroxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 15B),
Isomer A o/2~(5-(4-hydroxybenzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 16A),
Isomer B o/2-(5-(4-hydroxybenzyl)-2H-tetrazol-2-yl)-6- (hydroxymemyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 16B),
Isomer A o/2-(acetoxymethyl)-6-(5-phenethyl-2H-tetrazol-2-yl)tetrab.ydro- 2H-pyran~3 ,4,5-triyl triacetate (Compound No. 17A),
Isomer B <?/'2-(acetoxymethyl)-6-(5-phenethyl-2H-tetrazol-2-yl)tetraliydro- 2H-pyran-3,4,5-triyl triacetate (Compound No. 17B), Isomer A o/2-(hydroxymethyl)-6-(5-phenethyl-2H-tetrazol-2-yl)tetrahydro-
2H-pyran-3,4,5-triol (Compound No. 18A),
Isomer B o/2-(hydroxymethyl)-6-(5-phenethyl-2H-tetrazol-2-yl)tetrahydro- 2H-pyran-3,4,5-triol (Compound No. 18B),
Isomer A o/2-(acetoxymethyl)-6-(5-(2~oxo-2-phenylethyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3 ,4,5-triyl triacetate (Compound No. 19A),
Isomer B o/2-(acetoxymethyl)-6-(5-(2-oxo-2-phenylethyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 19B),
Isomer A o/l-phenyl-2-(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro- 2H-pyran-2-yl)-2H-tetrazol-5-yl)ethanone (Compound No. 20A), Isomer B o/7-phenyl-2-(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-
2H-pyran-2-yl)-2H-tetrazol-5-yl)ethanone (Compound No. 20B),
Isomer A o/2-(acetoxymethyl)-6-(5-(2-(4-chlorophenoxy)ethyl)-2H-tetrazol- 2-yl)tetrahydro-2H-pyran-3 ,4,5-triyl triacetate (Compound No. 21A),
/5iomer-5 o/2-(acetoxymethyl)-6-(5-(2-(4-chlorophenoxy)ethyl)-2H-tetrazol- 2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 21B),
/5O77ze/-^ o/2-(5-(2-(4-chlorophenoxy)ethyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 22A),
Ao/7zer5 o/2-(5-(2-(4-chlorophenoxy)ethyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-ρyran-3,4,5-triol (Compound No. 22B), Isomer A o/2-(acetoxymethyl)-6-(5-(4-methylbenzyl)-2H-tetrazol-2- yl)tetxahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 23A),
Λower 5 o/2-(acetoxymethyl)-6-(5-(4-methylbenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 23B), Isomer A o/2-(hydroxymethyl)-6-(5-(4-methylbenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 24A),
Isomer B o/2-(hydroxymethyl)-6-(5-(4-methylbenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 24B),
Isomer A o/2-(acetoxymethyl)-6-(5-(4-ethylbenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 25A),
Isomer B q/"2-(acetoxymethyl)-6-(5-(4-ethylbenzyl)-2H-tetrazol-2- yl)tetraliydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 25B),
Isomer A o/2-(5-(4-ethylbenzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 26A), Isomer B ø/2-(5-(4-emylbenzyl)-2H-tetrazol-2-yl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 26B),
Isomer A o/'2-(acetoxymethyl)-6-(5-(2-metlioxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 27A),
Isomer B o/2-(acetoxymethyl)-6-(5-(2-methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 27B),
Isomer A o/2-(hydroxymethyl)-6-(5-(2-methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 28A),
Isomer B q/"2-(hydroxymethyl)-6-(5-(2-methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 28B), Isomer A o/2-(acetoxymethyl)-6-(5-(3-methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 29A),
Isomer B o/2-(acetoxymethyl)-6-(5-(3-methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 29B),
Isomer A o/2-(hydroxymethyl)-6-(5-(3 -methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 30A),
Isomer B o/"2-(hydroxymethyl)-6-(5-(3-methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 30B),
Λ<?7K(2rJ4 o/2-(acetoxymethyl)-6-(5-(4-ethoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 31A), Isomer B o/2-(acetoxymethyl)-6-(5-(4-ethoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 31B),
Isomer A ø/2-(5-(4-ethoxybenzyl)-2H~tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 32A), Isomer B ø/2-(5-(4-ethoxybenzyl)-2H-tetrazol-2-yl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 32B),
Isomer A of 2-(acetoxymethyl)-4-hydroxy-6-(5-(4-isopropoxybenzyl)-2H- tetrazol-2-yl)tetrahydro-2H-pyran-3,5-diyl diacetate (Compound No. 33A),
Isomer B of 2-(acetoxymethyl)-4-hydroxy-6-(5-(4-isopropoxybenzyl)-2H- tetrazol-2-yl)tetrahydro-2H-pyran-3,5-diyl diacetate (Compound No. 33B),
Isomer A of 2-(hydroxymethyl)~6~(5-(4-isopropoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 34A),
Isomer B of 2-(hydroxymethyl)-6-(5-(4-isopropoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 34B), Isomer A of ethyl (3,4,5-trihydroxy-6~(5-(4-isopropoxybenzyl)-2H-tetrazol-
2-yl)tetrahydro-2H-pyran-2-yl)methyl carbonate (Compound No. 35A),
Isomer B of ethyl (3,4,5-trihydroxy-6-(5-(4-isopropoxybenzyl)-2H-tetrazol- 2-yl)tetrahydro-2H-pyran-2-yl)methyl carbonate (Compound No. 35B),
Isomer A of 2-(acetoxymethyl)-6-(5-(4-benzylbenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 36A),
Isomer B of 2-(acetoxymethyl)-6-(5-(4-benzylbenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 36B),
Isomer A of 2-(5-(4-benzylbenzyl)-2H-tetrazol-2-yl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 37A), Isomer B of 2-(5-(4-benzylbenzyl)-2H-tetrazol-2-yl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 37B),
Isomer A of 2-(acetoxymethyl)-6-(4-((2-ethyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 38A),
Isomer B of 2-(acetoxymethyl)-6-(4-((2-ethyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 38B),
Isomer A of 2-(4-((2-ethyl-2H-tetrazol-5-yl)methyl)phenoxy)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 39A),
Isomer B of 2-(4-((2-ethyl-2H-tetrazol-5-yl)methyl)phenoxy)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 39B), Isomer A of 2-(acetoxymethyl)-6-(4-((2-methyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 40A),
Isomer B of 2-(acetoxymethyl)-6-(4-((2-methyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 40B), Isomer A of 2-(hydroxymethyl)-6-(4-((2-methyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahydro-2H~pyran-3,4,5-trioI (Compound No. 41A),
Isomer B of 2-(hydroxymethyl)-6-(4-((2-methyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 41B),
Isomer A of 2-(acetoxymethyl)-6-(5-(2-oxo-2-(l-phenylethylamino)ethyl)- 2H-tetrazol-2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 42A),
Isomer B of 2-(acetoxymethyl)-6-(5-(2-oxo-2-(l-phenylethylammo)ethyl)- 2H-tetrazol-2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 42B),
Isomer A of N-(l-phenylethyl)-2-(2-(3,4,5-trihydroxy-6-
(hydroxymetriyl)tetrahydro-2H-pyran-2-yl)-2H-tetrazol-5-yl)acetamide (Compound No. 43A),
Isomer B of N-(l-phenylethyl)-2-(2-(3,4,5-trihydroxy-6-
(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-2H-tetrazol-5-yl)acetamide (Compound No. 43B),
Isomer A of 2-(acetoxymethyl)-6-(5-(2-(l-(4-methoxyphenyl)ethylamino)-2- oxoethyl)-2H-tetrazol-2-yl)teti-ahydro-2H-pyran-3,4,5-triyl triacetate (Compound
No. 44A),
Isomer B of 2-(acetoxymethyl)-6-(5-(2-(l -(4-methoxyphenyl)ethylamino)-2- oxoethyl)-2H-tetrazol-2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 44B), Isomer A of N-(l-(4-methoxyphenyl)ethyl)-2-(2-(3,4,5-trihydroxy-6-
(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-2H-tetrazol-5-yl)acetamide (Compound No. 45A),
Isomer B of N-(l-(4-methoxyphenyl)ethyl)-2-(2-(3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)-2H-tetrazol-5-yl)acetamide (Compound No. 45B), or pharmaceutically acceptable salts, solvates, isomers, including hydrates and prodrugs of compounds 1A-45B are also contemplated.
The invention also provides a pharmaceutical composition that includes at least one compound of described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compound(s) present in the composition may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or may be diluted by a carrier, or enclosed within a carrier which may be in the foπn of a capsule, sachet, paper or other container.
The compounds and pharmaceutical compositions described herein are useful in the treatment of diseases, conditions and/or disorders mediated by SGLT2 inhibitors. The invention further provides a method of treating a disease, condition and/or disorder mediated by SGLT2 inhibitors in a subject in need thereof by administering to the subject one or more compounds described herein in the amount effective to cause inhibition of such receptor.
Also provided are SGLT2 activity' of compounds of the formula (1), (IA) or (IB), at two different concentrations like 10 μm and 3 μm in BBMVs and cell based assay.
Also provided herein are processes for preparing compounds described herein.
The invention provides a method for preventing, ameliorating or treating a SGLT2 mediated disease, disorder or syndrome in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the invention. The invention further provides a method, wherein the
SGLT2 mediated disease, disorder or syndrome is diabetes, especially type I and type 11 diabetes, including complications of diabetes such as retinopathy, neuropathy, nephropathy and delayed wound healing, and related diseases such as insulin resistance and impaired glucose homeostasis (IGH), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hyperlipidemia including hypertriglyceridemia, Syndrome X, hypertension, atherosclerosis and related diseases, and for increasing high density lipid levels. The conditions, diseases, and maladies collectively referred to as "Syndrome X" (also known as Metabolic Syndrome).
The invention provides a method of treating diabetes in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to the invention. A number of assays have been published in the literature to assess the anti diabetes activity of the compounds. For example, in- vitro assays have been reported in Am J physiol Renal Physiol 286, Fl 27-Fl 33, 2004; Nature protocols, 2007, 2(6), 1356-59; EP Patent application EP 1813611 and J. Pharmacology and Experimental Therapeutics, 324, 985-991, 2008.
The invention provides a method of treating type I diabetes in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to the invention
The invention provides a method of treating type II diabetes in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to the invention.
The invention provides a process for the preparation of a compound of formula (I):
Figure imgf000019_0001
wherein,
X can be H, lower alkyl group, lower perfluoro alkyl group, aralkyl group, phenyl group, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxylgroup may be esterified);
Y can be
Figure imgf000019_0002
Ring A and B are independently can be selected from phenyl, naphthyl, heteroaryl, cycloalkyl or heterocyclyl which may contain 5 to 7 membered ring, which may contain 1 to 4 hetero atoms like N, O, S, SO or
SO2 in the ring; Z can be oxygen, methylene, (CH2)n, dimethylmethylene, difluoromethylene, carbonyl, O-alkyl, S-alkyl, SO2 alkyl, -C(O)-NH-R1R2 or Z may represent a bond between rings A and B; n can be an integer 0-3;
Y also can be
Figure imgf000020_0001
, substituted or unsubstituted aryl group more particularly substituted or unsubstituted phenyl group, substituted or unsubstituted aryl-C(O)-, substituted or unsubstituted aryl- CH2-, or substituted or unsubstituted aryloxy-CH2-, where in substituents are Ri and R2; Ri and R2 are independently can be selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, Ci-β-alkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-C4alkylcarbonyl, aryl carbonyl, heteroarylcarbonyl, amino carbonyl, Ci-4-alkylaminocarbonyl, hydroxyl, cyano, Ci-4 alkyl sulphonylamino, arylsulphonylamino, Ci- β alkoxy, C3-7 cycloalkoxy, aryloxy, aralkyloxy, aryloxyalkyl, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified); R3 and R4 are independently can be selected from hydrogen, alkyl, halo, perfluoroalkyl, CN, OH, O-alkyl, O-cycloalkyl, phenyl, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D- glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified);
R5 can be alkyl or perfluoroalkyl; an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N- oxide thereof, a tautomer thereof, a regeoisomers thereof, a stereoisomer thereof, a prodrug thereof or a polymorph thereof, the process comprising the steps of: (a) reacting the cyano compounds of formula (1)
Y'^CN 1 with the azide compounds of formula (2)
NaN3 2 to form tetrazole compounds of formula (3)
Figure imgf000021_0001
(b) reacting the tetrazole compounds of formula (3) with the acylated sugar compounds of formula (4)
Figure imgf000021_0002
to form the acylated sugar compounds of formula (5)
Figure imgf000021_0003
5
Formula (1), when X is acylated glucopyranosyl an(j
(c) hydrolysing the compounds of formula (5) to form the sugar compounds of formula (6)
Figure imgf000021_0004
6
Formula (1), when X is glucopyranosyl Alternatively, the invention provides a process for the preparation of a compound of formula (I):
Figure imgf000022_0001
wherein,
X can be H, lower alkyl group, lower perfluoro alkyl group, aralkyl group, phenyl group, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxylgroup may be esterified);
Y can be
Figure imgf000022_0002
Ring A and B are independently can be selected from phenyl, naphthyl, heteroaryl, cycloalkyl or heterocyclyl which may contain 5 to 7 membered ring, which may contain 1 to 4 hetero atoms like N, O, S, SO or SO2 in the ring;
Z can be oxygen, methylene, (CH2)n, dimethylmethylene, difluoromethylene, carbonyl, O-alkyl, S-alkyl, SO2 alkyl, -C(O)-NH-RiR2 or
Z may represent a bond between rings A and B; n can be an integer 0-3;
Y also can be
Figure imgf000022_0003
, substituted or unsubstituted aryl group more particularly substituted or unsubstituted phenyl group, substituted or unsubstituted aryl-C(O)-, substituted or unsubstituted aryl-
CH2-, or substituted or unsubstituted aryloxy-CH2-, where in substituents are Ri and R2;
R] and R2 are independently can be selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, d-e-alkyl, C2-6 alkynyl, C3-6 cycloalkyl, Ci-C4alkylcarbonyl, aryl carbonyl, heteroarylcarbonyl, amino carbonyl, C1-4-alkylaminocarbonyl, hydroxyl, cyano, C1-4 alkyl sulphonylamino, arylsulphonylamino, C1. 6 alkoxy, C3-7 cycloalkoxy, aryloxy, aralkyloxy, aryloxyalkyl, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified);
R3 and R4 are independently can be selected from hydrogen, alkyl, halo, perfluoroalkyl, CN, OH, O-alkyl, O-cycloalkyl, phenyl,
O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D- glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified); R5 can be alkyl or perfluoroalkyl; an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N- oxide thereof, a tautomer thereof, a regeoisomers thereof, a stereoisomer thereof, a prodrug thereof or a polymorph thereof, the process comprising the steps of:
(a) reacting the amino compounds of formula (7)
Figure imgf000023_0001
with the cyano acetic acid compounds of formula (8)
HOOC^CN 8 to foπn the amido compounds of formula (9)
Figure imgf000023_0002
(b) reacting the amido compounds of formula (9) with the azide compounds of formula (2)
NaN3 to form the tetrazole compounds of formula (10)
Figure imgf000024_0001
(c) reacting the tetrazole compounds of formula (10) with the acylated sugar compounds of formula (4)
Figure imgf000024_0002
4 to form the acylated sugar compounds of formula (11)
Figure imgf000024_0003
11
Formula 1, when X is acylated glucopyraiiosyl JJi1(J
(d) hydrolysing the acylated sugar compounds of formula (11) to form the sugar compounds of formula (12)
Figure imgf000024_0004
12
Formula 1, when X is I Q glucopyranosyl
Alternatively, the invention provides one more process for the preparation of a compound of formula (I):
Figure imgf000024_0005
wherein,
15 X can be H, lower allcyl group, lower perfluoro alkyl group, aralkyl group, phenyl group, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxylgroup may be esterified);
Y can be
Figure imgf000025_0001
Ring A and B are independently can be selected from phenyl, naphthyl, heteroaryl, cycloalkyl or heterocyclyl which may contain 5 to 7 membered ring, which may contain 1 to 4 hetero atoms like N, O, S, SO or SO2 in the ring;
Z can be oxygen, methylene, (CH2)n, dimethylmethylene, difluoromethylene, carbonyl, O-alkyl, S-alkyl, SO2 alkyl, -C(O)-NH-RiR2 or
Z may represent a bond between rings A and B; n can be an integer 0-3;
Y also can be
Figure imgf000025_0002
, substituted or unsubstituted aryl group more particularly substituted or unsubstituted phenyl group, substituted or unsubstituted aryl-C(O)-, substituted or unsubstituted aryl-
CH2-, or substituted or unsubstituted aryloxy-CH2-, where in substiτuents are Ri and R2;
Ri and R2 are independently can be selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, Ci-6-alkyl, C2-6 alkynyl, C3-6 cycloalkyl, Ci-C4alkylcarbonyl, aryl carbonyl, heteroarylcarbonyl, amino carbonyl, Ci-4-alkylaminocarbonyl, hydroxyl, cyano, Ci-4 alkyl sulphonylamino, arylsulphonylamino, Ci- 6 alkoxy, C3-7 cycloalkoxy, aryloxy, aralkyloxy, aryloxyalkyl, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified); R3 and R4 are independently can be selected from hydrogen, alkyl, halo, perfluoroalkyl, CN, OH, O-alkyl, O-cycloalkyl, phenyl, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D- glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterifled); R5 can be alkyl or perfluoroalkyl; an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N- oxide thereof, a tautomer thereof, a regeoisomers thereof, a stereoisomer thereof, a prodrug thereof or a polymorph thereof, the process comprising the steps of:
(a) reacting the cyano compounds of formula (13) (wherein, P is protecting group (benzyl or tertiary butyl))
Figure imgf000026_0001
with the azide compounds of formula (2)
NaN3 2 to form the tetrazole compounds of formula (14)
Figure imgf000026_0002
(b) reacting the tetrazole compounds of formula (14) with the halo compounds of formula (15)
XBr 15 to form the compounds of formula (16)
Figure imgf000026_0003
(c) deprotecting the compounds of formula (16) to form the compounds of formula (17)
Figure imgf000027_0001
(d) reacting the compounds of formula (17) with the acylated sugar compounds of formula (4)
Figure imgf000027_0002
4 to form the acylated sugar compounds of formula (18)
Figure imgf000027_0003
18
Formula 1, when Y is phenyl substituted by acylated glucopyranosyl ajj(J
(e) hydrolysing the acylated sugar compounds of formula (18) to form the sugar compounds of formula (19)
Figure imgf000027_0004
Formula 1, when Y is phenyl substituted by glucopyranosyl The invention provides for use of a compound of the invention for the manufacture of a medicament for, for example, preventing, ameliorating or treating a SGLT2 mediated disease, disorder or syndrome in a subject in need thereof. The invention further provides for the use wherein the SGLT2 mediated disease, disorder or syndrome is diabetes, especially type I and type II diabetes, including complications of diabetes such as retinopathy, neuropathy, nephropathy and delayed wound healing, and related diseases such as insulin resistance and impaired glucose homeostasis (IGH), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hyperlipidemia including hypertriglyceridemia, Syndrome X, hypertension, atherosclerosis and related diseases, and for increasing high density lipid levels, and the conditions, diseases, and maladies collectively referred to as
"Syndrome X" (also known as Metabolic Syndrome). Detailed Description of the Invention
The invention provides tetrazole glycoside derivatives, which may be used as SGLT2 inhibitors and processes for the synthesis of these compounds. Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, positional isomers, enantiomers, diastereomers, polymorphs of these compounds that may have the same type of activity are also provided. Pharmaceutical compositions containing the described compounds together with pharmaceutically acceptable carriers, excipients or diluents, which can be used for the treatment of diseases, condition and/or disorders mediated by SGLT2 inhibitors are further provided. The following definitions apply to the terms as used herein:
The terms "halogen" or "halo" includes fluorine, chlorine, bromine, or iodine.
The term "alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n- pentyl, and 1,1-dimethylethyl (t-butyl).
The term "alkenyl" refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be a straight or branched chain having from 2 to about 10 carbon atoms, e.g., ethenyl, 1-propenyl, 2-propenyl (allyl), iso- propenyl, 2-methyl- 1-propenyl, 1-butenyl, and 2-butenyl.
The term "haloalkyl" is used to denote a group comprised of an alkyl group substituted with halogen atom, where alkyl group is as defined above and halogen is used to denote fluorine, chlorine, bromine or iodine, an example of such group is trifluoromethyl, difluoromethyl.
The term "acyl group" is used to denote a linear or branched aliphatic acyl group (preferably a C2-6 alkanoyl group) or an aromatic acyl group, which contains 2 to 10 carbon atoms. Examples include an acetyl group, a propionyl group, a pivaloyl group, a butyryl group, an isobutyryl group, a valeryl group and a benzoyl group, with an acetyl group being preferred.
The term "alkoxy group" is used to denote a linear or branched alkoxy group containing 1 to 6 carbon atoms. Preferred are C1-4 alkoxy groups including a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a n-butoxy group, an isobutoxy group and a tert-butoxy group. The term "cycloalkyl" denotes a non-aromatic mono or multicyclic ring system of from 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Examples of multicyclic cycloalkyl groups include, but are not limited to, perhydronapththyl, adamantyl and norbornyl groups, bridged cyclic groups and spirobicyclic groups, e.g., spiro (4,4) non-2-yl.
The term "cycloalkylalkyl" refers to a cyclic ring-containing radical having from 3 to about 8 carbon atoms directly attached to an alkyl group. The cycloalkylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Non-limiting examples of such groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl.
The term "cycloalkenyl" refers to a cyclic ring-containing radical having from 3 to about 8 carbon atoms with at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, and cyclopentenyl. The term "aryl" refers to an aromatic radical having from 6 to 14 carbon atoms such as phenyl, naphthyl, tetrahydronapthyl, indanyl, and biphenyl.
The term "arylalkyl" refers to an aryl group as defined above directly bonded to an alkyl group as defined above, e.g., -CH2C6Hs and -C2H5C6Hs.
The terms "heterocyclyl" and "heterocyclic ring" refer to a stable 3- to 15- membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused, bridged or spiro ring systems, and the nitrogen, phosphorus, carbon, oxygen or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated (i.e., heterocyclic or heteroaryl). Examples of such heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxinyl benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, imidazolyl, tetrahydroisouinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxasolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzooxazolyl, furyl, tetrahydrofurtyl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl, oxadiazolyl, chromanyl, and isochromanyl. The heterocyclic ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure. The term "heterocyclylalkyl" refers to a heterocyclic ring radical directly bonded to an alkyl group. The heterocyclylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure.
The term "heteroaryl" refers to an aromatic heterocyclic ring radical. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
The term "heteroarylalkyl" refers to a heteroaryl ring radical directly bonded to an alkyl group. The heteroarylalkyl radical may be attached to the main structure at any carbon atom in the alkyl group that results in the creation of a stable structure. Unless otherwise specified, the term "substituted" as used herein refers to, for example, substitution with any one or any combination of the following substituents: hydroxy, halogen, carboxyl, cyano, nitro, oxo (=0), thio (=S), substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heterocyclic ring, substituted or unsubstiuted guanidine,
-COORX, -C(O)RX, -C(S)RX, -C(O)NRxRy, -C(O)ONRxRy, -NRxC0NRyRz, - N(Rx)SORy, -N(Rx)SO2Ry, -(=N-N(Rx)Ry), -NRxC(O)ORy, -NRxRy, -NRxC(O)Ry, - NRxC(S)Ry, -NRxC(S)NRyRz, -SONRxRy, -SO2NRxRy, -ORX, -ORxC(O)NRyRz, - ORxC(O)ORy, -OC(O)RX, -OC(O)NRxRy, -RxNRyC(O)Rz, -RxORy, -RxC(O)ORy, - RxC(O)NRyRz, -RxC(O)Ry, -RxOC(O)Ry, -SRX, -SORX, -SO2RX, and -ONO2, wherein Rx, Ry and Rz are independently selected from hydrogen, substituted or unsubstituted alkyl, haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocyclic ring. The substituents in the aforementioned "substituted" groups cannot be further substituted. For example, when the substituent on "substituted alkyl" is "substituted aryl", the substituent on "substituted aryl" cannot be "substituted alkenyl".
The term "prodrug" means a compound that is transformed in vivo to yield, for example, a compound of Formula (1), Formula (IA), or Formula (IB) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms, such as through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
The term "treating" or "treatment" of a state, disease, disorder or condition includes, for example:
(1) preventing or delaying the appearance of clinical symptoms of the state, disease, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disease, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disease, disorder or condition;
(2) inhibiting the state, disease, disorder or condition, e.g., arresting or reducing the development of the state, disease, disorder or condition or at least one clinical or subclinical symptom thereof; or
(3) relieving the state, disease, disorder or condition, e.g., causing regression of the state, disease, disorder or condition or at least one of its clinical or subclinical symptoms. The benefit to a subject receiving treatment is either statistically significant or at least perceptible to the subject or to the physician.
The term "subject" includes, for example, mammals (especially humans) and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non-domestic animals (such as wildlife).
A "therapeutically effective amount" means, for example, the amount of a compound that, when administered to a subject for treating a state, disease, disorder or condition, is sufficient to effect such treatment. The "therapeutically effective amount" will vary depending on the compound, the state, disease, disorder or condition and its severity and the age, weight, physical condition and responsiveness of the subject receiving treatment.
The term "diabetes" encompasses, for example, type I diabetes, type II diabetes, and other types of diabetes with specific etiology.
The term "diabetes-related diseases" includes, for example, adiposis, hyperinsulinemia, abnormal carbohydrate metabolism, hyperlipidernia, hypercholesterolemia, hypertriglyceridemia, abnormal lipid metabolism, hypertension, congestive heart failure, edema, hyperuricemia and gout.
The term "diabetic complications" can be classified into acute complications and chronic complications. The term "acute complications" includes, for example, hyperglycemia (e.g., ketoacidosis), infections (e.g., skin, soft tissue, biliary system, respiratory system and urinary tract infections), etc.
The term "chronic complications" includes, for example, microangiopathy (e.g., nephropathy, retinopathy), arteriosclerosis (e.g., atherosclerosis, heart infarction, brain infarction, or lower extremity arterial occlusion), neuropathy (e.g., sensory nerves, motor nerves, or autonomic nerves), foot gangrene, etc. Major complications are diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.
The compound of invention may form salts. Non-limiting examples of pharmaceutically acceptable salts forming part of the invention include salts derived from inorganic bases salts of organic bases salts of chiral bases, salts of natural amino acids and salts of non-natural amino acids. Certain compounds of invention are capable of existing in stereoisomeric forms (e.g. diastereomers and enantiomers) or as positional isomers. With respect to the overall compounds described by the Formula (I), the invention extends to these stereoisomer^ forms and to mixtures thereof. To the extent prior art teaches synthesis or separation of particular stereoisomers, the different stereo isomeric forms of the invention may be separated from one another by the method known in the art, or a given isomer may be obtained by stereospecific or asymmetric synthesis. Tautomeric forms and mixtures of compounds described herein are also contemplated.
All stereoisomers of the compounds of this invention are contemplated, either admixture or substantially pure form or in pure form. The compounds of present invention have asymmetric centers at any of the carbon atoms including any one of the R substituents. Thus the compounds of formula (1), formula (IA), or formula (IB) can exist in racemic, enantiomeric or diasteriomeric forms or in mixtures thereof. The process for preparation can utilize racemates, enantiomers, or diastereomers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods for example, chromatographic or fractional crystallization.
Pharmaceutically acceptable solvates includes, for example, hydrates and other solvents of crystallization (such as alcohols). The compounds of the present invention may form solvates with low molecular weight solvents by methods known in the art. Phannaceutical Compositions
The phannaceutical compositions provided in the invention include at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the contemplated pharmaceutical compositions include a compound(s) described herein in an amount sufficient to inhibit SGLT2 in a subject.
The subjects contemplated include, for example, a living cell and a mammal, including human mammal. The compound of the present invention may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
The carrier or diluent may include a sustained release material, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, emulsifying agents, suspending agents, preserving agents, salts for influencing osmotic pressure, buffers, sweetening agents, flavoring agents, colorants, or any combination of the foregoing. The pharmaceutical composition of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the subject by employing procedures known in the art.
The pharmaceutical compositions described herein may be prepared, e.g., as described in Remington: The Science and Practice of Pharmacy. 20th Ed., 2003 (Lippincott Williams & Wilkins). For example, the active compound can be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid container, for example, in a sachet.
The pharmaceutical compositions may be, for example, capsules, tablets, aerosols, solutions, suspensions or products for topical application.
The route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic (such as with an ophthalmic solution) or topical (such as with a topical ointment). The oral route is preferred. Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, cornstarch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
A typical tablet that may be prepared by conventional tabletting techniques may contain: (1) Core: Active compound (as free compound or salt thereof), 250 mg colloidal silicon dioxide (Aerosil®), 1.5 mg microcrystalline cellulose (Avicel®), 70 mg modified cellulose gum (Ac-Di-Sol®), and 7.5 mg magnesium stearate; (2) Coating: HPMC, approx. 9 mg Mywacett 9-40 T and approx. 0.9 mg acylated monoglyceride.
Liquid formulations include, but are not limited to, syrups, emulsions, soft gelatin and sterile injectable liquids, such as aqueous or non-aqueous liquid suspensions or solutions.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil. Methods of Treatment
The present invention provides compounds and pharmaceutical formulations thereof that are useful in the treatment of diseases, conditions and/or disorders mediated by SGLT2 inhibitors. The connection between therapeutic effect and inhibition of SGLT2 is illustrated. For example in PCT publication Nos. WO 01//016147, WO 02/08306, or WO 03/020737; J. Clin. Invest. Vol. 79, pp. 1510-
1515 (1987); J.Clin. Invest, Vol. 93, pp. 397-404 (1994); Diabetes; 57, 1723-1729, 2008 and references cited therein, all of which are incorporated herein by reference in their entirety and for the purpose stated.
The present invention further provides a method of treating a disease, condition and/or disorder mediated by SGLT2 inhibitors in a subject in need thereof by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present invention.
Diseases, conditions, and/or disorders that are mediated by SGLT2 inhibitors include, but are not limited to, diabetes, especially type I and type 11 diabetes, including complications of diabetes such as retinopathy, neuropathy, nephropathy and delayed wound healing, and related diseases such as insulin resistance and impaired glucose homeostasis (IGH), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hyperlipidemia including hypertriglyceridemia, Syndrome X, hypertension, atherosclerosis and related diseases, and for increasing high density lipid levels. The conditions, diseases, and maladies collectively referred to as "Syndrome X" (also known as Metabolic Syndrome) are detailed in Johannsson, J. CHn. Endrocrinol. Metab. , 82, 727-34 (1997) incorporated herein by reference. The compounds of the present invention can obtain more advantageous effects than additive effects in the prevention or treatment of the above diseases when using suitably in combination with the above drugs. Also, the administration dose can be decreased in comparison with administration of either drug alone, or adverse effects of co administrated drugs other than SGLT2 inhibitors can be avoided or declined.
Methods of Preparation
The compounds described herein may be prepared by techniques known in the art. In addition, the compounds described herein may be prepared by following the reaction sequence as depicted in Scheme 1-3. Further, in the following schemes, where specific bases, acids, reagents, solvents, coupling agents, etc., are mentioned, it is understood that other bases, acids, reagents, solvents, coupling agents etc., known in the art may also be used and are therefore included within the present invention. Variations in reaction conditions, for example, temperature and/or duration of the reaction, which may be used as known in the art, are also within the scope of the present invention. All the stereo isomers of the compounds in these schemes, unless otherwise specified, are also encompassed within the scope of this invention.
Scheme 1
X is
Figure imgf000036_0001
6
Formula (1), when X is glucopyranosyl
The compounds of Formula (1) (wherein, X and Y are same as defined above) can be prepared by the above procedure as described in Scheme 1. The nitrile compounds of formula 1 can be treated with sodium azide compounds of formula 2 to give the tetrazole compounds of formula 3 (as described in J. Organic chemistry, 2001, 66, 7945-7950) in presence of metal halides such as, zinc bromide or the like in the solvents for example, isopropyl alcohol in water, or the like. The tetrazole compounds of formula 3 can be reacted with the acylated-bromo sugar compounds of formula 4 (as described in Organic Synthesis Collective volume 3, page 11, 1955) to give the acylated sugar compounds of formula 5 in presence of a base such as, potassium or cesium carbonate or the like in the solvents such as, for example, acetonitrile, chloroform or the like. The acylated sugar compounds of formula 5 can be hydrolyzed to give the sugar compounds of formula 6 in the presence of hydrolyzing agents such as, for example methanolic ammonia, or the like. Produgs of compounds of formula 1 can be prepared by reacting the haloformates in the presence of a base like triethyl amines.
Sclleme-2
Figure imgf000037_0001
12 11
Formula 1, when X is Formula 1, when X is glucopyranosyl acylated glucopyranosyl The compounds of Formula (1) (wherein, X, Y, R3, R4, and R5 are same as defined above) also can be prepared by the above procedure as described in Scheme 2. The nitrile amine compounds of formula 7 can be treated with the acidic-nitrile compounds of formula 8 to give the amide-nitrile compounds of foπnula 9 in presence of coupling agents such as l-(3-dimethyl aminopropyl)-3 -ethyl carbodiimide hydrochloride, 1-hydroxy-benzotriazole or the like in the solvents such as dimethyl formamide or the like. The amide-nitrile compounds of formula 9 can be treated with sodium azide compounds of formula 2 to give the tetrazole compounds of formula 10 (as described in J. Organic chemistry, 2001, 66, 7945-7950) in presence of metal halides such as, zinc bromide or the like in the solvents for example, isopropyl alcohol in water, or the like. The tetrazole compounds of formula
10 can be reacted with the acylated-bromo sugar compounds of formula 4 (as described in Organic Synthesis Collective volume 3, page 11, 1955) to give the acylated sugar compounds of formula 11 in presence of a base such as, potassium or cesium carbonate or the like in the solvents such as, for example, acetonitrile, chloroform or the like. The acylated sugar compounds of formula 11 can be hydro lyzed to give the sugar compounds of formula 12 in the presence of hydrolyzing agents such as, for example methanolic ammonia, or the like. Produgs of compounds of formula 1 can be prepared by reacting the haloformates in the presence of a base like triethyl amines.
Figure imgf000038_0001
substituted by glucopyranosyl substituted by aoylated glucopyranosyl
The compounds of Formula (1) (wherein, P is protecting group (benzyl or tertiary butyl), X, and Y are same as defined above) also can be prepared by the above procedure as described in Scheme 3. The nitrile compounds of formula 13 can be reacted with sodium azide compounds of formula 2 to give the tetrazole compounds of formula 14 (as described in J. Organic chemistry, 2001, 66, 7945- 7950) in presence of metal halides such as, zinc bromide or the like in the solvents for example, isopropyl alcohol in water, or the like. The tetrazole compounds of formula 14 can be reacted with the bromo compounds of formula 15 to give the compounds of formula 16 in presence of base such as, potassium or cesium carbonate or the like in the solvents such as, for example, acetonitrile, chloroform or the like. The compounds of formula 16 can be deprotected in presence of deprotecting agents such as palladium on carbon or the like to give the hydroxy compounds of formula 17. The hydroxy compounds of formula 17 can be reacted with the acylated-bromo sugar compounds of formula 4 (as described in Organic Synthesis Collective volume 3, page 11, 1955) to give the acylated sugar compounds of formula 18 in presence of a base such as, potassium or cesium carbonate or the like in the solvents such as, for example, acetonitrile, chloroform or the like. The acylated sugar compounds of formula 18 can be hydrolyzed to give the sugar compounds of formula 19 in presence oh hydrolyzing agents such as, for example methanolic ammonia, or the like. Produgs of compounds of formula 1 can be prepared by reacting the haloformates in the presence of a base like triethyl amines.
It is known in the literature that the addition of sodium azide to nitriles to give tetrazoles may processed either a two step mechanism or a concepted 2+3 cyclo addition giving a scope of forming either of regeoisomers or a mixture of regeoisomers. These isomers are separable by chromatography either at this stage or at the later stage.
Experimental The present invention is further illustrated by the following examples, which are not to be construed in any way as imposing limitations upon the scope of this disclosure, but rather are intended to be illustrative only. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications, and equivalents thereof which, after reading the description herein, may suggest themselves to one of ordinary skill in the art without departing from the spirit of the present invention. Thus, the skilled artisan will appreciate how the experiments and Examples may be further implemented as disclosed by variously altering the following examples, substituents, reagents, or conditions.
Examples Example 1: Preparation of (6S)-2-facetoxymethyl)-6-f5-benzyl-2H-tetrazol-2- yl)tetrahvdro-2H-pyran-3 ,4,5-triyl triacetate:
Figure imgf000039_0001
Step 1: Synthesis of 5-benzyl-2H-tetrazole
Figure imgf000039_0002
Sodium azide (about 3 g, 4.7 equivalent) was added to a mixture of phenylacetonitrile (about 1 g, 1 equivalent) and Zinc Bromide (about 1.5 g, 0.7 equivalent) in isopropyl alcohol/water (10 ml/30 ml). Contents were refiuxed at about 80° C for about 48 hours under vigorous stirring. Completion of the reaction was monitored by TLC. The Reaction mixture was cooled to room temperature and the PH was adjusted to 1.0 with diluted HCl and stirred for about 10 minutes then extracted with ethyl acetate (3x20 ml). The combined organic layers were washed with NaHCO3 solution and brine solution, dried over magnesium sulphate (MgSO4) and concentrated in vacuo to afford the title compound as a white solid. Yield: 85%;
1H NMR (300 MHz, CDCl3): δ, 4.29 (s, 5H), 5.88 (s, 2H), 7.25-7.34 (m, 5H, Ar-H), 16.20 (Jars, IH, NH); Mass [M+Naf: 183(100%).
Step 2: Preparation of 2-(acetoxymethyl)-6-(5-benzyl-2H-tetrazol-2-yl)tetrahydro- 2H-pyran-3, 4, 5-triyl triacetate:
Figure imgf000040_0001
Anhydrous K2CO3 (about 1.28 g, 3 equivalent) was added to acetonitrile (10 ml) followed by 5-Benzyl-2H-Tetrazole (stepl, about 0.5 g, 1 equivalent), after stirring the contents for about five minutes, tetra acetyl bromoglucose (about 1.65 g, 1.3 equivalent),) was added and the mixture was refluxed at about 80°C for about 5 hours. Completion of the reaction was monitored by TLC. The reaction mixture was filtered and washed with CH3CN and filtrate was poured into ice water while stirring then extracted with ethyl acetate (3x10 ml) and washed with water and 12% brine solution. Solvent was removed under reduced pressure to give the isomers of title compound (Isomer A and Isomer B) then the isomers of mixture were separated by silica gel column chromatography using 12% EtOAc: Hexane to afford the final isomers.
Isomer A: Mp: 159.5-1610C; IR: 1741, 1754, 1377, 1254, 1227 cm4; 1H NMR: 1.78 (s, 3H), 2.05 (s, 3H), 2.10 (s, 6H), 4.0 (m, IH), 4.17 (d, IH), 4.25-4.31 (d, H & s, 2H), 5.30 (t, IH), 5.40 (t, IH), 5.92 (t, IH), 6.02 (d, IH); 7.2-7.4 (m, 5H); HPLC:
97.389%; Mass (M+Na)=513.
Isomer B: Mp: 152.1-1540C; IR: 1751, 1254, 1377, 1227 cm"1; 1H NMR: 1.82 (s, 3H), 2.0-2.18 (s, 9H), 3.65 (m, IH), 3.98 (dd, IH), 4.2 (dd, IH), 4.4 (dd, 2H), 5.2 (t, IH), 5.3 (t, IH), 5.5-5.62 (m, 2H), 7.2-7.4 (m, 5H); Mass (M+Na)=513; HPLC: 95.8%. Example 2: Σ-fS-benzyl-lH-tetrazol-Σ-ylVό-diydroxymethyDtetrahvdro^H-pyran- 3.4.5-triol:
Figure imgf000041_0001
2-(acetoxymethyl)-6-(5-benzyl-2H-tetrazol-2-yl)tetrahydro-2H-pyran-3,4,5- triyl triacetate (Example 1, about 1 g) was added in portion wise to methonolic ammonia solution (about 20 ml), and stirred for about 3 hours at room temperature. The reaction mixture was allowed for concentration under reduced pressure. The residue was taken in to ethyl acetate and washed with saturated brine solution (2x30 ml), dried over sodium sulphate, filtered and concentrated in vacuo to afford the title compound. Yield: 55%.
Isomer A: MP: 135.5-142.50C; IR: 3371, 3439 cm4; 1H NMR: 3.6-3.7 (m, 3H), 3.75-3.95 (m, 3H), 4.2-4.3 (m, 3H), 4.6 (brs, IH), 4.7 (brs, IH), 5.05 (bra, IH), 5.75 (brs, IH), 7.2-7.4 (m, 5H); Mass (M+Na)=345; HPLC: 97.1%. Isomer B: IR: 3410, 1459, 1069 cm"1; 1H NMR: 3.3 (S, IH), 3.4 (s, 3H), 3.6 (s, IH),
3.9 (s, 1,H), 4.4 (s, 2H), 4.6 (s, IH), 5.2 (s, IH), 5.25 (s, IH), 5.55 (s, IH), 5.65 (s, IH), 7.2-7.4 (m, 5H); Mass (M+Na)=345; HPLC: 97.3%.
Similarly, the following compounds have been prepared by above procedure with corresponding starting materials:
Example 3 : 2-(acetoxymethyl)-6-(5-f4-bromobenzyl)-2H-tetrazol-2-yl)tetrahydro- 2H-pyran-3 A5-triyl triacetate:
Figure imgf000041_0002
Isomer A: Mp: 154.2-156.00C; IR: 1746, 1372, 1248 cm"1; 1H NMR: 1.9 (s, 3H), 2.0-
2.18 (s, 9H), 4.05 (brs, IH), 4.08-4.18 (m, 4H), 5.25 (t, IH), 5.40 (t, IH), 5.82 (t, IH), 6.02 (d, IH), 7.2 (d, 2H), 7.43 (d, 2H); Mass (M+Na)=593; HPLC: 99.984%. Isomer B: Mp:161.6-163.5°C; IR: 1750, 1376, 1253, 1226 cm"1; 1H NMR: 1.92 (s, 3H), 2.0-2.18 (3 s, 9H), 3.9 (s, IH), 4.04 (s, IH), 4.2-4.4 (m, 3H), 5.2 (t, IH), 5.17 (t, IH), 5.22 (t, IH), 5.70 (d, IH), 7.19 (d, 2H), 7.45 (d, 2H); Mass (M+Na)=593; HPLC: 96.95%.
Example 4: 2-(5-(4-bromobenzyl)-2H-tetrazol-2-ylV6-fhvdroxymethγl')tetrahvdro- 2H-υyran-3.4,5-triol:
Figure imgf000042_0001
Isomer A: Mp: 92.8-101.20C; IR: 3436, 3352 cm4; 1H NMR: 3.2 (s, IH), 3.6-3.68 (m, 3H), 3.8 (m, IH), 3.9 (m, IH), 4.22 (s, 3H), 4.59 (s, IH), 4.62 (s, IH), 5.0 (s, IH), 5.8 (d, IH), 7.22 (d, 2H), 7.42 (d, 2H); Mass (M+Na)=423; HPLC: 98.62%. Isomer B: IR: 3392, 1662, 1071cm"1; 1H NMR: 3.3-3.37 (m, 2H), 3.44-3.75 (m, 4H), 3.78-3.82 (m, 2H), 4.18 (t, IH), 4.4 (s, 2H), 4.6 (s, IH), 5.59 (d, IH), 7.24 (d, 2H), 7.45 (d, 2H); Mass (M+Na)=423; HPLC: 95.04%.
Example 5j 2-(acetoxymethyl)-6-(5-f2,4-dicmorobenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate:
Figure imgf000042_0002
Isomer A: Mp: 96.2-97.20C; IR: 1739, 1746, 1753, 1372, 1249 Cm4; 1H NMR: 1.9 (s, 3H), 2.0-2.07 (s , 9H), 4.0 (s, IH), 4.2 (d, IH), 4.3 (m, IH), 4.4 (s, 2H), 5.25 (m, IH), 5.4 (m, IH), 5.8 (m, IH), 6.05 (d, IH), 7.25 (d, 2H), 7.4 (s, IH); Mass (M+Na)=581; HPLC: 97.48%.
Isomer B: Mp: 171.2-172.80C; IR: 1738, 1750, 1376, 1225 cm"1; 1H NMR: 1.94 (s, 3H), 2.0-2.18 (s , 9H), 3.95 (s, IH), 4.1 (d, IH), 4.2 (d, IH), 4.5 (q, 2H), 5.25 (t, IH), 5.4 (t, IH), 5.62 (t, IH), 5.8 (d, IH), 7.24 (m, 2H), 7.45 (s,lH); Mass (M+Na)=581; HPLC: 99.09%.
Example 6: 2-f5-C2.4-dichlorobenzyl)-2H-tetrazol-2-ylV6- divdroxymethvDtetrahvdro-2H-pyran-3,4.,5-triol:
Figure imgf000043_0001
Isomer A: Mp: 88.2-98.20C; IR: 3351, 1474, 1199, 1073 cm"1; 1H NMR: 3.05 (s, IH), 3.2 (m, IH), 3.38-3.54 (m, 2H), 3.68 (m, IH), 3.84 (m, IH), 4.38 (s, 2H), 4.64 (s, IH), 5.15-5.3 (dd, 2H), 5.45 (s, IH), 5.8 (d, IH), 7.4-7.5 (dd, 2H), 7.65 (s, IH); Mass (M+Na)=413; HPLC: 99.819%.
Isomer B: IR: 3368, 1664, 1066 cm4; 1H NMR: 3.3 (s, 2H), 3.5 (m, 3H), 3.65 (m, IH), 3.8 (m, IH), 4.1 (m, IH), 4.5 (m, 4H), 5.6 (m, IH), 7.3 (m, 2H), 7.5 (s, IH); Mass (M+Na)=413; HPLC: 93.54%.
Example 7 : 2-facetoxymethyl)-6-f 5-(4-methoxybenzylV2H-tetrazol-2-yl)tetrahydro- 2H-pyran-3.4.5-triyl triacetate:
Figure imgf000043_0002
Isomer A: Mp: 130.2-133.20C; IR: 1739, 1752, 1373, 1226 cm"1; 1H NMR: 1.78 (s, 3H), 2.0-2.12 (3 s, 9H), 3.8 (s, 3H), 4.0 (m, IH), 4.2 (m, 3H), 4.28 (m, IH), 5.25 (t, IH), 5.4 (t, IH), 5.86 (t, IH), 6.02 (d, IH), 6.84 (d, 2H), 7.22 (d, 2H); Mass (M+Na)=543; HPLC: 98.959%.
Isomer B: Mp: 163.9-1660C; IR: 1748, 1369, 1226 cm"1; 1H NMR: 1.65 (s, 3H), 2.0- 2.1 (3 s, 9H), 3.7 (m, IH), 3.8 (s, 3H), 4.02 (d, IH), 4.2 (dd, IH), 4.35 (m, 2H), 5.2 (t, IH), 5.3 (t, IH), 5.5-5.62 (m, 2H), 6.9 (d, 2H), 7.18 (d, 2H); Mass (M+Na)=543; HPLC: 94.4%.
Example 2-πivdroxymethyl)-6-(5-f4-methoxybenzyl)-2H-tetrazol-2- yl")tetrahvdro-2H-pyran-3,4.5-triol:
Figure imgf000043_0003
Isomer A: Mp: 92.1-98.80C; IR: 3371, 1515, 1252, 1672 cm'1; 1H NMR: 3.2 (s, IH), 3.42 (s, IH), 3.6-3.8 (m, 6H), 3.98 (s, 3H), 4.22 (s, IH), 4.98 (s, IH), 5.32 (s, IH)3 5.7 (s, IH), 6.7 (d, 2H), 7.1 (d, 2H); Mass (M+Na)=375; HPLC: 99.83%. Isomer B: Mp: 92.1-98.80C; IR: 3358, 1663, 1250, 1070 cm"1; 1H NMR: 3.3-3.4 (m, 5H), 3.5 (m, 2H), 3.7 (m, IH), 3.8 (m, 4H), 4.18 (m, IH), 4.38 (m, 2H), 5.52 (d,
IH), 6.9 (d, 2H), 7.24 (d, 2H); Mass (M+Na)=375; HPLC: 99.43%.
Example 9j 2-facetoxymethyl)-6-(5-f3,4-dichlorobenzyl)-2H-tetrazol-2- yl)tetrahγdro-2H-pyran-3 ,4.5-triyl triacetate:
Figure imgf000044_0001
Isomer A: Mp: 126.1-127.50C; IR: 1737, 1753, 1376, 1225 cm'1; 1H NMR: 1.6 (s, 3H), 2.0-2.12 (s , 9H), 4.05 (m, IH), 4.38-4.7 (m, 4H), 5.3 (t, IH), 5.4 (t, IH), 5.85 (t, IH), 6.05 (d, IH), 7.15 (d, IH), 7.4 (dd, 2H); Mass (M+Na)=581; HPLC: 97.1%. Isomer B: Mp: 150.5-151.90C; IR: 1747, 1759, 1369, 1223 cm'1; 1H NMR: 1.83 (s,
3H), 2.01-2.12 (s, 9H), 3.85 (m, IH), 4.1 (d, IH), 4.3-4.4 (m, 3H), 5.25 (t, IH), 5.4 (m, 2H), 5.8 (d, IH), 7.18 (d, IH), 7.45 (dd, 2H); Mass (M+Na)=581; HPLC: 98.58%.
Example 10: 2-f5-f3.4-dichlorobenzyl)-2H-tetrazol-2-ylV6-
(hydroxymethyl)tetøhvdro-2H-pyran-3A5-triol:
Isomer A: Mp: 150.5-151.90C; IR: 3351, 1369, 1073cm'1; 1H NMR: 3.2 (s, IH), 3.5 (t, IH), 3.65 (m, 2H), 3.85 (m, 2H), 4.25 (m, 3H), 4.55 (d, 2H), 4.85 (d, IH), 5.8 (d, IH), 7.2 (dd, IH), 7.4 (m, 2H); Mass (M+Na)=413; HPLC: 98.29%.
Isomer B: IR: 3357, 1665, 1071cm'1; 1H NMR: 3.25 (m, 3H), 3.5-3.7 (m, 4H), 3.660-3.9 (m, 2H), 4.14 (t, IH), 4.42 (s, 2H), 5.6 (d, IH), 7.25 (dd, IH), 7.43-7.59 (m, 2H); Mass (M+Na)=413; HPLC: 86.85%. Example 11 : 2-(acetoxymethylV6-(5-('4-('trifluoromethyl')benzylV2H-tetrazol-2- yl)tetrahydro-2H-pyran-3 ,4,5-triyl triacetate:
Figure imgf000045_0001
Isomer A: Mp: 168.2-169.80C; IR: 1746, 1328, 1227 cm"1; 1H NMR: 1.78 (s, 3H), 2.0-2.12 (s, 9H), 4.0 (m, IH), 4.12-4.3 (m, 2H), 4.34 (s, 2H), 5.22-5.38 (dd, IH),
5.42 (d, IH), 5.83 (t, IH), 6.04 (d, IH), 7.44 (d, 2H), 7.58 (d, 2H); Mass (M+Na)=581; HPLC: 99.40%.
Isomer B: Mp: 155.4-156.80C; IR: 1748, 1227 cm4; 1H NMR: 1.84 (s, 3H), 2.0-2.16 (s, 9H), 3.86 (dd, IH), 4.06 (dd,lH), 4.3 (dd, IH), 4.46 (s, 2H), 5.2 (m, IH), 5.38 (t, 2H), 5.8 (t, IH), 7.42 (d, 2H), 7.64 (d, 2H); Mass (M+Na)=581; HPLC: 97.87%.
Example 12: 2-rhydroxymethylV6-(5-f4-ftrifluoromethyl)benzylV2H-tetrazol-2- vDtetrahvdro-2H-ϋyran-3,4.5-triol:
Figure imgf000045_0002
Isomer A: Mp: 104.8-1120C; IR: 3431, 3352, 1335, 1119 cm4; 1H NMR: 3.5-3.78
(m, 4H), 3.8-3.95 (m, 2H), 4.18-4.35 (m, IH), 4.38 (s, 2H), 4.62 (d, 3H), 5.0 (d, IH), 5.8 (d, IH), 7.4-7.62 (m, 4H); Mass (M+Na)=413; HPLC: 99.73%. Isomer B: IR: 3364, 1664, 1328, 1067 cm"1; 1H NMR: 3.34 (m, 4H), 3.42-3.64 (m, 3H), 3.66-3.86 (m, 2H), 4.14 (t, IH), 4.54 (s, 2H), 5.6 (d, IH), 7.53 (d, 2H), 7.66 (d, 2H); Mass (M+Na)=413; HPLC: 96.48%.
Example 13 : 2-facetoxymethyl)-6-(5-('4-(benzyloxy)benzyl')-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4.5-triyl triacetate:
Figure imgf000045_0003
Isomer A: Mp: 150.1-151.80C; IR: 1748, 1370, 1226 cm"1; 1H NMR: 1.77 (s, 3H),
2.0-2.16 (s, 9H), 3.78-4.06 (m, IH), 4.2 (s, 3H), 4.3 (dd, IH), 5.02 (s, 2H), 5.32 (dd, IH), 5.42 (d, IH), 5.86 (t, IH), 6.03 (d, IH), 6.92 (d, 2H), 7.19-7.28 (m, 3H), 7.32- 7.44 (m, 4H); Mass (M+Na)=619; HPLC:98.83%.
Isomer B: Mp: 141.5-144.40C; IR: 1738, 1750, 1376, 1225 cm"1; 1H NMR: 1.8 (s, 3H), 2.0-2.16 (s, 9H), 3.66-3.76 (m, IH), 4.01 (dd, IH), 4.22 (dd, IH), 4.32 (s, 2H), 5.06 (s, 2H), 5.14-5.36 (m, 2H), 5.5-5.62 (m, 2H), 6.96 (d, 2H), 7.17 (d, 2H), 7.3- 7.48 (m, 5H); Mass (M+Na)=619; HPLC: 98.88%.
Example 14: 2-f5-f4-fbenzyloχy)benzylV2H-tetrazol-2-yl)-6- fhvdroxymethyl)tetrahvdro-2H-ρyran-3,4,5-triol:
Figure imgf000046_0001
Isomer A: Mp: 101.5-108.20C; IR: 3404, 1513, 1250 cm"1; 1H NMR: 3.2-3.32 (m, IH), 3.56-3.76 (m, 3H), 3.78-3.96 (m, 2H), 4.2 (s, 3H), 4.42 (s, 2H), 4.66 (d, IH), 5.04 (s, 2H), 5.78 (d, IH), 6.92 (d, IH), 7.22-7.32 (m, 3H), 7.34-7.46 (m, 4H); Mass (M+Na)=451; HPLC: 99.95%.
Isomer B: IR: 3351, 1662, 1510, 1244 cm"1; 1H NMR: 3.3-3.38 (m, 4H), 3.42-3.56 (m, 3H), 3.6-3.82 (m, 2H), 4.08-4.18 (m, IH), 4.36 (d, 2H), 5.08 (s, 2H), 5.5 (d, IH), 6.92-7.02 (m, 2H), 7.18-7.28 (m, 2H), 7.3-7.48 (m, 5H); Mass (M+Na)=451; HPLC: 99.25%.
Example L5j 2-(acetoxymemylV6-(5-f4-hvdroxybenzviy2H-tetrazol-2- yl)tetrahγdro-2H-pyran-3 A5-triyl triacetate:
Figure imgf000046_0002
Isomer A: Mp: 143.5-145.50C; IR: 3457, 1749, 1228 cm4; 1H NMR: 1.75 (s, 3H), 1.95-2.15 (2s, 9H), 4.0 (m, IH), 4.2 (s, 3H), 4.25 (m, IH), 5.2 (brs, IH), 5.3 (t, IH), 5.4 (t, IH), 5.85 (t, IH), 6.05 (d, IH), 6.8 (d, 2H), 7.2 (d, 2H); Mass (M+Na)=529; HPLC: 97.27%.
Isomer B: Mp: 191.3-192.50C; IR: 3344, 1751, 1224 cm"1; 1H NMR: 1.85 (s, 3H), 2.0-2.1 (s, 9H), 3.7 (m, IH), 4.0 (d, IH), 4.2 (dd, 2H), 4.35 (d, 2H), 5.2 (t, IH), 5.3 (t, IH), 5.55 (d, 2H), 5.65 (s, IH), 6.8 (d, 2H), 7.2 (d, 2H); Mass (M+Na)=529; HPLC: 96.5%.
Example 16j 2-(5-(4-hvdroxybenzyl)-2H-tetrazol-2-ylV6- fliydroxymetlivDtetrahvdro-2H-pyran-3,4,5-triol:
Figure imgf000047_0001
Isomer A: IR: 3400, 2927, 1517, 1238 cm4; 1H NMR: 3.35 (s, 2H), 3.5 (m, IH), 3.6-3.8 (m, 3H), 3.9 (d, IH), 4.15 (m, 3H), 4.65 (brs, IH), 5.9 (d, IH), 6.75 (d, 2H), 7.15 (d, 2H); Mass (M+l)=339; HPLC: 92.2%. Isomer B: Mp: 209-2110C; IR: 3439, 3371, 1495, 1074 cm'1; 1H NMR: 3.3 (m, 2H),
3.4 (m, 2H), 3.6 (m, IH), 3.9 (m, IH), 4.25 (s, 2H), 4.65 (m, IH), 5.2 (d, IH), 5.3 (d, IH), 6.7 (d, 2H), 7.1 (d, 2H), 9.4 (s, IH); Mass (M+Na)=361; HPLC: 92.2%.
Example 17 : 2-( acetoxymethyl)-6~f 5-phenethyl-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3 A5-triyl triacetate:
Figure imgf000047_0002
Isomer A: Mp: 92.0-99.90C; IR: 1748, 1370, 1222 cm'1; 1H NMR: 2.0-2.15 (4 s, 12H), 3.1 (t, 2H), 3.25 (t, 2H), 4.05 (dd, IH), 4.2 (dd, J=12.6Hz, IH), 4.3 (dd, J=12.75Hz, IH), 5.3 (t, J= 9.9, 9.6Hz, IH), 5.4 (t, J=9.3Hz, IH), 6.85 (t, J=9.6,9.3 Hz, IH), 6.05 (d, J= 9.3 Hz, IH), 7.2-7.35 (m,5H); HPLC: 99.6%; Mass
(M+Na)=527.
Isomer B: Mp: 125.4-131.10C; IR: 1763, 1745 , 1242, 1221cm"1; 1H NMR: 1.9 (s, 3H), 2.0 (s, 3H), 2.05 (2s, 6H), 3.25 (m, 4H), 3.9 (dd, dd, J=I 0.5, 4.8, 4.5Hz, IH), 4.15 (dd, J=12.6Hz, IH), 4.25 (dd, J=12.75 Hz, IH), 5.25 (t, J= 9.9, 9.6Hz, IH), 5.35 (t, J= 9.3Hz, IH), 5.6 (t, J=9.6, 9Hz, IH), 5.65 (d, J=9.6Hz, IH), 7.2-7.4 (m,
5H); HPLC: 99.3%; Mass (M+Na)=527.
Example 18: 2-giydroxymethyl)-6-('5-phenethyl-2H-tetrazol-2-yl)tetrahvdro-2H- ϋyran-3A5-triol:
Figure imgf000048_0001
Isomer A: IR: 3353, 1663 cm4; 1H NMR: 3.05 (m, 2H), 3.15 (m, 2H), 3.25 (m, IH), 3.5 (m, 2H), 3.7 (m, IH), 3.9 (m, IH), 4.7 (brs, IH), 5.2-5.4 (2 brs, 2H), 5.5 (bis, IH), 5.8 (d, J=15.5Hz, IH), 6.7 (brs, IH), 7.15-7.35 (m,5H); Mass (M+Na)=359; HPLC: 93.8%.
Isomer B: MP: 161.8-171.60C; IR: 3424, 3390, 3233 cm"1; 1R NMR: 3.05 (m, 2H), 3,25 (m, 2H), 3.45 (m, 2H), 3.55 (m, IH), 3.7(m, IH), 3.85 (m, IH), 4.7 (m, IH), 5.25 (d, J=9 Hz, IH), 5.3 (d, J=9Hz, IH), 5.55 (d, J=9.5Hz, IH), 5.65 (d, J=15 Hz, IH), 6.7 (brs, IH), 7.2-7.4 (m, 5H); Mass (M+Na)=359.
Example 19 : 2-(acetoxymetriyl)-6-r5-r2-oxo-2-phenylethylV2H-tetrazol-2- yl)tetrahydro-2H-pyran-3 A5-triyl triacetate:
Figure imgf000048_0002
Isomer A: Mp: 134.3-138.40C; IR: 1746, 1693, 1223 cm'1; 1H NMR: 1.85 (s, 3H)5 2.0-2.15 (3s, 9H), 4.0-4.1 (m, IH), 4.2 (m, IH), 4.3 (m, IH), 4.65 (s, 2H), 5.3 (m, IH), 5.4 (m, IH), 5.85 (m, IH), 6.1 (m, IH), 7.15 (t, J=13,12Hz, 2H), 7.6 (t, /=13,12.5 Hz, IH), 8.0 (d, J=12 Hz, IH); HPLC: 99.7%; Mass (M+Na)=541. Isomer B: Mp: 95.6-115.30C; IR: 1756, 1683, 1369, 1228 cm"1; 1H NMR: 1.95-2.1 (4 s, 12H), 3.45 (m, IH), 4.95 (m, IH), 4.2 (m, IH), 4.35 (m, IH), 5.2 (m, IH), 5.3 (m, IH), 5.7 (m, IH), 5.95 (d, IH, 15.5 Hz), 7.5 (m, 2H), 7.65 (m, 2H);HPLC: 90.3%; Mass (M+Na): 518.
Example 20: l-phenyl-2-('2-('3,4.5-trihvdroxy-6-('hvdroxymethvntetrahvdro-2H- Oyran-2-yl)-2H-tetrazol-5-yl)ethanone:
Figure imgf000049_0001
Isomer A: IR: 3358, 1664 cm"1; 1H NMR: 3.15 (m, 2H), 3.55 (m, IH), 3.7 (m, IH), 3.9 (m, IH), 4.75 (m, IH), 4.85 (d, J=8.5Hz, IH), 5.25 (d, J=9Hz, IH), 5.35 (d, J=9Hz, IH), 5.55 (d, J=IOHz5IH), 5.9 (d, J=15.5Hz, IH), 6.7 (brs, IH), 7.3 (brs, IH), 7.6 (t, J=13,12Hz, 2H), 7.7 (t, /=13,12.5 Hz, IH), 8.1 (d, J=12Hz, 2H); HPLC:
74.6%; Mass (M+Na): 373.
Isomer B: IR: 3358, 1664 cm"1; 1H NMR: 3.05 (m, 2H), 3.1-3.3 (m, 3H), 3.5 (m, IH), 3.7 (m, IH), 3.9 (m, IH), 4.7 (brs, IH), 5.3 (brs, IH), 5.55 (brs, IH), 5.8 (d, J=15.5Hz, IH), 6.7 (brs, IH), 7.15-7.40 (m, 5H); HPLC: 48+42 (isomers, 0.3 RT difference)% ; Mass (M+ 1 )=351 (molecular ion peak) .
Example 21 : 2-(acetoxymethyl)-6-(5-(2-(4-chlorophenoxy)ethyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3 ,4,5-triyl triacetate:
Figure imgf000049_0002
Isomer A: Mp: 142.7-143.8 0C; IR: 1754, 1246, 1228 cm"1; 1H NMR: 1.76 (S, 3H),
2.0-.1 (3S, 9H), 3.4 (t, J= 6.6 Hz, 2H), 4.05 (m, H), 19 (m, IH), 4.3 (d, J=4.8 Hz, IH), 4.35 (t, J=6.9, 6.6 Hz, 2H), 5.3 (t, J=9.6, 9.3 Hz, IH), 5.4 (t, J=9.6, 9.3Hz, IH), 4.85 (t, J= 9.9, 9.6 Hz, IH), 6.05 (d, J=9.3Hz, IH), 6.83 (d, J= 9Hz, 2H), 7.23 (d, J= 9Hz, 2H); HPLC: 99.7%; Mass : M+Na: 577. Isomer B: Mp: 108.9-113.90C; IR: 1743.7, 1225, 1224 cm"1; 1H NMR: 1.84 (S, 3H),
2.05 -2.09 (3S, 9H), 3.47-3.52 (m, 2H), 4.0 (m, IH), 4.2-4.25 (m, 2H), 4.42-4.46 (m, 2H), 5.3 (t, IH), 5.45 (t, J= 9.6, 9.3 Hz, IH), 5.7 (t, J=9.6, 9.3 Hz, IH), 6.0 (d, J=9.6 Hz, IH), 6.85 (d, J= 9Hz, 2H), 7.25 (d, J=9 Hz, 2H); Mass: M+Na: 577; HPLC: 91.2%.
Example 22j 2-f5-f2-f4-chloroOhenoxy^ethyD-2H-tetrazol-2-yr)-6- divdroxymethyl')tetrahvdro-2H-pyran-3,4,5-triol:
Figure imgf000050_0001
Isomer A: IR: 3338, 1493, 1248 cm4; 1H NMR: 3.25 (m, IH), 3.7 (m, IH), 3.65- 3.85 (m, 3H), 3.9 (m, IH), 4.4 (m, 4H), 4.6 (t, J=5.7, 5.4 Hz, IH), 5.25 (d, J=5.4 Hz, IH), 5.35 (d, J=5.4, Hz, IH), 5.55 (d, J=6 Hz, IH), 5.85 (d, J=9.3 Hz, IH), 6.9 (d, J=8.7Hz, 2H), 7.3 (d, J=8.7 Hz, 2H); Mass (M+Na): 409; HPLC: 95.6%. Isomer B: IR: 3403, 1243 cm'1; 1H NMR: 3.65 (m, 2H), 3.85 (m, IH), 4.4 (m, 2H), 4.5 (m, 2H), 4.7 (m, IH), 4.8 (m, IH), 4.9 (m, 3H), 5.2 (d, J=5.1 Hz, IH), 5.3 (d, J=5.1Hz, IH), 5.6 (d, J=5.7 Hz, IH), 5.7 (d, J=9 Hz, IH), 7.0 (d, J=9 Hz, 2H), 7.3 (d, J=9Hz, 2H); Mass (M+Na) =409; HPLC: 90.3%.
Example 23 : 2-(acetoxymethyl)-6-f 5-(4-methylbenzylV2H-tetrazol-2-yl)tetraliydro- 2H-υyran-3 A5-triyl triacetate:
Figure imgf000050_0002
Isomer A: Mp: 131.8-137 0C; IR: 1749, 1736, 1257, 1227 cm"1; 1H NMR: 1.75 (s, 3H), 2.0-2.1 (3s, 9H), 2.3 (s, 3H), 4.0 (m, IH), 4.15 (dd, /=14 Hz, IH), 4.22 (s, 2H), 4.29 (dd, J=16Hz, IH), 5.3 (t, J=16.5, 16 Hz, IH), 5.4 (t, J=16, 15.5Hz, IH), 5.88 (t, J=15.5 Hz, IH), 6.05 (d, J=16 Hz, IH), 7.12 (d, J=13Hz, 2H), 7.2 (d, J=13.5 Hz, 2H); Mass (M+Na)= 527; HPLC: 99.7%.
Isomer B: Mp: 144.2-149.9 0C; IR: 1742, 1369, 1255, 1226 cm"1; 1H NMR: 1.82 (s, 3H), 2.0-2.1 (3s, 9H), 2.35 (s, 3H), 3.7 (dd, J=13.8 Hz, IH), 3.98 (dd, J=21 Hz, IH), 4.2 (dd, J=21 Hz, IH), 4.35 (s, 2H), 5.2 (t, J=16 Hz, IH), 5.28 (m, IH), 5.58 (m, 2H), 7.1-7.2 (m,4H); Mass (M+Na)= 527; HPLC: 98.7%.
Example 24: 2-(hvdroxymethyl)-6-('5-(4-methylbenzylV2H-tetrazol-2-yl')tetrahvdro- 2H-pyran-3.4.5-triol:
Figure imgf000051_0001
Isomer A: IR: 3357, 1663, 1395, 1352 cm-1; 1H NMR: 2.25 (s, 3H), 3.2 (m, IH), 3.68 (m, IH), 3.88 (m, IH), 4.2 (s, 2H), 4.7 (m, IH), 5.25 (brs, IH), 5.35 (brs, IH), 5.5 (d, J= 8Hz, IH), 5.82 (d, 7=15 Hz, IH), 6.7 (brs, 2H), 7.15 (d, J=13Hz, 2H), 7.2 (d, J=13.5Hz, 2H), 7.35 (brs, 2H); Mass (M+Na)=359; HPLC: 83.8%. Isomer B: IR: 3351, 1660, 1393, 1257 cm"1; 1H NMR: 2.25 (s, 3H), 3.6 (m, IH), 3.85 (m, IH), 4.35 (s, 2H), 4.62 (m, IH), 5.22 (d, J=8.5 Hz, IH), 5.32 (d, J=9 Hz, IH), 5.58 (d, J=9 Hz, IH), 5.65 (d, J=15 Hz, IH), 6.72 (brs, 2H), 7.12 (d, J=13 Hz, 2H), 7.2 (d, J=I 3 Hz, 2H), 7.3 (brs, 2H); Mass (M+Na)= 359; HPLC: 78.85%.
Example 25 : 2-racetoxymethyl)-6-(5-(4-ethylbenzyl)-2H-tetrazol-2-yl)tetrahydro- 2H-pyran-3.4.5-triyl triacetate:
Figure imgf000051_0002
Isomer A: Mp: 139.8-149.4 0C; IR: 1748, 1251, 1228 , 1215 cm"1; 1H NMR: 1.2 (t, 7=7.8, 7.5 Hz, 3H), 2.0-2.15 (4s, 12H), 2.62 (m, 2H), 4.02 (m, IH), 4.15 (m, IH), 4.24 (s, 2H), 5.15 (m, IH), 5.3 (t, 7=10.2, 9.9 Hz, IH), 5.4 (t, 7=9.6, 9.3 Hz, IH), 5.85 (t, 7=9.3 Hz, IH), 6.05 (d, J=9.6 Hz, IH), 7.05-7.25 (m, 4H); Mass (M+Na)=541; HPLC: 95.7%.
Isomer B: Mp: 162.5-164.1 0C; IR: 1743, 1252, 1225 cm"1; 1H NMR: 1.2 (t, J= Hz, 3H), 1.82 (s, 3H), 2.0-2.1 (3s, 9H), 2.65 (q, J= 7.5Hz, 2H), 3.68 (m, IH), 3.96 (m, IH), 4.22 (m, IH), 4.35 (m, 2H), 5.2 (t, 7=9.9, 9.3 Hz, IH), 5.28 (t, 7=9.3, 8.7 Hz, IH), 5.55 (t, 7=9.3, 8.4 Hz, IH), 5.6 (d, J=9 Hz, IH), 7.19 (m, 4H, Ar-H); Mass (M+Na)=5541; HPLC: 99.21%.
Example 26: 2-f5-f4-ethylbenzyl)-2H-tetrazol-2-yl)-6-rhydroxymethγl)tetrahydro- 2H-pyran-3.4.5-triol:
Figure imgf000052_0001
Isomer A: Mp: 0C; IR: 3325, 1667, 1264 cm-1; 1H NMR: 1.15 (t, J=7.8, 7.5 Hz, 3H), 2.55 (m, 2H), 3.2 (m, IH), 3.52 (m, IH), 3.69 (m, IH), 3.85 (m, IH), 4.2 (s, 2H), 4.7(m, IH), 5.2-5.35 (2brs, 2H), 5.52 (m, IH), 5.82 (d, J=9Hz, IH), 6.72 (brs, 2H), 7.17 (d, J=9 Hz, 2H), 7.72 (brs, 2H); Mass (M+Na)=373; HPLC: 92.9%. Isomer B: IR: 3401, 1664, 1619, 1449, 1094, 1065 cm4; 1H NMR: 1.15 (t, J=7.8, 7.5Hz, 3H), 2.57 (m, 2H), 3.3 (m, IH), 3.85 (m, IH), 4.35 (s, 2H), 4.62 (m, IH), 5.2 (d, J=5.4 Hz, IH, OH), 5.3 (d, J=5.3Hz, IH, OH), 5.6 (d, J=5.7 Hz, IH), 5.67 (d, J=9 Hz, IH), 7.14 (d, J=7.8 Hz, 2H), 7.23 (d, J=8.1 Hz, 2H); Mass (M+Na)=373; HPLC: 95.23%.
Example 2_7j 2-facetoxyniethylV6-f5-(2-methoxybenzyl)-2H-tetrazol-2- vDtetrahydro-2H-pyran-3 A5-triyl triacetate:
Figure imgf000052_0002
Isomer A: Mp: 107.6-112.2 0C; IR: 1747,1369, 1223 cm"1; 1H NMR: 1.76 (s, 3H), 2.1 (2s, 9H), 3.8 (s, 3H, OCH3), 4.0 (m, IH), 4.18 (m, IH), 4.25-4.35 (m, 3H), 5.3 (t, J=9.6Hz, IH), 5.38 (t, J=9.3 Hz, IH)5 5.88 (t, J=9.3 Hz, IH), 6.05 (d, J=9.6 Hz, IH), 6.85-6.95 (m, 2H), 7.15-7.3 (m, 2H); Mass (M+Na)=543; HPLC: 99.28%. Isomer B: Mp: 124.1-130.6 0C; 1H NMR: 1.75 (s, 3H), 2.05 (3s, 9H), 3.7 (m, IH), 3.8 (s, 3H, OCH3), 4.0 (m, IH), 4.37 (m, 2H), 5.2-5.4 (m, 2H), 5.67-5.8 (m, 2H), 6.95 (t, J=8.1, 7.2 Hz, 2H), 7.2-7.35 (m, 2H), Mass (M+Na)=544; HPLC: 98.77%.
Example 28 : 2-( hvdroxymethylV 6-f 5-f 2-methoxyberizylV2H-tetrazol-2- yl)tetrahvdrc-2H-pyran-3A5-triol:
Figure imgf000053_0001
Isomer A: Mp: 78.9-94.7 0C; IR: 3416, 3299 cm"1; 1H NMR (300MHz, CDCl3): 3.7(m, IH), 3.52-3.72 (m, 3H), 3.8 (s, 3H, OCH3), 3.87 (m, IH), 4.1 (m, IH), 4.25 (s, 2H), 5.82 (d, J=9.3 Hz, IH), 6.88-7.0 (m, 2H), 7.15-7.3 (m, 2H); Mass (M+Na)=375; HPLC: 97.5%.
Isomer B: IR: 3424 cm"1; 1H NMR: 3.45 (m, IH), 3.45-3.5 (m, 2H), 3.65 (dd, IH), 3.75 (s, IH), 4.15 (m, IH), 4.35 (s, 2H), 5.52 (d, J=9 Hz, IH), 6.9-7.0 (m, 2H), 7.2- 7.35 (m, 2H); Mass (M+Na)=375; HPLC: 98.2%.
Example 29j 2-(acetoxymemylV6-(5-f3-methoxybenzylV2H-tetrazol-2- yl)tetrahydro-2H-pyran-3 ,4.5-triyl triacetate:
Figure imgf000053_0002
Isomer A: Mp: 153.6-156-6 0C; IR: cm"1; 1H NMR: 1.76 ( s, 3H), 2.0-2.14 (3 S, 9H), 3.8 (s, 3H, OCH3), 4.02 (m, IH), 4.19 (m, 2H), 4.25 (s, 2H), 4.3 (m, IH), 5.3 (t, J=9.9, IH), 5.4 (t, J=9.3, IH), 5.85 (t, J=9.3, IH), 6.05 (d, J=9.6, IH), 6.78-6.95 (m, 3H), 7.25 (t, J=8.1, 7.8 Hz, IH); HPLC: 98.67%; Mass (M+Na)=543. Isomer B: Mp: 153.3-154-6 0C; 1H NMR: 1.74 ( s, 3H), 1.98-2.1 (3 S, 9H), 3.77 (s, 3H, OCH3), 4.0 (m, IH), 4.12-4.28 (m, 2H), 4.42 (m, 2H), 5.23 (t, J=9.9, 9.3Hz, IH), 5.5 (t, J=9.6, 9.3Hz, IH), 5.65 (t, J=9.3Hz, IH), 6.24 (d, J=9 Hz, IH), 6.87 (m, 3H), 7.25 (t, J=8.7, 7.5 Hz, IH); HPLC: 98.29%; Mass (M+Na)=543.
Example 3Jh 2-(hydroxymethyl)-6-(5-('3-methoxybenzylV2H-tetrazol-2- yl)tetrahvdro-2H-pyran-3.4.5-triol:
[α-j
Figure imgf000053_0003
Isomer A: 1H NMR: 3.48 (t, IH), 3.55 (m, 2H), 3.62 (m, IH), 3.7 (t, IH), 3.75 (s, 3H, OCH3), 3.85 (m, IH)5 4.1 (m, IH), 4.22 (s, 2H), 5.8 (d, J=9 Hz, IH), 6.8 (m, 3H), 7.2 (t, J=8.1, 7.8 Hz, IH); Mass (M+Na)=375; HPLC: 97.34%. Isomer B: 1H NMR: 3.45-3.6 (m, 3H), 3.6-3.75 (m, 2H), 3.7 (s, 3H), 4.12 (t, J=9, 8.7Hz, IH), 4.32-4.46 (dd, J=16.2Hz, 2H), 5.55 (d, J=9Hz, IH), 6.85 (m, 3H), 7.24
(t, J=8.1, 7.8 Hz, IH); Mass (M+Na)=375; HPLC: 96.3%.
Example 31 : 2-(acetoxytαethyl)-6-('5-(4-ethoxybenzyl)-2H-tetra2ol-2-yl)tetrahvdro- 2H-ρyran-3.4,5-triyl triacetate:
Figure imgf000054_0001
Isomer A: Mp: 131.2-133.70C; 1H NMR: 1.39 (t, J=6.9Hz, 3H), 1.76 (s, 3H), 2.03 (s, 3H), 2.07 (s, 3H), 2.08 (s, 3H), 3.99 (q, J=7.2, 6.9 Hz, 2H), 4.18 (m, IH), 4.2 (s, 2H), 4.28 (m, IH), 5.3 (t, J=9.9Hz, IH), 5.4 (t, J= 9.3Hz, IH), 5.88 (t, J=9.6, 9.3 Hz, IH), 6.04 (d, J=9.3 Hz, IH), 6.84 (d, J=8.7 Hz, 2H), 7.2 (d, J=8.7 Hz, 2H); HPLC: 98.76%; Mass (M+Na)=557.
Isomer B: Mp: 131.7-147.80C; 1H NMR: 1.42 (t, J=6.9 Hz, 3H), 1.83 (s, 3H), 2.0- 2.08 (3 s, 9H), 3.71 (m, IH), 4.02 (q, J=7.2, 6.Hz, 2H), 4.22 (m, IH), 4.32 (s, 2H), 5.21 (m, IH), 5.3 (m, IH), 5.55 (m, 2H), 6.88 (d, J=8.7 Hz, 2H), 7.17 (d, J=8.7 Hz, 2H); HPLC: 99.3%; Mass (M+Na)=557.
Example 32: 2-(5-(4-ethoxybenzylV2H-tetrazol-2-ylV6-fhydroxymethγl)tetrahvdro-
2H-ρvran-3.4,5-triol:
Figure imgf000054_0002
Isomer A: Mp: 79.5-86.4 0C; 1H NMR: 1.36 (t, J= 7.2, 6.9 Hz, 3H), 3.42-355 (m, 3H), 3.67 (m, IH), 4.0 (q, J=I 2, 6.9 Hz, 2H), 4.1 (m, 3H), 4.35 (d, 2H), 5.5 (d, J=9.3
Hz, IH), 6.88 (d, J=8.7 Hz, 2H), 7.2 (d, J=8.7 Hz, 2H); HPLC: 98.68%; Mass (M+Na)=389.
Isomer B: Mp: 79.5-86.4 0C; 1H NMR: 1.35 (t, J=7.2, 6.9 Hz, 3H)5 3.48 (t5 J=7.2, 6.9 Hz, IH), 3.52-3.72 (m, 2H), 3.88 (m, 2H), 4.0 (q, J=7.2, 6.9 Hz, 2H), 4.12 (d, IH), 4.18 (s, 2H), 5.84 (d, J=9 Hz, IH), 6.83 (d, J=8.7 Hz, 2H), 7.20 (d, J=8.7 Hz, 2H); HPLC: 96.90%; Mass (M+Na)=389.
Example 33 : 2-facetoxymethyl)-4-hvdroxy-6-f5-f4-isopropoxybenzyl)-2H-tetrazol- 2-vDtetrahydro-2H-pyran-3 ,5-diyl diacetate:
Figure imgf000055_0001
!H NMR: 1.31 (2s, 6H), 1.83(s, 3H), 1.75 (s, 3H), 2.03-2.08 (3s, 9H), 4.0 (m, IH), 4.15 (m, IH), 4.2 (s, 2H), 4.28 (dd, J=12.6 Hz, IH), 4.5 (m,lH), 5.29 (t, J=9.9 Hz, IH), 5.38 (t, J=9.3 Hz, IH), 5.89 (t, J=8.7 Hz, IH), 6.03 (d, J=9.3 Hz, IH), 6.83 (d, J=8.7 Hz, 2H), 7.20 (d, J=8.7 Hz, 2H); Mass (M+Na)=571.
Example 34: 2-(hvdroxymethyl)-6-f5-f4-isopropoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3A5-triol:
Figure imgf000055_0002
Yield: 76 %; 1H NMR: 1.23 (2s, 6H), 3.2 (m, IH), 3.2-3.55 (m, 3H), 3.68 (m, IH), 3.85 (m, IH), 4.53 (m, IH), 4.6 (t, /=5.7 Hz, IH), 5.22 (d, J=5.4 Hz, IH), 5.3 (d, J=5.4 Hz, IH), 5.51 (d, J=6 Hz, IH), 5.81(d, J=9.3 Hz, IH), 6.85 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H); HPLC: 98.3%; Mass (M+Na)=403.
Example 35: ethyl f3.4,5-trihydroxy-6-(5-(4-isopropoxybenzyl)-2H-tetrazol-2- yl)tetrahvdro-2H-pyran-2-yl)methyl carbonate:
Figure imgf000055_0003
Yield: 71 %; 1H NMR: 1.16 (t, J=7.2, 3H), 1.23 (2s, 6H), 3.35 (m, 2H), 3.85 (m, 2H), 4.1 (m, 3H), 4.17 (s, 2H), 4.56 ( m,lH), 4.55 (m, IH), 5.52 (d, J=5.4 Hz, IH), 5.59 (d, J=6 Hz, IH), 5.92 (d, J=9.3 Hz, IH), 6.85 (d, J=8.7 Hz, 2H), 8.4 (d, J=8.7 Hz, 2H); HPLC: 95.8%; Mass (M+Na)=475.
Example 36: 2-(acetoxymethyl')-6-(5-f4-benzylbenzyl)-2H-tetrazol-2-yl)tetrahvdro- 2H-t)yran-3 A5-triyl triacetate:
Isomer A: Mp: 128.8-129.90C; IR :1746, 1224 cm'1; 1H NMR: 1.7 (s, 3H), 2.0-2.1 (s, 9H), 3.95 (s, 2H), 4.0 (m, IH), 4.15 (d, IH), 4.2 (s , 2H), 4.3 (dd, IH), 5.3 (t, IH), 5.35 (t, IH), 5.85 (t, IH), 6.05 (s, IH), 7.1-7.3 (m, 9H); HPLC: 99.92%; Mass (M+Na)=603.
Isomer B: Mp: 184-1850C; IR: 1752, 1742, 1225 cm'1; 1H NMR: 1.8 (s, 3H), 2.05 (s, 9H), 3.65 (m, IH), 3.9 (d, IH), 3.95 (S, 2H), 4.15 (dd, IH), 4.35 (s, 2H), 5.2 (t, IH), 5.25 (t, IH), 5.6 (m, 2H), 7.1-7.3 (m, 9H); Mass (M+l)=581; HPLC: 98.19%.
Example 37: 2-(5-(4-benzylbenzyl)-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3A5-triol:
Figure imgf000056_0002
Isomer A: MP: 100.1-101.20C; IR: 3351, 1665, 1361 cm"1; 1H NMR: 3.5 (m, 4H), 3.7 (m, 2H), 3.8 (s, 2H), 4.1 (s, 3H), 4.5 (d, 2H), 4.8 (s, IH), 5.65 (d, IH), 7.0-7.2 (m, 9H); Mass (M+Na)=435; HPLC: 97.83%.
Isomer B: IR: 3355, 1661, 1393 cm"1; H1 NMR: 3.35-3.45 (m, 3H), 3.45-3.75 (m, 2H), 3.95 (s, 2H), 4.1 (t, IH), 4.4 (d, IH), 4.65 (brs, 6H), 5.5 (d, IH), , 7.1-7.3 (m, 9H); Mass (M+Na)=435; HPLC: 92.2%.
Example 38: Preparation of 2-facetoxymethyl)-6-f4-ff2-ethyl-2H-tetrazol-5- yl)methyl)phenoxy)tetralivdro-2H-pyran-3.4.5 -triyl triacetate :
Figure imgf000057_0001
Step 1: Synthesis of5-(4-(benzyloxy)benzyl)-2-ethyl-2H-tetrazole:
Figure imgf000057_0002
To 5-(4-(benzyloxy)benzyl)-2H-tetrazole (about 0.2 g, 1 equivalent) was taken into acetonitrile, K2CO3 (about 0.31 g) and ethyl iodide (about 0.24 g, 2 equivalents) were added and allowed for heat to reflux for about 3 hours. Completion of the reaction was monitored by TLC. The reaction mixture was filtered off through celite pad, washed with acetonitrile and combined organic layers were evaporated. The crude was taken into EtOAc and washed with 5% HCl, water and brine, dried over Na2SO4 and concentrated. The resulting crude had two compounds which are separated by column chromatography using 15% EtOAc/Hexane to afford two isomers of title compound.
Isomer-Λ: Yield: 36%; 1H NMR (300 MHz, CDCl3): δ, 1.6 (t, /=7.2 Hz, 3H), 4.15 (s, 2H), 4.6(q, J=7.5Hz,2H),5.05(s,2H,OCH2) 7.25(d, J=8.7 Hz, 2H, Ar-H), 7.3- 7.45 (m, 5H); Mass [M+l]+: 294+1=295 (100%).
Isomer-B: Yield: 40%; 1H NMR (300 MHz, CDCl3): δ, 1.35 (t, J=7.2 Hz, 3H), 4.2 (q, J=7.2 Hz, 2H), 4.25 (s, 2H), 5.05 (s, 2H, OCH2), 6.9 (d, 2H), 7.1 (d, J=8.4Hz, 2H), 7.3-7.45 (m, 5H); Mass [M+l]+: 294+1=295 (100%).
Step 2: Synthesis of4-((2-ethyl-2H-tetrazol-5-yl)methyl)phenol:
Figure imgf000057_0003
5-(4-(benzyloxy)benzyl)-2-ethyl-2H-tetrazole (step 1, about 2 g) in ethanol, 10% Pd/C ( about Ig) was added at room temperature and stirred for overnight under H2 pressure and completion of the reaction monitored by TLC. The reaction mixture was filtered through celite pad and washed with ethanol. The organic layer was allowed for concentration to afford the title compound.
Isomer A: Yield: 66%; 1H NMR (300 MHz, CDCl3): δ, 1.6 (t, J=I 2, 7.5 Hz, 3H), 4.15 (s, 2H), 4.6 (q, J=I.2 Hz, 2H), 6.45 (brs, IH, OH), 6.7 (d, J=8.7 Hz, 2H), 7.15 (d, J=8.1 Hz, 2H); Mass [M+l]+: 204+1=205 (100%).
Isomer B: Yield: 72%; 1H NMR (300 MHz, CDCl3): δ, 1.35 (t, J=7.2 Hz, 3H), 4.2 (s, 2H), 4.3 (q, J=7.2Hz, 2H), 6.3 (brs, IH), 6.8 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.7 Hz, 2H); Mass [M+l]+: 204+1=205 (100%).
Step 3: Preparation of 2-(acetoxymethyl)-6-(4-((2-ethyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahydro-2H-pyran-3 ,4,5-triyl triacetate:
To 4-((2-ethyl-2H-tetrazol-5-yl)methyl)phenol (step 2, about 1 g, 1 equivalent) in acetonitrile, terra acetyl glucopyranosyl bromide (about 2.6 g, 1.3 equivalent) and anhydride K2CO3 (about 2.02 g, 3 equivalents) were added. Contents were stirred at reflux temperature for about 16 hours. Completion of the reaction was monitored by TLC. The reaction mixture was filtered, washed with acetonitrile and filtrate was poured into ice water while stirring then pH was adjusted to 6-7. Extracted with ethyl acetate and washed with 12% brine solution, dried and evaporated. The residue was purified by DIP then again purified by column chromatography to afford the title compound.
Isomer A: Yield: 62 %; 1H NMR (300 MHz, CDCl3): δ 1.6 (t, J=7.2 Hz, 3H), 1.95- 2.2 (4s, 12H), 4.05-4.2 (m, 2H), 4.25-4.35 (m, 2H), 4.6 (q, J=7.2 Hz, 2H), 5.1-5.2 (m, 2H), 5.2-5.4 (m, IH), 5.5 (t, IH), 5.72 (d, IH), 6.75 (d, J=8.7 Hz, 2H), 7.2 (d, J=8.7Hz, 2H); Mass [M+Naf: 534+23 (100%); IR: 1748, 1226 cm"1; HPLC: 86%. Isomer B: Yield: 68%; 1H NMR (300 MHz, CDCl3): δ 1.35 (t, J=7.5 Hz, 3H), 1.95-
2.15 (4s, 12H), 4.1-4.3 (m, 2H), 4.9 (m, IH), 4.6 (q, J=7.5 Hz, 2H), 5.1 (t, IH), 5.25 (t, IH), 5.45 (d, IH), 5.55 (t, Hz, IH), 6.8 (d, J=8.7 Hz, 2H), 7.0 (d, J=8.7 Hz, 2H); Mass [M+Naf: 534+23 (100%); IR: 1751, 1230, 1039 cm"1; HPLC: 85%.
Example 39: Preparation of 2-(4-((2-ethyl-2H-tetrazol-5-yl')methyl')phenoxy)-6- divdroxymethvDtetrahvdro-2H-pyran-3,4,5-triol:
Figure imgf000059_0001
2-(acetoxymethyl)-6-(4-((2-ethyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Example 39, about 1 g, 1 equivalent) was added in portion wise to Chilled NH3/CH3OH solution (about 20 ml), and stirred for about 3-4 hours. The reaction mixture was concentrated. The gummy mass obtained was repeatedly washed with hexane and DIP then triturated with MTBE to afford the title compound.
Isomer A: Yield: 63 %; IR: 3325, 1667, 1264 can"1; 1H NMR: 1.56 (t, J=7.2 Hz, 3H), 3.4 (m, 4H), 3.7 (m, IH), 3.89 (m, IH), 4.15 (s, 2H), 4.65 (q, J=7.2 Hz, 2H), 4.9 (s, IH, OH), 7.07 (d, J=8.1 Hz, 2H), 7.25 (d, J=8.1 Hz, 2H); Mass (M+Na)=521; HPLC: 98.2%.
Isomer B: Yield: 67 %; Mp: 181.4-192.1 0C; IR: 3350, 1513, 1267, 1240 cm'1; 1H NMR: 1.32 (t, J=7.2 Hz, 3H), 3.75 (m, IH), 4.35 (s, 2H), 4.4 (q, J=7.5 Hz, 2H), 4.65 (t, J=5.7Hz, IH), 4.9 (d, J=7.5Hz, IH, OH), 5.15 (d, J=5.1Hz, IH, OH), 5.22 (d, J=4.5Hz, IH), 5.22 (d, J=4.8 Hz, IH, OH), 7.07 (d, J=8.7Hz, 2H), 7.25 (d, J=8.4Hz, 2H); Mass (M+Na)=389; HPLC: 94.81%.
Similarly, the following compounds have been prepared by above procedure with corresponding starting materials:
Example 40: 2-(acetoxymethyl)-6-f4-(Y2-methyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahvdro-2H-pyran-3 ,4,5-triyl triacetate:
Figure imgf000059_0002
Isomer A: Yield: 75 %; Mp: 99.5-103.1 0C; IR: 1751, 1742, 1225 cm"1; 1H NMR: 2.02-2.15 (4s, 12H), 3.88 (m, IH), 4.25 (m, 3H), 4.3 (dd, IH), 4.35 (s, 3H), 5.06 (d, IH), 5.2 (t, IH), 5.3 (m, 2H), 6.95 (d, /=8.4 Hz, 2H), 7.3 (d, J=8.4 Hz, 2H); Mass (M+l)=521 (100 %); HPLC: 98.2%. Isomer B: Yield: 71 %; Mp: 173.0-176.00C; IR: 1754, 1742, 1231, 1210 cm4; 1H NMR: 2.02-2.1 (4s, 12H), 2.19 (s, 2H)5 3.88 (s, 3H)3 4.18 (m, IH), 4.25 (m, 3H), 5.08 (d, J=7.5 Hz, IH), 5.18 (t, J=9.9 Hz, IH), 5.25-5.32 (m, 2H), 6.97(d, J=8.7 Hz, 2H), 7.15 (d, J=8.7 Hz, 2H); Mass (M+Na)=543 (100 %); HPLC: 90.6%.
Example 41j 2-fhydroxmethyl)-6-f4-(f2-methyl-2H-tetrazol-5- yl)memyl)phenoxy)tetrahvdro-2H-pyran-3A5-triol:
Figure imgf000060_0001
Isomer A: Yield: 65 %; IR: 3356, 1663, 1394, 1234 cm"1; 1H NMR: 3.65 (m, IH), 4.15 (s, 2H), 4.3 (s, 3H), 4.58 (t, J=5.7 Hz, IH), 4.8 (d, J=7.2 Hz, IH), 5.05 (d,
J=5.1 Hz, IH), 5.12 (d, J=4.5 Hz, IH), 5.32(d, J=4.8 Hz, IH), 6.7 (brs, 2H,), 6.95
(d, J=8.4 Hz, 2H), 7.2 (d, J=8.7 Hz3 2H)3 7.3 (brs3 2H, ); Mass (M+Na)=375(100 %);
HPLC: 75 %.
Isomer B: Yield: 65 %; IR: 3365, 1661, 1396, 1235 cm"1; 1H NMR: 3.2 (d, IH), 3.68 (dd, IH), 3.95 (s, 3H), 4.25 (s, 2H), 4.6 (t, J=5.7 Hz, IH), 4.82 (d, J=7.2 Hz3
IH), 5.05 (d, J=5.4 Hz, IH), 5.12 (d, J=4.2 Hz, IH), 5.32 (d, J=4.8 Hz, IH), 6.7
(brs, 2H), 7.0 (d, J=8.7 Hz, 2H), 7.2 (d, J=8.4 Hz, 2H), 7.3 (brs, 2H); Mass
(M+Na)=375 (100 %); HPLC: 92.5%.
Example 42: Preparation of 2-(acetoxymethγl)-6-(5-(2-oxo-2-(l- phenylethylamino)ethyl)-2H-tetrazol-2-yl)tetrahvdro-2H-pyran-3.4.5-triyl triacetate:
Figure imgf000060_0002
Step 1: synthesis of2-cyano-N-(l-phenylethyl)acetamide:
Figure imgf000060_0003
Phenyl ethyl amine (about 4.2 g, 1 equivalent), cyano acetic acid (about 3 g,
1 equivalent), 1 -(3 -dimethyl aminopropyl)-3 -ethyl carbodiimide hydrochloride (about 1.5 equivalent) and 1-hydroxy-benzotriazole (about 4.72 g, 1 equivalent) were added to DMF (50 ml) and stirred at room temperature for about 24 hours. Completion of the reaction was monitored by TLC. The reaction mixture was poured into ice-cold water and acidified with 10% HCl [pH 3-4] then extracted with ethyl acetate (3x25 ml). The combined organic layers were washed with water, brine, dried over Na2So4 and concentrated under reduced pressure. The residue was purified by precipitation with dichloromethane/n-hexane to afford the title compound Yield: 70 %; 1HNMR (300 MHz, CDCl3): δ 1.55 (d, J=6.9Hz, 3H, CH3), 3.36 (s, 2H), 5.1 (m, IH), 6.3 (brs, IH), 7.26-7.37 (m, 5H); Mass [M+Naf: 211 (100%).
Step-2: synthesis ofN-(l-phenylethyl)-2-(2H-tetrazol-5-yl)acetamide:
Figure imgf000061_0001
A mixture of 2~cyano-N-(l-phenylethyl)acetamide (step 1, 2.5 g, 1 equivalent), sodiumazide (about 3.8 g, 4.7 equivalents) and zinc bromide (about 4.2 g, 0.7 equivalents), was taken in IPA/H2O (15 ml/45 ml) was refluxed at about 80°C under stirring for about 72 hours. Completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature and the PH was adjusted to 1.0 with diluted HCl and stirred for about 10 minutes then extracted with ethyl acetate (3x50 ml). The combined organic layers were washed with NaHCO3 solution, brine solution, dried over magnesium sulphate (MgSO4) and concentrated in vacuo to afford the title compound as a white solid. 1H NMR (300 MHz, CDCl3): δ 1.55 (d, J=6.9Hz, 3H CH3), 3.38 (s, 2H), 5.01 (m, IH), 7.18-7.28 (m, 5H), 7.8 (brs, IH); Mass [M+Na]+: 254 (100%).
Step 3: Preparation of 2-(acetoxymethyl)-6-(5-(2-oxo-2-(l- phenylethylamino)ethyl)-2H-tetrazol-2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate:
To a mixture of N-(l-phenylethyl)-2-(2H-tetrazol-5-yl)acetamide (step 2, about 1.5 g, 1 equivalent), terra acetyl bromoglucose (about 3.46 g, 1.3 equivalent), anhydrous K2CO3 (about 2.6 g, 3 equivalent) in acetonitrile (30 ml) was refluxed at about 80°C for about 3 hours and completion of the reaction monitored by TLC. The reaction mixture was filtered, washed with CH3CN and filtrate was poured into ice water while stirring then extracted with ethyl acetate (3x10 ml) and washed with water and brine solution. Solvent was removed under reduced pressure to give crude compound and which was purified by silica gel column chromatography using 20 % EtOAc: Hexane to afford the title compound. Yield: 62 %; Mp: 128-135.50C; IR: 3386, 1750, 1223 cm 1; 1H NMR: (1.5d, 3H), 1.7(s, 3H), 2.05 (s, 3H), 2.1 (s, 6H), 4.0 (s, 2H), 4.05 (dd, Ih), 4.2 (d, IH), 4.35 (dd, IH), 5.2 (m, IH), 5.3 (t, IH), 5.45
(t, IH), 5.65 (t, IH), 6.05 (d, IH), 6.6 (d, IH), 7.3 (m, 6H, Ar-H); HPLC:98.27%; Mass (M+Na)=584.
Example 43: Preparation of N-Q-phenylethylV2-f2-f3A5-trihvdroxy-6- fhydroxymethyl)tetrahydro-2H-pyran-2-yl')-2H-tetrazol-5-yl')acetamide:
Figure imgf000062_0001
2-(acetoxymethyl)-6-(5-(2-oxo-2-(l-phenylethylamino)ethyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Example 42, about 1 g) was added in portions wise to the cold NH3/CH3OH solution (about 30 ml), and stirred for about 3 hours at room temperature then the reaction mixture was allowed for concentration under reduced pressure. The residue was taken in to ethyl acetate and washed with saturated brine solution (2x50 ml), dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound. Yield: 50 %; MP: 102-1220C; IR: 3347, 1659, 1097 cm"1; 1H NMR: 1.4 (d, CH3), 3.2 (m, 2H), 3.5 (m, 2h), 3.7 (m, Ih), 3.9 (m, 3H), 4.75 (m, IH), 5.2 (d, IH), 5.3 (d, IH), 5.5 (d, IH), 5.85 (d, IH), 6.7 (brs, IH),
7.3 (m, 5H, Ar-H); HPLC: 99.63%; Mass (M+Na)= 416.
Similarly, the following compounds have been prepared by above procedure with corresponding starting materials:
Example 44: 2-facetoxymethyiy6-f 5-(2-f 1 -("4-methoxyρhenyl)ethylaminoV2- oxoethyl)-2H-tetrazol-2-yl)tetrahvdro-2H-pyran-3.4.5-triyl triacetate:
Figure imgf000062_0002
MP:159-161.3.°C; IR:3398,1750,1658,1217 cm'1; 1H NMR: 1.35(d,3H), 1.8(s,3H), 1.9-2.1(3 s,9H), 3.75(s,3H), 3.85(s,2H), 4.05(d,lH), 4.2(dd,lH), 4.45(m,lH), 4.85(t,3H), 5.15(t,3H), 5.6(m,2H), 6.7(d,lH), 6.9(d,2H), 7.2(d,2H), 8.65(d,lH); Mass (M+Na)=614; HPLC:96.51%.
Example 45j N-(I -f4-methoxyphenvnethylV2-f2-(3.4.5-trihvdroxy-6-
(hydroxymethyl')tetrahvdro-2H-pyran-2-yl)-2H-tetrazol-5-yl)acetamide:
Figure imgf000063_0001
MP 91.5-116.80C; IR:3354,1661, 1645,1251 cm"1; 1H NMR: 1.35(d,3H), 3.2(m,lH), 3.5(m,2H), 3.7(m,4H), 3.85(m&s,3H), 4.75(m,lH), 4.85(m,lH), 5.25(d,lH),
5.35(d,lH), 5.5(d,lH), 2.85(d,lH), 6.7(brs,lH), 6.9(d,2H), 7.3(d,2H), 8.7(d,lH); Mass: 423+23=446 (molecular ion peak); HPLC:96.53%
Pharmacological activity The compounds described herein can be tested for their activity for SGLT2 inhibitors following any procedures known to a person of ordinary skill in the art. For example, the following protocols may be employed for testing the compounds. These protocols are illustrative and do not limit to the scope of the invention. Example 46: Screening the activity of SGLT inhibitor in the rat renal BBMVs (Brush border membrane vesicles):
Brush border membrane vesicles were prepared from renal tissues of normal rats by the MgCl2 precipitation method (Jurg Biber et al., 2007). Na+-glucose co transporter activity (SGLT) was detennined by the rapid filtration method (Biochem. Biophys. Acta, 554: 259-273, 1979). Glucose uptake was initiated by mixing 10 μL (100 μg) of the BBMV membrane with 50 μL of buffer (100 mmol mannitol, 100 mmol NaCl and 10 mmol HEPES-Tris) containing D-[6 — 3H(N)] glucose (1 μCi, NEN, Boston, MA, USA) and test compounds. Then the reaction was terminated after ten seconds by diluting the 60 μL reaction mixture with 1 mL of ice-cold stop solution (300 mmol mannitol, 80 mmol Na2SO4, 10 mmol Tris H2SO4 and 0.3 mmol phlorizin pH 7.4), which was then filtered through wet Millipore filters (0.45 μm pore size) and kept under suction. The filters were washed twice with 1 mL of ice-cold stop solution and dissolved in 5 niL of scintillation fluid, and the experiments were performed in triplicate. The radioactivity on the membrane was measured with a liquid scintillation counter (Tricarb).
The above described examples were tested in this biological assay described above and were found following results as shown in table 1 at two different concentrations like 10 μm and 3 μm.
Table- 1
Figure imgf000064_0001
Figure imgf000065_0001
Example 47: Screening the activity of SGLT inhibitor in the rat cell based assay:
Cloning of rSGLT-2 and transferring to expression vector:
The total RNA of SD-Rat Kidney was reverse transcribed in to cDNA for PCR amplification using oligo-dT primers. By means of cDNA as a template, base sequence encoding Rat SGLT-2 (Accession number NM_022590, sequence from 6 to 2018) was amplified by PCR and inserted in to the multiple cloning site of pCl- neo vector (Promega). The base sequence of inserted DNA completely matched with the reported sequence.
Preparation of cells transiently expressing Rat SGLT2:
The above described plasmid pCl-neo carrying Rat SGLT2 DNA sequence was transfected to COS-7 cells by Lipofection method. Lipofectamine-2000 reagent (Invitrogen) was used as the lipofection reagent. The day before transfection plate 1.2 X 105 cells in 500 μl of growth medium Dulbecco's modified Eagle's medium, high glucose, pyridoxine HCl, and 25 mM HEPES (Invitrogen) supplemented with 10% heat-inactivated fetal bovine serum (Invitrogen), 100 units/ml penicillin, and lOOμg/ml streptomycin at 370C in 5% CO2. Cells were plated on 24-well flat bottom plates (BD biosciences). For each well 0.2 μg of Rat SGLT-2 plasmid was diluted in 50μl of plain DMEM and 0.6 μl of Lipofectamoine-2000 reagent in 50 μl of plain DMEM and combine both DNA and Lipofectamine mix after 5 min and keep for incubation for 20 min then add in to the well and replace the medium after 5hrs. Inhibition assay of Methyl-ά-D-glucopyranoside uptake activity:
Transport assays were carried out 48 h after transfections as described previously except that all steps were done at 37°C (Pajor and Valmonte, 1996). The sodium buffer contained 14OmM NaCl, 2 mM KCl, 1 mM MgC12, 1 mM CaC12, and 10 mM HEPES, pH adjusted to 7.4 with 1 M Tris. Choline buffer contained 140 mM choline chloride in place of NaCl. For the assays, each well was washed twice with 1 ml of choline buffer, then incubated with 0.2 ml of sodium buffer containing [14C]α-methyl-D-glucopyranoside for 60 min . Inhibitors were added to the transport solutions from dimethyl sulfoxide stocks, with a final volume of dimethyl sulfoxide less than 0.5%. The plates were incubated at 370C. The uptakes were stopped and extra cellular radioactivity removed with two 1-ml washes of choline buffer. After the last wash was removed, each well of cells was solubilized in 200 mM NaOH then transferred in to picoplates (Perkin Elmer) mixed with 1 ml of scintillation cocktail (Microscint-40, Perkin Elmer). The plates were sealed with plastic plate covers total counts per minute measured on the gamma counter (Top
Count Perkin Elmer). The uptake obtained by untreated cells (control wells) was considered as a 100% uptake. The reductions in CPMA in the drug treated wells with respect to control was expressed as % inhibition and calculated by the following formula:
% Inhibition= CPMA (control)-CPMA (treated) X 100
CPMA (control)
The above described examples were tested in this biological assay described above and were found following results as shown in table 2 at 3 μm concentration. Table-2
Figure imgf000066_0001
Figure imgf000067_0001
Example 48: Assay for the effect on urinary glucose excretion:
As experimental animals, overnight fasted SD rats male, 7-8 weeks age, 230- 250grams were used. The test compound was suspended with a solution of 5 % 1- methyl 2- pyrrolidinone, 20% polyethylene glycol (400), 20 mmol/ 1 sodium diphosphate (Tetra basic) and the suspension was used for administration. On the day before drug administration, the rats were transferred in metabolic cages and tested from the evening. Throughout the study, the rats were given water and libitum. The test compound was orally administered at the dose of lOmg/ kg and urine collection was performed for 24hrs after the compound administration. The rats were fed ad libitum from 4 hrs after the compound administration. The volume of urine collected was measured and apart of urine was used as a sample for glucose concentration measurement. The samples were diluted as appropriate and the glucose concentrations were measured.
The above described examples were tested in this biological assay described above and were found following results as shown in table 3.
Table-3
Figure imgf000067_0002
References:
1. Am Jphysiol Renal Physiol 286, Fl 27-Fl 33, 2004;
2. Nature protocols, 2007, 2(6), 1356-59;
3. J. Pharmacology and Experimental Therapeutics, 324, 985-991, 2008.
Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described above.
All publications and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

CLAIMS:
1. A compound of the formula (1):
Figure imgf000069_0001
Formula (1) wherein,
X is H, lower alkyl group, lower perfluoro alkyl group, aralkyl group, phenyl group, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified);
Y is
Figure imgf000069_0002
Ring A and B are independently selected from phenyl, naphthyl, heteroaryl, cycloalkyl or heterocyclyl which may contain 5 to 7 membered ring, which may contain 1 to 4 hetero atoms like N, O, S, SO or SO2 in the ring;
Z is oxygen, methylene, (CH2)n, dimethylmethylene, difluoromethylene, carbonyl, O-alkyl, S-alkyl, SO2 alkyl, -C(O)-NH-RiR2 or Z may represent a bond between rings A and B; n is an integer 0-3;
Y is also
Figure imgf000069_0003
, substituted or unsubstituted aryl group more particularly substituted or unsubstituted phenyl group, substituted or unsubstituted aryl-C(O)-, substituted or unsubstituted aryl- CH2-, or substituted or unsubstituted aryloxy-CH2-, where in the substituents are R] and R2;
Ri and R2 are independently selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, Ci-β-alkyl, C2.g alkynyl, C3-6 cycloalkyl, Ci-C4alkylcarbonyl, aryl carbonyl, heteroarylcarbonyl, amino carbonyl, CM-alkylaminocarbonyl, hydroxyl, cyano, C1-4 alkyl sulphonylamino, arylsulphonylamino, Ci-6 alkoxy, C3-7 cycloalkoxy, aryloxy, aralkyloxy, aryloxyalkyl, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified);
R3 and R4 are independently selected from hydrogen, alkyl, halo, perfluoroalkyl, CN, OH, O-alkyl, O-cycloalkyl, phenyl, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified);
R5 is alkyl or perfluoroalkyl; or an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N-oxide thereof, a tautomer thereof, a regeoisomer thereof, a stereoisomer thereof, a prodrug thereof, or a polymorph thereof.
2. The compound according to claim 1, which is a compound of formula
(IA):
Figure imgf000070_0001
wherein, XA is H, lower alkyl group, lower perfluoro alkyl group, O-α or β-D- glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxylgroup may be esterified);
RiA and R2A are independently selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, Ci-6-alkyl, hydroxyl, cyano, Ci-6 alkoxy, C3-7 cycloalkoxy, aryloxy, aralkyloxy, aryloxyalkyl, O-α or β-D-glucopyranosyl group, α or β-D- glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified); or an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N-oxide thereof, a tautomer thereof, a regeoisomer thereof, a stereoisomer thereof, a prodrug thereof, or a polymorph thereof.
3. The compound according to claim 1, which is a compound of formula
(IB):
Figure imgf000071_0001
Formula (IB) wherein,
XB is H, lower alkyl group, O-α or β-D-glucopyranosyl group, α or β-D- glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified);
YB is
Figure imgf000071_0002
wherein,
ZA is (CH2)n; n is an integer 0-1;
Ring AB and BB are independently a phenyl;
R1B and R2B are independently selected from H, -Cl, -Br, -OMe, or CF3; R3B and R4B are independently selected from H, alkyl, or O-alkyl;
R5B is methyl; or an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N-oxide thereof, a tautomer thereof, a regeoisomer thereof, a stereoisomer thereof, a prodrug thereof, or a polymorph thereof.
4. A compound selected from the group consisting of:
2-(acetoxymethyl)-6-(5-benzyl-2H-tetrazol-2-yl)tetrahydro-2H-pyran-3,4,5- triyl triacetate (Compound No. 1), 2-(5-benzyl-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5- triol (Compound No. 2),
2-(acetoxymethyl)-6-(5-(4-bromobenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. 3),
2-(5-(4-bromobenzyl)-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol (Compound No. 4),
2-(acetoxymethyl)-6-(5-(2,4-dichlorobenzyl)-2H-tetrazol-2-yl)tetrahydro- 2H-pyran-3,4,5-triyl triacetate (Compound No. 5),
2-(5-(2,4-dichlorobenzyl)-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3,4,5-triol (Compound No. 6), 2-(acetoxymethyl)-6-(5-(4-methoxybenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. 7),
2-(hydroxymethyl)-6-(5-(4-methoxybenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-trioI (Compound No. 8),
2-(acetoxymethyl)-6-(5-(3,4-dichlorobenzyl)-2H-tetrazol-2-yl)tetrahydro- 2H-pyran-3,4,5-triyl triacetate (Compound No. 9),
2-(5-(3,4-dichlorobenzyl)-2H-tefrazol-2-yl)-6-(hydroxymethyl)tetrahydro- 2H-pyran-3,4,5-triol (Compound No. 10),
2-(acetoxymethyl)-6-(5-(4-(trifluoromethyl)benzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 11), 2-(hydroxymethyl)-6-(5-(4-(trifluoromethyl)ben2yl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 12),
2-(acetoxymethyl)-6-(5-(4-(benzyloxy)benzyl)-2H-tetrazol-2-yl)tetrahydro- 2H-pyran-3,4,5-triyl triacetate (Compound No. 13), 2-(5-(4-(benzyloxy)benzyl)-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro-
2H-pyran-3,4,5-triol (Compound No. 14),
2-(acetoxymethyl)-6-(5-(4-hydroxybenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. 15),
2-(5-(4-hydroxybenzyl)-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol (Compound No. 16),
2-(acetoxymethyl)-6-(5-phenetliyl-2H-tetrazol-2-yl)tetrahydro-2H-pyran- 3, 4, 5 -triyl triacetate (Compound No. 17),
2-(hydroxymethyl)-6-(5-phenethyl-2H-tetrazol-2-yl)tetrahydro-2H-pyran- 3,4,5-triol (Compound No. 18), 2-(acetoxymethyl)-6-(5-(2-oxo-2-phenylethyl)-2H-tetrazol-2-yl)tetrahydro-
2H-pyran-3,4,5-triyl triacetate (Compound No. 19), l-phenyl-2-(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2- yl)-2H-tetrazol-5-yl)ethanone (Compound No. 20),
2-(acetoxymethyl)-6-(5-(2-(4-chlorophenoxy)ethyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3 ,4,5-triyl triacetate (Compound No. 21),
2-(5-(2-(4-chlorophenoxy)ethyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 22),
2-(acetoxymethyl)-6-(5-(4-methylbenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3 ,4,5-triyl triacetate (Compound No. 23), 2-(hydroxymethyl)-6-(5-(4-methylbenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- p}τ:an-3,4,5-triol (Compound No, 24),
2-(acetoxymethyl)-6-(5-(4-ethylbenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. 25),
2-(5-(4-ethylbenzyl)-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol (Compound No. 26),
2-(acetoxymethyl)-6-(5-(2-methoxybenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,'5-triyl triacetate (Compound No. 27),
2-(hydroxymethyl)-6-(5-(2-methoxybenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triol (Compound No. 28), 2-(acetoxymethyl)-6-(5-(3-metlioxybenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. 29),
2-(hydroxymethyl)-6-(5-(3-methoxybenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triol (Compound No. 30), 2-(acetoxymethyl)-6-(5-(4-ethoxybenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. 31),
2-(5-(4-ethoxybenzyl)-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol (Compound No. 32),
2-(acetoxymethyl)-4-hydroxy-6-(5~(4-isopropoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,5-diyl diacetate (Compound No. 33),
2-(hydroxymethyl)-6-(5-(4-isopropoxybenzyl)-2H-tetrazol-2-yl)tetrahydro- 2H-pyran-3,4,5-triol (Compound No. 34), ethyl (3,4,5-trihydroxy-6-(5-(4-isopropoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-2-yl)methyl carbonate (Compound No. 35), 2-(acetoxymethyl)-6-(5-(4-benzylbenzyl)-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. 36),
2-(5-(4-benzylbenzyl)-2H-tetrazol-2-yl)-6-(hydroxymeth.yl)tetrahydro-2H- pyran-3,4,5-triol (Compound No. 37),
2~(acetoxymethyl)-6-(4-((2-ethyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 38),
2-(4-((2-ethyl-2H-tetrazol-5-yl)methyl)phenoxy)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 39),
2-(acetoxymethyl)-6-(4-((2-methyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 40), 2-(hydroxymethyl)-6-(4-((2-methyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 41),
2-(acetoxymethyl)-6-(5-(2-oxo-2-(l-phenylethylamino)ethyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 42),
N-(l-phenylethyl)-2-(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H- pyran-2-yl)-2H-tetrazol-5-yl)acetamide (Compound No. 43),
2-(acetoxymethyl)-6-(5 -(2-( 1 -(4-methoxyphenyl)ethylamino)-2-oxoethyl)- 2H-tetrazol-2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 44), N-(l-(4-methoxyphenyl)ethyl)-2-(2-(3,4,5-trihydroxy-6-(hydroxymetliyl)tetrahydro- 2H-pyran-2-yl)-2H-tetrazol-5-yl)acetamide (Compound No. 45), isomers thereof, and pharmaceutically acceptable salts thereof.
5. The compound according to claim 4, wherein the compound is selected from the group consisting of: Isomer A o/2-(acetoxymethyl)-6-(5-benzyl-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. IA),
Isomer B o/2-(acetoxymethyl)-6-(5-benzyl-2H-tetrazol-2-yl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (Compound No. IB),
Isomer A o/2-(5-benzyl-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro-2H- pyran-3 ,4,5-triol (Compound No. 2A),
Isomer B o/2-(5-benzyl-2H-tetrazol-2-yl)-6-(hydroxymethyl)tetrahydro-2H- pyran-3,4,5-triol (Compound No. 2B),
Isomer A o/2-(acetoxymethyl)-6-(5-(4-bromobenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 3A), Isomer B of 2-(acetoxymethyl)-6-(5-(4-bromobenzyl)-2H-tetrazol~2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 3B),
Isomer A <9/r2-(5-(4-bromobenzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 4A),
Isomer B ø/2-(5-(4-bromobenzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3 ,4,5-triol (Compound No. 4B),
Isomer A o/2-(acetoxymethyl)-6~(5-(2,4-dichlorobenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 5A),
Isomer B o/2-(acetoxymethyl)-6-(5-(2,4-dichlorobenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 5B), Isomer A o/2-(5-(2,4-dichlorobenzyl)-2H-tetrazol-2-yl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 6A),
Isomer B o/2-(5-(2,4-dichlorobenzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 6B),
Isomer A o/2-(acetoxymethyl)-6-(5-(4-methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 7A),
Isomer B o/2-(acetoxymethyl)-6-(5-(4-methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 7B),
Isomer A o/2-(hydroxymethyl)-6-(5-(4-methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3 ,4,5-triol (Compound No. 8A), Isomer B ø/2-(hydroxymethyl)-6-(5-(4-methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 8B),
Isomer A o/2-(acetoxymethyl)-6-(5-(3,4-dichlorobenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 9A), Isomer B ø/2-(acetoxymethyl)-6-(5-(3,4-dichloroberizyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 9B),
Isomer A σ/2-(5-(3,4-dichlorobenzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 10A),
Isomer B o/2-(5-(3,4-dichlorobenzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3 ,4,5-triol (Compound No. 1 OB),
Isomer A o/2-(acetoxymethyl)-6-(5-(4-(trifluoromethyl)benzyl)-2H-tetrazol- 2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. HA),
Isomer B ^2-(acetoxymethyl)-6-(5-(4-(trifluoromethyl)benzyl)-2H-tetrazol- 2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. HB), Isomer A o/2-(hydroxymethyl)-6-(5-(4-(trifluoromethyl)benzyl)-2H-tetrazol-
2-yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 12A),
Isomer B o/2-(hydroxymethyl)-6-(5-(4-(trifluoromethyl)benzyl)-2H-tetrazol- 2-yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 12B),
Isomer A o/2-(acetoxymethyl)-6~(5-(4-(benzyloxy)benzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 13A),
Isomer B o/2-(acetoxymethyl)-6-(5-(4-(benzyloxy)benzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 13B),
Isomer A ø/"2-(5-(4-(benzyloxy)benzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 14A), Isomer B o/2-(5-(4-(benzyloxy)benzyl)-2H-tetrazol-2-yl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 14B),
Isomer A o/2-(acetoxymethyl)-6-(5-(4-hydroxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 15A),
Isomer B o/2-(acetoxymethyl)-6-(5-(4-hydroxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 15B),
Isomer A o/"2-(5-(4-hydroxybenzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3 ,4,5-triol (Compound No. 16A),
Isomer B o/2-(5-(4-hydroxybenzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 16B), Isomer A o/2-(acetoxymethyl)-6-(5-phenethyl-2H-tetrazol-2-yl)tetrahydro- 2H-pyran-3,4,5-triyl triacetate (Compound No. 17A),
Aomer5 o/2-(acetoxymethyl)-6-(5-phenethyl-2H-tetrazol-2-yl)tetrahydro- 2H-pyran-3,4,5-triyl triacetate (Compound No. 17B), Isomer A o/"2-(hydroxymethyl)-6-(5-phenethyl-2H-tetrazol-2-yl)tetrahydro-
2H-pyran-3,4,5-triol (Compound No. 18A),
Isomer B o/2-(hydroxymethyl)-6-(5-phenethyl-2H-tetrazol-2-yl)tetrahydro- 2H-pyran-3,4,5-triol (Compound No. 18B),
Isomer A o/2-(acetoxymethyl)-6-(5-(2-oxo-2-phenylethyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 19A),
Isomer B q/~2-(acetoxymethyl)-6-(5-(2-oxo-2-phenylemyl)~2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 19B),
Isomer A q/"l-phenyl-2-(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro- 2H-pyran-2-yl)-2H-tetrazol-5-yl)ethanone (Compound No. 20A), Isomer B o/"/-phenyl-2-(2-(3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-
2H-pyran-2-yl)-2H-tetrazol-5-yl)ethanone (Compound No. 20B),
Isomer A o/2-(acetoxymethyl)-6-(5-(2-(4-chlorophenoxy)ethyl)-2H-tetrazol- 2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 21A),
Isomer B o/r2-(acetoxymethyl)-6-(5-(2-(4-chlorophenoxy)ethyl)-2H-tetrazol- 2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 21B),
Isomer A ø/2-(5-(2-(4-chlorophenoxy)ethyl)-2H-tetrazol-2-yl)-6- (hydroxymemyl)tetøhydro-2H-pyran-3,4,5-triol (Compound No. 22A),
Isomer B o/2-(5-(2-(4-chlorophenoxy)ethyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 22B), Isomer A ø/2-(acetoxymethyl)-6-(5-(4-methylbenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 23A),
Isomer B o/2-(acetoxymethyl)-6-(5-(4-methylbenzyl)-2H~tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 23B),
Isomer A o/2-(hydroxymethyl)-6-(5-(4-methylbenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 24A),
Isomer B o/'2-(hydroxymethyl)-6-(5-(4-methylbenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 24B),
Isomer A o/2-(acetoxymethyl)-6-(5-(4-ethyϊbenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 25A), Isomer B ø/2-(acetoxymethyl)-6-(5-(4-ethylbenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 25B),
Isomer A o/2-(5-(4-ethylbenzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 26A), Isomer B o/2-(5~(4-ethylbenzyl)-2H-tetrazol-2-yl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4J5-triol (Compound No. 26B),
Isomer A q/"2-(acetoxymethyl)-6-(5-(2-methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 27A),
Isomer B o/"2-(acetoxymethyl)-6-(5-(2-methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 27B),
Isomer A ø/2-(hydroxymethyl)-6-(5-(2-methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 28A),
Isomer B o/"2-(hydroxymethyl)-6-(5-(2-methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H~pyran-3,4,5-triol (Compound No. 28B), Isomer A <9/~2-(acetoxymethyl)-6-(5-(3 -methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 29A),
Isomer B o/2-(acetoxymethyl)-6-(5-(3 -methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 29B),
Isomer A o/2-(hydroxymethyl)-6-(5-(3-methoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 30A),
Isomer B o/2-(liydroxymethyl)-6-(5-(3 -methoxybenzyl)~2H-tetrazol-2- yl)tetrahydro-2H-pyran-3;,4,5-triol (Compound No. 30B)5
Isomer A o/2-(acetoxymethyl)-6-(5-(4-ethoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 31A), Isomer B o/2-(acetoxymethyl)-6-(5~(4-ethoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3;,4,5-triyl triacetate (Compound No. 31B),
Isomer A o/2-(5-(4-ethoxybenzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 32A),
Isomer B o/2-(5-(4-ethoxybenzyl)-2H-tetrazol-2-yl)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 32B),
Isomer A of 2-(acetoxymethyl)-4-hydroxy-6-(5-(4-isopropoxybenzyl)-2H- tetrazol-2-yl)tetrahydro-2H-pyran-3,5-diyl diacetate (Compound No. 33A),
Isomer B of 2-(acetoxymethyl)-4-hydroxy-6-(5-(4-isopropoxybenzyl)-2H- tetrazol-2-yl)tetrahydro-2H-pyran-3,5-diyl diacetate (Compound No. 33B), Isomer A of 2-(hydroxymethyl)-6-(5-(4-isopropoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 34A),
Isomer- B of 2-(hydroxymethyl)-6-(5-(4-isopropoxybenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 34B), Isomer A of ethyl (3,4,5-trihydroxy-6-(5-(4-isopropoxybenzyl)-2H-tetrazol-
2-yl)tetrahydro-2H-pyran-2-yI)methyI carbonate (Compound No. 35A),
Isomer B of ethyl (3,4,5-trihydroxy-6-(5-(4-isopropoxybenzyl)-2H-tetrazol- 2-yl)tetrahydro-2H-pyran-2-yl)methyl carbonate (Compound No. 35B),
Isomer A of 2-(acetoxymethyl)-6-(5-(4-benzylbenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 36A),
Isomer B of 2-(acetoxymethyl)-6-(5-(4-benzylbenzyl)-2H-tetrazol-2- yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 36B),
Isomer A of 2-(5-(4-benzylbenzyl)-2H-tetrazol-2-yl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 37A), Isomer B of 2-(5-(4-benzyϊbenzyl)-2H-tetrazol-2-yl)-6-
(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 37B),
Isomer A of 2-(acetoxymethyl)-6~(4-((2-ethyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 38A),
Isomer B of 2-(acetoxymethyl)-6-(4-((2-ethyl-2H-tetrazol-5~ yl)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 38B),
Isomer A of 2-(4-((2-ethyl-2H-tetrazol-5-yl)methyl)phenoxy)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 39A),
Isomer B of 2-(4-((2-ethyl-2H-tetrazol-5-yl)methyl)phenoxy)-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 39B), Isomer A of 2-(acetoxymethyl)-6-(4-((2-methyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 40A),
Isomer B of 2-(acetoxymethyl)-6-(4-((2-methyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 40B),
Isomer A of 2-(hydroxymethyl)-6-(4-((2-methyl-2H-tetrazol~5- yl)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 41 A),
Isomer B of 2-(hydroxymethyl)-6-(4-((2-methyl-2H-tetrazol-5- yl)methyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triol (Compound No. 41B),
Isomer A of 2-(acetoxymethyl)-6-(5-(2-oxo-2-(l-phenylethylamino)ethyl)- 2H-tetrazol-2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 42A), Isomer B of 2-(acetoxymethyl)-6-(5-(2-oxo-2-(l-phenylemylamino)ethyl)- 2H-tetrazol-2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 42B),
Isomer A of N-(l-phenylethyl)-2-(2-(3,4,5-trihydroxy-6-
(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-2H-tetrazol-5-yl)acetamide (Compound No. 43A)3
Isomer B of N-(l-phenylethyl)-2-(2-(3,4,5-trihydroxy-6-
(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-2H-tetrazol-5-yl)acetamide (Compound No. 43B),
Isomer A of 2-(acetoxymethyl)-6-(5~(2-(l-(4-methoxyphenyl)emylamino)-2- oxoethyl)-2H-tetrazol-2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound
No. 44A),
Isomer B of 2-(acetoxymethyl)-6-(5-(2-(l -(4-methoxyphenyl)ethylamino)-2- oxoethyl)-2H-tetrazol-2-yl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (Compound No. 44B), Isomer A of N-(l-(4-memoxyphenyl)emyl)-2-(2-(3,4,5-trihydroxy-6-
(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-2H-tetrazol-5-yl)acetamide (Compound No. 45A),
Isomer B of N-(l-(4-methoxyphenyl)ethyl)-2-(2-(3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)-2H-tetrazol-5-yl)acetamide (Compound No. 45B), isomers thereof, and pharmaceutically acceptable salts thereof.
6. A pharmaceutical composition comprising a compound according to any one of claims 1-5 and a pharmaceutically acceptable excipient.
7. The pharmaceutical composition according to claim 6, wherein the pharmaceutically acceptable excipient is a carrier or diluent.
8. Use of a compound according to any one of claims 1-5 for the manufacture of a medicament for preventing, ameliorating or treating SGLT2 mediated disease, disorder or syndrome in a subject in need thereof.
9. The use according to claim 8, wherein the disease, disorder or syndrome is selected from the group consisting of type I diabetes, type II diabetes, including complications of diabetes such as retinopathy, neuropathy, nephropathy, and delayed wound healing.
10. The use according to claim 8, wherein the disease, disorder or syndrome is selected from the group consisting of diabetes, especially type I and type II diabetes, including complications of diabetes such as retinopathy, neuropathy, nephropathy and delayed wound healing, and related diseases such as insulin resistance and impaired glucose homeostasis (IGH), hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, obesity, hyperlipidemia including hypertriglyceridemia, Syndrome X, hypertension, and atherosclerosis.
11. Use of a compound according to any one of claims 1-5 for the manufacture of a medicament for treating type I diabetes in a subject in need thereof.
12. Use of a compound according to any one of claims 1-5 for the manufacture of a medicament for treating type II diabetes in a subject in need thereof.
13. Use of a compound according to any one of claims 1-5 for the manufacture of a medicament for treating diabetes complications such as retinopathy, neuropathy, nephropathy and delayed wound healing in a subject in need thereof.
14. A process for the preparation of a compound of formula (1):
Figure imgf000081_0001
Formula (1) wherein, X is H, lower alkyl group, lower perfluoro alkyl group, aralkyl group, phenyl group, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified); Y is
Figure imgf000082_0001
Ring A and B are independently selected from phenyl, naphthyl, heteroaryl, cycloalkyl or heterocyclyl which may contain 5 to 7 membered ring, which may contain 1 to 4 hetero atoms like N, O, S, SO or SO2 in the ring;
Z is oxygen, methylene, (CH2)n, dimethylmethylene, difluoromethylene, carbonyl, O-alkyl, S-alkyl, SO2 alkyl, -C(O)-NH-RiR2 or Z may represent a bond between rings A and B; n is an integer 0-3;
Y is also
Figure imgf000082_0002
5 substituted or unsubstituted aryl group more particularly substituted or unsubstituted phenyl group, substituted or unsubstituted aryl-C(O)-, substituted or unsubstituted aryl- CH2-, or substituted or unsubstituted aryloxy-CH2-, where in the substituents are Ri and R2; Ri and R2 are independently selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, Ci-e-alkyl, C2-6 alkynyl, C3-6 cycloalkyl, Ci-C4alkylcarbonyl, aryl carbonyl, heteroarylcarbonyl, amino carbonyl, Ci-4-alkylaminocarbonyl, hydroxyl, cyano, Ci_4 alkyl sulphonylamino, arylsulphonylamino, Ci-6 alkoxy, C3-7 cycloalkoxy, aryloxy, aralkyloxy, aryloxyalkyl, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified); R3 and R4 are independently selected from hydrogen, alkyl, halo, perfluoroalkyl, CN, OH, O-alkyl, O-cycloalkyl, phenyl, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified); R5 is alkyl or perfiuoroalkyl; an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N- oxide thereof, a tautomer thereof, a regeoisomers thereof, a stereoisomer thereof, a prodrug thereof, or a polymorph thereof, the process comprising the steps of: a) reacting the cyano compounds of formula (1)
Y'^CN i with the azide compounds of formula (2)
NaN3 2 to form tetrazole compounds of formula (3)
Figure imgf000083_0001
3 b) reacting the tetrazole compounds of formula (3) with the acylated sugar compounds of formula (4)
Figure imgf000083_0002
to form the acylated sugar compounds of formula (5)
Figure imgf000083_0003
5
Formula (1), when X is acylated glucopyranosyl ^n(j c) hydrolysing the compounds of formula (5) to form the sugar compounds of formula (6)
Figure imgf000084_0001
6
Formula (1), when X is glucopyranosyl
15. A process for the preparation of a compound of formula (1):
Figure imgf000084_0002
Formula (1) wherein,
X is H, lower alkyl group, lower perfluoro alkyl group, aralkyl group, phenyl group, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxylgroup may be esterified); Y is
Figure imgf000084_0003
Ring A and B are independently selected from phenyl, naphthyl, heteroaryl, cycloalkyl or heterocyclyl which may contain 5 to 7 membered ring, which may contain 1 to 4 hetero atoms like N, O, S, SO or SO2 in the ring;
Z is oxygen, methylene, (CH2)n, dimethylmethylene, difluoromethylene, carbonyl, O-alkyl, S-alkyl, SO2 alkyl, -C(O)-NH-R]R2 or Z may represent a bond between rings A and B; n is an integer 0-3; Y is also
Figure imgf000085_0001
5 substituted or unsubstituted aryl group more particularly substituted or unsubstituted phenyl group, substituted or unsubstituted aryl-C(O)-, substituted or unsubstituted aryl-
CH2-, or substituted or unsubstituted aryloxy-CH2-, where in the substituents are Ri and R2;
Ri and R2 are independently selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, Ci-6-alkyl, C2-β alkynyl, C3-6 cycloalkyl, Ci-C4alkylcarbonyl, aryl carbonyl, heteroarylcarbonyl, amino carbonyl,
Figure imgf000085_0002
hydroxyl, cyano, CM alkyl sulphonylamino, arylsulphonylamino, C1-6 alkoxy, C3-7 cycloalkoxy, aryloxy, aralkyloxy, aryloxyalkyl, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterifϊed);
R3 and R4 are independently selected from hydrogen, alkyl, halo, perfluoroalkyl, CN, OH, O-alkyl, O-cycloalkyl, phenyl, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterifϊed); R5 is alkyl or perfluoroalkyl; an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N- oxide thereof, a tautomer thereof, a regeoisomers thereof, a stereoisomer thereof, a prodrug thereof, or a polymorph thereof, the process comprising the steps of: (a) reacting the amino compounds of formula (7)
Figure imgf000085_0003
with the cyano acetic acid compounds of formula (8)
HOOC^~CN 8 to form the amido compounds of formula (9)
Figure imgf000086_0001
(b) reacting the amido compounds of formula (9) with the azide compounds of formula (2)
NaN3 2 to form the tetrazole compounds of formula (10)
Figure imgf000086_0002
(c) reacting the tetrazole compounds of formula (10) with the acylated sugar compounds of formula (4)
Figure imgf000086_0003
4 to form the acylated sugar compounds of formula (11)
Figure imgf000086_0004
11
Formula 1, when X is acylated glucopyranosyl and (d) hydrolysing the acylated sugar compounds of formula (11) to form the sugar compounds of formula (12)
Figure imgf000086_0005
12
Formula 1, when X is glucopyranosyl
16. A process for the preparation of a compound of formula (1):
Figure imgf000087_0001
Formula (1) wherein,
X is H, lower alkyl group, lower perfluoro alkyl group, aralkyl group, phenyl group, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified);
Y is
Figure imgf000087_0002
Ring A and B are independently selected from phenyl, naphthyl, heteroaryl, cycloalkyl or heterocyclyl which may contain 5 to 7 membered ring, which may contain 1 to 4 hetero atoms like N, O, S, SO or SO2 in the ring; Z is oxygen, methylene, (CH2)n, dimethylmethylene, difluoromethylene, carbonyl, O-alkyl, S-alkyl, SO2 alkyl, -C(O)-NH-RiR2 or Z may represent a bond between rings A and B; n is an integer 0-3;
Y is also
Figure imgf000087_0003
, substituted or unsubstituted aryl group more particularly substituted or unsubstituted phenyl group, substituted or unsubstituted aryl-C(O)-, substituted or unsubstituted aryl- CH2-, or substituted or unsubstituted aryloxy-CH2-, where in the substituents are Ri and R2; R1 and R2 are independently selected from hydrogen, fluorine, chlorine, bromine, trifluoromethyl, Ci-β-alkyl, C2-6 alkynyl, C3-6 cycloalkyl, C1-C4alkylcarbonyl, aryl carbonyl, heteroarylcarbonyl, amino carbonyl, CM-alkylaminocarbonyl, hydroxyl, cyano, C1-4 alkyl sulphonylamino, arylsulphonylamino, C1^ alkoxy, C3-7 cycloalkoxy, aryloxy, aralkyloxy, aryloxyalkyl, O-α or β-D-glucopyranosyl group, α or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified);
R3 and R4 are independently selected from hydrogen, alkyl, halo, perfluoroalkyl, CN, OH, O-alkyl, O-cycloalkyl, phenyl, O-α or β-D-glucopyranosyl group, a or β-D-glucopyranosyl group (of which one or more hydroxyl groups may be acylated) or β-D-glucuronyl group (of which one or more hydroxyl groups may be acylated and carboxyl group may be esterified); R5 is alkyl or perfluoroalkyl; an analog thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable solvate thereof, a pharmaceutically acceptable hydrate thereof, an N- oxide thereof, a tautomer thereof, a regeoisomers thereof, a stereoisomer thereof, a prodrug thereof, or a polymorph thereof, the process comprising the steps of:
(a) reacting the cyano compounds of formula (13) (wherein, P is protecting group (benzyl or tertiary butyl))
Figure imgf000088_0001
13 with the azide compounds of formula (2)
NaN3 2 to form the tetrazole compounds of formula (14)
Figure imgf000088_0002
(b) reacting the tetrazole compounds of formula (14) with the halo compounds of formula (15)
XBr 15 to form the compounds of formula (16)
Figure imgf000089_0001
(c) deprotecting the compounds of formula (16) to form the compounds of formula (17)
Figure imgf000089_0002
(d) reacting the compounds of formula (17) with the acylated sugar compounds of formula (4)
Figure imgf000089_0003
4 to form the acylated sugar compounds of formula (18)
Figure imgf000089_0004
18
Formula 1, when Y is phenyl substituted by acylated glucopyranosyl ajid
(e) hydrolysing the acylated sugar compounds of formula (18) to form the sugar compounds of formula (19)
Formula I1 when Y is phenyl substituted by glucopyranosyl
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WO2012004269A1 (en) 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
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WO2011161030A1 (en) 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
WO2012004269A1 (en) 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
WO2012004270A1 (en) 2010-07-05 2012-01-12 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, methods for the production thereof and use of the same as medicament
WO2012010413A1 (en) 2010-07-05 2012-01-26 Sanofi Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament
WO2013037390A1 (en) 2011-09-12 2013-03-21 Sanofi 6-(4-hydroxy-phenyl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors
WO2013045413A1 (en) 2011-09-27 2013-04-04 Sanofi 6-(4-hydroxy-phenyl)-3-alkyl-1h-pyrazolo[3,4-b]pyridine-4-carboxylic acid amide derivatives as kinase inhibitors

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