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WO2010018438A2 - Tétrazoles glycosides - Google Patents

Tétrazoles 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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WO2010018438A3 (fr
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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Hetero Research Foundation
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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:

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Abstract

L'invention concerne des dérivés de tétrazoles glycosides qui sont des inhibiteurs du co-transporteur du glucose dépendant du sodium (SGLT), en particulier SGLT2, et des procédés de traitement de maladies, d'états et/ou de troubles inhibés par SGLT2 avec eux, et des procédés de préparation de ceux-ci.
PCT/IB2009/006497 2008-08-11 2009-08-05 Tétrazoles glycosides Ceased WO2010018438A2 (fr)

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WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase

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EP1660509B1 (fr) * 2003-08-26 2009-02-04 Boehringer Ingelheim International GmbH Pyrazoles glucopyranosyloxy, medicaments contenant ces composes, leur utilisation et leur procede de production
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WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase

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