WO2011070592A2 - Nouveaux dérivés de sucres - Google Patents

Nouveaux dérivés de sucres Download PDF

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WO2011070592A2
WO2011070592A2 PCT/IN2010/000796 IN2010000796W WO2011070592A2 WO 2011070592 A2 WO2011070592 A2 WO 2011070592A2 IN 2010000796 W IN2010000796 W IN 2010000796W WO 2011070592 A2 WO2011070592 A2 WO 2011070592A2
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alkyl
aryl
formula
heteroaryl
substituted
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WO2011070592A3 (fr
Inventor
Rajesh Jain
Sanjay Trehan
Sastry V.R.S. Thungathurthi
Gurmeet Kaur Nanda
Jagattaran Das
Sitaram Kumar Magadi
Sudhir Kumar Sharma
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Panacea Biotec Ltd
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Panacea Biotec Ltd
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    • 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
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms

Definitions

  • the present invention relates to novel compounds of Formula I, their pharmaceutically acceptable derivatives, analogs, tautomeric forms, isomers, polymorphs, prodrugs, metabolites, salts or solvates thereof.
  • the invention also relates to the processes for the synthesis of novel compounds of Formula I, their pharmaceutically acceptable derivatives, analogs, tautomeric forms, isomers, polymorphs, prodrugs, metabolites, salts or solvates thereof.
  • the present invention also provides pharmaceutical compositions comprising novel compounds of Formula I and methods of treating or preventing one or more conditions or diseases that may be regulated or normalized via inhibition of Sodium Glucose Cotransporter-2 (SGLT-2).
  • SGLT-2 Sodium Glucose Cotransporter-2
  • the invention also relates to the use of compounds of Formula I, their pharmaceutically acceptable derivatives, analogs, tautomeric forms, isomers, polymorphs, prodrugs, metabolites, salts or solvates thereof, for the manufacture of a medicament for the prophylaxis, amelioration and/or treatment of conditions or diseases that may be regulated or normalized via inhibition of Sodium Glucose Cotransporter-2 (SGLT-2) and the related diseases, disorders and conditions, in a subject in need thereof.
  • SGLT-2 Sodium Glucose Cotransporter-2
  • Diabetes is a metabolic disorder which is rapidly emerging as a global health care problem that threatens to reach pandemic levels.
  • the number of people with diabetes worldwide is expected to rise from 285 million in 2009 to 435 million by 2030. Diabetes results from deficiency in insulin because of impaired pancreatic ⁇ -cell function or from resistance to insulin in body, thus leading to abnormally high levels of blood glucose.
  • Type 1 diabetes Diabetes which results from complete deficiency in insulin secretion is type 1 diabetes and the diabetes due to resistance to insulin activity together with an inadequate insulin secretion is type 2 diabetes.
  • Type 2 diabetes Non insulin dependent diabetes
  • An early defect in type 2 diabetes mellitus is insulin resistance which is a state of reduced responsiveness to circulating concentrations of insulin and is often present years before clinical diagnosis of diabetes.
  • a key component of the pathophysiology of type 2 diabetes mellitus involves an impaired pancreatic ⁇ -cell function which eventually contributes to decreased insulin secretion in response to elevated plasma glucose. The ⁇ -cell compensates for insulin resistance by increasing the insulin secretion, eventually resulting in reduced ⁇ -cell mass. Consequently, blood glucose levels stay at abnormally high levels (hyperglycemia).
  • Hyperglycemia is central to both the vascular consequences of diabetes and the progressive nature of the disease itself. Chronic hyperglycemia leads to decrease in insulin secretion and further to decrease in insulin sensitivity. As a result, the blood glucose concentration is increased, leading to diabetes, which is self-exacerbated. Chronic hyperglycemia has been shown to result in higher protein glycation, cell apoptosis and increased oxidative stress; leading to complications such as cardiovascular disease, stroke, nephropathy, retinopathy (leading to visual impairment or blindness), neuropathy, hypertension, dyslipidemia, premature atherosclerosis, diabetic foot ulcer and obesity. So, when a person suffers from diabetes, it becomes important to control the blood glucose level. Normalization of plasma glucose in type 2 diabetes patients improves insulin action and may offset the development of beta cell failure and diabetic complications in the advanced stages of the disease.
  • Diabetes is basically treated by diet and exercise therapies. However, when sufficient relief is not obtained by these therapies, medicament is prescribed alongwith.
  • Various anti-diabetic agents being currently used include biguanides (decrease glucose production in the liver and increase sensitivity to insulin), sulfonylureas and meglitinides (stimulate insulin production), a-glucosidase inhibitors (slow down starch absorption and glucose production) and thiazolidinediones (increase insulin sensitivity).
  • DPP-IV dipeptidyl peptidase-IV
  • GLP-1 glucagon like peptide- 1
  • GIP gastric inhibitory peptide
  • SGLTs sodium glucose co-transporters
  • SGLT-1 is a low capacity, high-affinity transporter expressed in the gut (small intestine epithelium), heart, and kidney (S3 segment of the renal proximal tubule), whereas SGLT-2 (a 672 amino acid protein containing 14 membrane-spanning segments), is a low affinity, high capacity glucose transporter, located mainly in the SI segment of the proximal tubule of the kidney.
  • SGLT-2 facilitates approximately 90% of glucose reabsorption and the rate of glucose filtration increases proportionally as the glycemic level increases.
  • the inhibition of SGLT-2 should be highly selective, because non-selective inhibition leads to complications such as severe, sometimes fatal diarrhea, dehydration, peripheral insulin resistance, hypoglycemia in CNS and an impaired glucose uptake in the intestine.
  • the first known non-selective SGLT-2 inhibitor was the natural product phlorizin
  • C-glycoside derivatives have been disclosed, for example, in PCT publications WO2004013118, WO2005085265, WO2006008038, WO2006034489, WO2006037537, WO2006010557, WO2006089872, WO2006002912, WO2006054629, WO2006064033, WO20071361 16, WO2007000445, WO2007093610, WO2008069327, WO200802001 1, WO2008013321, WO2008013277, WO2008122014, WO2008116195, WO2008042688, WO2009026537 and WO2010022313, US patents US6515117B2, US6936590B2 and US7202350B2 and Japanese patent application JP2004359630.
  • O-glycoside derivatives have been disclosed, for example, in PCT publications WO2002088157, WO2002064606, WO2003020737, WO2003000712, WO2004089966, WO2004058790, WO2004099230, WO2004087727, WO2005085267, WO2005095429, WO2005021566, WO200601 1469 and WO20071261 17 and US patents US6555519B2, US6683056B2, US6872706B2, US7056892B2, US7129381B2, US7189702B2, US7247616B2 and US7294618B2.
  • the compounds shown below are the SGLT-2 inhibitors which have reached advanced stages of human clinical trials: Bristol-Myers Squibb's "Dapagliflozin” with Formula A and Mitsubishi Tanabe and Johnson & Johnson's "Canagliflozin” with Formula B.
  • Various other compounds whose structures are not disclosed yet but are known to be in different phases of clinical trials are: Lexicon's Lx 421 1, Boehringer's BI 10773,
  • the present invention relates to the novel compounds of Formula I,
  • ring A represents aryl
  • ring B represents either aryl or heteroaryl
  • Y represents either O or S
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, Ci_i 2 alkyl, C 2 . ]2 alkenyl, C 2- i 2 alkynyl, C 2 _i 2 haloalkenyl, C 2 _i 2 haloalkynyl, Ci-i 2 alkoxy, Ci_ C]_i 2 alkylcarbonyl, Ci- 1 2 alkoxycarbonyl, C -2 ocycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n -cycloalkyl, cycloalkenyl, cycloalkynyl, -(CH 2 ) classroom-heterocyclyl, -(CH 2 ) n -aryl, -(CH 2 ) n -heteroary], - CN, -N0 2 , -NR 12 R 13 , -(CH2) n NR l2 R 13 ,
  • E can be absent or is selected from CH 2 , O, S or NR i6 ;
  • both R 5 and R 6 can not be hydrogen at the same time
  • both R 5 and R 6 can not be alkyl at the same time
  • R 5 and R 6 can not be a combination of hydrogen and alkyl at the same time
  • R 6 when E and G are absent and R 5 is hydrogen then R 6 can not represent -S(0) d R a (e) when R 7 represents C 2- i 2 alkenyl, C 2- i 2 alkynyl, -CH 2 OH or -(CH 2 ) n R e , wherein n is not equal to zero; one of R 5 and R 6 represents -H or Ci -6 alkyl and the other represents -S(0)dR a , wherein d represents 1 or 2; then R a can not be C ⁇ . 6alkyl, C 2 . 6 alkenyl, C 2-6 alkynyl, aryl or heteroaryl;
  • R 8 , R 9 , R 10 , R 12 , R 13 , R 14 and R 15 are independently selected from hydrogen, halogen, Cj . nalkyl, C 2- i 2 alkenyl, C 2 .i alkynyl, Ci_i 2 alkoxycarbonyl, C 3 .
  • R n is selected from hydrogen, halogen, Ci -]2 alkyl, C 2- i 2 alkenyl, C 2 _i 2 alkynyl, Ci_ i 2 haloalkyl, C 2 _i 2 haloalkenyl, C 2 _i 2 haloalkynyl, Ci_
  • i 2 alkyl C 2- i 2 alkenyl, C 2 .i 2 alkynyl, C 3-20 cycloalkyl, heterocyclyl, aryl, heteroaryl, , -CN, - N0 2 orNH 2 ;
  • R a , R b and R c are independently selected from hydrogen, halogen, C
  • n 0, 1, 2, 3, 4 or 5;
  • d is 1 or 2;
  • n 1, 2, 3, 4 or 5.
  • a further aspect of the present invention provides processes for the preparation of the novel compounds of Formula I, their pharmaceutically acceptable derivatives, tautomeric forms, isomers, polymorphs, prodrugs, metabolites, salts or solvates thereof.
  • compositions containing compounds of Formula I, their pharmaceutically acceptable derivatives, tautomeric forms, isomers, polymorphs, prodrugs, metabolites, salts or solvates thereof in combination with one or more pharmaceutically acceptable carrier(s), adjuvants and vehicles.
  • Another aspect of the present invention is the use of the compounds of Formula I, their pharmaceutically acceptable derivatives, tautomeric forms, isomers, polymorphs, prodrugs, metabolites, salts or solvates thereof, for the prophylaxis, amelioration and/or treatment of one or more condition(s)/disease(s)/ disorder(s), in a subject in need thereof.
  • Still another aspect of the present invention is the use of the compounds of Formula I, their pharmaceutically acceptable derivatives, tautomeric forms, isomers, polymorphs, prodrugs, metabolites, salts or solvates thereof, for the prophylaxis, amelioration and/or treatment of one or more condition(s)/disease(s)/ disorder(s) that may be regulated or normalized via inhibition of SGLT-2.
  • Yet another aspect of the invention is to provide methods of using the compounds of Formula I of the present invention or compositions comprising the compounds of Formula I for the prophylaxis, amelioration and/or treatment of disease(s)/ disorder(s) involving SGLT-2 inhibition which comprises administering to a subject in need thereof the compounds of Formula I or compositions comprising a pharmaceutically effective amount of the compounds of Formula I.
  • a further aspect of the present invention is the use of a compound of Formula I for the manufacture of a medicament for the prophylaxis, amelioration and/or treatment of one or more condition(s)/disease(s)/ disorder(s) involving SGLT-2 inhibition in a subject in need thereof.
  • the present invention also encompasses prodrugs and active metabolites of the compounds of the Formula I. 0796
  • the present invention relates to the novel compounds of Formula I,
  • ring A represents aryl
  • ring B represents either aryl or heteroaryl
  • Y represents either O or S
  • R 1 , R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, Ci_i 2 alkyl, C 2- i 2 alkenyl, C 2 _i 2 alkynyl, Ci-i 2 haloalkyl, C 2 -i 2 haloalkenyl, C 2 .i 2 haloalkynyl, Ci_i 2 alkoxy, C ⁇ . n haloalkoxy, Ci -6 alkoxyCi- 6 alkyl, C]- 6 alkoxyCi. 6 alkoxyCi.
  • E can be absent or is selected from CH 2 , O, S or NR 16 ;
  • both R 5 and R 6 can not be hydrogen at the same time
  • both R 5 and R 6 can not be alkyl at the same time
  • R 5 and R 6 can not be a combination of hydrogen and alkyl at the same time
  • R 7 represents Cu 2 alkyl, C 2- i 2 alkenyl, C 2- i 2 alkynyl, -CH 2 OH or -(CH 2 ) n R e , wherein n is not equal to zero; one of R 5 and R 6 represents -H or C 1-6 alkyl and the other represents -S(0) d R a , wherein d represents 1 or 2; then R a can not be Ci. 6alkyl, C 2- alkenyl, C 2-6 alkynyl, aryl or heteroaryl;
  • R 8 , R 9 , R 10 , R 12 , R 13 , R 14 and R 15 are independently selected from hydrogen, halogen, Q. i 2 alkyl, C 2- i 2 alkenyl, C 2- i 2 alkynyl, Ci -)2 alkylcarbonyl, Ci -)2 alkoxycarbonyl, C 3- 2 ocycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n -cycloalkyl, -(CH 2 ) n -heterocyclyl, - (CH 2 ) n -aryl, -(CH 2 ) n -heteroaryl, -CN, -N0 2, -NR a R b , -(CH 2 ) n NR a R b , -N 3 , -NCS, - (CH 2 ) complicatN 3 , -(CH 2 ) n NCS, -CR
  • R 1 1 is selected from hydrogen, halogen, Ci-i 2 alkyl, C 2 .i 2 alkenyl, C 2 -i 2 alkynyl, C
  • R a , R b and R c are independently selected from hydrogen, halogen, Ci-i 2 alkyl, C 2-12 alkenyl, C 2- i 2 alkynyl, Ci -12 alkoxy, Ci. 6 alkoxyCi -6 alkyl, Ci_i 2 alkylcarbonyl, Ci_i 2 alkoxycarbonyl, C 3-20 cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH 2 ) n -cycloalkyl, -(CH 2 ) n -heterocyclyl, -(-CH 2 ) n -aryl, -(CH 2 ) n -heteroaryl, -CN, -N0 2 , -N 3 , -NCS, -NR 8 R 9 , -(CH 2 ) n NR 8 R 9 , - (CH 2 ) 11 N 3 , -(CH 2 ) n NCS, -
  • n 0, 1, 2, 3, 4 or 5;
  • d is 1 or 2;
  • n 1, 2, 3, 4 or 5.
  • One embodiment of the present invention provides compounds of Formula la, wherein
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , U, V, W, E, G, ring A and ring B are as defined herein; their pharmaceutically acceptable derivatives, tautomeric forms, isomers, polymorphs, prodrugs, metabolites, salts or solvates thereof.
  • Another embodiment of the present invention provides compounds of Formula lb, wherein
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , E, G, ring A and ring B are as defined herein; their
  • Another embodiment of the present invention provides compounds of Fonnula Ic, wherein
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , E and G are as defined herein; their pharmaceutically acceptable derivatives, tautomeric forms, isomers, polymorphs, prodrugs, metabolites, salts or solvates thereof.
  • Another embodiment of the present invention provides compounds of Formula Id, wherein
  • R 5 , R 6 , R 7 , E and G are as defined herein; their pharmaceutically acceptable derivatives, tautomeric forms, isomers, polymorphs, prodrugs, metabolites, salts or solvates thereof.
  • E is selected from O or CH 2 .
  • G is C 1-12 alkylene which is unsubstituted or substituted at any available position by one or more substituents selected from R n .
  • R 7 is selected from the group consisting of -OCH3, -CH 2 OH, - CH 2 OCH 2 CF 3 , -CH 2 OCOCH 3 , -CH 2 OCOC 2 H 5 , -CH 2 OCOC 3 H 7 , -CH 2 OCOC 4 H 9 , - CH 2 OCO(CH 2 ) 5 CH 3 , -CH 2 OCO(CH 2 ) 7 CH 3 , -CH 2 OCO(CH 2 ) 10 CH 3 ,
  • R 5 and R 6 are independently selected from the group consisting of -H, -CH 3 , -S0 2 CH 3 ,
  • alkyl refers to a straight or branched chain aliphatic hydrocarbon chain, having from 1 to 12 carbon atoms.
  • alkyl include, but are not limited to methyl, ethyl, n-propyl, isoprppyl, n-butyl, n-pentyl, t-butyl and the like.
  • These groups may further be substituted with one or more substituents selected from but not limited to, for example, halogen, hydroxy, oxo, carboxy, carboxyalkyl, azido, cyano, amino, nitro, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl acyloxy, aryl, heterocyclyl or heteroaryl.
  • substituents selected from but not limited to, for example, halogen, hydroxy, oxo, carboxy, carboxyalkyl, azido, cyano, amino, nitro, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl acyloxy, aryl, heterocyclyl or heteroaryl.
  • alkenyl refers to a straight or branched chain aliphatic hydrocarbon group containing at least one carbon- carbon double bond, having from 2 to 12 carbon atoms.
  • alkenyl include, but are not limited to ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 1 -butenyl, 2-butenyl, and the like.
  • alkynyl refers to a straight or branched chain aliphatic hydrocarbon group containing at least one carbon- carbon triple bond, having from 2 to 12 carbon atoms.
  • alkynyl examples include, but are not limited to ethynyl, propynyl, and butynyl. These groups may further be substituted with one or more substituents selected from but not limited to, for example, halogen, hydroxy, oxo, carboxy, carboxyalkyl, azido, cyano, amino, nitro, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl acyloxy, aryl, heterocyclyl or heteroaryl.
  • alkylene refers to a divalent straight or branched chain aliphatic hydrocarbon group, having from 1 to 12 carbon atoms.
  • alkylene include, but are not limited to methylene, ethylene, isopropylene, n-butylene, 1 ,1 - dimethylethylene and the like. These groups may further be substituted with one or more substituents selected from but not limited to, for example, halogen, hydroxy, oxo, carboxy, carboxyalkyl, azido, cyano, amino, nitro, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl acyloxy, aryl, heterocyclyl or heteroaryl.
  • alkenylene refers to a divalent straight or branched chain aliphatic hydrocarbon group containing at least one carbon-carbon double bond, having from 2 to 12 carbon atoms.
  • alkenyl include, but are not limited to ethenylene, 1 -propenylene, 2-propenylene, iso-propenylene, 1 -butenylene, 2-butenylene, and the like.
  • These groups may further be substituted with one or more substituents selected from but not limited to, for example, halogen, hydroxy, oxo, carboxy, carboxyalkyl, azido, cyano, amino, nitro, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl acyloxy, aryl, heterocyclyl or heteroaryl.
  • substituents selected from but not limited to, for example, halogen, hydroxy, oxo, carboxy, carboxyalkyl, azido, cyano, amino, nitro, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl acyloxy, aryl, heterocyclyl or heteroaryl.
  • alkynylene refers to a divalent straight or branched chain aliphatic hydrocarbon group containing at least one carbon-carbon triple bond, having from 2 to 12 carbon atoms.
  • alkynyl include, but are not limited to ethynylene, propynylene, and butynylene. These groups may further be substituted with one or more substituents selected from but not limited to, for example, halogen, hydroxy, oxo, carboxy, carboxyalkyl, azido, cyano, amino, nitro, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl acyloxy, aryl, heterocyclyl or heteroaryl.
  • alkoxy refers to an above defined alkyl group attached via an oxygen linkage to the rest of the molecule. Non-limiting examples of such groups include -OCH 3 , -OC 2 3 ⁇ 4 and the like.
  • alkoxyalkyl refers to an above defined alkyl group, in which one or more hydrogen atoms are replaced by alkoxy group as defined herein. Non-limiting examples include -CH 2 OCH 3 , -CH 2 OC 2 H 5 , -CH 2 CH 2 OC 2 H 5 and the like.
  • alkoxyalkoxyalkyl refers to an above defined alkoxyalkyl group, in which one or more hydrogen atoms are replaced by above defined alkoxy group.
  • Non- limiting examples include -CH 2 OCH 2 OCH 3 , -CH 2 OCH 2 CH 2 OC 2 H 5 , CH 2 CH 2 OCH 2 OC 2 H 5 and the like.
  • alkyl carbonyl refers to an above defined alkyl group attached via a carbonyl linkage to the rest of the molecule.
  • Non-limiting examples of such groups include -C(0)CH 3 , -C(0)C 2 H 5 and the like.
  • alkoxycarbonyl refers to an above defined alkoxy group attached via a carbonyl linkage to the rest of the molecule.
  • Non-limiting examples of such groups include -C(0)-0 CH 3 , -C(0)-OC 2 H 5 , and the like.
  • halogen refers to F, CI, Br or I.
  • haloalkyl refers to an above-defined “alkyl” group, which is substituted with one or more "halogen” groups, as defined herein, at any one or more of the 1 to 12 carbon atoms of the alkyl group.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, fluoromethyl, trifluoromethyl, trichloromethyl, difluoroethyl, trifluoroethyl, dichloroethyl, and the like.
  • haloalkenyl refers to an above-defined “alkenyl” group, which is substituted with one or more "halogen” groups, as defined herein, at any one or more of the carbon atoms of the alkenyl group.
  • Representative examples of haloalkenyl include, but are not limited to, chloroethenyl, 2-fluroethenyl, triflurobutenyl, dichloropropenyl and the like.
  • haloalkynyl refers to an above-defined “alkynyl” group, which is substituted with one or more "halogen” groups, as defined herein, at any one or more of the carbon atoms of the alkynyl group.
  • Representative examples of haloalkynyl include, but are not limited to, 2-fluroethynyl, triflurobutynyl, dichloropropynyl and the like.
  • haloalkoxy refers to an above defined “haloalkyl” group, appended to the parent molecular moiety through an oxygen atom.
  • cycloalkyl refers to cyclic alkyl groups consisting of 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings, for example, fused or spiro systems, which may be partially unsaturated, unless otherwise constrained by the definition.
  • Such cycloalkyl groups include, by way of example, single ring structures, for example, cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexyl, cyclooctyl, and the like, or multiple ring structures, for example, adamantyl, and bicyclo[2.2.1] heptane, or cyclic alkyl groups to which is fused an aryl group, for example, indane and the like.
  • Cycloalkyl groups may further be substituted with one or more substituents selected from but not limited to, for example, halogen, hydroxy, oxo, carboxy, carboxyalkyl, azido, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl acyloxy, aryl, heterocyclyl or heteroaryl.
  • aryl refers to a mono- or poly- carbocyclic aromatic group, for example phenyl or naphthyl ring and the like optionally substituted with one or more substituents selected from but not limited to, for example, halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, amino, aryloxy, CF 3 , COOR d (wherein R d can be hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heterocyclylalkyl or heteroarylalkyl), cyano, nitro, carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl or heteroarylalkyl.
  • the aryl group may optionally be fused with cycloalkyl group, heteroaryl group, heterocyclyl group or another aryl group.
  • the fused group may be further substituted at any available position with one or more substituents selected from but not limited to, for example, halogen, hydroxy, oxo, carboxy, amino, nitro, cyano, carboxyalkyl, azido, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl, acyloxy, aryl or heterocyclyl, heteroaryl.
  • aryloxy refers to an above defined aryl group attached via an oxygen linkage to the rest of the molecule, for example -OPh and the like.
  • heteroaryl refers to an aromatic monocyclic or polycyclic ring structure, containing one or more heteroatoms independently selected from N, O, S or P.
  • Heteroaryl also includes, but is not limited to, bicyclic or tricyclic rings, wherein the heteroaryl ring is fused to one or two rings independently selected from the group consisting of an aryl ring, a cycloalkyl ring, a heterocyclyl ring and another monocyclic heteroaryl ring.
  • heteroaryl groups include, but not limited to, oxazolyl, imidazolyl, pyrrolyl, 1 ,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, ox_adiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, benzoxazolyl, imidazo[l,2-a]pyrimidine, imidazo[l ,2-a]pyrazine, and the like.
  • the bicyclic or tricyclic heteroaryl rings can be attached either through the heteroaryl group itself or the aryl, cycloalkyl or heterocyclyl group to which it is fused.
  • the heteroaryl group may be further substituted at any available position with one or more substituents selected from but not limited to, for example, halogen, hydroxy, oxo, carboxy, amino, nitro, cyano, carboxyalkyl, azido, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkynyl, acyl acyloxy, aryl, heterocyclyl or heteroaryl.
  • heterocyclyl refers to a non-aromatic monocyclic or polycyclic cycloalkyl group, for example, fused or spiro systems fully or partially unsaturated, containing one or more heteroatom(s) independently selected from N, O, S or P.
  • the nitrogen, sulphur and phosphorus heteroatoms may optionally be oxidized.
  • the nitrogen atoms may optionally be quaternerized.
  • the heterocyclyl ring may be fused with another cycloalkyl, aryl, heterocyclyl or heteroaryl ring and are optionally benzofused or fused heteroaryl of 5-6 ring members and/or are optionally substituted wherein the substituents are selected from but not limited to halogen, hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, aryl, alkoxy, aralkyl, cyano, nitro, amino, heterocyclyl, or heteroaryl.
  • heterocyclyl groups include but are not limited to, morpholinyl, oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, dihydropyridinyl, dihydroisooxazolyl, dihydrobenzofuryl, azabicyclohexyl, dihydroindonyl, piperidinyl or piperazinyl.
  • the fused group may be further substituted at any available position with one or more substituents selected from but not limited to, for example, halogen, hydroxy, oxo, carboxy, amino, nitro, cyano, carboxyalkyl, azido, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl acyloxy, aryl, heterocyclyl or heteroaryl.
  • substituents selected from but not limited to, for example, halogen, hydroxy, oxo, carboxy, amino, nitro, cyano, carboxyalkyl, azido, alkenyl, alkynyl, alkoxy, cycloalkyl, acyl acyloxy, aryl, heterocyclyl or heteroaryl.
  • hydroxy refers to the group -OH.
  • nitrogen, sulphur and phosphorus heteroatom can optionally be quaternerized or oxidized wherever possible.
  • Protecting Group refers to a group which is in a modified form to preclude undesired side reactions at the protected site.
  • protecting group may be used with groups, for example, hydroxy, amino, carboxy and examples of such groups are found in T.W. Greene, et al. "Protecting Groups in Organic Synthesis " 3 ld Ed, Wiley, New York, which is incorporated herein by reference.
  • the species of the carboxylic protecting groups, amino protecting groups or hydroxy protecting groups employed are not critical, as long as the derivatised moieties/moiety is/are stable to conditions of subsequent reactions and can be removed without disrupting the remainder of the molecule.
  • Suitable hydroxy and amino protecting groups include but are not limited to trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, f-butyldiphenylsilyl, i-butyldimethylsilyl, acetyl, trifluoroacetyl, benzyloxycarbonyl (CBz), t-butoxycarbonyl (Boc), 9-fluorenylnethylenoxycarbonyl (Fmoc), 2,2,2-trichloroethyloxycarbonyl, allyloxycarbonyl and the like.
  • carboxy protecting groups examples include benzhydryl, o-nitrobenzyl, -nitrobenzyl, 2- naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2- trichloroethyl, trimethylsilyl, t- butyldimethylsilyl, t-butyldiphenylsilyl, 2-(trimethylsilyl)ethyl, phenacyl, p- methoxybenzyl, acetonyl,/?-methoxyphenyl, 4-pyridylmethyl, -butyl and the like.
  • Subject includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle, horses, sheep and the like) or non-mammals (e.g., birds and the like).
  • non-human mammals e.g., dogs, cats, rabbits, cattle, horses, sheep and the like
  • non-mammals e.g., birds and the like
  • terapéuticaally effective amount means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity, weight, physical condition and responsiveness of the subject to be treated, among other factors. -.
  • a “pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • a “pharmaceutically acceptable salt” also encompasses any compound according to the present invention that is utilized in the form of a salt thereof.
  • Asymmetric centres may exist in the compounds of the present invention.
  • the compounds of Formula I may have one or more stereogenic centres and so can exhibit optical isomerism. All such isomers including enantiomers, diastereomers, and epimers are included within the scope of this invention.
  • the invention includes such compounds as single isomers (R and /or S) and as mixtures, including racemates. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated.
  • the separation may be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography.
  • Starting materials of particular stereochemistry may either be commercially available or may be made by the methods described herein and resolved by techniques well known in the art.
  • the independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modifications.
  • Certain compounds according to Formula I can also exist as tautomers, which have different points of attachment of hydrogen accompanied by one or more double bond shifts. These tautomers, either separately or as mixtures, are also considered to be within the scope of the invention.
  • Certain compounds according to Formula I may also exist as polymorphs.
  • the present invention also encompasses geometrical isomers of compounds of 5 Formula I and the mixtures thereof.
  • the geometrical isomers may exist in E or Z; Syn or anti configurations. These geometrical isomers, either separately or as mixtures, are also considered to be within the scope of the invention.
  • Particularly useful examples of the present invention include but are not limited to the compounds selected from Table 1, including their pharmaceutically acceptable 10 derivatives, tautomeric forms, isomers, polymorphs, prodrugs, metabolites, salts or solvates thereof:
  • the compounds disclosed herein may be prepared by techniques well known in the art and familiar to the skilled organic chemist.
  • the compounds of the present invention may be prepared by the following reaction sequences as depicted in for example Scheme No 1 to 5. All of the starting materials are either commercially available or can be prepared by procedures that would be well known to one of ordinary skill in organic chemistry.
  • Lg is used to denote an appropriate leaving group and as such may vary in nature depending on the exact reaction conditions employed. Some typical leaving groups may be fluoro, chloro, bromo, iodo, tosyl, mesyl, trifluoromethanesulfonyl and the like, but these should not be construed as limiting as many other leaving groups are also well known to those skilled in the art.
  • the compounds of the Formula I can be prepared from the compounds of Formula II following the steps provided in Scheme 2 or Scheme 3.
  • the compounds of the Formula II can be coupled with compounds of Formula III to obtain compounds of Formula IV.
  • the compounds of Formula III contain a N- protection group (PG) such as but not limited to ter -butoxycarbonyl, Fluorenyloxycarbonyl, Allyloxycarbonyl or Benzyloxycarbonyl etc. and a leaving group (Lg) for example but not limited to a halogen, triflate, mesylate, tosylate or boronate and the like.
  • PG N- protection group
  • Lg leaving group
  • the procedures to couple Formula II with Formula III include but not limited to, mitsunobu reaction involving reagents such as diethylazadicaorboxylate, diisopropylazadicarboxylate in presence of triphenylphosphene in a suitable solvent such as but not limited to THF, Dioxane, DCM and the like or catalytic reactions involving Pd, Cu etc metal derivatives in presence or absence of a ligand or procedures , involving treatment of Formula II with Formula III in presence of a base for example but not limited to NaH, KH, Cs 2 C0 , K 2 C0 3 , NEt 3 , pyridine and the like in a suitable solvent such as THF, Dioxane, DMF, DMSO, acetone, dichloroethane, DCM or combination there of.
  • a suitable solvent such as but not limited to THF, Dioxane, DMF, DMSO, acetone, dichloroethane, DCM or combination
  • the protection group from the compounds of Formula IV can be released by methods known to a person skilled in the art.
  • Such deprotection methods include but not limited to, treatment with acids such as trifluoro acetic acid, HCl, H2SO 4 , HBr, HI etc.in a suitable solvent like DCM, Dichloroethane, diethylether, diisopropylether, THF, dioxane, actonitrile etc. or combination there of.
  • Another type of deprotection methods include catalytic reductive methods involving Pd/C in presence of hydrogen in a suitable solvent such as but not limited to ethylacetate, methanol, acetic acid and the like or combination thereof.
  • the compounds of Formula IV after deprotection can be converted to Formula I by treatement with compounds of Formula R 6 -Lg in presence of bases such as, but not limited to triethylamine, N-ethyldiisopropylamine, pyridine and the like in suitable solvents such as DCM, dichloroethane, THF, acetonitrile or combination thereof.
  • bases such as, but not limited to triethylamine, N-ethyldiisopropylamine, pyridine and the like in suitable solvents such as DCM, dichloroethane, THF, acetonitrile or combination thereof.
  • the compounds of the Formula II, wherein Q represents particularly, - Ci-i2alkyl-OH can be reacted with reagents such as but not limited to, methanesulfonylchloride, p-toluenesulfonylchloride, trifuorosulfonicanhydride, thionylchloride, phosphorousoxychloride, carbontetrachloride, borontribromide, phosphoroustribromide, carbontetrabromide, iodine etc.
  • reagents such as but not limited to, methanesulfonylchloride, p-toluenesulfonylchloride, trifuorosulfonicanhydride, thionylchloride, phosphorousoxychloride, carbontetrachloride, borontribromide, phosphoroustribromide, carbontetrabromide, iodine etc.
  • the compounds of Formula V can be converted to compounds of Formula VI by treating with sodiumazide in solvents such as but not limited to DMF, DMSO etc.
  • the compounds of Formula VI can be converted to compounds of Formula VII by methods known to a person skilled in the art.
  • Such methods include but not limited to treatment with triphenylphosphene in solvent like THF in presence of water or reduction in hydrogen atmosphere in presence of Pd/C to afford compounds of Formula VII.
  • the compounds of Formula VII can be converted to Formula I by treatment with compounds of Formula R 6 -Lg in presence of bases such as, but not limited to triethylamine, JV-ethyldiisopropylamine, pyridine etc. in suitable solvents like DCM, dichloroethane, THF, acetonitrile or combination thereof.
  • the compounds of the Formula II can be prepared from Formula VIII and compounds of Formula IX by following Scheme 4.
  • Formula IX can be prepared by following the procedure given in NUCLEOSIDE, NUCLOETIDES & NUCLEIC ACIDS, 20(4-7), 649-652 (2001).
  • the compounds of Formula VIII can be reacted with metalated species generated by treating Formula IX (prepared according to the procedure given in US20070049537) with reagents such as but not limited to, "BuLi, 'BuLi or 'PrMgCl in presence or absence of LiCl etc. in a suitable solvent such as but not limited to, THF, diiethylether or combination thereof to obtain the compounds of Formula X.
  • the compounds of Formula X can be converted to the compounds of Formula II by deprotection methods kown to a person skilled in the art. These deprotection methods include but not limited to, treatment with acids such as trifluoro acetic acid, HC1, H 2 S0 4, HBr, HI etc.in a suitable solvent like DCM, Dichloroethane, diethylether, diisopropylether, THF, dioxane, actonitrile etc. or combination there of. eme 5
  • acids such as trifluoro acetic acid, HC1, H 2 S0 4, HBr, HI etc.in a suitable solvent like DCM, Dichloroethane, diethylether, diisopropylether, THF, dioxane, actonitrile etc. or combination there of. eme 5
  • Q-PG is -OPG, -SPG, -N(PG) 16 , -C ⁇ alkyl-OPG
  • Q-PG is -OPG, -SPG, -N(PG)R 16 , -C-,. 12 alkyl-OPG
  • Formula XI can be prepared by following the procedure given in US20070049537.
  • Formula XI can be reacted with metalated species generated by treating Formula IX (prepared according to the procedure given in US20070049537) with reagents such as but not limited to, "BuLi, 'BuLi or 'PrMgCl in presence or absence of LiCl and the like in a suitable solvent such as but not limited to, THF, diiethylether or combination thereof.
  • a suitable acetal formation reaction for example but not limited to, treatment with methanesulfonicacid in presence of methanol to obtain compounds of Formula XII.
  • the compounds of Formula XII can be reduced by treating with triethylsilane in presence of borotri fluoride etherate in acetonitrile to furnish the compounds of Formula XIII.
  • the compounds of Formula XIII can be converted to the compounds of Formula II by deprotection methods kown to a person skilled in the art. These deprotection methods include but not limited to, treatment with acids such as trifluoro acetic acid, HC1, H 2 S0 4j HBr, HI and the like in a suitable solvent like DCM, Dichloroethane, diethylether, diisopropylether, THF, dioxane, actonitrile and the like or combination there of.
  • compounds of Formula XIII can be converted to compounds of Formula II by deprotection reactions involving reagents such as but not limited to tetrabutylammoniumfluoride or Hydrogenfluoride in solvents such as DCM, dichloroethane, THF, dioxane or pyridine and the like.
  • reagents such as but not limited to tetrabutylammoniumfluoride or Hydrogenfluoride in solvents such as DCM, dichloroethane, THF, dioxane or pyridine and the like.
  • references to the compounds of structural Formula I are meant to also include the pharmaceutically acceptable salts, and also salts that are not pharmaceutically acceptable when they are used as precursors to the free compounds or their pharmaceutically acceptable salts or in other synthetic manipulations.
  • the compounds of the present invention may be administered in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. The salts may be prepared during the final isolation and purification of the compounds or separately by making basic or acidic addition salts.
  • Representative salts of basic compounds of the present invention can be prepared by reacting free base form of the compound with a suitable acid, including, but not limited to acetate, trifluoroacetate, adipate, citrate, aspartate, benzoate, benzenesulphonate, bisulfate, besylate, butyrate, camphorsulphonate, difluconate, hemisulfate, heptanoate, formate, fumarate, lactate, maleate, methanesulfonate, naphthylsulfonate, nicotinate, oxalate, picrate, pivalate, succinate, tartrate, tirchloracetat, glutamate, >-toluenesulphonate, hydrochloric, hydrobromic, sulphuric, phosphoric and the like.
  • a suitable acid including, but not limited to acetate, trifluoroacetate, adipate, citrate, aspartate, benzoate, benz
  • Representative salts of acidic compounds of the present invention can be prepared by reacting free acid form of the compound with a suitable base, including, but not limited to ammonium, calcium, magnesium, potassium, sodium salts, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring ones e.g., arginine, betaine, caffeine, choline, glucamine, glucosamine, histidine, lysine, morpholine, piperazine, piperidine, purine, triethylamine and the like.
  • a suitable base including, but not limited to ammonium, calcium, magnesium, potassium, sodium salts, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring ones e.g., arginine, betaine, caffeine, choline, glucamine, glucosamine, histidine, lysine, morpholine, piperazine, piperidine, purine, triethylamine and
  • solvates refer to solvates with water (i.e., hydrates) or pharmaceutically acceptable solvents, for example, ethanol and the like.
  • prodrugs of the compounds of the present invention which upon in-vivo administration undergo cleavage by metabolic processes before becoming active pharmacological substances.
  • prodrugs are derivatives of functional group of a compound of the invention which are readily convertible in vivo into the compound of the invention.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Targeted prodrug design to optimize drug delivery", AAPS PharmaSci (2000), 2(1), E6.
  • the invention also encompasses active "metabolites" of the compound of the present invention.
  • An active metabolite is an active derivative of a SGLT-2 inhibitor produced when the SGLT-2 inhibitor is metabolized.
  • polymorphs of a compound of general Formula I forming part of this invention may be prepared by crystallization of a compound of Formula I under different conditions. For example, by using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations, heating or melting the compound followed by gradual or fast cooling may also obtain polymorphs. The presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other techniques.
  • the present invention includes all pharmaceutically acceptable isotopically- labeled compounds of Formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the present invention comprises isotopes of hydrogen, such as 2 H and 3 H, carbon, such as "C, 13 C and l4 C, chlorine, such as 36 C1, fluorine, such as F, iodine, such as I and I, nitrogen, such as N and N, oxygen, such as O,
  • Isotopically- labeled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples and schemes using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • the present invention also includes all the intermediate complexes of the compounds of Formula I, which are active by themselves or can be readily converted to compounds having inhibitory effect on sodium-dependent glucose cotransporter (SGLT), preferably SGLT-2.
  • SGLT sodium-dependent glucose cotransporter
  • the present invention also provides pharmaceutical compositions, comprising compounds of general Formula I or their pharmaceutically acceptable analogs, derivatives, tautomeric forms, isomers, polymorphs, prodrugs, metabolites, salts or solvates thereof together with one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compound into preparations, which can be used pharmaceutically.
  • compositions may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions, emulsions, pills, granules, suppositories, pellets, depot formulations and the like, may contain flavourants, sweeteners etc in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • Such compositions typically contain from 0.1 to 99.9 % by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents.
  • compositions of the present invention can be manufactured by the processes well known in the art, for example, by means of conventional mixing, dissolving, dry granulation, wet granulation, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilizing processes or spray drying.
  • the compounds or the pharmaceutical compositions comprising such compounds of the present invention may be administered in the form of any pharmaceutical formulation.
  • the pharmaceutical formulation will depend upon the nature of the active compound and its route of administration.
  • any route of administration may be used, for example oral, buccal, pulmonary, topical, parenteral (including subcutaneous, intramuscular and intravenous), transdermal, ocular (ophthalmic), by inhalation, intranasal, transmucosal, implant or rectal administration.
  • parenteral including subcutaneous, intramuscular and intravenous
  • transdermal ocular
  • ocular ophthalmic
  • the compounds of the present invention are administered orally, parenterally or topically.
  • the amount of the novel compounds having the Formula I according to the present invention to be incorporated into the pharmaceutical compositions of the present invention can vary over a wide range depending on known factors such as, for example, the disorder to be treated, the severity of the disorder, the patient's body weight, the dosage form, the chosen route of administration and the number of administration per day.
  • the amount of the compound of Formula I in the pharmaceutical compositions of the present invention will range from approximately 0.01 mg to about 5000 mg.
  • the daily dose of composition comprising the novel compounds having the Formula I is in the range of about 0.01 mg/kg to about 100 mg/kg based on the body weight of the subject in need thereof which may be administered as a single or multiple doses.
  • novel compounds having the Formula I according to the present invention are particularly useful for the treatment of disease(s) or disorder(s), which are chronic or acute in nature, which favorably respond to or are alleviated by the novel compounds having the Formula I or compositions comprising them.
  • the compositions comprising the novel compounds having the Formula I are useful prophylactically or therapeutically depending upon the pathological condition intended to be prevented or treated respectively.
  • compounds of the present invention are useful in the prophylaxis, amelioration and/or treatment of one or more condition(s)/disease(s)/ disorder(s), in a subject in need thereof.
  • compounds of the present invention are useful in the prophylaxis, amelioration and/or treatment of one or more condition(s)/disease(s)/ disorder(s), which may be regulated or normalized via inhibition of Sodium Glucose Cotransporters (SGLT).
  • SGLT Sodium Glucose Cotransporters
  • the compounds of the present invention possess activity as selective inhibitors of SGLT-2 and are therefore useful for the prophylaxis, amelioration and/or treatment of variety of diseases, disorders and conditions, including, but not limited to, diabetes (including Type I and Type II), Metabolic Syndrome or 'Syndrome X' including impaired glucose tolerance, insulin resistance, metabolic acidosis or ketosis, disorders of food intake, satiety disorders, obesity, hyperinsulinemia, dyslipidemia (including hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL levels, high LDL levels), hypertension associated with metabolic disorders, congestive heart failure, edema, hyperuricemia, gout, wound healing and tissue ischemia.
  • diabetes including Type I and Type II
  • Metabolic Syndrome or 'Syndrome X' including impaired glucose tolerance, insulin resistance, metabolic acidosis or ketosis, disorders of food intake, satiety disorders, obesity, hyperinsulinemia, dyslipidemia (including hyperlipidemia, hypertriglycerid
  • the compounds of the present invention can also be used for the prophylaxis, amelioration and/or treatment of the diseases, disorders and conditions collectively referenced to as "diabetic complications” which include both acute complications and chronic complications.
  • disorders and conditions collectively referenced to as "diabetic complications” which include both acute complications and chronic complications.
  • acute complications include hyperglycemia (e.g., ketoacidosis), infections (e.g., skin, soft tissue, biliary system, respiratory system and urinary tract infections), etc.
  • chronic complications include microangiopathy (e.g., nephropathy, retinopathy), arteriosclerosis (e.g., atherosclerosis, heart infarction, brian infarction, lower extremity arterial occlusion), neuropathy (e.g, sensory nerves, motor nerves, autonomic nerves), foot gangrene, etc.
  • Major diabetic complications include diabetic retinopathy, diabetic nephropathy and diabetic neuropathy.
  • I for the manufacture of a medicament for the prophylaxis, amelioration and/or treatment of one or more condition(s)/ disease(s)/ disorder(s) involving SGLT-2 inhibition in a subject in need thereof.
  • Another embodiment of the present invention provides methods for the prophylaxis, amelioration and/or treatment of one or more condition(s)/ disease(s)/ disorder(s) involving SGLT-2 inhibition in a subject in need thereof that comprises administering a therapeutically effective amount of compound of Formula I.
  • compositions comprising the novel compounds of Formula I for the treatment of one or more condition(s)/ disease(s)/ disorder(s) involving SGLT-2 inhibition which comprises administrating to a subject in need thereof a pharmaceutically effective amount of the composition.
  • An embodiment of the present invention relates to methods of using the compounds of Formula I of the present invention or compositions comprising the compounds of Formula I for the prophylaxis, amelioration and/or treatment of any one or more condition(s)/ disease(s)/ disorder(s), which comprises administering to a subject in need thereof the compounds of Formula I or compositions comprising a pharmaceutically effective amount of the compounds of Formula I.
  • the compounds or their pharmaceutically acceptable salts according to the present invention are useful in the treatment of the aforementioned diseases, disorders and conditions in combination with at least one other therapeutic agent.
  • the compounds of the present invention may be used in combination with one or more other therapeutic agents in the treatment, prevention, suppression or amelioration of diseases or conditions for which compounds of the present invention or other therapeutic agents may have utility, where the combination of drugs together are safer or more effective than either drug alone.
  • therapeutic agents suitable for combination with the compounds of the present invention include, but are not limited to, known therapeutic agents useful in the treatment of the aforementioned disorders including: anti-diabetic agents; agents for prevention of complications of diabetes; anti-hyperglycemic agents; hypolipidemic/ lipid lowering agents; anti-obesity agents; anti-hypertensive agents, anti-platelet agents, anti- atherosclerotic agents, an ti -inflammatory agents, uricosuric agents, anti-TNF agent or c- AMP raising agents and appetite suppressants.
  • the use of the compounds of the present invention in combination with atleast one or more of the aforementioned other therapeutic agents may provide results greater than that possible from each of these medicaments alone or greater than the combined additive effects produced by these medicaments.
  • the present compounds and the other therapeutic agents may be administered in the same dosage form or in a separate dosage form by same or different administration route, in dosages and regimens as generally known in the art. Those agents which potentiate the therapeutic effect of SGLT- 2 inhibitors according to the invention may allow the dosage to be reduced.
  • Suitable anti-diabetic agents for use in combination with the compounds of the present invention include but are not limited to (a) other SGLT-2 inhibitors; (b) insulin sensitizers including (i) PPAR ⁇ agonists such as thiozolidinediones or glitazones (e.g.
  • PPAR ⁇ agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), PPARpan agonists, PPAR ⁇ / ⁇ agonists, PPAR ⁇ / ⁇ dual agonists, PPAR ⁇ / ⁇ dual agonists, PPAR ⁇ antagonists, PPAR ⁇ / ⁇ modulators and PPAR ⁇ / ⁇ / ⁇ modulators, (ii) biguanides such as metformin and phenformin, and (iii) protein tyrosine phosphatase- IB (PTP-IB) inhibitors; (c) insulin or insulin mimetics; (d) sulfonylureas and other insulin secretagogues, such as tolbutamide, chlorpropamide, tolazamide, glyburide (glibenclam), sulfonylureas and other insulin secretagogues, such as tolbutamide,
  • suitable agents to be used in combination with the compounds of the present invention, for treatment or prevention of complications of diabetes include but are not limited to GABA-receptor antagonists, Na-channel blockers (e.g. mexiletine hydrochloride, oxacarbazepine or the like), ⁇ -aminobutyric acid receptor antagonists (e.g. topiramat or the like), protein-kinase C inhibitors (e.g. midostaurin or the like), advanced glycation end product inhibitors (e.g. pyridoxamine or the like), transcript factor NF-KB inhibitors (e.g. dexlipotam or the like), lipid peroxide inhibitors (e.g.
  • tirilazad mesylate or the like a-linked-acid-dipeptidase inhibitors, carnitine derivatives (e.g. levacecamine, levocarnitine or the like), insulin like growth factor-I, platelet-derived growth factor, platelet-derived growth factor analogues, epidermal growth factor, nerve growth factor, biclomol, sulodexide or aldose reductase inhibitors (e.g. ascorbyl gamolenate, tolrestat, epalrestat or the like).
  • carnitine derivatives e.g. levacecamine, levocarnitine or the like
  • insulin like growth factor-I e.g. levacecamine, levocarnitine or the like
  • platelet-derived growth factor platelet-derived growth factor analogues
  • epidermal growth factor e.g. ascorbyl gamolenate, tolrestat, epalrestat or the like
  • aldose reductase inhibitors e
  • Suitable hypolipidemic/ lipid lowering agents include but are not limited to (a) cholesterol lowering agents such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, pravastatin, cerivastatin, fluvastatin, atorvastatin, itavastatin, and rosuvastatin, and other statins), (ii) bile acid sequestrants (cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) nicotinyl alcohol, nicotinic acid or a salt thereof, (iv) PPAR agonists as described herein, (v) inhibitors of cholesterol absorption, such as beta-sitosterol and ezetimibe, (vi) acyl CoA cholesterol acyltransferase inhibitors, such as avasimibe, and (vii) anti-oxide inhibitors (i) lovastatin
  • fibrates e.g. bezafibrate, fenofibrate, gemfibrozil, clofibrate, ciprofibrate, clinofibrate or the like); (g) MTP inhibitors; (h) squalene synthetase inhibitors and squalene epoxidase inhibitors; (i) upregulators of LDL receptor activity; (j) serum cholesterol lowering agents; (k) thyroid hormone receptor agonists (sodium liothyronine, sodium levothyroxine or the like); (1) carnitine palmitoyltransferase inhibitors (etomoxir or the like); (m) probcol and microsomal triglyceride transfer protein inhibitors.
  • MTP inhibitors e.g. bezafibrate, fenofibrate, gemfibrozil, clofibrate, ciprofibrate, clinofibrate or the like
  • Suitable anti-obesity compounds include but are not limited to (a) fenfluramine, dexfenfluramine, phenteimine, tetrahydrolipostatin, and the like; (b) neuropeptide Yi or Y 5 antagonists; (c) CB-1 receptor inverse agonists and antagonists; (d) ⁇ 3 adrenergic receptor agonists; (e) melanocortin receptor agonists, in particular melanocortin-4 receptor agonists; (f) ghrelin antagonists; (g) melanin-concentrating hormone (MCH) receptor antagonists; (h) lipase inhibitors like orlistat; (i) serotonin (and dopamine) reuptake inhibitors like sibutramine, topiramate or axokine; (j) thyroid hormone receptor beta drugs; (k) anorectic agents like dexamphetamine, phentermine or mazindol;
  • Suitable appetite suppressants for use in combination with the compounds of the present invention include but are not limited to (a) monoamine reuptake inhibitors; (b) dopamine agonists; (c) leptin analogues; (d) ot-melanocyte stimulating hormone; (e) enterostatin agonists; (f) CCK-A agonists; (g) corticotropin releasing hormone; (h) somatostatin; (i) brain-derived neurotrophic factor; (j) orexin receptor agonists.
  • Suitable anti-hypertensive agents include but are not limited to (a) vasopeptidase inhibitors like Neutral endopeptidase (neprilysin) inhibitors and/or ACE (angiotensin- converting enzyme) inhibitors or dual NEP/ACE inhibitors (enalapril, lisinopril, captopril, quinapril, trandolapril, fosinpril, benazepril, ramipril, enalaprilat, moexipril or perindopril and the like) and/or PKC inhibitors; (b) beta blockers (like metoprolol, propranolol, atenolol, carvedilol or sotalol) and calcium channel blockers (like amlodipine, diltiazem, nifedipine, verapamil or nicardipine ); (c) Angiopeptidase inhibitors like Neutral endo
  • Suitable anti-inflammatory agents for use in combination with the compounds of the present invention include but are not limited to aspirin, non-steroidal anti-inflammatory drugs, glucocorticoids, azulfidine, and selective cyclooxygenase-2 inhibitors.
  • Suitable agents to be used in combination with the compounds of the present invention, for the treatment or prevention of hyperuricemia or gout include but are not limited to (a) uric acid synthesis inhibitors e.g. allopurinol, oxypurinol or the like; (b) uricosuric agents e.g. benzbromarone, probenecid or the like; (c) urinary alkaiiizers e.g. sodium hydrogen carbonate, potassium citrate or the like.
  • Step 1 Preparation of ((3fl5',5 1 S',6 ⁇ ,6a 1 S -6-((/ert-butyldimethylsilyl)oxy)-2,2-dimethyl tetrahydrofuro[2,3- ⁇ ][l,3]dioxol-5-yl)(3-(4-((tert-butyldirnethylsilyl)oxy)benzyl)-4- chlorophenyl)methanol
  • reaction mixture was quenched by the addition of saturated NH 4 C1 solution and extracted with ethyl acetate (3 x 300 mL). The combined organic layers were dried over Na 2 S0 4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 1 :49 acetone: Pet. Ether) to afford the title compound (3.66 g, 25%)
  • Step 2 Preparation of (35,4i?,55,65)-6-(3-(4-acetoxybenzyl)-4-chlorophenyl)tetrahydro- 2H-pyran-2,3,4,5-tetrayl tetraacetate
  • Step 3 Preparation of (25',35',4 J R,55,65)-2-bromo-6-(4-chloro-3-(4-hydroxybenzyl) phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
  • Step 4 Preparation of (25,3 1 S,4 J R,55,65 -2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6- methoxytetrahydro-2H-pyran-3 ,4, 5 -triyl triacetate
  • Step 5 Preparation of (2S, S, 4R,5S,6S)-2- (3-(4-(2-((ter/-butoxycarbonyl) amino) ethoxy) benzyl)-4-chlorophenyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate
  • (2S, S, 4R,5S,6S)-2- (3-(4-(2-((ter/-butoxycarbonyl) amino) ethoxy) benzyl)-4-chlorophenyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate To a solution of (25,35,4i?,55,65)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6- methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (1.1 g, 2.35 mmol) in dry DMF (10 mL),
  • Step 6 Preparation of (2-5',35,4 ?,55 , ,6 l S)-2-(3-(4-(2-((fert-butoxycarbonyl)amino) ethoxy)benzyl)-4-chlorophenyl) -6-methoxytetrahydro-2H-pyran-3 ,4,5-triyl triacetate
  • Step 7 Preparation of (2 1 S',35,4i?,55,65)-2-(4-chloro-3-(4-(2-(methylsulfonamido) ethoxy)benzyl)phenyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate
  • Step 8 Preparation of N-(2-(4-(2-chloro-5-((25,3i?,4 ?,55,65)-3,4,5-trihydroxy-6- methoxytetrahydro-2H-pyran-2-yl)benzyl)phenoxy)ethyl)methanesulfonamide
  • reaction mixture was evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 1 : 15 MeOH: DCM) to afford title compound (60 mg, 59%) as off-white solid.
  • Step 2 Preparation of N-(2-(4-(2-chloro-5-((25,37?,4 ?,55,65)-3,4,5-trihydroxy-6- methoxytetrahydro-2H-pyran-2-yl)benzyl)phenoxy)ethyl)sulfamide
  • Step 1 Preparation of (25,3i?,45,55,6/?)-2-(3-(4-((1 ⁇ 2ri-butyldimethylsilyl)oxy)benzyl)-4- chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol
  • Step 2 Preparation of (2S,3/?,45,5R,6R)-6-(acetoxymethyl)-2-(3-(4-((ieri- butyldimethylsilyl) oxy)benzyl)-4-chlorophenyl)-2-methoxytetrahydro-2H-pyran-3,4,5- triyl triacetate
  • Step 3 Preparation of (2i?,3 J R,4i?,55,65)-2-(Acetoxymethyl)-6-(4-chloro-3-(4- hydroxybenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
  • Step 5 Preparation of (2/?,3/?,47?,55,65)-2-(acetoxymethyl)-6-(3-(4-(2-((tert- butoxycarbonyl) amino)ethoxy)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3 ,4,5-triyl triacetate
  • Step 6 Preparation of (2 ?,3i?,4/?,55 , ,65)-2-(acetoxymethyl)-6-(3-(4-(2- aminoethoxy)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3 ,4,5-triyl triacetate 2,2,2- trifiuoroacetate
  • Step 7 Preparation of (2 ⁇ ,37?,4 J /?,5 ⁇ ,6 , )-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2 (sulfamoylamino)ethoxy)benzyl) phenyl)tetrahydro-2H-pyran-3 ,4,5-triyl triacetate
  • Step 8 Preparation of (25,3i?,4i?,55,6i?)-2-(3-(4-(2-(sulfamoylamino)ethoxy)benzyl)-4- chlorophenyl)-tetrahydro-6-(hydroxymethyl)-2H-pyran-3 ,4,5-triol
  • Step 3 Preparation of (2i3 ⁇ 4,3 ⁇ ,4 ⁇ ,5S,6S)-2-(acetox methyl)-6-(3-(4-(3-((tert- butoxycarbonyl) amino)propoxy)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
  • Step 4 Preparation of (2 ?,3i?,4 ?,55,65)-2-(acetoxymethyl)-6-(3-(4-(3- aminopropoxy)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate 2,2,2- trifluoroacetate
  • Step 6 Preparation of (25',3/?,4i?,55,6 ?)-2-(3-(4-(3-(sulfamoylamino)propoxy)benzyl)-4- chlorophenyl)-tetrahydro-6-(hydroxymethyl)-2H-pyran-3,4,5-triol
  • Step 1 Preparation of (2i?,3i?,4i?,55,65)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(3- (cyclohexanesulfonamido) propoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
  • Step 2 Preparation of N-(3-(4-(2-chloro-5-((25,3 ?,4i?,55,6i?)-3,4,5-trihydroxy-6-
  • Step 1 Preparation of (2/?,3 ⁇ ,4 ⁇ ,55,65)-2-(3 ⁇ 6 ⁇ 1)-6-(4- ⁇ 1 ⁇ 1 ⁇ -3-(4-(2-)
  • reaction mixture was diluted with DCM (50 mL) and given water washings (2 x 10 mL). The organic layer was dried over anhydrous Na 2 S0 4 . Volatiles were evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 2.5:97.5 MeOH: DCM) to afford title compound as a white solid (180 mg 3 ⁇ 4 57.01%).
  • Step 2 Preparation of JV-(2-(4-(2-chloro-5-((2,S,3i?,4 J R,55,6 J R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)ethyl)- , J P- dimethylphosphinic amide
  • reaction mixture was evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 1 :10 MeOH: DCM) to afford title compound (92mg, 72.5%) as off-white solid.
  • Step 3 Preparation of dimethyl (3-(4-(2-chloro-5-((25,37i,4/?,55,6 ?)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)propyl)phosphoramidate
  • reaction mixture was stirred at the same temperature and progress of the reaction was monitored by TLC. On completion, the resulting mixture was evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 1 :9 MeOH: DCM) to provide title compound (100 mg, 35 %) as off white solid.
  • Step 4.1 To a solution of l-(2-(Allyloxy)ethyl)-4-bromobenzene (1 g, 4.14 mmol) in dry
  • Step 4.2 To a solution of (4-(2-(Allyloxy)ethyl)phenyl)(5-bromo-2- chlorophenyl)methanol (5.1 g, 13.36 mmol) in acetonitrile (40 mL) triethylsilane (6.82 mL, 42.75 mmol) was added at 10°C followed by the addition of boranetrifluoroetherate (3.35 mL, 26.72 mmol). The resulting mixture was stirred at r.t. for 4 h.
  • Step 5.1 To a solution of 2-(4-(2-(allyloxy)ethyl)benzyl)-4-bromo-l-chlorobenzene (300 mg, 0.818 mmol) in dry THF (5 mL), "BuLi (0.82 mL, 1.23 mmol, 1.5 M in hexane) was added at -78 °C and allowed to stir for 5 min.
  • Step 5.2 To a solution of (25,3i?,45,55,6 ?)-2-(3-(4-(2-(allyloxy)ethyl)benzyl)-4- chlorophenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (3.86 g, 8.05 mmol) in dry THF (42 mL), diisopropylethylamine (10.29 mL, 59.07 mmol), 4- •dimethylaminopyridine (354 mg, 2.89 mmol) were added. Acetic anhydride (4.94 mL, 52.32 mmol) was added to the resulting solution at 0 °C.
  • Step 6 Preparation of (2i?,3i?,4i?,5S,6S)-2-(acetoxymethyl)-6-(3-(4-(2- (allyloxy)ethyl)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
  • Step 7 Preparation of (2i?,3i?,4/?,5 1 S,65 -2-(acetoxymethyl)-6-(4-chloro-3-(4-(2- hydroxyethyl)benzyl)phenyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate
  • Step 8 Preparation of (2 ?,3R,4R,5S,6S)-2-(acetox methyl)-6-(4-chloro-3-(4-(2- ⁇ ((methylsulfonyl)oxy)ethyl)benzyl)phenyl)tetrahydro-2H-pyran-3 ,4,5 -triyl triacetate
  • reaction mixture was diluted with DCM (20 mL), washed with water (10 mL) and brine (10 mL) successively. The organic layer was dried over anhydrous Na 2 S0 4 and the volatiles were evaporated in vacuo to afford the title compound which was used as such in further steps.
  • Step 10 Preparation of (2i?,3i?,4 ,5S,6S)-2-(acetoxymethyl)-6-(3-(4-(2- aminoethyl)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
  • Step 11 Preparation of (2 ⁇ ,3 ⁇ ,4 ⁇ ,5- , ,65 , )-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2- (sulfamoylamino)ethyl)benzyl)phenyl) tetrahydro-2H-pyran-3 ,4,5-triyl triacetate
  • Step 1 Preparation of (2 ?,3/?,4 ⁇ ,55,65)-2-(acetoxymethyl)-6-(3-(4-(2- aminoethoxy)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
  • reaction mixture was diluted with ethyl acetate (20 mL), washed with 5 % HC1 (2 x 10 mL), water (10 mL) and brine (10 mL) successively.
  • the organic layer was dried over anhydrous Na 2 S0 4 and the volatiles were evaporated in vacuo.
  • the residue obtained was purified by column chromatography (silica gel, 3:7 ethylacetate: Pet. ether) to provide the title compound (80 mg, 65.5 %) as white solid.
  • Step 3 Preparation of N-(2-(4-(2-chloro-5-((25,3i?,4i?,55,6i?)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)ethyl)pyrrolidine-l- sulfonamide
  • Step 1 Preparation of ((2i?,35,4i?,5 J R,65)-6-(4-chloro-3-(4-(2-(sulfamoylamino)ethoxy) benzyl)phenyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl 4- methylbenzenesulfonate
  • reaction mixture was diluted with ethyl acetate (50 mL), washed with 5% HCl (2 x 20 mL), water (20 mL) and brine (20 mL) successively.
  • the organic layer was dried over anhydrous Na 2 S0 and the volatiles were evaporated in vacuo.
  • the residue obtained was purified by column chromatography (silica gel, 1 :4 MeOH: DCM) to provide the title compound (605 mg, 73 %) as white solid.
  • Step 2 Preparation of ((2 J R,35,4i?,5i?,65)-6-(4-chloro-3-(4-(2-(sulfamoylamino) ethoxy)benzyl)phenyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methylazide
  • Step 3 Preparation of ((2/?,35',4i?,5i?,65)-6-(4-chloro-3-(4-(2-(sulfamoylamino)ethoxy) benzyl)phenyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methylamine
  • ((2i?,35,4i?,5 ?,6 l S)-6-(4-cliloro-3-(4-(2-(sulfamoylamino)ethoxy) benzyl) phenyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methylazide 440 mg, 0.833 mmol
  • triphenylphosphine 328 mg, 1.24 mmol
  • Step 4 Preparation of (25,3i?,4i?,55,6i?)-2-(3-(4-(2-(sulfamoylamino)ethoxy)benzyl)-4- chlorophenyl)-tetrahydro-6-((3-cyclobutyl ureido) methyl)-2H-pyran-3,4,5-triol
  • Step 4.1 To a solution of cyclobutylamine (200 mg, 2.81 mmol) in dry DCM (14 mL), carbonyldiimidazole (755 mg, 4.21 mmol) was added at 0 °C. The resulting mixture was stirred at r.t. for 2h. Reaction mixture was diluted with DCM (25 mL) and washed with water (20 mL) and brine (20 mL) successively. Organic layer was dried over anhydrous Na 2 S0 4 and the volatiles were evaporated in vacuo to obtain N-cyclobutyl-lH-imidazoIe- 1 -carboxamide as crude mixture. This was used as such in the next step.
  • Step 4.2 To a solution of ((2i?,35',4 J R,5/?,6 1 S)-6-(4-chloro-3-(4-(2-(sulfamoylamino)ethoxy) benzyl )phenyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methylamine (120 mg, 0.24 mmol) in dry THF (1.15 mL), N-cyclobutyl-lH-imidazole-1 -carboxamide (39.4 mg, 0.24 mmol) was added at r.t. The resulting mixture was stirred at r.t. for 16 h and the reaction was monitored by TLC.
  • reaction mixture was diluted with ethyl acetate (20 mL), washed with water (10 mL) and brine (10 mL) successively.
  • the organic layer was dried over anhydrous Na 2 S0 4 and the volatiles were evaporated in vacuo.
  • the residue obtained was purified by column chromatography (silica gel, 1 :9 MeOH: DCM) to provide the title compound (130 mg, 91 %) as white solid.
  • Step 1 Preparation of (2R,3R,4R,5S,6S)-2-(acetoxymethy ⁇ )-6-(3-(4-((tert- butyldimethylsilyl)oxy)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
  • (2R,3R,4R,5S,6S)-2-(acetoxymethy ⁇ )-6-(3-(4-((tert- butyldimethylsilyl)oxy)benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate 500 mg, 0.91 mmol) in dry DCM (2.70 mL), triethyl amine (0.32 mL, 2.27 mmol) and 4-dimethylaminopyridine (10 mg, 0.08 mmol) were added at 0 °C followed by the addition of tert- buty
  • reaction mixture was stirred at r.t. for 16 h and the reaction was monitored by TLC. On completion, reaction mixture was diluted with DCM (20 mL), washed with water (10 mL) and brine (10 mL) successively. The organic layer was dried over anhydrous Na 2 S0 4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 2:3 acetone: Pet. ether) to provide the title compound (530 mg, 87.74 %) as white solid.
  • Step 2 Preparation of (2S,3/?,4i?,55,6i?)-2-(3-(4-((iert-butyldimethylsilyl)oxy)benzyl)-4- chlorophenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
  • Step 3 Preparation of ((27?,3 1 S',4i?,5i?,6 i S -6-(3-(4-((fer/-butyldimethylsilyl)oxy)benzyl)-4- chlorophenyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methy]-4- methylbenzenesulfonate
  • reaction mixture was diluted with ethyl acetate (50 mL), washed with 5% HC1 (2 x 20 mL), water (20 mL) and brine (20 mL) successively.
  • the organic layer was dried over anhydrous Na 2 S0 4 and the volatiles were evaporated in vacuo.
  • the residue obtained was purified by column chromatography (silica gel, 1 :9 acetone: DCM) to provide the title compound (400 mg, 89.9 %) as white solid.
  • Step 4 Preparation of (25 , ,3i?,4/?,55',6i?)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6- ((2,2,2-trifluoroethoxy)methyl)tetrahydro-2H-pyran-3,4,5-triol
  • Step 5 Preparation of tert-butyl (4-(4-(2-chloro-5-((2 1 S,3 ?,4 J R,55,6i?)-3,4,5-trihydroxy-6- ((2,2,2-trifluoroethoxy)methyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)butyl)caribamate
  • tert-butyl 4-(4-(2-chloro-5-((2 1 S,3 ?,4 J R,55,6i?)-3,4,5-trihydroxy-6- ((2,2,2-trifluoroethoxy)methyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)butyl)caribamate
  • reaction mixture was stirred at r.t. for 1 h and the reaction was monitored by TLC. On completion, reaction mixture was diluted with ethylacetate (20 mL), washed with water (10 mL) and brine (10 mL) successively. The organic layer was dried over anhydrous Na 2 S0 4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 3:7 acetone: Pet. ether) to provide the title compound (410 mg, 95.12 %) as white solid.
  • Step 7 Preparation of (25,35,4i?,5i?,6/?)-2-(3-(4-(4-aminobutoxy)benzyl)-4- chlorophenyl)-6-((2,2,2-trifluoroethoxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate 2,2,2-trifluoroacetate
  • Step 8 Preparation of (25,35,4ii,5 J R,6i?)-2-(4-chloro-3-(4-(4-(sulfamoylamino)butoxy) benzyl)phenyl)-6-((2,2,2-trifluoroethoxy)methyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
  • 2,2,2-trifluoroacetate 250 mg, 0.323 mmol
  • triethylamine (0.14 mL, 0.97 mmol
  • Step 9 Preparation of (2/?,3 l S',4v , ?,57?,65)-2-((2,2,2-trifluoroethoxy)methyl)-6-(3-(4-(4- aminosulfonylaminobutoxy)benzyl)-4-chlorophenyl)-tetrahydro-2H-pyran-3,4,5-triol
  • Step 1 Preparation of (2i?,37?,4i?,55,65)-2-(acetoxymethyl)-6-(3-(4-(2-((N- acetylsulfamoyl) amino)ethoxy) benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
  • reaction mixture was diluted with EtOAc (150 mL) and washed with water (5 x 10 mL). The organic layer was dried over anhydrous Na 2 S0 4 and volatiles were removed in vacuo. The residue obtained was purified by column chromatography (silica gel, 1 :24 MeOH: DCM) to afford title compound (100 mg, 55.0%) as a white solid.
  • Step 2 Preparation of N-(N-(2-(4-(2-chloro-5-((25,3 ?,4i?,55,6i?)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)ethyl)sulfamoyl)acetamide
  • (2/?,3R,4R,55,65)-2-(acetoxymethyl)-6-(3-(4-(2-(( ⁇ - acetylsulfamoyl) amino)ethoxy) benzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate 150 mg, 0.21 mmol
  • MeOH:THF:Water (3:2: 1, 2.1 mL) was added lithium hydroxide monohydrate (8.8 mg, 0.210 mmol) at 0 °C .
  • reaction mixture was stirred at r.t. for 1 h. After completion of reaction, as confirmed by TLC, the reaction mixture was evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 1 :9 MeOH: DCM) to afford the title compound (95mg, 83%) as white solid.
  • Step 1 Preparation of (2 J ,3i?,4 J R,5S,65)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2-((N,N- dimethylsulfamoyl)(methyl)amino)ethoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
  • (2i?,3i?,4i?,5S,65)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2 (sulfamoylamino)ethoxy)benzyl) phenyl )tetrahydro-2H-pyran-3,4,5-triyl triacetate 1 10 mg, 0.16 mmol) in dry DMF (3 mL), cesium carbonate (213 mg, 0.67 mmol) was added followed by the addition of methyl iodide (0.03 mL, 0.49 mmol) at 0
  • reaction was stirred at r.t. for 24 h. After completion, as confirmed by TLC, the reaction mixture was diluted with ethylacetate (150 mL) and washed with water (2 x 20 mL). The organic layer was dried over anhydrous Na 2 S0 4 volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 4:6 acetone: Pet. ether) to afford title compound as a white solid (105mg, 98.32%).
  • Step 2 Preparation of N-(2-(4-(2-chloro-5-((2S,3i?,4i?,55,6/?)-3,4,5-trihydroxy-6-
  • Step 1 Preparation of (2i?,3i?,4i?,5S,65)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2- (methylsulfonamido)ethoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
  • Step 2 Preparation of N-(2-(4-(2-chloro-5-((25,3 ⁇ ,4 ⁇ ,5 ⁇ ,6 ⁇ )-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)ethyl)methanesulfonamide
  • the title compound (350 mg, 9.45 %) was synthesized following the procedure reported for the synthesis of (25 , ,3 ⁇ ,4 ?,5.S , ,6 ⁇ )-2-(3-(4-(2- (sulfamoylamino)ethoxy)benzyl)-4-chlorophenyl)-tetrahydro-6-(hydroxymethyl)-2H- pyran-3,4,5-triol starting with (2i?,3i?,4 ?,55,65)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2- (methylsulfonamido)ethoxy)benzyl)pheny
  • Step 3 Preparation of ((2i ! ?,3 1 S',4 ⁇ ,5 ⁇ ,6 l )-6-(4-chloro-3-(4-(2-(methylsulfonamido) ethoxy)benzyl)phenyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-yl)methyl-4- methylbenzenesulfonate
  • Step 4 Preparation of N-(2-(4-(2-chloro-5-((25,3 ?,4i?,55,6i?)-3,4,5- trihydroxy-6- (piperidin- 1 -ylmethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)ethyl)
  • reaction mixture was diluted with ethylacetate (150 mL) and washed with water (3 x 10 mL). The organic layer was dried over anhydrous Na 2 S0 4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 2:3 Acetone: Pet. ether) to afford title compound (392 mg, 60.85%) as white solid.
  • Step 3 Preparation of (2 ?,3 ⁇ ,4i?,5 ⁇ ,65)-2-(acetoxymethyI)-6-(4-chloro-3-(4-(2- hydroxyethoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
  • reaction mixture was evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 2:3 EtOAc: Pet ether) to afford title compound (1.8g, 82 %) as a liquid.
  • Step 4 Preparation of (2/?,3i?,4 ?,55',65)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2- (tosyloxy)ethoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate
  • reaction mixture was diluted with ethyl acetate (150 mL) and washed with 2N HC1 (3 x 20 mL). The organic layer was dried over anhydrous Na 2 S0 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 1 : 1 EtOAc: Pet. ether) to afford title compound (130 mg, 35%) as white solid.
  • Step 5 Preparation of (2i?,3i?,4 ⁇ ,55,65)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2-(4- oxido-4-phenyl-l ,4-azaphosphinan-l-yl)ethoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5- triyl triacetate
  • reaction mixture was stirred at 80 °C for 36 h. After completion of reaction, as confirmed by TLC, the reaction mixture was diluted with EtOAc (150 mL) and washed with water (3 x 20 mL). The organic layer was dried over anhydrous Na 2 S0 4 and volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 2:48 MeOH: DCM) to afford title compound (65mg, 63.1%) as a white solid.
  • Step 6 Preparation of l-(2-(4-(2-chloro-5-((25,3 ⁇ ,4 ?,55,6i?)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)benzyl)phenoxy)ethyl)-4-phenyl-l ,4- azaphosphinane 4-oxide
  • reaction mixture was evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 3:7 MeOH: DCM) to afford title compound (58 mg, 80.3%) as off white solid.
  • Mouse SGLT-2 cDNA was amplified from C57BL/6J mouse kidneys and introduced in the pcDNA3.1(+) expression vector (Invitrogen, Inc.) and propagated in Escherichia coli strain DH5a using Luria-Bertani (LB) medium containing ampicillin.
  • Mouse SGLT-2 recombinant expression plasmid DNA was transfected into CHO-K1/HEK cells (American Type Culture Collection) using Superfect Transfection Reagent according to a manufacturer suggested protocol. Stably transfected cells were selected using G418 antibiotic selection pressure.
  • Cells expressing mSGLT-2 were seeded on 96-well tissue culture plates (Greiner, Inc.) in RPMI containing 10% FBS and 400 ⁇ g/mL G418 (0.8 x 10 5 cells per well in 200 ⁇ medium) and incubated at 37 °C under 5% carbon dioxide for 24 h prior to the assay.
  • HEK cells HEK cells
  • HEK cells HEK cells
  • HEK cells HEK cells
  • HEK cells HEK cells
  • HEK cells HEK cells
  • HEK cells HEK cells
  • HEK cells HEK cells
  • HEK cells HEK cells
  • HEK cells HEK cells
  • HEK cells HEK cells
  • HEK cells HEK cells
  • HEK cells HEK cells
  • Human SGLT-1 cDNA in the pCMV-XL-Neo expression vector was obtained from Origene Corporation and propagated in Escherichia coli strain DH5a using Luria- Bertani (LB) medium containing ampicillin.
  • Human SGLT-1 expression plasmid DNA was transfected into CHO-Kl cells (American Type Culture Collection) using Superfect Transfection Reagent according to a manufacturer suggested protocol. Stably transfected cells were selected using G418 antibiotic selection pressure.

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Abstract

L'invention concerne de nouveaux composés de formule I, leurs dérivés, analogues, formes tautomères, isomères, polymorphes, promédicaments, métabolites, sels ou solvates pharmaceutiquement acceptables. L'invention concerne également des procédés pour synthétiser de nouveaux composés de formule I, leurs dérivés, analogues, formes tautomères, isomères, polymorphes, promédicaments, métabolites, sels ou solvates pharmaceutiquement acceptables. L'invention concerne également des compositions pharmaceutiques comprenant de nouveaux composés de formule I et des procédés de traitement ou de prévention d'un ou de plusieurs états pathologiques ou maladies qui peuvent être régulés ou atténués par inhibition du cotransporteur sodium-glucose de type 2 (SGLT-2). L'invention concerne en outre l'utilisation de composés de formule I, de leurs dérivés, analogues, formes tautomères, isomères, polymorphes, promédicaments, métabolites, sels ou solvates pharmaceutiquement acceptables, pour fabriquer un médicament pour la prophylaxie, le soulagement et/ou le traitement d'états pathologiques ou de maladies qui peuvent être régulés ou atténués par inhibition du cotransporteur sodium-glucose de type 2 (SGLT-2) et de maladies, de troubles et d'états pathologiques associés, chez un sujet nécessitant un tel traitement.
PCT/IN2010/000796 2009-12-09 2010-12-09 Nouveaux dérivés de sucres Ceased WO2011070592A2 (fr)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013038429A2 (fr) 2011-09-13 2013-03-21 Panacea Biotec Ltd. Nouveaux inhibiteurs de sglt
US8697658B2 (en) 2011-12-15 2014-04-15 National Health Research Institutes Glycoside compounds
WO2014081660A1 (fr) * 2012-11-20 2014-05-30 Lexicon Pharmaceuticals, Inc. Inhibiteurs du cotransporteur sodium glucose 1
US9085517B2 (en) 2011-12-15 2015-07-21 Pfizer Limited Sulfonamide derivatives
WO2021018044A1 (fr) * 2019-07-26 2021-02-04 南京明德新药研发有限公司 Inhibiteur de sglt2/dpp4 et son application
WO2022160737A1 (fr) * 2021-01-26 2022-08-04 东宝紫星(杭州)生物医药有限公司 Forme cristalline d'un composé cyclique de tétrahydropyrane et son procédé de préparation
US20220259247A1 (en) * 2019-07-26 2022-08-18 Dongbao Purple Star (Hangzhou) Biopharmaceutical Co., Ltd. Sglts/dpp4 inhibitor and application thereof
WO2025245600A1 (fr) * 2024-05-31 2025-12-04 Aché Laboratórios Farmacêuticos S.A. Composés multi-cibles, procédé de préparation des composés, intermédiaires, composition pharmaceutique, sels pharmaceutiquement acceptables, association, médicament, utilisation d'un composé et méthode de traitement

Citations (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002064606A1 (fr) 2001-02-14 2002-08-22 Kissei Pharmaceutical Co., Ltd. Derives glucopyranosyloxybenzylbenzene et leur utilisation medicale
WO2002088157A1 (fr) 2001-04-27 2002-11-07 Ajinomoto Co., Inc. Derives pyrazolyl-o-glycoside n-substitues et medicament contre le diabete en contenant
WO2003000712A1 (fr) 2001-06-20 2003-01-03 Kissei Pharmaceutical Co., Ltd. Derive heterocyclique azote, composition medicinale contenant ce derive, leur utilisation medicinale et intermediaire associe
US6515117B2 (en) 1999-10-12 2003-02-04 Bristol-Myers Squibb Company C-aryl glucoside SGLT2 inhibitors and method
WO2003020737A1 (fr) 2001-09-05 2003-03-13 Bristol-Myers Squibb Company Inhibiteurs de sglt2 contenant du glucoside de o-pyrazole et methode d'utilisation
US6555519B2 (en) 2000-03-30 2003-04-29 Bristol-Myers Squibb Company O-glucosylated benzamide SGLT2 inhibitors and method
US6683056B2 (en) 2000-03-30 2004-01-27 Bristol-Myers Squibb Company O-aryl glucoside SGLT2 inhibitors and method
WO2004013118A1 (fr) 2002-08-05 2004-02-12 Yamanouchi Pharmaceutical Co., Ltd. Derives d'azulene et leurs sels
WO2004058790A1 (fr) 2002-12-25 2004-07-15 Kissei Pharmaceutical Co., Ltd. Derives heterocycliques contenant de l'azote, compositions medicinales contenant lesdits derives et utilisation medicale desdits derives
WO2004087727A1 (fr) 2003-03-31 2004-10-14 Kissei Pharmaceutical Co., Ltd. Derive heterocyclique fusionne, composition medicale le contenant et utilisation medicale associee
WO2004089966A1 (fr) 2003-04-01 2004-10-21 Taisho Pharmaceutical Co., Ltd. Procede de preparation selective de 5-thio-$g(b)-d-aldohexopyranoside heteroaryle
WO2004099230A1 (fr) 2003-05-12 2004-11-18 Fujisawa Pharmaceutical Co., Ltd. Composes de monosaccharide
JP2004359630A (ja) 2003-06-06 2004-12-24 Yamanouchi Pharmaceut Co Ltd ジフルオロジフェニルメタン誘導体及びその塩
WO2005021566A2 (fr) 2003-08-26 2005-03-10 Boehringer Ingelheim International Gmbh Pyrazoles glucopyranosyloxy, medicaments contenant ces composes, leur utilisation et leur procede de production
US6872706B2 (en) 2000-09-29 2005-03-29 Kissei Pharmaceutical Co., Ltd. Glucopyranosyloxybenzylbenzene derivatives and medicinal compositions containing the same
US6936590B2 (en) 2001-03-13 2005-08-30 Bristol Myers Squibb Company C-aryl glucoside SGLT2 inhibitors and method
WO2005085267A1 (fr) 2004-03-04 2005-09-15 Kissei Pharmaceutical Co., Ltd. Derivés de noyaux fondus azotés, compositions thérapeutiques contenant ces derivés et utilisation de ceux-ci en tant que médicaments
WO2005085265A1 (fr) 2004-03-04 2005-09-15 Kissei Pharmaceutical Co., Ltd. Derive heterocyclique accole, composition medicamenteuse en contenant, et son utilisation medicamenteuse
WO2005095429A1 (fr) 2004-03-31 2005-10-13 Kissei Pharmaceutical Co., Ltd. Dérivé phénolé, composition médicinale contenant ce dérivé, et son usage médicinal
WO2006002912A1 (fr) 2004-07-06 2006-01-12 Boehringer Ingelheim International Gmbh Phenyles substitues par d-xylopyranosyle, medicaments contenant ces composes, utilisation et procede de production de ces composes
WO2006008038A1 (fr) 2004-07-17 2006-01-26 Boehringer Ingelheim International Gmbh Phenyles substitues par methylidene-d-xylopyranosyle et oxo-d-xylopyranosyle, medicaments contenant lesdits composes, leur utilisation et procedes permettant de les produire
WO2006010557A1 (fr) 2004-07-27 2006-02-02 Boehringer Ingelheim International Gmbh Cyclenes substitues par d-glucopyranosyle-phenyle, medicaments contenant lesdits composes, leur utilisation et procede de production correspondant
WO2006011469A1 (fr) 2004-07-26 2006-02-02 Chugai Seiyaku Kabushiki Kaisha Nouveau dérivé de cyclohexane, promédicament et sel de dérivé de cyclohexane, et agent thérapeutique contenant ce dérivé pour traitement du diabète
WO2006034489A2 (fr) 2004-09-23 2006-03-30 Bristol-Myers Squibb Company Inhibiteurs de c-aryl glucoside sglt2 et methode
WO2006037537A2 (fr) 2004-10-01 2006-04-13 Boehringer Ingelheim International Gmbh Phenyles d-pyranosyl-substitues, agents pharmaceutiques contenant ces composes, leur utilisation et procede pour les preparer
WO2006054629A1 (fr) 2004-11-18 2006-05-26 Kissei Pharmaceutical Co., Ltd. COMPOSÉS HÉTÉROCYCLIQUES AZOTÉS SUBSTITUÉS EN POSITION 1 ET AYANT UN GROUPE β-D-GLUCOPYRANOSYLE EN POSITION 3 ET MÉDICAMENTS CONTENANT CEUX-CI
US7056892B2 (en) 1999-08-31 2006-06-06 Kissei Pharmaceutical Co., Ltd. Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof
WO2006064033A2 (fr) 2004-12-16 2006-06-22 Boehringer Ingelheim International Gmbh Derives de benzene substitues par glucopyranosyle, medicaments contenant ces composes, leur utilisation et leur procede de fabrication
WO2006089872A1 (fr) 2005-02-23 2006-08-31 Boehringer Ingelheim International Gmbh Derives d'(hetero)arylethynyl-benzyd-benzene a substitution glucopyranosyle et leur utilisation en tant que cotransporteur 2 de glucose dependant de sodium (sglt2)
US7129381B2 (en) 2000-11-30 2006-10-31 Kissei Pharmaceutical Co., Ltd. Glucopyranosyloxybenzylbenzene derivatives, medicinal compositions containing the same and intermediates in the production thereof
WO2007000445A1 (fr) 2005-06-29 2007-01-04 Boehringer Ingelheim International Gmbh Derives de benzyle-benzene a substitution glucopyranosyle, medicaments contenant de tels composes, utilisation et production de ces derniers
US20070049537A1 (en) 2005-08-30 2007-03-01 Matthias Eckhardt Glucopyranosyl-substituted benzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
US7189702B2 (en) 2001-02-26 2007-03-13 Kissei Pharmaceutical Co., Ltd. Glucopyranosyloxypyrazole derivatives and medicinal use thereof
US7202350B2 (en) 2003-03-14 2007-04-10 Astellas Pharma Inc. C-glycoside derivatives and salts thereof
US7247616B2 (en) 2000-11-02 2007-07-24 Ajinomoto Co., Inc. Pyrazole derivatives and diabetic medicine containing them
WO2007093610A1 (fr) 2006-02-15 2007-08-23 Boehringer Ingelheim International Gmbh Dérivés de benzonitrile substitués par glucopyranosyle, compositions pharmaceutiques contenant de tels composés, leurs applications et un procédé pour leur fabrication
WO2007126117A1 (fr) 2006-05-02 2007-11-08 Taisho Pharmaceutical Co., Ltd. Compose 5-thioglucoside de phenyle
US7294618B2 (en) 2001-02-27 2007-11-13 Kissei Pharmaceutical Co., Ltd. Glucopyranosyloxypyrazole derivatives and medicinal use thereof
WO2007136116A2 (fr) 2006-05-19 2007-11-29 Taisho Pharmaceutical Co., Ltd. Composé de c-phényl glycitol
WO2008013277A1 (fr) 2006-07-27 2008-01-31 Chugai Seiyaku Kabushiki Kaisha Dérivé spirocétal à cycles accolés et utilisation de celui-ci comme médicament dans le traitement du diabète
WO2008013321A1 (fr) 2006-07-28 2008-01-31 Mitsubishi Tanabe Pharma Corporation Nouveaux inhibiteurs de sglt
WO2008020011A1 (fr) 2006-08-15 2008-02-21 Boehringer Ingelheim International Gmbh Dérivés de cyclopropyl-benzène à substitution glucopyranosyle, compositions pharmaceutiques contenant de tels composés, leur utilisation en tant qu'inhibiteurs de sglt et leur procédé de fabrication
WO2008042688A2 (fr) 2006-09-29 2008-04-10 Lexicon Pharmaceuticals, Inc. Inhibiteurs de co-transporteur 2 de sodium glucose et procédés d'utilisation de ceux-ci
WO2008069327A1 (fr) 2006-12-04 2008-06-12 Mitsubishi Tanabe Pharma Corporation FORME CRISTALLINE DE 1- (β-D-GLUCOPYRANOSYL) -4 -MÉTHYLE- 3- [5- (4 -FLUOROPHÉNYL) -2-THIÉNYLMÉTHYLE] BENZÈNE HÉMIHYDRATE
WO2008090570A1 (fr) 2007-01-25 2008-07-31 Panacea Biotec Ltd Nouveaux antimicrobiens
WO2008116195A2 (fr) 2007-03-22 2008-09-25 Bristol-Myers Squibb Méthodes de traitement de l'obésité au moyen d'un inhibiteur du sglt2 et des compositions de celui-ci
WO2008122014A1 (fr) 2007-04-02 2008-10-09 Theracos, Inc. Dérivés de glycoside benzylique et procédés d'utilisation
WO2009026537A1 (fr) 2007-08-23 2009-02-26 Theracos, Inc. Dérivés de benzylbenzène et procédés d'utilisation
WO2009116090A2 (fr) 2008-03-18 2009-09-24 Panacea Biotec Limited Nouveaux antimicrobiens
WO2010022313A2 (fr) 2008-08-22 2010-02-25 Theracos, Inc. Procédés de préparation d'inhibiteurs de sglt2

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PH12000002657B1 (en) * 1999-10-12 2006-02-21 Bristol Myers Squibb Co C-aryl glucoside SGLT2 inhibitors

Patent Citations (50)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7056892B2 (en) 1999-08-31 2006-06-06 Kissei Pharmaceutical Co., Ltd. Glucopyranosyloxypyrazole derivatives, medicinal compositions containing the same and intermediates in the production thereof
US6515117B2 (en) 1999-10-12 2003-02-04 Bristol-Myers Squibb Company C-aryl glucoside SGLT2 inhibitors and method
US6683056B2 (en) 2000-03-30 2004-01-27 Bristol-Myers Squibb Company O-aryl glucoside SGLT2 inhibitors and method
US6555519B2 (en) 2000-03-30 2003-04-29 Bristol-Myers Squibb Company O-glucosylated benzamide SGLT2 inhibitors and method
US6872706B2 (en) 2000-09-29 2005-03-29 Kissei Pharmaceutical Co., Ltd. Glucopyranosyloxybenzylbenzene derivatives and medicinal compositions containing the same
US7247616B2 (en) 2000-11-02 2007-07-24 Ajinomoto Co., Inc. Pyrazole derivatives and diabetic medicine containing them
US7129381B2 (en) 2000-11-30 2006-10-31 Kissei Pharmaceutical Co., Ltd. Glucopyranosyloxybenzylbenzene derivatives, medicinal compositions containing the same and intermediates in the production thereof
WO2002064606A1 (fr) 2001-02-14 2002-08-22 Kissei Pharmaceutical Co., Ltd. Derives glucopyranosyloxybenzylbenzene et leur utilisation medicale
US7189702B2 (en) 2001-02-26 2007-03-13 Kissei Pharmaceutical Co., Ltd. Glucopyranosyloxypyrazole derivatives and medicinal use thereof
US7294618B2 (en) 2001-02-27 2007-11-13 Kissei Pharmaceutical Co., Ltd. Glucopyranosyloxypyrazole derivatives and medicinal use thereof
US6936590B2 (en) 2001-03-13 2005-08-30 Bristol Myers Squibb Company C-aryl glucoside SGLT2 inhibitors and method
WO2002088157A1 (fr) 2001-04-27 2002-11-07 Ajinomoto Co., Inc. Derives pyrazolyl-o-glycoside n-substitues et medicament contre le diabete en contenant
WO2003000712A1 (fr) 2001-06-20 2003-01-03 Kissei Pharmaceutical Co., Ltd. Derive heterocyclique azote, composition medicinale contenant ce derive, leur utilisation medicinale et intermediaire associe
WO2003020737A1 (fr) 2001-09-05 2003-03-13 Bristol-Myers Squibb Company Inhibiteurs de sglt2 contenant du glucoside de o-pyrazole et methode d'utilisation
WO2004013118A1 (fr) 2002-08-05 2004-02-12 Yamanouchi Pharmaceutical Co., Ltd. Derives d'azulene et leurs sels
WO2004058790A1 (fr) 2002-12-25 2004-07-15 Kissei Pharmaceutical Co., Ltd. Derives heterocycliques contenant de l'azote, compositions medicinales contenant lesdits derives et utilisation medicale desdits derives
US7202350B2 (en) 2003-03-14 2007-04-10 Astellas Pharma Inc. C-glycoside derivatives and salts thereof
WO2004087727A1 (fr) 2003-03-31 2004-10-14 Kissei Pharmaceutical Co., Ltd. Derive heterocyclique fusionne, composition medicale le contenant et utilisation medicale associee
WO2004089966A1 (fr) 2003-04-01 2004-10-21 Taisho Pharmaceutical Co., Ltd. Procede de preparation selective de 5-thio-$g(b)-d-aldohexopyranoside heteroaryle
WO2004099230A1 (fr) 2003-05-12 2004-11-18 Fujisawa Pharmaceutical Co., Ltd. Composes de monosaccharide
JP2004359630A (ja) 2003-06-06 2004-12-24 Yamanouchi Pharmaceut Co Ltd ジフルオロジフェニルメタン誘導体及びその塩
WO2005021566A2 (fr) 2003-08-26 2005-03-10 Boehringer Ingelheim International Gmbh Pyrazoles glucopyranosyloxy, medicaments contenant ces composes, leur utilisation et leur procede de production
WO2005085267A1 (fr) 2004-03-04 2005-09-15 Kissei Pharmaceutical Co., Ltd. Derivés de noyaux fondus azotés, compositions thérapeutiques contenant ces derivés et utilisation de ceux-ci en tant que médicaments
WO2005085265A1 (fr) 2004-03-04 2005-09-15 Kissei Pharmaceutical Co., Ltd. Derive heterocyclique accole, composition medicamenteuse en contenant, et son utilisation medicamenteuse
WO2005095429A1 (fr) 2004-03-31 2005-10-13 Kissei Pharmaceutical Co., Ltd. Dérivé phénolé, composition médicinale contenant ce dérivé, et son usage médicinal
WO2006002912A1 (fr) 2004-07-06 2006-01-12 Boehringer Ingelheim International Gmbh Phenyles substitues par d-xylopyranosyle, medicaments contenant ces composes, utilisation et procede de production de ces composes
WO2006008038A1 (fr) 2004-07-17 2006-01-26 Boehringer Ingelheim International Gmbh Phenyles substitues par methylidene-d-xylopyranosyle et oxo-d-xylopyranosyle, medicaments contenant lesdits composes, leur utilisation et procedes permettant de les produire
WO2006011469A1 (fr) 2004-07-26 2006-02-02 Chugai Seiyaku Kabushiki Kaisha Nouveau dérivé de cyclohexane, promédicament et sel de dérivé de cyclohexane, et agent thérapeutique contenant ce dérivé pour traitement du diabète
WO2006010557A1 (fr) 2004-07-27 2006-02-02 Boehringer Ingelheim International Gmbh Cyclenes substitues par d-glucopyranosyle-phenyle, medicaments contenant lesdits composes, leur utilisation et procede de production correspondant
WO2006034489A2 (fr) 2004-09-23 2006-03-30 Bristol-Myers Squibb Company Inhibiteurs de c-aryl glucoside sglt2 et methode
WO2006037537A2 (fr) 2004-10-01 2006-04-13 Boehringer Ingelheim International Gmbh Phenyles d-pyranosyl-substitues, agents pharmaceutiques contenant ces composes, leur utilisation et procede pour les preparer
WO2006054629A1 (fr) 2004-11-18 2006-05-26 Kissei Pharmaceutical Co., Ltd. COMPOSÉS HÉTÉROCYCLIQUES AZOTÉS SUBSTITUÉS EN POSITION 1 ET AYANT UN GROUPE β-D-GLUCOPYRANOSYLE EN POSITION 3 ET MÉDICAMENTS CONTENANT CEUX-CI
WO2006064033A2 (fr) 2004-12-16 2006-06-22 Boehringer Ingelheim International Gmbh Derives de benzene substitues par glucopyranosyle, medicaments contenant ces composes, leur utilisation et leur procede de fabrication
WO2006089872A1 (fr) 2005-02-23 2006-08-31 Boehringer Ingelheim International Gmbh Derives d'(hetero)arylethynyl-benzyd-benzene a substitution glucopyranosyle et leur utilisation en tant que cotransporteur 2 de glucose dependant de sodium (sglt2)
WO2007000445A1 (fr) 2005-06-29 2007-01-04 Boehringer Ingelheim International Gmbh Derives de benzyle-benzene a substitution glucopyranosyle, medicaments contenant de tels composes, utilisation et production de ces derniers
US20070049537A1 (en) 2005-08-30 2007-03-01 Matthias Eckhardt Glucopyranosyl-substituted benzyl-benzene derivatives, medicaments containing such compounds, their use and process for their manufacture
WO2007093610A1 (fr) 2006-02-15 2007-08-23 Boehringer Ingelheim International Gmbh Dérivés de benzonitrile substitués par glucopyranosyle, compositions pharmaceutiques contenant de tels composés, leurs applications et un procédé pour leur fabrication
WO2007126117A1 (fr) 2006-05-02 2007-11-08 Taisho Pharmaceutical Co., Ltd. Compose 5-thioglucoside de phenyle
WO2007136116A2 (fr) 2006-05-19 2007-11-29 Taisho Pharmaceutical Co., Ltd. Composé de c-phényl glycitol
WO2008013277A1 (fr) 2006-07-27 2008-01-31 Chugai Seiyaku Kabushiki Kaisha Dérivé spirocétal à cycles accolés et utilisation de celui-ci comme médicament dans le traitement du diabète
WO2008013321A1 (fr) 2006-07-28 2008-01-31 Mitsubishi Tanabe Pharma Corporation Nouveaux inhibiteurs de sglt
WO2008020011A1 (fr) 2006-08-15 2008-02-21 Boehringer Ingelheim International Gmbh Dérivés de cyclopropyl-benzène à substitution glucopyranosyle, compositions pharmaceutiques contenant de tels composés, leur utilisation en tant qu'inhibiteurs de sglt et leur procédé de fabrication
WO2008042688A2 (fr) 2006-09-29 2008-04-10 Lexicon Pharmaceuticals, Inc. Inhibiteurs de co-transporteur 2 de sodium glucose et procédés d'utilisation de ceux-ci
WO2008069327A1 (fr) 2006-12-04 2008-06-12 Mitsubishi Tanabe Pharma Corporation FORME CRISTALLINE DE 1- (β-D-GLUCOPYRANOSYL) -4 -MÉTHYLE- 3- [5- (4 -FLUOROPHÉNYL) -2-THIÉNYLMÉTHYLE] BENZÈNE HÉMIHYDRATE
WO2008090570A1 (fr) 2007-01-25 2008-07-31 Panacea Biotec Ltd Nouveaux antimicrobiens
WO2008116195A2 (fr) 2007-03-22 2008-09-25 Bristol-Myers Squibb Méthodes de traitement de l'obésité au moyen d'un inhibiteur du sglt2 et des compositions de celui-ci
WO2008122014A1 (fr) 2007-04-02 2008-10-09 Theracos, Inc. Dérivés de glycoside benzylique et procédés d'utilisation
WO2009026537A1 (fr) 2007-08-23 2009-02-26 Theracos, Inc. Dérivés de benzylbenzène et procédés d'utilisation
WO2009116090A2 (fr) 2008-03-18 2009-09-24 Panacea Biotec Limited Nouveaux antimicrobiens
WO2010022313A2 (fr) 2008-08-22 2010-02-25 Theracos, Inc. Procédés de préparation d'inhibiteurs de sglt2

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Targeted prodrug design to optimize drug delivery", AAPS PHARMASCI, vol. 2, no. 1, 2000, pages E6
NUCLEOSIDE, NUCLOETIDES & NUCLEIC ACIDS, vol. 20, no. 4-7, 2001, pages 649 - 652
PERRIN, D.D.; ARMAREGO, W.L.F.: "Purification of Laboratory Chemicals", 1988, PERGAMON PRESS

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013038429A3 (fr) * 2011-09-13 2013-11-28 Panacea Biotec Ltd. Nouveaux inhibiteurs de sglt
WO2013038429A2 (fr) 2011-09-13 2013-03-21 Panacea Biotec Ltd. Nouveaux inhibiteurs de sglt
US9018249B2 (en) 2011-09-13 2015-04-28 Panacea Biotec Limited SGLT inhibitors
US9085517B2 (en) 2011-12-15 2015-07-21 Pfizer Limited Sulfonamide derivatives
US8697658B2 (en) 2011-12-15 2014-04-15 National Health Research Institutes Glycoside compounds
CN108440614A (zh) * 2012-11-20 2018-08-24 莱西肯医药有限公司 钠葡萄糖协同转运蛋白1的抑制剂
KR20150085067A (ko) * 2012-11-20 2015-07-22 렉시컨 파마슈티컬스 인코퍼레이티드 나트륨 글루코스 공동수송체 1의 억제제
US9200025B2 (en) 2012-11-20 2015-12-01 Lexicon Pharmaceuticals, Inc. Inhibitors of sodium glucose cotransporter 1
JP2016504285A (ja) * 2012-11-20 2016-02-12 レクシコン ファーマシューティカルズ インコーポレイテッド ナトリウムグルコース共輸送体１の阻害剤
US9688710B2 (en) 2012-11-20 2017-06-27 Lexicon Pharmaceuticals, Inc. Inhibitors of sodium glucose cotransporter 1
WO2014081660A1 (fr) * 2012-11-20 2014-05-30 Lexicon Pharmaceuticals, Inc. Inhibiteurs du cotransporteur sodium glucose 1
EP3489226A1 (fr) * 2012-11-20 2019-05-29 Lexicon Pharmaceuticals, Inc. Inhibiteurs de cotransporteur 1 de glucose de sodium
KR102165224B1 (ko) * 2012-11-20 2020-10-13 렉시컨 파마슈티컬스 인코퍼레이티드 나트륨 글루코스 공동수송체 1의 억제제
CN114026079A (zh) * 2019-07-26 2022-02-08 南京明德新药研发有限公司 一种sglt2/dpp4抑制剂及其应用
WO2021018044A1 (fr) * 2019-07-26 2021-02-04 南京明德新药研发有限公司 Inhibiteur de sglt2/dpp4 et son application
JP2022533475A (ja) * 2019-07-26 2022-07-22 メッドシャイン ディスカバリー インコーポレイテッド Ｓｇｌｔ２／ｄｐｐ４阻害剤及びその使用
US20220259247A1 (en) * 2019-07-26 2022-08-18 Dongbao Purple Star (Hangzhou) Biopharmaceutical Co., Ltd. Sglts/dpp4 inhibitor and application thereof
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AU2020320890B2 (en) * 2019-07-26 2023-03-09 Cgenetech (Suzhou, China) Co., Ltd. SGLT2/DPP4 inhibitor and application thereof
US12378277B2 (en) * 2019-07-26 2025-08-05 Dongbao Purple Star (Hangzhou) Biopharmaceutical Co., Ltd. SGLTS/DPP4 inhibitor and application thereof
US12421269B2 (en) 2019-07-26 2025-09-23 Cgenetech (Suzhou, China) Co., Ltd. SGLT2/DPP4 inhibitor and application thereof
WO2022160737A1 (fr) * 2021-01-26 2022-08-04 东宝紫星(杭州)生物医药有限公司 Forme cristalline d'un composé cyclique de tétrahydropyrane et son procédé de préparation
WO2025245600A1 (fr) * 2024-05-31 2025-12-04 Aché Laboratórios Farmacêuticos S.A. Composés multi-cibles, procédé de préparation des composés, intermédiaires, composition pharmaceutique, sels pharmaceutiquement acceptables, association, médicament, utilisation d'un composé et méthode de traitement

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