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Claims for Patent: 6,414,126

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Claims for Patent: 6,414,126

Title: C-aryl glucoside SGLT2 inhibitors and method
Abstract:SGLT2 inhibiting compounds are provided having the formula ##STR1## where R.sup.1, R.sup.2, and R.sup.2a are independently hydrogen, OH, OR.sup.5, lower alkyl, CF.sub.3, OCHF.sub.2, OCF.sub.3, SR.sup.5i or halogen, or two of R.sup.1, R.sup.2 and R.sup.2a together with the carbons to which they are attached can form an annelated five, six or seven membered carbocycle or heterocycle; R.sup.3 and R.sup.4 are independently hydrogen, OH, OR.sup.5a, OAryl, OCH.sub.2 Aryl, lower alkyl, cycloalkyl, CF.sub.3, --OCHF.sub.2, --OCF.sub.3, halogen, --CN, --CO.sub.2 R.sup.5b, --CO.sub.2 H, --COR.sup.6b, --CH(OH)R.sup.6c, --CH(OR.sup.5h)R.sup.6d, --CONR.sup.6 R.sup.6a, --NHCOR.sup.5c, --NHSO.sub.2 R.sup.5d, --NHSO.sub.2 Aryl, Aryl, --SR.sup.5e, --SOR.sup.5f, --SO.sub.2 R.sup.5g, --SO.sub.2 Aryl, or a five, six or seven membered heterocycle, or R.sup.3 and R.sup.4 together with the carbons to which they are attached form an annelated five, six or seven membered carbocycle or heterocycle; R.sup.5, R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, R.sup.5e, R.sup.5f, R.sup.5g, R.sup.5h and R.sup.5i are independently lower alkyl; R.sup.6, R.sup.6a, R.sup.6b, R.sup.6c and R.sup.6d are independently hydrogen, alkyl,aryl, alkylaryl or cycloalkyl, or R.sup.6 and R.sup.6a together with the nitrogen to which they are attached form an annelated five, six or seven membered heterocycle; A is O, S, NH, or (CH.sub.2).sub.n where n is 0-3. A method is also provided for treating diabetes and related diseases employing an SGLT2 inhibiting amount of the above compound alone or in combination with another antidiabetic agent or other therapeutic agent.
Inventor(s): Ellsworth; Bruce (Princeton, NJ), Washburn; William N. (Titusville, NJ), Sher; Philip M. (Plainsboro, NJ), Wu; Gang (Princeton, NJ), Meng; Wei (Pennington, NJ)
Assignee: Bristol-Myers Squibb Company (Princeton, NJ)
Application Number:09/679,027
Patent Claims: 1. A compound having the structure ##STR115##

wherein

R.sup.1, R.sup.2 and R.sup.2a are independently hydrogen, OH, OR.sup.5, alkyl, CF.sub.3, OCHF.sub.2, OCF.sub.3, SR.sup.5i or halogen, or two of R.sup.1, R.sup.2 and R.sup.2a together with the carbons to which they are attached can form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO.sub.2 ;

R.sup.3 and R.sup.4 are independently hydrogen, OH, OR.sup.5a, OAryl, OCH.sub.2 Aryl, alkyl, cycloalkyl, CF.sub.3, --OCHF.sub.2, --OCF.sub.3, halogen, --CN, --CO.sub.2 R.sup.5b, --CO.sub.2 H, COR.sup.6b, --CH(OH)R.sup.6c, --CH (OR.sup.5h)R.sup.6d, --CONR.sup.6 R.sup.6a, --NHCOR.sup.5c, --NHSO.sub.2 R.sup.5d, --NHSO.sub.2 Aryl, Aryl, --SR.sup.5e, --SOR.sup.5f, --SO.sub.2 R.sup.5g, --SO.sub.2 Aryl, or a five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO.sub.2, or R.sup.3 and R.sup.4 together with the carbons to which they are attached form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO.sub.2 ;

R.sup.5, R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, R.sup.5e, R.sup.5f, R.sup.5g, R.sup.5h and R.sup.5i are independently alkyl;

R.sup.6, R.sup.6a, R.sup.6b, R.sup.6c, and R.sup.6d are independently hydrogen, alkyl, aryl, alkylaryl or cycloalkyl, or R.sup.6 and R.sup.6a together with the nitrogen to which they are attached form an annelated five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO.sub.2 ;

A is O, S, NH, or (CH.sub.2).sub.n, where n is 0-3, or a pharmaceutically acceptable salt, stereoisomer, or prodrug ester thereof;

with the proviso that where A is (CH.sub.2).sub.n where n is 0,1,2, or 3 or A is O, and at least one of R.sup.1, R.sup.2, and R.sup.2a is OH or OR.sup.5, then at least one of R.sup.1, R.sup.2, and R.sup.2a is CF.sub.3, OCF.sub.3, or OCHF.sub.2 and/or at least one of R.sup.3 and R.sup.4 is CF.sub.3, --OCHF.sub.2, --OCF.sub.3, --CN, --CO.sub.2 R.sup.5b, CH(OR.sup.5h)R.sup.6d, CH(OH)R.sup.6c, COR.sup.6b, --NHCOR.sup.5c, --NHSO.sub.2 R.sup.5d, --NHSO.sub.2 Aryl, Aryl, --SR.sup.5e, --SOR.sup.5f, --SO.sub.2 R.sup.5g or --SO.sub.2 Aryl.

2. The compound as defined in claim 1 with the proviso that where A is (CH.sub.2).sub.n where n is 0,1,2, or 3 or A is O, and at least one of R.sup.1, R.sup.2, R.sup.2a, R.sup.3 and R.sup.4 is OH or OR.sup.5, then at least one of R.sup.1, R.sup.2, and R.sup.2a is CF.sub.3, OCF.sub.3, or OCHF.sub.2 and/or at least one of R.sup.3 and R.sup.4 is CF.sub.3, --OCHF.sub.2, --OCF.sub.3, --CN, --CO.sub.2 R.sup.5b, CH(OR.sup.5h)R.sup.6d, --NHCOR.sup.5c, --NHSO.sub.2 R.sup.5d, --NHSO.sub.2 Aryl, Aryl, --SR.sup.5e, --SOR.sup.5f, --SO.sub.2 R.sup.5g, --SO.sub.2 Aryl or halogen.

3. The compound as defined in claim 1 having the structure ##STR116##

4. The compound as defined in claim 1 wherein A is (CH.sub.2).sub.n.

5. The compound as defined in claim 3 wherein A is CH.sub.2 or O or S.

6. The compound as defined in claim 1 wherein A is CH.sub.2 or O or S;

R.sup.1, R.sup.2 and R.sup.2a are independently selected from H, lower alkyl, halogen, OR.sup.5, or OCHF.sub.2, or two of R.sup.1, R.sup.2 and R.sup.2a are H and the other is lower alkyl, halogen, OR.sup.5, or OCHF.sub.2 ;

R.sup.3 and R.sup.4 are independently selected from lower alkyl, OR.sup.5a, --OCHF.sub.2, --SR.sup.5e, OH, CO.sub.2 R.sup.5b, -3,4-(O--CH.sub.2 --O)--, --COR.sup.6b, --CH(OH)R.sup.6c, --CH(OR.sup.5h)R.sup.6d, CF.sub.3, ##STR117##

--SOR.sup.5f, --SO.sub.2 R.sup.5g, Aryl, --NHSO.sub.2 Aryl, --NHSO.sub.2 R.sup.5d, CO.sub.2 H, thiadizole, tetrazole, OCH.sub.2 Aryl, --OCF.sub.3, OAryl, or H.

7. The compound as defined in claim 6 wherein A is CH.sub.2 ; R.sup.1 is hydrogen, halogen or lower alkyl; R.sup.2 and R.sup.2a are each H; R.sup.3 is H; R.sup.4 is lower alkyl, --COR.sup.6b, --CH(OH)R.sup.6c, --CH(OR.sup.5h)R.sup.6d, R.sup.5a O, --OCHF.sub.2, --OCF.sub.3 or --SR.sup.5e.

8. The compound as defined in claim 7 where A is CH.sub.2 ; R.sup.1 is hydrogen, halogen or lower alkyl; and R.sup.4 is lower alkyl, R.sup.5a O, --OCHF.sub.2, or --SR.sup.5e.

9. The compound as defined in claim 7 wherein R.sup.4 is 4-C.sub.2 H.sub.5.

10. The compound as defined in claim 3 having the structure ##STR118## ##STR119## ##STR120##

11. The compound as defined in claim 1 having the structure set out as follows: ##STR121##

where A is CH.sub.2 and meta to the glucoside, R.sup.1, R.sup.2 and R.sup.2a are each H, and R.sup.3 is as follows:

4-Me, 4-OH, 3-Me, H, 3-OMe, 4-CO.sub.2 Me, 3,4-(OCH.sub.2 O), 4-CF.sub.3, 4-NHAc, 4-SO.sub.2 Me, 4-Ph, 4-NHSO.sub.2 Ph-4'-Me, 4-NHSO.sub.2 Me, 4-CO.sub.2 H, 4-Thiadiazole, 4-Tetrazole, 4-OCH.sub.2 Ph-4'-CN, 4-OCHF.sub.2, 4-isopropyl, 2-isopropyl, 4-O-n-propyl, 4-Tetrazole-2'-Me, 4-Tetrazole-1'-Me, 4-OPh, 4-n-propyl, 4-n-butyl, 4-SO.sub.2 Et, 4-SO.sub.2 -n-propyl, 4-SO.sub.2 Ph or 4-SOMe.

12. The compound as defined in claim 1 having the structure:

13. The compound as defined in claim 1 having the structure: ##STR123##

where

14. The compound as defined in claim 1 having the structure ##STR124##

15. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefor.

16. A pharmaceutical combination comprising an SGLT2 inhibitor compound as defined in claim 1 and an antidiabetic agent other than an SGLT2 inhibitor, an agent for treating the complications of diabetes, an anti-obesity agent, an antihypertensive agent, an antiplatelet agent, an antiatherosclerotic agent, and/or a lipid-lowering agent.

17. The pharmaceutical combination as defined in claim 16 comprising said SGLT2 inhibitor compound and an antidiabetic agent.

18. The combination as defined in claim 17 wherein the antidiabetic agent is 1, 2, 3 or more of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR .gamma. agonist, a PPAR .alpha./.gamma. dual agonist, an aP2 inhibitor, a DP4 inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin, a meglitinide, a PTP1B inhibitor, a glycogen phosphorylase inhibitor, and/or a glucos-6-phosphatase inhibitor.

19. The combination as defined in claim 18 wherein the antidiabetic agent is 1, 2, 3 or more of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, Gl-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, AR-HO39242, GW-409544, KRP297, AC2993, LY315902, and/or NVP-DPP-728A.

20. The combination as defined in claim 17 wherein the SGLT2 inhibitor compound is present in a weight ratio to the antidiabetic agent within the range from about 0.01 to about 300:1.

21. The combination as defined in claim 16 wherein the anti-obesity agent is a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta compound, and/or an anorectic agent.

22. The combination as defined in claim 21 wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, and/or mazindol.

23. The combination as defined in claim 16 wherein the lipid lowering agent is an MTP inhibitor, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, or an ACAT inhibitor.

24. The combination as defined in claim 23 wherein the lipid lowering agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, atavastatin, rosuvastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962, MD-700, and/or LY295427.

25. The combination as defined in claim 23 wherein the SGLT2 inhibitor is present in a weight ratio to the lipid-lowering agent within the range from about 0.01 to about 300:1.

26. A method for treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, delayed wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, elevated blood levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, Syndrome X, diabetic complications, atherosclerosis or hypertension, or for increasing high density lipoprotein levels, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound as defined in claim 1.

27. The method as defined in claim 26 where the SGLT2 inhibitor compound has the structure ##STR125##

28. A method for treating type II diabetes which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound as defined in claim 1 alone or in combination with another antidiabetic agent, an agent for treating the complications of diabetes, an anti-obesity agent, an antihypertensive agent, an antiplatelet agent, an anti-atherosclerotic agent and/or a hypolipidemic agent.

29. A compound having the structure ##STR126##

wherein

R.sup.1 R.sup.2 and R.sup.2a are independently hydrogen, OH, OR.sup.5, lower alkyl, CF.sub.3, OCHF.sub.2, OCF.sub.3, SR.sup.5i or halogen, or two of R.sup.1, R.sup.2 and R.sup.2a together with the carbons to which they are attached can form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO.sub.2 ;

R.sup.3 and R.sup.4 are independently hydrogen, OH, OR.sup.5a, OAryl, OCH.sub.2 Aryl, lower alkyl, cycloalkyl, CF.sub.3, --OCHF.sub.2, --OCF.sub.3, halogen, --CN, --CO.sub.2 R.sup.5b, --CO.sub.2 H, --CONR.sup.6 R.sup.6a, --NHCOR.sup.5c, --NHSO.sub.2 R.sup.5d, --NHSO.sub.2 Aryl, Aryl, --SR.sup.5e, --SOR.sup.5f, --SO.sub.2 R.sup.5g, --SO.sub.2 Aryl, or a five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO.sub.2, or R.sup.3 and R.sup.4 together with the carbons to which they are attached form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO.sub.2 ;

R.sup.5, R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, R.sup.5e, R.sup.5f, R.sup.5g and R.sup.5i are independently lower alkyl;

R.sup.6 and R.sup.6a are independently hydrogen, alkyl,aryl, alkylaryl, cycloalkyl, or R.sup.6 and R.sup.6a together with the nitrogen to which they are attached form an annelated five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO.sub.2 ;

A is O, S, NH, or (CH.sub.2).sub.n where n is 0-3, or a pharmaceutically acceptable salt thereof, all steroisomers thereof, and a prodrug ester thereof with the proviso that where A is (CH.sub.2).sub.n where n is 0,1,2, or 3 or A is O, and at least one of R.sup.1, R.sup.2, R.sup.2a, R.sup.3 and R.sup.4 is OH or OR.sup.5, then at least one of R.sup.1, R.sup.2, and R.sup.2a is CF.sub.3, OCF.sub.3, or OCHF.sub.2 and/or at least one of R.sup.3 and R.sup.4 is CF.sub.3, --OCHF.sub.2, --OCF.sub.3, --CN, --CO.sub.2 R.sup.5b, CH(OR.sup.5h)R.sup.6d, CH(OH)R.sup.6c, COR.sup.6b, --NHCO.sup.5c, --NHSO.sub.2 R.sup.5d, --NHSO.sub.2 Aryl, Aryl, --SR.sup.5e, --SOR.sup.5f, --SO.sub.2 R.sup.5g, --SO.sub.2 Aryl or halogen;

or a compound of the structure ##STR127##

wherein

R.sup.1, R.sup.2 and R.sup.2a are independently hydrogen, OH, OR.sup.5, lower alkyl, CF.sub.3, OCHF.sub.2, OCF.sub.3, SR.sup.5i or halogen, or two of R.sup.1, R.sup.2 and R.sup.2a together with the carbons to which they are attached can form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO.sub.2 ;

R.sup.3 and R.sup.4 are independently hydrogen, OH, OR.sup.5a, OAryl, OCH.sub.2 Aryl, lower alkyl, cycloalkyl, CF.sub.3, --OCHF.sub.2, --OCF.sub.3, halogen, --CN, --CO.sub.2 R.sup.5b, --CO.sub.2 H, --CONR.sup.6 R.sup.6a, --NHCOR.sup.5c, --NHSO.sub.2 R.sup.5d, --NHSO.sub.2 Aryl, Aryl, --SR.sup.5e, --SOR.sup.5f, --SO.sub.2 R.sup.5g, --SO.sub.2 Aryl, or a five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO.sub.2, or R.sup.3 and R.sup.4 together with the carbons to which they are attached form an annelated five, six or seven membered carbocycle or heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO.sub.2 ;

R.sup.5, R.sup.5a, R.sup.5b, R.sup.5c, R.sup.5d, R.sup.5e, R.sup.5f, R.sup.5g and R.sup.5i are independently lower alkyl;

R.sup.6 and R.sup.6a are independently hydrogen, alkyl,aryl, alkylaryl, cycloalkyl, or R.sup.6 and R.sup.6a together with the nitrogen to which they are attached form an annelated five, six or seven membered heterocycle which may contain 1 to 4 heteroatoms in the ring which are N, O, S, SO, and/or SO.sub.2 ;

A is O, S, NH, or (CH.sub.2).sub.n where n is 0-3, or a pharmaceutically acceptable salt thereof, all steroisomers thereof, and a prodrug ester thereof.

30. A compound having the structure ##STR128##
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