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|Title:||C-aryl glucoside SGLT2 inhibitors and method|
|Abstract:||An SGLT2 inhibiting compound is provided having the formula ##STR1## 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)|
1. A compound having the structure ##STR25##
or a pharmaceutically acceptable salt, a stereoisomer thereof, or a prodrug ester thereof.
2. The compound as defined in claim 1 having the structure ##STR26##
3. A pharmaceutical composition comprising a compound as defined in claim 1 and a pharmaceutically acceptable carrier therefor.
4. A pharmaceutical combination comprising an SGLT2 inhibitor compound as defined in claim 3 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.
5. The pharmaceutical combination as defined in claim 4 comprising said SGLT2 inhibitor compound and an antidiabetic agent.
6. The combination as defined in claim 5 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.
7. The combination as defined in claim 6 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.
8. The combination as defined in claim 5 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.
9. The combination as defined in claim 4 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.
10. The combination as defined in claim 9 wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, and/or mazindol.
11. The combination as defined in claim 4 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.
12. The combination as defined in claim 11 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.
13. The combination as defined in claim 11 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.
14. 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.
15. The method as defined in claim 14 where the SGLT2 inhibitor compound has the structure ##STR27##
16. 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.
17. A compound having the structure ##STR28## ##STR29##
or a pharmaceutically acceptable salt thereof, all stereolsomers thereof, or a prodrug ester thereof.
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