Lactam glycogen phosphorylase inhibitors and method of use

• US 7,425,550 B2
• Filed: 02/13/2006
• Issued: 09/16/2008
• Est. Priority Date: 05/20/2002
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Wu, Gang, Stouch, Terry, Sher, Philip, Ellsworth, Bruce
• Primary Examiner(s): Solola; Taofiq A
• Application Number:
  US11/352,867
• Publication Number:
  US 20060128687A1
• Time in Patent Office: 946 Days
• Field of Search: 514/211.06, 540/491
• US Class Current: 514/211.06
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/541 Non-condensed thiazines containing further heterocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07D 209/42 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

A compound of formula I is provided having the structure

wherein

• • W is as defined herein;
  • X is —CHR⁵O—;
  • Y is a bond;
  • Z is an aryl or heteroaryl group; and
  • R¹, and R², are as described herein.

Further provided is a method for treating diabetes and related diseases employing the above compound, either alone or in combination with another therapeutic agent.

Claims

1. A compound of the formula I

2. The compound as defined in claim 1 wherein

Z is an aryl or heteroaryl group of the structure

3. A pharmaceutical composition comprising a compound of formula I

4. The pharmaceutical composition of claim 3 wherein

Z is an aryl or heteroaryl group of the structure

5. The pharmaceutical composition of claim 3 wherein

R¹ is hydrogen;

Z is

6. The pharmaceutical composition of claim 3 wherein

Z is

7. The pharmaceutical composition of claim 3 wherein W is 5-chloroindol-2-yl.

8. The pharmaceutical composition of claim 3

wherein

X is —

CHR⁵O—

;

Y is a bond; and

R⁵ is CO₂H.

9. The pharmaceutical composition of claim 3 wherein the compound of formula I has the structure:

(S)-3-(5-chloroindole-2-carbonylamino)-2,3-dihydro-1,5-benzoxazepin-4(5H)-one;

(R)-3-(5-chloroindole-2-carbonylamino)-2,3-dihydro-1,5-benzoxazepin-4(5H)-one;

(2S,3S)-3-(5-chloroindole-2-carbonylamino)-2-methyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one;

(2S,3R)-3-(5-chloroindole-2-carbonylamino)-2-methyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one;

(S)-1-carboxymethyl-3-(5-chloroindole-2-carbonylamino)-2,3-dihydro-1,5-benzoxazepin-4(5H)-one;

(S)-9-aza-3-(5-chloroindole-2-carbonylamino)-2,3-dihydro-1,5-benzoxazepin-4(5H)-one;

(S)-7-aza-3-(5-chloroindole-2-carbonylamino)-2,3-dihydro-1,5-benzoxazepin-4(5H)-one.

10. The pharmaceutical composition of claim 3 comprising a compound of formula I and at least one anti-diabetic agent, an anti-obesity agent or a lipid lowering agent.

11. The pharmaceutical composition of claim 10 wherein the antidiabetic agent is at least one agent selected from the group consisting of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR-alpha agonist, a PPAR-gamma agonist, a PPAR alpha/gamma dual agonist, an aP2 inhibitor, an SGLT2 inhibitor, a dipeptidyl peptidase-IV inhibitor, an insulin sensitizer, a thiazolidinedione, a glucagon-like peptide-1 (GLP-1), an aldose reductase inhibitor, a sorbitol dehydrogenase inhibitor, insulin and a meglitinide.

12. The pharmaceutical composition of claim 10 wherein the antidiabetic agent is at least one agent selected from the group consisting 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 NVP-DPP-728A.

13. The pharmaceutical composition of claim 10 wherein the anti-obesity agent is at least one agent selected from the group consisting of a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta compound and an anorectic agent.

14. The pharmaceutical composition of claim 10 wherein the anti-obesity agent is at least one agent selected from the group consisting of orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine and mazindol.

15. The pharmaceutical composition of claim 10 wherein the lipid lowering agent is at least one agent selected from the group consisting of an MTP inhibitor, cholesterol ester transfer protein, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, a cholesterol absorption inhibitor, an ileal Na+/bile cotransporter inhibitor, a bile acid sequestrant, a nicotinic acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor and an ACAT inhibitor.

16. The pharmaceutical composition of claim 10 wherein the lipid lowering agent is at least one agent selected from the group consisting of pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962, MD-700, CP-529414, and/or LY295427.

17. The pharmaceutical composition of claim 10 comprising a compound of formula I and at least one anti-hypertensive agent.

18. A method for treating diabetes, hyperglycemia, obesity, or glucose intolerance, which comprises administering to a mammalian patient in need of treatment a therapeutically effective amount of the pharmaceutical composition as defined in claim 3.

19. The method according to claim 18 further comprising administering, concurrently or sequentially, a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of other compounds of formula I, anti-diabetic agents, anti-obesity agents, anti-hypertensive agents, anti-atherosclerotic agents, and lipid-lowering agents.

20. The method of claim 18 wherein

Z is an aryl or heteroaryl group of the structure