Glycinenitrile-based inhibitors of dipeptidyl peptidase IV and methods

• US 20040259919A1
• Filed: 10/21/2003
• Published: 12/23/2004
• Est. Priority Date: 10/23/2002
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Hamann, Lawrence G., Magnin, David R.
• Granted Patent: US 6,995,180 B2
• Time in Patent Office: Days
• US Class Current: 514/357
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07C 255/29 containing cyano groups and acylated amino groups bound to the carbon skeleton
• CPC Class Codes: C07C 255/30 containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same unsaturated acyclic carbon skeleton
• CPC Class Codes: C07C 2601/02 with a three-membered ring
• CPC Class Codes: C07C 2601/04 with a four-membered ring
• CPC Class Codes: C07C 2602/42 the bicyclo ring system containing seven carbon atoms
• CPC Class Codes: C07C 2603/74 Adamantanes
• CPC Class Codes: C07D 211/28 to which a second hetero atom is attached
• CPC Class Codes: C07D 211/34 with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

A compound of the formula I:

wherein R¹, R², R³ and R⁴ are as defined herein.

Further provided are methods of using such compounds for the treatment of diabetes and related diseases, and to pharmaceutical compositions containing such compounds.

Claims

1. A compound of the formula I:

2. The compound as defined in claim 1 wherein

R¹ is H or C₁-C₆ alkyl;

R² is C₁-C₆ alkyl;

R³ is alkyl or cycloalkyl; and

R⁴ is H.

3. The compound as defined in claim 1 wherein

R¹ is H;

R² is C₁-C₆ alkyl;

R³ is a cycloalkyl containing 6 to 15 carbons; and

R⁴ is H.

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

5. The compounds as defined in claim 3 wherein the pharmaceutically acceptable salt is the hydrochloride salt or the trifluoroacetic acid salt.

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

7. A pharmaceutical combination comprising a compound as defined in claim 1 and at least one therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, a anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent.

8. The pharmaceutical combination as defined in claim 7 comprising the compound as defined in claim 1 and an antidiabetic agent.

9. The combination as defined in claim 8 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 γ

agonist, a PPAR α

/γ

dual agonist, an aP2 inhibitor, a SGLT2 inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and a meglitinide.

10. The combination as defined in claim 9 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, G1-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD 1129, AR-HO39242, GW-409544, KRP297, AC2993, LY315902, and NVP-DPP-728A.

11. The combination as defined in claim 8 wherein the compound is present in a weight ratio to the antidiabetic agent in the range of about 0.01 to about 300:

1.

12. The combination as defined in claim 7 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.

13. The combination as defined in claim 12 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.

14. The combination as defined in claim 7 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, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, or an ACAT inhibitor.

15. The combination as defined in claim 14 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.

16. The combination as defined in claim 14 wherein the compound as defined in claim 1 is present in a weight ratio to the lipid-lowering agent in the range of about 0.01 to about 100:

1.

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

18. A method according to claim 17 further comprising administering, concurrently or sequentially, a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, a anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent.