Pyrimidine-based inhibitors of dipeptidyl peptidase IV and methods

• US 20060142576A1
• Filed: 12/21/2005
• Published: 06/29/2006
• Est. Priority Date: 12/29/2004
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Meng, Wei, Hamann, Lawrence G., Brigance, Robert
• Granted Patent: US 7,589,088 B2
• Time in Patent Office: Days
• US Class Current: 544/314
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07D 239/26 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/42 One nitrogen atom nitro radicals C07D239/30

Abstract

Compounds are provided having the formula (I) wherein R, B, X and Y are as defined herein.

Claims

1. A compound of formula (I)

2. The compound as defined in claim 1 wherein n is 1.

3. The compound as defined in claim 1 selected from

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

5. A pharmaceutical combination comprising a compound of formula I 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.

6. The pharmaceutical combination as defined in claim 5 wherein the therapeutic agent is an antidiabetic agent.

7. The combination as defined in claim 6 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 gamma agonist, a PPAR alpha/gamma dual agonist, an aP2 inhibitor, a SGLT2 inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and a meglitinide.

8. The combination as defined in claim 7 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, isaglitazone, repaglinide and nateglinide.

9. The combination as defined in claim 6 wherein the compound of formula I is present in a weight ratio to the antidiabetic agent in the range of about 0.01 to about 300:

1.

10. The combination as defined in claim 5 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.

11. The combination as defined in claim 10 wherein the anti-obesity agent is at least one agent selected from the group consisting of orlistat, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine and mazindol.

12. The combination as defined in claim 5 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.

13. The combination as defined in claim 12 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 and avasimibe.

14. The combination as defined in claim 5 wherein the compound of formula I is present in a weight ratio to the lipid-lowering agent in the range of about 0.01 to about 100:

1.

15. 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.

16. A method according to claim 15 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, an agent for inhibiting allograft rejection in transplantation and a lipid-lowering agent.

17. A pharmaceutical composition that inhibits DPP-IV containing a compound as defined in claim 1.

18. A method of inhibiting DPP-W comprising administering a pharmaceutical composition comprising a compound as defined in claim 1.