Adamantylglycine-based inhibitors of dipeptidyl peptidase IV and methods

• US 20050239839A1
• Filed: 06/09/2005
• Published: 10/27/2005
• Est. Priority Date: 08/01/2003
• Status: Abandoned Application

• Current Assignee: Ashish Khanna, David R. Magnin, James C. Sutton, Jeffrey Robl, Lawrence G. Hamann, Ligaya M. Simpkins, Mark S. Kirby
• Original Assignee: Ashish Khanna, David R. Magnin, James C. Sutton, Jeffrey Robl, Lawrence G. Hamann, Ligaya M. Simpkins, Mark S. Kirby
• Inventors: Hamann, Lawrence G., Sutton, James C., Simpkins, Ligaya M., Khanna, Ashish, Magnin, David R., Kirby, Mark S., Robl, Jeffrey
• Application Number:
  US11/149,408
• Publication Number:
  US 20050239839A1
• Time in Patent Office: Days
• US Class Current: 514/319
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07C 255/46 to carbon atoms of non-condensed rings
• CPC Class Codes: C07C 255/47 to carbon atoms of rings being part of condensed ring systems
• CPC Class Codes: C07C 2601/08 the ring being saturated
• CPC Class Codes: C07C 2602/18 the ring system containing six carbon atoms
• CPC Class Codes: C07C 2603/74 Adamantanes
• CPC Class Codes: C07D 207/16 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 209/52 condensed with a ring other than six-membered
• CPC Class Codes: C07D 277/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 295/185 from aliphatic carboxylic acids

Abstract

Compounds are provided having the formula (I) wherein: n is 0, 1 or 2; m is 0, 1 or 2; the sum of n+m less then or equal to 2; the dashed bonds forming a cyclopropyl ring can only be present when Y is CH; X is H or CN;

• • Y is CH, CH₂, CHF, CF₂, O, S, SO, or SO₂; and A is adamantyl. Further provided are methods of using such compounds for the treatment of diabetes and related diseases, and to pharmaceutical compositions containing such compounds.

Claims

1-6. -6. (canceled)

7. A pharmaceutical combination comprising a compound of formula (I)

wherein:

n is 0, 1 or 2;

m is 0, 1 or 2;

the sum of n plus m is less then or equal to 2;

the dashed bonds forming a cyclopropyl ring when Y is CH;

X is hydrogen or CN;

Y is CH, CH₂, CHF, CF₂, O, S, SO, or SO₂

A is adamantyl which can be optionally substituted with from zero to six substituents each independently selected from OR¹, NR¹R², alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, bicycloalkylalkyl, alkylthioalkyl, arylalkylthioalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloheteroalkyl and cycloheteroalkylalkyl, all optionally substituted throuqh available carbon atoms with 1, 2, 3, 4 or 5 groups selected from hydrogen, halo, alkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, heteroarylamino, arylamino, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkylsulfonylamino, alkylaminocarbonylamino, alkoxycarbonylamino, alkylsulfonyl, aminosulfonyl, alkylsulfinyl, sulfonamido and sulfonyl;

R¹ and R² are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl and heteroaryl;

including pharmaceutically acceptable salts thereof, and prodrug esters thereof, and all stereoisomers thereof,

with the proviso that the compound of formula (I) is not selected from

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 wherein the therapeutic agent is 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 gamma agonist, a PPAR alpha/gamma dual agonist, an aP2 inhibitor, a SGLT2 inhibitor, an insulin sensitizer, a glucagon-like peptide-I (GLP-I), 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 mefformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, isaglitazone, repaglinide muraglitazar, peliglitizar and nateglinide.

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, 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 and avasimibe.

21. The pharmaceutical composition as defined in claim 7 wherein the compound of formula (I) is selected from

22. The pharmaceutical composition as defined in claim 7 wherein the compound of formula (I) is selected from

23. The pharmaceutical composition as defined in claim 7 wherein the compound of formula (I) is selected from

24. The pharmaceutical composition as defined in claim 7 wherein the compound of formula (I) is selected from

17-20. -20. (canceled)