Heterocyclic containing biphenyl aP2 inhibitors and method

• US 6,548,529 B1
• Filed: 03/06/2000
• Issued: 04/15/2003
• Est. Priority Date: 04/05/1999
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Sulsky, Richard B., Magnin, David R., Robl, Jeffrey A.
• Primary Examiner(s): McKane, Joseph K.
• Assistant Examiner(s): SHAMEEM, GOLAM M
• Application Number:
  US09/519,079
• Time in Patent Office: 1,135 Days
• Field of Search: 548/376.1, 514/406
• US Class Current: 514/406
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 37/06 Immunosuppressants, e.g. drugs for graft rejection
• 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: C07D 207/323 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atoms
• CPC Class Codes: C07D 207/452 with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/64 with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
• CPC Class Codes: C07D 249/12 Oxygen or sulfur atoms
• CPC Class Codes: C07D 263/32 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 307/42 Singly bound oxygen atoms
• CPC Class Codes: C07D 317/22 etherified
• CPC Class Codes: C07D 333/20 by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 403/10 linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/10 : linked by a carbon chain containing aromatic rings

Abstract

aP2 inhibiting compounds are provided having the formula

wherein R¹, R², R³, R⁴, X-Z and

are as described herein.

A method is also provided for treating diabetes and related diseases, especially Type II diabetes, employing such aP2 inhibitor or a combination of such aP2 inhibitor and another antidiabetic agent such as metformin, glyburide, troglitazone and/or insulin.

Claims

1. A compound having the structure

wherein R¹ and R² are the same or different and are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteroarylalkyl, aralkyl, cycloheteroalkyl or cycloheteroalkylalkyl;

R³ is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, alkylcarbonyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl, haloalkyl, polyhaloalkyl, cyano, nitro, hydroxy, amino, alkanoyl, alkylthio, alkylsulfonyl, alkoxycarbonyl, alkylaminocarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylaminosulfonyl, alkylamino, dialkylamino, all optionally substituted through 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, cycloheteroalkyl, cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl, aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl;

R⁴ is selected from hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl, polycycloalkylalkyl, cycloalkenyl, cycloalkynyl, alkylcarbonyl, arylcarbonyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkenylalkyl, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkynyl, polycycloalkynylalkyl, haloalkyl, polyhaloalkyl, cyano, nitro, hydroxy, amino, alkanoyl, aroyl, alkylsulfonyl, arylsulfonyl, alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, alkoxycarbonyloxy, alkylaminosulfonyl, arylaminosulfonyl, alkylamino, dialkylamino, all optionally substituted through available carbon atoms with 1, 2, 3, 4 or 5 groups selected from hydrogen, halo, alkyl, haloalkyl, polyhaloalkyl, alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, arylcycloalkyl, arylalkenyl, arylalkynyl, aryloxy, aryloxyalkyl, arylalkoxy, arylazo, heteroaryloxo, heteroarylalkyl, heteroarylalkenyl, heteroaryloxy, hydroxy, hydroxyalkyl, nitro, cyano, amino, substituted amino, alkylamino, dialkylamino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkylcarbonyl, arylcarbonyl, acyl, arylaminocarbonyl, alkoxycarbonyl, aminocarbonyl, alkynylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, alkylsulfonyl, aminosulfinyl, aminosulfonyl, arylsulfonylamino, heteroarylcarbonylamino, heteroarylsulfinyl, heteroarylthio, heteroarylsulfonyl, alkylsulfinyl, sulfonamido or sulfonyl;

X is a bond or a linker group selected from (CH₂)_n, O(CH₂)_n, S(CH₂)_n, cycloalkylene, N(R⁵) (CH₂)_n, NHCO, or CH═

CH where n=0-5 and R⁵ is hydrogen, alkyl, or alkanoyl;

Z is CO₂H or tetrazole of the formula

or its tautomer; and

the group

is pyrazole which may further be optionally substituted with alkyl, alkenyl, hydroxyalkyl, keto, carboxyalkyl, carboxy, cycloalkyl, alkoxy, formyl, alkanoyl, alkoxyalkyl or alkoxycarbonyl,

including all stereoisomers thereof;

or a pharmaceutically acceptable salt thereof, or a prodrug ester thereof;

with the proviso that n≠

when Z is CO₂H and X is O(CH₂)_n, S(CH₂)_n or N(R⁵) (CH₂)_n).

2. The compound as defined in claim 1 wherein R³ and R⁴ are the same or different and are independently selected from hydrogen, halogen, alkyl, alkoxy, alkylthio, haloalkyl, CF₃, cyano, hydroxy, or nitro.

3. The compound as defined in claim 1 wherein

is

where R⁸ is selected from H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkenyl, and

R⁹ is selected from H, alkyl, alkenyl, formyl, CO₂(lower alkyl), hydroxyalkyl, alkoxyalkyl, CO(alkyl), carboxyalkyl, haloalkyl, alkenyl or cycloalkyl.

4. The compound as defined in claim 1 wherein R¹ and R² are the same or different and are independently selected from aryl, cycloalkyl, heteroaryl or hydrogen.

5. The compound as defined in claim 1 wherein R¹ and R² are the same or different and are independently selected from phenyl, cyclohexyl, hydrogen or pyrido.

6. The compound as defined in claim 1 wherein R³ and R⁴ are the same or different and are independently selected from hydrogen, alkyl or halogen.

7. The compound as defined in claim 1 wherein —

X—

Z is

8. The compound as defined in claim 1 wherein

is

where R⁸ is H, lower alkyl, fluoroalkyl, or alkoxyalkyl, and R⁹ is H, lower alkyl, fluoroalkyl, alkoxy or hydroxyalkyl;

R¹ and R² are the same or different and are independently selected from phenyl or substituted phenyl;

R³ and R⁴ are the same or different are independently selected from H, halo, alkyl or alkoxy;

X is OCH₂, NHCH₂, CH₂ or CH₂CH₂; and

Z is CO₂H or tetrazole.

9. The compound as defined in claim 1 where

is

where R⁹ is H, lower alkyl, fluoroalkyl, or alkoxy;

R¹ and R² are each phenyl;

R³ and R⁴ are each H;

X is OCH₂, CH₂ or NHCH₂; and

Z is CO₂H or tetrazole.

10. The compound as defined in claim 1 wherein

R³ is H

R⁴ is H

and —

X—

Z is

11. The compound as defined in claim 1 which is

12. The compound as defined in claim 1 which is

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

14. A pharmaceutical combination comprising an aP2 inhibitor compound as defined in claim 1 and an antidiabetic agent other than an aP2 inhibitor, an anti-obesity agent, a lipid-lowering agent, an anti-hypertensive agent, an anti-platelet agent and/or an anti-infective agent.

15. The pharmaceutical combination as defined in claim 14 comprising said aP2 inhibitor compound and an antidiabetic agent.

16. The combination as defined in claim 15 wherein the antidiabetic agent is 1, 2, 3 or more of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ

agonist, a PPAR α

/γ

dual agonist, an SGLT2 inhibitor, a DP4 inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1), insulin and/or a meglitinide.

17. The combination as defined in claim 16 wherein the antidiabetic agent is 1, 2, 3 or more 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, KAD1129, AR-H039242, GW-409544, KRP297, AC2993, LY315902, and/or NVP-DPP-728A.

18. The combination as defined in claim 15 wherein the compound is present in a weight ratio to the antidiabetic agent within the range from about 0.01 to about 100:

1.

19. The combination as defined in claim 14 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.

20. The combination as defined in claim 19 wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, and/or mazindol.

21. The combination as defined in claim 14 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.

22. The combination as defined in claim 21 wherein the lipid lowering agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, avasimibe, TS-962, MD-700, and/or LY295427.

23. The combination as defined in claim 21 wherein the aP2 inhibitor is present in a weight ratio to the lipid-lowering agent within the range from about 0.01 to about 100:

1.

24. The combination as defined in claim 14 wherein the anti-hypertensive agent is an ACE inhibitor, a vasopeptidase inhibitor, an angiotensin-II antagonist, a calcium-channel blocker, an alpha-blocker, a beta-blocker, a potassium channel opener, a centrally acting alpha agonist, and/or a diuretic.

25. The combination as defined in claim 24 wherein the anti-hypertensive agent is omapatrilat, [S-(R*,R*)]-hexahydro-6-[(2-mercapto-1-oxo-3-phenylpropyl)amino]-2,2-dimethyl-7-oxo-1H-azepine-1-acetic acid, lisinopril, enalapril, quinapril, benazepril, fosinopril, ramipril, captopril, enalaprilat, moexipril, trandolapril, perindopril, losartan, valsartan, irbesartan, candesartan, telmisartan, amlodipine, diltiazem, nifedipine, verapamil, felodipine, nisoldipine, isradipine, nicardipine, terazosin, doxazosin, prazosin, nadolol, propranolol, metoprolol, atenolol, carvedilol, sotalol, hydrochlorthiazide, torasemide, furosemide, spironolactone, indapamide, clonidine and/or guanfacine.

26. The combination as defined in claim 14 wherein the anti-platelet agent is aspirin, clopidogrel, ticlopidine, abciximab, tirofiban, eptifibatide, anagrelide and/or dipyridamole.

27. The combination as defined in claim 14 wherein the anti-infective is azithromycin, gatifoxacin, ciprofloxacin, levofloxacin, or trovafloxacin.