Patent ID: 6200998
Filing Date: 2001-03-13
Classification: C07D

Abstract:
A method of treating, controlling or preventing one or more diseases, disorders, or conditions selected from the group consisting of diabetes mellitus, hyperglycemia, obesity, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, atherosclerosis, vascular restenosis, irritable bowel syndrome, pancreatitis, abdominal obesity, adipose cell tumors, adipose cell carcinomas, Syndrome X, polycystic ovarian syndrome, and other disorders where insulin resistance is a component, said method comprising the administration of an effective amount of a compound having Formula I, defined below, and an effective amount of a second compound selected from the group consisting of insulin sensitizers, PPAR.gamma. agonists, glitazones, troglitazone, pioglitazone, englitazone, MCC-555, BRL49653, biguanides, metformin, phenformin, insulin, insulin mimetics, sulfonylureas, tolbutamide, glipizide, .alpha.-glucosidase inhibitors, acarbose, cholesterol lowering agents, HMG-CoA reductase inhibitors, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, other statins, sequestrants, cholestyramine, colestipol, dialkylaminoalkyl derivatives of a cross-linked dextran, nicotinyl alcohol, nicotinic acid, a nicotinic acid salt, PPAR.alpha. agonists, fenofibric acid derivatives, gemfibrozil, clofibrate, fenofibrate, benzafibrate, inhibitors of cholesterol absorption, beta-sitosterol, acyl CoA:cholesterol acyltransferase inhibitors, melinamide, probucol, PPAR.delta. agonists, antiobesity compounds, fenfluramine, dexfenfluramine, phentiramine, sulbitramine, orlistat, neuropeptide Y5 inhibitors, .beta..sub.3 adrenergic receptor agonists, and ileal bile acid transporter inhibitors, wherein the compound of Formula I is defined as follows: ##STR91##whereinAr.sup.1 is (1) arylene or(2) heteroarylene,wherein arylene and heteroarylene are optionally substituted with from 1 to 4 groups selected from R.sup.a ;Ar.sup.2 is (1) ortho-substituted aryl or(2) ortho-substituted heteroaryl,wherein said ortho substituent is selected from R; and aryl and heteroaryl are optionally further substituted with from 1-4 groups independently selected from R.sup.a ;X and Y are independently O, S, N--R.sup.b, or CH.sub.2 ;Z is O or S;n is 0 to 3;R is (1) C.sub.3-10 alkyl optionally substituted with 1-4 groups selected from halo and C.sub.3-6 cycloalkyl,(2) C.sub.3-10 alkenyl, or(3) C.sub.3-8 cycloalkyl;R.sup.a is (1) C.sub.1-15 alkanoyl,(2) C.sub.1-15 alkyl,(3) C.sub.2-15 alkenyl,(4) C.sub.2-15 alkynyl,(5) halo,(6) OR.sup.b,(7) aryl, or(8) heteroaryl,wherein said alkyl, alkenyl, alkynyl, and alkanoyl are optionally substituted with from 1-5 groups selected from R.sup.c, and said aryl and heteroaryl optionally substituted with 1 to 5 groups selected from R.sup.d ;R.sup.b is (1) hydrogen,(2) C.sub.1-10 alkyl,(3) C.sub.2-10 alkenyl,(4) C.sub.2-10 alkynyl,(5) aryl,(6) heteroaryl,(7) aryl C.sub.1-15 alkyl,(8) heteroaryl C.sub.1-15 alkyl,(9) C.sub.1-15 alkanoyl,(10) C.sub.3-8 cycloalkyl,wherein alkyl, alkenyl, alkynyl are optionally substituted with one to four substituents independently selected from R.sup.c, and cycloalkyl, aryl and heteroaryl are optionally substituted with one to four substituents independently selected from R.sup.d ; orR.sup.c is (1) halo,(2) aryl,(3) heteroaryl,(4) CN,(5) NO.sub.2,(6) OR.sup.f ;(7) S(O).sub.m R.sup.f, m=0, 1 or 2, provided that R.sup.f is not H when m is 1 or 2;(8) NR.sup.f R.sup.f,(9) NR.sup.f COR.sup.f,(10) NR.sup.f CO.sub.2 R.sup.f,(11) NR.sup.f CON(R.sup.f).sub.2,(12) NR.sup.f SO.sub.2 R.sup.f, provided that R.sup.f is not H,(13) COR.sup.f,(14) CO.sub.2 R.sup.f,(15) CON(R.sup.f).sub.2,(16) SO.sub.2 N(R.sup.f).sub.2,(17) OCON(R.sup.f).sub.2, or(18) C.sub.3-8 cycloalkyl,wherein said cycloalkyl, aryl and heteroaryl are optionally substituted with 1 to 3 groups of halo or C.sub.1-6 alkyl;R.sup.d is (1) a group selected from R.sup.c,(2) C.sub.1-10 alkyl,(3) C.sub.2-10 alkenyl,(4) C.sub.2-10 alkynyl,(5) aryl C.sub.1-10 alkyl, or(6) heteroaryl C.sub.1-10 alkyl,wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substituted with a group independently selected from R.sup.e ;R.sup.e is (1) halogen,(2) amino,(3) carboxy,(4) C.sub.1-4 alkyl,(5) C.sub.1-4 alkoxy,(6) hydroxy,(7) aryl,(8) aryl C.sub.1-4 alkyl, or(9) aryloxy;R.sup.f is (1) hydrogen,(2) C.sub.1-10 alkyl,(3) C.sub.2-10 alkenyl,(4) C.sub.2-10 alkynyl,(5) aryl,(6) heteroaryl,(7) aryl C.sub.1-15 alkyl,(8) heteroaryl C.sub.1-15 alkyl,(9) C.sub.1-15 alkanoyl,(10) C.sub.3-8 cycloalkyl;wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkanoyl and cycloalkyl are optionally substituted with one to four groups selected from R.sup.e ;or a pharmaceutically acceptable salt thereof.