Heterocyclic compounds and methods of use

Abstract: provide pharmacological agents which are potent agonists of Peroxisome Proliferator-Activated Receptors (PPARs). Accordingly, the compounds of the instant invention are useful for the treatment of conditions mediated by the PPAR receptor activity in mammals. Such conditions include dyslipidemia, hyperlipidemia, hypercholesteremia, atherosclerosis, hypertriglyceridemia, heart failure, myocardial infarction, vascular diseases, cardiovascular diseases, hypertension, obesity, inflammation, arthritis, cancer, Alzheimer's disease, skin disorders, respiratory diseases, ophthalmic disorders, inflammatory bowel diseases, ulcerative colitis and Crohn's disease. The compounds of the present invention are particularly useful in mammals as hypoglycemic agents for the treatment and prevention of conditions in which impaired glucose tolerance, hyperglycemia and insulin resistance are implicated, such as type-1 and type-2 diabetes, and Syndrome X. Preferred are the compounds of the invention which are dual agonists of PPARα and PPARγ receptors. Compounds of the formula (end of abstract)

Heterocyclic compounds and methods of use description/claims

Brief Patent Description

Full Patent Description

Patent Application Claims

This application is a continuation of application Ser. No. 11/619,936, filed Jan. 4, 2007, which is a divisional of application Ser. No. 10/495,992, filed Jun. 14, 2004, U.S. Pat. No. 7,183,304, which is a 371 of PCT/EP02/13025, filed Nov. 20, 2002, which claims benefit of 60/396,906, filed Jul. 18, 2002, abandoned and also claims benefit of 60/331,986, filed Nov. 21, 2001, abandoned; the contents of which are incorporated herein in its entirety.

The present invention relates to heterocyclic compounds, pharmaceutical compositions containing them and to methods of treating conditions associated with the Retinoid X Receptor (RXR) and the Peroxisome Proliferator-Activated Receptor (PPAR) families with the three subtypes PPARα, PPARδ and PPARγ.

In one aspect the present invention provides compounds of the formula

wherein

L is

radical in which R₁is hydrogen, optionally substituted alkyl, aryl, heteroaryl, aralkyl or cycloalkyl;

- R₂is hydrogen, hydroxy, optionally substituted alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, alkylthio, arylthio or aralkylthio;
- R₃is hydrogen or aryl; or
- R₂and R₃combined are alkylene which together with the carbon atoms they are attached to form a 5- to 7-membered ring;
- n is zero or an integer from 1 to 2;