Naphthylene derivatives as cytochrome P450 inhibitors

Abstract

Compounds of the formula (I); and pharmaceutically acceptable salts thereof, wherein n1, n2, n3, n4, G <1>,Q<1>, Z, R<1>, R<2>, R<3>, R<4a>, R<4b>, R<5a>, and R<5b> are defined herein, inhibit the cytochrome P450RAI enzyme and are useful for the treatment and / or prevention of various diseases and conditions which respond to treatment by retinoids and by naturally occurring retinoic acid.

Description

Background of the invention The present invention relates to novel heteroaryl-naphthyl-alkylamines and salts thereof, processes for their preparation and compositions comprising them. The novel compounds of the present invention are useful for inhibiting the cytochrome P450 RAI enzyme (Cyp26) in animals, including humans, for the treatment and / or prevention of multiple diseases that respond to treatment with retinoids and naturally occurring retinoic acids. diseases and conditions. It is known in the art that retinoic acid, retinoids, and pharmaceutical compositions including retinoic acid or retinoids as active ingredients play an important role in the regulation and differentiation of epithelial cells. Such regulatory and differentiation effects, including the ability to promote cell differentiation, apoptosis, and inhibit cell proliferation, make retinoic acid and retinoid compounds useful agents in the treatment of tumors and, for example, in the treatment of skin-related...

AI Technical Summary

Problems solved by technology

Liarozole and other Cyp26 inhibitors inhibit other cytochrome P450-mediated responses and are therefore limited by their lack of specificity for other cytochrome P450 enzymes

This lack of specificity may account for the limited risk-benefit ratio observed in prostate cancer patients in the phase III trial of Liarozole (inadequate consideration of the activity / toxicity ratio by the FDA)

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