2-(5-bromo-4-(4-cyclopropylnaphthalen-1-yl)-4h-1,2,4-triazol-3-ylthio)acetic acid and methyl ester

Abstract

A series of S-triazolyl α-mercaptoacetanilides having general structure (I) are provided, where Q is CO2H, CONR2, SO3H, or SO2NR2. The compounds inhibit several variants of the reverse transcriptase of HIV, and are useful in the treatment of HIV infections.

Description

RELATED APPLICATIONS[0001]This application claims priority of U.S. provisional applications 60 / 604,219, filed Aug. 25, 2004, 60 / 604,220, filed Aug. 25, 2004, and 60 / 686,351, filed May 31, 2005, the contents of each of which are incorporated herein by reference in their entirety.FIELD OF THE INVENTION[0002]The field of the invention is enzyme inhibitors and the use of enzyme inhibitors for treatment of disease. More particularly, the invention deals with the in vitro and in vivo inhibition of HIV reverse transcriptase as a method of treating HIV infection.BACKGROUND OF THE INVENTION[0003]Numerous treatments for HIV are known in the art, and among other pharmaceutically active compounds, reverse transcriptase inhibitors have provided significant therapeutic effect to many HIV infected patients. For example, lamivudine (3TC) or zidovudine (AZT) are relatively well tolerated antiretroviral drugs. However, numerous viral strains have recently emerged with marked resistance against these ...

AI Technical Summary

Benefits of technology

[0031]Suitable reagents include but are not limited to iodoacetic acid and methyl bromoacetate, and ethyl α-bromopropionate when it is desired that R3 be methyl. If an ester is used, it is hydrolyzed after the S-alkylation to provide a free carboxylic acid. The acid and the aniline may be coupled with any of the usual carboxyl activating reagents or reagent mixtures, for example a carbodiimide in the presence of a tertiary amine base, optionally with N-hydroxybenzotriazole as catalyst, or thionyl or oxalyl chloride, with dimethylaminopyridine as catalyst. This scheme is advantageous when the aniline is valuable relative to the triazole.

Problems solved by technology

Unfortunately, development of resistance to one nucleoside-type inhibitor is often accompanied by the development of a degree of resistance to another nucleoside-type inhibitor, frequently necessitating a switch to a different class of drug.

However, the relatively complex administration regimen of such combinations often proves an organizational and financial challenge to many patients, and compliance is frequently less than desirable.

Unfortunately, combination therapies of protease inhibitors with nucleoside reverse transcriptase inhibitors are often poorly tolerated and frequently lead to premature termination of the therapy.

The HIV virus has a relatively high frequency of mutation, which often leads to drug resistance to current treatments.

Images