Substituted benzimidazoles as non-nucleoside inhibitors of reverse transcriptase

#The present invention is related to non-nucleoside inhibitors of reverse transcriptase (RT). In particular, the present invention relates to a novel class of substituted benzimidazoles effective in the inhibition of human immunodeficiency virus (HIV) RT.

#Since its recognition in 1981, the acquired immunodeficiency syndrome (AIDS) has become a major pandemic. The worldwide prevalence of HIV infection has been, estimated at more than 18,500,000 cases, with an additional estimate of 1.5 million infected children (R. Famighetti, 1996 World Almanac and Book of Facts, World Almanac Books, Mahwah, N.J., [1995], p. 840).

#The etiologic agent associated with AIDS was identified as the human immunodeficiency virus (HIV). HIV is classified as a retrovirus, as it contains reverse transcriptase (RT), a multi-functional enzyme that contains RNA-dependent DNA polymerase activity, as well as DNA-dependent DNA polymerase and ribonuclease H activities. These three activities are essential for the conversion of genomic retroviral RNA into double-stranded DNA that can then be integrated into an infected host cell genome.

#FIG. 1 shows the general structures of imidazole and benzimidazole.

#FIG. 2 is a schematic retrosynthetic analysis of N-benzyl-2-alkylbenzimidazoles by alkylation of 2-substituted benzimidazoles.

#FIG. 3 is a schematic synthesis of substituted 2-(2,6-difluorophenyl)benzimidazoles.

#The present invention provides substituted benzimidazole compounds, which act as non-nucleoside inhibitors of reverse transcriptase (RT). In particular, the present invention relates to a novel class of substituted benzimidazoles, effective in the inhibition of human immunodeficiency virus (HIV) RT.

#The Description of the Invention is subdived into I) Imidazoles and Benzimidazoles; II) Synthesis of Substituted Benzimidazoles; III) Biological Activity of Substituted Substituted Benzimidazoles; IV) Geometry of TBX and 1-(2,6-Difluorobenyl)-2-Phenylbenzimidazole; and V) Purity of the Substituted Benzimidazoles.

#I. Imidazoles and Benzimidazoles