Non nucleoside reverse transcriptase inhibitors

Abstract

Phosphorus-substituted imidazole compounds with anti-HIV properties having use as therapeutics and for other industrial purposes are disclosed. The compositions inhibit reverse transcriptase activity and are useful therapeutically for the inhibition of such enzymes, as well as in assays for the detection of such enzymes.

Description

[0001] This non-provisional application claims the benefit of Provisional Application No. 60 / 375,622, filed Apr. 26, 2002, Provisional Application No. 60 / 375,779 filed Apr. 26, 2002, Provisional Application No. 60 / 375,834 filed Apr. 26, 2002 and Provisional Application No. 60 / 375,665 filed Apr. 26, 2002, which are incorporated herein by reference. Additionally, copending applications Attorney Docket Nos. 257.P2C and 259.PC filed concurrently with this application are also incorporated herein by reference in their entirety.FIELD OF THE INVENTION [0002] The invention relates generally to compounds with antiviral activity and more specifically with anti-HIV properties. BACKGROUND OF THE INVENTION [0003] Human immunodeficiency virus (HIV) infection and related disease is a major public health problem worldwide. The retrovirus human immunodeficiency virus type 1 (HIV-1), a member of the primate lentivirus family (DeClercq E (1994) Annals of the New York Academy of Sciences, 724:438-456; ...

AI Technical Summary

Benefits of technology

[0874] Although certain embodiments have been described in detail above, those having ordinary skill in the art will clearly understand that many modifications are possible in the embodiments without departing from the teachings thereof. All such modifications are intended to be encompassed within the claims of the invention.

Problems solved by technology

Human immunodeficiency virus (HIV) infection and related disease is a major public health problem worldwide.

Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains have limited their usefulness (Palella, et al N. Engl. J. Med.

Unfortunately, 30 to 50% of patients currently fail combination therapy due to the development of drug resistance, non-compliance with complicated dosing regimens, pharmacokinetic interactions, toxicity, and lack of potency.

Though many attempts have been made to develop effective methods for importing biologically active molecules into cells, both in vivo and in vitro, none has proved to be entirely satisfactory.

Optimizing the association of the inhibitory drug with its intracellular target, while minimizing intercellular redistribution of the drug, e.g. to neighboring cells, is often difficult or inefficient.

Most agents currently administered to a patient parenterally are not targeted, resulting in systemic delivery of the agent to cells and tissues of the body where it is unnecessary, and often undesirable.

This may result in adverse drug side effects, and often limits the dose of a drug (e.g., cytotoxic agents and other anti-cancer or anti-viral drugs) that can be administered.

By comparison, although oral administration of drugs is generally recognized as a convenient and economical method of administration, oral administration can result in either (a) uptake of the drug through the cellular and tissue barriers, e.g. blood / brain, epithelial, cell membrane, resulting in undesirable systemic distribution, or (b) temporary residence of the drug within the gastrointestinal tract.

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