Imidazo[1,2-a]pyridine C-nucleosides as antiviral...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai

Reexamination Certificate

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C536S028900, C536S029200, C514S043000

Reexamination Certificate

active

06214801

ABSTRACT:

FIELD OF THE INVENTION
This invention pertains to nucleoside analogs which have antiviral activity and low cytotoxicity, compositions comprising them, and methods of antiviral treatment employing them. More particularly, this invention pertains to imidazo[1 ,2-a]pyridine C-nucleosides, as exemplified by compounds such imidazo[1,2-a]pyridine C5-nucleosides and imidazo[1,2-a]pyridine C3-nucleosides.
BACKGROUND OF THE INVENTION
Benzimidazole nucleosides are particularly attractive as potential antiviral agents because of their ability to avoid some major pathways of bioactive purine (bicyclic) nucleoside inactivation, e.g., deamination by adenosine deaminase and glycosidic bond cleavage by purine nucleoside phosphorylases. For example, current therapy for HCMV includes the use of drugs such as ganciclovir (also known as DHPG), foscanet, and cidofovir. However, known benzimidazole nucleosides such as 5,6-dichloro-1-(&bgr;-D-ribofuranosyl) benzimidazole (DRB) have demonstrated only marginal levels of activity or generally unacceptable levels of cytotoxicity, or both, thereby greatly diminishing their usefulness in the treatment of viral infections. Recently, benzimidazole compounds, such as TCRB (2,5,6-trichloro-1-(2′-&bgr;-D-ribofuranosyl)-benzimidazole) and BDCRB (2-bromo-5,6-dichloro-1-(2′-&bgr;-D-ribofuranosyl)-benzimidazole) have also been found to be useful against HCMV infections. See, for example, Townsend et al., J. Med. Chem., Vol. 38, pp. 4098-4105 (1995).
A number of benzimidazole nucleosides have been synthesized and tested for their antiviral activity and cytotoxicity in an effort to identify a compound with superior anti-human cytomegalovirus (HCMV) activity to ganciclovir and foscamet. Antiviral activity of polysubstituted benzimidazoles such as 5,6-dichloro-1-(-&bgr;-D-ribofuranosyl)benzimidazole (DRB) and some closely related derivatives have been previously described (I. Tamm,
Science
(1954) Vol. 120:847-848). Their activity against specific viruses, such as RNA rhinovirus and DNA herpes simplex virus type 1 and type 2, also has been reported.
Several of the 5′-deoxyribosyl benzimidazole analogs, including 2,5,6-trichloro-1-(-&bgr;-D-ribofuranosyl)benzimidazole (TCRB) have shown very potent activity against HCMV and low cellular toxicity at concentrations inhibiting viral growth. Structural activity relationships of TCRB and heterocycle and carbohydrate modified derivatives have been reported. (See, Revenkar, R. G. and Townsend, L. B. (1968)
J. Heterocyclic Chem
. Vol. 5:477-483; Townsend, L. B. and Drach, J. C., Fifth International Conference on Antiviral Research Vancouver, British Columbia, March 1992; Revenkar, R. G. and Townsend, L. B. (1968)
J. Heterocvclic Chem
. Vol. 5:615-620; Zou, R. et al. “Design, synthesis and antiviral evaluation of some TCRB analogs modified on the benzene moiety” Poster #142. Division of Medicinal Chemistry, 204th American Chemical Society National Meeting, Washington, D. C., Aug. 23-28, 1992; and Saluja, S. et al. “Synthesis and antiviral activity of certain 2-substituted-5,6-dichlorobenzimidazole acyclic nucleosides. Poster #146. Division of Medicinal Chemistry, 204th American Chemical Society National Meeting, Washington, D. C., Aug. 23-28, 1992.)
The present invention pertains to imidazo[1,2-a]pyridines, which are structurally analogous to benzimidazoles, as illustrated below. The imidazo[1,2-a]pyridines of the present invention have been shown to have antiviral activity and low cytotoxicity.
Throughout this application, various publications, patents, and published patent applications are referred to by an identifying citation. The disclosures of the publications, patents, and published patent specifications referenced in this application are hereby incorporated by reference into the present disclosure to more fully describe the state of the art to which this invention pertains.
SUMMARY OF THE INVENTION
One aspect of the present invention pertains to imidazo[1,2-a]pyridine C-nucleosides, such as imidazo[1,2-a]pyridine C3-nucleosides and imidazo[1,2-a]pyridine C5-nucleosides, as described herein.
Another aspect of the present invention pertains to pharmaceutical compositions for treating viral infections which comprise a therapeutically effective amount of one or more of the imidazo[1,2-a]pyridine C-nucleosides of the present invention, as described herein.
Yet another aspect of the present invention pertains to methods for treating viral infections in an animal patient comprising the step of administering a therapeutically effective amount of one or more of the imidazo[1,2-a]pyridine C-nucleosides of the present invention, as described herein.
Still another aspect of the present invention pertains to methods for inhibiting viral (e.g., HCMV) proliferation in a virally infected cell comprising contacting the cell with an effective amount of one or more of the imidazo[1,2-a]pyridine C-nucleosides of the present invention, as described herein, under suitable conditions such that viral proliferation is inhibited.
Still another aspect of the present invention pertains to methods for prophylactically treating a cell susceptible to viral (e.g., HCMV) infection, by contacting the cell with an effective amount of one or more of the imidazo[1,2-a]pyridine C-nucleosides of the present invention, as described herein, under suitable conditions such that viral infection is prevented.
As will become apparent, preferred features and characteristics of one aspect of the invention are applicable to any other aspect of the invention.


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Gudmundsson et al.(I), “Synthesis of Imidazo[1.2-a]pyridine C-Nucleosides with an Unexpected Site of Ribosylation,”Journal of Organic Chemistry,62(11), 3453-3459 (May 30, 1997).*
Gudmundsson et al.(II), “Synthesis of the First C3 Ribosylated Imidazo[1,2-a]pyridine C-Nucleoside by Enantioselective Construction of the Ribose Moiety,”Journal of Organic Chemistry,63(4), 984-989 (Feb. 20, 1998).*
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Chu, C. K. et al., “Nucleosides 135. Synthesis of Some 9-(2-deoxy-2-fluoro-&bgr;-D-arabinofurnosyl)-9H-purines and Their Biological Activities,”Chem. Pharm. Bull.37:336-339 (1989). (Issue No. 2; Feb., 1989).
Codington, J.F. et al., “Synthesis of 2′-Fluorothymidine, 2′-Fluorodeoxyuridine, and Other 2′-Halogeno-2′-Deoxy Nucleosides,”Org. Chem.29:558-564 (1964). (Mar., 1964).
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Devivar, R. et al., “Benzimidazole Ribonucleotides: Design, Synthesis, and Antiviral Activity of Certain 2-(Alkylthio)- and 2-(Benzylthio)-5,6-dichloro-(&bgr;-D-ribofuranosyl)benzimidazoles,”J. Med. Chem.37:2

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