Substituted nucleosides, preparation thereof and use as inhibitors of RNA viral polymerases

• US 20040229839A1
• Filed: 05/14/2004
• Published: 11/18/2004
• Est. Priority Date: 05/14/2003
• Status: Abandoned Application

• Current Assignee: Biocryst Pharmaceuticals Incorporated
• Original Assignee: Biocryst Pharmaceuticals Incorporated
• Inventors: Chand, Pooran, Babu, Yarlagadda S., El-Kattan, Yahya
• Application Number:
  US10/845,233
• Publication Number:
  US 20040229839A1
• Time in Patent Office: Days
• US Class Current: 514/47
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom

Abstract

Provided are compounds represented by:

X is O, S or NR₆,

R₁ is H or (CH₂)_mR₅,

R₂, R_2′, R₃ and R_3′ are independently NO₂, N₃ or (CH₂)_mR₅, OH

R₄ is H, OR₆, SR₆, NR₆R_6a, CN, C(O)OR₆, C(O)NR₆R_6a, R₆, OR₇ or (CH₂)_nR₇,

R₅ is H, halo, OR₆, SR₆, NR₆R_6a, CN, C(O)OR₆, C(O)NR₆R_6a, R₆, OR₇ or (CH₂)_mR₇,

R₆ and R_6a are individually H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl or substituted aryl,

R₇ is:

R₈ is H, F, SR₉ or OR₉,

R₉ is H, alkyl, alkenyl, alkynyl, aryl or hydroxyprotecting group,

Y is H, CH₃ or (CH₂)_mR₅,

Z is O or S

W is CH₂, CF₂, CHF or O,

m is 0-4,

B is adenine, guanine, cytosine, uracil, thymine, modified purines and pyrimidines substituted pyridines, five membered heterocycles substituted by at least one of amines, substituted amines, amides, substituted amides, esters, halogens, alkyls, ethers; and pharmaceutically acceptable salts thereof and prodrugs thereof. These ring systems may be substituted.

Claims

1. A compound represented by the structure:

2. A pharmaceutical composition containing at least one compound according to claim 1.

3. A method for inhibiting RNA polymerase in a patient by administering to the patient at least one compound according to claim 1 in an amount sufficient to inhibit viral RNA polymerase.

4. The method according to claim 3 wherein said RNA polymerase is selected from the group consisting of HCV, small pox, Ebola virus, and West Nile virus.

5. A method of treating a patient suffering from RNA viral infection by administering to the patient an effective amount of at least one compound according to claim 1.

6. The method according to claim 5 wherein the RNA viral infection is selected from the group consisting of HCV, HBV, and Rhino viral infection.

7. The compound of claim 1 wherein said modified purines and pyrimidines are selected from the group consisting of inosin-9-yl, 2-amino-purin-9-yl, 2-amino-6-chloro-purin-9-yl, 2-6-diamino-purin-9-yl, 3-carboxamido-1,2,4-triazol-1-yl, 3-deaza-adenin-9-yl, 3-deaza-guanin-9-yl, 3-deaza-inosin-9-yl, 3-deaza-2-amino-purin-9-yl, 3-deaza-2-amino-6-chloro-purin-9-yl, 3-deaza-2,6-diamino-purin-9-yl, 7-deaza-adenin-9-yl, 7-deaza-guanin-9-yl, 7-deaza-inosin-9-yl, 7-deaza-2-amino-purin-9-yl, 7-deaza-2-amino-6-chloro-purin-9-yl, 7-deaza-2-6-diamino-purin-9-yl, 7-deaza-8-aza-adenin-9-yl, 7-deaza-8-aza-guanin-9-yl, 7-deaza-8-aza-inosin-9-yl, 7-deaza-8-aza-2-amino-purin-9-yl, 7-deaza-8-aza-2-amino-6-chloro-purin-9-yl, 7-deaza-8-aza-2-6-diamino-purin-9-yl, 8-aza-adenin-9-yl, 8-aza-guanin-9-yl, 8-aza-inosin-9-yl, 8-aza-2-amino-purin-9-yl, 8-aza-2-amino-6-chloro-purin-9-yl, 8-aza-2-6-diamino-purin-9-yl, 5-aza-thymin-1-yl, 5-aza-cytosin-1-yl, 5-aza-uracil-1-yl, 6-aza-thymin-1-yl, 6-aza-cytosin-1-yl, 6-aza-uracil-1-yl, 2-thiouracil-1-yl, 4-thiouracil-1-yl, 2-thiocytosine-1-yl, uracil-5-yl, 2-thiouracil-5-yl, 4-thiouracil-5-yl, 6-azauracil, and azacytosine.

8. The compound of claim 1 wherein said five membered heterocycle is selected from the group consisting of triazole, thiazole, pyrazole, imidazole, pyrrole, thiophene, and furane.