4′-allene-substituted nucleoside derivatives

• US 8,163,707 B2
• Filed: 09/11/2009
• Issued: 04/24/2012
• Est. Priority Date: 09/15/2008
• Status: Active Grant

• Current Assignee: Enanta Pharmaceuticals Incorporated
• Original Assignee: Enanta Pharmaceuticals Incorporated
• Inventors: Qiu, Yao-Ling, Wang, Ce, Peng, Xiaowen, Ying, Lu, Or, Yat Sun
• Primary Examiner(s): McIntosh, III, Traviss C
• Application Number:
  US12/557,850
• Publication Number:
  US 20100074889A1
• Time in Patent Office: 956 Days
• Field of Search: None
• US Class Current: 514/42
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 23/00 Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12 esters with inorganic acids C07H11/00; metal salts, see parent compounds

Abstract

The present invention discloses compounds of formula (I), or its β-L enantiomer, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, prodrug, or combination thereof:

which inhibit, preventing or treating abnormal cellular proliferation and/or a viral infection, particularly by HIV, HCV or HBV. Consequently, the compounds of the present invention interfere with the replication cycle of a virus and are also useful as antiviral agents, or interfere with host cellular biochemical process and are also useful as antiproliferative agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from viral infection and/or cell proliferation. The invention also relates to methods of treating a viral infection and/or cell proliferation in a subject by administering a pharmaceutical composition comprising the compounds of the present invention. The present invention relates to novel antiviral/anti-proliferative compounds represented herein above, pharmaceutical compositions comprising such compounds, and methods for the treatment or prophylaxis of viral infection in a subject in need of such therapy with said compounds.

Claims

1. A compound represented by Formula (I):

2. A compound of claim 1 represented by Formula (Ia):

3. A compound of claim 1 represented by Formula (Ib):

4. A compound of claim 1 represented by Formula (Ic):

5. A compound of claim 1, wherein B at each occurrence is an optionally substituted pyrimidinyl or purinyl group of formula (B1) or (B2):

6. A pharmaceutical composition comprising a compound or a combination of compounds according to claim 1 or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer or combination thereof, in combination with a pharmaceutically acceptable carrier or excipient.

7. The pharmaceutical composition of claim 6 further comprising a compound selected from the group consisting of cytokines, protease inhibitors, antiviral agents, proteases, immunomodulators, caspase inhibitors, antibodies and polymerase inhibitors.

8. A method of inhibiting the replication of an RNA or DNA-containing virus comprising contacting said virus with a therapeutically effective amount of a compound or combination of compounds of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or combination thereof.

9. A method of treating abnormal cellular proliferation, a viral infection, or a symptom thereof in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound or combination of compounds of claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, or combination thereof.

10. The method of claim 8 wherein the virus is human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis B virus (HBV).

11. A process for preparing the compound of claim 1, comprising the step of:

(a) reacting a nucleoside derivative represented by formulae (1-1), (1-1a), (1-2) or (1-2a);

12. A compound of claim 1, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, solvate, or combination thereof, wherein the compound is selected from the group consisting of:

Compound of Formula (I), wherein R₁=R₂=R₃=R_4a=R_4b=R_4c=H, R_2a=R_3a=R₅=OTBS, X=O, L=CH₂, B=3-methoxycarbonyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl;

Compound of Formula (I), wherein R₁=R₂=R₃=R_4a=R_4b=R_4c=H, R_2a=R_3a=R₅=OTBS, X=O, L=CH₂, B=uracil-1-yl;

Compound of Formula (I), wherein R₁=R₂=R₃=R_4a=R_4b=R_4c=H, R_2a=R_3a=R₅=OTBS, X=O, L=CH₂, B=cytosine-1-yl;

Compound of Formula (I), wherein R₁=R₂=R₃=R_4a=R_4b=R_4c=H, R_2a=R_3a=R₅=OH, X=O, L=CH₂, B=cytosine-1-yl;

Compound of Formula (I), wherein R₁=R₂=R₃=R_4a=R_4b=R_4c=H, R_2a=R_3a=R₅=OH, X=O, L=CH₂, B=uracil-1-yl;

Compound of Formula (Ib), wherein R₁=R₂=R₃=R_4a=R_4b=R_4c=H, R_2a=R_3a=OH, R₅=—

OP(O)(OPh)(NHCHMeCO₂Me), X=O, L=CH₂, B=uracil-1-yl;

Compound of Formula (I), wherein R₁=R_2a=R₃=R_4a=R_4b=R_4c=H, R₂=F, R_3a=R₅=OTBS, X=O, L=CH₂, B=3-methoxycarbonyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl;

Compound of Formula (I), wherein R₁=R_2a=R₃=R_4a=R_4b=R_4c=H, R₂=F, R_3a=R₅=OTBS, X=O, L=CH₂, B=uracil-1-yl;

Compound of Formula (I), wherein R₁=R_2a=R₃=R_4a=R_4b=R_4c=H, R₂=F, R_3a=R₅=OTBS, X═

O, L=CH₂, B=cytosine-1-yl;

Compound of Formula (I), wherein R₁=R_2a=R₃=R_4a=R_4b=R_4c=H, R₂=F, R_3a=R₅=OH, X=O, L=CH₂, B=cytosine-1-yl;

Compound of Formula (I), wherein R₁=R₃=R_4a=R_4b=R_4c=H, R_2a=R_2a=F, R_3a=R₅=OTBS, X=O, L=CH₂, B=3-methoxycarbonyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl;

Compound of Formula (I), wherein R₁=R₃=R_4a=R_4b=R_4c=H, R₂=R_2a=F, R_3a=R₅=OTBS, X=O, L=CH₂, B=uracil-1-yl;

Compound of Formula (I), wherein R₁=R₃=R_4a=R_4b=R_4c=H, R₂=R_2a=F, R_3a=R₅=OTBS, X=O, L=CH₂, B=cytosine-1-yl; and

Compound of Formula (I), wherein R₁=R₃=R_4a=R_4b=R_4c=H, R₂=R_2a=F, R_3a=R₅=OH, X=O, L=CH₂, B=cytosine-1-yl.