Small Molecule Inhibitors of Retroviral Assembly and Maturation

• US 20100035912A1
• Filed: 08/06/2009
• Published: 02/11/2010
• Est. Priority Date: 08/08/2008
• Status: Active Grant

• Current Assignee: New York Blood Center Incorporated
• Original Assignee: New York Blood Center Incorporated
• Inventors: Zhang, Hongtao, Curreli, Francesca, Debnath, Asim Kumar
• Granted Patent: US 8,299,093 B2
• Time in Patent Office: Days
• US Class Current: 514/292
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Chemical compounds that disrupt retroviral assembly and maturation are presented herein. More particularly, this disclosure provides small molecule compounds that disrupt the formation and maturation of virus particles and methods of using such small molecules to treat HIV-1 infection.

Claims

1. A pharmaceutical composition comprising an inhibitor of human immunodeficiency virus, said inhibitor having a structure:

wherein R₁ and R₂ are independently a moiety selected from the group consisting of (C_1-6)alkyl, substituted or unsubstituted (C_1-6)alkyl, substituted or unsubstituted (C_1-6)alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzyloxy, substituted or unsubstituted alkyl phenyl, substituted or unsubstituted aminophenyl, cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, and substituted or unsubstituted alkyl heterocycle;

R₃ is a moiety selected from the group consisting of H, and substituted or unsubstituted (C_1-6)alkyl;

Z is C═

O, C═

S or S(═

O)═

O; and

T, U, V, W and X are independently selected from CR₄ or N, wherein R₄ is a moiety selected from the group consisting of hydrogen, substituted or unsubstituted (C_1-6)alkyl, substituted or unsubstituted (C_1-6)alkoxy, hydroxyl alkyl, halogen, nitrile, amino, nitro, carboxyl, alkyl amino sulphonyl, substituted or unsubstituted aryl amino sulphonyl, substituted or unsubstituted phenyl, and substituted or unsubstituted benzyl;

or a pharmaceutically acceptable salt or ester thereof.

2. The composition of claim 1, wherein said inhibitor is selected from the group consisting of:

3. The composition of claim 1, wherein said inhibitor has the structure:

4. The composition of claim 1 further comprising at least one pharmaceutically acceptable excipient.

5. The composition of claim 1 further comprising at least one additional therapeutically active agent.

6. A pharmaceutical composition comprising an inhibitor of human immunodeficiency virus, said inhibitor having a structure:

wherein R1 is a moiety selected from the group consisting of hydrogen, substituted or unsubstituted (C_1-6)alkyl, substituted or unsubstituted (C_1-6)alkoxy, hydroxyl, hydroxy alkyl, halogen, nitrile, nitro, amino, sulphonyl, sulphonamido;

R2 is a moiety selected from the group consisting of substituted or unsubstituted (C_1-6)alkyl, substituted or unsubstituted (C_1-6)alkoxy, carboxyl, alkyl amino sulphonyl, substituted or unsubstituted aryl amino sulphonyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzyloxy, substituted or unsubstituted alkyl phenyl, substituted or unsubstituted aminophenyl, cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, and substituted or unsubstituted alkyl heterocycle; and

A, V, W, X and Y are independently selected from CR3 or N, wherein R3 is a moiety selected from the group consisting of hydrogen, (C_1-6)alkyl, substituted or unsubstituted (C_1-6)alkyl, substituted or unsubstituted (C_1-6)alkoxy, hydroxyl, hydroxy alkyl, halogen, nitrile, amino, nitro;

or a pharmaceutically acceptable salt or ester thereof.

7. The composition of claim 6, wherein said inhibitor is selected from the group consisting of:

8. The composition of claim 6, wherein said inhibitor has the structure:

9. The composition of claim 6 further comprising at least one pharmaceutically acceptable excipient.

10. The composition of claim 6 further comprising at least one additional therapeutically active agent.

11. A method for disrupting HIV assembly and replication comprising:

administering to a patient in need thereof a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt or ester thereof,

wherein R₁ and R₂ are individually a moiety selected from the group consisting of (C_1-6)alkyl, substituted or unsubstituted (C_1-6)alkyl, substituted or unsubstituted (C_1-6)alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted benzyloxy, substituted or unsubstituted alkyl phenyl, substituted or unsubstituted aminophenyl, cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycle, and substituted or unsubstituted alkyl heterocycle;

R₃ is a moiety selected from the group consisting of H, and substituted or unsubstituted (C_1-6)alkyl;

Z is C═

O, C═

S or S(═

O)═

O;

T, U, V, W and X are independently selected from CR₄ or N, wherein R₄ is a moiety selected from the group consisting of hydrogen, substituted or unsubstituted (C_1-6)alkyl, substituted or unsubstituted (C_1-6)alkoxy, hydroxyl alkyl, halogen, nitrile, amino, nitro, carboxyl, alkyl amino sulphonyl, substituted or unsubstituted aryl amino sulphonyl, substituted or unsubstituted phenyl, and substituted or unsubstituted benzyl; and

disrupting HIV assembly and replication.

12. The method of claim 11, further comprising administering at least one additional therapeutic agent selected from the group consisting of reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, integrase inhibitors, chemokine receptor (CXCR4, CCR5) inhibitors, interleukin-2, hydroxyurea, monoclonal antibodies, and cytokines.

13. A method for disrupting HIV assembly and replication comprising:

administering to a patient in need thereof a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of formula II, or a pharmaceutically acceptable salt or ester thereof,