Bifunctional molecules with antibody-recruiting and entry inhibitory activity against the human immunodeficiency virus

Patent metadata

Field	Value
Publication number	US-10030008-B2
Application number	US-201615379969-A
Country	US
Kind code	B2
Filing date	Dec 15, 2016
Priority date	Nov 18, 2010
Publication date	Jul 24, 2018
Grant date	Jul 24, 2018

Abstract

The present invention is directed to new bifunctional compounds and methods for treating HIV infections. The bifunctional small molecules, generally referred to as ARM-HI's, function through orthogonal pathways, by inhibiting the gp120-CD4 interaction, and by recruiting anti-DNP antibodies to gp120-expressing cells, thereby preventing cell infection and spread of HIV. It has been shown that ARM-HI's bind to gp120 and gp-120 expressing cells competitively with CD4, thereby decreasing viral infectivity as shown by an MT-2 cell assay, the binding leading to formation of a ternary complex by recruiting anti-DNP antibodies to bind thereto, the antibodies present in the ternary complex promoting the complement-dependent destruction of the gp120-expressing cells. Compounds and methods are described herein.

First claim

The invention claimed is:

1. A method of treating an HIV infection in a patient in need thereof comprising administering to said patient an effective amount of a compound according to the chemical structure:

where R 1 is phenyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, p-ethylphenyl, p-isopropylphenyl, naphthyl, o-hydroxyphenyl, m-hydroxyphenyl, p-hydroxyphenyl, 3,5-dihydroxyphenyl, p-hydroxymethylphenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl,
or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 wherein 1 is phenyl, p-methylphenyl, p-ethylphenyl, o-hydroxylphenyl, m-hydroxyphenyl, p-hydroxyphenyl, 3,5-dihydroxylphenyl, p-hydroxymethylphenyl or 2-pyridyl.

3. The method according to claim 1 wherein R 1 is phenyl, o-hydroxylphenyl, m-hydroxyphenyl, p-hydroxyphenyl, 3,5-dihydroxylphenyl or p-hydroxymethylphenyl.

4. The method according to claim 1 wherein R 1 is phenyl, m-hydroxyphenyl or p-hydroxyphenyl.

5. The method according to claim 1 wherein R 1 is m-hydroxyphenyl or p-hydroxyphenyl.

6. The method according to claim 1 wherein R 1 is phenyl.

7. The method of claim 1 which treats HIV by reducing or abolishing HIV infected CD4 cells in said patient.

8. The method according to claim 7 wherein R 1 is phenyl, p-methylphenyl, p-ethylphenyl, o-hydroxylphenyl, m-hydroxyphenyl, p-hydroxyphenyl, 3,5-dihydroxylphenyl, p-hydroxymethylphenyl or 2-pyridyl.

9. The method according to claim 7 wherein R 1 is phenyl, o-hydroxylphenyl, m-hydroxyphenyl, p-hydroxyphenyl, 3,5-dihydroxylphenyl or p-hydroxymethylphenyl.

10. The method according to claim 7 wherein R 1 is phenyl, m-hydroxyphenyl or p-hydroxyphenyl.

11. The method according to claim 7 wherein R 1 is m-hydroxyphenyl or p-hydroxyphenyl.

12. The method according to claim 7 wherein R 1 is phenyl.

13. A method of inhibiting or abolishing HIV in a patient infected with HIV comprising administering to said patient an effective amount of a compound according to the chemical structure:

where R 1 is phenyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, p-ethylphenyl, p-isopropylphenyl, naphthyl, o-hydroxyphenyl, m-hydroxyphenyl, p-hydroxyphenyl, 3,5-dihydroxyphenyl, p-hydroxymethylphenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl,
or a pharmaceutically acceptable salt thereof.

14. The method according to claim 13 wherein R 1 is phenyl, o-hydroxylphenyl, m-hydroxyphenyl, p-hydroxyphenyl, 3,5-dihydroxylphenyl or p-hydroxymethylphenyl.

15. The method according to claim 13 wherein R 1 is phenyl, m-hydroxyphenyl or p-hydroxyphenyl.

16. The method according to claim 13 wherein R 1 is m-hydroxyphenyl or p-hydroxyphenyl.

17. The method according to claim 13 wherein R 1 is phenyl.

18. A method of reducing the likelihood of AIDS or ARC in a patient infected with HIV comprising administering to said patient an effective amount of a compound according to the chemical structure:

where R 1 is phenyl, o-methylphenyl, m-methylphenyl, p-methylphenyl, p-ethylphenyl, p-isopropylphenyl, naphthyl, o-hydroxyphenyl, m-hydroxyphenyl, p-hydroxyphenyl, 3,5-dihydroxyphenyl, p-hydroxymethylphenyl, 2-pyridyl, 3-pyridyl or 4-pyridyl,
or a pharmaceutically acceptable salt thereof.

19. The method according to claim 18 wherein R 1 is phenyl, p-methylphenyl, p-ethylphenyl, o-hydroxylphenyl, m-hydroxyphenyl, p-hydroxyphenyl, 3,5-dihydroxylphenyl, p-hydroxymethylphenyl or 2-pyridyl.

20. The method according to claim 18 wherein R 1 is phenyl, o-hydroxylphenyl, m-hydroxyphenyl, p-hydroxyphenyl, 3,5-dihydroxylphenyl or p-hydroxymethylphenyl.

21. The method according to claim 18 wherein R 1 is phenyl, m-hydroxyphenyl or p-hydroxyphenyl.

22. The method according to claim 18 wherein R 1 is m-hydroxyphenyl or p-hydroxyphenyl.

23. The method according to claim 18 wherein R 1 is phenyl.

Assignees

• Univ Yale

Inventors

• Spiegel David
• Parker Christopher

Classifications

• A61P31/18

  for HIV · CPC title

• C07D405/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K9/0014

  Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00) · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title