Lipophilic curcumin analogs and methods of inhibiting HIV-1, treating latent HIV in the brain, and preventing HIV-mediated cognitive decline and HIV dementia

Patent metadata

Field	Value
Publication number	US-11319273-B2
Application number	US-201514689827-A
Country	US
Kind code	B2
Filing date	Apr 17, 2015
Priority date	Aug 17, 2012
Publication date	May 3, 2022
Grant date	May 3, 2022

Abstract

Compounds having formulas (I) to (VIII), salts thereof, or combinations thereof and pharmaceutical compositions comprising one or more these compounds are described herein for the treatment of HIV and neurodegenerative effects caused by HIV. Also provided herein are methods and a kit for inhibiting HIV-1, treating latent HIV in the brain, and preventing HIV-mediated cognitive decline and HIV dementia comprising administering the compounds having the formulas (I) to (VIII) and pharmaceutical compositions comprising the compounds having these formulas. The compounds having formulas I through VIII are curcumin analogs which are advantageously characterized as having anti-retroviral, neuroprotective, anti-glucosidase, and anti-HIV integrase properties. In one aspect, the pharmaceutical composition is delivered intranasally.

First claim

What is claimed is:

1. A compound of any of formulas (II) to (VIII) or pharmaceutically acceptable salt thereof:

where each X is independently selected from H, CH, or F when n=1, 2, 3 or 5, wherein if n=1 a three membered ring is defined, if n=2 a four membered ring is defined, if n=3 a five membered ring is defined, if n=4 a six membered ring is defined and if n=5 a seven membered ring is defined, or each X is independently selected from CH or F when n=4,
where carbons of the ring may include —CH or —CH 2 and wherein the carbons of the ring optionally can be substituted with halogen or alkyl having 1 to 3 carbons;

where
X is O, NH, S, or CH 2 , and
Y is O, NH, S, or CH 2 ;

where n=1 to 5, wherein if n=1 a three membered ring is defined, if n=2 a four membered ring is defined, if n=3 a five membered ring is defined, if n=4 a six membered ring is defined and if n=5 a seven membered ring is defined,
where carbons of the ring may include —CH or —CH 2 and wherein the carbons of the ring optionally can be substituted with halogen or alkyl having 1 to 3 carbons;

where each X is independently selected from NH, O, or S;

where
R 1 =alkyl or phenyl which may be substituted or unsubstituted at any position with halogen or alkyl having 1-3 carbon atoms,
R 2 =halogen, ether, or thioether, and
n=1 to 5, wherein if n=1 a three membered ring is defined, if n=2 a four membered ring is defined, if n=3 a five membered ring is defined, if n=4 a six membered ring is defined and if n=5 a seven membered ring is defined,
where carbons of the ring may include —CH or —CH 2 and wherein the carbons of the ring optionally can be substituted with halogen or alkyl having 1 to 3 carbons;

where
R 1 =phenol, phenolic ether, thiophenol, thioether, halogen, or alkyl;
R 2 =phenol, phenolic ether, thiophenol, thioether, halogen, or alkyl;
each R 3 is independently selected from H, halogen, phenol, and phenolic ether; and
R 4 =H, F, phenol, or phenolic ether,
n=1 to 5, wherein if n=1 a three membered ring is defined, if n=2 a four membered ring is defined, if n=3 a five membered ring is defined, if n=4 a six membered ring is defined and if n=5 a seven membered ring is defined,
where carbons of the ring may include —CH or —CH 2 and wherein the carbons of the ring optionally can be substituted with halogen or alkyl having 1 to 3 carbons; or

where each R is independently selected from alkyl or phenyl, which may optionally be substituted at any position with halogen or alkyl having 1 to 3 carbons,
n=1 to 5, wherein if n=1 a three membered ring is defined, if n=2 a four membered ring is defined, if n=3 a five membered ring is defined, if n=4 a six membered ring is defined and if n=5 a seven membered ring is defined,
where carbons of the ring may include —CH or —CH 2 and wherein the carbons of the ring optionally can be substituted with halogen or alkyl having 1 to 3 carbons.

2. The compound according to claim 1 , wherein the compound is of formula (II) or pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , wherein the compound is of formula (III) or pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 , wherein the compound is of formula (IV) or pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 , wherein the compound is of formula (V) or pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 , wherein the compound is of formula (VI) or pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 , wherein the compound is of formula (VII) or pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 , wherein the compound is of formula (VIII) or pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising at least one compound of any of formulas (II) through (VIII) or a pharmaceutically acceptable salt thereof as defined in claim 1 .

10. The pharmaceutical composition according to claim 9 , further comprising a pharmaceutically acceptable excipient, diluent, and/or carrier.

11. The pharmaceutical composition according to claim 9 , further comprising an antiviral agent other than a compound of formulas (II) to (VIII).

12. The pharmaceutical composition according to claim 11 , wherein the antiviral agent is selected from the group consisting of nucleoside reverse transcriptase inhibitors, nonnucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, fusion inhibitors, chemokine receptor antagonists, and combinations thereof.

13. The pharmaceutical composition according to claim 9 , wherein compound is dispersed in a pharmaceutically acceptable oil.

14. The pharmaceutical composition according to claim 9 , wherein the compound is of formula (II) or pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition according to claim 9 , wherein the at least one compound is of formula (III) or pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition according to claim 9 , wherein the at least one compound is of formula (IV) or pharmaceutically acceptable salt thereof.

17. The pharmaceutical composition according to claim 9 , wherein the at least one compound is of formula (V) or pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition according to claim 9 , wherein the at least one compound is of formula (VI) or pharmaceutically acceptable salt thereof.

19. The pharmaceutical composition according to claim 9 , wherein the at least one compound is of formula (VII) or pharmaceutically acceptable salt thereof.

20. The pharmaceutical composition according to claim 9 , wherein the at least one compound is of formula (VIII) or pharmaceutically acceptable salt thereof.

21. The pharmaceutical composition of claim 9 , wherein the composition is configured for intranasal delivery.

22. The pharmaceutical composition of claim 9 , further comprising at least one chlorofluorohydrocarbon.

Assignees

• Univ Howard

Inventors

• Nwulia Evaristus A
• Kulkarni Amol

Classifications

• A61K31/381

  having five-membered rings · CPC title

• A61K31/12

  Ketones · CPC title

• C07D333/32

  Oxygen atoms · CPC title

• A61K31/4025

  not condensed and containing further heterocyclic rings, e.g. cromakalim · CPC title

• C07D265/02

  1,2-Oxazines; Hydrogenated 1,2-oxazines · CPC title