Methods of treating patients infected with HIV and HTLV

Patent metadata

Field	Value
Publication number	US-9517224-B2
Application number	US-201314442865-A
Country	US
Kind code	B2
Filing date	Nov 13, 2013
Priority date	Nov 15, 2012
Publication date	Dec 13, 2016
Grant date	Dec 13, 2016

Abstract

Disclosed is a method of activating protein kinase C theta (PKCθ) in an HIV or HTLV infected animal comprising administering to the animal an effective amount of a compound of formula (I): Formula (I), or an epimer thereof; wherein Ar and R 1 -R 6 are described herein. Examples of diseases or conditions associated with PKCθ include HIV1 infection, AIDS, HTLV infection, and adult T cell leukemia/lymphoma.

First claim

The invention claimed is:

1. A method of treating an HIV-infected animal or an HTLV-infected animal, increasing the activity of latent infected CD4+ cells of an animal carrying HIV, in inhibiting Treg activation and number in an animal carrying HTLV, and/or in decreasing Glut1 expression in an ATL cell in an animal carrying HTLV, comprising administering to the animal a compound of formula (I):

or an epimer thereof; wherein
Ar is an aryl group, optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halo, and nitro;
X is O, NH, or S;
R 2 and R 3 are independently C 1 -C 6 alkyl;
R 1 is isopropyl or isopropenyl;
“a” is a single bond or a double bond;
when “a” is a double bond, R 4 is hydrogen, and R 5 is halo or H;
when “a” is a single bond, R 4 is selected from the group consisting of halo, hydroxy, and C 1 -C 6 alkoxy and R 5 is halo or H; and

R 6 is H, C 1 -C 6 alkyl carbonyl, or hydroxy C 1 -C 6 alkyl carbonyl,
and at least one antiviral agent.

2. The method according to claim 1 , wherein the compound of formula (I) is englerin A, which is of the formula:

3. The method according to claim 1 , wherein R 6 is hydroxy C 1 -C 6 alkyl carbonyl or hydroxymethyl carbonyl.

4. The method according to claim 1 , wherein R 5 is halo.

5. The method according to claim 4 , wherein R 5 is chloro.

6. The method according to claim 1 , wherein Ar is phenyl, optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halo, and nitro.

7. The method according to claim 1 , wherein X is O.

8. The method according to claim 1 , wherein R 1 is isopropyl.

9. The method according to claim 1 , wherein “a” is a double bond and the double bond is E, Z, or a mixture of E and Z.

10. The method according to claim 1 , wherein “a” is a single bond.

11. The method according to claim 1 , wherein R 4 is hydroxy, chloro, or ethoxy.

12. The method according to claim 1 , wherein R 2 and R 3 are methyl.

13. The method according to claim 12 , wherein the compound of formula (I) is:

2′-Chloroenglerin A,

2′-Chloro, 3′-hydroxydihydroenglerin A (epimer 1, 2, 3, or 4),

2′,3′-Dichlorodihydroenglerin A (epimer 1 or 2), or

2′-Chloro, 3′-ethoxydihydroenglerin A,

wherein the double bond “a” in 2′-Chloroenglerin A is E, Z, or E/Z.

14. The method according to claim 1 , wherein the animal is a human.

15. The method according to claim 1 , which is in further combination with a highly active antiretroviral therapy regimen to the animal.

16. The method according to claim 1 , which results in an induction of NFκB transcriptional activity or an induction of HSF1 transcriptional activity in the animal.

17. The method according to claim 1 , wherein the animal is afflicted with an ailment selected from HIV1 infection, AIDS, HTLV infection, and adult T cell leukemia/lymphoma.

18. A pharmaceutical composition comprising a compound of formula (I):

or an epimer thereof; wherein
Ar is an aryl group, optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halo, and nitro;
X is O, NH, or S;
R 2 and R 3 are independently C 1 -C 6 alkyl;
R 1 is isopropyl or isopropenyl;
“a” is a single bond or a double bond;
when “a” is a double bond, R 4 is hydrogen, and R 5 is halo or H;
when “a” is a single bond, R 4 is selected from the group consisting of halo, hydroxy, and C 1 -C 6 alkoxy and R 5 is halo or H; and

R 6 is H, C 1 -C 6 alkyl carbonyl, or hydroxy C 1 -C 6 alkyl carbonyl,
and at least one anti-retroviral agent.

19. The pharmaceutical composition of claim 18 , wherein the compound of formula (I) is englerin A.

20. A kit for therapeutically treating an HIV-infected animal or an HTLV-infected animal comprising (a) a compound of formula (I),

or an epimer thereof; wherein
Ar is an aryl group, optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, halo, and nitro;
X is O, NH, or S;
R 2 and R 3 are independently C 1 -C 6 alkyl;
R 1 is isopropyl or isopropenyl;
“a” is a single bond or a double bond;
when “a” is a double bond, R 4 is hydrogen, and R 5 is halo or H;
when “a” is a single bond, R 4 is selected from the group consisting of halo, hydroxy, and C 1 -C 6 alkoxy and R 5 is halo or H; and

R 6 is H, C 1 -C 6 alkyl carbonyl, or hydroxy C 1 -C 6 alkyl carbonyl,
(b) at least one anti-retroviral agent, and (c) instructions for use.

Assignees

• Us Health

Inventors

• Neckers Leonard M
• Sourbier Carole
• Neckers Jane B
• Lee Min-Jung
• Beutler John A
• Linehan W Marston
• Scroggins Bradley T
• Lee Sunmin

Classifications

• A61P31/18

  for HIV · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P31/14

  for RNA viruses · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P35/00

  Antineoplastic agents · CPC title