# US 9,517,224 B2 · Methods of treating patients infected with HIV and HTLV

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- Number: US 9,517,224 B2
- Document ID: US9517224B2
- Status: Granted
- Kind: B2
- Application number: 14/442,865
- Filed: 2013-11-13
- Published: 2015-10-08
- Granted: 2016-12-13
- Earliest claimed: 2012-11-15
- Assignees: The United States of America, as represented by the Secretary, Department of Health and Human Services
- Applicants: The United States of America, AS Represented By the Secretary, Department of Health and Human Services
- Inventors: Leonard M. Neckers; Carole Sourbier; Jane B. Neckers; Min-Jung Lee; John A. Beutler; W. Marston Linehan; Bradley T. Scroggins; Sunmin Lee
- Web page: https://patentgrep.com/patent/US9517224B2

## CPC

- A61K 31/35: having six-membered rings with one oxygen as the only ring hetero atom
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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 R1-R6 are described herein. Examples of diseases or conditions associated with PKCθ include HIV1 infection, AIDS, HTLV infection, and adult T cell leukemia/lymphoma.

## Claims

### Claim 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 C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, halo, and nitro;
X is O, NH, or S;
R2 and R3 are independently C1-C6 alkyl;
R1 is isopropyl or isopropenyl;
“a” is a single bond or a double bond;
when “a” is a double bond, R4 is hydrogen, and R5 is halo or H;
when “a” is a single bond, R4 is selected from the group consisting of halo, hydroxy, and C1-C6 alkoxy and R5 is halo or H; and
R6 is H, C1-C6 alkyl carbonyl, or hydroxy C1-C6 alkyl carbonyl,
and at least one antiviral agent.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

The method according to claim 1, wherein R6 is hydroxy C1-C6 alkyl carbonyl or hydroxymethyl carbonyl.

### Claim 4 (depends on 1)

The method according to claim 1, wherein R5 is halo.

### Claim 5 (depends on 4)

The method according to claim 4, wherein R5 is chloro.

### Claim 6 (depends on 1)

The method according to claim 1, wherein Ar is phenyl, optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, halo, and nitro.

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

The method according to claim 1, wherein R1 is isopropyl.

### Claim 9 (depends on 1)

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.

### Claim 10 (depends on 1)

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

### Claim 11 (depends on 1)

The method according to claim 1, wherein R4 is hydroxy, chloro, or ethoxy.

### Claim 12 (depends on 1)

The method according to claim 1, wherein R2 and R3 are methyl.

### Claim 13 (depends on 12)

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.

### Claim 14 (depends on 1)

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

### Claim 15 (depends on 1)

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

### Claim 16 (depends on 1)

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.

### Claim 17 (depends on 1)

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.

### Claim 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 C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, halo, and nitro;
X is O, NH, or S;
R2 and R3 are independently C1-C6 alkyl;
R1 is isopropyl or isopropenyl;
“a” is a single bond or a double bond;
when “a” is a double bond, R4 is hydrogen, and R5 is halo or H;
when “a” is a single bond, R4 is selected from the group consisting of halo, hydroxy, and C1-C6 alkoxy and R5 is halo or H; and
R6 is H, C1-C6 alkyl carbonyl, or hydroxy C1-C6 alkyl carbonyl,
and at least one anti-retroviral agent.

### Claim 19 (depends on 18)

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

### Claim 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 C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, halo, and nitro;
X is O, NH, or S;
R2 and R3 are independently C1-C6 alkyl;
R1 is isopropyl or isopropenyl;
“a” is a single bond or a double bond;
when “a” is a double bond, R4 is hydrogen, and R5 is halo or H;
when “a” is a single bond, R4 is selected from the group consisting of halo, hydroxy, and C1-C6 alkoxy and R5 is halo or H; and
R6 is H, C1-C6 alkyl carbonyl, or hydroxy C1-C6 alkyl carbonyl,
(b) at least one anti-retroviral agent, and (c) instructions for use.