Compositions and methods of treating HIV-1 infections using same

Patent metadata

Field	Value
Publication number	US-9914709-B2
Application number	US-201414310564-A
Country	US
Kind code	B2
Filing date	Jun 20, 2014
Priority date	Jun 21, 2013
Publication date	Mar 13, 2018
Grant date	Mar 13, 2018

Abstract

The present invention includes novel compositions useful for preventing or treating an HIV-1 infection in a subject in need thereof. The present invention further includes a novel method of preventing or treating an HIV-1 infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention. In one embodiment, the subject is further administered at least one additional therapeutic agent.

First claim

What is claimed is:

1. A composition comprising at least one pharmaceutically acceptable carrier and at least one compound of formula (I):

wherein in formula (I):
ring A and ring B are each independently aryl;
each occurrence of R 1 , and R 2 is independently selected from the group consisting of H, —C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —C 2 -C 6 alkenyl, —F, —Cl, —CN, 2-cyanoethyl, and 2-cyanovinyl, wherein the alkyl, cycloalkyl, and alkenyl groups are optionally substituted;
X 1 is CH or N;
X 2 and X 3 are each —NH—;
X 4 is —O—;
L is —(CH 2 ) y —, wherein one or more —CH 2 — groups in L are independently and optionally replaced with —O—,
with the provisos that: no heteroatom-heteroatom bond exist within L, and L is not covalently linked to X 4 or M through a heteroatom-heteroatom bond;

M is morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl or imidazolyl, wherein the morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl or imidazolyl is independently optionally substituted;
m and n are each independently an integer from 0-5; and,
y is an integer from 0-19,

a salt, solvate, or N-oxide thereof.

2. The composition of claim 1 , wherein L is selected from the group consisting of —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 2 (OCH 2 CH 2 )—, —(CH 2 ) 2 (OCH 2 CH 2 ) 2 —, —(CH 2 ) 2 (OCH 2 CH 2 ) 3 —, and —(CH 2 ) 2 (OCH 2 CH 2 ) 5 —.

3. The composition of claim 2 , wherein L is —(CH 2 ) 3 —.

4. The composition of claim 1 , wherein M is selected from the group consisting of morpholin-4-yl, imidazol-1-yl, piperidin-1-yl, piperidin-4-yl, tetrahydropyranyl, piperizin-1-yl or 4-methyl-piperizin-1-yl.

5. The composition of claim 1 , wherein the at least one compound of formula (I) is a compound of formula (II):

wherein in formula (II):
each occurrence of R 1 and R 2 is independently selected from the group consisting of H, —C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —C 2 -C 6 alkenyl, —F, —Cl, —CN, 2-cyanoethyl, and 2-cyanovinyl, wherein the alkyl, cycloalkyl, and alkenyl groups are optionally substituted;
R 3 , and R 4 are each hydrogen;
X 1 is CH or N;
X 2 is —O—;
M is morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl or imidazolyl, wherein the morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl or imidazolyl is independently optionally substituted;
m and n are each independently an integer from 0-5; and,
y is an integer from 1-5,

a salt, solvate, or N-oxide thereof.

6. The composition of claim 1 , wherein the compound is at least one selected from the group consisting of 4-((4-(mesitylamino)-6-(2-morpholinoethoxy) pyrimidin-2-yl)amino)benzonitrile, 4-((4-(mesitylamino)-6-(3-morpholinopropoxy) pyrimidin-2-yl)amino)benzonitrile, 4-((4-(mesitylamino)-6-(2-morpholinoethoxy)-1,3,5-triazin-2-yl)amino)benzonitrile, 4-((4-(mesitylamino)-6-(3-morpholinopropoxy)-1,3,5-triazin-2-yl)amino)benzonitrile, 4-((4-((4-cyanophenyl)amino)-6-(3-morpholino propoxy)-1,3,5-triazin-2-yl)amino)-3,5-dimethylbenzonitrile, (E)-4-((4-((4-(2-cyanovinyl)-2,6-dimethylphenyl)amino)-6-(3-morpholinopropoxy)-1,3,5-triazin-2-yl)amino)benzonitrile, 4-((4-((2,6-difluoro-4-methylphenyl)amino)-6-(3-morpholino propoxy)-1,3,5-triazin-2-yl)amino)benzonitrile, 4-((4-((4-ethyl-2,6-difluorophenyl)amino)-6-(3-morpholinopropoxy)-1,3,5-triazin-2-yl)amino)benzonitrile, 4-((4-((2,6-difluoro-4-isopropylphenyl)amino)-6-(3-morpholinopropoxy)-1,3,5-triazin-2-yl)amino) benzonitrile, 4-((4-((4-cyclopropyl-2,6-difluorophenyl)amino)-6-(3-morpholinopropoxy)-1,3,5-triazin-2-yl)amino)benzonitrile, 4-((4-((4-(2-cyanoethyl)-2,6-difluorophenyl)amino)-6-(3-morpholinopropoxy)-1,3,5-triazin-2-yl)amino)benzonitrile, 4-((4-(mesitylamino)-6-(2-(piperidin-4-yl)ethoxy)-1,3,5-triazin-2-yl)amino)benzonitrile, 4-((4-(mesitylamino)-6-(3-(piperidin-4-yl)propoxy)-1,3,5-triazin-2-yl)amino)benzonitrile, (E)-4-((4-((4-(2-cyanovinyl)-2,6-difluorophenyl)amino)-6-(3-morpholinopropoxy)-1,3,5-triazin-2-yl)amino)benzonitrile, (E)-4-((4-((4-(2-cyanovinyl)-2,6-dimethylphenyl) amino)-6-((3-morpholinopropyl)amino)-1,3,5-triazin-2-yl)amino)benzonitrile, (E)-4-((4-((4-(2-cyanovinyl)-2,6-difluorophenyl)amino)-6-((3-morpholinopropyl)amino)-1,3,5-triazin-2-yl)amino)benzonitrile, (E)-4-((4-((4-(2-cyanovinyl)-2,6-dimethylphenyl) amino)-6-(3-morpholinopropoxy)pyrimidin-2-yl)amino)benzonitrile, (E)-4-((4-((4-(2-cyanovinyl)-2,6-difluorophenyl)amino)-6-(3-morpholinopropoxy)pyrimidin-2-yl)amino) benzonitrile, (E)-4-((4-((4-(2-cyanovinyl)-2,6-dimethylphenyl)amino)-6-((3-morpholinopropyl)amino)pyrimidin-2-yl)amino)benzonitrile, (E)-4-((4-((4-(2-cyanovinyl)-2,6-difluorophenyl)amino)-6-((3-morpholinopropyl)amino)pyrimidin-2-yl)amino)benzonitrile, and a salt thereof.

7. The composition of claim 1 , further comprising at least one additional therapeutic agent.

8. The composition of claim 7 , wherein the at least one additional therapeutic is at least one selected from the group consisting of nevirapine, delavirdine, efavirenz, etravirine, rilpivirine, and a salt thereof.

9. A method of treating an HIV-1 infection or for the prophylaxis of HIV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (I):

wherein in (I):
ring A and ring B are each independently aryl;
each occurrence of R 1 , and R 2 is independently selected from the group consisting of H, —C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —C 2 -C 6 alkenyl, F, —Cl, —CN, 2-cyanoethyl, and 2-cyanovinyl, wherein the alkyl, cycloalkyl, and alkenyl groups are optionally substituted;
X 1 is CH or N;
X 2 , and X 3 are each —NH—
X 4 is —O—;
L is —(CH 2 ) y —, wherein one or more —CH 2 — groups in L are independently and optionally replaced with —O—,
with the provisos that: no heteroatom-heteroatom bond exist within L, and L is not covalently linked to X 4 or M through a heteroatom-heteroatom bond;

M is morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl or imidazolyl, wherein the morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl or imidazolyl is independently optionally substituted;
m and n are each independently an integer from 0-5; and,
y is an integer from 0-19,

a salt, solvate, or N-oxide thereof.

10. The method of claim 9 , wherein the at least one compound of formula (I) is a compound of formula (II):

wherein in formula (II):
each occurrence of R 1 and R 2 is independently selected from the group consisting of H, —C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —C 2 -C 6 alkenyl, —F, —Cl, —CN, 2-cyanoethyl, and 2-cyanovinyl, wherein the alkyl, cycloalkyl, and alkenyl groups are optionally substituted;
R 3 , and R 4 , are each hydrogen;
X 1 is CH or N;
X 2 is —O—;
M is morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl or imidazolyl, wherein the morpholinyl, piperidinyl, piperazinyl, tetrahydropyranyl or imidazolyl is independently optionally substituted;
m and n are each independently an integer from 0-5; and,
y is an integer from 1-5,

a salt, solvate, or N-oxide thereof.

11. The method of claim 9 , wherein M is selected from the group consisting of morpholin-4-yl, imidazol-1-yl, piperidin-1-yl, piperidin-4-yl, tetrahydropyranyl, piperizin-1-yl or 4-methyl-pipe

Assignees

• Univ Yale

Inventors

• Jorgensen William L
• Anderson Karen S

Classifications

• A61K31/53

  having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495}) · CPC title

• C07D239/48 Primary

  Two nitrogen atoms · CPC title

• A61K31/536

  ortho- or peri-condensed with carbocyclic ring systems · CPC title

• C07D251/52

  with an oxygen or sulfur atom attached to the third ring carbon atom · CPC title

• A61K31/551

  having two nitrogen atoms, e.g. dilazep · CPC title