Male contraceptive compositions and methods of use

Patent metadata

Field	Value
Publication number	US-9789120-B2
Application number	US-201514977343-A
Country	US
Kind code	B2
Filing date	Dec 21, 2015
Priority date	May 14, 2010
Publication date	Oct 17, 2017
Grant date	Oct 17, 2017

Abstract

The invention relates to compositions and methods for effecting male contraception.

First claim

What is claimed is:

1. A method of reducing or inhibiting spermatogenesis in a healthy fertile male subject, the method comprising administering an effective amount of a compound or a salt thereof that inhibits a bromodomain testis-specific protein (BRDT) to the male subject, wherein the compound is of Formula (I):

wherein:
X is N or CR 5 ;
R 5 is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R B is H, alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, haloalkyl, hydroxy, alkoxy, or —COO—R 3 , wherein alkyl is optionally substituted with halogen or —OH;

ring A is phenyl or thienyl;
each R A is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with halogen, amino, or —OH; or any two R A together with the atoms to which each is attached, can form a fused aryl or heteroaryl group;

R is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of which is optionally substituted with halogen, alkyl, amino, —OH, or aryl;
R 1 is —(CH 2 ) n -L, in which n is 0-3 and L is H, —COO—R 3 , —CO—R 3 , —CO—N(R 3 R 4 ), —S(O) 2 —R 3 , —S(O) 2 —N(R 3 R 4 ), N(R 3 R 4 ), N(R 4 )C(O)R 3 , aryl optionally substituted with alkyl, halogen, amino, or —OH, or heteroaryl optionally substituted with alkyl, halogen, amino, or —OH;
R 2 is H, D (deuterium), halogen, or alkyl optionally substituted with halogen, amino, or —OH;
each R 3 is independently selected from the group consisting of:
(i) H, aryl, or heteroaryl;
(ii) heterocycloalkyl;
(iii) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl or —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl, —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl, each of which may be optionally substituted with halogen, alkyl, amino, —OH, or heterocyclyl;
(iv) N═CR 4 R 6 ;
each R 4 is independently H, alkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with halogen, alkyl, amino, —B(OH) 2 , —SO 2 Na, or —OH;
or R 3 and R 4 are taken together with the nitrogen atom to which they are attached to form a 4-10-membered ring;

R 6 is alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with halogen, alkyl, amino, —B(OH) 2 , —SO 2 Na, or —OH; or R 4 and R 6 are taken together with the carbon atom to which they are attached to form a 4-10-membered ring;

m is 0, 1, 2, or 3;
wherein the compound contains a fluorine or chlorine atom.

2. A method of reducing the rate of male fertility in a healthy fertile male subject, the method comprising administering an effective amount of a compound or a salt thereof that inhibits a BRDT to the male subject, wherein the compound is of Formula (I):

wherein:
X is N or CR 5 ;
R 5 is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;
R B is H, alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, haloalkyl, hydroxy, alkoxy, or —COO—R 3 , wherein alkyl is optionally substituted with halogen or —OH;

ring A is phenyl or thienyl;
each R A is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with halogen, amino, or —OH; or any two R A together with the atoms to which each is attached, can form a fused aryl or heteroaryl group;

R is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of which is optionally substituted with halogen, alkyl, amino, —OH, or aryl;
R 1 is —(CH 2 ) n -L, in which n is 0-3 and L is H, —COO—R 3 , —CO—R 3 , —CO—N(R 3 R 4 ), —S(O) 2 —R 3 , —S(O) 2 —N(R 3 R 4 ), N(R 3 R 4 ), N(R 4 )C(O)R 3 , aryl optionally substituted with alkyl, halogen, amino, or —OH, or heteroaryl optionally substituted with alkyl, halogen, amino, or —OH;
R 2 is H, D (deuterium), halogen, or alkyl optionally substituted with halogen, amino, or —OH;
each R 3 is independently selected from the group consisting of:
(i) H, aryl, or heteroaryl;
(ii) heterocycloalkyl;
(iii) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl or —C 2 -C 8 alkynyl, each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl, —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl, each of which may be optionally substituted with halogen, alkyl, amino, —OH, or heterocyclyl;
(iv) N═CR 4 R 6 ;
each R 4 is independently H, alkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with halogen, alkyl, amino, —B(OH) 2 , —SO 2 Na, or —OH;
or R 3 and R 4 are taken together with the nitrogen atom to which they are attached to form a 4-10-membered ring;
R 6 is alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with halogen, alkyl, amino, —B(OH) 2 , —SO 2 Na, or —OH; or R 4 and R 6 are taken together with the carbon atom to which they are attached to form a 4-10-membered ring;
m is 0, 1, 2, or 3;
wherein the compound contains a fluorine or chlorine atom.

3. The method of claim 1 , wherein the method comprises administering the compound or a salt thereof in an amount sufficient to reduce sperm number and/or reduce sperm motility.

4. The method of claim 1 , wherein the method comprises administering the compound or a salt thereof in an amount sufficient to induce azoospermia, oligozoospermia, and/or asthenozoospermia.

5. The method of claim 4 , wherein the method induces a contraceptive effect in the subject.

6. The method of claim 1 , wherein the compound or a salt thereof is administered to the subject orally, transdermally, or by injection.

7. The method of claim 6 , wherein the compound or a salt thereof is administered in the form of a tablet or capsule.

8. The method of claim 6 , wherein the compound or a salt thereof is administered by parenteral injection, intramuscular injection, intravenous injection, subcutaneous implantation, subcutaneous injection, or transdermal preparation.

9. The method of claim 1 , wherein the compound or a salt thereof is administered in combination with a pharmaceutically acceptable carrier, excipient, or diluent.

10. The method of claim 1 , wherein the compound is JQ1 or a compound of Formula II:

wherein
X is N or CR 5 ;
R 5 is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted;
R B is H, alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, haloalkyl, hydroxy, alkoxy, or —COO—R 3 , each of which wherein alkyl is optionally substituted with halogen or —OH;

each R A is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted with halogen, amino, or —OH; or any two R A together with the atoms to which each is attached, can form a fused aryl or heteroaryl group;
R is alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each of which is optionally substituted with halogen, alkyl, amino, —OH, or aryl;
R′ 1 is H, —COO—R 3 , —CO—R 3 , optionally substituted aryl, or optionally substituted heteroaryl, each of which is optionally substituted with halogen, amino, or —OH;
each R 3 is independently selected from the group consisting of:
(i) H, aryl, substituted aryl, or heteroaryl, or substituted heteroaryl;
(ii) heterocycloalkyl or substituted he

Assignees

• Dana Farber Cancer Inst Inc
• Baylor College Medicine

Inventors

• Bradner James Elliott
• Matzuk Martin
• Qi Jun

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P15/00

  Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives · CPC title

• A61P15/16

  Masculine contraceptives · CPC title

• A61K31/551 Primary

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

• C07D495/14 Primary

  Ortho-condensed systems · CPC title