Male contraceptive compositions and methods of use

Patent metadata

Field	Value
Publication number	US-9301962-B2
Application number	US-201113698006-A
Country	US
Kind code	B2
Filing date	May 16, 2011
Priority date	May 14, 2010
Publication date	Apr 5, 2016
Grant date	Apr 5, 2016

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 in need thereof, the method comprising administering an amount of a compound represented by structural formula (I) sufficient to induce at least one of azoospermia, oligozoospermia, or asthenozoospermia:

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 is optionally substituted;
ring A is aryl or heteroaryl;
each R A is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; 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;
R 1 is —(CH 2 ) n -L, in which n is 0-3 and L is —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 , optionally substituted aryl, or optionally substituted heteroaryl;
R 2 is H, D, (deuterium), halogen, or optionally substituted alkyl;
each R 3 is independently selected from the group consisting of:
(i) H, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
(ii) heterocycloalkyl or substituted 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; and
(iv) NH 2 , N═CR 4 R 6 ;
each R 4 is independently H, alkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted;
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; 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;

provided that
(a) if ring A is thienyl, X is N, R is phenyl or substituted phenyl, R 2 is H, R B is methyl, and R 1 is —(CH 2 ) n -L, in which n is 1 and L is —CO—N(R 3 R 4 ), then R 3 and R 4 are not taken together with nitrogen atom to which they are attached to form a morpholino ring;
(b) if ring A is thienyl, X is N, R is substituted phenyl, R 2 is H, R B is methyl, and R 1 is —(CH 2 ) n -L, in which n is 1 and L is —CO—N(R 3 R 4 ), and one of R 3 and R 4 is H, then the other of R 3 and R 4 is not methyl, hydroxyethyl, alkoxy, phenyl, substituted phenyl, pyridyl or substituted pyridyl; and
(c) if ring A is thienyl, X is N, R is substituted phenyl, R 2 is H, R B is methyl, and R 1 is —(CH 2 ) n -L, in which n is 1 and L is —COO—R 3 is not methyl or ethyl,
or a pharmaceutically acceptable salt thereof,
thereby inducing a contraceptive effect in the healthy fertile male subject.

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

3. The method of claim 2 , wherein the compound or a salt thereof is administered in the form of a tablet or capsule.

4. The method of claim 2 , wherein the compound or a salt thereof is administered by parenteral injection, intramuscular injection, intravenous injection, subcutaneous implantation, subcutaneous injection, or transdermal preparation.

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

6. The method of claim 1 , wherein the subject is human.

7. The method of claim 1 , wherein the compound is represented by structural formula IV:

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 is optionally substituted;
ring A is aryl or heteroaryl;
each R A is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; or any two R A together with the atoms to which each is attached, can form a fused aryl or heteroaryl group;
R 1 is —(CH 2 ) n -L, in which n is 0-2 and L is —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 , optionally substituted aryl, or optionally substituted heteroaryl;
R 2 is H, D, halogen, or optionally substituted alkyl;
each R 3 is independently selected from the group consisting of:
(i) H, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
(ii) heterocycloalkyl or substituted 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; and
(iv) NH 2 , N═CR 4 R 6 ;
each R 4 is independently H, alkyl, alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted;
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; 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; or
a pharmaceutically acceptable salt thereof.

8. The method of claim 7 , wherein
L is —COO—R 3 , optionally substituted aryl, or optionally substituted heteroaryl; and
R 3 is —C 1 -C 8 alkyl, which contains 0, 1, 2, or 3 heteroatoms selected from O, S, or N, and which may be optionally substituted.

9. The method of claim 1 , wherein the compound is represented by structural 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 is optionally substituted;
each R A is independently alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, each of which is optionally substituted; 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;
R′ 1 is —COO—R 3 , —CO—R 3 , optionally substituted aryl, or optionally substituted heteroaryl;
each R 3 is independently selected from the group consisting of:
(i) H, aryl, substituted aryl, heteroaryl, substituted heteroaryl;
(ii) heterocycloalkyl or substituted 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 cycloal

Assignees

• Bradner James Elliott
• Matzuk Martin
• Qi Jun
• Baylor College Medicine
• Dana Farber Cancer Inst Inc

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

• A61P15/16

  Masculine contraceptives · CPC title

• A61K31/5517

  condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam · CPC title

• C07D495/14 Primary

  Ortho-condensed systems · CPC title

• A61K31/551 Primary

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