Small molecules for inhibiting male fertility

Patent metadata

Field	Value
Publication number	US-10472334-B2
Application number	US-201515122528-A
Country	US
Kind code	B2
Filing date	Mar 13, 2015
Priority date	Mar 14, 2014
Publication date	Nov 12, 2019
Grant date	Nov 12, 2019

Abstract

Compounds suitable for use in providing male contraception, an assay method for identifying such compounds, and methods of providing contraception using the compounds, are provided. In one embodiment, the compounds described herein mimic the binding of anti-EPPIN antibodies to EPPIN, and thus inhibit the forward motility of sperm in humans and other primates. In another embodiment, the compounds described herein inhibit or enhance EPPIN-semenogelin binding, and inhibit forward motility of sperm. The assays described herein identify compounds which inhibit sperm motility, and can be carried out in a high throughput manner, using labeled recombinant EPPIN and semenogelin. The compounds can be used in oral or transdermal compositions to temporarily and reversibly inhibit male fertility. They can also be used in addition to, or in place of, spermicides in spermicidal compositions, such as those used in conjunction with condoms, diaphragms, and spermicidal jellies.

First claim

The invention claimed is:

1. A method of providing contraception, comprising administering an effective amount of a compound having one of the following formulas:

and tautomers, and pharmaceutically-acceptable salts thereof,
wherein:
R 1 is —CH 2 R 5 ,
R 2 is H, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, arylalkyl, alkylaryl, C(X)R 6 or C(X)XR 6 ,
R 3 is —NHR 7 , —C(X)NHR 7 , —NHC(X)R 7 , —NHC(X)XR 7 , —R 8 , or C(X)R 8 ;
R 4 is OR 7 or —C(X)OR 7 ,
R 5 is H, F, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, arylalkyl, alkylaryl, —XC(X)XR 6 , C(X)XR 6 , or C(X)R 6 ,
R 6 and R 7 are H, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, arylalkyl, or alkylaryl;
R 8 is

X is O, S, or NR 7 ,
Y is O, S, NR 7 , or C(R 7 ) 2 ,
Zj refers to j number of Z substituents, which substituents can be present at any carbon atom on the benzene ring, wherein j is 0, 1 or 2, each Z is, individually, a substituent species selected from the group consisting of C 1-8 alkyl, C 1-8 substituted alkyl, C 2-8 alkenyl, C 2-8 substituted alkenyl, C 3-8 cycloalkyl, C 3-8 substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, halo, —OR 7 , —N(R 7 ) 2 , —CF 3 , —CN, —NO 2 , —C 2 R 7 , —SR 7 , —N 3 , —C(═O)N(R 7 ) 2 , —NR 7 C(═O)R 7 , —C(═O)R 7 , —C(═O)OR 7 , —OC(═O)R 7 , —O(CR 6 R 7 ) r C(═O)R 7 —, —O(CR 6 R 7 ) r NR 7 C(═O)R 7 , —O(CR 6 R 7 ) r NR 7 SO 2 R 7 , —OC(═O)NR 6 R 7 , —NR 7 C(═O)OR 7 , —SO 2 R 7 , —SO 2 NR 6 R 7 , and —NR 7 SO 2 R 7 ,
r is an integer from 1 to 6, and
n is 0, 1, 2, or 3,
the term “substituted” as applied to alkyl, aryl, cycloalkyl and the like refers to the substituents described above, starting with halo and ending with —NR 7 SO 2 R 7 ;
and tautomers, and pharmaceutically-acceptable salts thereof,
wherein the compounds can exist as single stereoisomers or as mixtures of stereoisomers.

2. The method of claim 1 , wherein haloalkyl is mono-fluoromethyl.

3. The method of claim 1 , wherein R 5 is F, —XC(X)XR—, or C(X)XR 6 .

4. The method of claim 1 , wherein one or more C═X moieties are carbonyl (C═O).

5. A method of providing contraception, comprising an effective amount of a compound having one of the following formulas:

6. A pharmaceutical composition for providing male contraception, comprising an effective amount of a compound of claim 1 .

7. The composition of claim 6 , further comprising a water-soluble lubricant.

8. A compound having one of the following formulas:

and tautomers, and pharmaceutically-acceptable salts thereof,
wherein:
R 1 is —CH 2 R 5 ,
R 2 is H, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, arylalkyl, alkylaryl, C(X)R 6 or C(X)XR 6 ,
R 3 is —NHR 7 , —C(X)NHR 7 , —NHC(X)R 7 , —NHC(X)XR 7 , —R 8 , or C(X)R 8 ;
R 4 is OR′ or —C(X)OR 7 ,
R 5 is H, F, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, arylalkyl, alkylaryl, —XC(X)XR 6 , C(X)XR 6 , or C(X)R 6 ,
R 6 and R 7 are H, C 1-8 alkyl, C 1-8 haloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, arylalkyl, or alkylaryl;
R 8 is

X is O, S, or NR 7 ,
Y is O, S, NR′, or C(R 7 ) 2 ,
Zj refers to j number of Z substituents, which substituents can be present at any carbon atom on the benzene ring, wherein j is 0, 1 or 2, each Z is, individually, a substituent species selected from the group consisting of C 1-8 alkyl, C 1-8 substituted alkyl, C 2-8 alkenyl, aryl, alkylaryl, arylalkyl, halo, —OR 7 , —N(R 7 ) 2 , —CF 3 , —CN, —NO 2 , —C 2 R 7 , —SR 7 , —N 3 , —C(═O)N(R 7 ) 2 , —NR 7 C(═O)R 7 , —C(═O)R 7 , —C(═O)OR 7 , —OC(═O)R 7 , —O(CR 6 R 7 ) r C(═O)R 7 —, —O(CR 6 R 7 ) r NR 7 C(═O)R 7 , —O(CR 6 R 7 ) r NR 7 SO 2 R 7 , —OC(═O)NR 6 R 7 , —NR 7 C(═O)OR 7 , —SO 2 R 7 , —SO 2 NR 6 R 7 , and —NR 7 SO 2 R 7 ,
r is an integer from 1 to 6, and
n is 0, 1, 2, or 3,
and tautomers, and pharmaceutically-acceptable salts thereof,
wherein the compounds can exist as single stereoisomers or as mixtures of stereoisomers.

9. The compound of claim 8 , wherein haloalkyl is mono-fluoromethyl.

10. The compound of claim 8 , wherein R 5 is F, —XC(X)XR 6 , or C(X)XR 6 .

11. The compound of claim 8 , wherein one or more C═X moieties are carbonyl (C═O).

12. A compound of claim 8 , wherein the compound has the formula:

or a pharmaceutically acceptable salt, or tautomer thereof.

13. A compound of claim 8 , having one of the following formulas:

or a pharmaceutically acceptable salt, or tautomer thereof.

14. A compound of claim 8 , having the formula:

or a pharmaceutically acceptable salt, or tautomer thereof.

Assignees

• Univ North Carolina Chapel Hill

Inventors

• O'Rand Michael

Classifications

• A61P15/16

  Masculine contraceptives · CPC title

• C07D253/075

  Two hetero atoms, in positions 3 and 5 · CPC title

• C07D253/07

  with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• 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

• C07D498/04

  Ortho-condensed systems · CPC title