Thio-oxindole derivatives
View Patent ↗This invention relates to compounds which are agonists of the progesterone receptor which have the general structure: wherein: R 1 , R 2 , R 3 , R 4 , R 5 and Q 1 are as defined herein, or a pharmaceutically acceptable salt thereof, as well as methods of using these compounds to induce contraception or treat progesterone-related carcinomas and adenocarcinomas.
1. A compound of formula 1:
wherein:
R 1 and R 2 are independently selected from the group consisting of alkyl and substituted alkyl;
R 3 is selected from the group consisting of H, C 1 to C 6 alkyl, and substituted C 1 to C 6 alkyl;
R 4 is selected from the group consisting of H, halogen, CN, NH 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, and substituted C 1 to C 6 aminoalkyl;
R 5 is a substituted benzene ring containing the substituents X, and Z as shown below:
X is selected from the group consisting of H, halogen, OH, CN, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 thioalkyl, substituted C 1 to C 3 thioalkyl, S(O)alkyl, S(O) 2 alkyl, C 1 to C 3 aminoalkyl, substituted C 1 to C 3 aminoalkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing in its backbone to 3 heteroatoms, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , COR B , OCOR B , and NR C COR B ;
R B is selected from the group consisting of H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, and substituted C 1 to C 3 aminoalkyl;
R C is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
Y is halogen;
Z is selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 3 alkyl, and C 1 to C 3 thioalkyl;
Q 1 is CR 8 R 9 ;
R 8 is selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO 2 , CN, and CO 2 R 10 ;
R 9 is CN;
R 10 is C 1 to C 3 alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein:
R 5 is the benzene ring of the formula;
X is selected from the group consisting of halogen, CN, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , C 1 to C 3 alkoxy, C 1 to C 3 alkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, and C 1 to C 3 thioalkoxy;
Y is on the 4′ or 5′ position.
3. A compound of formula 1:
wherein:
R 1 and R 2 are CH 3 ;
R 3 is selected from the group consisting of H and C 1 to C 6 alkyl;
R 4 is selected from the group consisting of H, halogen, CN, NH 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, and substituted C 1 to C 6 aminoalkyl;
R 5 is a substituted benzene ring containing the substituents X, Y and Z as shown below:
X is selected from the group consisting of H, halogen, OH, CN, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 thioalkyl, substituted C 1 to C 3 thioalkyl, S(O)alkyl, S(O) 2 alkyl, C 1 to C 3 aminoalkyl, substituted C 1 to C 3 aminoalkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing in its backbone to 3 heteroatoms, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , COR B , OCOR B , and NR C COR B ;
R B is selected from the group consisting of H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy C 1 to C 3 aminoalkyl, and substituted C 1 to C 3 aminoalkyl,
R C is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
Y is halogen;
Z is selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 3 alkyl, and C 1 to C 3 thioalkyl;
Q 1 is CR 8 R 9 ;
R 8 is selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO 2 , CN, and CO 2 R 10 ;
R 9 is CN;
R 10 is C 1 to C 3 alkyl;
or a pharmaceutically acceptable salt thereof.
4. A compound of formula 1:
wherein:
R 1 and R 2 are independently selected from the group consisting of C 1 to C 6 alkyl;
R 3 and R 4 are H;
R 5 is a substituted benzene ring containing the substituents X, and Z as shown below:
X is selected from the group consisting of H, halogen, OH, CN, to C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy, C 1 to C 3 thioalkyl, substituted C 1 to C 3 thioalkyl, S(O)alkyl, S(O) 2 alkyl, C 1 to C 3 aminoalkyl, substituted C 1 to C 3 aminoalkyl, NO 2 , C 1 to C 3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing in its backbone to 3 heteroatoms, CONH 2 , CSNH 2 , CONHalkyl, CSNHalkyl, CON(alkyl) 2 , CSN(alkyl) 2 , COR B , OCOR B , and NR C COR B ;
R B is selected from the group consisting of H, C 1 to C 3 alkyl, substituted C 1 to C 3 alkyl, aryl, substituted aryl, C 1 to C 3 alkoxy, substituted C 1 to C 3 alkoxy C 1 to C 3 aminoalkyl, and substituted C 1 to C 3 aminoalkyl;
R C is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
Y is halogen;
Z is selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 3 alkyl, and C 1 to C 3 thioalkyl;
Q 1 is CR 8 R 9 ;
R 8 is selected from the group consisting of H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 8 cycloalkyl, substituted C 3 to C 8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO 2 , CN, and CO 2 R 10 ;
R 9 is CN;
R 10 is C 1 to C 3 alkyl;
or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
6. A method of inducing contraception in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
7. A method of treatment of dysfunctional bleeding in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
8. A method of treatment of carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, or prostate in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
9. A method of treatment of carcinomas and adenocarcinomas of uterine leiomyomata, endometriosis or polycystic ovary syndrome in a mammal, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
10. A method of hormone replacement therapy, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
11. The method according to claim 1 , wherein R 1 and R 2 are methyl.
12. The method according to claim 1 , wherein R 1 an R 2 are ethyl.
13. The method according to claim 1 , wherein R 8 is H.
14. The method according to claim 1 , wherein R 4 is H.
15. The method according to claim 1 , where Z and X are H.