IP Library › Granted Patent US 7,084,168
Granted Patent B2
US 7,084,168 · App. 10/456,892 · Granted Aug 1, 2006

Indoline derivatives

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Quick Facts
Patent No.
US 7,084,168
App. No.
10/456,892
Granted
Aug 1, 2006
Kind
B2
Abstract

This invention relates to substituted indoline derivative compounds which are antagonists of the progesterone receptor, their preparation and pharmaceutical utility, particularly including contraception and treatment of benign or malignant neoplastic diseases, having the general structure: wherein R 1 and R 2 may be single substituents or fused to form spirocyclic rings.

Claims (80)

1. A compound of the Formula 1:

wherein:

R 1 and R 2 are selected from the group consisting of H, alkyl, substituted alkyl, OH, O(alkyl), O(substituted alkyl), OAc, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, alkylheteroaryl, 1-propynyl, and 3-propynyl;

R 3 is selected from the group consisting of H, OH, NH 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 6 alkenyl, alkynyl, substituted alkynyl, and COR A ;

R A is selected from the group consisting of H, 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 aminoalkyl, and substituted C 1 to C 3 aminoalkyl;

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:

wherein:

X is selected from the group consisting of halogen, 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 1 to 3 heteroatoms, COR B , OCOR B , and NR C COR B ;

R B is 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, or 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 and Z are independently 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; or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 5 is a disubstituted benzene ring containing the substituents X and Y as shown below:

wherein:

X is selected from the group consisting of halogen, CN, 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; and

Y is on the 4′ or 5′ position of the di substituted benzene ring and is selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkoxy, C 1 to C 4 alkyl, and C 1 to C 3 thioalkyl;

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , which is selected from the group consisting of:

i) 5-(3-Nitro-phenyl)-1,3-dihydro-indol-2-one;

ii) 3-methyl-5-(3-nitrophenyl)-1,3-dibydro-indol-2-one;

iii) 5-(3-Methoxy-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one;

iv) 5-(3-Chloro-phenyl)-3,3-dimethyl-1,3-dibydro-indol-2-one;

v) 3,3-Dimethyl-5-(3-nitro-phenyl)-1,3-dihydro-indol-2-one;

vi) 5-(3-Chloro-phenyl)-3-ethyl-1,3-dihydro-indol-2-one;

vii) 5-(3-Chloro-phenyl)-3,3-diethyl-1,3-dihydro-indol-2-one;

viii) 5-(3-Chloro-phenyl)-3-methoxy-3-methyl-1,3-dihydro-indol-2-one;

ix) 5-(3-Chloro-phenyl)-3-methoxy-3-prop-1-ynyl-1,3-dihydro-indol-2-one; and

x) 5-(3-Chloro-phenyl)-1,3-dihydro-indol-2-one; or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 , which is selected from the group consisting of:

i) 5-(3-Chloro-4-fluoro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one;

ii) 3-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-benzonitrile;

iii) 5-(3-Chloro-5-fluoro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one;

iv) 5-(3-Fluoro-5-nitro-phenyl)-3,3-dimethyl-1,3-dihydro-indol-2-one;

v) 3-(3,3-Dimethyl-2-oxo-2,3-dihydro1H-indol-5-yl)-5-fluoro-benzonitrile; and

vi) 3-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-fluoro-benzonitrile; or a pharmaceutically acceptable salt thereof.

5. A pharmaceutical composition comprising a compound of 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 treating neoplastic disease selected from the group consisting of uterine myometrial fibroids, endometriosis, benign prostatic hypertrophy; carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary and meningioma, the method comprising administering to mammal in need thereof a pharmaceutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereot.

8. A compound of the Formula 1:

wherein:

R 1 is selected from the group consisting of H, alkyl, substituted alkyl, OH, O(alkyl), O(substituted alkyl), OAc, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, alkylheteroaryl, 1-propynyl, and 3-propynyl;

R 2 is selected from the group consisting of alkyl, substituted alkyl, OH, O(alkyl), O(substituted alkyl), OAc, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, alkylheteroaryl, 1-propynyl, and 3-propynyl;

R 3 is selected from the group consisting of H, OH, NH 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 6 alkenyl, alkynyl, substituted alkynyl, and COR A ;

R A is selected from the group consisting of H, 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 aminoalkyl, and substituted C 1 to C 3 aminoalkyl;

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:

wherein:

X is selected from the group consisting of 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 1 to 3 heteroatoms, COR B , OCOR B , and NR C COR B ;

R B is 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, or 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 and Z are independently 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; or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound of claim 8 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

10. 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 8 , or a pharmaceutically acceptable salt thereof.

11. A method of treating benign or malignant neoplastic disease, selected from the group consisting of uterine myometrial fibroids, endometriosis, benign prostatic hypertrophy, carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon, prostate, pituitary and meningioma the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of claim 8 , or a pharmaceutically acceptable salt thereof.

12. 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.

13. 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 8 , or a pharmaceutically acceptable salt thereof.

14. 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 the Formula 1:

wherein:

R 1 and R 2 are selected from the group consisting of H, alkyl, substituted alkyl, OH, O(alkyl), O(substituted alkyl), OAc, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, alkylheteroaryl, 1-propynyl, and 3-propynyl;

R 3 is selected from the group consisting of H, OH, NH 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 3 to C 6 alkenyl, alkynyl, substituted alkynyl, and COR A ;

R A is selected from the group consisting of H, 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 aminoalkyl, and substituted C 1 to C 3 aminoalkyl;

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:

wherein:

X is selected from the group consisting of 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 1 to 3 heteroatoms, COR B , OCOR B , and NR C COR B ;

R B is 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, or 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 and Z are independently 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; or a pharmaceutically acceptable salt thereof.

15. A method of hormone replacement therapy, the method comprising administering to a mammal in need thereof a pharmaceutically effective amount of a compound of the Formula 1:

wherein:

R 1 and R 2 are selected from the group consisting of H, alkyl, substituted alkyl, OH, O(alkyl), O(substituted alkyl), OAc, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, alkylheteroaryl, 1-propynyl, and 3-propynyl;

R 3 is selected from the group consisting of H, OH, NH 2 , C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkenyl, alkynyl, substituted alkynyl, and COR A ;

R A is selected from the group consisting of H, 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 aminoalkyl, and substituted C 1 to C 3 aminoalkyl;

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:

wherein:

X is selected from the group consisting of 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 1 to 3 heteroatoms, COR B , OCOR B , and NR C COR B ;

R B is 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, or 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 and Z are independently 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; or a pharmaceutically acceptable salt thereof.