Indoline derivatives
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.
1. 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 six membered heterocyclic ring having in its backbone 1 or 2 heteroatoms selected from the group consisting of O, S, SO, SO 2 and NR 6 and containing one or two independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkyl, C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, COR D , and NR E COR D ;
R D 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 E is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
R 6 is H or C 1 to C 3 alkyl; or
an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, the moiety being optionally substituted by from 1 to 3 substituents selected from the group consisting of halogen, lower alkyl, CN, NO 2 , lower alkoxy, and CF 3 ;
or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
3. 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, and substituted alkynyl;
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 five membered heterocyclic ring having in its backbone one O, S, SO, SO 2 or NR 6 heteroatom and containing one or two independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkyl, C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, COR D , and NR E COR D ;
with the proviso that when the five-membered heterocyclic ring having in its backbone one NR 6 heteroatom is attached at the 2-position on said ring, the CN substituent is attached at the 1-, 3-, 4-, or 5-position of said ring;
R D 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 E is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
R 6 is H or C 1 to C 3 alkyl;
or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 3 , wherein R 5 is a five membered ring of the structure:
wherein:
U is O, S, or NR 6 ;
R 6 is H, C 1 to C 3 alkyl, or C 1 to C 4 CO 2 alkyl,
X′ is selected from the group consisting of halogen, CN, NO 2 , C 1 to C 3 alkyl and C 1 to C 3 alkoxy; with the proviso that when X′ is CN, U is not NR 6 ;
Y′ is selected from the group consisting of H, F, CN, NO 2 , and C 1 to C 4 alkyl.
5. The compound according to claim 3 , which is selected from the group consisting of:
(i) 5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-4-methyl thiophene-2-carbonitrile;
(ii) 4-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-furan-2-carbonitrile;
(iii) 5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-furan-2-carbonitrile;
(iv) 2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-2-nitro-pyrrole;
(v) 5-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-thiophene2-carbonitrile; and
(vi) 3,3-Dimethyl-5-(5-nitro-thiophene-2-yl)-1,3-dihydro-indol-2-one;
or a pharmaceutically acceptable salt thereof.
6. A compound which is 2-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl)-pyrrole-1-carboxylic acid tert-butyl ester, or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a compound of claim 3 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
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 an indol-4-yl, indol-7-yl or benzo-2-thiophene moiety, the moiety being optionally substituted by from 1 to 3 substituents selected from the group consisting of halogen, lower alkyl, CN, NO 2 , lower alkoxy, and CF 3 ;
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 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 five membered heterocyclic ring having in its backbone 3 heteroatoms selected from the group consisting of O, S, SO, SO 2 and NR 6 and containing one or two independent substituents selected from the group consisting of H, halogen, CN, NO 2 , C 1 to C 3 alkyl, C 1 to C 3 alkoxy, C 1 to C 3 aminoalkyl, COR D , and NR E COR D ;
R D 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 E is H, C 1 to C 3 alkyl, or substituted C 1 to C 3 alkyl;
R 6 is H or C 1 to C 3 alkyl;
or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising a compound of claim 10 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.