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US 6,608,068 B2Granted
Indoline derivatives
AssigneesWyeth, Ligand Pharmaceuticals Incorporated
InventorsAndrew Fensome, Lori L. Miller, John W. Ullrich, Reinhold H. W. Bender, Puwen Zhang, Jay E. Wrobel, Lin Zhi, Todd K. Jones, James P. Edwards, Christopher M. Tegley
Life of this patent
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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 R1 and R2 may be single substituents or fused to form spirocyclic rings.
Claims26
A compound of the Formula 1:
- wherein:
- R1 and R2 are joined to form a ring selected from the group consisting of —CH2(CH2)nCH2—, —CH2CH2C(CH3)2CH2CH2—, —O(CH2)mCH2—, —CH2CH2OCH2CH2—, —CH2CH2N(H)CH2CH2—, and —CH2CH2N(alkyl)CH2CH2—;
- n is an integer from 0 to 5;
- m is an integer from 1 to 4;
- R3 is selected from the group consisting of H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, alkynyl, substituted alkynyl, and CORA;
- RA is selected from the group consisting of H, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, and substituted C1 to C3 aminoalkyl;
- R4 is selected from the group consisting of H, halogen, CN, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, and substituted C1 to C6 aminoalkyl;
- R5 is selected from the group consisting of a), b) and c):
- a) a five membered heterocyclic ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6 and containing one or two independent substituents selected from the group consisting of H, halogen, CN, NO2, C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, CORD, and NRECORD;
- with the proviso that when the five-membered heterocyclic ring having in its backbone one NR6 heteroatom and said ring is attached at the 2-position on said ring, the CN substituent is attached at the 3 or 4-position of said ring;
- b) a six membered heterocyclic ring having in its backbone 1 or 2 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6 and containing one or two independent substituents selected from the group consisting of H, halogen, CN, NO2, C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, CORD, and NRECORD;
- RD is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
- RE is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
- R6 is H or C1 to C3 alkyl;
- and
- c) 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, NO2, lower alkoxy, and CF3;
- or a pharmaceutically acceptable salt thereof.
14 more elements
A compound of the structure:
- wherein:
- R5 is the six membered ring of the structure:
- X1 is N or CX2;
- X2 is halogen, CN or NO2.
1 more element
A compound selected from the group consisting of 5-(1,2-dihydro-2-oxospiro[cyclohexane-1,3-[3H]indol])-5-n-butyl-2-thiophenecarbonitrile;
- Nitro-5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl-1H-pyrrole-1-carboxylic acid, tert-butyl ester;
- and 5-(1,2-dihydro-2-oxospiro[cyclopentane-1,3-[3H]indol]-5-yl)-1H-pyrrole-1-carboxylic acid, tert-butyl ester;
- or a pharmaceutically acceptable salt thereof.
A compound of the structure:
- wherein:
- R5 is a five membered ring of the structure:
- U is O, S, or NR6;
- R6 is H, C1 to C3 alkyl, or C1 to C4 CO2 alkyl;
- X′ is selected from the group consisting of halogen, CN, NO2, C1 to C3 alkyl, and C1 to C3 alkoxy;
- with the proviso that when X is CN, U is O or S;
- Y′ is selected from the group consisting of H, F, CN, NO2 and C1 to C4 alkyl;
- or a pharmaceutically acceptable salt thereof.
5 more elements
A compound of the Formula 1:
- wherein:
- R1 and R2 are joined to form a —O(CH2)pO— ring;
- p is an integer from 1 to 4;
- R3 is selected from the group consisting of H, OH, NH2, C1 to C6 alkyl, C3 to C6 alkenyl, alkynyl, substituted alkynyl, and CORA;
- RA is selected from the group consisting of H, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, and substituted C1 to C3 aminoalkyl;
- R4 is selected from the group consisting of H, halogen, CN, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C1 to C6 alkoxy, substituted C1 to C6 alkoxy, C1 to C6 aminoalkyl, and substituted C1 to C6 aminoalkyl;
- R5 is selected from the group consisting of a):
- b) and C):
- a) a five membered heterocyclic ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6 and containing one or two independent substituents selected from the group consisting of H, halogen, CN, NO2, C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, CORD, and NRECORD;
- with the proviso that when the five-membered heterocyclic ring having in its backbone one NR6 heteroatom and said ring is attached at the 2-position on said ring, the CN substituent is attached at the 3- or 4-position of said ring;
- b) a six membered heterocyclic ring having in its backbone 1 or 2 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR6 and containing one or two independent substituents selected from the group consisting of H, halogen, CN, NO2, C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, CORD, and NRECORD;
- RD is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl;
- RE is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
- R6 is H or C1 to C3 alkyl;
- and
- c) 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, NO2, lower alkoxy, and CF3;
- or a pharmaceutically acceptable salt thereof.
14 more elements
Dependencies are inferred from the claim text.