US 6,441,019 B2 · Cyclocarbamate and cyclic amide derivatives

Abstract

This invention provides compounds of the formula: wherein A and B are independent substituents selected from S, CH or N; provided that when A is S, B is CH or N; and when B is S, A is CH or N; and A and B cannot both be CH; and when A and B both equal N, one N may be optionally substituted with an C1 to C6 alkyl group; R1 and R2 are independent substituents selected from the group of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, CORA, or NRBCORA; or R1 and R2 are fused to form optionally substituted 3 to 8 membered spirocyclic alkyl, alkenyl or heterocyclic ring, the heterocyclic ring containing one to three heteroatoms selected from the group of O, S and N; or pharmaceutically useful salts thereof. The compounds of this invention are useful as agonists and antagonists of the progesterone receptor and in methods of inducing contraception and in the treatment or prevention of benign or malignant neoplastic diseases.

A compound having the structure:

wherein;
A and B are independent substituents selected from the group consisting of S and CH;
wherein
(i) when A is S, B is CH;
(ii) when B is S, A is CH;
(iii) A and B cannot both be CH;
and
R1 and R2 are independent substituents selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C2 to C6 alkenyl, substituted C2 to C6 alkenyl, C2 to C6 alkynyl, substituted C2 to C6 alkynyl, C3 to C8 cycloakyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, CORA, and NRBCORA;
or R1 and R2 are fused to form:
a) a C-based saturated 3 to 8 membered spirocyclic ring;
b) a C-based 3 to 8 membered spirocyclic ring having one or more carbon-carbon double bonds;
or
c) a 3 to 8 membered spirocyclic ring having in its backbone one to three heteroatoms selected from the group consisting of O, S and N;
RA 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;
RB is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
R3 is H, OH, NH2, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C6 alkenyl, substituted C3 to C6 alkenyl, alkynyl, substituted alkynyl, or CORC;
RC 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;
R4 is (v) or (vi):
(v) a substituted benzene ring containing the substituents X, Y and Z as shown below:
X is selected from the group consisting of halogen, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 thioalkyl, substituted C1 to C3 thioalkyl, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, 5 or 6 membered heterocyclic ring having in its backbone 1 to 3 heteroatoms, CORD, OCORD, 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;
Y and Z are independently selected from the group consisting of H, halogen, CN, NO2, C1 to C3 alkoxy, C1 to C3 alkyl, and C1 to C3 thioalkyl;
or
(vi) a five or six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR5, the five or six membered ring being optionally substituted by 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, CORF, and NRGCORF;
RF is H, C1 to C3 aklyl, 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;
RG is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
R5 is H or C1 to C3 alkyl;
Q is O, S, NR6,or CR7R8;
R6 is selected from the group consisting of CN, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, and SO2CF3;
R7 and R8 are independent substituents selected from the group consisting of H, C1 to C6 alkyl, substituted C1 to C6 alkyl, C3 to C8 cycloalkyl, substituted C3 to C8 cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, NO2, CN, and CO2R9;
R9 is C1 to C3 alkyl;
or CR7R8 may comprise a six membered ring of the structure below:
W is a bond,
wherein said substituted alkyl, alkenyl, and alkynyl groups have one or more substituents selected from the group consisting of halogen, CN, OH, NO2, amino, aryl, heterocyclic, substituted aryl, substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio;
said aryl groups are selected from the group consisting of phenyl, napthyl, biphenyl, anthryl, tetrahydronaphthyl, and phenanthyl;
said substituted aryl groups have one or more substituents selected from the group consisting of halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio;
said substituted alkyloxy groups have one or more substituents selected from the group consisting of halogen, CN, OH, NO2, amino, alkyl, cycloalkyl, alkenyl, alkynyl alkoxy, aryloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio;
said heterocyclic group is a stable 4- to 7-membered monocyclic or a stable multicyclic heterocyclic ring having in its backbone from one to four heteroatoms selected from the group consisting of N, O, and S atoms;
and
said substituted heterocyclic groups have one or more substituents selected from the group consisting of halogen, CN, OH, NO2, amino, alkyl, substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl, alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, and arylthio;
or a pharmaceutically acceptable salt thereof.

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Cyclocarbamate and cyclic amide derivatives

Life of this patent

Cyclocarbamate and cyclic amide derivatives

Life of this patent

Abstract

Claims10