US 2004/0110778 A1 · Heterocyclic compounds as ligands of the GABAA receptor

Abstract

Disclosed are heterocyclic compounds of the formula 1 and the pharmaceutically acceptable salts thereof wherein the variables A, V, Y, J, E, X, T, G, Q, W, Z, b, n and m are defined herein. These compounds are highly selective agonists, antagonists or inverse agonists for GABAA brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAA brain receptor.

A compound of the formula

724
or a pharmaceutically acceptable salt thereof wherein:
the b-ring is a 5-9 membered ring;
E represents (CR1R2)k, —CR1═CR2—, —O— (CR1R2)k—, —(CR1R2)k—O—, —N═CR1—, —CR═N—, —NR′—(CR1CR2)k—, or —(CR1R2)k—NR′—, —S—(CR1R2)k—, (CR1R2)k—S—, —SO— (CR1R2)k—, —(CR1R2)k—SO—, —SO2—(CR1R2)k—, —(CR1R2)k—SO2—,wherein
R1 and R2 independently represent
hydrogen, CL-C6 alkyl, CL-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di-(C1-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C1-C6)alkyl, or
phenyl, pyridyl, phenyl(C1-C6)alkyl, or pyridyl(C1-C6)alkyl, where each phenyl or pyridyl is optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- or di(C1-C6)alkylamino;
k is 0, 1, 2, or 3;
R2 represents
hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, C1-C6 alkoxy(C1-C6)alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, amino(C1-C6)alkyl, or mono- or di(C1-C6)alkylamino(C1-C6)alkyl, or
aryl, heteroaryl, aryl(C1-C6)alkyl, or heteroaryl(C1-C6)alkyl, where each aryl and heteroaryl is optionally substituted with up to 3 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- and di(C1-C6)alkylamino;
G is oxygen or NH;
J represents (CR5R6)d where
d is 0 or 1;
and
R5 and R6 together form a carbonyl group;
or
R5 and R6 are independently hydrogen or R100,
where each R100 is independently selected from halogen, hydroxy, nitro, cyano, R10, amino, —NH(R10), —N(R10) (R10), —COOH, —O(R10), —SO2NH2, —SO2NH(R10), —SO2N(R10) (R10), —NHCO(R10), —N(R10), CO(R10), —NHCO2 (R10), —N(R10)CO2 (R10), —NHSO2 (R10), —N(R10), SO2 (R10)—SO2NHCO(R10), —SO2N(R10)CO(R10), —CONHSO2(R10), —CON(R10)SO2(R10), —CONH2, —CONH(R10), —CON(R10) (R10), —CO2 (R10), —CO(R10), —SR10, SO(R10), —SO2 (R10), aryl having from 1 to 3 rings, and heteroaryl, said heteroaryl having from 1 to 3 rings, 5 to 7 ring members in each ring, and in at least one of said rings from 1 to about 3 heteroatoms selected from nitrogen, oxygen and sulfur, and where each aryl and heteroaryl is optionally substituted with 1, 2, or 3 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, and mono- or di(C1-C6)alkylamino;
each R10 is independently a straight, branched, or cyclic alkyl group having up to 8 carbon atoms, contains zero or one or more double or triple bonds, and is optionally substituted with one or more substituents independently selected from hydroxy, oxo, halogen, amino, mono- or di-(C1-C6)alkylamino, cyano, nitro, C1-C6alkoxy, —COOH, —SO2NH2, —SO2NH(C1-C6alkyl), —SO2N(C1-C6alkyl) (C1-C6alkyl), —NHCO(C1-C6alkyl), —N(C1-C6alkyl)CO(C1-C6alkyl), NHCO2(C1-C6alkyl), —N(C1-C6alkyl) CO2(C1-C6alkyl), —NHSO2 (C1-C6alkyl), —N(C1-C6alkyl) SO2 (C1-C6alkyl), —SO2N(C1-C6alkyl)CO(C1-C6alkyl), —SO2NHCO(C1-C6alkyl), —CON(C1-C6alkyl)SO2(C1-C6alkyl), —CONHSO2(C1-C6alkyl), —CONH2, —CONH(alkyl), —CON(alkyl)(alkyl), —CO2(alkyl), —CO(alkyl), —SO0-2(C1-C6alkyl), and C3-C7cycloalkyl;
the group
725
is the A ring and represents an optionally substituted saturated, partially unsaturated, or aromatic heterocyclic ring containing at least one nitrogen, oxygen, or sulfur atom,
where the A ring is optionally substituted with up to three groups independently selected from R100;
V is nitrogen, carbon, or CH;
Y is carbon or CH;
X is hydrogen, hydroxy, amino, mono- or di(C1-C6) alkylamino, C1-C6 alkyl, or C1-C6 alkoxy;
T is hydrogen, halogen, hydroxy, amino, mono- or di(C1-C6) alkylamino, C1-C6 alkyl, or C1-C6 alkoxy;
Q is a saturated carbocyclic or heterocyclic group, partially unsaturated carbocyclic or heterocyclic group, an aryl group, or heteroaryl group, where each group has from 1 to 3 rings where each ring contains from 3 to 8 ring members, and where each heterocyclic and heteroaryl group contains at least one ring having from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur;
and
where each carbocyclic, heterocyclic, aryl, or heteroaryl group is optionally substituted with 1, 2, or 3 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, oxo, cyano, nitro, amino, C1-C6 haloalkyl, C1-C6 haloalkoxy, and mono- or di(C1-C6)alkylamino;
W is a bond, oxygen, NH, sulfur, —CH═CH—, —C≡C—, or CR7R8 where R7 and R8 are the same or different and represent hydrogen, C1-C6 alkyl, halo(C1-C6)alkyl, amino(C1-C6)alkyl, hydroxy(C1-C6)alkyl, or C1-C6 alkoxy(C1-C6)alkyl, or CR7R8 represents C3-C7 cycloalkyl;
Z is hydrogen, hydroxy, hydroxy(C1-C6)alkyl, C1-C6 alkoxy, —CO(C1-C6)alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C6)alkyl, C3-C7 cycloalkyl(C1-C4)alkoxy, amino, mono- or di(C1-C6) alkylamino, or NR11 COR12 where R11 and R12 are the same or different and represent hydrogen or C1-C6 alkyl, or NCOR11R12 represents a heterocycloalkanone ring, or
Z is a saturated carbocyclic or heterocyclic group, a partially unsaturated carbocyclic or heterocyclic group, an aryl group, or a heteroaryl group, where each group has from 1 to 3 rings where each saturated ring contains from 3 to 8 ring members and each aromatic or partially unsaturated ring contains from 5-8 ring members, and where each heterocyclic and heteroaryl group contains at least one ring having from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur;
and
where each carbocyclic, heterocyclic, aryl, and heteroaryl group is optionally substituted with 1, 2, or 3 groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, C1-C6 haloalkyl, C1-C6 haloalkoxy, and mono- or di(C1-C6)alkylamino;
726
and
727
independently represent saturated carbon chains optionally substituted with one or more substituents independently selected from halogen, cyano, nitro, amino, mono- or di(C1-C6)alkylamino, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkyl, and C3-C7 cycloalkyl;
m is 0, 1, 2, or 3;
and
n is 0, 1, 2, or 3.

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Heterocyclic compounds as ligands of the GABAA receptor

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Heterocyclic compounds as ligands of the GABAA receptor

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Abstract

Claims123