Tetrahydroquinolinones and their use as antagonists of metabotropic glutamate receptors

A compound selected from those of Formula IA

• wherein
• R2 represents C2-6alkyl, cycloC3-12alkyl, cycloC3-12alkyl-C1-6alkyl, C2-6alkenyl, C2-6alkynyl, aryl, biaryl, aryl-heteroaryl, heteroaryl-heteroaryl, heteroaryl-aryl, arylC1-6alkyl, arylC2-6alkenyl, arylC2-6alkynyl, heteroaryl, heteroarylC1-6alkyl, heteroarylC2-6alkenyl, heteroarylC2-6alkynyl, 2,3-dihydro-1H-indenyl, C2-6alkoxy, hydroxy-C2-6alkoxy, cycloC3-12alkoxy, cycloC3-12alkyl-C1-6alkoxy, aryloxy, aryl-C1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkylthio, C4-6alkenylthio, cycloC3-12alkylthio, cycloC3-12alkyl-C1-6alkylthio, cycloC3-12alkyl-C3-6alkenylthio, C1-6alkoxyC1-6alkylthio, C1-6alkoxyC3-6alkenylthio, arylC3-6alkenylthio, heteroarylC1-6alkylthio, C1-6alkylsulfonyl, cycloC3-12alkyl-C1-6alkylsulfonyl, arylC1-6alkylsulfonyl, C1-6alkylamino, di-C1-6alkylamino, cycloC3-12alkylamino, C1-C6alkoxy-cycloC3-C12alkylamino, cycloC3-12alkyl-C1-6alkylamino, di-C1-6alkylamino-C1-6alkyl, C1-6alkoxy-C2-6alkylamino, arylamino, arylC1-6alkylamino, N-cycloC3-12alkyl-N—C1-6alkylamino, N-aryl-N—C1-6alkylamino, N-arylC1-6alkyl-N—C1-6alkylamino, 2-indanylamino, 1,2,3,4-tetrahydroisoquinolin-2-yl, tetrahydrofuryl, pyrrolidino, piperidino, 4-arylpiperidino, 4-heteroarylpiperidino, morpholino, piperazino, 4-C1-6alkylpiperazino, 4-arylpiperazino, hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H-isoindol-2-yl, heteroarylC1-6alkoxy, heteroarylamino, heteroarylC1-6alkylamino, —NHC(═O)—R11, —NHSO2—R11, —NHC(═O)OR11, —C(═O)NH—R11, —C1-6alkyl-C(═O)NH—R11, wherein the cycloC3-12alkyl is optionally unsaturated and wherein one carbon atom in the cycloC3-12alkyl moiety may be replaced by an oxygen atom or an NR12-moiety;
• R3 represents hydrogen, cyano, nitro, halogen, C1-6alkyl, CF3, heteroaryl, 2,3-dihydro-1H-indenyl, hydroxy, C1-6alkoxy, pyrrolidino, piperidino, morpholino;
• R4 represents hydrogen, halogen, nitro, C1-6alkoxy, hydroxy-C2-6alkoxy;
• R5 and R6 which may be the same or different, each independently represent hydrogen, hydroxy, C1-6alkyl;
• cycloC3-12alkyl, C2-6alkenyl, C1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkylthio, C3-6alkenylthio, C1-6alkylamino, di-C1-6alkylamino, cycloC3-12alkylamino, di-C1-6alkylaminoC1-6alkyl, arylC1-6alkylamino, aryl, arylC1-6alkyl, or arylC2-6alkenyl;
• or one of R5 and R6 and one of R7 and R8 together represent —(CH2)n— with n being 3, 4 or 5, while the remaining of R5 and R6 as well as R7 and R8 are both hydrogen;
• R7 and R8, which may be the same or different, each independently represent hydrogen, C1-6alkyl, cycloC3-12alkyl, C2-6alkenyl, cycloC3-12alkyl-C1-6alkyl, aryl, arylC1-6alkyl, heteroaryl, or heteroaryl-C1-6alkyl;
• or R7 and R8 may together represent —(CH2)m— with m being 4, 5 or 6;
• R9 and R10, which may be the same or different, each independently represent hydrogen, C1-6alkyl, hydroxy, or C1-6alkoxy;
• R11 represents hydrogen, C1-6alkyl, C2-6alkenyl, aryl;
• arylC1-6alkyl, arylC2-6alkenyl, heteroaryl, heteroarylC1-6alkyl, C1-6alkylamino, di-C1-6alkylamino, cycloC3-12alkylamino, di-C1-6alkylaminoC1-6alkyl, arylamino, arylC1-6alkylamino, arylC2-6alkenylamino, N-aryl-N—C1-6alkylamino, pyrrolidino, piperidino, morpholino, hexamethyleneimino, benzazepinyl, 1,3-dihydro-2H-isoindol-2-yl, cycloC3-12alkyl, or cycloC3-12alkylC1-6alkyl, wherein the cycloC3-12alkyl is optionally unsaturated and wherein one carbon atom in the cycloC3-12alkyl moiety may be replaced by an oxygen atom or an NR12-moiety;
• R12 represents hydrogen, C1-6alkyl, aryl, heteroaryl, arylC1-6alkyl or heteroarylC1-6alkyl;
• and optical isomers, pharmaceutically-acceptable acid and base addition salts, and hydrates thereof;
• it being understood that:
• R2 may not represent unsubstituted phenyl or naphthyl;
• R2 may not represent substituted phenyl having at least one ortho-substituent other than hydrogen, relative to the tetrahydroquinoline ring of formula IA to which the phenyl is attached;
• R2 may not represent dimethylamino;
• if one of R5 and R6 and one of R7 and R8 together represent —(CH2)n— with n being 3, 4 or 5, while the remaining of R5 and R6 as well as R7 and R8 are both hydrogen, then R2 may also be halogen;
• if R3 and R4 both represent hydrogen, then R2 may not represent aryl-heteroaryl, heteroaryl-heteroaryl, arylC2-6alkynyl, or heteroarylC2-6alkynyl;
• if R3, R4, R5, R6, R7, R8, R9 and R10 all represent hydrogen at the same time, then R2 may not represent C2-6alkyl;
• if R3 is cyano, then R2 may not represent methylthio or ethylthio;
• R7 and R8 may not represent furyl;
• and the compound of Formula IA may not represent:
• 2-Benzyloxy-7,8-dihydro-6H-quinoline-5-one, 2-Phenoxy-7,8-dihydro-6H-quinolin-5-one, 2-(1H-Indol-3-yl)-7,8-dihydro-6H-quinolin-5-one, 2-(1H-Indol-3-yl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-Thiophen-2-yl-7,8-dihydro-6H-quinolin-5-one, 2-Ethoxy-7,8-dihydro-6H-quinolin-5-one, 7,7-Dimethyl-2-(6-methyl-pyridin-3-ylmethylsulfanyl)-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile, 2-(1H-Benzoimidazol-2-ylmethylsulfanyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile, 2-(4-Methoxy-phenyl)-7,8-dihydro-6H-quinolin-5-one, 2-(4-Chloro-phenyl)-7,7-dimethyl-7,8-dihydro-6H-quinolin-5-one, 2-(4-Fluoro-phenyl)-7,8-dihydro-6H-quinolin-5-one, 2-(4-Isopropyl-phenyl)-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile, or 2-Cyclohexyl-7,8-dihydro-6H-quinolin-5-one.