New salts of tetrahydroisoquinoline-carboxylic acid derivatives, are N-methyl-D-aspartate (NMDA) receptor antagonists useful e.g. for treating anxiety, depression, epilepsy, Alzheimer's disease, cardiovascular disease or especially pain

摘要

Salts (A) of substituted 1,2,3,4-tetrahydro-quinoline-2-carboxylic acid derivatives (I) are new. Salts (A) of tetrahydro-isoquinoline derivatives of formula (I) (including racemates and enantiomers diastereomers or their mixtures) with physiologically acceptable cations or bases are new; R1+R2 = (CH2)n, CH=CHCH2, CH2CH=CH, CH=CH(CH2)2, (CH2)2CH=CH, CH2CH=CHCH2, CH2CH=CH(CH2)2, (CH2)2CH=CHCH2, (CH2)2CH=CH(CH2)2, O(CH2)2, (CH2)2O, O(CH2)3, (CH2)3O, CH2OCH2, CH2O(CH2)2, (CH2)2OCH2, -(CH2)2-o-C6H4-, -o-C6H4-(CH2)2-, cyclopentane-1,3-diyl, cyclopent-4-en-1,3-diyl, naphthalene-1,8-diyl, -CH2-o-C6H4-, -o-C6H4-CH2- or -X-o-C6H4- (all optionally substituted (os)); X = O or S; R3 = H; or 1-18C alkyl, 2-18C alkenyl, 2-18C alkynyl, Cyc, aryl or heteroaryl (all os); Cyc = 3-8C cycloalkyl (optionally unsaturated and optionally having at least one ring C replaced by N, S or O); R4 = R4a or ZR4a; Z = 1-6C alkylene, 2-6C alkenylene or 2-6C alkynyl, Cyc, aryl or heteroaryl (all os); R4a = H; 1-12C alkyl, 2-12C alkenyl, 2-12C alkynyl, Cyc, aryl or heteroaryl (all os); or COR9, COOR9, CSR9, CSOR9, SO2R9, SR10, CONR11R12, CONR11NR12R13, C(NR11)NR12R13, CSNR11R12 or CSNR11NR12R12; R9 = H; or 1-10C alkyl, 2-10C alkenyl, 2-10C alkynyl, Cyc, aryl, heteroaryl, arylalkyl or heteroarylalkyl (all os) (preferably phenethyl, 1- or 2-adamantyl, 1- or 2-naphthyl, 2-, 3- or 4-pyridyl or thiazolyl); R10 = aryl or heteroaryl (both os); R11-R13 = H or; 1-18C alkyl, 2-18C alkenyl, 2-18C alkynyl, Cyc, arylalkyl, heteroarylalkyl, aryl or heteroaryl (all os); R5-R8 = H, halo, CN or NO2; 1-10C alkyl, 2-10C alkenyl or 2-10C alkynyl (all os); or OR14, OCOR14, OCSR14, COR14, COOR14, CSR14, CSOR14, SR14, SOR14, SO2R14, NR15R16, NR15COR16, C(NR15)NR16R17, NR15CSR16, CSNR15R26, CSNR15NR16R17 or SO2NR15R16; or R5 + R6, R6 + R7 or R7 + R8 = =CR18-CH=CH-CH= or =CH-CR18=CH-CH=; R14 = H; or 1-10C alkyl, 2-10C alkenyl, 2-10C alkynyl, Cyc, arylalkyl, heteroarylalkyl, aryl or heteroaryl (all os); R15-R17 = H or O; or 1-18C alkyl, 2-18C alkenyl, 2-18C alkynyl, Cyc, arylalkyl, heteroarylalkyl, aryl or heteroaryl (all os); R15+R16 or R16+R17 = group completing optionally unsaturated, os 3-8C cycloalkyl, optionally having at least one C-atom in the ring replaced by S, O or N; R18 = H, halo or OH; or 1-10C alkyl, 2-10C alkenyl or 2-10C alkynyl (all os); Provided that: (1) if R1 + R2 = -CH2-o-C6H4- and R3 = (-)-p-methan-3-ol (specifically menthol or borneol), then R7 is not Cl if R5, R6 and R8 = H; (2) if R1 + R2 = -CH=CHCH2- and R3 = Me, then R7 is not H, Cl, Me or OMe if R5, R6 and R8 = H; (3) if R1 + R2 = -CH=CHCH2- and R3 = H, then R7 is not OMe or CONH2 if R5, R6 and R8 = H; R5 and R7 are not both Me if R6 and R9 = H; and R5 is not OMe if R6, R7 and R8 = H; and (4) if R1 + R2 = -CH2-o-C6H4- or OCH2CH2 and R3 = Et, then R7 is not H, Cl, Me, OMe or NO2 if R5, R6 and R8 = H; and R5 is not NO2 if R6, R7 and R8 = H. Alternatively in (I): R1 = optionally unsaturated 1-10C alkyl, Cyc, arylalkyl or aryl (all os); or OR19, SR19 or SO2R19; R19 = 1-10C alkyl, 2-10C alkenyl, 2-10C alkynyl, Cyc, aryl, heteroaryl, arylalkyl or heteroarylalkyl (all os); R2 = H, os 1-10C alkyl or os phenyl; provided that if R2 = phenyl then R1 is aryl, aryloxy or arylthio; R3-R8 = as above; Provided that: (i) if R4, R6-R8 = H, then R1 is not Me if R3 = H or Me and R2 = R5 = H; and R1 is not Ph if R3 = Et and R2 = R5 = H; (ii) if R4-R6, R8 = H, then R1 is not SPh if R2 = H, R7 = Cl and R3 = Me; and R1 is not 2-pyridylthio if R2 = Me, R7 = OMe and R3 = allyl; and (iii) if R2, R4, R5, R7 = H and R6 = R8 = Cl, then R1 is not dioxolan if R3 = CH2CH2OH. An Independent claim is also included for the preparation of (A).