Patent EA-004542-B1 (EA)
Title: 1,2-annelated quinoline derivatives
Inventor: ANGIBAUD PATRICK RENE
IPC: A61K31/498
Filed: 1999-12-17
Abstract: 1. A compound of formula (I) or a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof, wherein =X<1>-X<2>-X<3>- is a trivalent radical of formula =N-CR<6>=CR'-	(x-1),	=CR<6>-CR<7>=CR<8>-	(x-6), =N-N=CR<6>-	(x-2),	=CR<6>-N=CR<7>-	(x-7), =N-NH-C (=O)-	(x-3),	=CR<6>-NH-C (=O)-	(x-8), or =N-N=N-	(x-4),	=CR<6>-N=N-	(x-9); =N-CR<6>=N-	(x-5),		 wherein each R<6>, R<7> and R<8> are independently hydrogen, C1-4alkyl, hydroxy, C1-4alkyloxy, aryloxy, C1-4alkyloxycarbonylC1-4alkyl, mono- or di-(C1-4alkyl)amino C1-4alkyl, cyano, amino, thio, C1-4alkylthio, arylthio or aryl; > Y<1>-Y<2>- is a trivalent radical of formula > CH-CHR<9>-	(y-1), > C=N-	(y-2), > CH-NR<9>-	(y-3), or > C=CR<9>-	(y-4); wherein each R<9> independently is hydrogen, halo, halocarbonyl, aminocarbonyl, hydroxy C1-4alkyl, cyano, carboxyl, C1-4alkyl, C1-4alkoxy, alkyloxyC1-4alkyl, C1-4alkyloxycarbonyl, mono- or di(C1-4alkyl) amino, mono- or di (C14alkyl)amino C1-4alkyl, aryl; r and s are each independently 0,1,2,3,4 or 5; t is 0, 1, 2 or 3; each R<1> and R<2> are independently hydroxy, halo, cyano, C1-6alkyl, trihalomethyl, trihalomethoxy, C2-6alkenyl, C1-6alkoxy, hydroxyC1-6alkyloxy, C1-6alkylthio, C1-6alkyloxyC1-6alkyloxy, C1-6alkyloxycarbonyl, aminoC1-6alkyloxy, mono- or di(C1-6alkyl) aminocarbonyl, mono- or di(C1-6alkyl)amino C1-6alkyloxy, aryl, arylC1-6alkyl, aryloxy or arylC1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl, aminocarbonyl, amino C1-6alkyl, mono- or di (C1-6alkyl)amino C1-6alkyl; or two R<1> or R<2> substituents adjacent to one another on the phenyl ring may independently form together a bivalent radical of formula -O-CH2-O-	(a-1), -O-CH2-CH2-O-	(a-2), -O=CH=CH-	(a-3), -O-CH2-CH2-	(a-4), -O-CH2-CH2-CH2-	(a-5), or -CH=CH-CH=CH-	(a-6); R<3> is hydrogen, halo, C1-6alkyl, cyano, haloC1-6alkyl, hydroxyC1-6alkyl, cyanoC1-6alkyl, aminoC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkylthioC1-6alkyl, aminocarbonylC1-6alkyl, hydroxycarbonyl, hydroxycarbonylC1-6alkyl, C1-6alkylcarbonylC1-6alkyl, C1-6alkylcarbonylC1-6alkyl, C1-6alkyloxycarbonyl, aryl, arylC1-6alkyloxyC1-6alkyl, mono- or di(C1-6alkyl) amino C1-6alkyl; or a radical of formula -O-R<10>	(b-1), -S-R<10>	(b-2), -NR<11>R<12>	(b-3), wherein R<10> is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, aryl, arylC1-6alkyl, C1-6alkyloxycarbonyl C1-6alkyl, or a radical of formula-Alk-OR<13> or -Alk-NR<14>R<15>; or R<11> s hydrogen, C1-6alkyl, aryl, or arylC1-6alkyl; R<12> is hydrogen, C1-6alkyl, aryl, hydroxy, amino, C1-6alkyloxy, C1-6alkylcarbonyl C1-6alkyl, C1-6alkylcarbinylamino, mono- or di(C1-6alkyl) amino, C1-6alkylcarbonyl, aminocarbonyl, arylcarbonyl, halo C1-6alkylcarbonyl, aryl C1-6alkylcarbonyl, C1-6alkyloxycarbonyl, C1-6alkyloxy C1-6alkylcarbonyl, mono- or di(C1-6alkyl) aminocarbonyl, wherein the alkyl moiety may optionally be substituted by one or more substituents independently selected from aryl or C1-3alkyloxyearbonyl, aminocarbonylcarbonyl, or mono- or di (C1-6alkyl) aminoC1-6alkylcarbonyl, or a radical or radical of formula Alk-OR<13> or -Alk-NR<14>R<15>; wherein Alk is C1-6alkanediyl; R<13> is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxyC1-6alkyl, aryl or arylC1-6alkyl; R<14> is hydrogen, C1-6alkyl, aryl or arylC1-6alkyl; R<15> is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, aryl or arylC1-6alkyl; R<4> is a radical of formula wherein R<16> is hydrogen, halo, aryl, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, mono- or di(C1-4alkyl) amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylthioC1-6alkyl, C1-6alkylS(O) C1-6alkyl or C1-6alkylS(O)2 C1-6alkyl; R<16> is may also be bound to one of the nitrogen atoms in the imidazole ring of formula (c-1) or (c-2), in which case the meaning of R<16> when bound to the nitrogen is limited to hydrogen, aryl, C1-6alkyl, hydroxy C1-6alkyl, C1-6alkyloxy C1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)- C1-6alkyl or C1-6alkylS(O)2C1-6alkyl; R<17> is hydrogen, C1-6alkyl, C1-6alkyloxy C1-6alkyl, aryl C1-6alkyl, trifluoromethyl or di(C1-6alkyl)aminosulfonyl; R<5> is C1-6alkyl, C1-6alkyloxy or halo; aryl is phenyl, naphthalenyl or phenyl substituted with 1 or more substituents each independently selected from halo, C1-6alkyl, C1-6alkyloxy or trifluoromethyl. 2. A compound according to claim 1 wherein each R<1> and R<2> are independently hydroxy, halo, cyano, C1-6alkyl, trihalomethyl, trihalomethoxy, C1-6alkenyl, C1-6alkyloxy, hydroxy C1-6alkyloxy, C1-6alkylthio, C1-6alkyloxy C1-6alkyloxy, C1-6alkyloxycarbonyl, amino C1-6alkyloxy, mono- or di(C1-6alkyl)amino, mono- or di(C1-6alkyl)amino C1-6alkyloxy, aryl, aryl C1-6alkyl, aryloxy or aryl C1-6alkyloxy, hydroxycarbonyl, C1-6alkyloxycarbonyl; or two R<1> or R<2> substituents adjacent to one another on the phenyl ring may independently form together a bivalent radical of formula -O-CH2-O-	(a-1), -O-CH2-CH2-O-	(a-2), -O=CH=CH-	(a-3), -O-CH2-CH2-	(a-4), -O-CH2-CH2-CH2-	(a-5), or -CH=CH-CH=CH-	(a-6); wherein R<16> is hydrogen, halo, aryl, C1-6alkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, mono- or di(C1-4alkyl) amino, hydroxycarbonyl, C1-6alkyloxycarbonyl, C1-6alkylthioC1-6alkyl, C1-6alkylS(O) C1-6alkyl or C1-6alkylS(O)2 C1-6alkyl; R<16> is may also be bound to one of the nitrogen atoms in the imidazole ring of formula (c-1) or (c-2), in which case the meaning of R<16> when bound to the nitrogen is limited to hydrogen, aryl, C1-6alkyl, hydroxy C1-6alkyl, C1-6alkyloxy C1-6alkyl, C1-6alkyloxycarbonyl, C1-6alkylS(O)- C1-6alkyl or C1-6alkylS(O)2 C1-6alkyl; R<17> is hydrogen, C1-6alkyl, C1-6alkyloxy C1-6alkyl, aryl C1-6alkyl, trifluoromethyl or di(C1-6alkyl)aminosulfonyl. 3 A compound according to any of claims 1 to 2 wherein =X<1>-X<2>-X<3> is a trivalent radical of formula (x-1), (x-2), (x-3), (x-4) or (x-9) wherein each R<6> independently is hydrogen, C1-6alkyl, C1-6alkyloxycarbonyl, amino or aryl and R<7> is hydrogen, >Y<1>-Y<2>- is a trivalent radical of formula (y-1), (y-2), (y-3), or (y-4) wherein each R<9> independently is hydrogen, halo, carboxyl, C1-6alkyl or C1-6alkyloxycarbonyl; r is 0, 1 or 2; s is 0 or 1; t is 0; R<1> is halo, C1-6alkyl or two R<1> substituents ortho to one another on the phenyl ring may independently form together a bivalent radical of formula (a-1); R<2> is halo; R<3> is halo or a radical of formula (b-1) or (b-3) wherein R<10> is hydrogen or a radical of formula -Alk-OR<13>, R<11> is hydrogen; R<12> is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, hydroxy, C1-6alkyloxy or mono- or di(C1-6alkyl)amino C1-6alkylcarbonyl; Alk is C1-6alkanediyl and R<13> is hydrogen; R<4> is a radical of formula (c-1) or (c-2) wherein R<14> is hydrogen, halo or mono- or di(C1-6alkyl)ammo; R<17> is hydrogen or C1-6alkyl; aryl is phenyl. 4. A compound according to any of claims 1 to 3 wherein =X<L>-X<2>-X<3> is a trivalent radical of formula (x-1), >Y<1>-Y<2> is a trivalent radical of formula (y-4), r is 0 or 1, s is 1, t is 0, R<1> is 3-chloro, R<2> is 4-chloro or 4-fluoro, R<3> is hydrogen or a radical of formula (b-1) or (b-3), R<4> is a radical of formula (c-1) or (c-2), R<6> is hydrogen, R<7> is hydrogen, R<9> is hydrogen, R<10> is hydrogen, R<11> is hydrogen and R<12> is hydrogen. 5 A compound according to any one of claims 1 to 4 wherein =X<1>-X<2>-X<3> is a trivalent radical of formula (x-2) or (x-3), >Y'-Y<2> is a trivalent radical of formula (y-2), (y-3) or (y-4), r and s are 1, t is 0, R<1> is 3-chloro or 3-methyl, R<2> is 4-chloro, R<3> is a radical of formula (b-1) or (b-3), R<4> is a radical of formula (c-2), R<6> is C1-4alkyl, R<9> is hydrogen, R<10> and R<11> are hydrogen and R<12> is hydrogen or hydroxy. 6 A compound according to claim 1 or 2 selected from: 7-[(4-fluorophenyl)(1H-imidazol-1-yl)methyl]-5-phenylimidazo[1,2-a]quinoline; alpha-(4-chlorophenyl)-alpha-(1-methyl-1H-imidazol-5-yl)-5-phenyliinidazo[1,2-a]quinoline-7-methanol; 5-(3-chlorophenyl)-alpha-(4-chlorophenyl)-alpha-(1-methyl-1H-imidazol-5-yl)-imidazo[1,2-a]quinoline-7-methanol; 5-(3-chlorophenyl)-alpha-(4-chlorophenyl)-alpha-(1-methyl-1H-imidazol-5-yl)imidazo[1,2-a]quinoline-7-methanamine; 5-(3-chlorophenyl)-alpha-(4-chlorophenyl)-alpha-(1-methyl- 1H-imidazol-5-yl)tetrazolo[1,5-a]quinoline-7-methanamine; 5-(3-chlorophenyl)-alpha-(4-chlorophenyl)-1-methyl-alpha-(1-methyl-1H-imidazol-5-yl)-1,2,4-triazolo[4,3-a]quinoline-7-methanol; 5-(3-chlorophenyl)-alpha-(4-chlorophenyl)-alpha-(1-methyl-1H-imidazol-5-y])tetrazolo[1,5-a]quinoline-7-methanamine; 5-(3-chlorophenyl)-alpha-(4-chlorophenyl)-alpha-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanol; 5-(3-chlorophenyl)-alpha-(4-chlorophenyl)-4,5-dihydro-alpha-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanol; 5-(3-chlorophenyl)-alpha-(4-chlorophenyl)-alpha-(1-methyl-1H-imidazol-5-yl)tetrazolo[1,5-a]quinazoline-7-methanamine; 5-(3-chlorophenyl)-alpha-(4-chlorophenyl)-H-hydroxy-alpha-(1-methyl-1H-imidazol-5-yl)tetrahydro[1,5-a]quinoline-7-methanamine; alpha-(4-chlorophenyl)-alpha-(1-methyl-1H-imidazol-5-yl)-5-(3-methylphenyl)tetrazolo[1,5-a]quinoline-7-methanamine or pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof. 7. 5-(3-chlorophenyl)-alpha-(4-chlorophenyl)-alpha-(1-methyl-1H-imidazol-5-y])tetrazolo[1,5-a]quinoline-7-methanamine or pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof. 8. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as active ingredient a therapeutically effective amount of a compound as described in any one of claims 1 to 7. 9. A process for preparing a pharmaceutical composition as claimed in claim 8, wherein a therapeutically effective amount of a compound as claimed in any one of claims 1 to 7 is intimately mixed with a pharmaceutically acceptable carrier. 10. A compound according to any one of claims 1 to 7 for use as a medicine. 11. A medicament for use of claim 10 when said medicament is for inhibiting the abnormal