Patent EA-004248-B1 (EA)
Title: 4,5,6 and 7-indole and indoline derivatives, their preparation and use
Inventor: MOLTZEN EJNER KNUD
IPC: C07D403/14
Filed: 1999-06-14
Abstract: 1. A substituted 4-, 5-, 6-, or 7-indole or indoline derivative of Formula wherein W is N, C, CH or COH and the dotted lines indicate optional bonds and wherein A is a group having the formula wherein the dotted line indicates bond; n is 0, 1, 2, 3, 4 or 5, and m is 0, 1, 2, 3, 4 or 5; Z is CH2, O, S, CO, SO and SO2, provided that if n is 0 then Z is CH2; R<3>-R<9> and R<11>-R<12> are independently selected from hydrogen, halogen, cyano, nitro, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C1-6alkoxy, C1-6alkylthio, hydroxy, hydroxy-C1-6-alkyl, C1-6alkoxycarbonyl, C3-8cycloalkyl, C3-8cycloalkenyl, C3-8cycloalkyl-C1-6alkyl, C3-8cycloalkyl-C1-6alkenyl, C3-8cycloalkyl-C1-6alkynyl, C3-8cycloalkenyl-C1-6alkyl, C3-8cycloalkenyl-C1-6alkenyl, C3-8cycloalkenyl-C1-6alkynyl, C1-6alkylcarbonyl, phenylcarbonyl, halogen substituted phenylcarbonyl, trifluoromethyl, trifluoromethylsulfonyloxy, C1-6alkylsulfonyl, aryl and heteroaryl; and/or two adjacent groups taken from R<3>-R<9> may together form a methylenedioxy group, and/or two adjacent groups R<7>-R<9> may together form a cyclopentyl or cyclohexyl ring, which may be substituted with one or more methyl groups, and/or one of R<3>-R<9> may alternatively be a group -NR<13>R<14>, wherein R<13> is as defined for R<10> below and R<14> is hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkenyl, C3-8cycloalkyl-C1-6alkyl, C3-8cycloalkyl-C1-6alkenyl, C3-8cycloalkyl-C1-6alkynyl, C3-8cycloalkyl-C1-6alkyl, C3-8cycloalkyl-C1-6alkenyl, C3-8cycloalkyl-C1-6alkynyl, aryl, heteroaryl, aryl-C1-6alkyl or heteroaryl-C1-6alkyl; R<10> is hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C3-8cycloalkyl, C3-8cycloalkenyl, C3-8cycloalkyl-C1-6alkyl, C3-8cycloalkyl-C1-6alkenyl, C3-8cycloalkyl-C1-6alkynyl, C3-8cycloalkenyl-C1-6alkyl, C3-8cycloalkenyl-C1-6alkenyl, C3-8cycloalkynyl-C1-6alkenyl, aryl, heteroaryl, aryl-C1-6alkyl, heteroaryl-C1-6alkyl, acyl, thioacyl, C1-6alkylsulfonyl, trifluoromethylsulfonyl, arylsulfonyl or heteroarylsulfonyl; R<15>VCO, wherein V is O or S and R<15> is C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C3-8cycloalkyl, C3-8cycloalkenyl, C3-8cycloalkyl-C1-6alkyl, C3-8cycloalkyl-C1-6alkenyl, C3-8cycloalkyl-C1-6alkynyl, C3-8cycloalkenyl-C1-6alkyl, C3-8cycloalkenyl-C1-6alkenyl, C3-8cycloalkenyl-C1-6alkynyl, aryl, or heteroaryl; or a group R<16>R<17>NCO- or R<16>R<17>NCS-, wherein R<16> and R<17> are independently selected from hydrogen, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C3-8cycloalkyl, C3-8cycloalkenyl, C3-8cycloalkyl-C1-6alkyl, C3-8cycloalkyl-alkenyl, C3-8cycloalkyl-C1-6alkynyl, C3-8cycloalkenyl-C1-6alkyl, C3-8cycloalkenyl-C1-6alkenyl, C3-8cycloalkenyl-C1-6alkynyl, heteroaryl or aryl, or R<16> and R<17> together with the N-atom, to which they are linked, form a pyrrolidinyl, piperidinyl, morpholinyl or perhydroazepin group; or an acid addition salt thereof, with the proviso that a substituted 4-, 5-, 6-, or 7-indole derivative is not 3-[4-(1H-indole-5-yl)-3,6-dihydro-2H-pyridine-1-ylmethyl]-1H-indazolom and 7-chloro-3-[4-(1H-indole-5-yl)-3,6-dihydro-2H-pyridine-1-ylmethyl]-1H-indazolom. 2. A compound according to claim 1, wherein A is a group having the formula wherein R<3>-R<6> are as defined in claim 1 and the dotted line is bond. 3. A compound according to any of claims 1 and 2, wherein Z is CH2 and n + m is 0, 1, 2, 3, 4, 5, or 6. 4. A compound according to claim 1-3, wherein W is N. 5. A compound according to claim 1 having the formula wherein R<7> to R<12>, W, Z, n, m are as defined in claim 1 and the dotted lines are optional bonds and A is a group having the formula wherein X, Y and R<3>-R<6> are as defined in claim 1. 6. A compound according to claim 5, wherein A is a group having the formula wherein R<3>-R<6> are as defined in claim 5. 7. A compound of claims 1-6, wherein Z is CH2 and n + m is 0, 1, 2, 3, 4, 5, or 6 and R<3>-R<9> and R<11>-R<12> is hydrogen, halogen, cyano, nitro, C1-6alkyl, C1-6alkoxy, hydroxy, hydroxy-C1-6alkyl, C1-6alkoxycarbonyl and trifluoromethyl; and R<10> is hydrogen. 8. A compound according to any of claims 5-7, wherein W is N. 9. A compound according to claim 1, which is 1-(2-(3-Benzofuranyl) ethyl)-4-(1H-indol-4-yl) piperazine, 1-(3-Benzofuranylmethyl)-4-(1H-indol-4-yl) piperazine, 1-(2-(5-Fluoro-3-benzofuranyl)ethyl)-4-(1H-indol-4-yl) piperazine, 1-(4-(5-Fluoro-3-benzofuranyl)-1-butyl)-4-(1H-indol-4-yl)piperazine, 1-(2-(1H-Indol-3-yl) ethyl)-4-(1H-indol-4-yl) piperazine, 1-(3-(1H-Indol-3-yl)-1-propyl)-4-(1H-indol-4-yl) piperazine, 1-(4-(1H-Indol-3-yl)-1-butyl)-4-(1H-indol-4-yl)piperazine, 1-(3-(5-Fluoro-3-benzofuranyl)-1-propyl)-4-(1H-indol-4-yl) piperazine, 1-(2-(2-Methyl-4,5,6,7-tetrafluoro-3-benzofuranyl) ethyl)-4-(1H-indol-4-yl) piperazine, 1-(2-(3-Indazolyl) ethyl)-4-(1H-indol-4-yl) piperazine, 1-(2-(6-Chloro-3-indazolyl) ethyl)-4-(1H-indol-4-yl)piperazine, 1-(2-(7-Cyano-1H-indol-3-yl) ethyl)-4-(1H-indol-4-yl)piperazine, 1-(2-(6-Chloro-1H-indol-3-yl) ethyl)-4-(1H-indol-4-yl)piperazine, 1-(2-(4-Chloro-1H-indol-3-yl) ethyl)-4-(1H-indol-4-yl)piperazine, 1-(2-(5-Fluoro-1H-indol-3-yl) ethyl)-4-(1H-indol-4-yl)piperazine, 1-(2-(6-Chloro-1H-indol-3-yl) ethyl)-4-(1H-indol-4-yl)-1,2,3,6-tetrahydropyridine, 1-(2-(5-Fluoro-1H-indol-3-yl) ethyl)-4-(1H-indol-4-yl)-1,2,3,6-tetrahydropyridine, 1-(2-(7-Bromo-1H-indol-3-yl) ethyl)-4-(1H-indol-4-yl)piperazine, 1-(1-Allyl-1H-indol-4-yl)-4-(2-(6-chloro-1H-indol-3-yl)ethyl)piperazine, 1-(1-Allyl-1H-indol-4-yl)-4-(2-(5-fluoro-1H-indol-3-yl)ethyl)piperazine, 1-(1-Benzyl-1H-indol-4-yl)-4-(2-(6-chloro-1H-indol-3-yl)ethyl)piperazine, 1-(1-Benzyl-1H-indol-4-yl)-4-(2-(5-fluoro-1H-indol-3-yl)ethyl)piperazine, 1-(1-Benzyl-1H-indol-4-yl)-4-(2-(5-bromo-1H-indol-3-yl)ethyl)piperazine, 1-(2-(6-Chloro-1H-indol-3-yl) ethyl)-4-(1-propargyl-1H-indol-4-yl)piperazine, 1-(2-(1H-Indol-3-yl) ethyl)-4-(1-propargyl-1H-indol-4yl)piperazine, 1-(2-(5-Fluoro-1H-indol-3-yl) ethyl)-4-(1-propargyl-1H-indol-4-yl)piperazine, 1-(2-(5-Bromo-1H-indol-3-yl) ethyl)-4-(1-propargyl-1H-indol-4-yl)piperazine, 1-(1-Benzyl-1H-indol-4-yl)-4-(2-(1H-indol-3-yl)ethyl)piperazine, 1-(2-(5-Bromo-1H-indol-3-yl) ethyl)-4-(1H-indol-5-yl)piperazine, 1-(2-(5-Chloro-1H-indol-3-yl) ethyl)-4-(1H-indol-5-yl)piperazine, 1-(2-(5-Fluoro-1H-indol-3-yl) ethyl)-4-(6-hydroxymethyl-1H-indol-4-yl)piperazine, 1-(2-(6-Chloro-1H-indol-3-yl) ethyl)-4-(6-hydroxymethyl-1H-indol-4-yl)piperazine, 1-(2-(5-Bromo-1H-indol-3-yl) ethyl)-4-(6-hydroxymethyl-1H-indol-4-yl)piperazine, 1-(3-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-propyl)-4-(1H-indol-4-yl)piperazine, 1-(2-(1H-Indol-3-yl) ethyl)-4-(6-methoxycarbonyl-1H-indol-4-yl)piperazine, 1-(2-(6-Chloro-1H-indol-3-yl) ethyl)-4-(6-methoxycarbonyl-1H-indol-4-yl)piperazine, 1-(2-(5-Fluoro-3-benzofuranyl) ethyl)-4-(6-methoxycarbonyl-1H-indol-4-yl)piperazine, 1-(5-Fluoro-3-benzofuranylmethyl)-4-(1H-indol-4-yl)piperazine, 1-(3-Cyano-1H-indol-4-yl)-4-(2-(1H-indol-3-yl) ethyl)piperazine, 1-(3-Cyano-1H-indol-4-yl)-4-(2-(5-fluoro-3-benzofuranyl)ethyl)piperazine, 1-(2-(6-Chloro-1H-indol-3-yl) ethyl)-4-(3-cyano-1H-indol-4-yl)piperazine, 1-(2-(3-Benzofuranyl) ethyl)-4-(3-cyano-1H-indol-4-yl)piperazine, 1-(1H-Indol-4-yl)-4-(2-(5-methyl-3-benzofuranyl)ethyl)piperazine, 1-(1H-Indol-4-yl)-4-(2-(4-methyl-3-benzofuranyl)ethyl)piperazine, 1-(3-(5-Fluoro-3-benzofuranyl)-1-propyl)-4-(1H-indol-4-yl)-1,2,3,6 tetrahydopyridine, 1-(2-(5-Chloro-3-benzofuranyl) ethyl)-4-(1H-indol-4-yl)piperazine, 1-(1H-indol-4-yl)-4-(2-(6-methyl-3-benzofuranyl) ethyl)piperazine, 1-(2-(7-Chloro-3-benzofuranyl) ethyl)-4-(1H-indol-4-yl)piperazine, 1-(2-(4-Chloro-1H-indol-3-yl) ethyl)-4-(3-cyano-1H-indol-4-yl)piperazine, 1-(2-(6-Chloro-1H-indol-3-yl) ethyl)-4-(1H-indol-4-yl)piperazine, 1-(2-(5-Chloro-1H-indol-3-yl) ethyl)-4-(1H-indol-4-yl)piperazine, 1-(2-(7-Bromo-1H-indol-3-yl) ethyl)-4-(1H-indol-4-yl)piperazine, 1-(2-(4-Chloro-1H-indol-3-yl) ethyl)-4-(1H-indol-4-yl)piperazine, 1-(2-(6-Trifluoromethyl-1H-indol-3-yl) ethyl)-4-(1H-indol-4-yl)piperazine, 1-(1H-Indol-4-yl)-4-(2-(5-methyl-1H-indol-3-yl)ethyl)piperazine, 1-(1H-Indol-4-yl)-4-(2-(6-methyl-1H-indol-3-yl)ethyl)piperazine, 1-(1H-Indol-4-yl)-4-(2-(7-methyl-1H-indol-3-yl)ethyl)piperazine, 1-(2-(4,5-Dichloro-3-benzofuranyl) ethyl)-4-(1H-indol-4-yl)piperazine, 1-(2-(5-Bromo-3-benzofuranyl) ethyl)-4-(1H-indol-4-yl)piperazine, 1-(2-(4-Chloro-1H-indol-3-yl) ethyl-4-(1H-indol-4-yl)piperidine, 4-(1H-Indol-4-yl)-1-(2-(5-methyl-1H-indol-3-yl) ethyl)piperidine, 4-(1H-Indol-4-yl)-1-(2-(1H-indol-3-yl)ethyl)piperidine, 1-(1H-Indol-4-yl)-4-(3-(4-methyl-3-benzofuranyl)-1-propyl)piperazine, 4-(1H-Indol-4-yl)-1-(3-(4-methyl-3-benzofuranyl)-1-propyl)piperidine, 1-(3-(4-Chloro-3-benzofuranyl)-1-propyl)-4-(1H-indol-4-yl)piperazine, 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(6-chloro-1H-indol-4-yl)piperazine, 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(6-fluoro-1H-indol-4-yl)piperazine, 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(6-cyano-1H-indol-4-yl)piperazine, 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(7-chloro-1H-indol-4-yl)piperazine, 1-(2-(6-Chloro-1-indol-3-yl)ethyl)-4-(7-cyano-1H-indol-4-yl)piperazine, 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(2-cyano-1H-indol-4-yl)piperazine 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indolin-4-yl)piperazine, 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indol-6-yl)piperazine and 1-(2-(6-Chloro-1H-indol-3-yl)ethyl)-4-(1H-indol-7-yl)piperazine, or a pharmaceutically acceptable acid addition salt thereof. 10. A pharmaceutical composition comprising a compound according to claims 1 to 9 or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent. 11. The use of a compound according to claims 1 to 9 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of a disorder or disease responsive to the inhibition of serotonin reuptake and antagonism of 5-HT1A receptors. 12. The use of a compound according to claims 1 to 9 or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament f