Patent EA-001890-B1 (EA)
Title: Indole and 2,3-dihydroindole derivatives, their use, pharmaceutical composition and method of treatment
Inventor: MOLTZREN EJNER KNUD
IPC: C07D405/14
Filed: 1998-07-20
Abstract: 1. An indole or 2,3-dihydroindole derivative having the formula:   any of its enantiomers or any mixture thereof, or an acid addition salt thereof, wherein X is -O-, -S-, or -CR<4>R<5>-; and Y is -CR<6>R<7>-, -CR<6>R<7>-CR<8>R<9>-, or -CR<6>=CR<7>-; or X and Y together form a group -CR<4>=CR<5>-, or -CR<4>=CR<5>-CR<6>R<7>-; Z is-O-, or -S-; W is N, C, or CH; A is a group selected from a group of formula (II), (III) and (IV):   wherein the dotted lines mean an optional bond; R<1>, R<2>, R<3>, R<12>, R<13>, R<14>, R<15>, R<16> and R<17> are each independently selected from hydrogen, halogen, trifluoromethyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, C1-C4 alkoxy, hydroxy, formyl, CO-C1-4 alkyl, amino, C1-4 alkylamino, (C1-4)2-dialkylamino, CO-C1-4alkylamino, alkoxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, dialkylaminocarbonylamino, nitro and cyano; R<4>, R<5>, R<6>,R<7>, R<8> and R<9> are each independently selected form hydrogen and C1-4alkyl; and R<11> is selected from hydrogen, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C3-7cycloalkyl, aryl, aryl-C1-4alkyl, CO-C1-4alkyl and formyl. 2. The compounds according to Claim 1 wherein Z is -O-. 3. The compounds according to Claim 1 wherein Z is -S-. 4. The compounds according to Claim 1 wherein A is a group of formula (II). 5. The compounds according to Claim 1 wherein A is a group of formula (III). 6. The compounds according to Claim 1 wherein A is a group of formula (IV). 7. The compounds according to Claim 2 wherein A is a group of formula (II). 8. The compounds according to Claim 2 wherein A is a group of formula (III). 9. The compounds according to Claim 2 wherein A is a group of formula (IV). 10. The compounds according to Claim 3 wherein A is a group of formula (II). 11. The compounds according to Claim 3 wherein A is a group of formula (III). 12. The compounds according to Claim 3 wherein A is a group of formula (IV). 13. The compounds according to Claims 1 to 12 wherein R<4>, R<5>, R<6>, R<7>, R<8> and R<9> is selected from hydrogen or methyl. 14. The compound according to Claim 1 which is 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-bromo-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-2-methyl-1H-indole, 6-chloro-3-[2-[4-(2,2,5-trimethyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl]ethyl]-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-4-chloro-1H-indole, 6-chloro-3-[2-[4-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)piperidin-1-yl]-1H-indole, 6-chloro-3-[2-[4-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydro-1pyridyl]ethyl]-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-methoxy-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole, 3-[2-[4-(5-chloro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole, 6-chloro-3-[2-[4-(5-chloro-3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole, 6-chloro-3-[2-[4-(6-chloro-2,2-dimethyl-3,4-dihydro-2H-1-benzopyran-8-yl)piperazin-1yl]ethyl]-1H-indole, 6-chloro-3-[2-[4-(2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-methyl-1H-indole, or 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-methyl-1H-indole, 6-chloro-3-[2-[4-(6-chloro-1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indole, 5-chloro-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole, 3-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole, 3-[2-[4-(benzothiophen-7-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole, 3-[2-[4-(benzothiopyran-8-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole, 3-[2-[4-(benzothiopyran-8-yl)piperazin-1-yl]ethyl]-5-bromo-1H-indole, 3-[2-[4-(benzothiopyran-8-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-chloro-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)-1,2,3,6-tetrahydropyridan-1-yl]ethyl]-5-fluoro-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperidin-1-yl]ethyl]-6-chloro-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperidin-1-yl]ethyl]-5-chloro-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperidin-1-yl]ethyl]-5-fluoro-1H-indole, 6-chloro-3-[2-[4-(2,3-dihydrobenzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-1H-indole, 3-[2-[4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl-6-chloro-1H-indole, 3-[2-[4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-bromo-1H-indole, 3-[2-[4-(benzofuran-7-yl)-1,2,3,6-tetrahydropyridin-1-yl]ethyl]-5-fluoro-1H-indole, 3-[2-[4-(benzofuran-7-yl)piperidin-1-yl]ethyl]-6-chloro-1H-indole, 3-[2-[4-(benzofuran-7-yl)piperidin-1-yl]ethyl]-5-fluoro-1H-indole, 3-[2-[4-(benzofuran-7-yl)piperidin-1-yl]ethyl]-5-bromo-1H-indole, 1-acetyl-3-[2-[4-(1,4-benzodioxan-4-yl)piperazin-1-yl]ethyl]-2,3-dihydro-1H-indole, 1-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole, 1-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole, 1-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indole, 1-[2-[4-(2,3-dihydrobenzofuran-7-yl)piperazin-1-yl]ethyl]-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro-5-fluoro-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-2,3-dihydro-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1-butyl-1H-indole, 1-allyl-3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl-lH-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1-propargyl-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro-1-methyl-1H-indole, 3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1-benzyl-2,3-dihydro-1H-indole, 1-allyl-3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-2,3-dihydro-1H-indole, 1-acetyl-3-[2-[4-(1,4-benzodioxan-5-yl)piperazin-1-yl]ethyl]-1H-indole, 3-[2-[4-(benzo-1,4-dithian-5-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole, 3-[2-[4-(benzo-1,4-dithian-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole, 3-[2-[4-(benzo-1,4-dithian-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole, 3-[2-[4-(benzo-1-thia-4-oxan-5-yl)piperazin-1-yl]ethyl]-5-chloro-1H-indole, 3-[2-[4-(benzo-1-thia-4-oxan-5-yl)piperazin-1-yl]ethyl]-6-chloro-1H-indole, and 3-[2-[4-(benzo-1-thia-4-oxan-5-yl)piperazin-1-yl]ethyl]-5-fluoro-1H-indole,or an acid addition salt thereof. 15. A pharmaceutical composition comprising a compound according to Claims 1 to 14 or a pharmaceutically acceptable acid addition salt thereof and at least one pharmaceutically acceptable carrier or diluent. 16. The use of a compound according to Claims 1 to 14 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. 17. The use of a compound according to Claim 16 wherein the medicament is for the treatment of affective disorders, including depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder and obsessive compulsive disorder. 18. A method for the treatment of a disorder or disease of living animal body, including a human, which is responsive to the inhibition of serotonin reuptake and antagonism of 5-HT1A-receptors comprising administering to such animal, including a human, a therapeutically effective amount of a compound according to Claims 1 to 14 or a pharmaceutically acceptable acid addition salt thereof. 19. A method of treatment according to Claim 18 where the disorder or disease is an affective disorder, including depression, psychosis, anxiety disorders including general anxiety disorder, panic disorder and obsessive compulsive disorder.