1-(4'-fluorophenyl)-3,5-substituted indoles useful in the treatment of psychic disorders and pharmaceutical compositions thereof

Abstract

The present invention relates to novel indole derivatives which have interesting pharmacodynamic effects indicating pronounced activity in the treatment of psychic disorders, especially psychoses and, at the same time, a low degree of undesired side effects. Moreover, the invention relates to methods for the preparation of said indole derivatives, pharmaceutical compositions containing same, and methods for the treatment of psychic disorders, especially psychoses, by administering a therapeutically active amount of one of said derivatives to a living animal body, including human beings. The novel indole derivatives of the present invention are represented by the following formula; ##STR1## wherein R is phenyl, optionally substituted with halogen.[., lower alkyl or trifluoromethyl,.]. or a hetero aromatic group, such as 2-thienyl, 3-thienyl, .[.2-furoyl, 3-furoyl, 2-thiazol, 2-oxazol, 2-imidazole, 2-pyridyl, 3-pyridyl.]. .Iadd.2-oxazolyl, 2-imidazolyl, 2-pyridyl 3-pyridyl.Iaddend.or 4-pyridyl; R 1 is hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, lower alkylthio, trifluoromethyl, lower alkylsulfonyl, amino, lower alkylamino or lower di-alkylamino; "A" is nitrogen or carbon, and the dotted line indicates--when A is carbon--an optional bond; R 2 is hydrogen, cycloalkyl, lower alkyl or lower alkenyl, optionally substituted with one or two hydroxy groups, any hydroxy group present being optionally esterified with an aliphatic carboxylic acid radical having from two to twenty-four carbon atoms inclusive, or R 2 is the group ##STR2## wherein "n" is an integer of 2-6; X is oxygen or sulfur, or <C=X may constitute the group .[.>.]. =CH= when Y is =N-- or =CH--; Y is oxygen, sulfur, CH 2 or N R 3 , where R 3 is hydrogen.Iadd., .[.or.]. lower alkyl, lower alkenyl or a cycloalkylmethyl group, said "cycloalkyl" having from three to six carbon atoms inclusive; Z is --(CH 2 ) m --, "m" being 2 or 3, or Z is --CH=CH-- or 1,2-phenylene optionally substituted with halogen or trifluoromethyl, or Z is --CO(or S)CH 2 --; U is nitrogen or carbon provided that when R 1 is .Iadd.hydrogen, .Iaddend.chloro, .Iadd.lower alkyl, methoxy or hydroxy, .Iaddend.A is nitrogen and R 2 is .[.methyl or cyclohexyl.]. .Iadd.lower alky or .Iadd.cycloalkyl of C 3 --C 6 , .Iaddend.R may not be phenyl; as well as their pharmaceutically acceptable acid addition salts.

I claim: 
     
       1. A compound selected from the group consisting of (a) an indole derivative of the following formula: ##STR16## wherein R is selected from .Iadd.(a) .Iaddend.phenyl, optionally substituted with .[.one substituent selected from.]. halogen .[.and trifluoromethyl.]. and .Iadd.(b) .Iaddend.a hetero aromatic group selected from 2-thienyl, 3-thienyl, .[.2-furoyl, 3-furoyl, 2-thiazol, 2-oxazol, 2-imidazole, 2-pyridyl, 3-pyridy.]. .Iadd.2-oxazolyl, 2-imidazolyl, 2-pyridyl .Iaddend.and 4-pyridyl; R 1  is selected from hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, lower alkylthio, trifluoromethyl, lower alkylsulfonyl, amino, lower alkylamino and lower di-alkylamino;   "A" is selected from nitrogen and carbon, and the dotted line indicates--when A is carbon--an optional bond;   R 2  is selected from hydrogen, .[.cycloakyl.]. .Iadd.cycloalkyl .Iaddend.of .[.C 3  -C 4  .]. .Iadd.C 3  -C 6  .Iaddend..].inclusive.]. .Iadd.inclusive, .Iaddend.lower alkyl and lower alkenyl, optionally substituted with one or two hydroxy groups, any hydroxy group present being optionally esterified with an aliphatic carboxylic acid having from two to twenty-four carbon atoms inclusive, and the group ##STR17## wherein "n" is an integer of 2-6; X is selected from oxygen and sulfur, .[.C=X.]. .Iadd.>C=X .Iaddend.may constitute the group .[.CH.]. .Iadd.--CH .Iaddend.= when Y is selected from ═N-- and ═CH--;   Y is selected from oxygen, sulfur, CH 2  and N-R 3 , where R 3  is selected from .[.hydrogen and.]. .Iadd.hydrogen, .Iaddend.lower alkyl, lower alkenyl and a cycloalkylmethyl group, said "cycloalkyl" having from three to six carbon atoms inclusive;   Z is selected from --(CH 2 ) m  --, "m" being selected from 2 and 3, .[.and --CH═CH and.]. .Iadd.--CH═CH, .Iaddend.1,2-phenylene optionally substituted with a group selected from halogen and trifluoromethyl, and --CO (or S) CH 2  --;   U is selected from nitrogen and carbon, provided that when R 1  is .Iadd.hydrogen, .Iaddend.chloro, .Iadd.lower alkyl, methoxy or hydroxy, .Iaddend.A is nitrogen and R 2  is selected from .[.methyl.]. .Iadd.lower alkyl .Iaddend.and .[.cyclohexyl,.]. .Iadd.cycloalkyl of C 3  -C 6 , .Iaddend.R may not be phenyl; .[.and.]. .Iadd.or .Iaddend.   (b) a pharmaceutically acceptable acid addition salt thereof.   
     
     
       2. An indole derivative of claim 1, wherein R 1  is selected from chlorine, fluorine, trifluoromethyl, methyl, nitro and amino in the 5-position, R is phenyl substituted with fluorine in the 4'- or 2'-position, .[.R 2  is.]. .Iadd.R 2  is .Iaddend.selected from methyl, 2-hydroxyethyl and 3-hydroxypropyl, and A is as defined in claim 1. 
     
     
       3. .Iadd.An indole derivative of claim .Iaddend..[.Claim.]. 1 .Iadd.wherein the .Iaddend.compound .Iadd.is .Iaddend.selected from .[.1-(4'-Fluorophenyl)-3-(4-(2-hydroxyethyl)-piperazino)-5-trifluoromethyl-1H-indole,.]. .Iadd.1-(4'-Fluorophenyl)-3-(4-(2-hydroxyethyl)-1-piperazinyl-5-trifluoromethyl-1H-indole, 1-(4'-Fluorophenyl)-5-nitro-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole,   5-Chloro-1-(4'-fluorophenyl)-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole,   1-(4'-Fluorophenyl)-3-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole,   1(4'-Fluorophenyl)-3-(1-(2-hydroxyethyl)-1,2,3,6-tetrahydropyridin-4-yl)-5-trifluoromethyl-1H-indole,   5-Fluoro-1-(4'-fluorophenyl)-3-(1-(3-hydroxypropyl)-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole, .[.and.]. .Iadd.or .Iaddend.pharmaceutically acceptable acid addition salts thereof.   
     
     
       4. A neuroleptic or thymoleptic pharmaceutical composition suitable for use in the treatment of disorders amenable to such medication in unit dosage form comprising, as an active ingredient, a compound as defined in claim 1 in an amount effective for such purpose, together with one or more pharmaceutical diluents or carriers. 
     
     
       5. A pharmaceutical composition in unit dosage form, according to claim 4, wherein the active ingredient is present in an amount from 0.10 to 100 milligrams per unit dosage. 
     
     
       6. A pharmaceutical composition in unit dosage form, according to claim 4 wherein the active ingredient is a compound of claim 3. 
     
     
       7. A method for the treatment of disorders amenable to .[.neuroleptic or.]. thymoleptic medication comprising administering a .[.neuroleptic or.]. thymoleptically-effective amount in unit dosage form of a compound of claim 1, as an active ingredient, optionally together with one or more pharmaceutical diluents or carriers, to a warmblooded animal including a human being. 
     
     
       8. A method according to claim 7, wherein the active ingredient is present in an amount from 0.1 to about 100 mg per unit dosage. 
     
     
       9. A method according to claim 8, wherein the active ingredient is 1-(4'-fluorophenyl)-3-(4(2-hydroxyethyl)-1-piperazinyl)-5-trifluoromethyl-indole, or a pharmaceutically acceptable salt thereof.