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US 5,627,196 AGranted
Compounds having effects on serotonin-related systems
AssigneeEli Lilly and Company
InventorsJames E. Audia, David J. Hibschman, Joseph H. Krushinski, Jr., Thomas E. Mabry, Jeffrey S. Nissen, Kurt Rasmussen, Vincent P. Rocco, John M. Schaus, Dennis C. Thompson, David T. Wong
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Abstract
A series of hetero-oxy alkanamines are effective pharmaceuticals for the treatment of conditions related to or affected by the reuptake of serotonin and by the serotonin 1.sub.A receptor. The compounds are particularly useful for alleviating the symptoms of nicotine and tobacco withdrawal, and for the treatment of depression and other conditions for which serotonin reuptake inhibitors are used.
Claims56
A compound of the formula ##STR47## wherein r is 0-4;
- s is 0-1;
- D is a residue which combines with the carbon atoms to which it is attached to complete a pyrrolyl group;
- wherein
- X is hydrogen, phenyl, hydroxy or methoxy;
- provided that X is hydrogen or phenyl when r is 0;
- R is ##STR48## the dotted line is an optional double bond;
- R.sup.2 is hydroxy, hydrogen, cyano, C.sub.1 -C.sub.4 alkyl, or (phenyl or benzyl substituted with 0-2 C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy or halo groups);
- or R.sup.2 is amino substituted with phenyl or benzyl, substituted with 0-2 C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, halo or trifluoromethyl groups;
- or R.sup.2 is absent when the dotted line is a double bond;
- R.sup.3 is C.sub.1 -C.sub.4 alkyl, substituted with 0-2 phenyl groups, substituted with 0-2 C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy or halo groups;
- or R.sup.3 is C.sub.1 -C.sub.4 alkyl substituted with hydroxyimino or hydroxy;
- or R.sup.3 is phenoxy, substituted with 0-1 methylenedioxy or substituted with 0-2 C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, trifluoromethyl or halo groups;
- or R.sup.3 is dibenzocycloheptenyl, benzodioxolyl, benzodioxinyl, or dibenzocyclohexenyl;
- or R.sup.3 is phenyl, naphthyl, tetralinyl, tetrazolyl, benzimidazolyl, indolyl, benzofuryl, benzothienyl, piperidino or morpholino, substituted with 0-2 C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, C.sub.4 -C.sub.8 cycloalkylalkoxy, halo, nitro, trifluoromethyl, difluoromethyl, hydroxy or trifluoromethoxy groups;
- or substituted with 0-1 phenyl, piperidinonyl, hexahydropyridazinonyl or piperazinonyl group, substituted with 0-2 C.sub.1 -C.sub.3 alkyl, oxo, C.sub.1 -C.sub.3 alkoxy, halo or trifluoromethyl groups;
- provided that R.sup.3 is not halo- or trifluoromethyl-substituted phenyl when R.sup.2 is hydroxy;
- or R.sup.2 and R.sup.3 combine to form C.sub.1 -C.sub.4 alkylidene, substituted with 0-2 phenyl groups, substituted with 0-2 C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, halo or trifluoromethyl groups;
- R.sup.8 is hydrogen or C.sub.1 -C.sub.3 alkyl;
- or a pharmaceutically acceptable salt thereof.
16 more elements
A method of affecting the serotonin 1A receptor which comprises administering to a subject in need of such treatment an effective amount of a compound of the formula ##STR51## wherein r is 0-4;
- s is 0-1;
- D is a residue which combines with the carbon atoms to which it is attached to complete a pyrrolyl group;
- wherein X is hydrogen, phenyl, hydroxy or methoxy;
- provided that X is hydrogen or phenyl when r is 0;
- R is ##STR52## the dotted line is an optional double bond;
- R.sup.2 is hydroxy, hydrogen, cyano, C.sub.1 -C.sub.4 alkyl, or (phenyl or benzyl substituted with 0-2 C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy or halo groups);
- or R.sup.2 is amino substituted with phenyl or benzyl, substituted with 0-2 C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, halo or trifluoromethyl groups;
- or R.sup.2 is absent when the dotted line is a double bond;
- R.sup.3 is C.sub.1 -C.sub.4 alkyl, substituted with 0-2 phenyl groups, substituted with 0-2 C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy or halo groups;
- or R.sup.3 is C.sub.1 -C.sub.4 alkyl substituted with hydroxyimino or hydroxy;
- or R.sup.3 is phenoxy, substituted with 0-1 methylenedioxy or substituted with 0-2 C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, trifluoromethyl or halo groups;
- or R.sup.3 is dibenzocycloheptenyl, benzodioxolyl, benzodioxinyl, or dibenzocyclohexenyl;
- or R.sup.3 is phenyl, naphthyl, tetralinyl, tetrazolyl, benzimidazolyl, indolyl, benzofuryl, benzothienyl, piperidino or morpholino, substituted with 0-2 C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, C.sub.4 -C.sub.8 cycloalkylalkoxy, halo, nitro, trifluoromethyl, difluoromethyl, hydroxy or trifluoromethoxy groups;
- or substituted with 0-1 phenyl, piperidinonyl, hexahydropyridazinonyl or piperazinonyl group, substituted with 0-2 C.sub.1 -C.sub.3 alkyl, oxo, C.sub.1 -C.sub.3 alkoxy, halo or trifluoromethyl groups;
- or R.sup.2 and R.sup.3 combine to form C.sub.1 -C.sub.4 alkylidene, substituted with 0-2 phenyl groups, substituted with 0-2 C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, halo or trifluoromethyl groups;
- R.sup.8 is hydrogen or C.sub.1 -C.sub.3 alkyl;
- or a pharmaceutically acceptable salt thereof.
14 more elements
A method of inhibiting the reuptake of serotonin which comprises administering to a subject in need of such treatment an effective amount of a compound of formula ##STR53## wherein r is 0-3;
- X is hydrogen or hydroxy;
- R is ##STR54## the dotted line is an optional double bond;
- R.sup.2 is hydroxy or hydrogen, or is absent when the dotted line is a double bond;
- R.sup.3 is C.sub.1 -C.sub.4 alkyl, substituted with 1-2 phenyl groups, substituted with 0-2 halo groups;
- or R.sup.3 is dibenzocycloheptenyl or benzodioxinyl;
- or R.sup.3 is phenyl, benzothienyl, naphthyl, indolyl or piperidino, substituted with 0-2 C.sub.1 -C.sub.3 alkoxy, hydroxy, cyano, C.sub.1 -C.sub.3 alkyl, C.sub.4 -C.sub.8 cycloalkylalkoxy, halo, nitro, trifluoromethyl or trifluoromethoxy groups;
- or R.sup.2 and R.sup.3 combine to form C.sub.1 -C.sub.4 alkylidene, substituted with 1-2 phenyl groups, substituted with 0-2 halo groups;
- or pharmaceutically acceptable salt thereof.
5 more elements
Dependencies are inferred from the claim text.