4-(1H-indol-1-yl)-1-piperidinyl derivatives

Details 4-(1H-indol-1-yl)-1-piperidinyl derivatives 4-(1H-indol-1-yl)-1-piperidinyl derivatives

1997-06-27

1999-07-06

Chang, Ceila

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514269, 514278, 514322, 544278, 544281, 544282, 544315, 546 18, 546199, A61K 31505, C07D47104, C07D48704

Patent

active

059197889

DESCRIPTION:

BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 371, the national stage of application No. PCT/EP 96/00363, filed on Jan. 23, 1996, which application claims priority from EP 95.200.229.3, filed on Jan. 31, 1995.
The present invention concerns 4-(1H-indol-1-yl)-1-piperidinyl derivatives having therapeutic potential in psychotic disorders. It further relates to their preparation, compositions comprising them and their use as a medicine.
In EP-A-0,037,265, published on Oct. 7, 1981, EP-A-0,070,053, published on Jan. 19, 1983, and in EP-A-0,378,255, published on Jul. 18, 1990, there are described a number of having antipsychotic, antihistaminic and antiserotonergic activity. Structurally, the compounds of the present invention differ therefrom in that the 4 position of their piperidine moiety is invariably substituted by a 1H-indol-1-yl derivative.
EP-A-0,470,039, published on Feb. 5, 1992, discloses 4-(3-aryl-1H-indol-1-yl)-1-piperidinyl derivatives as selective antagonists of the serotonin 5-HT.sub.2 receptor without substantial dopamine D-2 antagonistic activity both in vivo and in vitro. Said selective antagonistic property is measured as the ratio between the dopamine D-2 receptor and the serotonin 5-HT.sub.2 receptor antagonistic activities. Unexpectedly, the compounds of the present invention differ therefrom in that they exhibit central dopamine and central serotonin antagonistic activity in vivo in similar dose-ranges, i.e. the ratio between central doparninergic and central serotonergic activity is about unity.
The compounds of the present invention show antipsychotic activity with an unexpected increased cardiovascular safety, i.e. they show an improved dissociation between the peripheral .alpha.-adrenergic antagonistic activity and the central dopamine and serotonin antagonistic activity.
The present invention concerns the compounds of formula ##STR2## the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein: alkyl or C.sub.1-6 alkyloxy; phenyl or phenyl substituted with one, two or three substituents selected from halo, hydroxy, nitro, cyano, trifluoromethyl, C.sub.1-6 alkyl, C.sub.1-6 alkyloxy, C.sub.1-6 alkylthio, mercapto, amino, mono- and di(C.sub.1-6 alkyl)amino, carboxyl, C.sub.1-6 alkyloxycarbonyl and C.sub.1-6 alkylcarbonyl; ##STR3## wherein R.sup.5 is hydrogen or C.sub.1-6 alkyl; alkylthio, amino or mono- or di(C.sub.1-6 alkyl)amino; and --R.sup.7 --, in particular, --R.sup.6 --R.sup.7 -- may be


______________________________________ --CH.sub.2 --CH.sub.2 --CH.sub.2 -- (a-1); --CH.sub.2 --CH.sub.2 --CH.sub.2 --CH.sub.2 -- (a-2); --CH.dbd.CH--CH.sub.2 -- (a-3); --CH.sub.2 --CH.dbd.CH-- (a-4) or --CH.dbd.CH--CH.dbd.CH-- (a-5); ______________________________________ independently may be replaced by C.sub.1-6 alkyl, hydroxy, C.sub.1-6 alkyloxy or C.sub.1-10 alkylcarbonyloxy; or --R.sup.6 --R.sup.7 -- may also be


______________________________________ --S--CH.sub.2 --CH.sub.2 -- (a-6); --S--CH.sub.2 --CH.sub.2 --CH.sub.2 -- (a-7); --S--CH.dbd.CH-- (a-8); --NH--CH.sub.2 --CH.sub.2 -- (a-9); --NH--CH.sub.2 --CH.sub.2 --CH.sub.2 -- (a-10); --NH--CH.dbd.CH-- (a-11); --NH--CH.dbd.N-- (a-12); --S--CH.dbd.N-- (a-13) or --CH.dbd.CH--O-- (a-14); ______________________________________ (a-6) to (a-14) each independently may be replaced by C.sub.1-6 alkyl; or D is a radical of formula ##STR4## wherein R.sup.8 is hydrogen or C.sub.1-6 alkyl.
As used in the foregoing definitions the term halogen is generic to fluoro, chloro, bromo and iodo. The term C.sub.1-4 alkyl defines straight and branched saturated hydrocarbons, having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl. The term C.sub.1-6 alkyl is meant to include C.sub.1-4 alkyl radicals and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pentyl, hexyl and the like. The term C.sub.1-10 alkyl is meant to include C.sub.1-6 alkyl radicals and the higher

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Andersen et al., "Selective Centrally Acting Serotonin 5-HT.sub.2 Antagonists. 2. Substituted 3-(4-Fluorophenyl)-1H-Indoles", J. Med. Chem., 1992, 35, 4823-4831.

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