Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-11-09
2000-05-02
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514269, 544278, 544279, 544281, 544282, 544311, 544319, 544321, 546 85, 546 86, A61K 31513, A61K 31519, C07D47104, C07D51900
Patent
active
060573252
DESCRIPTION:
BRIEF SUMMARY
This invention relates to hexahydro-pyrido[4,3-b]indole derivatives having therapeutic potential in psychotic disorders, and processes for their preparation; it further relates to compositions comprising these derivatives, as well as their use as a medicine.
A number of hexahydro-pyrido[4,3-b]indole compounds substituted on the 2-position with an alkyl group bearing a substituted phenyl and an hydroxy, which have antipsychotic properties as evidenced by their ability to block the action of dopamine receptors of the central nervous system, are disclosed in J. Med. Chem. 22:677-683 (1979) and J. Med. Chem. 29:2093-2099 (1986). J. Med. Chem. 23:949-952 (1980) describes 4a,9b-trans-8-fluoro-5-(4-fluorophenyl)-2-[4-(4-fluorophenyl)-4-hydroxy-bu tyl]-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole hydrochloride as a neuroleptic agent capable of blocking dopamine receptors.
The problem which this invention sets out to solve is to provide compounds having besides central dopamine antagonistic activity also central serotonin antagonistic activity at the same dosage, a combination which is considered advantageous in potential antipsychotic drugs.
The compounds of the present invention differ from the cited art compounds structurally, by the fact that the tricyclic hexahydro-pyrido[4,3-b]indole moiety, also known as a hexahydro .gamma.-carboline moiety, is invariably substituted on the 2-position with an alkyl group bearing a pyrimidinyl derivative, and by their favourable pharmacological properties, in particular by the fact that in addition to their excellent central dopamine antagonistic activity the compounds of the present invention also have potent central serotonin antagonistic activity.
The present invention concerns the compounds of formula ##STR2## the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein 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; alkylthio, or a radical of formula --NR.sup.8 R.sup.9, wherein R.sup.8 and R.sup.9 are each independently selected from hydrogen, C.sub.1-6 alkyl, phenyl or phenylC.sub.1-6 alkyl; --R.sup.6 --R.sup.7 --,
______________________________________ --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 halo, C.sub.1-6 alkyl, arylC.sub.1-6
alkyl, trifluoromethyl, amino, hydroxy, C.sub.1-6 alkyloxy or C.sub.1-10
alkylcarbonyloxy; or where possible, two geminal hydrogen atoms may be
replaced by C.sub.1-6 alkylidene or arylC.sub.1-6 alkylidene; or
______________________________________ --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
aryl; and
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.
As used in the foregoing definitions and hereinafter, halo is generic to fluoro, chloro, bromo and iodo; C.sub.1-6 alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl, pentyl, hexyl, 3-methylbutyl, 2-methylpentyl and the like; C.sub.1-10 alkyl is meant to comprise C.sub.1-6 alkyl and the hi
REFERENCES:
patent: 3991199 (1976-11-01), Berger
patent: 4337250 (1982-06-01), Welch et al.
Welch et al. Neuroleotics from the 4a,9b-trans-2,3,4,4a,5,9b-hexahJ. Med. Chem 29,2108-2111, 1986.
Welch et al. Neuroleotics from the 4a,9b-trans-2,3,4,4a,5,9b-hexa.. J.Med. Chem 29,2093-209908-2111, 1986.
Welch et al. 4a,9b-trans-8-fluoro-5-(fluorophenyl)-2-4-(4-fluoro-. . . J.Med. Chem 23, 994-952, 1980.
Nagai et al. Synthesis of 2,3,4,4a,5,9b-Hexahydro-1H-pyrido[4,3-b]..J.Med. Chem. 23, 677-683, 1979.
Nagai, Yasutake et al.: "Synthesis of 2,3,4,4a,5,9b-hexahydro-1H-yridol[4,3-b] in Dole Derivatives and Their Central Nervous System Activities" , J. Med. Chem. (1979), 22(6), 677-83.
Kennis Ludo Edmond Josephine
Mertens Josephus Carolus
Appollina Mary A.
Balasubramanian V
Janssen Pharmaceutia, N.V.
Shah Mukund J.
LandOfFree
Hexahydro-pyrido(4,3-b)indole derivatives as antipsychotic drugs does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Hexahydro-pyrido(4,3-b)indole derivatives as antipsychotic drugs, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Hexahydro-pyrido(4,3-b)indole derivatives as antipsychotic drugs will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1594059