Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-08-12
1998-08-04
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142282, 5142288, 5142352, 514274, 514315, 514369, 514376, 514392, 514415, 514418, 544 54, 544 97, 544 59, 544159, 544158, 544162, 544163, 544316, 546201, 546242, 546243, 546245, 5462774, 5462777, 546246, C07D40312, C07D20914, C07D20910, A61K 3140
Patent
active
057894043
DESCRIPTION:
BRIEF SUMMARY
This application is a national stage application under 35 U.S.C. .sctn.371 claiming priority of PCT International Application No. PCT/DK94/00470, filed 15 Dec. 1994.
FIELD OF THE INVENTION
The present invention relates to novel 3-substituted 1-arylindole compounds and their acid addition salts, to methods for preparing such compounds, pharmaceutical compositions comprising the compounds as an active ingredient and to their use. The novel compounds show central antiserotonergic activity and possibly also antidopaminergic activity and are, accordingly, useful in the treatment of central nervous system (CNS) disorders.
BACKGROUND OF THE INVENTION
It is well known that serotonin (5-HT) receptor antagonists, in particular 5-HT.sub.2 receptor antagonists, are useful in the treatment of CNS disorders. So, 5-HT.sub.2 receptor antagonists have been reported to show effects in the treatment of anxiety, agression, depression, sleep disturbances, migraine, negative symptoms of schizophrenia, extrapyramidal side effects induced by conventional antipsychotics, abuse of drugs and substances of abuse and Parkinson's disease. For example reference may be made to the following:
The selective 5-HT.sub.2 receptor antagonist ritanserin has been shown to be an antidepressant and to improve depressive symptoms of schizophrenia (E. Klieser, W. H. Strauss; Pharmacopsychiat. 21 (1988), pp. 391-393) and it has been demonstrated to exert effects in an animal test indicative of anxiolytic drug activity (F. C. Colpart et al.; Psychopharmacology (1985) 86; 303-305). Furthermore, ritanserin has been shown to improve the quality of sleep (P. A. J. Janssen; Pharmacopsychiat. 21 (1988), 33-37).
It is generally believed that 5-HT is involved in migraine attacks. The links between 5-HT and migraine attacks are several and they suggest a number of mechanisms whereby 5-HT may be involved (Scrip Report; "Migraine--Current trends in research and treatment"; PJB Publications Ltd.; May 1991).
Studies of the mixed serotonin and dopamine receptor antagonist setoperone indicate that blockade of 5-HT.sub.2 receptors may be related to improvement of negative symptoms of schizophrenia (Ceulemans et al., Psychopharmacology (1985) 85, 329-332).
Finally, ritanserin has been found to relieve neuroleptic-induced parkinsonism (Bersani et al.; Clinical Neuropharmacology, 13, No. 6 (1990), 500-506) and to reduce abuse of alcohol and drugs (Meert et al., Pharmacopsychiatry, 24 (5), 1991, 159-163).
Damping of dopamine (DA) overactivity by the use of DA receptor blocking drugs is today the most important principle in the treatment of schizophrenia, in particular the positive symptoms thereof. "Classical neuroleptics" such as haloperidol, cis-(Z)-flupentixol and chlorpromazine are believed to induce antipsychotic effect via DA receptor blockade.
U.S. Pat. No. 4,710,500, corresponding to European Patent No. 0200322, discloses a class of optionally 5-substituted 1-aryl-3-piperidinyl, 1-aryl-3-(1,2,3,6-tetrahydropyridinyl)- or 1-aryl-3-piperazinylindole derivatives having potent 5-HT.sub.2 antagonistic activity, and many of them additionally having potent dopamine D.sub.2 -antagonistic activity in vivo.
European Patent Application No.916010055.5 published as EP-A2-0465398 discloses a class of 6-substituted and/or 2-alkyl substituted indole and 2,3-dihydroindole derivatives having antiserotonergic activity.
It is the object of the present invention to provide new compounds having antiserotonergic, in particular 5-HT.sub.2 antagonistic activity, and possibly also antidopaminergic activity.
SUMMARY OF THE INVENTION
It has now been found that compounds of a novel class of 3-substituted 1-arylindole compounds possess central antiserotonergic activity and some of them additionally antidopaminergic activity.
Accordingly, the present invention relates to novel compounds of general Formula I ##STR2## wherein Ar is selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, and 4-pyridyl, and such groups substituted with o
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Andersen Kim
Perregaard Jens Kristian
H. Lundbeck A/S
Rao Deepak R.
Shah Mukund J.
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