Indole derivatives and drugs

Details Indole derivatives and drugs Indole derivatives and drugs

1993-02-26

1994-08-30

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

546133, A61K 31435, C07D45302

Patent

active

053428455

DESCRIPTION:

BRIEF SUMMARY
This application is based on International Application PCT/JP91/01148, filed Aug. 29, 1991 which in turn corresponds to:


TECHNICAL FIELD

The present invention relates to an indolecarboxamide derivative of the following general formula [I] ##STR2## (wherein R.sup.1 is a lower alkyl; R.sup.2 is hydrogen, a halogen, a lower alkyl or a lower alkoxy ) and a pharmaceutically acceptable salt thereof. The compound of the invention has a serotonin antagonistic activity and is of use as an antiemetic, a gastrointestinal motor activity regulator, an antimigraine, an antipsychotic, an antianxietic and the like.
Furthermore, the compound of the invention has an ameliorative effect on deficits of learning and memory improving activity and is therefore of use in the treatment of vascular dementia and Alzheimer's disease. In addition, the compound of the invention is useful as a therapeutic and prophylactic agent for orthostatic hypotension and syncope as well.


BACKGROUND ART

Serotonin (5-HT) is a neurotransmitter distributed widely in the animal and vegetable kingdoms and has a broad spectrum of physiological actions. It is generally considered that there are three subtypes of serotonin receptors, viz. 5-HT.sub.1, 5-HT.sub.2 and 5-HT.sub.3.
Regarding the functions of 5-HT.sub.3 receptors, promotion of release of transmitters (noradrenalin, acetylcholine) from the nerves, depoloralization of the sympathetic and parasympathetic ganglions, reflex bradycardia and dolorogenesis are known. However, much remains to be elucidated about the functions of 5-HT.sub.3 receptors and the mechanisms of the antiemetic and psychotropic effects of its antagonists have not been established as yet. GR-38032F (ondansetron), a selective antagonist of 5-HT.sub.3 receptors, is said to markedly inhibit the emesis associated with the administration of anticancer drugs and, moreover, exhibit excellent anxiolytic and antipsychotic actions.
As indole derivatives having an azabicyclic group, a variety of compounds have heretofore been reported (e.g. Japanese Kokai Tokkyo Koho 63-277622, 63-277623, 62-116580 and 61-212521 and Japanese Patent Application 1-130899).
However, indole-3-carboxamide derivatives having a phenyl group in the 2-position of the indole nucleus have never been described in literatures so far nor are they included in the claims of any of the above-cited patent and pending patent literature.


DISCLOSURE OF INVENTION

The inventors of the present invention did much explorations to obtain a compound surpassing any of the hitherto-known serotonin antagonists in efficacy, safety and duration of action. It is, therefore, an object of the invention to provide a novel compound having serotonin antagonistic activity.
The gist of the present invention resides in the very structure of compounds of general formula [I]. The compound of the invention is not only a novel compound but has excellent pharmacological actions and a low toxicity feature as will be described hereinafter.
Referring to general formula [I], the lower alkyl R.sup.1 is preferably a straight or branched alkyl group of 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec-butyl. The halogen as represented by R.sup.2 may be chlorine, fluorine, bromine or iodine and the lower alkyl is preferably a straight or branched alkyl group of 1 to 4 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec-butyl. And the lower alkoxy represented by R.sup.2 is preferably a straight or branched alkoxy group of 1 to 4 carbon atoms such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or sec-butoxy.
The compound of the present invention can be produced, for example, by the following and other processes. ##STR3## wherein R.sup.1 and R.sup.2 have the same meanings as defined hereinbefore.
An indole-3-carboxylic acid [II] or its reactive derivatives is reacted with quinuclidylamine [III] to synthesize [I].
This amidation reaction can be conducted in the per se known manner.
For example, there may be reckoned a proces

REFERENCES:
patent: 5175173 (1992-12-01), Sun

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