Condensed thiazole derivative, production process thereof and ph

Details Condensed thiazole derivative, production process thereof and ph Condensed thiazole derivative, production process thereof and ph

1995-04-28

1996-10-15

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

548149, 548150, 548151, A61K 31425, C07D41704, C07D41706

Patent

active

055654797

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/J93/01298 filed Sep. 10, 1993, and published as WO94/06791 Mar. 31, 1994.


TECHNICAL FIELD

This invention relates to novel condensed thiazole derivatives useful as pharmaceutical agents especially as a 5-HT.sub.3 receptor agonists, to pharmaceutically acceptable salts thereof, to a production process thereof and to a pharmaceutical composition comprising the same as an active ingredient.


BACKGROUND ART

The compounds of the present invention act as an effective and selective agonist for the neuronal serotonin (5-HT) receptor located in the primary afferent nerve of enteric nervous system or central nervous system. This type of receptor is now considered as a 5-HT.sub.3 receptor. The compounds of the present invention exert their function by releasing acetylcholine from the efferent nerve ending in the digestive tracts. It is known that stimulation of the acetylcholine receptor in the digestive tracts accelerates motility of the gastrointestinal tracts and improves functional reduction of the gastrointestinal tracts [Goonman and Gilman's, The Pharmacological Basis of Therapeutics 8th edition, p.125, (1990), Pergamon Press]. It is also known that the 5-HT.sub.3 receptor is present in the presynaptic area of central nervous system and inhibits nervous activities by its stimulation [J. Neurosci., 11, 1881 (1991)].
In consequence, it is considered that a 5-HT.sub.3 receptor agonist is useful especially against gastrointestinal disorders.
Though no compound having a selective agonistic activity on the 5-HT.sub.3 receptor had been found, the inventors of the present invention reported that thiazole derivatives disclosed in WO 92/07849 possess a selective 5-HT.sub.3 receptor agonistic activity.


DISCLOSURE OF THE INVENTION

The inventors of the present invention have continued a further investigation concerning agonistic activities on the 5-HT.sub.3 receptors, and found that a 2-(imidazolyl)alkylene-condensed thiazole derivative shows an excellent 5-HT.sub.3 receptor agonistic activity as a result of studies on the synthesis of compounds having a 5-HT.sub.3 receptor agonistic activity with taking notice of the contractile effects of 5-HT mediated through the 5-HT.sub.3 receptor in the isolated guinea pig colon as a marker, independent of the Bezold-Jarisch reflex [A. S. Paintal et al., Physiol. Rev., 53, 159 (1973)] which is conventionally used as a marker of the 5-HT.sub.3 receptor agonistic activity, hence resulting in the accomplishment of the present invention.
Though a 2-aminoindenothiazole derivative having an antiulcer activity disclosed in JP-A-62-252780 (the term "JP-A" as used herein means an "unexamined published Japanese patent application") and a 2-amino condensed thiazole derivative having a muscarine receptor agonistic activity disclosed in JP-A-63-243080 have been known as condensed thiazole derivatives, the compounds of the present invention are novel compounds whose structure and activity are completely different from that of these compounds.
The condensed thiazole derivatives represented by the following general formula (I) or pharmaceutically acceptable salts thereof are characterized in that they have a high affinity for the 5-HT.sub.3 receptor and show contractile effects in the isolated guinea pig colon used as the marker of a 5-HT.sub.3 receptor agonistic activity. ##STR3## (Symbols in the above formula mean; R: a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, a nitro group, an amino group, a cyano group or a protected hydroxyl group, direct bond and the other is interrupting oxygen or sulfur atom therein, ##STR4## R.sup.1, R.sup.2 and R.sup.3 : the same or different from one another, each representing a hydrogen atom or a lower alkyl group, R.sup.4, R.sup.5 and R.sup.6 : the same or different from one another, each representing a hydrogen atom or a lower alkyl group.)
Accordingly, an object of the present invention is to provide the condensed thiazole derivatives represented by the

REFERENCES:
patent: 4963689 (1990-10-01), Nagel et al.
patent: 5130313 (1992-07-01), Comte et al.
patent: 5378706 (1995-01-01), Biziere et al.
patent: 5424431 (1995-06-01), Ohta et al.

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