Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-05-21
1999-08-03
Morris, Patricia L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540480, A61K 3155, C07D40112
Patent
active
059325682
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to novel 6-methoxy-1H-benzotriazole-5-carboxamide derivatives which are characterized by their concurrent possession of excellent antiemetic activity and gastrointestinal motility enhancing activity, and less central nervous system (CNS) depressant activity. More particularly the invention relates to 6-methoxy-1H-benzotriazole-5-carboxamide derivatives whose nitrogen atom in the amide moiety (--CONH--) is substituted with 1-substituted-azacyclo-alkan-3-yl group of 7-, 8- or 9-membered ring, processes for their preparation, pharmaceutical compositions containing them, and novel intermediates.
BACKGROUND ART
JP-A 104572/1990 has disclosed that the compounds represented by the and are useful as antiemetic agent or gastrointestinal motility enhancing agent: ##STR2## (lower) alkyl, alkoxy (the substituent being halogen, hydroxy or oxo), --NH--N.dbd.N--, --S--, --SO--, --SO.sub.2 -- or --NR.sub.6 --, alkyl; or may form ethylene together with R.sub.1, --CH.sub.2 -- and n is 0, provided: optionally substituted aryl (lower) alkyl; and
Said JP-A-104572/1990, however, contains no specific disclosure about the compounds of the present invention which are represented by the later-appearing formula (I) which concurrently possess 1H-benzotriazole skelton and a nitrogen-containing 7-, 8- or 9-membered aliphatic ring, in particular, their optically active compounds and their pharmacological activities of optically active compounds.
JP-A-83737/1977 discloses that the compounds expressed by the following response, the apomorphine-induced stereotyped behavior response and the methamphetamine-induced stereotyped behavior, and hence are useful as CNS depressants, in particular, as anti-psychotic drugs: ##STR3## (in which A--CO signifies 4-amino-5-chloro-2-methoxybenzoyl, 5-ethylsulfonyl-2-methoxybenzoyl or 2-methoxy-4,5-azimidobenzoyl group; B signifies allyl or optionally substituted benzyl group; and m is 1 or 2).
Furthermore, JP-A-100473/1977 discloses the compounds represented by the ##STR4## (in which R.sup.1 signifies a lower alkoxy, R.sup.2 signifies an optionally substituted benzyl, and m is 1 or 2). ring bound to the amide moiety (--CONH--) is 5- or 6-membered, and the ring-constituting nitrogen atom is substituted with allyl or benzyl group, and in those points differ from the structure of the compounds represented by the later-appearing formula (I) of the present invention. Moreover, their pharmacological activity again differs from those of the compounds of the present invention.
On the other hand, name: metoclopramide; cf. Merck Index, 11th ed. 6063 (1989)! is known as having antiemetic activity and gastrointestinal motility enhancing activity concurrently, and has been used of old for treatments and prophylaxis of functional disorders of gastrointestinal tract, which are associated with various diseases and therapeutical treatments, as gastrointestinal motility enhancing agent. Metoclopramide, however, possesses CNS depressant activity derived from its dopamine D.sub.2 receptor antagonistic activity, which is a drawback for its clinical use. Accompanying the increasing complexity of life in human society and population of aging people, patients suffering from symptoms associated with gastrointestinal dysfunctions also are increasing, and for their treatments development of a compound or compounds exhibiting less CNS depressant activity while having concurrently excellent antiemetic activity and gastrointestinal motility enhancing activity are in demand.
DISCLOSURE OF INVENTION
We have made extensive investigations and found that 6-methoxy-1H-benzotriazole-5-carboxamide derivatives whose nitrogen atom in the amide moiety (--CONH--) is substituted with 1-substituted-azacycloalkan-3-yl group of 7-, 8- or 9-membered ring, in particular, (R)-6-methoxy-1H-benzotriazole-5-carboxamide derivatives whose configuration is R, concurrently possess excellent antiemetic activity and gastrointestinal motility enhancing activity and nevertheless exhibit surprisingly less CNS depressant
REFERENCES:
Fujisawa Pharmaceutical Co, "Preparation of hexahydrozepine, etc" CA 119:49254, 1992.
Hirokawa Yoshimi
Kato Shiro
Morie Toshiya
Yamazaki Hiroshi
Yoshida Naoyuki
Dainippon Pharmaceutical Co., Ltd.
Morris Patricia L.
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