Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-01-23
1999-08-31
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540575, A61K 3155, C07D24308
Patent
active
059454156
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to novel (R)-5-bromo-N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)-2-methoxy-6 -methylamino-3-pyridinecarboxamide which exhibits potent serotonin S.sub.3 (which may be hereafter referred to as 5-HT.sub.3) and dopamine D.sub.2 receptor antagonistic activities; process for preparation thereof; and pharmaceutical composition containing said compound.
BACKGROUND ART
Japanese Laid-open (KOKAI) Patent Application, KOKAI No. 92959/1993 broadly discloses a class of compounds represented by formula (A) below: ##STR2## hydrogen atom, lower alkyl or substituted lower alkyl group, etc. alkyl, etc. atom, lower alkoxy, amino, mono- or di-substituted amino group, etc. 1H-indazolyl group, signifies hydrogen atom or lower alkyl, etc. compound in which Het is 3-pyridyl group and which is disclosed in the specification is the one of Example 37, represented by the formula below: ##STR3## This compound of Example 37 clearly differs in structure from the compound of the present invention which is expressed by the later presented formula (I). In the former compound, 3-pyridyl group is unsubstituted and 4-position of hexahydro-1H-1,4-diazepine is substituted with methyl.
Said KOKAI Gazette, furthermore, teaches that the compounds of above formula (A) are serotonin S.sub.3 (5-HT.sub.3) receptor antagonists and are useful for therapeutic and prophylactic treatments of anorexia, nausea, emesis, abdominal fullness and the like accompanying acute and chronic gastritis, and such diseases as gastric and duodenal ulcer; or of nausea or emesis occurring with administration of anti-tumor agents, radioactive irradiation and motion sickness. The Gazette, however, is silent on their dopamine D.sub.2 receptor antagonism.
Furthermore, WO93/08186 discloses a group of compounds represented by formula (B) below: ##STR4## C.sub.3-8 cycloalkyl C.sub.1-4 alkoxy; R.sub.2 stands for hydrogen, halogen, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, or amino which may be substituted with 1 or 2 C.sub.1-6 alkyl; R.sub.3 stands for hydrogen, halogen or C.sub.1-6 alkyl; L is O or NH; and Z stands for di-azacyclic or azadicyclic side chain), treatments of pain, emesis, central nervous system disorder and gastrointestinal disorder, as 5-HT.sub.3 antagonists.
Said WO93/08186 cites, as one of adequate examples of di-azacyclic side chain Z. EP-A-358903 belonging to the patent family of afore-cited KOKAI Patent Application, KOKAI No. 92959/93, but contains no specific disclosure on a compound having a di-azacyclic side chain which is covered by the general formula (A) as above. Thus. WO93/08186 does not at all suggest the compound of the present invention. inyl!-1,3-dihydro-2H-benzimidazol-2-one; cf. eg. Merck Index, 11th ed. 3412 (1989)! which is a dopamine D.sub.2 receptor antagonistic agent, is effective to alleviate emesis accompanying various troubles of the digestive system and that accompanying infantile cold syndrome, but exhibits only insufficient effect on emesis occurring upon administration of anti-tumor agents such as cisplatin.
Recently, as a drug which can selectively and strongly inhibit the emesis occurring with administration of anti-tumor agents, serotonin S.sub.3 receptor antagonistic agent has been developed, and currently such oxamide hydrochloride; cf. eg., Merck Index, 11th ed. 4443 (1989)!, ondansetron hydrochloride (chemical name: zol-4-one hydrochloride; cf. eg., Merck Index, 11th ed., 6802 (1989)! and 1,4-benzoxazine-8-carboxamide hydrochloride; cf. eg., Drugs of the Future, 18(3), 206-211 (1993)! are clinically used. However, clinical application of these serotonin S.sub.3 receptor antagonists is limited to the emesis mainly occurring in occasions of administration of anti-tumor agents. They furthermore are said to exhibit only insufficient effect on late emesis.
Thus, while drugs effective on specific type of emesis do exist, an antiemetic agent of wide application range which can strongly inhibit emesis induced by various causes has not yet been developed. Hence development of an antiemetic agent
REFERENCES:
patent: 5017573 (1991-05-01), Kon et al.
patent: 5166341 (1992-11-01), Kon et al.
Hirokawa et al., "Synthesis and structure-activity relationships of N-(1-ethyl-4-methylhexahydro-1H-1,4-diazepin-6-yl)amides with potent dopamine D.sub.2 and serotonin 5-HT.sub.3 receptor antagonistic activities", AIMECS 95, AFMC International Medicinal Chemistry Symposium, Program, Abstracts and Handbook, Sep. 3-8, 1995, Tokyo, Japan.
Harada Hiroshi
Hirokawa Yoshimi
Kato Shiro
Morie Toshiya
Yoshida Naoyuki
Coleman Brenda
Dainippon Pharmaceutical Co., Ltd.
Shah Mukund J.
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