Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-12-23
1995-04-18
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544370, 5483064, 5483104, 564441, 564442, A61K 31495, C07D40304
Patent
active
054079365
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a novel benzimidazole derivative, a process for preparing the same, an antiemetic agent containing the same as an active ingredient and an intermediate compound for preparing the same.
BACKGROUND ART
Chemotherapeutics such as cisplatin are indispensable to the treatment of cancer. However, the chemotherapeutics cause side effects such as vomiting and hence make it difficult to continue the treatment.
Recently, it has become known that the occurrence of vomiting is associated with one of receptors of serotonin [5-hydroxytryptamine, hereinafter referred to as "5-HT"]. 5-HT is one of neurotransmitters in the living body and receptors of 5-HT have been classified into three groups, 5-HT.sub.1, 5-HT.sub.2 and 5-HT.sub.3. Among them, 5-HT.sub.3 receptor is associated with vomiting due to chemotherapeutic treatment of cancer. That is, 5-HT is released by administration of the chemotherapeutics and the released 5-HT is bound to the abdominal 5-HT.sub.3 receptor, and thereby the chemical receptor trigger in the bulb fourth ventricle is stimulated via the abdominal vagus nerve, and then the vomiting center is stimulated to induce vomiting.
It has been reported that Ondansetron (GR38032F, see the following formula) having 5-HT.sub.3 antagonistic activity is effective for inhibition of vomiting caused by the administration of the chemotherapeutics such as cisplatin [Cancer. Chemother. Pharmacol., 23, 389-391 (1989)]. ##STR2##
On the other hand, there has already been known the use of 2-(4-methyl-1-piperazinyl)benzimidazole derivatives as a drug. For example, Japanese Patent First Publication No. 50-126682 discloses 2-(4-methyl-1-piperazinyl)benzimidazole derivatives having analgesic and antiinflammatory activities, and 1-methyl-2-(4-methyl-1-piperazinyl)benzimidazole (Compound A) etc are exemplified. However, the 5-HT.sub.3 antagonistic activity and the resulting antiemetic activity of 2-(4-methyl-1-piperazinyl)benzimidazole derivatives have not yet been known (see Experiment 1 disclosed hereinafter).
The present inventors have conducted a variety of studies for developing a novel antiemetic agent having a strong and long-lasting inhibitory activity against vomiting due to chemotherapeutic treatment of cancer with cisplatin etc. based on the 5-HT.sub.3 antagonistic activity.
DISCLOSURE OF THE INVENTION
The present inventors have extensively studied, and as a result, have found that a novel benzimidazole derivative of the following formula (I) or a pharmaceutically acceptable acid addition salt thereof can satisfy the above requirement and so the present invention has been completed. ##STR3##
BEST MODE FOR PRACTICING THE INVENTION
The benzimidazole derivative (I) of the present invention can be prepared by treating the compound of the following formula (II): ##STR4## with usually 4 to 7 equivalents of a reducing agent in an inert solvent at a temperature between room temperature to reflux conditions for 1 to 10 hours. The reducing agent includes, for example, a combination of zinc and hydrochloric acid; iron and hydrochloric acid; stannous chloride and hydrochloric acid; and the like.
The compound (I) of the present invention can optionally be converted into a pharmaceutically acceptable acid addition salt thereof by the conventional procedure.
The pharmaceutically acceptable acid addition salt of the compound of the present invention includes a salt with an inorganic acid such as hydrochloric acid, sulfuric acid, etc, or a salt with an organic acid such as maleic acid, fumaric acid, etc.
The compound (II) (intermediate compound) used in the above process for preparation is a novel compound which has hitherto never been described in any literature and can be prepared, for example, by the following process (a) or (b). ##STR5##
In accordance with the process (a), the compound (III) is reacted with isopropylamine to give the compound (IV). Then, the compound (IV) is reacted with zinc in the presence of hydrochloric acid to give the compound (V), which is then reac
REFERENCES:
patent: 4093726 (1978-06-01), Winn et al.
Stevens et al, Chemical Abstracts, vol. 115, No. 49687 (1991).
Advanced Organic Chemistry by Jerry March (2nd ed.) pp. 1125-1126 (1977).
Morimoto Yasuo
Ohtaka Hiroshi
Ozaki Akio
Sukamoto Takayuki
Suzuki Kenji
Bernhardt Emily
Kanebo Ltd.
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