Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-05
2002-02-05
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S517000
Reexamination Certificate
active
06344452
ABSTRACT:
TECHNICAL FIELD
This present invention relates to benzodiazepine derivatives, which are important in the medical field. Specifically, the present invention is concerned with novel 1,5-benzodiazepine derivatives, which antagonize gastrin receptors and/or CCK-B (cholecystokinin-B) receptors, and also with medicines for preventing and/or treating diseases in which the receptors take part.
BACKGROUND ART
Cholecystokinin (CCK) is a gastrointestinal hormone produced at and released from the duodenal and jejunal mucosas, and is known to have actions such as pancreatic juice secretion stimulation, gallbladder contraction stimulation and insulin secretion stimulation. Further, CCK is also known to exist at high concentrations in the cerebral cortex, the hypothalamus and the hippocampus, and is also known to have actions such as suppressing food intake, enhancing memory, generating anxiety and the like. On the other hand, gastrin is a gastrointestinal hormone produced at and released from G cells which are distributed in the pylorus, and is known to have effects such as gastric acid secretion stimulation, pylorus contraction stimulation and gallbladder contraction stimulation.
These CCK and gastrin have the same five C-terminal amino acids, and both exhibit their effects via receptors. CCK receptors are classified into peripheral CCK-As distributed in the pancreas, the gallbladder, the intestinal tract and the like and central CCK-Bs distributed in the brain. Gastrin receptors and CCK-Bs show similar properties in receptor binding experiments and have high homology, so that they may be called “CCK-Bs/gastrin receptors”. Antagonistic compounds to these receptors, for example, gastrin receptors or CCK-B receptors can be used for the treatment and/or prevention of gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis, pancreatitis, Zollinger-Ellison syndrome, vacuolating G cell hyperplasia, basal mucosa hyperplasia, cholecystitis, biliary colic, gastrointestinal dysmotility, irritable bowel syndrome, certain types of tumors, eating disorder, anxiety, panic disorder, depression, schizophrenia, parkinsonism, tardive dyskinesia, Gilles de la Tourette's syndrome, drug dependance, and drug-withdrawal symptoms. They are also expected to have effects such as induction of ataralgesia and enhancement of ataralgesia induction by opioid drugs [Folia Pharmacologica Japonica, 106, 171-180 (1995); Drugs of the Future, 18, 919-931 (1993); American Journal of Physiology, 269, G628-G646 (1995); American Journal of Physiology, 259, G184-190 (1990); European Journal of Pharmacology, 261, 257-263 (1994); Trends in Pharmacological Science, 15, 65-66 (1994)].
As a gastrin receptor antagonist, proglumide is already known as a remedy for gastric ulcer and gastritis. However, proglumide has considerably low affinity to gastrin receptors or CCK-B receptors, and has a low curative effect. Further, some benzodiazepine derivatives such as L-365,718 (devazepide, Japanese Patent Application Laid-Open(Kokai) No.63666/1986) and L-365,260 (Japanese Patent Application Laid-Open (Kokai) No. 238069/1988) have been reported to exhibit CCK-A receptor antagonism and CCK-B receptor antagonism. In addition, it is disclosed that compounds having strong CCK-B antagonism inhibit pentagastrin-stimulated acid secretion (WO 94/438, WO 95/18110). These compounds are, however, not fully satisfactory when administered in vivo. Accordingly, clinically-applicable gastrin receptor or CCK-B receptor antagonists have not been provided yet.
Compounds which can strongly bind to gastrin receptors or CCK-B receptors are useful for the prevention and/or treatment of diseases in which the respective receptors take part in the alimentary tract and the central nervous system. There is hence an outstanding desire for such compounds.
DISCLOSURE OF THE INVENTION
Under such circumstances, the present inventors have proceeded with an extensive investigation to solve the above-described problems. As a result, it was found that 1,5-benzodiazepine derivatives having a specific structure have strong gastrin receptor and/or CCK-B receptor antagonism and achieve strong inhibition of acid secretion and are useful as medicines for the prevention and/or treatment of diseases in which these receptors take part, and an application for patent has already been filed (PCT/JP97/04534). The present inventors have proceeded with further research. As a result, it has been found that 1,5-benzodiazepine derivatives each of which contains a branched fatty acid group achieve still better inhibition of pentagastrin-stimulated acid secretion in rats and inhibition of pentagastrin-stimulated acid secretion in beagles with Heidenhain pouch, leading to the completion of the present invention.
Therefore, the present invention provides a 1,5-benzodiazepine derivative represented by the following formula (1):
wherein R
1
represents a lower alkyl group, R
2
and R
3
may be the same or different and represent a hydrogen atom or a lower alkyl group, R
4
represents a cyclohexyl group or phenyl group, and n stands for an integer of from 1 to 3; or a salt thereof.
The present invention also provides a medicament comprising as an effective ingredient the 1,5-benzodiazepine derivative (1) or the salt thereof.
The present invention also provides a medicinal composition comprising the 1,5-benzodiazepine derivative (1) or the salt thereof and a pharmaceutically acceptable carrier.
The present invention also provides the 1,5-benzo-diazepine derivative (1) or the salt thereof as a medicament.
The present invention further provides a treatment method of a disease in which a gastrin receptor and/or a CCK-B receptor takes part, which comprises administering the 1,5-benzo-diazepine derivative (1) or the salt thereof.
BEST MODES FOR CARRYING OUT THE INVENTION
The term “lower” as used herein means a linear or branched carbon chain having a carbon number of from 1 to 8.
Therefore, examples of the lower alkyl groups represented by R
1
, R
2
and R
3
in the formula (1) can include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, tert-pentyl, 1,2-dimethylpropyl, neopentyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethyl-butyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethyl-butyl, 3,3-dimethylbutyl, 1-methyl-1-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 1-propylbutyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methyl-heptyl, 1-ethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl-hexyl, 1-propylpentyl, 2-propylpentyl, 3,3,4-trimethylpentyl, 3,4,4-trimethylpentyl, 1,1,2,2-tetramethylbutyl, 2,2,3,3-tetramethylbutyl, and 1,1,3,3-tetramethylbutyl. Among these, alkyl groups the carbon numbers of which range from 1 to 4 are preferred, with methyl being particularly preferred.
Compounds of the formula (1) in which R
1
and R
2
are methyl groups, n is 1 and R
3
is a hydrogen atom, that is, of the following formula (1
a
) are particularly preferred:
wherein R
4
represents the same as defined above.
Illustrative of the salt of the compound (1) according to the present invention are acid addition salts with inorganic acids, such as the hydrochloride, the sulfate, the nitrate and the hydroiodate; acid addition salts with organic acids, such as the methanesulfonate and the ethanesulfonate; inorganic salts such as the sodium salt, the potassium salt, the calcium salt and the magnesium salt; and organic salts such as the ammonium salt, the pyridine salt, the triethylamine salt, the ethanolamine salt, the trans-4-aminocyclohexanol salt and the N,N′-dibenzylethylenediamine salt. Among these, the sodium salt, the trans-4-aminocyclohexanol salt and the N,N′-dibenzyl-ethylenediamine salt are particularly preferred.
In the p
Maeda Kiyoto
Miura Naoyoshi
Murata Masakazu
Shinozaki Katsuo
Yoneta Tomoyuki
Kifle Bruck
Zeria Pharmaceuticals Co., Ltd.
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