Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-08-15
2004-06-08
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
06747022
ABSTRACT:
TECHNICAL FIELD
The present invention relates to benzodiazepine derivatives having an important role in a medical field. More specifically, the invention relates to calcium salts of 1,5-benzodiazepine derivatives having a gastrin and/or CCK-B (cholecystokinin-B) receptor antagonism and at the same time having potent gastric acid secretion inhibitory action; preparation processes of the compounds; and drugs containing the compounds as an effective ingredient.
BACKGROUND ART
Cholecystokinin (CCK) is a gastrointestinal hormone which is produced by and released from duodenal and jejunal mucous membranes, and is known to have actions such as secretion of pancreatic juice, gallbladder constriction, and stimulation of insulin secretion. CCK is also known to be present in the cerebral cortex, hypothalamus, and hippocampus at a high concentration and exhibit actions such as inhibition of eating and hunger, augmentation of memory, and generation of anxiety. Gastrin is a gastrointestinal hormone which is produced by and released from G-cells distributed in the pylorus and is known to exhibit actions such as secretion of gastric acid and constriction of the pylorus and gallbladder. CCK and gastrin, having the same five amino acids in their C-terminals, express actions via receptors. CCK receptors are classified into CCK-A which are peripheral type receptors distributed in the pancreas, gallbladder, and intestines; and CCK-B which are central type receptors distributed in the brain. Since gastrin receptors and CCK-B receptors show similar properties in receptor-binding tests and have high homology, they are often called CCK-B/gastrin receptors. Compounds having antagonism to these receptors, for example, gastrin or CCK-B receptor, are presumed to be useful for prevention or treatment of gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis, pancreatitis, Zollinger-Ellison syndrome, vacuolating G-cell hyperplasia, basal-mucous-membrane hyperplasia, cholecystitis, attack of biliary colic, dysmotilities of alimentary canal, irritable bowel syndrome, certain types of tumors, eating disorders, anxiety, panic disorder, depression, schizophrenia, Parkinson's disease, tardive dyskinesia, Gilles de la Tourette syndrome, drug dependence, and drug-withdrawal symptoms. Moreover, the compounds are expected to induce pain relief or to accelerate induction of pain relief by opioid medications (Folia Pharmacologica Japonica, Vol. 106, 171-180 (1995), Drugs of the Future, Vol. 18. 919-931 (1993), American Journal of Physiology, Vol. 269, G628-G646 (1995), American Journal of Physiology, Vol. 259, G184-G190 (1990), European Journal of Pharmacology, 261, 257-263 (1994), Trends in Pharmacological Science, Vol. 15, 65-66 (1994)).
As a gastrin receptor antagonist, proglumide is known as a remedy for gastric ulcer and gastritis. Proglumide's affinity with gastrin or CCK-B receptors is however very low, and its curative effect is weak. It is reported that some benzodiazepine derivatives such as L-364,718 (devazepide, Japanese Patent Application Laid-Open (kokai) No. 63666/1986) and L-365,260 (Japanese Patent Application Laid-Open (kokai) No. 238069/1988) exhibit CCK-A receptor antagonism or CCK-B receptor antagonism. It is also disclosed that compounds having strong CCK-B receptor antagonism suppress pentagastrin-stimulated secretion of gastric acid (WO 94/438 and WO 95/18110). Administration in vivo of these compounds however does not always bring about satisfactory effects. In WO98/25911 and WO99/64403, the present inventors therefore disclosed 1,5-benzodiazepine derivatives having potent gastrin and/or CCK-B receptor antagonism and at the same time, having strong gastric acid secretion inhibitory action. There is however a demand for compounds which have potent gastrin and/or CCK-B receptor antagonism and gastric acid secretion inhibitory action, particularly strong in gastric acid secretion inhibitory action, and are suited for clinical use.
DISCLOSURE OF THE INVENTION
With the foregoing in view, the present inventors have carried out an extensive investigation. As a result, it has been found that compared with 1,5-benzodiazepine derivatives as specifically described in WO98/25911 and WO99/64403, calcium salts of 1,5-benzodiazepine derivatives having a specific structure, which salts fall within a range disclosed in WO98/25911 and WO99/64403 but are not specifically described therein, have markedly potent inhibitory activity against gastric acid secretion; and owing to low hygroscopicity and easy purification, are desirable as drugs from the viewpoint of quality maintenance so that they are useful as drugs, particularly preventives or remedies for various diseases of digestive tracts resulting from excessive secretion of gastric acid, leading to the completion of the invention.
In one aspect of the present invention, there are thus provided a calcium salt of a 1,5-benzodiazepine derivative represented by the following formula (I):
(wherein, R
1
represents a lower alkyl group, R
2
represents a phenyl or cyclohexyl group, and Y represents a single bond or a lower alkylene group); and a preparation process of the calcium salt.
In another aspect of the invention, there is also provided a gastric acid secretion inhibitor, which comprises, as an effective ingredient, a calcium salt of a 1,5-benzodiazepine derivative represented by the formula (I).
In a further aspect of the invention, there is also provided a drug comprising, as an effective ingredient, a calcium salt of a 1,5-benzodiazepine derivative represented by the formula (I), particularly, a preventive or remedy for gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis or Zollinger-Ellison syndrome.
In a still further aspect of the invention, there is also provided a pharmaceutical composition comprising a calcium salt of a 1,5-benzodiazepine derivative represented by the formula (I) and a pharmaceutically acceptable carrier, particularly, a pharmaceutical composition for preventing and/or treating gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis or Zollinger-Ellison syndrome.
In a still further aspect of the present invention, there is also provided the use of a calcium salt of a 1,5-benzodiazepine derivative represented by the formula (I) for the preparation of a preventive and/or remedy for gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis or Zollinger-Ellison syndrome.
In a still further aspect of the present invention, there is also provided a treating method of gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis or Zollinger-Ellison syndrome, which comprises administering a calcium salt of a 1,5-benzodiazepine derivative represented by the formula (I).
BEST MODE FOR CARRYING OUT THE INVENTION
The term “lower” as used herein means a linear or branched carbon chain having 1 to 4 carbon atoms.
Accordingly, examples of the “lower alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, while those of the “lower alkylene group” include methylene, ethylene, propylene, butylene, methylmethylene, dimethylmethylene, 1-methylethylene, 1,1-dimethylethylene, 1-methylpropylene and 2-methylpropylene.
The term “halogen atom” as used herein means a fluorine, chlorine, bromine or iodine atom.
The term “metal atom” as used herein means a metal atom which can be converted into a monovalent or divalent cation and examples include sodium, potassium and calcium atoms.
It is preferred that in the formula (I), R
1
represents a branched C
4
alkyl group, particularly, a tert-butyl group; R
2
represents a cyclohexyl group and Y represents a single bond or dimethylmethylene.
The present invention not only embraces optically active isomers and diastereomers but also solvates such as hydrates and polymorphs.
Of the invention compounds (I), particularly preferred from the viewpoint of inhibitory action against gastric acid secretion and storage stability are calcium (R)-(−)-3-[3-(1-tert-butylcarbonylmethyl-2-oxo-5-cyclohexyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl
Kawase Nobuo
Maeda Kiyoto
Miura Naoyoshi
Murata Masakazu
Shinozaki Katsuo
Kifle Bruck
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Zeria Pharmaceutical Co. Ltd.
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