Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-06-08
2001-05-29
Raymond, Richard L. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S517000
Reexamination Certificate
active
06239131
ABSTRACT:
TECHNICAL FIELD
The present invention relates to 1,5-benzodiazepine derivatives, which are important in the medical field. More specifically, the present invention relates to novel 1,5-benzodiazepine derivatives which have gastrin and/or CCK-B (cholecystokinin-B) receptor antagonism, and to preventive and therapeutic remedies for disorders in which the receptors participate.
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 at high concentration in the cerebral cortex, hypothalamus, and hippocampus. CCK is also known to exhibit various actions, including inhibition of eating and hunger, augmentation of memory, and generation of anxiety. Meanwhile, gastrin is a gastrointestinal hormone which is produced by and released from G-cells distributed in the pylorus. Gastrin is also 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, exert the aforementioned actions via receptors. The receptors of CCK are classified into CCK-A receptors, which are of the peripheral-type and are distributed in the pancreas, the gallbladder, and the intestines; and CCK-B receptors, which are of the central-type and are distributed within the brain. Since gastrin receptors and CCK-B receptors show similar properties in receptor-binding experiments, and thus are proven to have high homology, they are often called CCK-B/gastrin receptors. Compounds having antagonism to these receptors, i.e., gastrin or CCK-B receptor, are expected to be useful for prevention and treatment of the following diseases and disorders: gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis, pancreatitis, Zollinger-Ellison syndrome, vacuolating G-cell hyperplasia, basal-mucous-membrane hyperplasia, inflammation of the gallbladder, attack of biliary colic, motor disorders 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 augment the pain-relieving effect of opioid analgesics (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)).
Proglumide, which is a drug having gastrin receptor antagonism, has conventionally been known as a remedy for gastric ulcer and gastritis. However, proglumide has a very weak affinity with gastrin or CCK-B receptors, and has a low curative effect. It is described that some 1,4-benzodiazepine derivatives—such as L-364,718 (Dibazepaido, 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 known that compounds having strong CCK-B receptor antagonism suppress secretion of gastric acid stimulated by pentagastrin (WO 94/438 and WO 95/18110). However, these compounds do not provide satisfactory effects when administered in vivo. Drugs which exhibit gastrin or CCK-B receptor antagonism and are clinically useful have not yet been provided.
Compounds that can be strongly bound to gastrin or cholecystokinin receptors are expected to be useful as remedies and for prevention of diseases associated with respective receptors and found in the alimentary canal and the central nervous system.
DISCLOSURE OF THE INVENTION
In view of the foregoing, in order to solve the above-mentioned problems, the present inventors have conducted earnest studies, and have found that some 1,5-benzodiazepine derivatives exhibit gastrin and/or CCK-B receptor antagonism and strong effect in suppressing the secretion of gastric acid, and that the derivatives are useful as medicines, leading to completion of the invention.
Accordingly, the present invention provides a 1,5-benzodiazepine derivative represented by the following formula (I) and salts thereof:
[wherein
R
1
represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, or a halogen atom;
each of R
2
and R
3
, which may be the same or different, represents a hydrogen atom, a lower alkenyl group, a lower alkyl group which may be substituted by a halogen atom, a lower alkylsulfonyl group, a mono- or di-lower alkoxyalkyl group, a phenyl group which may have a substituent, a group represented by —CH(R
6
)R
7
(wherein R
6
represents a lower alkyl group, a lower alkoxyl group, a mono- or di-lower alkoxyalkyl group, a saturated or unsaturated hydrocarbon group having a C7-C10 condensed ring, or a phenyl or heterocyclic group which may have a substituent; and R
7
represents a hydrogen atom or a lower alkyl group), or a group represented by —CO—R
8
(wherein R
8
represents a lower alkyl group which may be substituted by a halogen atom; a lower alkenyl group; a lower alkoxyl group; a mono- or di-lower alkoxyalkyl group; an adamantyl group; a hydroxyl group; a benzyloxy group; a phenyl or heterocyclic group which may have a substituent; or a group represented by —N(R
9
)R
10
(wherein R
9
and R
10
may be the same or different, and each represents a hydrogen atom, a lower alkyl group, a hydroxyalkyl group, a mono- or di-lower alkylaminoalkyl group, a phenyl group, or a heterocyclic group which may have a substituent));
each of R
4
and R
5
, which may be identical to or different from each other, represents a hydrogen atom, a lower alkyl group which may be substituted by a halogen atom, a lower alkoxyl group, a halogen atom, a hydroxyalkyl group, an amino group, a nitro group, a mono- or di-lower alkylamino group, a lower alkylsulfonylaminocarbonyl group, a hydroxyaminocarbonyl group, a benzyloxyaminocarbonyl group, a tetrazolyl group, a 4-oxoxadiazolinyl group, a group represented by the following formula:
(wherein X represents an oxygen or sulfur atom), or a group represented by —Y—COOR
11
(wherein Y represents a single bond, alkylene, —O-alkylene, —S-alkylene, —SO-alkylene, —CONH— or CONH-alkylene; and R
11
represents a hydrogen atom, a lower alkyl group or a benzyl group);
Ar represents an aromatic hydrocarbon or an aromatic heterocyclic ring; and
n represents an integer between 0 and 2 inclusive].
The present invention also provides a medicine containing the above-described compound (I) as an active ingredient.
The present invention also provides a pharmaceutical composition containing the above-described compound (I) and a pharmaceutically acceptable carrier.
The present invention also provides use of the above-described compound (I) as a medicine.
The present invention also provides a method for prevention and treatment of a disease in which a gastrin receptor and/or cholecystokinin (CCK)-B receptor participates, which comprises administration of an effective amount of the above-described compound (I) to mammals, including humans.
BEST MODE FOR CARRYING OUT THE INVENTION
As used herein, “lower” refers to a straight, branched, or cyclic carbon chain having 1-8 carbon atoms, and “lower cyclic” refers to C3-C8 monocyclic.
Therefore, examples of a “lower alkyl group” include methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, cyclopropylmethyl, 1-methylcyclopropyl, 2-methylcyclopropyl, pentyl, 1-methylbutyl, 2-methylbutyl, isopentyl, tert-pentyl, 1,2-dimethylpropyl, neopentyl, 1-ethylpropyl, cyclopentyl, 1-methylcyclobutyl, 2-methylcyclobutyl, 3-methylcyclobutyl, cyclobutylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, (
Maeda Kiyoto
Miura Naoyoshi
Murata Masakazu
Shinozaki Katsuo
Yoneta Tomoyuki
Coleman Brenda
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
Raymond Richard L.
Zeria Pharmaceutical Co. Ltd.
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