Benzodiazepine derivatives

Details Benzodiazepine derivatives Benzodiazepine derivatives

1997-01-29

1998-06-09

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

540509, 540504, A61K 3155, C07D24314, C07D24324, C07D24326

Patent

active

057634378

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This application is a 371 of PCT/JP95/01497
This invention relates to new benzodiazepine derivatives or a pharmaceutically acceptable salts thereof which are useful as a medicament.


BACKGROUND ART

Some benzodiazepine derivatives have been known as described, for example, in European Patent Application Publication No. 349949.


DISCLOSURE OF INVENTION

This invention relates to new benzodiazepine derivatives or pharmaceutically acceptable salts thereof.
More particularly, it relates to new benzodiazepine derivatives and pharmaceutically acceptable salts thereof which are selective cholecystokinin-B (CCK-B) antagonists or cholecystokinin-A and B (CCK-A/B) antagonists and therefore useful as therapeutical and/or preventive agents for disorders of appetite regulatory systems (e.g., anorexia, etc.), disorders associated with intestinal smooth muscle hyperactivity (e.g., irritable bowel syndrome, sphincter spasm, etc.), panic disorder, psychosis (e.g., schizophrenia, etc.), pancreatitis, etc. and also useful as analgesics.
The benzodiazepine derivatives of this invention can be represented by the following formula (I): ##STR1##
wherein R.sup.1 is aryl or C.sub.3 -C.sub.8 cycloalkyl, each of which may have one or more suitable substituent(s), group, each of which may have one or more suitable substituent(s), tetrahydrofuryl, dioxolanyl, furyl, thienyl, isoxazolyl, pyridyl, benz imidazolyl, benzothiazolyl, benzoxazolyl, benzopyranyl, quinolyl, isoquinolyl, tetrahydroisoquinolyl, benzothienyl and benzofuryl, each of which may have one or more suitable substituent(s); or a group of the formula: --X--R.sup.4 ##STR2## and R.sup.4 is thiomorpholinyl; pyridyl; a bridged heterocyclic group containing at least one nitrogen atom, which may have one or more suitable substituent(s); or a bridged cyclic-hydrocarbon group), ##STR3## (in which R.sup.8 is hydrogen or lower alkyl), or a pharmaceutically acceptable salt thereof. According to the present invention, the new benzodiazepine derivatives (I) may be prepared by the processes which are illustrated in the following scheme. ##STR4## wherein R.sup.1, R.sup.2, R.sup.3, A, Y and Z are each as defined above, ##STR5## is a bridged heterocyclic group containing at least one nitrogen atom, which may have one or more suitable substituent(s), and R.sup.7 is a bridged cyclic-hydrocarbon group
The starting compounds (II) and (IV) may be prepared by the following processes. ##STR6## wherein R.sup.1, R.sup.2, R.sup.3, ##STR7## A, Y and Z are each as defined above, R.sup.5 is protected amino,
With regard to the object compound (I), in case that the compound (I) has the group of the formula: ##STR8## in R.sup.2 said group can also exist in the tautomeric form and such tautomeric equilibrium can be represented by the following scheme. ##STR9##
Both of the above tautomeric isomers are included within the scope of the present invention. In the present specification and claim, the compounds including the group of such tautomeric isomers are represented for the convenient sake by one expression of the group of the formula (A).
Further, in case that the compound (I) has the group of the formula: ##STR10## in R2, said group can also exist in the tautomeric from and such tautomeric equilibrium can be represented by the following scheme. ##STR11##
Both of the above tautomeric isomers are included within the scope of the present invention. In the present specification and claim, the compounds including the group of such tautomeric isomers are represented for the convenient sake by one expression of the group of the formula (C).


BEST MODE FOR CARRYING OUT THE INVENTION

Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and include a metal salts such as an alkali metal salt (e.g., sodium salt. potassium salt, etc.) and an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine sal

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