Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-10-23
1997-06-24
Bond, Robert T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540518, A61K 3155, C07D24312, C07D40312
Patent
active
056417756
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP 94/01252, filed 22 Apr. 1994.
This invention relates to novel 1,5-benzodiazepine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
Cholecystokinins (CCK) and gastrin are structurally related peptides which exist in gastrointestinal tissue and in the central nervous system. Cholecystokinins include CCK-33, a neuropeptide of thirty-three amino acids in its originally isolated form, its carboxy terminal octapeptide, CCK-8 (also a naturally-occurring neuropeptide), and 39- and 12-amino acid forms. Gastrin occurs in 34-, 17- and 14-amino acid forms, with the miniumum active sequence being the C-terminal tetrapeptide, Trp-Met-Asp-Phe-NH.sub.2 (CCK-4), which is the common structual element shared by both CCK and gastrin.
CCK and gastrin are gastrointestinal hormones and neurotransmitters in the neural and peripheral systems and perform their respective biological roles by binding to particular receptors located at various sites throughout the body.
There are at least two subtypes of cholecystokinin receptors termed CCK-A and CCK-B and both are found in the periphery and in the central nervous system. CCK and gastrin receptor antagonists have been disclosed for preventing and treating CCK-related and/or gastrin related disorders of the gastrointestinal and central nervous systems of animals, and more particularly humans.
U.S. Pat. No. 4,988,692 describes a group of 3-acylamino 1-alkyl-5-phenyl 1,5-benzodiazepine derivatives as cholecystokinin antagonists. Further the specification teaches that the compounds have a significantly greater affinity for the CCK-A receptor over the CCK-B receptor.
We have now found a novel group of 3-ureido 1,5-benzodiazepine compounds which are potent and specific antagonists of gastrin and/or CCK and in particular antagonists of gastrin and/or CCK at the CCK-B receptor.
Thus, the invention provides compounds of general formula (I) ##STR2## wherein R.sup.1 represents a phenyl, C.sub.3-7 cycloalkyl, C.sub.7-11 bridged cycloalkyl or C.sub.1-6 alkyl group which alkyl group may be substituted by a hydroxy, phenyl, C.sub.1-6 -alkoxycarbonyl, C.sub.3-7 cycloalkyl or C.sub.7-11 bridged cycloalkyl group; CONR.sup.4 SO.sub.2 R.sup.5, or a tetrazole, carboxamidotetrazole, or 3-trifluoromethyl-1,2,4-trizole group which groups may be substituted on one of the nitrogen atoms by a C.sub.1-4 alkyl group;
It will be appreciated that compounds of formula (I) possess at least one asymmetric carbon atom (namely the carbon atom occupying the 3-position of the diazepine ring) and the compounds of the invention thus include all stereoisomers and mixtures thereof including the racemates.
In the compounds of formula (I) `alkyl` when used as a substituent or part of a substituent group means that the group may be straight or branched. Thus, C.sub.1-6 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, n-pentyl, isopentyl neopentyl, n-hexyl, isohexyl, 1,3-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl.
For the group R.sup.1 the term C.sub.3-7 cycloalkyl as a group or part of a group refers to a monocyclic alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The term C.sub.7-11 bridged cycloalkyl as a group or part of a group refers to groups such as adamantyl, norbornanyl or norbornenyl.
For the groups R.sup.4, R.sup.5 and R.sup.7 (below) the term C.sub.1-4 alkyl includes 3-4 cycloalkyl (e.g. cyclopropyl or cyclobutyl) as well as straight or branched chain alkyl groups as defined above.
When R.sup.2 represents a tetrazole group suitable examples include ##STR3##
When R.sup.2 represents a carboxamidotetrazole grouping suitable examples include ##STR4##
When R.sup.2 represents a 3-trifluoromethyl 1,2,4-triazole grouping suitable examples include ##STR5##
The group R.sup.7 represents hydrogen or a C.sub.1-4 alkyl group. It will be appreciated that when R.sup.7 represents a hydrogen atom the various isomers for each heterocyclic group ar
Feriani Aldo
Finch Harry
Shah Pritom
Tarzia Giorgio
Trist David Gordon
Bond Robert T.
Glaxo SpA
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