Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-03-22
1998-02-10
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
Patent
active
057169535
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP94/02353, filed 18 Jul., 1994 which claims priority of GB 9314981.3, filed 20 Jul., 1993.
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 sulphate, 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 minimum 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-substituted 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 which exhibit a particularly advantageous profile of activity.
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 bridgedcycloalkyl 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 bridgedcycloalkyl group;
R.sup.2 represents a phenyl group optionally substituted by 1 or 2 substituents selected from, halogen, C.sub.1-4 alkyl, C.sub.1-4 alkylthio, cyano, nitro, trifluoromethyl, trifluoromethoxy, (CH.sub.2)nR.sup.4 or O(CH.sub.2)pR.sup.4 wherein R.sup.4 represents hydroxy, C.sub.1-4 alkoxy, CO.sub.2 R.sup.5 or NR.sup.6 R.sup.7 ; n is zero or 1; p is an integer from 1 to 4;
R.sup.3 represents the group AlkNR.sup.8 R.sup.9 ;
R.sup.5 represents hydrogen or C.sub.1-4 alkyl;
R.sup.6 represents hydrogen or C.sub.1-4 alkyl;
R.sup.7 represents hydrogen, C.sub.1-4 alkyl, acyl, or C.sub.2-6 alkyl substituted by one or more hydroxy, carboxyl and/or amino groups or R.sup.6 and R.sup.7 together with the nitrogen atom to which they are attached form a 5-7 saturated heterocyclic ring which contain an additional heteroatom selected from oxygen, sulphur or nitrogen and/or may be substituted by 1 or 2 C.sub.1-4 alkyl or hydroxy groups.
R.sup.8 and R.sup.9 independently represent hydrogen, C.sub.1-4 alkyl or C.sub.2-6 alkyl substituted by one or more hydroxy, carboxyl and/or amino groups or R.sup.8 and R.sup.9 together with the nitrogen atom to which they are attached represent a 5-7 saturated heterocyclic ring which may contain an additional heteroatom selected from oxygen, sulphur or nitrogen and/or may be substituted by 1 or 2 C.sub.1-4 alkyl or hydroxy groups; Alk represents a straight or branched C.sub.2-6 alkylene chain optionally substituted by an hydroxyl group;
R.sup.10 represents hydrogen or a halogen atom; m is zero, 1 or 2;
X is oxygen or NH; and pharmaceutically acceptable salts and or metabolically labile esters thereof.
It will be appreciated that compounds of f
Corsi Mauro
Donati Daniele
Ursini Antonella
Bond Robert T.
Glaxo Wellcome S.p.A.
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