Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-10-30
1996-12-17
Datlow, Philip I.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540518, A61K 3155, C07D40106, C07D40306
Patent
active
055853765
DESCRIPTION:
BRIEF SUMMARY
This is a national stage application under 35USC371 of application PCT/EP94/01130, filed Apr. 13, 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.
The present invention thus provides compounds of the general formula (I) ##STR2## and physiologically acceptable salts thereof wherein the group NR.sub.1 R.sub.2 represents a 5-7 membered saturated heterocylic ring which may be substituted by one or two methyl groups; substituted by 1 or 2 halogen atoms; halogen, C.sub.1-4 alkyl, trifluoromethyl, trifluoromethoxy or (CH.sub.2).sub.n R.sub.5 wherein n is zero or 1 and R.sub.5 represents C.sub.1-4 alkoxy, hydroxy, nitro, cyano, CO.sub.2 R.sub.6, S(O).sub.p CH.sub.3, NR.sub.7 R.sub.8, CONR.sub.7 R.sub.8, SO.sub.2 NR.sub.7 CO(C.sub.1-4 alkyl), tetrazolyl, carboxamidotetrazolyl, or a 3-trifluoromethyl 1,2,4-triazolyl;
R.sub.6 is hydrogen, C.sub.1-4 alkyl or benzyl;
R.sub.7 is hydrogen or C.sub.1-4 alkyl,
R.sub.8 is hydrogen, C.sub.1-4 alkyl, SO.sub.2 CH.sub.3 or SO.sub.2 CF.sub.3
X represents hydrogen, C.sub.1-4 alkyl or halogen;
m is zero, 1 or 2, and p is zero, 1 or 2.
The compounds of the invention possess at least one asymmetric carbon atom and the compounds of the invention include both enantiomers and mixtures thereof including the racemate.
The term alkyl as used herein refers to both straight chain and branched chain alkyl groups. For example C.sub.1-6 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl or hexyl.
The term halogen includes fluorine, chlorine, bromine or iodine.
When R.sub.5 represents a tetrazolyl, carboxamidotetrazolyl or 3-trifluoromethyl 1,2,4-triazolyl group these are linked to the rest of the molecule via a carbon atom therein and the invention includes all tautomers thereof and the C.sub.1-4 alkyl --N substituted derivatives thereof. Examples of such groups include (1H) tetrazol-5-yl, carboxamido-1H-tetrazol-5-yl, 2-methyltetrazol-5-yl and (3-trifluoromethyl-1,2,4-triazol-5-yl.
The group NR.sub.1 R.sub.2 is linked to the rest of the molecule via the nitrogen thereof examples of such groups include pyrrolidino, piperidino, hexamethylenimino-, 2,5-dimethylpyrrolidino, 3,3-dimethylpiperidino, 2,6-dimethylpiperidino or 4,4-dimethylpiperidino.
When R.sub.3 represents phenyl o
Carr Robin A. E.
Finch Harry
Shah Pritom
Datlow Philip I.
Glaxo Wellcome Inc.
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