Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-10-11
1998-04-14
Reamer, James H.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540518, A61K 3155
Patent
active
057391297
DESCRIPTION:
BRIEF SUMMARY
This invention relates to 5-heterocyclo-1,5-benzodiazepine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine. More particulary, it relates to compounds which exhibit agonist activity for CCK-A receptors thereby enabling them to modulate the hormones gastrin and cholecystokinin (CCK) in mammals.
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 carboxyl 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 minimum active sequence being the C-terminal tetrapeptide, Trp-Met-Asp-Phe-NH.sub.2 (CCK-4) which is the common structural 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.
The CCK-A receptor, commonly referred to as the "peripheral-type" receptor, is primarily found in the pancreas, gallbladder, lieure, pyloric sphincter and on vagal afferent nerve fibers. Type-A CCK receptors are also found in the brain in discrete regions and serve to provide a number of CNS effects. Due to the ability of CCK-8 and Type-A CCK-selective agonists to suppress food intake in several animal species, considerable interest has been generated toward the development of new substances which function as Type-A receptor-selective CCK agonists in order to serve as anorectic agents.
The CCK-B or gastrin receptors are found in peripheral neurons, gastrointestinal smooth muscle and gastrointestinal mucosa, most notably in parietal cells, ECL cells, D cells and chief cells. CCK-B receptors also predominate in the brain and have been implicated in the regulation of anxiety, arousal and the action of neuroleptic agents.
U.S. Pat. No. 4,988,692, to Gasc, et al. describes a group of 3-acylamino 1-alkyl-5-phenyl 1,5-benzodiazepine derivatives which behave as cholecystokinin antagonists to reverse or block the effects of the endogenous hormone at its receptors.
U.S. Pat. No. 4,490,304 and PTC applications No's WO90/06937 and WO91/19733 describe peptide derivatives that exhibit CCK-A agonist activity. Such compounds have been disclosed for appetite regulation as well as the treatment and/or prevention of gastrointestinal disorders or disorders of the central nervous in animals and, more particularly, humans.
U.S. Pat. No. 5,187,154 which is incorporated herein by reference describes the use of the neuropeptide cholecystokinin (CCK) to control gastric emptying in patients having an early non-insulin-dependent diabetic condition and exhibiting rapid gastric emptying. Further the specification teaches that compounds which inhibit gastric emptying may be useful to alleviate or eliminate symptoms associated with early or pre-diabetes. Particular symptoms include elevated blood glucose and insulin levels, insulin resistance, increased susceptibility to infection or glycosuria while also maintaining gastric emptying within normal levels.
We have now discovered a novel group of 5-heterocyclo-1,5-benzodiazepine derivatives which exhibit an agonist activity for the CCK-A receptor thereby enabling them to modulate the hormones gastrin and cholecystokinin (CCK) in mammals. Certain of these compounds also exhibit antagonist activity at CCK-B receptors.
The present invention thus provides compounds of the general Formula (I) ##STR2## and physiologically salts and solvate thereof wherein X is either hydrogen, trifluoromethyl, alkyl, C.sub.1-4 alkylthio, --O(C.sub.1-4 alkyl) or halogen; ##STR3## R.sup.2
REFERENCES:
patent: 4490364 (1984-12-01), Rivier et al.
patent: 4988692 (1991-01-01), Gasc et al.
patent: 5187154 (1993-02-01), Phillips et al.
patent: 5585376 (1996-12-01), Finch et al.
patent: 5597915 (1997-01-01), Chambus et al.
patent: 5618812 (1997-04-01), Pineiro et al.
patent: 5641775 (1997-06-01), Finich et al.
Aquino Christopher Joseph
Sugg Elizabeth Ellen
Szewczyk Jerzy Ryszard
Brink Robert H.
Glaxo Wellcome Inc.
Reamer James H.
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