Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-09-20
1997-10-28
Berch, Mark L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540504, A61K 3155, C07D40312, C07D24314, C07D24324
Patent
active
056818335
DESCRIPTION:
BRIEF SUMMARY
This application is a 35 U.S.C. .sctn. 371 application of PCT/GB93/00599, filed Mar. 23, 1993.
This invention relates to benzodiazepine compounds which are useful as antagonists of cholecystokinin and gastrin receptors.
Cholecystokinins (CCK) and gastrin are structurally related peptides which exist in gastrointestinal tissue and in the central nervous system (see, V. Mutt, Gastrointestinal Hormones, G. B. J. Green, Ed., Raven Press, N.Y., p.169 and G. Nission, ibid. p.127).
Cholecystokinins include CCK-33, a neuropeptide. Of thirty-three amino acids in its originally isolated form (see, Mutt and Jorpes, Biochem. J. 125, 678 (1971)), its carboxylterminal octapeptide, CCK-8 (also a naturally-occurring neuropeptide and the minimum fully active sequence), and 39- and 12-amino acid forms. Gastrin occurs in 34-, 17- and 14-amino acid forms, with he minimum active sequence being the C-terminal tetrapeptide, Trp-Met-Asp-Phe-NH.sub.2, which is the common structural element shared by both CCK and gastrin.
CCKs are believed to be physiological satiety hormones, thereby possibly playing an important role in appetite regulation (G. P. Smith, Eating and Its Disorders, A. J. Stunkard and E. Stellar, Eds, Raven Press, New York, 1984, p. 67), as well as stimulating colonic motility, gall bladder contraction, pancreatic enzyme secretion and inhibiting gastric emptying. They reportedly co-exist with dopamine in certain mid-brain neurons and thus may also play a role in the functioning of dopaminergic systems in the brain, in addition to serving as neurotransmitters in their own right (see A. J. Prange et el., "Peptides in the Central Nervous System", Ann.
The primary role of gastrin, on the other hand, appears to be stimulation of the secretion of water and electrolytes from the stomach and, as such, is involved in control of gastric acid and pepsin secretion. Other physiological effects of gastrin then include increased mucosal blood flow and increased antral motility. Rat studies have shown that gastrin has a positive trophic effect on the gastric mucosa, as evidenced by increased DNA, RNA and protein synthesis.
There are at least two subtypes of cholecystokinin receptors termed CCK-A and CCK-B (T. H. Moran et at., "Two brain cholecystokinin receptors: Both subtypes are found both 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 (GI) and central nervous (CNS) systems of animals, especially mammals, and more especially those of humans. Just as there is some overlap in the biological activities of CCK and gastrin, antagonists also tend to have affinity for both CCK-B receptors and gastrin receptors. Other antagonists have activity at the CCK-A subtype.
Selective CCK antagonists are themselves useful in treating CCK-related disorders of appetite regulatory systems of animals as well as in al., Science 226, 1215 (1984)!, thus having utility in the treatment of pain. CCK-B and CCK-A antagonists have also been shown to have a direct Selective CCK and gastrin antagonists are useful in the modulation of behaviour mediated by dopaminergic and serotonergic neuronal systems and thus have utility in the treatment of schizophrenia and depression (Rasmussen et. al., 1991, Eur. J. Pharmacol., 209, 135-138; Woodruff et. al., 1991, Neuropeptides, 19, 45-46; Cervo et. al., 1988, Eur. J. pharmacol., 158, 53-59), as a palliative for gastrointestinal neoplasms, and in the treatment and prevention of gastrin-related disorders of the gastrointestinal system in humans and animals, such as peptic ulcers, Zollinger-Ellison syndrome, antral G cell hyperplasia and other conditions in which reduced gastrin activity is of therapeutic value, see e.g. U.S. Pat. No. 4,820,834. Certain CCK antagonists are useful anxiolytic agents and can be used in the treatment of panic and anxiety disorders.
CCK has been reported to evoke the release of stress hormones such as adrenocorticotrophic hormone, .beta.-en
REFERENCES:
J. Med. Chem. 1989, vol. 32, pp. 13-16, Mark G. Bock, et al. entitled "Benzodiazepine Gastrin and Brain Cholecystokinin Receptor Ligands: L-365,260".
Patel, S. et al "Biological Properties of the Benzodiazepine AMidine Derivative L-740,093, a Cholecystokinin-B/Gastrin Receptor Antagonist with High Affinity in Vitro and High Potency In Vivo" Molecular Pharmacology:46 1994 pp. 943-948.
Kawabata, S. et al. "Effect of cholecystokinin receptor antagonists. MK-329 and L-365,260 on cholecystokinin-induced acid secretion and histidine decarboxylase activity in the rat" Regulatory Peptides: 35 1991 pp. 1-10.
Woodruff, Neuropeptides 19, (Suppl) pp. 45-56 (1991).
Castro Pineiro Jose Luis
Chambers Mark Stuart
Hobbs Sarah Christine
Matassa Victor Giulio
Berch Mark L.
Merck Sharp & Dohme Ltd.
North Robert J.
Winokur Melvin
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