Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-10-11
1998-08-18
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540509, 540517, A01N 4362, C07D24324, C07D24312
Patent
active
057958874
DESCRIPTION:
BRIEF SUMMARY
This invention relates to 1,4 benzodiazepine having cholecystokinin (CCK) agonist activity. More particularly it relates to the use of 1,4-benzodiazepine which exhibit CCK-A agonist activity in the manufacture of a medicament for the treatment of conditions where a modulation of the effects of gastrin or CCK is of therapeutic benefit and to a method of inducing a CCK-A receptor agonist response in a mammal in need of treatment for a gastrointestinal or central nervous system related disease.
Cholecystokinin (CCK) is a peptide found in the gastrointestinal tract and the central nervous system. see A. J. Prange et al., Ann. Reports Med. Chem. 17, 31, 33 (1982), J. A. Williams, Biomed Res. 3, 107 (1982) and V. Mutt, Gastrointestinal Hormones, G. B. J. Green, Ed., Raven Press, New York, 169. CCK has been implicated inter alia as a physiological satiety hormone involved in appetite regulation, see Della-Ferra et al, Science, 206, 471 (1979), Saito et al., Nature, 289, 599, (1981), G. P. Smith, Eating and Its Disorders, A. J. Stunkard and E. Stellar, Eds, Raven Press, New York, 67 (1984), as a regulator of gallbladder contraction and pancreatic enzyme secretion, an inhibitor of gastric emptying, and as a neurotransmitter, see A. J. Prange, supra, J. A. Williams, Biomed Res., 3,107 (1982), J. E. Morley, Life Sci. 30, 479, (1982). Gastrin is a peptide involved in gastric acid and pepsin secretion in the stomach, see L. Sandvik, et al, American J. Physiology, 260, G925 (1991), C. W. Lin, et al., Amercan J Physiology, 262, G1113, (1992). CCK and gastrin share structural homology in their C-terminal tetrapeptide: Trp-Met-Asp-Phe.
Two subtypes of CCK receptors have been identified, designated as CCK-A and CCK-B, and both have been found in the periphery and central nervous systems. It has recently been reported that CCK-B receptors are similar to the gastrin receptor, see Pisegna, J. R., de Weerth, A, Huppi, K, Wank, S. A., Biochem. Biophys. Res. Commun. 189, 296-303 (1992). CCK-A receptors are located predominantly in peripheral tissues including the pancreas, gallbladder, ileum, pyloric sphincter and vagal afferent nerve fibers; CCK-A receptors are found to a lesser extent in the brain, see T. H. Moran, et al., Brain Res., 362, 175-179 (1986), D. R. Hill, et al, Brain Res, 4545,101, (1988), D. R. Hill, et al, Neurosci Lett., 89, 133, (1988), R. W. Barret, et al., Mol. Pharmacol, 36, 285, (1989), D. R. Hill, et al., J Neurosci, 10, 1070 (1990), V. Dauge at al., Pharmacol Biochem Behac., 33, 637, (1989), while CCK-B receptors are found predominantly in the brain, see V. J. Lotti and R. S. L Chang, Proc. Natl. Acad. Sci. U.S.A., 83, 4923 (1986), J. N. Crawley, Trends Pharm. Sci., 88, 232, (1991).
The literature in the CCK area contains extensive discussion surrounding CCK antagonist activity relating to the increase of food intake and treating oncologic disorders, in particular relating to 1,4- and 1,5-benzodiazepines, see B. E. Evans, Drugs of the Future, 14, 971 (1989), M. A. Silverman, et al., Am. J. Gastroenterol, 82, 703 (1987), EPO 0538 945, published Apr. 28, 1993, EPO 0 523 845, published Jan. 20, 1993, EPO 0284 256, published 28 Sep., 1988, and relating to the regulation of anxiety, arousal, neuroleptic agents, and opioid -induced analgesia, see Lotti, supra, Crawley, supra, Singh, L., et al, Proc. Natl. Acad. Sci. U.S.A., 88, 1130 (1991).
On the other hand, CCK agonist activity has been linked to inhibition of food intake in animals and thus weight loss, see Della-Fera, et al, supra, K. E. Asin, et al, Intl. Conference on Obesity, abstract pp.40 (1990). It has been suggested that CCK acts in the periphery through vagal fibers and not directly on the brain to produce satiety, see Smith, G. P. and Cushin, B. J., Neuroscience Abstr., 4, 180 (1978), Smith, G. P., Jerome, C., Cushin, B. J., Eterno, R., and Simansky, K. J., Science, 212, 687-689, (1981). Compounds having CCK agonist activity have been reported to include peptide analogues, see U.S. Pat. No. 4,490,364, PCT WO 91/19733, published 26 Dec. 1991, K. Shi
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Aquino Christopher Joseph
Dezube Milana
Sherrill Ronald George
Sugg Elizabeth Ellen
Szewczyk Jerzy Ryszard
Brink Robert H.
Glaxo Wellcome Inc.
Makujina Shah R.
Ngo Tamthom T.
Shah Mukund J.
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