Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-12-20
1999-08-17
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514212, 514423, 514616, 564153, 548540, 546226, 540607, C07C23722, A61K 31165, C07D21382, C07D30768
Patent
active
059394374
DESCRIPTION:
BRIEF SUMMARY
This invention relates to compounds which bind to cholecystokinin and/or gastrin receptors. The invention also relates to methods for preparing such compounds.
Gastrin and the CCK's are structurally-related neuropeptides which exist in gastrointestinal tissue and in the CNS (see Mutt V., Gastrointestinal Hormones, Glass G. B. J., ed., Raven Press, New York, p 169 and Nisson G., ibid, p. 127).
Gastrin is one of the three primary stimulants of gastric acid secretion. Several forms of gastrin are found including 34-, 17-, and 14-amino acid species with the minimum active fragment being the C-terminal tetrapeptide (TrpMetAspPhe-NH.sub.2) which is reported in the literature to have full pharmacological activity (see Tracey H. J. and Gregory R. A., Nature (London), 1964, 204, 935). Much effort has been devoted to the synthesis of analogues of this tetrapeptide (and the N-protected derivative Boc-TrpMetAspPhe-NH.sub.2) in an attempt to elucidate the relationship between structure and activity.
Natural cholecystokinin is a 33 amino acid peptide (CCK-33), the C-terminal 5 amino acids of which are identical to those of gastrin. Also found naturally is the C-terminal octapeptide (CCK-8) of CCK-33.
The cholecystokinins are reported to be important in the regulation of appetite. They stimulate intestinal motility, gall bladder contraction, pancreatic enzyme secretion, and are known to have a trophic action on the pancreas. They also inhibit gastric emptying and have various effects in the CNS.
Compounds which bind to cholecystokinin and/or gastrin receptors are important because of their potential pharmaceutical use as antagonists of the natural peptides.
A number of gastrin antagonists have been proposed for various therapeutic applications, including the prevention of gastrin-related disorders, gastrointestinal ulcers, Zollinger-Ellison syndrome, antral G Cell hyperplasia and other conditions in which lowered gastrin activity is desirable. The hormone has also been shown to have a trophic action on cells and so an antagonist may be expected to be useful in the treatment of cancers, particularly in the stomach and the colon.
Possible therapeutic uses for cholecystokinin antagonists include the control of appetite disorders such as anorexia nervosa, and the treatment of pancreatic inflammation, biliary tract disease and various psychiatric disorders. Other possible uses are in the potentiation of opiate (e.g. morphine) analgesia, and in the treatment of cancers, especially of the pancreas. Moreover, ligands for cholecystokinin receptors in the brain (so-called CCK.sub.8 receptors) have been claimed to possess anxiolytic activity.
According to the present invention, there are provided compounds of the formula ##STR2## wherein Ar is a monocyclic aromatic group, amino, nitro, cyano, sulphamoyl, sulphonyl, trifluoromethyl, C.sub.1 to C.sub.3 alkyl, C.sub.1 to C.sub.3 alkylamino, C.sub.1 to C.sub.3 dialkylamino, phenyl, substituted phenyl, C.sub.1 to C.sub.3 alkoxy, hydroxy, esterified hydroxy, C.sub.1 to C.sub.3 hydroxyalkyl, C.sub.1 to C.sub.3 alkylcarboxyamino, carboxy, esterified carboxy and amidated carboxy exclusively halo, C.sub.1 to C.sub.3 alkylene link to an ortho carbon atom in the aromatic ring, hydrogen atoms of the hydrocarbyl group may be replaced by a halogen atom, and up to two of the carbon atoms may be replaced by a nitrogen, oxygen or sulphur atom, provided that R.sup.3 does not contain a --O--O-- group, cycloalkyl, and ##STR3## (wherein R.sup.6 is H or C.sub.1 to C.sub.3 alkyl, X is --CO.sub.2 H, esterified carboxy, amidated carboxy, tetrazolyl, hydroxy, cyano, amidino, --CH.sub.2 OH, --SO.sub.2 NHCOR.sup.7, --SONHCOR.sup.7, --COR.sup.7, --NHSO.sub.2 R.sup.7, --CONHSO.sub.2 R.sup.7, --NHCOR.sup.7 or --SO.sub.2 NHR.sup.8, in which R.sup.7 is alkyl (eg C.sub.1 to C.sub.6 alkyl), haloalkyl (eg C.sub.1 to C.sub.6 haloalkyl), aryl or substituted aryl, and R.sup.8 is --OH, --CN, or a group selected from those recited above for R.sup.7, Y is H or a group selected from those recited above for X, and
Included wi
REFERENCES:
Endres, W. (Arch. Pharm. (Weinheim), 308 (8), 571-579, 1972.
Nilsson, "Gastrin: Isolation, Characterization, and Functions", Gastrointestinal Hormones, (1980).
Mutt, "Cholecystokinin: Isolation, Structure, and Functions", Gastrointestinal Hormones, (1980).
Stella et al., "Prodrugs: Do They Have Advantages in Clinical Practice", Drugs, vol. 29, (1985), pp. 455-473.
Gross, "The Peptides: Analysis, Synthesis, Biology", Major Methods of Peptide Bond Formation, vol. 1, (1979).
Rich et al., "The Carbodiimide Method", The Peptides, vol. 1, (1979).
Buck Ildiko Maria
Dunstone David John
Kalindjian Sarkis Barret
Steel Katherine Isobel Mary
James Black Foundation Limited
Kifle Bruck
Shah Mukund J.
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