Benzodiazonine derivatives binding to cholecystokinin or gastrin

Details Benzodiazonine derivatives binding to cholecystokinin or gastrin Benzodiazonine derivatives binding to cholecystokinin or gastrin

1998-10-26

2000-05-02

Raymond, Richard L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

540460, 540461, A61K 31395, C07D24506, C07D25504

Patent

active

060573112

DESCRIPTION:

BRIEF SUMMARY
This invention relates to benzodiazonine derivatives, and more particularly to benzodiazonine derivatives which bind to cholecystokinin and/or gastrin receptors. The invention also relates to methods for preparing such benzodiazonine derivatives.
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, N. Y., 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.
Members of this family of hormones 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 of the gastrointestinal tract and so an antagonist may be expected to be useful in the treatment of cancers, particularly in the stomach.
Possible therapeutic uses for gastrin and 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 gastrin/cholecystokinin receptors in the brain (so-called CCK.sub.B receptors) have been claimed to possess anxiolytic activity.
U.S. Pat. No. 5,206,234 discloses certain benzolactam analogs which are said to be antagonists of gastrin and CCK.
According to the present invention, there are provided compounds of the formula ##STR1## wherein one of U and V is --CHR.sup.2 --, and the other of U and V is selected from --N(COR.sup.4)--, --CH(COR.sup.4)--, --N(SO.sub.2 R.sup.4)-- and --CH(SO.sub.2 R.sup.4)--, in which hydrocarbyl), --CONR.sup.6 R.sup.7 (wherein R.sup.6 is H or methyl and R.sup.7 is aryl, substituted aryl, or a group of the formula --(C.sub.1 to C.sub.4)alkylene-W, in which W is amidino, hydroxy, acyloxy, sulphamoyl, hydroxysulphonyl, carboxy, esterified carboxy, amidated carboxy, tetrazolyl, hydroxamyl, R.sup.14 --SO.sub.2 --NH--, R.sup.14 --SO.sub.2 --NH--CO--, R.sup.14 --SO.sub.2 --, R.sup.14 --SO--, R.sup.14 --CO--, R.sup.14 --CO--NH--, R.sup.14 --CO--NH--SO--, R.sup.14 --CO--NH--SO.sub.2 --, or R.sup.15 --NH--SO.sub.2 -- wherein R.sup.14 is H (except when R.sup.14 is attached to a sulphur atom), C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 haloalkyl, aryl or substituted aryl, and R.sup.15 is H, aryl, --OH or --CN; or R.sup.6 and R.sup.7 together form a carboxy-substituted propylene, butylene or pentylene group) or --COR.sup.7 (wherein R.sup.7 is as defined above); and carbo

REFERENCES:
patent: 5206234 (1993-04-01), Bock et al.
Kikugawa et al. (J. Chem. Soc., Chem. Commun. (1991), (19), 1354-5), 1991.

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