Gastrin and CCK antagonists

Details Gastrin and CCK antagonists Gastrin and CCK antagonists

1996-12-19

1999-06-15

Stockton, Laura L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

548250, 5483044, 548510, 514394, 514415, A61K 3140, A61K 31415, A61K 3141, C07D23506

Patent

active

059122609

DESCRIPTION:

BRIEF SUMMARY
This invention relates to gastrin and CCK antagonists. The invention also relates to methods for preparing such antagonists and to pharmaceutical compositions comprising such antagonists.
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, 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 gastrin and/or CCK 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.B receptors) have been claimed to possess anxiolytic activity.
The present invention provides compounds of the formula ##STR2## wherein L is .dbd.N-- or .dbd.CH--, or 1-adamantyl) and the other is ##STR3## in which R.sup.1 is H or methyl, T.sup.1 and T.sup.2 are independently H or Z(CH.sub.2).sub.m --, wherein m is from 0 to 3 and Z is a carboxy group, a tetrazolyl group, CF.sub.3 CONHSO.sub.2 --, PhCONHSO.sub.2 --, isopropyl-OC(O)NHSO.sub.2 -- or a group selected from ##STR4## (provided that T.sup.1 and T.sup.2 are not both H and that T.sup.1 and T.sup.2 are not both carboxy when L is .dbd.CH--); and n is from 0 to 5
Such compounds have been found to act as gastrin and/or CCK antagonists in in vitro tests. Most importantly, they have been found to be active when administered orally.
The compounds of the invention exist in enantiomeric and tautomeric forms. It will be understood that the invention comprehends the different enantiomers and tautomers in isolation from each other, and also as mixtures.
The invention also comprehends derivative compounds ("pro-drugs") which are degraded in vivo to yield the species of formula (I). Pro-drugs are usually (but not always) of lower potency at the target receptor than the species to which they are degraded. Pro-drugs are particularly useful when the desired species has chemical or physical properties which make its administration difficult or inefficient. For example, the desired species may be only poorl

REFERENCES:
patent: 5387600 (1995-02-01), Aikawa et al.
Tracey H.J. and Gregory R.A., Nature (London), 1964, vol. 204, pp. 935-938.

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