Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-03-18
1998-08-18
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514396, 514415, 514255, 514252, 514315, 514259, 5142222, 514311, 514314, 514307, 514256, 514278, 5142288, 5142312, 548181, 548214, 548253, 5483047, 5483061, 5483064, 5483071, 5483074, 5483351, 5483711, 548416, 548469, 548470, 548482, 546122, 546146, 546159, 5462734, 544 90, 544139, 544235, 544405, 544238, 544370, 544373, 544106, A61K 3140, A61K 31415, C07D41554, C07D45302
Patent
active
057959072
DESCRIPTION:
BRIEF SUMMARY
This application is a National Stage filing of PCT/GB94/01741, filed Aug. 9, 1994.
This invention relates to gastrin and CCK receptor ligands. The invention also relates to methods for preparing such ligands and to compounds which are useful as intermediates in such methods.
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.
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.B receptors) have been claimed to possess anxiolytic activity.
According to the present invention, there are provided compounds of the formula ##STR2## wherein A represents a bicyclic group (meaning a group having two fused rings, in which the atoms which are common to the two rings are joined by a single or multiple bond), W and X replacing hydrogen on adjacent atoms (most usually adjacent carbon atoms), or A is a group of the formula ##STR3## in which W and X replace hydrogen on adjacent carbon atoms, m is from 0 to 6, provided that m is not more than 2 unless R.sup.1 is exclusively halo, hydroxysulphonyl, carboxy, esterified carboxy, amidated carboxy, tetrazolyl, C.sub.1 to C.sub.8 alkyl (particularly C.sub.1 to C.sub.6 alkyl), aryl, substituted aryl, C.sub.1 to C.sub.6 hydroxyalkyl, C.sub.1 to C.sub.6 haloalkyl, C.sub.1 to C.sub.6 alkoxy, C.sub.1 to C.sub.6 alkylcarboxyamino, HON.dbd.C--, R.sup.27 --SO.sub.2 --NH--, R.sup.27 --SO.sub.2 --NH--CO--, R.sup.27 --CO--, R.sup.27 --CO--NH--, R.sup.27 --CO--NH--SO.sub.2 --, R.sup.27 --CO--NH--SO-- or R.sup.28 --NH--SO.sub.2 --, wherein R.sup.27 is H (except when R.sup.27 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.28 is H, C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 haloalkyl, aryl, substituted aryl, --OH or --CN (each
Buck Ildiko Maria
Davies Jonathan Michael Richard
Dunstone David John
Hudson Martin Lyn
Kalindjian Sarkis Barret
Ford John M.
James Black Foundation Limited
Sipada Pavanaram K.
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