Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1994-07-07
1998-12-08
Richter, Johann
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
546 16, 546 19, 560 16, 560 24, 560 38, 562427, C07D22332, C07D491113, C07D31710
Patent
active
058471251
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB93/00028 filed Jan. 8, 1995.
This invention relates to amino acid derivatives, and more particularly to amino acid derivatives which possess anticholecystokinin activity. The invention also relates to methods for preparing such cholecystokinin antagonists and to compounds which are useful as intermediates in such methods.
Cholecystokinins are peptides which have been found both in gastrointestinal tissue and in the central nervous system. Natural cholecystokinin is a 33 amino acid peptide (CCK-33), the C-terminal 5 amino acids of which are identical to those of gastrin and caerulein. Also found naturally is the C-terminal octapeptide (CCK-8) of CCK-33.
The cholecystokinins are believed to be important in the regulation of appetite. They stimulate intestinal motility, gall bladder contraction and pancreatic enzyme secretion, and they also inhibit gastric emptying.
A classification scheme for cholecystokinin receptors has recently been proposed in which the receptors coupled to contraction of the gall bladder are termed CCK-A, while those found in the brain are termed CCK-B.
A number of cholecystokinin-receptor antagonists have been reported in the literature. Possible therapeutic uses for CCK-A antagonists include the control of appetite disorders such as anorexia nervosa, and the treatment of pancreatic inflammation, pancreatic cancer, biliary tract disease, Zollinger-Ellison syndrome and various psychiatric disorders. Other possible uses are in the potentiation of opiate (eg. morphine) analgesia, and in the treatment of cancers. Moreover, ligands for CCK-B receptors have been claimed to possess anxiolytic activity.
EP-A-0433064 discloses a class of naphthylsulphonylalkanoic acid compounds which are said to be cholecystokinin antagonists. The compounds are of the general formula ##STR2## wherein R.sub.3 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a benzyl group; 1 and m are the same or different and are an integer of from 1 to 4; n is 1 or 2; and the definitions of R.sub.1 and R.sub.2 include groups such as C.sub.1 to C.sub.6 alkyl, C.sub.3 to C.sub.6 cycloalkyl and C.sub.1 to C.sub.6 alkoxy groups.
The present invention is based on the finding that the moiety ##STR3## which is an essential element of the compounds disclosed in EP-A-0433064, is not in fact essential for activity. We have found that it can be replaced by a 2-naphthylsulphonamido group, or by certain other arylsulphonamido groups. Also, we have found that certain 2-naphthylsulphonamido compounds and analogues possess antagonist activity at the gastrin receptor, in addition to (or instead of) activity at the CCK receptor.
A number of such 2-naphthylsulphonamido compounds and analogues are disclosed in our co-pending International Patent Application No. PCT/GB91/01111. These compounds are of the formula ##STR4## in which Ar is 2-naphthyl, 2-naphthylmethyl, 2-(1,2,3,4-tetrahydronaphthyl), phenethyl, styryl, indanyl (or a substituted derivative of any of the foregoing), or 3, 4-dichlorophenyl; R.sub.1 is H. C.sub.1 to C.sub.6 alkyl, C.sub.1 to C.sub.6 alkenyl, cycloalkyl, --(CH.sub.2).sub.q aryl, --(CH.sub.2).sub.q (substituted aryl) or --(CH.sub.2).sub.q heterocyclic, wherein q is 0 to 4; R.sub.2 is H, methyl or ethyl; R.sub.3 is --(CH.sub.2).sub.n --(wherein n is from 0 to 3); X is --C(O)--; T is carboxyl, --CONR.sub.4 R.sub.5 (wherein R.sub.4 and R.sub.5 are independently H or C.sub.1 to C.sub.4 alkyl) or tetrazolyl; and Y is ##STR5## wherein R is H. C.sub.1 to C.sub.5 alkyl, --(CH.sub.2).sub.r -aryl or --(CH.sub.2).sub.r -substituted aryl, r being from 0 to 4, C.sub.4 alkylthio, carboxy, C.sub.1 to C.sub.4 carboalkoxy, nitro, trihalomethyl, hydroxy, --NR'R" (R' and R" being independently H or C.sub.1 to C.sub.4 alkyl), C.sub.1 to C.sub.4 alkylaryl, C.sub.1 to C.sub.4 alkyl(substituted aryl) or halo, are inactive.
According to the present invention, there is provided a method of counteracting a physiological effect of cholecystokinin or gastrin in a patient, comprising administer
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James Black Foundation Limited
Richter Johann
Solola Taofiq A.
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