Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1993-01-12
1995-03-21
Dees, Jose G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
514381, 514510, 514533, 514539, 514562, 546176, 548252, 549253, 560 10, 560 13, 562428, 562430, C07C31137
Patent
active
053997484
DESCRIPTION:
BRIEF SUMMARY
This invention relates to amino acid derivatives, and more particularly to amino acid derivatives which possess anti-cholecystokinin 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, pancreatic enzyme secretion, and are known to have a trophic action. They also inhibit gastric emptying and have various effects in the CNS.
A classification scheme for cholecystokinin receptors has recently been proposed in which the receptors coupled to contraction of the gall bladder and pancreatic secretion are termed CCK-A, while those found in the cerebral cortex 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, biliary tract disease, Zollinger-Ellison syndrome and various psychiatric disorders. Other possible uses are in the potentiation of opiate (e.g. morphine) analgesia, and in the treatment of cancers. WO 89/02431 discloses a class of glutamic acid and aspartic acid derivatives which are said to be cholecystokinin antagonists. The compounds are of the general formula ##STR1## in which Ar is a heterocyclic group, and B may be a bond. Included in the definitions of Z, R.sub.6, n, D, R.sub.1 and R.sub.2 are that Z is --S(O).sub.2 --, R.sub.6 is H, n is 1 to 3, D is --CO.sub.2 H, R.sub.1 is H and R.sub.2 is phenethyl or substituted phenethyl.
The present invention is based on the surprising finding that the group Ar in the above formula may be 2-naphthyl or certain analogues of 2-naphthyl, although the corresponding 1-naphthyl derivatives are inactive. According to the present invention, therefore, there are provided compounds of the formula ##STR2## wherein Ar is ##STR3## R.sup.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, independently H or C.sub.1 to C.sub.4 alkyl) or tetrazolyl, ##STR4## wherein X is C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkoxy, C.sub.1 to C.sub.4 thioalkoxy, carboxy, C.sub.1 to C.sub.4 carboalkoxy, nitro, trihalomethyl, hydroxy, --NR.sup.7 R.sup.8 (wherein R.sup.7 and R.sup.8 are 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, wherein r is 0 to 4 and R.sup.4 is aryl or substituted aryl; and pharmaceutically acceptable salts thereof.
Pharmaceutically acceptable salts of the acidic compounds of the invention include salts with alkali metals and alkaline earth metals, such as sodium, potassium, calcium and magnesium, and salts with organic bases. Suitable organic bases include amines such as N-methyl-D-glucamine.
Pharmaceutically acceptable salts of the basic compounds of the invention include salts derived from organic or inorganic acids. Suitable acids include hydrochloric acid, phosphoric acid, oxalic acid, maleic acid, succinic acid and citric acid.
When Ar is a substituted group (other than 3,4-dichlorophenyl), substituents will generally be up to three in number, and may be at any position in the aromatic ring system. Preferably, Ar is unsubstituted 2-naphthyl or mono- or di-substituted 2-naphthyl, but perhalo-substituted compounds are also within the scope of the invention. Suitable substituents other than halo include C.sub.1 to C.sub.4 alkyl, C.sub.1 to C.sub.4 alkox
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Broughton Howard B.
Hull Robert A. D.
Kalindjian Sarkis B.
Low Caroline M. R.
McDonald Iain M.
Dees Jos,e G.
Frazier B.
James Black Foundation Limited
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