Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-06-10
1996-03-19
Gupta, Yogendra N.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 16, A61K 3146, C07D22120
Patent
active
055004300
DESCRIPTION:
BRIEF SUMMARY
The subject of the present invention is compounds with activities antagonistic towards gastrin or other peptides related thereto, which can be represented by the general formula indicated below: ##STR2## in which r is from 1 to 3, and R.sub.1 is selected from mono-, di-substituted phenyl groups, in which the substituents are selected from chlorine, linear and branched C1-C4 alkyl groups, cyano, nitro, methoxy, and trifluoromethyl groups, the 2(beta)-naphthyl group, and heterocyclic, monocyclic and bicyclic groups containing 1 heteroatom such as nitrogen, oxygen or sulphur and selected from furyl, thiophenyl, pyrrolyl, pyridinyl, and pyridinyl-N-oxide groups unsubstituted or mono- or disubstituted with methyl and chlorine, indolyl (2- or 3-yl), thionaphthyl (2- or 3-yl), benzofuranyl (2- or 3-yl), quinolinyl (2- or 3-yl), or isoquinolinyl (3-yl) groups and in which R.sub.2 is selected independently from: ##STR3## in which m and n are selected independently and may assume values between 1 and 3 provided that the ring formed consists of at least 5 atoms, TCH.sub.2 and CH.sub.2 T in which T is O, S, NH--C(O) or C(O)--NH, and in which R.sub.3 is a group selected independently from H, CH.sub.3, C.sub.2 H.sub.5, OCH.sub.3, OC.sub.2 H.sub.5, CH.sub.2 OH and OH and z may assume values of from 0 to 3, provided that the ring formed consists of at least 3 atoms. ##STR4## in which m, n, x, y and R.sub.3 have the meanings given in point 1 above and Q maybe selected independently from H and CH.sub.3. ##STR5## in which m and n are selected independently and may assume values of between 1 and 3 and x, y and R.sub.3 have the meanings given in point 1 above. ##STR6## in which m and n are selected independently and may assume values of between 1 and 3 and x, y R.sub.3 and Q have the meanings given in point 1 above. ##STR7## w is between 0 and 2, L is H, a methyl or methoxyl group and Ad is an adamantyl (1- or 2-yl) group.
The stereochemistry of the compounds claimed at the chiral centre marked with an asterisk in the formula (I) may be racemic (R, S) or, preferably, rectus (R); r is preferably 2, R.sub.1 is preferably selected from the group consisting of 3-chloro-phenyl and 3,5-dichlorophenyl, and R.sub.2 is preferably Selected from the group consisting of 8-azaspiro[4.5]decan-8-yl and 1-adamantyl-2-aminoethane.
The compounds of the present invention show potent antagonistic activity towards gastrin ("little gastrin" or G-17) and towards pentagastrin, which is its biologically active terminal peptide sequence.
Gastrin is a polypeptide hormone secreted by the cells of the antral and duodenal mucosae, its secretion being induced, in particular, by a nervous mechanism by means of vagal excitation.
Once secreted, the gastrin reaches the parietal cells, which are situated mainly in the fundic mucosa, via the bloodstream and activates the receptors of the cell membranes by binding thereto. This activation starts the process of the formation of HCl and its secretion into the gastric cavity.
Hyperactivity of this system results in the hypersecretion of plastric acid, which may have consequences which are harmful to the organism but can be eliminated with the use of specific antagonists.
The compounds of the invention show a high level of activity against the secretion of acid in vivo in the various animal species tested, blocking the secretory stimulus induced by pentagastrin in a dose-dependent manner. The activity is specific, since it does not block secretions induced by carbachol or histamine.
As already stated, the compounds can therefore be used, to advantage, in the treatment and prevention of various diseases in man, for example, ulcers or gastro-duodenitis resulting from excessive gastric secretion induced by a hypergastrinaemic condition, in Zollinger-Ellison syndrome, or in the treatment of some kinds of tumours which are activated by hypergastrinaemia, in which it is advantageous to block gastrin's activity in stimulating the secretion of acid.
On the basis of the considerable activity they show in vitro as inhibitors of
REFERENCES:
patent: 4791215 (1988-12-01), Rovati et al.
patent: 5064853 (1991-11-01), Gasc et al.
European Journal of Medicinal Chemistry. Chimica Therapeutica, vol. 21, No. 1, Jan. 1986, France "new glutamic and aspartic derivatives with potent CCK-antagonistic activity" by F. Makovec et al. pp. 9-20.
Makovec Francesco
Rovati Lucio C.
Rovati Luigi A.
Gupta Yogendra N.
Rotta Research Laboratorium S.p.A.
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