Ureidoacetamide derivatives, their preparation and the medicamen

Details Ureidoacetamide derivatives, their preparation and the medicamen Ureidoacetamide derivatives, their preparation and the medicamen

1995-03-10

1997-09-02

Conrad, Joseph

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing other than solely as a nitrogen in an...

562 41, A61K 3117, C07C30902

Patent

active

056632045

DESCRIPTION:

BRIEF SUMMARY
DESCRIPTION OF THE INVENTION

In Patent Applications WO 91/12264 and WO 91/13907, ureidoacetamide derivatives are described which are useful as cholecystokinin (CCK) and gastrin antagonists.
It has now been found that the compounds of formula: ##STR1## in which R represents a hydrogen atom or a methoxy radical, their salts, their racemates and their enantiomers unexpectedly have CCK antagonist properties which are much better than those of the ureidoacetamides of Patent Applications WO 91/12264 and WO 91/13907.
The subject of the present invention is thus the compounds of formula (I), their salts, their enantiomers, their preparation and the medicaments containing them.
The compounds of formula (I) can be prepared by reacting a derivative of formula: ##STR2## in which R represents a hydrogen atom or a methoxy radical, with an amine of formula: ##STR3## in the form of a salt.
This reaction is generally carried out in an inert solvent, such as benzene or toluene, at the boiling temperature of the reaction mixture. Tetraalkylammonium or trialkylphenylammonium salts, and preferably tetra-n-butylammonium salts, can be used as salts.
The derivatives of formula (II) can be obtained by application or adaptation of the methods described in the Patent Applications WO 91/12264 and WO 91/13907.
The enantiomers can be prepared from the chiral precursors of the compound of formula (III).
Preferably, the enantiomers are prepared from a tetraalkylammonium salt (Form B) of the amine of formula (III) or from the hydroquinine salt (Form A) of the amine of formula (III).
The compounds of formula (I) can be purified by the usual known methods, for example by crystallization, precipitation, chromatography or extraction.
The compounds of formula (I) and their enantiomers can be converted to metal salts or to addition salts with nitrogenous bases according to methods known per se. These salts can be obtained by reacting a metal base (alkali metal or alkaline-earth metal, for example), ammonia, an amine or a salt of an organic acid with a compound of formula (I) or its enantiomers, in a solvent.
As examples of pharmaceutically acceptable salts, there can be mentioned the salts with alkali metals (sodium, potassium, lithium) or with alkaline-earth metals (calcium, magnesium), the ammonium salt, or the salts of nitrogenous bases (ethanolamine, trimethylamine, methylamine, benzylamine, N-benzyl-.beta.-phenethylamine, choline, arginine, leucine, lysine, N-methylglucamine).
The compounds of formula (I) and their enantiomers have advantageous pharmacological properties. These compounds have a strong affinity for cholecystokinin (CCK) and gastrin receptors and are thus useful in the treatment and prevention of disorders linked to CCK and to gastrin in the nervous system and the gastrointestinal system.
In this way, these compounds can be used for the treatment of the prevention of psychoses, of anxious disorders, of panic attacks, of Parkinson's disease, of tardive dyskinesia, of irritable bowel syndrome, of acute pancreatitis, of ulcers, of disorders of intestinal motility, of certain tumours sensitive to CCK, as an appetite regulator, in weaning from chronic treatments and alcohol or medicinal abuse, and as a pupil constrictor.
These compounds also have a potentiating effect on the analgesic activity of narcotic and non-narcotic medicaments. Additionally, they can have their own analgesic effect.
Moreover, the compounds having a high affinity for CCK receptors modify memorising abilities. Consequently, these compounds can be effective in memory disorders.
Affinity of the compounds of formula (I) for CCK receptors was determined according to a technique inspired by that of A. Saito et al. (J. Neuro. Chem., 37, 483-490 (1981) in the cerebral cortex.
In this test, the IC.sub.50 of the compounds of formula (I) is less than 2 nM.
Moreover, it is known that the products which recognize the central receptors of CCK have a similar specificity for the receptors of gastrin in the gastrointestinal tract (Bock et al., J. Med. Chem., 32, 16-23 (198

REFERENCES:
patent: 5223529 (1993-06-01), Bourzat et al.
patent: 5382590 (1995-01-01), Bourzat et al.
patent: 5475106 (1995-12-01), Bourzat et al.

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