Pteridines suitable for the preparation of pharmaceutical compositions with antiamnesic activity

Abstract: Pteridines of general formula (I): in which Y and Z, which can be identical or different, are hydrogen, OH or NH₂, and X₁ and X₂, which can be identical or different, are hydrogen, OH, C₁-C₄ alkyl, phenyl, hydroxymethyl or carboxyl, for the preparation of pharmaceutical compositions for treating cognitive pathologies characterised by memory and vigilance disturbances, such as senile dementia of Alzheimer type, multiinfarctual dementia, metabolic encephalopathies, Korsakoff's syndrome, and the consequences of the abuse of certain therapies such as anxiolytic and neuroleptic.

Description: This invention relates to use of pteridines for the preparation of composition with antiamnesic activity. More particularly, the invention relates to the use of pteridines of the following general formula: in which Y and Z, which can be identical or different, are hydrogen, OH or NH₂, and X₁ and X₂, which can be identical or different, are hydrogen, OH, C₁-C₄ alkyl, phenyl, hydroxymethyl or carboxy, for the preparation of compositions with antiamnesic activity. The pteridines are a class of substances present in numerous living species ranging from the invertebrates and birds to higher mammals including man. They can also be prepared synthetically. Their biological significance and their participation in many enzymatic reactions have not yet been completely clarified, even though they have been the subject of numerous studies [H. Rembold and W.L. Gyure, Angew. Chem. Internat. Edit. vol II (1972), No. 12, pp 1061, 1072]. We have now surprisingly found that natural or synthetic pteridines of general formula (I) demonstrate activity of positive nootropic type in a test traditionally used in selecting molecules of antiamnesic activity, namely the test of activity towards amnesia induced by electroshock treatment. Said test, as described by Butler et al. (J. Medicinal Chem. 27, 684, 1984), enables the activity of products able to antagonise retrograde amnesia induced by electroconvulsive shock in the mouse to the evaluated. It consists of the following operations: a) conditioning the animal to avoid entering, in a single attempt, a dark chamber in which it would receive an electric shock its paws (passive avoidance); b) induce retrograde amnesia by electroshock treatment; c) administer the products under examination to the animal; d) evaluate the persistance or non-persistance of the conditioning as an index of the absence or, respectively, presence of the amnesia. The percentage of animals showing retention of the condition after introduction of the amnesia is an index of the antiamnesic activity of the product under examination. Table 1 shows the results of the use of pteridines of formula (I) in the aforesaid test, showing the percentages of inversion of the amnesia at various doses compared with the control group not subjected to electroshock treatment. The dose-effect curve is bell-shaped, ie increasing the dose first causes an increase in the effect and then a decrease therein. This pattern is typical of products which influence the cognitive functions. The greatest effect was observed in the tests at an orally administered dose of 2.5 mg/kg with the products BR 474 and BR 467. In these tests the amnesic action of the electroshock treatment is practically nullified, as demonstrated by the fact that the percentages of animals retaining the conditioning are entirely similar to the control group percentages not subjected to electroshock treatment. The products were administered orally 90 minutes before evaluating the retention of the conditioning. Those animals which did not enter the conditioning chamber within 60 seconds were considered amnesia-free. The pharmacological results obtained in the test demonstrate the effectiveness of the pteridines according to the invention in reducing experimentally induced amnesia and thus the importance of their use in the treatment of cognitive pathologies characterised by memory and vigilance disturbances which are encountered in old age, in some pathologies such as senile dementia of Alzheimer type, multiinfarctual dementia, metabolic encephalopathies and Korsakoff's syndrome, and as a consequence of the abuse of certain therapies (anxiolytic, neuroleptic). Said pteridines can be used for preparing both injectable forms and oral formulations such as tablets, pills, delayed release capsules, gastroresistant tablets, sachets, syrups, extemporaneous syrups, delayed release syrups and other forms normally used in pharmaceutics. The pteridines of formula (I) are known products which can be prepared by various methods, such as the method described by C.B. Storm et al. in J. Org. Chem., 36, 3925 (1971). Advantageously, pteridines of formula (I) are prepared by the process of the present invention, which is based on condensing suitable amino derivatives of pyrimidine with suitable dicarbonyl compounds, in an aqueous medium in the presence of sodium sulphite, at controlled pH. Some examples are also given of the preparation of pharmaceutical composition containing said pteridines for antiamnesic use. EXAMPLE 1 Preparation of tablets a) A 100 mg tablet contains: 2-amino-4-hydroxy-6,7-dimethyl pteridine 100 mg crosslinked carboxymethyl cellulose 50 mg magnesium stearate 10 mg microcrystalline cellulose to make up to 400 mg b) A 100 mg tablet contains: 2,4-diamino-6,7-dimethyl pteridine 100 mg corn starch 80 mg polyvinylpyrrolidone 20 mg magnesium stearate 10 mg c) A 100 mg tablet contains: 2,4-dihydroxy-6,7-dimethyl pteridine 100 mg sodium chloride 50 mg polyvinylpyrrolidone 20 mg corn starch to make up to 400 mg d) A 100 mg tablet contains: 2-amino-4-hydroxy pteridine 100 mg crosslinked carboxymethyl cellulose 50 mg magnesium stearate 10 mg microcrystalline cellulose to make up to 400 mg EXAMPLE 2 Preparation of capsules a) A 100 mg capsule contains: 2-amino-4-hydroxy-6,7-dimethyl pteridine 100mg mannitol 100 mg lactose 100 mg magnesium stearate 10 g b) A 100 mg capsule contains: 2,4-diamino-4-hydroxy-6,7-dimethyl pteridine 100 mg mannitol 100 mg lactose 100 mg magnesium stearate 10 g EXAMPLE 3 Preparation of gastroresistant tablets a) A 100 mg tablet contains: 2-amino-4-hydroxy-6,7-dimethyl pteridine 100 mg crosslinked carboxymethyl cellulose 70 mg microcrystalline cellulose to make up to 400 mg cellulose acetophthalate 20 mg diethylphthalate 6.4 mg silicone resin 3.6 mg b) A 100 mg tablet contains: 2,4-diamino-6,7-diethyl pteridine 100 mg crosslinked polyvinylpyrrolidone 100 mg sodium chloride 50 mg microcrystalline cellulose to make up to 400 mg cellulose acetophthalate 20 mg diethylphthalate 20 mg silicone resin 3.6 mg c) A 100 mg tablet contains: 2-amino-6,7-dimethyl pteridine 100 mg sodium bicarbonate 100 mg citric acid 50 mg cellulose acetophthalate 20 mg diethylphthalate 6.4 mg silicone resin 3.6 mg

Claims: The use of pteridines of general formula (I): in which Y and Z, which can be identical or different, are hydrogen, OH or NH₂, and X₁ and X₂, which can be identical or different, are hydrogen, OH, C₁-C₄ alkyl, phenyl, hydroxymethyl or carboxyl, for the preparation of pharmaceutical compositions for the treatment of cognitive pathologies characterised by memory and vigilance disturbances, such as senile dementia of Alzheimer type, multiinfarctual dementia, metabolic encephalopathies, Korsakoff's syndrome, and the consequences of the abuse of certain therapies such as anxiolytic and neuroleptic. The use as claimed in claim 2, wherein the pharmaceutical compositions are presented in injectable form. The use as claimed in claim 1, wherein the pharmaceutical compositions are presented in forms suitable for oral use such as tablets, pills, capsules, delayed release capsules, gastroresistant tablets, sachets, syrups, extemporaneous syrups and delayed release syrups.

Inventors: GENNARI FEDERICO, GENNARI, FEDERICO
Applicants: BIORESEARCH SPA, BIORESEARCH S.P.A.
Application year: 1988
Main classification: A61K31
IPC codes: C07D475, A61K31, A61P25