2-piperazinopyrimidine salt and pharmaceutical compositions cont

Details 2-piperazinopyrimidine salt and pharmaceutical compositions cont 2-piperazinopyrimidine salt and pharmaceutical compositions cont

1985-02-14

1986-07-22

Hollrah, Glennon H.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

544295, A61K 31495, C07D40304

Patent

active

046020152

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to a novel salt of 2-piperazinopyrimidine having a dopaminergic psychotropic action.
More particularly, the present invention concerns the 2-(1-piperazinyl)pyrimidine 2-naphtalenesulfonate, a process for its preparation and pharmaceutical compositions containing it as active ingredient.
The 2-(1-piperazinyl)pyrimidine, in the form of free base, is a compound well known in literature; it is used as a synthesis intermediate.
It has been tested among a number of compounds none of which has shown analgesic or antifilarial activity (H. W. Stewart et al., J. Org. Chem. 1953, 18, 1478-1483).
This compound has been isolated as an active metabolite of the anxiolytic agent buspirone (J. Chromatography 1982, 252, 310-314).
It has now been found that the 2-(1-piperazinyl)-pyrimidine 2-naphtalenesulfonate possesses a very good psychotropic activity with dopaminergic mechanism of action, particularly antipsychotic, antidepressive and tranquillizing-sedative activity.
It has also surprisingly been found that the salt of 2- (1-piperazinyl)pyrimidine with 2-naphtalenesulfonic acid is much more active, in the absolute sense, than both the corresponding free base and the hydrochloride thereof and that its very high activity is long-lasting and increases with time.
Thus, it is an object of the present invention, to provide the salt of 2- (1-piperazinyl)pyrimidine with 2-naphtalenesulfonic acid of formula ##STR1## hereinafter designated "2- (1-piperazinyl)pyrimidine napsilate".
The compound of the present invention is prepared according to another aspect of the present invention by a process of salification, characterised in that 2- (1-piperazinyl)-pyrimidine is treated with an equimolecular amount of 2-naphtalenesulfonic acid in an organic or aqueous organic solvent.
An alcohol, such as isopropanol, acetone or the like is preferably used as organic solvent.
The salt thus obtained is isolated according to conventional procedures by simple filtration and, if necessary, by crystallisation.
The salification may be carried out on the crude 2- (1-piperazinyl)pyrimidine as obtained from the reaction of 2-chloropyrimidine and piperazine according to known procedures.
According to a preferred mode operandi, the starting 2-(1-piperazinyl)pyrimidine is used in the form of hydrochloride and the 2-naphtalenesulfonic acid is used in the form of an alkaline salt, preferably sodium salt. Salification occurs at temperature of from 50.degree. to 70.degree. C. in an aqueous organic solvent, such as acetone, containing from 5 to 20% of water.
The antidepressive activity of the compound of the invention has been evaluated in the test of antagonism of prochlorperazine-induced catalepsy (K. Biziere et al., Arzneimittel Forschung, 1982, 32 (II), 824-831). The 2-(1-piperazinyl)pyrimidine napsilate and the corresponding free base, as reference compound, were administered orally to groups of 10 Wistar male rats weighing 220-240 g; at the same time control animals were treated with saline. One hour later, prochlorperazine was administered subcutaneously at a dose of 10 mg/kg. Five hours after this administration, the number of cataleptic animals was assessed by the cork test. According to this test the animals were placed with their forepaws on a stand formed by three superposed corks (11 cm total height) and forced to maintain this position for 20 seconds at least. The performances of each group of animals were compared with those of the controls having received the vehicle and prochlorperazine only.
Table I hereinbelow shows the ED50 of the tested compounds.


TABLE I ______________________________________ Prochlorperazine Catal. antag. Compound ED.sub.50 mcmol/kg ______________________________________ 2-(1-piperazinyl)- 5.7 pyrimidine napsilate (5.0-6.4) 2-(1-piperazinyl)- 24 pyrimidine base (12-45) ______________________________________
It results from this table that the 2-(1-piperazinyl)-pyrimidine napsilate of the present invention is about 4 times more active orally than the co

REFERENCES:
patent: 2472583 (1949-06-01), Gzemski
patent: 2606906 (1952-04-01), Hultquist et al.
patent: 2748125 (1956-05-01), Hofmann
patent: 2748129 (1956-05-01), Hofmann

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