MXPA00001161A - 2-{3-[4-(2-T-BUTYL-6- TRIFLUOROMETHYLPYRIDIN-4-YL) PIPERAZIN-1-YL]PROPYLMERCAPTO}PYRIMIDIN-4-OL-FUMARATE - Google Patents

Abstract

The invention relates to the fumaric acid salt from 2-{3-[4-(2-T-butyl-6- trifluoromethylpyridin-4-yl) piperazin-1-yl]propylmercapto}pyrimidin-4-ol and to pharmaceutical agents containing said salt. The salt can be used for treating diseases which respond to dopamine-D3 ligands. It is very stable at a low pH and is therefore especially suitable for oral administration.

Description

FUMARATE OF 2-. { -3- [4- (2-T-BUTIL-6-TRIFLUOROMETILPIRIMIDLN-4-IL) P! PERAZIN-1-IL] PROPYLMERCAPT} PIRIMlDIN-4-OL The invention relates to the fumaric acid salt of 2-. { -3- [4- (2-t-Butyl-6-tpfluoromethylpyrimidin-4-yl) piperazin-1-yl] propylmercapto} pyrimidin-4-ol and a pharmaceutical drug containing this compound. This compound possesses valuable therapeutic properties and is particularly suitable for the treatment of diseases that respond to the action of dopamine-D3 ligands. WO 96/02519 describes the aforementioned compound in free base form of the formula: which is also useful for the treatment of diseases that respond to dopamine-D3 ligands. However, a salt of this compound has not been revealed. Surprisingly, it has now been found that the acid addition salt of this compound with fumaric acid has particular advantages. The object of the present invention is, therefore, the fumaric acid salt of 2-. { -3- [4- (2-t-Butyl-6-trifluoromethyl-pyrimidin-4-yl) piperazin-1-yl] propylmercapto} pyrimidin-4-ol, as well as a pharmaceutical drug containing this compound. Also subject of this invention are the tautomeric forms (pyridone structure) as well as the soivates and hydrates of the fumaric acid salt.

The fumaric acid salt possesses very good affinity and great selectivity towards the D3I receptor, that is, it is a selective dopamine D3 receptor ligand that acts regioselectively in the limbic system. It has a selectivity K, D2 / Kj D3 of 120 (see WO 96/02519). Hence, the compound is suitable for the treatment of diseases that respond to the action of dopamine ligands D3I, eg for the treatment of diseases of the central nervous system, especially schizophrenia, depression, neurosis and psychosis. In addition, it is useful for the treatment of insomnia, discomforts and as an antihistamine. Analysis of the solubility of the substances showed that the salts are substantially more soluble in water than the free bases. This is considered a substantial advantage in oral and especially parenteral administration. In addition, fumarate is more soluble in polar solvents, such as d-C6-alkanols than the free base. As a result of its modified solubility it is also easier to purify, thus avoiding the use of physiologically unacceptable solvents. The free base can be prepared according to the general method described in WO 96/02519, preferably according to method (ii). The fumarate can be obtained by converting the free base with fumaric acid in a suitable solvent such as d-C-alkanols, especially methanol, ethanol, n-propanol, isopropanol and n-butanol, a mixture of water and one of the alcohols mentioned or an ester such as acetic acid ethyl ester. In general, it will work at high temperature, so that the desired fumarate crystallizes on cooling and can be isolated in a simple manner. The fumaric acid is added, in general, in equimolar amounts or with a small excess of up to 10%. In this way, the fumarate produced is of great purity. It can be further purified by stirring or recrystallization with a suitable solvent, such as, for example, water, one of the aforementioned alkanols, ester or mixtures thereof. For the treatment of the aforementioned diseases, the compound of the invention is administered conventionally orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally). Oral administration is preferred. The dose depends on the age, condition and weight of the patient, as well as on the way of application. As a rule, the daily dose of active substance is between about 10 and 1000 mg per patient / day when the administration is oral and of approx. 1 to 500 mg patient / day when the administration is parenteral. The invention also relates to pharmaceutical medicaments containing the compound of the invention. In the usual galenic application forms, these pharmaceutical drugs can be used in solid or liquid form, eg in the form of tablets, coated tablets, capsules, powders, granules, dragees, suppositories, solutions or sprays. For this purpose, the active substances can be made with the usual auxiliary galenic means, such as tablet binders, fillers, preservatives, substances that facilitate the fractionation of the tablets, flow regulating means, plasticizers, impregnants, dispersion media J, emulsifiers, solvents, retarders, antioxidants and / or propellant gases (see H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, 20 1978). Normally, the application forms thus obtained contain the active substance in amounts of between 1 and 99% by weight. The following examples serve as an explanation of the invention without limiting the same.

Example 1 Preparation of fumaric acid salt from 2 - (- 3-f4- (2-t-butyl-6-trifluoromethyl-pyrimidin-4-ippiperazin-1-n-propylmercapto> pyrimidin-4-ol 2- t-butyl-4-hydroxy-6-trifluoromethyl-pyrimidine (1) The starting materials are known from the literature, 50 g (0.37 mol) of 2,2-dimethylpropanimidamide hydrochloride dissolved in 200 ml of ethanol were mixed. at room temperature with 66.6 g (0.37 mol) of sodium methylate (30% in methanol) and after another 30 minutes, with 52 g (0.28 mol) of ethyl ester of trifluoroacetoacetic acid. After stirring for 17 hours under reflux, the solvent was removed in vacuo, the residue was mixed with 100 ml of water, acidified to pH 4 and the crystallized solid was isolated by filtration, resulting in 62.2 g (98% of the theory) CgHuFaNzO (MW 220) PF 187-188 ° C 2-t-butyl-4-chloro-6-trifluoromethylpyrimidine (2) To a solution of 60 g (0.27 mol) of 2-t-butyl-4-hydroxy -6-trifluoromethyl-pyrimidine in 800 ml of dichloromethane was added dropwise, firstly 86.5 ml of thionyl chloride, then 8 ml of DMF and then heated to boiling with reflux. The volatile components were removed in vacuo, the residue was taken up in 100 ml of dichloromethane and adjusted to pH 7 with saturated NaHCO 3 solution, obtaining after extraction, 67 g (96%) of a clear oil. 67 g (96% of theory) were obtained C9H10CIF3N2 (MW 239) 2-t-butyl-4- [piperazin-1 -yl] -6-trifluoromethylpyrimidine (3) A_ a solution of 129 g (1.5 g) mol) of piperazine in 500 ml of ethanol was added dropwise over the course of 2 h, a solution of 60 g (0.25 mol) of the chloropyrimidine described above in 200 ml of ethanol at boiling temperature and then followed stirring another 6 h at boiling temperature. After the end of the reaction, the solvent was removed in vacuo and the residue was mixed with 2 l of water. The product crystallized upon cooling and was then aspirated. We obtained 56 g (77% of the theory) > C "H, 9CIF3N4 (MW 288) 1 H-NMR (250 MHz, CDCl 3): delta = 1.3 (s, 9H); 1, 8 (s, 1 H); 3.0 (m, 4H); 4.7 (m, 4H); 6.6 (s, 1 H) ppm. 2-t-Butyl-4- [4- (3-chlorpropyl) -piperazin-1-yl] -6-trifluoromethylpyrimidine (4) To a mixture of 35.1 g (0.22 mol) of 1-bromo-3 -chlorine-propane and 16.0 g (0.16 mol) of triethylamine in 90 ml of boiling THF, 43.2 g (0.15 mol) of the described piperazine dissolved in 130 ml of THF were added dropwise and this temperature was stirred 8 h. After cooling to 4 ° C, it was removed by filtration of the inorganic salts, the THF phase was vaporized in vacuo and the residue was recrystallized with sodium propane. 32.1 g (61% of the theory) were obtained 1 H-NMR (250 MHz, CDCl 3): delta = 1.3 (s, 9H); 1, 9 (q, 2H); 2.5 (m, 6H); 3.7 (t, 2H); 3.8 (m, 4H); 6.6 (s, 1 H) ppm. 2-. { 3- [4- [2-t-Butyl-6-trifluoromethylpyrimidin-4-yl] -piperazin-1-yl] -propylmercapto} -pyrimidin-4-ol (5) 8.4 g (0.066 mol) of thiouracil, 1.6 g (0.066 mol) of lithium hydroxide and 1.0 g (0.066 mol) of sodium iodide were dissolved in 200 ml. of DMF and heated to 100 ° C. At this temperature, 20.1 g (0.055 mol) of the chlorine case described above, dissolved in SO ml of DMF were added and stirring was continued for another 30 min at 100 ° C. It was then mixed with 300 ml of sodium chloride solution and extracted twice with acetic acid ethyl ester. The organic phase was dried with sodium sulfate and after filtering it was vaporized in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane with 1-4% methanol). 18 g (72% of the theory) were obtained C20 H27F3N6OS (MW 457) P.f. 138-140 ° C 1 H-NMR (270 MHz, DMSO-d 6): delta = 1.3 (s, 9H); 1, 8 (q, 2H); 2.4 (m, 6H); 3.3 (t, 2H); 3.75 (m, 4H); 6.1 (d, 2H); 7.1 (s, 1 H); 7.9 (d, 2H) ppm. Preparation of the fumarate (6) 4.56 g (0.01 mol) of the base described above was dissolved in hot 25 ml of sodium propane and a hot solution of 1.16 g (0.01 mol) was added. fumaric acid in 15 ml of isopropanol. The substance, which crystallized upon cooling, was separated by filtration, yielding 4.4 g of the title compound as colorless crystals. 4.4 g (76% of the theory) were obtained C20 H27F3N6OS x C4H4O4 (MW 573) P.f. 200-202 ° C 1 H-NMR (250 MHz, DMSO-d 6): delta = 1.3 (s, 9H); 1, 9 (q, 2H); 2.5 (m, 6H); 3.2 (t, 2H); 3.8 (mbr, 6H); 6.2 (d, 2H); 6.7 (s, 2H); 7.1 (s, 1 H); 7.9 (d, 2H) ppm.

Claims (3)

1. CLAIMS 1. Fumaric acid salt of 2-. { -3- [4- (2-t-butyl-6-trifluoromethylpyrimidin-4-yl) piperazin-1-yl] propylmercapto} pyrimidin-4-ol of the formula and the tautomeric forms, solvates and hydrates thereof.
2. 2. Medicament containing the fumaric acid salt or a tautomeric form, a solvate or a hydrate thereof in accordance with clause 1, characterized in that it can be administered, if necessary, together with carriers and / or physiologically acceptable auxiliary substances.
3. 3. Use of the fumaric acid salt of a tautomeric form, a solvate or hydrate thereof of clause 1 characterized in that it serves to prepare I a medicament for the treatment of diseases that respond to the action of dopamine ligands D3.