CZ2000450A3 - Salt of 2-[3-/4-(2-tert-butyl-6-trifluoromethyl-4-pyrimidinyl)-1-piperazinyl/propylthio]-4-pyrimidinol with fumaric acid - Google Patents

Abstract

Salt of 2- [3- [4- (2-tert-butyl-6-trifluoromethyl-4-pyrimidinyl) -1-piperazinyl] propylthio] -4-pyrimidinol with fumaric acid can be used to treat dopamine ligand responses D3. It has a higher stability at low pH and is therefore particularly suitable for oral administration in pharmaceutical compositions containing this salt.

Description

Fumaric acid 2- {3- [4- (2-tert-butyl-6-trifluoromethyl-4-pyrimidinyl) -1-piperazinyl] propylthio} -4-pyrimidinol salt

Technical field

The present invention relates to a fumaric acid salt of 2- {3- [4- (2-tert-butyl-6-trifluoromethyl-4-pyrimidinyl) -1-piperazinyl] propylthio} -4-pyrimidinol and a pharmaceutical composition containing the compound. This compound has valuable therapeutic properties and is particularly useful for treating disorders responsive to dopamine D ₃ ligands.

BACKGROUND OF THE INVENTION

WO 96/02519 discloses this compound in the form of the free base of the formula

OH

CF _3, which is also useful for the treatment of disorders responsive to dopamine D ₃ ligands. However, the salt of this compound is not disclosed.

It has now surprisingly been found that the acid addition salt of this compound with fumaric acid is particularly preferred.

«··· 4 · 4 4 4 · ·

4 4 * ··· 4 · 444 44 44 4 4 44 4444 4444

4444 44 44> 64 44

SUMMARY OF THE INVENTION

Thus, the present invention relates to a fumaric acid salt of 2- {3- [4- (2-tert-butyl-6-trifluoromethyl-4-pyrimidinyl) -1-piperazinyl] propylthio} -4-pyrimidinol and a pharmaceutical composition comprising the compound.

The invention also relates to tautomeric forms (pyridone structure) as well as solvates and hydrates of the fumaric acid salt.

This fumaric acid salt has good affinity and high selectivity for D ₃ receptors, i.e., it is a selective dopamine D ₃ receptor ligand that acts regioselectively in the limbic system. Show selectivity D ₂ / D ₃ £ K of 120 (see WO 96/02519). Thus, the compound is useful for treating disorders responsive to dopamine D ₃ ligands, e.g., for treating central nervous system disorders, particularly schizophrenia, depression, neuroses, and psychoses. It is further useful for the treatment of sleep and nausea disorders and also as an antihistamine. Tissue solubility tests have shown a significantly higher solubility of the salts in water compared to the solubility of the free base. Therefore, resorption is substantially increased when administered orally and especially parenterally.

Further, fumarate is more soluble in polar solvents such as C 1 -C 6 alkanols than the free base.

Due to altered solubility characteristics, it can also be more easily purified using physiologically unacceptable solvents.

The free base can be prepared by the general methods described in WO 96/02519, preferably by method (ii). The fumaric acid salt may be obtained by reacting the free base with fumaric acid in a suitable solvent such as C 1 -C 8 alkanols, in particular methanol, ethanol, n-propanol, isopropanol and n-butanol, a mixture of water and one of these alcohols or an ester such as ethyl acetate. Generally, elevated temperature is used so that the desired fumaric acid salt crystallizes on cooling and can be separated directly. Fumaric acid is generally added in equimolar amounts or in a slight excess, up to about 10%. The fumaric acid salt formed in this way is already highly pure. It can also be purified by stirring in a suitable solvent or recrystallizing from a suitable solvent, such as water, one of the above-described alkanols, esters, or mixtures thereof.

For the treatment of the above-described disorders, this compound is administered orally or parenterally (subcutaneously, intravenously, intramuscularly, intraperitoneally) in a conventional manner. Oral administration is preferred.

The dosage depends on the age, condition and weight of the patient and the route of administration. Typically, the daily dose of active ingredient is about 10 to 1000 mg per patient per day for oral administration and about 1 to 500 mg per patient per day for parenteral administration.

The present invention also relates to pharmaceutical compositions comprising the compound. These compositions are in the form of conventional solid or liquid pharmaceutical forms, for example, as uncoated or film-coated tablets, capsules, powders, granules, suppositories, solutions or sprays. For this purpose, the active ingredient may be formulated with conventional pharmaceutical excipients such as tablet binders, bulking agents, preservatives, disintegrants, flow regulators, plasticizers, wetting agents, dispersing agents, emulsifiers, solvents, delaying agents. , antioxidants and / or propellants (see H. Sucker et al. Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The administration forms obtained in this manner normally contain from 1 to 99% by weight of active ingredient.

DETAILED DESCRIPTION OF THE INVENTION

The following examples serve to illustrate the invention without limiting it.

Example 1

Preparation of 2- {3- [4- (2-tert-butyl-6-trifluoromethyl-4-pyrimidinyl) -1-piperazinyl] propylthio} -4-pyrimidinol salt with fumaric acid

2-tert-Butyl-4-hydroxy-6-trifluoromethylpyrimidine (1)

Starting materials are known from the literature.

To 50 g (0.37 mol) of 2,2-dimethylpropionamidine hydrochloride dissolved in 200 ml of ethanol at room temperature was added 66.6 g (0.37 mol) of sodium methoxide (30% solution in methanol) and after 30 min. 52 g (0.28 mol) of ethyl trifluoroacetate. After refluxing for 17 h, the solvent was evaporated under reduced pressure to give a solvent. 200 ml of water are added to the residue and after acidification to pH 4, the crystallized solid is collected by filtration.

Yield: 62.2 g (98% of theory) ^C 9 ^H 11 ^F 3 ^N 2 ° (Mol. 220) Melting point

Mp 187-188 ° C

2-tert-Butyl-4-chloro-6-trifluoromethylpyrimidine (2)

Thionyl chloride (86.5 ml) and dimethylformamide (8 ml) were added dropwise to a solution of 2-tert-butyl-4-hydroxy-6-trifluoromethylpyrimidine (60 g, 0.27 mol) in dichloromethane (800 ml) and the mixture was refluxed.

The volatiles were evaporated under reduced pressure, the residue was taken up in 100 ml of dichloromethane, the pH was adjusted to 7 with saturated sodium bicarbonate solution and after extraction, 67 g (96%) of a clear oil was obtained.

Yield: 67 g (96% of theory)

C ₉ H _1O C1F ₃ N ₂ (Mol. Weight 239)

2-tert-Butyl-4- (1-piperazinyl) -6-trifluoromethylpyrimidine (3)

A solution of 60 g (0.25 mol) of chloropyrimidine described above in 200 ml of ethanol is added dropwise to a boiling solution of 129 g (1.5 mol) of piperazine in 500 ml of ethanol over 2 h and the mixture is then boiled for a further 6 h. After completion of the reaction, the solvent was evaporated under reduced pressure and the residue was treated with 2 L of water. The product crystallizing on cooling is then collected by suction filtration.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 00

Yield: 56 g of ^C 13 ^H 19 ^ClF 3 ^N 4 (77% of theory) (MW 288) melting point

78-80 ° C

NMR (250 MHz, CDCl ₃ ): 1.3 (s, 9H), (m, 4H), 4.7 (m, 4H), 6.6 (s, 1H) ppm.

1.9 (s, 1H); 3.0

2-tert-Butyl-4- [4- (3-chloropropyl) -1-piperazinyl] -6-trifluoromethylpyrimidine (4)

43.2 g (0.15 mol) of piperazine described above, dissolved in 130 ml of tetrahydrofuran, is added dropwise to a boiling mixture of 35.1 g (0.22 mol) of 1-bromo-3-chloropropane and 16.0 g ( 0.16 mol) of triethylamine in 90 ml of tetrahydrofuran and the mixture is stirred at this temperature for 8 h. After cooling to 4 ° C, the inorganic salts are filtered off, the tetrahydrofuran phases are evaporated under reduced pressure and the residue is crystallized from isopropanol.

Yield: 32.1 g (61% of theory)

Ο ₁₆ Η ₂₄ Ο1Ρ ₃ Ν ₄ (Mol. Weight 365) melting point

83-84 ° C ¹ H-NMR (250 MHz, CDCl ₃ ): 1.3 (s, 9H), 1.9 (q, 2H), 2.5 (m, 6H), 3.7 (t, 2H), 3.8 (m, 4H), 6.6 (s, 1H) ppm.

2- {3- [4- (2-tert-Butyl-6-trifluoromethyl-4-pyrimidinyl) -1-piperazinyl] propylthio} -4-pyrimidinol (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 are dissolved in 200 ml of dimethylformamide and heated to the temperature of

4 • 4 44

Mp 100 ° C. At this temperature, 20.1 g (0.055 mol) of the chlorine-containing base described above dissolved in 50 ml of dimethylformamide are added, followed by stirring at 100 ° C for 30 min. 300 ml of sodium chloride solution were then added and the mixture was extracted twice with 200 ml of ethyl acetate. The organic phase is dried over sodium sulphate and, after filtration, evaporated under reduced pressure.

The residue was purified by column chromatography on silica gel with dichloromethane containing 1-4% methanol.

Yield: 18 g (72% of theory) of ^C 20 ^H 27 ^F 3 ^N 6 ^OS (MW 457) melting point

138-140 ° C ¹ H-NMR (270 MHz, DMSO-d 6): 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, 1H), 7.9 (2 (2H) ppm.

Salt preparation with fumaric acid (6)

4.56 g (0.01 mol) of the base described above are dissolved in 25 ml of hot isopropanol and a hot solution of 1.16 g (0.01 mol) of fumaric acid in 15 ml of isopropanol is added. The material crystallized upon cooling and filtered to give 4.4 g of the title compound as colorless crystals.

Yield: 4.4 g (76% of theory) of ^C 20 ^H 27 ^F 3 ^N 6 ^O 5 ^S (Molecular Weight 573) Melting point x C ₄ H ₄ O ₄ 200-202 ° C 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 ¹ H-NMR (250 MHz, DMSO-d 6): 1.3 (s, 9H), 1.9 (q, 2H),

2.5 (m, 6), 3.2 (t, 2H), 3.8 (m broad, 6H), 6.2 (d, 2H), 6.7 (s, 2H), 7.1 (s, 1H). 7.9 (d, 2H).

Claims (3)

A fumaric acid salt of 2- {3- [4- (2-tert-butyl-6-trifluoromethyl-4-pyrimidinyl) -1-piperazinyl] propylthio} -4-pyrimidinol of the formula and tautomeric forms, solvates and hydrates thereof. 2. A pharmaceutical composition comprising the fumaric acid salt of claim 1, alone or together with physiologically acceptable vehicles and / or excipients. Use of a salt with fumaric acid or a tautomeric solvate or hydrate form thereof according to claim 1 for the preparation of a pharmaceutical composition for the treatment of dopamine Dg ligand responsive disorders.