CZ2000143A3 - Derivatives of acyl piperazinyl pyrimidines, process of their preparation and pharmaceutical composition based thereon - Google Patents

Abstract

Derivatives of acylpiperazinylpyrimidines of general formula (1) wherein X is O or S, R 1 is alkoxy or trifluoromethyl, R2 represents a group comprising alkyl, cycloalkyl, heterocycloalkyl, aryl, alkylalkyl, heteroaryl or heteroalkylalkyl, are useful for treating central disorders nervous system. Compounds (1) wherein X is O, is prepared by reacting a pyrimidine derivative with a derivative of piperazine or by reacting the piperazine-pyrimidine derivative with with carboxylic acid or with a salt or derivative thereof. Compounds (1) in which X is S can be prepared by reaction of the compounds (1) of which X is O with Lawesson with or with pentasulfide phosphorus. Said compounds (1) have sedative, anticonvulsant, hypnotic or overall anesthetic efficacy and can be used in human and / or veterinary medicine.

Description

Technical field

The present invention relates to novel acylpiperazinylpyrimidines of formula (I), their physiologically acceptable salts, processes for their preparation and their use as medicaments in human therapy and / or their use as veterinary medicaments and pharmaceutical compositions containing them.

These novel compounds of the invention can be used in the pharmaceutical industry as intermediates and for the preparation of medicaments.

BACKGROUND OF THE INVENTION

EP 382 637 and EP 497 659 disclose various alkylpiperazinylpyrimidines of formula (II) having the properties of anxiolytics or transients.

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N

N _N - _{(CH) n} / _ / (II)

4444 444 4

EP-0 115 713 discloses (piperazinyl-1) -2-pyrimidines having substituents in the 4-piperazine position which include an alkylcarbonyl group, an alkyl or amino-substituted alkylcarbonyl group, an alkylcarboxylate or alkylcarboxylate group, or a substituted carbonylalkyl group, which have psychotropic effects induced by the dopaminergic mechanism.

PCT application WO 94/14779 discloses (piperazinyl) -4-pyrimidines having substituents in the 4-piperazine position which include only straight or branched chain alkyl groups containing up to 4 carbon atoms, optionally terminated with a phenyl group which may be substituted, having an antagonist receptor activity

5-HT1, and which can be used in the treatment or prevention of conditions associated with excessive vasodilation.

US patent 4,547,505 relates to novel pharmacologically active compounds of the general formula comprising piperazine and in which one nitrogen atom is substituted by groups including especially pyrimidine, and the other nitrogen atom is replaced by a substituted acyl group, which compounds have analgesic activity.

SUMMARY OF THE INVENTION

The inventors have found that further substitution at the 4-position of the pyrimidine and replacement of the alkyl radical with an acyl radical yields novel compounds of formula (I). Said compounds have beneficial biological properties which allow their use in human and veterinary therapy. The compounds of the invention are useful as agents acting on the cebral nervous system of mammals, including humans. In particular, the novel compounds are useful as sedatives, anticonvulsants, sleep inducers and general anesthetics.

Description of the figures in the attached drawings

Figure 1 shows the results of determining the sedative effect of the compounds of the invention as determined by a decrease in physical activity.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides novel compounds which, when administered in an appropriate manner and at a suitable dose, can induce a sedative effect in the waking state, can be used as sleep inducing agents, anticonvulsants, analgesics, myorelaxants, antitussives, anxiolytics, antipsychotics, antidepressants, anti-cerebral ischemia agents, anti-migraine agents, agents used in sleep disorders, agents for treating neurodegenerative diseases, cognitive diseases, and Alzheimer's disease, and means to induce or maintain general anesthesia.

The compounds of the invention are represented by the general formula (I)

σ) ······························· 9 9 9 9 9 9 9 9 9 9 9 Where ·. · · · · · · · · · · · ·

X represents an oxygen atom or a sulfur atom;

R 1 represents a C 1-4 alkoxy- or trifluoromethyl radical

R 2 represents a radical selected from the group consisting of C 1-6 alkyl; C 3-6 saturated cycloalkyl; a heterocycloalkyl having a ring of 3 to 6 atoms in which the heteroatom is selected from the group consisting of oxygen, sulfur or nitrogen, optionally N- substituted with C 1 -C 6 alkyl; phenyl optionally substituted with 1, 2 or 3 with the same or different substituents selected from the group consisting of fluoro, chloro, bromo, amino, acetamido, nitro, methyl, trifluoromethyl and methoxy; arylalkyl containing a C 1-3 alkyl group substituted with a phenyl radical optionally substituted with 1, 2, or 3 substituents selected from the group consisting of fluoro, chloro, bromo, acetamido, nitro, methyl, trifluoromethyl and methoxy; heteroaryl containing a 5- or 6-membered heterocyclic, optionally substituted ring, or fused heteroaromatic, optionally substituted systems of 9 or 10 atoms comprising 1 or 2 heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, wherein the above substituents are selected from the group consisting of fluoro, chloro, bromo, amino, acetamido, nitro, methyl, trifluoromethyl and methoxy; and heteroarylalkyl having a C 1 -C 3 alkyl group substituted by a heteroaryl radical containing a 5 or 6-membered heteroaromatic, optionally substituted ring, or fused 9- or 10-membered heteroaromatic systems, optionally substituted, containing 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen, wherein the above substituents are selected from the group consisting of fluorine, chlorine, bromine, amino, acetamido, nitro, methyl, ,φφ φφφφφφφφφφφφφφφφφφφφφ Trifluoromethyl and methoxy; and physiologically acceptable salts thereof.

The term C 1-4 alkoxy as used herein means an OR 3 radical where R 3 is a straight or branched chain of 1 to 4 carbon atoms, and includes groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or a tert. butoxy.

The term alkyl means a radical derived from a straight or branched chain saturated hydrocarbon. The term C 1-6 alkyl means a straight or branched chain alkyl radical of 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl.

The term C 3-6 saturated cycloalkyl means a saturated ring having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

The term heterocycloalkyl means a ring containing from 3 to 6 atoms including a heteroatom such as an oxygen atom or a sulfur atom and, for example, a group such as 2-aziridinyl,

2-tetrahydrofuryl, 3-tetrahydrofuryl, 2-tetrahydrothienyl,

3-tetrahydrothienyl, or a nitrogen atom, which may or may not be substituted, and represents a group such as, for example

2-azetidinyl, 2-piperidinyl, 3-piperidinyl or 4-piperidinyl

The term aryl means an unsubstituted or substituted phenyl radical containing 1, 2, or 3 of the same or different substituents selected from fluoro, chloro, bromo, amino, acetamido, nitro, methyl, trifluoromethyl or methoxy, such as 2-fluorophenyl, 3- fluorophenyl, fluorophenyl, fluorophenyl, fluorophenyl

4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,

2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-aminophenyl,

3-aminophenyl, 4-aminophenyl, 2-nitrophenyl, 3-nitrophenyl,

4-nitrophenyl, 2-acetamidophenyl, 3-acetamidophenyl,

4-acetamidophenyl, 4-acetamidophenyl, 2-nitrophenyl,

3-nitrophenyl, 4-nitrophenyl, 2-methylphenyl, 3-methylphenyl,

4-methylphenyl, 2- (trifluoromethyl) phenyl,

3- (trifluoromethyl) phenyl, 4- (trifluoromethyl) phenyl,

2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,

2,3-difluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl,

2,3-dibromophenyl, 3,4-dibromophenyl, 2,4-dibromophenyl,

2,3-dimethylphenyl, 3,4-dimethylphenyl, 2,4-dimethylphenyl,

2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,4-dimethoxyphenyl.

The term arylalkyl means a straight or branched chain of 1 to 3 carbon atoms which is substituted by an aryl radical as defined above as aryl and which includes substituents such as phenylmethyl, 1-phenylethyl, 2-phenylethyl,

3-phenyl ethyl, 3-phenylpropyl, as well as other radicals in which the aromatic ring is substituted with a group selected from fluoro, chloro, bromo, amino, acetamido, nitro, methyl, trifluoromethyl or methoxy.

The term heteroryl means a substituted or unsubstituted 5-6 membered heteroaromatic ring or a 9 or 10 membered unsubstituted or substituted fused heteroaromatic system containing 1 or 2 heteroatoms from the group consisting of nitrogen, oxygen or sulfur, wherein the substituents are selected from fluorine, chlorine , bromo, amino, acetamido, nitro, methyl, trifluoromethyl or methoxy, and includes groups such as 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,

3-Methylthienyl, 5-methylthienyl, 3-methoxythienyl, ♦ · · ♦ · · · «« «« «« «« «« «« «« · · ······ · · · · · · · · · «« · · 9 · · · · ·

3-chloro-2-thienyl, 5-chloro-2-thienyl, 2-pyrrolyl, 3-pyrrolyl,

2-pyridyl, 3-pyridyl, 4-pyridyl, 2-indolyl, 3-indolyl,

2-benzo [b] thienyl, 3-benzo [b] thienyl,

3-chloro-2-benzo [b] thienyl, pirazolyl, imidazolyl, pyrimidinyl, piridazinil, pirazinyl, benzimidazolyl, quinolinyl, oxazolyl, and thiazolyl.

The term heteroarylalkyl means an alkyl group of 1 to 3 carbon atoms which is substituted with the heteroaryl radical described above as heteroaryl and which includes substituents such as 2-thienylmethyl,

2-benzo [b] thienylmethyl; and 3- (4-chloropyrazolyl) propyl.

Said novel compounds of formula (I) may contain an asymmetric carbon atom and may therefore be prepared either as optical isomers or in racemic form. Racemates of compounds (I) can be resolved into their optical isomers by conventional means, for example, by separation by chiral chromatography or by fractional crystallization of their diastereomeric salts. Similarly, these compounds can be obtained by asymmetric syntheses from chiral precursors.

The invention also relates to physiologically acceptable salts of the compounds of formula (I), in particular mineral acid addition salts such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, and organic acid addition salts such as p-toluenesulfonic acid and acid. methanesulfone.

Said novel derivatives of Formula (I) wherein X is O and R 1 and R 2 are as defined above may be prepared by Method A or B described below.

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Method A:

Compounds of formula (I) may be prepared by reacting a chloropyrimidine derivative of formula (III) wherein R 1 is as defined above with a piperazine derivative of formula (IV) wherein X and R 2 are as defined above.

The reaction is carried out in an organic solvent, for example a solution of a chlorinated hydrocarbon such as dichloromethane or chloroform, in a straight or cyclic chain ether such as 1,2-dimethoxyethane, tetrahydrofuran, or dioxane, in an aprotic polar solvent such as pyridine, dimethylsulfoxide or dimethylformamide or another solvent suitable for carrying out an aromatic nucleophilic substitution reaction. The reaction may be carried out in the presence of a mineral or organic base such as an aliphatic amine, preferably in the presence of triethylamine or N-methylmorpholine, by stirring at a temperature ranging between room temperature and the boiling point of the solvent used for 10 minutes to twenty-four hours. the preferred reaction time is thirty minutes to five hours.

Method B:

Reaction of amine of formula (V):

(V) φφφφ

φ φ φ · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ

wherein R 1 is as defined above, with the carboxylic acid R 2 COOH (VI), wherein P 2 is as defined above, or with a salt of said acid or a derivative of R 2 COY (VII).

Examples of salts include alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, ammonium salts and organic base salts such as triethylamine, trimethylamine, pyridine and picoline.

Examples of derivatives of the general formula R 2 COY (VII), wherein Y represents a halogen atom, preferably a chlorine or bromine atom, an azide group (-N 3), 1 -indiazazolyl group and O-CO-R 4, wherein R 4 may be alkyl or aryl a radical of 1 to 6 atoms, preferably substituted with one or more halogen atoms, or an OR 5 group, wherein R 5 represents an aromatic group consisting of one or two rings substituted with one or more halogen atoms or nitro groups, preferred groups include 4-nitrophenyls; 4-dinitrophenyl, pentachlorophenyl, pentafluorophenyl, 1-benzotriazolyl, or N-succinimide. Similarly, instead of using the above derivative, the compounds of formula (I) may be prepared directly by reacting the amine (V) with a carboxylic acid of formula (VI). In this case, it is preferable to

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The reaction was carried out in the presence of a carbonyl activating agent such as Ν, Ν'-dicyclohexylcarbodiimide, diisopropylcarbodimide, or 3- (3-dimethylamino) propyl-1-ethylcarbodiimide. This reaction can also be carried out using said carbodiimides in the presence of 1-benzotriazole or N-hydroxysuccinimide. The acids of formula (VI) and the amine of formula (V) also react directly in the presence

Ν, N'-carbonyl-diimidazole or propanephosphonic anhydride.

The reaction is carried out in an organic solvent, for example a chlorinated hydrocarbon such as dichloromethane or chloroform, in a straight or cyclic ether such as

1,2-dimethoxyethane, tetrahydrofuran or dioxane, in an aprotic polar solvent such as pyridine, dimethylsulfoxide or dimethylformamide, or another type of solvent suitable for carrying out a nucleophilic substitution reaction. The reaction may be carried out in the presence of a mineral or organic base, such as an aliphatic amine, preferably triethylamine or

N-methylmorphine, with stirring at a temperature ranging from room temperature to the boiling point of the solvent for a period of from 10 minutes to 24 hours, under preferred conditions, the reaction is carried out for a period of thirty minutes to five hours.

Method C

The novel derivatives of formula (I) in which X is a sulfur atom and R1 and R2 are as defined above are prepared as follows.

Treatment of a compound of formula (I) wherein R 1 and R 2 are as defined above and wherein X is an oxygen atom with Lawesson's reagent (2,4-bis (4-methoxyphenyl) -1,3,2,411

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9999 9999

99 99 99 99

-di thiadiophosphane-2,4-di-sulfide) or with phosphorus pentasulfide, prepare the corresponding thioamides in which X is a sulfur atom:

The reaction is carried out in an organic solvent such as toluene, benzene, heptane, pyridine or tetrahydrofuran. The reaction mixture is constantly shaken during the reaction time between one hour and twenty-four hours at a temperature lying between room temperature and the boiling point of the solvent, preferably the reaction is carried out for a period of one hour to sixteen hours at a reaction temperature of 80 ° C.

Method D

Salts of compounds of formula (I) may be prepared by reaction with a mineral acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, or by reaction with an organic acid such as p-toluenesulfonic acid or methanesulfonic acid in a suitable solvent such as methanol, ethanol, ethyl ether, ethyl acetate, acetonitrile or acetone, using conventional methods of precipitation or crystallization of the corresponding salts.

The invention also provides pharmaceutical compositions comprising, in addition to a pharmaceutically acceptable excipient, at least one compound of formula (I) or one compound thereof in the form of a pharmaceutically acceptable salt thereof. The invention also relates to the invention.

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99 99 99 relates to the use of a compound of formula (I) and a pharmaceutically acceptable salt thereof in the preparation of a medicament having central nervous system effects in mammals, including effects on the human central nervous system, particularly in the manufacture of a medicament with .

The following examples describe methods for preparing the novel compounds of the invention. Also described are some typical forms of use for various fields of application, and pharmaceutical formulations applicable to the compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Method A

Example 1

Preparation of 2- [4- (2-furylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine

A solution of 1.0 g (6.92 mmol) of 2-chloro-4-methoxypyrimidine,

1.49 g (8.30 mmol) of 1- (2-furylcarbonyl) piperazine and 1.39 g (13.84 mmol) of triethylamine in 20 ml of butanol were kept under gentle reflux overnight. The solvent was evaporated under reduced pressure and the crude residue was diluted with chloroform and washed with water. The organic phase was dried over Na2SO4 and evaporated to dryness to give the crude product which was purified by chromatography on silica gel using ethyl acetate / petroleum ether 70/30 to give an oil which solidified on standing. The solid product was then slurried in petroleum ether to give 1.4 g (4.86 mmol) of 2- [4- (2-furylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine. Mp = 85-86 ° C.

φ φ φ φ φ φ φ φ φ φ φ φ φ φ · · · · · · · · φ φ φ • φ φ φ φ φ φ φ φ φ φ φ φ φ φ φφ φφ

Method Β

Example 3

Preparation of 4-methoxy-2- [4- (2-thienylcarbonyl) -1-piperazinyl] pyrimidine

A solution of 1.0 g (5.15 mmol) of 4-methoxy-2- (1-piperazinyl) pyrimidine and 1 mL (7.18 mmol) of triethylamine in 30 mL of CH 2 Cl 2 was cooled to 0 ° C and 0.76 was slowly added. g (5.18 mmol)

Of 2-thienylcarbonyl chloride. This solution was kept at 0 ° C for one hour and then allowed to warm to room temperature. The organic phase was washed with H 2 O, dried over Na 2 SO 4, and the solvent was removed under reduced pressure. The crude residue was dissolved in ethyl ether and crystallized to give 1.0 g (3.28 mmol) of 4-methoxy-2- [4- (2-thienylcarbonyl) -1-piperazinyl] pyrimidine. M.p. M.p. = 71-73 ° C.

Example 12

Preparation of 4-methoxy-2- [4- (3-thienylcarbonyl) -1-piperazinyl] pyrimidine

To a solution of 1.0 g (7.81 mmol) of 3-thienylcarboxylic acid and 1 mL (7.86 mmol) of triethylamine in 30 mL of CH 2 Cl 2 cooled to 0 ° C was added 0.84 g (7.81 mmol) of ethyl chloroformate. This mixture was kept at 0 ° C for 20 minutes and then 1.5 g (7.81 mmol) of 4-methoxy-2- (1-piperazinyl) pyrimidine dissolved in 10 mL of CH 2 Cl 2 was added to the solution. The solution was allowed to warm to room temperature, stirred for 2 hours, the organic phase was washed with H 2 O, dried over Na 2 SO 4 and the solvent was removed under reduced pressure. The resulting oil was treated with ethyl ether to give a solid which was recrystallized from ethanol / H 2 O to give 0.8 g (2.63 mmol) of 4-methoxy-2- [4- (3-thienylcarbonyl) -1-piperazinyl] pyrimidine. M.p. M.p. = 90-92 ° C.

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Example 20

Preparation of 2- [4- (2-indolylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine

To a solution of indole-2-carboxylic acid (0.83 g, 5.15 mmol) in dry THF (15 mL) was added N, N'-carbonyldiimidazole (0.83 g, 5.15 mmol). After 30 minutes, 30 g (5.15 mmol) of 4-methoxy-2- (1-piperazinyl) pyrimidine was added to this solution and the reaction mixture was left stirring overnight. The solvent was then removed under reduced pressure and H2O was added. Addition of a precipitate which was filtered off and dried to give 1.7 g (5.04 mmol) of 2- [4- (2-indolylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine. M.p. MP 202-203 ° C.

Method C

Example 54

Preparation of 4-methoxy-2- (4-thiobenzoyl-1-piperazinyl) pyrimidine

0.56 g (1.9 mmol) of 2- (4-benzoyl-1-piperazinyl) -4-methoxypyrimidine are dissolved in 25 ml of dry toluene and 0.46 g (1.14 mmol) of Lawesson's reagent (2, 4-bis (4-methoxyphenyl) -1,3,2,4-triadiophosphorethane-2,4-disulfide. The mixture was heated at 80-90 ° C for 16 hours. Ethyl ether was then added, the residue was washed with alkaline water, and the organic extract was dried over Na 2 SO 4, then the solvent was removed under reduced pressure. The crude residue obtained was recrystallized from ethyl ether-pertol ether to give 160 mg (0.5 mmol).

2- (4-thiobenzoyl-1-piperazinyl) -4-methoxypyrimidine. M.p. = 125-129 OC.

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Example 2

Preparation of 2- [4- (2-furylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride

To 1.0 g (3.47 mmol) of 2- [4- (2-furylcarbonyl) -1-piperazinyl] -4-methoxy-pyrimidine in ethyl acetate was added a few drops of ethyl ether / hydrochloric acid to form a precipitate which was filtered off and dried. 1.07 g (3.29 mmol) of 2- [4- (2-furylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride are obtained. M.p. Mp = 162-164 ° C.

Example 4

Preparation of 4-methoxy-2- [4- (2-thienylcarbonyl) -1-piperazinyl] pyrimidine hydrochloride

Dissolve 1.0 g (3.29 mmol) of 4-methoxy-2- [4- (2-thienylcarbonyl) -1-piperazinyl] pyrimidine in acetone and add a few drops of ethyl ether / hydrochloric acid to form a precipitate which filtered and dried to give 1.05 g (3.08 mmol) of 4-methoxy-2- [4- (2-thienylcarbonyl) -1-piperazinyl] pyrimidine hydrochloride. M.p. MP 143-145 ° C.

Example 13

Preparation of 4-methoxy-2- [4- (3-thienylcarbonyl) -1-piperazinyl] pyrimidine hydrochloride

0.8 g (2.63 mmol) of 4-methoxy-2- [4- (3-thienylcarbonyl) -1-piperazinyl] pyrimidine is dissolved in ethanol and a few drops of ethyl ether / hydrochloric acid are added to form a precipitate which is filtered off and drying to give 0.6 g (1.76 mmol) of 4-methoxy-2- [4- (3-thienylcarbonyl) -1-piperazinyl] pyrimidine hydrochloride. M.p. MP 154-156 ° C.

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Effectiveness in inducing sleep in mice

The sleep inducing activity of the products of the invention was evaluated by determining their capacity to increase barbital-induced sleep time modified as described by David Sudgen (J. Pharmacol.Exp.Ther., 1983. 227, 3).

Fifteen minutes after administration of barbital (150 mg / kg, i.v.), mice are dosed with the test product at an initial dose of 100 mg / kg (i.p). For the most potent products, a dose efficiency of 50 (DE 50) was determined. Table 2 shows the assay results for some of the products of the invention using meprobamate as a reference.

Table 2

Barbital-induced sleep extension capacity

Example % activity (sleep) dose 100 mg / kg DE50 (mg / kg) 2 93 14.4 4 100 ALIGN! 8.7 8 97 9.7 9 67 28.1 10 74 11.6 1 1 89 10.5 13 77 41.3 15 Dec 86 8.2 17 56 84.2 18 82 27.3

· · · · · · · · · · · · · · · · · · · · ·

Table 2 (continued)

Barbital-induced sleep extension capacity

Example % activity (sleep) dose 100 mg / kg DE50 (mg / kg) 22nd 57 75 24 69 41, 5 26 60 74.1 30 75 37.2 32 73 56.5 34 98 7 55 70 31 57 100 ALIGN! 1.6 59 101 14 61 102 4,5 63 103 4 65 100 ALIGN! 7.7 67 96 15 Dec 69 97 10 73 98 9.5 81 99 8.3 83 100 ALIGN! 5.3 87 101 10 89 102 8 91 81 10 92 98 8 94 84 5.2

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Table 2 (continued) Induced sleep extension capacity

Example % activity (sleep) dose 100 mg / kg DEs o (mg / kg) 96 97 3 meprobamat 54 84.5

effectiveness under general anesthesia

Efficacy in general anesthesia was determined in a study conducted in mice after injection of the product of the invention into the caudal vein. The beginning and duration of sleep were recorded. The results obtained with some of the products of the invention are shown in Table 3 and it is clear that they later exhibit distinct anesthetic efficacy compared to the reference compound (Propofol) applied to the recovered animals.

Table 3

Anesthetic efficacy in mice after i.v. administration example dose (mg / kg) onset (s) duration of action (min) immediately

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Table 3 (continued)

Anesthetic efficacy in mice after i.v. administration • 0 0 * 00

example dose (mg / kg) origin (s) duration of action (min) 4 80 immediately 7.4 40 15 Dec 1.3 15 Dec 80 20 May 1.9 40 15 Dec 1.4 30 80 30 7.9 40 30 1,8 34 80 immediately 1.5 40 it is not 0 57 80 immediately 11 59 80 20 May 3.4 61 80 10 1.6 65 80 20 May 8.6 63 80 immediately 14.8 71 80 60 5.6

Table 3 (continued)

Anesthetic efficacy in mice after i.v. Submission ·· ·· · 4 · · · · · · · · · · · · · · · · · · · · · · · · ·

example dose (mg / kg) origin (s) duration of action (min) 73 80 immediately 9 77 80 immediately 10 79 80 immediately 19 Dec 81 80 immediately 10 85 80 immediately 8.4 89 80 immediately 4 91 80 immediately 7 92 80 even now 5 96 80 even now 6 101 80 immediately 2 Propof ol 106 30 6.2 120 20 May 3.9 80 it is not 0

9 ····

9 9

9 • · ·

9 * 9

Sedative effects

The sedative effects of some of the products of the invention were determined on the physical activity of mice after administration of various doses. The method used is described in T.G.Heffneren, J.Pharm.Exp. Ther., 1989, 251, 105-112. The determination of physical activity is performed after the rats are divided into groups of four by monitoring their movements in an automatic manner using a video device and a SMART program (Letica S.A) for recording analysis. Activity measurement is performed 5 minutes after i.p. administration of the product and continued for 20 minutes. The results (see Figure 1) show the sedative effect of the test compounds.

Myorelaxant efficacy

The myorelaxant efficacy of the products of the invention was evaluated by determining their effects on the abdominal tone of mice as described by S.Irwing (Gordon Res.Conf.On Medicinal Chem., 1959, p. 133).

Mice enrolled in the experiment are administered i.p. the 80 mg / kg dose, and at various time intervals after administration (1/2, 1, 2, 3, 4, and 5 hours), body tone and abdominal tone are evaluated by monitoring muscle tension as compared to control animals.

The results shown in Table 4 show that several of the products evaluated have remarkable myorelaxant effects.

These effects last longer than those induced by propofol and zolpidem, which have been used as reference agents.

Table 4 • 4 4 4 4 4

· 4 · 4

Myorelaxant effect in Irving test in mice (dose = 80 mg / kg, i.p.) • 4 4 44 4 · 4 444 · 4 444 · 4 · 4 · 4 · 4 44 4

4 4444 4444

4444 4 44 44 4

example % muscle relaxation in time: 1/2 h 1 h 2 h 3 h 4 h 5 h 4 100 ALIGN! 90 10 0 0 0 34 60 70 80 85 40 40 57 100 ALIGN! 100 ALIGN! 100 ALIGN! 80 55 0 63 100 ALIGN! 100 ALIGN! 90 75 20 May 0 71 100 ALIGN! 100 ALIGN! 100 ALIGN! 40 10 0 73 100 ALIGN! 100 ALIGN! 100 ALIGN! 0 0 0 75 100 ALIGN! 100 ALIGN! 100 ALIGN! 80 80 60 77 100 ALIGN! 100 ALIGN! 100 ALIGN! 60 0 0 79 100 ALIGN! 100 ALIGN! 100 ALIGN! 65 0 0 83 90 90 90 70 50 0 92 100 ALIGN! 100 ALIGN! 100 ALIGN! 0 0 0 propofo 1 100 ALIGN! 100 ALIGN! 70 0 0 0

Analgesic efficacy

The analgesic efficacy of the products of the invention was studied by studying its effects in a phenylbenzoquinone-induced concomitant test in mice, as described by Siegmund E. et al., Proc.

95: 729-731).

Mice were dosed with the products evaluated in the study at various doses and administered one hour after the administration.

• 9

9

4449 Φ φφφφ

Φ · ··

Φ ΦΦΦΦ · · · φ · · · · · ·

i.p. injection of phenylbenzoquinone at a dose of 5 mg / kg. For the next fifteen minutes, the induced indices were examined and compared with those induced in the control group. The DE 50 (dose efficiency 50) of the compound of Example 4 is shown below. This compound exhibits better analgesic efficacy than aspirin, both by subcutaneous and oral administration.

Table 5.

Analgesic activity. Protection against phenylbenzoquinone-induced connectors in mice.

Example DE 50 (mg / kg, s.c.) DE 50 (mg / kg orally) aspirin 84 120 4 48 72

Pharmaceutical formulations

1. For injection (i.m./i.v.):

Example compound 4 5 mg sodium chloride c. HCl 0.1 N or NaOH c. p. water for injection c.s.p. 3 ml Capsules: Example compound 4 0.5 to 4.0 mg colloidal silica 0.5 mg magnesium stearate 1.0 mg

• 9 9 9

9 · · 9

9 9 4

499 9 44 ····

44

4 4 4 4

9 9 4 5

. 4 9 4 4 9

. 4 9 4 9

94 44 lactose c.s.p.

3. Tablets:

compound of Example 4 colloidal silica magnesium stearate croscarmellose sodium lactose c.s.p.

formulation B (wet granulation) Example 4 colloidal silica magnesium stearate Povidone K-30 starch sodium carboxymethyl starch microcrystalline cellulose

Claims (17)

PATENT CLAIMS An acylpiperazinylpyrimidine derivative of the general formula (I) (I) wherein X represents an oxygen atom or a sulfur atom; R 1 represents a C 1-4 alkoxy- or trifluoromethyl radical R2 represents a radical selected from the group consisting of C1-6alkyl; C 3-6 saturated cycloalkyl; a heterocycloalkyl having a ring of 3 to 6 atoms in which the heteroatom is selected from the group consisting of oxygen, sulfur or nitrogen, optionally N- substituted with C 1 -C 6 alkyl; phenyl optionally substituted with 1, 2 or 3 with the same or different substituents selected from the group consisting of fluoro, chloro, bromo, amino, acetamido, nitro, methyl, trifluoromethyl and methoxy; arylalkyl containing a C 1-3 alkyl group substituted with a phenyl radical optionally substituted with 1, 2, or 3 substituents selected from the group consisting of fluoro, chloro, bromo, acetamido, nitro, methyl, trifluoromethyl and methoxy; heteroaryl containing a 5- or 6-membered heterocyclic, optionally substituted ring, or fused heteroaromatic, optionally substituted systems of 9 or 10 atoms comprising 1 or 2 heteroatoms selected from group i: Including oxygen, sulfur and nitrogen, wherein the above substituents are selected from the group consisting of fluorine, chlorine, bromine, amino, acetamido, nitro, methyl, trifluoromethyl and methoxy; and heteroarylalkyl having a C 1 -C 3 alkyl group substituted by a heteroaryl radical containing a 5 or 6-membered heteroaromatic ring, optionally substituted, or fused 9- or 10-membered heteroaromatic systems, optionally substituted, containing 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen, wherein the above substituents are selected from the group consisting of fluoro, chloro, bromo, amino, acetamido, nitro, methyl, trifluoromethyl and methoxy; and physiologically acceptable salts thereof. The compound of claim 1, wherein R 1 is methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy and tert-butoxy. A compound according to claim 1, wherein R 2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl and hexyl. The compound of claim 1, wherein R 2 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. The compound of claim 1, wherein R 2 is 2-azyridinyl, 2-tetrahydrofuryl, 3-tetrahydrofuryl, 2-tetrahydrothienyl, 3-tetrahydrothienyl, 2-azetidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl. • 0 · 000 0 0 0 0 0 0 0000 0 • 09 9 9 0 0 0 00 00 9 9 The compound of claim 1 wherein R 2 is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-acetamidophenyl, 3-acetamidophenyl, 4-acetamidophenyl, 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2- (trifluoromethyl) phenyl, 3- (trifluoromethyl) phenyl, 4- (trifluoromethyl) phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-difluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 2,3-dihromophenyl, 3,4-dibromophenyl, 2,4-dibromophenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl, 2,4-dimethylphenyl, 2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 2,4-dimethoxyphenyls. A compound according to claim 1, wherein R 2 is phenylmethyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, optionally substituted on the aromatic ring. A compound according to claim 1, wherein R 2 is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3-methyl-2-thienyl, 5-methyl-2-thienyl, 3-methoxy-2-thienyl, 3-chloro-2-thienyl, 5-chloro-2-thienyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-indolyl, 3-indolyl, 2-benzo [b] thienyl, 3-benzo [b] thienyl, 3-chloro-2-benzo [b] thienyl, pyrazolyl, imidazolyl, pyrimidinyl, pyrazinyl, benzimidazolyl, quinolyl, oxazolyl, and thiazolyl. The compound of claim 1 selected from the group consisting of: 2- [4- (2-furylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (2-Furylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine Φ φ »· ♦ · φφφφ φ hydrochloride, 4-methoxy-2- [4- (2-thienylcarbonyl) -1-piperazinyl] pyrimidine 4-methoxy-2- [4- (2-thienylcarbonyl) -1-piperazinyl] pyrimidine hydrochloride, 2- (4-Acetyl-1-piperazinyl) -4-methoxypyrimidine 2- {4- [4- (4-chloropyrazolyl) butanoyl] -1-piperazinyl} -4-methoxypyrimidine, 2- {4- [4- (4-chloropyrazolyl) butanoyl] -1-piperazinyl} -4-methoxypyrimidine hydrochloride, 2- (4-benzoyl-1-piperazinyl) -4-methoxypyrimidine, 2- (4-cyclopropylcarbonyl-1-piperazinyl) -4-methoxypyrimidine, 2- [4- (2-furylcarbonyl) -1-piperazinyl] -4- (trifluoromethyl) pyrimidine, 2- [4- (2-thienylcarbonyl) -1-piperazinyl] -4- (trifluoromethyl) pyrimidine, 4-methoxy-2- [4- (3-thienylcarbonyl) -1-piperazinyl] pyrimidine; 4-methoxy-2- [4- (3-thienylcarbonyl) -1-piperazinyl] pyrimidine hydrochloride, 2- [4- (5-methyl-2-thienylcarbonyl) -1-piperazinyl] - -4-metboxypyrimide η, 2- [4- (5-methyl-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine n-hydrochloride, 4-methoxy-2- [4- (3-methoxy-2-thienylcarbonyl) -1-piperazinyl] pyrimidine, 4-methoxy-2- [4- (3-methoxy-2-thienylcarbonyl) -1-piperazinyl] pyrimidine hydrochloride, 2- [4- (2-benzo [b] thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (2-benzo [b] thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, »9 9999 • 9» 999 • 9 9 ♦ 999 99 99 9 9 9 9 9 9. 9 9 9 9 9 9,999,999 9 9 99 9 9 99 · «99 99 99 99 2- [4- (2-Indolylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (3-chloro-2-benzo [b] thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (3-chloro-2-benzo [b] thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, 4-methoxy-2- [4- (2-pyrrolylcarbonyl) -1-piperazinyl] pyrimidine; 4-methoxy-2- [4- (2-pyrrolidinylcarbonyl) -1-piperazinyl] pyrimidine-hydrochloride, 4-methoxy-2- [4- (2-thienylacetyl) -1-piperazinyl] pyrimidine, 4-methoxy-2- [4- (2-thienylacetyl) -1-piperazinyl] pyrimidine hydrochloride, 2- [4- (3-methyl-2-thienylcarbonyl) -1-piperazinyl] -4-methoxy-pyrimidine, 2- [4- (3-methyl-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, 2- [4- (3-chloro-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (3-chloro-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, 2- [4- (3-indolylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (3-indolylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine n-hydrochloride, 2- [4- (3-benzo [b] thienylacetyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (5-chloro-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (5-chloro-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, 4-Methoxy-2- [4- (4-chlorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine, 4 * 444 4 44 44 4 4 4 4 4 4 4 * 4 4 4 4 4 4 4 4 44 44 4-methoxy-2- [4- (4-chlorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, 2- [4- (4-fluorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (4-fluorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, 2- [4- (4-chlorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, 2- [4- (4-chlorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, 4-methoxy-2- [4- (3-methoxybenzoyl) -1-piperazinyl] pyrimidine, 4-methoxy-2- [4- (3-methoxybenzoyl) -1-piperazinyl] pyrimidine hydrochloride, 2- [4- (3-fluorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (3-fluorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, 2- [4- (3-chlorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, 2- [4- (3-chlorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, 4-methoxy-2- [4- (2-methoxybenzoyl) -1-piperazinyl] pyrimidine; 4-methoxy-2- [4- (2-methoxybenzoyl) -1-piperazinyl] pyrimidine hydrochloride, 2- [4- (2-fluorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (2-fluorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, 2- [4- (2-chlorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (2-chlorobenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, 4-methoxy-2- [4- (2-tetrahydrofurylcarbonyl) -1-piperazinyl] pyrimidine; 4-methoxy-2- (4-thiobenzoyl-1-piperazinyl) pyrimidine, 4-methoxy-2- [4- (2-tetrhydrofurylcarbonyl) -1-piperazinyl] pyrimidine hydrochloride; 9 4 9 4 9 4 4444 4 9 · 9 9 • 9 4 4 • ♦ »8 4 9 4 9 4 4 9 « 4 4 4 4 9 9 9 4 9 4-methoxy-2- (4-thiobenzoyl-1-piperazinyl) pyrimidine hydrochloride, 2- (4-benzoyl-1-piperazinyl) -4-methoxypyrimidine, 4-methoxy-2- {4- [4- (trifluoromethyl) benzoyl] -1-piperazinyl] pyrimidine, 4-Methoxy-2- (4- [4- (trifluoromethyl) benzoyl] -1-piperazinyl} pyrimidine hydrochloride, 4-methoxy-2- {4- [3- (trifluoromethyl) benzoyl] -1-piperazinyl] pyrimidine, 4-methoxy-2- {4- [3- (trifluoromethyl) benzoyl] -1-piperazinyl} pyrimidine hydrochloride, 4-methoxy-2- {4- [2- (trifluoromethyl) benzoyl] -1-piperazinyl} pyrimidine, 4-methoxy-2- {4- [3- (trifluoromethyl) benzoyl] -1-piperazinyl} pyrimidine hydrochloride, 4-methoxy-2- (4-nicotinoyl-1-piperazinyl) pyrimidine, 4-methoxy-2- (4-nicotinoyl-1-piperazinyl) pyrimidine dihydrochloride, 2- (4-isonicotinoyl-1-piperazinyl) -4-methoxypyrimidine, 2- (4-isonicotinoyl-1-piperazinyl) -4-methoxypyrimidine dihydrochloride, 2- [4- (1-imidazolylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (1-imidazolylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, 2- (4-nicotinoyl-1-piperazinyl) -4- (trifluoromethyl) pyrimidine, 2- (4-nicotinoyl-1-piperazinyl) -4- (trifluoromethyl) pyrimidine hydrochloride, 4-methoxy-2- [4- (2-pyridylcarbonyl) -1-piperazinyl] pyrimidine, 4-Methoxy-2- [4- (2-pyridylcarbonyl) -1-piperazinyl] 55 9 99 99 99 99 99 99 99,999,999 * 9 · »9999999 9 9 9 9999 9999 9 99 99 99 99 pyrimidine hydrochloride, 4-ethoxy-2- [4- (2-thienylcarbonyl) -1-piperazinyl] pyrimidine, 4-ethoxy-2- [4- (2-thienylcarbonyl) -1-piperazinyl] pyrimidine hydrochloride, 2- [4- (3-chloro-2-thienylcarbonyl) -1-piperazinyl] -4-ethoxypyrimidine, 2- [4- (3-chloro-2-thienylcarbonyl) -1-piperazinyl] -4-ethoxypyrimidine hydrochloride, 4-ethoxy-2- {4- [2- (trifluoromethyl) benzoyl] -1-piperazinyl} pyrimidine, 4-ethoxy-2- {4- [2- (trifluoromethyl) benzoyl] -1-piperazinyl} pyrimidine hydrochloride, 2- [4- (2-methylbenzoyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (2-methylbenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, 2- [4- (4-fluorobenzoyl) -1-piperazinyl] -4-isopropoxypyrimidine, 2- [4- (4-fluorobenzoyl) -1-piperazinyl] -4-isopropoxypyrimidine hydrochloride, 4-isopropoxy-2- {4- [2- (trifluoromethyl) benzoyl] -1-piperazinyl] pyrimidine, 4-Isopropoxy-2- {4- [2- (trifluoromethyl) benzoyl] -1-piperazinyl] pyrimidine hydrochloride, 2- [4- (3-chloro-thiocarbonyl) -1-piperazinyl] -4-isopropoxypyrimidine, 2- [4- (3-chloro-thiocarbonyl) -1-piperazinyl] -4-isopropoxypyrimidine hydrochloride, 2- [4- (cyclohexylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (cyclohexylcarbonyl) -1-piperazinyl] -4-methoxypyrimidide hydrochloride, 4-ethoxy-2- [4- (4-fluorobenzoyl) -1-piperazinyl] pyrimidine, ΦΦ · - · φ • φ φ φ φ φ φ φ · · · · · · · φ φ • • • φ φ φ · · · · · 4-ethoxy-2- [4- (4-fluorobenzoyl) -1-piperazinyl] pyrimidine hydrochloride, 2- [4- (2-thiazolylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (2-aminobenzoyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (2-aminobenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, 2- [4- (3-fluoro-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (3-fluoro-2-thienylcarbonyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, 2- [4- (4-methoxy-2-pyrimidinyl) -1-piperazinylcarbonylbenzoic acid, 2- [4- (2-acetoxybenzoyl) -1-piperazinyl] -4-methoxypyrimidine, 2- [4- (2-hydroxybenzoyl) -1-piperazinyl] -4-methoxypyrimidine, Sodium 2- [4- (4-methoxy-2-pyrimidinyl) -1-piperazinylcarbonyl] benzoate, 2- [4- (2-hydroxybenzoyl) -1-piperazinyl] -4-methoxypyrimidine hydrochloride, 4-methoxy-2- [4- (2-methoxybenzoyl) -1-piperazinyl] -4-methoxypyrimidine, and 4-Ethoxy-2- [4- (2-pyridylcarbonyl) -1-piperazinyl] pyrimidine. A process for the preparation of a compound of formula (I), wherein X is an oxygen atom, according to claim 1, comprising reacting a chloropyrimidine derivative of formula (III) (III) 4 4 · 4 44 44 4 4 4 4 4 4 4 4 4 444 44 4 4 44 4 44 Wherein R 1 is as defined in claim 1, with a piperazine derivative of the general formula (IV) (iv) wherein R 2 is as defined in claim 1 and X is an oxygen atom. A process for the preparation of a compound of formula (I) wherein X is O, according to claim 1, comprising reacting an amine of formula (V) wherein R 1 is as defined in claim 1 with a carboxylic acid of formula (I). of formula R 2 COOH (VI) or a salt thereof, wherein R 2 is as defined in claim 1. A process for the preparation of a compound of formula (I), wherein X 9 · 9 9999 is an oxygen atom according to claim 1, comprising reacting an amine of formula (V) N NH (V) wherein R 1 is as defined in claim 1 with the derivative reagent R 2 COY (VII), wherein R 2 is as defined in claim 1 and Y represents a halogen atom, an azide group, 1-imidazolyl group, O-CO-R 4 represents an alkyl radical of 1 to 6 carbon atoms or an aryl radical, optionally substituted by one or more halogen atoms, or an OR5 group, wherein R5 represents an aromatic group or one or two rings optionally substituted by one or more halogen atoms or nitro radicals, or N -succinimide. A process for the preparation of a compound of formula (I) wherein X is a sulfur atom according to claim 1, comprising reacting a compound of formula (I) wherein X is an oxygen atom with a Lawesson reagent (2). 4-bis (4-methoxyphenyl) -1,3,2,4-di-thiadiophosphonethano-2,4-disulfide) or with phosphorus pentasulfide. A process for the preparation of physiologically acceptable salts of compounds of formula (I) according to claim 1, comprising reacting a compound of formula (I) with a mineral acid or an organic acid in a suitable solvent. · · Fefefe · fefe · fefe · fefe · fefe · fefe · fefe · fefe · fefe · fefe · fefe · fefe · fefe · fefe · fefe · fefe · fefe · fefe · fefe · fefe Pharmaceutical composition characterized in that the pharmaceutically acceptable excipients comprise at least one compound of formula (I) or one of its physiologically acceptable salts according to claims 1 to 10. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 in the preparation of a medicament having activity in the central nervous system of mammals including humans. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 in the preparation of a medicament having a sedative, anticonvulsant, analgesic, myorelaxant effect and drugs used as antitussives, anxiolytics, antipsychotics, antidepressants, drugs used against cerebral ischemia, used as an anti-migraine and in the preparation of medicaments for the treatment of sleep disorders, neurodegenerative diseases, cognitive diseases, and Alzheimer's disease, and used to induce sleep under general anesthesia, in mammals including humans.