MXPA00003771A - Cyclohexane derivatives difunctionalised in 1,4 as ligands of 5t h1a receptors - Google Patents

Abstract

The invention concerns novel cyclohexane derivatives difunctionalised in 1,4 of general formula (I) in which A represents a group such as (IIa) in which Ar itself represents an aromatic structure such as phenyl or pyrimidinyl optionally substituted by one or several groups such as C1-C3 alkyl, C1-C3 alkoxy, trifluoromethyl or halogen (IIb);B represents a heterocyclic group such as:3,5-dioxo-(2H, 4H)-1,2,4 triazine substituted in position 2 (IIIa);3-oxo-(2H)-1,2,4 triazine substituted in position 5 (IIIb);3,5-dioxo-6-amino-(2H,4H)-1,2,4-triazine (IIIc) in which R represents a C1-C3 alkyl group. The invention also concerns the salts of compounds of general formula I with pharmaceutically acceptable acids. It also concerns the various"cis"and"trans"isomers and the various enantiomers with asymmetric carbons.

Description

DOUBLE FUNCTIONALITY CYCLOMEXAN DERIVATIVES 1, 4 AS LIGANDS OF 5-HT RECEPTORS JA A subject subject of the present invention is novel 1, 4-functionalized hexane cyclo derivatives, their preparation or application in human therapeutics. The 5-HT A receptors have been claimed for their function in several pathologies, such as hypertension, sexual dysfunction, anorexia and memory. However, the main objective that suggests the involvement of 5-HT1A receptors is, disorders of the central nervous system, such as anxiety and depression. The hypothesis, supported by tests in animal models and clinical studies, suggests that more effective treatments of these pathologies can be contemplated with high affinity 5-HT-IA agonist compounds that are highly selective and highly effective. The derivatives of 3,5-dioxo- (2H, 4H) -1, 2,4-triazine and the derivatives of 3,5-d¡oxo-6-amino- (2H, 4H) -1, 2,4- triazna have been previously claimed by the applicant company (FR 2,707,294 of 07/06/93 and FR 2,727,682 of 02/12/94). The compounds of the present invention are characterized by their powerful affinity in relation to the 5-HTIA receptor in combination with a high selectivity, in particular in relation to the D2 and a? and a high intrinsic activity. The compounds of the invention correspond to the general formula I in which -A represents a group of the type wherein Ar itself represents a structure of aromatic type, such as phenyl or pyrimidinyl, optionally substituted by one or more groups, such as C1.3 alkyl, C1-C3 alkoxy, trifluoromethyl or halogen, -B represents a heterocyclic group of type 3,5-dioxo- (2H, 4H) -1, 2,4-triazine substituted at position 2, Illa 3-oxo- (2H) -1, 2,4-triazine substituted at position 5, lllb 3,5-dioxo-6-amino- (2H, 4H) -1, 2,4-triazine, lile wherein R represents an alkyl group of C C3. The invention encompasses the salts of the compounds of the general formula I with pharmaceutically acceptable acids. In addition, it covers the various "cis" and "trans" isomers and the various enantiomers of compounds that have asymmetric carbons.

Synthesis The compounds of the present invention can be synthesized using the synthetic routes described herein below, or by the use of synthetic methods known to the person skilled in the art.

Method 1 The synthesis of the compounds of general formula I is characterized in that a derivative of the general formula IV where A represents the groups Ha or llb described above or He.

/ \ M e N N Bz \ / is condensed with an intermediate type Va or Vb Intermediate IV where A = He is conveniently used in the case of coupling with Va-type derivatives to give access to compounds I, wherein A means Ha with Ar representing an optionally substituted pyrimidinyl group. The condensation compound between intermediates IV where A '= lie and Va is debenzylated by treatment, for example with chloroethyl chloroformate in methanol and then condensing with optionally substituted 2-chloropyrimidine in the presence of a base, such as triethylamine in toluene. The condensation between the IV and Va derivatives can be carried out according to the conditions of the Mitsunobu reaction. The condensation between the IV and Vb derivatives can be carried out in the presence of a base such as sodium hydride or potassium tert-butoxide in dioxane or THF.

Method 2 The synthesis of the compounds of the general formula I according to the method 2 is characterized in that a derivative of the general formula IV where A has the same meaning as the previous one, it is treated with an intermediary of general formula Ve.

The condensation is carried out in the presence of a base, such as triethylamine in butanol.

The optional separation of the enantiomers of the compounds obtained according to method 1 or method 2 which possess an asymmetric carbon, is generally carried out in the final products by liquid chromatography on a chiral column.

Synthesis of alcohols IV a) When A represents a group Ha or lie, the corresponding alcohols IVa or IVc can be obtained by condensing piperazine Vlla or Vllb with cyclohexanodion monoethylene ketal in the presence of a reducing agent, such as NaBH (OAc) 3 in dichloromethane or NaBH 3 CN in ethanol, to result in the intermediate Villa or Vlllb.

Villa Vlllb which is hydrolyzed in an aqueous medium, such as hydrochloric acid, to give the ketone IXa or IXb.

IXb 0 = -NN- Bz Ketone IXa is reduced to alcohol IVa by reducing agents, such as NaBH 4 in ethanol, to give predominant access to the "trans" alcohols IVa, or LS-selectride in THF, to predominantly result in "cis" alcohols IVa Ketone IXb, reduced in a manner analogous to that described above and then debenzylated by treatment, for example, with a-chloroethyl chloroformate in methanol, provides the alcohol IVc. This alcohol, condensed with 2-chloro-pyrimidine optionally substituted in a solvent such as toluene, in the presence of a base, such as triethylamine, provides the alcohol IVa with Ar which represents a pyrimidinyl type group. b) When A 'represents a group llb, the alcohol IVb can be obtained by condensation of the amine X. with cyclohexanedion monoethylene ketal in the presence of a reducing agent, such as NaBH (OAc) in dichloromethane or NaBH CN in ethanol, to result in the Villa intermediate which is hydrolyzed in a medium of aqueous hydrochloric acid to give the ketone IXc.

Ketone IXc is reduced to alcohol IVb by reducing agents, such as NaBH 4 in ethanol, to give predominant access to the "trans" IVb, or LS-selectride compounds in THF, to predominantly result in the "cis" IVb alcohols.

Synthesis of the amines VI The amines VI can be obtained from the corresponding ketones IX, A has the same meaning as the previous one, when treated with hydroxylamine in an aqueous / alcoholic medium, to result in the amines XI which are reduced by a hydride, such as LiAIH4 in THF.

Synthesis of the intermediates V The compounds Va and Ve are synthesized according to the methods previously described by the applicant company in patents FR 2,727,682 of 02/12/94 and FR 2,707,294 of 06/07/93 respectively. The compounds Vb can be obtained according to the process (scheme 1) characterized by the following steps: 1.- Condensation of glyoxylic acid with thiosemicarbazide, followed by a basic treatment, such as sodium hydroxide solution, 2.- Methylation by Methyl iodide in basic aqueous medium, followed by an acid treatment, such as hydrochloric acid, 3.- Sulfurization of the 5-position in the presence of Lawesson's reagent in a solvent such as pyridine, 4- Methylation by methyl iodide in medium aqueous base, such as sodium hydroxide solution, 5- Methylation of position 2 by methyl iodide in the presence of NaH in DMF.

Synthesis of compounds V (Scheme I) 1) a-H2O, 65 ° C and then at room temperature, 2 hours, b-1 N NaOH, at reflux, 1 hour. 2) a-CH3I, 2N NaOH, room temperature 16 hours, b-2N HCl, reflux, 0.5 hours. 3) Lawesson's reagent, pyridine, at reflux, 2 hours. 4) CH3I, aqueous NaOH, at room temperature, 2 hours.

) CH3I, NaH, DMF, at temperature The following examples illustrate the invention without limiting the scope thereof. The elemental analysis and the IR and NMR spectra confirm the structures of the compounds obtained according to the invention.

EXAMPLE 1 Cis-2-f4-r4- (3-chlorophenyl-9-piperazin-1-y-cyclohexp-4-methyl-2A7-ri, 2,41-triazine-3,5-dione fumarate (1) a) 2-acetyl-2H-ri, 2,41-triazine-3,5-dione (1a) 2H- [1,4] triazine-3,5-dione (100 g, 884 mmol) is placed in 600 ml of acetic anhydride at reflux for 1.5 hours. The reaction mixture is subsequently concentrated to dryness and the solid obtained is triturated in toluene. After filtering and rinsing with toluene, 130.5 g of beige crystals are isolated. P.f. = 148 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.68. b) 4-methylene-2H-M, 2,41-triazine-3,5-dione (1 b) NaH (60% in paraffin, 7 g, 175 mmol) is suspended in DMF under an inert atmosphere, the compound (25 g, 161 mmol), diluted in 200 ml of DMF, is slowly cured by dripping. The reaction mixture is stirred for 1 hour at room temperature and then CH3I (15 ml, 241 mmol) is added. The mixture is stirred for 3 hours at room temperature. After concentrating the reaction mixture until drying, the residue obtained is taken up in 190 ml of ethanol, to which 1.5 g of para-toluenesulfonic acid are added. This mixture is refluxed for 5 hours and then the solvent is evaporated under vacuum. The oil obtained is taken up in H20 then extracted with dichloromethane. The organic phases are dried over MgSO 4 and then concentrated. The precipitate formed is filtered and washed with ether. 10.5 g of yellow crystals are isolated. P.f. = 180 ° C CCD, Merck silica gel 60 F 254. CH2CI2 / AcOEt: 70/30, Rf = 0.46. c) 1- (3-chlorophenyl) -4- (1,4-dioxaspyrol4.51dec-8-yl) -piperazine (1c) Cyclohexanodion monoethylene ketal (18.3 g, 117.2 mmol) in 45 ml of Ti is placed (OiPr) 4 in the presence of 3-chlorophenylpiperazine (23 g, 117 mmoles). This mixture is stirred for 2 hours at room temperature and then 110 ml of absolute ethanol are added, followed by 6 g of NaBH 3 CN.

The reaction mixture is stirred for 20 hours at room temperature. After neutralizing using 24 ml of water, the titanium salts are removed by filtration. The filtrate is concentrated to dryness and the oil obtained is purified by flash chromatography with silica (eluent CH2Cl2AcOEt: 70/30). 29.6 g of oil (1c) are collected. CCD, silica gel Merck 60 F 254. CH2CI2 / AcOEt: 70/30, Rf = 0.18. d) 4-r4- (3-chlorophenyl) piperazin-1-1-cyclohexanone (1d) Compound 1c (29.6 g, 88 mmol) was placed in 195 ml of dioxane in the presence of 125 ml of a 6N hydrochloric acid solution and then the mixture is stirred for 22 hours at room temperature. The reaction mixture is neutralized with NaOH and then extracted with ethyl acetate. The organic phases are dried over MgSO4 and then concentrated until drying. The oil obtained (23.5 g) is used without further purification in the next step. CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 95/5, Rf = 0.36. e) trans-4-r4- (3-chlorophenyl) piperazin-1-yl-1-cyclohexanol (1e) LiAIH4 (3.4 g, 89.8 mmol) is suspended in 90 ml of THF under an inert atmosphere. Compound d, diluted in 41 ml of THF, is added dropwise and the mixture is refluxed for 2 hours. After neutralizing using 13 ml of water, the reaction mixture is dried over MgSO4. The inorganic materials are filtered and the filtrate is concentrated until dried. The residue obtained is purified by flash chromatography with silica (CH 2 Cl 2 / MeOH: 90/10). 5.7 g of oil are collected. CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.28. f) cis-2-r4-γ4- (3-chlorophenyl) piperazine-1-1-cyclohexyl-4-methyl-2H-p, 2,41-triazine-3,5-dione fumarate (1) Alcohol is added to it ( 0.96 g, 3.25 mmol) together with triphenylphosphine (0.86 g, 3.27 mmol) and compound b (0.46 g, 3.62 mmol), in 12 ml of THF under an inert atmosphere and cooled to 0 ° C on a bed of ice. DEAD (0.51 mL, 3.23 mmol) is added dropwise and then the temperature of the reaction mixture is returned to room temperature. This mixture is stirred for 24 hours at this temperature and then concentrated to dryness, and the residue obtained is purified by flash chromatography with silica (eluent CH2Cl2 / AcOEt: 70/30). After salification with fumaric acid in ethanol, 0.16 g of white solid are isolated. P.f. = 210 ° C CCD, Merck silica gel 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.68.

EXAMPLE 2 Hemifumarate (trans-2-r4-F (2,3-dydrobenzori, 41-dioxin-2-ylmethylamino-1-cyclohexyl-1-4-methyl-2 / -p, 2,41-triazine-3,5-dione-2) This compound is prepared according to the procedure described in example 1 using, in step f, a cis- and trans-mixture (30/70) of 4 - [(2,3-dihydrobenzo [1,4] dioxin-2 ylmethyl) amino] cyclohexanol (prepared according to the procedure described in Example 1 using NaBH 4 in EtOH in step e) and then salified with fumaric acid in methanol. P.f. = 238 ° C CCD, Merck silica gel 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.63.

EXAMPLE 3 Cis-4-methyl-2-r4- (4-pyrimidin-2-yl-piperazin-1-yl) cyclohexin-2H-M, 2,41-triazine-3,5-dione (3) This compound is prepared according to the procedure described in Example 2 using a cis- and trans-mixture (30/70) of 4- (4-pyrimidin-2-yl-piperazin-1-yl) cyclohexanol (prepared in accordance with the procedure described in Example 1 using NaBH 4 in EtOH in step e). P.f. = 166 ° C CCD, Merck silica gel 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.46.

EXAMPLE 4 Trans-4-metH-2-r4-pyrimidin-2-yl-piperazin-1-yl) cyclohexin-2H-ri, 2,41-triazine-3,5-dione (4) This compound is prepared according to the procedure described in example 3. P.f. = 222 ° C CCD, Merck silica gel 60 F 254 CH2CI2 / MeOH: 90/10, Rf = 0.31.

EXAMPLE 5 trans-methyl-2- ^ 4- ^ 4- (4,6-dimethylpyrimidin-2-yl) ie azin-1-inciclohe il-2 / ^ -ri, 2,41-triazino-3,5-dione (5 ) a) cis-4-α4- (4,6-dimethyl-pyridin-2-yl) piperazin-1-in-cyclohexanol Í5a) Place LS-selectride (1M solution in THF, 22.6 ml, 22.6 mmol) at -78 ° C under an inert atmosphere. C. 4- [4- (4,6-D.methylpyrimidin-2-yl) piperizin-1-yl-cyclohexanone (prepared according to Example 1 of (4,6-dimethyl-2-piperazin-1-yl) is run by dripping. pyrimidine) (5.9 g, 20.4 mmol), diluted in 25 ml of THF at 0 ° C. This mixture is stirred for 2 hours at -78 ° C and then the temperature is brought to room temperature. The reaction mixture is hydrolyzed with H20 and then extracted with dichloromethane. The organic phases are dried over magnesium sulfate and the concentrate is dried. The isolated residue is purified by flash chromatography with silica (eluent CH2Cl2 / MeOH: 90/9/1). 3.8 g of alcohol 5a are isolated. CCD, silica gel of Merck 60 F 254 CH2CI2 / MeOH: 90/9/1, Rf = 0.50. b trans-4-methyl-2- [4-f4- (4,6-dimethylpyrimidin-2-yl) piperizin-1-pccyclohexyp-2H-p, 2,41-triazine-3,5-dione (5) This compound is prepared according to the procedure described in example 1, using, in step f, alcohol 5a. P.f. = 255 ° C CCD, Merck silica gel 60 F 254 CH2Cl2 / MeOH / NH4OH: 90/9/1 /, Rf = 0.60.

EXAMPLE 6 trans-4-methyl-2-r4-r4- (4-methylpyrimidin-2-yl) piperizin-1-incyclohexyl-2Ay-p, 2.41triazine-3,5-dione (6) This compound is prepared according to the procedure described in example 1 using, in step f, cis-4- [4- (4-methylpyrimidin-2-yl) piperazin-1-yl] cyclohexanol (prepared according to procedure described in example 5 in step a). P.f. = 210 ° C CCD, Merck silica gel 60 F 254 CH2CI2 / MeOH: 90/10, Rf = 0.41.

EXAMPLE 7 trans, -2-f4-r4-f4-chloropyrimidin-2-yl) -piperizin-1-cyclohexyl-4-methyl-2 y-ri, 2,41-triazine-3,5-dione (7 ) a) cs-4-piperizin-1-yl-cyclohexanol (7a) cis-4- (4-benzylpiperzin-1-yl) cyclohexanol (prepared according to the procedure described in example 5) is placed using 4- (4-benzylpiperizin-1-yl) cyclohexanone in step a) (11.6 g, 30.3 mmol) in 80 ml of dichloromethane at 0 ° C. A-Chloroethyl chloroformate (9.9 mL, 90.9 mmol) is run by dropping and the mixture is stirred for 0.5 hour at 0 ° C. The reaction mixture is concentrated until dried and then taken up in 80 ml of methanol. After having refluxed this mixture for 45 min, the solution is concentrated until dried. The residue obtained is taken up in H 0 (pH = 11) and extracted with dichloromethane. The organic phases are dried (MgSO 4) and then concentrated until drying. After purification by flash chromatography with silica (eluent CH 2 Cl 2 / MeOH / NH 4 OH: 80/18/2) and then recrystallization from ether, 1.7 g are isolated. of solid coffee. CCD, Merck silica gel 60F 254 CH2CI2 / MeOH / NH4OH: 80/18/2, Rf = 0.30 b trans-2-r4-r4- (4-chloropyrimidin-2-yl) piperazin-1-yl) cyclohexin-4-methyl-2H-H .2,41 triazino-3,5-dione (7) Compound 7a (1.5 g, 5.1 mmol) is placed in 40 ml of toluene in the presence of 2,4-dichloropyrimidine (0.84 g, 5.6 mmol) and triethylamine (0.78 ml, 5.6 mmol). After having heated this mixture to reflux for 1.5 hours, the solvent is evaporated under vacuum. The residue is taken up in H20 and then extracted with CH2Cl2. After drying the organic phases over (MgSO) and concentrating until drying, the light-colored oil obtained is purified by flash chromatography with silica (eluent CH2Cl2 / MeOH: 95/5). 0.4 g of white solid are isolated. P.f = 201 ° C CCD, Merck silica gel 60F 254 CH2Cl2 / MeOH: 95/5, Rf = 0.22.

EXAMPLE 8 trans-2-r4-r4- (5-fluoropyrimidin-2-yl) piperazin-1-cyclohexyl-4-methyl-2H-H.2,41 triazine-3,5-dione (8) This compound is prepared according to example 7 using, in step b, 2-cioro-5-fluoro-pyrimidine P.f. = 220 ° C CCD, Merck silica gel 60F 254 CH2CI2 / MeOH: 90/10, Rf = 0.35.

EXAMPLE 9 trans-2-methyl-5-r4-β4-pyrimidin-2-yl-piperizin-1-incyclohexyl-1-2-tf-f1,2,41 triazin-3-one (9) a) 5-Thioxo-4,5-dihydro-2H-p, 2.41tr-azin-3-one (9a) 98.3 g (243 mmol) of Lawesson's reagent are added to a solution of 2 - / - [1, 2, 4] triazine-3,5-dione (50 g, 442 mmol) in 400 ml of pyridine. The mixture is refluxed for 4 hours. After evaporating the solvent under reduced pressure, the obtained residue is taken up in 400 ml of water. The brown precipitate that forms is isolated by filtration. These crystals are taken up in H20 and extracted with ethyl acetate. After drying the organic phases over (MgSO4) and concentrating them to dryness, the yellow crystals are obtained. The new water treatment (400 ml) by extraction with ethyl acetate makes it possible to isolate a new solid fraction. In total, after drying, 60 grams of yellow crystals are obtained. P.f = 239 ° C CCD, Merck silica gel 60F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.4. b) 5-Methylsulfanyl-2H-p. 2,41triazin-3-one (9b) Compound 9a (30 g, 232 mmol) and CH 3 I (15.9 mol, 255 mmol) in 300 ml of water are placed. 18.6 g of NaOH (465 mmoles) are added and the mixture is stirred for one hour at room temperature. The reaction mixture, cooled on a bed of ice, is neutralized using 27 ml of acetic acid and then extracted with dichloromethane. Dry the organic bases over (MgSO4) and then concentrate until drying. After recrystallization from ether, 29.9 g of compound 9b are isolated. P.f = 171 ° C CCD, Merck silica gel 60F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.5. c) 2-methyl-5-methylsulfanyl-2H M, 2,41-triazin-3-one- (9c) A suspension, placed under nitrogen, of NaH (60% in liquid paraffin, 4.4 g, 110 mmol) in 50 ml of DMF is cooled to 0 ° C on a bed of ice. Compound 9b (15.9 g, 111 mmol), diluted in 100 ml of DMF, is run into the suspension by dropping. The mixture is subsequently stirred for one hour at room temperature. After concentrating the reaction mixture until drying, the residue is taken up in H O and extracted with CH 2 Cl 2. The organic phases are dried over MgSO 4 and then evaporated under reduced pressure. After crystallization with EtOH / isopropyl ether and then by drying, 13.9 g of the product 9c are isolated in the form of beige crystals. P.f = 106 ° C CCD, Merck silica gel 60F 254 CH2Cl2 / MeOH: 95/5, Rf = 0.52. d) trans-2-methyl-5-γ4- (4-pyrimidin-2-yl-p-perizin-1-yl) cyclohexyloxy-2H-p, 2.41 triazin-3-one (9) NaH is suspended ( 60% in paraffin, 0.56 g, 14 mmol) in 20 ml of dioxane under an inert atmosphere at 0 ° C.

Trans-4- (4-Pyrimidin-2-yl-piperazin-1-yl) cyclohexane I (prepared according to the procedure described in Example 1 is then added using, in step e, NaBH 4 in ethanol ) (4.0 g, 15.4 mmol) diluted in 20 ml of dioxane. The mixture is stirred while the temperature is raised to room temperature. After having placed the reaction mixture back to the ice bed, then compound 9c (2.2 g, 14 mmol), diluted in 15 ml of dioxane is added and the reaction mixture is stirred for one hour at 0 ° C. After concentrating until drying, the residue obtained is taken up in water and then extracted with dichloromethane. The organic phases are dried over MgSO 4 and then concentrated until drying. The isolated oil is purified by flash chromatography with silica (eluent CH2Cl2 / MeOH / NH4OH: 90/9/1) After recrystallization from methanol, 2 grams of the white precipitate are isolated Pf = 200 ° C CCD, silica gel Merck 60F 254 CH2Cl2 / MeOH: 90/91, Rf = 0.35.

EXAMPLE 10 trans-2-methyl-5-r4-r4-methyl-pyridin-2-in-piperazin-1-cyclohexyloxy-2H-H, 2,41-triazin-3-one (10) a) trans-4-Piperazin-1-yl-cyclohexanol (10a) trans-4- (4-Benzylpiperazin-1-yl) cyclohexanol (prepared from benzylpiperazine according to the procedure described in example 1) is placed using, in step e, NaBH 4 in ethanol) (15 g, 54.6 mmoles) in 150 ml of ethanol under 4 bars of hydrogen in the presence of 10% palladium on carbon (1 g). After stirring for 72 hours, the catalyst is filtered over celite and the filtrate is concentrated until dried. 9.6 grams of light-colored oil are isolated. CCD, Merck silica gel 60F 254 CH2Cl2 / MeOH / NH4OH: 80/18/2, Rf = 0.42. b) trans -4- (4-methy1pyrimidn-2-yl) piperazin-1-cyclohexanol (10b) Compound 10a (4.3 g, 23.3 mmol) in 100 ml of toluene is placed in the the presence of 2-chloro-4-methylpyrimidine (3 g, 23.3 mmol) and of triethylamine (4.9 ml, 35.1 mmol) and subsequently heating this mixture to reflux for 16 hours. After evaporating the solvent under vacuum, the residue is taken up in basic H20 (pH = 11) and extracted with dichloromethane. Dry the organic phases over (MgSO4) and then concentrate until drying. The isolated residue is purified by flash chromatography with silica (eluent CH2Cl2 / MeOH / NH4OH: 80/18/2) and 4 g of compound 10b are isolated. CCD, Merck silica gel 60F 254 CH2Cl2 / MeOH / NH4OH: 80/18/2, Rf = 0.77. c) trans-2-methyl-5- [4-r4- (4-methylpyrimidin-2-yl) piperazin-1-H-cyclohexyloxy-2 H-1,41-triazin-3-one (10) The compound is prepared according to the procedure described in example 9 using intermediate 10b in step d. P.f = 189 ° C CCD, Merck silica gel 60F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.44.

EXAMPLE 11 trans-2-methyl-5-r4-r4-f4,6-dimethyl-pyrimidin-2-yl) piperazine-1-incyclohexyloxy-2 / Y-H, 2,41-triazin-3-one (11) This compound is prepared according to the procedure described in Example 10 using 2-chloro-4,6-dimethylpyrimidine in step b. P.f. = 211 ° C CCD, Merck silica gel 60F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.54.

EXAMPLE 12 trans-2-methyl-5-r4-r4- (4-chloropyrimidin-2-yl) piperazin-1-incyclohexylxp-2-p.2,41 triazin-3-one (12) This compound is prepared according to the procedure described in Example 10 using 2,4-dichloropyrimidine in step b. P.f. = 214 ° C CCD, Merck silica gel 60F 254 CH2CI2 / MeOH: 90/10, Rf = 0.57.

EXAMPLE 13 trans-2-methyl-5-r4-r4- (4-methoxypyrimidin-2-yl) piperazin-1-incyclohexyloxy-2H-M, 2,41-triazin-3-one (13) This compound is prepared according to the procedure described in Example 10 using 2-chloro-4-methoxypyrimidine in step b. P.f. = 196 ° C CCD, Merck silica gel 60F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.43.

EXAMPLE 14 trans-2-methy1-5-r4-r4- (4-trifluoromethyl-pyrimidin-2-yl) piperazin-1-yl-cyclohexyl-2H-H, 2,41-triazin-3-one (14) This compound is prepared according to the procedure described in Example 10 using 2-chloro-3- (trifluoromethyl) piperimidine in step b. P.f. = 184 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.73.

EXAMPLE 15 trans-2-methyl-5-r4-r4- (5-fluoropyrimidin-2-yl) piperazin-1-incyclohexyloxy1-2H- p .2.41triazin-3-one (15) This compound is prepared according to the procedure described in Example 10 using 2-chloro-5-fluoropyrimidine in step b. P.f. = 209 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.61.

EXAMPLE 16 trans-5-r4-r (2,3-dihydrobenzori, 41-dioxin-2-ylmethyl) amino-1-cyclohexyloxy-2-methyl-2-tf-n .2,41-triazin-3-one (16) This compound is prepared according to the procedure described in example 9 using trans-4 - [(2,3-dihydrobenzo [1,4] dioxin-2-ylmethyl) amino] cyclohexanol (prepared according to the procedure described in Example 1, using, in step e, NaBH 4 in ethanol) in step d. P.f. = 114 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.61.

EXAMPLE 17 trans-6-. { 4-r4- (3-chlorophenyl) piperazin-1-inccyclohexylamine > -2,4-dimethyl-2? '- M, 2,41-triazine-3,5-dione (17) a) 2,4-dimethyl-2H-p .2.41-triazine-3,5-dione (17a) NaH (60% in paraffin, 8.8 g, 220 mmol) is suspended in 100 ml of DMF under an inert atmosphere. A solution of 2 - / - [1, 2,4] triazine-3,5-dione (25 g, 220 mmol) is added dropwise and then this mixture is stirred for 0.5 hour at room temperature. CH3I (27.4 mL, 440 mmol) is added and then stirred overnight. The solvent is concentrated under vacuum until dry and then the residue is taken up in 300 ml of DMF, to which 8.8 g of NaH (60% in paraffin, 220 mmol) are added, under an inert atmosphere. After stirring for 4 hours, CH3I (27.4 ml, 440 mmol) is added and the mixture is stirred overnight at room temperature. The reaction mixture is concentrated in vacuo to dryness and the isolated residue is taken up in a saturated aqueous NaCl solution and extracted with ethyl acetate. The organic phases are dried over Na 2 SO 4 and then evaporated under vacuum. After crystallization and washing with water, 16.4 g of compound 17a are obtained. P.f. = 64 ° C CCD, silica gel Merck 60 F 254 CH2CI2 / AcOEt; 70/30, Rf = 0.53. b) 6-bromo-2,4-dimethyl-2 / - / - p .2.41tr¡azno-3,5-dione (17b) Compound 17a (13.3 g, 94.1 mmoles) is placed in 100 ml of water in the presence of bromine (18 ml, 351 mmol) and then this mixture is heated at 60 ° C for 12 hours. After concentrating until drying, the obtained residue is taken up in H2O and then extracted with ethyl acetate. The organic phases are dried over MgSO 4 and then evaporated under vacuum. After recrystallization from ether, 7.8 g of compound 17b are isolated. P.f. = 104 ° C CCD, Silica gel Merck 60 F 254 CH2CI2 / AcOEt; 70/30, Rf = 0.73. c) 4-r4- (3-chlorophenyl) piperazin-1-illcyclohexanone oxime (17c) Compound d (15.3 g, 52.3 mmol) is placed in a mixture of 143 mL of EtOH and 7 mL of water in the presence of hydroxylamine hydrochloride (5.9 g, 83.7 mmol) and sodium hydroxide (14.5 g, 130.7 mmol. ). The mixture is stirred for 1 hour at room temperature and then 70 ml of water are added. The reaction mixture is extracted with ethyl acetate. The organic phases are dried over MgSO4 and then concentrated until drying. 15.3 g of orange solid are isolated, the product of which is used without further purification in the next step. CCD, Silica gel Merck 60 F 254 CH2CI2 / MeOH: 95/5, Rf = 0.12. d) cis- and trans-4- [4- (3-chlorophenyl) piperazin-1-cyclohexylamine Ü7d) LiAIH4 (8.4 g, 221 mmol) is suspended in 219 ml of THF under an inert atmosphere. Compound 17c (20.8 g, 67.6 mmol), diluted in 227 ml of THF, is added dropwise and the mixture is refluxed for 2 hours. The reaction mixture is neutralized using 32 ml of water and then dried with MgSO4. After filtering through concreted glass, the filtrate is concentrated until dry. The isolated orange oil is purified by flash chromatography with silica (eluent CH2Cl2 / MeOH / NH4OH: 80/18/2). 3.4 g of the cis 17d compound and 3.7 g of the trans 17d CCD compound are recovered, Merck silica gel 60 F 254 CH 2 Cl 2 / MeOH / NH 4 OH: 80/18/2, Rfc s s = 0.43 R = 0.31. e) trans-6- (4- [4- (3-chlorophenol) piperazin-1-ip-cyclohexylamino) -2,4-dimethyl-2H-p, 2,41-triazine-3,5-dione ( 17) Compound 17d (3.7 g, 12.4 mmol) is placed in 45 ml of n-BuOH and triethylamine (3.6 ml, 25.8 mmol) in the presence of intermediate 17b. This mixture is refluxed for 36 hours and then the solvent is concentrated under vacuum, until drying. The obtained brown residue is taken up in H2O and extracted with ethyl acetate. The organic phases are dried over MgSO 4 and then evaporated under vacuum. After purification by flash chromatography with silica (eluent CH2Cl2 / MeOH: 95/5) and decolorization with animal charcoal in ethanol, a white precipitate (0.5 g) is isolated. P.f. = 178 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.67.

EXAMPLE 18 cis-6-f4-f4- (3-chlorophenyl) piperazin-1-incyclohexylamino > -2,4-dimethyl-2H-ri, 2,41-triazine-3,5-dione (18) This compound is prepared according to the procedure described in example 17 using, in step e, the cis 17d intermediate.

EXAMPLE 19 trans-6- (4'4- (3-chlorophenyl) piperazin-1-cyclohexyl) methylamino) -2,4-dimethyl-2H-p, 2,41-triazine-3,5-dione (19) Compound .17 (0.5 g, 1.2 mmol) is placed in 14 ml of THF under an inert atmosphere in the presence of NaBH4 (0.2 g, 5.3 mmol) and paraformaldehyde (0.3 g, 11.3 mmol). Trifluoroacetic acid (7 ml, 90.8 mmol) is added by dropping, and then this mixture is stirred for 20 hours at room temperature. The reaction mixture is added to a solution consisting of 19 ml of 25% NaOH and 19 ml of saturated aqueous NaCl solution. After extracting with dichloromethane, the organic phases are dried over MgSO0 and then concentrated until drying. The residue obtained is purified by flash chromatography with silica (eluent CH2Cl2 / MeOH: 95/5). After crystallization from methanol, 0.4 g of white solid are isolated. P.f. = 179 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 95/5, Rf = 0.38.

EXAMPLE 20 cs-6 - ((4-r4- (3-chlorophenyl) piperazin-1-incyclohexyl) methamino) -2,4-dimethyl-2H-M, 2,41-triazine-3,5-dione ( twenty) This compound is prepared from intermediate 18 according to the procedure described in Example 19. P.f. = 124 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 95/5, Rf = 0.58.

EXAMPLE 21 trans-2,4-dimethyl-6-r4- (4-pyrimidin-2-yl-piperazin-1-yl) -cyclohexylamino-1-2A-M, 2.41-triazine-3,5-dione ( twenty-one) This compound is prepared according to the procedure described in example 17 using trans-4- [4-pyrimidin-2-yl-piperazin-1-yl) cyclohexylamine in step e. P.f. = 173 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.46.

EXAMPLE 22 cis-2,4-dimethyl-6-r4- (4-pyrimidin-2-yl-piperazin-1-yl) cyclohexylamino-1-2A-H, 2,41-triazine-3,5-dione (22) This compound is prepared according to the procedure described in example 17 using cs-4- [4-pyrimidin-2-yl-piperazin-1-yl) cyclohexylamine in step e. P.f. = 170 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.47. The compounds of the invention have been subjected to pharmacological tests that have demonstrated their advantage as therapeutically active substances.

Union to the 5-HTIA receptors, D? dopaminergic and al-adrenergic: Brains of male Sprague-Dawley rats of 180-200 g [Ico: OFA SD (I.O.P.S. Cow); Iffa Credo, France], maintained at -70 ° C ,.

The affinity of the products for the various receptors was determined by the displacement of the radioactive ligands under the conditions summarized in Table 1. The reaction was stopped by rapid filtration, under vacuum, through Whatman GF / B filters and rinsed the tubes with 2 x 5 ml of 50 mM Tris-HCl, pH 7.4, pH regulator at 25 ° C. The radioactivity collected on the filter is analyzed by liquid scintillation after the addition of 4 ml of liquid scintillant (Emulsifier Safe, Packard). All experiments are carried out in triplicate. The inhibition constants (Ki) of the products are calculated from the displacement experiments using EBDA (equilibrium linkage data analysis) of the non-linear regression program Radlig Version 4 (Biosoft, Cambridge, UK, McPherson, 1985) . The values pKi (-log Ki) are given in the form of the meaning of ± SEM of at least 3 experiments (table 2).

TABLE 1 Experimental conditions for binding to receptors PH regulators: (A) 50 mM Tris HCl pH 7.4, 10 μM pargyline, 24 mM CaCl, 0.1% ascorbic acid; 15 (B) 50 mM Tris HCl pH 7.4, 120 mM NaCl, 5 mM KCl; (C) 50 mM Tris HCl pH 7.4.

TABLE 2 Serotoninergic syndrome: The central activity of the compounds of the invention was evaluated according to their ability to cause the 5-HT syndrome, which is characterized by: - an alternating flexion and stretching of the front legs (reciprocal foot tread: FPT) - retraction of the lower lip (retraction of the lower lip: LLR) - a position or the ventral surface of the animal is in contact with the ground and with the hind legs extended (posture position of the body : FBP). The experiments in the evaluation of the 5-HT syndrome are carried out with the male rat (Sprague-Dawley) according to the technique described by F.C. Colpaert et al. (Drug, Dev. Res., 26, 21-48, 1992) and M.S. Kleven et al. (J.P.E.T., 282, 747-759, 1997).

The active dose (ED50) for some derivatives of the invention, in comparison with the reference products such as Buspirone and Flesinoxane, are given in Table 3 by way of example.

TABLE 3 5-HT Syndrome Antidepressant activity: Forced swimming test: The compounds of the invention are tested according to the procedure described by R. Porsolt et al. (Eur. J. Pharmacol., 47, 379-391, 1978). The active dose (ED50) is calculated for each compound according to the percentage of animals that show a significant decrease, in comparison with the control animals (p <0.05), in the immobility time (table 4).

TABLE 4 The results of the various tests show that the compounds of the general formula I possess, in vitro, a high affinity for serotonergic receptors of type 5-HTIA and a good selectivity in relation to the ai and D2 receptors. These show, in vivo, an agonist activity in relation to the 5-HTIA receptors and are powerfully active in relation to behavioral models, such as the forced swim test. Therefore, the compounds of the invention can be useful in the treatment for anxiety, depression, pain, neurodegeneration, schizophrenia, Alzheimer's disease and sleep disorders, for the regulation of food intake, for the regulation of the gastric secretion and for the treatment of vascular, cardiovascular and cerebrovascular disorders, such as hypertension or migraine. Pharmaceutical preparations comprising compounds of the general formula I as the active ingredient can be formulated for oral, rectal or parenteral administration, for example in the form of capsules, including hard gelatin capsules, tablets, granules, liquid solutions, syrups or suspensions. which are administered orally, and may comprise suitable excipients. It is also possible to combine other pharmaceutically and therapeutically acceptable active ingredients therein.

Claims (8)

NOVELTY OF THE INVENTION CLAIMS

1. - Derivatives of hexane cycle of double functionality corresponding to the general formula I in which -A represents a formula group / \ l i a - N N- -Ar \ / wherein Ar itself represents a structure of aromatic type chosen from phenyl or pyripidinyl, optionally substituted by one or more C1-3 alkyl groups, C1-C3 alkoxy, trifluoromethyl or halogen,

-B represents a heterocyclic group of formulas: 3,5-dioxo- (2H, 4H) -1, 2,4, -triazine substituted at the 2-position, (Illa) 3-oxo- (2H) -1, 2, 4, -triazine substituted at position 5, (lllb) or: 3,5-dixo-6-amino- (2H, 4H) -1, 2,4-triazine, (lile) wherein R represents an alkyl group of C C3, and the salts of the compounds of the general formula I with pharmaceutically acceptable acids, it being possible for the compounds of the formula I to be provided in the form of different "cis" and "trans" isomers "and of several enantiomers of the compounds that have asymmetric carbons. 2. The compound according to claim 1, further characterized in that it is chosen from the following compounds: * cis-2- [4- [4- (3-chlorophenyl) piperazin-1-yl-cyclohexyl] fumarate] -4 -methyl-2H- [1, 2,4] triazino-3,5-dione, * trans-2- [4 - [(2,3-dihydrobenzo [1,4] dioxin-2-ylmethyl) amino hemifumarate] cyclohexyl] -4-methyl-2H- [1, 2,4] triazino-3,5-dione, * cs-4-methyl-2- [4- (4-pyridimidin-2-yl-piperizin -1-yl) cyclohexyl] -2H- [1, 2,4] triazino-3,5-dione, * trans-4-methyl-2- [4- (4-pyrimidin-2-yl-piperizin- 1 -yl) cyclohexyl] -2H- [1, 2,4] triazino-3,5-dione, * trans-4-methyl-2- [4- [4- (4,6-dimethylpyrimidin-2- L) piperizin-1 -iI] cyclohexyl] -2H- [1, 2,4] triazino-3,5-dione, * trans-4-methyl-2- [4- [4- (4-methyl) Rimidn-2-yl) piperazin-1-yl] cyclohexyl] -2H- [1, 2,4] triazino-3,5-dione, * trans-2- [4- [4- ( 4-chloropyrimidin-2-yl) piperazin-1-yl] cichlohexyl] -4-methylene-2H- [1, 2,4] triazine-3,5-dione, * trans-2- [4- [4- (5-fluoropyrimin-2-yl) p -perizin-1-yl] cyclohexyl] -4-methyl-2H [1, 2,4] triazino-3,5-d-one , * trans-2-methyl-5- [4- (4-pyrimidin-2-yl-p-per! zin-1-yl) cyclohexyl] -2H- [1, 2,4] tr azin-3-one, * trans-2-methyl-5- [4- [4- (4-methylpyrimidin-2-yl) piperazin-1-yl] cyclohexyloxy] -2H- [1, 2,4] triazine- 3-one, * trans-2-methyl-5- [4- [4- (4,6-dimethyl-pyrimidin-2-yl) piperazin-1-yl] -cyclohexyloxy] -2H- [1,2,4] triazin-3-one, * trans-2-methyl-5- [4- [4- (4-chloropyrimidin-2-yl) piperazin-1-yl] cyclohexyloxy] -2H- [1, 2,4] triazin-3-one, * trans-2-methyl-5- [4- [4- (4-methoxypyrimidin-2-yl) p -perazin-1-yl] -cyclohexyloxy] -2H- [1, 2, 4] triazin-3-one, * trans-2-methyl-5- [4- [4- (4-trifluoromethyl-pyrimidin-2-yl) piperazin-1-yl] -cyclohexyloxy] -2H- [1 , 2,4] triazin-3-one, * trans-2-methyl-5- [4- [4- (5-fluoropyrimidin-2-yl) piperazin-1-yl] cyclohexyloxy] -2H- [1, 2 , 4] triazin-3-one; * trans-5- [4 - [(2,3-d¡h¡drobenzo [1,4] dioxin-2-ylmethyl) amino] cyclohexyloxy] -2-methyl-2H- [1,2,4] triazin-3-one, * trans-6- (. {4- [4- (3-chlorophenyl) piperazin-1-yl] cyclohexyl] methylamino) -2,4-dimethyl-2H- [1, 2,4] triazino-3,5-dione, * cis-6- (. {4- [4- (3-Chlorophenyl) piperazin-1-yl] cyclohexyl] methylamino) -2,4-dimethyl-2H- [1, 2,4] triazino-3,5-dione.

3. Process for the preparation of the chemical compounds according to claims 1 and 2, further characterized in that a derivative of the general formula IV wherein A represents the lia or llb groups described above, is treated with an intermediate of type Va or Vb the condensation between the IV and Va derivatives can be carried out according to the conditions of the Mitsunobu reaction, and the condensation between the IV and Vb derivatives can be carried out in the presence of sodium hydride or tert-butoxide. potassium in dioxane or THF.

4. The use of 5-HT-IA receptor agonists, as defined in accordance with any of claims 1 and 2, for the manufacture of a medicament for the treatment of diseases requiring said agonists.

5. - The use as claimed in claim 4, wherein the diseases are anxiety, depression, pain, neurodegeneration, schizophrenia, Alzheimer's disease and sleep disorders, the regulation of food intake, the regulation of gastric secretion and the treatment of vascular, cardiovascular and cerebrovascular disorders.

6. The pharmaceutical composition, further characterized, because it comprises, as an active ingredient, a compound defined according to any of claims 1 and 2.

7. The pharmaceutical composition according to claim 6, further characterized in that it comprises a compound defined according to any of claims 1 and 2 in combination with any suitable excipient.

8. The pharmaceutical composition according to any of claims 6 and 7, further characterized in that it comprises a compound defined according to any of claims 1 and 2 in combination with another active principle.