MXPA00003772A - 3-oxo-2(h)-1,2,4-triazine derivatives as ligands of 5ht1a receptors - Google Patents

Abstract

The invention concerns novel 3-oxo-(2H)-1,2,4-triazine derivatives of general formula (I) in which R1 represents:hydrogen, when A is an optionally substituted nitrogen atom;a linear or branched C1-C4 alkyl group;a C1-C4 phenyl alkyl group, the phenyl ring being optionally substituted by one or several groups such as C1-C4 alkyl, C1-C3 alkoxy, halogen, trifluoromethyl. R2 represents:hydrogen;a linear or branched C1-C4 alkyl radical;a C1-C4 phenyl or phenylalkyl group, the phenyl ring being optionally substituted by one or several groups such as C1-C4 alkyl, C1-C3 alkoxy, halogen, trifluoromethyl. A represents an oxygen atom or a nitrogen atom optionally NR3 substituted. R3 represents hydrogen or a methyl group. B represents a group such as (IIa) in which Ar itself represents an aromatic structure such as phenyl, pyridyl or pyrimidyl, optionally substituted by one or several groups such as C1-C3 alkyl, C1-C3 alkoxy, hydroxy, trifluoromethyl or halogen and n can be whole numbers ranging between 3 and 5;(IIb) in which Ar is as defined in formula (IIa) and m can be a whole number ranging between 1 and 2;(IIc) in which R4 represents hydrogen or a C1-C3 alkyl group and n can be whole numbers ranging between 3 and 5.

Description

DERIVATIVES OF 3-OXO-2 (H) -1,2,4-TRIAZINE AS LIGANDS OF 5-HTIA RECEPTORS DESCRIPTIVE MEMORY A subject matter of the present invention are the novel derivatives of 3-oxo- (2 - /) - 1, 2,4-triazine functionalized in position 5, their preparation and their application in therapies. The 5-HT-IA receptors have been claimed for their function in several pathologies, such as hypertension, sexual dysfunction, anorexia or memory. The main objective that suggests the involvement of 5-HT-IA receptors, however, is composed of disorders of the central nervous system, such as anxiety and depression. The hypotheses, supported by the tests in animal models and clinical studies, suggest that more effective treatments of these pathologies can be predicted with 5-HT1A agonist compounds, with a high affinity, which are highly selective and highly effective. The derivatives of 3,5-Dioxo- (2 - /, 4H) -1, 2,4-triazine and the derivatives of 3,5-dioxo-6-amino- (2 -, 4H) -1, 2,4 -triazine have been previously claimed by the applicant company (FR 2,707,294 of 06/07/93 and FR 2,727,682 of 12/02/94). The compounds of the present invention are characterized by their high affinity with respect to the 5-HT? A receptor, in combination with a high selectivity, in particular with respect to the D2 and a-i receptors, and a high intrinsic activity. The compounds of the invention correspond to the general formula I. wherein Ri represents: • hydrogen, when A is an optionally substituted nitrogen atom, • a linear or branched C-? -C alkyl group, • a phenyl-C1-C4 alkyl group, the phenyl nucleus is optionally substituted by one or more groups, such as C4 alkyl, CrC3 alkoxy, halogen or trifluoromethyl, R2 represents: • hydrogen, • a linear or branched C? -C4 alkyl radical, • a phenyl or phenylalkyl group of C1-C4, the phenyl nucleus is optionally substituted by one or more groups, such as alkyl of C -? - C4, C Ca, halogen or trifluoromethyl alkoxy, A represents an oxygen atom or a nitrogen atom in NR3, optionally substituted.

R3 represents hydrogen or a methyl group, B represents a group of type. wherein the Ar itself represents an aromatic structure, such as phenyl, pyridyl or pyrimidyl, optionally substituted by one or more groups, such as C1-C3 alkyl, CrC3 alkoxy, hydroxyl, trifluoromethyl or halogen, and n can take the values integrals from 3 to 5, where Ar is as defined in the formula Na and m can take the integral values 1 and 2. wherein R represents hydrogen or a C1-C3 alkyl group, and n can take the integral values of 3 to 5. The invention encompasses the inorganic or organic salts of the compounds of the general formula I with pharmaceutically acceptable acids. In addition, it encompasses the various enantiomers and diastereoisomers of the compounds having one or more asymmetric carbons, as well as their mixtures in all proportions, including in particular the racemic mixtures.

Synthesis The compounds of the present invention can be prepared according to various methods. These can be synthesized by the use of synthetic routes described below or by the use of synthetic methods known to those skilled in the art. The synthesis of the compounds of the general formula I is characterized as a derivative of the general formula III (scheme 1). it is condensed with an alcohol B-OH-IV or an amine BHNR3, V, Ri, R2, R3 and B having the same meaning as above in general form I. Compounds III are obtained according to a procedure (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 of methyl iodide in basic aqueous medium, followed by an acidic treatment, such as hydrochloric acid. 3. Sulfurization of position 5 in the presence of Lawesson's reagent in a solvent such as pyridine. 4. - Methylation by methyl iodide in basic aqueous medium, such as sodium hydroxide solution. 5. Alkylation of position 2 by an alkyl halogenide R-iX in the presence of NaH in DMF, X representing Cl, Br or I.

Synthesis of compounds III (scheme I) 1) a-H20, 65 ° C and then at room temperature, 2h, b-1 N NaOH, reflux, 1 h. 2) a-CH3l, 2N NaOH, room temperature, 16h, b-2N HCl, reflux, 0.5h. 3) Lawesson's reagent, pyridine, reflux, 2h. 4) CH3I, aqueous NaOH, room temperature, 2h.

) R- | I, NaH, DMF, room temperature, 2h.

The condensation of the intermediates III with the alcohols IV or amines V is carried out in the presence of a base, such as sodium hydride or potassium tert-butoxide in dioxane, THF or toluene. The optional separation of the enantiomers or diastereoisomers of the compounds having one or more asymmetric carbons is generally carried out in the final products by liquid chromatography on a chiral column.

Synthesis of alcohols B-OH IV A- when B represents a group of type / \ Ha (CH2) n -N I N- Ar \ / you can get the corresponding alcohols / \ IVa HO- (CH2) n N N-Ar \ _ / 1) by treating piperazine with a haloalcohol VII HO- (CH2) n-Hal in the presence of K2CO3 and optionally K1, when Hal = Br or Cl, in acetonitrile at reflux, 2) when n = 4 or 5, by treatment of piperazine VI with a Vllll lactone in the presence of a Lewis acid, such as AICI3, and of triethylamine in dichloromethane, and by reduction of the amide IX formed with a hydride, such as LiAIH4 in THF, IX 3) when Ar represents a pyrimidine-type heterocycle, by the treatment of 2-chloropyrimidine optionally substituted with a hydroxyalkylpiperazine X in a solvent, such as toluene, in the presence of such an amine, triethylamine. ß- When B represents a group of type 1) when m = 1, according to the procedure described in the Pfizer patent WO 93 25552 (1992), 2) when m = 2, by oxidation of alcohol XI under the conditions of Swern and by the treatment of the aldehyde obtained XII with a Wittig reagent, such as methoxymethyltriphenylphosphonium chloride in THF, followed by hydrolysis in aqueous acidic medium of the enolic ether obtained XIII to result in the corresponding XIV aldehyde which is reduced to the alcohol with a hydride, such as NaBH 4 in ethanol.

C- When B represents a group of type you can prepare the corresponding alcohols 1) by the benzodioxanmethylamine treatment according to the procedure described in paragraph A-2, 2) By the condensation of benzodioxametanol with an aminoalcohol XV XV HO- (CH2) n-NH2 Synthesis of the amines B-NHR3 V 1) When R3 = H, the compounds V are commercial amines or can be obtained conventionally, such as the generation of the primary amine of the intermediate phthalimide. 2) When R3 = Me, the compounds are obtained from the amines BNH2 (whose method of preparation is described above) by forming the amine with formic anhydride in a solvent, such as pyridine, to result in the amide form XVI which is reduced with a hydride, such as LiAIH4 in THF. The following examples illustrate the invention without limiting the scope thereof. Elemental analyzes and IR and NMR spectra confirm the structures of the compounds obtained according to the invention.

EXAMPLE 1 2-MetH-5-r4- (4-pyrimidin-2-yl-piperazin-1-yl) butoxy1-2H-ri, 2,41-triazin-3-one III a) 5-thioxo-4,5-dihydro-2 - / - p, 2.41triazin-3-one (1a) 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 residue obtained is placed in 400 ml of water. The brown precipitate that forms is isolated by filtration. Said crystals are collected in H2O and extracted with ethyl acetate. After drying the organic faces (MgSO) and concentrating them until dry, yellow crystals are obtained. Retreatment of the aqueous solution (400 ml) by extraction with ethyl acetate makes it possible to isolate one or the other solid fraction. In total, after drying, 60 g of yellow crystals are obtained. p.f. 0 239 ° C CCD, Merck silica gel 60 F 254 CH2CI2 / MeOH: 90/10, RF = 0.4. b) 5-Methylsulfanyl-2-H, 2,41-triazin-3-one (1 b) The compound (30 g, 232 mmol) and CH 3 I (15.9 mL, 255 mmol) are placed in 300 mL of water. 18.6 g of NaOH (465 mmoles) are added and the mixture is stirred for 1 hour at room temperature. The reaction mixture, cooled on an ice bed, is neutralized using 27 ml of acetic acid and then extracted with dichloromethane. The organic phases are dried (MgSO 4) and then concentrated to dryness. After recrystallization from the ether, 29.9 g of compound I b are isolated. p.f. = 171 ° C CCD, silica gel Merck 60 F 254 CH2CI2 / MeOH: 90/10, RF = 0.5. c) 2-methyl-1-5-methylsulfanyl-2 / - / - í1.2,41 triazin-3-one (1c) A suspension of NaH, placed under nitrogen (60% in liquid paraffin, 4.4 g, 110 mmol) in 50 ml of DMF is cooled to 0 ° C in a bed of ice. Compound 1_b (15.9 g, 111 mmol), diluted in 100 ml of DMF, is run in this suspension by dropping. The mixture is subsequently stirred for 1 hour at room temperature. After concentrating the reaction mixture to dryness, the residue is placed in H2O and CH2Cl2 is extracted. The organic phases are dried with MgSO 4 and then evaporated under reduced pressure. After crystallization from EtOH / isopropyl ether and after drying, 13.9 g of the product e are isolated in the form of beige crystals. p.f. = 106 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 95/5, RF = 0.52. d) 4-hydroxy-1- (4-pyrimidin-2-yl-piperazin-1-yl) butan-1 -one (1 d) The AICI3 (18.5 g, 138.8 mmol) is suspended in 100 ml of dichloromethane under a inert atmosphere (N2). A solution of triethylamine (22.3 ml, 160 mmol) diluted in 40 ml of dry dichloroethane by dripping into said mixture cooled to 0 ° C in an ice bed. This mixture is returned to room temperature and then a solution of 2-pyrimidinylpiperazine (19.5 g, 119 mmol) and butyrolactone (8.2 ml, 107 mmol) in 80 ml of dichloroethane is added dropwise. This mixture is stirred for 2 hours at room temperature and then poured rapidly into 200 ml of ice. After extraction with diclomethane, drying of the organic phases (MgSO4) and their concentration until dried, 27 g of crystals are coated and used in the next step without further purification. e) 4- (4-pyrimidin-2-yl-p-piperazin-1-yl) butan-1-olde) The LiAIH4 (4.9 g, 129 mmol) is suspended in 100 ml of THF under nitrogen. The Id (27 g, 108 mmol), diluted in 150 ml of THF, is added by dripping while taking care to maintain the temperature at room temperature. This mixture is stirred for 1 hour, hydrolyzed with the minimum amount of water and dried with MgSO4. After filtering the aluminum salts, the filtrate is concentrated to dryness. The residue obtained is purified by flash chromatography on silica (eluent: CH 2 Cl 2 / MeOH: 95/5). 17.3 g of yellow oil are coated. After salification with fumaric acid in ethanol, a white solid is isolated. p.f. = 112 ° C CCD, silica gel Merck 60 F 254 CH2CI2 / MeOH / NH4OH: 90/9/1, RF = 0.54. f) 2-methyl-5-r4- (4-pyrimidin-2-yl-piperazin-1-yl) butox1-2H-1, 2,4-triazin-3-one (1) NaH ( 60% in liquid paraffin, 0.68 g, 17 mmol) is placed in dimethoxyethane (DME) under an inert atmosphere. A solution of the compound le (in the base form, 4.5 g, 19 mmol) diluted in 20 ml of DME is added dropwise to said mixture cooled to 0 ° C. The reaction mixture is stirred for 1 hour at room temperature and then returned to 0 ° C. A solution of le (3 g, 19.1 mmol) diluted in 40 ml of DME is then run by dripping. The temperature of the reaction mixture is subsequently returned to room temperature and the stirring is maintained for 1 hour.

The inorganic products are filtered under vacuum and the filtrate is concentrated to dryness. The residue obtained is purified by flash chromatography on silica (eluent: CH2Cl2 / MeOH: 95/5), which makes it possible to isolate a yellow oil which crystallizes. After recrystallization from acetone, 2 g of compound 1 are obtained. P.p. = 134 ° C CCD, silica gel Merck 60 F 254 CH2CI2 / MeOH: 90/10, RF = 0.46.

EXAMPLE 2 2-Methyl-5-r4-r4 - (- MethylpSrimidine-2-yl) piperazin-1-pbutoxyfl-2H-p, 2,41-triazin-3-one fumarate (2) a) 4- [4- (4-Methylpyrimidin-2-iQp-piperazin-1-pbutan-1-ol (2a) Dichlorohydrate 4-methyl-2-p-piperazin-1-yl- pyrimidine (7 g, 38.8 mmol) and 4-chlorobutanol (4.6 ml, 46 mmol) are placed in 150 ml of acetonitrile in the presence of K2CO3 (21.5 g, 155.5 mmol), this mixture is refluxed for 16 hours. After cooling, the inorganic products are removed by filtration and the filtrate is concentrated to dryness The residue obtained is purified by flash chromatography on silica (eluent: CH 2 Cl 2 / MeOH: 90/10) to obtain 4.7 g of white crystals. 76 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 90/10, RF = 0.41. b) 2-Methyl-5-r4r4- (4-methylpyrimidin-2-yl) piperazin-1-lbutoxy-2 / - -ri, 2,41-triazin-3-one fumarate (2) This compound is prepared according to the procedure described in step f of Example 1 using 4 [4- (4-methylpyrimidin-2-yl) piperazin-1-yl] butan-1-ol and then salified with fumaric acid in ethanol. p.f. = 144 ° C CCD, silica gel Merck 60 F 254 CH2CI2 / MeOH / NH4OH: 90/9/1, RF = 0.7.

EXAMPLE 3 Fumarate of 5-r4-r4- (4,6-dimethylpyrimidin-2-yl) piperazin-1-inbutoxy-2-methyl-2-tf-p, 2,41-triazin-3-one (3) This compound is prepared according to the procedure described in step f of Example 1 using 4 [4- (4,6-dimethylpyrimidin-2-yl) piperazin-1-yl] butan-1-ol (prepared according to procedure 2a) and THF, and then salified with fumaric acid in ethanol. p.f. = 180 ° C CCD, Merck silica gel 60 F 254 CH2CI2 / MeOH / NH4OH: 90/9/1, RF = 0.61.

EXAMPLE 4 5-R4r4- (4-methoxypyrimidin-2-yl) pyripezin-1-pbutoxy-2-methyl-2H-, 2,41-triazin-3-one fumarate (4) This compound is prepared according to the procedure described in step f of Example 1 using 4 [4- (4-methoxypyrimidin-2-yl) piperazin-1-yl] butan-1-ol (prepared according to the procedure 2a) and THF, and then salified with fumaric acid in ethanol. p.f. = 164 ° C CCD, Merck silica gel 60 F 254 CH2CI2 / MeOH / NH4OH: 90/9/1, RF = 0.6.

EXAMPLE 5 5-f4r4- (5-methoxypyrimidin-2-yl) piperazin-1-inbutoxy-2-methyl-2-t-p, 2,41-triazin-3-one (5) This compound is prepared according to the procedure described in step f of Example 1 using 4 [4- (5-methoxypyrimidin-2-yl) piperazin-1-yl] butan-1-ol (prepared according to procedure 2a) and dioxane. p.f. = 101 ° C CCD, silica gel Merck 60 F 254 CH2CI2 / MeOH: 90/10, RF = 0.58.

EXAMPLE 6 5-r4-r4- (4-Chloropyrimidin-2-yl) piperazine-1-8nbutoxy-2-methyl-2AY-p, 2,41-triazin-3-one (6) a) 4-Piperazin-1-yl-butan-1-ol (6a) Piperazine (50 g, 580 mmol) is placed in 500 ml of acetonitrile and the mixture is heated to 60 ° C. K2CO3 (96 g, 694 mmol) is added and the reaction mixture is brought to reflux. The 4-chlorobutanol (58 ml, 581 mmol) is then run by dripping and then the reflux is maintained for 4 hours. After filtering the inorganic products, the filtrate is concentrated until dried under vacuum. The obtained residue is purified by flash chromatography on silica (eluent: CH2Cl2 / MeOH / NH OH: 80/18/2) and 51 g of a lightly-stained oil 6a are recovered. CCD, Merck silica gel 60 F CH2Cl2 / MeOH / NH4OH: 80/18/2, Rf = 0.40. b) 4-r4- (4-Chloropyrimidin-2-yl) piperazin-1-inbutan-1-ol (6b) The compound of 6a (30 g, 189 mmol) and triethylamine (31.6 ml, 226 mmol) are placed in toluene and then the mixture is brought to reflux. Then 2,4-dichloropyrimidine (28.2 g, 189 mmol) is added and the reflux is maintained for 3 hours. After concentrating the reaction mixture to dryness, the residue is placed in H20 saturated with NaHCO 3 and extracted with dichloromethane. The organic phases are dried with MgSO then concentrated until dried. The residue obtained is purified by flash chromatography on silica (eluent: CH2Cl2 / MeOH: 95/5) and 9.13 g of product 6b are recovered in the form of an oil. CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 95/5, Rf = 0.56. c) 5-r4-r4- (4-Chloropyrimid-2-yl) piperazin-1-illbutoxy1-2-methyl-2-p .2.41 triazin-3-one (6) This compound is prepared according to the procedure described in step f of Example 1 using 4- [4- (4-chloropyrimidin-2-yl) piperazin-1-ii] butan-1-ol 6b and THF. p.f. = 96 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH / NH4OH: 90/9/1, Rf = 0.6.

EXAMPLE 7 5-f4-f4- (5-fiuoropyrimidin-2-yl) piperazin-1-inbutoxy-1-2-methyl-2H-p, 2,41-triazine-3-one (7) This compound is prepared according to the procedure described in Example 6 using, in step b, 5-fluoro-2-chloropyrimidine. p.f. = 102 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH / NH4OH: 90/10, Rf = 0.46.

EXAMPLE 8 2-Propyl-5-r4- (4-pyrimidin-2-yl-piperazin-1-l) butoxil-2H-ri, 2,41-triazn-3-one fumarate (8) This compound is prepared according to the procedure described in step f of Example 1 using 4- (4-pyrimid-2-yl-piperazin-1-yl) butan-1-ol (prepared from according to example 2a) and 2-propyl-5-methylsulfanyl-2 - / - [1, 2,4] triazin-3-one (prepared according to example 1c using propyl iodide) in THF, and then salify with fumaric acid in ethanol. p.f. = 131 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH / NH4OH: 90/9/1, Rf = 0.55.

EXAMPLE 9 2,6-D-methyl-5-r4- (4-pyrimidin-2-yl-piperazin-1-yl) butoxp-2f -ri, 2,41-triazin-3-one (9) This compound is prepared according to the procedure described in example 1 using 6-methyl-2 / - / - [1, 2,4] triazine-3,5-dione in step a and 4- (4-pyrimidin-2) -yl-p-piperazin-1-yl) butan-1-ol (prepared according to method 2a) and dioxane in step f. p.f. = 69 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.47.

EXAMPLE 10: 2-methyl-6-phenyl-5-r4- (4-pyrimidin-2-yl-piperazin-1-yl) butoxp-2H-ri, 2,41-triazin-3-one (10) This compound is prepared according to the procedure described in example 1 using 6-phenyl-2H [1, 2,4] triazine-3,5-dione in step a and 4- (4-pyrimidin-2) -yl) butan-1-ol (prepared according to method 2a) and dioxane in step f. p.f. = 99 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.48.

EXAMPLE 11: 2-methyl-6-benzyl-5-r4- (4-pyrimidin-2-yl-p-piperazin-1-yl) butoxp-2-fluor, 2,41-triaz-n-3-one ( eleven) This compound is prepared according to the procedure described in example 1 using 6-benzyl-2H [1, 2,4] triazine-3,5-dione in step a and 4- (4-pyrimidin-2-yl) -piperazin-1-yl) butan-1-ol (prepared according to method 2a) and dioxane in step f. p.f. = 86 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.33.

EXAMPLE 12: 2-benzyl-5-r4- (4-pyrimidin-2-yl-p-piperazin-1-yl) butoxp-2W-ri, 2,41-triazin-3-one (12) This compound is prepared according to the procedure described in Example 1 using benzyl chloride in step c and 4- (4-pyrimidin-2-yl-piperazin-1-yl) butan-1-ol (prepared according to method 2a) and dioxane in step f. p.f. = 86 ° C CCD, silica gel Merck 60 F 284 CH2Cl2 / MeOH: 90/10, Rf = 0.38.

EXAMPLE 13: 2-Methyl-5-r3- (4-pyrimidin-2-yl-piperazin-1-yl) propoxyl-2A7-n, 2,41-triazin-3-one fumarate (13) This compound is prepared according to the procedure described in Example 1, step f, using 4- (4-pyrimidin-2-yl-piperazin-1-yl) propan-1-ol (prepared according to the procedure 2a of 3-chloropropanol) and dioxane, and then salified with fumaric acid in methanol. p.f. = 167 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH / NH4OH: 90/9/1, Rf = 0.60.

EXAMPLE 14: 2-methyl-5-r5- (4-pyrimidin-2-yl-piperazin-1-yl) pentyloxp-2A -ri, 2,41-triazin-3-one (14) This example is prepared according to the procedure described in Example 1, step f, using 4- (4-pyrimidin-2-yl-piperazin-1-yl) pentan-1-ol (prepared according to the process 2a of 5-chloropentanol) and dioxane. p.f. = 98 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH / NH4OH: 90/9/1, Rf = 0.50.

EXAMPLE 15: 5-R4- (4- (3-Methoxypyridin-2-yl-piperazin-1-yl) butoxy-2-methyl-2-tf-p, 2,41-triazin-3-one fumarate (15) This example is prepared according to the procedure described in Example 1, step f, using 4- (4- (3-methoxypyridin-2-yl) piperazinbutan-1-ol (prepared according to example 2a) and THF and then it is salified with fumaric acid in ethanol, mp = 146 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.38.

EXAMPLE 16 5-R4-R4- (3-chlorophenyl) piperazine-1-p-2-methyl-2H-ri, 2,41-triazin-3-one fumarate (16) This compound is prepared according to the procedure described in Example 1 in step f using 4- (4- (3-chlorophenyl) piperazin-1-yl) butan-1-ol (prepared according to example 2a) in dioxane, and then salified with fumaric acid in ethanol. mp = 153 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.47.

EXAMPLE 17 5-R4-R4- (5-Chloro-2-methoxy-phenol) -piperazin-1-n-butoxy-2-methyl-2W-p.2,41-triazin-3-one fumarate (17) This compound is prepared according to the procedure described in example 1 in step f using 4- (4- (3- (trifluoromethyl) piperazin-1-yl) butan-1-ol (prepared according to example 2a ) in dioxane, and then salified with fumaric acid in ethanol, mp = 184 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.65.

EXAMPLE 18 4-f4-f4- (2-methyl-3-oxo-2,3-dihydro-ri, 2,41-triazin-5-yloxy) butynepiperazin-1-illbenzonitrile (18) This compound is prepared according to the procedure described in Example 1 in step f using 4- (4- (4-hydroxybutyl) piperazin-1-yl) benzonitrile (prepared according to example 2a) in dioxane. mp = 132 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.56.

EXAMPLE 19 5-R4-R4- (5-Chloro-2-methoxyphenyl) -piperazin-1-pbutoxy-2-methyl-2H-p, 2,41-triazin-3-one fumarate (19) This compound is prepared according to the procedure described in Example 1 in step f using 4- (4- (5-chloro-2-methoxyphenyl) piperazin-1-yl) butan-1-ol (prepared in accordance with example 2a) and dioxane, and then salified with fumaric acid in methanol. mp = 152 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.54.

EXAMPLE 20 5-f4-R fumarate (2,3-dihydrobenzori, 41-dioxin-2-ylmethyl) amino-1-butoxy-2-methyl-2H-p, 2,41-triazin-3-one (20) This compound is prepared according to Example 1 using C- (2,3-dihydrobenzo [1,4] dioxin-2-yl) methylamine in step d, and then salified with fumaric acid in ethanol mp = 152 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH / NH4OH: 90/9/1, Rf = 0.58.

EXAMPLE 21 Fumarate of (R) -5-r4-r (2,3-dihydrobenzori, 41-dioxin-2-methyl) amino-1-butoxy-2-methyl-2H-ri, 2,41-triazin-3-one (21) a] Ester-2,3-dydro-benzoF 1, 41dioxin-2-ylmethyl acid (R) trifluoromethanesulfonic acid (21a) The (R) - (2,3-dihydrobenzo [1,4] dioxin-2-yl) methanol (3.6 g, 21.7 mmol) was placed in 320 ml of dichloromethane at -5 ° C. The triflic anhydride (3.3 ml, 19.7 mmol) in 20 ml of CH2Cl2 is then run by dripping. This mixture is stirred for 5 hours at -5 ° C. The reaction mixture is subsequently washed with 50 ml of 1 N HCl and then with water. The organic phase is dried with MgSO and then concentrated to dryness. The oil 21a obtained is used without further purification in the next step. b) (R) -4-r (2,3-di- hdrobenzop, 41d yoxin-2-ylmethyl) amino-butan-1-ol 21b) Compound 21 a is placed in 30 ml of dichloromethane. The 4-aminobutanol (3.6 ml, 38.90 mmol), diluted in 10 ml of CH 2 Cl 2, is then run by dropping into the reaction mixture. The stirring of the mixture is maintained for 14 hours at room temperature. The reaction mixture is concentrated to dryness and the residue is placed in H2O. After extraction with CH 2 Cl 2, by drying the organic phases with MgSO 4 and the concentration to dryness, an oil is isolated. This is purified by flash chromatography on silica (eluent: CH 2 Cl 2 / MeOH / NH 4 OH: 90/9/1) and 2.5 g of slightly stained oil 21 b are obtained. CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH / NH4OH: 90/9/1, Rf = 0.33. c) Fumarate of (R) -5-y4-f (2,3-dihydrobenzop .41d-oxyn-2-ylmethyl) amino-1-butoxy-2-methyl-2H-ri, 2,41-triazin-3-one (21) The final compound is obtained according to the procedure described in example 1, step f, using aminoalcohol 21b and dioxane, and then salified with fumaric acid in methanol mp = 137 ° C CCD, Merck silica gel 60 F 254 CH2Cl2 / MeOH / NH 4 OH: 90/9/1, Rf = 0.65.

EXAMPLE 22 Fumarate of (S) -5-r4-r (2,3, -dihydrobenzori, 41d-oxin-2-ylmethyl) amino-1-butoxy-2-methyl-2H-ri, 2,41-triazin-3-one- ( 22) This compound is obtained according to the procedure described in Example 21 using (S) - (2,3-dihydrobenzo [1,4,] dioxin-2-yl) methanol. p.f. = 135 ° C CCD, silica gel Merck 60 F 254 CH2CI2 / MeOH / NH4OH: 90/9/1, Rf = 0.59 EXAMPLE 23 Trans-2-methyl-5- (2-pyrimidin-2-yl-octahydropyridine, 2-a1p -razin-7-ylmethoxy) -2H-p, 2,41-traizin-3-one ( 2. 3) This compound is obtained according to the procedure described in Example 1 in step f using trans- (2-pyrimidin-2-yl-octahydropyrido [1, 2a] pyrazin-7-yl) -methanol and tert-butoxide potassium, mp = 140 ° C CCD, silica gel Merck 60 F 254 CH2CI2 / MeOH: 90/10, Rf = 0.35 EXAMPLE 24 Trans-2-methyl-5-r2- (2-pyrimidin-2-yl-octahydropyridoi, 2-a1pyrazin-7-yl-ethoxy) -2rt-p, 2,41-traizin-3-one (24) a) 2-Pyrimidin-2-1-octahydro-pyridine | 1, 2-alprazole-7-carbaldehyde (24a) Oxalyl chloride (6.2 ml, 68.8 mmole) is placed in 220 ml. of dichloromethane at -50 [deg.] C. DMSO (10 ml, 140.9 mmol), diluted in ml of dichloromethane. The trans- (2-pyrimidin-2-yl-octahydropyrido [1-2a] -pyrazn-7-yl) methanol, diluted in 30 ml of CH2Cl2, is run by dripping into said mixture maintained at -50 ° C. After stirring for 0.5 h at -50 ° C, triethylamine (40.8 mL, 293 mmol) is added and the temperature of the reaction mixture is returned to room temperature. The reaction mixture is washed with H2O and then the organic phase is dried with MgSO4 and then concentrated to dryness. The oil obtained 24a is purified by flash chromatography, CH 2 Cl 2 / MeOH: 90/10. CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH / NH4OH: 90/9/1, Rf = 0.24 b) (2-Pyridin-2-yl-octahydropyridyl-2-alpyrazin-7-yl) acetaldehyde (24b) The methoxymethyltriphenylphosphonium chloride (41.4 g, 120.8 mmol) and the diisopropylamine (11.6 mL, 88.5 mmol) are placed in 180 mL of THF at 0 ° C under an inert atmosphere. The n-butyllithium (1.6M solution in THF, 55.2 ml, 88.3 mmole) is run by dropwise and this mixture is stirred for one hour at room temperature. The reaction mixture is returned to 0 ° C and 24a, diluted in 120 ml of THF, is run by dripping. This mixture is stirred overnight at room temperature and then concentrated to dryness. The residue is collected in H2O and extracted with ethyl acetate. The organic phases are washed with acidic H2O (pH = 1). This aqueous phase is washed with AcOEt, then it is returned to pH 12 (concentrated NaOH solution) and extracted with dichloromethane. These organic phases are dried (MgSO4) and then concentrated to dryness. The oil obtained is purified twice by flash chromatography on silica (eluent CH2Cl2 / MeOH: 90/10 AcOEt / acetone: 50/50). 6.3 g of yellow oil are recovered. CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH / NH4OH: 90/9/1, Rf = 0.34 c) 2- (2-pyrimidn-2-yl-octahydropyrido F 1, 2-a1pyrazin-7-yl) ethanol (24c) NaBH 4 (1 g, 10.2 mmol) is placed in 30 ml of ethanol and then 24b (6.3 g, 24.2 mmol), diluted in 40 ml of ethanol, run by dropwise. This mixture is stirred overnight at room temperature and then hydrolyzed with water. After extraction with dichloromethane, the organic phases are dried (MgSO 4) and then concentrated to dryness. The residue obtained is purified by flash chromatography on silica (eluent: CH 2 Cl 2 / MeOH / 90/10). 4.5 g of yellow oil are recovered. CCD, silica gel Merck 60 F 254 CH2CI2 / MeOH: 90/10, Rf = 0.12 d) Trans-2-methyl-5-! "2- (2-pyridyl-2-yl-octahydropyrid [1,2-alpyrazin-7-yl] ethoxy- 2H-p, 2,4-Triazin-3-one (24) This compound is obtained according to the procedure described in Example 1 in step f using the alcohol 24c and dioxane mp: 145 ° C CCD, Merck silica gel 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.33.

EXAMPLE 25 Trans - (-) - 2-methyl-5-r2- (2-pyrimidin-2-yl-octahydropyridoi, 2-a1-pyrazin-7-yl) -ethoxy-2H-M, 2,41-triazin-3-one (25) Trans (-) The racemate prepared according to Example 24 is separated by HPLC chromatography [grafted silica, Chiracel OD-20 μm, eluent: hexane / isopropanol: 65/35 and 1/1000 diethylamine]. An oil is isolated and again purified by flash chromatography (eluent: CH 2 Cl 2 / MeOH: 90/10). After crystallization from a mixture of ether / isopropyl ether, 0.31 g of white crystals, m.p. = 145 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.36.

EXAMPLE 26 Trans - (+) - 2-methyl-5-r2- (2-pyrimidin-2-yl-octahydropyridoi, 2-a1pyraz »n-7-) l) ethoxy-2H-M, 2,41-triazine-3 ona (26) Trans (+) This compound is isolated according to the procedure described in Example 25. 0.42 g of white solid are isolated. p.f. = 146 ° C CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH: 90/10, Rf = 0.36.

EXAMPLE 27 2-Methyl-5-f4- (4-pyrimidin-2-yl-p-piperazin-1-yl) butylamino1-2iL -ri, 2,41-triazin-3-one (27) a) 4- (4-Pyrimidin-2-yl-p-piperazin-1-yl) butylamine (27a) Pyrimidin-2-yl-piperazine dichlorohydrate (17.5 g, 73.8 mmol) and 4-bromobutylphthalimide (25 g, 88 mmol) are placed in 200 ml of n-butanol and heated at reflux for 8 hours. After concentrating the reaction mixture to dryness, the obtained residue is placed in 100 ml of ethylenediamine and heated to reflux for 5 hours. The reaction mixture is concentrated in vacuo, the residue is taken up in basic H 2 O (pH = 11) and said aqueous phase is extracted with dichloromethane. The organic phases are dried with MgSO 4 and then concentrated to dryness. The residue obtained is purified by flash chromatography on silica (CH2Cl2 / MeOH / NH4OH: 90/9/1) and 10 g of oil are recovered, corresponding to the product 27a. CCD, silica gel Merck 60 F 254 CH2Cl2 / MeOH / NH4OH: 80/18, Rf = 0.24. b) 2-methyl-5- 4- (4-pyridin-2-yl-piperazin-1-yl) butyllamine "l-2 / - / - p, 2.41 triazin -3-one (27) The amine 27a (2.2 g, 9.3 mmol) is placed in 30 ml of toluene in the presence of 1_c (1.7 g, 11.2 mmoles) and the mixture is heated at reflux for 4 hours. The reaction is concentrated to dryness in vacuo and the residue is placed in H2O / NaHCO3 and extracted with dichloromethane, the aqueous phases are dried with MgSO and then concentrated to dryness The residue obtained is purified by flash chromatography on silica (eluent: CH2Cl2 / MeOH: 90/10) and 2.50 g of white crystals are obtained pf = 188 ° C CCD, Merck silica gel 60 F 254 CH 2 Cl 2 / MeOH: 90/10, Rf = 0.26 The compounds of the invention have been subjected to Pharmacological tests that have shown their advantage as therapeutically active substances.

Links to the receptors of 5-HTIA, dopaminergic Dg and a1-adrenergic: The brains of male Sprague-Dawley rats of 180-200 g [Ico: OFA SD (I.O.P.S. Caw); Iffa Credo, France], maintained at -70 ° C, were used in all studies. 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, in vacuum, through the Whatman GF / B filters and the tubes were rinsed with 2 x 5 ml of 50 mM Tris-HCl, pH 7.4, pH regulator at 25 ° C. The radioactivity collected on the filter was analyzed by liquid scintillation after the addition of 4 ml of liquid scintillant (Emulsifier Safe, Packard). All the experiments were carried out in triplicate. The inhibition constants (Ki) of the products are estimated from the displacement experiments using the EBDA (equilibrium bond data analysis) of the Radlig nonlinear regression program version 4 (Biosoft, Cambridge, UK; McPherson , 1985).

The pKi (-log Ki) values are given in the form of ± SEM average of at least 3 experiments (table 2).

TABLE 1 Experimental conditions for binding to recipients PH regulators: (A) 50 mM Tris HCl pH 7.4, 10 μM pargyline, 4 mM CaCl 2, 0.1% ascorbic acid; (B) 50 mM Tris HCl pH 7.4, 120 mM NaCl, 120 mM KCl, 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 by its ability to cause the 5-HT syndrome, which is characterized by: - alternating flexion and stretching of the front legs (reciprocal cover of the front leg: FPT) - retraction of the lower lip (retraction of the lower lip: LLR) - a position of the abdominal surface of the animal is in contact with the ground and the extended hind legs (flat 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 doses (ED5o) for some derivatives of the invention, in comparison with the reference products such as buspirone and flesinoxane, are given in Table 3 together with the example.

TABLE 3 5-HT Syndrome Antidepressant activity: forced swim 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 doses (ED50) are calculated for each compound according to the percentages of animals that show a significant reduction, in comparison with the control animals (p <0.05), in the period of immobility (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 the serotonergic receptors of the 5-HT-? A type and good selectivity with respect to the ai and D2 receptors. These show, in vivo, an agonist activity with respect to 5-HTIA receptors and are potentially active with respect to behavioral models, such as the forced side test. The compounds of the invention can therefore be used in the treatment of anxiety, depression, pain, neurodegeneration, schizophrenia, Alzheimer's disease and sleep disorders, for the regulation of food interference, for the regulation of gastric secretion and for the treatment of vascular, cardiovascular and cerebrovascular disorders, such as hypertension or migraine. Pharmaceutical preparations comprising compounds of the formula I as 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 for taken orally, and can understand the appropriate excipients. It is also possible to combine other pharmaceutically or therapeutically acceptable active ingredients therein.

Claims (8)

NOVELTY OF THE INVENTION CLAIMS

1. - 3-oxo- (2 / -) -1, 2,4-triazine corresponding to general formula I wherein Ri represents: hydrogen, when A is an optionally substituted nitrogen atom, a straight or branched C -? - C4 alkyl group, a phenylalkyl group of C? -C4, the phenyl nucleus is optionally substituted by one or more groups, such as C 1 -C 4 alkyl, C 1 -C 3 alkoxy halogen or trifluoromethyl, R 2 represents: hydrogen, a linear or branched Cr C alkyl radical, a phenyl or phenylalkyl group of C - [alpha] -C 4, the phenyl nucleus is optionally substituted by one or more groups, such as C? -C alkyl, C?? C3 alkoxy? halogen or trifluoromethyl, A represents an oxygen atom or a nitrogen atom in NR3, optionally substituted. R3 represents hydrogen or a methyl group, B represents a group of type. wherein the Ar itself represents an aromatic structure, such as phenyl, pyridyl or pyrimidyl, optionally substituted by one or more groups, such as C?-C3 alkyl, CrC3 alkoxy, hydroxyl, trifluoromethyl or halogen, and n can take the integral values from 3 to 5, where Ar is as defined in the formula Na and m can take the integral values 1 and 2. wherein R4 represents hydrogen or a C1-C3 alkyl group, and n can take the integral values from 3 to 5. The compounds of the general formula I exist in the form of racemic mixtures and of various enantiomers or diastereomers or mixtures thereof , and the therapeutically acceptable inorganic or organic salts of the compounds of the general formula I.

2. The compound according to claim 1, further characterized in that it is selected from the following compounds: * 2-methyl-5- [4- (4-pyrimidin-2-yl-piperazin-1-yl) butoxy] -2 - - [1,4] triazin-3-one, * 2-methyl-5-fumarate [4- [4 - (4-Methylpyrimidin-2-yl) piperazin-1-yl] butoxy] -2 - / - [1, 2,4] triazin-3-one, * fumarate of 5- [4- [4 - (4,6-dimethyl-pyridin-2-yl) piperazin-1-yl] -butoxy] -2-methyl-2H- [1, 2,4] triazin-3-one, * fumarate of 5- [ 4- [4- (4-methoxypyrimidin-2-yl] butoxy] -2-methyl-2 - - [1,4] triazin-3-one, * 5- [4- [4- (5 -methoxypyrimidin-2-yl) piperazin-1-yl] butoxy] -2-methyl-2 - / - [1, 2,4] triazin-3-one, * 5- [4- [4- (4 -cI oropyrimidin-2-yl) piperazin-1-yl] butoxy] -2-methyl-2 / - / - [1, 2,4] -triazin-3-one, * 5- [4- [4- (5-fluoropyridin-2-yl) piperazin-1-yl] butoxy] -2-methyl-2H- [1, 2,4] triazin-3-one, * fumarate 2-propyl-5- [4- (4-pyrimidin-2-yl-piperazin-1-yl) butoxy] -2H- [1, 2,4] triazin-3-one, * 2,6-dimethyl -5- [4- (4-pyrimidin-2-yl-piperazin-1-yl) butox y] -2 - / - [1, 2,4] triazin-3-one, * 2-methyl-6 -phenyl-5- [4- (4-pyrimidin-2-yl-piperazin-1-yl) butoxy] -2 - [1,4] triazin-3-one, * 2-methyl-6 -benzyl-5- [4- (4-pyrimidin-2-yl-piperazin-1-yl) butoxy] -2 / - - [1,4] triazin-3-one, * 2-benzyl-5 - [4- (4-pyrimidin-2-yl-piperazin-1-yl) butoxy] -2 - / - [1, 2,4] triazin-3-one, * 2-methyl-5- [3] fumarate - (4-pyrimidin-2-yl-piperazin-1-yl) propoxyl] -2H- [1, 2,4] -triazin-3-one, * 2-methyl-5- [5- (4- pyrimidin-2-yl-piperazin-1-yl) pentyloxy] -2 - - [1, 2,4] triazin-3-one, * fumarate of 5- [4- [4- (3-methoxypyridin-2-yl ) piperazin-1-yl] butoxy] -2-methyl-2H- [1, 2,4] triazin-3-one, * fumarate of 5- [4- [4- (3-chlorophenyl) piperazine- 1-yl] butoxy] -2-methyl-2H- [1, 2,4] triazin-3 -one, 5- [4- [4- (5-chloro-2-methoxyphenyl) piperazin-1-yl] butoxy] -2-methyl-2H- [2,4] triazin-3-one fumarate, * 4- [4- [4- (2-methyl-3-oxo-2,3-dihydro- [1, 2,4] triazin-5-yloxy) butyl] piperazin-1-yl] benzonitrile, * 5- [4- [4- (5-chloro-2-methoxyphenyl) piperazin-1-yl] butoxy] -2-methyl-2 - - [1, 2,4] triazin-3-one fumarate, * fumarate of 5- [4 - [(2,3-dihydrobenzo [1,4] dioxan-2-methylmethyl] butoxy] -2-methylene-2H- [1,4] triazine-3 -one, fumarate of (R) -5- [4 - [(2,3-dihydrobenzo [1,4] dioxin-2-ylmethyl) amino] butoxy] -2-methyl-2H- [1, 2 , 4] triazin-3-one, * (S) -5- [4 - [(2,3-dihydrobenzo [1,4] dxoxin-2-methyl] amino] butoxy] -2 fumarate] -methyl-2H- [1, 2,4] triazin-3-one, * trans-2-methyl-5- (2-pyrimidin-2-yl-octahydropyrrho [1,2-a] pyrazine) 7-ylmethoxy) -2H- [1, 2,4] triazin-3-one, * trans - (-) - 2-methyl-5- [2- (2-pyrimidin-2-yl-octahydropyrido [1, 2 -a] pyrazin-7-yl) ethoxy] -2H- [1, 2.4] triazin-3-one, * trans - (+) - 2-methyl-5- [2- (2-pyrimidin-2-yl- Octahydropyrido [1,2- a] pyrazin-7-yl) ethoxy] -2 - - [1, 2,4] triazin-3-one, * 2-methyl-5- [4- (4-pyrimid n-2-¡l-piperaz¡n-1 -yl) butylamino] -2H- [1, 2,4] triazin-3-one.

3. A process for the preparation of the chemical compounds according to claims 1 and 2, characterized in that a derivative of the general formula III is treated with an alcohol B-OH IV or an amine BHNR3 V, Ri, R2, R3 and B are as defined in claim 1, in the presence of sodium hydride or potassium tert-butoxide in dioxane, THF or toluene .

4. The use of 5-HT-IA receptor agonists, as claimed in 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, regulation of food interference, regulation of the gastric secretion and the treatment of vascular, cardiovascular and cerebrovascular disorders.

6. A pharmaceutical composition, characterized in that 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 claims 1 and 2 in combination with a 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. SUMMARY OF THE INVENTION The invention relates to novel 3-oxo- (2H) -1,4-triazine derivatives of the general formula I. Ri represents: hydrogen, when A is an optionally substituted nitrogen atom, a linear or branched C? -C alkyl group, a phenylC.sub.alkyl group of CrC, the phenyl ring is optionally substituted by one or more groups, such as C? -C4? C.sub.3 C alkoxy, halogen or trifluoromethyl, R.sub.2 represents: hydrogen, a linear or branched C-? -C alkyl radical, a phenyl or phenylalkyl group of C.sub.1 -C.sub.4, the phenyl ring is optionally substituted by one or more groups, such as C alquilo-C4 alkyl, C?-C3 alkoxy > halogen or trifluoromethyl, A represents an oxygen atom or a nitrogen atom in NR3, optionally substituted; R3 represents hydrogen or a methyl group; B represents a group such as lia. wherein the Ar itself represents an aromatic structure, such as phenyl, pyridyl or pyrimidyl, optionally substituted by one or more groups, such as C 1 -C 3 alkyl, C 1 -C 3 alkoxy, hydroxyl, trifluoromethyl or halogen, and n can be integers from 3 to 5, IIB where Ar is as defined in the formula Ha and m can take the integral values 1 and 2; lie wherein R4 represents hydrogen or an alkyl group of CrC3, and n can be all numbers ranging from 3 to 5. P00 / 498F