MXPA98004536A - Derivatives of 5-naftalen-1-il-1,3-dioxan, preparation and therapeutic use of mis - Google Patents

Abstract

Compounds of the general formula (I), wherein R 1 is a hydrogen atom or a (C 1-4) alkyl, (C 3-6) cycloalkylmethyl or phenyl (C 1-3) alkyl group optionally substituted on the phenyl ring by one or more atoms or groups selected from halogens and methyl, trifluoromethyl, methoxy and cyano groups, R2 is a hydroxy or alkoxy group or a group of the general formula NR3R4 wherein each of R3 and R4 is a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkylmethyl group, a phenyl group, a phenylmethyl group or a pyridinyl group, or R3 and R4, taken together with the nitrogen atom, form a pyrrolidine or piperidine ring, and n is 1, 2 or 3. The compounds are for therapeutic use

Description

DERIVATIVES OF 5-NAFTALEN-1 -IL-1 .3-DIOXANE, PREPARATION AND THERAPEUTIC USE OF THEMSELVES The present invention relates to compounds of general formula (I) wherein R represents a hydrogen atom or a (C? -C4) alkyl, (C3-C6) cycloalkylmethyl or phenyl (C? -C3) alkyl group optionally substituted on the phenyl ring with one or more atoms or groups chosen from halogens and methyl, trifluoromethyl, methoxy and cyano groups, R 2 represents a hydroxyl group or (C 1 -C 4) alkoxy or a group of the general formula NR 3 R 4 in which R 3 and R 4, independently of each other, each represents a hydrogen atom, a linear or optionally branched (C? -C) alkyl group, a (C3-C6) cycloalkyl group, a (C3-C6) cycloalkylmethyl group, a phenyl group, a phenylmethyl group or a pyridyl group, or alternatively R3 and R form, together with the nitrogen atom, which supports them, a pyrrolidine or piperidine ring, and n represents the number 1, 2 or 3. The compounds of the invention can exist in the form of cis or trans stereoisomers of such isomers; they can also exist in the form of free bases or addition salts with acids. Preferred compounds are those of general formula (I) in which Ri represents a methyl, ethyl or phenylmethyl group optionally substituted on the phenyl ring, R 2 represents an amino or (Ci-C 4) alkylamino group and n equals 1; among the latter, the compound whose formula R represents a phenylmethyl group and R2 represents an amino group is particularly advantageous. The compounds according to the invention can be prepared by several processes. According to a first variant, an amine of general formula (II) wherein R-i represents a hydrogen atom or an alkyl group, it can be reacted with an α-halo alkanoate of general formula (I I I) wherein Z represents a chlorine or bromine atom and n is as defined above; a compound of general formula (I) is obtained in this manner, in which Ri represents a hydrogen atom or an alkyl group and R2 represents an ethoxy group. If desired in that manner, the compound thus obtained can then be saponified to convert it into the corresponding acid, or alternatively, it can be reacted with an amine of the general formula HNR3R4l in which R3 and R4 are as defined above, turn it into an amide. The conditions of these reactions are standard and well known to those skilled in the art. According to a second variant, the amides of the general formula (I) in which R ^ represents a hydrogen atom or an alkyl group can be obtained by reacting the amine of general formula (II) directly with a? -halo alkanamide of general formula (IV) (CHe) n N ^ (IV) R < wherein X represents a chlorine or bromine atom and R3I R4 and n are as defined above. The conditions of this reaction are well known to those skilled in the art. According to a third variant, the amides of the general formula (I) in which Ri represents a hydrogen atom or an alkyl group and n = 2 can be obtained by reacting the amine of the general formula (II) with a propenamide of the general formula (V) wherein R3 and R4 are as defined above. The conditions of this Michael reaction are well known. Finally and according to a fourth variant, the compounds of general formula (I) in which Ri does not represent a hydrogen atom can be prepared by alkylation of the corresponding compound and whose formula R- represents a hydrogen atom, in a solvent polar aprotic, for example acetonitrile, in the presence of a base, for example, potassium carbonate. The starting amines of general formula (II) in which R? represents an alkyl group can be obtained by reduction of the corresponding alkanamides, described in the patent application EP-461, 958; the starting amines of the general formula (I I) in which R, represents a hydrogen atom can be obtained by reaction of 2- (6-methoxynaphthalene) 1 - . 1-yl) propane-1,3-diol with 4,4-diethobutobutamine, as described in said patent application. The starting compounds of general formulas (III), (IV) and (V) are commercially available or can be obtained by known methods. The following examples illustrate the preparation of a few compounds of the invention. The elemental microanalysis and the IR and NMR spectra confirm the structures of the obtained compounds. The numbers indicated in the parentheses in the titles of the examples correspond to those in the first column of Table 1 given below. In the names of the compounds, the hyphen "-" is part of the name, and the stripe "_" only serves as a dashed hyphen; it should be removed in the absence of a line break, and should not be replaced by either a normal script or a space.

Example 1 (Compound No. 1) 2 - [[3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] ao] acetamide. eleven . 5- (6-Methoxynaphthalen-1-yl) -1,3-dioxane-2-propanamine hydrochloride 7.56 g (32.5 mmol) 2- (6-methoxynaphthalen-1-yl) propane-1,3-diol, 6.8 hydrochloride g (42.1 mmol) of 4,4-diethioxybutanamine and then 70 ml of hydrochloric ether are introduced into a 1 l round bottom flask containing 300 ml of toluene and the mixture is refluxed for 2 h.

The mixture is cooled and the precipitate is collected by filtration and rinsed with diethyl ether. 10.2 g of crude hydrochloride are obtained in the form of a beige solid. Melting point 224-226 ° C. 1 .2. 2 - [[3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] amino] acetamide. 1.2 g (4 mmol) of 5- (6-methoxynaphthalen-1-yl) -1,3-dioxan-2-propanamide, 0.8 (5.8 mmol) of potassium carbonate and 0.4 g (4.2 mmol) of chloroacetamide are introduced into a 100 ml round bottom flask containing 30 ml of acetonitrile and the mixture is heated at 80 ° C for 3 h. The mixture is allowed to cool, 50 ml of water are added and the resulting mixture is extracted with 50 ml of ethyl acetate twice. The organic phase is washed with water and dried over magnesium sulfate, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, levigating with a 95/5 mixture of dichloromethane and methanol. 0.4 g (1.1 mmol) of white solid is obtained, which is recrystallized from ethanol. Melting point: 148-150 ° C.

Example 2 (Compound No. 6) 2- [ethyl [3- [5- (6-methoxynaphthalen-1-yl) -1,3-dioxan-2-yl] propyl] amino] acetamide 2. 1. N-ethyl-5- (6-methoxynaphthalen-1-yl) -1,3-dioxane-2- hydrochloride Propanamine A suspension of 10 g (29.1 mmol) of N- [3- [5- (6-methoxynaphthalen-1-yl) -1,3-dioxan-2-yl] propyl] acetamide in 75 ml of tetrahydrofuran is added to a 500 ml round bottom flask containing a suspension of 1.66 g (43.6 mmol) of lithium aluminum hydride in 50 ml of tetrahydrofuran heated to reflux, and refluxing and stirring are maintained for 3 h. The mixture is cooled and hydrolysed by adding 10.5 ml of 1 M sodium potassium tartrate solution, stirring for 12 h, the solid is separated by filtration, washing the latter with tetrahydrofuran, and the filtrate is concentrated to dryness under reduced pressure. . 10.27 g of oily product are obtained, 0.5 g of which is taken to form the hydrochloride from ethanol. Melting point: 165 ° C (decomposition). 2. 2. 2- [Ethyl [3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] pro? Il] amino] _ acetamide. 3 g (8.2 mmol) of N-ethyl-5- (6-methoxynaphthalen-1-yl) -1,3-dioxane-2-propanamine hydrochloride, 5.6 g (40.5 mmol) of potassium carbonate and 0.9 g (9.6 g) mmol) of chloroacetamide are introduced into a 100 ml round bottom flask containing 40 ml of N, N-dimethylformamide, and the mixture is heated at 80 ° C for 4 h. The mixture was allowed to cool, 70 ml of water are added and the resulting mixture is extracted twice with 100 ml of ethyl acetate. The organic phase is washed with water, dried over sulphate of magnesium and filtered, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, levigating with a 98/2 mixture of dichloromethane and methanol. 2.6 g (6.7 mmol) of white solid are obtained, the product of which is recrystallized from a mixture of isopropyl ether and dichloromethane. Melting point: 120-121 ° C.

Example 3 (Compound No. 10). (E) -but-2-endioate of 2- [ethyl [3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] amino] -N-pyrid-2 -ylacetamide (1: 1). 1.4 g (4.24 mmol) of N-ethyl-5- (6-methoxynaphthalen-1-yl) -1,3-dioxan-2-propanamine, 0.6 g (4.3 mmol) of potassium carbonate and 0.72 g (4.2 g) mmol) of 2-chloro-N-pyrid-2-ylacetamide are introduced into a 100 ml round bottom flask containing 25 ml of acetonitrile, and the mixture is stirred at 25 ° C for 12 h. 50 ml of water are added and the resulting mixture is extracted with 50 ml of ethyl acetate twice. The organic phase is washed with water, dried over magnesium sulfate and filtered, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, levigating with a 70/30 mixture of petroleum and ethyl acetate. 1.46 g (3.15 mmol) of compound are obtained, said product is crystallized in the form of isopropyl ester fumarate. Melting point: 60-67 ° C Example 4 (Compound No. 17). 3- [Ethyl [3- [5- (6-methoxynaphthalen-1-yl) -1,3-dioxan-2-yl] propyl] -aminojpropanamide ethanedioate (1: 1). 1.3 g (4 mmol) of N-ethyl-5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-propanamine and 0.43 g (6 mmol) of acrylamide are introduced into a bottom flask 100 ml round containing 20 ml of acetonitrile, and the mixture is refluxed for 8 h. 0.3 g of additional acrylamide were added and the reflux was maintained for an additional 8 h. The mixture was cooled and concentrated to dryness under reduced pressure and the residue was taken up in 50 ml of water and extracted with 50 ml of ethyl acetate twice. The organic phase was washed with water, dried over magnesium sulfate and filtered, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, levigating with a 97/3 dichloromethane mixture and methanol 0.98 g of compound is obtained, which is crystallized in the form of 2-propanol oxalate. Melting point: 125 ° C (decomposition).

Example 5 (Compound No. 7). 2- [Ethyl [3- [5- (6-methoxynaphthalen-1-yl) -1,3-dioxan-2-yl] propyl] amino] -N-methylacetamide ethanedioate (1: 1). 5. 1. Ethyl 2- [ethyl [3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] amino] _ acetate 1.4 g (4.24 mmol) of N-ethyl -5- (6-methoxynaphthalen-1-yl) -1,3-dioxan-2-propanamine, 1.75 g (12.7 mmol) of potassium carbonate and 0.5 ml (4.45) mmol) of ethyl bromoacetate are introduced into a 100 ml round bottom flask containing 21 ml of acetonitrile, and the mixture was refluxed for 2 h. The mixture was cooled and concentrated to dryness under reduced pressure and the residue taken up in 50 ml of water and extracted with 50 ml of ethyl acetate twice. The organic phase is washed with water, dried over magnesium sulfate and filtered and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, levigating with a 99/1 mixture of dichloromethane and methanol, and 1.17 g (3 mmol) of compound are obtained in the form of a colorless oil. The oxalate is prepared therefrom in a conventional manner. Melting point: 124-127 ° C. . 2. 2- [Ethyl [3- [5- (6-methoxynaphthalen-1-yl) -1,3-dioxan-2-yl] propyl] amino] -N-methylacetamide ethanedioate (1: 1). 1.15 g (3 mmol) of ethyl 2- [ethyl [3- [5- (6-methoxy-naphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] amino] acetate are introduced into a 250-well reactor. my containing 11 ml of a 33% solution of methylamine in ethanol, and the sealed mixture is heated at 50 ° C for 5 days. The mixture is cooled and concentrated to dryness under reduced pressure and the residue is taken up in 50 ml of water and extracted with 50 ml of ethyl acetate twice. The organic phase is washed with water, dried over magnesium sulfate and filtered and the solvent is evaporated under reduced pressure. 1.16 g (2.89 mmol) of compound are obtained in the form of a yellow oil, which is crystallized in the form of oxalate from 2-propanol. Melting point: 140 ° C (decomposition).

Example 6 (Compound No. 18). Ethyl 4- [ethyl [3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] amino] butanoate ethanedioate. 7.31 g (20 mmol) of N-ethyl-5- (6-methoxynaphthalen-1-yl) -1,3-dioxane-2-propanamine hydrochloride, 2.76 g (20 mmol) of potassium carbonate and 3.9 g (20 g) mmol) of ethyl bromobutanoate are introduced into a 100 ml round bottom flask containing 50 ml of N, N-dimethylformamide, and the mixture is heated at 80 ° C for 7 h. The mixture is allowed to cool and concentrate to dryness under reduced pressure, the residue is taken up in 70 ml of water and extracted with 100 ml of ethyl acetate twice, the organic phase is washed with water, dried over magnesium sulfate and filtered, the solvent is evaporated under reduced pressure, and the residue is purified by chromatography on a column of silica gel, levigating with a 90/10 mixture of dichloromethane and methanol. 6.1 g (13.7 mmol) of oily compound are obtained, said product is crystallized in the form of the oxalate from ethyl acetate.

Melting point: 132-135 ° C.

Example 7 (Compound No. 15). 2 - [[3- [5- (6-Methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] hydrochloride (phenylmethyl) amino] acetamide. 0.5 g (1.39 mmol) of 2 - [[3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] -propyl] amino] acetamide, 0.29 g (2.1 mmol) of Potassium carbonate and 0.18 ml (1.5 mmol) of benzyl bromide are introduced into a 25 ml round bottom flask containing 8 ml of acetonitrile, and the mixture is heated at reflux for 2 h. The mixture is allowed to cool, 15 ml of water are added, the resulting mixture is extracted with 15 ml of ethyl acetate twice, the organic phase is washed with water, dried over magnesium sulfate and filtered, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, levigating with a 98/2 mixture of dichloromethane and methanol. 0.24 g (0.53 mmol) of compound is obtained in the form of an oil, which is crystallized in the form of isopropyl ether hydrochloride. Melting point: 218-220 ° C.

EXAMPLE 8 (Compound No. 21) 2- [Ethyl [3- [5- (6-methoxynaphthalen-1-yl) -1,3-dioxan-2-yl] propyl] amino] -N- (1) ethanedioate -methylethyl) acetamide (1: 1). 0.23 ml (2.73 mmol) of 1-methylethylamine, 0.38 ml (2.73 mmol) of triethylamine and then a solution of 0.22 ml (2.73 mmol) of chloroacetyl chloride in 10 ml of dioxane are introduced, under an inert atmosphere, into a flask 250 ml round bottom containing 20 ml of dioxane, and the mixture is left stirring for 15 h. ml of water, then 1 g (7.23 mmol) of potassium carbonate and then 1 g (2.73 mmol) of N-ethyl-5- (6-methoxynaphthalen-1-yl) -1,3-dioxan-2 hydrochloride. -propanamide are added and the mixture is heated at 80 ° C for 7 h. The mixture is cooled, 80 ml of water are added, the resulting mixture is extracted with 50 ml of ethyl acetate twice, the organic phase is washed with water, dried over magnesium sulfate and filtered and the solvent is evaporated under reduced pressure. . The product obtained is purified by chromatography on a column of silica gel, levigating with a 95/5 mixture of dichloromethane and methanol, and 0.8 g (1.86 mmol) of compound is obtained in the form of a colorless oil. The oxalate is prepared therefrom in a conventional manner. Melting point: 130-131 ° C.

Example 9 (Compound No. 37) 2 - [[(2-fluorophenyl) methyl] [3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] amino hydrochloride ] acetamide (1: 1). 1 g (2.79 mmol) of 2 - [[3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] amino] acetamide, 0.8 g (578 mmol) of carbonate of potassium and 0.5 ml (4.2 mmol) of 1- (chloromethyl) -2-fluorobenzene are introduced into a 100 ml round bottom flask containing 20 ml of acetonitrile, and the mixture is heated to reflux for 6 h. The mixture is allowed to cool, 30 ml of water are added and the resulting mixture is extracted with 20 ml of ethyl acetate twice.

The organic phase is washed with water, dried over magnesium sulfate and filtered and the solvent is evaporated under reduced pressure. The product obtained is purified by chromatography on a column of silica gel, levigating with a 98/2 mixture of dichloromethane and methanol. 0.34 g (0.73 mmol) of compound is obtained in the form of a colorless oil, which is crystallized in the form of the hydrochloride from 2-propanol. Melting point: 200-202 ° C.

Example 10 (Compound No. 30). (E) -2 - [(Cyclopropylmethyl) [3- [5- (6-methoxynaphthalen-1-yl) -1,3-dioxan-2-yl] propyl] amino] acetamide (1: 1) -2-butenedioate. 1 g (2.79 mmol) of 2 - [[3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] amino] acetamide, 0.8 g (5.78 mmol) of carbonate of potassium, 0.38 g (4.2 mmol) of (chloromethyl) cyclopropane and a catalytic amount of sodium iodide are introduced into a 250 ml round bottom flask containing 15 ml of N, N-dimethylformamide, and the mixture is heated to 100 g. ° C for 20 h. The mixture is allowed to cool, the solvent is evaporated under reduced pressure, the residue is taken up in dichloromethane, the insoluble material is separated by filtration, the filtrate is concentrated to dryness under reduced pressure and the product obtained is purified by chromatography on a column of silica gel, levigating with a 9/1 mixture of dichloromethane and methanol. 0.60 g (1.45 mmol) of The compound is obtained in the form of a colorless oil, which is crystallized in the form of the fumarate from 2-propanol. Melting point: 149-150 ° C. Example 1 1 (Compound No. 41). Ethyl 2 - [[3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] (phenylmethyl) amino] _ acetate. 1 1.1 Ethyl 2 - [[3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] amino] acetate. 6.64 g (22 mol) of 5- (6-methoxynaphthalen-1-yl) -1,3-dioxan-2-propanamine, 3 g (22 mmol) of potassium carbonate and 3.54 ml (33 mmol) of ethyl chloroacetate are introduced into a 50 ml round bottom flask containing 110 ml of N, N-dimethylformamide, and the mixture is heated at 80 ° C for 20 min. The mixture is allowed to cool, the solvent is evaporated under reduced pressure and the residue is taken up in 50 ml of water and extracted with 50 ml of ethyl acetate twice. The organic phase is washed with water, dried over magnesium sulfate and filtered, the filtrate is concentrated to dryness under reduced pressure and the product obtained is purified by chromatography on a column of silica gel, levigating with a 98/2 dichloromethane mixture. and methanol. 3.52 g (9.08 mmol) of compound are obtained in the form of a colorless oil, which is used without further purification in the next step. 11. 2. Ethyl 2 - [[3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl) (phenylmethyl) _ aminojacetate. 3.52 g (0.08 mmol) of ethyl 2 - [[3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] amino] acetate, 1.2 g of potassium carbonate and 1.05 ml (9.12 mmol) of (chloromethyl) benzene are introduced into a 250 ml round bottom flask containing 45 ml of acetonitrile, and the mixture is heated at 80 ° C for 6 h. The mixture is allowed to cool and concentrated to dryness under reduced pressure, the residue is taken up in 50 ml of water and extracted with 50 ml of ethyl acetate twice, the organic phase is washed with water, dried over magnesium sulfate and filtered and the solvent is evaporated under reduced pressure. 3.7 g of oily product are obtained, 1 g of which is purified by chromatography on a column of silica gel, levigating with a 99/1 mixture of dichloromethane and methanol. 0.5 g (2.09 mmol) of compound is obtained in the form of a colorless oil, which is crystallized from diisopropyl ether. Melting point: 58-60 ° C.

Example 12 (Compound No. 39). 2 - [[3- [5- (6-Methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] (phenylmethyl) amino] -N-methylacetamide hydrochloride (1: 1). 1 g (2.15 mmol) of ethyl 2 - [[3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] (phenylmethyl) amino] acetate is introduced into a reactor of 250 ml containing 8 ml of a 33% solution of methylamine in ethanol, and the sealed mixture was heated at 50 ° C for 3 days.

The mixture is allowed to cool, and concentrated to dryness under reduced pressure, the residue is taken up in 50 ml of water and extracted with 50 ml of ethyl acetate twice, the organic phase is washed with water, dried over sodium sulfate, magnesium and filtered and the solvent is evaporated under reduced pressure. The product obtained is purified by chromatography on a column of silica gel, levigating with a 98/2 mixture of dichloromethane and methanol. 0.51 g (1.1 mmol) of compound is obtained in the form of a colorless oil, which is crystallized in the form of the hydrochloride from diisopropyl ether. Melting point: 98-100 ° C. The following table illustrates the chemical structures and physical properties of a few compounds according to the invention.

Table (I) 1 In columns "R," and UR2", C3H5 represents a cyclopropyl group, C6Hn represents a cyclohexyl group, C6H5 represents a phenyl group, C6H4-p-Y represents a phenyl group bearing a Y substituent in the para position, 2-NC5H4 represents a 2-pyridyl group, NC H8 represents a 1-pyrrolidinyl group and NC5H10 represents a 1-piperidyl group. In the column "Salt", "-" denotes a compound in the form of the base, "ox." denotes an oxalate (or ethanedioate), "fum." denotes a fumarate (or (E) -2-butanedioate) and "HCl" denotes a hydrochloride; the molar ratio acid: base is indicated in parentheses. In the final column, the melting points p.f. (° C) or the refractive indices nD20 are indicated; "(d)" denotes a melting point with decomposition. All compounds are trans stereoisomers (1 H NMR), except for compound No. 24, which is a predominantly trans mixture of cis and trans steroisomers. The compounds according to the invention underwent pharmacological tests, which proved their value as therapeutic substances.

Neuroprotective activity with respect to focal ischemia in rats. The neuroprotective activity of compounds according to the invention was demonstrated in a model of permanent focal ischemia caused by intraluminal occlusion of the intermediate cerebral artery in rats, according to a method similar to that described in Stroke (1989) 20 84-91. Under anesthesia with sodium methohexital, the pterygopalatine artery, the common carotid artery and the left external carotid artery are ligated and a nylon thread is introduced into the internal carotid artery over a length of approximately 18 mm, corresponding to the distance which separates the origin of the internal carotid artery of the intermediate cerebral artery. The test compounds were administered after intravenous occlusion. 24 hours after the occlusion of the intermediate cerebral artery, the animals were sacrificed and the brain was removed. The volume of cerebral infarction is evaluated by measuring the surface area of the necrosis in 6 coronal slices stained with 2,3,5-triphenyltetrazolium chloride. By way of example, compounds No. 6 and No. 15 in the preceding table significantly reduced the infarct volume, by approximately 31% and 50% respectively, at a dose of 3 mg / kg administered intravenously at 10 min times, 1 h 30 min, 3 h and 6 h after the occlusion.

Activity towards tonic seizures introduced by supramaximal electrical shock.

The procedure of this test is described by E.A. Swinyard and J.H. Woodhead in Antiepileptic Drugs, Raven Press, New York, 111-126 (1982). 10 min after intravenous administration of the test compound, the number of mice exhibiting tonic seizures (extension of the front and rear limbs), immediately after application of an electric current (0.4 s, 60 mA, 50 Hz) using a Apelex ETC UNIT 7801MR machine, it is noticed. The results are expressed in terms of DAS0, the dose which protects 50% of the animals, calculated according to the method of J.T. Lichfield and F. Wilcoxon (J. Pharm. Exp. Ther., 96, 99-1 13 (1949)) using the ProbitMR program, of 3 or 4 doses each administered to a group of 8 mice. In this test, the DA 50 values of the compounds of the invention fall between 0.5 and 10 mg / kg. The results of the tests show that the compounds according to the invention have neuroprotective properties, and that they can be used in this way for the preparation of medicaments, which are useful in the treatment or prevention of cerebrovascular disorders of ischemic or hypoxic origin (infarct). cerebral, cranial or spinal trauma, cardiac or respiratory arrest, transient ischemic attack, perinatal asphyxia), glaucoma, progressive neurodegenerative diseases (senile dementias such as Alzheimer's disease, vascular dementias, Parkinson's disease, Hungtington's disease, olivopontocerebellar atrophy, lateral sclerosis amyotrophic, neurodegenerative diseases of viral origin, etc.) and in the prevention of accidents cerebral ischemics associated with vascular and heart surgery and endovascular therapy. Because of their anticonvulsant properties, they can also be used in the treatment of epilepsy. Finally, the treatment of other ailments, such as neuropathies, neurogenic pains (for example, those associated with nueropathies or with migraines), dyskinesias and neurological spasticity, can also be contemplated. For this purpose, they can be in all forms of pharmaceutical compositions, which are suitable for enteral or parenteral administration, such as tablets, sugar coated tablets, gelatin capsules, wafer capsules, suspensions or drinkable or injectable solutions such as syrups. or ampoules, etc., combined with suitable and dosed excipients to allow daily administration from 0 to 1000 mg of active substance.

Claims (9)

1. Compound, in the form of a pure stereoisomer or a mixture of stereoisomers, corresponding to the general formula (I) wherein RI represents a hydrogen atom or a (C? -C4) alkyl, (C3-C?) cycloalkylmethyl or phenyl (C? -C3) alkyl group optionally substituted on the phenyl ring with one or more selected atoms or groups of halogens and methyl, trifluoromethyl, methoxy and cyano groups, R 2 represents a hydroxyl group or (C 1 -C 4) alkoxy or a group of the general formula NR 3 R 4 in which R 3 and R 4, independently of each other, each represents an atom of hydrogen, a linear or optionally branched alkyl (d-C4) alkyl group, a (C3-C6) cycloalkyl group, a (C3-C6) cycloalkylmethyl group, a phenyl group, a phenylmethyl group or a pyridyl group, or alternatively R3 and R form, together with the nitrogen atom, which supports them, a pyrrolidine or piperidine ring, and n represents the number 1, 2 or 3, in the form of the free base or an addition salt with an acid.

Compound according to claim 1, characterized in that R ^ represents a methyl, ethyl or phenylmethyl group optionally substituted on the phenyl ring, R 2 represents an amino group or (C 1 -C 4) alkylamino and n is equal to 1.

3 Compound according to claim 1, characterized in that R1 represents a phenylmethyl group, R2 represents an amino group and n is equal to 1.

Process for the preparation of compounds according to claim 1, characterized in that an amine of general formula (II) wherein R 1 represents a hydrogen atom or an alkyl group, it is reacted with an α-halo alkanoate of general formula (III) (III) wherein Z represents a chlorine or bromine atom and n is as defined in claim 1, to obtain a compound of general formula (I), in which Ri represents a hydrogen atom or an alkyl group and R2 represents a group ethoxy, then, if desired, the compound thus obtained is saponified to convert it into the corresponding acid, or alternatively reacted with an amine of the general formula HNR3R4, wherein R3 and R are as defined in Claim 1, to convert it to amide.

5. Process for the preparation of compounds according to claim 1, characterized in that an amine of general formula (II) wherein Ri represents a hydrogen atom or an alkyl group, it is reacted with an? -halo alkanamide of general formula (IV) wherein X represents a chlorine or bromine atom and R3, R4 and n are as defined in claim 1.

6. Process for the preparation of compounds according to claim 1, characterized in that an amine of general formula (II) wherein Ri represents a hydrogen atom or an alkyl group, is reacted with a propenamide of general formula (V) or u (V) wherein R3 and R4 are as defined in claim 1.

7. Process for the preparation of compounds according to claim 1, characterized in that an alkylation is carried out in a compound of general formula (I) in which Ri represents a hydrogen atom.

8. Medicament, characterized in that it consists of a compound according to one of claims 1 to 3.

9. Pharmaceutical composition, characterized in that it contains a compound according to one of claims 1 to 3, combined with an excipient.