MXPA99011203A - 5-naphthalen-1-yl-1,3-dioxane derivatives, preparation and therapeutic application - Google Patents

Abstract

Compuestos de la fórmula general (I) en la cual R1 representa un grupo alquilo, V representa unátomo de hidrógeno, un grupo alquilo lineal o ramificado, un grupo cicloalquilo, un grupo cicloalquilmetilo, un grupo fenilalquilo que estáopcionalmente sustituido en el anillo de fenilo, un grupo carboximetilo, un grupo alcoxicarbonilmetilo o un grupo carbamoilmetilo que es opcionalmente monosubstituido o disubstituido en el nitrógeno, W representa un grupo carboximetilo, un grupo alcoxicarbonilmetilo, un grupo carbamoilmetilo que es opcionalmente monosubstituido o disubstituido en el nitrógeno, un grupo cíclico de 4 a 7 miembros que contiene unátomo de oxígeno o azufre, un grupo 2-piridimetilo, un grupo 3-piridilmetilo, un grupo 4-piridilmetilo, un grupo 1-metil-2-pirrolilmetilo, un grupo 2-furilmetilo, un grupo 2-tienilmetilo o un grupo 1,3-tiazol-2-il-metilo, o alternativamente una forma en V o W, junto con elátomo de nitrógeno que los porta, un grupo pirrolidinilo, piperidilo o 1,2,3,4-tetrahidroisoquinolilo. La presente invención tiene aplicación en terapia.

Description

DERIVATIVES OF 5-NAFTALEN-1-IL-1, 3-DIOXAN, ITS PREPARATION AND ITS THERAPEUTIC APPLICATION The present invention relates to compounds of the general formula (I) wherein R1 represents an alkyl group, V represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, a cycloalkylmethyl group, a phenylalkyl group which is optionally substituted on the phenyl ring, a carboxymethyl group, a group alkoxycarbonylmethyl or a carbamoMethyl group which is optionally monosubstituted or disubstituted on nitrogen, W represents a carboxymethyl group, an alkoxycarbonylmethyl group, a carbamoylmethyl group which is optionally monosubstituted or disubstituted on nitrogen, a 4- to 7-membered cyclic group containing an atom of oxygen or sulfur, a 2-pyridylmethyl group, a 3-pyridylmethyl group, a 4-pyridylmethyl group, a 1-methyl-2-pyrrolylmethyl group, a 2-furylmethyl group, a 2-thienylmethyl group or a group 1, 3-thiazol-2-yl-methyl, or alternatively a V or W form, together with the nitrogen atom that carries them, a pyrrolidinyl, piperidyl or 1, 2,3,4-tetrahydroisoquin group lilo The compounds of the invention correspond more particularly to one of the general formulas (IA), (IB), (IC) and (ID). In the general formula (IA) R., represents a hydrogen atom, a linear or branched C2-C4 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkylmethyl group, a C3-C6 cycloalkylmethyl group or a phenylalkyl group of C 1 Ca which is optionally substituted on the phenyl ring, R 2 represents a hydrogen atom, a linear or branched C 1 -C 4 alkyl group, a C 3 -C 6 cycloalkyl group, a C 3 cycloalkylmethyl group -C6 or a phenylalkyl group of d-C3 which is optionally substituted on the phenyl ring, R3 represents a hydroxyl group, a C? -C alkoxy group or a group of the general formula NR R5 in which R and R5, independently of each other, each represents a hydrogen atom, a linear or branched C?-C 4 alkyl group, a C 3 -C 6 cycloalkyl group or a C 3 -C 6 cycloalkylmethyl group The compounds of the general formula (IA) may exist in the form of cis or trans stereoisomers or mixtures of said isomers; they can also exist in the form of free bases or addition salts with acids. The compounds of the general formula (IA) can be prepared by various processes described below. According to a first variant, illustrated in the Scheme Next, the amide of the formula (HA) is subjected to a dealkylation in the presence of sodium sulphide, in a polar aprotic solvent, for example N-methylpyrrolidone, at a temperature of 100 to 150 ° C, in order to obtain the amide of the formula (IIIA), according to a method described in J. Am. Chem. Soc. (1976) 98 3237. This amide was then subjected to an alkylation using a derivative of the general formula Ri-X, in which Ri is as defined above, but is different from a hydrogen atom, and X represents a halogen atom or an equivalent group, in the presence of a base such as potassium carbonate and in a polar aprotic solvent, for example, N,? N-dimethylformamide, in order to obtain an amide of the general formula (IVA). This amide is then hydroxylated in basic medium, for example, sodium hydroxide, in a protic solvent, for example water or an aliphatic alcohol, at a temperature of 25 to 100 ° C, in order to obtain the corresponding primary amine, then of which this amine is treated, either with an aldehyde of the general formula R6-CHO, in which R6 is the lower homologue of the group R2, in the presence of a reducing agent such as sodium borohydride or sodium cyanoborohydride, under reductive amination conditions known to those skilled in the art, in order to obtain an amine of the general formula (VA). The amine of the general formula (VA) is then reacted with ethyl bromoacetate in order to obtain a compound of the general formula (IA) in which R-i and R2 represent an alkyl group, cycloalkyl, cycloalkylalkyl or phenylalkyl and R 3 represents an ethoxy group. If desired, the compound thus obtained can be saponified in order to convert it to the corresponding acid, or alternatively it can be reacted with an amine of the general formula HNR R5, in which R and R5 are as defined above in order to turn them into an amide. The conditions of these reactions are normal and well known to those skilled in the art. According to an alternative variant, the amides of the general formula (IA), in which R2 and R2 represent an alkyl or phenylalkyl group, can be obtained by reacting the amine of the general formula (VA) Scheme A directly with an α-halo alkamide of the general formula (VIA) (VIA) in which X represents a chlorine or bromine atom and R 4 and R 5 are as defined above. The conditions of this reaction are well known to those skilled in the art. According to a third variant, the amines of the general formula (VA), in which Rt represents a cyclopropylmethyl group and R 2 represents an alkyl or phenylalkyl group, can be prepared either by reduction of the corresponding alkanamides, described in the application of patent EP-461-958 or by hydrolysis of said alkanamides in the primary amines, followed by treatment of these amines under conditions of N-monoalkylation. All of these reactions are carried out according to methods that are well known to those skilled in the art. Finally, according to a final variant, a compound of the general formula (IA), in which R ^ represents a hydrogen atom, can be prepared by demethylation, using sodium sulfide in N, N-dimethylformamide, of the compound corresponding, in the formula in which R-representa represents a methyl group, described in the patent application FR-2, 742, 152. The following examples illustrate the preparation of a number of compounds of the general formula (IA). The elemental microanalyses and the IR and NMR spectra confirm the structures of the obtained compounds. The numbers indicated in parentheses in the titles of the examples correspond to those in the 1st. column of Table A given below. \ 8 In the names of the compounds, the hyphen "-" is part of the name, and the lower line "_" serves only to indicate the presence of a division of the line; it should be removed if a line split does not occur at that point and should not be replaced with either a normal hyphen or a separation. Example 1A (Compound No. 2A). 2 - [[3- [5- [6- (Cyclopropyl-methoxy) -1-naphil] -1,3-dioxan-2-yl] propyl] ethylamino] -N- (cyclopropyl-methyl) acetamide. 1 TO 1. 5- [6- (Cyclopropylmethoxy) -1-naphthyl] -N-ethyl-1,3-dioxane-2-propanamine. 0.8 g of lithium aluminum hydride suspended in 30 ml of tetrahydrofuran was placed in a 250 ml 2-necked round bottom flask, the mixture was heated to reflux, 4.0 g (10.43 mmoles) of N- [3- [5 - [6- (Cyclopropylmethoxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] acetamide dissolved in 200 ml of tetrahydrofuran were added and heating at reflux continued for 4 h. The mixture was cooled, 3.5 ml (2 eq.) Of aqueous 0.1M sodium potassium tartrate solution was slowly added and added slowly, the mixture was stirred and the solvents were evaporated under reduced pressure. 4.55 g of an oily product were obtained, the product of which was used without further purification in the next step. 1A.2. 2 - [[3- [5- [6- (Cyclopropyl methoxy) -1-naphtl] -1,3-dioxan-2-yl] propyl] ethylamino] -N- (cyclopropyl-methyl) acetamide 0.23 ml (2.6 moles) of cyclopropylmethanamine, 20 ml of dioxane and 0.36 ml of triethylamine were introduced into a 250 ml round bottom flask, a solution of 0.21 ml (2.6 mmoles) of chloroacetyl chloride in 5 ml of dioxane were added dropwise and the mixture was stirred at room temperature for 8 h. 30 ml of water, 1 g of potassium carbonate and 1.0 g (2.7 mmoles) of 5- [6- (cyclopropi I methoxy) -1-napht] - N -ethyl-1,3-dioxane-2-propanamine were added. and the mixture was heated at 80 ° C for 8 h and allowed to stand at room temperature overnight. Water and ethyl acetate were added, the organic phase was separated, washed with water and then with brine, dried over magnesium sulfate and filtered, the solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. 0.5 g of an oily product were obtained, which was dissolved in 2-propanol, 8 ml of 0.1M hydrochloric acid in 2-propanol were added, the solvents were evaporated and the residue was recrystallized with diisopropyl ether. 0.2 g of the hydrochloride were finally isolated. Melting point: 74-76 ° C. Example 2A (Compound No. 3A). N-cyclopropyl-2 - [[3- [5- [6- (cyclopropylmethoxy) -1-naphthyl] -1, 3-dioxan-2-yl] propyl] ethylamino] -acetamide. 2A.1. Chloro-N-cyclopropylacetamide. 2 g (17.7 mmoles) of chloroacetyl chloride dissolved in 10 ml of dioxane were introduced into a 100 ml round bottom flask, 1 g (17.7 mmoles) of cyclopropanamine were added dropwise and the mixture was stirred at room temperature for 2 hours. h. The bicarbonate solution and ethyl acetate were added, the organic phase was separated, washed with water, dried over magnesium sulfate and filtered and the solvent was evaporated under reduced pressure, which gives 0.7 g of a white solid. The aqueous phase was concentrated under reduced pressure and the residue was taken up in ethanol, which gives an additional 1.22 g of a white solid, ie a total of 1.92 of the compound, which was used without further purification in the next step. 2 A.2. N-cyclopropyl-2 - [[3- [5. { [6- (cyclopropylmethoxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] eyllamino] -aceta mide. 0.69 g (1.87 mmol) of 5- [6- (cyclopropyl-methoxy) -1-naphthyl] -N-ethyl-1,3-dioxan-2-propanamine dissolved in 20 ml of acetonitrile, 0.37 g (2.77 mmoles) of 2-chloro-N-cyclopropylacetamide and 0.26 g of potassium carbonate were placed in a 100 ml round bottom flask and the mixture was heated at 70 ° C for 4 h. The mixture was cooled, water and ethyl acetate were added, the organic phase was separated, washed with water and then with saturated sodium chloride solution, dried over magnesium sulfate and filtered and the solvent was evaporated under reduced pressure. . The residue was purified by chromatography on a column of silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. After crystallization of diisopropyl ether, 0.2 g of a white solid was isolated.

Melting point: 87-89 ° C. Example 3A (Compound No. 17A). 2 - [[3- [5- [6- (Cyclopropyl I methoxy) -1-naphtl] -1,3-d-x-2-yl] propyl] methylamino] -N- (cyclopropyl-methyl) acetamide 3A. 1.5- [6- (Cyclopropylmethoxy) -1-naphthyl) -1,3-dioxan-2-propanamine. 30.0 g (78.23 mmoles) of N- [3- [5- [6- (cyclo-propylmethoxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] -acetamide, 330 ml of ethanol and 300 ml of 30% sodium hydroxide were placed in a 1000 ml round bottom flask and the mixture was heated at 110 ° C for 24 h. The alcohol phase was separated after the phase settling was carried out and this phase was concentrated, water was added and the mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. 30.44 g of an oily product were obtained, said product was used without further purification in the next step. 3 A.2.5- [6- (Cyclopropi I methoxy) -1-naphthyl] - N -methyl-1,3-dioxane-2-propanamine. 2.4 ml (25.3 mmol) of acetic anhydride were introduced into a 50 ml round bottom flask, 1 ml of formic acid (26.5 mmol) were added dropwise and the mixture was heated in an oil bath at 50 ° C for 2 hours. h. The heating was removed, 2.5 ml of tetrahydrofuran anhydride were added and, while stirring the mixture, a solution of 6.0 g (17.5 mmoles) of 5- [6- (cyclopropylmethoxy) -1-naphthyl] -1, 3- was added. dioxane-2-propanamine in 7 ml of tetrahydrofuran were added dropwise without exceeding the temperature 40 ° C and the stirring was continued at room temperature overnight. The solvent was evaporated under reduced pressure, the residue was taken up in toluene, this solution was evaporated under reduced pressure and the residue was dried. 5.84 g (15.8 mmol) of a white solid were obtained. This solid was dissolved in 40 ml of tetrahydrofuran in a 250 ml round bottom flask, a suspension of 1.2 g of lithium aluminum hydride in 43 ml of tetrahydrofuran was added, at the reflux temperature and under an argon atmosphere and heating at reflux continued for 4 h. The mixture was cooled in a batch of ice-cooled water, 9 ml of potassium sodium tartrate and added dropwise and stirring continued overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure to give 5.89 g of an oily product. 0.23 g of this product were dissolved in 2-propanol and, after treatment with one equivalent of hydrochloric acid in 2-propanol, 0.188 g of hydrochloride was finally isolated. Melting point: 144-148 ° C. 3 A.3. 2 - [[3- [5- [6- (Cyclopropyl-1-methoxy) -1-naphthyl] -1, 3-dioxan-2-yl] propyl] methylamide]] - N- (cyclopropyl-methyl) acetamide . 0.24 ml (2.81 mmol) of cyclopropanmethanamine, 20 ml of dioxane and 0.4 ml of triethylamine were introduced into a 250 ml round bottom flask, a solution of 0.22 ml (2.81 mmol) of chloroacetyl chloride in 10 ml of dioxane was added. drip and the mixture was stirred at room temperature for 9 h. 30 ml of water, 1 g of potassium carbonate and 1 g (2.81 mmol) of 5- [6- (cyclopropyl) methoxy) -1-napht] N-methyl-1,3-d-xano-2- propanamine were added and the mixture was heated at 80 ° C for 3 h. It was cooled, water and ethyl acetate were added, the organic phase was separated, washed with water and with brine, dried over magnesium sulfate and filtered, the solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. 0.62 g of product was obtained, which was dissolved in ethanol. After treatment with an oxalic acid equivalent, 0.5 g of a white solid was isolated. Melting point: 156-158 ° C. Example 4A (Compound No. 19A). 2 - [[3- [5- (6-ethoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] (phenylmethyl) amino] acetamide. 4A.1. N- [3- [5- (6-hydroxy-1-naphthyl) -1, 3-dioxan-2-yl] propyl] acetamide. 3.4 g (9.9 mmoles) of N- [3- [5- (6-methoxy-1-naphthyl) -1, 3-dioxan-2-yl] propyl] acetamide and 20 ml of 1-methyl-2-pyrrolidinone are introduced into a 250 ml round bottom flask, under a nitrogen atmosphere, the mixture was stirred, 3.86 g (49.5 mmol) of sodium sulfide were added and the mixture was heated in a 150 ° oil bath overnight .

The mixture was allowed to cool to 25 ° C, 50 ml of ethyl acetate and 50 ml of water were added, the organic phase was separated, 10% hydrochloric acid was added to the aqueous phase at pH = 4 and this phase was extracted again with ethyl acetate. The organic phases were combined, washed with water and then with saturated sodium chloride solution and dried over magnesium sulfate. The solution was filtered, the solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. The purified fraction was treated with pentane, ultrasound, ethyl acetate and diisopropyl ether. 1.87 g of solid were finally isolated. Melting point: 135-137 ° C. 4A.2. N- [3: [5- (6-ethoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] acetamide. 4.5 g of (13.7 mmoles) of N- [3- [5- (6-hydroxy-1-naphthyl) -1, 3-dioxan-2-yl] propyl] acetamide were dissolved in 70 ml of N, N-dimethylformamide , 2.8 g of potassium carbonate and 1.53 ml (20.5 mmoles) of bromoethane were introduced into a 250 ml round bottom flask and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure by introducing it with toluene, the residue was taken up in water and ethyl acetate and a solid was separated by filtration. After rinsing with water and with ethyl acetate, and drying, 2.74 g of solid were isolated.

After the separation of the phases once the settlement took place, washing of the organic phase, drying, filtration and evaporation of the solvent, an additional 1.7 g was obtained, that is, a total of 4.44 g of the compound. 0.3 g of this product was recrystallized with a mixture of 6/4 ethanol and water and 0.2 g of the compound were finally isolated. Melting point: 140-142 ° C. 4 A.3.5- (6-ethoxy-1-naphthyl) -1, 3-dioxane-2-propanamine. 4.1 g (11.4 mmoles) of N- [3- (5- (6-ethoxy-1-naphthyl) -1, 3-dioxan-2-yl] propyl] acetamide were dissolved in 49 ml of ethanol and 43.5 ml of hydroxide of 30% sodium were introduced into a 250 ml round-bottom flask and the mixture was heated to reflux for 24 h.It was allowed to cool, the alcoholic phase was separated after the settling of phases took place, this phase was concentrated The residue was taken up in water and extracted with dichloromethane The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate This solution was filtered and the solvent was evaporated under eluted pressure. by chromatography on a column of silica gel, eluting with a mixture of 90/10/1 dichloromethane, methanol and aqueous ammonia, 1.87 g of a solid were obtained, said product was used without further purification in the next step. It was prepared from a 0.1N solution of hydrochloric acid in 2-propanol, melting point: 180-183 ° C. 4A.4. 5- (6-ethoxy-1-naphthi I) -N- (f-methyl) -1,3-dioxane-2-propanamine. 1.63 g (5.17 mmol) of 5- (6-ethoxy-1-naphthyl) -1,3-dioxane-2-propanamine dissolved in 450 ml of methanol was introduced into a 1000 ml round bottom flask fitted with Dean apparatus -Stark, followed by introduction of 0.604 g (5.69 mmol) of benzaldehyde and the mixture was heated to reflux until it was reduced to one third of the initial volume. The mixture was allowed to cool, placed in an ice bath, 1.56 g (41.3 mmoles) of sodium borohydride were added in portions and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, the white residue was taken up in water and ethyl acetate, the organic phase was washed twice with water and once with ethyl acetate, dried over magnesium sulfate and filtered, the solvent was evaporated under reduced pressure and the residual oil was purified by chromatography on a column of silica gel, eluting with a 95/5 mixture of dichloromethane and methanol. 1.15 g of base were obtained, 0.1 g of said product were taken in order to prepare the hydrochloride, by dissolving in hot 2-propanol, adding 2.46 ml of 0.1 N hydrochloric acid in 2-propanol, evaporating the solvent under reduced pressure , titration of the diisopropyl ether residue, filtration and drying under vacuum. 0.97 g of the hydrochloride was isolated. Melting point: 206-208 ° C. 4A.5.2- [3- [5- [6-ethoxy-1-naphthyl) -1,3-dioxan-2-yl] -propyl] (phenylmethyl) -amino] acetamide. 0.5 g (1.23 mmoles) of 5- (6-ethoxy-1-naphthyl) -N- (phenylethyl) -1, 3-dioxane-2-propanamine dissolved in 7 ml of acetonitrile, 0.17 g (1.23 mmoles) of carbonate potassium, 0.055 g (0.369 mmoles) of sodium iodide and 0.138 g (1.47 mmoles) of 2-chloroacetamide were introduced into a 50 ml round bottom flask and the mixture was heated to reflux for 5 h. The mixture was allowed to cool, water and ethyl acetate were added, the organic phase was separated, the aqueous phase was extracted once more, the organic phase was washed twice with water and once with saturated aqueous sodium chloride solution, it was dried under magnesium sulfate and filtered, the solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel, eluting with a 99/1 mixture of dichloromethane and methanol. 0.590 g of pure base were obtained in the form of a yellow oil, which was dissolved in hot 2-propanol and 12.3 ml of 0.1 N hydrochloric acid in 2-propanol were added. After evaporation of the solvent under reduced pressure, titration of the diisopropyl ether residue, filtration and drying under vacuum, 0.54 g of hydrochloride was isolated. Fusion Point: 190-193 ° C. Example 5A (Compound No. 20A). I 2 - [[3- [5- (6-ethoxy-1-naphthii) -1,3-dioxan-2-yl] -propyl] (phenylmethyl) amino] -N-methylacetamide. 5A.1. 2 - [[3- [5- (6-ethoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] (phenylmethyl] amino] ethyl acetate 0.5 g (1.23 mmol) of 5- ( 6-ethoxy-1-naphthyl) -N- (phenylmethyl) -1,3-dioxane-2-propanamine suspended in 15 ml of acetonitrile, 0.42 g (3.07 mmoles) of potassium carbonate and 0.2 ml (1.84 mmoles) of 2 Ethyl bromoacetate was added and the mixture was heated at 60 ° C for 2.5 h 20 ml of water and 15 ml of ethyl acetate were added, the organic phase was separated, washed with water, dried over sulphate of magnesium and filtered, the solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel, eluting with a mixture of 98/2 dichloromethane and methanol, 0.58 g of an oily product were obtained, which was used without further purification in the next step 5A.2 2 - [[3- [5- (6-ethoxy-1-naphthyl) -1,3-dioxan-2-yl] -propyl] (phenylmethyl) ) amino] -N-methylacetamide 0.58 g (1.18 mmol) of 2 - [[3- [5- (6-ethoxy-1-naphthyl) -1, 3-dioxan-2-i!] propii] - (phen iimethyl) amin] ethyl acetate were dissolved in a few ml of ethanol, 5 ml of 33% methanamine in ethanol were added and the mixture was placed in an oven at 50 ° C for 7 days.

The solvent was evaporated under reduced pressure and 0.8 g of an oily product was obtained, which was purified by chromatography on a column of silica gel, eluting with a mixture of 98/2 dichloromethane and methanol, to give 0.5 g of base pure in the form of an oil.

After treatment with 10.5 ml of 0.1N hydrochloric acid in 2-propanol, evaporation of the solvent, titration of diisopropyl ether, filtration and drying, 0.37 g of hydrochloride was finally isolated. Melting point: 88-90 ° C. Example 6A (Compound No. 23A9. 2 - [[3- [5- [6- (Cyclopentyloxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] (phenylmethyl) amino] acetamide. 1. N- [3- [5- [6- (Cyclopentyloxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] acetamide Starting with 4.5 g (13.6 mmol) of N- [3- [ 5- (6-hydroxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] acetamide and 3.0 g (20.1 mmoles) of bromocyclopentane, and working under conditions similar to those described in Example 4A.2, but at 80 ° C, 4.88 g of the crude compound were obtained, 0.388 g of this compound were purified by chromatography on a column of silica gel, eluting with a 90/10 mixture of dichloromethane and methanol, after recrystallization of a mixture of ethanol and water and then drying in the presence of phosphorous pentoxide, 0.22 g of the compound was isolated Melting point: 136-137 ° C. 6 A.2.5- [6- (cyclopentyloxy) -1-naphthyl] - 1,3-dioxane-2-propanamine.

Starting with 4.5 g (11.3 mmol) of N- [3- [5- (6-cyclopentyloxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] -acetamide and working under conditions similar to those described in Example 4A.3, 1.52 g of base were obtained, followed by 1.15 g of hydrochloride. 6A.3.5- [6- (Cyclopentyloxy) -1-naphthyl] -N- (phenyl-methyl-1,3-dioxane-2-propanamine Starting with 0.59 g (1.6 mmol) of 5- (6-cyclopenti-Ioxy-1) -naphthyl) -1,3-dioxane-2-propanamine and 0.194 g (1.82 mmoles) of benzaldehyde, and working under conditions similar to those described in Example 4A.4, 0.48 g of base were obtained, from which 0.435 g of hydrochloride was prepared Melting point: 186-190 ° C 6A.4 2 - [[3- [5- [6- (cyclopentyloxy) -1-naphthyl] -1,3-dioxan-2 i I] propyl] (phenylmethyl) amino] acetamide, starting with 0.710 g (1.59 mmoles) of 5- (6-cyclopentyloxy-1-naphthyl) -N- (phenylmethyl) -1, 3-dioxane-2-propanamine and 0.178 g (1.9 mmoles) of 2-chloroacetamide and working under conditions similar to those described in Example 4A.5, 0.640 g of base were obtained in the form of an oil, of which 0.628 g of hydrochloride was prepared Example 7A (Compound No. 26A) .2 - [[3- [5 - [(6-phenylmethoxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] (phenylmethyl) amino] acetamide 7A.1. N- [3- [5 - [( 6- (Phenylmethoxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] acetamide. Starting with 4.2 g (12.75 mmoles) of N- [3-5- (6-hydroxy-1-naphthyl) -1,3-dioxan-2-yl] -propyl] acetamide and 1.82 ml (15.3 mmoles) of (bromomethyl) benzene, and working under conditions similar to those described in Example 4A.2, 4.67 g of the product were obtained, 0.3 g of which were recrystallized with a mixture of 6/4 ethanol and water, to give 0.15 g of a white solid. Melting point: 138-140 ° C. 7A.2. 5- [6- (Phenylmethoxy) -1-naphthyl] -1,3-dioxane-2-propanamine. Starting with 4.03 g of N- [3- [5 - [(6- (phenyl-methoxy) -1-naphthyl] -1, 3-dioxan-2-yl] propyl] acetamide, and working under conditions similar to those described in Example 4A.3, 3.2 g of an oily product were obtained, said product was used without further purification in the next step.7A.3.5- [6- (f-methoxy) -1-naphthyl] -N- (f eni l-meti 1-1, 3-dioxane-2-propanamine Starting with 1.13 g (2.99 mmol) of 5- [6- (phenylmethoxy) -1-naphthyl] -1,3-dioxane-2-propanamine and 0.317 g (2.99 mmoles) of benzaldehyde and then 0.904 g (23.9 mmoles) of sodium borohydride and working under conditions similar to those described in Example 4A.4, 0.41 g of base were obtained, 0.1 g of which were taken in order to obtain 0.090 g of hydrochloride Melting point: 185-189 ° C 7A.4 2 - [[3- [5 - [(6- (phenylamethoxy) -1-naphthyl] -1, 3-dioxan-2-yl] propyl] (phenylethyl) amino] acetamide, starting with 0.30 g (0.64 mmol) of 5- [6- (phenylmethoxy) -1-naphthyl] -N- (phenylmethyl) -1,3- dioxane-2-propanamine and 0.072 g (0.768 mmoles) of 2-chloroacetamide and working under conditions similar to those described in example 4A.5, 0.310 g of base were obtained in the form of an oil, from which 0.285 g of hydrochloride was prepared. Melting point: 170-175 ° C. Table A below illustrates the chemical structures and physical properties of a number of compounds of the general formula (IA). In columns "Ri", "R2" and "R3", cC H5 represents a cyclopropyl group, cC5H9 represents a cyclopentyl group and C6H5 represents a phenyl group. In the "Salt" column, "-" denotes a compound in the form of a base, "ox." denotes an oxalate (or ethanedioate), "fum." denotes a fumarate (or (E) -2-butanedioate) and "HCl" denotes a hydrochloride; the molar ratio of acid / base is indicated in parentheses. In the column "p.f. (° C)", "d" denotes a melting point with decomposition. All compounds are trans stereoisomers (1 H NMR).

Table A In the general formula (IB) R represents a hydrogen atom either a hydrogen atom or a group of the general formula CH2CO in which Y represents a hydroxyl group or a C? -C alkoxy group, or alternatively a group of the general formula CH2CON R? R2 in which R-. and R2, independently of one another, each represents a hydrogen atom or an alkyl group of C? -C, X represents an oxygen or sulfur atom or a CH2 group, M represents 0 or 1, and N represents 0.1. or 2. The compounds of the general formula (IB) can exist in the form of cis or trans stereoisomers or mixtures of said isomers, furthermore, taking into account the chirality of the ring attached to the nitrogen atom, certain compounds can exist in the form of diastereoisomers and / or enantiomers. They can also exist in the form of free bases or addition salts with acids. The compounds of the general formula (I B) can be prepared by a process illustrated by scheme B below.

Scheme B 2- (6-Methoxy-1-naphthyl) propane-1,3-diol of the formula (IIB) is reacted, reacted with 4,4-diethoxybutanamine of the formula (II IB) in a non-protic solvent with heating at reflux such as toluene in the presence of a dry hydrochloric acid dissolved in diethyl ether as a catalyst, in order to obtain 5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-propanamine of the formula (IVB), and this compound is then reacted with a ketone of the general formula (VB), in which X, m and n are as defined above, in the presence of a reducing agent such as sodium borohydride or any other equivalent agent , in a neutral or acid medium, under reductive amination conditions that are well known to those skilled in the art. A compound of the general formula (Iba) corresponding to the general formula (I B) is obtained when R represents a hydrogen atom. The compound of the general formula (Iba) can, if desired, be alkylated with a C 1 -C 4 alkyl 2-bromoacetate in a polar aprotic solvent, for example acetonitrile, in the presence of a base, for example, potassium carbonate. in order to obtain a compound of the general formula (I Bb) in which Y represents an alkoxy group of C? -C4). If desired, this compound can be saponified under conditions that are well known to those skilled in the art, in order to obtain a compound of the general formula (IBb) in which Y represents a hydroxyl group. The general formula (I Bb) corresponds to the general formula (IB) when R- represents a group of the general formula CH2COY. If so desired, the compound of the general formula (IBb) can then be reacted with an amine of the general formula HNR1R2, in which R ^ and R2 are as defined above, in order to obtain an amide of the formula general (IBc). The conditions of this reaction are normal and are well known to those skilled in the art. An amide of the general formula (IBc) can also be obtained directly from a compound of the general formula (IBa) by alkylation with a halide of the general formula Z-CH2-CO-NR1R2, in which Z represents an chlorine or bromine and Ri and R2 are as defined above, in a polar aprotic solvent, for example, N, N-dimethylformamide, in the presence of a base, for example, potassium carbonate. 2- (6-methoxy-1-naphthyl) propane-1,3-diol of the formula (IIB) was described in the patent application EP-0,461, 958. 4,4-diethoxybutanamine is commercially available as the ketones of the general formula (VB). The following examples illustrate in greater detail the preparation of a certain number of compounds of the general formula (IB). The elemental microanalyses and the IR and NMR spectra confirm the structures of the obtained compounds. The compound numbers indicated in parentheses in the titles correspond to those in Table B given later.

Example 1B (Compound No. 1B) 2 - [(2,3-Dihydro-1 H -inden-1-yl) [3- [5- (6-methoxy-1-naphthyl) -1, 3-dioxan hydrochloride -2-yl] amino] ethyl acetate. 1B.1. 5- (6-Methoxy-1-naphthyl) -1,3-dioxane-2-propanamine hydrochloride. 7.56 g (32.5 mmol) of 2- (6-methoxy-1-naphthyl) propane-1,3-diol, 6. 8 g (42.1 mmoles) of 4,4-diethoxybutanamine and then 70 ml of hydrochloric ether were introduced into a 1 L round bottom flask containing 300 ml of toluene and the mixture was heated to reflux for 2 h. The mixture was cooled and the precipitate was recovered by filtration and rinsed with diethyl ether. 12.2 g of crude hydrochloride were obtained in the form of a beige-colored solid. Melting point: 224-226 ° C. 1B.2. N- (2,3-dihydro-1 H -inden-1-yl) -5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine. 3.0 g (9.95 mmoles) of 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine were dissolved in 250 ml of ethanol in a 500 ml round bottom flask, 1.32 g (9.95 mmoles) ) of 2,3-dihydro- (1 H) inden-1-one were added and the mixture was heated to reflux overnight. The mixture was allowed to cool2 g of potassium borohydride were added and stirring was continued for 2 h 30. 100 ml of water were added and the mixture was extracted three times with 50 ml of ethyl acetate. The solvent was evaporated from the organic phase and the residue was purified by chromatography on a column of silica gel, eluting with a 9/1 mixture of dichloromethane and methanol. 2.79 g of an oily product were obtained. 1B.3. 2 - [(2,3-Dihydro-1 H -inden-1-yl) [3- [5- (6-methoxy-1-naphthyl) -1, 3-dioxan-2-yl] propM] amino hydrochloride ]-ethyl acetate. 1.88 g (4.5 mmol) of N- (2,3-dihydro-1 H-inden-1-yl) -5- (6-methoxy-1-naphthyl) -1, 3-dioxan-2-propanamine, 0.8 g (5.8 mmol) of potassium carbonate, 0.96 g (5.8 mmol) of ethyl 2-bromoacetate, a catalytic amount of sodium iodide and 35 ml of N, N-dimethylformamide were introduced into a 250 ml round bottom flask and dried. The mixture was heated at 60 ° C for 3 h. 100 ml of water were added, the mixture was extracted with three times 150 ml of ethyl acetate and the organic phase was washed with aqueous sodium chloride and then with aqueous sodium hydrogen carbonate. After drying and evaporation of the solvent, 3.5 g of an oily product were obtained, said product was purified by chromatography on a silica gel column with an elution gradient of 5% to 10% ethyl acetate in cyclohexane. 1.97 g of pure ase were obtained, 0.55 g (1 mmol) of which were taken in order to prepare the hydrochloride using 11 ml of a 0.1N solution of hydrochloric acid in 2-propanol. After washing in diethyl ether, 0.44 g of hydrochloride was isolated. Melting point: 88-90 ° C. Example 2B (Compound No. 2B). 2 - [(2-2,3-Dihydro-1 H -inden-1-yl) [3- [5- (6-methoxy-1-naphthyl) -1, 3-dioxan-2-yl acetate hydrochloride ] propyl] amino] -N-methylacetamide 1.42 g (2.8 mmol) of 2 - [(2,3-dihydro-1 H -inden-1-yl) [3- [5- (6-methoxy-1-naphthyl)] -1,3-dioxan-2-yl] propyI] amino] ethyl acetate, were introduced into a 250 ml round bottom flask, 30 ml of a 33% solution of methylamine in ethanol were added and the mixture was stirred at room temperature for 2 days. The solvent was evaporated under pressure eluted and the residue was purified by chromatography on a column of silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, to give 1.16 g of an oily product. The hydrochloride thereof was prepared using 24 ml of a 0.1N solution of hydrochloric acid in 2-propanol. After washing in diethyl ether, 0.98 g of hydrochloride were isolated. Melting point: 112-114 ° C Example 3B (Compound No. 6B) 5- (6-Methoxy-1-naphthyl) -N- (1, 2,3,4-tetrahydro-1-naphthyl) -1 fumarate , 2-dioxane-2-propanamine. 3.0 g (9.95 mmoles) of 5- / 6-methoxy-1-naphthyl) -1, 3-dioxane-2-propanamine, 90 ml of ethanol and 1.4 g (9.95 mmoles) of 3,4-dihydrohydro-1-naphthyl (2H) -one were introduced into a 250 ml round bottom flask, and the mixture was refluxed for 48 hours. The mixture was allowed to cool, 3 g of potassium borohydride (55.6 mmoles) were added and the mixture was stirred at room temperature for 2 days.

Water was added, the mixture was extracted with ethyl acetate, the organic phase was washed with water and dried, the solvent was evaporated under reduced pressure, the residue was taken up in dichloromethane and the solvent was evaporated under reduced pressure. 4.86 g of an oily product were obtained, said product was purified by chromatography on a column of silica gel, eluting with a 9/1 mixture of dichloromethane and methanol. 1.6 g of base were obtained. 0.4 g of which were taken for the purpose of preparing the fumarate in 6 ml of ethanol with 0.11 g of fumaric acid. 0.27 g of salt were isolated. Melting point: 134-136 ° C. Example 4B (Compound No. 9B) 2 - [[3- [5- (6-Methoxy-1-naphthyl) -1, 3-dioxan-2-yl] propyl] hydrochloride] (1,2,3,4-tetrahydro-1-naphthyl) amino] acetamide. 0.85 g (1.97 mmol) of 5- (6-methoxy-1-naphthyl) -N- (1, 2,3,4-tetrahydro-1-naphthyl) -1,3-dioxane-2-propanamine, 20 ml of acetonitrile, 0.28 g (2.99 mmol) of 2-chloroacetamide, 0.54 g (3.94 mmol) of potassium carbonate and 0.29 g (1.9 mmol) of sodium iodide were introduced into a 250 ml round bottom flask and the mixture was heated reflux for 4 h. 50 ml of water and 25 ml of ethyl acetate were added, the organic phase was separated, the aqueous phase was extracted twice more with 25 ml of ethyl acetate, the solvent was evaporated under reduced pressure and the residue was purified by chromatography. on a column of silica gel, eluting with a 9/1 mixture of dichloromethane and methanol. 0. 6 g of base were obtained, which allows 0.25 g of hydrochloride to be prepared using a 0.1 N solution of hydrochloric acid in 2-propanol. Melting point: 142-143 ° C. Example 5B (Compound No. 13B) N- (3,4-Dihydro-2H-1-benzopyran-4-yl) -5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-hydrochloride Propanamine 2 g (6.6 mmoles) of 5- (6-methoxy-1-naphthii) -1,3-dioxane-2-propanamine were introduced into a 250 ml round bottom flask, 150 ml ethanol and 0.983 g (6.6 g. mmoles) of 3,4-dihydro-2H-1-benzopyran-4-one were added and the mixture was heated to reflux overnight. The mixture was cooled, 2 g of sodium borohydride were added, the mixture was stirred for 1 h, 10 ml of water were added, this mixture was extracted four times with 75 ml of ethyl acetate, the solvent was evaporated under reduced pressure. and the residue was dried under reduced pressure. 2.98 g of solid were obtained, said solid was purified by chromatography on a column of silica gel, eluting with a 9/1 mixture of dichloromethane and methanol to give 1.3 g of base in the form of a pale yellow oil. 0.30 g of this base was taken and hydrochloride was prepared therefrom using 5 ml of a 0.1M solution of hydrochloric acid in 2-propanol. After washing with diisopropyl ether and drying, 0.08 g of hydrochloride was obtained. 0. 30 g of this base were taken and the hydrochloride thereof was prepared using 5 ml of a 0.1M solution of hydrochloric acid in 2-propanol. After washing with diisopropyl ether and drying, 0.08 g of hydrochloride was obtained. Melting point: 172-173 ° C. Example 6B (Compound No. 14B) 2 - [(3,4-Dihydro-2H-1-benzopyran-4-yl) [3- [5- (6-methoxy-1-naphthyl) -1, 2- hydrochloride dioxan-2-yl] propyl] amino] acetamide. Starting with 0.5 g (1.15 mmoles) of N- (3,4-dihydro-2H-1-benzopyran-4-yl) -5- (6-methoxy-1-naphthyl) -1, 3-dioxane-2-propanamine and 0.16 g (1.72 mmoles) of 2-chloroacetamide and working under conditions similar to those described in Example 4B, and then chromatography, 0.37 g of the compound were obtained in the form of the base, from which 0.17 g of hydrochloride were obtained. . Melting point: 165-166 ° C. The following Table B illustrates the chemical structures and the physical properties of a number of compounds of the general formula (IB). In the "salt" column, "-" denotes a compound in the form of the base, "fum.", Denotes a fumarate (or (E) -2-butenedioate), "the." It denotes an oxalate (or ethanedioate) and "HCl" denotes a hydrochloride; the molar ratio of acid / base is indicated in parentheses.

TABLE B (+) The compounds in which the carbon atom joins the nitrogen atom that is chiral are racemic. In the "Salt" column, "-" denotes a compound in the form of the base, "fum." Denotes a fumarate (or (E) -2-butenedioate) and "HCl" denotes a hydrochloride; the molar ratio of acid / base is indicated in parentheses. The melting points p.f. (° C) are indicated in the final column. In the general formula (IC) Rt represents either a hydrogen atom or a group of the general formula CH2COY in which Y represents a hydroxyl group or an alkoxy group of C? -C, or alternatively a group of the general formula CH2CONR4R5 wherein R4 and R5, independently of each other, each represents a hydrogen atom or an alkyl group of C? -C4, and R2 represents a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group , a 1-methyl-2-pyrroyl group, a 2-furyl group, a 2-thienyl group, or a 1,3-thiazol-2-yl group, the respective formulas of which are the following: The compounds of the general formula (IC) may exist in the form of cis or trans stereoisomers or mixtures of said isomers; or mixtures of said isomers, these may exist in the form of free bases of addition salts with acids. The compounds of the general formula (IC) can be prepared by a process illustrated by Scheme C below. 2- (6-methoxy-1-naphthyl) propane-1,3-diol of the formula (HC) is reacted with 4,4-diethoxybutamine of the formula (IIC) in a non-protic reflux heating solvent such as toluene and in the presence of hydrochloric acid dissolved in diethyl ether, as a catalyst, in order to obtain 5- (6-methoxy-1-naphthyl) -1, 3-dioxane-2-propanamine of the formula (IVC), which then ration is made, in a protic solvent such as methanol, at a temperature of 25 to 60 ° C and with removal of the water formed during the reaction, with an aldehyde of the general formula (VC) in which R2 is as defined before, then the formed imine is reduced, for example, by using a reducing agent such as sodium borohydride and any other equivalent agent, in neutral or acidic medium, under reductive amination conditions which are well known to those skilled in the art. A compound of the general formula (ICa) is obtained then it can be alkylated with a haloacetate corresponding to the general formula (IC) when R ^ represents a hydrogen atom.

Scheme C V ÍVC) If desired, the compound of the general formula (ICa) can be alkylated with a haloacetate of the general formula Z-CH2-CO2-C1-C4 alkyl, in which Z represents a chlorine or bromine atom, in an aprotic solvent polar, for example, acetonitrile, in the presence of a base, for example, potassium carbonate, in order to obtain a compound of the general formula (ICb) in which Y represents an alkoxy group of C? -C4. If desired, this compound can be saponified under conditions that are well known to those skilled in the art, in order to obtain a compound of the general formula (ICb) in which Y represents a hydroxyl group. The general formula (ICb) corresponds to the general formula (IC) when R- represents a group of the general formula CH2COY. If desired, the compound of the general formula (ICb) can then be reacted with an amine of the general formula HNR4R5, in which R4 and R5 are as defined above, in order to obtain an amide of the formula generates ( IC). The conditions of this reaction are normal and are well known to those skilled in the art. An amide of the general formula (ICc) can also be obtained directly from a compound of the general formula (ICa) by the alkylation of a halide of the general formula Z-CH2-CO-NR R5, in which Z represents an atom of chlorine or bromine and R4 and R5 are as defined above, in a polar aprotic solvent, for example N, N-dimethylformamide, in the presence of a base, for example, potassium carbonate. The general formula (ICc) corresponds to the general formula (IC) when Ri represents a group of the general formula CH2CONR4R5. 2- (6-methoxy-1-naphthyl) propane-1,3-diol of the formula (IIC) is described in the patent application EP-0,461, 958. 4,4-diethoxybutamine is commercially available, as the aldehydes of the general formula (VC). The following examples illustrate in detail the preparation of a number of compounds of the general formula (IC). The elemental microanalyses and the IR and NMR spectra confirm the structures of the obtained compounds. The numbers of compounds indicated in parentheses in the titles correspond to those in Table C given later. Example 1C (Compound No. 1C). Di 5- (6-methoxy-1-naphthyl) -N- (4-pyridylmethyl) -1,3-dioxane-2-propanamide hydrochloride. 1C.1. 5- (6-Methoxy-1-naphthyl) -1,3-dioxane-2-propanamine hydrochloride. 7.56 g (32.5 mmol) of 2- (6-methoxy-1-naphthii) propane-1,3-diol,6. 8 g (42.1 mmoles) of 4,4-diethoxyethamine and then 70 ml of dry gaseous hydrochloric acid dissolved in diethyl ether were introduced into a 1 l round bottom flask containing 300 ml of toluene, and the mixture was heated to reflux for 2 h.

The mixture was cooled and the precipitate was collected by filtration and rinsed with diethyl ether. 12.2 g of crude hydrochloride were obtained in the form of a beige solid. Melting point: 224-226 ° C. 1C.2. 5- (6-Methoxy-1-naphthyl) -N- (4-pyridy-methyl) -1,3-dioxane-2-propanamine dihydrochloride. 0.5 g (1.67 mmol) of 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine and 200 ml of methanol were introduced into a 250 ml round bottom flask, 0.178 g (1.67 mmoles) ) of pyridine-4-carboxyaldehyde were added and the mixture was heated at 100 ° C for 2 h. The mixture was allowed to cool, 0.5 g of potassium borohydride was added and the mixture was stirred for 0.5 h. Half of the methanol was evaporated under reduced pressure, 10 ml of water were added, the mixture was extracted with three times 20 ml of ethyl acetate, the organic phase was concentrated under reduced pressure and the residue was purified by chromatography on a silica gel, eluting with a mixture of 9/1 dichloromethane and methanol. 0.57 g of base were obtained in the form of an oil. 0.15 g of this product was taken and dissolved in 5 ml of a 0.1 N solution of hydrochloric acid in 2-propanol. After washing with diisopropyl ether and drying, 0.12 g of dihydrochloride was obtained. Melting point: 207-208 ° C.

Example 2C (Compound No. 3C). 2 - [[3- [5- (6-Methoxy-1-naphthyl) -1, 3-dioxane-2-yl] propyl] -I- (4-pyridylmethyl) amino] acetamide hydrochloride. 1.2 g (3 mmoles) of 5- (6-methoxy-1-naphthyl) -N- (4-pyridylmethyl) -1,3-dioxane-2-propanamine was dissolved in 200 ml of acetonitrile, 0.138 g (0.9 mmol) of sodium iodide. 0.828 g (6 mmoles) of potassium carbonate and 0.42 g (4.5 mmoles) of 2-chloroacetamide were added and the mixture was heated to reflux for 3 h. Since the reaction is not complete, 0.2 g (1.5 mmoles) of potassium carbonate, 0.06 g (0.45 mmoles) of sodium iodide and 0.14 g (1.5 mmoles) of 2-chloroacetamide were added and the mixture was heated to Reflux for 1 additional hour. The mixture was allowed to cool, 140 ml of water were added and this mixture was extracted with four times 50 ml of ethyl acetate. After evaporation of the solvent under reduced pressure, the residue was purified by chromatography on a column of silica gel, eluting with a 9/1 mixture of dichloromethane and methanol and 0.3 g of pure base was obtained. The base was salified using 8 ml of a 0.1 N solution of hydrochloric acid in 2-propanol. After washing with ethyl acetate and drying, 0.12 g of dihydrochloride was obtained. Melting point: 169-170 ° C. Example 3C (Compound No. 19C). 5- (6-methoxy-1-naphthyl) -N- (2-thiazolylmethyl) -1,3-dioxane-2-propanamine. 2. 4 g (8 mmol) of 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine, 700 ml of methanol and 1 (8.8 mmol) of 1,3-tazole-2-carboxyaldehyde were added. introduced into a round bottom flask of 100 ml with Dean-Stark apparatus and the mixture was distilled until the volume of the reaction medium reaches approximately 200 ml. The mixture was cooled, 2.4 g of sodium borohydride were added in portions and the mixture was allowed to stir overnight.

The methanol was evaporated under reduced pressure, the residue was taken up in water and ethyl acetate, the organic phase was separated, washed and dried over magnesium sulfate and the solvent was evaporated under reduced pressure. 3.17 g of base were obtained, 0.5 g of which were taken to prepare hydrochloride under conditions similar to those described above. 0.5 g of hydrochloride were obtained. Melting point: 134-137 ° C. Example 4C (Compound No. 21C) 2 - [[3- [5- (6-Methoxy-1-naphthyl) -1, 3-dioxan-2-yl] propyl] (2-thiazolylmethyl) amino] acetamide hydrochloride. Starting with 0.7 g (1.75 mmoles) of 5- (6-methoxy-1-naphthii) -N- (2-thiazolylmethyl) -1, 3-dioxan-2-propanamine and 0.2 g (2.1 mmoles) of 2-chloroacetamide, and working under conditions similar to those of Example 2C, 0.76 g of base were obtained, from which 0.763 g of hydrochloride was prepared. Melting point: 189-191 ° C.

The following Table C illustrates the chemical structures and physical properties of a number of compounds of the general formula (IC). In the column "R2", CsH N-2- represents a 3-pyridyl group, C5H N-4- represents a 4-pyridyl group, CH3-1-C4H3N-2- represents a 1-methyl-2-pyrrolyl group, C4H3O-2- represents a 2-furyl group, C H3S-2- represents a 2-thienyl group and C3H2NS-2- represents a 1,3-thiazol-2-yl group. In the column "Salt", "-" denotes a compound in the form of the base, "fum." Denotes a fumarate (or (E) -2-butenedioate), "ox." It denotes an oxalate (or ethanedioate) and "HCl" denotes a hydrochloride; the molar ratio of acid / base is indicated in parentheses. In the column "p.f. (° C)" "(d)" denotes a melting point with decomposition.

Table C 15 20 25 In the general formula (ID) Y represents a hydroxyl group, an alkoxy group of d-C4 or a group of the general formula NR R5 in which R4 and R5, independently of each other, each represents a hydrogen atom or a alkyl group of C -? - C4, and Ri and R2 form, with the nitrogen atom and the carbon atom, which connect them, a pyrrolidine ring, a piperidine ring or a ring of 1, 2,3,4 -tetrahydroisoquinoline. The compounds of the general formula (ID) can exist in the form of cis or trans stereoisomers or mixtures of said isomers, in addition, and taking into account the carbon atom asymmetric to the group -C (O) Y, they can exist in the form of pure enantiomers or mixtures of enantiomers. They can also exist in the form of free bases or addition salts with acids.

The compounds of the general formula (ID) can be prepared by a process illustrated by Scheme D below. 2- (6-methoxy-1-naphthyl) propane-1,3-dioI of the formula (IID), in an acid medium and in an aprotic medium, in order to obtain 2- (3-chloropropyl) -5- ( 6-methoxy-1-naphthyl) -1, 3-dioxolane of the formula IVD), and finally this compound is reacted with an amine of the general formula (VD), in which Y, Ri and R2 are as defined before, in the presence of an organic or inorganic base, in an aprotic solvent, for example N, N-dimethylformamide, at a temperature of 20 to 110 ° C. Scheme D 2- (6-methoxy-1-naphthyl) propane-1,3-diol of the formula (IID) was described in the patent application EP-0,461, 958. 2- (3-Chloropropyl) -1,3-dioxolane is commercially available. The amines of the general formula (VD) are commercially available or described in the literature. The following examples illustrate the preparation of a number of compounds of the general formula (ID). The elemental microanalyses and the IR and NMR spectra confirm the structures of the obtained compounds. The numbers of compounds indicated in parentheses in the titles correspond to those in Tala D given below. Example 1 D (Compound No. 1D). 1- [3- [5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] -L-proline oxalate ethyl. 1D.1.2- (3-Chloropropyl) -5- (6-methoxy-1-naphthyl) -1,3-dioxane. 5 g (21.5 mmol) of 2- (6-methoxy-1-naphthyl) -propane-1,3-diol, 3.7 ml (28.05 mmol) of 2- (3-chloropropyl) -1, 3-dioxolane and then 40 g. ml of hydrochloric ether were introduced into a round bottom flask of 500 ml containing 150 ml of toluene and the mixture was heated to reflux for 6 h. The mixture was allowed to cool, 100 ml of 5% sodium hydrogen carbonate solution were added and this mixture was extracted with twice 100 ml of ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and filtered, the solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel, eluting with a 9/1 mixture of ether. of petroleum and ethyl acetate, 3.2 g of a white solid were obtained, the product of which was used without further purification in the next step. 1D.2. 1- [3 - [[5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] -L-proline-oxalate ethyl. 0.32 g (1 mmole) of 2- (3-chloropropyl) -6- (6-methoxy-1-naphthyl) -1, 3-dioxane, 0.22 (1.2 mmole) of ethyl L-prolinate0.3 g (2.2 mmol) of potassium carbonate and then 0.29 g (2 mmol) of potassium iodide were introduced into a 50 ml round bottom flask containing 10 ml of N, N-dimethylformamide and the mixture was heated to 100 g. ° C for 4 h. The mixture was allowed to cool, 50 ml of water was added and this mixture was extracted with twice 70 ml of ethyl acetate, the organic phase was washed with water, dried over magnesium sulfate and filtered, the solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel, eluting with a gradient of dichloromethane and methanol of 99.5 / 0.5 to 99/1. 0.22 g (0.5 mmol) of the compound were obtained, which was crystallized, in the form of the oxalate, from ethyl acetate. Melting point: 116-118 ° C. Example 2D (Compound No.2D) 1 - [3- [5- (6-methoxy-1-n af ti I) -1,3-d i oxan-2-i I] propyl-L-proline mide. 0. 5 g (1.6 mmol) of 2- (3-chloropropyl) -5- (6-methoxy-1-naphthyl) -1,3-dioxane. 0.2 g (19 mmoles) of L-prolinamide, 0.2 g (1.6 mmoles) of potassium carbonate and then 0.48 g (3.2 mmoles) of potassium iodide were introduced into a 50 ml round bottom flask containing 15 ml of N, N-dimethylformamide and the mixture was heated at 110 ° C for 30 h 30. The mixture was allowed to cool, 60 ml of water were added and the resulting mixture was extracted with twice 80 ml of ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and filtered, the solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel, eluting with a gradient of 99 dichloromethane and methanol. / 1 to 97/3. 0.3 g of the compound were obtained, which was crystallized in the form of the 2-propanol base. Melting point: 164-166 ° C. 3D Example (Compound No.6D) Oxalate of 2- [3- [5- (6-methoxy-1-naphthyl) -1, 3-dioxan-2-yl] propyl) -Nm ethyl-1, 2,3, 4-tetrahydroisoquinoline-3-carboxyamide. 3D.1. N-methyl-1,2,3,4-tetrahydroquinoline-3-carboxyamid ida. 1.75 g (8.5 mmol) of ethyl 1, 2,3,4-tetrahydroisoquinoline-3-carboxylate were introduced into a 100 ml round bottom flask containing 25 ml of a 33% solution of methylamine in ethanol and the mixture left at 25 ° C for 20 h. It was concentrated to dryness under reduced pressure and 1.7 g of the compound was obtained as a colorless oil, which was used without further purification in the next step. 3D.2. Oxalate of 2- [3- [5- (6-methoxy-1-naphthyl) -1, 3-dioxan-2-i I] pro pi I] - N -methyl 1-1, 2,3,4-tetrahidorisoquinoline -3-carboxyamide. 0.5 g (1.6 mmole) of 2- (3-chloropropyl) -5- (6-methoxy-1-naphthyl) -1,3-dioxane, 0.3 g (1.6 mmole) of N-methyl-1, 2,3, 4-tetrahydroisoquinoline-3-carboxyamide, 0.2 g (1.6 mmol) of potassium carbonate and then 0.23 g (1.5 mmol) of potassium iodide were introduced into a 100 ml round-bottomed flask containing 20 ml of acetonitrile and the mixture was stirred. heated at 80 ° C for 8 h. The mixture was allowed to cool, 20 ml of water were added and the resulting mixture was extracted with twice 20 ml of ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and filtered, the solvent was evaporated under reduced pressure and the residue was purified by chromatography on a column of silica gel, eluting with a mixture of 98/2 dichloromethane and methanol. 0.12 g (0.25 mmol) of the compound were obtained, which was crystallized, in the form of oxalate, from diisopropyl ether. Melting point: 88-90 ° C. Table D below illustrates the chemical structures and physical properties of a number of compounds of the general formula (ID). In the column "R1NCHR2", "pirrol", "piper" and "isoq." They mean that R1 and R2 form, with the nitrogen atom and the carbon atom connecting them, a pyrrolidine ring, a piperidine ring or a 1,2,3,4-tetrahydroisoquinoline ring, respectively.

In the column "Salt", "-" denotes a compound in the form of the base, "fum." Denotes a fumarate (or l E) -2-ethanedioate) and "HCI" denotes a hydrochloride, the molar ratio of acid / base is indicated in parentheses. In the column "p.f. (C)", "(d)" denotes a melting point with decomposition. Table D The compounds according to the pharmacological tests carried out in the invention which reveal their value as therapeutic substances. Properties of neuronal antisense The introduction of calcium by a depolarizing stimulus in cortical synaptosomes in rats can be measured using a fluorescent probe, according to the method described by A. Deffois et al., In Neurosciences Letters (1996) 220 117-120. The effects of sodium channel agonist such as veratridine (10 μM) on the increase in intracellular calcium levels in this model were inhibited by the compounds of the invention at IC50 values (concentrations that inhibit the response by 50%) from 0.1 to 10 μM. Activity on tonic convulsions induced in mice by supramaximal electric shock The procedure of this test was described by E.A. Swinyard and J.H. Woodhead in Antiepileptic Drugs, Raven Press, New York, 111-126 (1982). 10 minutes. after intravenous administration of the test compound, a note was made of the number of mice showing tonic seizures (extension of the front and back extremities), immediately after the application of an electric current (0.4 s, 60 mA, 50 Hz ) using an Apelex ETC UNIT 7801 ™ machine. The results are expressed by AD5o, the dose that protects 50 of the animals, which is calculated according to the method of J.T. Lichtfield and F. Wilcoxon (J. Pharm. Exp. Ther., 96, 99-113 (1949)), using the Probit ™ software, starting with 3 or 4 doses administered each one to a group of 8 mice. The AD50 values of the most active compounds vary from 1 to 10 mg / kg. Anti-ischemic properties The compounds were subjected to the global cerebral ischemia test in mice. Ischemia was caused by cardiac arrest induced by a rapid intravenous injection of magnesium chloride. In this test, the "survival time" was measured, that is, the interval between the time of injection of the magnesium chloride and the last respiratory movement observed in each mouse. This last movement was considered as the final indicator of the functioning of the central nervous system. Breathing stopped approximately 19 seconds after injection of magnesium chloride. Male mice (Charles River SD1) were studied in groups of ten. They were fed and given water freely before the tests. The survival time was measured 10 minutes after the intraperitoneal administration of the compounds of the invention. The results are given in the form of the difference between the survival time measured in a group of ten mice that received the compound and the survival time measured in a group of ten mice that received the liquid vehicle. The relationships between the changes in survival time and the dose of the compound were recorded graphically in a semilogarithmic curve. This curve makes it possible to calculate the "effective dose in 3 seconds" (ED3 »), that is, the dose (in mg / kg) that produces an increase in 3 seconds in the survival time in relation to the control group of ten untreated mice. A 3-second increase in survival time is both statistically significant and reproducible. The ED3 »values of the most active compounds of the invention are from about 0.05 to 0.2 mg / kg via the intravenous route. Antinociceptive activity The antinociceptive activity was evaluated in rats, during the second stage of a formalin test adapted from the work by A. Tjolsen, O.-. Berge, S. H unskaar, J. H. Rosland and K. Hole in Pain (1992) 51 5-17. Formalin (5%) was injected subcutaneously (100 μl) into the plantar arch of the left hind paw. The nociception was quantified, after the injection, measuring, for the injected leg, the total duration of the licking activity, between +20 and + 35 min, and by the number of shivering actions, measured in sequences of 2 minutes, every 5 minutes, between +35 and + 60 min.

The compounds were administered in doses of 30 and 60 mg / kg as a suspension (water + 1% Tween 80), orally (5 ml / kg), 30 min. Before the injection of formalin. A compound was considered active if, after treatment, by comparison with the values measured in animals that received the vehicle, a statistically significant reduction (p <0.05) was observed in the total duration of reed activity and / or in the number of shares of chills (calculations of the areas under the curve). The activity threshold for the compounds of the invention corresponds to reductions of 35 to 40%. The most active compounds result in a 50% reduction at a dose of 30 mg / kg via the oral route. The results of the tests show that the compounds according to the invention have neuroprotective properties and can therefore be used for the preparation of medicaments that are useful in the treatment or prevention of cerebrovascular disorders of ischemic or hypoxic origin (cerebral infarction, cranial or spinal trauma, cardiac or respiratory arrest, temporary ischemic attack, perinatal asphyxia), glaucoma, progressive neurodegenerative diseases (senile dementias such as Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease, olivopontocerebellar atrophy, amyotrophic lateral sclerosis, neurodegenerative diseases of viral origin, etc.), and in the prevention of ischemic accidents associated with cardiac and vascular surgery and endovascular therapy. Taking into account their anticonvulsant properties, they can also be used in the treatment of epilepsy. The compounds of the invention also have analgesic properties and can therefore be used in the treatment of any acute or chronic pain. Finally, the treatment of other discomforts, such as neuropathy, neurogenic pain (for example, pain associated with neuropathies or with migraine attacks), neurological spasticity and dyskinesia, can also be anticipated. The compounds of the invention may be in any form of pharmaceutical composition that is suitable for enteral or parenteral administration, such as tablets, coated tablets, gelatin capsules, olea capsules, suspensions or solutions for drinking or injection, such as syrups, ampoules , etc. , combined with suitable excipients, and dosed to allow daily administration of 1 to 1000 mg of active substance.

Claims (6)

1. CLAIMS 1. A compound, in the form of a pure stereoisomer or a mixture of stereoisomers, corresponding to the general formula (IA) wherein Ri represents a hydrogen atom, a linear or branched C2-C alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkylmethyl group, a C3-C6 cycloalkylmethyl group or a phenylalkyl group of C1-C3 which is optionally substituted on the phenyl ring; R 2 represents a hydrogen atom, a linear or branched C?-C 4 alkyl group, a C 3 -C 6 cycloalkyl group, a C 3 -C 6 cycloalkylmethyl group or a C fen ?C C phenylalkyl group which is optionally substituted in the phenyl ring, R3 represents a hydroxyl group, a d-C4 alkoxy group or a group of the general formula NR R5 in which R4 and R5, independently of each other, each represents a hydrogen atom, an alkyl group of C -? - linear or branched C4, a C3-C6 cycloalkyl group or a C3-C6 cycloalkylmethyl group, in the form of the base or of an addition salt with an acid.
2. 2. The compound, in the form of a pure stereoisomer or a mixture of stereoisomers, corresponding to the general formula (IB) wherein R represents either a hydrogen atom or a group of the general formula CH2COY in which Y represents a hydroxyl group or a C4-C4 alkoxy group, or alternatively a group of the general formula CH2CONR1R2 in which Ri and R2, independently of one another, each represents a hydrogen atom or an alkyl group of C? -C4, X represents an oxygen or sulfur atom or a CH2 group, M represents 0 or 1 and N represents 0, 1 or 2? , in the form of the free base or of an addition salt with an acid.
3. 3. The compound, in the form of a pure stereoisomer or a mixture of stereoisomers, corresponding to the general formula (IC) wherein Ri represents either a hydrogen atom or a group of the general formula CH2COY in which Y represents a hydroxyl group or a C1-C alkoxy group, or alternatively, a group of the general formula CH2CONR4R5 in which R4 and R5, independently of one another, each represents a hydrogen atom or an alkyl group of d-C4, and R2 represents a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 1-methyl group -2-pyrrolyl, a 2-furyl group, a 2-thienyl group or a 1,3-thiazole-2-yl group, in the form of the free base of an addition salt with an acid.
4. 4. The compound, in the form of a pure stereoisomer or a mixture of stereoisomers, corresponding to the general formula (ID) wherein Y represents a hydroxyl group, an alkoxy group of C? -C4 or a group of the general formula NR4R5 in which R and R5, independently of one another, can represent a hydrogen atom or an alkyl group of C? -C4, and Ri and R2 form, with the nitrogen atom and the carbon atom connecting them, a pyrrolidine ring, a piperidine ring or a 1, 2,3,4-tetrahydroisoquinoline ring, in the form of free base or an addition salt with an acid. Medicament, characterized in that it consists of a compound according to one of claims 1 to 4. 6. Pharmaceutical composition, characterized in that it contains a compound according to one of claims 1 to 4, combining with an excipient.