AU8025198A

AU8025198A - 5-naphthalen-1-yl-1,3-dioxane derivatives, preparation and therapeutic application

Info

Publication number: AU8025198A
Application number: AU80251/98A
Authority: AU
Inventors: Gihad Dargazanli; Jonathan Frost; Pascal George; Patrick Lardenois
Original assignee: Synthelabo SA
Current assignee: Sanofi Aventis France
Priority date: 1997-06-05
Filing date: 1998-06-03
Publication date: 1998-12-21
Also published as: TR199903022T2; WO1998055474A1; JP2002502412A; CO4940480A1; IL133242A0; BG103937A; PL337234A1; NO995966D0; HUP0002166A3; EE9900560A; EP0986552A1; BR9810742A; HUP0002166A2; CN1265658A; AR012908A1; NO995966L; CA2290695A1; KR20010013435A; SK166199A3

Description

WO 98/55474 1 PCT/FR98/01113 5-Naphthalene-1-yl-1,3-dioxane derivatives, their preparation and their therapeutic application The present invention relates to compounds of general formula (I) V N, 0 0(I o o 5 in which R, 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 10 substituted on the phenyl ring, a carboxymethyl group, an alkoxycarbonylmethyl group or a carbamoylmethyl group which is optionally monosubstituted or disubstituted on the nitrogen, W represents a carboxymethyl group, an 15 alkoxycarbonylmethyl group, a carbamoylmethyl group which is optionally monosubstituted or disubstituted on the nitrogen, a 4- to 7-membered cyclic group optionally containing an oxygen or sulphur atom, a REPLACEMENT SHEET (RULE 26) 2 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 1,3-thiazol-2-yl-methyl group, or alternatively 5 V and W form, together with the nitrogen atom which bears them, a pyrrolidinyl, piperidyl or 1,2,3,4 tetrahydroisoquinolyl group. The compounds of the invention correspond more particularly to one of the general formulae (IA), 10 (IB) , (IC) and (ID) In the general formula (IA)

R

1 represents a hydrogen atom, a linear or branched

(C

2

-C

4 )alkyl group, a cyclo(C 3

-C

6 )alkyl group, a cyclo (C 3

-C

6 ) alkylmethyl group or a phenyl (C 1

-C

3 ) alkyl 15 group 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 cyclo(C 3 -C,)alkyl group, a cyclo(C 3

-C

6 )alkylmethyl group or a phenyl (C 1

-C

3 )alkyl 20 group which is optionally substituted on the phenyl ring,

R

3 represents a hydroxyl group, a (C 1

-C

4 )alkoxy group or a group of general formula NR 4 R. in which R 4 and R 5 , independently of each other, each represent a hydrogen 25 atom, a linear or branched (C 1

-C

4 )alkyl group, a REPLACEMENT SHEET (RULE 26) 3 cyclo(C 3

-C

6 )alkyl group or a cyclo(C 3

-C

6 )alkylmethyl group.

R

2 0o R o 0 (IA) (IB N 0- N>CH2) Xa (IB) roe

H

3 C%. N. N. o 0 (IC) H ,C H3'0 (ID) - -1 The compounds of general formula (IA) can exist in the form of cis or trans stereoisomers or 5 mixtures of such isomers; they can also exist in the 4 form of free bases or of addition salts with acids. The compounds of general formula (IA) can be prepared by various processes described below. According to a first variant, illustrated by 5 Scheme A which follows, the amide of formula (IIA) 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 0 C, in order to obtain the amide of formula (IIIA), 10 according to a method described in J. Am. Chem. Soc. (1976) 98 3237. This amide is then subjected to an alkylation using a derivative of general formula R 1 -X, in which R 1 is as defined above, but is other than a hydrogen atom, 15 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 general formula (IVA). 20 This amide is then hydrolysed 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 0 C, in order to obtain the corresponding primary amine, after which this amine is 25 treated either with an aldehyde of general formula R.-CHO, in which R, is the lower homologue of the group 5

R

2 , in the presence of a reducing agent such as sodium borohyride or sodium cyanoborohydride, under reductive amination conditions known to those skilled in the art, in order to obtain an amine of general formula (VA). 5 This amine is then hydrolysed in basic medium, for example sodium hydroxide, in a protic solvent, for example water or an aliphatic alcohol at a temperature of from 25 to 100 0 C, in order to obtain the corresponding primary amine, and this amine is then 10 treated with an aldehyde of general formula R 6 -CHO, in which R 6 is the lower homologue of the group R 2 , 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 15 to obtain an amine of general formula (VA). The amine of general formula (VA) is then reacted with ethyl bromoacetate in order to obtain a compound of general formula (IA) in which R 1 and R 2 represent an alkyl, cycloalkyl, cycloalkylalkyl or 20 phenylalkyl group and R 3 represents an ethoxy group. If so desired, the compound thus obtained can then be saponified in order to convert it into the corresponding acid, or alternatively can be reacted with an amine of general formula HNR 4 R, in which R 4 and 25 R. are as defined above, in order to convert it into an amide. The conditions of these reactions are standard 6 and are well known to those skilled in the art. According to an alternative variant, the amides of general formula (IA) , in which R 1 and R 2 represent an alkyl or phenylalkyl group, can be 5 obtained by reacting the amine of general formula (VA) 7 Scheme A Y CH 3 Y rCH 3 0 0O 0 0. 0O (IIA) IIIIA) H3 , HOJ O1 0 0 (VA) (IVA) R, R1 . 0 0 ~ O 00 O - R 0 (IA) directly with an a-halo alkanamide of general formula

(VIA)

8 0 N-R 4 (VIA) in which X represents a chlorine or bromine atom and R 4 and R, 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 5 general formula (VA), in which R 1 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 patent application EP-461,958, or by hydrolysis of the said 10 alkanamides into 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. 15 Lastly, according to a final variant, a compound of general formula (IA), in which R 1 represents a hydrogen atom, can be prepared by demethylation, using sodium sulphide in N,N-dimethylformamide, of the corresponding compound, in the formula in which R, 20 represents a methyl group, described in patent application FR-2,742,152.

9 The examples which follow illustrate the preparation of a number of compounds of general formula (IA). The elemental microanalyses and the IR and NMR spectra confirm the structures of the compounds 5 obtained. The numbers indicated in parentheses in the example titles correspond to those in the 1st column of Table A given later. In the compound names, the hyphen "-" forms 10 part of the name, and the underscore line "_" serves merely to indicate the presence of a line break; it should be removed if a line break does not occur at that point, and should not be replaced either with a normal hyphen or with a space. 15 Example 1A (Compound No. 2A). 2-[[3-[5-[6-(Cyclopropylmethoxy)-1-naphthyl] 1,3-dioxan-2-yl]propyl]ethylamino]-N-(cyclopropyl methyl)acetamide. 1A.1. 5-[6-(Cyclopropylmethoxy)-l-naphthyl]-N-ethyl 20 1,3-dioxane-2-propanamine. 0.8 g of lithium aluminium hydride suspended in 30 ml of tetrahydrofuran is introduced into a 250 ml 2-necked round-bottomed flask, the mixture is heated to reflux, 4.0 g (10.43 mmol) of N-[3-[5-[6-(cyclopropyl- 10 methoxy)-1-naphthyl]-1,3-dioxan-2-yl]propyl]acetamide dissolved in 200 ml of tetrahydrofuran are added and refluxing is continued for 4 h. The mixture is cooled, 3.5 ml (2 eq.) of 5 aqueous 0.1M potassium sodium tartrate solution are added slowly, the mixture is stirred and the solvents are evaporated off under reduced pressure. 4.55 g of an oily product are obtained, which product is used without further purification in the following step. 10 1A.2. 2-[[3-[5-[6-(Cyclopropylmethoxy)-1-naphthyl] 1,3-dioxan-2-yl]propyl]ethylamino]-N-(cyclopropyl methyl)acetamide 0.23 ml (2.6 mmol) of cyclopropylmethanamine, 20 ml of dioxane and 0.36 ml of triethylamine are 15 introduced into a 250 ml round-bottomed flask, a solution of 0.21 ml (2.6 mmol) of chloroacetyl chloride in 5 ml of dioxane is added dropwise and the mixture is stirred at room temperature for 8 h. 30 ml of water, 1 g of potassium carbonate 20 and 1.0 g (2.7 mmol) of 5-[6-(cyclopropylmethoxy) 1-naphthyl]-N-ethyl-1,3-dioxane-2-propanamine are added and the mixture is heated at 80 0 C for 8 h and left to stand at room temperature overnight. Water and ethyl acetate are added, the 25 organic phase is separated out, washed with water and 11 then with brine, dried over magnesium sulphate and filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 98/2 mixture 5 of dichloromethane and methanol. 0.5 g of an oily product is obtained, which is dissolved in 2-propanol, 8 ml of 0.1M hydrochloric acid in 2-propanol are added, the solvents are evaporated off and the residue is recrystallized from 10 diisopropyl ether. 0.2 g of hydrochloride is finally isolated. Melting point: 74-76 0 C. Example 2A (Compound No. 3A). N-Cyclopropyl-2-[[3-[5-[6-(cyclopropylmethoxy) 15 1-naphthyl]-1,3-dioxan-2-yl]propyl]ethylamino] acetamide. 2A.1. Chloro-N-cyclopropylacetamide. 2 g (17.7 mmol) of chloroacetyl chloride dissolved in 10 ml of dioxane are introduced into a 20 100 ml round-bottomed flask, 1 g (17.7 mmol) of cyclo propanamine is added dropwise and the mixture is stirred at room temperature for 2 h. Bicarbonate solution and ethyl acetate are added, the organic phase is separated out, washed with 12 water, dried over magnesium sulphate and filtered and the solvent is evaporated off under reduced pressure, which gives 0.7 g of a white solid. The aqueous phase is concentrated under 5 reduced pressure and the residue is taken up in ethanol, which gives a further 1.22 g of a white solid, i.e. a total of 1.92 g of compound, which is used without further purification in the following step. 2A.2. N-Cyclopropyl-2-[[3-[5-[6-(cyclopropylmethoxy) 10 1-naphthyl]-1,3-dioxan-2-yl]propyl]ethylamino] acetamide. 0.69 g (1.87 mmol) of 5-[6-(cyclopropyl methoxy)-1-naphthyl]-N-ethyl-1,3-dioxane-2-propanamine dissolved in 20 ml of acetonitrile, 0.37 g (2.77 mmol) 15 of 2-chloro-N-cyclopropylacetamide and 0.26 g of potassium carbonate are introduced into a 100 ml round bottomed flask and the mixture is heated at 70 0 C for 4 h. The mixture is cooled, water and ethyl 20 acetate are added, the organic phase is separated out, washed with water and then with saturated sodium chloride solution, dried over magnesium sulphate and filtered and the solvent is evaporated off under reduced pressure. The residue is purified by 25 chromatography on a column of silica gel, eluting with 13 a 98/2 mixture of dichloromethane and methanol. After crystallization from diisopropyl ether, 0.2 g of a white solid is isolated. Melting point: 87-89 0 C. 5 Example 3A (Compound No. 17A). 2-[[3-[5-[6-(Cyclopropylmethoxy)-1-naphthyl] 1,3-dioxan-2-yl]propyl]methylamino]-N-(cyclopropyl methyl)acetamide. 3A.1. 5-[6-(Cyclopropylmethoxy)-l-naphthyl] 10 1,3-dioxane-2-propanamine. 30.0 g (78.23 mmol) 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 are introduced into a 1000 ml round-bottomed 15 flask and the mixture is heated at 110 0 C for 24 h. The alcoholic phase is separated out after settling of the phases has taken place and this phase is concentrated, water is added and the mixture is extracted with ethyl acetate. The organic phase is 20 dried over magnesium sulphate and the solvent is evaporated off under reduced pressure. 30.44 g of an oily product are obtained, which product is used without further purification in the following step.

14 3A.2. 5-[6-(Cyclopropylmethoxy)-1-naphthyl]-N-methyl 1,3-dioxane-2-propanamine. 2.4 ml (25.3 mmol) of acetic anhydride are introduced into a 50 ml round-bottomed flask, 1 ml 5 (26.5 mmol) of formic acid is added dropwise and the mixture is heated on an oil bath at 50'C for 2 h. The heating is removed, 2.5 ml of anhydrous tetrahydrofuran are added and, while stirring the mixture, a solution of 6.0 g (17.5 mmol) of 10 5-[6-(cyclopropylmethoxy)-1-naphthyll-1,3-dioxane 2-propanamine in 7 ml of tetrahydrofuran is added dropwise without the temperature exceeding 40 0 C, and stirring is continued at room temperature overnight. The solvent is evaporated off under reduced 15 pressure, the residue is taken up in toluene, this solution is evaporated under reduced pressure and the residue is dried. 5.84 g (15.8 mmol) of a white solid are obtained. This solid is dissolved in 40 ml of 20 tetrahydrofuran in a 250 ml round-bottomed flask, a suspension of 1.2 g of lithium aluminium hydride in 43 ml of tetrahydrofuran is added, at the reflux temperature and under an argon atmosphere, and refluxing is continued for 4 h. 25 The mixture is cooled in a bath of ice-cold water, 9 ml of sodium potassium tartrate are added 15 dropwise and stirring is continued overnight. The mixture is filtered and the filtrate is concentrated under reduced pressure to give 5.89 g of an oily product. 5 0.23 g of this product is dissolved in 2-propanol and, after treatment with one equivalent of hydrochloric acid in 2-propanol, 0.188 g of hydrochloride is finally isolated. Melting point: 144-148 0 C. 10 3A.3. 2-[[3-[5-[6r-(Cyclopropylmethoxy)-1-naphthyl] 1,3-dioxan-2-yl]propyl]methylaminol-N-(cyclopropyl methyl)acetamide. 0.24 ml (2.81 mmol) of cyclopropanemethan amine, 20 ml of dioxane and 0.4 ml of triethylamine are 15 introduced into a 250 ml round-bottomed flask, a solution of 0.22 ml (2.81 mmol) of chloroacetyl chloride in 10 ml of dioxane is added dropwise and the mixture is stirred at room temperature for 9 h. 30 ml of water, 1 g of potassium carbonate 20 and 1 g (2.81 mmol) of 5-[6-(cyclopropylmethoxy) 1-naphthyl]-N-methyl-1,3-dioxane-2-propanamine are added and the mixture is heated at 80'C for 3 h. It is cooled, water and ethyl acetate are added, the organic phase is separated out, washed with 25 water and with brine, dried over magnesium sulphate and 16 filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. 0.62 g of product is 5 obtained, which is dissolved in ethanol. After treatment with one equivalent of oxalic acid, 0.5 g of a white solid is isolated. Melting point: 156-158 0 C. Example 4A (Compound No. 19A). 10 2-[[3-[5-(6-Ethoxy-1-naphthyl)-1,3-dioxan 2-yllpropyl](phenylmethyl)amino]acetamide. 4A.1. N-[3-[5-(6-Hydroxy-1-naphthyl)-1,3-dioxan 2-yllpropyl]acetamide. 3.4 g (9.9 mmol) of N-[3-[5-(6-methoxy 15 1-naphthyl)-1,3-dioxan-2-yl]propyl]acetamide and 20 ml of 1-methyl-2-pyrrolidinone are introduced into a 250 ml round-bottomed flask, under a nitrogen atmosphere, the mixture is stirred, 3.86 g (49.5 mmol) of sodium sulphide are added and the mixture is heated on an oil 20 bath at 150 0 C overnight. The mixture is allowed to cool to 25 0 C, 50 ml of ethyl acetate and 50 ml of water are added, the organic phase is separated out, 10% hydrochloric acid is added to the aqueous phase to pH = 4 and this phase 17 is extracted again with ethyl acetate. The organic phases are combined, washed with water and then with saturated sodium chloride solution and are dried over magnesium sulphate. The solution is filtered, the 5 solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. The purified fraction is treated with 10 pentane, with ultrasound, with ethyl acetate and with diisopropyl ether. 1.87 g of solid are finally isolated. Melting point: 135-137 0 C. 4A.2. N-[3-[5-(6-Ethoxy-l-naphthyl)-1,3-dioxan 15 2-yl]propyl]acetamide. 4.5 g of (13.7 mmol) of N-[3-[5-(6-hydroxy 1-naphthyl)-1,3-dioxan-2-yl]propyl]acetamide dissolved in 70 ml of N,N-dimethylformamide, 2.8 g of potassium carbonate and 1.53 ml (20.5 mmol) of bromoethane are 20 introduced into a 250 ml round-bottomed flask and the mixture is stirred at room temperature overnight. The solvent is evaporated off under reduced pressure, by entrainment with toluene, the residue is taken up in water and ethyl acetate and a solid is 25 separated out by filtration. After rinsing with water 18 and with ethyl acetate, and drying, 2.74 g of solid are isolated. After separation of the phases once settling has taken place, washing of the organic phase, drying, 5 filtration and evaporation of the solvent, a further 1.7 g of solid are obtained, i.e. a total of 4.44 g of compound. 0.3 g of this product is recrystallized from a 6/4 mixture of ethanol and water and 0.2 g of 10 compound is finally isolated. Melting point: 140-142 0 C. 4A.3. 5-(6-Ethoxy-l-naphthyl)-1,3-dioxane 2-propanamine. 4.1 g (11.4 mmol) of N-[3-[5-(6-ethoxy 15 1-naphthyl)-1,3-dioxan-2-yl]propyl]acetamide dissolved in 49 ml of ethanol and 43.4 ml of 30% sodium hydroxide are introduced into a 250 ml round-bottomed flask and the mixture is refluxed for 24 h. It is allowed to cool, the alcoholic phase is 20 separated out after settling of the phases has taken place, this phase is concentrated and the residue is taken up in water and extracted with dichloromethane. The organic phase is washed with saturated sodium chloride solution and dried over magnesium sulphate. 25 This solution is filtered and the solvent is evaporated 19 off under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a 90/10/1 mixture of dichloromethane, methanol and aqueous ammonia. 5 1.87 g of a solid are obtained, which product is used without further purification in the following step. The hydrochloride thereof is prepared from a 0.1N solution of hydrochloric acid in 2-propanol. 10 Melting point: 180-183 0 C. 4A.4. 5-(6-Ethoxy-l-naphthyl)-N-(phenylmethyl) 1,3-dioxane-2-propanamine. 1.63 g (5.17 mmol) of 5-(6-ethoxy 1-naphthyl)-1,3-dioxane-2-propanamine dissolved in 15 450 ml of methanol are introduced into a 1000 ml round bottomed flask fitted with Dean-Stark apparatus, followed by introduction of 0.604 g (5.69 mmol) of benzaldehyde and the mixture is refluxed until it has reduced to one-third of the initial volume. 20 The mixture is allowed to cool, it is placed in an ice bath, 1.56 g (41.3 mmol) of sodium borohydride are added portionwise and the mixture is stirred overnight. The solvent is evaporated off under reduced 25 pressure, the white residue is taken up in water and 20 ethyl acetate, the organic phase is washed twice with water and once with ethyl acetate, dried over magnesium sulphate and filtered, the solvent is evaporated off under reduced pressure and the residual oil is purified 5 by chromatography on a column of silica gel, eluting with a 95/5 mixture of dichloromethane and methanol. 1.15 g of base are obtained, 0.1 g of which product is taken in order to prepare the hydrochloride, by dissolution in hot 2-propanol, addition of 2.46 ml 10 of 0.1N hydrochloric acid in 2-propanol, evaporation of the solvent under reduced pressure, trituration of the residue from diisopropyl ether, filtration and drying under vacuum. 0.97 g of hydrochloride is isolated. Melting point: 206-208 0 C. 15 4A.5. 2-[3-[5-(6-Ethoxy-l-naphthyl)-1,3-dioxan-2-yl] propyl](phenylmethyl)amino]acetamide. 0.5 g (1.23 mmol) of 5-(6-ethoxy-l-naphthyl) N-(phenylmethyl)-1,3-dioxane-2-propanamine dissolved in 7 ml of acetonitrile, 0.17 g (1.23 mmol) of potassium 20 carbonate, 0.055 g (0.369 mmol) of sodium iodide and 0.138 g (1.47 mmol) of 2-chloroacetamide are introduced into a 50 ml round-bottomed flask and the mixture is refluxed for 5 h. The mixture is allowed to cool, water and ethyl acetate are added, the organic phase is 25 separated out, the aqueous phase is extracted once 21 more, the organic phase is washed twice with water and once with saturated aqueous sodium chloride solution, dried over magnesium sulphate and filtered, the solvent is evaporated off under reduced pressure and the 5 residue is purified by chromatography on a column of silica gel, eluting with a 99/1 mixture of dichloro methane and methanol. 0.590 g of pure base is obtained in the form of a yellow oil, which is dissolved in hot 2-propanol 10 and 12.3 ml of 0.1N hydrochloric acid in 2-propanol are added. After evaporation of the solvent under reduced pressure, trituration of the residue from diisopropyl ether, filtration.and drying under vacuum, 0.54 g of hydrochloride is isolated. 15 Melting point: 190-193 0 C. Example 5A (Compound No. 20A). 2-[[3-[5-(6-Ethoxy-l-naphthyl)-1,3-dioxan-2-yl] propyll(phenylmethyl)amino]-N-methylacetamide. 5A.1. Ethyl 2-[[3-[5-(6-ethoxy-l-naphthyl)-1,3-dioxan 20 2-yl]propyl](phenylmethyl)amino]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 mmol) of potassium carbonate and 0.2 ml (1.84 mmol) of ethyl 2-bromo- 22 acetate are added and the mixture is heated at 60 0 C for 2.5 h. 20 ml of water and 15 ml of ethyl acetate are added, the organic phase is separated out, washed with 5 water, dried over magnesium sulphate and filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 98/2 mixture of dichloro methane and methanol. 0.58 g of an oily product is 10 obtained, which is used without further purification in the following step. 5A.2. 2-[[3-[5-(6-Ethoxy-l-naphthyl)-1,3-dioxan-2-yl] propyl](phenylmethyl)amino]-N-methylacetamide. 0.58 g (1.18 mmol) of ethyl 2-[[3-[5 15 (6-ethoxy-1-naphthyl)-1,3-dioxan-2-yllpropyl] (phenylmethyl)amino]acetate is dissolved in a few ml of ethanol, 5 ml of 33% methanamine in ethanol are added and the mixture is placed in an oven at 50 0 C for 7 days. 20 The solvent is evaporated off under reduced pressure and 0.8 g of an oily product is obtained, which is purified by chromatography on a column of silica gel, eluting with a 98/2 mixture of dichloro methane and methanol, to give 0.5 g of pure base in the 25 form of an oil.

23 After treatment with 10.5 ml of 0.1N hydrochloric acid in 2-propanol, evaporation of the solvent, trituration from diisopropyl ether, filtration and drying, 0.37 g of hydrochloride is finally 5 isolated. Melting point: 88-90 0 C. Example 6A (Compound No. 23A). 2-[[3-[5-[6-(Cyclopentyloxy)-1-naphthyl]-1,3-dioxan 2-yl]propyl] (phenylmethyl)amino]acetamide. 10 6A.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-l-naphthyl)-1,3-dioxan-2-yl]propyl]acetamide and 3.0 g (20.1 mmol) of bromocyclopentane, and working 15 under conditions similar to those described in Example 4A.2, but at 80 0 C, 4.88 g of crude compound are obtained. 0.388 g of this compound is purified by chromatography on a column of silica gel, eluting with a 90/10 mixture of dichloromethane and methanol. After 20 recrystallization from a mixture of ethanol and water and then drying in the presence of phosphorus pentoxide, 0.22 g of compound is isolated. Melting point: 136-137 0

C.

24 6A.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-l-naphthyl)-1,3-dioxan-2-yllpropyl] 5 acetamide, and working under conditions similar to those described in Example 4A.3, 1.52 g of base are obtained, followed by 1.15 g of hydrochloride. 6A.3. 5-[6-(Cyclopentyloxy)-1-naphthyl]-N-(phenyl methyl)-1,3-dioxane-2-propanamine. 10 Starting with 0.59 g (1.66 mmol) of 5-(6-cyclopentyloxy-l-naphthyl)-1,3-dioxane-2-propan amine and 0.194 g (1.82 mmol) of benzaldehyde, and working under conditions similar to those described in Example 4A.4, 0.48 g of base is obtained, from which 15 0.435 g of hydrochloride is prepared. Melting point: 186-190 0 C. 6A.4. 2-[[3-[5-[6-(Cyclopentyloxy)-1-naphthyl] 1,3-dioxan-2-yl]propyl](phenylmethyl)amino]acetamide. Starting with 0.710 g (1.59 mmol) of 20 5-(6-cyclopentyloxy-l-naphthyl)-N-(phenylmethyl) 1,3-dioxane-2-propanamine and 0.178 g (1.9 mmol) of 2-chloroacetamide, and working under conditions similar to those described in Example 4A.5, 0.640 g of base is obtained in the form of an oil, from which 0.628 g of 25 hydrochloride is prepared. Melting point: 212-215 0 C. Example 7A (Compound No. 26A). 2-[[3-[5-[(6-(Phenylmethoxy)-1-naphthyl]-1,3-dioxan 5 2-yllpropyl] (phenylmethyl) amino] acetamide. 7A.1. N-[3-[5-[(6-(Phenylmethoxy)-1-naphthyl] 1, 3-dioxan-2-yll]propyl] acetamide. Starting with 4.2 g (12.75 mmol) of N- [3-5- (6-hydroxy-1-naphthyl) -1,3-dioxan-2-yl] 10 propyl]acetamide and 1.82 ml (15.3 mmol) of (bromomethyl)benzene, and working under conditions similar to those described in Example 4A.2, 4.67 g of product are obtained, 0.3 g of which is recrystallized from a 6/4 mixture of ethanol and water, to give 0.15 g 15 of a white solid. Melting point: 138-140 0 C. 7A.2. 5-[6-(Phenylmethoxy)-1-naphthyl]-1,3-dioxane 2 -propanamine. Starting with 4.06 g of N-[3-[5-[(6-(phenyl 20 methoxy) -1-naphthyl] -1,3-dioxan-2-yllpropyl]acetamide, and working under conditions similar to those described in Example 4A.3, 3.2 g of an oily product are obtained, which product is used without further purification in 26 the following step. 7A.3. 5-[6-(Phenylmethoxy)-1-naphthyl]-N-(phenyl methyl)-1,3-dioxane-2-propanamine. Starting with 1.13 g (2.99 mmol) of 5 5-[6-(phenylmethoxy)-1-naphthyl]-1,3-dioxane-2-propan amine and 0.317 g (2.99 mmol) of benzaldehyde and then 0.904 g (23.9 mmol) of sodium borohydride, and working under conditions similar to those described in Example 4A.4, 0.41 g of base is obtained, 0.1 g of 10 which is taken in order to obtain 0.090 g of hydrochloride. Melting point: 185-189 0 C. 7A.4. 2-[[3-[5-[(6-(Phenylmethoxy)-l-naphthyl] 1,3-dioxan-2-yl]propyl] (phenylmethyl)amino]acetamide. 15 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 mmol) of 2-chloroacetamide, and working under conditions similar to those described in Example 4A.5, 0.310 g of base is 20 obtained in the form of an oil, from which 0.285 g of hydrochloride is prepared. Melting point: 170-175 0 C. Table A which follows illustrates the chemical structures and the physical properties of a 27 number of compounds of general formula (IA). In the "R 1 ", "R 2 " and "R 3 " columns, CC 3 H. represents a cyclopropyl group, cCHs represents a cyclopentyl group and CH 5 represents a phenyl group. 5 In the "Salt" column, "-" denotes a compound in the form of the base, "ox." denotes an oxalate (or ethanedioate), "fum" denotes a fumarate (or (E)-2-butenedioate) and "HCl" denotes a hydrochloride; the acid/base molar ratio is indicated in parentheses. 10 In the "m.p. ( 0 C)" column, " (d)" denotes a melting point with decomposition. All the compounds are trans stereoisomers (1H

NMR).

28 Table A R0 N 0 0 (IA) Oic No. R, R2 R3 Salt m.p.( 0 C) 1A -CH2CC3Hs -CH2CH3 -NHCH 3 - 90-92 2A -CH 2 cC 3

H

5

-CH

2

CH

3

-NHCH

2 cC 3 Hs HCl (1: 1) 74- 76 3A -CH2C 3 S -CH 2

CH

3 -NHcC 3 Hs - 87-89 4A -CH 2 cC 3 Hs -CH 2 cC 3

H

5

-NH

2 HC1 (1:1) 63 (d) SA -CH 2 cC 3

H

5

-CH

2 cC 3 HS -NHCH 3 HCl (1:1) 78-80 6A -CH 2

CC

3

H

5

-CH

2

CC

3 Hs -NHCH 2 cC 3

H

5 - 92-96 7A -CH 2 cC 3

H

5

-CH

2

CC

3 HS -NHCC 3 Hs HCl (1:1) 80-82 SA -CH 2 cC 3 HS -CH 2

C

6

H

5

-OCH

2

CH

3 HC1 (1:1) 66-68 9A -CH 2 cC 3 HS -CH 2

C

6 HS -NH 2 - 135-137 10A -CH 2 cC 3 HS -CH 2

C

6

H

5

-NHCH

3 - 115-117 11A -CH 2 cC 3

H

5

-CH

2

C

6 Hs -NHCH 2 cC 3 HS HC1 (1:1) 84-86 12A -CH 2 cC 3

H

5

-CH

2

C

6 HS -NHcC 3

H

5 HCl (1:1) 90-92 13A -CH 2 cC 3

H

5

-CH

3

-OCH

2

CH

3 HCl (1:1) 128-130 14A -CH 2 cC 3 HS -CH3 -NH 2 HCl (1:1) 98-110 15A -CH 2 cC 3

H

5

-CH

3

-NHCH

3 - 94-96 29 No. R, R2 R 3 Salt m.p. (*C) 16A -CH 2 cC 3

H

5 -CH3 -NHCC 3 HS HCl (1:1) 92-94 17A -CH 2 cC3H 5

-CH

3 -NHCH2CC 3 HS ox. (1:1) 156-158 18A -CH 2 cC 3

H

5

-CH

2

CH

3

-NH

2 - 127-129 19A -CH2CH 3

-CH

2

C

6 HS -NH2 HC1 (1:1) 190-193 20A -CM2CH 3

-CH

2

C

6

H

5 -NHCH3 HCl (1:1) 88-90 21A -CH(CH 3

)

2

-CH

2

C

6

H

5

-NH

2 HC1 (1:1) 174-176 22A -CH (CH 3 ) 2

-CH

2 CsH 5 -NHCH3 HCl (1:1) 88-90 23A -cC 5

H

9

-CH

2

C

6

H

5

-NH

2 HCl (1:1) 212-215 24A - (CH 2 ) 3CH 3

-CH

2

C

6 HS -NH 2 HCl (1:1) 192-195 25A - (CH 2 ) 3CH 3

-CH

2

C

6 HS -NHCH 3 ox. (1:1) 68-70 26A -CH 2

C

6 HS -CH 2 CSHS -NH 2 HCl (1:1) 170-175 27A -(CH 2 ) 3

CH

3

-CH

3

-NH

2 - 120-121 28A -CH 2

C

6 Hs -CH 3

-NHCH

3 - 114-116 29A -CH 2

C

6

H

5

-CH

2 C6HS -NHCH 3 - 108 -110 30A -CH 2

C

6

H

5

-CH

3 -NH HCl (1:1) 75-85 31A H -CH 2

C

6 Hs -NH 2 - 90 (d) 32A -cCSH 9

-CH

2

C

6 HS -NHCH 3 - 116-118 33A -CCsH 9

-CH

3

-NH

2 - 138-140 34A -CH2CH 3

CH

3

-NH

2 fum (1:1) 161-162 In the general formula (IB) R represents either a hydrogen atom or a group of general formula CH 2 COY in which Y represents a hydroxyl group or a (C 1

-C

4 )alkoxy group, or alternatively a group 5 of general formula CH 2

CONRR

2 in which R 1 and R 2

,

30 independently of each other, each represent a hydrogen atom or a (C 1

-C

4 ) alkyl group, X represents an oxygen or sulphur atom or a CH 2 group, m represents 0 or 1, and 5 n represents 0, 1 or 2. The compounds of general formula (IB) can exist in the form of cis or trans stereoisomers or mixtures of such isomers; moreover, on account of the chirality of the ring attached to the nitrogen atom, 10 certain compounds can exist in the form of diastereoisomers and/or enantiomers. They can also exist in the form of free bases or of addition salts with acids. The compounds of general formula (IB) can be 15 prepared by a process illustrated by Scheme B which follows. 2- (6-Methoxy-l-naphthyl)propane-1,3-diol of formula (IIB) is reacted with 4,4-diethoxybutanamine of formula (IIIB) in a refluxing non-protic solvent such 20 as toluene and in the presence of dry hydrochloric acid dissolved in diethyl ether as catalyst, in order to 31 Scheme B OH ON (IIB) 31'C' OC 11. (IVB) IMID)

H

3 C,0 0 (IBa)N (IBb) 0 0

-

X N (c3 2 ) HC, -. (IBc) 9 IC, 0jCN obtain 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2 propanamine of formula (IVB), and this compound is then reacted with a ketone of general formula (VB), in which 5 X, m and n are as defined above, in the presence of a 32 reducing agent such as sodium borohydride or any other equivalent agent, in a neutral or acidic medium, under reductive amination conditions that are well known to those skilled in the art. A compound of general formula 5 (IBa) which corresponds to the general formula (IB) when R represents a hydrogen atom is obtained. The compound of general formula (IBa) can then, if so desired, be alkylated with a (Cl-C,)alkyl 2 bromoacetate in a polar aprotic solvent, for example 10 acetonitrile, in the presence of a base, for example potassium carbonate, in order to obtain a compound of general formula (IBb) in which Y represents a (Ci

C

4 )alkoxy group. If so desired, this compound can be 15 saponified under conditions that are well known to those skilled in the art, in order to obtain a compound of general formula (IBb) in which Y represents a hydroxyl group. The general formula (IBb) corresponds to the general formula (IB) when R, represents a group 20 of general formula CH 2 COY. If so desired, the compound of general formula (IBb) can then be reacted with an amine of general formula HNRjR 2 , in which R 1 and R 2 are as defined above, in order to obtain an amide of general formula 25 (IBc). The conditions of this reaction are standard and are well known to those skilled in the art.

33 An amide of general formula (IBc) can also be obtained directly from a compound- of general formula (IBa) by alkylation with a halide of general formula

Z-CH

2

-CO-NRR

2 , in which Z represents a chlorine or 5 bromine atom and R, and R 2 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 10 formula (IIB) is described in patent application EP 0,461,958. 4,4-DiethoxybutanaminE is commercially available, as are the ketones of general formula (VB). The examples which follow illustrate in greater detail the preparation of a number of compounds 15 of general formula (IB) . The elemental microanalyses and the IR and NMR spectra confirm the structures of the compounds obtained. The compound numbers indicated in parentheses in the titles correspond to those in Table B given later. 20 Example 1B (Compound No. 1B). Ethyl 2-[(2,3-dihydro-1H-inden-1-yl) [3-[5-(6-methoxy-1 naphthyl)-1,3-dioxan-2-yl]amino]acetate hydrochloride. 1B.1. 5-(6-Methoxy-1-naphthyl)-1,3-dioxane-2 propanamine hydrochloride.

34 7.56 g (32.5 mmol) of 2-(6-methoxy-l naphthyl)propane-1,3-diol, 6.8 g (42.1 mmol) of 4,4 diethoxybutanamine and then 70 ml of hydrochloric ether are introduced into a 1 1 round-bottomed flask 5 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. 12.2 g of crude hydrochloride are obtained in 10 the form of a beige-coloured solid. Melting point: 224-226 0 C. 1B.2. N-(2,3-Dihydro-lH-inden-1-yl)-5-(6-methoxy-1 naphthyl)-1,3-dioxane-2-propanamine. 3.0 g (9.95 mmol) of 5-(6-methoxy-l 15 naphthyl)-1,3-dioxane-2-propanamine are dissolved in 250 ml of ethanol in a 500 ml round-bottomed flask, 1.32 g (9.95 mmol) of 2,3-dihydro-(1H)inden-1-one are added and the mixture is refluxed overnight. The mixture is allowed to cool, 2 g of 20 potassium borohydride are added and stirring is continued for 2 h 30. 100 ml of water are added and the mixture is extracted three times with 50 ml of ethyl acetate. The solvent is evaporated from the organic phase and the residue is purified by chromatography on 25 a column of silica gel, eluting with a 9/1 mixture of 35 dichloromethane and methanol. 2.79 g of an oily product are obtained. 1B.3. Ethyl 2-[(2,3-dihydro-lH-inden-1-yl) [3-[5-(6 methoxy-l-naphthyl)-1,3-dioxan-2-yl]propyl]amino] 5 acetate hydrochloride. 1.88 g (4.5 mmol) of N-(2,3-dihydro-lH-inden 1-yl)-5-(6-methoxy-l-naphthyl)-1,3-dioxane-2 propanamine, 0.8 g (5.8 mmol) of potassium carbonate, 0.96 g (5.8 mmol) of ethyl 2-bromoacetate, a catalytic 10 amount of sodium iodide and 35 ml of N,N dimethylformamide are introduced into a 250 ml round bottomed flask and the mixture is heated at 60 0 C for 3 h. 100 ml of water are added, the mixture is 15 extracted with three times 150 ml of ethyl acetate and the organic phase is 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 are obtained, which product is 20 purified by chromatography on a column of silica gel with an elution gradient of from 5% to 10% ethyl acetate in cyclohexane. 1.97 g of pure base are obtained, 0.55 g (1 mmol) of which is taken in order to prepare the hydrochloride using 11 ml of a 0.1N 25 solution of hydrochloric acid in 2-propanol. After 36 washing in diethyl ether, 0.44 g of hydrochloride is isolated. Melting point: 88-90 0 C. Example 2B (Compound No. 2B). 5 2-[(2,3-Dihydro-lH-inden-1-yl) [3-[5-(6-methoxy-l naphthyl) -1,3-dioxan-2-yl]propyl] amino -N methylacetamide hydrochloride. 1.42 g (2.8 mmol) of ethyl 2-[(2,3-dihydro 1H-inden-1-yl) [3- [5- (6-methoxy-l-naphthyl) -1,3-dioxan 10 2-yl]propyl]amino]ace.tate are introduced into a 250 ml round-bottomed flask, 30 ml of a 33% solution of methylamine in ethanol are added and the mixture is stirred at room temperature for 2 days. The solvent is evaporated off under reduced pressure and the residue 15 is 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 is prepared using 24 ml of a 0.1N solution of hydrochloric acid in 20 2-propanol. After washing in diethyl ether, 0.98 g of hydrochloride is isolated. Melting point: 112-114 0 C. Example 3B (Compound No. 6B). 5- (6-Methoxy-1-naphthyl) -N- (1,2,3,4-tetrahydro-l- 37 naphthyl)-1,3-dixoane-2-propanamine fumarate. 3.0 g (9.95 mmol) of 5- (6-methoxy-l naphthyl)-1,3-dioxane-2-propanamine, 90 ml of ethanol and 1.45 g (9.95 mmol) of 3,4-dihydrohydro-1 5 naphthyl(2H)-one are introduced into a 250 ml round bottomed flask, and the mixture is refluxed for 48 h. The mixture is allowed to cool, 3 g (55.6 mmol) of potassium borohydride are added and the mixture is stirred at room temperature for 2 days. 10 Water is added, the mixture is extracted with ethyl acetate, the organic phase is washed with water and dried, the solvent is evaporated off under reduced pressure, the residue is taken up in dichloromethane and the solvent is evaporated off under reduced 15 pressure. 4.86 g of an oily product are obtained, which product is purified by chromatography on a column of silica gel, eluting with a 9/1 mixture of dichloromethane and methanol. 20 1.6 g of base are obtained, 0.4 g of which are taken in order to prepare the fumarate in 6 ml of ethanol with 0.11 g of fumaric acid. 0.27 g of salt is isolated. Melting point: 134-136 0

C.

38 Example 4B (Compound No. 9B). 2-[[3-[5-(6-Methoxy-1-naphthyl)-1,3-dioxan-2 yl]propyl](1,2,3,4-tetrahydro-l naphthyl)amino]acetamide hydrochloride. 5 0.85 g (1.97 mmol) of 5-(6-methoxy-l 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 10 iodide are introduced into a 250 ml round-bottomed flask and the mixture is refluxed for 4 h. 50 ml of water and 25 ml of ethyl acetate are added, the organic phase is separated out, the aqueous phase is extracted twice more with 25 ml of ethyl acetate, the solvent is 15 evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 9/1 mixture of dichloromethane and methanol. 0.6 g of base is obtained, which allows 0.25 20 g of hydrochloride to be prepared using a 0.1N solution of hydrochloric acid in 2-propanol. Melting point: 142-143 0 C. Example 5B (Compound No. 13B). N-(3,4-Dihydro-2H-1-benzopyran-4-yl)-5-(6-methoxy-l 25 naphthyl)-1,3-dioxane-2-propanamine hydrochloride.

39 2 g (6.6 mmol) of 5-(6-methoxy-1-naphthyl) 1,3-dioxane-2-propanamine are introduced into a 250 ml round-bottomed flask, 150 ml of ethanol and 0.983 g (6.6 mmol) of 3,4-dihydro-2H-1-benzopyran-4-one are 5 added and the mixture is refluxed overnight. The mixture is cooled, 2 g of sodium borohydride are added, the mixture is stirred for 1 h, 100 ml of water are added, this mixture is extracted four times with 75 ml of ethyl acetate, the solvent is 10 evaporated off under reduced pressure and the residue is dried under reduced pressure. 2.98 g of solid are obtained, which solid is purified by chromatography on a column of silica gel, eluting with a 9/1 mixture of dichloromethane and 15 methanol to give 1.3 g of base in the form of a pale yellow oil. 0.30 g of this base is taken and the hydrochloride thereof is prepared using 5 ml of a 0.1M solution of hydrochloric acid in 2-propanol. After 20 washing with diisopropyl ether and drying, 0.08 g of hydrochloride is obtained. Melting point: 172-173 0 C. Example 6B (Compound No. 14B). 2-[(3,4-Dihydro-2H-1-benzopyran-4-yl) [3-[5-(6-methoxy 25 1-naphthyl)-1,3-dioxan-2-yl]propyl]amino]acetamide 40 hydrochloride. Starting with 0.5 g (1.15 mmol) of N-(3,4 dihydro-2H-1-benzopyran-4-yl)-5-(6-methoxy-l-naphthyl) 1,3-dioxane-2-propanamine and 0.16 g (1.72 mmol) of 5 2-chloroacetamide, and working under conditions similar to those described in Example 4B, and after chromatography, 0.37 g of compound is obtained in the form of the base, from which 0.17 g of hydrochloride is obtained. 10 Melting point: 165-166 0 C. Table B which follows illustrates the chemical structures and the physical properties of a number of compounds of general formula (IB). In the "salt" column, "-" denotes a compound 15 in the form of the base, "fum." denotes a fumarate (or (E)-2-butenedioate), "ox." denotes an oxalate (or ethanedioate) and "HCl" denotes a hydrochloride; the acid/base molar ratio is indicated in parentheses.

41 Table B R (IB) 23 -CH 2

CONHCH

3 CH2 0 1 HCl (1:1) 112-114 3B H CH2 1 0 Cl (1:1) 220-221 43 -CH 2

CO

2 CH2CH3 CH 2 1 0 MCl (1:1) 77-79 5B -CH 2

CONHCH

3 CH2 1 0 ox. (1:1) 84-86 NB H CH2 0 2 fum. (1:1) 134-136 7B -CH 2

CO

2 CH2CH 3 CH2 0 2 HCl (1:1) 77-79 SB -CH2CONHCH 3 CH2 0 2 HCI (1:1) 98-110 93B -CH 2

CON

2

CH

2 0 2 HCl (1:1) 142-143 10B -CH 2

CO

2

CH

2

CH

3

CH

2 1 1 MCi (1:1) 74-76 11B -CH 2

CONH

2

CH

2 1 1 OC1 (1:1) 208-210 12B -CH 2

CONHCH

3 CH2 1 1 fum. (1:1) 82-122 13B H 0 0 2 HCi (1:1) 172-173 14B -CH 2

CONH

2 0 0 2 HC1 (1:1) 165-166 15B -CH2CONHC 0 0 2 HCl (1:1) 117-119 42 No. R x m n Salt m.p.(0C) 16B H S 0 2 HC1 (1:1) 192-193 17B -CH2CO2CH2CH3 S 0 2 HC1 (1:1) 66-68 18B -CH 2 CONHCH3 S 0 2 HC1 (1:1) 114-116 19B -CH 2

CONH

2 CH2 0 1 - 106-108 20B H CH2 1 1 HC1 (1:1) 211-213 21B -CH 2

CO

2 H CH2 0 2 - 90-92 228 -CH 2

CO

2 H 0 0 2 - 108-112 23B H CH 2 0 1 HCl (1:1) 124-125 (*) The compounds in which the carbon atom attached to the nitrogen atom is chiral are racemic. In the "Salt" column, "-" denotes a compound in the form of the base, "fum. " denotes a fumarate (or (E)-2 5 butenedioate) and "HCl" denotes a hydrochloride; the acid/base molar ratio is indicated in parentheses. The melting points m.p. ('C) are indicated in the final column. In the general formula (IC) 10 R 1 represents either a hydrogen atom or a group of general formula CH 2 COY in which Y represents a hydroxyl group or a (C 1

-C

4 )alkoxy group, or alternatively a group of general formula CH 2

CONR

4 R, in which R 4 and R., independently of each other, each represent a hydrogen 15 atom or a (C 1

-C

4 )alkyl group, and 43

R

2 represents a 2-pyridyl group, a 3-pyridyl group, a 4 pyridyl group, a 1-methyl-2-pyrrolyl group, a 2-furyl group, a 2-thienyl group or a 1,3-thiazol-2-yl group, the respective formulae of which are as follows: N N A2n ZJC NO N 0 S 5 The compounds of general formula (IC) can exist in the form of cis or trans stereoisomers or mixtures of such isomers; they can also exist in the form of free bases or of addition salts with acids. The compounds of general formula (IC) can be 10 prepared by a process illustrated by Scheme C which follows. 2-(6-Methoxy-l-naphthyl)propane-1,3-diol of formula (IIC) is reacted with 4,4-diethoxybutanamine of formula (IIIC) in a refluxing non-protic solvent such 15 as toluene and in the presence of hydrochloric acid dissolved in diethyl ether, as catalyst, in order to obtain 5-(6-methoxy-l-naphthyl)-1,3-dioxane-2 propanamine of formula (IVC), which is then reacted, in a protic solvent such as methanol, at a temperature of 20 25 to 60 0 C and with removal of the water formed during the reaction, with an aldehyde of general formula (VC) in which R 2 is as defined above, then the imine formed is reduced for example using a reducing agent such as 44 sodium borohydride or any other equivalent agent, in neutral or acidic medium, under reductive amination conditions that are well known to those skilled in the art. A compound of general formula (ICa) is obtained, 45 Scheme C OR OR (IIC) (IVC) I , f R2 (VC) (ICA)( RN RC o o.o - ,. (ICb) 'C7 N N '* 2 N 0 00 (ICC) which corresponds to the general formula (IC) when R 1 represents a hydrogen atom. If so desired, the compound of general 5 formula (ICa) can then be alkylated with a haloacetate of general formula Z-CH 2 -CO2(C 1

-C

4 )alkyl, in which Z 46 represents a chlorine or bromine atom, 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 general formula (ICb) in 5 which Y represents a (C,-C 4 )alkoxy group. If so 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 general formula (ICb) in which Y represents a 10 hydroxyl group. The general formula (ICb) corresponds to the general formula (IC) when R 1 represents a group of general formula CH 2 COY. If so desired, the compound of general formula (ICb) can then be reacted with an amine of 15 general formula HNR 4

R

5 , in which R 4 and Rs are as defined above, in order to obtain an amide of general formula (ICc). The conditions of this reaction are standard and are well known to those skilled in the art. An amide of general formula (ICc) can also be 20 obtained directly from a compound of general formula (ICa) by alkylation using a halide of general formula

Z-CH

2

-CO-NR

4 ,R, in which Z represents a chlorine or bromine atom and R 4 and R 5 are as defined above, in a polar aprotic solvent, for example N,N 25 dimethylformamide, in the presence of a base, for example potassium carbonate.

47 The general formula (ICc) corresponds to the general formula (IC) when R, represents a group of general formula CH 2

CONR

4

R

5 . 2- (6-Methoxy-l-naphthyl)propane-1,3-diol of 5 formula (IIC) is described in patent application EP 0,461,958. 4,4-Diethoxybutanamine is commercially available, as are the aldehydes of general formula (VC). The examples which follow illustrate in 10 detail the preparation of a number of compounds of general formula (IC). The elemental microanalyses and the IR and NMR spectra confirm the structures of the compounds obtained. The compound numbers indicated in parentheses 15 in the titles correspond to those in Table C given later. Example 1C (Compound No. 1C). 5-(6-Methoxy-1-naphthyl)-N-(4-pyridylmethyl)-1,3 dioxane-2-propanamine dihydrochloride. 20 1C.1. 5-(6-Methoxy-l-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 mmol) of 4,4-diethoxybutanamine and then 70 ml of dry gaseous 48 hydrochloric acid dissolved in diethyl ether are introduced into a 1 1 round-bottomed flask containing 300 ml of toluene, and the mixture is refluxed for 2 h. The mixture is cooled and the precipitate is 5 collected by filtration and rinsed with diethyl ether. 12.2 g of crude hydrochloride are obtained in the form of a beige-coloured solid. Melting point: 224-226 0 C. 1C.2. 5-(6-Methoxy-1-naphthyl)-N-(4-pyridylmethyl)-1,3 10 dioxane-2-propanamine dihydrochloride. 0.5 g (1.67 mmol) of 5-(6-methoxy-l naphthyl)-1,3-dioxane-2-propanamine and 200 ml of methanol are introduced into a 250 ml round-bottomed flask, 0.178 g (1.67 mmol) of pyridine-4-carboxaldehyde 15 is added and the mixture is heated at 100 0 C for 2 h. The mixture is allowed to cool, 0.5 g of potassium borohydride is added and the mixture is stirred for 0.5 h. Half of the methanol is evaporated off under 20 reduced pressure, 100 ml of water are added, the mixture is extracted with three times 20 ml of ethyl acetate, the organic phase is concentrated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with 25 a 9/1 mixture of dichloromethane and methanol.

49 0.57 g of base is obtained in the form of an oil. 0.15 g of this product is taken and dissolved in 5 ml of a 0.1N solution of hydrochloric acid in 2 5 propanol. After washing with diisopropyl ether and drying, 0.12 g of dihydrochloride is obtained. Melting point: 207-208 0 C. Example 2C (Compound No. 3C). 2-[[3-[5-(6-Methoxy-l-naphthyl)-1,3-dioxane-2 10 yl]propyl](4-pyridylmethyl)amino]acetamide dihydrochloride. 1.2 g (3 mmol) of 5-(6-methoxy-l-naphthyl)-N (4-pyridylmethyl)-1,3-dioxane-2-propanamine are dissolved in 200 ml of acetonitrile, 0.138 g (0.9 mmol) 15 of sodium iodide, 0.828 g (6 mmol) of potassium carbonate and 0.42 g (4.5 mmol) of 2-chloroacetamide are added and the mixture is refluxed for 3 h. Since the reaction is not complete, a further 0.2 g (1.5 mmol) of potassium carbonate, 0.06 g 20 (0.45 mmol) [lacuna] and 0.14 g (1.5 mmol) of 2 chloroacetamide are added and the mixture is refluxed for a further 1 h. The mixture is left to cool, 140 ml of water are added and this mixture is extracted with four times 25 50 ml of ethyl acetate. After evaporation of the 50 solvent under reduced pressure, the residue is 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 is obtained. 5 The base is salified using 8 ml of a 0.1N solution of hydrochloric acid in 2-propanol. After washing with ethyl acetate and drying, 0.17 g of dihydrochloride is obtained. Melting point: 169-170 0 C. 10 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 g 15 (8.8 mmol) of 1,3-thiazole-2-carboxaldehyde are introduced into a 1000 ml round-bottomed flask fitted with Dean-Stark apparatus and the mixture is distilled until the volume of the reaction medium reaches about 200 ml. 20 The mixture is cooled, 2.4 g of sodium borohydride are added portionwise and the mixture is left stirring overnight. The methanol is evaporated off under reduced pressure, the residue is taken up in water and ethyl 25 acetate, the organic phase is separated out, washed and 51 dried over magnesium sulphate and the solvent is evaporated off under reduced pressure. 3.17 g of base are obtained, 0.5 g of which is taken in order to prepare the hydrochloride under conditions similar to 5 those described above. 0.5 g of hydrochloride is obtained. Melting point: 134-137 0 C. Example 4C (Compound No. 21C). 2-[[3-[5-(6-Methoxy-l-naphthyl)-1,3-dioxan-2 10 yl]propyl] (2-thiazolylmethyl)amino]acetamide hydrochloride. Starting with 0.7 g (1.75 mmol) of 5-(6 methoxy-1-naphthyl)-N-(2-thiazolylmethyl)-1,3-dioxane 2-propanamine and 0.2 g (2.1 mmol) of 2 15 chloroacetamide, and working under conditions similar to those of Example 2C, 0.76 g of base is obtained, from which 0.763 g of hydrochloride is prepared. Melting point: 189-191 0 C. Table C which follows illustrates the 20 chemical structures and the physical properties of a number of compounds of general formula (IC). In the "R 2 " column, CH 4 N-2- represents a 2 pyridyl group, CH 4 N-3- represents a 3-pyridyl group,

CH

4 N-4- represents a 4-pyridyl group, CH 3 -1-C 4

H

3 N-2 25 represents a 1-methyl-2-pyrrolyl group, C 4

H

3 0-2- 52 represents a 2-furyl group, C 4

H

3 S-2- represents a 2 thienyl group and C 3

H

2 NS-2- represents a 1,3 thiazol-2-yl group. In the "Salt" column, "-" denotes a compound 5 in the form of the base, "fum. " denotes a fumarate (or (E)-2-butenedioate), "ox." denotes an oxalate (or ethanedioate) and "HCl" denotes a hydrochloride; the acid/base molar ratio is indicated in parentheses. In the "m.p. ( 0 C)" column, "(d)" denotes a 10 melting point with decomposition.

53 Table C 0 0 (IC) No. RR2Salt M.P.(0C) IcH

C

5

H

4 N-4 - HC. (2: 1) 207-208 2C -CH 2

CO

2 H C 5

H

4 N-4- -115-125 3C -CH 2

CONH

2 CsH 4 N-4- ECI (2:1) 1.69-170 4C -CHCONHCH 3 CsH 4 N-4 - HCI (2:1) 80-90 sc H C 5

H

4 N-3- -80-81 6C -CH 2

CONH

2

CSH

4 N-3- HCI (1:1) 199-200 7C -C 2 C0NRCH 3

CSH

4 N-3- CDC. '(2: 1) 138-140 sc H

C

5

H

4 N-2 RCi (1:1) 158-159 9C -CH 2

CONN

2

C

5

H

4 N2- HC1 (1: 1) 174-175 loc -CHCONHCH3 CAHN-2- HCi (2:1) 93-96 lid R H 3 -1-CAHN-2- MCI (1:1) 183-186 12C -CH 2

CONH

2

CH

3 -1-C 4

H

3 N-2- Mdl (1:1) 188 (d) 13C -CH 2 CoNHCH 3 dH3-1-C 4

H

3 z1-2- Mdl (1:1) 89-95 24C HC 4

H

3 0-2- ECl (1:1) 186-187 1sc -CH 2 C0 2

CH

2 CX3, C 4 Ei 3 O-2- MCI (1:1) 62-65 54 No. R, R2 Salt m.p.(*C) 16C -CH 2

CONH

2

C

4

H

3 0-2- HCl (1:1) 205-206 17C H C 4

H

3 S-2- HCl (1:1) 174-176 18C -CH 2

CONH

2

C

4

R

3 S-2- HC1 (1:1) 220-225 19C H C3H 2 NS-2- HCl (1:1) 134-137 20C -CH 2

CO

2 CH2CH3 C 3

H

2 NS-2- HCi (1:1) 58-62 21C -CH 2

CONH

2

C

3

H

2 NS-2- HCl (1:1) 189-191 22C -CH 2

CO

2 H C 4

H

3 S-2- - 152-156 23C -CH 2

CO

2 H C 4

H

3 0-2- - 78-82 In the general formula (ID) Y represents a hydroxyl group, a (C 1

-C

4 ) alkoxy group or a group of general formula NR 4 RS in which R 4 and R 5 , independently of each other, each represent a hydrogen 5 atom or a (Cl-C 4 ) alkyl group, and

R

1 and R 2 form, with the nitrogen atom and the carbon atom which connect them, a pyrrolidine ring, a piperidine ring or a 1,2,3,4-tetrahydroisoquinoline ring. 10 The compounds of general formula (ID) can exist in the form of cis or trans stereoisomers or mixtures of such isomers; moreover, and on account of the asymmetric carbon atom a to the group -C(O)Y, they can exist in the form of pure enantiomers or mixtures 15 of enantiomers. They can also exist in the form of free bases or of addition salts with acids.

55 The compounds of general formula (ID) can be prepared by a process illustrated by Scheme D which follows. 2-(6-Methoxy-l-naphthyl)propane-1,3-diol of 5 formula (IID) is reacted with 2-(3-chloropropyl)-1,3 dioxolane of formula (IIID), in acidic medium and in an aprotic solvent, in order to obtain 2-(3-chloropropyl) 5-(6-methoxy-l-naphthyl)-1,3-dioxolane of formula (IVD), and finally this compound is reacted with an 10 amine of general formula (VD) , in which Y, R 1 and R 2 are as defined above, in the presence of an organic or inorganic base, in an aprotic solvent, for example N,N- 56 Scheme D OH OH (IID) H C C1 o 0 (IVD) I-1 HN R2 (VD) N R 2 o o o Y (ID) dimethylformamide, at a temperature of 20 to 110 0 C. 2- (6-Methoxy-l-naphthyl)propane-1,3-diol of formula (IID) is described in patent application EP- 57 0,461,958. 2-(3-Chloropropyl)-1,3-dioxolane is commercially available. The amines of general formula (VD) are commercially available or are described in the literature. 5 The examples which follow illustrate the preparation of a number of compounds of general formula (ID). The elemental microanalyses and the IR and NMR spectra confirm the structures of the compounds obtained. The compound numbers indicated in parentheses 10 in the titles correspond to those in Table D given later. Example 1D (Compound No. 1D). Ethyl 1-[3-[5-(6-methoxy-1-naphthyl)-1,3-dioxan-2 yl]propyl]-L-prolinate oxalate. 15 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 ml of 20 hydrochloric ether are introduced into a 500 ml round bottomed flask containing 150 ml of toluene, and the mixture is refluxed for 6 h. The mixture is allowed to cool, 100 ml of aqueous 5% sodium hydrogen carbonate solution are added 58 and this mixture is extracted with twice 100 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and filtered, the solvent is evaporated off under reduced pressure and the 5 residue is purified by chromatography on a column of silica gel, eluting with a 9/1 mixture of petroleum ether and ethyl acetate. 3.2 g of a white solid are obtained, which product is used without further purification in the following step. 10 1D.2. Ethyl 1-[3-[5-(6-methoxy-l-naphthyl)-1,3-dioxan 2-yl]propyl]-L-prolinate oxalate. 0.32 g (1 mmol) of 2-(3-chloropropyl)-5-(6 methoxy-l-naphthyl)-1,3-dioxane, 0.22 g (1.2 mmol).of ethyl L-prolinate, 0.3 g (2.2 mmol) of potassium 15 carbonate and then 0.29 g (2 mmol) of potassium iodide are introduced into a 50 ml round-bottomed flask containing 10 ml of N,N-dimethylformamide and the mixture is heated at 100 0 C for 4 h. The mixture is allowed to cool, 50 ml of 20 water are added and this mixture is extracted with twice 70 ml of ethyl acetate, the organic phase is washed with water, dried over magnesium sulphate and filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography 25 on a column of silica gel, eluting with a gradient of 59 dichloromethane and methanol of from 99.5/0.5 to 99/1. 0.22 g (0.5 mmol) of compound is obtained, which is crystallized, in the form of the oxalate, from ethyl acetate. 5 Melting point: 116-118 0 C. Example 2D (Compound No. 2D). 1-[3-[5-(6-Methoxy-1-naphthyl)-1,3-dioxan-2-yl]propyl] L-prolinamide. 0.5 g (1.6 mmol) of 2-(3-chloropropyl)-5-(6 10 methoxy-l-naphthyl)-1-,3-dioxane, 0.2 g (1.9 mmol) of L prolinamide, 0.2 g (1.6 mmol) of potassium carbonate and then 0.48 g (3.2 mmol) of potassium iodide are introduced into a 50 ml round-bottomed flask containing 15 ml of N,N-dimethylformamide and the mixture is 15 heated at 110 0 C for 3 h 30. The mixture is allowed to cool, 60 ml of water are added and the resulting mixture is extracted with twice 80 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and 20 filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a gradient of dichloromethane and methanol of from 99/1 to 97/3. 0.3 g of compound is obtained, which is crystallized in 25 the form of the base from 2-propanol.

60 Melting point: 164-166 0 C. Example 3D (Compound No. 6D). 2-[3-[5-(6-methoxy-l-naphthyl)-1,3-dioxan-2-yl]propyl] N-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide 5 oxalate. 3D.1. N-Methyl-1,2,3,4-tetrahydroisoquinoline-3 carboxamide. 1.75 g (8.5 mmol) of ethyl 1,2,3,4 tetrahydroisoquinoline-3-carboxylate are introduced 10 into a 100 ml round-bottomed flask containing 25 ml of a 33% solution of methylamine in ethanol and the mixture is left at 25 0 C for 20 h. It is concentrated to dryness under reduced pressure and 1.7 g of compound are obtained in the form of a colourless oil, which is 15 used without further purification in the following step. 3D.2. 2-[3-[5-(6-Methoxy-1-naphthyl)-1,3-dioxan-2 yllpropyl]-N-methyl-1,2,3,4-tetrahydroisoquinoline-3 carboxamide oxalate. 20 0.5 g (1.6 mmol) of 2-(3-chloropropyl)-5-(6 methoxy-1-naphthyl)-1,3-dioxane, 0.3 g (1.6 mmol) of N methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide, 0.2 g (1.6 mmol) of potassium carbonate and then 0.23 g 61 (1.5 mmol) of potassium iodide are introduced into a 100 ml round-bottomed flask containing 20 ml of acetonitrile and the mixture is heated at 80 0 C for 8 h. The mixture is allowed to cool, 20 ml of 5 water are added and the resulting mixture is extracted with twice 20 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography 10 on a column of silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. 0.12 g (0.25 mmol) of compound is obtained, which-is crystallized, in the form of the oxalate, from diisopropyl ether. Melting point: 88-90 0 C. 15 Table D which follows illustrates the chemical structures and the physical properties of a number of compounds of general formula (ID). In the "R 1

NCHR

2 " column, "pyrrol", "piper" and "isoq" mean that R 1 and R 2 form, with the nitrogen atom 20 and the carbon atom which connect them, a pyrrolidine ring, a piperidine ring or a 1,2,3,4 tetrahydroisoquinoline ring, respectively. In the "Salt" column, "-" denotes a compound in the form of the base, "fum." denotes a fumarate (or 25 (E)-2-butenedioate), "ox." denotes an oxalate (or ethanedioate) and "HCl" denotes a hydrochloride; the 62 acid/base molar ratio is indicated in parentheses. In the "m.p. ( 0 C)" column, "(d)" denotes a melting point with decomposition.

63 Table D N (ID) No. Y R 1

NCHR

2 Config. * Salt m.p.(OC) [a]20 1D -OCH2CH 3 pyrrol S ox. (1:1) 116-118 -26 2D -NH2 pyrrol S 164-166 n. d. 3D -NHCH 3 pyrrOl S 119-121 -30 4D -OCH 2

CH

3 piper RS ox. (1:1) 129-131 5D -NHCH 3 pyrrol RS 99-101 6D -NHCH 3 isoq RS Ox. (1:) 88-90 The compounds according to the invention underwent pharmacological tests which revealed their value as therapeutic substances. 5 Neuronal antisodium properties The entry of calcium brought about by a depolarizing stimulus in rat cortical synaptosomes can be measured using a fluorescent probe, according to the method described by A. Deffois et al. in Neurosciences 10 Letters (1996) 220 117-120. The effects of a sodium-channel agonist such 64 as veratridine (10 pM) on the increase in the levels of intracellular calcium in this model are inhibited by the compounds of the invention at IC 5 1 (concentrations which inhibit the response by 50%) values of from 0.1 5 to 10 pIM. Activity on tonic convulsions induced in mice by supramaximal electric shock The procedure of this test is described by E.A. Swinyard and J.H. Woodhead in Antiepileptic Drugs, 10 Raven Press, New York, 111-126 (1982). 10 min after intravenous administration of the test compound, a note is made of the number of mice showing tonic convulsions (extension of the fore- and hind limbs), immediately after application of an 15 electric current (0.4 s, 60 mA, 50 Hz) using an Apelex ETC UNIT 7801T machine. The results are expressed by the AD,,, the dose which protects 50 of the animals, which is calculated according to the method of J.T. Lichtfield and F. Wilcoxon (J. Pharm. Exp. Ther., 20 96, 99-113 (1949)), using the ProbitTM software, starting with 3 or 4 doses each administered to a group of 8 mice. The AD 50 values of the most active compounds range from 1 to 10 mg/kg. Anti-ischaemic proDerties 65 The compounds were subjected to the global cerebral ischaemia test in mice. The ischaemia is caused by a cardiac arrest induced by a rapid intravenous injection of magnesium 5 chloride. In this test, the "survival time", i.e. the interval between the moment of injection of the magnesium chloride and the last observable respiratory movement of each mouse, is measured. This last movement is considered as the final indicator of central nervous 10 system functioning. Breathing stops approximately 19 seconds after the injection of magnesium chloride. Male mice (Charles River CD1) are studied in groups of ten. They are fed and watered freely before the tests. The survival time is-measured 10 minutes 15 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 which received the compound, and the survival time measured in a group of 20 ten mice which received the liquid vehicle. The relationships between the changes in the survival time and the dose of the compound are recorded in graph form on a semilogarithmic curve. This curve makes it possible to calculate the 25 "3-second effective dose" (ED 3 "), i.e. the dose (in mg/kg) which produces a 3-second increase in the 66 survival time relative to the control group of ten untreated mice. A 3-second increase in the survival time is both statistically significant and reproducible. 5 The ED 3 - 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 is evaluated in 1C rats, during the second stage of a formalin test adapted from the work by A. Tjolsen, O.-G. Berge, S. Hunskaar, J.H. Rosland and K. Hole in Pain (1992) 51 5-17. Formalin (5%) is injected subcutaneously (100 15 pl) into the plantar arch of the left hind paw. The nociception is quantified, after injection, by measuring, for the injected paw, the total duration of licking activity, between +20 and +35 min, and by the number of shuddering actions, measured in 2-min 20 sequences, every 5 min, between +35 and +60 min. The compounds are administered at doses of 30 and 60 mg/kg, as a suspension (water + Tween 80 at 1%), orally (5 ml/kg), 30 min before the injection of formalin. 25 A compound is considered active if, after 67 treatment, by comparison with the values measured in animals which have received the vehicle, a statistically significant reduction (p<=0.05) in the total duration of the licking activity and/or in the 5 number of shuddering actions (calculated from the areas under the curve) is observed. 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 10 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 that they can therefore be used for the preparation of medicaments which are 15 useful in the treatment or prevention of cerebrovascular disorders of ischaemic or hypoxic origin (cerebral infarction, cranial or medullary trauma, cardiac or respiratory arrests, transient ischaemic attack, perinatal asphyxia), glaucoma, 20 progressive neurodegenerative diseases (senile dementias such as Alzheimer's disease, vascular dementia, Parkinson's disease, Huntingdon's disease, olivopontocerebellar atrophy, amyotrophic lateral sclerosis, neurodegenerative diseases of viral origin, 25 etc.), and in the prevention of cerebral ischaemic accidents associated with cardiac and vascular surgery 68 and endovascular therapy. On account of their anticonvulsive properties, they can also be used in the treatment of epilepsy. The compounds of the invention also have 5 analgesic properties and can thus be used in the treatment of any acute or chronic pain. Lastly, the treatment of other complaints, such as neuropathy, neurogenic pain (for example pain associated with neuropathies or with migraine attacks), 10 neurological spasticity and dyskinesia, can also be envisaged. The compounds of the invention can be in any pharmaceutical composition form which is suitable for enteral or parenteral administration, such as tablets, 15 coated tablets, gelatin capsules, wafer capsules, drinkable or injectable suspensions or solutions, such as syrups, vials, etc., combined with suitable excipients, and dosed to allow a daily administration of from 1 to 1000 mg of active substance.

Claims

1. Compound, in the form of a pure stereoisomer or a mixture of stereoisomers, corresponding to the general formula (IA) o o (IA) 5 in which R, represents a hydrogen atom, a linear or branched (C 2 C 4 )alkyl group, a cyclo(C 3 -C 6 )alkyl group, a cyclo(C 3 C,)alkylmethyl group or a phenyl(C 1 -C 3 )alkyl group which is optionally substituted on the phenyl ring, 10 R 2 represents a hydrogen atom, a linear or branched (C 1 C 4 )alkyl group, a cyclo(C 3 -C,)alkyl group, a cyclo(C 3 C,)alkylmethyl group or a phenyl(C 1 -C 3 )alkyl group which is optionally substituted on the phenyl ring, R 3 represents a hydroxyl group, a (Cl-C 4 )alkoxy group or 15 a group of general formula NR 4 R 5 in which R 3 and R 4 , independently of each other, each represent a hydrogen atom, a linear or branched (C 1 -C 4 )alkyl group, a cyclo(C 3 -C 6 )alkyl group or a cyclo(C 3 -C 6 )alkylmethyl group, 70 in the form of the base or of an addition salt with an acid.

2. Compound, in the form of a pure stereoisomer or a mixture of stereoisomers, 5 corresponding to the general formula (IB) R IB) HaC in which R represents either a hydrogen atom or a group of general formula CH 2 COY in which Y represents a hydroxyl group or a (Cl-C 4 )alkoxy group, or alternatively a group 10 of general formula CH 2 CONR 1 R 2 in which R, and R 2 , independently of each other, each represent a hydrogen atom or a (C 1 -C 4 )alkyl group, X represents an oxygen or sulphur atom or a CH 2 group, m represents 0 or 1, and 15 n represents 0, 1 or 2, in the form of the free base or of an addition salt with an acid.

3. Compound, in the form of a pure stereoisomer or a mixture of stereoisomers, 20 corresponding to the general formula (IC) 71 o 0 (IC) H,cs, Oza in which R 1 represents either a hydrogen atom or a group of general formula CH 2 COY in which Y represents a hydroxyl group or a (C 1 -C 4 )alkoxy group, or alternatively a group 5 of general formula CH 2 CONR 4 R 5 in which R 4 and R 5 , independently of each other, each represent a hydrogen atom or a (C 1 -C 4 )alkyl group, and R 2 represents a 2-pyridyl group, a 3-pyridyl group, a 4 pyridyl group, a 1-methyl-2-pyrrolyl group, a 2-furyl 10 group, a 2-thienyl group or a 1,3-thiazol-2-yl group, in the form of the free base or of an addition salt with an acid.

4. Compound, in the form of a pure stereoisomer or a mixture of stereoisomers, 15 corresponding to the general formula (ID) (ID) in which 72 Y represents a hydroxyl group, a (C 1 -C 4 )alkoxy group or a group of general formula NR 4 R 5 in which R 4 and R 5 , independently of each other, each represent a hydrogen atom or a (C 1 -C 4 )alkyl group, and 5 R 1 and R 2 form, with the nitrogen atom and the carbon atom which connect them, a pyrrolidine ring, a piperidine ring or a 1,2,3,4-tetrahydroisoquinoline ring, in the form of the free base or of an addition salt 10 with an acid.

5. Medicament, characterized in that it consists of a compound according to one of Claims 1 to 4.

6. Pharmaceutical composition, 15 characterized in that it contains a compound according to one of Claims 1 to 4, combined with an excipient.