EP0986552A1

EP0986552A1 - 5-naphthalen-1-yl-1,3-dioxane derivatives, preparation and therapeutic application

Info

Publication number: EP0986552A1
Application number: EP98928419A
Authority: EP
Inventors: Gihad Dargazanli; Patrick Lardenois; Jonathan Frost; Pascal George
Original assignee: Sanofi Synthelabo SA
Current assignee: Sanofi Aventis France
Priority date: 1997-06-05
Filing date: 1998-06-03
Publication date: 2000-03-22
Also published as: TR199903022T2; WO1998055474A1; JP2002502412A; CO4940480A1; IL133242A0; BG103937A; PL337234A1; NO995966D0; HUP0002166A3; EE9900560A; BR9810742A; HUP0002166A2; CN1265658A; AR012908A1; NO995966L; CA2290695A1; KR20010013435A; SK166199A3; AU8025198A

Abstract

The invention concerns compounds of formula (I) in which: R1 represents an alkyl group; V represents a hydrogen atom or a linear or branched alkyl, cycloalkyl, cycloalkylmethyl, phenylalkyl group optionally substituted on a phenyl ring, carboxymethyl, alkoxycarbonylmethyl, carbamoylmethyl optionally substituted on the nitrogen; W represents a carboxymethyl, alkoxycarbonylmethyl, carbamoylmethyl group optionally substituted on the nitrogen, a cyclic group with 4 to 7 apices and optionally containing an oxygen or sulphur atom, or a pyridinylmethyl, 1-methylpyrrolymethyl, furanyl-methyl, thienylmethyl or 1,3-thiazolylmethyl group, or V and W together, and with the nitrogen atom, form a pyrrolidinyl, piperidinyl, or 1,2,3,4-tetrahydroisoquinolinyl group. The invention is applicable in therapy.

Description

5-Naphthalen-1-yl-1, 3-dioxane derivatives, their preparation and their therapeutic use.

The subject of the present invention is compounds of general formula (I)

in which

R _x represents an alkyl group,

V represents a hydrogen atom or a linear or branched alkyl group, cycloalkyl, cycloalkylmethyl, phenylalkyl optionally substituted on the phenyl ring, carboxymethyl, alkoxycarbonylmethyl, carbamoylmethyl optionally monosubstituted or disubstituted on nitrogen, W represents a carboxymethyl group, alkoxycarbonylmethyl optionally monosubstitutes or disubstitutes on nitrogen, a cyclic group having from 4 to 7 vertices and optionally containing an oxygen or sulfur atom, a pyridin-2-ylmethyl group, a pyridin-3-ylmethyl group, a pyridin group 4-ylmethyl, an 1-methylpyrrol-2-ylmethyl group, a furan-2-ylmethyl group, a thien-2-ylmethyl group or a 1, 3-thiazol-2-ylmethyl group, or alternatively

V and W together form, and with the nitrogen atom which carries them, a pyrrolidinyl, piperidinyl or 1,2,3,4-tetrahydroisoquinoline group. The compounds of the invention more particularly correspond to one of the general formulas (IA), (IB), (IC) and (ID)

In the general formula (IA)

R _x represents a hydrogen atom or a linear or branched (C ₂ -C ₄ ) alkyl group, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) cycloalkylmethyl or phenyl (^^ ₃ ) alkyl optionally substituted on the phenyl ring,

R ₂ represents a hydrogen atom or a (C ₁ -C ₄ ) linear or branched alkyl group, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) cycloalkylmethyl or phenyl (C ₁ -C ₃ ) alkyl optionally substituted on the phenyl ring, R ₃ represents a hydroxy group or (C- _L -C) alkoxy or a group of general formula NR ₄ R ₅ in which R and R ₅ , independently of one another, each represent a hydrogen atom, a (C- _L -C ^ linear or branched alkyl group, a (C ₃ -C ₅ ) cycloalkyl group or a (C ₃ -C ₆ ) cycloalkylmethyl group.

The compounds of general formula (IA) can exist in the form of cis or trans stereoisomers or mixtures of such isomers; they may also exist in the form of free bases or of addition salts with acids.

The compounds of general formula (IA) can be prepared by various methods described below.

According to a first variant, illustrated by scheme A which follows, the amide of formula (IIA) is subjected to a dealkylation in the presence of sodium sulfide, in a polar aprotic solvent, for example N-methylpyrrolidone, at a temperature of 100 to 150 ° C, to obtain the amide of formula (IIIA), according to a method described in J. Am. Chem. Soc. (1976) 98 3237.

The latter is then subjected to alkylation by means of a derivative of general formula R -X, in which R ₁ is as defined above, but 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, to obtain an amide of general formula (IVA). Diagram A

The latter is then hydrolyzed in a 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., to obtain the corresponding primary amine, then it is treated the latter either with an aldehyde of general formula

R ₆ -CH0, in which R ₆ is the lower homolog of group R ₂ , in the presence of a reducing agent such as sodium borohydride or sodium cyanoborohydride, under reductive amination conditions known to man of career, to obtain an amine of general formula (VA). The amine of general formula (VA) is then reacted with ethyl bromoacetate, to obtain a compound of general formula (IA) in which R ₁ and R ₂ represent an alkyl, cycloalkyl, cycloalkylalkyl or phenylalkyl group and R ₃ represents an ethoxy group. If desired, the compound thus obtained can then be saponified to transform it into the corresponding acid, or it can be reacted with an amine of general formula HNR ₄ R ₅ , in which R ₄ and R ₅ are such as defined above, to transform it into an amide. The conditions for these reactions are conventional and are well known to those skilled in the art.

According to an alternative variant, it is possible to obtain the amides of general formula (IA) in which R _λ and R ₂ represent an alkyl or phenylalkyl group by directly reacting the amine of general formula (VA) with an alpha-halogenated alkanamide of formula general (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 general formula (VA) can be prepared in which R _x represents a cyclopropylmethyl group and R ₂ represents an alkyl or phenylalkyl group either by reduction of the corresponding alkanamides, described in patent application EP-461958, or by hydrolysis into primary amine of said alkanamides, then by treatment of these amines under N-monoalkylation conditions. All these reactions are carried out according to methods well known to those skilled in the art.

Finally, according to a last variant, a compound of general formula (IA) can be prepared in which R ₁ represents a hydrogen atom by demethylation, using sodium sulphide in N, N-dimethylformamide, of the corresponding compound, in the formula of which R represents a methyl group, described in patent application FR-2742152.

The examples which follow illustrate the preparation of some compounds of general formula (IA). Elementary microanalyses, and the spectra I.R. and R.M.N. confirm the structures of the compounds obtained. The numbers indicated in parentheses in the titles of the examples correspond to those in the 1st column of Table A given below.

In compound names, the dash "-" is part of the name, and the dash "_" is only used for breaking at the end of the line; it must be deleted in the absence of a break, and must not be replaced either by a normal dash or by a space.

Example IA (Compound No. 2A).

2- [[3- [5- [6- (Cyclopropylmethoxy) naphthalen-1-yl] -1, 3-dioxan-2-yljpropyl] ethylamino] -N- (cyclopropylmethyl) acetamide.

1A.1. 5- [6- (Cyclopropylmethoxy) naphthalen-1-yl] -N-ethyl - 1, 3-dioxane-2-propanamine. 0.8 g of double lithium aluminum hydride suspended in 30 ml of tetrahydrofuran is introduced into a 250 ml two-necked flask, the mixture is heated to reflux, 4.0 g (10.43 mmol) of N are added. - [3- [5- [6- (cyclopropylmethoxy) naphthalen-1- yl] -1, 3-dioxan-2-yl] propyl] acetamide dissolved in 200 ml of tetrahydrofuran, and heating is maintained at reflux for 4 h.

The mixture is cooled and 3.5 ml (2 equiv.) Of 0.1 M aqueous solution of potassium and sodium double tartrate are slowly added, the mixture is stirred and the solvents are evaporated off under reduced pressure. 4.55 g of oily product are obtained, which is used as it is in the next step. 1 TO 2. 2 - [[3- [5- [6- (Cyclopropylmethoxy) naphthalen-1-yl] -1,3- dioxan-2-yl] propyl] ethylamino] -N- (cyclopropylmethyl) _ acetamide. 0.23 ml (2.6 mmol) of cyclopropylmethanamine, 20 ml of dioxane and 0.36 ml of triethylamine are introduced into a 250 ml flask, a solution of 0.21 ml (2, 6 mmol) of chloroacetyl chloride in 5 ml of dioxane, and the mixture is stirred at room temperature for 8 h. 30 ml of water, 1 g of potassium carbonate and 1.0 g (2.7 mmol) of 5- [6- (cyclopropylmethoxy) naphthalen-1-yl] - N-ethyl - 1, 3-dioxane are added. -2-propanamine, the mixture is heated to 80 ° C for 8 h, and allowed to stand at room temperature overnight. Water and ethyl acetate are added, the organic phase is separated, washed with water and then with brine, dried over magnesium sulfate, filtered and the mixture is evaporated. solvent 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.

0.5 g of oily product is obtained which is dissolved in propan-2-ol, 8 ml of 0.1M hydrochloric acid is added in propan-2-ol, the solvents are evaporated and the residue is recrystallized from 1 diisopropyl ether.

Finally isolated 0.2 g of hydrochloride. Melting point: 74-76 ° C.

Example 2A (Compound Ν ° 3A). N-Cyclopropyl -2 - [[3- [5- [6- (cyclopropylmethoxy) naphthalen-1- yl] -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 100 ml flask, 1 g (17.7 mmol) of cyclopropanamine is added dropwise and the mixture is stirred at room temperature for 2 h. Bicarbonate water and ethyl acetate are added, the organic phase is separated, washed with water, dried over magnesium sulfate, filtered and the solvent is evaporated off under reduced pressure, which gives 0.7 g of white solid.

The aqueous phase is concentrated under reduced pressure, the residue is taken up with ethanol, which again provides 1.22 g of white solid, ie a total of 1.92 g of compound which is used as it is in the next step.

2A.2. N-Cyclopropyl -2 - [[3- [5- [6- (cyclopropylmethoxy) naphta_ lén-l-yl] -1,3 -dioxan-2 -yl] propyl] ethylamino] acetamide. 0.69 g (1.87 mmol) of 5- [6- (cyclopropylmethoxy) naphthalen-1-yl] -N-ethyl - 1,3-dioxane-2-propanamine in solution is introduced into a 100 ml flask. 20 ml of acetonitrile, 0.37 g (2.77 mmol) of 2-chloro-N-cyclopropylacetamide and 0.26 g of potassium carbonate, and the mixture is heated at 70 ° C. for 4 hours.

The mixture is cooled, water and ethyl acetate are added, the organic phase is separated, washed with water then with saturated sodium chloride solution, dried over magnesium sulfate , it is filtered and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. After crystallization from diisopropyl ether, 0.2 g of white solid is isolated. Melting point: 87-89 ° C.

Example 3A (Compound No. 17A). 2- [[3- [5- [6- (Cyclopropylmethoxy) naphthalen-1-yl] -1, 3-dioxan-2- yl] propyl] methylamino] -N- (cyclopropylmethyl) acetamide.

3A.1. 5- [6- (Cyclopropylmethoxy) naphthalen-1-yl] -1, 3-dioxane-2-propanamine. 30.0 g (78.23 mmol) of N- [3- [5- [6- (cyclopropylmethoxy) naphthalen-1-yl] -1,3-dioxan-2-yl] are introduced into a 1000 ml flask propyl] acetamide, 330 ml of ethanol and 300 ml of 30% sodium hydroxide, and the mixture is heated at 110 ° for 24 h. The alcoholic phase is separated by decantation, it is concentrated, water is added and extraction is carried out with ethyl acetate. The organic phase is dried over magnesium sulfate, and the solvent is evaporated off under reduced pressure. 30.44 g of oily product are obtained, which is used as it is in the next step.

3A.2. 5- [6- (cyclopropylmethoxy) naphthalen-1-yl] -N-methyl - 1, 3-dioxane-2 -propanamine. 2.4 ml (25.3 mmol) of acetic anhydride are introduced into a 50 ml flask, 1 ml (26.5 mmol) of formic acid is added dropwise and the mixture is heated in the bath oil 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) is added dropwise without the temperature exceeding 40 ° C. ) of 5- [6- (cyclopropylmethoxy) naphthalen-1- yl] -1, 3 -dioxane -2 -propanamine in 7 ml of tetrahydrofuran and stirring is continued at room temperature overnight.

The solvent is evaporated under reduced pressure, the residue is taken up in toluene and it is evaporated under reduced pressure, and the residue is dried.

5.84 g (15.8 mmol) of white solid are obtained. It is dissolved in 40 ml of tetrahydrofuran and, in a 250 ml flask, it is added, at reflux temperature and under an argon atmosphere, to a suspension of 1.2 g of aluminum hydride and lithium in 43 ml of tetrahydrofuran, and the reflux is maintained for 4 h. The mixture is cooled in an ice-water bath, 9 ml of double sodium and potassium tartrate are added thereto dropwise, and the stirring is continued overnight. The mixture is filtered, the filtrate is concentrated under reduced pressure and 5.89 g of oily product are obtained. 0.23 g of it is dissolved in propan-2-ol and, after treatment with an equivalent of hydrochloric acid in propan-2-ol, 0.188 g of hydrochloride is finally isolated. Melting point: 144-148 ° C. 3A.3. 2 - [[3- [5- [6- (Cyclopropylmethoxy) naphthalen-1-yl] -1,3- dioxan-2-yl] propyl] methylamino] -N- (cyclopropylmethyl) _ acetamide. 0.24 ml (2.81 mmol) of cyclopropanemethanamine, 20 ml of dioxane, and 0.4 ml of triethylamine are introduced into a 250 ml flask, and a solution of 0.22 ml is added dropwise ( 2.81 mmol) of chloroacetyl chloride) in 10 ml of dioxane, and the mixture is 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- (cyclopropylmethoxy) naphthalen-1-yl] -N- methyl-1,3-dioxane-2 are added. -propanamine, 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, washed with water and brine, dried over magnesium sulfate, filtered and 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 obtained which is dissolved in ethanol. After treatment with an equivalent of oxalic acid, 0.5 g of white solid is isolated. Melting point: 156-158 ° C.

Example 4A (Compound Ν ° 19A).

2- [[3- [5- (6-Ethoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] _ (phenylmethyl) amino] acetamide.

4A.1. N- [3- [5- (6-Hydroxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] acetamide.

3.4 g (9.9 mmol) of N- [3- [5- (6-methoxynaphthalen-1-yl) -1, 3 -dioxan- are introduced into a 250 ml flask under a nitrogen atmosphere. 2-yl] propyl] acetamide and 20 ml of 1-methyl-2-pyrrolidinone, the mixture is stirred, 3.86 g (49.5 mmol) of sodium sulfide are added and the mixture is heated in an oil bath at 150 ° C overnight.

The mixture is left to return to 25 ° C., 50 ml of ethyl acetate and 50 ml of water are added, the organic phase is separated, an addition of 10% hydrochloric acid is added to the aqueous phase until pH = 4 and extracted again with ethyl acetate. The organic phases are combined, washed with water and then with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is filtered and evaporated 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 pentane, ultrasound, ethyl acetate and diisopropyl ether. Finally isolated 1.87 g of solid. Melting point: 135-137 ° C.

4A.2. N- [3- [5- (6-Ethoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] ropyl] acetamide. 4.5 g (13.7 mmol) of N- [3- [5- (6-hydroxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] are introduced into a 250 ml flask acetamide dissolved in 70 ml of N, N-dimethylformamide, 2.8 g of potassium carbonate and 1.53 ml (20.5 mmol) of bromoethane, and the mixture is stirred at room temperature overnight.

The solvent is evaporated off under reduced pressure, with toluene, the residue is taken up with water and ethyl acetate, a solid is separated by filtration. After rinsing with water and ethyl acetate and drying, 2.74 g of solid are isolated.

After decantation, washing of the organic phase, drying, filtration and evaporation of the solvent, another 1.7 g of solid are obtained, ie a total of 4.44 g of compound. 0.3 g is recrystallized from a 6/4 mixture of ethanol and water and finally 0.2 g of compound is isolated.

Melting point: 140-142 ° C.

4A.3. 5- (6-Ethoxynaphthalen-1-yl) -1, 3-dioxane-2-propanamine. 4.1 g (11.4 mmol) of N- [3- [5- (6-ethoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] pro_ pyl] are introduced into a 250 ml flask. acetamide in solution in 49 ml of ethanol and 43.4 ml of 30% sodium hydroxide, and the mixture is heated at reflux for 24 h. It is allowed to cool, the alcoholic phase is separated by decantation, it is concentrated, the residue is taken up with water, and extraction is carried out with dichloromethane. The organic phase is washed with saturated sodium chloride solution and dried over magnesium sulfate. It is filtered and the solvent is evaporated 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 ammonia.

1.87 g of solid are obtained, which is used as it is in the next step.

The hydrochloride is prepared from a 0.1N solution of hydrochloric acid in propan-2-ol. Melting point: 180-183 ° C.

4A.4. 5- (6-Ethoxynaphthalen-1-yl) -N- (phenylmethyl) -1, 3-dioxane-2 -propanamine. 1.63 g (5.17 mmol) of 5- (6-ethoxynaphthalen-1-yl) - 1, 3 -dioxane-2 -propanamine are introduced into a 1000 ml flask fitted with a Dean-Stark apparatus. solution in 450 ml of methanol, then 0.604 g (5.69 mmol) of benzaldehyde, and the mixture is heated to reflux until reduction to a third of the initial volume.

The mixture is allowed to cool, placed in an ice bath, 1.56 g (41.3 mmol) of sodium borohydride is added in small portions, and the mixture is stirred overnight.

The solvent is evaporated off under reduced pressure, the white residue is taken up with water and ethyl acetate, the organic phase is washed twice with water and once with ethyl acetate, dried over magnesium sulfate, filtered, the solvent is evaporated off under reduced pressure, and the residual oil is purified 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 from which 0.1 g is taken to prepare the hydrochloride by dissolution in hot propan-2-ol, addition of 2.46 ml of 0.1 0,1 hydrochloric acid in propan-2 -ol, evaporation of the solvent under reduced pressure, trituration of the residue in diisopropyl ether, spin drying and vacuum drying. 0.97 g of hydrochloride are isolated. Melting point: 206-208 ° C.

4A.5. 2- [3- [5- (6-Ethoxynaphthalen-1-yl) -1,3-dioxan-2yl] propyl] (phenylmethyl) amino] acetamide.

0.5 g (1.23 mmol) of 5- (6-ethoxynaphthalen-1-yl) -N- (phenylmethyl) -1,3-dioxane-2-propanamine dissolved in 7 is introduced into a 50 ml flask ml of acetonitrile, 0.17 g (1.23 mmol) of potassium carbonate, 0.055 g (0.369 mmol) of sodium iodide and 0.138 g (1.47 mmol) of 2-chloro_acetamide, and the mixture is heated mix at reflux for 5 h. The mixture is allowed to cool, water and ethyl acetate are added, the organic phase is separated, the aqueous phase is extracted once more, the organic phase is washed twice with water and once with a saturated aqueous solution of sodium chloride, it is dried over magnesium sulphate, it is filtered, the solvent is evaporated under reduced pressure, and the residue is purified by chromatography on a column of silica gel, eluting with a 99 / 1 of dichloromethane and methanol.

0.590 g of pure base is obtained in the form of a yellow oil which is dissolved in hot propan-2-ol, 12.3 ml of hydrochloric acid are added in propan-2-ol to 0.1 N. After evaporation of the solvent under reduced pressure, trituration of the residue in diisopropyl ether, draining and drying under vacuum, 0.54 g of hydrochloride is isolated. Melting point: 190-193 ° C.

Example 5A (Compound No. 20A). 2- [[3- [5- (6-Ethoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] _ (phenylmethyl) amino] -N-methylacetamide.

5A.1. 2- [[3- [5- (6-Ethoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] (phenylmethyl) amino] ethyl acetate. 0.5 g (1.23 mmol) of

5- (6-ethoxynaphthalen-1-yl) -N- (phenylmethyl) -1, 3-dioxane-2-propanamine suspended in 15 ml of acetonitrile, 0.42 g (3.07 mmol) of carbonate is added potassium and 0.2 ml (1.84 mmol) ethyl 2-bromoacetate, and heated mixing at 60 ° C for 2.5 h.

20 ml of water and 15 ml of ethyl acetate are added, the organic phase is separated, washed with water, dried over magnesium sulfate, filtered, and the solvent is evaporated off under pressure reduced, and the residue is purified by chromatography on a column of silica gel, eluting with a 98/2 mixture of dichloromethane and methanol. 0.58 g of oily product is obtained, which is used as it is in the next step.

5A.2. 2- [[3- [5- (6-Ethoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] _ propyl] (phenylmethyl) amino] -N-methylacetamide.

0.58 g (1.18 mmol) of 2- [[3- [5- (6-ethoxynaphta_ lén-l-yl) -1, 3-dioxan-2-yl] propyl] (phenylmethyl) amino] is dissolved ethyl acetate 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 ° C. for 7 days.

The solvent is evaporated off under reduced pressure, and

0.8 g of oily product which is purified by chromatography on a column of silica gel, eluting with a 98/2 mixture of dichloromethane and methanol to obtain 0.5 g of pure base in the form of an oil.

After treatment with 10.5 ml of hydrochloric acid in propan-2-ol 0.1 N, evaporation of the solvent, trituration in diisopropyl ether, filtration and drying, 0.37 hydrochloride is finally isolated.

Melting point: 88-90 ° C.

Example 6A (Compound No. 23A). 2- [[3- [5- [6- (Cyclopentyloxy) naphthalen-1-yl] -1, 3-dioxan-2yl] propyl] (phenylmethyl) amino] acetamide.

6A.1. N- [3- [5- [6- (Cyclopentyloxy) naphthalen-1-yl] -1, 3-dioxan-2 -yl] propyl] acetamide. From 4.5 g (13.6 mmol) of N- [3- [5- (6-hydroxynaphta_ lén-l-yl) -1, 3-dioxan-2-yl] propyl] acetamide and from 3, 0 g (20.1 mmol) of bromocyclopentane, and operating under conditions analogous to those described in Example 4A.2, but at 80 ° C, 4.88 g of crude compound are obtained. We purify it 0.388 g by chromatography on a column of silica gel, eluting with a 90/10 mixture of dichloromethane and methanol. After recrystallization from a mixture of ethanol and water, then drying in the presence of phosphorus pentoxide, 0.22 g of compound is isolated. Melting point: 136-137 ° C.

6A.2. 5- [6- (Cyclopentyloxy) naphthalen-1-yl] -1, 3-dioxane-2-propanamine. From 4.5 g (11.3 mmol) of N- [3- [5- (6-cyclopentyl_ oxynaphthalen-1-yl) -1, 3-dioxan-2-yl] ropyl] acetamide, and operating under conditions analogous to those described in Example 4A.3, 1.52 g of base are obtained, then 1.15 g of hydrochloride.

6A.3. 5- [6- (Cyclopentyloxy) naphthalen-1-yl] -N- (phenylmethyl) -

1, 3 -dioxane-2 -propanamine. From 0.59 g (1.66 mmol) of 5- (6-cyclopentyloxy_naphthalen-1-yl) -1, 3 -dioxane-2 -propanamine and 0.194 g (1.82 mmol) of benzaldehyde, and operating under conditions similar to those described in Example 4A.4, 0.48 g of base is obtained from which 0.435 g of hydrochloride is prepared. Melting point: 186-190 ° C.

6A.4. 2- [[3- [5- [6- (Cyclopentyloxy) naphthalen-1-yl] -1, 3-dioxan-2yl] propyl] (phenylmethyl) amino] acetamide. From 0.710 g (1.59 mmol) of 5- (6-cyclopentyloxy, naphthalen-1-yl) -N- (phenylmethyl) -1, 3-2-dioxane-propanamine and 0.178 g (1.9 mmol) of 2-chloroacetamide, and operating under conditions analogous to those described in the example

4A.5, 0.640 g of base is obtained in the form of an oil, of which 0.628 g of hydrochloride is prepared. Melting point: 212-215 ° C. Example 7A (Compound No. 26A).

2- [[3- [5- [(6-Phenylmethoxy) naphthalen-1-yl] -1, 3-dioxan-

2yl] propyl] (phenylmethyl) amino] acetamide.

7A.1. N- [3- [5- [(6-Phenylmethoxy) naphthalen-1-yl] -1, 3-dioxan-2-yl] propyl] acetamide. From 4.2 g (12.75 mmol) of N- [3- [5- (6-hydroxy_ naphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] acetamide and 1.82 ml (15.3 mmol) of (bromomethyl) benzene, and operating under conditions analogous to those described in Example 4A.2, 4.67 g of product are obtained, of which 0.3 g is recrystallized from a mixture 6 / 4 ethanol and water, to obtain 0.15 g of white solid. Melting point: 138-140 ° C.

7A.2. 5- [6- (Phenylmethoxy) naphthalen-1-yl] -1, 3 -dioxane-2-propanamine. From 4.06 g of N- [3- [5- [(6-phenylmethoxy) naphthalen-1- yl] -1, 3-dioxan-2-yl] propyl] acetamide, and operating under analogous conditions to those described in Example 4A.3, 3.2 g of oily product is obtained which is used as it is in the next step.

7A.3. 5- [6- (Phenylmethoxy) naphthalen-1-yl] -N- (phenylmethyl) - 1, 3 -dioxane-2 -propanamine.

From 1.13 g (2.99 mmol) of 5- [6- (phenylmethoxy) _ naphthalen-1-yl] -1, 3-dioxane-2-propanamine and from 0.317 g (2.99 mmol) of benzaldehyde, then 0.904 g (23.9 mmol) of sodium borohydride, and operating under conditions analogous to those described in Example 4A.4, 0.41 g of base is obtained from which 0.1 g is taken to obtain 0.090 g of hydrochloride. Melting point: 185-189 ° C.

7A.4. 2- [[3- [5- [(6-Phenylmethoxy) naphthalen-1-yl] -1,3-dioxan-2yl] propyl] (phenylmethyl) amino] acetamide. From 0.30 g (0.64 mmol) of 5- [6- (phenylmethoxy) _ naphthalen-1-yl] -N- (phenylmethyl) -1, 3-2-dioxane-propanamine and 0.072 g ( 0.768 mmol) of 2-chloroacetamide), and by operating under conditions analogous to those described in Example 4A.5, 0.310 g of base is obtained in the form of an oil, from which 0.285 g of hydrochloride is prepared.

Melting point: 170-175 ° C.

Table A which follows illustrates the chemical structures and the physical properties of some compounds of general formula (IA).

In the columns "Rx", "R ₂ " and "R ₃ ", cC ₃ H ₅ represents a cyclopropyl group, cC ₅ H ₉ represents a cyclopentyl group,

C ₆ H ₅ represents a phenyl group.

In the "Salt" column, "-" denotes a compound in the basic state, "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.

In the column "F (° C)", "(d)" indicates a melting point with decomposition.

All of the compounds are trans stereoisomers ( ¹ H NMR).

Table A

In the general formula (IB)

R represents either a hydrogen atom or a group of general formula CH ₂ C0Y in which Y represents a hydroxy group or a (C ₁ -C ₄ ) alkoxy group, or also a group of general formula C ^ CONR ^^ in wherein R _x and R ₂ , independently of each other, each represent a hydrogen atom or a (C- _L -C, ^) alkyl group,

X represents an oxygen or sulfur atom or a CH ₂ group, m represents 0 or 1, and 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; on the other hand, certain compounds, due to the chirality of the cycle linked to the nitrogen atom, 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 prepared by a process illustrated by scheme B which follows. The 2- (6-methoxynaphthalen-1-yl) propane-1, 3-diol of formula (IIB) is reacted with 4, 4-diethoxybutanamine of formula (IIIB) at reflux of a non-protic solvent such as toluene and in the presence of dry hydrochloric acid in solution in diethyl ether as catalyst to obtain 5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-propanamine of formula (IVB), then reacts the latter with a ketone of 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 the medium neutral or acid, under reducing amination conditions well known to those skilled in the art. A compound of general formula (IBa) is obtained which corresponds to the general formula (IB) when R represents a hydrogen atom. Scheme B

It is then possible, if desired, to alkylate the compound of general formula (IBa) with a 2-bromoacetate of (C- _L -C ^ alkyl in an aprotic polar solvent, for example acetonitrile, in the presence of a base , for example potassium carbonate to obtain a compound of general formula (IBb) in which Y represents a (C ₁ -C) alkoxy group. If desired, the latter can be saponified under conditions well known to man of trade to obtain a compound of general formula (IBb) in which Y represents a hydroxy group The general formula (IBb) corresponds to the general formula (IB) when R _x represents a group of general formula CH ₂ COY.

If desired, the compound of general formula (IBb) can then be reacted with an amine of general formula HNR _X R ₂ , in which R _x and R ₂ are as defined above, to obtain an amide of general formula (IBc). The conditions for this reaction are conventional and are well known to those skilled in the art. 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-NR- _L R ₂ , in which Z represents a chlorine or bromine atom and R _λ 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 of potassium carbonate.

2- (6-methoxynaphthalen-1-yl) propane-1, 3-diol of formula (IIB) is described in patent application EP-0 461 958. 4, 4-diethoxybutanamine is commercially available, as well than the ketones of general formula (VB).

The following examples illustrate in detail the preparation of some compounds of general formula (IB). Elementary microanalyses and IR and NMR spectra confirm the structures of the compounds obtained. The numbers of the compounds indicated in parentheses in the titles correspond to those of Table B given below. Example IB (Compound No. 1B).

2- [(2,3-Dihydro-1H-inden-1-yl) [3- [5-

(6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] amino] _ ethyl acetate.

1B.1. 5- (6-methoxynaphthalen-1-yl) -1, 3-dioxane-2-propanamine hydrochloride.

7.56 g (32.5 mmol) of 2- (6-methoxynaphthalen-1-yl) pro_ pane-1, 3-diol, 6.8 g (42) are introduced into a 1 liter flask containing 300 ml of toluene , 1 mmol) of 4, 4-diethoxybutanamine, then 70 ml of hydrochloric ether, and the mixture is heated at reflux for 2 h.

It is cooled, the precipitate is collected by filtration, and rinsed with diethyl ether. 12.2 g of crude hydrochloride are obtained in the form of a beige solid.

Melting point: 224-226 ° C.

1B.2. N- (2,3-Dihydro-1H-inden-1-yl) -5- (6-methoxynaphthalen-1-yl) -1, 3 -dioxane-2-propanamine.

In a 500 ml flask, 3.0 g (9.95 mmol) of 5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-propanamine are dissolved in 250 ml of ethanol, 1 , 32 g (9.95 mmol) of 2, 3-dihydro- (1H) inden-1-one, and the mixture is heated at reflux overnight.

It is allowed to cool, 2 g of potassium borohydride are added and stirring is continued for 2 h 30 min. 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 a column of silica gel, eluting with a 9/1 mixture of dichloromethane and methanol.

2.79 g of oily product are obtained.

1B.3. 2- [(2,3-dihydro-1H-inden-1-yl) [3- [5- (6-methoxynaphthalen-1-yl) -1,3-dioxan-2-yl] propyl] _ hydrochloride ] ethyl acetate. 1.88 g (4.5 mmol) of N- (2,3-dihydro-1H-inden-1-yl) -5- (6-methoxynaphthalen-1-yl) are introduced into a 250 ml flask 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 amount of iodide of sodium and 35 ml of N, N-dimethylformamide, and the mixture is heated at 60 ° C for 3 h.

100 ml of water are added, the mixture is extracted with three times 150 ml of ethyl acetate, the organic phase is washed with aqueous sodium chloride and then with aqueous sodium hydrogen carbonate. After drying and evaporating the solvent, 3.5 g of oily product is obtained which is purified by chromatography on a column of silica gel with a gradient of elution of ethyl acetate from 5% to 10% in cyclohexane. 1.97 g of pure base are obtained from which 0.55 g (1 mmol) is taken to prepare the hydrochloride from 11 ml of 0.1 N solution of hydrochloric acid in propan-2-ol. After washing in diethyl ether, 0.44 g of hydrochloride is isolated. Melting point: 88-90 ° C.

Example 2B (Compound No. 2B).

2- [(2,3-dihydro-1H-inden-1-yl) [3- [5- (6-methoxynaphthalen-1-yl) -1,3-dioxan-2-yl] propyl] amino] hydrochloride -N- methylacetamide.

1.42 g (2.8 mmol) of 2- [(2,3-dihydro-1H-inden-l-yl) [3- [5- (6-methoxynaphthalen-l-) are introduced into a 250 ml flask yl) -1, 3 -dioxan-2-yl] propyl] amino] ethyl acetate, 30 ml of a 33% solution of methylamine in ethanol are added, and the mixture is stirred at room temperature for 2 j. The solvent is evaporated off under reduced pressure, the residue is purified by chromatography on a column of silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, to obtain 1.16 g of oily product. The hydrochloride is prepared from 24 ml of 0.1 N solution of hydrochloric acid in propan-2-ol. After washing in diethyl ether, 0.98 g of hydrochloride is isolated. Melting point: 112-114 ° C. Example 3B (Compound No. 6B).

5- (6-methoxynaphthalen-1-yl) -N- (1,2,3,4-tetra-hydronaphthalen-1-yl) -1,3-2-dioxane-2-propanamine fumarate.

5 3.0 g (9.95 mmol) of 5- (6-methoxynaphthalen-1-yl) -1, 3 -dioxane-2 -propanamine, 90 ml of ethanol and 1 are introduced into a 250 ml flask. 45 g (9.95 mmol) of 3, 4-dihydrohydro naphthalen-1 (2H) -one, and the mixture is heated at reflux for 48 h.

It is allowed to cool, 3 g (55.6 mmol) of potassium borohydride are added, and the mixture is stirred at room temperature for 2 d.

Add water, extract with ethyl acetate, wash the organic phase with water, dry it, evaporate the sol-

- _| _5 before under reduced pressure, the residue is taken up in dichloromethane, and the solvent is evaporated off under reduced pressure. 4.86 g of oily product are obtained, which is purified by chromatography on a column of silica gel, eluting with a 9/1 mixture of dichloromethane and methanol.

1.6 g of base are obtained, from which 0.4 g is taken 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 ° C.

Example 4B (Compound No. 9B).

2- [[3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] (1,2,3,4-tetrahydronaphthalen-1-yl) hydrochloride] acetamide.

30 0.85 g (1.97 mmol) of 5- (6-methoxynaphthalen-1-yl) -N- (1,2,3,4-tetrahydronaphthalen-1-yl) is introduced into a 250 ml flask - 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) iodide

35 sodium, and the mixture is heated to reflux for 4 h.

50 ml of water and 25 ml of ethyl acetate are added, the organic phase is separated, the mixture is extracted twice with 25 ml of ethyl acetate, the solvent is evaporated off under reduced pressure, and the residue by chromatography on silica gel column, eluting with a 9/1 mixture of dichloromethane and methanol.

0.6 g of base is obtained which makes it possible to prepare 0.25 g of hydrochloride by means of a 0.1 N solution of hydrochloric acid in propan-2-ol. Melting point: 142-143 ° C.

Example 5B (Compound No. 13B).

N- (3,4-dihydro-2H-1-benzopyran-4-yl) -5- (6-methoxynaphthalen-1-yl) -1,3-2-dioxane-2-propanamine hydrochloride.

2 g (6.6 mmol) of 5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-propanamine are added to a 250 ml flask, 150 ml of ethanol, 0.983 g ( 6.6 mmol) of 3,4-dihydro-2H-1-benzopyran-4-one and the mixture is heated at reflux 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, the mixture is extracted four times with 75 ml of ethyl acetate, the solvent is evaporated under pressure reduced and the residue is dried under reduced pressure.

2.98 g of solid are obtained which is purified by chromatography on a column of silica gel, eluting with a 9/1 mixture of dichloromethane and methanol to obtain 1.3 g of base in the form of a pale yellow oil.

0.30 g is taken from which the hydrochloride is prepared using 5 ml of a 0.1 M solution of hydrochloric acid in propan-2-ol. After washing with diisopropyl ether and drying, 0.08 g of hydrochloride is obtained. Melting point: 172-173 ° C.

Example 6B (Compound No. 14B).

2- [(3,4-dihydro-2H-1-benzopyran-4-yl) [3- [5- (6-methoxynaphthalen-l-yl) -1,3-dioxan-2-yl] propyl hydrochloride] amino] _ acetamide.

From 0.5 g (1.15 mmol) of N- (3, 4-dihydro-2H-1-benzopyran-4-yl) -5- (6-methoxynaphthalen-1-yl) -1, 3- dioxane-2-propanamine and 0.16 g (1.72 mmol) of 2-chloroacetamide, and by operating under conditions similar to those described in Example 4B, 0.37 g of compound in the basic state is obtained, after chromatography, from which 0.17 g of hydrochloride is obtained. Melting point: 165-166 ° C.

Table B which follows illustrates the chemical structures and the physical properties of some compounds of general formula (IB).

In the "Salt" column, "-" denotes a compound in the basic state, "fum." denotes a fumarate (or (B) -2-butenedioate), "ox." denotes an oxalate (or ethanedioate), and "HCl" denotes a hydrochloride; the acid: base molar ratio is indicated in parentheses.

Table B

N ° R X m n Salt F (° C)

IB -CH ₂ C0 ₂ CH ₂ CH ₃ CH, 1 i HCl (1: 1) 88-90

2B -CH ₂ CONHCH ₂ CH, HCl (1: 1) 112-114

3B H CH, HCl (1: 1) 220-221

4B -CH ₂ C0 ₂ CH ₂ CH ₃ CH, HCl (1: 1) 77-79

5B -CH ₂ C0NHCH ₂ CH, ox. (1: 1) 84-86

6B H CH, smoke. (1: 1) 134-136

7B -CH ₂ C0 ₂ CH ₂ CH ₃ CH, HCl (1: 1) 77-79

8B -CH ₂ CONHCH ₃ CH ₂ HCl (1: 1) 98-110

9B -CH ₂ CONH ₂ CH, HCl (1: 1) 142-143

0B -CH ₂ C0 ₂ CH ₂ CH ₃ CH, HCl (1: 1) 74-76

IB -CH ₂ CONH ₂ CH, HCl (1: 1) 208-210

2B -CH ₂ CONHCH ₃ CH, smoke. (1: 1) 82-122

3B H O HCl (1: 1) 172-173

4B -CH ₂ CONH ₂ O HCl (1: 1) 165-166

5B • CH ₂ CONHCH ₃ O HCl: i: i: 117-119

(*) The compounds in which the carbon atom linked to the nitrogen atom is chiral, are racemic.

In the "Salt" column, "-" denotes a compound in the basic state, "fum." denotes a fumarate (or {E) -2-butenedioate) and

"HCl" means a hydrochloride; the acid: base molar ratio is indicated in parentheses.

In the last column are indicated the melting points

F (° C).

In the general formula (CI)

R- _L represents either a hydrogen atom or a group of general formula CH ₂ C0Y in which Y represents a hydroxy group or a (C ₁ -C ₄ ) alkoxy group, or also a group 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 pyridin-2-yl group, a pyridin-3-yl group, a pyridin-4-yl group, an l-methylpyrrol-2-yl group, a furan-2-yl group, a thien-2 group -yle or a group 1, 3-thiazol-2-yl, the respective formulas of which are as follows:

CL. ₃ The compounds of general formula (IC) can exist in the form of cis or trans stereoisomers or mixtures of such isomers; they may also exist in the form of free bases or of addition salts with acids.

The compounds of general formula (IC) can be prepared by a process illustrated by scheme C which follows.

The 2- (6-methoxynaphthalen-1-yl) propane-1, 3-diol of formula (IIC) is reacted with 4, 4-diethoxybutanamine of formula (IIIC) at reflux of a non-protic solvent such as toluene and in the presence of hydrochloric acid in solution in diethyl ether as catalyst, to obtain 5- (6-methoxy-naphthalen-1-yl) -1, 3 -dioxane-2 -propanamine of formula (IVC), then reacting the latter, in a protic solvent such as methanol, at a temperature of 25 to 60 ° C, and removing 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 by means of a reducing agent such as sodium borohydride or any other equivalent agent, in neutral or acidic medium, under reducing amination conditions well known to those skilled in the art. Diagram C

, R.

T (VC)

A compound of general formula (ICa) is obtained which corresponds to the general formula (IC) when R represents a hydrogen atom.

It is then possible, if desired, to alkylate the compound of general formula (ICa) with a haloacetate of general formula Z-CH ₂ -C0 ₂ (C ₁ -C ₄ ) alkyl, in which Z represents a chlorine atom or bromine, in a polar aprotic solvent, for example acetonitrile, in the presence of a base, for example potassium carbonate to obtain a compound of general formula (ICb) in which Y represents a group (C ₁ -C ₄ ) alkoxy.

If desired, the latter can be saponified under conditions well known to those skilled in the art to obtain a compound of general formula (ICb) in which Y represents a hydroxy group. The general formula (ICb) corresponds to the general formula (IC) when R _x represents a group of general formula CH ₂ C0Y.

If desired, the compound of general formula (ICb) can then be reacted with an amine of general formula HNR ₄ R ₅ , in which R ₄ and R ₅ are as defined above, to obtain an amide of general formula (ICc). The conditions for this reaction are conventional and are well known to those skilled in the art.

An amide of general formula (ICc) can also be obtained directly from a compound of general formula (ICa) by alkylation using a halide of general formula Z-CH ₂ -CO-NR ₄ R ₅ , in which Z represents a chlorine or bromine atom and R ₄ and R ₅ are as defined above in an aprotic polar 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 R _x represents a group of general formula CH ₂ CONR ₄ R ₅

2- (6-methoxynaphthalen-1-yl) propane-1, 3-diol of formula (IIC) is described in patent application EP-0 461 958. 4, 4-diethoxybutanamine is commercially available, as well than the aldehydes of general formula (VC). The following examples illustrate in detail the preparation of some compounds of general formula (IC). Elementary microanalyses and IR and NMR spectra confirm the structures of the compounds obtained. The numbers of the compounds indicated in parentheses in the titles correspond to those of Table C given below.

Example IC (Compound No. 1C).

5- (6-Methoxynaphthalen-1-yl) -N- (pyridin-4-ylmethyl) -1,3-2-dioxan-2-propanamine dihydrochloride.

HERE. 5- (6-methoxynaphthalen-1-yl) -1, 3-dioxane-2-propanamine hydrochloride.

7.56 g (32.5 mmol) of 2- (6-methoxynaphthalen-1-yl) pro_ pane-1, 3-diol, 6.8 g are introduced into a 1 liter flask containing 300 ml of toluene (42.1 mmol) of 4, 4-diethoxybutanamine, then 70 ml of dry gaseous hydrochloric acid dissolved in diethyl ether, and the mixture is heated at reflux for 2 h. It is cooled, the precipitate is collected by filtration, and rinsed with diethyl ether.

12.2 g of crude hydrochloride are obtained in the form of a beige solid.

Melting point: 224-226 ° C.

1C.2. 5- (6-methoxynaphthalen-l-yl) dihydrochloride -

N- (pyridin-4 -ylmethyl) -1, 3 -dioxane-2 -propanamine.

0.5 g (1.67 mmol) of

5- (6-methoxynaphthalen-1-yl) -1, 3-dioxane-2-propanamine and 200 ml of methanol, 0.178 g (1.67 mmol) of pyri_ dine-4-carboxaldehyde is added, and the mixture is heated at 100 ° 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 under reduced pressure, 100 ml of water are added and 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 column chromatography silica gel, eluting with a 9/1 mixture of dichloromethane and methanol. 0.57 g of base is obtained in the form of an oil. 0.15 g is taken and dissolved in 5 ml of a 0.1 N solution of hydrochloric acid in propan-2-ol. After washing with diisopropyl ether and drying, 0.12 g of dihydrochloride is obtained. Melting point: 207-208 ° C.

Example 2C (Compound No. 3C). 2- [[3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] (pyridin-4-ylmethyl) amino] acetamide dihydrochloride

1.2 g (3 mmol) of 5- (6-methoxynaphthalen-1-yl) are dissolved -

N- (pyridin-4-ylmethyl) -1, 3 -dioxane-2 -propanamine in 200 ml of acetonitrile, 0.138 g (0.9 mmol) of sodium iodide, 0.828 g (6 mmol) of carbonate are added potassium and

0.42 g (4.5 mmol) of 2-chloroacetamide, and the mixture is heated to reflux for 3 h.

The reaction not being completed, another 0.2 g (1.5 mmol) of potassium carbonate, 0.06 g (0.45 mmol) and

0.14 g (1.5 mmol) of 2-chloroacetamide, and the mixture is heated to reflux for another 1 h.

The mixture is allowed to cool, 140 ml of water are added and the mixture is extracted with four times 50 ml of ethyl acetate. After evaporation of the 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.

The base is salified by means of 8 ml of 0.1 N solution of hydrochloric acid in propan-2-ol. After washing with ethyl acetate and drying, 0.17 g of dihydrochloride is obtained.

Melting point: 169-170 ° C.

Example 3C (Compound No. 19C). 5- (6-methoxynaphthalen-1-yl) -N- (thiazol-2-ylmethyl) -1,3-dioxan-2-propanamine hydrochloride.

2.4 g (8 mmol) of 5- (6-methoxynaphthalen-1-yl) are introduced into a 1000 ml flask equipped with a Dean-Stark apparatus. 1, 3 -dioxane-2 -propanamine, 700 ml of methanol and 1 g (8.8 mmol) of 1, 3-thiazole-2-carboxaldehyde, and the mixture is distilled until the volume of the reaction medium reaches about 200 ml. The mixture is cooled, 2.4 g of sodium borohydride are added in small portions, and the mixture is left to stir overnight.

The methanol is evaporated under reduced pressure, the residue is taken up with water and ethyl acetate, the organic phase is separated, washed and dried over magnesium sulfate, and the solvent is evaporated off reduced pressure.

3.17 g of base are obtained, from which 0.5 g is taken to prepare the hydrochloride under conditions analogous to those described above. 0.5 g of hydrochloride are obtained.

Melting point: 134-137 ° C.

Example 4C (Compound No. 21C).

2- [[3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] (thiazol-2-ylmethyl) amino] acetamide hydrochloride.

From 0.7 g (1.75 mmol) of 5- (6-methoxynaphthalen-1-yl) -N- (2-thiazol-ylmethyl) -1, 3-2-dioxane-propanamine and 0.2 g (2.1 mmol) of 2-chloroacetamide, and operating under conditions analogous to those of Example 2C, 0.76 g of base is obtained from which 0.763 of hydrochloride is prepared. Melting point: 189-191 ° C.

Table C which follows illustrates the chemical structures and physical properties of some compounds of general formula (CI).

In the column "R ₂ ", C ₅ H ₄ N-2- represents a pyridin-2-yl group, C ₅ H ₄ N-3- represents a pyridin-3-yl group, C ₅ H ₄ N-4- represents a pyridin-4-yl group, CH ₃ -lC ₄ H ₃ N-2- represents a l-methylpyrrol-2-yl group, C ₄ H ₃ 0-2- represents a furan-2-yl group, C ₄ H ₃ S-2- represents a thien-2-yl group and C ₃ H ₂ NS-2- represents a 1, 3-thiazol-2-yl group. In the "Salt" column, "-" denotes a compound in the basic state, "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 column "F (° C)", "(d)" indicates a melting point with decomposition.

Table C

In the general formula (ID)

Y represents a hydroxy 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 one another, each represent an atom of hydrogen or a (C ₁ -C ₄ ) alkyl group, and

R- _L and R ₂ form, with the nitrogen atom and the carbon atom which connect them, a pyrrolidine cycle, a piperidine cycle or a 1,2,3,4-tetrahydroisoquinoline cycle.

The compounds of general formula (ID) can exist in the form of cis or trans stereoisomers or mixtures of such isomers; moreover, and because of the asymmetric carbon atom in α of the group -C (0) 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 of addition salts with acids.

The compounds of general formula (ID) can be prepared by a process illustrated by scheme D which follows.

The 2- (6-methoxynaphthalen-1-yl) propane-1,3-diol of formula (IID) is reacted with 2- (3-chloropropyl) -1, 3-dioxolane of formula (IIID), in the medium acid and in an aprotic solvent, to obtain 2- (3-chloropropyl) -5- (6-methoxynaphthalen-1-yl) -1, 3-dioxolane of formula (IVD), and finally the latter is reacted with a amine of general formula (VD), in which Y, R and R ₂ are as defined above, in the presence of an organic or inorganic base, in an aprotic solvent, for example N, N-dimethylformamide, at a temperature from 20 to 110 ° C.

2- (6-methoxynaphthalen-1-yl) propane-1,3-diol of formula (IID) is described in patent application EP-0 461 958. 2- (3-chloropropyl) -1, 3- dioxolane is commercially available. The amines of general formula (VD) are commercially available or described in the literature. Scheme D

The following examples illustrate the preparation of some compounds of general formula (ID). Elementary microanalyses and IR and NMR spectra confirm the structures of the compounds obtained. The numbers of the compounds indicated in parentheses in the titles correspond to those of Table D given below.

Example ID (Compound No. 1D).

Ethyl 1- [3- [5- (6-Methoxynaphthalen-1-yl) -1,3-dioxan-2-yl] propyl] -L-prolinate oxalate.

ID.1. 2- (3-chloropropyl) -5- (6-methoxynaphthalen-1-yl) -1,3-dioxane. 5 g (21.5 mmol) of 2- (6-methoxynaphthalen-1-yl) propane-1,3-diol, 3.7 ml (28.05 mmol) are introduced into a 500 ml flask containing 150 ml of toluene ) of 2- (3-chloro_ propyl) -1, 3 -dioxolane, then 40 ml of hydrochloric ether, and the mixture is heated to reflux for 6 h. It is allowed to cool, 100 ml of a 5% aqueous sodium hydrogen carbonate solution are added and it is extracted with twice 100 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, 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 9/1 mixture petroleum ether and ethyl acetate. 3.2 g of white solid are obtained, which is used as it is in the next step.

1D.2 Ethyl 1- [3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] -L-prolinate oxalate.

0.32 g (1 mmol) of 2- (3-chloropro_ pyl) -5- (6-methoxynaphthalen-1-yl) -1 is introduced into a 50 ml flask containing 10 ml of N, N-dimethyl _ formamide , 3-dioxane, 0.22 g (1.2 mmol) of ethyl L-prolinate, 0.3 g (2.2 mmol) of potassium carbonate, then 0.29 g (2 mmol) of iodide potassium, and the mixture is heated at 100 ° C for 4 h. It is allowed to cool, 50 ml of water are added and it is extracted with twice 70 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, the filter, 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 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 oxalate from ethyl acetate. Melting point: 116-118 ° C.

Example 2D (Compound N ° 2D). 1- [3- [5- (6-Methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] -L- prolinamide.

In a 50 ml flask containing 15 ml of N, N-dimethylforra _. amide is introduced 0.5 g (1.6 mmol) of 2- (3-chloropropyl) - 5- (6-methoxynaphthalen-1-yl) -1, 3-dioxane, 0.2 g (1.9 mmol) L-prolinamide, 0.2 g (1.6 mmol) of potassium carbonate, then 0.48 g (3.2 mmol) of potassium iodide, and the mixture is heated at 110 ° C for 3 h 30 It is allowed to cool, 60 ml of water are added and it is extracted with twice 80 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate, filtered, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a gradient of dichloromethane and methanol from 99/1 to 97/3. 0.3 g of compound is obtained which is crystallized in the form of the base from propan-2-ol. Melting point: 164-166 ° C.

Example 3D (Compound Ν ° 6D). 2- [3- [5- (6-methoxynaphthalen-1-yl) -1,3-dioxan-2-yl] propyl] -N-methyl oxalate - 1,2,3,4-tetrahydroisoquinoline-3-carbox_ amide.

3D.1 N-Methyl - 1,2,3,4-tetrahydroisoquinoline-3-carboxamide. 1.75 g (8.5 mmol) 1,2,3,4-tetrahydroisoquinoline-3-ethyl carboxylate are introduced into a 100 ml flask containing 25 ml of a 33% methylamine solution in ethanol. and the mixture is left at 25 ° C for 20 h. It is concentrated to dryness under reduced pressure and we obtain 1.7 g of compound in the form of a colorless oil which is used as it is in the next step.

3D.2 2- [3- [5- (6-methoxynaphthalen-1-yl) -1, 3-dioxan-2-yl] propyl] -N-methyl oxalate - 1, 2, 3, 4-tetrahydro_ isoquinoline -3-carboxamide. 0.5 g (1.6 mmol) of 2- (3-chloropropyl) -5- (6-metho_ xynaphthalen-1-yl) -1, 3 - is introduced into a 100 ml flask containing 20 ml of acetonitrile. 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, then 0.23 g (1.5 mmol) of potassium iodide, and the mixture is heated at 80 ° C for 8 h. It is allowed to cool, 20 ml of water are added and it is extracted with twice 20 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate, 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 dichloromethane and methanol. 0.12 g (0.25 mmol) of compound is obtained which is crystallized in the form of oxalate from diisopropyl ether. Melting point: 88-90 ° C.

Table D which follows illustrates the chemical structures and the physical properties of some compounds of general formula (ID).

In the column "R- _L NCHR ^ '," pyrrol "," pipér "and" isoq "mean that R _x and R ₂ form, with the nitrogen atom and the carbon atom which connect them, respectively, a pyrrolidine cycle, a piperidine cycle or a 1,2,3,4-tetra-hydroisoquinoline cycle.

In the "Salt" column, "-" denotes a compound in the basic state, "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 column "F (° C)", "(d)" indicates a melting point with decomposition. Table D

1

N ° Y RNCHRs Config. * Salt F (° C) [α] ² _D °

ID -OCH ₂ CH ₃ pyrrol S ox. (1: 1) 116-118 - 26;

2D -NH ₂ ! pyrrol S - 164-166 nd

1

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

1 f

6D -NHCH ₃ isoq RS ox. (1 :) 88-90

The compounds according to the invention have been the subject of pharmacological tests which have demonstrated their interest as therapeutic substances.

Neuronal antisodium properties.

The entry of calcium caused by a depolarizing stimulus into the cortical synaptosomes of the rat 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 a sodium channel agonist such as veratridine (10 μM) on the increase in intracellular calcium levels in this model are inhibited by the compounds of the invention at IC ₅₀ (concentrations inhibiting the response by 50%) from 0.1 to 10 μM.

Activity vis-à-vis the tonic convulsions induced in mice by supramaximal electroshock.

The protocol for this trial is described by E. A. Swinyard and J. H. Woodhead in Antiepileptic Drugs, Raven Press, New York, 111-126 (1982).

10 min after intravenous administration of the test compound, the number of mice with tonic convulsions (extensions of the front and hind legs) is noted, immediately after application of an electric current

(0.4 s, 60 mA, 50 Hz) using an Apelex ETC UNIT 7801 ™ device. The results are expressed by the DA ₅₀ , a dose which protects 50% of the animals, calculated according to the method of JT Lichtfield and F. Wilcoxon [J. Pharm. Exp. Ther. , 96, 99-113 (1949)), using the Probit ™ software, from 3 or 4 doses each administered to a group of 8 mice. The DA ₅₀ of the most active compounds range from 1 to 10 mg / kg.

Anti-ischemic properties. The compounds were subjected to the global cerebral ischemia test in mice.

The ischemia is due to cardiac arrest induced by a rapid intravenous injection of magnesium chloride. In this test we measure the "survival time", that is to say the interval between the time of injection of magnesium chloride and the last observable respiratory movement of each mouse. This last movement is considered the ultimate index of a function of the central nervous system. Respiratory arrest occurs approximately 19 seconds after the injection of magnesium chloride. Male mice (Charles River CD1) are studied in groups of 10. They are fed and watered ad libitum before the tests. The survival time is 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 10 mice having received the compound and the survival time measured in a group of 10 mice having received the carrier liquid. The relationships between the modifications in the survival term and the dose of the compound are recorded graphically according to a semilogarithmic curve.

This curve allows the calculation of the "effective dose 3 seconds" (DE ₃ .J, that is to say the dose (in mg / kg) which produces a 3 second increase in survival time compared to the control group. of 10 untreated mice. An increase in survival time of 3 seconds is both statistically significant and reproducible. The ED ₃ „of the most active compounds of the invention are of the order of 0.05 to 0.2 mg / kg intravenously.

Antinociceptive activity

The antinociceptive activity is evaluated in the rat, during the second phase of a formal test adapted from the work of Tjolsen A., Berge O.-G., Hunskaar S., Rosland J. H. and

Hole K. in Pain (1992) 51 5-17.

Formalin (5%) is injected subcutaneously (100 μl) into the arch of the left hind paw. The nociception is quantified, after injection, by the measurement, for the injected paw, of the total duration of licks, between +20 and +35 min, and by the number of tremors, measured by sequences of 2 min, every 5 min , between +35 and +60 min. The compounds are administered at doses of 30 and 60 mg / kg, in suspension (water + 1% Tween 80), orally (5 ml / kg), 30 min before the formalin injection.

A compound is considered active if, after treatment, by comparison with the values measured in animals that have received the vehicle, a statistically significant reduction (p <= 0.05) in the total duration of licks and / or the number of tremors (calculation of 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 cause a reduction of 50% at a dose of 30 mg / kg orally.

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 useful in the treatment or prevention of cerebrovascular disorders of ischemic or hypoxic origin (infarction). cerebral, cranial or medullary trauma, cardiac or respiratory arrest, transient ischemic attack, perinatal asphyxia), glaucoma, progressive neurodegenerative diseases (senile dementias such as Alzheimer's disease, vascular dementias, Parkinson's disease, Huntington's disease, olivo-ponto-cerebellar atrophy, amyotrophic lateral sclerosis, neurodegenerative diseases of viral origin, etc.) and in the prevention of ischemic strokes associated with cardiac and vascular surgery and endovascular therapy. Due to 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 all acute or chronic pain. Finally, the treatment of other conditions, such as neuropathies, neurogenic pain (for example linked to neuropathies or migraine attack), neurological spasticity and dyskinesias, can also be considered. The compounds of the invention can be presented in all forms of pharmaceutical compositions suitable for enteral or parenteral administration, such as tablets, dragees, capsules, suspensions or oral or injectable solutions such as syrups, ampoules, etc., associated with suitable excipients, and dosed to allow daily administration of 1 to 1000 mg of active substance.

Claims

claims

1. Compound, in the form of pure stereoisomer or mixture of stereoisomers, corresponding to the general formula (IA)

in which

R _x represents a hydrogen atom or a (C ₂ -C ₄ ) linear or branched alkyl group, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) cycloalkylmethyl or phenyl (C ^ C ^ alkyl optionally substituted on the phenyl ring, R ₂ represents a hydrogen atom or a (C ₁ -C ₄ ) linear or branched alkyl group, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) cycloalkylmethyl or phenyl (C ^ C- _} ) alkyl optionally substituted on the phenyl ring, R ₃ represents a hydroxy group or (C ₁ -C ₄ ) alkoxy or a group of general formula NR ₄ R ₅ in which R ₃ and R ₄ independently l '' of each other, each represent a hydrogen atom, a linear or branched (C _x -C ₄ ) alkyl group, a (C ₃ -C ₆ ) cycloalkyl group or a (C ₃ -C ₆ ) cycloalkylmethyl group , as a base or as an addition salt with an acid.

2. Compound, in the form of a pure stereoisomer or a mixture of stereoisomers, corresponding to the general formula (IB)

in which

R represents either a hydrogen atom or a group of general formula CH ₂ C0Y in which Y represents a hydroxy group or a (C ₁ -C) alkoxy group, or else a group of general formula CH ₂ C0NR ₁ R ₂ in which, R _x 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 sulfur atom or a CH ₂ group, m represents 0 or 1, and n represents 0, 1 or 2, in the form of the free base or of addition salt with an acid.

3. Compound, in the form of a pure stereoisomer or a mixture of stereoisomers, corresponding to the general formula (IC)

in which

Rx represents either a hydrogen atom or a group of general formula CH ₂ C0Y in which Y represents a hydroxy group or a (C ₁ -C) alkoxy group, or also a group 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 pyridin-2-yl group, a pyridin-3-yl group, a pyridin-4-yl group, an l-methylpyrrol-2-yl group, a furan-2-yl group, a thien-2 group -yle or a 1,3 -thiazol -2 -yle group, in the form of a free base or of an addition salt with an acid.

4. Compound, in the form of pure stereoisomer or mixture of stereoisomers, corresponding to the general formula (ID)

in which

Y represents a hydroxy group, a (C- _L -C ₄ ) alkoxy group, or a group of general formula NR ₄ R _B in which R ₄ and R ₅ , independently of one another, each represent an atom d hydrogen or a (C ₁ -C ₄ ) alkyl group, and

R- _L and R ₂ form, with the nitrogen atom and the carbon atom which connect them, a pyrrolidine cycle, a piperidine cycle or a 1,2,3,4-tetrahydroisoquinoline cycle, existing in the state free base or acid addition salt.

5. 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, associated with an excipient.