KR20010013435A - 5-naphthalen-1-yl-1,3-dioxane derivatives, preparation and therapeutic application - Google Patents

Abstract

Compounds of formula (I).

Formula I

Wherein R ₁ represents an alkyl group, V is a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, a cycloalkylmethyl group, a phenylalkyl group optionally substituted in a phenyl ring, a carboxymethyl group, an alkoxycarbonylmethyl group or nitrogen Substituted carbamoylmethyl group, W represents a carboxymethyl group, an alkoxycarbonylmethyl group, a carbamoylmethyl group optionally substituted in nitrogen, a 4 to 7 ring group optionally containing an oxygen or sulfur atom, or a pyridylmethyl group, 1- Methylpyrrolylmethyl, furylmethyl, thienylmethyl or 1,3-diazolylmethyl group, or alternatively V and W together with a nitrogen atom pyrrolidinyl, piperidyl or 1,2,3,4- Tetrahydroisoquinolyl group is formed.

Use for treatment.

Description

5-naphthalen-1-yl-1,3-dioxane derivative, use in the manufacture and treatment {5-NAPHTHALEN-1-YL-1,3-DIOXANE DERIVATIVES, PREPARATION AND THERAPEUTIC APPLICATION}

The present invention is formula (I)

R ₁ represents an alkyl group, V represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, a cycloalkylmethyl group, a phenylalkyl group optionally substituted in a phenyl ring, a carboxymethyl group, optionally a monocyclic ring in nitrogen Or a di-substituted alkoxycarbonylmethyl group or carbamoylmethyl group, W is a 4-7 manuscript optionally comprising a carboxymethyl group, an alkoxycarbonylmethyl group, optionally a mono- or di-substituted carbamoylmethyl group, an oxygen or sulfur atom Li group, 2-pyridylmethyl group, 3-pyridylmethyl group. 4-pyridylmethyl group, 1-methyl-2-pyrrolymethylmethyl group, 2-furylmethyl group, 2-thienylmethyl group or 1,3-thiazol-2-yl-methyl group, or alternatively V and W Genie together with nitrogen form a pyrrolidinyl, piperidyl or 1,2,3,4-tetrahydroisoquinolyl group.

The compounds of the present invention more specifically correspond to one of the formulas IA, IB, IC and ID.

In formula (IA), R ₁ is a hydrogen atom, a straight or branched chain (C ₂ -C ₄ ) alkyl group, a cyclo (C ₃ -C ₆ ) alkyl group, a cyclo (C ₃ -C ₆ ) alkylmethyl group optionally substituted at the phenyl ring Or a phenyl (C ₁ -C ₃ ) alkyl group. R ₂ represents a hydrogen atom, a linear or branched (C ₁ -C ₄ ) alkyl group, a cyclo (C ₃ -C ₆ ) alkylmethyl group or a phenyl (C ₁ -C ₃ ) alkyl group optionally substituted at the phenyl ring. R ₃ is a hydroxyl group, a (C ₁ -C ₄ ) alkoxy group or a formula NR ₄ R ₅ (R ₄ and R ₅ are each independently a hydrogen atom, a linear or branched (C ₁ -C ₄ ) alkyl group, a cyclo A (C ₃ -C ₆ ) alkyl group or a cyclo (C ₃ -C ₆ ) alkylmethyl group).

Compounds of formula (IA) may exist in the form of cis or trans stereoisomers or mixtures of such isomers; It may also be present in the form of addition salts with free base or acid.

Compounds of formula (IA) can be prepared by several methods described below.

According to a first variant, the amide of formula (IA) described by Scheme A, described below, is described in J. Am. Chem. In order to obtain the amide of formula IIIA according to the method described in Soc. (1976) 98 3237, in the presence of sodium sulfide in a polar aprotic solvent, for example N-methylpyrrolidone, at a temperature of 100-150 ° C. Alkylated.

The polyamide will then a polar aprotic solvent, such as N, N- dimethylformamide in the formula R ₁ -X in the presence of a base such as potassium carbonate (R ₁ is defined above, except a hydrogen atom, X Is alkylated using a derivative of a halogen atom or equivalent group) to obtain an amide of formula IVA.

This amide is then hydrolyzed in a protic solvent such as water or an aliphatic alcohol in a basic medium such as sodium hydroxide at a temperature of 25 to 100 ° C. to obtain the corresponding primary amine, which is known to those skilled in the art. Under reducing amine conditions, in the presence of a reducing agent such as sodium borohydride or sodium cyanoborohydride, this amine is treated with an aldehyde of the formula R ₆ -CHO (R ₆ is the lower homologue of the R 2 group) to obtain an amine of the formula VA. .

The amine of formula VA is then reacted with ethyl bromoacetate to obtain a compound of formula IA, wherein R ₁ and R ₂ represent alkyl, cycloalkyl, cycloalkylalkyl or phenylalkyl groups and R ₃ represents ethoxy groups. If desired, the compounds thus obtained can be hydrolyzed to convert to the corresponding acid or alternatively reacted with amines of the formula HNR ₄ R ₅ (R ₄ and R ₅ as defined above) to convert to amide. . The conditions of this reaction are standard and well known to those skilled in the art.

According to a second variant, the amide of formula IA (R ₁ and R ₂ represent an alkyl or phenylalkyl group) represents an amine of formula VA with an α-halo alkanamide of formula VIA wherein 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 amine of the formula VA (R 1 represents a cyclopropylmethyl group and R ₂ represents an alkyl or phenylalkyl group) is obtained by reduction of the corresponding alkanamide, as described in patent application EP-461,958 or by said alkane. Amides can be prepared by hydrolyzing the primary amines and then treating these amines under conditions of N-monoalkylation. All of these reactions were performed according to methods well known to those skilled in the art.

Finally, according to the final modification, the compound of formula IA (R ₁ represents a hydrogen atom) is N, N-dimethyl-formamide of the corresponding compound of formula wherein R ₁ as described in patent application FR-2,742,152 represents a methyl group. It may be prepared by demethylation with sodium bisulfide.

The examples below illustrate the preparation of many compounds of formula (IA). Elemental microanalysis and IR and NMR spectra confirm the structure of the obtained compound.

The numbers indicated in parentheses in the example names correspond to those in the first column of Tables Aa and Ab given later.

Among the compound names, the hyphen “-” forms part of the name.

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) -1-naphthyl] -1-naphthyl] -N-ethyl-1,3-dioxane-2-propanamine

0.8 g of lithium aluminum hydride suspended in 30 ml of tetrahydrofuran was introduced into a 250 ml two-neck round bottom flask, the mixture was heated to reflux and dissolved in 200 ml of tetrahydrofuran N- [3- [5- [6- 4.0 g (10.43 mmol) of (cyclopropyl-methoxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] acetamide are added and refluxing is continued for 4 hours.

The mixture is cooled, 3.5 ml (2 equivalents) of 0.1 M aqueous sodium potassium tartrate solution is slowly added, the mixture is stirred and the solvent is evaporated under reduced pressure. 4.55 g of oily product were obtained, which product was used without further purification in the next step.

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 were introduced into a 250 ml round bottom flask, dropwise adding a solution of 0.21 ml (2.6 mmol) of chloroacetyl chloride in 5 ml of dioxane and mixing Stir at room temperature for 8 hours.

30 ml of water, 1 g of potassium carbonate and 1.0 g (2.7 mmol) of 5- [6- (cyclopropylmethoxy) -1-naphthyl] -N-ethyl-1,3-dioxane-2-propanamine were added and the mixture was added. Heat at 80 ° C. for 8 hours and leave at room temperature overnight.

Water and ethyl acetate are added, the organic phase is separated off, washed with water, washed with brine, dried over magnesium sulfate and filtered, the solvent is evaporated under reduced pressure and the residue is eluted with a 98/2 mixture of dichloromethane and methanol. Purification by chromatography on a silica gel column.

0.5 g of oily product is obtained, dissolved in 2-propanol, 8 ml of 0.1 M hydrochloric acid in 2-propanol is added, and the solvent is evaporated to recrystallize the residue from diisopropyl ether.

0.2 g hydrochloride is finally separated.

m.p. : 74-76 ℃

Example 2A (Compound No. 3A)

N-cyclopropyl-2-[[3- [5- [6- (cyclopropylmethoxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] ethylamino] -acetamide

2A.1. Chloro-N-cyclopropylacetamide

2 g (17.7 mmol) of chloroacetyl chloride are introduced into a 100 ml round bottom flask, 1 g (17.7 mmol) of cyclopropanamine is added dropwise and the mixture is stirred at room temperature for 2 hours.

Bicarbonate solution and ethyl acetate are added, the organic phase is separated off, washed with water, dried over magnesium sulfate, filtered and the solvent is evaporated under reduced pressure to give 0.7 g of a white solid.

The aqueous phase is concentrated under reduced pressure and the residue is taken up in ethanol to further yield 1.22 g of a white solid, ie, 1.92 g in total, which is used without further purification in the next step.

2A.2. N-cyclopropyl-2-[[3- [5- [6- (cyclopropylmethoxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] ethylamino] -acetamide

0.6 g (1.87 mmol) of 2- [6- (cyclopropyl-methoxy) -1-naphthyl] -N-ethyl-1,3-dioxane-2-propanamine dissolved in 20 ml of acetonitrile 0.37 g (2.77 mmol) of chloro-N-cyclopropylacetamide and 0.26 g of potassium carbonate are introduced into a 100 ml round bottom flask 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 off, washed with water and washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on a silica gel column eluting with a 98/2 mixture of dichloromethane and methanol. After crystallization from diisopropyl ether, 0.2 g of a white solid is separated.

m.p .: 87-89 ° C

Example 3A (Compound No. 17A)

2-[[3- [5- [6- (cyclopropylmethoxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] methylamino] -N- (cyclopropylmethyl) acet amides

3A.1. 5- [6- (cyclopropylmethoxy) -1-naphthyl] -1,3-dioxane-2-propanamine

N- [3- [5- [6- (cyclopropylmethoxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] -acetamide 30.0 g (78.23 mmol), 330 ml of ethanol And 300 ml of 30% sodium hydroxide were introduced into a 1000 ml round bottom flask to heat the mixture at 110 ° C. for 24 h.

After the phase is fixed, the alcohol phase is separated off and concentrated, water is added and the mixture is extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and the solvent was evaporated under reduced pressure to give 30.44 g of oily product which was used without further purification in the next step.

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 bottom flask, 1 ml (26.5 mmol) of formic acid is added dropwise and the mixture is heat treated in an oil bath at 50 ° C. for 2 hours.

Remove the heating device, add 2.5 ml of anhydrous tetrahydrofuran and stir the mixture, stirring 5- [6- (cyclopropylmethoxy) -1-naphthyl] -1,3-dioxane- in 7 ml of tetrahydrofuran. A solution of 6.0 g (17.5 mmol) of 2-propanamine is added dropwise at a temperature not exceeding 40 ° C. and stirring is continued at room temperature overnight.

The solvent is evaporated under reduced pressure, the residue is taken up in toluene, the 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 tetrahydrofuran in a 250 ml round bottom flask, a suspension of 1.2 g of lithium aluminum hydride in 43 ml of tetrahydrofuran is added at reflux and under an argon atmosphere, and reflux is continued for 4 hours.

The mixture is cooled in an ice cold water bath, 9 ml of potassium sodium tartrate is added dropwise and stirring is continued overnight. The mixture is filtered and the filtrate is concentrated under reduced pressure to give 5.89 g of oily product.

0.23 g of this product is dissolved in 2-propanol, treated with 1 equivalent of hydrochloric acid in 2-propanol, and 0.188 g of hydrochloride is finally separated.

m.p. : 144-148 ° C

3A.3. 2-[[3- [5- [6- (cyclopropylmethoxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] methylamino] -N- (cyclopropyl-methyl) Acetamide

0.24 ml (2.81 mmol) of cyclopropanemethaneamine, 20 ml of dioxane and 0.4 ml of triethylamine were introduced into a 250 ml round bottom flask, a solution of 0.22 ml (2.81 mmol) of chloroacetyl chloride in 10 ml of dioxane was added dropwise and the mixture was Stir at room temperature for 9 hours.

30 ml of water, 1 g of potassium carbonate and 1 g of 5- [6- (cyclopropylmethoxy) -1-naphthyl] -N-methyl-1,3-dioxane-2-propanamine (2.81 mmol) were added and the mixture was added 3 Heat treatment at 80 ° C. for time.

Cool, add water and ethyl acetate to separate the organic phase, rinse with water and rinse with brine, dry with magnesium sulfate and filter, evaporate the solvent under reduced pressure and residue with 98/2 mixture of dichloromethane and methanol Elution is purified by chromatography on a silica gel column. 0.62 g of product is obtained, which is dissolved in ethanol. After treating with 1 equivalent of oxalic acid, 0.5 g of a white solid is separated.

m.p .: 156-158 ° C

Example 4A (Compound No. 19A)

2-[[3- [5- (6-ethoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] (phenylmethyl) amino] acetamide

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

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

The mixture is cooled to 25 ° C., 50 ml of ethyl acetate and 50 ml of water are added to separate the organic phase, 10% hydrochloric acid is added to the aqueous phase until pH = 4 and the phase is extracted again with ethyl acetate. The combined organic phases are washed with water, washed with saturated sodium chloride solution and dried over magnesium sulfate. The solution is filtered, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a silica gel column eluting with a mixture of dichloromethane and methanol 98/2.

The purified fractions are treated with pentane, ultrasound, ethyl acetate and diisopropyl ether. 1.87 g of solids are finally separated.

m.p. 135-137 ℃

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

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

The solvent was entrained with toluene and evaporated under reduced pressure, the residue was taken up in water and ethyl acetate and the solids were separated by filtration. After washing with water, washing with ethyl acetate and drying, 2.74 g of solid was separated.

Once settled, after phase separation, washing of the organic phase, drying, filtration and evaporation of the solvent 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 compound is finally separated.

m.p. : 140-142 ℃

4A.3. 5- (6-ethoxy-1-naphthyl) -1,3-dioxane-2-propanamine

4.1 g (11.4 mmol) of N- [3- [5- (6-ethoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] acetamide dissolved in 49 ml of ethanol and 30% hydroxide 43.4 ml of sodium are introduced into a 250 ml round bottom flask and the mixture is refluxed for 24 hours.

After cooling, the phase has settled and the alcohol phase is separated off, the 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 sulfate. This solution is filtered and the solvent is evaporated under reduced pressure. The residue is purified by chromatography on a silica gel column eluting with a 90/10/1 mixture of dichloromethane, methanol and aqueous ammonia.

1.87 g of solid were obtained, which product was used without further purification in the next step.

Its hydrochloride is prepared from 0.1 N hydrochloric acid solution in 2-propanol.

m.p. : 180-183 ℃

4A.4. 5- (6-ethoxy-1-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 450 ml of methanol was added to 1000 ml with Dean-Stark apparatus. After introduction into the round bottom flask, 0.604 g (5.69 mmol) of benzoaldehyde is introduced and the mixture is refluxed until reduced to one third of the initial volume.

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

The solution is evaporated under reduced pressure, the white residue is taken up in water and ethyl acetate, the organic phase is washed twice with water and once with ethyl acetate, dried over magnesium sulfate and filtered, the solvent is evaporated under reduced pressure and the residual oil is dichloro Purification by chromatography on a silica gel column eluting with a 95/5 mixture of methane and methanol.

Obtain 1.15 g of base, dissolved in hot 2-propanol with 0.1 g of the product, addition of 2.46 ml of 0.1 N hydrochloric acid in 2-propanol, evaporation of solvent under reduced pressure, grinding of residue from diisopropyl ether, filtration and Hydrochloride is prepared by vacuum drying. 0.97 g of hydrochloride is isolated.

m.p. : 206-208 ℃

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

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

0.590 g of pure base is obtained in the form of a yellow oil, dissolved in hot 2-propanol and 12.3 ml of 0.1 N 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 are separated.

m.p. : 190-193 ℃

Example 5A (Compound No. 20A)

2-[[3- [5- (6-ethoxy-1-naphthyl) -1,3-dioxan-2-yl] -propyl] (phenylmethyl) amino] -N-methylacetamide

5A.1. 2-[[3- [5- (6-ethoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] (phenylmethyl) amino] ethyl acetate

0.5 g (1.23 mmol) of 5- (6-ethoxy-1-naphthyl) -N- (phenylmethyl) -1,3-dioxane-2-propanamine suspended in 15 ml of acetonitrile, 0.42 g of potassium carbonate ( 3.07 mmol) and 2-bromo-ethyl acetate are added and the mixture is heat treated at 60 ° C. for 2.5 hours.

20 ml of water and 15 ml of ethyl acetate are added, the organic phase is separated off, washed with water, dried over magnesium sulfate and filtered, the solvent is evaporated under reduced pressure, the residue is eluted with a 98/2 mixture of dichloromethane and methanol to give a silica gel column. Purify by chromatography on. 0.58 g of oily product is obtained and used in the next step without further purification.

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

0.58 g (1.18 mmol) of ethyl 2-[[3- [5- (6-ethoxy-1-naphthyl) -1,3-dioxan-2-yl] -propyl] (phenylmethyl) amino] acetic acid Dissolve in a few ml of ethanol, add 5 ml of 33% methanamine in ethanol and leave the mixture in an oven at 50 ° C. for 7 days.

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

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

m.p. : 88-90 ℃

Example 6A (Compound No. 23A)

2-[[3- [5- [6- (cyclopentyloxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] (phenylmethyl) amino] acetamide

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

4.5 g (13.6 mmol) of N- [3- [5- (6-hydroxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] acetamide and 3.0 g (20.1) of bromocyclopentane mmol) and working under conditions similar to those described in Example 4A.2 (except at 80 ° C) to afford 4.88 g of crude compound. 0.388 g of this compound is purified by chromatography on a silica gel column eluting with a 90/10 mixture of dichloromethane and methanol. After recrystallization from a mixture of ethanol and water, 0.22 g of a compound is separated by drying in the presence of phosphorus pentoxide.

m.p. : 136-137 ℃

6A.2. 5- [6- (cyclopentyloxy) -1-naphthyl] -1,3-dioxane-2-propanamine

Starting with N- [3- [5- (6-cyclopentyloxy) -1-naphthyl) -1,3-dioxan-2-yl] propyl] -acetamide and described in Examples 4A.3. Working under similar conditions, 1.52 g of base is obtained, followed by 1.15 g of hydrochloride.

6A.3. 5- [6- (cyclopentyloxy) -1-naphthyl] -N- (phenylmethyl) -1,3-dioxane-2-propanamine

Starting from 0.59 g (1.66 mmol) of 5- (6-cyclopentyloxy-1-naphthyl) -1,3-dioxane-2-propanamine and 0.194 g (1.82 mmol) of benzoaldehyde, Example 4A.4 Working under conditions similar to those described, 0.48 g of base is obtained to prepare 0.435 g of hydrochloride therefrom.

m.p. : 186-190 ℃

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

0.710 g (1.59 mmol) of 5- (6-cyclopentyloxy-1-naphthyl) -N- (phenylmethyl) -1,3-dioxane-2-propanamine and 0.178 g (1.9 mmol) of 2-chloroacetamide ) And work under conditions similar to those described in Example 4A.5 to obtain 0.640 g of base in the form of an oil to prepare 0.628 g of hydrochloride.

m.p. : 212-215 ℃

Example 7A (Compound No. 26A)

2-[[3- [5-[(6- (phenylmethoxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] (phenylmethyl) amino] acetamide

7A.1. N- [3- [5-[(6- (phenylmethoxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] acetamide

4.2 g (12.75 mmol) of N- [3-5- (6-hydroxy-1-naphthyl) -1,3-dioxan-2-yl] -propyl] acetamide and 1.82 ml (bromomethyl) benzene Starting at (15.3 mmol) and working under conditions similar to those described in Example 4A.2, yielding 4.67 g of product, of which 0.3 g was recrystallized from a 6/4 mixture of ethanol and water to give 0.15 g of a white solid. Get

m.p. : 138-140 ℃

7A.2. 5- [6- (phenylmethoxy) -1-naphthyl] -1,3-dioxane-2-propanamine

Starting with N- [3- [5-[(6- (phenylmethoxy) -naphthyl] -1,3-dioxan-2-yl] propyl] acetamide, as described in Example 4A.3 Working under similar conditions to give 3.2 g of oily product which is used without further purification in the next step.

7A.3. 5- [6- (phenylmethoxy) -1-naphthyl] -N- (phenylmethyl) -1,3-dioxane-2-propanamine

Starting from 1.13 g (2.99 mmol) of 5- [6- (phenylmethoxy) -1-naphthyl] -1,3-dioxane-2-propanamine and 0.317 g (2.99 mmol) of benzoaldehyde, Example 4A Working under conditions similar to those described in .4, 0.41 g of base are taken, of which 0.1 g is taken to obtain 0.090 g of hydrochloride.

m.p. : 185-189 ℃

7A.4. 2-[[3- [5-[(6- (phenylmethoxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] (phenylmethyl) amino] acetamide

0.30 g (0.64 mmol) of 5- [6- (phenylmethoxy) -1-naphthyl] -N- (phenylmethyl) -1,3-dioxane-2-propanamine and 0.072 g of 2-chloroacetamide ( 0.768 mmol) and operate under conditions similar to those described in Example 4A.5 to give 0.310 g of base in the form of an oil, to prepare 0.285 g of hydrochloride.

m.p. : 170-175 ℃

Tables Aa and Ab which follow describe the chemical structures and physical properties of many compounds of Formula (IA).

In the “R ₁ ”, “R ₂ ”, and “R ₃ ” columns, cC ₅ H ₉ represents a cyclopentyl group and C ₆ H ₅ represents a phenyl group.

In the "salt" column, "-" represents a compound in base form, "ox." Represents oxalate (or ethanedioate), and "fum." Represents fumarate (or (E) -2-butenedio Ate) and “HC1” represent hydrochloride; acid / base molar ratios are indicated in parentheses.

In the “m.p. (° C.)” column, “(d)” refers to the melting point at which decomposition occurs.

All compounds are trans stereoisomers ( ¹ H NMR).

In formula (IB), R is a hydrogen atom or a group of formula CH ₂ COY, wherein Y represents a hydroxyl group or a (C ₁ -C ₄ ) alkoxy group, or alternatively formula CH ₂ CONR ₁ R ₂ , wherein R ₁ and R ₂ independently of each other represents a group of a hydrogen atom or a (C ₁ -C ₄ ) alkyl group), X represents an oxygen or sulfur atom or a CH ₂ group, and n represents 0, 1, 2.

Compounds of formula (IB) may exist in the form of cis or trans stereoisomers or mixtures of such isomers; Moreover, because of the chirality of the ring attached to nitrogen, it may exist in the form of the monodentate and / or enantiomers. It may also be present in the form of addition salts with free base or acid.

Compounds of formula (IB) can be prepared by the method described by Scheme B below.

In the presence of dry hydrochloric acid dissolved in diethyl ether as a catalyst of 2- (6-methoxy-1-naphthyl) propane-1,3-diol of formula IIB and in an aprotic solvent such as toluene Reacted with, 4-diethoxybutanamine to give 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine of formula IVB, followed by reducing amine conditions well known to those skilled in the art Below, in a neutral or acidic medium, the compound is reacted with a ketone of the formula VB, wherein x, m and n are as defined above, in the presence of a reducing agent such as sodium borohydride or any other comparable agent. When R represents a hydrogen atom, a compound of formula IBa corresponding to formula IB is obtained.

The compound of formula IBa is then alkylated with 2-bromoacetic acid (C ₁ -C ₄ ) alkyl in the presence of a base such as potassium carbonate, if desired, in a polar aprotic solvent such as acetonitrile A compound of formula IBb (Y represents a (C ₁ -C ₄ ) alkoxy group) can be obtained.

If desired, this compound is hydrolyzed under conditions well known to those skilled in the art to obtain a compound of formula IBb (Y represents a hydroxyl group). Formula IBb corresponds to formula IB when R ₁ represents a group of formula CH ₂ COY.

If desired, the compound of formula IBb can then be reacted with an amine of formula HNR ₁ R ₂ , wherein R ₁ and R ₂ are as defined above, to obtain an amide of formula IBc. The conditions of this reaction are standard and well known to those skilled in the art.

The amides of formula IBc are also formulated in a polar aprotic solvent, for example N, N-dimethylformamide, in the presence of a base, for example potassium carbonate, in which Z-CH ₂ -CO-NR ₁ R ₂ , wherein Z Can be obtained directly from the compound of formula (IBa) by alkylation with a halide of a chlorine or bromine atom, R ₁ and R ₂ as defined above.

2- (6-methoxy-1-naphthyl) propane-1,3-diol of formula IIB is described in patent application EP-0,461,958. 4,4-diethoxybutanamine is commercially available as a ketone of formula VB.

The following examples illustrate the preparation of many compounds of formula (IB) in more detail. Elemental trace analysis, IR and NMR spectra confirm the structure of the obtained compound. The compound number indicated in parentheses in the designation corresponds to that of Table Ba and Table Bb given later.

Example 1B (Compound No. 1B)

2-[(2,3-dihydro-1H-inden-1-yl) [3- [5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] Amino] acetic acid ethyl hydrochloride

1B.1. 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine hydrochloride

7.56 g (32.5 mmol) of 2- (6-methoxy-1-naphthyl) propane-1,3-diol, 6.8 g (42.1 mmol) of 4,4-diethoxybutanamine and then 70 ml of hydrochloric acid ether 300 ml of toluene It is introduced into a 1 L round bottom flask containing and the mixture is refluxed for 2 hours.

The mixture is cooled and the precipitate is collected by filtration and washed with diethyl ether.

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

m.p. : 224-226 ℃

1B.2. N- (2,3-dihydro-1H-inden-1-yl) -5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine

3.0 g (9.95 mmol) of 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine are dissolved in 250 ml of ethanol in a 500 ml round bottom flask and 2,3-dihydro 1.32 g (9.95 mmol) of-(1H) inden-1-one are added and the mixture is refluxed overnight.

The mixture is cooled, 2 g of potassium borohydride is 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 silica gel column 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-methoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] Amino] acetic acid ethyl hydrochloride

1.88 g (4.5 mmol) N- (2,3-dihydro-1H-inden-1-yl) -5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine , 0.8 g (5.8 mmol) of potassium carbonate, 0.96 g (5.8 mmol) of 2-bromoacetic acid, catalytic amount of sodium iodide and 35 ml of N, N-dimethylformamide were introduced into a 250 ml round bottom flask, and the mixture was heated for 60 hours. Heat treatment at ℃.

100 ml of water are added, the mixture is extracted three times with 150 ml of ethyl acetate and the organic phase is washed with aqueous sodium chloride solution and then with sodium hydrogen carbonate. After drying and evaporating the solvent, 3.5 g of an oily product is obtained, which is purified by chromatography on a silica gel column with an elution gradient of 5% to 10% ethyl acetate in cyclohexane. Obtain 1.97 g of pure base, 0.55 g (1 mmol) of which is prepared, and hydrochloride is prepared using 11 ml of a 0.1 N hydrochloric acid solution in 2-propanol. After washing in diethyl ether, 0.44 g of hydrochloride is separated.

m.p. : 88-90 ℃

Example 2B (Compound No. 2B)

2-[(2,3-dihydro-1H-inden-1-yl) [3- [5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] Amino] -N-methylacetamide hydrochloride

2-[(2,3-dihydro-1H-inden-1-yl) [3- [5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] 1.42 g (2.8 mmol) of amino] ethyl acetate are introduced into a 250 ml round bottom flask, 30 ml of a 33% methylamine solution in ethanol is added and the mixture is stirred at room temperature for 2 days. The solvent is evaporated under reduced pressure and the residue is purified by chromatography on a silica gel column eluting with a mixture of dichloromethane and methanol 98/2 to afford 1.16 g of an oily product.

Its hydrochloride is prepared using 24 ml of a 0.1 N hydrochloric acid solution in 2-propanol. After washing in diethyl ether, 0.98 g of hydrochloride is separated.

m.p. : 112-114 ℃

Example 3B (Compound No. 6B)

5- (6-methoxy-1-naphthyl) -N- (1.2.3.4-tetrahydro-1-naphthyl) -1,3-dioxane-2-propanamine

3.0 g (9.95 mmol) of 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine, 90 ml of ethanol and 3,4-dihydro-1-naphthyl (2H)- ON 1.45 g (9.95 mmol) are introduced into a 250 ml round bottom flask and the mixture is refluxed for 48 hours.

Cool the mixture, add 3 g (55.6 mmol) of potassium borohydride and stir the mixture for 2 days at room temperature.

Water is added, the mixture is extracted with ethyl acetate, the organic phase is washed with water and dried, the solvent is evaporated under reduced pressure, the residue is taken up in dichloromethane and the solvent is evaporated under reduced pressure.

4.86 g of oily product is obtained, which is purified by chromatography on a silica gel column eluting with a 9/1 mixture of dichloromethane and methanol.

1.6 g of base is taken, 0.4 g of which is prepared from 0.11 g of fumaric acid to prepare fumarate in 6 ml of ethanol. 0.27 g of salt is separated.

m.p. : 134-136 ℃

Example 4B (Compound No. 9B)

2-[[3- [5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] (1,2,3,4-tetrahydro-1-naphthyl ) Amino] acetamide hydrochloride

5- (6-methoxy-1-naphthyl) -N- (1,2,3,4-tetrahydro-1-naphthyl) -1,3-dioxane-2-propanamine 0.85 g (1.97 mmol) ), 20 ml of acetonitrile, 0.28 g (2.99 mmol) 2-chloroacetamide, 0.54 g (3.94 mmol) potassium carbonate and 0.29 g (1.9 mmol) sodium iodide are introduced into a 250 ml round bottom flask and the mixture is refluxed for 4 hours. . 50 ml of water and 25 ml of ethyl acetate are added, the organic phase is separated off, the aqueous phase is extracted two more times with 25 ml of ethyl acetate, the solvent is evaporated under reduced pressure, eluting with a 9/1 mixture of dichloromethane and methanol to give the residue a silica gel column Purify by chromatography on.

0.6 g of base are obtained and 0.25 g of hydrochloride is prepared using 0.1N hydrochloric acid solution in 2-propanol.

m.p. : 142-143 ℃

Example 5B (Compound No. 13B)

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

2 g (6.6 mmol) of 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine were introduced into a 250 ml round bottom flask and 150 ml of ethanol and 3,4-dihydro-2H 0.983 g (6.6 mmol) of -1-benzopyran-4-one are added and the mixture is refluxed overnight.

The mixture is cooled, 2 g of sodium borohydride is added and the mixture is extracted four times with 75 ml of ethyl acetate, the solvent is evaporated under reduced pressure and the residue is dried under reduced pressure.

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

Take 0.30 g of this base to prepare its hydrochloride using 5 ml of a 0.1 m hydrochloric acid solution in 2-propanol. After washing with diisopropyl and drying, 0.08 g of hydrochloride is obtained.

m.p. : 172-173 ℃

Example 6B (Compound No. 14B)

2-[(3,4-dihydro-2H-1-benzopyran-4-yl) [3- [5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl ] Propyl] amino] acetamide hydrochloride

0.5 g of N- (3,4-dihydro-2H-1-benzopyran-4-yl) -5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine ( 1.15 mmol) and 0.16 g (1.72 mmol) of 2-chloroacetamide, and working under conditions similar to those described in Example 4B, after chromatography, 0.37 g of the compound is obtained in the form of a base from which hydrochloride 0.17 get g

m.p. : 165-166 ℃

Tables Ba and Bb below describe the chemical structures and physical properties of many compounds of formula IB.

In the "salt" column, "-" represents a compound in base form, "fum." Is fumarate (or (E) -2-butenedioate), and "ox." Is oxalate (or ethanedioate) "HC1" stands for hydrochloride; acid / base molar ratios are shown in parentheses.

(*) A compound in which the carbon atom attached to the nitrogen atom is chiral is a racemic compound.

In the "salt" column, "-" represents a compound in base form, "article" represents fumarate (or (E) -2-butenedioate), "hydrochloric acid" represents hydrochloride; acid / base molar ratio Are shown in parentheses. Melting point m.p. (° C.) is shown in the last column.

R ₁ in formula IC is a hydrogen atom or a group of formula CH ₂ COY, wherein Y is a hydroxyl group or (C ₁ -C ₄ ) alkoxy group, or other formula CH ₂ CONR ₄ R ₅ , wherein R ₄ and R ₅ Each independently represents a group of a hydrogen atom or a (C ₁ -C ₄ ) alkyl group), R ₂ represents a 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 1-methyl-2-pyrrolyl group, 2-furyl group, 2-dienyl group, or 1,3-thiazol-2-yl group, each formula is as follows:

Compounds of formula IC may exist in the form of cis or trans stereoisomers or mixtures of such isomers; It may also be present in the form of addition salts with free base or acid.

Compounds of formula (IC) may be prepared by the process described by Scheme C below.

2- (6-methoxy-1-naphthyl) propane-1,3-diol of formula (IC), in the presence of hydrochloric acid dissolved in diethyl ether as a catalyst, in the aprotic solvent for reflux such as toluene Reaction with 4,4-diethoxybutanamine to give 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine of formula IVC, followed by The water produced during the reaction is removed at the temperature, reacted with an aldehyde of formula VC (where R ₂ is as defined above), and the imine formed is then exemplified in neutral or acidic media under reducing amination conditions well known to those skilled in the art. For example using a reducing agent such as sodium borohydride or any other comparable agent.

The compound of formula ICa is obtained and corresponds to formula IC when R ₁ represents a hydrogen atom.

If so desired, the compound of formula ICa is then formulated in a polar aprotic solvent, for example acetonitrile, in the presence of a base, for example potassium carbonate, with the formula Z—CH ₂ —CO ₂ (C ₁ -C ₄ ) alkyl ( Wherein Z is alkylated with a haloacetate of chlorine or bromine atom to obtain a compound of formula ICb wherein Y represents a (C ₁ -C ₄ ) alkoxy group.

If desired, this compound may be hydrolyzed under conditions well known to those skilled in the art to obtain a compound of formula ICb wherein Y represents a hydroxyl group. Formula ICb corresponds to formula IC when R ₁ represents a group of formula CH ₂ COY.

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

The amide of formula ICc is also formulated in a polar aprotic solvent, for example N, N-dimethylformamide, in the presence of a base, such as potassium carbonate, wherein Z is a Z-CH ₂ -CO-NR ₄ R ₅ , wherein Z is A chlorine or bromine atom, R ₄ and R ₅ can be obtained directly from the compound of formula ICa by alkylation with a halide of).

Formula ICc corresponds to formula IC when R ₁ represents a group of formula CH ₂ CONR ₄ R ₅ .

2- (6-methoxy-1-naphthyl) propane-1,3-diol of formula IIC is described in patent application EP-0,461,958. 4,4-diethoxybutanamine is commercially available, such as an aldehyde of formula VC.

The following examples illustrate the preparation of many compounds of formula IC. Elemental trace analysis and IR and NMR spectra confirm the structure of the obtained compound.

The compound numbers indicated in parentheses in the designations correspond to those in Tables Ca and Cb given later.

Example 1C (Compound No. 1C)

5- (6-methoxy-1-naphthyl) -N- (4-pyridylmethyl) -1,3-dioxane-2-propanamine dihydrochloride.

1C.1. 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine hydrochloride

7.56 g (32.5 mmol) of 2- (6-methoxy-1-naphthyl) propane-1,3-diol, 6.8 g (42.1 mmol) of 4,4-diethoxybutanamine and then dissolved in diethyl ether 70 ml of dry gaseous hydrochloric acid are introduced into a 1 L round bottom flask containing 300 ml of toluene and the mixture is refluxed for 2 hours.

The mixture is cooled and the precipitate is collected by filtration and washed with diethyl ether.

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

m.p. : 224-226 ℃

1C.2. 5- (6-methoxy-1-naphthyl) -N- (4-pyridylmethyl) -1,3-dioxane-2-propanamine dihydrochloride

Pyridine-4-carboxaldehyde by introducing 0.5 g (1.67 mmol) of 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine and 200 ml of methanol into a 250 ml round bottom flask 0.178 g (1.67 mmol) is added and the mixture is heated at 100 ° C. for 2 hours.

Cool the mixture, add 0.5 g of potassium borohydride and stir the mixture for 0.5 h.

Half of the methanol was evaporated under reduced pressure, 100 ml of water was added, the mixture was extracted three times with 20 ml of ethyl acetate, the organic phase was concentrated under reduced pressure and the residue was chromatographed on a silica gel column eluting with a 9/1 mixture of dichloromethane and methanol. Purification by

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 0.1 N hydrochloric acid solution in 2-propanol. After washing and drying with diisopropyl ether, 0.12 g of dihydrochloride is obtained.

m.p. : 207-208 ℃

Example 2C (Compound No. 3C)

2-[[3- [5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] (4-pyridylmethyl) amino] acetamide dihydrochloride

1.2 g (3 mmol) of 5- (6-methoxy-1-naphthyl) -N- (4-pyridylmethyl) -1,3-dioxane-2-propanamine was dissolved in 200 ml of acetonitrile and sodium iodide 0.138 g (0.9 mmol), 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 hours.

Since the reaction was not complete, 0.2 g (1.5 mmol) of potassium carbonate, 0.06 g (0.45 mmol) of sodium iodide and 0.14 g (1.5 mmol) of 2-chloroacetamide were added and the mixture was further refluxed for 1 hour.

The mixture is left to cool, 140 ml of water is added and the mixture is extracted four times with 50 ml of ethyl acetate. After evaporation of the solvent under reduced pressure, the residue is purified by chromatography on a silica gel column eluting with a 9/1 mixture of dichloromethane and methanol to give 0.3 g of pure base.

The base is chlorided using 8 ml of a 0.1 N hydrochloric acid solution in 2-propanol. After washing with ethyl acetate and drying, 0.17 g of dihydrochloride is obtained.

m.p. : 169-170 ℃

Example 3C (Compound No. 19C)

5- (6-methoxy-1-naphthyl) -N- (2-diazolylmethyl) -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 (8.8 mmol) of 1,3-thiazole-2-carboxaldehyde ) Is introduced into a 1000 ml round bottom flask with Dean-Stark apparatus and the mixture is distilled until the volume of the reaction medium reaches about 200 ml.

The mixture is cooled, 2.4 g sodium borohydride is added in portions and the mixture is left to stir overnight.

Methanol is evaporated under reduced pressure, the residue is taken up in water and ethyl acetate, the organic phase is separated off, washed, dried over magnesium sulfate and the solvent is evaporated under reduced pressure. Obtain 3.17 g of base, 0.5 g of which is made hydrochloride under conditions similar to those described above. 0.5 g of hydrochloride are obtained.

m.p. : 134-137 ℃

Example 4C (Compound No. 21C)

2-[[3- [5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] (2-diazolylmethyl) amino] acetamide hydrochloride

0.7 g (1.75 mmol) of 5- (6-methoxy-1-naphthyl) -N- (2-diazolylmethyl) -1,3-dioxane-2-propanamine and 0.2 g of 2-chloroacetamide 2.1 mmol) and work under conditions similar to those of Example 2C to give 0.76 g of base, from which 0.763 g of hydrochloride.

m.p. : 189-191 ℃

Tables Ca and Cb below describe the chemical structures and physical properties of many compounds of Formula IC.

In the column “R ₂ ”, C ₅ H ₄ N-2- represents a 2-pyridyl group, C ₅ H ₄ N-3- represents a 3-pyridyl group, and C ₅ H ₄ N-4- represents 4- represents a _{pyridyl, CH 3 -1-C 4 H} 3 N-2- represents a 1-methyl-2-pyrrolyl, C ₄ H ₃ O-2 represents a 2-furyl, 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, "-" represents a compound in base form, "fum." Is fumarate (or (E) -2-butenedioate), and "ox." Is oxalate (or ethanedioate) "HC1" stands for hydrochloride; the acid / base molar ratio is shown in parentheses.

In the column “m.p. (° C.)”, “(d)” refers to m.p. in which decomposition occurs together.

In formula ID, Y represents a hydroxy group, a (C ₁ -C ₄ ) alkoxy group or a formula NR ₄ R ₅ , wherein R ₄ and R ₅ independently of each other represent a hydrogen atom or a (C ₁ -C ₄ ) alkyl group, respectively. And R ₁ and R ₂ together with the nitrogen and carbon atoms connecting them form a pyrrolidine ring, a piperidine ring or a 1,2,3,4-tetrahydroisoquinoline ring.

Compounds of formula ID may exist in the form of cis or trans stereoisomers or mixtures of such isomers; Furthermore, and due to the asymmetric carbon atom α for the —C (O) Y group, it may exist in the form of pure enantiomers or mixtures of enantiomers. It may also be present in the form of addition salts with organic bases or acids.

Compounds of formula ID can be prepared by the methods described in Scheme D below.

2- (6-methoxy-1-naphthyl) propane-1,3-diol of formula (ID) in acidic medium and aprotic solvent, 2- (3-chloropropyl) -1,3- of formula (IIID) Reaction with dioxolane affords 2- (3-chloropropyl) -5- (6-methoxy-1-naphthyl) -1,3-dioxolane of formula IVD, which finally yields this compound Reaction with an amine of formula VD (Y, R ₁ and R ₂ as defined above) in the presence of an organic or inorganic base in an aprotic solvent such as N, N-dimethylformamide at a temperature of 110 ° C. Let's do it.

2- (6-methoxy-1-naphthyl) 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. Amines of formula VD are commercially available or described in the literature.

The following examples illustrate the preparation of many compounds of Formula ID. Elemental trace analysis and IR and NMR spectra confirm the structure of the obtained compound. The compound number indicated in parentheses in the designation corresponds to that in Table D given later.

Example 1D (Compound No. 1D)

1- [3- [5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] -L-proline ethyl oxalate

1D.1. 2- (3-chloropropyl) -5- (6-methoxy-1-naphthyl) -1,3-dioxane

5 g (21.5 mmol) 2- (6-methoxy-1-naphthyl) propane-1,3-diol, 3.7 ml (28.05 mmol) 2- (3-chloropropyl) -1,3-dioxolane and its 40 ml of hydrochloric acid ether are then introduced into a 500 ml round bottom flask containing 150 ml of toluene and the mixture is refluxed for 6 hours.

The mixture is cooled, 100 ml of 5% aqueous sodium hydrogen carbonate solution is added and the mixture is extracted twice with 100 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a silica gel column eluting with a mixture of petroleum ether and ethyl acetate 9/1. 3.2 g of a white solid are obtained and used in the next step without further purification.

1D.2. 1- [3- [5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] -L-proline ethyl oxalate

2- (3-chloropropyl) -5- (6-methoxy-1-naphthyl) -1,3-dioxane 0.32 g (1 mmol), ethyl L-proline 0.22 g (1.2 mmol), potassium carbonate 0.3 g (2.2 mmol) and then 0.29 g (2 mmol) of potassium iodide are introduced into a 50 ml round bottom flask containing 10 ml of N, N-dimethylformamide and the mixture is heated at 100 ° C. for 4 hours.

The mixture is cooled, 50 ml of water is added and the mixture is extracted twice with 70 ml of ethyl acetate, the organic phase is washed with water, the solvent is evaporated under reduced pressure and the residue is made up with a gradient of dichloromethane and methanol of 99.5 / 0.5 to 99/1. Elution is purified by chromatography on a silica gel column.

0.22 g (0.5 mmol) of a compound are obtained and crystallized from ethyl acetate in the form of an oxalate.

m.p. : 116-118 ℃

Example 2D (Compound No. 2D)

1- [3- [5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] -L-prolineamide

2- (3-chloropropyl) -5- (6-methoxy-1-naphthyl) -1,3-dioxane 0.5 g (1.6 mmol), L-prolineamide 0.2 g (1.9 mmol), potassium carbonate 0.2 g (1.6 mmol) and then 0.48 g (3.2 mmol) of potassium iodide are introduced into a 50 ml round bottom flask containing 15 ml of N, N-dimethylformamide and the mixture is heated at 110 ° C. for 3 h 30 min.

The mixture is cooled, 60 ml of water are added and the resulting mixture is extracted twice with 80 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a silica gel column eluting with a gradient of dichloromethane and methanol from 99/1 to 97/3. 0.3 g of the compound is obtained and crystallized in the form of a base from 2-propanol.

m.p. : 164-166 ℃

Example 3D (Compound No. 6D)

Oxalic acid 2- [3- [5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] -N-methyl-1,2, 3,4-tetrahydroiso Quinoline-3-carboxamide

3D.1. N-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide

1.75 g (8.5 mmol) of 1,2,3,4-tetrahydrosoisoquinoline-3-carboxylic acid ethyl are introduced into a 100 ml round bottom flask containing 25 ml of a 33% methylamine solution in ethanol and the mixture for 20 hours. It is left at 25 ° C. Concentrate to dryness under reduced pressure and 1.7 g of compound are obtained in the form of a colorless oil which is used without further purification in the next step.

3D.2. Oxalic acid 2- [3- [5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] -N-methyl-1,2,3,4-tetrahydroiso Quinoline-3-carboxamide

2- (3-chloropropyl) -5- (6-methoxy-1-naphthyl) -1,3-dioxane 0.5 g (1.6 mmol), N-methyl-1,2,3,4-tetrahydro 0.3 g (1.6 mmol) of isoquinoline-3-carboxamide, 0.2 g (1.6 mmol) of potassium carbonate and then 0.23 g (1.5 mmol) of potassium iodide were introduced into a 100 ml round bottom flask containing 20 ml of acetonitrile and the mixture was Heat at 80 ° C. for 8 hours.

The mixture is cooled, 20 ml of water is added and the resulting mixture is extracted twice with 20 ml of ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate and filtered, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a silica gel column eluting with a 98/2 mixture of dichloromethane and methanol. 0.12 g (0.25 mmol) of the compound are obtained and crystallized in the form of oxalate from diisopropyl ether.

m.p. : 88-90 ℃

Table D below describes the chemical structures and physical properties of many compounds of Formula ID.

In the column “R ₁ NCHR ₂ ”, “pyrrol”, “piper” and “isoq” are those in which R ₁ and R ₂ are pyrrolidine ring, piperidine ring or 1,2,3,4-tetrahydroisoquinoline, respectively. It means forming a ring, together with the nitrogen and carbon atoms connecting it.

In the "Salt" column, "-" represents a compound in base form, "fum." Is fumarate (or (E) -2-butenedioate), and "ox." Is oxalate (or ethanedioate) "HC1" stands for hydrochloride; the acid / base molar ratio is shown in parentheses.

In the “m.p. (° C.)” column, “(d)” denotes the m.p. Indicates.

The compounds according to the invention have been subjected to pharmaceutical tests which reveal their value as therapeutic substances.

Neuronal antisodium properties

The introduction of calcium caused by stimulation stimulation in rat cortical synaptosomes can be measured using a fluorescence test according to the method described by A. Deffois et al. (Neurosciences Letters (1996) 220 117-120). have.

The effect of sodium channel agonists such as veratridine (10 μM) on the increase in the level of intracellular calcium in this model is inhibited by the compounds of the present invention at IC ₅₀ (concentrations inhibiting the reaction by 50%) of 0.1 to 10 μM. do.

Activity on Stiffness-induced Spasm in Mice by Ultramaximal Electric Shock

Methods of this test are described in Antiepileptic Drugs (Raven Press, New York, 111-126 (1982)). Swinyard and J.H. Explained by Woodhead.

Ten minutes after intravenous administration of the test compound, the number of mice showing an immediate spasticity (extension of the anterior hind limb) immediately after using the Apelex ETC UNIT 7801 ^™ device (0.4 s, 60 mA, 50 Hz) is recorded. The results, starting at 3 or 4 doses administered to 8 groups of mice, respectively, and using Probit ^™ software, were used in JT Lichtfield and F. Wilcoxon (J. Pharm. Exp. Ther., 96, 99-113 (1949) A dose protecting 50 animals, calculated according to the method of), is denoted by AD ₅₀ . The AD ₅₀ value of most active compounds is in the range of 1 to 10 mg / kg.

Anti-ischemic properties

The compound was subjected to extensive cerebral ischemic testing in mice.

Ischemia is due to cardiac arrest caused by rapid intravenous injection of magnesium chloride. In this test, the “survival time”, ie the interval between the timing of injection of magnesium chloride and the last observed respiratory activity of each mouse, is measured. This eventual activity is considered the final marker of central nervous system function. The point of respiratory arrest is about 19 seconds after the injection of magnesium chloride.

Male mice (Charles River CD1) are studied in 10 groups. Feed and water freely before the test. The survival time is measured for 10 minutes after intraperitoneal administration of the compounds of the present invention. The results are given in the form of the difference between the survival time measured in the group of 10 mice containing the compound and the survival time measured in the group of 10 mice containing the liquid excipient. The relationship between the change in survival time and the dose of the compound is recorded in graph form on a semilog curve.

This curve makes it possible to calculate a “3-second effective dose” (ED _{3 ″} ), ie, a dose that results in a 3-second increase in survival time relative to the control group of 10 untreated mice.

The 3-second increase in survival time is statistically significant and reproducible.

The ED _{3 ″} value of most of the effective compounds of the present invention is about 0.05 to 0.2 mg / kg via the intravenous route.

Anti-alcoholic activity

Antinociceptive action is described in A. Tjolsen, O.-G. Berge, S. Hunskaar, J.H. During the second phase of the formalin test, which was determined from the study of Rosland and K. Hole (Pain (1992) 51 5-17), rats are evaluated.

Formalin (5%) is injected subcutaneously (100 μl) into the curvature of the sole of the left hind paw. The number of floating behaviors measured for two consecutive minutes every 5 minutes between +35 and +60 minutes, by measuring the total time of licking activity between +20 and +35 minutes for pain injecting pain after injection It is quantified by.

Compounds are administered orally (5 ml / kg) at 30 and 60 mg / kg doses as suspensions (water + 1% Tween 80) 30 minutes before injection of formalin.

Compounds were measured in animals receiving excipients if a statistically significant decrease in the total time of licking activity after treatment (p <= 0.05) and / or the number of floating behaviors (calculated from the area under the curve) was observed. It is considered to be valid in comparison with.

Activity thresholds for the compounds of the invention correspond to a reduction of 35 to 40%. Most effective compounds are reduced by 50% at the dosage of 30 mg / kg via the oral route.

The results of the test show that the compounds according to the invention have neuroprotective properties and are therefore cerebrovascular disorders (cerebral infarction, cranial or bone marrow trauma, cardiac or respiratory arrest, transient ischemic attack, perinatal asphyxia), glaucoma, progressive nerves that cause ischemia or hypoxia Treatment or prevention of degenerative diseases (Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's chorea, olive atrophy, muscular dystrophy, neurodegenerative diseases caused by viruses) and heart and vascular surgery and endovascular treatment It can be used in the manufacture of a medicament useful for the prevention of cerebral ischemic events associated with.

Because of their anticonvulsive properties, it can also be used for the treatment of epilepsy. The compounds of the present invention also have analgesic properties and can therefore be used for the treatment of any acute or chronic pain.

Finally, it can also be considered in the treatment of other diseases such as neuropathy, neuropathic pain (eg, pain associated with neuropathy or migraine attacks), neuropathic spasms and dyskinesia.

The compounds of the present invention may be combined with a suitable excipient to form any pharmaceutical composition suitable for enteric or parenteral administration such as tablets, capsules, gelatin capsules, wafer capsules, drinking or injectable suspensions or solutions (syrups, vials, etc.). It may be divided into batches to allow daily administration of 1 to 1000 mg of the active substance.

Claims (6)

A compound according to formula (IA) in the form of a pure stereoisomer or a mixture of stereoisomers and in the form of an addition salt with a base or an acid. Formula IA Wherein R ₁ is optionally substituted on a hydrogen atom, a straight 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 ring A phenyl (C ₁ -C ₃ ) alkyl group, R ₂ is a hydrogen atom, a straight or branched chain (C ₁ -C ₄ ) alkyl group, a cyclo (C ₃ -C ₆ ) alkyl group, a cyclo (C ₃ -C ₆ ) alkylmethyl group or a phenyl ring optionally substituted in the phenyl ring _1- C ₃ ) alkyl group, R ₃ represents a hydroxyl group, a (C ₁ -C ₄ ) alkoxy group or a group of formula NR ₄ R ₅ , wherein R ₄ and R ₅ are independently of each other hydrogen, straight or branched chain (C ₁ -C ₄ ) An alkyl group, a cyclo (C ₃ -C ₆ ) alkyl group, or a cyclo (C ₃ -C ₆ ) alkylmethyl group is shown. Compounds corresponding to formula (IB) in the form of pure stereoisomers or mixtures of stereoisomers and in the form of addition salts with free bases or acids. Formula IB Wherein R is a hydrogen atom or a group of formula CH ₂ COY, where Y represents a hydroxyl group or a (C ₁ -C ₄ ) alkoxy group, or alternatively a formula CH ₂ CONR ₁ R ₂ , wherein R ₁ and R ₂ independently of each other represent a group of 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, n represents 0, 1 or 2. Compounds corresponding to formula IC in the form of pure stereoisomers or mixtures of stereoisomers, and in the form of addition salts with free bases or acids. (Formula IC) Wherein R ₁ is a hydrogen atom or a group of formula CH ₂ COY, wherein Y represents a hydroxyl group or a (C ₁ -C ₄ ) alkoxy group, or alternatively a formula CH ₂ CONR ₄ R ₅ , wherein R ₄ and R ₅ independently of each other represent a group of a hydrogen atom or a (C ₁ -C ₄ ) alkyl group), R ₂ represents a 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 1-methyl-2-pyrrolyl group, 2-furyl group, 2-thienyl group or 1,3-thiazol-2-yl group. Compounds corresponding to Formula ID in the form of pure stereoisomers or mixtures of stereoisomers and in the form of free bases or addition salts with acids. (Formula ID) Wherein Y represents a hydroxyl group, a (C ₁ -C ₄ ) alkoxy group or a formula NR ₄ R ₅ , wherein R ₄ and R ₅ independently of each other represent a hydrogen atom or a (C ₁ -C ₄ ) alkyl group Represents a group of R ₁ and R ₂ together with the nitrogen and carbon atoms connecting them form a pyrrolidine ring, a piperidine ring or a 1,2,3,4-tetrahydroisoquinoline ring. A pharmaceutical comprising the compound of any one of claims 1 to 4. A pharmaceutical composition comprising the compound of any one of claims 1 to 4 in combination with an excipient.