CZ430699A3 - Derivatives of 5-naphthalen-1-yl-1,3-dioxan, process of their preparation and their therapeutical use - Google Patents

Abstract

Compounds of formula I wherein R is alkyl, V is hydrogen, linear or branched alkyl, cycloalkyl, cycloalkylmethyl, phenylalkyl, which is optionally substituted on the phenyl ring, carboxymethyl, alkoxycarbonylmethyl or carbamoylmethyl, which is optionally substituted on a nitrogen atom, W is carboxymethyl, alkoxycarbonylmethyl, carbamoylmethyl, which is optionally substituted on nitrogen, 4- to 7- a membered cyclic group optionally containing an oxygen atom or atomsulfides, pyridylmethyl, 1-methylpyrrolymethyl, furylmethyl, thienylmethyl or 1,3-thiazolylmethyl; alternatively, V and W together form a nitrogen atom pyrrolidinyl, piperidyl or 1,2,3,4-tetrahydroisoquinolyl. Use for healing.

Description

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

Technical field

The present invention relates to 5-naphthalen-1-yl-1,3-dioxane derivatives, a process for their preparation and their therapeutic use.

SUMMARY OF THE INVENTION

More particularly, the present invention relates to compounds of formula I

(i) where

R 1 is 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 on the phenyl ring, a carboxymethyl group, an alkoxycarbonylmethyl group or a carbamoylmethyl group optionally mono- or disubstituted on a nitrogen atom,

W is a carboxymethyl group, an alkoxycarbonylmethyl group, a carbamoylmethyl group which is optionally monosubstituted or disubstituted on a nitrogen atom, a 4- to 7-membered cyclic group optionally containing an oxygen or sulfur atom, a 2-pyridylmethyl group, a 3-pyridylmethyl group,

4-pyridylmethyl, 1-methyl-2-pyrrolylmethyl, 2-furylmethyl, 2-thienylmethyl or 1,3-thiazol-2-ylmethyl or alternatively V and W form, together with the nitrogen atom which is carries a pyrrolidinyl group, a piperidyl group or a 1,2,3,4-tetrahydroisoquinolyl group.

In particular, the compounds of the present invention have one of the following formulas IA, IB, IC and ID.

R, O <x,

(IA) (IB) (ID) (ID)

• · ·

In the general formula IA

R 1 is hydrogen, a linear or branched alkyl group having 2 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms in the alkyl portion, a cycloalkylmethyl group having 3 to 6 carbon atoms in the alkyl portion, or a phenylalkyl group having 1 to 3 alkyl portions carbon atoms optionally substituted on the phenyl ring,

R ₂ is hydrogen, C 1 -C 4 linear or branched alkyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylmethyl or C 1 -C 6 phenylalkyl 3 carbon atoms optionally substituted on the phenyl ring,

R ₃ is hydroxyl, C 1 -C 4 alkoxy or NR ₄ R ₅ , wherein R ₄ and R ₅ are independently hydrogen, linear or branched C 1 -C 4 alkyl, cycloalkyl C 3 -C 6 alkyl or C 3 -C 6 cycloalkylmethyl.

Compounds of formula IA may exist in the form of cis or trans stereoisomers or mixtures of these isomers; they may also exist in the form of free bases or acid addition salts.

Compounds of formula IA can be prepared by various methods described below.

According to a first embodiment, which is illustrated in Scheme A below, the amide of formula IIA is dealkylated in the presence of sodium sulfide, in a polar aprotic solvent such as N-methylpyrrolidone, at a temperature of 100 to 150 ° C, at a temperature of 100-150 ° C.

9 * 9 ·····

9 9 · 9 9 9 999999 999 99 99

99 9 99 99 9 999 9 9 9 99 to obtain an amide of formula IIIA, according to the method described in J. Am. Chem. Soc. (1976) 983237.

The amide is then alkylated using a derivative of the formula R 1 -X, wherein R x is as defined above but is other than a hydrogen atom and X is a halogen atom or equivalent, in the presence of a base such as potassium carbonate and in a polar aprotic solvent, e.g. in N, N-dimethylformamide to give the amide of formula IVA.

The amide is then hydrolyzed in a basic medium such as sodium hydroxide in a protic solvent such as water or an aliphatic alcohol at 25 to 100 ° C to give the corresponding primary amine which is then reacted with either an aldehyde of formula R ₆ -CHO, wherein R ₆ is a lower homolog of the R ₂ group, in the presence of a reducing agent such as sodium borohydride or sodium cyanoborohydride, under reductive amination conditions known to those skilled in the art, to yield an amine of formula VA.

The amine of formula (VA) is then reacted with ethyl bromoacetate to give a compound of formula (IA) wherein R 1 and R ₂ are alkyl, cycloalkyl, cycloalkylalkyl or phenylalkyl and R ₃ is ethoxy. If appropriate, the compound so obtained is then saponified and converted to the corresponding acid, or alternatively may be reacted with an amine of the formula HNR ₄ R ₅ , where R ₄ and R ₅ are as defined above to convert the compound to the amide. The conditions of these reactions are standard and known to those skilled in the art.

According to an alternative embodiment, the amides of formula IA, wherein R x and R ₂ are alkyl or phenylalkyl, can be prepared by reaction of an amine of formula VA

Scheme A

directly with the α-haloalkanamide of formula VIA

(VIA) wherein X is chlorine or bromine and R ₄ and R ₅ are as defined above. The conditions of this reaction are known to those skilled in the art.

According to a third variant, the amines of formula VA, wherein R ₁ is a cyclopropylmethyl group and R ₂ is an alkyl group or a phenylalkyl group, can be prepared either by reduction corresponding to: · · · · · · · · · · · · · · · · · · ·

The alkanamides described in patent application EP-461,958 or by hydrolyzing said alkanamides to primary amines, and then reacting these amines under N-monoalkylation conditions. All of these reactions are carried out according to procedures known to those skilled in the art.

Finally, according to a last variant, compounds of formula IA wherein R 1 is hydrogen can be prepared by demethylation using sodium sulfide in N, N-dimethylformamide, the corresponding compound wherein R _x is a methyl group as described in patent application FR- 2,742,152.

The examples which follow illustrate the preparation of many compounds of formula IA. Elemental analyzes and IR and NMR spectra confirm the structures of the compounds obtained. The numbers in parentheses after the example names correspond to those in the first column of Table A below.

In the title of a compound, the hyphen forms part of the title and the underline is used only to indicate the division of the word; if the word is not hyphenated, it may be removed or replaced by a normal dash or space.

DETAILED DESCRIPTION OF THE INVENTION

Example IA (Compound No. 2A)

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

ΙΑ. 1. 5- [6- (Cyclopropylmethoxy) -1-naphthyl] -N-ethyl-1,3-dioxane-2-propanamine

0.8 g of lithium aluminum hydride suspended in 30 ml of tetrahydrofuran is introduced into a 250 ml two-necked round-bottomed flask, heated to boiling and 4.0 g (10.43 mmol) of N- [3- [5 [6- ( cyclopropylmethoxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] acetamide dissolved in 200 mL of tetrahydrofuran. and the mixture was heated to boiling for 4 hours.

The mixture was cooled, 3.5 ml (2 equivalents) of aqueous 0.1M sodium potassium tartrate solution was added slowly, the mixture was stirred and the solvent was evaporated under reduced pressure. 4.55 g of an oily product are obtained, which product is used as is in the following stage.

IA. 2. 2 - [[3- (5- [6- (Cyclopropylmethoxy) -1-naphthyl] -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 round-bottom flask, a solution of 0.21 ml (2.6 mmol) of chloroacetyl chloride with 5 ml of dioxane is added dropwise and the mixture is stirred 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 are added and the mixture Heat at 80 ° C for 8 hours and allow to stand at room temperature overnight.

Water and ethyl acetate were added, the organic layer was separated, washed with water and then brine, dried over magnesium sulfate and filtered, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography eluting with dichloromethane / methanol 98 / 2.

0.5 g of an oily product is obtained, which is dissolved in 2-propanol, 8 ml of 0.1M hydrogen chloride in 2-propanol are added, the solvents are evaporated and the residue is recrystallized from diisopropyl ether. 0.2 g of hydrochloride is finally isolated. M.p. 74-76 ° C.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 2A (compound number 3A)

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

2A.1. Chloro-N-cyclopropylacetamide g (17.7 mmol) chloroacetyl chloride was dissolved in 10 ml dioxane and introduced into a 100 ml round bottom flask, 1 g (17.7 mmol) cyclopropanamine was added dropwise and the mixture was stirred at room temperature for 2 hours.

Add bicarbonate and ethyl acetate, separate the organic layer, wash with water, dry over magnesium sulfate and filter, and remove the solvent under reduced pressure to give 0.7 g of a white solid.

The aqueous layer was evaporated under reduced pressure and the residue was taken up in ethanol to give an additional 1.22 g of white solid, i.e. a total of 1.92 g of compound was obtained, which was used in the next step without further purification.

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

0.69 g (1.87 mmol) of 5- [6- (cyclopropylmethoxy) -1-naphthyl] -Nethyl-1,3-dioxane-2-propanamine dissolved in 20 ml of acetonitrile, 0.37 g (2.77 mmol) 2-Chloro-N-cyclopropylacetamide and 0.26 g of potassium carbonate were introduced into a 100 ml round bottom flask and the mixture was heated at 70 ° C for 4 hours.

The mixture was cooled, water and ethyl acetate were added, the organic layer was separated, washed with water and then with saturated sodium chloride solution, dried over magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The residue is purified by silica gel column chromatography eluting with a dichloromethane / methanol 98/2 mixture. Crystallization from diisopropyl ether yielded 0.2 g of a white solid, m.p. 8789 ° C.

Example 3A (Compound No. 17A)

2 - [[3- [5- [6- (Cyclopropylmethoxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] methylamino] -N- (cyclopropylmethyl) acetamide

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

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

The alcoholic phase is separated after settling and this phase is concentrated, water is added and the mixture is extracted with ethyl acetate. The organic phase is dried over magnesium sulphate and the solvent is evaporated off under reduced pressure. 30.44 g of an oily product are obtained, which product is used as is in the following stage.

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 heated in an oil bath at 50 ° C for 2 hours.

Remove the heating and, while stirring the mixture, at a temperature not exceeding 40 ° C, add 6.0 g (17.5 mmol) of 5- [6- (cyclopropylmethoxy) -1-naphthyl] -1,3-dioxane-2-propanamine dropwise. in 7 ml of tetrahydrofuran.

The solvent was evaporated under reduced pressure, the residue was taken up in toluene, this solution was evaporated under reduced pressure, and the residue was dried.

· E e e e e e e e e e e e e e e · ·

- [(Λ · · · · ·)

Αν | · ··· · «· ···· ·· ··

5.84 g (15.8 mmol) of a white solid are obtained. This was dissolved in 40 ml of tetrahydrofuran in a 250 ml round-bottom flask, boiling under argon, and a suspension of 1.2 g of lithium aluminum hydride in 43 ml of tetrahydrofuran was added and stirring was continued for 4 hours.

The mixture was cooled in an ice-water bath, 9 ml of sodium potassium tartrate was added dropwise and stirring was continued overnight.

The mixture was filtered and the filtrate was evaporated under reduced pressure to give 5.89 g of an oily product.

0.23 g of this product is dissolved in 2-propanol and treated with one equivalent of hydrogen chloride in 2-propanol to give 0.188 g of hydrochloride, m.p. 144-148 ° C.

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

0.24 ml (2.81 mmol) of cyclopropanmethanamine, 20 ml of dioxane and 0.4 ml of triethylamine are introduced into a 250 ml round-bottom flask and a solution of 0.22 ml (2.81 mmol) of chloroacetyl chloride in 10 ml of dioxane is added dropwise. is stirred at room temperature for 9 hours. 30 ml of water, 1 g of potassium carbonate and 1 g (2.81 mmol) of 5- [6- (cyclopropylmethoxy) -1-naphthyl] -N-methyl-1,3-dioxane-2-propanamine are added and the mixture is heated for 3 hours. to 80 ° C.

The mixture was cooled, water and ethyl acetate were added, the organic phase was separated, washed with water and brine, dried over magnesium sulfate and filtered, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography eluting with dichloromethane and of methanol 98/2. 0.62 g of product is obtained, which is dissolved in ethanol. After treatment with one equivalent of oxalic acid, 0.5 g of a white solid is obtained, 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 20 ml of 1-methyl-2-pyrrolidinone were added in argon The mixture was introduced into a 250 ml round bottom flask, stirred, 3.86 g (49.5 mmol) of sodium sulfide was added and the mixture was heated in an oil bath at 150 ° C overnight.

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

The purified fractions were treated with pentane and sonication, with ethyl acetate and diisopropyl ether. Finally, 1.87 g of solid are isolated, m.p. 135-137 ° C.

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

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

• · · ··· · · · ·····

-λ · · · · · _ · _ ··· ··· ··· ··· ···

The solvent was evaporated under reduced pressure using toluene, the residue was taken up in water and ethyl acetate and the solid was filtered off. Rinsing with water and ethyl acetate and drying gave 2.74 g of a solid.

After separation of the two phases once settling has occurred, the organic phase is washed, dried, filtered and the solvent is evaporated to give an additional 1.7 g of solid, i.e. a total of 4.44 g of compound is obtained.

0.3 g of this product is crystallized from a 6/4 ethanol / water mixture and finally 0.2 g of compound is isolated, m.p. 140142 ° C.

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 ethanol and 43.4 ml 30 The% sodium hydroxide solution is introduced into a 250 ml round bottom flask and the mixture is heated to boiling for 24 hours.

It is then allowed to cool, the alcoholic phase is separated after settling, this phase is evaporated and the residue is taken up in water and extracted with dichloromethane. The organic phase was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. This solution was filtered and the solvent was evaporated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a dichloromethane / methanol / aqueous 90/10/1 mixture of ammonia.

1.87 g of solid are obtained, which solid is used as is in the following stage. Its hydrochloride is prepared from a 0.1 N solution of hydrogen chloride in 2-propanol. Mp 180183 ° C.

4A.4. 5- (6-Ethoxy-1-naphthyl) -N- (phenylmethyl) -1,3-dioxane-2-propanamine · Η * 3 ·· «·· ··

1.63 g (5.17 mmol) of 5- (6-ethoxy-1-naphthyl) -1,3-dioxane-2-propanamine dissolved in 450 ml of methanol are introduced into a 100 ml round bottom flask equipped with a Dean-Stark apparatus. which allows the introduction of 0.604 g (5.69 mmol) of benzaldehyde and the mixture is heated to boiling until its volume is reduced to a third of the original volume.

The mixture was allowed to cool, placed in an ice bath, 1.56 g (41.3 g) of sodium tert-borohydride was added portionwise, and the mixture was stirred overnight.

The solvent 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, the solvent is evaporated under reduced pressure and the oil is purified by silica gel column chromatography eluting with 95/5 dichloromethane / methanol. .

1.15 g of base are obtained, 0.1 g of which is used for the preparation of the hydrochloride by dissolving in hot 2-propanol, adding 2.4 6 ml of 0.1N hydrogen chloride in 2-propanol, evaporating the solvent under reduced pressure, trituration and vacuum drying. 0.97 g of the hydrochloride of melting point 206-208 ° C is obtained.

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-dioxan-2-propanamine dissolved in 7 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-chloroacetamide are placed in a 50 ml round bottom flask and the mixture is refluxed for 5 hours. The mixture is allowed to cool, water and ethyl acetate are added, the organic phase is separated, the aqueous phase is extracted again, the organic phase is washed twice with water and once with saturated sodium chloride solution, dried over magnesium sulphate and filtered, The solvent is evaporated off under reduced pressure and the residue is purified by means of a solvent. silica gel column chromatography 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, which is dissolved in hot 2-propanol and 12.3 ml of 0.1N hydrogen chloride in 2-propanol are added. Evaporation of the solvent under reduced pressure, trituration of the residue from diisopropyl ether, filtration and drying in vacuo yielded 0.54 g of the hydrochloride, m.p. 190193 ° C.

Example 5A (Compound No. 20A)

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

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

0.5 g (1.23 mmol) of 5- (6-ethoxy-1-naphthyl) -N- (phenylmethyl) -1,3-dioxane-2-propanamine suspended in 15 ml of acetonitrile, 0.42 g ( 3.07 mmol) of potassium carbonate and 0.2 ml (1.84 mmol) of ethyl 2-bromoacetate were added and the mixture was heated at 60 ° C for 2.5 hours.

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

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

0 · 0 0 0 0 0 • 0000000 «0 00 000 000 0 * 00 00 00

0.58 g (1.18 mmol) of ethyl 2 - [[3- [5- (6-ethoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] (phenylmethyl) amino] acetate was added. Dissolve in a few ml of ethanol, add 5 ml of 33% methanamine in ethanol and place in the oven for 7 days.

The solvent was evaporated under reduced pressure to give 0.8 g of an oily product which was purified by silica gel column chromatography eluting with dichloromethane / methanol 98/2 to give the pure base as an oil.

After treatment with 10.5 ml of 0.1N hydrogen chloride in 2-propanol, evaporation of the solvent, trituration from diisopropyl ether, filtration and drying, 0.37 g of the target hydrochloride is obtained, m.p. 88-90 ° C.

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

Starting from 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 g of ethyl acetate). (1 mmol) of bromocyclopentane and using the same conditions as described in Example 4A.2 at 80 ° C to give 4.88 g of the crude compound. This compound (0.388 g) is purified by silica gel column chromatography eluting with a dichloromethane / methanol 90/10 mixture. After recrystallization from ethanol / water and then drying in the presence of phosphorus pentoxide, 0.22 g of compound with a melting point of 136-137 ° C is isolated.

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

Starting from 4.5 g (11.3 mmol) of N- [3- [5- (6-cyclopentyloxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] acetamide, the procedure is the same, As described in Example 4A, c is described in Example 4A. 3 to give 1.52 g of base, from which 1.15 g of hydrochloride is prepared.

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 benzaldehyde, proceed under the same conditions, as described in Example 4A.4 to give 0.48 g of base, from which 0.435 g of hydrochloride is prepared with a melting point of 186-190 ° C.

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

Starting from 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 working under the conditions described in Example 4A.5 to give 0.640 g of base as an oil from which 0.628 g of hydrochloride is obtained, m.p. 212215 ° C.

Example 7A (Compound No. 26A)

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

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

Starting from 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 (15, 3 mmol) of (bromomethyl) benzene and working under the conditions described in Example 4A.2 to give 4.67 g of the product from which 0.3 g is recrystallized from ethanol / water 6/4 to give 0, 15 g of white solid, m.p. 138-140 ° C.

• · ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

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

Starting from 4.06 g of N- [3- [5 - [(6- (phenylmethoxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] acetamide and proceeding as described in of Example 4A.3 to give 3.2 g of an oily product which was used in the next step without purification.

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 benzaldehyde and then 0.904 g Sodium perborate (23.9 mmol) and proceed as described in Example 4A.4 to give 0.41 g of base, from which 0.190 g of hydrochloride is prepared from 0.1 g. M.p. 185-189 ° C.

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

Starting from 0.30 g (0.64 mmol) of 5- (6- (phenylmethoxy) -1-naphthyl) -N (phenylmethyl) -1,3-dioxane-2-propanamine and 0.072 g (0.768 mmol)

Of 2-chloroacetamide and worked up as in Example 4A.5 to give 0.310 g of base as an oil from which 0.285 g of hydrochloride was prepared. Melting point 170-175 ° C.

Table A, which follows, illustrates the chemical structures and physical properties of some compounds of Formula IA.

In columns R x, R ₂ and R ₃ , cC ₃ H is _a cyclopropyl group, c C ₅ H ₉ is a cyclopentyl group, and C ₅ H ₅ is a phenyl group.

In the column, salt means the compound in the form of a base, ox.

means oxalate (or ethanedioate), fum means fumarate (or (E) -2-butenedioate) and HCl means hydrochloride; the acid / base molar ratio is indicated in parentheses.

• ·

In the column m.p. (° C) means (d) the melting point with decomposition.

All compounds are trans isomers ( ¹ H NMR).

Table A

C. r ₃ Salt mp (° C) IA -CHjCCjiís -ch ₂ ch ₃ -nhch ₃ - 90-92 2A -CH ₂ C ₃ H ₅ -ch ₂ ch ₃ -NHCH ₂ C ₃ H ₅ HCI (2: 1) 74 - 3A -CH ₂ C ₃ H ₅ -ck ₂ ch ₃ -NHcC ₃ H _s - 87-89 4A -CH ₂ C ₃ H ₅ -CH ₂ C ₃ H _s -nh ₂ HCI (2: 1) 63 d SA -CHjCCjHj -CH ₂ C ₃ H _s -nhch ₃ HCI (2: 1) 78-80 6A CH 3 CC 1 H 3 CH 2 CC 3 H 5 -NHCH ₂ C ₃ H ₅ - 92-96 7A -CH ₂ C ₃ H ₅ -CH ₂ C ₃ H ₅ -NHcC ₃ H ₅ KC1 (2: 1) 80-B2 8A —OH 2 cC ₃ -ch ₂ c h h ₅ -OCHjCHj HCI (2: 1) 66-63 9A -CH ₂ C ₃ H ₅ -CH ₂ C ₅ H ₅ -nh ₂ - 135-137 10A -CH ₂ C ₃ H ₅ -CH ₂ C _e H _p -nhch ₃ - 115-117 11A -CH ₂ C ₃ H _s -CH ₂ C _e H ₅ -NHCH ₂ C ₃ H ₅ HCI (2: 1) 84-86 12A -CH ₂ C ₃ H ₅ -CH ₂ C ₄ H _p -NHcC ₃ H ₅ HCI (2: 1) 90-92 13A -CH ₂ C ₃ H ₅ -ch ₃ -OCHjCHj HCI (2: 1) 128-130 14A -CH ₂ C ₃ H ₅ -ch ₃ -nh ₂ HCI (2: 1) 98-110 15A -CH ₂ C ₃ H _s -CH ₃ -NHCHi - 94-96

• ·

C. * 1 r ₂ * 3 Salt mp (° C) 16 A -CHjCCjHj -ch ₃ -NHcC ₃ H _s HCl (1: 1) 92-94 17A -CH ₂ C ₃ H ₅ -ch ₃ -NHCH ₂ C ₃ H ₅ ox. (1: 1) 156-158 18A QÍjCCjHj -ch ₂ ch ₃ -NHj - 127-129 19A -CHjCHj -CH ₂ C _with H _s -NHj HCl (1: 1) 190-193 20A -CHjCHj -ch ₂ c $ h ₅ -nhch ₃ HCl (1: 1) 88-90 21A -CH (CH _{3) 2} -ch ₂ c _s h ₅ -nh ₂ HCl (1: 1) 174-176 22A -CH (CH _{3) 2} -O ₂ C _e H _p -nhch ₃ HCl (1: 1) 88-90 23A -cC ₅ H, -CH ₂ C ₆ H _p -nh ₂ HCl (1: 1) 212-215 24A - (CH ₂ ) ₃ CH ₃ -ch ₂ c ₆ h ₅ -nh ₂ HCl (1: 1) 192-195 25A - (CH ₂ ) ₃ ch ₃ -ch ₂ c ₆ h _p -nhch ₃ ox. (1: 1) 68-70 26A -ch ₂ c ₆ y ₅ -CHjCsKs -nh ₂ HCl (1: 1) 170-175 27A - (CH ₂ ) ₃ CH ₃ -ch ₃ -nh ₂ - 120-121 28A -CH ₂ C _with H _s -ch ₃ -nhch ₃ - 114-116 29A -CH ₂ C _with H _s -ch ₂ c ₆ h ₅ -nhch ₃ - 108-110 30A -CH ₂ C ₅ H _t -ch ₃ -NH HCl (1: 1) 75-85 31A H -CH ₂ C _with H ₅ -nh ₂ - 90 (d) 32A -cC _with H, -ch ₂ c ₆ to _p -nhch ₃ - - 116-118 33A -cC _with H, -ch ₃ -nh ₂ - 138-140 34A -ch ₂ ch ₃ ch ₃ -NHj fum (1: 1) 161-162

9 9 9 9 9 9 9 9 10 11 12 13 14 15 16 17 18 19 20 ··· · «··

In the general formula IB

R is either hydrogen or CH ₂ COY, where Y is a hydroxyl or C 1 -C 4 alkoxy group, or alternatively CH ₂ CONR ₁ R ₂ , wherein R 1 and R ₂ are independently hydrogen or alkyl containing 1-4 carbon atoms,

X is oxygen or sulfur or CH ₂ .

m is 0 or 1 and n is 0, 1 or 2.

Compounds of formula IB may exist in the form of cos or trans stereoisomers or mixtures of such isomers; furthermore, with respect to the chirality of the ring attached to the nitrogen atom, certain compounds may exist in the form of diastereoisomers and / or enantiomers. They may also exist in the form of free bases or acid addition salts.

Compounds of formula IB may be prepared by the method illustrated in Scheme B which follows.

The 2- (6-methoxy-1-naphthyl) propane-1,3-diol of formula IIB is reacted with 4,4-diethoxybutanamine of formula IIIB in a boiling aprotic solvent such as toluene and in the presence of dry hydrogen chloride dissolved in diethyl ether as catalyst, to to obtain 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine of formula IVB and this compound is then reacted with a ketone of formula VB wherein X, m and n are as defined above in the presence of a reducing agent such as is sodium borohydride or any other equivalent reagent, in neutral or acidic medium, under reductive amination conditions known to those skilled in the art. A compound of formula (IBa) is obtained which corresponds to formula (IB) when R is hydrogen.

• · ·

(IIB) IXIB

The compound of formula (IBa) may then, if appropriate, be alkylated with C1-C4 alkyl-2-bromoacetate in a polar aprotic solvent, for example acetonitrile, in the presence of a base, for example potassium carbonate, to give a compound of formula (IBb) wherein Y is C 1 -C 4 alkoxy.

· · E e e e e e e e e e e e e e e e

If appropriate, the compound can be saponified under conditions known to those skilled in the art to give a compound of formula IBb wherein Y is a hydroxyl group. The formula IBb corresponds to the formula IB when R ₂ is a group of the formula CH ₂ COY.

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

An amide of formula IBc can also be obtained directly from a compound of formula IBa by alkylation with a halide of formula Z-CH ₂ -CO-NR ₂ R ₂ , wherein Z is chlorine or bromine and R ₂ and R ₂ are as defined above, in the polar an aprotic solvent such as N, N-dimethylformamide in the presence of a base such as potassium carbonate.

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 well as ketones of formula VB.

The examples that follow illustrate in more detail the preparation of some compounds of Formula IB. Elemental analyzes and IR and NMR spectra confirm the structures of the compounds obtained. The compound numbers in parentheses correspond to those in Table B below.

Example IB (compound number IB)

Ethyl 2 - [(2,3-dihydro-1H-inden-1-yl) [3- (5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl] amino] acetate hydrochloride

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

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 hydrogen chloride in of ether was introduced into a 11-liter round-bottom flask containing 300 ml of toluene and heated to reflux for 2 hours.

The mixture was cooled and then the precipitate was filtered off and washed with diethyl ether.

12.2 g of crude hydrochloride are obtained in the form of a beige solid, m.p. 224-226 ° C.

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

Dissolve 3.0 g (9,95 mmol) of 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine in 250 ml of ethanol in a 500 ml round-bottom flask, add 1,32 g (9.95 mmol) of 2,3-dihydro- (1H) -inden-1-one and the mixture was heated to boiling overnight.

The mixture was allowed to cool, potassium borohydride (2 g) was added and stirring continued for 2.5 hours. Water (100 ml) was added and the mixture was extracted with ethyl acetate (3.times.50 ml). The solvent was evaporated from the organic phase and the residue was purified by silica gel column chromatography eluting with a 9/1 mixture of dichloromethane and methanol. 2.79 g of an oily product are obtained.

1B.3. Ethyl 2 - [(2,3-dihydro-1H-inden-1-yl) [3- [5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] amino] hydrochloride acetate

1.88 g (4.5 mmol) of N- (2,3-dihydro-1H-inden-1-yl) -5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine, 8 g (5.8 mmol) of potassium carbonate, 0.96 g (5.8 mmol) of ethyl 2-bromoacetate, and a catalytic amount of sodium iodide and 35 ml of N, N-dimethylformamide are placed in a 250 ml round-bottom flask and the mixture is stirred Heat at 60 ° C for three hours. 100 ml of water are added and the mixture is extracted three times with 150 ml of ethyl acetate and the organic phase is washed with an aqueous solution of sodium chloride and then with an aqueous solution. Sodium bicarbonate. After drying and evaporation of the solvent, 3.5 g of an oily product are obtained which is purified by silica gel column chromatography eluting with a gradient of 5% to 10% ethyl acetate in cyclohexane. 1.97 g of pure base are obtained, of which 0.55 g (1 mmol) is used for the preparation of the hydrochloride using 11 ml of a 0.1 N solution of hydrogen chloride in 2-propanol. After washing with diethyl ether, 0.44 g of hydrochloride is obtained. Mp 88-89 ° C.

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

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

Its hydrochloride is prepared using 24 ml of a 0.1N solution of hydrogen chloride in 2-propanol. After washing with diethyl ether, 0.98 g of hydrochloride is isolated. Melting point 112-114 ° C.

Example 2B (Compound No. 6B)

5- (6-Methoxy-1-naphthyl) -N- (1,2,3,4-tetrahydro-1-naphthyl) -1,3-dixoan-2-propanamine fumarate

3.0 g (9.95 mmol) of 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine, 90 mL of ethanol and 1.45 g (9.95 mmol) of 3,4- The dihydrohydro-naphthyl (2H) -one was placed in a 250 ml round bottom flask and the mixture was heated to boiling for 48 hours. The mixture is allowed to cool, 3 g (55.6 mmol) of sodium borohydride are added and the mixture is stirred at room temperature for 2 days.

Water is added and 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 an oily product are obtained, which product is purified by silica gel column chromatography, eluting with a 9/1 mixture of dichloromethane and methanol. 1.6 g of base are obtained, of which 0.4 g is used for the preparation of fumarate in 6 ml of ethanol with 0.11 g of fumaric acid. 0.27 g of salt is obtained. Melting point 134135 ° C.

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) amine] acetamide hydrochloride

0.85 g (1.97 mmol) of 5- (6-methoxy-1-naphthyl) -1- (1,2,3,4-tetrahydro-1-naphthyl) -1,3-dioxane-2-propanamine, 20 ml of acetonitrile, 0.28 g (2.99 mmol) of 2-chloroacetamide, 0.54 g (3.94 mmol) of potassium carbonate and 0.29 g (1.9 mmol) of sodium iodide are placed in a 250 ml round-bottomed flask. The mixture was heated to reflux for 4 hours. 50 ml of water and 25 ml of ethyl acetate are added, the organic layer is separated, the aqueous layer is extracted twice with 25 ml of ethyl acetate, the solvent is evaporated off under reduced pressure and the residue is purified by silica gel column chromatography eluting with dichloromethane / methanol 9/1.

0.6 g of base is obtained, from which 0.25 g of hydrochloride is prepared with a 0.1N solution of hydrogen chloride in 2-propanol. M.p. 142-143 ° C.

· · · · · · · «« · · · · · · · · · · · · ·

Example 5B (Compound No. 13B)

N- (3,4-dihydro-2H-1-benzopyran-4-yl) -5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine hydrochloride g (6.6 mmol) 5 - (6-Methoxy-1-naphthyl) -1,3-dioxane-2-propanamine is placed in a 250 ml round-bottom flask and 150 ml of ethanol and 0.983 g (6.6 mmol) of 3,4-dihydro-2H are added. Of 1-benzopyran-4-one and the mixture was heated to boiling overnight.

The mixture is cooled, 2 g of sodium borohydride are added, the mixture is stirred for 1 hour, 100 ml of water are added, 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 a solid are obtained, which is purified by chromatography on silica gel, eluting with a 9/1 mixture of dichloromethane and methanol, to give 1.3 g of the base as a yellowish oil.

0.30 g of this base was used to prepare the hydrochloride using 5 ml of a 0.1 M solution of hydrogen chloride in 2-propanol. 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-methoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] amino hydrochloride acetamide

Starting from 0.5 g (1.15 mmol) of N- (3,4-dihydro-2H-1-benzopyran-4-yl) -5- (6-methoxy-1-naphthyl) -1,3-dioxan-2. -propanamine and 0.16 g (1.72 mmol) of 2-chloroacetamide were carried out under similar conditions to those described in Example 4B and chromatographed to give 0.37 g of the base compound from which 0.17 g was obtained. g of hydrochloride. M.p. 165-166 ° C.

Table B below illustrates the chemical structures and physical properties of some compounds of Formula IB.

In the column, salt means the compound in the form of a base, ox. means oxalate (or ethanedioate), fum means fumarate (or (E) -2-butenedioate) and HCl means hydrochloride; the acid / base molar ratio is indicated in parentheses.

Table B

(IB)

C. R X m n 1 Salt m.p. (° C) IB -CH ₂ CO ₂ CH ₃ CH ₃ ch ₂ 0 1 HCl (1: 1) 88-90 2B -CHjCONHCKj ch ₂ 0 1 HCl (1: 1) 112-114 3B H ch ₂ 1 0 HCl (1: 1) 220-221 43 -CH ₂ CO ₂ CH ₃ CH ₃ CHj 1 0 HCl (1: 1) 77-79 SB -ch ₂ conhch ₃ CHj 1 0 ox. (1: 1) 84-86 6B H CHj 0 2 fum. (1: 1) 134-136 7B -CH ₂ CO ₂ CH ₂ CH ₃ ch ₂ 0 2 HCl (1: 1) 77-79 8B -ch ₂ conhch ₃ CHj 0 2 HCl (1: 1) 98-110 9B -ch ₂ conh ₂ CHj 0 2 HCl (1: 1) 142-143 10B -CH ₂ CO ₂ CH ₃ CH ₃ CHj 1 1 HCl (1: 1) 74-76 11B -ch ₂ conh ₂ CHj 1 1 HCl (1: 1) 208-210 12B -CHjCONHCHj CHj 1 1 fusi. (1: 1) 82-122 13B H 0 0 2 HCl (1: 1) 172-173 14B -CHjCONHj 0 0 2 HCl (1: 1) 165? 166 15B -CH ₂ CONHCH ₃ 0 0 2 HCl (1: 1) 117-119

• · • ·· ··

C. R X tn n Salt mp (° c) 16B H with 0 2 HCl (1: 1) 192-193 17B -CH ₂ CO ₂ CH ₂ CH ₃ with 0 2 HCl (1: 1) 66-68 18B -CHjCONHCHj with 0 2 HCl (1: 1) 114-116 19B -CHjCONHj ch ₂ 0 1 - 106-108 20B H ch ₂ 1 1 HCl (1: 1) 211-213 21B -CH ₂ CO ₂ H ch ₂ 0 2 - 90-92 22B -ch ₂ every ₂ h 0 0 2 - 108-112 233 H ch ₂ 0 1 HCl (1: 1) 124-125

(*) Compounds in which a carbon atom attached to a nitrogen atom is chiral are racemic. In the column, salt means the compound in the form of a base, ox. means oxalate (or ethanedioate), fum means fumarate (or (E) -2-butenedioate) and HCl means hydrochloride; the acid / base molar ratio is indicated in parentheses. Melting points. (° C) are given in the last column.

In the general formula IC

R 1 is either hydrogen or CH ₂ COY, wherein

Y is hydroxyl or alkoxy having 1 to 4 carbon atoms or alternatively a group of general formula CH2CONR4R5 in which _R4 and _R5 are independently hydrogen or alkyl of 1 to 4 carbon atoms and

R ₂ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-2-pyrrolyl, 2-furyl, 2-thienyl or 1,3-thiazol-2-yl group, wherein the respective the formulas are as follows:

• φ · «· φ · · · · · · · · · · · · · · · · · · · · · φ · φφ

Compounds of formula IC may 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 acid addition salts.

Compounds of formula (IC) may be prepared by the procedure illustrated in Scheme C which follows.

2- (6-Methoxy-1-naphthyl) propane-1,3-diol of formula IIC is reacted with 4,4-diethoxybutanamine of formula HIC in a boiling aprotic solvent such as toluene and in the presence of hydrogen chloride dissolved in diethyl ether as catalyst to give 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine of formula IVC, which is then reacted in a protic solvent such as methanol at 25 to 60 ° C to remove water formed during the reaction, with an aldehyde of formula Vc wherein R ₂ is as defined above, and the resulting imine is reduced, for example using a reducing agent such as sodium borohydride or an equivalent agent, in neutral or acidic medium, under reductive amination conditions known to those skilled in the art . This gives a compound of formula ICa, which corresponds to the general formula IC, wherein R 1 is hydrogen.

If appropriate, the compound of formula ICa may be alkylated with a haloacetate of formula Z-CH ₂ -CO ₂ -alkyl containing from 1 to 4 carbon atoms in the alkyl group, wherein Z is chlorine or bromine, in a polar aprotic solvent such as acetonitrile, in the presence of a base such as potassium carbonate to give a compound of formula Icb wherein Y is C 1 -C 4 alkoxy.

If desired, the compound can be saponified under conditions known to those skilled in the art to give a compound of formula ICb wherein Y is a hydroxyl group. The formula IC b corresponds to the formula IC wherein R ₂ is a group of the formula CH ₂ COY.

Scheme C

(IIC) (IIIC) last

ÍVC)

If appropriate, a compound of Formula ICb may then be reacted with an amine HNR ₄ R ₅ wherein R ₄ and R _s are as defined above, to give the amide of the ICC. This reaction is carried out under standard conditions known to those skilled in the art.

··· · ····· · «· · · ······ ♦ · · · · · · · · · · ·

An amide of formula ICc can also be prepared directly from a compound of formula ICa by alkylation using a halide of formula Z-CH 2 -CO-NR ₄ R ₅ , wherein Z is chlorine or bromine and R ₄ and R ₅ are as defined above, in polar aprotic a solvent such as N, N-dimethylformamide in the presence of a base such as potassium carbonate.

The formula ICc corresponds to the formula IC, wherein R _x is a group of the 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 as well as aldehydes of formula VC.

The examples that follow illustrate in more detail the preparation of some compounds of Formula IC. Elemental analyzes and IR and NMR spectra confirm the structures of the compounds obtained.

The compound numbers listed in Table C below.

in parentheses correspond to the numbers given

Example IC (compound number IC)

5- (6-Methoxy-1-naphthyl) -N- (4-pyridylmethyl) -1,3-dioxan-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 70 ml of dry of hydrogen chloride gas dissolved in diethyl ether is placed in an 11 round bottom flask containing 300 ml of toluene and the mixture is heated at reflux for 2 hours.

The mixture was cooled and the precipitate was filtered off and washed with diethyl ether.

9 · 9 · · · · · · · · · · · · · · ·

12.2 g of crude hydrochloride are obtained in the form of a beige solid. Melting point 224-226 ° C.

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

0.5 g (1.67 mmol) of 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine and 200 ml of methanol are placed in a 250 ml round bottom flask, 0.178 g (1 (67 mmol) of pyridine-4-carboxaldehyde and the mixture was heated at 100 ° C for 2 h.

The mixture was allowed to cool, 0.5 g of sodium borohydride was added and the mixture was stirred for 0.5 hour.

Half of the methanol is evaporated under reduced pressure, 100 ml of water are added, the mixture is extracted three times with 20 ml of ethyl acetate, the organic layer is evaporated under reduced pressure and the residue is purified by silica gel column chromatography eluting with dichloromethane / methanol 9/1. .

0.57 g of base is obtained in the form of an oil.

0.15 g of this product is dissolved in 5 ml of a 0.1N solution of hydrogen chloride in 2-propanol. After washing with diisopropyl ether and drying, 0.12 g of dihydrochloride is obtained. Mp 207-208 ° C.

Example 2C (Compound No. 3C)

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

Dissolve 1,2 g (3 mmol) of 5- (6-methoxy-1-naphthyl) -N- (4-pyridylmethyl) -1,3-dioxane-2-propanamine in 200 ml of acetonitrile, add 0,138 g (0, 9 mmol) of sodium iodide, 0.828 g (6 mmol) of potassium carbonate and 0.42 g (4.5 mmol) of 2-chloroacetamide and the mixture was heated under reflux for 3 hours.

«·

»· 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 · ··

Since the reaction is not complete, another 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 are added and the mixture is heated to boiling for a further 1 hour.

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

The base is converted into a salt with 8 ml of a 0.1 N solution of hydrogen chloride in propanol. 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-Methoxy-1-naphthyl) -N- (2-thiazolylmethyl) -1,3-dioxane-2-propanamine

2.4 g (8 mmol) of 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine, 700 ml of methanol and 1 g (8.8 mmol) of 1,3-thiazole-2- The carboxaldehyde was placed in a 100 ml round bottom flask equipped with a Dean-Stark apparatus and the mixture was distilled until the volume of the reaction mixture was reduced to about 200 ml.

The mixture was cooled, 2.4 g of sodium borohydride were added in portions and the mixture was allowed to stir overnight.

The methanol is evaporated under reduced pressure, the residue is taken up in water and ethyl acetate, the organic phase is separated, washed and dried over magnesium sulphate and the solvent is evaporated under reduced pressure. 3.17 g of base are obtained, from which 0.5 g is taken, from which the hydrochloride is prepared under the conditions described above. 0.5 g of the hydrochloride is obtained. Melting point 134-137 ° C.

• · · · · · · · · · ·

Example 4C (Compound No. 21C)

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

Starting from 0.7 g (1.75 mmol) of 5- (6-methoxy-1-naphthyl) -N- (2-thiazolylmethyl) -1,3-dioxane-2-propanamine and 0.2 g (2.1 mmol) of 2-chloroacetamide and working under the conditions described in Example 2C to give 0.76 g of the base from which 0.763 g of the hydrochloride is obtained. Melting point: 189-191 ° C.

Table C which follows illustrates the chemical structures and physical properties of some compounds of Formula IC.

In column R ₂ is C ₅ H ₄ N-2- 2-pyridyl, C ₅ H ₄ N-3- is 3-pyridyl, C ₅ H ₄ N-4- is 4-pyridyl, CH ₃ -1C ₄ H ₃ N-2 - is 1-methyl-2-pyrrolyl, C ₄ H ₃ O-2- is 2-furyl, C ₄ H ₃ S-2- is 2-thienyl and C ₃ H ₂ NS-2 is 1,3-thiazole- 2-yl.

In the column, salt means the compound in the form of a base, ox. means oxalate (or ethanedioate), fum means fumarate (or (E) -2-butenedioate) and HCl means hydrochloride; the acid / base molar ratio is indicated in parentheses.

In the column m.p. (° C) means d melting point with decomposition.

Table C

(IC)

C. r ₂ Salt mp (° C) IC H C _with H ₄ N-4- HCl (1: 1) 207-203 2C -ch ₂ every ₂ h C _with H ₄ N-4- - 115-125 3C -ch ₂ conh ₂ C _with H ₄ N-4- HCl (1: 1) 169-170 4C -CHjCONHCHj CjK ₄ N-4 HCl (1: 1) 80-90 5C H C ₅ H ₄ N-3 - 80-81 6C -CH ₂ CONH i C _with H ₄ N-3- HCl (1: 1) 199-200 7C -CH ₂ CONHCH ₃ C _with H ₄ N-3- ox. (1: 1) 138-140 8C H C _with H ₄ N-2- HCl (1: 1) 158-159 9C -CHjCONHj C ₅ H ₄ N-2- HCl (1: 1, 174-175 10C -CHjCONHCHj C _with H ₄ N-2- HCl (1: 1) 93-96 11C 5 CH ₃ -lC ₄ H ₃ N-2- HCl (1: 1) 183-186 12C -CHjCONHj CH ₃ -1-C ₄ H ₃ N-2- HCl (1: 1, 188 d 13C -CHjCONHCHj CH ₃ -lC ₄ H ₃ N-2- HCl (1: 1) 89-95 14C H C ₄ H ₃ O-2- HCl (1: 1) 186-187 15C -CHjCOjCHjCHj C ₄ H ₃ 0-2- HCl (1: 1, 6? -65

· · · · «· · · · · · · · · · • • * • • • • • • •

C. Rl r ₂ Salt mp (° C) 16C -CHjCONHj C ₄ H ₃ O-2- HCl (1: 2) 205-206 17C H C ₄ H ₃ S-2- HC1 (1: 1) 174-176 18C -CHjCONHj C ₄ H ₃ S-2- HCl (1: 2) 220-225 19C H C ₃ H ₂ NS-2 HCl (1: 2) 134-137 20C -CH ₂ CO ₂ CH ₂ CH ₃ C ₃ H ₂ NS-2 HCl (1: 2) 58-62 21C -CH ₂ CONH ₂ C ₃ H ₂ NS-2 HCl (1: 2) 189-191 22C -ch ₂ every ₂ h C ₄ H ₃ S-2- - 152-156 23C -CH 3 CO 3 H C ₄ H ₃ O-2- - 78-82

In the general formula ID

Y is hydroxyl, C 1 -C 4 alkoxy or NR ₄ R ₅ , wherein R ₄ and R ₅ are independently hydrogen or C 1 -C 4 alkyl; and

R 1 and R ₂ together with the nitrogen atom and the carbon atom 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; due to the presence of asymmetric carbon and to the -C (O) Y group, they may also exist in the form of enantiomers or mixtures of enantiomers. They may also exist in the form of free bases or acid addition salts.

Compounds of formula ID can be prepared by the procedure illustrated in Scheme D, which follows.

• I • II (IID)

Scheme D

(IIID)

H, C

Cl (IVB)

(VD) (ID)

H, C

2- (6-Methoxy-1-naphthyl) propane-1,3-diol of formula IID is reacted with 2- (3-chloropropyl) -1,3-dioxolane of formula IIID, in an acidic medium and in an aprotic solvent to give 2 - (3-chloropropyl) -5- (6-methoxy-1-naphthyl) -1,3-dioxolane of formula IVD and finally this compound is reacted with an amine of formula IVD · · ····· · · · · · · ······ * * · · · · ·

VD, wherein Y, R 1 and R ₂ are 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 20 to 110 ° C.

- (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. The amines of formula VD are commercially available or described in the literature.

The examples that follow illustrate in more detail the preparation of some compounds of Formula ID. Elemental analyzes and IR and NMR spectra confirm the structures of the compounds obtained. The compound numbers in parentheses correspond to those in Table D below.

Example ID (Compound ID)

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

ID.1. 2- (3-Chloropropyl) -5- (6-methoxy-1-naphthyl) -1,3-dioxane g (21.5 mmol) 2- (6-methoxy-1-naphthyl) -propane-1,3- diol, 3.7 mL (28.05 mmol) of 2- (3-chloropropyl) -1,3-dioxolane and then 40 mL of hydrogen chloride in ether were placed in a 500 mL round bottom flask containing 150 mL of toluene and heated for 6 hours to boil.

The mixture was allowed to cool, 100 mL of aqueous 5% sodium bicarbonate solution was added, and the mixture was extracted twice with 100 mL of ethyl acetate. The organic phase is washed with water, dried over magnesium sulphate and filtered, the solvent is evaporated off under reduced pressure and the residue is purified by silica gel column chromatography eluting with a mixture of petroleum ether and ethyl acetate 9/1. 3.2 g of a white solid are obtained, which solid is used as is in the following stage.

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · 0 ·

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

0.32 g (1 mmol) of 2- (3-chloropropyl) -5- (6-methoxy-1-naphthyl) -1,3 dioxane, 0.22 g (1.2 mmol) of ethyl L-prolinate, 0 3 g (2.2 mmol) of potassium carbonate and then 0.29 g (2 mmol) of potassium iodide are introduced into a 50 ml round-bottom flask containing 10 ml of Ν, Ν-dimethylformamide and the mixture is heated at 100 ° C for 4 hours.

The mixture is allowed to cool, 50 ml of water are added and the mixture is extracted twice with 70 ml of ethyl acetate, the organic phase is washed with water, dried over magnesium sulphate, the solvent is evaporated under reduced pressure and the residue is purified by silica gel column chromatography of dichloromethane / methanol 99.5 / 0.5 to 99/1.

0.22 g of compound is obtained, which is crystallized as oxalate from ethyl acetate. Melting point 116-118 ° C.

Example 2D (compound number 2D)

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

0.5 g (1.6 mmol) of 2- (3-chloropropyl) -5- (6-methoxy-1-naphthyl) -1,3-dioxane, 0.2 g (1.9 mmol) of L-prolinamide, 2 g (1.6 mmol) of potassium carbonate and then 0.48 g (3.2 mmol) of potassium iodide are placed in a 50 ml round-bottom flask containing 15 ml of Ν, Ν-dimethylformamide and the mixture is heated at 110 DEG C. for 3.5 hours. Deň: 32 ° C.

The mixture was allowed to cool, water (60 ml) was added and the mixture was extracted with ethyl acetate (2.times.80 ml). The organic layer was washed with water, dried over magnesium sulfate and filtered, the solvent was evaporated under reduced pressure and the residue purified by silica gel column chromatography eluting with a gradient of dichloromethane / methanol 99/1 to 97/3. 0.3 g of compound is obtained. recrystallized as a base from 2-propanol. Melting point 164-166 ° C.

Example 3D (compound number 6D)

2- [3- [5- (6-Methoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] -N-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide oxalate

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

1.75 g (8.5 mmol) of ethyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate are placed in a 100 ml round bottom flask containing 25 ml of a 33% solution of methylamine in ethanol and the mixture is stirred for 20 hours at 25 ° C. Deň: 32 ° C. Evaporate to dryness under reduced pressure to give 1.7 g of the compound as a colorless oil, which is used without purification in the next step.

3D.2. 2- [3- [5- (6-Methoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] -N-methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide oxalate

0.5 g (1.6 mmol) of 2- (3-chloropropyl) -5- (6-methoxy-1-naphthyl) -1,3 dioxane, 0.3 g (1.6 mmol) of N-methyl-1 2,3,4-tetrahydroisoquinoline-3-carboxamide, 0.2 g (1.6 mmol) of potassium carbonate and then 0.23 g (1.5 mmol) of potassium iodide are placed in a 100 ml round-bottom flask containing 2 0 ml of acetonitrile and the mixture was heated at 80 ° C for 8 hours.

The mixture was allowed to cool, 20 mL of water was added and the resulting mixture was extracted with 20 mL of ethyl acetate. The organic phase was washed with water, dried over magnesium sulphate and filtered, the solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography eluting with a dichloromethane / methanol 98/2 mixture. 0.12 g (0.25 mmol) of compound is obtained, which is crystallized as oxalate from diisopropyl ether. Melting point 88-90 ° C.

• · · · · · · · · · · · · · ·

Table D, which follows, illustrates the chemical structures and physical properties of some compounds of Formula ID.

Column RiNCHRz denote pyrrole, Piper and isoch that R _x and R ₂ together with the nitrogen atom to which they are attached, a pyrrolidone ring, a piperidine ring or ring 1,2,3,4tetrahydroisochinolinový.

In the sul column, the compound represents the base, ox. means oxalate (or ethanedioate), fum means fumarate (or (E) -2-butenedioate) and HCl means hydrochloride; the acid / base molar ratio is indicated in parentheses.

In the column, mp (° C), d means the melting point with decomposition.

C. Y RjNCHRj Config. * Salt mp (®C) [a],, ⁰ ID -OCHjCHj pyrrol WITH OX. (1: 1) 116-118 -26 2D -NHj pyrrol with 164-166 n. d 3D -nhch ₃ pyrrol with - 119-121 -30 4D -och ₃ ch ₃ piper RS ox. (1: 1) 129-131 - 5D -NKCHj pyrrol RS - 99-101 - 6D -NHCHi isoch RS ox. (1 :) 88-90 -

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

The compounds of the present invention have been subjected to pharmacological tests which demonstrate that they are valuable as therapeutic agents.

Inhibition of the action of sodium channel agonists in neurons

The calcium flux caused by the depolarization stimulus of rat cortical synaptosomes can be measured using a fluorescence assay according to the method described by A. Deffois et al., Neurosciences Letters (1996) 220 117-120.

The effect of sodium channel agonists such as veratridine (10 μΜ) on intracellular calcium levels in this model is inhibited by compounds of the present invention at IC ₅₀ values (concentration that inhibits 50% response) of 0.1 to 10 μΜ.

Effects on convulsions induced in mice by supramaximal electric shock

The assay procedure is described in E.A. Swinyard and J.H. Woodhead, Antiepileptic Drugs, Raven Press, New York, pp. 111-126 (1982).

Ten minutes after intravenous administration of the test compound, the number of mice exhibiting convulsions (stretching of the forelimbs and hind limbs) is recorded immediately after application of the electrical current (0.4 sec, 60 mA, 50 Hz) using an Apelex ETC UNIT 7801 ™ device. The results are expressed as AD ₅₀ , which is the dose that protects 50 animals, calculated according to the procedure of JT Lichtfield and F. Wilcoxon (J. Pharm. Exp. Ther., 96, 99/113 (1949)), using Probit ™ software, starting with 3 or 4 doses, each given to a group of 8 mice. AD ₅₀ values of the most active compounds range from 1 to 10 mg / kg.

Antiischemické vlastnosti /

Compounds were subjected to a global cerebral ischemic test in mice.

Ischemia was caused by cardiac arrest induced by rapid intravenous administration of magnesium chloride. In this test, the survival time is measured, ie. the interval between the injection of magnesium chloride and the last visible breathing movement in each mouse. This last movement is considered to be the ultimate indicator of central nervous system functioning. Breathing stopped about 19 seconds after the injection of magnesium chloride.

Male mice (Charles River CD1) were tested in groups of ten. They were freely fed and watered before the test. Survival time was measured 10 minutes after intraperitoneal administration of the compounds of the present invention. The results are presented as the difference between the survival time measured in the group of ten mice receiving the compound and the survival time in the group of ten mice receiving the liquid vehicle. Relationships between changes in survival and dose of compound were plotted on a semi-logarithmic curve.

This curve makes it possible to calculate the three-second effective dose (ED ₃ -), ie. dose (in mg / kg) that provides a three-second increase in survival time relative to the untreated control group.

A three-second increase in survival time is both statistically significant and reproducible.

The ED ₃ values of the most active compounds of the present invention range from 0.05 to 0.2 mg / kg when administered intravenously.

··· · ····· · · · · · · · 9 · <· 999 999999 9999 99 99

Antinociceptive activity?

Antinociceptive activity was evaluated in rats during the second step of the formalin assay modified according to A. Tjolsen, O.-G. Berge, S. Hunskaar, J.H. Rosland and K. Hole, Pain (1992), 51, 5-17.

Formalin (5%) is injected subcutaneously (100 μΐ) into the foot arch of the left hind limb. Nocioception is evaluated for injected limb according to the total licking time between +20 to +35 minutes and by the number of shakes measured in 2-minute sequences every 5 minutes between +35 to +60 minutes.

The compounds are administered at doses of 30 and 60 mg / kg, as a suspension (water + Tween 80 at 1%), orally (5 ml / kg), 30 minutes before the formalin injection.

Compounds are considered to be active if, after treatment, a statistically significant reduction (p <0.05) of total licking time and / or shaking (calculated from area under the curve) compared to the values measured in animals receiving only the vehicle. ).

The activity threshold for the compounds of the present invention corresponds to a reduction of 35 to 40%. The most active compounds cause a 50% reduction at the 30 mg / kg dose when administered orally.

The test results show that the compounds of the present invention have neuroprotective properties and can therefore be used for the preparation of medicaments that are suitable for treating or preventing cerebrovascular diseases of ischemic or hypoxic origin (cerebral infarction, cranial or medullary trauma, cardiac or respiratory arrest, transient ischemic attack, perinatal asphyxia), glaiicoma, progressive neuro45 degenerative diseases (senile dementia such as Alzheimer's disease, vascular dementia, Parkinson's disease, Huntingdon's disease, olivopontocerebral atrophy, amyotrophic lateral sclerosis, neurodegenerative and viral disease) cerebral ischemic events associated with cardiac and vascular surgery and endovascular therapy.

Since the compounds of the present invention have anticonvulsant properties, they can be used to treat epilepsy. The compounds of the present invention also have analgesic properties and can therefore be used in the treatment of acute or chronic pain.

Finally, it is also contemplated to treat other diseases such as neuropathy, neurogenic pain (e.g., pain associated with neuropathy or migraine attacks), neurological convulsion and dyskinesia.

The compounds of the present invention may be in any form of a pharmaceutical composition suitable for enteral or parenteral administration, such as tablets, coated tablets, gelatin capsules, vaginal capsules, suspensions or drinking solutions such as syrups, vials and so on, in in combination with suitable additives and in dosages allowing daily administration of 1 to 1000 mg of the active ingredient.

Claims (6)

Claims Compound in the form of pure stereoisomer or mixtures of stereoisomers of formula IA wherein (IA) R 1 is hydrogen, a linear or branched alkyl group having 2 to 4 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms in the alkyl portion, a cycloalkylmethyl group having 3 to 6 carbon atoms in the alkyl portion, or a phenylalkyl group having 1 to 3 alkyl portions carbon atoms optionally substituted on the phenyl ring, R ₂ is hydrogen, linear or branched alkyl group having 1 to 4 carbon atoms, cycloalkyl-containing alkyl 3-6 carbon atoms, a cycloalkylmethyl group the alkyl portion contains 3-6 carbon atoms or phenylalkyl group the alkyl portion contains 1 to 3 carbon atoms optionally substituted on the phenyl ring, R ₃ is hydroxyl, C 1 -C 4 alkoxy or NR ₄ R ₅ , wherein R ₄ and R ₅ are independently hydrogen, linear or branched C 1 -C 4 alkyl, cycloalkyl containing in the alkyl moiety of 3 to 6 carbon atoms or a cycloalkylmethyl group containing in the alkyl moiety of 3 to 6 carbon atoms, in the form of a base or an acid addition salt. 2. A compound in the form of pure ¹ stereoisomer or mixtures of stereoisomers of formula IB R R is either hydrogen or CH ₂ COY, where Y is a hydroxyl or C 1 -C 4 alkoxy group, or alternatively CH ₂ CONR ₁ R ₂ , wherein R _x and R ₂ are each independently hydrogen or alkyl; (C 1 -C 4) group X is an oxygen or sulfur atom or a CH ₂ group, m is 0 or 1 and is 0, 1 or 2, in the form of the free base or acid addition salt. 3. A compound in the form of a pure stereoisomer or a stereoisomer of formula (IC) by mixture R 1 is either a hydrogen atom or a group of the formula CH ₂ COY, where Y is a hydroxyl group or a (C 1 -C 4) alkoxy group, or alternatively a group of the formula · Φ · · »· · · · · CH ₂ CONR ₄ R _S, wherein R ₄ and R _s are independently hydrogen or alkyl of 1 to 4 carbon atoms and R ₂ is 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-2-pyrrolyl, 2-furyl, 2-thienyl or 1,3-thiazol-2-yl group, in the form free base or acid addition salt. A compound in the form of the pure stereoisomer of the stereoisomers of the general formula ID or mixtures thereof (ID) Y is hydroxyl, alkoxy having 1 to 4 carbon atoms or a radical of the formula NR ₄ R ₅ wherein R ₄ and R _s are independently hydrogen or alkyl of 1 to 4 carbon atoms and R 1 and R ₂ together with the nitrogen atom and the carbon atom connecting them form a pyrrolidine ring, piperidine ring or 1,2,3,4-tetrahydroisoquinoline ring, in the form of the free base or an acid addition salt. A medicament comprising a compound according to any one of claims 1 to 4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4 in combination with an additive.