SK166199A3 - 5-naphthalen-1-yl-1,3-dioxane derivatives, preparation and therapeutic application - Google Patents

Abstract

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

Description

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

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 which is optionally monosubstituted or disubstituted on the atom

W is carboxymethyl, alkoxycarbonylmethyl, carbamoylmethyl optionally monosubstituted or disubstituted on nitrogen, 4- to 7-membered cyclic group optionally containing oxygen or sulfur, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl a group, 1-methyl-2-pyrrolylmethyl, 2-furylmethyl, 2-thienylmethyl or 1,3-thiazol-2-ylmethyl, or alternatively V and W together with the nitrogen atom carrying them form a pyrrolidinyl group, piperidyl or 1,2,3,4-tetrahydroisoquinolyl.

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

In the general formula IA

R ¹ is a hydrogen atom, a linear or branched alkyl group having 2-4 carbon atoms, cycloalkyl having alkyl with 3 to 6 carbon atoms, a cycloalkylmethyl group having alkyl with 3 to 6 carbon atoms or phenylalkyl of alkyl from 1 to 3 carbon atoms optionally substituted on the phenyl ring,

R ² is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, cycloalkyl having alkyl with 3 to 6 carbon atoms, a cycloalkylmethyl group having alkyl with 3 to 6 carbon atoms or phenylalkyl of alkyl from 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 each independently hydrogen, linear or branched C 1 -C 4 alkyl; , a cycloalkyl group having 3 to 6 carbon atoms in the alkyl moiety or a cycloalkylmethyl group having 3 to 6 carbon atoms in the alkyl moiety.

The 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 in the next section of the present invention.

According to a first embodiment, illustrated in Scheme A, 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 to give the amide of formula IIIA according to method described in J. Am. Chem. Soc. 98, 3237 (1976).

The amide is then alkylated using a derivative of the general formula R ^x -X, where R ¹ is as defined above but is other than hydrogen, and X is a halogen atom or an equivalent group, in the presence of a base such as potassium carbonate a polar aprotic solvent, for example in Ν, Ν-dimethylformamide to give the amide of formula IVA.

Scheme A

R ²

R <

O-

M-K3

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 a temperature of 25 to 100 ° C to give the corresponding primary amine, which is then reacted with either an aldehyde R ⁶ -CHO wherein R ⁶ is a lower homolog of the group R ² , in the presence of a reducing agent such as sodium borohydride or sodium cyanoborohydride, under reductive amination conditions known to those skilled in the art to provide 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 or phenylalkyl and R ³ is ethoxy. If appropriate, the compound so obtained is then saponified and converted to the corresponding acid, or alternatively, can be reacted with an amine of the formula HNR ⁴ R ⁵ , where R ⁴ and R ⁵ are already defined 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 ¹ and R ² are alkyl or phenylalkyl, can be prepared by reacting an amine of formula VA directly with an α-haloalkanamide of formula VIA

wherein X is a chlorine atom or a bromine atom and R ⁴ and R ⁵ have already been defined. The conditions of this reaction are known to those skilled in the art.

According to a third variant, amines of formula VA wherein R ¹ is cyclopropylmethyl and R ² is alkyl or phenylalkyl may be prepared either by reduction of the corresponding alkanamides described in patent application EP-461958 or by hydrolysis of said alkanamides to primary amines, and then by reaction of these amines under monoalkylation conditions. All of these reactions are carried out according to procedures known to those skilled in the art.

Finally, according to the 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 ¹ is the methyl group described in the 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 brackets after the example names correspond to the numbers in the first column of Table A.

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

DETAILED DESCRIPTION OF THE INVENTION

Example IA (Compound No. 2A)

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

ΙΑ. 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 point and 4.0 g (10.43 mmol) of N- (3- {5- [6] are added). - (cyclopropylmethoxy) -1-naphthyl] -1,3-dioxan-2-yl} propyl) acetamide dissolved in 200 ml of tetrahydrofuran and the mixture is heated at reflux for 4 hours.

The mixture was cooled, slowly added 3.5 mL (2 equivalents) of aqueous 0.1 M sodium potassium tartrate solution, 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.

1A.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 in 5 ml of dioxane is added dropwise, and the mixture was stirred for 8 hours at room temperature.

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 was heated at 80 ° C for 8 hours and allowed to stand overnight at room temperature.

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 0.1 M hydrogen chloride in 2-propanol are added, the solvents are evaporated and the residue is recrystallized from diisopropyl ether. Finally, 0.2 g of the hydrochloride is isolated. Mp 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 is dissolved in 10 ml dioxane and introduced into a 100 ml round bottom flask, 1 g (17.7 mmol) cyclopropanamine is added dropwise and the mixture is stirred for 2 hours. hours at room temperature.

Aqueous bicarbonate and ethyl acetate were added, the organic layer was separated, washed with water, dried over magnesium sulfate, filtered and the solvent was evaporated 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 a white solid, m.p. j. in total 1.92 g of compound are obtained, which compound is used as is in the following stage.

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] -N-ethyl-1,3-dioxane-2-propanamine dissolved in 20 ml of acetonitrile, 0.37 g (2, 77 mmol) of 2-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 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, 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. Recrystallization from diisopropyl ether gave 0.2 g of a white solid, mp 87-89 ° 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 was introduced into a 1000 ml round bottom flask and 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 dropwise 6.0 g (17.5 mmol) of 5- [6- (cyclopropylmethoxy) -1-naphthyl] -1,3-dioxane-2-propanamine in 7 ml tetrahydrofuran.

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

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

The mixture is cooled in an ice-water bath, 9 ml of sodium potassium tartrate is added dropwise and stirring is 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 cyclopropanethanamine, 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 and the mixture was 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 at 80 ° C.

The mixture is cooled, water and ethyl acetate are added, the organic phase is separated, washed with water and brine, dried over magnesium sulphate, filtered, the solvent is evaporated under reduced pressure and the residue is purified by silica gel column chromatography eluting with a mixture dichloromethane and 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) -1'-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-pyrrolidone are added under argon, introduce into a 250 ml round bottom flask, stir the mixture, add 3.86 g (49.5 mmol) of sodium sulfide and heat the mixture 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 are combined, washed with water and then with saturated sodium chloride solution and dried over magnesium sulphate. 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 ultrasound and 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.

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 for ¹ t 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 recrystallized from ethanol / water 6/4 and finally 0.2 g of compound is isolated, m.p. 140-142 ° 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-dioxane-213

-yl] propyl} acetamide dissolved in 49 ml of ethanol and 43.4 ml of a 30% sodium hydroxide solution is introduced into a 250 ml round bottom flask and the mixture is heated at reflux 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 is washed with saturated sodium chloride solution and dried over magnesium sulphate. This solution was filtered and the solvent was evaporated under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a 90/10/1 mixture of dichloromethane, methanol and aqueous 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. Melting point 180-183 ° C.

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 are introduced into a 1000 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.

Allow the mixture to cool, place in an ice bath, add 1.56 g (41.3 romol) of sodium borohydride in portions and stir 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 dichloromethane / methanol 95 / 5th

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 2.46 ml of 0.1 N hydrogen chloride in 2-propanol, evaporating the solvent under reduced pressure, trituration diisopropyl ether and drying under vacuum. 0.97 g of hydrochloride is obtained, m.p. 206-208 ° C.

4A. 5 N- [{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 (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 heated at reflux 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 under reduced pressure and the residue is purified by silica gel column chromatography eluting with a 99/1 mixture of dichloromethane and methanol.

0.5 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 0.1 N hydrogen chloride in 2-propanol are added. After evaporation of the solvent under reduced pressure, trituration of the residue with diisopropyl ether, filtration and drying under vacuum, 0.54 g of the hydrochloride is obtained, m.p. 190-193 ° C. .

i _k

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- (phenyl-15-methyl) -1,3-dioxane-2-propanamine suspended in 15 ml of acetonitrile, 0.42 g are mixed. (3.07 mmol) of potassium carbonate and 0.2 ml (1.84 mmol) of ethyl 2-bromoacetate 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 a dichloromethane / methanol mixture. 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

0.58 g (1.18 mmol) of ethyl 2 - [{3- [5- (6-ethoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl]} (phenylmethyl) amino] acetate Dissolve in a few ml of ethanol, add 5 ml of 33% methanamine in ethanol and place the mixture in an oven at 50 ° C 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 0.1 N hydrogen chloride in 2-propanol, evaporation of the solvent, trituration with diisopropyl ether, filtration and drying, 0.37 g of the hydrochloride is obtained, m.p. 88-90 ° C.

Example 6A (Compound No. 23A)

N - [{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 ( 20.1 mmol) of bromocyclopentane and using the same conditions as described in Example 4A.2 at 80 ° C, yielding 4.88 g of crude product. This compound (0.388 g) is purified by silica gel column chromatography eluting with a 90/10 mixture of dichloromethane and methanol. After recrystallization from ethanol / water and drying in the presence of phosphorus pentoxide, 0.22 g of compound is isolated, m.p. 136-137 ° C.

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 as described above. 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 with 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 are followed using the same procedure. The conditions were as described in Example 4A.4 to give 0.48 g of base, from which 0.435 g of hydrochloride was prepared with a melting point of 186-190 ° C.

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

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 the conditions described in Example 4A.5 are used, yielding 0.640 g of base as an oil, from which 0.628 g of hydrochloride is obtained, m.p. 212-215 ° C.

Example 7A (Compound No. 26A)

2 - [{3- [5- (Phenylmethoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] (phenyl17 methyl) amino] acetamide

7A. 1 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 operating under the conditions described in Example 4A.2 to give 4.67 g of the product, from which 0.3 g is recrystallized from a mixture of ethanol and water 6/4, to give 0.15 g of a 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 Example 4A.3. 3.2 g of an oily product are obtained, which product is used as is in the following stage.

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

Starting with 1.13 g (2.99 mmol) of 5- [6- (phenylmethoxy) -1-naphthyl] -1,3-dioxane-2-propanamine and 0.317 g (2.99 mmol) of benzaldehyde followed by 0.904 g. Sodium borohydride (23.9 mmol) was carried out as described in Example 4A.4 to give 0.41 g of base, from which 0.190 g of hydrochloride was 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 described in Example 4A.5 to give 0.310 g of base as an oil from which 0.285 g of hydrochloride was obtained. Melting point 170-175 ° C.

The following Table A illustrates the chemical structures and the physical properties of some compounds of Formula IA

In columns R ¹ , R ² and R ³ , CC ³ H ⁵ represents a cyclopropyl group, CC 5 H 9 is a cyclopentyl group and C 8 H 5 is a phenyl group.

In the column, the salt means - a 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 shown in brackets.

In column tt [° C] (d) means the melting point with decomposition. All compounds are trans isomers ( ¹ H-NMR).

Table A

No. R ¹ R ² R ³ Sol t. t. [’C] [ 1A -CH _{2 C 3} H ₅ -ch ₂ ch ₃ 1 -nhch ₃ . - 90-92 I 2A -CH2CC3H5 -ch ₂ ch ₃ -NHCH _{2 C 3} H ₅ HCl (1: 2) 74-76 3A -CH _{2 C 3} H ₅ -ch ₂ ch ₃ -NHcCl ₃ Hs - 87-89 4A -CH _{2 C 3} H ₅ -CH _{2 C 3} H ₅ -nh ₂ HCl (1: 2) 63 d 5A -CH _{2 C 3} H ₅ -CH2CC3H5 NHCH3 HCl (1: 2) 78-80 6A -CH _{2 C 3} H ₅ -CH _{2 C 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 HCl (1: 2) 80-82 8A -CH _{2 C 3} H ₅ -ch ₂ c ₆ h ₅ -och ₂ ch ₃ HCl (1: 2) 66-68 9A -CH _{2 C 3} H ₅ -ch ₂ c ₆ h ₅ -nh ₂ - 135-137 10A -CH _{2 C 3} H ₅ -ch ₂ c ₆ h ₅ -nhch ₃ - 115-117

No. R ¹ R ² R ³ Sol t. t. [’C] I 11A -CH2CC3H5 -ch ₂ c ₆ h ₅ -NHCH _{2 C 3} H ₅ HC1 (1: 1) 84-86 12A -CH2CC3H5 -ch ₂ c ₆ h ₅ -NHcC ₃ H ₅ HC1 (1: 1) 90-92 13A -CH2CC3H5 -ch ₃ OCH2CH3 HC1 (1: 1) 128-130 14A -CH2CC3H5 -ch ₃ -nh ₂ HC1 (1: 1) 98-110 15A -CH2CC3H5 -ch ₃ -nhch ₃ - 94-96 16A -CH2CC3H5 -ch ₃ -NHcC ₃ H ₅ HC1 (1: 1) 92-94 17A -CH2CC3H5 -ch ₃ -NHCH _{2 C 3} H ₅ ox. (1: 1) 156-158 18A -CH2CC3H5 -ch ₂ ch ₃ -nh ₂ - 127-129 19A -CH2CH3 -ch ₂ c ₆ h ₅ -nh ₂ HC1 (1: 1) 190-193 20A -CH2CH3 -ch ₂ c ₆ h ₅ -nhch ₃ HC1 (1: 1) 88-90 21A CH _{(CH3) 2} -ch ₂ c ₆ h ₅ -nh ₂ HC1 (1: 1) 174-176 22A CH _{(CH3) 2} -ch ₂ c ₆ h ₅ -nhch ₃ HC1 (1: 1) 88-90 23A -CC5H9 -ch ₂ c ₆ h ₅ -nh ₂ HC1 (1: 1) 212-215 24A - (CH ₂ ) ₃ CH ₃ -CH ₂ C ₆ H 5 -nh ₂ HC1 (1: 1) 192-195 25A - (CH ₂ ) ₃ CH ₃ -ch ₂ c ₆ h ₅ -nhch ₃ ox. (1: 1) 68-70 26A -ch ₂ c ₆ h ₅ -ch ₂ c ₆ h ₅ -nh ₂ HC1 (1: 1) 170-175 27A - (ch ₂ ) ₃ ch ₃ -ch ₃ -nh ₂ - 120-121 28A -ch ₂ c ₆ h ₅ -ch ₃ -nhch ₃ - 114-116 29A -ch ₂ c ₆ h ₅ -ch ₂ c ₆ h ₅ -nhch ₃ - 108-110 30A -ch ₂ c ₆ h ₅ -ch ₃ -nh ₂ HC1 (1: 1) 75-85 31A H -ch ₂ c ₆ h ₅ -nh ₂ - 90 (d) 32A -CC5H9 -ch ₂ c ₆ h ₅ -nhch ₃ - 116-118 33A -CC5H9 -ch ₃ -nh ₂ - 138-140 34A -CH2CH3 -ch ₃ -nh ₂ fum. (1: 1) 161-162

.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 each independently hydrogen or C 1 -C 1 alkyl; up to 4 carbon atoms

X is oxygen or sulfur or CH ₂ , m is 0 or 1, and n is 0, 1 or 2.

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

Compounds of formula IB can be prepared by the method illustrated in Scheme B.

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 a catalyst thereby to give 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 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.

Scheme B

(IIB)

(IVB) (IVB)

IClM _n ^ X '(UK)

h ₃ c _x

0 '

) n ^ X (IBc)

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

If desired, the compound can be saponified under conditions known to those skilled in the art to provide a compound of formula IBb wherein Y is hydroxyl. Formula IBb corresponds to Formula IB when R ¹ is 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 give the 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 ¹ R ² , wherein Z is chlorine or bromine and R ¹ and R ² are as defined above, in the polar an aprotic solvent, for example Ν, Ν-dimethylformamide, in the presence of a base, for example 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-Dimethoxybutanamine 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 brackets correspond to those in Table B.

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

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 the ether was introduced into a 1 L round bottom flask containing 300 mL of toluene and the mixture was heated at 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 ^e C.

1B. 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 a 250 mL ethanol and 500 mL round bottom flask, add 1.32 g (9.95 mmol) of 2,3-dihydro-1H-inden-1-one and the mixture is heated at reflux overnight.

The mixture is allowed to cool, 2 g of potassium borohydride are added and stirring is continued for 2.5 hours. Water (100 ml) was added and the mixture was extracted with ethyl acetate (3.times.50 ml). The solvent is evaporated from the organic phase and the residue is evaporated

I ' ^»1 purified by silica gel column chromatography, eluting with dichloromethane: methanol 9/1. 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] hydrochloride aminoJacetátu

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, 0.8 g (5.8 mmol) of potassium carbonate, 0.96 g (5.8 mmol) of ethyl 2-bromoacetate, a catalytic amount of sodium iodide and 35 ml of Ν, Ν-dimethylformamide are placed in a 250 ml round-bottom flask. and the mixture is heated at 60 ° C for 3 hours. 100 ml of water are added, the mixture is extracted three times with 150 ml of ethyl acetate, the organic phase is washed with aqueous sodium chloride solution and then with aqueous sodium bicarbonate solution. 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. M.p. 88-89 ° C.

Example 2B (compound number 2B)

2 - [(2,3-Dihydro-1H-inden-1-yl)] - {3- [5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl] 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) - Place 1,3-dioxan-2-yl] amino} acetate in a 250 mL round bottom flask, add 30 mL of a 33% solution of methylamine in ethanol, and stir 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 0,1 N solution r

of hydrogen chloride in 2-propanol. After washing with diethyl ether, 0.98 g of hydrochloride is isolated. Melting point 112-114 ° C.

Example 3B (Compound No. 6B)

5- (6-Methoxy-1-naphthyl) -N- (1,2,3,4-tetrahydro-1-naphthyl) -1,3-dioxane-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- Place the dihydronaphthyl-1 (2Η) -one in a 250 ml round bottom flask and heat the mixture at reflux 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 off under reduced pressure, the residue is taken up in dichloromethane and the solvent is evaporated off 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 134-136 ° 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) amino] acetamide hydrochloride

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

0.6 g of base is obtained, from which 0.25 g of hydrochloride is prepared with a 0.1 N 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, 150 ml of ethanol and 0.983 g (6.6 mmol) of 3,4-dihydro- Of 2H-1-benzopyran-4-one and the mixture is heated at reflux overnight.

The mixture is cooled, 2 g of sodium borohydride are added, the mixture is stirred for 1 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 silica gel column chromatography eluting with a 9/1 mixture of dichloromethane and methanol to give 1.3 g of 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. M.p. 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 -dioxane-2-propanamine and 0.16 g (1.72 mmol) of 2-chloroacetamide were followed using similar conditions to those described in Example 4B and after chromatography, 0.37 g of the compound was obtained as a base from which 0.17 g of hydrochloride is obtained. Mp 165-166 ° C.

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

In the column, the salt is a base, ox.

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

Table B

No. R X m n Sol t. t. f C] 1B -CH2CO2CH2CH3 ch ₂ 0 1 HCl (1: 2) 88-90 2B -CH2CONHCH3 ch ₂ 0 1 HCl (1: 2) 112-114 3B H ch ₂ 1 0 HCl (1: 2) 220-221 4B -CH2CO2CH2CH3 CH ₂ 1 0 HCl (1: 2) 77-79 5B -CH2CONHCH3 ch ₂ 1 0 ox. (1: 1) 84-86 6B H ch ₂ 0 2 fum. (1: 1) 134-136 7B -CH2CO2CH2CH3 ch ₂ 0 2 HCl (1: 2) 77-79 8B -CH2CONHCH3 ch ₂ 0 2 HCl (1: 2) 98-110 9B -CH2CONH2 ch ₂ 0 2 HCl (1: 2) 142-143 10B -CH2CO2CH2CH3 ch ₂ 1 1 HCl (1: 2) 74-76 11B -CH2CONH2 ch ₂ 1 1 HCl (1: 1) 208-210. 12B -CH2CONHCH3 ch ₂ 1 1 fum. (1: 1) 82-122 13B H 0 0 2 HCl (1: 2) 172-173 14B -CH2CONH2 0 0 2 HCl (1: 2) 165-166 15B -CH2CONHCH3 0 0 2 HCl (1: 2) 117-119 16B H with 0 2 HCl (1: 2) 192-193 17B -CH2CO2CH2CH3 with 0 2 HCl (1: 2) 66-68 18B -CH2CONHCH3 with 0 2 HCl (1: 2) 114-116 19B -CH2CONH2 ch ₂ 0 1 - 106-108

No. R X m n Sol t. t. [° C] 20B H ch ₂ 1 1 HC1 (1: 1) 211-213 21B -CH2CO2H ch ₂ 0 2 - 90-92 22B -CH2CO2H 0 0 2 - 108-112 23B H ch ₂ 0 1 HC1 (1: 1) 124-125

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

In the general formula IC

R ¹ is either a hydrogen atom or a group of the formula CH 2 COY, wherein Y is a hydroxyl or alkoxy group having 1 to 4 carbon atoms, or alternatively a group of the formula CH ² CONR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are independently hydrogen or alkyl containing 1 to 4 carbon atoms, and

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

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) can be prepared by the procedure illustrated in the following Scheme C.

2- (6-Methoxy-1-naphthyl) propane-1,3-diol of formula IIC is reacted with 4,4-diethoxybutanamine of formula IIIC in a boiling aprotic solvent such as toluene and in the presence of hydrogen chloride dissolved in diethyl ether as a 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 a temperature of 25 to 60 ° C to remove the water formed during the reaction; an aldehyde of formula VC, where R ² is as defined above, and then the resulting imine is reduced, for example, using a reducing agent such as sodium borohydride or an equivalent reagent in a neutral or acidic medium under reductive amination conditions known to those skilled in the art. This yields a compound of formula ICa, which corresponds to formula IC, wherein R ¹ is hydrogen.

(ICC)

If appropriate, the compound of formula ICa may be alkylated with a haloacetate of the formula Z-CH 2 -CO 2 -alkyl having 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, for example potassium carbonate, to give a compound of formula ICb wherein Y is a C 1 -C 4 alkoxy group.

If desired, this compound can be saponified using conditions known to those skilled in the art to give a compound of formula ICb wherein Y is hydroxyl. The formula ICb corresponds to the formula IC, wherein R ¹ is a group of the formula CH 2 COY.

If appropriate, 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 amide of formula ICc. This reaction is carried out using standard conditions known to those skilled in the art.

An amide of formula ICc may 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 where Z is chlorine or bromine and R ⁴ and R ⁵ are already as defined in a polar aprotic solvent such as N, N-dimethylformamide in the presence of a base such as potassium carbonate.

The general formula ICc corresponds to the general formula IC, where

I

R ¹ 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 in brackets correspond to those in Table C.

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 70 ml of dry gas of hydrogen chloride dissolved in diethyl ether is placed in a 1 L round bottom flask containing 300 ml of toluene and the mixture is refluxed for 2 hours.

The mixture was cooled and 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. Melting point 224-226 ° C.

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

0.5 g (1.67 mmol) of 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanamine and 200 ml of methanol 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 hours.

The mixture is allowed to cool, 0.5 g of sodium borohydride is added and the mixture is 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 0.1 N solution of hydrogen chloride in 2-propanol. After washing with diisopropyl ether and drying, 0.12 dihydrochloride is obtained. Mp 207-208 ° C.

Example 2C (compound number 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 Sodium iodide (9 mmol), potassium carbonate (0.828 g, 6 mmol) and 2-chloroacetamide (0.42 g, 4.5 mmol) were heated at reflux for 3 hours.

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 the 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 mixture of dichloromethane and methanol 9.1 to give 0.3 g of pure base.

The base is converted to the 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 number 19C)

5- (6-Methoxy-1-naphthyl) -N- (2-thiazolylmethyl) -1,3-dioxane-2-propanamine hydrochloride

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 ml) of 1,3-thiazole-2- of carboxaldehyde is placed in a 1000 ml round-bottomed flask provided

Dean-Stark apparatus and distillation until the volume of the reaction mixture is reduced to about 200 mL.

The mixture is cooled, 2.4 g of sodium borohydride are added in portions and the mixture is left stirring 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 and the hydrochloride is prepared using 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)

2-chloroacetamide and working under the conditions described in Example 2C to give 0.76 g of base, from which 0.763 g of 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 7-2 -pyridyl, C ₅ H ₄ N 3 - is

3-pyridyl, C5H4N-4- is 4-pyridyl, CH3-I-C4H3N-2- is 1-methyl-2-pyrrolyl, C4H3O-2- is 2-furyl, C4H3S-2- is 2- thienyl and C3H2NS-2- is 1,3-thiazol-2-yl.

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

In column t. t. [° C] means (d) the melting point with decomposition.

Table C

(IC)

No. R ¹ R ² Sol t. t. [° C] IC H C5H4N-4- HC1 (2: 1) 207-208 2C -CH ₂ CO ₂ H C5H4N-4- - 115-125 3C -CH2CONH2 C5H4N-4- HC1 (2: 1) 169-170 4C -CH2CONHCH3 C5H4N-4- HC1 (2: 1) 80-90 5C H 3-C5H4N - 80-81 6C -CH2CONH2 3-C5H4N HC1 (1: 1) 199-200 7C -CH ₂ CONHCH ₃ 3-C5H4N ox. (2: 1) 138-140 8C H C5H4N-2- HC1 (1: 1) 158-159 9C -CH2CONH2 C5H4N-2- HC1 (1: 1) 174-175 10C -CH2CONHCH3 C ₅ H4N-2- HC1 (2: 1) 93-96 11C ' H CH3 .I-C4H3N-2- HC | ‘(0: 1) 183-Ί86 12C -CH2CONH2 CH3-I-C4H3N-2- HC1 (1: 1) 188 d 13C -CH2CONHCH3 CH3-I-C4H3N-2- HC1 (1: 1) 89-95 14C H C4H3O-2- HC1 (1: 1) 186-187 15C -CH2CO2CH2CH3 C4H3O-2- HC1 (1: 1) 62-65 16C -CH2CONH2 C4H3O-2- HC1 (1: 1) 205-206 17C H 2-C4H3S HC1 (1: 1) 174-176 18C -CH2CONH2 2-C4H3S HC1 (1: 1) 220-225 19C H C3H2NS-2- HC1 (1: 1) 134-137 20C -CH2CO2CH2CH3 C3H2NS-2- HC1 (1: 1) 58-62

No. R ¹ R ² Sol t. t. [° C] 21C CH ₂ CONH ₂ C ₃ H ₂ NS-2 HC1 (1: 1) 189-191 22C -ch ₂ every ₂ h 2-C4H3S - 152-156 23C -ch ₂ every ₂ h C4H3O-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 each 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 these isomers; due to the presence of asymmetric carbon and due 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.

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 acidic medium and in an aprotic solvent to give 2 - (3-chloropropyl) -5- (6-methoxy-1-naphthyl) -1,3-dioxane of formula IVD and finally this compound reacts with an amine of formula VD, where Y, R ¹ and R ² are as defined in in the presence of an organic or inorganic base, in an aprotic solvent, for example N, N-dimethylformamide, at a temperature of 20 to 110 ° C.

2- (6-Methoxy-1-naphthyl) propane-1,3-diol of formula IID is described in patent application EP-0,461,958. 2- (3-chloropropyl) -1.337

-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 brackets correspond to those in Table D.

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 the ether placed to 500 ml banks with round bottom containing 150 ml toluene and mixture the heated on the boiling point for 6 hours. The mixture is left cool, added 110 ml aqueous 5 %

sodium bicarbonate solution and extracted twice with 100 mL 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 petroleum ether / ethyl acetate 9/1 mixture. 3.2 g of a white solid are obtained, which solid is used as is in the following stage.

1D.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 0.29 g (2 mmoles) of potassium iodide are introduced into a 50 ml round bottom flask containing a ^"1, ₀ ml Ν, Ν-dimethylformamide, and the mixture was heated to room 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. eluting with a gradient of dichloromethane / methanol 99.5 / 0.5 to 99/1.

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

Example 2D (Compound No. 2D) 1- {3- [5- (6-Methoxy-1-naphthyl) -1,3-dioxan-2-yl] -propyl} -L-prolinamide

0.5 g (1.6 mmol) of 2- (3-chloropropyl) -5- (6-methoxy-1-naphthyl) -1,3-dioxane, 0.2 g (1.9 mmol) of L-proline amide 0.2 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 to 110 ° C for 3.5 hours.

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 was 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, which is recrystallized in the form of 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- ^1- methyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide oxalate à

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 a temperature of Deň: 18 ° C. It was then evaporated to dryness under reduced pressure to give 1.7 g of the compound as a colorless oil, which was 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 oxalate carboxamide

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-bottomed flask containing 20 ml of acetonitrile and the mixture was heated to 80 ° C for 8 hours.

The mixture was allowed to cool, water (20 ml) was added and the resulting mixture was extracted with ethyl acetate (20 ml). 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 98/2 mixture of dichloromethane and methanol. 0.12 g (0.25 mmol) of compound is obtained, which compound is recrystallized as oxalate from diisopropyl ether. Melting point: 88γ90.

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

In column R ^1, NCHR ² is pyrrole, piper. and is that R ¹ and R ² together with the nitrogen atom to which they are attached form a pyrrolidine ring, piperidine ring or 1,2,3,4-tetrahydroisoquinoline ring.

In the column, the salt is a base, ox.

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

In column t. t. [° C] means (d) the melting point with decomposition.

Table D

R ¹

I

(ID)

No. Y R ^X NCHR ² Configuration. * Sol mp [° C] [a] D ²⁰ ID OCH2CH3 pyrrole. WITH ox. (1: 1) 116-118 - 26 2D -nh ₂ pyrrole. WITH - 164-166 n. d. 3D -NHCH ₃ pyrrole. WITH - 119-121 - 30 4D OCH2CH3 piper. RS ox. (1: 1) 129-131 - 5D -NHCH ₃ pyrrole. RS - 99-101 - 6D -NHCH ₃ -isoquinoline. RS ox. (1: 1) 88-90 -

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

Inhibition of the action of sodium channel agonists in neurons

I »►. · * H, I ₍

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

The effect of sodium channel agonists such as veratridine (10 μΜ) on the increase in intracellular calcium levels in this model is inhibited by the compounds of the present invention at IC50 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 was described by E. A. Swinyard and J. H. Woodhead in Antiepileptic Drugs, Raven Press, New York, 111-126 (1982).

Ten minutes after intravenous administration of the test compound, the number of cramping mice (forelegs and hind limbs stretching) was recorded immediately after application of the electrical current (0.4 sec, 60 mA, 50 Hz) using an Apelex ETC UNIT 7801 ™. The results are expressed as AD 50, which is the dose that protects 50 animals, calculated according to the procedure of J. T. Lichtfield and F. Wilcoxon in J. Pharm. Exp. Ther. 96, 99-113 (1949) using Software Probit ™ and starting with 3 to 4 doses, each administered to a group of 8 mice. The AD50 values of the most active compounds range from 1 to 10 mg / kg.

Anti-ischemic properties

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, i. j. 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 was stopped for 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 prior to the test. Survival time was measured 10 minutes after intraperitoneal administration of the compounds of the present invention. Results are reported 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. The relationships between changes in survival time and dose of compound were plotted on a plot of a semi-logarithmic curve.

This curve makes it possible to calculate the three-second effective dose (ED3 · '), i. j. dose (in mg / kg) that provides a three-second increase in survival time relative to the control group of untreated mice.

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

The ED3 values of the most active compounds of the present invention range from 0.05 to 0.2 mg / kg by intravenous administration.

Antinociceptive activity

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

Formalin (5%) is injected subcutaneously (100 μΐ) into the foot arch of the left hind limb. Nocioception after injection is evaluated for the injected limb by total licking duration 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 to 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, there is a statistically significant reduction (p <0.05) in total licking duration and / or shaking (calculated from area under the curve) compared to those measured in animals receiving only the vehicle. ).

The activity threshold for compounds of the present invention corresponds to a reduction of 35-40%. The most active compounds cause a 50% reduction at a dose of 30 mg / kg 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 suitable for the treatment or prevention of cerebrovascular diseases of ischemic or hypoxic origin (cerebral infarction, cranial or medullary trauma, cardiac or respiratory arrest, transient ischemic seizure, perinatal asphyxia), glaucoma, progressive neurodegenerative diseases (senile dementia such as Alzheimer's disease, vascular dementia, Parkinson's disease, Huntington's disease, olivopontocerebral atrophy, amyotrophic lateral sclerosis and prevention, neurodegenerative sclerosis, neurodegenerative sclerosis, neurodegenerative sclerosis, neurodegenerative diseases and neurodegenerative diseases) 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, treatment of other diseases such as neuropathy, neurogenic pain (e.g., pain associated with neuropathy or migraine attacks), neurological convulsion and dyskinesia can also be envisaged. ·,

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 combination with suitable ingredients and at dosages allowing for daily administration of 1 to 100 mg of the active ingredient.

Claims (6)

PATENT CLAIMS A compound in the form of pure stereoisomer or mixtures of stereoisomers of formula IA (IA) wherein R ¹ is a hydrogen atom, a linear or branched alkyl group having 2-4 carbon atoms, cycloalkyl having alkyl with 3 to 6 carbon atoms, a cycloalkylmethyl group having alkyl with 3 to 6 carbon atoms or phenylalkyl of alkyl from 1 to 3 carbon atoms optionally substituted on the phenyl ring, R ² is a hydrogen atom, a linear or branched alkyl group having 1 to 4 carbon atoms, cycloalkyl having alkyl with 3 to 6 carbon atoms, cycloalkylmethyl • group having alkyl with 3 to 6 carbon atoms or phenylalkyl of alkyl 1 to 3 carbon 'and' ¹ I, alkyl optionally substituted on the phenyl ring ·, I · I R ³ is hydroxyl, C 1 -C 4 alkoxy or NR ⁴ R ⁵ , wherein R ⁴ and R ⁵ are each independently hydrogen, linear or branched C 1 -C 4 alkyl, cycloalkyl containing C 3 -C 6 alkyl or C 3 -C 6 cycloalkylmethyl in the form of a base or acid addition salt. A compound in the form of pure stereoisomer or mixtures of stereoisomers of general formula IB (IB) wherein R is either a hydrogen atom or a group of the formula CH ₂ COY, wherein Y is a hydroxyl or alkoxy group having 1 to 4 carbon atoms, or alternatively a group of the formula CH ₂ CONR ¹ R ² , wherein R ¹ and R ² are independently hydrogen or (1-4C) alkyl; X is an oxygen or sulfur atom or a CH ₂ group, m is 0 or 1, and n is 0, 1 or 2, in the form of the free base or acid addition salt. 3. A compound in the form of pure stereoisomer or mixtures of stereoisomers of the general formula IC wherein (IC) R ¹ is either a hydrogen atom or a group of the formula CH ₂ COY, where Y is a hydroxyl group or an alkoxy group having 1 to 4 carbon atoms, or alternatively a group of the formula CH ₂ CONR ⁴ R ⁵ where R ⁴ and R ⁵ are independently hydrogen or (1-4C) alkyl; and R ² is 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-2-pyrrolyl, 2-furyl, 2-thienyl or 1,3-thiazol-2-yl, in the form of free base or acid addition salt. A compound in the form of the pure stereoisomer or mixtures of stereoisomers of the general formula ID wherein Y is hydroxy, alkoxy of 1 to 4 carbon atoms or a group of the formula NR ⁴ R ⁵ wherein R ⁴ and R ⁵ are independently H or alkyl group has ¹ II Jucá 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, a piperidine ring or a 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.