JP2002502412A - 5-Naphthalen-1-yl-1,3-dioxane derivative, production method and therapeutic use - Google Patents

Abstract

(57) [Summary] The present invention relates to a compound represented by the general formula (I): [Wherein, R ₁ represents an alkyl group; V is a hydrogen atom, or linear or branched alkyl, cycloalkyl, cycloalkylmethyl, and phenyl optionally substituted on a phenyl ring. Alkyl, carboxymethyl, alkoxycarbonylmethyl, carbamoylmethyl optionally substituted on nitrogen; W is carboxymethyl, alkoxycarbonylmethyl, carbamoylmethyl optionally substituted on nitrogen A 4- to 7-membered cyclic group optionally containing an oxygen or sulfur atom, or a pyridinylmethyl, 1-methylpyrrolylmethyl, furanyl-methyl, thienylmethyl or 1,3-thiazolyl-methyl group Or V and W together with a nitrogen atom are pyrrolidinyl, It relates to compounds represented by the lysinyl or form a 1,2,3,4-tetrahydroisoquinolinyl group. The invention is applicable to therapy.

Description

DETAILED DESCRIPTION OF THE INVENTION   5-Naphthalen-1-yl-1,3-dioxane derivative, production method and treatment Use   The present invention relates to a compound of the formula (I) [Where,   R₁Represents an alkyl group,   V represents a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group, Loalkylmethyl group, phenyl optionally substituted on a phenyl ring An alkyl group, a carboxymethyl group, an alkoxycarbonylmethyl group, or A carbamoylmethyl group optionally mono- or di-substituted on nitrogen Represents   W represents a carboxymethyl group, an alkoxycarbonylmethyl group, and optionally nitrogen A carbamoylmethyl group which may be mono- or di-substituted above, 4- to 7-membered cyclic group optionally containing an oxygen or sulfur atom, Tyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 1-methyl-2-pyro Rylmethyl group, 2-furylmethyl group, 2-thienylmethyl group, or 1,3-thio Represents an azole-2-yl-methyl group, or   V and W, together with the nitrogen atom connecting them, are pyrrolidinyl Forms a piperidinyl or 1,2,3,4-tetrahydroisoquinolinyl group ] The compound shown by these.   The compounds of the present invention are more specifically represented by the general formulas (IA), (IB), (IC) and And (ID).   In the general formula (IA),   R₁Is a hydrogen atom, linear or branched (C_Two-C_Four) Alkyl group, cyclo (C_Three -C₆) Alkyl group, cyclo (C_Three-C₆) Alkylmethyl group, or optionally Phenyl (C)₁-C_Three) Represents an alkyl group,   R_TwoIs a hydrogen atom, linear or branched (C₁-C_Four) Alkyl group, cyclo (C_Three -C₆) Alkyl group, cyclo (C_Three-C₆) Alkylmethyl group, or optionally Phenyl (C)₁-C_Three) Represents an alkyl group,   R_ThreeIs a hydroxyl group, (C₁-C_Four) Alkoxy group or general formula NR_FourR_Five[formula Medium, R_FourAnd R_FiveAre each independently a hydrogen atom, a linear or branched (C₁− C_Four) Alkyl group, cyclo (C_Three-C₆) Alkyl or cyclo (C_Three-C₆) Alkyl Represents a methyl group].   The compound represented by the general formula (IA) may be a cis or trans stereoisomer or They can exist in the form of a mixture of such isomers; It can be in the form of an addition salt.   The compound represented by the general formula (IA) can be produced by various methods described below. Wear.   According to the first method shown by Scheme A below, Am. Chem. Soc. (1976)98  According to the method described in 3237, the amide of formula (IIA) is converted to sodium sulfide In a polar aprotic solvent such as N-methylpyrrolidone in the presence of Dealkylation at a temperature of 50 ° C. gives the amide of formula (IIIA) .   This amide is then reacted with N, N-dimethyl in the presence of a base such as potassium carbonate. In a polar aprotic solvent such as formamide, the compound of formula R₁-X [wherein, R₁Is Is the same as the meaning, except that it is other than a hydrogen atom, and X represents a halogen atom or an equivalent group Represented by the general formula (IVA) To obtain an amide.                                Scheme A  The amide is then added to water or fat in a basic medium such as sodium hydroxide. Hydrolysis in a protic solvent such as an aromatic alcohol at a temperature of 25 to 100 ° C., The corresponding primary amine is obtained, which is then converted to a reductive amination known to those skilled in the art. Under conditions, such as sodium borohydride or sodium cyanoborohydride In the presence of the base agent, the general formula R₆-CHO [wherein R₆Is a group R_TwoIs a lower homolog of To give an amine of the general formula (VA).   Then, the amine represented by the general formula (VA) is reacted with ethyl bromoacetate , A compound of the general formula (IA)₁And R_TwoIs alkyl, cycloalkyl, cyclo Represents an alkylalkyl or phenylalkyl group;_ThreeRepresents an ethoxy group Is obtained. If desired, the resulting compound is then saponified to Can be converted to the corresponding acid or have the general formula HNR_FourR_Five[Wherein, R_FourAnd R_FiveIs The same as defined above], can be converted to an amide. This These reaction conditions are standard and are well known to those skilled in the art.   According to another method, a compound of the general formula (IA) wherein R₁And R_TwoIs an alkyl or An amide represented by the general formula (VA) Min is represented by the general formula (VIA): [Wherein, X represents a chlorine or bromine atom;_FourAnd R_FiveIs the same as defined above is there] Can be obtained by directly reacting with an α-haloalkaneamide represented by You. This reaction condition is well known to those skilled in the art.   According to the third method, a compound represented by the general formula (VA):₁Is cyclopropylmethyl R represents a group_TwoRepresents an alkyl or phenylalkyl group] Are the corresponding alkanes described in European Patent Application EP-461,958. Reduction of the amide or hydrolysis of the alkane amide to a primary amine, then It can be prepared by treatment of these amines under N-monoalkylation conditions. these Are performed according to methods well known to those skilled in the art.   Following the last method, the general formula (IA)₁Represents a hydrogen atom] The compound to be purified is prepared using sodium sulfide in N, N-dimethylformamide. R described in Lance patent application FR-2,742,152₁Represents a methyl group It can be produced by demethylation of the corresponding compound represented by the formula.   The following examples illustrate the preparation of a number of compounds of general formula (IA). Elemental microanalysis and IR and NMR spectra indicate the structure of the compound obtained. Confirm.   In the titles of the examples, the numbers in parentheses are the numbers in the first column of Table A below. Is equivalent toExample 1A (Compound No. 2A) 2-[[3- [5- [6- (cyclopropylmethoxy) -1-naphthyl] -1,3-dio Xan-2-yl] propyl] ethylamino] -N- (cyclopropylmethyl) ace Toamide 1A. 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 Was introduced into a 250 ml two-neck round bottom flask, and the mixture was heated to reflux, N- [3- [5- [6- (cyclopropylmethoxy) dissolved in 200 ml of lofuran -1-Naphthyl] -1,3-dioxan-2-yl] propyl] acetamide 4.0 g (10.43 mmol) are added and reflux is continued for 4 hours.   The mixture was cooled and 3.5 ml of a 0.1 M aqueous solution of sodium potassium tartrate (2 mL). Eq) is added slowly, the mixture is stirred and the solvent is evaporated off under reduced pressure. Oily raw 4.55 g of product are obtained, which product is used in the next step without further purification. 1A. 2. 2-[[3- [5- [6- (cyclopropylmethoxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] ethylamino] -N- (cyclopropyl (Methyl) acetamide   0.23 ml (2.6 mmol) of cyclopropylmethanamine, dioxane 2 0 ml and 0.36 ml of triethylamine are introduced into a 250 ml round bottom flask And 0.21 ml (2.6 mmol) of chloroacetyl chloride in 5 m of dioxane solution is added dropwise and the mixture is stirred at room temperature for 8 hours.   30 ml of water, 1 g of potassium carbonate and 5- [6- (cyclopropylmethoxy)- 1-Naphthyl] -N-ethyl-1,3-dioxane-2-propanamine 1.0 g (2.7 mmol) was added and the mixture was heated at 80 ° C. for 8 hours and left at room temperature overnight. Place.   Add water and ethyl acetate, remove the organic phase, wash with water and then brine And dried over magnesium sulfate, filtered, evaporated under reduced pressure to remove the residue, Dichloromethane and methanol after silica gel column chromatography By eluting with a 98/2 mixture of   0.5 g of an oily product was obtained, which was dissolved in 2-propanol to give 2-propanol. 8 ml of 0.1 M hydrochloric acid in water, evaporate the solvent and distill the residue Recrystallize from the tel.   Finally, 0.2 g of the hydrochloride salt is isolated.   Melting point: 74-76 [deg.] C.Example 2A (Compound No. 3A) N-cyclopropyl-2-[[3- [5- [6- (cyclopropylmethoxy) -1-na Phthyl] -1,3-dioxan-2-yl] propyl] ethylamino] acetamide 2A. 1. Chloro-N-cyclopropylacetamide   2 g of chloroacetyl chloride dissolved in 10 ml of dioxane (17.7 mmol Was introduced into a 100 ml round bottom flask, and 1 g of cyclopropanamine (17. 7 mmol) and the mixture is stirred at room temperature for 2 hours.   Add bicarbonate solution and ethyl acetate, remove the organic phase, wash with water, Dry over magnesium acid, filter and evaporate the solvent under reduced pressure to give a white solid 0.7 g.   The aqueous phase is concentrated under reduced pressure, the residue is taken up in ethanol and further treated with a white solid 1.2. 2 g, ie a total of 1.92 g of compound, which was further purified Used in the next step without any further action. 2A. 2 N-cyclopropyl-2-[[3- [5- [6- (cyclopropylmethoxy) B) -1-Naphthyl] -1,3-dioxan-2-yl] propyl] ethylamino] a Cetamide   5- [6- (cyclopropylmethoxy) -1 dissolved in 20 ml of acetonitrile -Naphthyl] -N-ethyl-1,3-dioxane-2-propanamine 0.69 g (1.87 mmol), 2-chloro-N-cyclopropylacetamide 0.37 g (2.77 mmol) and 0.26 g of potassium carbonate in a 100 ml round bottom flask. Introduce the mixture and heat the mixture at 70 ° C. for 4 hours.   The mixture was cooled, water and ethyl acetate were added and the organic phase was removed and extracted with water, Wash with saturated sodium chloride solution, dry over magnesium sulfate, filter Evaporate the solvent under reduced pressure. The residue was subjected to silica gel column chromatography. By eluting with a 98/2 mixture of dichloromethane and methanol Purify. After crystallization from diisopropyl ether, 0.2 g of white solid is isolated I do.   Melting point: 87-89C.Example 3A (Compound No. 17A) 2-[[3- [5- [6- (cyclopropylmethoxy) -1-naphthyl] -1,3-dio Xan-2-yl] propyl] methylamino] -N- (cyclopropylmethyl) ace Toamide 3A. 1. 5- [6- (cyclopropylmethoxy) -1-naphthyl] -1,3-di Oxan-2-propanamine   N- [3- [5- [6- (cyclopropylmethoxy) -1-naphthyl] -1,3-di Oxan-2-yl] propyl] acetamide 30.0 g (78.23 mmol) 1000 ml of ethanol, 330 ml of ethanol and 300 ml of 30% sodium hydroxide and the mixture is heated at 110 ° C. for 24 hours.   After the phases have separated, the alcoholic phase is removed, the phase is concentrated, water is added, The mixture is extracted with ethyl acetate. Dry the organic phase over magnesium sulfate and reduce pressure Below, the solvent is evaporated. 30.44 g of an oily product are obtained, which is purified further. Used in the next step without production. 3A. 2. 5- [6- (cyclopropylmethoxy) -1-naphthyl] -N-methyl -1,3-dioxane-2-propanamine   2.4 ml (25.3 mmol) of acetic anhydride were introduced into a 50 ml round bottom flask. , 1 ml (26.5 mmol) of formic acid are added dropwise and the mixture is placed on a 50 ° C. oil bath for 2 hours. Heat for a while.   Stop heating, add 2.5 ml of anhydrous tetrahydrofuran and stir the mixture. While 5- [6- (cyclopropylmethoxy) -1-naphthyl] -1,3-dioxa 2-propanamine 6.0 g (17.5 mmol) in tetrahydrofuran 7 solution is added dropwise so that the temperature does not exceed 40 ° C., and stirring is continued at room temperature overnight. I did.   Evaporate the solvent under reduced pressure, take up the residue in toluene and evaporate the solution under reduced pressure And the residue is dried.   5.84 g (15.8 mmol) of a white solid are obtained. 250 ml of this solid Dissolve in 40 ml of tetrahydrofuran in a round bottom flask, In an atmosphere, 43 ml of tetrahydrofuran containing 1.2 g of lithium aluminum hydride The medium suspension is added and reflux is continued for 4 hours.   The mixture was cooled in an ice-water bath and 9 ml of potassium sodium tartrate was added dropwise, Stirring is continued overnight. The mixture is filtered and the filtrate is concentrated under reduced pressure to give an oily product 5 . 89 g are obtained.   Dissolve 0.23 g of this product in 2-propanol and add 1 After treatment with an equivalent amount of hydrochloric acid, 0.188 g of the hydrochloride is finally isolated.   Melting point: 144-148 [deg.] C. 3A. 3. 2-[[3- [5- [6- (cyclopropylmethoxy) -1-naphthyl] -1,3-dioxan-2-yl] propyl] methylamino] -N- (cyclopropyl (Methyl) acetamide   0.24 ml (2.81 mmol) of cyclopropanemethanamine, dioxane Introduce 20 ml and 0.4 ml of triethylamine into a 250 ml round bottom flask And 0.22 ml (2.81 mmol) of dioxane 1 in chloroacetyl chloride The solution in 0 ml is added dropwise and the mixture is stirred at room temperature for 9 hours.   30 ml of water, 1 g of potassium carbonate and 5- [6- (cyclopropylmethoxy)- 1-naphthyl] -N-methyl-1,3-dioxane-2-propanamine 1 g (2 . 81 mmol) and the mixture is heated at 80 ° C. for 3 hours.   It is then cooled, water and ethyl acetate are added, the organic phase is removed, and water and Wash with brine, dry over magnesium sulfate, filter and evaporate the solvent under reduced pressure. And the residue was subjected to silica gel column chromatography to give dichloromethane and Purification by eluting with a 98/2 mixture of methanol and methanol. Product 0.62 g are dissolved in ethanol. After treatment with 1 equivalent of oxalic acid, Isolate 0.5 g of body.   Melting point: 156-158 [deg.] 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-dioxy San-2-yl] propyl] acetamide   N- [3- [5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-i [Propyl] acetamide 3.4 g (9.9 mmol) and 1-methyl-2- 20 ml of pyrrolidinone was introduced into a 250 ml round bottom flask under a nitrogen atmosphere, The mixture is stirred and 3.86 g (49.5 mmol) of sodium sulfide are added, The mixture is heated on a 150 ° C. oil bath overnight.   The mixture was cooled to 25 ° C., 50 ml of ethyl acetate and 50 ml of water were added, The organic phase is removed, the aqueous phase is brought to pH = 4 by addition of 10% hydrochloric acid and the phase is treated with acetic acid. Extract again with ethyl. Combine the organic phases, water and then a saturated solution of sodium chloride And dried over magnesium sulfate. The solution was filtered and the solvent was evaporated under reduced pressure. And the residue was subjected to silica gel column chromatography to give dichloromethane. And eluted with a 98/2 mixture of methanol.   The purified fraction is treated with pentane, sonication, ethyl acetate and then di Treat with isopropyl ether. Finally, 1.87 g of solid are isolated.   Melting point: 135-137 [deg.] C. 4A. 2. N- [3- [5- (6-ethoxy-1-naphthyl) -1,3-dioxa N-2-yl] propyl] acetamide   N- [3- [5- (6-hydro) dissolved in 70 ml of N, N-dimethylformamide [Xy-1-naphthyl) -1,3-dioxan-2-yl] propyl] acetamide 4 . 5 g (13.7 mmol), 2.8 g potassium carbonate and 1.5 bromoethane 3 ml (20.5 mmol) are introduced into a 250 ml round bottom flask and the mixture is Stir at room temperature overnight.   Under reduced pressure, the solvent was evaporated by entrainment with toluene and the residue was washed with water and acetic acid. Take up in ethyl and remove the solid by filtration. Rinse with water and ethyl acetate, dry After allowing 2.74 g of solid to be isolated.   The phases were separated, the organic phase was washed, dried, filtered and the solvent was evaporated before further 1.7 g of solid are obtained, ie a total of 4.44 g of compound are obtained.   0.3 g of this product was recrystallized from a 6/4 mixture of ethanol and water, 0.2 g of the compound is isolated.   Melting point: 140-142 ° C. 4A. 3. 5- (6-ethoxy-1-naphthyl) -1,3-dioxane-2-p Lopanamine   N- [3- [5- (6-ethoxy-1-naphthyl) dissolved in 49 ml of ethanol 4.1 g of (-1,3-dioxan-2-yl] propyl] acetamide (11.4 mi 4 mol) and 30% sodium hydroxide (43.4 ml) in a 250 ml round bottom flask. And the mixture is refluxed for 24 hours.   It is then cooled and after the phases have separated, the alcoholic phase is removed and the phase is concentrated. And the residue is taken up in water and extracted with dichloromethane. The organic phase was saturated with sodium chloride. Wash with the sum solution and dry over magnesium sulfate. The solution is filtered and under reduced pressure Evaporate the solvent. The residue was subjected to silica gel column chromatography Elution with a 90/10/1 mixture of dichloromethane, methanol and aqueous ammonia To purify.   1.87 g of a solid are obtained, which product is used in the next step without further purification.   The hydrochloride is prepared from a 0.1 N solution of hydrochloric acid in 2-propanol.   Melting point: 180-183 [deg.] C. 4A. 4. 5- (6-ethoxy-1-naphthyl) -N- (phenylmethyl) -1, 3-dioxane-2-propanamine   5- (6-ethoxy-1-naphthyl) -1,3 dissolved in 450 ml of methanol 1.63 g (5.17 mmol) of dioxane-2-propanamine Into a 1000 ml round bottom flask equipped with a 0.604 g (5.69 mmol) of ndusaldehyde are introduced and the mixture is initially Reflux until reduced to one third of volume.   The mixture was cooled, placed in an ice bath, and 1.56 g of sodium borohydride (41 . 3 mmol) and the mixture is stirred overnight.   The solvent was evaporated under reduced pressure, the white residue was taken up in water and ethyl acetate and the organic phase was separated. Wash twice with water, then once with ethyl acetate, dry over magnesium sulfate and filter. The solvent was evaporated under reduced pressure, and the residual oil was separated by silica gel column chromatography. And elute with a 95/5 mixture of dichloromethane and methanol. And purify.   1.15 g of base are obtained, and 0.1 g of the product is dissolved in hot 2-propanol, 2.46 ml of 0.1 N hydrochloric acid in propanol were added and the solvent was evaporated under reduced pressure, The residue was triturated from diisopropyl ether, filtered and dried in vacuo. To produce the hydrochloride. 0.97 g of the hydrochloride salt is isolated.   Melting point: 206-208 [deg.] C. 4A. 5. 2- [3- [5- (6-ethoxy-1-naphthyl) -1,3-dioxa N-2-yl] propyl] (phenylmethyl) amino] acetamide   5- (6-ethoxy-1-naphthyl) -N-(-) dissolved in 7 ml of acetonitrile (Phenylmethyl) -1,3-dioxane-2-propanamine 0.5 g (1.23 Mmol), 0.17 g (1.23 mmol) of potassium carbonate, sodium iodide 0.055 g (0.369 mmol) and 0.138 of 2-chloroacetamide g (1.47 mmol) was introduced into a 50 ml round bottom flask and the mixture was Reflux. The mixture is cooled, water and ethyl acetate are added, and the organic phase is removed. The aqueous phase is extracted once more, the organic phase is extracted twice with water and then saturated with sodium chloride. Wash once with an aqueous solution, dry over magnesium sulfate, filter and evaporate the solvent under reduced pressure. And the residue was subjected to silica gel column chromatography to give dichloromethane. And eluting with a 99/1 mixture of methanol.   0.590 g of pure base are obtained in the form of a yellow oil, which is obtained with hot 2-propanol. And add 12.3 ml of 0.1N hydrochloric acid in 2-propanol. Under reduced pressure, After evaporation of the solvent, the residue was triturated from diisopropyl ether, Filter and dry under reduced pressure to isolate 0.54 g of the hydrochloride salt.   Melting point: 190-193C.Example 5A (Compound No. 20A) 2-[[3- [5- (6-ethoxy-1-naphthyl) -1,3-dioxan-2-yl ] Propyl] (phenylmethyl) amino] -N-methylacetamide 5A. 1. 2-[[3- [5- (6-ethoxy-1-naphthyl) -1,3-dioxa N-2-yl] propyl] (phenylmethyl) amino] ethyl acetate   5- (6-ethoxy-1-naphthyl) -N- suspended in 15 ml of acetonitrile 0.5 g of (phenylmethyl) -1,3-dioxane-2-propanamine (1.2 3 mmol), 0.42 g (3.07 mmol) of potassium carbonate and 2-bromo 0.2 ml (1.84 mmol) of ethyl acetate are added and the mixture is treated at 60 ° C. with 2. Heat for 5 hours.   20 ml of water and 15 ml of ethyl acetate are added, the organic phase is removed and washed with water And dried over magnesium sulfate, filtered, evaporated under reduced pressure to remove the residue, Dichloromethane and methanol after silica gel column chromatography By eluting with a 98/2 mixture of 0.58 g of an oily product is obtained, This is used in the next step without further purification. 5A. 2. 2-[[3- [5- (6-ethoxy-1-naphthyl) -1,3-dioxa N-2-yl] propyl] (phenylmethyl) amino] -N-methylacetamide   2-[[3- [5- (6-ethoxy-1-naphthyl) -1,3-dioxane-2-i [Propyl] (phenylmethyl) amino] ethyl acetate 0.58 g (1.18 mmol Is dissolved in several ml of ethanol, and 5 ml of 33% methanamine in ethanol is added. And leave the mixture in a 50 ° C. oven for 7 days.   Evaporation of the solvent under reduced pressure gave 0.8 g of an oily product, which was Chromatographically a 98/2 mixture of dichloromethane and methanol To give 0.5 g of pure base in the form of an oil.   After treatment with 10.5 ml of 0.1N hydrochloric acid in 2-propanol, the solvent was evaporated. , Triturated from diisopropyl ether, filtered, dried and finally 0.37 g of the hydrochloride is isolated.   Melting point: 88-90C.Example 6A (Compound No. 23A) 2-[[3- [5- [6- (cyclopentyloxy) -1-naphthyl] -1,3-dioxy San-2-yl] propyl] (phenylmethyl) amino] acetamide 6A. 1. N- [3- [5- [6- (cyclopentyloxy) -1-naphthyl) -1 , 3-Dioxan-2-yl] propyl] acetamide   N- [3- [5- (6-hydroxy-1-naphthyl) -1,3-dioxane-2- 4.5 g (13.6 mmol) of yl] propyl] acetamide and bromocyclo Example 1 except starting with 3.0 g (20.1 mmol) of pentane and running at 80 ° C 4A. Treatment under the same conditions as described in 2 gives 4.88 g of crude compound . 0.388 g of this compound was subjected to silica gel column chromatography Purify by eluting with a 90/10 mixture of dichloromethane and methanol . Recrystallize from a mixture of ethanol and water, then dry in the presence of phosphorus pentoxide. After drying, 0.22 g of the compound is isolated.   Melting point: 136-137 [deg.] C. 6A. 2. 5- [6- (cyclopentyloxy) -1-naphthyl] -1,3-dio Xan-2-propanamine   N- [3- [5- (6-cyclopentyloxy-1-naphthyl) -1,3-dioxy Starting with 4.5 g (11.3 mmol) of san-2-yl] propyl] acetamide Example 4A. Treatment under the same conditions as described in 3 gave 1.52 g of base. Then 1.15 g of the hydrochloride are obtained. 6A. 3. 5- [6- (cyclopentyloxy) -1-naphthyl] -N- (phenyl (Methyl) -1,3-dioxane-2-propanamine   5- (6-cyclopentyloxy-1-naphthyl) -1,3-dioxane-2- 0.59 g (1.66 mmol) of propanamine and 0.1 of benzaldehyde Starting with 94 g (1.82 mmol), Example 4A. Articles similar to the conditions described in 4 To give 0.48 g of the base, from which 0.435 g of the hydrochloride salt is prepared. You.   Melting point: 186-190C. 6A. 4. 2-[[3- [5- [6- (cyclopentyloxy) -1-naphthyl]- 1,3-dioxan-2-yl] propyl] (phenylmethyl) amino] acetamide   5- (6-cyclopentyloxy-1-naphthyl) -N- (phenylmethyl) -1 0.710 g (1.59 mmol) of 3-dioxane-2-propanamine and Starting with 0.178 g (1.9 mmol) of 2-chloroacetamide, Example 4A . Under the same conditions as described in 5 above, 0.640 g of the base was obtained in the form of an oil. And 0.628 g of the hydrochloride is prepared from the base.   Melting point: 212-215 [deg.] C.Example 7A (Compound No. 26A) 2-[[3- [5-[(6- (phenylmethoxy) -1-naphthyl] -1,3-dioxa N-2-yl] propyl] (phenylmethyl) amino] acetamide 7A. 1. N- [3- [5-[(6- (phenylmethoxy) -1-naphthyl] -1,3 -Dioxan-2-yl] propyl] acetamide   N- [3- [5- (6-hydroxy-1-naphthyl) -1,3-dioxane-2- 4.2 g (12.75 mmol) of [yl] propyl] acetamide and Starting with 1.82 ml (15.3 mmol) of tyl) benzene, Example 4A. To two Treatment under the same conditions as described gives 4.67 g of the product, 0.3 g from a 6/4 mixture of ethanol and water to give 0.15 g of a white solid. obtain.   Melting point: 138-140C. 7A. 2. 5- [6- (phenylmethoxy) -1-naphthyl] -1,3-dioxa 2-propanamine   N- [3- [5-[(6-phenylmethoxy) -1-naphthyl] -1,3-dioxa Starting with 2-N-yl] propyl] acetamide, Example 4A. The conditions described in 3 Treatment under similar conditions gives 3.2 g of an oily product, which is purified further Is used in the next step without performing the above. 7A. 3. 5- [6- (phenylmethoxy) -1-naphthyl] -N- (phenylmeth (Tyl) -1,3-dioxane-2-propanamine   5- [6- (phenylmethoxy) -1-naphthyl] -1,3-dioxane-2-p 1.13 g (2.99 mmol) of lopanamine and 0.31 of benzaldehyde 7 g (2.99 mmol) followed by 0.904 g of sodium borohydride (2 3.9 mmol) in Example 4A. Treated under the same conditions as described in 4 To obtain 0.41 g of a base, and using 0.1 g of the base, 0.090 g of a hydrochloride is obtained. .   Melting point: 185-189C. 7A. 4 2-[[3- [5-[(6-phenylmethoxy) -1-naphthyl] -1,3- Dioxan-2-yl] propyl] (phenylmethyl) amino] acetamide   5- [6- (phenylmethoxy) -1-naphthyl] -N- (phenylmethyl) -1, 0.30 g (0.64 mmol) of 3-dioxane-2-propanamine and 2 -Starting with 0.072 g (0.768 mmol) of chloroacetamide, Example 4 A. Under the same conditions as described in 5 above, 0.310 g of the base was obtained in the form of an oil. 0.285 g of the hydrochloride is prepared from the base.   Melting point: 170-175 [deg.] C.   Table A below shows the chemical structures and physical characteristics of a number of compounds represented by the general formula (IA). Shows sex.   "R₁”,“ R_TwoAnd R_Three"Column, cC_ThreeH_FiveIs cyclopropyl Represents a group, cC_FiveH₉Represents a cyclopentyl group;₆H_FiveRepresents a phenyl group .   In the column of "salt", "-" indicates a compound in the form of a base, and "ox." Stands for oxalate (or ethanedioate), "fum" for fumarate (or (E) -2-butennate) and “HCl” represents the hydrochloride salt; the acid / salt The group molar ratio is shown in parentheses.   In the column of “melting point (° C.)”, “(d)” indicates a decomposition melting point.   The compounds are all trans stereoisomers (¹1 H NMR).   In the general formula (IB),   R represents a hydrogen atom or a general formula CH_TwoCOY wherein Y is a hydroxyl group Or (C₁-C_Four) Represents an alkoxy group] or a general formula CH_TwoC ONR₁R_Two[Wherein, R₁And R_TwoIndependently represent a hydrogen atom or (C₁-C_Four ) Represents an alkyl group].   X is an oxygen or sulfur atom or CH_TwoRepresents a group,   m represents 0 or 1,   n represents 0, 1 or 2.   The compound represented by the general formula (IB) may be a cis or trans stereoisomer or It can exist in the form of a mixture of such isomers; furthermore, a ring attached to the nitrogen atom Due to the chirality of certain compounds, certain compounds may be diastereomers and / or It can exist in the form of an enantiomer. They can be in the form of free bases or acid addition salts Can exist.   The compound represented by the general formula (IB) can be produced by the method shown in Scheme B below. Wear.   2- (6-methoxy-1-naphthyl) propane-1,3 represented by the formula (IIB) -Diol as a catalyst in a refluxing aprotic solvent such as toluene 4,4-diethyl compound of the formula (IIIB) in the presence of dry hydrochloric acid dissolved in Reaction with xybutanamine gives 5- (6-methoxy-) of the formula (IVB) 1-naphthyl) -1,3-dioxane-2-propanamine was obtained. The compound is subjected to sodium borohydride under reductive amination conditions well known to those skilled in the art. Neutral or acidic medium in the presence of a reducing agent such as Wherein X, m and n are the same as defined above. With ketones. A general formula corresponding to the general formula (IB) wherein R represents a hydrogen atom The compound represented by (IBa) is obtained.                                Scheme B  The compound represented by the general formula (IBa) is, if desired, then acetonitrile. 2-bromo in a polar aprotic solvent such as Acetic acid (C₁-C_Four) Alkyl, Y is (C₁-C_Four) Represents an alkoxy group The compound represented by the general formula (IBb) is obtained.   If desired, the compound can be saponified under conditions well known to those skilled in the art to yield Y Can be obtained a compound represented by the general formula (IBb), wherein . General formula (IBb) is represented by R₁Is the general formula CH_TwoFormula (I) representing a group represented by COY B).   If desired, the compound represented by general formula (IBb) is then converted to a compound represented by general formula HNR₁R_Two [Wherein, R₁And R_TwoIs the same as defined above]. Thus, an amide represented by the general formula (IBc) can be obtained. The reaction conditions are: It is standard and well known to those skilled in the art.   The amide represented by the general formula (IBc) is also N, N-dimethylformamide In a polar aprotic solvent such as, for example, in the presence of a base such as potassium carbonate; CH_Two-CO-NR₁R_TwoWherein Z represents a chlorine or bromine atom;₁And R_Two Is the same as defined above] by alkylation with a halide represented by the formula: It can be obtained directly from the compound represented by the general formula (IBa).   2- (6-methoxy-1-naphthyl) propane-1 represented by the general formula (IIB) , 3-diols are described in European Patent Application EP-0,461,958. I have. 4,4-Diethoxybutanamine is commercially available and has the general formula (VB) The same applies to the ketone shown.   The following examples further illustrate the preparation of the compounds of general formula (IB). You. Elemental microanalysis and IR and NMR spectra show the structure of the compound obtained. Check the structure. The compound numbers shown in parentheses in the title are the chemical formulas in Table B below. It corresponds to the compound number.Example 1B (Compound No. 1B) 2-[(2,3-dihydro-1H-inden-1-yl) [3- [5- (6-methoxy -1-Naphthyl) -1,3-dioxan-2-yl] amino] ethyl acetate / hydrochloride 1B. 1. 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-p Lopanamine hydrochloride   7.56 g of 2- (6-methoxy-1-naphthyl) propane-1,3-diol ( 6.8 g (42.1 mmol) of 4,4-diethoxybutanamine Mol), and 70 ml of hydrochloric ether were added to 1 l of 300 ml of toluene. The mixture is introduced into a round-bottomed flask and the mixture is refluxed for 2 hours.   The mixture is cooled and the precipitate is collected by filtration and rinsed with diethyl ether.   12.2 g of crude hydrochloride are obtained in the form of a beige solid.   Melting point: 224-226 [deg.] C. 1B. 2. N- (2,3-dihydro-1H-inden-1-yl) -5- (6-meth (Toxy-1-naphthyl) -1,3-dioxane-2-propanamine   In a 500 ml round bottom flask, 5- (6-methoxy- 1-naphthyl) -1,3-dioxane-2-propanamine 3.0 g (9.95 mi) Was dissolved in 1.32 g of 2,3-dihydro- (1H) inden-1-one (1.32 g). 9.95 mmol) and the mixture is refluxed overnight.   The mixture is cooled, 2 g of potassium borohydride are added and stirring is continued for 2.5 hours I can. 100 ml of water are added and the mixture is extracted three times with 50 ml of ethyl acetate. The solvent is evaporated from the organic phase and the residue is subjected to silica gel column chromatography. And purified by eluting with a 9/1 mixture of dichloromethane and methanol I do.   2.79 g of an oily product are obtained. 1B. 3. 2-[(2,3-dihydro-1H-inden-1-yl) [3- [5- ( 6-methoxy-1-naphthyl) -1,3-dioxan-2-yl] propyl] amino ] Ethyl acetate / hydrochloride   N- (2,3-dihydro-1H-inden-1-yl) -5- (6-methoxy-1 -Naphthyl) -1,3-dioxane-2-propanamine 1.88 g (4.5 mm) Mol), 0.8 g (5.8 mmol) of potassium carbonate, 0.1 g of ethyl 2-bromoacetate. 96 g (5.8 mmol), catalytic amounts of sodium iodide and N, N-dimethyl 35 ml of formamide are introduced into a 250 ml round bottom flask and the mixture is brought to 60 ° C. And heat for 3 hours.   100 ml of water are added and the mixture is extracted three times with 150 ml of ethyl acetate, The phases are washed with aqueous sodium chloride and then with aqueous sodium bicarbonate. Dry After drying and evaporation of the solvent, 3.5 g of an oily product are obtained, which product is Silica gel column chromatography using a gradient elution of 5% to 10% ethyl acetate in xane Purify by chromatography. 1.97 g of pure base are obtained, and the base is obtained in 0.1 g. 55 g (1 mmol) and 11 ml of a 0.1 N solution of hydrochloric acid in 2-propanol To produce the hydrochloride salt. After washing with diethyl ether, 0.44 g of the hydrochloride was added. Isolate.   Melting point: 88-90C.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-methyl Ruacetamide / hydrochloride   2-[(2,3-dihydro-1H-inden-1-yl) [3- [5- (6-methoxy C-1- (naphthyl) -1,3-dioxan-2-yl] propyl] amino] ethyl acetate Was introduced into a 250 ml round bottom flask, and methyl 30 ml of a 33% solution of the amine in ethanol are added and the mixture is stirred at room temperature for 2 days. Mix. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography. And eluting with a 98/2 mixture of dichloromethane and methanol Further purification gives 1.16 g of an oily product.   The hydrochloride is prepared using 24 ml of a 0.1 N solution of hydrochloric acid in 2-propanol. You. After washing with diethyl ether, 0.98 g of the hydrochloride is isolated.   Melting point: 112-114 [deg.] C.Example 3B (Compound No. 6B) 5- (6-methoxy-1-naphthyl) -N- (1,2,3,4-tetrahydro-1-na (Futyl) -1,3-dioxane-2-propanamine fumarate   5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanami 3.0 g (9.95 mmol) of ethanol, 90 ml of ethanol and 3,4-dihydro -1-Naphthyl (2H) -one 1.45 g (9.95 mmol) was added to a 250 ml Introduce into the bottom flask and reflux the mixture for 48 hours.   The mixture was cooled and 3 g (55.6 mmol) of potassium borohydride were added. The mixture is stirred for 2 days at room temperature.   Water is added, the mixture is extracted with ethyl acetate, the organic phase is washed with water and dried The solvent was evaporated under reduced pressure, the residue was taken up in dichloromethane and the solvent was evaporated under reduced pressure. Fire.   4.86 g of an oily product are obtained, which product is subjected to silica gel column chromatography. By eluting with a 9/1 mixture of dichloromethane and methanol Purify.   1.6 g of base are obtained, 0.4 g of fumaric acid in 0.4 g of said base and 6 ml of ethanol. The fumarate is prepared using 11 g. 0.27 g of the salt is isolated.   Melting point: 134-136 [deg.] 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   5- (6-methoxy-1-naphthyl) -N- (1,2,3,4-tetrahydro-1- Naphthyl) -1,3-dioxane-2-propanamine 0.85 g (1.97 mm Mol), acetonitrile 20 ml, 2-chloroacetamide 0.28 g (2.9 9 mmol), 0.54 g (3.94 mmol) of potassium carbonate and nato iodide 0.29 g (1.9 mmol) of lithium was introduced into a 250 ml round bottom flask. The mixture is refluxed for 4 hours. 50 ml of water and 25 ml of ethyl acetate are added, The phase is removed, the aqueous phase is extracted twice more with 25 ml of ethyl acetate and the solvent is removed under reduced pressure. Was evaporated and the residue was subjected to silica gel column chromatography to dichloromethine. Purify by eluting with a 9/1 mixture of tan and methanol.   0.6 g of the base is obtained and the hydrochloride is prepared using a 0.1 N solution of hydrochloric acid in 2-propanol. . 25 g are produced.   Melting point: 142-143 [deg.] C.Example 5B (Compound No. 13B) N- (3,4-dihydro-2H-1-benzopyran-4-yl) -5- (6-methoxy (1--1-naphthyl) -1,3-dioxane-2-propanamine hydrochloride   5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanami 2 g (6.6 mmol) were introduced into a 250 ml round bottom flask, and ethanol 1 50 ml and 3,4-dihydro-2H-1-benzopyran-4-one 0.98 3 g (6.6 mmol) are added and the mixture is refluxed overnight.   The mixture is cooled, 2 g of sodium borohydride are added and the mixture is After stirring, 100 ml of water are added and the mixture is extracted four times with 75 ml of ethyl acetate. The solvent is evaporated off under reduced pressure and the residue is dried under reduced pressure.   2.98 g of a solid were obtained, which was subjected to silica gel column chromatography. Purified by eluting with a 9/1 mixture of dichloromethane and methanol 1.3 g of base are obtained in the form of a pale yellow oil.   0.30 g of this base and 5 ml of a 0.1 M solution of hydrochloric acid in 2-propanol were used. To produce the hydrochloride. After washing with diisopropyl ether and drying, 0.08 g of the hydrochloride is obtained.   Melting point: 172-173C.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] a Cetamide / hydrochloride   N- (3,4-dihydro-2H-1-benzopyran-4-yl) -5- (6-meth 0.5 g of (xy-1-naphthyl) -1,3-dioxane-2-propanamine (1. 15 mmol) and 0.16 g (1.72 mmol) of 2-chloroacetamide And treated under conditions similar to those described in Example 4B, After exposure to water, 0.37 g of the compound is obtained in the form of a base, from which the hydrochloride 0.1% is obtained. 7 g are obtained.   165-166 ° C.   Table B below shows the chemical structures and physical properties of a number of compounds represented by general formula (IB). Shows sex.   In the column of "salt", "-" indicates a compound in the form of a base, and "fum." , Fumarate (or (E) -2-butenate), and "ox." Refers to the acid salt (or ethanedioate) and "HCl" refers to the hydrochloride salt; the acid / salt The group molar ratio is shown in parentheses. (^*) Compounds in which the carbon atom bonded to the nitrogen atom is chiral are racemic compounds You. In the column of "salt", "-" indicates a compound in the form of a base, and "fum." Fumarate (or (E) -2-butenedioate); “HCl” refers to hydrochloride The acid / base molar ratio is shown in parentheses. The melting point (° C.) is shown in the last column.   In the general formula (IC),   R₁Is a hydrogen atom or a general formula CH_TwoCOY wherein Y is a hydroxyl group or Is (C₁-C_Four) Represents an alkoxy group], or a general formula CH_TwoCONR_Four R_Five[Wherein, R_FourAnd R_FiveIndependently represent a hydrogen atom or (C₁-C_Four) Al Represents a kill group].   R_TwoIs 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-2 -Pyrrolyl, 2-furyl, 2-thienyl or 1,3-thiazole-2- Ill group [wherein each of the following formulas:Indicated by].   The compound represented by the general formula (IC) may be a cis or trans stereoisomer or They can exist in the form of a mixture of such isomers; It can be in the form of an addition salt.   The compound represented by the general formula (IC) can be produced by the method shown in the following Scheme C. Wear.   2- (6-methoxy-1-naphthyl) propane-1,3 represented by the formula (IIC) -Diol as a catalyst in a refluxing aprotic solvent such as toluene 4,4-diethoxy represented by (IIIC) in the presence of hydrochloride dissolved in water By reacting with butanamine, 5- (6-methoxy-1-) of the formula (IVC) Naphthyl) -1,3-dioxane-2-propanamine, followed by methanol In a protic solvent such as at a temperature of 25 to 60 ° C, water formed during the reaction period is removed. While leaving, the general formula (VC) (where R_TwoIs the same as defined above) Reacting with the aldehyde and then forming the imine with, for example, sodium borohydride. Neutral or acid with a reducing agent such as thorium or any other equivalent agent It is reduced in a neutral medium under reductive amination conditions well known to those skilled in the art. R₁But water A compound represented by the general formula (ICa) corresponding to the general formula (IC) when representing an elementary atom Get things. Scheme C  If desired, the compound represented by the general formula (ICa) is then converted to acetonitrile In a polar aprotic solvent such as, for example, in the presence of a base such as potassium carbonate; CH_Two-CO_Two(C₁-C_Four) Alkyl wherein Z represents a chlorine or bromine atom Alkylation with the indicated haloacetate shows that Y is (C₁-C_Four) Represents an alkoxy group The compound represented by the general formula (ICb) can be obtained.   If desired, the compound can be saponified under conditions well known to those skilled in the art to yield Y Can be obtained a compound represented by the general formula (ICb) wherein . The general formula (ICb) is represented by R₁Is the general formula CH_TwoGeneral when representing a group represented by COY This corresponds to equation (IC).   If desired, the compound of general formula (ICb) is then converted to a compound of general formula HNR_Four R_Five[Wherein, R_FourAnd R_FiveIs the same as defined above.] As a result, an amide represented by the general formula (ICc) can be obtained. This reaction condition Is standard and is well known to those skilled in the art.   The amide represented by the general formula (ICc) is also N, N-dimethylformamide In a polar aprotic solvent such as, for example, in the presence of a base such as potassium carbonate; CH_Two-CO-NR_FourR_FiveWherein Z represents a chlorine or bromine atom;_FourAnd R_Five Is the same as defined above]. As a result, the compound can be directly obtained from the compound represented by the general formula (ICa).   The general formula (ICc) is represented by R₁Is the general formula CH_TwoCONR_FourR_FiveWhen representing a group represented by Of the general formula (IC).   2- (6-methoxy-1-naphthyl) propane-1,3 represented by the formula (IIC) -Diols are described in European patent application EP-0,461,958. . 4,4-Diethoxybutanamine is commercially available and has the general formula (VC) The same applies to aldehydes that are used.   The following examples describe in detail the preparation of a number of compounds of general formula (IC). You. Elemental microanalysis and IR and NMR spectra show the structure of the compound obtained. Check the structure.   The compound numbers shown in parentheses in the title correspond to the compound numbers in Table C below. You.Example 1C (Compound No. 1C) 5- (6-methoxy-1-naphthyl) -N- (4-pyridylmethyl) -1,3-dio Xan-2-propanamine dihydrochloride 1C. 1. 5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-p Lopanamine hydrochloride   7.56 g of 2- (6-methoxy-1-naphthyl) propane-1,3-diol ( 6.8 g (42.1 mmol) of 4,4-diethoxybutanamine Mol) and then 70 ml of dry hydrogen chloride gas dissolved in diethyl ether. Introduce the mixture into a 1 liter round bottom flask containing 300 ml Reflux for a while.   The mixture is cooled and the precipitate is collected by filtration and rinsed with diethyl ether.   12.2 g of crude hydrochloride are obtained in the form of a beige solid.   Melting point: 224-226 [deg.] C. 1C. 2. 5- (6-methoxy-1-naphthyl) -N- (4-pyridylmethyl)- 1,3-dioxane-2-propanamine dihydrochloride   5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanami 0.5 g (1.67 mmol) of methanol and 200 ml of methanol were added to a 250 ml It was introduced into a bottom flask and 0.178 g of pyridine-4-carboxaldehyde (1. 67 mmol) and the mixture is heated at 100 ° C. for 2 hours.   The mixture was cooled, 0.5 g of potassium borohydride was added and the mixture was added to 0.1 g. Stir for 5 hours.   Under reduced pressure, half the methanol was evaporated, 100 ml of water were added and the mixture was treated with acetic acid. Extract three times with 20 ml of ethyl, concentrate the organic phase under reduced pressure, and filter the residue over silica gel. 9/1 mixture of dichloromethane and methanol by column chromatography Purify by eluting with material.   0.57 g of the 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 hydrochloric acid in 2-propanol I do. After washing with diisopropyl ether and drying, 0.12 g of dihydrochloride was added. obtain.   Melting point: 207-208 [deg.] C.Example 2C (Compound No. 3C) 2-[[3- [5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl ] Propyl] (4-pyridylmethyl) amino] acetamide dihydrochloride   5- (6-methoxy-1-naphthyl) -N- (4-pyridylmethyl) -1,3-di 1.2 g (3 mmol) of oxan-2-propanamine was added to acetonitrile 200 0.138 g (0.9 mmol) of sodium iodide, potassium carbonate 0.828 g (6 mmol) and 2-chloroacetamide 0.42 g (4. 5 mmol) and the mixture is refluxed for 3 hours.   Since the reaction was not completed, 0.2 g (1.5 mmol) of potassium carbonate was further added. 0.06 g (0.45 mmol) of sodium iodide and 2-chloroacetamido 0.14 g (1.5 mmol) are added and the mixture is refluxed for a further hour.   The mixture is cooled, 140 ml of water are added and the mixture is extracted four times with ethyl acetate I do. After evaporating the solvent under reduced pressure, the residue was separated by silica gel column chromatography. Eluting with a 9/1 mixture of dichloromethane and methanol Further purification gives 0.3 g of pure base.   The base is salted with 8 ml of a 0.1 N solution of hydrochloric acid in 2-propanol. . After washing with ethyl acetate and drying, 0.17 g of the dihydrochloride is obtained.   Melting point: 169-170C.Example 3C (Compound No. 19C) 5- (6-methoxy-1-naphthyl) -N- (2-thiazolylmethyl) -1,3-di Oxan-2-propanamine   5- (6-methoxy-1-naphthyl) -1,3-dioxane-2-propanami 2.4 g (8 mmol) of methanol, 700 ml of methanol and 1,3-thiazole- 1 g (8.8 mmol) of 2-carboxaldehyde is transferred to a Dean-Stark apparatus Into a 1000 ml round bottom flask equipped with To about 200 ml.   The mixture is cooled, 2.4 g of sodium borohydride are added dropwise and the mixture is left overnight. Stir.   The methanol was evaporated under reduced pressure, the residue was taken up in water and ethyl acetate and the organic phase was evaporated. Take out, wash, dry over magnesium sulfate and evaporate the solvent under reduced pressure . 3.17 g of a base was obtained, and 0.5 g of the base was used under the same conditions as described above. To produce the hydrochloride.   0.5 g of the hydrochloride are obtained.   Melting point: 134-137 [deg.] C.Example 4C (Compound No. 21C) 2-[[3- [5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl ] Propyl] (2-thiazolylmethyl) amino] acetamide hydrochloride   5- (6-methoxy-1-naphthyl) -N- (2-thiazolylmethyl) -1,3- 0.7 g (1.75 mmol) of dioxane-2-propanamine and 2-chloro Starting with 0.2 g (2.1 mmol) of loacetamide, under the same conditions as in Example 2C To give 0.76 g of base, from which 0.763 g of hydrochloride salt was prepared. Build.   Melting point: 189-191C.   Table C below shows the chemical structures and physical properties of a number of compounds represented by general formula (IC). Shows sex.   "R_Two”Column, C_FiveH_FourN-2- represents a 2-pyridyl group;_FiveH_FourN -3- represents a 3-pyridyl group;_FiveH_FourN-4- represents a 4-pyridyl group, CH_Three-1-C_FourH_ThreeN-2- represents a 1-methyl-2-pyrrolyl group;_FourH_ThreeO -2- represents a 2-furyl group;_FourH_ThreeS-2- represents a 2-thienyl group;_Three H_TwoNS-2- represents a 1,3-thiazol-2-yl group.   In the column of "salt", "-" indicates a compound in the form of a base, and "fum." , Fumarate (or (E) -2-butenedioate), and "ox." Refers to the acid salt (or ethanedioate) and "HCl" refers to the hydrochloride salt; the acid / salt The group molar ratio is shown in parentheses.   In the column of “melting point (° C.)”, “(d)” indicates a decomposition melting point.   In the general formula (ID),   Y is a hydroxyl group, (C₁-C_Four) Alkoxy group or general formula NR_FourR_Five[In the formula , R_FourAnd R_FiveIndependently represent a hydrogen atom or (C₁-C_Four) Alkyl group Represents a group represented by   R₁And R_TwoTogether with the nitrogen and carbon atoms connecting them Pyrrolidine ring, piperidine ring or 1,2,3,4-tetrahydroisoquinoline Form a ring.   The compound represented by the general formula (ID) is a cis or trans stereoisomer or It can exist in the form of a mixture of such isomers; furthermore, for the group -C (O) Y Due to the asymmetric carbon atom α, they can be pure enantiomers or enantiomers. -Can be present in the form of a mixture. They may also be in the form of free base or acid addition salts. Can exist in a state. The compound represented by the general formula (ID) is prepared according to the method described in the following Scheme D. Can be manufactured.   2- (6-methoxy-1-naphthyl) propane-1,3 represented by the formula (IID) Diol in an aprotic solvent in an acidic medium in an aprotic solvent Reacting with-(3-chloropropyl) -1,3-dioxolane to form a compound of formula (IVD) Shown 2- (3-chloropropyl) -5- (6-methoxy-1-naphthyl) -1, 3-Dioxolane is obtained, and finally the compound is treated with an organic compound at a temperature of 20-110 ° C. Or in an inorganic base, in an aprotic solvent such as N, N-dimethylformamide, General formula (VD) [wherein, Y and R₁And R_TwoIs the same as defined above] React with the amine.                                Scheme D  2- (6-methoxy-1-naphthyl) propane-1,3 represented by the formula (IID) -Diols are described in European Patent Application EP-0,461,958 . 2- (3-chloropropyl) -1,3-dioxolan is commercially available. General The amines of formula (VD) are commercially available or described in the literature I have.   The following examples illustrate the preparation of a number of compounds of general formula (ID). You. Elemental microanalysis and IR and NMR spectra indicate the structure of the compound obtained. Check. The compound numbers shown in parentheses in the title are the compounds in Table D below. It corresponds to the object number.Example 1D (Compound No. 1D) Ethyl 1- [3- [5- (6-methoxy-1-naphthyl) -1,3-dioxane-2 -Yl] propyl] -L-prolinate oxalate 1D. 1. 2- (3-chloropropyl) -5- (6-methoxy-1-naphthyl)- 1,3-dioxane   5 g of 2- (6-methoxy-1-naphthyl) propane-1,3-diol (21. 5 mmol), 3.7 ml of 2- (3-chloropropyl) -1,3-dioxolane ( 28.05 mmol) and then 40 ml of hydrochloric ether were added to 150 ml of toluene. into a 500 ml round bottom flask and reflux the mixture for 6 hours.   The mixture was cooled and 100 ml of a 5% aqueous sodium hydrogen carbonate solution was added. The mixture is extracted twice with 100 ml of ethyl acetate. The organic phase is washed with water and Dry with cesium, filter, evaporate the solvent under reduced pressure and concentrate the residue on silica gel. 9/1 mixture of petroleum ether and ethyl acetate after ram chromatography Purify by eluting with 3.2 g of a white solid are obtained and the product is purified further. Used in the next step without production. 1D. 2. Ethyl 1- [3- [5- (6-methoxy-1-naphthyl) -1,3-di Oxan-2-yl] propyl] -L-prolinate oxalate   2- (3-chloropropyl) -5- (6-methoxy-1-naphthyl) -1,3-di Oxane 0.32 g (1 mmol), ethyl L-prolinate 0.22 g (1. 2 mmol), 0.3 g (2.2 mmol) of potassium carbonate, and then potassium iodide. 0.29 g (2 mmol) of N, N-dimethylformamide in 10 ml. Into a 50 ml round bottom flask and heat the mixture at 100 ° C. for 4 hours.   The mixture is cooled, 50 ml of water are added and the mixture is treated with 70 ml of ethyl acetate. Extract twice, wash the organic phase with water, dry over magnesium sulfate, filter, and evaporate Under reduced pressure, the solvent is evaporated and the residue is subjected to silica gel column chromatography. Elution with a gradient of 99.5 / 0.5 to 99/1 of chloromethane and methanol To purify.   0.22 g (0.5 mmol) of the compound was obtained, which was converted from ethyl acetate to oxalate. Crystallizes in the form of   Melting point: 116-118 [deg.] C.Example 2D (Compound No. 2D) 1- [3- [5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl] Propyl] -L-prolinamide   2- (3-chloropropyl) -5- (6-methoxy-1-naphthyl) -1,3-di Oxane 0.5 g (1.6 mmol), L-prolinamide 0.2 g (1.9 mi) Remol), potassium carbonate 0.2 g (1.6 mmol), and then potassium iodide 0.48 g (3.2 mmol) and 15 ml of N, N-dimethylformamide Into a sealed 50 ml round bottom flask and heat the mixture at 110 ° C. for 3.5 hours You.   The mixture was cooled, 60 ml of water were added and the resulting mixture was Extract twice with l. The organic phase is washed with water, dried over magnesium sulfate, filtered and The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography. And elute with a gradient from 99/1 to 97/3 of dichloromethane and methanol To purify. 0.3 g of compound was obtained, which was converted from 2-propanol to the base. Crystallizes in form.   Melting point: 164-166C.Example 3D (Compound No. 6D) 2- [3- [5- (6-methoxy-1-naphthyl) -1,3-dioxan-2-yl] Propyl] -N-methyl-1,2,3,4-tetrahydroisoquinoline-3-carbo Oxamide oxalate 3D. 1. N-methyl-1,2,3,4-tetrahydroisoquinoline-3-cal Boxamide   1.75 g of ethyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (8.5 mmol) in 25 ml of a 33% solution of methylamine in ethanol Into a 100 ml round bottom flask and leave the mixture at 25 ° C. for 20 hours. Concentrate to dryness under reduced pressure to obtain 1.7 g of the compound in the form of a colorless oil. Used in the next step without further purification. 3D. 2. 2- [3- [5- (6-methoxy-1-naphthyl) -1,3-dioxa 2-Nyl] propyl] -N-methyl-1,2,3,4-tetrahydroisoquinolyl N-3-carboxamide oxalate   2- (3-chloropropyl) -5- (6-methoxy-1-naphthyl) -1,3-di 0.5 g (1.6 mmol) of oxane, N-methyl-1,2,3,4-tetrahydride 0.3 g (1.6 mmol) of loisoquinoline-3-carboxamide, potassium carbonate 0.2 g (1.6 mmol) of potassium iodide followed by 0.23 g (1.5 mmol) of potassium iodide Lmol) into a 100 ml round bottom flask containing 20 ml of acetonitrile And heat the mixture at 80 ° C. for 8 hours.   The mixture was cooled, 20 ml of water were added and the resulting mixture was Extract twice with l. The organic phase is washed with water, dried over magnesium sulfate, filtered and The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography. And eluted with a 98/2 mixture of dichloromethane and methanol. To make. 0.12 g (0.25 mmol) of the compound was obtained, Crystallizes from ether in the form of oxalate.   88-90 ° C.   Table D below shows the chemical structures and physical properties of a number of compounds represented by the general formula (ID). Shows sex.   "R₁NCHR_Two”Column,“ pyrrol ”,“ piper ”and“ i soq ”is R₁And R_TwoIs the same as the nitrogen and carbon atoms to which they are attached. A pyrrolidine ring, a piperidine ring, or 1,2,3,4-tetra It means forming a hydroisoquinoline ring.   In the column of "salt", "-" indicates a compound in the form of a base, and "fum." , Fumarate (or (E) -2-butenate), and "ox." Refers to the acid salt (or ethanenate) and "HCl" refers to the hydrochloride salt; the acid / salt The group molar ratio is shown in parentheses.   In the column of “melting point (° C.)”, “(d)” indicates a decomposition melting point.   The compounds of the present invention are subjected to pharmacological tests to elucidate their value as therapeutic substances. did.Neuronal antisodium properties   Calcium entry induced by depolarization stimulation in rat cortical synaptosomes Is Neurosciences Letters (1996)220 117-120. Deffois et al. To According to the method described more fully, it can be measured using a fluorescent probe.   Veratridine ( 10 μM), the effect of a sodium-channel agonist is 0.1-10 μm. M IC₅₀(Concentration that inhibits the response by 50%) by the compound of the present invention. It is.Activity against tonic convulsions induced in mice by ultra-maximal electric shock   This test method is described in Antipiepileptic Drugs, Raven Press, New York, 111-126 (19 82) in E.A. Swinyard and J.H. Written by Woodhead.   Ten minutes after intravenous administration of the test compound, Apelex ETC UNIT 7801^TMDress Immediately after applying a current using a device (0.4 seconds, 60 mA, 50 Hz), tonic convulsions The number of mice showing (forelimb and hindlimb extension) is recorded. 3 or 4 results Was administered to groups of 8 mice each, and Probit was administered.^TMSoftware Using J.T. Lichtfield and F.S. Wilcoxon's method (J. Pharm. Exp. Ther.,96, 99-113 (1949)), which is the dose that protects 50% of the animals, AD₅₀ Expressed by AD of the most active compound₅₀Values range from 1 to 10 mg / kg.Anti-ischemic properties   Compounds were subjected to a global cerebral ischemia test in mice.   Ischemia is caused by cardiac arrest induced by rapid intravenous injection of magnesium chloride. Is caused. In this test, the "survival time", that is, magnesium chloride The interval between the time of injection of the mouse and the last observable respiratory movement of each mouse is measured. This Is considered to be the final indicator of central nervous system function. Breathing chloride Stop approximately 9 seconds after magnesium injection.   1 male mouse (Charles River CD1) Experiment as a loop. They can be fed and watered freely before the test. The present invention Survival time is measured 10 minutes after intraperitoneal administration of the compound. The results show that Time and liquid biomass measured in a group of 10 With the survival time measured in a group of 10 mice receiving vehicle. In the form of differences between them. The correlation between changes in survival time and compound dose is Recorded in graphical form on a logarithmic curve.   This curve shows the “3 second effective amount” (ED_{3 "}), Ie, from 10 untreated mice Calculate the dose (mg / kg) that increases the survival time by 3 seconds compared to the control group Make it available.   The 3 second increase in survival time is statistically significant and reproducible. You.   ED of the most active compounds of the invention_{3 "}Values range from about 0.05-0. 2 mg / kg.Antinociceptive activity   Antinociceptive activity was measured by Pain (1992)51 A. in 5-17 Tjolsen, O.-G. Berge, S. Hunskaar, J.H. Rosland and K.S. Formalin test improved from Hole study Are evaluated in rats during the second stage of the test.   Inject (5 μl) subcutaneously with formalin (5%) into the plantar arch of the left hind limb. Injected limb By measuring the total time of licking activity between +20 and +35 minutes And between +35 and +60 minutes, the number of tremors measured for 2 consecutive minutes every 5 minutes. And quantifies nociception.   Compounds are given at doses of 30 and 60 mg / kg 30 minutes before formalin injection. Orally (5 ml / kg) as a suspension (water + 1% Tween 80).   Compounds are compared to values measured in animals receiving vehicle after treatment, A statistically significant reduction in the total time of licking activity and / or the number of shaking movements ( (p <= 0.05) is considered active if observed.   The activity threshold for the compounds according to the invention corresponds to a reduction of 35 to 40%. most Active compound causes 50% reduction at 30 mg / kg dose via oral route You.   The results of the tests show that the compounds of the invention have neuroprotective activity and that Therefore, if they are cerebrovascular disorders of ischemic or hypoxic origin (cerebral infarction, Are bone marrow trauma, heartbeat or respiratory arrest, transient ischemic attacks, perinatal asphyxia), glaucoma, Progressive neurodegenerative diseases (senile dementia such as Alzheimer's disease, vascular dementia, parkin Nsonson's disease, Huntington's disease, Olive bridge cerebellar atrophy, amyotrophic lateral sclerosis, Will In the treatment or prevention of neurodegenerative diseases of cardiac origin and in the heart and blood Of a medicament useful for prevention of cerebral ischemic accidents associated with vascular surgery and endovascular treatment It can be used for   Because of their anticonvulsant properties, they can also be used to treat epilepsy Wear. The compounds of the present invention also have analgesic properties, and are therefore Can be used to treat chronic pain.   Finally, neuropathy, nervous pain (eg, neuropathy or one-headed Pain associated with pain attacks), treatment of other complaints such as neurological spasms and dyskinesia Also predictable.   The compounds of the present invention can be used in combination with suitable excipients in an amount of Tablets, coated tablets, gelatin capsules, Fur capsules, drinkable or injectable suspensions or solutions (e.g., syrups, Any pharmaceutical compositions suitable for oral or parenteral administration, such as State.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/4433 A61K 31/4433 31/4725 31/4725 A61P 9/10 A61P 9/10 25/00 25 / 00 25/04 25/04 25/08 25/08 25/14 25/14 25/16 25/16 25/28 25/28 27/06 27/06 43/00 111 43/00 111 C07D 405/12 C07D 405/12 407/12 407/12 409/12 409/12 417/12 417/12 (31) Priority claim number 97/06946 (32) Priority date June 5, 1997 (1997.6.5) (33) Priority claim country France (FR) (31) Priority claim number 97/06947 (32) Priority date June 5, 1997 (6.5 June 1997) (33) Priority claim country France (FR (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS) , MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR , BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, GW, HU, ID, IL, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI , SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Georges, Pascal F, France-78730 Saint-Arnaud-le-en-Yveline, Rue des Cartes van 19

Claims (1)

[Claims]   1. General formula (IA): [Where,   R₁Is a hydrogen atom, linear or branched (C_Two-C_Four) Alkyl group, cyclo (C_Three -C₆) Alkyl group, cyclo (C_Three-C₆) Alkylmethyl group, or optionally Phenyl (C)₁-C_Three) Represents an alkyl group,   R_TwoIs a hydrogen atom, linear or branched (C₁-C_Four) Alkyl group, cyclo (C_Three -C₆) Alkyl group, cyclo (C_Three-C₆) Alkylmethyl group, or optionally Phenyl (C)₁-C_Three) Represents an alkyl group,   R_ThreeIs a hydroxyl group, (C₁-C_Four) Alkoxy group or general formula NR_FourR_Five(formula Medium, R_FourAnd R_FiveAre each independently a hydrogen atom, a linear or branched (C₁− C_Four) Alkyl group, cyclo (C_Three-C₆) Alkyl or cyclo (C_Three-C₆) Alkyl Represents a methyl group) A pure stereoisomer or a stereoisomer in the form of a base or acid addition salt represented by In the form of a mixture of   2. General formula (IB):[Where,   R represents a hydrogen atom or a general formula CH_TwoCOY (where Y is a hydroxyl group Or (C₁-C_Four) Represents an alkoxy group) or a general formula CH_TwoC ONR₁R_Two(Where R₁And R_TwoIndependently represent a hydrogen atom or (C₁-C_Four ) Represents an alkyl group),   X is an oxygen or sulfur atom or CH_TwoRepresents a group,   m represents 0 or 1,   n represents 0, 1 or 2] A pure stereoisomer or stereoisomer in the form of a free base or acid addition salt represented by A compound in the form of a mixture of sexes.   3. General formula (IC): [Where,   R₁Is a hydrogen atom or a general formula CH_TwoCOY (where Y is a hydroxyl group or Or (C₁-C_Four) Represents an alkoxy group) or a general formula CH_TwoCON R_FourR_Five(Where R_FourAnd R_FiveIndependently represent a hydrogen atom or (C₁-C_FourA) Represents a alkyl group),   R_TwoIs 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-methyl-2 -Pyrrolyl, 2-furyl, 2-thienyl or 1,3-thiazole-2- Represents an yl group] A pure stereoisomer or stereoisomer in the form of a free base or acid addition salt represented by A compound in the form of a mixture of sexes.   4. General formula (ID): [Where,   Y is a hydroxyl group, (C₁-C_Four) Alkoxy group or general formula NR_FourR_Five(In the formula , R_FourAnd R_FiveIndependently represent a hydrogen atom or (C₁-C_Four) Alkyl group Represents a group represented by   R₁And R_TwoTogether with the nitrogen and carbon atoms connecting them Pyrrolidine ring, piperidine ring or 1,2,3,4-tetrahydroisoquinoline Form a ring] A pure stereoisomer or stereoisomer in the form of a free base or acid addition salt represented by A compound in the form of a mixture of sexes.   5. A medicament comprising the compound according to any one of claims 1 to 4.   6. A compound according to any one of claims 1 to 4 in combination with an excipient. A pharmaceutical composition comprising: