KR910008202B1 - Process for the preparation of benzamide deriviatives - Google Patents

Abstract

No content.

Description

Method for preparing benzamide derivative

The present invention relates to a process for preparing benzamide derivatives, in particular N-aminoethyl-substituted benzamides of general formula (I) and pharmaceutically useful acid addition salts thereof:

Wherein R ¹ and R ² are each independently hydrogen, halogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, sulfamoyl, mono (lower alkyl) sulfamoyl or di (lower alkyl) sulfamoyl; Or R ¹ and R ² together represent an methylenedioxy group on adjacent carbon atoms, provided that when R ¹ is bromine in the 3-position, R ² is not hydrogen.

Such compounds are somewhat known, for example, in JP 2,458,908 but surprisingly it has been found by the present invention that they are important and exhibit therapeutically useful low toxicity pharmacodynamic properties. Accordingly, it was found in the present invention that the compounds of the general formula (I) and pharmaceutically useful acid addition salts thereof have monoamine oxidase (MAO) inhibitory properties in the present invention.

An object of the present invention is a pharmaceutically active substance comprising a compound of formula (I) and a pharmaceutically useful acid addition salt thereof, a compound of formula (I) or a pharmaceutically useful acid addition salt thereof, such a medicament A method of preparing and the use of a compound of formula (I) or a pharmaceutically useful acid addition salt thereof, useful for the treatment and prevention of diseases or for the promotion of health, in particular for the treatment and prevention of depression and Parkinson's syndrome.

Among the compounds contained in the above general formula (I), the benzamide of the general formula (Ia) and acid addition salts thereof are novel, and in themselves are also objects of the invention.

Wherein R ¹¹ is halogen, cyano or trifluoromethyl, R ²¹ is hydrogen, or R ¹¹ and R ²¹ are each chlorine, or R ¹¹ and R ²¹ are methylenedioxy groups together on adjacent carbon atoms Indicates.

The final object of the present invention is a method for preparing compounds of general formula (Ia) and pharmaceutically useful acid addition salts thereof.

The term "lower alkyl" as used herein refers to straight and branched chain hydrocarbon groups of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, tert-butyl, etc.). The term "lower alkoxy" refers to a lower alkyl ester group wherein the term "lower alkyl" is the same as defined above. The term "halogen" includes four halogens (ie fluorine, chlorine, bromine and iodine). The term "leaving group" in the context of the present invention is a known group such as halogen, preferably chlorine or bromine, arylsulfonyloxy (e.g. tosyloxy), alkylsulfonyloxy (e.g. mesyloxy) and the like.

The term “pharmaceutically useful acid addition salts” includes salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluene Sulfonic acid and the like). Such salts can be readily prepared by those skilled in the art at a considerable technical level, remembering the properties of the compounds that can be converted into such salts.

Preferred compounds of formula (I) are those in which R ¹ and R ² are each independently hydrogen, halogen, lower alkyl, lower alkoxy, cyano or trifluoromethyl.

Particularly preferred compounds of formula (I) are those wherein R ¹ and R ² are each independently hydrogen, halogen or lower alkyl.

When the compound of formula (I) is disubstituted, the substituents are 2, 3-, 2, 4-, 2, 5-, 3, 4- or 3, 6-positions, in particular 2, 4- or 3, 4- It is preferably present at the location.

Particularly preferred compounds of general formula (I) are as follows:

N- (2-aminoethyl) -p-chlorobenzamide; N- (2-aminoethyl) -p-fluorobenzamide; N- (2-aminoethyl) -p-bromobenzamide; N- (2-aminoethyl) -3, 4-dichlorobenzamide; N- (2-aminoethyl) -2, 4-dichlorobenzamide; And N- (2-aminoethyl) benzamide.

Compounds of formula (Ia) and pharmaceutically useful acid addition salts thereof include (a) reacting a compound of formula (II) with ethylenediamine in the form of a free acid or in the form of a reactive functional derivative thereof, or (b) Reacting the compound of formula (III) with ammonia, or (c) converting the R ⁵ group in the compound of formula (IV) to an amino group and optionally converting the obtained compound into a pharmaceutically useful acid addition salt It can be prepared according to the invention by converting to:

Wherein R ¹¹ and R ²¹ are as defined above; R ³ is hydrogen and R ⁴ is a leaving group or R ³ and R ⁴ together represent an additional bond and R ⁵ is a group which can be converted to an amino group.

Reactive functional derivatives of acids of general formula (II) include, for example, halides (eg chlorides), symmetric or mixed anhydrides, esters (eg methyl esters, p-nitrophenyl esters or N-hydroxy succinimide esters). ), Azide and amide such as imidazolide or succinimide.

According to the method (a) in the above process, the reaction of the acid of formula (II) or a reactive functional derivative thereof with ethylenediamine can be carried out according to a conventional method. Thus, for example, the free acid of general formula (II) and ethylenediamine can be made to react in presence of a condensing agent in an inert solvent. When carbodiimide (eg dicyclohexyl carbodiimide) is used as a condensing agent, the reaction is conveniently carried out with alkancarboxylic acid esters (eg ethyl acetate), ethers (eg tetrahydrofuran or dioxane), chlorinated hydrocarbons (E.g. methylene chloride or chloroform), aromatic hydrocarbons (e.g. benzene, toluene or xylene), acetonitrile or dimethylformamide at about -20 ° C to room temperature, preferably about 0 ° C. When phosphorus trichloride is used as a condensing agent, the reaction is conveniently carried out at a temperature of about 0 ° C. to the reflux temperature of the reaction mixture, preferably about 90 ° C., in a solvent such as pyridine. In another embodiment of process (a), ethylenediamine is reacted with one of the reactive functional derivatives of the acid of general formula (II) mentioned above. Thus, for example, the halide (eg chloride) of the acid of formula (II) and ethylenediamine can be reacted at about 0 ° C. in the presence of a solvent (eg diethyl ether).

Examples of the compound of formula (III) wherein R ³ is hydrogen and R ⁴ is a leaving group include, for example, N- (2-haloethyl) benzamide [e.g., N- (2-chloroethyl) benzamide, N- (2-methylsulfonylethyl) benzamide or N- [2- (p-toluenesulfonyl) ethyl) benzamide and the like]. As the compound of the general formula (III) in which R ³ and R ⁴ together represent additional bonds, for example, benzoylaziridine (eg, p-chlorobenzoylaziridine, etc.).

According to the in-process method (b), the compound of formula (III) and ammonia are optionally from about -40 ° C to 50 in the presence of a solvent (e.g., dimethylformamide, dimethylacetamide, dimethyl sulfoxide, etc.). It can react by a well-known method at the temperature of ° C. The reaction is conveniently carried out at about room temperature in the presence of a solvent. When benzoylaziridine of formula (III) is used, the reaction is preferably carried out in the presence of an inert solvent such as dimethylformamide, toluene or benzene.

According to the method (c) in the above process, the conversion of the R ⁵ group to the amino group is performed similarly to the known method depending on the characteristics of the R ⁵ group. If R ⁵ is an amide group, this conversion is conveniently carried out by acidic or basic hydrolysis. Acidic hydrolysis advantageously uses inorganic acid solutions (e.g. hydrochloric acid, aqueous hydrobromic acid, sulfuric acid, phosphoric acid, etc.) in an inert solvent such as alcohol (e.g. methanol or ethanol) or ether (e.g. tetrahydrofuran or dioxane). It is preferable to carry out. Basic hydrolysis can be carried out using an aqueous solution of alkali metal hydroxides (eg potassium hydroxide or sodium hydroxide). Inert organic solvents such as those mentioned above in connection with acidic hydrolysis can be added as solubilizers. Acidic and basic hydrolysis can be carried out at about room temperature to the reflux temperature of the mixture, preferably at or below the boiling point of the mixture. When R ⁵ is a phthalimido group, it can be converted to amino groups by ammonolysis using an aqueous solution of lower alkylamines (eg methylamine or ethylamine) as well as acidic and basic hydrolysis. Lower alkanols such as ethanol can be used as the organic solvent. It is preferable to perform this reaction at room temperature. A third method of converting phthalimido groups to amino groups is to use compounds of the general formula (IV) (wherein R ⁵ is a phthalimido group) and hydrazine with an inert solvent (e.g., a mixture of ethanol, ethanol and chloroform, tetra Hydrofuran or aqueous ethanol). The reaction temperature can be varied in the range of from about room temperature to about 100 ° C. and is preferably the boiling point of the selected solvent. The obtained product can be extracted with dilute inorganic acid and then basified to obtain from acidic solution. The conversion of the trichloroethoxy carbonylamino group to the amino group is carried out using zinc or cadmium under acidic conditions, while the conversion of the t-butoxycarbonylamino group to the amino group is usually in the presence of an inert solvent or In the absence at about room temperature using trifluoroacetic acid or formic acid. Acidic conditions can conveniently be obtained by subjecting the reaction in acetic acid in the presence or absence of additional inert solvents such as alcohols (eg methanol). Benzylolcarbonylamino groups can be converted to amino groups by known methods by acidic hydrolysis or hydrogenolysis described above. Azido groups can be converted to amino groups according to methods known per se, using hydrogen elements, for example in the presence of catalysts (eg palladium / carbon, Raney-nickel, platinum oxide, etc.). In addition, hexamethylenetetraammonium groups can also be converted to amino groups by acidic hydrolysis according to known methods.

The compounds of formula (II) and their reactive functional derivatives used as starting materials in process (a) above are known or can be prepared analogously to the preparation of known compounds.

The compounds of formula (III) used as starting materials in process (b) above are also known or analogues of known compounds, and can themselves be prepared by known methods. Thus, for example, a compound of formula (II) or a reactive functional derivative thereof and ethanolamine are reacted under the reaction conditions described in connection with method (a) above, and the resulting N- (2-hydroxyethyl) Benz amides are known per se by, for example, halogenating agents (e.g., phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, etc.), arylsulfonyl halides (e.g. tosyl chloride) or alkylsulfonyl By reacting with a halide such as mesyl chloride to the desired compound of formula III, compounds of formula III can be prepared wherein R ³ is hydrogen and R ⁴ is leaving group have. Compounds of formula (III), wherein R ³ and R ⁴ together represent additional defects, can be prepared, for example, by reacting reactive functional derivatives of compounds of formula (II) with ethyleneimine. . This reaction can be carried out under the reaction conditions described in connection with method (a) above.

The compounds of formula (IV) used as starting materials in process (c) are also known, or are themselves analogues of known compounds and can be prepared by known methods. Thus, for example, a compound of formula (II) or a reactive functional derivative thereof and a compound of formula (V) can be reacted under the conditions described in the above method (a).

Wherein R ⁵ is as defined above.

Compounds of general formula (V) are known or can be prepared analogously to the preparation of known compounds.

According to another method, the compound of the general formula (IV), wherein R ⁵ is phthalimido, azido or hexamethyltetraammonium, is a compound of the general formula (III) with potassium phthalimide, an alkali metal It can be prepared by reacting with azide or hexamethylenetetramine. This method is carried out by known methods under the reaction conditions described above in connection with method (b).

As mentioned above, the compound of Ilbab (I) and pharmaceutically useful acid addition salts thereof have monoamine oxidase (MAO) inhibitory activity. Based on this activity, the compounds of formula (I) and pharmaceutically useful acid addition salts thereof can be used for the treatment of depression and Parkinson's syndrome.

MAO inhibitory activity of the compounds according to the invention can be detected using standard methods. Therefore, the material to be tested is parentally administered to the rat. After 2 hours, rats were killed and phenethylamine (2 · 10 ⁻⁵ mol · 1 ⁻¹ ) instead of tyramine as substrate was used to inhibit MAO in brain and liver disruption, according to the method described below. Measure action [Biochem. Pharmacol. 12 (1963) 1439-1441. In addition to the thus detected activity of the representative compounds according to the invention, their toxicity is also determined by the following ED ₅₀ values (μmol / kg, parenteral administration to rats) and LD ₅₀ values (mg / kg, parenteral administration to mice) Becomes obvious.

Compounds of formula (I) and pharmaceutically useful acid addition salts thereof can be used in pharmaceuticals, for example pharmaceutical formulations. Pharmaceutical formulations may be administered orally (eg in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solvents, emulsions or suspensions). However, it may also be administered rectally (eg in the form of suppositories) or parenterally (eg in the form of injection solutions).

To prepare tablets, coated tablets, dragees and hard gelatine capsules, the compounds of formula (I) and pharmaceutically useful acid addition salts thereof can be processed with pharmaceutically inert, inorganic or organic excipients. Examples of such excipients that can be used in tablets, dragees and hard gelatin capsules are lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof.

Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolids, liquid polyols and the like.

Suitable excipients for the preparation of solvents and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like.

Suitable excipients for injection solutions include, for example, water, alcohols, polyols, glycerin, vegetable oils and the like.

Suitable excipients for suppositories include, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

Pharmaceutical formulations may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts that change the osmotic pressure, buffers, coatings or antioxidants. They may also contain other pharmaceutically useful substances.

According to the invention, the compounds of formula (I) and pharmaceutically useful acid addition salts thereof can be used for the treatment or prevention of depression and Parkinson's syndrome. Dosages can vary widely and are adjusted to the individual needs in each particular case. Typically, in the case of oral administration, it should be pointed out that a daily dosage of about 10 to 100 mg of compound of formula (I) is suitable, but may exceed its upper limit given above.

The following examples illustrate the invention but are not intended to limit its scope. All temperatures are given in degrees Celsius (° C.).

Example 1

18.5 g of ethyl 4-chlorobenzoate and 24 g of ethylenediamine are stirred at 130 ° C. for 17 hours. The mixture is cooled to room temperature and evaporated before the residue is treated with 200 ml of ethyl acetate. 2.3 g of insoluble N, N'-ethylenebis (4-chlorobenzamide) having a melting point of 266 to 268 ° C are filtered off by suction, the filtrate is washed three times with 50 ml of water each time and evaporated. The residue is treated with 100 ml of 1N hydrochloric acid, 1.0 g of insoluble N, N'-ethylenebis (4-chlorobenzamide) is suction filtered and the filtrate is evaporated to dryness. The residue is evaporated twice with 100 ml of ethanol / benzene each time and recrystallized from ethanol / ether. 13.7 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride having a melting point of 216 to 217 ° C is obtained.

Example 2

9.25 g of ethyl 4-chlorobenzoate and 16.0 g of N- (t-butoxycarbonyl) ethylenediamine are stirred at 130 ° C. for 15 hours. The mixture is cooled to room temperature and dissolved in 100 ml of water and extracted three times with 50 ml of ethyl acetate each time. The ethyl acetate extract is washed twice with 50 ml of water each time, dried over sodium hydroxide and evaporated to dryness. The crystalline residue is dissolved in isopropyl ether and filtered off by suction. 3.9 g of t-butyl [2- (4-chlorobenzamido) ethyl] carbamate having a melting point of 141 to 143 ° C is obtained.

A solution of 2.8 g of t-butyl [2- (4-chlorobenzamido) ethyl] carbamate in 50 ml of formic acid is allowed to stand for 1.5 hours at room temperature. The mixture is concentrated to dryness and the residue is dissolved in 50 ml of hydrochloric acid (1: 1 V / V). The solution is concentrated and the residue is evaporated twice with ethanol / benzene and then recrystallized with ethanol. 2.1 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride as the product obtained in Example 1 is obtained.

Example 3

23 ml of triethylamine (0.17 water) were added dropwise to a suspension of 23.5 g (0.15 mol) of 4-chlorobenzoic acid and 15 ml (0.16 mol) of ethyl chloroformate in 200 ml of chloroform at 0 ° C. After completion of the dropwise addition (30 minutes), the obtained solution is added dropwise to 50 ml (0.75 mol) of an ethylenediamine solution in 100 ml of chloroform at 0 ° C. After the reaction was completed, 115 ml of concentrated hydrochloric acid was added dropwise at 0 ° C. The acidic mixture is filtered and the remaining neutral component is extracted by chloroform and removed. The aqueous phase is made basic with sodium hydroxide solution and extracted several times with chloroform. Chloroform extract is dried and concentrated. The residue is converted to hydrochloride and recrystallized from ethanol / ether. 15.1 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride having a melting point of 212 to 214 ° C is obtained. The free base is melted at 43 to 45 ° C.

Example 4

19.1 g (0.1 mol) of 2,4-dichlorobenzoic acid are suspended in 200 ml of methylene chloride and 15.3 ml (0.11 mol) of triethylamine are added to the solution. 10 ml (0.1 mol) of ethyl chloroformate are added dropwise at 0 ° C. After the dropping is complete (30 minutes), pour the mixture into ice / water. The methylene chloride phase is separated, dried over magnesium sulphate and concentrated to about 30 ml. This solution is added dropwise to 20 ml (0.3 mol) of an ethylenediamine solution in 100 ml of tetrahydrofuran at 0 ° C. After completion of the dropwise addition (30 minutes), the mixture is filtered, the filtrate is acidified with dilute hydrochloric acid, and the neutral component is extracted and removed with ethyl acetate. The aqueous phase is made basic with sodium hydroxide solution and extracted several times with chloroform. After drying, the chloroform phase is concentrated and the residue is converted to hydrochloride. After recrystallization with ethanol / ether, 7.1 g of N- (2-aminoethyl) -2,4-dichlorobenzamide hydrochloride having a melting point of from 179 to 182 ° C are obtained.

Example 5

22.1 ml (0.16 mol) of triethylamine are added dropwise to a suspension of 23.5 g (0.15 mol) of 2-chlorobenzoic acid in 200 ml of chloroform at 10 ° C. Then 14.8 ml (0.155 mol) of ethyl chloroformate are added dropwise at the same temperature. After the dropping is complete (1 hour), the mixture is poured into ice / water. The chloroform phase is separated, dried over magnesium sulfate and then slowly concentrated to about 60 ml. The solution thus obtained is added dropwise to 40.1 ml (0.6 mol) of an ethylenediamine solution in 400 ml of chloroform at 10 ° C. After completion of the dropwise addition, the poorly soluble components are filtered and the filtrate is concentrated, and the mass of ethylenediamine is removed under high vacuum. The residue obtained (31.5 g) is converted to hydrochloride and purified by recrystallization from ethanol / ether. 19.2 g of N- (2-aminoethyl) -2-chlorobenzamide hydrogen chloride having a melting point of 155 to 158 ° C. (see Example 6 of JP 2,362,568) are obtained. Analytical pure samples melt at 159-161 ° C.

In a similar manner, 13.5 g of N- (2-aminoethyl) -3-chlorobenzamide hydrochloride having a melting point of 201 to 203 ° C from 23.5 g (0.15 mole) of 3-chlorobenzoic acid [Ref. 2, 616, 486]. The free base (from ethyl acetate / n-hexane) is dissolved at 69-71 ° C.

Example 6

24.4 g of benzoic acid are reacted with triethylamine and ethyl chloroformate in a similar manner as described in Example 5 and added dropwise to 53.5 ml (0.8 mole) of ethylenediamine solution in 750 ml of chloroform at 10 ° C. After the poorly soluble neutral component is removed by filtration, the chloroform solution is concentrated and excess ethylenediamine is removed in high vacuum. 36.3 g of an oily residue is dissolved in 200 ml of 2N sodium hydroxide solution, saturated with solid sodium chloride, and extracted several times with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate and concentrated. The crude product was converted to hydrochloride and then recrystallized with ethanol and purified to give 5.2 g of N- (2-aminoethyl) benzamide hydrochloride having a melting point of 163 to 165 [deg.] C. J. Amer. Chem. Soc. 61, 822 (1939).

Example 7

To a suspension of 6.4 g (0.04 mol) of 4-methoxybenzoic acid in 60 ml of chloroform was added dropwise 5.5 ml (0.04 mol) of triethylamine at 10 ° C., followed by dropwise addition of 3.8 ml (0.04 mol) of ethyl chloroformate. The resulting solution was added dropwise to a solution of 10.7 ml (0.16 mol) of ethylenediamine in 100 ml of chloroform at 5 ° C. After stirring for 2 hours at room temperature, the mixture is filtered. The filtrate is concentrated under reduced pressure and excess ethylene diamine is removed under high vacuum. The residue is acidified with hydrochloric acid and extracted several times with ethyl acetate. The aqueous phase is made basic with 28% sodium hydroxide solution and extracted three times with chloroform. After drying and the chloroform extract is concentrated, the residue is converted to hydrochloride. Recrystallization with ethanol / ether gave 3.4 g of N- (2-aminoethyl) -4-anisamide hydrochloride having a melting point of 186 to 189 ° C (see Example 7 of JP 2,616,486). do. The free base melts at 37 to 38 ° C.

In a manner similar to the above, 8.7 g of N- (2-aminoethyl) -4-toluamide hydrochloride having a melting point of 164 to 166 DEG C from 20.4 g (0.15 mol) of 4-methylbenzoic acid [Ref. Publication 2,616,486; From 17.2 g (0.09 mol) of 3,4-dichlorobenzoic acid, 9.1 g of N- (2-aminoethyl) -3,4-dichlorobenzamide hydrochloride having a melting point of 183 to 185 ° C was obtained (free base is 98 to 100). Melt at ° C.); 9.3 g of N- (2-aminoethyl) -2-anisamide hydrochlorite having a melting point from 12.2 g (0.08 mol) of 2-methoxybenzoic acid to 109 to 111 ° C. [Ref. 2,362,568] Example 6 of the call; 6.2 g of N- (2-aminoethyl) -3-anisamide hydrochloroide having a melting point of 96 to 98 ° C. was obtained from 12.2 g (0.08 mol) of 3-methoxybenzoic acid; N- (2-aminoethyl) -5- (dimethylsulfamoyl) -2-no having a melting point of 193 to 195 ° C. (decomposition) from 3.9 g (0.015 mol) of 5- (dimethylsulfamoyl) -2-methoxybenzoic acid 1.4 g of samide hydrochloride is obtained (our base melts at 118-123 ° C.).

Example 8

In a manner similar to that described in Example 7, 11.8 g (0.08 mole) of 4-cyano benzoic acid was reacted with triethylamine and ethylchloroformate and worked up, followed by dropwise addition to 21.4 ml of ethylenediamine solution in 350 ml of chloroform. After adding 45 ml of dimethylformamide, the mixture is heated to 60 ° C. for 1 hour. After filtration, the filtrate is concentrated and the residue is treated in the same manner as described in Example 7. 3.5 g of N- (2-aminoethyl) -4-cyanobenzamide hydrochloride having a melting point of 212 to 215 ° C (decomposition) is obtained. The free base melts at 124-126 ° C.

In a similar manner, N- (2-aminoethyl) -α, α, α-trifluoro-4-toluimid hydro having a melting point of 196-199 ° C. from 4.5 g (0.023 mol) of 4-trifluoromethylbenzoic acid. 3.1 g of chloride are obtained. The free base melts at 66-68 ° C.

Example 9

6.2 ml (0.05 mol) of 4-chlorobenzoyl chloride solution in 150 ml ether are added dropwise to a solution of 10 ml (0.15 mol) ethylenediamine in 150 ml ether over 30 minutes at −10 ° C. The mixture is allowed to warm to rt and filtered, then the white residue is washed twice with ether. After concentrating the ether solution, the residue is acidified with dilute hydrochloric acid and extracted several times with ethyl acetate to remove the neutral component. The aqueous phase is made basic with sodium hydroxide solution and extracted several times with chloroform. After evaporating chloroform, the residue was converted to hydrochloride, recrystallized from ethanol / ether, and then 1.8 g of N- (2-aminoethyl) -4-chlorobenzamide hydrogen chloride as the product obtained in Example 1 To obtain.

In a similar manner, N- (2-aminoethyl) -2, 4-dichlorobenzamide with a melting point of 178-179 ° C., such as the product obtained in Example 4 from 7 ml (0.05 mol) of 2, 4-dichlorobenzoyl chloride Obtain 1.7 g of hydrochloride

Example 10

7 g (0.039 mol) of methyl 3, 4-methylenedioxybenzoate and 8.5 ml (0.126 mol) of ethylenediamine are heated to 100 ° C. (bath temperature) for 2.5 hours. After cooling, excess ethylenediamine is removed at high vacuum. The residue is acidified with dilute hydrochloric acid and extracted with chloroform. The aqueous phase is basified with sodium hydroxide and then extracted several times with chloroform. After evaporation of the solvent and recrystallization of the residue with chloroform / hexane, 3.4 g of N- (2-aminoethyl) -1, 3-benzdioxol-5-carboxamide having a melting point of 120 to 123 ° C are obtained. Hydrochloride is dissolved at 210 to 213 ° C.

Example 11

10.7 g (0.05 mol) of methyl 4-bromobenzoate and 10.4 ml (0.15 mol) of ethylenediamine are heated to 130 ° C. (bath temperature) for 30 minutes. Post-treatment in a manner similar to that described in Example 10 followed by recrystallization with methanol / ether to give 6.5 g of N- (2-aminoethyl) -4-bromobenzamide hydrochloride having a melting point of 229 to 232 ° C. do.

Example 12

10.7 ml (0.16 mol) of ethylenediamine are added to 6.65 g (0.04 mol) of methyl 4-methoxybenzoate. The solution is heated to 130 ° C. (bath temperature) for 2 hours and after cooling, excess ethylenediamine is removed in high vacuum. The residue is acidified with dilute hydrochloric acid. The poorly soluble neutral component is removed by filtration and then extracted with ethyl acetate. The aqueous phase is made basic with 28% sodium hydroxide solution, saturated with sodium chloride and extracted three times with chloroform. The chloroform extract is dried over magnesium sulfate and concentrated. The residue is converted to hydrochloride and recrystallized from ethanol / ether. 3.8 g of N- (2-aminoethyl) -4-anisamide hydrochloride having a melting point of 201 to 204 DEG C (see Example 7 of JP 2,616,468) are obtained.

In a similar manner, N- (2-aminoethyl) -4 having a melting point of 132 to 135 ° C (decomposition) from 20 g (0.1 mol) of methyl 4-chloro-2-methoxybenzoate and 20.1 ml (0.3 mol) of ethylenediamine. 8.9 g of -chloro-2-anisamide hydrochloride are obtained.

Example 13

7.7 g (0.05 mol) of methyl 4-fluorobenzoate and 10 ml (0.15 mol) of ethylenediamine are heated to 130 ° C. (bath temperature) for 2 hours. The mixture is poured onto ice / hydrochloric acid and extracted with ethyl acetate to remove neutral components. The aqueous phase is made basic with sodium hydroxide solution and extracted several times with chloroform. After drying and concentrating the chloroform extract, the residue (7.6 g) is recrystallized from ethyl acetate / hexanes to give N- (2-aminoethyl) -4-fluorobenzamide having a melting point of 57 to 60 ° C. . Hydrochloride melts at 214-216 ° C.

Example 14

A 1.3 ml (0.01 mol) solution of 4-chlorobenzoyl chloride in 15 ml of chloroform was added to 1.02 g (0.01 mol) of acetylethylenediamine [J. Amer. Chem. Soc. 61, 822 (1939) and a solution of 1.4 ml (0.01 mol) of triethylamine in 25 ml of chloroform are added dropwise at 0 ° C. After 15 minutes the resulting crystals are filtered off, washed with chloroform and dried. 1.9 g of N- (2-acetylaminoethyl) -4-chlorobenzamide having a melting point of 222 to 224 ° C is obtained.

To remove the protecting group, the obtained N- (2-acetylaminoethyl) -4-chlorobenzamide was heated to reflux for 22 hours in a mixture of 24 ml of 2N hydrochloric acid and 15 ml of ethanol. After concentration of the solution, the crude product is recrystallized from ethanol / ether. 1.2 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride having a melting point of 211 to 213 ° C, like the product obtained in Example 1, is obtained.

Example 15

2.6 ml (0.02 mol) of 4-chlorobenzoyl chloride are added dropwise to a solution of 1.2 ml (0.02 mol) of ethanolamine and 3 ml (about 0.02 mol) of triethylamine in 30 ml of methylene chloride at 0 ° C. The mixture is poured into dilute hydrochloric acid and extracted twice with methylene chloride. The methylene chloride extract is dried over magnesium sulfate and concentrated. After purification on silica gel using chloroform and chloroform / methanol (9: 1) as eluent, 3.1 g of N- (2-hydroxyethyl) -4-chlorobenzamide are obtained.

0.6 ml of methanesulfonyl chloride solution in 3 ml of methylene chloride was added dropwise to a solution of 1.5 g (0.0075 mol) of N- (2-hydroxyethyl) -4-chlorobenzamide and 1 ml of triethylamine in 15 ml of methylene chloride at 0 ° C. do. After 15 minutes, the mixture is poured into ice / water and extracted. 2.1 g of crystalline form N- (2-methylsulfonyloxyethyl) -4-chlorobenzamide is obtained, which is used without further purification in the next step.

The obtained N- (2-methylsulfonyloxyethyl) -4-chlorobenzamide is dissolved in 5 ml of dimethylformamide and added dropwise to ammonia solution in dimethylformamide at room temperature. After stirring for 2 hours, the mixture is worked up and N- (2-aminoethyl) -4-chlorobenzamide is obtained as in the product obtained in Example 1.

Example A

Peristaltic Gelatin Capsule (5mg)

ingredient

*) Corresponds to 5 mg of base.

Way :

Components 1 to 5 are mixed and the mixture is filtered through a 0.5 mm mesh sieve. Add component 6 and mix the resulting mixture. The processed mixture is filled into peristaltic gelatin capsules of the appropriate size (e.g. 2) with an individual filling amount of 240 mg.

Example B

Tablets (5 mg)

ingredient

*) Corresponds to 5 mg of base.

Way :

Ingredients 1-3 are mixed and the mixture is sieved through a 0.5 mm mesh size sieve. The powder mixture is moistened with a solution of component 4 and kneaded. The wet mass is granulated, dried and then converted to the appropriate molecular size. 5, 6 and 7 are subsequently added to the dried granules and the resulting mixture is mixed. The processed mixture is compressed into tablets of the appropriate size so that the individual weight is 200 mg.

Example C

Peristaltic Gelatin Capsule (10mg)

ingredient

*) Corresponds to 10 mg of base.

Way :

Ingredients 1 to 5 are mixed and the mixture is sieved through a 0.5 mm mesh size sieve. Add component 6 and mix the resulting mixture. The finished mixture is filled into peristaltic gelatin capsules of suitable size (e.g. 2) with an individual filling amount of 240 mg.

Example D

Tablets (10 mg)

ingredient

*) Corresponds to 10 mg of base.

Way :

Ingredients 1-3 are mixed and the mixture is sieved through a 0.5 mm mesh size sieve. The powder mixture is moistened with an alcoholic solution of component 4 and kneaded. The wet mass is granulated, dried and then converted to the appropriate molecular size. 5, 6 and 7 are subsequently added to the dried granules and the resulting mixture is mixed. The processed mixture is compressed into tablets of the appropriate size with a 200 mg individual dose.

Claims (6)

A process for preparing a benzamide derivative of formula (Ia) or a pharmaceutically useful acid addition salt thereof, characterized by reacting a compound of formula (II) with ethylenediamine in the form of a free acid or a reactive functional derivative thereof.

Wherein R ¹¹ is halogen, cyano or trifluoromethyl, R ²¹ is hydrogen, R ¹¹ and R ²¹ are each chlorine or R ¹¹ and R ²¹ together are on methylenedioxy group Indicates. The process according to claim 1, wherein a compound of formula (II) wherein R ¹¹ is halogen and R ²¹ is hydrogen or R ¹¹ and R ²¹ are each chlorine is used as starting material. A process for preparing a benzamide derivative of formula (Ia) or a pharmaceutically useful acid addition salt thereof, characterized by reacting a compound of formula (III) with ammonia

Wherein R ¹¹ is halogen, cyano or trifluoromethyl, R ²¹ is hydrogen, R ¹¹ and R ²¹ are each chlorine or R ¹¹ and R ²¹ are methylenedioxy groups together on adjacent carbon atoms R ³ is hydrogen and R ⁴ is a leaving group, or R ³ and R ⁴ together represent an additional bond. 4. A process according to claim 3, wherein the compound of formula III is used as starting material wherein R ¹¹ is halogen and R ²¹ is hydrogen or R ¹¹ and R ²¹ are each chlorine. A process for preparing a benzamide derivative of formula (Ia) or a pharmaceutically useful acid addition salt thereof, characterized by the conversion of the R ⁵ group to an amino group in the compound of formula (IV).

Wherein R ¹¹ is halogen, cyano or trifluoromethyl, R ²¹ is hydrogen, R ¹¹ and R ²¹ are each chlorine or R ¹¹ and R ²¹ are methylenedioxy groups together on adjacent carbon atoms R ⁵ is a group which can be converted into an amino group. The process according to claim 5, wherein the compound of formula IV is used as starting material, wherein R ¹¹ is halogen and R ²¹ is hydrogen or R ¹¹ and R ²¹ are each chlorine.