JPH0430389B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to benzamide derivatives. More specifically, the present invention relates to the general formula In the formula, R ¹ and R ² each independently represent hydrogen, halogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, sulfamoyl, mono(lower alkyl)sulfamoyl or di(lower alkyl)sulfamoyl, or are adjacent to each other. R ¹ and R ² on the carbon atom together represent a methylenedioxy group, provided that R ² is different from hydrogen when R ¹ represents bromine in the 3-position, -Aminoethyl-substituted benzamides and pharmaceutically usable acid addition salts thereof. It has now been found that some of these compounds, which are known for example from German Patent Application No. 2458908, exhibit interesting and therapeutic pharmacological properties with low toxicity. . Thus, in animal experiments, compounds of the above formula and their pharmaceutically usable acid addition salts were found to have monoamine oxidase (MAO) inhibiting properties. The object of the present invention is to contain compounds of the general formula and their pharmaceutically usable acid addition salts as pharmaceutically active substances, compounds of the general formula or their pharmaceutically usable acid addition salts. Compounds of the general formula and their pharmaceutically usable acid additions in medicaments, the manufacture of such medicaments and the control or prevention of diseases or the improvement of health, in particular in the control or prevention of depressive conditions and parkisonism. This is the use of salt. Among the compounds included in the above formula, the general formula where R ¹¹ represents halogen, cyano or trifluoromethyl, and R ²¹ represents hydrogen, or R ¹¹ and R ²¹ each represent chlorine;
The benzamides and acid addition salts thereof, in which R ¹¹ and R ¹² on adjacent carbon atoms together represent a methylenedioxy group, are new and likewise are an object of the present invention. . A final object of the invention is a process for the preparation of compounds of formula a above and their pharmaceutically usable acid addition salts. As used herein, the term "lower alkyl" refers to straight-chain and branched hydrocarbons containing 1 to 6, preferably 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-
Indicates butyl, isobutyl, tert-butyl, etc.
The term "lower alkoxy" means "lower alkyl"
represents a lower alkyl ether group having the above meaning. The term "halogen" includes the four halogens, fluorine, chlorine, bromine and iodine. "Leaving group" is understood within the scope of the invention to mean any of the known groups such as halogen, preferably chlorine or bromine,
Arylsulfonyloxy, such as tosyloxy, alkylsulfonyloxy, such as mesyloxy, and the like. The term "pharmaceutically usable acid addition salts" includes 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, Includes salts with acids, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid, and the like. Such salts can be readily prepared by those skilled in the art having regard to the state of the art and the nature of the compound to be converted into the salt. Preferred compounds of the formula are those in which R ¹ and R ² each independently represent hydrogen, halogen, lower alkyl, lower alkoxy, cyano or trifluoromethyl. Particularly preferred compounds of the formula are those in which R ¹ and R ² each independently represent hydrogen, halogen or lower alkyl. If the compound of formula is disubstituted, this substituent is preferably 2,3-, 2,4-, 2,5-
-, 3,4- or 3,6-position, especially 2,4-
or in the 3,4-position. Particularly preferred compounds of the formula are: N-(2-aminoethyl)p-chlorobenzamide, N-(2-aminoethyl)p-fluorobenzamide, N-(2-aminoethyl)p-bromo Benzamide, N-(2-aminoethyl)-3,4-dichlorobenzamide, N-(2-aminoethyl)-2,4-dichlorobenzamide and N-(2-aminoethyl)benzamide. According to the invention, the compounds of formula a and their pharmaceutically usable acid addition salts have: (a) the general formula In the formula, R ¹¹ and R ¹² have the above meanings,
(b) in its free acid form or in its reactive functional derivative form with ethylenediamine; In the formula, R ¹¹ and R ¹² have the above meanings, and R ³
represents hydrogen and R ⁴ represents a leaving group or R ³ and R ⁴ together represent an additional bond, or (c) a compound of the general formula In the formula, R ¹¹ and R ²¹ have the above meanings, and R ⁵ represents a group that can be converted into an amino group, converting the group R ⁵ in the compound into an amino group,
If necessary, it can be produced by converting the obtained compound into a pharmaceutically usable acid addition salt. Examples of reactive functional derivatives of acids of the formula include halides (e.g. chloride), symmetrical or mixed anhydrides, esters (e.g. methyl ester, p
-nitrophenyl esters or N-hydroxysuccinimide esters), azides and amides (for example imidazolides or succinimides). The reaction of the acid of formula or its reactive functional derivative with ethylenediamine according to method (a) above can be carried out according to conventional methods. Thus, for example, a free acid of formula can be reacted with ethylenediamine in an inert solvent in the presence of a condensing agent. When using a carbodiimide, e.g. dicyclohexylcarbodiimide, as condensing agent, the reaction can be carried out using an alkane carboxylic ester, e.g. ethyl acetate, an ether, e.g. tetrahydrofuran or dioxane, a chlorinated hydrocarbon, e.g. methylene chloride or chloroform, an aromatic hydrocarbon, e.g. benzene, toluene or xylene,
in acetonitrile or dimethylformamide at a temperature between about -20°C and room temperature, preferably about 0°C.
is carried out advantageously. When using phosphorus trichloride as condensing agent, the reaction is advantageously carried out in a solvent, for example pyridine, at a temperature between about 0°C and the reflux temperature of the reaction mixture, preferably about 90°C. In another embodiment of method (a), ethylenediamine is reacted with one of the reactive functional derivatives of the acid of the above formula. Thus, for example, a halide (eg chloride) of an acid of the formula can be reacted with ethylenediamine in the presence of a solvent such as diethyl ether at about 0°C. Compounds of the formula in which R ³ represents hydrogen and R ⁴ represents a leaving group are, for example, N-(2-haloethyl)
Benzamide, e.g. N-(2-chloroethyl)
benzamide, N-(2-methylsulfonylethyl)benzamide, N-[2-(p-toluenesulfonyl)ethyl]benzamide, and the like.
Compounds of the formula in which both R ³ and R ⁴ represent an additional bond are benzoylaziridines, such as p-chlorobenzoylaziridine. According to method (b) above, a compound of the formula is prepared in a manner known per se at a temperature between about -40°C and 50°C, optionally in the presence of a solvent such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, etc. It can be reacted with ammonia below. This reaction is advantageously carried out in the presence of a solvent at about room temperature. When using benzoylaziridines of the formula, the reaction is preferably carried out in the presence of an inert solvent, such as dimethylformamide, toluene or benzene. The conversion of the group R ⁵ to an amino group by the above method (c) is
Depending on the nature of the radical R ⁵ , this is likewise carried out in a manner known per se. If R ⁵ represents an amide group, this conversion is advantageously carried out by acidic or basic hydrolysis. Acidic hydrolysis uses an inert solvent,
It is advantageously carried out, for example, using solutions of inorganic acids such as hydrochloric acid, aqueous hydrogen bromide, sulfuric acid, phosphoric acid, etc. in alcohols (eg methanol or ethanol) or ethers (eg tetrahydrofuran or dioxane). Basic hydrolysis can be carried out using aqueous solutions of alkali metal hydroxides, such as potassium hydroxide or sodium hydroxide. For acidic hydrolysis, inert organic solvents such as those mentioned above can be added as solubilizing agents. Acidic and basic hydrolysis can be carried out at temperatures ranging from about room temperature to the reflux temperature of the mixture, with temperatures at or slightly below the boiling point of the mixture being preferred.
If R ⁵ represents a phthalimide group, this group can be converted into an amino group not only by acidic and basic hydrolysis but also by aminolysis with aqueous solutions of lower alkylamines such as methylamine or ethylamine. can. Lower alkanols, such as ethanol, can be used as organic solvents. This reaction is preferably carried out at room temperature. A third method for the conversion of a phthalimide group into an amino group consists in reacting a compound of the formula in which R ⁵ represents a phthalimide group with hydrazine in an inert solvent such as ethanol, a mixture of ethanol and chloroform, tetrahydrofuran or aqueous ethanol. Become. The reaction temperature can vary from about room temperature to 100°C, preferably the boiling point of the chosen solvent. The resulting product can be extracted with dilute inorganic acid and then basified and obtained from the acidic solution. The tert-butoxycarbonylamino group is advantageously converted to an amino group using trifluoroacetic acid or formic acid in the presence or absence of an inert solvent at about room temperature, while the amino group of the trichloroethoxycarbonylamino group The conversion to is carried out using zinc or cadmium under acidic conditions. Acidic conditions are advantageously achieved by carrying out the reaction in acetic acid in the presence or absence of an additional inert solvent, such as an alcohol (eg methanol).
A benzyloxycarbonylamino group can be converted to an amino group in known manner by acidic hydrolysis as described above or by hydrogenolysis. The azide group can be prepared in a manner known per se, for example palladium/carbon, Raney nickel,
Elemental hydrogen can be used to reflux the amino groups in the presence of a catalyst such as platinum oxide. Hexamethylenetetraammonium groups can also be converted to amino groups by acidic hydrolysis according to known methods. The compound of the formula and its reactive functional derivative used as a starting material in the above method (a) are known or can be produced by a method similar to the production of known compounds. The compounds of the formula used as starting materials in process (b) above are likewise known or are homologs of known compounds and can be prepared in processes known per se. Thus, for example, a compound of the formula in which R ³ represents hydrogen and R ⁴ represents a leaving group can be prepared by reacting a compound of the formula or a reactive functional derivative thereof with ethanolamine under the reaction conditions described for process (a) above. and the resulting N
-(2-hydroxyethyl)benzamide in a manner known per se, e.g. with a halogenating agent,
For example, phosphorus trichloride, phosphorus tribromide, phosphorus oxychloride, etc., arylsulfonyl halides such as tosyl chloride, or alkylsulfonyl halides,
It can be prepared by conversion to the desired compound of formula, for example by reaction with mesylcroside. Compounds of the formula in which R ³ and R ⁴ both represent an additional bond can be prepared, for example, by reacting a reactive functional derivative of a compound of the formula with ethyleneimine. This reaction can be carried out under the reaction conditions mentioned for method (a). Similarly, the compounds of the formula used as starting materials in process (c) above are known or are homologues of known compounds and can be prepared in processes known per se. Thus, for example, a compound of the formula or a reactive functional derivative thereof may be prepared under the conditions mentioned in connection with process (a) above with the general formula _H2N - _CH2 - _CH2 - ^R5 ...where ^R5 has the above meaning. It can be reacted with a compound having . Compounds of formula are known or can be prepared analogously to the preparation of known compounds. According to a variant of this method, R ⁵ is phthalimide,
A compound of the formula representing azide or hexamethyltetraammonium can be prepared by reacting a compound of the formula with potassium phthalimide, an alkali metal azide or hexamethylenetetramine. This reaction is carried out in a manner known per se.
The above method is carried out under the reaction conditions mentioned for method (b) above. As noted above, compounds of formula and their pharmaceutically usable acid addition salts have monoamine oxidase (MAO) inhibiting activity. Based on this activity,
Compounds of formula and their pharmaceutically acceptable acid addition salts can be used in the treatment of depressive conditions and parkinsonismus. The MAO inhibitory activity of compounds according to the invention can be demonstrated using standard methods. That is, the test substance was orally administered to rats. Two hours later, the animals were sacrificed and the MAO inhibitory activity was determined using Biochem.
Pharmacol. 12 (1963) 1439-1441, but using phenethylamine (2 x 10 ^-5 mol/) instead of tyramine as the substrate.
The homogeneity of the brain and liver was determined. The activity of representative compounds according to the invention thus determined as well as their toxicity are evident from the following ED ₅₀ values (μmol/Kg in rats, p.o.) and LD ₅₀ (mg/Kg in mice, p.o.), respectively:

Table: The compounds of the formula and their pharmaceutically usable acid addition salts can be used as medicaments, eg in the form of pharmaceutical preparations. Pharmaceutical preparations can be administered orally (eg in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions). however,
Administration can also be carried out rectally (eg in the form of suppositories) or parenterally (eg in the form of injection solutions). Compounds of formula and their pharmaceutically acceptable acid addition salts are treated with therapeutically inert inorganic or organic excipients to produce tablets, coated tablets, dragees and hard gelatin capsules. can do. Examples of such excipients that can be used in tablets, dragees and hard gelatin capsules are lactose,
Corn starch or its derivatives, talc, stearic acid or its salts, etc. Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semisolid and liquid polyols, and the like. Suitable excipients for preparing solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose and the like. Suitable excipients for injection solutions are, for example, water, alcohols, polyols, glycerin, vegetable oils and the like. Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, and the like. Pharmaceutical preparations also include preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents,
Salts, buffers, coatings or antioxidants can be included to alter the osmotic pressure. In addition, the pharmaceutical preparation may also contain other therapeutically valuable substances. According to the invention, compounds of the general formula and their pharmaceutically usable acid addition salts can be used in the prevention or prevention of depressive conditions and parkinsonismus. Dosage can vary within a wide range;
Of course, it can be adapted to the individual needs in each particular case. Generally, for oral administration, a dosage of about 10 to 100 mg/day of a compound of the general formula will be suitable, although it may sometimes be necessary to exceed the above-mentioned upper limit. The following examples further illustrate the invention, but do not limit its scope. Example 1 18.5 g of ethyl 4-chlorobenzoate and 24 g of ethylenediamine were stirred at 130°C for 17 hours. The mixture was cooled to room temperature, evaporated and the residue was treated with 200ml of ethyl acetate. Insoluble N,N'-ethylenebis(4-chlorobenzamide) (2.3g), melting point
At 266-268℃, aspirate and dilute the solution with 50ml of water each.
Washed twice and evaporated. 100% of the residue in 1N hydrochloric acid
ml, insoluble N,N'-ethylenebis(4-chlorobenzamide) (1.0 g) was removed by suction, and the liquid was evaporated to dryness. The residue was then evaporated twice with 100 ml each of ethanol/benzene and recrystallized from ethanol/ether. Melting point 216-217
13.7 g of N-(2-aminoethyl)-4-chlorobenzamide hydrochloride was obtained. Example 2 9.5 g of ethyl 4-chlorobenzoate and N-(tert
-butoxycarbonyl)ethylenediamine 16.0g
was stirred at 130°C for 15 hours. The mixture was cooled to room temperature, taken up in 100 ml of water and 50 ml each of ethyl acetate.
Extracted three times. The ethyl acetate extract was washed twice with 50 ml each of water, dried over sodium sulfate and evaporated to dryness. The crystalline residue was taken up in isopropyl ether and filtered off with suction. Melting point 141-143℃
3.9 g of tert-butyl [2-(4-chlorobenzamido)ethyl]carbamate was obtained. [2-(4-chlorobenzamide) in 50 ml of formic acid
A solution of 2.8 g of tert-butyl]carbamate was allowed to stand at room temperature for 1.5 hours. The mixture was then concentrated to dryness and the residue was dissolved in 50 ml of hydrochloric acid (1:1; V/V). The solution was concentrated and the residue was evaporated twice with ethanol/benzene and then recrystallized from ethanol. 2.1 g of N-(2-aminoethyl)-4-chlorobenzamide hydrochloride were obtained, which was identical to the product obtained in Example 1. Example 3 23 ml (0.17 mol) of triethylamine was dissolved in 23.5 g (0.15 mol) of 4-chlorobenzoic acid in 200 ml of chloroform.
The mixture was added dropwise to a suspension of 15 ml (0.16 mol) of ethyl chloroformate at 0°C. After addition (0.5 hours),
The resulting solution was added dropwise to a solution of 50 ml (0.75 mol) of ethylenediamine 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 was filtered and the remaining neutral components were removed by extraction with chloroform. The aqueous phase was then made alkaline with sodium hydroxide solution and extracted several times with chloroform. The chloroform extract was dried and concentrated. Converting the residue to the hydrochloride,
This was recrystallized from ethanol/ether. N-(2-aminoethyl)- with melting point 212-214°C
15.1 g of 4-chlorobenzamide hydrochloride was obtained. The free base melted at 43-45°C. Example 4 2,4-dichlorobenzoic acid 19.1g (0.1 mol)
was suspended in 200 ml of methylene chloride and brought into solution by addition of 15.3 ml (0.11 mol) of triethylamine. Next, add 10 ml (0.1 mol) of ethyl chloroformate to 0.
It was added dropwise at ℃. After the addition was complete (0.5 h), the mixture was poured onto ice/water. The methylene chloride phase was separated, dried over magnesium sulphate and concentrated to a volume of approximately 30 ml. This solution was added dropwise to a solution of 20 ml (0.3 mol) of ethylenediamine in 100 ml of tetrahydrofuran at 0°C. After the addition was complete (0.5 h), the mixture was filtered, the liquid was made acidic with dilute hydrochloric acid, and the neutral components were removed by extraction with ethyl acetate. The aqueous phase was made alkaline with sodium hydroxide solution and extracted several times with chloroform. After drying and concentrating the chloroform phase, the residue was converted to the hydrochloride. ethanol/
After recrystallization from ether, N- with a melting point of 179-182°C
7.1 g of (2-aminoethyl)-2,4-dichlorobenzamide hydrochloride was obtained. Example 5 22.1 g (0.16 mol) of triethylamine were added dropwise to a suspension of 23.5 (0.15 mol) 2-chlorobenzoic acid in 200 ml of chloroform at 10°C. Next, 14.8 ml (0.155 mol) of ethyl chloroformate was added dropwise at the same temperature. After the addition was complete (1 hour), the mixture was poured onto ice/water. The chloroform phase was separated, dried over magnesium sulfate, and gently concentrated to a volume of approximately 60 ml. The solution thus obtained was added to a solution of 40.1 ml (0.6 mol) of ethylenediamine in 400 ml of chloroform at 10°C.
It was dripped. After the addition was complete, the poorly soluble neutral components were separated, the liquid was concentrated, and the excess ethylenediamine was removed under high vacuum. The resulting residue (31.5
g) was converted into the hydrochloride salt, which was purified by recrystallization from ethanol. N with melting point 155-158℃
-(2-Aminoethyl)-2-chlorobenzamide hydrochloride (German Patent Application No. 2362568)
(see Example 6) 19.2 g was obtained. Analytically pure samples melted at 159-161 °C. In a similar manner, 3-chlorobenzoic acid 23.5
g (0.15 mol) to N-(2-
13.5 g of (aminoethyl)-3-chlorobenzamide hydrochloride (see Example 7 of DE-A-2616486) were obtained. Free base is 69-71
(crystallized from ethyl acetate/n-hexane). Example 6 24.4 g (0.2 mol) of benzoic acid were reacted with triethylamine and ethyl chloroformate in a manner analogous to that described in Example 5 and added to a solution of 53.5 ml (0.8 mol) of ethylenediamine in 750 ml of chloroform.
It was added dropwise at ℃. After removing the poorly soluble neutral components by filtration, the chloroform solution was concentrated and excess ethylenediamine was removed under high vacuum. The oily residue (36.3 g) was dissolved in 2N sodium hydroxide solution at 200 g.
ml, saturated with solid sodium chloride and extracted several times with ethyl acetate. The ethyl acetate extract was dried over magnesium sulfate and concentrated. The crude product was converted to the hydrochloride salt, which was purified by recrystallization from ethanol and had a melting point of 163.
N-(2-aminoethyl)benzamide hydrochloride at ~165°C [J.Amer.Chem.Soc. 61 , 822 (1939)] 5.2
g was obtained. Example 7 4-methoxybenzoic acid in 60 ml of chloroform
A suspension of 6.4 g (0.04 mol) of triethylamine (5.5 ml (0.04 mol)) at 10°C, followed by ethyl chloroformate
3.8 ml (0.04 mol) was added dropwise. The resulting solution was dissolved in ethylenediamine in 100 ml of chloroform at 5°C.
It was added dropwise to a 10.7 ml (0.16 mol) solution. 2 at room temperature
After stirring for an hour, the mixture was filtered. The liquid was concentrated under reduced pressure and excess ethylenediamine was removed under high vacuum. The residue was made acidic with dilute hydrochloric acid and extracted several times with ethyl acetate. The aqueous phase was made alkaline with 28% sodium hydroxide solution and extracted three times with chloroform. After drying and concentrating the chloroform extract, the residue was converted to the hydrochloride salt. Recrystallized from ethanol/ether with a melting point of 186-189°C.
3.4 g of -(2-aminoethyl)-4-anisamide hydrochloride (see Example 7 of DE 26 16 486) were obtained. Free base is 37-38
Melted at °C. In the same method as above, from 20.4 g (0.15 mol) of 4-methylbenzoic acid,
N-(2-aminoethyl)-4- with a melting point of 164-166°C
8.7 g of toluamide hydrochloride (see example 7 of DE 2616486) were obtained; 17.2 g (0.09 mol) of 3,4-dichlorobenzoic acid.
, N-(2-aminoethyl) with a melting point of 183-185°C
9.1 g of -3,4-dichlorobenzamide hydrochloride are obtained; the free base melts at 98-100°C; from 12.2 g (0.08 mol) of 2-methoxybenzoic acid, N-(2- aminoethyl)-
9.3 g of 2-anisamide hydrochloride (see Example 6 of DE 2362568) are obtained; from 12.20 g (0.08 mol) of 3-methoxybenzoic acid, N-( 2-aminoethyl)-3
- 6.2 g of anisamide hydrochloride are obtained; from 3.9 g (0.015 mol) of 5-(dimethylsulfamoyl)2-methoxybenzoic acid, melting point 193-195
1.4 g of N-(2-aminoethyl)-5-(dimethylsulfamoyl)-2-anisamide at °C (decomposition)
was gotten. The free base melted at 118-123°C. Example 8 Analogously to the method described in Example 7, 11.8 g (0.08 mol) of 4-cyanobenzoic acid are reacted and treated with triethylamine and ethyl chloroformate and then treated with 21.4 g of ethylenediamine in 350 ml of chloroform.
ml solution. After addition of 45 ml of dimethylformamide, the mixture was heated to 60° C. for 1 hour. After filtration, the liquid was concentrated and the residue was treated in the same manner as described in Example 7. Melting point 212-215℃ (decomposition)
3.5 g of N-(2-aminoethyl)-4-cyanobenzamide hydrochloride was obtained. Free base is 124~
Melted at 126°C. In a similar manner, from 4.5 g (0.023 mol) of 4-trifluoromethylbenzoic acid, melting point 196-199
3.1 g of N-(2-aminoethyl)-α,α,α-trifluoro-4-toluamide hydrochloride at 66-68°C were obtained; the free base melted at 66-68°C. Example 9 A solution of 6.2 ml (0.05 mol) of 4-chlorobenzoyl chloride in 150 ml of ether was added dropwise over 0.5 h at -10<0>C to a solution of 10 ml (0.15 mol) of ethylenediamine in 150 ml of ether. The mixture was allowed to warm to room temperature, filtered and the white residue was rinsed twice with ether. After concentrating the ether solution, the residue was acidified with dilute hydrochloric acid and extracted several times with ethyl acetate to remove neutral components. The aqueous phase was made alkaline with sodium hydroxide solution and extracted several times with chloroform. After evaporation of the chloroform, the residue was converted to the hydrochloride salt, which was recrystallized from ethanol/ether to give N-(2-aminoethyl)-
1.8 g of 4-chlorobenzamide hydrochloride was obtained,
This was identical to the product obtained in Example 1. In the same method, from 7 ml (0.05 mol) of 2,4-dichlorobenzoyl chloride, melting point 178
1.7 g of N-(2-aminoethyl)-2,4-chlorobenzamide hydrochloride at ~189 DEG C. was obtained, which was identical to the product obtained in Example 4. Example 10 7 g of methyl 3,4-methylenedioxybenzoate
(0.039 mol) and ethylenediamine 8.5 ml (0.126
mol) was heated to 100°C (bath temperature) for 2.5 hours. After cooling, excess ethylenediamine was removed under high vacuum. The residue was made acidic with dilute hydrochloric acid and extracted with chloroform. The aqueous phase was made alkaline with sodium hydroxide solution and then extracted several times with chloroform. After evaporation of the solvent and recrystallization of the residue from chloroform/hexane, N-(2-(2
-aminoethyl)-1,3-benzoxole-
3.4 g of 5-carboxamide was obtained. The hydrochloride salt melted at 210-213°C. Example 11 Methyl 4-bromobenzoate 10.7 g (0.05 mol)
and 10.ml (0.15 mol) of ethylenediamine at 130℃
(bath temperature) for 30 minutes. N-(2-aminoethyl)-4-bromobenzamide hydrochloride 6.5%, melting point 229-232°C after treatment analogously to the method described in Example 10 and recrystallization from methanol/ether.
g was obtained. Example 12 10.7 ml (0.16 mol) of ethylenediamine was added to 6.65 g (0.04 mol) of methyl 4-methoxybenzoate. This solution was heated to 130°C (bath temperature) for 2 hours,
After cooling, excess ethylenediamine was removed under high vacuum. The residue was made acidic with dilute hydrochloric acid. Neutral components that are difficult to dissolve were removed by filtration and then extracted with ethyl acetate. The aqueous phase was made alkaline with 28% sodium hydroxide solution and saturated with sodium chloride,
Extracted with chloroform three times. The chloroform extract was dried over magnesium sulfate and concentrated. The residue was converted to the hydrochloride salt, which was recrystallized from ethanol/ether. 3.80 g of N-(2-aminoethyl)-4-anisamide hydrochloride (see Example 7 of DE 26 16 486) having a melting point of 201 DEG -204 DEG C. was obtained. In a similar manner, 20 g (0.1 mol) of methyl 4-chloro-2-methoxybenzoate and 20.1 ml (0.3 mol) of ethylenediamine were prepared with a melting point of 132-135
8.9 g of N-(2-aminoethyl)-4-chloro-2-anisamide hydrochloride at 0.degree. C. (decomposed) was obtained. Example 13 Methyl 4-fluorobenzoate 7.7 g (0.05 mol)
and 10 ml (0.15 mol) of ethylenediamine at 130℃
(bath temperature) for 2 hours. The mixture was poured into ice/hydrochloric acid and extracted with ethyl acetate to remove neutral components. The aqueous phase was made alkaline with sodium hydroxide solution and extracted several times with chloroform. After drying and concentrating the chloroform extract, the residue (7.6 g) was recrystallized from ethyl acetate/hexane and
N-(2-aminoethyl)-4-fluorobenzamide was obtained with a melting point of 57-60°C. Hydrochloride is 214~
Melted at 216°C. Example 14 A solution of 1.3 ml (0.01 mol) of 4-chlorobenzoyl chloride in 15 ml of chloroform was prepared at 0°C by acetylethylenediamine [J.
61 , 822 (1939)] and 1.4 ml (0.01 mol) of triethylamine. After 15 minutes, separate the formed crystals and
Washed with chloroform and dried. melting point
N-(2-acetylaminoethyl)- at 222-224℃
1.9 g of 4-chlorobenzamide was obtained. In order to cleave the protecting group, the obtained N-(2
-acetylaminoethyl)-4-chlorobenzamide was heated under reflux for 22 hours in a mixture of 24 ml of 2N hydrochloric acid and 15 ml of ethanol. After concentrating the solution, the crude product was recrystallized from ethanol/ether. 1.2 g of N-(2-aminoethyl)-4-chlorobenzamide hydrochloride having a melting point of 211 DEG -213 DEG C. are obtained, which is identical to the product obtained in Example 1. Example 15 4-chlorobenzoyl chloride 2.6ml (0.02
mol) of ethanolamine in 30 ml of methylene chloride
1.2ml (0.02mol) and 3ml triethylamine
(approximately 0.02 mol) at 0°C. The mixture was then poured into dilute hydrochloric acid and extracted twice with methylene chloride. The methylene chloride extract was dried over magnesium sulfate and concentrated. After purification on silica gel using chloroform and chloroform/methanol (9:1) as eluent, N-(2-hydroxyethyl)-4-chlorobenzamide was obtained. A solution of 0.6 ml of methanesulfonyl chloride in 3 ml of methylene chloride was dissolved in N-(2
-hydroxyethyl)-4-chlorobenzamide
1.5g (0.0075mol) and 1ml triethylamine
was added dropwise to the solution at 0°C. After 15 minutes, place the mixture on ice/
Pour into water and extract. N-(2-
2.1 g of methylsulfonyloxyethyl)-4-chlorobenzamide was obtained, which was used in the next step without further purification. The resulting N-(2-methylsulfonyloxyethyl)-4-chlorobenzamide was dissolved in 5 ml of dimethylformamide and added dropwise to a solution of ammonia in dimethylformamide at room temperature. After stirring for 2 hours, the mixture was worked up to give N-(2-aminoethyl)-4-chlorobenzamide, which was identical to the product obtained in Example 1. Example A Interlocking gelatin capsule (5
mg) Ingredients: 1 N-(2-aminoethyl)-2,4-dichlorobenzamide hydrochloride 5.78mg ^(*) 2 Lactose (powder) 80.22mg 3 Corn starch 40.00mg 4 Talc 3.60mg 5 Magnesium stearate 0.40mg 6 Lactose (crystalline) 110.00mg Capsule filling weight 240.00mg (*) Equivalent to 5mg of base. Manufacturing method: 1 to 5 were mixed, the mixture was sieved through a sieve with a mesh size of 0.5 mm, and the resulting mixture was mixed. The finished mixture was filled into appropriately sized (eg No. 2) interlocking gelatin capsules having an individual fill weight of 240 mg. Example B Tablet (5 mg) Ingredients: 1 N-(2-aminoethyl)-2,4-dichlorobenzamide hydrochloride 5.78 mg ^(*) 2 Lactose (powder) 104.22 mg 3 Corn starch 45.00 mg 4 Polyvinylpyrrolidone K30 15.00 mg 5 Corn sludge 25.00mg 6 Talc 4.50mg 7 Magnesium stearate 0.50mg Tablet weight 200.00 (*) Equivalent to 5mg of base. Manufacturing method: 1 to 3 were mixed and the mixture was sieved through a sieve with a mesh size of 0.5 mm. The powder mixture was moistened with the alcoholic solution of 4 and kneaded. The wet mass was granulated, dried and converted to the appropriate particle size. 5, 6 and 7 were added sequentially to the dry granules and the resulting mixture was mixed. The finished mixture was compressed into appropriately sized tablets having an individual weight of 200 mg. Example C Interlocking gelatin capsules (10
mg) Ingredients: 1 N-(2-aminoethyl)-p-chlorobenzamide hydrochloride 11.84mg ^(*) 2 Lactose (powder) 74.16mg 3 Corn starch 40.00mg 4 Talc 3.60mg 5 Magnesium stearate 0.40mg 6 Lactose (Crystalline) 110.00mg Capsule filling weight 240.00mg (*) Equivalent to 10mg of base. Manufacturing method: 1 to 5 were mixed and the mixture was sieved through a sieve with a mesh size of 0.5 mm. 6 was then added and the resulting mixture was mixed. The finished mixture was filled into appropriately sized (eg No. 2) interlocking gelatin capsules having an individual fill weight of 240 mg. Example D Tablet (10 mg) Ingredients: 1 N-(2-aminoethyl)-p-chlorobenzamide hydrochloride 11.84 mg ^(*) 2 Lactose (powder) 103.16 mg 3 Corn starch 40.00 mg 4 Polyvinylpyrrolidone K30 15.00 mg 5 Corn starch 25.00mg 6 Talc 4.50mg 7 Magnesium stearate 0.50mg Tablet weight 200.00mg (*) Equivalent to 10mg of base. Manufacturing method: 1 to 3 were mixed and the mixture was sieved through a sieve with a mesh size of 0.5 mm. The powder mixture was moistened with the alcoholic solution of 4 and kneaded. The wet mass was granulated, dried and converted to the appropriate particle size. 5, 6 and 7 were added sequentially to the dry granules and the resulting mixture was mixed. The finished mixture was compressed into appropriately sized tablets having an individual weight of 200 mg.

Claims (1)

[Claims] 1. General formula where R ¹¹ represents halogen, cyano or trifluoromethyl, and R ²¹ represents hydrogen, or R ¹¹ and R ²¹ each represent chlorine;
or a benzamide derivative and a pharmaceutically usable acid addition salt thereof, wherein R ¹¹ and each R ²¹ on adjacent carbon atoms together represent a methylenedioxy group. 2 R ¹¹ represents halogen, cyano or trifluoromethyl and R ²¹ represents hydrogen,
Alternatively, the compound according to claim 1, wherein R ¹¹ and R ²¹ each represent chlorine. 3. A compound according to claim 2, wherein R ¹¹ represents halogen and R ²¹ represents hydrogen, or R ¹¹ and R ²¹ each represent chlorine. 4. The compound according to claim 1, which is N-(2-aminoethyl)-p-chlorobenzamide or a pharmaceutically usable acid addition salt thereof. 5. The compound according to claim 1, which is N-(2-aminoethyl)-p-fluorobenzamide or a pharmaceutically usable acid addition salt thereof. 6. The compound according to claim 1, which is N-(2-aminoethyl)-p-bromobenzamide or a pharmaceutically usable acid addition salt thereof. 7. The compound according to claim 1, which is N-(2-aminoethyl)-3,4-dichlorobenzamide or a pharmaceutically usable acid addition salt thereof. 8. The compound according to claim 1, which is N-(2-aminoethyl)-2,4-dichlorobenzamide or a pharmaceutically usable acid addition salt thereof. 9 General formula where R ¹¹ represents halogen, cyano or trifluoromethyl, and R ²¹ represents hydrogen, or R ¹¹ and R ²¹ each represent chlorine;
or R ¹¹ on adjacent carbon atoms, each R ²¹ taken together represents a methylenedioxy group, and for producing a benzamide derivative and a pharmaceutically usable acid addition salt thereof, (a) general formula In the formula, R ¹¹ and R ²¹ have the above meanings,
(b) in its free acid form or in its reactive functional derivative form with ethylenediamine; In the formula, R ¹¹ and R ²¹ have the above meanings, and R ³
represents hydrogen and R ⁴ represents a leaving group or R ³ and R ⁴ together represent an additional bond, or (c) a compound of the general formula In the formula, R ¹¹ and R ²¹ have the above meanings, and R ⁵ represents a group that can be converted into an amino group, converting the group R ⁵ in the compound into an amino group,
and, if necessary, converting the obtained compound into a pharmaceutically usable acid addition salt. Production method. 10 General formula where R ¹¹ represents halogen, cyano or trifluoromethyl, and R ²¹ represents hydrogen, or R ¹¹ and R ²¹ each represent chlorine;
or a benzamide derivative or a pharmaceutically usable acid addition salt thereof as an active ingredient, wherein R ¹¹ and R ²¹ on adjacent carbon atoms together represent a methylenedioxy group. Depressants or antiparkinsonism agents.