HU193556B - Process for preparing benzamide derivatives - Google Patents

Abstract

Benzamides of the formula <IMAGE> wherein R<1> and R<2> each independently signify hydrogen, halogen, lower alkyl, lower alkoxy, cyano, trifluoromethyl, sulphamoyl, mono(lower alkyl)sulphamoyl or di(lower alkyl)sulphamoyl or R<1> and R<2> on adjacent carbon atoms together signify a methylenedioxy group, with the proviso that R<2> is different from hydrogen when R<1> signifies bromine in the 3-position, and their pharmaceutically usable acid addition salts have interesting monoamine oxidase inhibiting properties with low toxicity and can accordingly be used for the treatment of depressive states and Parkinsonism. Those compounds of formula I in which R<1> signifies halogen, cyano or trifluoromethyl in the para-position and R<2> signifies hydrogen or R<1> and R<2> together signify 2,4-dichloro, 3,4-dichloro or 3,4-methylenedioxy are novel; these novel compounds can be manufactured according to methods known per se.

Description

The present invention relates to the preparation of pharmaceutically valuable benzamide derivatives, their acid addition salts and pharmaceutical compositions containing them.

The present invention relates, on the one hand, to the preparation of a pharmaceutical composition comprising a compound of formula (I) and pharmaceutically acceptable acid addition salts thereof. In the formula

R 1 and R ² are each independently hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, cyano, trifluoromethyl or di- (C 1-4 alkyl) sulfamoyl, or adjacent to each other; R ¹ and R ² together form a methylenedioxy group; with the proviso that when R ¹ is the isopropoxy or n-butoxy group at the 2-position or the bromine at the 3-position, then R ^{2 is not} hydrogen.

The above compounds are disclosed in U.S. Patent No. 2,458,908. They are known in part from German Patent Application, but surprisingly have been found to possess interesting and pharmacologically valuable pharmacodynamic properties at low toxicity. Animal experiments have shown that the compounds of formula I and their pharmaceutically acceptable acid addition salts exhibit monoamine oxidase (MAO) inhibitory activity.

The present invention relates, on the one hand, to the preparation of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof. These pharmaceutical compositions are useful for the treatment and prevention of diseases and for the improvement of health, in particular for the treatment and prevention of depressive disorders and Parkinsonism.

Among the benzamide derivatives represented by the general formula (I), the novel compounds of the general formula (Ia)

R ¹¹ is halogen, cyano or trifluoromethyl and

R ²¹ is hydrogen;

or R ¹¹ and R ²¹ are chlorine;

or the adjacent R and R ²¹ groups together form a methylenedioxy group) and their pharmaceutically acceptable acid addition salts.

The present invention also provides a process for the preparation of the above novel compounds of formula (Ia) and pharmaceutically acceptable acid addition salts thereof.

As used herein, the term "lower alkyl" refers to straight or branched chain hydrocarbon radicals having from 1 to 4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, η-butyl, isobutyl, tert-butyl, etc.). .). The term "lower alkoxy" refers to lower alkyl ether groups containing lower alkyl groups as defined above. The term "halogen" includes fluorine, chlorine, bromine and iodine. The term "leaving group" refers to known groups, e.g. halogen (preferably chlorine or bromine), arylsulfonyloxy (e.g. tosyloxy) or alkylsulfonyloxy (e.g. mesyloxy, etc.).

The term "pharmaceutically acceptable acid addition salt" refers to salts with inorganic or organic acids (e.g. hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, tartaric acid, tartaric acid, etc.). . The salts are prepared by methods well known in the art and readily apparent to those skilled in the art.

Preferred properties are those compounds of formula (I) wherein R ¹ and R ² is hydrogen, halogen, lower alkyl, lower alkoxy, cyano or trifluoromethyl group independently.

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

The divalent substituted compounds of formula I are preferably substituted at the 2,3-, 2,4-, 2,5-, 3,4-, or 3,6-position, particularly preferably at the 2,4- or 3,4-position. position.

Particularly preferred compounds of the formula I are the following:

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.

According to the process of the present invention, the compounds of formula (Ia) and pharmaceutically acceptable acid addition salts thereof can be prepared by:

a) reacting a compound of formula II (wherein R 'and R ²¹ are as defined above) with ethylenediamine in the form of the free carboxylic acid or a reactive functional derivative thereof, preferably an ester, an acid chloride or an anhydride thereof; obsession

b) a compound of formula III (wherein R ¹¹ and R ²¹ are as defined above; R ³ is hydrogen and R ⁴ is a leaving group, preferably an aryl or alkylsulfonyl group, or R ³ and R ⁴ together forming a further bond) by reaction with ammonia; obsession

c) in a compound of Formula IV (wherein R ¹¹ and R ²¹ are as defined above and R ⁵ is a convertible group, preferably 1-4);

C2-C19556 alkylcarbonylamino

C 1-6 alkoxycarbonylamino), R ^{5 is} converted to amino;

and optionally, a resulting compound of formula (I) into a pharmaceutically acceptable acid addition salt. We converted.

As the reactive derivative of the carboxylic acids of formula (II), it is preferable to use halides (e.g. chlorides), symmetric or asymmetric anhydrides, esters (e.g. methyl, p-nitrophenyl or N-hydroxysuccinimide esters), azides or amides (e.g. imidazolides or succinimides).

The reaction of the carboxylic acid or reactive functional derivative of formula (II) with ethylenediamine can be carried out in a manner known per se according to process (a). so e.g. the free carboxylic acid II can be reacted with ethylenediamine in the presence of a condensing agent in an inert solvent. When carbodiimides (e.g., dicyclohexylcarbodiimide) are used as the condensing agent, the reaction is conveniently carried out in an alkane carboxylic acid ester (e.g. ethyl acetate), an ether (e.g. tetrahydrofuran or dioxane), a chlorinated hydrocarbon (e.g. methylene chloride or chloroform), aromatic benzene, toluene or xylene), acetonitrile or dimethylformamide, ca. -20 ° C to room temperature - preferably approx. 0 ° C - can be performed. When using phosphorus trichloride as a condensing agent, the reaction is carried out in a solvent (e.g. At a temperature between 0 ° C and the reflux temperature of the reaction mixture, preferably about 10 ° C. 90 ° C. In another embodiment of process (a), ethylenediamine is added to one of the aforementioned reactive derivatives of the carboxylic acid of formula (II). so e.g. The reaction may be carried out by reacting the chloride of the carboxylic acid of formula (II) with ethylenediamine at a temperature of about 0 ° C in the presence of a solvent such as diethyl ether.

As a compound of formula III wherein R ³ is hydrogen and R ⁴ is a leaving group, e.g. N- (2-haloethyl) -benzamide derivatives - e.g. N- (2-chloroethyl) benzamide or N- (2-methylsulfonylethyl) benzamide or N- (2-p-toluenesulfonylethyl) benzamide and the like. They can be used. A compound of the formula together form an additional bond, R ³ and R ⁴ is (III) benzoyl aziridines - eg. p-chlorobenzoyl aziridine and the like. - can be used.

In process (b) of the present invention, a compound of formula (III) is reacted with ammonia at a temperature of ca. -40 to 50 ° C, optionally in the presence of a solvent (e.g. dimethylformamide, dimethylacetamide, dimethylsulfoxide, etc.). The reaction may conveniently be carried out at about room temperature. When a benzoyl aziridine is used as starting material of general formula (III), it is preferable to work in the presence of an inert solvent such as dimethylformamide, toluene or benzene.

In process (c) of the present invention, the R ⁵ group is converted into an amino group in a manner known per se. In the case of an amide, the conversion is conveniently carried out by acidic or basic hydrolysis. Solutions of mineral acids (e.g. hydrochloric acid, aqueous hydrobromic acid, sulfuric acid, phosphoric acid, etc.) are preferably used for acid hydrolysis. Inert solvents (e. G. Lower alcohol such as methanol or ethanol; ether such as tetrahydrofuran or dioxane etc.) may be employed. Basic hydrolysis may be carried out with an aqueous solution of an alkali metal hydroxide (e.g., sodium or potassium hydroxide). Use organic solvents such as. acid hydrolysis may also be used as a solubilization agent. The acidic and basic hydrolysis may be carried out at a temperature between room temperature and the boiling point of the reaction mixture, preferably under reflux.

When using compounds of the formula R ⁵ represents a phthalimide (IV) can be used to aminolysis in aqueous solution is lower alkylamine (eg. Methyl amine or ethylamine) in addition to the acidic and basic hydrolysis. · Organic solvents lower alkanols (e.g. ethanol, etc.). The reaction is preferably carried out at room temperature. A third method of converting a thalimido group to an amino group is by reacting a compound of formula IV with hydrazine in an inert solvent (e.g., ethanol or a mixture of ethanol and chloroform, tetrahydrofuran or aqueous ethanol). The reaction may be carried out at room temperature to 100 ° C, preferably at the reflux temperature of the solvent. The resulting product is shaken with dilute mineral acid and then basified with the resulting acidic solution to give the desired product.

The tertiary butoxycarbonylamino group may conveniently be converted to the amino group at room temperature with or without trifluoroacetic acid or formic acid in the presence or absence of an inert solvent. The trichloroethoxycarbonylamino group can be converted to an amino group under acidic conditions with zinc or cadmium. The acidic conditions are suitably provided by the addition of acetic acid, optionally in the presence of additional inert solvents (e.g., alkanols, such as methanol).

The benzyloxycarbonylamino group can be converted to the amino group by hydrolysis or hydrogenolysis of the acid described above in a manner known per se. The conversion of the azido group into an amino group is itself3

-3193556 by known methods, e.g. elemental hydrogen in the presence of a catalyst (pJ. palladium carbon, Raney nickel, platinum oxide, etc.). The hexamethylene tetrammonium group may also be acidically hydrolyzed to an amino group in a known manner.

The carboxylic acids of formula (II) or their reactive functional derivatives used as starting materials in process (a) may be prepared analogously to known compounds or known compounds.

The compounds of formula (III) used as starting materials in process (b) of the present invention are also known or may be prepared analogously to known compounds by methods known per se. so e.g. compounds of formula (III) wherein R ³ is hydrogen and R ⁴ is a leaving group may be prepared by reacting the appropriate compound (II) or a reactive functional derivative thereof with ethanolamine under the conditions described in process (a); obtained N- (2-hydroxyethyl) -benzamide in a manner known per se, e.g. a halogenating agent (e.g., phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus oxychloride, etc.), an arylsulfonyl halide (e.g. tosyl chloride) or an alkylsulfonyl halide (e.g. mesyl chloride). reaction to give the desired compound of formula (III). Compounds of formula (III) wherein R ³ and R ⁴ together form an additional bond, e.g. by reaction of the corresponding carboxylic acid or a reactive functional derivative thereof of formula II with ethyleneimine. The reaction may be carried out analogously to process a).

The compounds of formula (IV) used as starting materials in process (c) are also known or can be prepared analogously to known compounds by methods known per se. so e.g. reacting a carboxylic acid of formula (II) or a reactive functional derivative thereof with a compound of formula (V) (wherein R ⁵ is as defined above) under the reaction conditions described in process (a). Compounds of formula (V) are known or may be prepared in an analogous manner to known compounds.

Alternatively, the ⁵ appropriate phthalimido, azido or Compounds of formula containing hexamethylenetetraammonium group (IV) to (III) compounds and potassium phthalimide, an alkali metal azide or hexamethylenetetramine of formula by reaction with R we produce it. The reaction may be carried out under the conditions described in process b).

The compounds of formula (I) and their pharmaceutically acceptable acid addition salts, as mentioned above, have a monoamine oxidase (MAO) inhibitory activity and, by virtue of this property, are useful in the treatment of depressive disorders and Parkinsonism.

The MAO inhibitory activity of the compounds of the present invention is demonstrated by standard test methods. The test compound is administered orally to rats. Two hours later, the animals were sacrificed and the MAO inhibitory effect in the brain and liver homogenate was determined by Biochem. Pharmacol. 12, 1439-1441 (1963) was determined by the method described in a manner that a substrate phenyl-ethylamine (2-ΚΓ ⁵ mol ^Γ-1) instead alkalma15 tyramine., Αζ (I) compounds thus determined, activity and toxicity are given in Table I below. The table shows the ED ₅₀ / pmol kg (rat rat) and LD ₅₀ / mg / kg po mouse).

I, Table

25 Test compound EDg 0 LD ₅ 0 N- / 2-aminoethyl / -p-chlorobenzamide 5.5 1000-2000 30 N- (2-aminoethyl) -p-fluorobenzamide 4 > 5000 N- / 2-aminoethyl / -p- bromo-benzamide 4 500-1000 35 N- (2-aminoethyl) -3,4-dichlorobenzamide 10.3 1000-2000 N- / 2-aminoethyl / - -2,4-dichlorobenzamide 1.5 625-1250 40 N- / 2-aminoethyl / -benzamide 20 > 5000

In order to demonstrate the MAO inhibitory activity of the compounds of formula (I), the following experiment is also carried out with other compounds of formula (I). However, the results are not evaluated by providing the ED ₅₀ , but the test compound is administered to the rat at a constant dose (100 pmol / kg, po) and the% inhibition determined by rpeg. Toxicity data in mice after LD administration is LD _S0 , mg / kg.

The results obtained are shown in Table II. are summarized in Table.

^{55 11} · Table

Test Compound Z LD ₅₀ Inhibition

N- (2-aminoethyl) -p-anisoylamide 33.1 2500-5000

N- (2-aminoethyl) -m-anisoylamide 63.7 1000-2000

-4193556

II. Table (continued)

Test compound %-ancestor inhibition LD5 o N- / 2-aminoethyl / o-anisoyl amide 80.7 1250-2500 N- / 2-aminoethyl / -p-toluoyl-amide 89.4 1000-2000 N- / 2-aminoethyl / p-cyanobenzamide 28.1 > 5000 N- / 2-aminoethyl / -p- chloro-p-anisoyl-amide 87.2 1000-2000 N- / 2-amino-ethyl / -3,4-methylenedioxy-benzamide 59.0 2000-4000

It is a further object of the present invention to provide a process for the manufacture of a medicament, in particular an antidepressant or anti-Parkinson's medicament, by

(a) by reacting a free carboxylic acid or ester of formula (II '), an acid chloride or an anhydride thereof, with ethylenediamine; obsession

b) by reaction of a compound of formula III 'with ammonia; obsession

c) Compound of Formula I prepared by converting a group R ^{5 to} an amino group of a compound of Formula IV

R ¹ and R ² are independently hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy, cyano, trifluoromethyl or di (C 1-4 alkyl) sulfamoyl, or adjacent to each other; R ¹ and R ² together form a methylenedioxy group; with the proviso that when R ¹ is an isopropoxy or n-butoxy group at the 2-position or a bromine attached to the 3-position, then R ^{2 is not} hydrogen;

R ³ is hydrogen;

R ⁴ is aryl or alkylsulfonyl and

R ⁵ is C 1-5 alkylcarbonylamino or C 1-6 alkoxycarbonylamino, or a pharmaceutically acceptable acid addition salt thereof, admixed with inhaled organic or inorganic pharmaceutical carriers, and prepared in a pharmaceutically acceptable form.

The compounds of formula (I) above

Processes a), b) and c) for the preparation of a),

or (c). The pharmaceutical composition may be in a form suitable for oral (e.g., tablet, coated tablet, dragee, hard 8 or soft gelatin capsule) or rectal (e.g., suppository) or parenteral (e.g., injection solution).

The tablets, coated tablets, dragees and hard gelatine capsules may contain inorganic or organic excipients in addition to the compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof. As an excipient for the preparation of tablets, dragees and hard gelatine capsules, e.g. lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof.

For the preparation of soft gelatine capsules, e.g. vegetable oils, waxes, fats, semi-solid or liquid polyols, etc. hunger can diminish.

The solutions and syrups are excipients, e.g. water, polyols, sucrose, invert sugar, glucose, etc. contain.

For the preparation of injection solutions, excipients, e.g. water, alcohols, polyols, glycerol, vegetable oils, etc. can be used

The suppositories are e.g. natural or hardened oils, waxes, fats, semi-liquid or liquid polyols, etc. contain.

The pharmaceutical compositions may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for altering the osmotic pressure, buffers, coating agents or antioxidants and, if desired, other pharmaceutically valuable substances.

The compounds of formula (I) or pharmaceutically acceptable acid addition salts thereof, which are obtainable by the process of the present invention, are useful in the treatment and prevention of depressive disorders and Parkinsonism. The dosage of the active ingredient may vary within wide limits and will, of course, depend on the requirements of the particular case. Generally, the daily oral dose of active ingredient will be about. 10 mg and ca. 100 mg. However, it should be noted that these data are for information purposes only and that lower or higher doses may be administered if necessary.

The following examples further illustrate the process without limiting the invention to the examples.

Example 1

A mixture of 13.5 g of ethyl 4-chlorobenzoic acid and 24 g of ethylenediamine is stirred at 130 ° C for 17 hours. The reaction mixture was cooled to room temperature, evaporated and the residue was mixed with 200 ml of ethyl acetate. Insoluble N, N'-ethylene-bis (4-chlorobenzamide) (2.3 g; m.p. 266-268 ° C) was filtered and the filtrate was washed with water (3 x 50 mL) and evaporated. The residue is taken up in 100 ml of 1N hydrochloric acid, the insoluble Ν, Ν'-ethylene-bis (4-chlorobenzamide) (1.0 g) is filtered off and the filtrate is evaporated to dryness. The residue was taken up in 100 ml of ethanol5

The mixture was again concentrated twice with -5193556 zol and recrystallized from ethanol-ether. 13.7 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride are obtained, m.p. 216-217 ° C.

Example 2

A mixture of 9.25 g of ethyl 4-chlorobenzoic acid and 16.0 g of N- (tert-butoxycarbonyl) ethylenediamine is stirred at 130 ° C for 15 hours. The reaction mixture was cooled to room temperature, taken up in water (100 mL) and extracted with ethyl acetate (3 x 50 mL). The ethyl acetate extracts were washed with water (2 x 50 mL), dried over sodium sulfate and evaporated to dryness. The crystalline residue was taken up in isopropyl ether and filtered. 3.9 g of tert-butyl [2- (4-chlorobenzoylamino) ethyl] carbamate are obtained, m.p. 141-143 ° C.

A solution of 2.8 g of tert-butyl [2- (4-chlorobenzoylamino) ethyl] carbamate and 50 ml of formic acid was allowed to stand at room temperature for 1.5 hours. The reaction mixture is evaporated to dryness and the residue is taken up in 50 ml of 1: 1 aqueous hydrochloric acid. The solution is evaporated and the residue is taken up twice in ethanol-benzene and recrystallized from ethanol. 2.1 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride are obtained. The product was identical to the compound prepared in Example 1.

Example 3

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 is added 23 ml (0.07 mol) of triethylamine. dropwise. After the addition was complete (half an hour), the resulting solution was added dropwise to a solution of 50 ml (0.75 mol) of ethylenediamine and 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 neutral portions were removed by chloroform extraction. The aqueous phase was extracted several times with sodium hydroxide solution and chloroform. The chloroform extract was dried and evaporated. The residue was converted to the hydrochloride and recrystallized from ethanol-ether. 15.1 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride are obtained. M.p. 212-214 ° C. The free base melts at 43-45 ° 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 were added to the solution. Then 10 ml (0.1 mol) of ethyl chloroformate was added dropwise at 0 ° C. After the addition was complete (half an hour), the mixture was poured into ice water. The methylene chloride phase was separated, dried over magnesium sulfate and dried for ca. Concentrate to 30 ml. The solution was added dropwise at 0 ° C to a solution of ethylenediamine (20 mL, 0.3 mol) in tetrahydrofuran (100 mL). After the addition was complete (half an hour), the mixture was filtered and the filtrate was acidified with dilute hydrochloric acid and the neutral portions were removed by ethyl acetate extraction. The aqueous phase was made basic with sodium hydroxide solution (6) and extracted again with chloroform. The chloroform layer was dried, evaporated and the residue was converted to the hydrochloride. 7.1 g of N- (2-aminoethyl) -2,4-dichlorobenzamide hydrochloride are obtained, m.p. 179-182 ° C after recrystallization from ethanol-ether.

Example 5

To a suspension of 23.5 g (0.15 mol) of 2-chlorobenzoic acid in 200 ml of chloroform at 10 ° C

Triethylamine (33.1 mL, 0.16 mol) was added dropwise. 14.8 ml (0.155 mol) of ethyl chloroformate were added dropwise at the above temperature. After the addition was complete (1 hour), the reaction mixture was poured into ice water. The chloroform layer was separated, dried over magnesium sulfate, and carefully cautiously dried for approx. Concentrate to 60 ml. The resulting solution was added dropwise at 10 ° C to a solution of 40.1 mL (0.6 mol) of ethylenediamine and 400 mL of chloroform. After the addition was complete, the poorly soluble neutral portions were filtered off and the filtrate was concentrated under high vacuum to remove excess ethylene diamine. The residue (31.5 g) was converted to the hydrochloride and purified by recrystallization from ethanol-ether. 19.2 g of N- (2-aminoethyl) -2-chlorobenzamide hydrochloride (see Example 6 of German Patent Publication No. 2,362,568), m.p. 155-158 ° C. Melting point 159-161 ° C of sample of analytical purity.

Analogously to the above procedure, starting from 23.5 g (0.15 mol) of 3-chlorobenzoic acid

13.5 g of N- (2-aminoethyl) -3-chlorobenzamide hydrochloride (see Example 7 of German Patent Application 2,616,486, m.p. 201-203 ° C). The free base melts at 69-71 ° C (from ethyl acetate / n-hexane).

Example 6

Benzoic acid (24.4 g, 0.2 mole) was treated with triethylamine and ethyl ester of chloroformate in the same manner as in Example 5 and then at 10 ° C.

A solution of ethylene diamine (53.6 ml, 0.8 mol) in chloroform (750 ml) was added dropwise. The poorly soluble neutral portions are filtered off, the chloroform solution is evaporated and excess ethylenediamine is removed under high vacuum. The oily residue (36.3 g) was taken up in 200 ml of 2N sodium hydroxide solution, saturated with solid sodium chloride and extracted several times with ethyl acetate. The ethyl acetate extracts were dried over magnesium sulfate and evaporated. The crude product was converted to the hydrochloride and further purified by recrystallization from ethanol. 5.2 g of N- (2-araminoethyl) -benzamide hydrochloride are obtained, m.p. 163-165 ° C (see 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 at 10 ° C

5.5 ml (0.04 mol) of triethylamine followed by 3.8 ml (0.04 mol) of ethyl chloroformate are added dropwise. The resulting reaction solution was 10.7 ml at 5 ° C

To a solution of -6193556 (0.16 mol) in ethylenediamine and 100 ml of chloroform was added dropwise, followed by stirring at room temperature for 2 hours and filtration. The filtrate was concentrated in vacuo and excess ethylenediamine was removed under high vacuum. The residue was acidified with dilute hydrochloric acid and extracted several times with ethyl acetate. The aqueous phase was made basic with 28% sodium hydroxide solution and extracted three times with chloroform. The chloroform extract was dried and evaporated, and the residue was converted to the hydrochloride. After recrystallization from ethanol-ether, 3.4 g of N- (2-aminoethyl) -4-anisoylamide hydrochloride are obtained. See, e.g., 2,616,486. Example 7 of German Federal Republic), m.p. 186-189 ° C. The free base melts at 37-38 ° C.

In an analogous manner to the above procedure

Starting from 20.4 g (0.15 mol) of 4-methylbenzoic acid, 8.7 g of N- (2-aminoethyl) -4-toluoylamide hydrochloride (see German Patent Publication No. 2,616,486 7) mp 164-166 ° C);

Starting from 17.2 g (0.09 mol) of 3,4-dichlorobenzoic acid, 9.1 g of N- (2-aminoethyl) -3,4-dichlorobenzamide hydrochloride (m.p. 183-185 ° C). free base mp 98-100 ° C);

Starting from 12.2 g (0.08 mol) of 2-methoxybenzoic acid, 9.3 g of N- (2-aminoethyl) -2-anisoyl amide hydrochloride, m.p. 109-111 ° C; (German Patent Publication No. 6, Example 6);

Starting from 12.2 g (0.08 mol) of 3-methoxybenzoic acid, 6.2 g of N- (2-aminoethyl) -3-anisoylamide hydrochloride (m.p. 96-98 ° C); and

Starting from 5- (dimethylsulfamoyl) -2-methoxybenzoic acid (3.9 g, 0.015 mol), 1.4 g of N- (2-aminoethyl) -5- (dimethylsulfamoyl) -2-aisoyl- amide hydrochloride (m.p. 193-195 ° C, dec.; free base melting at 118-123 ° C).

Example 8

11.8 g (0.08 mol) of 4-cyanobenzoic acid a

In a manner analogous to that described in Example 7, the reaction was treated with triethylamine and ethyl chloroformate and, after work up, added dropwise to a solution of 21.4 ml of ethylenediamine in 350 ml of chloroform. After the addition of 45 ml of dimethylformamide, the reaction mixture was heated at 60 ° C for 1 hour. The mixture was filtered, the filtrate was evaporated and the residue was treated as in Example 7. 3.5 g of N- (2-aminoethyl) -4-cyanobenzamide hydrochloride are obtained, m.p. 212-215 ° C (dec.). The free base melts at 124-126 ° C.

Starting from 4.5 g (0.023 mol) of 4- (trifluoromethyl) benzoic acid, 3.1 g of N- (2-aminoethyl) -oc, a, a-trifluoro-4-toluoylamide are obtained analogously to the procedure described above. m.p. 196-199 ° C.

The free base melts at 66-68 ° C.

Example 9 To a solution of ml (0.15 mol) of ethylenediamine and 150 ml of ether at -10 ° C was added dropwise a solution of 6.2 ml (0.05 mol) of 4-chlorobenzoyl chloride and 150 ml of ether in half an hour. . The reaction mixture was allowed to warm to room temperature, then filtered and the white precipitate was washed twice with ether. The ethereal solution was evaporated, the residue acidified with dilute hydrochloric acid and extracted several times with ethyl acetate to remove the neutral portions. The aqueous phase was made basic with sodium hydroxide solution and extracted several times with chloroform. After distilling off the chloroform, the residue is converted to the hydrochloride and recrystallized from ethanol-ether. 1.8 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride are obtained, which is identical to the compound prepared in Example 1.

In analogy to the procedure described above, starting from 7 ml (0.05 mol) of 2,4-dichlorobenzoyl chloride, 1.7 g of N- (2-aminoaminoethyl) -2,4-dichlorobenzamide hydrochloride are obtained, m.p. 178-179 ° C. The product was identical to the compound of Example 4.

Example 10 A mixture of g (0.039 mol) of methyl 3,4-methylenedioxybenzoic acid and 8.5 ml (0.126 mol) of ethylenediamine was heated at 100 ° C (bath temperature) for 2.5 hours. After cooling, excess ethylenediamine was removed under high vacuum. The residue was acidified with dilute hydrochloric acid and extracted with chloroform. The aqueous phase was made basic with sodium hydroxide solution and extracted several times with chloroform. After distilling off the solvent and recrystallizing the residue from chloroform-hexane, 3.4 g of N- (2-aminoethyl) -3,4-methylenedioxybenzamide are obtained. Mp 120-123 ° C. The hydrochloride melts at 210-213 ° C

Example 11

A mixture of 10.7 g (0.05 mol) of methyl 4-bromobenzoic acid and 10.4 ml (0.15 mol) of ethylenediamine was heated at 130 ° C (bath temperature) for 30 minutes. The reaction mixture was worked up in a manner analogous to that described in Example 10. Recrystallization from methanol / ether gave 6.5 g of N- (2-aminoethyl) -4-bromobenzamide hydrochloride. Mp 229-232 ° C. .

Example 12

To 6.65 g (0.04 mol) of methyl 4-methoxybenzoic acid is added 10.7 ml (0.16 mol) of ethylenediamine. The solution was heated at 130 ° C (bath temperature) for 2 hours and then excess ethylene diamine was removed under high vacuum. The residue is acidified with dilute hydrochloric acid. The poorly soluble neutral portions are filtered and removed by ethyl acetate extraction. The aqueous phase was made basic with 28% sodium hydroxide solution, saturated with sodium chloride and extracted three times with chloroform. The chloroform extracts were dried over magnesium sulfate and evaporated. The residue was converted to the hydrochloride and recrystallized from ethanol-ether. 3.8 g of N- (2-aminoethyl) -4-anisoylamide hydrochloride are obtained (see German Patent Publication No. 2,616,484, Example 7). Mp 201-204 ° C.

-7193556

In an analogous manner to the procedure described above, 20 g (0.1 mol) of methyl 4-chloro-2-methoxybenzoic acid were reacted with 21.1 ml (0.3 mol) of ethylenediamine.

8.9 g of N- (2-aminoethyl) -4-chloro-2-anisoylamide hydrochloride are obtained, m.p. 132-135 ° C (dec.).

Example 13

A mixture of 7.7 g of methyl 4-fluorobenzoic acid and 10 ml (0.15 mol) of ethylenediamine was heated at 130 ° C (bath temperature) for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate to remove the neutral portions. The aqueous phase was made basic with sodium hydroxide and extracted several times with chloroform. The chloroform extracts were dried and evaporated. The residue (7.6 g) was recrystallized from ethyl acetate-hexane. The resulting N- (2-aminoethyl) -4-fluorobenzamide has a melting point of 57-60 ° C. The hydrochloride melts at 214-216 ° C.

Example 14

1.02 g (0.01 mol) of acetyl ethylenediamine [J. But. Chem. Soc., 61, 822 (1939)], a solution of 1.4 ml (0.01 mol) of triethylamine and 25 ml of chloroform at 0 ° C in 1.3 ml (0.01 mol) of 4-chlorobenzoyl. chloride and 15 ml of chloroform are added dropwise. After 15 minutes, the precipitated crystals were filtered off, washed with chloroform and dried.

1.9 g of N- (2-acetylaminoethyl) -4-chlorobenzamide are obtained, m.p. 222-224 ° C.

To remove the protecting group, the resulting N - (2-acetylaminoethyl) -4-chlorobenzamide was refluxed in a mixture of 24 ml of 2N hydrochloric acid and 15 ml of ethanol for 22 hours. The reaction mixture was evaporated. The crude product was recrystallized from ethanol-ether. 1.2 g of N- (2-aminoethyl) -4-chlorobenzamide hydrochloride are obtained, m.p. 211-213 ° C. The product was identical to the compound prepared in Example 1.

Example 15

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 was added 2.6 ml (0.02 mol) of chlorobenzoyl chloride is added dropwise. The reaction mixture was poured into dilute hydrochloric acid and extracted twice with methylene chloride. The methylene chloride extracts were dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel eluting with chloroform followed by 9: 1 chloroform-methanol. 3.1 g of N- (2-hydroxyethyl) -4-chlorobenzamide are obtained.

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 was added 0.6 ml of methanesulfonic acid. chloride and 3 ml of methylene chloride are added dropwise. After 15 minutes, the reaction mixture was poured into ice water and extracted. 2.1 g of N- (2-methylsulfonyloxyethyl) -4-chlorobenzamide are obtained, which can be used directly in the next step as a crystalline material without further purification.

The resulting N- (2-methylsulfonyloxyethyl) -4-chlorobenzamide was dissolved in 5 ml of dimethylformamide and added dropwise to dimethylformamide ammonia at room temperature. After 2 hours, the reaction mixture was worked up. The resulting N- (2-aminoethyl) -4-chlorobenzamide was identical to the compound prepared in Example 1.

Example 16 Preparation of mg gelatin capsules Component Quantity

1. N- (2-Aminoethyl) -2,4-di-5.78 mg * ² chlorobenzamide hydrochloride

2. Lactose powder. 80.22 mg

3. Corn starch 40.00 mg

4. Talkum 3.60 mg

5. Magnesium stearate 0.40 mg

6. Crystalline milk sugar 110.00 mg

Capsule fill weight: 240.00 mg

The production process is as follows:

1-5. s. The components are mixed and passed through a sieve with a mesh size of 0.5 mm. Thereafter, no. component is mixed and mixed. The ready-to-download mixture is filled into suitable size gelatin capsules (e.g., No. 2) of 240 mg. * / = 5 mg of base.

Example 17 Preparation of mg tablets

Component Quantity

1. N- (2-Aminoethyl) -2,4-dichlorobenzamide hydrochloride 5.78 mg * ⁷

2. Lactose powder. 104.22 mg

3. Corn starch 45.00 mg

4. Polyvinylpyrrolidone K 30 15.00 mg

5. Corn starch 25.00 mg

6. Talc 4.50 mg

7. Magnesium stearate 0.50 mg

Tablet weight: 200.00 mg

The production process is as follows:

1-3. s. component is mixed and passed through a sieve with a mesh size of 0.5 mm. The powder mixture is described in Art. moistened with an alcoholic solution of component II and kneaded. The wet mass is granulated, dried and brought to a suitable particle size. 5, .6 for the dried granulate sequentially. 7 and 7 component is added and mixed. 200 mg of tablets are pressed from the ready-to-compress mixture.

* '= 5 mg of base.

Example 18 Preparation of mg gelatin capsules Component Quantity

1. N- (2-Aminoethyl) -p-chlorobenzamide hydrochloride 11.84 mg * /

2. Lactose powder. 74.16 mg

3. Corn starch 40.00 mg

4. Talkum 3.60 mg

5. Magnesium stearate 0.40 mg

6. Milk sugar cryst. 110.0 mg

Capsule Weight: 240.00 mg The process of preparation is as follows:

1-5. s. component is mixed and passed through a sieve with a mesh size of 0.5 mm. Thereafter, no. component is added and mixed. Ready to download mixture

-8193556 is filled into capsules of suitable weight (e.g., No. 2). ^{x /} = 10 mg of base.

Example 19 Preparation of mg Tablets Component

1. N- (2-Aminoethyl) -p-chlorobenzamide hydrochloride

2. Lactose powder.

3. Corn starch

4. Polyvinylpyrrolidone K 30

5. Corn starch

6. Talkum

7. Magnesium stearate

240 mg fill Quantity

11.84 mg * 103.16 mg 40.00 mg

15.00 mg 25.00 mg

4.50 mg 0.50 mg

Tablet weight: 200.00 mg

The production process is as follows:

1-3. s. component is mixed and passed through a sieve with a mesh size of 0.5 mm. The powder mixture is described in Art. moistened with an alcoholic solution of component II and kneaded. The wet mass is granulated, dried and brought to a suitable particle size. 5, 6 and 7 for dried granules. component is added and mixed. 200 mg of tablets of suitable size were pressed from the ready-to-compress mixture. ^v = 10 mg of base.

Claims (10)

PATENT CLAIMS A process for the preparation of a novel benzamide derivative of formula Ia R is halogen, cyano or trifluoromethyl; and R ²¹ is hydrogen; or R and R ²¹ are chlorine; or the adjacent R ¹¹ and R ²¹ groups together form a methylenedioxy group - and pharmaceutically acceptable acid addition salts thereof, characterized in that a) reacting a compound of formula II, wherein R ¹¹ and R ²¹ are as defined above, with ethylenediamine in the form of the free carboxylic acid or its ester, acid chloride or acid anhydride; obsession b) a compound of Formula III wherein R ' ¹ and R ^2a are as defined above; R ³ is hydrogen and R ⁴ is aryl or alkylsulfonyl, with ammonia; obsession c) in a compound of Formula IV wherein R ¹¹ and R ²¹ are as defined above and R ^{5 is C} 1-5 alkylcarbonylamino or C 1-6 alkoxycarbonylamino; ⁵ groups are converted to amino groups and, if desired, the resulting compound of formula I is converted into a pharmaceutically acceptable acid addition salt. 2. A process according to claim 1, wherein R ¹¹ is halogen, cis 35 ano or trifluoromethyl and R ²¹ is hydrogen or R and R ^{21 are} chlorine atoms (II), (III) and (IV). ). 3. A process according to claim 2 wherein R ¹¹ is a halogen atom and R ¹ is a hydrogen atom or R ²¹ and R is chlorine starting materials of formulas II, III and IV. Process according to claim 3, characterized in that the starting materials of the general formulas (II), (III) and (IV) containing R in the form of chlorine and R ²¹ in the hydrogen atom are used. 5. A process according to claim 3, wherein R is a fluorine atom and R ²¹ is a hydrogen atom and a starting material of formula (II), (III) and (IV). 6. The process according to claim 3, wherein R ¹¹ is bromine and R ²¹ is hydrogen, starting materials of formulas II, ΠΙ and IV. 7. A process according to claim 3 wherein R 'is a starting material of formula (II), (III) and (IV) containing a chlorine atom and a R ²¹ position at the 3-position chlorine atom. 8. A process according to claim 3 wherein R ¹¹ is a chlorine atom and R ² 'is a 2-position chlorine starting material of formulas II, III and IV. 9. Process for the preparation of pharmaceutical preparations, in particular antidepressant or anti-Parkinson medicinal products (a) by reaction of a free carboxylic acid or ester of formula (ΙΓ) with an acid chloride or acid anhydride and ethylenediamine; obsession b) by reaction of a compound of formula III 'with ammonia; obsession c) from compounds of formula I prepared by converting a group R ^{5 to} an amino group of a compound of formula IV wherein R ¹ and R ² are independently selected from hydrogen, halogen, C 1-4 alkyl, 1-4 alkyl; C 1 -C 4 alkoxy, cyano, trifluoromethyl or di (C 1 -C 4 alkyl) sulfamoyl or the adjacent R ¹ and R ² groups together form a methylenedioxy group; with the proviso that when R ¹ is an isopropoxy or n-butoxy group at the 2-position or a bromine atom attached to the 3-position, then R ^{2 is not} hydrogen; -9193556 R ³ is hydrogen; R ⁴ is aryl or alkylsulfonyl and R ⁵ is C 1 -C 5 alkylcarbonylamino or C 1 -C 6 alkoxycarbonylamino - characterized in that a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof is admixed with inorganic organic or inorganic pharmaceutical carriers. and in a form suitable for use in medicine. 10. The method of claim 9, wherein the active ingredient is a Use of a benzamide derivative of the formula (Ia) according to claim 1, wherein R and R ²¹ are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof.