CH639374A5 - N- (4-PYRAZOLIDINYL) -BENZAMIDES, INCLUDING ANTIEMETIC AND Gastric emptying properties in particular. - Google Patents

Description

The present invention relates to heterocyclic compounds having antiemetic and gastric emptying properties and relates in particular to certain N- (4-pyrazoldinyl) benzamides, as well as compositions of these compounds which can be used to control vomiting and gastric emptying properties, in warm-blooded animals, with minimal side effects.

The prior art describes various derivatives of the benzamido type, in which one of the substituents attached to the nitrogen atom of the benzamido group can be a pyrrolidinyl or piperidinyl radical. U.S. Patent No. 3342826 describes heterocyclic aminoalkylbenzamides having antiemetic properties. U.S. Patent No. 3,577,440 describes 3-amidopyrrolidines, substituted in position 1, having analgesic and antisedative properties. U.S. Patents Nos. 3966957 and 3963745 describe N- (1-substituted-3-pyr-rolidinyl) benzamides and thiobenzamides, useful in particular for controlling vomiting.

The new compounds according to the invention are the N- (1,2-hydro-carbyl-4-pyrazolidinyl) benzamides I corresponding to the following formula:

R

R-N

-NOT.

1

(in)

R

in which

R and R1 represent an alkyl radical Q-Cg, cycloalkyl or 45 alkylcycloalkyle in Q-c12, or phenyl-c1-c8-alkyl,

R2 represents a hydrogen atom, a Q-Cg, phenyl or phenyl-substituted alkyl radical,

R3 represents a hydroxy, cyano, nitro, amino, fluoro, chloro, bromo, trifluoromethyl, Q-Cg alkyl, alkoxy CfCg, sulfa-50 or acetamido group, R3 can represent the same radical or different radicals, and n is a whole number ranging from 0 to 3 inclusive,

and its acid addition salts.

The addition salts of non-toxic acids, pharmaceutically acceptable, of the basic compounds corresponding to formula I also form part of the invention, insofar as these salts can also be used as antiemetic or gastric emptying compounds. Organic or inorganic acids can be used to form the pharmaceutically acceptable acid addition salts. Examples of such acids include sulfuric, nitric, phosphoric, citric, acetic, lactic, tartaric, sulfa, succinic, fumaric, maleic, hydrochloric, hydrobromic, benzoic and the like. These salts can be prepared in known manner.

"5 The antiemetic properties are determined by modifying the operating procedures of Chen and Enxor," J. Pharmac. Exp. Ther. ", 98, 245-250 (1950) and de Leonard et al.," J. Pharmac. Exp. Ther. ", 154, 339-345 (1966).

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The gastric emptying activity is determined using the following procedure. Female Sprague-Dawley rats, weighing 117-221 g, are fasted for 24 hours in cages with a screen at the bottom, with unlimited water. The animals are placed in groups of eight. At time 0, 9 mg / kg of a test compound is administered intraperitoneally to rats, in 5% acacia (0.4 ml / 100 g body weight). 4 ml / kg of acacia alone is administered intraperitoneally to the control group. 30 min after administration, rats are administered, orally, using a gastric tube, 3 ml of a test meal consisting of a methylcellulose base to which beef broth is added, casein, powdered sugar and corn starch to obtain a homogeneous semi-solid paste. 60 min after the test meal (90 min of total time), the rats are sacrificed by rupture of the cervical vertebrae, a laparotomy is carried out and the stomachs are removed. We weigh the full stomachs on an analytical balance then we open them, we rinse them and we weigh the empty stomachs. The difference in weight between the empty stomach and the full stomach represents the amount of meal remaining in the stomach, and this amount is subtracted from the weight of 3.0 ml of the test meal to obtain the amount of the meal that has was emptied from the stomach during the trial period.

The preferred compound of Example 6 reduces vomiting to 87% when administered in the amount of 5 mg / kg (sc) and significantly increases the gastric emptying time when administered in the amount of 0.33 to 9.0 mg / kg.

The first object of the invention is therefore new N- (4-pyrazolidinyl) benzamides having antiemetic and gastric emptying properties. The invention also relates to a process for the preparation of these compounds as well as new compositions, useful as antiemetics and for controlling gastric emptying.

The term substituted or unsubstituted C4-CI2 cycloalkyl first of all means cyclic C4-C12 alkyl radicals, and groups such as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclopentyl, ethylcyclohexyl and the like.

The term substituted phenyl means radicals substituted by one or more radicals which are not reactive or troublesome under the reaction conditions described here, such as the lower alkyl, lower alkoxy, trifluoromethyl, bromine, chlorine, chlorine atoms. fluorine and the like. The substituted phenyl radicals preferably have no more than three substituents, such as those mentioned in the various possible positions on the phenyl ring, and when there is more than one substituent, these may be the same or and can be placed in different combinations of positions relative to each other. The lower alkyl and lower alkoxy substituents are preferably each in CV C4 and can be linear or branched. As examples of preferred substituents, mention may be made of methyl, ethyl, propyl,

butyl, fluoro, bromo, chloro, iodo, amino, hydroxy, cyano, acetamido, sulfamoyl, methoxy, ethoxy, propoxy, butoxy and trifluoro-2o methyl.

The term C1-C8 alkyl means linear or branched C1-C8 radicals, such as for example methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, amyl, isoamyl, n-hexyl, n-heptyl groups. and n-octyl. A lower alkoxy radical corresponds to the formula 25-O-lower alkyl.

The term phenyl- (CrC8) -alkyl means groups such as benzyl, phenethyl, phenylpropyl, a-methylbenzyl and the like.

The benzamido-type compounds corresponding to formula I are prepared by bringing a 4-amino-1,2-hydrocarbylpyr-azolidine II into contact with an appropriately substituted benzoyl chloride III, according to the following scheme:

R

C0C1

R-N

_NH

■ N

'1 R

R-N

(II)

(III)

wherein R, R1, R2, R3 and n have the meanings mentioned above, with the proviso that R3 does not represent a primary amino group.

The compounds of formula I, in which R3 represents a primary amino group, are generally prepared by catalytic hydrogenation of the precursor compounds of formula I, in which R3 represents a nitro group. It is also possible to prepare a compound of formula I in which R3 represents an acetamido group, then to hydrolyze the compound in dilute acid to generate the amino radical.

According to another preparation procedure, 1,2-hydrocarbyl-4-phthalimidopyrazolidines can be used as reagents. The latter are prepared for example by reacting a 4-chloro-1,2-hydrocarbylpyrazolidine and potassium phthalimide. The 1,2-hydrocarbyl-4-phthalimidopyrazolidine can be hydrolyzed in dilute mineral acid, the mixture is filtered and the acid filtrate is made basic to release the free 4-amino-1,2-hydrocarbylpyrazolidine, which can be reacted with a benzoyl chloride chosen to obtain the N- (1,2-hydrocarbyl-4-pyrazolidinyl) benzamide desired.

According to another procedure also possible for preparing the new compounds of formula I, an appropriately substituted benzoic acid is used, which is brought into contact with ethyl chlorocarbonate, in the presence of triethylamine in methylene chloride. at 0-5 ° C, to form the mixed anhydride of benzoic acid. After about 1 hour at low temperature, add

45 a solution of 4-amino-1,2-hydrocarbylpyrazolidine. After an additional period of stirring, an aqueous solution of sodium bicarbonate is added to the reaction mixture, the organic phase is separated and the benzamide compound is isolated therefrom.

N / A The substituted benzoyl chlorides III useful for practicing the invention either are known compounds or can be prepared according to known procedures. As nonlimiting examples of such benzoyl chlorides, there may be mentioned:

2-fluorobenzoyl chloride,

55 3-bromobenzoyl chloride,

4-bromobenzoyl chloride,

3,5-dinitrobenzoyl chloride,

3,4-dichlorobenzoyl chloride,

3,4-diethoxybenzoyl chloride,

60 3-trifluoromethylbenzoyl chloride,

4-tert.-butylbenzoyl chloride,

4-butoxybenzoyl chloride,

2,4-dimethoxybenzoyl chloride,

4-methylbenzoyl chloride,

65 4-cyanobenzoyl chloride,

2-methoxy-5-sulfamoylbenzoyl chloride,

2-methoxy-4-dimethylaminobenzoyl chloride,

2-methoxy-4-nitrobenzoyl chloride,

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2-methoxy-3-fluoro-5-chlorobenzoyl chloride,

2-ethoxy-4-bromobenzoyl chloride,

2-methoxy-3-acetamido-5-trifluoromethylbenzoyl chloride, 2-methoxy-3-fluoro-5-chlorobenzoyl chloride.

In formula I there are centers of asymmetry. These compounds can be resolved into their optically active forms by combining these compounds with optically active organic acids and by separating the optically active forms by fractional crystallization. Optically active forms are also part of the invention.

The following examples illustrate the invention without, however, limiting its scope.

Preparation 1:

4-Chloro-1,2-diethylpyrazolidine

A solution of 52 g (0.2 mol) of triphenylphosphine in 150 ml of chloroform is treated with chlorine gas, and the temperature of the mixture is simultaneously raised to 60 ° C. until an excess of chlorine gas appears at the surface of the mixture. Air is passed through the mixture until the yellow-green gas disappears. To the mixture cooled to 30 ° C. and stirred, 28.8 g (0.2 mol) of 1,2-diethyl-4-pyrazolidinol are added dropwise, at a rate such that the temperature of the reaction mixture rises to 40 ° C. After this addition, the stirred solution is heated to reflux for 2 h, it is cooled to ambient temperature and then it is extracted with water. The combined aqueous extracts are made basic with a concentrated solution of sodium hydroxide and the basic mixture is extracted with chloroform. The dry chloroform extract (sodium sulfate) is concentrated under reduced pressure, and the residual product is distilled at 92-94: C / 30 mmHg, to obtain 24.5 g (75%) of product.

Elementary analysis for C7HI5N2C1:

Calculated: C 51.68 H 9.29 N 17.22%

Found: C 51.45 H 9.30 N 17.29%

Preparation 2:

4-Amino-1,2-diethylpyrazolidine

Heated to 150 ° C, in a closed steel enclosure, a mixture of 100 g (0.165 mol) of 4-chloro-1,2-diethylpyrazolidine and 200 ml of concentrated ammonium hydroxide, for about 36 h. The cooled reaction mixture is extracted with isopropyl ether, the aqueous phase is saturated with potassium carbonate, then extracted continuously with chloroform for 6 h. The dry chloroform extract (sodium sulfate) is concentrated under reduced pressure, and the residue is distilled at 113-115 ° C / 40 mmHg, to obtain 40.5 g (45.5%) of product.

Preparation 3:

4-Amino-1,2-dimethylpyrazolidine

A mixture of 300 g (2.22 mol) of 4-chloro-1,2-di-methylpyrazolidine and 600 ml of concentrated ammonium hydroxide is heated at 150 ° C for 18 h in a spray can. steel. The cooled mixture is saturated with potassium carbonate and then extracted continuously for 18 h with chloroform. The residual product is distilled after concentration of the chloroform extract at 90-100 ° C / 40 mmHg, to obtain 73 g of product.

Preparation 4:

4-Anilina-1,2-dimethylpyrazolidine

A stirred suspension of 40 g (1.02 mol) of sodium amide in dry toluene is treated dropwise with 116 g (1.0 mol) of 1,2-dimethyl-4-pyrazolidinol at 80 ° C. After 4.5 h at reflux, the mixture is cooled and kept at a temperature below 20 ° C, while 161.0 g (1.0 mol) of benzenesulfonyl chloride is added dropwise. After stirring for 1.0 h, the reaction mixture is shaken with dilute sodium hydroxide, the separated toluene phase is dried over sodium sulfate and concentrated under reduced pressure. The residue is dissolved in 300 ml of aniline, the mixture is heated for 2.5 h in a water bath and then at reflux for 3.0 h. The cooled mixture is extracted with a dilute sodium hydroxide solution and the separated aqueous phase is extracted with isopropyl ether. The combined organic phases are concentrated after drying over sodium sulfate and the residue is distilled (temperature of the container 140 ° C / 80 mmHg). The residue, which should not crystallize, is distilled at 110-125 ° C / 0.1 mmHg, to obtain 86 g of product.

Preparation 5:

4-Anilino-1,2-diethylpyrazolidine

To a stirred suspension of 7.9 g (0.2 mol) of sodium amide in 100 ml of dry toluene, 28.8 g (0.2 mol) of 1,2-diethyl-4-pyrazolidinol are added, at a speed such that the temperature of the container is maintained at 30-35 ° C. After stirring for 2.0 h at room temperature, the solution is added dropwise to a solution of 38.0 g (0.2 mol ) of p-toluenesulfonyl chloride in 200 ml of dry toluene, the temperature being maintained below 30 ° C. After having stirred for approximately 1 h at room temperature, the reaction mixture is washed twice with water, then it is dried over sodium sulfate. The dry filtered solution is concentrated until a volume of approximately 100 ml is obtained, 100 ml of aniline are added, the solution is heated to reflux for 3.0 h and then concentrated. The residue is partitioned between chloroform and dilute sodium hydroxide. The dried chloroform phase is concentrated and the residue is distilled at 120 ° C / 0.1 mmHg, to obtain 4.0 g of product.

Preparation 6:

1,2-Diethyl-4-phthalimidopyrazolidine maleate

To 100 ml of dimethylsulfoxide, 32.4 g (0.2 mol) of 4-chloro-1,2-diethylpyrazolidine and 37 g (0.2 mol) of potassium phthalimide are added. The solution is stirred at 115 ° C for 48 h, cooled and filtered. The filtrate is treated with an equal volume of water, then extracted twice with 150 ml of ethyl acetate. The extracts are combined and concentrated. The residue is distributed between dilute hydrochloric acid and ethyl acetate. The acid phase is made basic with potassium carbonate, then extracted with chloroform. The chloroform (sodium sulfate) phase is dried and concentrated. The residue (22 g) is treated with 22 g of maleic acid and 75 ml of isopropyl alcohol and 75 ml of isopropyl ether. The maleate is recrystallized twice from the same solvent system to obtain 11.5 g (15%) of product, mp 144-147 ° C.

Elementary analysis for Ci9H23N306:

Calculated: C 58.60 H 5.95 N 10.79%

Found: C 58.64 H 6.03 N 10.73%

Preparation 7:

4-Amino-1-benzyl-2-methylpyrazolidine

4-amino-1-benzyl-2-methylpyrazolidine, E. 115-125 'C / 1.0 mmHg, is prepared from l-benzyl-2-methyl-4-pyrazolidinol, according to the procedures described in preparations 1 and 2.

Preparation 8:

4-amino-1-cyclohexyl-2-methylpyrazolidine fumarate

4-amino-1-cyclohexyl-2-methylpyrazolidine, E. 90-100 ° C / 0.5-1.0 mmHg, is prepared from l-cyclohexyl-2-methyl-pyrazolidinol, according to the procedures described. in preparations 1 and 2. The fumarate melts at 149-151 ° C.

Preparation 9:

4-Amino-1-isopropyl-2-methylpyrazolidine

4-amino-1-isopropyl-2-methylpyrazolidine, E. 110-115 ° C / 50 mmHg, is prepared from l-isopropyl-2-methylpyrazolidinol, according to the procedures described in preparations 1 and 2.

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639,374

IO preparation:

Preparation 2 is resumed, the concentrated ammonium hydroxide is replaced by an equal molar amount of methylamine in methanol and 4-methylamino-1,2-diethylpyrazolidine is obtained.

Example 1:

4-Chloro-N-phenyl-N- (1,2-dimethyl-4-pyrazolidinyl) benzamide

To a solution of 10 g (0.0525 mol) of 1,2-dimethyl-4-anilino-pyrazolidine in 50 ml of chloroform, 9.15 g (0.0525 mol) of p-chlorobenzoyl chloride are added with stirring , the temperature not exceeding 50 C. When the addition is complete, the solution is heated to reflux for 1 h, it is cooled to ambient temperature, then it is extracted with dilute sodium hydroxide. The chloroform phase is dried over sodium sulfate, then concentrated under reduced pressure to obtain an oil which crystallizes when it is cooled. The solid is recrystallized twice from ligroin. Yield: 13.1 g (76%), F. 104-108 C.

Elementary analysis for C18H2oC1N30:

Calculated: C 65.54 H 6.11 N 12.74%

Found: C 65.77 H 6.08 N 12.86%

Example 2:

4-Fluoro-N- (1,2-diethyl-4-pyrazolidinyl) benzamide A solution of 10 g (0.026 mol) of 1,2-diethyl-4-phthalimidopyrazolidine maleate in 25 ml of 6N hydrochloric acid is heated. reflux for 2 h, the mixture obtained is cooled and filtered. The filter cake is washed with water which is combined with the acid solution. The solution is made basic with dilute sodium hydroxide and cooled with ice. To the resulting solution, 8.2 g (0.052 mol) of p-fluoro-benzoyl chloride is added and the mixture is shaken for 10 min. The resulting mixture is extracted with chloroform, the chloroform is diluted with an equal volume of isopropyl ether and the resulting solution is extracted with dilute hydrochloric acid. The acid phase is made basic with dilute sodium hydroxide and extracted with chloroform. The chloroform (sodium sulfate) is dried and concentrated. The residue is crystallized from an isooctane / isopropyl ether mixture and recrystallized from an isooctane / isopropyl ether mixture containing a few drops of ethyl acetate and clarified by treatment with charcoal. The product (2.0 g, 29%) melts at 114-116 ° C.

Elementary analysis for C14H20N3OF:

Calculated: C 63.38 H 7.60 N 15.84%

Found: C 63.36 H 7.61 N 15.96%

Example 3:

3,4,5-Trimethoxy-N- (1,2-dimethyl-4-pyrazolidinyl) benzamide 10 g (0.09 mol) of 4-amino-1,2-dimethylpyrazolidine in chloroform are added with stirring. , 7 g (0.09 mol) of 3,4,5-trimethoxybenzoyl chloride. After stirring for 30 min, the solution is extracted with dilute sodium hydroxide. The chloroform solution (sodium sulfate) is dried, filtered and the filtrate is concentrated. The resulting crystalline material is recrystallized from equal portions of ethyl acetate and isopropyl ether. The product (12.1 g, 44%) melts at 163-166 ° C.

Elementary analysis for Ci5H23N304:

Calculated: C 58.24 H 7.49 N 13.58%

Found: C 58.20 H 7.45 N 13.19%

Example 4:

4-nitro-N- (1,2-diethyl-4-pyrazolidinyl) benzamide hydrochloride To a solution of 40.5 g (0.28 mol) of 4-amino-1,2-diethyl-pyrazolidine in 200 ml of chloroform, added with stirring 52 g

(0.28 mol) of p-nitrobenzoyl chloride in 200 ml of chloroform. The solution is left to stand overnight, then extracted with dilute sodium hydroxide. The chloroform (sodium sulfate) is dried and concentrated. The residue is crystallized twice from an isopropyl ether / ethyl acetate mixture to obtain 73 g (80%) of the free base.

Elementary analysis for CI4H20N4O3:

Calculated: C 57.52 H 6.90 N 19.17%

Found: C 57.56 H 6.94 N 18.99%

The base is transformed into the hydrochloride which is crystallized from isopropyl alcohol, mp 189-191 ° C (decomposition).

Elementary analysis for C14H21N403C1:

Calculated: C 51.14 H 6.44 N 17.04%

Found: C 50.96 H 6.59 N 16.58%

Example 5:

4-Amino-N- (1,2-diethyl-4-pyrazolidinyl) benzamide

A 20 g (0.069 mol) solution of 4-nitro-N- (1,2-diethyl-4-pyrazolidinyl) benzamide in ethanol is treated with Raney nickel and shaken under 3 atm of hydrogen in a Parr device, at room temperature for 2 h. The mixture is filtered, the filtrate is concentrated and the residue is crystallized from an isopropyl ether / ethyl acetate mixture. The product (12.0 g, 66.5%) melts at 119-12rC.

Elementary analysis for C14H22N40:

Calculated: C 64.09 H 8.45 N 21.36%

Found: C 63.98 H 8.55 N 21.37%

Example 6:

4-Amino-5-chloro-2-methoxy-N- (1,2-diethyl-4-pyrazolidinyl) benzamide

To 75 ml of thionyl chloride, 12 g (0.05 mol) are added

of 4-acetamido-5-chloro-2-methoxybenzoic acid, and the stirred suspension is heated at reflux for 1 h. The resulting solution is concentrated and 100 ml of chloroform are added to the residue which is concentrated to remove traces of thionyl chloride. The residue is dissolved in 100 ml of chloroform and the solution is quickly added dropwise to 7 g (0.05 mol) of 4-amino-1,2-diethylpyrazoli-dine in 100 ml of chloroform, with stirring and cooling. at 20-25 C by an ice bath. After 30 min, the chloroform solution is extracted twice with 100 ml of 3N hydrochloric acid and the chloroform solution is retained. The acid extract is boiled for 10 min, cooled with ice, made basic with concentrated sodium hydroxide, while cooling, and extracted with chloroform. The chloroform (sodium sulfate) is dried, concentrated and the residue is crystallized from an isopropyl ether / isooctane mixture to obtain 3 g of product, F. 116-118 C. The chloroform solution retained is extracted with dilute sodium hydroxide, and concentrate. The residue is dissolved in 3N hydrochloric acid and extracted with isopropyl ether. The acid solution is heated at reflux for 10 min, cooled by an ice bath, made basic by sodium hydroxide while cooling and extracted with chloroform. The chloroform (sodium sulfate) is dried and concentrated. The residue is crystallized three times from isopropyl ether to obtain 0.7 g of product, F. 117-119 C. When the two products are mixed, no reduction in the melting point is observed. The combined yield is 3.7 g (23%).

Elementary analysis for C1SH23C1N402:

Calculated: C 55.13 H 7.09 N 17.14%

Found: C 55.23 H 7.10 N 17.17%

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Example 7:

When, in the procedure of Example 3, the 3,4,5-trimethoxybenzoyl chloride is replaced by equimolar amounts of:

4-cyanobenzoyl chloride,

3-trifluoromethylbenzoyl chloride,

4-methylbenzoyl chloride,

4-methoxybenzoyl chloride,

4-acetamidobenzoyl chloride, and 2-methoxy-5-sulfamoylbenzoyl chloride,

we obtain:

cyano-N- (1,2-dimethyl-4-pyrazolidinyl) benzamide, 3-trifluoromethyl-N- (1,2-dimethyl-4-pyrazolidinyl) benzamide, 4-methyl-N- (1,2- dimethyl-4-pyrazolidinyl) benzamide, 4-methoxy-N- (1,2-dimethyl-4-pyrazolidinyl) benzamide, 4-acetamido-N- (1,2-dimethyl-4-pyrazolidinyl) benzamide, and 2-methoxy-5-sulfamoyl-N- (1,2-dimethyl-4-pyrazolidinyl) benz-amide.

Example S:

r

4-Amino-5-chloro-2-methoxy-N- (1,2-dimethyl-4-pyrazolidinyl) benzamide

A stirred solution of equimolar amounts of 4-amino-5-chloro-2-methoxybenzoic acid and triethylamine in methylene chloride (0-5 ° C) is treated dropwise with a slight excess of chlorocarbonate. ethyl. After 1.0 h, a solution of 4-amino-1,2-dimethylpyrazolidine in methylene chloride is added and the mixture is stirred for about 2 h at room temperature. An aqueous solution of sodium bicarbonate is added to the reaction mixture, the organic phase is separated and concentrated to obtain the product, mp 169-171 ° C.

Example 9:

4-amino-5-chloro-2-methoxy-N- (1-benzyl-2-methyl-4-pyrazolidinyl) benzamide fumarate

4-amino-5-chloro-2-methoxy-N- (1-benzyl-2-methyl-4-pyrazolidinyl) benzamide is prepared from 4-amino-5-chloro-2-methoxybenzoic acid and 4 -amino-1-benzyl-2-methylpyra-zolidine, according to the procedure of Example 8. The fumarate is prepared, mp 129-131 ° C.

Example 10:

4-amino-5-chloro-2-methoxy-N- (1-cyclohexyl-2-methyl-4-pyrazoIidinyl) benzamide is prepared from 4-amino-5-chloro-2-methoxybenzoic acid and 4 -amino-1-cyclohexyl-2-methyl-pyrazolidine according to the procedure of Example 8. Hydrochloride hydrate: mp 105-120 ° C.

Example 11:

4-amino-5-chloro-2-methoxy-N- (I-isopropyl-2-) hydrochloride

methyl-4-pyrazolidinyl) benzamide

4-amino-5-chloro-2-methoxy-N- (1-isopropyl-2-methyl-4-pyrazolidinyl) benzamide is prepared from 4-amino-5-chloro-2-methoxybenzoic acid and 4 -amino-1-isopropyl-2-methyl-pyrazolidine, according to the procedure of Example 8. The dihydrochloride is prepared, mp 182-186 ° C.

The pharmaceutical compositions according to the invention contain compounds of formula I above in an amount such that an antiemetic and emptying action of the effective stomach is obtained. These compositions contain 1.0 to 100 mg of active drug per unit dose. Preferably, the compositions contain from about 5 to 100 mg of drug, or more preferably from about 5 to about 50 mg per unit dose.

The pharmaceutical carrier used in the composition can be either liquid or solid. Examples of solid supports that may be mentioned include lactose, magnesium stearate, Terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia. Examples of liquid carriers include vegetable oils and water. Similarly, the carrier or diluent may contain a continuous release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.

A wide variety of pharmaceutical forms can be used, according to well known procedures. Consequently, if a solid support is used, the composition can be presented in the form of tablets, or it can be prepared in the form of a powder, a lozenge or a tablet. Gelatin capsules containing the drug can also be prepared. If a liquid support is used, the composition may be in the form of a flexible gelatin capsule, a liquid suspension or a syrup. Forms of parenteral administration are obtained by dissolving a soluble salt of the active agent in water or in a saline solution, at a concentration such that 1 cm3 of the solution contains from 1.0 to 25 mg of active agent. The solution can be put in single or multiple dose ampoules.

The treatment consists in administering internally, to warm-blooded animals including humans, certain N- (4-pyra-zolidinyl) benzamides or a non-toxic organic or inorganic acid addition salt of these compounds, preferably with a non-toxic pharmaceutical carrier as described above, in sufficient quantity to control vomiting and / or facilitate gastric emptying. The active agent is administered orally or parenterally, in repeated doses, until a satisfactory result is obtained. The daily dose ranges from about 10 to about 300 mg of active drug, preferably from about 5 to 50 mg.

It is understood that the invention is not limited to the embodiments described above and that those skilled in the art can make various modifications to it without however departing from the scope and spirit of the invention .

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R

Claims (7)

639,374 1 R in which R and R1 represent a Cj-Cg alkyl, cycloalkyl or C4-CI2 alkylcycloalkyl, or phenyl-CI-C8-alkyl radical, R2 represents a hydrogen atom, a CrC8, phenyl or phenyl-substituted alkyl radical, R3 represents a hydroxy, cyano, nitro, amino, fluoro, chloro, bromo, trifluoromethyl, Ci-Ca alkyl, alkoxy Q-Cg, sulfa-medium or acetamido group, R3 being able to represent the same radical or different radicals, and n is an integer ranging from 0 to 3 inclusive, and its acid addition salts. 1. Compound chosen from N- (4-pyrazolidinyl) benzamides, characterized in that it corresponds to the formula: (R3) R-N R -NOT. not 2. Compound according to claim 1, characterized in that it consists of 4-chloro-N-phenyl-N- (1,2-dimethyl-4-pyrazolidinyl) benz-amide. 2 3. Compound according to claim 1, characterized in that it consists of 4-fluoro-N- (1,2-diethyl-4-pyrazolidinyl) benzamide. 4. Compound according to claim 1, characterized in that it consists of 4-amino-5-chloro-2-methoxy-N- (1,2-diethyl-4-pyrazoli-dinyl) benzamide. 5. Process for the preparation of compounds of formula I, in which the symbols have the meaning given in claim 1, with the exception of R3 which does not represent a primary amino group, characterized in that a 4 -aminopyrazolidine of the formula: _ RZ R — N • H (he) sN- R1 with a correspondingly substituted benzoyl chloride of the formula: co Cl ■ CR3) not R, R1, R2 and R3 and n having the same meaning as in formula I, but R3 cannot be a primary amino group. 6. Process for the preparation of compounds of formula I according to claim 1, in which R3 represents a primary amino group, characterized in that a compound of formula I is prepared in which R3 is a nitro group according to the process of claim 5, and subjected to catalytic hydrogenation. 7. Therapeutic compositions, characterized in that they contain, as active ingredient, a compound according to one of claims 1 to 4. (I)