SE444434B - N- (4-pyrazolidinyl) benzamides - Google Patents

Description

s3s0ß694-9, wherein R3 is the same or different groups and n represents 0, 1, 2 or 3.

The non-toxic pharmacologically acceptable acid addition salts of the base compounds of formula I also fall within the scope of the invention because such salts can be used in a similar manner as an anti-emetic or compound for gastric emptying; Both organic and inorganic compounds can be used to form pharmacologically acceptable acid addition salts, for example sulfuric acid, nitric acid, phosphoric acid, citric acid, acetic acid, lactic acid, tartaric acid, sulfamic acid, succinic acid, fumaric acid, maleic acid , hydrobromic acid, benzoic acid and the like. The salts are prepared in known sweetness. The anti-emetic properties were determined using a modification of the method described by Chen and Enxor, J. Pharmac.

Exp. Ther. Zå, 245-250 (1950) and Leonard et al., J-Pharmac. Exp. Ther. 121, 339-345 (1966).

The gastric emptying activity was determined by the following procedure. She Sprague-Dawley rats weighing from 117-221 g were allowed to starve for 24 hours in individual viscous cages with water ad libitum.

The animals were arranged in groups of eight. At time 0, 9 mg / kg of the test compound was administered intraperitoneally to the rats in 5% acacia (0.4 ml / 100 g body weight). The control group received acacia alone, 4 ml / kg intraperitoneally. Thirty minutes after dosing, the rats received orally with gastric tube, 3 ml of a test cell consisting of methylcellulose to which meat broth, casein, powdered sugar and corn starch had been added to give a semi-solid homogeneous paste. 60 minutes after the test goal (after a total time of 90 minutes), the rats were killed by cervical dislocation, laparotomized and the stomach was removed. The full stomach was weighed on a analytical balance scale after which it was cut and emptied, after which the empty stomach was weighed. The difference between full and empty stomach weight represented the amount of food remaining in the stomach and was subtracted from the weight of 3 ml of the test meal, whereby the amount of the meal that was emptied from the stomach during the test period was obtained.

The preferred compounds of Example 6 reduced emesis 87% when administered at a dose level of 5 mg / kg (s.c.) and significantly increased the gastric emptying time when administered at doses from 0.33 ° C to 9.0 mg / kg.

Thus, according to the present invention, primarily new N- (4-pyrazolidinyl) benzamides are obtained. A further object is to provide new N- (4-pyrazolidinyl) benzamides with antiemetic and gastric emptying properties. A further object is to provide new compositions useful as anti-emetics and to regulate gastric emptying.

Additional objects and advantages of the present invention will become apparent to those skilled in the art and others will become apparent from the following description of most preferred embodiments of the present invention and appended claims.

The lower alkyl moiety contains 1-4 carbon atoms.

The term "lower cycloalkyl" as used herein refers to primary cyclic alkyl groups containing from 4 to 12 carbon atoms and includes such groups as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclopentyl, ethylcyclohexyl and the like.

The term "phenyl" is used herein to denote unsubstituted compounds. ,> .....,. ,, ..._. ».__... ~ ......-._.. - .._._...... ¿,. ..._ .. __.._-.-. ..N .____....._........ 7808694-9 nyl groups and phenyl groups substituted by any group or groups which are not reactive or otherwise interfere with the reaction conditions used, such as lower alkyl, lower alkoxy, trifluoromethyl, bromo, chloro, fluoro and the like. The substituted phenyl groups preferably have at most three substituents and as defined above and further, these substituents may have different positions in the phenyl nucleus and when more than one substituent is present they may be the same or different and be in different positions and combinations in relation to each other. The lower alkyl and lower alkoxy substituents each preferably have 1-4 carbon atoms and may be arranged as straight or branched chains. Examples of preferred substituents are methyl, ethyl, propyl, butyl, fluoro, bromo, chloro, iodo, amino, hydroxy, cyanoacetamido, sulfamoyl, methoxy, ethoxy, propoxy, butoxy and trifluoromethyl groups.

The term "lower alkyl" includes straight or branched chain having 1-8 carbon atoms, for example methyl, ethyl, propyl, isopropyl, n-butyl tertiary butyl, amyl, isoamyl, n-hexyl, n-heptyl and n-octyl lower alkoxy groups have the form O-lower alkyl.

The term "phenyl lower alkyl" includes such groups as benzyl, phenethyl, phenpropyl, α-methylbenzyl and the like. Also within the scope of the present invention are novel 4-amino-1,2-hydrocarbylpyrazolidines (II). The compounds of formula II have the formula: wherein R represents lower alkyl, lower cycloalkyl or phenyl lower alkyl wherein R 1 represents lower alkyl or lower cycloalkyl. and R 2 represents hydrogen or phenyl.

The compounds of formula II wherein R 2 represents hydrogen are prepared by heating a mixture of 4-halo-1,2-hydrocarbylpyrazolidine and concentrated ammonium hydroxide in a steel bomb at a temperature of from about 125 to about 100 ° C for several hours. The process is also applicable to prepare compounds where R? denotes lower alkyl, such as methyl, ethyl, or propyl. In the latter case, a solution of the appropriate lower alkylamine in a lower alkanol is preferably used.

The compounds of formula II wherein R 2 represents phenyl I-I 'are prepared by reacting a 1,2-hydrocarbyl-4-arylsulfonyloxy + pyrazolidine and aniline or a substituted aniline together with a suitable solvent. 1,2-Hydrocarbyl-4-arylsulfonyloxy-pyrazolidine is generally prepared by reacting the sodium salt of 1,2-hydrocarbyl-4-pyrazolidinol with benzenesulfonyl chloride or p-tolylsulfonyl chloride in a dry aprotic solvent such as toluene. The 1,2-hydrocarbyl-4-pyrazolidinols from which the respective 4-amino-pyrazolidinols are prepared are either shown in or can be prepared by the process disclosed in U.S. Pat. No. 3,660,426.

These basic compounds of formulas I and II form fluorosilicic acid addition salts which are useful as milling agents according to U.S. Pat. Nos. 1,915,334 and 2,075,359. The preparation of the benzamido compounds of formula I can be carried out. 6 A by sweetening a 4-amino-1,2-Hydrocarbylpyrazolidine II in contact with an appropriately substituted benzoyl chloride III according to the reaction scheme - as follows: 2 - T cooc1 in _ 32 0 -3 NH '/ 3 * i: ca - (R) -NRII 'I \ / R \ N + \ () n - à R__N \ N /. __ 11 i, _ 1.

R 11 111, R 11 where R 1, R 1, R 2 and R 3 and n are previously defined and where R 3 cannot be primary amine.

The compounds of formula I wherein R3 is the primary amino are generally prepared by catalytic hydrogenation of the precursor compound of Formula I where R3 is nitro. Alternatively, a compound of formula I can be prepared with R 3 as an acetamido group and this compound is hydrolyzed with dilute acid to form an amino group. In an alternative process for the preparation, 1,2-hydrocarbyl-4-phthalimidopyrazolidines are used as reactant. The latter is prepared by the reaction of 4-chloro-1,2-hydrocarbylpyrazolidine with potassium phthalimide. 1,2-Hydrocarbyl-4-phthalimidopyrazolidine is hydrolyzed in dilute mineral acid, the mixture is filtered and the acidic filtrate is made basic to liberate the free 4-amino-1,2-hydrocarbylpyrazolidine which is reacted with a selected benzoyl chloride to give the desired Nf (ly2-hydrocarbyl-4-pyrazolidinyl) benzamides.

An alternative process which may be used for the preparation of novel compounds of formula I utilizes an proximally substituted benzoic acid which is sweetened in contact with ethyl chlorocarbonate in the presence of triethylamine in methylene chloride at 0 DEG-5 DEG C. Blotting of benzoic acid vanhydride. After 1 hour at low temperature, a solution of 4-omino-1,2-hydrocarbylpylo rozolidinef is added. After a superficial period of stirring, a aqueous solution of sodium hydrogen carbonate was added to the reoquion mixture and the organic phase was separated and the benzumide compound was isolated 'doors on suitable juice.' The substifuberated benioyl chloride no. III, useful in the practice of the present invention, are antigen-free compounds or can be prepared per se sex-sweet and in-buffer but are not limited by the following listed compounds: 2-fluorobenzoyl chloride , 4-åiklorobenzoylklorid 3,4-díetoxibensoylkloríd 3 ~ trifluorometylbenzoylklorïd- tertíör butylbenzoylklorid 4-I 4-bhtoxíbenzoylkloríd 2,4Ådimetoxíbenzoylklorid 4-metylbenzoylklorid 4-cyanobenzoyl chloride 2-sulfumoylbenzoylklprid mefoxí45 ~ 2 ~ methoxy-4-dímetylamínobenzoylklorid 2-methoxy-4 ~ nitrobenzoylklorid 2 Methoxy-3-fluoro-5-chlorobenzoyl chloride 2-Ethoxy-4-bromobenzoyl chloride 2-Methoxy-3-ocetamido-5-trifluoromethylhenzoyl chloride In formula I The symmetry is present. Compounds can be dissolved in β-chloro-1,2-diethylpyrazolidine their optically active forms by combining the compounds with optically active organic acids and separating the optically active forms by fractional crystallization. The optically active forms are included within the scope of the present invention.

Preparation 1 A solution of triphenylphosphine (52 g; 0.2 mol) in 150 ml of chloroform was treated with chlorine gas which was followed by a temperature increase of the mixture to 60 ° until excess chlorine gas appeared over the surface of the mixture. Air had to pass the landing until the greenish-yellow gas disappeared. To the cooled (30 ° C) stirred mixture was added dropwise 28.8 g (0.2 mol) of 1,2-diethyl-4-pyrazolidinal at a rate which caused the reaction mixture to drop to 40 ° C.

After the addition of the stirred solution, it was refluxed for two hours, cooled to room temperature and extracted with water.

The combined aqueous extracts were basified with concentrated sodium hydroxide solution and the basic mixture was extracted with chloroform. The dried chloroform extracts (sodium sulfate) were concentrated under reduced pressure and the remaining material was distilled at 92 DEG-94 DEG C./4 mm Hg to give 24.5 g (75%) of the product. fAn @ 1ys = ßerakn @ {for cin N cl; cl 51.68; H 9.29; H 17.22 7 15 2 obtained = c 51.45; H 9.30; H 17.29 Preparation 2 4-Amino-1,2-diethylpyrazolidine I A mixture of 100 g (0.615 ml) of 4-chloro-1,2-diethylpyrazolidine and 200 ml of concentrated ammonium hydroxide in a closed steel container was heated to 150 ° Cunder about 36 hours. The cooled reaction mixture was extracted with isopropyl ether, the aqueous phase was met with potassium carbonate and extracted continuously with chloroform for six hours. The dried chlorout extract (sodium sulfate) was concentrated under reduced pressure and the residue was distilled at 113-115 ° C / 40 mm Hg to give 40.5 g (45.5%) of the product.

Preparation 3 4-Amino-1,2-dimethylpyrazolidine -A mixture of 300 g (2.22 mol) of 4-chloro-1,2-dimethylpyrazolidine and 600 ml of concentrated ammonium hydroxide was heated to 150 ° C for 18 hours in a steel bomb. The cooled mixture was met with potassium carbonate and extracted continuously for 18 hours with a chlorotorm. The residual material after concentration of the chloroform extract was distilled at 90-100 ° C / 40 mm Hg to give 73 g of the product. A stirred suspension of 4 g (1.02 mol) of sodium amide in dry toluene was treated dropwise with 116 g (1.0 mol) of 1,2-dimethyl-4-pyrazoline. lidinol at 80 ° C. After 4.5 hours at reflux, the mixture was cooled and kept below 20 ° C while adding 161.0 g (1.0 mol) of benzene / sulfonyl chloride dropwise. After stirring for 1.0 hour, the reaction mixture was shaken with dilute sodium hydroxide, the separated toluene phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 300 ml of aniline, the mixture was heated for 2.5 hours on a steam bath and refluxed. flow 3.0 hours. The cooled mixture was extracted with dilute sodium hydroxide solution and the separated aqueous phase was extracted with isopropyl ether. The combined organic layers after drying over sodium sulfate were concentrated and the residue was distilled at a container temperature of 140 ° C / 80 mm Hg. The residue which did not crystallize was distilled at 110-125 ° C / 0.1 mm Hg. whereby se g of a product was obtained.

Preparation 5 4-Anilino-1,2-diethylpyrazolidine To a stirred solution of 7.8 g (0.2 mol) of sodium amide in 100 ml of dry toluene was added 28.8 g (0.2 mol) of 1,2-diethyl-4-pyrazolidinol at a rate so that a container temperature of 30-35 ° C could be maintained.

After stirring for 2 hours at room temperature, the solution was added dropwise to a solution of 38.0 g (0.2 mol) of p-toluenesulfonyl chloride in 200 ml of dry toluene with a container temperature maintained below 30 ° C.

After stirring for one hour at room temperature, the reaction mixture was washed twice with water and dried over sodium sulfate.

The dry, filtered solution was concentrated to a volume of about 100 ml, aniline (100 ml) was added, the solution was refluxed for 3 hours and concentrated. The residue was partitioned between chloroform and dilute sodium hydroxide. The dried chloroform phase was concentrated and the residue was distilled at 120 ° C / 0.1 mm Hg to give 4.0 g of the product.

Preparation of 1,2-Diethyl-4-phthalimido-pyrazolidine maleate To 100 ml of dimethyl sulfoxide were added 32.4 g (0.2 mol) of 4-chloro-1,2-diethylpyrazolidine and 37 g (0.2 mol) of potassium phthalimide. The solution was stirred at 115 ° C for 8 hours, cooled and filtered. The filtrate was treated with an equal volume of water and extracted twice with 150 ml of ethyl acetate. The extracts were combined and concentrated. The residue was partitioned between dilute hydrochloric acid and ethyl acetate. The acid phase was quenched with potassium carbonate and extracted with chloroform. The chloroform was dried (sodium sulfate) and concentrated. The residue (22 g) was treated with 22 g of maleic acid and 75 ml of isopropyl alcohol and 75 ml of isopropyl ether. The maleate salt crystalline crystallized twice from the same solution system to give 11.5 g (15%) of a product melting at 144 DEG-147 DEG.

Analysis: Calculated for C H N O '19 23 3 6. C 58.6Ö; H 5.95; N 1Q.79 Obtained c 58.64; H 6.03; N 10.73 Preparation 17 4-Amino-1-benzyl-2-methylpyrazolidine 4-Amino-1-benzyl-2-methylpyrazolidine, b.p. 115 DEG-125 DEG C./1.0 mm Hg was prepared from 1-benzyl-2-methyl-4-pyrazolidinol according to Preparation 1 and 2.

Initial form 8-Amino-1-cyclohexyl-2-methylpyrazolidine fumarate 4-Amino-1-cyclohexyl-2-methylpyruzolidine, b.p. and 2. The fumarate salt melted at 149-151 ° C.

Preparation 9 4-Amino-1-isopropyl-2-methylpyrazolidine 4-Amino-1-isopropyl-2-methylpyrazolidine, b.p. 110-115 ° C / 50 mm Hg was prepared from 1-isopropyl-2-methylpyrazolidinol according to Preparation 1 and 2. In Preparation 10 In Preparation 2, instead of concentrated ammonium hydroxide equimolar amounts of methylamine in methanol, 4-methylamino] 1,2-diethylpyrazolidine was obtained. 7808694-9 Example gel 1 4-Chloro-N-phenyl-N- (1,2-dimethyl-4-pyraiolidinyl) benzamide.

To a solution of 10 g (0.0525 mol) of 1,2-dimethyl-4'anilinopverazolidine in 50 ml of chloroform was added with stirring 9¿15 g (0.0525 mol) of chlorobenzoyl claride at a temperature ioke exceeding 50 ° C. After the addition was complete, the solution was refluxed for 1 hour, cooled to room temperature and extracted with dilute sodium hydroxide. The chloroform phase was dried over sodium sulphate and counter-charged under reduced pressure to give an oil which crystallized on cooling. The solid was recrystallized twice from ligroin. Yield 13.1 g (76%); melting point 104-10800; V Analysis: Calculated for C 18 H 20 ClN 3 O: C 65.54; H 6.11; N 12.74 Found: C 65.77; H 6.08; N 12.86 Example gel 2 4-Fluoro-N- (1,2-diethyl-4-pyrazolidinyl) benzamide A solution of 10 g (0.026 ml) of 1,2-diethyl-4-phthalimidopyrazolidine maleate in 25 ml of 6N hydrochloric acid was boiled under reflux two hours, after which the resulting mixture was cooled and filtered. The filter cake was washed with water, which was combined with the acidic solution. The acidic solution was basified with dilute sodium hydroxide and cooled with ice. To the remaining solution was added 8.2 g (0.052 ml) of p-fluorobenzoyl chloride and the mixture was shaken for 10 minutes. The resulting mixture was extracted with chloroform; the chloroform was diluted with an equal volume of isopropyl ether and the resulting solution was extracted with dilute hydrochloric acid. The acid phase was basified with dilute sodium hydroxide and extracted with chloroform. The chloroform was dried (sodium sulfate) and concentrated. The residue was crystallized from isooctane-isopropyl ether and recrystallized from isooctane-isopropyl ether containing a few drops of ethyl acetate and clarified by treatment with activated carbon. The product (2.0 g; 29%) melted at 114 DEG-166 DEG C., Analysis: Calculated for C14 H2 ON3 O 3 F: C 63.38; ÜH 7.ó0; * »N'15l84 obtained, = c 6s.sa, H 7.ó1; ' N 15.96 Example gel 3 3,4,5-Trimethoxy-N- (1,2-dimethyl-4-pyrazolidinyl) benzamide To 10 g (0.09 mol) of 4-amino-1,2-dimethylpyrazolidine in chloroform was added with stirring 20.7 g ( 0.09 mol) 3,4,5-trimethylbenzobyl chloride. After stirring for 30 minutes, the solution was extracted with: dilute sodium hydroxide. The chloroform solution was dried (sodium sulfate), filtered and the tiltrate was concentrated. The resulting crystalline material was recrystallized from equal amounts of ethyl acetate and isopropyl ether. The product (12.1 g; 44%) melted at 163 DEG-166 DEG. * C 58.24; H 7.49; N 13.58 'Analysis: Calculated for C 15 H 23 N 3 O 4: Obtained C 58.20; H 7.45; in H 13.19 Example gel 4 4-Nitre-N- (1,2-diethyl-4-pyrazolidinyl) benzamide hydrochloride To a solution of 40.5 g (0228 mol) of 4-amino-1,2-diethylpyrazolidine in 200 ml chloroform was added with stirring 52 g (0.28 mol) of p-nitrobenzoyl chloride in 200 ml of chloroform. The solution was allowed to stand overnight and then extruded with dilute sodium hydroxide. The chloroform was dried (sodium sulfate) and concentrated. The residue was crystallized twice from isopropyl ether-ethyl acetate to give 73 g (80%) of the free base.

Analysis: Calculated for C 14 H 20 N 4 O 3: C 57.52: N 6.90; N 19.17.

Found C 57.56; N 6.94; N 18.99 The base was converted into the hydrochloride salt and crystallized from isopropyl alcohol, melting at 189 DEG-191 DEG C. (decomposition). 10 15 20 25 30, 78Û8694 ~ 9 14 Analysis; neraknof fö; c H N o cl; c 51.14; H 6.44; M 17.04 14 21 4 3, Found: C 50.96; H 6.59; N 16.58.Exemgel 5 - 44Amino-N- (1,2-diethyl-4-pyrazolidinyl) benzamide A solution of 20 g (0.069 mol) of 4-nitro-N- (1,2-diethyl-4-pyra- ' zolidinyl) benzamide in ethanol was treated with Raney nickel and shaken in three atmospheres of hydrogen in a Parr apparatus at room temperature for two hours. The mixture was filtered, the filtrate was concentrated and the residue was crystallized from isopropyl ether-ethyl acetate.

The pressure (12.o 9; 66.5%) melted at 119-121 ° C; Analysis: Calculated-For C 14 H 22 N 4 O: C 64.09; H 8; 45; N 21¿36 receives = c 63.98; H 8.55; H 21.37 _ _ _ Exemgel 6. 4-Amina-5-chloro-2-methoxy-N- (1,2-diethyl-4-pyrazolidinyl) benzamide To 75 ml of thionyl chloride was added 129 (0.05 ml) of 4-acetamido-52-chloro-2-methoxy-benzoic acid and the stirred suspension was refluxed for one hour. The resulting solution was concentrated and 100 ml of chloroform was added to the residue, which was concentrated to remove sores of thionyl chloride. The residue was dissolved in 100 ml of chloroform and the solution was added as a rapid drop to 7 g (0.05 ml) of 4-amino-1,2-diethylpyrazolidine in 100 ml of chloroform under stirring and cooling to 20-25 ° C with an ice bath. After 30 minutes, the chloroform solution was extracted two times with 100 ml of 3N hydrochloric acid and the chloroform solution was maintained. The acid extract was boiled for 10 minutes, cooled with ice, basified with concentrated sodium hydroxide under cooling and extracted with chloroform. The chloroform was dried (sodium sulfate), concentrated and the residue was crystallized from isopropyl ether-isooctane to give 3 g of a material melting at 116-11800. The retained chloroformless ~ oh 15 20. 3.7 g (23%). The mixture was extracted with dilute sodium hydroxide and concentrated. The reflux was dissolved in SN hydrochloric acid and extracted with isopropyl ether. The acidic solution was refluxed for 10 minutes, cooled with an ice bath and basified with sodium hydroxide under cooling and extracted with chloroform. The chloroform was dried (sodium sulfate) and concentrated. The red root was crystallized three times from isopropyl ether to give 0.79 g of a material melt at 117 DEG-191 DEG C. A mixed melt point For both materials there was no lowering of the melt melt. The total unchanged was H 7.09; w.17.14 H 7; 1o; N 17.17 Analysis; Calculated fa; c15H23c1N4o2 = c 55.13; Found C 55.23; Example 7 When following the procedure of Example 3 but substituting 3,4,5-trimethoxybenzoyl chloride, equimolar amounts of: 5-sulfamoylbenzoyl chloride, obtained: 4-cyano-N- (1; 2-dimethyl-4-pyrazolidinyl) benzamide, V 3-trifluoromethyl-N- (1,2-dimethyl-4-pyrazolidinyl) benzamide, 4-methyl-N - (1,2-dimethyl-4-pyruzolidinyl) benzamide, 4-methoxy-N- (1,2-dimethyl-4-pyrazolidinyl) benzamide, 4-acetamido-N- (1,2-dimethyl-4-pyrazolidinyl) benzamide and 2-meroxy-5-sulfamoyl-N- (1,2-dimethyl-4-pyrazolidinyl) benzamide.

Example 8 4-Amino-5-chloro-2-methoxy-N- (1,2-dimethyl-4-pyrazolidinyl) benzamide A so 16 A converted solution of equimoluro amounts of 4-amino-5 Chloro-2-methoxybenzoic acid and triethylamine in methylene chloride (0-5 ° C) were treated dropwise with a slight excess of ethyl chlorocarbonyl. After 1 hour, a solution of 4-omino-1,2-dimethylpyruzolidine in methylene chloride was added and the mixture was stirred. two hours at room temperature. An aqueous solution of sodium hydrogencarbonate was added to the reaction blend, the ofgonic phase was separated and concentrated, and the product was obtained, melting at 169 DEG-171 DEG. Example 9 9 4-Amino-5-chloro-2-methoxy-N- (1-benzul-2-methyl-4-pyruzolidinyl) benzomidum-fumute V 4 I 4-Amino-5-chloro-24-methoxy-N - (1-Benzyl-2-methyl-4-pyrozolidinyl) benzamide was prepared from 4-omino-5-chloro-2-methoxybenzoic acid and 4-quino-1-benzyl-2-methylpyrazolidine according to the procedure of Example 8. The root starch was prepared and melted at 132 ° C at 31 ° C. Example 10 4-Amino-5-chloro-2-methoxy-N- (1-cyclohexyl-2-methyl-4-pyrozolidinyl) benzomide was prepared from 4-amino-5 -chloro-2-methoxybenzoic acid and 4-ominoe1-cyclohexyl-2-methylpyroliolidine according to the procedure of Example 3. The narrow point of hydrolysis of hydrogen chloride was 105 DEG-120 DEG C.

Enemgel 11 4-Amino-5-chloro-2-methoxy-N- (1-isopropyl-2-methyl-4-pyridzolidinyl) -benzamide dihydrochloride 4-Amino-5-chloro-2-methoxy-N- (1- isopropyl-2-methyl-4-pyrozolidinyl) -benzumide was prepared from 4-amino-5-chloro-2-methoxybenzoic acid and 4-amino-1-Isopropyl-2-methylpyruzolidine according to the procedure of Example 8. The dihydrochloride hunger was prepared and melted at 18 ° C. C. Pharmaceutical compositions of the present invention consist of compounds of formula I above in an amount which provides effective anti-inflammatory properties. emetic and gastritic emptying effect. The compositions contain 1.0 mg to 100 mg of active drug per unit dose Preferably, the compositions contain from about 5 mg to 100 mg of drug *, preferably from about 5 mg to 50 mg per unit dose.

The pharmaceutical carriers used in the composition may be either solid or liquid. Examples of solid carriers are lactose; magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia gum. Examples of liquid carriers are vegetable oils and water. Similarly, the carriers or diluent may include sustained release materials, such as glyceryl, monostearate or glyceryl dysterate alone or with a VOX.

A very large number of pharmaceutical forms can be used on oeh known per se. Thus, if a solid carrier is used, the composition may be tableted or prepared as a powder. Gel-V capsules containing drugs can also be prepared. If a liquid carrier is used, the composition may be in the form of soft gelatin capsules, liquid suspensions or a syrup. Parenteral dosage forms are obtained by dissolving a water-soluble salt of the active agent in water or 1 saline solution in concentrations so that 1 ml of the solution contains from 1.0 to 25 mg of active agent. The solution can be filled into a single or multiple dose ampoules.

The compositions according to the present invention may be administered internally to warm-blooded animals including humans and constituting special N- (4-pyrazolidinyl) benzamides or non-toxic organic or inorganic acid addition salts thereof, preferably with a non-toxic pharmaceutical boron. , as described above, in an amount sufficient to regulate emesis and / or facilitate gostritic A emptying. The active agent was orally or poreñterol administered in repeated doses until satisfactory results were obtained. The daily dose ranges from 10 mg to about 300 mg of active drug, preferably about 5 to 50 mg. m ...., .., ......- ~.-....._-.-_ ~ ».-.-.,. w -.-......._ __. _... ....._.._......, ....-...__. ,, _.,. ~ ..... _. _.

Claims (4)

1. 0 20 25 “@ L 7808694-9 Eatentkrav ul. N- (4-pyrazolidinyl) benzamides of the formula! Aff.). n. k? o 'f. ""' _ l @ ® c M l \ / R represents lower alkyl, lower cycloalkyl or phenyl- where »lower alkyl where R1 represents lower alkyl or Lower cycloalkyl, where R2 represents hydrogen or phenyl, where R3 represents cyano , nitro, amino; fluoro, chloro, trifluoro-Iromethyl, lower alkyl, lower alkoxy, sulfamoyl or acetamido and where R 3 may be the same or different groups and where n represents 0.1; 2 or 3 and pharmaceutically acceptable acid addition salts thereof. A compound according to claim 1, characterized in that it is 4-chloro-N-phenyl-N- (1,2-dimethyl-4-pyrazolidinyl) -benamide. " A compound according to claim 1, characterized in that it is 4-fluoro-N- (1,2-diethyl-4-pyrazolidinyl) -benzamide; IN 4. A compound according to claim 1, characterized in that it is 4-amino-5-chloro-2-methoxy-N- (1,2-diethyl-4-pyrazolidinyl) benzamide.