FI68044C - REFERENCE TO THERAPEUTIC ACTIVATION OF THERAPEUTIC ACTIVE N- (4-PYRAZOLIDINYL) BENZENIDE - Google Patents

Description

I -. «^ '" 1 ,, ADVERTISEMENT

• ^ ΙΙίΙ B 11 UTLÄG G NIN GSSKRI FT 6 8044 c <45> v ^ y (51) Kv.lk.4 / lnt.CI.4 C 07 D 231/04 (21) Patents »- Patentantöknlng 782507 ( 22) Application date - Ansöknlngsdag 16.08.78 (23) Starting date - Giltighetsdag 16.08.78 (41) Become Public - Blivlt offentlig 20.02.79

National Board of Patents and Registration ^ Date of Submission and Publication—

Patent- och register Styrelsen '' Ansttkan utlagd och utl.skriften publlcerad 29.03 »85 (32) (33) (31) Privilege requested - Begärd priority 19-08.77 26.04.78, 01.08.78 USA (US) 826031, 900369, 930125 (71) AH Robins Company, Incorporated, 1047 Cummings Drive, Richmond, Virginia 23220, USA (72) Carl Dalton Lunsford, Richmond, Virginia,

Albert Duncan Cale, Jr., Mechanicsville, Virginia, USA (74) Berggren Oy Ab (54) Process for the preparation of therapeutically active N- (4-pyrazolidinyl) benzamides - For the preparation of therapeutically active N- (4-pyrazolidinyl) benzamides This invention relates to a process for the preparation of therapeutically active N- (4-pyrazolidinyl) benzamides of the formula R 2 O Jx, D 3, RN J -

"" N

R 1 and pharmaceutically acceptable acid addition salts thereof, wherein R is C 1-6 alkyl,

1 1 J

R is C 1-6 alkyl, cyclohexyl or benzyl, R 2 is hydrogen or phenyl, 3 R is nitro, amino, fluoro, chloro or alkoxy, wherein the groups 3 R may be the same or different and n is 1 or 3.

The compounds of formula I have antiemetic and intestinal depleting properties when administered to warm-blooded animals with very few side effects.

68044

Various benzamido derivatives are known in the art, in which case one substituent attached to the benzamido nitrogen may be a pyrrolidinyl or piperidinyl radical. U.S. Patent 3,342,826 discloses heterocyclic aminoalkylbenzamides having antiemetic properties. U.S. Patent 3,577,440 describes 1-substituted 3-amidopyrrolidines having analgesic and antidepressant properties. U.S. Patent Nos. 3,966,957 and 3,963,745 describe N- (1-substituted-3-pyrrolidinyl) benzamides and thiobenzamides which are highly useful in controlling emesis.

The compounds of formula I are prepared by a) 4-amino-1,2-substituted-pyrazolidine of formula R2

(--NH

R-N J II

X N

I,

R

1 2 wherein R, R and R are as defined above is reacted with benzoyl chloride of the formula COCl

1 - (R 3) n III

3 wherein R and n are as defined above, provided, however, that R is not a primary amino, or b) 1,2-substituted-4-phthalimidopyrazolidine of formula

i r N

RN JVC ° -W ^ R1 wherein R and R are as defined above are hydrolyzed in dilute mineral acid, then the solution is basified to liberate free 4-amino-1,2-substituted-pyrazolidine, which is then reacted with a substituted compound of formula III. with benzoyl chloride, or c) benzoic acid of formula 3

<R

COOH

wherein R 3 and n are as defined above, are reacted with ethyl chlorocarbonate in the presence of triethylamine and the resulting compound is reacted with a 4-amino-1,2-substituted-pyrazolidine of formula II, followed, if desired, by a), b) or c) in the resulting compound of formula I, the group R 3, when it is nitro, is catalytically reduced to amino and / or the resulting compound is converted into a pharmaceutically acceptable acid addition salt.

Non-toxic pharmaceutically acceptable acid addition salts of the parent compounds of formula I may also be used as anti-emetic or gastric emptying compounds. Both organic and inorganic acids can be used to prepare pharmaceutically acceptable acid addition salts, and typical such acids include sulfur, nitrogen, phosphorus, citric, acetic, lactic, tartaric, sulfamic, succinic, fumaric, maleic, hydrochloric, hydrobromic, benzoic, etc. acids. The salts are prepared using methods known per se.

Asymmetric centers are present in the compounds of formula I.

These compounds can be resolved into their optically active forms by combining the compounds with optically active organic acids and separating the optically active forms by fractional crystallization.

3

Compounds of formula I wherein R is a primary amino are usually prepared by catalytic hydrogenation of a precursor of formula I wherein R is nitro. Alternatively, a compound of formula I wherein 3 R is an acetamido group can be prepared and this compound is hydrolyzed in a dilute 468044 acid to give the amino group.

Process b) uses 1,2-substituted-4-phthalimidopyrazolidines as reactants. The latter are prepared by the reaction of 4-chloro-1,2-substituted-pyrazolidine with potassium phthalimide. The 1,2-substituted-4-phthalimido-pyrazolidine is hydrolyzed in dilute mineral acid, the mixture is filtered, and the acidic filtrate is basified to liberate free 4-amino-1,2-substituted-pyrazolidine, which is reacted with the selected benzoyl chloride to give the desired N- (1,2-substituted-4-pyrazolidinyl) benz-amide.

Process c) uses an appropriately substituted benzoic acid which is reacted with ethyl chlorocarbonate in the presence of triethylamine in methylene chloride at a temperature of 0-5 ° C to give a mixture of benzoic anhydrides. After about one hour at a lower temperature, a solution of 4-amino-1,2-substituted-pyrazolidine is added. After the next stirring step, an aqueous solution of sodium bicarbonate is added to the reaction mixture, the organic phase is separated and the benzamide compound is separated therefrom in a suitable manner.

The substituted benzoyl chlorides III which can be used in the practice of the invention are either known compounds or can be prepared by methods known in the art.

The starting materials of formula II are new.

2

Compounds of formula II wherein R is hydrogen are prepared by heating a mixture of 4-halo-1,2-substituted-pyrazolidine and concentrated ammonium hydroxide in a steel bomb at a temperature of about 125-200 ° C for several hours.

2

Compounds of formula II wherein R is phenyl are prepared by reacting 1,2-substituted-4-phenylsulfonyloxypyrazolidine and aniline or substituted aniline in a suitable solvent. 1,2-Substituted-4-phenylsulfonyl-oxypyrazolidine is usually prepared by reacting the sodium salt of 1,2-substituted-4-pyrazolidinol with benzenesulfonyl chloride or p-tolylsulfonyl chloride in a dry aprotic solvent such as toluene.

The 1,2-substituted-4-pyrazolidinols from which the corresponding 4-aminopyrazolidines are prepared are either disclosed in U.S. Patent 3,660,426 or can be prepared using the methods set forth therein.

The antiemetic properties of the compounds were determined using modifications of the methods presented by Chen and Enxor, J. Pharmac. Exp. Ther. 9j8, 245-250 (1950), and Leonard et al.

J. Pharmac. Exp. Ther. 154, 339-345 (1966).

Gastric and intestinal depletion activity was determined using the following method. Female Spraque-Dawley rats weighing 117-221 g were not fed for 24 hours in separate screened cages, but water ad libitum. The animals were divided into groups of eight animals. The test compound was administered intraperitoneally to these rats at 0.9 mg / kg in 5% acacia solution (0.4 ml / 100 g body weight). The control group was given acacia alone 4 ml / kg intraperitoneally.

Thirty minutes after dosing, rats were orally gavaged with 3 ml of a test diet based on methylcellulose supplemented with broth, casein, powdered sugar, and corn starch to give a semi-solid, homogeneous paste. 60 minutes after the test breakfast (after a total time of 90 minutes), the rats were sacrificed and their stomachs removed. The stomachs were weighed to analytical equilibrium, after which they were opened, rinsed, and the empty stomach weighed. The difference between the weight of a full and an empty stomach corresponds to the weight of the food left in the stomach and this was divided by the weight of 3.0 ml of the test meal to give the amount of food that was emptied from the stomach during the test period.

The preferred compound of Example 6, 4-amino-5-chloro-2-methoxy-N- (1,2-diethyl-4-pyrazolidinyl) -benzamide, reduced emes by 87% when administered at a dose of 5 mg / kg (sc) and increased gastric emptying time significantly when administered at a dose of 0.33-9.0 mg / kg.

6 68044

The compounds of formula I may be incorporated into pharmaceutical compositions in an amount which provides an effective antiemetic and gastric emptying effect. These compositions contain 1.0 to 100 mg of active drug per dosage unit. The compositions preferably contain about 5 to 100 mg of drug, more preferably about 5 to 50 mg, per dosage unit.

Preparation 1 4-Chloro-1,2-diethylpyrazolidine

A solution of triphenylphosphine (52 g; 0.2 mol) in 150 ml of chloroform was treated with chlorine gas, after which the temperature of the mixture was raised to 60 ° C until excess chlorine gas appeared on the surface of the mixture. Air was therefore introduced into the mixture until the greenish-yellow gas disappeared. To the cooled (30 ° C) stirred mixture was added dropwise 28.8 g (0.2 moles) of 1,2-diethyl-4-pyrazolidinol at a rate that caused the temperature of the reaction mixture to rise to 40 ° C. After the addition, the stirred solution was heated to reflux for 2 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 extract (sodium urea sulfate) was concentrated under reduced pressure, and the residual material was distilled at 92-94 ° C / 30 mm to give 24.5 g (75%) of product.

Analysis: Calculated for C 18 H 18 N 2 Cl: C, 51.68; H 9.29; H 17.22 / I o i.

Found: C, 51.45; H 9.30; H 17.29 68044

Preparation 2 4-Amino-1,2-diethylpyrazolidine

A mixture of 100 g (0.615 moles) of 4-chloro-1,2-diethylpyrazolidine and 200 ml of concentrated ammonium hydroxide in a sealed steel vessel was heated at 150 ° C for about 36 hours. The cooled reaction mixture was extracted with isopropyl ether, the aqueous layer was saturated with potassium carbonate and extracted continuously with chloroform for 6 hours. The dried chloroform extract (sodium sulfate) was concentrated under reduced pressure, and the residue was distilled at 113-115 ° C / 40 mm to give 40.5 g (45.5%) of product.

Preparation 3 4-Amino-1,2-dimethylpyrazolidine

A mixture of 300 g (2.22 moles) of 4-chloro-1,2-dimethylpyrazolidine and 600 ml of concentrated ammonium hydroxide was heated at 150 ° C for 18 hours in a steel bomb. The cooled mixture was saturated with potassium carbonate and extracted continuously with chloroform for 18 hours. After concentrating the chloroform extract, the residual material was distilled at 90-100 ° C / 40 mm to give 73 g of product.

Preparation 4 4-Anilino-1,2-dimethylpyrazolidine

A stirred suspension of 40 g (1.02 moles) of sodium amide in dry toluene was treated by dropwise addition of 116 g (1.0 moles) of 1,2-dimethyl-4-pyrazolidinol at 80 ° C. After heating for 4.5 hours under reflux, the mixture was cooled and kept below 20 ° C while 161.0 g (1.0 mol) of benzenesulfonyl chloride was added dropwise. After stirring for 1.0 hour, the reaction mixture was shaken with dilute sodium hydroxide, the separated toluene layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 300 parts of aniline, the mixture was heated in a steam bath for 2.5 h and refluxed for 3.0 h. The cooled mixture was extracted with dilute sodium hydroxide solution and the separated aqueous layer was extracted with isopropyl ether. After drying, the combined organic layers were concentrated with sodium sulfate, and the residue was distilled at 140 ° C / 80 mm. The crystalline residue was distilled at 110-125 ° C / 0.1 mm to give 86 g of product.

8 68044

Preparation 5 4-Anilino-1,2-diethylpyrazolidine

To a stirred suspension of 7.8 g (0.2 moles) of sodium amide in 100 ml of dry toluene was added 28.8 g (0.2 moles) of 1,2-diethyl-4-pyrazolidinol at such a rate that the temperature was 30-35 ° C. After stirring for 2.0 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 at a vessel temperature below 30 ° C. After stirring for about 1 hour at room temperature, the reaction mixture was washed twice with water and dried over sodium sulfate. The dried filtered solution was concentrated to a volume of about 100 mL, aniline (100 mL) was added, the solution was heated at reflux for 3.0 h, and then concentrated. The residue was partitioned between chloroform and dilute sodium hydroxide. The dried chloroform layer was concentrated, and the residue was distilled at 120 ° C / 0.1 mm to give 4.0 g of product.

Preparation 6 1,2-Diethyl 4-phthalimido-pyrazolidine maleate To 100 ml of dimethyl sulfoxide were added 32.4 g (0.2 moles) of 4-chloro-1,2-diethylpyrazolidine and 37 g (0.2 moles) of ) potassium phthalimide. The solution was stirred at 115 ° C for 48 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 layer was basified 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 was recrystallized twice from the same solvent system to give 11.5 g (15%) of product, m.p. 144-147 ° C.

Analysis: Calculated for C 19 H 23 N 3 O 6: 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, b.p. 115-125 ° C / 1.0 mm, was prepared from 1-benzyl-2-methyl-4-pyrazolidinol by Methods 1 and 2.

? 68044

Preparation 8 4-Amino-1-cyclohexyl-2-methylpyrazolidine fumarate 4-Amino-1-cyclohexyl-2-methylpyrazolidine, b.p. 90-100 ° C / 0.5-1.0 mm, was prepared from 1-cyclohexyl-2-methylpyrazolidinol by Methods 1 and 2. Fumarate salt m.p. was 149-151 ° C.

Preparation 9 4-Amino-1-isopropyl-2-methylpyrazolidine 4-Amino-1-isopropyl-2-methylpyrazolidine, b.p. 110-115 ° C / 50 mm, was prepared from 1-isopropyl-2-methylpyrazolidinol according to Methods 1 and 2.

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: chloroform, 9.15 g (0.0.525 moles) of p-chlorobenzoyl chloride was added with stirring at a temperature not exceeding 50 ° C. After the addition was complete, the solution was heated to reflux for 1 hour, cooled to room temperature and extracted with dilute sodium hydroxide. The chloroform layer was dried over sodium sulfate and concentrated under reduced pressure to give an oil which crystallized on cooling. This solid was recrystallized twice from naphtha. Yield 13.1 g (76 S), m.p. 104-108 ° C.

Analysis: Calculated for C 18 H 20 Cl 2 N 3 O: 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-phthalimido-pyrazolidine maleate in 25 ml of 6N hydrochloric acid was heated at reflux for 2 hours and the resulting mixture was cooled and filtered. The filter cake was washed with water combined with the acidic solution. The resulting acidic solution was basified with dilute 10,68044 sodium hydroxide and cooled with ice. To the resulting solution was added 8.2 g (0.052 mol) of p-fluorobenzoyl chloride, and the mixture was shaken for 10 minutes. The resulting mixture was aided with chloroform, the chloroform was diluted with an equal volume of isopropyl ether, and the resulting solution was extracted with dilute hydrochloric acid. The acidic layer 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 with a few drops of ethyl acetate and clarified by carbon treatment. The product (2.0 g; 29%) m.p. was 114-116 ° C.

Analysis: Calculated for C 24 H 20 N 3 OF: 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 To 10 g (0.09 moles) of 4-amino-1,2-dimethylpyrazolidine in chloroform was added with stirring 20.7 g. g (0.09 mol) of 3,4,5-trimethoxybenzoyl chloride. After stirring for 30 minutes, the solution was extracted with dilute sodium hydroxide. The chloroform solution was dried (sodium sulfate), filtered and the filtrate was concentrated. The resulting crystalline material was recrystallized from equal portions of ethyl acetate and isopropyl ether. The product (12.1 g, 44%) m.p. was 163-166 ° C.

Analysis: Calculated for C 25 H 23 N 3 O 4: 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-diethylpyrazolidine in 200 ml: chloroform, 52 g (0.28 moles) of p-nitrobenzoyl chloride in 200 ml of chloroform were added with stirring. The solution was allowed to stand overnight and then extracted 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 24 H 20 N 4 O 3: C ^ 7f52; H 6.90; N 19.17 Found: C 57.56; H 6.94; N 18.99 68044

The base was converted to the hydrochloride salt and crystallized from isopropyl alcohol, m.p. 189-191 ° C (decomposes).

Analysis: Calculated for C 14 H 21 N 4 O 3 Cl: 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 solution of 20 g (0.069 mol) of 4-nitro-N- (1,2-diethyl-4-pyrazolidinyl) benzamide in ethanol, treated with Raney nickel and shaken under 3 atmospheres of hydrogen pressure 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 product (12.0 g, 66.5%) m.p. 119-121 ° C.

Analysis: Calculated for C 18 H 18 N 2 O 2: 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 was added 12 g (0.05 mol) of 4-acetamido-5-chloro. 2-Methoxy-benzoic acid and the stirred suspension were heated to reflux for 1 hour. The resulting solution was concentrated, and 100 ml of chloroform was added to the residue, which was concentrated to remove residual thionyl chloride. The residue was dissolved in 100 ml of chloroform, and the solution was added dropwise rapidly to 7 g (0.05 mol) of 4-amino-1,2-diethylpyrazolidine in 100 ml of chloroform while stirring and cooling at 20-25 ° C with an ice bath.

After 30 minutes, the chloroform solution was extracted twice with 100 ml of 3N hydrochloric acid, and the chloroform solution was collected. The acidic extract was boiled for 10 minutes, cooled with ice, basified with concentrated sodium hydroxide while cooling, and extracted with chloroform. The chloroform extract was dried (sodium sulfate) and concentrated, and the residue was crystallized from isopropyl ether-isooctane to give 3 g of product, m.p. 116-118 ° C. The recovered chloroform solution was extracted with dilute sodium hydroxide and concentrated. The residue was dissolved in 3N hydrochloric acid and extracted with isopropyl ether. The acidic solution was heated at reflux for 10 minutes, cooled in an ice bath, basified with sodium hydroxide while cooling and extracted with chloroform. The chloroform was dried (sodium sulfate) and concentrated. The residue was crystallized three times from isopropyl ether to give 0.7 g of product, m.p. 117-119 ° C. The melting point of the mixture of these two products did not decrease. The total yield was 3.7 g (23%).

Analysis: Calculated for C 15 H 23 ClN 4 O 2: C 55-13 H 7/09; N 17.14 Found: C 55.23; H 7.10; N 17.17

Example 7 4-Amino-5-chloro-2-methoxy-N-1,2-dimethyl-4-pyrazolidinyl-benzamide

A stirred solution of equal molar amounts of 4-amino-5-chloro-2-methoxybenzoic acid and triethylamine in methylene chloride (0-5 ° C) was treated dropwise using a slight excess of ethyl chlorocarbonate. After 1.0 hour, a solution of 4-amino-1,2-dimethylpyrazolidine in methylene chloride was added and the mixture was stirred for about 2 hours at room temperature. Aqueous sodium bicarbonate solution was added to the reaction mixture, the organic phase was separated and concentrated to give the product, m.p. 169-171 ° C.

Example 8 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 was prepared from 4-amino-5-chloro-2-methoxybenzoic acid and 4-amino-1-benzyl-2-methylpyrazolidine by the method of Example 7. The fumarate salt, m.p. 129-131 ° C.

Example 9 4-Amino-5-chloro-2-methoxy-N- (1-cyclohexyl-2-methyl-4-pyrazolidinyl) benzamide was prepared from 4-amino-5-chloro-2-methoxybenzoic acid and 4-amino -1-cyclohexyl-2-methylpyrazolide by the method of Example 7. The melting point of the hydrochloride hydrate was 105-120 ° C.

13 68044

Example 10 4-Amino-5-chloro-2-methoxy-N- (1-isopropyl-2-methyl-4-pyrazol-1-ylyl) benzamide dihydrochloride 4-amino-5-chloro-2-methoxy-N- (1 -isopropyl-2-methyl-4-pyrazolidinyl) benzamide was prepared from 4-amino-5-chloro-2-methoxybenzoic acid and 4-amino-1-isopropyl-2-methylpyrazolidine by the method of Example 7. The dihydrochloride salt was then prepared, m.p. 182-186 ° C.

Claims (3)

68044 14 1. A process for the preparation of therapeutically active N- (4-pyrazolidinyl) -benzamides of the formula f2? (R 3, ni-r N-9 RN J x 7 R 1 and pharmaceutically acceptable acid addition salts thereof, wherein R is C 1-2 alkyl, R 1 is C 1-4 alkyl, cyclohexyl or benzyl, 2 R is hydrogen or phenyl, 3 R is nitro, amino, fluorine, chlorine or alkoxy, the groups 3 R may be the same or different, 1 is 3 or 3, characterized in that a) 4-amino-1,2-substituted-pyrazolidine of the formula R 2 I-— NH RN J II R1 1 2 wherein R, R and R are as defined above, are reacted with benzoyl chloride of the formula COCl11 3 wherein R and n are as defined above, provided, however, that R is not is not a primary amino, or b) 1,2-substituted-4-phthalimidopyrazolidine of the formula 15 680 4 4 ι-rN ^ I "co-J RN \ nN ^ R1 in which R and R are as defined above is hydrolyzed in dilute mineral acid, after which the solution is basified to liberate free 4-amino-1,2-substituted-pyrazolidine, which is then reacted with a substituted benzoyl chloride of formula III wherein R is as defined above but not a primary amino, or c) a benzoic acid of formula rS n klL COOH 3 wherein R and n are as defined above is reacted with ethyl chlorocarbonate in the presence of triethylamine and reacting the resulting compound with 4-amino-1,2-substituted-pyrazolidine of formula II, followed, if desired, by the group R in the compound of formula I obtained by method a), b) or c) when it is nitro , is catalytically reduced to the amino and / or the resulting compound is converted into a pharmaceutically acceptable acid addition salt. Process according to Claim 1, characterized in that 4-amino-5-chloro-2-methoxy-N- (1,2-diethyl-4-pyrazolidinyl) benzamide is prepared. A compound for the preparation of a therapeutically active N- (4-pyrazolidinyl) benzamide with the formula R2 0 / = \ ^ (R3) ni — r - ”- 1 RN J N- 'R1 68044 and a pharmaceutically acceptable syrup addition salt, in which form R Sr is C1-3 alkyl, is C1-4 alkyl, cyclohexyl or benzyl, 2 R is a substance or phenyl, R 1 is nitro, amino, fluorine, chlorine or alkoxy, a color group R 1 is a substance or an oil, och n Sr 1 or 3, kSnnetecknat av att a) ett 4-amino-1,2 -substituted pyrazolidine with the formula R2 | - NH RN J II 1 2 color R, R and R with an angular beta, omsStts with en benzoyl chloride with the formula COC1 [^ - (R3) n HI 3 color R and n with an angular betydel , dock förutsatt att 3 R icke är en primary amino, or b) that 1,2-substituent-4-phthalimidopyrazolidine in the form of | -rN RN ^ C0 R1 color R och R is an angular addition, hydrolysers and utspSdd minerals, a copper-containing solution Figure 4 contains 4-amino-1,2-substituted-pyrazolidine, which is then substituted with benzoyl chloride in formula III, var. R is an angettable letter with an intermediate of primSr amino, or c) and benzenesvra med formeln