CH645356A5 - 4-AMINOPYRAZOLIDINES. - Google Patents

Description

The present invention relates to new 4-amino-1,2-hydro-carbylpyrazolidines (II), corresponding to formula II:

, 2

R

R-N

. N-H

, 1

in which

R and R1 represent a C 1 -C 8 alkyl, cycloalkyl or C 4 -C 12 alkylcycloalkyl or phenyl-C, -C 8, phenyl or substituted phenyl radical, and its acid addition salts.

following diagram:

35 (II) R-N

COCl

R-N

(IH)

(I)

(II)

45 R

in which R, R1, R2 have the meanings mentioned above, R3 represents a hydroxy, cyano, nitro, fluoro, chloro, bromo, trifluoromethyl, lower alkyl, lower alkoxy, sulfa-medium or acetamido group, R3 being able to represent the same radical or 50 different radicals, and n is an integer ranging from 0 to 3 inclusive, and its acid addition salts.

Antiemetic properties are determined by modifying the procedures of Chen and Enxor, "J. Pharmac. Exp. Ther. " 98, 245-250 (1950) and Leonard et al., "J. Pharmac. Exp. Ther. " 154, 55 339-345 (1966).

The gastric emptying activity is determined using the following procedure. Female Sprague-Dawley rats, weighing 117-221 g, are made to fast for 24 h in cages provided with a screen at the bottom, with unlimited water. The animals are placed in groups of 60 pesos 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 later, rats are administered, orally, using a gastric tube, 3 ml 65 of a test meal consisting of a methylcellulose base to which beef broth, casein, powdered sugar and corn starch to obtain a homogeneous semi-solid paste. 60 min after the test meal (90 min total time), we

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scares the rats by rupturing the cervical vertebrae, laparotomy is performed 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 from 0.33 to 9.0 mg / kg.

The lower alkyl radicals are Cj-C ^.

The term substituted or unsubstituted cycloalkyl first includes C4-C12 cyclic alkyl radicals, such as cyclobu-tyle, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclopentyl, ethylcyclohexyl and the like.

The term phenyl, as used herein, includes the unsubstituted phenyl radical and phenyl radicals substituted by one or more radicals which are not reactive or troublesome under the reaction conditions described here, such as lower alkyl, lower alkoxy radicals , trifluoromethyl, bromine, chlorine, fluorine and the like. The substituted phenyl radicals preferably have no more than three substituents, such as those mentioned above; moreover, these substituents can be in the various possible positions on the phenyl ring and, when there is more than one substituent, these can be identical or different and can be placed according to various combinations of positions by compared to others. The lower alkyl and lower alkoxy substituents are preferably each at Ct-C4 and can be linear or branched. As an example 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 trifluoromethyl groups.

The term alkyl includes linear or branched C 1 -C 6 radicals, such as for example methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, amyl, isoamyl, n-hexyl, n-heptyl and n- octyl.

The term phenyl-C1-C8-alkyl includes groups such as benzyl, phenethyl, phenylpropyl, a-methylbenzyl and the like.

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,

3-bromobenzoyl chloride,

4-bromobenzoyl chloride,

3,5-dinitrobenzoyl chloride,

3,4-dichlorobenzoyl chloride,

3,4-diethoxybenzoyl chloride,

3-trifluoromethylbenzoyl chloride,

4-tert.-butylbenzoyl chloride,

4-butoxybenzoyl chloride,

2,4-dimethoxybenzoyl chloride,

4-methylbenzoyl chloride,

4-cyanobenzoyl chloride,

2-methoxy-5-sulfamoylbenzoyl chloride,

2-methoxy-4-dimethylaminobenzoyl chloride,

2-methoxy-4-nitrobenzoyl chloride,

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

2-ethoxy-4-bromobenzoyl chloride,

2-methoxy-3-acetamido-5-trifluoromethyl-benzoyl 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.

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, sulfamic, succinic, fumaric, maleic, hydrochloric, hydrobromic, benzoic and the like. These salts are prepared in a known manner.

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

Example 1:

A. 4-Chloro-1,2-diethylpyrazolidine

A solution of 52 g (0.2 mol) of triphenylphosphine in 150 ml of chloroform is treated with gaseous chloride, 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, 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 C7H15N2C1:

Calculated: C 51.58 H 9.29 N 17.22%

Found: C 51.45 H 9.30 N 17.29%

B. 4-Amino-1,2-diethylpyrazolidine

Heated to 150 ° C, in a closed steel enclosure, a mixture of 100 g (0.615 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.

Example 2:

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 is heated at 150 ° C for 18 h in a steel bomb. The cooled mixture is saturated with potassium carbonate, then it is extracted continuously for 18 h with chloroform. The residual product is distilled after concentration of the chloroform extract at 90 to 100 ° C / 40 mmHg, to obtain 73 g of product.

Example 3:

4- Anilino-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 bath

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30

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60

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marie, 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 to 125 ° C / 0.1 mmHg, to obtain 86 g of product.

Example 4:

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 to 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, 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.

Example 5:

4-Amino-1-benzyl-2-methylpyrazolidine

4-amino-1-benzyl-2-methylpyrazolidine, Eb is prepared. 115 to 125 ° C / 1.0 mmHg, from 1-benzyl-2-methyl-4-pyrazolidinol, according to the procedures described in Example 1.

Example 6:

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

4-amino-1-cyclohexyl-2-methylpyrazolidine, Eb, 90 to 100 ° C / 0.5 to 1.0 mmHg, is prepared from l-cyclohexyl-2-methylpyra-zolidinol, according to the procedures described. in Example 1. The fuma-rate melts at 149-151 ° C.

Example 7:

4-Amino-1-isopropyl-2-methylpyrazolidine

4-amino-1-isopropyl-2-methylpyrazolidine, Eb is prepared. 110 at 115 ° C / 50mmHg, from 1-isopropyl-2-methylpyrazol-idinol, according to the procedures of Example 1.

Example 8:

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

Example 9:

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, cooled to room temperature, then 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%), m.p. 104-108 ° C.

Elementary analysis for Q 8H20ClN3O:

Calculated: C 65.54 H 6.11 N 12.74%

Found: C 65.77 H 6.08 N 12.86%

Example 10:

3,4,5-Trimethoxy-N- (1,2-dimethyl-4-pyrazolidine) benzamide

To 10 g (0.09 mol) of 4-amino-1,2-dimethylpyrazolidine in chloroform is added with stirring 20.7 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 to 166 ° C.

Elementary analysis for C15H23N304:

Calculated: C 58.24 H 7.49 N 13.58%

I5 Found: C 58.20 H 7.45 N 13.19%

Example 11:

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-diethylpyra-20 zolidine in 200 ml of chloroform, 52 g (0.28 mol) of p- chloride are added with stirring nitrobenzoyl 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 C14H20N4O3:

Calculated: C 57.52 H 6.90 N 19.17%

30 Found: C 57.56 H 6.94 N 18.99%

The base is transformed into the hydrochloride which is crystallized from isopropyl alcohol, m.p. 189 at 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 12:

When, in the procedure of Example 10, the 3,4,5-trimethoxybenzoyl chloride is replaced by equimolar amounts of:

4-cyanobenzoyl chloride,

3-trifluoromethylbenzoyl chloride,

45 4-methylbenzoyl chloride,

4-methoxybenzoyl chloride,

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

we obtain:

50 of 4-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 55 2-methoxy-5-sulfamoyl-N- (1,2-dimethyl-4 -pyrazolidinyl) -benzamide.

Pharmaceutical compositions contain compounds of formula I above in an amount such that an effective antiemetic and emptying of the stomach is obtained. These con-60 compositions hold 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. As examples of solid supports, mention will be made of 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 can

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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 solution of physiological saline, at a concentration such that 1 cm 3 of the solution contains 1.0 25 mg of active agent. The solution can be put in single or multiple dose ampoules.

The treatment consists of administering internally to warm-blooded animals comprising humans, certain N- (4-pyrazoli-dinyl) 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 an amount sufficient 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 1 to about 300 mg of active drug, preferably from about 5 to 50 mg.

R

Claims (4)

645,356 1. Compound chosen from 4-aminopyrazolidines, characterized in that it corresponds to formula (II): R2 I -N-H R-N (II) R in which R and R1 represent a C, -C8 alkyl, cycloalkyl or C4-C12 alkylcycloalkyl or phenyl-Q -C8 -alkyl radical, R2 represents a hydrogen atom, a C1-C6 alkyl radical, phenyl or substituted phenyl, and its acid addition salts. 2. Use of a compound of formula (II) according to claim 1 for the preparation of compounds chosen from N- (4-pyrazolidinyl) benzamides corresponding to formula (I): R-N R I -NOT- (I) in which R and R1 represent a C 1 -C 5 alkyl, cycloalkyl or C 1 -C 4 alkylcycloalkyl or phenyl-C, -C 8 -alkyl radical, R2 represents a hydrogen atom, a Ct -C8 alkyl radical, phenyl or substituted phenyl, R3 represents a hydroxy, cyano, nitro, amino, fluoro, chloro, bromo, trifluoromethyl, C1-C8 alkyl, C1-C8 alkoxy, sulfa-medium or acetamido group, R3 can represent the same radical or different radicals, and n is an integer ranging from 0 to 3 inclusive, and its acid addition salts, characterized in that a compound of formula (II) is reacted with a substituted benzoyl chloride of formula (III): COCl (IH) The compounds of formula II, in which R2 represents a hydrogen atom, can be prepared by heating a mixture of a 4-halo-1,2-hydrocarbylpyrazolidine and concentrated ammonium hydroxide in a steel bomb. at a temperature between about 125 and 200 ° C, for several hours. This procedure can also be used to prepare the compounds in which R2 represents a lower alkyl radical, such as a methyl, ethyl or propyl radical. In the latter case, preferably a solution of the appropriate lower alkylamine in a lower alkanol is used. The compounds of formula II, in which R2 represents a phenyl radical, can be prepared by reacting a 1,2-hydrocarbyl-4-arylsulfonyloxypyrazolidine and aniline or a substituted aniline in an appropriate solvent. The 1,2-hydrocarbyl-4-arylsulfonyloxypyrazolidine can generally be prepared by reacting the sodium salt of a 1,2-hydrocarbyl-4-pyrazolidinol with benzenesulfonyl chloride or p-tolylsulfonyl chloride in an aprotic solvent dry, such as toluene. U.S. Patent No. 3,660,426 either describes or indicates procedures for preparing 1,2-hydrocarby-4-pyrazolidinols, from which the respective 4-aminopyrazol-idinols are prepared. The new basic compounds of formulas II and I (see below) form addition salts of fluorosilicic acids which are useful as antiemetic agents, according to United States Patent Nos. 1915334 and 2075359. The compounds of formula II are useful for the preparation of benzamido-type compounds corresponding to formula I by contacting a 4-amino-1,2-hydrocarbylpyrazolidine II with an appropriately substituted benzoyl chloride III, according to in which R3 has the same meaning as in formula (I). 2 3. Use according to claim 2, for the preparation of 4-chloro-N-phenyl-N- (1,2-dimethyl-4-pyrazolidinyl) benzamide. 4. Use according to claim 2, for the preparation of 4-fluoro-N- (1,2-diethyl-4-pyrazolidinyl) benzamide.