JPS6331466B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to intermediates for the production of heterocyclic compounds having anti-emetic and gastric emptying properties, in particular 4-Aminopyrazolidine, which is an intermediate in the production of pyrazolidinyl)benzamide.

PRIOR ART Various benzamide derivatives (one of the substituents attached to the benzamide nitrogen can be pyrrolidinyl or piperidinyl) have been disclosed in the past.
US Pat. No. 3,342,826 discloses heterocyclic aminoalkylbenzamides with anti-emetic properties. US Pat. No. 3,577,440 describes 1-substituted-3-amidopyrrolidines with analgesic and anti-depressant properties. american patent
No. 3966957 and No. 3963745 describe N-(1-substituted-3-pyrrolidinyl)benzamide and thiobenzamide which are particularly useful for suppressing emesis.

(Problems to be Solved by the Invention) The present invention provides a novel 4-aminopyrazolidine useful as an intermediate for the production of a novel N-(4-pyrazolidinyl)benzamide having anti-emetic properties and gastric emptying properties. It is to be.

(Structure of the Invention) The 4-aminopyrazolidine of the present invention has the following formula: (In the formula, R is a lower alkyl group, R ¹ is a lower alkyl group, cyclohexyl group, or benzyl group, and R ² is H, a lower alkyl group, or a phenyl group.)

The compound of the present invention has the following general formula: (wherein R, R ¹ and R ² have the above meanings,
R ³ is H, a lower alkyl group or a phenyl group, and n is an integer of 1 to 3. ) N-(1,2-hydrocarbyl-4-
This is an intermediate for the production of pyrazolidinyl)benzamide ().

Also included within the scope of this invention are the non-toxic pharmaceutically acceptable acid addition salts of basic compounds of general formula and general formula. This is because salts of such formulas can be used as antiemetic or gastric emptying compounds as well. Both organic and inorganic acids can be used to form pharmaceutically acceptable acid addition salts;
Examples include sulfuric acid, nitric acid, phosphoric acid, citric acid, acetic acid, lactic acid, tartaric acid, sulfamic acid, succinic acid,
Fumaric acid, maleic acid, hydrochloric acid, hydrobromic acid, benzoic acid, etc. The salts are manufactured by methods well known in the art.

Anti-emetic properties were determined by the method of Chen and Enxor [J.
Pharmac Exp Ther 98 , 245-250 (1950),
The method of Leonard et al. (J.Pharmac.Exp.Ther. 154 ,
339-345 (1966)].

Gastric emptying activity was measured using the following method. Female Spragne-Dawley rats weighing 117-221 g were fasted for 24 hours in each screen-bottom cage. However, water was provided ad libitum. Divided into 8 groups.
At zero time, 9 mg/Kg of the test compound was administered intraperitoneally to rats as 5% in gum arabic (body weight: 100 g).
0.4ml per bottle). The control group received gum arabic alone.
Administer ml/Kg intraperitoneally. Thirty minutes after dosing, a test meal consisting of a methylcellulose base to which beef broth, casein, powdered sugar and cornstarch have been previously added to form a semi-solid material paste is administered orally via stomach tube. Sixty minutes after administration of the test meal (90 minutes after the start of the test), the animals were sacrificed by cervical dislocation, the abdomen was opened, and the stomachs were removed. The still-filled stomachs were weighed with an analytical knife, then cut open, rinsed, and the empty stomachs weighed. The difference between the two weights represents the amount of meal remaining in the stomach. Subtracting this amount from 3 ml (test meal dose) gives the amount of meal excreted from the stomach during the test period.

As an example of the compound of the formula produced from the intermediate of the present invention, the preferred compound of Reference Example 6 below is 5mg/Kg
(SC) dose reduced emesis by 87%, 0.33~
A dose of 9.0 mg/Kg significantly reduced the time required to empty the stomach.

The compound of the present invention is produced as follows. A compound in which R ² is H is 4-halo-
A mixture of 1,2-hydrocarbyl pyrazolidine and concentrated ammonium hydroxide was added in a steel bomb to approx.
Produced by heating at 125-200°C for several hours. This method is also applicable to the production of compounds where R ² is lower alkyl such as methyl, ethyl, propyl. In this case, it is preferable to use a lower alkanol solution of an appropriate lower alkylamine.

A compound in which R ² is phenyl in the general formula is 1,
It is produced by reacting 2-hydrocarbyl-4-arylsulfonyloxy-pyrazolidine with aniline or substituted aniline in a suitable solvent. 1,2-Hydrocarbyl-4-arylsulfonyloxy-pyrazolidines are generally prepared by reacting the Na salt of 1,2-hydrocarbyl-4-pyrazolidinol with benzenesulfonyl chloride or p-tolylsulfonyl chloride in a dry neutral solvent such as toluene. Manufactured by

The 1,2-hydrocarbyl-4-pyrazolidinol for producing each 4-aminopyrazolidinol can be produced by the method disclosed or disclosed in U.S. Pat. No. 3,660,426.

A novel basic compound of the general formula forms a fluorosilicic acid addition salt, and this salt is patented in the U.S.
According to the inventions of Nos. 1915334 and 2075359, it is useful as a moth repellent.

The benzamide compound of the general formula can be produced by contacting 4-amino-1,2-hydrocarbylpyrazolidine () with an appropriately substituted benzoyl chloride () according to the following reaction formula.

(wherein R, R ¹ , R ² and n are as defined above,
However, R ³ cannot be a primary amino group. ) Compounds in which R ³ is a primary amino group in the general formula are generally prepared by catalytic reduction of precursors in which R ³ is nitro. Alternatively, in the general formula
A compound in which R ³ is acetamide is prepared and hydrolyzed in dilute acid to generate an amino group.

Substituted benzoyl chlorides useful in the preparation of compounds of formula are known compounds or can be prepared by methods well known in the art, such as:

2-fluorobenzoyl chloride 3-brombenzoyl chloride 4-brombenzoyl chloride 3,5-dinitrobenzoyl chloride 3,4-dichlorobenzoyl chloride 3,4-diethoxybenzoyl chloride 3-trifluoromethoxybenzoyl chloride 4-t chloride -Butylbenzoyl 4-Butoxybenzoyl chloride 2,4-dimethoxybenzoyl chloride 4-Methylbenzoyl chloride 4-cyanobenzoyl chloride 2-methoxy-5-sulfamoylbenzoyl chloride 2-Memethoxy-4-dimethylaminobenzoyl chloride 2-methoxy chloride -4-Nitrobenzoyl 2-methoxy-3-fluoro-5-chlorobenzoyl chloride 2-methoxy-4-brombenzoyl chloride 2-methoxy-3-acetamido-5-trifluoromethylbenzoyl chloride.

A non-satile center exists in the compound of the general formula. It can be divided into optically active forms by combining it with an optically active organic acid and separating the optically active forms by fractional crystallization.

Example 1 (a) 4-chloro-1,2-diethylpyrazolidine triphenylphosphine (52 g; 0.2 mol)
A solution of in chloroform (150 ml) was treated with chlorine gas until excess chlorine gas appeared on the surface of the mixture. Accordingly, the temperature of the mixture is 60℃
It rose to . The mixture was bubbled until the green-yellow gas disappeared. To this cooled (30°C) stirring mixture, add 28.8 g at a rate that the reaction mixture rises to 40°C.
(0.2 mol) of 1,2-diethyl-4-pyrazolidinol was added dropwise. After addition, the stirred solution was refluxed for 2 hours, cooled to room temperature, and extracted with water. The extracts were combined, made basic with concentrated NaOH solution, and extracted with chloroform. After drying (sodium sulfate), concentrate under reduced pressure and collect the residue at 92-94℃/30mm.
Evaporation at 24.5 g (75%) of product was obtained.

Analysis Calculated value = C, 51.68; H, 9.29; N, 17.22 (C ₇ H ₁₅ N ₂ Cl) Measured value = C, 51.45; H, 9.30; N, 17.29 (b) 4-amino-1,2- Diethylpyrazolidine A mixture of 100 g (0.615 mol) of 4-chloro-1,2-diethylpyrazolidine from (a) above and 200 ml of concentrated ammonium hydroxide is heated at 150°C for about 36 hours in a closed steel chamber. did. After cooling,
Extraction was carried out with isopropyl ether, and the aqueous layer was saturated with potassium carbonate and extracted continuously with chloroform for 6 hours. After drying (sodium sulfate), concentrate under reduced pressure and distill the residue at 113-115℃/40mm to give 40.5g.
(45.5%) of product was obtained.

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 was heated at 150° C. in a steel bomb. at 18
heated for an hour. The residue after concentrating the chloroform extract was distilled at 90-100°C/40mm to obtain 73g of product.

Example 3 4-anilino-1,2-dimethylpyrazolidine A stirred suspension of soda amide (40 g, 1.02 mol) in dry toluene was added dropwise to 116 g (1.0 mol) of 1,2-dimethyl-4-pyrazolidinol at 40°C. Processed. After 4.5 hours had passed at the reflux point, the mixture was cooled and maintained at 20° C. or lower, during which time 161.0 g (1.0 mol) of benzenesulfonyl chloride was added dropwise. After stirring for 1 hour, the reaction mixture was shaken with dilute NaOH, and the separated toluene layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 300 ml of aniline, heated in a steam bath for 2.5 hours, and refluxed for 3 hours.

After cooling, it was extracted with dilute NaOH solution, and the separated aqueous layer was extracted with isopropyl ether. Combine the extracts, dry with sodium sulfate, concentrate, and remove the residue.
Distilled at a pot temperature of 140°C/80mm. Distill the residue (uncrystallized) at 110-125℃/0.1mm.
86 g of product was obtained.

Example 4 4-anilino-1,2-diethylpyrazolidine 28.8 g (0.2
1,2-diethyl-4-pyrazolidinol (mol) was added at a rate that maintained a pot temperature of 30-35°C. After stirring at room temperature for 2 hours, it was added dropwise to a solution of P-toluenesulfonyl chloride (38.0 g, 0.2 mol) in dry toluene (200 ml) while maintaining the pot 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 solution was concentrated to about 100 ml, aniline (100 ml) was added, refluxed for 3 hours, and then concentrated. The residue was partitioned between chloroform and dilute NaOH. Concentrate the dry chloroform layer and reduce the residue to 120%
Distillation at °C/0.1 mm yielded 4.0 g of product.

Example 5 4-Amino-1-benzyl-2-methylpyrazolidine 4-Amino-1-benzyl-2-methylpyrazolidine was converted to 1-benzyl-2-methylpyrazolidine by the method of Example 1.
-Methyl-4-pyrazolidinol.
bp115~125℃/1.0mm.

Example 6 4-Amino-1-cyclohexyl-2-methylpyrazolidine fumarate 4-Amino-1-cyclohexyl-2-methylpyrazolidine was converted to 1-cyclohexyl-2-methylpyrazolidine by the method of Example 1. Manufactured from ginol. bp90~100℃/0.5~1.0mm.

The fumarate salt melted at 149-151 °C.

Example 7 4-Amino-1-isopropyl-2-methylpyrazolidine 4-amino-1-isopropyl-2-methylpyrazolidine bp 110-115°C/50mm was converted into 1-isopropyl-2-methylpyrazolidine by the method of Example 1. - prepared from methylpyrazolidinol.

Example 8 4-Methylamino-1,2-diethylpyrazolidine was obtained by the method of Example 1(b) using an equimolar amount of methylamine in methanol instead of concentrated ammonium hydroxide.

Next, as a reference example, an example of manufacturing a compound of the formula will be described.

Reference example 1 4-chloro-N-phenyl-N-(1,2-dimethyl-4-pyrazolidinyl)benzamide A solution of 1,2-dimethyl-4-anilinopyrazolidine (10 g, 0.0525 mol) in chloroform (50 ml) 9.15 g (0.0525 mol) of p-chlorobenzoyl chloride was added to the mixture with stirring (temperature not exceeding 50° C.). After the addition was complete, it was refluxed for 1 hour, cooled to room temperature, and extracted with dilute NaOH. The chloroform layer was dried over sodium sulfate and concentrated under reduced pressure to obtain an extract, which crystallized upon cooling. The solid was recrystallized twice from ligroin. Yield = 13.1g (76
%); mp104-108℃.

Analysis Calculated value (C ₁₈ H ₂₀ ClN ₃ O) = C, 65.54; H,
6.11; N, 12.74 Measured value = C, 65.77; H, 6.08; N, 12,86 Reference example 2 4-Fluoro-N-(1,2-diethyl-4-
pyrazolidinyl)benzamide 1,2-diethyl-4-phthalimidopyrazolidine maleate (10 g, 0.026 mol) in 6NHCl
(25ml) The solution was refluxed for 2 hours, cooled and filtered.
The mass was washed with water and the washing water was combined with an acidic solution. Rare
Made basic with NaOH and cooled with ice. 8.2 g (0.052 mol) of p-fluorobenzoyl chloride was added to the resulting solution and shaken for 10 minutes. Extracted with chloroform, diluted the extract with an equal volume of isopropyl ether, and extracted with dilute HCl. The acid layer was made basic with dilute NaOH and extracted with chloroform. The extract was dried (sodium sulfate) and concentrated. The residue was crystallized from isooctane-isopropyl ether and dissolved in isooctane-isopropyl ether with 2-3 drops of ethyl acetate.
It was recrystallized from isopropyl ether and clarified by charcoal treatment. Product (2.0g, 29%) is 114-116
Melted at °C.

Analysis Calculated value (C ₁₄ H ₂₀ N ₃ OF) = C, 63.38; H,
7.60; N, 15.84 Measured value = C, 63.36; mol) of 4-amino-1,2-dimethylpyrazolidine under stirring,
20.7 g (0.09 mol) of 3,4,5-trimethoxybenzoyl chloride was added. Dilute after stirring for 30 minutes.
Extracted with NaOH. Dry (sodium sulfate),
The solution was concentrated. The resulting crystalline material was recrystallized from equal parts of ethyl acetate and isopropyl ether. Product (12.1g, 44%) 163-166℃
It melted.

Analysis Calculated value (C ₁₅ H ₂₃ N ₃ O ₄ ) = C, 58.24; H, 7.49;
N, 13.58 Measured value = C, 58.20; H, 7.45; N, 13.19 Reference example 4 4-nitro-N-(1,2-diethyl-4-pyrazolidinyl)benzamide hydrochloride 4-amino-1,2-diethylpyra To a stirred solution of zolidine (40.5 g, 0.28 mol) in chloroform (200 ml) was added p-nitrobenzoyl chloride (52 g,
A solution of 0.28 mol) in chloroform (200 ml) was added. It was left overnight and then extracted with dilute NaOH.
Dry the chloroform solution (sodium sulfate),
Concentrated. The residue was crystallized from isopropyl ether-ethyl acetate to give 73 g (80%) of the free base.

Analysis Calculated value (C ₁₄ H ₂₀ N ₄ C ₃ ) = C, 57, 52; H,
6.90; N, 19.17 Measured value = C, 57.56; H, 6.94; N, 18.99 When the base was changed to the hydrochloride and crystallized from isopropyl alcohol, it melted at 189-191°C (decomposition).

Analysis Calculated value (C ₁₄ H ₂₁ N ₄ O ₃ Cl) = C, 51.14; H,
6.44; N, 17.04 Measured value = C, 50.96; -diethyl-4-pyrazolidinyl)benzamide (20 g, 0.069 mol)
The ethanol solution of was treated with Raney Ni and shaken in a Parr apparatus at 3 atmospheres of hydrogen pressure at room temperature for 2 hours. The solution was concentrated and the residue was crystallized from isopropyl ether-ethyl acetate. The product (12.0g 66.5%) melted at 119-121°C.

Analysis Calculated value (C ₁₄ H ₂₂ N ₄ O) = C, 64.09; H, 8.45;
N, 21.36 Measured value = C, 63.98; H, 8.55; N, 21.37 Reference example 6 4-amino-5-chloro-2-methoxy-N-
(1,2-diethyl-4-pyrazolidinyl)benzamide 12 g (0.05 mol) of 4-benzamide in 75 ml of thionyl chloride
Acetamido-5-chloro-2-methoxybenzoic acid was added and the resulting suspension was stirred and refluxed for 1 hour. The resulting solution was concentrated and 100 ml of chloroform was added to the residue and concentrated to remove traces of thionyl chloride. Dissolve the residue in 100 ml of chloroform and add 4-amino-1,2-diethylpyrazolidine (7 g, 0.05 mol) in chloroform (100 ml).
Dropped rapidly into the solution. Stir during this time and place in an ice bath again.
Cooled at 20-25°C. After 30 minutes, the chloroform solution was extracted twice with 100 ml of 3NHCl and the chloroform solution was retained.

The acid extract was boiled for 10 minutes, cooled with ice, basified with concentrated NaOH while cooling, and extracted with chloroform. Dry the extract (sodium sulfate)
The residue was crystallized from isopropyl ether-isooctane to give 3 g of material (mp116~
118°C). Dilute the retained chloroform solution.
Extracted with NaOH and concentrated. The residue was dissolved in 3NHCl and extracted with isopropyl ether. Reflux the acid solution for 10 min, cool in an ice bath, and cool while cooling.
It was made basic with NaOH and extracted with chloroform. The extract was dried (sodium sulfate) and concentrated. The residue was crystallized three times from isopropyl ether to give 0.7 g of material (mp 117-119°C). The melting point of the mixture of both substances showed no melting point depression. Total yield was 3.7g (23%).

Analysis Calculated value (C ₁₅ H ₂₃ ClN ₄ O ₂ ) = C, 55.13; H,
7.09; N, 17.14 Measured value = C, 55.23; 3-trifluoromethylbenzoyl, 4-methylbenzoyl chloride, 4-methoxybenzoyl chloride, 4-acetamidobenzoyl chloride, 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, 2-methoxy-5-sulfamoyl-N-(1,
2-dimethyl-4-pyrazolidinyl)benzamide is also obtained.

Reference example 8 4-amino-5-chloro-2-methoxy-N-
1,2-dimethyl-4-pyrazolidinylbenzamide A stirred solution of equimolar amounts of 4-amino-5-chloro-2-methoxybenzoic acid and triethylamine in methylene chloride (0-5°C) is added in slight excess. The mixture was treated dropwise with ethyl chlorocarbonate. After 1 hour, a methylene chloride solution of 4-amino-1,2-dimethylpyrazolidine was added, and the mixture was stirred at room temperature for about 2 hours. Aqueous sodium bicarbonate solution was added to the reaction mixture and the organic phase was separated and concentrated to give the product (mp 169-171°C).

Reference 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 was mixed with 4-amino-5-chloro-2-methoxybenzoic acid and 4-amino-5-chloro-2-methoxybenzoic acid by the method of Reference Example 8.
Prepared from amino-1-benzyl-2-methylpyrazolidine. The fumarate salt was prepared.
mp129-131℃.

Reference example 10 4-amino-5-chloro-2-methoxy-N-
(1-cyclohexyl-2-methyl-4-pyrazolidinyl)benzamide 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-methylpyrazolidine by the method of Reference Example 8. Manufactured. Its hydrochloride hydrate
MP was 105-120℃.

Reference example 11 4-amino-5-chloro-2-methoxy-N-
(1-isopropyl-2-methyl-4-pyrazolidinyl)benzamide dihydrochloride 4-amino-5-chloro-2-methoxy-N-
(1-isopropyl-2-methyl-4-pyrazolidinyl)benzamide by the method of Reference Example 8.
-Amino-5-chloro-2-methoxybenzoic acid and 4-amino-1-isopropyl-2-methylpyrazolidine. The dihydrochloride salt was prepared. mp182~186℃.

A compound of formula can be made into a pharmaceutical composition in an amount that provides antiemetic and gastric emptying effects. The compositions contain from 1.0 to 100 mg of active ingredient per unit dosage form. Preferably from about 5 to 100 mg of active ingredient per unit dosage, more preferably from about 5 to 50 mg.
Contains mg of active ingredient.

Pharmaceutical carriers used in the compositions can be solid or liquid. Examples of solid carriers are lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or gum arabic. Examples of liquid carriers are vegetable oil and water. Similarly, the carrier or diluent may include release retardants such as glyceryl monostearate, glyceryl distearate, alone or with a wax.

A variety of pharmaceutical forms can be used according to methods well known in the art. For example, the composition can be compressed into tablets if a solid carrier is used, or it can be formulated as a powder, troche, or lozenge. Gelatin capsules containing the active ingredient can also be produced. If a liquid carrier is used, the compositions can be in the form of soft gelatin capsules, liquid suspensions, or syrups. Parenteral dosage forms are prepared by adding 1 part water-soluble salt of the active ingredient to water or saline.
Obtained by dissolving at a concentration of ~25 mg/cc.

The formula N-(4-
pyrazolidinyl)benzamide or a non-toxic organic or inorganic acid addition salt thereof, preferably in conjunction with a non-toxic pharmaceutically acceptable carrier such as those described above, to inhibit emesis and/or promote gastric emptying. It can be administered in sufficient amounts. The active ingredient is administered orally or parenterally repeatedly until a satisfactory response is obtained. The daily dose is about 10-300 as the active ingredient
mg, preferably about 5-50 mg.

Claims (1)

[Claims] 1. General formula: (wherein R is a lower alkyl group, R ¹ is a lower alkyl group, cyclohexyl group, or benzyl group, and R ² is H, a lower alkyl group, or a phenyl group.) 4-Aminopyrazolidine and pharmaceutically acceptable acid addition salts thereof.