CA1109880A - N-(4-pyrazolidinyl) benzamides - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

4-Aminopyrazolidines having the formula are disclosed wherein R is lower alkyl, lower cycloalkyl or phenyllower-alkyl;
R1 is lower alkyl, lower cycloalkyl, or phenyllower-alkyl; and R2 is hydrogen, lower alkyl or phenyl. These compounds are useful intermediates in the preparation of certain N-(4-pyrazolidinyl)benzamides which have anti-emetic and gastric emptying properties.

Description

!8~30 BACKGROIJND OF THE INVENTION
1. FIELD OF INVENTION
Our Canadlan Patent Application Serial No. 3O9J651 is concerned with heterocyclic compounds possessing anti-emetic and gastric emptying properties and is particularly concerned with certain N-(4-pyrazolidinyl)benzamides which are useful for controlling emesis and which display gastric emptying proper-ties in warm blooded animals with minimal side effects. This application, which is divided out of Application Serial No. 309,6Sl, is concerned with certain 4-aminopyrazolidines which are useful intermediates in the preparation of the N-(4-pyrazolidinyl~benzamides.

2. DESCRIPTION OF THE PRIOR ART
The prior art discloses various benzamido derivatives wherein one of the substituents attached to the benzamido nitrogen can be a pyrrolidinyl or a piperidinyl radical. United States Patent 3,342,826 discloses hetero-cyclic aminoalkyl benæamides having anti-emetic properties. United States Patent 3,577,440 describes 1-substituted-3-amidopyrrolidines having analgetic and anti~depressant properties. United States Patents 3,966,957 and 3,963,745 describe N-(l-substituted-3-pyrrolidinyl)benzamides and thiobenzamides as particularly useful in controlling emesis.
SUMMARY OF THE INVENTION
The novel compounds of Application Serial No. 309,651 are N-(1,2-hydrocarbyl-4-pyrazolidinyl)benzamides (I) which have the formula:

¦ O ~ (R )n ~ N _ C
R - N ~N
Il I

wherein;

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R is low~r alkyl, lower cycloalkyl or phenyllower alkyl, Rl is lower alkyl,lower cycloalkyl or phenyllower alkyl, R2 is hydrogen, lower alkyl or phenyl, R3 is hydroxy, cyano, nitro, amino, fluoro, chloro, bromo, trifluoro-methyl, lower alkyl, lower alkoxy, sulfamoyl or acetamido, R3 can be the same radical or different radicals, and n is an integer from zero to three inclusive.
The non-toxic pharmaceutically acceptable acid addition salts of the basic compounds of Formula I are also included within the scope of the invention, since such salts can likewise be used as anti-emetics or ~astric emptying compounds. Both organic and inorganic acids can be employed to form the pharmaceutically acceptable acid addition salts, illustrative acids being sulfuric, nitric, phosphoric, citric, acetic, lactic, tartaric, sulfamic, succinic, fumaric, maleic, hydrochloric, hydrobromic, benzoic, and the like.
The salts are prepared by methods well known to the art.
The anti-emetic properties were determined using a modification of the methods of Chen and Enxor, J. Pharmac. Exp. Ther. 98, 245-250 ~1950) and of Leonard et al., J. Pharmac. Exp. Ther. 154, 339-345 (1966).
The gastric emptying activity was determined using the following procedure. Female Sprague-Dawley rats weighing 117-221 g. were starved 24 hours in individual screen-bottom cages with water ad libitum. Animals were arranged in groups of eight. At time 0, 9 mg/kg of a test compound is adminis-tered intraperitoneally to the rats in 5% acacia (0.4 ml/100 g. body weight).
The control group is dosed with acacia alone, 4 ml/kg intraperitoneally.
Thirty minutes following dosing, the rats are given orally, by stomach tube,

3 ml. of a test meal consisting of methylcellulose base to which had been added beef bouillon, casein, powdered sugar and corn starch to yield a semi-solid homogenous paste. Sixty minutes following the test meal (ninety minutes total time), the rats are sacrificed by cervical dislocation, laparotomized and the stomachs removed. The full stomachs are weighed on an analytical 8~

balance after which they are cut open, rinsed and the empty stomach weighed.
The difference between full and empty stomach weights represents the amount of meal remaining in the stomach and is substracted from the weight of 3.0 ml. of test meal to yield the amount of meal emptied from the stomach during the test period.
The preferred compound of Example 6 reduced emesis 87% when adminis-tered at a dose level of 5 mg/kg ~s.c.) and increased the gastric emptying time significantly when administered at doses from 0.33 to 9.0 mg/kg.
The lower alkyl moiety has 1 - ~ carbon atoms.
The term "lower cycloalkyl" as used herein includes primarily cyclic alkyl radicals containing from four up to twelve carbon atoms inclusive and includes such groups as cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, methylcyclopentyl, ethylcyclohexyl and the like.
The term "phenyl" as used herein includes the unsubstituted phenyl radical and phenyl radicals substituted by any radical or radicals which are not reactive or otherwise interfering under the conditions of reaction de-scribed herein such as lower-alkyl, lower-alkoxy, trifluoromethyl, bromo, chloro, fluoro, and the like. The substituted phenyl radicals have preferably no more than three substituents such as those given above and, furthermore, these substituents can be in various available positions of the phenyl nucleus ~ and when more than one substituent is present, can be the same or different - and can be in various position combinations relative to each other. The lower-alkyl and lower-alkoxy substituents each have preferably from one to four carbon atoms which can be arranged as straight or branched chains. Examples of the preferred substituents are methyl, ethyl, propyl, butyl, fluoro, bromo, chloro, iodo, amino, hydroxy, cyano, acetamido, sulfamoxyl, methoxy, ethoxy, propoxy, butoxy and trifluoromethyl radicals.
The term "lower-alkyl" includes straight and branched chain radicals containing 1 to 8 carbon atoms as, for example, methyl, ethyl, propyl, iso-propyl, n-butyl, tertiary butyl, amyl, isoamyl, n-hexyl, n-heptyl, and n-octyl 8~

radicals. A "lower-alkoxy" radical has the formula -O-lower alkyl.
Included in the term "phenyllower-alkyl" are such groups as benzyl, phenethyl, phenpropyl, ~-methylbenzyl, and the like.
This present application relates to novel 4-amino-1,2-hydrocarbyl-pyrazolidines of formula II

lR2 l l N H

R - N J ~II) ~ Rl wherein R is lower alkyl, lower cycloalkyl or phenyllower alkyl; R is lower alkyl, lower cycloalkyl or phenyllower alkyl; R is hydrogen, lower alkyl or phenyl.
The compounds of formula II are prepared by:
(a) reacting a compound of formula X (V) R
wherein X is halogen, preferably chlorine, and R and Rl are as defined above, with ammonia or a lower alkylamine under pressure at an elevated temperature to provide a compound of formula II wherein R is hydrogen or lower alkyl and R and R are as defined above; or (b) reacting a compound of formula R6 (VI) N ~ N

R

. - 5 -wherein R and Rl are as defined above and R6 is an arylsulfonyloxy radical with an aniline whic}l may be substituted, to prepare a compound of formula II above wherein R2 is a phenyl group, or (c) hydrolysing a 1,2-hydrocarbyl-4-phthalimidopyrazolidine which is substituted in the 1- and 2-position by substituents R and R as defined above.
The compounds of Formula II wherein R2 is hydrogen can be prepared by heating a mixture of a 4-halo-1,2-hydrocarbylpyrazolldine and concentrated ammonium hydroxide in a steel bomb at a temperature of from about 125C to about 200~C for a period of several hours. The procedure is also applicable to prepare compounds wherein R2 is lower alkyl such as methyl, ethyl, o-r pro-pyl. 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 is phenyl can be prepared by reacting a 1,2-hydrocarbyl-4-arylsulfonyloxypyrazolidine and aniline or a substituted aniline together in a suitable solvent. The 1,2-hydrocarbyl-4-arylsulfonyloxypyrazolidine is generally prepared by reacting the sodium salt of a 1,2-hydrocarbyl-4-pyrazolidinol with benzenesulfonyl chloride or p-tolyl-sulfonyl chloride in a dry aprotic solvent such as toluene.
The 1,2~hydrocarbyl-4-pyrazolidinols from which the respective 4-aminopyrazolidinols are prepared are either disclosed in or they can be pre-pared by the procedures disclosed in United States Patent No. 3,660,426.

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Another alternate method which can be used in preparing th~ novel compounds of Formula I utilizes an appropriately substituted benzoic acid which is contacted with ethylchlorocarbonate in the presence of triethylamine 5 in methylene chloride at 0-5C to form the mixed anhydride of the benzoic acid. After approximately one hour at the lower temperature, a solution of the 4-amino-1,2-; hydrocarbylpyrazolidine is added. Subsequent to an additional period of stirring, an aqueous sodium 10 bicarbonate solution is added to the reaction mixture, the organic phase is separated and the benzamide compound is isolated therefrom by suitable means.
~ The substituted benzoyl chlorides III useful in I practicing the present invention are either known ' 7 15 compounds or they can be prepared by procedures well ,' ~ known to the art and include but are not limited to the -' following:
: 2-fluorobenzoyl chloride ' 3-bromobenzoyl chloride ; 20 4-bromobenzoyl chloride ; 3,5-dinitrobenzoyl chloride . 3,4-dichlorobenzoyl chloride 3,4-diethoxybenzoyl chloride 3-trifluoromethylbenzoyl chloride , 25 4-tertiarybutylbenzoyl chloride

4-butoxybenzoyl chloride 2,4-dimethoxybenzoyl chloxide ; 4-methylbenzoyl chloride 3 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-trifluoromethylbenzoyl chloride ,~

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f 346-CIP-l ' . In Formula I centers of asymmetry are present. The - ~ compounds can be resolved Lnto their optically active .~ forms by combining the compounds with optically active ; organic acids and separating the optically active forms ~ 5 by fractional crystallization. The optically active - . forms are included within the scope of the present invention.

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' Prepara~ion 1 , , 4-Chloro-1,2-diethylpvrazolidine.
A solution of triphenyl phosphine (52 g.; 0.2 mole) in 150 ml. of chloroform was treated with chlorine gas

- 5 which was accompanied by a rise in the temperature of the mixture to 60C. until excess chlorine gas appeared over the surface of the mixture. Air was passed into - the mixture until the greenish yellow gas disappeared.
To the cooled (30C.) stirred mixture was added dropwise 28.8 g. (0.2 mole) of 1,2-diethyl-4-pyrazolidinol at a rate which caused the reaction mixture to rise to 40C.
Subsequent to the addition, the stirred solution was refluxed two hours, cooled to room tempera~ure and extracted with water. The combined aqueous extracts ; 15 were basified with concentrated sodium hydroxide solution , and the basic mixture extract~d with chloroform. The Ç, : dried chloroform extract (sodium sulfate) was concentrated . at reduced pressure and the residual material distilled at 92-94C./30 mm. to give 24.5 g. (75%) of product.
Analysis: Calculated for C7X15N2Cl: C,51.68; H,9.29; H,17.22 Found : C,51.45; H,9.30; H,17.29 s Preparation 2 4-Amino-1,2-diethylp~razolidine.
A mixture of 100 g. (0.615 mole) of 4-chloro-1,2-diethyl-25 pyrazolidine and 200 ml. of concentrated ammonium hydroxide ; in a closed steel chamber was heated at 150C. for . approximately 36 hours. The cooled reaction mixture was extracted with isopropyl ether, the aqueous layer saturated with potassium carbonate and continuously extracted with 30 chloroform for six hours. The dried chloroform extract (sodium sulfate~ was concentrated at reduced pressure ~` and the residue distilled at 113-115C./40 mm. to give 40.5 g. (45.5%) of product.
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f ,, j Pre~aration 3 4-Amino~1,2-dimethvl~vrazolidine.
A mixture of 300 g. ~2.22 mole) of 4-chloro-1,2-dimethylpyrazolidine and 600 ml. of conc. ammonium hydroxide was heated at 150C. for 18 hrs. in a steel bomb. The cooled mixture was saturated with potassium carbonate and continuously extracted for 18 hrs. with chloroform. The residual material after concentration of the chloroform e~tract was distilled at 9o-100C./40 mm. to give 73 g. of product.
Preparation 4 4-Anilino-1,2-dimethYlpYrazolidine.
A stirred suspension of 40 g. (1.02 mole) of sodamide in dry toluene was treated dropwise with 116 g.
15 (1.0 mole) of 1,2-dimethyl-4-pyr~zolidinol at 80C.
` After 4.5 hrs. at reflux the mixture was cooled and maintained below 20C. while 161.0 g. (1.0 mole) of benzenesulfonyl chloride was added dropwise. After stirring 1.0 hr. the reaction mixture was shaken with dilute sodium hydroxide, the separated toluene layer dried over sodium sulfate and concentrated at reduced pressure. The residue was dissolved in 300 ml. of aniline, the mixture heated 2.5 hrs. on the steam bath and refluxed for 3.0 hrs. The cooled mixture was extracted with dilute sodium hydroxide solution and the separated aqueous layer extracted with isopropyl ether.
The combined organic layers after drying over sodium sulfate were concentrated and the residue distilled to a pot temperature of 140C./80 mm. The residue which 30 would not crystallize was distilled at 110-125C./0.1 mm. to give 86 g. of product.
Preparation 5 4-Anilino-1,2-diethvlpYrazolidine.
~ To a stirred suspension of 7.9 g. (0.2 mole) of _ 35 sodamide in 100 ml. of dry toluene was added 28.8 g.
~ (0.2 mole) of 1,2-diethyl-4-pyrazolidinol at a rate so ,~

- - .

8~ (-that a pot temperature of 30-35C. was maintained.
After stirring 2.0 hrs. at room temperature, the solu-tion was added dropwise to a solution of 38.0 g. (0.2 mole) of p-toluenesulfon~l chloride in 200 ml. of dry toluene with the pot temperature maintained below 30C.
After stirring for about one hr. at room temperature, the reaction mi~ture was washed twice with water and dried over sodium sulfate. The dried filtered solution , was concentrated to a volume of about loo ml., aniline (loO ml.) was added, the solution refluxed for 3.0 hrs.
~` and then concentrated. The residue was partitioned between chloroform and dilute sodium hydroxide. The dried chloroform layer was concentrated and the residue I distilled at 120C./0.1 mm. to give 4.0 ~. of product.
Pre~aration 6 1,2-Diethyl-4-~hthalimido-~vrazolidine Maleate.
To.100 ml. of dimethyl sulfoxide was added 32.4 g.
(.2 mole) of 4-chloro-1,2-diethylpyrazolidine and 37 g.
(.2 mole) of potassium phthalimide. The solution was stirred at 115C. for 48 hours., cooled and filtered.
The filtrate was treated with an equal volume of water and extracted 2 times with 150 ml. of ethyl acetate.
The extracts were combined and concentrated. The resi-due was partitioned between dilute hydrochloric acid and ethyl acetate. The acid layer was made basic 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 7S ml. of isopropyl ether. The maleate salt was recrystallized twice from the same solvent system to give ll.S g. (15%) of product which ~elted at 144-147~C.
Analysis: Calculated for ClgH23N3O6 C,58.60; H,5.95; N,10.79 Found : C,58.64; H,6.03; n,10.73 . .

` ~ 1~l~9~30 346-CIP-l Preparation 7 4-Amino-l-benzYl-2-methylpyrazolidine.
4-Amino-l-benzyl-2-methylpyrazolidine, b.p. 115-125C./l.0 mm., was prepared from 1-benzyl-2-methyl-4-pyrazolidinol according to preparations 1 and 2.
Pre~aration 8 4-Amino-l-cyclohexyl-2-methylpyrazolidine Fumarate.
4-Amino-1-cyclohexyl-2-methylpyrazolidine, b.p.
90-100C./0.5-1.0 mm., was prepared from 1-cyclohexyl-2-methylpyrazolidinol according to preparations 1 and 2.
The fumarate salt melted at 149-151C.
Preparation 9 4-Amino-l-iso~ropvl-2-methYlpyrazolidine.
4-Amino-l-isopropyl-2-methylpyrazolidine, b.p.
110-115C./50 mm., was prepared from 1-isopropyl-2-methylpyrazolidinol according to preparations 1 and 2.
PreParation 10 ^ When in the procedure of Preparation 2, concentrated - ammonium hydroxide is replaced by an e~ual molar amount of methylamine in methanol, there is obtained 4-- methylamino-1,2-diethylpyrazolidine.

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E;~ am ~i 1 e 4-Chloro-N-phenyl-N-(1,2-dimethyl-4-p~razolidlnyl)-benzamide.
To a solution of 10 g. (0.0525 mole) of 1,2-dimethyl-4~anilinopyrazolidine in 50 ml. of chloroform was addedwith stirring 9.15 g. (O.0525 mo]e) of p-chlorobenzoyl chloride with the temperature not exceeding 50C. On completion of addition the solution was refluxed for one hour, cooled to room t~mperature and extracted with dilute sodium hydroxide. The chloroform layer was dried over sodium sulfate and concentrated at reduced pressure to give an oil which cr~stallized upon cooling. The ; solid was recrystallized twice from ligroin. Yield 13.1 ! g. (76%); m.p. 104-108C.
Analysis: Calculated for C18H20ClN30: C,65.54; H,6.11; N,12.74 Found : C,65.77; H,6.08; N,12.86 Ex~n~le 2 4-Fluoro-N-(1,2-diethyl-4-pyrazolidinyl)benzamide~
A solution of lO ~. (0.026 mole) of 1,2-diethyl-4-phthalimidopyrazolidine maleate in 25 ml. of 6N hydrochloricacid was refluxed two hours, 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 made basic with dilute sodium , 25 hydroxide and cooled with ice. To the resulting solu-tion was added 8.2 g. ~0.052 mole) of p-fluorobenzoyl chloride and the mixture shaken for lO minutes. The resulting mixture was extracted with chloroform, the chloroform diluted with an equal volume of isopropyl ether and the resulting solution extracted with dilute hydrochloric acid. The acid layer was made basic with dilute sodium hydroxide and extracted with chloroform.
The chloroform was dried (sodium sulfate) and concen-- trated. The residue was crystallized from isooctane-isopropyl ether and recrystallized from isooctane-isopropyl ether containing a few drops of ethyl acetate f ' 346-CIP-1 1~

and clarified hy charc~al tre~aLrr,erlt. The product (2.0 g; 29%) melted at 114-116C.
Analysis: Calc~llated for C~ 32o~l3~: C,63.38; H,7.60; N,15.84 Found : C,63.36; H,7.61; N,15.96 EXamD1e ~
3, 4, 5-Tr1methOX~-N- ( 1, 2 -d1methY1-4-PVraZO1idinY1 ~-benzamide.
To 10 g (0.09 mole) of ~-~nino-1,2-dimethylpyrazolidine in chlorofol~ was added with stirring 20.7 g. (0.09 mole) of 3,4,5-trimethoxybenzoyl chloride.
After 30 minutes of stirring the solution was extracted with dilute sodium hydroxide. The chloroform solution was dried (sodium sulfat~), filtered, and the filtrate concentrated. The resulting crystalline material was recrystallized from equal portions of ethyl acetate and ~ isopropyl ether. The product (12.1 g~; 44%) melted at ; 163-166~C.
Analysis: Calculated for Cl5H23N304: 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 mole) of 4-amino-1,2-diethylpyra701idine in 200 ml of chloroform was added ; 25 with stirring 52 g (0.28 mole) of p-nitrobenzoyl chloride - in 200 ml chloroform. 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 Cl~H20N~03: C,57.52i H,6.90; N,19.17 Found : C,57.56; H,6.94i N,18.99 ~ The base was converted to the hydrochloride salt and ,~ crystallized from isopropyl alcohol which melted at 35 139-191C (dec.).

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, 0 346-CIP-l Analysis: Calculated for Cl9H~lN.I03Cl: C,51.14; H,6.44; N,17.04 Found : C,50.96; H,6.59; N,16.58 . ExamDle 5 4-Amino-N-(1, 2-diethyl-4-pyrazolldinyl)benzamide.
A solution of 20 g. (0.069 mole) of 4-nitro-N-(1,2-diethyl-4-pyrazolidinyl)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 concen-trated and the residue crystallized from isopropyl ether-ethyl acetate. The product (12.0 g.; 66.5%) melted at 119-121C.
Analysis: Calculated for C14H22N40: C,64.09; H,8.45; N,21.36 ! Found : C,63.98; H,8.55; N,21.37 ; 15 Exam~le 6 . 4-Amino-5-chloro-2-methoxv-N-(1,2-diethyl-4-;~ pyrazolidinyl~ben2amide.
To 75 ml. of thionyl chloride was added 12 g. (0.05 - mole) of 4-acetamido-5-chloro 2-methoxy-benzoic acid and the stirred suspension refluxed one hour. The resulting solution was concentrated and 100 ml. of chloroform added to the residue which was concentrated to remove traces of thionyl chloride. The residue was dissolved in 100 ml. of chloroform and the solution added at a rapid drop to 7 g. (0.05 mole) of 4-amino-1,2-diethylpyrazolidine in 100 ml. of chloroform while stirring and cooling to 20-25C. with an ice bath. After 30 minutes the chloro-form solution was extracted two times with 100 ml. of 3N
I hydrochloric acid and the chloroform solution retained.
The acid extract was boiled 10 minutes, cooled with ice, '~ made basic with concentrated sodium hydroxide while cooling and extracted with chloroform. The chloroform was dried (sodium sulfate), concentrated and the residue crystallized from isopropyl ether-isooctane to give 3 g.
; 35 of material which melted at 116-118C. The retained chloroform solution was extracted with dilute sodium ,, .

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hydroxide and concentrated. The residue was dissolved in 3N hydrochloric acid and extracted with isopropyl ether. The acid solution was refluxed for 10 minutes, cooled with ice bath, made basic with sodium hydroxide S whlle cooling and extracted with chloroform. The chloro-form was dried (sodium sulfate) and concentrated. The residue was crystallized three times from isopropyl ether to give 0.7 g. of material which melted at 117-119C.
A mixture melting point of both materials gave no depres-sion of the melting point. The combined yield was 3.7 g.
(23~).
Analysis: Calculated for C15H23ClN4O2: C,55.13; H,7.09; N,17.14 Found : C,55.23; H,7.10; N,17.17 ~;i Exam~le 7 When in the procedure of Example 3 there is substituted for 3,4,5-trimethoxybenzoyl chloride equal molar amounts of:
4-cyanobenzoyl chloride, 3-trifluoromethylbenzoyl chloride, 20 4-methylbenzoyl chloride, 4-metho~ybenzoyl chloride, 4-acetamidobenzoyl chloride, and 2-methoxy-5-sulfamoylbenzoyl chloride, there are obtained:
- 25 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, 1 4-methoxy-N-(1,2-dimethyl-4-pyrazolidinyl)-benzamide, 4-acetamido~N-(1,2-dimethyl-4-pyrazolidinyl)-benzamide, and t 2-methoxy-5-sulfamoyl-N-(1,2-dimethyl- 4-pyrazolidinyl)benzamide.

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~ 80 346-CIP-1 Exam~ e 8 4-Amino-5-chloro-2-methoxy-N-1,2-dimethyl-4-., Yrazol-idinylbenzamid -e .
A stirred solution of equal molar amounts of 4-amino-S-chloro-2-methoxybenzoic acid and triethylamine in methylene chloride (0-5C) was treated dropwise with a slight excess of ethylchlorocarbonate. After 1.0 hour a solution of 4-amlno-1,2-dimethylpyrazolidine in methylene chloride was added and the mixture stirred for about two hours at room temperature. An agueous solution of ` sodium bicarbonate was added to the reaction mixture, the organic phase separated and concentrated to give the ` ' product which melted at 169-171C.
Example 9 4-Amino-5-chloro-2-methoxY-N-(l-benzYl-2-methYl-4-~yrazolidinYl)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-~; 20 methylpyrazolidine according to the procedure of Example 8. The fumarate salt was prepared and it melted at 129-131~C.

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Example 10 4-Amino-5-chloro-2-methoxy-N-(l-cyclohexyl-2-methyl-4-pyrazolidinyl)benzamide was prepared from 4-amino-5-chloro-2-methoxybenzoic acid and 4-amino-S 1-cyclohexyl-2-methylpyrazolidine according to the procedure of Example 8. Melting point of the hydro-chloride hydrate was 105-120C.
Example 11 4-Amino-5-chloro-2-methoxy-N-(l-isoPropyl-2 `. 10 methYl-4-~vrazolidinYl)benzamide Dihydrochloride.
4-Amino-5-chloro-2-methoxy-N-(l-isopropyl-2-methyl-4-pyrazolidinyl~benzamide was prepared from 4-amino-5-chloro-2-methoxybenzoic acid and 4-amino-1-isopropyl-2-methylpyrazolidine according to the procedure of Example 8. The dihydrochloride salt was prepared and it melted at 162-166C.

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11~39~80 The pharmaceutical compositions comprise compounds of Formula I
above in an amount to provide effective anti-emetic and gastric emptying ac-tion. The compositions contain 1.0 mg. to 100 mg. active medicament per unit dose. Preferably, the compositions contain from about 5 mg. to 100 mg. of medicament, advantageously from about 5 mg. to about 50 mg. per unit dose.
The pharmaceutical carrier employed in the composition can be either solid or liquid. Exemplary of solid carriers are lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia.
Exemplary of liquid carriers are vegetable oils and water. Similarly, the carrier or diluent may include a sustained release material such as glyceryl monostearate or glyceryl distearate alone or with a wax.
A wide variety of pharmaceutical forms can be employed by methods well known to the art. Thus, if a solid carrier is used the composition can be tableted or prepared as a powder, a troche or a lozenge. Gelatin capsules ' containing the medicament can also be prepared. If a liquid carrier is used, the composition can be in the form of a soft gelatin capsule, a liquid suspen-sion or a syrup. Parenteral dosage forms are obtained-by dissolving a water-soluble salt of the active agent in water or saline solution in a concentration such that 1 cc. of the solution contains from 1.0 mg. to 25 mg. of active . 20 agent. The solution can be filled into single or multiple dose ampules.
The method of use of the compounds comprises administering inter-, nally to warm blooded animals including human beings certain N-~4-pyrazolidi-nyl)benzamides or a non-toxic organic or inorganic acid addition salt thereof, preferably with a non-toxic pharmaceutical carrier such as described above, in an amount sufficient to control emesis and/or 346-CIP-l facilitate gastric emptying. The active agent is administered orally or parenterally in repeated doses until satisfactory response is obtained. The daily dosage is from about 10 my. to about 300 mg. of active S ~edicsment, advantageously from about 5 mg. to 50 mg.

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Claims (21)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a 4-aminopyrazolidine of the formula (II) wherein: R is lower alkyl, lower cycloalkyl or phenyllower alkyl, R1 is lower alkyl, lower cycloalkyl or phenyllower alkyl, and R2 is hydrogen, lower alkyl or phenyl, which comprises:
(a) reacting a compound of formula (V) wherein X is halogen, R and R1 are as defined above, with ammonia or a lower alkylamine under pressure at an elevated temperature to provide a compound of formula II wherein R2 is hydrogen or lower alkyl and R and R1 are as defined above; or (b) reacting a compound of formula (VI) wherein R and R1 are as defined above and R6 is an arylsulfonyloxy radical with an aniline which may be substituted, to prepare a compound of formula II
above wherein R2 is a phenyl group, or (c) hydrolysing a 1,2-hydrocarbyl-4-phthalimidopyrazolidine which is substituted in the 1- and 2-position by substituents R and R1 as defined above.

2. A compound of formula II as defined in claim 1, or an acid addition salt thereof whenever prepared by a process according to claim 1 or by an obvious chemical equivalent thereof.

3. A process according to claim 1 wherein R and R are both methyl and R2 is phenyl.

4. A process according to claim 1 wherein in formula V X is chlorine.

5. A process for preparing 4-anilino-1,2-dimethylpyrazolidine which comprises reacting the product of reaction of 1,2-dimethyl-4-pyrazolidinol and benzylsulfonyl chloride with aniline.

6. The compound 4-anilino-1,2-dimethylpyrazolidine when prepared by a process according to claim 5 or an obvious chemical equivalent thereof.

7. A process according to claim 1 wherein R and R1 are both ethyl and R2 is hydrogen.

8. A process for preparing 4-amino-1,2-diethylpyrazolidine which com-prises heating 4-chloro-1,2-diethylpyrazolidine with ammonium hydroxide in a closed chamber.

9. The compound 4-amino-1,2-diethylpyrazolidine when prepared by a process according to claim 8 or an obvious chemical equivalent thereof.

10. A process according to claim 1 wherein R and R1 are both methyl and R2 is hydrogen.

11. A process for preparing 4-amino-1,2-dimethylpyrazolidine which com-prises heating 4-chloro-1,2-dimethylpyrazolidine with ammonium hydroxide in a closed chamber.

12. The compound 4-amino-1,2-dimethylpyrazolidine when prepared by a process according to claim 11 or an obvious chemical equivalent thereof.

13. A process according to claim 1 wherein R is methyl, R1 is benzyl, and R2 is hydrogen.

14. A process for preparing 4-amino-1-benzyl-2-methylpyrazolidine which comprises heating 4-chloro-1-benzyl-2-methylpyrazolidine with ammonium hy-droxide in a closed chamber.

15. The compound 4-amino-1-benzyl-2-methylpyrazolidine when prepared by a process according to claim 14 or an obvious chemical equivalent thereof.

16. A process according to claim 1 wherein R is methyl, R1 is cyclo-hexyl, and R2 is hydrogen.

17. A process for preparing 4-amino-1-cyclohexyl-2-methylpyrazolidine and its fumarate salt which comprises heating 4-chloro-1-cyclohexyl-2-methyl-pyrazolidine with ammonium hydroxide in a closed chamber and, if the fumarate salt is required, reacting the product with fumaric acid.

18. The compound 4-amino-1-cyclohexyl-2-methylpyrazolidine and its fumarate salt when prepared by a process according to claim 17 or an obvious chemical equivalent thereof.

19. A process according to claim 1 wherein R is methyl, R1 is isopropyl, and R2 is hydrogen.

20. A process for preparing 4-amino-1-isopropyl-2-methylpyrazolidine which comprises heating 4-chloro-1-isopropyl-2-methylpyrazolidine with ammon-ium hydroxide in a closed chamber.

21. The compound 4-amino-1-isopropyl-2-methylpyrazolidine when prepared by a process according to claim 20 or an obvious chemical equivalent thereof.