CA1105037A - N-(4-pyrazolidinyl) benzamides - Google Patents
N-(4-pyrazolidinyl) benzamidesInfo
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- CA1105037A CA1105037A CA309,651A CA309651A CA1105037A CA 1105037 A CA1105037 A CA 1105037A CA 309651 A CA309651 A CA 309651A CA 1105037 A CA1105037 A CA 1105037A
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- chloro
- methoxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/04—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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Abstract
N-(4-PYRAZOLIDINYL)BENZAMIDES
ABSTRACT OF THE DISCLOSURE
N-(4-Pyrazolidinyl)benzamides having the formula
ABSTRACT OF THE DISCLOSURE
N-(4-Pyrazolidinyl)benzamides having the formula
Description
2 ~ 3~
BACKGROUND OF TEIE INVENTION
1 . F I ELD OF I NVENT I ON
The present invention is concerned with heteiro-cyclic compounds possessing anti-emetic and gastric emptying properties and is particularly concerned with certain N-~4-pyrazolidinyl)benzamides, compositions thereof and methods for employing the compositions in controlling emesis and ~astric emptying properties in warm blooded animal~ with minimal side effects. ,:
2. DESCRIPTION OF THE PRIO~ ART
: : The~prior art discloses various benzamido derivatives whereln.:one of the substituents attached to : ' the benzamido nitrogen can be a pyrrolidinyl or a piperidinyl radical. United States Patent 3,34~,826 disclose~ heterocyclic aminoalkyl ben~amides having anti-emetic properties. United States Patent 3,577,440 describes l~substituted-3,-~midopyrrolidines having analgetic and anti-depressant properties. United 5tates ,, : Patents 3,966,957 and 3,963j745 describe N~ s~bstituted-~: ~ 20 ~ 3-pyrrolidinyl)benzamides and thiobenz~mides as ,particularly useful in:controlling emesis. ` -: : -. .
'3~7 SUMMARY OF THE INVENTION
The novel compounds of the present invention are N- ~1, 2-hydrocarbyl-4-pyrazolidinyl)benzamides ~1). The novel compounds of the invention have ~he formula:
IR2 1l (R3) R-NrTN--C {~ I :
N
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, R is hydroxy, cyano, nitro, amino, fluoro, chloro, bromo, trifluoro-methyl, lower alkyl, lower alkoxy, sulfamoyl or acetamido, R can be the same radical or different radicals, and n is an integer from zero to three inclu-sive.
The compounds of the invention can be prepared by:
~a) reacting a compound of formula 2 .:
I
-- I N-~l II
R-N J
R
with a compound of formula - ;`
COX :
~- tR3} III
wherein R, Rl, R , and n are as defined above R3 is as defined above o~her :
than primary amino, and X is halogen; or ~b) reacting a compound of formula II as defined above with a :~ ~20 mixed anhydride which is the:product o:E reaction between a compound of for]nula _ ,, _ .
f~ 3'~
CO-X
~ (R ) IV
wherein R3 is as defined for formula ~I) above, and ethylchlorocarbonateJ
~ c) hydrolysing a compound of formula I as de:Eined above wherein R3 is acetamido; or ~ d) reducing a compound of formula I as defined above wherein R3 is cyano;
and, if required, converting the compound of formula I into a pharmaceutically acceptable acid addition salt.
The non-toxic pharmaceutically acceptable acid addition salts o:E
the basic compounds of formula I are also included within the scope of this invention, since such sa].ts can likewise be used as anti-emetics or gastric 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 modificati.on of the methods of ~hen and Enxor, J. Pharmac. Exp. Ther. 98, 245-250 ~1950) and oE Leonard et al., J. Pharmac. Exp. Ther. 154, 339-345 ~1966).
~ - 3a ,~:
~ 3 ~ 346-CIP-l The gastric em~tying actlvity 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 administered intraperitoneally to the rats in 5% acacia ~0.4 ml/lO0 g. body weight). The control group is dosed with acacia alone, 4 ml/kg intra-pertioneally. Thirty minutes following dosing, ~le rats are given orally, by stomach tube, 3 ml. of a test meal consisting of methylcellulose base to which had been added be~f bouillon, casein, powdered sugar and corn starch to yield a semi-solid homogenous paste. Sixty minutes ~ollowing 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 balance after which they are cut open, rinsed and the empty stomach weighed. The difference between full and empty stomach weights repre-sents the amount of meal remaining in the stomach and issubtracted from the weight of 3.0 ml. of test meal to yie1d the amount of meal emptied from the stomach during the test period.
The preferred compound of Example 6 reduced emesis 87% when administered at a dose level of 5 mg/kg ~s.c.) and increased ~he gastric emptying time significantly when administered at doses from 0.33 to ~.O mg/kg.
It is, therefore, a primary object of the present invention to provide novel N-(4-pyrazolidinyl)benzamides.
A further object is to provide novel N-(4-pyrazolidinyl) benzamides having anti-emetic and gastric emptying properties. A still urther object is to provi.de novel compositions useful as anti-emetics and for controlling ~ gastric emptying.
Additional objects and advantages of the present invention will be apparent to one skilled in the art and '.
~ - .. . .
~ 3 ~ 346 CIP 1 still others will become apparent from the following description of ~he best mode of carrying out the pre~ent invention and from the appended claims.
The lower alkyl moiety has 1 - 4 carbon atoms.
The term "lower cycloalkyl 1l as used herein includes primarily cyclic alkyl radicals containing from four up to twelve carbon atoms inclusive and includes such groups as cyclobutyl, cyclopentyl, cyclohe~yl, 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 ox otherwise interfering under the conditions o~ reaction described herein such as lower-alkyl, lower-alkoxy, trifluoromethyl, bromo, chloro, fluoro, and the like.
The substituted phenyl radicals have prefera~ly 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 diferent 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, acetam.ido, sulfamoxyl, methoxy, ethoxy, propoxy, butoxy an~ trifluoromethyl radicals.
The term "lower-alkyl" includes straight and branched chain radicals containing ~ to ~ carbon atoms as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, tertiary butyl, amyl, isoamyl, n-hexyl, n-heptyl, and n-octyl radicals. A l'lower-alkoxy" radical has the formula -0-lower alkyl.
Included in the term "phenyllower-alkyl" are such groups as henzyl, phenethyl, phenpropyl, ame~hylbenzyl, and the like.
.,, . , . ... ,,. - . ~
~.~r~3~7~
Our copending application Serial No~ 7l, which B is divided ou~ of this application, relates to novel 4~amino-1,2-hydrocarbylpyraæolidines of formula II
N - H
` N
. 1 1 , . . .
wherein R is lower alkyl, lower cycloalkyl or phenyllower alkyl; Rl is lower alkyl, lower cycloalkyl or phenyllower .. :
alkyl; ~ is hydrogen, lo~er alkyl or phenyl. .
The compounds of Formula II wherein R2 i5 hydrogen are prepared by heatiny a mixture o a 4-halo-1,2-hydrocarbyl~
pyrazolidine and concentrated ammonium hydroxide in a steel bomb at a temperature of ~rom about 125C to about 200C o.r a per~od o~ several hours. The procedure is also applicable to prepare compounds wh.erein R2 is lower alkyl such as methyl, ethyl, or propyl. In the latter case a solution of the appropriate lo~er alkylamine in a lo~er alkanol is preferably used. 2 The compounds o~ Formula II wherein R is phenyl are prepared b~ reacting a l r 2~hydrocarhyl-4-arylsul~onyloxy-pyxazoli.dlne and aniline or a substituted aniline together in a sui.table ~olvent. The l/2-hydrocarbyl-4-arylsulonyloxy-pyrazoli.dine is generally prepared by reacting the sodium sal-t o~ a 1,2-hydrQcarbyl 4-p~razolidinol with.benzenesulfonyl chlor-ide or p-tolylsulfonyl ahloride 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 prepared by the procedures disclosed in U.S. Patent No. 3,660,426.
-6a-~ 37 346-CIP-l The novel basic compoundfi of Formulas I and II form fluosilicic acid addition salts which are useful as moth-proofing agents according to U.S. Patents 1,915,334 and 2,075,359.
Method of Preparation The preparation of the benzamido compounds of Formula I may be accomplished by contacting a 4~amino~
1,2-hydrocarbylpyrazolidin~ II, with an appropriately substituted benzoyl chloride III according to the fol lowing xeaction sequence:
R2 R~
R-N~NH ~_ (R3) ~ ~N--I ~~ (R3)n L~ 1 ~T 1 II III I
wherein R, R1, R2, and n are as defined above with the proviso that R3 cannot be primary amino.
Compounds of Formula I whexein R3 is primary amino are generally prepared by catalytic hydrogenation of the precursor compound of Formul~ I wherein ~3 iS nitro.
Alternately, a compound of Formula I is prepared having R3 as an acetamido radical and the compound is hydrolyzed in dilute acid to generate the amino radical.
In an alternate method of preparation 1,2-~0 hydrocarbyl-4-ph~halimidopyrazolidines are used as a reactant. The latter are prepared by the reaction between a 4-chloro-1,2-hydrocarbylpyrazolidine and potassium phthalimide. The 1,2-hydrocarbyl-4-phthalimidopyrazolidine is hydrolyzed in dilute mineral acid, the mixture filtexed and the acid filtrate basi~
fied to liberate the free 4-ami~o-1,2~
hydrocarbylpyrazolidine which is reacted with a ~elected benæoyl chloride to give the desired N-(1,2-hydrocarbyl-4-pyraæolld.nyl)benæamide.
!
: . ' , . . ' ' '.
BACKGROUND OF TEIE INVENTION
1 . F I ELD OF I NVENT I ON
The present invention is concerned with heteiro-cyclic compounds possessing anti-emetic and gastric emptying properties and is particularly concerned with certain N-~4-pyrazolidinyl)benzamides, compositions thereof and methods for employing the compositions in controlling emesis and ~astric emptying properties in warm blooded animal~ with minimal side effects. ,:
2. DESCRIPTION OF THE PRIO~ ART
: : The~prior art discloses various benzamido derivatives whereln.:one of the substituents attached to : ' the benzamido nitrogen can be a pyrrolidinyl or a piperidinyl radical. United States Patent 3,34~,826 disclose~ heterocyclic aminoalkyl ben~amides having anti-emetic properties. United States Patent 3,577,440 describes l~substituted-3,-~midopyrrolidines having analgetic and anti-depressant properties. United 5tates ,, : Patents 3,966,957 and 3,963j745 describe N~ s~bstituted-~: ~ 20 ~ 3-pyrrolidinyl)benzamides and thiobenz~mides as ,particularly useful in:controlling emesis. ` -: : -. .
'3~7 SUMMARY OF THE INVENTION
The novel compounds of the present invention are N- ~1, 2-hydrocarbyl-4-pyrazolidinyl)benzamides ~1). The novel compounds of the invention have ~he formula:
IR2 1l (R3) R-NrTN--C {~ I :
N
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, R is hydroxy, cyano, nitro, amino, fluoro, chloro, bromo, trifluoro-methyl, lower alkyl, lower alkoxy, sulfamoyl or acetamido, R can be the same radical or different radicals, and n is an integer from zero to three inclu-sive.
The compounds of the invention can be prepared by:
~a) reacting a compound of formula 2 .:
I
-- I N-~l II
R-N J
R
with a compound of formula - ;`
COX :
~- tR3} III
wherein R, Rl, R , and n are as defined above R3 is as defined above o~her :
than primary amino, and X is halogen; or ~b) reacting a compound of formula II as defined above with a :~ ~20 mixed anhydride which is the:product o:E reaction between a compound of for]nula _ ,, _ .
f~ 3'~
CO-X
~ (R ) IV
wherein R3 is as defined for formula ~I) above, and ethylchlorocarbonateJ
~ c) hydrolysing a compound of formula I as de:Eined above wherein R3 is acetamido; or ~ d) reducing a compound of formula I as defined above wherein R3 is cyano;
and, if required, converting the compound of formula I into a pharmaceutically acceptable acid addition salt.
The non-toxic pharmaceutically acceptable acid addition salts o:E
the basic compounds of formula I are also included within the scope of this invention, since such sa].ts can likewise be used as anti-emetics or gastric 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 modificati.on of the methods of ~hen and Enxor, J. Pharmac. Exp. Ther. 98, 245-250 ~1950) and oE Leonard et al., J. Pharmac. Exp. Ther. 154, 339-345 ~1966).
~ - 3a ,~:
~ 3 ~ 346-CIP-l The gastric em~tying actlvity 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 administered intraperitoneally to the rats in 5% acacia ~0.4 ml/lO0 g. body weight). The control group is dosed with acacia alone, 4 ml/kg intra-pertioneally. Thirty minutes following dosing, ~le rats are given orally, by stomach tube, 3 ml. of a test meal consisting of methylcellulose base to which had been added be~f bouillon, casein, powdered sugar and corn starch to yield a semi-solid homogenous paste. Sixty minutes ~ollowing 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 balance after which they are cut open, rinsed and the empty stomach weighed. The difference between full and empty stomach weights repre-sents the amount of meal remaining in the stomach and issubtracted from the weight of 3.0 ml. of test meal to yie1d the amount of meal emptied from the stomach during the test period.
The preferred compound of Example 6 reduced emesis 87% when administered at a dose level of 5 mg/kg ~s.c.) and increased ~he gastric emptying time significantly when administered at doses from 0.33 to ~.O mg/kg.
It is, therefore, a primary object of the present invention to provide novel N-(4-pyrazolidinyl)benzamides.
A further object is to provide novel N-(4-pyrazolidinyl) benzamides having anti-emetic and gastric emptying properties. A still urther object is to provi.de novel compositions useful as anti-emetics and for controlling ~ gastric emptying.
Additional objects and advantages of the present invention will be apparent to one skilled in the art and '.
~ - .. . .
~ 3 ~ 346 CIP 1 still others will become apparent from the following description of ~he best mode of carrying out the pre~ent invention and from the appended claims.
The lower alkyl moiety has 1 - 4 carbon atoms.
The term "lower cycloalkyl 1l as used herein includes primarily cyclic alkyl radicals containing from four up to twelve carbon atoms inclusive and includes such groups as cyclobutyl, cyclopentyl, cyclohe~yl, 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 ox otherwise interfering under the conditions o~ reaction described herein such as lower-alkyl, lower-alkoxy, trifluoromethyl, bromo, chloro, fluoro, and the like.
The substituted phenyl radicals have prefera~ly 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 diferent 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, acetam.ido, sulfamoxyl, methoxy, ethoxy, propoxy, butoxy an~ trifluoromethyl radicals.
The term "lower-alkyl" includes straight and branched chain radicals containing ~ to ~ carbon atoms as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, tertiary butyl, amyl, isoamyl, n-hexyl, n-heptyl, and n-octyl radicals. A l'lower-alkoxy" radical has the formula -0-lower alkyl.
Included in the term "phenyllower-alkyl" are such groups as henzyl, phenethyl, phenpropyl, ame~hylbenzyl, and the like.
.,, . , . ... ,,. - . ~
~.~r~3~7~
Our copending application Serial No~ 7l, which B is divided ou~ of this application, relates to novel 4~amino-1,2-hydrocarbylpyraæolidines of formula II
N - H
` N
. 1 1 , . . .
wherein R is lower alkyl, lower cycloalkyl or phenyllower alkyl; Rl is lower alkyl, lower cycloalkyl or phenyllower .. :
alkyl; ~ is hydrogen, lo~er alkyl or phenyl. .
The compounds of Formula II wherein R2 i5 hydrogen are prepared by heatiny a mixture o a 4-halo-1,2-hydrocarbyl~
pyrazolidine and concentrated ammonium hydroxide in a steel bomb at a temperature of ~rom about 125C to about 200C o.r a per~od o~ several hours. The procedure is also applicable to prepare compounds wh.erein R2 is lower alkyl such as methyl, ethyl, or propyl. In the latter case a solution of the appropriate lo~er alkylamine in a lo~er alkanol is preferably used. 2 The compounds o~ Formula II wherein R is phenyl are prepared b~ reacting a l r 2~hydrocarhyl-4-arylsul~onyloxy-pyxazoli.dlne and aniline or a substituted aniline together in a sui.table ~olvent. The l/2-hydrocarbyl-4-arylsulonyloxy-pyrazoli.dine is generally prepared by reacting the sodium sal-t o~ a 1,2-hydrQcarbyl 4-p~razolidinol with.benzenesulfonyl chlor-ide or p-tolylsulfonyl ahloride 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 prepared by the procedures disclosed in U.S. Patent No. 3,660,426.
-6a-~ 37 346-CIP-l The novel basic compoundfi of Formulas I and II form fluosilicic acid addition salts which are useful as moth-proofing agents according to U.S. Patents 1,915,334 and 2,075,359.
Method of Preparation The preparation of the benzamido compounds of Formula I may be accomplished by contacting a 4~amino~
1,2-hydrocarbylpyrazolidin~ II, with an appropriately substituted benzoyl chloride III according to the fol lowing xeaction sequence:
R2 R~
R-N~NH ~_ (R3) ~ ~N--I ~~ (R3)n L~ 1 ~T 1 II III I
wherein R, R1, R2, and n are as defined above with the proviso that R3 cannot be primary amino.
Compounds of Formula I whexein R3 is primary amino are generally prepared by catalytic hydrogenation of the precursor compound of Formul~ I wherein ~3 iS nitro.
Alternately, a compound of Formula I is prepared having R3 as an acetamido radical and the compound is hydrolyzed in dilute acid to generate the amino radical.
In an alternate method of preparation 1,2-~0 hydrocarbyl-4-ph~halimidopyrazolidines are used as a reactant. The latter are prepared by the reaction between a 4-chloro-1,2-hydrocarbylpyrazolidine and potassium phthalimide. The 1,2-hydrocarbyl-4-phthalimidopyrazolidine is hydrolyzed in dilute mineral acid, the mixture filtexed and the acid filtrate basi~
fied to liberate the free 4-ami~o-1,2~
hydrocarbylpyrazolidine which is reacted with a ~elected benæoyl chloride to give the desired N-(1,2-hydrocarbyl-4-pyraæolld.nyl)benæamide.
!
: . ' , . . ' ' '.
3~
Another alternate method which can be used in preparing the novel compo~mds of formula I utilizes an appropriately substituted benzoic acid which is contacted with ethylchlorocarbonate in the presence of triethylamine, preferably in methylene chloride at 0-5C to form the mixed anhydride of the benzoic acid. A~ter approximately one hour at the lower temperature, a solution of the 4-ami.no-1,2-hydrocarbylpyrazolidine is added. Subsequent to an additional period of stirring, an aqueous sodium bicarbonate solution is added to the reaction mixture, the organic phase is separated and the benz-amide compound is isolated therefrom by suitable means.
The substituted benzoyl chlorides III useful in practicing the present invention are either known compounds or they can be prepared by pro-cedures well known to the art and include but are not limited to the following:
2-fluorobenzoyl chloride, 3-bromobenzoyl chloride, ~-bromobenzoyl chloride, 3,5-dinitrobenzoyl chloride, 3,4-dichlorobenzoyl chloride, 3,4-diethoxybenzoyl chloride, 3-trifluoromethylbenzoyl chloride, ~-tertiarybutylbenzoyl chloride,
Another alternate method which can be used in preparing the novel compo~mds of formula I utilizes an appropriately substituted benzoic acid which is contacted with ethylchlorocarbonate in the presence of triethylamine, preferably in methylene chloride at 0-5C to form the mixed anhydride of the benzoic acid. A~ter approximately one hour at the lower temperature, a solution of the 4-ami.no-1,2-hydrocarbylpyrazolidine is added. Subsequent to an additional period of stirring, an aqueous sodium bicarbonate solution is added to the reaction mixture, the organic phase is separated and the benz-amide compound is isolated therefrom by suitable means.
The substituted benzoyl chlorides III useful in practicing the present invention are either known compounds or they can be prepared by pro-cedures well known to the art and include but are not limited to the following:
2-fluorobenzoyl chloride, 3-bromobenzoyl chloride, ~-bromobenzoyl chloride, 3,5-dinitrobenzoyl chloride, 3,4-dichlorobenzoyl chloride, 3,4-diethoxybenzoyl chloride, 3-trifluoromethylbenzoyl chloride, ~-tertiarybutylbenzoyl chloride,
4-butoxybenzoyl chloride, 2,4-dimethoxybenzoyl chloride, ~-methylbenzoyl chloride, 4-cyanobenzoyl chloride, 2-methoxy-5-sulfamoylbenzoyl chlo~ide, 2-metho~y-4-dimethylaminobenzoyl chloride, 2-methoxy-4-nitrobenzoyl chloride, 2-methoxy-3-fluoro-5-chlorobenzoyl chloride, 2-ethoxy-~-bromobenzoyl chloride, 2-methoxy-3-acetamido-5-trifluoromethylbenz.oyl chloride.
~ - 8 -P`~,'3 ~ .
346 CIP-l In Formula I centers of asymmetry are present. The compounds can be resolved into their optically active forms by combining the compounds with optically active organic acids and ~eparating the optically active forms by fractional crystallization. The optically active forms are included within the scope of the present invention.
.
~ - 8 -P`~,'3 ~ .
346 CIP-l In Formula I centers of asymmetry are present. The compounds can be resolved into their optically active forms by combining the compounds with optically active organic acids and ~eparating the optically active forms by fractional crystallization. The optically active forms are included within the scope of the present invention.
.
5~ r 3 7 346~-CIP~l :Lo Pxeparation 1 4-Chloro-1,2-die~hylpyraæolidine.
R solution of triphenyl phosphine t52 g.; 0.2 mole) in 150 ml. of chloroform was treated with chlorine gas which was accompanied by a rise in ~he temperature of the mixture to 60C. until excess chlorine yas app~ared 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 40~C.
Subsequent to the addition, the stirred solution was reflu~ed two hours, cooled to room temperature and extracted with water. The combined aqueous extracts were basified with concentrated sodium hydroxide solution and the basic mixture extracted with chloroform. The 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 C~Hl6N2Cl: C,51.68; H,9.29; H,17.22 Found : C,51.45; ~,9.30, H,17.29 PreParation 2 4-Amino-1,2-diethylpyrazolidi~e.
A mixture of I00 g. (0.615 mole) o~ 4-chloro~1,2-diethyl-pyrazolidine and 200 ml. of concentrated ~mmonium hydro~ide in a closed ~teel chambex was heated at 150C. for approximately 36 hours. The cooled reaction mixtuxe was extracted~with i~opropyl ether, the aqueous layer saturated with potassium carbona-te and continuously extracted with 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.
, - - : . .
P3~
Prepara~ion 3 4-Amino-1,2~dimethylpyrazolidlneO
-A mixture of 300 g. (2.22 mole) of 4-chloro-1,2-dimethylpyrazolidine and 600 ml. of conc. ammonium 5 hydroxide was heated at 150C. for 18 hrs. in a steel bomb. The cooled mixture was saturated wi~h potassium c:arbonate and continuously extracted for 18 hrs. with chlorofox~n. The residual material after concentration of the chloroform extract was distilled at 90-lOO~C./40 10 mm. to yive 73 g. of product.
Preparation 4 4-Anilino-1, 2-dimethylpyraæolidine .
A stirred suspension of 40 g . ( 1. 02 mole) of sodamide in dry toluene was treated dropwise with 116 g.
(1.0 mole) o~ 1,2-dimethyl-4 pyrazolidinol 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 reactiGn mixture was shaken with dilute sodium hydroxide, the separated toluene layer dried over sodium sulfate and concentrated a-t reduced pressure. The residue was dissolved in 300 ml. of aniline, the mixture heated 2 . 5 hrs . on the steam bath and ref}uxed for 3 . 0 hrs . The cooled mixture was extracted with dilute sodium hydroxide solution and the separated a;Lueous layer extracted with isopropyl ether.
The com~ined organic layers after drying over sodium sulfate were concentrated and the residue distilled to a pot temperature of 140C./80 mm. The residue which would not crystallize was distilled at 110-125C./0.1 mm. to give 86 g. of product.
Preparation 5 ilino-l,2-die hylpyr zolidine.
To a stirred suspensiorl of 7 . 9 g . t O . 2 mole ) of sodamide in 100 ml . of dxy toluene was added 28 . a g .
( 0 . 2 mole ) of 1, 2-diethyl-4-pyrazolidinol at a rate ~o ' ~ tf ~3 ~ 346~CIP-1 that a pot temperature of 30 ~5C. was maintained.
~fter ~tirring 2.0 hrs. at room temperature, ~he 601u-tion was added dropwise to a 601ution of 38.0 g. ~0.2 mole) of p-toluenesulfonyl chloride in 200 ml. of dry toluene with the pot temperatuxe maintained below 30C.
Ater stirring for abouk one hr. at room temperature, ~he reaction mi~ture was washed twice with water and dried over sodium sulfate. The dried filtered ~olution was concentrated to a volume of about 100 ml., aniline ~lO0 ml.) was added, the solu~ion refluxed for 3.0 hrs.
and then concentrated. The residue was partitioned between chloroform and dilute ~odium hydroxide. The dried chloroform layer was concentrated and the residue distilled at 1~0C./0.1 mm. to give 4.0 g. of product.
Preparation 6 1,2-Diethyl-4~phthalimido-pyrazolidine Ma ate.
To 100 ml. of dimethyl ~ulfoxide 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 ~olume 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 hydroch].oric acid and ethyl acetate. The acid layer was made basic with potassium carbonate and extracted w.ith chloroform. The chloroform waæ dried (sodium sulfate) and concentrated.
The residue (2~ 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 recrystalli~ed : twice from the ~ame solvent ~ystem to give 11.5 g. (15%) of product which melted at 144-147C.
Analysis: Calculated for ClgH23N306: C,$8.60; ~,5.95; N,10.79 Found : C,58.64; H,6.03; n,10.73 . ~ .
Preparation 7 4-Amino-l-benzyl-? methylpyrazolidine.
4~Amino i-benzyl~2-methylpyrazolidine, b.p. 115-125C./l.0 mm., was prepared from 1-benzyl-2-methyl-4-S pyrazolidinol according to preparations 1 and 2.
~=
4-~mino-1-cyclohexyl-2-methylpyrazolidine Fumarate.
4-Amino-1-cyclohe~yl-2-methylpyrazolidine, b.p.
90-100C./O.S-l.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~ opropyl-~-methy~yrazolidine.
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 amnlonium hydroxide is replaced by an equal molar amount of methylamine in methanol, there is obtained 4-methylamino-1,2-diethylpyrazolidine.
:
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f~5~7 346-CIP-l Exam~le 1 4-Chloro-N-phenyl-N-~1,2-dimethyl- -ny benzamide.
To a solution of 10 g. (0.0525 mole) of 1,2~dimethyl~
4-anilinopyrazolidine in 50 ml. of chloroform was added with stirring 9.15 g. (0~0525 mole) of p-chlorobenzoyl chloride with the temperature not exceeding 50C. On completion of addition the solution was refluxed for one hour~ cooled to room temperature and extracted with dilute ~odium hydroxide. ~he chlorofo~n layer was dried over sodi~n sulfate and concentrated at reduced pre~sure to give an oil which crystallized upon cooling, The solid was recrystallized twice from ligroin. Yield 13.1 g. (7~%); m.p. }04 108C. 5 Analysis: Calculaked for Cl8H~oClN30: 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-diethy~-4 pyrazolidlnyl)benz~ lde.
A solution of lO g. (O.026 mole) of 1,2~diethyl-4-phthalimidopyrazolidine maleate in ~5 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 ~vlution was made basic with dilute sodium hydroxide and cooled with ice. To the resulting solu-tion was added a . 2 g. (0.052 mole~ of p-fluorobenzoyl chloride and the mi.xture shaken for lO minutes. The resulting mixture was extracted with chloroform, the chlorofoYm diluted wi~h an equal volume of isopropyl ether and the resulting solution extracted with dilute hydrochloxic acid. The acid layer was made basic with dilute sodium hydroxide and extracted with chloroform.
The chloroform was dried (sodium sulf~ke) and concen-trated. The residue was crystalli2ed from isooctane-isopropyl ether and recrystallized from isooctane~isopropyl ether containing a few dxops of ethyl acetate '3~
346-CIP-l and clarified by charcoal txeatment. ~he product ~2.0 g; 29%) melted at 114-116C.
Analysis: Calculated for C14~2~N3OF: C,63.38; ~,1.6~; N,15.84 Found C,63.36; H,7.61; N,15.96 Example 3 3,4,5-Trimethoxy_N~ dimethyl-4-pyrazolidinyl ben2amide.
To 10 g (O.09 mole) of 4-amino~1,2-dimethylpyrazolidine in chloroform was added with ~tirring 20.7 ~. (0.09 mole) of 3,4,5-trimethoxybenzoyl chloride.
After 30 minutes of stirring the solution was extracted with dilute sodi~m h~droxide. The chloroform solution was dried ~sodium sulfate), filtered, and the filtrate - concentrated. The resulting crystalline material was recrystallized from equal port.ions of ethyl acetate and isopropyl ether. The product (12.1 g.; 44%) melted at 163-166C .
Analysis: Calculated for C15H23N3O~: C,58.24; H,7.49; N,13.58 Found : C,58.20; H,7.45; N,13.19 Examæle 4 4-Nitro-N- ~1, 2~diethyl 4-pyrazolidin~l ~benzamide ~ydrochloride.
To a solution of ~0.5 g (0.28 mole) of 4-amino-1,2-diethylpyraæolidine in 200 ml of chloroform was added 2S 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 wl~h 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.Prlalysis: Calcul~t2d for C1~H20N~O3: C,57~.52; H,6.90; N,19.17 Found : C,57.56; H,6.94; N,18.99 The base was converted to the hydrochloride salt and cr~stalli~ed from isopropyl alcohol which m~lted at 189-191C ~c.).
~, ~
~nalysis: Calculated for Cl~H~lN~03Cl: C,51.14; H,6.44; N,17.04 Found : C,50.96; H,6.59; N,16.58 Example 5 4-Amlno-N~1,2-diethyl~4-pyrazolidinyl)benzamlde.
A solution of 20 g. (0.06g 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 fil~ered, the filtrate concen-trated and the residue crystallized rom isopropyl ether-ethyl acetate. The product (12.0 g.; 66.5%) melted at llg~121C.
~nalysis: Calculated for Cl4~72N40: C,64.0g; H,8.45; N,21.36 Found : C,63.98; H,8.55; N,21.37 Example 6 _ 4-Amino-5-chloro~2-methox~-N-(1,2-diethyl-4-p~razolidi~y~benzamide.
To 75 ml. of thionyl chlor.ide was added 12 g. (0.05 mole) of 4-acetamido-5-chloro 2-methoxy-benzoic acid and the stirred suspension refluxed one hour. The re~ulting 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 chloro~orm and the solution added at a rapid drop ko 7 g. (0.05 mole) o 4-amino-1,2-diethylpyrazolidine in 100 ml. of chlorofo~ while stirxing and cooling to 20-25C. with an ice bath. After 30 minutes the chloro-form ~olution was e~tracted two times with 100 ml. of 3N
hydrochloric acid and the chloroform solution retained.
The acid extract was boi.led 10 minutes, cooled with ice, made basic with concentrated ~odium hydroxide while cooling and extracted with chloroform. The chloroform was dried ~sodium sulfate), concentra~ed and the residue crystallized from isopropyl ether-isooctane to give 3 g.
of material which melked at 116W118~C. The retained chloroform solution was extracted with dilute sodium ~r~
346~CIP-1 hydroxide and concentxated. The residue was dissolved in 3N hydrochloric acid and extracted with isopropyl ether. The acid solution was reflu~ed for 10 minutes, cooled with ice bath, made ~asic with ~odium hydroxide S while cooling and extracted with chloroform. The chloro-form was dried (sodium sulfate~ and concentrated. The re~idue was rystallize~ thr e 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-~ion of the melting point. The combined yield was 3.7 g.
(23%~. .
Analysis: Calculated for Cl5H23ClN402: C,55.13; H,7.09; N,17.14 Found : C,55.~3; H,7.10; N,17.17 Example 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, 4-methylbenzoyl chloride, ~-methoxybenzoyl chloride, 4-acetamidobenzoyl chloride, and 2-me~hoxy 5-sulfamoylbenzoyl chloride, there are obtained:
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-pyrazolidiny})~
benzamide, 4-acetamido-N-(1,2-dimethyl-4-pyrazolidinyl)-b~nzamide, and 2-methoxy-5-sulfamoyl~N~(1,2-dimethyl-4-pyrazolidinyl)benzamide.
. .
346-CIP-l Example 8 4 Amino-5-chlo.ro-2-me hoxy-N-1,2-dime~hyl-4-~yrazolidinylbenzamide.
A stirred solution of egual mol~r amounts of 4-amino~
5-chloro-2-metho~ybenzoic acid a~d triethylamine in methylene chloride (0-5C~ was trea~ed dropwise with a slight e~cess of ethylchlorocarbonate. After 1.0 hour a solution of 4-amino-1,2 dimethylpyrazolidine in methylene chloride was added and the mi~ture stirred for about two hours at room temperature. An aqueous solution of sodium bicarbonate was added to the reaction mixture, ~he organic phase separated and concentrated to give ~he pxoduct which melted at 169-171~C.
Example_9 4-Amino-5-chloro-2-methoxy-N-~l-ben2yl-2-methyl-4-pyrazolidinyl)benzamide Fum~rate.
4-Amino-S-chloro-2-me~hoxy-N-(l-benzyl~2-methyl-4-pyrazolidinyl)benzamide wa~ prepared from 4-amino-5-chloro-2-methoxybenzoic acid ~nd 4~amino-l~benzyl~2-methylpyrazolidine according to the procedure of Example 8. The fumarate salt was prepared and it melted at 12g-131C.
- - . , .
" ~ ~ 346-CIP-l lg Exampl~ 10 4-Amino-5-chloro~2-methoxy~N~ cyclohexyl-2-methyl-4-pyrazolidinyl)benzamide was prepared from 4-amino-5-chloro-2-methoxybenzoic acid and 4-amino-1-cyclohexyl-2-methylpyrazolidine according to ~he 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-methyl-4-p-yrazvlidinyl)benzamlde ~ihydrochloride.
4-Amino~5--chloro 2-methoxy-N~ 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 m~lted at 182-186C.
~5~i 3 ~ 346-CIP-l The pharmaceutical compositions of this invention comprise compounds of Formula I above in an amount to provide effective anti-emetîc and ~astric emptying action. 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 medicamerlt, advantageously from about 5 mg. to about 50 mg. per unit dose.
The pharmaceutical carrier employed in the composi tion can be either solid or li~aid. Exemplary of solid carriers are lactose, magnesi~n stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia. Exemplary of liguid carriers are vegetable oils and water. Similarly, the carrier or diluent may lS 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. ~hus, if a solid carrier is used the composition can be tableted or prepared as a powder, a troche or a lozenge. Gelatin capsules containing ~he 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 suspension or a syrup. Parenteral dosage forms are obtained by dissolving a water-sol~ble salt of the active agent in water or saline solution in a concentration ~uch that 1 cc. of the solution contains from 1.0 mg. to 25 mg. of active agent. The solution can be filled into single or multiple dose ampules.
The method in accordance with this invention comprises administerins internally to warm blooded animals includin~ human beings certain N-(4-pyrazolidinyl~benzamides or a non-toxic organic or inorganic acid addition salt thereof, preferably with a non-toxic pharmaceutical carrier such as descri~ed above, in an amount sufficient to control emesis and~or facilitate yastric emptying. I'he active agent is administered orally or parenterally in repeated doses until satisfactory response is obtained. The daily dosage is from about 10 mg. to about 300 mg. of active medicament, advantageously from about 5 mg. to 53 mg.
R solution of triphenyl phosphine t52 g.; 0.2 mole) in 150 ml. of chloroform was treated with chlorine gas which was accompanied by a rise in ~he temperature of the mixture to 60C. until excess chlorine yas app~ared 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 40~C.
Subsequent to the addition, the stirred solution was reflu~ed two hours, cooled to room temperature and extracted with water. The combined aqueous extracts were basified with concentrated sodium hydroxide solution and the basic mixture extracted with chloroform. The 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 C~Hl6N2Cl: C,51.68; H,9.29; H,17.22 Found : C,51.45; ~,9.30, H,17.29 PreParation 2 4-Amino-1,2-diethylpyrazolidi~e.
A mixture of I00 g. (0.615 mole) o~ 4-chloro~1,2-diethyl-pyrazolidine and 200 ml. of concentrated ~mmonium hydro~ide in a closed ~teel chambex was heated at 150C. for approximately 36 hours. The cooled reaction mixtuxe was extracted~with i~opropyl ether, the aqueous layer saturated with potassium carbona-te and continuously extracted with 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.
, - - : . .
P3~
Prepara~ion 3 4-Amino-1,2~dimethylpyrazolidlneO
-A mixture of 300 g. (2.22 mole) of 4-chloro-1,2-dimethylpyrazolidine and 600 ml. of conc. ammonium 5 hydroxide was heated at 150C. for 18 hrs. in a steel bomb. The cooled mixture was saturated wi~h potassium c:arbonate and continuously extracted for 18 hrs. with chlorofox~n. The residual material after concentration of the chloroform extract was distilled at 90-lOO~C./40 10 mm. to yive 73 g. of product.
Preparation 4 4-Anilino-1, 2-dimethylpyraæolidine .
A stirred suspension of 40 g . ( 1. 02 mole) of sodamide in dry toluene was treated dropwise with 116 g.
(1.0 mole) o~ 1,2-dimethyl-4 pyrazolidinol 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 reactiGn mixture was shaken with dilute sodium hydroxide, the separated toluene layer dried over sodium sulfate and concentrated a-t reduced pressure. The residue was dissolved in 300 ml. of aniline, the mixture heated 2 . 5 hrs . on the steam bath and ref}uxed for 3 . 0 hrs . The cooled mixture was extracted with dilute sodium hydroxide solution and the separated a;Lueous layer extracted with isopropyl ether.
The com~ined organic layers after drying over sodium sulfate were concentrated and the residue distilled to a pot temperature of 140C./80 mm. The residue which would not crystallize was distilled at 110-125C./0.1 mm. to give 86 g. of product.
Preparation 5 ilino-l,2-die hylpyr zolidine.
To a stirred suspensiorl of 7 . 9 g . t O . 2 mole ) of sodamide in 100 ml . of dxy toluene was added 28 . a g .
( 0 . 2 mole ) of 1, 2-diethyl-4-pyrazolidinol at a rate ~o ' ~ tf ~3 ~ 346~CIP-1 that a pot temperature of 30 ~5C. was maintained.
~fter ~tirring 2.0 hrs. at room temperature, ~he 601u-tion was added dropwise to a 601ution of 38.0 g. ~0.2 mole) of p-toluenesulfonyl chloride in 200 ml. of dry toluene with the pot temperatuxe maintained below 30C.
Ater stirring for abouk one hr. at room temperature, ~he reaction mi~ture was washed twice with water and dried over sodium sulfate. The dried filtered ~olution was concentrated to a volume of about 100 ml., aniline ~lO0 ml.) was added, the solu~ion refluxed for 3.0 hrs.
and then concentrated. The residue was partitioned between chloroform and dilute ~odium hydroxide. The dried chloroform layer was concentrated and the residue distilled at 1~0C./0.1 mm. to give 4.0 g. of product.
Preparation 6 1,2-Diethyl-4~phthalimido-pyrazolidine Ma ate.
To 100 ml. of dimethyl ~ulfoxide 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 ~olume 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 hydroch].oric acid and ethyl acetate. The acid layer was made basic with potassium carbonate and extracted w.ith chloroform. The chloroform waæ dried (sodium sulfate) and concentrated.
The residue (2~ 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 recrystalli~ed : twice from the ~ame solvent ~ystem to give 11.5 g. (15%) of product which melted at 144-147C.
Analysis: Calculated for ClgH23N306: C,$8.60; ~,5.95; N,10.79 Found : C,58.64; H,6.03; n,10.73 . ~ .
Preparation 7 4-Amino-l-benzyl-? methylpyrazolidine.
4~Amino i-benzyl~2-methylpyrazolidine, b.p. 115-125C./l.0 mm., was prepared from 1-benzyl-2-methyl-4-S pyrazolidinol according to preparations 1 and 2.
~=
4-~mino-1-cyclohexyl-2-methylpyrazolidine Fumarate.
4-Amino-1-cyclohe~yl-2-methylpyrazolidine, b.p.
90-100C./O.S-l.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~ opropyl-~-methy~yrazolidine.
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 amnlonium hydroxide is replaced by an equal molar amount of methylamine in methanol, there is obtained 4-methylamino-1,2-diethylpyrazolidine.
:
~' ;
f~5~7 346-CIP-l Exam~le 1 4-Chloro-N-phenyl-N-~1,2-dimethyl- -ny benzamide.
To a solution of 10 g. (0.0525 mole) of 1,2~dimethyl~
4-anilinopyrazolidine in 50 ml. of chloroform was added with stirring 9.15 g. (0~0525 mole) of p-chlorobenzoyl chloride with the temperature not exceeding 50C. On completion of addition the solution was refluxed for one hour~ cooled to room temperature and extracted with dilute ~odium hydroxide. ~he chlorofo~n layer was dried over sodi~n sulfate and concentrated at reduced pre~sure to give an oil which crystallized upon cooling, The solid was recrystallized twice from ligroin. Yield 13.1 g. (7~%); m.p. }04 108C. 5 Analysis: Calculaked for Cl8H~oClN30: 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-diethy~-4 pyrazolidlnyl)benz~ lde.
A solution of lO g. (O.026 mole) of 1,2~diethyl-4-phthalimidopyrazolidine maleate in ~5 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 ~vlution was made basic with dilute sodium hydroxide and cooled with ice. To the resulting solu-tion was added a . 2 g. (0.052 mole~ of p-fluorobenzoyl chloride and the mi.xture shaken for lO minutes. The resulting mixture was extracted with chloroform, the chlorofoYm diluted wi~h an equal volume of isopropyl ether and the resulting solution extracted with dilute hydrochloxic acid. The acid layer was made basic with dilute sodium hydroxide and extracted with chloroform.
The chloroform was dried (sodium sulf~ke) and concen-trated. The residue was crystalli2ed from isooctane-isopropyl ether and recrystallized from isooctane~isopropyl ether containing a few dxops of ethyl acetate '3~
346-CIP-l and clarified by charcoal txeatment. ~he product ~2.0 g; 29%) melted at 114-116C.
Analysis: Calculated for C14~2~N3OF: C,63.38; ~,1.6~; N,15.84 Found C,63.36; H,7.61; N,15.96 Example 3 3,4,5-Trimethoxy_N~ dimethyl-4-pyrazolidinyl ben2amide.
To 10 g (O.09 mole) of 4-amino~1,2-dimethylpyrazolidine in chloroform was added with ~tirring 20.7 ~. (0.09 mole) of 3,4,5-trimethoxybenzoyl chloride.
After 30 minutes of stirring the solution was extracted with dilute sodi~m h~droxide. The chloroform solution was dried ~sodium sulfate), filtered, and the filtrate - concentrated. The resulting crystalline material was recrystallized from equal port.ions of ethyl acetate and isopropyl ether. The product (12.1 g.; 44%) melted at 163-166C .
Analysis: Calculated for C15H23N3O~: C,58.24; H,7.49; N,13.58 Found : C,58.20; H,7.45; N,13.19 Examæle 4 4-Nitro-N- ~1, 2~diethyl 4-pyrazolidin~l ~benzamide ~ydrochloride.
To a solution of ~0.5 g (0.28 mole) of 4-amino-1,2-diethylpyraæolidine in 200 ml of chloroform was added 2S 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 wl~h 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.Prlalysis: Calcul~t2d for C1~H20N~O3: C,57~.52; H,6.90; N,19.17 Found : C,57.56; H,6.94; N,18.99 The base was converted to the hydrochloride salt and cr~stalli~ed from isopropyl alcohol which m~lted at 189-191C ~c.).
~, ~
~nalysis: Calculated for Cl~H~lN~03Cl: C,51.14; H,6.44; N,17.04 Found : C,50.96; H,6.59; N,16.58 Example 5 4-Amlno-N~1,2-diethyl~4-pyrazolidinyl)benzamlde.
A solution of 20 g. (0.06g 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 fil~ered, the filtrate concen-trated and the residue crystallized rom isopropyl ether-ethyl acetate. The product (12.0 g.; 66.5%) melted at llg~121C.
~nalysis: Calculated for Cl4~72N40: C,64.0g; H,8.45; N,21.36 Found : C,63.98; H,8.55; N,21.37 Example 6 _ 4-Amino-5-chloro~2-methox~-N-(1,2-diethyl-4-p~razolidi~y~benzamide.
To 75 ml. of thionyl chlor.ide was added 12 g. (0.05 mole) of 4-acetamido-5-chloro 2-methoxy-benzoic acid and the stirred suspension refluxed one hour. The re~ulting 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 chloro~orm and the solution added at a rapid drop ko 7 g. (0.05 mole) o 4-amino-1,2-diethylpyrazolidine in 100 ml. of chlorofo~ while stirxing and cooling to 20-25C. with an ice bath. After 30 minutes the chloro-form ~olution was e~tracted two times with 100 ml. of 3N
hydrochloric acid and the chloroform solution retained.
The acid extract was boi.led 10 minutes, cooled with ice, made basic with concentrated ~odium hydroxide while cooling and extracted with chloroform. The chloroform was dried ~sodium sulfate), concentra~ed and the residue crystallized from isopropyl ether-isooctane to give 3 g.
of material which melked at 116W118~C. The retained chloroform solution was extracted with dilute sodium ~r~
346~CIP-1 hydroxide and concentxated. The residue was dissolved in 3N hydrochloric acid and extracted with isopropyl ether. The acid solution was reflu~ed for 10 minutes, cooled with ice bath, made ~asic with ~odium hydroxide S while cooling and extracted with chloroform. The chloro-form was dried (sodium sulfate~ and concentrated. The re~idue was rystallize~ thr e 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-~ion of the melting point. The combined yield was 3.7 g.
(23%~. .
Analysis: Calculated for Cl5H23ClN402: C,55.13; H,7.09; N,17.14 Found : C,55.~3; H,7.10; N,17.17 Example 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, 4-methylbenzoyl chloride, ~-methoxybenzoyl chloride, 4-acetamidobenzoyl chloride, and 2-me~hoxy 5-sulfamoylbenzoyl chloride, there are obtained:
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-pyrazolidiny})~
benzamide, 4-acetamido-N-(1,2-dimethyl-4-pyrazolidinyl)-b~nzamide, and 2-methoxy-5-sulfamoyl~N~(1,2-dimethyl-4-pyrazolidinyl)benzamide.
. .
346-CIP-l Example 8 4 Amino-5-chlo.ro-2-me hoxy-N-1,2-dime~hyl-4-~yrazolidinylbenzamide.
A stirred solution of egual mol~r amounts of 4-amino~
5-chloro-2-metho~ybenzoic acid a~d triethylamine in methylene chloride (0-5C~ was trea~ed dropwise with a slight e~cess of ethylchlorocarbonate. After 1.0 hour a solution of 4-amino-1,2 dimethylpyrazolidine in methylene chloride was added and the mi~ture stirred for about two hours at room temperature. An aqueous solution of sodium bicarbonate was added to the reaction mixture, ~he organic phase separated and concentrated to give ~he pxoduct which melted at 169-171~C.
Example_9 4-Amino-5-chloro-2-methoxy-N-~l-ben2yl-2-methyl-4-pyrazolidinyl)benzamide Fum~rate.
4-Amino-S-chloro-2-me~hoxy-N-(l-benzyl~2-methyl-4-pyrazolidinyl)benzamide wa~ prepared from 4-amino-5-chloro-2-methoxybenzoic acid ~nd 4~amino-l~benzyl~2-methylpyrazolidine according to the procedure of Example 8. The fumarate salt was prepared and it melted at 12g-131C.
- - . , .
" ~ ~ 346-CIP-l lg Exampl~ 10 4-Amino-5-chloro~2-methoxy~N~ cyclohexyl-2-methyl-4-pyrazolidinyl)benzamide was prepared from 4-amino-5-chloro-2-methoxybenzoic acid and 4-amino-1-cyclohexyl-2-methylpyrazolidine according to ~he 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-methyl-4-p-yrazvlidinyl)benzamlde ~ihydrochloride.
4-Amino~5--chloro 2-methoxy-N~ 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 m~lted at 182-186C.
~5~i 3 ~ 346-CIP-l The pharmaceutical compositions of this invention comprise compounds of Formula I above in an amount to provide effective anti-emetîc and ~astric emptying action. 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 medicamerlt, advantageously from about 5 mg. to about 50 mg. per unit dose.
The pharmaceutical carrier employed in the composi tion can be either solid or li~aid. Exemplary of solid carriers are lactose, magnesi~n stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin or acacia. Exemplary of liguid carriers are vegetable oils and water. Similarly, the carrier or diluent may lS 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. ~hus, if a solid carrier is used the composition can be tableted or prepared as a powder, a troche or a lozenge. Gelatin capsules containing ~he 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 suspension or a syrup. Parenteral dosage forms are obtained by dissolving a water-sol~ble salt of the active agent in water or saline solution in a concentration ~uch that 1 cc. of the solution contains from 1.0 mg. to 25 mg. of active agent. The solution can be filled into single or multiple dose ampules.
The method in accordance with this invention comprises administerins internally to warm blooded animals includin~ human beings certain N-(4-pyrazolidinyl~benzamides or a non-toxic organic or inorganic acid addition salt thereof, preferably with a non-toxic pharmaceutical carrier such as descri~ed above, in an amount sufficient to control emesis and~or facilitate yastric emptying. I'he active agent is administered orally or parenterally in repeated doses until satisfactory response is obtained. The daily dosage is from about 10 mg. to about 300 mg. of active medicament, advantageously from about 5 mg. to 53 mg.
Claims (30)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing N-(4-pyrazolidinyl)benzamides of the formula (I) and pharmaceutically acceptable acid addition salts thereof wherein;
R is lower alkyl, lower cycloalkyl or phenyllower alkyl, R1 is lower alkyl, lower cycloalkyl or phenyllower alkyl, R2 is hydrogen, lower alkyl or phenyl, R3 is hydroxy, cyano, nitro, amino, fluoro, chloro, bromo, trifluoromethyl, lower alkyl, lower alkoxy, sulfamoyl or acetamido and R3 can be the same radical or different radicals, and n is an integer from zero to three inclusive, which comprises:
(a) reacting a compound of formula (II) with a compound of formula III
wherein R, R1, R2, and n are as defined above, R3 is as defined above other than primary amino, and X is halogen; or (b) reacting a compound of formula II as defined above with a mixed anhydride which is the product of reaction between a compound of formula IV
wherein R3 is as defined for formula I above, and ethylchlorocarbonate, (c) hydrolysing a compound of formula I as defined above wherein R3 is acetamido; or (d) reducing a compound of formula I as defined above wherein R3 is cyano;
and, if required, converting the compound of formula I into a pharmaceutically acceptable acid addition salt.
R is lower alkyl, lower cycloalkyl or phenyllower alkyl, R1 is lower alkyl, lower cycloalkyl or phenyllower alkyl, R2 is hydrogen, lower alkyl or phenyl, R3 is hydroxy, cyano, nitro, amino, fluoro, chloro, bromo, trifluoromethyl, lower alkyl, lower alkoxy, sulfamoyl or acetamido and R3 can be the same radical or different radicals, and n is an integer from zero to three inclusive, which comprises:
(a) reacting a compound of formula (II) with a compound of formula III
wherein R, R1, R2, and n are as defined above, R3 is as defined above other than primary amino, and X is halogen; or (b) reacting a compound of formula II as defined above with a mixed anhydride which is the product of reaction between a compound of formula IV
wherein R3 is as defined for formula I above, and ethylchlorocarbonate, (c) hydrolysing a compound of formula I as defined above wherein R3 is acetamido; or (d) reducing a compound of formula I as defined above wherein R3 is cyano;
and, if required, converting the compound of formula I into a pharmaceutically acceptable acid addition salt.
2. A process according to claim 1 wherein process (c) or (d) is used and the starting material of formula I is obtained by process (a) or (b) of claim 1.
3. A process according to claim 1 wherein the compound of formula II
is obtained by hydrolysing a 1,2-hydrocarbyl-4-phthalimidopyrazolidine which is substituted in the 1- and 2-positions by substituents R and R1, respect-ively.
is obtained by hydrolysing a 1,2-hydrocarbyl-4-phthalimidopyrazolidine which is substituted in the 1- and 2-positions by substituents R and R1, respect-ively.
4. A process according to claim l wherein the compound of formula II
in which R2 is hydrogen or lower alkyl is obtained by reacting a compound of formula V
V
wherein R and R1 are as defined above, with ammonia or a lower alkylamine under pressure and at elevated temperature.
in which R2 is hydrogen or lower alkyl is obtained by reacting a compound of formula V
V
wherein R and R1 are as defined above, with ammonia or a lower alkylamine under pressure and at elevated temperature.
5. A process according to claim 1 wherein the compound of formula II
is obtained by reacting a compound of formula VI
VI
wherein R and R1 are as defined above and R6 is an arylsulfonyloxy radical, with an aniline, to obtain a compound of formula II wherein R2 is a phenyl group.
is obtained by reacting a compound of formula VI
VI
wherein R and R1 are as defined above and R6 is an arylsulfonyloxy radical, with an aniline, to obtain a compound of formula II wherein R2 is a phenyl group.
6. A process according to claim 1 wherein process (b) is used and the mixed anhydride is prepared by reacting the compound oE formula IV with ethyl chlorocarbonate in the presence of triethylamine.
7. A compound of formula I as defined in claim 1, or a pharmaceutical-ly acceptable acid additlon salt thereof, whenever prepared by a process according to claim 1, or by an obvious chemical equivalent thereof.
8. A process according to claim 1 wherein R and R1 are both methyl, R2 is phenyl, n is one and R3 is chlorine in the 4-position.
9. A process for preparing 4-chloro-N-phenyl-N-(1,2-dimethyl-4-pyrazolidinyl)-benzamide which comprises reacting 1,2-dimethyl-4-anilino-pyrazolidine with p-chlorobenzoyl chloride.
10. A process according to claim 1 wherein R and R1 are both ethyl, R2 is hydrogen, n is one and R3 is fluorine in the 4-position.
11. A process for preparing 4-fluoro-N-(1,2-diethyl-4-pyrazolidinyl)-benzamide which comprises hydrolysing 1,2-diethyl-4-phthalimidopyrazolidine and reacting the resulting product with p-fluorobenzoyl chloride.
12. A process according to claim 1 wherein R and R1 are both ethyl, R2 is hydrogen, n is three and the values of R3 are amino in the 4-position, chloro in the 5-position and methoxy in the 2-position.
13. A process for preparing 4-amino-5-chloro-2-methoxy-N-(1,2-diethyl-4-pyrazolidinyl)benzamide which comprises reacting 4-acetamido-5-chloro-2-methoxy benzoic acid and 4-amino-1,2-diethylpyrazolidine and hydrolysing the resulting product.
14. A process for preparing 4-amino-5-chloro-2-methoxy-N-(1,2-diethyl-4-pyrazolidinyl)benzamide which comprises hydrolysing 4-acetamido-5-chloro-2-methoxy-N-(1,2-diethyl-4-pyrazolidinyl)benzamide.
15. A process according to claim 14 wherein the 4-acetamido-5-chloro-2-methoxy-N-(1,2-diethyl-4-pyrazolidinyl)benzamide is prepared by reacting 4-acetamido-5-chloro-2-methoxy-benzoic acid with 4-amino-1,2-diethylpyrazoli-dine.
16. A process according to claim 1 wherein R and R1 are both methyl, R2 is hydrogen, n is three and the values of R3 are amino in the 4-position, chloro in the 5-position and methoxy in the 2-position.
17. A process for preparing 4-amino-5-chloro-2-methoxy-N-(1,2-dimethyl-4-pyrazolidinyl)benzamide which comprises reacting the reaction product of 4-amino-5-chloro-2-metiloxybenzoic acid and ethylchlorocarbonate with 4-amino-1,2-dimethylpyrazolidine.
18. A process according to claim 1 wherein R is benzyl, R1 is methyl, R2 is hydrogen, n is three and the values of R3 are amino in the 4-position, chloro in the 5-position and methoxy in the 2-position.
19. A process according to claim 1, for preparing 4-amino-5-chloro-2-methoxy-N-(1-benzyl-2-methyl-4-pyrazolidinyl)benzamide and its fumarate salt which comprises reacting 4-amino-5-chloro-2-methoxy-benzoic acid with 4-amino-1-benzyl-2-methylpyrazolidine and, if the fumarate salt is required, reacting the product with fumaric acid.
20. A process according to claim 1 wherein R is cyclohexyl, R1 is methyl, R2 is hydrogen, n is 3 and the values of R3 are amino in the 4-position, chloro in the 5-position and methoxy in the 2-position.
21. A process for preparing 4-amino-5-chloro-2-methoxy-N-(1-cyclohexyl-2-methyl-4-pyrazolidinyl)benzamide which comprises reacting the reaction product of 4-amino-5-chloro-2-methoxy-benzoic acid and ethylchlorocarbonate with 4-amino-1-cyclohexyl-2-methylpyrazolidine.
22. A process according to claim 1 wherein R is isopropyl, R1 is methyl, R2 is hydrogen, n is 3 and the values of R3 are amino in the 4-position, chloro in the 5-position and methoxy in the 2-position.
23. A process for preparing 4-amino-5-chloro-2-methoxy-N-(1-isopropyl-2-methyl-4-pyrazolidinyl)benzamide and its dihydrochloride salt which com-prises reacting 4-amino-5-chloro-2-methoxy-benzoic acid with 4-amino-1-isopropyl-2-methylpyrazolidine and, if the dihydrochloride salt is required, reacting the product with hydrochloric acid.
24. 4-Chloro-N-phenyl-N-(1,2-dimethyl-4-pyrazolidinyl)benzamide thereof whenever prepared by a process according to claim 9, or by an obvious chemical equivalent thereof.
25. 4-Fluoro-N-(1,2-diethyl-4-pyrazolidinyl)benzamide whenever prepared by a process according to claim 11, or by an obvious chemical equivalent thereof.
26. 4-Amino-5-chloro-2-methoxy-N-(1,2-diethyl-4-pyrazolidinyl)benzamide whenever prepared by a process according to claim 13, 14 or 15, or by an obvious chemical equivalent thereof.
27. 4-Amino-5-chloro-2-methoxy-N-(1,2-dimethyl-4-pyrazolidinyl)-benzamide whenever prepared by a process according to claim 17, or by an obvious chemical equivalent thereof.
28. 4-Amino-5-chloro-2-methoxy-N-(1-cyclohexyl-2-methyl-4-pyrazolidinyl)-benzamide thereof whenever prepared by a process according to claim 21, or by an obvious chemical equivalent thereof.
29. 4-Amino-5-chloro-2-methoxy-N-(1-benzyl-2-methyl-4-pyrazolidinyl)-benzamide and its fumarate, whenever prepared by a process according to claim 19 or by an obvious chemical equivalent thereof.
30. 4-Amino-5-chloro-2-methoxy-N-(1-isopropyl-2-methyl-4-pyrazolidinyl)-benzamide and its dihydrochloride, whenever prepared by a process according to claim 23 or by an obvious chemical equivalent thereof.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA362,371A CA1109880A (en) | 1977-08-19 | 1980-10-14 | N-(4-pyrazolidinyl) benzamides |
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
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US82603177A | 1977-08-19 | 1977-08-19 | |
US826,031 | 1977-08-19 | ||
US90036978A | 1978-04-26 | 1978-04-26 | |
US900,369 | 1978-04-26 | ||
US93012578A | 1978-08-01 | 1978-08-01 | |
US930,125 | 1992-08-14 |
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CA1105037A true CA1105037A (en) | 1981-07-14 |
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CA309,651A Expired CA1105037A (en) | 1977-08-19 | 1978-08-18 | N-(4-pyrazolidinyl) benzamides |
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JP (1) | JPS5441873A (en) |
AU (1) | AU521421B2 (en) |
BR (1) | BR7805288A (en) |
CA (1) | CA1105037A (en) |
CH (2) | CH639374A5 (en) |
DE (1) | DE2836062A1 (en) |
DK (1) | DK152361C (en) |
ES (1) | ES472686A1 (en) |
FI (1) | FI68044C (en) |
FR (1) | FR2400511A1 (en) |
GB (2) | GB2017678B (en) |
HK (1) | HK42282A (en) |
IE (1) | IE47430B1 (en) |
MX (1) | MX5469E (en) |
NL (1) | NL7808596A (en) |
NO (1) | NO149107C (en) |
NZ (1) | NZ188189A (en) |
PH (1) | PH13331A (en) |
PT (1) | PT68442A (en) |
SE (2) | SE444434B (en) |
YU (1) | YU41116B (en) |
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US4309552A (en) * | 1980-08-07 | 1982-01-05 | A. H. Robins Company, Inc. | Synthesis of 4-nitro-1,2-hydrocarbyl pyrazolidines and process for preparation thereof |
US5126343A (en) * | 1989-09-11 | 1992-06-30 | G. D. Searle & Co. | N-azabicyclo [3.3.0]octane amides of aromatic acids |
JP3065506B2 (en) * | 1995-04-03 | 2000-07-17 | 株式会社資生堂 | Pyrazolidine derivative and radical scavenger, cerebral infarction inhibitor, cerebral edema inhibitor |
AR086587A1 (en) | 2011-05-31 | 2014-01-08 | Syngenta Participations Ag | INSECTICIDE COMPOUNDS |
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US3966957A (en) * | 1972-04-03 | 1976-06-29 | A. H. Robins Company, Incorporated | Method for controlling emesis with N-(1-substituted-3-pyrrolidinyl)benzamides and thiobenzamides |
-
1976
- 1976-08-14 PH PH21489A patent/PH13331A/en unknown
-
1978
- 1978-08-15 CH CH867478A patent/CH639374A5/en not_active IP Right Cessation
- 1978-08-16 FI FI782507A patent/FI68044C/en not_active IP Right Cessation
- 1978-08-16 SE SE7808694A patent/SE444434B/en not_active IP Right Cessation
- 1978-08-17 DE DE19782836062 patent/DE2836062A1/en not_active Withdrawn
- 1978-08-17 BR BR7805288A patent/BR7805288A/en unknown
- 1978-08-17 GB GB7901821A patent/GB2017678B/en not_active Expired
- 1978-08-17 GB GB7833696A patent/GB2003153B/en not_active Expired
- 1978-08-18 NZ NZ188189A patent/NZ188189A/en unknown
- 1978-08-18 ES ES472686A patent/ES472686A1/en not_active Expired
- 1978-08-18 PT PT68442A patent/PT68442A/en unknown
- 1978-08-18 CA CA309,651A patent/CA1105037A/en not_active Expired
- 1978-08-18 FR FR7824138A patent/FR2400511A1/en active Granted
- 1978-08-18 IE IE1682/78A patent/IE47430B1/en unknown
- 1978-08-18 AU AU39061/78A patent/AU521421B2/en not_active Expired
- 1978-08-18 NL NL7808596A patent/NL7808596A/en not_active Application Discontinuation
- 1978-08-18 MX MX787322U patent/MX5469E/en unknown
- 1978-08-18 NO NO782812A patent/NO149107C/en unknown
- 1978-08-18 DK DK366978A patent/DK152361C/en not_active IP Right Cessation
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- 1978-08-19 JP JP10136878A patent/JPS5441873A/en active Granted
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1982
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