CA1047504A - N-(2-pyrrolidinyl alkyl) substitutes and derivatives thereof - Google Patents
N-(2-pyrrolidinyl alkyl) substitutes and derivatives thereofInfo
- Publication number
- CA1047504A CA1047504A CA221,240A CA221240A CA1047504A CA 1047504 A CA1047504 A CA 1047504A CA 221240 A CA221240 A CA 221240A CA 1047504 A CA1047504 A CA 1047504A
- Authority
- CA
- Canada
- Prior art keywords
- methoxy
- group
- pyrrolidinylmethyl
- amino
- hydrogen atom
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
- C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
- C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
-
- 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
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
Abstract
A B S T R A C T
The invention relates to novel N-(2-pyrrolidinyl-alkyl)benzamides of the formula:
The invention relates to novel N-(2-pyrrolidinyl-alkyl)benzamides of the formula:
Description
7~Q~
The present invention concerns novel substituted N--(2-pyrrolidinylalkyl)benzamides of general formula I, their pharmaceutically acceptable acid addition salts, their quaternary ammonium salts, their dextrorotatory and levo-rotatory isomers, and the process for the preparation thereof.
The benzamides of the present invention have the following formula:
(CH2)m CO - NH - W ~ N J
~ H (I) in which:
A represents a hydrogen atom, a Cl 5 alkyl group or a C2 5 alkenyl group;
X represents a hydrogen atom, a Cl 5 alkoxy group, a Cl 5 alkyl group, a C2 5 alkenyloxy group or a C2 5 alkenyl group;
Y represents a hydrogen atom, a halogen atom, a Cl 5 alkyl, Cl 5 alkoxy, amino, or amino substituted group, such as alkylamino, acylamino, benzylamino, or alkoxycarbonylamino;
Z represents a hydrogen atom, a halogen atom, a Cl 5 alkoxy group, a Cl 5 alkylsulfonyl group, or a S02NRlR2 group in which Rl and R2 which can be identical or different are hydrogen or a Cl 5 lower alkyl group, or together with the nitrogen atom to which they are attached form a heterocycle, possibly containing another heteroatom;
l.n~s~
W represents an alkylene group having from 1 to 4 carbon atoms which can form a straight or branched chain, and m represents an integer of 1, 2 or 3.
The benzamides of the present invention can be prepared by the reaction of a compound having the formula:
COB
~ OA
ZJ~LX ( I I ) in which:
B represents a halogen group, a hydroxy group or an organic residue;
A, X, Y, Z are as def;ned above, on a dextrorotatory, levorotatory or racemic amine having the formula:
I_(CH2 )m ( I I I ) H2N-W--~ J
in which:
W, m are as defined above;
R3 represents a benzyl group or a hydrogen atom, or by reaction of their reactive derivatives.
Of the amino substituted groups represented by Y, alkyl amino can be selected from the mono or dialkylamino Cl 5 groups, and acylamino can be selected from the acetamido, formamido, propionamido, butyramido, benzamido, phthalimido~
etc groups.
In the case where R3 is a benzyl group, this is converted into hydrogen atom by catalytic reduction by means ~ ~47504 of hydrogen in the presence of catalysts such as Raney nickel, palladium-bearing carbon, platinum black, etc. The hydrogen-ation pressure used varies from atmospheric pressure to 200 atmospheres.
In the starting compound (II), the organic residue includes groups capable of forming acid reactive derivatives.
These can be carboxylic esters such as methyl, ethyl, propyl, butyric, isobutyric, pentanoic, etc. esters, reactive acid esters such as cyanomethyl or methoxymethyl esters, or N-hydroxyimide esters, or substituted or unsubstituted aromaticesters; acid hydrazides; acid azides; symmetrical anhydrides;
mixed anhydrides, for example formed with lower alkyl halo-formiates; azolides such as triazolides, tetrazolides or imidazolides; or acid isocyanates. The invention however is not limited to the derivatives listed above.
According to the process of the invention, the following compounds can be used as reactive derivatives of the amine (III): the products of reaction of the amine with phosphorus chlorides, phosphorus oxychloride, dialkyl, diaryl or orthophenylenechlorophosphites, alkyl or aryl dichloro-phosphites, or the isothiocyanate of the amine. The reactive derivatives listed above can react with the acid in situ or after having first been isolated.
It is also possible to carry out the reaction of the free acid and the free amine in the presence of a condensing agent such as silicon tetrachloride, phosphoric anhydride or a carbodiimide such as dicyclohexyl carbodiimide.
The amidification reaction of the invention can be carried out in the presence or in the absence of solvent. The systems used as a solvent, which are inert with respect to the amidification reaction, are for example alcohols, polyols, benzene, toluene, dioxan, chloroform, diethyleneglycol ~ U~7~Q4 dimethylether. It is also possible to use as a solvent an excess of the amine used as the starting material. It may be preferable to heat the reaction mixture during amidification, for example to the boiling point of the solvents listed above.
The compound produced according to the process of the invention can react if necessary with pharmaceutically acceptable mineral or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric ac;d, phosphoric acid, acetic acid, tartric acid, citric acid or methane sulfonic acid, to give acid addition salts. It can also react if necessary with alkyl sulfates or halides, to give quaternary ammonium salts.
The benzamides of the invention have attractive therapeutic properties, in particular as anti-e~etics, anti-ulcer agents and agents for modifying the central nervous system. Their low level of toxicity is compatible with use in human therapy, without the danger of causing side effects.
In order to illustrate the technical characteristics of the present invention, some embodiments will now be described, it being apparent that these are not limiting on the invention as regards the manner in which they are per-formed and the uses to which they can be put.
N-(2'-pyrrolidinylmethyl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride 51.5 9 of methyl 2-methoxy-4-acetamido-5-chloro-benzoate, 20 ml of water and 40 9 of 2-aminomethylpyrrolidine were introduced into a balloon flask provided with a stirrer, a thermometer and a condenser. The mixture was heated for 7 hours at reflux temperature, and then cooled. After the addition of 50 ml of water and 50 ml of 40% sodium hydroxide lye, the mixture was heated for 2 hours at reflux temperature.
The crystals formed by cooling were washed with water and ~ ~247S(.~
dr-ied in a drying oven at 50C. 32 9 of benzamide was obtained, in the form of a base.
The hydrochloride was formed by dissolution of the base in alcohol at boiling temperature, filtration in the hot state and addition of hydrochloric acid (d 1.18). The crystals formed by cooling were filtered, washed with ethanol and dried in a drying oven at 50C. 24.2 9 of N-(2'-pyrroli-dinylmethyl)-2-methoxy-4-amino-5-chlorobenzamidehydrochloride was produced (melting point: 167C).
N-(2'-pyrrolidinylmethyl)-2-methoxy-4-amino-5-sulfamoyl-benzamide 140 9 of methyl 2-methoxy-4-amino-5-sulfamoyl-benzoate, 48.5 ml of water and 80 9 of 2-aminomethylpyrrolidine were introduced into a 1 litre balloon flask provided with a condenser. The suspension obtained was heated in a water bath.
After cooling the reaction mixture was diluted with 540 ml of water. The solid formed was drained, washed with water and dried at 45C.
The base produced was purified by conversion to the hydrochloride and re-precipitation with 20% ammonia, then drained, washed and dried at 50C. 97 9 of N-(2'-pyrrolidinyl-methyl)-2-methoxy-4-amino-5-sulfamoylbenzamide was produced (yield: 54.8%; melting point: 205-206C).
N-(2'-pyrrolidinylmethyl)-2-methoxy-5-ethylsulfonylbenzamide 130 9 of N-benzyl-2-aminomethylpyrrolidine, 620 ml of methylethylketone, then with the temperature being main-tained at from 5 to 10C, 162.6 9 of 2-methoxy-5-ethylsulfonyl-benzoylchloride were introduced into a 2 litre balloon flask provided with a stirrer, a condenser and a thermometer.
Stirring of the mixture was continued without heating for 1 1~475~4 hour. The solid formed was filtered, washed with a little methylethylketone and then dissolved in hot ethanol. The crystals obtained on cooling were f;ltered, washed, dried and then introduced into a 1 litre autoclave with 500 ml of water, 150 g of Raney nickel and hydrogen, until a pressure of 170 kg was obtained. The mixture was heated for 4 hours at 100C;
after cooling, the nickel was filtered and rinsed with water.
The solvents were evaporated under reduced pressure; the residue was treated by means of a mixture of 25 ml of 36%
hydrochloric acid and water, until 500 ml of solution was obtained. After heating at 80C, and filtration, the medium was rendered alkaline by means of 40% sodium hydroxide. The crystals obtained after cooling were filtered, washed with water and dried. 111.5 g of N-(2'-pyrrolidinylmethyl)-2-methoxy-5-ethylsulfonylbenzamide was obtained (yield: 70.3%;
melting point: 150C).
N-(2'-pyrrolidinylmethyl)-2-methoxy-4-aminobenzamide A solution of 1.4 9 of phosphorus trichloride in 8 ml of pyridine was poured dropwise, and with the temperature being maintained at from 0 to 5C, with stirring, into a solution of 2 9 of 2-aminomethylpyrrolidine in pyridine.
Stirring was continued at from 0 to 5C, and then at ambient temperature. After the addition of 1.6 g of 2-methoxy-4-aminobenzoid acid, the mixture was heated with stirring for several hours.
- After the mixture had been cooled and the solvent removed, the residue was dissolved in chloroform, then the solution was washed with aqueous sodium carbonate and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 1.5 9 of N-(2'-pyrrolidinylmethyl)-2-methoxy-lS.~4~ 4 4-aminobenzamide was produced (yield: 62.8%; melting point:
98C).
N-(2'-pyrrolidinylmethyl)-2-methoxy-5-methylsulfonylbenzamide 750 ml of methylethyl ketone, 103 9 of N-benzyl-2-aminomethylpyrrolidine and then, with the temperature being maintained at 15 to 20, 133 9 of 2-methoxy-5-methylsulfonyl-benzoylchloride were introduced into a balloon flask provided with a mechanical stirrer and a thermometer. Stirring of the reaction mixture was maintained for 2 hours at ambient temper-ature. The solid formed was drained and treated with ice-cold methylethyl ketone, then dissolved in hot ethanol. The crystals obtained upon cooling were filtered, washed, dried and then introduced into a 5 litre autoclave with 1 litre of water and 20 9 of Raney nickel. After the usual purging operations, hydrogen was introduced to a pressure of 130 kg and the mixture was heated at 100C for 4 hours.
After cooling, the nickel was filtered and washed.
The solvents were then evaporated under vacuum. The residue was treated with water and hydrochloric acid until a volume of 500 ml was obtained. The solution formed was heated at 80C, filtered and rendered alkaline by means of sodium hydroxide.
After cooling, the crystals formed were filtered, washed with water and dried. 98 9 of N-(2'-pyrrolidinylmethyl)-2-methoxy-5-methylsulfonylbenzamide was produced (yield: 68.9%; melting point: 152.5C).
N-(2'-pyrrolidinylmethyl)-2-methoxy-5-ethylsulfonylbenzamide 7.3 9 of 2-methoxy-5-ethylsulfonyl benzoic acid, 200 ml of tetrahydrofuran, and 7.3 9 of carbonyldiimidazole were introduced into a balloon flask provided with a stirrer and a condenser.
75(~4 After the mixture had been stirred at ambient temper-ature for 30 minutes, 4.8 9 of 2-aminomethylpyrrolid;ne was added. Stirring of the mixture was continued at ambient temperature, and then the solvent was evaporated under vacuum.
The residue was dissolved in hydrochloric acid and the solution obtained was filtered and then treated with sodium hydroxide until the pH-value was 12-13. The mixture was extracted with chloroform. After drying and filtration, the solvent was evaporated under vacuum. After purification in ethanol, 6.5 9 10 of N-(2'-pyrrolidinylmethyl)-2-methoxy-5-ethylsulfonylbenzamide was obtained (yield: 66.5%; melting point: 150C).
N-(2'-pyrrolidinylmethyl)-2,3-dimethoxy-5-sulfamoylbenzamide-hvdrochloride -1 litre of acetone and 200 9 of N-benzyl-2-amino-methylpyrrolidine were introduced into a 4 litre balloon flask provided with a mechanical stirrer and a thermometer. The mixture was cooled to 0C and 280 9 of 2,3-dimethoxy-5-sulfamoylbenzoylchloride was added, the temperature of the 20 reaction medium being kept below 10C.
The mixture was then stirred for 4 hours. The precipitate formed was drained, washed over a filter with acetone and then introduced into an autoclave with 1200 ml of water, 40 ml of hydrochloric acid (d = 1.18) and 5 spoonfuls of Raney nickel.
After the usual purge operations, hydrogen was intro-duced to give a pressure of 140 kg. The mixture was heated at 100C for 4 hours. After cooling the nickel was filtered and the mixture was rendered alkaline with 150 ml of ammonia. The 30 precipitate obtained was filtered and dried, then dissolved at boiling temperature in 150 ml of absolute ethanol and acidified with 40 ml of hydrochloric ethanol. The crystals obtained by ~ ~47504 cooling were filtered, washed and dried at 5QC. 95 9 of N-(2'-pyrrolidinylmethyl)-2,3-dimethoxy-5-sulfamoylbenzamide-hydrochloride was produced (melting point: 195-198C).
N-(2'-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide 51.8 9 of ethyl 2-methoxy-5-sulfamoylbenzoate, 24 9 of 2-aminomethylpyrrolidine and 200 ml of butanol were intro-duced into a 1 litre balloon flask.
The mixture was heated for 7 hours at reflux temper-ature. After cooling, and evaporation under vacuum of thesolvent, the residue was recrystallized from dimethylformamide.
51 9 of benzamide was produced (yield: 73%).
A second recrystallization step provided 43 9 of N-(2'-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide (yield: 61.5%; melting point: 185C).
The present invention concerns novel substituted N--(2-pyrrolidinylalkyl)benzamides of general formula I, their pharmaceutically acceptable acid addition salts, their quaternary ammonium salts, their dextrorotatory and levo-rotatory isomers, and the process for the preparation thereof.
The benzamides of the present invention have the following formula:
(CH2)m CO - NH - W ~ N J
~ H (I) in which:
A represents a hydrogen atom, a Cl 5 alkyl group or a C2 5 alkenyl group;
X represents a hydrogen atom, a Cl 5 alkoxy group, a Cl 5 alkyl group, a C2 5 alkenyloxy group or a C2 5 alkenyl group;
Y represents a hydrogen atom, a halogen atom, a Cl 5 alkyl, Cl 5 alkoxy, amino, or amino substituted group, such as alkylamino, acylamino, benzylamino, or alkoxycarbonylamino;
Z represents a hydrogen atom, a halogen atom, a Cl 5 alkoxy group, a Cl 5 alkylsulfonyl group, or a S02NRlR2 group in which Rl and R2 which can be identical or different are hydrogen or a Cl 5 lower alkyl group, or together with the nitrogen atom to which they are attached form a heterocycle, possibly containing another heteroatom;
l.n~s~
W represents an alkylene group having from 1 to 4 carbon atoms which can form a straight or branched chain, and m represents an integer of 1, 2 or 3.
The benzamides of the present invention can be prepared by the reaction of a compound having the formula:
COB
~ OA
ZJ~LX ( I I ) in which:
B represents a halogen group, a hydroxy group or an organic residue;
A, X, Y, Z are as def;ned above, on a dextrorotatory, levorotatory or racemic amine having the formula:
I_(CH2 )m ( I I I ) H2N-W--~ J
in which:
W, m are as defined above;
R3 represents a benzyl group or a hydrogen atom, or by reaction of their reactive derivatives.
Of the amino substituted groups represented by Y, alkyl amino can be selected from the mono or dialkylamino Cl 5 groups, and acylamino can be selected from the acetamido, formamido, propionamido, butyramido, benzamido, phthalimido~
etc groups.
In the case where R3 is a benzyl group, this is converted into hydrogen atom by catalytic reduction by means ~ ~47504 of hydrogen in the presence of catalysts such as Raney nickel, palladium-bearing carbon, platinum black, etc. The hydrogen-ation pressure used varies from atmospheric pressure to 200 atmospheres.
In the starting compound (II), the organic residue includes groups capable of forming acid reactive derivatives.
These can be carboxylic esters such as methyl, ethyl, propyl, butyric, isobutyric, pentanoic, etc. esters, reactive acid esters such as cyanomethyl or methoxymethyl esters, or N-hydroxyimide esters, or substituted or unsubstituted aromaticesters; acid hydrazides; acid azides; symmetrical anhydrides;
mixed anhydrides, for example formed with lower alkyl halo-formiates; azolides such as triazolides, tetrazolides or imidazolides; or acid isocyanates. The invention however is not limited to the derivatives listed above.
According to the process of the invention, the following compounds can be used as reactive derivatives of the amine (III): the products of reaction of the amine with phosphorus chlorides, phosphorus oxychloride, dialkyl, diaryl or orthophenylenechlorophosphites, alkyl or aryl dichloro-phosphites, or the isothiocyanate of the amine. The reactive derivatives listed above can react with the acid in situ or after having first been isolated.
It is also possible to carry out the reaction of the free acid and the free amine in the presence of a condensing agent such as silicon tetrachloride, phosphoric anhydride or a carbodiimide such as dicyclohexyl carbodiimide.
The amidification reaction of the invention can be carried out in the presence or in the absence of solvent. The systems used as a solvent, which are inert with respect to the amidification reaction, are for example alcohols, polyols, benzene, toluene, dioxan, chloroform, diethyleneglycol ~ U~7~Q4 dimethylether. It is also possible to use as a solvent an excess of the amine used as the starting material. It may be preferable to heat the reaction mixture during amidification, for example to the boiling point of the solvents listed above.
The compound produced according to the process of the invention can react if necessary with pharmaceutically acceptable mineral or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric ac;d, phosphoric acid, acetic acid, tartric acid, citric acid or methane sulfonic acid, to give acid addition salts. It can also react if necessary with alkyl sulfates or halides, to give quaternary ammonium salts.
The benzamides of the invention have attractive therapeutic properties, in particular as anti-e~etics, anti-ulcer agents and agents for modifying the central nervous system. Their low level of toxicity is compatible with use in human therapy, without the danger of causing side effects.
In order to illustrate the technical characteristics of the present invention, some embodiments will now be described, it being apparent that these are not limiting on the invention as regards the manner in which they are per-formed and the uses to which they can be put.
N-(2'-pyrrolidinylmethyl)-2-methoxy-4-amino-5-chlorobenzamide hydrochloride 51.5 9 of methyl 2-methoxy-4-acetamido-5-chloro-benzoate, 20 ml of water and 40 9 of 2-aminomethylpyrrolidine were introduced into a balloon flask provided with a stirrer, a thermometer and a condenser. The mixture was heated for 7 hours at reflux temperature, and then cooled. After the addition of 50 ml of water and 50 ml of 40% sodium hydroxide lye, the mixture was heated for 2 hours at reflux temperature.
The crystals formed by cooling were washed with water and ~ ~247S(.~
dr-ied in a drying oven at 50C. 32 9 of benzamide was obtained, in the form of a base.
The hydrochloride was formed by dissolution of the base in alcohol at boiling temperature, filtration in the hot state and addition of hydrochloric acid (d 1.18). The crystals formed by cooling were filtered, washed with ethanol and dried in a drying oven at 50C. 24.2 9 of N-(2'-pyrroli-dinylmethyl)-2-methoxy-4-amino-5-chlorobenzamidehydrochloride was produced (melting point: 167C).
N-(2'-pyrrolidinylmethyl)-2-methoxy-4-amino-5-sulfamoyl-benzamide 140 9 of methyl 2-methoxy-4-amino-5-sulfamoyl-benzoate, 48.5 ml of water and 80 9 of 2-aminomethylpyrrolidine were introduced into a 1 litre balloon flask provided with a condenser. The suspension obtained was heated in a water bath.
After cooling the reaction mixture was diluted with 540 ml of water. The solid formed was drained, washed with water and dried at 45C.
The base produced was purified by conversion to the hydrochloride and re-precipitation with 20% ammonia, then drained, washed and dried at 50C. 97 9 of N-(2'-pyrrolidinyl-methyl)-2-methoxy-4-amino-5-sulfamoylbenzamide was produced (yield: 54.8%; melting point: 205-206C).
N-(2'-pyrrolidinylmethyl)-2-methoxy-5-ethylsulfonylbenzamide 130 9 of N-benzyl-2-aminomethylpyrrolidine, 620 ml of methylethylketone, then with the temperature being main-tained at from 5 to 10C, 162.6 9 of 2-methoxy-5-ethylsulfonyl-benzoylchloride were introduced into a 2 litre balloon flask provided with a stirrer, a condenser and a thermometer.
Stirring of the mixture was continued without heating for 1 1~475~4 hour. The solid formed was filtered, washed with a little methylethylketone and then dissolved in hot ethanol. The crystals obtained on cooling were f;ltered, washed, dried and then introduced into a 1 litre autoclave with 500 ml of water, 150 g of Raney nickel and hydrogen, until a pressure of 170 kg was obtained. The mixture was heated for 4 hours at 100C;
after cooling, the nickel was filtered and rinsed with water.
The solvents were evaporated under reduced pressure; the residue was treated by means of a mixture of 25 ml of 36%
hydrochloric acid and water, until 500 ml of solution was obtained. After heating at 80C, and filtration, the medium was rendered alkaline by means of 40% sodium hydroxide. The crystals obtained after cooling were filtered, washed with water and dried. 111.5 g of N-(2'-pyrrolidinylmethyl)-2-methoxy-5-ethylsulfonylbenzamide was obtained (yield: 70.3%;
melting point: 150C).
N-(2'-pyrrolidinylmethyl)-2-methoxy-4-aminobenzamide A solution of 1.4 9 of phosphorus trichloride in 8 ml of pyridine was poured dropwise, and with the temperature being maintained at from 0 to 5C, with stirring, into a solution of 2 9 of 2-aminomethylpyrrolidine in pyridine.
Stirring was continued at from 0 to 5C, and then at ambient temperature. After the addition of 1.6 g of 2-methoxy-4-aminobenzoid acid, the mixture was heated with stirring for several hours.
- After the mixture had been cooled and the solvent removed, the residue was dissolved in chloroform, then the solution was washed with aqueous sodium carbonate and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 1.5 9 of N-(2'-pyrrolidinylmethyl)-2-methoxy-lS.~4~ 4 4-aminobenzamide was produced (yield: 62.8%; melting point:
98C).
N-(2'-pyrrolidinylmethyl)-2-methoxy-5-methylsulfonylbenzamide 750 ml of methylethyl ketone, 103 9 of N-benzyl-2-aminomethylpyrrolidine and then, with the temperature being maintained at 15 to 20, 133 9 of 2-methoxy-5-methylsulfonyl-benzoylchloride were introduced into a balloon flask provided with a mechanical stirrer and a thermometer. Stirring of the reaction mixture was maintained for 2 hours at ambient temper-ature. The solid formed was drained and treated with ice-cold methylethyl ketone, then dissolved in hot ethanol. The crystals obtained upon cooling were filtered, washed, dried and then introduced into a 5 litre autoclave with 1 litre of water and 20 9 of Raney nickel. After the usual purging operations, hydrogen was introduced to a pressure of 130 kg and the mixture was heated at 100C for 4 hours.
After cooling, the nickel was filtered and washed.
The solvents were then evaporated under vacuum. The residue was treated with water and hydrochloric acid until a volume of 500 ml was obtained. The solution formed was heated at 80C, filtered and rendered alkaline by means of sodium hydroxide.
After cooling, the crystals formed were filtered, washed with water and dried. 98 9 of N-(2'-pyrrolidinylmethyl)-2-methoxy-5-methylsulfonylbenzamide was produced (yield: 68.9%; melting point: 152.5C).
N-(2'-pyrrolidinylmethyl)-2-methoxy-5-ethylsulfonylbenzamide 7.3 9 of 2-methoxy-5-ethylsulfonyl benzoic acid, 200 ml of tetrahydrofuran, and 7.3 9 of carbonyldiimidazole were introduced into a balloon flask provided with a stirrer and a condenser.
75(~4 After the mixture had been stirred at ambient temper-ature for 30 minutes, 4.8 9 of 2-aminomethylpyrrolid;ne was added. Stirring of the mixture was continued at ambient temperature, and then the solvent was evaporated under vacuum.
The residue was dissolved in hydrochloric acid and the solution obtained was filtered and then treated with sodium hydroxide until the pH-value was 12-13. The mixture was extracted with chloroform. After drying and filtration, the solvent was evaporated under vacuum. After purification in ethanol, 6.5 9 10 of N-(2'-pyrrolidinylmethyl)-2-methoxy-5-ethylsulfonylbenzamide was obtained (yield: 66.5%; melting point: 150C).
N-(2'-pyrrolidinylmethyl)-2,3-dimethoxy-5-sulfamoylbenzamide-hvdrochloride -1 litre of acetone and 200 9 of N-benzyl-2-amino-methylpyrrolidine were introduced into a 4 litre balloon flask provided with a mechanical stirrer and a thermometer. The mixture was cooled to 0C and 280 9 of 2,3-dimethoxy-5-sulfamoylbenzoylchloride was added, the temperature of the 20 reaction medium being kept below 10C.
The mixture was then stirred for 4 hours. The precipitate formed was drained, washed over a filter with acetone and then introduced into an autoclave with 1200 ml of water, 40 ml of hydrochloric acid (d = 1.18) and 5 spoonfuls of Raney nickel.
After the usual purge operations, hydrogen was intro-duced to give a pressure of 140 kg. The mixture was heated at 100C for 4 hours. After cooling the nickel was filtered and the mixture was rendered alkaline with 150 ml of ammonia. The 30 precipitate obtained was filtered and dried, then dissolved at boiling temperature in 150 ml of absolute ethanol and acidified with 40 ml of hydrochloric ethanol. The crystals obtained by ~ ~47504 cooling were filtered, washed and dried at 5QC. 95 9 of N-(2'-pyrrolidinylmethyl)-2,3-dimethoxy-5-sulfamoylbenzamide-hydrochloride was produced (melting point: 195-198C).
N-(2'-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide 51.8 9 of ethyl 2-methoxy-5-sulfamoylbenzoate, 24 9 of 2-aminomethylpyrrolidine and 200 ml of butanol were intro-duced into a 1 litre balloon flask.
The mixture was heated for 7 hours at reflux temper-ature. After cooling, and evaporation under vacuum of thesolvent, the residue was recrystallized from dimethylformamide.
51 9 of benzamide was produced (yield: 73%).
A second recrystallization step provided 43 9 of N-(2'-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide (yield: 61.5%; melting point: 185C).
Claims (17)
1. The process for preparing substituted N-(2-pyrrolidinylalkyl)benzamides and salts thereof corresponding to the general formula:
in which:
A represents a hydrogen atom, a C1-5 alkyl group or a C2-5 alkenyl group;
X represents a hydrogen atom, a C1-5 alkoxy group, a C1-5 alkyl group, a C2-5 alkenyloxy group or a C2-5 alkenyl group;
Y represents a hydrogen atom, a halogen atom, a C1-5 alkyl, C1-5 alkoxy, amino, or amino substituted group selected from alkylamino, acylamino, benzyl-amino or alkoxycarbonylamino;
Z represents a hydrogen atom, a halogen atom, a C1-5 alkoxy group or a C1-5 alkylsulfonyl group;
W represents an alkylene group having from 1 to 4 carbon atoms which can form a straight or branched chain, and m represents the integer 1, which comprises reacting a compound of the formula:
in which:
B is a halogen atom, hydroxy, alkoxy or an imidazolyl group;
A, X, Y and Z are as defined above, with an amine of the formula:
in which:
W, m are as defined above;
R3 represents hydrogen or benzyl, and when R3 is benzyl, reducing the compound obtained.
in which:
A represents a hydrogen atom, a C1-5 alkyl group or a C2-5 alkenyl group;
X represents a hydrogen atom, a C1-5 alkoxy group, a C1-5 alkyl group, a C2-5 alkenyloxy group or a C2-5 alkenyl group;
Y represents a hydrogen atom, a halogen atom, a C1-5 alkyl, C1-5 alkoxy, amino, or amino substituted group selected from alkylamino, acylamino, benzyl-amino or alkoxycarbonylamino;
Z represents a hydrogen atom, a halogen atom, a C1-5 alkoxy group or a C1-5 alkylsulfonyl group;
W represents an alkylene group having from 1 to 4 carbon atoms which can form a straight or branched chain, and m represents the integer 1, which comprises reacting a compound of the formula:
in which:
B is a halogen atom, hydroxy, alkoxy or an imidazolyl group;
A, X, Y and Z are as defined above, with an amine of the formula:
in which:
W, m are as defined above;
R3 represents hydrogen or benzyl, and when R3 is benzyl, reducing the compound obtained.
2. The process of Claim 1, wherein methyl 2-methoxy-4-acetamino-5-chlorobenzoate is reacted with 2-aminopyrrolidine and hydrolyzing the intermediate obtained to form the N-(2'-pyrrolidinylmethyl)-2-methoxy-4-amino-5-chlorobenzamide.
3. The process of Claim 1, wherein methyl 2-methoxy-4-amino-5-sulfamoylbenzoate is reacted with 2-aminomethyl-pyrrolidine to form the N-(2'-pyrrolidinylmethyl)-2-methoxy-4-amino-5-sulfamoylbenzamide.
4. The process of Claim 1, wherein N-benzyl-2-amino-methylpyrrolidine is reacted with 2-methoxy-5-ethylsulfonyl-benzoylchloride and reducing the intermediate formed to yield the N-(2'-pyrrolidinylmethyl)-2 methoxy-5-ethylsulfonyl-benzamide.
5. The process of Claim 1, wherein 2-methoxy-4-aminobenzoic acid is reacted with 2-aminomethylpyrrolidine in the presence of phosphorous trichloride to form the N-(2'-pyrrolidinylmethyl)-2-methoxy-4-aminobenzamide.
6. The process of Claim 1, wherein N-benzyl-2-aminomethylpyrrolidine is reacted with 2-methoxy-5-methyl-sulfonylbenzoylchloride and reducing the intermediate formed to yield the N-(2'-pyrrolidinylmethyl)-2-methoxy-5-methyl-sulfonylbenzamide.
7. The process of Claim 1, wherein 2-aminomethyl-pyrrolidine is reacted with 2-methoxy-5-ethylsulfonylbenzoic acid in the presence of carbonyldiimidazole to form the N-(2'-pyrrolidinylmethyl)-2-methoxy-5-ethylsulfonylbenzamide.
8. The process of Claim 1, wherein N-benzyl-2-aminomethylpyrrolidine is reacted with 2,3-dimethoxy-5-sulfamoylbenzoylchloride and reducing the intermediate form to yield the N-(2'-pyrrolidinylmethyl)-2,3-dimethoxy-5-sulfamoylbenzamide.
9. The process of Claim 1, wherein ethyl 2-methoxy-5-sulfamoylbenzoate is reacted with 2-aminomethylpyrrolidine to form the N-(2'-pyrrolidinylmethyl)-2-methoxy-5-sulfamoyl-benzamide.
10. The substituted N-(2-pyrrolidinylalkyl)benzamides and their pharmaceutically acceptable salts having the follow-ing general formula:
in which:
A represents a hydrogen atom, a C1-5 alkyl group or a C2-5 alkenyl group;
X represents a hydrogen atom, a C1-5 alkoxy group, a C1-5 alkyl group, a C2-5 alkenyloxy group or a C2-5 alkenyl group;
Y represents a hydrogen atom, a halogen atom, a C1-5 alkyl, C1-5 alkoxy, amino, or amino substituted group selected from alkylamino, acylamino, benzyl-amino or alkoxycarbonylamino;
Z represents a hydrogen atom, a halogen atom, a C1-5 alkoxy group or a C1-5 alkylsulfonyl group;
W represents an alkylene group having from 1 to 4 carbon atoms which can form a straight or branched chain, and m represents the integer 1, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.
in which:
A represents a hydrogen atom, a C1-5 alkyl group or a C2-5 alkenyl group;
X represents a hydrogen atom, a C1-5 alkoxy group, a C1-5 alkyl group, a C2-5 alkenyloxy group or a C2-5 alkenyl group;
Y represents a hydrogen atom, a halogen atom, a C1-5 alkyl, C1-5 alkoxy, amino, or amino substituted group selected from alkylamino, acylamino, benzyl-amino or alkoxycarbonylamino;
Z represents a hydrogen atom, a halogen atom, a C1-5 alkoxy group or a C1-5 alkylsulfonyl group;
W represents an alkylene group having from 1 to 4 carbon atoms which can form a straight or branched chain, and m represents the integer 1, when prepared by the process defined in Claim 1 or by an obvious chemical equivalent.
11. The N-(2'-pyrrolidinylmethyl)-2-methoxy-4-amino-5-chlorobenzamide, when prepared by the process defined in Claim 2 or by an obvious chemical equivalent.
12. The N-(2'-pyrrolidinylmethyl)-2-methoxy-4-amino-5-sulfamoylbenzamide, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.
13. The N-(2'-pyrrolidinylmethyl)-2-methoxy-5-ethylsulfonylbenzamide, when prepared by the process defined in Claim 4 or 7 or by an obvious chemical equivalent.
14. The N-(2'-pyrrolidinylmethyl)-2-methoxy-5-aminobenzamide, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.
15. The N-(2'-pyrrolidinylmethyl)-2-methoxy-5-methylsulfonylbenzamide, when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.
16. The N-(2'-pyrrolidinylmethyl)-2,3-dimethoxy-5-sulfamoylbenzamide, when prepared by the process defined in Claim 8 or by an obvious chemical equivalent.
17. The N-(2'-pyrrolidinylmethyl)-2-methoxy-5-sulfamoylbenzamide, when prepared by the process defined in Claim 9 or by an obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7407535A FR2262966A1 (en) | 1974-03-05 | 1974-03-05 | N-(2-azacycloalkyl-alkyl)-benzamide derivs. - with antiemetic, antiulcer and CNS activity |
| FR7503800A FR2299863B1 (en) | 1975-02-07 | 1975-02-07 | Novel substituted N- (Z-pyrrolidiny alkyl) benzamides, their derivatives and process for their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1047504A true CA1047504A (en) | 1979-01-30 |
Family
ID=26218210
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA221,240A Expired CA1047504A (en) | 1974-03-05 | 1975-03-04 | N-(2-pyrrolidinyl alkyl) substitutes and derivatives thereof |
Country Status (27)
| Country | Link |
|---|---|
| JP (1) | JPS6015616B2 (en) |
| AR (1) | AR206621A1 (en) |
| AT (1) | AT358570B (en) |
| BG (1) | BG24666A3 (en) |
| CA (1) | CA1047504A (en) |
| CH (1) | CH605794A5 (en) |
| CS (1) | CS189692B2 (en) |
| DD (1) | DD119420A5 (en) |
| DE (1) | DE2507989A1 (en) |
| DK (1) | DK145377C (en) |
| EG (1) | EG12577A (en) |
| ES (1) | ES435274A1 (en) |
| FI (1) | FI750620A (en) |
| GB (1) | GB1466822A (en) |
| HK (1) | HK14078A (en) |
| HU (1) | HU170637B (en) |
| IE (1) | IE40818B1 (en) |
| IL (1) | IL46696A (en) |
| LU (1) | LU71949A1 (en) |
| NL (1) | NL7502608A (en) |
| NO (1) | NO750713L (en) |
| OA (1) | OA04966A (en) |
| PH (1) | PH14197A (en) |
| PL (1) | PL97091B1 (en) |
| RO (2) | RO70647A (en) |
| SE (1) | SE411754B (en) |
| SU (1) | SU609464A3 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ186175A (en) * | 1977-01-27 | 1980-03-05 | Shionogi & Co | Meta-sulphonamidobenzamide derivatives |
| SE8503054D0 (en) * | 1985-06-19 | 1985-06-19 | Astra Laekemedel Ab | CATECHOLCARBOXAMIDES |
| US4772459A (en) * | 1986-09-09 | 1988-09-20 | Erbamont, Inc. | Method for controlling emesis caused by chemotherapeutic agents and antiemetic agents useful therein |
| EP0314483A1 (en) * | 1987-10-29 | 1989-05-03 | Erbamont, Inc. | Preparation of benzamides |
| FR2699533A1 (en) * | 1992-12-21 | 1994-06-24 | Mouhtaram Mohamed | N-2-piperazinyl 4-amino:benzamide derivs. having antiemetic and antipsychotic activity |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3078497A (en) * | 1960-12-29 | 1963-02-26 | Leeds And Mieallef | Dispensing containers |
-
1975
- 1975-02-24 IL IL46696A patent/IL46696A/en unknown
- 1975-02-25 DE DE19752507989 patent/DE2507989A1/en not_active Withdrawn
- 1975-02-26 GB GB809575A patent/GB1466822A/en not_active Expired
- 1975-03-03 EG EG109/75A patent/EG12577A/en active
- 1975-03-03 AT AT160775A patent/AT358570B/en not_active IP Right Cessation
- 1975-03-03 SE SE7502342A patent/SE411754B/en not_active IP Right Cessation
- 1975-03-03 LU LU71949A patent/LU71949A1/xx unknown
- 1975-03-04 CA CA221,240A patent/CA1047504A/en not_active Expired
- 1975-03-04 NO NO750713A patent/NO750713L/no unknown
- 1975-03-04 OA OA55430A patent/OA04966A/en unknown
- 1975-03-04 HU HUSO1137A patent/HU170637B/hu not_active IP Right Cessation
- 1975-03-04 SU SU2112487A patent/SU609464A3/en active
- 1975-03-04 CS CS751445A patent/CS189692B2/en unknown
- 1975-03-04 ES ES435274A patent/ES435274A1/en not_active Expired
- 1975-03-04 BG BG7500029148A patent/BG24666A3/en unknown
- 1975-03-04 DK DK86975A patent/DK145377C/en active
- 1975-03-04 FI FI750620A patent/FI750620A/fi not_active Application Discontinuation
- 1975-03-04 IE IE457/75A patent/IE40818B1/en unknown
- 1975-03-05 RO RO7588831A patent/RO70647A/en unknown
- 1975-03-05 PL PL1975178533A patent/PL97091B1/en unknown
- 1975-03-05 DD DD184579A patent/DD119420A5/xx unknown
- 1975-03-05 NL NL7502608A patent/NL7502608A/en not_active Application Discontinuation
- 1975-03-05 JP JP50027573A patent/JPS6015616B2/en not_active Expired
- 1975-03-05 RO RO7581558A patent/RO72844A/en unknown
- 1975-03-05 CH CH279975A patent/CH605794A5/xx not_active IP Right Cessation
- 1975-04-04 AR AR257837A patent/AR206621A1/en active
-
1977
- 1977-08-22 PH PH20152A patent/PH14197A/en unknown
-
1978
- 1978-03-16 HK HK140/78A patent/HK14078A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| BG24666A3 (en) | 1978-04-12 |
| DK145377B (en) | 1982-11-08 |
| JPS50123668A (en) | 1975-09-29 |
| NO750713L (en) | 1975-09-08 |
| IE40818L (en) | 1975-09-05 |
| JPS6015616B2 (en) | 1985-04-20 |
| DK145377C (en) | 1983-04-11 |
| AT358570B (en) | 1980-09-25 |
| HK14078A (en) | 1978-03-23 |
| LU71949A1 (en) | 1976-02-04 |
| ATA160775A (en) | 1980-02-15 |
| SE411754B (en) | 1980-02-04 |
| FI750620A (en) | 1975-09-06 |
| AR206621A1 (en) | 1976-08-06 |
| AU7874075A (en) | 1976-09-09 |
| RO72844A (en) | 1981-09-24 |
| DK86975A (en) | 1975-11-03 |
| ES435274A1 (en) | 1976-12-16 |
| SU609464A3 (en) | 1978-05-30 |
| DE2507989A1 (en) | 1975-09-11 |
| PH14197A (en) | 1981-03-26 |
| SE7502342L (en) | 1975-09-06 |
| CH605794A5 (en) | 1978-10-13 |
| CS189692B2 (en) | 1979-04-30 |
| PL97091B1 (en) | 1978-02-28 |
| IL46696A (en) | 1978-07-31 |
| DD119420A5 (en) | 1976-04-20 |
| HU170637B (en) | 1977-07-28 |
| SU609464A1 (en) | 1978-05-30 |
| RO70647A (en) | 1980-04-15 |
| OA04966A (en) | 1980-10-31 |
| EG12577A (en) | 1979-09-30 |
| GB1466822A (en) | 1977-03-09 |
| NL7502608A (en) | 1975-09-09 |
| IL46696A0 (en) | 1975-04-25 |
| IE40818B1 (en) | 1979-08-29 |
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