CA1105937A - Process for preparing (cycloalkyl)-alkylbenzamides - Google Patents
Process for preparing (cycloalkyl)-alkylbenzamidesInfo
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- CA1105937A CA1105937A CA322,283A CA322283A CA1105937A CA 1105937 A CA1105937 A CA 1105937A CA 322283 A CA322283 A CA 322283A CA 1105937 A CA1105937 A CA 1105937A
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- methoxy
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- cyclopropylmethylpyrrolidin
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
A B S T R A C T
A process for preparing benzamides, in the form of racemates or enantiomers, corresponding to the formula (I) (I) in which n and m are independently of one another equal to 1, 2, 3 or 4 and R is the radical CF3 or an alkylthio radical in which the alkyl is linear or branched and has from 1 to 6 carbon atoms, and also their addition salts with pharmaceutically acceptable acids, which process comprises reacting a 2-methoxy-5-R-benzoic acid (II) or one of its functionally equivalent derivatives (II) with a pyrrolidine, in the form of the racemate or an enantiomer, of the formula (III) (III) .
The compounds are useful in treating disorders of the central nervous system.
A process for preparing benzamides, in the form of racemates or enantiomers, corresponding to the formula (I) (I) in which n and m are independently of one another equal to 1, 2, 3 or 4 and R is the radical CF3 or an alkylthio radical in which the alkyl is linear or branched and has from 1 to 6 carbon atoms, and also their addition salts with pharmaceutically acceptable acids, which process comprises reacting a 2-methoxy-5-R-benzoic acid (II) or one of its functionally equivalent derivatives (II) with a pyrrolidine, in the form of the racemate or an enantiomer, of the formula (III) (III) .
The compounds are useful in treating disorders of the central nervous system.
Description
11~5~37 DESCRIPTION
"PROCESS FOR PREPARING (CYCLOALKYL)-ALKYLBENZAMIDES"
The present invention relates to a process for preparing 2-methoxybenzamides in the form of racemates or enantiomers, or their addition salts with pharmaceutically acceptable acids.
The compounds in question correspond to the formula (I) R ~ ~IH2)m (CH2)n CH2 in which n and m are independently of one another equal to 1, 2, 3 or 4 and R is the radical CF3 or an alkylthio radical in which t~e alkyl is linear or branched and has from 1 to 6 carbon atoms.
The compounds are active inthe field of the central nervous system.
According to the invention, the compounds are prepared by the condensation of a 2-methoxy-5-R-benzoic acid (II) or one of its functional derivatives (halide or ester) with a pyrrolidine, in the form of the racemate or an enantiomer, of the formula (III) i
"PROCESS FOR PREPARING (CYCLOALKYL)-ALKYLBENZAMIDES"
The present invention relates to a process for preparing 2-methoxybenzamides in the form of racemates or enantiomers, or their addition salts with pharmaceutically acceptable acids.
The compounds in question correspond to the formula (I) R ~ ~IH2)m (CH2)n CH2 in which n and m are independently of one another equal to 1, 2, 3 or 4 and R is the radical CF3 or an alkylthio radical in which t~e alkyl is linear or branched and has from 1 to 6 carbon atoms.
The compounds are active inthe field of the central nervous system.
According to the invention, the compounds are prepared by the condensation of a 2-methoxy-5-R-benzoic acid (II) or one of its functional derivatives (halide or ester) with a pyrrolidine, in the form of the racemate or an enantiomer, of the formula (III) i
- 2 - 1~5937 ~L
(CH2 )m (III) CH
( 2)n CH2 2-Methoxy-trifluoromethylbenzoic acid has already been described in the literature.
The 2-methoxy-5-alkylthiobenzoic acids (II) and their chlorides are obtained in accordance with the following reaction scheme:
OOH Cl SO2 ~ OOH
+Cl SO3 H ~ ~ OCH3 C~,/
HOOC ~ ~ ~ S _ S ~ 2 4 ~ ~ b C33 ~ SO C12 RS ~ O Cl ~ CH3 The (cycloalkyl)-alkylpyrrolidines (III) are obtained, for example, in accordance with the processes ~5$37 described by the Applicant Company in her French Patents 74/41,718 and 77/19,391.
The condensation is carried out at a temperature of 0 to 30C, in a solvent such as acetone.
The following examples illustrate the present invention. The analyses and the IR and NMR spectra con-firm the structure of the compounds.
Example 1 N-[(l-Cyclopropylmethylpyrrolidin-2-yl)-methyl]-2-methoxy-5-methylthiobenzamide and its hydro-chloride.
1. 2-Methoxy-5-chlorosulphonylbenzoic acid.
44 ml (0.506 mol) of chlorosulphonic acid are intro-duced into a three-necked flask equipped with a stirrer and a condenser, and the system is cooled to 5. 20 g of 2-methoxybenzoic acid are then added in small portions at a rate which is such that the temperature can be kept between 10 and 15. Once the addition is complete, the medium is allowed to return to ambient temperature and then to remain at this temperature for 1 hour. The temper-ature is then gradually increased to 60-70 and kept at this value for 1 hour, this corresponding to the end of the evolution of gas. The medium is then allowed to cool and this brown liquid is poured into a mixture of 60 ml of water and 250 g of ice. A solid appears which is filtered off and washed several times with ice-cooled water. It is then dried in vacuo at 80C.
Melting point = 143-5C.
~-'A-~3 2. Dithio-bis-~4-methoxybenzoic-3) acid.
100 g (0.4 mol) of 2-methoxy-5-chlorosulphonylbenzoic acid, 750 ml of ethanol and 500 ml of 12 N concentrated hydrochloric acid are introduced into a reactor equipped with a mechanical stirrer.
130.8 g (2 mols) of zinc powder are added in portions to the vigorously stirred suspension in the course of about 2 hours, in such a way as to keep the temperature at 15-20C, whilst cooling, if necessary, with a bath of ice-cooled water.
At the end of the operation, the medium is filtered.
1 litre of water and, whilst stirring, 70 g of ferric chloride are added to the filtrate. The mixture is stirred for 1 hour and the product which has precipitated is then filtered off and washed 3 times with water. It is purified by dissolving it in a solution of sodium bicarbonate in the presence of charcoal. The insoluble material is filtered off.
The filtrate is acidified with excess hydrochloric acid and the resulting precipitate is filtered off, washed 3 times with water and then dried.
The compound is obtained after recrystallisation from acetic acid, washing with ether and drying for 8 hours at 80C in vacuo.
Melting point = 212-212.5C.
(CH2 )m (III) CH
( 2)n CH2 2-Methoxy-trifluoromethylbenzoic acid has already been described in the literature.
The 2-methoxy-5-alkylthiobenzoic acids (II) and their chlorides are obtained in accordance with the following reaction scheme:
OOH Cl SO2 ~ OOH
+Cl SO3 H ~ ~ OCH3 C~,/
HOOC ~ ~ ~ S _ S ~ 2 4 ~ ~ b C33 ~ SO C12 RS ~ O Cl ~ CH3 The (cycloalkyl)-alkylpyrrolidines (III) are obtained, for example, in accordance with the processes ~5$37 described by the Applicant Company in her French Patents 74/41,718 and 77/19,391.
The condensation is carried out at a temperature of 0 to 30C, in a solvent such as acetone.
The following examples illustrate the present invention. The analyses and the IR and NMR spectra con-firm the structure of the compounds.
Example 1 N-[(l-Cyclopropylmethylpyrrolidin-2-yl)-methyl]-2-methoxy-5-methylthiobenzamide and its hydro-chloride.
1. 2-Methoxy-5-chlorosulphonylbenzoic acid.
44 ml (0.506 mol) of chlorosulphonic acid are intro-duced into a three-necked flask equipped with a stirrer and a condenser, and the system is cooled to 5. 20 g of 2-methoxybenzoic acid are then added in small portions at a rate which is such that the temperature can be kept between 10 and 15. Once the addition is complete, the medium is allowed to return to ambient temperature and then to remain at this temperature for 1 hour. The temper-ature is then gradually increased to 60-70 and kept at this value for 1 hour, this corresponding to the end of the evolution of gas. The medium is then allowed to cool and this brown liquid is poured into a mixture of 60 ml of water and 250 g of ice. A solid appears which is filtered off and washed several times with ice-cooled water. It is then dried in vacuo at 80C.
Melting point = 143-5C.
~-'A-~3 2. Dithio-bis-~4-methoxybenzoic-3) acid.
100 g (0.4 mol) of 2-methoxy-5-chlorosulphonylbenzoic acid, 750 ml of ethanol and 500 ml of 12 N concentrated hydrochloric acid are introduced into a reactor equipped with a mechanical stirrer.
130.8 g (2 mols) of zinc powder are added in portions to the vigorously stirred suspension in the course of about 2 hours, in such a way as to keep the temperature at 15-20C, whilst cooling, if necessary, with a bath of ice-cooled water.
At the end of the operation, the medium is filtered.
1 litre of water and, whilst stirring, 70 g of ferric chloride are added to the filtrate. The mixture is stirred for 1 hour and the product which has precipitated is then filtered off and washed 3 times with water. It is purified by dissolving it in a solution of sodium bicarbonate in the presence of charcoal. The insoluble material is filtered off.
The filtrate is acidified with excess hydrochloric acid and the resulting precipitate is filtered off, washed 3 times with water and then dried.
The compound is obtained after recrystallisation from acetic acid, washing with ether and drying for 8 hours at 80C in vacuo.
Melting point = 212-212.5C.
3. 2-Methoxy-5-methylthiobenzoic acid and its chloride.
50 g (0.136 mol) of dithio-bis-(4-methoxybenzoic-3) acid are introduced into a reactor and a solution of 27.3 g (0.682 mol) of NaOH in 1 litre of water is added.
_ 5 - ~L~S$37 34.8 g (0.275 mol) of methylsulphate are added drop-wise to the resulting solution. The mixture is stirred for 4 hours and then extracted with ether. The aqueous phase is collected and acidified. The resulting oil is extracted with ether and the extract is dried over magnesium sulphate and evaporated. A solid is collected which is triturated with cyclohexane.
Melting point = 68.5-69C.
14.4 ml (0.2 mol) of thionyl chloride and 19.8 g (0.1 mol) of the acid are introduced into an Erlenmeyer flask.
The mixture is stirred at ambient temperature and heated under reflux for 4 hours.
It is evaporated to dryness and the residual oil is distilled in a bulbed tube.
Boiling point (0.1 mm Hg) = 180C.
50 g (0.136 mol) of dithio-bis-(4-methoxybenzoic-3) acid are introduced into a reactor and a solution of 27.3 g (0.682 mol) of NaOH in 1 litre of water is added.
_ 5 - ~L~S$37 34.8 g (0.275 mol) of methylsulphate are added drop-wise to the resulting solution. The mixture is stirred for 4 hours and then extracted with ether. The aqueous phase is collected and acidified. The resulting oil is extracted with ether and the extract is dried over magnesium sulphate and evaporated. A solid is collected which is triturated with cyclohexane.
Melting point = 68.5-69C.
14.4 ml (0.2 mol) of thionyl chloride and 19.8 g (0.1 mol) of the acid are introduced into an Erlenmeyer flask.
The mixture is stirred at ambient temperature and heated under reflux for 4 hours.
It is evaporated to dryness and the residual oil is distilled in a bulbed tube.
Boiling point (0.1 mm Hg) = 180C.
4. N-[(l-Cyclopropylmethylpyrrolidin-2-yl)-methyl]-2-methoxy-5-methylthiobenzamide.
10.7 g (0.069 mol) of 1-cyclopropylmethyl-2-amino-methylpyrrolidine, 9.6 g (0.069 mol) of potassium carbonate and some acetone are introduced into an Erlenmeyer flask.
15 g (0.069 mol) of 2-methoxy-5-methylthiobenzoic acid chloride are added dropwise, whilst cooling with an ice bath and under a stream of nitrogen. The mixture is stirred for 2 hours at ambient temperature. It is evaporated to dryness at a temperature < 30C and the residue is taken up in water and chloroform. The organic phase is collected and extracted in an acid medium and the aqueous phase is .
- 6 - ~5~3~7 rendered alkaline and extracted with chloroform. The extract is dried over magnesium sulphate and evaporated. An oil is collected which is passed through a silica column, using acetone as the eluant.
Boiling point (0.05 mm Hg) = 240C.
10.7 g (0.069 mol) of 1-cyclopropylmethyl-2-amino-methylpyrrolidine, 9.6 g (0.069 mol) of potassium carbonate and some acetone are introduced into an Erlenmeyer flask.
15 g (0.069 mol) of 2-methoxy-5-methylthiobenzoic acid chloride are added dropwise, whilst cooling with an ice bath and under a stream of nitrogen. The mixture is stirred for 2 hours at ambient temperature. It is evaporated to dryness at a temperature < 30C and the residue is taken up in water and chloroform. The organic phase is collected and extracted in an acid medium and the aqueous phase is .
- 6 - ~5~3~7 rendered alkaline and extracted with chloroform. The extract is dried over magnesium sulphate and evaporated. An oil is collected which is passed through a silica column, using acetone as the eluant.
Boiling point (0.05 mm Hg) = 240C.
5. Hydrochloride.
6.68 g (0.02 mol) of N-[(1-cyclopropylmethyl-pyrrolidin-2-yl)-methyl]-2-methoxy-5-methylthiobenzamide are introduced into 100 ml of ether. An equimolecular amount of a solution of hydrogen chloride in ether is added dropwise and the oil is - separated off.
The oil is taken up in 100 ml of ether and the mixture is stirred and then evaporated to dryness.
The residual oil is triturated with 100 ml of ethyl acetate. A white solid appears after one hour. It is filtered off and dried.
I~elting point = 111.5-112C
Example 2 (S)(-) Isomer of N-[(l-cyclopropylmethylpyrrolidin-2-yl)-methyl]-2-methoxy-5-methylthiobenzamide.
10.7 g (0.069 mol) of (S)-2-aminomethyl-1-cyclopropyl-methylpyrrolidine, 9.6 g (0.069 mol) of potassium carbonate and some acetone are introduced into an Erlenmeyer flask.
15 g (0.069 mol) of 2-methoxy-5-methylthiobenzoic acid chloride in acetone solution are added dropwise, whilst cooling with an ice bath and under a stream of nitrogen.
The mixture is allowed to return to ambient temperature and stirred for two hours. It is evaporated to dryness and the residual oil is triturated with water and ether. The organic phase is collected and extracted in an acid medium and the ex-tract is rendered alkaline with sodium carbonate and extracted ~, .
_ 7 ~ 5~7 with ether. The extract is dried over magnesium sulphate and evaporated and an oil is collected which is passed through a silica column, using ethyl acetate and then acetone as the eluants. The oil obtained is distilled.
Boiling point (0.05 mm Hg) = 220C.[~]D = -83 (c - 1, DMF).
The hydrochloride is obtained in a solution of hydrogen chloride in ether.
Melting point = 116-116.5C.
[~]D0 = +21 (c = 1, DMF).
Example 3 N-[(l-Cyclopropylmethylpyrrolidin-2-yl)-methyl]-2-methoxy-5-ethylthiobenzamide.
1. 2-Methoxy-5-ethylthiobenzoic acid and its chloride.
The procedure of Example 1 is followed, the methyl sulphate being replaced by ethyl sulphate.
Melting point = 58-9C for the acid.
Boiling point (0.05 mm Hg) = 160C for the acid chloride.
2. N-[(l-Cyclopropylmethylpyrrolidin-2-yl)-methyl]-2-methoxy-5-ethylthiobenzamide.
9.4 g (0.0611 mol) of l-cyclopropylmethyl-2-amino-methylpyrrolidine, 8.5 g (0.0611 mol) of potassium carbonate and some acetone are introduced into an Erlenmeyer flask.
14.1 g (0.0611 mol) of 2-methoxy-5-ethylthiobenzoic acid chloride in acetone are added dropwise at a temperature < 10C and under a stream of nitrogen. The mixture is stirred for 2 hours at ambient temperature. It is evaporated to dryness and the residue is taken up in water and chloroform; the organic phase is separated off and extracted in an acid medium, the extract is rendered alkaline and extracted with chloroform ~5~7 and the extract is dried over magnesium sulphate and evaporated.
An oil is collected which is passed through a silica column, using acetone as the eluant. An oil is collected which is distilled.
Boiling point (0.05 mm Hg) = 240C.
Example 4 N-[(l-Cyclopropylmethylpyrrolidin-2~yl)-methyl]-2-methoxy-5-trifluoromethylbenzamide and its hydrochloride.
6.37 g (0.0413 mol) of 2-aminomethyl-1-cyclopropyl-methylpyrrolidine, 5.7 g (0.0413 mol) of potassium carbonate and 125 ml of acetone are introduced into an Erlenmeyer flask, the mixture is then cooled to about 5C and 9.85 g (0.0413 mol) of 2-methoxy-5-trifluoromethylbenzoic acid chloride in 50 ml of acetone are poured dropwise into the mixture, slowly (T< 8C) and under a stream of nitrogen.
After the addition, the mixture is stirred for 2 hours in melting ice and for 1 hour at ambient temperature and then evaporated to dryness. The residue is taken up in water and ether, the ether phase is decanted, the mother liquors are re-extracted twice and the organic extracts are washed before drying them over magnesium sulphate. They are filtered, the filtrate is evaporated to dryness and a yellow oil is obtained.
The benzamide hyrochloride is prepared by stirring the product in dry ether, using a solution of HCl in ether.
The solid is filtcred off, washed and dried. The solid is recrystallised twice from acetone and a fine white powder is obtained:
Melting point = 149.5-150C.
Example 5 (S)(-) Isomer of N-[(l-cyclopropylmethylpyrrolidin-2-yl)-methyl]-2-methoxy-5-trifluoromethylbenzamide. --2.15 g (0.0139 mol) of (S)-2-aminomethyl-1-cyclo-propylmethylpyrrolidine, 1.92 g (0.0139 mol) of potassium carbonate and 100 ml of acetone are introduced into an Erlenmeyer flask. 3.32 g (0.0139 mol) of 2-methoxy-5-trifluoromethylbenzoic acid chloride in acetone are added ~5~37 g dropwise, whilst cooling in an ice bath and under a stream of nitrogen. The mixture is allowed to return to ambient - temperature and stirred for two hours.
It is evaporated to dryness and the residue is taken up in water and ether. The organic phase is collect-ed and extracted in an acid medium. The extract is render-ed alkaline with sodium carbonate and extracted with ether and the extract is dried over magnesium sulphate and evaporated.
An oil is collected which is distilled.
Boiling point ~0.05 mm Hg) = 250C.
[~]20 = _75.5o [c = 1, DMF].
TABLE
Compound R Melting point or Boiling point (C) 1 3 1 1 base Boiling point (0.05 mm Hg) = 240 111.5-112 (S) CH3S 1 1 base Boiling point (0.05 mm Hg) = 220 HCl Melt ng polnt =
3 C2H5S 1 1 base Boiling point (0.05 mm Hg) = 240 4 CF~ 1 1 149.5-150 i (S)5 CF3 1 1 base Boiling point (0,05 mm Hg) = 250 ~5`~7 The compounds of the invention have been subject-ed to pharmacological tests in the field of the central nervous system.
The toxicity was evaluated in male mice of the Swiss CDl strain, having a mean weight of 20 g, using intraperitoneal administration.
The LD 50 varies from 75 to 200 mg/kg.
The neuroleptic activity was determined by the antogonism towards the "climbing" induced by apomorphine in mice [C. Gouret (1973) J. Pharmacol. (Paris) 4, 341].
The AD 50 varies from 0.03 to 0.08 mg/kg, admin-istered intraperitoneally.
The compounds of the invention can be used in the treatment of various psychosomatic complaints and psychic disorders (depressive states and psychoses).
The invention comprises all pharmaceutical compositions which contain the compounds (I) and their salts as active principles, in association with any excipients which are appropriate to their oral, endorectal or parenteral administration.
All the pharmaceutical forms appropriate to oral, endorectal or parenteral administration are suitable.
The daily dosage can range from l to 200 mg.
The oil is taken up in 100 ml of ether and the mixture is stirred and then evaporated to dryness.
The residual oil is triturated with 100 ml of ethyl acetate. A white solid appears after one hour. It is filtered off and dried.
I~elting point = 111.5-112C
Example 2 (S)(-) Isomer of N-[(l-cyclopropylmethylpyrrolidin-2-yl)-methyl]-2-methoxy-5-methylthiobenzamide.
10.7 g (0.069 mol) of (S)-2-aminomethyl-1-cyclopropyl-methylpyrrolidine, 9.6 g (0.069 mol) of potassium carbonate and some acetone are introduced into an Erlenmeyer flask.
15 g (0.069 mol) of 2-methoxy-5-methylthiobenzoic acid chloride in acetone solution are added dropwise, whilst cooling with an ice bath and under a stream of nitrogen.
The mixture is allowed to return to ambient temperature and stirred for two hours. It is evaporated to dryness and the residual oil is triturated with water and ether. The organic phase is collected and extracted in an acid medium and the ex-tract is rendered alkaline with sodium carbonate and extracted ~, .
_ 7 ~ 5~7 with ether. The extract is dried over magnesium sulphate and evaporated and an oil is collected which is passed through a silica column, using ethyl acetate and then acetone as the eluants. The oil obtained is distilled.
Boiling point (0.05 mm Hg) = 220C.[~]D = -83 (c - 1, DMF).
The hydrochloride is obtained in a solution of hydrogen chloride in ether.
Melting point = 116-116.5C.
[~]D0 = +21 (c = 1, DMF).
Example 3 N-[(l-Cyclopropylmethylpyrrolidin-2-yl)-methyl]-2-methoxy-5-ethylthiobenzamide.
1. 2-Methoxy-5-ethylthiobenzoic acid and its chloride.
The procedure of Example 1 is followed, the methyl sulphate being replaced by ethyl sulphate.
Melting point = 58-9C for the acid.
Boiling point (0.05 mm Hg) = 160C for the acid chloride.
2. N-[(l-Cyclopropylmethylpyrrolidin-2-yl)-methyl]-2-methoxy-5-ethylthiobenzamide.
9.4 g (0.0611 mol) of l-cyclopropylmethyl-2-amino-methylpyrrolidine, 8.5 g (0.0611 mol) of potassium carbonate and some acetone are introduced into an Erlenmeyer flask.
14.1 g (0.0611 mol) of 2-methoxy-5-ethylthiobenzoic acid chloride in acetone are added dropwise at a temperature < 10C and under a stream of nitrogen. The mixture is stirred for 2 hours at ambient temperature. It is evaporated to dryness and the residue is taken up in water and chloroform; the organic phase is separated off and extracted in an acid medium, the extract is rendered alkaline and extracted with chloroform ~5~7 and the extract is dried over magnesium sulphate and evaporated.
An oil is collected which is passed through a silica column, using acetone as the eluant. An oil is collected which is distilled.
Boiling point (0.05 mm Hg) = 240C.
Example 4 N-[(l-Cyclopropylmethylpyrrolidin-2~yl)-methyl]-2-methoxy-5-trifluoromethylbenzamide and its hydrochloride.
6.37 g (0.0413 mol) of 2-aminomethyl-1-cyclopropyl-methylpyrrolidine, 5.7 g (0.0413 mol) of potassium carbonate and 125 ml of acetone are introduced into an Erlenmeyer flask, the mixture is then cooled to about 5C and 9.85 g (0.0413 mol) of 2-methoxy-5-trifluoromethylbenzoic acid chloride in 50 ml of acetone are poured dropwise into the mixture, slowly (T< 8C) and under a stream of nitrogen.
After the addition, the mixture is stirred for 2 hours in melting ice and for 1 hour at ambient temperature and then evaporated to dryness. The residue is taken up in water and ether, the ether phase is decanted, the mother liquors are re-extracted twice and the organic extracts are washed before drying them over magnesium sulphate. They are filtered, the filtrate is evaporated to dryness and a yellow oil is obtained.
The benzamide hyrochloride is prepared by stirring the product in dry ether, using a solution of HCl in ether.
The solid is filtcred off, washed and dried. The solid is recrystallised twice from acetone and a fine white powder is obtained:
Melting point = 149.5-150C.
Example 5 (S)(-) Isomer of N-[(l-cyclopropylmethylpyrrolidin-2-yl)-methyl]-2-methoxy-5-trifluoromethylbenzamide. --2.15 g (0.0139 mol) of (S)-2-aminomethyl-1-cyclo-propylmethylpyrrolidine, 1.92 g (0.0139 mol) of potassium carbonate and 100 ml of acetone are introduced into an Erlenmeyer flask. 3.32 g (0.0139 mol) of 2-methoxy-5-trifluoromethylbenzoic acid chloride in acetone are added ~5~37 g dropwise, whilst cooling in an ice bath and under a stream of nitrogen. The mixture is allowed to return to ambient - temperature and stirred for two hours.
It is evaporated to dryness and the residue is taken up in water and ether. The organic phase is collect-ed and extracted in an acid medium. The extract is render-ed alkaline with sodium carbonate and extracted with ether and the extract is dried over magnesium sulphate and evaporated.
An oil is collected which is distilled.
Boiling point ~0.05 mm Hg) = 250C.
[~]20 = _75.5o [c = 1, DMF].
TABLE
Compound R Melting point or Boiling point (C) 1 3 1 1 base Boiling point (0.05 mm Hg) = 240 111.5-112 (S) CH3S 1 1 base Boiling point (0.05 mm Hg) = 220 HCl Melt ng polnt =
3 C2H5S 1 1 base Boiling point (0.05 mm Hg) = 240 4 CF~ 1 1 149.5-150 i (S)5 CF3 1 1 base Boiling point (0,05 mm Hg) = 250 ~5`~7 The compounds of the invention have been subject-ed to pharmacological tests in the field of the central nervous system.
The toxicity was evaluated in male mice of the Swiss CDl strain, having a mean weight of 20 g, using intraperitoneal administration.
The LD 50 varies from 75 to 200 mg/kg.
The neuroleptic activity was determined by the antogonism towards the "climbing" induced by apomorphine in mice [C. Gouret (1973) J. Pharmacol. (Paris) 4, 341].
The AD 50 varies from 0.03 to 0.08 mg/kg, admin-istered intraperitoneally.
The compounds of the invention can be used in the treatment of various psychosomatic complaints and psychic disorders (depressive states and psychoses).
The invention comprises all pharmaceutical compositions which contain the compounds (I) and their salts as active principles, in association with any excipients which are appropriate to their oral, endorectal or parenteral administration.
All the pharmaceutical forms appropriate to oral, endorectal or parenteral administration are suitable.
The daily dosage can range from l to 200 mg.
Claims (8)
1. A process for preparing benzamides, in the form of racemates or enantiomers, corresponding to the formula (I) (I) in which n and m are independently of one another equal to 1, 2, 3 or 4 and R is the radical CF3 or an alkylthio radical in which the alkyl is linear or branched and has from 1 to 6 carbon atoms, and also their addition salts with pharmaceutically acceptable acids, which process comprises reacting a 2-methoxy-5-R-benzoic acid (II) or one of its functionally equivalent derivatives (II) with a pyrrolidine, in the form of the racemate or an enantiomer, of the formula (III) (III)
2. A process according to claim 1, wherein m and n are each 1.
3. A process according to claim 1 or 2, wherein R is CF3, CH3S, or C2H5S.
4. A process according to claim 1, wherein N-[(l-cyclopropylmethylpyrrolidin-2-yl)-methyl]-2-methoxy-5-methylthiobenzamide or its hydrochloride is produced.
5. A process according to claim 1, wherein (S)(-) Isomer of N-[(l-cyclopropylmethylpyrrolidin-2-yl)-methyl]-2-methoxy-5-methylthiobenzamide is produced.
6. A process according to claim 1, wherein N-[(l-cyclopropylmethylpyrrolidin-2-yl)-methyl]-2-methoxy-5-ethylthiobenzamide is produced.
7. A process according to claim 1, wherein N-[(l-cyclopropylmethylpyrrolidin-2-yl)-methyl]-2-methoxy-5-trifluoromethylbenzamide or its hydrochloride is produced.
8. A process according to claim 1, wherein (S)(-) Isomer of N-[(l-cyclopropylmethylpyrrolidin-2-yl)-methyl]-2-methoxy-5-trifluoromethylbenzamide is produced.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7805580 | 1978-02-27 | ||
| FR7805580A FR2418226A1 (en) | 1978-02-27 | 1978-02-27 | METHOXY-2 ALKYLTHIO-5 BENZAMIDES AND THEIR THERAPEUTIC APPLICATION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1105937A true CA1105937A (en) | 1981-07-28 |
Family
ID=9205110
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA322,283A Expired CA1105937A (en) | 1978-02-27 | 1979-02-26 | Process for preparing (cycloalkyl)-alkylbenzamides |
Country Status (23)
| Country | Link |
|---|---|
| JP (1) | JPS54122269A (en) |
| AT (1) | AT373581B (en) |
| AU (1) | AU521854B2 (en) |
| BE (1) | BE874490A (en) |
| CA (1) | CA1105937A (en) |
| CH (1) | CH637378A5 (en) |
| DE (1) | DE2907377A1 (en) |
| DK (1) | DK82379A (en) |
| ES (1) | ES478073A1 (en) |
| FI (1) | FI790658A (en) |
| FR (1) | FR2418226A1 (en) |
| GB (1) | GB2014995B (en) |
| GR (1) | GR66973B (en) |
| IE (1) | IE47897B1 (en) |
| IL (1) | IL56747A0 (en) |
| IT (1) | IT1114210B (en) |
| LU (1) | LU80976A1 (en) |
| NL (1) | NL7901472A (en) |
| NO (1) | NO790648L (en) |
| NZ (1) | NZ189771A (en) |
| PT (1) | PT69290A (en) |
| SE (1) | SE430501B (en) |
| ZA (1) | ZA799808B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH02500291A (en) * | 1987-05-25 | 1990-02-01 | フォーショア プロテクション ピーティーワイ リミテッド | seawall mattress |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2245628B1 (en) * | 1973-09-28 | 1977-03-11 | Ile De France |
-
1978
- 1978-02-27 FR FR7805580A patent/FR2418226A1/en active Granted
-
1979
- 1979-02-26 CH CH188379A patent/CH637378A5/en not_active IP Right Cessation
- 1979-02-26 ES ES478073A patent/ES478073A1/en not_active Expired
- 1979-02-26 IT IT20542/79A patent/IT1114210B/en active
- 1979-02-26 CA CA322,283A patent/CA1105937A/en not_active Expired
- 1979-02-26 NL NL7901472A patent/NL7901472A/en not_active Application Discontinuation
- 1979-02-26 NZ NZ189771A patent/NZ189771A/en unknown
- 1979-02-26 AU AU44604/79A patent/AU521854B2/en not_active Ceased
- 1979-02-26 NO NO790648A patent/NO790648L/en unknown
- 1979-02-26 DK DK82379A patent/DK82379A/en not_active Application Discontinuation
- 1979-02-26 DE DE19792907377 patent/DE2907377A1/en not_active Withdrawn
- 1979-02-26 SE SE7901708A patent/SE430501B/en unknown
- 1979-02-26 PT PT69290A patent/PT69290A/en unknown
- 1979-02-26 JP JP2247679A patent/JPS54122269A/en active Pending
- 1979-02-26 ZA ZA00799808A patent/ZA799808B/en unknown
- 1979-02-27 IL IL56747A patent/IL56747A0/en unknown
- 1979-02-27 AT AT0149479A patent/AT373581B/en not_active IP Right Cessation
- 1979-02-27 GR GR58492A patent/GR66973B/el unknown
- 1979-02-27 FI FI790658A patent/FI790658A/en not_active Application Discontinuation
- 1979-02-27 BE BE0/193730A patent/BE874490A/en not_active IP Right Cessation
- 1979-02-27 GB GB7906954A patent/GB2014995B/en not_active Expired
- 1979-02-27 LU LU80976A patent/LU80976A1/en unknown
- 1979-08-08 IE IE558/79A patent/IE47897B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CH637378A5 (en) | 1983-07-29 |
| LU80976A1 (en) | 1980-09-24 |
| AU4460479A (en) | 1979-09-06 |
| IT7920542A0 (en) | 1979-02-26 |
| FI790658A (en) | 1979-08-28 |
| AT373581B (en) | 1984-02-10 |
| GR66973B (en) | 1981-05-15 |
| IE790558L (en) | 1979-08-27 |
| IE47897B1 (en) | 1984-07-11 |
| NO790648L (en) | 1979-08-28 |
| ES478073A1 (en) | 1979-05-16 |
| GB2014995A (en) | 1979-09-05 |
| FR2418226B1 (en) | 1980-11-07 |
| FR2418226A1 (en) | 1979-09-21 |
| DE2907377A1 (en) | 1979-09-06 |
| SE7901708L (en) | 1979-08-28 |
| ZA799808B (en) | 1980-06-25 |
| ATA149479A (en) | 1983-06-15 |
| SE430501B (en) | 1983-11-21 |
| DK82379A (en) | 1979-08-28 |
| GB2014995B (en) | 1982-07-28 |
| JPS54122269A (en) | 1979-09-21 |
| NZ189771A (en) | 1980-11-14 |
| NL7901472A (en) | 1979-08-29 |
| PT69290A (en) | 1979-03-01 |
| AU521854B2 (en) | 1982-05-06 |
| IL56747A0 (en) | 1979-05-31 |
| BE874490A (en) | 1979-08-27 |
| IT1114210B (en) | 1986-01-27 |
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| MKEX | Expiry |