DE2907377A1 - 2-METHOXY BENZAMIDES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THE SAME - Google Patents

Description

DESCRIPTION

The invention relates to 2-methoxy-benzamides in the form of the racemates or the enantiomers , their salts with pharmaceutically acceptable acids and medicaments containing these compounds as active ingredients.

The compounds of the present invention are as follows general formula I.

I ^ ■ 1 I.

(D

(CH -) - CH, 2 η 2

in the

η and m independently of one another 1,2,3 or 4 and R is a trifluoromethyl group or an alkylthio group, whose alkyl radical can be straight-chain or branched and have 1 to 6 carbon atoms.

The compounds according to the invention have an effect on the central nervous system.

In the process according to the invention, these compounds are obtained by condensation of a 2-methoxy-5-R-benzoic acid of the general formula II

COOH

(II)

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SYNTHELÄBO SET 23

in which R has the meanings given above, or a functional derivative thereof (such as a halide or an ester) with a pyrrolidine, which is in the form of the racemate or of an enantiomer, of the general formula III

(III)

^(CH 2> m

(CH,) - CH

in which η and m have the meanings given above.

The 2-methoxy-5-trifluoromethylbenzoic acid used as starting material has already been described in the literature.

The other 2-methoxy-5-alkylthio-benzoic acids used as starting materials of the above general formula I and their chlorides are obtained according to the following reaction scheme:

SYNTHELABO SET 23

HOOC

OH

+ • Cl SO ₃ H

CH

The cycloalkylalkyls also used as starting materials Pyrrolidines of the general formula III are obtained, for example according to the procedure described in FR-PS 74 41718 and 77 19391.

The condensation is effected preferably at a temperature of 0 to 3O ⁰ C in a solvent such as acetone.

The following examples serve to further illustrate the invention. The structure of the compounds was based on the Analysis and IR and NMR spectra confirmed. 30th

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EXAMPLE 1

N- £ (1-cyclopropylmethyl-pyrrolidin-2-yl) -methy ^^ - methoxy-5-methylthio-benzamide and its hydrochloride. 5

1. 2-Methoxy-5-chlorosulfonylbenzoic acid

Into a flask equipped with a stirrer and a condenser three-necked flask with 44ml (0.506 moles) of chlorosulfonic acid and cooled to 5 ⁰ C. Then 20 g of 2-methoxy-benzoic acid are added in small portions at such a rate that the temperature is maintained between 10 and 15 ° C. After the addition is complete, the medium is allowed to warm to room temperature and is then kept at this temperature for one hour. The temperature is then increased gradually to 60 to 70 ^° C., which temperature is maintained for one hour, after which the evolution of gas ceases. The reaction medium is then allowed to cool and the brown liquid obtained is poured into a mixture of 60 ml of water and 250 g of ice. A solid precipitates out and is filtered off, washed several times with ice-cold water and then dried ^{at 80 ° C. in vacuo.} F = 143-145 ⁰ C.

2. Dithio-bis (4-methoxy-3-benzoic acid)

A reaction vessel equipped with a mechanical stirrer is charged with 100 g (0.4 mol) of 2-methoxy-5-chlorosulfonylbenzoic acid, 750 ml of ethanol and 500 ml of concentrated hydrochloric acid (12N). To the vigorously stirred suspension (moles of 2) of powdered zinc are added in portions in the course of about 2 hours 130,8g in such a manner that the temperature at 15 is held until 20 ⁰ C to obtain, if necessary, is cooled with the aid of an ice water bath. After the reaction has ended, the medium is filtered off, after which 1 liter of water is added to the filtrate and 70 g of iron (III) -

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Chloride adds. The mixture is stirred for one hour, the precipitated product is filtered off, washed three times with water and purified by dissolving it in a sodium bicarbonate solution in the presence of activated charcoal. The insoluble constituents are separated off by filtration, the filtrate is acidified with excess hydrochloric acid, the precipitate formed is filtered off, washed three times with water and dried. After Umkristallxsation from acetic acid and washing and drying for 8 hours at 80 ⁰ C in a vacuum, the title compound is obtained. F = 212-212.5 ⁰ C.

3. 2-Methoxy-5-methylthio-benzoic acid and its chloride.

A reaction vessel is charged with 50 g (0.136 mol) of dithiobis (4-methoxy-3-benzoic acid) and a solution of 27.3 g (0.682 mol) of sodium hydroxide in one liter of water is added. 34.8 g (0.275 mol) of methyl sulfate are added dropwise to the resulting solution. The mixture is stirred for 4 hours and then extracted with ether. The aqueous phase is collected, acidified and the oil formed is extracted with ether. It is dried over magnesium sulphate and evaporated, and a solid is obtained which is triturated in cyclohexane. F = 68.5-69 ⁰ C.

An Erlenmeyer flask is charged with 14.4 ml (0.2 mol) of thionyl chloride and 19.8 g (0.1 mol) of the acid obtained. The mixture is stirred at room temperature and then heated to reflux for 4 hours. Then it is evaporated to dryness and the remaining oil is distilled using a ball cooler.
Kp = 180 ° C / 0.1mm Hg.

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4. N -C (1-Cyclopropylmethyl-pyrrolidin-2-yl) -methyll-2-methoxy-5-methylthio-benzamide.

An Erlenmeyer flask is charged with 10.7 g (0.069 mol) of i-cyclopropylmethyl-2-aminomethylpyrrolidine, 9.6 g (0.069 mol) of potassium carbonate and acetone. Then, while cooling with an ice bath and under a stream of nitrogen, 15 g (0.069 mol) of 2-methoxy-5-methylthio-benzoic acid chloride are added dropwise. The mixture is stirred for 2 hours at room temperature, then evaporated at a temperature of at most 30 ⁰ C to dryness, taken up with water and chloroform, wins the organic phase and extracted in acidic medium. The aqueous phase is made alkaline and extracted with chloroform. It is dried over magnesium sulphate and evaporated to give an oil which is passed through a column filled with silica, eluting with acetone. Bp = 240 ° C / 0.05mmHg.

5. Hydrochloride
20th

6.68 g (0.02 mol) of N - [(1-cyclopropylmethyl-pyrrolidin-2-yl) -methyl3-2-methoxy-5-methylthiobenzamide are added to 100 ml of ether. An equimolar amount of hydrogen chloride dissolved in ether is then added dropwise, and the oil is separated off, takes up with 100ml ether, stirs and concentrates to dryness. The remaining oil is triturated with 100 ml of ethyl acetate, a white solid appearing after one hour. It is filtered off and dried. F = 111.5-112 ° C.

EXAMPLE 2

(S) (~) -Isomer of N-f [(i-Cyclopropylmethyl-pyrrolidin-2-yl) -methyl] -2-methoxy-5-methylthio-benzamide.

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Man.beschickt an Erlenmeyer flask with 10 _/ 7g (0.069 MoI) of 2-aminomethyl-i-cyclopropylmethyl-pyrrolidine (S), 9.6 g (0.069 mol) of potassium carbonate and acetone. Then, while cooling with an ice bath and under a stream of nitrogen, 15 g (0.069 mol) of 2-methoxy-5-methylthio-benzoic acid chloride in the form of a solution in acetone are added dropwise. The reaction mixture is allowed to warm to room temperature, stirred for 2 hours, evaporated to dryness and the remaining oil is triturated with water and ether. The organic phase is separated off, extracted in an acidic medium, made alkaline with sodium carbonate and extracted with ether. It is dried over magnesium sulphate and evaporated to give an oil which is passed through a column filled with silica, eluting first with ethyl acetate and then with acetone. The oil obtained is

distilled. " _N

Γ I ²⁰
Bp = 220 ° C / 0.05mmHg. CxL = -83 ° (c = 1, dimethylformamide)

The hydrochloride is obtained in a solution of chlorinated water

substance in ether. "_

Γ Ί ²⁰
F = 116 to 116.5 ⁰ C. o £ = + 21 ° (c = 1 dimethylformamide).

L Jd

EXAMPLE 3

N- £ (1-Cyclopropylmethyl-pyrrolidin-2-yl) -methyl [] -2-methoxy-5-ethylthio- ^ benzamide.

1. 2-Methoxy-5-ethylthio-benzoic acid and its chloride.

The procedure of Example 1 is followed, replaced but methyl sulfate by ethyl sulfate. The acid obtained melts at 58 to 59 ° C, while the acid chloride has a boiling point of 160 ° C / 0.05mmHg.

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2. N-nd-Cyclopropyl-methyl-pyrrolidin (-yl) -methyl]] 2- - methoxy-5-ethylthio-benzamide.

A conical flask is charged with 9.4 g (0.0611 mol) of i-cyclopropylmethyl-2-aminomethylpyrrolidine, 8.5 g (0.0611 mol) of potassium carbonate and acetone. Are then added = 10 ⁰ C at a temperature and under a nitrogen stream dropwise 14,1g (0.0611 moles) of 2-methoxy-5-ethylthio-benzoic acid chloride in acetone. The mixture is stirred for 2 hours at room temperature, evaporated to dryness, taken up in water and chloroform, the organic phase is separated off, extracted in an acidic medium, made alkaline, extracted with chloroform, dried over magnesium sulfate and evaporated. An oil is obtained which is passed through a column filled with silica, eluting with acetone. In this way an oil is obtained which is distilled.
Bp = 240 ° C / 0.05mmHg.

EXAMPLE 4

N- £ (1-Cyclopropylmethyl-pyrrolidin-2-yl) -methyl] -2-methoxy-5-trifluoromethyl-benzamide and its hydrochloride.

An Erlenmeyer flask is charged with 6.37 g (0.0413 mol) of 2-aminomethyl-i-cyclopropylmethyl-pyrrolidine, 5.7 g (0.0413 mol) of potassium carbonate and 125 ml of acetone, after which it is cooled to about 5 ° C. and slowly added dropwise ( T <8 ⁰ C) 9,85g (0.0413 mol) of 2-methoxy-5-trifluoromethyl-benzoic acid chloride in 50 ml of acetone is added, operating under a nitrogen stream. After the addition, stir

for 2 hours in melting ice and for 1 hour at room temperature, after which it is evaporated to dryness. Man takes up the residue with water and ether, decanted off, extracted the mother liquors twice and washes the 35

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organic extracts before drying over magnesium fullfate. Mari * filtered, evaporated to dryness and got a yellow oil.

The benzamide hydrochloride is prepared by stirring in dry ether using a solution of hydrogen chloride in ether. The solid is filtered off with suction and washed him and dries him. It is recrystallized twice from acetone and a fine white powder is obtained.

10P = 149.5 - 150 ⁰ C.

EXAMPLE 5

(S) (-) - isomer of N- £ (1 ~ cyclopropylmethyl-pyrrolidin-2-yl) -methyl3-2'-methoxy-'5-trifluoromethyl-benzamide.

An Erlenmeyer flask is charged with 2.15 g (0.0139 mol) 2-aminomethyl-i-cyclopropylmethyl-pyrrolidine (S), 1.92g (0.0139 mol) potassium carbonate and 100 ml acetone. Then add while cooling in an ice bath and under a stream of nitrogen 3.32 g (0.0139 mol) of 2-methoxy-5-trifluoromethyl-benzoic acid chloride in acetone are added dropwise. It is left to room temperature heat and stir for 2 hours. Then you evaporate to dryness, take up with water and ether, separate the organic phase and extracted it in acidic medium.

It is made alkaline with sodium carbonate, extracted with ether, dried over magnesium sulfate and evaporated. An oil is obtained that is distilled.
Kp = 250 ° C / 0.05mmHg.

,! 20
I oc
30th

I ^20
0 ^ J ₀ = -75.5 ° (c =!, Dimethylformamide).

The table below shows the compounds according to the invention prepared according to the above examples compiled.

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29Q7377

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TABEL

link R. m η Melting point or boiling point
( ⁰ C) .... 1 CH ₃ S 1 1 Base Kp = 240 / Q.05mmHg
HCl F = 111.5-112 2
(S) CH ₃ S 1 1 Base b.p. 220 / 0.05 inHg
HCl F = 116-116.5 3 C ₂ H ₅ S 1 1 Base Kp = 24Q / 0.05mmHg 4th CF ₃ 1 1 HCl F = 149 "5-150 5
(S) CF ₃ 1 1 Base Kp = 250 / 0.05mmHg

The compounds according to the invention were subjected to pharmacological studies in order to determine their effect on the central nervous system ascertain.

Their toxicity was investigated in male mice of the Swiss CDI strain with a mean weight of _{20 g} when administered intraperitoneally. The DL 5Q value determined varied from 75 to 200 mg / kg.

The neuroleptic effect of the compounds according to the invention was via the antagonism against the by the administration of Apomorpiiin. ^{"Climbing 11} (climbing) caused in mice according to the procedure of C. Gouret (J. Pharmacol. , Paris, 4, C1973) 341) investigated * The DA _cn values determined vary

0KS3S / 068 ©

SES 23

at. iiitraperitoneal processing range from © _Γ (ϋ3 to @ _r @B mg / kg «

The inventive ties are for them vrerscMedemer psycfoosoiiiatic diseases end psyefiiscfter StSrangeii fEfegressioiESZiisfeäiiicie iirid Fsyeiiaseiiil suitable.

the inventions are dalier atrc & i grfearraazetEfciscIie Ztt—

the XTerfeiHdartgeiL the formula Σ aJLIgenieiiEeiB or ΐ & Εβ salts as active compounds in Koin & ination with the Verabreicliang on oralenr. ,, endorekfealem vein parenteralenE Cleaning product suitable binder "irrägerraaterialien and / or excipients entnalten. For this, särotlicfie pficanna: zea.tischeni preparation farms are suitable _p which can be given orally, endorectally or parenterally,

The daily dosage can be adjusted by T ^! to 2® @ nig.

Claims (5)

PATENTANWÄLTE TER MEER-MÜLLER-STEINMEISTER Authorized representatives at the European Patent Office - Professional Representatives before the European Patent Ofllce Mandalairos agrees pres! 'Office european des brevets Dipl.-Chem. Dr. N. ter Meer Dipl.-Ing. H. Steinmeister Dipl.-Ing, F. E. Müller o. Triftstrasse 4, S.ekerwall 7, D-8OOO MÜNCHEN 23 D-48OO BIELEFELD 1 Case: SET 23 26> February 1979 tM / hm SYNTHELABO, 1, avenue de Villars, 75341 PARTS CEDEX 07 France 2-methoxy-benzamide, procedure for their manufacture and medicinal products containing them. Priority: February 27, 1978, France, No. 78 05 580 PATENT CLAIMS 1. 2-Methoxy-benzamides, in the form of the racemates or the enantiomers , of the general formula I. CO-NH- 2'm (I) CH (CH,) - _CH, 2 η _t 909836/0688 SYNTHELABO - SET in the η and m independently of one another 1,2,3 or 4 and R is a trifluoromethyl group or an alkylthio group, whose alkyl radical can be straight-chain or branched and can have 1 to 6 carbon atoms, as well as the Addition salts of these compounds with pharmaceutically acceptable acids. 2. Compounds according to claim 1, characterized in that 1 own. through this that m and η have the value 3. Compounds according to claim 2, characterized characterized in that the group R is a Represents trifluoromethyl group, a methylthio group or an ethylthio group. 4. Process for the preparation of the compounds according to claim 1, characterized in that one a 2-methoxy-5-R-benzoic acid of the general formula II , COOH (II) OCH ₃ in which R has the meanings given in claim 1, or a functional derivative of this acid with a Pyrrolidine, in the form of the racemate or the enantiomer, of the general formula III CH ₂ NH ₂ (C. (CH ₂ ) - (III) ^CH 909836/0688 SYNTHELABO - SET 23 - 3 - in which η and m have the meanings given in claim 1. 5. Medicinal product / characterized in that it consists of at least one compound according to claims 1 to 3 and customary, pharmaceutically acceptable binders / carrier materials and / or auxiliary materials. 9 0 9836/0688