CH637378A5 - CYCLOALKYLALKYLIC BENZAMIDES. - Google Patents

Description

The present invention relates to 2-methoxy benzamides in the form of racemates or enantiomers, their addition salts with

(CH2 »n

2-methoxy-5-trifluoromethyl benzoic acid has already been described in the literature.

The 2-methoxy-5-alkylthio-5 benzoic acids (II) and their chlorides are obtained according to the following reaction scheme:

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(See head of next page)

The cycloalkylalkylpyrrolidines (III) are obtained, for example, according to the methods described by the holder in its patents Nos. 74.41718 and 77.19391.

The condensation is carried out at a temperature of 0 to 30 ° C in a solvent such as acetone.

The following examples illustrate the present invention.

IR and NMR analyzes and spectra confirm the structure of the compounds.

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Example 1:

N- [(1-cyclopropylmethyl-2-pyrrolidinyl) methyl] 2-methoxy

5-methylthio benzamide and its hydrochloride.

1. 2-Methoxy-5-chlorosulfonyl benzoic acid.

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44 ml (0.506 mol) of sulfuric hydrochloride are introduced into a three-necked flask with stirring and refrigerant and the mixture is cooled to 5 °.

20 g of 2-methoxy-benzoic acid are then added in small portions at such a speed that the temperature can be maintained.

60 between 10 and 15 °. Once the addition is complete, the medium is allowed to return to ambient temperature and then to remain there for 1 h. The temperature is then gradually brought to 60-70 ° where it is maintained for 1 h, which corresponds to the end of the gassing. The medium is then allowed to cool and this brown liquid is poured into a

65 mixture of 60 ml of water and 250 g of ice. A solid appears which is filtered and washed several times with ice water. It is then dried under vacuum at 80 ° C.

F = 143-145 ° C

5

637,378

COOH

Cl SO.

+ Cl S03 H

COOH

OCH-

HOOC

RS

(he)

2. 4-dithiobisfmethoxy-benzoic acid-3).

100 g (0.4 mol) of 2-methoxy-5-chlorosulfonyl benzoic acid, 750 ml of ethanol and 500 ml of 12N concentrated hydrochloric acid are introduced into a reactor fitted with a mechanical stirrer.

To the suspension, vigorously stirred, 130.8 g of zinc powder (2 mol) are added in portions, over approximately 2 hours, so as to maintain the temperature at 15-20 ° C., cooling if necessary by a bath of 'frozen water.

At the end of the operation, the medium is filtered.

To the filtrate, 1 l of water is added and, with stirring, 70 g of ferric chloride. It is left stirring for 1 hour, then the precipitated product is filtered, which is washed 3 times with water. It is purified by dissolving in a solution of sodium bicarbonate in the presence of black. The insoluble material is separated by filtration. The filtrate is acidified with excess hydrochloric acid, and the resulting precipitate is filtered, is washed 3 times with water, then dried.

After recrystallization from acetic acid, washing with ether and drying for 8 h at 80 ° C. under vacuum, the compound is obtained.

F = 212-212.5 ° C

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

50 g (0.136 mol) of dithiobis (4-methoxy-benzoic-3) acid are introduced into a reactor and a solution of 27.3 g (0.682 mol) of NaOH in 11 of water is added.

To the resulting solution is added dropwise 34.8 g (0.275 mol) of methyl sulfate. Agitation is carried out for 4 h, then the ether is extracted. The aqueous phase is collected and acidified. The resulting oil is extracted with ether, dried over magnesium sulfate and evaporated. A solid is collected which is triturated in cyclohexane.

F = 68.5-69 ° C

14.4 ml (0.2 mol) of thionyl chloride and 19.8 g (0.1 mol) of acid are introduced into an Erlenmeyer flask. The mixture is stirred at ambient temperature and then heated to reflux for 4 h.

It is evaporated to dryness, and the residual oil is distilled in a ball tube.

Eb0jl = 180 ° C

4. N- [(1-cyclopropylmethyl-2-pyrrolidinyl) methyl] 2-methoxy

5-methylthio benzamide.

10.7 g (0.069 mol) of cyclo-propylmethyl-1-aminomethyl-2 pyrrolidine, 9.6 g (0.069 mol) of potassium carbonate and acetone are introduced into an Erlenmeyer flask. While cooling in 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. Stir 2 h at room temperature. It is evaporated to dryness at a temperature of <40 ° C. and it is taken up in water and chloroform. The organic phase is collected, it is extracted in an acid medium, the aqueous phase is alkali-nized and extracted with chloroform. It is dried over magnesium sulfate and evaporated. An oil is collected which is passed through a column of silica, eluting with acetone.

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Eb005 = 240 ° C

5. Hydrochloride.

6.68 g (0.02 mol) of N - [(cyclopropylmethyl-1 pyrrolidinyl-2) methyl] 2-methoxy-5-methylthio-benzamide are introduced into 50 100 ml of ether. An equimolar quantity of hydrochloric ether is added dropwise, the oil is separated.

It is taken up in 100 ml of ether and stirred, then evaporated to dryness. The residual oil is triturated in 100 ml of ethyl acetate. After 1 hour, a white solid appears. It is filtered and dried.

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F = 111.5-112 ° C

Example 2:

(S) (-) Isomer of N- [(1-cyclopropylmethyl-2-pyrrolidinyl) M methyl] 2-methoxy-5-methylthio-benzamide.

10.7 g (0.069 mol) of 2-amino-methyl-cyclopropylmethyl-1 Pyrrolidine (S), 9.6 g (0.069 mol) of potassium carbonate and acetone are introduced into an Erlenmeyer flask. While cooling with an ice bath and under a stream of nitrogen, 65 g (0.069 mol) of 2-methoxy-5-methylthio-benzoic acid chloride dissolved in acetone are added dropwise.

The mixture is left to return to ambient temperature and stirred for 2 h. The residual oil is evaporated to dryness and triturated in water and ether.

637,378

The organic phase is collected which is extracted in an acid medium, it is basified with sodium carbonate and extracted with ether. It is dried over magnesium sulfate and evaporated, an oil is collected which is passed over a column of silica, eluting with ethyl acetate and then with acetone. The oil obtained is distilled.

Eb0> 05 = 220 ° C [a] 2D ° = -83 ° (c = 1, DM F) The hydrochloride is obtained in hydrochloric ether.

F = 116-116.5 ° C [a] $ = + 21 ° C (c = l, DMF) Example 3:

N- [(1-cyclopropylmethyl-2-pyrrolidinyl) methyl] 2-methoxy-5-ethylthio-benzamide.

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

The procedure is as in Example 1, replacing the methyl sulfate with ethyl sulfate.

Mp 58-59 ° C for the acid. Eb0 05 = 160 ° C for the acid chloride.

2. N - [(1-cyclopropylmethyl-2-pyrrolidinyl-methyl] 2-methoxy-5-ethylthio-benzamide.

9.4 g (0.0611 mol) of cyclo-propylmethyl-1-aminomethyl-2 pyrrolidine, 8.5 g (0.0611 mol) of potassium carbonate and acetone are introduced into an Erlenmeyer flask. At a temperature <10 ° C. and under a stream of nitrogen, 14.1 g (0.0611 mol) of 2-methoxy-5-ethylthio-benzoic acid chloride in acetone are added dropwise. The mixture is stirred for 2 h at room temperature. Evaporated to dryness, taken up in water and chloroform; the organic phase is separated, the extract in an acid medium, alkalized, extracted with chloroform, dried over magnesium sulfate and evaporated. An oil is collected which is passed over a column of silica, eluting with acetone. An oil is collected which is distilled.

Eb005 = 240 ° C

Example 4:

N- [(1-cyclopropylmethyl-2-pyrrolidinyl) methyl] 2-methoxy-5-trifluoromethyl-benzamide and its hydrochloride.

6.37 g (0.0413 mol) of 2-amino-methyl-cyclopropylmethyl-1 pyrrolidine, 5.7 g (0.0413 mol) of potassium carbonate and 125 ml of acetone are introduced into an Erlenmeyer flask. cooled to about 5 ° C and poured slowly dropwise (T <8 ° C) 9.85 g (0.0413 mol) of 2-methoxy-5-trifluoromethyl benzoic acid chloride in 50 ml of acetone, under a stream of nitrogen. After the addition, the mixture is stirred for 2 h in melting ice and 1 h at room temperature, then it is evaporated to dryness. The residue is taken up between water and ether, decanted, reextracted 2 times the mother liquors and washed the organic extracts before drying over magnesium sulfate. It is filtered, evaporated to dryness and a yellow oil is obtained.

The benzamide hydrochloride is prepared by stirring in dry ether using HCl in ether. The solid is drained, washed and dried. The solid is recrystallized twice from acetone and a fine white powder is obtained.

F = 149.5-150 ° C

Example 5:

(S) (-) Isomer of N- [(1-cyclopropylmethyl-2-pyrrolidinyl) methyl] 2-methoxy-5-trifluoromethyl-benzamide.

2.15 g (0.0139 mol) of 2-amino-methyl-cyclopropylmethyl-1 pyrrolidine (S), 1.92 g (0.0139 mol) of potassium carbonate and 100 ml of are introduced into an Erlenmeyer flask. acetone. While cooling in an ice bath and under a stream of nitrogen, 3.32 g (0.0139 mol) of 2-methoxy-5-trifluoromethyl-5-benzoic acid chloride in acetone is added dropwise. The mixture is left to return to ambient temperature and stirred for 2 h.

Evaporated to dryness, taken up in water and ether. The organic phase and the extract are collected in an acid medium. Basified with sodium carbonate, extracted with ether, dried over magnesium sulfate and evaporated.

An oil is collected which is distilled.

Eb005 = 250 ° C = —75.5 ° (c = 1, DMF)

Board

Compound

R

m n

Melting or boiling (° c)

1

ch3s

1

1

Base Eb005 = 240 HCl F = Ìli, 5-112

2

(S)

ch3s

1

1

Base Eb0 05 = 220 HCl f = i 16-116.5

3

C2HsS

1

1

Base Eb005 = 240

4

cf3

1

1

HCl F = 149.5-150

5

(S)

cf3

1

1

Base Eb005 = 250

The compounds of the invention have been subjected to pharmacological tests in the field of the central nervous system.

The toxicity was evaluated in Swiss CD1 male mice, with an average weight of 20 g i.p.

The LDS0 ranges from 75 to 200 mg / kg.

Neuroleptic activity was determined by the antagonism towards climbing induced by apomorphine in mice [Gouret C. (1973), "J. Pharmacol." (Paris), 4, 341],

The SAR 0 varies from 0.03 to 0.08 mg / kg, i.p.

The compounds of the invention can be used in the treatment of various psychomatic affections and mental disorders (depressive states and psychoses).

The invention includes all pharmaceutical compositions containing the compounds (I) and their salts as active ingredients, in combination with any excipients suitable for their administration by oral, endorectal or parenteral route.

All pharmaceutical forms suitable for the oral, endorectal or parenteral routes are suitable.

The daily dosage can range from 1 to 200 mg.

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R

Claims (9)

637,378 CLAIMS 1. Benzamides corresponding to the formula: r ^. co - nh - ch_ —1. \> ^ \ OCH. (ch_) 2 n in which n and m are equal, independently of one another, to 1, 2,3 or 4, and R represents the radical CF3 or an alkylthio radical in which the alkyl is straight or branched and has from 1 with 6 carbon atoms, as well as their pharmaceutically acceptable addition salts with acids. 2. Benzamides of formula I according to claim 1, in the form of racemates. 3. Benzamides of formula I according to claim 1, in the form of enantiomers. 4. Benzamides according to one of claims 1 to 3, characterized in that m and n are equal to 1. 5. Benzamides according to claim 4, characterized in that R represents CF3, CH3S or C2HsS. 6. Process for preparing the compounds according to claim 1 and their addition salts with acceptable pharmaceutical acids, characterized in that a 2-methoxy-R-5 benzoic acid of formula is reacted: , pharmaceutically acceptable cooh acids, their preparation and their therapeutic use. The compounds of the invention correspond to the formula: co - nh - ch2 —i sth „ or one of its functional derivatives with a Pyrrolidine of formula: 2 m ch2nh2 cch_) 2 n in the form of a racemate or an enantiomer. 7. Method according to claim 6, characterized in that an acid ester of formula (II) or a halide is involved, the latter preferably in the presence of an acid acceptor agent. 8. Method according to claim 6, characterized in that the compounds of formula (I) obtained are converted into their addition salts with pharmaceutically acceptable acids, by the action of a corresponding acid. 9. Use of the compounds of formula (I) according to claim 1 for the preparation of a medicament intended for the treatment of depressive states and psychoses. och, (ch_) 2 n in which n and m are equal, independently of one another, to 1,2, 3 or 4, and R is the radical CF3 or an alkylthio radical in which the alkyl is straight or branched and has from 1 to 6 carbon atoms. The compounds of the invention are active in the field of the central nervous system. According to the invention, the compounds are prepared by condensation of a 2-methoxy-R-5 benzoic acid (II) or of one of its functional derivatives (halide, ester) and of a Pyrrolidine, in the form of a racemate or d 'enantiomer, of formula: 30 (ii) ch2 nh2 (III)