FR2663025A1 - 2-Aminomethylpyrrolidine derivatives, their preparation and their application in therapeutics - Google Patents

Abstract

2-Aminomethylpyrrolidine derivatives, in the form of racemates or enantiomers, corresponding to the formula (I) in which Ar represents a phenyl, alpha -naphthyl or beta -naphthyl aromatic group, optionally substituted by one or a number of atoms or groups chosen from the following: halogen, (C1-3)alkoxy, linear or branched (C1-3)alkyl and trifluoromethyl, R1 represents a hydrogen atom or a methyl group, R2 represents a hydrogen atom, a (C1-3)alkyl group, a (C1-3)alkoxyethyl group, a (C1-3)alkoxypropyl group, a phenylalkyl group of formula C6H5-(CH2)n- in which n is 1, 2, 3 or 4, a di(C1-3)alkylaminoethyl group or a di(C1-3)alkylaminopropyl group, with the exception of the compound in which Ar is phenyl and R1 and R2 are H, and their addition salts with pharmaceutically acceptable acids. Application in therapeutics.

Description

The present invention relates to 2-aminomethylpyrrolidine derivatives, their preparation and their therapeutic application.

The compounds of the invention correspond to the formula (I) given in the annex in which
Ar represents a phenyl, a-naphthyl or a naphthyl aromatic group, optionally substituted with one or more atoms or groups selected from: halogen, (C1 3) linear or branched alkyl, (C13) alkoxy and trifluormethyl,
R1 represents a hydrogen atom or a methyl group,
R2 represents a hydrogen atom, a (C1 3) alkyl group, a (C13) alkoxyethyl group, a (C1 3) alkoxypropyl group, a phenylalkyl group of formula C6H5- (CH2) n in which n is 1, 2, 3 or 4, a di (C1 3) alkylaminoethyl group or a di (C1 3) alkylaminopropyl group, with the exception of the compound for which Ar is phenyl and R1 and
R2 are H.

The compounds of the invention exist in the form of racemates or enantiomers.

The addition salts of compounds (I) with pharmaceutically acceptable acids form part of the invention.

The compounds of the invention may be prepared according to the reaction scheme given in the appendix: the proline (II) is reacted with an aromatic halide of formula ArX (III), in which Ar has the meaning given above and X represents a halogen atom, in the presence of either salt of
Cu ++ in the form of CuO, that is to say metallic copper, in a basic medium, for example K 2 CO 3, in an aprotic solvent, such as DMF or N-methylpyrrolidone, at a temperature ranging from 100 to 1500 ° C., according to the conditions described in the reaction Ullmann (Synthesis 9 (1974)) to obtain an acid of formula (IV).

The conversion of the acid (IV) to amide (VI) is carried out in a conventional manner by treating the acid (IV) with carbonyldiimidazole in a solvent, such as tetrahydrofuran (THF) or methylene chloride ( CH 2 Cl 2), at a temperature ranging from 20 to 400 ° C to form the intermediate imidazolide which is treated in situ with an amine of formula R 1 R 2 NH (V) in which R 1 and R 2 have the meanings given above.

Compound (VI) is reduced to the amine of formula (I) by means of an alkaline hydride, such as lithium aluminum hydride or by any other appropriate means, in an ethereal inert solvent of the diethyl ether type, THF. or dioxane, at a temperature of 20 to 1000C.

Racemates can be obtained from (D, L) -proline. Pure enantiomers can be obtained either from L (-) - proline or (D) -proline, or by resolution of the racemic mixture by means of a resolving agent such as a tartaric acid derivative.

The preferred compounds of the invention are those for which
R 1 is a hydrogen atom and R 2 is either a hydrogen atom or a phenylalkyl radical and, among these, the compounds for which R 1 and R 2 are hydrogen atoms.

Among these, the compounds of choice are those for which the radical Ar is a phenyl radical bearing a substituent at the 3-position, this substituent preferably being an alkyl radical or a halogen atom.

The following examples illustrate the preparation of some compounds according to the invention.

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

Example 1 1- (3-methylphenyl) pyrrolidine-2-methylamine and its hydrochloride.

1.1. 1- (3-methylphenyl) pyrrolidine-2-carboxylic acid.

In a two-necked 2 liter flask is charged 79.0 g (0.685 mol) of DL-proline, 119.9 g (0.701 mol) of 3-bromotoluene, 97 g (0.703 mol) of K 2 CO 3 and 5.0 g of CuO in 150 cm3 of
DMF.

The mixture is heated at reflux temperature for 27 hours. The solid formed in 2 l of water is taken up, filtered, the decarboxylated product is extracted with filtered CH 2 Cl 2 and acidified with dilute HCl to pH = 4.0.

A slightly greenish solid is obtained which is filtered, rinsed with water and dried in the presence of P205.

1.2 1- (3-methylphenyl) pyrrolidine-2-carboxamide.

To 10.0 g (0.0487 mol) of the acid obtained under 1.1. in 400 cm 3 of CH 2 Cl 2 is added in portions 12.2 g (0.0755 mole) of carbonyldiimidazole and left the mixture at room temperature for 4 hours.

A limpid, yellow solution is formed.

Ammonia is bubbled through for 2 hours and the mixture is stirred at room temperature for 17 hours.

The mixture is treated with water, decanted, washed with water, dried and concentrated. A solid is obtained which is recrystallized from toluene. Mp: 147.5-1490C.

Yield = 95.5%.

1.3. 1- (3-methylphenyl) pyrrolidine-2-methylamine and its hydrochloride.

0.5 g (0.0690 mol) of LiAlH 4 in 60 cm 3 of dry THF are introduced into argon flask in a three-neck flask, then 0 ° to 5 ° C., 9.4 g (0.degree. 0460 mol) of the amide obtained under 1.2. in 120 cm3 of dry THF. The mixture is left in contact for 30 minutes and the mixture is refluxed for 9.5 hours.

The solution obtained is treated with 20 cm3 of 6.5% NaOH.

The precipitate is filtered off, rinsed with THF, dried and the solution is concentrated.

A yellow oil is formed.

The hydrochloride is prepared by reacting 8.7 g (0.0457 mole) of base and 457 cm 3 of a solution of HCl in isopropanol (0.1 mole).
A clear yellow solution is formed. It is concentrated by half and ethyl acetate is added. a white solid is formed which is filtered and recrystallized twice in an isopropanol / ethanol mixture (1/1). Mp: 228-2310C.

Yield: 71.2%.

Example 2

Isomer (S) (-) of 1- (3-methylphenyl) pyrrolidine-2-methylamine and its hydrochloride.

2.1. (S) (-) 1- (3-methylphenyl) pyrrolidine-2-carboxylic acid.

In a 500 cc flask, 16.0 g (0.138 mol) of
L (-) proline, 24.1 g (0.141 mol) of 3-bromotoluene, 19.8 g (0.143 mol) of K 2 CO 3 and 1.0 g of CuO in 30 cm 3 of DMF.

The mixture is brought to the reflux temperature for 23 hours.

The solution is taken up in 500 cm3 of water, filtered, the decarboxylated product is extracted with CH 2 Cl 2, filtered again and acidified with dilute HCl to pH = 4.0.

A brown oil is formed which is extracted with CH 2 Cl 2, dried and concentrated. Yield: 90.2%.

 2.2 (S) (-) 1- (3-methylphenyl) pyrrolidine-2-carboxamide.

In a 2 l three-neck flask, 25.4 g (0.124 mol) of the acid obtained under 2.1 are introduced under argon. gross, in 800 cm
CH 2 Cl 2 and 31.1 g (0.192 mol) of carbonyldiimidazole are added portionwise. The mixture is stirred for 5 hours at room temperature.

The solution formed is cooled with a water + ice mixture and a stream of ammonia is passed over for 2 hours.

The solution is stirred overnight, treated with water, dried and concentrated to obtain a solid which is recrystallized from a cyclohexane / toluene mixture (1/1). Yield = 18.6%. Mp 157-1590 ° C.

2.3. (S) (-) 1- (3-methylphenyl) pyrrolidine-2-methylamine and its hydrochloride.

In a three-neck flask of 500 cm 3, 1.3 g (0.0338 mol) of LiAlH 4 in 40 cm 3 of dry THF are introduced under argon and then 4.6 g (0.0225 mol) are added at 0 ° -50 ° C. of the amide obtained in 2.2.

in 100 cm3 of THF. The mixture is left in contact for 30 minutes and the mixture is refluxed for 14.5 hours. The solution is treated with 15 cm3 of NaOH at 6.5 while cooling. The precipitate is filtered off, the solution is rinsed with ethyl acetate, dried and concentrated. A brown oil is obtained.

The hydrochloride is prepared by reacting 4.25 g (0.0223 mole) of base and 230 cm3 of HCl in isopropanol (0.1 m / l). A clear and yellow solution is formed which is concentrated to 3/4, and added ethyl acetate.

The solid formed is recrystallized from an isopropanol / ethanol mixture (9/1). Mp 253.5-2570 ° C.

Yield = 77.5%. [α] D20 ad = 510 (MeOH c = 0.107).

Example 3 (R) (+) isomer of 1- (3-methylphenyl) pyrrolidine-2-methylamine and its hydrochloride.

11.85 g (0.0623 mol) of 1- (3-methyl-phenyl) -pyrrolidine-2-methylamine and 23.45 g (0.0623 mol) of (L) (-) dibenzoyltartric acid are reacted. in the form of monohydrate in 800 cm3 of methanol. A clear yellow solution is obtained at 400C. The solution is totally concentrated to give a pinkish white solid which is taken up in 600 cm 3 of ethanol. The temperature is refluxed for 4 hours. The solution is filtered hot and a white solid is obtained which is rinsed with ethyl acetate and then with ether. M.p. 187-188.50 ° C.

 [α] D -61.8 (methanol, c = 0.110).

The base is released from the salt in water, treated with saturated sodium bicarbonate solution and extracted with methylene chloride. The compound is washed with water, dried and concentrated. A yellow oil is obtained from which the hydrochloride is prepared (by reaction of 0.0145 mol of base and 145 cm 3 of hydrochloric acid in isopropanol (0.1 mol / l). light yellow, which is concentrated and the solid obtained is recrystallized from an isopropanol / ethanol mixture (9/1), mp = 258-260.5 ° C.

 [α] D20 = +49.5 (methanol, c = 0.107).

Example 4.

 1- (4-chlorophenyl) pyrrolidine-2-methylamine and its hydrochloride.

4.1 1- (4-Chlorophenyl) pyrrolidine-2-carboxylic acid.

79.0 g (0.685 mol) of (D, L) -proline, 34.2 g (0.701 mol) of 4-bromo-1-chlorobenzene, 97 g (0.703 mol) are introduced into a two-necked flask. of K2CO3 and 5.0 g of CuO in 150 cm3 of DMF.

The mixture is brought to reflux temperature for 30 hours. The solid formed in 1.5 l of water is taken up, filtered, the decarboxylated product is extracted with CH 2 Cl 2, filtered again and acidified with dilute HCl, to pH = 3.0.

A solid is obtained which is filtered and dried over MgSO 4.

It is recrystallized from a toluene / ethyl acetate (III) mixture. M = 139-143 C. Yield = 39.6%.

4.2. 1- (4-chlorphényl) pyrrolidine-2-carboxylic acid.

In a three-necked flask of 500 cm 3, the acid obtained under 1.1 is introduced under argon (0.0268 mol). in 180 cm3 of CH2Cl2 and 6.8 g (0.0417 mole) of carbonyldiimidazole are added portionwise. The mixture is left at room temperature for 4 hours.

A limpid, orange solution is formed.

Ammonia was bubbled through for 2 hours and the mixture stirred at room temperature overnight.

The mixture is treated with water, decanted, washed with water, dried and concentrated. A solid is obtained which is recrystallized in toluene. Mp 136-137.5 ° C.

Yield = 83.3%.

4.3. 1- (4-chlorphenyl) pyrrolidine-2-methylamine and the hydrochloride salt.

In a 250 cm 3 three-neck flask, 1.27 g (0.0335 mol) of LiAlH 4 in 30 cm 3 of dry THF are introduced under argon, and then 5.0 g (0.223 mol) of toluene are added at 0.degree.-50.degree. amide obtained under 4.2. in 60 cm3 of dry THF. The mixture is left in contact for 30 minutes and the mixture is refluxed for 11 hours.

The solution obtained is treated with 12 cm 3 of 6.5% NaOH.

The precipitate is filtered off, rinsed with THF, dried and the solution is concentrated.

A yellow oil is formed.

The hydrochloride is prepared by reacting 4.6 g (0.0218 mol) of base and 218 cm 3 of a solution of HCl in isopropanol (0.1 mol / l).

A clear yellow solution is formed. It is concentrated to 3/4 and ethyl acetate is added. A white solid is formed which is filtered and recrystallized twice in isopropanol. M = 215-217 C. Yield: 67.3%.

Example 5. (S) (-) - N- (phenylethyl) -1-phenylpyrrolidine-2-methanamine and its fumarate.

5.1. 1-Phenylpyrrolidine-2-carboxylic acid hydrochloride.

In a 1 L three-necked flask, 158 g (1.37 moles) of (L) (-) proline), 220 g (1.40 moles of bromobenzene, 194 g (1.40 moles) of K 2 CO 3 and g of CuO in 450 ml of DMF.

The mixture is heated at reflux temperature for 37 hours. 1 liter of water is added, the mixture is filtered through celite, the decarboxylated product is extracted with CH 2 Cl 2, filtered again and acidified with dilute HCl to pH 4.0.

It is extracted with CH 2 Cl 2, washed with water, dried and evaporated. The product is taken up in ethyl acetate and gaseous HCl is bubbled through. A solid is obtained which is filtered, rinsed with a little alcohol and dried in the presence of P2O5.

Yield = 64%.

5.2. (S) -N-phenylethyl-1-phenylpyrrolidine-2-carboxamide.

In a three-necked flask of 500 ml, 20 g (0.0878 mol) of the acid obtained under 5.1 are introduced under argon. in 150 ml of THF.

20 g (0.12 mol) of carbonyldiimidazole are added portionwise and the mixture heated at 400 ° C. for 1/2 hour and allowed to cool to room temperature. 12.5 ml (0.10 mol) of phenyl ethylamine diluted in 20 ml of THF are then added to the reaction mixture. The mixture is left stirring for 17 hours at room temperature. The THF is removed in a rotary evaporator and the mixture is taken up in water (300 ml) + 1N NaOH (50 ml). It is extracted with CH 2 Cl 2, washed with water, dried over Na 2 SO 4 and evaporated. A solid is obtained which is purified by chromatography CH2Cl2 / AcOEt. 98/2. Mp 74-760C. Yield = 85%.

5.3. (S) -N-phenylethyl-1-phenylpyrrolidine-2-methanamine and its fumarate.

0.55 g of LiAlH 4 in 80 ml of dry dioxane are introduced under argon into a 1.5 L three-neck flask and then 8 g (0.027 mol) of the amide obtained under 5.2 are added. in 80 ml of dry dioxane. The mixture is brought to the reflux temperature for 8 hours.

The solution obtained is hydrolyzed with 50 ml of 1N NaOH with cooling. Filter, extract with CH 2 Cl 2, dry and concentrate the solution. The oil thus obtained is purified by chromatography on silica using a mixture
99/1 CH2Cl2 / MeOH.

The fumarate of the compound is prepared by reacting 4.8 g (0.0174 mol) of base dissolved in 10 ml of AcOEt and 2 g (0.0174 mol) of fumaric acid dissolved in 10 ml of absolute ethanol. A white solid is formed which is recrystallized from CH3CN-MeOH (1/1).

24
Mp 193-1950 ° C. Yield: 72 8. Ea = 37.50 (c = 0.11, EtOH).

 Example 6. (S) -N- (phenylpropyl) -1-phenylpyrrolidine methanamine and its hydrochloride.

6.1. The hydrochloride of 1-phenylpyrrolidine-2-carboxylic acid is obtained in the same manner as in Example 5.1 6.2. N- (phenylpropyl) -1-phenylpyrrolidine-2-carboxamide.

In a three-necked 100 ml flask, 5 g (0.022 mol) of the acid obtained under 6.1 are introduced under argon. in 50 ml of THF is added in portions 5 g (0.022 mole) of carbonyldiimidazole and heated the mixture at 400C for 1/2 hour. It is allowed to cool to room temperature, 4.4 ml (0.031 mol) of 3-phenyl-1-propylamine diluted in 10 ml of THF are added to the reaction mixture. It is stirred for 17 hours at room temperature.

The THF is rotovaporated and the mixture is taken up in water (100 ml) and 1N sodium hydroxide (20 ml). It is extracted
CH2Cl2, wash with water, dry and evaporate. A solid is obtained which is purified by chromatography with a CH 2 Cl 2 /
MeOH (98/2). Yield 56.8%.

6.3. (S) -N- (phenylpropyl) -1-phenylpyrrolidine-2-methanamine and its hydrochloride.

In a three-necked flask of 100 ml and under argon, 0.570 g (0.015 mole) of AlLiH4 in 25 ml of anhydrous dioxane are introduced and then 2 g (0.0065 mole) of amide obtained under 6.2 are added. The mixture is refluxed for 6 hours. The solution obtained is treated with 30 ml of 1N NaOH while cooling. The precipitate is filtered off, extracted with CH 2 Cl 2, dried and concentrated. The base is obtained in the form of oil.

The hydrochloride is prepared by reacting 1.3 g (0.0044 mmol) of base and 40 ml of HCl in isopropanol (0.1 m / l). a white precipitate is formed by the addition of ether. Mp 174-175 ° C.

24
Yield = 56%. (aJ = -30.4 (c = 0.12, EtOH).

Board

Compound <SEP> Ar <SEP> R1 <SEP> R2 <SEP>[&alpha;] D <SEP> salt <SEP> F (C)
<tb> 1 <SEP> C6H5 <SEP> CH3 <SEP> CH3 <SEP> dl <SEP> HCl <SEP> 190-1
<tb> 2 <SEP> C6H5 <SEP> CH3 <SEP> CH3 <SEP> dl <SEP> HCl <SEP> 225-7
<tb> 3 <SEP> C6H5 <SEP> CH3 <SEP> CH3 <SEP> dl <SEP> HCl <SEP> 260-3
<tb> 4 <SEP> C6H5 <SEP> CH3 <SEP> CH3 <SEP> -51 <SEP> HCl <SEP> 278-280
<tb><SEP> (c = 0.12, <SEP> MeOH)
<tb> 5 <SEP> C6H5 <SEP> CH3 <SEP> CH3 <SEP> +50.5 <SEP> HCl <SEP> 277-9
<tb><SEP> (c = 0.105, <SEP> MeOH)
<tb> 6 <SEP> 4-CH3-C6H4 <SEP> H <SEP> H <SEP> dl <SEP> HCl <SEP> 240-2
<tb> 7 <SEP> 4-Cl-C6H4 <SEP> H <SEP> H <SEP> dl <SEP> HCl <SEP> 215-7
<Tb>

Compound <SEP> Ar <SEP> R1 <SEP> R2 <SEP>[&alpha;;] D <SEP> salt <SEP> F (C)
<tb> 8 <SEP> 4-CH3-C6H4 <SEP> H <SEP> H <SEP> dl <SEP> HCl <SEP> 206-8
<tb> 9 <SEP> 3-CH3-C6H4 <SEP> H <SEP> H <SEP> dl <SEP> HCl <SEP> 228-231
<tb> 10 <SEP> 3-CH3-C6H4 <SEP> H <SEP> H <SEP> -51 <SEP> HCl <SEP> 253.5-257
<tb><SEP> (c = 0.107, <SEP> MeOH)
<tb> 11 <SEP> 3-CH3-C6H4 <SEP> H <SEP> H <SEP> + <SEP> 49.5 <SEP> HCl <SEP> 258-260.5
<tb><SEP> (c = 0.107, <SEP> MeOH)
<tb> 12 <SEP> 3-Cl-C6H4 <SEP> H <SEP> H <SEP> dl <SEP> HCl <SEP> 247-250
<tb> 13 <SEP> 2-CH3-C6H4 <SEP> H <SEP> H <SEP> dl <SEP> HCl <SEP> 207-209.5
<tb> 14 <SEP> 3-CH3O-C6H4 <SEP> H <SEP> H <SEP> dl <SEP> HCl <SEP> 212-5
<tb> 15 <SEP> 2-CH3O-C6H4 <SEP> H <SEP> H <SEP> dl <SEP> HCl <SEP> 163-6
<tb> 16 <SEP> ss-C10H8 <SEP> H <SEP> H <SEP> dl <SEP> HCl <SEP> 248-251
<tb> 17 <SEP>&alpha;; - C10H8 <SEP> H <SEP> H <SEP> dl <SEP> HCl <SEP> 228-231
<tb> 18 <SEP> C6H5 <SEP> H <SEP> - (CH2) 2N (CH3) 2 <SEP> dl <SEP> HCl <SEP> 235-238
<Tb>

Compound <SEP> Ar <SEP> R1 <SEP> R2 <SEP>[&alpha;] D <SEP> salt <SEP> F (C)
<tb> 19 <SEP> 2,3- (CH3) 2-C6H3 <SEP> H <SEP> H <SEP> dl <SEP> HCl <SEP> 187-9
<tb> 20 <SEP> C6H5 <SEP> H <SEP> - (CH2) -3N (CH3) 2 <SEP> d1 <SEP> diHCl <SEP> 230-3
<tb> 21 <SEP> C6H5 <SEP> H <SEP> (CH2) 3-C6H5 <SEP> -30.4 <SEP> HCl <SEP> 174-5
<tb><SEP> (c = 0.12-C2H5OH)
<tb> 22 <SEP> C6H5 <SEP> CH3 <SEP> (CH2) 3-C6H5 <SEP> -26.5 <SEP> HCl <SEP> 109-110
<tb><SEP> (c = 0.12-C2H5OH)
<tb> 23 <SEP> C6H5 <SEP> H <SEP> (CH2) 4-C6H5 <SEP> -30 <SEP> HCl <SEP> 137-8
<tb><SEP> (c = 0.09-C2H5)
<tb> 24 <SEP> C6H5 <SEP> H <SEP> (CH2) 3-C6H5 <SEP> -53.33 <SEQ> fumarate <SEP> 163-4
<tb><SEP> (c = 0.12-C2H5OH)
<tb> 25 <SEP> C6H5 <SEP> H <SEP> CH2-C6H5 <SEP> -34.54 <SEQ> fumarate <SEP> 174-6
<tb><SEP> (c = 0.11, C2H5OH)
<tb> 26 <SEP> C6H5 <SEP> CH3 <SEP> CH2-C6H5 <SEP> -118.57 <SEQ> fumarate <SEP> 153-155
<tb><SEP> (c = 0.14, C2H5OH)
<tb> 27 <SEP> 3-CF3-C6H5 <SEP> H <SEP> H <SEP> dl <SEP> HCl <SEP> 240-244
<Tb>

Compound <SEP> Ar <SEP> R1 <SEP> R2 <SEP>[&alpha;;] D <SEP> salt <SEP> F (C)
<tb> 28 <SEP> C6H5 <SEP> H <SEP> (CH2) 2-C6H5 <SEP> -3.7 <SEP> fumarate <SEP> 193-5
<tb><SEP> (c = 0.10, <SEP> C2H5OH)
<tb> 29 <SEP> C6H5 <SEP> H <SEP> (CH2) 2-C6H5 <SEP> -70.1 <SEQ> fumarate <SEP> 160-2
<tb><SEP> (c = 0.0884, <SEP> C2H5OH)
<tb> 30 <SEP> C6H5 <SEP> H <SEP> (CH2) 2-OCH3 <SEP> -24.7 <SEQ> fumarate <SEP> 160-2
<tb><SEP> (c = 0.26, <SEP> C2H5OH)
<tb> 31 <SEP> C6H5 <SEP> H <SEP> (CH2) 2-OCH3 <SEP> -84.5 <SEQ> fumarate <SEP> 98-100
<tb><SEP> (c = 0.2, <SEP> C2H5OH)
<tb> 32 <SEP> C6H5 <SEP> H <SEP> (CH2) 3-OCH3 <SEP> -36.6 <SEQ> fumarate <SEP> 155-7
<tb><SEP> (c = 0.23, <SEP> C2H5OH)
<tb> 33 <SEP> C6H5 <SEP> H <SEP> (CH2) 3-OCH3 <SEP> -6.7 <SEQ> fumarate <SEP> 102-4
<tb><SEP> (c = 0.23, <SEP> C2H5OH)
<tb> 34 <SEP> -3,4- (CH3) -2-C6H5 <SEP> H <SEP> dl <SEP> HCl <SEP> 261-3
<tb> 35 <SEP> 3-F-C6H5 <SEP> H <SEP> -30 <SEP> fumarate <SEP> 170-2
<tb><SEP> (c = 0.14, <SEP> C2H5OH)
<Tb>

Compound <SEP> Ar <SEP> R1 <SEP> R2 <SEP>[&alpha;] D <SEP> salt <SEP> F (C)
<tb> 36 <SEP> 3-i-C3H7C6H5 <SEP> H <SEP> H <SEP> -32.5 <SEQ> fumarate <SEP> 176-8
<tb><SEP> (c = 0.16, <SEP> C2H5OH)
<tb> 37 <SEP> 3-C2H5-C6H4 <SEP> H <SEP> H <SEP> -20.7 <SEP> fumarate <SEP> 177-9
<tb><SEP> (c = 13, <SEP> C2H5OH)
<tb> 38 <SEP> 3-C2H5-C6H4 <SEP> CH3 <SEP> CH3 <SEP> -58.6 <SEQ> fumarate <SEP> 165-7
<tb><SEP> (c = 0.14, C2H5OH)
<tb> 39 <SEP> 3-C2H7-C6H4 <SEP> H <SEP> H <SEP> -43 <SEP> fumarate <SEP> 170-2
<tb><SEP> (c = 0.2, C2H5OH)
<tb> 40 <SEP> 3-CH3O-C6H4 <SEP> CH3 <SEP> CH3 <SEP> -42.7 <SEP> fumarate <SEP> 185-7
<tb><SEP> (c = 0.26, C2H5OH)
<Tb>
The compounds of the invention have been the subject of a series of pharmacological tests which have demonstrated their interest as substances with therapeutic activities.

Anticonvulsant activity
They inhibit tonic convulsions induced in mice by supramaximal electroshock. The compounds being administered intraperitoneally 30 minutes, or orally 60 minutes, before the application on the cornea of an electric shock (10 mA, 50 Hz for 0.5s), the DA50s, doses which inhibit the convulsive effects of electroshock in 50% of animals.

For the compounds of the invention the DA50s are between 5 and 50 mg / kg intraperitoneally
Antasonism activity of excitatory amino acids
They inhibit the stimulatory effects of N-methyl-D-aspartate (NMDA) on the cyclic guanosine 3 ', 5' monophosphate (cGMP) level in immature rat cerebellum, according to an assay as described in J. Neurochem . (1987), 49, No. 1, 195-200. The IC 50 concentrations, which inhibit by 50% the effects of NMDA, are of the order of 1 to 100 μM for the compounds of the invention.

Antiischemic activity
The anti-ischemic cerebral properties of the compounds of the invention were evaluated on the test of global cerebral ischemia in mice.

Overall cerebral ischemia is induced in mice after cardiac arrest caused by injection of a saturated solution of MgCl2 into the tail vein. Preliminary studies have shown that the drop in blood pressure is similar in all animals and that it is practically nil after 6.3 + 0.8 s. Cardiac arrest is sufficiently abrupt that magnesium chloride does not reach the cerebrovascular capillary bed.

The "survival time" is the time that separates the injection of magnesium chloride from the last inspiratory movement. The complete disappearance of the cerebral energy reserves or, more precisely, the loss of the autorythmicity of the cerebral respiratory centers results in a stop of the thoracic movements. This respiratory arrest occurs approximately 19 seconds after the injection of magnesium chloride.

The survival time is measured 10 minutes after an intraperitoneal injection or 30 minutes after the oral administration of the test compound. The difference between the survival time of the treated animals and the survival time of the control animals is plotted on a graph according to the logarithm of the dose (expressed in base). The dose EQ is the dose which increases the survival time of the treated animals by 3 seconds. This value is reproducible and always statistically significant.

The EQ doses of the compounds of the invention are between 10 and 100 mg / kg intraperitoneally and between 20 and 100 mg / kg orally.

Finally, the acute toxicity of the compounds of the invention was evaluated in the mouse. The LD50 lethal doses, which cause 50% mortality in animals, are between 30 and 300 mg / kg intraperitoneally, and between 100 and 1000 mg / kg orally.

The results of the tests show that, in vitro, the compounds partially or completely inhibit the effects of excitatory amino acids, more particularly NMDA. In vivo they possess anticonvulsant and anti -ischemic properties.

They can therefore be used for the treatment of neurological disorders such as convulsive states in general, epilepsy and spasticity in particular, and states of stress and anxiety.

They can also be used for the treatment or protection against cerebral ischemia of various origins such as hypoglycemic, hypoxic and, in general, in the treatment of metabolic encephalopathies, in the protection against neuronal degeneration and as amino acidopathies involving a disorder of neuronal function, and in the treatment of neurological diseases.

For this purpose they may be presented in any form suitable for their oral or parenteral administration, combined with any suitable excipients, and dosed to allow a daily dosage of i to 1000 mg.

Annex

Claims (8)

R2 are H, as well as their pharmaceutically acceptable acid addition salts. R2 represents a hydrogen atom, a (C1 3) alkyl group, a (C1-3) alkoxyethyl group, a (C13) alkoxypropyl group, a phenylalkyl group of formula C6H5- (CH2) n- in which n is 1, 2, 3 or 4, a di (C1 3) alkylaminoethyl group or a di (C1 3) alkylaminopropyl group, with the exception of the compound for which Ar is phenyl and R1 and R1 represents a hydrogen atom or a methyl group, Ar represents a phenyl, a-naphthyl or a naphthyl aromatic group, optionally substituted by one or more atoms or groups chosen from the following: halogen, (C1-3) linear or branched alkyl, (C1 3) alkoxy and trifluoromethyl,  in which

 Claims 1. Derivatives of 2-amino-methylpyrrolidine, in the form of racemates or enantiomers, corresponding to formula (I) 2. Derivatives according to claim 1, characterized in that R1 represents a hydrogen atom and R2 represents either a hydrogen atom or a phenylalkyl radical as defined above. 3. Derivatives according to claim 2, characterized in that R1 and R2 are hydrogen atoms. 4. Derivatives according to claim 3, characterized in that Ar is a phenyl radical bearing a substituent at the 3-position. 5. Derivatives according to claim 4, characterized in that Ar is a phenyl radical carrying in position 3 a linear or branched (C1-3) alkyl radical or a halogen atom. 6. Process for the preparation of the compounds according to claim 1, characterized in that the proline is reacted

 with an aromatic halide of formula ArX (III) in which Ar has the meaning given above and X represents a halogen atom, in the presence of copper salt in the form of CuO or metallic copper, in a basic medium, in a aprotic solvent, at a temperature ranging from 100 to 1500C, to obtain an acid of formula (IV)

 the transformation of the acid (IV) into amide (VI),

 in a conventional manner, by treating the acid (IV) with carbonyldiimidazole in a solvent, such as tetrahydrofuran (THF) or methylene chloride (CH2Cl2), at a temperature ranging from 20 to 400 ° C. to form the intermediate imidazolide that is treated in situ with an amine of formula R1R2NH (V) in which R1 and R2 have the meanings given above, and finally the compound (VI) is reduced

 amine of formula (I) by means of an alkaline hydride, such as lithium aluminum hydride or by any other suitable means, in an ethereal inert solvent at a temperature of 20 to 1000C. 7. Medicinal product characterized in that it consists of a compound according to any one of claims 1 to 5. 8. Pharmaceutical composition characterized in that it contains a compound according to any one of claims 1 to 5, associated with a suitable excipient.