NZ238710A - 4-aminobutyric acid derivatives and pharmaceutical - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £38710 * 23 8 7 1 Priority Dat8(s): a.Turn. .tlfffo.....

Complete Specification Filed: Jff' Clsss: cpnoaa&lu*. teivtefJityh;. (.QIcqh/VI-Calami^, f°ioty&/.Q.x Publication Date: ,. X 5 J. P.?. J??!*. P.O. Journal, No: ......IsCTTl pass Cont: J?p; %. fflrnikZyZtySl, &?;. fRlP2.7j](* h. tj&F.MS.kZf. .St \ pass Cont: , 1>,\ ,^^7, NEW ZEALAND PATENTS ACT, 1953 NO DRAWINGS No.: Date: 28 ,Ufl 199lM A\ A COMPLETE SPECIFICATION NEW 4-AMINOBUTYRIC ACID COMPOUNDS, PROCESS FOR THE PREPARATION THEREOF AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM f ADIR ET COMPAGNIE, a French body corporate, of 1, rue Carle Hebert,192415, J Courbevoie, Cedex, France, hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement (foilwed by page la) 23 8 7 1 0 - 10.- The invention relates to new 4-aminobutyric acid compounds, a process for the preparation thereof and pharmaceutical preparations containing them.

Numerous arylpropionic compounds are known from the literature that have, in particular, analgesic and antiinflammatory properties. Also known is baclofen or 4-amino-3-(4-chlorophenyl)butyric acid, a compound agonistic to GABAb receptors which is used in human therapeutics on account of its antispastic properties. Other lo 4-amino-3-arylbutyric acids, especially heteroarylbutyric compounds, which exhibit an affinity to the GABAb receptor, have also been described (J. Med. Chem. 1987, 30, 743 - 746).

In comparison with the compounds of the prior art, 15 the compounds of the present invention exhibit a very selective and distinctly greater affinity. In addition, some of them antagonise the excitation induced by convul-sants at doses lower than that of baclofen. Others exhibit the property of stimulating the synthesis of 20 cyclic AMP in the cerebral cortex, and therefore of increasing the metabolic capacities of the brain. The intensity of that affinity to the GABAb receptor and the strength of their activity renders possible, in human or animal therapeutics, the administration of lower doses 25 of the compounds of the invention. This reduced dosage goes hand in hand with a reduction in the side effects that are observed with less active compounds since it is generally recognised that toxicity has no connection with the mechanism of pharmacological action but depends 30 essentially on the chemical structure of the compounds.

Thus, small amounts of the compounds of the invention produce an effect comparable to that obtained with much greater amounts of the compounds of the prior art; the risks of toxic effects, especially hepatic ones, are 2387 10 greatly reduced. That advantage is particularly valuable in the case of the weak populations for which the compounds are intended, generally individuals suffering from spastic disorders or elderly individuals (Alzheimer's disease, individuals suffering from senile dementia or affected by disorders connected with senescence) , these populations often already suffering from disorders of the hepatic functions.

More specifically, the invention relates to new 4-10 aminobutyric acid compounds corresponding to the general formula (I): CH2_ CO— R1 R— CH (I) CH2— NH— R2 in which: - Ri represents a hydroxy, amino, lower alkylamino or lower alkoxy group, or a halogen atom, - R2 represents a hydrogen atom, a lower alkyl radical, a lower acyl radical, or a lower alkoxy-carbonyl radical, - R represents: • a radical of the formula 23 8 7 1 0. in which: X represents an oxygen or sulphur atom or an NH group, Y represents a carbon, oxygen or nitrogen atom, R'l and R'2* which are identical or different, represent a halogen or hydrogen atom or a lower alkyl, lower alkoxy, hydroxy, nitro, amino, lower alkylamino or tri-fluoromethyl radical, with the proviso that, when X is an oxygen atom, Y is a carbon atom and each of R'i and R2 is a hydrogen atom, then R'2 can represent neither a hydrogen atom nor a methoxy group, . a radical of the formula in which: Z represents an oxygen or sulphur atom or an NH group, T represents a carbon or nitrogen atom, R'3 and R14, which are identical or different, represent a radical selected from hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, nitro, amino, lower alkylamino or tri-fluoromethyl, with the proviso that, when Z is a sulphur atom, T is a carbon atom and 23 8 7 1 R'3 is a hydrogen atom, R*4 may not be a methyl grouping or a hydrogen, chlorine or bromine atom, and that, when Z is an oxygen atom, T is a carbon atom and R*3 is a hydrogen atom, R'4 may not be a hydrogen atom or a methyl group, . a cycloalkyl radical having 4 or 5 carbon atoms or a cycloalkylalkyl or dicycloalkylalkyl radical having from 4 to 16 carbon atoms, optionally substituted at rings level by a group selected from halogen, hydroxy, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino or trifluoromethyl, . an optionally substituted aromatic radical having 6 ring members that includes 2 or 3 nitrogen atoms in its carbon skeleton, . an aromatic radical having 6 ring members that includes from 1 to 3 nitrogen atoms in its carbon skeleton and is fused to a benzene ring, it being optionally possible for each of these 2 rings to be substituted, . or a saturated or unsaturated ring having seven ring members that includes one or two nitrogen atoms in its carbon skeleton and is optionally fused to a benzene ring and is optionally substituted on the nitrogen and/or benzene ring, the term "substituted" indicating that the groups so qualified can be substituted by one or more groups selected from halogen atom, lower alkyl, lower alkoxy, hydroxy, trifluoromethyl, nitro, amino or lower alkylamino 23 8 7 1 their optical isomers and also, where appropriate, their salts of addition with a pharmaceutically acceptable base or acid, it being understood that, unless otherwise indicated, the terms "lower alkyl", "lower alkoxycarbonyl", "lower alkoxy", "lower alkylamino" and "lower acyl" indicate groups containing from 1 to 6 carbon atoms in a straight or branched chain.

Of the pharmaceutically acceptable acids or bases that can be used to convert the compounds of the invention into salts there may be mentioned, by way of non-limiting examples, hydrochloric, hydrobromic, sulphuric, nitric, oxalic, malic, maleic, succinic, tartaric, methanesulphonic, camphoric and camphosulphonic acid, sodium hydroxide, potassium hydroxide, triethylamine, diethylamine, ethanolamine or diethanolamine, arginine, lysine, ...

The invention also includes the process for the preparation of the compounds of formula (I), characterised in that there is used as starting material a compound of formula (II): R —CH— CH2 \ | > = 0 (II) CH2— NH^ in which R is as defined in formula (I), which can be: - either hydrolysed by the action of a metal hydroxide to obtain, after optional purification, a compound of formula (I/a): R—CH— CH2— COOH | (I/a) CH2— NH2 a particular form of the compounds of formula (I) in which Ri represents a hydroxy group, R2 represents a hydrogen atom and R is as defined in formula (I), - or converted by the action of a lower alkyl dicarbonate in the presence of a strong base into a compound of formula (III): R —CH— CH2 1 ^ — 0 /TTT> CH2—N-— (HI) R23 in which R is as defined above and R23 represents a lower alkoxycarbonyl group, which is treated, after optional purification, with an alkali metal hydroxide in an anhydrous medium, and then with an acid to obtain a compound of formula (I/b): R —CH— CH2— COOH I CH2— NH— r23 in which R and R23 are as defined above, a particular form of the compounds of formula (I) in which Ri represents a hydroxy group, R2 represents a lower alkoxycarbonyl radical and R is as defined in formula (I), which, treated in an acidic medium, yields a compound of 20 formula (I/a) such as defined above, (I/b) which compound of formula (I/a), irrespective of the process by which it has been obtained, may, if desired, be converted by a halogenating agent into its halide of 23 8 7 1 0 formula (I/c): CH2 CO—Hal R—CH (I/c) I CH2— NH2 in which Hal represents a halogen atom and R is as defined in formula (I), a particular form of the compounds of formula (I) in which Ri represents a halogen atom, R2 represents a hydrogen atom and R is as defined in formula (I), which compound of formula (I/a) or (I/c) can be treated, if desired: - with a compound of the formula: Rl" - H in which Ri" represents an amino, lower alkylamino or lower alkoxy group, to yield a compound of formula (I) in which Ri represents an amino, lower alkylamino or lower alkoxy group, - and, if desired, with an alkylating agent such as dimethyl sulphate or an alkyl halide of the formula: R21 - X in which R21 represents a lower alkyl group and X represents a halogen atom, 23 8 7 | to yield a compound of formula (I) in which R2 represents a lower alkyl group, - or, if desired, with an acid chloride of the formula: ) R22CI - or an acid anhydride of the formula: R22OR22 R22 representing a lower acyl grouping, to yield a compound of formula (I) in which R2 represents a lower acyl group, the compounds of formula (I) then, if desired, being either resolved into their optical isomers and then converted into salts by the addition of a pharmaceutically acceptable base or acid, or converted directly into salts in racemic form by the addition of a pharmaceutically acceptable base or acid.

The compounds of formula (II) can be obtained: - either by condensing, in an aprotic apolar solvent, an aldehyde of formula (V): R - CHO (V) in which R is as defined in formula (I), with a carboxymethylidenetriphenylphosphorane ester of formula (VI): (C6H5)3 - P = CH - COOR' (VI) 23 8 7 - 9 in which R' represents a lower alkyl radical, to obtain an ester of formula (VII): R - CH = CH - COOR' (VII) in which R and R' are as defined above, which is condensed in a protic polar medium with nitro-methane in the presence of a strong base, to obtain a compound of formula (VIII): r_ch_ch2_coo8' (vm) CH2— N02 in which R and R' are as defined above, io which is reduced in an alcoholic medium by the action of hydrogen in the presence of a metal catalyst, to form a compound of formula (IX): R—CH—CH2—COOR' | * CH2— NH2 in which R and R' are as defined above, which is cyclised by heating to form a compound of formula (II): r —CH— CH2 \ I j;c=o {id CH2— NH. in which R is as defined in formula (I), - or by treating a compound of formula (X): 23 RCOCH3 (X) in which R is as defined in formula (I), at elevated temperature and in the presence of zinc with a compound of formula (XI): Br - CH2 - COOA (XI) in which A represents a lower alkyl grouping, to yield, after optional acidic hydrolysis, extraction and purification, a compound of formula (XII): R — C = CH — COOA I CH3 in which R and A are as defined above, which is treated with N-bromosuccinimide to yield a compound of formula (XIII): R — C = CH — COOA CH2 Br in which R and A are as defined above, which is treated with ammonia, preferably an excess thereof, to yield a compound of formula (XIV): R—C = CH CH2— H (XII) (XIII) \ (XIV) C —0 »/ in which R is as defined above, 23 8 7 1 0 which is subjected to catalytic hydrogenation to obtain a compound of formula (II) as defined above.

The compounds of formula (II), wherein R does not represent: - a 2-benzofuryl group substituted in the benzene nucleus by a chlorine atom, a bromine atom or a methoxy group, - or a 2-benzothienyl group, and the compounds of formula (III) are new and are an integral part of the present invention in their capacity as starting materials that can be used for the synthesis of the compounds of the invention.

The compounds of formula (I) possess valuable pharmacological properties. They have a very great and selective affinity to the GABAb receptor, which is greater than that of the compounds of the prior art.

Some of them exhibit a GABAb receptor-antagonising activity and can therefore be administered in the treatment of memory disorders, mental disorders connected with senescence, and also in the treatment of Alzheimer's disease.

Other compounds, on the other hand, exhibit an agonist activity and are therefore suitable for spastic individuals or individuals suffering from Angina pectoris.

The present invention also relates to pharmaceutical compositions containing the compounds of formula (I) or 23 8 7 one of their salts of addition with a pharmaceutically acceptable acid or base, alone or in combination with one or more pharmaceutically acceptable inert, non-toxic excipients or carriers.

Of the pharmaceutical compositions according to the invention there may be mentioned more particularly those that are suitable for oral, parenteral, nasal, rectal, perlingual, ocular or pulmonary administration, and especially injectable preparations, aerosols, eye or nose drops, tablets or dragees, sublingual tablets, soft gelatin capsules, sachets, suppositories, creams, ointments, dermal gels, ....

The dosage varies according to the age and weight of the patient, the route of administration, the nature of the disorder and any associated treatment and ranges from 1 mg to 1 gram per 24 hours.

The following Examples illustrate the invention and do not limit it in any way.

The starting materials are described in the literature or can be prepared in a similar manner.

The 1H nuclear magnetic resonance spectra (NMR) were produced using tetramethylsilane (TMS) as the internal reference. The chemical displacements are expressed in parts per million (ppm).

The infrared spectra were effected in the form of potassium bromide discs containing approximately 1 % of the product to be analysed. 23 8 7 1 EXAMPLE 1: 3-(2-(5-isopropylbenzofuryl))-4-aminobutanoic acid STAGE A : ethyl 3-(2-(5-isopropylbenzofuryl))-propenoate A solution containing 0.1 mol of 2-(5-isopropyl)-benzofurylcarbaldehyde and 0.1 mol of ethoxycarbonyl-methylidenetriphenylphosphorane in 200 cm3 of benzene is heated under reflux for 4 hours under a nitrogen atmosphere. It is then cooled and the solvent is evaporated under reduced pressure. The residue is taken up in 200 cm3 of ether, the insoluble material is removed by suction-filtering and the filtrate is evaporated to dryness and then the evaporation residue is distilled under reduced pressure. The compound of stage A is obtained: b.p. (3 mm Hg) = 186°C.

STAGE B ; ethyl 3-(2-(5-isopropylbenzofuryl) )-4-nitrobutanoate 0.05 mol of the compound obtained in stage A of Example 1 is heated for 18 hours at 70°C in 50 cm3 of nitromethane and 2 cm3 of a 40 % methanolic solution of Triton B. The whole is cooled, neutralised with a molar solution of hydrochloric acid and extracted with ether. The ethereal phase is washed with water, dried, filtered and then evaporated to dryness. The compound of stage B is obtained after purification by high performance liquid chromatography.

STAGE C ; 4-( 2-( 5-isopropylbenzof uryl))-2-oxopyr-rolidine 0.05 mol of the compound obtained in stage B of Example 1 is reduced in an ethanolic solution by hydrogen at atmospheric pressure and at ambient temperature in the presence of Raney nickel. The whole is filtered and evaporated under reduced pressure, and then the residue is heated for 2 hours and recrystallised from petroleum ether.

Melting point; 151°C Spectral characteristics: - infrared: 1690 cm-1: v CO 3300 m-l; vNH " NMR (CDCli): 8 • • 1.26 ppm : doublet : ((CH3)2C) S • • 2.75 ppm : doublet : (CH2 CO) 8 • • 2.80 - 3. ppm : multiplet : (CH (013)2) 8 • • 3.40 - 4. ppm : multiplet: (CH, CH2 N) 8 • • .70 ppm : singlet : (NH) 8 • • 6.50 ppm : singlet : (H3', benzofuran) 8 • • 7.00 - 7. 50 ppm : multiplet : {H4', Hg', H7*; benzofuran) STAGE D : 3-{2-(5-isopropylbenzofuryl))-4-amino-butanoic acid 0.01 mol of the compound obtained in stage C of Example 1 is heated under reflux for one hour in 20 cm3 of 95 % ethanol in the presence of 5 cm3 of 40 % sodium hydroxide solution. The whole is cooled and evaporated to dryness. The residue is taken up in from 15 to 20 cm3 of water that has been acidified to pH = 1 by 10 % HC1. The whole is evaporated to dryness, taken up in from 1 to 3 cm3 of trifluoroacetic acid and chromatographed over an ion exchange resin (DOWEX 50 WH+) using a 5 % ammonium hydroxide solution as eluant. The eluant is evaporated to dryness and the residue is recrystallised from ethanol. Melting point: 190°C 23 8 Spectral characteristics: ~ infrared: 1580 cm-i; vCO 2300 - 3200 cm-l; vOH EXAMPLE 2: 3-(2-(5-methylbenzofuryl))-4-aminobutanoic acid By following the instructions in stages A to D of Example 1, but replacing the 2-(5-isopropyl)benzofuryl-carbaldehyde in stage A of Example 1 by 2-(5-methyl)-benzofurylcarbaldehyde, there are obtained in succession, after a purification stage by high performance liquid chromatography, as appropriate, the following compounds : STAGE A : ethyl 3-(2-(5-methylbenzofuryl))prop-enoate Melting point: 73°C STAGE B : ethyl 3-{2-(5-methylbenzofuryl))-4-nitrobutanoate STAGE C : 4-(2-(5-methylbenzofuryl))-2-oxopyrrol-idine Melting point; 151°C Spectral characteristics: " infrared; 1690 cm-i; v CO 3300 m-l; v NH ~ NMR (CDCIO; 8 : 2.41 ppm : singlet : (CH3) 8 : 2.69 ppm : doublet : (CH2CO) 8 : 3.50 - 4.10 ppm : multiplet : (CH2N, CH) 8 : 6.00 ppm : singlet ; (NH) 8 : 6.46 ppm : singlet ; {H3', benzofuran) w 6.90 - 7.50 ppm : multiplet s (H4'r Eta1, H7'; benzofuran) STAGE D : 3-(2-(5-methylbenzofuryl))-4-amino-butanoic acid Melting point: 191°C Spectral characteristics: - infrared: 1580 cm-*: v CO 2300 - 3200 cm-l: v (C00-, NH3+) EXAMPLE 3: 3-(2-(5-ethylbenzofuryl))-4-aminobutanoic acid By following the instructions in stages A to D of Example lf but replacing the 2-(5-isopropyl)benzofuryl-carbaldehyde in stage A of Example 1 by 2-(5~ethyl)-benzofurylcarbaldehyde, there are obtained in succession, after a purification stage by high performance liquid chromatography, as appropriate, the following compounds : STAGE A : ethyl 3-(2-(5-ethylbenzofuryl))prop-enoate Melting point: 52°C STAGE B : ethyl 3-(2-(5-ethylbenzofuryl))-4-nitrobutanoate STAGE C : 4-(2-(5-ethylbenzofuryl))-2-oxopyrrol idine Melting point: 125 - 127°C Spectral characteristics: - infrared: 1670 cm-*: v CO 3200 m-l: v NH 2387 10 - NMR (CDC1-Q : 8 8 8 8 8 8 1.25 ppm : triplet : {CH2 - CHa) 2.50 - 3.00 ppm : multiplet : (CH2 - CH3, CH2CO) 3.40 - 4.10 ppm : multiplet : (CH2N, CH) 5.93 ppm : singlet : (NH) 6.46 ppm : singlet : (H3'r benzofuran) 7.00 - 8.00 ppm : multiplet : (H^, H61, H71; benzofuran) STAGE D : Melting point: 195°C Spectral characteristics; 3-(2-(5-ethylbenzofuryl))-4-aminobutanoic acid - infrared: 1580 cm-i: v CO 15 2300 - 3200 cm-1; v OH EXAMPLE 4: 3-(2-(5-(l-methylpropyl)benzofuryl))-4-^ aminobutanoic acid By following the instructions in stages A to D of Example 1, but replacing the 2-(5-isopropyl)benzofuryl-20 carbaldehyde in stage A of Example 1 by 2-(5-(l-methyl-propyl))benzofurylcarbaldehyde/ there are obtained in succession, after a purification stage by high performance liquid chromatography, as appropriate, the following compounds: STAGE A : ethyl 3-(2-(5-(l-methylpropyl)benzo-furyl))propenoate b.p. (0.5 mm Hg) = 165°C STAGE B i ethyl 3-(2-(5-(l-methylpropyl)benzo-furyl))-4-nitrobutanoate 23 87 1 0 18 - STAGE C : 4-(2-(5-(1-methylpropyl)benzofuryl))-2-oxopyrrolidine Melting point; 111 - 113°C Spectral characteristics; - infrared; 1700 cm-i; v CO 3200 m-ls v NH - NMR (CDCIt); 8 ; 0.80 ppm : triplet : (CHi - CH2 -) 8 : 1.28 ppm ; doublet : (CH3 - CH -) 8 : 1.45 - 1.80 ppm : multiplet : (- CH2 - CH) 8 : 2.68 ppm : doublet : (CH2CO) 8 : 3.50 - 4.10 ppm ; multiplet : (CH2N, CH) 8 : 5.66 ppm : singlet : (NH) 8 : 6.49 ppm ; singlet : (H3*r benzofuran) 8 : 7.00 - 7.50 ppm ; multiplet : (H41, He', H7' ; benzofuran) STAGE D : 3-(2-(5-(1-methylpropyl)benzofuryl))-4-aminobutanoic acid Melting point: 200°C Spectral characteristics: - infrared: 1580 cm-i; v CO 2300 - 3200 cm-l; v OH EXAMPLE 5: 3-(2-(5-fluorobenzofuryl))-4-aminobutanoic acid By following the instructions in stages A to D of Example 1, but replacing the 2-(5-isopropyl)benzofuryl-carbaldehyde in stage A of Example 1 by 2-(5-fluoro)-benzofurylcarbaldehyde, there are obtained in succession, after a purification stage by high performance liquid chromatography, as appropriate, the following compounds : 2387 10 STAGE A : ethyl 3-(2- {5-f luorobenzof uryl) )prop-enoate Melting point; 112°C STAGE B : ethyl 3-(2-(5-fluorobenzofuryl))-4-nitrobutanoate STAGE C ; 4-( 2-( 5-f luorobenzof uryl) )-2-oxopyrrol-idine Melting point; 178 - 180°C Spectral characteristics; - infrared: 1690 cm-i; v CO 3200 m-l; v NH - NMR (CDCli): 8 : 2.70 ppm : doublet : (CH2 CO) 8 : 3.40 - 4.10 ppm : multiplet : (CH2N, CH) 8 : 5.75 ppm : singlet : (NH) 8 : 6.50 ppm : singlet : (H3* ; benzofuran) 8 : 6.80 - 7.50 ppm : multiplet : (H4*r He'r H7'; benzofuran) STAGE D : 3-(2-(5-f luorobenzof uryl) )-4-amino-butanoic acid Melting point; 200 - 202°C Spectral characteristics; - infrared; 1580 cm-l; v CO 2300 - 3200 cm-l; v OH - NMR (D9O) : 8 j 2.76 ppm : doublet : (CH2 CO) 8 : 3.30 - 4.00 ppm : multiplet : (CH2N, CH) 8 : 6.88 ppm : singlet : (H31 ; benzofuran) 8 : 6.90 - 7.90 ppm : multiplet : (H4', Hg'r H71 ; benzofuran) 2387 10 - 20 EXAMPLE 6; 3-(2-(5-bromobenzofuryl))-4-aminobutanoic acid By following the instructions in stages A to D of Example 1, but replacing the 2-(5-isopropyl)benzofuryl-carbaldehyde in stage A of Example 1 by 2-(5-bromo)ben-zofurylcarbaldehyde, there are obtained in succession, after a purification stage by high performance liquid chromatography, as appropriate, the following compounds: STAGE A : ethyl 3-(2-(5-bromobenzofuryl))prop-enoate STAGE B s ethyl 3-{2-(5-bromobenzofuryl))-4-nitrobutanoate STAGE C : 4-(2-(5-bromobenzofuryl))-2-oxopyrrol-idine STAGE D : 3-(2-(5-bromobenzofuryl))-4-amino-butanoic acid Melting point: 200 - 202°C Spectral characteristics: - infrared: 1580 cm-l; v CO 2300 - 3200 cm-1: v OH - NMR (D7O) : 8 : 2.76 ppm : doublet : {CH2 CO) 8 : 3.30 - 4.00 ppm : multiplet : (CH2N, CH) 8 : 6.88 ppm : singlet : (H31 ; benzofuran) 8 : 6.90 - 7.90 ppm : multiplet : (H^, Hg1, H71; benzofuran) EXAMPLE 7: 3-(2-(4,5-dichlorothienyl))-4-aminobutanoic acid 23 8 7 By following the instructions in stages A to D of Example 1, but replacing the 2-(5-isopropyl)benzofuryl-carbaldehyde in stage A of Example 1 by 2-(4,5-dichloro) thienylcarbaldehyde, there are obtained in succession, after a purification stage by high performance liquid chromatography, as appropriate, the following compounds: STAGE A : ethyl 3-(2-(4,5-dichlorothienyl))prop-enoate Melting point: 76 - 78°C STAGE B : ethyl 3-(2-(4,5-dichlorothienyl))-4-nitrobutanoate STAGE C : 4-{2-(4,5-dichlorothienyl))-2-oxopyr-rolidine STAGE D : 3-(2-(4,5-dichlorothienyl))-4-amino-butanoic acid Melting point: 188 - 195°C Spectral characteristics: - infrared: 2500 - 3400 cm-*: wide band (NH3+,C00-) 1590 cm-1: v CO - NMR (D?0) : 8 : 2.6 ppm : doublet : (CH? CO) 8 : 3.1 - 3.5 ppm : multiplet : (CH - CH2 - CO I CH? - NH2) 8 : 7 ppm : singlet : (H ; thiophene) EXAMPLE 8; 3-(2-imidazolyl)-4-aminobutanoic acid 23 8 7 1 0 By following the instructions in stages A to D of Example 1, but replacing the 2-(5-isopropyl)benzofuryl-carbaldehyde in stage A of Example 1 by 2-imidazolyl-carbaldehyde, there are obtained in succession, after a purification stage by high performance liquid chromatography, as appropriate, the following compounds: STAGE A : ethyl 3-(2-imidazolylJpropenoate STAGE B : ethyl 3-(2-imidazolyl)-4-nitrobutanoate STAGE C : 4-(2-imidazolyl)-2-oxopyrrolidine Spectral characteristics: - infrared: 3200 - 3100 cm-*: v NH 1700 cm-1: v CO - NMR (DMSO): 8 : 2.5 ppm : doublet : (CH? CO) 8 : 3.5 ppm : multiplet : (- CH - I CHs> - NH -) 8 : 6.9 ppm : singlet : (H21 ; imidazole) 8 : 7.5 ppm : singlet : (NH - CO) 8 : 10 - 11 ppm : singlet : (NH ; imidazole) STAGE D: 3-(2-imidazolyl)-4-aminobutanoic acid Melting point: 175 - 180°C Spectral characteristics: - infrared: 2700 - 3400 cm-1: v (COO-, NH3+) 1590 cm-1: v CO - NMR (D?0) : 8 : 2.6 ppm : doublet : (CH2 CO) 8 : 3.2 - 3.7 ppm : multiplet : (CH - CH? - NH) 8 : 7.05 ppm : singlet : (H2' ; imidazole) 8 23 - EXAMPLE 9: 3-(2-(5-chlorobenzofuryl))-4-aminobutanoic acid By following the instructions in stages A to C of Example 1, but replacing the 2-(5-isopropyl)benzofuryl-5 carbaldehyde in stage A of Example 1 by 2-(5-chloro) benzofurylcarbaldehyde, the following compounds are obtained in succession: STAGE A : ethyl 3-(2-(5-chlorobenzofuryl))prop-enoate STAGE B : ethyl 3-(2-(5-chlorobenzofuryl))-4- nitrobutanoate STAGE C : 4-{2-(5-chlorobenzofuryl))-2-oxopyr-rolidine STAGE D : l-tert.-butoxycarbonyl-2-oxo-4-(2-(5-chlorobenzofuryl))pyrrolidine 0.01 mol of triethylamine, 0.02 mol of di-tert.-butyl dicarbonate and 0.01 mol of dimethylaminopyridine are added under a nitrogen atmosphere and at ambient temperature to 0.01 mol of the compound obtained in stage 20 C of Example 9 in solution in 50 cm3 of methylene chloride. The reaction mixture is stirred for 7 hours and then evaporated to dryness. The residue obtained is taken up in 25 cm3 of ether and the precipitate formed is removed by filtration. The ethereal phase is washed with 25 water, dried and recrystallised from diisopropyl ether. Melting point : 123°C Spectral characteristics: 23 3 7 1 3100 cm-l : v NH 1800 cm-l : v CO (tert.-butoxycarbonyl) 1690 cm-l • v CO (lactam) 8 : 1.5 ppm : singlet : (tert.-butoxycarbonyl) 8 : 2.9 ppm : doublet : (CH? - CO) 8 : 4 ppm : multiplet : (CH - CH? - N) 8 : 6.5 ppm : singlet : (H3* ; benzofuran) 8 : 7.15 ppm : doublet : (He' ; benzofuran) 8 : 7.25 ppm : doublet : (H7* ; benzofuran) 8 : 7.5 ppm : doublet : (H4' ; benzofuran) STAGE E : 4-tert.-butoxycarbonylamino-3-(2-(5-chlorobenzofuryl))butanoic acid 0.01 mol of a molar solution of lithium hydroxide is added at ambient temperature to 0.01 mol of the compound obtained in stage D of Example 9 in solution in tetra-hydrofuran. The reaction mixture is stirred for thirty minutes, the solvent is evaporated, the residue is taken up in 25 cm3 of water and then acidified with a 10 % acetic acid solution. The whole is extracted with ether, dried, filtered, evaporated and recrystallised from hexane.

M.p.°C : 104°C STAGE F : 3-(2-(5-chlorobenzofuryl))-4-amino-butanoic acid A mixture of 0.005 mol of the compound obtained in stage E of Example 9 and 0.25 mol of trifluoroacetic acid in 100 cm3 of dichloromethane is stirred for one hour at ambient temperature and then evaporated to dryness. The residue is taken up in 25 cm3 of water and then acidified to pH = 1 with a solution of 10 % hydrochloric acid, taken up in from 1 to 3 cm3 of trifluoroacetic acid, and - infrared: - NMR (CDCli); 23 8 7 1 0 chromatographed on an ion exchange resin (DOWEX 50 WH+) using a 5 % ammonium hydroxide solution as eluant. The eluant is evaporated to dryness and the residue is recrystallised from water.

M.p.°C : 190 - 192°C IR s 2300 - 3300 cm-l : v (COO-, NH3+) 1590 cm-l • v CO - NMR (D?Q): 8 : 2.75 ppm : doublet, 2H : (CH2 - COOH) 8 : 3.25-4 ppm : multiplet - 3H : (CH - CH2 - NH2) 8 : 6.8 ppm : singlet - 1H : (furan) 8 ; 7.25 - 7.75 ppm : multiplet - 3H : (benzene) EXAMPLE 10: 3-(2-benzothienyl)-4-aminobutanoic acid By proceeding as in Example 9, but initially using 2-benzothienylcarbaldehyde in stage A of Example 9, there are obtained: STAGE D : 1-tert.-butoxycarbonyl-2-oxo-4-(2-benzothienyl)pyrrolidine and in STAGE F : the title product: M.p.°C: 192 - 197°C IR : 2300 - 3200 cm-l ; v (COO-, NH3+) 1575 cm-1 : v CO NMR {D2O): 8 : 2.7 ppm : doublet - 2H : (CH2 - CO) 8 : 3.3 - 3.5 ppm : multiplet - 2H : (CH2 - NH2) 8 : 3.75 ppm : multiplet - 1H : (CH) 8 : 7.25 - 8.10 ppm : multiplet - 5H : (benzothiophene) EXAMPLE 11: 3-(2-(5-ethoxybenzofuryl))-4-aminobutanoic 23 acid By proceeding as in Example 9, but initially using 2-(5-ethoxy)benzofurylcarbaldehyde in stage A of Example 9, there are obtained: STAGE C : 4-(2-(5-ethoxybenzofuryl)-2-oxo-pyrrolidine Melting point: 146 - 148°C Spectral characteristics: ~ infrared: 1675 cm-l : v CO 10 3250 cm-l • v NH NMR (CDCli): s • • 1. ppm : triplet : (0 - CH2 - CHi) 8 • • 2. 50 - 2. 70 ppm : doublet : (CH2, CO) 8 • • 3. 50 - 4. ppm : multiplet : (CH2 N, CH, 0 ■ - CH2 - CH3) 8 • • 6. ppm : singlet : (NH) 8 • • 6. 47 ppm : singlet : (H3' ; benzofuran) 8 • • 6. 85 ppm : doublet : (H4« ; benzofuran) 8 • • 7. 00 ppm : doublet : (H6' ; benzofuran) 8 • • 7. ppm : doublet s (H7' ; benzofuran) STAGE D : 1-tert.-butoxycarbonyl-2-oxo-4- ( 2-ethoxybenzofuryl))pyrrolidine and in STAGE F : the title product: Melting point: 200°C 25 Spectral characteristics: - infrared: 2300 - 3200 cm-l : v (COO-, NH3+) 1620 cm-l ; v CO NMR (D9O): 8 : 1.40 ppm : triplet : (CH3) 8 : 2.60 : doublet : (CH2CO) 23 8 7 1 8 : 3.30 - 3.95 ppm : multiplet : (CH - CH2 - NH2) 8 : 4.10 ppm : quintuplet : (OCH2) 8 : 6.75 ppm : singlet : (£[3' ; benzofuran) 8 : 7.00 ppm : doublet : (He' ; benzofuran) 8 : 7.20 ppm : doublet : (114' ; benzofuran) EXAMPLE 12: 3-(2-benzothiazolyl)-4-aminobutanoic acid By proceeding as in Example 9, but initially using 2-benzothiazolylcarbaldehyde in stage A of Example 9, there are obtained: STAGE C : 4-(2-benzothiazolyl)-2-oxo-pyrrolidine STAGE D : 1-tert.-butoxycarbonyl-2-oxo-4-(2-benzothiazolyl)pyrrolidine and in STAGE F : the title product.

EXAMPLE 13: 3-(2-(5-trifluoromethylbenzofuryl))-4-aminobutanoic acid By proceeding as in Example 9, but initially using 2-(5-trifluoromethyl)benzofurylcarbaldehyde in stage A of Example 9, there are obtained: STAGE C : 4-(2-(5-trifluoromethylbenzofuryl))-2-oxopyrrolidine STAGE D : 1-tert. -butoxycarbonyl-2-oxo-4-( 2-( 5-trifluoromethylbenzofuryl))pyrrolidine and in STAGE F : the title product. 2387 10 - 28 EXAMPLE 14; 3-( 2-( 4-trif luoromethylthienyl) )-4-amino- butanoic acid By proceeding as in Example 9, but initially using 2-(4-trifluoromethyl)thienylcarbaldehyde in stage A of Example 9, there are obtained: STAGE C : 4-(2-(4-trifluoromethylthienyl))-2-oxopyrrolidine STAGE D : 1-tert.-butoxycarbonyl-2-oxo-4-(2-(5-trifluoromethylthienyl))pyrrolidine and in STAGE F : the title product.

EXAMPLE 15: 3-dicyclopropylmethyl-4-aminobutanoic acid By proceeding as in Example 9, but initially using 2-dicyclopropylmethylcarbaldehyde in stage A of Example 9, there are obtained: STAGE C : 4-dicyclopropylmethyl-2-oxopyrrolidine STAGE D : 1-tert.-butoxycarbonyl-2-oxo-4-dicyclo-propylmethylpyrrolidine and in STAGE F : the title product.

EXAMPLE 16: 3- (2-imidazolyl)-4-aminobutanoic acid methyl ester STAGE A : 3-(2-imidazolyl)-4-aminobutanoic acid chloride 23 8 7 0.01 mol of 3-(2-imidazolyl)-4-aminobutyric acid chloride is dissolved in 30 cm3 of methylene chloride. 0.025 mol of thionyl chloride is added and the whole is stirred at ambient temperature for 2 hours. The reaction medium is evaporated and the residue is extracted twice with chloroform after being rendered alkaline. The chloroform phases are combined and dried over calcium chloride and the chloroform is evaporated off. The residue is recrystallised.

STAGE B : 3-(2-imidazolyl)-4-aminobutanoic acid methyl ester 0.01 mol of the compound obtained in stage A of Example 16 is dissolved in 30 cm3 of pyridine. 1 cm3 of methanol is added. The whole is heated under reflux for 15 five hours, the reaction medium is evaporated in vacuo on a water bath. The residue is dried and purified by chromatography.

EXAMPLE 17: 3- (2-imidazolyl) -4-aminobutyramide 0.01 mol of the 3-(2-imidazolyl)-4-aminobutanoic 20 acid chloride obtained in Example 12, stage A, is dissolved in 50 cm3 of chloroform. A current of ammonia is bubbled in over a period of 2 hours. The reaction medium is evaporated to dryness and the residue is recrystallised.

EXAMPLE 18: 3-(2-imidazolyl )-4-amino-N-propylbutyramide 0.01 mol of the compound obtained in stage A of Example 16 is dissolved in 50 cm3 of chloroform. 0.025 mol of propylamine is added and the whole is heated under reflux for 5 hours while stirring and then cooled. 30 The reaction mixture is then evaporated to dryness and 23 8 7 1 extracted twice with chloroform. The chloroform phases are combined and dried over calcium chloride and the solvent is evaporated in vacuo on a water bath. The residue is purified by chromatography.

EXAMPLE 19 : 3—{2—{5-isopropylbenzofuryl))-4-aminobutanoic acid methyl ester By proceeding as in Example 16, but replacing the 3-(2-imidazolyl)-4-aminobutyric acid in stage A of Example 16 by 3-(2-(5-isopropylbenzofuryl))-4-aminobutyric acid, the title compound is obtained.

EXAMPLE 20; 3-(2-(5-isopropylbenzofuryl) )-4-methylamino-butanoic acid methyl ester 0.01 mol of the compound of Example 19 is dissolved in 100 cm3 of chloroform. 0.011 mol of dimethyl sulphate is added dropwise. The whole is stirred for 3 hours and the organic phase is washed with water and dried. The organic phase is evaporated to dryness and the residue is purified by chromatography.

EXAMPLE 21; 3-cyclopropylmethyl-4-aminobutanoic acid By proceeding as in Example 1, but replacing the 2-(5-isopropyl)benzofurylcarbaldehyde in stage A of Example 1 by cyclopropylacetaldehyde, there are obtained; in STAGE C : 4-cyclopropylmethyl-2-oxopyrrolidine, and in STAGE D : the title compound.

EXAMPLE 22 ; 3-(2-(4,5-dichloroimidazolyl)) -4-aminobutanoic acid 2387 10 By proceeding as in Example 1, but replacing the 2-(5-isopropyl)benzofurylcarbaldehyde in stage A of Example 1 by 2-(4,5-dichloro)imidazolylcarbaldehyde there are obtained: in STAGE C : 4-(2-(4,5-dichloroimidazolyl))-2-oxopyrrolidine, and in STAGE D : the title compound.

EXAMPLE 23; 3-( 2-( 4-methylimidazolyl))-4-aminobutanoic acid io By proceeding as in Example 1, but replacing the 2- (5-isopropyl)benzofurylcarbaldehyde in stage A of Example 1 by 2-(4-methyl)imidazolylcarbaldehyde there are obtained: in STAGE C : 4-(2-(4-methylimidazolyl))-2-oxopyrrolidine, and in STAGE D : the title compound.

EXAMPLE 24: 3- (2- {4,5-dichlorofuryl))-4-aminobutanoic acid By proceeding as in Example 1, but replacing the 2-20 (5-isopropyl)benzofurylcarbaldehyde in stage A of Example 1 by 2-(4,5-dichloro)furylcarbaldehyde, there are obtained: in STAGE C : 4-(2-(4,5-dichlorofuryl))-2-oxopyrrolidine, and in STAGE D : the title compound. 23 8 7 EXAMPLE 25: 3-(2-(4-methoxybenzothienyl))-4-aminobutanoic acid By proceeding as in Example 9, but using initially in stage A of Example 9 2-(4-methoxyJbenzothienylcarbal-dehyde, there are obtained: in STAGE C : 4—{2—(4-methoxybenzothienyl))-2-oxopyrrolidine, in STAGE D : 1-tert.-butoxycarbonyl-2-oxo-4-(2-(4 methoxybenzothienyl))pyrrolidine, and in STAGE F : the title compound.

EXAMPLE 26: 3-{2-imidazolyl)-4-acetylaminobutanoic acid methyl ester 0.01 mol of the compound obtained in stage B of Example 16 is dissolved in 50 cm3 of chloroform. 0.01 mol of acetic anhydride and 0.015 mol of sodium carbonate are added. The whole is heated under reflux for five hours while stirring. The reaction mixture is then cooled, evaporated to dryness and extracted with chloroform twice. The chloroform phases are combined and 20 dried over calcium chloride and the solvent is evaporated in vacuo on a water bath. The residue is purified by chromatography.

EXAMPLE 27: 3-(2-(4-methoxyfuryl))-4-aminobutanoic acid By proceeding as in Example 1, but using 2—(4— 25 methoxy)furylcarbaldehyde in stage A of Example 1 instead of 2-(5-isopropyl)benzofurylcarbaldehyde, there are obtained: in STAGE C : 4— (2—(4-methoxyfuryl) )-2-oxopyrrol- idine, and in STAGE D : the title compound.

EXAMPLE 28; 3- (4-pyridazinyl)-4-aminobutanoic acid By proceeding as in Example 1, but using 4-pyrid-azinylcarbaldehyde in stage A of Example 1 instead of 2-(5-isopropyl)benzofurylcarbaldehyde, there are obtained: in STAGE C : 4-(4-pyridazinyl)-2-oxopyrrolidine, and in STAGE D : the title compound.

EXAMPLE 29; 3-(2-pyrimidinyl)-4-aminobutanoic acid By proceeding as in Example 1, but using 2-pyrimid-inylcarbaldehyde in stage A of Example 1 instead of 2-(5-isopropyl)benzofurylcarbaldehyde, there are obtained: in STAGE C : 4-(2-pyrimidinyl)-2-oxopyrrolidine, and in STAGE D : the title compound.

EXAMPLE 30; 3-(2-benzimidazolyl)-4-aminobutanoic acid By proceeding as in Example 1, but using 2-benz-imidazolylcarbaldehyde in stage A of Example 1 instead of 2-(5-isopropy1)benzofurylcarbaldehyde, there are obtained: in STAGE C : 2-(2-benzimidazolyl)-2-oxopyrrolidine, and in STAGE D : the title compound. 23 87 10 EXAMPLE 31s 3-(3-azepinyl)-4-aminobutanoic acid By proceeding as in Example 1, but using 3-azepinyl-carboxaldehyde in stage A of Example 1 instead of 2—(5— isopropyl)benzofurylcarbaldehyde, there are obtained: in STAGE C : 4-(3-azepinyl)-2-oxopyrrolidine, and in STAGE D : the title compound.

EXAMPLE 32; 3-(3-(1,4-diazepinyl))-4-aminobutanoic acid By proceeding as in Example 1, but using (3-(l,4-diazepinyl))carboxaldehyde in stage A of Example 1 instead of 2-(5-isopropyl)benzofurylcarbaldehydef there are obtained: in STAGE C : 4-(3-(1,4-diazepinyl))-2-oxopyrrol- idine, and in STAGE D : the title compound.

EXAMPLE 33; 3-(3-benzo[b]azepinyl)-4-aminobutanoic acid By proceeding as in Example 1, but using (3-benzo-[b]azepinylcarbaldehyde in stage A of Example 1 instead of 2-(5-isopropy1)benzofurylcarbaldehyde, there are obtained: in STAGE C : 4-(3-benzo[b]azepinyl)-2-oxopyr-rolidine, and in STAGE D : the title compound.

EXAMPLE 34; 3-(2-(lr3,5-triazinyl))-4-aminobutanoic acid 23 8 7 By proceeding as in Example 1, but using (2-(1,3,5-triazinyl))carbaldehyde in stage A of Example 1 instead of 2-(5-isopropyl)benzofurylcarbaldehyde, there are obtained: in STAGE C : 4-(2-(1,3,5-triazinyl))-2-oxopyrrol-idine, and in STAGE D : the title compound.

EXAMPLE 35: 3-(2-indolyl)-4-aminobutanoic acid By proceeding as in Example 9, but using initially in stage A of Example 9 2-indolylcarbaldehyde, there are obtained: STAGE C : 4-{2-indolyl)-2-oxopyrrolidine, STAGE D : 1-tert.-butoxycarbonyl-2-oxo-4-( 2-indolyl)pyr rolidine, and in STAGE F : the title compound.

EXAMPLE 36s 3-(2-(5-methoxyindolyl))-4-aminobutanoic acid By proceeding as in Example 9, but using initially in stage A of Example 9 2-(5-methoxy)indolylcarbal-dehyde, there are obtained: STAGE C s 4-(2-(5-methoxyindolyl))-2-oxopyrrolidine, STAGE D : 1-1ert.-butoxycarbony1-2-oxo-4-(2-(5 methoxyindolyl)pyrrolidine. 23 8 7 1 0 and in STAGE F : the title compound.

EXAMPLE 37: 3- (2- (5-methylindolyl))-4-aminobutanoic acid By proceeding as in Example 9, but using initially in stage A of Example 9 2-(5-methyl)indolylcarbaldehyde, there are obtained: STAGE C : 4-(2-(5-methylindolyl))-2-oxopyrrol-idine, STAGE D : 1-tert.-butoxycarbonyl-2-oxo-4-(2-(5-methylindolyl)pyrrolidine, and in STAGE F : the title compound.

EXAMPLE 38: 3- (2- (5-chloroindolyl))-4-aminobutanoic acid By proceeding as in Example 9, but using initially in stage A of Example 9 2-(5-chloro)indolylcarbaldehyde, there are obtained: STAGE C : 4-(2-(5-chloroindolyl))-2-oxopyrrol-idine, STAGE D : 1 - t e r t . - b u t o x y c a r b o n y 1 - 2 - o x o - 4 - ( 3 - ( 5 -chloroindolyl)pyrrolidine, and in STAGE F : the title compound.

EXAMPLE 39: 4-tert. -butoxycarbonylamino-3-( 2- (5-methoxy-benzofuryl)Jbutanoic acid By proceeding as in Example 9, but initially using 2-(5-methoxy)benzofurylcarbaldehyde in Stage A of Example 9, there is obtained: 23 8 7 1 0 37 - in STAGE D 1-tert.-butoxycarbonyl-2-oxo-4-(2—(5-methoxybenzofuryl)pyrrolidine Melting point : 90 - 92°C Spectral characteristics: - infrared : - NMR (CDCIT) 1710 - 1740 cm-l : v CO 8 8 8 8 8 8 8 1.53 ppm 2.87 ppm 3.83 ppm 6.48 ppm 6.87 ppm 7.00 ppm 7.44 ppm singlet : (C(CH3)3) doublet : (CH2CO) multiplet : (CH3O, CH, CH2 N) sinnipt- • (H3' ; benzofuran) (H6' (H4' (H7' singlet doublet doublet doublet benzofuran) benzofuran) benzofuran) and in STAGE E : the title product: Melting point : 149 - 153°C Spectral characteristics: - infrared : - NMR (CDCl-n 1700 - 1720 cm-l 3420 cm-l ; v NH CO 8 1 .40 ppm : singlet (C(CH3)3) 8 2 .70 - 2. 90 ppm : multiplet : (CH2CO) 8 3 .40 - 3. 70 ppm : multiplet : (CH2N, CH) 8 3 .82 ppm : singlet (CH3O) 8 4 .70 ppm : singlet (NH) 8 6 .45 ppm : singlet (H3« ; benzofuran) 8 6 .82 ppm : doublet (H6' ; benzofuran) 8 6 .95 ppm : doublet (H4 * ; benzofuran) 8 7 .33 ppm : doublet (H7' ; benzofuran) EXAMPLE 40: 4-tert.-butoxycarbonylamino-3-(2-(5-methoxy-30 benzofuryl))butanamide STAGE A : 4-tert .-butoxycarbonylamino-3-( 2-(5 methoxybenzofuryl)Jbutanamide acid chloride By proceeding as in stage A of Example 16, but replacing the 3-(2-imidazolyl)-4-aminobutyric acid by the compound of Example 39, the product of stage A is obtained.

STAGE B : 4-tert .-butoxycarbonylamino-3-( 2-( 5 methoxybenzofuryl))butanamide By proceeding as in Example 17, but replacing the 3-(2-imidazolyl)-4-aminobutanoic acid chloride by the compound obtained in stage A of Example 40, the title product is obtained: Melting point : 175 - 177°C Spectral characteristics: - infrared : 1665 - 1700 cm-l • v CO 3400 cm-l ; v nh PHARMACOLOGICAL STUDY OP THE COHPODNDS OF THE INVENTION EXAMPLE 41: ACUTE TOXICITY STUDY Acute toxicity was assessed after the oral administration to groups of 5 mice (20+2 grams) of increasing doses (0.05; 0.1; 0.25; 0.50; 0.75 g/kg). The animals were observed at regular intervals over the course of the first day and daily for the two weeks following treatment. 2387 10 It appears that the compounds of the invention are atoxic.

EXAMPLE 42; STUDY OP THE AFFINITY TO GABAb RECEPTORS This study was carried out in accordance with conventional binding study techniques.

It appears that the compounds of the invention have a very strong affinity to GABAb receptors.

Thus, some of the compounds of the invention have an IC50 of 0.05 p.M in the presence of R(-) [3H] baclofen. By way of comparison, the best compound of the prior art having a similar structure (J. Med. Chem. 1987, 30, 743-746) had an IC50 in this test of 0.61 11M and baclofen had an IC50 of 0.33 pM.

EXAMPLE 43: STODY OP THE INHIBITION OF EXCITATION ACTIVITY INDUCED BY CONVULSANTS The compounds of the invention antagonise the excitatory activity induced by convulsants in hippocampal preparations.

Hippocampal preparations were prepared from the brains of sacrificed adult female rats. Transverse sections were placed in a preservative medium. After 1 hour and 30 minutes' incubation, the isolated preparations were placed under registration, perfused with a z saline solution and oxygenated. Spontaneous potentials appear which are associated with CA3 pyramidal cells. Excitation is induced by the addition of bicucullin (50 iiM).

The compounds of the invention, at various concentrations, or baclofen are then added.

The baclofen or the compounds of the invention are perfused for periods of 10 minutes. The excitation rate is calculated during the four minutes preceding the perfusion of baclofen or the compounds of the invention and during the last four minutes of the perfusion of the products to be studied.

The inhibition is expressed as percentage excitation in relation to the initial rate, which permits the determination of an inhibiting concentration 50 (IC50). The compounds of the invention have an IC50 of from 5 to 20 11M; baclofen in this test has an IC50 of approximately 50 jiM.

EXAMPLE 44: STIMULATION OP THE SYNTHESIS OP CYCLIC AMP IN THE BRAIN The compounds to be tested are administered intra peritoneally at a dose of 10 mg/kg to mice of the OF1 / IFFA Credo strain. 24 hours after the last injection, the animals are sacrificed by freezing, the cAMP present in these cerebral structures is dosed by radioimmunology according to Amersham's method (specific binding protein). Some of the compounds of the invention appear to be capable of greatly increasing the cerebral synthesis of cyclic AMP.

EXAMPLE 45:

Claims (28)

- 41 - 2387 10 PHARMACEUTICAL COMPOSITION: TABLETS Tablets each containing 1.5 mg of 3-(2-imidazolyl)-4-aminobutanoic acid. Formula for 1000 tablets: 3-(2-imidazolyl)-4-aminobutanoic acid 1.5 g wheat starch 15 g cornstarch 15 g lactose 90 g magnesium stearate 2 g silica 1 g hydroxypropylcellulose 2 g - 42 - 23 8 7 1 0 iJSffiS.CUii: :3;

1. Compounds of the general formula (I): CH2— CO— R1 R—CH (i) CH2— NH— R2 in which: - Ri represents a hydroxy, amino, lower alkylamino or lower alkoxy group, or a halogen atom, - R2 represents a hydrogen atom, a lower alkyl radical, a lower acyl radical, or a lower alkoxycarbonyl radical, and R represents: . a radical of the formula R»1 R'2 in which: X represents an oxygen or sulphur atom or an NH group, Y represents =CH- or a nitrogen atom, and R'l and R'2/ which are identical or different, represent a halogen or hydrogen atom 7 or a lower alkyl, lower alkoxy, hydroxy, ■''v ■("23 SEP I?93 23 8 7 1 0 - 43 - nitro, amino, lower alkylamino or tri-fluoromethyl radical, with the proviso that, when X is an oxygen atom, Y is =ch- and each of R'i and R2 is a hydrogen atom, then R'2 can represent neither a hydrogen atom nor a methoxy group, a radical of the formula R*3 X T Ex R'U 1 in which: Z represents an oxygen or sulphur atom or an NH group, T represents =ch- or a nitrogen atom, and R' 3 and R14, which are identical or different, represent a radical selected from hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, nitro, amino, lower alkylamino and trifluoromethyl, with the proviso that, when Z is a sulphur atom, T is =ch- and R13 is a hydrogen atom, R'4 may not be a methyl group or a hydrogen £ ri ■ - • O C' chlorine or bromine atom, and that, when Z V is an oxygen atom, T is =ch- and R13 is a hydrogen atom, R'4 may not be a \ 23 SEP 1993 hydrogen atom or a methyl group, . a cycloalkyl radical having 4 or 5 carbon atoms or a cycloalkylalkyl radical having from 4 to 16 carbon atoms, or a dieycloalkylalkyl radical having up to 16 carbon atoms, radicals forming the ring or rings being optionally substituted by a group selected from 23 8 7 1 0 - 44 - halogen, hydroxy, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino and trifiuoromethyi; . an optionally substituted aromatic radical having 6 ring members that includes 2 or 3 nitrogen atoms in its carbon skeleton, . an aromatic radical having 6 ring members that includes from 1 to 3 nitrogen atoms in its carbon skeleton and is fused to a benzene ring, it being optionally possible for each of these 2 rings to be substituted, . or a saturated or unsaturated ring having seven ring members that includes one or two nitrogen atoms in its carbon skeleton and is optionally fused to a benzene ring and is optionally substituted on the nitrogen and/or benzene ring, the term "substituted" indicating that the groupings so qualified can be substituted by one or more groups selected from halogen atom, lower alkyl, lower alkoxy, hydroxy, trifiuoromethyi, nitro, amino, and lower alkylamino, their optical isomers and also, where appropriate, their salts of addition with a pharmaceutically acceptable base or acid, it being understood that, unless otherwise indicated, the terms "lower alkyl", "lower alkoxy", "lower alkylamino" and "lower acyl" indicate •••'£* 6w • 'l groups containing from 1 to 6 carbon atoms in a V straight or branched chain. > <" „ 23 SEP 1953 238 7 10 45

2. Compounds of formula (I) according to claim 1 in which R represents a radical of the formula: R'1 R'2 in which R'i, R*2r X and Y are as defined in claim 1, their optical isomers and also, where appropriate, their salts of addition with a pharmaceutically acceptable base or acid.

3. Compounds of formula (I) according to claim 1, in which R represents a radical of the formula: in which Z, T, R'3 and R*4 are as defined in claim 1, their optical isomers and also, where appropriate, their salts of addition with a pharmaceutically acceptable acid or base.

4. Compounds of formula (I) according to claim 1, in which R represents a cycloalkyl radical having 4 or 5 carbon atoms, a cycloalkylalkyl radical having from 4 to 16 carbon atoms, or a dicycloalkylalkyl radical having up to 16 carbon atoms, their optical isomers and also, where appropriate, their salts of addition with a pharmaceutically acceptable base or acid.

5. Compounds of formula (I) according to claim 1, in ; Q which R is a radical of the formula: // 23 SEP f99 - 46 - r'2 in which R'i and R'21 which are identical or different, represent a halogen or hydrogen atom or a lower alkyl, lower alkoxy or trifluoromethyl radical, with the proviso that, when R'i and R2 are hydrogen atoms, R*2 can represent neither a hydrogen atom nor a methoxy group, their optical isomers and also, where appropriate, their salts of addition with a pharmaceutically acceptable base or acid.

6. Compounds of formula (I) according to claim 1, in which R is a radical of the formula: in which R'i and R'2r which are identical or different, represent a hydrogen or halogen atom or a lower alkyl, lower alkoxy or trifluoromethyl radical, their optical isomers and also, where appropriate, their salts of addition with a pharmaceutically acceptable base or acid. R'2

7. Compounds according to claim 1, in which R represents a group : 2 3 8 7 1 (T -Alio in which R'3 and R'4/ which are identical or different, represent a radical selected from hydrogen, halogen, lower alkyl, lower alkoxy and trifluoromethyl, with the proviso that, if R'3 is a hydrogen atom, then R'4 may not be a hydrogen, chlorine or bromine atom or a methyl group, their optical isomers and also, where appropriate, their salts of addition with a pharmaceutically acceptable base or acid.

8. Compounds according to claim 1, in which R represents a group : R'3 V u / 0 R'4 in which R'3 and R'4, which are identical or different, represent a radical selected from hydrogen, halogen, lower alkyl, lower alkoxy and trifluoromethyl, with the proviso that, if R'3 is a hydrogen atom, then R'4 may not be a hydrogen atom or a methyl group, their optical isomers and also, where appropriate, their salts of addition with a pharmaceutically acceptable base or acid.

9. Compounds according to claim 1, in which R represents a group : R'3 N S R'4 H A 238 710 10 15 - 48 - in which R'3 and Rf4, which are identical or different/ represent a radical selected from hydrogen, halogen, lower alkyl, lower alkoxy and trifluoromethyl, their optical isomers and also, where appropriate, their salts of addition with a pharmaceutically acceptable base or acid.

10. Compounds according to claim 1 in which R represents: - an optionally substituted aromatic radical having 6 ring members that includes 2 or 3 nitrogen atoms in its carbon skeleton, - an aromatic radical having 6 ring members that includes from 1 to 3 nitrogen atoms in its carbon skeleton and is fused to a benzene ring, it being optionally possible for each of these 2 rings to be substituted, - or a saturated or unsaturated ring having seven ring members that includes 1 or 2 nitrogen atoms in its carbon skeleton and is optionally fused to a benzene ring and is optionally substituted on the nitrogen and/or benzene ring, the term "substituted" indicating that the groups so qualified can be substituted by one or more groups ^ selected from halogen atom, lower alkyl, lower alkoxy, 25 hydroxy, trifluoromethyl, amino, lower alkylamino, and nitro, their optical isomers and also their salts of addition with a pharmaceutically acceptable acid or base.

11. Compounds according to claim 1, in which R represents an indolyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl or 30 azepinyl radical optionally substituted by a lower alkyl, lower alkoxy or trifluoromethyl group or by one or more halogen atoms, their optical isomers and also their salts of addition with a pharmaceutically acceptable acid or base. 20 i ' - 49 -

12. Compound according to claim 1 which is 3-(2-imida-zolyl)-4-aminobutanoic acid, its isomers and also its salts of addition with a pharmaceutically acceptable acid or base.

13. Compound according to claim 1 which is 3—(2—(5— isopropylbenzofuryl))-4-aminobutanoic acid, its isomers and also its salts of addition with a pharmaceutically acceptable acid or base.

14. Compound according to claim 1 which is 3—(2—(5— ethylbenzofuryl))-4-aminobutanoic acid/ its isomers and also its salts of addition with a pharmaceutically acceptable acid or base.

15. Compound according to claim 1 which is 3—(2—(5—(1— methylpropyl)benzofuryl))-4-aminobutanoic acid, its isomers and also its salts of addition with a pharmaceutically acceptable acid or base.

16. Compound according to claim 1 which is 3—(2—(5— fluorobenzofuryl))-4-aminobutanoic acid, its isomers and also its salts of addition with a pharmaceutically acceptable acid or base.

17. Compound according to claim 1 which is 3-(2-(4,5-dichlorothienyl )) -4-aminobutanoic acid, its isomers and also its salts of addition with a pharmaceutically acceptable acid or base.

18. Compound according to claim 1 which is 3—(2—(5— chlorobenzofuryl))-4-aminobutanoic acid, its isomers and also its salts of addition with a pharmaceutically acceptable acid or base. 50 238710

19. Compound according to claim 1 which is 3-(2-benzo-thienyl)-4-aminobutanoic acid, its isomers and also its salts of addition with a pharmaceutically acceptable acid or base.

20. Compound according to claim 1 which is 3—(2—(5— methylbenzofuryl))-4-aminobutanoic acid, its isomers and also its salts of addition with a pharmaceutically acceptable acid or base.

21. Compound according to claim 1 which is 3—(2—(5— ethoxybenzofuryl))-4-aminobutanoic acid, its isomers and also its salts of addition with a pharmaceutically acceptable acid or base.

22. Process for the preparation of the compounds of formula (I) as defined in claim 1, characterised in that there is used as starting material a compound of formula (II): in which R is as defined in formula (I), which can be: - either hydrolysed by the action of a metal hydroxide to obtain, after optional purification, a compound of formula (I/a): r—CH— CH2\ 'C = 0 (II) CH2— NH^ r —CH CH2— COOH I CH2— NH2 a particular form of the compounds of formula (I) irr f/N which Ri represents a hydroxy group, R2 represents ^ hydrogen atom and R is as defined in formula (I), i. - 51 - 238710 - or converted by the action of a C^-Cg alkyl dicarbonate in the presence of a strong base into a compound of formula (III): r —ch— ch2 C = ° CH2—N (HI) R23 5 in which R is as defined above and R23 represents a Ci-C6 alkoxycarbonyl group, which is treated, after optional purification, with an alkali metal hydroxide in an anhydrous medium, and then with an acid to obtain a compound of formula (I/b): r —ch— ch2— cooh 10 I CH2— NH— R23 20 in which R and R23 are as defined above, a particular form of the compounds of formula (I) in which Ri represents a hydroxy group, R2 represents a " cl~c6 alkoxycarbonyl radical and R is as defined in 1(- formula (I), which, treated in an acidic medium, yields a compound^of formula (I/a) such as defined above, ^ j & ^ + ^ ■ which compound of formula (I/a), irrespective of the process by which it has been obtained, may, if desired, be converted by a halogenating agent into its halide of ■ formula (I/c): CH2—CO - Hal R—CH (I/c) I CH2— NH2 52 238710 in which Hal represents a halogen atom and R is as defined in formula (I), a particular form of the compounds of formula (I) in which Ri represents a halogen atom, R2 represents a hydrogen atom and R is as defined in formula (I), which compound of formula (I/a) or (I/c) can be treated, if desired: - with a compound of the formula: in which Ri" represents an amino, Ci-Cg alkylamino or Cl_C6 alkoxy group, to yield a compound of formula (I) in which Ri represents an amino, lower alkylamino or lower alkoxy group, - and, if desired, with an alkylating agent a Ci-Cg alkyl group, -or, if desired, with an acid chloride of the formula: R22CI Rl" - H - or an acid anhydride of the formula: # - 53 - 238710 R220R22 R22 representing a C^-Cg acyl group, to yield a compound of formula (I) in which R2 represents a lower acyl group, 5 the compounds of formula (I) then, if desired, being either resolved into their optical isomers and then converted into salts by the addition of a pharmaceutically acceptable base or acid, or converted directly into salts in racemic form by the addition of a pharmaceuti-10 cally acceptable base or acid.

23- A process according to claim 22 wherein said alkylating agent is dimethyl sulphate.

24. A process according to claim 22 wherein said alkylating agent is an alkyl halide of the formula *21 - X 15 in which R2i represents a C^-Cg alkyl group and X represents a halogen atom. - 54 - 238710

25. Pharmaceutical composition containing as active principle at least one compound according to one of claims 1 to 21 in combination with one or more pharmaceutically acceptable non-toxic inert excipients or carriers.

26. Pharmaceutical composition according to claim 25 containing at least one active principle according to one of claims 1 to 21 that can be used in the treatment of spastic disorders and disorders connected with senescence.

27. A compound of the general formula (I) as defined in claim 1 substantially as herein described with reference to examples 1 to 40.

28. A process for the preparation of a compound of formula ;(I) as defined in claim 1 substantially as herein described with reference to examples 1 to 40. M IT LOHPfim By M$^er/their authorised Agents A. J. PARK & SON