FR2738821A1 - INDENO [1,2-E] PYRAZIN-4-ONES, THEIR PREPARATION AND THE MEDICINAL PRODUCTS CONTAINING THEM - Google Patents

Abstract

Compounds of formula (I), wherein R is a C=CH-R2, C(R3)R4, CH-NH2, CH-CH(OH)-COOH or CH-CH(OH)-COOalk radical, R1 is an -alk-NH2 or alk-NH-CO-R5 radical, R2 is a -COOH or -COOalk radical, R3 is an alkyl, -alk-Ar or -alk-Het radical, R4 is an -NH2, -NH-alk, -N(alk)-alk', -NH-CO-alk, -NH-CO-Ar', -NH-CO-ALK-Ar', -NH-CO-Het, -NH-CO-alk-Het, -NH-CO-alk-COOH, -NH-CO-alk-COOalk', -alk-COOH, -alk-COOalk', -NH-CO-NH2, -NH-CO-NH-alk, -NH-CO-NH-Ar' or -NH-CO-NH-alk-Ar' radical, or R3 and R4, together with the carbon atom to which they are attached, form a 2- or 3-pyrrolidine, 2- or 4-piperidine or 2-azacycloheptane substituted or unsubstituted ring, R5 is an -NH2, -NH-alk, -NH-Ar', -NH-cycloalkyl, -NH-alk-Ar' or -N(alk)-alk' radical, the salts thereof, the preparation thereof and medicaments containing same are described.

Description

leurs sels, leur préparation et les médicaments les contenant.INDENO [1,2-e] PYRAZIN-4-ONES, THEIR PREPARATION
AND THE MEDICINES CONTAINING THEM
The present invention relates to compounds of formula:

their salts, their preparation and the drugs containing them.

 In formula (I), - R represents a radical C = CH-R2, C (R3) R4, CH-NH2, CH-CH (OH) -COOH or CH-CH (OH) -Coealk, - R1 represents a radical -alk-NH2 or -alk-NH-CO-Rs, - R2 represents a radical -COOH1 -CoOalk, - R3 represents an alkyl radical, -alk-Ar or -alk-Het, - R4 represents a radical -NH2, -NH-alk, -N (alk) -alk ', -NH-CO-alk, -N H-CO-Ar', -N H-CO-alk-Ar ', -N H-CO-Het, - N H-CO-alk-Het, -N H-CO-alk-COOH, -NH-CO-alk-COOalk ', -alk-COOH, -alk-COOalk', -N H-CO-N H2, - N H-CO-N H-alk, -N H-CO-N H-Ar 'or -N H-CO-N H-alk-Ar', or R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine or 2-azacycloheptane ring, these rings being unsubstituted or substituted on the nitrogen atom by an alkyl radical, -COOalk, -CO-alk-COOH , -CO-alk-COOalk ', -CO-alk-NH2, -CO-alk-N H-alk', -CO-alk-N (alk ') alk ", -CO-alk, -CO-Ar' , -CO-alk-Ar ', -COHet, -CO-alk-Het, -CO-NH2, -CO-NH-alk, -CO-NH-Ar', -CO-NH-alk-Ar, -alk -COOH, -alk-COOalk ', -alk-Ar' or - alk-Het, -Rs represents a radical -NH2, -NH-alk, -N H-Ar ', -NH-cycloalkyle, -NH-alk-Ar' or -N (alk) -alk ', - alk and alk 'represent alkyl or alkylene radicals, - Ar represents a phenyl radical, - Ar' represents a phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, nitro, amino, hydroxy radicals, - COOH, -COOalk, -alk-NH2, -alk-COOH and -alk-COOalk '- Het represents a saturated or unsaturated mono or polycyclic heterocycle containing 1 to 9 carbon atoms and one or more heteroatoms chosen from O, S, N , the heterocycle being optionally substituted by one or more aikyl, phenyl, phenylalkyl or halogen atoms radicals or a phthalimido radical.

Unless otherwise stated, in the definitions above and those which follow, the alkyl and alkylene radicals and portions contain 1 to 6 carbon atoms in a straight or branched chain, the cycloalkyl radicals contain 3 to 6 carbon atoms and the halogen atoms are chosen from fluorine, chlorine, bromine and iodine.

Preferably Het represents a furyl, pyridyl, pyrimidinyl, thiazolinyl, pyrazinyl, thiazolyl, triazolyl, tetrazolyl, imidazolinyl, morpholinyl, imidazolyl, pyrrolyl, pyrrol idinyl, azetidinyl, piperazinyl, piperidinyl, thienyl, oxazolylazin ring. by one or more alkyl, phenyl, phenylalkyl or halogen atoms.

The compounds of formula (I) for which R represents a radical C = CH-R2 have isomeric forms (E and Z). These isomers and their mixtures are part of the invention.

The enantiomers and diastereoisomers of the compounds of formula (I) for which R represents a radical C (R3) R4, CH-NH2, CH-CH (OH) -COOH or
CH-CH (OH) -COOalk also form part of the invention.

The compounds of formula (I) for which R represents a radical C = CH-R2 can be prepared by dehydration of a corresponding compound of formula (I) for which R represents a radical CH-CH (OH) -COOH or
CH-CH (OH) -COOalk optionally followed by hydrolysis of the ester.

This reaction is generally carried out in an inert solvent such as dimethylformamide, at a temperature close to 10,000 or in acetic anhydride, in the presence of a quatalytic amount of zinc chloride, at the temperature of boiling of the reaction medium. The hydrolysis is carried out by any known method making it possible to pass from an ester to an acid without modifying the rest of the molecule. Preferably, it is hydrolyzed by means of a base such as an alkali metal hydroxide (soda or potash for example), within a water-lower aliphatic alcohol mixture (ethanol for example), at a temperature in the region of 20 at 30 "C.

dans lequel R1 a les mêmes significations que dans la formule (I) sur un dérivé OHC-COORa pour lequel Ra représente un atome d'hydrogène ou un radical alkyle.The compounds of formula (I) for which R represents a radical
CH-CH (OH) COOH or CH-CH (OH) COOalk can be prepared by condensation of a derivative of formula:

in which R1 has the same meanings as in formula (I) on an OHC-COORa derivative for which Ra represents a hydrogen atom or an alkyl radical.

This condensation is generally carried out in an inert solvent such as dimethylformamide or dimethylsulfoxide, in the presence of an alkali metal hydride such as sodium hydride, at a temperature between 20 and 80 "C.

The OHC-COORa derivatives are marketed or can be obtained by application or adaptation of the methods described by MT REETZ et al.,
Tetrahedron Letters, 25, 511 (1984) and AJL COOPER et al., Chem. Rev., 83, 321 (1983).

dans laquelle R1 a les mêmes significations que dans la formule (I), Rb représente un radical alkyle et Hal représente un atome d'halogène et, de pre férence, un atome de brome.The derivatives of formula (II) can be obtained by dealkylation and dealkification of the derivatives of formula:

in which R1 has the same meanings as in formula (I), Rb represents an alkyl radical and Hal represents a halogen atom and, preferably, a bromine atom.

This reaction is preferably carried out in the presence of imidazole, at a temperature between 1,100 and 200 ° C. and in particular at 16,000.

dans laquelle R1 a les mêmes significations que dans la formule (I) et Hal représente un atome d'halogène et, de préférence, un atome de brome.The derivatives of formula (III) can be obtained by the action of a 1-alkyl 1 H-imidazole-2earboxamide on a 2-haloindanone of formula:

in which R1 has the same meanings as in formula (I) and Hal represents a halogen atom and, preferably, a bromine atom.

This reaction is generally carried out in an inert solvent such as dimethylformamide, at a temperature between 50 and 15,000 and, preferably, at 115 C.

The derivatives of formula (IV) can be obtained by halogenation of the corresponding indanones by means of a halogenating agent such as bromine, chlorine, in an inert solvent such as a chlorinated solvent (methylene chloride, chloroform for example), at a temperature of -15 "C or within acetic acid, at a temperature close to 20" C, or a copper halide, within dioxane, at a temperature close to 10000 or by application or adaptation of the methods described by K. MORI, Agr.

Biol. Chem., 27 (1), 22 (1963); J. CHAKRAVARTY, Indian J. Chem., 7 (3), 215 (1969), F. G. HOLLIMAN et al., J. Chem. Soc., 9 (1960), D.

MUKHOPADHYA et al., J. Indian Chem. Soc., 47 (5), 450 (1970), in patents DE 2640358, EP 346107 and in the examples.

Indanones can be obtained by application or adaptation of the mS methods described by M. OLIVIER et al., Bull. Soc. Chim. de France, 3092 (1973), R. SEKA et al., Chem. Ber., 75B, 1730 (1942), J.J. HOWBERT et al., Synth. Commun., 20 (20), 3197 (1990), D.F. BIGGS et al., J. Med.

Chem., 19 (4), 472 (1976), C.K. INGOLD et al., J. Chem. Soc., 1469 (1923), in US patents 4263319, 4096173, JP 80161237 and EP 314400 and in the examples.

dans laquelle R1 a les mêmes significations que dans la formule (I) et Rc représente un radical -NH2 ou -Oalk dans lequel alk représente un radical alkyle.The derivatives of formula (II) can also be prepared by cyclization optionally in the presence of ammonium acetate of a derivative of formula:

in which R1 has the same meanings as in formula (I) and Rc represents a radical -NH2 or -Oalk in which alk represents an alkyl radical.

This cyclization is carried out by means of an acid such as acetic acid,
Hydrochloric acid, in an aqueous medium or in a lower aliphatic alcohol such as ethanol or methanol, at the boiling temperature of the reaction medium.

The derivatives of formula (V) for which Rc represents a radical -NH2 can be obtained by the action of ammonia on a derivative of formula (V) corresponding for which Rc represents a radical -Oalk.

This reaction is generally carried out in an inert solvent such as a lower aliphatic alcohol, at a temperature between 20 ° C. and the boiling point of the reaction medium.

The derivatives of formula (V) for which Rc represents an -Oalk radical can be obtained by the action of a 2-haloindanone of formula (IV) on a 2-alkoxycarbonylimidazole.

This reaction is carried out either by fusion at a temperature between 130 and 180 C, or in an inert solvent such as dimethylformamide in the presence of a base such as an alkali metal hydride (sodium hydride for example ), at a temperature in the region of 20 "C, either in an inert solvent such as a chlorinated solvent (chloroform for example) in the presence of an organic nitrogenous base (1, 8-diazabicyclo [5,4,01 undec-7-ene for example), at a temperature in the region of 20 "C, either in an inert solvent such as a lower aliphatic alcohol (ethanol-propanol for example), an aromatic solvent (toluene for example), a chlorinated solvent (chloroform for example), optionally in the presence of sodium iodide, at the boiling temperature of the reaction medium, ie in acetone, in the presence of an alkali metal carbonate, at a temperature between 20 "C and the boiling temperature of the reaction medium.

The 2-alkoxycarbonylimidazoles can be obtained by application or adaptation of the method described in US Pat. No. 3,600,399.

dans laquelle R1 a les mêmes significations que dans la formule (I).The compounds of formula (I) for which R represents a CH-NH2 radical can be prepared by reduction of a derivative of formula:

in which R1 has the same meanings as in formula (I).

This reduction is generally carried out using zinc, in the presence of ammonium acetate and ammonia at 28%, in a lower aliphatic alcohol such as ethanol, at the boiling point of the reaction medium. .

The derivatives of formula (VI) can be prepared by the action of an alkyl nitrite on a derivative of formula (II) corresponding.

This reaction is preferably carried out in an inert solvent such as dimethylsulfoxide, in the presence of an alkali metal hydride such as sodium hydride, at a temperature in the region of 20 "C. Preferably, isoamyl nitrite.

dans laquelle R1 a les mêmes significations que dans la formule (I) et alk représente un radical aIkyle. The compounds of formula (I) for which R represents a CH-NH2 radical can also be prepared by hydrolysis of a derivative of formula:

in which R1 has the same meanings as in formula (I) and alk represents an alkyl radical.

This hydrolysis is generally carried out using an acid such as hydrochloric acid, in an aqueous medium, at the boiling temperature of the reaction medium.

The derivatives of formula (VII) can be prepared by the action of a reducing agent on a derivative of formula (Vl) for which R1 has the same meanings as in formula (I) and then of treatment with an anhydride (RdCO ) 2O for which Rd represents an alkyl radical (1-5C).

This reaction is generally carried out within acetic acid, at a temperature between 50 and 10,000. As reducing agent, zinc is preferably used.

The compounds of formula (I) for which R represents a radical C (R3) R4,
R3 represents an alkyl radical, -alk-Ar or -alk-Het and R4 represents a radical -NH2 can be prepared by the action of a derivative of formula (VII) in which R1 has the same meanings as in formula (I) and alk represents an alkyl radical on a halide Hal-R3 for which Hal represents a halogen atom and R3 has the same meanings as in formula (I), followed by hydrolysis to release the amino function.

This reaction is preferably carried out in an inert solvent such as dimethylsu ifoxide, dimethylformamide, tetrahydrofuran, dioxane, in the presence of a base such as an alkali metal hydroxide (soda, potash for example) , optionally in the presence of tetrabutylammonium bromide in dimethylsulfoxide or in the presence of an alkali metal hydride (sodium hydride for example), at a temperature between 20 "C and the boiling point of the reaction medium. hydrolysis is generally carried out using a mineral acid such as hydrochloric acid, in an aqueous medium, at the boiling temperature of the reaction medium.

dans laquelle R3 a les mêmes significations que dans la formule (I) sur un halogénure Hal-alk-COOalk' pour lequel Hal représente un atome d'halogène, alk et alk' ont les mêmes significations que dans la formule (I), éventuellement suivie d'une hydrolyse de l'ester.The compounds of formula (I) for which R represents a radical C (R3) R4,
R3 represents an alkyl radical, -alk-Ar or -alk-Het and R4 represents a radical -alk-COOH or -alk-COOalk 'can be prepared by the action of a derivative of formula:

in which R3 has the same meanings as in formula (I) on a halide Hal-alk-COOalk 'for which Hal represents a halogen atom, alk and alk' have the same meanings as in formula (I), optionally followed by hydrolysis of the ester.

This reaction is preferably carried out in an inert solvent such as d imethylsu lfoxide, dimethylformam ide, tetrahydrofuran, dioxane, in the presence of a base such as an alkali metal hydroxide (sodium hydroxide, potassium hydroxide). example), optionally in the presence of tetrabutylammonium bromide in dimethylsulfoxide or in the presence of an alkali metal hydride (sodium hydride for example), at a temperature between 20 "C and the boiling point of the reaction medium. The hydrolysis is carried out by any known method making it possible to pass from an ester to an acid without modifying the rest of the molecule. Preferably, it is hydrolyzed by means of a base such as an alkali metal hydroxide (sodium hydroxide or potash for example), in a mixture of water and lower aliphatic alcohol (ethanol for example), at a temperature in the region of 20 to 30 "C.

The derivatives of formula (VIII) can be obtained by application or adaptation of the methods described in patent application WO95 / 02601.

The compounds of formula (I) for which R represents a radical C (R3) R4,
R3 represents an alkyl radical, -alk-Ar or -alk-Het and R4 represents a radical -NH-alk, -NH-CO-alk, -NH-CO-Ar ', -NH-CO-alk-Ar', -NH-CO-Het, -NH-CO-alk-Het, -NH-CO-alk-COOH or -NH-CO-alk-COOalk 'can be prepared by the action of a compound of formula (I) corresponding to which R represents a radical C (R3) R4, R3 represents an alkyl radical, -alk-Ar or -alk-Het and R4 represents a radical -NH2 on a halide Hal-Re for which Hal represents a halogen atom and Re represents an alkyl radical, -00-alk, -CO-Ar ', -CO-alk-Ar', -CO-Het, -CO-alk-Het or -CO-alk-COOalk ', alk, alk', Ar 'and Het having the same meanings as in formula (I) optionally followed by hydrolysis of the ester.

This reaction is preferably carried out in an inert solvent such as dimethylsulfoxide, dimethylformamide, tetrahydrofuran, dioxane, in the presence of a base such as an alkali metal hydroxide (sodium hydroxide, potassium hydroxide for example), optionally in the presence of tetrabutylammonium bromide in dimethylsulfoxide or in the presence of an alkali metal hydride (sodium hydride for example), at a temperature between 20 ° C. and the boiling point of the reaction medium. Preferably, it is hydrolyzed by means of a base such as an alkali metal hydroxide (soda or potash for example), in a water-lower aliphatic alcohol mixture (ethanol for example), at a temperature in the region of 20 to 30 " vs.

The compounds of formula (I) for which R represents a radical C (R3) R4,
R3 represents an alkyl radical, -alk-Ar or -alk-Het and R4 represents a radical -NH-CO-NH2, -NH-CO-NH-alk, -NH-CO-NH-Ar 'or -NH-CO -NH-alk-Ar can be prepared by the action of a corresponding compound of formula (I) for which R represents a radical C (R3) R4, R3 represents an alkyl radical, -alk-Ar or -alk-Het and R4 represents a radical -NH2 on a derivative O = C = N-Rf for which Rf represents a trimethylsilyl, alkyl, -Ar 'or -alk-Ar', alk and Ar 'radical having the same meanings as in formula (I) , followed for the compounds for which R4 represents a radical -NH-CO-NH2 of a hydrolysis of the silylated derivative.

This reaction is generally carried out in an inert solvent such as dimethylformamide, tetrahydrofuran or dioxane, at a temperature between 20 "C and the boiling temperature of the reaction medium.

The hydrolysis of the silylated derivative previously obtained is generally carried out using an aqueous solution, at a temperature between 20 and 50 "C.

The derivatives O = C = N-Rf are marketed or can be obtained by the action of phosgene on the corresponding primary amine H2N-Rf, by adaptation of the methods described by RL SHRINER et al., Organic
Synth., Il, 453; GM DYON, Organic Synth., I, 165; RJ SLOCOMPIE et al., J. Am. Chem. Soc., 72, 1888 (1950) and S. PATAI, "The chemistry of cyanates and their thio derivatives", Ed. John Wiley and Sons, page 619 (1977). The corresponding primary amines are marketed or those for which Rf represents an -alk-Ar 'radical are obtained from the corresponding halides by the action of NaN (SiCH3) 3 or the potassium salt of phthalimide, in an inert solvent such as dimethylformamide, in the presence of an organic base such than a trialkylamine or pyridine, at a temperature between OOC and the boiling temperature of the reaction medium followed by hydrolysis in an acid medium (HCl for example), at a temperature between 20 "C and the temperature of Boiling of the reaction medium The amines for which Rf represents an -alk-Ar 'radical can also be obtained by application or adaptation of the methods described by JF KING et al., J. Am. Chem. Soc., 114, 3028 (1992 ); BMADGER et al., Tetrahedron Let t., 25 (45), 5219 (1984); R.

SCARPATI et al., Gazz. Chim. Ital., 97 (5), 654 (1967). Amines
H2N-Ar 'can be obtained by application or adaptation of the methods described by BA TERTOV et al., Khim. Geterotsikl. Soedin, Il, 1552 (1972) and RC LAROCK, "Comprehensive Organic Transformations", Ed. VCH, page 399, which consists in reacting the organolithian or organomagnesium of the optionally substituted benzene considered on Phi3, in the presence of acid acetic acid, (PhO) 2PON3, NH2OCH3 or N3CH2Si (CH3) 3. Organolithiens or organomagnesiensiens can be obtained by application or adaptation of the methods described by DL COMINS et al., J. Org.

Chem., 52, 104 (1987); N. FURUKANA et al., Tetrahedron Lett., 28 (47), 5845 (1987); A.R. KATRITZKY et al., Org. Prep. Procedure Int., 20 (6), 585 (1988); A.J. CLARKE et al., Tetrahedron Lett., 27, 2373 (1974) and kW.

GSCHWEND et al., Organic Reaction, 26, (1979).

The compounds of formula (I) for which R represents a radical C (R3) R4,
R3 represents an alkyl radical, -alk-Ar or -alk-Het and R4 represents a radical -N (alk) -alk 'can be prepared by the action of a compound of formula (I) corresponding for which R represents a radical C (R3) R4, R3 represents an alkyl radical, -alk-Ar or -alk-Het and R4 represents a radical -NH-alk on a halide Hal-alk 'for which Hal represents a halogen atom and alk' represents a alkyl radical.

This reaction is preferably carried out in an inert solvent such as dimethyHormamide, in the presence of an acid acceptor such as an organic nitrogenous base (pyridine or triethylamine for example), at a temperature between 0 C and the boiling point of the reaction medium.

The compounds of formula (I) for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2-pyrrolidine, 2-piperidine or 2-azacycloheptane ring can be prepared by the action of a corresponding compound of formula (I) for which R represents a CH-NH2 radical in which the NH2 is protected by a protective group such as a tert-butoxycarbonyl radical on a derivative
Hal- (CH2) p-Hal 'for which Hal and Hal' are the same or different and represent halogen atoms (preferably chlorine or bromine) and p is equal to 3,4 or 5.

This reaction is carried out in an inert solvent such as dimethyl sulphoxide, in the presence of an alkali metal hydride (sodium hydride for example), at a temperature in the region of 20 "C. The deprotection is carried out by any method known to a person skilled in the art. In particular, when the protective group is a tert-butoxycarbonyl radical, the operation is carried out by means of trifluoroacetic acid, at a temperature in the region of 20 "C.

dans laquelle R1 a les mêmes significations que dans la formule (I), suivie d'une débenzylation du NH. The compounds of formula (I) for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 3-pyrrolidine ring can be prepared by condensation of Nn butoxymethyl-N- trimethylsilylmethyl-benzylamine on a derivative of formula:

in which R1 has the same meanings as in formula (I), followed by debenzylation of NH.

The condensation is preferably carried out in an inert solvent such as dimethylformamide1 in the presence of a catalytic amount of trifluoroacetic acid, at a temperature between 15 and 700C. Debenzylation is generally carried out using hydrogen, in an inert solvent (dimethylformamide, acetic acid for example), in the presence of a hydrogenation catalyst such as carbon palladium,
Palladium hydroxide or palladium, under a hydrogen pressure between 1 and 20 bar, at a temperature between 20 and 500C.

N-n-butoxymethyl-N-trimethylsilylmethyl-benzylamine can be obtained by the method described by Y. TERAO et al., Chem. Pharm. Bull., 33, 2762 (1985).

The derivatives of formula (IX) can be obtained according to the following reaction scheme:

In these formulas R1 has the same meanings as in formula (I).

Stage a is carried out using tert-butoxybis (dimethylamino) methane, in an inert solvent such as dimethylformamide, at a temperature around 25 "C. Stage b is carried out using 'a 5N hydrochloric acid solution at a temperature in the region of 25 "C. Step c is carried out using sodium borohydride, in methanol, at a temperature in the region of 20 "C. Step d is carried out using a sodium hydroxide solution, in a inert solvent such as a lower aliphatic alcohol, dimethylsulfoxide or a mixture of these solvents, at a temperature in the region of 20 "C.

The compounds of formula (I) for which R represents a radical C (R3) R4 in which R3 and R4 form with the nitrogen atom to which they are attached a 4-piperidine ring can be prepared by the action of N, N- bis (2-chloroB-thyl) p-toluenesulfonamide on a derivative of formula (II) in which R1 has the same meanings as in formula (I), followed by hydrolysis of the sulfonam ido function.

This reaction is preferably carried out in an inert solvent such as dimethylsulfoxide, in the presence of an alkali metal hydride (sodium hydride for example), at a temperature in the region of 20 "C. The hydrolysis of the sulfonamido function is preferably carried out in an acid such as hydrobromic acid, at the boiling temperature of the reaction medium.

The compounds of formula (I) for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine ring or 2-azacycloheptane in which the nitrogen atom is substituted by an alkyl radical (1C) can be prepared by the action of formaldehyde and formic acid on a corresponding compound of formula (I) for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4piperidine or 2-azacycloheptane ring.

This reaction is carried out at a temperature between 20 and 35 "C.

dans laquelle Hal représente un atome d'halogène et alk représente un radical alkyle puis déprotection du NH2.The compounds of formula (I) for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine ring or 2-azacycloheptane in which the nitrogen atom is substituted by a radical -CO-alk-NH2 can be prepared by the action of a corresponding compound of formula (I) for which
R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-peripididine or 2-azacycloheptane ring on a derivative of formula:

in which Hal represents a halogen atom and alk represents an alkyl radical followed by deprotection of NH2.

This reaction is generally carried out in an inert solvent such as dimethylformamide, in the presence of an acid acceptor such as a nitrogenous organic base (pyridine, trialkylamine such as triethylamine for example), at a temperature between 0 C and the boiling temperature of the reaction medium. The deprotection is generally carried out in a lower aliphatic alcohol (ethanol for example), in the presence of hydrazine, at the boiling temperature of the reaction medium.

The derivatives of formula (X) can be obtained by application or adaptation of the method described by K. BALENOVIC et al., J. Org. Chem., 17, 1149 (1952).

The compounds of formula (I) for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine ring or 2-azacycloheptane whose nitrogen atom is substituted by an alkyl radical (2-6C), -COOalk, -alk-Het, -alk-Ar ', -CO-alk, -CO-alk-COOH, -CO -alk-COOalk ', -CO-Ar', -CO-alk-Ar ', -CO-Het or -CO-alk-Het can be prepared by the action of a corresponding compound of formula (I) for which R represents a radical
C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine or 2-azacycloheptane ring on a Hal-Rg halide in which Hal represents a halogen atom and Rg represents an alkyl radical (2-6C), -COOalk, -alk-Het, -alk-Ar ', -00-aI k, -CO-alk-COOalk', -CO-Ar ' , -CO-alk-Ar ', -CO-Het or -CO-alk-Het, alk, alk', Het and Ar 'having the same meanings as in formula (I), optionally followed by hydrolysis of l 'ester.

This reaction is generally carried out in an inert solvent such as dimethylformamide, in the presence of an acid acceptor such as an alkali metal carbonate (sodium or potassium carbonate for example), a trialkylamine (triethylamine for example) or pyridine, at a temperature between 0 C and the boiling temperature of the reaction medium. Preferably, it is hydrolyzed by means of a base such as an alkali metal hydroxide (soda or potash for example), within a mixture of lower aliphatic alcohol-alcohol (ethanol for example), at a temperature in the region of 20 to 30 "VS.

The compounds of formula (I) for which R represents a radical C (R) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine ring or 2-azacycloheptane, the nitrogen atom of which is substituted by a radical -CO-NH2, -CO-NH-alk, -CO-NH-Ar 'or -CO-NH-alk-Ar' can be prepared by the action of '' a compound of corresponding formula (I) for which R represents a radical
C (R3) R4 in which R3 and R4 form, with the carbon atom to which they are attached, a 2- or 3-pyrrolidine, 2- or 4-piperidine or 2-azacycloheptane ring on a derivative O = C = N-Rh for which Rh represents an alkyl radical, -Ar ', -alk-Ar' or trimethylsilyl, alk and Ar 'having the same meanings as in formula (I), followed, for the silylated product obtained, by hydrolysis.

This reaction is generally carried out in an inert solvent such as dimethylformamide, tetrahydrofuran or dioxane, at a temperature between 20 "C and the boiling temperature of the reaction medium.

The hydrolysis of the silylated derivative previously obtained is generally carried out using an aqueous solution, at a temperature between 20 and 50 "C.

The compounds of formula (I) for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine ring or 2-azacycloheptane whose nitrogen atom is substituted by a radical -CO-alk-COOH, -CO-alk-CO0alk ', -CO-Ar', -CO-alk-Ar ', -00-alk, - CO-Het or -CO-alk-Het can also be prepared by the action of a corresponding compound of formula (I) for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached to a 2 or 3-pyrrolidine, 2- or 4-piperidine or 2-azacycloheptane ring on a derivative
HOOC-Ri in which Ri represents a radical -alk-COOalk ', -Ar', -alk-Ar ', -Het, -alk-Het or aIkyle, alk, alk', Het and Ar 'having the same meanings as in formula (I), optionally followed by hydrolysis of the ester.

This reaction is generally carried out in an inert solvent such as dimethylformam ide, in the presence of hydroxybenzotriazole or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide and an organic base such as a trialkylamine (triethylamine for example), at a temperature between 0 and 300C. Preferably, it is hydrolyzed by means of a base such as an alkali metal hydroxide (soda or potash for example), within a water-lower aliphatic alcohol mixture (ethanol for example), at a temperature in the region of 20 at 30 "C.

dans laquelle A représente un radical alkyle (1-3C en chaîne droite), -CH2-C(CH3)2-CH2-, -CH2-CH2-C(CH3)2- ou -CH2-C(CH3)2- sur un composé de formule (I) correspondant pour lequel R représente un radical
C(R3)R4 dans lequel R3 et R4 forment avec l'atome de carbone auquel ils sont rattachés un cycle 2- ou 3-pyrrolidine, 2- ou 4-pipéridine ou 2-azacycloheptane.The compounds of formula (I) for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine ring or 2-azacycloheptane in which the nitrogen atom is substituted by a radical -CO-alk-COOH in which alk represents an alkyl radical (1 to 3 carbon atoms) in a straight chain, -CH2-C (CH3) 2-CH2 -, -cH2-cH2-c (cH3) 2- or -CH2-C (CH3) 2- can be prepared by the action of an anhydride of formula:

in which A represents an alkyl radical (1-3C in a straight chain), -CH2-C (CH3) 2-CH2-, -CH2-CH2-C (CH3) 2- or -CH2-C (CH3) 2- on a corresponding compound of formula (I) for which R represents a radical
C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine or 2-azacycloheptane ring.

This reaction is generally carried out in an inert solvent such as acetic acid, at a temperature in the region of 20 "C or in the presence of 4dimethylaminopyridine, in dioxane, at the boiling temperature of the reaction medium.

The compounds of formula (I) for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine ring or 2-azacycloheptane whose nitrogen atom is substituted by a radical -CO-alk-NH-alk 'or -COalk-N (alk alk "can be prepared by the action of a corresponding compound of formula (I) for which R represents a C (R3) R4 radical in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine or 2-azacycloheptane ring on a Hal-CO derivative -alk-NH-alk 'or Hal-CO-alk-N (alk') alk "in which Hal represents a halogen atom, alk, alk 'and alk" have the same meanings as in formula (I).

This reaction is preferably carried out in an inert solvent such as dimethylformamide, in the presence of an acid acceptor such as an organic nitrogenous base (pyridine or trialkylamine such as triethylamine), at a temperature between 0 C and the boiling temperature of the reaction medium.

The Hal-CO-alk-NH-alk 'or Hal-CO-alk-N (alk') alk "derivatives can be obtained by heating the corresponding carboxylic acid and a halogenation reagent such as thionyl, in an inert solvent such as 1,2-dichloroethane, at a temperature in the region of 60 "C. The corresponding acids are commercially available or can be obtained by the action of the derivatives Hal-alk-COOalk 'for which Hal represents a halogen atom, alk and alk' represent alkyl radicals, on an amine H2N-alk 'or
HN (alk ') alk ", in an inert solvent such as dimethylformamide, in the presence of an alkali metal carbonate or a trialkylamine, at a temperature between 0 C and the boiling point of the recation medium followed optionally hydrolysis in a basic medium, in a lower aliphatic alcohol-water mixture, at a temperature between 0 and 60 ° C. and acidification by means of an acid such as hydrochloric acid, a temperature between 20 and 60 "C.

dans laquelle Rj représente un radical -NH-alk, -N H-Ar', -NH-cycloalkyle, -NH-alk-Ar' ou -N(alk)alk', alk, Ar' et alk' ayant les mêmes significations que dans la formule (I).The compounds of formula (I) for which R1 represents a radical -alk-NH-C0-R5 for which R5 represents a radical -NH-alk, -N H-Ar, '-NH-cycloalkyle, -NH-alk-Ar 'or -N (alk) alk' can also be prepared by the action of a corresponding compound of formula (I) for which R1 represents an -alk-NH2 radical on a derivative of formula:

in which Rj represents a radical -NH-alk, -N H-Ar ', -NH-cycloalkyle, -NH-alk-Ar' or -N (alk) alk ', alk, Ar' and alk 'having the same meanings as in formula (I).

This reaction is generally carried out in an inert solvent such as dimethylformamide, tetrahydrofuran, dioxane, at a temperature between 20 "C and the boiling temperature of the reaction medium.

The derivatives of formula (XII) can be obtained by application or adaptation of the methods described by J. IZDEBSKI et al., Synthesis, 423 (1989) and
T. KONAKAHARA et al., Synthesis, 103 (1993).

The various halides Hal-alk-0OOalk ', Hal-R3, Hal-Re and Hal-Rg used in the processes described above are sold or can be obtained according to the following methods: - Halides hal-alk-COOalk' can be obtained by the action of a Hal-alk-Hal derivative in which Hal represents a halogen atom and alk represents an alkyl radical on an alkaline cyanide (sodium or potassium cyanide), within a water-alcohol mixture, with a temperature between 0 C and the boiling temperature of the reaction medium, followed by the action of a strong acid such as hydrochloric acid, in the presence of an aliphatic alcohol C1-C6 in straight or branched chain, at a temperature between 0 C and the boiling temperature of the reaction medium, - halides Hal-CO-alk, Hal-CO-alk-COOalk ', Hal-COAr',
Hal-CO-alk-Ar ', Hal-CO-Het and Hal-CO-alk-Het can be obtained by heating a corresponding acid HOOC-Rk in which Rk represents a radical -alk, -alk-COOalk', -Ar ', -alk-Ar', -Het or -alk-Het and a halogenation reagent such as thionyl chloride, thionyl bromide, a phosphorus halide (Ils, POC13 for example), at within an inert solvent such as a chlorinated solvent (1,2-dichloroethane for example), at a temperature between 20 "C and the boiling point of the reaction medium. The corresponding acids are marketed or the acids
HOOC-Het, HOOC-Ar ', HOOC-alk-Ar' and HOOC-alk-Het can be obtained from the heterocycle and the corresponding optionally substituted benzene by application or adaptation of the methods described by L.

ESTEL et al., J. Heterocyclic Chem., 26, 105 (1989); N.S. NARASIMHAN et al., Synthesis, 957 (1983); A. TURCK et al., Synthesis, 881 (1988), A.J.

CLARKE et al., Tetrahedron Lett., 27, 2373 (1974); AR KATRITZKY and coîl. 1 Org. Perp. Procedure Int., 20 (6), 585 (1988); N. FURUKAWA et al.,
Tetrahedron Lett., 28 (47), 5845 (1987); HW GSCHWEND et al., Organic
Reactions, 26, 1 (1979) and V. SNIECKUS, Chem. Rev., 90, 879 (1990). Preferably, the corresponding organometallic derivative of the heterocycle or of the optionally substituted benzene (organolithium, organomagnesium for example) is prepared and reacted either on CO 2 or on a Hal-alk derivative -COOalk 'in which Hal represents a halogen atom, alk and alk' represent an alkyl radical followed by a hydrolysis reaction which is generally carried out by means of a base such as an alkali metal hydroxide (sodium hydroxide , for example potash) in a lower aliphatic alcohol-water mixture, at a temperature between 20 and 80 "C - the halides Hal-alk-Ar 'and Hal-alk-Het can be obtained from the corresponding alcohols HOH2C- alk-Ar 'and HOH2C-alk-Het by application or adaptation of the methods described by RC LAROCK, "Comprehensive
Organic Transformations ", ed.VCH, page 353 (1989). The corresponding alcohols are sold or can be obtained from the corresponding organometallic derivatives by application or adaptation of the methods described by L. ESTEL et al., J. Heterocyclic Chem., 26, 105 (1989); NS NARASIMHAN et al., Synthesis, 957 (1983) and Tetrahedron
Lett., 22 (29), 2797 (1981); HW GSCHWEND et al., Organic Reactions, 26, (1979), V. SNIECKUS, Chem. Rev., 90, 879 (1990) and F. MARCHAIS et al., J. Heterocyclic Chem, 25, 81 (1988). Preferably, the organolithian or organomagnesium of the heterocycle or of benzene optionally substituted is reacted on formalin or Hal-alk-OP where P is a protective group (methyl ether, tetrahydropyranylether, benzyl ether or triethylsilyl ether for example) then releases the alcohol function by application or adaptation of the methods described by W. GREENE et al., Protecting
Groups in Organic Synthesis, second edition, 1991, John Wiley & Sons. The corresponding alcohols can also be obtained by reduction of the carboxylic acids or of the corresponding esters by means of lithium aluminum hydride, in an inert solvent such as tetrahydrofuran or diethyl ether, at the boiling point of the reaction medium.

The enantiomers of the compounds of formula (I) can be obtained by resolution of the racemates, for example by chromatography on a chiral column according to WH PIRCKLE et al., Asymetric synthesis, vol. 1,
Academic Press (1983) or by synthesis from chiral precursors.

The isomers and diastereoisomers of the compounds of formula (I) can be separated by the usual known methods, for example by crystallization or chromatography.

It is understood by a person skilled in the art that, for the implementation of the methods according to the invention described above, it may be necessary to introduce groups protecting the amino, hydroxy and carboxy functions in order to avoid side reactions . These groups are those that allow them to be eliminated without affecting the rest of the molecule. As examples of groups which protect the amino function, mention may be made of tert-butyl or methyl carbamates with regeneration of the amine by means of iodotrimethylsilane and phthalimido with regeneration of the amine by means of hydrazine. As examples of protecting groups for the hydroxy function, mention may be made of triethylsilyl and benzyl. As protecting groups for carboxy functions, mention may be made of esters (methoxymethylester, tetrahydropyranylester, benzylester for example, oxazoles and 2-alkyl-1, 3 -oxazolines Other protecting groups which can be used are described by W. GREENE et al., Protecting Groups in Organic
Synthesis, second edition, 1991, John Wiley & Sons.

The compounds of formula (I) can be purified by the usual known methods, for example by crystallization, chromatography or extraction.

The compounds of formula (I) comprising a basic residue can optionally be converted into addition salts with a mineral or organic acid by the action of such an acid within an organic solvent such as an alcohol, a ketone, a ether or a chlorinated solvent.

The compounds of formula (I) comprising an acid residue can optionally be converted into metal salts or into addition salts with nitrogenous bases according to methods known per se. These salts can be obtained by the action of a metal base (alkaline or alkaline-earth for example), ammonia, an amine or a salt of an amine on a compound of formula (I), in a solvent. The salt formed is separated by the usual methods.

These salts are also part of the invention.

As examples of pharmaceutically acceptable salts, there may be mentioned the addition salts with mineral or organic acids (such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, me thanesunonate, isethionate, theophyllinacetate, salicylate, methylene-bis -en oxynaphthoate, hydrochloride, sulphate, nitrate and phosphate), salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (calcium, magnesium), ammonium salt, salts of nitrogenous bases (ethanolamine , trimethylamine, methylamine, benzylamine, N-benzyl-frphé nethylamine, choline, arginine, leucine, lysine, N-methyl glucamine).

The compounds of formula (I) have interesting pharmacological properties. These compounds are antagonists of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, also known as the quisqualate receptor.

Furthermore, the compounds of formula (I) are non-competitive antagonists of the N-methyl-D-aspartate receptor (NMDA) and, more particularly, they are ligands for the glycine modulator sites of the receptor
NMDA.

These compounds are therefore useful for treating or preventing all ischemias (such as focal or global ischemia) consecutive to cerebrovascular accidents, cardiac arrest, hypotension, cardiac or pulmonary surgery or severe hypoglycemia. They are also useful in the treatment of the effects due to anoxia, whether it is perinatal or following drowning or cerebro-spinal lesions.

These compounds can also be used to treat or prevent the development of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease, amyotrophic lateral sclerosis, olivo-pontocerebellar atrophy and PARKINSON disease . These compounds can also be used with respect to epileptogenic and / or convulsive manifestations, for the treatment of cerebral or spinal traumas, traumas linked to degeneration of the inner ear (R. PUJOL et al.,
Neuroreport, 3, 299-302 (1992) or the retina (JL MONSINGER et al.,
Exp. Neurol., 113, 10-17 (1991), anxiety (KEHNE et al., Eur. J.

Pharmacol., 193, 283 (1991)), depression (TRULLAS et al., Eur. J.

Pharmacol., 185, 1 (1990)), schizophrenia (REYNOLDS, TIPS, 13, 116 (1992)), TOURETTE syndrome, hepatic encephalopathies, as analgesics (DICKENSON et al., Neurosc. Letters , 121, 263 (1991)), anti-inflammatory drugs (SLUTA et al., Neurosci. Letters, 149, 99-102 (1993)) anti-anorexics (SORRELS et al., Brain Res., 572, 265 (1992)), anti-migraine, antiemetics and to treat poisoning by neurotoxins or other NMDA receptor agonist substances, as well as neurological disorders associated with viral diseases such as AIDS (LIPTON et al., Neuron, 7, 111 (1991)), rabies , measles and tetanus (BAGETTA et al., Br. J. Pharmacol., 101, 776 (1990)). These compounds are also useful for the prevention of symptoms of abstinence from drugs and alcohol and inhibition of opiate addiction and dependence.

They can also be used in the treatment of deficits linked to mitochondrial anomalies such as mitochondrial myopathy, LEBER syndrome, WERNICKE encephalopathy, RETT syndrome, homocysteinemia, hyperprolinaemia, hydroxybutiric-aminoaciduria , Saturnine cephalopathy (chronic lead poisoning) and sulfite oxidase deficiency.

The affinity of the compounds of formula (I) vis-à-vis the AMPA receptor was determined by studying the antagonism of the specific binding of [3H] -AMPA on membranes of rat cerebral cortex (HONORE et al. .,
Neuroscience letters, 54, 27 (1985)). [3H] -AMPA is incubated in the presence of 0.2 mg of protein at 4 "C for 30 minutes in buffer
KH2PO4 10mM, KSCN 100mM, pH7.5. Non-specific binding is determined in the presence of L-glutamate 1 mu. The bound radioactivity is separated by filtration on PHARMACIA filters (Printed Filtermate A). The inhibitory activity of these products is less than or equal to 100 zM.

The affinity of the compounds of formula (I) for the glycine site linked to the receptor
NMDA was determined by studying the antagonism of the specific binding of [3H] -DCKA on membranes of rat cerebral cortex according to the method described by T. CANTON et al., J. Pharm. Pharmacol., 44, 812 (1992).

The [3H] -DCKA (20nM) is incubated in the presence of 0.1 mg of proteins at 4 ° C. for 30 minutes in 50 mM HEPES buffer, pH 7.5. Non-specific binding is determined in the presence of 1 mu glycine. The bound radioactivity is separated by filtration on Whatman GF / B filters. The inhibitory activity of these products is less than or equal to 100 zM.

The compounds of formula (I) have a low toxicity. Their LD50 is greater than 50 mg / kg by the IP route in mice.

Preferred are the compounds of formula (I) for which R represents a radical CH-NH2 or CH-CH (OH) COOH, R1 represents a radical -alk-NH-CO-R5 and R5 represents a radical -NH-alk, their enantiomers and diastereoisomers and their salts.

The following examples illustrate the invention.

EXAMPLE 1
A mixture of 1.76 g of 10-hydrnxyimino- (3-methylureido) methyl- 5H, 10H-imidazo [1,2-a] indeno [1,2-e] pyrazin-4-one, 50 ml of trifluoroacetic acid, 30 ml of acetic acid and 0.2 g of 10% palladium on charcoal is placed under a hydrogen atmosphere at a temperature of 40 ° C. and at a pressure of 1.5 bar for 3 hours. After cooling, the reaction medium is filtered through celite and the filtrate is evaporated. The residue obtained is taken up in 50 ml of ethanol, filtered through sintered glass, washed with 2x30 ml of ethanol, then 2x30 ml of ethyl ether and dried under vacuum at 60 ° C. for 18 hours. The white powder thus obtained is put dissolved in 10 ml of acetic acid and 2 ml of 12N hydrochloric acid. After one hour of stirring at a temperature close to 20 ° C., the reaction medium is concentrated, taken up in 50 ml of isopropyl ether and left under stirring for 18 hours. The suspension is filtered, washed with 2x30 ml of ethyl ether and dried under reduced pressure for 4 hours at 60 C. This gives 0.41 g of (1 0-RS) - 1 O-amino-9- dihydrochloride ( 3-methylureido) m8thyl-5H, 1 OH-imidazoEl, 2-a] indé no [1,2-e] pyrazin-4-one in the form of white powder melting above 260 C (Analysis C16H18Cl2N6O2, 1.36 H2O:% cal-culé C: 48.38, H: 4.57,
Cl: 17.85, N: 21.15, O: 8.05. % found C: 48.4, H: 4.3, Cl: 17.6, N: 20.5).

1 O-hydroxyimino-9- (3-methylureido) methyl-5H, 1 OH-imidazo [1, 2-a] indé no [1, 2-e] pyrazin-4-one can be prepared as follows: to a solution of 1.6 g of 9- (3-methylureido) methyl-5H, 10H-imidazo [1, 2-a] indé no [1, 2-e] pyrazin4-one in 60 ml of dimethyl sulfoxide, we add 0.4 g of 80% sodium hydride while maintaining the reaction medium at a temperature in the region of 20 C. After 30 minutes of stirring at this temperature, 0.7 ml of isoamyl nitrite is added and stirring is continued for 2 hours. The reaction medium is brought to a pH close to 2 by adding 5.5 ml of 6N hydrochloric acid, then poured into 250 ml of water and the suspension is filtered through sintered glass. The gel thus obtained is washed with 3 × 30 ml of water and stirred in the presence of 250 ml of acetone for 30 minutes. The suspension obtained is filtered, washed with acetone, then dried under reduced pressure for 3 hours at 60 C. This gives 2 g of 10-hydroxyimino-9- (3-methylureido) methyl-5H, 10H-imidazo [1 , 2-a] indeno [1,2-e] pyrazin-4-one (mixture of the Z and E isomers) in the form of an orange solid with a melting point above 260 C [Rf = 0.23; thin layer chromatography on silica gel, eluent: 28% chloroform-methanol-ammonia (12/3 / 0.5 by volume)].

9- (3-methylureido) methyl-5H, 10H-imidazo [1,2-a] indeno [1,2-e] pyrazin-4one can be synthesized as follows: a mixture of 17.1 g of hydrochloride of 5-aminomethyl-5H, 10H-imidazo [1,2-a] indeno [1,2-e] pyrazin 4-one, 25.2 g of 4nitrophenyl-N-methylcarbamate and 16 ml of triethylamine in 800 ml of dimethylformamide is stirred for 60 hours at a temperature in the region of 20 C. The reaction medium is filtered and the solid is washed with 2 × 100 ml of dimethylformamide, 2 × 100 ml of distilled water, 2 × 100 ml of methyl tert-butyl ether and dried under reduced pressure at 60 ° C. for 20 hours. 16.6 g of 9- (3-methylureido) methyl-5H, 10H-imidazo [1,2- a] indeno [1, 2-e] pyrazin-4-one are thus obtained in the form of a solid. gray with a melting point above 260 C. [Rf = 0.37; thin layer chromatography on silica gel, eluent: 28% chloroform-methanol-ammonia (12/3 / 0.5 by volume)].

4nitrophenyl-N-methylcarbamate can be prepared as described by T.

KONAKAHARA et al., Synthesis, 103 (1993).

9-aminomethyl-5H, 1 OH-imidazo [1, 2-a] indeno [1, 2-e] pyrazin-4-one can be synthesized as follows: a solution of 25.3 g of 9-phthali midomethyl-5H, 1 OH-imidazo [1, 2-a] indeno [1, 2.e] pyrazin-4-one, 800 ml of ethanol, 250 ml of distilled water and 28 ml of hydrazine hydrate is brought to reflux for 20 hours. The reaction medium is then brought to a temperature in the region of 30 C, then the suspension is filtered through sintered glass and washed with 2x250 ml of water and 2x250 ml of ethanol. The solid thus obtained is stirred in 300 ml of 2N hydrochloric acid for 2 hours at a temperature in the region of 20 C. The suspension thus obtained is filtered and the solid rinsed with 3 × 100 ml of water and 3 × 100 ml of acetone. The product is taken up in 300 ml of dimethylformamide, stirred for 45 minutes at 90 ° C. and the suspension is filtered at a temperature in the region of 20 ° C., washed with 2x100 ml of dimethylformamide and 2x100 ml of methyl tert-butyl ether. The solid thus obtained is dried under reduced pressure at 60 ° C. for 20 hours. 14 g of 9-aminomethyl-5H, 10H-imidazo [1,2-a] indeno [1,2-e] pyrazin hydrochloride are thus obtained. 4-one in the form of a gray solid whose melting point is greater than 260 C [Rf = 0.23; thin layer chromatography on silica gel, eluent: 28% chloroform-methanol-ammonia (12/3 / 0.5 by volume)].

9-phthalimidomethyl-5H, 1 OH-imidazoEl, 2-a] indBnoEl, 2-e] pyrazin-4-one can be obtained as follows: a mixture of 33.8 g of 1- (4-phthalimi- domethyl-1-oxo-indan-2-yl) ethyl imidazole-2-carboxylate, 1.4 liters of acetic acid and 300 g of ammonium acetate is brought to reflux for 75 minutes. After cooling to a temperature between 10 and 15 ° C., the reaction medium is poured into 1.5 liters of water and stirred for one hour. The precipitate thus obtained is filtered through sintered glass, rinsed with 3 × 300 ml of water, then dried in an oven under reduced pressure at 60 ° C. for 18 hours. This gives 25.3 g of 9-phthalimidomethyl-5H, 1 OH-imidazdl, 2-a] indBnoEl, 2-e] pyrazin-4One in the form of a beige solid melting above 260 ° C. [Rf = 0.23; thin layer chromatography on silica gel, eluent: dichloromethane methanol-ammonia at 28% (40/5 / 0.5 by volume)].

The ethyl 1 - (4-phthalimidomethyl-1-oxoindan-2-yl) imidazole-2arboxylate can be obtained in the following manner: a solution of 9.7 g of ethyl imidazole-2-carboxylate in 400 ml of acetone is added with 45.8 g of potassium carbonate. This suspension is brought to reflux for 15 minutes, then a solution of 25.6 g of 2-bromo-4-phthalimi domethylindan-1 -one in 350 ml of acetone is added. After 4 hours of stirring at reflux, the reaction medium is brought to a temperature in the region of 20 ° C. and filtered through sintered glass. The filtrate is evaporated and 27.8 g of a green yellow solid are obtained. Purification by flash chromatography on a silica column (eluent: dichloromethane-ethyl acetate (60-40 by volume)) of 5 g of this solid leads to 2.1 g of ethyl 1- (4-phthalimidomethyl-1-oxo-indan-2-yl) imidazole-2-carboxylate in the form of a beige solid melting at 202 ° C.

Ethyl imidazole-2-carboxylate can be prepared as described in US Pat. No. 3,600,399.

The 2-bromo-4-phthalimidomethylindan-1 -one can be synthesized as follows: a solution of 23.7 g of 4-phthalimidomethylindan-1 -one in 160 ml of acetic acid is added with 0.1 ml of hydrobromic acid (47%), then maintained at a temperature below 18 C. A solution of 4.2 ml of bromine in 40 ml of acetic acid is then added dropwise and over one hour 15 minutes. After 20 hours at a temperature in the region of 22 "C, the reaction medium is filtered through sintered glass and the solid residue thus obtained is rinsed with 2x150 ml of water, 2x150 ml of methyltertbutylether, then dried under reduced pressure for 4 hours at 60 C. 25.6 g of 2-bromo-4-phthalimidomethylindan-1-one are thus obtained in the form of a white solid melting at 175 C.

4phthalimidomethylindan-1-one can be prepared as follows: to a solution of 19.1 ml of thionyl chloride and 160 ml of dichloromethane are added 40.6 g of 3- [2- (phthalimidomethyl) phenyl acid] propanoic.

After adding 10 ml of dimethylformamide, the reaction medium is brought to 35 ° C. for 4 hours. Evaporation of the medium leads to an ocher yellow powder. This powder is dissolved in 250 ml of 1, 2-dichloroethane, then is added dropwise at 0 C under an argon atmosphere to a solution of 52.4 g of aluminum chloride and 400 ml of 1,2- dichloroe thane. After 18 hours of reaction at a temperature in the region of 20 "C., the reaction medium is poured onto 500 g of ice. The solution is then neutralized with a saturated aqueous solution of sodium carbonate, then the mixture is extracted with 2x300 ml of dichloromethane. The combined organic phases are washed with 2x300 ml of water, dried over magnesium sulphate and evaporated.The solid residue thus obtained is purified by flash chromatography on a silica column (eluent: ethyl dichloromethanvacetate (97/3 by volume) 23.7 g of 4phthalimidomethylindan-1 -one, melting at 198 ° C., are thus obtained.

3- [2- (phthalimidomethyl) phenyl] propanoic acid can be prepared as follows: a solution of 61 g of 2- (phthalimidomethyl) cinnamic acid in 500 ml of dimethyliformamide is added with 59 palladium on carbon at 10 %, and placed under hydrogen at a pressure close to 1.7 bar and at a temperature close to 20 C overnight. The reaction medium is then filtered through celite and the filtrate is evaporated under reduced pressure. The oil thus obtained is taken up in 300 ml of ethyl ether and the precipitate formed is filtered, washed with 2 × 300 ml of ethyl ether and dried under reduced pressure at a temperature in the region of 20 "C.

40.6 g of 3- [2- (phthalimidomethyl) phenyl] propanolic acid are thus obtained in the form of a white solid melting at 185 C.

2- (phthalimidomethyl) cinnamic acid can be obtained as follows: 79 g of 1-bromo-2- (phthalimidomethyl) benzene, 180 ml of tributylamine, 3 g of are successively introduced into a flask under a nitrogen atmosphere tri-o-tolylphosphine, 0.56 g of palladium acetate, then 21.4 ml of acrylic acid. The mixture is heated for 2 hours and 30 minutes at 105 "C.

After returning to a temperature in the region of 20 ° C., the reaction medium is decanted and the upper phase eliminated. The lower phase is taken up in 500 ml of water and 100 ml of aqueous hydrochloric acid (12N). The gray precipitate thus obtained is filtered through a sintered glass and washed with 3 × 500 ml of water. The solid obtained is supplemented with 250 ml of dimethylformamide and 2 g of animal black. The suspension is heated for 15 minutes at 80 ° C., filtered through celite and the filtrate is evaporated under reduced pressure. The residue is washed with 2x200 ml of ethyl ether and dried under reduced pressure at 60 C for 4 hours.

61 g of 2- (phthalimidomethyl) cinnamic acid are thus obtained in the form of a white solid melting at 230 C.

1-Bromo-2- (phthalimidomethyl) benzene can be obtained as follows: a solution of 150 g of 2-bromobenzyl bromide in 1.2 liters of dimethylformamide, supplemented with 155.5 g of potassium phthalimidate, is heated for 5 hours at 60 ° C., then left stirring at a temperature in the region of 20 ° C. for 60 hours. The reaction medium is again brought to 60 ° C. for 8 hours and 11.1 g of potassium phthalimidate are added. After 2 hours at 60 "C, the reaction mixture is brought to a temperature in the region of 20" C, filtered through sintered glass and the filtrate is evaporated. The residue is taken up in 200 ml of ethyl ether, filtered and the filtrate is evaporated. new residue is taken up in 200 ml of methanol. 128.5 g of 1-bromo-2- (phthalimidomethyl) benzene are isolated by filtration in the form of a white solid melting at 172 C.

EXAMPLE 2
To a solution of 4.02 g of 9- (3-methylureido) methyl-5H, 1 OH-imidazo [1, 2- a] indeno [1, 2-e] pyrazin-4-one and 1.8 g 2.25 g of 80% sodium hydride are slowly added with glyoxylic acid monohydrate in 140 ml of dimethyl sulfoxide. The reaction medium is stirred for 20 hours at a temperature in the region of 20 C. 15 ml of acetic acid are then added and the medium is brought to 80 ° C. for one hour. After cooling to a temperature in the region of 20 ° C., the medium is poured into 1.3 liters of acetone and stirred for 30 minutes. The suspension is filtered, then taken up in 160 ml of water and acidified to a pH in the region of 1 with 18 ml of 4N hydrochloric acid.

After 30 minutes of stirring, the precipitate formed is filtered, rinsed with 2x200 ml of water, then with 2x200 ml of methyltertbutylether and dried under reduced pressure at 60 ° C. for 20 hours. To 120 mg of the powder thus obtained are added 3 ml of water and 3 ml of 0.1N aqueous sodium hydroxide and the resulting solution is stirred for 15 minutes, then filtered. The filtrate is concentrated, taken up in acetone and the solid formed is filtered through sintered glass and dried under reduced pressure. This gives 120 mg of the mixture of diastereoisomers of sodium disel of 10- (1-carboxy-1-hydroxymethyl ) -9- (3-methyluréido) methyl- 5H, 1 OH-imidazo [1, 2-a] indeno [1, 2-e] pyrazin-one as an ocher powder with a melting point above 260 C (Analysis C18H15N5Na2O5:,% calculated C: 50.59, H: 3.54, N: 16.39, Na 10.76, O 18.76,% found C: 50.6, H: 3.1, N : 16.4).

The medicaments according to the invention consist of a compound of formula (I) or a salt of such a compound, in the pure state or in the form of a composition in which it is associated with any other pharmaceutically compatible product, which can be inert or physiologically active. The medicaments according to the invention can be used orally, parenterally, rectally or topically.

As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, under a stream of argon. These compositions can also include substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a coating (dragees) or a varnish.

As liquid compositions for oral administration, there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water,
Ethanol, glycerol, vegetable oils or paraffin oil. These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.

The sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other organic solvents can be used. suitable. These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be carried out in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.

In human therapy, the compounds according to the invention are particularly useful for the treatment and prevention of the conditions which require the administration of an AMPA receptor antagonist or an NMDA receptor antagonist. These compounds are in particular useful for treating or preventing all ischemias and in particular cerebral ischemia, the effects due to anoxia, the development of neurodegenerative diseases, HUNTINGTON chorea, ALZHEIMER disease, amyotrophic lateral sclerosis, olivo-pontocerebellar atrophy and PAR disease
KINSON, vis-à-vis epileptogenic and / or convulsive manifestations, for the treatment of cerebral and spinal trauma, trauma related to degeneration of the inner ear or retina, anxiety, depression, schizophrenia , TOURETTE syndrome, hepatic encephalopathy, as analgesics, anti-inflammatories, anti-anorexics, antimigraine, antiemetics and to treat poisonings by neurotoxins or other substances agonists of the NMDA receptor, as well as associated neurological disorders viral diseases such as AIDS, rabies, measles and tetanus. These compounds are also useful for the prevention of symptoms of drug and alcohol abstinence and the inhibition of addiction and dependence with opiates as well as for the treatment of deficits linked to mitochondrial anomalies such as mitochondrial myopathy, LEBER syndrome, encephalopa thie's
WERNICKE, RETT syndrome, homocysteinemia, hyperprolinemia,
Hydroxybutiric aminoaciduria, saturnine encephalopathy (chronic lead poisoning) and sulfite oxidase deficiency.

The doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 10 mg and 100 mg per day orally for an adult with unit doses ranging from 5 mg to 50 mg of active substance.

In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated.

The following examples illustrate compositions according to the invention:
EXAMPLE A
Using the usual technique, capsules containing 50 mg of active product having the following composition are prepared:
- Compound of formula (I) .............. 50 mg
- Cellulose ... .. ... 18 mg
- Lactose ...................... .......................... ........... 55 mg
- Colloidal silica ..................... ........... .............. 1 mg
- Sodium carboxymethyl starch ................. ................. 10 mg
- Talc ..................... ........................... ........ 10 mg
- Magnesium stearate .............. .......... 1 mg
EXAMPLE B
Tablets containing 50 mg of active product having the following composition are prepared according to the usual technique:
- Compound of formula (I) ........................................... 50 mg - Lactose
- Cellulose .............. .................................. 40 mg
- Polyvidone 10 mg
- Carboxymethyl starch sodium .............................. 22 mg
- Talc ......................... ....................... ..... 10 mg
- Magnesium stearate ...................................... 2 mg
- Colloidal silica 2 mg
- Mixture of hydroxymethylcellulose, glycerin, oxide of
titanium (72-3.5-24.5) qs 1 film-coated tablet finished at 245 mg
EXAMPLE C
A solution for injection containing 10 mg of active product having the following composition is prepared:
- Compound of formula (l) ..... .............................. 10 mg
- Benzoic acid ...... ... .. ............................. 80 mg
- Benzyl alcohol ... 0.06 ml
-Benzoatedesodium 8Omg
- 95% ethanol ............................................. 0.4 ml
- Sodium hydroxide ......................................... 24 mg
- Propylene glycol ............................................ 1.6 ml
- Water ............ .................................... .qsp 4 ml

Claims (23)

CLAIMS 1 - Compounds of formula: in which - R represents a radical C = CH-R2, C (R3) R4, CH-NH2, CH-CH (OH) -COOH or CH-CH (OH) -COOalk, - R1 represents a radical -alk-NH2 or -alk-NH-CO-R5, - R2 represents a radical -COOH, -COOalk, - R3 represents an alkyl radical, -alk-Ar or -alk-Het, - R4 represents a radical -NH2, -NH-alk, -N (alk) -alk ', -NH-CO-alk, -NH-CO-Ar', -NH-CO-alk-Ar ', -NH-CO-Het, - NH-CO-alk-Het, -NH-CO-alk-COOH, -NH-CO-alk-COOalk ', -alk-COOH, -alk-COOalk', -N H-CO-N H2, -N H -CO-N H-alk, -N H-CO-N H-Ar 'or -N H-CON H-alk-Ar', or R3 and R4 form with the carbon atom to which they are attached a ring 2- or 3-pyrrolidine, 2- or 4-piperidine or 2-azacycloheptane, these rings being unsubstituted or substituted on the nitrogen atom by an alkyl radical, -COOalk, -CO-alk-COOH, -CO- alk-COOalk ', -CO-alk-NH2, -CO-alk-NH-alk', -CO-alk-N (alk ') alk ", -CO-alk, -CO-Ar', -CO-alk -Ar ', -COHet, -CO-alk-Het, -00-N H2, -CO-N H-alk, -CO-N H-Ar', -CO-N H-alk-Ar, -alk- VS OOH, -alk-COOalk ', -alk-Ar' or -alk-Het, -Rs represents a radical -NH2, -NH-alk, -N H-Ar ', -NH-cycloalkyle, -NH-alk-Ar 'or -N (alk) -alk', - alk and alk 'represent alkyl or alkylene radicals, - Ar represents a phenyl radical, - Ar' represents a phenyl radical optionally substituted by one or more substituents chosen from atoms of halogen and alkyl, alkoxy, nitro, amino, hydroxy, -COOH, -COOalk, -alk-NH2, -alk-COOH and -alk-COOalk '- Het represents a saturated or unsaturated mono or polycyclic heterocycle containing 1 to 9 carbon atoms and one or more heteroatoms chosen from O, S, N, the heterocycle being optionally substituted by one or more alkyl, phenyl, phenylalkyl or halogen atoms or a phthalimido radical. it being understood that the alkyl and alkylene radicals and portions contain 1 to 6 carbon atoms in a straight or branched chain, the cycloalkyl radicals contain 3 to 6 carbon atoms, the isomers of the compounds for which R represents a radical C = CH-R2, the enantiomers and diastereoisomers of the compounds for which R represents a radical C (R3) R4, CH-NH2, CH-CH (OH) -COOH or CH-CH (OH) -COOalk, and their salts. 2 - Compounds of formula (I) according to claim 1 for which Het represents a furyl, pyridyl, pyrimidinyl, thiazolinyl, pyrazinyl, thiazolyl, triazolyl, tetrazolyl, imidazolinyl, morpholinyl, imidazolyl, pyrrolyl, pyrrolidinyl, azetidinyl, piperidinyl ring thienyl, oxazolyl, oxazolinyl, these rings being optionally substituted by one or more alkyl, phenyl or phenylalkyl radicals, their isomers, enantiomers and diastereoisomers and their salts. 3 - Compounds of formula (I) according to claim 1 for which R represents a CH-NH2 or CH-CH (OH) -COOH radical, R1 represents an -alk-NH-CO-Rs radical and R5 represents a -NH radical -alk, their isomers, enantiomers and diastereoisomers and their salts. 4 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical C = CH-R2 characterized in that one dehydrates a compound of formula (I) corresponding for which R represents a radical CH -CH (OH) -COOH or CH-CH (OH) COOalk and optionally hydrolyzes the ester, isolates the product and optionally transforms it into salt. 5 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a CH-CH (OH) COOH radical or CH-CH (OH) COOalk characterized in that a derivative of formula:

 in which R1 has the same meanings as in claim 1 on an OHC-COORa derivative for which Ra represents a hydrogen atom or an aikyl radical, isolates the product and optionally transforms it into a salt. 6 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a CH-NH2 radical characterized in that a derivative of formula is reduced:

 in which R1 has the same meanings as in claim 1, isolates the product and optionally transforms it into salt. 7 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a CH-NH2 radical characterized in that a derivative of formula is hydrolyzed:

 in which R1 has the same meanings as in claim 1 and alk represents an alkyl radical, isolates the product and optionally transforms it into a salt. 8 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical C (R3) R4, R3 represents an alkyl radical, -alk-Ar or -alk-Het and R4 represents a radical -NH2 characterized in that a derivative of formula is reacted:

 in which R1 has the same meanings as in claim 1 and alk represents an alkyl radical on a halide R-R3 for which Hal represents a halogen atom and R3 has the same meanings as in claim 1, then hydrolysis to release the amino function, isolates the product and optionally transforms it into salt. 9 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical C (R3) R4, R3 represents an alkyl radical, -alk-Ar or -alk-Het and R4 represents a radical -alk -COOH or -alk-COOalk 'characterized in that a compound of formula is reacted:

 in which R3 has the same meanings as in claim 1 on a halide Hal-alk-COOalk 'for which Hal represents a halogen atom, alk and alk' have the same meanings as in claim 1 and optionally hydrolyzes the ester , isolates the product and possibly transforms it into salt. 10 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical C (R3) R4, R3 represents an alkyl radical, -alk-Ar or -alk-Het and R4 represents a radical -N H-alk, -NH-CO-alk, -NH-CO-Ar ', -NH-CO-alk-Ar', -NH-CO-Het, -NH-CO-alk-Het, -NH-CO- alk-COOH or -NH-CO-alk-COOalk 'characterized in that one reacts a compound of formula (I) corresponding for which R represents a radical C (R3) R4, R3 represents an alkyl radical, -alk -Ar or -alk-Het and R4 represents a radical -NH2 on a halide Hal-Re for which Hal represents a halogen atom and Re represents an alkyl radical, -CO-alk, -CO-Ar ', -CO- alk-Ar ', -CO-Het, -CO-alk-Het or -CO-alk-COOalk', alk, alk ', Ar', Het having the same meanings as in claim 1, and optionally hydrolyzes the ester , isolates the product and possibly transforms it into salt.  1 1 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical C (R3) R4, R3 represents an alkyl radical, -alk-Ar or -alk-Het and R4 represents a radical - N H-CO-N H2, -N H-CO-N H-alk, -NH-CO-NH-Ar 'or -N H-CO-N H-alk-Ar' characterized in that one makes react a corresponding compound of formula (I) for which R represents a radical C (R3) R4, R3 represents an alkyl radical, -alk-Ar or -alk-Het and R4 represents a radical -NH2 on a derivative O = C = N-Rf for which Rf represents a trimethylsilyl, aikyl, -Ar 'or -alk-Ar' radical, alk and Ar 'having the same meanings as in claim 1, then for the compounds for which R4 represents a radical -NH- CONH2 hydrolyzes the silylated derivative, isolates the product and optionally transforms it into salt. 12 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical C (R3) R4, R3 represents an alkyl radical, -alk-Ar or -alk-Het and R4 represents a radical -N (alk) -alk 'characterized in that a compound of formula (I) corresponding to which R represents a radical C (R3) R4, R3 represents an alkyl radical, -alk-Ar or -alk-Het is reacted and R4 represents a radical -NH-alk on a halide Hal-alk 'for which Hal represents a halogen atom and alk' represents an alkyl radical, isolates the product and optionally transforms it into salt. 13 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2-pyrrolidine, 2-piperidine or 2-azacycloheptane ring characterized in that a compound of formula (I) corresponding to which R represents a radical is reacted CH-NH2 in which the NH2 is protected by a protective group on a derivative Hal- (CH2) p-Hal 'for which Hal and Hal' are identical or different and represent halogen atoms and p is equal to 3, 4 or 5, isolates the product and optionally transforms it into salt. 14 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 3-pyrrolidine ring characterized in that the N-n-butoxymethyl-N trimethylsilylmethyl-benzylamine is condensed on a derivative of formula:

 wherein R1 has the same meanings as in claim 1, followed by debenzylation of NH, isolates the product and optionally converts it to salt. 15 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical C (R3) R4 in which R3 and R4 form, with the nitrogen atom to which they are attached, a 4-piperidine ring characterized in that the N, N-bis (2-chloroethyl) p-toluenesulfonamide is reacted on a derivative of formula:

 in which R1 has the same meanings as in claim 1, and hydrolyzes the sulfonamido function, isolates the product and optionally transforms it into salt. 16 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine or 2-azacycloheptane ring in which the nitrogen atom is substituted by an alkyl radical (1 C) characterized in that the formaldehyde and the formic acid are reacted with a corresponding compound of formula (I) for which R represents a C (R3) R4 radical in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine or 2-azacycloheptane ring, isolates the product and optionally transforms it into salt. 17 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine or 2-azacycloheptane ring in which the nitrogen atom is substituted by a radical -CO-alk- NH2 characterized in that a compound of formula (I) corresponding to which R represents a radical C (R3) R4 in which R3 and R4 form, with the carbon atom to which they are attached, react a 2- or 3-pyrrolidine, 2- or 4-piperidine or 2-azacycloheptane on a derivative of formula:

 in which Hal represents a halogen atom and alk represents an alkyl radical then deprotects the amino, isolates the product and optionally transforms it into salt. 18 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine or 2-azacycloheptane ring in which the nitrogen atom is substituted by an alkyl radical (2-6C ), -COOalk, -alk-Het, -alk-Ar ', -CO-alk, -CO-alk-COOH, -CO-alk-COOalk', -CO-Ar ', -CO-alk-Ar', -COHet or -CO-alk-Het characterized in that a compound of formula (I) corresponding to which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom which is reacted they are attached to a 2 or 3-pyrrolidine cycle,  2- or 4-piperidine or 2-azacycloheptane on a halide Hal-Rg in which Hal represents a halogen atom and Rg represents an alkyl radical (2-6C), -COOalk, -alk-Het, -alk-Ar ', -CO-alk, -COalk-COOalk', - CO-Ar ', -COalk-Ar', -CO-Het or -CO-alk-Het, alk, alk ', Het and Ar' having the same meanings as in claim 1 and optionally hydrolyzes the ester, isolates the product and eventually transforms it into salt. 19 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical C (R3) R4 in which R3 and R4 form, with the carbon atom to which they are attached, a 2- or 3-pyrrolidine, 2- or 4-piperidine or 2-azacycloheptane ring in which the nitrogen atom is substituted by a radical -CO-NH2, -CONH-alk, -CON H-Ar 'or -CO-NH-alk-Ar' characterized in that a compound of formula (I) corresponding to which R represents a radical C (R3) R4 is reacted in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine or 2-azacycloheptane ring on a derivative O = C = N-Rh for which Rh represents an alkyl radical, -Ar ', -alk-Ar' or trimethylsilyl, alk and Ar 'having the same meanings as in claim 1, then, for the silylated derivative, hydrolysis is carried out , isolates the product and possibly transforms it into salt. 20 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine or 2-azacycloheptane ring in which the nitrogen atom is substituted by a radical -CO-alk- COOH, -CO-alk-COOalk ', -CO-Ar', -CO-alk-Ar ', -CO-alk, -CO-Het or -CO-alk-Het characterized in that a compound of corresponding formula (I) for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine ring or 2-azacycloheptane on a HOOC-Ri derivative in which Ri represents a radical -alk-COOalk ', -Ar', -alk-Ar ', -Het, -alk-Het or aIkyle, alk, alk', Het and Ar ' having the same meanings as in claim 1 and optionally hydrolyzing the ester, isolating the product and optionally transforming it into salt. 21 - Process for preparing the compounds of formula (I) according to claim 1 for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine or 2-azacycloheptane ring in which the nitrogen atom is substituted by a radical -CO-alk- COOH in which alk represents a straight chain alkyl radical (1 to 3 carbon atoms), -CHz-C (CH3) 2-CH2-, -CH2-CH2-C (CH3) 2- or -CH2-C (CH3 ) 2- characterized in that an anhydride of formula:

 in which A represents an alkyl radical (1-3C in a straight chain), -CH2-C (CH3) 2-CH2-, -CH2-CH2-C (CH3) 2- or -CH2-C (CH3) 2- on a corresponding compound of formula (I) for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4-piperidine or 2-azacycloheptane ring, isolates the product and optionally transforms it into a salt . 22 - Process for preparing the compounds of formula (I) for which R represents a radical C (R3) R4 in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine ring, 2- or 4-piperidine or 2-azacycloheptane the nitrogen atom of which is substituted by a radical -CO-alk-NH-alk 'or -CO-alk-N (alk') alk "characterized in that one does reacting a corresponding compound of formula (I) for which R represents a C (R3) R4 radical in which R3 and R4 form with the carbon atom to which they are attached a 2- or 3-pyrrolidine, 2- or 4- ring piperidine or 2-azacycloheptane on a Hal-CO-alk-NH-alk 'or Hal-COalk-N (alk') alk "derivative in which Hal represents a halogen atom, alk, alk 'and alk" have the same means that in claim 1, isolates the product and optionally transforms it into salt. 23 - Process for preparing the compounds of formula (I) according to claim 1 for which R1 represents a radical -alk-NH-CO-R5 for which R5 represents a radical -NH-alk, -N H-Ar, '-NHcycloalkyle , -NH-alk-Ar 'or -N (alk) alk' characterized in that one reacts a compound of formula (I) corresponding for which R1 represents a radical -alk-NH2 on a derivative of formula:

 in which Rj represents a radical -NH-alk, -N H-Ar ', -NH-cycloalkyle, -NH-alk-Ar' or -N (alk) alk ', alk, Ar' and alk 'having the same meanings that in claim 1, isolates the product and optionally transforms it into salt. 24 - Medicines containing as active principle at least one compound of formula (I) according to claim 1 or a salt of such a compound.