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Definitions

• pyrrolyl-1 optionally substituted with a radical -COOR-jo.
• -NH-CO-NH-alk-Ar in which Ar is optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, -COOR- radicals J O and -alk-COORirj.
• R4 and R5 form together with the carbon atom to which they are attached a cycloalkyl radical
• - R5 represents a hydrogen atom or a hydroxy, alkyl (1-11C straight or branched chain), -alk-OH, -NR-
• R-jrj represents a hydrogen atom or an alkyl radical
• 1 represents a hydrogen atom or an alkyl radical (1-9C in a straight or branched chain), alkoxy, -alk-COOR-
• phenyl optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, carboxy, alkoxycarbonyl, cyano and
• R13 represents an alkyl, Het or alkoxycarbonyl radical
• R-J4 and RJ 5 identical or different, each represent an alkyl radical or else R-14 represents a hydrogen atom and R-15 represents a hydrogen atom or an alkyl radical, -COR22- -CSR23 or -SO2R24 .
• R-J6 represents a chain -CHOH- or -CH (OH) -alk (1-5C),
• - R-j8 represents a hydrogen atom or an alkyl radical
• - R-jg represents a hydroxy, alkyl, -alk-Het, -NR25R26 '-alk-COORio, -Het, phenyl radical optionally substituted by one or more substituents chosen from halogen atoms and alkyl radicals ,.
• R20 represents a hydrogen atom or an alkyl radical
• R21 represents a hydrogen atom or an alkyl radical
• - R23 represents a radical -NH-alk, -NH-Ar, -NH-Het or -NH2,
• R24 represents an alkyl or phenyl radical
• alk represents an alkyl or alkylene radical
• - alk ' represents an alkyl radical
• Het represents a saturated or unsaturated mono or polycyclic heterocycle containing 1 to 9 carbon atoms and one or more heteroatoms (O, S,
• N optionally substituted by one or more alkyl, phenyl or phenylalkyl radicals.
• the alkyl, alkylene and alkoxy radicals and portions contain 1 to 6 carbon atoms and are in a straight or branched chain
• the acyl radicals and portions contain 2 to 4 carbon atoms
• the cycloalkyl radicals contain 3 to 6 carbon atoms
• the halogen atoms are chosen from fluorine, chlorine, bromine and iodine.
• Het is chosen from the pyrrolyl, pyridyl, pyrimidinyl, imidazolyl, thiazolyl, oxazolinyl, thiazolinyl, pyrazinyl, tetrazolyl, triazolyl, pyrrolidinyie, piperazinyl, piperidinyl, thienyl, furyl, azetidinyl, substituted urinocycline ring. or more alkyl, phenyl or phenylalkyl radicals. Preferred substituents are methyl, phenyl and benzyl.
• the polyfiuoroalkoxy radicals are trifluoromethoxy radicals.
• R represents an N-alk or CH-Rg radical in which Rg represents a hydrogen atom and R3 represents a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl, phenylalkyl, phenyl or -Het
• Rg represents a hydrogen atom
• R3 represents a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl, phenylalkyl, phenyl or -Het
• R represents an N-alk or CH-Rg radical in which alk represents an alkyl radical and Rg represents a hydrogen atom on a derivative Ra- C (Oalk) 3 for which alk represents an alkyl radical and Ra represents a hydrogen atom or an alkyl, cycloalkyl, alkylcycloalkyl, phenylalkyl, phenyl or -Het radical in which Het has the same meanings as in formula (I).
• This reaction is preferably carried out in an inert solvent such as toluene or xylene, at the boiling point of the reaction medium.
• an inert solvent such as toluene or xylene
• the derivatives of formula (II) can be obtained by the action of hydrazine on a derivative of formula:
• R represents an N-alk or CH-Rg radical in which alk represents an alkyl radical and Rg represents a hydrogen atom.
• This reaction is preferably carried out in an aqueous medium, at the boiling temperature of the reaction medium.
• R represents an N-alk or CH-Rg radical in which alk represents an alkyl radical and Rg represents a hydrogen atom.
• This reaction is carried out, preferably within acetic acid, at the boiling temperature of the reaction medium.
• the derivatives of formula (IV) can be obtained by the action of ethyloxalate chloride on a derivative of formula:
• Ra-C (Oalk) 3 derivatives can be obtained by application or adaptation of the methods described by S.R. SANDLER et al., "Organic functionnal group preparations", Vol III, 41 to 68 (1971), Académie Press Inc. London.
• R represents a C (R4) Rs or CH-Rg radical in which Rg represents a hydrogen atom and R3 represents an alkyl, cycloalkyl, alkylcycloalkyl, phenylalkyl or phenyl radical
• R4 represents an alkyl, cycloalkyl, alkylcycloalkyl, phenylalkyl or phenyl radical
• R represents a radical C (R4) Rs in which R4 and R5 have the same meanings as in formula (I) or CH-Rg in which Rg represents a hydrogen atom and Rx represents an alkyl, cycloalkyl, alkylcycloalkyl, phenylalkyl or phenyl radical.
• This cyclization is generally carried out in an inert solvent such as a lower aliphatic alcohol (ethanol for example), in the presence of a condensing agent such as chloramine T, at the boiling point of the reaction medium or under the conditions described by J. MORTIER et al., Synthetic Comm., 23 (22), 3195 (1993).
• an inert solvent such as a lower aliphatic alcohol (ethanol for example)
• a condensing agent such as chloramine T
• the derivatives of formula (VI) can be obtained by the action of a compound of formula (II) for which Ri and R2 have the same meanings as in formula (I), R represents a radical C (R4) Rs in which R4 and R5 have the same meanings as in formula (I) or CH-Rg, Rg represents a hydrogen atom on an aldehyde OHC-Rx in which Rx has the same meanings as in formula (VI).
• R represents an N-alk or CH-Rg radical in which Rg represents a hydrogen atom and R3 represents an amino radical
• R represents an N-alk or CH-Rg radical in which alk represents an alkyl radical and Rg represents a hydrogen atom.
• This reaction is generally carried out in a mixture of methanol and water (preferably 6 volumes of methanol per 1 volume of water) at the boiling temperature of the reaction medium.
• This reaction is generally carried out using an acid, in an aqueous medium, at the boiling temperature of the reaction medium.
• an acid hydrochloric acid is preferably used.
• This reaction is preferably carried out in an inert solvent such as dimethyl sulfoxide, in the presence of an alkali metal hydride such as hy- sodium drure, at a temperature close to 20 ° C.
• an alkali metal hydride such as hy- sodium drure
• the isoamyl nitrite is used.
• This reaction is preferably carried out in the presence of a base such as an alkali metal hydride such as sodium hydride, in an inert solvent such as dimethylsulfoxide, at a temperature in the region of 20 ° C.
• a base such as an alkali metal hydride such as sodium hydride
• an inert solvent such as dimethylsulfoxide
• Hal-Rb derivatives for which Rb represents an -alk-COORio radical are marketed or can be obtained by the action of Hal-alk-Hal in which Hal represents a halogen atom and alk represents an alkyl radical on an alkaline cyanide (cyanide sodium or potassium), in a water-alcohol mixture, at a temperature between 0 ° C and the boiling point of the reaction medium, followed by the action of a strong acid such as acid hydrochloric acid, optionally in the presence of a lower aliphatic alcohol (methanol, ethanol for example), at a temperature between 0 ° C. and the boiling point of the reaction medium.
• a strong acid such as acid hydrochloric acid
• This reaction is preferably carried out using an acid such as hydrochloric acid, in an aqueous medium, at a temperature between 20 and 40 ° C.
• -NR25R26 can be prepared by the action of a compound of formula (I) correspondent for which R represents a radical -CH-Rg and Rg represents a hydrogen atom on a derivative HC (Rc) (Rd) Re in which either Rc and Re, identical or different, each represent a radical -NR25R26 in which R25 and R2g have the same meanings as in formula (I) and Rd represents an alkoxy radical such as tert-butoxy, ie Rc, Rd and Re, identical, each represent a radical -NR25R26 in which R25 and R2g have the same meanings as in formula (I).
• This reaction is generally carried out in an inert solvent such as dimethylformamide, at a temperature between 20 and 40 ° C.
• HC (Rc) (Rd) Re derivatives can be obtained by application or adaptation of the method described by H. BREDERECK, Liebigs Ann. Chem., 762, 62 (1972).
• R represents a CH-Rg radical and Rg represents a hydrogen atom on an aldehyde of formula OHC-Rf in which Rf represents a radical alkyl, phenyl optionally substituted with one or more substituents chosen from halogen atoms and alkyl, alkoxy, nitro, amino, hydroxy, -alk-NH2, -COOR10, cyano and -alk-COORio, -alk-Het radicals, phenylalkyl in which the phenyl nucleus is optionally substituted
• This reaction is generally carried out either in an inert solvent such as dimethylformamide, 1,2-dimethoxyethane, an alcohol (methanol, ethanol for example) or a mixture of these solvents, in the presence of a base such as soda, potash, a strong organic base such as 1, 8-diazabicyclo [5,4,0] undec-7-ene, at a temperature between 20 and 100 ° C, or within dimethyl sulfoxide, in the presence an alkaline hydride such as sodium hydride, at a temperature in the region of 20 ° C., either in the presence of tetrabutylammonium bromide and a base such as an alkali metal hydroxide (sodium hydroxide, potassium hydroxide for example), within dimethyl sulfoxide, at a temperature between 20 and 100 ° C, either within acetic acid or acetic anhydride, in the presence of ammonium acetate, at a temperature between 20 ° C and the boiling temperature of reaction medium
• the OHC-Rf derivatives are marketed or can be obtained (a) by oxidation of the corresponding alcohols HOH2C-Rf (using K2Cr2 ⁇ 7, in a sulfuric medium; Cr ⁇ 3 in pyridine or Mn ⁇ 2 in a solvent chlorinated (dichloromethane for example), at a temperature close to 20 ° C or using dimethyl sulfoxide and CICO-COCI by adaptation or application of the method described by D. SWERN et al., J. Org.
• the corresponding alcohols HOH2C-Rf for which Rf represents an -alk-Het or -alk-Ar radical in which Ar is optionally substituted 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 corresponding organometallic derivative of the corresponding heterocycle or optionally substituted benzene is prepared and reacted either on CO2 or on a Hal-alk-COOalk derivative in which Hal represents a halogen atom and alk an alkyl radical followed by hydrolysis of the ester.
• Hal-alk-COOalk derivatives are marketed or prepared by the action of Hal-alk-Hal in which Hal represents a halogen atom on an alkaline cyanide such as sodium or potassium cyanide in a water-alcohol mixture , at a temperature between 0 ° C and the boiling point of the reaction medium, followed by the action of an acid such as hydrochloric acid, in the presence of an alcohol, at a temperature between 0 ° C and the boiling point of the reaction medium.
• Hal represents a halogen atom on an alkaline cyanide such as sodium or potassium cyanide in a water-alcohol mixture
• an acid such as hydrochloric acid
• Hal-alk-Hal derivatives can be obtained from the corresponding dialcohols by application or adaptation of the methods described by C. LAROCK, "Comprehensive Organic Transformations", Ed. VHC, page 353 (1989).
• OHC-Rf derivatives for which Rf represents an -alk-COORio radical are commercially available or can be obtained by reduction of the corresponding carboxylic acids by application or adaptation of the methods described by HC BROWN et al., J. Am. Chem . Soc, 106, 8001 (1984) and J. Org. Chem., 52, 5400 (1987).
• the corresponding acids are marketed or can be obtained by application or adaptation of the methods described by H. HUNSDIECKER et al., Chem. Ber., 75, 256 (1942) and R.F. NAYLOR, J. Chem. Soc, 1108 (1947).
• R7 represents a radical NR10
• R7 represents a radical NR10
• R7 represents a radical NR10
• This reaction is generally carried out in an inert solvent such as dimethylformamide, at a temperature in the region of 60 ° C.
• Ri, R2 and R3 have the same meanings as in formula (I) and Rg represents a radical -C (R2 ⁇ ) (OH) -COOR ⁇ o in which R20 and R O have the same meanings as in formula (I).
• This reaction is generally carried out within acetic anhydride, at the boiling temperature of the reaction medium.
• This reaction takes place within dimethyl sulfoxide, in the presence of an alkali metal hydride such as sodium hydride, at a temperature in the region of 20 ° C or in the presence of tetrabutylammonium bromide and a base such than an alkali metal hydroxide (soda, potash for example), within dimethylsulfoxide, at a temperature between 20 and 100 ° C.
• the acetic acid treatment is carried out at a temperature below 20 ° C.
• the derivatives of formula R20-CO-COOR10 in which R10 and R20 have the same meanings as in formula (I) are marketed or can be obtained by application or adaptation of the methods described by LA CARPINO, J. Org. Chem., 29, 2820 (1964) and HH WASSERMAN, J. Org. Chem., 50, 3573 (1985).
• the operation is carried out in the presence of a condensing agent used in peptide chemistry such as a carbodiimide (for example N, N'-dicyclohexylcarbodiimide) or N, N'- diimidazole carbonyl, in an inert solvent such as an ether (tetrahydrofuran, dioxane for example), an amide (dimethylformamide) or a chlorinated solvent (methylene chloride, 1,2-dichloro ethane, chloroform for example) at a temperature between 0 ° C and the reflux temperature of the reaction mixture.
• a condensing agent used in peptide chemistry such as a carbodiimide (for example N, N'-dicyclohexylcarbodiimide) or N, N'- diimidazole carbonyl
• an inert solvent such as an ether (tetrahydrofuran, dioxane for example), an amide (dimethylformamide)
• an ester When an ester is used, it is then carried out either in an organic medium, possibly in the presence of an acid acceptor such as an organic nitrogenous base (trialkylamine, pyridine, diaza-1, 8 bicyclo [5.4 .0] undecene-7 or diaza-1, 5 bi-cyclo [4.3.0] nonene-5 for example), in a solvent as mentioned above, or a mixture of these solvents, at a temperature between 0 ° C and the reflux temperature of the reaction mixture, either in a two-phase hydroorganic medium in the presence of an alkaline or alkaline-earth base (soda, potash) or of a carbonate or bicarbonate of an alkali or alkaline-earth metal at a temperature between 0 and 40 ° C.
• an acid acceptor such as an organic nitrogenous base (trialkylamine, pyridine, diaza-1, 8 bicyclo [5.4 .0] undecene-7 or diaza-1, 5 bi-cyclo [4.3.0
• R4 represents an alkyl, -alk-Het or phenylalkyl radical in which the phenyl nucleus is optionally substituted by one or more substituents chosen from halogen atoms and the alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, -COOR10 and -alk-COORio radicals and R5 is identical to R4
• R5 represents a radical C (R4) R5, R4 represents an alkyl, -alk-Het or phenylalkyl radical in which the phenyl nucleus is optionally substituted by one or several substituents chosen from halogen atoms and alkyl, alkoxy, nitro, amino, hydroxy, cyano, -al
• R represents a radical C (R4) Rs, R5 represents an alkyl radical (1-11C in straight or branched chain), -alk-CN, -alk-Het, -alk-NR ⁇ oR 8 > -alk-CO-NR ⁇ oR ⁇ - -COOR10 or phenylalkyl, the phenyl nucleus of which is optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk- radicals NH2, -COOR10 and -alk-COORio, can be prepared by the action of a corresponding compound of formula (I) for which R represents a CH-Rg radical and Rg represents an alkyl, -alk-Het or phenylalkyl radical whose nucleus phenyl is optionally substituted by one or more substituents chosen from halogen atoms and alky
• 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 tetrabutyammonium bromide in dimethyl sulfoxide 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 .
• a base such as an alkali metal hydroxide (sodium hydroxide, potassium hydroxide for example )
• tetrabutyammonium bromide in dimethyl sulfoxide or in the presence of an alkali metal hydride (sodium hydride for example)
• the hydrolysis is preferably carried out 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 about 20 to 30 ° C.
• a base such as an alkali metal hydroxide (soda or potash for example)
• a water-lower aliphatic alcohol mixture ethanol for example
• Hal-Ri derivatives are marketed or those for which Ri represents an -alk-CO-NR ⁇ oRl8 radical can be prepared by the action of an amine HNR10R18 on a Hal-alk-CO-Hal derivative in which Hal represents a halogen atom and alk represents an alkyl radical, within an inert solvent such as dimethylformamide, tetrahydrofuran, a chlorinated solvent, in the presence of an organic base such as a trialkylamine or pyridine, at a temperature between 0 ° C. and the boiling point of the reaction medium.
• an inert solvent such as dimethylformamide, tetrahydrofuran, a chlorinated solvent
• Hal-alk-CO-Hal derivatives are sold or can be obtained by halogenation of the corresponding carboxylic acids by means of a halogenating agent such as thionyl chloride, in an inert solvent such as 1,2. -dichloroethane, at a temperature close to 60 ° C.
• a halogenating agent such as thionyl chloride
• an inert solvent such as 1,2. -dichloroethane
• the Hal-alk-COOH acids can be obtained by the action of an alkali metal cyanide on a Hal-alk-Hal derivative in which alk represents an alkyl radical and Hal represents a halogen atom, within a water mixture -alcohol, at a temperature between 0 ° C and the boiling point of the reaction medium followed by the action of a strong acid such as hydrochloric acid, in aqueous medium, at a temperature between 0 ° C and the boiling temperature of the reaction medium.
• a strong acid such as hydrochloric acid
• R represents a radical C (R4) Rs and R4 and R5 form with the carbon atom to which they are attached a cycloalkyl radical
• R represents a radical C (R4)
• R4 and R5 form with the carbon atom to which they are attached a cycloalkyl radical
• Rg represents a hydrogen atom on a derivative of formula Hal-alk-Hal in which Hal represents a halogen atom and alk represents an alkyl radical (2-5C).
• This reaction is generally carried out in an inert solvent such as dimethylformamide, an alcohol (methanol, ethanol for example) or a mixture of these solvents, in the presence of tetrabutylammonium and of a base such as a hydroxide. of alkali metal (sodium hydroxide, potassium hydroxide for example) within dimethylsulfoxide, at a temperature between 20 ° C. and the boiling temperature of the reaction medium.
• an inert solvent such as dimethylformamide, an alcohol (methanol, ethanol for example) or a mixture of these solvents
• a base such as a hydroxide.
• alkali metal sodium hydroxide, potassium hydroxide for example
• This reaction is generally 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.
• the 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.
• R represents a radical C (R4) Rs in which R5 represents a radical -NRgRg, Rg represents a hydrogen atom and Rg represents an alkyl radical, -alk-COORio. -alk-NR ⁇ oR21. -alk-Het or phenylalkyl in which the phenyl nucleus is optionally substituted
• R4 represents a radical C (R4)
• R5 represents a radical -NRgRg
• Rs and Rg represent hydrogen atoms on a Hal-Rg halide in which Rg has the same meanings as above.
• This reaction is generally carried out in an inert solvent such as dimethylformamide, in the presence of an alkali metal carbonate such as sodium or potassium carbonate or a trialkylamine such as triethylamine or pyridine, with a temperature between 0 ° C and the boiling temperature of the reaction medium.
• an alkali metal carbonate such as sodium or potassium carbonate
• a trialkylamine such as triethylamine or pyridine
• Halides Hal-Rg are marketed or those for which R ⁇ re ⁇ presents a radical -alk-NR ⁇ oR2l can be obtained by action of the amine HNR10R21 in which R10 and R21 have the same meanings as in formula (I) on a halide Hal-alk-Hal in which Hal represents a halogen atom and alk represents an alkyl radical, within an inert solvent such as dimethylformamide, in the presence of an acid acceptor such as a nitrogenous base, with a temperature between 0 and 25 ° C.
• Rg represents an -alk-COORio radical
• a derivative Hal-alk-Hal in which Hal represents a halogen atom and alk represents an alkyl radical on an alkaline cyanide (sodium cyanide or potassium), in a water-alcohol mixture, at a temperature between 0 ° C and the boiling temperature of the reaction medium, followed by the action of a strong acid such as HCl, optionally in the presence of a lower aliphatic alcohol, at a temperature between 0 ° C. and the boiling point of the reaction medium.
• a strong acid such as HCl
• This reaction is carried out in an inert solvent such as dimethylforamide, " in the presence of an acid acceptor such as a nitrogenous organic base (pyridine or trialkylamine such as triethylamine), at a temperature between 0 ° C and the boiling temperature of the reaction medium.
• an acid acceptor such as a nitrogenous organic base (pyridine or trialkylamine such as triethylamine
• Hal-Rg derivatives are marketed or can be obtained by application or adaptation of the methods described by C. LAROCK, "Comprehensive Organic Transformations", Ed. VCH, pages 345 and 353 (1989).
• R represents a radical C (R4)
• R5 represents a radical -alk-COORio
• R10 has the same meanings as in formula (I) on a halide R-R4 in which R4 has the same meanings as in formula (I).
• This reaction is carried out in an inert solvent such as dimethylforamide, in the presence of an alkali metal hydride such as sodium or potassium hydride, at a temperature in the region of 20 ° C.
• an alkali metal hydride such as sodium or potassium hydride
• R represents a radical C (R4)
• R5 represents a radical -alk (2-6C) OH
• (COCD2 on a compound of formula (I) corresponding to le ⁇ which R represents a radical C (R4)
• R5 in which R5 represents a radical -alk-COORio and R 0 represents a hydrogen atom followed by a reduction.
• This reaction is carried out in an inert solvent such as dioxane.
• the reduction is preferably carried out by means of sodium borohydride, in an inert solvent such as dimethylformamide, at a temperature between 10 and 20 ° C.
• R represents a radical C (R4)
• R5 represents a radical -alkOQOH
• Rg represents an alkyl, -alk-Het or phenylalkyl radical in which the phenyl nucleus is optionally substituted by one or more substituents chosen from halogen atoms and alkyl, alkoxy, nitro, amino, hydroxy, cyano, -alk-NH2, -COOR10 and -alk-COORio radicals, followed by trioxane action.
• This reaction is generally carried out in an inert solvent such as dimethylformamide, in the presence of sodium hydride then reaction with the trioxane at a temperature between 0 and 25 ° C.
• R5 in which R5 represents a radical -NH-CHO or a radical CH-Rg in which Rg represents a radical -NH-CHO can be prepared by action of a compound of corresponding formula (I) for which R represents either a C (R4) Rs radical in which R5 represents a -NRgRg radical, Rg and Rg represent hydrogen atoms or a CH-Rg radical in which Rg represents a radical -NR14R15, R14 and R15 represent hydrogen atoms on CH3COOCHO.
• This reaction is preferably carried out within formic acid, in the presence of sodium acetate, at a temperature in the region of 20 ° C.
• R represents either a radical C (R4) R5 in which R5 represents a radical -NH-COOR17, -NH-CO-Het, -NH-CO-alk-COORio, -NH-CO -alk-NR ⁇ oRi8- -NH-CO-Ar in which Ar is EVEN ⁇ tuellement substituted, -NH-CO-alk-Ar in which Ar is optionally substituted, -NH-SO2-R24.
• -NH-CO-alk-Het -NH-CO-alk or -NH-CO-cycloalkyle is a CH-Rg radical in which Rg represents a radical -NR14R15 or -alk-NRi4Ri5, R14 represents a hydrogen atom, R15 represents an alkyl radical, -CO-R22 or -SO2R24.
• R22 represents an alkyl, cycloalkyl, -COOalk, -alk-Het, -ORi7, Het, -alk-COORio, -alk-NR ⁇ oRi2 radical.
• This reaction is generally carried out in an inert solvent such as dimethylformamide, in the presence of hydroxybenzotriazole, 1- (3-dimethylaminopropyl) -3 ethylcabodiimide and an organic base such as a trialkylamine (triethylamine for example ), at a temperature between 0 ° C and 5 ° C.
• an inert solvent such as dimethylformamide
• R5 in which R5 represents a pyrrolyl-1 radical optionally substituted by a radical -COOR10 or a radical CH-Rg in which Rg represents a pyrrolyl-1 radical optionally substituted with a radical -COOR10 can be prepared by the action of a compound of formula (I) correspondent for which R represents either a radical C (R4) Rg in which R5 represents a radical -NRsRg, R ⁇ and Rg represent hydrogen atoms, or a radical CH-Rg in which Rg represents a radical -NR14R15, R14 and R15 represent hydrogen atoms on a derivative of formula:
• RI represents a hydrogen atom or a radical -COOR10 and RiO has the same meanings as in formula (I).
• This reaction is generally carried out in an inert solvent such as acetic acid, at the boiling temperature of the reaction medium, possibly in the presence of an acid acceptor such as sodium acetate.
• an inert solvent such as acetic acid
• 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.
• an inert solvent such as dimethylformamide, tetrahydrofuran or dioxane
• this reaction is followed by hydrolysis of the silylated derivative previously obtained by means of an aqueous solution, at a temperature of between 20 and 50 ° C.
• the amines for which Rn represents an -alk-Het or -alk-Ar radical in which Ar is optionally substituted are marketed or are obtained from the corresponding halides by the action of NaN (SiCH3) 3 or of the potassium salt of phthalimide, within of an inert solvent such as dimethylformamide, in the presence of an organic base such as a trialkylamine or pyridine, at a temperature between 0 ° C. and the boiling temperature of the reaction medium followed by hydrolysis in an acid medium (HCI for example), at a temperature between 20 ° C and the boiling temperature of the reaction medium or hydrolysis by hydrazine in ethanol, at a temperature between 20 ° C and the temperature of boiling of the reaction medium.
• an organic base such as a trialkylamine or pyridine
• H2N-alk-Ar derivatives in which Ar is optionally substituted can also be obtained by application or adaptation of the methods described by JF KING et al., J. Am. Chem. Soc, 114, 3028 (1992); BM ADGER et al., Tetrahedron Lett., 25 (45), 5219 (1984); R. SCARPATI et al., Gazz. Chim. Ital., 97 (5), 654 (1967).
• This reduction is carried out by means of hydrogen at a pressure of 1 to 20 bar, in the presence of a hydrogenation catalyst such as palladium on carbon, palladium hydroxide or palladium (N. RICO et al. ., Wunsch Journal de Chimie, 10, 1, 25 (1986)), in an inert solvent such as dimethylformamide, acetic acid, ethyl acetate, an alcohol (methanol or ethanol for example) or a mixture of these solvents, at a temperature between 20 and 60 ° C or by adaptation of the method of LM STRAWN et al., J. Med.
• a hydrogenation catalyst such as palladium on carbon, palladium hydroxide or palladium
• an inert solvent such as dimethylformamide, acetic acid, ethyl acetate, an alcohol (methanol or ethanol for example) or a mixture of these solvents
• This reduction is generally carried out using a reducing agent such as sodium borohydride, in an inert solvent such as an alcohol (methanol, ethanol for example), at a temperature in the region of 20 ° C. .
• This reduction is preferably carried out by means of hydrogen, at a pressure of 1 to 50 bar, in the presence of a catalyst such as palladium carbon, palladium hydroxide, in an inert solvent such as that dimé ⁇ thylformamide, acetic acid, an alcohol, ethyl acetate, at a temperature between 20 and 60 ° C.
• a catalyst such as palladium carbon, palladium hydroxide
• an inert solvent such as that dimé ⁇ thylformamide, acetic acid, an alcohol, ethyl acetate
• R represents a CH-Rg radical in which Rg represents a radical -NR14R15, R14 and R15 represent hydrogen atoms
• R14 and R15 represent hydrogen atoms
• the compounds of formula (I) for which R represents a CH-Rg radical in which Rg represents a radical -NR14R15, R14 represents a hydrogen atom and R15 represents a radical -COR22 and R22 represents an alkyl radical can also be prepared by the action of a corresponding compound of formula (I) for which R represents a CH-Rg radical in which Rg represents a radical -NR14R15, R14 and R15 represent hydrogen atoms on a 2 ⁇ anhydride (alkCO) in which alk represents an alkyl radical.
• This reaction is generally carried out in pyridine, at a temperature in the region of 25 ° C.
• R15 represents a radical -COR22 in which R22 represents a radical -alk- COORio in which R10 represents a hydrogen atom and alk represents a straight chain alkyl (1-3C), -CH2-C (CH 3 ) 2-CH 2 -, -CH2-CH2-C (CH3) 2- or -CH2-C (CH 3 ) - or R22 represents a phenyl radical substituted by a radical -COOR10 in which R10 is a hydrogen atom, or R represents a radical C (R4) Rs in which R5 represents a radical -NH- CO-alk-COORio in which R 0 is a hydrogen atom and alk represents alkyl (1-3C in a straight chain), -CH2-C (CH 3 ) 2-CH 2 -, -CH -CH2-C (CH 3
• This reaction is generally carried out in pyridine, at a temperature in the region of 25 ° C.
• R represents a CH-Rg radical and Rg represents a -NR14R15 or -alk-NR 4R 5 radical in which R14 and R 5, identical or different, each represents an alkyl radical
• Rg represents a radical -NR14R 5 or -alk-NRi4Ri5 in which R14 and R15 each represent a hydrogen atom on a halide of formula Hal-Rq in which Rq represents an alkyl radical.
• This reaction is preferably carried out in an inert solvent such as dimethylformamide, tetrahydrofuran or dimethylsulfoxide, in the presence of a base such as a tertiary amine (triethylamine for example) or aromatic (pyridine by example) or a mineral base such as an alkali metal hydroxide (sodium hydroxide, potassium hydroxide for example), at a temperature between 20 ° C. and the boiling point of the reaction medium.
• a base such as a tertiary amine (triethylamine for example) or aromatic (pyridine by example) or a mineral base such as an alkali metal hydroxide (sodium hydroxide, potassium hydroxide for example)
• This reaction is preferably carried out in an inert solvent such as dimethylformamide, in the presence of hydroxybenzotriazole, 1- (3-dimethyl-laminopropyl) -3 ethylcarbodiimide and an organic base such as trialkyamine (triethylamine for example), at a temperature between 0 and 5 ° C.
• the hydrolysis is generally carried out using trifluoroacetic acid, at a temperature in the region of 20 ° C.
• Rg represents a radical R14 and R15 each represent a hydrogen atom
• R12 represent hydrogen atoms
• Rg represents a radical -alk-CO-NR ⁇
• R21 can be prepared by the action of a corresponding compound of formula (I) for which R represents a radical CH-Rg and Rg represents a radical -alk-COORio on an amine HNR10R21 in which R10 and R21 have the same meanings as in formula (I).
• the operation is carried out in the presence of a condensing agent used in peptide chemistry such as a carbodiimide (for example N, N'-dicyclohexylcarbodiimide) or N, N'- diimidazole carbonyl, in an inert solvent such as an ether (tetrahydrofuran, dioxane for example), an amide (dimethylformamide) or a chlorinated solvent (methylene chloride, 1,2-dichloro ethane, chloroform for example) at a temperature between 0 ° C and the reflux temperature of the reaction mixture.
• a condensing agent used in peptide chemistry such as a carbodiimide (for example N, N'-dicyclohexylcarbodiimide) or N, N'- diimidazole carbonyl
• an inert solvent such as an ether (tetrahydrofuran, dioxane for example), an amide (dimethylformamide)
• an ester When an ester is used, the operation is then carried out either in an organic medium, optionally in the presence of an acid acceptor such as an organic nitrogenous base (trialkylamine, pyridine, diaza-1, 8 bicycio [5.4 .0] undecene-7 or diaza-1, 5 bi ⁇ cycio [4.3.0] nonene-5 for example), in a solvent as mentioned above, or a mixture of these solvents, at a temperature between 0 ° C and the reflux temperature of the reaction mixture, either in a two-phase hydroorganic medium in the presence of an alkaline or alkaline-earth base (soda, potash) or of a carbonate or bicarbonate of an alkali or alkaline-earth metal at a temperature between 0 and 40 ° C.
• an acid acceptor such as an organic nitrogenous base (trialkylamine, pyridine, diaza-1, 8 bicycio [5.4 .0] undecene-7 or di
• the amines HNR10 21 are marketed or can be obtained from the corresponding halides by application or adaptation of the methods described by R.C. LAROCK, "Comprehensive Organic Transformations", Ed. VCH, page 397 (1989).
• Rg represents a radical -alk (1C) -CO-NR ⁇ *
• R21 and R10 and R21 represent hydrogen atoms
• R21 and R10 and R21 represent hydrogen atoms
• Ri, R2 and R3 have the same meanings as in formula (I) and Ro represents a radical -CONH2-
• This reaction is generally carried out either by means of hydrogen, in an inert solvent such as dimethylformamide, in the presence of a hydrogenation catalyst such as palladium on carbon or palladium, at a temperature close to 20 to 30 ° C, either by application or adaptation of the LM method.
• a hydrogenation catalyst such as palladium on carbon or palladium
• the compounds of formula (I) for which R represents a radical CH-Rg and Rg represents a radical -Rig-COORio can be prepared by the action of a corresponding compound of formula (I) for which R represents a radical CH- Rg and Rg represents a hydrogen atom on a derivative of formula OHC-alk (0-5C) -COOR ⁇ o in which alk represents an alkyl radical and R10 has the same meanings as in formula (I).
• This reaction is preferably carried out in an inert solvent such as dimethyl sulfoxide, in the presence of an alkali metal hydride such as sodium hydride, at a temperature in the region of 20 ° C.
• an alkali metal hydride such as sodium hydride
• This oxidation is preferably carried out by means of potassium permanganate, within a 3N sodium hydroxide solution, at a temperature in the region of -3 ° C or by means of platinum on carbon, within a 2N sodium hydroxide solution. , at a temperature of 70 ° C.
• the esterification is preferably carried out using an alcohol, in the presence of an acid such as hydrochloric or sulfuric acid, at the boiling temperature of the reaction medium.
• Ri, R2 and R3 have the same meanings as in formula (I) and alk represents an alkyl radical.
• This reaction is generally carried out in an inert solvent such as tetrahydrofuran, at a temperature of 0 ° C.
• an inert solvent such as tetrahydrofuran
• hydrochloric acid is preferably used, in a 1N aqueous solution.
• the derivatives of formula (X) can be obtained by the action of a corresponding compound of formula (I) for which R represents a CH-Rg radical and Rg represents a hydrogen atom on a Hal-COOalk halide in which alk represents a alkyl radical.
• This reaction is generally carried out in an inert solvent such as dioxane, in the presence of an alkali metal hydride (sodium for example), at a temperature between 20 ° C. and the boiling point of the reaction medium.
• Hal-COOalk derivatives are sold or can be obtained by application or adaptation of the methods described in HOUBEN-WEYL, band 8, page 102 (1952).
• This reaction is generally carried out in an inert solvent such as dimethylformamide, optionally in the presence of a trialkylamine, at a temperature between 20 and 100 ° C.
• an inert solvent such as dimethylformamide
• groups protecting the amino, hydroxy and carboxy functions are those that allow them to be eliminated without affecting the rest of the molecule.
• groups protecting the amino function mention may be made of tert-butyl or methyl carbamates which can be regenerated by means of iodotrimethylsilane.
• protecting groups for the hydroxy function mention may be made of triethylsilyl, benzyl.
• esters methoxymethylester, tetrahydropyranylester, benzylester for example, oxazoles and 2-alkyl-1, 3-oxazolines.
• Other protective 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, an ether or a chlorinated solvent.
• organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent.
• 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 modulating sites of the NMDA receptor.
• NMDA N-methyl-D-aspartate receptor
• 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 effects due to anoxia, whether perinatal or consecutive to drowning or cerebro-spinal lesions. These compounds can also be used to treat or prevent the development of neurodegenerative diseases, HUNTINGTON's chorea, ALZHEIMER's disease, amyotrophic lateral sclerosis, olivo-pontocerebellar atrophy and the disease by PARKINSON.
• 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)).
• the [3H] -AMPA is incubated in the presence of 0.2 mg of protein at 4 ° C for 30 minutes in 10mM KH2PO4 buffer, 100mM KSCN, pH7.5.
• the non-specific binding is determined in the presence of 1 mM L-glutamate.
• 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 ⁇ M.
• the affinity of the compounds of formula (I) for the glycine site linked to the NMDA receptor 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 [ ⁇ KI-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.
• the non-specific fixation is determined in the presence of 1 mM 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 ⁇ M.
• the compounds of formula (I) have a low toxicity. Their LD50 is greater than 50 mg / kg by the IP route in mice.
• the 2-amino-1-indanone hydrochloride can be obtained in the following manner: a sodium ethylate solution, prepared from 15.2 g of sodium and 770 ml of absolute ethanol, is added drop by drop, at 0 ° C. and under nitrogen, to 200 g of 1-indanone oxime p-toluenesulfonate dissolved in 3.7 liters of anhydrous toluene. The reaction is continued for 40 hours at 0 ° C. The suspension is then filtered through celite and the filtrate washed with water (400 ml).
• the 1-indanone oxime p-toluenesulfonate can be prepared as follows: 532 g of p-toluenesulfonate chloride dissolved in 600 ml of pyridine are added dropwise to 186.1 g of 1-indanone oxime in so ⁇ lution in 900 ml of pyridine at 0 ° C and under nitrogen. After 3 hours of reaction at 0 ° C., the reaction medium is poured into 3 liters of ice water. The precipitate formed is filtered, washed with water and dried. 354 g of expected product are thus obtained in the form of a white solid, melting at 150 ° C.
• 1-indanone-oxime can be obtained in the following manner: to 200 g of 1-indanone dissolved in 3.4 I of methanol, 366 g of hydroxyamine hydrochloride, 366 g of potassium carbonate are added and 340 ml of distilled water. The mixture is brought to reflux for 18 hours. After cooling, the suspension formed is filtered, washed with water and then with methanol and dried under reduced pressure (1 mm Hg; 0.13 kPa) to yield 186.1 g of the expected product in the form of a white, melting solid. at 154 ° C.
• Example 2 The procedure is as in Example 1, but starting with 4 ml of triethylorthopropionate, 0.5 g of 3-hydrazino-1H-indeno [1,2-b] pyrazine-2-one and 15 ml of xylene. After recrystallization from acetic acid and drying under pressure reduced (1 mmHg, 0.13 KPa, 50 ° C), 0.17 g of 1-ethyl 5H.10H- indeno [1, 2-e] -1, 2,4-triazolo [4,3- is obtained a] pyrazine-4-one in the form of a cream solid with a melting point above 260 ° C.
• EXAMPLE 5 The procedure is as in Example 3, but using 0.62 g of 3-hydrazino-1 H-indeno [1, 2-b] pyrazine-2-one, 13 ml of xylene and 5 g of trimethylorthovalerate.
• the crude product (0.31 g) is purified by crystallization from dimethylsulfoxide (2.5 ml). The crystals are washed with distilled water and dried at 60 ° C under vacuum (1 mmHg; 0.13 kPa).
• 3- (cyclopropylidenehydrazino) -1 H-indeno [1, 2-b] pyrazine-2-one can be prepared as follows: the procedure is as in Example 6 but starting with 4.55 g of 3- hydrazino-1 H-indeno [1, 2-b] pyrazine-2-one, 100 ml of propanol and 1.6 ml of cyclopropanecarboxaldehyde.
• a mixture of 3.25 g of 1-butyl-10-hydroxyimino-5H, 10H-indeno [1, 2-e] 1, 2,4-triazolo [4 is hydrogenated for 5 hours at a temperature in the region of 25 ° C. , 3-a] pyrazine-4-one, 54 ml of acetic acid, 65 ml of trifluoroacetic acid and 0.6 g of 10% palladium on carbon under a pressure of 1.8 bar of hydrogen.
• the catalyst is filtered under an inert atmosphere and the filtrate is concentrated on a rotary evaporator. The evaporation residue is added with 50 ml of water and the crystals formed are filtered, washed with ethyl ether and dried.
• a suspension of 10-amino-1-butyl-5H, 10H-indeno [1,2-e] 1,2,4-triazolo [4,3-a] is stirred for 1 hour at a temperature in the region of 25 ° C.
• pyrazine-4-one hydrochloride in 4.8 ml of pyridine, then 0.18 ml of anhydride is added acetic and continue to stir for 2 hours.
• 25 ml of distilled water are added to the reaction mixture and the precipitate formed is filtered, washed with ethyl ether (3x15 ml) and dried at 60 ° C under vacuum (1 mmHg; 0.13 kPa).
• 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 product.
• pharmaceutically compatible which may be inert or physiologically active.
• the medicaments according to the invention can be used orally, parenterally, rectally or topically.
• compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants and stabilizers. Sterilization can be done 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 compounds according to the invention are particularly useful for the treatment and / or prevention of 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 ⁇ KINSON disease, vis-à-vis epileptogenic and / or convulsive manifestations, for the treatment of cerebral and spinal trauma, trauma linked to degeneration inner ear or retina, anxiety, depression, schizophrenia, TOURETTE syndrome, hepatic encephalopathy, as analgesics, anti-inflammatories, anti-anxiety drugs, antimigraine, antiemetic and to treat poisoning by neurotoxins or other NMDA receptor agonist substances, as well as neurological disorders associated with viral diseases such as AIDS, rabies, mea
• These compounds are also useful for the prevention of symptoms of abstinence from drugs and alcohol and the inhibition of addiction and dependence on opiates as well as for the treatment of deficits associated with mitochondrial abnormalities such as mitochondrial myopathy, Leber syndrome, Wernicke encephalopathies, RETT syndrome, homocysteinemia, hyperprolinemia, hydroxybutirin-amino acid disease, saturnine encephalopathy (chronic lead poisoning) and sulfite deficiency oxidase.
• mitochondrial abnormalities such as mitochondrial myopathy, Leber syndrome, Wernicke encephalopathies, RETT syndrome, homocysteinemia, hyperprolinemia, hydroxybutirin-amino acid disease, saturnine encephalopathy (chronic lead poisoning) and sulfite deficiency oxidase.
• 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.
• the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated.
• capsules containing 50 mg of active product having the following composition are prepared:
• EXAMPLE B Tablets containing 50 mg of active product having the following composition are prepared according to the usual technique:

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