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Definitions

• the present invention relates to new amino acid derivatives and their application as medicaments. These derivatives exhibit an inhibitory activity of the NO-synthase enzymes producing nitric oxide NO and / or (as desired): either a scavenging activity of reactive oxygen forms (ROS for "reactive oxygen species”); either a regenerative activity of antioxidants such as glutathione or of trapping entities of reactive forms of oxygen (ROS for "reactive oxygen species”) and more generally an influence in the redox status of the thiol groups.
• ROS reactive oxygen forms
• antioxidants such as glutathione or of trapping entities of reactive forms of oxygen
• the invention therefore relates in particular to the derivatives corresponding to the general formula (I) defined below, their methods of preparation, the pharmaceutical preparations containing them and their use for therapeutic purposes, in particular their use as inhibitors of NO-synthases and / or (optional): either as ROS entrapment entities; - Either as agents allowing the regeneration of antioxidants like glutathione or of trapping entities of ROS and intervening more generally in the redox status of thiol groups.
• cardiovascular and cerebrovascular disorders including, for example, atherosclerosis, migraine, high blood pressure, septic shock, cardiac or cerebral infarction of ischemic or hemorrhagic origin, ischemia and thrombosis;
• disorders of the central or peripheral nervous system such as, for example, neurodegenerative diseases in which we can especially cite cerebral infarctions, sub arachnoid hemorrhage, aging, senile dementia, including Alzheimer's disease, Huntington's chorea, Par inson disease, Freiderich's ataxia, Creutzfeld Jacob's disease and prion diseases, lateral sclerosis amyotrophic but also pain, cerebral or spinal cord trauma, addiction to opiates, alcohol and addictive substances, erection and reproduction disorders, cognitive disorders, encephalopathies, encephalopathies of viral or toxic origin, depression, anxiety, schizophrenia, epilepsy, sleep disorders, eating disorders (anorexia, bulimia ...);
• proliferative and inflammatory diseases such as atherosclerosis, pulmonary hypertension, respiratory distress, glomerulonephritis, cataracts, portal hypertension, psoriasis, osteoarthritis and rheumatoid arthritis, fibrosis, amyloidosis , inflammation of the gastrointestinal system (colitis,
• autoimmune and viral diseases such as, for example, lupus, AIDS, parasitic and viral infections, diabetes and its complications including retinopathies, nephropathies and polyneuropathies, multiple sclerosis, myopathies;
• R 1 represents a hydrogen atom or an alkyl radical
• a and A ' represent a hydrogen atom or one of the following radicals - a radical
• R 2 , R 3 , R 4 , R 5 , R 6 independently represent a hydrogen atom, a halogen, the OH group, an alkyl, alkoxy, cyano, nitro or NR 8 R 9 , R 8 radical and R 9 independently representing a hydrogen atom, an alkyl radical or a group -COR 10 , or else R 8 and R 9 forming together with the nitrogen atom an optionally substituted heterocycle having 4 to 7 members and from 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being independently chosen from the group consisting of O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, R 10 representing a hydrogen atom, an alkyl, alkoxy or NR 1 'R 12 radical,
• R 11 and R 12 independently representing a hydrogen atom or an alkyl radical, or else R 1 1 and R 12 forming together with the nitrogen atom an optionally substituted heterocycle having 4 to 7 members and from 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being independently chosen from the group consisting of O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,
• R 7 represents a hydrogen atom, an alkyl radical or a group -COR 13 , R 13 representing a hydrogen atom, an alkyl or alkoxy radical or NR 14 R 15 , R 14 and R 15 independently representing an atom d hydrogen or an alkyl radical, or else R 14 and R 15 forming together with the nitrogen atom an optionally substituted heterocycle having 4 to 7 members and from 1 to 3 heteroatoms including the nitrogen atom already present, additional heteroatoms being independently selected from the group consisting of O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, and ⁇ does not exist, or represents a bond, O or S or another NR 16 radical, in which R 16 represents a hydrogen atom or an alkyl radical;
• R 17 , R 18 and R 19 represent, independently, a hydrogen, a halogen, the group OH or SR 20 or an alkyl, alkenyl or alkoxy radical or a radical NR 21 R 22 , R 20 representing a hydrogen atom or an alkyl radical, R 21 and R 22 independently representing a hydrogen atom, an alkyl radical or a group -COR 23 , or else R 21 and R 22 forming together with the nitrogen atom an optionally substituted heterocycle counting from 4 to 7 chain links and from 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being independently chosen from the group consisting of O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, R 23 representing a hydrogen atom, an alkyl, alkoxy or NR 24 R 25 R 24 and R 25 radical representing, independently, a hydrogen atom or an alkyl radical, or else
• R 8 and R 9 independently representing a hydrogen atom, an alkyl radical or a group -COR 10 , or else R 8 and R 9 forming together with the nitrogen atom an optionally substituted heterocycle counting from 4 to 7 chain links and from 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being independently chosen from the group consisting of O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, R 10 representing a hydrogen atom, an alkyl, alkoxy or NR 1 'R 12 radical, R 11 and R 12 representing, independently, a hydrogen atom or an alkyl radical, or else R 1 1 and R 12 forming together with the nitrogen atom an optionally substituted heterocycle having 4 to 7 members and from 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group consisting of O, N and S atoms, said heterocycle being for
• R 27 represents a hydrogen atom, an alkyl radical or an aralkyl radical
• R 28 represents a hydrogen atom, an alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or aralkyl radical in which the aryl group is optionally substituted by one or more substituents chosen independently from the group OH, a halogen atom, an alkyl or alkoxy radical , nitro or -NR 29 R 30 , in which R 29 and R 30 independently represent a hydrogen atom, an alkyl radical or a group -COR 31 , or else R 29 and R 30 form together with the atom d nitrogen an optionally substituted heterocycle with 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being independently chosen from the group consisting of O, N and S atoms, said heterocycle being by example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,
• R 34 and R 35 independently represent a hydrogen atom or an alkyl or aralkyl radical in which the aryl group is optionally substituted by one or more substituents such as the OH group, the alkyl, halogen, nitro, alkoxy or -NR radicals 36 R 37 , in which R 36 and R 37 independently represent a hydrogen atom, an alkyl radical or a group -COR 38 , or else R 36 and R 37 form together with the nitrogen atom a heterocycle optionally substituted with 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being independently chosen from the group consisting of O, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine,
• R 41 represents a hydrogen atom, the OH group, or an alkyl or alkoxy radical
• D represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, 5 or 6-membered carbocyclic or heterocyclic aryl containing from 1 to 4 heteroatoms chosen from O, S and N (and in particular the thiophene, furan, pyrrole or thiazole), said carbocyclic or heterocyclic aryl radical being optionally substituted by one or more groups independently chosen from linear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6 carbon atoms, or D represents a radical NR 42 R 43 , in which R 42 and R 43 independently representing a hydrogen atom or a linear or branched alkyl, alkenyl or alkynyl radical having from 1 to 6 carbon atoms or a cyano, nitro or amino radical, or R 42 and R 43 form with the nitrogen atom a non-aromatic heterocycle of five to six members, the elements of the chain being chosen from a group composed of -CH 2 -,
• W represents -O- or -NR 45 -, and R 45 represents a hydrogen atom or an alkyl radical
• Y represents a radical chosen from - (CH 2 ) r , - (CH 2 ) q -O-, - (CH 2 ) q -S- and - (CH 2 ) q -NR 46 - and R 46 representing an atom d hydrogen or an alkyl radical, t being an integer from 0 to 6 and q being an integer from 2 to 6;
• V represents a radical chosen from the radicals - (CH 2 ) r-, - (CH 2 ) r -O- (CH 2 ) s -, - (CH 2 ) r -S- (CH 2 ) s -, - ( CH 2 ) r -S (O) - (CH 2 ) s - and - (CH 2 ) r -S (O) 2 - (CH 2 ) s - r being an integer from 1 to 6, s being an integer of 2 to 6;
• alkyl when no further details are given, is meant a linear or branched alkyl radical containing from 1 to 12 carbon atoms, and preferably from 1 to 6 carbon atoms.
• alkenyl when it is not given more precision, is meant a linear or branched alkyl radical having from 1 to 6 carbon atoms and having at least one unsaturation (double bond).
• alkynyl when no further details are given, is meant a linear or branched alkyl radical containing from 1 to 6 carbon atoms and having at least one double unsaturation (triple bond).
• aryl when it is not given more precision, one understands a carbocyclic aryl radical.
• carbocyclic or heterocyclic aryl is meant a carbocyclic or heterocyclic system comprising at least one aromatic ring, a system being said to be heterocyclic when at least one of the rings which compose it comprises a heteroatom (O, N or S).
• haloalkyl is meant an alkyl radical in which at least one of the hydrogen atoms (and possibly all) is replaced by a halogen atom.
• alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl, aralkyl radicals are meant respectively the alkylthio, alkoxy, haloalkyl, haloalkoxy, aminoalkyl, alkenyl, alkynyl, aralkyl radicals whose alkyl radical has the meaning indicated above.
• linear or branched alkyl having from 1 to 6 carbon atoms is meant in particular the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl radicals.
• halogen is meant the fluorine, chlorine, bromine or iodine atoms.
• the compounds according to the present invention may contain asymmetric carbon atoms. Consequently, the compounds according to the present invention have two possible enantiomeric forms, that is to say the "R" and "S" configurations.
• the present invention includes the two enantiomeric forms and all combinations of these forms, including the "RS" racemic mixtures.
• the two enantiomeric forms and their mixtures are represented.
• R 27 will preferably represent a hydrogen atom or an alkyl radical and T will preferably represent the radical - (CH 2 ) 2 -.
• R 34 and R 35 will preferably represent radicals chosen independently from a hydrogen atom and an alkyl radical and T will preferably represent the radical - (CH 2 ) -.
• the compounds of general formula (I) according to the invention will include at least one of the following characteristics:
• R 2 , R 3 , R 4 , R 5 , R 6 represent, independently, a hydrogen atom or an alkyl or alkoxy radical, R 7 represents a hydrogen atom and ⁇ does not exist or represents a bond or S;
• Q represents -OR 26 or -SR 26 and R 17 , R 18 and R 19 independently represent a hydrogen atom, the group OH, SR 20 or NR 21 R 22 or an alkyl or alkoxy radical,
• R 26 representing a hydrogen atom or an alkyl radical
• R 20 representing a hydrogen atom or an alkyl radical
• R 21 and R 22 representing, independently, a hydrogen atom or an alkyl radical
• D representing a 5- or 6-membered carbocyclic or heterocyclic aryl radical containing from 1 to 4 heteroatoms chosen from O, S and N, said aryl radical carbocyclic or heterocyclic being optionally substituted by one or more groups independently chosen from linear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6 carbon atoms, or alternatively D representing a radical NR 42 R 43 , in which R 42 and R 43 independently represent a hydrogen atom or a linear or branched alkyl, alkenyl or alkynyl radical having from 1 to 6 carbon atoms or a cyano, nitro or amino radical, or R 42 and R 43 form with the atom d nitrogen a five to six membered non-aromatic heterocycle, the chain elements being selected from a group consisting of -CH 2 -, -NH-, -O- or -S-;
• V representing a radical - (CH 2 ) r -, - (CH 2 ) r -O- (CH 2 ) s- or - (CH 2 ) r -S- (CH 2 ) s-, r being an integer of 1 to 6 and s an integer from 2 to 6;
• X representing a radical - (CH 2 ) n -, - (CH 2 ) n -CO-, -O- (CH 2 ) p - or -S- (CH 2 ) p -, n being an integer from 0 to 6 and p an integer from 1 to 6; • Y representing a radical chosen from - (CH 2 ) t -, - (CH 2 ) q -O- and - (CH 2 ) q -NR 46 -, R 46 representing a hydrogen atom or an alkyl radical, t representing an integer from 0 to 6 and q an integer from 2 to 6.
• the compounds of general formula (I) according to the invention will include at least one of the following characteristics:
• R 2 , R 3 , R 4 , R 5 , R 6 represent, independently, a hydrogen atom or an alkyl or alkoxy radical
• R 7 represents a hydrogen atom and ⁇ does not exist or represents a bond or S; - either the radical
• Q represents OH and R 17 , R 18 and R 19 independently represent a hydrogen atom, the group OH, SR 20 or NR 1 R 22 or an alkyl or alkoxy radical, R 20 representing an alkyl radical,
• R 21 and R 22 independently representing a hydrogen atom or an alkyl radical
• R 28 represent an alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or aralkyl radical
• D representing a 5-membered heterocyclic aryl radical containing from 1 to 4 heteroatoms chosen from O, S and N, or D representing a radical NR 42 R 43 , in which R 42 and R 43 independently represent an atom of hydrogen or a linear or branched alkyl radical having from 1 to 6 carbon atoms or a nitro radical, or R 42 and R 43 form with the nitrogen atom a non-aromatic heterocycle of five to six members, the elements of the chain being selected from a group consisting of -CH 2 -, -NH-, -O- or -S-;
• V representing a radical - (CH 2 ) r -, r being an integer from 1 to 6;
• Y representing a radical chosen from - (CH 2 ) t -, - (CH 2 ) q -O- and - (CH 2 ) q -NH-, t representing an integer from 0 to 6 and q an integer from 2 to 6.
• the compounds of general formula (I) according to the invention will include at least one of the following characteristics:
• R 2 , R 3 , R 4 , R 5 , R 6 represent, independently, a hydrogen atom or an alkyl or alkoxy radical, R 7 represents a hydrogen atom and ⁇ does not exist or represents a bond or S;
• R 17 , R 18 and R 19 represent alkyl radicals, the third being chosen from a hydrogen atom and an alkyl, alkoxy or alkylthio radical;
• R 28 represent an alkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl radical; - or finally the radical
• N representing a radical - (CH 2 ) r -, r being an integer from 1 to 5 and preferably an integer from 2 to 4;
• Y representing a radical - (CH 2 ) t -, t representing an integer from 0 to 6.
• a subject of the invention is also, as medicaments, the compounds of general formula (I) described above or their pharmaceutically acceptable salts. It also relates to pharmaceutical compositions containing these compounds or their pharmaceutically acceptable salts, with one or more pharmaceutically acceptable excipients. It also relates to the use of these compounds or of their pharmaceutically acceptable salts for manufacturing medicaments intended:
• the compounds of general formula (I) previously defined or the pharmaceutically acceptable salts of such compounds will be used to prepare a medicament intended to treat the cardiovascular and cerebrovascular disorders or the disorders of the central or peripheral nervous system.
• pharmaceutically acceptable salt means in particular the addition salts of inorganic acids such as hydrochloride, hydrobromide, iodhydrate, sulfate, phosphate, diphosphate and nitrate or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate , lactate, methanesulfonate, p-toluenesulfonate, pamoate and stearate.
• inorganic acids such as hydrochloride, hydrobromide, iodhydrate, sulfate, phosphate, diphosphate and nitrate or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate , lactate, methanesulfonate, p-toluenesulfonate, pamoate and stearate.
• bases such as sodium or potassium hydroxide.
• the pharmaceutical composition can be in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories.
• Suitable solid carriers can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, carboxymethyl cellulose sodium, polyvinylpyrrolidine and wax.
• compositions containing a compound of the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups.
• suitable liquid carriers can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.
• the administration of a medicament according to the invention can be done by topical, oral, parenteral route, by intramuscular injection, etc.
• the administration dose envisaged for a medicament according to the invention is between 0.1 mg to 10 g depending on the type of active compound used.
• the compounds of general formula (I) can be prepared by the methods described below.
• Bodanszky The Practice of Peptide Synthesis, 145 (Springer-Nerlag, 1984)) in THF, dichloromethane, pyridine or DMF in the presence of a coupling reagent such as dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford , 1991)) to lead to the carboxamides of general formula (II).
• DCC dicyclohexylcarbodiimide
• CDI 1,1'-carbonyldiimidazole
• EDC or WSCI 1- (3-dimethylaminopropyl) -3-ethylcarbodi
• the protective group Gpj is then cut conventionally, for example in the presence of a strong acid, of a secondary amine or under hydrogenolysis conditions, according to methods described in the literature (TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)), to lead to the final compounds of general formula (I).
• the non-commercial syntheses of the compounds of general formula (III) and (IV) are described below.
• the amino ester derivatives of general formula (V) are accessible, during a reductive amination step, by the condensation of aldehydes of general formula (VI) and ⁇ -amino esters of general formula (VII).
• This condensation is conventionally carried out at 20 ° C. in an alcoholic solvent such as methanol in the presence of a dehydrating agent, such as molecular sieves, and a reducing agent such as, for example, NaBH 3 CN.
• This step leads to the mono-alkylation product of general formula (V).
• the deprotection of the acid function is then conventionally carried out according to the nature of Gp 2 , for example, by saponification using LiOH or else according to methods described in the literature (TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)), to lead to the amino acids of general formula (I).
• the syntheses of the compounds of general formula (VI) and (VII), which are not commercial, are described below.
• the compounds of general formula (III) can be prepared from the intermediates of general formula (III.2) according to scheme 1.1 where D, N and R 1 are as defined above, Gp, being a protective group of the type carbamate and Gp 2 is an alkyl or arylalkyl group. (III.2)
• the amines of general formula (III.2) can be condensed on compounds of general formula (III.3), in which L represents a leaving group (an alkoxy, alkylthio, aralkylthio radical, sulfonic acid, halide, aryl alcohol or tosyl ), by heating in an alcohol (for example in methanol or isopropanol), optionally in the presence of DMF, at a temperature between 20 and 100 ° C for a period generally between a few hours and one night, to drive intermediaries of general formula (III.8).
• L represents a leaving group (an alkoxy, alkylthio, aralkylthio radical, sulfonic acid, halide, aryl alcohol or tosyl )
• the intermediates of general formula (III) are guanidines. These can be prepared, for example, by the condensation of the amines of general formula (III.2) with the derivatives of general formula (III.5) or (III.6).
• the reagents of general formula (III.5) in which L represents, for example, a pyrazole ring are condensed on the amines of general formula (III.2) according to the conditions described in the literature (J. Org. Chem. (1992) 57, 2497-2502) likewise for the reagents of general formula (III.6) in which L represents, for example, a pyrazole ring and Gp the Boc group (Tetrahedron Lett.
• the intermediates of general formula (III.8) can be prepared, for example, by the condensation of the amines of general formula (III.2) with the reagent of general formula (III.7 ) (N-methyl-N'-nitro-N-nitrosoguanidine) according to the conditions described in the literature (J. Amer. Chem. Soc. (1947), 69, 3028-3030).
• the isothiourea derivatives of general formula (III.8) are prepared in 3 stages starting from the primary amine of general formula (III.2).
• the thioureas thus obtained are then alkylated with a halogen derivative R 44 -Hal, by heating in an inert solvent, to yield the isothioureas of general formula (III.8).
• the alkylation of the amine is conventionally carried out by a strong base such as, for example, NaH, in a polar aprotic solvent such as, for example, DMF in the presence of a halogen derivative R 28 -Hal, such as for example, 3-dimethylaminopropane chloride or benzyl bromide.
• a strong base such as, for example, NaH
• a polar aprotic solvent such as, for example, DMF
• a halogen derivative R 28 -Hal such as for example, 3-dimethylaminopropane chloride or benzyl bromide.
• R 28 -Hal such as for example, 3-dimethylaminopropane chloride or benzyl bromide.
• the nitro derivative of general formula (IV.2) obtained intermediately is then reduced, for example, by Raney nickel in the presence of hydrazine hydrate to yield the anilines of general formula (IV).
• the anilines of general formula (IV) are obtained by hydrogenation, in the presence of Pd / C, of the precursor nitrophenol derivatives.
• the nitro derivatives of di-alkylphenols are accessible according to a method described in J. Org. Chem. (1968) 33 (1), 223-226.
• a ′ is a carbazole derivative ( ⁇ then represents a direct bond)
• the methods for preparing the aminocarbazoles of general formula (IV) involve the synthesis of a nitrocarbazole intermediate. These methods are described in Pharmazie (1993) 48 (11), 817-820; Synth. Common. (1994) 24 (1), 1-10; J. Org. Chem. (1980) 45, 1493-1496; J. Org. Chem. (1964) 29 (8), 2474-2476; Org. Prep. Procedé. Int. (1981) 13 (6), 419-421 or J. Org. Chem. (1963) 28, 884.
• the reduction of the nitro function of the nitrocarbazole intermediates is, in this case, preferably carried out using hydrazine hydrate in the presence of Raney nickel.
• the esters of general formula (IV.5) obtained intermediately are then deprotected (in an acid medium in the case of tert-butyl esters) to yield the acids of general formula (IV.6).
• the primary carboxamides of general formula (IV.7) are prepared using a concentrated aqueous solution of ammonia, DCC and HOBT in a solvent such as DMF.
• the reduction step is carried out in an anhydrous medium, by heating to 70-80 ° C., in the presence of a selective reagent for carboxamides such as, for example, BH 3 .THF, in a solvent such as, for example, THF to lead to the amines of general formula (IV).
• the aldehydes of general formula ( VI) can be prepared from the corresponding nitriles or carboxylic esters during a reduction step in the presence, for example, of DIBAL or of another boron derivative, in an anhydrous solvent such as, for example, THF or dichloromethane, at a temperature varying from -78 ° C to 20 ° C.
• anhydrous solvent such as, for example, THF or dichloromethane
• the compounds of general formula (VII), scheme 4.1 can be prepared starting from the intermediates of general formula (III.8), described in scheme 1.1, where D, V and R 1 are as defined above, Gp , being a protective group of carbamate type and Gp 2 is an alkyl or arylalkyl group.
• the deprotection of the amine function is conventionally carried out according to the nature of Gp ,, for example, using a strong acid, such as for example HC1 4N in dioxane, or else according to methods described in the literature. (TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)).
• reaction is finally neutralized, at 0 ° C., with 20 ml of a saturated NH 4 Cl solution.
• the reaction mixture is then diluted with 20 ml of water and 50 ml of AcOEt. After decantation, the organic phase is washed successively with 20 ml of water, 20 ml of brine, dried over magnesium sulfate, filtered and concentrated in vacuo. A dark yellow powder is obtained.
• the suspension is then filtered through Buchner and the filtrate is diluted with 150 ml of AcOEt and 50 ml of water. After stirring and decanting, the organic phase is washed with 50 ml of brine. The organic solution is then dried over sodium sulfate, filtered and concentrated to dryness under vacuum. The evaporation residue is then purified on a silica column (eluent: heptane / AcOEt 1/9). A clear salmon powder is obtained with a yield of 31%. Melting point: 55-56 ° C.
• the product is extracted using 3 times 200 ml of dichloromethane.
• the organic solution is dried over magnesium sulfate, filtered and concentrated in vacuo.
• the solid obtained is purified by recrystallization from a mixture of isopropyl acetate and dichloromethane (80/20), filtered and rinsed with diethyl ether to obtain, after drying, 1.77 g of a yellow solid with a 84% yield. Melting point: 96.6-97 ° C.
• the inhibitory activity of the products of the invention is determined by measuring their effects on the transformation by NO synthase of [H] L-argmine into [H] L-citrulline in accordance with the modified method of Bredt and Snyder (Proc. Natl. Acad. Sci. USA, (1990) 87: 682-685). Cerebrals of Sprague-Dawley rats (300g - Charles River) are quickly removed, dissected at 4 ° C and homogenized in a volume of extraction buffer (HEPES 50 mM, EDTA 1 mM, pH 7.4, pepstatin A 10 mg / ml, leupeptin 10 mg / ml).
• the homogenates are then centrifuged at 21,000 g for 15 min at 4 ° C.
• the assay is carried out in glass test tubes in which 100 ⁇ l of incubation buffer containing 100 mM of HEPES (pH 7.4), 2 mM of EDTA, 2.5 mM of CaCl 2 , 2 mM of are distributed. dithiotreitol, 2 mM reduced NADPH and 10 ⁇ g / ml calmodulin.
• the inhibitory activity of the products of the invention is determined by measuring their capacity to protect the cells of a hippocampal mouse line (HT-22) from oxidative stress caused by glutamate.
• the cells are cultured at 37 ° C.

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