FR2808525A1 - NOVEL AMINO ACID DERIVATIVES AND THEIR APPLICATION AS MEDICAMENTS - Google Patents

Abstract

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 nitrogen monoxide NO and / or (as desired): - either a scavenging activity of reactive oxygen forms (ROS for "reactive oxygen species"); 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.

Description

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 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 thiol groups.

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 trapping 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.

Given the potential role of NO, ROS and the metabolism of glutathione in pathophysiology, the new derivatives described corresponding to general formula (I) can produce beneficial or favorable effects in the treatment of pathologies where nitrogen monoxide, ROS and the metabolism of glutathione as well as the redox status of the thiol groups are involved, and in particular: # cardiovascular and cerebrovascular disorders including, for example, atherosclerosis, migraine, high blood pressure, septic shock, cardiac or cerebral infarction d ischemic or hemorrhagic origin, ischemia and thrombosis; # disorders of the central or peripheral nervous system such as, for example, neurodegenerative diseases where one can in particular cite cerebral infarctions,

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sub arachnoid hemorrhage, aging, senile dementia, including Alzheimer's disease, Huntington's chorea, Parkinson's disease, ataxia
Freiderich, Creutzfeld Jacob disease and prion diseases, amyotrophic lateral sclerosis but also pain, trauma to the brain or spinal cord, addiction to opiates, alcohol and addictive substances, disorders erection and reproduction, cognitive disorders, encephalopathies, encephalopathies of viral or toxic origin, depression, anxiety, schizophrenia, epilepsy, sleep disorders, eating disorders (anorexia, bulimia ...); # disorders of the skeletal muscle and neuromuscular junctions (myopathy, myositis) as well as skin diseases; # 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,
Crohn) or of the pulmonary and airways system (asthma, sinusitis, rhinitis) as well as contact or delayed hypersensitivities; # organ transplants; # 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; # the cancer ; # autosomal genetic diseases such as Unverricht-Lunborg disease; # neurological diseases associated with poisoning (poisoning
Cadmium, inhalation of n-hexane, pesticide, herbicide), treatments (radiotherapy) or disorders of genetic origin (Wilson disease); # impotence linked to diabetes; # all pathologies characterized by the production or dysfunction of nitric oxide and / or ROS or of the metabolism of glutathione and of the redox status of the thiol groups.

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 In all of these pathologies, there is experimental evidence demonstrating the involvement of nitric oxide or a dysfunction of glutathione metabolism (Kerwin et al., Nitric oxide: new paradigm for second messengers, J. Med.

Chem. 38.4343-4362, 1995; Packer et al., Alpha-lipoic acid as biological antioxidant, Free Radical Biology & Medicine 19,227-250, 1995). In this context, drugs that can inhibit the formation of nitric oxide, trap ROS or restore the biological functionality of thiol groups or glutathione can provide beneficial effects.

The applicant has already described in previous patent applications compounds comprising both NO synthase inhibiting properties and ROS trapping properties (cf. PCT applications WO 98/42696, WO 98/58934, WO 00 / 02860, WO 00/17190 and WO 00/17191). It has also more recently described in a not yet published application derivatives of lipoic acid having both inhibitory properties of NO synthases and regenerative properties of antioxidants or ROS trapping entities and in a more general influence on the redox status of thiol groups.

dans laquelle R' représente un atome d'hydrogène ou un radical alkyle ; A et A' représentent un atome d'hydrogène ou l'un des radicaux suivants : - un radical

The compounds of the invention correspond to the general formula (I)

wherein R 'represents a hydrogen atom or an alkyl radical; A and A 'represent a hydrogen atom or one of the following radicals: - a radical

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dans lequel R17, R18 et R19 représentent, indépendamment, un hydrogène, un halogène, le groupe OH ou SR20 ou un radical alkyle, alkényle ou alkoxy ou un radical NR21R22, R20 représentant un atome d'hydrogène ou un radical alkyle, in which R2, R3, R4, R5, R6 independently represent a hydrogen atom, a halogen, the OH group, an alkyl, alkoxy, cyano, nitro or NR8R9 radical,
R8 and R9 independently representing a hydrogen atom, an alkyl radical or a group -COR10, or else R8 and R9 forming together with the nitrogen atom an optionally substituted heterocycle having 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 0, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, R10 representing an atom of hydrogen, an alkyl, alkoxy or NR11R12 radical, R11and R12 representing, independently, a hydrogen atom or an alkyl radical, or else R11 and R12 forming together with the nitrogen atom an optionally substituted heterocycle counting from 4 to 7 links and from 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group consisting of ato mes 0, N and S, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, R7 represents a hydrogen atom, an alkyl radical or a group -COR13, R13 representing a hydrogen atom, a alkyl or alkoxy radical or NR14R15, R14and R15 independently representing a hydrogen atom or an alkyl radical, or else R14 and R15 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 0, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, and Q n ' does not exist, or represents a bond, 0 or S or also a radical NR16, in which R16 represents a hydrogen atom or an alkyl radical; - or a radical

in which R17, R18 and R19 independently represent a hydrogen, a halogen, the OH or SR20 group or an alkyl, alkenyl or alkoxy radical or a NR21R22 radical, R20 representing a hydrogen atom or an alkyl radical,

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 R21 and R22 independently representing a hydrogen atom, an alkyl radical or a group -COR23, or else R21 and R22 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 selected from the group consisting of 0, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, R23 representing a hydrogen atom, an alkyl, alkoxy or NR24R25 R24 and R25 radical representing, independently, a hydrogen atom or an alkyl radical, or else R24 and R25 forming together with the nitrogen atom an optionally substituted heterocycle having 4 with 7 links and from 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being independently chosen from the group consisting of es atoms 0, N and S, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, and Q represents -OR26, -SR26 or a phenyl radical substituted by one or more substituents chosen from a halogen, the group OH, an alkyl, alkoxy, cyano, nitro or NR8R9 radical, R26 representing a hydrogen atom or an alkyl radical, R8 and R9 representing, independently, a hydrogen atom, an alkyl radical or a group -CORIO, or alternatively R8 and R9 forming together with the nitrogen atom 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 atoms 0, N and S, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, R10 representing a hydrogen atom, an alkyl, alkoxy or NR radical 11R12, R11 and R12 independently representing a hydrogen atom or an alkyl radical, or else R11 and R12 forming together with the nitrogen atom an optionally substituted heterocycle having 4 to 7 members and 1 to 3 heteroatoms including l nitrogen atom already present, the additional heteroatoms being independently chosen from the group consisting of 0, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, - or a radical

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dans lequel R27 représente un atome d'hydrogène, un radical alkyle ou un radical aralkyle, T représentant un radical -(CH2)m- avec m = 1 ou 2 ; - ou un radical

dans lequel R28 représente un atome d'hydrogène, un radical alkyle, arylalkyle, aminoalkyle, alkylaminoalkyle ou dialkylaminoalkyle, le groupement aryle étant éventuellement substitué par un ou plusieurs substituants tels que le groupe OH, les radicaux alkyle, halogène, nitro, alkoxy ou -NR29R30, dans lequel R29 et R30 représentent, indépendamment, un atome d'hydrogène, un radical alkyle ou un groupe COR31, ou bien R29 et R30 forment ensemble avec l'atome d'azote un hétérocycle éventuellement substitué comptant de 4 à 7 chaînons et de 1 à 3 hétéroatomes incluant l'atome d'azote déjà présent, les hétéroatomes supplémentaires étant choisis indépendamment dans le groupe constitué des atomes 0, N et S, ledit hétérocycle étant par exemple azétidine, pyrrolidine, pipéridine, pipérazine, morpholine ou thiomorpholine, R31 représentant un atome d'hydrogène, un radical alkyle ou alkoxy ou NR32R33, R32 et R33 représentant, indépendamment, un atome d'hydrogène ou un radical alkyle, ou bien R32 et R33 formant ensemble avec l'atome d'azote un hétérocycle éventuellement substitué comptant de 4 à 7 chaînons et de 1 à 3 hétéroatomes incluant l'atome d'azote déjà présent, les hétéroatomes supplémentaires étant choisis indépendamment dans le groupe constitué des atomes 0, N et S, ledit hétérocycle étant par exemple azétidine, pyrrolidine, pipéridine, pipérazine, morpholine ou thiomorpholine, T représentant un radical -(CH2)m- avec m = 1 ou 2 ; - ou un radical

in which R27 represents a hydrogen atom, an alkyl radical or an aralkyl radical, T representing a radical - (CH2) m- with m = 1 or 2; - or a radical

in which R28 represents a hydrogen atom, an alkyl, arylalkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl radical, the aryl group being optionally substituted with one or more substituents such as the OH group, alkyl, halogen, nitro, alkoxy or - radicals NR29R30, in which R29 and R30 independently represent a hydrogen atom, an alkyl radical or a group COR31, or else R29 and R30 together with the nitrogen atom form an optionally substituted heterocycle with 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 atoms 0, N and S, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, R31 representing a hydrogen atom, an alkyl or alkoxy radical or NR32R33, R32 and R33 representing, independently, a hydrogen atom or an alkyl radical, or else R32 and R33 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 in the group consisting of atoms 0, N and S, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, T representing a radical - (CH2) m- with m = 1 or 2; - or a radical

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dans lequel R34 et R35 représentent indépendamment un atome d'hydrogène ou un radical alkyle ou arylalkyle, le groupement aryle étant éventuellement substitué par un ou plusieurs substituants tels que le groupe OH, les radicaux alkyle, halogène, nitro, alkoxy ou -NR36R37, dans lequel R36 et R37 représentent, indépendamment, un atome d'hydrogène, un radical alkyle ou un groupe -COR38, ou bien R36 et R37 forment ensemble avec l'atome d'azote un hétérocycle éventuellement substitué comptant de 4 à 7 chaînons et de 1 à 3 hétéroatomes incluant l'atome d'azote déjà présent, les hétéroatomes supplémentaires étant choisis indépendamment dans le groupe constitué des atomes 0, N et S, ledit hétérocycle étant par exemple azétidine, pyrrolidine, pipéridine, pipérazine, morpholine ou thiomorpholine, R38 représentant un atome d'hydrogène, un radical alkyle ou alkoxy ou NR39R40, R39 et R40 représentant, indépendamment, un atome d'hydrogène ou un radical alkyle, ou bien R39 et R40 formant ensemble avec l'atome d'azote un hétérocycle éventuellement substitué comptant de 4 à 7 chaînons et de 1 à 3 hétéroatomes incluant l'atome d'azote déjà présent, les hétéroatomes supplémentaires étant choisis indépendamment dans le groupe constitué des atomes 0, N et S, ledit hétérocycle étant par exemple azétidine, pyrrolidine, pipéridine, pipérazine, morpholine ou thiomorpholine, T représentant un radical -(CH2)m- avec m = 1 ou 2 ; - ou un radical

dans lequel R41 représente un atome d'hydrogène, le groupe OH, ou un radical alkyle ou alkoxy ;

in which R34 and R35 independently represent a hydrogen atom or an alkyl or arylalkyl radical, the aryl group being optionally substituted by one or more substituents such as the OH group, the alkyl, halogen, nitro, alkoxy or -NR36R37 radicals, in which R36 and R37 independently represent a hydrogen atom, an alkyl radical or a group -COR38, or else R36 and R37 form together with the nitrogen atom an optionally substituted heterocycle having 4 to 7 members and 1 with 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being independently chosen from the group consisting of atoms 0, N and S, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, R38 representing a hydrogen atom, an alkyl or alkoxy or NR39R40, R39 and R40 radical independently representing a hydrogen atom or an alkyl radical, or else R39 and R40 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 formed 0, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, T representing a radical - (CH2) m- with m = 1 or 2; - or a radical

in which R41 represents a hydrogen atom, the OH group, or an alkyl or alkoxy radical;

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D représente un radical alkyle linéaire ou ramifié ayant de 1 à 6 atomes de carbone, aryle carbocyclique ou hétérocyclique à 5 ou 6 chaînons contenant de 1 à 4 hétéroatomes choisis parmi 0, S, N et notamment les radicaux thiophène, furanne, pyrrole ou thiazole, le radical aryle carbocyclique ou hétérocyclique étant éventuellement substitué par un ou plusieurs groupes choisis parmi les radicaux alkyle, alkényle ou alkoxy linéaires ou ramifiés ayant de 1 à 6 atomes de carbone, ou D représente un radical NR42R43, dans lequel R42 et R43 représentant, indépendamment, un atome d'hydrogène ou un radical alkyle, alkényle ou alkynyle linéaire ou ramifié ayant de 1 à 6 atomes de carbone ou un radical cyano, nitro ou amino, ou R42 et R43 forment avec l'atome d'azote un hétérocycle non aromatique de cinq à six chaînons, les éléments de la chaîne étant choisis parmi un groupe composé de-CH2-, NH-, -O- ou-S- ; ou encore D représente un radical -Se, dans lequel R44 représente un radical alkyle linéaire ou ramifié ayant de 1 à 6 atomes de carbone éventuellement substitué par un groupe choisi parmi : -OH, halogène, amino, cyano et aralkyle ; X représente -(CH2)n-CO-, -(CH2)p-, -0-(CH2)p-, -S-(CH2)p-, -CH=CH-(CH2)p- ou CH=CH-(CH2)n-CO-, n étant un entier de 0 à 6 et p étant un entier de 1 à 6 ; W représente -0- ou -NR45 -, et R45 représentant un atome d'hydrogène ou un radical alkyle Y représente un radical choisi parmi -(CH2)t-, -(CH2)q-O-, - (CH2)q-S- et -(CH2)q-NR46- et R46 représentant un atome d'hydrogène ou un radical alkyle, t étant un entier de 0 à 6 et q étant un entier de 2 à 6 ; V représente un radical choisi parmi les radicaux-(CH2)r-, -(CH2)r-O-(CH2)s-, -(CH2)r-S-(CH2)s-, -(CH2)r-S(O)-(CH2)s- et -(CH2)1-S(O)2-(CH2)sr étant un entier de 1 à 6, s étant un entier de 2 à 6 ; 5 10 15 20 25 30 - or finally a 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 0, S, N and in particular the thiophene, furan, pyrrole or thiazole radicals , the carbocyclic or heterocyclic aryl radical being optionally substituted by one or more groups chosen from linear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6 carbon atoms, or D represents a radical NR42R43, in which R42 and R43 represent, independently, 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 R42 and R43 form with the nitrogen atom a non-heterocycle five to six membered aromatic, the chain elements being selected from a group consisting of -CH2-, NH-, -O- or-S-; or D represents a radical -Se, in which R44 represents a linear or branched alkyl radical having from 1 to 6 carbon atoms optionally substituted by a group chosen from: -OH, halogen, amino, cyano and aralkyl; X represents - (CH2) n-CO-, - (CH2) p-, -0- (CH2) p-, -S- (CH2) p-, -CH = CH- (CH2) p- or CH = CH - (CH2) n-CO-, n being an integer from 0 to 6 and p being an integer from 1 to 6; W represents -0- or -NR45 -, and R45 represents a hydrogen atom or an alkyl radical Y represents a radical chosen from - (CH2) t-, - (CH2) qO-, - (CH2) qS- and - (CH2) q-NR46- and R46 representing a hydrogen atom 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- (CH2) r-, - (CH2) rO- (CH2) s-, - (CH2) rS- (CH2) s-, - (CH2) rS (O) - (CH2 ) s- and - (CH2) 1-S (O) 2- (CH2) sr being an integer from 1 to 6, s being an integer from 2 to 6;

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- soit une activité régénératrice d'antioxydants ou d'entités piégeuses des formes réactives de l'oxygène (ROS pour "reactive oxygen species") et d'une façon plus générale une influence dans le statut rédox des groupement thiols, ceci dans le cas particulier où l'un de A ou A' représente le radical

Par alkyle, lorsqu'il n'est pas donné plus de précision, on entend un radical alkyle linéaire ou ramifié comptant de 1 à 6 atomes de carbone. Par alkényle, lorsqu'il n'est pas donné plus de précision, on entend un radical alkyle linéaire ou ramifié comptant de 1 à 6 atomes de carbone et présentant au moins une insaturation (double liaison). Par alkynyle, lorsqu'il n'est pas donné plus de précision, on entend un radical alkyle linéaire ou ramifié comptant de 1 à 6 atomes de carbone et présentant au moins une double insaturation (triple liaison). Par aryle carbocyclique ou hétérocyclique, on entend un système carbocyclique ou hétérocyclique comprenant au moins un cycle aromatique, un système étant dit hétérocyclique lorsque l'un au moins des cycles qui le composent comporte un hétéroatome (0, N ou S). Par haloalkyle, on entend un radical alkyle dont au moins l'un des atomes d'hydrogène (et éventuellement tous) est remplacé par un atome halogène. it being understood that one of A and A 'represents a hydrogen atom and the other does not represent a hydrogen atom; or are salts of the compounds of general formula (I) as defined above. These compounds exhibit an inhibitory activity of the NO-synthase enzymes producing nitrogen monoxide NO and / or (as desired): - either a scavenging activity of reactive oxygen forms (ROS for "reactive oxygen species") when none of A and A 'does represent the radical

- either a regenerative activity of antioxidants or trapping entities of reactive forms of oxygen (ROS for "reactive oxygen species") and more generally an influence in the redox status of thiol groups, this in the case particular where one of A or A 'represents the radical

By alkyl, when no further details are given, is meant a linear or branched alkyl radical containing from 1 to 6 carbon atoms. By 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). By 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). By 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 (0, N or S). By haloalkyl is meant an alkyl radical in which at least one of the hydrogen atoms (and possibly all) is replaced by a halogen atom.

By 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.

By 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

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 tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl. Finally, by halogen is meant the fluorine, chlorine, bromine or iodine atoms.

In some cases, 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. For the sake of simplicity, when no specific configuration is indicated in the structural formulas, it should be understood that the two enantiomeric forms and their mixtures are represented.

dans lequel R2, R3, R4, R5, R6 représentent, indépendamment, un atome d'hydrogène ou un radical alkyle ou alkoxy, R7 représente un atome d'hydrogène et Q n'existe pas ou représente une liaison ou S ; - soit le radical

dans lequel Q représente OH et deux de R17, R18 et R'9 représentent des radicaux alkyle, le troisième étant choisi parmi un atome d'hydrogène et un radical alkyle, alkoxy ou alkylthio ; In particular, the compounds of general formula (I) will be preferred in which at least one of the following characteristics will be found: # a group A or A ′ representing one of the following radicals: either the radical

in which R2, R3, R4, R5, R6 represent, independently, a hydrogen atom or an alkyl or alkoxy radical, R7 represents a hydrogen atom and Q does not exist or represents a bond or S; - either the radical

in which Q represents OH and two of R17, R18 and R'9 represent alkyl radicals, the third being chosen from a hydrogen atom and an alkyl, alkoxy or alkylthio radical;

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dans lequel R28 représentent un radical alkyle, aminoalkyle, alkylaminoalkyle o dialkylaminoalkyle ; - soit enfin le radical

# D représentant le radical -NH-N02. - either the radical

in which R28 represent an alkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl radical; - or finally the radical

# D representing the radical -NH-N02.

(2S)-2-amino-N-( 4-anilinophényl)-5-{ [imino(2-oxido 2-oxohydrazino)méthyl]amino}pentanamide ; (2S-2-amino-5-{[imino(2-oxido-2-oxohydrazino)méthyl]amino}-N-(1-méthyl 2,3-dihydro-1H indol-5-yl)pentanamide ; - acide (2S-2-[(3,5-ditert-butyl-4-hydroxybenzyl)amino]-5-{[imino(2-oxido 2-oxohydrazino)méthyl]amino}pentanoïque ; (2S)-2-{ [5-(1,2-dithiolan-3-yl)pentanoyl]amino}-5-{ [imino(2-oxido 2-oxohydrazino)méthyl]amino}pentanoate de méthyle ; acide (2S)-2-{[5-(1,2-dithiolan-3-yl)pentanoyl]amino}-5-{[imino(2-oxido 2-oxohydrazino)méthyl]amino}pentanoïque ; ainsi que leurs sels. In particular, the subject of the invention is the following compounds described in the examples:

(2S) -2-amino-N- (4-anilinophenyl) -5- {[imino (2-oxido 2-oxohydrazino) methyl] amino} pentanamide; (2S-2-amino-5 - {[imino (2-oxido-2-oxohydrazino) methyl] amino} -N- (1-methyl 2,3-dihydro-1H indol-5-yl) pentanamide; - acid ( 2S-2 - [(3,5-ditert-butyl-4-hydroxybenzyl) amino] -5 - {[imino (2-oxido 2-oxohydrazino) methyl] amino} pentanoic; (2S) -2- {[5- (1,2-dithiolan-3-yl) pentanoyl] amino} -5- {[imino (2-oxido 2-oxohydrazino) methyl] amino} methyl pentanoate; acid (2S) -2 - {[5- (1 , 2-dithiolan-3-yl) pentanoyl] amino} -5 - {[imino (2-oxido 2-oxohydrazino) methyl] amino} pentanoic acid; and their salts.

A subject of the invention is also, as medicaments, the compounds of general formul (I) described above or their pharmaceutically acceptable salts. It also relates to pharmaceutical compositions containing these compounds or their salts.

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2) à inhiber la NO synthase neuronale ou la NO synthase inductible ; à régénérer les antioxydants ou les entités piégeuses des ROS et d'une façon plus générale à intervenir dans le statut rédox des groupement thiols ; ou enfin à assurer la double fonction d'inhibition de la NO synthase et de régénération des antioxydants ou des entités piégeuses des ROS et d'une façon plus générale d'intervention dans le statut rédox des groupement thiols, ceci lorsque l'un de A et de A' représente le radical

Par sel pharmaceutiquement acceptable, on entend notamment des sels d'addition d'acides inorganiques tels que chlorhydrate, bromhydrate, iodhydrate, sulfate, phosphate, diphosphate et nitrate ou d'acides organiques tels que acétate, maléate, fumarate, tartrate, succinate, citrate, lactate, méthanesulfonate, p-toluènesulfonate, benzènesulfonate, pamoate, oxalate et stéarate. Entrent également dans le champ de la présente invention, lorsqu'ils sont utilisables, les sels formés à partir de bases telles que l'hydroxyde de sodium ou de potassium ou certaines bases organiques telles que par exemple la dicyclohexylamine, la diéthylamine, la lysine, l'arginine, la morpholine et la choline. Pour d'autres exemples de sels pharmaceutiquement acceptables, on peut se référer à "Pharmaceutical salts", J. Pharm. Sci. 66 :1 (1977). pharmaceutically acceptable, and the use of these compounds or their pharmaceutically acceptable salts for the manufacture of medicaments intended: 1) to inhibit neuronal NO synthase or inducible NO synthase; to inhibit lipid peroxidation; or finally to ensure the dual function of inhibiting NO synthase and inhibiting lipid peroxidation, this when none of A and A 'represents the radical

2) to inhibit neuronal NO synthase or inducible NO synthase; to regenerate antioxidants or trapping entities of ROS and more generally to intervene in the redox status of thiol groups; or finally to ensure the double function of inhibition of NO synthase and of regeneration of antioxidants or trapping entities of ROS and more generally of intervention in the redox status of thiol groups, this when one of A and from A 'represents the radical

The term “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, benzenesulfonate, pamoate, oxalate and stearate. Also falling within the scope of the present invention, when they can be used, the salts formed from bases such as sodium or potassium hydroxide or certain organic bases such as, for example, dicyclohexylamine, diethylamine, lysine, arginine, morpholine and choline. For other examples of pharmaceutically acceptable salts, reference may be made to "Pharmaceutical salts", J. Pharm. Sci. 66: 1 (1977).

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.

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 The pharmaceutical 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.

According to the invention, the compounds of general formula (I) can be prepared by the methods described below.

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Preparation of the compounds of general formula (I): The compounds of general formula (I) can be prepared according to different synthesis strategies which are described in the following schemes: A)

Scheme 1 The aminocarboxamides of general formula (I), scheme 1, in which A ', D, V, Y and R1 are as defined above with, in particular, A representing a hydrogen atom, X = - ( CH2) n- (n = 0) and W = -NR45- are prepared in two stages, starting from protected amino acids (Gp, being a carbamate-type protective group) of

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 general formula (III) and amines of general formula (IV). Their condensation is carried out under the conventional conditions of peptide synthesis (M. Bodanszky and A.

Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 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). The protective group Gp 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 (WileyInterscience, 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.

B) Alternatively, the amino acid derivatives of general formula (I) can be prepared according to the strategy described in scheme 2, in which A, D, V and R 'are as defined above with A' representing an atom d 'hydrogen, W = -O-, Y = - (CH2) t- (t = 0), X = - (CH2) p-, -O- (CH2) p, -S- (CH2) p- or - CH = CH- (CH2) p- (p being an integer from 1 to 6) and Gp2 being an alkyl or arylalkyl group.

Diagram 2

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 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 α-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, NaBH3CN. 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 Gp2, 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.

C) Furthermore, the carboxamides of general formula (I) can also be prepared according to the strategy described in scheme 3, in which A, D, V and R 'are as defined above with A' representing an atom d 'hydrogen, W = -O-, Y = - (CH2) t- (t = 0), X = - (CH2) n-CO- or -CH = CH- (CH2) n-CO- (n being a integer from 0 to 6) and Gp2 being an alkyl or arylalkyl group.

 Scheme 3 The condensation of the carboxylic acids of general formula (IX) with the α-aminoesters of general formula (VII) is carried out under the conventional conditions of

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 peptide synthesis as previously described. The carboxamido-ester of general formula (VIII) obtained is then deprotected according to a protocol described in scheme 2 to lead to the carboxamido-acids of general formula (I). The syntheses of the compounds of general formula (IX), which are not commercial, are described below.

Preparation of intermediates of general formula (III): The compounds of general formula (III) can be prepared from intermediates of general formula (111.2) according to scheme 1.1 where D, V and R 'are as defined above, Gp, being a carbamate-type protecting group and Gp2 is an alkyl or arylalkyl group.

Schéma 1.1 (111.2)

Figure 1.1

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The amines of general formula (111.2) can be condensed on compounds of general formula (111.3), 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 lead to the intermediaries of general formula (111.8).

In the cases where D is an amine, the intermediates of general formula (III) are guanidines. These can be prepared, for example, by the condensation of the amines of general formula (111.2) with the derivatives of general formula (111.5) or (111.6). The reagents of general formula (111.5) in which L represents, for example, a pyrazole ring are condensed on the amines of general formula (111.2) according to the conditions described in the literature (J Org. Chem. (1992) 57,2497- 2502) similarly for the reagents of general formula (111.6) in which L represents, for example, a pyrazole ring and Gp the group Boc (Tetrahedron Lett. (1993) 34 (21), 3389-3392) or else when L represents the group -N-SO2-CF3 and Gp the group Boc (J. Org. Chem. (1998) 63,3804-3805). The deprotection of the guanidine function can then be carried out, for example, in the presence of a strong acid such as for example trifluoroacetic acid to yield the intermediates of general formula (111.8).

In cases where D = -NHN02, the intermediates of general formula (111.8) can be prepared, for example, by the condensation of amines of general formula (111.2) with the reagent of general formula (111.7) (N-methyl-N '-nitro-N-nitrosoguanidine) according to the conditions described in the literature (J. Amer. Chem. Soc. (1947), 69.3028-3030).

In the cases where D is a radical -SR44, the isothiourea derivatives of general formula (111.8), are prepared in 3 stages starting from the primary amine of general formula (111.2). The reaction of benzoylisothiocyanate on the amine of general formula (111.2) in a solvent such as, for example, acetone, leads to benzoylthiourea intermediates which are then conventionally hydrolyzed by heating in basic medium.

The thioureas thus obtained are then alkylated with a halogenated derivative R44-Hal, by heating in an inert solvent, to yield the isothioureas of general formula (111.8).

The deprotection of the acid function of the intermediates of general formula (111.8) is then conventionally carried out according to the nature of Gp2, for example, by saponification using LiOH or else according to methods described in the literature.

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 (T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)).

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Preparation of intermediates of general formula (IV): A) When A 'is as defined above, W = -NR45- and Y = - (CH2) t- (t = 0), the amines of general formula (IV ) are prepared according to the following synthesis strategies: The anilines of general formula (IV), non-commercial, derivatives of indoline or 1,2,3,4-tetrahydroquinoline, scheme 2.1, in which T and R28 are as defined above, can be prepared from the corresponding nitro derivatives of general formula (IV.l). 6-nitro-1,2,3,4-tetrahydroquinoline is described in Can. J Chem. (1952), 30,720-722. 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 halogenated derivative R28-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).

(IV.1) (IV. 2) (IV)
Scheme 2.1 In the particular case of phenolic derivatives, the anilines of general formula (IV) are obtained by hydrogenation, in the presence of Pd / C, of the nitrophenol derivative precursors. The nitro derivatives of di-alkylphenols are accessible according to a method described in J Org. Chem. (1968) 33 (1), 223-226.

The intermediates of general formula (IV) in which A 'is a diphenylamine, are accessible from the methods described in the literature (Synthesis (1990) 430; Indian J Chem. (1981) 20B, 611-613; J. Med. Chem. (1975) 18 (4), which pass through the reduction of a nitrodiphenylamine intermediate The reduction of the nitro function is conventionally carried out by hydrogenation in the presence of a catalytic amount of Pd / C to access the aminodiphenylamines of general formula (IV).

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When 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. Proced. Int. (nineteen eighty one)
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 intermediates of general formula (IV) in which A 'is a phenothiazine derivative (# represents a sulfur atom), are accessible from methods of the literature which pass through the synthesis of a nitrophenothiazine derivative. In particular 3-nitrophenothiazine is described in J. Org. Chem. (1972) 37, 2691. The reduction of the nitro function to access the aminophenothiazines of general formula (IV) is carried out conventionally by hydrogenation in the presence of a catalytic amount of
Pd / C in a solvent such as ethanol.

B) Alternatively when Y = - (CH2) qO- and W = -NR45-, the amines of general formula (IV), scheme 2.2 (in which Alk represents an alkyl radical), can be prepared from the hydroquinones of general formula (IV. 3) obtained according to the literature (J. Chem. Soc. Perkin 1 (1981) 303-306). Condensation on commercial halogenesters of general formula (IV. 4) is carried out in the presence of a base such as, for example K2CO3, by heating in a polar solvent such as, for example, THF for at least 5 hours. 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, BH3. THF, in a solvent such as, for example, THF to lead to the amines of general formula (IV).

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A'-OH + Hal-(CHZ q~ 1 COZAIk ### A'-O-(CHZ q~1 CO,Alk @q-1 q-1 (IV.3) (IV. 4) (IV.5) NH40H

###A'-O-CCH,)# CO,H 30 A'-O-(CHZq~1 CONHZ @q-1 q-1 (IV.6) (IV.7) #A'-O- (CH2)q-NH2 (IV)
Schéma 2.2 C) Par ailleurs, lorsque Y = -(CH2)t- (t# 0) et W = -NR45-, les amines de formule générale (IV), schéma 2. 3, sont également accessibles, par exemple, en deux étapes à partir des acides carboxyliques de formule générale (IV. 8) selon une stratégie analogue à celle décrite au schéma 2. 2 pour l'intermédiaire (IV. 6). Les synthèses des acides carboxyliques de formule générale (IV.8), non commerciaux, sont décrites au chapitre Préparation des intermédiaires de formule générale (IX).

A'-OH + Hal- (CHZ q ~ 1 COZAIk ### A'-O- (CHZ q ~ 1 CO, Alk @ q-1 q-1 (IV.3) (IV. 4) (IV.5 ) NH40H

### A'-O-CCH,) # CO, H 30 A'-O- (CHZq ~ 1 CONHZ @ q-1 q-1 (IV.6) (IV.7) # A'-O- ( CH2) q-NH2 (IV)
Diagram 2.2 C) In addition, when Y = - (CH2) t- (t # 0) and W = -NR45-, the amines of general formula (IV), diagram 2. 3, are also accessible, for example, by two stages starting from the carboxylic acids of general formula (IV. 8) according to a strategy analogous to that described in scheme 2.2 for the intermediate (IV. 6). The non-commercial syntheses of carboxylic acids of general formula (IV.8) are described in the chapter Preparation of intermediates of general formula (IX).

(IV.8) (IV. 9) (IV)
Diagram 2.3 Preparation of the intermediaries of general formula (VI): A) When A is as defined above and X = - (CH2) p- or X = -CH = CH- (CH2) p- with p = 1, 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. Certain aldehydes are also accessible using methods described in the literature: Bull. Chem. Soc. Jpn. (1978) 51 (8), 2433-2434, Bioorg. Med. Chem Lett. (1998) 8, 3453-3458.

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B) Alternatively, when A is as defined above and X = -0- (CH2) p-, the aldehydes of general formula (VI), scheme 3.1 (in which Alk represents an alkyl radical), can be prepared to starting from the hydroquinones of general formula (VI. 1) obtained according to the literature (J. Chem. Soc. Perkin 1 (1981) 303-306). Condensation on commercial haloesters of general formula (VI.2) is carried out under the conditions previously described (diagram 2.2) as well as the reduction of the ester to aldehyde (paragraph A).

(VI)
Schéma 3.1 Préparation des intermédiaires de formule générale (VII)- Les composés de formule générale (VII), schéma 4.1, peuvent être préparés à partir des intermédiaires de formule générale (111.8), décrits dans le schéma 1.1, où D, V et R' sont tels que définis ci-dessus, Gp, étant un groupe protecteur de type carbamate et Gp2 est un groupement alkyle ou arylalkyle. La déprotection de la fonction amine est classiquement effectuée en fonction de la nature de Gp1, par exemple, à l'aide d'un acide fort, tel que par exemple HC1 4N dans le dioxane, ou bien selon des méthodes décrites dans la littérature (T. W. Greene et P. G.M. Wuts, Protective Groups in Organic Synthesis, Second edition (Wiley-Interscience, 1991)). A-OH + Hal- (CHZp ~ 1 COZAIk AO- (CH2p = 1 C02Alk (VL1) (VI.2) (VL3)

(VI)
Scheme 3.1 Preparation of intermediates of general formula (VII) - The compounds of general formula (VII), scheme 4.1, can be prepared from intermediates of general formula (111.8), described in scheme 1.1, where D, V and R 'are as defined above, Gp, being a protective group of carbamate type and Gp2 is an alkyl or arylalkyl group. The deprotection of the amine function is conventionally carried out according to the nature of Gp1, 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)).

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(III.8) (SEEN)
Diagram 4.1 Preparation of the intermediates of general formula (IX): The acids of general formula (IX), not commercial, are accessible starting from methods of the literature. For example, trisnorlipoic acid [2- (1,2-dithiolan- 3-yl) acetic acid] is obtained in 5 steps according to an experimental protocol described in Tetrahedron Letters. (1997), 38 (33), 5785-5788 . The syntheses of acids derived from phenothiazine are described in particular in J Med. Chem. (1998), 41 (2), or Bull. Soc. Chim. Fr. (1960), 1049-1066.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as that commonly understood by an ordinary specialist in the field to which this invention belongs. Likewise, all publications, patent applications, all patents and all other references mentioned herein are incorporated by reference.

The following examples are presented to illustrate the above procedures and should in no way be taken as limiting the scope of the invention.

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1.1) tert-butyl (IS)-I-[(4-anilinoanilino)carbonyl]-4-([imino(2-oxido-2- oxohydrazino)méthyl]amino}butylcarbamate : On ajoute 1,03 g (5 mmol) de 1,3-dicyclohexylcarbodiimide à une solution de 1,6 g (5 mmol) de N-tert-butoxycarbonyl-L-nitroarginine et de 0,92 g (5 mmol) N'-phényl- 1,4-benzènediamine dans 50 ml de DMF. Le mélange réactionnel est agité pendant 15 heures et finalement concentré sous vide. Le résidu d'évaporation est repris par 50 ml d'AcOEt et filtré pour éliminer le précipité. Le filtrat est ensuite lavé par 2 fois 50 ml d'une solution saturée de carbonate de sodium et 50 ml de saumure. Après séchage sur sulfate de sodium, la solution organique est filtrée et concentrée à sec sous vide. Le résidu obtenu est purifié sur une colonne de silice (éluant : heptane/AcOEt : 3/7 à 0/10). EXAMPLES: Example 1: (2S) -2-amino-N- (4-anilinophenyl) -5 - {[imino (2-oxido-2-oxohydrazino) methyl] amino} pentanamide:

1.1) tert-butyl (IS) -I - [(4-anilinoanilino) carbonyl] -4 - ([imino (2-oxido-2-oxohydrazino) methyl] amino} butylcarbamate: 1.03 g (5 mmol) is added of 1,3-dicyclohexylcarbodiimide to a solution of 1.6 g (5 mmol) of N-tert-butoxycarbonyl-L-nitroarginine and 0.92 g (5 mmol) N'-phenyl-1,4-benzenediamine in 50 ml of DMF. The reaction mixture is stirred for 15 hours and finally concentrated under vacuum. The evaporation residue is taken up in 50 ml of AcOEt and filtered to remove the precipitate. The filtrate is then washed twice with 50 ml of saturated sodium carbonate solution and 50 ml of brine After drying over sodium sulfate, the organic solution is filtered and concentrated to dryness under vacuum The residue obtained is purified on a silica column (eluent: heptane / AcOEt: 3 / 7 to 0/10).

0.8 g of a beige powder is obtained. Melting point: 93-94 C.

1.2) (2S) -2-amino-N- (4-anilinophenyl) -5 - {[imino (2-oxido-2-oxohydrazino) methyl] - amino} pentanamide: To a solution of 0.4 g (0, 8 mmol) of intermediate 1.1 in 10 ml of methanol, cooled to 0 C, 2 ml (8 mmol) of a 4N solution of HCl in 1,4-dioxane are added. The reaction mixture is then stirred for 4 hours at 23 C. At the end of the reaction, the whole is concentrated under vacuum to yield a beige powder which is purified by chromatography on a silica column (eluent CH2Cl2 / MeOH: 9 / 1 to 8/2). The expected product is obtained in the form of a light gray powder. Melting point: 68-72 C.

Example 2: (25) -2-amino-5 - ([iminof2-oxido-2-oxohydrazino) methyl] amino} -7V- (1-methyl-2,3-dihydro-1 / y-indol-5-yl) pentanamide : 2.1) 1-methyl-5-nitroindoline: In a 150 ml three-necked flask, under an inert atmosphere, 25 ml of anhydrous DMF are introduced followed by 0.84 g (21 mmol) of 60% NaH. The reaction mixture is cooled using an ice bath before the dropwise addition of a solution of 3.28 g (20 mmol) of 5-nitroindoline in 5 ml of anhydrous DMF. At the end of the addition, the stirring is continued for 1 hour at 23 ° C., before introducing a 1.31 ml solution dropwise.

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 (21 mmol) of Mel in 5 ml of anhydrous DMF. Stirring is continued for 15 hours at 23 ° C. The 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.

2. 2) 1-methyl-5-aminoindoline: To a mixture of 2.84 g (15.9 mmol) of 1-methyl-5-nitroindoline and 4 ml (80 mmol) of hydrazine hydrate in 60 ml of absolute ethanol, about 400 mg of Raney nickel is added. The reaction mixture is heated at reflux for 5 hours. After returning to 23 ° C., a little silica is added to the flask and the solvent is evaporated under vacuum. The evaporation residue is placed directly at the top of a chromatography column. The expected product is eluted using a heptane / AcOEt mixture (3/7). A purple powder (65%) is obtained which is invested directly in the next step.

2. 3) (2S) -2-amino-5 - ([imino (2-oxido-2-oxohydrazino) methyl] amino) -N- (1-methyl-2,3-dihydro-1H-indol-5- yl) -pentanamide: The experimental protocol used is the same as that described for Example 1, intermediate 2.2 replacing the N1-phenyl-1,4-benzenediamine. After purification on a silica column (eluent: CH2Cl2 / EtOH: 10/1), an off-white solid is obtained.

Melting point: 140-142 C.

Example 3: (2S-2 - [(3,5-ditert-butyl-4-hydroxybenzyl) amino] -5 - {[imino (2oxido-2-oxohydrazino) methyl] amino} pentanoic acid: 3.1) (2S) - 2 - [(3,5-ditert-butyl-4-hydroxybenzyl) amino] -5 - {[imino (2-oxido-2-oxohydrazino) methyl] amino} methyl pentanoate: In a three-necked flask, under an argon atmosphere , containing 3 g of powdered molecular sieve 3Â, previously activated, suspended in 50 ml of anhydrous MeOH, 1.17 g (5 mmol) of 3,5-ditert-butyl-4-hydroxybenzaldehyde, 1.35 g are successively introduced (5 mmol) of the methyl ester of L-nitroarginine followed by 0.7 ml (5 mmol) of Et3N. The reaction mixture is stirred for 15 hours at 23 ° C. before the addition, at 0 ° C., of 0.35 g (5.5 mmol) of sodium cyanoborohydride. Stirring is continued for an additional 4 hours at 23 C. The suspension is then filtered through Büchner and the filtrate is diluted with 150 ml of AcOEt and 50 ml of water. After agitation and decantation,

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 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.

3. 2) (2S) -2- (3, 5-ditert-butyl-4-hydroxybenzyl) amicoJ-5-imino (2-oxido-2-oxohydrazino) methyl] amino} pentanoic acid: Add at 0 C , a solution of 90 mg (2.1 mmol) of LiOH in 10 ml of water to a solution of 0.45 g (1 mmol) of intermediate 3. 1 in 10 ml of THF. The mixture is stirred for 1 hour at 23 ° C. before dilution with 25 ml of AcOEt. After stirring, the whole is decanted and the aqueous phase, basic, is again washed with 25 ml of AcOEt. The basic solution is then neutralized, at 0 ° C., with HC1 IN. The precipitate which appears is then filtered and washed successively with 25 ml of water and 25 ml of AcOEt.

After drying, a white powder is obtained with a yield of 35%. Melting point: 196-197 C.

Example 4: Methyl (2S) -2- {| 5- (1,2-dithiolan-3-yI) pentanoyl] amino) -5 - {[imino (2-oxido-2-oxohydrazino) methyl] amino} pentanoate : To a solution of 1.03 g (5 mmol) of (DL) -thioctic acid in 50 ml of dichloromethane, 1.35 g (5 mmol) of the hydrochloride of the methyl ester of L-nitroarginine are successively added , triethylamine (2.1 ml), 0.676 g (5 mmol) of hydroxybenzotriazole and 0.956 g (5 mmol) of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride. After having stirred the reaction mixture overnight at 25 ° C., the whole is diluted with 400 ml of water and stirring is continued for 30 minutes more. 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.

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Exemple 5 : acide (2S)-2-{[5-(1,2-dithiolan-3-yl)pentanoyl]amino}-5-{(imino(2- oxido-2-oxohydrazino)méthyl]amino}pentanoïque : A une solution de 0,632g (1,50 mmol) du composé 4 dans lOmls de THF, on ajoute goutte à goutte 2,3 ml d'une solution (1M dans H20) d'hydroxyde de lithium et on laisse agiter à température ambiante pendant une heure. Le pH est ajusté à 5-6 avec HC1 (1M) puis l'on extrait à l'éther diéthylique. La solution organique est séchée sur sulfate de magnésium, filtrée et évaporée sous pression réduite. Le solide obtenu est purifié par recristallisation dans l'éthanol filtré et rincé à l'éther diéthylique pour obtenir, après séchage, 0,370 g d'un solide jaune pâle avec un rendement de 61 %. Point de fusion :
140-143. 1 C.

Example 5: (2S) -2 - {[5- (1,2-dithiolan-3-yl) pentanoyl] amino} -5 - {(imino (2-oxido-2-oxohydrazino) methyl] amino} pentanoic acid: To a solution of 0.632 g (1.50 mmol) of compound 4 in 10 mls of THF, 2.3 ml of a solution (1 M in H 2 O) of lithium hydroxide is added dropwise and the mixture is left to stir at room temperature for one hour, the pH is adjusted to 5-6 with HCl (1M) and then extracted with diethyl ether The organic solution is dried over magnesium sulphate, filtered and evaporated under reduced pressure The solid obtained is purified by recrystallization from filtered ethanol and rinsed with diethyl ether to obtain, after drying, 0.370 g of a pale yellow solid with a yield of 61%.
140-143. 1 C.

Pharmacological study of the products of the invention Study of the effects on the neuronal constitutive NO svnthase of rat cerebellum The inhibitory activity of the products of the invention is determined by measuring their effects on the transformation by NO synthase of [3H ] L-arginine in [3H] L-citrulline in accordance with the modified method of Bredt and Snyder (Proc. Natl. Acad. Sci. USA, (1990) 87: Cerebellum 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 21000 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 CaCl2, 2 mM are distributed. dithiotreitol, 2 mM reduced NADPH and 10 µg / ml calmodulin. 25 l of a solution containing 100 nM of [3 H] L-arginine (specific activity: 56.4 Ci / mmol, Amersham) and 40 M of non-radioactive L-arginine are added. The reaction is initiated by adding 50 l of homogenate, the final volume being 200 l (the 25 l missing are either water or the product tested. After 15 min, the reaction is stopped with 2 ml of buffer d stop (20 mM HEPES, pH 5.5, 2 mM EDTA) After passing the samples over a column of 1 ml of DOWEX resin, the radioactivity is quantified by a liquid scintillation spectrometer. 1 and 2 described above have an IC 50 of less than 10 M.

Study of the effects on oxidative stress induced by glutamate on cultured cells (HT-22).

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 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 biosynthesis of glutathione, an essential element in the cellular detoxification of free radicals, requires the active transport of cystine inside the cell. Glutamate by opposing the penetration of cystine causes a reduction in the level of glutathione which leads to cell death by oxidative stress (Demerlé-Pallardy, C. et al., J Neurochem. (2000) 74, 2079 -2086; Murphy, TH et al., Neuron, (1989) 2: The cells are cultured at 37 ° C. in DMEM medium supplemented with 10% fetal calf serum. The tests are carried out in 96-well plates containing 5000 cells per well. Glutamate (5 mM) is added to the medium containing or not containing the products to be tested. Cell viability is tested after 24 h by the MTT method (Hansen, MB et al., J Immunol. Methods (1989 ), 119,203-210) The capacity of the compounds to protect cells from the toxic action of glutamate is estimated in EC50, calculated relative to the viability of cells not subjected to the action of glutamate considered to be 100% viability. compounds of examples 1 and 2 described above have a lower EC50 re at 25 M.

Claims (9)

 in which R2, R3, R4, R5, R6 represent, independently, a hydrogen atom, a halogen, the group OH, an alkyl, alkoxy, cyano, nitro or NR8R9, R8 and R9 group representing, independently, a d atom hydrogen, an alkyl radical or a group -CORIO, or else R8 and R9 forming together with the nitrogen atom an optionally substituted heterocycle having 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 atoms 0, N and S, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, RIO representing a hydrogen atom, an alkyl or alkoxy radical or NR1 1R12, R11 and R12 representing, independently, a hydrogen atom or an alkyl radical,

 (I) in which RI represents a hydrogen atom or an alkyl radical; A and A 'represent a hydrogen atom or one of the following radicals: - a radical

 Claims: 1. Compound of general formula (I) <Desc / Clms Page number 31>  in which R17, R18 and R19 represent, independently, a hydrogen, a halogen, the group OH or SR20 or an alkyl, alkenyl or alkoxy radical or a radical NR21R22, R20 representing a hydrogen atom or an alkyl radical, R21 and R22 independently representing a hydrogen atom, an alkyl radical or a group -COR23, or else R21 and R22 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 0, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, R23 representing an atom of hydrogen, an alkyl, alkoxy or NR24R25 R24 and R25 radical independently representing a hydrogen atom or an alkyl radical,

 or else R11 and R12 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 formed atoms 0, N and S, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, R7 represents a hydrogen atom, an alkyl radical or a group -COR13, R13 representing a hydrogen atom, a alkyl or alkoxy radical or NR14R15, R14 and R15 independently representing a hydrogen atom or an alkyl radical, or else R14 and R15 forming together with the nitrogen atom an optionally substituted heterocycle with 4 to 7 members and 1 with 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being independently chosen from the group consisting of atoms 0, N and S, said h eterocycle being for example azetidine, pyrrolidine, pipéridine, pipérazine, morpholine or thiomorpholine, and # does not exist, or represents a bond, 0 or S or a radical NR16, in which R16 represents a hydrogen atom or an alkyl radical ; - or a radical <Desc / Clms Page number 32>  in which R27 represents a hydrogen atom, an alkyl radical or an aralkyl radical, T representing a radical - (CH2) m- with m = 1 or 2; - or a radical

 or else R24 and R25 forming together with the nitrogen atom an optionally substituted heterocycle having 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the additional heteroatoms being chosen independently from the group consisting atoms 0, N and S, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, and Q represents -OR26, -SR26 or a phenyl radical substituted by one or more substituents chosen from a halogen, the group OH, an alkyl, alkoxy, cyano, nitro or NR8R9 radical, R26 representing a hydrogen atom or an alkyl radical, R8 and R9 representing, independently, a hydrogen atom, an alkyl radical or a group -CORIO, or alternatively R8 and R9 forming together with the nitrogen atom an optionally substituted heterocycle with 4 to 7 members and 1 to 3 heteroatoms including the nitrogen atom already present, the hetero additional volumes being independently selected from the group consisting of 0, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, RIO representing a hydrogen atom, an alkyl, alkoxy or NR11R12 radical, R11 and R12 independently representing a hydrogen atom or an alkyl radical, or else R11 and R12 forming together with the nitrogen atom an optionally substituted heterocycle having 4 to 7 members and 1 to 3 heteroatoms including the atom d nitrogen already present, the additional heteroatoms being independently chosen from the group consisting of 0, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, - or a radical <Desc / Clms Page number 33>  in which R34 and R35 independently represent a hydrogen atom or an alkyl or arylalkyl radical, the aryl group being optionally substituted by one or more substituents such as the OH group, the alkyl, halogen, nitro, alkoxy or -NR36R37 radicals, in which R36 and R37 independently represent a hydrogen atom, an alkyl radical or a group -COR38, or else R36 and R37 form together with the nitrogen atom an optionally substituted heterocycle having 4 to 7 members and 1 with 3 heteroatoms including the nitrogen atom already present, the

 in which R28 represents a hydrogen atom, an alkyl, arylalkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl radical, the aryl group being optionally substituted with one or more substituents such as the OH group, alkyl, halogen, nitro, alkoxy or - radicals NR29R30, in which R29 and R30 independently represent a hydrogen atom, an alkyl radical or a group - COR31, or else R29 and R30 together with the nitrogen atom form an optionally substituted heterocycle with 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 atoms 0, N and S, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine , R31 representing a hydrogen atom, an alkyl or alkoxy radical or NR32R33, R32 and R33 representing, independently, a hydrogen atom ne or an alkyl radical, or else R32 and R33 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 selected from the group consisting of 0, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, T representing a radical - (CH2) m- with m = 1 or 2; - or a radical

<Desc / Clms Page number 34>  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 0, S, N and in particular the thiophene, furan, pyrrole or thiazole radicals , the carbocyclic or heterocyclic aryl radical being optionally substituted by one or more groups chosen from linear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6 carbon atoms, or D represents a radical NR42R43, in which R42 and R43 represent, independently, 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 R42 and R43 form with the nitrogen atom a non-heterocycle five to six membered aromatic, the chain elements being selected from a group consisting of CH2-, -NH-, -0- or -S-;

 in which R41 represents a hydrogen atom, the OH group, or an alkyl or alkoxy radical; - or finally a radical

 additional heteroatoms being independently selected from the group consisting of 0, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, R38 representing a hydrogen atom, an alkyl or alkoxy radical or NR39R40, R39 and R40 independently representing a hydrogen atom or an alkyl radical, or else R39 and R40 forming together with the nitrogen atom an optionally substituted heterocycle having 4 to 7 members and 1 to 3 heteroatoms including nitrogen atom already present, the additional heteroatoms being independently chosen from the group consisting of 0, N and S atoms, said heterocycle being for example azetidine, pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, T representing a radical - (CH2) m- with m = 1 or 2; - or a radical <Desc / Clms Page number 35>  or else D represents a radical -SR44, in which R44 represents a linear or branched alkyl radical having from 1 to 6 carbon atoms optionally substituted by a group chosen from: -OH, halogen, amino, cyano and aralkyl; X represents - (CH2) n-CO-, - (CH2) p-, -0- (CH2) p-, -S- (CH2) p-, -CH = CH- (CH2) p- or CH = CH - (CH2) n-CO-, n being an integer from 0 to 6 and p being an integer from 1 to 6; W represents -0- or -NR4s -, and R45 represents a hydrogen atom or an alkyl radical Y represents a radical chosen from - (CH2) t-, - (CH2) qO-, - (CH2) qS- and - ( CH2) q-NR46- and R46 representing a hydrogen atom 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- (CH2) r-, - (CH2) rO- (CH2) s-, - (CH2) rS- (CH2) s-, - (CH2) rS (O) - (CH2 ) s- and - (CH2) rS (O) 2- (CH2) sr being an integer from 1 to 6, s being an integer from 2 to 6; it being understood that one of A and A 'represents a hydrogen atom and the other does not represent a hydrogen atom; or salt of a compound of general formula (I). 2. Compound of general formula (I), characterized in that D represents the radical -NHN02. 3. Compound according to claim 1 or 2, characterized in that it is one of the following compounds: (2S) -2-amino-N- (4-anilinophenyl) -5 - {[imino (2 -oxido-2-oxohydrazino) methyl] amino} pentanamide;

 (25) -2-amino-5- (imino (2-oxido-2-oxohydrazino) methyl] amino} -N- (1 -methyl- 2,3-dihydro-1H-indoI-5-yI) pentanamide; acid (2S) -2- (3,5-ditert-butyl-4-hydroxybenzyl) amino] -5- {{[imino (2-oxido 2-oxohydrazino) methyl] amino} pentanoic; <Desc / Clms Page number 36>  (2S) -2 - {[5- (1,2-dithiolan-3-yl) pentanoyl] amino} -5 - {[imino (2-oxido-2-oxohydrazino) methyl] amino} pentanoic acid; or a salt of one of these.

 (2S) -2 - {[5- (1,2-dithiolan-3-yl) pentanoyl] amino} -5 - {[methyl imino (2-oxido-2-oxohydrazino) methyl] amino} pentanoate; 4. As a medicament, a compound according to one of claims 1 to 3. 5. Use of a compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for preparing a medicament intended to inhibit neuronal NO synthase or inducible NO synthase. 6. Use of a compound of general formula (I) according to claim 1 in which neither A nor A 'represents the radical

 or a pharmaceutically acceptable salt thereof, to prepare a medicament for inhibiting lipid peroxidation. 7. Use of a compound of general formula (I) according to claim 1 in which one of A and A 'represents the radical

 or a pharmaceutically acceptable salt thereof, for preparing a medicament for regenerating antioxidants or scavenging entities of reactive oxygen species. 8. Use of a compound of general formula (I) according to claim 1 in which neither A nor A 'represents the radical

<Desc / Clms Page number 37>  or a pharmaceutically acceptable salt thereof, for preparing a medicament for inhibiting both neuronal NO synthase or inducible NO synthase and lipid peroxidation. 9. Use of a compound of general formula (I) according to claim 1 in which one of A and A 'represents the radical

 or a pharmaceutically acceptable salt thereof, for preparing a medicament for both inhibiting neuronal NO synthase or inducible NO synthase and regenerating antioxidants or scavenging entities of reactive oxygen species.