FR2872158A1 - NOVEL DIAZENIUMDIOLATE COMPOUNDS, PROCESS FOR THEIR PREPARATION AND THEIR THERAPEUTIC USE - Google Patents

Abstract

The present invention relates to the compounds of formula (I): their preparation process and their therapeutic use, in particular their use as an antioxidant, NO generator, and inhibitors of the proliferation of smooth muscle cells.

Description

N // O

  The invention relates to novel diazeniumdiolate derivatives, pharmaceutical compositions containing them and their use for the preparation of medicaments for use in the treatment of proliferative diseases.

  The migration and proliferation of smooth muscle cells in the vascular intima are involved in the development of atherosclerosis (Ross, Nature, 1990 362: 801-809, Schwartz et al, Diabetes Care, 1992, 9: 1156-1167). and also play a role in restenosis or stenosis after angioplasty with or without stent, bypass surgery, cardiac transplantation ... (Hanke et al., Circ Res 1991, 67: 651-659, Ueda et al, Circulation, 1991 , 83: 1327-1332).

  Molecules that inhibit the proliferation of smooth muscle cells can therefore be very useful in inhibiting the excessive proliferation of smooth muscle cells associated with vascular diseases such as atherosclerosis and restenosis or in treating and preventing any other pathological conditions or complication associated with excessive proliferation. smooth muscle cells.

  Nitric oxide (or nitric oxide NO) is an important mediator in the physiology of the cardiovascular, immune, central and peripheral nervous systems. It acts, among other mechanisms, by activation of guanylate cyclase.

  Its action is ubiquitous: it is vasodilatory, gives a basal tone to the entire vascular system. It has an anti-aggregating action: its production by normal endothelial cells inhibits the formation of thrombi. It is antiproliferative, especially on the smooth muscle cells underlying endothelial cells, which is involved in the development process of atherosclerosis. It also inhibits the adhesion of monocytes to the vascular wall and thereby its transformation into a macrophage. It regulates the endothelial permeability.

  There is therefore, in the physiological state, a situation of equilibrium between the production of radical species and the availability of NO.

  The imbalance of this balance, the result of which is an excess of superoxide anions in the face of a NO defect, leads to the development of numerous pathologies.

  Oxidative stress is caused by many factors such as hyperglycemia, dyslipidemia (production of low-density lipoproteins (LDL) oxidized, very atherogenic), hypoxia, insulin resistance, atherosclerosis, revascularization techniques (the angioplasty with or without stent), chronic rejection after transplantation, the majority of inflammatory processes, smoking. Oxidative stress is characterized at the vascular level by an increase of free radicals, in particular superoxide anions (O 2 -).

  These 02E - will be able to trap endogenously produced NO endothelial cells to form even more deleterious radical species such as peroxynitrites.

  Among the pathologies concerned by a lack of production of endothelial nitric oxide and / or an increase in tissue oxidative stress, mention may be made (Recent Progress in Human Research (1988), 53, 43-60, Table V): ischemia related to atherosclerosis (lipid peroxidation, development, progression and rupture of atheromatous plaque, platelet activation); restenosis after angioplasty; stenosis after vascular surgery; diabetes; insulin resistance; retinal and renal microvascular complications of diabetes; the cardiovascular risk of diabetics insofar as it is not explained by classical factors; male erectile dysfunction; cerebral hypoxia; chronic rejection after organ transplantation; articular pathologies.

  The administration of active ingredients capable of decreasing the biological activity of oxidizing radical species (such as superoxide anions and peroxynitrites) and increasing the nitric oxide rate by a double mechanism: non-transformation into peroxynitrites and exogenous contribution , is therefore particularly desirable in the treatment of these pathologies.

  The present invention provides compounds of formula (I) defined below having these two effects, antioxidant and nitrogen monoxide donor in the same molecule.

  These compounds are capable of generating nitric oxide and trapping oxidative free radicals.

  Compounds close to those of the invention corresponding to the general formula (I) for which 1) n = 0, p = 1, Ar represents a phenyl group, Y = -CH 2 -, and m = 0 or m = 1, and A is 4-terBu, 4-OMe, 4-Cl, 4-OH, 3-OH, 2-OH, 3-Cl, 2-F, 3-10 Me, 4-Me, 4-NMe2, 4 -CN, or m = 2, and A represents a 2,4-di OH or 2,5-di OH group; 2) n = 0, p = 3, Ar represents a phenyl group, Y = -CH2-, and m = 0 have been described in Bioorg. Chem. 2003, 31 (2), 129-135; J. Chem. Soc., Perkin Trans.2, 2001, 11, 2059-2062; Bioorg. and Med. Chem. 2001, 9 (5), 1233-1240; J. Org. Chem. 1981, 46 (3), 562-8; Russian Chem. Bull., 1997, 46 (8), 1421-1429. However, their antioxidant and / or nitric oxide donor activity is neither described nor suggested.

  According to a first subject, the present invention therefore relates to the compounds of formula (I): ## STR5 ## wherein: m is an integer understood; between 0 and 3; É n is an integer chosen between 0 and 1; É p is an integer chosen between 1 and 7; X represents an oxygen atom -O-, a group -NR1- or, when n = 0, X represents a single bond; where R 1 represents a hydrogen atom, a -Alkyl, -Aryl group, each optionally substituted by one or more group (s) chosen from -OH, -Oalkyl, -CN, -NO 2, perfluoroalkyl, -NR 2 R 3 where R2 is H, Alkyl and R3 is -Alkyl, -Aryle Y is -CH2-; É Ar represents a phenyl group; Ar is optionally substituted with 1 to 3 substituents A where E two of A may represent a phenyl fused heterocycle, such as benzodioxolane or where; Each of the A is independently a group selected from: E-OH; É -CN; E-Hal; C1-C6alkyl, optionally substituted with one or more groups selected from -OH, -Oalkyl, -CN, -NO2, perfluoroalkyl, -NR2R3 wherein R2 represents H, -Alkyl and R3 represents -Alkyl , -Aryle; Alkyl-O-Aryl wherein Aryl is optionally substituted with one or more groups selected from -OH, -Oalkyl, -CN, -NO2, -perfluoroalkyl, -NR "2 R" 3 where R " 2 represents H, -Alkyl, -NO and R "3 represents -Alkyl, -Aryl; E -Oalkyl, optionally substituted with one or more groups selected from -OH, -Oalkyl, -CN, -NO2, -perfluoroalkyl, -NR2R3 wherein R2 is H, -Alkyl and R3 is -Alkyl, aryl; E-Alkyl Alryl, optionally substituted with one or more groups selected from OH, -Alkyl, -Oalkyl, -CN, -NO2, -perfluoroalkyl, -NR2R3 wherein R2 represents H, -Alkyl and R3 represents- Alkyl, -Aryl; --Aryl optionally substituted with one or more groups selected from -OH, -Oalkyl, -CN, -NO2, -perfluoroalkyl, -NR'2R'3 wherein R'2 represents H, -Alkyl and R 3 represents -Alkyl, -Aryl, -C (= O) Alkyl, -C (= O) Aryl; Wherein R is 0 or 1, R7 is Alkyl, -OR8, NR9R10; where R8 represents a hydrogen atom, an alkyl group; R 9, R 10 independently represent a hydrogen atom, an alkyl, -Alkenyl, -N = alkyl, -N = alkenyl group where the alkyl or alkenyl group is optionally substituted by one or more group (s) chosen from - Aryl, -Het, themselves optionally substituted by one or more group (s) chosen from a halogen atom, a -OH group, an alkyl group, -Oalkyl; Wherein R 11 is -Alkyl, -Aryl optionally substituted with one or more groups selected from OH, -Alkyl, -Oalkyl, -AlkylAryl, -C (= O) alkyl, optionally substituted with one or more group (s) selected from -Aryle, -Het; - C (= O) Alkenyl, optionally substituted with -Aryl, -Het; - C (= O) NR12R13, where R12, R13 independently represent a hydrogen atom, an -Alkyl group; -N (NO) -A-aryl, optionally substituted by one or more groups selected from OH, -Oalkyl, -CN, -perfluoroalkyl, -NR2R3 wherein R2 represents H, -Alkyl and R3 represents -Alkyl, aryl; -NR 4 R 5 where R 4 is H, Alkyl and R 5 is -Alkyl, -Aryl, -AlkylAryl, where the -Aryl group is optionally substituted with one or more groups selected from -OH, -Alkyl, -Oalkyl , -CN, -NO2, - perfluoroalkyl, -NR'2R'3 where R'2 is H, -Alkyl and R'3 is -Alkyl, -Aryle, -C (= O) Alkyl, -C (= O ) Aryl; -S (O) qR6 where q represents 0, 1 or 2, R6 represents a group -Alkyl, Aryl each optionally substituted by one or more group (s) chosen from -OH, -Oalkyl, -CN, -NO2 -, perfluoroalkyl, -Alkyl, Alkyl, -NR14R15, where R14, R15 independently represent a hydrogen atom, a -Alkyl group, -C (= O) alkyl, -C (= O) aryl, -C (= O In these last three cases, Alkyl, Aryl and Het may be optionally substituted by one or more groups chosen from OH, -CN, O-Alkyl, -NO 2, -perfluoroalkyl, -NR 2 R 3, where R 2 represents H, Alkyl and R3 represents -Alkyl, -Aryl; Perfluoroalkyl; É -Hét; AlkylHet; -OHet; or the corresponding salts, as well as enantiomers, diastereoisomers, racemic mixtures and pharmaceutically acceptable salts; with the exception of compounds for which: 1) n = 0, p = 1, Ar represents a phenyl group, Y = -CH2-, and m = 0 or m = 1, and A represents 4-terBu group, 4- OMe, 4-Cl, 4-OH, 3-OH, 2-OH, 3-Cl, 2-F, 3-Me, 4-Me, 4-NMe 2, 4-CN, or m = 2, and A represents a 2,4-di OH or 2,5-di OH group; 2) n = 0, p = 3, Ar represents a phenyl group, Y = -CH2-, and m = 0.

  The salts of the compounds of formula (I) may be represented by the formula

WE

  (A) m -Ar- (X), - (Y) p N-O-M + wherein A, Ar, X, Y, m, n, p are as previously defined and M + 5 represents a cation. Preferably, M + is NH 4 + or the cation of an alkali metal, such as Na + or K +.

  Preferably, in the formula (I) or (I '), X represents a single bond, -O- or -NR1- where R1 represents an optionally substituted Aryl group and A, Ar, Y, m, n, p are such than previously defined.

  Preferably, in the formula (I) or (I '), each of the same or different A is independently a group selected from: E-S (O) q-R6, where q = 0 and R6 represents an optionally substituted Aryl group by one or more group (s) chosen from -Oalkyl, E -Oalkyl, E -OalkylOR11, where R11 represents a C (= O) alkenyl group where Alkenyl is optionally substituted with Het, or an optionally substituted -Aryl group by one or more group (s) selected from OH, -Alkyl.

  An Aryl group where Aryl is optionally substituted by one or more groups selected from Alkyl, -NR4R5 where R4 is Alkyl and R5 is Aryl, optionally substituted with Alkyl, E-Alkyl-O; -Aryl wherein Aryl is optionally substituted with NR "2R" 3, where R "2 represents a hydrogen atom or a group -N = O, and R" 3 represents an Aryl group; --Alkyl Aryl, wherein Aryl is optionally substituted with one or more groups selected from -OH, -Alkyl; E -Alkyl-C (= O) R7 where R7 is NR9RIO where R9 is H and R10 is -N = Alkyl or -N = Alkenyl where the group -Alkyl or -Alkenyl is optionally substituted with one or more groups selected from Aryl, -Net, themselves optionally substituted by one or more group (s) chosen from Oalkyl, OH, -Hal.

  Alkyl, -Hal, -OH, -N (NO) -Aryl, or where two of the A form with the phenyl a fused heterocycle, for example the dioxolane group.

  Preferably, in formula (I) or (I '), p = 1, n = 0 and Y represents the group CH 2 - and Ar, A, m are defined as above.

  In this case, the compounds for which Ar represents the phenyl group are preferred, and m = 1 and A represents an Aryl group in which Aryl is optionally substituted by one or more group (s) chosen from alkyl; S-Aryl optionally substituted with one or more -Oalkyl, and -N (Alkyl) -A-aryl is substituted by Alkyl, E -Alkyl-O-Aryl wherein Aryl is optionally substituted with NR "2R" 3, where R "2 and R "3 are defined as above, E -OalkylAryl, E -Oalkyl wherein Alkyl is C2-C6E -Oalkyl-C (= O) R7 where R7 is NR9R10 where R9 is H and R10 is -N = NAlkyl or -N = Alkenyl wherein the alkyl or alkenyl group is optionally substituted by one or more groups selected from Aryl, -Het, themselves optionally substituted with one or more groups selected from alkyl, OH, -Hal, or m = 2, 3, 4 or 5 and each of A is independently selected from Alkyl, -Alkyl, -Hal, -OH, or where two of the A's form a heterocycle fused with phenyl, for example the benzodioxolane group.

  Preferably, in formula (I) or (I '), p = 1, n = 1 and Ar, A, X, Y are defined as above.

  In this case, the compounds are preferred for which Y = -alkyl-, X = -O or NR1- where R1 represents a -Ar1 group optionally substituted with -NO2, Ar represents a phenyl- group, m = 1 and A represents- N (NO) -Aryl, -Oalkyl.

  In the foregoing, preferably, R1 is -Nyl substituted with NO2.

  In the above, preferably, R2 represents a hydrogen atom and R3 represents a -Alkyl group.

  In the foregoing, preferably R'2 represents a hydrogen atom and R'3 represents a C (= O) Aryl group.

  In the foregoing, preferably, R "2 represents a hydrogen atom and R" 3 represents a -Aryl group.

  In the foregoing, preferably, R4 is -Alkyl, and R5 is Aryl substituted by Alkyl.

  In the foregoing, preferably, R6 represents an Aryl group substituted with an alkyl group.

  In the foregoing, preferably, R7 is -NR9R10, where R9 is hydrogen, and R10 is -N = Alkenyl, or -N = Alkyl, substituted with -Het or -Aryl, itself substituted by one or more groups selected from a halogen atom, a group -Oalkyl, -OH.

  In the foregoing, preferably, R 11 represents a C (= O) -Het-substituted alkenyl group, or an -Aryl group substituted with one or more groups selected from OH, Alkyl.

  The preferred embodiments mentioned above or hereafter include both singly and in combination with each other or with the general embodiment of the invention.

  According to another preferred aspect, the compounds of formula (I) or (I ') are chosen from: ammonium 1- [4- (4-methoxyphenoxy) benzyl] -2-oxohydrazinolate; ammonium 1- {4 - [(4-methoxyphenyl) thio] benzyl} -2-oxohydrazinolate; Ammonium 1- (2,4-dimethoxybenzyl) -2-oxohydrazinolate; ammonium 1- [4 (benzyloxy) benzyl] -2-oxohydrazinolate; ammonium 1- (4-butoxybenzyl) -2oxohydrazinolate; ammonium 1- (1,3-benzodioxol-5-ylmethyl) -2oxohydrazinolate; ammonium 2-oxo-1- (2,3,4-trimethoxybenzyl) hydrazinolate; ammonium 1- (4-methoxy-3-methylbenzyl) -2-oxohydrazinolate; ammonium 1- (3,4-dimethoxybenzyl) -2-oxohydrazinolate; ammonium 1- (3-fluoro-4-methoxybenzyl) -2-oxohydrazinolate; ammonium 1- (3,5-di-tert-butyl-4-hydroxybenzyl) -2oxohydrazinolate; 2,6-di-tert-butyl-4- [2- (4 - {[methoxy (nitroso) amino] methyl} -phenoxy) ethyl] phenol; ammonium 1- {4 - [(4-methoxyphenyl) (methyl) amino] benzyl} -2-oxohydrazinolate; ammonium 1- {2 - [(4-anilinophenoxy) methyl] benzyl} -2-oxohydrazinolate; 4 [(2 {[hydroxy (nitroso) amino] methyl} benzyl) oxy] phenyl} nitroso (phenyl) amine; ammonium 1- (7- {4-nitroso (phenyl) amino] phenoxy} heptyl) -2oxohydrazinolate; ammonium 1- {5 - [(4-methoxyphenyl) (4-nitrophenyl) amino] pentyl} -2-oxohydrazinolate; ammonium 1- (4- {2 - [(2E) -2- (2-hydroxy-4-methoxybenzylidene) hydrazino] -2-oxoethoxy} benzyl) -2-oxohydrazinolate; ammonium 2-oxo-1- (4- (2-oxo-2 - [(2E) -2- (pyridin-3-ylmethylene) hydrazino] ethoxy} benzyl) hydrazinolate; N '- [(1 E) - (5-chloro-2-hydroxyphenyl) methylene] -2- (4 - {[hydroxy (nitroso) -amino] methyl} phenoxy) acetohydrazide; ammonium 1- (4- {2 - [(2E) -2-benzylidenehydrazino] -2-oxoethoxy} benzyl) -2oxohydrazinolate; ammonium 2-oxo-1- [4- (2-oxo-2 - {(2E) -2 - [(2E) -3-phenylprop-2-en-1-ylidene] hydrazino} ethoxy) benzyl] hydrazinolate; in free form or their salt as well as enantiomers, diastereoisomers, racemic mixtures and pharmaceutically acceptable salts.

  More particularly, the compounds chosen from: ammonium 1- {2 - [(4-anilinophenoxy) methyl] benzyl} -2-oxohydrazinolate; ammonium 1- {5 - [(4-methoxyphenyl) (4-nitrophenyl) amino] pentyl} -2-oxohydrazinolate; ammonium 1- (4- {2 - [(2E) -2- (2-hydroxy-4-methoxybenzylidene) hydrazino] -2-oxoethoxy} benzyl) -2-oxohydrazinolate; in free form or their salt as well as enantiomers, diastereoisomers, racemic mixtures and pharmaceutically acceptable salts.

  According to the present invention, the alkyl groups represent saturated hydrocarbon groups, in straight or branched chain, of 1 to 20 carbon atoms, preferably of 1 to 5 carbon atoms.

  Mention may in particular be made, when they are linear, methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl, hexadecyl, and octadecyl groups.

  When they are branched or substituted by one or more alkyl groups, mention may be made especially of isopropyl, tert-butyl, 2-ethylhexyl, 2-methylbutyl, 2-methylpentyl, 1-methylpentyl and 3-methylheptyl groups.

  The alkoxy groups according to the present invention are groups of formula -O-alkyl, the alkyl being as defined previously.

  Among the halogen atoms, mention is made more particularly of the fluorine, chlorine, bromine and iodine atoms, preferably fluorine.

  The alkenyl groups represent hydrocarbon groups, straight or linear, and include one or more ethylenic unsaturations.

  Among the alkenyl groups, there may be mentioned the allyl or vinyl groups.

  The Alkynyl groups represent hydrocarbon groups, straight or linear, and include one or more acetylenic unsaturations. Among the Alkynyl groups, there may be mentioned acetylene.

  The Cycloalkyl group is a saturated or partially unsaturated, non-aromatic mono-, bi- or tricyclic hydrocarbon group of 3 to 10 carbon atoms, such as in particular cyclopropyl, cyclopentyl, cyclohexyl or adamantyl, and the corresponding rings containing one or several unsaturations.

  Aryl denotes a hydrocarbon aromatic system, mono or bicyclic of 6 to 10 carbon atoms.

  Among the Aryl groups, there may be mentioned the phenyl or naphthyl group, more particularly substituted with at least one halogen atom.

  Among the Alkyl Aryl groups, mention may be made especially of the benzyl or phenethyl group.

  Het means a heteroaryl or heterocyclyl group.

  Heteroaryl groups denote aromatic systems comprising one or more heteroatoms chosen from nitrogen, oxygen or sulfur, mono or bicyclic, of 5 to 10 carbon atoms. Among the heteroaryl groups, mention may be made of pyrazinyl, thienyl, oxazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl, naphthyridinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo [1 , 2-a] pyridine, imidazo [2,1-b] thiazolyl, cinnolinyl, triazinyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidinyl, pyrrolopyridyl, imidazopyridyl , benzoazaindole, 1,2,4-triazinyl, benzothiazolyl, furanyl, imidazolyl, indolyl, triazolyl, tetrazolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, purinyl, quinazolinyl, quinolinyl, isoquinolyl, 1,3,4-thiadiazolyl, thiazolyl, triazinyl, isothiazolyl, carbazolyl, as well as the corresponding groups resulting from their fusion or from the fusion with the phenyl nucleus. Preferred heteroaryl groups include thienyl, pyrrolyl, quinoxalinyl, furanyl, imidazolyl, indolyl, isoxazolyl, isothiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl and quinazolinyl. , quinolinyl, thiazolyl, carbazolyl, thiadiazolyl, and groups derived from the fusion with a phenyl ring, and more particularly quinolynyl, carbazolyl, thiadiazolyl.

  Heterocycles groups denote mono or bicyclic systems, saturated or partially unsaturated, nonaromatic, of 5 to 10 carbon atoms, comprising one or more heteroatoms chosen from N, O or S. Among the heterocycles, mention may be made in particular of epoxyethyl , oxiranyl, aziridinyl, tetrahydrofuranyl, dioxolanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl, dithiolanyl, thiazolidinyl, tetrahydropyranyl, dioxanyl, morpholinyl, piperidyl, piperazinyl, tetrahydrothiopyranyl, dithianyl, thiomorpholinyl, dihydrofuranyl, 2-imidazolinyl, 2, -3-pyrrolinyl, pyrazolinyl, dihydrothiophenyl, dihydropyranyl, pyranyl, tetrahydropyridyl, dihydropyridyl, tetrahydropyrinidinyl, dihydrothiopyranyl, and the corresponding groups resulting from the fusion with a phenyl ring, and more particularly the morpholinyl, dioxalanyl rings e, benzothiazolidinyl, pyrrolidinyl, benzopyrrolidinyl.

  The term pharmaceutically acceptable salts refers to relatively non-toxic, inorganic and organic acid addition salts, and base addition salts, of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds. In particular, the acid addition salts can be prepared by separately reacting the purified compound in its purified form with an organic or inorganic acid and isolating the salt thus formed. Examples of the acid addition salts are the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate and citrate salts. , maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptanate, lactobionate, sulfamates, malonates, salicylates, propionates, methylenebis-b-hydroxynaphthoates, gentisic acid, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulfonates, p- toluenesulfonates, cyclohexyl sulfamates and quinateslaurylsulfonate, and the like. (See, for example, M. M. Berge et al., Pharmaceutical Salts, J. Pharm Soi, 66: p.1-19 (1977) which is incorporated herein by reference). The acid addition salts may also be prepared by separately reacting the purified compound in its acid form with an organic or inorganic base and isolating the salt thus formed. Acidic addition salts include amine and metal salts. Suitable metal salts include sodium, potassium, calcium, barium, zinc, magnesium and aluminum salts. Ammonium, sodium and potassium salts are preferred. Suitable basic inorganic addition salts are prepared from metal bases which include sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide . Suitable base amino acid addition salts are prepared from amines which have sufficient alkalinity to form a stable salt, and preferably include those amines which are often used in medicinal chemistry because of their low toxicity and acceptability. for medical use: ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine , tris (hydroxymethyl) -amino-methane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethyl-piperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids for example, lysine and arginine, and dicyclohexylamine, and the like.

  The invention also relates to tautomeric forms, enantiomers, diastereoisomers, epimers and organic or inorganic salts of the compounds of general formula (I).

  Compounds of the invention of formula (I) defined as above having a sufficiently acid function or a sufficiently basic function or both, may include the corresponding salts of organic or inorganic acid or organic or inorganic base pharmaceutically acceptable.

  According to another object, the present application also relates to the method of preparation of the invention according to the above. According to the invention, the process comprises the step of performing a nitrosation on the -NH-OH group of a corresponding compound. More specifically, it is a question of transforming the -NH-OH group into -N (N = O) -OH group or the corresponding salt N (N = O) -O- / M + from the products of formula (II) corresponding: (A) m-Ar- (X), - (Y) p H OH (II) in which A, Ar, Y, m, n, p are as defined above.

  This step can be performed by any means within the reach of those skilled in the art.

  In particular, this reaction can be carried out by application or adaptation of reactions making it possible to form the group -N (N = O) -OH or the corresponding salt N (N = O) -O- / M + described by Larock in Comprehensive Organic Transformations.

  Generally, the nitrosation is carried out using a nitrite compound, such as an alkyl nitrite, especially tert-butyl-nitrite, or ethyl-nitrite, or an alkali metal nitrite such as sodium nitrite or of potassium. Those skilled in the art may nevertheless use any of the nitrosation agents known in the art such as AgONO, BF4NO, HOSO3NO, nBuONO and tBuONO, or else Et-ONO.

  The amount of nitrosating agent required depends on the nature of the nitrosating agent used and the reactivity of the substrate of formula II. It is at least stoichiometric. In general, the molar ratio of the nitrosating agent to the substrate of formula II varies between 1 and 30 equivalents, preferably between 1 and 20 equivalents.

  When the nitrosating agent is an alkali metal nitrite, a person skilled in the art can easily adapt the reaction conditions so as to employ only from 1 to 10, preferably from 1 to 5, better still from 1 to 3 equivalents. of nitrite with respect to the substrate of formula II.

  When the nitrosating agent is an alkyl nitrite, it is preferable to operate in the presence of 10 to 25 molar equivalents of nitrite, preferably 15 to 20 molar equivalents, based on the amount of substrate of formula II.

  The choice of the solvent and the temperature conditions are in particular a function of the type of nitrosating agent selected for the reaction.

  When the nitrosating agent is AgONO, nBuONO, or tBuONO, the solvent is advantageously selected from a cyclic or non-cyclic ether (such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or ether dimethyl diethylene glycol), a halogenated aliphatic or aromatic hydrocarbon (such as chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, or dichlorobenzene). Preferably the solvent is tetrahydrofuran, diethyl ether or chloroform.

  The reaction temperature will generally be maintained between -33 and 70 ° C., more preferably between -33 ° and 60 ° C., in the case of AgONO, nBuONO, tBuONO and EtONO.

  More particularly in the case of EtONO, one operates between 15 and 30 C.

  More particularly in the case of AgONO and nBuONO, it will operate in tetrahydrofuran or diethyl ether at a temperature between 0 and 30 C, for example between 0 and 5 C.

  In the case of tBuONO, it will preferably be carried out in ether or tetrahydrofuran in the presence of liquid ammonia at a temperature between -33 and 20 ° C.

  When the nitrosating agent is AgONO, it is desirable to add thionyl chloride to the reaction medium.

  When the nitrosating agent is HOSO3NO, the reaction is preferably carried out in an alkali metal salt of lower carboxylic acid (at CI-05), such as sodium acetate, at a reaction temperature of between -10.degree. C and 30 C, more preferably between -5 and 25 C.

  When the nitrosating agent is BF4NO, a suitable solvent is a nitrite such as acetonitrile or isobutyronitrile. It is desirable to add pyridine or N-dimethylaminopyridine to the reaction medium, the reaction temperature being maintained between -30 and 10 ° C., preferably between -25 ° C. and 5 ° C.

  When the nitrosating agent is an alkali metal nitrite, the nitrosation reaction is preferably carried out in a strongly polar protic medium. Advantageously, the reaction medium contains water and a Bronsted or Lewis acid.

  Suitable acids are a hydrohalic acid (such as HCl), sulfuric acid, Al2 (SO4) 3, acetic acid and mixtures thereof.

  According to a particular embodiment of the invention, it is possible to add an aliphatic alcohol of the (C1-C4) alkanol type (such as methanol or butanol).

  Thus, one of the following systems may be selected as suitable reaction medium: a mixture of methanol, water, hydrochloric acid and sulfuric acid; a mixture of water and sulfuric acid; a mixture of water and acetic acid; a mixture of water, butanol and hydrochloric acid; a mixture of water and Al 2 (SO 4) 3; or - a mixture of water and hydrochloric acid.

  Advantageously, the reaction of the alkali metal nitrite on the substrate of formula II is carried out in a mixture of acetic acid and water, the ratio of acetic acid to water varying between 80:20 and 20: 80, preferably between 60:40 and 40:60, for example a 50:50 mixture. According to a preferred embodiment, the alkali metal nitrite, previously dissolved in water, is added dropwise to a solution of the substrate of formula II in acetic acid.

  The reaction of the alkali metal nitrite on the substrate of formula II is carried out at a temperature which is a function of the reactivity of the species present; this generally varies between -10 and 50 ° C., preferably between -5 ° and 25 ° C.

  When the nitrosation reaction is carried out in a mixture of acetic acid and water, a temperature of between 15 and 25 ° C is particularly suitable.

  The reaction of the alkyl nitrite on the substrate of formula II is preferably carried out in the presence of a C1-C4 alkanol in an aprotic polar solvent.

  As suitable alkanol include methanol, ethanol, isopropanol, tert-butanol, ethanol being particularly preferred.

  As a polar solvent, halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene are preferred; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether; nitriles, such as acetonitrile or isobutyronitrile; amides, such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidinone or hexamethylphosphorylamide; and mixtures in any proportions of these solvents.

  Preferably, the process according to the invention allows the preparation of the corresponding ammonium salt (I ') in situ, by bubbling gaseous ammonia.

  Optionally, the process according to the invention also comprises the step of preparing the free form (I) from the corresponding ammonium salt (I '). This step can be performed by applying or adapting any method known per se.

  To form the free species (I) from the corresponding salt (I '), any method of regeneration of the free species is carried out, in particular by addition of base, for example an aqueous sodium bicarbonate solution or a solution aqueous ammonia.

  According to the invention, the compounds of formula (II) can be prepared by any means within the reach of those skilled in the art. In particular, this reaction can be carried out by application or adaptation of reactions making it possible to form the -NH-OH group described by Larock in Comprehensive Organic Transformations.

  In a first aspect, the -NHOH group is obtained from the NO2 group. For this, reduction is carried out starting from the corresponding compounds of formula (III): (A) m -Ar- (X) n- (Y) p NO 2 (III) in which A, Ar, Y, m, n, p are as defined above.

  This reaction can be carried out by any method of forming hydroxylamine group usually used from the nitro group and not interfering with other functional groups present. Generally, sulfuric acid or hydrochloric acid is used in EtOH medium and electrolysis; AI-HG, in an aqueous medium in the presence of alcohol or THF, ethyl acetate Ether; Sodium NH3 liquid; Zn n presence of aqueous NH4Cl and / or THF, EtOH; hydrogenation in the presence of Pd-C (oxalic acid) EtOH HCl, Zn in the presence of alcohol + acetic acid; SMI2 in the presence of THF MeOH; BH 3 in the presence of THF NaBH 4 THF; Sn (SPh) 2 PhSH in the presence of Et3N / Benzene; SnCl2, PhSH in the presence of Et3N / Acetonitrile.

  More precisely, it is possible to operate with zinc in the presence of NH 4 Cl in a suitable solvent medium at a temperature between room temperature and the reflux temperature of the solvent. It is preferred to operate using 1 to 5 equivalents of zinc, preferably about 2 equivalents, in a polar, protic solvent medium such as water, alcohols, and more preferably the ethanol / water mixture. In general, the temperature is of the order of the boiling temperature of the solvent used, preferably between 50 ° C. and 80 ° C., still more preferably about 70 ° C.

  More precisely, hydrazine hydrate may also be used in the presence of a catalyst such as Raney nickel in a suitable solvent medium at a temperature of between 0 ° C. and room temperature. It is preferred to operate by means of from 1 to 10 equivalents of hydrazine hydrate, preferably about 6 equivalents, in a solvent mixture, such as the 1,2-dichloroethane / ethanol mixture. In general, the temperature is between 5 C and room temperature.

  In a second aspect, the NHOH group is obtained from the group = N-OH. For this, one operates by reduction of the oxime from the corresponding compounds of formula (IV) (A) m-Ar- (X) n- (Y) p = N-OH (IV) in which A, Ar, X, Y, m, n, p are as defined above.

  This reaction can be carried out by any oxime reduction method usually used and not interfering with the other functional groups present.

  Generally, sodium borohydride or NaCNBH 3 is used as the reagent.

  More precisely, sodium borohydride NaBH 4 may be operated in the presence of an acid in a suitable solvent medium at a temperature of between 0 ° C. and room temperature. It is preferred to operate with 1 to 5 equivalents of NaBH 4, preferably about 3 equivalents, in a polar, protic solvent medium such as alcohols, especially ethanol. In general, the temperature is between 5 C and room temperature. As acid, any organic or inorganic acid can be used. It is preferred to use hydrochloric acid HCl.

  More precisely, it is also possible to operate using NaCNBH 3 in the presence of acid, in a suitable solvent medium, at a temperature of between 0 ° C. and room temperature. It is preferred to operate by means of from 1 to 5 equivalents of NaCNBH 3, preferably about 3 equivalents, in a polar, protic solvent medium, such as alcohols, such as ethanol, or water. In general, the temperature is between 5 C and room temperature. As acid, any organic or inorganic acid can be used. It is preferred to use hydrochloric acid.

  The compounds of formula (III) or (IV) are commercially available or may be prepared by application or adaptation of methods known per se.

  In particular, the products of formula (III) and (IV) may be prepared by application or adaptation of the representative procedures described in the examples below.

  The starting materials are commercially available or can be prepared by application or adaptation of methods known per se.

  Optionally, said method may also include the step of isolating the product obtained.

  In the reactions described below, it may be necessary to protect the reactive functional groups, for example the hydroxy, amino, imino, thio, carboxy groups, when desired in the final product, to avoid their undesirable participation in the reactions. Traditional protection groups can be used according to standard practice, for examples see T.W. Green and P.G.M. Wuts in Protective Groups in Organic Chemistry, John Wiley and Sons, 1991; J. F. W. McOmie in Protective Groups in Organic Chemistry, Plenum Press, 1973.

  The compound thus prepared can be recovered from the reaction mixture by conventional means. For example, the compounds can be recovered by distilling the solvent from the reaction mixture or if necessary after distilling the solvent from the solution mixture, pouring the remainder into water followed by extraction with an organic solvent immiscible in the reaction mixture. water, and distilling the solvent from the extract. In addition, the product may, if desired, be further purified by various techniques, such as recrystallization, reprecipitation or various chromatography techniques, including column chromatography or preparative thin layer chromatography.

  It will be appreciated that the compounds useful in the present invention may contain asymmetric centers. These asymmetric centers may be independently in the R or S configuration. It will be apparent to those skilled in the art that certain compounds useful according to the invention may also have geometric isomerism. It should be understood that the present invention includes individual geometric isomers and stereoisomers and mixtures thereof, including racemic mixtures, of compounds of formula (I) above. These types of isomers can be separated from their mixtures by the application or adaptation of known methods, for example chromatography techniques or recrystallization techniques, or they are prepared separately from the appropriate isomers of their intermediates.

  For purposes of this text, it is understood that the tautomeric forms are included in the citation of a given group, for example thio / mercapto or oxo / hydroxy.

  The acid addition salts are formed with the compounds useful according to the invention in which a basic function such as an amino, alkylamino or dialkylamino group is present. The pharmaceutically acceptable, i.e., nontoxic, acid addition salts are preferred. The selected salts are optimally selected to be compatible with the usual pharmaceutical vehicles and adapted for oral or parenteral administration. The acid addition salts of the compounds useful in this invention may be prepared by reaction of the free base with the appropriate acid, by the application or adaptation of known methods. For example, the acid addition salts of the compounds useful in this invention can be prepared either by dissolving the free base in water or an alcoholic aqueous solution or suitable solvents containing the appropriate acid and isolating the salt. evaporating the solution, or by reacting the free base and the acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution. Among the acids suitable for use in the preparation of these salts are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, various organic carboxylic and sulphonic acids, such as acetic acid, citric acid, propionic acid, succinic acid, acid benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid, methanesulfonic acid, toluenesulfonic acid, fatty acids, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, cyclopentane propionate, digluconate, dodecylsulfate, bisulfate, butyrate, lactate, laurate, lauryl sulfate, malate, hydroiodide, 2hydroxyethanesulfonate, glycerophosphate, picrate, pivalate, pamoate, pectinate, persulfate, 3-phenylpropionate, thiocyanate, 2-naphthalenesulfonate, undecanoate, nicotinate, hemisulfate, heptonate, hexanoate, camphorate, camphersulfonate and others.

  The acid addition salts of the compounds useful according to this invention can be regenerated from the salts by the application or adaptation of known methods. For example, parent compounds useful according to the invention can be regenerated from their acid addition salts by treatment with an alkali, for example an aqueous sodium bicarbonate solution or an aqueous ammonia solution.

  The compounds useful according to this invention can be regenerated from their base addition salts by the application or adaptation of known methods. For example, parent compounds useful according to the invention can be regenerated from their base addition salts by treatment with an acid, for example hydrochloric acid.

  The base addition salts may be formed when the compound useful according to the invention contains a carboxyl group, or a sufficiently acidic bioisosteric acid. The bases which can be used to prepare the base addition salts preferably include those which, when combined with a free acid, produce pharmaceutically acceptable salts, i.e. salts whose cations are not toxic to the patient in the pharmaceutical doses of the salts, so that the beneficial inhibitory effects inherent in the free base are not nullified by the cation-attributable side effects. Pharmaceutically acceptable salts, including those derived from alkaline earth metal salts, within the scope of the invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide , lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methylglucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) amino methane, tetramethylammonium hydroxide and the like.

  Compounds useful in the present invention can be easily prepared, or formed during the process of the invention, as solvates (e.g., hydrates). The hydrates of the compounds useful according to the present invention can be easily prepared by recrystallizing an aqueous / organic solvent mixture, using organic solvents such as dioxan, tetrahydrofuran or methanol.

  The base products or reagents used are commercially available and / or may be prepared by the application or adaptation of known methods, for example processes as described in the Reference Examples or their obvious chemical equivalents.

  According to another object, the present invention also relates to the compounds of formula (I) as a medicament. The present invention thus relates to pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier or excipient.

  According to one object of the present invention, the compounds of formula (I) exhibit an inhibitory activity for the proliferation of smooth muscle cells.

  According to a first aspect, the present invention therefore relates to the use of a compound of general formula (I) for the preparation of pharmaceutical compositions intended to inhibit the proliferation of smooth muscle cells.

  According to a second aspect, the present invention relates to the use of a compound of general formula (I) for preventing and / or treating vascular pathologies related to the proliferation of smooth muscle cells.

  According to another aspect, the present invention relates to the use of a compound of general formula (I) for preventing and / or treating a pathology chosen from atherosclerosis, restenosis or stenosis.

  In another aspect, the present invention relates to the use of a compound of general formula (I) for preventing and / or treating any complication related to angioplasty with or without stent, bypass surgery or transplantation.

  According to another object of the present invention, the compounds of formula (I) exhibit an antioxidant and NO generating activity.

  According to a first aspect, the present invention therefore relates to the use of a compound of general formula (I) for the preparation of pharmaceutical compositions for inhibiting oxidative radical species and generating NO.

  According to a second aspect, the present invention relates to the use of a compound of general formula (I) for preventing and / or treating pathologies related to a lack of NO production and / or an increase in tissue oxidative stress.

  According to another aspect, the present invention relates to the use of a compound of general formula (I) for preventing and / or treating a pathology chosen from atherosclerosis, restenosis, stenosis, hyperglycemia, insulin resistance, diabetes, dyslipidemia, retinal vascular and / or renal complications of diabetes, hypoxia, inflammatory processes, cardiovascular diseases, joint pathologies, male erectile dysfunction, smoking.

  The pharmaceutical compositions according to the invention may be presented in forms intended for parenteral, oral, rectal, permucous or percutaneous administration.

  They will therefore be presented in the form of injectable solutes or suspensions or multi-dose vials, in the form of naked or coated tablets, coated tablets, capsules, capsules, pills, cachets, powders, suppositories or rectal capsules. , solutions or suspensions, for percutaneous use in a polar solvent, for permselective use.

  Suitable excipients for such administrations are derivatives of cellulose or microcrystalline cellulose, alkaline earth carbonates, magnesium phosphate, starches, modified starches, lactose for solid forms.

  For rectal use, cocoa butter or polyethylene glycol stearates are the preferred excipients.

  For parenteral use, water, aqueous solutes, physiological saline, isotonic solutes are the most conveniently used vehicles.

  The dosage may vary within the important limits (0.5 mg to 1000 mg) depending on the therapeutic indication and the route of administration, as well as the age and weight of the subject.

  The following examples are given by way of non-limiting illustration of the present invention.

EXAMPLES

  1. Synthesis of the compounds according to the invention: Preferably, the process according to the invention can be carried out by application or adaptation of the various routes presented above under the following operating conditions, where are mentioned by way of indication Ra-Re which represents any suitable substituent, Z which represents a carbon, nitrogen or oxygen atom, Gr which represents an optionally substituted aryl group and p represents 0 or 1.

Track 1 Rb

HO HO NHZOH Rb

OH

OH i Rb

Way 2

OH

NH2OH to EtONO N INN2

O O

OH

Way 3

O H2 Hal

R

OH tBuON0 Ra Way 4 R2.O x

O

OJJ N--. R2 n R2 n

H

  H2N-NH2 tBuONO H4N + ROUTE 1 Formation of oxime Reagent: NH4Cl Base: pyridine Solvent: EtOH Temperature: ambient Duration: 10 to 12h Reduction of oxime Reagent: NaCNBH3 3.03 eq.

  Acid: HCl Solvent: ethanol Temperature: ambient Duration: 3h to 16h Nitrosation Reagent: tert-butyl-nitrite Catalyst: NH3 Solvent: Ether Temperature: 0 C to ambient CHANNEL 2 Alkylation with halide Reagent: 1,2eq halide Base: CS2CO3 1,1 eq . Catalyst: KI Solvent: acetone Temperature: reflux Time: 1h to 12h Formation of oxime Reagent 1: DIBAL 1, 2 eq Reagent 2: NH4Cl 3, eq. Solvent: THF Temperature: ambient Duration: 3h to 6h Reduction of oxime Reagent: NaBH4 3 eq. Acid: HCl 3N Solvent: ethanol Temperature: ambient Duration: 3h to 12h Mono Nitrosation Same as route 1 Di-Nitrosation Reagent: EtONO 10 eq Solvent: DCM Temperature: 0 C to ambient Time: 1 h CHANNEL 3 Coupling reaction Reagent: aryl halide Base: CS2CO3 or tBuONa or tBuOK Catalyst: Pd2 (dba) 3 2.5% M eq Ligand: racemic BINAP 7.5% M eq.

  Solvent: diglyme Temperature: 80 to 130 C Duration: 6 to 12 h Reduction of the ester Reagent: DIBAL 3.3 eq Solvent: THF Temperature: -78 C to ambient Duration: 2h to 4h Coupling reaction with the protected hydroxylamine Reagent 1 : tert-butyl N- (tert-butoxycarbonyloxy) carbonate 2 eq Reagent 2: DBAD 1.5 eq Reagent 3: triphenylphosphine 1.5 eq Solvent: THF Temperature: 0 C to ambient Duration: 4 h to 6 h Deprotection BOC Reagent: TFA or HCI Solvent: DCM or Dioxane Temperature: ambient Duration: 5 min to 2 hours Nitrosation Same as channel 1 CHANNEL 4 Coupling reaction with protected hydroxylamine Same as route 3 Formation of hydroxamic acid Reagent: hydrazine hydrate Solvent : MeOH DCM Temperature: reflux Time: 30 min Formation hydrazone Reagent: aldehyde Base: pyridine Solvent: EtOH Temperature: ambient Duration: 10 to 12 h Deprotection of BOC Idem route 7 Nitrosation Same as route 1 Route 1 Examples 20, 21 and 22: 3 , 5-Di-tert-butyl-4-hydrixy-benzaldehyde oxime (20) Chlorine 3 g of hydroxylammonium (90 mmol, 6.25 g) is dissolved in 50 ml of ethanol and then 3,5-di-tert-butyl-4-hydroxybenzaldehyde (30 mmol; 7.3 g) and pyridine 3 eq (90 mmol, 7.3 ml) dissolved in 400 ml of ethanol are added. The reaction medium is stirred at room temperature for 16 hours.

  The reaction medium is evaporated to dryness, taken up in H 2 O and extracted with dichloromethane. The organic phase is washed (twice), dried over Na 2 SO 4 and evaporated to dryness. The oil obtained is dispersed in hexane, filtered and dried.

  The product is chromatographed on silica (elution hexanelAcOEt 7: 1). The product obtained is then recrystallized from hexane to give 3.94 g of white crystals after drying.

  Yield = 52.7% 1H NMR (CDCl3) = 8.00 (1H, s); 7.80 (1H, s); 7.30 (2H, s); 5, 35 (1H, s exchangeable); 1.40 (18H, s).

  2,6-Di-tert-butyl-4-hydroxyaminomethylphenol (21) 3,5-Di-tert-butyl-4-hydroxybenzaldehyde oxime (8 mmol, 2 g) is dissolved in 100 ml of ethanol and sodium cyanoborohydride 3.03 eq (24.2 mmol, 1.52 g) is added. The pH of the solution is kept below 3 by addition of 3N HCl / EtOH solution.

  After 3 hours at room temperature, the reaction medium is left standing for 12 hours and then the solution is basified with 10% NaOH (pH z, 9-10). The solution is evaporated to dryness and the residue is taken up in ethyl acetate, washed with water (3 times), dried over Na 2 SO 4 and evaporated to dryness. The crude is taken up in CH 2 Cl 2 and evaporated to dryness to give 2 g as an oil.

Yield = quantitative.

  1H NMR (DMSO-d6) = 1.36 (18H, s); 3.73 (2H, $); 5.76 (1H, brs); 6.76 (1H, brs); 7.04 (2H, $); 7.19 (1H, s).

  Ammonium salt of [(2,6-di-tert-butyl-4-hydroxyaminomethyl) -N-nitroso] phenol (22) The dry residue is taken up in anhydrous ether. The reaction medium is cooled to 0 ° C. and then NH 3 gas is bubbled through.

  TBu ONO 1.5 eq is added dropwise. The reaction medium is stirred for 1 h at 0 ° C. The precipitate is filtered and washed with ether and then dried to give the expected product.

Yield = 18.5%.

  1H NMR (DMSO-d6) = 1.36 (18H, s); 3.08-3.59 (4H, brs); 3.29 (2H, $); 7.11 (2H, $).

Route 2 Examples 29, 30, 31 and 32: 2- (4-Phenylamino-phenoxymethyl) -benzonitrile (29a) 4-Phenylaminophenol (3.7 g, 20 mmol) is dissolved in 75 ml of acetone and then Cs2CO3 1.1 eq (22 mmol, 7.17 g), 2-bromomethylbenzonitrile 1.2 eq (24 mmol, 4.7 g) and 1 KI crystal are added.

  The reaction medium is refluxed for one hour, then is filtered and rinsed with acetone. The organic phases are combined and evaporated to dryness. The residue is taken up in ether, washed with water (3 times). The organic phase is dried over Na 2 SO 4, evaporated to dryness and then chromatographed on silica gel (elution AcOEt / Hexane 1: 5) to give 4.85 g of the expected product.

  Yield = 80.8 TLC: AcOEt / hexane 1: 3 Rf = 0.34 1H NMR (CDCl3) = 6.6-7.6 (13H, m); 5.80 (1H, s exchangeable); 5.10 (2H, s).

  2- (4-Phenylamino-phenoxymethyl) -benzaldehyde oxime (29) 2- (4-Phenylamino-phenoxymethyl) -benzonitrile (510 mg, 1.7 mmol) is dissolved in 5 ml of anhydrous dichloromethane under an inert atmosphere. The 1.0 M DIBAL in 1.2 g of THF (2 mmol, 2 ml) is added dropwise, the reaction medium is left at ambient temperature for 1 h 30, and then the hydroxylammonium chloride 3 eq (51 mmol 350 mg) is added.

  The reaction medium is left at ambient temperature for 1 h 30, then filtered and evaporated to dryness. The residue is taken up in ether and filtered. The ether phase is washed with water, dried over Na 2 SO 4, evaporated to dryness and chromatographed (eluting CH 2 Cl 2 / hexane 3: 1) to give 83 mg of oxime.

  Yield = 15.3% TLC: AcOEtlhexane 1: 3 Rf = 0.4 1H NMR (CDCl3) = 5.18 (2H, δ), 5.57 (1H, brs); 6.68-7.79 (14H, m); 8.42 (1H, $).

  N- [2- (4-Phenylamino-phenoxymethyl) -benzyl] -hydroxylamine (30) 2- (4-Phenylamino-phenoxymethyl) -benzaldehyde oxime (1.15 g: 3.6 mmol) is dissolved in 40 ml of ethanol then sodium borohydride 3 eq (10.8 mmol, 690 mg) is added. The reaction medium is left stirring for 3 hours while maintaining the pH <3 by addition of 3N HCl in ethanol, followed by stirring for 12 hours.

  The reaction medium is evaporated to dryness, taken up in AcOEt, washed with water (twice), dried over Na 2 SO 4 and evaporated to dryness. The crude is chromatographed on silica gel (CH 2 Cl 2 elution with CH 2 Cl 2 / AcOEt 9: 1) to give 690 mg of hydroxylamine.

  Yield = 60H NMR (CDCl3) = 4.14 (2H, s); 5.11 (2H, s); 5.50 (1H, brs); 6.65-7.63 (13H, m) N-Nitroso-N- [2- (4-phenylaminophenoxymethyl) -benzyl] -hydroxylamine ammonium salt (31) Same as lane 1: Yield = 50% 1H NMR ( DMSOd6) = 5.19 (2H, s); 5.26 (2H, $); 5.86 (4H, brs); 6.58-7.59 (13H, m); 7, 84 (1H, $).

  N- [2- (4-Phenyl nitrosamine-phenoxymethyl) -benzyl] -N-nitroso-hydroxylamine (32) N- [2- (4-Phenylamino-phenoxymethyl) -benzyl] -hydroxylamine (500 mg; mmol) is dissolved in 50 ml of dichloroethane and is placed at 0 C.

  Ethyl nitrite 10 eq (156 mmol, 9.6 ml) is added dropwise and the reaction mixture is stirred for 1 hour. The reaction medium is evaporated to dryness and the oil obtained crystallizes in the cold state to quantitatively give the expected product.

  1H NMR (DMSOd6) = 5.03-5.80 (4H, m); 6.88-7.78 (14H, m); 12.83 (1H, brs).

Route 3 Examples 36, 37 and 38: Ethyl 5 - [(4-methoxy-phenyl) - (4-nitro-phenyl) -amino] -pentanoate (36a) 1-Bromo-4-nitro-benzene (10) mmol, 2.02 g), ethyl 5- (4-methoxyphenylamino) pentanoate 1.05 eq (10.5 mmol, 2.64 g) (prepared according to the method described in Journal of Medicinal Chemistry, 1983 26 ( 10) 1418), Pd2 (dba) 3 2.5% Meq (0.25 mmol, 229 g), racemic BINAP 7.5% Meq (0.75 mmol, 467 mg), Cs 2 CO 3 1, 4 eq (14 mmol, 4.56 g) are dissolved in 30 ml of dry diglyme under an inert atmosphere.

  The reaction medium is brought to 100 C for 6 hours and then left for 12 hours at room temperature. The reaction medium is poured into water and then extracted with ether (3 times). The ethereal phases are combined, washed with water (2 times), dried over Na 2 SO 4, evaporated to dryness and chromatographed on silica gel (AcOEt / hexane elution 1: 2 Rf = 0.48) to give 3.15 g.

Yield = 84.7%.

  1H NMR (CDCl3) = 6.45-7.95 (8H, m); 3.80 (3H, s); 3.60 (4H, m); 1.65 (2H, m); 1.55 (2H, m); 1.50 (1H, s exchangeable); 1.4 (2H, m).

  5 - [(4-Methoxy-phenyl) - (4-nitro-phenyl) -amino] -pentan-1-ol (36b) 5 - [(4-Methoxy-phenyl) - (4-nitro-phenyl) -amino] ethylpentanoate (3.5 mmol 1.3 g) is dissolved in 13 ml of anhydrous THF under an inert atmosphere and is placed at -78.degree. C., then the 1M DIBAL in THF is treated with 3.3 eq (11%), 6 mmol, 11.6 mol) is added dropwise.

  The reaction medium is allowed to return to 0 C over 2H. The reaction medium is again cooled to -78 ° C. and 4 ml of water are slowly added while allowing to return to ambient temperature. AcOEt and excess NaHCO 3 are then added, the mixture is left stirring for 15 minutes, and the reaction medium is then filtered through Celite.

  The organic phase is dried over Na 2 SO 4 and then evaporated to dryness. The crude is chromatographed on silica gel (CH 2 Cl 2 elution) to give 740 mg of orange oil.

  Yield = 64% TLC: AcOEt / hexane 1: 1 Rf = 0.27 1H NMR (CDCl3) = 6.3-8.2 (8H, m); 3.8 (3H, s); 3.5-3.7 (4H, m); 1.3-1.8 (6H, m); 1.25 (1H, s exchangeable).

  N- (tert-Butoxycarbonyl) -N- (5- [4-methoxy-phenyl) -4-nitro-phenyl) -amino] pentyl} -O- (tert-butoxycarbonyl) -hydroxylamine (36) 5- [ (4-Methoxyphenyl) - (4-nitro-phenyl) -amino] -pentan-1-ol (897 mg, 2.72 mmol) is dissolved in 27 ml of anhydrous THF under an inert atmosphere, followed by triphenylphosphine 1, 5 eq (4.08 mmol, 1.07 g) and tert-butyl N (tertbutoxycarbonyloxy) carbonate 2 eq (5.4 mmol, 1.27 g) are added. The reaction medium is placed at 0 ° C. and the DBAD 1.5 eq (4.08 mmol, 938 mg) is added. The reaction medium is stirred at room temperature for 4 hours. The reaction medium is evaporated to dryness and the crude is chromatographed on silica gel (CH 2 Cl 2 elution) to give the expected product quantitatively.

  TLC: AcOEtlhexane 1: 2 Rf = 0.48 1H NMR (CDCl3) = 1.18-1.78 (24H, s); 3.43-3.78 (4H, m); 3.84 (3H, s); 6.40-6.59 (2H, m); 6.89-7.20 (4H, m); 7,878.14 (2H, m) 5 - [(4-Methoxy-phenyl) - (4-nitro-phenyl) -amino] -pentyl) -hydroxylamine (37) N- (tert-Butoxycarbonyl) -N- {5 - [4-methoxy-phenyl) - (4-nitro-phenyl) -amino] -pentyl} -O- (tert-butoxycarbonyl) -hydroxylamine (1.48 g, 2.72 mmol) is dissolved in 10 ml dichloromethane then trifluoroacetic acid (10 ml) is added dropwise. The reaction medium is left stirring for 30 minutes at ambient temperature and is then evaporated to dryness.

  The crude product is taken up in dichloromethane, washed with saturated NaHCO 3 solution, dried over Na 2 SO 4 and evaporated to dryness to give 920 mg of the expected hydroxylamine in the form of an orange oil.

  Yield = 97.9% TLC: MeOH / AcEOtICH 2 Cl 2 2: 4: 4 Rf = 0.52 1 H NMR (DMSOd 6) = 1.19-1.73 (6H, m); 2.59-2.78 (2H, m); 3.59-3.75 (2H, m); 3.79- (3H, s); 5. 58 (1H, brs); 5.75 (1H, $); 6.47-6.75 (2H, m); 6.89-7.39 (4H, m); 7.84-8.14.

  N-Nitroso-N- (5 - [(4-methoxy-phenyl) - (4-nitro-phenyl) amino] -pentyl) hydroxylamine ammonium salt (38) Same as lane 1 Yield = 57.6% 1H NMR (DMSOd6) = 1.17-1.93 (6H, m); 3.56-3.74 (2H, m); 3.79 (3H, $); 3.91-4.09 (2H, m); 6.48-6.73 (2H, m); 6.93-7.30 (4H, m); 7.79-8.16 (2H, m).

  Route 4 Examples 42 and 43: {4- [N, -bis- (tert-Butyloxycarbonyl) hydroxyaminomethyl] -phenoxy}} -methyl acetate (42a) Idem Route 3: N (tert-Butoxycarbonyl) -N- (5- [4-methoxy-phenyl) -4-nitro-phenyl) -amino] pentyl} -O- (tert-butoxycarbonyl) -hydroxylamine Yd = 50% 1H NMR (CDCl3) = 6.6-7.4 (4H, m.p. m); 4.60 (2H, s); 4.56 (2H, s); 3.75 (3H, s); 1.4 (18H, s).

  {4- [N, O-Bis- (tert-Butyloxycarbonyl) -hydroxyamino-methyl] -25-phenoxy} -acetic acid hydrazide (42b) {4- [N, O-bis (tert-Butyloxycarbonyl) hydroxyaminomethyl} ] -phenoxy} -methyl acetate (500 mg, 1.2 mmol) is dissolved in 15 ml of CH 2 Cl 2 / MeOH 2: 1, and then the hydrazine monohydrate (1 ml) is added. The reaction medium is refluxed for 1 hour, then evaporated to dryness and chromatographed on silica gel (CH 2 Cl 2 elution) to give 370 mg of the expected product.

  Yield = 75% 1H NMR (CDCl3) = 7.8 (1H, s exchangeable); 6.6-7.4 (4H, m); 4, 6 (2H, s); 4.45 (2H, s); 3.8 (2H, s exchangeable); 1.4 (18H, s).

  {4- [N, O-bis- (tert-Butyloxycarbonyl) -hydroxyaminomethyl] phenoxy} -acetic acid hydrazide and benzylidene (42c) {4- [N, O-bis- (tert) acid hydrazide -Butyloxycarbonyl) -hydroxyaminomethyl] -phenoxy} -acetic acid (272 mg, 0.66 mmol) is dissolved in 10 ml of a 9: 1 EtOH / pyridine mixture and then the benzaldehyde is 1.5 eq (1 mmol, 106 mg). ) is added. The reaction medium is stirred for 12 hours and then evaporated to dryness.

  The crude product is taken up in CH 2 Cl 2, washed with saturated NaHCO 3 solution, dried over Na 2 SO 4, evaporated to dryness and then chromatographed on silica gel (elution with a 0-20% CH 2 Cl 2 / MeOH gradient) to give 189 mg of the expected product.

  Yield = 57.3% 1H NMR (DMSO-d6) = 6.8-7.8 (10H, m); 5.9 (1H, s exchangeable); 4.8 (2H, s); 4.6 (2H, s); 1.35 (18H, s).

  (4-Hydroxyaminomethyl-phenoxy-acetic acid and benzylidene acid hydrazide (42) Idem route 3: 5 - [(4-Methoxy-phenyl) - (4-nitro-phenyl) amino] -pentyl) -hydroxylamine Yield = 90 1H NMR (DMSO-d6) = 4.10-5.45 (4H, m); 6.80-7.26 (3H, m); 7.26-7.81 (7H, m); 10.85-11.82 (3H, brs).

  Ammonium salt of [N-Nitroso- (4-hydroxyamino-methyl) -25-phenoxy] -acetic acid hydrazide and benzylidene (43) Idem route 1 Yield = 27 1H-NMR DMSOd6) = 4.47 and 4 , 66 (2H, 2s); 5.01 (2H, $); 6.73-7.07 (2H, m); 7.20-7.56 (5H, m); 7.57-7.81 (2H, m); 8.00 (1H, $) The following compounds according to the invention were prepared by application or adaptation of one or the other of the routes presented above.

  Structure N NMR (Acetone-d6) = 3.78 (3H,)), 3.93 S (2H,)); 5.64 (1H, brs); 6.53 (1H, s, broad HN'OH, 6.78-7.04 (6H, m), 7.21-7.39 (2H, m)) (DMSO-d6) = 3.74 (3H); , $); 4.97 (2H, s) N: o 2; 6.22 (4H, very broad); 6.79-7.11 N, o NH (6H, m); 7.22-7.42 (2H, m) (Acetone-d6) = 3.69 (3H, s); 4.86 o S 3 (2H, $); 6.82-6.91 (2H, m); 6, 94-7.04 HN-OH (2H, m); 7.17-7.35 (4H, m); (DMSO-d6) = 3.77 (3H, s); 5.00 4 (2H, $); 6.92-7.21 (4H, m); 7.24-7.47 NH 4 α, N (4H, m); 7.24-7.47 (4H, m) N0 N / aH (DMSO-d6) = 3.77 (3H, s); 3.80 (3H, $); 4.18 (2H, $); 6.44-6.71 (2H, m); H, 7.19-7.44 (1H, m); 10.83 (1H, brs); 11.35 (2H, brs) DMSO-d6) = 3.75 (3H, s); 3.76 (3H, s); NH? 6.49 (2H, s); 5.62 (4H, brs); 6.42-6.66 (2H, m); 7.07-7.27 (1H, m) (DMSO-d6) = 3.77 (2H, s); 5.07N / 7H (2H, s); 5.84 (1H, brs); 6.85-6.97 el (2H, m); 7.14-7.48 (8H, m) NO (DMSO-d6) = 5.04 (2H, s); 5.10 o, N 8 (2H, s); 6.84-7.11 (2H, m); 7.16-7.53 o NH (6H, m) (DMSO-d6) = 0.83-1.01 (2H, m); 1.30-N, OH 1.56 (2H, m); 1.56-1.81 (2H, m); 3.81 (2H, δ), 6.81-7.13 (2H, m), 7.17-7.56 (2H, m.p. m), 10.86 (1H, brs), 11.54 (2H, brs) (DMSO-d6) = 0.76-1.07 (3H, m), 1.28-N 1.55 (m.p. 2H, m), 1.55-1.80 (2H, m), 3.84-4 NH 4 4.06 (2H, m), 4.94 (2H, s), 6.54-7; 57 (8H, m) (DMSO-d6) = 3.76 (2H, s); 5.89 (1H, as broad as); 5.95 (2H, $); 6.66-6.97 (3H, m); 7.21 (1H, brs) (DMSO-d6) = 4.91 (2H, s); 5.99 NH 4 (2H, br); 6.74-7.00 (3H, m) No (DMSO-d6) = 3.72 (3H, s), 3.76 (3H, s), H 3.77 (3H, s), 3; 79 (2H, s), 5.71 (1H, brs), 6.65-6.81 (1H, m), 6.95-7.07 (1H, m), 7.25 (1H, m.p. O (DMSO-d6) = 3.73 (3H, s), 3.76 (3H, s), NH 3, 78 (3H, s), 4.99 (2H, s), 6.56 (b), 4H, s 14 1 large), 6.74-6.89 (1H, m), 6.95-7.14 (1H, m) N (DMSO-d6) = 2.12 (3H, s); , 76 (3H, s), N NH 1 δ 4.88 (2H, s), 6.63 (4H, brs), 6.81-6.97 (1H, m), 7.02-7. 23 (2H, m) NH (DMSO-d6) = 3.71 (3H, s); 3.73 (3H, s); 3.78 (2H, s); 5.87 (1H, ss); 6.73-7.04 (3H, m), 7.21 (1H, brs) (DMSO-d6) = 3.72 (6H, br), 4.05 (4H, m.p. 4.93 (2H, s); 6.64-7.17 (2H, m) N-OH (DMSO-d6) = 3.78 (2H, s); 3.80 (2H, m.p. $), 5.97 (1H, brs), 6.97-7.34 (4H, m) NH NH NH 19 (DMSO-d6) = 3.81 (3H,)), 4.94 (2H, $); NN 6.23 (4H, brs); 7.01-7.31 (3H, m);

F O-

  (DMSO-d6) = 1.45 (18H, s); 5.43 HOL (1H, s); 7.39 (1H, $); 7.89 (1H, $); 8.07 ", OH (1H, δ) (DMSO-d6) = 1.36 (18H,)), 3.73 HO Ç (2H,)), 5.76 (1H, brs), 6, 76 (1H, br H); 7.04 (2H, $); 7.19 (1H, s);

OH

  (DMSO-d6) = 1.36 (18H, s); 3.08-3.59 HO Ç NH 22 (4H, brs); 3.29 (2H, $); 7.11 (2H, s) (DMSO-d6) = 1.36 (18H, s); 2.79-2.96 OH 23 (2H, m); 3.31 (2H, $); 3.94-4.19 (2H, m); 5.85 (1H, brs); 6.66-6.90 (3H, m) 7.01 (2H, br); 7.09-7.27 (3H, m) (DMSO-d6) = 1.4 (18H, s); 2.9 (2H, t, J O = 7.0 Hz); 3.2 (3H, $); 4.1 (2H, t, J = 11H-N, 24 Hz), 4.3 (2H, δ), 6.7 (1H, δ), 6.9 (2H, d, J); = 7.7 Hz), 7.0 (2Hs), 7.2 (2H, d, J = 8.7 Hz) N (DMSO-d6) = 3.24 (2H, s), 3.36 and 3.37 (3H, 2s), 6.65-6.85 (2H, m), 7.13-N OH 7.63 (4H, m), 7.93-8.17 (2H, m) (m.p. CDCl3) = 3.28 (3H, s), 3.82 and 3.84 "-OH (3H, 2s); 6.60-7.20 (6H, m); 7.34-7.47 (2H, m); 8.02 (1H, $) (CDCl3) = 3.23 (3H, s); 3.80 (3H, $); 3.92 (2H, $); 5.06 (2H, brs); 6.38 OH 6.97 (4H, m); 6.98-7.22 (4H, m) (DMSO-d6) = 3.17 (3H, s); 3.74 (3H, $); ## STR2 ## 4.88 (2H, s), 5.42-6.60 (4H, brs), 6.60-6.80 (2H, m), 6.83-7, 39 (6H, m) OH (CDCl3) = 5.18 (2H, s), 5.57 (1H, sH29 wide), 6.68-7.79 (14H, m), 8.42-1 (1H, s) OH (CDCl3) = 4.14 (2H, s); 5.11 (2H, s); H, 5.50 (1H, brs); 6.65-7.63 (13H, m) (DMSOd6) = 5.19 (2H, s); 5.26 (2H, $); N * O N NH N, where 5.86 (4H, brs); 6.58-7.59 (13H, m); Δ 7.84 (1H, s) (DMSOd6) = 5.03-5.80 (4H, m); 6.88- N 'OH 7.78 (14H, m); 12.83 (1H, bs) N32H (CDCl3) = 1.24-1.96 (6H, m); 2.12- "OH 2.48 (3H, m), 3.31-3.48 (1H, m), 3.78-33 4.07 (2H, m), 6.64-7.24; 1H, m), 7.34-7.52 (1H, m) H (CDCl3) = 1.28-1.97 (10H, m), 2.83- N 3.05 (2H, m); , 84-4.04 (2H, m), 5.47 (34H, bs), 6.75-7, 24 (9H, m) H (CDCl3) = 1.00-2.25 (10H, m), 3.29-4.0N0 3.69 (2H, m), 4.07-4.53 (2H, m), 6.72-7N, 7.23 (6H, m). 7.27-7.52 (3H, m) N1- (CDCl3) = 1.18-1.78 (24H, s); 3.43-O, 3.78 (4H, m); , 84 (3H, δ), 6.40-6.59 (36H, m) 6.89-7.20 (4H, m), 7.87-8.14 X (2H, m). (DMSOd6) = 1.19-1.73 (6H, m); 2.59-2.78 (2H, m); 3.59-3.75 (2H, m); 3.79 to 37 (3H, s); 5.58 (1H, brs); 5.75 (1H, $); o 6.47-6.75 (2H, m); 6.89-7.39 (4H, m); 7.84-8.14 (DMSO-d6) = 1.17-1.93 (6H, m); 3.56 N N N 3.74 (2H, m); 3.79 (3H, $); 3.91-4.09 N NH? + (2H, m) 6.48-6.73 (2H, m); 6.93-7.30 o N N ((4H, m) 7.79-8.16 (2H, m) (DMSO-d6) = 3.73 and 53.75 (3H, 2s); N, N, 4.67 (2H, $); 5.08 (2H, $); 6.32-6.61 o / o N / N 39 (2H, m); 6.77-7.15 (3H, m); 7.23-7.53 OH (3H, m) 8.20 (1H, brs), 8.45 (1H, brs) N (DMSO-d6) = 4.31-5.27 (4H, m) ); 6.76- / N-N NH 7.63 (6H, m); 7.75-8.97 (3H, m); 11.74 N-N 40 (1H, s) n (DMSO-d6) = 4.28-5.47 (4H, m); 6.74 N N, 8.69 (8H, m); 11.47-12.03 (3H, s wide) o to HO 0 41

N -M

OH

  H (DMSO-d6) = 4.10-5.45 (4H, m); 6,80-

HO-N

  N, N 7.26 (3H, m); 7.26-7.81 (7H, m); 10.85-11.82 (3H, brs) (DMSO-d6) = 4.47 and 4.66 (2H, 2s); N +) 5.01 (2H, s); 6.73-7.07 (2H, m); 7.20 - / NH, N, o, 7.56 (5H, m); 7.57-7.81 (2H, m); 8.00 (1H, s) (DMSO-d6) = 4.25 (2H, s); 4.65 and 44.47 (2H, 2s); 6.67-8.22 (12H, m); H-OH 10.72-11.60 (2H, brs) (DMSO-d6) = 3.46 (5H, brs); 4.47 N- and 4.64 (2H, 2s); 5.03 and 5.04 (2H, 2s); NH N, N-o6, 77-8.22 (12H, m) 2. Increasing nitric oxide content A solution of a compound of the invention spontaneously releases nitric oxide. The resulting nitrite ions are titrated by colorimetry using a specific reagent (Griess). To take into account the possible release of nitrate ions in addition to nitrites, bacterial nitrate reductase is added to the reaction medium, which makes it possible to reduce the nitrate ions formed.

  The reactions and measurements are made in transparent 96-well plates. The products to be tested are dissolved extemporaneously at a concentration of 3 mM in dimethylsulfoxide. 95 μl of a reagent containing the nitrate of the solution of the product to be tested (final concentration of 150 μM) are then introduced into each well. After stirring, it is incubated for 4 hours at 37 ° C. The reaction is then stopped by the addition of 100 μl of Griess reagent (Sigma G4410). Allowed to act for 5 minutes at room temperature, then read the optical density at 540 nm. This value is proportional to the concentration of nitrite + nitrate in the medium. A calibration range is made at each plate from NaNO2.

  The results in Table A are expressed in pmolesII (pM) of released nitrites + nitrates.

  3. Decrease in the biological activity of oxidative radical species Human LDLs dissolved in aqueous solution in the presence of cupric ion spontaneously oxidize on their protein component, apolipoprotein-B. This oxidation makes the particle fluorescent, which is used to measure a pharmacological effect.

  Reactions and measurements are made in 96-well black plates. 10 μl of a solution of the test product dissolved in dimethylsulfoxide is first mixed with 170 μl of a solution of human LDL at 120 μg / ml and 20 μl of 100 μM CuCl 2. After stirring, the mixture is incubated for 2 hours at 37 ° C., and a first fluorescence reading is carried out (excitation at 360 nm, reading at 460 nm). It is then allowed to incubate again for 22 hours, to carry out a second reading under the same conditions. The difference is even lower than the tested product has an antioxidant power. Probucol is used as a reference product at 10 μM.

  The percentage of inhibition at 10 M and the inhibitory concentrations of 50 (Cl 50) of the oxidation are carried out starting from 3 product concentrations. They are reported in the following Table A.

Table A

  EXAMPLE Structure Effect Antioxidant Effect: Antioxidant: With IC50 (pM) inhibition at 10 μM N-0

H

31 N N99 5.4 N 'HQ 32 N cl 33

I I

   N, N, N, B 5.7 NO. N Hy Nâ O "

39 N-N 91 7.2 HO 0 É -NH

OH

41 N-N 44 9.8 'o HO O / N-NH

OH

  4. Inhibition of smooth muscle cell proliferation The proliferation of muscle cells is assessed by DNA synthesis which is measured by the incorporation of tritiated thymidine into the DNA of the cells.

  Human smooth muscle cells are from PromoCell (Heidelberg, Germany). They are thawed at 37 ° C. for 3 minutes and are immediately placed in a culture medium containing growth factors (PromoCell: basal medium supplemented with fetal calf serum (5%), epidermal growth factor (10 ng / ml) fibroblast growth factor (2 ng / ml), dexamethasone (0.39 μg / ml), amphoterine (50 ng / ml), gentamycin (50 μg / ml)).

  For the experiment, the smooth muscle cells are placed in culture plates 24 and then treated with collagen at a rate of 4x104 cells per well in 500 μl of medium.

  After 24 hours of incubation, the medium (500 μl) is renewed and the products dissolved in dimethylsulfoxide (DMSO) are added to the cells so that the final concentration of DMSO does not exceed 0.2%. After 22 hours of incubation at 37 C, the medium containing the products is removed.

  The tritiated thymidine ([methyl 3H] -thymidine, Amersham, specific activity 70-86 Ci / mmol) is added to the cells so as to have 1 μCi per well in a volume of 500 μl. Incubation is continued for 6 hours. The radioactive medium is then removed and the cells are rinsed twice with phosphate buffer. The reaction is stopped by the addition of a 4 C solution of 5% trichloroacetic acid (TCA). After 15 minutes at 4 ° C., the TCA solution is removed. The precipitate in each well is solubilized by stirring for 3 minutes at room temperature with 500 μl of a 1.0% sodium dodecyl sulfate solution in 0.1 N NaOH containing 2% Na 2 CO 3. The tritiated thymidine present in the resolubilized sample is quantified by liquid scintillation counting.

* The results are expressed as percentage inhibition with respect to cells that received no product but only DMSO (0.2% final).

  The SNAP product used as a reference in the test spontaneously releases NO in aqueous solution and inhibits DNA synthesis and proliferation of vascular smooth muscle cells in culture. SNAP inhibits proliferation by about 80% at the concentration of 100 μM. The results expressed as% inhibition of the proliferation of smooth muscle cells are shown in Table B. Example Structure Inhibition of proliferation of smooth muscle cells (%) oH N NH, 68 o N 31 o 90 N *

H "

    NI N'H4 32 N * o OH 76

I I

  N N \ N% O 38 N 96 N v v Y N H H 4

O

39 Ho '"" "o 86 / N NH

OH

41 N N 41 CI o HO O NH aoleau

Claims (3)

1. Compounds of formula (I): O NOT I   (A) ,, - Ar- (X) - (Y) p N OH (I) wherein: wherein: Em is an integer from 0 to 3; É n is an integer chosen between 0 and 1; É p is an integer chosen between 1 and 7; X represents an oxygen atom -O-, a group -NR1- or, when n = 0, X represents a single bond; wherein R1 represents a hydrogen atom, a -Alkyl, -Aryle group, each optionally substituted by one or more group (s) selected from -OH, -Oalkyl, -CN, -NO2, perfluoroalkyl, -NR2R3 where R2 is H, -Alkyl and R3 is - Alkyl, -Aryle Y is -CH2-; É Ar represents a phenyl group; Ar is optionally substituted with 1 to 3 substituents A where E two of A may represent a phenyl fused heterocycle, such as benzodioxolane or where; Each of the A is independently a group selected from: E-OH; - CN; Hal; C1-C6alkyl, optionally substituted with one or more groups selected from -OH, -Oalkyl, -CN, -NO2, perfluoroalkyl, -NR2R3 wherein R2 represents H, -Alkyl and R3 represents -Alkyl , -Aryle; - Alkyl-O-Aryl where Aryl is optionally substituted by one or more group (s) chosen from -OH, -Oalkyl, -CN, -NO2, -perfluoroalkyl, - NR "2 R" 3 where R "2 is H, -Alkyl, -NO and R "3 is -Alkyl, -Aryl; Alkyl, optionally substituted by one or more groups selected from -OH, -Oalkyl, -CN, -NO2, -perfluoroalkyl, -NR2R3 wherein R2 is H, -Alkyl and R3 is -Alkyl, -Aryl; Alkyl Aryl, optionally substituted with one or more groups selected from OH, -Alkyl, -Oalkyl, -CN, -NO2, -perfluoroalkyl, -NR2R3 wherein R2 represents H, -Alkyl and R3 represents -Alkyl, aryl; -O-Aryl optionally substituted by one or more group (s) chosen from -OH, -Oalkyl, -CN, -NO2, -perfluoroalkyl, -NR'2R'3 where R'2 represents H, -Alkyle and R ' 3 represents -Alkyl, -Aryl, -C (= O) Alkyl, -C (= O) Aryl; -O (Alkyl) r-C (= O) -R7 where r is 0 or 1, R7 is -alkyl, -OR8, NR9R10; where R8 represents a hydrogen atom, an - Alkyl group; R9, R10 independently represent a hydrogen atom, an alkyl group, -Alkenyl, -N = alkyl, -N = alkenyl where the alkyl or alkenyl group is optionally substituted with one or more group (s) chosen from - Aryl, -Het, themselves optionally substituted by one or more group (s) chosen from a halogen atom, a -OH group, a -Alkyl group, -Oalkyl; Alkyl-O-RI1 wherein R11 represents a group -Alkyl, -Aryl optionally substituted with one or more group (s) chosen from OH, -Alkyl, -Oalkyl, -AlkylAryl, -C (= O) Alkyl, optionally substituted by one or more group (s) chosen from -Aryle, -Het; -C (= O) Alkenyl, optionally substituted with -Aryl, -Het; -C (= O) NR12R13, wherein R12, R13 independently represent a hydrogen atom, an - Alkyl group; o -N (NO) -Aryl, optionally substituted with one or more groups selected from OH, -Oalkyl, -CN, -perfluoroalkyl, -NR2R3 wherein R2 represents H, -Alkyl and R3 represents -Alkyl, aryl; -NR4R5 wherein R4 is H, Alkyl and R5 is -Alkyl, -Aryl, -AlkylAryl, where the -Ar1 group is optionally substituted with one or more groups selected from -OH, -Alkyl, -Oalkyl, -CN, -NO2, -perfluoroalkyl, -NR'2R'3 wherein R'2 is H, -Alkyl and R'3 is -Alkyl, -Aryl, -C (= O) Alkyl, -C (= O ) Aryl; -S (O) qR6 wherein q represents 0, 1 or 2, R6 represents a -Alkyl, -Aryl group each optionally substituted with one or more group (s) chosen from -OH, -Oalkyl, -CN, - NO2-, perfluoroalkyl, -Alkyl, -Oalkyl, -NR14R15, wherein R14, R15 are independently hydrogen, -alkyl, -C (= O) alkyl, -C (= O) aryl, -C ( Where in the latter three cases, Alkyl, Aryl and Het may be optionally substituted by one or more group (s) chosen from OH, -CN, OAlkyl, -NO2, -perfluoroalkyl, -NR2R3 where R2 is H, -Alkyl and R3 is -Alkyl, -Aryl; perfluoroalkyl; Het; -AlkyleHét; -OHet; or the corresponding salts, as well as enantiomers, diastereoisomers, racemic mixtures and pharmaceutically acceptable salts; with the exception of those compounds for which: 1) n = 0, p = 1, Ar represents a phenyl group, Y = -CH2-, and m = 0 or m = 1, and A represents group 4-tBu, 4- OMe, 4-Cl, 4-OH, 3-OH, 2-OH, 3-Cl, 2-F, 3-Me, 4-Me, 4-NMe 2, 4-CN, or m = 2, and A represents a 2,4-di OH or 2,5-di OH group; 2) n = 0, p = 3, Ar represents a phenyl group, Y = -CH2-, and m = 0.   Compounds according to claim 1 as represented by formula (I '): O NOT   (A) n, -Ar- (X) n- (Y) pNO-M + wherein A, Ar, X, Y, m, n, p are as defined in claim 1 and M + represents a cation 3. Compounds according to claim 2 such that M + is selected from NH4 + or the cation of an alkali metal.   4. Compounds according to claim 1 or 2, such that X represents a single bond, -O- or NR1- where R1 represents an optionally substituted Aryl group and A, Ar, Y, m, n, p are as defined according to US Pat. any preceding claim.   Compounds according to any one of the preceding claims, such that each of A is independently a group selected from E-S (O) q-R6, where q = O and R6 represents an Aryl group optionally substituted by one or more groups (s) chosen from -Oalkyl, E -Oalkyl, E -OalkylOR11, where R11 represents a group C (= O) Alkenyl where Alkenyl is optionally substituted with Het, or an -Aryl group optionally substituted by one or more groups (s) selected from OH, -Alkyl.   An Aryl group where Aryl is optionally substituted with one or more of O-alkyl, -NR4R5 where R4 is Alkyl and R5 is Aryl, optionally substituted by Alkyl, -Alkyl- O-Aryl wherein Aryl is optionally substituted with NR "2R" 3, wherein R "2 represents a hydrogen atom or a group -N = O, and R" 3 represents an Aryl group; --Alkyl Aryl, wherein Aryl is optionally substituted with one or more groups selected from -OH, -Alkyl; E -Oalkyl-C (= O) R7 where R7 is NR9R10 where R9 is H and R10 is -N = Alkyl or -N = Alkenyl where the group -Alkyl or -Alkenyl is optionally substituted with one or more groups selected from -Aryle , -Net, themselves optionally substituted by one or more group (s) chosen from alkyl, OH, -Hal.   And wherein two of the A's form with the phenyl a fused heterocycle, for example the dioxolane group.   6. Compounds according to any one of the preceding claims, such that p = 1, n = 0, Y, Ar, A, m are defined according to any one of the preceding claims.   Compounds according to claim 6, wherein Ar is Phenyl-, and m = 1 and A is O-Aryl where Aryl is optionally substituted with one or more of O-alkyl, S-Aryl optionally substituted with one or more -Oalkyl, and -N (Alkyl) -A-aryl is substituted by Alkyl, E -Alkyl-O-Aryl wherein Aryl is optionally substituted with NR "2R" 3, where R "2 and R "3 are defined as above, E -OalkylAryl, E -Oalkyl wherein Alkyl is C2-C6E -Oalkyl-C (= O) R7 where R7 is NR9R10 where R9 is H and R10 is -N = NAlkyl or -N = Alkenyl wherein the alkyl or alkenyl group is optionally substituted by one or more groups selected from -Aryle, -Het, themselves optionally substituted with one or more groups selected from alkyl, OH, -Hal, or m = 2, 3,  4 or 5 and each of A is independently selected from Alkyl, -Alkyl, -Hal, -OH, or wherein two of A form a heterocycle fused with phenyl, for example benzodioxolane.   Compounds according to any one of the preceding claims, such that p = 1, n = 1 and Ar, A, X, Y are as defined in any one of the preceding claims.   9. Compounds according to claim 8, such that Y = -Alkyl-, X = -O- or NR1-where R1 represents an -Aryl group optionally substituted with -NO2, Ar represents a phenyl- group, m = 1 and A represents -N (NO) -Aryle, Alkyl.   10. Compounds according to any one of the preceding claims, such that the compounds of formula (I) or (I ') are chosen from: ammonium 1- [4 (4-methoxyphenoxy) benzyl] -2-oxohydrazinolate; ammonium 1- {4 - [(4methoxyphenyl) thio] benzyl} -2-oxohydrazinolate; ammonium 1- (2,4-dimethoxybenzyl) -2-oxohydrazinolate; ammonium 1- [4- (benzyloxy) benzyl] -2oxohydrazinolate; ammonium 1- (4-butoxybenzyl) -2-oxohydrazinolate; ammonium 1- (1,3-benzodioxol-5-ylmethyl) -2-oxohydrazinolate; ammonium 2oxo-1- (2,3,4-trimethoxybenzyl) hydrazinolate; ammonium 1- (4-methoxy-3-methylbenzyl) -2-oxohydrazinolate; ammonium 1- (3,4-dimethoxybenzyl) -2oxohydrazinolate; ammonium 1- (3-fluoro-4-methoxybenzyl) -2oxohydrazinolate; ammonium 1- (3,5-di-tert-butyl-4-hydroxybenzyl) -2oxohydrazinolate; 2,6-di-tert-butyl-4- [2- (4 - {[methoxy (nitroso) amino] methyl} -phenoxy) ethyl] phenol; ammonium 1- {4 - [(4-methoxyphenyl) (methyl) amino] benzyl} -2-oxohydrazinolate; ammonium 1- {2 - [(4-anilinophenoxy) methyl] benzyl} -2-oxohydrazinolate; 4 - [(2 - {[hydroxy (nitroso) amino] methyl} benzyl) oxy] phenyl} nitroso (phenyl) amine; ammonium 1- (7- {4- [nitroso (phenyl) amino] phenoxy} heptyl) -2-oxohydrazinolate; ammonium 1- {5 - [(4-methoxyphenyl) (4-nitro-phenyl) amino] pentyl} -2-oxohydrazinolate; ammonium 1- (4- {2 - [(2E) -2- (2-hydroxy-4-methoxybenzylidene) hydrazino] -2-oxoethoxy} benzyl) -2-oxohydrazinolate; ammonium 2-oxo-1- (4- (2-oxo-2 - [(2E) -2- (pyridin-3-ylmethylene) hydrazino] ethoxy} benzyl) hydrazinolate; N '- [(1 E) - (5-chloro-2-hydroxyphenyl) methylene] -2- (4 - {[hydroxy (nitroso) -amino] methyl} phenoxy) acetohydrazide; ammonium 1- (4- {2 - [(2E) -2-benzylidenehydrazino] -2-oxoethoxy} benzyl) -2oxohydrazinolate; ammonium 2-oxo-1- [4- (2-oxo-2 - {(2E) -2 - [(2E) -3-phenylprop-2-en-1-ylidene] hydrazino} ethoxy) benzyl] hydrazinolate; in free form or their salt as well as enantiomers, diastereoisomers, racemic mixtures and pharmaceutically acceptable salts.   11. Compounds according to any one of the preceding claims, such that the compounds of formula (I) or (I ') are chosen from: ammonium 1- {2 [(4-anilinophenoxy) methyl] benzyl} -2-oxohydrazinolate; ammonium 1- {5 - [(4-methoxyphenyl) (4-nitrophenyl) amino] pentyl} -2-oxohydrazinolate; ammonium 1- (4- {2 - [(2E) -2- (2-hydroxy-4-methoxybenzylidene) hydrazino] -2-oxoethoxy} benzyl) -2-oxohydrazinolate; in free form or their salt as well as enantiomers, diastereoisomers, racemic mixtures and pharmaceutically acceptable salts.   A process for preparing a compound according to any one of the preceding claims comprising the step of nitrosating the -NH-OH group of a corresponding compound.   13. The method of claim 12, as one operates from the products of formula (II) corresponding: (A) m-Ar- (X) n- (Y) p H OH (II) wherein A, Ar, Y, m, n, p are as defined in any one of claims 1 to 11 by means of a nitrite compound.   The process of claim 13, such that the nitrite compound is an alkyl-nitrite or an alkali metal nitrite.   15. The method of claim 14, wherein the nitrite is selected from tertbutyl-nitrite, or ethyl-nitrite, or sodium or potassium nitrite.   16. A process according to any one of claims 12 to 15 wherein ammonia gas is operated.   17. The method according to any one of claims 12 to 16 further comprising the step of preparing the free form of the compound (I) from the corresponding salt.   18. The method of claim 17, as one operates by adding base.   19. Compounds of formula (II): (A) m -Ar- (X) n- (Y) p H OH (II) in which A, Ar, Y, m, n, p are as defined according to any of claims 1 to 11.   20. Process for the preparation of the compounds of formula (II) according to claim 19, which is carried out by reduction from the corresponding compounds of formula (III): (A) m-Ar- (X) n- (Y) NO2 (III) wherein A, Ar, Y, m, n, p are as defined in any one of claims 1 to 11.   21. The process according to claim 20, which is carried out by means of zinc, in the presence of NH 4 Cl, in a suitable solvent medium, at a temperature between room temperature and the reflux temperature of the solvent.   22. The process according to claim 20, which is carried out using hydrazine hydrate, in the presence of a catalyst such as Raney nickel, in a suitable solvent medium at a temperature of between 0 ° C. and room temperature. .   23. Process for the preparation of the compounds of formula (II) according to claim 19, which is carried out by reduction from the corresponding compounds of formula (IV): (A) ,, - Ar- (X), - ( Y) p = N-OH (IV) wherein A, Ar, X, Y, m, n, p are as defined in any one of claims 1 to 11.   24. The process as claimed in claim 23, which is carried out using sodium borohydride NaBH4, in the presence of acid, in a suitable solvent medium at a temperature of between 0 ° C. and room temperature.   25. The method of claim 23, as one operates using NaCNH3 in the presence of acid, in a suitable solvent medium at a temperature between 0 C and room temperature.   The method of any of claims 12 to 25, further comprising the step of isolating the obtained product of formula (I), (I ') or (II).   27. Pharmaceutical compositions comprising a compound according to any one of claims 1 to 11 and a pharmaceutically acceptable carrier or excipient.   28. Use of a compound of formula (I): ## STR5 ## wherein: m is an integer between 0 and 3; ; É n is an integer chosen between 0 and 1; É p is an integer chosen between 1 and 7; X represents an oxygen atom -O-, a group -NR1- or, when n = 0, X represents a single bond; where R 1 represents a hydrogen atom, a -Alkyl, -Aryl group, each optionally substituted by one or more group (s) chosen from -OH, -Oalkyl, -CN, -NO 2, perfluoroalkyl, -NR 2 R 3 where R2 is H, -Alkyl and R3 is Alkyl, -Aryle Y is -CH2-; É Ar represents a phenyl group; Ar is optionally substituted with 1 to 3 substituents A where E two of A may represent a phenyl fused heterocycle, such as benzodioxolane or where; Each of the A is independently a group selected from: -OH; CN; - Hal; C1-C6 alkyl, optionally substituted with one or more groups selected from -OH, -Oalkyl, -CN, -NO2, perfluoroalkyl, -NR2R3 wherein R2 represents H, -Alkyl and R3 represents -Alkyl , -Aryle; -Alkyl-O-Aryl where Aryl is optionally substituted with one or more groups selected from -OH, -Oalkyl, -CN, -NO2, -perfluoroalkyl, -NR "2 R" 3 where R "2 is H, -Alkyl, -NO and R "3 is -Alkyl, -Aryl; E -Oalkyl, optionally substituted by one or more groups selected from -OH, -Oalkyl, -CN, -NO2, -perfluoroalkyl, -NR2R3 wherein R2 represents H, -Alkyl and R3 represents -Alkyl, - aryl; E-Alkyl Alryl, optionally substituted with one or more groups selected from OH, -Alkyl, -Oalkyl, -CN, -NO2, -perfluoroalkyl, -NR2R3 wherein R2 represents H, -Alkyl and R3 represents -Alkyl , -Aryle; - Aryl optionally substituted with one or more group (s) chosen from -OH, -Oalkyl, -CN, -NO2, -perfluoroalkyl, -NR'2R'3 where R'2 represents H, alkyl and R'3 is -Alkyl, -Aryl, C (= O) Alkyl, -C (= O) Aryl; Wherein R is 0 or 1, R7 is - Alkyl, -OR8, NR9RIO; where R8 represents a hydrogen atom, an - Alkyl group; R 9, R 10 independently represent a hydrogen atom, an alkyl, -Alkenyl, -N = alkyl, -N = alkenyl group where the alkyl or alkenyl group is optionally substituted by one or more group (s) chosen from - Aryl, -Het, themselves optionally oo substituted with one or more group (s) chosen from a halogen atom, an -OH group, an alkyl group, -Oalkyl; -Oalkyl-O-R11 wherein R11 is -Alkyl, -Aryl optionally substituted with one or more groups selected from OH, -Alkyl, -Oalkyl, -AlkylAryl, -C (= O) alkyl, optionally substituted with one or more group (s) selected from -Aryle, -Het; - C (= O) Alkenyl, optionally substituted with -Aryl, -Het; - C (= O) NR12R13, where R12, R13 independently represent a hydrogen atom, an -Alkyl group; -N (NO) -A-aryl, optionally substituted by one or more groups selected from OH, -Oalkyl, -CN, -perfluoroalkyl, -NR2R3 wherein R2 represents H, -Alkyl and R3 represents -Alkyl, aryl; -NR 4 R 5 where R 4 is H, Alkyl and R 5 is -Alkyl, -Aryl, -AlkylAryl, where the -Aryl group is optionally substituted with one or more groups selected from -OH, -Alkyl, -Oalkyl , -CN, -NO2, - perfluoroalkyl, -NR'2R'3 where R'2 is H, -Alkyl and R'3 is -Alkyl, -Aryle, -C (= O) Alkyl, -C (= O) Aryl; Where q is 0, 1 or 2, R6 is -Alkyl, -Aryl each optionally substituted with one or more groups selected from -OH, -Oalkyl, -N, -NO2-, perfluoroalkyl, -Alkyl, -Oalkyl, -NR14R15, wherein R14, R15 are independently hydrogen, -Alkyl, -C (= O) Alkyl, -C (= O) Aryl, -C (= O) Het where, in the latter three cases, Alkyl, Aryl and Het may be optionally substituted by one or more group (s) chosen from OH, -CN, OAlkyl, -NO2, -perfluoroalkyl, -NR2R3 where R2 is H, -Alkyl and R3 is -Alkyl, -Aryl; Perfluoroalkyl; Het; AlkylHet; É -OHét; or the corresponding salts, as well as the enantiomers, diastereoisomers, racemic mixtures and pharmaceutically acceptable salts, for the preparation of pharmaceutical compositions for preventing and / or treating vascular pathologies related to the proliferation of smooth muscle cells.   29. The use according to claim 28, wherein said pathologies are chosen from atherosclerosis, restenosis and stenosis.   30. Use according to claim 28 such that said pathologies are complications related to angioplasty with or without stent, bypass surgery or transplantation.   31. Use of a compound of formula (I): WE   (A) n, -Ar- (X) n- (Y) p N OH (1) wherein: E m is an integer from 0 to 3; É n is an integer chosen between 0 and 1; É p is an integer chosen between 1 and 7; X represents an oxygen atom -O-, a group -NR1- or, when n = 0, X represents a single bond; where R 1 represents a hydrogen atom, a -Alkyl, -Aryl group, each optionally substituted by one or more group (s) chosen from -OH, -Oalkyl, -CN, -NO 2, perfluoroalkyl, -NR 2 R 3 where R2 is H, - Alkyl and R3 is -Alkyl, -Aryle Y is -CH2-; É Ar represents a phenyl group; Ar is optionally substituted with 1 to 3 substituents A where deux two of A may represent a phenyl fused heterocycle, such as benzodioxolane or where; Each of A is independently a group selected from: E-OH; É -CN; E-Hal; E-C 1 -C 6 alkyl, optionally substituted by one or more groups selected from -OH, -Oalkyl, -CN, -NO 2, perfluoroalkyl, -NR 2 R 3 wherein R 2 represents H, -Alkyl and R 3 represents - Alkyl, -Aryl; E -Alkyl-O-Aryl wherein Aryl is optionally substituted with one or more groups selected from -OH, -Oalkyl, -CN, -NO2, -perfluoroalkyl, -NR "2 R" 3 where R " 2 represents H, -Alkyl, -NO and R "3 represents -Alkyl, -Aryl; E -Oalkyl, optionally substituted with one or more groups selected from -OH, -Oalkyl, -CN, -NO2, -perfluoroalkyl, -NR2R3 wherein R2 represents H, -Alkyl and R3 represents -Alkyl, Aryl ; Alkyl Aryl, optionally substituted with one or more groups selected from OH, -Alkyl, -Oalkyl, -CN, -NO2, -perfluoroalkyl, -NR2R3 wherein R2 represents H, -Alkyl and R3 represents -Alkyl, aryl; -O-Aryl optionally substituted by one or more group (s) chosen from -OH, -Oalkyl, -CN, -NO2, -perfluoroalkyl, -NR'2R'3 where R'2 represents H, -Alkyle and R ' 3 represents -Alkyl, -Aryl, -C (= O) Alkyl, -C (= O) Aryl; -O (Alkyl) r-C (= O) -R7 wherein r is 0 or 1, R7 is -alkyl, -OR8, NR9R10; where R8 represents a hydrogen atom, an - Alkyl group; R9, R10 independently represent a hydrogen atom, an alkyl group, -Alkenyl, -N = alkyl, -N = alkenyl where the alkyl or alkenyl group is optionally substituted with one or more group (s) chosen from - Aryl, -Het, themselves optionally substituted by one or more group (s) chosen from a halogen atom, a -OH group, an alkyl group, -Oalkyl; Alkyl-O-R 11 wherein R 11 is -Alkyl, -Aryl optionally substituted with one or more groups selected from OH, -Alkyl, -Oalkyl, AlkylAryl, -C (= O) Alkyl, optionally substituted by one or more group (s) chosen from -Aryle, -Het; - C (= O) Alkenyl, optionally substituted with -Aryl, -Het; - C (= O) NR12R13, where R12, R13 independently represent a hydrogen atom, an -Alkyl group; -N (NO) -A-aryl, optionally substituted by one or more groups selected from OH, -Oalkyl, -CN, -perfluoroalkyl, -NR2R3 wherein R2 represents H, -Alkyl and R3 represents -Alkyl, - aryl; -NR4R5 wherein R4 is H, Alkyl and R5 is -Alkyl, -Aryl, -AlkylAryl, wherein the -Ar1 group is optionally substituted with one or more groups selected from -OH, -Alkyl, -Oalkyl , -CN, -NO2, -perfluoroalkyl, -NR'2R'3 where R'2 is H, -Alkyl and R'3 is -Alkyl, -Aryl, -C (= O) Alkyl, -C (= O) Aryl; Where q represents 0, 1 or 2, R6 represents a group -Alkyl, -Aryl each optionally substituted by one or more group (s) chosen from -OH, -Oalkyl, -CN, -NO2-, perfluoroalkyl, -Alkyl, -Alkyl, -NR14R15, wherein R14, R15 are independently hydrogen, -Alkyl, -C (= O) Alkyl, -C (= O) Aryl, -C (= O) Het where, in the latter three cases, Alkyl, Aryl and Het may be optionally substituted by one or more group (s) chosen from OH, -CN, OAlkyl, -NO2, -perfluoroalkyl, -NR2R3 where R 2 is H, Alkyl and R 3 is -Alkyl, -Aryl; Perfluoroalkyl; É -Hét; AlkylHet; É -OHét; or the corresponding salts, as well as enantiomers, diastereoisomers, racemic mixtures and pharmaceutically acceptable salts; for the preparation of pharmaceutical compositions for preventing and / or treating pathologies selected from atherosclerosis, restenosis, stenosis, hyperglycemia, insulin resistance, diabetes, dyslipidemia, retinal vascular and / or renal complications. diabetes, hypoxia, inflammatory processes, cardiovascular diseases, joint pathologies, male erectile dysfunction, smoking.   32. Use according to any one of claims 28 to 31 for which the compounds of formula (I) are as defined according to any one of claims 1 to 11.