WO2003103567A2

WO2003103567A2 - Nitrosodiphenylamine derivatives, compositions comprising them, and the use thereof as antioxidants and spontaneous nitric oxide donors

Info

Publication number: WO2003103567A2
Application number: PCT/EP2003/004919
Authority: WO
Inventors: Claude Lardy; Philippe Guedat; Isabelle Berard; Lidia Caputo
Original assignee: Merck Patent Gmbh
Priority date: 2002-06-05
Filing date: 2003-05-12
Publication date: 2003-12-18
Also published as: AU2003250328A1; WO2003103567A3; FR2840609A1; UY27821A1; AU2003250328A8

Abstract

The invention relates to compounds of the general formula (I) in which R i, A, n, B and Z are as defined in Claim 1. These compounds can be used for the preparation of antioxidant medicinal products that function as free-radical scavengers or are useful in the treatment of pathologies characterised by an oxidative stress condition and a lack of availability of endothelial nitrogen monoxide. The invention also relates to the pharmaceutical compositions comprising them.

Description

NITROSODIPHENYLAMINE DERIVATIVES, COMPOSITIONS COMPRISING THEM, AND THE USE THEREOF AS ANTIOXIDANTS AND SPONTANEOUS NITRIC OXIDE DONORS

The invention relates to nitrosodiphenylamine derivatives, to pharmaceutical compositions comprising them, and to their use for the preparation of medicinal products that may be used for treating pathologies characterised by an oxidative stress condition and a lack of availability of endothelial nitrogen monoxide (NO^#).

Nitrogen monoxide (or nitric oxide NO*) is an important mediator in the physiology of cardiovascular, immune and central and peripheral nervous systems. It acts, among other mechanisms, by activating guanylate cyclase. Its action is ubiquitous: it is vasodilatory and gives a basal tonus to the entire vascular system. It has anti-clotting activity: its production by normal endothelial cells inhibits the formation of a thrombus. It is anti-proliferative, especially on the smooth muscle cells underlying the endothelial cells. It also inhibits the adhesion of monocytes to the vascular wall and, consequently, its conversion to a macrophage. It regulates endothelial permeability.

There is thus, in the physiological state, a state of equilibrium between the production of free-radical species and the availability of NO.

Disequilibrium of this balance, the result of which is an excess of superoxide anions in the face of a lack of NO, leads to the development of many pathologies.

Oxidative stress is generated by many factors, such as hyper- glycaemia, dyslipidaemias (production of oxidised, highly atherogenic "low- density" lipoproteins (LDL)), hypoxia, insulin resistance, atherosclerosis, revascularisation techniques (including angioplasties with or without a stent), chronic rejection after transplantation, the majority of inflammatory processes, and smoking. Oxidative stress is characterised at the vascular level by an increase in free radicals, in particular of superoxide anions (θ2* "). These 02*^~ radicals are capable of trapping the NO endogenously produced by the endothelial cells to form free-radical species that are even more deleterious, for instance peroxynitrites.

Among the pathologies concerned by a lack of production of endothelial nitrogen monoxide and/or an increase in oxidative tissue stress, mention may be made of (Recent Progress in Hormone Research (1988), 53, 43-60, table V):

^■ atherosclerosis-associated ischaemias (lipid peroxidation, development, progress and rupture of atheroma plaques, platelet activation); ■ restenosis after angioplasty; stenosis after vascular surgery; diabetes; insulin resistance; retinal and renal microvascular complications of diabetes; " the cardiovascular risk of diabetes in so far as it is not explained by the conventional factors; male erectile dysfunction; cerebral hypoxia; chronic rejection after organ transplantation; ■ articular pathologies; cold ischaemia in organ transplantation; extracorporeal circulation.

In the context of these pathologies, a set of adverse changes representing cardiovascular risk factors has been grouped under the term syndrome X or metabolic insulin-resistance syndrome (MIRS) (Reaven GM: Role of Insulin resistance in human disease, Diabetes 1988; 37: 1595-1607); it includes insulin resistance, hyperinsulinism, glucose intolerance or diabetes, arterial hypertension and hypertriglyceridaemia.

Other anomalies are frequently associated with this syndrome: android obesity, microalbuminia, hyperycaemia, and anomalies of fibrinolysis clotting. Hepatic steatosis of non-alcoholic origin may also be included therein. The administration of active principles capable of reducing the biological activity of oxidative free-radical species (such as superoxide anions and peroxynitrites) and of increasing the content of nitrogen monoxide by a twofold mechanism: non-conversion into peroxynitrites and exogenous supply, is thus particularly desirable in the treatment of these pathologies.

The present invention provides compounds that have these two effects, antioxidant and nitrogen monoxide donating, in the same molecule.

These compounds are capable of spontaneously generating nitrogen monoxide under physiological conditions and of trapping oxidative free radicals.

The spontaneous NO-donating effect does not induce a tachy- phylactic effect, unlike compounds that are substrates of NO synthase, and unlike nitro derivatives or derivatives of the oxadiazole or oxatriazole type which mobilise endogenous thiols groups to release NO. The spontaneous NO-donating effect makes it possible to achieve pharmacological NO activity in pathologies in which the activity of NO synthase is insufficient.

More particularly, the invention relates to compounds of the formula I:

in which:

R represents a hydrogen atom; a h alogen atom; a saturated aliphatic hydrocarbon-based group optionally substituted and/or optionally interrupted by one or more oxygen and sulfur atoms; n is an integer between 1 and 5; i is an integer chosen from 0, 1 , 2, 3, 4 and 5;

A represents O or S;

B represents -NW, in which W is a hydrogen atom or a saturated aliphatic hydrocarbon-based group; O; or -N-NO; Z represents a group from the following: -OH; amino; alkylamino; dialkylamino; -nitro; aminoalkyl; alkylaminoalkyl; dialkylaminoalkyl; -alk-Ar, in which alk represents nothing or represents a saturated aliphatic hydrocarbon-based divalent chain and Ar represents an optionally substituted carbocyclic or heterocyclic, saturated, unsaturated and/or aromatic radical; or alternatively a group of the formula:

- ^{N =}\

Ar' in which Ar' is as defined above for Ar; and also the pharmaceutically acceptable salts thereof. Halogen atoms are, for example, bromine, iodine, chlorine or fluorine.

The expression "saturated aliphatic hydrocarbon-based group" means a linear or branched aliphatic hydrocarbon-based group preferably containing from 1 to 14 carbon atoms, preferentially from 1 to 10 carbon atoms and better still from 1 to 6 carbon atoms, for example from 1 to 4 carbon atoms.

Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, 2-methylbutyl, 1-ethylpropyl, hexyl, isohexyl, neohexyl, 1-methylpentyl, 3-methylpentyl, 1 ,1-dimethylbutyl, 1 ,3- di methyl butyl, 2-ethylbutyl, 1-methyl-1-ethylpropyl, heptyl, 1-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methyl hexyl, 5,5- dimethylhexyl, nonyl, decyl, 1-methylnonyl, 3,7-dimethyloctyl and 7,7- dimethyloctyl.

The expression "optionally interrupted by O and/or S" means that any carbon atom of the hydrocarbon-based chain may be replaced with an oxygen or sulfur atom, this carbon atom not being able to be located at the free end of the hydrocarbon-based chain. The hydrocarbon-based chain, which may be alkyl, may comprise several oxygen and/or sulfur atoms, the hetero atoms preferably being separated from each other by at least one carbon atom and better still by at least two carbon atoms. An example of an aliphatic hydrocarbon-based chain interrupted with O or S is alkoxy or thioalkoxy.

The expression "saturated aliphatic hydrocarbon-based divalent chain" means a chain derived from a saturated aliphatic hydrocarbon-based group by abstraction of a hydrogen atom. This chain is preferably alkylene, more particularly C1-C₁4, for example C-₁-C₁₀ and better still C-ι-C₆ or C1-C4 alkylene.

The carbocyclic and heterocyclic radicals are mono- or polycyclic radicals; these radicals preferably denote mono-, bi- or tricyclic radicals. In the case of polycyclic radicals, it should be understood that they consist of monocycles fused in pairs (for example ortho-fused or peri-fused), i.e. having in pairs at least two carbon atoms in common. Preferably, each monocycle is 3- to 8-membered and better still 5- to 7-membered.

The aryl groups are examples of aromatic carbocyclic hydro- carbon-based groups, preferably of C-₆-C1₈. Among these, mention may be made especially of phenyl, naphthyl, anthryl and phenanthryl radicals.

Preferably, each monocycle constituting the heterocycle contains from 1 to 4 hetero atoms and better still from 1 to 3 hetero atoms. These hetero atoms are chosen from O, N and S, optionally in oxidised form (in the case of S and N).

Examples of monocyclic aromatic heterocyclic groups are 5- to 7- membered monocyclic heteroaryls, such as pyridine, furan, thiophene, pyrrole, pyrazole, imidazole, thiazole, isoxazole, isothiazole, furazane, pyridazine, pyrimidine, pyrazine, thiazines, oxazole, pyrazole, oxadiazole, triazole and thiadiazole.

Examples of bicyclic aromatic heterocyclic groups in which each monocycle is 5- to 7-membered are indolizine, indole, isoindole, benzofuran, benzopyran, benzothiophene, indazole, benzimidazole, benzothiazole, benzofurazane, benzothiofurazane, purine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, naphthyridine, pyrazolotriazine (such as pyrazolo-1 ,3,4-triazine), pyrazolopyrimidine and pteridine groups. Examples of aromatic tricyclic heterocyclic groups are those consisting of 5- to 7-membered monocycles, such as acridine or carbazole.

Examples of saturated monocyclic, bicyclic or tricyclic heterocyclic groups are the saturated derivatives of the aromatic heterocyclic groups mentioned above.

The expression "saturated and/or unsaturated carbocyclic or heterocyclic radicals" means that the carbocyclic or heterocyclic radical may comprise a saturated carbocyclic or heterocyclic portion, or an aromatic carbocyclic or heterocyclic portion.

Examples of aromatic and/or saturated carbocyclic groups are:

Examples of s aturated, u nsaturated a nd/or a romatic heterocyclic nuclei are the following:

in which P° represents O, S or S0₂ and M represents N or C. Preferably, in B1 , P° represents O or S; in B2, P° represents O; in B3, P° represents O; in B4, P° represents O; in B5, P° represents S; in B6, P° represents N; in B7, P° represents O; in B8, P° represents S; in B9, M represents NO and P represents S; in B 10, P represents O; in B11, P represents O.

As examples of salts with organic or mineral bases, mention may be made of the salts formed with metals and in particular alkali metals, alkaline- earth metals and transition metals (such as sodium, potassium, calcium, magnesium or aluminium) or with bases, such as ammonia or secondary or tertiary amines (such as diethylamine, triethylamine, piperidine, piperazine or morpholine) or with basic amino acids, or with osamines (such as meglumine) or with amino alcohols (such as 3-aminobutanol and 2-aminoethanol. If the compound of the formula I comprises a basic function, and for example a nitrogen atom, this compound may form a salt with an organic or mineral acid.

The salts with organic or mineral acids are, for example, the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate, citrate, maleate, fumarate, 2-naphthalenesulfonate and para- toluenesulfonate.

The invention also covers salts that allow a suitable separation or crystallisation of the compounds of the formula I, such as picric acid, oxalic acid or an optically active acid, for example tartaric acid, dibenzoyltartaric acid, mandelic acid or camphorsulfonic acid. However, a preferred sub-group of salts consists of salts of the compounds of the formula I with pharmaceutically acceptable acids or bases.

Preferably, i represents 0 or 1. A is preferably an oxygen atom. It is preferred for B to represent NH, O and N-NO. Advantageously, R represents a hydrogen atom; a halogen atom; an optionally halogenated alkyl group; optionally halogenated alkoxy; or optionally halogenated alkylthio.

An example of a haloalkyl group is a perhalo group, such as a perfluoro group, for example a trifluoromethyl or 2,2,3,3,3-pentafluoroethyl group. More particularly, Z represents an optionally halogenated aliphatic hydrocarbon-based group; a hydroxyl group; an amino group; alkylamino; dialkylamino; a group:

in which k represents an integer chosen from 0, 1, 2, 3, 4 and 5 and L is as defined below; a group:

in which k is as defined above and L is as defined below; a saturated, unsaturated and/or aromatic heterocyclic group Het optionally substituted by one or m ore s ubstituents L as defined below a nd c omprising o ne or m ore h etero atoms chosen from O, N and S; or a group:

— Q— Het in which Het represents a saturated, unsaturated and/or aromatic heterocyclic group as defined above, optionally substituted by one or more substituents L as defined below and Q represents alkylene; and a group of the formula:

in which j is an integer chosen from 0, 1 , 2, 3, 4 and 5; Het is as defined above and L is as defined below; or Z represents aminoalkyl; alkylaminoalkyl; or dialkylaminoalkyl; L represents a saturated heterocycle comprising one or more hetero atoms chosen from O, N and S and optionally substituted, such as morpholinyl; a halogen atom; hydroxyl; nitro; optionally halogenated alkyl; optionally halogenated alkoxy; amino; aminoalkyl; and dialkylamino; a group O-alk'-COOH in which alk' represents alkyl. The term "alkylene" means a linear or branched saturated aliphatic divalent radical preferably containing from 1 to 14 carbon atoms, preferentially from 1 to 10 carbon atoms and better still from 1 to 6 carbon atoms, for example from 1 to 4 carbon atoms. Preferred examples of alkyl chains are -CH₂-; -CH₂-CH₂- and -CH₂-CH₂-CH₂.

Preferably, n represents 1.

A first sub-group of preferred compounds consists of the compounds i n which A represents O ; B represents O ; Z is chosen from O H a nd alkyl. A second sub-group of preferred compounds consists of the compounds of the formula I in which: A represents O; B represents NH; Z represents a group:

in which L and j are as defined in Claim 6; amino; alkyiamino; dialkylamino; a group:

- N =\

Het in which Het is as defined in Claim 6; a group: -Q-Het in which Het is as defined in Claim 6 and Q represents alkylene; a group:

in which L and k are as defined above, a group ofthe formula:

in which L and k are as defined above; aminoalkyl; alkylaminoalkyl; dialkylaminoalkyl; an optionally substituted aromatic or saturated heterocyclic group comprising one or more hetero atoms chosen from O, N and S.

A third sub-group of preferred compounds consists of the compounds for which B represents -NW in which W is as defined above.

A fourth sub-group of preferred compounds consists of the compounds for which B represents O.

A fifth sub-group of preferred compounds consists of compounds for which B represents N-NO. A sixth sub-group of the preferred compounds consists of the compounds of the third sub-group above in which R represents a hydrogen atom.

A seventh sub-group of preferred compounds consists of the compounds of the third sub-group above in which R represents a saturated aliphatic hydrocarbon-based group optionally substituted and/or optionally interrupted by one or more oxygen or sulfur atoms.

An eighth sub-group of preferred compounds consists of the compounds of the fourth sub-group above in which R represents a hydrogen atom. A ninth sub-group of preferred compounds consists of the compounds of the fourth sub-group above in which R represents a saturated aliphatic hydrocarbon-based group optionally substituted and/or optionally interrupted by one or more oxygen or sulfur atoms.

A tenth sub-group of preferred compounds consists of the compounds of the fifth sub-group above in which R represents a hydrogen atom.

An eleventh sub-group of preferred compounds consists of the compounds of the fifth sub-group above in which R represents a saturated aliphatic hydrocarbon-based group optionally substituted and/or optionally interrupted by one or more oxygen or sulfur atoms. Table 1 below defines the preferred sub-groups 12 to 71. These sub-groups are, respectively, derived from the 6th, 7th, 8th, 9th, 10th and 11th preferred sub-groups above.

More specifically, the sub-groups of the first column are sub- groups of the 6th sub-group.

The sub-groups of the second column are sub-groups of the 7th sub-group.

The sub-groups of the third column are sub-groups of the 8th subgroup, More generally, the sub-groups of the i^th column are sub-groups of the (i + 5)^th sub-group.

Sub-groups 12 to 17, of the first line, are characterised in that Z represents OH.

Sub-groups 18 to 23, of the second line, are characterised in that Z represents amino.

Sub-groups 24 to 29, of the third line, are characterised in that Z represents alkyiamino.

More generally, the sub-groups of line j are characterised in that Z has the meaning given for the said line.

TABLE 1

Table 2 below, constructed on the same model as Table 1, collates the preferred sub-groups 54 to 57, which are also derived from the 6th and 7th sub-groups.

More specifically, the sub-groups of the first column are subgroups ofthe 6th sub-group.

The sub-groups of the second column are sub-groups of the 7th sub-group.

Sub-groups 54 and 55, of the first line, are characterised in that Z represents OH.

Sub-groups 56 and 57, of the second line, are characterised in that Z represents amino.

TABLE 2

Sub-group

No. 6^th 7^th

Z

OH 54 55

Amino 56 57

Table 3 below collates sub-groups 58 to 61 for which Z is nitro, which are derived from the 6th, 7th, 8th and 9th sub-groups, respectively.

TABLE 3

Sub-groups 62 to 85 derived from sub-groups 42 to 47 for which Z represents -alk-Ar are defined in Table 4.

In general, the sub-groups of the i^th column are derived from the (41 + i)^th sub-group.

Moreover, the sub-groups of line j are characterised in that Z takes the meaning Z' given for the said line in the table.

Sub-groups 86 to 97 derived from sub-groups 48 to 53, and for which Z represents:

are defined in Table 5.

The sub-groups of the i^th column are derived from the (47 + i)^th sub-group.

The sub-groups of the j^th line are characterised by the meaning of Z" given to the said line in the table.

TABLE 5

In this table L, j and Het are as defined above. In a particularly preferred manner, Het in Tables 2 and 3 represents a pyridine, imidazole, pyrrolidine, piperazine, morpholine or quinuclidine nucleus, each of the said nuclei optionally being substituted.

As compounds that are more particularly preferred, mention may be made of :

-N-[4-(N-nitroso-4-nitrophenylamino)phenoxymethyicarbonyl](2-hydroxy-5- methoxybenzylidene)hydrazide; and -N-nitroso-N-(4-methoxyphenyl)-N-[4-(3-pyridylmethylaminocarbonylmethoxy)- phenyi)phenyl]amine.

The aliphatic hydrocarbon-based groups and the carbocyclic and heterocyclic groups are optionally substituted by one or more of the following groups: oxo; halogen; alkyl optionally halogenated and/or optionally interrupted with one or more oxygen or sulfur atoms; a saturated and/or aromatic heterocycle comprising one or more hetero atoms chosen from O, N and S, optionally substituted by alkyl, alkoxy, halogen, nitro or oxo; hydroxyl; nitro; amino; aminoalkyl; dialkylamino; alk¹- O-CO-R⁴ in which alk¹ is an alkylene radical and R⁴ represents alkyl or alkyiamino; a!k²-CO-0-R⁵ in which alk² is an alkylene radical and R⁵ is as defined above for R⁴;

-COR⁶ in which R⁶ is as defined above for R⁴; hydroxyalkyl; or an aliphatic hydrocarbon-based group substituted by a saturated and/or aromatic heterocycle comprising one or more hetero atoms chosen from O, S and N, which is itself optionally substituted by alkyl, alkoxy, halogen, nitro or oxo; or a group -O-alk'-COOH in which alk' represents alkyl. It should be understood that the only groups that may be substituted by oxo are saturated carbocyclic or heterocyclic groups or alternatively the saturated heterocyclic or carbocyclic portions of aromatic and saturated carbocyclic groups or of aromatic and saturated heterocyclic groups. In a more particularly preferred manner, if the substituent comprises a heterocycle, this is a morpholine, a pyridine, a quinuclidine, an imidazole, a pyrrolidine or a piperazine.

The compounds of the formula I may be prepared by the action of a nitrosating agent, such as an alkali metal nitrite, in acidic medium, on a compound of the formula II:

(R)i A-(CH₂)_n-CO-B-Z II

in which R, i, n, A, B and Z are as defined above for formula I.

Examples of nitrosating agents are alkali metal nitrites (and in particular sodium or potassium nitrite) or a C-i-C₄ alkyl nitrite.

A preferred alkali metal nitrite that may be mentioned is sodium nitrite.

A preferred alkyl nitrite that may be mentioned is ethyl nitrite.

Nevertheless, a person skilled in the art can use any nitrosating agent known in the art, such as AgONO, BF₄NO, HOS0₃NO, nBuONO and tBuONO, or Et-ONO.

The amount of nitrosating agent required depends on the nature of the nitrosating agent used and on the reactivity of the substrate of the formula

II. It is at least stoichiometric. In general, the molar ratio of the nitrosating agent to the substrate of the formula II ranges between 1 and 30 equivalents and preferably between 1 and 20 equivalents.

If the nitrosating agent is an alkali metal nitrite, a person skilled in the art may readily adapt the reaction conditions so as to use only 1 to 10, preferably from 1 to 5 and better still from 1 to 3 equivalents of nitrite relative to the substrate of the formula II.

If the nitrosating agent is an alkyl nitrite, the process is preferably carried out in the presence of 10 to 25 molar equivalents of nitrite, and preferably from 15 to 20 molar equivalents, relative to the amount of substrate of the formula II.

The choice of solvent and the temperature conditions depend in particular on the type of nitrosating agent selected for the reaction.

If the nitrosating agent is AgONO, nBuONO or tBuONO, the solvent is advantageously chosen from a cyclic or non-cyclic ether (such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or diethylene glycol dimethyl ether) and an aliphatic or aromatic halogenated 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 and better still between -33° and 60°C, in the case of AgONO, nBuONO, tBuONO and EtONO.

More particularly, in the case of EtONO, the process is carried out between 15 and 30°C.

More particularly, in the case of AgONO and nBuONO, the process will be carried out in tetrahydrofuran or diethyl ether at a temperature of between 0° and 30°C, for example between 0° and 5°C.

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

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

If the nitrosating agent is HOSO₃NO, the reaction is preferably carried o ut i n an alkali m etal s alt of a I ower ( C₁-C5) c arboxylic a cid, s uch a s sodium acetate, at a reaction temperature of between -10°C and 30°C and better still between -5 °C and 25°C. If the nitrosating agent is BF₄NO, a suitable solvent is a nitrile, 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°C and 10°C and preferably between -25°C and 5°C.

If 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 comprises water and a Brδnsted or Lewis acid.

Suitable acids are a hydrohalic acid (such as HCI), sulfuric acid, AI₂(SO )₃ and acetic acid, and mixtures thereof.

According to one particular embodiment of the invention, an aliphatic alcohol of the (Cι-C₄)alkanol type (such as methanol or butanol) may be added.

Thus, a suitable reaction medium that may be selected is one of the following systems:

- 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 Al₂(Sθ₄)₃, or

- a mixture of water and hydrochloric acid.

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

The reaction of the alkali metal nitrite with the substrate of the formula II is carried out at a temperature that depends on the reactivity of the species present; this temperature generally ranges between -10°C and 50°C and preferably between -5°C and 25°C. If the nitrosation reaction is carried out in a mixture of acetic acid and water, a temperature of between 15°C and 25°C is particularly suitable.

The reaction of the alkyl nitrite with the substrate of the formula II is preferably carried out in the presence of a Cι-C alkanol in a polar aprotic solvent.

Suitable alkanols that may be mentioned are methanol, ethanol, isopropanol and tert-butanol, ethanol being particularly preferred.

Preferred polar solvents are halogenated hydrocarbons, such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; 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 hexamethylphosphoramide; and mixtures of these solvents in any proportions. The compounds of the formula II in which B represents -NW may be prepared from the compounds of the formula III:

in which R, i, A and n are as defined above for formula II, either by reacting the compounds of the formula 111 with an amine of the formula HNWZ, or alternatively by reacting an activated derivative of a compound of the formula III with an amine of the formula HNWZ.

According to one preferred embodiment of the invention, the amine HNWZ is condensed onto an activated form of the carboxylic acid.

Activating groups that are preferred for the carboxylic acid function and that are well known in the art are, for example, chlorine, bromine, an azide, imidazoiide, p-nitrophenoxy or 1-benzotriazole group, or an O-succinimide, acyloxy and more particularly pivaloyloxy, (C₁-C₄ alkoxy)carbonyloxy, such as

C2H5O-CO-O-, or dialkyl- or dicycloalkyl-O-ureide group. The reaction of the amine of the formula HNWZ with the carboxylic acid of the formula III, optionally in activated form, is preferably carried out in the presence of a coupling agent, such as a carbodiimide or bis(2-oxo-3- oxazolidinyl)phosphonyl chloride. Examples of carbodiimides are especially dicyclohexyl- and diisopropylcarbodiimides, 1 -(3-dimethylaminopropyl)-3- ethylcarbodiimide, or carbodiimides that are soluble in an aqueous medium. Another type of coupling agent is oxalyl chloride.

The p rocess i s advantageously carried o ut in t he p resence of a base, such as an organic base. Preferred examples of bases are triethylamine, tributylamine and diisopropylethylamine.

If the process is carried out in the presence of 1-(3-dimethyl- aminopropyl)-3-ethylcarbodiimide, by direct coupling of the amine with the acid in -COOH form, the base may be abstracted without harming the reaction yield.

The process is generally carried out in a polar aprotic solvent, such as an optionally halogenated aromatic or aliphatic hydrocarbon; an ether (diethyl ether or diisopropyl ether), tetrahydrofuran, dioxane, dimethoxyethane or a glyme, such as diethylene glycol dimethyl ether; a ketone (acetone, methyl ethyl ketone, isophorone or cyclohexanone); a nitrile (acetonitrile or isobutyronitrile); an amide (formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidinone or hexamethylphosphorylamide).

Optionally halogenated aliphatic or aromatic hydrocarbons that may be mentioned included benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene. Preferred solvents that will mainly be selected are a glyme, such as diglyme, dimethylformamide and methylene chloride, and mixtures thereof.

The a mount of coupling a gent i s preferably a 1 1 east equal (as a molar percentage) to the amount of acid of the formula III. Preferably, the molar ratio of the coupling agent to the acid of the formula III ranges between 1 and 3 equivalents, for example between 1 and 2. As regards the molar ratio of the base to the acid, it is preferably ranges between 1 and 3 equivalents and preferentially between 1 and 2 equivalents.

If the process is carried out without activation of the carboxylic acid function of the acid of the formula III, the preferred coupling agents are 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide and bis(2-oxo-3-oxazolid- inyl)phosphonyl chloride.

A preferred base for this type of "direct" coupling that will be mentioned is triethylamine. The operating procedure generally followed comprises the reaction of the acid with the coupling agent, optionally in the presence of the base, at a temperature that ranges between 15°C and 55°C, for example between room temperature and 45°C and more particularly between 20 and 25°C. In a second stage, the amine of the formula HNWZ, optionally in combination with the base selected for the reaction, is introduced into the reaction medium. Where appropriate, the reaction medium may then be raised to a temperature of between 80°C and 150°C, for example between 110°C and 130°C. The compounds of the formula III may be prepared by saponi- fication of the corresponding esters of the formula IV under the usual conditions known to those skilled in the art:

in which R, i, A and n are as defined above for formula III and alk represents alkyl.

Any mineral base chosen from potassium hydroxide, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, potassium carbonate and sodium carbonate may be used for the saponification. This reaction is generally carried out in a water-miscible solvent, such as a lower alcohol, for instance methanol, ethanol or isopropanol.

For this reaction, the reaction temperature may range between 15 and 150°C, for example between 20 and 120°C. The compounds of the formula IV may readily be obtained by alkylation of the corresponding compounds of the formula V:

in which R, i and A are as defined above for formula V by alkylation using a halide of the formula VI:

Hal-(CH₂)_n-COO-aIk VI in which Hal is halogen and n and alk are as defined above, in the presence of a base, such as a mineral base, preferably a carbonate and especially caesium carbonate.

For this reaction, a water-miscible polar aprotic solvent is particularly desirable, such as, for example, a ketone, such as acetone, the temperature preferably being between 15 and 150°C and more preferably between 20 and 120°C. It is desirable to add potassium iodide to the reaction medium so as to accelerate the reaction.

The base is used in excess, for example in a proportion of 1 to 3 equivalents relative to the compound of the formula VI.

Advantageously, the molar ratio of the compound of the formula VI to t he compound of the formula V ranges between 1 .5 a nd 5 a nd p referably between 2 and 3.

The compounds of the formula V may be obtained by coupling a compound of the formula VII: in which R and i are as defined for formula V, with a compound of the formula

VIII:

in which A is as defined above for formula V, under conditions of acid catalysis.

The acid chosen is preferably a strong mineral acid, such as hydrochloric acid, nitric acid or sulfuric acid, or an acidic solid catalyst, for instance clays, such as aluminosilicate, natural montmorillonite or bentonite, with an amount of from 5 to 20 g per mole of VIII.

This coupling reaction is usually carried out at between 150°C and 300°C, for example between 180°C and 250°C.

The reaction may be carried out in the absence of a solvent.

The compounds of the formula II in which B represents NH and Z represents a group of the formula:

- N

Λ Ar' in which Ar' is as defined above, may be prepared by reacting a compound of the formula IX:

in which R, i, A and n are as defined above, with a compound of the formula X:

in which Ar' is as defined above for formula II, preferably in the presence of a base. As bases that are particularly preferred, mention may be made of organic bases, such as N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-(1- pyrrolidinyl)pyridine, picoline, 4-(N-N-dimethylamino)pyridine, 2,6-di-f-butyl-4- methylpyridine, quinoline, N,N-dimethylaniline and N,N-diethylaniline.

If so d esired, it is possible to u se a catalytic a mount of 4-(N,N- dimethylamino)pyridine or 4-(1-pyrrolidinyl)pyridine in combination with other bases.

The base used is preferably pyridine. A suitable solvent is a water-miscible solvent, such as a lower alcohol, of the type, such as methanol, ethanol or isopropanol.

The reaction temperature is usually maintained between 15 and 50°C, for example between 20 and 30°.

Advantageously, the molar ratio of the aldehyde formula X to the hydrazide of the formula IX ranges between 1 and 3 and preferably between 1 and 2.

If the base used is pyridine, it may be added to the reaction medium in large excess.

The compounds of the formula IX may readily be prepared by the action of hydrazine or of a salt thereof on a compound of the formula IV.

According to one preferred embodiment, the hydrazine is used in the form of hydrazine hydrate.

As solvent, it is possible to use a polar solvent that is preferably water-miscible, such as a lower alcohol (methanol, ethanol or isopropanol). The reaction temperature is a temperature of between 30 and

120°C and preferably between 50 and 100°C.

The hydrazine is generally used in large excess. For example, from 5 to 15 equivalents of hydrazine will be used relative to the ester of the formula IV. An alternative to the preparation of the compounds of the formula

IV consists in reacting a compound of the formula XI: Hal⁰

in which R and i are as defined above and Hal⁰ represents a halogen atom, such as bromine, with a compound of the formula XII:

in which A, n and alk are as defined above, in the presence of a base, a palladium (0) complex and a diphosphine, such as BINAP.

The solvent for this reaction is advantageously a glyme, for example diglyme, toluene or dimethylformamide.

The reaction is preferably carried out at a temperature of between 80 and 130°C.

A type of catalyst complex that may be mentioned is Pd₂(dba)3. An example of a diphosphine that may be mentioned BINAP. These two compounds are preferably used in catalytic amounts.

The compounds of the formula XII may be prepared simply by carrying out the reaction scheme illustrated in Figure 1 below:

Figure 1 A-(CH₂)_n-COOalk In Figure 1 , A, alk and n are as defined above for formula XII, Hal' represents a halogen atom and P represents a protecting group for an amine function.

Examples of protecting groups are described in "Protective Groups in Organic Synthesis", Greene T.W. and Wuts P.G.M., published by John Wiley and Sons, 1991 , and "Protecting Groups", Kocienski P.J., 1994, Georg Thieme Verlag.

Other protecting groups for the amino function are acyl groups of the type R-CO (in which R is a hydrogen atom or an alkyl, cycloalkyl, aryl, arylalkyl or heteroarylalkyl radical, R optionally being substituted by alkyl, alkoxy or halogen), urea-forming groups of the formula -CO-NA₂B₂ or urethane- forming groups of the formula -CO-OA₂ (in which A₂ and B₂ are, independently, alkyl, aryl, arylalkyl or cycloalkyl - optionally substituted by alkyl, alkoxy or halogen - or alternatively A₂ and B₂ form, together with the nitrogen atom which bears them, a mono- or polynuclear, preferably mono- or binuclear, saturated, unsaturated or aromatic heterocycle optionally substituted by alkyl, alkoxy or halogen), thiourethane-forming groups of the formula -CS-NA₂B₂ (in which A₂ and B₂ are as defined above), diacyl groups in which :

^N— P / in formulae III and IV represents the group :

in which :

Ai and Bi are, independently, alkyl, aryl, arylalkyl or cycloalkyl - optionally substituted by alkyl, alkoxy or halogen, or alternatively Ai and Bi form, together with N and the two carbonyl groups, a mono- or polynuclear, preferably mono- or binuclear, saturated, unsaturated or aromatic heterocycle optionally substituted by alkyl, alkoxy or halogen -, such as phthalamide, tetrahydropyranyl groups and, less commonly, alkyl, alkenyl (allyl or iso- propenyl) and arylalkyl groups, such as trityl or benzyl, and groups of the benzylidene type.

Examples of protecting groups for the amino group which may be mentioned are the formyl group, the acetyl group, the chloroacetyl group, the dichloroacetyl group, the phenylacetyl group, the thienylacetyl group, the tert- butoxycarbonyl group, the benzyloxycarbonyl group, the trityl group, the p-methoxybenzyl group, the diphenylmethyl group, the benzylidene group, the p-nitrobenzylidene group, the m-nitrobenzylidene group, the 3,4-methyl- enedioxybenzylidene group and the m-chlorobenzylidene group. Protecting groups that are particularly preferred are especially (C-i-

Cβjalkoxycarbonyl and (C₈-Cιo)aryl-(Cι-C6)alkoxycarbonyl, such as tert- butoxycarbonyl and benzyloxycarbonyl.

In step i), protection of the amino group is carried out using, for example, a tert-butoxycarbonyl function. A reagent that may be used is di-tert-butyl carbonate in a proportion of 1 to 3 equivalents, for example 1 to 2 equivalents, in a solvent, such as a polar aprotic solvent of the cyclic ether type, such as tetrahydrofuran or dioxane, or of the linear ether type, such as diethyl ether or di-tert-butyl ether, or dimethylformamide. The reaction temperature is preferably maintained between 0°C and 150°C.

In step ii), alkylation of the -AH function is carried out by the action of a compound of the formula VI as defined above. The alkylation reaction is carried out under the conditions generally described above for the preparation of the compounds of the formula IV, starting with the compounds of the formula V.

The compounds of the formula II are novel and form a subject of the invention. They have the formula

in which R, i, n, A and B are as defined above.

Among the novel intermediate compounds of the formula II, the following two compounds are particularly preferred:

- N-[4-(4-nitrophenylamino)phenoxymethylcarbonyl](2-hydroxy-5- methoxybenzylidene)hydrazide; and

- N-(4-methoxyphenyl)-N-[4-(3-pyridylmethylaminocarbonyl- methoxy)phenyl]amine.

The compounds of the invention increase the level of nitric oxide.

A solution of a compound of the invention spontaneously releases nitric oxide. The nitrite ions resulting therefrom are titrated by colorimetry using a special reagent (Griess). To take account of the possible release of nitrate ions in addition to the nitrite ions, bacterial n itrate reductase is added to the reaction medium to reduce the nitrate ions formed.

The reactions and measurements are carried out in transparent 96-well plates. The test products are dissolved extemporaneously at a concentration of 3 mM in dimethyl sulfoxide. 95 μl of a reagent comprising the nitrate from the solution ofthe test product (final concentration of 1 50 μM) is then introduced into each well. After stirring, the mixture is incubated for four hours at 37°C. The reaction is then quenched by addition of 100 μl of the Griess reagent (Sigma G4410). The reagent is left to act for five minutes at room temperature, and the optical density is then read at 540 nm. This value is proportional to the concentration of nitrites + nitrates in the medium. A calibration range is made for each plate using NaNO₂.

The results are expressed in μmol/l (μM) of nitrites + nitrates released, in Table A.

Table A

The compounds of the invention reduce the biological activity of oxidative free-radical species.

Human LDLs placed in aqueous solution in the presence of cupric ion are oxidised spontaneously on their protein component, apolipoprotein-B. This oxidation makes the particle fluorescent, which is exploited to measure a pharmacological effect.

The reactions and measurements are carried out in black 96-well plates. 10 μl of a solution of the test product dissolved in dimethyl sulfoxide are first mixed with 170 μl of a solution of human LDL at a concentration of 120 μg/ml and 20 μl of 100 μM CuCI₂. After stirring, the mixture is incubated for two hours at 37°C, and a first fluorescence reading is taken (excitation at 360 nm, reading at 460 nm). The mixture is then incubated for a further 22 hours, to take a second reading under the same conditions. The difference is proportionately smaller the greater the antioxidant power of the test product. Probucol is used as reference product, at a concentration of 10 μM.

The 50% inhibitory concentrations (IC₅o) for the oxidation are prepared from 3 concentrations of product. They are given in Table B below.

The compounds of the formula II above are not only usable as intermediates in the synthesis of the compounds of the formula I, but also show antioxidant activity that makes them capable of limiting the destructive activity of oxidative free-radical species. The antioxidant activity of the compounds of the formula II is revealed in vitro, for example, by evaluating the ability of the compounds of the formula II to prevent the oxidation of low molecular weight human lipoproteins.

In the test carried out, the low-molecular-weight human lipoproteins are oxidised with cupric ions for 24 hours at 37°C. The apoprotein B borne by these lipoproteins becomes fluorescent on oxidation (excitation at 360 nm, emission at 460 nm). In the presence of the compounds of the formula II, a decrease in the fluorescence is observed, which reflects the antioxidant power of the compounds of the formula II. The results are expressed in the form of a 50% inhibitory concentration (IC50). The IC50 values measured in the case of a certain number of compounds of the formula II are given in Table B.

Table B

According to another of its aspects, the invention relates to a pharmaceutical composition comprising at least one compound of the formula I as defined above, in combination with at least one pharmaceutically acceptable excipient.

According to yet another of its aspects, the invention relates to a pharmaceutical composition comprising at least one compound of the formula II, in combination with at least one pharmaceutically acceptable excipient.

These compositions may be administered orally in the form of tablets, gel capsules or granules with immediate release or controlled release, intravenously in the form of an injectable solution, transdermally in the form of an adhesive transdermal device, or locally in the form of a solution, cream or gel. A solid composition for oral administration is prepared by adding to the active principle a filler and, where appropriate, a binder, a crumbling agent, a lubricant, a colorant or a flavour corrector, and by shaping the mixture into a tablet, a coated tablet, a granule, a powder or a capsule. Examples of fillers include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide, and examples of binders include poly(vinyl alcohol), poly(vinyl ether), ethylcellulose, methylcellulose, acacia, gum tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin and pectin. Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica and hardened plant oils. The colorant may be any colorant permitted for use in medicinal products. Examples of flavour correctors include cocoa powder, mint in herb form, aromatic powder, mint in oil form, borneol and cinnamon powder. Needless to say, the tablet or granulate may be suitably coated with sugar, gelatin or the like.

An injectable form comprising the compound of the present invention as active principle is prepared, where appropriate, by mixing the said compound with a pH regulator, a buffer agent, a suspending agent, a solubilising agent, a stabiliser, a tonicity agent and/or a preserving agent, and by converting the mixture into an a form for intravenous, subcutaneous or intramuscular injection, according to a conventional process. Where appropriate, the injectable form obtained may be freeze-dried by a conventional process.

Examples of suspending agents include methylcellulose, poly- sorbate 80, hydroxyethylcellulose, acacia, powdered gum tragacanth, sodium carboxymethylcellulose and polyethoxylated sorbitan monolaurate.

Examples of solubilising agents include castor oil solidified with polyoxyethylene, polysorbate 80, nicotinamide, polyethoxylated sorbitan monolaurate and the ethyl ester of castor oil fatty acid. In addition, the stabiliser encompasses sodium sulfite, sodium metasulfite and ether, while the preserving agent encompasses methyl p- hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, cresol and chloro- cresol.

According to yet another of its aspects, the invention relates to the use of a compound of the formula I as defined above, for the preparation of a medicinal p roduct for treating p athologies c haracterised b y a I ack of nitrogen monoxide production and/or an oxidative stress condition.

The compounds of the formula I and the physiologically acceptable salts thereof may be used in the treatment and prophylaxis of pathologies or disorders characterised by an oxidative stress condition and a lack of availability of endothelial nitrogen monoxide.

According to one of its final aspects, the invention relates to the use of a compound of the formula II for the preparation of an antioxidant medicinal product that may be used as a free-radical scavenger.

The compounds of the formula II and the physiologically acceptable salts thereof may be used as antioxidants that may be used as free- radical scavengers.

In general, the compounds of the invention of the formula I or of the formula II are preferably administered in doses ranging approximately between 1 and 500 mg and in particular between 5 and 100 mg per unit dose. The daily dose is preferably approximately between 0.02 and 10 mg/kg of body weight. However, the specific dose for each patient depends on all kinds of factors, for example the efficacy of the compound used, the age, body weight, general state of health and sex, the diet, the time and route of administration and the level of excretion, medicinal products taken in conjunction, and the severity of the particular disorders for which the therapy is applied.

Oral administration is preferred.

The present invention is illustrated below in the light of the following examples.

The frequency of the NMR machine used to record the proton spectra in the examples given below is 300 MHz.

The LC-MS spectra are obtained on a simple quadrupole machine equipped with an electron-spray probe. EXAMPLES

Example 1

Step a : Methyl (4-tert-butoxycarbonylaminophenoxy)acetate. tert-Butyl (4-hydroxyphenyl)carbamate (prepared by the method J.

Med. Chem., 1995, 38, (20), pp. 3983-3994), (13.12 g, 62.7 mmol) is dissolved in 150 ml of acetone, followed by addition of caesium carbonate (1.1 eq,

69 mmol; 22.5 g) and one crystal of potassium iodide. The reaction medium is refluxed for four hours. The crude product is filtered off and then evaporated to dryness. The residue is taken up in ethyl acetate and washed with saturated bicarbonate solution. The organic phase is dried over Na₂SO₄ and then evaporated to dryness.

The product is obtained is chromatographed on silica with 4:1 hexane/EtOAc (Rf = 0.25) to give 12.3 g of the expected compound.

Yield = 70%

¹H NMR (CDCI3): 1.49 (9H, s); 3.79 (3H, s); 4.59 (2H, s); 6.34 (1H, broad s);

6.79-6.89 (2H, m); 7.15-7.32 (9H, s)

Step b :

Methyl (4-aminophenoxy)acetate.

Methyl (4-tert-butoxycarbonylaminophenoxy)acetate (12.3 g; 43.7 mmol) is d issolved in 40 ml of dioxane, followed by addition of 40 ml of trifluoroacetic acid. The reaction medium is left at room temperature for one hour and is then evaporated to dryness. The crude product is taken up in CH₂CI₂ and washed with saturated bicarbonate solution. The organic phase is dried over Na₂SO₄ and evaporated to dryness to give 6.6 g of the expected product.

Yield = 85% ¹H NMR (CDCI₃): 3.13-3.63 (2H, broad exchangeable s); 3.77 (3H, s); 4.54 (2H, s); 6.53-6.68 (2H, m); 6.69-6.82 (2H, m)

Step c :

Methyl [4-(4-nitrophenyiamino)phenoxy]acetate. CS2CO3 (13.7 g, 42 mmol), 2.5 M% Pd₂(dba)₃ (0.687 g;

0.75 mmol), racemic 7.5 M % 2 ,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl ( 1.40 g; 2.25 mmol), para-bromonitrobenzene (6.06 g; 30 mmol) and methyl (4-tert- butoxycarbony!aminophenoxy)acetate (6.52 g; 42 mmol) are dissolved in 90 ml of anhydrous diglyme under nitrogen. The reaction medium is heated for 12 hours at 100°C. The crude product is poured into ice-cold water, ether is added and the two phases are filtered through Celite. The organic phase is then washed with water (twice), dried over Na₂SO₄ and chromatographed on silica. Elution with 3:7 to 2:8 hexane/CH₂CI₂. Rf = 0.6 for 1 :1 hexane/EtOAc.

1.94 g of the expected compound are obtained in the form of a yellow solid. Yield = 21.4%

IR: NH = 3347 cm^'1; CO = 1742 cm^"1.

¹H NMR (CDCI₃) = 3.82 (3H, s); 4.65 (2H, s); 6.10 (1 H, broad s); 6.73-6.83 (2H, m); 6.88-6.99 (2H, m); 7.05-7.21 (2H, m); 7.94-8.23 (2H, m).

Step d :

[4-(4-Nitrophenylamino)phenoxy]acetic acid hydrazide.

Methyl [4-(4-nitrophenylamino)phenoxy]acetate (1.65 g;

5.45 mmol) is dissolved in 150 ml of methanol. Hydrazine hydrate (8 eq; 43.66 mmol, 2.1 ml) is added and the reaction medium is refluxed for 30 minutes. The reaction medium is then evaporated to dryness to give 1.65 g of the expected hydrazide. Quantitative yield.

¹H NMR (DMSO-d6) = 4.33 (2H, broad s); 4.47 (2H, s); 6.80-7.10 (4H, m); 7.11- 7.31 (2H, m); 7.97-8.09 (2H, m); 9.12 (1 H, broad s); 9.34 (1 H, broad s)

Step e :

[4-(4-Nitropheny!amino)phenoxy]ethanoyl (2-hydroxy-5-methoxy- benzylidene)hydrazide. [4-(4-Nitrophenylamino)phenoxy]acetic acid hydrazide (126.9 mg,

0.42 mmol) is dissolved in 12 ml of ethanol, pyridine (2 ml) and 2-hydroxy-5- methoxybenzaldehyde (1.5 eq., 0.63 mmol, 95.8 mg) are added and the reaction medium is left overnight at room temperature. The expected product precipitates out, and is filtered off, rinsed with ethanol and dried to give 130 mg of the expected compound. Yield = 71%

¹H NMR (DMSO-d6) = 3.69 and 3.71 (3H, sd); 4.68 (1H, s); 5.13 (1H, s); 6.69- 7.35 (9H, m); 7.89-8.16 (2H, m); 8.16-8.66 (1H, m); 9.12 (1H, m); 10.52 (1H, broad s); 11,71 (1H, broad s).

Step f :

N-Nitroso[4«(4-nitrophenylamino)phenoxy]ethanoyl (2-hydroxy-5- methoxybenzylidene)hydrazide.

[4-(4-Nitrophenylamino)phenoxy]ethanoyl (2-hydroxy-5-methoxy- benzylidene)hydrazide (125 mg; 0.29 mmol) is dissolved in a 1/1/1 THF/CH₃CN/EtOH mixture (30 ml), and 3.2 ml of a 15% solution of ethyl nitrite in ethanol are then added. The reaction medium is stirred for 12 hours and is then evaporated to dryness. The product is taken up in the minimum amount of acetonitrile, precipitated from water and freeze-dried to give the nitrosated product quantitatively: expected, compound 1. ¹H NMR (DMSO-d6) = 3.80 (3H, s); 4.83 (1H, s); 5.26 (1 H, s); 6.80-7.80 (9H, m); 8.19-8.70 (3H, m); 11.82 (1 H, broad s); 12.15 (1H, broad s).

Example 2

Step a :

Methyl [4-(4-methoxyphenylamino)phenoxy]acetate.

4-Hydroxy-4'-methoxydiphenylamine (prepared as in CA. (1958), 52, 7183i), (5.23 g; 15 mmol) is dissolved in acetone (150 ml), followed by addition of K₂CO₃ (1.5 eq; 22.5 mmol, 3.9 g), methyl bromoacetate (2.3 eq. ,34 mmol, 3.2 ml) and KI (one crystal). The reaction medium is refluxed for 2.5 hours and is then filtered, evaporated to dryness, taken up in EtOAc and washed successively with saturated bicarbonate solution, water and saturated NaCl solution. The organic phase is dried over Na₂S0₄ and evaporated to dryness. The crude product is chromatographed on silica, eluting with CH₂CI₂ and then with 19:1 CH₂CI₂/EtOAc. Rf = 0.8 for 1:1 CH₂CI₂/EtOAc. To give 4.0 g ofthe expected compound. Yield = 93% IR : 3422 cm^'1 (NH); 1768 cm^'1 (CO). ¹H NMR (DMSO-d6) = 3.67 and 3.69 (6H, sd); 4.67 (2H, s); 6.64-7.21 (8H, m); 7.66 (1H, broad s).

Step b :

Methyl [4-(4-methoxyphenylamino)phenoxy]acetate (287 mg; 1.0 mmol) is dissolved in acetic acid (15 ml), followed by addition of NaNO₂ (1.2 eq. 1.2 mmol; 83 mg) dissolved in H₂O (2 ml). The reaction medium is stirred at room temperature for 2 hours and then poured into water, and the solution is neutralised with 30% NH₄OH solution.

The solution is extracted with EtOAc. The organic phase is washed with water (twice) and then dried over Na₂S0₄ and evaporated to dryness to give 290 mg of the expected compound in the form of a red-brown oil: compound 2. Yield = 92 %

¹H NMR (DMSO) = 3.69 and 3.71 (3H, sd); 3.78 and 3.79 (3H, sd); 4.84 and 4.86 (2H, sd); 6.91-7.56 (8H, m)

Example 3

Step a:

Potassium [4-(4-methoxyphenylamino)phenoxyJacetate Methyl [4-(4-methoxyphenylamino)phenoxy]acetate (3.65 g,

127 mmol) is dissolved in methanol (120 ml), followed by addition of KOH (1.2 eq., 1 52.4 mmol, 0.86 g ) d issolved i n water (3.8 ml). The reaction medium is stirred at room temperature for 2 hours. The precipitate is filtered off, washed successively with MeOH and ether (three times) and is then dried under vacuum to give 3.95 g of the expected compound. Yield = 82 % ¹H NMR (D₂O) = 3.77 (3H, s); 4.41 (2H, s); 6.73-7.38 (8H, m) Step b : {4-[4-Methoxyphenyl]-2,2-oxahydrazino]phenoxy}acetic acid

By carrying out an operating protocol similar to that of Example 2, step b, the expected compound is prepared starting with the compound obtained in step a). Yield = 79 %

¹H NMR (DMSO) = 3.78 and 3.79 (3H, sd); 4.71 and 4.73 (2H, sd); 6.67-7.94 (9H, m)

Example 4

Step a :

N-(2-Diisopropylaminoethy!)-2-[4-(4-methoxyphenylamino)phenoxy]- acetamide

[4-(4-Methoxyphenylamino)phenoxy]acetic acid (343 mg; 1.1 mmol) is dissolved in 10 ml of THF. 1-(3-Dimethylaminopropyl)-3-ethyl- carbodiimide hydrochloride (1 eq., 1.1 mmol, 210 mg) and 2-(diisopropyl- amino)ethylamine (0.91 eq., 1.0 mmol) are added. The reaction medium is stirred for 12 hours at room temperature and is then evaporated to dryness. The crude product is taken up with EtOAc and the insoluble materials are removed by filtration. The organic phase is washed with saturated bicarbonate solution, water and saturated NaCl solution, and then dried over Na₂SO and evaporated and dried to give 0.3 g of the expected compound. Yield = 76 %

¹H NMR (DMSO-d6) = 0.94 (12H, m ); 1.95-2.28 (2H, m ); 2.82-2.94 (2H, m); 3.45-3.78 (5H, m); 4.35 (1 H, s); 4.90 (1 H, s); 6.31-6.19 (8H, m); 7.79 (1 H, s); 8,90 (1 H, s) Step b :

N-[2-(Diisopropylamino)ethyl]-2-{4-[1-(4-methoxyphenyl)-2-oxo- hydrazino]phenoxy}acetamide

By carrying out an operating protocol similar to that of Example 2, step b), the expected compound is prepared starting with the compound obtained in step a. Yield = 90 %

¹H NMR (DMSO-d6) = 0.94 (12H, m); 1.49-1.76 (2H, m); 2.82-3.23 (4H, m); 3.78 and 3.79 (3H, sd); 4.50 and 4.52 (1H ,sd); 5.08 and 5.09 (1H, sd); 6.90- 7.50 (8H, m); 8.75-9.07 (1 H, m)

Table 4 below collates Examples 5 to 25, of the formula:

TABLE 4

EXAMPLE 25

¹H NMR (DMSO-de) δ (ppm) = 4.74 (1H, m); 5.21 (1H, m); 6.71-7.93 (15H, m). Table 5 below collates Examples 26 to 52, of the formula:

TABLE 5

Table 6 below collates Examples 53 to 62, of the formula:

TABLE 6

Table 7 collates the compounds of the formula II, numbered 63 to 94. TABLE 7

Table 8 collates the compounds ofthe formula II, numbered 95 to 133. TABLE 8

Claims

1. Compound of the formula

in which:

R represents a hydrogen atom; a halogen atom; a saturated a liphatic hydrocarbon-based group optionally substituted and/or optionally interrupted by one or more oxygen and sulfur atoms; n is an integer between 1 and 5; i is an integer chosen from 0, 1 , 2, 3, 4 and 5; A represents O or S;

B represents -NW, in which W is a hydrogen atom or a saturated aliphatic hydrocarbon-based group; O; or -N-NO; Z represents a hydrogen atom; a group from the following: amino; alkyiamino; dialkylamino; -nitro; aminoalkyl; alkylaminoalkyl; dialkylaminoalkyl; -alk-Ar, in which alk represents nothing or represents a saturated aliphatic hydrocarbon- based divalent chain and Ar represents an optionally substituted carbocyclic or heterocyclic, saturated, unsaturated and/or aromatic radical; or alternatively a group of the formula:

_ N =^χχ

Ar' in which Ar' is as defined above for Ar; and also the pharmaceutically acceptable salts thereof.

2. Compound according to Claim 1 , in which i represents 0 or 1.

3. Compound according to either of the preceding claims, characterised in that A represents O.

4. Compound according to any one of the preceding claims, characterised in that B represents NH, O or N-NO.

5. Compound according to any one of the preceding claims, characterised in that R is a hydrogen atom; a halogen atom; an optionally halogenated alkyl group; optionally halogenated alkoxy; or optionally halogenated alkylthio.

6. Compound according to any one of the preceding claims, characterised in that Z represents an optionally halogenated aliphatic hydrocarbon-based group; a hydroxyl group; an amino group; alkyiamino; dialkylamino; a group:

in which k represents an integer chosen from 0, 1 , 2, 3, 4 and 5 and L is as defined below; a group:

in which k is as defined above and L is as defined below; a saturated, unsaturated and/or aromatic heterocyclic group Het optionally substituted by one or m ore s ubstituents L as defined below a nd comprising o ne or m ore h etero atoms chosen from O, N and S; or a group: — Q — Het in which Het represents a saturated, unsaturated and/or aromatic heterocyclic group as defined above, optionally substituted by one or more substituents L as defined below and Q represents alkylene; or a group of the formula:

in which j is an integer chosen from 0, 1 , 2, 3, 4 and 5; Het is as defined above and L is as defined below; or Z represents aminoalkyl; alkylaminoalkyl; or dialkylaminoalkyl; L represents a saturated heterocycle comprising one or more hetero atoms chosen from O, N and S optionally substituted by alkyl, alkoxy, halogen, nitro or oxo, such as morpholinyl; a halogen atom; hydroxyl; nitro; optionally halogenated alkyl; optionally halogenated alkoxy; amino; aminoalkyl; and dialkylamino; a group O-alk'-COOH in which alk' represents alkyl.

7. Compound according to any one of the preceding claims, in which n represents 1.

8. Compound according to any one of the preceding claims of the formula I, in which:

A represents O; B represents O; Z is chosen from OH; and alkyl.

9. Compound according to any one of the preceding claims of the formula I, in which:

A represents O; B represents NH; Z represents a group:

in which Het is as defined in Claim 6; a group -Q-Het in which Het is as defined in Claim 6 and Q represents alkylene; a group:

in which L and k are as defined in Claim 6, a group of the formula:

in which L and k are as defined a xbove; aminoalkyl; alkylaminoalkyl; dialkylaminoalkyl; an optionally substituted aromatic or saturated heterocyclic group comprising one or more hetero atoms chosen from O, N and S.

10. Compound according to Claim 1 , chosen from: -N-[4-(N-nitroso-4-nitrophenylamino)phenoxymethylcarbonyl](2-hydroxy-5- methoxybenzylidene)hydrazide; and

-N-nitroso-N-(4-methoxyphenyl)-N-[4-(3-pyridylmethylaminocarbonylmethoxy)- phenyl)phenyl]amine.

11. Process for the preparation of a compound of the formula I according to Claim 1, comprising the reaction of a compound of the formula II:

in which R, i, A, n, B and Z are as defined for formula I in Claim 1, with a nitrosating agent, such as an alkali metal nitrite, in acidic medium.

12. Compound of the formula II

in which R, i, A, B, n and Z are as defined in Claim 1 for formula l.

13. Compound ofthe formula II according to Claim 12, chosen from:

- N-[4-(4-nitrophenylamino)phenoxymethylcarbonyl](2-hydroxy-5-methoxy- benzylidene)hydrazide; and

- N-(4-methoxyphenyl)-N-[4-(3-pyridylmethylaminocarbonylmethoxy)- phenyl]amine.

14. Pharmaceutical composition comprising at least one compound of the formula I according to any one of Claims 1 to 10, in combination with one or more pharmaceutically acceptable excipients.

15. Use of a compound of the formula I according to any one of Claims 1 to 10, for the preparation of an antioxidant medicinal product that may be used as a free-radical scavenger.

16. Use of a compound of the formula I according to any one of Claims 1 to 10, for the preparation of a medicinal product that may be used in the treatment of pathologies characterised by an oxidative stress condition and a lack of availability of endothelial nitrogen monoxide.