FR2832406A1 - New 3-substituted-7-nitro indazole derivatives are neuronal nitric oxide synthase inhibitors used for treating substance, particularly alcohol dependence - Google Patents

Abstract

3-Substituted-7-nitro indazole derivatives (I) and their salts are new. 3-Substituted-7-nitro indazole derivatives of formula (I) and their salts are new. R = H, and R' = N-(R1)(R1a), NH-CO-NH-R3, N=C(R2)(R2a) or CH2-CH2-N(R4)(R5), or R-N-R' = 5- or 6-membered ring optionally a further hetero atom and optionally substituted by 1-4C alkyl, or R is R1, R1a = H, 1-6C alkyl, 3-6C cycloalkyl or 1-4C alkanoyl; R3 = phenyl optionally substituted by halo, 1-4C alkyl, 1-4C haloalkyl or 1-4C alkoxy; R2, R2a = 1-3C alkyl or R2 = H, and R2a = phenyl optionally substituted by halo, 1-4C alkyl, 1-4C haloalkyl or 1-4C alkoxy, or R2 + R2a = 3-6C cycloalkyl, and R4, R5 = H or 1-4C alkyl. An Independent claim is included for the preparation of (I).

Description

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 The subject of the present invention is derivatives of substituted 7-nitroindazoles 3 as well as their salts. It also relates to a process for the preparation of said derivatives and salts as well as the application of these derivatives and salts in human and animal therapy, and more particularly with regard to the treatment of alcohol dependence.

dans laquelle R et R'sont tels que : - R et R'sont reliés l'un à l'autre de manière à former, avec l'atome d'azote, un cycle comprenant de 5 à 6 atomes, l'un au moins des atomes dudit cycle pouvant être un hétéroatome, ledit cycle pouvant être saturé ou non, et substitué par un groupement alkyle en Ci-&num;4 ou non, ou - R est l'atome d'hydrogène et R'est choisi parmi : - un groupement de formule

dans laquelle RI et R'1 sont indépendamment : - un atome d'hydrogène, ou - un groupe alkyle en CI-C6, ou - un groupe cycloalkyle en C3-C6, ou - un groupe alcanoyle en CI-C4 - un groupement de fonnule -NH-CO-NH-R3 dans laquelle R3 représente un groupe phényle, ledit groupe phényle pouvant être substitué par au moins : The invention relates to compounds of formula (I).

in which R and R 'are such that: - R and R' are linked to each other so as to form, with the nitrogen atom, a cycle comprising from 5 to 6 atoms, one at less of the atoms of the said ring being able to be a heteroatom, the said ring being able to be saturated or not, and substituted by an alkyl group in Ci- &num; 4 or not, or - R is the hydrogen atom and R is chosen from: - a grouping of formula

in which RI and R'1 are independently: - a hydrogen atom, or - a C1-C6 alkyl group, or - a C3-C6 cycloalkyl group, or - a C1-C4 alkanoyl group - a group of formula -NH-CO-NH-R3 in which R3 represents a phenyl group, said phenyl group being able to be substituted by at least:

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- un groupe alkoxy en CI-C4 - un groupement de formule

dans laquelle R2 et R'2 sont tels que : - R2 et R'2 représentent un groupe alkyle en CI-C3, ou - R2 et R'2 sont reliés l'un à l'autre de façon à former un groupe cycloalkyle en C3-C6, ou

- R2 est l'atome d'hydrogène et R'2 est un groupement phényle, pouvant être substitué par au moins : un atome d'halogène, ou un groupe alkyle en Ci-C4, ou - un groupe halogénoalkyle en Ci-C4 ou - un groupe alkoxy en Cl-C4 ; un groupement de formule

dans laquelle R4 et R5 sont, de manière indépendante, des atomes

d'hydrogènes ou des groupements alkyles en CI-C4, à l'état de base ou de sel d'addition d'un acide pharmaceutiquement acceptable. a halogen atom or - a C1-C4 alkyl group or - a C1-C4 haloalkyl group, or

- a C1-C4 alkoxy group - a group of formula

in which R2 and R'2 are such that: - R2 and R'2 represent a C1-C3 alkyl group, or - R2 and R'2 are linked to each other so as to form a cycloalkyl group in C3-C6, or

- R2 is the hydrogen atom and R'2 is a phenyl group, which can be substituted by at least: a halogen atom, or a C1-C4 alkyl group, or - a C1-C4 haloalkyl group or - a C1-C4 alkoxy group; a grouping of formula

in which R4 and R5 are, independently, atoms

of hydrogens or of C1-C4 alkyl groups, in the base state or of an addition salt of a pharmaceutically acceptable acid.

 In a particular case of the invention, RI and R'l are not both hydrogen atoms.

 The compounds of formula (1) may have one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures are part of the invention. Likewise, the present invention also relates to compounds having a formula different from

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 the formula (I) but which, by administration to a living being, human or animal, are converted directly or indirectly in vivo into compounds of formula (I).

 The compounds of the invention may exist in the form of bases or of addition salts with pharmaceutically acceptable acids, which are well known in the field. Thus, the salts of the compounds of the invention include the addition salts of a mineral acid, for example nitric, hydrochloric, hydrobromic, sulfuric, perchloric or phosphoric acid, or of an organic acid, for example acetic, propionic, glycolic, lactic, oxalic, mlaonic, malic, fumaric, maleic, tartaric, citric, benzoic, cinnamic, mandelic or salicylic acid.

un atome d'halogène, un fluor, un chlore, un brome ou un iode, - un groupe halogénoalkyle, un groupe alkyle dont un ou plusieurs atomes d'hydrogène ont été substitués par un atome d'halogène, - un groupe cycloalkyle, un groupe alkyle cyclique ; On peut notamment citer les groupes cyclopropyle, cyclobutyle, cyclopetnyle, cyclohexyl etc... un groupe alkényle, un groupe aliphatique mono ou poly-insaturé, linéaire ou ramifié, comprenant de préférence une ou deux saturations éthyléniques, - un hétéroatome, un atome choisi dans le groupe constitué des atomes d'azote, d'oxygène et de soufre, - un groupe alcanoyle, un groupe-RjoO-Rii dans lequel RIO et Rn sont de manière indépendante des groupes alkyles, tels que définis ci-dessus. Les groupes alcanoyles selon l'invention peuvent être substitués. In the context of the present invention, the term “an alkyl group” means a linear or branched saturated aliphatic group; Mention may in particular be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl groups, etc. In the context of the present invention, lower alkyl groups are preferred, that is to say having 1 to 4 carbon atoms.

a halogen atom, a fluorine, a chlorine, a bromine or an iodine, - a haloalkyl group, an alkyl group in which one or more hydrogen atoms have been substituted by a halogen atom, - a cycloalkyl group, a cyclic alkyl group; Mention may in particular be made of cyclopropyl, cyclobutyl, cyclopetnyl, cyclohexyl groups, etc. an alkenyl group, a mono or polyunsaturated aliphatic group, linear or branched, preferably comprising one or two ethylenic saturations, - a heteroatom, a chosen atom in the group consisting of nitrogen, oxygen and sulfur atoms, - an alkanoyl group, a group-RjoO-Rii in which RIO and Rn are independently alkyl groups, as defined above. The alkanoyl groups according to the invention can be substituted.

 - An alkoxy group, a group R120-, in which R12 is an alkyl group, as defined above. Mention may in particular be made of methoxy, ethoxy, t-butoxy groups, and the like. The alkoxy groups according to the invention can also be substituted.

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 It is known that the treatment of 2,7-dinitroindazole with a low molecular weight amine leads simultaneously to isomerization into 3,7-dinitroindazole accompanied by the formation of 3-amino-7-nitroindazole derivatives, the relative proportions being variable; cyclic amines lead to the preferential formation of amino derivatives, acyclic amines to those of 3,7dinitrates derivatives (Wrzeciono et al, Pharmazie, 39, pp 389-391).

 The present invention shows that this reaction can, unexpectedly, be extended to the use of diamine derivatives such as hydrazine, aminoalkylamines, piperazine, imidazole leading in good yields, unlike ammonia, to derivatives 3 -substituted 7 nitroindazole.

In the case of the treatment of 2,7-dinitroindazole with imidazole, the reaction leads to a mixture of 3- (imidazol-1-yl) -7-nitroindazole and of a stable complex between 3,7-dinitroindazole and imidazole, the imidazolinium salt of 3,7dinitroindazole of formula (3).

 The complex of formula (3) above is also an object of the invention, in that this specific complex is considered, in the context of the present invention, as being a salt of the compound of formula (4), defined more after.

 The reaction of 3-hydrazino-7-nitroindazole with either aliphatic ketone derivatives, or aromatic aldehydes, or acid chlorides, or isocyananates leads respectively with good yields to 3alkylidene hydrazino, to 3- (benzylideneimine) hydrazino , to 3-acetylhydrazino and to the corresponding semicarbazides, according to the reactions described in FIG. 1.

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 In a particular embodiment of the invention, the compound of formula (I) according to the invention is such that R and R 'form, with the nitrogen atom, a heteroaryl group, and in another embodiment preferred, the nucleus of said heteroaryl group comprises at least one nitrogen atom.

dans laquelle R7 et R8 représentent, de manière indépendante, CH ou un atome d'azote. In a preferred embodiment, R and R 'form, with the nitrogen atom, a heteroaryl group, of formula

in which R7 and R8 independently represent CH or a nitrogen atom.

In a preferred embodiment of the invention, R7 is a nitrogen atom and R8 represents a CH group, and the compound of the invention is the compound of formula (4):

dans laquelle R représente un atome d'hydrogène ou un groupement alkyle en CI-C4, et de préférence, R représente un groupe méthyle, le composé étant alors le composé (2) décrit plus bas. In another embodiment, the compound of formula (1) according to the invention is such that R and R 'form, with the nitrogen atom, a cycle of formula

in which R represents a hydrogen atom or a C1-C4 alkyl group, and preferably, R represents a methyl group, the compound then being the compound (2) described below.

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dans laquelle R4 et R5 sont, de manière indépendante, des atomes d'hydrogènes ou des groupements alkyles en CI-C4-
Dans ce mode de réalisation, R4 et R5 sont préférentiellement des groupements méthyle, et le composé présente la formule (a) des exemples. In another embodiment, the invention relates to a compound of formula (1), in which R represents a hydrogen atom and R'represent group of formula

in which R4 and R5 are, independently, hydrogen atoms or C1-C4alkyl groups
In this embodiment, R4 and R5 are preferably methyl groups, and the compound has the formula (a) from the examples.

dans lequel RI et R'I sont choisis de façon indépendante parmi un atome d'hydrogène et un groupe méthyle, et on obtient alors les composés de formule (5), (6), ou (7). In another embodiment, the invention relates to a compound of formula (I), in which R represents a hydrogen atom and R ′ represents a group of formula

in which RI and R'I are independently chosen from a hydrogen atom and a methyl group, and the compounds of formula (5), (6) or (7) are then obtained.

 In a particular embodiment, RI and R'1 are not both a hydrogen atom.

dans laquelle R2 et R'2 sont tels que : - R2 et R'2 représentent de façon indépendante un groupe alkyle en
CI-C3, et de façon plus préférée, R2 et R'2 représentent chacun un groupe méthyle. On obtient alors le composé de formule (8) selon l'invention. In another embodiment of the invention, the compound of formula (I) according to the invention is such that R represents a hydrogen atom and R'represent a group of formula

in which R2 and R'2 are such that: - R2 and R'2 independently represent an alkyl group in
CI-C3, and more preferably, R2 and R'2 each represent a methyl group. The compound of formula (8) according to the invention is then obtained.

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dans laquelle R2 et R'2 sont reliés l'un à l'autre de façon à former un groupe cycloalkyle en C3-C6. In an alternative embodiment, the invention relates to a compound of formula (I), in which R represents a hydrogen atom and R ′ represents a group of formula

in which R2 and R'2 are connected to each other so as to form a C3-C6 cycloalkyl group.

A particular embodiment of the invention is such that said cycloalkyl group is at C5, the compound according to the invention of formula (9) is then obtained:

dans laquelle R2 est l'atome d'hydrogène et R'2 est un groupement phényle, pouvant être substitué par au moins : un atome d'halogène, ou un groupe alkyle en CI-C4, ou - un groupe halogénoalkyle en CI-C4 ou - un groupe alkoxy en CI-C4 ;
Des composés préférés dans ce mode de réalisation sont choisi parmi les composés In another embodiment, the invention relates to a compound of formula (1), in which R represents a hydrogen atom and R ′ represents a group of formula

in which R2 is the hydrogen atom and R'2 is a phenyl group, which may be substituted by at least: a halogen atom, or a C1-C4 alkyl group, or - a C1-C4 haloalkyl group or - a C1-C4 alkoxy group;
Preferred compounds in this embodiment are selected from the compounds

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Dans un autre mode de réalisation, celle-ci se rapporte à un composé de formule (1), dans lequel R est l'atome d'hydrogène et R'représente un groupement de fonnule -NH-CO-NH-R3 dans laquelle R3 représente un groupe phényle, ledit groupe phényle pouvant être substitué par au moins : un atome d'halogène ou - un groupe alkyle en CI-C4 ou - un groupe halogénoalkyle en Ci-C4, ou - un groupe alkoxy en CI-C4

In another embodiment, this relates to a compound of formula (1), in which R is the hydrogen atom and R'represent a group of formula -NH-CO-NH-R3 in which R3 represents a phenyl group, said phenyl group being able to be substituted by at least: a halogen atom or - a C1-C4 alkyl group or - a C1-C4 haloalkyl group, or - a C1-C4 alkoxy group

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Preferred compounds in this embodiment are chosen from the compounds of formula:

In one of the preferred embodiments, the compound according to the invention is in the form of a salt of the compound of general formula (I), said salt having the formula:

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avec un cation pharmaceutiquement acceptable, tel que les sels d'acides déjà cités. i
L'invention se rapporte également à un composé de formule générale (I) selon l'invention, à titre de médicament.

with a pharmaceutically acceptable cation, such as the acid salts already mentioned. i
The invention also relates to a compound of general formula (I) according to the invention, as a medicament.

 The present invention also relates to pharmaceutical compositions comprising, as active principle, one of the compounds defined above and an appropriate excipient. These compositions can be formulated for administration to mammals, including humans. The dosage varies depending on the treatment and the condition in question. In general, the appropriate dose could be in the range of 0.1 to 2 mg / kg / day, for oral or parenteral administration. The daily dosage for an adult weighing 70 kg would therefore be between 7 and 140 mg, although the upper limit may be exceeded. This dosage can also be adapted to the sex of the patient, as well as to other physiological factors relating to him.

 These compositions are produced so that they can be administered by the digestive or parenteral route.

 In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, the active ingredient can be administered in unit administration forms, in admixture with excipients and / or other active ingredients, to animals or humans. Suitable unit administration forms include oral forms such as tablets, coated tablets, dragees, soft gelatin capsules and capsules, powders, granules and oral solutions or suspensions, administration forms sublingual and oral, subcutaneous administration forms,

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 intramuscular, intravenous, intranasal or intraocular and forms of rectal administration.

 The pharmaceutical compositions can also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorings, flavors, salts intended to modify the osmotic pressure, buffers, taste correctors or antioxidants. They may also contain other therapeutically active substances.

 When preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, stearic acid or magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or other suitable materials or they can be treated in such a way that they have a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.

 A preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules, with vegetable oils, waxes, fats, semisolid or liquid polyols etc. as an excipient.

actif conjointement avec un édulcorant, un antiseptique, ainsi qu'un agent donnant i du goût et un colorant approprié. On utilise des excipients tels l'eau, les polyols, le saccharose, le sucre inverti, le glucose... A preparation in the form of syrup or elixir may contain the ingredient

active together with a sweetener, an antiseptic, as well as a flavoring agent and an appropriate color. Excipients are used such as water, polyols, sucrose, invert sugar, glucose ...

 The water-dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, as well as with flavor correctors or sweeteners.

 For rectal administration, suppositories are used which are prepared with binders which melt at rectal temperature, for example semi-solid or liquid polyols such as polyethylene glycols, waxes, natural or hydrogenated oils, fats, etc.

 For parenteral, intranasal or intraocular administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used which contain dispersing agents and / or wetting agents.

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 pharmacologically compatible. As an excipient, water, alcohols, polyols, glycerol, vegetable oils, etc. can be used.

 The active principle can also be formulated in the form of microcapsules, optionally with one or more additive supports.

 The invention also relates to the use of a compound according to the invention for the preparation of a medicament intended for treating an addiction or dependence, and in particular alcohol dependence. However, other types of addiction can be considered, such as addictions linked to the abuse of psychotropic substances, such as cocaine, amphetamines, heroin and opiates, but also dependence induced by taking drugs.

 The invention also relates to the use of a compound according to the invention for the preparation of a medicament intended to be used as an analgesic.

 The invention also relates to the use of a compound according to the invention for the preparation of a medicament intended to be used as an anxiolytic.

 In a particular embodiment, as we have seen, the medicament is administered by injectable route, but can also be administered by oral route.

 The invention also relates to a method of treatment of a mammal, preferably human, suffering from an addiction, in which said mammal is administered a therapeutically effective dose of the compound of formula (I) according to the invention, alone or in a pharmaceutical composition according to the invention.

 The invention also relates to a process for the preparation of a compound of formula (I) according to the invention, and more precisely when R represents a hydrogen atom and R'represent a group of formula

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dans lequel RI et R'1 sont choisis de façon indépendante parmi un atome d'hydrogène et un groupe méthyle, comprenant l'étape de réaction du 2,7dinitroindazole avec un composé de formule NHRIR'I.

wherein RI and R'1 are independently selected from a hydrogen atom and a methyl group, comprising the step of reacting 2,7dinitroindazole with a compound of formula NHRIR'I.

dans laquelle Rl et R'l sont indépendamment : un atome d'hydrogène, ou - un groupe alkyle en Cl-C6, ou un groupe cycloalkyle en C3-C6, ou - un groupe alcanoyle en Cl-C4, - un groupement de formule

dans laquelle R4 et R5 sont, de manière indépendante, des atomes d'hydrogènes ou des groupements alkyles en CI-C4. The invention also relates to a process for the preparation of a compound of formula (I) according to the invention, comprising the step of reacting 2,7dinitroindazole with a compound of formula
NHRR 'in which R, and R' are such that: - R and R 'are linked to each other so as to form, with the nitrogen atom, a cycle comprising from 5 to 6 atoms, l '' at least one of the atoms of the said ring being able to be a heteroatom, the said ring being able to be saturated or not, and substituted by a C1-C4 alkyl group or not, or - R is the hydrogen atom and R is chosen from : - a grouping of formula

in which R1 and R'l are independently: a hydrogen atom, or - a C1-C6 alkyl group, or a C3-C6 cycloalkyl group, or - a C1-C4 alkanoyl group, - a group of formula

wherein R4 and R5 are, independently, hydrogen atoms or C1-C4 alkyl groups.

 This preparation process is preferably carried out in a polar aprotic solvent, in particular tetrahydrofuran.

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dans laquelle R2 et R'2 sont tels que : - R2 et R'2 représentent un groupe alkyle en C1-C3, ou - dans laquelle R2 et R'2 sont reliés l'un à l'autre de façon à former un groupe cycloalkyle en C3-C6, ou - dans laquelle R2 est l'atome d'hydrogène et R'2 est un groupement phényle, pouvant être substitué par au moins : un atome d'halogène, ou - un groupe alkyle en Ci-C4, ou - un groupe halogénoalkyle en CI-C4 ou - un groupe alkoxy en Cl-C4 ; ledit procédé comprenant l'étape de réaction du 3-hydrazino-7-nitroindazole avec un composé de formule

The subject of the invention is also a process for the preparation of a compound of formula (I) in which R represents a hydrogen atom and R'represent: - a group of formula

in which R2 and R'2 are such that: - R2 and R'2 represent a C1-C3 alkyl group, or - in which R2 and R'2 are linked to each other so as to form a group C3-C6 cycloalkyl, or - in which R2 is the hydrogen atom and R'2 is a phenyl group, which can be substituted by at least: a halogen atom, or - a C1-C4 alkyl group, or - a C1-C4 haloalkyl group or - a C1-C4 alkoxy group; said process comprising the step of reacting 3-hydrazino-7-nitroindazole with a compound of formula

In another embodiment, the invention also relates to a process for the preparation of a compound of formula (1) according to the invention, in which R is the hydrogen atom and R're represents a group of formula -NH-CONH-R3 in which R3 represents a phenyl group, said phenyl group being able to be substituted by at least: a halogen atom or - a C1-C4 alkyl group OR - a C1-C4 haloalkyl group, or a C1-C4 alkoxy group

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 said process comprising the step of reacting 3-hydrazino-7-nitroindazole with a compound of formula: R3-NCO.

 DESCRIPTION OF THE FIGURES Figure 1: Scheme for obtaining compounds according to the invention Figure 2: Dose effect of the compound (4) (mg / kg) on alcohol consumption Figure 3: Study of the effect of the compound (4) , in chronic treatment for 12 days Figure 4: Study of alcohol consumption during treatment with compound (4), at a dose = 11.5 mg / kg / d for 5 days, and repeated a second time.

Figure 5: Comparison of alcohol consumption, between compound 4 and 7-NI.

Figure 6: Effect of compound (4) in oral treatment for 3 days on alcohol consumption.

 The examples which follow are intended to illustrate certain aspects of the invention and should not be considered as limiting.

A une solution de 2g (9,6 mmole) de 2,7-dinitroindazole dans 30 ml de

tetrahydrofuranne agité à la température de 0 C, sont additionnés 2, 1 ml (14, 4 mmole) de N, N-diméthyléthylènediamine. Le mélange réactionnel est ensuite agité pendant une heure, puis à température ambiante pendant 2 heures. On obtient 1, 7g (62%) d'une huile brune constituée par le composé recherché. Cette huile est chauffée dans 30 ml d'acétone. A chaud, est ajouté 0,7g (6 mmole) d'acide fumarique. Puis le mélange réactionnel est laissé revenir à température ambiante. EXAMPLES Example 1: 3- (2- (N, N-dimethylamino) -ethylamino] -7-nitroindazole, fumarate (a)

To a solution of 2g (9.6 mmol) of 2,7-dinitroindazole in 30 ml of

2.1 ml (14.4 mmol) of N, N-dimethylethylenediamine are added to tetrahydrofuran, stirred at a temperature of 0 ° C. The reaction mixture is then stirred for one hour, then at room temperature for 2 hours. 1.7 g (62%) of a brown oil are obtained, consisting of the desired compound. This oil is heated in 30 ml of acetone. When hot, 0.7 g (6 mmol) of fumaric acid is added. Then the reaction mixture is allowed to return to ambient temperature.

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 The crystals obtained are drained, dried and recrystallized from acetone. 2g of fumarate (1) are obtained in the form of red crystals.

A une solution de 2g (9,6 mmole) de 2,7-dinitroindazole en solution dans 30

ml de tétrahydrofuranne agitée à 0 C sont additionnés 1, 6 ml de Nméthylpipérazine. Le mélange réactionnel est ensuite agité à 0 C pendant une heure puis à température ambiante pendant deux heures. Le précipité obtenu est essoré, rincé à l'eau, séché et recristallisé dans le méthanol. Nous obtenons 2,1 g (65%) du composé recherché (2) sous forme de cristaux rouges. 1 H-NMR (DMSO-d6); 8 ppm = 12.49 (s, NH); 8.25 (m, H4 and H6); 7.12 (t, HS); 6.80 (s, NH); 6.55 (s, CH = CH); 3.50 (m, CH2-NH); 2.88 (t, CH2N) (CH3) 2; 2.50 (s, 2CH3) Melting point = 248 C IR (KBr) vom-l = 3290 (NH), 1631 (C = N) Analysis (C15HIgNsO6) Example 2: 3- (4'-methylpiperazino) -7 -nitroindazole (2)

To a solution of 2g (9.6 mmol) of 2,7-dinitroindazole in solution in 30

1.6 ml of N-methylpiperazine are added to ml of tetrahydrofuran stirred at 0 ° C. The reaction mixture is then stirred at 0 C for one hour and then at room temperature for two hours. The precipitate obtained is drained, rinsed with water, dried and recrystallized from methanol. We obtain 2.1 g (65%) of the desired compound (2) in the form of red crystals.

1N NMR (DMSO-d6); 8 ppm = 12.95 (s, NH); 8.38-8.29 (m, H4 and H6); 7.20 (t, H5); 3.36 (m, 2CH2); 2.53 (m, 2CH2); 2.25 (s, CH3) Melting point = 244 oC IR (KBr) vcm - '= 3100 (NH), 1625 (C = N Analysis (C12H1sNs02)

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Exemple (3) et (4) : sel d'imidazolinium du 3, 7-dinitroindazole (3) et 3- (imidazol-l- yl)-7-nitroindazole (4)

Example (3) and (4): imidazolinium salt of 3, 7-dinitroindazole (3) and 3- (imidazol-1-yl) -7-nitroindazole (4)

A une solution de 2 g (9, 6 mmole) de 2, 7-dinitroindazole dans 30 ml de tetrahydrofuranne agitée à la température de 0 C sont additionnés 1, 3 g d'imidazole. Le mélange réactionnel est agité à 0 C pendant une heure puis abandonnée à température ambiante pendant 2 heures. Il si forme un précipité de couleur brune, lequel est essoré, séché puis recristallisé dans l'éthanol pour donner le sel (3) sous forme de cristaux jaunes (1, 3 g ; 63%).

1.3 g of imidazole are added to a solution of 2 g (9.6 mmol) of 2, 7-dinitroindazole in 30 ml of tetrahydrofuran stirred at 0 ° C. The reaction mixture is stirred at 0 C for one hour and then left at room temperature for 2 hours. It forms a brown precipitate, which is drained, dried and then recrystallized from ethanol to give the salt (3) in the form of yellow crystals (1, 3 g; 63%).

The filtrate from the previous reaction is concentrated to dryness under reduced pressure. The solid residue is dissolved in 50 ml of ethyl ether. The ethereal solution thus obtained is discolored on animal charcoal, filtered and then concentrated in vacuo to half. It is left in the refrigerator for 12 hours. The yellow crystals formed are drained to give 0.3 grams (15%) of compound 4.

Compound (3): 1 H NMR (DMSO-d6); ppm ppm = 12.29 (s, NH); 8.59 (d, H6); 8.47 (d, H4); 7.84 (s, H2); 7.68 (t, Hs); 7, ll (d, H4 and Hs) Melting point = 192 C IR (KBr) v cm - '= 3160 (NH), 1625 (C = N) Analysis (CIOHsN604) Compound (4):

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1 H-NMR (DMSO-d6); 8 ppm = 12.29 (s, NH); 8.42 (d, H6); 8.27 (d, H4); 7.92 (m, H2, Hs); 7.32 (d, 14 and Hs) Melting point = 230 C IR (KBr) v cm - '= 3100 (NH), 1620 (C = N) Analysis (C10H7N5O2) Example 5: 3-hydrazino-7-nitroindazole (5)

To a solution of 2 g (9.6 mmol) of 2,7-dinitroindazole in 30 ml of tetrahydrofuran stirred at 0 C is added 0.7 ml (14.4 mmol) of hydrazine then the reaction mixture is stirred at 0 C for one hour then at room temperature for 2 hours. The precipitate obtained is drained, then dried. After recrystallization from water, 1.2 g (65%) of the desired compound (5) are obtained in the form of brown crystals.

1 H NMR (DMSO-c4); ppm ppm = 12.60 (s, NH); 8.25 (m, H4 and H6); 7.63 (s, NH); 4.20 (s, NH2); 7.68 (t, HS); 7.11 (d, H4 and Hs) Melting point = 225 C IR (KBr) cm '' = 3400-3200 (NH), 1630 (C = N), 1520 (C = N) Analysis (C7H7N502) Example 6 : 3- (2'-methylhydrazino) -7-nitroindazole (6)

According to the same operating protocol as in Example (5), 2 g (9.6 mmol) of 2,7-dinitroindazole and 0.8 ml (14.4 mmol) of methylhydrazine are used.

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 to obtain 1.40 g (68%) of the desired compound (6) in the form of brown crystals after recrystallization from ethanol.

1 H-NMR (DMSO-d6); 8 ppm = 12.67 (s, NH); 8.76 (d, H6); 8.26 (d, H4); 7.13 (t, H5); 4.75 (s, NH); 3.14 (s, CH3) Melting point> 260 C IR (KBr) cm '' = 3350-3260 (NH), 1627 (C = N) Analysis (C8H9N502) Example 7: 3- (N, N-dimethylhydrazino ) -7-nitroindazole (7)

According to the same operating protocol as in example (5), 2 g (9.6 mmol) of 2,7-dinitroindazole and 1.1 ml (14.4 mmol) of N, N-dimethyl hydrazine are used. obtain 1.1 g (52%) of the desired compound (7) in the form of yellow crystals after recrystallization from acetonitrile.

1 H-NMR (DMSO-d6); 8 ppm = 12.65 (s, NH); 8.67 (d, H6); 8.51 (d, H4); 7.56 (t, Hs); 7.15 (s, 2NH); 3.93 (s, 2 CH3) Melting point> 2600C IR (KBr) cm - '= 3235 (NH), 1635 (C = N) Analysis (C9HIlNs02) Example 8: 3- (isopropylidenehydrazino) -7-nitroindazole ( 8)

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A solution of 1 g (5.2 mmol) of 3-hydrazino-7-nitroindazole (5) in 30 ml of acetone is heated at reflux for one hour. The solvent is removed in vacuo and the residue recrystallized from ethanol. 0.9 g (73%) of the desired compound (8) are obtained in the form of brown crystals.

1 H-NMR (DMSO-d6); 5 ppm = 12, 80 (s, NH); 9.50 (s, HI); 8, 65 (d, H; 8, 29 (d, H6); 7.18 (t, H5) Melting point = 205 C IR (KBr) cm-1 '= 3350 (NH), 1640 and 1615 (C = N) Analysis (CHOx) Example 9: 3- (cyclopentylidene hydrazino) -7-nitro indazole (9)

A solution of 1 g (5.2 mmol) of 3-hydrazino-7-nitroindazole (5) in 25 ml of cyclopentanone is heated at reflux for 1 hour. The solvent is removed in vacuo and the residue recrystallized from ether. 1 g (76%) of the desired derivative (9) is obtained in the form of brown crystals.

H6) ; 7, 18 (t, Hs) ; 2, 41 (m, 2CH2) ; 1, 81-1, 71 (m, 2CH2) Point de fusion = 224 C IR (KBr) cm-'= 3480 et 3230 (NH), 1630 (C=N) Analyse (C12H13N502) Exemple 10 : 3- (2-acétylhydrazino)-7-nitroindazole (10)

1 H-NMR (DMSO-d6); 8 ppm = 12.79 (s, NH); 9.39 (s, NH); 8.60 (d, H4); 8.29 (d,

H6); 7.18 (t, Hs); 2.41 (m, 2CH2); 1, 81-1, 71 (m, 2CH2) Melting point = 224 C IR (KBr) cm - '= 3480 and 3230 (NH), 1630 (C = N) Analysis (C12H13N502) Example 10: 3- (2 -acetylhydrazino) -7-nitroindazole (10)

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A solution containing 1 g (5.2 mmol) of 3-hydrazino-7-nitroindazole (5), 0.45 ml (6.2 mmol) of acetyl chloride and 0.85 ml of triethylamine in 25 ml of toluene is heated to around 70 ° C. for 2 hours. The precipitate obtained is drained, rinsed with ether and then with water. This solid is then taken up in 40 ml of ethyl acetate and washed twice with 25 ml of a saturated solution of sodium hydrogencarbonate. The organic phase is then dried (magnesium sulfate) and then concentrated in vacuo. After recrystallization from isopropanol, we obtain 0.75 g (63%) of the desired derivative (10) in the form of yellow crystals.

1 H-NMR (DMSO-d); S ppm = 12.71 (s, NH); 9.95 (s, NH); 8.62 (s, NH); 8.29 (m, H4 and H6); 7.81 (t, Hs); 1.88 (s, CH3) Melting point> 260 C IR (KBr) cm - '= 3396, 3352 and 3275 (NH), 1661 (C = O), 1635 (C = N) Analysis (C9H9N403) Example 11 : 1- (7-nitroindazole-3-yl) -4-phenyl-semicarbazide (11)

A solution of 1 g (5.2 mmol) of 3-hydrazino-7-nitroindazole (5) and 0.6 ml (5.7 mmol) of phenylisocyanate in 30 ml of toluene is heated under reflux for 1 hour. The precipitate obtained is drained, rinsed with ether and recrystallized from acetone. 1.1 g (72%) of sought compound (11) are obtained in the form of red crystals.

1 H-NMR (DMSO-dt;); 8 ppm = 12.80 (s, NH); 8.86 (s, NH); 8.66 (s, NH); 8.28 (m, 3H aromatic); 7.50 (s, NH): 7.22 (m, 3H aromatic); 6.91 (t, 1 aromatic H) Melting point> 260 C IR (KBr) cm - '= 3340-3210 (NH), 1691 (C = O), 1634 (C = N) Analysis (Cl4Hl2N503)

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Example 12: 1- (7-nitroindazole-3-yl) -4- (4-fluorophenyl) semicarbazide (12)
According to the same operating protocol as in Example (11), 1 g (5.2 mmol) of 3-hydrazino-7-nitroindazole (5) and 0.65 ml (5.7 mmol) of 4 are used. -fluorophenylisocyanate to obtain 1.1 g (68%) of the desired compound (12) in the form of yellow crystals after recrystallization from ethanol.

T-NMR (DMSO-d6); 8 ppm = 12.80 (s, NH); 8.94 (s, NH); 8.65 (s, NH); 8.29 (m, 3H aromatic); 7.53 (s, NH): 7.21 (m, NH); 7.05 (s, 2H aromatic) Melting point> 260 C IR (KBr) cm-l = 3339 and 3200 (NH), 1680 (C = O), 1635 (C = N) Analysis (Cl4HllNs03F) Example 13: 1- (7-nitroindazole-3-yl) 4- (3-trifluoromethyl) -phenyl) semicarbazide (13)

According to the same operating protocol as in Example (12), 1 g (5.2 mmol) of 3-hydrazino-7-nitroindazole (5) and 0.80 ml (5.7 mmol) of 3 are used. -trifluorophenylisocyanate to obtain 1.2g (64%) of the desired derivative (14) in the form of yellow crystals after recrystallization from acetonitrile

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 1 H-NMR (DMSO-d6); 8 ppm = 12.81 (s, Hl); 9.28 (s, NH); 8.70 (s, NH); 8.53 (s, 1H aromatic); 8.26 (m, 2H aromatic) 8.04 (m, 1H aromatic); 7.68 (s, NH); 7.45 (m, 1H aromatic); 7.25 (m, 2H aromatic).

Melting point> 260 C IR (KBr) cm - '= 3325 and 3215 (NH), 1690 (C = O), 1635 (C = N) Analysis (ClsHIIN603F3) Example 14: 1- (7-nitroindazole-3- yl) -4- (2,4-dimethoxy) phenyl) semicarbazide (14)

According to the same operating protocol as in Example (12), 1 g (5.2 mmol) of 3-hydrazino-7-nitroindazole (5) and 1 g (5.7 mmol) of 2,4dimethoxyphenylisocyanate are used. to obtain 1.4 g (73%) of the desired derivative (15) in the form of orange crystals after recrystallization from ethanol.

1 H-NMR (DMSO-d6); 8 ppm = 12.57 (s, NH); 8.65 (s, NH); 8.55 (s, NH); 8.30 (m, 2H aromatic); 8.20 (m, 1 aromatic H); 7.90 (m, 1 H aromatic); 7.25 (m, 1H aromatic); 6.60 (s, NH); 6.40 (m, 1H aromatic); 3.50 (s, CH3).

Melting point> 260 C IR (KBr) cm '= 3310 and 3265 (NH), 1660 (C = O), 1620 (C = N) Analysis (Cl6Hl6N605) Example 15: 3- [(benzylidene imine) hydrazino] - 7-nitroindazole (15)

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A solution containing 19 (5.2 mmol) of 3-hydrazino-7-nitroindazole (5) and 0.7 ml (7.2 mmol) of benzaldehyde in 25 ml of cyclopentanone is heated under reflux for one hour. The precipitate obtained is drained, rinsed with ethanol and recrystallized from acetone. After recrystallization from acetone, the desired compound (15) (1.1 g; 77%) is obtained in the form of brown crystals.

1 H-NMR (DMSO-d6); 5 ppm: 12.59 s, NH); 10.24 (s, NH); 8.72 (s, CH); 8.38 (d, H6); 8.21-7.18 (m, 7H aromatic).

Melting Point: 250 C IR (KBr) cm '': 3295 (NH), 1630 (C = N) Analysis: (CHnNsOz) Example 16: 3 - [(2'-trifluoromethylbenzylidene imine) -hydrazino] -7-nitroindazole (16)

According to the same protocol as in Example (15), 1 g (5.2 mmol) of 3-hydrazino-7-nitroindazole and 1 ml (7.7 mmol) of 2trifluoromethylbenzaldehyde are used. After recrystallization from methanol, 1.35 g (75%) of the desired compound (16) are obtained in the form of brown crystals.

1 H-NMR (DMSO-d6); 8 ppm = 13.02 (s, NH); 11.61 (s, NH); 8.65 (s, CH); 8.39-7.27 (s, 7H aromatic) Melting Point:> 260 C IR (KBr) cm- ': 3470 (NH), 1615 (C = N).

Analysis: (C14H10N5O2F3)

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Example 17: 3- [(2 ', 3', 4'-trimethoxybenzylidene imine) -hydrazino] -7-nitroindazole (17)

Selon le même protocole que dans l'exemple (15), on met en oeuvre 1 g (5, 2 mmole) de 3-hydrazino-7-nitroindazole et 1, 3g (7, 2mmole) de 2, 34triméthoxybenzaldéhyde pour obtenir 1, 5g (80%) du dérivé recherché (17) sous forme de cristaux marrons après recristallisation dans l'éthanol.

According to the same protocol as in Example (15), 1 g (5.2 mmol) of 3-hydrazino-7-nitroindazole and 1.3 g (7.2 mmol) of 2.34 trimethoxybenzaldehyde are used to obtain 1, 5g (80%) of the desired derivative (17) in the form of brown crystals after recrystallization from ethanol.

1 H NMR (DMSO-de) = ppm ppm = 12.88 (s, NH); 11, 10 (s, NH); 8.69 (s, CH); 8.33-6.93 (s, 5H aromatic); 3, 48-3, 78 (s, 3CH3).

Melting Point:> 260 C IR (KBr) cm '': 3440 and 3230 (NH), 1620 (C = N).

Analysis: (CnHnNsOs) Example 18: Study of the properties of the compounds according to the invention The compounds of formula (1) and their acceptable pharmacological salts were studied ex vivo and then in vivo with the aim of demonstrating pharmaceutical activities. i) Ex vivo study The ex vivo protocol consists of the study of the inhibition of neuronal NOS or NOS1 (nitric oxide synthase). The effects of the compounds of the invention on the NOS1 activity are carried out on rat cerebellum preparations by measuring the conversion of L- [H] arginine to L-jH] citrulline.

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(CI50) sont respectivement égales à : 0, 45 ; 0, 85 et 0, 90 ! lu. ii) Etude in vivo, effet antinociceptif Une première étude in vivo a permis de mesurer l'effet antinociceptif des composés dans le test des constrictions abdominales mesurées chez la souris. Among the results obtained, the NOS 1 inhibitory activities of compounds (4), (5) and (8) expressed in value of the inhibitory concentration at 50%

(IC50) are respectively equal to: 0.45; 0.85 and 0.90! read. ii) In vivo study, antinociceptive effect A first in vivo study made it possible to measure the antinociceptive effect of the compounds in the test of abdominal constrictions measured in mice.

 At a dose of 50mg / kg i. p., compound (8) completely abolishes the abdominal contractions induced by acetic acid.

 At a dose of 10 mg / kg, the derivative (4) induces a significant reduction (40%) in the number of abdominal constrictions.

 A similar intensity effect was found for the derivative (5) at a dose of 25 mg / kg.

These compounds therefore have therapeutic potential as an analgesic. iii) In vivo study, effect on alcohol dependence
After testing several derivatives, compound (4) was chosen to study for its alcoholic anti-dependence potential in vivo.

 First of all, in order to verify the specificity of NOS1 inhibition in vivo by the compound (4), the blood pressure (BP) was measured in healthy animals during a chronic treatment of 19 days with 2 treatment groups treated with doses of 20 and 40 mg / kg / day intraperitoneally (ip).

 In fact, the inhibition of endothelial NOS induces an increase in BP because NO has significant vasodilator properties. No increase in systolic BP was noted in animals. In addition, a histopathological study carried out on the heart, liver, kidneys and lungs of these animals did not show any deleterious effect of the treatment.

 Compound (4) was then tested in an animal model of behavioral alcohol dependence. This model, performed on rats, consists of a

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 progressive pulmonary alcoholization for four weeks followed by a period of free choice between water and 10% alcohol.

 Rats (adult males, Wistar strain) are placed in an enclosure, with food and water ad libitum and subjected to pulmonary alcoholization, by exposure to an alcoholic atmosphere (between 15 and 25 mg of ethanol / liter of air) for four weeks.

 After this period of time, the animals are placed in an alcohol-free environment in the air where they have a bottle of water, then a free choice of water / alcohol 10% 16 hours later.

 After intoxication, nearly 80% of animals choose to preferentially drink alcohol, and the average consumption is greater than 7 g of pure alcohol / kg of body mass, leading to a positive blood alcohol level.

 The animals thus treated are dependent on alcohol and present disorders similar to those of alcoholic patients with regard to disorders linked to alcohol consumption.

 A study on the effects of compound (4) administered i. p. dependent animals in a situation of free choice was carried out. These rats were of Wistar strain and, in one experiment, animals selected for their preference for alcohol (AA).

 In all cases, compound (4) resulted in a decrease in consumption and alcohol preference in animals. This reduction was either transient (dose effect of 3-day subacute treatments, Figure 2) or apparently definitive (chronic 12-day treatment, Figure 3) leading to moderate consumption. Injection treatment i. p. of five days administered a second time in animals still dependent after the first treatment showed that in the end 8 animals out of 9 were no longer dependent on alcohol and presented a moderate consumption (figure n 4).

 A fully computerized continuous consumption measurement system that tracks animal consumption in real time was also used.

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 Thanks to this system, it has been possible to show that, when the compound (4) and the 7NI (7-nitroindazole) are administered at the same dose, that is to say 65flmo1 / kg / d, the compound (4) is more effective than 7-NI in reducing alcohol consumption during a 3-day treatment (figure no).

 Since the oral route is a preferred route of administration for human therapy, the trial of treatment by this route has also shown a significant reducing effect on alcohol consumption (FIG. 6) and on alcohol preference by compound (4).

 A study based on the measurement of animal activity has shown that this molecule has anxiolytic properties.

 Finally, a protocol for measuring the ethyloxidation coefficient did not demonstrate any interaction of this product with the elimination of alcohol when it is administered by the i route. p ..

 In conclusion, this inhibitor shows an important reducing power of alcohol dependence superior to other inhibitors currently on the market (such as 7-NI). In addition, it has no toxic effects on locomotricity or weight gain at doses of 20 mg / kg /) and 40 mg / kg / day or on the organs studied in histopathology. All the pharmacologically active doses used in the studies are at least 6 times lower than the LD50.

Claims (23)

Claims 1. Compound corresponding to formula (I) in which R and R's are such that: - R and R's are connected to each other so as to form, with the nitrogen atom, a ring comprising from 5 to 6 atoms, at least one of the atoms of the said ring being able to be a heteroatom, the said ring being able to be saturated or not, and substituted by a C1-C4 alkyl group or not, or - R is the atom d 'hydrogen and R' is chosen from: - a group of formula in which Ri and R'l are independently: - a hydrogen atom, or - a C1-C6 alkyl group, or - a C3-C6 cycloalkyl group , or - a C1-C4 alkanoyl group - a group of formula -NH-CO-NH-R3 in which R3 represents a phenyl group, said phenyl group being able to be substituted by at least: a halogen atom or - a group C1-C4 alkyl - a C1-C4 haloalkyl group, or - a C1-C4 alkoxy group <Desc / Clms Page number 30> - a group of formula in which R2 and R'2 are such that: - R2 and R'2 represent a C1-C3 alkyl group, or - R2 and R'2 are linked to each other so as to form a C3-C6 cycloalkyl group, or - R2 is l hydrogen atom and R'2 is a phenyl group, which can be substituted by at least: a halogen atom, or - a C1-C4 alkyl group, or - a C1-C4 haloalkyl group or - a group C1-C4 alkoxy; a group of formula in which R4 and R5 are, independently, hydrogen atoms or C1-C4 alkyl groups, in the base state or as an addition salt of a pharmaceutically acceptable acid. 2. Compound of formula (1) according to claim 1, in which R and R ′ form, with the nitrogen atom, a heteroaryl group, the nucleus of said heteroaryl group comprising at least one nitrogen atom. 3. Compound according to claim 1, in which R and R 'form, with the nitrogen atom, a heteroaryl group, of formula

 in which R / and R8 represent, independently, CH or a nitrogen atom. <Desc / Clms Page number 31>  4. A compound according to claim 3, in which R7 is a nitrogen atom and R8 represents a CH group. 5. Compound of formula (I) according to claim 1, in which R and R 'form, with the nitrogen atom, a cycle of formula

 in which Rs represents a hydrogen atom or a C1-C4 alkyl group. 6. A compound according to claim 5, wherein R6 represents a methyl group. 7. Compound of formula (1) according to claim 1, in which R represents a hydrogen atom and R'represent group of formula

 wherein R4 and R5 are, independently, hydrogen atoms or C1-C4 alkyl groups. 8. A compound according to claim 7, in which R4 and R5 are methyl groups. 9. Compound of formula (1) according to claim 1, in which R represents a hydrogen atom and R'represent a group of formula

 wherein Ri and R'1 are independently selected from a hydrogen atom and a methyl group. 10. Compound of formula (1) according to claim 1, in which R represents a hydrogen atom and R'represent a group of formula <Desc / Clms Page number 32>

 in which R2 and R'2 are such that: - R2 and R'2 represent a Ct-C3 alkyl group, 11. A compound according to claim 10, in which R2 and R'2 represent a methyl group. 12. Compound of formula (I) according to claim 1, in which R represents a hydrogen atom and R'represent a group of formula

 in which R2 and R'2 are connected to each other so as to form a C3-C6 cycloalkyl group. 13. Compound according to claim 12, of formula:

 14. Compound of formula (I) according to claim 1, in which R represents a hydrogen atom and R'represent a group of formula

 in which K2 is the hydrogen atom and K'2 is a phenyl group, which may be substituted by at least: a halogen atom, or - a C1-C4 alkyl group, or <Desc / Clms Page number 33>  - a C1-C4 haloalkyl group or - a C1-C4 alkoxy group; 15. Compound according to claim 14, chosen from the compounds

 16. Compound of formula (I) according to claim 1, in which R is the hydrogen atom and R'represent a group of formula -NH-CO-NH-R3 in which R3 represents a phenyl group, said phenyl group may be substituted by at least: a halogen atom or <Desc / Clms Page number 34>

 - a C1-C4 alkyl group - a C1-C4 haloalkyl group, or - a C1-C4 alkoxy group 17. Compound according to claim 16, chosen from the compounds

 18. Compound according to one of claims 1 to 17, in the form of a salt of the compound of general formula (1), said salt having the formula: <Desc / Clms Page number 35>

 with a pharmaceutically acceptable cation. 19. Compound according to one of claims 1 to 18, as a medicament. 20. Pharmaceutical composition characterized in that it comprises a compound according to one of claims 1 to 18, in combination with any suitable excipient.  21. Use of a compound according to one of claims 1 to 18 for the preparation of a medicament intended to treat an addiction or an addiction. 22. Use according to claim 21, in which the type of addiction is alcohol dependence. 23. Use of a compound according to one of claims 1 to 18 for the preparation of a medicament intended to be used as an analgesic. 24. Use of a compound according to one of claims 1 to 18 for the preparation of a medicament intended to be used as an anxiolytic. 25. Use according to one of claims 21 to 24, in which the medicament is administered by injectable route. 26. Use according to one of claims 21 to 24, wherein the medicament is administered orally. <Desc / Clms Page number 36> 27. Process for the preparation of a compound of formula (1) according to one of claims 1 to 9, comprising the step of reacting 2,7-dinitroindazole with a compound of formula

 in which R, and R 'are such that: - R and R' are linked to each other so as to form, with the nitrogen atom, a cycle comprising from 5 to 6 atoms, one at least atoms of the said ring being able to be a heteroatom, the said ring being able to be saturated or not, and substituted by a C1-C4 alkyl group or not, or - R is the hydrogen atom and R is chosen from: - a grouping of formula

 in which RI and R'1 are independently: a hydrogen atom, or - a C1-C6 alkyl group, or a C3-C6 cycloalkyl group, or - a C1-C4 alkanoyl group, - a group of formula

 in which R4 and R5 are, independently, hydrogen atoms or C1-C4 alkyl groups, 28. Method according to claim 27, characterized in that the reaction step is carried out in a polar aprotic solvent, preferably tetrahydrofuran. 29. Process for the preparation of a compound of formula (I) according to one of claims 1,10 to 15, comprising the step of reacting 3-hydrazino-7nitroindazole with a compound of formula

<Desc / Clms Page number 37>  in which R2 and R'2 have the same meanings as in claim 1. 30. A method of preparing a compound of formula (1) according to one of claims 1,16 or 17, comprising the step of reacting 3-hydrazino-7nitroindazole with a compound of formula R3-NCO in which R3 has the same meaning as in claim 1.