FR2831822A1 - Use of 4-mercapto and 4-seleno imidazole derivatives for the treatment of disorders due to absence of superoxide dismutase, pyruvate dehydrogenase, or intracellular glutathione - Google Patents

Abstract

The use of 4-mercapto and 4-seleno imidazole derivatives (I) and their salts in the manufacture of medicines to treat pathological states due to an organic or functional deficiency of superoxide dismutase, pyruvate dehydrogenase, or intracellular glutathione. The use of 4-mercapto and 4-seleno imidazole derivatives (I) and their salts. Y = S or Se; Z' = O, S, or NR2; R2 = H, alkyl, cycloalkyl, aryl, aralkyl, heteroalkyl, heteroaryl, CO-alkyl, CO-cycloalkyl, CO-aryl, CO-aralkyl, SO2-alkyl, SO2-cycloalkyl, SO2-aryl, or SO2-aralkyl; R1 and R3 = H, alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl, aralkyl or -C(R4R5)-A-B; R4 and R5 = H, alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl, or aralkyl; A = CO, (C(R6)(R7))n; n = undefined in specification; R6, R7 = H, alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl, or aralkyl; B = -N(R8R9), OR8, or SR8; R8 and R9 = H, alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl, or aralkyl; and X = H or a group of formula (ii).

Description

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 The subject of the present invention is the use of 4-mercaptoimidazoles or 4-selenoimidazoles derivatives for preparing a pharmaceutical composition intended in particular for the treatment of genetic diseases called rare diseases.

 4-mercapto- and 4-seleno-imidazoles, in reduced or oxidized form, are already used in therapy for their enzymatic activity, glutathione peroxidase and more particularly to compensate for a biological deficit of this enzyme.

 The enzyme glutathione peroxidase plays a decisive role in the prevention of oxidative stress linked mainly to an overproduction of cytotoxic hydroperoxides. It naturally ensures the degradation of these hydroperoxides.

 Advantageously, 4-mercapto- and 4-seleno-imidazoles also have antioxidant and cytoprotective properties which precisely allow them to degrade the endogenous and exogenous cytotoxic forms of hydroperoxides, like glutathione peroxidase.

 Consequently, the reduced chemical derivatives 4-mercapto- and 4-selenoimidazoles are currently proposed for the treatment of pathologies associated with an overproduction of cytotoxic hydroperoxides and / or a deficit in glutathione peroxidase.

 As a representative of this type of pathology, mention may more particularly be made of ischemic and / or inflammatory cardiovascular and cerebrovascular diseases such as arterial restenosis and stenosis, ischemic and / or inflammatory digestive diseases such as Crohn's disease, respiratory stress syndromes, AIDS, post-radiotherapy fibrosis and ophthalmic, ischemic and / or inflammatory pathologies such as glaucoma or cataracts.

 The present invention for its part relates to the characterization of new enzymatic activities and properties of these molecules.

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dans laquelle : . Y représente S ou Se, * Z = O ; S ; et de préférence NRz, avec R2 représentant H, un groupe alkyle, cycloalkyle, aryle, arylalkyle, hétéroalkyle ou hétéroaryle, CO (alkyle),

CO (cycloalkyl), CO (ary) e), C0 (ary ! atkyte), S02 (atkyte), S02 (cydoa ! kyie), S02 (aryle), S02 (arylalkyle) ; et . R3 et Ri représentent indépendamment l'un de l'autre H, un groupe alkyle, cycloalkyle, aryle, hétéroalkyle, hétéroaryle, arylalkyle, ou -C(R4R5)-A-B, avec - R4 et R5 représentant indépendamment 1'un de l'autre H, un groupe alkyle, cycloalkyle, aryle, hétéroalkyle, hétéroaryle ou arylalkyle ; et - A représentant un motif CO ; [C (R6) (R7)] n avec R6 et R7 représentant indépendamment l'un de l'autre H, un groupe alkyle, cycloalkyle, aryle, hétéroalkyle, hétéroaryle ou arylalkyle ; et

- B représentant un groupe-rRgRg) et ses sels ; OR8 ; SR8 ; avec Rg et Rg représentant indépendamment l'un de l'autre H, un groupe alkyle, cycloalkyle, aryle, hétéroalkyle, hétéroaryle ou arylalkyle ; . X représente H ou

avec Y, R3, Z et Ri tels que définis ci-dessus, More specifically, the present invention relates to the use of a 4-mercapto- or 4-seleno-imidazole derivative of general formula (1):

in which : . Y represents S or Se, * Z = O; S; and preferably NRz, with R2 representing H, an alkyl, cycloalkyl, aryl, arylalkyl, heteroalkyl or heteroaryl group, CO (alkyl),

CO (cycloalkyl), CO (ary) e), C0 (ary! Atkyte), S02 (atkyte), S02 (cydoa! Kyie), S02 (aryl), S02 (arylalkyl); and. R3 and R1 represent, independently of each other, H, an alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl, arylalkyl, or -C (R4R5) -AB group, with - R4 and R5 representing independently of one of the other H, an alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl or arylalkyl group; and - A representing a CO motif; [C (R6) (R7)] n with R6 and R7 representing, independently of each other H, an alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl or arylalkyl group; and

- B representing a group (rRgRg) and its salts; OR8; SR8; with Rg and Rg representing, independently of each other H, an alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl or arylalkyl group; . X represents H or

with Y, R3, Z and Ri as defined above,

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et leurs sels pharmaceutiquement acceptables, pour la fabrication d'un médicament destiné au traitement de pathologies liées à un déficit organique ou fonctionnel en superoxyde dismutase, pyruvate déshydrogénase, et/ou glutathion intracellulaire.

and their pharmaceutically acceptable salts, for the manufacture of a medicament intended for the treatment of pathologies linked to an organic or functional deficit in superoxide dismutase, pyruvate dehydrogenase, and / or intracellular glutathione.

The general formula (1) includes any stereoisomer, epimer and diastereoisomer as well as a mixture or isolated form of the compounds of formula 1 claimed. It also covers the pharmaceutically acceptable, acid or basic salts of the said compounds of formula (1).

Mention may more particularly be made, as representative of these pharmaceutically acceptable salts, of those derived from hydrochloric, hydrobromic, hydroiodic, sulfuric, tartaric, methane sulphonic and trifluoromethane sulphonic acids. By way of illustration of the pharmaceutically acceptable basic salts, mention may in particular be made of those derived from sodium hydroxide, potash, carbonates of alkali and / or alkaline earth metals or of organic bases such as triethylamine or arginine.

For the purposes of the present invention, the following terms are intended to define: - lower alkyl or alkoxy, any group or linear or branched aliphatic carbon chain having 1 to 8 carbon atoms; - cycloalkyl, any saturated carbon group of cyclic, mono- or poly-cyclic nature of 5 to 12 carbon atoms such as, for example, 1- or 2- adamantyl groups; - heteroalkyl, any alkyl or any cycloalkyl which may comprise in its carbon skeleton one or more heteroatoms chosen from nitrogen, oxygen and sulfur; - aryl, any cyclic unsaturated mono-, bi- or tri-cyclic group composed of ring (s) of 5 to 12 carbon atoms, and in particular the phenyl and naphthyl groups;

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 - heteroaryl, any aryl group which may comprise in its carbon skeleton one or more heteroatoms chosen from nitrogen, oxygen and sulfur; - Arylalkyl or aralkyl, any group composed of both an alkyl and an aryl, and in particular the alkylnaphthyl (Ci-Cg) and alkyl heteroalkyl (C1-Cg) groups.

 Of course, the claimed compounds can be substituted. These substituents can be chosen from the groups consisting of C1-C8 alkyl, trifluoromethyl, C1-C8 alkoxy, hydroxy, nitro, amino, C1-C8 alkylamino, C1-C8 dialkylamino, sulfonyl, sulfoxy, sulfonamide, C1-C6 sulfurized alkyl, carboxy, carbalkoxyl, carbamide, as well as the halogen atoms.

 Surprisingly, the inventors have thus demonstrated that the reduced forms of the 4-mercapto- or 4-seleno-imidazole derivatives appear, on the one hand, to have superoxide dismutase activity and, on the other hand, capable of replacing glutathione in the reaction catalyzed by glutathione peroxidase. As regards the oxidized forms of the 4-mercapto- and 4-seleno-imidazole derivatives, they turn out to have a stimulating activity on pyruvate dehydrogenase.

 Consequently, the present invention aims to take advantage of the properties mentioned above of the 4-mercapto- and 4-seleno-imidazole derivatives, for the treatment of pathologies linked to a dysregulation of the enzymatic metabolism involving an organic or functional deficit in superoxide dismutase, by pyruvate dehydrogenase and / or intracellular glutathione.

 For the purposes of the present invention, the term "organic deficit" is intended to cover the deficits directly linked to a deficiency in the enzyme considered. These are so-called direct or primary deficits that constitutionally affect the peptide or protein structure considered.

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 The expression "functional deficit" for its part more particularly relates to a non-constitutional disorder of the peptide or protein structure considered.

 Thus, from the field of the invention are all pathologies characterized by a deficit or which may benefit from a supply of superoxide dismutase, pyruvate dehydrogenase or even of enzymes involved in the biosynthesis of glutathione.

 With regard to SOD deficiency, a link has recently been established between SOD1 deficiency, superoxide dismutase Cu / Zn, and the manifestation of amyotrophic lateral sclerosis (ALS). Consequently, the supply of 4-mercapto- or 4-seleno-imidazoles derivatives should make it possible to compensate for a deficiency in superoxide dismutase activity and therefore to effectively treat this type of pathology.

 As for the organic deficit in pyruvate dehydrogenase, it covers the genetic deficits affecting one of the subunits of this enzyme including lipoamide dehydrogenase. As for the functional deficit in pyruvate dehydrogenase, it covers disorders which secondarily affect the activity of this protein, for example via the reduction of recycling of NAD + (cofactor of pyruvate dehydrogenase) occurring in respiratory chain disorders (eg deficiency in complex 1). More specifically, the activity of pyruvate dehydrogenase represents a decisive metabolic target in cell function. A functional disturbance of its activity may be secondary to the manifestation of disorders of the mitochondrial respiratory chain, such as for example a deficiency in complex 1. This complex makes it possible to recycle the oxidized intramitochondrial NAD +, necessary for the proper functioning of the pyruvate dehydrogenase, from local reduced NADH. In this case, the absence of recycling of NAD + by the mitochondrial respiratory chain results in the activity deficit of pyruvate dehydrogenase. Unexpectedly, the oxidized forms of the 4-mercapto and 4-seleno- derivatives

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 imidazoles demonstrate the property of replacing NAD + in the reaction catalyzed by pyruvate dehydrogenase.

 Consequently, it is possible to envisage making up for the absence of NAD +, thanks to the lipoamide dehydrogenase activity of the oxidized forms of 4-mercapto and 4-seleno-imidazoles and therefore to thus treat the deficits of the mitochondrial respiratory chain resulting from this specific dysfunction affecting the recycling of intramitochondrial NAD. The beneficial mechanism is probably in this case the saving of use of intramitochondrial NAD + by pyruvate dehydrogenase (intramitochondrial enzyme) which can, in place of NAD +, use the oxidized forms of 4-mercapto and 4-seleno-imidazoles.

 As regards the property of the reduced forms of the compounds in accordance with the present invention, of being a substrate for glutathione peroxidase, it is very particularly advantageous for treating pathologies linked to a deficit in the synthesis of glutathione. In this case, we can distinguish two types of deficits. The first type is of genetic origin and includes in particular the deficit in glutathione synthetase, in γ-glutamyl-cysteine synthetase as well as in 5-oxoprolinase. The second type relates to acquired deficit such as exposure to inhibitors of glutathione synthesis (eg buthionine sulfoxymide) or any other condition leading to depletion of intracellular glutathione (eg magnesium deficiency).

 As is apparent from the examples presented below, the reduced forms of the claimed compounds prove to be substrates of glutathione peroxidase. As for the oxidized forms, they have the property of recycling the reduced forms of these same compounds in the presence of L-cysteine or of pyruvate dehydrogenase. Consequently, these respective properties of the compounds according to the invention prove to be advantageous for treating rare diseases affecting the biosynthesis of glutathione. As an illustration of these pathologies, one can more particularly cite the deficit in glutathione synthetase, pyroglutamic aciduria, the deficit in gamma-glutamyl-cysteine synthetase and the deficit in 5-oxoprolinase.

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dans laquelle R3, Z, Ri et Y sont tels que définis en formule générale 1 pour la préparation d'un médicament destiné à traiter les pathologies liées à un déficit fonctionnel en superoxyde dismutase et notamment la sclérose latérale amyotrophique. A first variant of the invention therefore relates to the use of a compound of general formula II

in which R3, Z, Ri and Y are as defined in general formula 1 for the preparation of a medicament intended for treating pathologies linked to a functional deficit in superoxide dismutase and in particular amyotrophic lateral sclerosis.

dans laquelle R3, Z, Ri et Y sont tels que définis en formule générale 1 pour la préparation d'un médicament destiné à traiter les pathologies liées à un déficit organique en glutathion intracellulaire et notamment les maladies rares affectant la biosynthèse du glutathion. A second variant of the present invention the use of a compound of general formula II

in which R3, Z, Ri and Y are as defined in general formula 1 for the preparation of a medicament intended for treating pathologies linked to an organic deficit in intracellular glutathione and in particular the rare diseases affecting the biosynthesis of glutathione.

dans laquelle R3, Z, Ri et Y sont tels que définis en formule générale 1 pour la préparation d'un médicament destiné à traiter les pathologies liées à Finally, a third variant of the invention relates to the use of a compound of general formula lil

in which R3, Z, Ri and Y are as defined in general formula 1 for the preparation of a medicament intended to treat pathologies linked to

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 a functional deficit in pyruvate dehydrogenase. Are particularly covered by this specific use of the compounds of general formula H), pathologies associated with an organic or functional deficit in one or more enzymatic complexes of the a-ketoacid dehydrogenase type containing the lipoamide dehydrogenase such as for example the acetoglutarate dehydrogenase, a-ketoadipate dehydrogenase, and ketoacid dehydrogenase involved in the metabolism of branched chain amino acids, or pathologies such as rare genetic diseases including dysfunction of the mitochondrial respiratory chain such as for example mitochondriopathies.

 More particularly preferred in the context of the present invention are the compounds in which Z represents a group NRz with R2 preferably representing an alkyl group or an aryl group, optionally substituted.

 Preferably, Y represents a sulfur atom.

 Mention may in particular be made, as representative of the groups R1, of the methyl group, the hydrogen atom and the phenyl groups substituted in the ortho-or para-position by a trifluoromethyl, methoxy or a halogen group such as chlorine.

 Mention may in particular be made, as representative of the R3 groups, of the hydrogen atom and the phenyl group, optionally substituted in the para, meta or ortho position by a halogen atom and / or a trifluoromethyl group.

 As for the groups R, they preferably contain a methyl group or a phenyl group mono- or di-substituted by a methoxy group.

 In general, the reduced and oxidized forms of the thiol compounds, proposed above, prove to be advantageously interconvertible in vivo, so that for reasons of pharmaceutical preservation, it is the compounds of oxidized type which are recommended, insofar as the

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formes réduites sont moins stables. Toutefois, si la conservation de la forme réduite est pharmaceutiquement peu favorable, la conservation de l'activité biologique qui lui est liée, elle, est à l'inverse pharmaceutiquement stable, puisque la forme oxydée à laquelle elle donne spontanément naissance peut restituer in vivo la forme réduite.

reduced forms are less stable. However, if the conservation of the reduced form is pharmaceutically unfavorable, the conservation of the biological activity which is linked to it, on the other hand, is pharmaceutically stable, since the oxidized form to which it spontaneously gives rise can restore in vivo the reduced form.

As a representative but not limiting of the compounds in accordance with the present invention, one can more particularly quote the reduced and oxidized forms of: - 1-methyl-2- [3-trifluoromethylphenyl] -4-mercaptoimidazole, - 1-methyl-2- [3-chlorophenyl] -4-mercaptoimidazole, 1-methyt-2- [4-methoxyphenyt] -4-mercaptoimid nitrogen, - 1- (4-methoxyphenyi) -4-mercaptoimidazole, - 1- (2-methoxyphenyl) -4- mercaptoimidazole, - 1,5-dimethyl-4-mercaptoimidazole, 1- (3, 4-dimethyoxypheny!) - 4-mercaptoimid nitrogen, 1-methyt-2- (4-ch! orophény)) - 4-mercaptoimidazo) e, - 1-methyl-2- (2-chlorophenyl) -4-mercaptoimidazole, 1-méthyi-2- (2-triftuorométhytphényi) -4-mercaptoimidazote, 1-méthy) -5- (2-trif) uorométhytphenén)) - 4- mercaptoimidazo! e, - 1-methyl-5- (2-chloromethylphenyl) -4-mercaptoimidazole, - 1-methyl-5- (4-chloromethylphenyl) -4-merca ptoimidazole, - 1-methyl-5- (4-methoxyphenyl) - 4-mercaptoimidazole, - 1-methyl-2-trifluoromethyl-5- (2-methoxyphenyl) -4mercaptoimidazole, and the 4-selenoimidazoles corresponding to the 4-mercaptoimidazoles mentioned above.

Particularly preferred is 1-methyl-2- [3trifluoromethylphenyl] -4-mercaptoimidazole in its reduced and oxidized form.

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 The synthesis of the compounds in accordance with the invention falls within the competence of a person skilled in the art. However, reference can be made to the protocols described in the title EP 0 850 924.

 The pharmaceutical compositions in accordance with the invention generally contain the compound of general formula (1) combined with a pharmaceutically acceptable excipient or vehicle.

 According to an advantageous mode, these pharmaceutical compositions contain approximately from 0.1 to 5% and preferably from 0.1 to 1% by weight of said compound.

 The pharmaceutical compositions according to the invention can be formulated for oral, rectal or topical administration, as well as by intraventricular, intramuscular, subcutaneous or intravenous injection.

 As regards the pharmaceutically acceptable excipients or vehicles, these may be those commonly used in the pharmaceutical field.

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

FIGURES:
Figures 1: Reactivity of the reduced form of 1-methyl -2- [3-trifluoro methylphenyl] -4-mercaptoimídazole in the absence and in the presence of radish peroxidase (1A), or bovine erythrocyte peroxidase glutathione (1 B).

 Figure 2: Demonstration of the stimulating effect of oxidized 1-methyl-2- [3-trifluoromethylphenyl] -4-mercaptoimidazole on pyruvate dehydrogenase activity.

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EXAMPLE 1
Characterization of the superoxide dismutase activity of the reduced form of 1-methyl-2- [3-trifluoromethylphenyl] -4-mercaptoimidazole.

 Two experimental aspects have been demonstrated: on the one hand, the capacity of the reduced form of 1-methyl-2 [3-trifluoromethylphenyl] -4- mercaptoimidazole to consume the superoxide anion, and on the other hand, the production in these hydrogen peroxide conditions. These two characteristics relate the reaction studied to that of superoxide dismutase, an enzyme which converts the superoxide anion into hydrogen peroxide.

 The ability of the reduced form of 1-methyl-2 [3-trifluoromethylphenyl] -4-mercaptoimidazole to consume the superoxide anion has been demonstrated by inhibiting the autooxidation of pyrogallol.

Indeed, the autooxidation of pyrogallol is mediated by the formation of superoxide anion, so that any enzyme or any compound consuming the superoxide anion decreases the speed of autooxidation of pyrogallol (this is the case of superoxide dismutase, this is also the case for the reduced form of 1-methyl- 2 [3-trifluoromethylphenyl] -4-mercaptoimidazole). The autooxidation of pyrogallol was measured in accordance with the protocol described by Marklund, S., and Marklund, G. (1974), Eur. J. Biochem. 47.469-474.

 The production of hydrogen peroxide concomitant with the inhibition of the autooxidation of pyrogallol (inhibition induced by the reduced form of 1- methyl-2 [3-trifluoromethylphenyl] -4-mercaptoimidazole) was measured by adapting the protocol described by Vamecq, J. (1990) Anal.

Biochem. 186.340 to 349. Pyrogallol alone does not induce, during its self-oxidation, the formation of hydrogen peroxide. Conversely, pyrogallol in the presence of the reduced form of 1-methyl-2 [3-trifluoromethylphenyl] -4-mercaptoimidazole generates the formation of hydrogen peroxide, indicating that the inhibition of the autooxidation of pyrogallol by reduced form of 1-methyl-2 [3-trifluoromethylphenyl] -4- mercaptoimidazole is associated with the production of hydrogen peroxide,

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 therefore resembling the synthetic thiol reduced to superoxide dismutase in its property of consuming the superoxide anion while concomitantly producing hydrogen peroxide.

EXAMPLE 2
Characterization of the capacity of the reduced form of 1-methyl-2- [3-trifluoromethylphenyl] -4-mercaptoimidazole to react with glutathione oxidoreductase.

 The reactivity of the reduced form of 1-methyl-2- [3-trifluoromethylphenyl] -4-mercaptoimidazole with hydrogen peroxide was studied by consumption of the first substrate, that is to say by following the decrease in the reduced form of 1-methyl-2- [3-trifluoromethylphenyl] -4-mercaptoimidazole (RSH) (Figure 1, parts A and B). This decrease in synthetic thiol dependent on hydrogen peroxide is greatly accelerated by the inclusion in the reaction medium of peroxidase of radish peroxidase type (FIG. 1A), or bovine erythrocytic glutathione peroxidase (FIG. 1B), at the same time as the addition of peroxidase in the absence of peroxide does not make it possible to reproduce this accelerated consumption of synthetic thiol. These data therefore demonstrate that 1-methyl-2- [3-trifluoromethylphenyl] -4-mercaptoimidazole is a substrate for these peroxidases.

 Similarly, with regard to glutathione peroxidase, it has been shown that it can use this synthetic thiol as the first substrate by using as second substrate peroxides other than hydrogen peroxide such as for example cumene hydroperoxide or else l tert-butyl hydroperoxide. On the other hand, the catalase which can catalyze either a reaction of the catalase type or of the peroxidase type does not use, under the same experimental conditions, synthetic thiol as substrate for its second activity cited.

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 Consequently, the reduced form of 1-methyl-2- [3-trifluoromethylphenyl] -4-mercaptoimidazole is capable of replacing glutathione in the reaction catalyzed by glutathione peroxidase and this property can therefore be used under the characterized conditions. by an intracellular depletion of glutathione of genetic origin (glutathione synthetase deficiency, pyroglutamic aciduria, gamma-glutamylcysteine synthetase deficiency and 5-oxoprolinase deficiency) or acquired (for example, exposure to inhibitors of gluthation synthesis (ex. buthionine suifoxymide) or any other acquired condition leading to the depletion of intracellular glutathione (magnesium deficiency)).

EXAMPLE 3
Stimulation of pyruvate dehydrogenase activity by the oxidized form of 1-methyl-2- [3-trifluoromethylphenyl] -4-mercaptoimidazole.

mercaptoimidazole avec la forme réduite de l'acide lipoïque. Il s'ensuit la génération de la forme réduite du mercaptoimidazole et de la forme oxydée de l'acide lipoïque. The interaction of the oxidized form of 1-methyl-2- [3-trifluoromethylphenyl] -4-mercaptoimidazole with the metabolic conversion considered implies first of all the interaction of the oxidized form of

mercaptoimidazole with the reduced form of lipoic acid. This results in the generation of the reduced form of mercaptoimidazole and the oxidized form of lipoic acid.

 It is precisely the formation of the reduced form of mercaptoimidazole which has been studied in: (i) a 25 mM phosphate phosphate buffer of pH 7.6 and in the presence of co-factors for the pyruvate dehydrogenase activity of porcine hearts (NAD + excluded ), i.e. 0.5 mM magnesium chloride, 0.5 mM thiamine pyrophosphate and 0.5 mM reduced coenzyme A.

 (ii) in a control test, in the presence in addition of porcine pyruvate dehydrogenase (10; J of a porcine heart enzyme); and

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 (iii) in the presence of 10 mM of pyruvate in order to determine the dependence of the reduction rate of the mercaptoimidazole with respect to the pyruvate.

 The interaction of oxidized 1-methyl-2- [3-trifluoromethyl] -4-mercaptoimidazole with the reaction catalyzed by pyruvate dehydrogenase is followed by measuring the initial rates of acetyl-CoA formation.

 FIG. 2 illustrates the rates of formation of acetyl-CoA (that is to say of the product of pyruvate dehydrogenase) under different experimental conditions. The white represents the pyruvate dehydrogenase incubated in the presence of its substrate (pyruvate) and its cofactors with the exception of NAD + (thiamine pyrophosphate, coenzyme A and magnesium chloride).

oxydée du 1-méthyl-2[3-trifluorométhylphényle]-4-mercaptoimidazole (conditions RSSR, figure2) augmente un peu cette formation d'acétyl-CoA et ce dans une mesure proche de la formation d'acétyl-CoA induite par le rajout aux conditions"blanc"de l'acide lipoïque sous sa forme réduite (conditions Red, LPA, figure 2). Mais le rajout de la forme oxydée du 1-méthyl-2[3- trifluorométhylphényle]-4-mercaptoimidazole à ces dernières conditions "Red. LPA" (conditions RSSR/Red. LPA, figure 2) induit une stimulation importante de la formation d'acétyl-CoA, laquelle représente un pourcentage respectable de la formation d'acétyl-CoA obtenue par le rajout du NAD+ aux conditions "blanc" (conditions NAD+, figure 2). En d'autres termes, la pyruvate déshydrogénase peut travailler à une vitesse faible ou plus rapide en l'absence de son cofacteur NAD+ à condition que la forme oxydée du 1- méthyt-2[3-trifluorométhylphényle]-4-mercaptoimidazole soit présentée à cette enzyme respectivement en l'absence ou en présence de l'acide lipoïque sous sa forme réduite.Under these conditions (White conditions, Figure 2), very little or no acetyl-CoA can be formed. Addition to the "white" conditions of the form

oxidized 1-methyl-2 [3-trifluoromethylphenyl] -4-mercaptoimidazole (RSSR conditions, figure2) slightly increases this formation of acetyl-CoA and this to an extent close to the formation of acetyl-CoA induced by the addition under the "white" conditions of lipoic acid in its reduced form (Red conditions, LPA, FIG. 2). However, the addition of the oxidized form of 1-methyl-2 [3-trifluoromethylphenyl] -4-mercaptoimidazole to these latter conditions "Red. LPA" (conditions RSSR / Red. LPA, FIG. 2) induces a significant stimulation of the formation of acetyl-CoA, which represents a respectable percentage of the formation of acetyl-CoA obtained by adding NAD + to the "white" conditions (NAD + conditions, FIG. 2). In other words, pyruvate dehydrogenase can work at a low or faster rate in the absence of its NAD + cofactor provided that the oxidized form of 1- methyt-2 [3-trifluoromethylphenyl] -4-mercaptoimidazole is presented to this enzyme respectively in the absence or in the presence of lipoic acid in its reduced form.

Claims (12)

1. Use of a 4-mercapto- or 4-seleno-imidazole derivative of general formula (1):

 in which: 'Y represents S or Se,' Z = 0; S; and preferably NR2, with R2 representing H, an alkyl, cycloalkyl, aryl, arylalkyl, heteroalkyl or heteroaryl group, CO (alkyl), CO (cycloalkyl), CO (aryl), CO (arylalkyl), SO2 (alkyl), SC (cycloalkyl), SO2 (aryl), SO2 (arylalkyl); and s R3 and R1 represent, independently of each other H, an alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl, e arylalkyl, or -C (R4R5) -AB group, with - R4 and R5 representing independently one on the other H, an alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl or arylalkyl group; and

 - A representing a CO motif; [C (R6) (R7) n with R6 and R7 representing, independently of each other H, an alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl or arylakyl group; and - B representing a group -N (R8R9) and its salts; ORs; SR8; with Re and Rg representing, independently of one another, H, an alkyl, cycloalkyl, aryl, heteroalkyl, heteroaryl or arylalkyl group; <Desc / Clms Page number 16>  with Y, R3, Z and Ri as defined above, and their pharmaceutically acceptable salts, for the manufacture of a medicament intended for the treatment of pathologies linked to an organic or functional deficit in superoxide dismutase, pyruvate dehydrogenase, and / or intracellular glutathione.

 e X represents H or  2. Use of a compound of general formula t!

 in which R3, Z, R1 and Y are as defined in claim 1 for the preparation of a medicament intended to treat pathologies linked to a functional deficit of superoxide dismutase.  3. Use according to claim 2, characterized in that said pathology is amyotrophic lateral sclerosis (ALS).  4. Use of a compound of general formula II

<Desc / Clms Page number 17>  in which R3, Z, R1 and Y are as defined in claim 1 for the preparation of a medicament intended to treat pathologies linked to an organic deficit in intracellular glutathione.  5. Use of a compound of general formula 111

 wherein R3, Z, Ri and Y are as defined in claim 1 for the preparation of a medicament intended to treat pathologies linked to a functional deficiency in pyruvate dehydrogenase.  6. Use according to claim 5, characterized in that the pathology is a rare genetic disease including a dysfunction of the mitochondrial respiratory chain.  7. Use according to one of claims 1 to 6, characterized in that Z represents an NR2 group with Rz representing an alkyl group or an aryl group, optionally substituted.  8. Use according to one of the preceding claims, characterized in that Y represents a sulfur atom.  9. Use according to one of the preceding claims, characterized in that:. R1 represents a methyl group, a hydrogen atom or a phenyl group substituted in the ortho-or para-position by a trifluoromethyl, methoxy group or a halogen such as chlorine and / or <Desc / Clms Page number 18>  . R3 represents a hydrogen atom or a phenyl group optionally substituted in the para, meta or ortho position by a halogen atom and / or a trifluoromethyl group.

10. Use according to one of the preceding claims, characterized in that R2 represents a methyl group or a phenyl group mono-or di-substituted by a methoxy group. 11. Use according to one of the preceding claims, characterized in that the compound is chosen from reduced and oxidized forms of: - 1-methyl-2- [3-trifluoromethylphenyl] -4-mercaptoimidazo! e, 1-methyt-2- [3-chtorophényte] -4-mercaptoimidazo! e, - 1-methyl-2- [4-methoxyphenyl] -4-mercaptoimidazole, - 1- (4-methoxyphenyl) -4-mercaptoimidazole, - 1- (2-methoxyphenyl) -4-mercaptoimidazole, - 1, 5- dimethyl-4-mercaptoimidazole, - 1- (3, 4-dimethyloxyphenyl) -4-mercaptoimidazole, - 1-methyl-2- (4-chlorophenyl) -4-mercaptoimidazole, - 1-methyl-2- (2-chlorophenyl) -4-mercaptoimidazole, 1-methyl-2- (2-trifluoromethylphenyl) -4-mercaptoimidazole, - 1-methyl-5- (2-trifluoromethylphenyl) -4-mercaptoimidazole, - 1-methyl-5- (2-chloromethylphenyl) -4-mercaptoimidazole, - 1-methyl-5- (4-chloromethylphenyl) -4-mercaptoimidazole, 1-methyl! -5- (4-methoxypheny <) -4-mercaptoimidazo! e, - 1-methyl-2-trifluoromethyl-5- (2-methoxyphenyl) -4mercaptoimidazole, and your 4-selenoimidazoles corresponding to the 4-mercaptoimidazoles mentioned above. <Desc / Clms Page number 19>  12. Use according to one of the preceding claims, characterized in that the compound is the reduced or oxidized form of 1-

 methy! -2- [3-trif! uorométhy) pheny) e] -4-mercaptoimidazoie.