FR2806409A1 - NOVEL HETEROCYCLIC DERIVATIVES OF LIPOIC ACID, THEIR PREPARATION, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents

Abstract

The subject of the invention is new heterocyclic or benzene derivatives comprising a side chain derived from lipoic acid, which have an inhibitory activity on the NO synthase enzymes producing nitrogen monoxide NO and I or are agents allowing the regeneration of antioxidants or trapping entities of reactive forms of oxygen (ROS for "reactive oxygen species") and involved more generally in the redox status of thiol groups. A subject of the invention is also their methods of preparation, the pharmaceutical preparations containing them and their use for therapeutic purposes, in particular their use as inhibitors of NO-synthases and I or as agents intervening in a more generally in the redox status of thiol groups.

Description

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 The present invention relates to new heterocyclic or benzenic derivatives comprising a side chain derived from lipoic acid, which have a inhibitory activity of the NO-synthase enzymes producing NO monoxide and / or are agents allowing the regeneration of antioxidants or trapping entities of reactive forms of oxygen (ROS for "reactive oxygen species") and intervening d 'more generally in the redox status of thiol groups. These antioxidants or trapping entities of reactive forms of oxygen can be of natural origin, such as for example vitamin E or glutathione, or of synthetic origin such as certain ROS trapping products or products exhibiting both an inhibitory activity NO synthases and a ROS trapping activity.

Examples of such products of synthetic origin can in particular be found in PCT patent applications WO 96/09653, WO 98/42696 and WO 98/58934.

The invention therefore relates in particular to the derivatives corresponding to the general formula (I) defined below, their methods of preparation, the pharmaceutical preparations containing them and their use for therapeutic purposes, in particular their use as inhibitors of NO-synthases and / or agents allowing the regeneration of antioxidants or trapping entities of ROS and intervening more generally in the redox status of thiol groups.

Given the potential role of NO, ROS and glutathione metabolism in pathophysiology, the new derivatives described corresponding to the general formula (I) can produce beneficial or favorable effects in the treatment of pathologies where nitric oxide and Glutathione metabolism as well as the redox status of the thiol groups are involved, and in particular:. cardiovascular and cerebrovascular disorders including for example atherosclerosis, migraine, high blood pressure, septic shock, infarction

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 ischemic or hemorrhagic heart or cerebral origin, ischemia and thrombosis; # disorders of the central or peripheral nervous system such as, for example, neurodegenerative diseases where one can notably cite cerebral infarctions, sub arachnoid hemorrhage, aging, senile dementias, including Alzheimer's disease, Huntington's chorea , Parkinson's disease, Creutzfeld Jacob's disease and prion diseases, amyotrophic lateral sclerosis but also pain, trauma to the brain or spinal cord, addiction to opiates, alcohol and substances inducing addiction, erection and reproduction disorders, cognitive disorders, encephalopathies, encephalopathies of viral or toxic origin, depression, anxiety, schizophrenia, epilepsy, sleep disorders, disorders food (anorexia, bulimia ...); # disorders of the skeletal muscle and neuromuscular junctions (myopathy, myositis) as well as skin diseases.

# proliferative and inflammatory diseases such as atherosclerosis, pulmonary hypertension, respiratory distress, glomerulonephritis, cataracts, portal hypertension, psoriasis, osteoarthritis and rheumatoid arthritis, fibrosis, amyloidosis , inflammation of the gastrointestinal system (colitis,
Crohn) or of the pulmonary and airways system (asthma, sinusitis, rhinitis) as well as contact or delayed hypersensitivities.

 # organ transplants.

 # autoimmune and viral diseases such as lupus, AIDS, parasitic and viral infections, diabetes and its complications including retinopathies, nephropathies and polyneuropathies, multiple sclerosis, myopathies.

 # the cancer.

# autosomal genetic diseases such as Unverricht-Lunborg disease # neurological diseases associated with poisoning (poisoning
Cadmium, inhalation of n-hexane, pesticide, herbicide), treatments (radiotherapy) or disorders of genetic origin (Wilson's disease).

 # impotence linked to diabetes;

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 # all pathologies characterized by the production or dysfunction of nitric oxide and / or glutathione metabolism and the redox status of the thiol groups.

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

Chem. 38.4343-4362, 1995; Packer et al., Alpha-lipoic acid as biological antioxidant, Free Radical Biology & Medicine 19,227-250, 1995). This is particularly the case in Parkinson's disease which illustrates the invention (Beal MF, Excitotoxicity and nitric oxide in Parkison's disease pathogenesis, Ann. Neurol. 44 [Suppl 1], S110-S114, 1998; Donato A et al. , Gluthathione in Parkinson's disease: a link between oxidative stress and mitochondrial damage, Ann. Neurol. 32, SI 11 -SI 15, 1992). In this context, drugs that can inhibit the formation of nitric oxide or restore the biological functionality of thiol groups or glutathione can provide beneficial effects.

Furthermore, the inventors have already described in prior patents inhibitors of NO Synthases and their use (US Patents 5,081,148; US 5,360,925), and more recently the association of these inhibitors with products having antioxidant or anti-free radical properties (patent application PCT WO 98/09653). They also described amidine derivatives in PCT patent applications WO 98/42696 and WO 98/58934 and aminopyridine derivatives in PCT patent application WO 00/02860. These amidine or aminopyridine derivatives have the particularity of being both inhibitors of NO Synthases and inhibitors of ROS.

The present invention relates to new heterocyclic or benzene derivatives comprising a side chain derived from lipoic acid, their preparation and their therapeutic application.

The invention therefore relates to a product of general formula (I), characterized in that it comprises the products of sub-formulas (I) a and (I) b

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CO(CH2)r-, -(CHZ)r-CO-N(R3)-(CH2)r-, -(CHZ)r-N(R4)-CO-(CHZ)r-, ou -(CHZ)r-N(R3)- CO-N(R4)-(CH2)r-, r représentant indépendamment à chaque fois qu'il intervient un entier de 0 à 6 ; # représente un hétérocycle aromatique à 5 ou 6 chaînons, un hétérocycle non aromatique de 4 à 7 chaînons ou un radical phénylène substitué par un radical R5, R5 représentant un atome d'hydrogène, un radical alkyle linéaire ou ramifié de 1 à 6 atomes de carbone ou un radical -(CH2)m-Q dans lequel Q représente un atome halogène ou un radical hydroxy, cyano, amino, alkoxy, alkylamino ou dialkylamino, m représentant un entier de 0 à 6 ; P représente -(CH2)g-, g représente un entier de 0 à 6, ou encore P représente un radical

dans lequel R6 représente un atome d'hydrogène, un radical alkyle linéaire ou ramifié ayant de 1 à 6 atomes de carbone ou un radical -(CH2)n-Q' dans lequel Q' représente un radical hydroxy, amino, alkoxy, alkylthio, alkylamino ou dialkylamino et n représente un entier de 0 à 6, ou encore R6 représente un hétérocycle de 5 à 6 chaînons dont les chaînons hétérocycliques sont choisis parmi les radicaux -O-, -N(R7)- et-S-, R7 représentant un atome d'hydrogène ou un alkyle linéaire ou ramifié ayant de 1 à 6 atomes de carbone ; et enfin A représente le radical

in which n represents an integer from 0 to 6; R1 and R2 independently represent a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; XY represents -O- (CH2) r-, -N (R3) - (CH2) r-, -CO (CH2) r-, -CO-N (R3) - (CH,) r-, -N (R4 ) -CO- (CH2) r-, or -N (R3) -CO-N (R4) - (CH2) r-, X'-Y 'represents- (CH2) r-, - (CH2) rO- ( CH2) r-, - (CH2) rN (R3) - (CH2) r-, - (CH2) r-

CO (CH2) r-, - (CHZ) r-CO-N (R3) - (CH2) r-, - (CHZ) rN (R4) -CO- (CHZ) r-, or - (CHZ) rN ( R3) - CO-N (R4) - (CH2) r-, r independently representing each time it intervenes an integer from 0 to 6; # represents a 5 or 6-membered aromatic heterocycle, a 4 to 7-membered non-aromatic heterocycle or a phenylene radical substituted by an R5 radical, R5 representing a hydrogen atom, a linear or branched alkyl radical of 1 to 6 atoms carbon or a radical - (CH2) mQ in which Q represents a halogen atom or a hydroxy, cyano, amino, alkoxy, alkylamino or dialkylamino radical, m representing an integer from 0 to 6; P represents - (CH2) g-, g represents an integer from 0 to 6, or P represents a radical

in which R6 represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a - (CH2) nQ 'radical in which Q' represents a hydroxy, amino, alkoxy, alkylthio, alkylamino or dialkylamino and n represents an integer from 0 to 6, or alternatively R6 represents a 5 to 6-membered heterocycle whose heterocyclic links are chosen from the radicals -O-, -N (R7) - and -S-, R7 representing an atom hydrogen or linear or branched alkyl having 1 to 6 carbon atoms; and finally A represents the radical

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 in which: B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 members containing from 1 to 4 heteroatoms chosen from 0, S, N and in particular the thiophene, furan radicals, pyrrole or thiazole, the aryl radical optionally being substituted by one or more groups chosen from linear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6 carbon atoms, or B represents NR8R9, in which R8 and R9 represent, independently, a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms, or one of Rg and R9 represents a nitro radical while the other represents a hydrogen atom or a linear alkyl radical or branched having from 1 to 6 carbon atoms, or Rg and R9 taken together form with the nitrogen atom a non-aromatic heterocycle of five to six members, the elements of the chain being chosen s from a group composed of -CH2-, -NH-, -0- or -S-, or alternatively B represents a SRIO radical in which R10 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; or a salt of a product of general formula (I).

Preferably, the invention relates to the compounds of general formula (I) in which at least one of the following characteristics are found: # R6 represents a pyrrole, imidazole or pyrazole radical; # # represents a piperazinyl radical.

N'-(4-{4-[2-( 1,2-dithiolan-3-yl)acëtyl]-1-pipérazinyl } phényl)-2- thiophènecarboximidamide ; N'-[3-({4-[5-(l,2-dithiolan-3-yl)pentanoyl]-l-pipérazinyl}méthyl)phényl]-2- thiophènecarboximidamide ;

N'-[3-( 4-[2-(1,2-dithiolan-3-yl)acétyl]- 1 -pipérazinyl}méthyl)phényl]-2- thiophènecarboximidamide ; More particularly, the invention relates to the following products described in the examples (sometimes in the form of salts): N '- (4- {4- [5- (1,2-dithiolan-3-yl) pentanoyl] -l- piperazinyl} phenyl) -2-thiophenecarboximidamide;

N '- (4- {4- [2- (1,2-dithiolan-3-yl) acetyl] -1-piperazinyl} phenyl) -2-thiophenecarboximidamide; N '- [3 - ({4- [5- (1,2-dithiolan-3-yl) pentanoyl] -1-piperazinyl} methyl) phenyl] -2-thiophenecarboximidamide;

N '- [3- (4- [2- (1,2-dithiolan-3-yl) acetyl] - 1-piperazinyl} methyl) phenyl] -2-thiophenecarboximidamide;

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4- (4- {[amino (2-thienyl) methylidene] amino} phenyl) - N- [4- (1,2-dithiolan-3-yl) butyl] -1-piperazinecarboxamide; and their salts, in particular the corresponding hydrochlorides.

The invention further provides a number of methods for accessing the products of general formula (I) described above, methods whose preferred conditions are described below.

(II) dans laquelle n, X, Y, #, X', Y' et P ont la même signification que dans la formule générale (I), a) avec le composé de formule générale (I.i)

dans laquelle B a la même signification que dans la formule générale (I) et L représente un groupe partant, par exemple un radical alkoxy, alkylthio, acide sulfonique, halogénure, alcool arylique ou tosyle, b) ou avec le composé de formule générale (I.ii)

dans laquelle L représente un groupe partant, par exemple un radical alkoxy, alkylthio, acide sulfonique, halogénure, alcool arylique ou tosyle, The invention therefore relates in particular to a process for the preparation of a compound of general formula (I) as defined above, characterized in that a compound of general formula (II) is reacted

(II) in which n, X, Y, #, X ', Y' and P have the same meaning as in the general formula (I), a) with the compound of general formula (Ii)

in which B has the same meaning as in the general formula (I) and L represents a leaving group, for example an alkoxy, alkylthio, sulfonic acid, halide, aryl or tosyl alcohol, b) or with the compound of general formula ( I.ii)

in which L represents a leaving group, for example an alkoxy, alkylthio, sulfonic acid, halide, aryl or tosyl alcohol radical,

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dans laquelle L représente un groupe partant, par exemple un radical alkoxy, alkylthio, acide sulfonique, halogénure, alcool arylique ou tosyle, et Gp un groupe protecteur de type carbamate, par exemple le groupe t-butoxycarbonyle, cette réaction étant suivie, dans le cas où l'on opte pour la réaction avec le composé de formule générale (I.iii), par une hydrolyse en présence d'un acide fort, par exemple l'acide trifluoroacétique, d) ou avec le dérivé de formule (I.iv) (N-méthyl-N'-nitro-N-nitrosoguanidine)

e) ou enfin avec le dérivé de formule (I.v) dans laquelle Gp représente un groupe protecteur

(I.V) L'invention concerne également un procédé de préparation d'un produit de formule générale (I) dans laquelle le groupe X-Y représente -CO-N(R3)-(CH2)r-, caractérisé en ce que l'on fait réagir l'acide de formule générale (I.vi)

(I.vi) dans laquelle n a la même signification que dans la formule générale (I), avec une amine de formule générale (X) ou (Xbis) c) or with the compound of general formula (I.iii)

in which L represents a leaving group, for example an alkoxy, alkylthio, sulphonic acid, halide, aryl or tosyl alcohol radical, and Gp a protective group of carbamate type, for example the t-butoxycarbonyl group, this reaction being followed, in the case where one opts for the reaction with the compound of general formula (I.iii), by hydrolysis in the presence of a strong acid, for example trifluoroacetic acid, d) or with the derivative of formula (I. iv) (N-methyl-N'-nitro-N-nitrosoguanidine)

e) or finally with the derivative of formula (Iv) in which Gp represents a protective group

(IV) The invention also relates to a process for the preparation of a product of general formula (I) in which the group XY represents -CO-N (R3) - (CH2) r-, characterized in that: react the acid of general formula (I.vi)

(I.vi) in which has the same meaning as in general formula (I), with an amine of general formula (X) or (Xbis)

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(X) (Xbis) dans lesquelles r, R3, #, X', Y', P et A ont la même signification que dans la formule générale (I), le composé de formule générale (Xbis) étant en outre tel que son hétérocycle # comprend un atome d'azote.

(X) (Xbis) in which r, R3, #, X ', Y', P and A have the same meaning as in general formula (I), the compound of general formula (Xbis) being further such that its heterocycle # includes a nitrogen atom.

A subject of the invention is also, as new products, synthetic intermediates useful for the preparation of compounds of general formula (I), namely the compounds of general formulas (II), (III), (IV), (X), (Xbis), (XI) and (Xlbis) as defined above for (II), (X) and (Xbis), and further on for (III), (IV), (XI) and (Xlbis).

In certain cases, the compounds according to the present invention may contain asymmetric carbon atoms, and therefore have two possible enantiomeric forms, that is to say the "R" and "S" configurations. The present invention includes the two enantiomeric forms and all combinations of these forms, including the "RS" racemic mixtures. For the sake of simplicity, when no specific configuration is indicated in the structural formulas, it should be understood that the two enantiomeric forms and their mixtures are represented.

A subject of the invention is also, as medicaments, the compounds described above or their pharmaceutically acceptable salts. It also relates to pharmaceutical compositions containing these compounds or their pharmaceutically acceptable salts, and the use of these compounds or their pharmaceutically acceptable salts for manufacturing medicaments intended to inhibit neuronal NO synthase or inducible NO synthase, to regenerate anti oxidants, which can be natural or synthetic) or provide the dual function of inhibiting NO synthase and regenerating antioxidants.

The term “pharmaceutically acceptable salt” means in particular the addition salts of inorganic acids such as hydrochloride, hydrobromide, iodhydrate, sulfate, phosphate, diphosphate and nitrate or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate , lactate, methanesulfonate, p-toluenesulfonate, pamoate, oxalate and stearate. Also falling within the scope of the present invention, when they can be used, the salts formed from bases such as sodium or potassium hydroxide. For other examples of pharmaceutically acceptable salts, reference may be made to "Pharmaceutical salts", J. Pharm. Sci. 66: 1 (1977).

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 A subject of the invention is also the use of a product of general formula (I) or of a pharmaceutically acceptable salt of this product for manufacturing a medicament intended for treating pathologies in which nitric oxide and / or redox status of thiol groups are involved, pathologies such as disorders of the central or peripheral nervous system particularly well represented by Parkinson's disease, cerebrovascular disorders, proliferative and inflammatory diseases, vomiting, septic shock, pathologies resulting from irradiation radioactive, solar radiation or organ transplants, autoimmune and autosomal diseases, cancer and all pathologies characterized by a production or a dysfunction involving nitric oxide and / or involving the redox status of thiol groups.

The subject of the invention is also the use of a product of general formula (I) or of a pharmaceutically acceptable salt of this product, for manufacturing a medicament intended for treating cerebrovascular disorders such as migraine, cerebral infarctions d ischemic or hemorrhagic origin, ischemia and thrombosis.

A subject of the invention is finally the use of a product of general formula (I) or of a pharmaceutically acceptable salt of this product for manufacturing a medicament intended for treating disorders of the central or peripheral nervous system such as neurodegenerative diseases , pain, trauma to the brain or spinal cord, addiction to opioid drugs, alcohol and addictive substances, erectile and reproductive disorders, cognitive disorders, encephalopathies, depression, anxiety, schizophrenia, epilepsy, sleep disorders and eating disorders.

The pharmaceutical compositions can be in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories. Suitable solid carriers can be, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, carboxymethyl cellulose sodium, polyvinylpyrrolidine and wax.

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The pharmaceutical compositions containing a compound of the invention can also be presented in liquid form, for example, solutions, emulsions, suspensions or syrups. Suitable liquid carriers can be, for example, water, organic solvents such as glycerol or glycols, as well as their mixtures, in varying proportions, in water.

The administration of a medicament according to the invention can be done by topical, oral, parenteral route, by intramuscular injection, etc.

The administration dose envisaged for a medicament according to the invention is between 0.1 mg to 10 g depending on the type of active compound used.

In accordance with the invention, the compounds of general formula (I) can be prepared by the methods below.

A) FIRST APPROACH The compounds of general formula (I) can be prepared from intermediates of general formula (II), (III) and (IV) according to scheme 1 where n, X, X ', Y, Y', #, P and A are as defined above and Gp is a carbamate-type protecting group.

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 Scheme 1 The aniline and amine derivatives of general formula (II), can be condensed on compounds of general formula (Ii), in which L represents a leaving group (in particular an alkoxy, thioalkyl, sulfonic acid, halide, aryl alcohol or tosyl), to lead to the final compounds of general formula (I) of the substituted amidine type (cf. diagram 1). For example, for B = thiophene, the derivatives of general formula (II) can be condensed on S-methylthiophene thiocarboxamide iodhydrate, prepared according to a method of the literature (Ann. Chim. (1962), 7, 303-337 ). The condensation can be carried out by heating in an alcohol (for example in methanol or isopropanol), optionally in the presence of DMF at a temperature preferably between 50 and 100 C for a period generally between a few hours and a night.

In cases where B = SR10, for example S-CH3, these can be prepared by the condensation of the amines or anilines of general formula (II) with the isothiocyanate (Iv) in which Gp represents a protective group such as by example the group

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 benzoyl. It is then deprotected by cleavage of the protective group under suitable conditions and the thiourea formed is finally treated with, for example, a haloalkane to yield the final compounds of general formula (I).

In cases where B = NRgR the final compounds of general formula (I) are guanidines. These can be prepared, for example, by the condensation of the amines or anilines of general formula (II) with the derivatives of general formula (I.ii) or (Him). The reagents of general formula (I.ii) in which L represents, for example, a pyrazole ring are condensed on the amines of general formula (II) according to the conditions described in the literature (J. Org. Chem. (1992) 57 , 2497-2502). Similarly for the reagents of general formula (Lui) in which L represents, for example, a pyrazole ring and Gp the group tBuOCO (Tetrahedron Lett. (1993) 34 (21), 3389-3392) or else when L represents the group -N-SO2-CF3 and Gp the group tBuOCO (J. Org. Chem. (1998) 63,3804-3805). During the final stage of the synthesis, the deprotection of the guanidine function is carried out in the presence of a strong acid such as for example trifluoroacetic acid.

In cases where B = -NHN02 the final compounds of general formula (I) can be prepared, for example, by the condensation of amines or anilines of general formula (II) with the reagent of formula (I.iv) (N- methyl-N'-nitro-N-nitrosoguanidine) according to the conditions described in the literature (J. Amer. Chem. Soc. (1947), 69, 3028-3030).

The compounds of general formula (I) b, are obtained from the compounds of general formula (I) a where n, X, X ', Y, Y', Q, P and A are as defined above. The transformation of the lipoic compounds of general formula (I) a into the corresponding dihydrolipoic derivatives (I) b where R, = R2 = H is carried out in an alcoholic solvent such as, for example, methanol, in the presence of a reducing agent such as for example NaBH4, NaBH3CN or aluminum and lithium hydride (LAH). The compounds for which R, and R2 do not both represent H are prepared by reacting the compounds of general formula (I) b with a compound of formula R, - halogen and / or R2-halogen where R, and R2 are such as defined above and the halogen atom is a leaving group. The reaction is carried out, for example, in an appropriate solvent such as THF, acetone, ethyl acetate in the presence of a base such as K2CO3 or triethylamine, to yield the compounds of general formula (I) b .

Preparation of the compounds of general formula (II): The intermediates of general formula (II) are obtained from the cleavage of a protective group (Gp) or by reduction of a nitro group.

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The intermediates of general formula (II), in which n, X, X ', Y, Y', Q, and P are as defined above, can be prepared from the intermediates of general formula (III) or ( IV), scheme 1, which are compounds respectively comprising a protected amine or aniline (NHGp) in the form, for example, of a carbamate or a nitro group. In the particular case of BOC groups, these are conventionally deprotected using TFA or HCI, to finally lead to the primary amines and anilines of general formula (II). The reduction of the nitro function of the intermediates of general formula (IV), scheme 1, in which n, X, X ', Y, Y', Q, and P are as defined above, is carried out, for example, by heating the product in a suitable solvent such as ethyl acetate with a little ethanol in the presence of SnCl2 (J Heterocyclic Chem. (1987), 24, 927-930; Tetrahedron Letters (1984), 25 (8 ), 839-842) in the presence of SnCl2 / Zn (Synthesis. (1996), 9,1076-1078), using NaBH4-BiCl3 (Synth. Com. (1995) 25 (23), 3799-3803 ) in a solvent such as ethanol, or else using Ni Raney added with hydrazine hydrate (Monatshefte für Chemie, (1995), 126,725-732), or else using indium in a mixture ethanol and ammonium chloride at reflux (Synlett (1998) 9, 1028). Then the double reduction product is re-oxidized in the presence of ferric chloride (FeCl3) (Synlett (1991) 10, 717-718) or iodine (Tetrahedron Letters. (1997), 38 (33), 5785-5788) to finally lead to the amines and anilines of general formula (II) again containing the dithiolane motif.

Preparation of the compounds of general formula (III) and (IV): Synthesis of the carboxamides of general formula (III) and (IV): The carboxamides of general formula (III) and (IV) in which n, X, Y, X ' , Y ', Q and P are as defined above, which can have either an amide function in which the nitrogen belongs to heterocycle Q, or in an amide function in which the nitrogen is attached to the radical Q or to a alkylene chain linked to this radical, diagram 2, are prepared by condensation of the acids of general formula (I.vi) with the monoprotected amines or anilines of general formula (VI) and (VIII) or the nitro derivatives of general formula (VII) and (IX). Carboxamide bonds are formed under conventional conditions of peptide synthesis (M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)) in THF, dichloromethane or DMF in the presence of a coupling reagent such as dicyclohexylcarbodiimide (DCC), 1,1'carbonyldiimidazole (CDI) (J Med. Chem. (1992), 35 (23), 4464-4472) or

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 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, 1991)) or in the presence of isobutyl chloroformate and N- methyl morpholine (Org. Prep. Proced.

Int., (1975), 35, 215). The syntheses of carboxylic acids of general formula (Lvi) and of the non-commercial amines / anilines of general formula (VI), (VII), (VIII) and (IX) are described below.

0 Vl / n) # X'-Y'-P-NHGp H0-X'-Y'-P-NHGP - 0t0-X'-Y'-P-NHGP (VI) ss (III) Enz> \ y # tin / "~ \ V- x'-y'-p-no2 0 HN - Ci) # X'-Y'-P-NO, ## \ '7n (+ (VII) ss a (IV) (Iv; ) (R,) HNX'-Y'-P-NHGP - 0tNX'-Y'-P-NHGP SS (VIII) (III) or Xn / x'-rp-NO2 (R3) HNSZrX'-Y'-P -NO2 - 0tNX'-Y'-P-NO, (IX) ss (IV)
Diagram 2 B) SECOND APPROACH The compounds of general formula (I) can also be prepared from intermediates of general formula (X), (XI), (XII) and (XIII) (or (Xbis), (XIbis), (XIIbis) and (XIIIbis) when the amine function is part of the heterocycle Q) according to scheme 3 in which n, X, X ', Y, Y', Q, P and A are as defined above and Gp, and Gp2 are protecting groups: for example, when Y = -NR3-, Gp1 can be a carbamate-type protecting group or when Y = -O-, Gp, can be a benzyl-type protecting group or others protective groups (Gpl) known to those skilled in the art. Gp2 can also be a protective group of carbamate type or other protective groups (Gp2) known to those skilled in the art.

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Schéma 3

Diagram 3

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Preparation of the compounds of general formula (I): Synthesis of the carboxamides of general formula (I): The carboxamides of general formula (I), scheme 4, in which n, X ', Y', Q, P and A are such that defined above, are prepared by condensation of the acids of general formula (I.vi) with the amines / anilines of general formula (X) and (X) bis. Carboxamide bonds are formed under conventional conditions of peptide synthesis (M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, 145 (SpringerVerlag, 1984)) in THF, dichloromethane or DMF, in the presence of a reagent coupling agents such as dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI) (J Med. Chem. (1992), 35 (23), 4464-4472) or 1- (3-dimethylaminopropyl) hydrochloride -3-ethylcarbodiimide (EDC or WSCI) (John Jones, The chemical synthesis of peptides, 54 (Clarendon Press, Oxford, 1991)) or in the presence of isobutyl chloroformate and N-methyl morpholine (Org. Prep. Proced. Int., (1975), 35,215). The syntheses of non-commercial carboxylic acids of general formula (I.vi) are described below.

 Diagram 4 Synthesis of ureas of general formula (I) The ureas of general formula (I), diagram 5, in which n, X ′, Y \ #, P and A are as defined above, are prepared, for example , by condensation of the acids of general formula (I.vi) with the amines / anilines of general formula (X) and (X) bis in toluene in the presence of diphenylphosphoryl azide (DPPA) and triethylamine, for example at a temperature of 80 C and for 2 to 3 hours.

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 Scheme 5 Preparation of the compounds of general formula (X), (X) bis, (XI), (XI) bis, (XII), (XII) bis, (XIII) and (XIII) bis: The compounds of general formula ( X) and (X) bis are obtained from the cleavage of a protecting group. The compounds of general formula (X) and (X) bis, in which X ', Y, Y', Q, P and A are as defined above, can be prepared from the compounds of general formula (XI) and (XI) bis, scheme 3, which are compounds comprising a protected amine / aniline (NHGp) in the form, for example, of a carbamate or an alcohol or phenol protected by a benzyl group (O-benzyl) or by other protective groups (Gp1, Gp2) known to those skilled in the art. In the particular case of the BOC groups, these are conventionally deprotected using trifluoroacetic acid (TFA) or HCl, the O-benzyl groups being conventionally deprotected by catalytic hydrogenation in the presence of Pd on carbon, and finally the compounds of general formula (X) and (X) bis are obtained.

The compounds of general formula (XI) and (XI) bis can be prepared from the intermediates of general formula (XII) and (XII) bis and (XIII) and (XIII) bis according to scheme 3 where Q, Y, X ', Y', P are as defined above and Gp, and Gp2 are protecting groups.

The aniline / amine derivatives of general formula (XII) and (XII) bis can be condensed on compounds of general formula (Ii, Iii, and Iiii), in which L represents a leaving group and with (I. iv and Iv) as previously described for

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 compounds of general formula (I) in scheme 1, to finally lead to the compounds of general formula (X) and (X) bis, scheme 3.

The compounds of general formula (XII) and (XII) bis are obtained from the reduction of a nitro group of the compounds of general formula (XIII) and (XIII) bis.

The reduction of the nitro function of the compounds of general formula (XIII) and (XIII) bis, scheme 3, in which Q, Y, X ', Y' and P are as defined above, is carried out, for example, conventionally by catalytic hydrogenation in the presence of Pd on charcoal, or else by heating the product in an appropriate solvent such as ethyl acetate with a little ethanol in the presence of SnCl2 (J. Heterocyclic Chem. (1987), 24 , 927-930; Tetrahedron Letters (1984), 25 (8), 839-842), in the presence of SnCl2 / Zn (Synthesis. (1996), 9,1076-1078) or also using NaBH4-BiCl3 (Synth. Com. (1995) 25 (23), 3799-3803) in a solvent such as ethanol, or else using Ni Raney added with hydrazine hydrate (Monatshefte für Chemie, (1995), 126,725 -732), or finally using indium in a mixture of ethanol and ammonium chloride at reflux (Synlett (1998) 9, 1028), to finally lead to the primary amines and anilines of general formula (XII ) and (XII) bis.

The synthesis of the non-commercial compounds of general formula (XIII) and (XIII) bis, is described below.

Preparation of certain non-commercial synthesis intermediates: The non-commercial acids of general formula (I.vi), in which m is as defined above are accessible from methods of the literature. For example, trisnorlipoic acid [2- (1,2-dithiolan-3-yl) acetic acid] is obtained in 5 steps according to an experimental protocol described in Tetrahedron Letters. (1997), 38 (33), 5785-5788 .

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

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l.A.l) l-[5-(l,2-dithiolan-3-yl)pentanoyl]-4-(4-nitrophényl)pipérazine : A une solution de 5,0 g (24,13 mmol) d'acide (DL) -thioctique dans 120 ml de dichlorométhane, on ajoute successivement 5,0 g (24,13 mmol) de nitrophénylpipérazine, triéthylamine (14,Oml), 4. 24 g (31,37 mmol) d'hydroxybenzotriazole, 12,0 g (62,73 mmol) de chlorhydrate de l-(3-diméthylaminopropyl)-3-éthyl-carbodiimide. Après avoir agité le mélange réactionnel une nuit à 25 C, on dilue l'ensemble avec 400 ml d'eau et l'agitation est maintenue 30 minutes supplémentaires. Le produit est extrait à l'aide de 3 fois 200 ml de dichlorométhane. La solution organique est séchée sur sulfate de magnésium, filtrée et concentrée sous vide. Le solide obtenu est filtré et rincé à l'éther diéthylique pour obtenir, après séchage, 6,21 g d'un produit solide jaune avec un rendement de 65 %. EXAMPLES Example 1: N '- (4- {4- [5- (1,2-dithiolan-3-yl) pentanoyl] -1piperazinyl} phenyl) -2-thiophenecarboximidamide: A. Method according to the first approach:

lAl) l- [5- (1,2-dithiolan-3-yl) pentanoyl] -4- (4-nitrophenyl) piperazine: To a solution of 5.0 g (24.13 mmol) of acid (DL) -thioctic in 120 ml of dichloromethane, 5.0 g (24.13 mmol) of nitrophenylpiperazine, triethylamine (14, Oml) are successively added. 4.24 g (31.37 mmol) of hydroxybenzotriazole, 12.0 g ( 62.73 mmol) of 1- (3-dimethylaminopropyl) -3-ethyl-carbodiimide hydrochloride. After having stirred the reaction mixture overnight at 25 ° C., the whole is diluted with 400 ml of water and stirring is continued for 30 minutes more. The product is extracted using 3 times 200 ml of dichloromethane. The organic solution is dried over magnesium sulfate, filtered and concentrated in vacuo. The solid obtained is filtered and rinsed with diethyl ether to obtain, after drying, 6.21 g of a yellow solid product with a yield of 65%.

Melting point: 97.6-98.5 C.

1.A.2) 4- (4-5- (1,2-dithiolan-3 yl) pentanoylJ-1 piperazinylaniline: To a solution of 5.2 g (13.20 mmol) of intermediate lAl in 60 ml of ethanol, 16 ml of a saturated aqueous ammonium chloride solution and 21.0 g (0.183 mol) of powdered indium are successively added, then the reaction medium is refluxed for 5 hours (Synlett ( 1998) 9.1028) The whole is cooled to room temperature and filtered through celite. The filtrate is made alkaline at pH 10 with a 50% sodium hydroxide solution. The reduced product is extracted using 4 150 ml of dichloromethane The organic solution is dried over magnesium sulphate, filtered and concentrated in vacuo to give a yellow oil, the oil is dissolved in a mixture of 15 ml of dimethylformamide and 20 ml of ethyl acetate. The whole is cooled using an ice bath, to 0 ° C., and an aqueous solution of 10% potassium bicarbonate is added dropwise. The reaction mixture is stirred for approximately 10 minutes at 0 ° C., the iodine solution (3.45 g in 40 ml of ethyl acetate) is added dropwise until the coloring of the iodine persists. The product is extracted using 4 times 100 ml of ethyl acetate, the organic solution is dried over magnesium sulfate, filtered and concentrated in vacuo. Purification is then carried out on a silica column (eluent = 5% ethanol in dichloromethane) to yield a yellow oil, 3.03 g, with a yield of 63%.

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 MH + = 366.2.

1H NMR (DMSO d6,400 MHz, 8): 1.39 (m, 2H, CH2); 1.50-1.70 (m, 4H, CH2); 1.87 (m, 1H, CH2); 2.32 (m, 2H, CH2); 2.34 (m, 1H, CH2); 2.80-2.88 (m, 4H, CH2-piperazine); 3.17 (m, 2H, CH2); 3.53 (m, 4H, CH2-piperazine); 3.59 (m, 1H, -S-CH-); 4.58 (s, 2H, NH2); 6.50 (d, 2H, aroma, J = 7.0 Hz); 6.69 (d, 2H, aroma, J = 7.0 Hz).

l-pipérazinyl}phényl)-2-thiophènecarboximidamide : L'intermédiaire 1.A.2 (0,5 g ; mmol) est dissous dans du 2-propanol (15 ml) et on ajoute 0,582 g d'iodhydrate de S-méthyl-2-thiophène thiocarboximide (2,04 mmol) (Ann. Chim., (1962), 7,303-337). Après agitation à 25 C pendant 15 heures, le mélange réactionnel est concentré à sec sous vide. Le résidu est repris dans du dichlorométhane et une solution aqueuse saturée de NaHC03. Après décantation, la phase organique est lavée successivement avec 50 ml d'une solution saturée de NaHC03, d'eau puis de saumure. La solution organique est séchée sur sulfate de magnésium, filtrée et évaporée sous pression réduite. On dissout ensuite la base libre dans 5 ml d'éthanol et la solution est refroidie à l'aide d'un bain de glace avant l'addition goutte à goutte de 0,3 ml d'une solution IN de HCl dans de l'éther éthylique anhydre. IA3) N 'hydrochloride - (4- {4- [5- (1,2-dithiolan-3-yl) pentanoyl] -

1-piperazinyl} phenyl) -2-thiophenecarboximidamide: Intermediate 1.A.2 (0.5 g; mmol) is dissolved in 2-propanol (15 ml) and 0.582 g of S-methyl iodhydrate is added -2-thiophene thiocarboximide (2.04 mmol) (Ann. Chim., (1962), 7,303-337). After stirring at 25 ° C. for 15 hours, the reaction mixture is concentrated to dryness under vacuum. The residue is taken up in dichloromethane and a saturated aqueous solution of NaHCO3. After decantation, the organic phase is washed successively with 50 ml of a saturated NaHCO3 solution, water and then brine. The organic solution is dried over magnesium sulfate, filtered and evaporated under reduced pressure. The free base is then dissolved in 5 ml of ethanol and the solution is cooled using an ice bath before the dropwise addition of 0.3 ml of an IN solution of HCl in anhydrous ethyl ether.

After 15 hours of stirring at 25 ° C., the crystals obtained are filtered and rinsed with diethyl ether to obtain, after drying, 0.320 g of a yellow solid product with a yield of 43%. Melting point: 203-203.7 C.

: ~ Mh9-ç! - -J.9.J} ~! -Ç !! ~ pp.9 ~ çh ~~: 1.B.1) 4- (4-nitrophenyl) -1-tert-butyl piperazinecarboxylate 5.55 g (26.5 mmol) of 1- (4-nitrophenyl) are dissolved piperazine in a mixture of 60 ml of dichloromethane and 8.2 ml of triethylamine. The whole is cooled using an ice bath before the addition in several portions of 6.4 g (29.2 mmol) of (Boc) 20. The reaction mixture is stirred at 23 ° C. for 12 hours and poured into an ice-water mixture. The organic phase is decanted, washed successively with 20 ml of water and 20 ml of brine. After drying over sodium sulfate, filtration and concentration under vacuum, then trituration with isopropyl ether, a yellow solid is obtained with a quantitative yield. Melting point: 143.7-145.7 C.

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1.B.2) 4- (4-aminophenyl) -l-piperazinecarboxylate tert-butyl In a stainless steel autoclave equipped with a magnetic bar, a solution of intermediate lB1 (7.63 g; 25) is introduced. , 0 mmol) in 40 ml of a dichloromethane / ethanol mixture (30 ml / 50 ml) as well as 1.0 g of Pd / C at 10%. The reaction mixture is stirred under hydrogen pressure (1.5 bar) for 12 hours at a temperature of 20 C. The Pd / C is then removed by filtration and the filtrate is concentrated in vacuo. The evaporation residue is purified by trituration with ether, a gray powder (4.96 g; 71%) is obtained. Melting point: 145 C.

1.B.4) N-[4-(I-pipérazinyl)phényl]-2-thiophènecarboximidamide Dans une solution à 0 C de l'intermédiaire 1.B.3 (5,40 g ; mmol) dans de l'acétate d'éthyle (200 ml), on passe un courant d'HCl gaz bulle à bulle. On laisse le mélange revenir à température ambiante durant la nuit. On fait passer un courant d'Argon à travers la masse réactionnelle, puis la poudre obtenue est filtrée et lavée avec l'acétate d'éthyle pour conduire à un solide blanc-beige (5,0 g ; rendement de 99 %). Point de fusion: 180 C. 1.B.3) 4- (4- (amino (2-thienyl) methylideneJamino) phenyl) -1- tert-butyl piperazinecarboxylate Intermediate 1.B.2 (4.96 g; 17.9 mmol) is dissolved in 2-propanol (150 ml) and 7.66 g of S-methyl-2-thiophene thiocarboximide iodhydrate (26.8 mmol) are added (Ann. Chim., (1962), 7,303-337 ). After stirring at 25 ° C. for 15 hours, the reaction mixture is concentrated to dryness under vacuum. The residue is taken up in dichloromethane and a saturated aqueous solution of NaHCO3. After decantation, the organic phase is washed successively with 50 ml of a saturated NaHCO3 solution, water and brine. The organic solution is dried over magnesium sulfate, filtered and evaporated under reduced pressure. The solid obtained is filtered and rinsed with isopentane to obtain, after drying, 6.91 g of a yellow solid product (yield 78%). Melting point: 164 C

1.B.4) N- [4- (I-piperazinyl) phenyl] -2-thiophenecarboximidamide In a 0 ° C solution of intermediate 1.B.3 (5.40 g; mmol) in acetate of ethyl (200 ml), a stream of HCl gas is passed bubble to bubble. The mixture is allowed to return to room temperature overnight. An Argon stream is passed through the reaction mass, then the powder obtained is filtered and washed with ethyl acetate to yield a white-beige solid (5.0 g; 99% yield). Melting point: 180 C.

pipérazinyl} phényl)- 2 -thiophènecarboximidamide : Le protocole expérimental utilisé est analogue à celui décrit pour le composé 1.A.1. Le chlorhydrate est fait de la même façon que pour l'intermédiaire LA. 3. On obtient le solide jaune attendu. 1.B.5) N 'hydrochloride - (4- {4- [5- (1,2-dithiolan-3-yl) pentanoyl] -1-

piperazinyl} phenyl) - 2 -thiophenecarboximidamide: The experimental protocol used is analogous to that described for compound 1.A.1. The hydrochloride is made in the same way as for the intermediate LA. 3. The expected yellow solid is obtained.

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Exemple 2 : N'-(4-{4-[2-(1,2-dithiolan-3-yl)acétyl]-1-pipérazinyl}phényl)-2- thiophènecarboximidamide : Le protocole expérimental utilisé est le même que celui décrit pour le composé 1, méthode A. L'acide norlipoïque, (Tetrahedron Letters (1997), 38 (33), 5785-5788), remplaçant l'acide lipoïque, pour conduire à un solide jaune (0,126 g).

Example 2: N '- (4- {4- [2- (1,2-dithiolan-3-yl) acetyl] -1-piperazinyl} phenyl) -2- thiophenecarboximidamide: The experimental protocol used is the same as that described for compound 1, method A. Norlipoic acid, (Tetrahedron Letters (1997), 38 (33), 5785-5788), replacing lipoic acid, to yield a yellow solid (0.126 g).

MH + = 433.2.

1H NMR (DMSO d6, 400 MHz, 8): 1.97 (m, 1H, CH2); 2.40 (m, 1H, CH2); 2.75 (m, 1H, CH2); 2.87 (m, 1H, CH2); 3. 04 (m, 4H, CH2-piperazine); 3.09 (m, 1H, CH2); 3.21 (m, 1H, CH2); 3.59 (m, 4H, CH2-piperazine); 3.97 (m, 1H, -S-CH-); 6.26 (br s, 2H, NH2); (d, 2H, aroma, J = 8.6 Hz); 6.94 (d, 2H, aroma, J = 8.6 Hz); 7.07 (m, 1H, CH-thiophene); 7.57 (m, 1H, CH-thiophene); 7.70 (m, 1H, CH-thiophene).

Example 3: N '- [3 - ({4- [5- (1,2-dithiolan-3-yl) pentanoyl] -1-piperazinyl} methyl) phenyl] -2-thiophenecarboximidamide hydrochloride: The experimental protocol used is the same as that described for compound 1, method A. A white solid is obtained (0.220 g). Melting point: 240.0-240.5 C.

Example 4: N '- [3 - ({4- [2- (1,2-dithiolan-3-yl) acetyl] -1-piperazinyl} methyl) phenyl] - 2-thiophenecarboximidamide: The experimental protocol used is the same than that described for compound 1, method A. Norlipoic acid, (Tetrahedron Letters (1997), 38 (33), 5785-5788), replacing lipoic acid, to lead to a yellow foam (0.20 g ).

MH + = 447.2.

1H NMR (DMSO d6,400 MHz, #): 1.96 (m, 1H, CH2); 2.34-2.40 (m, 4H, CH2-piperazine); 2.49 (m, 1H, CH2); 2.71 (m, 1H, CH2); 2.80 (m, 1H, CH2); 3.08 (m, 1H, CH2); 3.28 (m, 1H, CH2); 3.41 (m, 4H, CH2-piperazine); 3.46 (3.2H, CH2); 3.93 (m, 1H, -S-CH-); 6.54 (br s, 2H, NH2); 6.77 (d, 1H, aroma, J = 7.60 Hz); 6.82 (s, 1H, arom); 6.95 (d, 1H, aroma, J = 7.60 Hz); (m, 1H, CH-thiophene); 7.26 (t, 1H, aroma, J = 7.60 Hz); 7.63 (m, 1H, CH-thiophene); 7.74 (m, 1H, CH-thiophene).

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Exemple 5 : 4-(4- f [amino(2-thiényl)méthylidène]amino}phényl)N-[4-(1,2-dithiolan-3-yl)butyl]-1-pipérazinecarboxamide : Sous atmosphère d'argon, on solubilise 0,206 g (1,0 mmol) d'acide lipoïque dans du dioxane (5 ml), de l'acétonitrile (5 ml) et de la triéthylamine (0,3 ml). Du diphénylphosphoryl azide (0,24ml; 1,0 mmol) est ajouté puis le milieu réactionnel porté à 80 C pendant 2 heures. Le milieu réactionnel est alors refroidi à l'aide d'un bain de glace puis l'intermédiaire 1.B.4 (0,395 g ; 1,0 mmol) additionné. Après avoir agité le mélange réactionnel une nuit à 25 C, on dilue l'ensemble avec 100 ml d'eau et l'agitation est maintenue 30 minutes supplémentaires. Le produit est extrait à l'aide de 3 fois 25 ml d'acétate d'éthyle. La solution organique est séchée sur sulfate de magnésium, filtrée et concentrée sous vide. On procède alors à une purification sur colonne de silice (éluant = 10 % d'éthanol dans du dichlorométhane) pour conduire à un solide jaune. Le solide jaune est purifié davantage par recristallisation dans de l'éthanol pour donner 0,25 g de produit (rendement de 46,4%). Point de fusion : 201,1-201,8 C Etude pharmacologique des produits de l'invention Etude des effets sur la NO synthase constitutive neuronale de cervelet de rat L'activité inhibitrice des produits de l'invention est déterminée par la mesure de leur effets sur la transformation par la NO synthase de la [3H]L-arginine en [ H]L-citrulline en accord avec la méthode modifiée de Bredt et Snyder (Proc. Natl. Acad. Sci. USA, (1990) 87 : Des cervelets de rats Sprague-Dawley (300g - Charles River) sont rapidement prélevés, disséqués à 4 C et homogénéisés dans un volume de tampon d'extraction (HEPES 50 mM, EDTA 1 mM, pH 7,4, pepstatin A 10 mg/ml, leupeptine 10 mg/ml). Les homogénats sont ensuite centrifugés à 21000 g pendant 15 min à 4 C.

Example 5: 4- (4- f [amino (2-thienyl) methylidene] amino} phenyl) N- [4- (1,2-dithiolan-3-yl) butyl] -1-piperazinecarboxamide: Under argon atmosphere , 0.206 g (1.0 mmol) of lipoic acid is dissolved in dioxane (5 ml), acetonitrile (5 ml) and triethylamine (0.3 ml). Diphenylphosphoryl azide (0.24 ml; 1.0 mmol) is added and then the reaction medium brought to 80 ° C. for 2 hours. The reaction medium is then cooled using an ice bath and then intermediate 1.B.4 (0.395 g; 1.0 mmol) added. After having stirred the reaction mixture overnight at 25 ° C., the whole is diluted with 100 ml of water and the stirring is continued for a further 30 minutes. The product is extracted using 3 times 25 ml of ethyl acetate. The organic solution is dried over magnesium sulfate, filtered and concentrated in vacuo. Purification is then carried out on a silica column (eluent = 10% ethanol in dichloromethane) to yield a yellow solid. The yellow solid is further purified by recrystallization from ethanol to give 0.25 g of product (46.4% yield). Melting point: 201.1-201.8 C Pharmacological study of the products of the invention Study of the effects on the neuronal constitutive NO synthase of rat cerebellum The inhibitory activity of the products of the invention is determined by measuring their effects on the transformation by NO synthase of [3H] L-arginine into [H] L-citrulline in accordance with the modified method of Bredt and Snyder (Proc. Natl. Acad. Sci. USA, (1990) 87: Des cerebellum of Sprague-Dawley rats (300g - Charles River) are quickly removed, dissected at 4 C and homogenized in a volume of extraction buffer (HEPES 50 mM, EDTA 1 mM, pH 7.4, pepstatin A 10 mg / ml , leupeptin 10 mg / ml) The homogenates are then centrifuged at 21000 g for 15 min at 4 C.

The assay is carried out in glass test tubes in which are distributed 100 III of incubation buffer containing 100 mM of HEPES (pH 7.4), 2 mM of EDTA, 2.5 mM of CaCl2, 2 mM dithiotreitol, 2 mM reduced NADPH and 10 g / ml calmodulin.

25 III of a solution containing 100 nM of [3 H] L-arginine (specific activity: 56.4 Ci / mmol, Amersham) and 40 M of non-radioactive L-arginine are added. The reaction is initiated by adding 50 III of homogenate, the final volume being 200 III (the 25 missing IIIs are either water or the product tested. After 15 min, the reaction is stopped with 2 ml of buffer d stop (20 mM HEPES, pH 5.5.2 mM EDTA).

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 passage of the samples on a column of 1 ml of DOWEX resin, the radioactivity is quantified by a liquid scintillation spectrometer.

The compounds of Examples 1, 2, 3, 4 and 5 described above have an IC 50 of less than 4.5 M.

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

The inhibitory activity of the products of the invention is determined by measuring their capacity to protect the cells of a hippocampal mouse line (HT-22) from oxidative stress caused by glutamate. Glutative biosynthesis, an essential element in the cellular detoxification of free radicals, requires the active transport of cystine inside the cell. Glutamate by opposing the penetration of cystine causes a reduction in the gluthation rate which leads to cell death by oxidative stress (Davis, JB and Maher, P., Brain Res., (1994) 652: 169 -173; Murphy, TH et al., Neuron, (1989) 2: The cells are cultured at 37 ° C. in DMEM medium supplemented with 10% fetal calf serum. The tests are carried out in 96-well plates containing 5000 cells per well. Glutamate (5 mM) is added to the medium containing or not containing the products to be tested. Cell viability is tested after 24 h by the MTT method (Hansen, MB et al., J Immunol.Methods (1989 ) 119: 203-210) The capacity of the compounds to protect cells from the toxic action of glutamate is estimated in EC50, calculated relative to the viability of cells not subjected to the action of glutamate considered as 100% viability.

Claims (13)

 (I) a (I) b in which n represents an integer from 0 to 6; R1 and R2 independently represent a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; XY represents -O- (CH2) r-, -N (R3) - (CH2) r- '-CO (CH2) r-' -CO-N (R3) - (CH2) r-, -N (R4) -CO- (CH2) r-, or -N (R3) -CO-N (R4) - (CH2) r-, X'-Y 'represents - (CH2) r-' - (CH2) rO- (CH2 ) r-, - (CH2) rN (R3) - (CH2) r- '- (CH2) r-CO (CH2) r-' - (CH2) r-CO-N (R3) - (CH2) r- , - (CH2) rN (R4) -CO- (CH2) r-, or - (CH2) rN (R3) -CO-N (R4) - (CH2) r-, r representing independently each time it intervenes an integer from 0 to 6; Q represents a 5 or 6-membered aromatic heterocycle, a 4 to 7-membered non-aromatic heterocycle or a phenylene radical substituted by a radical R5, R5 representing a hydrogen atom, a linear or branched alkyl radical of 1 to 6 atoms carbon or a radical - (CH2) mQ in which Q represents a halogen atom or a hydroxy, cyano, amino, alkoxy, alkylamino or dialkylamino radical, m representing an integer from 0 to 6; P represents- (CH2) g-, g represents an integer from 0 to 6, or P represents a radical

 Claims 1. Product of general formula (I), characterized in that it comprises the products of sub-formulas (I) a and (I) b <Desc / Clms Page number 26>  in which: B represents a linear or branched alkyl radical having from 1 to 6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 members containing from 1 to 4 heteroatoms chosen from 0, S, N and in particular the thiophene, furan radicals, pyrrole or thiazole, the aryl radical being optionally substituted by one or more groups chosen from linear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6 carbon atoms, or B represents NRgR9, in which Rg and R9 represent, independently, a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms, or one of R8 and R9 represents a nitro radical while the other represents a hydrogen atom or a linear alkyl radical or branched having from 1 to 6 carbon atoms, or Rg and R9 taken together form with the nitrogen atom a non-aromatic heterocycle of five to six members, the elements of the chain being chosen s from a group composed of -CH2-, -NH-, -0- or -S-, or else B represents a SRIO radical in which RIO represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; or a salt of a product of general formula (I).

 in which R6 represents a hydrogen atom, a linear or branched alkyl radical having from 1 to 6 carbon atoms or a - (CH2) nQ 'radical in which Q' represents a hydroxy, amino, alkoxy, alkylthio, alkylamino or dialkylamino and n represents an integer from 0 to 6, or alternatively R6 represents a 5 to 6-membered heterocycle whose heterocyclic links are chosen from the radicals -O-, -N (R7) - and -S-, R7 representing an atom hydrogen or linear or branched alkyl having 1 to 6 carbon atoms; and finally A represents the radical

<Desc / Clms Page number 27>  N- [4- (1,2-dithiolan-3-yl) butyl] -1-piperazinecarboxamide; or one of their salts.

 N '- [3 - ({4- [5- (1,2-dithiolan-3-yl) pentanoyl] -1-piperazinyl} methyl) phenyl] -2-thiophenecarboximidamide; N '- [3 - ({4- [2- (1,2-dithiolan-3-yl) acetyl] -1-piperazinyl} methyl) phenyl] -2-thiophenecarboximidamide; 4- (4 - {[amino (2-thienyl) methylidene] amino} phenyl) -

 N '- (4- 4- [2- (1,2-dithiolan-3-yl) acetyl] -1-piperazinyl} phenyl) -2-thiophenecarboximidamide;

 N '- (4- {4- [5- (1,2-dithiolan-3-yl) pentanoyl] -1-piperazinyl} phenyl) -2-thiophenecarboximidamide;

 2. Product according to claim 1, characterized in that it is one of the following compounds: 3. Process for the preparation of a compound of general formula (I) according to claim 1, characterized in that a compound of general formula (II) is reacted

 (II) in which n, X, Y, #, X ', Y' and P have the same meaning as in the general formula (I) of claim 1, a) with the compound of general formula (I.i)

 in which B has the same meaning as in the general formula (I) and L represents a leaving group, for example an alkoxy, alkylthio, sulfonic acid, halide, aryl or tosyl alcohol, <Desc / Clms Page number 28>  (Liv) e) or finally with the derivative of formula (I.v) in which Gp represents a protective group S = # = N-Gp (I.v) 4. Process for the preparation of a product of general formula (I) according to claim 1 in which the group XY represents -CO-N (R3) - (CH2) r-, characterized in that the acid of general formula (I.vi)

 in which L represents a leaving group, for example an alkoxy, alkylthio, sulphonic acid, halide, aryl or tosyl alcohol radical, and Gp a protective group of carbamate type, for example the t-butoxycarbonyl group, this reaction being followed, in the case where one opts for the reaction with the compound of general formula (I.iii), by hydrolysis in the presence of a strong acid, for example trifluoroacetic acid, d) or with the derivative of formula (I. iv) (N-methyl-N'-nitro-N-nitrosoguanidine)

 in which L represents a leaving group, for example an alkoxy, alkylthio, sulfonic acid, halide, aryl or tosyl alcohol, c) or with the compound of general formula (I.iii)

 b) or with the compound of general formula (I.ii) <Desc / Clms Page number 29>  in which r, R3, #, X ', Y', P and A have the same meaning as in the general formula (I) of claim 1, the compound of general formula (Xbis) being further such that its heterocycle # includes a nitrogen atom.

 in which n has the same meaning as in the general formula (I) of claim 1, with an amine of general formula (X) or (Xbis)

5. As new industrial products, the synthesis intermediaries of general formulas (II), (III) and (IV)

 in which n, X ', Y', P and A have the same meaning as in the general formula (I) of claim 1; Q has the same meaning as in the general formula (I) of claim 1; X-Y has the same meaning as in the general formula (I) of claim 1 with regard to the compounds of general formulas (II), (III) and (IV), Y representing <Desc / Clms Page number 30>  a radical -O- (CH2) r- or -N (R3) - (CH2) r- as regards the compounds of general formulas (X) and (XI); Gp represents a carbamate-type protective group, for example the t-butoxycarbonyl group; r being an integer from 0 to 6. 6. As a medicament, a product of general formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof. 7. Pharmaceutical composition containing as active ingredient at least one product according to claim 1 or 2, or a pharmaceutically acceptable salt of said product. 8. Use of a product of general formula (1) according to claim 1 or 2, or of a pharmaceutically acceptable salt of this product, for manufacturing a medicament intended to inhibit NO synthase. 9. Use of a product of general formula (1) according to claim 1 or 2, or of a pharmaceutically acceptable salt of this product, for manufacturing a medicament intended to regenerate antioxidants. 10. Use of a product of general formula (I) according to claim 1 or 2, or of a pharmaceutically acceptable salt of this product, for manufacturing a medicament having both an activity of inhibiting NO synthase and of antioxidant regeneration. 11. Use of a product of general formula (I) according to claim 1 or 2, or of a pharmaceutically acceptable salt of this product, for manufacturing a medicament intended to treat pathologies in which nitric oxide and / or the redox status of the thiol groups are involved, pathologies such as disorders of the central or peripheral nervous system particularly well represented by Parkinson's disease, cerebrovascular disorders, proliferative and inflammatory diseases, vomiting, septic shock, pathologies resulting from radioactive irradiation, solar radiation or organ transplants, autoimmune and autosomal diseases, cancer and all pathologies characterized by a production or dysfunction involving nitric oxide and / or involving the redox status of thiol groups. 12. Use of a product of general formula (I) according to claim 1 or 2, or of a pharmaceutically acceptable salt of this product, for manufacturing a medicament <Desc / Clms Page number 31>  intended to treat cerebrovascular disorders such as migraine, cerebral infarction of ischemic or hemorrhagic origin, ischemia and thrombosis. 13. Use of a product of general formula (I) according to claim 1 or 2, or of a pharmaceutically acceptable salt of this product, for manufacturing a medicament intended to treat disorders of the central or peripheral nervous system such as diseases neurodegenerative, pain, trauma to the brain or spinal cord, addiction to opioid drugs, alcohol and addictive substances, erection and reproduction disorders, cognitive disorders, encephalopathies, depression, anxiety, schizophrenia, epilepsy, sleep disturbances and eating disorders.