FR2835254A1 - THIAZOLE DERIVATIVES IN THE TREATMENT OF NEUROLOGICAL DISEASES - Google Patents

Abstract

The invention relates to thiazole derivatives useful in particular in the treatment of neurological diseases, and in particular the compounds of general formula (I ') in which A represents one of the radicals A1 and A2 in which R4, R5, R6, R7, R8, R9 and R10 may in particular independently represent H or an alkyl radical; B represents H or an alkyl radical; represents a heterocycle optionally comprising a carbon-carbon double bond in which X may represent CH or N and R1 and R2 independently represent H or an alkyl radical, R3 being a substituent attached to said heterocycle by one of its members; carbon atoms and being chosen in particular from H and -OH, it being understood, however, that if A represents a radical A1, X represents CH and R2 and R3 both represent hydrogen atoms, then R1 does not represent a hydrogen atom; .

Description

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 FIELD OF THE INVENTION The present invention relates to thiazole derivatives useful in the treatment of neurological diseases.

Most neurological diseases are currently incurable and the pharmaceutical industry is therefore investing a lot of effort into finding chemical entities that would slow down their progression or, better, prevent or treat them.

Among the fruits of this research, a number of imidazole derivatives or thiazoles have already been shown to treat neurological diseases.

dans laquelle Rl représente notamment un radical phényle optionnellement substitué par un à trois substituants choisis indépendamment parmi (notamment) le radical OH, alkyle ou alkoxy ; X représente NR2, R2 représentant H ou alkyle ; Y représente N ou CR3 ; Z représente CR3 ou N ; à la condition toutefois que Y et Z ne sont pas tous deux CR3 ou N en même temps ; R3 représente notamment H, alkyle, hydroxyalkyle ou phényle éventuellement substitué par 1 à 3 substituants choisis parmi (notamment) H, OH, alkyle ou alkoxy ; m représente 0,1 ou 2 ; R4 représente H ou alkyle ; In particular, the compounds of general formula (P1)

in which R1 represents in particular a phenyl radical optionally substituted with one to three substituents chosen independently from (in particular) the OH, alkyl or alkoxy radical; X is NR2, R2 is H or alkyl; Y is N or CR3; Z represents CR3 or N; provided, however, that Y and Z are not both CR3 or N at the same time; R3 represents in particular H, alkyl, hydroxyalkyl or phenyl optionally substituted with 1 to 3 substituents chosen from (in particular) H, OH, alkyl or alkoxy; m is 0.1 or 2; R4 is H or alkyl;

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 when Z is CR3, then R3 and R4 may also be together - (CH2) n1- with a range of 2 to 4 or R2 and R4 may also be together - (CK1) - with n2 integer from 2 to 4; R5 and R6 are (especially) independently H, alkyl, alkoxy, aryl or aralkyl; R4 and R5 may also represent - (CH2) n3- with n3 integer from 2 to 3; have been described in PCT patent application WO 96/16040 as partial agonists or antagonists of dopamine sub-receptors of the brain or as prodrug forms of such partial or antagonistic agonists. These compounds would therefore have interesting properties in the diagnosis and treatment of affective disorders such as schizophrenia and depression as well as certain movement disorders such as Parkinson's disease.

sous forme racémique, d'énantiomère ou toute combinaison de ces formes, dans laquelle Het est un hétérocycle à 5 chaînons comportant 2 hétéroatomes et tel que la formule générale (P2) corresponde notamment à l'une des sous-formules suivantes :

The Applicant has itself recently described in PCT Patent Application WO 01/26656 that the thiazole derivatives of general formula (P2)

in racemic, enantiomeric form or any combination thereof, wherein Het is a 5-membered heterocycle having 2 heteroatoms and such that the general formula (P2) corresponds in particular to one of the following sub-formulas:

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dans lequel Q représente notamment H ou -OR22, R22 représentant un atome d'hydrogène, un radical alkyle ou un radical aryle éventuellement substitué par un ou plusieurs substituants choisis parmi les radicaux alkyle, OH, halogène, nitro et alkoxy, et R19, R20 et R21 représentent notamment, indépendamment, un atome d'hydrogène, le groupe OH ou un radical alkyle ou alkoxy ; X représente notamment S ; RI représente notamment un atome d'hydrogène ou un radical alkyle, aminoalkyle, cycloalkyle ou cycloalkylalkyle, et R2 représente notamment un atome d'hydrogène, un radical alkyle, aminoalkyle, cycloalkyle ou cycloalkylalkyle ; ou bien R1 et R2, pris ensemble avec l'atome de carbone qui les porte, forment un carbocycle de 3 à 7 chaînons ; B représente notamment un atome d'hydrogène ou un radical alkyle ; Q représente l'un des radicaux NR46R47 ou OR48, dans lesquels : R46 et R47 représentent notamment, indépendamment, un atome d'hydrogène ou un radical alkyle, ou R46 et R47 pris ensemble forment avec l'atome d'azote un hétérocycle non aromatique de 4 à 8 chaînons, les éléments de la chaîne étant choisis parmi un groupe composé de -CH(R53)-, -NR54-, -O-, -S- et -CO-, R53 et R54 représentant, indépendamment, un atome d'hydrogène ou un radical -(CH2)k-Z7R60, Z7 représentant une liaison, -O-, -NR62- ou-S-, R60 et R62 représentant notamment, indépendamment, un atome d'hydrogène ou un radical alkyle, in which A represents in particular a radical

in which Q represents in particular H or -OR22, R22 representing a hydrogen atom, an alkyl radical or an aryl radical optionally substituted by one or more substituents chosen from alkyl, OH, halogen, nitro and alkoxy radicals, and R19, R20 and R21 represent in particular, independently, a hydrogen atom, the OH group or an alkyl or alkoxy radical; X is especially S; RI represents in particular a hydrogen atom or an alkyl, aminoalkyl, cycloalkyl or cycloalkylalkyl radical, and R2 represents in particular a hydrogen atom, an alkyl, aminoalkyl, cycloalkyl or cycloalkylalkyl radical; or R1 and R2, taken together with the carbon atom which carries them, form a carbocycle of 3 to 7 members; B represents in particular a hydrogen atom or an alkyl radical; Q represents one of the radicals NR46R47 or OR48, in which: R46 and R47 represent in particular, independently, a hydrogen atom or an alkyl radical, or R46 and R47 taken together form with the nitrogen atom a non-aromatic heterocycle; from 4 to 8 members, the members of the chain being selected from a group consisting of -CH (R53) -, -NR54-, -O-, -S- and -CO-, R53 and R54 representing, independently, an atom of hydrogen or a radical - (CH2) k -Z7R60, Z7 representing a bond, -O-, -NR62- or -S-, R60 and R62 representing in particular, independently, a hydrogen atom or an alkyl radical,

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 and R48 represents in particular a hydrogen atom or an alkyl radical; k and n, whenever they occur, being independently integers from 0 to 6; or pharmaceutically acceptable salts of compounds of the general formula (P2); may be used to prepare a medicinal product intended to have at least one of the following three activities: - to inhibit monoamine oxidases, in particular monoamine oxidase B, - to inhibit lipid peroxidation, - to have a modulatory activity with respect to sodium channels.

As a result, the compounds of general formula (P2) can in particular be used in the treatment of disorders of the central or peripheral nervous system (including, in particular, diseases such as Parkinson's disease, epilepsy, Alzheimer's disease, chorea Huntington or amyotrophic lateral sclerosis).

dans laquelle RI représente notamment un atome d'hydrogène ;

représente notamment un noyau thiazole ; A représente notamment un radical -(CH2)n-Ar dans lequel n représente un entier de 0 à 4 et Ar représente notamment un radical phényle éventuellement substitué de 1 à 3 fois par des substituants choisis indépendamment parmi (notamment) un atome d'hydrogène, un radical alkyle inférieur ou alkoxy inférieur et un groupe hydroxyle ; More recently still, the compounds of general formula (P3)

in which RI represents in particular a hydrogen atom;

especially represents a thiazole ring; A in particular represents a radical - (CH2) n-Ar in which n represents an integer of 0 to 4 and Ar represents in particular a phenyl radical optionally substituted with 1 to 3 times by substituents chosen independently from (in particular) a hydrogen atom; a lower alkyl or lower alkoxy radical and a hydroxyl group;

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représente un heterocycle comptant de 4 a o chaînons dans lequel il n'y a pas plus d'un des atomes du cycle qui soit 0 ou S ; ont été décrits dans la demande de brevet PCT WO 01/04116 comme des agents prévenant et traitant les désordres caractérisés par des dommages neuronaux, et notamment la maladie de Parkinson, la maladie d'Alzheimer, la Sclérose Latérale amyotrophique (SLA) ou la maladie de Huntington.

represents a 4-membered heterocycle having no more than one of the ring atoms 0 or S; have been described in PCT patent application WO 01/04116 as agents preventing and treating disorders characterized by neuronal damage, and in particular Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) or the disease from Huntington.

The Applicant has now come to discover a new family of thiazole derivatives, namely the compounds of general formula (I) described below. The thiazole derivatives belonging to this family have very interesting pharmacological properties (in particular the inhibition of lipid peroxidation and / or the modulation of sodium channels), which make it possible to envisage their use in therapeutics, particularly in the field of neurological diseases. .

Indeed, given the potential role of ROS (reactive oxygen species or reactive oxygen species, at the origin of lipid peroxidation) and sodium channels in physiopathology, the new derivatives described correspond to the general formula (I) can produce beneficial or favorable effects in the treatment of pathologies where these radical species and / or these ion channels are involved. In particular, it is envisaged to use the compounds of general formula (I) to prepare medicaments for treating the following disorders / diseases: # central or peripheral nervous system disorders such as neurological diseases where the These include Parkinson's disease, traumatic brain or spinal cord injury, cerebral infarction, epilepsy, senile dementia, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, peripheral neuropathy. pain (particularly pain of neuropathic origin and migraine); # schizophrenia, depression and psychosis; # autoimmune diseases such as lupus and multiple sclerosis or the complications of diabetes; # gliomas and neuroblastomas; # inflammatory pathologies such as arthritis;

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 # nerve complications of viral diseases such as AIDS complications; # addiction to toxic substances; # and more generally all pathologies characterized by an excessive production of ROS and / or a dysfunction of the sodium channels.

In all these pathologies, there is experimental evidence demonstrating the involvement of ROS (Free Radie Biol Med (1996), 20, 675-705, Antioxid, Health Dis (1997), 4 (Handbook of Synthetic Antioxidants), 1-52) and the involvement of sodium channels.

sous forme racémique, d'énantiomères ou toute combinaison de ces formes, dans laquelle A représente le radical A,

dans lequel R4, R5 et R6 sont choisis indépendamment parmi le groupe composé d'un atome d'hydrogène, d'un atome halogène, d'un groupe-OH et d'un radical alkyle ou alkoxy et R7 représente un atome d'hydrogène ou un radical alkyle, According to the invention, the compounds of general formula (I), which comprises the compounds of general formula (I ')

in racemic form, enantiomers or any combination thereof, wherein A represents radical A,

wherein R4, R5 and R6 are independently selected from the group consisting of a hydrogen atom, a halogen atom, an -OH group and an alkyl or alkoxy radical and R7 represents a hydrogen atom or an alkyl radical,

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dans lequel R8 représente un atome d'hydrogène ou un radical alkyle, R9 représente un atome d'hydrogène, un atome halogène ou un radical alkyle ou alkoxy, et R10 représente un atome d'hydrogène, un atome halogène ou un radical alkyle ou alkoxy ; B représente un atome d'hydrogène ou un radical alkyle ;

représente un hétérocycle comptant de 4 à 6 chaînons et de 1 à 2 hétéroatomes choisis parmi des atomes d'azote, ledit hétérocycle pouvant comprendre une double liaison carbone-carbone lorsqu'il compte 5 ou 6 chaînons, ledit hétérocycle étant de plus lié par un atome de carbone au noyau thiazole adjacent et comprenant les chaînons -NR1- et -XR2- dans lesquels X représente CH ou N et R' et R2représentent indépendamment un atome d'hydrogène ou un radical alkyle, R3étant un substituant attaché audit hétérocycle par un de ses atomes de carbone et étant choisi parmi un atome d'hydrogène, un radical alkyle ou alkoxy et un groupe-OH, étant entendu toutefois que : i) X ne peut représenter N que lorsque ledit hétérocycle compte 6 chaînons ; ii) lorsque X représente N, R3représente un atome d'hydrogène ou un radical alkyle ; iii) lorsque A représente un radical A1, X représente CH et R2et R3 représentent tous deux des atomes d'hydrogène, alors R' ne représente pas un atome d'hydrogène ; iv) lorsqu'il y a une double liaison dans l'hétérocycle, R3 représente un atome d'hydrogène ; or else A represents the radical A2

in which R8 represents a hydrogen atom or an alkyl radical, R9 represents a hydrogen atom, a halogen atom or an alkyl or alkoxy radical, and R10 represents a hydrogen atom, a halogen atom or an alkyl or alkoxy radical; ; B represents a hydrogen atom or an alkyl radical;

represents a heterocycle having 4 to 6 members and 1 to 2 heteroatoms selected from nitrogen atoms, said heterocycle may comprise a carbon-carbon double bond when it has 5 or 6 members, said heterocycle being further bound by a a carbon atom at the adjacent thiazole ring and comprising the -NR1- and -XR2- links wherein X is CH or N and R 'and R2 are independently hydrogen or alkyl, R3 being a substituent attached to said heterocycle by one of its carbon atoms and being selected from a hydrogen atom, an alkyl or alkoxy radical and an -OH group, it being understood however that: i) X can only represent N when said heterocycle has 6 members; ii) when X represents N, R3 represents a hydrogen atom or an alkyl radical; iii) when A represents a radical A1, X represents CH and R2 and R3 both represent hydrogen atoms, then R 'does not represent a hydrogen atom; iv) when there is a double bond in the heterocycle, R3 represents a hydrogen atom;

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- 2,6-di-te7t-butyl-4-(2-pyrrolidin-2-yl- l,3-thiazol-4-yl)phénol ; ou les sels pharmaceutiquement acceptables des composés de formule générale (I) ; peuvent être utilisés pour préparer un médicament destiné à prévenir ou traiter l'une des maladies suivantes / l'un des désordres suivants : les troubles du système nerveux central ou périphérique comme par exemple les maladies neurologiques où l'on peut notamment citer la maladie de Parkinson, les traumatismes cérébraux ou de la moelle épinière, l'infarctus cérébral, l'épilepsie, les démences séniles, la maladie d'Alzheimer, la chorée de Huntington, la sclérose latérale amyotrophique, les neuropathies périphériques, la douleur (notamment les douleurs d'origine neuropathique et la migraine) ; la schizophrénie, les dépressions et les psychoses ; les maladies autoimmunes comme par exemple le lupus et la sclérose en plaques ou encore les complications du diabète ; les gliomes et les neuroblastomes ; les pathologies inflammatoires comme par exemple l'arthrite ; les complications nerveuses des maladies virales comme par exemple les complications du sida; l'addiction aux substances toxiques ; et plus généralement toutes les pathologies caractérisées par une production excessive des ROS et/ou un dysfonctionnement des canaux sodiques. as well as the following compounds: 2,6-di-tert-butyl-4- (2-piperidin-2-yl-1,3-thiazol-4-yl) phenol; 2,6-di-tert-butyl-4- (2-piperidin-4-yl-1,3-thiazol-4-yl) phenol; 2,6-di-tert-butyl-4- (2-piperidin-3-yl-1,3-thiazol-4-yl) phenol;

2,6-di-tert-butyl-4- (2-pyrrolidin-2-yl-1,3-thiazol-4-yl) phenol; or the pharmaceutically acceptable salts of the compounds of the general formula (I); may be used to prepare a medicament for preventing or treating one of the following diseases / disorders: central or peripheral nervous disorders such as neurological diseases, which may include Parkinson, traumatic brain or spinal cord, cerebral infarction, epilepsy, senile dementia, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, peripheral neuropathies, pain (including pain of neuropathic origin and migraine); schizophrenia, depression and psychosis; autoimmune diseases such as lupus and multiple sclerosis or the complications of diabetes; gliomas and neuroblastomas; inflammatory pathologies such as arthritis; nerve complications of viral diseases such as AIDS complications; addiction to toxic substances; and more generally all the pathologies characterized by an excessive production of the ROS and / or a dysfunction of the sodium channels.

By alkyl, when not more precise is meant a linear or branched alkyl radical having 1 to 12 carbon atoms, and preferably 1 to 6 carbon atoms. Alkoxy, when not more precise, is understood to mean a linear or branched alkoxy radical containing from 1 to 6 carbon atoms, and preferably from 1 to 4 carbon atoms. Finally, halogen atom means an atom chosen from fluorine, chlorine, bromine and iodine atoms.

By linear or branched alkyl having 1 to 6 carbon atoms is meant in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl. By linear or branched alkoxy containing from 1 to 6 carbon atoms is meant especially the methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy and tert-butoxy radicals, and in particular the methoxy and ethoxy radicals.

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 Preferably, the treated diseases / disorders treated with the compounds of general formula (I) according to the invention will be selected from disorders of the central or peripheral nervous system and autoimmune diseases. In particular, the treated diseases / disorders treated with the compounds of general formula (I) according to the invention will be chosen from Parkinson's disease, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, pain ( including neuropathic pain and migraine) and multiple sclerosis.

In general, when X represents N, it will be preferred that R3 is chosen from a hydrogen atom and a methyl radical, and in particular that R3 represents a hydrogen atom.

dans lequel R4, R5 et R6 sont choisis indépendamment parmi le groupe composé d'un atome d'hydrogène, d'un groupe-OH et d'un radical alkyle ou alkoxy et R7 représente un atome d'hydrogène, ou encore A représentant un radical A2

dans lequel R8 représente un atome d'hydrogène ou un radical alkyle, R9 représente un atome d'hydrogène ou un radical alkoxy, et R10 représente un atome d'hydrogène ou un radical alkoxy ; Preferably, the compounds of general formula (I ') will be such that they contain at least one of the following additional characteristics: # A representing an Al radical

wherein R4, R5 and R6 are independently selected from the group consisting of hydrogen, OH and alkyl or alkoxy and R7 is hydrogen, or A is radical A2

wherein R8 is hydrogen or alkyl, R9 is hydrogen or alkoxy, and R10 is hydrogen or alkoxy;

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représentant un hétérocycle comptant de 4 à 6 chaînons et de 1 à 2 hétéroatomes choisis parmi des atomes d'azote, ledit hétérocycle pouvant comprendre une double liaison carbone-carbone lorsqu'il compte 5 ou 6 chaînons, ledit hétérocycle étant de plus lié par un atome de carbone au noyau thiazole adjacent et comprenant les chaînons -NR1- et -XR2- dans lesquels X représente CH ou N et R1 et R2 représentent indépendamment un atome d'hydrogène ou un radical alkyle, R3 étant un substituant attaché audit hétérocycle par un de ses atomes de carbone et étant choisi parmi un atome d'hydrogène, un radical alkyle ou alkoxy et un groupe-OH, étant entendu que : i) X ne peut représenter N que lorsque ledit hétérocycle compte 6 chaînons ; ii) lorsque X représente N, R3 représente un atome d'hydrogène ou un radical alkyle ; iii) lorsque A représente un radical A, et X représente CH, l'un de R2 et R3 représente un radical alkyle ou un groupe -OH ; et iv) lorsqu'il y a une double liaison dans l'hétérocycle, R3 représente un atome d'hydrogène. # B representing a hydrogen atom or a linear or branched alkyl radical having 1 to 4 carbon atoms;

representing a heterocycle having 4 to 6 members and 1 to 2 heteroatoms selected from nitrogen atoms, said heterocycle may comprise a carbon-carbon double bond when it has 5 or 6 members, said heterocycle being further bound by a a carbon atom at the adjacent thiazole ring and comprising the -NR1- and -XR2- links in which X is CH or N and R1 and R2 independently represent a hydrogen atom or an alkyl radical, R3 being a substituent attached to said heterocycle by a of its carbon atoms and being chosen from a hydrogen atom, an alkyl or alkoxy radical and an -OH group, it being understood that: i) X can only represent N when said heterocycle has 6 members; ii) when X represents N, R3 represents a hydrogen atom or an alkyl radical; iii) when A represents a radical A, and X represents CH, one of R2 and R3 represents an alkyl radical or an -OH group; and iv) when there is a double bond in the heterocycle, R3 represents a hydrogen atom.

dans lequel deux des radicaux R4, R5 et R6 sont des radicaux alkyle, et de préférence des radicaux alkyle comptant de 3 à 6 atomes de carbone (lesdits radicaux étant en outre de préférence ramifiés) tandis que le troisième est un atome d'hydrogène More preferably, the compounds of general formula (I ') will be such that they contain at least one of the following additional characteristics: # A representing a radical A,

wherein two of the radicals R4, R5 and R6 are alkyl radicals, and preferably alkyl radicals having 3 to 6 carbon atoms (said radicals being further preferably branched) while the third is a hydrogen atom

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dans lequel R8 représente un atome d'hydrogène ou un radical méthyle et
R9 et R10 représentent des atomes d'hydrogène ; # B représentant un atome d'hydrogène ou le radical méthyle ;

représentant un hétérocycle saturé comptant de 4 à 6 chaînons et de 1 à 2 hétéroatomes choisis parmi des atomes d'azote, ledit hétérocycle étant lié par un atome de carbone au noyau thiazole adjacent et comprenant les chaînons -NR1- et XR2- dans lesquels X représente CH ou N et R1 et R2 représentent indépendamment un atome d'hydrogène ou un radical alkyle, R3 étant un substituant attaché audit hétérocycle par un de ses atomes de carbone et étant choisi parmi un atome d'hydrogène, un radical alkyle et un groupe-OH, étant entendu que : i) X ne peut représenter N que lorsque ledit hétérocycle compte 6 chaînons ; ii) lorsque X représente N, R3 représente un atome d'hydrogène ou un radical alkyle ; iii) lorsque A représente un radical A1 et X représente CH, l'un de R2 et R3 représente un radical alkyle ou un groupe-OH. and R7 represents a hydrogen atom; or else A representing a radical A2

in which R8 represents a hydrogen atom or a methyl radical and
R9 and R10 represent hydrogen atoms; # B representing a hydrogen atom or the methyl radical;

4 to 6-membered saturated heterocycle and 1 to 2 heteroatoms selected from nitrogen atoms, said heterocycle being bonded by a carbon atom to the adjacent thiazole ring and including the -NR1- and XR2- links in which X represents CH or N and R1 and R2 independently represent a hydrogen atom or an alkyl radical, R3 being a substituent attached to said heterocycle by one of its carbon atoms and being selected from a hydrogen atom, an alkyl radical and a group -OH, provided that: i) X can only represent N when said heterocycle has 6 members; ii) when X represents N, R3 represents a hydrogen atom or an alkyl radical; iii) when A represents a radical A1 and X represents CH, one of R2 and R3 represents an alkyl radical or an -OH group.

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dans lequel deux des radicaux R4, R5 et R6 sont des radicaux tert-butyle ou isopropyle tandis que le troisième est un atome d'hydrogène et R7 représente un atome d'hydrogène ; ou encore A représentant le radical suivant :

# B représentant un atome d'hydrogène ;

représentant: i) soit un radical pyrrolidinyle ou pipéridinyle dont l'un des atomes de carbone est substitué par un groupe -OH ; ii) soit un radical pipérazinyle dont l'un des atomes d'azote est éventuellement substitué par un radical alkyle (de préférence méthyle ou éthyle). Even more preferably, the compounds of general formula (I ') will be such that they contain at least one of the following additional characteristics: # A representing a radical A,

wherein two of R4, R5 and R6 are tert-butyl or isopropyl while the third is hydrogen and R7 is hydrogen; or else A representing the following radical:

# B representing a hydrogen atom;

representing: i) either a pyrrolidinyl or piperidinyl radical in which one of the carbon atoms is substituted with an -OH group; ii) a piperazinyl radical, one of the nitrogen atoms of which is optionally substituted by an alkyl radical (preferably methyl or ethyl).

A generally preferred variant of the invention will be that in which the radical A represents a radical A ,.

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dans lequel R4et R5 sont choisis indépendamment parmi des radicaux alkyle ; et, de préférence, A représente le radical

Selon une autre variante préférée, A représente un radical A2, dans lequel R8 représentera de préférence un atome d'hydrogène ou un radical alkyle (et plus préférentiellement un atome d'hydrogène), R9 représentera de préférence un atome d'hydrogène ou un radical alkoxy, et R10 représentera de préférence un atome d'hydrogène ou un radical alkoxy ; et, de préférence selon cette variante, A représente le radical :

According to a particularly preferred variant of the invention, A represents the radical A,

wherein R4 and R5 are independently selected from alkyl radicals; and, preferably, A represents the radical

According to another preferred variant, A represents a radical A2, in which R 8 will preferably represent a hydrogen atom or an alkyl radical (and more preferably a hydrogen atom), R 9 will preferably represent a hydrogen atom or a radical alkoxy, and R10 will preferably represent a hydrogen atom or an alkoxy radical; and preferably according to this variant, A represents the radical:

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sera choisi parmi le groupe composé des radicaux :

La flèche émanant d'une structure chimique indique le point d'attache de la structure au reste de la molécule. Par exemple :

indique que le radical

est attaché au reste de la molécule par l'atome de carbone en position a par rapport à l'atome d'azote (position 2 du noyau pyrrolidinyle). According to yet another preferred variant, the radical

will be chosen from the group consisting of radicals:

The arrow emanating from a chemical structure indicates the point of attachment of the structure to the rest of the molecule. For example :

indicates that the radical

is attached to the rest of the molecule by the carbon atom in position a relative to the nitrogen atom (position 2 of the pyrrolidinyl ring).

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représentera de préférence un radical pipérazinyle dont l'un des atomes d'azote est éventuellement substitué par un radical alkyle (de préférence méthyle ou éthyle). According to said preferred variant, the radical

will preferably represent a piperazinyl radical in which one of the nitrogen atoms is optionally substituted by an alkyl radical (preferably methyl or ethyl).

représentera tout préférentiellement un noyau pipérazinyle non substitué (R, R et R représentent chacun un atome d'hydrogène) ; alternativement, il représentera un noyau pipérazinyle substitué par un radical alkyle (de préférence méthyle ou éthyle et plus préférentiellement méthyle). In particular, the radical

will most preferably represent an unsubstituted piperazinyl ring (R, R and R each represent a hydrogen atom); alternatively, it will represent a piperazinyl nucleus substituted with an alkyl radical (preferably methyl or ethyl and more preferably methyl).

sera tel qu'il comprenne une double liaison carbone-carbone. Selon ladite variante, ledit radical sera de préférence choisi parmi les radicaux

According to a particular variant of the invention, the radical

will be such that it includes a carbon-carbon double bond. According to said variant, said radical will preferably be chosen from radicals

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dans lesquels R' représente un atome d'hydrogène et R2représente un atome d'hydrogène ou un radical alkyle. and especially among the radicals

in which R 'represents a hydrogen atom and R2 represents a hydrogen atom or an alkyl radical.

In addition, the compounds described in Examples 1 to 13, and more particularly the compounds of Examples 1, 2, 6, 7, 9, 11 and 13, will be particularly preferred for use according to the invention.

The invention also relates, as new products, to the compounds of general formula (I) or their salts. It also concerns, as medicaments, the compounds of general formula (1) or their pharmaceutically acceptable salts. It also relates to pharmaceutical compositions comprising, as active principle, at least one compound of general formula (I) or a pharmaceutically acceptable salt of such a compound.

At the level of the compounds of general formula (I), the same preferences as for the uses described above are applicable mutatis mutandis to the products, medicaments and compositions according to the invention.

By pharmaceutically acceptable salt is meant in particular inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, diphosphate and nitrate or organic acids such as acetate, maleate, fumarate, tartrate, succinate, citrate. , lactate, methanesulfonate, p-toluenesulfonate, pamoate and stearate. Also within the scope of the present invention, when used, are salts formed from bases such as sodium or potassium hydroxide. For other examples of pharmaceutically acceptable salts, reference may be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.

The pharmaceutical compositions containing a compound of the invention may be in the form of a solid, for example powders, granules, tablets, capsules, liposomes, suppositories or patches. Suitable solid carriers may 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 may also be in liquid form, for example, solutions, emulsions, suspensions or syrups. Suitable liquid carriers may 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 may be carried out topically, orally, parenterally, by intramuscular injection, by subcutaneous injection, intravenous injection, etc.

The dose of a product according to the present invention, to be provided for the treatment of the diseases or disorders mentioned above, varies according to the mode of administration, the age and the body weight of the subject to be treated as well as the state of the latter, and it will ultimately be decided by the attending physician or veterinarian. Such a quantity determined by the attending physician or veterinarian is referred to herein as a "therapeutically effective amount".

As an indication, the envisaged administration dose for a drug according to the invention is between 0.1 mg and 10 g depending on the type of active compound used.

The compounds of general formula (I) according to the invention may be prepared according to the procedures described in the following part.

 PREPARATION OF COMPOUNDS OF GENERAL FORMULA (I) or (I '): The compounds of general formula (I) which do not correspond to the general subformula (I') are prepared, for example, using the general methods described in US Pat. PCT Patent Application WO 01/26656. The compounds of general subformula (I ') may be prepared, for example, by methods analogous to the general methods described in PCT Patent Application WO 01/26656.

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A. Preparation of Compounds of General Formula (I '): Scheme 1 below provides a summary of a general synthetic strategy that can be employed to prepare the general subformula (I') compounds:

According to said general strategy, α-chloro- or α-bromoketone of general formula (II), in which A and B have the same meaning as in general formula (I ') and Hal represents an atom of chlorine or a bromine atom is reacted, according to an experimental protocol described in the literature (J. Org Chem (1995), 60.5638-5642), with a thioamide of general formula (III), in which the groups R 1 ', R 2' and R 3 'are either the groups R', R 2 and R 3 as defined in the general formula (I ') in the case where these groups are inert under the reaction conditions, or a protective group replacing the radicals R 'and / or R2 (when R' = H and / or XR2 = NH, R '' and R2 'may be chosen in particular from the tert-butoxycarbonyl (Boc) and benzyloxycarbonyl (Cbz) groups) or the group R3 which has been protected with a protective group insensitive to the reaction conditions (when R3 = OH, R3 'may especially represent -O-CO-CH3 or -O-CH2-Ph (i.e. OBn)). Protective groups

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 if desired are then selectively removed under conditions known to those skilled in the art to give the compound of the general formula (I ').

The preparation of the intermediates of general formula (II) or (III) noncommercial is respectively detailed in parts B and C below.

The synthetic strategy for obtaining compounds of general formula (I ') from compounds of general formula (IV) will differ slightly depending on the nature of X and the type of thiazole derivative desired, as discussed below. Two cases will mainly be distinguished: that in which X represents CH and that in which X represents N.

CAS 1: X = CH: a) When R 3 represents a hydrogen atom or an alkyl or alkoxy radical, the synthesis of the compound of general formula (I ') starting from the compound of general formula (IV) may be carried out according to method shown in Figure 2 below.

 According to this method, the amine function of the compound of general formula (IV) in which R1 'represents a Boc or Cbz group (n being an integer from 0 to 2, the double bond represented in dashed lines being optionally present when n = 1 ) is deprotected by action of an acid such as HCl (in the case where R1 'represents a Boc group) or by hydrogenation or action of a mixture of HCl / glacial acetic acid (in the case where R1' represents a Cbz group) . The compound of general formula (I ') is then optionally alkylated in the case where R' represents an alkyl radical (for example by a reductive amination reaction analogous to that presented for CAS 2, scheme 5), these reactions being carried out under conventional conditions for those skilled in the art. Other protecting groups than the Boc group can of course be used by those skilled in the art who will then refer to the methods of protection / deprotection described in Protective groups in organic synthesis, 2nd ed., (John Wiley & Sons Inc., 1991).

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b) When R3 represents an OH group, the synthesis of the compound of general formula (I ') from the compound of general formula (IV) may be carried out according to the method shown in diagram 3 below.

 Scheme 3 The synthesis method is similar to that presented in the preceding paragraph a) (n being always an integer from 0 to 2), an ultimate deprotection reaction of the alcoholic function of the intermediate of general formula (IV.1 ) or (IV.2). For example, when Gp will be benzyl, the intermediate of general formula (IV.1) or (IV.2) will be subjected to a hydrogenation reaction catalyzed by a palladium on carbon catalyst. Other Gp protecting groups can of course be used by those skilled in the art who will then refer to the methods of protection / deprotection described in Protective groups in organic synthesis, 2nd ed., (John Wiley & Sons Inc., 1991). In some cases (option not shown in diagram 3), it will be possible to dispense with the protective group Gp and work with the intermediate of general formula (IV) in which R 3 '= OH.

CAS 2: X = N: a) When X = N and the compound of general formula (I ') desired is of the piperazinylthiazole type, the synthesis of the compound of general formula (I') from the compound of general formula (IV) can be carried out as summarized in diagrams 4 to 6 below.

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When at least one of R 'and R2 represents an alkyl radical, a method for synthesizing the compounds of general formula (I') from the compound of general formula (IV) may be that represented in diagram 4 below. .

 When the compound of general formula (I ') desired is such that at least one of R' and R2 represents an alkyl radical, the compound of general formula (IV) in which R1 '= Cbz and R2' = Boc ( or vice versa, only one of the options being shown in the scheme) is first subjected to a palladium-on-charcoal catalyzed hydrogenation reaction to give the intermediate of general formula (IV.3) . Said intermediate can then be alkylated, for example by a reductive amination reaction or any other suitable alkylation reaction of an amine available to a person skilled in the art. The deletion of the Boc protecting group is then carried out in an acidic medium (for example using HCl) to give a compound of general formula (I ') in which one of R1 and R2 represents an alkyl radical and the other represents an atom. hydrogen. This hydrogen atom may then be replaced, if it is desired to have a compound of general formula (I ') in which one of R' and R2 each represent an alkyl radical, by another alkyl radical (Alk ') by means of a second alkylation reaction.

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According to a particular variant, the compound of general formula (I ') desired will be such that R' = CH3 or R2 = CH3. The preparation of the compound of general formula (I ') from the compound of general formula (IV) can then be carried out as shown in Scheme 4a.

 In this particular case, the compound of general formula (IV) in which R1 '= Cbz or R2' = Cbz and the other of R1 'and R2' represents the Boc radical may be treated with lithium hydride and aluminum (LAH) to directly give the intermediate of general formula (IV.5). This intermediate is then treated in an acid medium (for example using HCl) to give the compound of general formula (I ') before being, in the case where the other of R' and R2 represents an alkyl radical (Alk ' ), alkylated according to methods well known to those skilled in the art.

Another particular variant, represented in Scheme 5 below, relates to certain compounds of general formula (I ') in which R' and R2 represent the same alkyl radical.

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 According to said variant, the compound of general formula (I ') in which R1 and R2 represent hydrogen atoms may be subjected to a reductive amination reaction, for example by treating it, in an anhydrous solvent such as, for example methanol or acetonitrile, with an aldehyde of the general formula R-CHO in which R represents a hydrogen atom or an alkyl radical in the presence of a reducing agent such as NaBH4 or NaBH3CN, to give the compound of general formula ( I ') in which R' and R2 represent the same alkyl radical.

Alternatively, one can also use the intermediate of general formula (IV.3) and subject to a deprotection reaction by action of an acid such as HCl to obtain the compound of general formula (I ') in which R1 and R2representent hydrogen atoms.

Finally, when the compound of general formula (I ') desired is such that R' = H and R2 = H, the compound of general formula (IV) in which R1 '= Bn and R2' = Bn can be debenzylated by action of chloroethylchloroformate in a solvent such as dichloroethane (which makes it possible to obtain the mono-debenzylated intermediate of general formula (IV.6), which may be another route for obtaining monoalkylated derivatives) followed by catalyzed catalyzed hydrogenation palladium on charcoal, or, alternatively, by a hydrogenation catalyzed by a palladium-on-carbon catalyst, the latter making it possible to obtain directly the compound of general formula (I) in which R '= H and R2 = H (cf. Figure 6 below).

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 Scheme 6 b) When X = N and the compound of general formula (I ') desired is of the tetrahydropyrazinylthiazole type, the synthesis of the compound of general formula (I') from the compound of general formula (IV) can be carried out as summary in diagrams 7 and 8 below.

When at least one of R 1 and R 2 represents an alkyl radical, a method for synthesizing the compounds of general formula (I ') from the compound of general formula (IV) may be that shown in scheme 7 below.

 The intermediate of general formula (IV) of the starting tetrahydropyrazinylthiazole type, in which (for example) Z, represents CH3 and Z2 represents OtBu (or vice versa) or Z, represents OBn and Z2 represents OtBu (or vice versa). versa) or Z1 represents Boc and Z2 represents Cbz (or vice versa), is subjected to selective deprotection of one of the enamine functions to give the intermediate of general formula (IV.7) or (IV.9)

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 before being subjected to an alkylation reaction (for example a reductive amination reaction as described in CAS 2, a)) to give the intermediate of general formula (IV.8) or (IV.10). Said intermediate of general formula (IV.8) or (IV.10) is then deprotected under conditions conventional to those skilled in the art. The compound of general formula (I ') obtained in which one of R' and R2 represents an alkyl radical (Alk or Alk ') and the other represents a hydrogen atom may then be optionally alkylated a second time to give a compound of general formula (I ') in which each of R' and R2 represents an alkyl radical.

When, on the other hand, the compound of general formula (I ') desired is such that R' = H and R 2 = H, the compound of general formula (I ') may be prepared in one or two stages as shown in scheme 8 below. after.

 According to this variant, the intermediate of general formula (IV) of the tetrahydropyrazinylthiazole starting type is subjected to a double deprotection (one or two steps depending on the case) enamine functions to give the compound of general formula (I ') in which R '= H and R2 = H. Preferably, the groups Z1 and Z2 will be identical (for example Z1 = Z2 = CH3, Z1 = Z2 = OtBu or Z1 = Z2 = OBn), which will allow double deprotection in one step. In particular, these two groups may each be OtBu, which will allow deprotection in acidic medium, for example by means of HCl.

B. Preparation of Intermediates of General Formula (II): The α-chloro or α-bromo ketones of general formula (II) are prepared, scheme 9, by chlorination or bromination of the corresponding ketones of general formula (II.i) according to techniques known to those skilled in the art. In particular, in the case of bromination, the α-bromo-ketone may be obtained by reaction of the ketone with a brominating agent such as CuBr 2 (J. Org Chem (1964), 29, 3459), bromine (J. Het Chem (1988), 25,337), N-bromosuccinimide (J. Amer Chem Soc. (1980), 102, 2838) in the presence of acetic acid in a solvent such as acetate of ethyl or

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 dichloromethane, HBr or Br2 in ether, ethanol or acetic acid (Biorg.

 Med. Chem. Lett. (1996), 6 (3), J. Med. Chem. (1988), 31 (10), 1910-1918; J. Am. Chem. Soc. (1999), 121, 24) using a brominating resin (J. Macromol, Sci Chem (1977), A11, (3) 507-514) or using a selective brominating agent. such as 5,5-dibromo-2,2-dimethyl-4,6-dioxo-1,3-dioxane (cf.

Synthesis (1978), 140-142).

 In the case where the ketones of general formula (II.i) would not be commercial, the skilled person can prepare them using reactions which are known to him, for example those described in patent application PCT WO 01 / 26656 (see especially pages 87 to 99 of this document).

C. Preparation of intermediates of general formula (III) The thioamides of general formula (III) can be obtained, for example, scheme 10, by reaction of carboxamides of general formula (III.2) with Lawesson's reagent or with (P2S5) 2 , the carboxamides of general formula (III.2) being themselves obtained from the corresponding acids of general formula (III.1) according to reactions well known to those skilled in the art.

Figure 10

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, par exemple à l'aide d'un groupement Boc ou Cbz. In the case where X represents CH, it may be necessary to protect, during the synthesis of the compounds of general formula (I), the nitrogen atom of the heterocycle

for example using a group Boc or Cbz.

In the case where the compounds of general formula (I) are such that X represents a nitrogen atom, one of R1 and R2 represents a hydrogen atom and the other represents an alkyl radical or else R 'and R2 represent different alkyl radicals, it will generally be useful to synthesize intermediates of general formula (III) in which R '. and R2 'will respectively represent protecting groups Gp, and Gp2. For example, we can choose Gp1 representing the radical Boc and Gp2 representing the radical Cbz or vice versa.

In the case where the compounds of general formula (I) are such that X represents a nitrogen atom and R 'and R2 represent hydrogen atoms, the intermediates of general formula (III) may be such that R1' and R2 represent respectively protecting groups Gp1 and Gp2. In this case, the following choices may be made in particular: Gp1 representing the radical Boc and Gp2 the radical Cbz (or vice versa), or Gp, and Gp2 representing two benzyl radicals, or else Gp, and Gp2 representing two Boc radicals.

ne comporte pas de double liaison, Gp1 représente le radical Boc et Gp2 représente le radical Cbz (ou vice-versa), la conversion représentée dans le schéma 11 du dérivé de formule générale (IIL3) en le dérivé di-protégé de formule générale (111.4) peut être effectuée, par exemple, selon le protocole décrit dans le brevet US 5,455,351 et les références suivantes : J. Med. Chem. (1999), 33, 2916 ; J. When the radical

does not comprise a double bond, Gp1 represents the Boc radical and Gp2 represents the Cbz radical (or vice versa), the conversion represented in Scheme 11 of the derivative of general formula (IIL3) to the di-protected derivative of general formula ( 111.4) can be performed, for example, according to the protocol described in US Patent 5,455,351 and the following references: J. Med. Chem. (1999), 33, 2916; J.

Org. Chem. (1997), 62, 6439; and Tetrahedron Lett. (1989), 30, 5193.

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est un radical tétrahydropyrazinyle, l'acide intermédiaire de formule générale (111.8) dans laquelle Gp, représente le radical Boc et Gp2 représente le radical Cbz ou vice-versa(Gp1 et Gp2 pouvant être également les autres groupes protecteurs décrit dans Tetrahedron Lett. (1995), 36,6419-22) peut être obtenu selon la procédure résumée dans le schéma 12 (les deux premières étapes étant décrites dans Tetrahedron Lett. (1995), 36,6419-22 et les références qui y sont citées) via l'ester correspondant (R représentant un radical alkyle) qui peut ensuite être hydrolysé selon des réactions bien connues de l'homme du métier.

Figure 11 In the particular case where the radical

is a tetrahydropyrazinyl radical, the intermediate acid of general formula (III.8) in which Gp represents the radical Boc and Gp2 represents the Cbz radical or vice versa (Gp1 and Gp2 may also be the other protective groups described in Tetrahedron Lett. 1995), 36, 649-22) can be obtained according to the procedure summarized in Scheme 12 (the first two steps being described in Tetrahedron Lett (1995), 36, 649-22 and the references cited therein) via corresponding ester (R representing an alkyl radical) which can then be hydrolysed according to reactions well known to those skilled in the art.

Figure 12

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 In the case where the compounds of general formula (I) are such that R 3 represents an OH group, it may be necessary to protect this group according to methods known to those skilled in the art (see Protective groups in organic synthesis, 2nd ed. (John Wiley & Sons Inc., 1991), for example by means of a protecting group such as acetyl, tetrahydropyranyl or benzyl.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by an ordinary specialist in the field to which this invention belongs. Likewise, all publications, patent applications, patents and all other references mentioned herein are incorporated by reference.

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

1.1) Acide 1-(tert-butoxycarbonyl)pipéridine-2-carboxylique : De l'acide pipéridine-2-carboxylique (acide pipécolinique ; g ; mol) est mis en solution dans du dichlorométhane (100 ml) contenant de la diisopropyléthylamine (16,2 ml ; mol). Le mélange est refroidi à 0 C puis on ajoute par fractions Boc-O-Boc (20,3 g ; 0,0929 mol) et on laisse agiter le mélange une nuit à température ambiante. Le milieu réactionnel est alors versé sur de l'eau glacée et extrait avec de l'acétate d'éthyle. La phase organique est lavée successivement avec une solution aqueuse de bicarbonate de sodium à 10% et à l'eau, puis enfin avec une solution de chlorure de sodium saturée. La phase organique est ensuite séchée sur sulfate de magnésium, filtrée et concentrée sous vide. Le produit obtenu est utilisé tel quel dans l'étape suivante. EXAMPLES Example 1 2,6-di-tert-butyl-4- (2-piperidin-2-yl-1,3-thiazol-4-yl) phenol hydrochloride

1.1) 1- (tert-Butoxycarbonyl) piperidine-2-carboxylic acid: Piperidine-2-carboxylic acid (pipecolinic acid, g, mol) is dissolved in dichloromethane (100 ml) containing diisopropylethylamine (16 ml). , 2 ml, mol). The mixture is cooled to 0 ° C., then Boc-O-Boc (20.3 g, 0.0929 mol) is added in portions and the mixture is stirred overnight at room temperature. The reaction medium is then poured into ice water and extracted with ethyl acetate. The organic phase is washed successively with a 10% aqueous solution of sodium bicarbonate and with water, then finally with a saturated sodium chloride solution. The organic phase is then dried over magnesium sulfate, filtered and concentrated in vacuo. The product obtained is used as it is in the next step.

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1. 2) 2- (aminocarbonyl) piperidine-1-carboxylic acid tert-butyl ester: Intermediate 1.1 (17.75 g, 0.0774 mol) dissolved in dichloromethane (200 ml) is added successively hydrochloride 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (14.8 g, 0.0774 mol), and hydroxybenzotriazole (10.46 g, 0.0774 mol). Triethylamine (10.8 mL, 0.0774 mol) followed by 20% ammonium hydroxide solution (13.6 mL) was added dropwise sequentially. After stirring the reaction mixture overnight at 25 ° C., the whole is diluted with 200 ml of water. The product is extracted with dichloromethane and washed with saturated sodium chloride solution. The organic solution is dried over magnesium sulfate, filtered and concentrated in vacuo. The yellow oil obtained is purified by crystallization from ether to give a white solid with a yield of 53%. Melting point: 108-110 C.

1. 3) Tert-Butyl 2- (aminocarbonothioyl) piperidine-1-carboxylate: Intermediate 1. 2 (4.56 g, mol) is dissolved in dimethoxyethane (100 ml) and the resulting solution is cooled to 0.degree. C. Sodium bicarbonate (6.72 g, mol) followed by small portions of phosphorus pentasulfide (P2S5) 2 (17.8 g, 0.04 mol) are added. The reaction medium is allowed to return to ambient temperature while being stirred for 24 hours. After evaporation of the solvents under vacuum, the residue is added to the aqueous solution of 10% sodium bicarbonate and the solution is extracted with ethyl acetate. The organic phase is washed successively with a 10% aqueous solution of sodium bicarbonate and with water, then finally with a saturated sodium chloride solution. The organic phase is then dried over magnesium sulfate, filtered and concentrated in vacuo. The product obtained is purified by crystallization from diisopropyl ether to give a white solid with a yield of 40%. Melting point: 144 C.

1.4) 2,6-Di-tert-butyl-4- (2-piperidin-2-yl-1,3-thiazol-4-yl) phenol hydrochloride: Intermediate 1. (1.4 g; 5.73 mmol) and bromo-1- (3,5-ditert-butyl-4-hydroxyphenyl) ethanone (1.88 g, mmol) are dissolved in toluene (30 ml) under an argon atmosphere and then The mixture is stirred and heated at 85 ° C. for 18 hours.

The residue is diluted with ice water and the mixture extracted with ethyl acetate. After washing with saturated NaCl solution, the organic phase is separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The light brown paste obtained is purified by crystallization in diisopropyl ether. The white solid obtained is dissolved in anhydrous ether (20 ml). The solution is cooled to 0 C and then added

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 dropwise a solution of 1N HCl in ether (4.5 ml). The mixture is allowed to warm to room temperature while stirring. After filtration, washing with isopentane and drying under vacuum, a white-gray solid is recovered with a yield of 18%. Melting point: 252.2-253.6 ° C.

Example 2 2,6-di-tert-butyl-4- (2-piperidin-4-yl-1,3-thiazol-4-yl) phenol hydrochloride: The experimental protocol used is identical to that described for the Example 1, piperidine-4-carboxylic acid being used as a starting material in place of piperidine-2-carboxylic acid. A white solid is obtained. Melting point:> 280 C.

Example 3: 2- (2-Piperidin-4-yl-1,3-thiazol-4-yl) -1H-phenothiazine hydrochloride: The experimental protocol used is identical to that described for example 1, piperidine acid -4-carboxylic acid being used as starting material in place of piperidine-2-carboxylic acid and 2-chloro-1- (10H-phenothiazin-3-yl) ethanone replacing bromo-1- (3,5 -ditert-butyl-4-hydroxyphenyl) ethanone. A dark green solid is obtained. Melting point:> 200 C.

Example 4: 2,6-Di-tert-butyl-4- [2- (1-methylpiperidin-4-yl) -1,3-thiazol-4-yl] phenol hydrochloride: A balloon containing acetonitrile (30 ml), under an inert atmosphere, the compound of Example 2 (0.7 g, 1.57 mmol), triethylamine (0.48 ml) and formaldehyde (7 ml) were added successively. The reaction mixture is stirred vigorously for 18 hours before adding, in portions, an excess of sodium borohydride (0.2 g, 5.28 mmol). Stirring is maintained for a further 48 hours before the addition of ice water. The mixture obtained is extracted twice with 100 ml of dichloromethane. The organic phase is washed successively with 50 ml of water and then 50 ml of brine, dried over sodium sulphate, filtered and concentrated in vacuo. The residue is purified on a silica column (eluent: 5% ethanol in dichloromethane). The white solid obtained is salified in hydrochloride form in the same manner as described in the protocol of Example 1 to give a white solid with a yield of 69%. MH + = 387.2.

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Example 5 2,6-di-tert-butyl-4- [2- (1-methylpiperidin-2-yl) -1,3-thiazol-4-yl] phenol hydrochloride: The experimental protocol used is identical to that described for Example 4, the compound of Example 1 replacing the compound of Example 2. A white solid is obtained. Melting point:> 148 C (decomposition).

Example 6 2,6-di-tert-butyl-4- (2-piperazin-2-yl-1,3-thiazol-4-yl) phenol hydrochloride 6.1) 1,4-dibenzylpiperazine-2-carboxylic acid Ethyl 1,4-dibenzylpiperazine-2-carboxylate (10.0 g, 0.0295 mol) is dissolved in ethanol (44 ml). A 10% aqueous solution of potassium hydroxide (44.3 ml, 0.0443 mol) is added dropwise to this solution and the reaction medium is then refluxed for 4.5 hours. The reaction medium is then allowed to return to ambient temperature and the ethanol evaporated. The residue is poured into ice water and the aqueous phase is neutralized with 1N HCl solution before being extracted with dichloromethane, washed with brine, dried over magnesium sulphate, filtered and concentrated under vacuum. . The product is purified by crystallization from ether. After filtration, washing with isopentane and drying under vacuum, a white solid is obtained with a yield of 67%.

6. 2) 1,4-dibenzylpiperazine-2-carboxamide: Intermediate 6. 1 (3.3 g, mol) in tetrahydrofuran (50 ml) is added successively 1- (3-dimethylaminopropyl) hydrochloride. -3-ethylcarbodiimide (1.91 g, O, Olmol), and hydroxybenzotriazole (1.35 g, mol). Triethylamine (1.4 ml) is then added dropwise and the mixture is stirred for 18 hours at room temperature. Ammonia (gas) is bubbled for 20 minutes through the reaction medium which is again allowed to stir for 18 hours. The reaction medium is then poured into ice water and extracted with dichloromethane. The organic phase, washed with brine, is dried over magnesium sulfate, filtered and concentrated in vacuo. The brown paste obtained is purified by crystallization in ether to conduct, after filtration and drying, a light beige solid with a yield of 58%. Melting point: 128 C.

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6. 3) 1,4-dibenzylpiperazine-2-carbothioamide: The experimental protocol used is identical to that described for intermediate 1.3, except that the reaction mixture is heated at 70 ° C. for 3 days and that the intermediate 6. 2 replaces intermediate 1. 2. An orange oil is obtained with a yield of 14%. MH + = 326.3.

6.4) 2,6-di-tert-butyl-4- [2- (1,4-dibenzylpiperazin-2-yl) -1,3-thiazol-4-yl] phenol: The experimental protocol used is identical to that described for intermediate 1.4, intermediate 6. 3 replacing intermediate 1. 3. A white solid is obtained with a yield of 59%. Melting point: 197.0-198.1 C.

6.5) 2,6-di-tert-butyl-4- (2- (1,4-dibenzylpiperazin-2-yl) -1,3-thiazol-4-yl] phenol: Under the argon atmosphere, intermediate 6.4 ( 1.0 g, 1.81 mmol) is dissolved in 1,2-dichloroethane (70 ml) and then cooled to 0 ° C. 1-chloroethylchloroformate is added dropwise (0.2 ml, mmol). then refluxed for 1 hour.

After evaporation to dryness, the residue is taken up in methanol and the mixture is refluxed again for 2 hours before being allowed to return to ambient temperature. After further evaporation to dryness, the residue is taken up in a 10% aqueous solution of sodium bicarbonate. It is extracted with dichloromethane and the organic phase is washed with brine before being dried over magnesium sulphate, filtered and concentrated in vacuo. The residue is purified on a silica column (eluent: 3% ethanol in dichloromethane) to yield a beige foam with a yield of 68%. The product obtained is the mono-debenzylated derivative. MH + = 464.2.

The mono-debenzylated derivative (0.760 g, 1.64 mmol) is solubilized in a mixture of ethanol (30 ml) and concentrated HCl (4 ml) and a catalytic amount of 10% palladium on carbon is added to the mixture. The whole is placed under a pressure of 3 bars of hydrogen for 12 hours. The catalyst is filtered and rinsed with ethanol.

After evaporation to dryness, the residue is taken up in a 10% aqueous solution of sodium bicarbonate. Ethyl acetate (100 ml) is added, the mixture is stirred and decanted. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified on a silica column (eluent: 10% ethanol in dichloromethane). The beige foam obtained is dissolved in anhydrous ether (30 ml). The solution is cooled to 0 ° C. and then an excess of 1N solution of HCl in ether is added dropwise. The mixture is allowed to warm to room temperature while stirring. After filtration and drying under vacuum, a white solid is recovered with a yield of 23%. Melting point: 260.0-262.0 C.

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Example 7: 2,6-Di-tert-butyl-4- (2-piperidin-3-yl-1,3-thiazol-4-yl) phenol hydrochloride: 7. 1) 3- (aminocarbonyl) piperidine-1 Benzylcarboxylate: Nipecotamide (6.4 g, 0.05 mol) is dissolved in a 50/50 dioxane / water mixture (70 ml) and then the pH is adjusted to 11 with a 1N aqueous NaOH solution. A solution of N- (benzoyloxycarbonyloxy) succinimide is added dropwise (13.69 g, mol) in dioxane (30 ml) and the mixture is stirred for 18 hours before pouring onto ice water. and extract with ethyl acetate. The organic phase is washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is taken up in diisopropyl ether, filtered and then rinsed with isopentane to give, after drying, a white solid with a yield of 90%. Melting point: 127-128 C.

7. 2) 3- (aminocarbonothioyl) piperidine-1-carboxylic acid benzyl ester: The experimental protocol used is identical to that described for intermediate 1.3, intermediate 7. 1 replacing intermediate 1. 2. A solid is obtained White. Melting point: 149.9-151.6 C.

7.3) Benzyl 3- [4- (3,5-di-tert-butyl-4-hydroxyphenyl) -1,3-thiazol-2-yl] piperidine-1-carboxylate: The experimental protocol used is identical to that described for intermediate 1.4, intermediate 7. 2 replacing intermediate 1. 3. A pale yellow oil is obtained.

7. 4) 2,6-Di-tert-butyl-4- (2-piperidin-3-yl-1,3-thiazol-4-yl) phenol: Intermediate 7.3 (3.04 g; mmol) is dissolved in glacial acetic acid (130 ml). Concentrated HCl (41 ml) is added dropwise and the reaction medium is heated at 110 ° C. for 1.5 hours. The acid is evaporated and the pH adjusted to 11 with 10% aqueous NaHCO 3 solution. The mixture is extracted with dichloromethane and the organic phase washed until neutral. The product obtained is salified by dissolving it in ether (50 ml) and then adding dropwise a solution of 1N HCl in ether (10.5 ml) dropwise before stirring the mixture for 12 hours. After filtration and drying under vacuum, an off-white solid is recovered with a yield of 56%. Melting point: 208.5-210.4 C.

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Example 8 2,6-di-tert-butyl-4- [2- (1-methylpiperidin-3-yl) -1,3-thiazol-4-yl] phenol hydrochloride: The experimental protocol used is identical to that described for Example 4, the compound of Example 7 replacing the compound of Example 2 and sodium cyanoborohydride replacing sodium borohydride. A white solid is obtained. Melting point: 137.0-139.0 C.

Example 9: 2,6-Di-tert-butyl-4- (2-pyrrolidin-2-yl-1,3-thiazol-4-yl) phenol hydrochloride: 9. 1) 2- (aminocarbonyl) pyrrolidine-1 benzylcarboxylate: The experimental protocol used is identical to that described for intermediate 7. 1, HD, L-Pro-NH2.HCl (D, L-prolinamide hydrochloride) replacing nipecotamide.

A yellow oil is obtained with a yield of 46%. MH + = 249.1.

9. 2) 2- (aminocarbonothioyl) pyrrolidine-1-carboxylic acid benzyl ester: The experimental protocol used is identical to that described for intermediate 1.3, intermediate 9. 1 replacing intermediate 1. 2. A solid is obtained white with a yield of 85%. Melting point: 137.4-139.2 C.

9.3) Benzyl 2- [4- (3,5-di-tert-butyl-4-hydroxyphenyl) -1,3-thiazol-2-yl] pyrrolidine-1-carboxylate: The experimental protocol used is identical to that described for intermediate 1.4, intermediate 9. 2 replacing intermediate 1. 3. A yellow oil is obtained with a yield of 99%. MH + = 493.2.

9.4) 2,6-di-tert-butyl-4- (2-piperidin-3-yl-1,3-thia, zol-4-yl) phenol: Under argon atmosphere, mix in acetonitrile anhydrous (20 ml) trimethylsilane chloride and sodium iodide. Intermediate 9 (1.5 g, 3.04 mmol) dissolved in anhydrous acetonitrile (10 ml) is then added dropwise and the reaction mixture is stirred for 48 hours. Methanol (10 ml) is then added and the resulting mixture is allowed to stir for another hour. After evaporation to dryness, the residue is taken up in an aqueous solution of 1N HCl (30 ml) and then extracted with ether. The organic phase is washed with 10% aqueous HCl solution and the acidic aqueous phase is neutralized (pH about 7-8) with 10% aqueous ammonium hydroxide solution. The resulting aqueous phase is extracted with

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 dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified on a silica column (eluent: 3% ethanol in dichloromethane). The white solid obtained is taken up in ether, filtered and washed with isopentane. The product obtained is salified by dissolving it in ether (30 ml) before adding an excess of HCl solution in 1 N ether (5 ml) dropwise, the mixture being then left to stir for 12 hours. After filtration, washing with isopentane and drying under vacuum, a pale yellow solid is recovered with a yield of 33%. Melting point: 226.2-227.8 C.

Example 10 2,6-di-tert-butyl-4- [2- (1-methylpyrrolidin-2-yl) -1,3-thiazol-4-yl] phenol hydrochloride: The experimental protocol used is identical to that described for Example 4, the compound of Example 9 replacing the compound of Example 2 and sodium cyanoborohydride replacing sodium borohydride. An off-white solid is obtained.

Melting point: 146.9-147.6 ° C.

11.1) 2-j4-(IOH phénothiazin-2-yl)-1,3-thiazol-2-yljpyrrolidine-1-carboxylate de benzyle : L'intermédiaire 9. 2 (1,377 g ; 5 mmol) et de la 2-chloro-l-(10H-phénothiazine- 3-yl) éthanone (1,32 g ; mmol) sont dissous dans du toluène (25 ml) sous atmosphère d'argon puis le mélange est agité et chauffé à 85 C durant 14 heures. Le résidu est dilué avec de l'eau glacée. Après extraction avec de l'acétate d'éthyle, la phase organique est lavée avec une solution saturée en NaCl, séchée sur sulfate de magnésium, filtrée et concentrée sous vide pour conduire un produit huileux avec une rendement brut de 72,7%, utilisé tel quel dans l'étape suivante. MH+ = 486,1.

Example 11 2- (2-Pyrrolidin-2-yl-1,3-thiazol-4-yl) -10H-phenothiazine

11.1) Benzyl 2- [4- (1H-phenothiazin-2-yl) -1,3-thiazol-2-yl] pyrrolidine-1-carboxylate: Intermediate 9.2 (1.377 g, 5 mmol) and 2-chloro 1- (10H-Phenothiazin-3-yl) ethanone (1.32 g, mmol) are dissolved in toluene (25 ml) under an argon atmosphere and the mixture is stirred and heated at 85 ° C. for 14 hours. The residue is diluted with ice water. After extraction with ethyl acetate, the organic phase is washed with a saturated solution of NaCl, dried over magnesium sulphate, filtered and concentrated in vacuo to yield an oily product with a crude yield of 72.7%, used as is in the next step. MH + = 486.1.

11.2) 2- (2-Pyrrolidin-2-yl-1,3-thiazol-4-yl) -10H-phenothiazine: Intermediate 11.1 (4.0 g, 0.01 mol) is dissolved in dioxane (200 ml). ). After adding, dropwise, a solution of 6N HCl (50 ml), the reaction medium is refluxed for 2 hours. The acid is then evaporated and the pH adjusted to 9 with a 1N NaOH solution. The mixture is extracted with ethyl acetate and the organic phase washed to neutrality. After crystallization from ether, filtration and drying under vacuum, a white solid is obtained with a yield of 69%. Melting point: 125.0-127.0 C.

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Example 12: 2,6-di-tert-butyl-4- [2- (1,4-dimethylpiperazin-2-yl) -1,3-thiazol-4-yl] phenol hydrochloride: The experimental protocol used is identical to that described for Example 4, the compound of Example 6 replacing the compound of Example 2, sodium cyanoborohydride replacing sodium borohydride and formaldehyde being used in excess.

A white solid is obtained. Melting point:> 148 C (decomposition).

Example 13: 2,6-Di-tert-butyl-4- [2- (4-methylpiperazin-2-yl) -1,3-thiazol-4-yl] phenol hydrochloride 13.1) 4-j (benzyloxy) carbonyl] acid -1- (tert-butoxycarbohyl) piperazine-2-carboxylic acid: This product is obtained according to the procedure described in US Pat. No. 5,455,351.

13. 2) 2- (aminocarbonyl) piperazine-1,4-dicarboxylate of 1-tert-butyl and 4-benzyl: The experimental protocol used is identical to that described for intermediate 6.2, intermediate 13. 1 substitute Intermediate 6. 1. A yellow oil is obtained with a yield of 63%. MH + = 364.3.

13. 3) 2- (aminocarbonothioyl) piperazine-1,4-dicarboxylate of 1-tert-butyl and 4-benzyl: The experimental protocol used is identical to that described for intermediate 1. 3, intermediate 13. 2 replacing intermediate 1. 2. A yellow oil is obtained with a yield of 16%. MH + = 380.2.

13.4) 1- [4- (3-S-di-tert-butyl-4-hydroxyphenyl) -1,3-thiazol-2-yl] piperazine-1,4-dicarboxylate, 1-tert-butyl and 4- benzyl: The experimental protocol used is identical to that described for intermediate 1.4, intermediate 13. 3 replacing intermediate 1. 3. A yellow foam is obtained with a yield of 51%.

13.5) tert -butyl 2- (4- (3,5-di-tert-butyl-4-hydroxyphenyl) -1,3-thiazol-2-yl] -4-methylpiperazine-1-carboxylate: Intermediate 13.4 ( 0.140 g, 0.23 mmol) is dissolved in anhydrous tetrahydrofuran (10 ml) To this solution is added dropwise a 1M solution of lithium aluminum hydride in tetrahydrofuran (0.46 ml; 46mmol) then the

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The reaction medium is refluxed for 3 hours. It is then allowed to cool to room temperature before pouring the mixture into ice water and extracting with dichloromethane. After washing with salt water, the organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The product is purified on a silica column (eluent: 5% ethanol in dichloromethane) to yield a purplish-colored foam with a yield of 95%. MH + = 488.3.

13.6) 2,6-di-tert-butyl-4- [2- (4-methylpiperazin-2-yl) -1,3-thiazol-4-yl] phenol: In a solution of Intermediate 13. ( 0.110 g, mmol) in ethyl acetate (20 ml), a stream of HCl gas bubble is passed for 15 minutes and then stir at room temperature for 2 hours. A stream of argon is passed through the reaction mass before evaporating to dryness. The residue is taken up in a mixture of aqueous solution of 10% sodium bicarbonate and dichloromethane. After stirring and decantation, the organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The residue is purified on a silica column (eluent: 5% ethanol in dichloromethane). The slightly yellowish solid obtained is dissolved in anhydrous ether (10 ml) and then an excess of 1N HCl solution in ether (0.8 ml) is added dropwise. After filtration and drying under vacuum, a hygroscopic beige solid is recovered with a yield of 23%. Melting point: becomes an adhesive at 180 C. MH + = 388.3.

PHARMACOLOGICAL PROPERTIES OF THE COMPOUNDS OF THE INVENTION: Study of the effects on lipid peroxidation of the rat cerebral cortex The inhibitory activity of the products of the invention is determined by measuring their effects on the degree of lipid peroxidation, determined by the concentration in malondialdehyde (MDA). MDA produced by peroxidation of unsaturated fatty acids is a good index of lipid peroxidation (H Esterbauer and KH Cheeseman, Meth Enzymol, (1990) 186: Male Sprague Dawley rats of 200 to 250 g (Charles River) were sacrificed by decapitation The cerebral cortex is removed and then homogenized with Thomas's potter in 20 mM Tris-HCl buffer, pH 7.4 The homogenate is centrifuged twice at 50000 g for 10 minutes at 4 C. is stored at -80 C. On the day of the experiment, the pellet is resuspended

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 at a concentration of 1 g / 15 ml and centrifuged at 515 g for 10 minutes at 4 C. The supernatant is used immediately for the determination of lipid peroxidation.

The homogenate of rat cerebral cortex (500 l) is incubated at 37 ° C. for 15 minutes in the presence of the compounds to be tested or of the solvent (10 l). The lipid peroxidation reaction is initiated by the addition of 50 μl of 1 mM FeCl 2, 1 mM EDTA and 4 mM ascorbic acid. After 30 minutes of incubation at 37 ° C., the reaction is stopped by the addition of 50 μl of a solution of di tert butyl toluene hydroxylated (BHT, 0.2%). The MDA is quantified using a colorimetric test, by reacting a color-forming reagent (R) N-methyl-2-phenylindole (650 l) with 200 l of the homogenate for 1 hour at 45 C. Condensation of an MDA molecule with two reagent molecules R produces a stable chromophore whose maximum absorbance wavelength is 586 nm. (Caldwell et al., European J. Pharmacol.

(1995) 285,203-206). The compounds of Examples 1 to 12 described above all have an IC 50 less than or equal to 10 M.

Rat Cerebral Cortex Sodium Channel Binding Assay The assay consists of measuring the interaction of the compounds with respect to the binding of tritiated batrachotoxin to voltage-dependent sodium channels according to the protocol described by Brown (J. Neurosci (1986), 6, 2064-2070).

Preparation of homogenates of rat cerebral cortex Sprague-Dawley rat cerebral cortex of 230-250 g (Charles River, France) is collected, weighed and homogenized using a Potter mill equipped with a Teflon piston ( 10 rounds) in 10 volumes of isolation buffer, the composition of which is as follows (0.32 M sucrose, 5 mM K2PHO4, pH 7.4). The homogenate undergoes a first centrifugation at 1000 g for 10 minutes. The supernatant is removed and centrifuged at 20000 g for 15 minutes. The pellet is taken up in the isolation buffer and centrifuged at 20000 g for 15 minutes. The pellet obtained is resuspended in incubation buffer (50 mM HEPES, 5.4 mM KCl, 0.8 mM MgSO4, 5.5 mM glucose, 130 mM choline chloride, pH 7.4), then aliquoted and stored. at -80 C until the day of dosing. The final protein concentration is between 4 and 8 mg / ml. The protein assay is done by a kit marketed by BioRad (France).

Measurement of the binding of tritiated batrachotoxin The binding reaction is carried out by incubating for 1 h 30 to 25 C 100 μl of rat cortex homogenate containing 75 g of proteins with 100 l of [3 H] batrachotoxine A 20-alpha benzoate ( 37.5 Ci / mmol, NEN) at 5 nM (final concentration), 200 l of

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 tetrodotoxin at 1 M (final concentration) and scorpion venom at 40 g / ml (final concentration) and 100 l of incubation buffer alone or in the presence of test products at different concentrations. Nonspecific binding is determined in the presence of 300 M veratridine and the value of this nonspecific binding is subtracted from all other values. The samples are then filtered using a Brandel (Gaithersburg, Maryland, USA) using Unifilter GF / C plates preincubated with 0.1% polyethylene imine (20 μl / well) and rinsed twice with 2 ml of filtration buffer (5 mM HEPES, 1.8 mM CaCl 2, 0.8 mM MgSO 4, 130 mM choline chloride, BSA 0.01%, pH 7.4). After adding 20 Microscint 0 # wire, the radioactivity is counted using a liquid scintillation counter (Topcount, Packard). The measurement is done in duplicate. The results are expressed in% of the specific binding of the tritiated batrachotoxin relative to the control.

Results The compounds of Examples 1,2, 6 and 9 to 11 described above all have an IC 50 less than or equal to 5 M.

Claims (2)

 wherein R4, RS and R6 are independently selected from the group consisting of a hydrogen atom, a halogen atom, an -OH group and an alkyl or alkoxy radical and R7 represents a hydrogen atom or an alkyl radical, or A represents the radical A2

 in racemic form, enantiomers or any combination thereof, wherein A represents radical A,

 1. Compound of general formula (I), which comprises the compounds of general formula (I ') <Desc / Clms Page number 42>  represents a heterocycle having 4 to 6 members and 1 to 2 heteroatoms selected from nitrogen atoms, said heterocycle may comprise a carbon-carbon double bond when it has 5 or 6 members, said heterocycle being further bound by a a carbon atom at the adjacent thiazole ring and comprising the -NR'- and -XR2- links in which X is CH or N and R1 and R2 represent independently a hydrogen atom or an alkyl radical, R3 being a substituent attached to said heterocycle by a of its carbon atoms and being chosen from a hydrogen atom, an alkyl or alkoxy radical and an -OH group, it being understood however that: i) X can only represent N when said heterocycle has 6 members;

 in which R8 represents a hydrogen atom or an alkyl radical, R9 represents a hydrogen atom, a halogen atom or an alkyl or alkoxy radical, and R10 represents a hydrogen atom, a halogen atom or an alkyl or alkoxy radical; ; B represents a hydrogen atom or an alkyl radical;  2,6-di-tert-butyl-4- (2-piperidin-2-yl-1,3-thiazol-4-yl) phenol; 2,6-di-tert-butyl-4- (2-piperidin-4-yl-1,3-thiazol-4-yl) phenol; 2,6-di-tert-butyl-4- (2-piperidin-3-yl-1,3-thiazol-4-yl) phenol; 2,6-di-tert-butyl-4- (2-pyrrolidin-2-yl-1,3-thiazol-4-yl) phenol; or salt of a compound of general formula (I).

 ii) when X represents N, R3 represents a hydrogen atom or an alkyl radical; iii) when A is A, X is CH and R2 and R3 are both hydrogen, then R 'is not hydrogen; iv) when there is a double bond in the heterocycle, R3 represents a hydrogen atom; as well as the following compounds: <Desc / Clms Page number 43>  2. Compound according to claim 1, characterized in that it is a compound of general formula (I ') in which A represents a radical A ,. 3. Compound according to claim 1, characterized in that it is a compound of general formula (I ') in which A represents an A2 radical. R10 represents a hydrogen atom or an alkoxy radical; # B represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 4 carbon atoms; R9 represents a hydrogen atom or an alkoxy radical, and  in which R8 represents a hydrogen atom or an alkyl radical,

 wherein R4, R5 and R6 are independently selected from the group consisting of a hydrogen atom, an -OH group and an alkyl or alkoxy radical and R7 represents a hydrogen atom, or A represents a radical A

4. Compound according to claim 1, characterized in that it is a compound of general formula (I ') in which # A represents a radical A1 <Desc / Clms Page number 44>  representing a heterocycle having 4 to 6 members and 1 to 2 heteroatoms selected from nitrogen atoms, said heterocycle may comprise a carbon-carbon double bond when it has 5 or 6 members, said heterocycle being further bound by a a carbon atom at the adjacent thiazole ring and comprising the -NR1- and -XR2- links in which X is CH or N and R1 and R2 independently represent a hydrogen atom or an alkyl radical, R3 being a substituent attached to said heterocycle by one of its carbon atoms and being chosen from a hydrogen atom, an alkyl or alkoxy radical and an -OH group, it being understood that: i) X can only represent N when said heterocycle has 6 members;

 ii) when X represents N, R3 represents a hydrogen atom or an alkyl radical; iii) when A represents a radical A, and X represents CH, one of R2 and R3 represents an alkyl radical or an -OH group; and iv) when there is a double bond in the heterocycle, R3 represents a hydrogen atom. or salt of such a compound.  wherein two of the radicals R4, R5 and R6 are alkyl radicals, and preferably alkyl radicals having 3 to 6 carbon atoms (said radicals being further preferably branched) while the third is a hydrogen atom and R7 represents a hydrogen atom;

5. Compound according to claim 4, characterized in that it is a compound of general formula (I ') in which # A represents a radical A, <Desc / Clms Page number 45> XR2- wherein X is CH or N and R 'and R2represent independently a hydrogen atom or an alkyl radical, R3 being a substituent attached to said heterocycle by one of its carbon atoms and being selected from a hydrogen atom, a alkyl radical and an -OH group, it being understood that: i) X can only represent N when said heterocycle has 6 members; ii) when X represents N, R3 represents a hydrogen atom or an alkyl radical; 2 heteroatoms selected from nitrogen atoms, said heterocycle being linked by a carbon atom to the adjacent thiazole ring and comprising the -NR1- and -  representing a saturated heterocycle having 4 to 6 members and 1 to

R9 and R10 represent hydrogen atoms; # B represents a hydrogen atom or the methyl radical;  in which R8 represents a hydrogen atom or a methyl radical and

 or else A represents a radical A2  iii) when A represents a radical A, and X represents CH, one of R2 and R3 represents an alkyl radical or an -OH group. or salt of such a compound. <Desc / Clms Page number 46>  represents: i) either a pyrrolidinyl or piperidinyl radical in which one of the carbon atoms is substituted with an -OH group;

 # B represents a hydrogen atom;

 wherein two of R4, R5 and R6 are tert-butyl or isopropyl while the third is hydrogen and R7 is hydrogen; or A represents the following radical:

 6. Compound according to claim 5, characterized in that it is a compound of general formula (I ') in which # A represents a radical A,  ii) a piperazinyl radical, one of the nitrogen atoms of which is optionally substituted by an alkyl radical (preferably methyl or ethyl).  2- (2-piperidin-4-yl-1,3-thiazol-4-yl) -10H-phenothiazine;

7. Compound according to claim 1, characterized in that it is one of the following compounds: - 2,6-di-tert-butyl-4- (2-piperidin-2-yl-1,3) thiazol-4-yl) phenol; 2,6-di-tert-butyl-4- (2-piperidin-4-yl-1,3-thiazol-4-yl) phenol; <Desc / Clms Page number 47>  2- (2-pyrrolidin-2-yl-1,3-thiazol-4-yl) -10H-phenothiazine; 2,6-di-tert-butyl-4- [2- (1,4-dimethylpiperazin-2-yl) -1,3-thiazol-4-yl] phenol; 2,6-di-tert-butyl-4- [2- (4-methylpiperazin-2-yl) -1,3-thiazol-4-yl] phenol; or a salt of these.

 2,6-di-tert-butyl-4- [2- (1-methylpiperidin-4-yl) -1,3-thiazol-4-yl] phenol; 2,6-di-tert-butyl-4- [2- (1-methylpiperidin-2-yl) -1,3-thiazol-4-yl] phenol; 2,6-di-tert-butyl-4- (2-piperazin-2-yl-1,3-thiazol-4-yl) phenol; 2,6-di-tert-butyl-4- (2-piperidin-3-yl-1,3-thiazol-4-yl) phenol; -2,6-di-tert-butyl-4- [2- (1-methylpiperidin-3-yl) -1,3-thiazol-4-yl] phenol; 2,6-di-tert-butyl-4- (2-pyrrolidin-2-yl-1,3-thiazol-4-yl) phenol; 2,6-di-tert-butyl-4- [2- (1-methylpyrrolidin-2-yl) -1,3-thiazol-4-yl] phenol;

8. As a medicament, a compound of general formula (I) as described in claim 1 or a pharmaceutically acceptable salt of such a compound. 9. A pharmaceutical composition comprising, as active ingredient, a compound of general formula (I) as described in claim 1 or a pharmaceutically acceptable salt of such a compound. 10. Use of a compound of general formula (I) as described in claim 1 or a pharmaceutically acceptable salt thereof for preparing a medicament for treating one of the following diseases / one of the following disorders : disorders of the central or peripheral nervous system; schizophrenia, depression and psychosis; autoimmune diseases; gliomas and neuroblastomas; inflammatory pathologies; nerve complications of viral diseases; and addiction to toxic substances. 11. Use according to claim 10, characterized in that the medicament prepared is intended to treat one of the following diseases / one of the following disorders: disorders of the central or peripheral nervous system and autoimmune diseases. 12. Use according to claim 11, characterized in that the medicament prepared is intended to treat one of the following diseases / one of the following disorders: Parkinson's disease, Alzheimer's disease, Huntington's chorea, amyotrophic lateral sclerosis, pain and multiple sclerosis.