WO2007144503A2

WO2007144503A2 - Novel process for preparing nitrones and n-hydroxylamines comprising at least one hydroxyl group, and products thus obtained

Info

Publication number: WO2007144503A2
Application number: PCT/FR2007/000973
Authority: WO
Inventors: Sandrine Py; Stéphanie DEVERGNES; Yannick Vallee
Original assignee: Universite Joseph Fourier; Centre National Da La Recherche Scientifique
Priority date: 2006-06-13
Filing date: 2007-06-13
Publication date: 2007-12-21
Also published as: FR2902097A1; WO2007144503A3

Abstract

The present invention relates to the use of a Lewis acid, in particular chosen from: - boron trihalides (BI3, BBr3, BCl3, BF3), - complexes of the abovementioned boron trihalides with Lewis bases such as ethers, thioethers, phosphines or amines, or - trialkylsilane halides (TMSI, TMSBr), for converting one or more alkoxyl groups to one or more hydroxyl groups, wherein said alkoxyl groups are present on cyclic or noncyclic compounds bearing a nitrone or N-hydroxylamine nitrogenous functional group, it being possible for said nitrogenous functional group to be integrated into a ring, without affecting the nitrogenous functional group.

Description

A NOVEL PROCESS FOR THE PREPARATION OF NITRONES AND 7-HYDROXYLAMINES COMPRISING AT LEAST ONE HYDROXYL GROUP, AND PRODUCTS SUCH AS OBTAINED

The present invention relates to a new process for preparing nitrones and N-hydroxylamines containing at least one hydroxyl group from nitrones and N-hydroxylamines containing at least one alkoxyl group.

The subject of the present invention is also the nitrones and N-hydroxylamines comprising at least one hydroxyl group thus obtained, as well as their pharmaceutical, cosmetological or food additive uses, in particular as glycomimetics and as free radical scavengers.

Nitrones are precursors of nitrogen compounds particularly polyvalent in synthesis which can react with a great diversity of species (dipolarophiles, nucleophiles, but also electrophilic), and their use allows the design of synthetic routes leading to a wide variety of products.

For many years, nitrones have been recognized as good free radical scavengers, with which they react to form oxyaminyl adducts, the latter being stabilized by resonance and having a longer life than the radicals of which they are from, especially oxygenated radicals. This property of nitrones has been used in biology to detect the presence of oxygen free radicals and also to protect cells against oxidative stress.

Boron trichloride (BCl ₃ ) is a Lewis acid reagent, previously used to deprotect benzyl groups, but it has never been used to deprotect nitrones or N-hydroxylamines having at least one hydroxyl group.

To date, the most commonly used method for deprotecting benzyl groups is hydrogenolysis; however, the conditions of this hydrogenolysis reaction are not compatible with nitrone or hydroxylamine functions, since the N-O bond is itself susceptible to hydrogenolysis.

The methods currently used to obtain nitrones comprising at least one hydroxyl group are not used on nitrones comprising at least one alkoxyl group. Thus, the article by Golik et al. (Teirahedron LeIt., 1991, 32, 1851-1854) discloses the preparation of a nitrone having two hydroxyl groups from a nitrone protected by esters (benzoates), said process corresponding to an ester methanolysis in a basic medium. The article by Akai et al. (Chem., 2005, 2369-2371) discloses the preparation of a nitrone having a hydroxyl group from an acetal protected (THP) nitrone. said process corresponding to methanolysis of acetal in a protic acid medium. Thus, none of the processes of the state of the art describes a process for the preparation of nitrones and N-hydroxylamines containing at least one hydroxyl group from nitrones and N-hydroxylamines protected by protective groups of ether type.

It is therefore an object of the present invention to provide a novel process for the preparation of nitrones and N-hydroxylamines having at least one hydroxyl group from nitrones and hydroxylamines having at least one alkoxy group through deprotection of groups. alkoxylated without degradation of the nitrone function or 7V-hydroxylamine.

The present invention also aims to provide new nitrones and N-hydroxylamines having at least one hydroxyl group.

The present invention relates to the use of a Lewis acid, in particular chosen from:

boron trihalides (BI ₃ , BBr ₃ , BCl ₃ , BF ₃ ),

complexes of the above-mentioned boron trihalides with Lewis bases such as ethers, thioethers, phosphines or amines, or

trialkylsilane halides (TMSI, TMSBr), for converting one or more alkoxylated groups into one or more hydroxyl groups, said alkoxylated groups being present on cyclic or non-cyclic compounds bearing a nitrone or N-hydroxylamine nitrogen function, said function nitrogen that can be integrated into a cycle, without affecting the nitrogen function.

It has been found that the reaction of nitrones or N-hydroxylamines with Lewis acids does not lead to a degradation of the nitrogen function, that is to say that the nitrone or N-hydroxylamine function is resistant to Lewis acids. used in the present invention under conditions where groups such as benzyl or isopropylidene groups present on oxygen atoms are cut off. This is particularly original in that one skilled in the art would expect the Lewis acid to react with either the basic oxygen (CT) of the nitrone function or the OH group doublets of the N-function. hydroxylamine, which could lead to degradation of the starting molecules, either by acidolysis (case of nitrones), either by dehydration (in the case of N-hydroxylamines), these transformations competing with the deprotection of the alkoxyl groups.

The present invention can therefore be implemented for nitrones or non-cyclic N-hydroxylamines, for cyclic nitrones or TV-hydroxylamines whose nitrogen function is not integrated in a ring, or for nitrones or N-hydroxylamines. endocyclics, that is to say nitrones or ΛMi hydroxylamines whose nitrogen function is integrated in a cycle.

The present invention also relates to the use as defined above of a Lewis acid for converting one or more alkoxyl groups to one or more hydroxyl groups, said alkoxyl groups being present on compounds, cyclic or otherwise, having a function nitrone, said nitride function being integrated into a cycle.

The present invention also relates to the use as defined above of a Lewis acid for converting one or more alkoxyl groups to one or more hydroxyl groups, said alkoxyl groups being present on compounds, cyclic or otherwise, having a function TV-hydroxyl amine, said function

N-hydroxylamine that can be integrated into a cycle.

The present invention relates to a process for the preparation of a compound corresponding to the following formula (0):

in which: n is equal to 0.1 or 2:

- x is an integer ranging from 0 to n + 1, provided that two OH groups are not present on the same carbon atom;

y is an integer equal to 2n + 2-x;

- i is an integer ranging from 1 to y; a represents a single bond or a double bond;

b represents a single bond;

+

- A represents one of the following groups: ψ or ψ;

OH O ^~ . a representing a single bond when A - N - OH; . a representing a double bond when A = N -O ^" ; b representing a single bond when A = N-OH; b does not exist when A = N ⁺ -O ^" ;

RS, R- ₃ , R ₄ , R ₅ and R ₇ represent, independently of each other, one of the following groups:

* a hydrogen atom,

an alkyl group comprising from 1 to 18 carbon atoms, said alkyl group being a linear or branched group, saturated or unsaturated, or an aryl, alkaryl, aralkyl or heteroaryl group comprising from 6 to 30 carbon atoms, said alkyl groups aryl, alkaryl, aralkyl or heteroaryl being optionally substituted with:

. at least one halogen atom, especially chosen from: Br. Cl and F, at least one OR group _has ,

. at least a SR _group,. at least one NR ₃ R _{b group} . at least one COOR ₃ group,. at least one CONR _a R _b , R _a and R _b independently of one another: a hydrogen atom, an alkyl group comprising 1 to 18 carbon atoms, an alkanoyl group comprising from 1 to 18 carbon atoms, an aryl or heteroaryl group comprising from 6 to 30 carbon atoms or a silyl group, a -OR ₆ group, R ₆ being an alkyl group of 1 to 4 carbon atoms,

at least two of the substituents chosen from the groups RS, R ₃ , R ₄ , R ₅ , R ₆ and R _{7 which} may optionally form a ring with each other, at least one of the groups R ' ₂ , R 3, R ₄ or R ₅ represents an alkyl, aryl, alkaryl, aralkyl or heteroaryl group, substituted by at least one OR group _a , preferably by at least one OH group, when x = 0;

said process comprising a reaction step of a Lewis acid, in particular chosen from:

boron trihalides (BI ₃ , BBr ₃ , BCl ₃ , BF ₃ ), complexes of the above-mentioned boron trihalides with Lewis bases such as ethers, thioethers, phosphines or amines, or

halides of trialkylsilanes (TMSI, TMSBr), with a compound corresponding to the following formula (O '):

wherein: - a, b, A, n, i, x and y are as defined above for formula (0);

- j is an integer ranging from 1 to x;

- R ^J i represents one of the following groups:

an alkyl group, linear or branched, saturated or unsaturated, comprising from 1 to 18 carbon atoms, a silyl group,

an alkaryl group comprising from 6 to 30 carbon atoms, said alkyl or alkaryl groups being optionally substituted by: at least one halogen atom, especially chosen from: Br, Cl and F, at least one OR group _c . at least one SR _C group,

. at least one NR ₀ Ra group, at least one group COOR _C ,. at least one group CONR _c R _d ,

R ₀ and R 1 satisfying the same definition as that given previously for R _a and R _b ,

R ^J i preferably representing a group chosen from:

. trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl,

. benzyl, optionally substituted in particular with one or more methoxy, nitro, cyano, bromo, iodo, chloro, fluoro or methylenedioxyacetal groups,

. methyl,. trityle,. benzhydryl,. benzyloxymethyl (BOM), and . methoxymethyl (MOM), when x is greater than or equal to 2, two OR ^J i groups carried by two adjacent or 1,3-linked carbon atoms may form a cyclic ketal or acetal group, especially chosen from the following groups: isopropylidene cyclohexylidene, cyclopentylidene, benzylidene, silylene and 1,1,3,3-tetraisopropyldisiloxanylidene,

- R '' ₂ , R ' ₃ , R' ₄ , R ' ₅ and R' ₇ represent independently of each other one of the following groups:

a hydrogen atom, an alkyl group comprising 1 to 18 carbon atoms, said alkyl group being a linear or branched group, saturated or unsaturated, or

an aryl, alkaryl, aralkyl or heteroaryl group comprising from 6 to 30 carbon atoms, said alkyl, aryl, alkaryl, aralkyl or heteroaryl groups being optionally substituted with:

. at least one halogen atom, especially chosen from: Br, Cl and F, at least one group OR ' _a ,. at least one SR ',,, group. at least one group NR ' _to R ^' _b , at least one COOR group _has ,

. at least one group CONR ' _a R'b,

R ' _a and R'b corresponding to the same definition as that given above for R _a and Ri,

a group -OR ' ₆ , R' ₆ being an alkyl group of 1 to 3 carbon atoms,

* At least two substituents selected from R _"2, R _'3, R' 4, R '5, R' _e and R _'7 may optionally form a ring between them, at least one of R'S, R'3, _R'4 or R'5 is alkyl, aryl, alkaryl, aralkyl or heteroaryl, substituted with at least one group oR _'is when x is equal to 0.

The compounds of formula (0) wherein A is N-OH group are τV-hydroxylamines and compounds of formula (0) wherein A is N ⁺ -O ^"are nitrones. The term "saturated or unsaturated alkyl group" refers to an alkyl group optionally comprising one or more unsaturations. Among such groups, there may be mentioned alkenyl or alkynyl groups.

In the above-mentioned compounds of formula (O '), two groups R ^J i carried by two adjacent or 1,3-linked carbon atoms may form a cyclic ketal or acetal group, i.e. a group corresponding to the following formula: ^~ O ^~ C- O- R _a and R _b being as defined above, said R _a and R _b may

R R

^b, if appropriate, forming a ring comprising from 3 to 10 ring members The process for the preparation of the invention as described above is carried out in a chlorinated solvent chosen especially from: CH ₂ Cl ₂ , ClCH ₂ CH ₂ Cl, CHCl ₃ and CCl ₄ , at a temperature ranging from about -80 ^° C. to 25 ^° C.

The present invention is the first method for preparing nitrones having at least one hydroxyl group from benzyl or alkoxyl ethers.

The reagent employed is, for example, boron trichloride in solution (1M in hexane) and the conversion is preferably carried out, for example, in dichloromethane. In general, 3 equivalents of BCl _{3 are used} per ether function to be converted to hydroxyl, according to the following standard procedure:

To a solution of nitrone or N-hydroxylamine in CH ₂ Cl ₂ cooled to

0 ⁰ C, under argon and with magnetic stirring, was added dropwise to a drop BCl ₃ solution 0 ⁰ C. The reaction mixture is maintained at this temperature for 15 h. Methanol is then added and the mixture is concentrated in vacuo.

The residue is dissolved in a minimum of methanol or ethanol and then treated with a basic resin until the pH of the solution reaches a value of about 4 to 6.

After filtration, the filtrate is concentrated under vacuum and purified by chromatography on silica gel or washed with CH ₂ Cl ₂ to provide the nitrone or the N-hydroxyl amine containing at least one hydroxyl group.

in which :

n is 1 or 2; - x is an integer ranging from 1 to n + 1, provided that two OH groups are not present on the same carbon atom;

y is an integer equal to 2n + 2-x;

b represents a single bond;

- A represents one of the following groups: N ^OR N ^

OH 0 ^~

. a representing a single bond when A = N-OH; . a representing a double bond when A = N ⁺ -0 ^~ ;

. b represents a single bond when A = N-OH; . b does not exist when A = N ⁺ -O ^{^} ;

RS, R ₃ , R ₄ , R ₅ and R ₇ represent, independently of one another, one of the following groups:

* a hydrogen atom,

an alkyl group comprising from 1 to 18 carbon atoms, said alkyl group being a linear or branched group, saturated or unsaturated, or

. at least one halogen atom, especially chosen from: Br, Cl and F, at least one OR _group,. at least one SR group _has ,

. at least one group NR _a R _b -. at least one COOR group _has ,. at least one group CONR ₂ R _b ,

R _a and R _b represent independently of one another: a hydrogen atom, an alkyl group comprising 1 to 18 carbon atoms, an alkanoyl group comprising 1 to 18 carbon atoms, an aryl or heteroaryl group; comprising from 6 to 30 carbon atoms or a silyl group,

an -OR ₆ group, R ₆ being an alkyl group of 1 to 4 carbon atoms, at least two of the substituents chosen from R 1, R ₃ , R ₄ , R ₅ and R ₇ may optionally form a ring with one another, said process comprising a reaction step of a Lewis acid, chosen in particular from :

boron trihalides (BI ₃ , BBr ₃ , BCl ₃ , BF ₃ ),

halides of trialkylsilanes (TMSI, TMSBr), with a compound corresponding to the following formula (O ¹ ):

wherein: - a, b, A, n, i, x and y are as defined above for formula (0);

- j is an integer ranging from 1 to x;

- R ^J i represents one of the following groups:

an alkaryl group comprising from 6 to 30 carbon atoms, said alkyl or alkaryl groups being optionally substituted by: at least one halogen atom, especially chosen from: Br, Cl and F, at least one group OR ₀ , at least one SR ₀ group,

. at least one NR ₀ R ₁ group, at least one group COOR _C ,. at least one group CONR ₀ R ( _J ,

R _c and R _d meeting the same definition as that given above for R _a and R _b ,

R ^J i preferably representing a group chosen from:

. trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl, . benzyl, optionally substituted in particular with one or more methoxy, nitro, cyano, bromo, iodo, chloro, fluoro or methylenedioxyacetal groups,

. methyl,

. trityle,. benzhydryl,

. benzyloxymethyl (BOM), and

. methoxymethyl (MOM), when x is greater than or equal to 2, two OR ^J i groups carried by two adjacent or 1,3-linked carbon atoms may form a cyclic ketal or acetal group, especially chosen from the following groups: isopropylidene , cyclohexylidene, cyclopentylidene, benzylidene, silylene and 1,1,3,3-tetraisopropyldisiloxanylidene, - R ' ¹ ?, R' ₃ , R'4, R ' ₅ and R' ₇ represent independently of each other one of the following groups: * a hydrogen atom,

. at least one halogen atom, especially chosen from: Br, Cl and F, at least one group OR ' _a ,. at least one group SR ' _a ,. at least one group NR ' _to R' _b ,

. at least one group COOR ' _a ,. at least one group CONR ' _a R' _b ,

R ' _a and R'b corresponding to the same definition as that given above for R _a and R _b , * a group -OR' ₆ , R ' ₆ being an alkyl group of 1 to 3 carbon atoms,

at least two of the substituents chosen from the groups R '' ₂ , R ' ₃ , R' ₄ , R ' ₅ , R' ₆ and R ' _{7 being} able to form a ring with each other, The present invention relates to a process for the preparation of a compound corresponding to the following formula (I):

n is 0, 1 or 2;

y is an integer equal to 2n + 2-x;

- i is an integer ranging from 1 to y;

a represents a single bond or a double bond;

- A represents one of the following groups: N or N; OH O ^~

. a representing a single bond when A = N-OH;

. a representing a double bond when A = N ⁺ -O ^" ;

- R ' ₂ , R ₃ , R ₄ and R ₅ represent independently of each other one of the following groups: * a hydrogen atom,

. at least one halogen atom, especially chosen from: Br, Cl and F, at least one OR ₃ group, at least one SR ₈ group, at least one NR ₈ Rb group,

. at least one group COOR _n ,. at least one group CONR ₈ R _b ,

R ₃ and Rb represent independently of one another: a hydrogen atom, an alkyl group comprising from 1 to 18 atoms of carbon, an alkanoyl group comprising from 1 to 18 carbon atoms, an aryl or heteroaryl group comprising from 6 to 30 carbon atoms or a silyl group, R ₃ preferably representing a hydrogen atom, a group -OR ₆ , R _f1 is an alkyl group of 1 to 4 carbon atoms.

at least two of the substituents chosen from the groups RS, Ri, R ₄ , R? and R ₆ may optionally form a ring therebetween, at least one of the groups R ' ₂ , R ₃ , R ₄ or R ₅ representing an alkyl, aryl, alkaryl, aralkyl or heteroaryl group, substituted by at least one OR group _a , preferably by at least one OH group, when x = 0; said process comprising a reaction step of a Lewis acid, in particular chosen from:

boron trihalides (BI ₃ , BBr ₃ , BCl ₃ , BF ₃ ),

halides of trialkylsilanes (TMSI, TMSBr), with a compound corresponding to the following formula (II):

in which :

- a, A, n, i, x and y are as defined above for formula (I);

- j is an integer ranging from 1 to x; - R ^J i represents one of the following groups:

an alkyl group, linear or branched, saturated or unsaturated, comprising from 1 to 18 carbon atoms,

* a silyl group,

an alkaryl group comprising from 6 to 30 carbon atoms, said alkyl or alkaryl groups being optionally substituted by:

. at least one halogen atom, especially chosen from: Br, Cl and F, at least one group OR _C , at least one SR ₀ group, at least one group NR ₀ Rj, . at least one group COOR _C ,. at least one group CONR _c Rd,

R _c and R _d meeting the same definition as that given above for R ₃ and Rb, R ^J i preferably representing a group chosen from:

. trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl and t-butyl diphenylsilyl,

. benzyl, optionally substituted in particular with one or more methoxy, nitro, cyano, bromo, iodo, chloro, fluoro or metiylenedioxyacetal groups, methyl,

. trityle,. benzhydryl,

. benzyloxymethyl (BOM), and. methoxymethyl (MOM), R 1 representing for example a p-methoxybenzyl group, when x is greater than or equal to 2, two OR ^J } groups carried by two adjacent or 1,3-linked carbon atoms may form a ketal group or cyclic acetal, chosen in particular from the following groups: isopropylidene, cyclohexylidene, cyclopentylidene, benzylidene, silylene and 1,1,3,3-tetraisopropyldisiloxanylidene,

- R " ₂ , R ' ₃ , R' ₄ and R ' ₅ represent independently of each other one of the following groups:

* a hydrogen atom,

an aryl, alkaryl, aralkyl or heteroaryl group comprising from 6 to 30 carbon atoms, said alkyl, aryl, alkaryl, aralkyl or heteroaryl groups being optionally substituted with: at least one halogen atom, especially chosen from: Br, Cl and F,

. at least one group OR ' _a ,. at least one group SR ' _a ,. at least one group NR ' _to R' _b , . at least one group COOR Y,. at least one group CONR ' _a R ^" b,

R ' _a and R' _{b having} the same definition as that given above for R _a and Rh, * a group -OR ' _ό , R' ₆ being an alkyl group of 1 to 3 carbon atoms,

* At least two substituents selected from R'S, R _'3, R' _4, R 'and R' may optionally _O Fonner a ring between them. at least one of R ¹ S, R _'3, R' ₄ or R 'is alkyl, aryl, alkaryl, aralkyl or heteroaryl, substituted with at least one group OR' _a when x is O.

The present invention also relates to a process for the preparation of a compound corresponding to the following formula (I):

in which :

n is 0, 1 or 2;

- x is an integer ranging from 1 to n + 1, provided that two OH groups are not present on the same carbon atom;

y is an integer equal to 2n + 2-x;

- i is an integer ranging from 1 to y;

a represents a single bond or a double bond;

- A represents one of the following groups: N or

. a representing a single bond when A = N-OH; . a representing a double bond when A = N ⁺ -O ^" ;

an alkyl group comprising from 1 to 18 carbon atoms, said alkyl group being a linear or branched group, saturated or unsaturated, or an aryl, alkaryl, aralkyl or heteroaryl group comprising from 6 to 30 carbon atoms, said alkyl, aryl, alkaryl, aralkyl or heteroaryl groups being optionally substituted with:

5. at least one halogen atom, especially chosen from: Br. Cl and F.

. at least one OR group _n . at least one SR ₁₁ group, at least one NR ₈ Rb group, at least one group COOR _a , 10. at least one group CONR ₈ Rb,

* mi -OR ₆ group, R ₆ being an alkyl group of 1 to 4 carbon atoms,

at least two of the substituents chosen from the groups R 1, R ₃ , R ₄ , R ₅ and R ₆ possibly being able to form a ring with each other, at least one of the groups R ' ₂ , R ₃ , R ₄ or R ₅ representing an alkyl group, 20 aryl, alkaryl, aralkyl or heteroaryl, substituted with at least one oR _group, preferably by at least one OH group, when x = 1; said process comprising a reaction step of a Lewis acid, in particular chosen from:

boron trihalides (BI ₃ , BBr ₃ , BCl ₃ , BF ₃ ),

Complexes of the above boron trihalides with Lewis bases such as ethers, thioethers, phosphines or amines, or

- a, A, n, i, x and y are as defined above for the formula (i); - j is an integer ranging from 1 to x;

- R ^J i represents one of the following groups:

an alkaryl or aralkyl group comprising from 6 to 30 carbon atoms, said alkyl or alkaryl groups being optionally substituted by: at least one halogen atom, especially chosen from: Br, Cl and F, at least one group OR ₀ , at least one SR _C group,

. at least one group NR _c R ₁ ], at least one COOR ₀ group, at least one group CONR _c Rd,

R ₀ and R _d corresponding to the same definition as that previously given for R _a and R _b ,

R ^J i preferably representing a group chosen from:

. methyl,. trityle,. benzhydryl,

. benzyloxymethyl (BOM), and. methoxymethyl (MOM),

R ^J i representing for example a p-methoxybenzyl group, when x is greater than or equal to 2, two OR groups ^J i borne by two adjacent carbon atoms or located in relation 1.3 may form a cyclic acetal or ketal group, including chosen from the following groups: isopropylidene, cyclohexylidene, cyclopentylidene, benzylidene, silylene and 1,1,3,3-tetraisopropyldisiloxanylidene,

- R " ₂ , R ' ₃ , R'4 and R' ₅ represent independently of each other one of the following groups: * a hydrogen atom.

. at least one halogen atom, especially chosen from: Br, Cl and F. at least one group OR ' _a ,. at least one SR 'group _a,

. at least one group NR ' _to R' _b , at least one group COOR ' _a ,. at least one group CONR ' _a R'b,

R ' _a and R' _{b having} the same definition as that given previously for R _a and R _b ,

a group -OR ' ₆ , R' ₆ being an alkyl group of 1 to 3 carbon atoms,

at least two of the substituents chosen from R'S groups, R ' ₃ , R 1, R' ₅ and R ' ₆ possibly being able to form a ring between them. at least one of R _"2, R _'3, R' ₄ or R 'is alkyl, aryl, alkaryl, aralkyl or heteroaryl, substituted with at least one group OR' _is when x is equal to 1.

The present invention also relates to a method of preparation as defined above, of a compound corresponding to the following formula (I):

in which :

n is 1 or 2;

y is an integer equal to 2n + 2-x;

- i is an integer ranging from 1 to y;

a represents a single bond or a double bond; A represents one of the following groups: N or N ⁺ ;

. OH O ^"a represents a single bond when A = N-OH;

. a representing a double bond when A = N ⁺ -O ^" ; - R ' ₂ , R ₃ , R ₄ and R ₅ represent, independently of each other, one of the following groups:

* a hydrogen atom,

. at least one halogen atom, especially chosen from: Br, Cl and F, at least one OR group _has ,

. at least a SR _group,. at least one NR ₃ R _{b group} . at least one COOR group _has ,. at least one CONR ₃ Rb, R ₃ and R _b independently representing one of the antrum: a hydrogen atom, an alkyl group comprising 1 to 18 carbon atoms, an alkanoyl group comprising from 1 to 18 atoms of carbon, an aryl or heteroaryl group comprising from 6 to 30 carbon atoms or a silyl group, the group -OR ₆ group, R 1 being an alkyl group of 1 to 4 carbon atoms,

at least two of the substituents chosen from the groups R ' ₂ , R ₃ , R ₄ , R ₅ and R ₆ possibly being able to form a ring with each other, said process comprising a reaction step of a Lewis acid, in particular chosen from : boron trihalides (BI ₃ , BBr ₃ , BCl ₃ , BF ₃ ),

trialkylsilane halides (TMSI, TMSBr), with a compound corresponding to the following formula (II):

in which :

- a, A, n, i, x and y are as defined above for the formula (I):

- j is an integer ranging from 1 to x;

- R ^J i represents one of the following groups: alkyl, linear or branched, saturated or unsaturated, comprising from 1 to 1 8 carbon atoms,

* a silyl group,

an alkaryl group comprising from 6 to 30 carbon atoms, said alkyl or alkaryl groups being optionally substituted by: at least one halogen atom, especially chosen from: Br, Cl and F,

. at least one group OR ₀ , at least one SR _C group. at least one group NR ₀ R _1I , at least one COOR group _c . at least one group CONR ₀ Rd,

R _c and R _d corresponding to the same definition as that given above for R ₁ , and R _b , R ^J i preferably representing LUI group chosen from:

. benzyl, optionally substituted in particular with one or more methoxy, nitro, cyano, bromo, iodo, chloro, fluoro or methylenedioxyacetal groups, methyl,. trityle,. benzhydryl,

. benzyloxymethyl (BOM), and. methoxymethyl (MOM), when x is greater than or equal to 2, two OR ^J i groups carried by two adjacent carbon atoms or located in relation 1, 3 may form a ketal group or cyclic acetal, chosen in particular from the following groups: isopropylidene, cyclohexylidene, cyclopentylidene, benzylidene, silylene and 1,1,3,3-tetraisopropyldisiloxanylidene,

- R " ₂ , R'a, R ' ₄ and R' ₅ represent independently of each other one of the following groups:

* a hydrogen atom,

. at least one halogen atom, especially chosen from: Br, Cl and F, at least one group OR ' _a ,. at least one SR'a group,

. at least one NR ' _to R'b, at least one group COOR ' _a ,. at least one group CONR ' _a R'b,

a group -OR ' ₆ , R' ₆ being an alkyl group of 1 to 3 carbon atoms,

at least two of the substituents chosen from the groups R '' ₂ , R ' ₃ , R' ₄ , R ' ₅ and R' ₆ possibly being able to form a ring with each other,

The present invention also relates to a process for the preparation as defined above, of a compound corresponding to the following formula (I-1):

in which :

n, x, y, i, R ' ₂ , R ₃ , R ₄ and R ₅ are as defined above for the formula (I); at least one of the groups R ' ₂ , R ₃ , R ₄ or R ₅ representing an alkyl, aryl, alkaryl, aralkyl or heteroaryl group, substituted by at least one OR _d group, preferably substituted by at least one OH group; when x = 0; said process comprising a reaction step of a Lewis acid, in particular chosen from:

boron trihalides (BI ₃ , BBr ₃ , BCl ₃ , BF ₃ ),

trialkylsilane halides (TMSI, TMSBr), with a compound corresponding to the following formula (II-1):

in which :

n, i, x and y are as defined above for the formula (I);

R 1, R ' ¹ , R' ₃ , R ' ₄ and R' ₅ are as defined above for the formula (II); at least one of R _"2, R _'3, R' ₄ or R _'5 is alkyl, aryl, alkaryl, aralkyl or heteroaryl, substituted with at least one group OR' _is when x is equal to 0 .

The compounds of formula (I-1) are endocyclic nitrones having at least one hydroxyl group.

In the formula (I-1), when x = 0, that is to say when the compound of formula (1-1) does not comprise a hydroxyl group attached directly to the ring, at least one of the groups R ' ₂ , R ₃ , R ₄ or R ₅ represents an alkyl, aryl, alkaryl, aralkyl or heteroaryl group, substituted by at least one OR group _a , preferably substituted by at least one OH group. Thus, when the compound of formula (I-1) does not comprise a hydroxyl group attached directly to the ring, said compound comprises at least one group containing a hydroxyl group. According to a preferred embodiment, the present invention relates to a process for the preparation of a compound corresponding to the following formula (1-2):

in which :

n, x, y, i, R 1, R ₃ , R ₄ and R ₅ are as defined above for the formula (I); at least one of R ' ₂ , R ₃ , R ₄ or R ₅ representing an alkyl, aryl, alkaryl, aralkyl or heteroaryl group, substituted by at least one OR ₃ group when x = 0; said process comprising a reaction step of a Lewis acid, in particular chosen from: boron trihalides (BI ₃ , BBr ₃ , BCl ₃ , BF ₃ ),

trialkylsilane halides (TMSI, TMSBr), with a compound corresponding to the following formula (II-2):

in which :

n, i, x and y are as defined above for the formula (I);

- j, ^J R i, R _'2, R' _3, R '4 and R' ₅ are as defined above for formula (II) at least one of R'S, R _'3, R _'4 or R' ₅ is alkyl, aryl, alkaryl, aralkyl or heteroaryl, substituted with at least one group oR _'is when x is equal to 0.

The compounds of formula (1-2) are endocyclic N-hydroxylamines having at least one hydroxyl group.

According to a preferred embodiment, the present invention relates to a process as defined above for the preparation of an N-hydroxylamine comprising at least one hydroxyl group of formula (1-2) as defined above, comprising a step subsequent to the above-mentioned reaction step with the Lewis acid, said subsequent step corresponding for example:

or to a hydrogenation in the presence of a catalyst (Murahashi, S-I, Tsuji, T., Ito, S. Chem., 2000, 409-410, Tetrahedron Lett., 1994, 35, 7015-7018;

Tetrahedron 1993, 49, 4339-4354),

or to hydrosilylation (Murahashi, S.I., Watanabe, S., Shiota, T.J. Chem Soc, Chem.Commun 1994, 725-726),

or to a reduction with a hydride, in particular chosen from: NaBH ₄ (Synlett 1995, 935-937, J. Chem Res, Synop 1994, 32-33, Tetrahedron 1993, 49, 4339-4354),

NaBH ₃ CN (Tetrahedron 1999, 55, 943-954, J. Org Chem 1997, 62, 2314-2315;

Tetrahedron Lett. 1994, 35, 7015-7018), LiBH ₄ (Pennings, MLM, Reinhoudt, DN;

Harkema, S .; Van Hummel, G.TJ Org. Chem. 1982, 47, 4419-4425), LiAlH ₄ (Merino,

P .; Revuelta, J .; Tejero, T .; Cicchi, S .; Goti, A. Ew: J. Org. Chem. 2004, 4, 776-782), trialkyl or triaryltin hydrides (Ueda, Miyabe, H., Namba, M .;

Nakabayashi, T .; Naito, T. Tetrahedron Lett. 2002, 43, 4369-4371), or a trihalosilane hydride (Rivière, P. Richelme, S. Rivière-Baudet, M. Satge, J. Riley, P. L .;

Lappert, M. F .; Dunogues, J .; Calas, R. J. Chem. Res., Synapses 1981, 130-131;

Hortmann, A. G .; Koo, J-Y .; Yu, C-C J. Org. Chem. 1978, 43, 2289-2291), a compound of formula (1-1) as defined above, that is to say a nitrone having at least one hydroxyl group.

Said subsequent step can also correspond to:

a nucleophilic addition step (for a review, see: Merino, P. Science of Synthesis, 2004, 27, 511-580) or at a reducing coupling step (Masson, G., Py, S; , Y. Angew.

Chem. Int. Ed. 2002, 41, 1772-1775; Masson, G .; Cividino, P .; Py, S .; Valley, Y.

Angew. Chem. Int. Ed. 2003, 42, 2265-2268; Zhong, Y. W .; Xu, M.H .; Lin, G. Q. Org.

Lett. 2004, 6, 3953-3956), involving a compound of formula (1-1) as defined above, that is to say a nitrone having at least one hydroxyl group.

According to a preferred embodiment, the present invention relates to a process as defined above for the preparation of a N-hydroxylamine of formula (I-2) having at least one hydroxyl group, characterized in that the compound of formula

(II-2) corresponding to a N-hydroxylamine having at least one alkoxyl group is obtained by reduction with a hydride, in particular selected from NaBH _4, NaBH ₃ CN, LiAlH _4, hydrides of trialkyl- or triaryltin, or hydride trihalosilane, a compound of formula (II-1) as defined above, corresponding to a nitrone having at least one alkoxyl group. The present invention also relates to a process for the preparation of an N-hydroxylamine of formula (1-2) comprising at least one hydroxyl group starting from a nitrone of formula (II-1) comprising at least one alkoxyl group, for example intermediate of a N-hydroxy amine of formula (II-2) having at least one alkoxyl group, said process comprising: a first step of reducing, nucleophilic addition or reducing coupling of a compound of formula (II) -l) as defined above, to obtain a compound of formula (II-2) as defined above; and

A final reaction step of said compound of formula (II-2) with a Lewis acid chosen from: boron trihalides (BI ₃ , BBr _3, BCl ₃ , BF ₃ ),

halides of trialkylsilanes (TMSI, TMSBr), in order to obtain the product of formula (1-2) as defined above. The present invention also relates to a process for the preparation of an N-hydroxylamine of formula (1-2) comprising at least one hydroxyl group starting from a nitrone of formula (II-1) comprising at least one alkoxyl group, for example intermediate of a nitrone of formula (I-1) having at least one hydroxyl group, said process comprising: a first reaction step of a Lewis acid selected from:

boron trihalides (BI ₃ , BBr ₃ , BCl ₃ , BF ₃ ),

trialkylsilane halides (TMSI, TMSBr), with a compound of formula (II-1) as defined above, to obtain LUI compound of formula (I-1) as defined above; and

A final step of reducing a compound of formula (I-1) as defined above, to obtain a compound of formula (1-2) as defined above. The present invention also relates to compounds of the following formula (0)

in which :

n is 0, 1 or 2;

- x is an integer ranging from 0 to n + 1, provided that two OH groups are not present on the same carbon atom; y is an integer equal to 2n + 2-x ';

- i is an integer ranging from 1 to y;

a represents a single bond or a double bond;

b represents a single bond;

+ - A represents one of the following groups: N or N;

OH O ^~

. a representing a single bond when A = N-OH; . a representing a double bond when A = N ⁺ -O ^" ; b representing a single bond when A = N-OH; b does not exist when A = N ⁺ -O ^" ;

RS, R ₃ , R ₄ , R ₅ and R ₇ represent, independently of each other, one of the following groups:

a hydrogen atom, an alkyl group comprising from 1 to 18 carbon atoms, said alkyl group being a linear or branched group, saturated or unsaturated, or

. at least one halogen atom, especially chosen from: Br, Cl and F, at least one OR ₈ group, at least a SR _group,. at least one NR ₈ R _{b group} , . at least one COOR ₃ group,

. at least one group CONR _a R [,,

an -OR ₆ group, R ₆ being an alkyl group of 1 to 4 carbon atoms,

at least two of the substituents chosen from the groups R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ possibly being able to form a ring with each other, at least one of the groups RS, R ₃ , R ₄ or R ₅ represents an alkyl, aryl, alkaryl, aralkyl or heteroaryl group, substituted by at least one OH group when x = 0; said compounds of formula (0) may be in the form of stereoisomers, namely in the form of enantiomers and diastereoisomers or of mixtures of these different forms, including racemic mixtures, or in the form, if appropriate, of salts (hydrochloride, oxalate, tartrate ...) provided that the following compounds are excluded:

R ₀ , being chosen paπni one of the following groups: H, TyrH, TyrFmoc, TyrCbz, (CVBu) TyrCbz and TyrAc,

Wherein Rp is selected from one of the following groups: OH, O.Bu., O.Hex, OMe, OEt, NHCH ₂ CH ₂ Ph, NHCH ₂ Ph, NH / Bu and NHwBu,

R ₇ being selected from one of the following groups: H, Ac and CONHPh,

R¹ being selected from one of the following groups: 2-furyl, 2,4-dimethoxybenzyl and 2,4,6-trimethoxybenzyl, the hydrochlorides and carboxylates of these compounds also being excluded.

The present invention also relates to compounds of formula (O) below:

in which :

y is an integer equal to 2n + 2-x;

b represents a single bond;

+

- A represents one of the following groups: N or N;

OH 0 ^~ . a representing a single bond when A = N-OH;

. a representing a double bond when A = N ⁺ -O ^" ; b representing a single bond when A = N-OH; b does not exist when A = N ⁺ -O ^" ;

R'2, R ₃ , R ₄ , R ₅ and R ₇ represent, independently of each other, one of the following groups:

* a hydrogen atom,

. at least one halogen atom, especially chosen from: Br, Cl and F, at least one 0R _group,. at least one SR ₃ group,

. at least one NR ₃ R _{b group} . at least one COOR group _has ,. at least one group CONR ₈ R _b ,

R _a and Rb represent independently of one another: a hydrogen atom, an alkyl group comprising from 1 to 18 carbon atoms, an alkanoyl group comprising from 1 to 18 carbon atoms, an aryl or heteroaryl group comprising from 6 to 30 carbon atoms or a silyl group, a group -OR ₆ , R ₆ being an alkyl group of 1 to 4 carbon atoms, * At least two substituents selected from the groups R'2, R3, RA, R _5, R ₆ and R ₇ may optionally form a ring therebetween, said compounds of formula (0) can be in the form of stereoisomers namely in enantiomeric forms and diastereoisomers or mixtures of these different forms, including racemic mixtures, or in the form, if appropriate, of salts (hydrochloride, oxalate, tartrate ...) provided that the following compounds are excluded:

R _a being selected from one of the following groups: H, TyrH, TyrFmoc, TyrCbz, (O / Bu) TyrCbz and TyrAc,

R _β being selected from one of the following groups: OH, O; Bu, OtiHex, OMe, OEt, NHCH ₂ CH ₂ Ph, NHCH ₂ Ph, NH / Bu and NHHBU,

R _χ being selected from one of the following groups: H, Ac and CONHPh,

Rg being selected from one of the following groups: 2-furyl, 2,4-dimethoxybenzyl and 2,4,6-trimethoxybenzyl, the hydrochlorides and carboxylates of these compounds also being excluded.

The present invention also relates to compounds of formula (I) below:

in which :

n is 0, 1 or 2;

y is an integer equal to 2n + 2-x;

- i is an integer ranging from 1 to y;

a represents a single bond or a double bond;

- A represents one of the following groups: N or N;

OH O ^~

. at least one halogen atom, especially chosen from: Br ₅ Cl and F,

. at least one group OR ₈ ,

. at least one SR group _has ,

. at least one NR ₃ Rb group,

. at least one COOR ₈ group,

. at least one group CONR ₃ R _b ,

a group -OR 1, R ₆ being an alkyl group of 1 to 4 carbon atoms,

at least two of the substituents chosen from the groups R ' ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R _{7 which} may optionally form a ring with one another, at least one of the groups R ₂ , R ₃ and R ₄ or R ₅ is alkyl, aryl, alkaryl, aralkyl or heteroaryl, substituted by at least one OH group when x = 0; said compounds of formula (I) may be in the form of stereoisomers, namely in the form of enantiomers and diastereoisomers or mixtures of these different forms, including racemic mixtures, or in the form, if appropriate, of salts (hydrochloride , oxalate, tartrate ...), provided that the following compounds are excluded:

R _α being selected from one of the following groups: H, TyrH, TyrFmoc, TyrCbz, (OfBu) TyrCbz and TyrAc,

Wherein R _β is selected from one of the following groups: OH ₅ OnBu, O "Hex, OMe, OEt, NHCH ₂ CH ₂ Ph, NHCH ₂ Ph, NH / Bu and NHwBu, R _χ being selected from one of the following groups: H, Ac and CONHPh, wherein Rs is selected from one of the following groups: 2-furyl, 2,4-dimethoxybenzyl and 2,4,6-trimethoxybenzyl, hydrochlorides and the carboxylates of these compounds are also excluded. The present invention also relates to compounds of formula (I) below:

in which :

n is 0, 1 or 2;

y is an integer equal to 2n + 2-x; - i is an integer ranging from 1 to y;

a represents a single bond or a double bond;

- A represents one of the following groups: N or N ⁺ ;

OH Cf

- R 1, R ₃ , R ₄ and R ₅ independently of one another represent one of the following groups:

* a hydrogen atom,

. at least one OR group ₃ ,

. at least one SR ₃ group,

. at least one group NR _a R _b , . at least one COOR group _has ,

. at least one group CONR _n R _b ,

a group -ORe, R ₆ being an alkyl group of 1 to 4 carbon atoms,

at least two of the substituents chosen from the groups RS, R ₃ , R 4, R 5, R ₆ and R _{7 which} may optionally form a ring with each other, at least one of the groups R ' ₂ , R ₃ , R ₄ or R ₅ representing an alkyl, aryl, alkaryl, aralkyl or heteroaryl, substituted with at least one OH group when x = 1; said compounds of formula (I) may be in the form of stereoisomers, namely in the form of enantiomers and diastereoisomers or mixtures of these different forms, including racemic mixtures, or in the form, if appropriate, of salts (hydrochloride , oxalate, tartrate ...), provided that the following compounds are excluded:

R _a being selected from one of the following groups: H, TyrH, TyrFmoc, TyrCbz, (OriBu) TyrCbz and TyrAc,

Rp being selected from one of the following groups: OH, O / 7Bu, OwHex, OMe, OEt, NHCH ₂ CH ₂ Ph, NHCH ₂ Ph, NH / Bu and NHnBu,

R _x being selected from one of the following groups: H, Ac and CONHPh,

Rs being selected from one of the following groups: 2-furyl, 2,4-dimethoxybenzyl and 2,4,6-trimethoxybenzyl, the hydrochlorides and carboxylates of these compounds being also excluded.

The present invention also relates to the compounds as defined above, of formula (I) below:

in which :

y is an integer equal to 2n + 2-x;

- A represents one of the following groups: N or N;

OH 0 ^~

. a representing a single bond when A = N-OH; . a representative double bond when A = N ⁺ -O ^" ;

- R ' ₂ , R ₃ , R ₄ and R ₅ represent independently of each other one of the following groups:

* a hydrogen atom,

an aryl, alkaryl, aralkyl or heteroaryl group comprising from 6 to 30 carbon atoms, said alkyl, aryl, alkaryl, aralkyl or heteroaryl groups being optionally substituted with: at least one halogen atom, especially chosen from: Br. Cl and F,

. at least one OR group _d . at least a SR _group,. at least one NR ₃ R _{b group} . at least one COOR group _has ,. at least one group CONR ₈ Rb,

an -OR ₆ group, R ₆ being an alkyl group of 1 to 4 carbon atoms,

at least two of the substituents chosen from the groups R ' ₂ , R ₃ , R ₄ , R ₅ and R ₆ possibly being able to form a ring with each other, said compounds of formula (I) may be in the form of stereoisomers namely in the form of enantiomers and diastereoisomers or mixtures of these different forms, including racemic mixtures, or in the form, if appropriate, of salts (hydrochloride, oxalate, tartrate ...) provided that the following compounds are excluded:

R _a being selected from one of the following groups: H, TyrH, TyrFmoc, TyrCbz, (Offiu) TyrCbz and TyrAc,

Rp being selected from one of the following groups: OH, OnBu, O / Hex, OMe, OEt, NHCH ₂ CH ₂ Ph, NHCH ₂ Ph, NHzBu and NHwBu,

R _χ being chosen from one of the following groups: H, Ac and CONHPh, R _δ being chosen from one of the following groups: 2-furyl, 2,4-dimethoxybenzyl and 2,4,6-trimethoxybenzyl, the hydrochlorides and the carboxylates of these being also excluded.

The present invention also relates to the compounds as defined above, of formula (VII) below:

in which :

- A, a, n, i, R ' ₂ , R ₃ , R ₄ and Rs are as defined above for the formula (I);

y is an integer equal to 2n; provided that the following compounds are excluded:

The present invention also relates to the compounds as defined above, of formula (1-1) below:

in which :

n, x, y, i, R 1, R ₃ , R ₄ and R ₅ are as defined above for the formula (I); at least one of the groups R ¹ , R ₃ , R ₄ or R ₅ representing an alkyl, aryl or alkaryl group. aralkyl or heteroaryl, substituted by at least one OH group when x = 0; provided that the following compounds are excluded:

Formula (I-1) corresponds to the formula (I) wherein A is N ⁺ -O ^"and represents a double bond.

Some preferred compounds of the invention have the following formula (1-1):

(M)

in which :

n, x, y, i, R ' ₂ , R ₃ , R ₄ and R ₅ are as defined above for the formula (I); at least one of RS, R ₃ , R ₄ or R ₅ representing an alkyl group. aryl, alkaryl, aralkyl or heteroaryl, substituted by at least one OH group when x = 1; provided that the following compounds are excluded:

According to a preferred embodiment, the present invention relates to compounds as defined above, corresponding to the following formula (IV):

in which :

R ₃ , R ₄ and R ₅ are as defined above for formula (I),

- R ₆ and R ₇ represent independently of each other one of the following groups:

* a hydrogen atom,

a hydroxyl group,

. at least one halogen atom, especially chosen from: Br, Cl and F. at least one group OR ,,,. at least one SR ₃ group, at least one NR group _has Rt _> ,. at least one COOR ₃ group,. at least one group CONR ₈ Rb,

R _a and R _b being as defined above for the formula (I-1), with the proviso that only one of the groups R ₆ or R ₇ represents a hydroxyl group, and provided that if none of the groups R ₆ or R ₇ represents a hydroxyl group, at least one of R ₃ , R ₄ , R 1, R ₆ or R ₇ represents an alkyl, aryl or heteroaryl group substituted with at least one OH group. The formula (IV) corresponds to the formula (I-1), in which n is equal to 0. Some preferred compounds according to the invention are compounds as defined above, corresponding to the formula (V)

in which :

x is an integer ranging from 0 to 2;

y is an integer equal to 4-x;

- i, R ₂ , R ₃ , R ₄ and R ₅ are as defined above for the formula (I), at least one of the groups R ' ₂ , R ₃ , R ₄ or R ₅ representing a group alkyl, aryl, alkaryl, aralkyl or heteroaryl, substituted by at least one OH group when x = 0;

The formula (V) corresponds to the formula (I-1), in which n is equal to 1. Preferred compounds according to the present invention are compounds corresponding to the following formula (V-I):

in which R ₃ , R ₄ and R ₅ are as defined above for the formula (I), provided that the following compounds are excluded:

The formula (V-I) corresponds to the formula (V), in which x is equal to 2.

Thus, the compounds of formula (V-I) correspond to nitrones comprising at least two hydroxyl groups on the ring.

The present invention also relates to compounds of formula (VI) as defined above, characterized in that R ₃ represents a hydrogen atom.

Thus, such a compound has the following formula (V-I-bis):

provided that the following compounds are excluded:

According to a preferred embodiment, the compounds of formula (VI) or (VI-bis) are characterized in that at least one of the groups R ₃ , R ₄ and R ₅ represents an alkyl group substituted by at least one group OH, especially a methyl group substituted by an OH group (-CH ₂ -OH) or an ethyl group substituted by two OH groups (-CHOH-CH ₂ OH).

The present invention also provides compounds of the following formula (V-2):

in which :

x and y are as defined above for formula (V);

- i, R ' ₂ , R ₄ and R ₅ are as defined above for the formula (1), at least one of the groups R 1, R ₄ or R ₅ representing an alkyl, aryl or alkaryl group, aralkyl or heteroaryl, substituted by at least one OH group when x = 0; provided that the following compounds are excluded:

The formula (V-2) corresponds to the formula (V), in which R ₃ represents a hydrogen atom.

The present invention also provides compounds of the following formula (V-bis):

in which :

x is an integer equal to 1 or 2;

y is an integer equal to 4-x; - i, R ₂ , R ₃ , R ₄ and R ₅ are as defined above for the formula (I), at least one of the groups R ' ₂ , R ₃ , R 1 or R ₅ representing an alkyl group aryl, alkaryl, aralkyl or heteroaryl substituted by at least one OH group when x = 1; provided that the following compounds are excluded:

The compounds of formula (V-bis) correspond to compounds of formula (V) in which x is greater than or equal to 1: they are therefore nitrones comprising at least one OH group directly attached to the ring.

The present invention also provides compounds of the following formula (V-3):

in which :

R ₃ , R ₄ and R ₅ are as defined above for formula (I),

- R ₈ , R ₉ , Rio and Ri _{1 having} the same definition as that given above for R ₆ and R ₇ in the formula (IV), it being understood that only one of the groups R ₈ and R ₉ may represent a hydroxyl group and that only one of the groups Rio and Rn can represent a hydroxyl group, at least one of the groups R ₈ , R ₉ , Rio or Ru representing a hydroxyl group, and at least one of the groups Rs, Rg, Rio, Rn, R ₃ , R ₄ or R ₅ representing an alkyl, aryl, alkaryl, aralkyl or heteroaryl group, substituted by at least one group hydroxyl when only one of R ₈ , R ₁₀ , R _{10 and} R _{11 is} hydroxyl, with the proviso that the following compounds are excluded:

The compounds of formula (V-3) correspond to compounds of formula (V). More particularly, they are therefore nitrones comprising at least one hydroxyl group attached directly to the ring and at least one hydroxyl group attached to an alkyl, aryl, alkaryl, aralkyl or heteroaryl group.

According to an advantageous embodiment, the compounds of formula (V-3) are characterized in that R ₃ represents a hydrogen atom, and therefore correspond to the following formula (V-3-bis):

the following compounds being excluded:

00973

According to an advantageous embodiment, the compounds of formula (V-3) are characterized in that R ₈ and Rn represent an OH group, and therefore correspond to the following formula (V-3 -ter):

it being understood that Rq and Rio do not represent a hydroxyl group, and it being understood that the following compounds are excluded:

According to a preferred embodiment, the compounds of formula (V-3-ter) are characterized in that the groups Rg and Rio represent a hydrogen atom, and correspond to the following formula:

it being understood that the following compounds are excluded:

The present invention also relates to a compound of the formula

(V-3-1) following:

in which :

R ₃ , R ₄ and R ₅ are as defined above for formula (I),

- R'g, R ' ₉ , R' ₁₀ and R ' _H represent independently of one another: * a hydrogen atom,

. at least one halogen atom, especially chosen from: Br, Cl and F, at least one OR _group,. at least a SR _group,. at least one NR ₃ Rb group,

. at least one COOR ₈ group,. at least im group CONR ₈ Rb,

R _a and R _b being as defined above for the formula (I-1), at least one of the groups R ₃ , R 4, R ₅ , R ', R' ₉ , R '10 and R' represent an alkyl, aryl, alkaryl, aralkyl or heteroaryl group substituted by at least one OH group, and preferably an alkyl group substituted by an OH group. The compounds of formula (V-3-1) correspond to compounds of formula (V) in which x is equal to 0, that is to say compounds not comprising a hydroxyl group attached directly to the ring but comprising at least one hydroxyl attached to an alkyl, aryl, alkaryl, aralkyl or heteroaryl group. The present invention also relates to a compound of the following formula (V-3-3):

wherein R ₃ , R ₄ and R ₅ are as defined above for formula (1), and

R ', R' ₉ , R 'io and R' _H are as defined for R ₂ ¹ for formula (I), at least one of R'g, R ' ₉ , R' ₁₀ or R'π representing a hydroxyl group, at least one of the groups R ₃ , R 4, R ₅ , R '8, R' 9, R '10 and R' 1 representing a linear or branched alkyl chain substituted by at least one OH group. provided that the following compounds are excluded:

The compounds of formula (V-3-3) correspond to compounds of formula (V), comprising at least one hydroxyl group attached directly to the ring and comprising at least one hydroxyl attached to a linear or branched alkyl chain.

Preferred compounds of formula (V-3-3) correspond to compounds of formula (V), comprising at least one hydroxyl group attached directly to the ring and comprising at least one hydroxyl attached to a linear or branched alkyl chain, said group hydroxyl not being attached to the α position of the nitrone or α-hydroxyl amine ring.

According to an advantageous embodiment, the compounds of formula (V-3-3) as defined above are characterized in that at least one of the groups R ₄ , R ₅ , R'g, R ' ₉ , R _'10 and R'π represents an alkyl, aryl, alkaryl, aralkyl or heteroaryl group, substituted by at least 2 OH groups. The present invention also relates to compounds of the formula

(VI) next

in which :

x is an integer ranging from 0 to 3;

y is an integer equal to 6-x;

- i, R'i, R ₃ , R ₄ and R ₅ are as defined above for the formula (I), at least one of the groups RS, R ₃ , R ₄ or R ₅ representing an alkyl group , aryl, alkaryl, aralkyl or heteroaryl, substituted by at least one OH group when x is 0.

The formula (VI) corresponds to the formula (1-1), in which n is equal to 2.

The present invention also relates to compounds of the formula

(VI) next

in which :

x is an integer ranging from 1 to 3;

y is an integer equal to 6-x;

- i, R ' ₂ , R ₃ , R ₄ and R ₅ are as defined above for the formula (I), at least one of the groups R' ₂ , R ₃ , R ₄ or R ₅ representing preferably an alkyl, aryl, alkaryl, aralkyl or heteroaryl group, substituted by at least one OH group when x is equal to 1. The present invention also relates to compounds corresponding to the following formula (VIII)

in which :

- i, R ' ₂ , R ₃ , R ₄ and R ₅ are as defined above for the formula (I); - is equal to 4.

The present invention also provides compounds of the following formula (IX):

in which :

- i, R ' ₂ , R ₃ , R ₄ and R ₅ are as defined above in formula (I);

- is equal to 3.

The preferred compounds according to the invention correspond to one of the following formulas:

The present invention also relates to compounds of formula (1-2) below:

in which :

n, x, y, i, RS, R ₃ , R ₄ and R ₅ are as defined above for the formula (I). provided that two OH groups are not present on the same carbon atom; at least one of R ' ₂ , R ₃ , R ₄ or R ₅ representing an alkyl, aryl, alkaryl, aralkyl or heteroaryl group, substituted by at least one OH group when x is 0; provided that the following compounds are excluded:

R ₀ , Rp, R _x and Rs being as defined above for the formula (I). The formula (1-2) corresponds to the formula (I), in which A represents an N-OH group and a represents a single bond. The present invention also relates to compounds of the formula

(1-2) next

in which :

n, x, y, R ₁ , R ₃ , R ₄ and R ₅ are as defined above for formula (I), provided that two OH groups are not present on the same atom of carbon; at least one of RS, R ₃ , R ₄ or R ₅ representing an alkyl group. aryl, alkaryl, aralkyl or heteroaryl substituted by at least one OH group when x is 1; provided that the following compounds are excluded:

R ₀ ,, R _β , R _x and Rg being as defined above for the formula (I). The present invention also relates to compounds of formula (1-2-2) below:

in which :

R ₃ , R ₄ and R 1 are as defined above for formula (I),

* a hydrogen atom,

a hydroxyl group,

. at least a SR _group,. at least one group NR _a R _b , at least one COOR group _has ,. at least one CONR ₈ R _b , R _a and R 1 group being as defined above for the formula (I-1), provided that only one of the R ₆ or R _{7 groups} represents a hydroxyl group, and provided that if none of the groups R ₆ or R ₇ represents a hydroxyl group, at least one of the groups R ₃ , R ₄ , R ₅ , R ₆ or R ₇ represents an alkyl, aryl or heteroaryl group substituted with at least one an OH group. The present invention also relates to a compound of formula (1-2-1) below:

in which :

x is an integer ranging from 0 to 2;

y is an integer equal to 4-x;

- i, R ' ₂ , R ₃ , R ₄ and R ₅ are as defined above for the formula (I), provided that two OH groups are not present on the same carbon atom; at least one of R 1, R ₃ , R ₄ or R ₅ represents an alkyl, aryl, alkaryl, aralkyl or heteroaryl group, substituted by at least one OH group when x is 0; provided that the following compounds are excluded:

The present invention also relates to a compound of formula (I-2bis) below:

in which :

i varies from 1 to 2,

RS, R ₃ , R ₄ and R ₅ are as defined above for the formula (I), at least one of RS, R ₃ , R ₄ or R ₅ is preferably an alkyl, aryl, alkaryl, aralkyl or heteroaryl group, substituted by at least one OH group;

provided that the following compound is excluded:

The present invention also relates to compounds of the following formula (VI-bis):

in which :

x is an integer ranging from 0 to 3;

y is an integer equal to 6-x;

- i, R ^! ₂ , R ₃ , R ₄ and R ₅ are as defined above for the formula (I), at least one of the groups R 1, R ₃ , R ₄ or R ₅ representing an alkyl, aryl or alkaryl group , aralkyl or heteroaryl, substituted by at least one OH group when x is 0, provided that the following compounds are excluded:

R _(t , R _β , _Rχ and Rs being as defined above for formula (I) The preferred compounds according to the invention correspond to one of the following formulas:

The present invention also relates to the use of compounds of formula

(I) as defined above as glycomimetics or as water-soluble scavengers of free radicals.

The present invention also relates to the use of compounds of formula

(I) as defined above in the context of the preparation of food supplements or additives for the cosmetic industry.

The compounds of the invention, in particular the nitrones of the invention containing at least one hydroxyl group, exhibit interesting properties such as: free radical traps and water-soluble antioxidants,

- Glycomimetics recognized by sugar carriers,

- Glycomimetic enzyme inhibitors involved in the synthesis and in the metabolism of oligosaccharides, and - glycomimetics involved in cell recognition and adhesion phenomena.

The nitrones of the invention constitute a new family of water soluble radical scavengers as well as stable glycomimetics capable of interacting with biological targets involved in the recognition, transport and transformation of sugars and oligosaccharides.

In addition to behaving as free radical scavengers, the nitrones and the N-hydroxylamines of the invention have glycomimetic properties (mimics of sugars) and can thus be recognized by specific carriers of sugars, such as for example GLUT -I or GLUT-5. Such recognition by carriers allows selective routing and vectorization of these nitrones and N-hydroxylamines to certain cell organelles. For example, GLUT-I transporters are known to be involved in the transport of glucose to mitochondria, where it is used as a source of energy, as a substrate of the respiratory chain. Thus, such nitrones and N-hydroxylamines, recognized by sugar transporters, can be selectively transported by these transporters to the production sites of the species responsible for the oxidative stress.

The nitrones and N-hydroxylamines of the invention comprising at least one hydroxyl group are similar to iminosugars, cyclic compounds comprising at least one hydroxyl substituent and having an endocyclic nitrogen atom, replacing the oxygen atom of the sugars. Iminosugar, natural or synthetic glycomimetics, arouse great interest in the search for treatments against diabetes, but also against diseases such as cancer, autoimmune diseases or AIDS (Wong, CH., Carbohydrate-based Dnig Discovery, Wiley-VCH, Weinheim, 2003, Martin, OR and Compain, P., Iminosiigars: Recent Impacts on their Bioactivity and Potential Therapeutic Agents in Curr Top Med Med, Chem., 5, issue 5, Martin, OR and Compain, P. Eds., Bentham, Neth, 2003. Alper, J. Science 2001, 291, 2338-2343). In most therapeutic approaches, iminosugars are considered mimes of the transitional state of R2007 / 000973 biotransformations of oligosaccharides. They have mainly been studied as glycosidase inhibitors (Stϋtz, AE Iminosugars as glycosidase inhibitors: nojirimycin and beyond, Wiley-VCH, Weinheim, 1999, Heightman, TD, Vasella, AT Angew Chem Int.Ed. 1999, 38, 750 Asano, N .: Nash, RJ, Molyneux, RJ, Fleet, GWJ Tetrahedron: Asymmetry 2000, 11, 1645-1680) and, more recently, glycosyltransferases (Compain, P. Martin, OR Cwr Top. Med Chem 2003, 3, 541-560, Compain, P. Martin, OR BioGem Med Chem 2001, 9, 3077-3092).

The nitrates and β-hydroxylamines of the invention represent stable glycomimetics of well-defined configuration and conformations and, as such, they represent a new class of molecules interacting with the enzymes involved in the biosynthesis and transformation of oligosaccharides, glycolipids and glycoproteins.

Moreover, the nitrones and N-hydroxylamines of the invention can behave like mimes of sugars and thus be recognized by lectins. Lectins are proteins on the surface of cells that can specifically recognize oligosaccharides on the surface of other cells. This recognition precedes any phenomenon of cell adhesion and is therefore essential in infectious and invasive processes. Bacteria, viruses and even cancer cells bind to host cells after their lectins interact with oligosaccharides on the surface of host cells. Thus, if the nitrones and N-hydroxylamines of the invention interact with lectins, they can be useful as "anti-adhesion" agents and thus be used as anti-infectives, antivirals or anti-metastases.

EXAMPLES

A. DESCRIPTION OF PROCESSES AND PRODUCTS

Process for the preparation of polyhydroxylated endocyclic nitrones from polyalkoxylated nitrones

Typical procedure:

To a solution of nitrone (1 mmol) in CH ₂ Cl ₂ (30 mL) cooled to 0 ^° C., placed under argon and with magnetic stirring, a solution of BCl ₃ (1M solution in hexane, 3 equivalents per function ether or oxygen to be deprotected) is added at 0 ^° C. The reaction mixture is maintained at this temperature for 15 hours. Methanol (30 mL) is then added thereto and the mixture is concentrated in vacuo. The residue is dissolved in a minimum of water, then treated with DOWEX 1X8 or IRA 1X4-50 resin (OH ^" form) until the pH of the solution reaches a value between 4 and 6. After filtration, the filtrate is concentrated under vacuum and purified by chromatography on silica gel (CH ₂ Cl ₂ ZMeOH:

90/10, then 80/20) to provide pure polyhydroxylated nitrone (54-88%).

Example 1 of endocellular nitrone

Preparation of (2R, 31R, 4R) -3,4-dihydroxy-2- (hydroxymethyl) -3,4-dihydro-2H-pyrrole-1-oxide from (2H, 31H, 41H) -3 4-bis (benzyloxy) -2- (benzyloxymethyl) -3,4-dihydro-2H-pyrrole 1-oxide:

[α] ²⁰ _D = -45.3 (c 1.17, MeOH).

LRMS (DCI) m / z (%): 130 (22) [M + HH ₂ 0] ^+, 148 (100) [M + H] ^+.

IR: ν (cm ^-1 ) 3293, 2932, 2872, 1595.

¹ H NMR (300 MHz, CD ₃ OD): δ 3.73-3.78 (m, 2H); 4.10 (dd, 1H, J = 4.12.5 Hz); 4.21 (brt, 1H, J = 3Hz); 4.54 (brs, 1H); 7.09 (brs, 1H).

¹³ C NMR (75 MHz, CD ₃ OD): δ 58.4; 76.6; 78.3; 82.2; 140.2. Example 2 Endocyclic Nitronc

Preparation of (2S, 3Λ, 4Λ) -3,4-dihydroxy-2- (hydroxymethyl) -3,4-dihydro-2H-pyrrole-1-oxide from (2S, 3Λ, 4H) -3.4 bis (benzyloxy) -2- (benzyloxymethyl) -3,4-dihydro-2H-pyrrole 1-oxide:

[α] ²⁰ _D = -46 (c 1.28, MeOH).

MS (DCI) m / z (%): 148 (100) [M + H] ⁺ .

IR: ν (cm ^-1 ) 3180, 2962, 2921, 2846, 1621.

¹ H NMR (300 MHz, CD ₃ OD): δ 4.00 (dd, 2H, J = 2.0, 3.0 Hz); 4.06-4.10 (m, 1H); 4.39 (dd,

1H, J = 4.5, 7.5 Hz); 4.73 (td, 1H, J = 1.5, 4.5 Hz); 7.09 (t, 1H, J = 1.5 Hz).

¹³ C NMR (75 MHz, CD ₃ OD): δ 58.9; 78.1; 78.8; 80.1; 141.8.

Example 3 Endocyclic Nitrone Preparation of (25,35,4R) -2 - ((S) -1,2-dihydroxyethyl) -3,4-dihydroxy-3,4-dihydro-2H-pyrrole 1-oxide from _(J 3a5,45,6a R) -4 - ((S) -2,2-dimethyl-l, 3-dioxolan-4-yl) -2,2-dimethyl-4.6A-dihydro-3aH- [t , 3] dioxolo [4,5-c] pyrrole 5-oxide:

[Ot] D ²⁰ = -72 (c 1.13, MeOH).

MS (DCI) m / z (%): 178 (100) [M + H] ⁺ .

IR: v (cm ⁴ ) 3300, 2932, 2884, 1591.

¹ R NMR (300 MHz, CD ₃ OD): δ 3.71-3.82 (m, 2H); 4.00-4.05 (m, 1H); 4.07 (s, 1H); 4.41

(dd, 1H, J = 1.5, 5.5 Hz); 4.90 (d, 1H, J = 1.5 Hz); 7.12 (s, 1H).

¹³ C NMR (75 MHz, CD ₃ OD): δ 64.5; 72.3; 72.5; 73.2; 83.2; 142.1.

UV: λ _max (H ₂ O) = 234 nm (ε = 3528 molΛL.cm ^-1 ) Example 4 Endocyclic Nitrone

Preparation of (2S3S, 4S) -2 - ((S) -1,2-dihydroxyethyl) -3,4-dihydroxy-3,4-dihydro-2H-pyrrole 1-oxide from (25,3S, 4S) -3,4-bis (benzyloxy) -2 - ((S) -1,2-bis (benzyloxy) ethyl) 3,4-dihydro-2H-pyrrole 1-oxide:

[α] ²⁰ _D = + 34.4 (c 0.9, MeOH).

MS (DCI) m / z (%): 178 (100) [M + H] ⁺ .

IR: ν (cm- ¹ ) 3362, 2942, 2880, 1593.

¹ H NMR (300 MHz, CD ₃ OD): δ 3.75-3.86 (m, 2H); 3.96-4.04 (m, 2H); 4.18 (brt, IH, J -

2.4 Hz); 4.54 (br t, IH ₅ J = 1.9 Hz); 7.14 (brs, 1H).

¹³ C NMR (75 MHz, CD ₃ OD): δ 64.4; 72.2; 78.0; 78.5; 82.0; 140.7.

EXAMPLE 5 Endocyclic Nitrone Preparation of (3S, 4R) -3,4-dihydroxy-3,4-dihydro-2H-7-pyrrole 1-oxide from (3aS, 6aR) -2,2-dimethyl-4, 6α-dihydro-3α / 7- [1,3] dioxolo [4,5-c] pyrrole 5-oxide:

F ⁰ = 105-107 ° C.

[CX] ²⁰ _D = -110.7 (c 1.04, MeOH).

MS (DCI) m / z (%): 118 (100) [M + H] ⁺ .

¹ H NMR (300 MHz, CD ₃ OD): δ 3.79 (ddd, 1H, J = 1.1, 2.2, 14.2 Hz); 4.15 (dddd, IH, J =

1.3, 2.2, 5.6, 14.2 Hz); 4.50 (td, 1H, J = 2.2, 5.6 Hz); 4.87 (Id, 1H,, J = 5.6 Hz); 7.06 (s, 1H). ¹³ C NMR (75 MHz, CD ₃ OD): δ 68.8; 69.8; 73.8; 140.6. Example 6 Endocyclic Nitrone

Preparation of (2S, 3R, 4S> 3,4-dihydroxy-2- (hydimymethyl) -3,4-dihydiO-2H-pyrrole 1-oxide from (2S, 3 _^> 4>S> 3,4 bis (benzyloxy) -2- (benzyloxymethyl) -3,4-dihydro-2H-pyrrole 1-oxide:

[α] ^2ϋ _D = + 14.9 (c 1.0, MeOH)

MS (DCI) m / z (%): 148 (75) [M + H] ⁺ ; 130 (100) [M + HH ₂ O] ⁺ . IR: ν (cm ^-1 ) 3358, 2950, 2877, 1658, 1588.

¹ H NMR (400 MHz, CD ₃ OD): δ 3.89 (dd, 1H, J = 3.8, 12.7 Hz); 4.03-4.06 (m, 2H); 4.61 (t, 1H, J = 6.5 Hz); 4.70 (dd, 1H, J = 1.9, 6.2 Hz); 7.19 (s, 1H). ¹³ C NMR (100 MHz, CD ₃ OD): δ 57.0; 68.4; 71.4; 77.2; 140.2.

Example 7 Endocyclic Nitrone

Preparation of (2R, 3I, 4S) -3,4-dihydroxy-2- (hydroxymethyl) -3,4-dihydro-2H-pyrrole-1-oxide from (3H, 3H, 4S) -3,4- bis (benzyloxy) -2- (benzyloxymethyl) -3,4-dihydro-2H-pyrrole 1-oxide:

[α] ²⁰ , = + 78.5 (c 0.47, MeOH), IR: ν (cm ^-1 ) 3362, 2937, 2881, 1601.

¹ H NMR (300 MHz, CD ₃ OD): δ 3.80-3.88 (m, 2H); 4.10 (dd, 1H, J = 2.2, 11.7 Hz); 4.48 (dd, 1H, J = 2.3, 6.0Hz); 4.78-4.82 (m, 1H); 7.10 (s, 1H).

¹³ C NMR (75 MHz, CD ₃ OD): δ 59.1; 70.9; 72.1; 83.2; 141.0. Example 8 Endocyclic Nitrone

Preparation of (3 R, 4 R, 5 H) -3,4,5-trihydroxy-6- (hydroxymethyl) -2,3,4,5-tetrahydropyridine 1-oxide from (3H, 4H, 5H); ) -3,4,5-tris (benzyloxy) -6- (benzyloxymethyl) -2,3,4,5-tetrahydropyridine 1-oxide:

LRMS (DCI) m / z (%): 160 (100) [M + HH ₂ 0] ^+. (+) MS (ESI): m / z = 200 [M + Na] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD) δ: 3.78-3.95 (m, 3H); 4.20-4.24 (m, 1H); 4.48 (d, 1H, J ^: 17.3 Hz); 4.59-4.64 (m, 1H); 4.65 (d, 1H, J = 17.3 Hz). ¹³ C NMR (75 MHz, CD ₃ OD) δ: 59.8; 61.6; 65.6; 68.6; 71.4.

Example 9 Endocyclic Nitrone Preparation of (3 R, 4 R, 5 R) -3,4,5-trihydroxy-6-methyl-2,3,4,5-tetrahydropyridine-1-oxide from (3Λ, 41?, 5Λ) ) -3,4,5-tris (benzyloxy) -6-methyl-2,3,4,5-tetrahydropyridine 1-oxide:

LRMS (DCI) m / z (%): 162 (85) [M + H] ⁺ ; 144 (100) [M + HH ₂ O] ⁺ .

¹ H NMR (300 MHz, CD ₃ OD) δ: 2.16 (s, 3H); 3.78-3.88 (m, 2H); 4.00 (br d, 1H, J = 15.6

Hz); 4.14-4.20 (m, 1H); 4.30 (br d, 1H, J = 5.9 Hz).

¹³ C NMR (75 MHz, CD ₃ OD) δ: 15.4; 62.7; 66.6; 71.8; 152.3. Process for the preparation of non-cyclic hydroxyl nitrones from alkoxylated nitrones

Typical procedure:

To a solution of nitrone comprising benzyl ether (1 mmol) in CH ₂ Cl ₂ (30 mL) cooled to 0 ^° C., placed under argon and with magnetic stirring, a solution of BCl ₃ (1M solution in hexane, 3 equivalents) is added at 0 ^° C. The reaction mixture is maintained at this temperature for 15 hours. Methanol (30 mL) is then added thereto and the mixture is concentrated in vacuo. The residue is dissolved in dichloromethane, and this solution is added a saturated aqueous solution of NaHCO ₃ . The aqueous phase is extracted three times with dichloromethane, and the combined organic phases are washed with a saturated aqueous solution of NaCl and then dried over MgSO ₄ . After filtration, the filtrate is concentrated in vacuo and purified by chromatography on silica gel (CH ₂ Cl ₂ ZMeOH: 95/5) to provide the pure debenzylated nitrone (52%).

Example 1 of non-cyclic nitrone

Preparation of (Z) -N- (3-hydroxy-2,2-dimethylpropylidene) -1-phenylmethanamine oxide from (Z) -N- (3- (benzyloxy) -2,2-dimethylpropylidene) -1-phenylmethanamine oxide:

F ^0: 94-95 ° C.

MS (DCI) m / z (%): 208 (94) [M + H] ⁺ ; 192 (100) [M + H-0] ⁺ .

IR: ν (cm ^-1 ) 3240, 3053, 2968, 2872, 1596.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.18 (s, 6H); 3.60 (s, 2H); 4.07 (s, 1H); 4.88 (s, 2H); 6.50 (s,

H); 7.39 (s, 5H). ¹³ C NMR (75 MHz, CDCl ₃ ): δ 22.9; 39.7; 69.3; 70.2; 128.8; 129.0; 132.8; 146.1.

Anal. Wedge, for C ₁₂ H ₁₇ NO ₂ : C, 69.54; H, 8.27; N, 6.76. Exp .: C, 69.80; H, 8.26; N, 6.36. Process for the preparation of cyclic N-hydroxylamines polydropylated from polyalkoxylated cyclic N-hydroxylamines Typical procedure:

To a solution of cyclic N-hydroxylamine (1 mmol) in CH ₂ Cl ₂ (30 mL) cooled to 0 ° C., placed under argon and with magnetic stirring, a solution of BCl 3 (1M solution in hexane, 3 equivalents per ether function) is added at 0 ^° C. The reaction mixture is maintained at this temperature for 15 hours. Methanol (100 mL) or ethanol in the case of ethyl esters is then added thereto and the mixture is concentrated in vacuo. The residue is dissolved in a minimum of water, then treated with DOWEX 1X8 or IRA 1X4-50 resin (OH ^" form) until the pH of the solution reaches a value between 4 and 6. After filtration, the filtrate is concentrated under vacuum and purified by chromatography on silica gel (CH ₂ Cl ₂ / MeOH: 90/10, then 80/20) to provide the pure polyhydroxy-N-hydroxylamine (50-97%).

Example 1 Cyclic N-hydroxylamine

Preparation of (3Λ, 4Λ, 5R) -5- (hydroxymethyl) pyrrolidine-1,3,4-triol from (3Λ, 4Λ, 5J) -3,4-bis (benzyloxy) -5- (benzyloxymethyl) -pyrrolidin-1-ol:

MS (DCI) m / z (%): 150 (100) [M + H] ⁺

¹ R RMΝ (200 MHz, D ₂ O): δ 2.69 (dt, 1H, J = 11.0, 6.5 Hz); 3.08 (d, 2H, J = 7.5 Hz); 3.66 (d, 2H, J = 6.5 Hz); 3.75 (dd, 1H, J = 11.0, 5.5 Hz); 4.05 (m, 1H). ¹³ C RMΝ (150 MHz, D ₂ O): δ 59.6; 63.0; 74.7; 75.1; 77.4. Example 2 of cyclic β-hydroxylamine

Preparation of ethyl 3 - ((2S, 3 £, 4S ', 5S) -5 - ₍₍₁ S> l, 2-dihydroxyethyl) -l, 3,4- trihydroxypyrrolidin-2-yl) propanoate from ethyl 3 - ((2S, 3S, 4S, 5S) -3,4-bis (benzyloxy) -5 - ((S) -1,2-bis (benzyloxy) ethyl) -1-hydroxypyrrolidin-2-yl ) propanoate:

[α] _D = -7 (cl.l; MeOH)

(+) MS (ESI): m / z = 280 [M + H] ⁺ ; 264 [M + HH ₂ O] ⁺ .

IR: v (cm ^-1 ) 3349, 2981, 2932, 1715. ^ι Η NMR (300 MHz, CD ₃ OD): δ 1.21 (t, 3H, J = 7.1 Hz): 1.85-2.00 (m, 1H); 2.02-2.16 (m,

H); 2.43-2.64 (m, 2H); 2.90-2.98 (m, 1H); 3.04-3.12 (m, 1H); 3.66-3.78 (m, 3H); 3.88-3.98

(m, 2H); 4.09 (q, 2H, J = 7.1 Hz).

¹³ C NMR (75 MHz, CD ₃ OD): δ 14.9; 25.3; 32.8; 61.9; 65.8; 72.0; 73.4; 76.6; 80.5; 82.3;

176.1.

Example 3 cyclic TV-hydroxylamine

Preparation of (2S, 3 R, 47 R, 5 R) -methyl 1,3,4-trihydroxy-5- (hydroxymethyl) pyrrolidine-2-carboxylate from (2S, 3R, 47H, 5H) -methyl-3 4-bis (benzyloxy) -5- (benzyloxymethyl) -1-hydroxypyrrolidine-2-carboxylate:

OH OH

Brtff ^ ₀ Bn BCI ₃₁ CH ₂ Cl ₂ , _H (/ ^V _0H O ⁰ C

[CC] ²⁰ _D = -1.5 (c 0.80, MeOH) LRMS (DCI) m / z (%): 190 (100) [M + HH ₂ 0] ^+.

¹ H NMR (300 MHz, CD ₃ OD): δ 3.26-3.29 (m, 2H); 3.74 (d, 1H, J = 6.7 Hz); 3.78 (dd, 1H, J = 1.4, 4.5 Hz); 3.89 (s, 3H); 3.98-4.04 (m, 1H); 4.08 (t, 1H, J = 3.3 Hz); 4.72 (dd, 1H, J = 0.7, 3.1 Hz).

¹³ C NMR (75 MHz, CD ₃ OD): δ 53.1; 62.5; 79.9; 81.0; 83.7; 170.8. HRMS (ESI); Wedge, for C ₇ HJ ₄ NO ₆ : 208.0816; Exp .: 208.0819. Example 4 Cyclic JV Hydroxylamine

Preparation of (2H, 3H, 4H, 5H) -2,5-bis (hydroxymethyl) pyrrolidine-1,3,4-triol from

(2α, 3α, 4α, 5ι) -3,4-bis (benzyloxy) -2- (benzyloxymethyl) -5- (hydroxymethyl) pyrrolidin-1-ol:

[α] ²⁰ _D = +8.7 (c 1.0, MeOH)

LRMS (DCI) m / z (%): 180 (80) [M + H] ⁺ ; 164 (100) [M + HH ₂ O] ⁺ . ¹ H NMR (300 MHz, CD ₃ OD): δ 3.09 (brs, 2H); 3.75 (d, 4H, J = 4.7 Hz); 3.88 (br d, 2H, J = 4.9 Hz).

¹³ C NMR (75 MHz, CD ₃ OD): δ 60.9; 74.2; 78.3. HRMS (ESI) Cal, for C ₆ H ₁₄ NO ₅ : 180.0867; Exp .: 180.0868.

Example 5 Cyclic JV Hydroxylamine

Preparation of (2H, 3H, 4H, 55) -In-triolyl-1,3,4-trihydroxy-5- (hydroxymethyl) pyrrolidine-2-carboxylate from (2H, 3H, 4H) 5S) -methyl 3,4-bis (benzyloxy) -5- (benzyloxymethyl) -1-hydroxypyrrolidine-2-carboxylate:

[α] ²⁰ _D = -40.6 (c 1.5, MeOH) LRMS (DCI) m / z (%): 190 (100) [M + HH ₂ 0] ^+.

¹ H NMR (300 MHz, CD ₃ OD): δ 3.28-3.32 (m, 2H); 3.78 (d, 1H); 3.88 (s, 3H); 3.92-3.96 (m, 1H); 4.25 (brs, 2H); 4.75-4.85 (m, 1H).

¹³ C NMR (75 MHz, CD ₃ OD): δ 53.4; 60.8; 76.5; 79.0; 83.4; 171.3. HRMS (ESI) Cal, for C ₇ H ₁₄ NO ₆ : 208.0816; Exp .: 208.0819. Example 6 dc / cyclic V-hydroxylamine

Preparation of (2S, 3R, 4J, 5S) -2,5-bis (hydroxymethyl) pyrrolidine-1,3,4-triol from

(25,3 ^ 4i _5, 55?) -3,4-bis (benzyloxy) -2- (benzyloxymethyI) -5- (hydroxymethyl) pyrrolidin-l- ol:

[α] ²⁰ _D = -2 (c l.5, MeOH) LRMS (DCI) m / z (%): 180 (100) [M + H] ^+. ¹ H NMR (300 MHz, CD ₃ OD): δ 3.50-3.55 (m, 2H); 3.85 (br d, 4H, J = 5.5 Hz); 4.14 (d, 2H, J = 4.9 Hz).

¹³ C NMR (75 MHz, CD ₃ OD): δ 59.4; 71.9; 78.0. HRMS (ESI) Cal, for C ₆ H ₁₄ NO ₅ : 180.0867; Exp .: 180.0868.

Example 7 cyclic TV-hydroxylamine

Preparation of (2S, 3Λ, 4J, 5R) -2- (hydroxymethyl) -5- (3-methoxyprop-1-ynyl) pyriOlidine-1,3,4-triol from (2S, 3Λ, 4R, 5Λ) -3,4-bis (benzyloxy) -2- (benzyloxymethyl) -5- (3-methoxyprop-1-ynyl) pyrrolidin-1-ol:

[α] ²⁰ _D = -14 (c 1.0, MeOH). (+) MS (ESI): m / z = 218 [M + H] ⁺ , 240 [M + Na] ⁺ .

¹ H NMR (250 MHz, D ₂ O): £ 3.13-3.20 (m, IH), 3.43 (s), 3.57 (dd, IH, J = 1.4, 8.1 Hz), 3.76-3.93 (m, 2H), 3.97 (dd, 1H, J = 3.9, 8.1Hz), 4.21 (dd, 1H, J = 3.9, 7.5Hz), 4.25 (d, 2H, J = 1.8Hz). ¹³ C NMR (62.5 MHz, D ₂ O): δ 56.3, 57.6, 58.6, 63.4, 69.2, 73.4, 79.2, 79.7, 82.8. Example 8 dc / cyclic V-hydroxylamine

Preparation of (2S, 3R, 4Λ, 5S) -2- (hydroxymethyl) -5- (3-methoxyprop-1-ynyl) pyrrolidine-1,3,4-triol from (2S, 3R, 4Λ, 5S) -3,4-bis (benzyloxy) -2- (benzyloxymethyl) -5- (3-methoxyprop-1-ynyl) pyrrolidin-1-ol:

¹ H NMR (250 MHz, D ₂ O): (J3.39-3.44 (m, 4H), 3.76-3.90 (m, 2H), 4.11 (t, IH, J = 5.7 Hz), 4.25 (d, 2H , J = 1.5 Hz), 4.32 (dd, IH ₅ J = 5.5, 8.5 Hz), 4.40 (d, IH, J = 6.0 Hz).

Example 9 Cyclic N-hydroxylamine

Preparation of (25,3Λ, 4Λ, 5R) -2- (hydroxymethyl) -5- (phenylethynyl) pyrrolidine-1,3,4-triol from (2S, 3Λ, 4jR, 571) -3,4-bis (benzyloxy) -2- (benzyloxymethyl) -5- (phenylethynyl) pyrrolidin-1-ol:

[α] ²ⁿ _D = -17 (c 0.3, MeOH).

(+) MS (ESI): m / z = 250 [M + H] ⁺ , 272 [M + Na] ⁺ .

¹ H NMR (250 MHz, MeOD): £ 2.98-3.08 (m, IH), 3.54 (d, IH, J = 7.5 Hz), 3.79 (dd, IH, J

= 4.0, 11.0 Hz), 3.91 (dd, 1H, J = 7.3, 11.0 Hz), 3.97 (dd, 1H, J = 3.1, 7.5 Hz), 4.08 (dd, 1H, J).

= 3.1, 7.1 Hz), 7.30-7.34 (m, 3H), 7.43-7.47 (m, 2H). ¹³ C NMR (62.5 MHz, MeOD) :. δ 60.4, 67.7, 72.2, 76.7, 82.9, 84.7, 89.0, 124.5, 129.3-

132.7. Example 10 cyclic TV-hydroxylamine

Preparation of (2 R, 3 R, 4 R, 5 S) -2- (hepM-ynyl) -5- (hydroxymethyl) pyrrolidine-1,3,4-triol from (25,3Λ, 4Λ, 5β) - 3 4-bis (benzyloxy) -2- (benzyloxymethyl) -5- (hept-1-ynyl) pyrrolidin-1-ol:

[α] ²⁰ D = +53 (c 0.7, MeOH).

(+) MS (ESI): m / z = 244 [M + H] ⁺ , 266 [M + Na] ⁺ . ¹ H NMR (250 MHz, MeOD): δ 0.97 (t, 3H, J = 6.9 Hz), 1.34-1.60 (m, 6H), 2.27 (td, 2H, J

= 1.9, 6.9 Hz), 2.93-3.01 (m, IH), 3.33-3.37 (m, IH), 3.77-3.95 (m, 3H), 4.05 (dd, IH ₅ J =

3.2, 7.2 Hz).

¹³ C NMR (62.5 MHz, MeOD): δ. 14.3, 19.5, 23.3. 29.6, 32.2. 60.3. 67.2, 72.0. 76.6, 79.4,

82.9, 85.1.

Example 11 Cyclic N-hydroxylamine

Preparation of (2S, 3R, 4I, 5S) -2- (hept-1-ynyl) -5- (hydroxymethyl) pyrrolidine-1,3,4-triol from (2S, 3R, 4R, 5S) -3 4-bis (benzyloxy) -2- (benzyloxymethyl) -5- (hept-1-ynyl) pyrrolidin-1-ol:

[α] ²⁰ D = +33 (c 0.2, MeOH). (+) MS (ESI): m / z = 244 [M + H] ⁺ . ¹ H NMR (250 MHz, MeOD): δ 0.92 (t, 3H, J = 6.9 Hz), 1.29-1.45 (m, 4H), 1.49-1.57 (m, 2H), 2.25 (td, 2H, J = 2.2 , 6.9 Hz), 3.27-3.34 (m, 1H), 3.72-3.88 (m, 2H), 3.96 (t, 1H, J = 5.8Hz), 4.12-4.21 (m, 2H).

¹³ C NMR (62.5 MHz, MeOD): δ 14.4, 19.6, 23.3, 29.6, 32.2, 60.7, 63.0, 69.5, 74.6, 74.6, 77.9, 89.9. B. EVALUATION OF BIOLOGICAL PROPERTIES

1- Evaluation of the ability of polyhydroxylated nitrones to behave like spin trapping agents, ie to trap free radicals: study by RPE. The ability of polyhydroxy cyclic nitrones to react with free radicals was evaluated by initiating a Fenton reaction in the presence of nitrone, and recording EPR spectra immediately after addition of H ₂ O ₂ , and then three minutes after addition of H ₂ O ₂ . The appearance of a weak signal at the beginning of the reaction shows that the nitrones trap free radicals (probably hydroxyl radicals), but the adduct formed is not stable and decomposes rapidly.

Fenton's reaction:

[Belle, C.; Pierre, J.-L. Lepretre, J.-C. J. Chim. Phys. 1997, 94, 1533-1542.] In an Eppendorff tube, are successively introduced: - 25 μl of nitrone solution (1 M solution in water)

- 5 μl of TRIS buffer (1 M solution in water)

- 10 μL of FeSO ₄ H ₂ O solution (0.1 M solution in water)

- 5 μL of ascorbic acid (9 mM solution in water)

- 5 μL of H ₂ O ₂ (50 mM solution in water) This solution (50 μL) is transferred into a sealed Pasteur pipette immediately after addition of H ₂ O ₂ and the Pasteur pipette is placed in the field of the spectrometer for recording of the EPR spectrum.

2- Evaluation of the properties of polyhydroxylated nitrones as "antioxidant" agents.

Several types of tests exist to test the "antioxidant" capacities of new chemicals, depending on whether the activity sought is a protection against lipid peroxidation, against the oxidation of proteins, against the oxidation of nucleic acids, etc. A number of these tests have been described in the book "Analysis of Free Radicals", edited by AE Favier, J. Cadet, B. Kalyanaraman, M. Fontecave, J.-L Pierre, Editions Birkhaϋser (1995). ). 7000973

3- Evaluation of the interaction with glucose transporters in humans (GLUT 1)

If the products are recognized by glucose and / or fructose transporters

(GLUT) in humans they could benefit from a favorable transport (vectorization) towards certain organs, in particular towards the brain. The polyhydroxylated products prepared according to this patent then behave as glycomimetics and take the transport routes usually specific to sugars.

They could be routed to cell sites with high mitochondrial activity, or large amounts of sugars are consumed. In the vicinity of the mitochondria, they could act as scavengers of free radicals and thus limit the damage caused by oxidative stress (in particular oxygen free radicals, byproducts of respiration) to their vicinity.

4- Evaluation of the interaction with glucose transporters in Plasmodium falciparum (PfHT)

If the products are specifically recognized by the Plasmodium falciparum glucose transporter (PfHT) and not by GLUT-I, it may be possible to selectively inhibit the glucose supply of the parasite cells without affecting the metabolism of human cells. This approach is currently under study to develop a new treatment strategy for malaria [(a) ^' Joet, T.; Morin, C.; Fischbarg, J.; Louw, AI; Eckstein-Ludwig, U .; Woodrow, C.; Krishna S. Expert Opin. Ther. Targets, 2003, 7, 1-10. (h) Woodrow, CJ; Burchmore, RJ; Krishna, S. Proc. Nat. Acad. Sci. USA, 2000, 97, 9931-9936.]. By their structure close to natural sugars, the molecules prepared from the process described in this patent are potentially glycomimetics that can interact with PfHT carriers.

5- Evaluation of the interaction with lectins

The affinity of the products described in this patent vis-à-vis lectins, will be evaluated [For an article "perspective on lectins as therapeutic targets see: Ambrosi, M.; Cameron, NR; Davis, BG Org. Biomol Chem. 2005, 3, 1593-1608.]. Lectins are proteins on the surface of cells that selectively recognize certain oligosaccharides. For example, PA-IIL lectin [Mitchell, E.; Houles, C.; Sudakevitz, D.; Wimmerova, M.; Gautier, C.; Perez, S.; Wu, AM; Gilboa-Garber, N.; Imberty, A. Nature Struct. Biol, 2002, P, 918-921.], The first object of our study, is a lectin found on the surface of bacterial cells (Pseudomonas aeruginosa) that selectively recognizes fucosylated oligosaccharides. This surface protein, when it interacts with fucosylated oligosaccharides present on the surface of other cells (human lung cells for example) will allow the adhesion of bacterial cells on the host cells, adhesion prior to infection [(a) Imberty, A.; Wimmerova, M.; Mitchell, EP; Gilboa-Garber, N. Microbes and Infection, 2004, 6, 221-228. (b) Tielker, D.; Hackers. ; Loris, R.; Strathmann, M.; Wingender, J.; Wilhelm, S.; Rosenau, F.; Jaeger, KE. Microhiolog., 2005, 151, 1313-1323.]. If certain molecules described in this patent, as glycomimetics, are recognized and bind to lectins with high affinity, these molecules could be active as cell anti-adhesion agents. They would thus find applications in treatments against bacterial infections, but also viral. According to the same principle, if the adhesion between cancerous cells and healthy cells can be inhibited by a strong interaction between these glycomimetics and specific lectins present on the surface of cancerous cells, the molecules described in this patent could be used in the treatment of cancer cells. cancers, for example as anti-metastases.

Description of ELLA (Enzyme-Linked Lectin Assay) Assays on PA-IIL lectin: [Perret, S.; Sabin, C.; Dumon, C.; Pokorna, M.; Gautier, C.; Galanina, O .; IHa, S.; Bovine, N.; Nicaise, M.; Desmadril, M.; Gilboa-Garber, N.; Wimmerova, M.; Mitchell, E.P .; Imberty, A. Biochem. J., 2005, 389, 325-332.]

In each of the 96 wells of a microplate (Nunc Maxisorb), 100 μl of PA-IIL (20 μg / ml) in solution in 0.05 M carbonate buffer at pH 9.6 are incubated for 1 hour at 37 ^° C. for the purpose of fix the protein at the bottom of the wells. After emptying and spinning, 100 μl of BSA (Bovine Serum Albumin) in PBS buffer (3% w / v) are added for quenching and incubated for 1 hour at 37 ^° C. After emptying and spinning, 50 μl of PBS- 0.3% BSA are added to each well. In the first wells, after having added 10 μL of potential inhibitor (~ 20 mM) and then 40 μL of PBS-BSA 0.3%, 50 μL are taken and placed in the next row of wells, mixed, and the procedure is followed. following (50 μL samples, introduction into the following wells and mixing) to carry out the successive dilutions in the rows of wells. Finally, 50 μL of biotinylated fucose (Lectinity Holding, Inc.) at 10 μg / mL are added to each well and the plates are incubated for 1 hour at 37 ^° C. After three washes with T-PBS (PBS buffer containing 0.05% Tween). 100 μl of streptavidin-peroxidase conjugate (dilution 1: 5000, Boehringer-Mannheim) is added to each well and incubated for 1 hour at 37 ^° C. After three more washes with T-PBS, the color of the wells is revealed in FIG. using 100 μL per well of 0.05 M phosphate / citrate buffer containing Ophenylenediamine dihydrochloride (0.4 mg / mL) and urea hydroperoxide (0.4 mg / mL) (Sigma-Aldrich). The reaction is stopped by adding 50 μl of 30% H 2 SO 4. The absorbance is read at 490 nr using a microplate reader (Bio-Rad, model 680).

6- Evaluation of the interaction with enzymes involved in biosynthesis, isomerization, biodegradation, or any transformation of saccharides, oligosaccharides and nucleosides.

Numerous Glycomimetics [(a) Glycochemislry: Principles, Synthesis, and Applications, eds. P. Wang and C. Bertozzi, Marcel Dekker, New York - Basel, 2001. (b) Alper, J. Science 2001, 291, 2338-2343. (C) Wong, CH. Carbohydrate-based Drug Discovery; Wiley-VCH. Weinheim, 2003. (d) Stϋtz, AE Iminosugars as Glycosidase Inhibitors: Nojirimycin and Beyond; Wiley-VCH, Weinheim, 1999. (e) Heightman, TD; Vasella, AT Angew. Chem. Int. Ed. 1999, 38, 750-770. (f) Asano, N .; Nash, RJ; Molyneux, RJ; Fleet, GWJ Tetrahedron: Asymmetry 2000, 11, 1645-1680. (g) Martin, OR; Compain, P. Iminosugars: Recent Insights Info their Bioactivity and Potential as Therapeutic Agents in Curr. Top. Med. Chem., 3, issue 5; Martin, OR; Compain, P. Eds. ; Bentham, Neth. 2003.] have been evaluated as inhibitors of glycosidases, glycosyltransferases or nucleoside phosphorylases in order to develop new treatments for diseases as diverse as diabetes [Johnston, PS; Lebovitz, HE; Coniff, RF; Simonson, DC; Raskin, P.; Mimera, CLJ Clin. Endocrrinυl. Metab. 1998, 83, 1515], Gaucher disease [Sawkar, AR; Cheng, W.-C .; Beutler, E.; Wong, CH. ; Balch, WE; Kelly, JW Proc. Natl. Acad. Sci. USA 2002, 99, 15428.], cancer [a) Gruters, RA; Neefjes, JJ; Tersmette, M.; from Goede, REY; TuIp, A.; Huisman, HG; Miedema, F.; Ploegh, HL Nature, 1987, 330, 74. b) Tsuruoka, T.; Fukuyasu, H.; Ishii, M.; Usui, T.; Shibahara, S.; Inouye, SJ Antibiot. 1996, 49, 155.], AIDS or bacterial infections [Clinch, K.; Evans, GB; Fleet, GWJ; Furneaux, RH; Johnson, SW; Lenz, DH; Mee, SPH; Rands, PR; Schramm, VL; Taylor, Ringia, EA; Tyler, PC Org. Biomol Chem. 2006, 4, 1131-1139 and references cited]. Because their structure gives them a structural similarity with sugars, the compounds described in this patent can be considered as glycomimetics potentially inhibiting some of the enzymes involved in the biosynthesis, isomerization, biodegradation, or any transformation of saccharides, oligosaccharides and nucleosides.

Claims

1. Use of a Lewis acid, in particular chosen from:

boron trihalides (BI ₃ , BBr ₃ , BCl ₃ , BF ₃ ); complexes of the above boron trihalides with Lewis bases such as ethers, thioethers, phosphines or amines, or

trialkylsilane halides (TMSI, TMSBr), for converting one or more alkoxyl groups into one or more hydroxyl groups, said alkoxyl groups being present on cyclic or non-cyclic compounds bearing a nitrone or N-hydroxylamine nitrogen function, said function nitrogen that can be integrated into a cycle, without affecting the nitrogen function.

2. Process for the preparation of a compound corresponding to the following formula (I):

in which :

y is an integer equal to 2n + 2-x;

- i is an integer ranging from 1 to y;

a represents a single bond or a double bond:

- A represents one of the following groups: N or N;

OH O ^"

- R ' ₂ , R ₃ , R ₄ and Rj represent independently of each other one of the following groups:

* a hydrogen atom, an alkyl group comprising from 1 to 18 carbon atoms, said alkyl group being a linear or branched group, saturated or unsaturated, or

. at least one halogen atom, especially chosen from: Br, Cl and F, at least one OR ₈ group, at least one SR ₈ group, at least one NR ₃ Rb group,

. at least one COOR ₃ group,. at least one group CONR ₃ R _b ,

an -OR ₆ group, R ₆ being an alkyl group of 1 to 4 carbon atoms,

at least two of the substituents chosen from the groups RS, R ₃ , R ₄ , R 5 and R ₆ possibly being able to form a ring with each other,

in which :

- a, A, n, i, x and y are as defined above for formula (I); - j is an integer ranging from 1 to x;

- R ^J i represents one of the following groups:

an alkaryl group comprising from 6 to 30 carbon atoms, said alkyl or alkaryl groups being optionally substituted by: at least one halogen atom, especially chosen from: Br, Cl and F, at least one OR group _c . at least one SR ₀ group,

. at least one NR _c group R 1, at least one group COOR _C ,. at least one group CONRcR _d ,

R ^J i preferably representing a group chosen from:

. methyl,. trityle,. benzhydryl,

. benzyloxymethyl (BOM), and. methoxymethyl (MOM), when x is greater than or equal to 2, two OR 'i groups carried by two adjacent or 1,3-linked carbon atoms may form a cyclic ketal or acetal group, especially chosen from the following groups: isopropylidene cyclohexylidene, cyclopentylidene, benzylidene, silylene and 1,1,3,3-tetraisopropyldisiloxanylidene,

- R " ₂ , R ' ₃ , R'4 and R' ₅ represent independently of each other one of the following groups: * a hydrogen atom,

. at least one halogen atom, especially chosen from: Br. Cl and F, aυ least one group OR _'a. at least one SR 'group _a,

. at least one NR 'group, R' b,. at least one group COOR ' _a ,. at least one group CONR ' _a R't _> ,

* -OR _'O, R' ₆ is an alkyl group of 1 to 3 carbon atoms,

at least two of the substituents chosen from the groups R'S, R ' ₃ , R' ₄ , R ' ₅ and R' ₆ possibly being able to form a ring with each other,

3. Process according to claim 2 for the preparation of a compound corresponding to the following formula (I-1):

in which :

- n, x, y, i, R ¹ , R ₃ , R ₄ and R ₅

claim 2;

said process comprising a reaction step of a Lewis acid, in particular chosen from: boron trihalides (BI ₃ , BBr ₃ , BCl ₃ , BF ₃ ),

trialkylsilane halides (TMSI, TMSBr), with a compound of the following formula (II-1):

in which :

n, i, x and y are as defined in claim 2;

- j, ^J R i, R _'2, R' _3, R% and R _'5 are as defined in claim 2j.

4. Process according to claim 2 for the preparation of a compound corresponding to the following formula (1-2):

in which :

n, x, y, i, R ' ₂ , R ₃ , R ₄ and R ₅ are as defined in claim 2;

boron trihalides (BLu BBr ₃ , BCl ₃ , BF ₃ ),

complexes of the above-mentioned boron trihalides with Lewis bases such as ethers, thioethers, phosphines or amines, or trialkylsilane halides (TMSI, TMSBr), with a compound corresponding to the formula (II-2) ) next :

in which :

n, i, x and y are as defined in claim 2;

- j, R'i, R ^5l 2, R ' ₃ , R'4 and R' ₅ are as defined in claim 2.

5. Process according to claim 2, for the preparation of a compound of formula (1-2) as defined in claim 4, comprising:

A first step of reduction, nucleophilic addition or reducing coupling of a compound of formula (II-1) as defined in claim 3, to obtain a compound of formula (II-2) as defined in claim 4; and

A final reaction step of said compound of formula (II-2) with a Lewis acid chosen from:

boron trihalides (BI ₃ , BBr ₃ , BCl ₃ , BF ₃ ),

halides of trialkylsilanes (TMSI, TMSBr), in order to obtain the product of formula (1-2) as defined above.

6. Preparation process according to claim 2, for the preparation of a compound of formula (1-2) as defined in claim 4, comprising:

A first reaction step of a Lewis acid chosen from:

boron trihalides (BI ₃ , BBr ₃ , BCl ₃ , BF ₃ ),

complexes of the above-mentioned boron trihalides with Lewis bases such as ethers, thioethers, phosphines or amines, or trialkylsilane halides (TMSI, TMSBr), with a compound of formula (II-1) such as as defined in claim 3, to obtain a compound of formula (I-1) as defined in claim 3; and

A final step of reducing a compound of formula (I-1) as defined above, to obtain a compound of formula (1-2) as defined above.

7. Compound of formula (I) below:

in which :

- 11 is 1 or 2; - x is an integer ranging from 1 to n + 1, provided that two OH groups are not present on the same carbon atom:

y is an integer equal to 2n + 2-x;

- A represents one of the following groups: N or N ⁺ ;

OH o ^"

. a representing a single bond when A = N-OH; . a representing a double bond when A = N ⁺ -O ^" ; - R ' ₂ , R ₃ , R ₄ and R ₅ represent, independently of each other, one of the following groups:

* a hydrogen atom,

. at least one halogen atom, especially chosen from: Br, Cl and F, at least one OR group ₃ ,

. at least a SR _group,. at least one NR ₃ R _{b group} . at least one COOR ₈ group,. at least one CONR ₃ R _b , R ₃ and R _{b group} independently of one another: a hydrogen atom, an alkyl group comprising from 1 to 18 carbon atoms, an alkanoyl group comprising from 1 to 18 carbon atoms, an aryl or heteroaryl group comprising from 6 to 30 carbon atoms or a silyl group, a -OR ₆ group, R ₆ being an alkyl group of 1 to 4 carbon atoms,

at least two of the substituents chosen from the groups R ₂ , R ₃ , R ₄ , R ₅ and R ₆ possibly being able to form a ring with each other, said compounds of formula (I) may be in the form of stereoisomers namely in the form of enantiomers and diastereoisomers or mixtures of these different forms, including racemic mixtures, or in the form, if appropriate, of salts (hydrochloride, oxalate, tartrate ...)

provided that the following compounds are excluded:

Rp being selected from one of the following groups: OH, OnBu, O, Hex, OMe, OEt, NHCH ₂ CH ₂ Ph, NHCH ₂ Ph, NH / Bu and NH "Bu,

R _χ being selected from one of the following groups: H, Ac and CONHPh,

R _δ being selected from one of the following groups: 2-furyl, 2,4-dimethoxybenzyl and 2,4,6-trimethoxybenzyl, the hydrochlorides and carboxylates of these compounds are also excluded.

8. Compound according to claim 7, of formula (VII) below:

in which :

- A, a, n, i, R ' ₂ , R ₃ , R ₄ and R ₅ are as defined in claim 7;

9. Compound according to claim 7, of formula (I-1) below:

in which :

n, x, y, i, R ' ₂ , R 3, R ₄ and R ₅ are as defined in claim 7;

provided that the following compounds are excluded:

The compound of claim 9 having the following formula (V)

R2007 / 000973

in which :

x is an integer ranging from 1 to 2;

y is an integer equal to 4-x;

- i, R ' ₂ , R ₃ , R ₄ and R ₅ are as defined in claim 7,

excluded

11. The compound of claim 10 having the following formula (V-3)

in which :

R ₃ , R ₄ and R ₅ are as defined in claim 7,

- R ₈ , R ₉ , Rio and Rn represent independently of each other one of the following groups:

* a hydrogen atom,

a hydroxyl group,

. at least one halogen atom, especially chosen from: Br, Cl and F,

. at least one OR group _has ,

. at least one SR group _has ,

. at least one group NR _a R _b ,

. at least one COOR ₁₁ group,

. at least one group CONRj ₁ R _b ,

R _a and R _b being as defined in claim 7, it being understood that only one of the groups R ₈ and R ₁₀ can represent a hydroxyl group and that only one of the groups R ₁₀ and R ₁₁ can represent a hydroxyl group, one at least one of groups R _8, _Rc>, Rio or Rn represents a hydroxyl group, and at least one of Rg, R _9, R _10, Rn, R _3, R ₄ or R ₅ representing an alkyl, aryl , alkaryl, aralkyl or heteroaryl, substituted by at least one hydroxyl group when only one of R ₈ , R ₉ , Rio and Rn represents a hydroxyl group,

provided that the following compounds are excluded:

The compound of claim 11 having the following formula (V-3-3):

wherein R ₃ , R ₄ and R ₅ are as defined in claim 7, and R's, R ' ₉ .

R ' ₁ 0 and R' _{1 1} correspond to the definition of R ₂ ¹ in claim 7, at least one of R 1, R ' ₉ , R' ₁₀ or R 'π representing a hydroxyl group, at least one of R ₃ , R ₄ , R ₅ , R ', R' ₉ , R ' ₁ 0 and R' ₁ representing a linear or branched alkyl chain substituted by at least one OH group;

provided that the following compounds are excluded