FR3057772A1 - POLYSUBSTITUTED QUINIC ACID DERIVATIVES AND USES THEREOF - Google Patents

Abstract

The present invention relates to poly substituted quinic acid ester derivatives (abbreviated as "QPS") of the general formula (IA): wherein R represents a linear or branched, cyclic or cyclic branched, saturated or branched C2-CP alkyl group. unsaturated, wherein said group may be substituted or unsubstituted, wherein p is a natural integer of 3 to 18, and Q1, Q3, Q4 and Q5 are each, independently of one another, a hydrogen atom or a group chosen from among the caffeoyl, maloyl, c-alkyloylmaloyl and maloylcaféoyl groups, provided that at least one of these radicals is not a hydrogen atom, their stereoisomers and their pharmaceutically or nutraceutically acceptable salts, for the prevention and / or treatment of a neurodegenerative disease, including Alzheimer's disease. The subject of the invention is also compounds of formula (IA) as such; a process for the preparation of such compounds, compounds according to the invention intended to be used as a medicament, especially for the prevention and / or treatment of a neurodegenerative disease, in particular Alzheimer's disease and a pharmaceutical composition comprising at least a compound according to the invention.

Description

FIELD OF THE INVENTION

The present invention relates to ester derivatives of polysubstituted quinic acids, abbreviated as "QPS", as well as their preparation process, their use as a medicament, in particular for the prevention and / or treatment of neurodegenerative diseases, in particular of the disease. Alzheimer's, and pharmaceutical or nutraceutical compositions containing them.

PRIOR ART

Compositions comprising substituted quinic acids, and in particular dicafeoylquinic acids, have been cited for the prevention or treatment of diseases associated with senescence, in particular for Alzheimer's disease (WO 2015/044 649).

The inventors have demonstrated that new ester derivatives of QPS, and in particular ester derivatives of polycafeoylquinic acids, abbreviated as "PCQ", not only have neuroprotective properties, and in particular capacities in the prevention and / or treatment of neurodegenerative diseases, in particular Alzheimer's disease, but that these are significantly superior to the properties described for the various isomers of dicaféoylquinic acid.

SUMMARY OF THE INVENTION

Surprisingly, the inventors have shown that certain QPS ester derivatives exhibit quite remarkable neuroprotective effects and therefore are of interest in the prevention and / or treatment of neurodegenerative diseases, in particular Alzheimer's disease.

In a first aspect, the present invention relates to compounds of general formula (IA):

(ΙΑ) in which

R represents a linear or branched, saturated or unsaturated cyclic or cyclic C2-C _P alkyl group, said group possibly being substituted by one or more substituents chosen from the group comprising: - ORi, NR1R2, - NO2, -CORi, -COORi, -CF3, -CR1F2, -CR1R2F, = 0, -CN, halogen, -SRi, -SO2R1, aryl, in which

- p is a natural integer between 3 and 18,

-Ri and R2 are identical or different and each represents, independently of one another,

- or a substituent chosen from the group comprising: -H, -OH, -NH2,

- NO2, -COOH, -CF ₃ , -CHF2, -CH2F, = 0, -CN, halogen, -SH, -SO2H,

either a linear or branched C2-C6 alkyl group, cyclic or cyclic branched, saturated or unsaturated, which may be substituted by one or more substituents chosen from the group comprising: -H, - OH, - NH2, -NO2,

- COOH, -CF3, -CHF2, -CH2F, = 0, -CN, halogen, -SH, - SO2H, and

Qi, Q3, Q4 and Qs each represent, independently of one another, a radical chosen from the group comprising: a hydrogen atom and a caféoyl, maloyl, caféoylmaloyl or maloylcaféoyl group, provided that at least one of these radicals is not a hydrogen atom, their stereo isomers and their pharmaceutically or nutraceutically acceptable salts, for their use in the prevention and / or treatment of a neurodegenerative disease, in particular Alzheimer's disease.

According to a second aspect, the present invention relates to compounds of general formula (IA), wherein R represents an alkyl group C2-C _P linear or branched, cyclic or cyclic branched, saturated or unsaturated and said group can be substituted by one or more substituents chosen from the group comprising -ORi, -NR1R2, NO2, -CORi, -COORi, -CF3, -CR1F2, -CR1R2F, = 0, - CN, halogen, -SRi, -SO2R1, aryl, in which p is a natural integer between 3 and 18,

Ri and R2 are identical or different and each represents, independently of one another,

- or a substituent chosen from the group comprising: -H, -OH, -NH2, - NO2, -COOH, -CF ₃ , -CHF2, -CH2F, = 0, -CN, halogen, -SH, -SO2H,

either a linear or branched C2-C6 alkyl group, cyclic or cyclic branched, saturated or unsaturated, which may be substituted by one or more substituents chosen from the group comprising: -H, - OH, -NH2, -NO2, COOH, -CF3, -CHF2, -CH ₂ F, = 0, -CN, halogen, -SH, -SO2H, and Qi, Q3, Q4 and Qs each represent, independently of one another, a radical chosen from the group comprising: a hydrogen atom and a caféoyl, maloyl, caféoylmaloyl or maloylcaféoyl group, provided that at least one of these radicals is not a hydrogen atom, with the exception of the following compounds:

• Compounds of general formula (IB)

in which :

R3 is a linear or branched C2-C6 alkoxyl, in particular an ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, npentoxy, isopentoxy and n-hexoxy group,

- R4, Rs and Rô are each independently chosen from: a group - OH and a group represented by the following formula (X):

Ο y

ο (X) in which R.7 represents a group -OH and n is an integer between 1 and 5, with at least one of R4, Rs or Rô corresponding to said formula (X), l- (2-hydroxypropoxy ) propan-2-yl ester of cyclohexanecarboxylic acid, 3,5-bis [[(2 £) -3- (3,4-dihydroxyphenyl) -l-oxo2-propen-1-yl] oxy] -l, 4-dihydroxy- (lS, 3Æ, 4S, 5Æ) • l- (l-hydroxypropan-2-yloxy) propan-2-yl ester of cyclohexanecarboxylic acid, 3,5-bis [[(2 £) -3 - (3,4-dihydroxyphenyl) -l-oxo2-propen-l-yl] oxy] -l, 4-dihydroxy- (lS, 3Æ, 4S, 5Æ) • 2- (l-hydroxypropan-2-yloxy) propyl cyclohexanecarboxylic acid ester, 3,5-bis [[(2 £) -3- (3,4-dihydroxyphenyl) -l-oxo2-propen-l-yl] oxy] -l, 4-dihydroxy- (lS , 3Æ, 4S, 5Æ) • 2- (2-hydroxypropoxy) propyl ester of cyclohexanecarboxylic acid, 3,5-bis [[(2 £) -3- (3,4-dihydroxyphenyl) -l-oxo-2 -propen-l-yl] oxy] -l, 4dihydroxy- (lS, 3Æ, 4S, 5Æ) • The ethyl ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4dihydroxyphenyl) -l-oxo- 2-propen-l-yl] oxy] -l, 4,5-trihydroxy (1S, 3R, 4R, 5R) • The pr cyclohexanecarboxylic acid opyl ester, 3 - [[(2 £) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen-1-yl] oxy] -l, 4,5-trihydroxy (1S, 3R, 4R, 5R) • The 1-methylethyl ester of cyclohexanecarboxylic acid, 3 - [[(2 £) -3 (3,4-dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -1,4,5-trihydroxy (1S, 3R, 4R, 5R) • The butyl ester of cyclohexanecarboxylic acid, 3 - [[(2 £) -3- (3,4dihydroxyphenyl) -l-oxo-2- propen-l-yl] oxy] -l, 4,5-trihydroxy (1S, 3R, 4R, 5R) • Butyl ester of cyclohexanecarboxylic acid, 3 - [[(2 £) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4,5-trihydroxy (1 / ?, 3S, 4S, 5S) • The octyl ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4,5-trihydroxy (1S, 3R, 4R, 5R) • Acetic anhydride (1S, 3Æ, 4Æ, 5Æ ) cyclohexanecarboxylic acid 3 - [[3- (3,4-dihydroxyphenyl) -l-oxo-2-propen-1-yl] oxy] -l, 4,5tri hy d roxy- (1S, 3R, 4R , 5R) • The dodecyl ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen-1-yl] oxy] -l, 4,5-trihydroxy (1S, 3R, 4R, 5R) • The 2-ethylhexyl ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4.5 -trihydroxy (1S, 3R, 4R, 5R) • 2-methylhexyl ester of cyclohexanecarboxylic acid 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l , 4,5-trihydroxy (1S, 3R, 4R, 5R) • The hexadecyl ester of cyclohexanecarboxylic acid 3 - [[(2 £) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen- l-yl] oxy] -l, 4,5-trihydroxy (1S, 3R, 4R, 5R) • The octadecyl ester of cyclohexanecarboxylic acid 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2 -propen-l-yl] oxy] -l, 4,5-trihydroxy (1S, 3R, 4R, 5R) • The eicosyl ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4dihydroxyphenyl) -l -oxo-2-propen-l-yl] oxy] -l, 4,5-trihydroxy (1S, 3R, 4R, 5R) • 2,3-butadien-l-yl ester of cyclohexanecarboxylic acid, 3- [[(2 £) 3- [4- (2,3-butadien-l-yloxy) -3-hydroxyphenyl] -l-oxo-2-propen-lyl] oxy] -l, 4,5-trihydroxy- ( lS, 3Æ, 4Æ, 5Æ) • The phenylmethyl ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-pr openyl] oxy] -l, 4,5-trihydroxy- (lS, 3Æ, 4Æ, 5Æ) • The (25) -3,7-dimethyl-2,6-octadien-l-yl ester of cyclohexanecarboxylic acid, 3 - [[(25) -3- (3,4-dihydroxyphenyl) -l-oxo-2propen-l-yl] oxy] -l, 4,5-trihydroxy- (lÆ, 3S, 4S, 5Æ) • The 2-chloroethyl ester of cyclohexanecarboxylic acid, 1,3,4trihydroxy-5 - [[(25) -3- (4-hydroxy-3-methoxyphenyl) -l-oxo-2-propen-lyl] oxy] - ( lÆ, 3Æ, 4S, 5Æ) • The ethyl ester of cyclohexanecarboxylic acid, 3,4-bis [[(25) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 5-dihydroxy- 1S, 3Æ, 4Æ, 5Æ) • The ethyl ester of cyclohexanecarboxylic acid, 3,5-bis [[(25) -3- (3,4dihydroxyphenyl) -l-oxo -2-propen-l-yl] oxy] -l, 4-dihydroxy (la, 3Æ, 4a, 5Æ) • The ethyl ester of cyclohexanecarboxylic acid, 3,4-bis [[(25) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 5-dihydroxy (l / ?, 3 / ?, 4S, 5Z?) • Cyclohexanecarboxylic acid anhydride 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen-1-yl] oxy] -l, 4,5-trihydroxy- and 3- (4-hydroxyphenyl) -2-propenoic acid (1S, 3Æ, 4Æ , 5Æ) • The butyl ester of cyclohexanecarboxylic acid, 3,5-bis [[(25) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4 -dihydroxy (1S, 3Æ, 4S, 5Æ) • The butyl ester of cyclohexanecarboxylic acid, 3,4-bis [[(25) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l- yl] oxy] -1.5-dihydroxy (1Æ, 3S, 4S, 5S) • The propyl ester of cyclohexanecarboxylic acid, 3,5-bis [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen -l-yl] oxy] -l, 4-dihydroxy (1S, 3Æ, 4S, 5Æ) • (2E, 2'E) - ((lR, 2S, 3R., 5S) -2,5-dihydroxy-5 - ((3hydroxypropoxy) carbonyl) cyclohexane-1,3-diyl) bis (3- (3,4dihydroxyphenyl) acrylate) their stereo isomers and their pharmaceutically or nutraceutically acceptable salts.

According to a third aspect, the invention relates to compounds according to the invention intended for use as a medicament, in particular for the prevention and / or treatment of a neurodegenerative disease, in particular Alzheimer's disease.

According to a fourth aspect, the invention relates to a pharmaceutical composition comprising at least one compound, or a mixture of compounds, according to the invention, more particularly to such a pharmaceutical composition for its use in the prevention and / or treatment of neurodegenerative disease, in particular Alzheimer's disease. The invention also relates to a nutraceutical composition comprising an effective amount of at least one compound according to the invention.

DESCRIPTION OF THE FIGURES

Figures IA to 1D show the survival, in percentage of living neurons compared to the control, of primary cortical neurons intoxicated for 24 hours by the peptβ1-42 peptide added at a final concentration of 20 μΜ, in the presence of acid 3 respectively , 5 di-caféoylquinique (Fig. IA), ethyl ester of 3,5 di-caféoylquinic acid (Fig. IB), of 2-hydroxy-propyl ester of 3,5 di-caféoylquinic acid (2 -HPE DCQ) (Fig. IC) or 2-hydroxy hexyl ester of 3,5 di-caffeoylquinic acid (2-HHE DCQ) (Fig. 1D) at concentrations varying from 10 nM to 10 μΜ in accordance with l 'example 2.

Figures 2A to 2D show the growth of the network of neurites intoxicated for 24 hours by the peptide of Αβ1-42 added to a final concentration of 20 pM, in the presence respectively of 3.5 dicafeoylquinic acid (Fig. 2A), ethyl DCQ ester (Fig. 2B), 2-HPE DCQ (Fig. 2C) or 2-HHE DCQ (Fig. 2D) at concentrations varying from 10 nM to 10 pM in accordance with Example 2.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention relates to compounds of general formula (IA):

(ΙΑ) in which

R represents a linear or branched, saturated or unsaturated, branched or cyclic C2-C _P alkyl group, said group possibly being substituted by one or more substituents chosen from the group comprising: -ORi, - NR1R2, -NO2, -CORi , -COORi, -CF3, -CR1F2, -CR1R2F, = 0, -CN, halogen, -SRi, -SO2R1, aryl, in which

- p is a natural integer between 3 and 18,

- Ri and R2 are identical or different and represent, each independently of the other

or a substituent chosen from the group comprising: -H, -OH, NH ₂ , - NO2, -COOH, -CF ₃ , -CHF2, -CH2F, = 0, -CN, halogen, -SH, SO2H,

-or a linear or branched C2-C6 alkyl group, cyclic or cyclic branched, saturated or unsaturated, which may be substituted by one or more substituents chosen from the group comprising: -H, - OH, -NH2, -NO2, - COOH , -CF ₃ , -CHF2, -CH2F, = 0, -CN, halogen, -SH, -SO2H, and

Qi, Q ₃ , Q4 and Qs each represent, independently of one another, a radical chosen from the group comprising: a hydrogen atom and a caféoyl, maloyl, caféoylmaloyl or maloylcaféoyl group, provided that at least one of these radicals is not a hydrogen atom, their stereoisomers and their pharmaceutically or nutraceutically acceptable salts, for their use in the prevention and / or treatment of a neurodegenerative disease, in particular Alzheimer's disease.

The compounds of general formula (IA) can be used alone or in the form of a mixture of compounds of formula (IA).

By “C2-C _P alkyl group” is meant, within the meaning of the present invention, a monovalent saturated or unsaturated, linear or branched, cyclic or cyclic branched hydrocarbon chain, comprising from 2 to p carbon atoms, p being a natural whole between 3 and 18.

According to the invention, R. preferably represents a saturated or unsaturated, linear or branched, cyclic or cyclic branched monovalent hydrocarbon chain of 2 to 18 carbon atoms, preferably of 2 to 17 carbon atoms, and more preferably of 2 to 16 carbon atoms, from 2 to 15 carbon atoms, from 2 to 14 carbon atoms, from 2 to 13 carbon atoms, from 2 to 12 carbon atoms, from 2 to 11 carbon atoms, from 2 to 10 carbon atoms, from 2 to 9 carbon atoms, from 2 to 8 carbon atoms, from 2 to 7 carbon atoms, preferably from 2, 3, 4, 5 or 6 carbon atoms, and in particular from 2, 5 or 6 carbon atoms.

By way of example and in a non-exhaustive manner, mention may be made of ethyl, n-propyl, isopropyl, n-butyl, isobuyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl groups. tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, geranyl, farnesyl, cyclopropyl, cyclobutyl, cyclohexyl, ethylenyl, propylenyl, butylenyl, cyclopropenyl, cyclobutenyl, cyclcopentenyl, cyclohexenyl, cyclohexenyl, cyclohexenyl dienyl, cyclohexa-1,5-dienyl, said groups possibly being linear or branched.

In a preferred embodiment of the invention, the alkyl groups are linear.

By “aryl group” is meant an aromatic Cô ring, which may be substituted by one or more substituents chosen from the group comprising: -H, -OH, -NH ₂ , -NO2, -COOH, -CF ₃ , -CHF ₂ , -CH ₂ F, = 0, -CN, halogen, -SH, - SO ₂ H.

By “coffeeoyl group” is meant a radical of formula (II), derived from caffeic acid:

(II)

By “maloyl group” is meant a radical of formula (Ilia) or (Illb), derived

By “caféoylmaloyl group” is meant a radical of formula (IVa) or (IVb):

(IVa)

By “maloylcaféoyl group” is meant a radical of formula (Va), (Vb), (Vc) or (Vd):

OH Ο nr ° © ^ ° ^H

ΠΓ ° 3ι © ¹ ' ^0Η • ÿ ^ AA _0H ° «

By “polysubstituted quinic acid”, abbreviated as “QPS” throughout this description, is meant a mono, di, tri or tetra ester composed of a molecule of quinic acid of which one, two, three or the four alcohol functions have been esterified with caffeic acid, malic acid, or a mixture of caffeic acid and malic acid. The QPS are therefore acids of general formula (VI):

in which Qi, Q3, Q4 and Qs represent, independently of each other, a hydrogen atom, a caféoyl, maloyl, caféoylmaloyl or maloylcaféoyl group, as defined above, provided that at least one of these radicals is not a hydrogen atom.

In a preferred embodiment of the invention, QPS is a polycafeoylquinic acid, abbreviated as "PCQ" throughout this description, corresponding to a mono, di, tri or tetra ester composed of a quinic acid molecule, one of which , two, three or four alcohol functions have been esterified with caffeic acid. PCQs are therefore acids of general formula (VI) as defined above in which Qi, Q3, Q4 and Qs represent, independently of one another, a hydrogen atom or a caffeoyl group, provided that at at least one of these radicals is not a hydrogen atom.

The various isomers of QPS are part of the invention. By way of example, mention may be made of the isomers of PCQ which are acids of general formula (VI), with Qi, Q3, Q4 and Qs chosen independently of one another from the hydrogen atom and a caffeoyl radical, under provided that at least one of the Qi, Q3, Q4 and Qs is not a hydrogen atom.

PCQ or QPS isomers are given in Tables 1 to 4 below.

Acid name Qi Qa Q4 Qs 1- Caffeoylquinic acid Cafeoyle H H H 3- Caffeoylquinic acid H Cafeoyle H H 4- caffeoylquinic acid H H Cafeoyle H 5- Caffeoylquinic acid H H H Cafeoyle Table 1. Examples of e structure of PCQ d have three

radicals Qi, Q3, Q4 and Qs represent a hydrogen atom

Acid name Qi Q3 Q4 Q5 1,3-dicaféoylquinique (1,3-DCQ) Cafeoyle Cafeoyle H H 1,4- dicaféoylquinique (1,4-DCQ) Cafeoyle H Cafeoyle H 1,5- dicaféoylquinique (1,5-DCQ) Cafeoyle H H Cafeoyle 3,4-dicaféoylquinique (3,4-DCQ) (= isochlorogenic acid B) H Cafeoyle Cafeoyle H 3,5- dicaféoylquinique (3,5-DCQ) (= isochlorogenic acid A) H Cafeoyle H Cafeoyle 4,5- dicaféoylquinique (4,5-DCQ) (= isochlorogenic acid C) H H Cafeoyle Cafeoyle

Table 2. Examples of the structure of PCQ in which two of the radicals Qi, Q3, Q4 and Qs represent a hydrogen atom.

Acid name Qi Qa Q4 Qs 1,3,4- tricaféoylquinique acid (1,3,4-TCQ) Cafeoyle Cafeoyle Cafeoyle H 1,3,5- tricaféoylquinique acid (1,3,5-TCQ) Cafeoyle Cafeoyle H Cafeoyle 1,4,5- tricaféoylquinique acid (1,4,5-TCQ) Cafeoyle H Cafeoyle Cafeoyle 3,4,5- tricaféoylquinique acid (3,4,5-TCQ) H Cafeoyle Cafeoyle Cafeoyle Acid 1- (2- caféoylmaloyl) - (3,5- dicaféoyl) quinique Coffeeoyl maloyle Cafeoyle H Cafeoyle 1- maloyl- acid (3,4,5- tricaféoyl) quinique Maloyle Cafeoyle Cafeoyle Cafeoyle

Table 3. Examples of the structure of QPS in which at most one of the radicals Qi, Q3, Q4 and Qs represents a hydrogen atom.

Acid name Qi Qa Q4 Qs 1,3,4,5- tetracafeoylquinic acid (TétraCQ) Cafeoyle Cafeoyle Cafeoyle Cafeoyle Acid 1- (2- caféoylmaloyl) - (3,4,5- tricaféoyl) quinique Caféoylmaloyle Cafeoyle Cafeoyle Cafeoyle

Table 4. Example of a structure of QPS in which none of the radicals Qi, Q3, Q4 and Qs represents a hydrogen atom.

In the present invention, the term "pharmaceutically or nutraceutically acceptable" means any ingredient which is useful in the preparation of a pharmaceutical or nutraceutical composition, which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for a veterinary or human use.

The term “pharmaceutically or nutraceutically acceptable salts” of a compound means salts which are pharmaceutically or nutraceutically acceptable, as defined above, and which have the desired pharmacological activity of the parent compound. Such salts include:

(1) hydrates and solvates, (2) pharmaceutically or nutraceutically acceptable acid addition salts formed with pharmaceutically or nutraceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with pharmaceutically or nutraceutically acceptable organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphresulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, l glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid , methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, acid p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid and the like, or (3) the pharmaceutically or nutraceutically acceptable base addition salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, for example a metal ion alkaline, an alkaline earth metal ion or an aluminum ion; is coordinated with a pharmaceutically or nutraceutically acceptable organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

In the context of the present invention, the term "neurodegenerative disease" means a disease mainly involving a deterioration in the functioning, and possibly death, of nerve cells, and in particular of neurons. These diseases induce cognitive, behavioral, sensory and motor disorders.

According to a particular aspect, said neurodegenerative disease is chosen from: Alzheimer's disease, spinocerebellar ataxia, multisystematized atrophy, Alexander disease, Alpers disease, Creutzfeldt-Jakob disease, Huntington, Parkinson's disease, Pick's disease, macrophage myofasciitis, progressive supranuclear palsy, multiple sclerosis and amyotrophic lateral sclerosis.

In the context of the present invention, a neurodegenerative disease can be a neurodegenerative disease due to oxidative stress. This is particularly the case with Alzheimer's disease.

"Alzheimer's disease" (AD) is a disease that mainly affects people over the age of 65, suffering from various clinical symptoms such as progressive decline in memory, thinking, language and ability to learning. The toxic role of the βamyloid peptide (Αβ) has now gone from insoluble Αβ fibrils to smaller soluble aggregates of Αβ oligomers.

Soluble Αβ oligomers isolated from the cortex of patients with Alzheimer's disease have been shown to directly induce hyperphosphorylation of the Tau (T) protein and degeneration of neurites (Jin M, Shepardson N, Yang T, Chen G , Walsh D, Selkoe DJ. Soluble amyloid betaprotein dimers isolated from Alzheimer cortex directty induce Tau hyperphosphorytation and neuritic degeneration. Proc Natl Acad Sci US A. 2011 Apr 5; 108 (14): 5819-24). Thus, all substances having a property which reduces the neurotoxicity of the Αβ peptide may be useful as a new therapeutic agent for the treatment or prevention of Alzheimer's disease.

According to a particular aspect, the subject of the present invention is derivative compounds of PCQ esters, of general formula (IA) as defined above, in which Qi, Q3, Q4 and Qs represent, independently of each other, an atom of hydrogen or a caffeoyl group, provided that at least one of these radicals is not a hydrogen atom, for their use in the prevention and / or treatment of a neurodegenerative disease.

More particularly, a compound for its use in the prevention and / or treatment of a neurodegenerative disease according to the invention is characterized in that any two of the radicals Qi, Q3, Q4 and Qs represent a caffeoyl group, and the other two radicals represent a hydrogen atom.

According to a particular aspect, the compounds for their use according to the invention are characterized in that Qi represents a hydrogen atom, and more particularly in that Qi and Q4 each represent a hydrogen atom.

According to another particular aspect, the compounds for their use according to the invention are characterized in that R. is a C2-C15 alkyl group, advantageously a C2-C12 alkyl group, more advantageously a C2-C6 alkyl group, and even more advantageously a C2, C5 or C6 alkyl group, said groups possibly being substituted as mentioned previously.

According to a more particular aspect, the compounds for their use according to the invention are characterized in that Qi and Q4 represent a hydrogen atom, Q3 and Qs represent a caffeoyl group and R. is a C2-C6 alkyl group substituted by an —OH group, in particular R is a 2-hydroxypentyl group or a 2-hydroxy-hexyl group.

Among the compounds of formula (IA) for their use according to the present invention, there may be mentioned the ester derivatives of:

- 3-Caféoylquinic acid (Qi = Q4 = Qs = H and Q3 = coffeeoyl radical)

- 5-Caféoylquinic acid (Qi = Q3 = Q4 = H and Qs = coffeeoyl radical)

- 1,3-dicafeoylquinic acid (Q4 = Qs = H and Qi = Q3 = coffeeoyl radical)

- 1,4-Dicafeoylquinic acid (Q3 = Qs = H and Qi = Q4 = coffeeoyl radical)

- 1,5-dicaféoylquinique acid (Q3 = Q4 = H and Qi = Qs = coffeeoyl radical)

- 3,4-dicafeoylquinic acid (Qi = Qs = H and Q3 = Q4 = coffeeoyl radical)

- 3,5-dicafeoylquinic acid (Qi = Q4 = H and Q3 = Qs = coffeeoyl radical)

- 4,5-dicafeoylquinic acid (Qi = Q3 = H and Q4 = Qs = coffeeoyl radical)

- 1,3,4-tricaféoylquinique acid (Qs = H and Qi = Q3 = Q4 = coffeeoyl radical)

- 1,3,5-tricaféoylquinique acid (Q4 = H and Qi = Q3 = Qs = coffeeoyl radical)

- 1,4,5-tricaféoylquinique acid (Q3 = H and and Qi = Q4 = Q5 = coffeeoyl radical)

- 3,4,5-tricafeoylquinic acid (Qi = H and and Q3 = Q4 = Qs = coffeeoyl radical) and

- 1,3,4,5- tetracafeoylquinic acid and Qi = Q3 = Q4 = Q5 = coffeeoyl radical)

In particular, among the compounds of formula (IA) advantageous for their use according to the present invention, there may be mentioned the ester derivatives of:

- 1,3-dicaféoylquinique acid;

- 1,4-dicaféoylquinique acid;

- 1,5-dicaféoylquinique acid;

- 3,4-dicaféoylquinique acid;

- 3,5-dicaféoylquinique acid; and

- 4,5-dicaféoylquinique acid.

The compounds of general formula (IA) for their use according to the invention which are particularly advantageous are those characterized in that Qi and Q4 represent a hydrogen atom and Q3 and Qs represent a caffeoyl group, thus corresponding to the ester derivatives of the acid 3,5-dicaféoylquinique (3,5-DCQ).

Among the compounds advantageous for their use according to the present invention, mention may be made of the following ester derivatives:

- The ethyl ester of 3,5 di-caffeoylquinic acid (ethyl ester of DCQ), of formula VII below:

- The 2-hydroxy-pentyl ester of 3,5 di-caféoylquinic acid (2-HPE-DCQ), of formula VIII below:

and

- The 2-hydroxy-hexyl ester of 3,5 di-caffeoylquinic acid (2-HHE-DCQ), of formula IX below:

(IX)

According to a more particular aspect, the invention relates to compounds characterized in that Qi and Q4 each represent a hydrogen atom, and in that R. is a C2-C15 alkyl group, advantageously a C2-alkyl group -C6, their stereoisomers and their pharmaceutically or nutraceutically acceptable salts, for their use for the prevention and / or treatment of Alzheimer's disease.

According to another more particular aspect, the invention relates to compounds characterized in that Qi and Q4 each represent a hydrogen atom, Q3 and Qs each represent a caffeoyl group, and in that R. is an alkyl group in C2-C6, optionally substituted by a group -OH, in particular R is a 2-hydroxy-pentyl group or a 2-hydroxy-hexyl group, their stereoisomers and their pharmaceutically or nutraceutically acceptable salts, for their use for prevention and / or treatment of Alzheimer's disease.

In a particularly preferred manner, the subject of the invention is a compound chosen from: ethyl ester of 3,5 di-caféoylquinic acid, 2-hydroxy-pentyl ester of 3,5 di-caféoylquinic acid and 2-hydroxy-hexyl ester of 3,5 di-caffeoylquinic acid, for its use for the prevention and / or treatment of Alzheimer's disease.

According to a second aspect, the invention relates to compounds of general formula (IA)

(IA), in which

R represents a linear or branched, cyclic or cyclic branched, saturated or unsaturated C2-C _P alkyl group, which may be substituted by one or more of the following groups: -ORi, -NR1R2, -NO2, -CORi, -COORi , -CF ₃ , -CR1F2, -CR1R2F, = 0, -CN, halogen, -SRi, -SO2R1, aryl, in which

- p is a natural integer between 3 and 18,

-Ri and R2 are the same or different and each represents, independently of each other

- or a substituent chosen from the group comprising: -H, -OH, - NH2,

- NO2, -COOH, -CF ₃ , -CHF2, -CH2F, = 0, -CN, halogen, -SH, -SO2H,

either a linear or branched C2-C6 alkyl group, cyclic or cyclic branched, saturated or unsaturated, which may be substituted by one or more substituents chosen from the group comprising: -H, - OH, -NH2, -NO2,

- COOH, -CF3, -CHF2, -CH ₂ F, = 0, -CN, halogen, -SH, -SO2H, and

Qi, Q ₃ , Q4 and Qs each represent, independently of one another, a radical chosen from the group comprising: a hydrogen atom, a caféoyl, maloyl, caféoylmaloyl or maloylcaféoyl group, provided that at least one of these radicals is not a hydrogen atom, with the exception of the following compounds:

• Compounds of general formula (IB)

in which :

R.3 is a linear or branched C2-C6 alkoxyl, in particular an ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, npentoxy, isopentoxy and n-hexoxy group,

- R4, Rs and Rô are each independently chosen from: a group - OH and a group represented by the following formula (X):

in which R7 represents a group -OH and n is an integer between 1 and 5, with at least one of R4, Rs or R6 corresponding to said formula (X), • l- (2-hydroxypropoxy) propan-2- yl ester of cyclohexanecarboxylic acid, 3,5-bis [[(2 £) -3- (3,4-dihydroxyphenyl) -l-oxo20 2-propen-l-yl] oxy] -l, 4-dihydroxy- (lS, 3Æ, 4S, 5Æ) • l- (l-hydroxypropan-2-yloxy) propan-2-yl ester of cyclohexanecarboxylic acid, 3,5-bis [[(2 £) -3- (3, 4-dihydroxyphenyl) -l-oxo2-propen-l-yl] oxy] -l, 4-dihydroxy- (lS, 3Æ, 4S, 5Æ) • 2- (l-hydroxypropan-2-yloxy) propyl ester cyclohexanecarboxylic acid, 3,5-bis [[(2 £) -3- (3,4-dihydroxyphenyl) -l-oxo2-propen-l-yl] oxy] -l, 4-dihydroxy- (lS, 3Æ, 4S , 5Æ) • 2- (2-hydroxypropoxy) propyl ester of cyclohexanecarboxylic acid, 3,5-bis [[(2 £) -3- (3,4-dihydroxyphenyl) -l-oxo-2-propen-l -yl] oxy] -l, 4dihydroxy- (lS, 3Æ, 4S, 5Æ) • The ethyl ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen- l-yl] oxy] -l, 4,5-trihydroxy (1S, 3Æ, 4Æ, 5Æ) • The cyclohexanecarboxylic acid propyl ester, 3 - [[(2 £) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4,5-trihydroxy (1S, 3 / ?, 4Z?, 5 /?) • The 1-methylethyl ester of cyclohexanecarboxylic acid, 3 - [[(2 £) -3 (3,4-dihydroxyphenyl) -l-oxo-2-propen-l -yl] oxy] -l, 4,5-trihydroxy (1S, 3 / ?, 4Z?, 5 /?) • The butyl ester of cyclohexanecarboxylic acid, 3 - [[(2 £) -3- (3 , 4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4,5-trihydroxy (1S, 3 / ?, 4Z?, 5 /?) • Butyl ester of cyclohexanecarboxylic acid, 3 - [[(2 £) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4,5-trihydroxy (1Æ, 3S, 4S, 5S) • L ' octyl ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4,5-trihydroxy (lS, 3Æ, 4Æ, 5Æ) Acetic anhydride (1S, 3Æ, 4Æ, 5Æ) of cyclohexanecarboxylic acid 3 - [[3- (3,4-dihydroxyphenyl) -l-oxo-2-propenl-yl] oxy] -l, 4.5 -trihydroxy- (lS, 3Æ, 4Æ, 5Æ) • The dodecyl ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l , 4,5-trihydro xy (1S, 3 / ?, 4Z?, 5 /?) • 2-ethylhexyl ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl ] oxy] -l, 4,5-trihydroxy (1S, 3 / ?, 4Z?, 5 /?) • 2-methylhexyl ester of cyclohexanecarboxylic acid 3 - [[3- (3,4dihydroxyphenyl) -l- oxo-2-propen-l-yl] oxy] -l, 4,5-trihydroxy (1S, 3 / ?, 4Z?, 5 /?) • The hexadecyl ester of cyclohexanecarboxylic acid 3 - [[(2 £) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4,5-trihydroxy (1S, 3 /?, 4Z?, 5 /?) • L ' octadecyl ester of cyclohexanecarboxylic acid 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen-1-yl] oxy] -l, 4,5-trihydroxy (1S, 3R, 4R, 5R ' ) • The eicosyl ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4,5-trihydroxy (1S, 3R , 4R, 5R ') • The 2,3-butadien-1-yl ester of cyclohexanecarboxylic acid, 3 - [[((2 £) 3- [4- (2,3-butadien-l-yloxy) -3 -hydroxyphenyl] -l-oxo-2-propen-lyl] oxy] -l, 4,5-trihydroxy- (lS, 3Æ, 4Æ, 5Æ) • The phenylmethyl ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4dihydroxy phenyl) -l-oxo-2-propenyl] oxy] -l, 4,5-trihydroxy- (lS, 3Æ, 4Æ, 5Æ) • Le (2 £) -3,7-dimethyl-2,6-octadien- l-yl ester of cyclohexanecarboxylic acid, 3 - [[(2 £) -3- (3,4-dihydroxyphenyl) -l-oxo-2propen-l-yl] oxy] -l, 4,5-trihydroxy- (lÆ, 3S, 4S, 5Æ) • The 2-chloroethyl ester of cyclohexanecarboxylic acid, 1,3,4trihydroxy-5 - [[(2 £) -3- (4-hydroxy-3-methoxyphenyl) -l- oxo-2-propen-lyl] oxy] - (lÆ, 3Æ, 4S, 5Æ) • The ethyl ester of cyclohexanecarboxylic acid, 3,4-bis [[(2 £) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 5-dihydroxy- 1S, 3Æ, 4Æ, 5Æ) • The ethyl ester of cyclohexanecarboxylic acid, 3,5-bis [[(2 £) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4-dihydroxy (la, 3Æ, 4a, 5Æ) • The ethyl ester of cyclohexanecarboxylic acid , 3,4-bis [[(2 £) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 5-dihydroxy (1R, 3R, 4S, 5R ' ) • Cyclohexanecarboxylic acid anhydride 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen-1-yl] oxy] -l, 4,5-trihydroxy- and acid 3- (4-hydroxyphenyl) -2-p ropenoique (1S, 3Æ, 4Æ, 5Æ) • The butyl ester of cyclohexanecarboxylic acid, 3,5-bis [[(2 £) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l- yl] oxy] -l, 4-dihydroxy (1S, 3Æ, 4S, 5Æ) • The butyl ester of cyclohexanecarboxylic acid, 3,4-bis [[(2 £) -3- (3,4dihydroxyphenyl) -l -oxo-2-propen-1-yl] oxy] -l, 5-dihydroxy (1 / ?, 3S, 4S, 5S) • The propyl ester of cyclohexanecarboxylic acid, 3,5-bis [[3- (3 , 4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4-dihydroxy (1S, 3Æ, 4S, 5Æ) • (2E, 2'E) - ((lR, 2S, 3R, 5S) -2,5-dihydroxy-5 - ((3hydroxypropoxy) carbonyl) cyclohexane-1,3-diyl) bis (3- (3,4dihydroxyphenyl) acrylate) their isomeric stereos and their pharmaceutically or nutraceutically acceptable salts.

According to an advantageous embodiment of the invention, in the compounds of formula (IA) any two of the radicals Qi, Q3, Q4 and Qs represent a caffeoyl group, and the other two radicals represent a hydrogen atom.

According to an even more advantageous embodiment of the invention, in the compounds of formula (IA) Qi represents a hydrogen atom, and more particularly Qi and Q4 each represent a hydrogen atom.

According to another even more advantageous embodiment of the invention, in the compounds of formula (IA) Qi, Q3, Q4 and Qs each represent, independently of one another, a hydrogen atom or a caffeoyl group , provided that at least one of these radicals is not a hydrogen atom.

According to another particular aspect, a compound according to the invention is characterized in that R is a C2-C15 alkyl group, advantageously a C2-C12 alkyl group, more advantageously a C2-C6 alkyl group, and even more advantageously a C2, Cs or C6 alkyl group.

According to a more particular aspect, a compound according to the invention is characterized in that Qi and Q4 represent a hydrogen atom, Q3 and Qs represent a caffeoyl group and R is a C2-C6 alkyl group substituted by a -OH group , and in particular R is a 2-hydroxypentyl group or a 2-hydroxyhexyl group.

Among the advantageous compounds according to the present invention, the following ester derivatives may be mentioned:

- The 2-hydroxy-pentyl ester of 3,5 di-caffeoylquinic acid (2-HPE-DCQ), of formula VIII, and

- The 2-hydroxy-hexyl ester of 3,5 di-caffeoylquinic acid (2-HHE-DCQ), of formula IX.

The compounds of general formula (IA) according to the invention are prepared by the implementation of an esterification process of an acid function with an appropriate alcohol according to the methods known to those skilled in the art. Said method preferably comprises a step during which a polysubstituted quinic acid (QPS) reacts with an alcohol of formula R-OH.

According to this method, said QPS is a PCQ, advantageously chosen from 3-caffeoylquinic acid, 3,5-DCQ, 3,4-DCQ, 4,5-DCQ, 3,4,5-TCQ and TetraCQ, advantageously the PCQ is 3,5-DCQ, 3,4-DCQ, 4,5-DCQ, more advantageously the PCQ is 3,5-DCQ.

The inventors have developed a process for the preparation of QPS ester derivatives in one step by hemi-synthesis from a particular QPS allowing the ester derivatives of this QPS to be obtained in the form of a single regioisomer. This preparation process used corresponds to the esterification reaction described in the article by Hanessian et al. (2001) (Stephen Hanessian, Hoan K Huynh, Gurijala V Reddy, Rudolph O Duthaler, Andréas Katopodis, Markus B Streiff, Willy Kinzy, Reinhold Oehrlein. Synthesis of Gai determinant epitopes, their glycomimetic variants, and trimeric clusters — reievance to tumor associated antigens and to discordant xenografts. Tetrahedron, April 16, 2001, Volume 57, Issue 16, Pages 3281-3290).

The alcohol is chosen from alcohols of formula R-OH, in which R represents a linear or branched, cyclic or cyclic branched, saturated or unsaturated C2-C alkyl group _P , where p is a natural integer between 3 and 18 , said group possibly being substituted by one or more substituents chosen from the group comprising: -ORi, -NR1R2, -NO2, -CORi, -COORi, -CF3, -CR1F2, -CR1R2F, = 0, CN, halogen, -SRi , -SO2R1, aryl, where Ri and R2 are identical or different and represent, each independently of the other, either an alkyl group in

C2-C6 linear or branched, cyclic or cyclic branched, saturated or unsaturated, which can be substituted by one or more substituents chosen from the group comprising: -H, -OH, -NH ₂ , -NOz, - COOH, -CF3, - CHF2, -CH2F, = 0, -CN halogen, -SH, -SO2H, or a substituent chosen from the group comprising: H, -OH, -NH ₂ , -NOz, -COOH, -CF ₃ , -CHF2, - CH2F, = 0, -CN, halogen, -SH, -SO2H.

More particularly, the alcohol is chosen from the alcohols of formula R-OH, in which R. represents a C2-C15 alkyl group, advantageously a C2-C12 alkyl group, more advantageously a C2-C6 alkyl group, and even more advantageously a C2, C5 or C6 alkyl group.

Even more particularly, the alcohol is chosen from the alcohols of formula ROH, in which R is a C2-C6 alkyl group substituted by a group -OH, and in particular R is a 2-hydroxy-pentyl group or a group 2- hydroxyhexyl.

Even more preferably, the alcohol is chosen from: ethanol, 2hydroxy-pentan-1-ol and 2-hydroxy-hexan-1-ol.

In one embodiment of the invention, the step of the method during which a QPS, advantageously a PCQ, more advantageously 3,5-DCQ reacts with an alcohol compound of formula R-OH is optionally preceded by a step d activation of the carboxyl group of a QPS, in particular of PCQ, and more particularly 3,5-DCQ, in particular by an agent for activating carboxyl groups, such as l- (3-dimethylaminopropyl) -3-ethylcarbodiimide in combination with 1-hydroxybenzotriazole hydrate.

By “agent for activating the carboxyl group” is meant according to the present invention any reagent or combination of reagents making it possible to activate the carboxylic acid function to allow its coupling with a nucleophile under mild reaction conditions. By way of example and in a non-exhaustive manner, mention may be made of activating agents from the carbodiimide family such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), N-ethylN (3-dimethylaminopropyl) carbodiimide (EDCI) alone or in combination with alcohols allowing the transient formation of activated esters such as, for example, 1-hydroxybenzotriazole (HOBT), l-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxysuccinimide (HOSu) or even l 'ethyl (hydroxyimino) cyanoacetate. The activating agent which can be used can also be part of the family of phosphonium, uronium and / or guanidinium salts. By way of example, mention may be made of benzotriazol-1yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (BOP), benzotriazol-l-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), (l-Cyano-2-ethoxy-2-oxoethylidenaminooxy ) dimethylamino-morpholinocarbenium hexafluorophosphate (COMU), N, N, N ', N' -Tetra methy 1-0- (1Hbenzotriazol-l-yl) uronium hexafluorophosphate (HBTU), (O- (6-Chloro-lhydrocibenzotriazol-l- yl) -l, l, 3,3-tetramethyluronium tetrafluoroborate) (TCTU), (2- (7-Aza-1H-benzotriazole-l-yl) -l, l, 3,3-tetramethyluronium hexafluorophosphate) (HATU).

More particularly, the agent for activating the carboxyl groups is chosen from diisopropylcarbodiimide (DIC) and 1-hydroxybenzotriazole (HOBT).

The processes for preparing the compounds according to the invention may optionally include additional steps of protection and / or deprotection in order to avoid side reactions well known to those skilled in the art, or in order to avoid the formation of several regioisomers of the compounds according to the invention.

The compounds obtained by the methods according to the invention can also be purified by methods known to those skilled in the art. Mention may be made, for example, of purification methods by crystallization, by chromatography or by extraction.

In a third aspect, the invention therefore relates to a compound of general formula (IA)

with the exception of the compounds of general formula (IB)

in which :

- R.3 is a linear or branched C2-C6 alkoxyl chain, in particular an ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, isobutoxy, tertbutoxy, n-pentoxy, isopentoxy, n-hexoxy group;

- R4, Rs and Rô are each independently chosen from: a group - OH and a group represented by the following formula (X):

in which R7 represents a linear or branched -OH or C2-C6 alkoxy group and n is an integer between 1 and 5, with at least one of R4, Rs or R6 corresponding to said formula (X), or its salts and stereo isomers pharmaceutically or nutraceutically acceptable, for use as a medicament.

According to a more particular aspect, the present invention relates to compounds of general formula (IA):

(ΙΑ), in which R, Qi, Q3, Q4 and Qs are as defined above, or its pharmaceutically or nutraceutically acceptable salts and stereo isomers, for their use as a medicament for the prevention and / or treatment of neurodegenerative disease, including Alzheimer's disease.

The invention also relates to a method of preventing and / or treating a neurodegenerative disease, in particular one of the diseases mentioned above, comprising the administration of a therapeutically effective amount of at least one compound of formula (IA) according to the invention to a patient in need thereof. More particularly, the subject of the invention is a method of prevention and / or treatment of Alzheimer's disease, comprising the administration of a therapeutically effective amount of at least one compound of formula (IA) according to the invention to a patient in need thereof, and comprising in particular the administration of a compound chosen from: ethyl ester of 3,5 di-caffeoylquinic acid, 1-hydroxy-pentyl ester of 3,5 di acid -caféoylquinique and the 2-hydroxy-hexyl ester of 3,5 di-caféoylquinique acid.

The present invention also relates to a pharmaceutical composition comprising as active agent at least one compound or a mixture of compounds of general formula (IA) in which R, Qi, Q3, Q4 and Qs are as defined above , or its pharmaceutically acceptable salts and stereoisomers, and advantageously a pharmaceutically acceptable excipient.

The optimal modes of administration, the dosages and the galenical forms of a pharmaceutical composition according to the invention can be determined according to the criteria generally taken into account in the establishment of a pharmaceutical treatment adapted to a subject such as for example the age or body weight of the patient, severity of his general condition, tolerance to treatment, observed side effects, skin type. Depending on the type of administration desired, the pharmaceutical composition according to the invention may also comprise at least one pharmaceutically acceptable excipient. The pharmaceutical composition according to the present invention may also comprise at least one adjuvant pharmaceutically known to those skilled in the art, chosen from thickeners, preservatives, perfumes, dyes, chemical or mineral filters, hydrating agents, waters spas, etc.

Advantageously, the pharmaceutical composition comprises at least one compound of general formula (IA) according to the invention in an amount between 0.01 and 10%, in particular between 0.05 and 5%, more particularly between 0.1 and 2 %, by weight relative to the total weight of the composition.

The pharmaceutical composition is particularly suitable for oral, nasal, transdermal, parenteral, topical, rectal, and mucosal administration. It can be in dry form, such as for example: soft capsule, capsule, tablet, lyophilisate, powder, granule, or patch, or in liquid form, such as: solution, suspension, spray, cream or gel.

The pharmaceutically acceptable excipient is known to those skilled in the art and is chosen according to the mode of administration of the pharmaceutical composition. By way of example, the pharmaceutically acceptable excipient can be chosen from the group consisting of diluents, binders, disintegrants, dyes, lubricants, solubilizing agents, absorption-promoting agents, film-forming agents, gelling agents , and mixtures thereof.

The pharmaceutical composition according to the invention may also comprise at least one compound chosen from the group consisting of emollients, moisturizing active agents, activators of keratin synthesis, keratorregulators, keratolytics, agents which restructure the skin barrier ( activators of skin lipid synthesis, agonists PPARs or Peroxysome Proliferator Activated Receptor), activators of keratinocyte differentiation (retinoids, calcidone®, calcium), antibiotics, antibacterial agents, antifungal compounds, anti-viral agents , sebum regulators, immunomodulators, such as tacrolimus, pimecrolimus, oxazolines, preservatives, anti-irritant agents, soothing agents, filters and sunscreens, anti-oxidant agents, growth factors, agents healing or eutrophic molecules, drugs and anti-Alzheimer's agents.

The present invention also relates to a pharmaceutical composition according to the invention for its use in the prevention and / or treatment of neurodegenerative diseases, in particular Alzheimer's disease.

A subject of the invention is also a method of prevention and / or treatment, in particular of neurodegenerative diseases, in particular of one of the diseases mentioned above, and in particular Alzheimer's disease, comprising the administration of an amount therapeutically effective of a pharmaceutical composition according to the invention to a patient in need thereof.

The present invention also relates to a nutraceutical composition comprising a compound of formula (IA) according to the invention, and advantageously a nutraceutically acceptable excipient, for improving cognitive functions in a patient suffering from a neurodegenerative disease, and in particular Alzheimer's disease. .

The following examples and Figures 1 and 2 are intended to illustrate the present invention, without however limiting its scope.

EXAMPLES

Example 1: Hemisynthesis of 3,5-DCQ ester derivatives from 3,5DCQ (isochlorogenic acid A)

The esters: 3,5-DCQ ethyl ester, 3,5-DCQ 2-hydroxy-pentyl ester and 3,5-DCQ 2-hydroxy-hexyl ester are prepared according to the esterification reaction, the protocol of which is described in l article by Hanessian et al. (2001) previously cited. The starting reagents are 3,5-DCQ and the corresponding alcohol, either ethanol, 2-hydroxy-pentan-1-ol or 2-hydroxy-hexanl-ol. The esterification is preceded by a step of activating the carboxyl group of 3,5-DCQ with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (EDCI) in combination with the hydrate 1-hydroxybenzotriazole (HOBT).

3,5-DCQ is dissolved in a mixture of dichloromethane and dimethylformamide. The HOBT is added in stoichiometric quantity at 0 ° C., followed by an addition of EDCI. Two equivalents of alcohol are then added and the solution is stirred at room temperature for 18 hours.

Example 2 Effect of a DCQ ester on the survival of primary cortical neurons and on a neurite network of primary cortical neurons injured by the Αβ peptide.

The aim of this study is to assess the effects of 3,5-DCQ ester derivatives on primary rat cortical neurons, intoxicated by the Αβ peptide according to the in vitro model of Alzheimer's disease described in Callizot et al ( 2013). The survival of neurons, the neurite network, astrocytes and the potential proliferation of astrocytes are assessed.

2.1. Materials and methods

Compounds tested

The esters tested are as follows:

• 3,5-DCQ ethyl ester • 3,5-DCQ 2-hydroxy-pentyl ester (2-HPE-DCQ) • 3,5-DCQ 2-hydroxy-hexyl ester (2-HHE -DCQ)

Four concentrations are tested: 10 nM, 100 nM, 1 μΜ and 10 μΜ. The vehicle used is the culture medium (see section below) containing 0.1% DMSO (Pan Biotech, Batch: H130813). In parallel, the 3.5 DCQ acid is tested under the same conditions.

Cell culture of cortical neurons

Rat cortical neurons are cultured as described in Singer C, Figueroa-Masot X, Batchelor R, Dorsa D. Mitogen-activated protein kinase pathway mediates estrogen neuroprotection after glutamate toxicity in primary cortical neurons. J Neurosci. 1999, 19: 2455-2463 and Callizot et al (2013). In summary, pregnant female rats are killed by cervical dislocation after 15 days of gestation. The fetuses are collected and immediately placed in an ice-cold L15 Leibovitz medium (Pan Biotech, Batch: 8810315) supplemented with 2% penicillin (10,000 U / ml) and a streptomycin solution (10 mg / ml) (PS; Pan Biotech , batch: 1451013) and 1% bovine serum albumin (BSA; Pan Biotech, batch: K180713). The cortex is treated for 20 min at 37 ° C. with a solution of trypsin-EDTA (Pan Biotech, Batch: 3330914) at a final concentration of 0.05% trypsin and 0.02% EDTA. Dissociation is stopped by adding DMEM medium (Dulbecco's modified Eagle's medium) with 4.5 g / L of glucose (Pan Biotech, Batch: 8530315), containing DNAse I grade II (final concentration 0.5 mg / ml; Pan Biotech, Batch: H140508) and 10% fetal calf serum (FCS; Invitrogen, Batch: 41Q1613K). The cells are mechanically dissociated by three forced passages through 10 ml pipette tips. The cells are then centrifuged at 515 g for 10 min at 4 ° C. The supernatant is discarded, and the residue is suspended in a defined culture medium consisting of a Neurobasal medium (Invitrogen, batch: 1715722) with a 2% solution of supplement B27 (Invitrogen, batch: 1709534), 2 mmol / L of Lglutamine (Pan Biotech, lot: 6620314), 2% PS solution, and 10 ng / ml of neurotrophic factor derived from the brain (BDNF; Pan Biotech, Batch: H140108). Viable cells are counted with a Neubauer cytometer, using the trypan blue exclusion test. The cells are seeded at a density of 30,000 per 96-well plate pre-coated with poly-L-lysine (Biocoat, Batch: 21614030) and are cultured at 37 ° C in an incubator containing 95% air and 5% CO2. The environment is changed every day. After 11 days of culture, the cortical neurons are intoxicated by a solution of Αβ peptides (see below).

Preparation of the Αβ1-42 peptide and exposure of the ester to the peptide

The preparation of the Αβ1-42 peptide is carried out according to the procedure described in Callizot et al (2013). In summary, the peptide Αβ1-42 (Bachem, Batch: 1014012) is dissolved in the defined culture medium mentioned above, devoid of serum, at an initial concentration of 40 pmol / L. This solution is gently stirred for 3 days at 37 ° C. in the dark and immediately used after having been diluted in the culture medium to the concentration tested (20 μΜ).

On the eleventh day of culture, the ester tested at the 4 different concentrations is dissolved in the culture medium and is then preincubated with the primary cortical neurons for 1 hour before the application of the peptide Αβ1-42. The Αβ1-42 peptide solution is added to a final concentration of 20 μΜ diluted in the culture medium in the presence of the ester and the whole is left for 24 h. In parallel, 3,5 di-caffeoylquinic acid is tested under the same conditions.

Evaluation of the survival of neurons, the neurite network and astrocytes hours after poisoning by the parβ1-42 peptide, the cell culture supernatant was removed and the cultures of cortical neurons were fixed with a cold ethanol solution ( 95%, Sigma, Batch: SZBD3080V) and acetic acid (5%, Sigma, Batch: SZBD1760V) for 5 min at -20 ° C. After permeabilization with 0.1% saponin (Sigma, Batch: BCBJ8417V), the cells are incubated for 2 h:

a) with an anti microtubule-associatedprotein 2 monoclonal mouse antibody (MAP-2, (Callizot N, Combes M, Steinschneider R, Poindron P. A new long term in vitro model of myelination. Experimental Cell Research, October 2011. Volume 317 , Issue 16, Pages 2374-2383), Sigma, batch: 063M4802) diluted 1/400 in PBS (PAN, Batch: 1870415) containing 1% fetal calf serum (FCS) and 0.1% saponin (this antibody specific to cell bodies and neurites allows the study of the death of neuronal cells as well as the effect of the ester on the growth of neurites) for 2 hours at room temperature,

b) with a rabbit polyclonal antibody to glial fibrillar acid protein (GFAP, Sigma, Batch: 083M4830) at a dilution of 1/400 in PBS containing 1% FCS, 0.1% saponin, for 2 h at room temperature. This antibody is specific for astrocytes.

These antibodies are revealed by an anti-mouse goat IgG marked with an Alexa Fluor 488 (Molecular Probe, Batch: 1664729) and a anti-rabbit goat IgG marked with an Alexa Fluor 568 (Molecular Probe, Batch: 1386541). 1/400 dilution in PBS containing 1% FCS, 0.1% saponin, for 1 h at room temperature.

The ester is tested for a culture. For each ester concentration and the controls, 6 wells are evaluated, 30 photos per plate are taken using ImageXpress (Molecular Devices) with 20x magnification, to evaluate the neurite network, the number of neurons and the number of astrocytes . Photo analysis is performed using the Custom Module Editor (Molecular Devices). The results are presented in terms of the number of positive cells or neurite network labeled by given marker (MAP-2, GFAP).

Each line of the plate is organized as follows:

No treatment (negative control) / 0.1% DMSO

Peptide β Amyloid 1-42 20 μΜ (positive control) / 0.1% DMSO

Peptide β Amyloid 1-42 20 μΜ + product 10 nM / 0.1% DMSO

Peptide β Amyloid 1-42 20 pM + product 100 nM / 0.1% DMSO

Peptide β Amyloid 1-42 20 pM + product 1 pM / 0.1% DMSO

Peptide β Amyloid 1-42 20 pM + product 10 pM / 0.1% DMSO

Each line is repeated 6 times.

Statistical analysis

All data are expressed as a percentage of the condition check (control = 100%). All values are expressed as mean +/- standard error of the mean (Standard Error of the Mean SEM) (s.e.mean) of n = 6 wells per condition. The statistical analyzes performed for the different conditions are analyzes of variances or ANOVA followed by the Fischer PLSD test or the Dunnett test using the GraphPad Prism software.

2.2. Results

Figures IA to 1D show the survival, in percentage of living neurons compared to the control, of primary cortical neurons intoxicated for 24 hours by the peptβ1-42 peptide added at a final concentration of 20 μΜ, in the presence of acid 3 respectively , 5 di-caféoylquinique (Fig. IA), ethyl ester of 3,5 di-caféoylquinic acid (Fig. IB), 2-hydroxy-pentyl ester of 3,5 di-caféoylquinic acid (2 -HPE-DCQ) (Fig. IC) or 2-hydroxy hexyl ester of 3,5 di-caffeoylquinic acid (2-HHE-DCQ) (Fig. 1D) at concentrations varying from 10 nM to 10 μΜ. On each of the histograms, the neuronal survival, in percentage of the control is indicated with, from left to right: the positive control, the control in the presence of Αβ1-42 peptide, and the molecule tested, at the respective concentrations of 10 nM, 100 nM, 1 pM and 10 pM.

FIGS. 2A to 2D show the growth of the neurite network intoxicated for 24 h by the peptide of Αβ1-42 added at a final concentration of 20 pM, in the presence respectively of 3.5 dicafeoylquinic acid (FIG. 2A), 3,5-DCQ ethyl ester (Fig. 2B), 2-HPE-DCQ (Fig. 2C) or 2-HHE-DCQ (Fig. 2D) at concentrations varying from 10 nM to 10 pM. On each of the histograms, the neurite network, in percentage of the control is indicated with, from left to right: the positive control, the control in the presence of Αβ1-42 peptide, and the molecule tested, at the respective concentrations of 10 nM, 100 nM, 1 pM and 10 pM.

These data make it possible to check the state of health of cortical neurons, because the stress caused by Alzheimer's pathology through the peptide Αβ1-42 affects the number of neuronal connections (neurites).

The control witness was not treated with the peptide Αβ1-42. Only the vehicle (the culture medium containing 0.1% DMSO) was added to the cell culture of cortical neurons. We observe 100% survival of neurons in this condition.

The addition of the peptide Αβ1-42 to a final concentration of 20 μΜ induces after 24 hours a significant death of the neurons (Figures 1A-1D) as well as a significant loss of the neurite network (Figures 2A-2D) as previously indicated in the literature (Callizot et al., 2013).

The 3,5-DCQ acid pre-incubated for one hour before the addition of the Αβ1-42 peptide shows a significant effect on the neurite network at its lowest concentration (10 nM, Figure 2A), and a strong neuroprotective effect and significant at all its concentrations (Figure IA). On the contrary, no effect (neither protective nor on proliferation) was observed on astrocytes (results not shown).

The 3,5-DCQ ethyl ester pre-incubated one hour before the addition of the Αβ1-42 peptide shows a significant effect on the neurite network at its lowest concentration (10 nM, Figure 2B) and a neuroprotective effect strong and significant at all concentrations (Figure IB). A marginal protective effect of astrocytes was observed only for the concentration of 100 nM. On the contrary, no effect (neither protective nor on proliferation) was observed for the other concentrations (results not shown).

The 2-hydroxy-pentyl ester of 3,5-DCQ (2-HPE-DCQ) pre-incubated one hour before the addition of the Αβ1-42 peptide shows a strong and significant effect on the survival of neurons at all tested concentrations (Figure IC). In particular, the strongest protective effect on neuron survival was observed at 1 pM (Figure IC). At this concentration the protection is total (no neuronal death has been observed). The protective effect follows a bell-shaped curve. At the highest concentration of 10 μΜ, although a protective effect is still observed on the neurite network, no additional protective effect was observed on the survival of the neurons. 2-HPE-DCQ pre-incubated one hour before the addition of the peptβ1-42 peptide shows a significant effect on the neurite network at its two highest concentrations (1 pM and 10 pM, Figure 2C). No effect (neither protective nor on proliferation) was observed on astrocytes (results not shown).

The 2-hydroxy-hexyl ester of 3,5-DCQ (2-HHE-DCQ) pre-incubated one hour before the addition of the Αβί-42 peptide shows a protective effect on the neurite network at all the concentrations tested except at the lowest concentration (10 nM) (Figure 2D).

These results show that 3,5-DCQ ethyl ester and 2-HPE-DCQ allow complete protection of cultured neurons in vitro poisoned by the Αβί-42 peptide. A significant effect on the neurite network was observed for the lowest concentrations. In addition, a significant significant effect was observed on the survival of primary cortical neurons.

The 3,5-DCQ esters tested, that is to say the 3,5-DCQ ethyl ester, the 3,5-DCQ 2hydroxy-pentyl ester and the 3-hydroxy-hexyl ester of 3, 5-DCQ are therefore good candidates for the protection of cortical neurons, the maintenance of their connections, ie less disorganization of the neurite network, without causing cellular multiplications. Thus, compared with already existing compounds such as the various isomers of dicaféoylquinique acids, these compounds are of interest as new therapeutic agents for the prevention or the treatment of a neurodegenerative disease, and in particular Alzheimer's disease. The higher activity of QPS ester derivatives compared to unmodified QPS can be explained in particular by an improvement in the bioavailability of the molecule, or by the fact that the addition of the radical R. to QPS makes it possible to create new interactions with the active sites of biological targets.

Claims (9)

1. Compounds of general formula (IA) in which R represents a linear or branched, cyclic or branched, saturated or unsaturated C2-C _p alkyl group, said group possibly being substituted by one or more substituents chosen from the group comprising: -ORi, -NR1R2, -NO2, 10 -CORi, -COORi, -CF3, -CR1F2, -CR1R2F, = 0, -CN, halogen, -SRi, -SO2R1, aryl, in which - p is a natural integer between 3 and 18, - Ri and R2 are identical or different and each represents, independently of one another, - or a substituent chosen from the group comprising: -H, -OH, -NH2, -NO2, -COOH, - CF ₃ , -CHF2, -CH ₂ F, = 0, -CN, halogen, -SH, -SO2H, - or a linear or branched C2-C6 alkyl group, cyclic or cyclic branched, saturated or unsaturated, which may be substituted by a 20 or more substituents chosen from the group comprising: -H, -OH, -NH2, -NO2, -COOH, -CF ₃ , -CHF2, -CH2F, = 0, -CN, halogen, -SH, -SO2H, and Qi, Q3, Q4 and Qs each represent, independently of one another, a radical 25 selected from the group comprising a hydrogen atom, a caféoyl, maloyl, caféoylmaloyl or maloylcaféoyl group, provided that at least one of these radicals is not a hydrogen atom, their stereoisomers and their pharmaceutically or nutraceutically acceptable salts , for their use in the prevention and / or treatment of a neurodegenerative disease. 2. Compounds for their use according to claim 1, characterized in that any two of the radicals Qi, Q ₃ , Q4 and Qs represent a caffeoyl group, and the other two radicals represent a hydrogen atom. 3. Compounds for their use according to any one of claims 1 or 2, characterized in that they are chosen from the following group: - The ethyl ester of 3,5 di-caféoylquinic acid - The 2-hydroxy-pentyl ester of 3,5 di-caféoylquinic acid, and - The 2-hydroxy-hexyl ester of 3,5 di-caféoylquinic acid. 4. Compounds for their use according to any one of claims 1 to 3, characterized in that said neurodegenerative disease is chosen from: Alzheimer's disease, spinocerebellar ataxia, multisystematized atrophy, Alexander disease, Alpers disease, Creutzfeldt-Jakob disease, Huntington's disease, Parkinson's disease, Pick's disease, macrophage myofasciitis, progressive supranuclear palsy, multiple sclerosis and amyotrophic lateral sclerosis. 5. Compounds of general formula (IA) in which R represents a linear or branched, cyclic or cyclic branched, saturated or unsaturated C2-C _p alkyl group, which can be substituted by one or more of the following groups: -ORi, -NR1R2, -NO2, -CORi, -COORi , - CF3, -CR1F2, -CR1R2F, = 0, -CN, halogen, -SRi, -SO2R1, aryl in which p is a natural integer between 3 and 18, Ri and R2 are identical or different and each represents, independently of one another, - or a substituent chosen from the group comprising: -H, -OH, -NH ₂ , -NO2, -COOH, -CF ₃ , -CHF ₂ , -CH2F, = 0, -CN, halogen, -SH, - SO ₂ H, - either a linear or branched C2-C6 alkyl group, cyclic or cyclic branched, saturated or unsaturated, which may be substituted by one or more substituents chosen from the group comprising: -H, -OH, -NH ₂ , -NO2, - COOH, -CF ₃ , -CHF ₂ , -CH ₂ F, = 0, -CN, halogen, -SH, -SO2H, and Qi, Q3, Q4 and Qs each represent, independently of one another, a hydrogen atom, a caféoyl, maloyl, caféoylmaloyl or maloylcaféoyl group, provided that at least one of these radicals is not an atom of hydrogen, with the exception of the following compounds: • The compounds of general formula (IB) in which: R ₃ is a linear or branched C2-C6 alkoxyl, in particular an ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, te / T-butoxy, npentoxy, isopentoxy and n-hexoxy group, - R ₄ , Rs and Rô are each independently chosen from: a group - OH and a group represented by the following formula (X): (X) in which R7 represents a group -OH and n is an integer between 1 and 5, with at least one of R4, Rs or R6 corresponding to said formula (X). • The 1- (2-hydroxypropoxy) propan-2-yl ester of cyclohexanecarboxylic acid, 3,5-bis [[(2E) -3- (3,4-dihydroxyphenyl) -l-oxo2-propen-l- yl] oxy] -l, 4-dihydroxy- (lS, 3R, 4S, 5Æ) • The l- (l-hydroxypropan-2-yloxy) propan-2-yl ester of cyclohexanecarboxylic acid, 3,5-bis [[(25) -3- (3,4-dihydroxyphenyl) -l-oxo2-propen-l-yl] oxy] -l, 4-dihydroxy- (lS, 3Æ, 4S, 5Æ) • Le 2- (l -hydroxypropan-2-yloxy) propyl ester of cyclohexanecarboxylic acid, 3,5-bis [[(2E) -3- (3,4-dihydroxyphenyl) -l-oxo2-propen-1-yl] oxy] -l , 4-dihydroxy- (lS, 3R, 4S, 5Æ) • 2- (2-hydroxypropoxy) propyl ester of cyclohexanecarboxylic acid, 3,5-bis [[(25) -3- (3,4-dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4dihydroxy- (lS, 3R, 4S, 5R) • Cyclohexanecarboxylic acid ethyl ester, 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen-1-yl] oxy] -l, 4,5-trihydroxy (1S, 3R, 4Æ , 5R) • The propyl ester of cyclohexanecarboxylic acid, 3 - [[(2E) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4,5- trihydroxy (1S, 3R, 4R, 5R) • The 1-methylethyl ester of cyclohexanecarboxylic acid, 3 - [[(2E) -3 (3,4-dihydroxyphenyl) -l-oxo-2-propen-l-yl ] oxy] -l, 4,5-trihydroxy (1S, 3Æ, 4 / ?, 5R) • The butyl ester of cyclohexanecarboxylic acid, 3 - [[(2 £ F) -3- (3,4dihydroxyphenyl) - l-oxo-2-propen-l-yl] oxy] -l, 4,5-trihydroxy (1S, 3 / ?, 4R, 5R) • The butyl ester of cyclohexanecarboxylic acid, 3 - [[(2ZF) - 3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4,5-trihydroxy (1Æ, 3S, 4S, 5S) • Octo ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4,5-trihydroxy (lS, 3Æ, 4Æ, 5R) Acetic anhydride (1S, 3R , 4R, 5R) of cyclohexan acid ecarboxylic 3 - [[3- (3,4-dihydroxyphenyl) -l-oxo-2-propenl-yl] oxy] -l, 4,5-trihydroxy- (lS, 3Æ, 4Æ, 5Æ) • The dodecyl ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4,5-trihydroxy (lS, 3R _t 4R, 5R) • Le 2-ethylhexyl ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4,5-trihydroxy (1S, 3R, 4R , 5R) • The 2-methylhexyl ester of cyclohexanecarboxylic acid 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4,5-trihydroxy (1S , 3 / ?, 4R, 5R) • The hexadecyl ester of cyclohexanecarboxylic acid 3 - [[(2F) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] - 1,4,5-trihydroxy (1S, 3R, 4R, 5R) • The octadecyl ester of cyclohexanecarboxylic acid 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4,5-trihydroxy (1S, 3R, 4R, 5Æ) • The eicosyl ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen- l-yl] oxy] -l, 4,5-trihydroxy (1S, 3R, 4R, 5R) • 2,3-butadien-l-yl ester of cyclo acid hexanecarboxylic, 3 - [[(2E) 3- [4- (2,3-butadien-l-yloxy) -3-hydroxyphenyl] -l-oxo-2-propen-lyl] oxy] -l, 4.5- trihydroxy- (lS, 3R, 4Æ, 5Æ) • The phenylmethyl ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4dihydroxyphenyl) -l-oxo-2-propenyl] oxy] -l, 4,5- trihydroxy- (lS, 3R, 4Æ, 5Æ) • The (2f) -3,7-dimethyl-2,6-octadien-l-yl ester of cyclohexanecarboxylic acid, 3 - [[(2E) -3- ( 3,4-dihydroxyphenyl) -l-oxo-2propen-l-yl] oxy] -l, 4,5-trihydroxy- (l / ?, 3S, 4S, 5Æ) • The 2-chloroethyl ester of cyclohexanecarboxylic acid , 1,3,4trihydroxy-5 - [[(2E) -3- (4-hydroxy-3-methoxyphenyl) -l-oxo-2-propen-lyl] oxy] - (lÆ, 3 / ?, 4S, 5Æ ) • The ethyl ester of cyclohexanecarboxylic acid, 3,4-bis [[(2E) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen-1-yl] oxy] -l, 5- dihydroxy- 1S, 3R, 4R, 5R) • The ethyl ester of cyclohexanecarboxylic acid, 3,5-bis [[(2E) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l- yl] oxy] -l, 4-dihydroxy (la, 3R, 4a, 5Æ) • The ethyl ester of cyclohexanecarboxylic acid, 3,4-bis [[(2E) -3- (3,4dihydroxyphenyl) -l -oxo-2-pr open-l-yl] oxy] -l, 5-dihydroxy (1 / ?, 3R, 4S, 5R) • Cyclohexanecarboxylic acid anhydride 3 - [[3- (3,4dihydroxyphenyl) -l-oxo- 2-propen-l-yl] oxy] -l, 4,5-trihydroxy- and 3- (4-hydroxyphenyl) -2-propenoic acid (1S, 3R, 4R, 5R) • The butyl ester of l cyclohexanecarboxylic acid, 3,5-bis [[(2E) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen-1-yl] oxy] -l, 4-dihydroxy (1S, 3R, 4S, 5R) • The butyl ester of cyclohexanecarboxylic acid, 3,4-bis [[(2F) -3- (3,4dihydroxyphenyl) -l-oxo-2-propen-1-yl] oxy] -l, 5- dihydroxy (1R, 3S, 4S, 5S) • The propyl ester of cyclohexanecarboxylic acid, 3,5-bis [[3- (3,4dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l , 4-dihydroxy (1S, 3Æ, 4S, 5R) • Le (2E, 2'E) - ((lR, 2S, 3R, 5S) -2,5-dihydroxy-5 - ((3hydroxypropoxy) carbonyl) cyclohexane- 1,3-diyl) bis (3- (3,4dihydroxyphenyl) acrylate), their stereoisomers and their pharmaceutically or nutraceutically acceptable salts. 6. Compounds according to claim 5, characterized in that any two of the radicals Qi, Q3, Q4 and Q5 represent a caffeoyl group, and the other two radicals represent a hydrogen atom. 7. Compounds according to claim 5 or 6, characterized in that they are chosen from the following group: - The 2-hydroxy-pentyl ester of 3,5 di-caféoylquinic acid, and - The 2-hydroxy-hexyl ester of 3,5 di-caféoylquinic acid. 8. Compounds according to any one of claims 5 to 7, intended for use as a medicament. 9. Pharmaceutical composition comprising at least one compound according to one 10 any of the claims pharmaceutically acceptable. 5 at 7, and at less an excipient 10. Nutraceutical composition comprising less a compound according to one any of the claims 5 at 7, and at less an excipient 15 nutraceutically acceptable. 1/2 110 S.irvie (% di. Ccnt-o e) 5 r ·, · e i $ i cl. rerrr.'s. JL * Œ '/ Z / Z' .Z Z Z Z, .Ο Z '>%' · - Z a100901070 "50" 110 TOO "8070" ® "* x, -jc Th Z Z Z Z ...... 7 .7 Z, Z