WO2018078010A1 - Polysubstituted quinic acid derivatives and use thereof for the treatment of neurodegenerative diseases - Google Patents

Abstract

The present invention relates to polysubstituted quinic acid derivatives (abbreviated to "PSQs") of general formula (IA): in which R represents a linear or branched, cyclic or branched cyclic, saturated or unsaturated C₂-C_p alkyl group, said group being able to be substituted or unsubstituted, p being a natural integer between 3 and 18, and Q₁, Q₃, Q₄ and Q₅ each representing, independently of one another, a hydrogen atom or a group selected from caffeoyl, maloyl, caffeoylmaloyl and maloylcaffeoyl groups, with the proviso that at least one of these radicals is not a hydrogen atom, the stereoisomers thereof and the pharmaceutically or nutraceutically acceptable salts thereof, for the prevention and/or the treatment of a neurodegenerative disease, especially Alzheimer's disease. Another subject of the invention is compounds of formula (IA) per se, a process for preparing such compounds, compounds according to the invention intended to be used as medicament, especially for the prevention and/or treatment of a neurodegenerative disease, in particular Alzheimer's disease, and a pharmaceutical composition comprising at least one compound according to the invention.

Description

 POLYSUBSTITUTED QUINIC ACID DERIVATIVES AND THEIR USE FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES

FIELD OF THE INVENTION

 The present invention relates to polysubstituted quinic acid ester derivatives, abbreviated as "QPS", as well as to a process for their preparation, to their use as a medicament, especially 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).

Quinic acid ester derivatives are described in the publications of Ning Li et al. (J. Functional Foods, 2015, 17, 837-846), Laguerre et al. (J. Pharmacy and Pharmacology, 2011, Vol 63, No. 4, pp. 531-540), Zhixin Jia et al. (Rapid Communication in Mass Spectrometry, 2014, 28, 21, 2237-51), Arpad et al. (J. Pharmaceutical and Biomedical Analysis, 2011, NY, vol 59, pp 83-89) and JP 2014 227 395, CN 103 494 806 and JP 2004 345 971.

The inventors have demonstrated that new ester derivatives of QPS, and in particular polycafoylquinic acid ester derivatives, abbreviated as "PCQ", not only have neuroprotective properties, and especially 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 different isomers of dicaffeoylquinic acid. SUMMARY OF THE INVENTION

 Surprisingly, the inventors have shown that certain ester derivatives of QPS have quite remarkable neuroprotective effects and are therefore 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):

OQ ₄

 (IA) in which

R represents a linear C ₂ -C alkyl group _P or branched, cyclic or cyclic branched, saturated or unsaturated, said group may be substituted by one or more substituents selected from the group comprising: - ORi, NRiR _2, - N0 _2, -CORi, -COOR, -CF _3, -CR1F2, -CR1R2F, = 0, -CN, halogen, -SRI, -SO2R1, aryl, wherein

 p is a natural number between 3 and 18,

-Ri and R ₂ are identical or different and each represent, independently of one another,

or a substituent chosen from the group comprising: -H, -OH, -NH ₂ ,

- NO2, -COOH, -CF _3, -CHF _2, -CH ₂ F, = 0, -CN, halogen, -SH, -SO2H,

or a linear or branched, cyclic or cyclic branched, saturated or unsaturated C 2 -C 6 alkyl group which may be substituted with one or more substituents chosen from the group comprising: -H, -OH, -NH ₂ , -NO ₂ ,

COOH, -CF3, -CHF ₂ , -CH ₂ F, = O, -CN, halogen, -SH, -SO 2 H, and

Qi, Qs, Q4 and Q5 are each independently of one another a radical selected from the group consisting of: a hydrogen atom and a group caffeoyl, maloyl, caféoylmaloyl or maloylcaféoyl, 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, including Alzheimer's disease.

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

wherein R is an alkyl C ₂ -C _P linear or branched, cyclic or cyclic branched, saturated or unsaturated, said group may be substituted by one or more substituents selected from the group comprising -OR, -NRiR ₂ - N0 ₂ , -COR1, -COORi, -CF ₃ , -CR1F2, -CR1R2F, = 0, -NC, halogen, -SR1, -SO2R1, aryl, wherein

p is a natural number between 3 and 18,

Ri and R ₂ 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, -CH ₂ F, = 0, -CN, halogen, -SH, -SO2H,

or a linear or branched, cyclic or cyclic branched, saturated or unsaturated C 2 -C 6 alkyl group which may be substituted with one or more substituents chosen from the group comprising: -H, -OH, -NH ₂ , -NO ₂ ,

COOH, -CF3, -CHF ₂ , -CH ₂ F, = O, -CN, halogen, -SH, -SO 2 H,

and Q 1, Q 3, Q 4 and Q 5 are each independently of one another a radical selected from the group consisting of: hydrogen, and a caffeoyl, maloyl, coffeeoylmaloyl or maloylcaféoyl group, provided that at least one of these radicals is not a hydrogen atom,

except for the compounds listed in the following Table A: Compounds of general formula (IB)

 in which :

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

- R ₄ , R5 and Re are each independently selected from: - OH group and a group represented by the following formula (X):

wherein R7 is -OH and n is an integer of 1 to 5,

with at least one of R ₄ , R 5 or Re corresponding to said formula (X), 1- (2-hydroxypropoxy) propan-2-yl ester of cyclohexanecarboxylic acid, 3,5-bis [[(2E) -3 (3,4-Dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4-dihydroxy- (1S, 3K, 4S, 5K)

 Cyclohexanecarboxylic acid 1- (1-hydroxypropan-2-yloxy) propan-2-yl ester, 3,5-bis [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo] -2- propen-l-yl] oxy] -l, 4-dihydroxy- (s, 3H, 4S, 5K)

 2- (1-hydroxypropan-2-yloxy) propyl ester of cyclohexanecarboxylic acid, 3,5-bis [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen] yl] oxy] -1,4-dihydroxy- (1S, 3K, 4S, 5K)

2- (2-hydroxypropoxy) propyl ester of cyclohexanecarboxylic acid, 3,5-bis [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4-dihydroxy- (1S, 3K, 4S, 5K) The ethyl ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- (1S, 3 /, 4 /, 5 /)

The propyl ester of cyclohexanecarboxylic acid, 3 - [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- (lS, 3 /, 4 /, 5 /)

Cyclohexanecarboxylic acid 1-methylethyl ester, 3 - [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5- trihydroxy- (1S, 3 /, 4 /, 5 /)

Butyl ester of cyclohexanecarboxylic acid, 3 - [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- (lS, 3 /, 4 /, 5 /)

Cyclohexanecarboxylic acid butyl ester, 3 - [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- ( 1, 3S, 4S, 5S)

Cyclohexanecarboxylic acid octyl ester, 3 - [[3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- (1S, 3 ') , 4fl, 5FL)

 Acetic anhydride (1S, 3R, 4R, 5R) of cyclohexanecarboxylic acid 3-

[[3- (3,4-dihydroxyphenyl) -l-oxo-2-propen-l-yl] oxy] -l, 4,5-trihydroxy

(1S, 3R, 4R, 5R)

 The cyclohexanecarboxylic acid dodecyl ester, 3 - [[3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- (1S, 3 /, 4 /, 5 /)

Cyclohexanecarboxylic acid 2-ethylhexyl ester, 3 - [[3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- (1S) , 3 /, 4 /, 5 /)

Cyclohexanecarboxylic acid 2-methylhexyl ester 3 - [[3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- (1S); 3 /, 4 /, 5 /)

The hexadecyl ester of cyclohexanecarboxylic acid 3 - [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- (lS, 3 /, 4 /, 5 /)

The octadecyl ester of cyclohexanecarboxylic acid 3 - [[3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- (1S, 3 /, 4 /, 5 /)

The cyclohexanecarboxylic acid eicosyl ester, 3 - [[3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- (1S, 3 /, 4 /, 5 /)

The 2,3-butadien-1-yl ester of cyclohexanecarboxylic acid, 3 - [[(2E) -3- [4-

(2,3-Butadien-1-yloxy) -3-hydroxyphenyl] -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- (1S, 3K, 4K, 5K)

The phenylmethyl ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4-dihydroxyphenyl) -1-oxo-2-propenyl] oxy] -1,4,5-trihydroxy- (1S, 3 ', 4', 5 ') ) Cyclohexanecarboxylic acid (2E) -3,7-dimethyl-2,6-octadien-1-yl ester, 3 - [(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2 propen-1-yl] oxy] -1,4,5-trihydroxy- (1H, 3S, 4S, 5fl)

 Cyclohexanecarboxylic acid 2-chloroethyl ester, 1,3,4-trihydroxy-

5 - [[(2E) -3- (4-hydroxy-3-methoxyphenyl) -l-oxo-2-propen-l-yl] oxy] -

(1R, 3R, 4S, 5R)

 The ethyl ester of cyclohexanecarboxylic acid, 3,4-bis [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,5 dihydroxy-1S, 3R, 4R, 5R) The ethyl ester of cyclohexanecarboxylic acid, 3,5-bis [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1 1-yl] oxy] -1,4-dihydroxy- (1a, 3a, 4a, 5H) ethyl ester of cyclohexanecarboxylic acid, 3,4-bis [[(2E) -3- dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,5-dihydroxy- (1H, 3H, 4S, 5H) cyclohexanecarboxylic acid anhydride 3 - [[3 - (3,4-Dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- and 3- (4-hydroxyphenyl) -2-propenoic acid (1S , 3R, 4R, 5R) -

The butyl ester of cyclohexanecarboxylic acid, 3,5-bis [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4-dihydroxy (1S, 3f, 4S, 5f) Butyl ester of cyclohexanecarboxylic acid, 3,4-bis [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1- yl] oxy] -1,5-dihydroxy- (1H, 3S, 4S, 5S) The propyl ester of cyclohexanecarboxylic acid, 3,5-bis [[3- (3,4-dihydroxyphenyl) -1-oxo] 2-propen-1-yl] oxy] -1,4-dihydroxy- (1S, 3H, 4S, 5H) (2E, 2'E) - ((1R, 2S, 3R, 5S) -2.5 Dihydroxy-5 - ((3-hydroxypropoxy) carbonyl) cyclohexane-1,3-diyl) bis (3- (3,4-dihydroxyphenyl) acrylate)

 Table A

their stereoisomers and their pharmaceutically or nutraceutically acceptable salts. According to a third aspect, the invention relates to 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. 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 a neurodegenerative disease, especially 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

FIGS. 1A to 1D show the survival, as a percentage of live neurons compared to the control, of primary cortical neurons intoxicated for 24 hours by the peptide of Αβ1-42 added to a final concentration of 20 μΜ, respectively in the presence of the acid , 5-diocoyamoylquinic acid (Fig. 1A), 3,5-dicarboxoylquinic acid ethyl ester (Fig. 1B), 3,5-dicarboxoylquinic acid 2-hydroxypropyl ester (2). -HPE DCQ) (Fig. 1C) or 2-hydroxy hexyl ester of 3,5-diocoyoylquinic acid (2-HHE DCQ) (Fig. 1D) at concentrations ranging from 10 nM to 10 μM according to US Pat. Example 2

FIGS. 2A to 2D show the growth of the latent neurite network for 24 hours by the β1-42 peptide added to a final concentration of 20 μl, respectively in the presence of 3,5-dicaffeoylquinic acid (FIG. ester of DCQ (FIG 2B), 2-HPE DCQ (FIG 2C) or 2-HHE DCQ (FIG 2D) at concentrations ranging from 10 nM to 10 μΜ according to example 2. DETAILED DESCRIPTION OF THE INVENTION

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

OQ ₄ (IA) in which

R represents a linear C ₂ -C alkyl group _P or branched, cyclic or cyclic branched, saturated or unsaturated, said group may be substituted by one or more substituents selected from the group consisting of -OR, - NRiR _2, -N0 ₂ , -CORi, -COOR, -CF _3, -CR1F2, -CR1R2F, = 0, -CN, halogen, -SRI, -SO2R1, aryl, wherein

 p is a natural number between 3 and 18,

Ri and R ₂ are identical or different and represent, each independently of one another

- is a substituent selected from the group consisting of -H, -OH, - NH _2, - NO2, -COOH, -CF _3, -CHF _2, -CH ₂ F, = 0, -CN, halogen, -SH, -

or a linear or branched, cyclic or cyclic branched, saturated or unsaturated C 2 -C 6 alkyl group which may be substituted by one or more substituents chosen from the group comprising: -H, -OH, -NH ₂ , -NO ₂ , COOH, -CF ₃ , -CHF ₂ , -CH ₂ F, = O, -CN, halogen,

 Q 1, Q 4, Q 4 and Q 5 are each independently of one another a radical selected from the group consisting of: a hydrogen atom and a caffeoyl, maloyl, coffeeoylmaloyl or maloylcaféoyl group, with the proviso that at least one these radicals are 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). "Alkyl group of C ₂ -C _P" is understood within the meaning of the present invention, a monovalent saturated hydrocarbon chain or unsaturated, linear or branched, branched, cyclic or cyclic, having from 2 to p carbon atoms, p being a natural integer between 3 and 18. According to the invention, R preferably represents a saturated or unsaturated, linear or branched, cyclic or cyclic monovalent hydrocarbon chain of 2 to 18 carbon atoms, preferably 2 to 17 carbon atoms, and more preferably 2 to 17 carbon atoms. 16 carbon atoms, 2 to 15 carbon atoms, 2 to 14 carbon atoms, 2 to 13 carbon atoms, 2 to 12 carbon atoms, 2 to 11 carbon atoms, 2 to 10 carbon atoms carbon, 2 to 9 carbon atoms, 2 to 8 carbon atoms, 2 to 7 carbon atoms, preferably 2, 3, 4, 5 or 6 carbon atoms, and in particular 2, 5 or 6 carbon atoms.

By way of example and non-exhaustively, mention may be made of ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl groups. tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, geranyl, farnesyl, cyclopropyl, cyclobutyl, cyclohexyl, ethylenyl, propylenyl, butylenyl, cyclopropenyl, cyclobutenyl, cylcopentenyl, cyclohexenyl, cycloheptenyl, cyclohexa-1,3-dienyl, cyclohexa-1, 4-dienyl, cyclohexa-1,5-dienyl, said groups may be linear or branched. In a preferred embodiment of the invention, the alkyl groups are linear.

By "aryl group" is meant an aromatic ring in Ce, which may be substituted by one or more substituents chosen from the group comprising: -H, -OH, -NH 2, -NO 2, -COOH, -CF ₃ , -CH F ₂ , -CH ₂ F, = 0, -CN, halogen, -SH,

By "caffeoyl group" is meant a radical of formula (II), derived from caffeic acid:

(Π)

(Π)

By "maloyl group" is meant a radical of formula (IIIa) or (IIIb), derived from malic acid:

(Illa) (1Hb) "alkyloylmaloyl group" means a radical of formula (IVa) or (IVb)

 (IVa) (IVb)

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

(Va) (Vb)

 (Vc) (Vd)

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

(VI):

OQ ₄

 (VI)

in which Q 1, Q 3, Q 4 and Q 5 represent, independently of each other, a hydrogen atom, a caffeoyl, maloyl, c-alkyloyl or maloylcafeoyl group, as defined above, with the proviso that at least one of these radicals are not a hydrogen atom. In another preferred embodiment of the invention, QPS is a polycafoylquinic acid, abbreviated as "PCQ" throughout the present description, corresponding to a mono, di, tri or tetra ester composed of a quinic acid molecule of which one, two, three or four alcohol functions have been esterified with a caffeic acid. The PCQs are therefore acids of general formula (VI) as defined above in which Q 1, Q 3, CM and Q 5 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.

The different 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 Q 1, Q 3, CM and Q 5 chosen independently of each other from a hydrogen atom and a caffeoyl radical, under provided that at least one of Qi, Q 3, Q ₄ and Q 5 is not a hydrogen atom.

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

radicals Qi, Q3, Q4 and Q5 represent a hydrogen atom By "chlorogenic acid" is meant 3 - [(3- (3,4-dihydroxyphenyl) oxo-2-propenyl] oxy] -l acid, 4,5-Trihydroxycyclohexanecarboxylic, according to IUPAC definition.

Name of the acid Qi Q3 Q4

 1,3-dicaféoylquinique (1,3-DCQ) Caféoyl Caféoyl H H

1,4-dicaffeoylquinic acid (1,4-DCQ).

1,5-dicaffeoylquinic acid (1,5-DCQ)

3,4-dicaffeoylquinic (3,4-DCQ)

 H Coffeeoyl Caffeoyl H (= isochlorogenic acid B)

 3,5-dicaféoylquinique (3,5-DCQ)

 H Coffeeoyl H Coffeeoyl (= isochlorogenic acid A)

 4,5-dicaffeoylquinic (4,5-DCQ)

 H H Coffeeoyl Caffeoyl (= isochlorogenic acid C)

 Table 2. Examples of PCQ structures in which two of the radials Qi, Q3, Q4 and Q5 represent a hydrogens atom.

 Table 3. Examples of QPS structure of which at most one of the radials Qi, Q3, Q4 and Q5 represents a hydrogens atom.

Table 4. Example of a QPS structure whose radials Qi, Q3, Q4 and Q5 do not represent 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 to a pharmaceutical or nutraceutical composition. veterinary use or in humans.

The term "pharmaceutically or nutraceutically acceptable salts" of a compound means salts which are pharmaceutically or nutraceutically acceptable, as defined above, and which possess 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, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, 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) 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 an alkali metal ion, an alkaline earth metal ion or a 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 of the functioning, and possibly the death, of the nerve cells, and in particular neurons. These diseases induce cognitive-behavioral, sensory and motor disorders.

According to one particular aspect, said neurodegenerative disease is selected from: Alzheimer's disease, spinocerebellar ataxia, multisystem atrophy, Alexander's disease, Alpers disease, Creutzfeldt-Jakob disease, Alzheimer's 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 may be a neurodegenerative disease due to oxidative stress. This is particularly the case of Alzheimer's disease.

Alzheimer's disease (AD) is defined as a disease that primarily affects persons over 65 years of age, who have various clinical symptoms, such as progressive decline in memory, thinking, language, and ability to learning. The toxic role of the β-amyloid peptide (Αβ) has now shifted from insoluble β-fibrils to smaller soluble β-oligomer aggregates. Soluble oligomers of Αβ isolated from the cortex of patients with Alzheimer's disease have been shown to directly induce hyperphosphorylation of Tau protein (T) and degeneration of neurites (Jin M, Shepardson N, Yang T, Chen G, Walsh D, Selkoe DJ Soluble amyloid beta-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. Proc Natl Acad Sci US A. 2011 Apr 5; 108 (14): 5819-24). Thus, all substances having a reducing property of β-peptide neurotoxicity may be useful as a novel therapeutic agent for the treatment or prevention of Alzheimer's disease.

Also, the subject of the present invention is compounds derived from QPS esters of general formula (IA) as defined above, in which Qi, Q3, CM and Qs represent, independently of one another, a hydrogen atom. or a caffeoyl, maloyl, cocoylmaloyl or maloylcaféoyl group, as defined above, with the proviso that one, two, three or four of the radicals Qi, Q3, Q4 or Q5 is not a hydrogen atom, for their use in the prevention and / or treatment of a neurodegenerative disease. According to one particular aspect, the invention relates to QPS-derived ester compounds of formula (IA) with Qi, Q3, Q4 and Q5 as defined above for their use in the prevention and / or treatment of a neurodegenerative disease. with the exception of the ester derivatives of the compounds chlorogenic acid, wherein Q5 represents a group caféoyle and Qi, Q 3 and Q ₄ each represents a hydrogen atom.

According to another particular aspect, the invention relates to QPS-derived ester compounds of formula (IA) for their use according to the invention, with the exception of compounds in which:

- Q5 represents a group caféoyle, Qi, Q 3 and Q ₄ represent a hydrogen atom and R represents a linear alkyl group of C _4.

According to a more particular aspect, the invention relates to QPS-derived ester compounds of formula (IA) for their use according to the invention, with the exception of compounds in which:

Q ₅ represents a caffeoyl group, Q _1, Q ₃ and Q ₄ represent a hydrogen atom, and R represents a C ₂ , C ₃ , C ₄ , C ₅ , C 12 or C 16 linear alkyl group, a branched C ₃ or C 6 alkyl group or a substituted C2-C18 cyclic alkyl group; - Q 3 and Q ₄ represent a group caféoyle, Qi and Qs represent a hydrogen atom, and R represents a linear alkyl group C2;

Qs and Qs represent a caffeoyl group, Q ₁ and Q ₄ represent a hydrogen atom, and R represents a linear C 2 alkyl group.

According to another particular aspect, the subject of the invention is ester compounds derived from QPS of formula (IA) for their use according to the invention, said QPS being a di, tri or tetra ester composed of a quinic acid molecule of which two, three or four alcohol functions have been esterified with a caffeic acid, a malic acid or a mixture of caffeic acid and malic acid.

According to another particular aspect, the subject of the present invention is compounds derived from PCQ esters of general formula (IA) as defined above, in which Q ₁ , Q ₃ , Q ₄ and Q ₅ 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, for their use in the prevention and / or treatment of a neurodegenerative disease.

More particularly, a compound for use in the prevention and / or treatment of a neurodegenerative disease according to the invention is characterized in that any two of the radicals Q ₁ , Q ₃ , Q ₄ and Q ₅ represent a caffeoyl group, and both other 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 Q ₄ 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 C 2 -C 15 alkyl group, advantageously a C 2 -C 12 alkyl group, more preferably a C 2 -C 6 alkyl group, and still more preferably C ₂ -C ₃ , C ₄ , C 5 or C ₆ alkyl, said groups being substitutable as previously mentioned. According to a more particular aspect, the compounds for their use according to the invention are characterized in that Qi and Q ₄ represent a hydrogen atom, Q3 and Qs represent a caffeoyl group and R is a C2-C6 alkyl group substituted by an -OH group, especially R is a 2-hydroxy-pentyl group or a 2-hydroxy-hexyl group.

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

3-coffeeoylquinic acid (Qi = Q ₄ = Qs = H and Q3 = caffeoyl radical),

- The 5-caffeoylquinic acid (Qi = Q 3 = Q ₄ = H and Qs = caféoyle radical), with the exception of compounds of general formula (IA) where Qs represents a group caféoyle, Qi, Q 3 and Q ₄ represent a hydrogen atom, and R represents a linear C ₂ , C ₃ , C ₄ , C ₈ , C 12 or C 16 alkyl group, a branched C ₃ or C 8 alkyl group or a substituted C 2 -C 18 cyclic alkyl group.

1,3-dicaffeoylquinic acid (Q ₄ = Qs = H and Qi = Q3 = caffeoyl radical)

- 1,4-dicaffeoylquinic acid (Q3 = Qs = H and Q = Q ₄ = radical caféoyle)

- 1,5-dicaffeoylquinic acid (Q3 = _Q4 = H and Q = Qs = radical caféoyle) - The 3,4-dicaffeoylquinic acid (Q = Qs = H and Q 3 = Q ₄ = radical caféoyle) to with the exception of the compound wherein Q ₃ and Q ₄ are caffeoyl, Q ₁ and Q ₅ are hydrogen, and R is a linear C 2 alkyl group;

- 3,5-dicaffeoylquinic acid (Qi = Q ₄ = H and Q3 = Qs = caféoyle radical), with the exception of the compound wherein Q3 and Qs represent caféoyle group, Qi and Q ₄ represent a halogen atom, hydrogen, and R is a linear C2 alkyl group;

- 4,5-dicaffeoylquinic acid (Q = Q3 = H and Q = Qs = ₄ radical caféoyle)

- The acid 1,3,4 tricaféoylquinique (Qs = H and Q = Q 3 = Q ₄ = radical caféoyle) - The acid 1,3,5 tricaféoylquinique (Q ₄ = H and Q = Q3 = Qs = radical caféoyle)

- The acid 1,4,5 tricaféoylquinique (Q3 = H and Q = Q ₄ = Qs = radical caféoyle)

- The acid 3,4,5 tricaféoylquinique (Qi = H and Q = ₄ and Q3 = Qs = caféoyle radical) and

1,3,4,5-tetracaféoylquinique acid and Qi = Q3 = Q ₄ = Qs = caffeoyl radical) In particular, among the compounds of formula (IA) that are advantageous for their use according to the present invention, mention may be made of the ester derivatives of:

1,3-dicaffeoylquinic acid;

 1,4-dicaffeoylquinic acid;

 1,5-dicaffeoylquinic acid;

3,4-dicaffeoylquinic acid; except the compound wherein Q3et Q ₄ represent a group caféoyle, Qi and Qs represent a hydrogen atom, and R represents a linear alkyl group;

3,5-dicaffeoylquinic acid; except the compound wherein Q3et Qs represent caféoyle group, Qi and Q ₄ represent a hydrogen atom, and R represents a linear alkyl group C2; and

 4,5-dicaffeoylquinic acid.

The compounds of general formula (IA) for their use according to the invention which are particularly advantageous are those characterized in that Q ₁ and Q ₄ represent a hydrogen atom and Q ₃ and Q ₅ represent a caffeoyl group, thus corresponding to the ester derivatives of 3,5-dicaffeoylquinic acid (3,5-DCQ).

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

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

(VII)

(VII)

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

and

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

According to a more particular aspect, the subject of the invention is compounds characterized in that Q ₁ and Q ₄ each represent a hydrogen atom, and in that R is a C 2 -C 15 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 subject of the invention is compounds characterized in that Q ₁ and Q ₄ each represent a hydrogen atom, Q ₃ and Q ₅ each represent a caffeoyl group, and that R is a lower alkyl group. C2-C6, optionally substituted with an -OH group, 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 the prevention and / or the 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-dicarboxoylquinic acid, 2-hydroxy-pentyl 3,5-dicarboxoylquinic acid ester and 3,5-dicaroylquinic acid 2-hydroxyhexyl ester for its use for the prevention and / or treatment of Alzheimer's disease. According to a second aspect, the subject of the invention is compounds of general formula (IA)

OQ ₄

 (IA), in which

R represents a linear C ₂ -C alkyl group _P or branched, cyclic or cyclic branched, saturated or unsaturated, possibly being substituted with one or more of the following groups: -OR, - N R1R2, - NO2, -CORi, -COORi, -CF ₃ , -CR ₁ F ₂ , -CR ₁ R ₂ F, = O, -CN, halogen, -SR 1, -SO ₂ R 1, aryl, wherein

p is a natural number between 3 and 18,

-Ri and R ₂ are identical or different and represent each independently of one another

or a substituent chosen from the group comprising: -H, -OH, -NH ₂ ,

N0 ₂ , -COOH, -CF ₃ , -CHF ₂ , -CH ₂ F, = O, -CN, halogen, -SH, -SO ₂ H,

or a linear or branched, cyclic or cyclic branched, saturated or unsaturated C ₂ -C 6 alkyl group which may be substituted with one or more substituents chosen from the group comprising: -H, -OH, -NH ₂ , -NO ₂ ,

COOH, -CF3, -CHF ₂ , -CH ₂ F, = O, -CN, halogen, -SH, -SO ₂ H, and

Q 1, Q 4, Q 4 and Q 5 are each independently of one another a radical selected from the group consisting of: a hydrogen atom, a caffeoyl, maloyl, c-alkyloyl or maloylcaféoyl group, provided that at least one of these radicals is not a hydrogen atom, with the exception of the compounds listed in Table A, their stereoisomers and their pharmaceutically or nutraceutically acceptable salts. In a more particular aspect, the invention relates to QPS-derived ester compounds of formula (IA) with Q 1, Q 3, CM and Q 5 as defined above, with the exception of the compounds of Table A and the ester compounds derived from chlorogenic acid, wherein Q5 represents a group caféoyle and Qi, Q 3 and Q ₄ each represents a hydrogen atom.

According to another particular aspect, the subject of the invention is ester compounds derived from QPS of formula (IA), with Qi, Q3, Q4 and Q5 as defined previously, with the exception of the compounds of Table A and the compounds in which :

- Q5 represents a group caféoyle, Qi, Q 3 and Q ₄ represent a hydrogen atom and R represents a linear alkyl group of C _4.

In a more particular aspect, the invention relates to ester compounds derived from QPS of formula (IA) wherein Qi, Q 3, Q ₄ and Q 5 are as defined above, with the exception of the compounds of Table A and compounds in which:

- Q5 represents a group caféoyle, Qi, Q 3 and Q ₄ represent a hydrogen atom, and R represents a linear alkyl group of C2, C3, _C4, Cs, C12 or IC6, alkyl branched C3 or Cs or a substituted C 2 -C 18 cyclic alkyl group;

Q ₃ and Q ₄ represent a caffeoyl group, Q ₁ and Q ₅ represent a hydrogen atom, and R represents a linear C 2 alkyl group;

Qs and Qs represent a caffeoyl group, Q ₁ and Q ₄ represent a hydrogen atom, and R represents a linear C 2 alkyl group.

According to another particular aspect, the invention relates to polysubstituted quinic acid ester (QPS) compounds, said QPS being a di, tri or tetra ester composed of a quinic acid molecule of which two, three or four functions The alcohols were esterified with a caffeic acid, a malic acid or a mixture of caffeic acid and malic acid, with the exception of the compounds listed above. According to an advantageous embodiment of the invention, in the compounds of formula (IA) any two radicals Qi, Q3, Q4 and Q5 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) Q ₁ represents a hydrogen atom, and more particularly Q ₁ and Q ₄ each represent a hydrogen atom.

According to another even more advantageous embodiment of the invention, in the compounds of formula (IA) Q ₁ , Q ₃ , Q ₄ and Q ₅ represent, independently of one another, a hydrogen atom or a group caffeoyl, 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 C 2 -C 15 alkyl group, advantageously a C 2 -C 12 alkyl group, more preferably a C 2 -C 6 alkyl group, and even more advantageously a C2, Cs or Ce alkyl group.

According to a more particular aspect, a compound according to the invention is characterized in that Q ₁ and Q ₄ represent a hydrogen atom, Q ₃ and Q ₅ represent a caffeoyl group and R is a C 2 -C 6 alkyl group substituted with a group - OH, and especially R is a 2-hydroxypentyl group or a 2-hydroxyhexyl group.

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

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

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

The compounds of general formula (IA) according to the invention are prepared by the implementation of a method of esterification 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) is reacted with an alcohol of formula R-OH.

According to this process, 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 PCQ is 3,5-DCQ, 3,4-DCQ, 4,5-DCQ, more preferably PCQ is 3,5-DCQ.

The inventors have developed a process for the preparation of the ester derivatives of QPS in one step by semisynthesis from a specific QPS allowing the production of ester derivatives of this QPS in the form of a single regioisomer. This preparation method 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, Andreas Katopodis, Markus B Streiff, Willy Kinzy, Reinhold Oehrlein.) Synthesis of Gai determining epitopes, their glycomimetic variants, and trimeric clusters-relevance to tumor associated Tetrahedron, 16 April 2001, Volume 57, Issue 16, Pages 3281-3290). The alcohol is chosen from the alcohols of formula R-OH, in which R represents a linear or branched, cyclic or cyclic branched, saturated or unsaturated C ₂ -C _P alkyl group, where p is a natural integer between 3 and 18, said group may be substituted by one or more substituents selected from the group consisting of -OR, - N R1R2, - NO2, -CORi, -COOR, -CF _3, -CR1F2, -CRiR ₂ F, = 0, - CN, halogen, -SR 1, -SO ₂ R 1, aryl, wherein R 1 and R ₂ are the same or different and represent, each independently of one another, a linear or branched, cyclic C ₂ -C 6 alkyl group or branched, saturated or unsaturated cyclic, which may be substituted by one or more substituents selected from the group consisting of: -H, -OH, -NH ₂ , -NO ₂ , -COOH, -CF 3, -CHF ₂ , -CH ₂ F, = 0, -CN halogen, -SH, -SO ₂ H, or a substituent selected from the group consisting of:

- H, -OH, - IM H2, - NO2, -COOH, -CF _3, -CHF _2, -CH ₂ F, = 0, -CN, halogen, -SH,

- S0 ₂ H. More particularly, the alcohol is chosen from alcohols of formula R-OH, in which R represents a C 2 -C 15 alkyl group, advantageously a C 2 -C 12 alkyl group, more advantageously a C 2 -C 6 alkyl group, and even more preferably more preferably a C2, Cs or Ce alkyl group.

Even more particularly, the alcohol is chosen from alcohols of formula R-OH, in which R is a C 2 -C 6 alkyl group substituted with an -OH group, and in particular R is a 2-hydroxy-pentyl group or a group 2-hydroxyhexyl.

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

In one embodiment of the invention, the step of the process 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 of activation of the carboxyl group of a QPS, in particular PCQ, and more particularly 3,5-DCQ, in particular with a carboxyl group activating agent, such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, combination with 1-hydroxybenzotriazole hydrate.

By "carboxyl group activating agent" is meant according to the present invention any reagent or combination of reagents for activating 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 the activation agents of the family of carbodiimides, such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC) and N-ethyl-N (3-dimethylaminopropyl) carbodiimide ( EDCI) alone or in combination with alcohols allowing the transient formation of activated esters such as, for example, 1-hydroxybenzotriazole (HOBT), 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxysuccinimide (HOSu) or still ethyl (hydroxyimino) cyanoacetate. The activatable activating agent may also be part of the family of phosphonium, uronium and / or guanidinium salts. By way of example, mention may be made of benzotriazol-1 yloxy) tris (dimethylamino) phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), (1-Cyano-2-ethoxy-2-oxoethylidenaminooxy) dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), N-α-N-tetramethyl-O-ClH-benzotriazol-1-yl) uronium hexafluorophosphate (HBTU), (O- (6-chloro-1-hydrocibenzotriazol-1-yl) -1,3,3, 3-tetramethyluronium tetrafluoroborate) (TCTU), (2- (7-Aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate) (HATU). More particularly, the carboxyl group activating agent is chosen from diisopropylcarbodiimide (DIC) and 1-hydroxybenzotriazole (HOBT).

The processes for preparing the compounds according to the invention may optionally comprise 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 processes according to the invention may further be purified by methods known to those skilled in the art. For example, purification methods by crystallization, chromatography or extraction may be mentioned.

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

 OQ,

^<4 (IA),

wherein R, Q 1, Q 3, Q 4 and Q 5 are as defined above,

except for compounds of general formula (IB)

 in which :

 R3 is a linear or branched C2-C6 alkoxy chain, especially ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy, n-hexoxy;

- R ₄ , R5 and Re are each independently selected from: - OH group and a group represented by the following formula (X):

dans laquelle R7 représente un groupe -OH ou aikoxy en C2-C6 linéaire ou ramifié et n est un nombre entier compris entre 1 et 5,

wherein R7 is a linear or branched C2-C6 -OH or alkoxy group and n is an integer of 1 to 5,

with at least one of R ₄ , R 5 or Re corresponding to said formula (X),

or its pharmaceutically or nutraceutically acceptable salts and stereoisomers for use as a medicament. According to a more particular aspect, the present invention relates to compounds of general formula (IA):

dans laquelle R, Qi, Q3, CM et Q5 sont tels que définis ci-dessus, ou ses sels et stéréoisomères pharmaceutiquement ou nutraceutiquement acceptables, pour leur utilisation en tant que médicament pour la prévention et/ou le traitement d'une maladie neurodégénérative, notamment la maladie d'Alzheimer.

wherein R, Q 1, Q 3, CM and Q 5 are as defined above, or its pharmaceutically or nutraceutically acceptable salts and stereoisomers, for use as a medicament for the prevention and / or treatment of a neurodegenerative disease, including Alzheimer's disease.

According to a more particular aspect, the subject of the invention is compounds of general formula (IA), in which R, Q 1, Q 3, Q 4 and Q 5 are as defined above, with the exception of the compounds of Table A and ester compounds derived from chlorogenic acid wherein Q5 represents a group caféoyle and Qi, Q 3 and Q ₄ each represents a hydrogen atom, or their salts and stereoisomers pharmaceutically or nutraceutically acceptable for use as a medicament, especially for the prevention and / or treatment of a neurodegenerative disease, in particular Alzheimer's disease.

According to another particular aspect, the subject of the invention is ester compounds derived from QPS of formula (IA), with Qi, Q3, Q4 and Q5 as defined previously, with the exception of the compounds of Table A and the compounds in which :

- Q5 represents a group caféoyle, Qi, Q 3 and Q ₄ represent a hydrogen atom and R represents a linear alkyl group having _4,

or their pharmaceutically or nutraceutically acceptable salts and stereoisomers for use as a medicament, especially for the prevention and / or treatment of a neurodegenerative disease, especially Alzheimer's disease.

In a more particular aspect, the invention relates to ester derivatives of compounds of QPS formula (IA) wherein Qi, Q 3, Q ₄ and Q 5 are as defined above, with the exception of the compounds listed above and compounds in which:

- Q5 represents a group caféoyle, Qi, Q 3 and Q ₄ represent a hydrogen atom, and R represents a linear alkyl group of C2, C3, _C4, Cs, C12 or C16, a branched C3 or C8 alkyl group or a substituted C2-C18 cyclic alkyl group;

Q ₃ and Q ₄ represent a caffeoyl group, Q ₁ and Q ₅ represent a hydrogen atom, and R represents a linear C 2 alkyl group;

Qs and Qs represent a caffeoyl group, Q ₁ and Q ₄ represent a hydrogen atom, and R represents a linear C 2 alkyl group,

or their pharmaceutically or nutraceutically acceptable salts and stereoisomers for use as a medicament, especially for the prevention and / or treatment of a neurodegenerative disease, especially Alzheimer's disease.

The invention also relates to a method for preventing and / or treating a neurodegenerative disease, in particular one of the diseases mentioned above, comprising administering a therapeutically effective amount of at least one compound of formula ( IA) according to the invention to a patient in need. More particularly, the subject of the invention is a method for preventing and / or treating Alzheimer's disease, comprising administering a therapeutically effective amount of at least one compound of formula (IA) according to the invention. to a patient in need, and comprising in particular the administration of a compound chosen from: ethyl ester of 3,5-diocoyoylquinic acid, 3,5-di-1-hydroxypentyl ester of -Caffeoylquinic acid and the 2-hydroxy-hexyl ester of 3,5-diocoyoylquinic 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, Q ₁ , Q ₃ , Q ₄ and Q ₅ are as defined above. or pharmaceutically acceptable salts and stereoisomers thereof, and preferably a pharmaceutically acceptable excipient.

The modes of administration, the dosages and the optimal dosage 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, age or the body weight of the patient, the severity of his general condition, the tolerance to treatment, the observed side effects, the type of skin. Depending on the type of administration desired, the pharmaceutical composition according to the invention may further comprise at least one pharmaceutically acceptable excipient. The pharmaceutical composition according to the present invention may further comprise at least one adjuvant pharmaceutically known to a person skilled in the art, chosen from thickeners, preservatives, perfumes, dyes, chemical or mineral filters, moisturizing agents, water thermal baths, etc.

Advantageously, the pharmaceutical composition comprises at least one compound of general formula (IA) according to the invention in an amount of 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 may 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 method of administration of the pharmaceutical composition. By way of example, the pharmaceutically acceptable excipient may be chosen from the group consisting of diluents, binders, disintegrants, dyes, lubricants, solubilizing agents, absorption promoters, film-forming agents and gelling agents. , and their mixtures. The pharmaceutical composition according to the invention may further comprise at least one compound chosen from the group consisting of emollients, moisturizing active agents, activators of keratin synthesis, kératorégulateurs, keratolytiques, agents restructuring the cutaneous barrier ( activators of skin lipid synthesis, PPAR agonists or Peroxysome Proliferator Activated Receptor), activators of differentiation of keratinocytes (retinoids, calcidone®, calcium), antibiotics, antibacterial agents, antifungal compounds, anti-viral agents, sebum-regulators, immunomodulators, such as tacrolimus , pimecrolimus, oxazolines, preservatives, anti-irritants, soothing agents, filters and sunscreens, anti-oxidants, growth factors, healing agents or eutrophic molecules, drugs and agents anti-Alzheimer's. 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.

The 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 particularly Alzheimer's disease, comprising the administration of a therapeutically therapeutic amount. effective of a pharmaceutical composition according to the invention to a patient in need. 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 particularly Alzheimer's disease. .

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

EXAMPLES

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

The 3,5-DCQ ethyl ester 3,5-DCQ esters, 3,5-DCQ-2-hydroxy-pentyl ester and 3,5-DCQ 2-hydroxy-hexyl ester are prepared according to the esterification reaction. whose protocol is described in the article by Hanessian et al. (2001) previously cited. The starting reagents are 3,5-DCQ and the corresponding alcohol is ethanol, 2-hydroxy-pentan-1-ol or 2-hydroxy-hexanol. 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 1-hydroxybenzotriazole hydrate (HOBT).

3,5-DCQ is dissolved in a mixture of dichloromethane and dimethylformamide. HOBT is added in stoichiometric amount at 0 ° C, followed by 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 an ester of DCQ on the survival of primary cortical neurons and on a neurite network of primary cortical neurons injured by the β-peptide.

The aim of this study is to evaluate the effects of 3,5-DCQ ester derivatives on rat primary cortical neurons, intoxicated by the β-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 evaluated.

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)

 • The 2-hydroxy-hexyl ester of 3,5-DCQ (2-HHE-DCQ)

 Four concentrations are tested: 10 nM, 100 nM, 1 μΜ and 10 μM. The vehicle used is the culture medium (see section below) containing 0.1% DMSO (Pan Biotech, Batch: H130813). In parallel, 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 solution of streptomycin (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 trypsin-EDTA solution (Pan Biotech, Batch: 3330914) at a final concentration of 0.05% trypsin and 0.02% EDTA. The dissociation is stopped by the addition of 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 pellet is suspended in a defined culture medium consisting of a Neurobasal medium (Invitrogen, batch: 1715722) with a 2% solution of supplement B27 (Invitrogen, lot: 1709534), 2 mmol / L of L-glutamine (Pan Biotech, lot: 6620314), 2% PS solution, and 10 ng / ml brain-derived neurotrophic factor (BDNF, Pan Biotech, Batch: H 140108). 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 cultured at 37 ° C in an incubator containing 95% air and 5% CO 2. The medium is changed every day. After 11 days of culture, the cortical neurons are intoxicated by a solution of β peptides (see below).

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

The preparation of the β1-42 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 serum-free, defined, above-mentioned culture medium at an initial concentration of 40 pmol / L. This solution is gently shaken for 3 days at 37 ° C in the dark and immediately used after being diluted culture medium at the tested concentration (20 μl).

On the eleventh day of culture, the ester tested at the different concentrations is dissolved in the culture medium and is then preincubated with the primary cortical neurons for 1 hour before application of the β1-42 peptide. The peptide solution Αβ1-42 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 hours. In parallel, 3,5-diocoyoylquinic acid is tested under the same conditions. Evaluation of the survival of neurons, the neurite network and astrocytes

 24 hours after intoxication with the peptide Αβ1-42, the supernatant of the cell culture was removed and the cortical neuron cultures were fixed by a cold solution of ethanol (95%, Sigma, Batch: SZBD3080V) and acid 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-associated-protein 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 to 1/400 in PBS (PAN, Batch: 1870415) containing 1% fetal calf serum (FCS) and 0.1% saponin ( this antibody specific for cell bodies and neurites allows the study of neuronal cell death as well as the effect of the ester on the growth of neurites) for 2 hours at room temperature,

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

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

 The ester is tested for a culture. For each ester concentration and 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 Custom Module Editor (Molecular Devices). The results are presented in terms of the number of positive cells or labeled marker-specific neurite network (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 μM + product 100 nM / 0.1% DMSO

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

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

Each line is repeated 6 times.

Statistical analysis

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

2.2. Results

Figures 1A to 1D show survival, as a percentage of live versus control neurons, of primary cortical neurons intoxicated during 24h with the β1-42 peptide added to a final concentration of 20 μl, respectively in the presence of 3,5-diocoyoylquinic acid (Figure 1A), the ethyl ester of 3,5-di- caffeoylquinique (Fig. 1B), 3,5-dicaroylquinic acid 2-hydroxy-pentyl ester (2-HPE-DCQ) (Fig. 1C) or 3,5-dihydroxyethyl ester of 2-hydroxy hexyl ester -Caffeoylquinic (2-HHE-DCQ) (Fig. 1D) at concentrations ranging from 10 nM to 10 μM. On each of the histograms, the neuronal survival as a percentage of the control is indicated with, from left to right: the positive control, the control in the presence of β1-42 peptide, and the molecule tested, at the respective concentrations of 10 nM, 100 nM, 1 μΜ and 10 μΜ.

2A to 2D show the growth of the neurite network intoxicated for 24 h by the peptide of Αβ1-42 added to a final concentration of 20 μΜ, respectively in the presence of 3,5 dicaffeoylquinic acid (FIG. ethyl ester of 3,5-DCQ (FIG 2B), 2-HPE-DCQ (FIG 2C) or 2-HHE-DCQ (FIG 2D) at concentrations ranging from 10 nM to 10 μΜ. On each of the histograms, the neurite network, as a percentage of the control, is indicated with, from left to right: the positive control, the control in the presence of β1-42 peptide, and the molecule tested, at the respective concentrations of 10 nM, 100 nM, 1 μΜ and 10 μΜ.

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

The control control was not treated with the β1-42 peptide. Only the vehicle (culture medium containing 0.1% DMSO) was added to the cell culture of cortical neurons. 100% survival of neurons is observed in this condition.

The addition of the peptide Αβ1-42 to a final concentration of 20 μΜ induced after 24 hours a significant death of the neurons (FIGS. 1A-1 D) as well as a significant loss of the neurite network (FIGS. 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 β1-42 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 concentrations (Figure 1A). On the contrary, no effect (neither protective nor proliferation) was observed on astrocytes (results not shown).

The 3,5-DCQ ethyl ester preincubated one hour before the addition of the β1-42 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 1B). 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 3,5-DCQ-2-hydroxy-pentyl ester (2-HPE-DCQ) pre-incubated one hour before the addition of the β1-42 peptide shows a strong and significant effect on the survival of the neurons at all concentrations tested. (Figure 1C). In particular, the strongest protective effect on neuron survival was observed at 1 μΜ (Figure 1C). At this concentration the protection is total (no neuronal death was 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 neuron survival. The 2-HPE-DCQ pre-incubated one hour before the addition of the peptide Αβ1-42 shows a significant effect on the neurite network at its two highest concentrations (1 μΜ and 10 μΜ, Figure 2C). No effects (neither protective nor proliferation) were 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 peptide Αβ1-42 shows a protective effect on the neurite network at all concentrations tested except for the lowest concentration (10 nM) (Figure 2D). These results show that the ethyl ester of 3,5-DCQ and 2-HPE-DCQ allow a complete protection of neurons in vitro culture intoxicated by the peptide Αβ1-42. A significant effect on the neurite network was observed for the lowest concentrations. In addition, a significant significant effect was observed on 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-2-hydroxy-pentyl ester and the 2-hydroxy-hexyl ester of 3,5-DCQ are therefore good candidates for the protection of cortical neurons, the maintenance of their connections, that is to say less disorganization of neurite network, without causing cell multiplications. Thus, with respect to already existing compounds such as the different isomers of dicaffeoylquinic acids, these compounds are of interest as new therapeutic agents for the prevention or treatment of a neurodegenerative disease, and in particular Alzheimer's disease. The higher activity of ester derivatives of QPS 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 the QPS makes it possible to create new interactions with active sites of biological targets.

Example 3: Butyl chlorogenate (2E, 2'E) - ((1R 2S 3R 5S) -5- (butylcarbamoyl) -2-5-dihydroxycyclohexane-1-diyl) bis (3- (3,4-dihydroxyphenyl) Hemisynthesis) acrylate)

 Butyl chlorogenate is prepared from 3-chlorogenic acid and according to the method described in Example 1 using butan-1-ol as the starting alcohol.

The solid obtained is purified by preparative HPLC (Vydac Denali column C18.50 × 250 mm, 10 μm) with a solvent A (H ₂ O + 0.1% HCOOH) and a solvent B (MeOH) in an isocratic fashion of 50% of B for 30 minutes at a flow rate of 20 mL / min. The compound obtained is a white solid.

 - Isolated yield: 13% (13 mg);

 - Molecular formula C20H26NO9;

 Molecular weight: 410.41 g / mol;

- ^J H (400MHz, CD3OD, 300K)? (Ppm) 7.43 (d, 3 = 16.0 Hz, 1H), 7.00 - 6.77 (m, 2H), 6.68 (d, J = 8.2 Hz, 1H), 6.11 (d, J = 16.0Hz, 1H), 5.31 - 5.01 (m, 1H), 4.12 - 3.85 (m, 3H), 3.64 (d, J = 4.4 Hz, 1H), 2.19 - 2.01 (m, 3H), 2.01 - 1.76 (m, 1H), 1.61 - 1.39 (m, 2H), 1.39 - 1.10 (m, 2H), 0.79 (t. , 3 = 7.2 Hz, 3H).

LC / MS analyzes were performed on Zorbax Eclipse column (Cis, 3.0x100mm, 1.8pm) with solvent A (H ₂ O + 0.1% HCOOH) and solvent B (acetonitrile) following a linear gradient of 5 to 95% B for 15 minutes, a linear gradient of 95% to 100% for 1 minute and then a 100% isocratic mode of B for 2 minutes at a flow rate of 0.4 ml / min. Rt = 9.54 min, m / z (ESI + APCI Negative mode) [M-H] - 409.1

Claims

1. Compounds of general formula (IA)

 OCL (IA), in which R represents a linear C ₂ -C alkyl group _P or branched, cyclic or cyclic branched, saturated or unsaturated, said group may be substituted by one or more substituents selected from the group comprising: -OR, -NRiR _2, -N0 ₂ , -CORi, -COORi, -CF ₃ , -CRiF ₂ , -CRiR ₂ F, = O, -CN, halogen, -SR 1, -SO ₂ R 1, aryl, in which  p is a natural number between 3 and 18, R 1 and R ₂ are identical or different and each represents, independently of one another, or a substituent chosen from the group comprising: -H, -OH, -NH ₂ , -NO ₂ , -COOH, -FC ₃ , -CHF ₂ , -CH ₂ F, = O, -CN, halogen, -SH , -S0 ₂ H, or a linear or branched, cyclic or cyclic branched, saturated or unsaturated C ₂ -C ₂₀ alkyl group which may be substituted with one or more substituents chosen from the group comprising: -H, -OH, -NH ₂ , -NO ₂ , -COOH, -CF ₃ , -CHF ₂ , -CH ₂ F, = O, -CN, halogen, -SH, -SO ₂ H, and Q1, Q3, Q4 and Q5 are each independently of one another a radical selected from the group consisting of hydrogen, caffeoyl, maloyl, c-alkyloyl or maloyl-cauloyl, with the proviso 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, Q3, CM and Q5 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 selected from the following group:  - The ethyl ester of 3,5-diocoyoylquinic acid  2-hydroxy-pentyl ester of 3,5-diocoyoylquinic acid, and  - The 2-hydroxy-hexyl ester of 3,5-diocoyoylquinic acid. 4. Compounds for their use according to any one of claims 1 to 3, characterized in that said neurodegenerative disease is selected from: Alzheimer's disease, spinocerebellar ataxia, multisystem atrophy, Alexander's 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 the general formula (IA)

OQ ₄ (IA), in which R represents a linear C ₂ -C alkyl group _P or branched, cyclic or cyclic branched, saturated or unsaturated, possibly being substituted with one or more of the following groups: -OR, - N R1R2, - NO2, -CORi, -COORi, - CF ₃ , -CR ₁ F ₂ , -CR ₁ R ₂ F, = O, -CN, halogen, -SR 1, -SO ₂ R 1, aryl in which  p is a natural number between 3 and 18, Ri and R ₂ are identical or different and each represents, independently of one another, or a substituent chosen from the group comprising: H, -OH, -NH ₂ , -NO ₂ , -COOH, -CF ₃ , -CH F ₂ , -CH ₂ F, = O, -CN, halogen, -SH , - S0 ₂ H, or a linear or branched, cyclic or cyclic branched, saturated or unsaturated C ₂ -C 6 alkyl group which may be substituted with one or more substituents chosen from the group comprising: -H, -OH, -INH 2, -NO 2, COOH, -CF ₃ , -CH F ₂ , -CH ₂ F, = O, -CN, halogen, -SH, -SO ₂ H, and  Q 1, Q 4, Q 4 and Q 5 each independently represent a hydrogen atom, a caffeoyl, a maloyl, a c-alkyloylmaloyl or a maloylcafeoyl group, provided that at least one of these radicals is not an atom of hydrogen, except for the following compounds:  Compounds of general formula (IB)

in which R3 is a linear or branched C2-C6 alkoxy, in particular an ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, isopentoxy and n-hexoxy group, - R ₄ , Rs and Re are each independently selected from: an -OH group and a group represented by the following formula (X):

wherein R7 is -OH and n is an integer of 1 to 5, with at least one of R ₄ , Rs or Re corresponding to said formula (X).  • Cyclohexanecarboxylic acid, 1- (2-hydroxypropoxy) propan-2-yl, 3,5-bis [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propenediol) 1-yl] oxy] -1,4-dihydroxy- (1S, 3K, 4S, 5K)  • Cyclohexanecarboxylic acid 1- (1-hydroxypropan-2-yloxy) propan-2-yl ester, 3,5-bis [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo] 2-propenyl-yl] oxy] -1,4-dihydroxy- (1S, 3K, 4S, 5K)  • Cyclohexanecarboxylic acid, 2- (1-hydroxypropan-2-yloxy) propyl ester, 3,5-bis [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propenyl) 1-yl] oxy] -1,4-dihydroxy- (1S, 3K, 4S, 5K)  • Cyclohexanecarboxylic acid, 2- (2-hydroxypropoxy) propyl ester, 3,5-bis [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-yl] oxy] -1,4-dihydroxy- (1S, 3K, 4S, 5K)  • The ethyl ester of cyclohexanecarboxylic acid, 3 - [[3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- (1S) , 3R, 4R, 5R) • The propyl ester of cyclohexanecarboxylic acid, 3 - [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy - (1S, 3R, 4R, 5R) • Cyclohexanecarboxylic acid 1-methylethyl ester, 3 - [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5 -trihydroxy- (1S, 3R, 4R, 5R)  • Butyl ester of cyclohexanecarboxylic acid, 3 - [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy - (1S, 3R, 4R, 5R)  • Cyclohexanecarboxylic acid butyl ester, 3 - [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- (1K, 3S, 4S, 5S)  Cyclohexanecarboxylic acid octyl ester, 3 - [[3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- (1S); 3K, 4K, 5K) 3 - [[3- (3,4-Dihydroxyphenyl) -1-oxo-2-propenyl] cyclohexanecarboxylic acid acetic anhydride (1S, 3R, 4R, 5R) oxy] -l, 4,5-trihydroxy (lS, 3 ", 4", 5 ")  The cyclohexanecarboxylic acid dodecyl ester, 3 - [[3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy-1S, 3R, 4R, 5R)  Cyclohexanecarboxylic acid 2-ethylhexyl ester, 3 - [[3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- 1S, 3R, 4R, 5R)  • Cyclohexanecarboxylic acid 2-methylhexyl ester 3 - [[3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- (1S) , 3R, 4R, 5R)  • Cyclohexanecarboxylic acid hexadecyl ester 3 - [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy - (1S, 3R, 4R, 5R)  • The octadecyl ester of cyclohexanecarboxylic acid 3 - [[3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- (1S, 3R, 4R, 5R) Cyclohexanecarboxylic acid eicosyl, 3 - [[3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- (1S) , 3R, 4R, 5R) Cyclohexanecarboxylic acid, 2,3-butadien-1-yl, 3 - [[(2E) - 3- [4- (2,3-butadien-1-yloxy) -3-hydroxyphenyl] -1- oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- (1S, 3K, 4K, 5K)  Cyclohexanecarboxylic acid phenylmethyl ester, 3 - [[3- (3,4-dihydroxyphenyl) -1-oxo-2-propenyl] oxy] -1,4,5-trihydroxy- (1S, 3fl, 4fl); 5FL) Cyclohexanecarboxylic acid (2E) -3,7-dimethyl-2,6-octadien-1-yl ester, 3 - [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo] 2-propen-1-yl] oxy] -1,4,5-trihydroxy- (1H, 3S, 4S, 5fl)  2-chloroethyl ester of cyclohexanecarboxylic acid, 1,3,4-trihydroxy-5 - [[(2E) -3- (4-hydroxy-3-methoxyphenyl) -1-oxo-2-propen] yl] oxy] - (lK, 3K, 4S, 5K)  • The ethyl ester of cyclohexanecarboxylic acid, 3,4-bis [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,5 1-dihydroxy-1S, 3R, 4R, 5R) • The ethyl ester of cyclohexanecarboxylic acid, 3,5-bis [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4 -dihydroxy- (la, 3R, 4a, 5R)  • The ethyl ester of cyclohexanecarboxylic acid, 3,4-bis [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,5 -dihydroxy- (1R, 3R, 4S, 5R)  • The anhydride of cyclohexanecarboxylic acid 3 - [[3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy- and the 3- (4-hydroxyphenyl) -2-propenoic acid (1S, 3R, 4R, 5R) - • Butyl ester of cyclohexanecarboxylic acid, 3,5-bis [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4 dihydroxy- (1S, 3 ", 4S, 5")  • Butyl ester of cyclohexanecarboxylic acid, 3,4-bis [[(2E) -3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,5 dihydroxy- (1K, 3S, 4S, 5S)  Cyclohexanecarboxylic acid propyl ester, 3,5-bis [[3- (3,4-dihydroxyphenyl) -1-oxo-2-propen-1-yl] oxy] -1,4-dihydroxy- (1S); 3 ", 4 S, 5") (2E, 2'E) - ((1R, 2S, 3R, 5S) -2,5-dihydroxy-5 - ((3-hydroxypropoxy) carbonyl) cyclohexane-1,3-diyl) bis (3- ( 3,4-dihydroxyphenyl) acrylate), their stereoisomers and their pharmaceutically or nutraceutically acceptable salts. 6. Compounds according to claim 5, characterized in that any two radicals Qi, Q3, CM and Q5 represent a caffeoyl group, and the other two radicals represent a hydrogen atom. Compounds according to claim 5 or 6, characterized in that they are selected from the following group: 2-hydroxy-pentyl ester of 3,5-diocoyoylquinic acid, and - The 2-hydroxy-hexyl ester of 3,5-diocoyoylquinic acid. Compounds according to any one of claims 5 to 7 for use as a medicament. 9. A pharmaceutical composition comprising at least one compound according to any one of claims 5 to 7, and at least one pharmaceutically acceptable excipient, or nutraceutical composition comprising at least one compound according to any one of claims 5 to 7, and at least one a nutraceutically acceptable excipient. 10. Pharmaceutical composition according to claim 9 for use in the prevention and / or treatment of a neurodegenerative disease, including Alzheimer's disease.