Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
  • C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
  • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• 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.
• QPS polysubstituted quinic acid ester derivatives
• 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).
• PCQ polycafoylquinic acid ester derivatives
• the present invention relates to compounds of general formula (IA):
• p is a natural number between 3 and 18,
• -Ri and R 2 are identical or different and each represent, independently of one another,
• 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.
• the present invention relates to compounds of general formula (IA),
• p is a natural number between 3 and 18,
• Ri and R 2 are identical or different and each represents, independently of one another,
• 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,
• 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):
• R7 is -OH and n is an integer of 1 to 5,
• 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.
• 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.
• 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 ⁇ 1-42 added to a final concentration of 20 ⁇ , 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
• 2-hydroxy hexyl ester of 3,5-diocoyoylquinic acid (2-HHE DCQ) Fig. 1D
• concentrations ranging from 10 nM to 10 ⁇ M according to US Pat.
• Example 2 Example 2
• FIGS. 2A to 2D show the growth of the latent neurite network for 24 hours by the ⁇ 1-42 peptide added to a final concentration of 20 ⁇ l, 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 ⁇ according to example 2.
• FIGS. 2A to 2D show the growth of the latent neurite network for 24 hours by the ⁇ 1-42 peptide added to a final concentration of 20 ⁇ l, 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 ⁇ according to example 2.
• the present invention relates to compounds of general formula (IA):
• p is a natural number between 3 and 18,
• Ri and R 2 are identical or different and represent, each independently of one another
• 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.
• 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.
• 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.
• caffeoyl group is meant a radical of formula (II), derived from caffeic acid:
• maloyl group is meant a radical of formula (IIIa) or (IIIb), derived from malic acid:
• alkyloylmaloyl group means a radical of formula (IVa) or (IVb)
• maloylcaféoyl group is meant a radical of formula (Va), (Vb), (Vc) or (Vd):
• polysubstituted quinic acid 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
• 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.
• radicals Qi, Q3, Q4 and Q5 represent a hydrogen atom
• chlorogenic acid is meant 3 - [(3- (3,4-dihydroxyphenyl) oxo-2-propenyl] oxy] -l acid, 4,5-Trihydroxycyclohexanecarboxylic, according to IUPAC definition.
• 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.
• salts which are pharmaceutically or nutraceutically acceptable, as defined above, and which possess the desired pharmacological activity of the parent compound.
• Such salts include:
• compositions 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.
• 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.
• 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.
• a neurodegenerative disease may be a neurodegenerative disease due to oxidative stress. This is particularly the case of Alzheimer's disease.
• Alzheimer's disease 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 ⁇ -amyloid peptide ( ⁇ ) has now shifted from insoluble ⁇ -fibrils to smaller soluble ⁇ -oligomer aggregates.
• Soluble oligomers of ⁇ 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).
• all substances having a reducing property of ⁇ -peptide neurotoxicity may be useful as a novel therapeutic agent for the treatment or prevention of Alzheimer's disease.
• 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.
• Qi, Q3, CM and Qs represent, independently of one another, a hydrogen atom.
• 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
• 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.
• Q5 represents a group caféoyle
• Qi, Q 3 and Q 4 each represents a hydrogen atom.
• 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
• R represents a linear alkyl group of C 4.
• 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
• 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
• R represents a linear alkyl group C2;
• Qs and Qs represent a caffeoyl group
• Q 1 and Q 4 represent a hydrogen atom
• R represents a linear C 2 alkyl group
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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).
• 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.
• Q 1 and Q 4 each represent a hydrogen atom
• 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.
• 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.
• 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.
• the subject of the invention is compounds of general formula (IA)
• p is a natural number between 3 and 18,
• -Ri and R 2 are identical or different and represent each independently of one another
• N0 2 , -COOH, -CF 3 , -CHF 2 , -CH 2 F, O, -CN, halogen, -SH, -SO 2 H,
• 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.
• 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.
• 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
• R represents a linear alkyl group of C 4.
• 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
• 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
• R represents a linear C 2 alkyl group
• Qs and Qs represent a caffeoyl group
• Q 1 and Q 4 represent a hydrogen atom
• R represents a linear C 2 alkyl group
• 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.
• any two radicals Qi, Q3, Q4 and Q5 represent a caffeoyl group, and the other two radicals represent a hydrogen atom.
• Q 1 represents a hydrogen atom
• Q 1 and Q 4 each represent a hydrogen atom.
• 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.
• 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.
• 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.
• 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.
• QPS polysubstituted quinic acid
• 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.
• 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.
• 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.
• the alcohol is selected from: ethanol, 2-hydroxy-pentan-1-ol and 2-hydroxy-hexan-1-ol.
• 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.
• a carboxyl group activating agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, combination with 1-hydroxybenzotriazole hydrate.
• carboxyl group activating agent any reagent or combination of reagents for activating the carboxylic acid function to allow its coupling with a nucleophile under mild reaction conditions.
• 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.
• HOBT 1-hydroxybenzotriazole
• HOAt 1-hydroxy-7-azabenzotriazole
• HOSu 1-hydroxysuccinimide
• HESu 1-hydroxysuccinimide
• the activatable activating agent may also be part of the family of phosphonium, uronium and / or guanidinium salts.
• 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.
• the invention therefore relates to compounds of general formula (IA)
• 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):
• R7 is a linear or branched C2-C6 -OH or alkoxy group and n is an integer of 1 to 5,
• the present invention relates to compounds of general formula (IA):
• 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.
• 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.
• 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.
• 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
• R represents a linear alkyl group having 4,
• 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
• 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
• R represents a linear C 2 alkyl group
• Qs and Qs represent a caffeoyl group
• Q 1 and Q 4 represent a hydrogen atom
• R represents a linear C 2 alkyl group
• 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.
• the present invention also relates to a pharmaceutical composition
• 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.
• 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.
• 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.
• 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, keratolymila, 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,
• 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 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 ⁇ -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 ⁇ -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.
• esters tested are as follows:
• the vehicle used is the culture medium (see section below) containing 0.1% DMSO (Pan Biotech, Batch: H130813).
• 3,5 DCQ acid is tested under the same conditions.
• 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).
• DMEM medium Dulbecco's modified Eagle's medium
• FCS 10% fetal calf serum
• 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.
• BDNF brain-derived neurotrophic factor
• 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 ⁇ peptides (see below).
• ⁇ 1-42 peptide The preparation of the ⁇ 1-42 peptide is carried out according to the procedure described in Callizot et al (2013).
• the peptide ⁇ 1-42 (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 ⁇ l).
• 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 ⁇ 1-42 peptide.
• the peptide solution ⁇ 1-42 is added to a final concentration of 20 ⁇ diluted in the culture medium in the presence of the ester and the whole is left for 24 hours.
• 3,5-diocoyoylquinic acid is tested under the same conditions. Evaluation of the survival of neurons, the neurite network and astrocytes
• MAP-2 anti-microtubule-associated-protein 2 monoclonal mouse antibody
• FCS fetal calf serum
• 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
• GFAP rabbit polyclonal anti-glial fibrillary acid protein antibody
• 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).
• 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.
• Figures 1A to 1D show survival, as a percentage of live versus control neurons, of primary cortical neurons intoxicated during 24h with the ⁇ 1-42 peptide added to a final concentration of 20 ⁇ l, 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.
• 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 ⁇ 1-42 peptide, and the molecule tested, at the respective concentrations of 10 nM, 100 nM, 1 ⁇ and 10 ⁇ .
• FIGS. 2A to 2D show the growth of the neurite network intoxicated for 24 h by the peptide of ⁇ 1-42 added to a final concentration of 20 ⁇ , 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 ⁇ .
• the neurite network 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 ⁇ 1-42 peptide, and the molecule tested, at the respective concentrations of 10 nM, 100 nM, 1 ⁇ and 10 ⁇ .
• the control control was not treated with the ⁇ 1-42 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 3,5-DCQ ethyl ester preincubated one hour before the addition of the ⁇ 1-42 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 2-HPE-DCQ pre-incubated one hour before the addition of the peptide ⁇ 1-42 shows a significant effect on the neurite network at its two highest concentrations (1 ⁇ and 10 ⁇ , 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 ⁇ 1-42 shows a protective effect on the neurite network at all concentrations tested except for the lowest concentration (10 nM) ( Figure 2D).
• 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.
• these compounds are of interest as new therapeutic agents for the prevention or treatment of a neurodegenerative disease, and in particular Alzheimer's disease.
• 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.
• 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 ⁇ m) 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.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Engineering & Computer Science (AREA)
• Biomedical Technology (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Psychiatry (AREA)
• Hospice & Palliative Care (AREA)
• Emergency Medicine (AREA)
• Epidemiology (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=58401644

Family Applications (1)

Country Status (3)

Families Citing this family (2)

Family Cites Families (4)

• 2016
  • 2016-10-26 FR FR1660403A patent/FR3057772B1/fr active Active
• 2017
  • 2017-10-26 EP EP17797101.7A patent/EP3532048A1/de active Pending
  • 2017-10-26 WO PCT/EP2017/077430 patent/WO2018078010A1/fr unknown

Also Published As

Similar Documents

Legal Events