EP3448376A1 - Amidderivate von polycaffeoylchinasäuren, verfahren zu davon herstellung und verwendungen davon - Google Patents

Amidderivate von polycaffeoylchinasäuren, verfahren zu davon herstellung und verwendungen davon

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Publication number
EP3448376A1
EP3448376A1 EP17719591.4A EP17719591A EP3448376A1 EP 3448376 A1 EP3448376 A1 EP 3448376A1 EP 17719591 A EP17719591 A EP 17719591A EP 3448376 A1 EP3448376 A1 EP 3448376A1
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EP
European Patent Office
Prior art keywords
group
compound
acid
compounds
pat1657
Prior art date
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EP17719591.4A
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English (en)
French (fr)
Inventor
Damien Boeglin
Pierre WARNAULT
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Temisis
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Temisis
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/37—Esters of carboxylic acids
    • A61K8/375—Esters of carboxylic acids the alcohol moiety containing more than one hydroxy group
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
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    • A—HUMAN NECESSITIES
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    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
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    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • 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 poly substituted quinic acid amide derivatives (abbreviated as "QPS"), as well as to a process for their preparation, to their use as a medicament, especially for the treatment and / or prevention of inflammation, and pharmaceutical, cosmetic or nutraceutical compositions containing them.
  • QPS poly substituted quinic acid amide derivatives
  • PRIOR ART Inflammation is a set of reactions generated by the body in response to an aggression undergone.
  • Inflammation can be caused by physical aggressions (such as hot, cold, ionizing radiation) or chemical (caused by acidic or basic compounds, bacterial toxins). It can also be the consequence of an infection (in relation to the presence in the organism of pathogenic living organisms such as bacteria, viruses, parasites or fungi). It can also be caused by an immune reaction secondary to the reintroduction into the body of an antigen (allergy) such as an antibiotic. Finally, it is often the consequence of tissue necrosis, itself secondary to many causes, for example an arterial occlusion.
  • the inflammatory reaction aims at the defense of the organism and the inflammation when it is visible is manifested classically by four clinical signs: a redness, a pain, a swelling and / or an increase of the heat.
  • Acute inflammation is the elimination of the agent responsible for the inflammation as well as the repair of the damaged tissue. Its manifestations are multiple: redness of the skin during a burn, the swelling of the tonsil during angina, inflammation of the joint during a sprain or the occurrence of coughing during bronchitis to eliminate pathogens. It is reversible in minutes or even days.
  • Chronic inflammation is an inflammation of prolonged duration, due to the persistence of the aggression factor (s), to which the body can no longer end spontaneously and which can become harmful to the body.
  • Predisposing factors are persistent aggression (such as gastric acid in peptic ulcer), inadequate response of the host to infection, chronic autoimmune disease (such as rheumatoid arthritis or ulcerative colitis) .
  • It is inflammation and its consequences that become the disease itself, often serious and disabling.
  • Each organ may be concerned by this chronic inflammation: digestive tract (Crohn's disease), lungs (asthma), skin (psoriasis), mucous membranes of the nasal cavity (rhinitis), vessels (vascular accidents), nervous system (multiple sclerosis) , joints (all rheumatism).
  • a better knowledge of chronic inflammation has also highlighted its presence, in situations where other mechanisms are involved: cancers, immunity of transplant, age-related macular degeneration (AMD) etc.
  • Cells in infected or injured tissue are the first cells activated by danger signals.
  • active compounds known mediators of inflammation such as histamine, pro-inflammatory cytokines and leukotrienes or prostaglandins.
  • the functional consequences of this activation are elimination of the pathogen (eg by phagocytosis) and / or repair of the lesion (remodeling of the extracellular matrix).
  • Cytokines are small proteins secreted by cells in response to various stimuli. At the level of the immune response, they allow the communication between the immune cells and the orientation of the response depending on the nature of the detected signal.
  • IL-6 Interleukin-6
  • IL-8 Interleukin-8
  • TNF ⁇ Tumor Necrosis Factor
  • IL-6 is produced by phagocytes (macrophages and dendritic cells) and endothelial cells in case of inflammation. It induces local activation of phagocytes and modification of the endothelium. It promotes the recruitment of blood monocytes to tissues and the production of acute phase proteins by hepatocytes.
  • IL-8 (IL-8 or CX-CL8) is produced in particular by epithelial cells following the detection of potentially pathogenic microbiological or chemical agents. His The main role is to ensure the recruitment of neutrophils at the site of infection by creating a chemotactic gradient that guides phagocytic cells with corresponding receptors on their surface.
  • TNF ⁇ is produced by macrophages, resident dendritic cells and mast cells.
  • TNFa stimulates the expression of adhesion molecules and the production of chemokines by endothelial cells allowing the recruitment of blood leukocytes (neutrophils, eosinophils, monocytes or NK lymphocytes) to the inflammatory focus.
  • TNFa also activates the microbicidal systems of phagocytes and is mitogenic for T and B lymphocytes (for the establishment of adaptive response if the innate response is not sufficient to resolve the infection).
  • TNFa activates the production of growth factors, which will be essential for the repair of the damaged tissue.
  • Prostaglandins including prostaglandin E2 (PGE 2 ), and leukotrienes, particularly leukotriene B 4 (LTB 4 ), are lipid mediators of inflammation and induce increased vessel dilatation and permeability, facilitating arrival of leukocytes at the site of inflammation.
  • PGE 2 prostaglandin E2
  • LTB 4 leukotriene B 4
  • caffeic acid such as phenethylated coffee ester (CAPE)
  • CEPAE phenethylated coffee ester
  • LTB 4 phenethylated coffee ester
  • HO-1 Theme oxygenase-1
  • HO-1 plays a crucial role in cytoprotection against cellular oxidative stress. It is highly inducible by various stimuli that cause cellular stress. Since the enzyme limits the rate of heme metabolism, HO-1 exerts its protective effects by maintaining appropriate levels of cellular heme and the release of bioactive molecules, including biliverdin, free iron and monoxide. carbon. Biliverdin and its reduced form, bilirubin, are potent antioxidants that can contribute to the beneficial effects of THO-1 (Baranano et al, 2002, Stocker et al, 1987). Carbon monoxide has an effect on the mediation of ⁇ -1 protection and has anti-inflammatory and anti-apoptotic effects (Otterbein et al., 2003).
  • Dicaffeoylquinic acids especially 3,4-O-dicaffeoylquinic acid and 4,5-O-dicaffeoylquinic acid, are also known in the art for their anti-inflammatory activity. These compounds are especially known for inhibiting the synthesis of leukotrienes B 4 (LTB 4 ) and the production of IL-8 (Gianfranco Peluso et al.).
  • 3,4,5-tricaffeoylquinic acid inhibits the production of mediators of inflammation (particularly cytokines and chemokines) in treated Keratinocytes with Lipopolysaccharide involved in the pathogenesis of inflammatory skin diseases (Lee, SA et al.).
  • caffeic acid derivatives such as methylated coffee or chlorogenic acid
  • methylated coffee or chlorogenic acid have been shown to have no significant anti-inflammatory effect (Xinyu Wang et al.), which shows that small structural variations can lead to an abolition of anti-inflammatory abilities.
  • EP 2 128 125 describes the anti-viral effects of certain dicaffeoylquinic acid amide derivatives, and their use, in particular in the treatment of infection with the HIV virus, the hepatitis B virus and the respiratory syncytial virus. The anti-inflammatory abilities of these compounds have not been evaluated.
  • the inventors have discovered that certain amide derivatives of QPS exhibit remarkable anti-inflammatory effects and can be used in the treatment of inflammation.
  • the inventors have also discovered that the amide derivatives of QPS have a major cytoprotective potential, especially on cells in an inflammatory state.
  • the present invention therefore relates to a compound (amide derivative of QPS or a mixture of compounds of general formula (IA):
  • R and R 2 A represent independently of each other:
  • R 1 and R 2 A are not both hydrogen, A butyl group,
  • Q 1, Q 3, Q 4 and (3 ⁇ 4 represent, independently of one another, an OH, a caffeoyl, a maloyl, a coyloylmaloyl or a maloylcafoyl group, provided that at least one of these radicals is not an OH group,
  • the invention relates to a process for preparing a compound of general formula (IA)
  • R and R 2 A represent independently of each other:
  • R 1 and R 2 A are not both a hydrogen atom, a butyl group
  • Q 1, Q 3, Q 4 and Q 5 represent, independently of each other, an OH, a caffeoyl, a maloyl, a caffeoylmaloyl or a maloylcafoyl group, provided that at least one of these radicals is not an OH group,
  • the present invention relates to a compound obtainable by said process according to the invention.
  • the present invention relates to a compound or a mixture of compounds of general formula (IB):
  • RIB and R 2 B represent independently of each other:
  • Qi, Q3, Q.4 and (3 ⁇ 4 represent, independently of each other, an OH, caffeoyl, maloyl, caféoylmaloyl or maloylcaféoyl group, provided that at least one of these radicals is not an OH group,
  • the present invention further relates to a compound or a mixture of compounds (amide derivative of QPS) of general formula (IA):
  • R and R 2 A represent independently of each other:
  • R and R 2 A are not both hydrogen, - a butyl group, a C 7 -C 30 alkyl group,
  • Q1, Q3, Q4 and (3 ⁇ 4 represent, independently of one another, an OH, a caffeoyl, a maloyl, a coyloylmaloyl or a maloylcafoyl group, provided that at least one of these radicals is not an OH group,
  • Figure 1 Schemes of the inductions carried out for the various inflammatory mediators studied: A. Diagram of induction of I L-8, PGE2, I L-6 and TNF- ⁇ ; B. Induction pattern of LTB4.
  • Figure 2. Measurements of the viability of NHEK keratinocytes after 26 h of treatment with different concentrations of the compounds PAT965, PAT964, PAT967, PAT1658, PAT1657 or PAT1648. Viability percentages were calculated based on the untreated negative control (untreated CTL) set at 100% and the positive cytotoxicity control (SDS at 0.008%). DMSO 1%: vehicle control of PAT compounds. The error bar is the standard deviation around the mean.
  • FIG. 3 Measurements of the viability of NHEK keratinocytes after 50 h of treatment with different concentrations of the compounds PAT965, PAT964, PAT967, PAT1658, PAT1657 or PAT1648. Viability percentages were calculated based on the untreated negative control (untreated CTL) set at 100% and the positive cytotoxicity control (SDS at 0.008%). DMSO 1%: vehicle control of PAT compounds. The error bar is the standard deviation around the mean.
  • FIG. 4 Quantification of I L-8 production by inflammatory NHEK keratinocytes treated with PAT965, PAT964, PAT967, PAT1658, PAT1657 or PAT1648. The results are expressed as a percentage of the 100% PMA treated condition (CTL). The graph shows the mean of the IL-8 measurements in the supernatants from 3 independent cultures, as well as the standard deviation. Values of p (p-value) less than 0.001 are considered very highly significant (***) (ANOVA analysis of variance and Dunnett comparison test compared to PMA-induced condition). Dexamethasone was used as the reference molecule. Figure 5.
  • FIG. 7 Quantification of the production of TNF- ⁇ by NHEKs keratinocytes in inflammatory state treated with the compounds PAT965, PAT964, PAT967, PAT1658, PAT1657 or PAT1648. The results are expressed in percent relative to the condition treated with PMA combined with calcium ionophore in a medium containing 0.06 mM Ca 2+ (CTL) set at 100%. The graph shows the average of TNF- ⁇ measurements in supernatants from 3 independent cultures, as well as the standard deviation. Values of p ⁇ 0.001 are considered very highly significant (***) (ANOVA analysis of variance and Dunnett comparison test versus PMA / calcium ionophore induced condition). Dexamethasone was used as the reference molecule.
  • FIG. 8 Quantification of LTB4 production by inflammatory NHEK keratinocytes treated with PAT965, PAT964, PAT967, PAT1658, PAT1657 or PAT1648. The results are expressed in percent relative to the condition treated with arachidonic acid combined with calcium ionophore (CTL) set at 100%. The graph shows the mean of LTB4 measurements in supernatants from 3 independent cultures, as well as the standard deviation. Values of p ⁇ 0.001 are considered very highly significant (***) (ANOVA analysis of variance and comparison test of Dunnett with respect to arachidonic acid / calcium ionophore induced condition). Nordihydroguaiaretic acid (NDGA) was used as the reference molecule.
  • Figure 9 Quantification of LTB4 production by inflammatory NHEK keratinocytes treated with PAT965, PAT964, PAT967, PAT1658, PAT1657 or PAT1648. The results are expressed in percent relative to the condition treated with arachidonic acid combined
  • Zone A zone of application of the acetone solution of TPA
  • Zones A and B Areas of application of ointments (control and two concentrations of compound PAT1657);
  • Zone C the remainder of the back for which no application has been made.
  • Figure 10. Representative curve of the degree of inflammation in the area of application of the TPA acetone solution and the treatment area (Area A, Figure 9). The curves described by a circle, a triangle and a square correspond respectively to the control (Excipial® ointment alone), to treatment with compound PAT1657 incorporated at 1.33% and 2.67% in the Excipial® ointment.
  • Figure 1 Representative curve of the degree of inflammation in the area of application of the treatment and outside the area of application of the acetone solution of TPA (zone B, Figure 9). The curves described by a circle, a triangle and a square correspond respectively to the control (Excipial® ointment alone), to treatment with compound PAT1657 incorporated at 1.33% and 2.67% in the Excipial® ointment.
  • FIG 12. Representative curve of the degree of inflammation in the rest of the back (Area C, Figure 9). The curves described by a circle, a triangle and a square correspond respectively to the control (Excipial® ointment alone), to treatment with compound PAT1657 incorporated at 1.33% and 2.67% in the Excipial® ointment.
  • Figure 13 Representative curve of the global macroscopic score of cutaneous inflammation (sum of zones A, B and C) as a function of treatment. The curves described by a circle, a triangle and a square correspond respectively to the control (Excipial® ointment alone), to treatment with compound PAT1657 incorporated at 1.33% and 2.67% in the Excipial® ointment.
  • Figure 14 Representative curve of the average psoriasis severity score (PASI on the ordinate) of the mice of the treatment groups during the experiment (time in days on the abscissa).
  • the curves described by a circle, a cross, a black triangle, a white square and a black square respectively correspond to the positive ALD / EP control (induction of psoriasis and Excipial® neutral ointment application), to the negative control EP / EP (no induction of psoriasis and Excipial® neutral ointment application), treatment with the reference compound Dermoval® (ALD / Dermoval®), treatment with compound PAT1657 incorporated at 1.33% (ALD / PAT / PAT 1657-1, 33%) and 2.67% (ALD / PAT 1657-2.67%) in Excipial® ointment.
  • ALD / EP control induction of psoriasis and Excipial® neutral oin
  • alkyl group C x -C y is meant within the meaning of the present invention, a monovalent saturated hydrocarbon chain or unsaturated, linear or branched, cyclic or cyclic branched, containing from x to y carbon atoms.
  • C 7 -C 30 alkyl group is meant, in the sense of the present invention, a linear or branched, cyclic or cyclic branched or unsaturated saturated or unsaturated hydrocarbon chain comprising from 7 to 30 carbon atoms, preferably from From 7 to 26 carbon atoms, more preferably from 7 to 24 carbon atoms, more preferably from 7 to 22 carbon atoms, more preferably from 7 to 20 carbon atoms, in particular from 7 to 18 carbon atoms.
  • heptyl By way of example and in a non-exhaustive manner, mention may be made of heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, docosyl, tetracosyl and hexacosyl groups. geranyl, farnesyl, geranylgeranyl, oleyl, citronelly and squalenyl.
  • the alkyl groups are linear.
  • An aryl group C x -C y used in the context of the present invention, an aromatic hydrocarbon complying with the Hückel rule for aromaticity on, mono- or polycyclic, and having from x to y carbon atoms.
  • C x -C y aryl is meant, in the sense of the present invention, an aromatic hydrocarbon respecting the rule of Huckel on aromaticity, mono- or polycyclic, having from x to y carbon atoms .
  • aromatic hydrocarbon respecting the rule of Huckel on aromaticity, mono- or polycyclic, having from x to y carbon atoms .
  • a C 7 -C 30 alkylaryl group is understood to mean a C 1 -C 24 alkyl group covalently bonded to an aryl group.
  • an arylalkyl group C7-C30, used in the context of the present invention, an aryl group C O -cis covalently bonded to an alkyl group
  • caffeoyl group is meant a radical of general formula (VI), derived from caffeic acid:
  • maloyl group is meant a radical of general formula (VIIa) or (VIIb), derived from malic acid:
  • maloylcaféoyl group is meant a radical of general formula (IXa) (IXb) or (IXc) or (IXd):
  • substituted poly quinic acid (abbreviated as "QPS" throughout the present description) is meant a mono, di, tri or tetra ester composed of an acid molecule. quinique of which one, two, three or the four alcohol functions have been esterified with a caffeic acid, a malic acid, or a mixture of caffeic acid and malic acid. QPS are therefore acids of general formula (IV):
  • Oj, QB, Q 4 and 3 ⁇ 4 represent, independently of one another, an OH, a coffeeoyl, a maloyl, a coffeeoylmaloyl or a maloylcaféoyl group, provided that at least one of these radicals is not an OH group.
  • QPS is a polycafeoylquinique 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 all four alcohols were esterified with caffeic acid.
  • PCQs are therefore acids of general formula (IV) as defined above in which Qi, QB, Q 4 and Qs represent, independently of each other, an OH or a caffeoyl group, provided that at least one of these radicals is not an OH group.
  • the different isomers of QPS are thus acids of general formula (IV), with Qi, QB, Q4 and Q5 as defined in a non-exhaustive manner in Tables 1 to 4 below.
  • Coffeeoyl Coffeeoyl OH also called isochlorogenic acid B
  • Coffeeoyl also called isochlorogenic acid A
  • Coffeeoyl also called isochlorogenic acid C
  • 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 carbodiimide family 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
  • the activatable activating agent may also be part of the family of phosphonium, uronium and / or guanidinium salts.
  • the agent for activating the carboxyl groups is chosen from diisopropylcarbodiimide (DIC) and 1-hydroxybenzotriazole (HOBT).
  • the term "pharmaceutically acceptable” is intended to mean that which is useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for veterinary use as well as human pharmaceutical.
  • salts which are pharmaceutically acceptable, as defined herein, and which possess the desired pharmacological activity of the parent compound.
  • Such salts include:
  • pharmaceutically acceptable acid addition salts formed with pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with pharmaceutically acceptable organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, acid glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, the acid muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic
  • 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.
  • the term "inflammation” means a set of reactions generated by the body in response to aggression undergone. These reactions are clinically manifested by redness, pain, swelling and / or increased heat, and biologically by the recruitment of immune system cells and the release of inflammatory mediators such as pro-inflammatory cytokines, leukotrienes or prostaglandins.
  • inflammatory disease means a disease resulting from excessive and often chronic inflammation.
  • diseases include inflammatory diseases resulting from an excessive specific response of the immune system, such as asthma, psoriasis, rhinitis, osteoarthritis and autoimmune diseases including Raynaud's syndrome, autoimmune thyroiditis, dermatitis, multiple sclerosis, rheumatoid arthritis, insulin-dependent diabetes mellitus, uveitis, inflammatory bowel disease (including Crohn's disease and ulcerative colitis), systemic lupus erythematosus; and diseases resulting from an excessive non-specific response of the immune system, such as diseases due to respiratory distress syndrome in adults, septic shock, oxygen toxicity, multi-organ failure syndrome secondary to sepsis, multi-organ failure syndrome secondary to trauma, tissue reperfusion injury due to extracorporeal circulation, myocardial infarction, acute glomerulonephritis, vasculitis, reactive arthritis, acute inflammatory component dermatitis, stroke cerebral, thermal
  • the present invention therefore relates to compounds or a mixture of compounds, amide derivatives of QPS, of general formula (IA):
  • R and R 2 A represent independently of each other:
  • Q 1, QB, Q 4 and (3 ⁇ 4 represent, independently of one another, an OH, a C, C, C, C, or C -C alkyl group, provided that at least one of these groups is not an OH group;
  • the present invention relates to compounds or a mixture of compounds, derivatives PCQ amides of the general formula (IA) as defined above wherein Q 1, Q, Q 4 and Q 5 are independently each other, an OH or coffeeoyl group, provided that at least one of these radicals is not an OH group.
  • the present invention relates to compounds or a mixture of compounds, derivatives PCQ amides of the general formula (IA) as defined above in which any two of Q1 radicals, QB, Q 4 and Q 5 represent a caffeoyl group the other two represent an OH group.
  • the compounds of general formula (IA) according to the invention are characterized in that Qi represents an OH group.
  • Qi represents an OH group.
  • the compounds of general formula (IA) according to the invention which are particularly advantageous are those characterized in that Qi and Q4 represent an OH group and Q and Q5 represent a caffeoyl group, thus corresponding to the amide derivatives of 3,5-O-acid. -dicaffeoylquinic (3,5-DCQ).
  • the amide derivatives of QPS, in particular the amide derivatives of PCQ, according to the invention are characterized in that R is a hydrogen atom.
  • R is a hydrogen atom and R 2 A is a butyl group or an alkyl group, advantageously linear, C 7 -C 30, in particular OC 26, preferably C 7 -C 24 , preferentially C 7 -C 22 , even more preferentially C 7 -C 2 o, in in particular C 7 -C 18, especially an alkyl group chosen from heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, docosyl, tetracosyl, hexacosyl, geranyl, farnesyl, geranylgeranyl, oleyl, citronelly and squalenyl, preferably an alkyl group selected from
  • the amide derivatives of QPS in particular the amide derivatives of PCQ, according to the invention are characterized in that R is a hydrogen atom and R 2 A is a C 7 -C 10 aryl group, in which especially a naphthyl, or a C 7 -C 30 arylalkyl group, in particular a phenyl- (C 1 -C 4) alkyl, more particularly a phenylbutyl.
  • the compounds according to the invention are of general formula (II)
  • n is 3 or is greater than or equal to 6, in particular n is 3, 7, 11 or 17.
  • the amide derivatives of PCQ are finally obtained by acylation of the hydroxyl groups of the amide derivatives of quinic acid with allyl-caffeic acid chloride and then by a deprotection reaction of the allyl groups in the presence of Rh (PPh 3 ) 3 Cl / DABCO / EtOH or Pd (PPH 3 ) 4 / morpholine / THF.
  • the inventors have discovered that the preparation of the amide derivatives of QPS can be carried out in one step by semisynthesis from a particular QPS allowing amide derivatives of this QPS to be obtained in the form of a single regioisomer.
  • the present invention also relates to a process for preparing a compound of general formula (IA)
  • R, R 2 A, Q 1, Q, Q 4 and Q 5 are as defined above;
  • said QPS is a PCQ, advantageously chosen from 3-O-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 the PCQ is 3,5-DCQ.
  • Qi, QB, Q 4 and Qs represent, independently of each other, an OH or a caffeoyl group, provided that at least one of these radicals is not an OH group.
  • any two of the radicals Q 1 , QB, Q 4 and Q 5 represent a coffee group, the other two representing an OH group.
  • the present invention relates to a process for the preparation of a compound of general formula (IA), wherein R is a hydrogen atom, more particularly R is a hydrogen atom and R 2 A is a butyl group or an alkyl group, advantageously linear, C 7 -C 30 , in particular C 7 -C 6, more particularly C 7 -C 24 , preferably C 7 -C 22 , preferentially C 7 -C 20 , in particular C7-C18, especially an alkyl group chosen from heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, docosyl, tetracosyl, hexacosyl, geranyl, farnesyl,
  • the compound of formula H NRURZA is chosen from alkylamines, particularly butan-1 -amine or alkylamines C7-C30, particularly C7-C2 6, especially C7-C 24, still more preferably C7 -C20, preferably C7-C18.
  • the compound of formula HNRuR2A is chosen from one of the following compounds: octan-1-amine, laurylamine, 1-octadecylamine, 4-phenylbutan-1-amine or 2-naphthylamine.
  • the present invention relates to a process for the preparation of a compound of general formula (I I) or (II I):
  • n is an integer of 3 or 6 to 29, in particular 3 or 6 to 25, most preferably n is 3, 7, 1 1 or 17 , characterized in that it comprises a step a) during which a 3,5-DCQ reacts with a compound of formula of general formula (V)
  • the present invention relates to a process for preparing one of the following compounds of the respective formulas (IIa), (Mb), (IIc) and (IId):
  • step a) is carried out in the presence of an inert solvent such as dichloromethane, ⁇ , ⁇ -dimethylformamide or tetrahydrofuran, especially at a temperature of between -15 ° C. and the reflux of the solvent.
  • an inert solvent such as dichloromethane, ⁇ , ⁇ -dimethylformamide or tetrahydrofuran
  • step a) of the process according to the invention is optionally preceded by a step of activating the carboxyl group of a QPS, in particular PCQ, in particular with a carboxyl group activating agent, such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide in combination with 1-hydroxybenzotriazole hydrate.
  • a carboxyl group activating agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide in combination with 1-hydroxybenzotriazole hydrate.
  • 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 also relates to a compound obtainable by the processes according to the invention, as described above.
  • the inventors have discovered that the compounds according to the invention have anti-inflammatory properties.
  • the compounds according to the invention can be used in the treatment of inflammation or inflammatory diseases, in particular inflammatory diseases resulting from an excessive specific response of the immune system, such as asthma.
  • inflammatory diseases resulting from an excessive specific response of the immune system
  • psoriasis, rhinitis, osteoarthritis and autoimmune diseases including Raynaud's syndrome, autoimmune thyroiditis, dermatitis, multiple sclerosis, rheumatoid arthritis, insulin-dependent diabetes mellitus, uveitis inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), systemic lupus erythematosus; and diseases resulting from an excessive non-specific response of the immune system, such as diseases due to respiratory distress syndrome in adults, septic shock, oxygen toxicity, multi-organ failure syndrome secondary to sepsis, multi-organ failure syndrome secondary to trauma, tissue reperfusion injury due to cardiopulmonary bypass, myocardial infarction, acute glomerulonephritis, vasculitis, reactive arthritis
  • the inflammation may have a physical origin (heat, cold, ionizing radiation, infra-red radiation, solar radiation), mechanical (friction), chemical (contact with irritating or allergenic products) or biological ( microbe, fungus), or may be due to oxidative stress.
  • the invention therefore relates to a compound or a mixture of compounds of general formula (I B),
  • RIB, R 2 B, R, Q 1, QB, Q 4 and 3 ⁇ 4 are as defined above,
  • the invention also relates to a compound or a mixture of compounds of general formula (IB) according to the invention for its use for the prevention and / or treatment of any inflammatory diseases mentioned above.
  • the invention relates to the use of a compound or a mixture of compounds of general formula (IB) according to the invention for the manufacture of a medicament for the prevention and / or treatment of inflammation or inflammation.
  • an inflammatory disease including one of the diseases mentioned above.
  • the invention also relates to a method for preventing or treating inflammation or an inflammatory disease, especially one of the diseases mentioned above, comprising administering a therapeutically effective amount of at least one compound of formula (IB) according to the invention to a patient in need.
  • the invention relates to a compound or a mixture of compounds of general formula (IA)
  • R, R 2 A, R, QI, QB, Q.4 and 3 ⁇ 4 are as defined above,
  • the invention also relates to a compound or a mixture of compounds of formula (IA) according to the invention for its use as a medicament for the prevention and / or treatment of inflammation or inflammatory disease, in particular of one of the diseases mentioned above.
  • the present invention relates in particular to a compound or a mixture of compounds of formula (IA) according to the invention for use as a medicament for the prevention and / or treatment of psoriasis.
  • the invention relates to the use of a compound or a mixture of compounds of general formula (IA) according to the invention for the manufacture of a medicament, especially for the prevention and / or treatment of inflammation or an inflammatory disease, particularly one of the diseases mentioned above.
  • the invention particularly relates to the use of a compound or a mixture of compounds of general formula (IA) according to the invention for the manufacture of a medicament for the prevention and / or treatment of psoriasis.
  • the invention also relates to a method of preventing or treating, particularly inflammation or inflammatory disease, particularly one of the diseases mentioned above, comprising administering a therapeutically effective amount of least one compound of formula (IA) according to the invention to a patient in need thereof.
  • the invention particularly relates to a method for preventing and / or treating psoriasis, comprising administering a therapeutically effective amount of at least one compound of formula (IA) according to the invention to a patient in need thereof
  • the present invention also relates to a cosmetic or pharmaceutical composition
  • a cosmetic or pharmaceutical composition comprising as active agent at least one compound according to the invention or an extract according to the invention and advantageously a cosmetically or pharmaceutically acceptable excipient.
  • the modes of administration, the dosages and the optimal dosage forms of the pharmaceutical or cosmetic compositions according to the invention can be determined according to the criteria generally taken into account in the establishment of a pharmaceutical or cosmetic treatment adapted to a subject such as, for example the age or 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 or cosmetic composition according to the invention may further comprise at least one pharmaceutically or cosmetically acceptable excipient.
  • the cosmetic or pharmaceutical composition according to the present invention may further comprise at least one adjuvant which is pharmaceutically or cosmetically known to those skilled in the art, chosen from thickeners, preservatives, perfumes, dyes, chemical or mineral filters, agents moisturizers, thermal waters, etc.
  • the cosmetic or 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 present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active agent at least one compound of general formula (IA)
  • R, R 2 A, R, Ch, Q 3, Q 4 and 3 ⁇ 4 are as defined above,
  • 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 ( skin lipid synthesis activators, PPAR agonists or Peroxysome Proliferator Activated Receptor), activators of keratinocyte differentiation (retinoids, calcidone °, calcium), antibiotics, anti-bacterial agents, antifungal compounds, antiviral agents , sebum-regulators, immunomodulators, such as tacrolimus, pimecrolimus, oxazolines, preservatives, anti-irritants, soothing agents, filters and sunscreens, antioxidants, growth, healing agents or eutrophic molecules, drugs and anti-inflammatory agents.
  • emollients moisturizing active agents
  • activators of keratin synthesis kératorégulateurs
  • keratolytiques agents restructuring the cutaneous barrier
  • the present invention also relates to a pharmaceutical composition according to the invention for its use in the treatment and / or prevention of inflammation, in particular cutaneous inflammation.
  • the present invention also relates to a pharmaceutical composition according to the invention for its use as a medicament for the prevention and / or treatment of psoriasis.
  • the present invention also relates to the use of a pharmaceutical composition according to the invention, for the preparation of a medicament for the treatment and / or prevention of inflammation, in particular cutaneous inflammation.
  • the invention relates in particular to the use of a pharmaceutical composition according to the invention for the manufacture of a medicament for the prevention and / or treatment of psoriasis.
  • the invention provides a method for treating and / or preventing inflammation, including skin inflammation, in a subject in need thereof, comprising administering to a therapeutically effective amount of a composition pharmaceutical composition according to the invention.
  • the invention particularly relates to a method for preventing and / or treating psoriasis, comprising administering a therapeutically effective amount of a pharmaceutical composition according to the invention to a patient in need thereof.
  • the present invention also relates to a pharmaceutical composition according to the invention, for its use to prevent or slow skin aging, for scarring of the skin and / or to promote the regeneration of dermal tissues.
  • the present invention also relates to the use of a pharmaceutical composition according to the invention, for the preparation of a medicament for preventing or slowing skin aging, for scarring the skin and / or for promoting the regeneration of dermal tissues.
  • the invention relates to a method for preventing or slowing down skin aging, for scarring of the skin and / or for promoting regeneration of dermal tissues, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to the invention.
  • the present invention thus relates to a cosmetic composition
  • a cosmetic composition comprising as active agent at least one compound according to the invention or an extract according to the invention and advantageously a cosmetically acceptable excipient.
  • the cosmetic composition according to the invention may further comprise other cosmetically active agents, such as other anti-aging agents; or moisturizing agents; agents having calming, soothing or relaxing activity; agents that stimulate cutaneous microcirculation; sebum-regulating agents for the care of oily skin; cleaning or purifying agents; anti-radical agents; anti-inflammatory agents; chemical or mineral sunscreens, etc.
  • the cosmetically acceptable excipient may be chosen from polymers, silicone compounds, surfactants, rheology agents, humectants, penetration agents, oily components, waxes, emulsifiers, film-forming agents and perfumes. , electrolytes, pH adjusters, antioxidants, preservatives, dyes, pearlescent agents, pigments and mixtures thereof.
  • the cosmetic composition according to the invention is advantageously intended for topical application. It may especially be in the form of a cream, a milk, a lotion, a gel, a serum, a spray, a mousse, a solution, an ointment, an emulsion, a patch or a mask.
  • the invention also relates to the use as active agent of a compound of formula (IB) or of formula (IA) according to the invention, in a cosmetic composition or for the preparation of a cosmetic composition, for treating or prevent skin aging, inflammation of the skin (soothing or soothing effect), and / or to promote healing and regeneration of dermal tissues.
  • the cosmetic composition according to the invention may in particular be intended to prevent or slow skin aging.
  • the cosmetic composition according to the invention may especially be intended to prevent or treat inflammation of the skin.
  • the cosmetic composition according to the invention may especially be intended to obtain a soothing effect of the skin or a soothing effect of the skin.
  • the cosmetic composition according to the invention may especially be intended to promote healing.
  • the cosmetic composition according to the invention may especially be intended to promote regeneration of the dermal tissues.
  • the invention furthermore relates to a cosmetic skin care method for preventing or treating cutaneous aging and / or inflammation of the skin, characterized in that it comprises the application to at least part of the skin body or face of a cosmetic composition according to the invention.
  • the invention furthermore relates to a cosmetic skin care method for obtaining a soothing effect of the skin or a soothing effect of the skin and / or for promoting the regeneration of the tissues of the dermis, characterized in that it comprises the application to at least a portion of the skin of the body or face of a cosmetic composition according to the invention.
  • the cosmetic composition is applied to a subject in need thereof, in particular in anticipation of or following a single or repeated exposure of the skin to oxidative stress.
  • the latter can generate an excess of free radicals that can accelerate the signs of skin aging.
  • the fight against various pathologies or pro-inflammatory conditions are also generating reactive species of oxygen.
  • Example 1 Hemisynthesis of amide derivatives of 3,5-DCQ from 3,5-DCQ (isochlorogenic acid A)
  • reaction mixture is stirred for 15 minutes at 0 ° C., then a solution of the octan-amine (241 ⁇ l, 1.452 mmol) in anhydrous dichloromethane (1000 ⁇ l, 15.54 mmol) is added over 45 minutes.
  • reaction mixture is stirred for 1 hour at 0 ° C and then for 2 hours at room temperature.
  • the reaction is then stopped by adding a solution of 1M aqueous HCl (30 mL).
  • the organic phase is then extracted with 3 times 30 ml of EtOAc and then washed with 50 ml of a solution of 1M HCl and brine (50 ml) and then dried over MgSO 4 , filtered and evaporated under vacuum to obtain a solid.
  • the solid obtained is purified by preparative HPLC (Vydac Denali column C18.50 ⁇ 250 mm, 10 ⁇ ) with a solvent A (H 2 0 + 0.1% HCOOH) and a solvent B (MeOH) following a linear gradient of 80 to 100. % B for 15 minutes at a flow rate of 60 mL / min.
  • the compound obtained is a white solid.
  • Butyl-lyschlorogenamide A is prepared as previously described using butan-1-amine as the starting amine.
  • the solid obtained is purified by preparative HPLC (Vydac Denali column C18.50 ⁇ 250 mm, 10 ⁇ ) with a solvent A (H2O + 0.1% HCOOH) and a solvent B (MeOH) in an isocratic mode of 60% of B during 20 minutes at a rate of 60 mL / min.
  • the compound obtained is a white solid.
  • Lauryl-lsochlorogenamide A is prepared as previously described using laurylamine as the starting amine.
  • the solid obtained is purified by HPLC (Luna Column C18, ⁇ , 21.2 ⁇ 250 mm) with a solvent A (H 2 O + 0.1% HCOOH) and a solvent B (acetonitrile) in an isocratic mode. 72% B for 20 minutes at a flow rate of 20 mL / min.
  • the compound obtained is a white solid.
  • Octadecyl-lsochlorogenamide A is prepared as previously described using 1-octadecylamine as the starting amine.
  • the solid obtained is dissolved in 20 ml of a mixture of MeOH / DCM (1/1 v / v) and 3 g of Dowex 50WX8-100 are added. The reaction mixture is stirred for 30 minutes and then filtered. The filtrate is evaporated under vacuum and the product obtained is purified by HPLC (Luna Column C18, 5 ⁇ , 21.2 ⁇ 250 mm) with a solvent A (H 2 O + 0.1% HCOOH) and a solvent B (acetonitrile) following an isocratic mode of 96% of B for 5 minutes then an isocratic mode of 100% of B for 20 minutes at a flow rate of 20 mL / minutes. The compound obtained is a white solid.
  • the solid obtained is purified by preparative HPLC (Luna C18 column, 21.5 x 250 mm, 5 ⁇ ) with a solvent A (H 2 O + 0.1% HCOOH) and a solvent B (MeOH) in a 70% isocratic mode. of B for 20 minutes at a rate of 1 mL / min.
  • the compound obtained is a white solid.
  • the 2-naphthyl-lsochlorogenamide A is prepared as previously described using 2-naphthylamine as the starting amine.
  • the solid obtained is purified by preparative HPLC (Luna C18 column, 21.5 x 250 mm, 5 ⁇ ) with a solvent A (H2O + 0.1% HCOOH) and a solvent B (MeOH) in an isocratic mode of 70% of B. for 20 minutes at a rate of 1 mL / min.
  • the compound obtained is a white solid.
  • Octyl chloroamide is prepared as previously described using 1-octylamine as the starting amine and 3-chlorogenic acid as the starting acid.
  • the solid obtained is purified by preparative HPLC (Luna C18 column, 21.5 x 250 mm, 5 ⁇ ) with a solvent A (H 2 O + 0.1% HCOOH) and a solvent B (MeOH) in a 70% isocratic mode. of B for 20 minutes at a rate of 1 mL / min.
  • the compound obtained is a white solid.
  • EXAMPLE 2 Analysis of the Effects of the Compounds According to the Invention on the Production of Inflammatory Mediators IL-6, IL-8, TNF- ⁇ , Leukotriene B 4 and Prostaglandin E 2 by NHEK Keratinocytes in an Inflammatory State
  • the study measured the anti-inflammatory effects of 6 compounds by analyzing the production of target inflammatory mediators: Interleukin 8 (IL-8), Prostaglandin E2 (PGE2), Interleukin 6 (IL-6), Tumor Necrosis Factor alpha (TNF- ⁇ ) and Leukotriene B4 (LTB4).
  • IL-8 Interleukin 8
  • PGE2 Prostaglandin E2
  • IL-6 Interleukin 6
  • TNF- ⁇ Tumor Necrosis Factor alpha
  • LTB4 Leukotriene B4
  • NHEKs human keratinocytes (Lonza, CC-2507, origin: foreskin) grown in monolayer in Epilife medium (Invitrogen, M-EPI-500-A) containing the components of the HKGS (Human Keratinocyte Growth Supplement) mixture. , Invitrogen, S-001-K) added separately, except hydrocortisone having anti-inflammatory properties.
  • IL-8 and PGE2 For the quantification of IL-8 and PGE2, the inflammatory state of cultured NHEK keratinocytes was induced by treatment with PMA (Phorbol Myristate Acetate / 10 ng / ml / H 2 0) for 24 h. Induction of IL-6 was obtained by treatment with PMA (10 ng / ml / H2O) combined with calcium ionophore A23187 (2 ⁇ l / DMSO) in a medium containing calcium at a concentration of 0.8 mM.
  • PMA Phorbol Myristate Acetate / 10 ng / ml / H 2 0
  • TNF- ⁇ The secretion of TNF- ⁇ was induced by a combination of PMA (10 ng / ml / H 2 0) and calcium ionophore A23187 (2 ⁇ / DMSO) applied for 24h (TNF- ⁇ ) in medium containing 0 , 06 mM calcium.
  • the reference molecules used are dexamethasone (10 ⁇ / H 2 0) and indomethacin (10 ⁇ g / ml / ethanol). Since the induction of LTB4 production has a very fast kinetics, the scheme has been adapted.
  • the induction of the inflammatory state was carried out for 2 hours by the application of arachidonic acid (aa / 1 ⁇ / ethanol) combined with calcium ionophore A23187 (2 ⁇ / DMSO). Nordihydroguaiaretic acid (NDGA) was used as the reference molecule (2 ⁇ / ethanol).
  • NDGA Nordihydroguaiaretic acid
  • the effect of the compounds was studied by application of these in the keratinocyte culture medium 2h prior to the induction of the inflammatory state as well as during induction (2h for LTB4, 24h for IL-8, PGE2 , IL-6 and TNF- ⁇ ).
  • the culture supernatants were harvested at the end of each studied kinetics. These were aliquoted and frozen at -20 ° C until the day of analysis.
  • the quantification of the various inflammatory mediators was performed with specific kits, based on a standard straight line, according to the instructions provided by the kits suppliers, R & D Systems, Cayman chemical.
  • a cytotoxicity study on keratinocytes NHEKs was carried out, based on 5 concentrations (100 ⁇ , 50 ⁇ , 25 ⁇ , 12.5 ⁇ , 6.25 ⁇ ) of each of the 6 compounds prepared in DMSO.
  • the experimental parameters were identical to those used later for the study of the effects on inflammatory mediators, in terms of cell culture passages, confluence and contact time (26 h for IL-6, IL-8 , TNF- ⁇ , LTB4 and PGE2).
  • the NHEK keratinocytes were treated with the reference compounds and molecules for 2 h.
  • the inflammatory state was then induced according to the conditions described in the methodology part, the culture supernatants were collected and the various inflammatory mediators were quantified by the ELISA technique.
  • the effect of the compounds on the production of IL-8 is presented in FIG. 4.
  • the data are expressed with respect to the IL-8 production by the keratinocytes in inflammatory state (treated with PMA), whose condition was arbitrarily set at 100%.
  • PGE2 The production of PGE2 is well induced following treatment with PMA and indomethacin reduces to a level almost undetectable this production of PGE2 in culture supernatants.
  • each of the compounds very significantly decreases the production of IL-6 by NHEK keratinocytes in an inflammatory state.
  • the two compounds PAT1648 and PAT1657 allow the largest decreases and are more effective than dexamethasone itself.
  • the compounds all act as inhibitors of TNF- ⁇ production in a very highly significant way. Again, it is PAT1648 and PAT1657 that have the most marked effects and are more effective than dexamethasone itself.
  • NHEK keratinocytes were contacted or not with the test compounds. After 2 h, the cells have or have not undergone inflammation treatment (PMA 10 ng / mL / H 2 O + calcium ionophore A23187 2 ⁇ / 0 ⁇ 5 ⁇ ). The cells were observed under an optical microscope 48h after the inflammatory treatment.
  • the reference molecule (dexamethasone), as well as the compounds PAT965, PAT964 and PAT967 have little or no effect on cell survival.
  • the PAT1658 compounds, and especially PAT1657 and PAT1648 show a strong cellular protection against inflammation.
  • the 3 compounds PAT1648, PAT1657 and PAT1658 demonstrate a major protective effect on the cytotoxicity induced on keratinocytes in inflammatory state since 48H. These observations are based on the microscopic analysis of the cells 48 hours after the inflammatory treatment.
  • the compounds to be tested are the following:
  • G2 induced skin inflammation + treatment with PAT1657 incorporated at 1.33% by weight in Excipial® ointment (PAT1657 / 1, 33%)
  • G3 induced skin inflammation + treatment with PAT1657 incorporated into
  • Cutaneous inflammation is induced for each mouse by daily dermal dermal application on zone A (FIG. 9) for 7 days (D1 to D7) of 100 ⁇ l of acetone solution of TPA at a concentration of 0.2. mg / ml.
  • the daily treatment of the animals (G1) is by dermal application 0.125 g of ointment on the back of the mice off the area of application of the TPA acetone solution (area of approximately 5 cm 2 corresponding to the zones A and B shown in Figure 9), for 7 days from D8 to D14.
  • the treatment of the animals is done by dermal application of 0.125 g of ointment on the back of the mice off the area of application of the TPA acetone solution (area of about 5 cm 2 corresponding to the zones A and B shown in Figure 9), to J8, J1 1 and J14.
  • the macroscopic visual scoring of cutaneous inflammation is carried out daily for each mouse from J8 to J15 by quantifying it according to the following scale (Guenon-Macé et al., 2015):
  • the compounds to be tested are the following:
  • Dermoval® cream containing 0.05% clobetasol propionate and used for the topical treatment of psoriasis The treatment groups are distributed as follows: Group 1: no induction of psoriasis but cutaneous application of neutral ointment from J1 to J10 and treatment with Excipial® neutral ointment from J7 to J10 (negative control) (EP / EP);
  • Group 2 Induction of psoriasis by dermal application of Aldara® cream containing imiquimod from D1 to D10 and treatment with Excipial® neutral ointment from D7 to D10 (positive control) (ALD / EP);
  • Group 3 Induction of psoriasis by dermal application of Aldara® cream containing imiquimod from D1 to D10 and treatment with neutral ointment containing 1.33% PAT1657 compound from D7 to D10 (ALD / PAT1657-1, 33%) ;
  • Group 4 psoriasis induction by dermal application of Aldara® cream containing imiquimod from D1 to D10 and treatment with neutral ointment containing 2.67% compound PAT1657 from D7 to D10 (ALD / PAT1657-2.67%) );
  • Group 5 induction of psoriasis by dermal application of Aldara® cream containing imiquimod from D1 to D10 and treatment with Dermoval® cream from D7 to D10 (ALD / Dermoval®).
  • Psoriasis was induced on all mice of groups 2 to 5 by daily skin application for 10 days, from D1 to D10, of approximately 70 mg of Aldara® cream. The cream was applied to the back of the mice previously shaved with a silk brush.
  • a daily dermal application of Excipial® neutral ointment was performed under the same conditions: approximately 70 mg were applied for 10 days from D1 to D10 in the morning using a silk brush .
  • ointments containing compound PAT1657 at the 2 doses to be tested, Excipial® neutral ointment and Dermoval® cream were administered by skin application for 4 days from D7 to D10 on the back of the mice in the region of induction of psoriasis. .
  • approximately 100 mg of ointment or cream was applied with a silk brush, at least 4 hours after application of Aldara® cream or Excipial® neutral ointment for induction or not of psoriasis .
  • Psoriasis severity score (PASI)
  • the erythema, degree of induration and desquamation presence scores and the psoriasis severity score (PASI) were analyzed at the end of the experiment.
  • An analysis of the variance (ANOVA) was performed in non-parametric mode using the Kruskal-Wallis test followed in case of significance by the Mann-Whitney test to compare the groups treated with negative EP / EP control groups, positive control ALD / EP and ALD / Dermoval®.
  • Statistical treatments were performed using the Statview®5 software (SAS, Institute Inc., USA) and the differences were considered significant for values of P ⁇ 0.05.
  • the average scores of erythema at the psoriasis induction region of the ALD / PAT1657-1, 33% and ALD / PAT1657-2.67% mice were significantly lower than the mice in the group.
  • Mean induration level scores at the psoriasis induction region of ALD / PAT1657-1, 33% and ALD / PAT1657-2.67% mice were significantly higher than the mice in the group.
  • the mean induration level score in the psoriasis induction region of mice in the ALD / PAT1657-1 group, 33%, showed a tendency to be significantly higher than that of ALD / Dermoval ® mice ( P 0.063).
  • Psoriasis severity score Psoriasis severity score
  • the psoriasis severity score is the sum of the erythema score, the degree of induration, and the degree of desquamation in the region of psoriasis induction and treatment.
  • Figure 14 shows mean psoriasis severity scores of the mice of the treatment groups during the experiment.
  • the compound PAT1657 at the 2 doses tested showed significant effects on the treatment of psoriasis.
  • the compound PAT1657 significantly and comparably reduced the presence of erythema at the level of the psoriasis induction region, the degree of induration at the region of induction of psoriasis and the degree of induration of the Dermoval® cream. degree of desquamation at the level of the psoriasis induction region, thus making it possible to significantly reduce the psoriasis severity score.
  • the study measured the effects of the qRT-PCR compound PAT1657 on the expression of 94 genes involved in dermal biology, connective tissue remodeling and aging.
  • the protocol consisted in applying the PAT1657 compound for 24 hours in the monolayer human fibroblast (NHDFs) human fibroblast culture medium, and analyzing the different RNA populations to identify the genes differentially expressed by qRT-PCR in time. real.
  • NHDFs Normal Human Dermal Fibroblasts
  • ATCC Human dermal fibroblasts
  • ATCC CRL-2522, origin: foreskin
  • DMEM medium Invitrogen, 31885- 049
  • antibiotics penicillin / streptomycin, Invitrogen, 15140-122
  • serum serum
  • a preliminary cytotoxicity study defined a working concentration of 4 ⁇ M (prepared in DMSO) for PAT1657 for the gene expression study.
  • the technical details of implementation of this paragraph are detailed in the Materials and Methods section relating to example 1 patent application FR1650745 and more particularly the subpart entitled Gene expression modification analysis (page 26 line 22 to page 28 line 9).
  • Active-induced gene expression modifications are expressed as a relative amount (RQ) relative to the respective DMSO solvent controls.
  • the compound PAT1657 induces many remarkable inductions.
  • MMP1 matrix metalloproteinase 1 (interstitial 6.91 0.0447 collagenase)
  • RORA Nuclear receptor ROR-alpha (“Retinoid-4,41 0,0317 related orphan receptor-alpha")
  • GADD45A "Growth arrest and DNA-damage-inducible, 3.68 0.0024 alpha"
  • MMP3 matrix metalloproteinase 3 (stromelysin 1) 3.12 0.007
  • Table 7 Genes that increase significantly with the PAT1657 extract (at 4 ⁇ l) applied for 24 hours on human dermis fibroblasts NHDFs.
  • the gene symbol, gene name, relative expression (RQ) versus 1% DMSO vehicle, and p (p-value) are presented.
  • the acceleration of healing is particularly favored by the migration of fibroblasts to the site of cutaneous lesion, the stimulation of angiogenesis and the deposition of collagen.
  • the compound PAT1657 increases the expression of the CCL5 (28.13 x) and VEGFA (8.3x) genes coding respectively for a chemokine and an angiogenesis mediator which play a role in skin healing.
  • This chemokine has been shown to play an important role in the skin healing process. She is involved in the migration of dermal stem cells (DSC) to the skin lesion site. This process is essential for re-epithelialization, repopulation of fibroblasts in the dermis and angiogenesis (Kroeze et al., 2009).
  • MMP1 (6.9x) or MMP3 (3.1x).
  • MMPs Metalloproteinases
  • MMP1 Metalloproteinases
  • the compound PAT1657 could therefore prove to be pro-cicatrizing by accelerating the reepithelialization of keratinocytes, angiogenesis and thus promoting closure of the wound.
  • the genes POU5F1 and NANOG and KLF4 are markers of the dermal stem cells (respectively 5.1 x, 4.7 x and 1.9 x). They participate in the process of reprogramming differentiated cells into pluripotent stem cells. These are important for maintaining dermal homeostasis, repairing damage and regenerating tissues (Jerabek et al., 201).
  • SOD2 4.7x
  • RORA 4.4x
  • TXNRD1 2.8x
  • FTL 2.1x
  • MTNR1A NOX1, RBP2 and GSS.
  • Superoxide dismutase 2 SOD2 encoded by the gene is a protein mitochond n 'have involved first line of defense against ROS. It converts the superoxide anion into hydroperoxide, which itself is converted to oxygen and water by catalase and peroxypedoxins (Weyemi et al., 2012).

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