FR2864956A1 - New 1,3-diphenyl-2-propen-1-one derivatives, useful in pharmaceutical or cosmetic compositions e.g. for treating cardiovascular diseases, dyslipidemia, diabetes, obesity, hypertension or inflammatory diseases, are PPAR activators - Google Patents

Abstract

1,3-Diphenyl-2-propen-1-one derivatives (I) are new. 1,3-Diphenyl-2-propen-1-one derivatives of formula (I) are new: X 7= OR 7 or SR 7; R 7= alkyl substituted by C(O)OR a, C(O)NR bR c, tetrazolyl, SO 3H or SO 2NR bR c and optionally substituted by aryl; R a, R b, R c= H or optionally substituted alkyl; X 1-X 5= halo, thionitroso or (G iR i) nG' iR' i; n= 0 or 1; G i, G' i= bond, O or S; R i, R' i= alkyl, alkenyl, aryl or heterocyclyl and R' i may also be H; X 6, X 8= halo or G' iR' i, but not both H; provided that X 1-X 6 and X 8 are not heterocyclyl and that compounds (I) where one of X 1-X 5 is OH, X 7 is OR 7 and X 6 or X 8 is H, halo, OH or alkoxy and compounds (I) where X 1, X 2 and X 4 are H and X 3 or X 5 is H, halo, alkyl, alkoxy, alkylthio, OH, SH or thionitroso are excluded. Independent claims are also included for: (1) a process for preparing (I); (2) the new compounds 1-(4-(2-pentylthioethoxy)phenyl)-3-(4-hydroxy-3,5-dimethylphenyl)-2-propen-1-one, 1-(4-((RS)-5-(1,2-dithiolan-3-yl)pentyloxy)phenyl)-3-(4-hydroxy-3,5-dimethylphenyl)-2-propen-1-one and 1-(4-methylthiophenyl)-3-(4-hydroxy-3,5-dibromophenyl)-2-propen-1-one. [Image] ACTIVITY : Antiarteriosclerotic; Cardiant; Vasotropic; Cerebroprotective; Antilipemic; Antidiabetic; Anorectic; Hypotensive; Antiinflammatory; Dermatological; Antipsoriatic; Antiseborrheic. MECHANISM OF ACTION : Peroxisome proliferator activated receptor (PPAR) activator; Antioxidant. 1-(4-(2-Pentylthioethoxy)phenyl)-3-(4-(2-carboxy-2-propyl)-3,5-dimethylphenyl)-2-propen-1-one reduced the rate of copper-induced oxidation of low-density lipoprotein from > 1.5 to 0.5 mmole/mg/minute.

Description

COMPOUNDS DERIVED FROM 1,3-DIPHENYLPROP-2-IN-1-ONE, PREPARATION

AND USES

  The present invention relates to substituted 1,3-diphenylprop-2-en-1-one derivatives, the pharmaceutical and / or cosmetic compositions comprising them, their applications in therapeutics and / or in cosmetics, particularly in the fields of human health. and animal. The present invention also relates to a process for the preparation of these derivatives.

  The compounds according to the invention represent an advantageous therapeutic tool for the amelioration of pathologies related to disorders of lipid and / or carbohydrate metabolism (hyperlipidemia, diabetes, obesity, etc.) and can be used in particular for preventing or treating cardiovascular diseases (especially coronary heart disease, cerebral ischemia and peripheral arterial diseases), dyslipidemias, syndrome X, diabetes, obesity, hypertension, inflammatory diseases, dermatological diseases (psoriasis, atopic dermatitis, acne ..), disorders related to oxidative stress, the effects of aging in general, for example skin aging, especially in the cosmetic field (the appearance of wrinkles, etc.). The compounds according to the invention are capable of exerting a prophylactic activity in terms of neuroprotection, and also of ensuring active neuroprotection in the acute phase of ischemic cerebral accidents, which constitute one of the major complications of cardiovascular diseases.

  By their simultaneous action on several cardiovascular disease risk factors, the compounds according to the invention make it possible to reduce the overall cardiovascular risk.

  Coronary artery disease, cerebral ischemia and peripheral arterial diseases are the major cardiovascular diseases according to the International Atherosclerosis Society (Harmonized Clinical Guidelines on the Prevention of Atherosclerotic Vascular Disease, 2003).

  Cardiovascular disease is now one of the leading causes of adult mortality in most developed and some developing countries. Among cardiovascular diseases, cerebrovascular pathology represents the third leading cause of death and the leading cause of disability in adults. The need for effective treatment and / or prevention strategies against these conditions has become a global emergency.

  Dyslipidemia (hypercholesterolemia, hypertriglyceridemia), diabetes and hypertension are among the clearly identified cardiovascular risk factors (IAS, 2003). It also appears that insufficient protection of lipoproteins against oxidation is an identified risk factor.

  Epidemiological studies have shown that there is a synergistic effect between these different factors. The concomitant presence of several of them leads to a dramatic aggravation of the cardiovascular risk. It is therefore appropriate to speak of global risk for cardiovascular diseases.

  There is therefore a real need for products capable of acting concomitantly on these various risk factors and therefore of reducing the risk of cardiovascular diseases, but also of treating each disorder and its consequences independently (dyslipidemia, diabetes, hypertension, cerebral ischemia). syndrome X, obesity ...).

  The inventors have surprisingly shown that the compounds according to the invention are PPAR activators and that they therefore represent an advantageous therapeutic tool.

  It is well known that PPARs are associated with the metabolism of lipids and glucose. Activators of PPARs, such as fibrates, regulate plasma cholesterol and triglyceride concentration via PPARα activation (Houdon, Delerive et al., 2001). Treatment with fibrates results in increased oxidation of fatty acids in the liver. They also reduce the synthesis and expression of triglycerides (Staels and Auwerx 1998). PPARα activators are also able to correct hyperglycemia as well as insulin concentration. Fibrates also reduce adipose tissue mass through a mechanism independent of food intake and the expression of the gene encoding leptin (Guerre-Millo, Gervois et al., 2000).

  The therapeutic value of PPARγ agonists has been widely studied in the treatment of type II diabetes (Spiegelman 1998). PPARy agonists have been shown to restore insulin sensitivity in target tissues as well as to reduce plasma glucose, lipid and insulin levels in both animal models of type II diabetes and the man (Ram 2003).

  Activation of PPARs by ligands is also involved in regulating the expression of genes involved in processes such as inflammation, angiogenesis, cell proliferation and differentiation, apoptosis and iNOS activities, MMPase and TIMPs. Activation of PPARα in keratinocytes causes arrest of proliferation and expression of genes involved in cell differentiation (Komuves, Hanley et al., 2000). PPARs have anti-inflammatory properties because they interfere negatively in transcription mechanisms involving other transcription factors such as NF-kB or transcriptional activators (STAT) and AP-1 (Desvergne and Wahli 1999). These anti-inflammatory and anti-proliferative properties make PPARs therapeutic targets of interest for the treatment of diseases such as vascular occlusive diseases (atherosclerosis, etc.), cerebral ischemia, hypertension, neo-related diseases. -vascularization (diabetic retinopathies, etc.), inflammatory diseases (Bowel's disease, psoriasis, etc.) and neoplastic diseases (carcinogenesis, etc.).

  In addition, the compounds according to the invention have the advantage of being antioxidants.

  Free radicals are involved in a very broad spectrum of pathologies such as cardiovascular pathologies (atherosclerosis, etc.), cerebral ischemia, genetic and metabolic disorders (diabetes, etc.) but also infectious and degenerative diseases (Alzheimer, Parkinson, Prion, etc.), ophthalmic problems, aging, allergies, initiation and cancer promotion (Mates, Perez-Gomez et al., 1999).

  Oxygen reactive species (ROS) are produced during normal cell operation. ROS consist of hydroxyl radicals ('OH), superoxide anion (O2), hydrogen peroxide (H2O2) and nitric oxide (NO). These species are very labile and because of their high chemical reactivity, they can also be a danger for the biological functions of cells by causing lipid peroxidation reactions, oxidation of certain enzymes and very important oxidations of proteins that lead to their degradation.

  The management of ROS is via an antioxidant system comprising an enzymatic component (superoxide dismutase, catalase and glutathione peroxidase) and a non-enzymatic component (mainly carotenoids, vitamin C and vitamin E (Gilgun-Sherki, Melamed et al. 2001)).

  In addition, the results of numerous in vitro and in vivo studies have shown the potential involvement of oxidized LDL (low density lipoproteins) atherosclerosis. The slowly developing atherosclerotic plaque has a high cholesterol core surrounded by a fibrous tissue shell. Plaque cracking is increasingly seen as the result of chronic inflammatory changes in the fibrous shell region. Inflammation mediators such as cytokines influence several biological processes in the fibrous shell of the plaque, decreasing its resistance to rupture.

  Inflammatory cytokines in atheromatous plaque, including interleukin I, tumor necrosis factor (TNF-α, and the TNFα surface homologue called CD-40 ligand) lead to macrophage and smooth muscle cell production. enzymes that can weaken the extracellular matrix. Cracking of the shell may result in occlusive thromboses.

  Finally, the compounds according to the invention are advantageous therapeutic tools for the treatment and / or the prevention of cerebral ischemia by virtue of their pharmacological and in particular anti-inflammatory properties.

  The first event of cerebral ischemia occurs in the early hours, and consists of a massive release of glutamate that results in neuronal depolarization as well as cellular edema. The entry of calcium into the cell induces mitochondrial damage promoting the release of free radicals as well as the induction of enzymes that cause membrane degradation of neurons. The entry of calcium and the production of free radicals in turn activate certain transcription factors, such as NF-KB. This activation induces inflammatory processes such as induction of endothelial adhesion proteins, ischemic focus infiltration by neutrophils, microglial activation, induction of enzymes such as nitric oxide (NO) synthase type II or cyclooxygenase type II. These inflammatory processes lead to the release of NO or prostanoids that are toxic to the cell. All of these processes result in an apoptosis phenomenon causing irreversible lesions (Dimagl, ladecola et al., 1999).

  The concept of prophylactic neuroprotection is based on experimental evidence of resistance to ischemia in animal models. Different mechanisms of resistance to cerebral ischemia have been identified: cytokines, inflammation pathways, free radicals, NO, ATP-dependent potassium channels, adenosine. The compounds according to the invention thus have the advantage of acting as a neuroprotector.

  The present invention relates to novel substituted 1,3-diphenylprop-2en-1-one derivatives, pharmaceutical and / or cosmetic compositions comprising them, their applications in therapeutics and / or in cosmetics, in particular in the fields of human health and animal. The present invention also relates to a process for the preparation of these derivatives.

  The inventors have demonstrated, surprisingly, that the compounds according to the invention possess PPAR agonist activity and antioxidant properties. The compounds according to the invention are therefore capable of interfering with at least two signaling pathways which are activated in particular during inflammation: the production of cytokines as well as the production of free radicals. By acting synergistically, the compounds according to the invention represent an advantageous therapeutic and / or cosmetic means for the treatment of cardiovascular diseases, syndrome X, dyslipidemias, diabetes, obesity, hypertension and inflammatory diseases. , dermatological diseases (psoriasis, atopic dermatitis, acne ..), disorders related to oxidative stress, aging in general, for example skin aging, especially in the cosmetic field (the appearance of wrinkles, etc.).

  On the other hand, the compounds according to the invention are capable of exerting a prophylactic activity in terms of neuroprotection, and also of ensuring active neuroprotection in the acute phase of ischemic cerebral accidents.

  Finally, the compounds according to the invention represent an advantageous therapeutic tool for preventing and / or treating several cardiovascular risk factors related to disorders of lipid and / or carbohydrate metabolism (hyperlipidemia, diabetes, obesity, etc.). They allow the reduction of the overall risk.

  It is therefore an object of the present invention to provide novel substituted 1,3-diphenylprop-2-en-1-one derivatives having improved formula and satisfactory therapeutic efficacy.

  These and other objects are achieved by the present invention which relates in particular to substituted 1,3-diphenylprop-2-en-1-one derivatives of the following general formula (I): (I) in which: X7 represents a group corresponding to the following formula: G7-R7 in which G7 is an oxygen or sulfur atom and R7 is an alkyl chain as defined below, substituted with a group of group 1 or a group of group 2, R7 may optionally also be substituted by an aryl group, the substituents of group 1 are chosen from carboxy groups of formula: -COORa, carbamoyl groups of formula: -CONRbRC or the tetrazolyl group, the substituents of group 2 are chosen from sulfonic acid (-SO3H) and sulfonamide groups of formula: - SO2NRbRC, with Ra, Rb and Rb, identical or different, representing a hydrogen atom or a substituted or unsubstituted alkyl radical, X groups; with i = 1, 2, 3, 4 or 5, identical or different, represent a halogen atom or a thionitroso group or they respectively correspond to the formula (G; -R;) -G '; -R'; where: ^ n can be 0 or 1 ^ G; and G ', which are identical or different, represent a single bond, an oxygen atom or a sulfur atom, R; and R ', which may be identical or different, represent an alkyl, alkenyl, aryl or heterocycle radical, R'; can also represent a hydrogen atom, X groups; with i = 6 or i = 8, identical or different, represent a halogen atom or correspond to the formula G'i-R '; , BOY WUT'; and R '; being as defined above, X6 and X8 not simultaneously representing a hydrogen atom, Xi with i = 1, 2, 3, 4, 5, 6 or 8 not being able to represent a heterocycle directly linked to the aromatic ring of the 1, 3-diphenyl prop-2-en-1-one, excluding the compounds of formula (I) for which at the same time: one of the groups X1, X2, X3, X4 or X5 is a hydroxyl group, G7 is an oxygen atom, and one of the X 6 or X 8 groups is a hydrogen or halogen atom or a hydroxyl or an alkyloxy group, with the exception of the compounds of formula (I) for which simultaneously the groups X1, X2 and X4 simultaneously represent a hydrogen atom, and X3 or X5 represents a hydrogen atom or a halogen or an alkyl radical or an alkyloxy radical or an alkylthio radical or a hydroxyl group or a group thiol or a thionitroso group.

  Preferably, a particular object of the invention relates to the compounds of general formula (Ia) which correspond to the compounds of general formula (I) in which XI and X5 are hydrogen atoms.

  Preferably, the present invention relates to compounds of the general formula (Ib) which correspond to the compounds of the general formula (I) in which X 2 and X 4 are alkyl radicals and more preferably in which X 1 and X 5 are hydrogen atoms .

  A particular object of the invention relates to the compounds of general formula (Ic) which are compounds of general formula (I) in which X1, X3 and X4 are alkyl radicals.

  Another particular object of the invention relates to the compounds of general formula (Id) which are compounds of general formula (I) in which XI, X2, X4 and X5 are hydrogen atoms.

  Another subject of the invention relates to the compounds of general formula (II) which are compounds of general formula (I) in which X 6 and X 3 are alkyl radicals.

  Even more preferably, the compounds of general formula (II) are those in which X1 and X5 are hydrogen atoms and preferably X2 and X4 are alkyl radicals.

  Another particular object of the invention relates to the compounds of general formula (II) in which XI, X3, X4, X6 and X are alkyl radicals.

  Another particular object of the invention relates to the compounds of general formula (II) wherein X6 and X5 are alkyl radicals and X1, X2, X4 and X5 are hydrogen atoms.

  According to a particular aspect of the invention, the compounds of formula of formula (I) are as defined above with X 3 which represents a halogen atom or a thionitroso group or corresponds to the formula (GiR1) n-G ' ; -R ', as previously defined, wherein G '; represents an oxygen atom or a sulfur atom.

  The present invention also includes optical and geometric isomers, racemates, tautomers, salts, hydrates and mixtures of the compounds of the invention.

  The present invention also preferably includes the prodrugs of the compounds according to the invention which, after administration in a subject, are converted into compounds according to the invention and / or the metabolites of the compounds according to the invention which have therapeutic activities comparable to the compounds according to the invention.

  Preferably, at least one of the groups G 1 or G '1 represents a sulfur atom with i which can take one of the values 1, 2, 3, 4, 5, 6, 7 or 8.

  In the context of the present invention, the derivatives according to the invention as described above can adopt the cis or trans conformation.

  According to the present invention, the term "alkyl" denotes a linear, branched or cyclic saturated hydrocarbon radical, halogenated or not, having more particularly from 1 to 24, preferably 1 to 10, carbon atoms such as methyl, ethyl, propyl, isopropyl , n-butyl, isobutyl, tert-butyl, pentyl, neopentyl, n-hexyl, or cyclohexyl. Groups having one or two carbon atoms or having from two to seven carbon atoms are particularly preferred. The methyl and ethyl groups are very particularly preferred.

  According to the present invention, the term alkenyl denotes a linear, branched or cyclic unsaturated hydrocarbon radical, halogenated or not, having more particularly from 1 to 24, preferably 1 to 10, carbon atoms.

  According to the present invention, the term aryl denotes a substituted or unsubstituted aromatic hydrocarbon radical, in particular substituted with at least one halogen atom, an alkyl, hydroxyl, thiol, alkyloxy, alkylthio, oxime or thionitroso radical. Phenyl groups are particularly preferred.

  According to the present invention, the term heterocycle denotes a saturated or unsaturated or aromatic cyclic radical comprising one or more heteroatoms, such as nitrogen, sulfur and oxygen. They may be substituted, advantageously with at least one alkyl group as defined above. Heterocycles such as dithiolanes, pyridine, furan, thiophene or morpholine are particularly preferred. In the context of the present invention, the piperidine and piperazine heterocycles are advantageously substituted with at least one alkyl group as defined above.

  The term thionitroso refers to a nitroso group linked to the aromatic ring via a sulfur atom.

  The term alkyloxy refers to an alkyl chain linked to the ring via an oxygen atom. The alkyl chain is as previously defined.

  The term alkylthio refers to an alkyl chain linked to the aromatic ring via a sulfur atom (thioether bond). The alkyl chain meets the previously stated definition.

  The halogen atom is preferably a chlorine, bromine, iodine or fluorine atom.

  According to a particular embodiment of the invention, the preferred compounds are indicated below with the formulas associated with them: 1- (4 (Pentylthioethyloxy) phenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) -prop- 2-en-1-one

OH

  1- (4- (Cyclohexylthioethyloxy) phenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) -prop-2-en-1-one:

OH

  1- (4-Methylthiophenyl) -3- (4-carboxydimethylmethyloxy-3,5-dibromophenyl) -prop-2-en-1-one: 1- (4-Hydroxy-3,5-dimethylphenyl) -3 (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) prop-2-en-1-one:

OH

OH

  1- (4-Methoxy-3,5-dimethylphenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) -prop-2-en-1-one:

OH

  1- (4 - ((R, S) -5- [1,2] dithiolan-3-ylpentyloxy) -3,5-dimethylphenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) prop-2- 1-en-1-one: 1- (4 - ((R, S) -5- [1,2] dithiolan-3-ylpentyloxy) phenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) prop-2 -en-1-one:

O

OH

  1- (4-Bromophenyl) -3- (4-carboxyphenylmethyloxy-3,5-dimethylphenyl) prop2-en-1-one:

OH

  1- (4-Mercapto-3,5-dimethylphenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) -prop-2-en-1-one: o

OH

  1- (4-Methythio-3,5-dimethylphenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) -prop-2-en-1-one:

OH

  1- (4-Cyclohexylethylthio-3,5-dimethylphenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) prop-2-en-1-one:

OH

  1- (4-Hexylthio-3,5-dimethylphenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) -prop-2-en-1-one: 1- (2,5-Dihydroxy-3, 4,6triméthylphényl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) prop-2en-1-one:

OH

  1- (2,5-Dimethoxy-3,4,6-trimethylphenyl) -3- (4-carboxydimethylmethoxy-3,5-dimethylphenyl) prop-2-en-1-one:

OH

  1- (2,5-Dihydroxyphenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) -prop-2-en-1-one:

HO

OH

  1- (2,5-Dimethoxyphenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) -15-prop-2-en-1-one:

OH

  1- (4-Phenylethyloxyphenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) -prop-2-en-1-one:

OH

  1- (4- (Morpholin-4-ylethyloxy) phenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) -prop-2-en-1-one:

OH

  The present invention also relates to a process for preparing compounds of formula (I).

  This preparation process has many advantages. It is simple to use industrially and makes it possible to obtain a high yield of compounds of formula (I).

  The process of the present invention comprises bringing into contact, in basic medium or in acidic medium, at least one compound of formula (A) with at least one compound of formula (B), formulas (A) and (B) being (B) formulas in which X1, X2, X3, X4, X5, X6 and X7 have the definitions given above, X7 may also represent a hydroxyl or thiol group. The conditions for carrying out this reaction in acidic or basic medium are within the abilities of those skilled in the art and may vary to a large extent.

  The bringing into contact of these two compounds is advantageously carried out stoichiometrically. It is preferably carried out at ambient temperature (between about 18 ° C. and 25 ° C.) and at atmospheric pressure.

  In basic medium, the reaction is preferably carried out in the presence of a base, such as an alkali metal hydroxide, such as sodium hydroxide or an alkali metal alcoholate such as sodium ethoxide.

  In acidic medium, the reaction is preferably carried out in the presence of a strong acid, such as hydrochloric acid.

  The reaction scheme can be represented as follows: (A) o (B) The synthesis in basic medium can be carried out as follows: The ketone (compound (A)) at 1 molar equivalent and the aldehyde (compound (B) )) at 1 molar equivalent are solubilized in a hydroalcoholic solution of sodium hydroxide at 20 molar equivalents. The mixture is stirred for approximately 18 hours at room temperature (between 18 and 25 ° C.). The medium is then acidified (to reach in particular a pH of about 2) in particular with hydrochloric acid.

  The expected substituted 1,3-diphenylprop-2-en-1-one can be obtained by precipitation or solid / liquid extraction after evaporation of the reaction medium. It can then be purified by chromatography on silica gel or by recrystallization.

  The synthesis in an acidic medium can be carried out as follows: The ketone (compound (A)) at 1 molar equivalent and the aldehyde (compound (B)) at 1 molar equivalent are solubilized in a saturated ethanol solution gaseous hydrochloric acid. The whole is stirred at room temperature for about 6 hours, the solvent is removed, in particular by evaporation under reduced pressure. The substituted 1,3-diphenylprop-2-en-1-one is purified, in particular by chromatography on silica gel.

  The process for the preparation of the compounds of formula (I) makes it possible to prepare compounds referred to below as intermediate compounds. The present invention also relates to certain raw materials and intermediate compounds obtained in the context of the present invention.

  These intermediate compounds are more particularly chosen from: 1- (4- (4- (Pentylthioethyloxy) phenyl) -3- (4-hydroxy-3,5-dimethylphenyl) prop-2-en-1-one 1- (4 - ((R S) -5- [1,2-dithiolan-3-ylpentyloxy) phenyl) -3- (4-hydroxy-3,5-dimethylphenyl) -prop-2-en-1-one-1- (4-methylthiophenyl) - 3- (4-hydroxy-3,5-dibromophenyl) prop-2-en-1-one The subject of the present invention is also the compounds of general formula (I) as described above, as medicaments.

  The present invention also relates to a pharmaceutical and / or cosmetic composition comprising, in a pharmaceutically and / or cosmetically acceptable carrier, at least one compound of general formula (I) as described above, optionally in combination with another therapeutic and / or cosmetic active agent.

  It is advantageously a pharmaceutical and / or cosmetic composition for the treatment of cardiovascular diseases, dyslipidemias, syndrome X, diabetes, obesity, hypertension, inflammatory diseases, dermatological diseases (psoriasis , atopic dermatitis, acne ..), disorders related to oxidative stress, aging in general and for example skin aging, particularly in the cosmetic field (the appearance of wrinkles, etc.).

  On the other hand, the pharmaceutical and / or cosmetic compositions according to the invention are capable of exerting a prophylactic activity in terms of neuroprotection, and also make it possible to ensure active neuroprotection in the acute phase of cerebral ischemic accidents. Finally, it is advantageously a pharmaceutical and / or cosmetic composition for preventing and / or treating the appearance of several cardiovascular risk factors related to disorders of lipid and / or carbohydrate metabolism (hyperlipidemia, diabetes, obesity, etc.). by allowing the reduction of the overall risk.

  The invention also relates to the use of at least one compound of formula (I) for the preparation of a pharmaceutical and / or cosmetic composition intended for the implementation of a method of treatment or prophylaxis of the human body or animal.

  The invention also relates to a method for treating pathologies related to the metabolism of lipids and / or carbohydrates comprisingadministration to a subject, in particular a human subject, of an effective dose of a compound or a pharmaceutical composition as defined herein. -before.

  The pharmaceutical compositions according to the invention advantageously comprise one or more excipients or vehicles, which are pharmaceutically acceptable. For example, saline, physiological, isotonic, buffered, etc., solutions compatible with a pharmaceutical use and known to those skilled in the art may be mentioned. The compositions may contain one or more agents or vehicles selected from dispersants, solubilizers, stabilizers, preservatives, etc. Agents or vehicles that can be used in formulations (liquid and / or injectable and / or solid) include methylcellulose, hydroxymethylcellulose, carboxymethylcellulose, polysorbate 80, mannitol, gelatin, lactose, vegetable oils, and the like. acacia, etc. The compositions may be formulated as injectable suspensions, gels, oils, tablets, suppositories, powders, capsules, capsules, etc., optionally using dosage forms or devices providing sustained and / or delayed release. For this type of formulation, an agent such as cellulose, carbonates or starches is advantageously used.

  The compounds or compositions according to the invention can be administered in different ways and in different forms. Thus, they can be injected orally or systemically, such as, for example, intravenously, intramuscularly, subcutaneously, trans-dermally, intraarterially, etc. For injections, the compounds are generally packaged as liquid suspensions, which can be injected by means of syringes or infusions, for example. It is understood that the flow rate and / or the injected dose can be adapted by those skilled in the art depending on the patient, the pathology, the mode of administration, etc. Typically, the compounds are administered at doses ranging between 1 μg and 2 g / administration, preferably from 0.1 mg to 1 g / administration. Administrations can be daily or repeated several times a day, if necessary. On the other hand, the compositions according to the invention may comprise, in addition, other agents or active principles.

  LEGENDES OF FIGURES: Figures la, lb, 1c illustrate the antioxidant nature of the compound 2 (Cpd 2) according to the invention.

  Figure la represents the kinetics of formation of conjugated dienes over time. Lag-Phase is 120 minutes when LDL is incubated with copper alone. This delay is 314 minutes when the medium also contains the compound 2.

  Figure lb illustrates the rate of formation of dienes. This is 1.8 nmollmin / mg of LDL in the presence of copper alone, it is only 0.1 nmol / min / mg of LDL when the compound 2 is present in the medium.

  Figure 1c shows the maximum amount of dienes formed during the experiment. Copper alone induces the formation of 372 nmol / mg conjugated dienes, this amount is 35 nmol / mg when the medium also contains compound 2, which represents a 90% decrease in the amount of dienes formed.

  Figures 2a, 2b, 2c illustrate the antioxidant nature of compounds 4 (Cpd 4), compound 6 (Cpd 6) and compound 8 (Cpd 8) according to the invention.

  Figure 2a shows the kinetics of formation of conjugated dienes.

  Lag-Phase is 132 minutes when LDL is incubated with copper alone. The value of the lag phase is 401, 205 and 169 minutes respectively in the presence of compounds 4, 6 and 8.

  Figure 2b shows the calculation of the formation rate of dienes. The rate of formation of conjugated dienes by copper is 2.2 nmol / min / mg of LDL. The presence of compounds 4, 6 and 8 causes a decrease in the rate of the oxidation reaction of the dienes. It is 0.2 nmol / min / mg in the presence of compound 4 and 1.7 nmol / min / mg in the presence of compound 6 or compound 8.

  The total amount of dienes formed (FIG. 2c) is 511 nmol / mg of LDL in the presence of copper alone. In the presence of compounds 4, 6 and 8, this amount increases to 138, 443 and 474 nmol / mg.

  The delay in the formation of conjugated dienes, the decrease in the rate of formation of dienes and the decrease in the total amount of dienes formed are three parameters which attest to the antioxidant nature of the products.

  Figures 3a and 313: Evaluation of PPARα and PPARy agonist properties of the compounds according to the invention with the PPARalGaI4 and PPARylGaI4 transactivation system in RK13 cells.

  The RK13 cells are incubated with compound 2 at concentrations of between 0.01 and 10 μM for 24 hours. The results are represented by the induction factor (ratio between the luminescent signal obtained with the compound and the luminescent signal obtained without a compound) as a function of the different treatments. The higher the induction factor, the better the agonist property for PPARa or PPARy.

  Figure 3a: The results presented in Figure 3a show the induction factors of Compound 2 with the PPARalGaI4 transactivation system. The values of these induction factors are noted in the following table.

  Compound Treatment Induction Factor Cpd 2 1 μM 8.83 10 μM 18.49 The induction factor measured with compound 2 is maximal for the dose of 10 μM and reaches the value of 18.49.

  FIG. 3b: The results presented in FIG. 3b show the induction factors of compound 2 with the PPARylGaI4 transactivation system. The values of these induction factors are noted in the following table: Compound Treatment Induction Factor Cpd 2 0.01 pM 1.31 0.03pM 1.18 0.1pM 1.73 0.3pM 4.58 1 pM 9.50 3pM 16 , 64 10pM 31.00 With regard to the PPARy / GaI4 system, the induction factor varies from 1.31 to 31.00, it increases with the concentration of compound 2 in the medium.

  FIGS. 4a and 4b: Evaluation of PPARα and PPARγ agonist properties of the compounds according to the invention with the PPARαGGα14 and PPARγGal4 transactivation system using COS-7 cells.

  COS-7 cells are incubated with compounds 4, 6 and 8 at concentrations of 1 and 10 μM for 24 hours. The results are represented by the induction factor (ratio between the luminescent signal obtained with the compound and the luminescent signal obtained without a compound) as a function of the different treatments. The results presented in FIG. 4a show the induction factors of compounds 4, compound 6 and compound 8 with the PPARalGal4 transactivation system. The values of these induction factors are noted in the following table: Compound Treatment Induction Factor Cpd 4 lpM 1.67 10pM 9.92 Cpd 6 1 pM 5.48 10pM 7.01 Cpd8 1 pM 15.67 10pM 12 The maximum induction factor measured for compound 4 is 9.92 to 10 NM. This value is 7.01 for compound 6 (10 μM) and 15.67 for compound 8 (1 μM).

  The results presented in FIG. 4b show the induction factors of compound 4, compound 6 and compound 8 with the PPARylGal4 transactivation system. The values of these induction factors are noted in the following table: Compound Treatment Induction Factor Cpd 4 1 pM 2.00 10pM 5.82 Cpd 6 1 pM 4.12 10pM 6.83 Cpd 8 1NM 2.13 10pM 2.74 Compound 4 has a maximum induction factor of 5.82, and is observed at a concentration of 10 μM.

  The maximum value of the induction factor observed with compound 6 is 6.83 (10 μM) with compound 6 and 2.74 with compound 8 (10 μM).

  The results illustrated by the figures show that the compounds according to the invention tested have the ligand property with respect to PPARα and PPARγ and also allow its activation at the transcriptional level.

  FIGS. 5a, 5b, 5c and 5d show the effects of treatment with compound 2 on triglyceride and cholesterol metabolism in Apo E2IE2 transgenic mice. The animals were treated by gavage with 50 mg of compound 2 per kg and per day for 7 days.

  Figures 5a and 5b show the decrease in plasma levels of triglycerides and cholesterol induced by the compound.

  Figures 5c and 5d show the distribution of triglycerides and cholesterol in the lipoparticles evaluated by exclusion chromatography. A typical distribution of triglycerides and cholesterol is found mainly in large lipoparticles. There is also a decrease in triglycerides and cholesterol in this class of lipoparticles induced by the treatment with compound 2.

  Other aspects and advantages of the present invention will become apparent from the following examples, which should be considered as illustrative and not limiting.

EXAMPLES

  Example 1 Synthesis of the compounds according to the invention The compounds of the invention are prepared according to the general methods described below.

  Description of the general synthetic methods according to the invention: Synthesis of 1,3-diphenylprop-2-en-1-ones: General Method 1: Synthesis of 1,3-diphenylprop-2-en-1-ones in an acid medium: The ketone (1 eq) and the aldehyde (1 eq) are solubilized in a solution of ethanol saturated with gaseous hydrochloric acid. The mixture is stirred at ambient temperature for 6 hours and then the solvent is removed by evaporation under reduced pressure. 1,3-Diphenylprop-2-en-1-one is purified by chromatography on silica gel or by recrystallization.

  General Method 2: Synthesis of 1,3-diphenylprop-2-en-1-ones in the Presence of Sodium Hydroxide: Ketone (1 eq) and aldehyde (1 eq) are solubilized in a hydroalcoholic solution of hydroxide sodium (20 eq). The whole is stirred for 18 hours at room temperature. The medium is acidified (pH = 2) with hydrochloric acid.

  1,3-Diphenylprop-2-en-1-one is obtained by precipitation or solid liquid extraction after evaporation of the reaction medium. It is purified by chromatography on silica gel or by recrystallization.

  General Method 3: Synthesis of 1,3-diphenylprop-2-en-1-ones substituted in the presence of sodium ethoxide: Sodium (1 eq) is dissolved in absolute ethanol. Ketone (1 eq) and aldehyde (1 eq) are added. The mixture is stirred at room temperature for 12 hours and then a 2N sodium hydroxide solution (5 eq) is added. The whole is kept at 100 C for 12 hours. The reaction medium is acidified by adding an aqueous solution of 6N hydrochloric acid. The solvent is removed by evaporation under reduced pressure. The residue is purified by chromatography on silica gel or by recrystallization.

  O-Alkylation of Phenols or Thiophenols: General Method 4: Phenol (1 eq) or thiophenol (1 eq) is solubilized in acetonitrile, the halogenated derivative (1 to 10 eq), and potassium carbonate (5 eq) are added. The reaction medium is maintained for about 10 hours with vigorous stirring under reflux. The salts are removed by filtration, the solvent and the excess of reagent are removed by evaporation under reduced pressure, the expected product is purified by chromatography on silica gel.

  General Method 5: Alcohol (1 eq), phenol (1 eq) and triphenylphosphine are solubilized in dichloromethane. Diisopropylazodicarboxylate (1 eq) is added, the whole is left for 12 hours, with stirring at room temperature.

  The reaction medium is washed with water, dried over magnesium sulphate and evaporated under reduced pressure. The evaporation residue is purified by chromatography on silica gel Acidolysis of tertiobutyl esters: General method 6: The tert-butyl ester (1 eq) is solubilized in dichloromethane, the trifluoroacetic acid (10 eq) is added, the The mixture is stirred for 12 hours at room temperature. The product formed is purified by chromatography on silica gel or by recrystallization.

  Synthesis of the raw materials used for the synthesis of the compounds according to the invention: Raw material 1: 4 '- (Bromoethyloxy) acetophenone: Ho This compound is synthesized from 4'-hydroxyacetophenone and dibromoethane according to the general method 4 previously described.

  Purification by chromatography on silica gel (elution: ethyl cyclohexaneacetate: 9-1).

  1H NMR CDCl3 δppm: 2.55 (s, 3H), 3.66 (t, 2H, J = 6.5Hz), 4.35 (t, 2H, J = 6.5Hz), 6.94 (d, 2H, J = 7.23Hz), 7.94. (d, 2H, J = 7.23Hz) Starting material 2: 4 '- (Pentylthioethyloxy) acetophenone:

B

  The raw material 1 (1 eq) and the penthanethiol (1 eq) are solubilized in methanol in the presence of triethylamine (2 eq). The reaction medium is maintained at reflux for 18 hours, the solvent is removed by evaporation under reduced pressure. The oil is taken up in ethyl acetate and washed with aqueous 2N hydrochloric acid solution. 4 '(pentylthioethyloxy) acetophenone is obtained after purification on silica gel (elution: cyclohexane-ethyl acetate: 9-1).

  1H NMR CDCl3 δppm: 0.85 (m, 3H), 1.24-1.39 (m, 4H), 1.52-1.62 (m, 2H), 2.50 (s, 3H), 2.64 (t, 2H, J = 7.2Hz) , 2.94 (t, 2H, J = 6.8Hz), 4.14 (t, 2H, J = 6.8Hz), 6.88 (d, 2H, J = 8.7Hz), 7.89 (d, 2H, J = 8.7Hz).

  3: 3,5-Dimethyl-4-tert-butyloxycarbonyl-dimethylmethyloxybenzaldehyde: This compound is synthesized from 4-hydroxy-3,5-dimethylbenzaldehyde and tert-butyl bromoisobutyrate according to general method 4.

  Purification by chromatography on silica gel (elution: ethyl cyclohexaneacetate: 8-2).

  1H NMR CDCl3 δppm: 1.43 (s, 6H), 1.49 (s, 9H), 2.28 (s, 6H), 7.53 (s, 2H), 9.88 (s, 1H).

  Raw material 4: 4'-Hydroxy-3,5-dimethylbenzaldehyde: 2,6-Dimethylphenol (1 eq) is solubilized in methylene chloride, the solution is cooled to 0 ° C., then the aluminum chloride (3 eq) is added and the acetyl bromide (2 eq). The mixture is stirred for 3 hours at room temperature and then poured on ice. The aqueous phase is extracted with dichloromethane, the organic phase is washed with water until neutral, dried over magnesium sulfate and the solvent is removed by evaporation under reduced pressure. The intermediate ester obtained is purified by chromatography on silica gel (eluent: cyclohexane-ethyl acetate: 9-1) and then taken up in aqueous 2N sodium hydroxide solution (2.5 eq). The mixture is stirred for 48 hours at room temperature and then acidified with a dilute hydrochloric acid solution. The precipitate is washed with water until the washing water is neutral. 1H NMR CDCl3 δppm: 2.3 (s, 6H), 2.54 (s, 3H), 7.65 (s, 2H).

  Starting material 5: 4 '- ((R, S) -5- [1,2] dithiolan-3-ylpentyloxy) acetophenone: OH +

HO

  This compound is synthesized from 4'-hydroxyacetophenone and (R, S) 5- [1,2] dithiolan-3-ylpentanol according to the general method previously described. Purification by chromatography on silica gel (elution: cyclohexane-ethyl acetate: 95-5).

  1H NMR CDCl3 δppm: 1.42-1.62 (m, 4H), 1.62-1.75 (m, 2H), 1.75-1.89 (m, 2H), 1.89-1.98 (m, 1H), 2.42-2.51 (m, 1H). , 2.56 (s, 3H), 3.08-3.21 (m, 2H), 3. 55-3.61 (m, 1H), 4.06 (t, 2H, J = 6.2Hz), 6.92 (d, 2H, J = 8.7 Hz ), 7.93 (d, 2H, J = 8.7Hz) Starting material 6: (R, S) -2-phenyl-2- (4-formyl-1,6-dimethylphenyloxy) ethyl acetate: This compound is synthesized from of 4-hydroxy-3,5-dimethylbenzaldehyde and 2-hydroxy-2-phenyl ethyl acetate according to the general method previously described.

  Purification by chromatography on silica gel (elution: ethyl cyclohexaneacetate: 9-1).

  1H NMR CDCl3 Spp: 1.22 (t, 3H, J = 7.35Hz), 2.20 (s, 6H), 4.16-4.28 (m, 2H), 5.3 (s, 1H), 7.38-7.51 (m, 7H), 9.87. (s, 1H) Synthesis of Intermediate Compounds for the Synthesis of the Compounds According to the Invention: Intermediate Compound 1: 1- (4- (Pentylthioethyloxy) phenyl) -3- (4-hydoxy-3,5-dimethylphenyl) This compound is synthesized from the raw material 2 and 4-hydroxy-3,5-dimethylbenzaldehyde according to the general method 1 previously described. Purification by chromatography on silica gel (elution: cyclohexane-ethyl acetate: 85-15).

  1 H NMR CDCl3 Spp: 0.91 (m, 3H), 1.33-1.42 (m, 4H), 1.59-1.67 (m, 2H), 2. 29 (s, 6H), 2.64 (t, 2H, J = 7.6 Hz). , 2.96 (t, 2H, J = 6.8Hz), 4.24 (t, 2H, J = 6.8Hz), 6.97 (d, 2H, J = 8.7Hz), 7.31 (s, 2H), 7.37 (d, 1H). , J = 15.54Hz), 7. 72 (d, 1H, J = 15.54Hz), 8.03 (d, 2H, J = 8.7Hz).

  Intermediate Compound 2: 1- (4 - ((R, S) -5- [1,2] diethylolan-3-ylpentyloxy) phenyl) -3- (4-hydroxy-3,5-dimethylphenyl) prop-2 This compound is synthesized from the raw material 5 and 4-hydroxy-3,5-dimethylbenzaldehyde according to the general method 1 previously described. Purification by chromatography on silica gel (elution: cyclohexane-ethyl acetate: 8-2).

  1 H NMR CDCl3 Spp: 1.45-1.65 (m, 4H), 1.65-1.77 (m, 2H), 1.77-1.87 (m, 2H), 1.87-2.0 (m, 1H), 2.30 (s, 6H), 2.43-. 2.51 (m, 1H), 3.09-3.22 (m, 2H), 3.56-3. 62 (m, 1H), 4.04 (t, 2H, J = 6.4Hz), 6.96 (d, 2H, J = 8.5Hz), 7.31 (s, 2H), 7.41 (d, 1H, J = 15.4Hz), 7.73 (d, 1H, J = 15.4Hz), 8.04 (d, 2H, J = 8.5Hz).

  Intermediate Compound 3: 1- (4-Methylthiophenyl) -3- (4-hydoxy-3,5-dibromophenyl) prop-2-en-1-one: + This compound is synthesized from 4-methylthioacetophenone and 3,5-dibromo-4-hydroxybenzaldehyde according to general method 1 previously described.

  Purification by chromatography on silica gel (elution: ethyl cyclohexaneacetate: 8-2).

  1H NMR CDCl3 Spp: 2.55 (s, 3H), 6.19 (s, 1H), 7.32 (d, 2H, J = 8.7Hz), 7.41 (1H, J = 15.4Hz), 7.63 (d, 1H, J). = 15.4), 7.75 (s, 2H), 7.96 (d, 2H, J = 8. 7Hz) Synthesis of the compounds according to the invention: Compound 1 according to the invention: 1- (4- (Pentylthioethyloxy) phenyl) -3 This compound is synthesized from the intermediate compound 1 and tertiobutyl bromoisobutyrate according to the general method 4 previously described.

  Purification by silica gel chromatography (elution: ethyl cyclohexaneacetate: 9-1).

  1H NMR CDCl3 Spp: 0.91 (t, 3H, J = 7.1Hz), 1.37-1.69 (m, 21H) 2.27 (s, 6H), 2.63 (t, 2H, J = 7.1Hz), 2.93 (t, 2H, J = 7.1 Hz), 4.21 (t, 2H, J = 7.1 Hz); 6.97 (d, 2H, J = 8.7Hz), 7.28 (s, 2H), 7.44 (d, 1H, J = 15.8Hz), 7.70 (d, 1H, J = 15.8Hz), 8.03 (d, 2H, J); = 8.7 Hz) Compound 2 according to the invention: 1- (4 (Pentylthioethyloxy) phenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) prop-2-en-1-one

OH

  This compound is synthesized from the compound 1 according to the general method 6 previously described.

  Purification by chromatography on silica gel (elution: dichloromethane-methanol: 98-2).

  1H NMR CDCl3 Spp: 0.84-0.89 (m, 3H), 1.39-1.24 (m, 4H), 1.39 (s, 6H), 1. 50-1.57 (m, 2H), 2.22 (s, 6H), 2.61 (m.p. t, 2H, J = 7.4Hz), 2.90 (t, 2H, J = 6.2Hz), 4.26 (t, 2H, J = 6.2Hz), 7.09 (d, 2H, J = 8.5Hz), 7.57 (s). , 7.59 (d, 1H, J = 15. 4Hz), 7.83 (d, 1H, J = 15.4Hz), 8.15 (d, 2H, J = 8.5Hz), 12.90 (s, 1H) MS (ES MS): 483.2 (m-1) Compound 3 according to the invention: 1- (4-Hydroxy-3,5-dimethylphenyl) -3- (4-tert-butyloxycarbonylmethylmethyloxy-3,5-dimethylphenyl) propylene 2-ene-1-one: This compound is synthesized from the raw material 3 and the raw material 4 according to the general method 1 previously described.

  Purification by chromatography on silica gel (elution: dichloromethanemethanol: 95-5).

  1 H NMR CDCl3 Spp: 1.46 (s, 6H), 1.53 (s, 9H), 2.27 (s, 6H), 2.33 (s, 6H), 7.28 (s, 15H), 7.43 (d, 1H, J); = 15.8 Hz), 7.69 (d, 1H, J = 15.8 Hz), 7.74 (s, 2H) Compound 4 according to the invention: 1- (4-Hydroxy-3,5-dimethylphenyl) -3- (4-carboxydimethylmethyloxy-3.5) -dimethylphenyl) -prop-2-en-1-one: This compound is synthesized from compound 3 according to the general method 6 previously described.

  Purification by chromatography on silica gel (elution: dichloromethanemethanol: 98-2).

  1H NMR CDCl3 Spp: 1.39 (s, 6H), 2.22 (s, 6H), 2.25 (s, 6H), 7.33 (s, 2H), 7.45 (d, 1H, J = 15.5Hz), , 1H, J = 15.5Hz), 7.75 (s, 2H)

OH

  MS (ES-MS): 381 (m-1) Compound 5 according to the invention: 1- (4 - ((R, S) -5- [1,2] dithiolan-3-ylpentyloxy) phenyl) -3- (4-tert-butyloxycarbonyl dimethyl-methyloxy-3,5-dimethylphenyl) -prop-2-en-1-one: This compound is synthesized from intermediate compound 2 and tert-butyl bromoisobutyrate according to the general method 4 previously described.

  Purification by chromatography on silica gel (elution: ethyl cyclohexaneacetate: 85-15).

  1H NMR CDCl3 δppm: 1.43 (s, 6H), 1.53 (m, 13H), 1.65-1.75 (m, 2H), 1.75-1. 85 (m, 2H), 1.85-1.97 (m, 1H), 2.28 (s, 6H), 1.46-1.52 (m, 1H), 3.12-3.21 (m, 2H), 3.58-3.63 (m, 1H); , 4.05 (t, 2H, J = 6.21 Hz), 6.97 (d, 2H, J = 8.3Hz), 7.29 (s, 2H), 7.45 (d, 1H, J = 15.5Hz), 7.70 (d, 1H, J = 15.5Hz), 8.03 (d, 2H, J = 8.3Hz).

  Compound 6 according to the invention: 1- (4 - ((R, S) -5- [1,2] dithiolan-3-ylpentyloxy) phenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) prop -2-en-1-one:

OH

  This compound is synthesized from compound 5 according to the general method 6 previously described.

  Purification by chromatography on silica gel (elution: dichloromethanemethanol: 98-2).

  1H NMR CDCl3 δppm: 1.56 (m, 10H), 1.67-1.77 (m, 2H), 1.77-1.90 (m, 2H), 1.901.97 (m, 1H), 2.30 (s, 6H), 2.43-2.52 (m.p. m, 1H), 3.11-3.22 (m, 2H), 3.58-3.63 (m, 1H), 4.05 (t, 2H, J = 6.2Hz), 6.98 (d, 2H, J = 8.8Hz), 7.31 (s, 1H), , 7.46 (d, 1H, J = 15.8Hz), 7.71 (d, 1H, J = 15.8Hz), 8.03 (d, 2H, J = 8.8Hz).

  MS (ES-MS): 529.1 (M + 1) Compound 7 according to the invention: 1- (4-Methylthiophenyl) -3- (4-tert-butyloxycarbonyl-dimethyl-methyl-3,5-dibromophenyl) -prop-2-en-1-one This compound is synthesized from the intermediate compound 3 and tertiobutyl bromoisobutyrate according to the general method 4 previously described.

  Purification by chromatography on silica gel (elution: ethyl cyclohexaneacetate: 9-1).

  1H NMR CDCl3 δppm: 1.54 (s, 9H), 1.63 (s, 6H), 2.56 (s, 3H), 7.33 (d, 2H, J = 8.5Hz), 7.44 (d, 1H, J = 15.7Hz). , 7.62 (d, 1H, J = 15.7Hz), 7.78 (s, 2H), 7.96 (d, 2H, J = 8.5Hz) Compound 8 according to the invention: 1- (4-Methylthiophenyl) -3- (4 -carboxydimethylmethyloxy-3,5-dibromo phenyl) -p-rop-2-en-1-one:

OH

  This compound is synthesized from compound 7 according to the general method 6 previously described.

  Purification by chromatography on silica gel (elution: 5-dichloromethane-methanol 98-2).

  1H NMR CDCl3 Spp: 1.54 (s, 6H), 2.51 (s, 3H), 7.41 (d, 2H, J = 8.5Hz), 7. 64 (d, 1H, J = 15.4Hz), 8.04 (d, 1H). , J = 15.4Hz), 8.15 (d, 2H, J = 8.5Hz), 29 (s, 2H), 12.93 (s, 1H) MS (ES-MS): 513.2 (m-1) Compound 9 according to the invention: 1- (4-Bromophenyl) -3- (3,5-dimethyl-4-ethyloxycarbonylphenylmethyloxyphenyl) -prop-2-en-1-one: + This compound is synthesized from 4'-bromoacetophenone and the material first 6 according to the general method 1 previously described.

  Purification by chromatography on silica gel (elution: ethyl cyclohexaneacetate: 8-2).

  1 H NMR CDCl3 Spp: 1.23 (t, 3H, J = 7.08Hz), 2.16 (s, 6H), 4.2 (m, 2H), 5.7 (s, 1H), 7.28 (s, 2H), 7.31. 7.52 (m, 6H), 7.64 (d, 2H, J = 8.70Hz), 71 (d, 1H, J = 15.8z), 7.9 (d, 2H, J = 8.70Hz). Antioxidants of the compounds according to the invention Protection of the oxidation of LDL induced by copper: The compounds tested are the compounds according to the invention, the preparation of which is described in the examples described above.

  LDL oxidation is an important modification and plays a major role in the establishment and development of atherosclerosis (Jurgens, Hoff et al., 1987). The following protocol makes it possible to demonstrate the antioxidant properties of the compounds. Unless otherwise stated, the reagents are from Sigma (St Quentin, France).

  LDL are prepared according to the method described by Lebeau et al. (Lebeau, Furman et al., 2000).

  The test compound solutions are prepared at 10.2 M in bicarbonate buffer (pH = 9) and diluted in PBS to have final concentrations ranging from 0.1 to 100 μM.

  Prior to oxidation, EDTA is removed from the LDL preparation by dialysis. The oxidation then takes place at 30 ° C. by adding 100 μl of a 16.6 μM solution of CuSO4 to 160 μL of LDL (125 μg of protein / ml) and 20 μl of a solution of the test compound. The formation of dienes, the species to be observed, is measured by optical density at 232 nm in the samples treated with compounds with or without copper. The measurement of the optical density at 232 nm is carried out every 10 minutes for 8 hours using a thermostated spectrophotometer (Tecan Ultra 380). The analyzes are performed in triplicate. We consider that the compounds have an antioxidant activity when they induce retardation of the lag phase, decrease the rate of oxidation and the amount of dienes formed relative to the control sample. The inventors demonstrate that the compounds according to the invention have at least one of the antioxidant properties mentioned above, this indicating that the compounds according to the invention possess an intrinsic antioxidant character.

  Examples of results are given in Figures 1a, 1b, 1c, 2a, 2b, 2c where the antioxidant properties of the compounds according to the invention are illustrated.

  Example 3 Measurement of the Antioxidant Properties of the Compounds According to the Invention on Cell Culture Culture Protocol: The cell lines used for this type of experiment are of the neuronal type, neuroblastoma (human) and PC12 (rat) cells. PC12 cells were prepared from rat pheochromocytoma and characterized by the method of Greene and Tischler (Greene and Tischler, 1976). These cells are commonly used for studies of neuronal differentiation, signal transduction and neuronal death. PC12 cells are cultured as previously described (Farinelli, Park et al., 1996) in RPMI complete medium (Invitrogen) supplemented with 10% horse serum and 5% fetal calf serum.

  (Primary) cultures of endothelial cells and smooth muscle are also used. The cells are ordered from Promocell (Promocell GmBH, Heidelberg) and are grown according to the indications of the supplier.

  The cells are treated with different doses of compounds from 5 to 300 μM for 24 hours. the cells are then recovered and the increase in the expression of the target genes is evaluated by quantitative PCR.

  Measurement of the mRNAs: The mRNAs are extracted from cells in culture treated or not treated with the compounds according to the invention. The extraction is carried out using the reagents of the kit Absolutely RNA RT-PCR miniprep Kit (Stratagene, France) according to the indications of the supplier. The mRNAs are then assayed by spectrometry and quantified by quantitative RTPCR using the Light Cycler Kit Fast Start Master DNA Sybr Green I kit (Roche) on a Light Cycler System (Roche, France). Primer pairs specific for the genes Superoxide Dismutase (SOD), Catalase and Glutathione Peroxidase (GPx), antioxidant enzymes, are used as probes. Gene-specific primer pairs (i-actin and cyclophilin are used as control probes.

  The increase in mRNA expression, measured by quantitative RT-PCR, of the genes of the antioxidant enzymes is demonstrated in the different cell types used, when the cells are treated with the compounds according to the invention.

  Stress control Oxidative: Measurement of oxidizing species in cells in culture: The antioxidant properties of the compounds are also evaluated using a fluorescent indicator whose oxidation is followed by the appearance of a fluorescent signal. The decrease in intensity of the fluorescent signal emitted is measured in the cells treated with the compounds in the following manner: the PC12 cells cultured as previously described (black plates, 96 transparent background wells, Falcon) are incubated with increasing doses of H2O2 (0 25 mM -1 mM) in serum-free medium for 2 to 24 hours. After incubation the medium is removed and the cells are incubated with a solution of dichlorodihydrofluorescein diacetate (DCFDA, Molecular Probes, Eugene, USA) 10 μM in PBS for 30 min at 37 ° C and in an atmosphere containing 5% CO 2. The cells are then rinsed with PBS. The detection of the fluorescence emitted by the oxidation indicator is measured using a fluorimeter (Tecan Ultra 384) at an excitation wavelength of 495 nm and an emission wavelength. 535 nm. The results are expressed as a percentage of protection relative to the oxidized control.

  The fluorescence intensity is lower in the cells incubated with the compounds according to the invention than in the untreated cells. These results indicate that the compounds according to the invention promote the inhibition of the production of oxidizing species in cells subjected to oxidative stress. The antioxidant properties described above are also effective in inducing free radical protection in cells in culture.

  Measurement of lipid peroxidation: The protective effect of the compounds on lipid peroxidation on cell cultures (cell models mentioned above) is determined in the following way: the different cell lines as well as the cells in primary culture are treated as previously, the supernatant of the cells is recovered after the treatment and the cells are lysed and recovered for the determination of the protein concentration. Detection of lipid peroxidation is determined in the following manner Lipid peroxidation is measured using thiobarbituric acid (TBA) which reacts with the lipoperoxidation of aldehydes such as malondialdehyde (MDA). After the treatments, the cell supernatant is collected (900 μl) and 90 μl of butylated hydroxytoluene is added thereto (Morliere, Moysan et al., 1991). One ml of a 0.375% TBA solution in 0.25M HCL containing 15% trichloroacetic acid is also added to the reaction media. The mixture is heated at 80 ° C. for 15 minutes, cooled on ice and the organic phase is extracted with butanol. The analysis of the organic phase is carried out by spectrofluorometry (? Max = 515 nm and% em = 550 nm) using the Shimazu 1501 spectrofluorometer (Shimadzu Corporation, Kyoto, Japan). TBARS are expressed in MDA equivalents using a tetra-ethoxypropane standard. The results are normalized with respect to the protein content.

  The decrease in lipid peroxidation observed in the cells treated with the compounds according to the invention confirms the results obtained previously.

  The compounds according to the invention advantageously have intrinsic antioxidant properties which make it possible to slow down and / or to inhibit the effects of oxidative stress. The inventors also show that the compounds according to the invention are capable of inducing the expression of antioxidant enzyme genes. These particular characteristics of the compounds according to the invention allow the cells to fight more effectively against oxidative stress and thus to be protected against damage induced by free radicals.

  EXAMPLE 4 Evaluation of the Activation of PPARs in Vitro by the Compounds According to the Invention The compounds according to the invention tested are the compounds having a carboxylic acid function and the preparation of which is described in the examples described above.

  The nuclear receptors members of the subfamily PPARs, which are activated by two major classes of pharmaceutical compounds, fibrates and glitazones, which are widely used in human clinics for the treatment of dyslipidemias and diabetes, play an important role in homeostasis. lipid and carbohydrate. The following experimental data show that the compounds according to the invention activate PPARα and PPARγ in vitro.

  The activation of PPARs is evaluated in vitro in epitheloid-type RK13 or COS-7 lines by measuring the transcriptional activity of chimeras consisting of the DNA binding domain of the yeast transcription factor GaI4 and the ligand binding of the different PPARs. These latter results are then confirmed in cell lines according to the following protocols: The example is given for RK13 cells and COS-7 cells.

  Culture Protocols RK13 cells originate from ECACC (Porton Down, UK), COS-7 cells are from ATCC and are grown in DMEM supplemented with 10% vol / vol fetal calf serum, 100 U / ml penicillin ( Gibco, Paisley, UK) and 2 mM L-Glutamine (Gibco, Paisley, UK). The culture medium is changed every two days. The cells are stored at 37 ° C. in a humid atmosphere containing 5% of CO2 and 95% of air.

  Description of plasmids used in transfection

  Plasmids pG5TkpGL3, pRL-CMV, pGaI4-hPPARa, pGaI4-hPPARy and pGal4- were described by Raspe, Madsen et al. (1999). The pGal4mPPARa and pGaI4-hPPARy constructs were obtained by cloning into the pGaI44 vector of PCR amplified DNA fragments corresponding to the DEF domains of the human PPAR? And PPAR? Nuclear receptors.

  Transfection The RK13 cells are seeded in 24-well culture dishes at 5 × 10 4 cells / well, the COS-7 cells in 96-well plates at 5 × 10 4 cells / well and are transfected for 2 hours with the reporter plasmid. pG5TkpGL3 (50 ng / well), pGaI4-4 expression vectors, pGaI4-mPPARa, pGal4-hPPARa, pGal4-hPPARy (100 ng / well) and the pRL-CMV transfection efficiency control vector (1). ng / well) according to the previously described protocol (Raspe, Madsen et al., 1999) and incubated for 36 hours with the compounds tested. At the end of the experiment, the cells are lysed (Gibco, Paisley, UK) and the luciferase activities are determined using the Dual-LuciferaseTM Reporter Assay System assay kit (Promega, Madison, WI, USA) for RK13 cells and Steady Glow Luciferase (Promega) for COS-7 according to the supplier's instructions as previously described. The protein content of the cell extracts is then evaluated using the Bio-Rad Protein Assay assay kit (Bio-Rad, München, Germany) according to the supplier's instructions.

  The inventors demonstrate an increase in luciferase activity in the cells treated with the compounds according to the invention and transfected with the plasmid pGa14-hPPARa. This induction of luciferase activity indicates that the compounds according to the invention are activators of PPARα. An example of results is given in FIGS. 3a and 4a where the PPARα activating properties of the compounds according to the invention are illustrated.

  The inventors demonstrate an increase in luciferase activity in the cells treated with the compounds according to the invention and transfected with the plasmid pGal4-hPPARy. This induction of luciferase activity indicates that the compounds according to the invention are activators of PPARγ.

  Examples of results are shown in Figure 3b and 4b where the PPARy activating properties of the compounds are illustrated.

  EXAMPLE 5 Evaluation of the Anti-Inflammatory Properties of the Compounds According to the Invention The inflammatory response appears in numerous neurological disorders, such as multiple sclerosis, Alzheimer's and Parkinson's disease, cerebral ischemia and traumatic brain injury. In addition, inflammation is one of the important factors of neurodegeneration. In cerebral accidents, one of the first reactions of glia cells is to release cytokines and free radicals. The consequence of this release of cytokines and free radicals is an inflammatory response at the brain level that can lead to the death of neurons (Rothwell 1997).

  Cell lines and primary cells are cultured as previously described.

  LPS (LipoPolySaccaharide), a bacterial endotoxin (Escherichia col / 0111: B4) (Sigma, France), is reconstituted in distilled water and stored at 4 ° C. The cells are treated with an LPS concentration of 1 μg / ml. for 24 hours. To avoid any interference with other factors the culture medium of the cells is totally changed.

  TNF-a is an important factor in the inflammatory response to stress (for example oxidant). To evaluate the secretion of TNF-α in response to stimulation by increasing doses of LPS, the culture medium of the stimulated cells is removed and the amount of TNF-α is evaluated with an ELISA-TNF-a kit (Immunotech, France). ). The samples are diluted 50 times in order to be in line with the standard range (Chang, Hudson et al., 2000).

  The anti-inflammatory property of the compounds is characterized in the following manner: the culture medium of the cells is totally changed and the cells are incubated with the test compounds for 2 hours. After this incubation, LPS is added to the culture medium at a final concentration of 1 μg / ml. After 24 hours of incubation, the cell supernatant is recovered and stored at -80 ° C when not treated directly. The cells are lysed and the amount of protein is quantified using the Bio-Rad Protein Assay assay kit (Bio-Rad, München, Germany) according to the supplier's instructions.

  The measurement of the decrease in secretion of TNF-α favored by the treatment with the test compounds is expressed in pg / ml of protein and reported as a percentage relative to the control. These results show that the compounds according to the invention possess anti-inflammatory properties.

  EXAMPLE 6 Evaluation of Effects on Lipid Metabolism in Vivo The compounds according to the invention tested are the compounds whose preparation is described in the examples described above.

  Fibrates, extensively used in the human clinic for the treatment of dyslipidemias involved in the development of atherosclerosis, a major cause of mortality and morbidity in Western societies, are potent activators of the PPARα nuclear receptor. This regulates the expression of genes involved in transport (apolipoproteins such as Apo AI, Apo AII and Apo CIII, membrane transporters such as FAT) or lipid catabolism (ACO, CPT-I or CPT-II). Treatment with PPARα activators therefore results, in humans and in rodents, in a decrease in the circulating levels of cholesterol and triglycerides.

  The following protocols make it possible to demonstrate a decrease in the level of triglycerides and circulating cholesterol, as well as the interest of the compounds according to the invention in the context of the prevention and / or treatment of cardiovascular diseases.

  a) Treatment of animals Apo E2 / E2 transgenic mice are kept in a light / dark cycle of 12/12 hours at a constant temperature of 20 3 C. After one week acclimatization, the mice are weighed and grouped together. of 6 animals selected so that the distribution of their body weight is uniform. The compounds tested are suspended in carboxymethylcellulose and administered by intra-gastric gavage, once a day for 7, at the indicated doses. Animals have free access to water and food. At the end of the experiment the animals are weighed and sacrificed under anesthesia. The blood is collected on EDTA. The plasma is prepared by centrifugation at 3000 rpm for 20 minutes. Liver samples are taken and stored frozen in liquid nitrogen for later analysis.

  Measurement of lipids and serum apolipoproteins Serum lipid concentrations (total and free cholesterol, triglycerides and phospholipids) are measured by colorimetric assay (Boehringer, Mannheim, Germany) as indicated by the supplier. The serum concentrations of apolipoproteins Al, AII and CIII are measured according to the methods described above (Raspé et al., 1999, Asset G et al., Lipids, 1999).

  An example of results is given in Figures 5a, 5b, 5c and 5d where the activity of compound 2 on the metabolism of triglycerides and cholesterol is illustrated.

  b) Analysis of the RNAs Total RNA was isolated from the liver fragments by extraction using the guanidine thiocyanate / acid phenol / chloroform mixture according to the protocol described above (Raspé et al., 1999). The messenger RNAs were quantified by quantitative RT-PCR using the Light Cycler Fast Start DNA Master Kit Sybr Green Kit (Hoffman-La Roche, Basel, Switzerland) on a Light Cycler System (Hoffman-La Roche, Basel). , Swiss). Primer pairs specific for the ACO, Apo CIII and Apo AII genes were used as probes. Primer pairs specific for the 36B4, fi-actin and cyclophilin genes were used as control probes. Alternatively, the total RNA was analyzed by Northern Blot or Dot Blot according to the protocol described previously (Raspé et al., 1999).

  EXAMPLE 7 Evaluation of the Neuroprotective Effects of the Compounds According to the Invention in a Model of Cerebral Ischemia-Reperfusion Prophylactic Model: 1 / Animal Treatments 1.1 Animals and Administration of the Compounds C57 black / 6 (wild) mice are used to this experience.

  The animals are kept under a light / dark cycle of 12/12 hours at a temperature of 20 + 1-3 C. Animals have free access to water and food. Food intake and weight gain are recorded.

  The animals are treated by gavage with the compounds according to the invention or the vehicle (carboxycellulose 0.5%) for 14 days before the induction of ischemia of the middle cerebral artery.

  1.2 Induction of ischemia-reperfusion by intraluminal occlusion of the middle cerebral artery: The animals are anesthetized with an intraperitoneal injection of 300 mg / kg of chloral hydrate. A rectal probe is put in place and the body temperature is maintained at 37 + 1- 0.5 C. The blood pressure is measured during the whole experiment.

  Under a surgical microscope, the right carotid artery is updated with a medial cervical incision. The pterygopalatine artery was ligated at its origin and an artery is performed in the external carotid artery to slip a nylon monofilament. This filament is then gently advanced in the common carotid artery and then in the internal carotid artery to close the origin of the middle cerebral artery. After 1 hour, the filament is removed to allow reperfusion.

  2! Measurement of the volume of cerebral infarction: 24 hours after reperfusion, the animals previously treated or not treated with the compounds are killed by an overdose of pentobarbital.

  The brains are quickly frozen and severed. The sections are colored Cresyl violet. The uncolored areas of the brain sections were considered to be injured by the infarction. The areas were measured and the volume of the infarct and both hemispheres were calculated by the following formula (Infarcted volume corrected = Infarcted volume - (right hemisphere volume - hemisphere volume left)) to compensate for cerebral edema.

  The analysis of the brain sections of treated animals shows a marked decrease in the volume of infarction compared to untreated animals. When the compounds according to the invention are administered to animals before ischemia (prophylactic effect), they are capable of inducing neuroprotection.

  3! Measurement of Antioxidant Enzyme Activity: The brains of the mice are frozen, crushed and reduced to powders and then resuspended in saline. The different enzymatic activities are then measured as described by the following authors: superoxide dismutase (Flohe and Otting 1984); glutathione peroxidase (Paglia and Valentine 1967); glutathione reductase (Spooner, Delides et al., 1981); glutathione-S-transferase (Habig and Jakoby 1981); catalase (Aebi 1984).

The various enzymatic activities mentioned above are increased in the brain preparations of the animals treated with the compounds according to the invention.

  Curative model or treatment of the acute phase Induction of ischemia-reperfusion by intraluminal occlusion of the middle cerebral artery.

  Animals as described above are used for this experiment. The animals are anesthetized with an intraperitoneal injection of 300 mg / kg of chloral hydrate. A rectal probe is put in place and the body temperature is maintained at 37 + 1- 0.5 C. The blood pressure is measured during the whole experiment.

  Under a surgical microscope, the right carotid artery is updated with a medial cervical incision. The pterygopalatine artery was ligated to its origin and an arteriotomy was performed in the external carotid artery to slip a nylon monofilament. This filament is then gently advanced in the common carotid artery and then in the internal carotid artery to seal the origin of the middle cerebral artery. After 1 hour, the filament is removed to allow reperfusion.

  2 / Treatment of the animals: The animals having undergone ischemiereinfusion beforehand are treated with the compounds according to the invention for 24 or 72 hours orally (gavage), twice a day.

  3 / Measurement of the volume of the cerebral infarction: 24 or 72 hours after the reperfusion, the animals previously treated or not treated with the compounds are killed by an overdose of pentobarbital.

  The brains are quickly frozen and severed. The sections are colored Cresyl violet. The uncolored areas of the brain sections were considered to be injured by the infarction. The areas were measured and the volume of the infarct and both hemispheres were calculated by the following formula (Infarcted volume corrected = Infarcted volume - (right hemisphere volume - hemisphere volume left)) to compensate for cerebral edema.

  In cases of curative treatment (treatment of the acute phase), animals treated with the compounds according to the invention have reduced brain damage compared to untreated animals. Indeed the volume of the infarct is decreased when the compounds according to the invention are administered one or more times after ischemia-reperfusion.

  EXAMPLE 8 Evaluation of the Protective Effects of the Compounds According to the Invention in an Animal Model of Atherosclerosis The compounds according to the invention, by virtue of their activating and antioxidant PPAR properties, have a beneficial action on the progression of the atheromatous plaque.

  1M-alternating animals: Female Apo E2 / E2 transgenic mice approximately 2 months old are kept under a light / dark cycle of 12/12 hours at a constant temperature of 20 3 C during the acclimation period and the entire duration of the experiment.

  After the one-week acclimation period, the mice are weighed and collected in groups of 8 animals selected so that the distribution of their body weight is uniform.

  The animals have free access to water and food, they are fed a western diet containing 21% fat and 0.15% cholesterol for a period of two weeks before treatment.

  At the end of this period, the compounds to be tested are introduced into the food at the indicated doses. The treatment lasts 6 weeks.

  The animals are weighed and sacrificed under anesthesia, by cervical dislocation.

  The heart is perfused in situ and prepared for histological analysis, a needle is introduced into the right ventricle and the aorta is cut in its abdominal area. Blood samples are taken before the start of the experiment. each week then at the end of the experiment. The blood is collected on EDTA. The plasma is prepared by centrifugation at 3000 rpm for 20 minutes (measurements of plasma cholesterol and triglyceride levels).

  2 / Preparation of sections for histological analysis: A Krebs Ringer solution is introduced for 10 minutes. Tissues are fixed with 4% PAF in 10mM PBS at -4 ° C overnight. The samples are then washed with a 100mM solution of PBS the hearts are placed in a 30% solution of sucrose Tris for one day then immersed in OCT (tissue Teck) under vacuum for 30 minutes and then in a mold containing the OCT, immersed in isopentane and cooled with liquid nitrogen. The samples are stored at -80 C.

  Cryosections 10 μm thick are made from the aortic arch until the valves disappear. They are collected on slides coated with gelatin.

  3 / Histological analysis: The slides are stained with a solution of red oil and hematoxylin so as to differentiate the medial part of the intima. The different morphogenic parameters are determined using an Olympus microscope and a color camera coupled to the Analysis image analysis system. The quantification of the damaged surfaces is done manually by means of a graphics tablet coupled to the same computer system.

  The overall area of the atherosclerotic lesions is expressed in pM2 and is compared to the control group. The compounds according to the invention tested allow a significant reduction of the surface of the lesions, thus reducing the progression of the lesions.

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Claims (18)

  1. Compounds derived from 1,3-diphenylprop-2-en-1-one substituted of the following general formula (I): wherein X7 represents a group corresponding to the following formula: G7-R7 in which G7 is an oxygen or sulfur atom and R7 is an alkyl chain substituted by a group 1 or a group 2 group, R7 may optionally also be substituted by an aryl group, the substituents of group 1 are chosen from groups carboxy of formula: -COORa, the carbamoyl groups of formula: -CONRbRc or the tetrazolyl group, the substituents of group 2 are chosen from sulphonic acid (-SO3H) and sulphonamide groups of formula: -SO2NRbRc, with Ra, Rb and Rc, identical or different, representing a hydrogen atom or a substituted or unsubstituted alkyl radical, the X groups; with i = 1, 2, 3, 4 or 5, identical or different, represent a halogen atom or a thionitroso group or respectively correspond to the formula (Gi-R;) - G'i-R '; where: ^ n can be 0 or 1 ^ G; and G ', which may be identical or different, represent a single bond, an oxygen atom or a sulfur atom; R 1 and R' 1, which may be identical or different, represent an alkyl, alkenyl, aryl or heterocycle radical; '; can also represent a hydrogen atom, the groups Xi with i = 6 or i = 8, identical or different, represent a halogen atom or correspond to the formula G ', R'i, G'; and R '; being as defined above, X6 and X8 not simultaneously representing a hydrogen atom, Xi with i = 1, 2, 3, 4, 5, 6 or 8 not being able to represent a heterocycle directly linked to the aromatic ring of the 1, 3-diphenyl prop-2-en-1-one, excluding the compounds of formula (I) for which at the same time: one of the groups XI, X2, X3, X4 or X5 is a hydroxyl group, G7 is a oxygen atom, and one of the groups X6 or X8 is a hydrogen or halogen atom or a hydroxyl or an alkyloxy group, with the exception of the compounds of formula (I) for which simultaneously the groups XI X2 and X4 simultaneously represent a hydrogen atom, and X3 or X5 represents a hydrogen atom or a halogen or an alkyl radical or an alkyloxy radical or an alkylthio radical or a hydroxyl group or a thiol group or a thionitroso group.   2. Compounds according to claim 1, characterized in that XI and X5 are hydrogen atoms.   3. Compounds according to claim 1 or 2, characterized in that X2 and X4 are alkyl radicals.   4. Compounds according to claim 1, characterized in that XI, X3 and X4 are alkyl radicals.   5. Compounds according to claim 1, characterized in that XI, X2, X4 and X5 are hydrogen atoms.   6. Compounds according to any one of the preceding claims, characterized in that X6 and X8 are alkyl radicals.   7. Compounds according to the preceding claim, characterized in that XI and X5 are hydrogen atoms.   8. Compounds according to the preceding claim, characterized in that X2 and X4 are alkyl radicals.   9. Compounds according to claim 1, characterized in that XI, X3, X4, X6 and X8 are alkyl radicals.   10. Compounds according to claim 1, characterized in that X6 and X8 are alkyl radicals and X1, X2, X4 and X5 are hydrogen atoms.   11. Compounds according to any one of the preceding claims, characterized in that X3 which represents a halogen atom or a thionitroso group or which corresponds to the formula (G; -R;) -G '; R'i such that defined in claim 1, wherein G '; represents an oxygen atom or a sulfur atom.   12. Compounds according to any one of the preceding claims, characterized in that at least one of the groups G 1 or G '1 represents a sulfur atom with i which can take one of the values 1, 2, 3, 4, 5, 6, 7 or 8.   13. Compounds according to any one of the preceding claims, characterized in that they are chosen from: 1- (4- (Pentylthioethyloxy) phenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) prop-2- 1- (4- (Cyclohexylthioethyloxy) phenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) -prop-2-en-1-one, 1- (4-Methylthiophenyl) -3-en-1-one - (4-carboxydimethylmethyloxy-3,5-dibromophenyl) prop-2-en-1-one, 1- (4-Hydroxy-3,5-dimethylphenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) propane 2-en-1-one, 1- (4-methoxy-3,5-dimethylphenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) prop-2-en-1-one, La 1 - (4 - ((R, S) -5- [1,2] dithiolan-3-ylpentyloxy) -3,5-dimethylphenyl) -3- (4carboxydiméthylméthyloxy-3,5-dimethylphenyl) -prop-2-en- 1-one, 1- (4 - ((R, S) -5- [1,2] dithiolan-3-ylpentyloxy) phenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) prop-2-en -1-one, 1- (4-Bromophenyl) -3- (4-carboxyphenylmethyloxy-3,5-dimethylphenyl) 1) -prop-2-en-1-one, 1- (4-Mercapto-3,5-dimethylphenyl) -3- (4-carboxydimethyl) methyloxy-3,5-dimethylphenyl) prop-2-en 1 -one, 1- (4-Methythio-3,5-dimethylphenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) prop-2-en-1-one, Cyclohexylethythio-3,5-dimethylphenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) -prop-2-en-1-one, 1- (4-hexylthio-3,5-dimethylphenyl) -3- (4- carboxydimethylmethyloxy-3,5-dimethylphenyl) -prop-2-en-1-one, 1- (2,5-Dihydroxy-3,4,6-trimethylphenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) ) -prop-2-en-1-one, 1- (2,5-Dimethoxy-3,4,6-tri methylphenyl) -3- (4-carboxydimethylmethoxy-3,5-dimethylphenyl) -prop-2-en-1-one. ) -prop-2-en-1-one, 1- (2,5-Dihydroxyphenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) -30-prop-2-en-1-one (1- (2,5-Dimethoxyphenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) prop-2-en-1-one, 1- (4-Phenylethyloxyphenyl) -3- carboxydim ethylmethyloxy-3,5-dimethylphenyl) -prop-2-en-1-one, and 1- (4- (4-morpholin-4-ylethyloxy) phenyl) -3- (4-carboxydimethylmethyloxy-3,5-dimethylphenyl) prop-2- en-1-one.   14. Process for the preparation of compounds of formula (I) as defined in one of the preceding claims, characterized in that it comprises bringing into contact in basic medium or in acidic medium at least one compound of formula ( A) with at least one compound of formula (B), the formulas (A) and (B) being: (A) (B) formulas in which XI, X2, X3, X4, X5, X6 and X7 have the given definitions in one of the preceding claims, X7 may also be a hydroxyl or thiol group.   15. Compounds, characterized in that they are selected from: 1- (4- (4- (Pentylthioethyloxy) phenyl) -3- (4-hydroxy-3,5-dimethylphenyl) prop-2-en-1-one 4 - ((R, S) -5- [1,2] dithiolan-3-ylpentyloxy) phenyl) -3- (4-hydroxy-3,5-dimethylphenyl) prop-2-en-1-one-1 ( 4-Methylthiophenyl) -3- (4-hydroxy-3,5-dibromophenyl) prop-2-en-1-one 16. Compounds according to any one of the preceding claims 1 to 13, as medicaments.   17. A pharmaceutical or cosmetic composition comprising, in a pharmaceutically or cosmetically acceptable carrier, at least one compound of general formula (I) as defined in one of claims 1 to 13, optionally in combination with another active ingredient. therapeutic and / or cosmetic.   18. Pharmaceutical or cosmetic composition according to claim 17, for the treatment of cardiovascular diseases, dyslipidemias, syndrome X, diabetes, obesity, hypertension, inflammatory diseases, dermatological diseases (psoriasis, dermatitis). atopic, acne ..), disorders related to oxidative stress, or the treatment of aging in general, particularly skin aging.