MXPA01006590A - Benzopyrans and benzoxepines, pharmaceutical compositions comprising them and preparation process - Google Patents

Abstract

The present invention relates to benzopyrans and benzoxepines of formula (I), wherein X, A, R1, R2 and (R)p have the meanings as given in claim 1, which can be used in the treatment of dislipidaemias, atherosclerosis and diabetes, to pharmaceutical compositions comprising them and to processes allowing the preparation of these compounds.

Description

BENZOPIRANOS AND BENZOXEPINAS, PHARMACEUTICAL COMPOSITIONS THAT. THEY UNDERSTAND AND PROCESS FOR ITS PREPARATION FIELD OF THE INVENTION The present invention relates to benzopyrans and berizoxepins which can be used in the treatment of dyslipidemias, atherosclerosis and diabetes, with pharmaceutical compositions comprising them and with processes that allow the preparation of those compounds. The invention also relates to the use of these compounds in the preparation of drugs intended to treat dyslipidemias, atherosclerosis and diabetes.

BACKGROUND OF THE INVENTION Cardiovascular diseases remain, in most countries, one of the main diseases and the main cause of mortality. Approximately one third of men develop major cardiovascular disease before the age of 60, with women exhibiting a lower risk (ratio of 1 to 10). This disease becomes more prevalent with age (only after the age of 65, women become as vulnerable to cardiovascular diseases as men). The diseases REF: 129578 vascular, such as coronary disease, stroke, restenosis and peripheral vascular disease, remain the leading cause of mortality and disability worldwide. Although diet and lifestyle may accelerate the development of cardiovascular disease, a genetic predisposition that leads to dyslipidemia is a significant factor in strokes and deaths. The development of atherosclerosis seems to be related mainly to dyslipidemia, which means abnormal levels of lipoproteins in the blood plasma. This dysfunction is particularly evident in coronary disease, diabetes and obesity. The concept that is intended to explain the development of atherosclerosis was focused mainly on the metabolism of cholesterol and on the metabolism of triglycerides. However, from the studies of Randle et al. (Lancet, 1963, 785-78D), a novel concept has been proposed: a glucose-fatty acid cycle or Randle cycle, which describes the regulation of the balance between lipid metabolism, in terms of triglycerides and cholesterol, the oxidation of glucose. According to this concept, the inventors have developed a novel program whose main purpose is to find new compounds that can act simultaneously on the metabolism of lipids and glucose metabolism. Fibrates are well-known therapeutic agents with a mechanism of action via the "Activated Receptors of the Peroxisome Proliferator". These receptors are the main regulators of lipid metabolism in the liver (isoform of PPARa). In the last ten years, thiazolidinediones have been described as powerful hypoglycemic agents in animals and man. It has been reported that thiazolidinediones are powerful selective activators of another isoform of PPARs: the different PPAR? (Lehman et al., J. Biol. Chem., 1995, 270, 12953-12956).

BRIEF DESCRIPTION OF THE INVENTION The inventors have discovered a new class of compounds which are powerful activators of PPARa and PPAR? Isoforms. Due to this activity, these compounds exhibit a significant hypolipidemic and hypoglycemic effect. The compounds of the invention correspond to the following formula (I): wherein: X represents O or S; A represents the bivalent radical - (CH2) s-CO- (CH2) t- or the bivalent radical - (CH2) S-CR3CR- (CH2) t ~ radicals in which s = t = 0 or in addition one of syt has the value of 0 and the other has the value of 1. R4 represents a hydrogen atom or an alkyl group (of C1-C15); Ri and R2 independently represent the Z chain defined below; a hydrogen atom; an alkyl group (of Ci-Cis); an alkenyl group (of C2-C18); an alkynyl group (of C2-C18); an aryl group (of C6-C? 0) optionally substituted by a halogen atom, by an optionally halogenated (C1-C5) alkyl group or by optionally halogenated (C1-C5) alkoxy; or a monocyclic or bicyclic heteroaryl group (C4-C2) comprising one or more heteroatoms selected from O, N and S, which is optionally substituted by a halogen atom, by an alkyl group (from C1-C5) optionally halogenated or by an optionally halogenated (C1-C5) alkoxy group; R3 has any of the meanings data previously for Rj. and R2, with the exception of the Z chain; or in addition R3 and R4 together form an alkylene chain (of C2-C6) optionally substituted by a halogen atom or by optionally halogenated (C1-C5) alkoxy; R is chosen from a halogen atom; a cyano group; a nitro group; a carboxy group; an alkoxycarbonyl group (from Ci-Cis) optionally halogenated; a Ra-CO-NH- or RaRbN-CO- group [in which Ra and Rb independently represent optionally halogenated (Ci-Giß) alkyl; a hydrogen atom; aryl (from C6-C? 0) or aryl (from C1-C10) alkyl (from C1-C5) (wherein the aryl portions are optionally substituted by a halogen atom, by an optionally halogenated (C1-C5) alkyl group or by an optionally halogenated (C1-C5) alkoxy group); cycloalkyl (from C3-C2) optionally substituted by a halogen atom, by an optionally halogenated (C1-C5) alkyl group or by an optionally halogenated (C1-C5) alkoxy group]; an optionally halogenated (Ci-Ciß) alkyl group; optionally halogenated (Ci-Cis) alkoxy; and aryl (from C6-C10), aryl (from C6-C? O) alkyl (from C1-C5), aryloxy (from C6-C? 0), cycloalkyl (from C3-Cx2), cycloalkenyl (from C3-C12), cycloalkyloxy (from C3-Cx2), cycloalkenyloxy (from C3-C? 2) or aryloxycarbonyl (from C6-C? 0) in which the aryl, cycloalkyl and cycloalkenyl portions they are optionally substituted by a halogen atom, by optionally halogenated (C? -C5) alkyl or by optionally halogenated (C? -C5) alkoxy; p represents 0, 1, 2, 3 or 4; Z represents the radical: where n is 1 or 2; the R 'groups independently represent a hydrogen atom; an alkyl group (of C1-C5); an aryl group (of Cg-Cio) optionally substituted by a halogen atom, by an optionally halogenated (C1-C5) alkyl group. or by optionally halogenated (C1-C5) alkoxy; or a monocyclic or bicyclic heteroaryl group (C4-C2) comprising one or more heteroatoms selected from O, N and S, which is optionally substituted by a halogen atom, by an alkyl group (from C1-C5) optionally halogenated or by an optionally halogenated (C1-C5) alkoxy group; And represents -OH; alkoxy (from C1-C5); or the group -NRcRd [in which Rc and Rd independently represent a hydrogen atom; alkyl (of C1-C5); cycloalkyl (C3-C8) optionally substituted by a halogen atom, by optionally halogenated (C1-C5) alkyl or by optionally halogenated (C1-C5) alkoxy; aryl (from Ce-Cι) optionally substituted by a halogen atom, by optionally halogenated (C 1 -C 5) alkyl or by optionally halogenated (C 1 -C 5) alkoxy; it being understood that one and only one of Ri and R2 represents the chain Z. The invention is also directed, depending on the functional groups present in the molecule, to the salts of those compounds with pharmaceutically acceptable acids or bases. When the compound of formula (I) comprises an acid functional group, for example a carboxylic functional group, the latter can form a salt with an inorganic or organic base. Mention may be made, as an example [sic] of salts with organic or inorganic bases of the salts formed with metals and in particular alkali metals, alkaline earth metals and transition metals (such as sodium, potassium, calcium, magnesium or aluminum), or with bases , such as ammonia or secondary or tertiary amines (such as diethylamine, triethylamine, piperidine, piperazine or morpholine), or with basic amino acids or with osamines (such as meglumine) or with aminoalcohols (such as 3-aminobutanol and 2-aminoethanol). When the compound of formula (I) comprises a basic functional group, for example a nitrogen atom, the latter can form a salt with an organic or inorganic acid. Salts with organic or inorganic acids are, for example, salts of hydrochloride, hydrobromide, sulfate, acid sulfate, diacid sulfate, maleate, fumarate, 2- naphthalenesulfonate and para-toluene sulfonate. The invention also covers salts which make possible an adequate separation or a suitable crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example tartaric acid, dibenzoyltartaric acid, mandelic acid or camphorsulfonic acid. Formula (I) encompasses all types of geometric isomers and stereoisomers of the compounds of formula (I). According to the invention, the term "alkyl" denotes a radical comprising a linear or branched hydrocarbon, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl. , decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl. When the alkyl group is substituted by one or more halogen atoms, it preferably represents perfluoroalkyl and in particular pentafluoroethyl or trifluoxomethyl. The term "alkoxy" denotes an alkyl group as defined above attached to a halogen atom. Examples thereof are the methoxy, ethoxy, isopropyloxy, butoxy and hexyloxy radicals. It is to be understood that the term "alkylene group" means linear or branched alkylene groups, ie bivalent radicals which are linear or branched divalent alkyl radicals. The term "cycloalkyl" denotes groups comprising saturated hydrocarbons which may be mono or polycyclic, and comprise from 3 to. 12 carbon atoms, preferably from 3 to 8. Particular preference is given particularly to monocyclic cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. It is to be understood that the term "cycloalkenyl" means, according to the invention, a cycloalkyl group that exhibits one or more double bonds. It should be understood that the term "halogen" means a fluorine, chlorine, bromine or iodine atom. The term "aryl" represents a group comprising a mono- or bicyclic aromatic hydrocarbon comprising from 6 to 10 carbon atoms, such as phenyl or naphthyl. The term "mono- or bicyclic heteroaryl" denotes monocyclic or bicyclic aromatic groups comprising one or more endocyclic heteroatoms. Examples thereof are the furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, triazinyl, indinolyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, purinyl, quinolinyl, quinolicinyl, icoquinolyl [sic], cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, pteridinyl and benzoxepinyl. Preferred heteroaryls comprise from 4 to 10 carbon atoms and from 1 to 2 heteroatoms. The alkenyl and alkynyl groups may comprise more than one unsaturation. The alkenyl groups comprise ethylenic type initiations and the alkynyl groups comprise acetylenic type inestations. The aryl (C6-C10), cycloalkyl (C3-C8), heteroaryl and cycloalkenyl groups are optionally substituted.

The expression "optionally substituted by a halogen atom, by an optionally halogenated (Ci-Cs) alkyl group or by an optionally halogenated (C1-C5) alkoxy group" indicates that the aryl, cycloalkyl, heteroaryl and cycloalkenyl groups are optionally substituted by one or more substituents chosen from: - halogen atoms; alkyl groups optionally substituted by one or more halogen atoms; and - alkoxy groups optionally substituted by one or more halogen atoms. In the same way, the alkylene chain, when substituted, can comprise one or more identical or different substituents chosen from halogen atoms and optionally halogenated alkoxy groups. The term "optionally halogenated" means, in the context of the invention, optionally substituted by one or more halogen atoms. In the context of the present invention, the term "benzoxepin" has been used to denote the structure of the benzo [o] oxepin of formula: According to the invention, preference is given to the compounds in which A represents the radical: - (CH2) s-CR3CR4- (CH2) t- where s, t, R3 and R4 are as defined above for the formula ( I). Another preferred group of compounds of formula (I) is the compound of: • of the compounds in which: X represents 0; A represents -CR3CR4- or -CH2-CR3CR4- in which the unsubstituted methylene group is attached to X; Ri and Ri independently represent Z; H; alkyl (of C1-C15); alkenyl (from C1-C15) [sic]; or phenyl optionally substituted by alkyl (from C? -C5); alkoxy (of C -Cs), a halogen atom or -CF3; R3 has any of the meanings given above for Ri and R2, with the exception of Z; R is chosen from alkyl (from Cj-Cg); alkoxy (from C1-C5); phenyl or phenylcarbonyl optionally substituted by a halogen atom, (C1-C5) alkyl, (C1-C5) alkoxy, -CF3 or -0CF3; a halogen atom; and -0CF3; Z represents the radical: where n represents 1; R 'represents alkyl (of C1-C5). Preference is given, among those compounds, those in which: X represents 0; A represents -CR3CR4-; Z represents • or alternatively those in which: X represents O; A represents -CH2-CR3CR4- in which the unsubstituted methylene group is attached to X; Ri and R2 independently represent Z, a hydrogen atom or alkyl (of Cj-Cs); R3 takes any of the meanings given above for Ri and R2, with the exception of Z; Z represents: R 'represents methyl or phenyl. The preferred meanings of Y are: -OH-alkoxy (from C1-C5); and -NRcRd where Rc and Rd are as defined above for formula (I). Most preferably, Y represents -OH or (C1-C5) alkoxy. Similarly, it is preferable that p has the value of 0, 1 or 2. According to a particularly advantageous embodiment of the invention, the compounds of the groups that are preferred defined above are such that p and Y take one of those meanings. Mention may be made, for example [sic] of preferred compounds, of the following compounds: (2E, 4E) -5- (2-pentyl-2H-1-benzopyran-3-yl) -3-methyl-penta-2 acid , 4-dienoic; - (2Z, 4E) -5- (2-Pentyl-2H-1-benzopyran-3-yl) -3-methyl-penta-2,4-dienoic acid; (2E, 4E) -5- (2, 2-dimethyl-6-methoxy-2H-1-benzopyran-3-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (2H-1-benzopyran-3-yl) -3-methylpenta-2,4-d-enoic acid; (2E, 4E) -5- (2, 2-dimethyl-2H-l-benzopyran-3-yl) -3-methylpenta-2,4-dienoic acid; (2Z, 4E) -5- (2, 2-dimethyl-2H-l-benzopyran-3-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- [2- (Non-6-enyl) -2H-1-benzopyran-3-yl) -3-methyl-penta-2,4-dienoic acid; (2E, 4E) -5- (4-phenyl-2H-1-benzopyran-3-yl) -3-methyl-perita-2,4-dienoic acid; - (2E, 4E) -5- (6-Nonyl-2H-l-benzopyran-3-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (6-phenyl-2H-1-benzopyran-3-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (2-nonyl-2H-l-benzopyran-3-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (4-methyl-2H-1-benzopyran-3-yl) -3-methylpenta-2,4-dienoic acid; (2Z, 4E) -5- (2H-1-benzopyran-3-yl) -3-methylpenta-2,4-dienoic acid; - (2E, 4E) -5- (2-undecanyl-2H-l-benzopyran-3-yl) -3-methylpenta-2, -dienoic acid; (2E, 4E) -5- (2-phenyl-2H-1-benzopyran-3-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (5-methyl-2,3-dihydro-benzoxepin-4-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (3, 3-dimethyl-7-methoxy-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2, -dienoic acid; and [sic] (2E, 4E) -5- (2,3-dihydrozozoepin-4-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (3, 3-dimethyl-7-methoxy-2,3-dihydrobenzoxepin-5-yl) -3-phenylpenta-2,4-dienoic acid; (2Z, 4E) -5- (3,3-Dimethyl-7-methoxy-2,3-dihydrobenzoxepin-5-yl) -3-phenylpenta-2,4-dienoic acid; - (2Z, 4E) -5- (3, 3-dimethyl-7-methoxy-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5 ~ (3, 3-dimethyl-7,8-dimethoxy-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2, -dienoic acid; (2E, 4E) -5- (3,3-Dimethyl-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (3, 3-dimethyl-2,3-dihydro-7- (para-chloro-benzoyl) benzoxepin-5-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (3, 3-dimethyl-7-chloro-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (3, 3-dimethyl-7,8-dichloro-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2, -dienoic acid; - (2E, 4E) -5- (3, 3-dimethyl-7-bromo-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2, -dienoic acid; - (2E, 4E) -5- (3, 3-dimethyl-7-fluoro-8-chloro-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2, -dienoic acid; (2E, 4E) -5- (3, 3-dimethyl-7-fluoro-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (3,3-Dimethyl-7-trifluoromethyl-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2, -dienoic acid; (2E, 4E) -5- (3, 3-dimethyl-7-phenyl-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2, -dienoic acid; (2E, 4E) -5- (3,3-7-Trimethyl-2,3-dihydro-benzoxepin-5-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (3,3-dimethyl-2,3-dihydro-benzoxepin-5-yl) -3-methylpenta-2, -dienoic acid; (2E, 4E) -5- (9-methoxy-3,3-dimethyl-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2,4-dienoic acid; and their pharmaceutically acceptable esters, such as their ethylester. FR 2,698,893 describes the compounds of the formula: which are potent activators of the potassium channels of the cell membrane. According to this document, none of the substituents of Ri to R7 represents the Z chain as defined in the invention. US 5,391,569 relates to benzopyrans of the formula: of use in the treatment of osteoporosis and inflammations. These compounds differ from the compounds of the invention in that the alkenyl chain comprises three double bonds, while, according to the invention, the Z chain comprises two or four double bonds. It should be noted that the hypolipidemic and hypoglycemic activity of the compounds of the invention is not related to the activity of the compounds described in US 5,391,569 and FR 2,698,273. The compounds of formula (Z) can be prepared using one of the following Processes A or B, processes which form another subject matter of the invention. Process A makes possible the preparation of the compounds of formula (T) in which n represents 1. This process comprises the steps comprised of: (a) preparing an ylide either • by the reaction of a base with a phosphonate of formula : wherein R 'is as defined in Claim 1 [sic]; Ti and T2 independently represent alkyl (from C? -C5); and Y represents (C1-C5) alkoxy, or by the reaction of a base with a phosphonium salt of formula (Ilb): wherein R 'is as defined in Claim 1 [sic]; T3, T4 and T5 independently represent alkyl (of C1-C5) or aryl (of Cß-Cio) optionally substituted by alkyl (of C? -C5); and Y represents (C1-C5) alkoxy; and hal represents a halogen atom; (bl) reacting the ylide obtained in Step (a) with an aldehyde of formula: wherein R ', p, X and A are as defined in Claim 1 [sic]; one and only one of R 'i and R'2 represents -CHO and the other one takes one of the meanings given in the Claim • 1 [sic] for Ri and R2, with the exception of the chain Z, to obtain the compound of formula (I) in which n represents 1 and Y represents alkoxy (of C1-C5); (cl) if appropriate, converting the ester obtained in the above Step (bl) in acidic or basic medium to the corresponding carboxylic acid of formula (I) in which Y represents OH; (d) if appropriate, react the carboxylic acid functional group of the compound of formula (I) resulting from Step (cl) with an amine of formula HNRcRd in which Rc and Rd are as defined in Claim 1 [sic] ], optionally after activation of the carboxyl functional group, to prepare the corresponding compound of formula (I) in which Y represents -NRcRd.

The reaction employed in Step (bl) is either a Witting reaction or a Horner-Emmons or Wadsworth-Emmons reaction. This results in the preparation of a reactive ilide. When the ylide is prepared from a phosphonium salt (compound Ilb), the reaction employed is a Wittig reaction. When the ylide is prepared from a phosphonate (compound lia), the reaction employed is a reaction of Horner-Emmons or Wadsworth-Emmons. In Step a [sic], the ylide is prepared by the reaction of a base with either a compound lia [sic] or a compound Ib [sic]. The base used must be strong enough to detach the proton at position a to the phosphorus. The base is generally chosen from an alkali metal hydride, an alkali metal carbonate, an alkali metal amide, an alkylthio (of C? -C?) And an alkali metal alkoxide. Mention may be made, by way of example [sic], of sodium hydride, potassium carbonate, n-butyllithium, potassium tert-butoxide, a lithium amide [sic] or a sodium amide [sic].

In the context of the invention, sodium hydride and potassium tert-butoxide are preferred as bases. The reaction of the base with the compound (bundle) or (Ilb) is carried out in solution, preferably in an aprotic solvent and more particularly in a solvent capable of dissolving the phosphonate (lia) or the phosphonium salt (Ilb), respectively. Suitable solvents are aprotic solvents, such as, for example and without limitation, aromatic hydrocarbons (such as benzene and toluene), ethers (such as diethyl ether, dioxane or tetrahydrofuran) and mixtures thereof. The choice of solvent depends in particular on the type of ylide (compounds lia or Ilb). According to a preferred embodiment of the invention, the step (b2) [sic] of reaction of the aldehyde with the ylide is carried out by the addition of the aldehyde (III) to the crude reaction mixture resulting from step (a) , ie without isolation of the intermediate ilide. Thus, it is desirable that the solvent of step (a) also be capable of dissolving the aldehyde (III). However, another embodiment of the invention comprises the addition of a solution of the aldehyde (III) in a solvent to the crude reaction mixture resulting from Step (a). Under these conditions, it is not necessary to select, in Step (a), a solvent capable of dissolving the compound (III). The temperature at which the Stage (a) is carried out depends on the acidity of the compound (lia) or (Ilb) respectively, ie the ease with which the proton in the position a to phosphorus can be released. It can not be said that the type of base used directly influences the choice of reaction temperature. In this way, the stronger the base, the lower the reaction temperature. When the base used is n-butyllithium, a temperature between -80 ° C and -40 ° C, preferably between -80 ° C and -70 ° C, is generally desirable. In this case, the solvent is chosen so as to make possible such severe reaction conditions: the ethers are very particularly very suitable. When the base is an alkali metal alkoxide, a temperature between 10 and 100 ° C is generally suitable. If, in addition, this base is reacted with a phosphate (lia); at a temperature between 15 and 70 ° C is generally sufficient. When the base used is an alkali metal hydride, the temperature is generally between -10 ° C and 50 C. If additionally, this base is reacted with a phosphonate (lia), a temperature between -5 ° C and 30 ° C. ° C is generally sufficient.

A stoichiometric amount of the base is required in Step (a) to release the proton at position a to the phosphorus in the compound (Ha) or (Hb) respectively. However, it is possible to use a very light excess of base, so that the reaction for the formation of the ylide is complete. In this way, the molar ratio of the base to the compound (Ha) or (Hb) respectively is maintained between 1 and 1.2, preferably between 1 and 1.1, better still between 1 and 1.05. The concentration of the compound (Ha) or (Hb) respectively in the reaction mixture is not critical according to the invention. The concentration generally ranges from 0.01 mol / l to 10 mol / l, preferably from 0.1 to 1 mol / l. . In Step (bl), the aldehyde (III) is reacted with the ylide resulting from Step (a). The aldehyde (III) is advantageously added to the crude reaction mixture resulting from Step (a). The aldehyde (III) can be added to the reaction mixture or also in solution in a solvent, preferably an aprotic solvent. Mention may be made, as preferred solvents, of aromatic hydrocarbon solvents, ether, N-dimethylformamide [sic], dimethisulfoxide, N-methylpyrrolidone or of the P [N (CH3) 2] 3 type and mixtures thereof which were cited above. Whatever the operating procedure, it is preferable that the concentration of aldehyde (III) in the reaction mixture vary between 6 x 10"3 and 0.6 mol / 1, preferably between 0.01 and 0.7 mol / 1. which reacts the ylide with the aldehyde (III) depends on the respective reactivity of the two reactants.It should be noted that the ylide prepared from the phosphonate (Ha) is more reactive than the compound prepared yluro (Hb). Thus, Process A, which involves the implementation of a Horner-Emmons-type reaction with the use of the phosphonate (Ha), is particularly advantageous. In general, a temperature between -10 ° C and 50 ° C is suitable for the reaction of the ylide with the aldehyde (III), particularly in a temperature between -5 ° C and 30 ° C. It may be necessary to bring the crude reaction mixture resulting from Step (al) to this temperature before carrying out Step (bl), as long as the temperature conditions involved in Steps (a) and (bl) differ. More generally, one skilled in the art can be inspired by the operating conditions described in the literature for the Wittig and Horner-Emmons reactions for the purpose of preparing the compound of formula (I), in which n is 1 and Y represents alkoxy (of C1-C5) obtained at the conclusion of steps (al) and (bl). Step (cl) makes possible the hydrolysis of the ester of formula (I) resulting from Step (bl). This step is advantageously carried out in a basic medium. The bases generally used for saponification of esters can be used for the implementation of the Stage (cl). These bases are preferably inorganic bases of the alkali metal hydroxide (NaOH, KOH) type or the alkali metal carbonate type (K2C03, Na2C03). The hydrolysis of the ester functional group is generally carried out in a solvent, such as a protic solvent. The alkanol (of C1-C5) [sic], water and mixtures thereof are particularly well suited. The hydrolysis is advantageously carried out at a temperature of from 0 to 100 ° C, for example from 20 to 80 ° C, in a mixture of methanol and water, by the reaction with sodium hydroxide. The amount of base required is usually between 1 to 5 equivalents with respect to the ester of formula (I), preferably between 1 and 2 equivalents. Although this does not correspond to a preferred embodiment of the invention, the hydrolysis of the ester functional group can be carried out in an acid medium.

To determine ideal conditions for hydrolysis of the ester functional group, one skilled in the art would refer, for example, to Protective Groups in Organic Synthesis, Greene T.W. and Wuts P.G.M., published by John Wilwy & Sons, 1991, and Protective Groups, Kocienski P.J., 1994, Georg Thieme Verlag. Step (di) is carried out for the preparation of the compounds of formula (I) in which Y represents HSHRcRd '. This comprises a conventional reaction of the carboxylic acid obtained in Step (cl) with an amine of the formula NHRcRd. It is particularly advantageous to react an activated form of the carboxylic acid of formula (I) with an amine NHRcRd. Such an activated form is, for example, a carboxylic acid anhydride, an acid chloride or a mixed anhydride. The amidation of the carboxylic functional group will be carried out in a manner known per se by one skilled in the art. Process B makes possible the preparation of the compounds of formula (I) in which n = 2. This process comprises the steps composed of: (a2) preparing an ylide either • by the reaction of a base with a phosphonate of formula (IVa): wherein R'j and R'k independently represent a group R 'as defined in Claim 1 [sic]; T6 and T7 independently represent alkyl (from C? -C5); and Y represents alkoxy (from C? -C5), or by the reaction of a base with a phosphonium salt of formula (IVb): wherein R 'j and R' i: independently represent a group R 'as defined in Claim 1 [sic]; T8, T9 and Unio independently represent alkyl (of C1-C5) or aryl (of C6-C? 0) optionally substituted by alkyl (of C1-C5); and Y represents (C1-C5) alkoxy; and hal represents a halogen atom; (b2) reacting the ylide obtained in Step (a2) with an aldehyde of formula: wherein R, p, X and A are as defined in Claim 1 [sic]; one and only one of R 'i and R'2 represents -CHO and the other one takes one of the meanings given in Claim 1 [sic] for Ri and R2, with the exception of the Z chain, to obtain the compound of formula ( I) [sic] wherein n represents 2 and Y represents alkoxy (from C1-C5); (c2) if appropriate, converting the ester obtained in the above Step (b2) in acidic or basic medium to the corresponding carboxylic acid of formula (I) in which Y represents OH; (d2) if appropriate, reacting the carboxylic acid functional group of the compound of formula (I) resulting from Step (c2) with an amine of formula HNRcRd in which Rc and Rd are as defined in Claim 1 [sic] ], optionally after activation of the carboxyl functional group, to prepare the corresponding compound of formula (I) in which Y represents -NRcRd.

The general conditions for carrying out Stages (a) to (di) are also applied to carry out the previous steps (a2) to (d2). The phosphonate (Ha) is prepared conventionally, for example by carrying out the Arbuzov reaction. More specifically, when Ti and T2 are identical, a phosphite (IX): P (OT?) 3 (IX) in which Tx has the meaning given above for the formula (Ha), is reacted with a halide ( X): in which R 'and Y are as previously defined for the formula. { Ha) and hal represents a halogen atom. The same type of reaction results in the preparation of the phosphonate (IVa). The phosphonium salts of formula (Hb) are readily prepared in a manner known per se by the reaction of a phosphine (V): in which T3, T4 and T5 are as defined for the formula (Ilb), with a halide (VI) in which R ', Y and hal are as defined above, for the formula (Hb). Likewise, the phosphonium salt of formula (IVb) is easily prepared by the reaction of phosphine (VII) in which T8, T9 and Uncle are as previously defined for formula (IVb), with the halide (HIV): wherein hal, R ', R'3, R'k and Y are as defined above for formula (IVb). Reference may be made to the experimental conditions described by A. Zumbrunn et al. in Helv. Chi. Acta, 1985, 68, 1519. The aldehydes of formula (III) are commercially available or are readily prepared from commercial products using one of the following processes. Process C for the preparation of aldehydes of formula (III): in which R 'i represents -CHO. The reaction sequence of Process C is illustrated in Reaction Scheme 1. Step (i) makes possible the reductive alkylation of the ketone (XI). This reaction comprises the reaction of the ketone (XI) with an organometallic compound. CH3-M in which M is -Mg-hal (where hal is a halogen atom) or in addition M is Li.

Reaction Scheme 1 (XI) (XII) (¡I) H + (XIV) (XIII) (1) Hexamethylenetetramine (iv) (2) HCl, AcOH. (lll) In Step (i), the nature of the organometallic compound determines the operating conditions. When the organometallic compound [sic] is a Grignard reagent, advantageous use is made of a solvent which may be diethyl ether, tetrahydrofuran, dioxane, benzene, toluene or the like. The reaction temperature is from -78 ° C to 100 ° C, preferably from -10 ° C to 70 ° C. Step (ii) makes possible the dehydration of the compound of formula (XII). This dehydration can be obtained by the action of an organic or inorganic acid on the compound (XII). Mention can be made, as an example [sic] of acids, of hydrochloric acid, sulfuric acid, nitric acid, trifluoromethanesulfonic acid, acetic acid, trifluoroacetic acid, para-toluenesulfonic acid or p-nitrobenzoic acid. Suitable solvents for this reaction are those conventionally used in the art, which are also capable of dissolving the compounds of formula (XII). The preferred solvents are aromatic hydrocarbons, such as benzene and toluene. In Step (iii), bromination of the radical of the compound of formula (XIII) is carried out. This reaction can be carried out in a conventional manner by the action of a brominating agent, either by irradiation or under the action of heat, optionally in the presence of an initiator, such as a peroxide or an azo compound. The brominating agents are, for example, bromine or n-bromosuccinimide.

Examples of radical initiators are a, a, azobisisobutyronitrile and tert-butyl peroxide. A particularly suitable solvent is carbon tetrachloride. Step (iv) involves the reaction of hexamethylenetetramine with the compound (XIV) in a first step and treatment with a mixture of acetic acid and hydrochloric acid in a second step. The molar ratio of the hexamethylenetetramine to the compound (XIV) is preferably between 1 and 3, preferably between 1 and 2. The temperature for the reaction of the hexamethylenetetramine with the compound (XIV) preferably varies between 20 and 120 ° C , better still between 30 and 80 ° C. The reaction is carried out advantageously in a solvent. Mention may be made, as the appropriate solvent, of aliphatic, aromatic or optionally halogenated cycloaliphatic hydrocarbons, for example chloroform, carbon tetrachloride, tetrachloroethylene and chlorobenzene. The following acid treatment comprises the treatment, in a first step, of the resulting reaction mixture with an acetic acid solution at a temperature of 20 to 120 ° C, preferably 30 to 80 ° C. In a second step, the hydrochloric acid is added to the reaction mixture, which is maintained at a temperature between 20 and 120 ° C, preferably between 30 and 80 ° C. Process D for the preparation of the compounds of formula (III): wherein R 'is -CHO, A represents -CR3R- as defined above and X represents O. According to this process, an aldehyde of formula (XV): wherein R and p are as defined above for formula (III), reacted with a compound of formula (XVI): wherein R3 and R are as defined above for formula (III), in the presence of a strong base. This reaction is stoichiometric. However, it is preferable to carry out the reaction in the presence of a slight excess of the compound (XV), so that the molar ratio of the compound (XV) to the compound (XVI) varies generally from 1 to 1.5, better still from 1 to 1.3. The base that can be used in this reaction is advantageously an inorganic base, such as, for example, NaOH, KOH, NaHCO3, Na2CO3, KHC03 or K2C03. According to a preferred embodiment of the invention, the base is K2C03. The amount of base that has to be used corresponds to the amount of compound (XV) involved. In this way, the molar ratio of the base to the compound (XV) is preferably between 1 and 1.2. This reaction can be carried out in a solvent. The nature of the solvent depends on the base used and the reactants present. When the base is K2C03, the ethers are the preferential solvents and in particular the dioxane, tetrahydrofuran or diethyl ether. When the reaction is carried out in the presence of a solvent, the concentration of the reactants in the reaction mixture is preferably maintained between 0.5 mol / 1 and 5 mol / 1, better still between 0.08 mol / 1 and 1.2 mol / 1. The reaction temperature is advantageously between 30 and 150 ° C, even better between 50 and 120 ° C, for example between 90 and 100 ° C. Process E for the preparation of an aldehyde (III) of formula: in which R'2 represents the group -COH [sic]. The reaction scheme of Process E is illustrated in Reaction Scheme 2.

(Reduction (XX) (XIX) Process E comprises the use of conventional reactions of organic chemistry. In Step (i), the carboxylic acid (XVII) is esterified by an alcohol of formula RHOH in which RH is an alkyl group (of C? -C6). The esterification is carried out generally in an acid medium. Catalytic amounts of acids of the para-toluenesulfonic acid type or of the sulfuric acid type are particularly suitable. However, the reaction can be carried out in the presence of an excess of acid. It is desirable to use a large excess of the RH-OH alcohol. Likewise, it is advantageous to introduce a dehydrating agent, such as a molecular sieve, into the reaction mixture. A reaction temperature between 20 and 120 ° C, preferably between 50 and 100 ° C, is ideal. It is possible in many cases to use alcohol RH-OH as a solvent. According to the invention, the nature of the RH group introduced in Step (i) is not of any importance. In the next step, the ester (XVIII) is reduced to an alcohol (XIX). The reaction can be carried out according to any of the methods known in the art. It can be used, as a reducing agent, of, for example, lithium aluminum hydride, lithium borohydride, diisobutylaluminum hydride, lithium triethylborohydride, BH3-SMe2 at reflux in tetrahydrofuran, HSi (OEt) 3 or still borohydride. sodium.

In Step (iii), the alcohol (XIX) is oxidized to an aldehyde, to obtain the expected aldehyde (XX). The oxidation is carried out in a manner known per se. It is possible to avoid the subsequent oxidation of the aldehyde to an acid. For this reason, the oxidizing agent will be suitably selected from Mn02, dimethyl sulfoxide, Collins reagent, Corey reagent, pyridinium dichromate, Ag2C03 in celite, hot HN03 in aqueous gliA, Pb (OAc) 4-pyridine, cerium ammonium nitrate or N-methylmorpholine N-oxide. Process F for the preparation of compounds of formula (III) "[sic]: in which R'2 represents the group -CHO. According to this process, the compounds of formula (III) are prepared by the reaction of a mixture of phosphorus oxychloride and dimethylformamide with a compound of formula (XXI): (XXI) in which R, p, X, A and R 'i are as defined above for the formula (III). Preferably use is made of a molar ratio of phosphorus oxychloride to compound (XXI) and of a molar ratio of dimethylformamide to the compound of formula (XXI) ranging from 1 to 3, better still between 1 and 2, for example between 1 and 1.5. Dimethylformamide and phosphorus oxychloride are advantageously used in equal amounts. One way of carrying out the reaction comprises preparing a solution of the reactants, phosphorus oxychloride and dimethylformamide, in a solvent, and then making a solution of the compound (XXI) in this solution. The solution of the reagents is generally prepared by the addition of phosphorus oxychloride to a solution of dimethylformamide in a solvent. A halogenated aliphatic hydrocarbon (such as dichloromethane) or acetonitrile can be chosen as the appropriate solvent. The addition of P0C13 to the DMF solution is preferably carried out under cold conditions, namely at a temperature between -40 and 15 ° C, advantageously between -10 and 10 ° C, better still between -5 and + 5 ° C. The compound of formula (XXI) is preferably added in solution in a solvent to this solution. According to a preferred embodiment of the invention, the solvent is the same as that used to prepare the solution of the reagents. The reaction of the compound (XXI) with the reagent system DMF / P0C13 is carried out at a temperature between 15 and 100 ° C, preferably between 18 and 70 ° C. The compound of formula (XXI) is easily prepared from the corresponding ketone of formula (XI): wherein R, p, X, and A are as defined above for formula (XXI). It is possible, for example, to prepare this compound by carrying out reactions analogous to those described above in the context of Process C (Reaction Scheme 1: Steps (i) and (ii)). Briefly, the above ketone (XI) can be reacted with an organometallic compound of the formula: R '? -M, where M is a lithium atom or represents -Mg-hal, where halo is a halogen atom. The resulting compound of formula: (XI) in which R, p, X and A are as defined above, is then treated in acid medium. The ketones of the formula (XI), the aldehydes of the formula (XV) and the acids of the formula (XVII) are commercial compounds or are easily prepared from commercially available products using conventional processes of the state of the art. Another subject matter of the invention is the new compounds of the formula: • in which: A represents the bivalent radical - (CH2) S-CR3CR4- (CH2) t- where one of s and t represents 0 and the other 1; R, R, R, p and X are as defined above for formula (I); and only one of R '? and R'2 represents -CHO, the other taking one of the meanings given above for Rx and R2 for formula (I), with the exception of the Z chain. Preference is given, among those compounds, to those in which R '? represents -CHO.

Another group of preferred compounds is comprised of the compounds of formula (Illa) above in which X represents 0; A represents -CH2-CR3CR4- in which the unsubstituted methylene group is attached to X; R 'i or R'2 represent H; alkyl (of C1-C15); alkenyl (from C1-C15), rsic]; or phenyl optionally substituted by alkyl (of C1-C5); (C 1 -C 5) alkoxy, a halogen atom or -CF 3; R3 has any of the meanings given above for R '1 or R'2 but does not represent -CHO; R4 represents a halogen atom or alkyl (of C1-C15); R is chosen from alkyl (from C1-C9); alkoxy (from C1-C5); phenyl; [sic] or phenylcarbonyl optionally substituted by a halogen atom, (C1-C5) alkyl, (C1-C5) alkoxy; [sic [-CF3 or -OCF3; a halogen atom; and -OCF3; and p is 0, 1 or 2. Better still, preference is given to the compounds in which: X represents O; A represents -CH2-CR3CR4- in which the unsubstituted methylene group is attached to X; R'i or R'2 represent a halogen atom; R3 represents a hydrogen atom or an alkyl group (of C1-C5), such as methyl; R4 represents (C1-C15) alkyl, preferably (C1-C5) alkyl, such as methyl; R is chosen from a halogen atom, -CF3, (C1-C5) alkoxy, phenel "and para-chlorobenzoyl, p is 0, 1 or 2. Mention may be made, as examples of such compounds, of: 3, 3 -dimethyl-5-formyl-7-bromo-2,3-dihydrobenzo-xepma, 3,3-dimethyl-5-f ormil-9-methoxy-2,3-dihydrobenzo-xepma, 3,3-dimethyl-5- formyl-7, 8-dichloro-2,3-dihydrobenzo-xepine, 3,3-dimethyl-5-formyl-7-fluoro-8-chloro-2,3-dihydro-benzoxepine, 3, 3-dimethyl-5- formyl-7- (para-chlorobenzoyl) -2, 3-dihydrobenzoxepine, 3,3-dimethyl-5-formyl-7-trifluoromethyl-2,3-dihydro-benzoxepine, 3,3-dimethyl-5-formyl-7- fluoro-2, 3-dihydrobenzo-xepine, 3, 3-dimethyl-5-formyl-7-chloro-2,3-dihydrobenzo-xepine, 3,3-dimethyl-5-formyl-7,8-dimethoxy-2, 3-dihydrobenzo-xepine, 3, 3-dimethyl-5-formyl-7-phenyl-2,3-dihydrobenzo-xepine, 3,3-dimethyl-5-formyl-2,3-dihydrobenzoxepine, 3, 3-dimethyl- 5-formyl-7-methoxy-2,3-dihydrobenzo-xepine According to another of its aspects, the ition relates to the intermediary compounds of formula: wherein: A represents the bivalent radical - (CH2)? -CR3R4- (CH2) t- where one of s and t represent 0 and the other 1; R3, R4, R, p and X are as defined above for formula (I); and W0 represents -CH3 or -CH2Br. Preference is given, among those compounds, to those in which: R3 represents H, (C1-C15) alkyl; alkenyl (of C1-C15 [sic] or phenyl optionally substituted by alkyl (of C1-C5); alkoxy (of Cx-Cs), a halogen atom or -CF3; R represents a hydrogen atom or an alkyl (from C1-C15); R is chosen from alkyl (from C1-C9); alkoxy (from C1-C5); phenyl; [sic] or phenylcarbonyl optionally substituted by a halogen atom, (C1-C5) alkyl, (C1-C5) alkoxy, -CF or -OCF3; a halogen atom; -CF3 and -OCF3; and p is 0, 1 or 2. Better still, the meanings of R3, R4, R and p will be chosen from the following groups: R3 represents a hydrogen atom or an alkyl group (from C1-C5), such as methyl; R4 represents alkyl (of C] -C? S), preferably alkyl (of C1-C5), such as methyl; R is chosen from a halogen atom, -CF3, (C1-C5) alkoxy, phenyl, and para-chlorobenzoyl; p is 0, 1 or 2. Examples of compounds in which o = -CH3 are shown in Table 4, which appears after the examples. Mention may also be made of 3, 3, 5-trimethyl-7-methoxy-2,3-dihydrobenzoxepine. Examples of compounds in which W0 = -CH2Br are represented in Table 5, which appears after the examples.

Mention may also be made of 3,3-dimethyl-5-bromomethyl-7-methoxy-2,3-dihydrobenzoxepine. The ition additionally relates to intermediate compounds of formula (IHb): wherein: R 'i represents a halogen atom, an (C 1 -C 5) alkyl or biphenyl group; R3 and R4 are independently selected from a halogen atom, an alkyl group (from C? -C? 8) or an alkenyl group (from Preference is given, among those compounds, to those in which R '1 represents a hydrogen atom. Mention may be made, as examples, of: -2,2-dimethyl-3-formyl-2H-1-benzopyran; -2- [non-3-enyl] -3-formyl-2H-l-benzopyran; -2-undecyl-3-formyl-2H-l-benzopyran; -2-pentyl-3-formyl-2H-l-benzopyran; -2-noni1-3-formyl-2H-l-benzopyran; -4-methyl-3-formyl-2H-l-benzopyran; and -4-phenyl-3-formyl-2H-l-benzopyran.

The ition further relates to pharmaceutical compositions comprising a pharmaceutically effective amount of a compound of formula (I) as defined above in combination with one or more pharmaceutically acceptable carriers. These compositions can be administered orally in the form of immediate release or controlled release granules, hard gelatin capsules or tablets, intravenously in the form of an injectable solution., transdermally in the form of a transdermal adhesive device, or locally in the form of a solution, cream or gel. A solid composition for oral administration is prepared by the addition of a filler and, if appropriate, a binder, a disintegrating agent, a lubricant, a dye or a flavor enhancer to the active principle and forming the mixture as a tablet, a coated tablet, a granule, a powder or a capsule. Examples of fillers include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose and silicon dioxide, and examples of binders include polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose [sic] ], acacia [sic], gum tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose [sic], calcium citrate, dextrin and pectin. Examples of lubricants include magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oils. The dye can be any of those authorized for use in medicines. Examples of flavor improvers include cocoa powder, mint in herbal form, aromatic powder, peppermint in the form of oil, borneol and cinnamon powder. Of course, the tablet or the granule can be suitably coated with sugar, gelatin or the like. An injectable form comprising the compound of the present invention as active ingredient is prepared, if appropriate, by mixing the compound with a pH regulator, a buffer, a suspending agent, a solubilizing agent, a stabilizer, a tonicity agent and / or a condom and converting the mixture into a form for intravenous, subcutaneous or intramuscular injection, according to a conventional process. If appropriate, the injectable form obtained can be lyophilized by a conventional process. Examples of suspending agents include methylcellulose [sic], polysorbate 80, hydroxyethylcellulose, acacia [sic], tragacanth gum powder, sodium carboxymethylcellulose and polyethoxylated sorbitan monolaurate. Examples of solubilizing agents [sic] include castor oil solidified with polyoxyethylene, polysorbate 80, nicotinamide, polyethoxylated sorbitan monolaurate and the fatty acid ethyl ester of castor oil. In addition, the stabilizer covers sodium sulfite, sodium metasulfite and ether, while the condom includes methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenyl [sic], cresol and chlorocresol. The invention is further directed to the use of a selected active ingredient of a compound of formula (I) as defined above in the preparation of a medicament that is intended to prevent or treat dyslipidemias, atherosclerosis or diabetes. The hypolipidemic and hypoglycemic activity of the compounds of the invention was demonstrated in vi tro and in vivo using the following tests: 1) Demonstration of the activity in vi tro. The hypolipidemic and hypoglycemic effect of the compounds of the invention results from their ability to inactivate PPARa and PPAR? Isoforms. Analysis of the activation of PPARa and PPAR? is based on the transfection of a DNA that allows the expression of a reporter gene (the luciferase gene) under the control of PPARs, whether endogenous in the case of PPAR? or exogenous in the PPARa cascf. The reporter plasmid J3TkLuc comprises three copies of the response elements for the PPARs of the human apo A-II gene (Staels, B et al. (1995), J. Clin. Invest., 95, 705-712), which are cloned upstream of the herpes simplex virus thymidine kinase gel promoter in plasmid pGL3. This reporter gene was obtained by subcloning, in plasmid pGL3, the plasmid J3TkCAT described above (Fajas, L et al. (1997), J. Biol. Chem., 272, 18779-18789). The cells used are green monkey CV1 cells transformed by the SV40 virus. which expresses PPAR? (Forman, B. et al. (1995), Cell, 83, 803-812), and human SK-Hepl cells, which do not express PPAR. These cells were inoculated at a rate of 20,000 cells per well (96-well plates) and transfected with 150 ng of reporter DNA complexed with a mixture of lipids. In the case of SK-Hepl cells, an expression vector for PPARa, described by Sher, T. et al. (1993), Biochemistry, 32, 5598-5604, is cotransfected. After 5 hours, the cells are washed twice and incubated for 36 hours in the presence of the test compound in a fresh culture medium comprising 10% fetal sheep serum. At the end of the incubation, the cells are used and the luciferase activity is measured. This activity is expressed in relation to the control value.

By way of example, the compound of Example 16b described below acid ((2E, 4E) -5- (3,3-dimethyl-7-methoxy-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2 , 4-dienoic) increases, under these conditions, the luciferase signal by 300% in CV1 cells and by 250% in SK-Hepl cells. In the presence of a reporter vector pGL3 devoid of a PPAR response element, the compound of Example 16b is inactive in both cell types. 2) Demonstration of in vivo activity The antidiabetic and hypolipidemic activity of the compounds of formula I [sic] was demonstrated by the oral route in db / db mice. Two-month-old db / db mice are treated per os for 15 days with the compound of Example 16 (100 mg / kg / day). Each study group comprises seven animals. After treating for three days (D3) and fifteen days (D15), retro-orbital samples are taken after a light anesthesia and fasting for 4 hours. The following measurements were taken: the quantitative determination of glycemia (glucose oxidase) to D3 and D15 and lipid parameters with respect to serum D15 (COBAS); triglycerides, total cholesterol (CHOL), HDL cholesterol (HDL-C) and free fatty acids (FFA) (Quantitative determination equipment of BioMérieux and Wako Chemicals).

The results obtained have been reported in the following table. The measurements that appear in this table are the average values ± standard error.

Control Example 16% variation with respect to control Glycemia D3 (mM) 23.3 ± 4.4 15.4 ± 3.8- -28 Glycemia D15 (mM) 28.1 ± 4.2 16.7 ± 4.4 * • 40 Triglycerides D15 2.11 ± 0.62 0.69 ± 0.09 * • 68 (mM) CHOL D15 (mM) 3.71 ± 0.37 4.44 ± 0.09 * +19 HDL-C D15 (mM) 2.96 ± 0.25 3.50 ± 0.37- + 18 FFA (mM) 1.01 ± 0.12 0.82 ± 0.23 • 20 (ns) Mann-Whitney test: *: p < 0.05 in relation to the control; ns: not significant.

These results unambiguously demonstrate the hypolipidemic and antidiabetic activity of the compounds of the invention. The following examples illustrate the invention without limitation involved. The following abbreviations have been used in the nuclear magnetic resonance (NMR) data of the proton: s for simplete, d for doublet, t for triplet, c for quartet, or for octet and m for multiplet. The chemical shifts d are expressed in ppm; P.f. represents the melting point and P.e. the boiling point.

EXAMPLE 1 Acid (2E, 4E) -5- (2-pentyl-2H-l-benzopyran-3-yl) -3-methylpenta-2,4-dienoic acid and ethyl ester (I: p = 0, Ri = H; X = O; A = -CR3R4-; R3 = H; R4 = n-C5Hn; R2 = Z; n = 1; R '= -CH3; composed [sic]: Y = -OCH2CH3; compound Ib [sic]: Y = -OH). a) 2-n-Pentyl-3-formyl-2H-l-benzopyran A mixture of 22.0 g (0.18 mmol) of salicylaldehyde, 25.0 g (0.198 mol) of 2-octenal and 24.8 g (0.18 mol) of potassium carbonate in 200 ml of dioxane, kept under an inert atmosphere, is heated at reflux for 2.5 h. The reaction mixture is subsequently brought to room temperature (20-25 ° C) and then diluted by the addition of 1.5 liters of water.The formation of an oil, which is extracted with methylene chloride, is observed. The organic compound is dried over anhydrous sodium sulfate and then concentrated under reduced pressure, obtaining the title compound in the form of an orange oil, which oil is distilled under reduced pressure (Pe (0.44 mm Hg): 132- 140 ° C.) 20 g of the title product are obtained by distillation (48% yield). b) Ethyl ester of (2E, 4E) -5- (2-pentyl-2H-l-benzopyran-3-yl) -3-methylpenta-2, -dienoic acid (compound la) 3 g (75.5 mmol) of hydride of sodium, as a 60% suspension in oil, are added at 0 ° C to a solution, maintained under an inert atmosphere, of 19.9 g (75.5 mmol) of the ethyl ester of (2-methyl-3-carboxyprop-2-enyl) ) diethyl phosphonate in 200 ml of tetrahydrofuran. The combined mixture is allowed to react for 20 minutes at 0 ° C and then for 15 minutes at room temperature (20 to 25 ° C). Subsequently 2 ml of DMPU are added (1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone). The reaction mixture is then cooled to 0 ° C and a solution of 14.5 g (62.9 mmol) of 2-n-pentyl-3-formyl-2H-1-benzopyran in 145 ml of tetrahydrofuran is added at this temperature. The combined mixture is allowed to react for 1 hour at 0 ° C and then the excess of sodium hydride is destroyed by the addition of cold water (approximately 0 ° C). The extraction is then carried out with ethyl acetate. The organic phase is washed with water and dried over sodium sulfate and then concentrated under reduced pressure. The title compound is obtained in the form of an oil, which oil is purified by flash chromatography using a cyclohexane / ethyl acetate mixture 98/2 as eluent. In this way 2.4 g of the 2Z isomer of acid [sic] and 7.5 g of the 2E isomer of [sic] acid are obtained. Compound 2Z: H NMR (CDC1, 300 MHz) d (ppm): 0.8 (3H, m), 1.2-1.8 (11H, m), 2.0 (3H, s), 4.1 (2H, c, J = 7 Hz) , 5.2 (1H, m), 5.6 (1H, s), 6.4 (1H, s), 6.5 (1H, d, J = 16 Hz), 6.8-7.1 (4H, m), 7.7 (1H, d, J = 16 Hz). Compound 2E: H NMR. { CDCl 3, 300 MHz) d (ppm): 0.8 (3H, t, J = 7 Hz), 1.2-1.8 (11H, m), 2.3 (3H, s), 4.1 (2H, c, J = 7 Hz), . 0 (1H, m), 5.8 (1H, s)., 6.1 (1H, d, J = 16 Hz), 6.4 (1H, s), 6.8-7.1 (4H, m). c) Acid (2E, 4E) -5- (2-pentyl-2H-l-benzopyran-3-yl) -3-methylpenta-2,4-dienoic acid (compound Ib). 5.0 g (30.8 mmol) of sodium hydroxide, in solution in 100 ml of water, are added to a solution of 10.5 g (30.8 mmol) of the ethyl ester obtained in the preceding Step b) in solution [sic] in 105 ml of methanol The reaction mixture is brought to reflux for 3 hours. This becomes clear. The reaction mixture is then allowed to return to room temperature (20-25 ° C) and the methanol is evaporated under reduced pressure. The residue is taken up in 600 ml of water and then the mixture is washed twice with diethyl ether.

The aqueous phase is then acidified with 5N aqueous hydrochloric acid solution, a pasty precipitate is formed and extracted with methylene chloride, the organic phase is then dried over anhydrous sodium sulfate and then concentrated under reduced pressure. obtained a solid, solid, which is recrystallized from 50 ml of methanol.The title compound is isolated in the form of a white solid ( 86%). Compound 2E: Mp: 118-120 ° C 1 H NMR (DMSO [sic], 300 MHz) d (ppm): 0.88 (3H, t, J - 7 Hz), 1.7-1.3 (8H, 'm), 2.3 ( 3H, s), 5.3 (1H, d, J = 2.3 Hz), 6.0 (1H, s), 6.6 (1H, d, J = 16 Hz), 7.2-6.8 (6H, m). Compound 2Z: P.f. : 161-163 ° CH NMR (d6-DMSO, 300 MHz) d (ppm): 0.8 (3H, t, J = 3 Hz), 1.8-1.2 (8H, m), 2.0 (3H, s), 5.1 ( 1H, d, J = 10 Hz), 5.7_ (1H, s), 6.5 (1H, s), 6.6 (1H, d, J = 16 Hz), 7.1-6.8 (4H, m), 7.7 (1H, d, J - 16 Hz).

EXAMPLE 2 Acid (2E, 4E) -5- (2, 2-dimethyl-6-methoxy-2H-1-benzopyran-3-yl) -3-methylpenta-2,4-dienoic acid and ethyl ester (I: p = 1, R = 6-OCH3, X = O, A = -CR3R4-, R3 = R4 = -CH3, Rx = Z, R2 = H, n = 1, R '= -CH3, and compound 2a [sis]: Y = -OCH2CH3; compound 2b fsic]: Y = -OH). a) 6-Methoxy-2, 2-dimethylchroman-4-one 19.8 ml (1.6 equivalents) of pyrrolidine are added dropwise to a solution, cooled below 25 ° C, of 25 g (0.15 mol) of 2 '- hydroxy-5'-methoxyacetophenone, 12.1 ml (1.1 equivalents) of acetone and 140 ml of toluene. The reaction mixture is allowed to stir for 16 hours at 25 ° C.

Then 290 ml of acetone are added and the reaction mixture is refluxed for 4 hours. This is then concentrated under reduced pressure and then extracted with ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution, then with a 1N sodium hydroxide solution and then with an IN hydrochloric acid solution, and finally washed with water. The organic phase is then dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue (an orange compound) is dissolved in diisopropyl ether.

The insoluble material is filtered and the organic phase is concentrated under reduced pressure. A brown paste is obtained, which is purified by flash chromatography using dichloromethane as eluent. 9.4 g of yellow oil are obtained. 1 H NMR (CDC 13, 300 MHz) d (ppm): 7.2 (1 H, d, J = 3.15 Hz), 7 (1 H, d, J = 3.17 Hz), 6.75 (1 H, d, J = 8.99 Hz), 3.7 (3H, s), 2.6 (2H, s), 1.35 (6H, s). IR (cm "1) 1638.4 b) 6-Methoxy-2, 2,4-trimethylchroman-4-ol. 9.4 g (45.6 mmol) of 6-methoxy-2,2-dimethylchroman-4-one, dissolved in 150 ml of tetrahydrofuran, are added dropwise to a solution [sic], kept under an inert atmosphere and brought to 50 ° C, of 33.5 ml (0.1 mol) of 3M methylmagnesium chloride in tetrahydrofuran solution. The combined mixture is heated to reflux for 4 hours. The reaction mixture is subsequently cooled with an ice bath and hydrolyzed by running in dripping water. The reaction mixture is subsequently poured over a solution of ammonium chloride. After extracting with ethyl acetate, the organic phase is dried. on anhydrous sodium sulfate and concentrated under reduced pressure. 10 g of the title compound are obtained. IR (cm "1) 3400-3500. c) 6-Methoxy-2, 2,4-trimethyl-2H-l-benzopyran. A mixture of 10 g (0.045 mol) of 6-methoxy-2,2,4-trimethylchroman-4-ol, 0.25 g (1.45 mmol) of para-toluenesulfonic acid and 150 ml of toluene is heated at reflux for 4 hours. hours in a 500 ml four-necked flask equipped with a Dean and Stark apparatus. Once the solution has returned to room temperature (25 ° C), the organic phase is washed with a solution of sodium bicarbonate and then with water. The organic phase is dried over anhydrous sodium sulfate and then concentrated under reduced pressure. In this way a dark oil is obtained: 9.4 g. d) 4-Bromomethyl-6-methoxy-2,2-dimethyl-2H-l-benzopyran. A solution of 9.1 g (0.045 mol) of 6-methoxy-2,2,4-trimethyl-2H-l-benzopyran, 8 g (0.045 mol) of N-bromosuccinimide and 0.25 g of a, a'-azobisisobutyronitrile at 100 ml of carbon tetrachloride is heated at reflux for 4 hours. The insoluble material is filtered and then the organic solution is washed with warm water (30 ° C), then dried over anhydrous sodium sulfate and concentrated under reduced pressure. In this way 13 g of a dark oil are obtained. ^ H NMR (CDC13, 300 MHz) d (ppm): 6.6 to 6.85 (3H,), 5.75 (1H, s), 4.15 (2H, s), 3.7 (3H, s), 1.3 (6H, s). e) 6-Methoxy-4-formyl-2,2-dimethyl-2H-1-benzo-pyran. A mixture of 12.7 g (0.045 mol) of 4-bromomethyl-6-methoxy-2, 2-dimethyl-2H-1-benzopyran, 125 ml of chloroform and 8.8 g (0.059 mol) of hexamethylenetetramine is heated at reflux for 2 hours . The reaction mixture is subsequently concentrated under reduced pressure. An orange precipitate is obtained, which precipitate is removed in a 75% aqueous acetic acid solution (133 ml). This solution is heated to reflux for 90 minutes, then 20 ml of concentrated hydrochloric acid is added to the solution and this is heated again under reflux for 30 minutes. 80 ml of water are added to this hot solution. The combined mixture is allowed to stand at 25 ° C for 30 minutes with stirring, then extracted with diethyl ether and 1 ether phase is dried over anhydrous sodium sulfate. The organic phase is then concentrated under reduced pressure. In this way, 8.6 g of a dark oil is obtained, which oil is purified by flash chromatography using dichloromethane as eluent. 2.7 g of a yellow oil are isolated. IR (was "1) 1696.3, 1487, 1261. * H NMR (CDC13, 300 MHz) d (ppm): 9.6 (1H, s), 7.75 (1H, s), 6.7 (2H, s), 6.4 (1H , s), 3.75 (3H, s), 1.4 (6H, s). f) Ethyl ester of (2E, 4E) -5- (2, 2-dimethyl-6-methoxy-2H-1-benzopyran-3-yl) -3-methylpenta-2,4-dienoic acid (compound 2a). A solution of 3 ml (12.3 mmol) of diethyl (2-methyl-3-carboxyprop-2-enyl) phosphonate ethyl ester (41% trans) in 20 ml of tetrahydrofuran is added to a solution, maintained under one atmosphere inert, of 1.38 g (12.3 mmol) of potassium tert-butoxide and 20 ml of tetrahydrofuran (exothermic reaction). The reaction mixture is allowed to stir for 1 hour and then cooled to 10 ° C. 2.7 g (12.3 mmol) of 6-methoxy-4-formyl-2,2-dimethyl-2H-1-benzo-pyran in 20 ml of tetrahydrofuran are added to the solution. The combined mixture is allowed to stir for 16 hours at 25 ° C and then cooled, and water is added thereto. The reaction mixture is extracted with diethyl ether. The organic phase is then dried over anhydrous sodium sulfate and then concentrated under reduced pressure. 4 g of an orange oil are obtained, oil which is purified by flash chromatography using a mixture of cyclohexane and diisopropyl ether as eluent. 1.9 g of a yellow oil are obtained. 1 H NMR (CDC13, 300 MHz) d (ppm): 6.8-6.5 (5H, s), 5.8 (2H, s), 4.1 (2H, c), 3.7 (3H, s), 2.3 (3H, s), 1.3 (6H, s), 1.2 (3H, m). g) Acid (2E, 4E) -5- (2,2-dimethyl-6-methoxy-2H-1-benzopyran-3-yl) -3-methylpenta-2,4-dienoic acid (compound 2b). A solution of 1.9 ml (5.7 mmol) of the ethyl ester obtained in the preceding Step f), it is heated in 30 ml of methanol, 0.3 g (1.3 equivalents) of sodium hydroxide and 10 ml of water at reflux for 2 h. The reaction mixture is then concentrated under reduced pressure and the residue is removed in water. The combined mixture is acidified with IN aqueous hydrochloric acid solution. The formed precipitate (yellow) is filtered first, then washed with water and dried under reduced pressure. 1.3 g of the title compound are isolated in solid form. P.f. = 140 ° C. 'IR (cm "1) 1685, 1602, 1487, 1266. XH NMR (CDC13, 300 MHz) d (ppm): 6.55 to 6.8 (5H,), 5.8 (2H, s), 3.7 (3H, s), 2.35 (3H, s), 1.4 (6H, s) Microanalysis: Theoretical: C = 72%, H = 6.66%, 0 = 21.33% Calculated: C = 71.74%, H = 6.81%, OR = 20.76% Examples 3 to 14 Using the process illustrated in Examples 1 and 2 above, the compounds of the following Examples 3 to 14 were synthesized (where Et denotes ethyl, Ph denotes phenyl and TFA denotes trifluoroacetic acid).

TABLE 1 TABLE 1 (continued) TABLE 1 (continued) TABLE 1 (continued) TABLE 1 (continued) TABLE 1 (continued) EXAMPLE 15 Acid (2E, 4E) -5- (5-methyl-2, 3-dihydrobenzoxepin-4-yl) -3-methylpenta-2,4-dienoic acid (I: p = 0; Rj = -CH3; X = O; A = -CH2-CH2-; R2 = Z; n = 1; R '[lacuna] -CH3; and compound 15a [sic]: Y = -0-CH2-CH3; compound 15b [sic]: Y = -OH). a) 5-Methyl-2, 3,4, 5-tetrahydrobenzoxepin-5-ol Ona solution [sic], maintained under an inert atmosphere, of 33.5 ml (0.1 mol) of 3M methylmagnesium chloride in tetrahydrofuran solution is heated to 50 ° C. 11.3 g (0.069 mol) of 3,4-dihydro-2H-benzoxepin-5-one, dissolved in 150 ml of tetrahydrofuran, are added very rapidly. This solution is brought to reflux for 4 hours and then allowed to stir overnight at room temperature. The reaction mixture is then hydrolyzed gently with water under cold conditions. A solution of ammonium chloride (120 g per liter) is then poured into the reaction mixture. The latter is extracted with ethyl acetate and then the organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. 14.7 g of a yellow oil are obtained, oil which is purified by crystallization of isooctane. In this way 11.9 g of the title compound are obtained, the melting point of which is 92 ° C.

? RMN (CDC13 300 MHz) d (ppm): 7.5 (1H, d, J = 1.73 Hz), 7.2 to 7 (3H, m), 4.15-3.9 (2H, m), 2.5 (1H, s), 2.1 (2H, m),. 1.95 (2H, m), 1.6 (3H, s). b) 5-Methyl-2,3-dihydrobenzoxepine 14.9 ml (0.1 mol) of 5-methyl-2, 3, 4, 5-tetrahydrobenzoxepin-5-ol, 300 ml of toluene and a spatula tip of para acid. Toluenesulfonic are charged to a 1 liter reactor equipped with a Dean and Stark apparatus. The combined solution is brought to reflux for 2 hours, then the water is removed as it is formed. The reaction mixture is then neutralized with a 5% aqueous sodium bicarbonate solution and the organic solution is washed with water. The organic phase is subsequently dried over anhydrous sodium sulfate and concentrated under reduced pressure. 16 g of the title compound are obtained, which compound is purified by distillation, P.e. (2.5 mm Hg) = 80-90 ° C. 10 g of a colorless liquid are obtained. tti NMR (CDCl 3, 300 MHz) d (ppm): 7.3-6.9 (4H, m), 5.9 (1H, m), 4.15 (2H, t), 2.4 (2H, m), 2.05 (3H, s). c) 5-Methyl-4-f ormyl-2,3-di-idrobenzoxepine. 24 ml of dimethylformamide are added to 150 ml of acetonitrile under an inert atmosphere in a 500 ml four-necked flask. The solution is cooled to 0 ° C, and then 28.8 ml of phosphorus oxychloride is added to the solution. The reaction mixture is left after stirring at 5 ° C for 20 minutes. Subsequently, a solution of 8.2 g (0.051 mol) of 5-methyl-2,3-dihydrobenzoxepine in 24 ml of dimethylformamide and 20 ml of acetonitrile is added to the reaction mixture. The temperature is allowed to rise slightly to room temperature and then the reaction mixture is heated to 60 ° C. This is left stirring later for 16 hours after the heating has been interrupted. The reaction mixture is then brought to reflux and treated with ice-cold water. The combined mixture is neutralized with sodium hydroxide and then extracted with ethyl acetate. The organic phase is washed three times with an aqueous solution [lacuna] and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product obtained is purified by flash chromatography using dichloromethane as eluent. 4 g of the title compound are obtained. 1 H NMR (CDC13, 300 MHz) d (ppm): 10.45 (1H, s), 7.25-7.5 (4H, m), 4.6 (2H,), 2.7 (5H, s +). d) Ethyl ester of (2E, 4E) -5- (5-methyl-2, 3-cüh.ydrobenzoxepin-4-yl) -3-methylpenta-2,4-dienoic acid (compound 15a). A solution of 2.3 g (0.02 mol) of potassium tert-butoxide in 40 ml of tetrahydrofuran in a 250 ml four-necked flask is brought to 50 ° C under an inert atmosphere. A solution of 6.1 ml (0.02 mol) of the ethyl ester of diethyl (2-methyl-3-carboxyprop-2-enyl) phosphonate in 20 ml of tetrahydrofuran is subsequently added to the solution, which solution is maintained under an inert atmosphere . The reaction mixture is allowed to stir at 50 ° C for 20 minutes. The combined mixture is then cooled to 0 ° C and a solution of 4 g is added dropwise to the reaction mixture. (0.02 mol) _ of 5-methyl-4-formyl-2,3-dihydrobenzoxepine in 20 ml of tetrahydrofuran. The reaction is allowed to stir at room temperature (20-25 ° C) for 16 hours. After cooling, water is added to the reaction mixture, which mixture is extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. 7.2 g of an orange oil are obtained, which oil is purified by flash chromatography using a mixture of cyclohexane / diisopropyl ether 80/20 as eluent, thereby obtaining 3.4 g of the title compound.

* H NMR (CDCl 3, 300 MHz) d (ppm): 7.25-7 (5H, m), 6.3 (1H, d, J = 15.78 Hz), 5.8 (1H, s), 4.4 (2H, m), 4.1 (2H, m), 2.35 (5H, m + s), 2.2 (3H, s), 1.2 (3H, t). e) Acid (2E, 4E) -5- (5-methyl-2,3-dihydro-benzoxepin-4-yl) -3-methylpenta-2,4-dienoic acid (compound 15b). 0.7 g (0.175 mol) of sodium hydroxide, dissolved in 60 ml of water, are added to a solution of 3.4 g (0.011 mol) of the ethyl ester obtained in the above step d) in 60 ml of methanol. The reaction mixture is brought to reflux for 2 hours. The reaction mixture is then concentrated under reduced pressure. The residue is removed in water (insoluble). The combined mixture is acidified with a 5N hydrochloric acid solution. The precipitate formed is then filtered and washed with water and then dried. Recrystallization from ethanol results in 1.5 g of the title compound, the melting point of which is 199-202 ° C. GO . { cm'1): acid peak at 2500-3000, 1674. H NMR (DMSO [sic], 300 MHz) d (ppm): 7.3 to 6.9 (5H, m), 6.5-6.6 (1J [sic], d, J = 15.81 Hz), 5.8 (1H, s), 4.3 (2H, t), 2.4 (2H, t), 2.25 (3H, s), 2.1 (3H, s).

EXAMPLE 16 Acid (2E, 4E) -5- (3,3-dimethyl-7-methoxy-2,3-dihydrobenzoxepin-5-yl) -3-methylpntan-2,4-dienoic acid (I: p = 1; R = 7-O-CH3, X = O, A = -CH2-CR3R4-, R3 = R = -CH3: R2 = H, Rj = Z, n = 1, R '= -CH3, and compound 16a [sic] : Y = -0-CH2-CH3, compound 16b [sic]: Y = -OH). a) 3- (4-para-Methoxyphenoxy) -2, 2-dimethyl-propan-1-ol. A solution of 391 g (1.19 mol) of potassium [3- (4-para-methoxyfenpxy) -2,2-dimethylpropane] sulfonate in 1.69 liters of. Water is heated at 50 ° C for 15 minutes to obtain complete dissolution of the sulfonate. "156 ml of concentrated hydrochloric acid (1.5 equivalents) are added to this solution, which is then brought to reflux for 2.5 hours.A precipitate is formed by cooling the reaction mixture in an ice bath, which precipitate is dissolved by the addition of diethyl ether The organic phase is washed with water and then dried over anhydrous sodium sulfate After filtering, the organic phase is concentrated under reduced pressure, thereby obtaining 241.2 g of the title compound (yield = 96). %), the melting point of which is 68 ° C.

X H NMR (CDC13, 300 MHz) d (ppm): 7.05 (4H, s), 4 (3H, s), 3.97 (2H, s), 3.8 (2H, s), 2.35 (1H, s), 1.25 (6H, s). IR (orf1): 3350-3250, 2995, 1520, 1470. b) 3- (4-Para-methoxyphenoxy) -2,2-dimethylpropyl methanesulfonate. • 191.5 ml (1.38 mol) of triethylamine are added to a solution, maintained between -10 ° C and 0 ° C, of 241 g (1.15 mol) of the alcohol prepared in Stage a) above in 700 ml of toluene. 100 ml (1,265 mol) of methanesulfonyl chloride are added to this solution, being the temperature maintained below 10 CC. After reacting for 2 hours, 550 ml of normal hydrochloric acid are added and the extraction is carried out with ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The organic phase is subsequently filtered and concentrated under reduced pressure. 321 g of orange oil are obtained, oil which crystallizes at room temperature and has a melting point of 78 ° C (96% yield).

X H NMR (CDCl 3, 300 MHz) d (ppm): 6.75 (4 H, s), 4.1 (3 H, s), 3.7 (3 H, s), 3.6 (2 H, s), 2.85 (3 H, s), 1.05 ( 6H, s). c) 4- (4-para-Methoxyphenoxy) -3,3-dimethylbutyro-nitrile. 40 g (1.5 equivalents) of sodium cyanide are added to a solution of 160.8 g (0.557 mol) of the methanesulfonate prepared in Step b) above dissolved in 600 ml of dimethyl sulfoxide. The solution is brought to 150 ° C and maintained at this temperature for 3 hours and then the reaction mixture is allowed to return to room temperature for 16 hours. The reaction mixture is then cooled in an ice bath and then water is added. A precipitate appears and is extracted with ethyl acetate. The organic phase is washed twice with 400 ml of an aqueous sodium hydroxide solution (5 g per liter) and dried over anhydrous sodium sulfate. The organic phase is then concentrated under reduced pressure and results in 122 g of an orange oil, which oil crystallises (100% yield) and has a melting point of 6 ° C. H NMR (CDCl 3, 300 MHz) d (ppm): 6.75 (4H, s), 3.7 (3H, s), 3.6 (2Hr s), 2.4 (2H, s), 1.15 (6H, s). d) 4- (para-methoxyphenoxy) -3,3-dimethylbutyric acid. A solution of 47 g (0.215 mol) of the compound obtained in the preceding Step c), 41.3 g (4 equivalents) of potassium hydroxide and 280 ml of ethylene glycol is brought to 150 ° C for 3.75 hours. After cooling, water is added to the reaction mixture and extraction is carried out with diethyl ether. The aqueous phase is acidified with 5N hydrochloric acid to pH 1 with stirring. The precipitate is filtered and washed with H20 and then extracted with methylene chloride. The organic phase is dried over anhydrous sodium sulfate and then filtered under reduced pressure. 37 g of an orange oil are obtained, oil which crystallizes at room temperature and has a melting point of 66 ° C (73% yield). IR (cpf1): acid peak at 1695. 1 H NMR (CDC13, 300 MHz) d (ppm): 6.7 (4H, s), 3.6 (3H, s), 3.55 (2H, s), 2.3 (2H, s) , 1 (6H, s). e) 7-Methoxy-3,3-dimethyl-3,4-dihydro-2H-benzo-xepin-5-one. A solution of 900 g of polyphosphoric acid in 1.1 liters of toluene is brought to 90 ° C. 200 g (0.839 mmol) of 4- (4-para-methoxyphenoxy) -3,3-dimethyl-butyric acid, dissolved in 550 ml of toluene, are added to this solution. The combined mixture is maintained under stirring at 90 ° C for 4 hours. The reaction mixture is then cooled to room temperature (20-25 ° C). The thick oil is separated from toluene. After cooling, the oil is removed in 500 ml of ice water and extracted with ethyl acetate. The organic phase is washed with 500 ml of an aqueous solution of sodium hydroxide (IN) and then with 500 ml of water. The organic phase is dried over anhydrous sodium sulfate. The ethyl acetate and toluene are evaporated under reduced pressure. 165 g of a yellow oil are obtained, total yield: 89%. IR (crrf1) 2960, 1680, 1489, 1462, 1419. ^ H NMR (CDC13, 300 MHz) d (ppm): 7.1 (1H, m), 6.95 (2H, s), 3.7 (2H, s), 3.65 (3H, s), 2.6 (2H, s), 1.05 (6H, s). f) 7-Methoxy-3, 3, 5-trimethyl-2, 3,4,5-tetrahydro-benzoxepin-5-ol. 190 ml (0.57 mol) of 3M methylmagnesium chloride in tetrahydrofuran solution is charged to a 2 liter reactor maintained under an inert atmosphere. The solution is brought to 50 ° C and then 82 g (0.372 mol) of the acetone prepared in Stage e) above, dissolved in 1.1 liters of tetrahydrofuran, are quickly added thereto. The obtained solution is heated to reflux for 4 hours. The reaction mixture is then cooled in an ice bath and then water is added to it. The combined mixture is then poured onto a saturated aqueous ammonium chloride solution. Extraction is carried out with ethyl acetate and the organic phase is separated by sedimentation and then dried over anhydrous sodium sulfate. This organic phase is concentrated under reduced pressure and results in 85 g of an orange oil, which crystallizes at room temperature (96% yield). XH NMR (CDC13, 300 MHz) [lacuna] 7.05-6.6 (3H, m), 3.75 (5H, s), 2.15 (1H, s), 1.8 (2H, d), 1.55 (3H, s), 1.05 ( 3H, s), 1 (3H, s). g) 7-Methoxy-3, 3, 5-trimethyl-2,3-dihydrobenzo-xepine. 169 g (0.716 mol) of the compound prepared in the preceding Step f) in 2.25 liters of toluene and 5 g of para-toluenesulfonic acid are introduced into a 4 liter reactor equipped with a Dean and Stark apparatus. The combined mixture is refluxed for 4 hours. The water formed is removed as it forms. In this way, 11.5 ml of water are removed. The reaction mixture is allowed to return to room temperature. The reaction mixture is poured into a 5% aqueous sodium bicarbonate solution. The separation is allowed to take place by sedimentation and then the organic phase is washed with water and dried over anhydrous sodium sulfate. The organic phase is subsequently concentrated under reduced pressure. 155 g of a dark oil are obtained. Performance: 99%. X H NMR (CDC13, 300 MHz) d (ppm): 6.9-6.6 (3H, m), 5.6 (1H, s), 3.7 (5H, 2s), 2.05 (3H, s), 1.05 (6H, s). ) 5-Bromomethyl-7-methoxy-3, 3-dimethyl-2,3-dihydro-benzoxepin. 155 g (0.71 mol) of the compound prepared in the preceding step, 130 g (0.73 mol) of N-bromosuccinimide and 4 g of a, a'-azobisisobutyronitrile are introduced into 1.6 liters of carbon tetrachloride. The solution is brought to reflux for 4 hours and then it is cooled to 25 ° C. The solid formed is filtered and the organic phase is washed several times with warm water (30-40 ° C). The separation is carried out by sedimentation and then the organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. In this way 210 g of brown oil are obtained, oil which corresponds to the product of the title.

* H NMR (CDCl 3, 300 MHz) d (ppm): 7.1-6.7 (3H, m), 6 1H, s), 4.3 (2H, s), 3.75 (5H, s), 1.1 (6H, s). i) 7-Methoxy-5-formyl-3,4-dimethyl-2,3-dihydro-benzoxepine. 210 g (0.71 mol) of the compound prepared in the preceding Step h) and 150 g (1.5 equivalents) of hexamethylenetetramine are introduced into 2 liters of chloroform. The solution is brought to reflux for 2 hours. The reaction mixture is subsequently concentrated under reduced pressure. The brown residue obtained is then removed in 2.55 liters [sic] of a 75% aqueous acetic acid solution. The combined mixture is heated to reflux for 90 minutes, then 385 ml of concentrated hydrochloric acid is added thereto and the combined mixture is refluxed again for 30 minutes. Water is added under hot conditions to the reaction mixture. The reaction mixture is again left [sic] for 30 minutes at room temperature (20-25 ° C) and then extraction is carried out with ethyl acetate. The organic phase is separated by sedimentation, then washed with a solution of aqueous sodium bicarbonate, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. In this way, 140 g of a dark brown oil is obtained, which oil is purified by flash chromatography using dichloromethane as eluent. After purification, 98 g of the title compound are isolated. Yield: 60%. t H NMR (CDC13, 300 MHz) d (ppm): 9.5 (1 H, s), 7.6 (1 H, s), 6.9 (1 H, d), 6.7 (1 H, d, J = 8.85 Hz), 6.48 (1 H, s), 3.82 (2H, s), 3.73 (3H, s), 1.18 (6H, s). j) Ethyl ester of (2E, 4E) -5- (3, 3-dimethyl-7-methoxy-2,3-dihydrobenzoxepin-5-yl) -3-mepenta-2,4-dienoic acid (compound 16a) . * 64.5 ml (0.263 mol) of diethyl (2-methyl-3-carboxyprop-2-enyl) phosphonate ethyl ester (41% trans) in 250 ml of tetrahydrofuran are added dropwise to a solution of 29.6 g (0.263 mol). ) of potassium tert-butoxide in 500 ml of tetrahydrofuran. The reaction mixture is left stirring for 1 hour, then cooled in an ice bath and 43 g (0.185 mol) of the compound prepared in the preceding Step i), dissolved in 250 ml of tetrahydrofuran, are added thereto dropwise. The reaction mixture is again allowed to stir at 25 ° C for 16 hours, after which the reaction mixture is cooled in an ice bath and then hydrolyzed by the addition of water. The extraction is then carried out with ethyl acetate and then the organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. In this way 88 g of a dark orange oil are obtained, which oil is purified by flash chromatography using a mixture of cyclohexane / diisopropyl ether as eluent. In this way 46.8 g of a yellow oil are obtained. 1R NMR (CDC13, 300 MHz) d (ppm): 6.9 (1H, d, J = 2.95 Hz), 6.7-6.6 (3H, m), 6.35 (1H, d, J = 15.42 Hz), 6 (1H, s), 5.8 (1H, s), 4.1 (2H, m), 3.8 (2H, s), 3.7 (3H, s), 2.3 (3H, s), 1.25 (3H, s), 1.08 (6H, s) ). k) Acid (2E, 4E) -5- (3,3-dimethyl-7-methoxy-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2,4-dienoic acid (compound 16b). 7.2 g (0.18 mol) of sodium hydroxide, dissolved in 500 ml of water, are added to a solution of 46 g (0.134 mol) of the compound prepared in the above step j) in 500 ml of methanol. This mixture is brought to reflux for 4 hours and then the reaction mixture is concentrated under reduced pressure. The paste obtained as residue is dissolved in diethyl ether and then washed with water. The aqueous phase is then acidified with 5N hydrochloric acid to pH 1. A yellow residue is obtained, which residue is dissolved in methylene chloride. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. 44 g of an oil are obtained, which oil is recrystallized from ethanol. In this way 18 g of the title compound are isolated. IR (c "1): 3000, 2900, 1680, 1599, 1271, acid peak between 2400 and 2800. XH NMR (CDC13, 300 MHz) d (ppm): 7.1 (1H, d, J = 8.64 Hz), 7 to 6.85 (3H, m), 6.65 (1H, d, J = 15.36 Hz), 6.2 (1H, s), 6 (1H, s), 4.05 (2H, s), 3.95 (3H, s), 2.55 ( 3H, s), 1.3 (6H, s).

EXAMPLE 17 Acid (2E, 4E) -5- (2,3-di-idrobezoxepin-4-yl) -3-methylpenta-2,4-dienoic acid (I: p = 0; Rx = H; X = O; A = -CH2-CH2-, R2 = Z, n = 1, R '= CH3, and compound 17a [sic]: Y = -0-CH2-CH3, compound 17b [sic]: Y = -OH). a) 2, 3-Dihydro-4- (ethoxycarbonyl) -benzoxepine. A mixture of 8.2 g (0.043 mol) of 2,3-dihydro-4-carboxybenzoxepine in 150 ml of ethanol and 5 ml of concentrated sulfuric acid is brought to reflux for 6 hours. The reaction mixture is subsequently concentrated under reduced pressure and the residue is removed in water. The combined mixture is extracted with ethyl acetate. The organic phase is then washed with sodium bicarbonate and then with water and dried over anhydrous sodium sulfate before being concentrated under reduced pressure. In this way 8.5 g of an orange oil are obtained. 1 H NMR (CDCl 3, 300 MHz) d (ppm): 7.6 (1H, s), 7.35-7 (4H, m), 4.2 (4H, m), 3 (2H, m), 1.3 (3H, m). IR (cm "" 1): 1705. b) 2, 3-Di-idro-4- (hydroxymethyl) -benzoxepine. A solution of 1.4 g (0.036 mol) of lithium aluminum hydride in 80 ml of diethyl ether and kept under an inert atmosphere. This solution is cooled in an ice bath and salt at 0 ° C and then 8 g (0.036 mol) of the compound prepared in the preceding Step a), dissolved in 80 ml of diethyl ether, are added to this solution. The reaction mixture is left at 0 ° C for 1 hour and then water is added to it while maintaining the temperature of the reaction mixture between 0 and 10 ° C. Subsequently, the extraction is carried out with diethyl ether and the aqueous mother liquors are saturated with sodium chloride. The organic phases are then dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 7 g of a colorless oil. The presence of an alcohol OH peak is confirmed by infrared spectroscopy. 2 H NMR (CDCl 3, 300 MHz) d (ppm): 7.15 to 6.9 (4H, m), 6.3 (1H, s), 4.2 (4H, m), 2.6 (2H, m), 1.8 (1H, s). c) 2, 3-Dihydro-4-formylbenzoxepine. A mixture of 6.3 g (0.026 mol) of the compound prepared in the preceding Step b), 250 ml of chloroform and 50 g (0.575 mol) of manganese dioxide is kept stirring for 16 hours at room temperature (25 ° C). After filtering through silica, the reaction mixture is concentrated under reduced pressure and 5 g of a yellow oil are obtained. H NMR (CDCl 3, 300 MHz) d (ppm): 9.5 (1H, s), 7.3 to 7 (5H, m), 4.2 (2H, m), 2.8 (2H, m). d) Ethyl ester of (2E, 4E) -5- (2,3-dihydrozozoepin-4-yl) -3-methylpenta-2,4-dienoic acid (compound 17a). 0.72 g (0.03 mol) of sodium hydride and 20 ml of tetrahydrofuran were charged into a 250 ml four-necked flask maintained under an inert atmosphere. A solution of 7.5 ml (1.03 mol) of the ethyl ester of diethyl acid (2-methyl-3-carboxyprop-2-enyl) phosphonate acid [sic] in 20 ml of tetrahydrofuran is added to this solution. The combined mixture is allowed to stir for 1 hour at room temperature (25 ° C) and then 5 g (0.0287 mol) of the compound prepared in the preceding Step c) are added to the reaction mixture., in 40 ml of tetrahydrofuran. The combined mixture is again allowed to stir for 16 hours at 25 ° C. The reaction mixture is subsequently hydrolyzed with water and poured onto the saturated aqueous sodium chloride solution. Subsequently, the extraction is carried out with ethyl acetate and the organic phase is dried over sodium sulfate anhydride. The organic phase is subsequently concentrated under reduced pressure. From this, 9.3 g of an oil is obtained, which oil is purified by flash chromatography using a mixture of cyclohexane and ethyl acetate as eluent. In this way 5.8 g of an oil is isolated, which crystallizes at room temperature. This product is crystallized from diisopropyl ether and 2.7 g of the title compound are obtained, which compound has a melting point of 100 ° C. IR (cirf1): peak at 1700.? H NMR (CDC13, 300 MHz) [lacuna] 7.4 to 7 (4H, m), 6.9 (1H, d, J = 15.82 Hz), 6.65 (1H, s), 6.3 (1H, d, J = 15.8 Hz), 5.95 (1H, s), 4. 4 (2H, m), 4.3 (2H, m), 2.95 (2H, m), 2.5 (3H, s), 1.4 (3H, m). e) Acid (2E, 4E) -5- (2,3-dihydrozoxy-3-yl) -3-methylpenta-2,4-dienoic acid (compound 17b). A solution of 0.4 g (0.01 mol) of sodium hydroxide in 40 ml of water is added to a solution of 2.7 g of the compound prepared in the above step d) in 40 ml of methanol. This solution is brought to reflux for 3 hours. 50 ml of methanol are again added to this mixture and the reflux is continued for 3 hours. The reaction mixture is subsequently concentrated under reduced pressure and then the residue is removed in water. The resulting solution is then acidified to pH 1 using IN hydrochloric acid. The formed precipitate is filtered, washed with water, and then dried. 2.3 g of the title compound are obtained, which compound is recrystallized from methanol. 1.1 g of the purified product with a melting point of 220-222 ° C are isolated. IR (crrf1): 1669, 1588, 1262, 2400-3200. aH NMR (CDC13, 300 MHz) [lacuna] 7.3-6.9 (5H, m), 6.7 (1H, s), 6.5-6.4 (1H, d, J = 15.87 Hz), 5.8 (1H, s), 4.2 ( 2H, m), 2.8 (2H, m), 2.3 (3H, s).

EXAMPLES 18 to 30 Examples 18 to 30 in the following Table 2 were prepared using one of the methods illustrated in the preceding examples.

TABLE 2 TABLE 2 (continued) TABLE 2 (continued) TABLE 2 (continued) TABLE 2 (continued) TABLE 2 (continued) TABLE 2 (continued) TABLE 2 (continued) TABLE 2 (continued) TABLE 2 (continued) TABLE 2 (continued) TABLE 2 (continued) TABLE 2 (continued) TABLE 2 (continued) TABLE 2 (continued) TABLE 2 (continued) TABLE 2 (continued) In addition, the following preparations illustrate the synthesis of intermediary compounds of use in the preparation of the compounds of Examples 1 to 31 above.

Preparation 1 3, 3-Dimethyl-7-phenyl-3, 4-dihydro-2H-benzoxepin-5-one 8.5 g of 7-bromo-3,3-dimethyl-3,4-dihydro-2H-benzoxepin-5- one (0.0316 mol), 95 ml of toluene, 34.7 ml of a 2M sodium carbon solution, 46 ml of ethanol, 4.19 g of feniboric acid [sic] (0.0344 mol, 1.09 equivalents) and 0.677 g of tetracis (trofenilfosfin) palladium are charged to a 250 ml reactor. The reaction mixture is refluxed for 8 h and then allowed to return to room temperature. The reaction mass is poured into a mixture of 70 ml of water, 56.8 ml of a 30% aqueous ammonium hydroxide solution and 78 ml of a 2M aqueous sodium carbon solution. The catalyst is filtered through silica. The extraction is then carried out three times with 100 ml of ethyl acetate and the organic phases are washed three times with 100 ml of water and dried over anhydrous sodium sulfate before being concentrated under reduced pressure. 14 g of an oil are isolated, oil which is purified by column chromatography using a hexane / ethyl acetate 4/1 mixture. In this way, 8.5 g of the title compound are obtained in the form of a liquid. X H NMR (CDC13, 300 MHz) d (ppm): 7.88-7.25 (8H, m), 3.98 (2H, s), 2.74 (2H, s), 1.15 (6H, s).

Preparation 2 (4-para-chlorophenyl) (3,3,5-triimethyl-2,3-dihydro-benzoxepin-7-yl) ketone [sic] 0.627 g of magnesium filings [sic] (0.0258 mol), 20 ml of anhydrous tetrahydrofuran and a crystal of iodine are introduced into a 250 ml reactor. A mixture of 8.3 g of 7-bromo-3,3,5,5-trimethyl-2,3-dihydrobenzoxepine in 30 ml of anhydrous tetrahydrofuran is slowly added to this solution. The combined mixture is refluxed for 1.5 h and then the reaction mixture is allowed to return to room temperature (solution A). 5 g of para-chlorobenzoyl chloride and 20 ml of anhydrous tetrahydrofuran are introduced into a second reactor of 250 ml. This solution is cooled to 0 ° C and then the solution A prepared above is slowly added to it, to maintain the temperature of the reaction mixture below 5 ° C. The combined mixture is allowed to return to room temperature and then the reaction mixture is kept stirring for 20 h. After cooling to 5 ° C, the hydrolysis is carried out by the slow addition of 3.2 ml of an aqueous hydrochloric acid solution IN, and then the mixture is diluted with water and 3 times extracted with 100 ml of diethyl ether. The organic phase is washed with a solution of aqueous sodium hydroxide IN and then twice with 100 ml of water and dried over anhydrous sodium sulfate before being concentrated under reduced pressure. In this way, 10.5 g of an oil are obtained, which oil is purified by column chromatography using a hexane / ethyl acetate 10/1 mixture as eluent. After purification, 3.6 g of the title compound are isolated in the form of a liquid. Performance of 38.7%. X H NMR (DMSO [sic], 300 MHz) d (ppm): 8.04-6.96 (7H, m), 5.73 (1H, s), 3.83 (2H, s), 2.06 (3H, s), 1.05 (6H, s).

Preparation 3 4-Methyl-3-formyl-2H-a-benzo-urane 6.3 g (40.63 mol) of P0C13, at 0 ° C, are added to a 50 ml three-necked flask, kept under an inert atmospheric, which it contains 3.0 g (40.63 mmol) of dimethylformamide. The reaction mixture is kept at 5 ° C for 15 minutes and then a solution of 4.8 g (32.5 mmol) of 4-methyl-2H-1-benzopyran in 25 ml of methylene chloride is added at this temperature. The reaction mixture was allowed to return to room temperature and was kept stirring for 2 hours. The reaction mixture is then poured rapidly into a mixture of water and ice and then extracted with ethyl acetate. The organic phase is washed with a 5% aqueous sodium bicarbonate solution and then with water.

After drying over anhydrous sodium sulfate, the organic phase is concentrated under reduced pressure. An oil is obtained, oil which crystallizes slowly. This recrystallizes from 25 ml of isopropyl ether. In this way 2.0 g of the title compound are obtained in the form of a solid, the melting point of which is between 68 and 70 ° C (yield = 35%). ? NMR (CDC13, 300 MHz) d (ppm): 2.4 (3H, s), 4.8 (2H, s), 6.8-7.0 (2H, m), 7.2-7.4 (2H, m), 10.1 (1H, s). P.f. = 68-70 ° C Preparation 4 4-Phenyl-3-formyl-2H-1-benzopyran 71 ml (0.773 mol) of phosphorus oxychloride are added dropwise to 300 ml of dimethylformamide maintained at 0 ° C. The reaction mixture is allowed to stir for 20 minutes at a temperature between 0 and 5 ° C. A solution of 16.1 g (77.3 mmol) of 4-phenyl-2H-1-benzopyran in 22.5 ml of dimethylformamide is then added to the reaction mixture. The reaction mixture is allowed to return to room temperature and then brought to 60 ° C for 7 hours. The reaction mixture is then poured into a mixture of ice and water which is nautralized with NaOH. The organic phase is extracted with ethyl acetate and then the organic phase is washed 3 times with water. After drying over anhydrous sodium sulfate, the organic phase is concentrated under reduced pressure. In this way, a solid solid OO is obtained which, after column chromatography on silica using a methylene chloride / cyclohexane 1/1 mixture as eluent, results in 15.3 g of the title compound as a yellow solid. , the melting point of which is 82-83 ° C (yield = 83%). * H NMR (CDC13, 300 MHz) d (ppm): 5 (2H, s), 6.79 to 6.89 (3H, m), 7.21 to 7.26 (3H, m), from 7.39 to 7.42 (3H, m), 9.38 (1H, s).

The physicochemical data of the characterization of the other intermediate carboxaldehydes are specified in Table 3. The physicochemical data of the characterization of some intermediate products have been reported in the following Table 3.

TABLE 3 TABLE 3 (continued) TABLE 3 (continued) The physicochemical data of the characterization of a few intermediates of the 5-methyl-2,3-dihydrobenzoxepine type are specified in Table 4.

TABLE 4 Compound lH NMR (CDClj, 300 MHz) d (ppm): 7. 08 (1H, d, J = 11.5 Hz), 6.95 GIH, d, J = 6.95 Hz), 5.68 (1H, s), 3.74 (2H, s), 2.01 (3H, s), 1.02 (6H, s) 6. 95-7.5 (8H, m), 5.75 (1H, s), 3.77 (2H, s), 2.11 (3H, s), 1.05 (6H, s) 7. 34-6.89 (4H,), 5.63 (1H, s). 3.77 (2H, s), 2.07 (3H, s), 1.03 (6H, s) TABLE 4 (continued) The physicochemical data of the characterization of a few derivatives of 5-bromomethyl-2, 3-dihydrobenzoxepine are specified in Table 5. TABLE 5 TABLE 5 (continued) It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (22)

2. Having described the invention as above, the content of the following claims is claimed as property:
3. A compound of formula: characterized in that: X represents O or S; A represents the bivalent radical - (CH2) s-CO- (CH2) t- or the bivalent radical - (CH2) S-CR3CR4- (CH2) t- radicals in which s = t = 0 or in addition one of syt has the value of 0 and the other has the value of 1. R4 represents a hydrogen atom or an alkyl group (of C1-C15); Ri and R2 independently represent the Z chain defined below; a hydrogen atom; an alkyl group (of C? -C? a); an alkenyl group (of C2-C? 8); an alkynyl group (of C2-C18); an aryl group (of C6-C? Q) optionally substituted by a halogen atom, by an optionally halogenated (C1-C5) alkyl group or by optionally halogenated (C1-C5) alkoxy; or a mono- or bicyclic heteroaryl group (of C-C12) comprising one or more heteroatoms selected from. 0, N and S, which is optionally substituted by a halogen atom, by an optionally halogenated (C1-C5) alkyl group or by an optionally halogenated (C1-C5) alkoxy group; R3 has any of the above data meanings for Ri and R2, with the exception of the Z chain; or in addition R3 and R4 together form an alkylene chain (of C2-C6) optionally substituted by a halogen atom or by optionally halogenated (C1-C5) alkoxy; R is chosen from a halogen atom; a cyano group; a nitro group; a carboxy group; an alkoxycarbonyl group (of i-Ciß) optionally halogenads; a group Ra-CO-NH- or RaRbN-CO- [in which Ra and Rb independently represent optionally halogenated (C? -C? 8) alkyl; a hydrogen atom; aryl (of C6-C? 0) or aryl (of C? -C10) alkyl (of C1-C5) (where the aryl portions are optionally substituted by a halogen atom, by an alkyl group (of C1-C5) optionally p halogenated or by an optionally halogenated (C1-C5) alkoxy group); cycloalkyl (from C3-C2) optionally substituted by a halogen atom, by an optionally halogenated (C1-C5) alkyl group or by an optionally halogenated (C1-C5) alkoxy group]; an optionally halogenated (C? -C? 8) alkyl group; optionally halogenated (C? -C? 8) alkoxy; and aryl (of C6-C? 0), aryl (of C6-C? o) alkyl (of C1-C5), aryloxy (of C6-C? 0), cycloalkyl (of C3-C? 2), cycloalkenyl ( of C3-C? 2), cycloalkyloxy (of C3-C12), cycloalkenyloxy (of C3-C12) in which the aryl, cycloalkyl and cycloalkenyl portions are optionally substituted by a halogen atom, by alkyl (of C1-C5) optionally halogenated or by optionally halogenated (C-C5) alkoxy; p represents 0, 1, 2, 3 or 4; Z represents the radical: where n is 1 or 2; the R 'groups independently represent a hydrogen atom; an alkyl group (of C1-C5); an aryl group (from Ce-Cio) optionally substituted by a halogen atom, by an optionally halogenated (C1-C5) alkyl group or by optionally halogenated (C1-C5) alkoxy; or a monocyclic or bicyclic heteroaryl group (C4-C2) comprising one or more heteroatoms selected from O, N and S, which is optionally substituted by a halogen atom, by an alkyl group (from C1-C5) optionally halogenated or by an optionally halogenated (C1-C5) alkoxy group; And represents -OH; alkoxy (from C1-C5); or the group -NRcRd [in which Rc and Rd independently represent a hydrogen atom; alkyl (of C1-C5); cycloalkyl (C3-C8) optionally substituted by a halogen atom, by optionally halogenated (C1-C5) alkyl or by optionally halogenated (C1-C5) alkoxy; aryl (of C6-C? o) optionally substituted by a halogen atom, by optionally halogenated (C1-C5) alkyl or by optionally halogenated (C1-C5) alkoxy; it being understood that one and only one of Ri and R2 represents the chain Z; and their pharmaceutically acceptable salts [sic] with acids or bases. 2. The compound of formula I [sic] according to claim 1, characterized in that A represents the divalent radical - (CH2) S-CR3CR4- (CH2) t in which s, t, R3 and R4 are as defined in claim 1. 3. The compound of formula I [sic] according to claim 1, characterized in that: X represents 0; A represents -CR3CR4- or -CH2-CR3CR4- in which the unsubstituted methylene group is attached to X;
4. Rx and R2 independently represent Z; H; alkyl (of C1-C15); alkenyl (from Ca-C? 5) [sic]; or phenyl optionally substituted by alkyl (of Cj-Cs); (C 1 -C 5) alkoxy, a halogen atom or -CF 3; R3 has any of the meanings given above for Ri and R2, with the exception of Z; R is chosen from alkyl (from C1-C9); alkoxy (from C1-C5); phenyl or phenylcarbonyl optionally substituted by a halogen atom, (C1-C5) alkyl, (C1-C5) alkoxy, -CF3 or -OCF3; a halogen atom; and -OCF3; Z represents the radical: where n represents 1; and R 'represents alkyl (of Cj_-C5). 4. The compound according to any of claims 1 to 3, characterized in that: X represents O; A represents -CR3CR-; and Z represents
5. 5. The compound according to any of claims 1 to 3, characterized in that: X represents O; A represents -CH2-CR3CR4- in which the unsubstituted methylene group is attached to X; Ri and R2 independently represent Z, a hydrogen atom or alkyl (of C1-C5); R3 takes any of the meanings given above for Ri and R2, with the exception of Z; Z represents:
6. R 'represents methyl or phenyl. 6. The compound according to any of claims 1 to 5, characterized in that: Y represents -OH; alkoxy (from C1-C5); or -NRcRd in which Rc and Rd are as defined in claim 1.
7. 7. The compound according to any of claims 1 to 6, characterized in that p represents 0, 1 or 2.
8. 8. The compound in accordance with Claim 1, characterized in that it is chosen from: (2E, 4E) -5- (2-pentyl-2H-1-benzopyran-3-yl) -3-methyl-penta-2, -dienoic acid; (2Z, 4E) -5- (2-Pentyl-2H-1-benzopyran-3-yl) -3-methyl-penta-2,4-dienoic acid; - (2E, 4E) -5- (2,2-Dimethyl-6-methoxy-2H-1-benzopyran-3-yl) -3-methylpenta-2, -dienoic acid; (2E, 4E) -5- (2H-1-benzopyran-3-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (2,2-Dimethyl-2H-l-benzopyran-3-yl) -3-methylpenta-2, -dienoic acid; (2Z, 4E) -5- (2,2-Dimethyl-2H-l-benzopyran-3-yl) -3-methylpenta-2, -dienoic acid; (2E, 4E) -5- [2- (Non-6-enyl) -2H-1-benzopyran-3-yl) -3-methyl-penta-2, -dienoic acid; - (2E, 4E) -5- (4-phenyl-2H-1-benzopyran-3-yl) -3-methyl-penta-2, -dienoic acid; (2E, 4E) -5- (6-Nonyl-2H-1-benzopyran-3-yl) -3-methylpenta-2, -dienoic acid; (2E, 4E) -5- (6-phenyl-2H-1-benzopyran-3-yl) -3-methylpenta-2, -dienoic acid; (2E, 4E) -5- (2-Nonyl-2H-l-benzopyran-3-yl) -3-methylpenta-2, -dienoic acid; (2E, 4E) -5- (4-Methyl-2H-l-benzopyran-3-yl) -3-methylpenta-2, -dienoic acid; (2Z, 4E) -5- (2H-1-benzopyran-3-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (2-undecanyl-2H-l-benzopyran-3-yl) -3-methylpenta-2, -dienoic acid; - (2E, 4E) -5- (2-phenyl-2H-l-benzopyran-3-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (5-Methyl-2,3-dihydro-benzoxepin-4-yl) -3-methylpenta-2, -dienoic acid; (2E, 4E) -5- (3, 3-dimethyl-7-methoxy-2, 3-dihydrobenzoxepin-5-yl) -3-methylpenta-2,4-dienoic acid; and [sic] (2E, 4E) -5- (2,3-dihydrozozoepin-4-yl) -3-methylpenta-2, -dienoic acid; (2E, 4E) -5- (3, 3-dimethyl-7-methoxy-2,3-dihydrobenzoxe? in-5-yl) -3-phenylpenta-2, -dienoic acid; - (2Z, 4E) -5- (3,3-dimethyl-7-methoxy-2,3-dihydrobenzoxepin-5-yl) -3-phenylpenta-2,4-dienoic acid; (2Z, 4E) -5- (3, 3-dimethyl-7-methoxy-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2, -dienoic acid; (2E, 4E) -5- (3,3-Dimethyl-7,8-dimethoxy-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (3,3-dimethyl-2,3-dihydro-benzoxepin-5-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (3,3-Dimethyl-2,3-dihydro-7- (para-chloro-benzoyl) benzoxepin-5-yl) -3-methylpenta-2, -dienoic acid; (2E, 4E) -5- (3, 3-dimethyl-7-chloro-2, 3-dihydrobenzoxepin-5-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (3, 3-dimethyl-7,8-dichloro-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2, -dienoic acid; - (2E, 4E) -5- (3, 3-dimethyl-7-bromo-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (3,3-Dimethyl-7-fluoro-8-chloro-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (3, 3-dimethyl-7-fluoro-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2, -dienoic acid; (2E, 4E) -5- (3,3-Dimethyl-7-trifluoromethyl-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2, -dienoic acid; (2E, 4E) -5- (3,3-Dimethyl-7-phenyl-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2, -dienoic acid; - (2E, 4E) -5- (3, 3,7-Trimethyl-2,3-dihydro-benzoxepin-5-yl) -3-methypentane-2, -dienoic acid; (2E, 4E) -5- (3, 3-dimethyl-2,3-dihydro-benzoxepin-5-yl) -3-methylpenta-2,4-dienoic acid; (2E, 4E) -5- (9-methoxy-3,3-dimethyl-2,3-dihydrobenzoxepin-5-yl) -3-methylpenta-2,4-dienoic acid; and its pharmaceutically acceptable esters.
9. 9. A process for the preparation of a compound of formula (I) according to claim 1, wherein n represents 1, characterized in that it comprises the steps comprised of: (a) preparing an ylide either • by the reaction of a base with a phosphonate of formula: wherein R 'is as defined in Claim 1; Ti and T2 independently represent alkyl (from 10 C? -C5); and Y represents (C1-C5) alkoxy, or by the reaction of a base with a phosphonium salt of formula (Ilb): wherein R 'is as defined in Claim 1; 0 T3, T4 and T5 independently represent alkyl (of C1-C5) or aryl (of C6-C? 0) optionally substituted by alkyl (of C1-C5); and Y represents (C1-C5) alkoxy; and hal represents a halogen atom; 5 (bl) reacting the ylide obtained in Step (a) with an aldehyde of formula: wherein R ', p, X and A are as defined in Claim 1; one and only one of R 'i and R'2 represents -CHO and the other one takes one of the meanings given in Claim 1 [sic] for Rx and R2, with the exception of the Z chain, to obtain the compound of formula ( I) in which n represents 1 and Y represents alkoxy (from C1-C5); (cl) if appropriate, converting the ester obtained in the above Step (bl) in acidic or basic medium to the corresponding carboxylic acid of formula (I) in which Y represents OH; (d) if appropriate, reacting the carboxylic acid functional group of the compound of formula (I) resulting from Step (cl) with an amine of formula HNRcRd in which Rc and Rd are as defined in Claim 1, optionally after activation of the carboxyl functional group, to prepare the corresponding compound of formula (I) in which Y represents -NRcRd.
10. 10. The process for the preparation of a compound of formula (I) according to claim 1, wherein n represents 2, characterized in that it comprises the steps composed of: (a2) preparing an ylide either • by the reaction of a base with a phosphonate of formula (IVa): wherein R'-, and R 'independently represent a group R' as defined in Claim 1 [sic]; Te and T7 independently represent alkyl (from C? -c5); and Y represents (C1-C5) alkoxy, or by the reaction of a base with a phosphonium salt of formula (IVb): wherein R'D and R 'k independently represent a group R' as defined in Claim 1; T8, T9 and I represent independently alkyl (of C? -C5) or aryl (of C6-C10) optionally substituted by alkyl (of C1-C5); and Y represents (C1-C5) alkoxy; and hal represents a halogen atom; (b2) reacting the ylide obtained in Step (a2) with an aldehyde of formula: - wherein R, p, X and A are as defined in Claim 1; one and only one of R '1 and R'2 represents -CHO and the other one takes one of the meanings given in Claim 1 for Rx and R2, with the exception of the Z chain, to obtain the compound of formula (I) [sic] wherein n represents 2 and Y represents alkoxy (from C1-C5); (c2) if appropriate, converting the ester obtained in the above Step (b2) in acidic or basic medium to the corresponding carboxylic acid of formula (I) in which Y represents OH; (d2) if appropriate, reacting the carboxylic acid functional group of the compound of formula (I) resulting from Step (c2) with an amine of formula HNRcRd in which Rc and Rd are as defined in Claim 1 [sic] ], optionally after activation of the carboxyl functional group, to prepare the corresponding compound of formula (I) in which Y represents -NRcRd. The process according to one of claims 9 and 10, characterized in that the ylide is prepared in Steps (a) or (a2), respectively, by the reaction of a base with a phosphonate. The process according to any of claims 9 to 11, characterized in that the base is selected from an alkali metal hydride, an alkali metal carbonate, an alkali metal amide, an alkylthio (Ci-Cio) and a Alkali metal alkoxide 13. The process according to any of claims 9 to 12, characterized in the solvent in Step (a) or (a2) is respectively a protic solvent chosen from aromatic hydrocarbons., ethers and their mixtures. The process according to any of claims 9 to 13, characterized, in Step (bl) or (b2) respectively, the aldehyde (III) is added to the crude reaction mixture resulting from Step (a) or (a2) respectively. 15. The process according to any of claims 9 to 14, characterized in Step (a) or (a2) respectively, the ylide is prepared by the reaction of a metal hydride with a phosphonate at a temperature between -10 ° C and 50 ° C, preferably between -5 ° C and 30 ° C. 16. The process according to any of claims 9 to 15, characterized, in Step (a) or (a2) respectively, the ylide is prepared by the reaction of an alkali metal alkoxide with a phosphonate at a temperature of between 10 and 100 ° C, preferably between 20 and 70 ° C. 17. The process according to any of claims 9 to 16, characterized in Step (bl) or (b2) respectively, the reaction of the ylide with the aldehyde (III) is carried out in an aprotic solvent at a temperature between -10 ° C and 50 ° C, preferably between -5 ° C and 30 ° C. The compound of formula: (Illa) characterized in that: A represents the bivalent radical - (CH2) S-CR3CR4- (CH2) t- where one of s and t have the value of 0 and the other has the value of 1; R3, R4, R, X and p are as defined in Claim 1 for the formula (I); and only one of R'i and R'2 represents -CHO, and the other one taking one of the meanings given in Claim 1 for. and R2 / with the exception of the Z chain. "19. The compound of the formula: characterized in that: A represents the bivalent radical - (CH2) S-CR3CR4- (CH2) t- where one of s and t have the value of 0 and the other has the value of 1; R3, R4, R, X and p are as defined for (I) in Claim 1; and W0 represents the methyl or bromoethyl group. where 5-ethyl-2, 3-dihydrobenzo [b] oxepin is excluded. 20. The compound of formula: characterized in that: R'i represents a hydrogen atom, an alkyl group (of C 1 -C 5) or phenyl; R3 and R4 are independently selected from a halogen atom, an alkyl group (from C? -C? 8) or an alkenyl group (from C2-C? 8), where 2H-chromen-3-carbaldehyde and 3-methyl-2? -f-chromen-3-carbaldehyde are excluded. 21. The pharmaceutical composition, characterized in that it comprises an effective amount of at least one compound of formula (I) according to any of claims 1 to 8 in combination with at least one pharmaceutically acceptable carrier. 22. The use of a compound of formula (I) according to any of claims 1 to 8 in the preparation of a medicament that is intended to prevent or treat dyslipidemias, atherosclerosis and diabetes.