MXPA01000562A - Cyclic compounds useful in the treatment of dyslipidaemia, atherosclerosis and diabetes, pharmaceutical compositions and preparation process - Google Patents

Abstract

The present invention relates to cyclic compounds which can be used in the treatment of dyslipidaemia, atherosclerosis and diabetes, to processes for preparing these compounds. The compounds of the invention correspond to formula (I) wherein the radicals X, Y, R, R1, R2, R3, R4, R5, R6, R7 have meanings as given in claim 1.

Description

USEFUL CYCLIC COMPOUNDS FOR. THE TREATMENT OF DISLIPIDEMIA, ATHEROSCLEROSIS AND DIABETES, PHARMACEUTICAL COMPOSITIONS AND PROCESSES OF PREPARATION Description of the Invention The present invention relates to cyclic compounds that can be used in the treatment of dyslipidemia, atherosclerosis and diabetes, to pharmaceutical compositions containing them and to processes for preparing these compounds. The invention also relates to the use of these compounds for the production of medicinal products intended for the treatment of dyslipidemia, atherosclerosis and diabetes. In most countries, cardiovascular diseases remain one of the main diseases and the main cause of mortality. Approximately one third of men develop a major cardiovascular disease before the age of 60, women show a lower risk (ratio of 1 to 10). This disease becomes Ref: 125339 even more prevalent according to age (after the age of 65, women in their age become as vulnerable to cardiovascular diseases as men). Vascular diseases such as coronary heart disease, cerebrovascular accidents, restenosis and peripheral vascular diseases remain the leading cause of mortality and disability throughout the world. Although diet and lifestyle can accelerate the development of cardiovascular diseases, the genetic predisposition that leads to dyslipidemia is a significant factor in cardiovascular attacks and death. The development of atherosclerosis seems to be linked mainly to dyslipidemia, which means abnormal levels of lipoproteins in the blood plasma. This dysfunction is particularly evident in coronary heart disease, diabetes and obesity. The concept that aims to explain the development of atherosclerosis has focused mainly on the metabolism of cholesterol and the metabolism of triglycerides.

However, from the research studies done by Randle et al. (Lancet, 1963, 785-789), an original concept has been proposed: a glucose-fatty acid cycle or the Randle cycle, which describes the regulation of the balance between lipid metabolism, in terms of triglycerides and cholesterol, and the oxidation of glucose. According to this concept, the inventors have developed an original program, the objective of which is to find novel compounds that act simultaneously on the metabolism of lipids such as glucose. Fibrates are well-known therapeutic agents with a mechanism of action by means of "activated peroxisome proliferator receptors". These receptors are the main regulators of lipid metabolism in the liver (PPARa isoform). During the last ten years, thiazolidinediones have been described as powerful hypoglycemic agents in animals and man. It has been found that thiazolidinediones are selectively powerful activators of another form of PPARs: PPAR? (Lehmann et al., J. Biol. Chem., 1995, 270, 12953-12956).

The inventors have discovered a novel class of compounds that are powerful activators of the PPARa and PPAR? Isoforms. Because of this activity, these compounds have a substantial hypolipidemic and hypoglycemic effect. The compounds of the invention correspond to the following formula I: wherein X and Y represent, independently of one another, a methylene group; an oxygen or sulfur atom; or -NRa-wherein R a represents a hydrogen atom, a group of (C 1 -C 7) alkyl, (C 6 -C 0) aryl or a 3- to 10-membered heterocycle comprising from 1 to 4 selected endocyclic heteroatoms from O, S and N; this aryl group and this heterocycle are replaced in a optional with one or more Z radicals as defined below; R represents a hydrogen atom; an alkyl group (Ci-C7); an alkyl group eftalamido (C1-C7); cycloalkyl (C3-C12); a group - (CH2) P-COORb wherein p is an integer from 0 to 6 and Rb represents a hydrogen atom or a (C1-C7) alkyl group; an aryl group (C6-C? o); a 3- to 10-membered heterocycle comprising from 1 to 4 endocyclic heteroatoms which are selected from 0, S and N; an aryl group (C5-C? 0) (C1-C7) alkyl; it is understood that the aryl groups that are present in R and the heterocyclic are optionally substituted with one or more substituents that are selected from a radical Z as defined below and an alkylene chain (C 1 -C 7); Ri represents a hydrogen atom; an alkyl group (Ci-C7); hydroxyalkyl (C1-C7); an aryl group (C6-C? 0) optionally substituted with one or more radicals W as defined below; a group -P (0) (OR8) (OR9) wherein R8 and Rg are, independently, a hydrogen atom or a (C1-C7) alkyl group; a group - (CH2) t -COORc where t is an integer from 0 to 6 and Rc represents a hydrogen atom or an alkyl group (Ci- C7); a group -CONRioRn wherein Rio and Rn independently represent a hydrogen atom, a (C1-C7) alkyl group, a RdO-CO- (C1-C7) alkyl group in which Rd represents H or (C1-C7) alkyl, or alternatively Rio Y R11 together form a chain - (CH2) r- where r is an integer equal to 4, 5 or 6; R2 and R3 independently represent a hydrogen atom; a (C 1 -C 7) alkyl group; cycloalkyl (C3-C12); aryl (C6-C? o); aryl (C6-C? 0) (C1-C7) alkyl; a 3- to 10-membered heterocyclic comprising from 1 to 4 endocyclic heteroatoms selected from 0, N and S; or a fluorenyl group; these aryl groups that are present in R2 or R3, the heterocycle and the fluorenyl are optionally substituted with one or more radicals Z as defined below; or alternatively, R2 and R3 together form a chain - (CH2) r? ~ where ri is an integer equal to 2, 3, 4 or 5; or alternatively R2 and R3 together form the group wherein Ai and A2 independently represent aryl (Cedo) or a 5- to 10-membered aromatic heterocycle comprising from 1 to 4 endocyclic heteroatoms selected from N, 0 and S, this aryl group and the heterocycle optionally harbor, in addition of the substituents Ri2 and R13, one or more substituents selected from the radicals Z as defined below; and wherein Ri2 and R13 together form a chain - (CH2) m-E- (CH2) n- OR-CHR14 = CHR15 - wherein m and n are, independently, an integer from 0 to 6; E represents a bond, O, S, -NRe-, where Re represents a hydrogen atom or alkyl (Ci-C7) or alternatively E represents an alkylene (C1-C7) or arylene (C6-C? 0) chain or a 3- to 10-membered bivalent heterocyclic radical comprising from 1 to 4 endocyclic heteroatoms selected from 0, N and S; and R 14 and R 15 are, independently, selected from a hydrogen atom, (C 1 -C 7) alkyl and aryl (C 6 -C 0 0); R4 R5, R6 and R7 independently represent a hydrogen atom; (C 1 -C 7) alkyl; aryl (C6-C? o) optionally substituted with one or more radicals Z as defined below; or a 3- to 10-membered heterocycle comprising 4 endocyclic heteroatoms selected from 0, N, and S, the heterocycle is optionally substituted with one or more Z radicals as defined below; Z is selected from a halogen atom; a hydroxyl group; nitro; cyano; phenyl; phenyl alkyl (C? ~ Ci); trifluoromethoxy; (C 1 -C 7) alkyl optionally substituted with one or more halogen atoms; alkoxyl (C1-C7); alkylthiol (C? -C7); acylthiol (C2-C7); alkylsulfonyl (C1-C7); alkylsulfinyl (C 1 -C 7); carbamoyl; N-alkylcarbamoyl (C? -C7); N, N-dialkylcarbamoyl (C 1 -C 7); alkylamino (C1-C7); di (C 1 -C 7) alkylamino; a group -A-C00Rf wherein Rf represents a hydrogen atom or an alkyl group (Ci- C7) and A represents (C1-C7) alkylene, (C2-C7) alkenylene, (C1-C7) oxyalkylene wherein the alkylene chain is linked to the group COORf or alternatively A is nothing; or a group - B-P (0) (0RX) (0Ry) where B takes one of the values given for A above and Rx and Ry independently take one of the values given for Rf above; W represents -G-C00Rg wherein G represents alkylene (Ci-C7), alkenylene (C2-C7), oxyalkylene (C1-C7) wherein the alkylene chain is linked to the group C00Rg or alternatively G is nothing, and Rg represents a hydrogen atom or a (C 1 -C 7) alkyl group; or alternatively represents -D-P (0) (0RZ) (0Rt) wherein D takes one of the values given above for G and Rz and Rt independently take one of the given values given above for Rg; and pharmaceutically acceptable salts thereof, it is understood that (i) when R2, R3, R5 and R7 represent a hydrogen atom; X and Y represent an oxygen atom; R 4 represents methyl; and R6 represents a hydrogen atom or a methyl group, then Ri and R, together with the carbon atom that houses them, do not form any of the following divalent radicals: and (ii) when R4, R5 Re and R7 represent a hydrogen atom; X and Y represent O; and R represents pyridyl, piperidyl or substituted piperidyl; then Ri does not represent an optionally substituted phenyl. Formula I covers all types of geometric isomers and stereoisomers of the compounds of the formula: The physiologically acceptable salts of the compounds of the formula (I) comprise the salts that are formed with the metals and in particular with the alkali metals, alkaline earth metals and metals of transition (such as sodium, potassium, calcium, magnesium or aluminum) or with bases such as aqueous ammonia or secondary or tertiary amines (such as diethylamine, triethylamine, piperidine, piperazine or morpholino) or with alkaline amino acids (such as lysine or arginine) or with osamines (such as meglumine) or with aminoalcohols (such as 3-aminobutanol and 2-aminoethanol). According to the invention, the term "alkyl" denotes a straight or branched radical based on hydrocarbons such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl or heptyl. one or more halogen atoms, preferably represents perfluoroalkyl and in particular pentafluoroalkyl The term "alkoxy" denotes an alkyl group as defined above, linked to an oxygen atom. Examples of these are methoxy, ethoxy, isopropyloxy, butoxy and hexyloxy radicals. The term "cycloalkyl" denotes saturated groups based on hydrocarbons which may be mono- or polycyclic and comprising from 3 to 12 carbon atoms. carbon, preferably from 3 to 8. The most particularly preferred groups are monocyclic cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. The term "halogen" means a fluorine, chlorine, bromine or iodine atom The term "aryl" represents a mono- or bicyclic aromatic group based on hydrocarbons comprising from 6 to 10 carbon atoms, such as phenyl or naphthyl. The term "heterocycle" denotes a mono- or bicyclic ring of aromatic or non-aromatic nature comprising from 3 to 10 ring members, of which 1 to 4 are occupied by identical or different heteroatoms, selected from oxygen, sulfur and nitrogen , such as, for example, aziridinyl, oxiranyl, oxazolyl, furyl, tetrahydrofuryl, benzothiazolyl, pyrimidinyl, pyridazinyl, piperidinyl, quinolyl, tetrahydroquinolyl, tetrazolyl, phthalazinyl, purinyl, indolyl, chromonyl, chromanyl, isochromanyl and pyrrolyl, as radicals.

The term "heterocycle" preferably denotes thienyl, furyl or pyrrolyl The alkylene-phthalamido group (C 1 -C 7) preferably denotes the radical of the formula: When R represents aryl (C6-C? O), aryl (C? • Cι) (C 1 -C 7) alkyl or a heterocycle, the aryl group and the heterocycle can be substituted with an (C 1 -C 7) alkylene chain. In this case, the two free valences of this alkylene chain are linked to the two members of the aryl group, or the heterocycle, respectively. By designating the aryl group or the heterocycle as a C, the structure that is formed can be presented as follows: where n 'represents 1, 2, 3, 4, 5, 6 or 7. When Rx represents a group -CONRioRn where Rio and Rn together form a chain - (CH2) r -, Rio, Rn and the nitrogen atom which houses them together form a 5- to 7- membered nitrogen ring comprising a nitrogen endocyclic atom. When R2 or R3 represent fluorenyl, it is preferably the 9-fluorenyl group. When R2 and R3 together form a chain - (CH2) ri-R2 and R3 and the carbon atom that houses them, they preferably together form a cyclopropyl group. The benzyl group can be mentioned as a preferred aryl group (C6-C? 0) (C1-C7) alkyl. When R2 and R3 together form group (a) wherein Ai, A2, Ri2 and Ri3 are as defined above, Ai and A2 are based on hydrocarbons or heterocyclic rings comprising at least one ethylenic unsaturation > C = C < and they harbor at least the radical Ri2, or Ri3, respectively, in the manner of a substituent, but possibly harbor other substituents selected from the Z radicals as defined above. It is preferred that Ai and A2 represent the optionally substituted phenyl of one to four Z substituents. It is noted that the schematic representation for Ai and A2 given above means that Ax and A2 are linked to the same carbon atom (carbon 1) by medium of the simple carbon-carbon bonds (link 1-2, or 1-2 ', respectively), the carbon atom of ring i, or ring A2, respectively, involved in this bond (2, or 2 ', respectively), is of the sp type, ie it forms a double bond with an adjacent carbon atom, located at a position a (carbon 3, or 3', respectively). Substituent Ri2 is located at any position on ring Ai, and similarly, R13 is linked to ring A2 by any of the ring members of A2. However, it is preferred for R12 and R13 to substitute, respectively, the sp2 carbons at the a position, that is, the carbons of type (3 and 3 ') as represented in the above reaction scheme. According to the invention, the preferred values of group (a) are: The term 'acyl' means an alkylcarbonyl radical (C 1 -C 7) and the term 'acylthiol' means an alkylthiocarbonyl (C 1 -C 7) radical of the formula.

I rent According to the invention, the term radical 'alkenylene' also means a divalent radical based on hydrocarbons which contain one or more ethylenic double bonds, such as, for example, -CH = Ch- or or The radical 'carbamoyl' denotes the monovalent radical of the formula -CO-NH 2 The radical '(C 1 -C 7) alkylcarbamoyl denotes a carbamoyl radical substituted by a C 1 -C 7 alkyl group at the nitrogen atom, the radical' dialkylcarbamoyl '( C1-C7) "denotes a substituted carbamoyl radical on the nitrogen atom with two (C1-C7) alkyl groups The radical '(C1-C7 alkylamino)" denotes a substituted amino group on the nitrogen atom with a radical (C 1 -C 7) alkyl and the radical '(C 1 -C 7) dialkylamino "denotes a substituted amino group on the nitrogen atom with two (C 1 -C 7) alkyl radicals. [0007] US 4,056,540 discloses compounds such as 4-phenyl -1, 3-benzodioxane harboring a carboxylic function in the 2-position of the benzodioxane ring, which have anticonvulsant or antiarrhythmic activity, more recently, [4H] -1,3-benzodioxine-2-carboxylic acids and esters endowed with activity Lipid-lowering agents have been described in Eur. J. Med. Chem. Ther., 1983, 67. However, the benzodioxane structure of these compounds differs completely from the structure of the compounds of the invention. 3, No. 8, 1075-1086, 1992 describes the asymmetric synthesis of chiral ketals and in particular, the synthesis of certain compounds of the formula: wherein R0 represents -C00CH3 or -CH20H. However, this document does not refer, at all, to the pharmacological value of these compounds. In addition, J. Med. Chem., 1969, 51 describes the anti-inflammatory compounds of the 2-aryl-2-a-piperidyl-l, 3-dioxane type. Among these compounds, those corresponding to some of the following formulas are relatively close to the compounds of the invention: wherein R 'represents a hydrogen atom, a chlorine atom or a methoxyl group; R °? and R 2 represent either a hydrogen atom, an alkyl group or an aryl group; Y R 3 is a methyl or methoxy group.

However, the anti-inflammatory activity of these compounds is in no way comparable to the hypolipidemic and hypoglycemic activity of the compounds of the invention. Certain compounds are preferred among the compounds of the invention. A first group of preferred compounds consists of the compounds of the formula I as defined above, for which X and Y represent an oxygen atom. A second group of preferred compounds consists of the compounds of the formula I wherein R4, R5, R6 and R? they represent a hydrogen atom. A third group of preferred compounds consists of the compounds of formula I wherein: R represents a hydrogen atom; a (C 1 -C 7) alkyl group; an alkylphthalamido (C1-C7) group; cycloalkyl (C3-C? 2); a heterocycle as defined above for formula I; an aryl group (C6-C? o); or an aryl group (C6-C? 0) (C1-C7) alkyl; it is understood that the aryl groups that are present in R and this heterocycle are optionally substituted with one or more substituents selected from the alkylene chain (C1-C7); a halogen atom; a phenyl group and (C 1 -C 7) alkyl optionally substituted with one or more halogen atoms; (C 1 -C 7) alkoxy; or a group -A-COORf wherein A and Rf are as defined above for formula I; Ri represents a hydrogen atom; an alkyl group (Ci-C7); - (CH2) t -COORc wherein t and Rc are as defined above for formula I; R2 and R3 independently represent a hydrogen atom; an aryl (Cß-Cio) or aryl (C6-C? 0) alkyl group (Ci-C7); the aryl groups present in R2 and R3 which are optionally substituted with one or more radicals selected from the halogen atom; a (C 1 -C 7) alkyl group, optionally substituted with one or more halogen atoms; (C 1 -C 7) alkoxy; N-C 1 -C 7 alkylcarbamoyl; alkylamino (C1-C7); nitro; cyano; and -A-COORf wherein A and Rf are as defined above for formula I; or alternatively, R2 and R3 together form group (a) as defined above for formula I wherein Ai and A2 represent a phenyl group; and Ri2 and R13 together form a chain - (CH2) m-E- (CH2) n- in where m, n and E are as defined above for formula I, or a chain -CHR? 4 = CHR? 5- where Ri4 and R15 are as defined above for formula I; or alternatively R2 and R3 together form a chain - (CH2) rx- where rx is an integer equal to 2, 3, 4 or . A fourth group of the preferred compounds consists of the compounds of the formula I wherein R represents a hydrogen atom; a (C 1 -C 7) alkyl group; cycloalkyl (C3-C12); - (CH2) p-C00Rb in 'where p and Rb are as defined above for formula I; -aryl (Cß-Cio) or a heterocycle as defined above for formula I, it is understood that this aryl group and the heterocycle are optionally substituted with one or more substituents selected from the halogen atom; a (C 1 -C 7) alkyl group; alkoxy (C? ~ C7); or -A-COORf wherein A and Rf are as defined above for formula I; Ri represents a (C1-C7) alkyl or - (CH2) t -COORc group wherein t and Rc are as defined above for formula I; a group -CONRioRn wherein Ri0 and Rn are as defined above for formula I; R2 and R3 together form group (a) as defined above for formula I wherein Ai and A2 represent phenyl; and Ri2 and R13 together form a chain - (CH2) m-E- (CH2) n- where m and n represent 0, and E represents a bond. Among these compounds, those for which R represents a hydrogen atom; alkyl (C? ~ C4); - (CH2) p-COORb wherein p represents 1, 2 or 3 and Rb represents a hydrogen atom or (C1-C4) alkyl; the phenyl is optionally substituted with a radical selected from halogen, (C1-C4) alkyl, (C1-C4) alkoxy or -A-COORf wherein A represents (C1-C4) alkylene or a bond, and Rf represents H or (C1-C) alkyl; Furyl thienyl; or pyrrolyl; Ri represents an alkyl group (C? -C4); or alternatively - (CH2) t -COORc wherein t represents 0, 1, 2, 3 or 4 and Rc represents a hydrogen atom or (C1-C4) alkyl; R2 and R3 form together with the group (a) as defined above for formula I, Ai and A2 represent phenyl, and Ri2 and Ri3 together form a bond or an alkylene chain (C1-C4) which is particularly preferred. A fifth group of preferred compounds consists of the compounds of the formula I wherein R represents aryl (Ce-Cio) optionally substituted with a halogen atom; Ri represents -COORc wherein Rc is as defined above for formula I; R2 and R3 together form group (a) as defined above for formula I wherein Ai and A2 represent phenyl; and Ri2 and R3 together form a chain - (CH2) mE- (CH2) n ~ where m and n represent 0 and E represents a bond, O or S. A sixth group of preferred compounds consists of the compounds of the formula I wherein R represents aryl (Cß-Cio) optionally substituted with a halogen atom; Ri represents -COORc wherein Rc is as defined above for formula I; R2 and R3 together form group (a) as defined above for formula I wherein Ai and A2 represent phenyl; and Ri2 and R13 together form a chain -CHR? 4 = CHRi5- wherein R? 4 and R15 are as defined above for formula I. A seventh group of preferred compounds consists of the components of formula I for which one of the radicals R or Ri contains a carboxylic group which is optionally in its esterified form or in the form of an amide. Among these compounds, the most preferred are those for which R represents - (CH2) P-COORb [lacuna] and Rb are as defined above for formula I; or alternatively, R represents aryl (C6-C? o) or aryl (C6-C? 0) (C1-C7) alkyl wherein the aryl group present in R is substituted with a radical -A-COORf wherein A and Rf they are as defined above for formula I; or alternatively Ri represents - (CH2) t -COORc wherein t and Rc are as defined above for formula I; or alternatively Ri represents aryl (C6-C? 0) substituted with -G-COORg wherein G and Rg are as defined above for formula I; or alternatively Rx represents -CONR10R11 wherein Ri0 and Rn are as defined above for formula I.

Among this seventh group of preferred compounds, those which satisfy at least one of the following conditions are particularly preferred: X and Y represent an oxygen atom, - R4 to R7 represent a hydrogen atom; only one of the groups R or Ri houses a carboxyl group which is optionally esterified or is in the form of an amide, the other is as defined for the third group of the above preferred compounds; and R2 and R3 are as defined for the third group of the preferred compounds; only one of the groups R or Ri houses a carboxyl group which is optionally esterified or which is in the form of an amide, the other is as defined for the fourth group of the above preferred compounds; and R2 and R3 are as defined for the fourth group of the preferred compounds: When R harbors a carboxylic group optionally in the ester form, it preferably represents a phenyl substituted with -COOH; with -A-COORf wherein A represents alkenylene (C2-C6) and Rf represents H or (C1-C4) alkyl; or with alkoxycarbonyl (C1-C). When Ri houses a carboxylic group optionally in ester or amide form, it preferably represents - (CH2) t-COORc wherein t is 0, 1, 2, 3 or 4 and Rc is H or (C1-C4) alkyl; or alternatively -CONR10R11 wherein Ri0 and Rn are as defined above for formula I, but wherein Rio and Rn do not together form a chain - (CH2) r -. Examples of the compounds of the invention are the following: methyl 2-methyl-5,5-diphenyl [1,3] dioxane-2-carboxylate 2-methyl-5,5-diphenyl [1,3] dioxane acid 2-carboxylic; 2- (4-chlorophenyl) -5,5-diphenyl [1,3] dioxane-2-carboxylic acid ethyl ester; 2- (4-Chlorophenyl) -5,5-diphenyl [1,3] dioxan-2-carboxylic acid 2- (4-methoxyphenyl) -5,5-diphenyl [1,3] dioxan-2-carboxylate of Ethyl Acid 2- (4-methoxyphenyl) -5,5-diphenyl [1,3] dioxan-2-carboxylic acid 2- (4-methoxyphenyl) -5,5-diphenyl [1,3] dioxan-2-carboxylate from Ethyl 2- (4-methylphenyl) -5,5-diphenyl [1,3] dioxan-2-carboxylic acid , 5-diphenyl-2-thiophen-2-yl [1,3] dioxan-2-carboxylate Ethyl 5, 5-diphenyl-2-thiophen-2-yl [1,3] dioxan-3-carboxylic acid , 5-diphenyl [1,3] dioxan-2-carboxylate from Ethyl 5,5-diphenyl [1,3] dioxan-2-carboxylic acid 2,5,5-triphenyl [1,3] dioxan-2-carboxylate of Ethyl 2,5,5-triphenyl [1,3] dioxan-2-carboxylic acid 2- (4-fluorophenyl) -5,5-diphenyl [1,3] dioxan-2-carboxylate Ethyl 2- (4-Fluorophenyl) -5,5-diphenyl [1,3] dioxan-2-carboxylic acid 5,5-diphenyl-2- (5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthyl) - [1, 3] dioxan-2-carboxylate from Ethyl 2-furan-2-yl-5,5-diphenyl [1,3] dioxan-2-carboxylate Ethyl 2- (3-chlorophenyl) -5,5-diphenyl [1,3] dioxan-2-carboxylate Ethyl 2- (3-Chlorophenyl) -5,5-diphenyl [1,3] dioxan-2-carboxylic acid 2-isopropyl-5,5-diphenyl [1,3] dioxan-2-carboxylate from Ethyl 2-Phenethyl-5,5-diphenyl [1,3] dioxan-2-carboxylate from Ethyl 2-phenethyl-5,5-diphenyl [1,3] dioxan-2-carboxylic acid 2-difeni1- -i1-5, 5-diphenyl [1,3] dioxan-2-carboxylate from Ethyl 2- (3,4-dichlorophenyl) -5,5-diphenyl [1,3] dioxan-2-carboxylate from Ethyl Acid 2- (3, -dichlorophenyl) -5,5-diphenyl [1,3] dioxan 2-carboxylic acid [lacuna] 2-biphenyl-1-4-yl-5,5-diphenyl [1,3] dioxan-2-carboxylic acid 2- [2- (4-chlorophenyl) -5,5-diphenyl [1,3] dioxan-2-yl] ethyl acetate 2- [2- (4-chlorophenyl) -5,5-diphenyl [1, 3] dioxan-2-yl] acetic acid 2-cyclohexyl-5, 5-di phenyl [1, 3] dioxan-2-carboxylate Ethyl 2- (5, 5-diphenyl [1, 3] dioxan-2-yl) benzoate of Ethyl Acid 2- (5,5-diphenyl [1,3] dioxan-2-yl) benzoic acid 5,5-diphenyl -2- (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) - [1,3] dioxan-2-carboxylic acid 2-furan-2-yl-5,5-diphenyl [1,3] dioxan-2-carboxylic acid 2- (1-naphthyl) -5,5-diphenyl [1,3] dioxan-2-carboxylic acid 2 -isopropyl-5,5-diphenyl [1,3] dioxan-2-carboxylic acid [2- (4-chlorophenyl) -5,5-diphenyl [1,3] dioxan-2-yl] methanol 2-cyclohexyl-5 acid , 5-diphenyl [1,3] dioxan-2-carboxylic acid [2- (4-chlorophenyl) -5,5-diphenyl [1,3] dioxan-2-yl] -1-piperidyl ketone 2- [(2-methyl) -5,5-diphenyl [1,3] dioxan-2-yl) methyl] isoindol-1,3-dione 5- [4- (5,5-diphenyl [1,3] dioxan-2-yl) phenyl] Ethyl-3-methylpenta-2,4-dienoate 5- [4- (5,5-Diphenyl [1,3] dioxan-2-yl) phenyl] -3-methylpenta-2,4-dienoic acid 2- ( ethoxycarbonylmethylaminocarbonyl) -2- (4-chlorophenyl) -5,5-diphenyl [1,3] dioxane 2-carboxymethylaminocarbonyl-2- (4-chlorophenyl) -5,5-diphenyl [1,3] dioxane 5,5-diphenol -2- (4-trifluoromethylphenyl) - [1,3] dioxane-2-carboxylic acid ethyl 2- [4- (5,5-diphenyl [1,3] dioxan-2-yl) phenoxy] -2-methylpropionic acid 2- [4-Trifluoromethylphenyl) -5,5-diphenyl [1,3] dioxan-2-yl-carboxylic acid 2,5,5-tris (4-chlorophenyl) - [1,3] dioxan-2-carboxylate acid Ethyl 2, 5, 5-tris (4-chlorophenyl) - [1, 3] dioxan-2-carboxylic acid 2- (4-chlorophenyl) -5,5-bis (4-fluorophenyl) - [1,3] dioxan-2-carboxylate from Ethyl 2- (4-chlorophenyl) -5,5-bis (4-fluorophenyl) acid - [1,3] dioxan-2-carboxylic acid 2- (4-chlorophenyl) -5,5-bis (3-trifluoromethyl-phenyl) - [1,3] dioxan-2-carboxylate Ethyl Acid 2- (4- chlorophenyl) -5,5-bis (3-trifluoromethyl-phenyl) - [1,3] dioxan-2-carboxylic 2- (4-chlorophenyl) spiro [[1,3] dioxane-5,5'-5'H -dibenzo [a, d] cyclohepten] -2-carboxylate of Ethyl Acid 2- (4-chlorophenyl) spiro [[1,3] dioxane-5,5 '-5'H-dibenzo [a, d] cyclohepten] - 2-carboxylic acid 2- (4-chlorophenyl) spiro [[1,3] dioxane-5, 9'-xanten] -2-carboxylic acid 2- (4-chlorophenyl) spiro [1,3-dioxan-5, 9 '-xanten] -2-carboxylic acid 2- (4-chlorophenyl) -5- (9H-fluoren-9-yl) - [1,3] dioxan-2-carboxylate from Ethyl 2 '- (4-chlorophenyl) spiro [cyclobutane-1, 5' - [ 1, 3] dioxan] -2'-carboxylate of Ethyl 2 '- (4-chlorophenyl) spiro [cyclobutane-1,5' - [1,3] dioxan] -2'-carboxylic acid 5,5-dibenzyl- 2- (-chlorophenyl) - [1,3] dioxan-2-carboxylic acid 2-methylspiro [[1,3] dioxan-5, 9 '-fluoren] -2-carboxylate of Methyl 2-methylspiro acid [[1,3 ] dioxan-5, 9 '-fluoren] -2-carboxylic acid 2- (2-methylspiro [[1,3] dioxan-5, 9' -fluoren] -2-yl) ethyl acetate 2- (2-methylpyrrolidone) [[1, 3] dioxan-5, 9'-fluoren] -2-yl) -acetic 2- (2-methoxycarbonyl ethylpiro [[1,3] dioxan-5, 9 '-fluoren] -2-yl) acetate Methyl Acid 2- (2-Carboxytilespiro [[1,3] dioxan-5, 9 '-fluoren] -2-yl) acetic acid 4- (2-methylspiro [[1,3] dioxan-5, 9' -fluoren] -2-il) Methyl benzoate Spiro [[1,3] dioxan-5, 9 '-fluoren] -2-carboxylate Butyl Spiro acid [[1,3] dioxan-5, 9' -fluoren] -2-carboxylic acid 2-phenylspiro [[1,3] dioxan-5, 9 '-fluoren] -2-carboxylate from Methyl 2-phenylspiro [[1, 3] dioxan-5, 9 '-fluoren] -2-carboxylic acid 2- [4-methylphenyl] spiro [[1,3] dioxan-5, 9' -fluoren] -2- Ethyl 2- [4-methoxyphenyl] spiro [[1,3] dioxan-5, 9 '-fluoren] -2-carboxylate carboxylate Ethyl 2- [4-methoxyphenyl] spiro [[1,3] dioxan-5] , 9 '-fluoren] -2-carboxylic acid 2- [4-chlorophenyl] spiro [[1,3] dioxan-5, 9' -fluoren] -2-carboxylate of Ethyl Acid 2- [4-chlorophenyl] spiro [[ 1, 3] dioxan-5, 9 '-fluoren] -2-carboxylic acid 2- [2-thienyl] spiro [[1,3] dioxan-5, 9' -fluoren] -2-carboxylate of Ethyl Acid 2- [ 2-thienyl] spiro [[1,3] dioxan-5, 9 '-fluoren] -2-carboxylic 2- (4-chlorophenyl) -5,5-diphenyl [1,3] oxazine Among these compounds, the following are particularly preferred: 2- (4-chlorophenyl) -5,5-diphenyl [1,3] dioxane-2-carboxylate from Ethyl 2- (4-chlorophenyl) -5,5-diphenyl [1, 3] dioxane-2-carboxylic 2,5,5-tris (-chlorophenyl) - [1,3] dioxan-2-carboxylate from Ethyl 2, 5, 5-tris (4-clsphenyl) - [1 , 3] dioxan-2-carboxylic 2- (4-chlorophenyl) spiro [[1, 3] dioxan-5, 9 '-fluoren] -2-carboxylate of Ethyl 2- (-chlorophenyl) spiro [[1,3 ] dioxane-5, 9 '-fluorene] -2-carboxylic acid. The compounds of the invention and those defined in points (i) and (ii) above can be prepared by using any of the following processes. In general, the compounds of the formula I can be prepared by the reaction of a compound of the formula: wherein X, Y and R2 to R7 are as defined above for formula I, it is understood that X or Y may also represent a nitrogen atom substituted with a function which is a precursor of the radical Ra, with a ketone of the Formula III: RCO-Ri wherein R and Ri are as defined above for formula I. When, in formula I, X and Y are an oxygen atom, processes A, B, C or D can be used.

Process A: A diol of formula II I I wherein R2 to R7 are as defined for formula I, it is reacted with a carbonyl derivative of formula III: RCO-Ri wherein R and Ri are as defined above for formula I, to give a compound of the Formula I where X and Y represent an oxygen atom. The reaction that is used is a cyclization reaction. This reaction is carried out under conventional conditions, either in the presence of a specific catalyst as described in: S. Fukusawa et al., Synlett, 1995, 1077. G.C.G. Country, J. Chem. Research, 1996, 426. B.P. Bandgar, Synth. Commun., 1997, 27 (4), 627. K. Ishihara, Synlett, 1987, 839. S.B. Lee, Synthesis, 1991, 368 or in the absence of a catalyst, as described in F.A.J. Meskens, Synthesis, 1981, 501. H. Suemune et al., Chem. Pharm. Bull., 1990, 38 (11), 3155.

Typically, the reaction is carried out in an aprotic solvent that forms an azeotrope with water, such as toluene, at a temperature ranging from 50 to 150 ° C, better still from 90 to 120 ° C, in the presence of an excess of compound III. The molar ratio of compound III to diol II is preferably between 1.1 and 2, for example between 1.3 and 1.7. In order to increase production, it is recommended to react the diol with the carbonyl compound in the presence of an acid catalyst such as para-toluenesulfonic acid, while removing the water from the reaction medium. By way of example, the diol II can be reacted with the carbonyl derivative III in the presence of 0.2 equivalents of para-toluenesulfonic acid at the reflux point of toluene in a Dean-Stark apparatus for 6 to 8 hours. As a variant, the reaction can be carried out in a halogenated aliphatic hydrocarbon at a temperature ranging between 15 and 30 ° C in the presence of a Lewis acid. In this case, it is preferred that the relationship Molar of diol II for the carbonyl derivative III, range between 1.5 and 3, better still, between 1.8 and 2.2. By way of example, the diol II can be reacted with two equivalents of the derivative III in methylene chloride in the presence of one equivalent of BF3-etherate at room temperature for 12 to 48 hours.

Process B: The compounds of the formula I wherein X and Y represent an oxygen atom, can be prepared by reacting an alkali metal or an alkaline earth metal salt of a diol of the formula II wherein R to R7 are as defined for I above, with a dihalo compound of formula IV X X wherein R and Ri are as defined for I above and X represents a halogen atom. The metal salt of diol II which is used as a reactant is a salt wherein the two hydroxyl functions are salified, either with the same metal cation M + of an alkaline earth metal, or with two M + cations of an alkali metal. It is preferred to carry out this reaction starting with an alkali metal salt and in particular the sodium salt. According to a preferred embodiment of the invention, the metal salt is formed in situ in the reaction medium by the reaction of a metal hydride (and for example a sodium hydride) with the diol of the formula II. The reaction of the salt of the diol II with the compound IV is preferably carried out in a polar aprotic solvent, such as an ether, at a temperature ranging between 15 and 30 ° C, preferably with a slight excess of the metal salt of diol II.

In order to increase the productions, the process is carried out, for example, in the presence of a crown ether as taught in Eur. J. Med. Chem. Chim. Ther. 1983, 67. By way of example, 1.1 to 1.5 equivalents of diol II are reacted with compound IV wherein X represents chlorine, in anhydrous dioxane as a solvent, in the presence of sodium hydride and 18-crown-6. at room temperature (20 ° C).

Process C: The compounds of the formula I wherein X and Y represent an oxygen atom, can also be obtained by the transacetalization reaction, and more specifically by reacting the diol of the formula II. wherein R2 to R7 are as defined above for formula I, with a ketamine of formula V wherein R and Ri are as defined above for formula I and Ri6 and Ri7 independently represent alkyl (C? -C7) or jointly form an alkylene chain of the type ~ (CH2) r '~ wherein r1 is an equal integer at 4, 5 or 6. Preferably, this reaction is carried out in an aprotic solvent which forms an azeotrope with water, such as toluene, at a temperature ranging between 80 and 150 ° C, for example at a temperature of temperature between 90 and 120 ° C. In order to increase the productions, it is necessary to carry out the process in the presence of an excess of the diol of the formula II (from 1.5 to 3 equivalents, preferably from 1.8 to 2.2 equivalents) and of an acid catalyst, such as the acid para-toluenesulfonic. Ideas can be taken from document J. Am. Chem. Soc. 1958, 80, 6613.

By way of example, two equivalents of the diol II are reacted with one equivalent of the compound V in the presence of 0.2 equivalents of para-toluenesulfonic acid in toluene which is kept under reflux in a Dean-Stark apparatus for 1 to 4 hours.

Process D: The compounds of the formula I wherein X and Y represent an oxygen atom, can be synthesized from the diols of the formula II by forming intermediate silyl derivatives according to the following reaction scheme 3: Reaction Scheme 3 In this reaction scheme, R and Ri up to R7 are as defined for formula I and Ti up to T3 independently represent (C1-C4) alkyl. According to this process, the disilyl derivative XI is prepared in a conventional manner. To do this, a person skilled in the art refers, for example, to the document Tetrahedron 1994, 50, 42, 12143 and Chem. Lett. 1994, 263. The disylyl derivative XI is preferably formed in situ in the presence of a ketone III with which it reacts while it is being formed. In this case, these two reactions are preferably carried out in a polar aprotic solvent such as a halogenated aliphatic hydrocarbon. The molar ratio of the ketone III to the diol II preferably ranges from 1.1 to 2, better still between 1.3 and 1.7. The silylation process is carried out, for example, by the action of an alkoxytrialkylsilane derivative (wherein the alkyl parts are Ci-Cß). Preferably, a large excess of alkoxytrialkylsilane is reacted with the diol II in the presence of trifluoromethanesulfonate as a catalyst. The molar ratio of alkoxytrialkylsilane for the diol it is, for example, between 2 and 6, better still between 3 and 5. The temperature of the reaction medium is normally maintained between -40 and -10 ° C. As an example, an equivalent of the ketone of [sic] III can be reacted with 1.3 equivalents of diol II in anhydrous methylene chloride in the presence of 4 equivalents of isopropoxytrimethylsilane at temperatures ranging from -20 ° C in the presence of 0.01 equivalents of trimethylsilyl trifluoromethane sulfonate. Typically, the reaction time spans about 3 hours. The compounds of formulas III, IV and V are commercially available or are readily prepared from active compounds by carrying out conventional methods of organic chemistry. For the synthesis of the acetals of the formula V, a person skilled in the art can also refer to Synthesis. 1983, 203. Certain diols of the formula II are described in the literature.

The diols of the formula II can be obtained by carrying out any of the processes a), b) or c) described below.

Process a): The reaction scheme is presented below Reaction Scheme 4 VII Step 2 II VI In this reaction scheme, Ai, A2, R12 and R13 are as defined for formula I and Alk represents alkyl (C? -C6). To synthesize epoxide VII from ketone VIII, a skilled person in the art can be based on the research described in: J. Am. Chem. Soc. 1958, 80, 6398o J. Am. Chem. Soc. 1931, 53, 205. The ketone of the formula VIII can, for example, be reacted with a compound of the formula IX wherein Grp represents a residual group (such as a chlorine atom) and Alk represents alkyl (Ci-Cß) in the presence of a base such as an alkali metal hydride or an alkali metal alkoxide. Preferably, the reaction is carried out in a polar aprotic solvent, such as ether, at a temperature not exceeding 45 ° C. Since in certain cases the reaction is exothermic, the reaction medium must be cooled during the reaction. Advantageously, an excess of compound IX is used in relation to compound VIII. A molar ratio of compound IX to compound VIII which is between 1.2 and 2 is appropriate. By way of example, compound VIII is reacted with 1.5 equivalents of ethyl chloroacetate in the presence of sodium hydride or sodium ethoxide in tetrahydrofuran, the medium of reaction is maintained at a temperature below 45 ° C. The aldehyde of formula VI is obtained from epoxide VII by a conventional manner. It is possible, for example, to refer to J. Med. Chem. 1968, 11, 380. In general, the epoxide of formula VII is subjected to treatment, in step 2, with a base such as potassium hydroxide a a temperature that covers between 15 and 120 ° C. For example, when Alk represents ethyl, the epoxide VII is refluxed in the presence of KOH for 8 hours. In order to convert the aldehyde obtained from formula VI into a diol of formula II, the process is carried out as indicated in J. Med. 1969, 12, 462 and J. Am. Chem. Soc. 1949, 2031. By way of example, the diol II is obtained by treating the aldehyde VI with formaldehyde in a aqueous solution (from 1.2 to 2 equivalents of formaldehyde) in the presence of a base such as potassium carbonate (from 1 to 2 equivalents). Advantageously, the reaction temperature is between 15 and 130 ° C, preferably between 80 and 120 ° C. Ketones of formula VIII are commercially available or are readily prepared from commercial compounds.

Process b): Another way to carry out the process is illustrated in the following reaction scheme 5.

Reaction Scheme 5 Starting with ketone VIII, aldehyde VI is prepared by forming the intermediate epoxide X by carrying out a process similar to that illustrated in J. Org. Chem. 1972, 35, 25, 4075. In order to convert aldehyde VI to the diol of formula II, the process is carried out as described above for process a). Typically, aldehyde VI is reacted in ethanol, such as, for example, 0.2 mol of a 37% formaldehyde aqueous solution in the presence of a base that can be potassium carbonate (0.05 mol) under reflux for 20 hours. Advantageously, an amount of water representing about 1/5 of the ethanol is added to the medium.

Process c): According to a third variant, the diol of formula II can be obtained according to the following Reaction Scheme 6, wherein Alk represents alkyl (C? -C6) and Ai, A2, Ri2 and R13 are as defined above for formula I: Reaction Scheme 6 II The ester XI can be metalated by the action of butyllithium in tetrahydrofuran at a temperature ranging between -70 and -30 ° C. The reaction mixture is then subjected to treatment with gaseous formaldehyde at a temperature ranging from 0 to 25 ° C, which gives the α-hydroxymethyl derivative. This compound is reduced, in a conventional manner, by the action of a suitable reducing agent. The lithium aluminum hydride can be mentioned as reducing agents. In this case, the reduction is complete after a period of two hours, the reaction medium is maintained at a temperature below 10 ° C. Certain compounds of formula II are novel. According to one of its aspects, the invention relates to the diols of the formula II selected from: 2,2-bis (4-fluorophenyl) propane-1,3-diol; 2, 2-bis (3-trifluoromethylphenyl) propane-1,3-diol; 5-hydroxymethyl-5H-dibenzo [a, d] cycloheptene-5-ylmethanol; and (9-hydroxymethyl-9H-xanthene-9-yl) methanol which are novel. Esters of formula XI are commercial products or are prepared easily from commercial products. The following process E, allows the formation of the compounds of the formula I wherein X represents O and Y represents S.

Process E According to this process, a compound of formula XII wherein R2 to R7 are as defined above for formula I, reacted with the ketone of formula III. RCO-Ri III This reaction can be carried out by analogy with the processes described in the following publications, which also illustrate the preparation of the compounds for formula XII: E.L. Eliel et al., J. Am. Chem. Soc, 1962, 84, 2377 A.J. Liepa et al., Aust. J. Chem., 1986, 39, 1747 R. Caputo et al., Synthesis, 1987, 386 B. Burczyk et al., Synthesis, 1982, 831 F.E. Ziegler et al., Tretrahedron Lett., 1978, 31, 2767 A technique based on that described in Caputo et al., Synthesis, 1987, 386 is to react ketone III with compound XII in the presence of iodide. of polystyryldiphenynylophosphonium in a polar aprotic solvent such as acetonitrile, at a temperature ranging between 10 and 40 ° C, preferably at room temperature (about 20 ° C). When using anhydrous acetonitrile at 20 ° C, the reaction is complete within a period of 30 minutes to 2 hours. For the synthesis of the compounds of the formula I wherein X and Y are a group -NRa-, the following process F may be used.

Process F According to this process, diamine XIII wherein R2 to R7 are as defined for formula I and R18 and Rig independently have one of the values given for Ra in formula I or represent a precursor radical leading to any of these values, are reacted with the ketone of the formula III: RCO-Ri III The operating conditions for carrying out this reaction are easily determined by a skilled person in the art, which can carry out the process, for example, as is displayed in: PM Hardy et al., J. Chem. Soc., Perkin Trans. 1, 1977, 1954 T. Araki et al., Macromolecules, 1995, 21 (7), 1988 Carpentier et al., Tetrahedron, 1985, 41 (18), 3803 R. Gosmini et al., Synlett, 1991, 111 A Alexakis et al., Synlett, 1991, 625 M. Gray et al., Synlett, 1991, 729 T. Okawara et al., J. Chem. Soc., Chem. Commun., 1990, 20, 1385. , the reaction of XIII with III, is carried out in an aprotic solvent such as an aromatic hydrocarbon at a temperature ranging from 80 to 150 ° C, preferably from 90 to 120 ° C. The molar ratio of III to XIII can be between 1 and 5, better still between 1 and 3. In order to increase the Reaction kinetics and production, this reaction can be carried out advantageously, in the presence of an acid catalyst, such as para-toluenesulfonic acid. By way of example, an equivalent of XIII is reacted with 1 to 3 equivalents of the ketone III in refluxing toluene in the presence of 0.2 to 2.2 equivalents of para-toluenesulfonic acid in a Dean-Stark apparatus for 6 to 24 hours. When Ris or R? 9 represents a radical which is a precursor of Ra, the reaction of XIII with III is followed by a step of converting the resulting compound to the compound of formula I. The operating conditions for this conversion are easily determined by a person skilled in the technique of using his general knowledge. Compounds of type XIII can be synthesized, for example, according to the Reaction Schemes described in H .P. Kaufmann et al., Chem. Ber., 1959, 2810. For the synthesis of the compounds of the formula I wherein X represents O and Y represents -NRa-, the following G process can be carried out below.

Process G The next compound XIV, wherein R2 to R7 are as defined for I and R20 has one of the values given for Ri7 above, it is reacted with the ketone of formula III: RCO-Ri where R and Ri are as defined for formula I The compounds of the formula I wherein Ra is other than H, can be obtained from the corresponding compounds of the formula I, wherein Ra is H by the N-alkylation process. The N-alkylation can be carried out in a manner that is known per se by those skilled in the art, for example, by the action of an alkyldiode or a dialkylsulfate. The operating conditions for the reaction of compound XIV with ketone III are those which are used in the technique in a conventional manner, for this type of reactions. They can be derived from any of the following publications: Shnei-der et al., Arch. Pharm. Ber. Dtsch. Pharm. Ges., 1966, 299, 997 G. Bernath et al., Pharmazie, 1983, 38, 2, 89 E.D. Bergmann et al., J. Chem. Soc., 1963, 3736 E. Biekert et al., Chem. Ber., 1961, 1664 In general, the operating conditions prescribed in the case of process F may be adequate. By way of example, the aminoalcohol XIV can be reacted with 1 to 3 equivalents of the ketone III in toluene under reflux in the presence of 0.2 to 1. 2 equivalents of para-toluenesulfonic acid in a Dean-Stark apparatus for 4 to 10 hours. The aminoalcohols XIV can be prepared, for example, according to the reaction schemes described in C.A. Grob et al., Helv. Chem. Acta, 1972, 501. The publications mentioned above also illustrate the preparation of the aminoalcohols of the formula XIV.

The compounds of the formula I wherein X and Y represent S, can be prepared by carrying out the following H process.

Process H: According to this process, the dithiol of the formula XV where R to R7 are as defined for formula I, it is reacted with the ketone of formula III: RCO-Ri where R and Ri are as defined above for I. Preferably, the process is carried out in a polar aprotic solvent such as in an ether at a temperature ranging from 15 to 30 ° C, better still, from 18 ° C to 25 ° C, in the presence of a slight excess of ketone III.

The molar ratio of compound XV to compound III is usually between 1 and 2, preferably between 1.3 and 1.7. More generally, reference is made to I. Shahak et al., J. Chem. Soc. 1966, 1005 G.A. Olah et al., Synthesis, 1981, 282 for the implementation of this reaction. By way of example, compound XV is reacted with 1.2 equivalents of the ketone III in dioxane at 20 ° C until the reaction is complete (from 5 minutes to 2 hours are generally sufficient). The dithiols of the formula XV are prepared in a manner that is known per se and are exemplified in particular in J. Houk et al., J. Amer. Chem. Soc., 1987, 6825-6836 and E.L. Eliet et al., J. Amer. Chem. Soc, 1976, 3583-3590. The hypolipidemic and hypoglycemic activity of the compounds of the invention results due to their ability to activate the receptors type PPARa and PPAR ?. Activation of PPARa receptors has been illustrated by using rat primary hepatocytes in the case of the compound of Example 4.

More specifically, the effects of the compounds of the invention on the expression of the genes involved in lipid metabolism (Acyl CoA oxidase) or lipid transport (apo AI, apo C-III) are studied in the hepatocyte model of rat in primary cultures that are obtained according to a modification of the initial procedure of Berry and Friend (Berry M, Friend D. 1969. J. Cell. Biol. 43: 506-520) previously described (Berthou L, Saladin R, YaQoob P, Branellec D, Calder P, Fruchart JC, Denéfle P, Auwerx J, Staels B. 1995. Eur. J. Biochem .: 232, 179-187). These genes are modulated in a coordinated manner by PPAR and therefore represent good markers of PPARa activation that is expressed mainly in liver tissue (Braissant O, Foufelle F, Scotto C, Dauca M, Wahli W, 1995.

Endocrinology: 137, 354-366). Hepatocytes are isolated by a 'in situ' hepatic infusion of collagenase (Wistar rats weighing between 200 and 250 g), homogenization of the tissue, filtration through Nylon, low speed centrifugation and inoculation at a rate of 107 cells per plate (if the viability estimated by the blue analysis of Tripan exceeds 90%). The cells are stimulated from the beginning of the inoculation (compounds dissolved in DMSO) in an L15 culture medium supplemented with 10% fetal bovine serum, 0.2% (mass / volume) of bovine serum albumin (BSA), 3 g / 1 glucose and 26mM bicarbonate, 2mM glutamine and antibiotics. After inoculation for 24 hours at 37 ° C in a humid atmosphere of 5% C02 / 95% air, the cells are lysed in a solution of guanidine thiocyanate, the RNAs are extracted with phenol (pH4) and chloroform, titrated by a spectrophotometer, and it is transferred to a membrane (blot, Northern blot) and hybridized with specific molecular probes according to the procedures previously described by (Staels B, Van Tol A, Andreu T, Auwerx J, 1992. Atherioscler, Thromb. 12: 286-294). The cDNA of clone 36B4 encoding the ribosomal acid phosphoprotein PO of human (Masiakowski P, Breathnach R, Bioch J, Gannon F, Krust A, Chambon P, 1982. Nucí.Aids.Res.10: 7895-7903), whose Tissue expression is stable, it is used as a control probe. The cDNA probes are labeled with 32P by using random primers through the reagent kit sold by Boehringer Mannheim. The membranes are hybridized with 1.5x106 cpm / ml of each probe according to the procedure previously described by (Staels B, Van Tol A, Andreu T, Auwerx J; 1992. Atherioscler. Thromb. 12: 286-294). Wash once in 0.5x SSC buffer and 0. 1% SDS at room temperature for 10 minutes and twice in the same buffer at 65 ° C for 30 minutes, and then autoradiography is performed (X-OMAT-AR film, Kodak). The autoradiographies are analyzed by densitometry (Biorad GS670 densitometer). The effects of the compound of Example 4 on the expression of the hepatic gene are studied. The hepatic expression of the ACO gene increases with a treatment period of 24 hours with the compound of Example 4 (25 μM). This response is typical of the previously observed effects (Berthou L, Saladin R, YaQoob P, Branellec D, Calder P, Fruchart JC, Denéfle P, Auwerx J, Staels B. 1995. Eur. J. Biochem .: 232, 179- 187). (Staels B, Vu-Dac N, Kosykh VA, Saladin R, Fruchart JC, Dallongeville J., Auwerx "J, 1995. J. Clin.Invest.95: 705-712) when hepatocytes undergo treatment with the fibrates that are ligands and ARa activators (Devchand P, Keller H, Peters J, Vasquez M, Gonzales F, Wahli W .; 1996. Nautre; 384: 39-43).

These results suggest that the compounds of the invention act by means of PPARa. Similar results can be reproduced in two independent experiments. Expression of the mRNAs encoding the ACO genes in the -rata hepatocytes in primary cultures treated over a period of 24 hours with the compound of Example 4 (25μm). The values are expressed in relation to the base value The activation of PPAR? similarly demonstrated in the case of the compound of Example 4. Analysis of the activation of PPAR? is based on DNA transfection that allows expression for a reporter gene (CAT (chloramphenicol acetyltransferase)) under the control of PPAR in cells expressing for PPAR ?. The indicator plasmid J3TkCAT previously described by (Strips L, Auboeuf D, Raspé E, Schoonjans K, Lefebvre AM, Saladin R, Naj ib J, Laville M, Fruchart JC, Deeb S, Vidal-Puig A, Flier J, Briggs M, Staels B, Vidal H, Auwerx J, 1997. J. Biol. Chem. 272: 18779-18789) comprising three copies of the PPAR response element for the human apo A-II gene which are cloned in the 5 'direction of the promoter. for the thymidine kinase gene of herpes simplex virus in the plasmid pBLCAT4 (Staels B, Vu-Dac N, Kosykh VA, Saladin R, Fruchart JC, Dallongeville J, Auwerx J.; 1995. J. Clin. Invest. 95: 705-712). The cells that are used are the CV1 cells of African green monkey and COS cells that are transformed by the SV40 virus and that express for PPAR? (Forman B, Tontonoz P, Chen J, Brun R, Spiegelman B, Evans R, 1995. Cell 83: 803-812). These cells are inoculated to an amount of 300,000 cells per plate (plates of 5 cm in diameter) and are transfected with 500 ng of the indicator DNA according to a process previously described by (Strips L, Auboeuf D, Raspé E, Schoonjans K, Lefebvre AM , Saladin R, Najib J, Laville M, Fruchart JC, Deeb S, Vidal-Puig A, Flier J, Briggs M, Staels B, Vidal H, Auwerx J.; 1997. J. Biol. Chem. 272: 18779-18789).

After a period of 5 to 6 hours, the cells are washed twice with PBS and incubated for 36 hours in a fresh culture medium (DMEM) containing 10% fetal bovine serum. After transfection, the cells are lysed and the CAT activity is quantified according to the procedure previously described by (Fajas L, Auboeuf D, Raspé E, Schoonjans K, Lefebvre A.M., Saladin R, Najib J, Laville M, Fruchard J.C., Deeb S, Vidal-Puig A, Flier J, Briggs M, Staels B, Vidal H, Auwerx J.; 1997. J. Biol.

Chem. 272: 18779-18789). It is expressed in relation to the value of the witnesses. The effects of the compound of Example 4 are given in Figure 1. The activity of the CAT reporter gene of Cos cells that are transfected with the J3TkCAT structure is increased when these cells are incubated in the presence of the compound of Example 4. On the other hand, when the Cos cells are transfected with the plasmid pBLCAT4 which lacks the PPAR response element, the compound of Example 4 is inactive.

In Figure 1, T represents the value of the token for each indicator (TkCAT or J3TkCAT). In a final analysis, the hypolipidemic and hypoglycemic activity of the compound of Example 4 is evaluated in db / db mice. Two-month-old db / db mice are orally treated for 15 days with the compound of Example 4 (100 mg / kg / day). Each study group comprises seven animals. After three days (D3) and 15 days (D15) of treatment, retro-orbital samples are taken after a light anesthesia and without fasting. The follg quantifications are taken: evaluation of the glycemia (glucose oxidase) in D3 and D15 of the serum lipid parameters in D15 (COBAS): triglycerides, total cholesterol (CHOL), HDL cholesterol (HDL-C) and fatty acids Free (FFA) (reagent kit for the titration of BioMérieux and Wako Chemicals). The results obtained are given in the follg table. The quantifications given in this table are average values + of the standard error. *: p < 0.05 in relation to the control in the Mann-Whitney analysis.

A subject of the invention is also a pharmaceutical composition comprising an effective amount of at least one active ingredient selected from a compound of formula I as described above, and a compound of formula XVI where R and Ri together form one of the radicals: XCOOCH3 CH, C- ßKp5 C N / NCH70H R2 R3 s and R represent a hydrogen atom; X and Y represent an oxygen atom; R4 represents a methyl; and R represents a hydrogen atom or a methyl group; and a pharmaceutically acceptable salt of these compounds, in combination with at least one pharmaceutically acceptable carrier.

These compositions can be administered orally in the form of immediate release or controlled release granules, 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 is prepared for oral administration by adding a bulking agent and, where appropriate, a binding agent, a disintegrating agent, a lubricant, a dye or a flavor enhancer, in the active ingredient and by shaping the mixture into form of 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 the binding agents include polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose , acacia, gum tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin and pectin. The examples of Lubricants include magnesium stearate, talc, polyethylene glycol, silica and vegetable fat. The dye can be any of those that are authorized for use in medicinal products. Examples of flavor enhancers include cocoa powder, mint in the form of herbs, aromatic powders, peppermint in oily form, borneol and cinnamon powder. Needless to say, the tablet or the granule can be adequately coated with sugar, gelatin or the like. An injectable formula containing the compound of the present invention is prepared as an active ingredient, where appropriate, by mixing this compound with a pH regulator, a buffer, a suspending agent, a solubilizing agent, a stabilizing agent , a tonicity agent and / or a preserving agent, and by converting the mixture into a form that is for intravenous, subcutaneous or intramuscular injection, according to a conventional process. Where appropriate, the injectable form obtained can be lyophilized by conventional processes. Examples of the suspending agents include methylcellulose, polysorbate-80, hydroxyethylcellulose, acacia, powdered gum tragacanth, sodium carboxymethylcellulose and polyethoxylated sorbitan monolaurate. Examples of the solubilizing agents include solidified castor oil with polyoxyethylene, polysorbate-80, nicotinamide, polyethoxylated sorbitan monolaurate and the fatty acid ethyl ester of castor oil. In addition, the stabilizing agent includes sodium sulfite, sodium metasulfite and ether, while the preserving agent includes methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenyl [sic], cresol and chlorocresol. The invention also focuses on the use of an active ingredient selected from the compound of formula I as described above, a compound of formula XVI as defined above, and a compound of formula XVII: VTI wherein X and Y represent an oxygen atom; R4, R5, R6 and R7 represent a hydrogen atom; R represents pyridyl, piperidyl; pyridyl optionally substituted with one or more radicals selected from the radical Z as defined above for formula I and an alkylene chain (C 1 -C 7); and piperidyl optionally substituted with one or more of the radicals selected from the radical Z as defined above and an alkylene chain (C 1 -C 7); and Ri represents phenyl optionally substituted with one or more radicals W as defined above for formula I; and a pharmaceutically acceptable salt of these compounds, for the preparation of a medicinal product intended to prevent or treat dyslipidemia, atherosclerosis and diabetes. The following examples illustrate the invention in a non-limiting manner. The following abbreviations are used in the data for proton nuclear magnetic resonance (NMR): s for singlet, d for doublet, t for triplet, q for quartet, or for group of octets and m for a group of multiples. The chemical changes d are expressed in ppm; p.f. represents the melting point and e.g. represents the boiling point.

Example 1: Methyl 2-methyl-5,5-diphenyl [1,3] dioxane-2-carboxylate A mixture of 22.8 g (0.1 M) of 2,2-diphenyl-1,3-propanediol and 100 g (0.98) M) of methyl pyruvate is heated to 70 ° C in a 500 ml round bottom flask under a nitrogen atmosphere. It is added, by portions, 22.4 g (0.156 M) of P2O5. An exothermic reaction takes place and the temperature rises to 98 ° C. The mixture is allowed to return to room temperature and slowly poured into ice water. This mixture is extracted with methylene chloride and the extracts are washed with sodium hydroxide and water. The extracts are concentrated and the residue is chromatographed by flash chromatography (70 CH2Cl2 / 50 eluent of cyclohexane). Then the product turns to crystallize from 40 ml of diisopropyl ether. 7 g of a product of one m.p. 116 ° C.

Example 2: 2-Methyl-5,5-diphenyl [1,3] dioxane-2-carboxylic acid 7 g of 2-methyl-5,5-diphenyl [1,3] -dioxane-2-carboxylate are refluxed of methyl in the presence of 2.6 g of NaOH in a mixture of 120 ml of methanol and 30 ml of water. At the end of the reaction, the medium is concentrated and a solid is obtained which is dissolved in 300 ml of water. After acidification with HCl, the white solid formed is filtered. It is recrystallized from a mixture of 50 ml of cyclohexane and 50 ml of diisopropyl ether. 4.1 g of a product of one m.p. 148-150 ° C.

Example 3: Ethyl 2- (4-chlorophenyl) -5,5-diphenyl [1,3] -dioxane-2-carboxylate 42.5 g (0.2 M) of 2-oxo-2- (4-chlorophenyl) acetate are placed of ethyl in 400 ml of CH2C12 in a 500 ml reactor 22.8 g (0.1 M) of 2,2-diphenylpropane-1,3-diol and then 14.2 g (0.1 M) of BF3-Et20 are added. The mixture is allowed to react under stirring for 72 hours at room temperature. The reaction mixture is then lowered into a solution of NaHCO 3. The organic phase is washed with a saturated solution of NaCl. After drying over Na 2 SO 4 and concentrating, a very thick oil is obtained. 150 ml of isopropyl ether are added and a white precipitate is formed. After filtration, 30 g of a product is obtained which is melted at 156-158 ° C (production: 71%). - < i0 - Example 42: Ethyl 5- [4- (5,5-diphenyl [1,3] dioxane-2-yl) -phenyl] -3-methylpenta-2-dienoate The following products are placed in a 250 ml reactor. provided with a Dean-Stark apparatus: 70 ml of toluene, 3.5 g (0.011 M) of ethyl 5- (4-diethoxymethyl) -3-methylpenta-2,4-dienoate, 5.0 g (0.011 M) of 2.2 -diphenylpropanediol and finally 0.5 g of para-toluenesulfonic acid.

The mixture is refluxed for one hour while the first distilled fractions are removed. After cooling to room temperature, the reaction medium is washed with a 5% NaHC03 solution. The organic phase is separated after the settling has taken place and is dried over Na2SO4. After concentrating until dry, a thick oil is obtained.

The product is purified by flash chromatography with a mixture of cyclohexane / ethyl acetate as eluent. This gives 3.5 g of the product in the form of a foam that is recrystallized from the diisopropyl ether to give 2.3 g of the product that melts at 115-117 ° C.

Example 52: ethyl 3,3 '-bis (4-fluorophenyl) oxirane-2-carboxylate 23.6 ml (0.220 M) of ethyl chloroacetate and 30 g (0.137 M) of 4,' -difluorobenzophenone are introduced into 80 ml of tetrahydrofuran in a 500 ml round bottom flask under a nitrogen atmosphere. It is added by portions, a total of 8.8 g of 60% sodium hydride to this medium every 30 minutes. At the end of the addition, an exothermic reaction takes place, during which the reaction is maintained at 40-45 ° C by an ice bath. After being left overnight at room temperature, the medium is hydrolyzed by the addition of dilute hydrochloric acid and then extracted with ether. After concentration, 62 g of an orange oil are obtained, the product of which is purified by means of a flash chromatography (70 cyclohexane / 30 CH2C12 as eluent). In this way, 34.7 g of a product that is slowly crystallized are obtained, and this product is finally ground from 40 ml of pentane. Another flash chromatography (95 cyclohexanes / 5 diisopropyl ether as eluent) provides 27.5 g of pure ester. NMR (CDC13): 0.88 (3H, t, J = 7.1 Hz); 3.81 (ÍH, s); 3.83 to 3.93 (2H,); 6.85 to 6.95 (4H, m); 7.11 to 7.16 (2H, m); 7.25 to 7.30 (2H, m). 2-bis (4-Fluorophenyl) ethanal 27.5 g of ethyl 3,3'-bis (4-fluorophenyl) -oxirane-2-carboxylate in 210 ml of ethanol are refluxed in the presence of 55 ml of KOH (at 20% in water) in a 500 ml round bottom flask. The reaction medium is concentrated and the residue is reduced to 600 ml of water. An insoluble material is removed by filtration and the filtrate is acidified with hydrochloric acid and extracted with ether. The oil obtained after the concentration is subjected to treatment (oil bath) at 150 ° C for one hour. 17.5 g of 2-bis (4-fluorophenyl) ethanal are obtained in this way. NMR (CDC13): 4.88 to 4.89 (ÍH, m); 7.04 to 7.20 (8H, m); 9.89 to 9.90 (ÍH, m). 2, 2'-bis (4-Fluorophenyl) -1,3-propanediol A mixture of 17.5 g of 2-bis (4-flurophenyl) -ethanol, 16.1 ml (0.153 M) in formaldehyde is refluxed for 7 hours at room temperature. 37%, 7.6 g of potassium carbonate, 18 ml of water and 70 ml of ethanol in a 250 ml round bottom flask. After the concentration of the medium, the residue is reduced to 200 ml of water and extracted with methylene chloride, which is concentrated. 21.1 g of an oil are obtained and this product is purified by flash chromatography (eluent: 98 methylene chloride / 2 methanol). In this way, 17.8 g of 2, 2 '(4-fluorophenyl) -1,3-propanediol [sic] (m.p. 74 ° C). NMR (CDC13): 2.16 to 2.18 (2H, m, exchangeable with D20); 4. 11 to 4.21 (4H, m); 6.91 to 7.18 (8H,). 2- (4-chloropheni) -5,5-bis (4-fluorophenyl) - [1,3] dioxane-2-ethyl carboxylate (Example 51) 1.7 g of para-toluenesulfonic acid are refluxed in 120 ml of toluene for 30 minutes in a 250 ml round bottom flask fitted with a Dean-Stark apparatus. 8 g (0.0302 M) of 2,2'-bis (4-fluorophenyl) -1,3-propane-diol and 7 g (0.0332 M) of ethyl (4-chlorophenyl) -oxoacetate are added and the mixture is placed under reflux for 8 hours. The reaction medium is cooled, diluted with 200 ml of ethyl ether, washed with normal sodium hydroxide and then separated after the settling has taken place, dried and concentrated. The residue is washed with isoctane and then returns to crystallize from isopropyl ether. A white solid of a p.f.150 ° C is obtained in this way. 2- (4-Chlorophenyl) -5,5-bis (4-fluorophenyl) - [1,3] dioxane-2-carboxylic acid (Example 52) 2.8 g of 2- (4-chlorophenyl) -5 are refluxed , 5-bis (4-fluorophenyl) - [1, 3] dioxane-2-carboxylate for 7 hours in 60 ml of methanol and 15 ml of water containing 0.7 g of NaOH. After concentrating, the residue is diluted with water and stirred until a solution is obtained. This solution is washed with ether and the aqueous phase is acidified with HCl. The solid that forms is filtered and washed with water and pentane. The product is recrystallized from 100 ml of toluene, (mp = 228-30 ° C, weight obtained: 1.9 g).

Example 54: Ethyl 3,3'-bis (3-trifluoromethylphenyl) -oxirane-2-carboxylate. Into portions, 5.9 g of 60% sodium hydride are introduced in 3 portions every 30 minutes in a 500 ml.

Round bottom under a nitrogen atmosphere containing 16.2 ml (0.15 M) of ethyl chloroacetate, 29.9 g (0.0938 M) of 3,3'-bis (trifluoromethyl) benzophenone and 80 ml of tetrahydrofuran at 40 ° C. The mixture is kept under stirring for another 2 hours at 40 ° C and then overnight at room temperature. The medium is hydrolyzed with 50 ml of HCl and then extracted with ether. The extracts are washed with water, dried and concentrated. The oil obtained is purified by means of a flash chromatography (Eluent: 95 cyclohexane / 5 isopropyl ether). 31 g of ethyl ester are obtained. NMR (CDC13): 0.89 to 0.93 (3H, m); 3.90 to 3.98 (3H, m); 7.38 to 7.66 (8H, m). 2- bis (3-trifluoromethylphenyl) ethanal A mixture of 31 g of ethyl 3'-3'-bis (3-trifluoromethylphenyl) oxirane-2-carboxylate and 56.7 ml of a 20% aqueous solution is refluxed for 8 hours. of KOH in 210 ml of ethanol. The reaction medium is concentrated and the residue is lowered into water and washed with ether. The aqueous phase is acidified and extracted with ether. The residue is heated in an oil bath at 150 ° C for an hour. The product in its natural state is purified by means of a flash chromatography (Eluent: 70 CH 2 Cl 2/30 heptane) to give 15.5 g of 2-bis (3-trifluoromethylphenyl) ethanal. NMR (CDC13): 4.86 to 4.89 (ÍH, m); 7.06 to 7.88 (8H, m) / 9. 77 to 9.78 (ÍH, m). 2- bis (3-trifluoromethylphenyl) -1,3-propanediol A mixture of 12.2 g of 2- bis (3-trifluoromethylphenyl) ethanal, 7.7 ml of 37% aldehyde, 3. 5 g of potassium carbonate, 8.8 ml of water and 35 ml of ethanol are refluxed in a 500 ml round bottom flask for 6 hours. The reaction medium is concentrated and the residue is diluted with water and extracted with ether. After concentrating, the residue is purified by means of a flash chromatography (Eluent: 98 CH2Cl2 / 2 MeOH). After trituration of 20 ml of pentane, 5 g of 2-bis (3-trifluoromethylphenyl) -1,3-propanediol (p.f. = 70 ° C) are obtained. NMR (CDCl 3): 2.35 (2H,, exchangeable with D20); 4.26 (4H, m); 7.18 to 7.48 (8H, m). 2- (4-chlorophenyl) -5,5-bis (3-trifluoromethylphenyl) - [1,3] dioxane-2-carboxylate * (Example 53) 1.2 g of para-toluenesulfonic acid in 90 ml of toluene are refluxed in a 250 ml round bottom flask fitted with a Dean-Stark apparatus. 4.9 g of Ethyl (4-chlorophenyl) oxoacetate and 7.1 g of 2-bis (3- trifluoromethylphenyl) -1,3-propanediol. The reflux continues for 8 hours. The reaction medium is cooled, diluted with 150 ml of diethyl ether, washed with IN sodium hydroxide and dried. The residue obtained is purified by means of a flash chromatography (Eluent: 95 CH2Cl2 / 5 heptane). 2.8 g of the product are obtained (p.f. 110 ° C.). 2- (4-Chlorophenyl) -5,5-bis (3-trifluoromethylphenyl) - [1,3] dioxane-2-carboxylic acid (Example 54) 2.8 g of the above ester are refluxed for 5 hours in 60 ml of methanol, 15 ml of water and 0.6 g of NaOH The reaction medium is concentrated and the residue is diluted in 100 ml of water.After washing with ether, the aqueous phase is acidified with hydrochloric acid. ether, the extracts are concentrate and the product is recrystallized from toluene. 1.4 g of a product of one m.p. = 197-199 ° C.

Example 55: Diethyl 2- (9H-fluoren-9-yl) malonate 16.3 g (0.051 M) of ethyl malonate are introduced into 300 ml of toluene in a 500 ml reactor under a nitrogen atmosphere. 4.6 g (0.056 M) of 60% NaH in oil at room temperature is added in portions. The temperature rises to 32 ° C. Then the reaction medium is maintained at 80 ° C for 15 minutes. A white color is formed. A solution of 25 g (0.051 M) of 9-bromofluorene in 60 ml of toluene is added at this temperature. The mixture is kept so that it reacts for 8 hours at 80 ° C. 100 ml of ice water are added at a temperature below 20 ° C. The organic phase is separated after the settling has taken place and washed with water. Dry over Na2SO4 and concentrate until dry. An oil (31 g) is obtained which crystallizes.

The recrystallization is carried out in 160 ml of diisopropyl ether to give 23.7 g of a product that is melted at 71 ° C (70% yield). NMR CDC13): 1.0 (3H, t, J = 7.1 Hz); 3.9 (ÍH, d, J = 5.5 Hz); 4.0 (2H, q, J = 7.1 Hz); 4.6 (1H, d, J = 5.5 Hz); 7.1-7.3 (4H, m); 7.5 (2H, d, J = 7.4 Hz); 7.7 (2H, d, J = 7.4 Hz). 2- (9H-Fluoren-9-yl) propane-1,3-diol 200 ml of anesthetic ether and then 4.5 g of (0.118 M) of LiAlH4 are placed in a 500 ml reactor under a nitrogen atmosphere. A solution of 9.6 g (0.0296 M) of diethyl 2- (9H-fluororen-9-yl) malonate in 100 ml of anesthetic ether is added at a temperature below 20 ° C. The mixture is kept so that it reacts for 2 hours at room temperature and then refluxed for 2 hours. The reaction medium is cooled to 0 ° C [lacuna] and then cautiously added 100 ml of water. This mixture is acidified with dilute H2SO4 and extracted with ethyl acetate. The extracts are washed with water and then concentrated until dry, after drying over sodium sulfate. An oil is obtained which is recrystallized from 130 ml of isopropyl ether. 6.3 g of a white solid are obtained which is melted at 101 ° C (88% yield). NMR (CDC13): 2.2"2H, s, interchangeable with D20), 2.9 (HH, m), 3.8-4.0 (4H, m), 4.3 (HH, d, J = 2.7 Hz), 7.4-7.6 (4H, m), 7.7 (2H, d, J = 7.4 Hz), 7.9 (2H, d, J = 7.4 Hz). 2- (4-chlorophenyl) -5- (9H-fluoren-9-yl) - [1,3] dioxane-2-carboxylate. (Example 55) The product is obtained by reacting the above diol with ethyl 2- (4-chlorophenyl) -2-oxoacetate according to the method already described, when refluxing with toluene in the presence of para-toluenesulfonic acid.

Example 77: Ethyl 9-hydroxymethyl-9H-xanthene-9-carboxylate A mixture of 1.5 g (5.9 mmol) of ethyl 9H-xanthene-9-carboxylate in 20 ml of THF and 1.6 ml is cooled to -50 ° C. of DMPU under an inert atmosphere. 4 ml (6.4 mmol) of BuLi (1.6M in hexane) are added dropwise to this medium by stirring, and then the medium is maintained with stirring for 10 minutes at -40 ° C. After allowing the reaction medium to warm to 10 ° C, a flow of formaldehyde generated is added by bubbling. from 5.4 g (0.18 mol) of sublimed paraformaldehyde entrained by a stream of nitrogen. After being stirred for a period of 2 hours at room temperature, the suspension is dispersed in 50 ml. of water. The reaction medium is then extracted twice with 100 ml. of ether. The combined organic phases are dried over Na2S04. After evaporation, the residual oil is chromatographed on silica. Eluent: CH2C12 is obtained. 1.1 g of a yellow oil (production: 68%). NMR (CDC13): 1.07 (3H, t, J = 7.1 Hz); 2.38 (ÍH, t, J = 7.4 Hz); 3.9 (2H, d, J = 7.5 Hz); 4.1 (2H, q, J = 7.1 Hz); 6.9-7.26 (8H, m). (9-Hydroxymethyl-9H-xanthen-9-yl) methanol 1.10 g (3.8 mmol) of the ester prepared above are added dropwise in 10 ml of THF to a mixture of 0.18 g (4.7 mmol) of LiAlH4 dispersed in 30 ml of THF and cooled by a cardanic ice bath. After being stirred for 2 hours at room temperature, 20 ml are cautiously added. of water to the reaction medium. Then, this mixture is extracted twice with 100 ml. of EtOAc. The combined organic phases are dried over Na2SO4. After evaporating to dryness, 0.7 g of a yellow oil is obtained (yield: 75%).

NMR (CDC13): 1-36 (2H, m); 3.83 (4H, d, J = 6.0 Hz); 6.95 (2H, t, J = 7.9 Hz); 6.96 (2H, d, J = 7.9 Hz); 7.11 (2H, t, J = 7.9 Hz); 7.32 (2H, d, J = 7.9 Hz). 2- (4-chlorophenyl) spiro [1,3-dioxane-5, 9'-xanthene] -2- ethyl carboxylate (Example 77) 0.3 ml are added dropwise. of BF3-OEt2 to a mixture of 1 g (4.7 mmol) of ethyl para-chlorophenyloxoacetate and 0.7 g of the diol prepared above in 20 ml. of CH2C12, and stirred at room temperature. After being stirred for 2 hours at room temperature, the reaction medium is washed twice with 20 ml of saturated NaHCO 3. The organic phase is dried over Na 2 SO 4 and then evaporated. The residual oil is chromatographed on a silica column and eluted with a mixture of EtOAc / cyclohexane (1: 9). 0.4 g of white crystals are obtained and this product is recrystallized from acetone. 0.32 g of white crystals are collected (yield: 25%). p.f. = 131-132 ° C.

Example 78: 2- (Chlorophenyl) spiro [1,3-dioxane-5, 9'-xanthene] -2-carboxylic acid A mixture of 0.09 g (0.2 mmol) of the ester prepared in example 77, example [ sic], 0.5 g (9 mmol) of KOH, 20 ml of ethanol and 10 ml of water are stirred under reflux for 3 hours. After cooling, the reaction medium is acidified with a concentrated HCl solution to pH = 5 and extracted with ethyl acetate. The combined organic phases are dried over Na 2 SO and then evaporated. The residual oil is crystallized from a suitable solvent. 0.06 g of a white solid are isolated (yield = 64%). p.f. = 244-246 ° C.

Example 79: (5-Hydroxymethyl-5H-dibenzo [a, d] cycloheptene-5-yl) methanol A mixture of 11 g (0.05 mol) of 5H-dibenzo [a, d] cycloheptene-5-carboxaldehyde (which is prepared according to the method of L. SALISBURY, J. Org. Chem., 1972, 37, 4075), 66 ml of ethanol, 16.2 ml. (0.2 mol) of an aqueous solution of 37% formaldehyde, 11 ml of water and 6.6 g (0.05 mol) of K2C03 are refluxed for 20 hours. The reaction medium is then poured into 1 liter of water by stirring and the mixture is extracted with CH2C12. The combined organic phases are dried over Na 2 SO 4 and evaporated. The residual mass is triturated from 60 ml of absolute ethanol and dispersed as a light brown solid, which is filtered and dried. 5 g of the product are obtained (production 40%). p.f. = 162-163 ° C. NMR (DMSO d6): 3.9-5 (4H, m); 7 (2H, s); 7.2-7.5 (8H,). 2- (4-chlorophenyl) spiro [1,3-dioxane-5,5'-5'H-dibenzo [a, d] cycloheptene] -2-carboxylic acid ethyl ester (Example 79) A mixture of 2.9 g (15 mmol) ) of para-toluenesulfonic acid monohydrate and 50 ml of toluene in a reactor equipped with a Dean-Stark apparatus are refluxed until the water has been completely removed. Then add 12.6 g (0.05 mol) of the diol prepared above and 16 g (75 mmol) para-chlorophene loxoacetate ethyl. The mixture is refluxed for 8 hours.

After cooling, the reaction medium is washed with 300 ml of a saturated aqueous solution of NaHCO 3 and then with 300 ml. of water. The organic phase is dried over Na 2 SO 4 and then evaporated. The residual oil is chromatographed on a silica column and eluted with a 5/95 EtOAc / cyclohexane mixture. The product is then washed with isopropyl ether and dried. 3 g of a white solid are obtained (yield: 14%). p.f. = 206-208 ° C. Example 80: 2- (4-Chlorophenyl) spiro [1,3-dioxane-5 * 5 '-5' H -dibenzo [a, d] cycloheptenoj -2-carboxylic acid A mixture of 0.6 g (8 mmol) of hydroxide potassium, 17 ml. of water, 70 ml. of ethanol and 1.8 g (4 mmol) of the ester prepared according to example 12 are refluxed for 5 hours. Then the solvent evaporates. The resulting gum is dissolved in 50 ml of water and this aqueous phase is washed with ether and then acidified. The aqueous phase is extracted with CH2C12. The combined organic phases are dried over Na 2 SO < j and then evaporate. The residue is recrystallized from a suitable solvent. HE they obtain 1.1 g of a white solid (production: 65%). p.f. > 260 ° C.

Example 81: 2- (4-Chlorophenyl) -5,5-diphenyl [1,3] oxazine This product is obtained by reacting 3-amino-2, 2-diphenyl-1-propanol with 4-chlorobenzaldehyde in refluxing toluene in the presence of p-toluenesulfonic acid for 5 hours. The usual preparation allows the product to be obtained: p.f. = 169-170 ° C NMR (CDC13): 1.72 (1H, exchangeable with D20); 3.69 to 4.25 (3H, m); 4.9 to 4.96 (ÍH, m); 5.31 (ÍH, s); 7.19 to 7.6 (14H, m).

It is noted that in relation to this date, the best known method for the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (14)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A compound of the formula I: characterized in that; X and Y represent, independently of one another, a methylene group; an oxygen or sulfur atom; or -NRa-wherein R a represents a hydrogen atom, a (C 1 -C 7) alkyl, an aryl group (C 6 -C 0) or a 3- to 10-membered heterocycle comprising from 1 to 4 selected endocyclic heteroatoms from 0, S and N; the aryl group and the heterocycle optionally are substituted with one or more radicals Z as defined below; R represents a hydrogen atom; an alkyl group (Ci- C7); an alkylphthalamido (C1-C7) group; cycloalkyl (C3-Ci2); a group - (CH2) p-COORb wherein p is an integer from 0 to 6 and Rb represents a hydrogen atom or a (C1-C7) alkyl group; an aryl group (Cedo); a 3- to 10-membered heterocycle comprising from 1 to 4 endocyclic heteroatoms selected from O, S and N; an aryl (Cß-Cio) alkyl group (C 1 -C 7); it is understood that the aryl groups present in R and the heterocycle, are optionally substituted with one or more substituents selected from a radical Z as defined below, and from an alkylene chain (C 1 -C 7); Ri represents a hydrogen atom; an alkyl group (Cj.Ci); hydroxyalkyl (C1-C7); an aryl group (C6-Ci0) optionally substituted with one or more radicals W as defined below; a group -P (0) (OR8) (OR9) wherein Re and Rg are, independently, a hydrogen atom or a (C1-C7) alkyl group; a group - (CH2) t -COORc wherein t is an integer from 0 to 6 and Rc represents a hydrogen atom or an alkyl group (Ci-C7); a group -CONR10R11 where Rio and Ru independently represent a hydrogen atom, a (C1-C7) alkyl group, a RdO-CO- (C1-C7) alkyl group in which Rd represents H or (C1-C7) alkyl, or alternatively Rio and R11 together form a chain - (CH2) r - where r is an integer equal to 4, 5 or 6; R2 and R3 independently represent a hydrogen atom; a (C 1 -C 7) alkyl group; cycloalkyl (C3 ~ C? 2); aryl (Ce-Cio); aryl (Cß-Cio) (C 1 -C 7) alkyl; a 3- to 10-membered heterocycle comprising from 1 to 4 endocyclic heteroatoms selected from 0, N and S; or a fluorenyl group; the aryl groups represent in R2 or R3, the heterocycle and the fluorenyl optionally substituted with one or more radicals Z as defined below; or alternatively, R2 and R3 together form a chain - (CH2) r? - where r1 is an integer equal to 2, 3, 4 or 5; or alternatively R2 and R3 together form group (a) wherein i and A2 independently represent aryl (Cedo) or a 5- to 10-membered aromatic heterocycle comprising from 1 to 4 endocyclic heteroatoms selected from N, O and S, the aryl group and the heterocycle optionally harbor, in addition to the substituents Ri2 and R3, one or more different substituents selected from the radicals Z as defined below; and where R 2 and R 13 together form a chain where m and n are, independently, an integer from 0 to 6; E represents a bond, O, S, -NRe-, wherein Re represents a hydrogen atom or (C 1 -C 7) alkyl or alternatively E represents an alkylene chain (Ci-C 7) or arylene (C 6 -C 7) or a 3- to 10-membered divalent heterocyclic radical comprising from 1 to 4 endocyclic heteroatoms selected from 0, N and S; and Ri4 and Ris are independently selected from a hydrogen atom, (C1-C7) alkyl and aryl (d-Cio); R4 R5, R6 and R7 independently represent a hydrogen atom; (C 1 -C 7) alkyl; aryl (C6-C? 0) optionally substituted with one or more radicals Z as defined below; or a 3- to 10-membered heterocycle comprising from 1 to 4 endocyclic heteroatoms selected from 0, N, and S, the heterocycle is optionally substituted with one or more Z radicals as defined below; Z is selected from a halogen atom; a hydroxyl group; nitro; cyano; phenyl; phenylalkyl (Ci-C7); trifluoromethoxy; (C 1 -C 7) alkyl optionally substituted with one or more halogen atoms; alkoxy (Ci-C7); alkylthiol (C1-C7); acylthiol (C2-C7); alkylsufonyl (d ~ C7); alkylsufinyl (C1-C7); carbamoyl; N-C 1 -C 7 alkylcarbamoyl; N, N-dialkylcarbamoyl (C 1 -C 7); (C 1 -C 7) alkyl-amino; dialkylamino (C1-C7); a group -A-COORf wherein Rf represents a hydrogen atom or a (C1-C7) alkyl group and A represents alkylene (d-d), alkenylene (C; -C7), oxyalkylene (C1-C7) wherein the alkylene chain is linked to the group COORf or alternatively A is nothing; or a group -B-P (0) (0RX) (0Ry) where B, takes one of the values given for A above and Rx and Ry independently take one of the values given for Rf above; W represents -G-C00Rg wherein G represents alkylene (Ci-d), alkenylene (C2-C7), oxyalkylene (d ~ d) wherein the alkylene chain is linked to the group C00Rg or alternatively G is nothing, and Rg represents a hydrogen atom or a (C1-C7) alkyl group; or alternatively W represents -D-P (0) (0RZ) (0Rt) where D takes one of the values given above for G and Rz and Rt independently take one of the values given above for Rq; and pharmaceutically acceptable salts thereof, it is understood that (i) when R2, R3, Rs and R7 represent a hydrogen atom; X and Y represent an oxygen atom; R 4 represents methyl; and R6 represents a hydrogen atom or a methyl group, then Rx and R, together with the carbon that houses them, do not form any of the following divalent radicals: CH, ßH5: C H ^ CßH3 C and% COOCH-, / "CH2-OH / coc / CH, 0H and (ii) when R4, R5, R6 and R7 represent a hydrogen atom; X and Y represent 0; and R represents pyridyl, piperidyl or substituted piperidyl; then Ri does not represent the optionally substituted phenyl, with the proviso that at least one of the radicals R or Ri contains a carboxyl group optionally in its esterified form or in the form of an amide.

2. A compound of the formula I according to claim 1, characterized in that X and Y represent an oxygen atom.

3. A compound of the formula I according to claims 1 and 2, characterized in that R 4 R 5, R 6 and R 7 represent a hydrogen atom.

4. A compound of the formula I according to any one of Claims 1 to 3, characterized in that: R represents a hydrogen atom; an alkyl group (Ci-d); an alkylphthalamido group (Ci-d); cycloalkyl (C3-C3.2); a heterocycle as defined in accordance with Claim 1; an aryl group (d-Cio); or an aryl (Ce-Cio) alkyl group (C1-C7); it is understood that the aryl groups present in R and the heterocycle are optionally substituted with one or more substituents selected from an (C 1 -C 7) alkylene chain; a halogen atom; a phenyl group; (C 1 -C 7) alkyl optionally substituted with one or more halogen atoms; alkoxy (Ci-d); or a group -A-COORf wherein A and Rf are as defined in accordance with Reinvindication 1; Ri represents a hydrogen atom; an alkyl group (Ci-d); - (CH2) t-COORc wherein t and Rc are as defined according to Claim 1; R2 and R3 independently represent a hydrogen atom; an aryl group (C6-C? 0); or aryl (Cß-C10) (C 1 -C 7) alkyl; the aryl groups present in R2 and R3 are optionally substituted with one or more radicals selected from a halogen atom; a (C 1 -C 7) alkyl group optionally substituted with one or more halogen atoms; (C 1 -C 7) alkoxy; N-alkyl (Ci- C7) carbamoyl; alkylamino (C1-C7); nitro; cyano; and -A-COORf wherein A and Rf are as defined in accordance with Claim 1; or alternatively R2 and R3 together form group (a) as defined in accordance with Claim 1 characterized in that Ai and A2 represent a phenyl group; and R12 and R13 together form a chain - (CH2) m-E- (CH2) n- wherein m, n and E are as defined in accordance with Claim 1, or a chain wherein R 4 and R 15 are as defined in accordance with Claim 1; or alternatively R2 and R3 together form a chain - (CH2) rX- where rx is an integer equal to 2, 3, 4 or 5.

5. The compound of the formula I according to any of claims 1 to 4, characterized in that: R represents a hydrogen atom; an alkyl group (Ci-d); cycloalkyl (C3-C12); - (CH2) p-COORb wherein p and Rb are as defined according to Claim 1; aryl (C6-C? 0) or a heterocycle as defined according to Claim 1; it is understood that the aryl group and the heterocycle are optionally substituted with one or more substitutes selected from a halogen atom; an alkyl group (Ci-d); alkoxy (d_d); or -A-COORf wherein A and Rf are as defined in accordance with Claim 1; Ri represents an alkyl group (C? -C7) or a group - (CH2) t-COORc wherein t and Rc are as defined in Claim 1; a group -CONR? 0Rn wherein Rio and Rn are as defined in accordance with Claim 1; R2 and R3 together form group (a) as defined in accordance with Claim 1 wherein Ai and A2 represent phenyl; and Ri2 and Ri3 together form a chain - (CH2) m-E- (CH2) n- where m and n represent 0, and E represents a bond.

6. The compound of formula I according to any one of Claims 1 to 4, characterized in that R represents aryl (C6-C? o) optionally substituted with a halogen atom; Ri represents -COORc wherein Rc is as defined in accordance with Claim 1; R2 and R3 together form group (a) as defined in accordance with Claim 1 wherein Ai and A2 represent phenyl; and R 2 and R 13 together form a chain - (CH 2) m-E- (CH 2) n- where m and n represent 0, and E represents a bond, O or S.

7. The compound of the formula I according to any of claims 1, 2, 3 or 4, characterized in that; R represents aryl (C6-C? O) optionally substituted with a halogen atom; Ri represents -COORc wherein Rc is as defined in accordance with Claim 1; R2 and R3 together form group (a) as defined in accordance with Claim 1 wherein Ai and A2 represent phenyl; and Ri2 and Ri3 together form a chain -CHR? 4 = CHR? 5 wherein Ri4 and Ri5 are as defined according to Claim 1.

8. The compound of the formula I according to claim 1, characterized in that it is selected from ethyl 2- (4-chlorophenyl) -5,5-diphenyl [1,3] -dioxane-2-carboxylate, 2- (4 -chlorophenyl) -5,5-diphenyl- [1,3] dioxane-2-carboxylic acid, 2,5,5-tris (4-chlorophenyl) - [1,3] dioxane-2-carboxylic acid ethyl ester, acid 2, 5, 5-tris (4-chlorophenyl) - [1,3] dioxane-2-carboxylic acid, 2- (4-chlorophenyl) spiro [[1,3] dioxane-5,9 '-fluorene] -2-carboxylate ethyl, 2- (4-chlorophenyl) spiro [[1,3] dioxane-5, 9'-fluoro] -2-carboxylic acid.

9. The process for preparing a compound of the formula I according to claim 1, characterized in that it comprises the reaction of a compound of the formula: wherein X, Y and R2 to R7 are as defined in accordance with Claim 1, it is understood that X or And they may also represent a nitrogen atom substituted with a function which is a precursor of Ra with a carbonyl derivative of formula III wherein R and Rl are as defined in accordance with Claim 1.

10. The process for preparing a compound of the formula I according to claim 1, characterized in that X and Y represent an oxygen atom, comprising the reaction of an alkali metal or an alkaline earth metal salt of a diol of the formula II. wherein R2 to R7 are as defined according to Claim 1, with a dihalo compound of the formula IV X X wherein R and Ri are as defined in Claim 1 and X represents a halogen atom.

11. A diol selected from 2,2-bis (4-fluorephenyl) propane-1,3-diol; 2, 2-bis (3-trifluoromethyl phenyl) propane-1,3-diol; 5-hydroxymethyl-5H-dibenzo [a, d] cycloheptene-5-ylmethanol; and (9-hydroxymethyl-9H-xanthene-9-yl) methanol.

12. A pharmaceutical composition comprising an effective amount of at least one active ingredient selected from the compound of formula I according to claim 1 and a compound of formula I as defined in (i) according to claim 1 , characterized in that it is found in combination with at least one pharmaceutically acceptable carrier.

13. A composition in accordance with Claim 12, characterized in that it is in the form of an immediate-release tablet, a controlled-release tablet, a gelatin capsule, an injectable solution or a cream.

14. The use of an active ingredient selected from the compound of formula I according to claim 1, and a compound of formula I as defined in (i) or (ii), according to claim 1, characterized because it is for the preparation of a medicinal product that is intended to be used to prevent or treat dyslipidemia, atherosclerosis and diabetes.