WO2004037829A1 - Novel benzoxazole or oxazolopyridine compounds, method for preparing same and pharmaceutical compositions containing same - Google Patents

Abstract

The invention concerns compounds of formula (I), wherein: A represents a phenyl or pyridine; X and Y represent an oxygen or sulphur atom; R<1> and R<2> represent a COOR<5> group; R<3> and R<4> are such as defined in the description. The invention is useful for preparing medicines.

Description

 NOVEL BENZOXAZOLIC OR OXAZOLOPYRIDINE COMPOUNDS,

THEIR PREPARATION PROCESS

AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The present invention relates to new benzoxazole or oxazolopyridine derivatives, their preparation process and the pharmaceutical compositions containing them.

The compounds described in the present invention are new and exhibit modulating properties of human receptors activated by peroxisomes, in particular the delta subtype (hPPARδ). Three receptors activated by peroxisomes have been isolated and called PPARα, PPARγ and PPARδ (also known as NUC1 or PPARβ). These PPAR (s) are nuclear transcription factors which regulate, by their binding to response elements present in the promoter of the target genes (PPRE: Element of Response to PPAR), the expression of these genes. These PPREs have mainly been identified on genes which code for proteins which regulate lipid and carbohydrate metabolism, suggesting a pivotal role for PPAR (s) in the adipogenic signal cascade and lipid homeostasis (Trends Endo. Met., 1993, 4, 291-296). The deregulation of these metabolisms has been implicated in the appearance and development of many pathologies. It is considered to be a risk factor often associated with cardiovascular disease, including hypertension, increases in fibrinogen levels, elevated triglyceride levels, LDL cholesterol, total cholesterol and low HDL cholesterol levels.

Syndrome X (including metabolic syndrome) is also defined as a series of abnormalities including hyperinsulinemia, obesity, high levels of triglycerides, uric acid, fibrinogen, dense LDL particles, activator of plasminogen and low HDLc levels (Curr. Pharm. Des., 1998, 4, 53-70).

The treatment of type II non-insulin-dependent diabetes remains unsatisfactory despite the marketing of many oral hypoglycemic derivatives intended to facilitate the secretion of insulin and to promote its action in peripheral target tissues. This pathology describes insulin resistance, manifested in particular by poor uptake of glucose in the skeletal muscle and low hepatic glucose production (New Engl. Med., 19, 321, 1231-1245).

Certain compounds belonging to the fibrate class can lower the triglyceride level and improve the clearance of NLDL (very low density lipoproteins) and reduce the level of small very atherogenic LDL particles. Experimental results indicate that the effects of fibrates on plasma lipids are mediated by PPARα (Curr. Pharm. Des., 1997, l, 1-14). The activation of PPARα results from the transcription of enzymes which increase the catabolism of fatty acids and decrease the endogenous synthesis of fatty acids in the liver leading to a decrease in the synthesis of triglycerides and the production / secretion of NLDL (Atherosclerosis , 1996, 124, S29-S37).

Certain compounds that activate or interact with more than one PPAR subtype (s) have been implicated in the regulation of triglyceride and cholesterol levels in animal models (WO97 / 28149).

The development of new less toxic and long-term active therapeutic agents is absolutely necessary in these pathologies.

In addition, hyperlipidemia is often observed in diabetics (Diabetes Care, 1995, 18 (supplement 1), 86/8/93). The association of hyperglycemia with hyperlipidemia promotes the risk of cardiovascular disease in diabetics. Hyperglycemia, hyperlipidemia and obesity have become pathologies of the modern world marked by a large amount of food and a chronic lack of exercise. The increase in the frequency of these pathologies calls for the development of new therapeutic agents active in these diseases: compounds having excellent hypoglycaemic and lipid-lowering activity while avoiding the side effects observed with tbiazolidinediones are therefore very useful in the treatment and / or the prophylaxis of these pathologies and particularly indicated in the treatment of type II non-insulin-dependent diabetes to reduce peripheral insulin resistance and normalize glucose control. The compounds of the present invention, in addition to their novelty, are excellent ligands for receptors activated by peroxisomes and meet these pharmacological criteria.

The present invention relates more particularly to the compounds of formula (I)

dans laquelle :

in which :

- A represents an unsubstituted or substituted phenyl, or an unsubstituted or substituted pyridine,

- X represents an oxygen or sulfur atom,

- Y represents an oxygen or sulfur atom,

R and R, identical or different, each represent a COOR group in which R ⁵ represents a hydrogen atom or an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl group,

R ³ and R ⁴ each represent a hydrogen atom or together form when they are on two adjacent carbon atoms a fused mono or polycyclic group,

Being heard that :

* "alkyl" means a linear or branched (Ci-C ₆ ) alkyl group,

* "alkenyl" means a linear or branched (C ₂ -C ₆ ) alkenyl group,

* "alkynyl" means a linear or branched (C ₂ -C ₆ ) alkynyl group,

* “substituted phenyl” and “substituted pyridine” means a phenyl or pyridine group substituted by 1 to 3 groups chosen from alkyl, alkoxy, hydroxy, COOR (where R represents a hydrogen atom or an alkyl group), formyl , amino, alkylamino, dialkylamino, trihaloalkyl, or halogen atoms,

* "fused mono or polycyclic group" means any mono or polycyclic group containing 5 to 10 links, which may contain one or more unsaturations and which may contain from 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, the mono or polycyclic fused group thus defined can be substituted by 1 to 3 groups chosen from alkyl, alkoxy, hydroxy, COOR (where R represents a hydrogen atom or an alkyl group), formyl, amino, alkylamino, dialkylamino, CONRR ' (where R and R ', identical or different, represent a hydrogen atom or an alkyl group), NRCOR' (where R and R ', identical or different, represent a hydrogen atom or an alkyl group), trihaloalkyl, spiro-alkylenedioxy, or halogen atoms,

Being heard that :

d'hydrogène ou un groupement alkyle,A cannot represent a group in which R represents an atom

hydrogen or an alkyl group,

their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base.

Among the pharmaceutically acceptable acids, non-limiting mention may be made of hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methane acids. sulfonic, camphoric, etc.

Among the pharmaceutically acceptable bases, non-limiting mention may be made of sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.

The preferred compounds of the invention are the compounds of formula (I) for which X represents an oxygen atom.

Y advantageously represents an oxygen atom.

Preferably, A represents an unsubstituted phenyl or an unsubstituted pyridine. 1 9 •

The preferred R and R groups according to the invention are the COOH and COOR 'groups where R' represents an alkyl group and more particularly a methyl group.

R ³ and R ⁴ preferably represent a hydrogen atom or form together with the two carbon atoms which carry them a cyclic structure such that it forms with the

phenyl nucleus which carries it a group

dibenzo [b, d] fur ane * ώûo> or benzo [g] -l, 4-dioxaspiro [4.5] decane

Even more preferably, the invention relates to dimethyl 4- (2-oxo- [1,3] oxazolo [4,5-b] pyridm-3 (2H) -yl) -1,2-oxanthrenedicarboxylate, and spiro [1,3-dioxolan-2: 7'-dimethyl-4 '- (2'-oxo-1,3'-benzoxazol-3' (2Η) -yl) -5 ', 6', 7 ', 8' -tetrahydro-l ', 2'- naphthalenedicarboxylate].

The enantiomers, diastereoisomers and addition salts with a pharmaceutically acceptable acid or base of the preferred compounds of the invention form an integral part of the invention.

The present invention also relates to the process for preparing the compounds of formula (I) characterized in that a compound of formula (II) is used as starting material:

dans laquelle A et X sont tels que définis dans la formule (I) dont on protège la fonction aminé pour conduire au composé de formule (III) :

dans laquelle A et X sont tels que définis précédemment et P_G représente un groupement tert-butyloxycarbonyle ou phénoxycarbonyle, composé de formule (III) que l'on traite avec du diisopropylamidure de lithium suivi de chlorophosphate de diphényle pour obtenir le composé de formule (IV) :

in which A and X are as defined in formula (I), the amino function of which is protected to yield the compound of formula (III):

in which A and X are as defined above and P _G represents a tert-butyloxycarbonyl or phenoxycarbonyl group, compound of formula (III) which is treated with lithium diisopropylamide followed by diphenyl chlorophosphate to obtain the compound of formula ( IV):

dans laquelle A, X et P_G sont définis comme précédemment, sur lequel on fait agir : * soit en présence de Pd(PPh₃)₄ un composé de formule (V) :

in which A, X and P _G are defined as above, on which one acts: * either in the presence of Pd (PPh ₃ ) ₄ a compound of formula (V):

dans laquelle R³ et R⁴ sont tels que définis dans la formule (I), * soit en présence de PdCl (PPh₃)₂ un composé de formule (VI) :

in which R ³ and R ⁴ are as defined in formula (I), * either in the presence of PdCl (PPh ₃ ) ₂ a compound of formula (VI):

dans laquelle R³ et R sont tels que définis précédemment, pour obtenir le composé de formule (VII) :

in which R ³ and R are as defined above, to obtain the compound of formula (VII):

1 9 in which A, X, R, R and P _G are defined as above, compound of formula (Nil) which is subjected to the action of the compound of formula (NUI): R'OOC- -COOR'- (VIII) in which R ' ⁵ and R " ⁵ can take the same values as R ⁵ with the exception of the hydrogen atom, to lead to the compound of formula (17a), special case of the compounds of formula (I):

dans laquelle A, X, R³ et R⁴ sont tels que définis précédemment et R'¹ et R'² représentent un groupement COOR'⁵ et COOR"⁵ respectivement tels que défini précédemment, composé de formule (Va) que l'on peut soumettre à une saponification complète ou partielle pour conduire au composé de formule (I/b), cas particulier des composés de formule (I) :

in which A, X, R ³ and R ⁴ are as defined above and R ' ¹ and R' ² represent a group COOR ' ⁵ and COOR " ⁵ respectively as defined above, composed of formula (Va) which is may submit to a complete or partial saponification to lead to the compound of formula (I / b), special case of the compounds of formula (I):

dans laquelle A, X, R², R³ et R⁴ sont tels que définis précédemment et R'¹ représente un groupement COOR'⁵ tel que défini précédemment, composés de formule (I/a) et (I/b) qui peuvent être soumis à l'action d'un agent de thionation comme le réactif de Lawesson pour conduire au composé de formule (l/c), cas particulier des composés de formule (I) :

dans laquelle A, X, R¹, R², R³ et R⁴ sont tels que définis précédemment,

in which A, X, R ² , R ³ and R ⁴ are as defined above and R ' ¹ represents a group COOR' ⁵ as defined above, compounds of formula (I / a) and (I / b) which can be subjected to the action of a thionating agent such as the Lawesson reagent to yield the compound of formula (l / c), special case of the compounds of formula (I):

in which A, X, R ¹ , R ² , R ³ and R ⁴ are as defined above,

the compounds of formula (Va), (I / b) and (Vc) forming all of the compounds of the invention which can be purified according to a conventional separation technique, which is transformed, if desired, into their addition salts with a pharmaceutically acceptable acid or base and the isomers of which are optionally separated according to a conventional separation technique.

The compounds of the present invention also have very advantageous pharmacological properties. They show in particular an excellent in vivo activity on the reduction of the level of triglycerides, LDLc and fibrinogen.

These properties justify their therapeutic application in the treatment and / or prophylaxis of hyperglycaemia, dyshpidemia and more particularly in the treatment of non-insulin-dependent type II diabetes, glucose intolerance, disorders linked to syndrome X (including hypertension, obesity, insulin resistance, atherosclerosis, hyperlipidemia), coronary artery disease and other cardiovascular diseases (including high blood pressure, heart failure, venous insufficiency ), kidney disease (including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis), retinopathies, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome, dementia, diabetic complications and osteoporosis.

They can be used as paldose reductase inhibitors, to improve cognitive functions in dementia and complications of diabetes, inflammatory bowel disease, myotonic dystrophies, pancreatitis, arteriosclerosis, xanthoma. The activity of these compounds is also recommended for the treatment and / or prophylaxis of other diseases including type I diabetes, hypertriglyceridemia, syndrome X, insulin resistance, dyshpidemia in diabetics, hyperlipidemia , high cholesterol, high blood pressure, heart failure, cardiovascular disease including atherosclerosis.

In addition, these compounds are indicated for use in the regulation of appetite, in particular in the regulation of food intake in subjects suffering from disorders such as obesity, anorexia, bulimia and nervous anorexia . Thus, these compounds can be used in prevention or for the treatment of hypercholesterolemia, obesity with beneficial effects on hyperlipidemia, hyperglycemia, osteoporosis, glucose intolerance, resistance to insulin or diseases in which insulin resistance is a secondary pathophysiological mechanism. The use of these compounds makes it possible to reduce total cholesterol, body weight, resistance to leptin, plasma glucose, triglycerides, LDL, VLDL as well as plasma free fatty acids. They can be used in combination with HMG CoA reductase inhibitors, fibrates, nicotinic acid, cholestyramine, colestipol or probucol, and can be administered together or at different times to act synergistically in the treated patient. .

They also exhibit activity in cancer pathologies and in particular hormone-dependent cancers such as breast cancer and colon cancer, as well as an inhibitory effect on the angiogenesis processes involved in these pathologies.

Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those which are suitable for oral, parenteral, nasal, per or transcutaneous, rectal, perlingual, ocular or respiratory administration and in particular simple or coated tablets, sublingual tablets, sachets, packages, capsules, lollipops, tablets, suppositories, creams, ointments, dermal gels, and oral or injectable ampoules. The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or possibly associated treatments and ranges from 0.1 mg to 1 g per 24 hours. in 1 or more takes.

The following examples illustrate the invention and do not limit it in any way. The following preparations lead to synthesis intermediates useful in the preparation of the invention.

Preparation 1: 3 - [(DiphenoxyphosphoryI) oxyl-4H-pyrido [3,2-i l [l, 4] oxazîιιe-4- phenyl carboxylate

Stage A: 3-Oxo-2,3-dihvdro-4H-pyrido f 3,2-61 [1, 41 phenazine oxazine-4-carboxylate

Under an anhydrous atmosphere, a solution of 10 mmol of 2H-pyrido [3,2-b] [1,4] oxazine-

3 (4H) -one in 50 ml of THF is cooled to -78 ° C. At this temperature, 6.9 ml (11 mmol) of a 1.6M solution of n-butyllithium are added dropwise. After 30 minutes of contact time at -78 ° C, 1.38 ml (1 mmol) of phenyl chloroformate are added dropwise and stirring is continued for an additional 2 hours. After returning to room temperature, the solution is hydrolyzed and then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered, evaporated and purified by chromatography on silica gel (petroleum ether / ethyl acetate: 8/2) to yield the title product in the form of a white solid. Melting point: 97 ° C

Stage B: 3-r (Diphenoxyphosphoryl) oxyl-4H-pyrido [3,2-> Ul, phenylphenoxox-4-carboxylate

Under an anhydrous atmosphere, 6 ml (12 mmol) of 2M lithium diisopropylamide (in a heptane / THF solution) are added dropwise to a solution of 10 mmol of the compound obtained in stage A in 50 ml of anhydrous THF at -78 ° C. After 2 hours of contact time, 2.5 ml (12 mmol) of diphenyl chlorophosphate are added dropwise and stirring is continued for an additional 2 hours at -78 ° C. After returning to room temperature, the solution is hydrolyzed and then extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated to yield the title product after chromatography on silica gel.

Preparation 2: 3 - [(Diphenoxyphosphoryl) oxy] -4H-1,4-benzoxazine-4-phenyl carboxylate Stage A: 3-Oxo-2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate phenyl

The procedure is carried out as in stage A of Preparation 1, starting with 2H-1,4-benzoxazin-3 (4H) -one. The title product is obtained by chromatography on silica gel (petroleum ether / ethyl acetate: 6/4) to yield the title product in the form of a colorless oil.

Mass spectrum: m / z = 271 (M + l)

Stage B: phenyl 3 - [(Diphenoxyphosphoryl) oxyl-4H-1,4-benzoxazine-4-carboxylate

The procedure is carried out as in stage B of Preparation 1 starting from the compound obtained in stage A.

The title product is obtained by chromatography on silica gel (petroleum ether / ethyl acetate: 6/4) to yield the title product in the form of a colorless oil.

Mass spectrum: m / z = 502 (M + l)

Example 1: Dimethyl 4- (2-Oxo [1,3oxazolo [4,5-ô] pyridin-3 (2H) -yI) -1,2-oxanthrene-diearboxylate

Stage A: phenyl 3- (1,4-Benzodioxin-2-yl) -4H-pyridoF3,2-6iri., 41oxazine-4-carboxylate

Under an inert atmosphere, a mixture of 1 equivalent of the compound obtained in the Preparation 1, 2 equivalents of 2- (trimethylstannyl) benzodioxine, 3 equivalents of lithium chloride and 5% tetrakis (triphenylphosphine) palladium (0) in 5 ml of THF is heated to reflux. After cooling and concentration, the residue is taken up in ethyl acetate, washed with a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by chromatography on silica gel (eluent: petroleum ether / ethyl acetate: 6/4) to yield the title product in the form of a white solid. Melting point: 142 ° C

Stage B: 4- (2-Oxofl, 31oxazolo [4,5- £ 1pyridin-3 (2H -yl) -1-2-oxanthrenedicarboxylate

In a closed system, 1 equivalent of the compound obtained in stage A and 3 equivalents of dimethyl acetylene dicarboxylate are stirred for 15 hours at 70 ° C. The reaction mixture is taken up in dichloromethane to which a few drops of triethylamine are added. The solution is stirred at room temperature until the cycloadduit disappears (TLC monitoring). The product is purified by chromatography on silica gel

(eluent: petroleum ether / ethyl acetate: 4/6) in the form of an orange solid.

Melting point: gum around 100 ° C Mass spectrum: m / z = 435 (M + l)

Example 2: 4- (2 ~ Oxo ~ l * 3 ~ benzoxazol-3 (2H) -yl) dimethyl phthalate

Stage A: phenyl 3-VinvI-4H-1,4,4-benzoxazine-4-carboxylate

The procedure is carried out as in stage A of Example 1 starting from the compound obtained in Preparation 2 and replacing 2- (trimethylstannyl) benzodioxine with tributyl (vinyl) stannane. The title compound is obtained after purification by chromatography on silica gel (petroleum ether / ethyl acetate: 6/4) in the form of a yellow solid. Melting point: 70-72 ° C

Stage B: 4- (2-Oxo-1,3-benzoxazol-3 (2H) -yl) dimethyl phthalate

The procedure is carried out as in stage B of Example 1 starting from the compound obtained in stage A (reaction time: 3 hours at 95 ° C.). The title compound is obtained after purification by chromatography on silica gel (petroleum ether / ethyl acetate: 6/4) in the form of a white solid.

Melting point: 85 ° C

Example 3: 4- (2-Oxo [1,3] oxazolo [4,5-6] pyridra-3 (2i?) - yl) dibenzo [ô, </ Ifuran-l _s 2- dimethyl diearboxylate

Stage A: 3- (1-Benzofuran-2-yl) -4H-pyridof3,2-i? L ri * -41oxazine-4-carboxylate

Under an inert atmosphere, a 1M solution of an equivalent of the compound obtained in Preparation 1 and 5% of tetrakis (triphenylphosphine) palladium (0) in DME is stirred for 10 minutes at room temperature. 1.5 equivalents of l-benzofuran-2-ylboronic acid, a few drops of ethanol and 2 equivalents of an aqueous solution of sodium carbonate

2M are added to the reaction mixture. This is brought to reflux for 30 minutes. After cooling and hydrolysis, the solution is extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by chromatography on silica gel (eluent: petroleum ether / ethyl acetate: 2/8) to yield the title product in the form of a white solid.

Melting point: 143 ° C

Stage B: 4- (2-Oxo [l, 31oxazolol4,5-61pyridin-3 (2H) -yl dibenzor6, </ lfuran-l, 2- dimethyl dicarboxylate The procedure is carried out as in stage B of Example 1 starting from the compound obtained in stage A (reaction time: 5 hours at 95 ° C.). The title compound is obtained after purification by chromatography on silica gel (petroleum ether / ethyl acetate: 6/4) in the form of an orange solid.

Melting point: rubber around 70 ° C Mass spectrum: m / z = 419 (M + l)

Example 4: Dimethyl 4- (2-Oxo-1,3-benzoxazol-3 (2H) -yl) -1,2-oxanthrenedicarboxylate

Stage A: 3- (1,4-Benzodioxin-2-yl) -4H-1,4-benzoxazine-4-carboxyPhenylate

The procedure is as in stage A of Example 1 starting from the compound obtained in the

Preparation 2. The title compound is obtained after purification by chromatography on silica gel (petroleum ether / ethyl acetate: 6/4) in the form of a white solid.

Melting point: rubber around 75 ° C Mass spectrum: m / z = 386 (M + l)

Stage B: 4- (2-Oxo-1,3-benzoxazol-3 (2H -yI) -1,2-dimethyl-oxanthrenedicarboxylate

The procedure is carried out as in stage B of Example 1 starting from the compound obtained in stage A (reaction time: 2 hours at 95 ° C.). The title compound is obtained after purification by chromatography on silica gel (petroleum ether / ethyl acetate: 4/6) in the form of a white solid.

Melting point: 173 ° C

Exam ^p 5: Spiro [l, 3-dioxolan-2, 7'-dimethyl-4 '- ^{_{(2'-oxo-3'J-benzoxazol-3}} (2H) -yl) - 5', 6 ' , 7 *, 8'-tetrahydro-l ', 2 * -naphtalènedicarboxylate] Stage A: 1,4-Dioxaspiro [4.51dec-7-en-8-yl trifluoromethanesulfonate

Under an anhydrous atmosphere, a solution of 3.2 ml (6.4 mmol) of LDA 2M in a THF / heptane mixture is diluted in 8 ml of THF. The temperature is lowered to -78 ° C, then 1 g (6.4 mmol) of 1,4-dioxaspiro [4.5] decan-8-one dissolved in 8 ml of THF are added slowly. The reaction medium is stirred for 2 hours at this temperature and 3.42 g (9.6 mmol) of N-phenyltrifluoromethanesulfonimide in solution in 8 ml of THF are added. After stirring for 15 minutes at -78 ° C, return to room temperature overnight and concentration, the title triflate is purified directly on neutral alumina gel (eluent: petroleum ether / ethyl acetate: 95/5) and recovered as a colorless oil.

Stage B: 8- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-ylVl., 4-dioxaspiror4.51dec-7- ene

Under an inert atmosphere, 618 mg (2.14 mmol) of the compound obtained in stage A, 611 mg (2.36 mmol) of bis (pinacolato) diborane, 631 mg (6.43 mmol) of potassium acetate and 75 mg (0.11 mmol) of bis (triphenylphosphine) palladium (II) chloride are mixed in 13 ml of 1,4-dioxane and then heated at 80 ° C for 4 hours. After cooling, the residue is taken up in ethyl acetate, washed with a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated. The residue is purified by chromatography on silica gel (eluent: petroleum ether / ethyl acetate: 9/1) in the form of white crystals.

Melting point: 58 ° C

Stage C: phenyl 3- (1,4-Dioxaspiro [4.51dec-7-en-8-yl) -4H-1,4-benzoxazine-4-carboxylate

The procedure is carried out as in stage A of Example 3 starting from the compound obtained in Preparation 2 and from the compound obtained in stage B. The title compound is obtained after purification by chromatography on silica gel (petroleum ether / acetate ethyl: 6/4) in the form of a colorless oil. Mass spectrum: m / z = 392 (M + l)

Stage D; Spirori, 3-dioxolan-2: 7 ^, -dimethyl-4 '- (2 ^, -oxo-l, 3'-benzoxazol-3' (2H, -ylV 5 '., 6% 7' *, 8'-tetrahvdro -l ', 2'-naphtalènedicarboxylatel

The procedure is carried out as in Stage B of Example 1 starting from the compound obtained in Stage C (reaction time: 3 hours at 95 ° C.). The title compound is obtained after purification by chromatography on silica gel (petroleum ether / ethyl acetate: 4/6) in the form of a white solid.

Melting point: rubber around 80 ° C Mass spectrum: m / z = 440 (M + l)

Example 6: 4- (2-Oxo [1,3] oxazolo [4,5-ô] pyrîdin-3 (2H) -yl) dimethyl phthalate

Stage A: Phenyl 3-Ninyl-4H-pyrido [3,2-Mfl-, 41oxazine-4-carboxylate

The procedure is carried out as in Stage A of Example 1, replacing 2- (trimethylstannyl) benzodioxin with tributyl (vinyl) stannane. The title compound is obtained after purification by chromatography on silica gel (petroleum ether / ethyl acetate: 6/4) in the form of a light brown solid.

Melting point: 120 ° C

Stage B: 4- (2-Oxori, 31oxazolor4,5-61pyridin-3 (2H) -yr) dimethyl phthalate

The procedure is carried out as in Stage B of Example 1 starting from the compound obtained in Stage A (reaction time: 2 hours at 70 ° C.). The title compound is purified by chromatography on silica gel (petroleum ether / ethyl acetate: 4/6) in the form of a white solid.

Melting point: 77 ° C PHARMACOLOGICAL STUDY

Example A; Acute toxicity study

Acute toxicity was assessed after oral administration in groups of 8 mice (26 + 2 g). The animals were observed at regular intervals during the first day and daily for two weeks after treatment. The LD ₅₀ , resulting in the death of 50% of the animals, was evaluated and showed the low toxicity of the compounds of the invention.

Example B; Cell transaetivation tests

The compounds are tested for potential functionality on Cos cells transiently transfected with human PPAR subtypes (J. Biol. Chem., 1995, 270, 12953-

12956). The binding domains for ligands (LBD) of human PPARα, PPARγ or PPARδ are fused with a DNA binding domain originating from the transcription factor of the yeast GALA The response element to GAL4, UAS is coupled to the gene luciferase reporter. Rosiglitazone, WY14,643 and L 165,041 are used respectively as positive controls on PPARγ, PPARα or PPARδ.

The compounds of the present invention are selective for PPARδ and PPARα receptors (EC ₅₀ <1000 nM) with at least 30% transaetivation for agonists and an IC ₅₀ <1 μM for antagonists. By way of example, the compound of Example 1 has an EC ₅₀ of 821 nM on the PPARα receptor and an EC ₅₀ of 34 nM on the PPARδ receptor and the compound of Example 5 has an EC ₅₀ of 13 nM on the PPARα receptor.

Example C: Pharmaceutical composition

1000 tablets containing 5 mg of 4- (2-oxo [1,3] oxazolo [4,5-b] pyridin-3 (2H) -yl) -1,2-dimethyl oxanthrenedicarboxylate (Example 1) 5 g

Wheat starch 20 g Corn starch 20 g Lactose 30 g

Magnesium stearate 2 g

Silica 1 g

Hydroxypropylcellulose 2 g

Claims

RENENDICATIONS 1- Compounds of formula (I)

in which : - A represents an unsubstituted or substituted phenyl, or an unsubstituted or substituted pyridine, - X represents an oxygen or sulfur atom, - Y represents an oxygen or sulfur atom, - R ¹ and R ² , identical or different, each represent a COOR ⁵ group in which R ⁵ represents a hydrogen atom or an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkylalkyl group, R ³ and R ⁴ each represent a hydrogen atom or together form when they are on two adjacent carbon atoms a fused mono or polycyclic group, it being understood that: * "alkyl" means a linear or branched (C C-s) alkyl group, * "alkenyl" means a linear or branched (C ₂ -C ₆ ) alkenyl group, * "alkynyl" means a linear or branched (C ₂ -C ₆ ) alkynyl group, * “substituted phenyl” and “substituted pyridine” means a phenyl or pyridine group substituted by 1 to 3 groups chosen from alkyl, alkoxy, hydroxy, COOR (where R represents a hydrogen atom or an alkyl group), formyl , amino, alkylamino, dialkylamino, trihaloalkyl, or halogen atoms, * by "fused mono or polycyclic group" is meant any mono or polycyclic group containing 5 to 10 links, which may contain one or more unsaturations and may contain from 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, the fused mono or polycyclic group thus defined can be substituted by 1 to 3 groups chosen from alkyl, alkoxy, hydroxy, COOR (where R represents a hydrogen atom or an alkyl group), formyl, amino, alkylamino, dialkylamino, CONRR '(where R and R', identical or different, represent a hydrogen atom or an alkyl group), NRCOR '(where R and R', identical or different, represent a hydrogen atom or an alkyl group), trihaloalkyl, spiro-alkylenedioxy, or halogen atoms, Being heard that : A cannot represent a group in which R represents an atom

hydrogen or an alkyl group, their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base. 2- Compounds of formula (I) according to claim 1 for which X represents an oxygen atom, their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base. 3- Compounds of formula (I) according to claim 1 for which Y represents an oxygen atom, their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base. 4- Compounds of formula (I) according to claim 1 for which A represents an unsubstituted phenyl, their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base. 5- Compounds of formula (I) according to claim 1 for which A represents an unsubstituted pyridine, their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base. 6- Compounds of formula (I) according to claim 1 for which R ¹ represents a COOH group, their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base. 7- Compounds of formula (I) according to claim 1 for which R ¹ represents a group COOR 'in which R' represents an alkyl group, their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base . 8- Compounds of formula (I) according to claim 1 for which R represents a COOH group, their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base. 9- Compounds of formula (I) according to claim 1 for which R ² represents a group COOR 'in which R' represents an alkyl group, their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base . 10- Compounds of formula (I) according to claim 1 for which R ¹ and R ² , identical or different, represent a group COOR 'in which R' represents an alkyl group, their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base. 11- Compounds of formula (I) according to claim 1 for which R and R, identical or different, represent a COOMe group, their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base. 12- Compounds of formula (I) according to claim 1 for which R ³ and R ⁴ represent a hydrogen atom, their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base. 13- Compounds of formula (I) according to claim 1 for which R ³ and R ⁴ form together, with the two carbon atoms which carry them a cyclic structure such that it forms with the phenyl nucleus which carries it an oxanthrene group

their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base. 14- Compounds of formula (I) according to claim 1 for which R ³ and R ⁴ form together, with the two carbon atoms which carry them a cyclic structure such that it forms with the phenyl nucleus which carries it a dibenzo group [ b, d] furan

their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base. 15- Compounds of formula (I) according to claim 1 for which R ³ and R ⁴ form together, with the two carbon atoms which carry them a cyclic structure such that it forms with the phenyl nucleus which carries it a benzo group [ g] -l, 4- dioxaspiro [4.5] decane

their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base. 16- Compound of formula (I) according to claim 1 which is 4- (2-oxo- [1,3] oxazolo [4,5- b] pyridin-3 (2H) -yl) -1,2-oxanthrenedicarboxylate dimethyl, as well as its addition salts with a pharmaceutically acceptable acid or base. 17- Process for preparing the compounds of formula (I) according to claim 1 characterized in that a compound of formula (II) is used as the starting material

in which A and X are as defined in formula (I), the amino function of which is protected to yield the compound of formula (III):

in which A and X are as defined above and PQ represents a tert-butyloxycarbonyl or phenoxycarbonyl group, compound of formula (III) which is treated with lithium dusopropylamide followed by diphenyl chlorophosphate to obtain the compound of formula (TV ):

in which A, X and P _G are defined as above, on which we act * or in the presence of Pd (PPh ₃ ) ₄ a compound of formula (V):

in which R> 3 e „jt. ^* Rr, 4 are as defined in formula (I), * either in the presence of PdCl ₂ (PPh) ₂ a compound of formula (NI):

in which R ³ and R ⁴ are as defined above, to obtain the compound of formula (Nïï):

in which A, X, R ¹ , R ² and P _G are defined as above, compound of formula (VII) which is subjected to the action of the compound of formula (VIII): R " ⁵ OOC. = COOR ' ⁵ (VIII) in which R' ⁵ and R" ⁵ can take the same values as R ⁵ with the exception of the hydrogen atom, to lead to the compound of formula (Va) , special case of the compounds of formula (I):

in which A, X, R ³ and R ⁴ are as defined above and R ' ¹ and R' ² represent a group COOR ' ⁵ and COOR " ⁵ respectively as defined above, composed of formula (I / a) that l '' one can submit to a complete or partial saponification to yield the compound of formula (I / b), particular case of the compounds of formula (I):

in which A, X, R ² , R ³ and R ⁴ are as defined above and R ' ¹ represents a group COOR' ⁵ as defined above, compounds of formula (I / a) and (I / b) which can be subjected to the action of a thionating agent such as Lawesson's reagent for lead to the compound of formula (I / c), special case of the compounds of formula (I)

in which A, X, R ¹ , R ² , R ³ and R ⁴ are as defined above, the compounds of formula (I / a), (I / b) and (I / c) forming all of the compounds of the invention which can be purified according to a conventional separation technique, which is transformed, if one so desired, in their addition salts with an acid or with a pharmaceutically acceptable base and from which the isomers are optionally separated according to a conventional separation technique. 18. Pharmaceutical compositions containing as active principle at least one compound of formula (I) according to any one of claims 1 to 16 or one of its addition salts with a pharmaceutically acceptable acid or base, alone or in combination with one or more pharmaceutically acceptable excipients. 19- Pharmaceutical compositions according to claim 18 useful for the manufacture of a medicament for the treatment and / or prophylaxis of pathologies involving PPAR receptors. 20- Pharmaceutical compositions according to claim 18 useful for the manufacture of a medicament for the treatment and / or prophylaxis of hyperglycaemia, dyshpidemia, and more particularly in the treatment of non-insulin-dependent type II diabetes, resistance to insulin, glucose intolerance, disorders related to syndrome X, renal diseases, retinopathies, disorders related to the activation of endothelial cells, psoriasis, polycystic ovarian syndrome, dementia, osteoporosis, inflammatory bowel disease, myotonic dystrophies, pancreatitis, arteriosclerosis, xanthoma, but also in the treatment or prevention of type I diabetes, hypertriglyceridemia, hyperlipidemia, high cholesterol, high blood pressure, heart failure, obesity, appetite regulation, anorexia, bulimia nervosa, anorexia nervosa, as well as cancer pathologies and in particular hormone-dependent cancers such as breast cancer and colon cancer, and as angiogenesis inhibitors.