FR2941457A1 - New thiadiazole and oxadiazole derivatives are triglyceride biosynthesis inhibitors useful to treat or prevent e.g. obesity, dyslipidemia, hepatic steatosis, insulin resistance, metabolic syndrome, coronary heart disease and hypertension - Google Patents

Abstract

Thiadiazole and oxadiazole derivatives (I) and their base or acid addition salts or bases are new. Thiadiazole and oxadiazole derivatives of formula (I) and their base or acid addition salts or bases are new. n : 0-3; p : 0 or 1; D : O or a bond; X : heteroatom comprising O or S; either R1, R2 : H or 1-6C alkyl; or R1R2 : a cycloalkyl group; and Y1 : aryl, heteroaryl, aryloxy, 1-6C alkyl or 3-10C cycloalkyl (all optionally substituted by one or more substituents of halo, 1-6C alkyl or 1-6C alkoxy). Independent claims are included for: (1) the preparation of (I); and (2) 4-cyclohexyl-benzoic acid compound of formula (III), 4-cyclohexyl-benzamide compound of formula (V), 4-cyclohexyloxy-benzamide compound of formula (XXIII), and 4-cyclohexyloxy-benzoic acid compound of formula (XXI). R : -C(R1R2)-Y1 a group; and R1a : a protecting group. [Image] [Image] ACTIVITY : Anorectic; Antilipemic; Antidiabetic; Vasotropic; Metabolic; Hepatotropic; Cardiant; Hypotensive; Dermatological; Neuroprotective; Nootropic; Immunomodulator; Anti-HIV; Antiinflammatory; Gastrointestinal-Gen.; Cytostatic; Analgesic; Antianginal. MECHANISM OF ACTION : Triglyceride biosynthesis inhibitor. The ability of (I) to inhibit triglyceride biosynthesis was tested in vitro. The result showed that (4-{4-[5-(3-fluoro-benzyl)-[1,3,4]thiadiazol-2-ylcarbamoyl]-phenyl}-cyclohexyl)-acetic acid exhibited an IC 5 0 value of 0.046 mu M.

Description

1 DERIVATIVES OF THIADIAZOLES AND OXADIAZOLES PREPARATION AND THERAPEUTIC APPLICATION

The present invention relates to thiadiazole and oxadiazole derivatives, their preparation and their therapeutic application.

Triacylglycerides represent the main form of energy storage in eukaryotes, and can also cause disorders or imbalance in the metabolism of triacylglycerides, involved in the pathogenesis and increased risk of several pathologies such as obesity, insulin resistance, type 2 diabetes (Reasner CA, Cardiovasc Pharmacol 52: 136-44, 2008) and complications arising from this pathology (Krane and Wanner, Minerva Urol Nefrol. 3): 299-316, 2007, King GL, J Periodontol 79: 1527-34, 2008), dyslipidemia which is characterized by elevated levels of plasma triglycerides, low levels of high density lipoprotein (HDL), and the appearance of small and dense low density lipoproteins (sdLDL) and excessive postprandial lipidemia (Ginsberg et al., Obesity (Silver Spring) 14: 41S-49S, 2006, Adiels et al., Curr Opin Lipidol 17: 238- 246, 2006, Adiels et al., ATVB 28: 12 25-1236,2008), fasting glucose alteration conditions, metabolic acidosis, ketosis, metabolic syndrome (Eschwège E. Diabetes Metab. 29: 6S19-27, 2003), hepatic steatosis (Parekh and Anania, gastroenterology 132: 2191-2207, 2007), coronary heart disease (Lewis, et al., Endocrine review 23: 701, 2002, Ridker and Silvertown, J Periodontol 79: 1544-51, 2008; McBride P. Curr Atheroscler Rep.10: 386-90, 2008), skin diseases (Chen et al., J Clin Invest 109: 175-81, 2002; Yosipovitch et al. J Am Acad Dermatol 56: 901-16, 2007), Alzheimer's disease, various immunomodulatory diseases (Pahan K. Cell Mol Life Sci 63: 1165-78, 2006), HIV infection (Kotler DP, J Acquir Immune Defic Syndrome 49: S79-85 2008), inflammatory bowel syndrome (Schaffler et al Nat Clin Pract Gastroenterol Hepatol 2: 103-11, 2005). Excess storage of triacylglycerides in lean tissues, such as liver, muscle, and other peripheral tissues, leads to dysfunction in these tissues; whereas reducing the accumulation of these fats in these peripheral tissues appears to be beneficial in the treatment of lipotoxicity (Unger, Endocrinology, 144: 159-5165, 2003). The accumulation and excess of triacylglycerides in the adipose tissue (WAT) leads to obesity, a condition that is associated with decreased life span, type II diabetes, coronary heart disease, hypertension , cerebrovascular accidents, and the development of certain cancers (Grundy, Endocrine 13 (2): 155-165, 2000).

Obesity, type 2 diabetes and these complications are very common pathologies in modern society and currently the options for pharmacological treatment are limited, hence the need to develop pharmaceutical agents for treatment, prevention, delay or treatment of conditions related to obesity, type 2 diabetes and these complications, which are safe and effective.

The compounds of the invention inhibit the biosynthesis of triglycerides and are useful for the treatment of pathologies in which such inhibition is beneficial, as in the case of obesity, dyslipidemia, hepatic steatosis, type 2 diabetes , metabolic syndrome and coronary heart disease.

The subject of the present invention is compounds corresponding to formula (I): wherein n is an integer between 0 and 3, p is 0 or 1, D represents an oxygen atom or a bond, X represents a heteroatom selected from an oxygen atom or a sulfur atom, R1, R2 represent, independently of one another, a hydrogen atom or a (C1-6) alkyl group or R1, R2 may form a cycloalkyl group, Y represents an aryl, heteroaryl, aryloxy, (C1-6) alkyl, (C3-10) cycloalkyl group, said groups being optionally substituted by one or more substituents chosen from a halogen atom, a group (C1 -6) alkyl or (C1-6) alkoxy. The compounds of formula (I) may have one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or

3 diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention.

In the compounds of formula (I), the substituents borne by the cyclohexyl group may be in the cis or trans position. The compounds of formula (I) may therefore exist in the form of position isomers as defined above. These isomers of position and their mixture are part of the invention.

The compounds of formula (I) may exist in the form of bases or salified with acids or bases, in particular pharmaceutically acceptable acids or bases. Such addition salts are part of the invention. These salts are advantageously prepared with pharmaceutically acceptable bases, but the salts of other bases which are useful, for example, for the purification or the isolation of the compounds of formula (I), also form part of the invention. In the context of the present invention, and unless otherwise indicated in the text, is meant by: a halogen atom: a fluorine, a chlorine, a bromine or an iodine; An alkyl group: a linear or branched saturated aliphatic group which may have from 1 to 6 carbon atoms (C1-6). By way of examples, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, and the like; a cycloalkyl group: a cyclic alkyl group may contain from 3 to 10 carbon atoms. By way of examples, mention may be made of cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and adamantyl groups, and the like; an alkoxy group: a radical of formula O-alkyl, in which the alkyl group is as defined previously; an aryl group: a cyclic aromatic group comprising between 5 and 6 carbon atoms. As examples of aryl groups, there may be mentioned a phenyl group; an aryloxy group: a radical of formula O-aryl, where the aryl group is as defined previously; a heteroaryl group: a cyclic aromatic group comprising between 5 and 6 carbon atoms and comprising at least one heteroatom, such as nitrogen, oxygen or sulfur. As examples of heteroaryl groups, there may be mentioned a pyridinyl group.

Among the compounds of formula (I) which are subjects of the invention, there may be mentioned a group in which: n is an integer between 0 and 3, and / or p is equal to 0 or 1, and / or D represents a oxygen atom or a bond, and / or X represents a heteroatom selected from an oxygen atom or a sulfur atom, and / or R1, R2 represent, independently of one another, a hydrogen atom or R1 , R2 may form a cycloalkyl group, and / or Y represents an aryl, heteroaryl, aryloxy, (C1-6) alkyl, (C3-10) cycloalkyl group, said groups being optionally substituted by one or more substituents selected from an atom halogen, a (C1-6) alkyl or (C1-6) alkoxy group.

Among the compounds of formula (I) that are the subject of the invention, mention may be made of another group of compounds in which D represents an oxygen atom.

Among the compounds of formula (I) that are the subject of the invention, mention may be made of another group of compounds in which D represents a bond.

Among the compounds of formula (I) which are subjects of the invention, there may be mentioned another group of compounds in which X represents an oxygen atom.

Among the compounds of formula (I) which are subjects of the invention, there may be mentioned another group of compounds in which X represents a sulfur atom. Among the compounds of formula (I) that are the subject of the invention, mention may be made of another group of compounds in which R 1 and R 2 represent, independently of one another, a hydrogen atom.

Among the compounds of formula (I) which are subjects of the invention, there may be mentioned another group of compounds in which R 1 and R 2 form a cycloalkyl group. Advantageously, R 1 and R 2 form a cyclopropyl or cyclobutyl group. Among the compounds of formula (I) which are subjects of the invention, mention may be made of another group of compounds in which Y is an aryl group. Advantageously, Y represents a phenyl group. Among the compounds of formula (I) which are subjects of the invention, there may be mentioned another group of compounds in which Y is a heteroaryl group. Advantageously, Y represents a pyridinyl group.

Among the compounds of formula (I) which are subjects of the invention, there may be mentioned another group of compounds in which Y is an aryloxy group. Advantageously, Y represents a phenoxy group.

Among the compounds of formula (I) which are subjects of the invention, there may be mentioned another group of compounds in which Y is a cycloalkyl group. Advantageously, Y represents a cyclopentyl or adamantyl group.

Among the compounds of formula (I) that are the subject of the invention, mention may be made of another group of compounds in which D is a bond and p is equal to 1. Among the compounds of formula (I) that are the subject of the invention, another group of compounds in which D is an oxygen atom and p is 0.

Among the compounds of formula (I) which are subjects of the invention, mention may be made in particular of the following compounds: - {4- [4- (5-benzyl- [1,3,4] thiadiazol-2-ylcarbamoyl) - phenyl] -cyclohexyl} -acetic acid (4- {4- [5- (4-methyl-benzyl) - [1,3,4] thiadiazol-2-ylcarbamoyl] -phenyl} -cyclohexyl) -acetic acid ( 4- {4- [5- (2-Fluoro-benzyl) - [1,3,4] thiadiazol-2-ylcarbamoyl] -phenyl} -cyclohexyl) -acetic acid (4- {4- [5- ( 3-Fluoro-benzyl) - [1,3,4] thiadiazol-2-ylcarbamoyl] -phenyl} -cyclohexyl) -acetic acid - (4- {4- [5- (4-Fluoro-benzyl) - [1, 3,4] thiadiazol-2-ylcarbamoyl] -phenyl} -cyclohexyl) -acetic acid (4- {4- [5- (2,4,5-trifluorobenzyl) - [1,3,4] thiadiazole} -2-ylcarbamoyl] phenyl} cyclohexyl) -acetic acid

6-[4- (4- {5- [1- (phenyl) -cyclopropyl] - [1,3,4] thiadiazol-2-ylcarbamoyl} -phenyl) -cyclohexyl] -acetic acid - acid - {5- [1- (4-Fluoro-phenyl) -cyclopropyl] - [1,3,4] thiadiazol-2-ylcarbamoyl} phenyl) -cyclohexyl] -acetic acid [4- (4- {5- [1- (3-Fluoro-phenyl) -cyclobutyl] - [1,3,4] thiadiazol-2-ylcarbamoyl} -phenyl) -cyclohexyl] -acetic acid (4- {4- [5- (4-chloro)} benzyl) - [1,3,4] thiadiazol-2-ylcarbamoyl] -phenyl} -cyclohexyl) acetic acid - (4- {4- [5- (3-chloro-benzyl) - [1,3,4 ] thiadiazol-2-ylcarbamoyl] -phenyl} -cyclohexyl) -acetic acid (4- {4- [5- (2-chloro-benzyl) - [1,3,4] thiadiazol-2-ylcarbamoyl] -phenyl} cyclohexyl) -acetic acid (4- {4- [5- (4-methoxy-benzyl) - [1,3,4] thiadiazol-2-ylcarbamoyl] -phenyl} -cyclohexyl) -acetic acid-4- [4- (5-tert-butyl- [1,3,4] thiadiazol-2-ylcarbamoyl) -phenyl] -cyclohexyl} -acetic acid {4- [4- (5-adamantan-1-yl)} 3,4,4-thiadiazol-2-ylcarbamoyl) -phenyl] -cyclohexyl} -acetic acid {4- [4- (5-cyclopentyl- [1,3,4] thiadiazol-2-ylcarbamoyl) -phenyl yl] cyclohexyl} acetic acid {4- [4- (5-cyclopentylmethyl- [1,3,4] thiadiazol-2-ylcarbamoyl) -phenyl] -cyclohexyl} acetic acid -acid (4- {4- [ 5- (2-Cyclopentyl-ethyl) - [1,3,4] thiadiazol-2-ylcarbamoyl] -phenyl} -cyclohexyl) -acetic acid - {4- [4- (5-isobutyl- [1,3,4 ] thiadiazol-2-ylcarbamoyl) -phenyl] -cyclohexyl} -acetic acid {4- [4- (5-phenethyl- [1,3,4] thiadiazol-2-ylcarbamoyl) -phenyl] -cyclohexyl} -acetic acid - [4- (4- {5- [2- (4-Fluoro-phenyl) -ethyl] - [1,3,4] thiadiazol-2-ylcarbamoyl} -phenyl) -cyclohexyl] -acetic acid - acid [4- (5-Phenoxymethyl- [1,3,4] thiadiazol-2-ylcarbamoyl) -phenyl] -cyclohexyl} acetic acid - [4- (4- {5- [3- (4-Fluoro-phenyl)} propyl] - [1,3,4] thiadiazol-2-ylcarbamoyl} -phenyl) -cyclohexyl] -acetic acid (4- {4- [5- (4-fluoro-phenoxymethyl) - [1,3,4] ] thiadiazol-2-ylcarbamoyl] -phenyl} -cyclohexyl) -acetic acid - {4- [4- (5-phenyl- [1,3,4] thiadiazol-2-ylcarbamoyl) -phenyl] -cyclohexyl} -acetic acid - (4- {4- [5- (3-phenoxy-phenyl) - [1,3,4] thiadiazol-2-ylcarbamoyl] -phi nyl} -cyclohexyl) - acetic

7-{4- [4- (5-Pyridin-4-yl - [1,3,4] thiadiazol-2-ylcarbamoyl) -phenyl] -cyclohexyl} -acetic acid -acid (4- {4- [5- (3-Chloro-phenyl) - [1,3,4] thiadiazol-2-ylcarbamoyl] -phenyl} -cyclohexyl) -acetic acid (4- {4- [5- (3-fluoro-phenyl) - [1] 3,4,4-thiadiazol-2-ylcarbamoyl] -phenyl} -cyclohexyl) -acetic acid (4- {4- {5- (4-fluoro-phenyl) - [1,3,4] thiadiazol-2-ylcarbamoyl} ] -phenyl} -cyclohexyl) -acetic acid (4- {4- [5- (4-methoxy-phenyl) - [1,3,4] thiadiazol-2-ylcarbamoyl] -phenyl} -cyclohexyl) -10-acetic acid (4- {4- [5- (benzyl) - [1,3,4] oxadiazol-2-ylcarbamoyl] -phenyl} -cyclohexyl) -acetic acid-acid (4- {4- [5- fluoro-benzyl) - [1,3,4] oxadiazol-2-ylcarbamoyl] -phenyl} -cyclohexyl) -acetic acid-cis-4- [4- (5-benzyl- [1,3,4] thiadiazol-2-acid -ylcarbamoyl) -phenoxy] -cyclohexanecarboxylic acid-trans-4- [4- (5-benzyl- [1,3,4] thiadiazol-2-ylcarbamoyl) -phenoxy] -cyclohexanecarboxylic acid-trans-4- [4- acid] (5-phenyl- [1,3,4] thiadiazol-2-ylcarbamoyl) -phenoxy] -cyclohexanecarboxylic acid it is meant by protecting group such as a group R 'or R ", a group which makes it possible, on the one hand, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, on the other hand to regenerate the intact reactive function at the end of synthesis. Examples of protecting groups as well as methods of protection and deprotection are given in Protective Groups in Organic Synthesis, Green et al., 3rd Edition (John Wiley & Sons, Inc., New York).

The term "leaving group" in the following is understood to mean a group that can be easily cleaved from a molecule by breaking a heterolytic link, with the departure of an electronic pair. This group can thus be easily replaced by another group during a substitution reaction, for example. Such leaving groups are, for example, halogens or an activated hydroxy group such as mesyl, tosyl, triflate, acetyl, etc. Examples of leaving groups and references for their preparation are given in Advances in Organic Chemistry, J. March, 3rd Edition, Wiley Interscience, p. 310-316.

In Schemes 1, 2, 3, 4 and 5, the starting compounds and reagents, when their method of preparation is not described, are commercially available or described in the literature, or may be prepared according to methods described therein or which are known to those skilled in the art. According to the invention, the compounds of general formula (I) can be prepared according to the following methods: The group R used hereinafter represents a group -C (R 1 R 2) -Y with R 1, R 2 and Y such that previously defined. Scheme 1 describes the synthesis of the compounds of formula (I) in which D is a bond, n = 0, p = 1, these compounds will be called hereinafter compounds of formula (Ia).

Scheme 1 (Method 1) R X y NH 2 H (II) O X N (III) R '= t-Bu: (IIIa) R' = Et: (Ilib)

In Scheme 1, the intermediates of formulas (V), for which R and X are as defined above, and R 'is a protecting group such as a group (see FIG. C1-C6) alkyl, for example an ethyl or tert-butyl group, are obtained by coupling the acid of formula (III) with the aminothiadiazoles or aminooxadiazoles of formula (II) in the presence of a coupling agent (for example , bromotris-pyrrolidinophosphonium hexafluorophosphonate) in a polar solvent such as dimethylformamide or acetonitrile at 20 to 100 ° C. The acids of formula (Ia) are obtained by the deprotection of the esters of formula (V) by methods chosen from those known to those skilled in the art, these methods taking into account the stability of the compound of formula (V) in the medium acid. They include, inter alia, the use of trifluoroacetic acid or hydrochloric acid in a polar solvent such as dichloromethane or dioxane at room temperature for tert-butyl ester or lithium hydroxide in a mixture of polar solvents such as as water, methanol or tetrahydrofuran for the ethyl ester.

Scheme 2 details a synthesis of the compounds of formula (II) for which X represents a sulfur atom, these compounds will be called hereinafter compounds of formula (IIa). Scheme 2 S (vil) H2N-N NH H 2 RvO 2 ~ ryO S RSyNH 2 OH HN, NN (VI) (VIII) H NH 2 (IIa) In Scheme 1, the compounds of formulas (IV) can be prepared by reaction of a carboxylic acid and thiosemicarbazide in the presence of a coupling agent (for example 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide) in a polar solvent such as dichloromethane or dimethylformamide at room temperature. The derivatives of formula (VIII) are then cyclized in an acid such as sulfuric acid at room temperature to yield the aminothiadiazoles of formula (IIa). It should be noted that certain compounds of general formulas (II) for which X represents a sulfur or oxygen atom are commercially available. Scheme 3 details a synthesis of the compounds of formula (III) for which R 'represents a tert-butyl group. These compounds will hereinafter be called compounds of formula (IIIa). In Scheme 3, the compound of formula (XI) is prepared by a Horner-Wadsworth-Emmons reaction from the derivatives of formulas (IX) and (X) in a polar solvent such as dimethylformamide or tetrahydrofuran at room temperature. Compound (XI) is hydrogenated in the presence of a transition metal such as palladium in a polar solvent such as to give the compound of formula (XII).

The acid of formula (IIIa) is obtained by hydrolysis of the ester of formula (XII) in the presence of trifluoroacetic acid or hydrochloric acid in a polar solvent at room temperature. The compound of formula (IX) may be prepared according to a scheme described in the literature (WO2003 / 099772). Scheme 4 details a synthesis of the compounds for which R 'represents an ethyl group. These compounds will hereinafter be called compounds of formula (IIIb). In Scheme 4, the compound of formula (XV) is prepared by a Horner-Wadsworth-Emmons reaction from derivatives of formulas (X111) and (XIV) in a polar solvent at room temperature. The compound of formula (XV) is hydrogenated in the presence of a transition metal such as palladium in a polar solvent such as ethanol or ethyl acetate to give the compound of formula (XVI). The compound of formula (XVI) is converted to the acid of formula (IIIb) by triflation in a polar solvent such as dichloromethane at 0 to 25 ° C of the compound of formula (XVI) followed by a hydroxycarbonylation in a polar solvent such as dioxane between 100 and 120 ° C of the intermediate of formula (XVII).

Scheme 5 describes the synthesis of the compounds of formula (I) in which D is an oxygen atom and p = 0, these compounds will be called hereinafter compounds of formula (Ib). Scheme 5 (XVIII) (XIX) (XX) ## STR1 ## In Scheme 5, the compound of formula (XIX) for which R "is a protecting group such that a (C 1 -C 6) alkyl group, for example a methyl group, is obtained from the acid of formula (XVIII) by selective reaction with a compound known to man the art such as trimethylsilyl diazomethane in a mixture of apolar and polar solvent such as toluene and methanol, respectively, at room temperature. The alcohol of formula (XIX) wherein R "'is a (C1-C6) alkyl group such as a tert-butyl group, is engaged in a Mitsunobu reaction with an alcohol such as a 4-hydroxy type alcohol (C 1 -C 6) -benzoate, for example tert-butyl 4-hydroxybenzoate in a polar solvent such as tetrahydrofuran at room temperature to give the ether of formula (XX) The acid of formula (XXI) ) is obtained by the deprotection of the ester function -COOR "'of the compound of formula (XX) by methods chosen from those known to those skilled in the art. They include inter alia the use of trifluoroacetic acid or hydrochloric acid in polar solvents such as dichloromethane or dioxane. The intermediates of formulas (XXIII) are obtained by coupling the acid of formula (XXI) with the aminothiadiazoles or aminooxadiazoles of formula (II) in the presence of a coupling agent (for example bromine-hexafluorophosphonate).

13 pyrrolidinophosphonium) in a polar solvent such as dimethylformamide or acetonitrile at room temperature. The acids of formula (Ib) are obtained after deprotection of the ester of formula (XXIII) by methods chosen from those known to those skilled in the art. They include, inter alia, the use of lithium hydroxide in a mixture of polar solvents such as water and tetrahydrofuran.

The invention, according to another of its aspects, also relates to the compounds of formulas (III), (IIIa), (IIIb), (V), (XXI) and (XXIII). These compounds are useful as synthesis intermediates for the compounds of formula (I).

The following examples describe the preparation of certain compounds according to the invention. These examples are not limiting and only illustrate the present invention. The numbers of the compounds exemplified refer to those given in the table below, which illustrates the chemical structures and the physical properties of some compounds according to the invention.

The following abbreviations and raw formulas are used:

ACN Acetonitrile BSA Bovine serum albumin ° C Celsius LC-MS liquid chromatography-mass spectrometry 002 carbon dioxide cm2 Centimeter square dec Decomposition DMEM Dulbecco's Minimum Essential Modified DMF Dimethylformamide EDTA ethylene-diamine-tetraacetic acid eq. Equivalent ESI + Electrospray lonization g gram NMR nuclear magnetic resonance h H2O HPLC water HPLC Hertz M mass MHz megahertz mL milliliter mm millimeter mmol millimoles N Normal N-Boc-N-tert-Butyloxycarbonyl nM nanomolar mm millimeter PBS phosphate buffer saline ppm parts per million psi pound per square inch SVF Fetal calf serum SO2 Sulfur dioxide TFA Trifluoroacetic acid THF Tetrahydrofuran

15 UPLC Ultra High Performance Liquid Chromatography UV Ultra Violet HIV Human Immunodeficiency Virus pCi Microcuria% Percent

The measurement of radioactivity is done on a Flo One device C625TR (Perkin Elmer).

Proton magnetic resonance spectra (1 H NMR), as described below, are recorded at 400 MHz in DMSO-d6, using the DMSO-d5 peak as a reference. The chemical shifts 8 are expressed in parts per million (ppm). The signals observed are expressed as follows: s = singlet; d = doublet; t = triplet; m = solid or broad singlet; In the LC / MS column and in the examples is indicated the peak MH + identified by mass spectrometry. The compounds are analyzed by liquid chromatography (UV detector at 220 nm) coupled to a mass spectrometer with an electrospray ionization detector. The analytical method is detailed below UPLC / MS at 3 min / ACN / TFA T Omin gradient: 98% A 1.6 to T2.1min: 100% Btu2.5 at T 3min: 98% A Channel A: water + 0.05% TFA, lane B: ACN + 0.035% TFA Flow rate: 1, OmLlmin û T ° = 40 ° C Injection 2 μL Acquity column BEH C18 (50 * 2.1mm, 1.7 * μm) Example 1: 5- (4-fluorobenzyl) -1,3,4-thiadiazol-2-amine

1.1 Synthesis of 2- (4-fluorophenyl) acetyl) diazinecarbothioamide 5 g of 4-fluorophenylacetic acid (32.44 mmol, 1 eq) are placed in 50 ml of dichloromethane with stirring. 3.25 g of thiosemicarbazide (35.68 mmol, 1 eq.), 4.38 g of hydroxybenzotriazole (32.44 mmol, 1 eq.), 6.22 g of toluene are added successively with stirring at room temperature. 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (32.44 mmol, 1.2 eq.). After 18 h at room temperature the dichloromethane is evaporated. The residue is taken up in ethyl acetate, washed 3 times with water, once with brine and 3 times with acid.

The organic phase is dried over sodium sulphate and evaporated to give 5 g of 2 - [(4-fluorophenyl) acetyl] hydrazinecarbothioamide. M-isobutene + = 228. 1.2 Synthesis of 5- (4-fluorobenzyl) -1,3,4-thiadiazol-2-amine 5 ml of sulfuric acid are placed in a flask which is cooled to between 0 and -10. ° C by placing in a bath of ice and sodium chloride. 0.38 g of 2 - [(4-fluorophenyl) acetyl] hydrazinecarbothioamide (1.67 mmol) are added portionwise with stirring. After stirring for 3 h at 0-10 ° C, water is added dropwise and then brought back to basic pH with sodium hydroxide while maintaining a temperature between 0 and -10 ° C. The precipitate is filtered, washed with water and dried. 0.264 g of 5- (4-fluorobenzyl) -1,3,4-thiadiazol-2-amine are obtained. M + H + = 210.

Example 2: 4- (4-tert-butoxycarbonylmethylcyclohexyl) benzoic acid

2.1 Synthesis of ethyl 4- (4-tert-butoxycarbonylmethylenecyclohexyl) benzoate 5.63 g of t-butyl diethylphosphoacetate (20.3 mmol, 1 eq) are placed in 20 ml of dimethylformamide with stirring. The solution is cooled to a temperature of 4 ° C by placing the solution in an ice bath and then 0.536 g of sodium hydride (22.33 mmol, 1.1 eq) is added in portions. After 30 minutes, 5 g of ethyl 4- (4-oxo-cyclohexyl) -benzoate (20.3 mmol, 1 eq) are added and the ice bath is removed. After stirring for one hour, the flask is placed in an ice bath to cool the reaction medium to a temperature of 4 ° C. and 0.049 g of sodium hydride (2.04 mmol, 0.1 eq. .). The ice bath is removed and after 30 minutes, poured into 200 mL of 1 N potassium hydrogen sulfate and extracted with 300 mL of diethyl ether. The organic phase is washed 4 times with brine. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on silica gel eluting with a gradient of methanol in dichloromethane ranging from 0% to 5%. 5.04 g of ethyl 4- (4-tertbutoxycarbonylmethylenecyclohexyl) benzoate are obtained. M + H + = 345.35

2.2 Synthesis of ethyl 4- (4-tert-butoxycarbonylmethylcyclohexyl) benzoate 5.04 g of ethyl 4- (4-tert-butoxycarbonylmethylenecyclohexyl) benzoate (14.63 mmol, 1 eq.) And 15 ml are placed of ethanol in a bottle of Parr. 0.31 g of 10% palladium on charcoal (0.29 mmol, 0.02 eq.) Is added and the reaction medium is put under 50psi of hydrogen for 3 h at a temperature of 25 ° C. The reaction medium is filtered and concentrated to give 4.31 g of ethyl 4- (4-tertbutoxycarbonylmethylcyclohexyl) benzoate. M-isobutene + = 291. 2.3 Synthesis of 4- (4-tert-butoxycarbonylmethyl) cyclohexyl) benzoic acid 3.3 g of ethyl 4- (4-tert-butoxycarbonylmethylcyclohexyl) benzoate (9.52 mmol, 1 eq.) are dissolved in 40 mL of a 2/1/1 mixture of tetrahydrofuran / methanol / water. The reaction medium is stirred for 4 h at room temperature. The solvents are evaporated and an aqueous solution of SO2 is added. The solid obtained is filtered, washed with water and dried to give 2 g of 4- (4-tert-butoxycarbonylmethylcyclohexyl) benzoic acid.

2.4. Synthesis of trans-4- (4-tert-butoxycarbonylmethylcyclohexyl) benzoic acid 0.5 g of 4- (4-tert-butoxycarbonylmethylcyclohexyl) benzoic acid is recrystallized from ethyl acetate under reflux of the solution. After filtration and drying, 0.17 g of trans-4- (4-tert-butoxycarbonylmethylcyclohexyl) benzoic acid is obtained.

1 H NMR (400 MHz, DMSO-d 6) δ ppm 12.77 (m, 1H), 7.87 (m, J = 9 Hz, 2H), 7.36 (m, J = 9 Hz, 2H), 2 , 54 (m, 1H), 2.13 (d, J = 7.3 Hz, 2H), 1.87 to 1.68 (m, 5H), 1.49 (m, 2H), 1.43 (m, 5H), s, 9H), 1.14 (m, 2H).

Example 3 4- (4-ethylcarbonylmethylcyclohexyl) benzoic acid

3.1 Synthesis of 4- (4-hydroxy-phenyl) -cyclohexylidene-ethyl acetate In a 250 ml flask under nitrogen, 10 g of 4- (4-hydroxy-phenyl) -cyclohexanone (52.56 mmol, 1 eq.) In 150 mL of tetrahydrofuran. The solution is cooled to 4 ° C in an ice bath and 2.523 g of 60% sodium hydride (63.08 mmol, 1.2 eq) are added in portions. In another 250 ml flask under nitrogen, 14.141 g of ethyl diethylphosphoacetate (63.08 mmol, 1.2 eq) are placed in 150 ml of tetrahydrofuran. This second solution is cooled in an ice bath and 2.523 g of 60% sodium hydride (63.08 mmol, 1.2 eq.) Are added portionwise. The ice baths are removed and the media are stirred at room temperature for 30 minutes. The solution of 4- (4-hydroxy-phenyl) -cyclohexanone is added to the solution of diethylphosphoacetate ethyl. The reaction medium is stirred for 1 hour 30 minutes. A saturated aqueous solution of ammonium chloride is added and the reaction medium is extracted 3 times with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and evaporated to give 13.5 g of ethyl [4- (4-hydroxy-phenyl) -cyclohexylidene] -acetate. M + H + = 261. 3.2 Synthesis of 4- (4-hydroxy-phenyl) -cyclohexyl-ethyl acetate In a bottle of Parr under nitrogen, 6.646 g of [4- (4-hydroxy-phenyl) -cyclohexylidene ] ethyl acetate (26.53 mmol, 1 eq) in 150 mL of ethyl acetate. 0.77 g of 10% palladium on charcoal (0.72 mmol, 0.03 eq) is added and the reaction medium is brought to 50 psi of hydrogen for 3 h at 25 ° C. The reaction medium is filtered and concentrated to give 6.27 g of ethyl [4- (4-hydroxy-phenyl) -cyclohexyl] acetate. M + CH3CN + = 304.

3.3 Synthesis of [4- (4-trifluoromethanesulfonyloxy-phenyl) -cyclohexyl] -ethyl acetate 6.27 g of ethyl [4- (4-hydroxy-phenyl) -cyclohexyl] acetate (23.90 mmol) , 1 eq.) In 100 mL of dichloromethane. The solution is cooled in an ice bath and 6.3 ml of diisopropylethylamine (35.85 mmol, 1.5 eq) and 4.4 ml of triflic anhydride (26.29 mmol, 1.1 eq. ). The ice bath is removed and the reaction medium is stirred for 16 hours. The medium is poured into ice water and extracted with 250 mL of dichloromethane. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue is chromatographed on silica gel eluting with a gradient of ethyl acetate in heptane ranging from 5% to 10%. 5.76 g of ethyl [4- (4-trifluoromethanesulfonyloxy-phenyl) -cyclohexyl] -acetate M + CH3CN + = 436 are obtained.

3.4 Synthesis of 4- (4-ethoxycarbonylmethyl-cyclohexyl) -benzoic acid In 3 microwavable tubes of 20 ml, one third of the 3 g of [4- (4-trifluoromethanesulfonyloxy-phenyl) -cyclohexyl] are respectively placed. ethyl acetate (3 g, 7.61 mmol, 1 eq.) in 1/3 of the 18 ml of dioxane. One and a third of each quantity of reagents are added successively to each tube of molybdenum hexacarbonyl

19 (1 g, 3.80 mmol, 0.5 eq.), 0.171 g of palladium (II) acetate (0.76 mmol, 0.1 eq), 0.422 g of 1,1'bis (diphenylphosphino) ferrocene (0.76 mmol, 0.1 eq), 1.859 g of 4-dimethylaminopyridine (15.21 mmol, 2 eq), 3.1 mL of diisopropylethylamine (17.49 mmol, 2.3 eq.) and 2.74 mL of water. The tubes are heated at 120 ° C for 20 minutes in a Biotage microwave apparatus. The reaction media are filtered on celite. The filtrate is diluted with 200 mL of dichloromethane and washed twice with 100 mL of a saturated solution of sodium carbonate. 10 ml of diethyl ether are added. After decantation, the aqueous phase is acidified to pH = 1 with a 5N hydrochloric acid solution and extracted with 2 times 200 ml of dichloromethane. The organic phase is concentrated to dryness to give 0.560 g of 4- (4-ethoxycarbonylmethylcyclohexyl) -benzoic acid. M + CH3CN + = 332.

Example 4: 4- {4- [5- (4-Fluoro-benzyl) - [1,3,4] oxadiazol-2-ylcarbamoyl] -phenyl} -cyclohexyl) -acetic acid (Compound No. 33)

4.1 Synthesis of (4- {4- [5- (4-fluoro-benzyl) -1,3,41-oxadiazol-2-yl-carbamoyl-phenyl] -cyclohexyl) -acetate 0.183 g of 5- (4) -fluoro-benzyl) - [1,3,4] oxadiazol-2-ylamine (0.95 mmol, 1.1 eq.) in 5 mL of acetonitrile at room temperature with stirring. 0.25 g of 4- (4-ethoxycarbonylmethylcyclohexyl) -benzoic acid (0.86 mmol, 1 eq), 0.128 g of hydroxybenzotriazole (0.95 mmol, 1.1 eq. ), 0.182 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (0.95 mmol, 1.1 eq.). After 18 h, the dichloromethane is evaporated. The residue is chromatographed on silica gel eluting with a gradient of ethyl acetate in heptane. 0.37 g of activated ester is obtained which is placed in a 20 ml microwave tube with 5- (4-fluoro-benzyl) - [1,3,4] oxadiazol-2-ylamine (0.183 g). 0.95 mmol, 1.1 eq.) And 5 mL of dimethylformamide. The tube is heated at 100 ° C for 30 minutes and at 120 ° C for 30 minutes in a Biotage microwave apparatus. The reaction medium is diluted with ethyl acetate, washed 3 times with water and finally with brine. The organic phase is dried over magnesium sulfate, filtered and evaporated. The residue is chromatographed on silica gel eluting with a gradient of ethyl acetate in heptane ranging from 20% to 33%. 0.1 g of ethyl (4- {4- [5- (4-fluoro-benzyl) - [1,3,4] oxadiazol-2-ylcarbamoyl] -phenyl} -cyclohexyl) -acetate are obtained.

M + H + = 466.

4.2 Synthesis of (4- {4- [5- (4-fluoro-benzol) -f-1,3,41-oxadiazol-2-ylcarbamoyl-phenyl} -cyclohexyl) -acetic acid 0.1 g Ethyl {4- [5- (4-fluoro-benzyl) - [1,3,4] oxadiazol-2-ylcarbamoyl] -phenyl} -cyclohexyl) -acetate (0.21 mmol, 1 eq.) And 0.036 1 g of lithium hydroxide hydrate (0.86 mmol, 4 eq) are dissolved in 4 ml of a 2/1/1 mixture of tetrahydrofuran / methanol / water cooled to 4 ° C. using a bath. of ice. The reaction medium is stirred for 4 hours at room temperature. The solvents are evaporated and an aqueous solution of SO2 is added. The solid obtained is filtered off, washed with water and dried to give 0.05 g of (4- {4- [5- (4-fluoro-benzyl) - [1,3,4] oxadiazol-2- ylcarbamoyl] -phenyl} -cyclohexyl) -acetic acid. M + H + = 438. 1 H NMR (400 MHz, DMSO-d 6) δ ppm 11.9 (m, 2H), 7.92 (d, J = 8.4 Hz, 1H), 7.41 (m, 4H), 7.21 (m, J = 8.8 Hz, 2H), 4.28 (s, 2H), 2.63-2.12 (m, 3H), 1.90-1.43 (m. , 7H), 1.14 (m, 2H).

Example 5: 4- {4- [5- (4-Fluorobenzyl) - [1,3,4] thiadiazol-2-ylcarbamoyl] phenyl} cyclohexyl) acetic acid (Compound No. 5)

5.1 Synthesis of tert-butyl (4- {4- [5- (4-fluorobenzyl) -f-1,3,41-thiadiazol-2-ylbamoyl] phenyl} -cyclohexyl) acetate 0.3 g of 4- (4- tert-butoxycarbonylmethylcyclohexyl) benzoic acid (0.94 mmol, 1 eq) in a mixture of 5 mL of dichloromethane and 2 mL of dimethylformamide at room temperature. 0.394 g of 5- (4-fluorobenzyl) -1,3,4-thiadiazol-2-amine (1.88 mmol, 2 eq), 1.054 g of bromo-tris-pyrrolidinophosphonium hexafluorophosphonate (2, 26 mmol, 2.4 eq.) And 0.66 mL of diisopropylethylamine (3.76 mmol, 4 eq). The reaction mixture is stirred for 6 days at room temperature, diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, washed twice with water and once with brine. The organic phase is concentrated and the residue is chromatographed on silica gel, eluting with a gradient of ethyl acetate in heptane ranging from 10% to 33%. 0.35 g of tert-butyl (4- {4- [5- (4-fluorobenzyl) - [1,3,4] thiadiazol-2-ylcarbamoyl] phenyl} cyclohexyl) acetate are obtained. M + H + = 510

21

5.2 Synthesis of (4- {445- (4-fluorobenzyl) -1,3,4-thiadiazol-2-ylcarbamoyl] phenyl] cyclohexyl} acetic acid 0.35 g of (4- {4- [5- (4 tert-Butyl (-fluorobenzyl) - [1,3,4] thiadiazol-2-ylcarbamoyl] phenyl} cyclohexyl) acetate (0.69 mmol, 1 eq) in 5 mL of dichloromethane. 1 ml of trifluoroacetic acid (13.46 mmol, 19.6 eq.) Is added and the reaction mixture is stirred for 18 hours at room temperature. The solvent is evaporated and the residue is taken up in ethyl acetate, ethanol and methanol to give 117 mg of (4- {4- [5- (4-fluorobenzyl) - [1, 3,4] thiadiazol-2-ylcarbamoyl] phenyl} cyclohexyl) acetic acid. M + H + = 454 1H NMR (400 MHz, DMSO-d6) ppm 13.02 to 11.66 (m, 2H), 8.01 (m, 2H), 7.46 to 7.36 (m, 4H) , 7.18 (m, 2H), 4.37 (s, 2H), 2.69 to 2.51 (m, 1H), 2.41 to 2.10 (m, 2H), 1.89 to 1. (m, 9H).

Example 6 4- [4- (5-Benzyl- [1,3,4] thiadiazol-2-ylcarbamoyl) -phenoxy] -cyclohexanecarboxylic acid (Compound No. 35) 6.1 Synthesis of cis-4-hydroxy-cyclohexanecarboxylate Methyl 2 g of cis-4-hydroxy-cyclohexanecarboxylic acid (13.87 mmol, 1 eq) are placed in 50 ml of a mixture comprising 4/1 toluene / methanol at room temperature. Trimethylsilyl diazomethane (111 mL, 221.96 mmol, 16 eq.) Is poured onto the reaction medium with stirring. After 3 hours at room temperature, the reaction medium is evaporated to give 2.6 g of methyl cis-4-hydroxycyclohexanecarboxylate.

6.2 Synthesis of tert-butyl trans-4- (4-methoxycarbonyl-cyclohexyloxy) benzoate 2.20 g of methyl cis-4-hydroxy-cyclohexanecarboxylate (13.88 mmol, 1 eq), 2.70 tert-butyl 4-hydroxy-benzoate (13.88 mmol, 1 eq) and 5.46 g of triphenylphosphine (20.82 mmol, 1.5 eq) in 30 mL of tetrahydrofuran at room temperature. 4.04 mL of diisopropyl azodicarboxylate (20.82 mmol, 1.5 eq.) Is added dropwise to the reaction medium with stirring. After 3 hours at room temperature, the medium is concentrated to dryness and taken up in diethyl ether. The triphenylphosphine oxide is filtered. The organic phase is washed successively with a solution of sodium hydroxide and then with water, dried

On sodium sulfate, filtered and evaporated to give a residue. This is chromatographed on silica gel eluting with a gradient of ethyl acetate in heptane ranging from 10% to 50%. 1.6 g of tert-butyl trans-4- (4-methoxycarbonylcyclohexyloxy) benzoate are obtained. 6.3 Synthesis of trans-4- (4-methoxycarbonyl-cyclohexyloxy) -benzoic acid 1.6 g of tert-butyl trans-4- (4-methoxycarbonyl-cyclohexyloxy) benzoate (4.78 mmol, 1 g. eq.) in dichloromethane. The reaction medium is cooled to a temperature of 4 ° C with stirring in an ice bath. 3 ml of trifluoroacetic acid (40.39 mmol, 8.44 eq.) Are added and the ice bath is removed. After stirring for 17 hours at room temperature, the mixture is concentrated, taken up in diethyl ether and filtered to give 1.0 g of trans-4- (4-methoxycarbonylcyclohexyloxy) -benzoic acid. Mp = 162 ° C. 6.4 Synthesis of methyl trans-4- [4- (5-benzol- [1,3,41thiadiazol-2-yl] carbamoyl) -phenoxycyclohexanecarboxylate This compound is prepared according to Preparation 4.1 from trans-4- (4-aminobenzene) acid. -methoxycarbonyl-cyclohexyloxy) -benzoic acid and 5-benzyl-1,3,4-thiadiazol-2-amine. M + H + = 452.

6.5 Synthesis of trans-4- [4- (5-benzyl- [1,3,4-thiadiazol-2-ylcarbamoyl] -phenoxyl) cyclohexanecarboxylic acid 0.128 g of 4- [4- (5-benzyl- [1,3] Methyl 4-thiadiazol-2-ylcarbamoyl) phenoxy] -cyclohexanecarboxylate (0.28 mmol, 1 eq) in 2 mL of a mixture of tetrahydrofuran and water at room temperature. 0.024 g of lithium hydroxide monohydrate (0.57 mmol, 2 eq.) In 1 ml of water are added. After stirring for 2 h at room temperature, the tetrahydrofuran is evaporated and water is added. The aqueous phase is washed with dichloromethane. The aqueous phase is cooled to a temperature of 4 ° C in an ice bath and acidified with a 1 N solution of hydrochloric acid. The solid is filtered, washed successively with water, with ethanol then with diethyl ether to give 0.069 g of 4- [4- (5-benzyl- [1,3,4] thiadiazol-2 -ylcarbamoyl) -phenoxy] -cyclohexanecarboxylic acid. M + H + = 438.

1H NMR (400MHz, DMSO-d6) δ ppm: 13.92-11.69 (m, 2H), 8.06 (m, J = 9Hz, 2H), 7.37 (m, 4H), 7.30 (m, 1H), 7.08 (m, J = 9 Hz, 2H), 4.48 (m, 1H), 4.38 (s, 2H), 2.28 (m, 1H), 2.09 (m, 2H), 1.96 (m, 2H), 1.56 (m, 2H), 1.43 (m, 2H). The following tables illustrate the chemical structures and the physical properties of some compounds according to the invention, corresponding to formula (I).

Table I illustrates compounds of formula (I) according to the invention for which, D is a bond and p = 0, these compounds are hereinafter referred to as compounds of formula (Ia).

Table II illustrates compounds of formula (I) according to the invention for which, D is an oxygen atom and p = 1, these compounds are hereinafter called compounds of formula (Ib). In these tables: the compounds of Table I are predominantly in trans form or in trans form only, * indicates the bonding atom, 20-Me, Et, n-Pr, i-Pr, t-Bu and i-Bu represent respectively methyl, ethyl, n-propyl, isopropyl, tert-butyl and isobutyl groups, PF represents the melting point of the compound, expressed in degrees Celsius (° C); M + H 'represents the mass of the compound, obtained by LC-MS (Liquid Chromatography - Mass Spectroscopy). COMPONENT TABLES TABLE I COOH No. R1 R2 XY MH + PF 1 1 HHS * 436> 250 ° C 2 1 HHS 450> 250 ° C 3 1 HHS * 454 271 4 1 HHS * 454 277 1 HHS * 454> 250 ° CF 6 1 HHSF * F 490 242 FN ° n R1 R2 XY MH + PF 7 1 S 462> 250 ° C 8 1 S 480> 250 ° C 9 1 OS 494 275 10 1 HHS Cl 470> 250 ° C 11 1 HHS 470 255 260 12 1 HHSZ Cl 470 245-250 13 1 HHS OMe 466 254 14 0 - - S -tBu 402 298 15 0 - S * 480 320 16 0 - - S 414 274 No. n R1 R2 XY MH + PF 17 1 - - S 428 268 18 2 HHS 442 235 and Dec. 19 0 - - S-iBu 402 263 20 2 HHS 450 270 21 2 HHS 468 270 22 1 HHS 452 261 1 23 3 HHS 482 229 24 1 HHSF 470 275 25 0 - S 422 then 240dec. 26 0 - - S O 514 240 then dec.

## EQU1 ## HH 438 215 TABLE II COOH N ° n R1 R2 XY MH + PF 34 1 HHS * 438 266 cis 35 1 HHS 438 270 trans trans 36 0 S 424 306 The compounds according to the invention have been the subject of pharmacological tests which make it possible to determine their inhibitory effect on triglyceride biosynthesis.

These tests consisted in measuring the in vitro inhibitory activity of the compounds of the invention on a cellular test

The Chang Liver cells at 80% confluence are detached with trypsin-EDTA, 4 ml per flask of 175 cm 2. After centrifugation 1300 g for 5 min, the cell pellet is washed once with PBS before being resuspended in complete medium. The number of cells and their viability are determined on Mallassez cells by the trypan blue exclusion method. 150,000 cells are seeded per well of a 24-well plate for at least 3 hours in DMEM medium 4.5 g / l of glucose supplemented with 10% of FCS and antibiotics and are maintained at 37 ° C. in the CO2 incubator (5%). After 3 h, the cells adhered, the medium was removed and replaced overnight with DMEM medium 4.5 g / l glucose with 2% BSA / oleate. At the end of these 18 hours of culture without serum, the test compounds are incubated for 30 min (of 1.3, 10, 30, 100, 300 and 1000 nM) with the cells before adding the [14C] glycerol (0.4 μCi / ml / well) for an incorporation time of 6 h. The supernatant is aspirated and the cells are recovered by trypsin-EDTA treatment, 100 μl / well, 5 min at 37 ° C. This cell suspension is then recovered in an eppendorf tube and washed with 2 washes of 500 μl of PBS. Centrifugation at 1300 xg for 5 min recovered the pelleted cells which could be frozen at -20 ° C. In order to extract the lipids from the cell pellet, 400 μl of a methanol / dichloromethane / trifluoroacetic acid (50/50 / 0.1%) mixture is used to resuspend the cells. Then, the cell membranes are destroyed by sonication in a water bath, 30 min. The samples are filtered through 0.45 μm before injection on HPLC on a C18 column of 4.6 × 75 mm, 3 μm with a mobile phase of 5% (H2O + 0.1% TFA), 70% methanol, 25%. dichloromethane with a flow rate of 1.5 ml / minute. Radioactivity is measured using a Flo One C625TR (Perkin Elmer).

The inhibitory activity with respect to the biosynthesis of triglycerides is given by the concentration which inhibits 50% of the activity. The activities of the compounds according to the invention are generally between 0.01M and 10M and more particularly between 0.01 and 1M. For example, the activities of compounds 4, 23 and 25 are 0.046, respectively. , 0.181 and 0.590 M.

It thus appears that the compounds according to the invention have a triglyceride inhibitory activity.

The compounds according to the invention can therefore be used for the preparation of medicaments, in particular of triglyceride-inhibiting drugs.

Thus, according to another of its aspects, the invention relates to medicaments which comprise a compound of formula (I), or an addition salt thereof to a pharmaceutically acceptable acid or base of the compound of formula (I).

These drugs find use in therapy, particularly in the treatment and / or prevention of obesity, dyslipidemia, fasting glucose alteration conditions, metabolic acidosis, ketosis, steatosis. Hepatitis, insulin resistance, type 2 diabetes and complications arising from this pathology, lipotoxicity, accumulation and excess of triacylglycerides in adipose tissue (WAT), metabolic syndrome , coronary heart disease, hypertension, skin diseases, Alzheimer's disease, immunomodulatory diseases, HIV infection, inflammatory bowel syndrome, certain cancers.

According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as an active ingredient, a compound according to the invention. These pharmaceutical compositions comprise an effective dose of at least one compound according to the invention or a pharmaceutically acceptable salt of said compound, as well as at least one pharmaceutically acceptable excipient. Said excipients are selected according to the desired pharmaceutical form and mode of administration, among the usual excipients which are known to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or its salt, if any, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases.

Suitable unit dosage forms include oral forms, such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, Intranasal, inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions.

By way of example, a unitary form of administration of a compound according to the invention in tablet form may comprise the following components: Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscaramellose sodium 6.0 mg Corn starch 15.0 mg Hydroxypropyl methylcellulose 2.25 mg Magnesium stearate 3.0 mg There may be special cases where higher or lower dosages are appropriate; such dosages are not outside the scope of the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode of administration, the weight and the response of said patient. The present invention, according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or one of pharmaceutically acceptable salts thereof. 31 30

Claims (10)

REVENDICATIONS1. A compound having the formula (I) wherein R2 is an integer from 0 to 3, p is 0 or 1, D is an oxygen atom or a bond, X is a heteroatom selected from oxygen atom or a sulfur atom, R1, R2 represent independently of each other a hydrogen atom or a (C1-6) alkyl group or R1, R2 may form a cycloalkyl group, Y represents a group aryloxy, heteroaryl, aryloxy, (C1-6) alkyl, (C3-10) cycloalkyl, said groups being optionally substituted by one or more substituents selected from a halogen atom, a (C1-6) alkyl group or ( C1-6) alkoxy, in the form of a base or an addition salt with an acid or a base. 2. Compound of formula (I) according to claim 1, characterized in that D represents a bond and p is equal to 1. 3. Compound of formula (I) according to claim 1, characterized in that D represents an oxygen atom and p is equal to 0. 25 4. Process for the preparation of a compound of formula (I) according to any one of claims 1 to 3, characterized in that the ester function of a compound chosen from a compound of formula (V) H is deprotected. Wherein R is -C (R 1 R 2) -Y and X, Y, R 1, R 2 are as defined in claim 1 and R 'is a protecting group; (XXIII) wherein R is -C (R 1 R 2) -Y and X, Y, R 1, R 2 are as defined in claim 1 and R "is a protecting group. 5. Process for preparing a compound of formula (I) according to any one of claims 1, 2 and 4, characterized in that obtaining the compound of formula (V) is by reaction of a compound of formula (II): wherein R is -C (R 1 R 2) -Y and X, Y, R 1, R 2 are as defined in claim 1, with a compound of formula (III) or a compound of formula (XXIII): R <NOXO OH wherein R 'represents a protecting group. 6. Process for the preparation of a compound of formula (I) according to any one of claims 1, 3 and 4, characterized in that obtaining the compound of formula (XXIII), is by reaction of a compound of formula (II): wherein R is -C (R 1 R 2) -Y and X, Y, R 1, R 2 are as defined in claim 1, with a compound of formula (XXI) (XXI) wherein R "represents a protecting group. 7. Compounds of formulas (III), (V), (XXIII) and (XXI): ## STR2 ## wherein R represents a group C (R 1 R 2) -Y and X, Y, R1, R2 are as defined in claim 1 and R 'is a protecting group. 8. Medicament, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 3, or a salt of addition of this compound to a pharmaceutically acceptable acid or base of the compound of formula (I). 9. Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. 20 10. Use of a compound of formula (I) according to any one of claims 1 to 3 for the preparation of a medicament for the treatment or prevention of obesity, dyslipidemia, alteration conditions fasting glucose, metabolic acidosis, ketosis, hepatic steatosis, insulin resistance, type 2 diabetes and complications arising from this pathology, lipotoxicity, and excess triacylglycerides in adipose tissue (WAT), metabolic syndrome, coronary heart disease, hypertension, skin diseases, Alzheimer's disease, immunomodulatory diseases, HIV infection , inflammatory bowel syndrome, some cancers. 15