WO2005080354A1

WO2005080354A1 - 1,2,4-triazines derivatives, preparation thereof and use thereof in human therapeutics

Info

Publication number: WO2005080354A1
Application number: PCT/IB2005/000648
Authority: WO
Inventors: Elisabeth Dupont-Passelaigue; Isabelle Leroy; Jean-François Patoiseau; Didier Junquero; Yves Rival; André Delhon
Original assignee: Pierre Fabre Medicament
Priority date: 2004-02-18
Filing date: 2005-02-17
Publication date: 2005-09-01
Also published as: FR2866339B1; TW200538445A; FR2866339A1; AR047748A1

Abstract

The invention relates to 3,5-dioxo-(2H,4H)-1,2,4-triazine derivatives of general formulae (I or II), in which in particular: R1 represents hydrogen, a linear or branched C1-C6 alkyl or alkoxy radical, a C5-C6 cycloalkyl radical, a phenyl (C1-C2) alkyl radical or a phenyl radical;-R2 represents hydrogen, a linear or branched Cl-C7 alkyl radical, or a C1-C6 alkyl radical substituted with groups such as trifluoromethyl or phenyl;- linker represents a C2-C6 alkyl chain or -(CH2)n-O- (n = 2 to 5), - R3 represents a group of general formula below for which X = O, linker can be connected to the ortho-, meta- or para-positions of the aromatic of the group R3, R4, R5, R6, R7 and R8 represent hydrogen or fluorine, R9, Rio and R11 represent hydrogen or a linear or branched Cl-C5 alkyl group, in particular R9 and Rio represent the methyl group and R11 represents hydrogen or the ethyl group.

Description

1.2.4-TRIAZINE DERIVATIVES. PREPARATION THEREOF AND USE THEREOF IN HUMAN THERAPEUTICS The present invention relates to novel 3,5-dioxo-(2H,4H)-1 ,2,4- triazine derivatives functionalized in the 2-, 4- and 6-positions, which activate PPAR alpha and/or gamma receptors, to the preparation thereof and to the use thereof in human therapeutics. The metabolic syndrome is the result of an increased peripheral resistance to insulin, and is characterized by hyperinsulinaemia, glycose intolerance, an alteration in lipid metabolism, and arterial hypertension (Grundy, S.M.: Hypertriglyceridemia, insulin resistance, and the metabolic syndrome. Am. J. Cardiol. 1999, 83, 25F-29F). Obesity is often associated with these metabolic disorders, and the coming together of these multiple risk factors promotes the development of the atheromatous pathology that causes arterial thrombosis, which is today the primary cause of mortality in industrialized regions. Peroxisome proliferator activated receptors (PPARs) belong to the superfamily of transcription factor nuclear receptors. After activation, they form a heterodimer with the 9-cis-retinoic acid receptor (RXR); this complex (PPAR-RXR) binds specifically to DNA sequences located in regions that regulate genes involved in lipid and carbohydrate metabolism (Pineda Torra, I., Gervois, P. and Staels, B.: Peroxisome proliferator-activated receptor alpha in metabolic disease, inflammation, atherosclerosis and aging. Curr. Opin. Lipidol. 1999, 10, 151-159, Vamecq. J. and Latruffe, N.: Medical significance of peroxisome proliferator-activated receptors. Lancet 1999, 354, 141-148). The activation of PPARs, firstly, restores certain altered metabolic pathways which predispose to atherosclerosis and, secondly, reduces the inflammatory events which promote the development and fissuration of the atheroma plaque. The compounds of the present invention are characterized by means of their original structure, their affinity with respect to PPAR-alpha and/or PPAR-gamma receptors and their pharmacological profile. The compounds of the invention correspond to general formulae I or II

I II in which

-Ri represents hydrogen, a linear or branched C-ι-C₆ alkyl, alkoxy or alkenyl radical, a C₃ or Cs-C₆ cycloalkyl radical, a phenyl (C-ι-C₂) alkyl radical or a phenyl radical (the phenyl ring being optionally substituted with one or more groups such as C-₁-C₄ alkyl, C₁-C₄ alkoxy, nitrile, nitro, halogen or trifluoromethyl), a thiophen-2-yl heterocycle, a secondary C₁-C₇ alkylamine or a C₅-C₆ cycloalkylamine, or a halogen; -R₂ represents hydrogen, a linear or branched C₁-C₇ alkyl or alkenyl radical, or one of the following radicals: C-i-Cβ alkyl substituted with groups such as trifluoromethyl, monofluoroethyl or polyfluoroethyl, C₅-C₆ cycloalkyl, nitrile, benzodioxan-2-yl, phthalimido, pyridinyl, 2,2,2-trifluoroacetylamino, C1-C₄ alkoxy- carbonylvinyl, hydroxycarbonylvinyl, C₁-C4 alkoxycarbonyl, carboxylate, thiophen-2-carbonyl, indolyl, phenylcarbamoyl (for which the phenyl ring is optionally substituted with one or more groups such as Cι-C₂ alkyl or nitro), C₁-C₄ alkoxy or alkoxyalkyl (C-rC-₄ for the alkoxy, C₂-C₄ for the alkyl), phenyloxy or benzyloxy or phenyl or benzhydryl or benzoyl (for which the phenyl ring is optionally substituted with one or more groups such as C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, halogen or trifluoromethyl); linker represents a C₂-C₆ alkyl chain, -(CH₂)_n-C≡C-, -(CH₂)_n-C ≡C- or -(CH₂)_n-0-, where n = 1 to 5; R₃ represents a group of general formula below

for which X = O or S, linker can be connected to the ortho-, meta- or para- positions of the aromatic of the group R₃, R₄ and R₈ represent hydrogen, fluorine or a linear or branched C₅-C₁₀ alkenyl group, R₅, Rε and R₇ represent hydrogen or fluorine, Rg, R₁₀ and Rn represent hydrogen or a linear or branched C₁-C₅ alkyl group, and also the addition salts with pharmaceutically acceptable bases, and the various enantiomers of the compounds having asymmetric carbons, and also mixtures thereof in any proportions, including in particular racemic mixtures. The invention relates in particular to the compounds of formula I and II in which:

-Ri represents hydrogen, a linear or branched Cι-C₆ alkyl or alkoxy radical, a C₅-C₆ cycloalkyl radical, a phenyl (CrC₂) alkyl radical or a phenyl radical, a thiophen-2-yl heterocycle or a C₅-C₆ cycloalkylamine, or a halogen. - R₂ represents hydrogen, a linear or branched C₁-C₇ alkyl or alkenyl radical, or one of the following radicals: Ci-Cβ alkyl substituted with groups such as trifluoromethyl, monofluoroethyl or polyfluoroethyl, C₅-C₆ cycloalkyl, nitrile, benzodioxan-2-yl, phthalimido, pyridinyl, 2,2,2-trifluoroacetylamino, C1-C4 alkoxy- carbonylvinyl, hydroxycarbonylvinyl, C C₄ alkoxycarbonyl, carboxylate, thiophen-2-carbonyl, indolyl, phenylcarbamoyl (for which the phenyl ring is optionally substituted with one or more groups such as CrC₂ alkyl or nitro), C1-C4 alkoxy, or alkoxyalkyl (C₁-C₄ for the alkoxy, C₂-C₄ for the alkyl), phenyloxy or benzyloxy or phenyl or benzhydryl or benzoyl (for which the phenyl ring is optionally substituted with one or more groups such as C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, halogen or trifluoromethyl);

- linker represents a C₂-C₆ alkyl chain or -(CH₂)_n-0- where n = 1 to 5;

- R₃ represents a group of general formula below

for which X = O, linker can be connected to the ortho-, meta- or para- positions of the aromatic of the group R₃, R₄, R₅, Re, R₇ and Rs represent hydrogen or fluorine, R₉, R₁₀ and Rn represent hydrogen or a linear or branched C₁-C₅ alkyl group. The invention relates more particularly to the compounds of formulae I and II in which: -Ri represents hydrogen, a linear or branched C₁-C₆ alkyl or alkoxy radical, a C₅-C₆ cycloalkyl radical, a phenyl (C-i-C₂) alkyl radical or a phenyl radical; -R₂ represents hydrogen, a linear or branched C₁-C₇ alkyl radical, or a Cι-C₆ alkyl radical substituted with groups such as trifluoromethyl or phenyl;

- linker represents a C₂-C₆ alkyl chain or -(CH₂)_n-0- where n = 1 to 5;

- R₃ represents a group of general formula below

for which X = O, linker can be connected to the ortho-, meta- or para- positions of the aromatic of the group R₃, R₄, R₅, R₆, R₇ and R₈ represent hydrogen or fluorine, R₉, R₁₀ and Rn represent hydrogen or a linear or branched C₁-C₅ alkyl group, in particular Rg and R₁₀ represent the methyl group and Rn represents hydrogen or the ethyl group. The invention relates even more particularly to the 3,5-dioxo- (2H,4H)-1 ,2,4-triazine derivatives of formulae I or II in which:

-Ri represents a linear or branched C-rCβ alkyl or alkoxy radical or a phenyl radical;

-R₂ represents a linear or branched C₁-C₇ alkyl radical optionally substituted at the end of the chain with a trifluoromethyl radical; linker represents a C₂-C₆ alkylene chain;

R₃ represents a group of general formula below:

for which:

linker can be connected to the meta- or para-positions of the aromatic of the group R₃ X = O

R₄ to Rs represent hydrogen

R₉ and R₁₀ represent a methyl radical

R₁₁ represents hydrogen or an ethyl radical. The invention covers the salts of the compounds of general formulae I and II with pharmaceutically acceptable bases, and also the various enantiomers of the compounds having asymmetric carbons, and also mixtures thereof in any proportions, in particular including racemic mixtures.

SYNTHESIS The compounds of the present invention can be synthesized using the synthetic pathways described below or using methods of synthesis known to those skilled in the art. Method 1 The synthesis of the compounds of general formulae I and II is characterized (Scheme 1 ) in that: a) a derivative of general formula III

in which Ri represents the groups as described above in formulae I and II is condensed with a halogenated derivative of formula R₂Y (for the compounds corresponding to formula II) and R₃-linker-(Y or OTs) (for the compounds corresponding to formula I) where R₂, R₃ and linker are as described above in formulae I and II, and Y represents a halogen such as chlorine, bromine or iodine. This reaction can be carried out in the presence of a base such as sodium hydride or potassium tert-butoxide in dimethylformamide; b) deacetylation is carried out in an acid medium such as para- toluenesulphonic acid in ethanol; c) the product is treated with halogenated derivative of formula R₂Y (for the compounds corresponding to formula I) and R₃-llnker-(Y or OTs) (for the compounds corresponding to formula II) where R₂, R3, linker and Y and the reaction conditions are as described in paragraph a) above.

alkylation

^d alkylation

Scheme 1 : method 1

Method 2 It is characterized (Scheme 2) in that: 1 ) a compound of general formula IV

in which Ri represents the groups as described above in formulae I and II is treated with a halogenated derivative R₂Y (for the compounds corresponding to formula I) and R₃-linker-(Y or OTs) (for the compounds corresponding to formula II) where R₂, R₃ and linker are as described for formulae I and II and Y represents a halogen such as chlorine, bromine or iodine. This reaction can be carried out in the presence of a base such as sodium hydride or potassium tert-butoxide in dimethylformamide; 2) after acid hydrolysis in an alcoholic medium (such as HCl in ethanol), the product is treated with a halogenated derivative of formula R₂Y (for the compounds corresponding to formula II) and R₃-linker-(Y or OTs) (for the compounds corresponding to formula I) where R₂, R_3> linker and Y and the reaction conditions are as described in the paragraph above.

R-k NH O^N^'

Scheme 2: method 2

Method 3 This method, which makes it possible to obtain exclusively compounds of type I (Scheme 3), is characterized in that: 1 ) a solid support of resin type, such as, for example, Wang resin or SASRIN resin, is treated with a compound V

in which R4, Rs, Re, R7, Rs, R9, R10, R11, X and linker are as described above in general formulae I and II, and Gp represents a protective group, among which is tetrahydropyran. The coupling reaction with the resin is carried out under conditions known to those skilled in the art, among which is the use of diisopropylcarbodiimide in THF in the presence of DMAP; 2) after hydrolysis in acid medium such as para-toluenesulphonic acid in a methanol/dichloromethane mixture, the hydroxyl group thus liberated is activated in the form described in formula VI

in which R4, R_s, R₆, R7, Rs, R9, R10, R11, X and linker are as described above in general formulae I and II, Y represents a halogen such as chlorine, bromine or iodine, and Z represents a sulphonyl group S0₂Rι₂ where R1₂ represents groups such as methyl or 4-methylphenyl. For this, the resin is treated with a sulphonyl halide such as para- toluenesulphonyl chloride in the presence of a base such as triethylamine in dichloromethane; 3) the resin is treated with a compound of formula VII

in which Ri is as defined for formulae I and II. The reaction is carried out in the presence of a base such as sodium hydride or potassium tert-butoxide in dimethylformamide; 4) the resin thus obtained is fractionated and reacts with various alkylating agents R₂Y where R₂ is as defined above for formulae I or II, and Y represents a halogen such as chlorine, bromine or iodine. The reaction conditions are the same as those defined in paragraph a) of method 1. After cleavage of the resin in an acid medium such as trifluoroacetic acid in dichloromethane, the compounds obtained with this method of synthesis correspond only to formula I.

Scheme 3: method Method 4 It is characterized (Scheme 4) in that: a) a compound of general formula III

in which Ri represents the groups as defined above in formulae I and II is treated with a halogenated derivative R₂Y (for the compounds corresponding to formula II) and Y-(CH₂)_n0₂C-Me (for the compounds corresponding to formula I) where R₂ and n are as described for formulae I and II, and Y represents a halogen such as chlorine, bromine or iodine. This reaction can be carried out in the presence of a base such as sodium hydride or potassium tert-butoxide in dimethylformamide; b) hydrolysis is carried out in an acid medium such as para- toluenesulphonic acid in ethanol; c) the product is treated with a halogenated derivative of formula R₂Y (for the compounds corresponding to formula I) and Y-(CH₂)_n0₂C-Me (for the compounds corresponding to formula II) where R₂, n and Y and the reaction conditions are as described in paragraph a) above. d) in the case of the compounds of formula VIII,

an additional hydrolysis in a basic medium such as LiOH in a THF/H₂0 mixture is necessary; e) the alcohols thus obtained are coupled with compounds of formula IX

for which the hydroxyl function can be in the ortho-, meta- or para-position of the aromatic of the compounds IX, and R4, Rs, Re, R7, Rs, R9, R10, R11 and X are as defined in formulae I and II. The coupling conditions are those of the Mitsunobu reaction.

Scheme 4: method 4 The intermediate and final compounds can, if desired, be purified according to one or more purification methods chosen from extraction, filtration, silica gel chromatography, normal-phase or reverse-phase preparative HPLC, and crystallization. The starting materials used in the processes described above are commercial or are readily accessible to those skilled in the art according to processes described in the literature. The following examples illustrate the invention without limiting the scope thereof. The elemental analyses and the IR and NMR spectra confirm the structures of the compounds.

Intermediates 1: a) Ethyl 2-oxooctanoate (1a)

Diethyl oxalate (22.6 ml, 166.7 mmol) is placed in 340 ml of a 1/1 THF/diethyl ether mixture under nitrogen at -58°C. Hexylmagnesium bromide in solution in 2M diethyl ether (100 ml, 200 mmol) is run in dropwise over half an hour while maintaining the temperature at -58°C. The temperature is then allowed to rise to 0°C and the reaction medium is neutralized with 150 ml of 2N H₂S0₄. After extraction with diethyl ether, the organic phases are dried over MgSU₄. After filtration, the filtrate is concentrated to dryness and 32.3 g of a yellow oil (quantitative yield) are recovered. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.49. b) Ethyl cvclopentyloxoacetate (1b)

1b is prepared as described in the paragraph above, using cyclopentylmagnesium bromide. It is isolated in the form of a brown oil (quantitative yield). TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.44.

Intermediates 2: a) 6-Hexyl-3-thioxo-3.4-dihvdro-2H-ri,2,41triazin-5-one (2a)

1a (30.2 g, 162.1 mmol) is placed in 300 ml of EtOH in the presence of thiosemicarbazide (12.3 g, 135.1 mmol). The reaction medium is heated at 90°C for half an hour and is then concentrated to dryness. After purification by flash chromatography (petroleum ether-EtOAc: 80-20), 38.9 g of white solid (quantitative yield) are isolated. This solid is placed in the presence of sodium hydroxide (10.7 g, 269.9 mmol) in 160 ml of water and refluxed for 30 min. The reaction medium is acidified at pH = 4 with acetic acid and is then extracted with ethyl acetate. After drying over MgS0₄, the organic phases are concentrated to dryness. The residue obtained is taken up in petroleum ether and is then filtered. After drying, 24.8 g of 2a are recovered in the form of crystals (yield = 86%). TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.63. b) 6-Benzyl-3-thioxo-3.4-dihvdro-2H-π.2,41triazin-5-one (2b)

The synthesis of 2b is carried out using 2-oxo-3-phenylpropionic acid according to the procedure described for the synthesis of 2a. 2b is recovered in the form of a white sold (yield = 93%), TLC Merck silica gel 60 F 254, CH₂Cl₂-MeOH-NH₄OH: 75-20-5, Rf = 0.32. c) 6-Hexyl-2H-H ,2,41triazine-3.5-dione(2c)

2a (22.2 g, 104 mmol) is placed in 300 ml of 1 N NaOH solution into which are run, dropwise, 47 ml of a 30% solution of H₂0₂ in water. The reaction medium is stirred for half an hour at ambient temperature and the pH is then acidified with concentrated HCl. After extraction with ethyl acetate and drying over MgSU₄, the organic phases are concentrated to dryness. The solid residue obtained is taken up with petroleum ether and isolated by filtration. After drying, 2c is recovered in the form of 19 g of cream solid (yield = 93%), TLC Merck silica gel 60 F 254, CH₂CI₂-EtOAc: 70-30, Rf = 0.38. d) 6-Benzv)-2H-π,2.41triazine-3,5-dione (2d)

The synthesis of 2d is carried out using 2b according to the procedure described for 2c above. 2d is recovered in the form of a white solid (yield = 79%), TLC Merck silica gel 60 F 254, CH₂CI₂-EtOAc: 70-30, Rf = 0.29. e) 6-Cvclopentyl-2H-H.2,41triazine-3.5-dione (2e)

The synthesis of 2e is carried out using 1b according to the procedures described for the synthesis of 2a and then 2c. 2e is recovered in the form of a white solid (yield = 79%), TLC Merck silica gel 60 F 254, CH₂CI₂-EtOAc: 70-30, Rf = 0.34. f) 6-Methyl-2H-ri,2.41triazine-3.5-dione (2f)

The synthesis of 2f is carried out using 2-oxo-propionic acid according to the procedures described for the synthesis of 2a and then 2c. 2f is recovered in the form of a solid (yield = 63%), TLC Merck silica gel 60 F 254, CH₂Cl₂-EtOAc: 70-30, Rf = 0.15. g) 6-Phenyl-2H-π,2,4Ttriazine-3,5-dione (2g)

The synthesis of 2g is carried out using oxophenylacetic acid according to the procedures described for the synthesis of 2a and then 2c. 2g is recovered in the form of a solid (yield = 72%), TLC Merck silica gel 60 F 254, CH₂CI₂-MeOH-NH₄OH: 80-18-2, Rf = 0.51. h) 6-Thiophen-2-yl-2H-ri.2,41triazine-3.5-dione (2h)

The synthesis of 2h is carried out using ethyl oxothiophen- 2-ylacetate according to the procedures described for the synthesis of 2a and then 2c. 2h is recovered in the form of a yellow solid (yield = 39%), TLC Merck silica gel 60 F 254, CH₂CI₂-MeOH: 90-10, Rf = 0.46.

1) 6-Bromo-2H-ri.2,41triazine-3,5-dione (2i)

2H-[1 ,2,4]triazin-3,5-dione (50 g, 442 mmol) is placed in the presence of 60 ml of bromine in 800 ml of water at 60°C for 10 h. The reaction medium is then run slowly onto a solution of aqueous ammonia until pH = 5. It is then extracted with ethyl acetate and the organic phases are dried over MgS0₄. After filtration and concentration to dryness, 2i is isolated in the form of a white solid (79.2 g, yield = 93%). TLC Merck silica gel 60 F 254, CH₂CI₂-MeOH: 90-10, Rf = 0.32. i) 6-Hexyl-3-methylsulphanyl-2H-π,2.41triazin-5-one (2D

2a (5 g, 23.4 mmol) is placed in 60 ml of a 2N sodium hydroxide solution to which 2.2 ml of CH₃I are added. The reaction medium is stirred at ambient temperature for 2 h and is then acidified with acetic acid. The white precipitate formed is isolated by filtration and washed with water. After drying, 5 g of crystalline 2j are isolated (yield = 94%). TLC Merck silica gel 60 F 254, CH₂CI₂-EtOAc: 70-30, Rf = 0.36. k) 6-Benzyl-3-methylsulphanyl-2H-π.2.41triazin-5-one (2k)

The synthesis of 2k is carried out using 2b according to the procedure described for the synthesis of 2j. 2k is recovered in the form of a yellow solid (yield = 96%), TLC Merck silica gel 60 F 254, CH₂CI₂-MeOH: 95-5, Rf = 0.52.

I) 6-Bromo-4-methyl-2H-ri.2.41triazine-3.5-dione (21)

20.3 g (105.7 mmol) of triazine 2i are placed in 150 ml of acetic anhydride at reflux for 4 h 30 min. After the reaction medium has been concentrated to dryness, a precipitate is isolated and then recrystallized from ether: 24.3 g of crystals (yield = 98%) are isolated. 4.5 g (114.2 mmol) of NaH (60% in paraffin) are placed in 50 ml of DMF under nitrogen. A solution of 24.3 g (103.8 mmol) of previously isolated crystals in 150 ml of DMF is run in dropwise. The reaction medium is stirred at ambient temperature for 45 min, and then 7 ml (114.2 mmol) of methyl iodide are added, and stirring is then continued for 21 h at ambient temperature. After concentration to dryness, the residue obtained is taken up with H₂O and extracted with ethyl acetate. After drying over MgS0₄, the organic phases are evaporated and the light-coloured oil obtained is purified by flash chromatography on silica (CH₂CI₂-EtOAc: 90-10). 22.9 g of crystals (yield = 89%) are isolated and are placed in 300 ml of ethanol in the presence of 0.6 g of para-toluenesulphonic acid. This mixture is refluxed for 4 h 30 min and then concentrated to dryness. The residue is taken up with H2O and then extracted with ethyl acetate. After drying and evaporation of the organic phases, 17 g of intermediate 21 are isolated in the form of a solid (yield = 89%). TLC Merck silica gel 60 F 254, CH₂Cl₂-EtOAc: 90-10, Rf = 0.29. m) 6-Hexyl-4-(4.4,4-trifluorobutyl)-2H-π.2,41triazine-3,5-dione (2m)

The synthesis of 2m is carried out using 2c according to the procedure described for the synthesis of 21 using 1 ,1 ,1-trifluoro-4-iodobutane instead of the methyl iodide. 2m is recovered in the form of an oil (total yield = 56%>), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 50-50, Rf = 0.58. n) 6-Hexyl-4-(2-hvdroxyethyl)-2H-ri,2.41triazine-3.5-dione (2n)

The synthesis of 2n is carried out using 2c according to the procedure described for the synthesis of 21 using 2-bromoethyl acetate instead of methyl iodide. 2n is recovered in the form of an oil (total yield = 31%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 30-70, Rf = 0.42. o) 4-Methyl-6-pyrrolιdin-1-yl-2H-π.2, 41triazme-3,5-dione (2o)

2 g (9.7 mmol) of triazine 21 and the tip of a spatula of KI are placed in 5 ml of pyrrolidine and refluxed for 17 h. After concentration to dryness, the residue obtained is taken up with H2O and extracted with CH₂CI₂. After drying over MgS0 , the organic phases are evaporated and the oil obtained is purified by flash chromatography (EtOAc). 2o is recovered in the form of a yellow solid (1.6 g, yield = 84%). TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 50-50, Rf = 0.29. p) 6-Hexyl-4-(2-hvdroxyethyl)-2-(4.4,4-trifluorobutyl)-2H- π.2.41triazine-3.5-dione (2p)

0.16 g (4.15 mmol) of NaH (60% in paraffin) are placed in 20 ml of DMF at 0°C under nitrogen. A solution of 1 g (4.15 mmol) of triazine 2n in 15 ml of DMF is run in dropwise. The reaction medium is stirred for half an hour at 0°C and then 1.09 g (4.56 mmol) of 1 ,1 ,1-trifluoro-4-iodobutane are added, and stirring is then continued for 24 h at ambient temperature. After concentration to dryness, the residue obtained is taken up with H 0 and extracted with CH₂CI₂. After drying over MgS0₄, the organic phases are evaporated and the light-coloured oil obtained is purified by flash chromatography on silica (petroleum ether-EtOAc: 80-20). 1.29 g of intermediate 2p (yield = 88%) are isolated. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 50-50, Rf = 0.30. α) 6-Hexyl-2-(2-hvdroxyethyl)-4-(4.4,4-trifluorobutyl)-2H- H.2.41triazine-3,5-dione (2q)

The synthesis of 2q is carried out using 2m according to the procedure described for the synthesis of 2p using 2-bromoethyl acetate instead of 1 ,1 ,1-trifluoro-4-iodobutane and hydrolysing the acetate (LiOH/THF/H₂θ-ambient temperature-24h). 2q is recovered in the form of an oil (total yield = 77%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 50-50, Rf = 0.32.

Intermediates 3: a) Methyl 3-(3-hydroxyphenyl)acrylate (3a)

10 g of 3-(3-hydroxyphenyl)acrylic acid (60.9 mmol) are placed in 100 ml of MeOH in the presence of 1 ml of concentrated H₂SO₄ and refluxed for 5 h. After cooling, 150 ml of water are then added and the medium is extracted with CH₂CI₂. The organic phases are dried over MgS0₄, and then concentrated to dryness and 3a is isolated in the form of a solid (10.8 g, quantitative yield). TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30, Rf = 0.56. b) 3-(3-Hvdroxypropenyl)phenol (3b)

3a (2.5 g, 14 mmol) is placed in 35 ml of toluene under nitrogen at 0°C and then 29 ml of a solution of DIBAL (1.5M in toluene) are run in dropwise. After stirring at this temperature for 3 h 30 min, the reaction medium is neutralized with methanol and then filtered through celite. After having concentrated the filtrate to dryness, the residue obtained is purified by flash chromatography on silica (CH₂CI₂-EtOAc: 70-30) and 1.65 g of 3b are recovered in the form of a solid (yield = 78%). TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30, Rf = 0.53. c) 4-(3-Hvdroxypropyl)-2-(3-methylbut-2-enyl)phenol (3c)

3a (6.8 g, 38 mmol) is placed in the presence of palladium-on- charcoal in 100 ml of EtOAc under 4 bar of hydrogen for 24 h. The reaction medium is filtered through celite and then concentrated to dryness and a light-coloured oil is recovered (6.9 g, quantitative yield). 4 g of this oil are placed in 60 ml of toluene under nitrogen, 1 g of NaH (60% in paraffin- 25 mmol) is added, and the mixture is stirred at 50°C for 2 h. Prenyl bromide (3.5 ml, 30.3 mmol) is run in dropwise and the reaction medium is then stirred at 35°C for 24 h. The mixture is added to ice and the pH is then acidified with 1N HCl. After extraction with EtOAc, the organic phases are washed with brine, dried over MgS0₄, and then concentrated to dryness. The residue obtained is purified by flash chromatography on silica (petroleum ether- EtOAc: 90-10 then 80-20) and 2.7 g of a light-coloured oil are isolated (yield = 48%). They are placed in 20 ml of THF at 0°C under nitrogen and 13 ml of a solution of LiAIH₄ (1M in THF) is run in dropwise. The reaction medium is placed at reflux for 2 h, neutralized with water and then acidified with 1 N HCl. After extraction with diethyl ether, the organic phases are rinsed with a saturated sodium bicarbonate solution, dried, and concentrated to dryness. 3c is isolated in the form of an oil (2.31 g, yield = 97%). TLC Merck silica gel 60 F 254, CH₂CI₂-EtOAc: 90-10, Rf = 0.35.

Intermediates 4: a) Ethyl 2-(3-bromophenoxy)-2-methylpropionate (4a)

25 g (144.5 mmol) of 3-bromophenol are placed in the presence of K₂C0₃ (21 g, 152 mmol) in 75 ml of ethyl 2-bromoisobutyrate and refluxed for 7 h. After elimination of K₂C0₃ by filtration, the reaction medium is concentrated to dryness. After purification by flash chromatography on silica (petroleum ether-EtOAc: 90-10), 37 g of a light-coloured oil are recovered (yield = 89%). TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.40. b) Ethyl 2-(3-bromophenylsulphanyl)-2-methylpropionate (4b)

10 g (52.9 mmol) of 3-bromothiophenol are placed in the presence of 9.4 ml (63.5 mmol) of ethyl bromoisobutyrate and 8 g (57.9 mmol) of K₂C0₃ in 100 ml of EtOH. This mixture is stirred at reflux for 4 h and then concentrated to dryness. The residue is taken up with water and, after extraction with EtOAc, the organic phases are concentrated to dryness. The oil obtained is purified by flash chromatography on silica (petroleum either- EtOAc: 90-10) and 4b is isolated in the form of a light-coloured oil (16.8 g, quantitative yield). TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.72. c) Ethyl 2-r3-(3-hvdroχypropenyl)phenoxy1-2-methyl- propionate (4c)

The synthesis of 4c is carried out using 3b according to the procedure described for the synthesis of 4a. 4c is recovered in the form of an oil (yield = 70%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30, Rf = 0.34. d) Ethyl 2-r4-(3-hvdroχypropyl)-2-(3-methylbut-2-enyl)- phenoxyl-2-methylepropionate (4d)

The synthesis of 4d is carried out using 3c according to the procedure described for the synthesis of 4a. 4d is recovered in the form of an oil (yield = 39%), TLC Merck silica gel 60 F 254, CH₂CI₂-EtOAc: 90-10, Rf = 0.32. e) Ethyl 2-r4-(3-hvdroxypropyl)phenoxy1-2-methylpropanoate (4jQ

The synthesis of 4e is carried out using 4-(3-hydroxypropyl)phenol according to the procedure described for the synthesis of 4a. 4e is recovered in the form of an oil (yield = 72%), TLC Merck silica gel 60 F 254, CH₂CI₂-EtOAc: 90-10, Rf = 0.26. f) Ethyl 2-r4-(2-hvdroxyethyl)phenoxy1-2-methylpropanoate (4f)

The synthesis of 4f is carried out using 4-(2-hydroxyethyl)phenol according to the procedure described for the synthesis of 4a. 4f is recovered in the form of an oil (yield = 65%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30, Rf = 0.25. g) Ethyl 2-(2-bromophenoxy)-2-methylpropionate (4g)

The synthesis of 4g is carried out using 2-bromophenol according to the procedure described for the synthesis of 4a. 4g is recovered in the form of an oil (quantitative yield), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.60. h) Ethyl 2-(5-bromo-2,3-difluorophenoxy)-2-methylpropionate (4hl

The synthesis of 4h is carried out using 5-bromo-2,3-difluoro- phenol according to the procedure described for the synthesis of 4a. 4h is recovered in the form of an oil (yield = 89%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 95-5, Rf = 0.36. i) Ethyl 2-(4-hvdroxyphenoxy)-2-methylpropionate (40

1.5 g (13.6 mmol) of hydroquinone are placed in the presence of 5.6 g (40.9 mmol) of K₂C0₃ in 45 ml of DMF. This mixture is stirred at 90°C for 1 h 45 min, and then 2 ml (13.6 mmol) of ethyl bromoisobutyrate are added and heating is maintained for 17 h. The reaction medium is concentrated to dryness, and the residue obtained is taken up with water and then extracted with EtOAc. After drying, the organic phases are concentrated to dryness and the oil obtained is purified by flash chromatography on silica (petroleum ether-EtOAc: 70-30). 4i is isolated in the form of a light-coloured oil (0.71 g, yield 33%). TLC Merck silica gel 60 F 254, petroleum ether- EtOAc: 50-50, Rf = 0.60. j) Ethyl 2-(3-hvdroxyphenoxy)-2-methylpropionate (4j)

The synthesis of 4j is carried out using resorcinol according to the procedure described for the synthesis of 4i. 4j is recovered in the form of an oil (yield = 39%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 50-50, Rf = 0.60.

Intermediates 5: a) Ethyl 2-r3-(4-hvdroxybut-1-vnyl)phenoxy1-2-methyl- propionate (5a)

4a (10 g, 34.8 mmol) is placed in the presence of 3-butynol (3.16 ml, 41.7 mmol) in 90 ml of diisopropylamine, under nitrogen. Pd(PPh₃)₂CI₂ (0.73 g) and Cul (46 mg) are added and the reaction medium is stirred at reflux for 6 h. The precipitate formed in the course of the reaction is filtered off through celite and the reaction medium is concentrated to dryness. After purification by flash chromatography on silica (petroleum ether- EtOAc: 60-40), 5a is isolated in the form of a light-coloured oil (7.9 g, yield = 81%). TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 50-50, Rf = 0.43. b) Ethyl 2-f3-(4-hvdroxybutyl)phenoxy1-2-methylpropionate (5b)

5a (5.9 g, 28.6 mmol) is placed in 80 ml of ethanol in the presence of palladium-on-charcoal under 4 bar of hydrogen for 48 h. The reaction medium is filtered through celite and then concentrated to dryness. 5b is isolated in the form of a light-coloured oil (7.5 g, yield = 92%). TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 50-50, Rf = 0.38. c) Ethyl 2-r3-(5-hvdroxypentyl)phenoxy1-2-methylpropanoate (5c)

The synthesis of 5c is carried out using 4a and 4-pentynol according to the procedures described for the synthesis of 5a and 5b. 5c is recovered in the form of an oil (yield = 76%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 60-40, Rf = 0.37. d) Ethyl 2-r3-(6-hvdroxyhexyl)phenoxy1-2-methylpropanoate (5d)

The synthesis of 5d is carried out using 4a and 5-hexynol according to the procedures described for the synthesis of 5a and 5b. 5d is recovered in the form of an oil (yield = 63%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 60-40, Rf = 0.46. e) Ethyl 2-r3-(3-hvdroxypropyl)phenoxy1-2-methylpropanoate (5e)

The synthesis of 5e is carried out using 4a and 2-propynol according to the procedures described for the synthesis of 5a and 5b. 5e is recovered in the form of an oil (yield = 69%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.56. f) Ethyl 2-r3-(4-hvdroxybutyl)phenylsulphanvn-2-methyl- propanoate (5f)

The synthesis of 5f is carried out using 4b and 3-butynol according to the procedures described for the synthesis of 5a and 5b (using the Wilkinson catalyst for the reduction). 5f is recovered in the form of an oil (yield = 77%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 50-50, Rf = 0.38. g) Ethyl 2-r3-(3-hvdroxypropyl)phenylsulphanyl1-2-methyl- propanoate (5g)

The synthesis of 5g is carried out using 4b and 2-propynol according to the procedures described for the synthesis of 5a and 5b (using the Wilkinson catalyst for the reduction). 5g is recovered in the form of an oil (yield = 73%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30, Rf = 0.26. h) Ethyl 2-r2-(4-hvdroxybutyl)phenoxy1-2-methylpropanoate (5h)

The synthesis of 5h is carried out using 4g and 3-butynol according to the procedures described for the synthesis of 5a and 5b. 5h is recovered in the form of an oil (yield = 53%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30, Rf = 0.45. i) Ethyl 2-r2,3-difluoro-5-(4-hvdroxybutyl)phenoxy1-2-methyl- propanoate (5i)

The synthesis of 5i is carried out using 4h and 3-butynol according to the procedures described for the synthesis of 5a and 5b. 5i is recovered in the form of an oil (yield = 64%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 60-40, Rf = 0.32.

Intermediates 6: a) Ethyl 2-r3-(3-bromopropyl)phenoxy1-2-methylpropanoate (6a)

4.6 g (17.7 mmol) of triphenylphosphine are placed in 40 ml of CH₂CI₂ at 0°C and 3.1 g of N-bromosuccinimide (17.7 mmol) are added. 5e (2.3 g, 8.8 mmol) diluted in 20 ml of CH₂CI₂ is then added dropwise. The reaction medium is stirred at ambient temperature for 24 h and then filtered. After the addition of 60 ml of water, the reaction medium is extracted with CH₂CI₂. After drying, the organic phases are concentrated to dryness and the residue obtained is purified by flash chromatography on silica (petroleum ether-EtOAc: 90-10). 6a is isolated in the form of a light-coloured oil (1.9 g, yield = 67%). TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 95-5, Rf = 0.27. b) Ethyl 2-r3-(4-bromobutyl)phenoxy1-2-methylpropanoate (6b)

The synthesis of 6b is carried out using 5b according to the procedure described for the synthesis of 6a. 6b is recovered in the form of an oil (yield = 64%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.61. c) Ethyl 2-r3-(5-bromopentyl)phenoxy1-2-methylpropanoate (6c)

The synthesis of 6c is carried out using 5c according to the procedure described for the synthesis of 6a. 6c is recovered in the form of an oil (yield = 68%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 95-5, Rf = 0.29. d) Ethyl 2-r3-(6-bromohexyl)phenoxy1-2-methylpropanoate (6d)

The synthesis of 6d is carried out using 5d according to the procedure described for the synthesis of 6a. 6d is recovered in the form of an oil (yield = 69%). TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 95-5, Rf = 0.31. e) Ethyl 2 3-(4-bromobutyl)phenylsulphanyl1-2-methyl- propanoate (6e)

The synthesis of 6e is carried out using 5f according to the procedure described for the synthesis of 6a. 6e is recovered in the form of an oil (yield = 56%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.64. f) Ethyl 2-r3-(3-bromopropyl)phenylsulphanvn-2-methyl- propanoate (6f)

The synthesis of 6f is carried out using 5g according to the procedure described for the synthesis of 6a. 6f is recovered in the form of an oil (yield = 39%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.81. g) Ethyl 2-r4-(3-bromopropyl)-2-(3-methylbut-2-enyl)phenoxy1- 2-methylpropanoate (6g)

The synthesis of 6g is carried out using 4d according to the procedure described for the synthesis of 6a. 6g is recovered in the form of an oil (yield = 37%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 95-5, Rf = 0.31. h) Ethyl 2-f4-(3-bromopropyl)phenoxy1-2-methylpropanoate (6h)

The synthesis of 6h is carried out using 4e according to the procedure described for the synthesis of 6a. 6h is recovered in the form of an oil (yield = 80%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 95-5, Rf = 0.35. i) Ethyl 2-r2-(4-bromobutyl)phenoxy1-2-methylpropanoate (60

The synthesis of 6i is carried out using 5h according to the procedure described for the synthesis of 6a. 6i is recovered in the form of an oil (yield = 75%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.50.

0 Ethyl 2-r5-(4-bromobutyl)-2,3-difluorophenoxy1-2-methyl- propanoate (60

The synthesis of 6j is carried out using 5i according to the procedure described for the synthesis of 6a. 6j is recovered in the form of an oil (yield = 74%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.43. k) Ethyl 2-methyl-2-(3-r3-(toluene-4-sulphonyloxy)propyπ- phenoxylpropanoate (6k)

5e (10.3 g, 38.6 mmol) is placed in the presence of triethylamine (5.9 ml, 42.2 mmol) in 150 ml of CH₂CI₂. Tosyl chloride (7.35 g, 38.5 mmol) is added to this solution and the mixture is stirred for 24 h. After the addition of 150 ml of water, the reaction medium is extracted with CH2CI2 and the organic phases are concentrated to dryness after drying. The residue obtained is purified by flash chromatography on silica (petroleum ether- EtOAc: 90-10 then 70-30). 6k is isolated in the form of a light-coloured oil (9.8 g, yield = 60%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.74.

I) Ethyl 2-methyl-2-f3-r4-(toluene-4-sulphonyloxy)butvn- phenoxy)propanoate (60

The synthesis of 6I is carried out using 5b according to the procedure described for the synthesis of 6k. 6I is recovered in the form of an oil (yield = 81 %), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.42. m) Ethyl 2-methyl-2-(3-r4-(toluene-4-sulphonyloxy)-but- 1-ynvπphenoxy)propanoate (6m)

The synthesis of 6m is carried out using 5a according to the procedure described for the synthesis of 6k. 6m is recovered in the form of an oil (yield = 15%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.28. n) Ethyl 2-methyl-2-{3-r3-(toluene-4-sulphonyloxy)propenyl1- phenoxylpropanoate (6n)

The synthesis of 6n is carried out using 4c according to the procedure described for the synthesis of 6k. 6n is recovered in the form of an oil (yield = 35%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.30. o) Ethyl 2-methyl-2-(4-f2-(toluene-4-sulphonyloxy)ethvn- phenoxy)propanoate (6o)

The synthesis of 6o is carried out using 4f according to the procedure described for the synthesis of 6k. 6o is recovered in the form of an oil (yield = 75%), TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30, Rf = 0.64.

Solid-support synthesis of libraries: general procedure The library syntheses are carried out according to the general procedure described in Scheme 5 mperature, 35mn, 80%

ambient temperature, 6h 30 min

Scheme 5 5b (8.6 g, 30.7 mmol) is placed in 130 ml of chloroform and then 3.9 ml (42.9 mmol) of dihydropyran are added slowly, followed by 0.12 g (0.6 mmol) of PTSA. The medium is stirred for 35 min and then concentrated to dryness. The oil obtained is taken up with H₂O, and this solution is extracte l with EtOAc. After drying over MgS0₄, the organic phases are concentrated to dryness and the residue obtained is purified by flash chromatography (petroleum ether-EtOAc: 90-10). 9 g of a light-coloured oil are isolated (yield = 80%, TLC Merck silica gel 60 F 254, petroleum ether- EtOAc: 90-10, Rf = 0.27). They are then placed in 150 ml of ethanol in the presence of 82 ml of 1 N NaOH and are then refluxed for 1 h. After concentration to dryness, the residue is taken up with H₂0 and the pH is then brought to 1 with 1 N HCl. Finally, this solution is extracted with EtOAc. After drying and concentration to dryness of the organic phases, the residue obtained is purified by flash chromatography (CH₂CI₂, then CH₂CI₂-MeOH: 95-5). 6 g of a light-coloured oil are isolated (yield = 72%, TLC Merck silica gel 60 F 254, CH₂CI₂-MeOH: 95-5, Rf = 0.25). They are then dissolved in a CH₂CI₂/DMF mixture (1/1-70 ml) in the presence of 5.9 g of Wang SS resin (Advanced ChemTech, loading 1 mmol/g). Diisopropylcarbodiimide (2.7 ml, 17.8 mmol) and DMAP (0.21 g, 1.8 mmol) are introduced and the mixture is stirred at ambient temperature for 5 h. After filtration of the solvents, the resin is washed alternately with 60 ml of MeOH and then 60 ml of CH₂CI₂ and, finally, dried under vacuum at 50°C (7.77 g of dry resin are isolated). This resin is then suspended in a CH₂CI₂/MeOH mixture (97/3, 80 ml) and then 0.56 g (2.9 mmol) of PTSA are added and stirring at ambient temperature is maintained for 6 h 30 min. After filtration of the solvents, the resin is washed alternately with 80 ml of MeOH and then 80 ml of CH₂CI₂ and, finally, dried under vacuum at 50°C. It is then placed in 80 ml of CH₂CI₂ to which 2.5 ml (17.6 mmol) of Et₃N are slowly added, followed by 3.36 g (17.6 mmol) of tosyl chloride, and stirring is maintained at ambient temperature for 24 h. After a series of washes (80 ml of MeOH and then 80 ml of CH₂CI2), the resin is dried under vacuum. 1 mmol of triazine (chosen from intermediates 2c-2i or azauracil) in solution in 6 ml of DMF is placed in each reactor of a Quest 210 automated device, under nitrogen. NaH (60% paraffin, 0.5 mmol) is added (the suspension is stirred for 30 min, followed by 0.5 g of resin obtained previously, and these mixtures are then heated at 80°C for 6 h. After filtration, a series of washes is carried out with, successively,

3 x 6 ml of DMF, 3 x 6 ml of MeOH and 3 x 6 ml of CH₂Cl₂, and the reactors are then maintained under a stream of nitrogen at 40°C for 3 h. Each reactor is again filled with 6 ml of DMF and then 1 mmol of

NaH per well is introduced, followed by 1 mmol of the various alkylating agents (see the various R₂ values in Tables 1 to 4) and the tip of a spatula of

KI. These mixtures are stirred at 70°C for 24 h. After filtration, a series of washes is carried out with, successively, 3 x 6 ml of DMF, 3 x 6 ml of MeOH and 3 x 6 ml of CH₂CI₂, and the reactors are then maintained under a stream of nitrogen at 40°C for 3 h. Finally, a solution of TFA/CH₂CI₂ (1/1 , 5 ml) is introduced into each reactor, the mixture is stirred at ambient temperature for 1 h, and the filtrates are isolated. The resin is rinsed with 2 x 6 ml of CH₂Cl₂ and these rinsing fractions are then added to the filtrates previously collected, and the entire mixture is then concentrated to dryness under vacuum. The various reaction crudes are purified by preparative HPLC

(Waters C18 symmetry column, 7μm, 19 x 150 mm, gradient 2-98/CH₃CN- H₂O+0.1%TFA to 100 CH₃CN) and then lyophilized. Table 1 gives the various substituents Ri and R₂ and also the retention times and purity obtained by analytical HPLC analysis of the isolated products (Waters C18 symmetry column, 5μm, 4.6 x 50 mm, gradient 0-100/H₂O-CH₃CN+0.1% TFA to 100 CH₃CN, 220 nm, flow rate 2.5 ml/min). This procedure was applied to intermediates 4e, 4f and 5e (see, respectively, Tables 2 to 4). Table 1: Substituents Ri and R₂, tr (retention time in minutes) and purity (analytical HPLC, Waters C18 symmetry column, 5 μ, 4.6 x 50 mm, gradient 0-100/H₂O-CH₃CN+0.1 % TFA to 100 CH₃CN, 220 nm, flow rate 2.5 ml/min).

Table 2: Substituents Ri and R₂, tr (retention time in minutes) and purity (analytical HPLC, Waters C18 symmetry column, 5μ, 4.6 x 50 mm, gradient 0-100/H₂O-CH₃CN+0.1% TFA to 100 CH₃CN, 220 nm, flow rate 2.5 ml/min).

Table 3: Substituents R-i and R , tr (retention time in minutes) and purity (analytical HPLC, Waters C18 symmetry column, 5 μ, 4.6 x 50 mm, gradient 0-100/H₂O-CH₃CN+0.1% TFA to 100 CH₃CN, 220 nm, flow rate 2.5 ml/min).

Table 4: Substituents Ri and R₂, tr (retention time in minutes) and purity (analytical HPLC, Waters C18 symmetry column, 5 μ, 4.6 x 50 mm, gradient 0-100/H₂O-CH₃CN+0.1% TFA to 100 CH₃CN, 220 nm, flow rate 2.5 ml/min).

EXAMPLES

Example 1: Ethyl 2-(4-f3-r6-hexvl-3.5-dioxo-2-(4,4,4-trifluorobutv0-2,5- dihydro-3H-[1,2,4]triazin-4-yl]propyl}phenoxy)-2-methylpropionate (1)

Compound 1 is prepared according to the method of synthesis 1: 5 g (25.3 mmol) of triazine 2c are placed in 35 ml of acetic anhydride at reflux for 1 h 30 min. After concentration of the reaction medium to dryness, the solid obtained is filtered and then rinsed with petroleum ether (3.8 g, yield = 62%). 0.6 g (2.59 mmol) of crystals isolated above are placed in 10 ml of DMF at 0°C under nitrogen. 0.1 g of NaH (60% in paraffin, 2.59 mmol) is added fractionwise and the solution is stirred at ambient temperature for 30 min. A solution of 0.71 g (2.16 mmol) of intermediate 6h in 10 ml of DMF is then run in dropwise and stirring is continued at 80°C for 2 h 30 min. After concentration to dryness, the residue obtained is taken up with H₂0 and extracted with ethyl acetate. After drying over MgS0₄, the organic phases are evaporated and the light-coloured oil obtained is placed in 17 ml of ethanol in the presence of 0.04 g of para-toluenesulphonic acid. This mixture is refluxed for 2 h and then concentrated to dryness. The residue is taken up with H₂0 and then extracted with ethyl acetate. After drying and evaporation of the organic phases, the light-coloured oil obtained is purified by flash chromatography on silica (petroleum ether-EtOAc: 90-10) and 0.87g of crystals is isolated (yield = 90%). They are then placed in 15 ml of DMF at 0°C under nitrogen and 0.09g (2.34 mmol) of NaH (60% in paraffin) is added. The reaction medium is stirred at ambient temperature for 30 min and 1 ,1 ,1- trifluoro-4-iodobutane (0.56g, 2.34 mmol) diluted in 10 ml of DMF is then run in and stirring is continued for 15 h at ambient temperature and then for 13 h at 80°C. After concentration to dryness, the residue obtained is taken up with H₂0 and extracted with ethyl acetate. After drying over MgSθ4, the organic phases are evaporated and the light-coloured oil obtained is purified by flash chromatography on silica (petroleum ether-EtOAc: 80-20). 0.8 g of a light- coloured oil (yield :80%) is isolated. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.71. ¹H NMR (DMSO): 0.85 ppm (t, 3H, J = 6.8 Hz), 1.16 ppm (t, 3H,

J = 7.2 Hz), 1.27 ppm (m, 6H), 1.48 ppm (s, 6H), 1.53 ppm (m, 2H), 1.83 ppm (m, 4H), 2.32 ppm (m, 2H), 2.47 ppm (m, 4H), 3.79 ppm (t, 2H, J = 7.2

Hz), 3.91 ppm (t, 2H, J = 6.8 Hz), 4.15 ppm (q, 2H, J = 7.2 Hz), 6.69 ppm (d,

2H, J = 8.4 Hz), 7.08 ppm (d, 2H, J = 8.4Hz).

Example 2: Ethyl 2-{4-[2-(2-benzyl-6-hexyl-3,5-dioxo-2,5-dihydro-3H-

[1 ,2,4]triazin-4-yl)ethyl]phenoxy}-2-methylpropionate (2)

The compound 2 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using the intermediate 6o for the first alkylation and benzyl bromide for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.65. Example 3: Ethyl 2-(4-{2-[6-hexyl-3,5-dioxo-2-(3-phenylpropyl)-2,5- dihydro-3H-[1,2,4]triazin-4-yl]ethyl}phenoxy)-2-methylpropionate (3)

The compound 3 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using the intermediate 6o for the first alkylation and (3-bromopropyl)benzene for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30, Rf = 0.65.

Example 4: 2-{4-[2-(2-Benzyl-6-cyclopentyl-3,5-dioxo-2,5-dihydro-3H- [1,2,4]triazin-4-yl)ethyl]phenoxy}-2-methylpropionic acid (4)

The compound 4 is prepared using the triazine 2e according to the method of synthesis 1 using the intermediate 6o for the first alkylation and benzyl bromide for the second. After saponification (LiOH/THF/H₂0-ambient temperature-12h-60%), it is isolated in the form of an oil. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.40. Example 5: Ethyl 2-{4-[2-(4-benzyl-6-hexyl-3,5-dioxo-4,5- dihydro-3H-[1,2,4]triazin-2-yl)ethyl]phenoxy}-2-methylpropionate (5)

The compound 5 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using benzyl bromide for the first alkylation and the intermediate 6o for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.52.

Example 6: Ethyl 2-(4-{2-[6-hexyl-3,5-dioxo-4-(3-phenylpropyl)-4,5- dihydro-3H-[1,2,4]triazin-2-yl]ethyl}phenoxy)-2-methylpropionate (6)

The compound 6 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using (3-bromopropyl)benzene for the first alkylation and the intermediate 6o for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30, Rf = 0.74. Example 7: Ethyl 2-{4-[2-(4-benzyl-6-cyclopentyl-3,5-dioxo-4,5- dihydro-3H-[1,2,4]triazin-2-yl)ethyl]phenoxy}-2-methylpropionate (7)

The compound 7 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using benzyl bromide for the first alkylation and the intermediate 6o for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.50.

Example 8: Ethyl 2-methyl-2-{4-[2-(4-methyl-3,5-dioxo-6-pyrrolidin-1 -yl- 4,5-dihydro-3H-[1,2,4]triazin-2-yl)ethyl]phenoxy}propionate (8)

The compound 8 (oil) is prepared by alkylating the triazine 2o (operating conditions described in the method of synthesis 1 with the intermediate 6o). TLC Merck silica gel 60 F 254, CH₂CI₂-EtOAc:95-5, Rf = 0.35. Example 9: Ethyl 2-{4-[2-(6-bromo-4-methyl-3,5-dioxo-4,5- dihydro-3H-[1,2,4]triazin-2-yl)ethyl]phenoxy)-2-methylpropionate (9)

The compound 9 (oil) is prepared using the triazine 2i according to the method of synthesis 1 using methyl iodide for the first alkylation and the intermediate 6o for the second. TLC Merck silica gel 60 F 254, CH₂CI₂-EtOAc: 95-5, Rf = 0.53.

Example 10: Ethyl 2-(4-{3-[6-hexyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5- dihydro-3H-[1 ,2,4]triazin-2-yl]propyl}phenoxy)-2-methylpropionate (10)

The compound 10 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using 1 ,1 ,1-trifluoro-4-iodobutane for the first alkylation and the intermediate 6h for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20,

Rf = 0.61. Example 11 : 2-(4-(3-r6-Hexvl-3,5-dioxo-4-(4.4.4-trifluorobutyl)-4,5- dihydro-3H-[1,2,4]triazin-2-yl]propyl}phenoxy)-2-methylpropionic acid (11)

After saponification of the compound 10 (LiOH/THF/H₂0-reflux- 12 h-quantitative yield), the compound 11 is isolated in the form of an oil. TLC Merck silica gel 60 F 254, CH₂CI₂-MeOH: 90-10, Rf = 0.25.

Example 12: Ethyl 2-[4-{3-[6-hexyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5- dihydro-3H-[1,2,4]triazin-2-yl]propyl}-2-(3-methylbut-2-enyl)phenoxy]- 2-methylpropionate (12)

The compound 12 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using 1 ,1 ,1-trifluoro-4-iodobutane for the first alkylation and the intermediate 6g for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 85-15, Rf = 0.49. Example 13: Ethyl 2-{4-[3-(4-benzyl-6-cyclopentyl-3,5-dioxo- 4,5-dihydro-3H-[1,2,4]triazin-2-yl)propyl]phenoxy}-2-methylpropionate (13)

The compound 13 (oil) is prepared using the triazine 2e according to the method of synthesis T using benzyl bromide for the first alkylation and the intermediate 6h for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.50.

Example 14: Ethyl 2-{4-[3-(6-bromo-4-heptyl-3,5-dioxo-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)propyl]phenoxy}-2-methylpropionate (14)

The compound 14 (oil) is prepared using the triazine 2i according to the method of synthesis 1 using bromoheptane for the first alkylation and the intermediate 6h for the second. TLC Merck silica gel 60 F 254, CH₂CI₂-MeOH:90-10, Rf = 0.73. Example 15: Ethyl 2-[4-[3-(6-bromo-4-heptyl-3,5-dioxo-4,5-dϊhydro-3H- [1,2,4]trlazin-2-yl)propyl]-2-(3-methyl-but-2-enyl)phenoxy]-2-methyl- propionate (15)

The compound 15 (oil) is prepared using the triazine 2i according to the method of synthesis 1 using bromoheptane for the first alkylation and the intermediate 6g for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.31.

Example 16: Ethyl 2-{3-[3-(2-Benzyl-6-hexyl-3,5-dioxo-2,5-dihydro-3H- [1 ,2,4]triazin-4-yl)propyl]phenoxy}-2-methylpropionate (16)

The compound 16 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using the intermediate 6a for the first alkylation and benzyl bromide for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.50. Example 17: Ethyl 2-[3-(3-{6-hexyl-2-[2-(2-nitrophenyl)- 2-oxoethyl]-3,5-dioxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl}propyl)phenoxy]- 2-methylpropionate (17)

The compound 17 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using the intermediate 6a for the first alkylation and 2-bromo-1-(2-nitrophenyl)ethanone for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30, Rf = 0.30.

Example 18: Ethyl 2-(3-{3-[6-cyclopentyl-3,5-dioxo-2-(4,4,4-trifluoro- butyl)-2,5-dihydro-3H-[1,2,4]triazin-4-yl]propyl}phenoxy)-2-methyl- propionate (18)

The compound 18 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using the intermediate 6a for the first alkylation and 1 ,1 ,1 -trifluoro-4-iodobutane for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.29. Example 19: Ethyl 4-(6-cyclopentyl-4-{3-[3-(1-ethoxycarbonyl-1-methyI- ethoxy)phenyl]propyl}-3,5-dioxo-2,5-dihydro-3H-[1,2,4]triazin-2-yl)but- 2-enoate (19)

The compound 19 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using the intermediate 6a for the first alkylation and ethyl 4-bromobut-2-enoate for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.28.

Example 20: Ethyl 2-{3-[3-(2-benzyl-6-cyclopentyl-3,5-dioxo-2,5-dihydro- 3H-[1 ,2,4]triazin-4-yl)propyl]phenoxy}-2-methylpropionate (20)

The compound 20 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using the intermediate 6k for the first alkylation and benzyl bromide for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20,

Rf = 0.40. Example 21 : Ethyl 2-(3-{3-[2-(3-cyclohexylpropyl)-6-cyclopentyl-3,5- dioxo-2,5-dihydro-3H-[1,2,4]trϊazin-4-yl]propyl}phenoxy)-2-methyl- propionate (21)

The compound 21 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using the intermediate 6a for the first alkylation and (3-bromopropyl)cyclohexane for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.47.

Example 22: Ethyl 2-[3-(3-{6-benzyl-2-[4-(4-methoxyphenyl)-4-oxobutyl]- 3,5-dioxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl}propyl)phenoxy]-2-methyl- propionate (22)

The compound 22 (oil) is prepared using the triazine 2d according to the method of synthesis 1 using the intermediate 6a for the first alkylation and 4-chloro-1-(4-methoxyphenyl)butan-1-one for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.29. Example 23: Ethyl 2-{3-[3-(4-benzyl-6-hexyl-3,5-dioxo-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)propyl]phenoxy}-2-methylpropionate (23)

The compound 23 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using benzyl bromide for the first alkylation and the intermediate 6k for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30, Rf = 0.30.

Example 24: 2-{3-[3-(4-Benzyl-6-hexyl-3,5-dioxo-4,5-dihydro-3H« [1 ,2,4]triazin-2-yl)propyl]phenoxy}-2-methylpropionic acid (24)

After saponification of the compound 23 (LiOH/THF/H₂0-reflux-

12h-quantitative yield), the compound 24 is isolated in the form of an oil. TLC Merck silica gel 60 F 254, CH₂CI₂-MeOH: 95-5, Rf = 0.40. Example 25: Ethyl 2-[3-(3-{6-hexyl-4-[2-(2-nitrophenyl)-2-oxoethyl]-3,5- dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl}propyl)phenoxy]-2-methyl- propionate (25)

The compound 25 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using 2-bromo-1-(2-nitrophenyl)ethanone for the first alkylation and the intermediate 6k for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30, Rf = 0.30.

Example 26: Ethyl 2-(3-{3-[6-cyclopentyl-3,5-dioxo-4-(4,4,4-trifluoro- butyl)-4,5-dihydro-3H-[1,2,4]triazin-2-yl]propyl}phenoxy)-2-methyl- propionate (26)

The compound 26 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using 1 ,1 ,1-trifluoro-4-iodobutane for the first alkylation and the intermediate 6k for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30, Rf = 0.61. Example 27: 2-(3-(3-r6-Cvclopentvl-3.5-dioxo-4-(4,4,4-trifluorobutvl)-4,5- dϊhydro-3H-[1,2,4]trϊazin-2-yl]propyl}phenoxy)-2-methylpropionic acid (27)

After saponification of the compound 26 (LiOH/THF/H₂0-reflux-

16 h-quantitative yield), the compound 27 is isolated in the form of an oil.

TLC Merck silica gel 60 F 254, CH₂CI₂-MeOH: 90-10, Rf = 0.48.

Example 28: Ethyl 2-[3-(3-{6-cyclopentyl-3,5-dioxo-4-[2-(2,2,2-trifluoro- acetylamino)ethyl]-4,5-dihydro-3H-[1,2,4]triazin-2-yl}propyl)phenoxy]- 2-methylpropionate (28)

The compound 28 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using N-(2-iodoethyl)-2,2,2-trifluoroacetamide for the first alkylation and the intermediate 6k for the second. TLC Merck silica gel 60 F 254, CH₂CI₂-EtOAc: 90-10, Rf = 0.30. Example 29: Ethyl 4-(6-cyclopentyl-2-{3-[3-(1-ethoxycarbonyl-1-methyl- ethoxy)phenyl]propyl}-3,5-dioxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)but- 2-enoate (29)

The compound 29 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using ethyl 4-bromo-but-2-enoate for the first alkylation and the intermediate 6k for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30, Rf = 0.32.

Example 30: 4-(2-{3-[3-(1 -Carboxy-1 -methylethoxy)phenyl]propyl}- 6-cyclopentyl-3,5-dioxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)but-2-enoic acid (30)

After saponification of the compound 29 (LiOH/THF/H₂0-reflux-

3 h-50%), the compound 30 is isolated in the form of an oil. TLC Merck silica gel 60 F 254, CH₂CI₂-MeOH-AcOH: 90-9-1 , Rf = 0.49. Example 31 : Ethyl 2-{3-[3-(4-benzyl-6-cyclopentyl-3,5-dioxo- 4,5-dihydro-3H-[1,2,4]triazin-2-yl)propyl]phenoxy}-2-methylpropionate (31)

The compound 31 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using benzyl bromide for the first alkylation and the intermediate 6k for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.50.

Example 32: Ethyl 2-{3-[3-(4-benzyl-6-cyclopentyl-3,5-dioxo-4,5-dϊhydro- 3H-[1,2,4]triazin-2-yl)propenyl]phenoxy}-2-methylpropionate (32)

The compound 32 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using benzyl bromide for the first alkylation and the intermediate 6n for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.33. Example 33: Ethyl 2-{3-[3-(4-cyclohexylmethyl-6-cyclopentyl-3,5-dioxo-

4,5-dihydro-3H-[1,2,4]triazin-2-yl)propyl]phenoxy}-2-methylpropionate

(33)

The compound 33 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using bromomethylcyclohexane for the first alkylation and the intermediate 6k for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.70.

Example 34: Ethyl 2-(3-{3-[6-cyclopentyl-3,5-dioxo-4-(4-oxo-4-thiophen- 2-ylbutyl)-4,5-dihydro-3H-[1,2,4]triazin-2-yl]propyl}phenoxy)-2-methyl- propionate (34)

The compound 34 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using 4-chloro-1-thiophen-2-ylbutan-1-one for the first alkylation and the intermediate 6k for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30,

Rf = 0.55. Example 35: Ethyl 2-{3-[3-(4-benzyloxymethyl-6-cyclopentyl-3,5-dioxo-

4,5-dihydro-3H-[1,2,4]triazin-2-yl)propyl]phenoxy}-2-methylpropionate

(35)

The compound 35 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using chloromethoxymethylbenzene for the first alkylation and the intermediate 6a for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30, Rf = 0.58.

Example 36: Ethyl 2-(3-{3-[4-(3-cyclohexylpropyl)-6-cyclopentyl-3,5- dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]propyl}phenoxy)-2-methyl- propionate (36)

The compound 36 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using (3-chloropropyl)cyclohexane for the first alkylation and the intermediate 6k for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.26. Example 37: 2-(3-(3-r4-(3-Cvclohexvlpropvl)-6-cvclopentyl-3,5-dioxo-4.5- dihydro-3H-[1,2,4]triazin-2-yl]propyl}phenoxy)-2-methylpropionic acid

(37)

After saponification of the compound 36 (LiOH/THF/H₂0-reflux-

12h-85%), the compound 37 is isolated in the form of an oil. TLC Merck silica gel 60 F 254, CH₂Cl₂-MeOH: 95-5, Rf = 0.25.

Example 38: Ethyl 2-[3-(3-{6-cyclopentyl-4-[2-(1H-indol-3-yl)ethyl]-3,5- dioxo-4,5-dihydro-3H-[1 ,2,4]triazin-2-yl}propyl)phenoxy]-2-methyl- propionate (38)

The compound 38 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using 3-(2-bromoethyl)-1 H-indole for the first alkylation and the intermediate 6k for the second. TLC Merck silica gel 60 F 254, CH₂CI₂-EtOAc: 70-30, Rf = 0.68. Example 39: Ethyl 2-[3-(3-{6-cyclopentyl-4-[4-(4-methoxy- phenyI)-4-oxobutyl]-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl}propyl)- phenoxy]-2-methylpropionate (39)

The compound 39 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using 4-chloro-1-(4-methoxyphenyl)butan-1-one for the first alkylation and the intermediate 6k for the second. TLC Merck silica gel 60 F 254, CH₂CI₂-EtOAc: 90-10, Rf = 0.68.

Example 40: Ethyl 2-(3-{3-[6-cyclopentyl-4-(3,3-diphenylpropyl)-3,5- dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl]propyl}phenoxy)-2-methyl- propionate (40)

The compound 40 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using 3,3'-diphenylbromopropane for the first alkylation and the intermediate 6k for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf =0.41. Example 41 : Ethyl 2-{3-[3-(6-bromo-4-heptyl-3,5-dioxo-4,5- dihydro-3H-[1 ,2,4]triazin-2-yl)propyl]phenoxy}-2-methylpropionate (41 )

The compound 41 (oil) is prepared using the triazine 2i according to the method of synthesis 1 using bromoheptane for the first alkylation and the intermediate 6k for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.33.

Example 42: Ethyl 2-{3-[3-(4-benzyl-3,5-dioxo-6-thiophen-2-yl-4,5- dihydro-3H-[1,2,4]triazin-2-yl)propyl]phenoxy}-2-methylpropϊonate (42)

The compound 42 (oil) is prepared using the triazine 2h according to the method of synthesis 1 using benzyl bromide for the first alkylation and the intermediate 6k for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30, Rf = 0.70. Example 43: Ethyl 2-(3-{4-[6-hexyl-3,5-dioxo-2-(4,4,4-trifluorobutyl)-2,5- dihydro-3H-[1,2,4]triazin-4-yl]butyl}phenoxy)-2-methylpropionate (43)

The compound 43 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using the intermediate 6b for the first alkylation and 1 ,1,1-trifluoro-4-iodobutane forthe second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 85-15, Rf = 0.41.

Example 44: Ethyl 4-(4-{4-[3-(1-ethoxycarbonyl-1-methylethoxy)- phenyl]butyl}-6-hexyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)but- 2-enoate (44)

The compound 44 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using the intermediate 6b for the first alkylation and ethyl 4-bromobut-2-enoate for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.46. Example 45: Ethyl 2-{3-[4-(2-heptyl-6-hexyl-3,5-dioxo-2,5-dihydro-3H- [1 ,2,4]triazin-4-yl)butyl]phenoxy}-2-methylpropionate (45)

The compound 45 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using the intermediate 6b for the first alkylation and bromoheptane for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.80.

Example 46: Ethyl 2-(3-{4-[6-cyclopentyl-3,5-dioxo-2-(4-phenylbutyl)-2,5- dihydro-3H-[1,2,4]triazin-4-yl]butyl}phenoxy)-2-methylpropionate (46)

The compound 46 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using the intermediate 6b for the first alkylation and (4-chlorobutyl)benzene for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.57. Example 47: Ethyl 2-(3-{4-[3,5-dioxo-6-phenyl-2-(4,4,4-trifluorobutyl)-2,5- dihydro-3H-[1,2,4]triazin-4-yl]butyl}phenoxy)-2-methylpropionate (47)

The compound 47 (oil) is prepared using the triazine 2g according to the method of synthesis 1 using the intermediate 6b for the first alkylation and 1 ,1 ,1-trifluoro-4-iodobutane for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30, Rf = 0.55.

Example 48: Ethyl 2-{3-[4-(2-heptyl-3,5-dioxo-6-phenyl-2,5-dihydro-3H- [1 ,2,4]triazin-4-yl)-butyl]phenoxy}-2-methylpropionate (48)

The compound 48 (oil) is prepared using the triazine 2g according to the method of synthesis 1 using the intermediate 6b for the first alkylation and bromoheptane for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.30. Example 49: 2-(3-r4-(2-Heptvl-3.5-dioxo-6-phenvl-2.5-dihvdro-3H- [1,2,4]trϊazin-4-yl)butyl]phenoxy}-2-methylpropionic acid (49)

After saponification of the compound 48 (LiOH/THF/H₂0-reflux- 72h-yield 78%), the compound 49 is isolated in the form of an oil. TLC Merck silica gel 60 F 254, CH₂CI₂-EtOAc: 70-30, Rf = 0.52.

Example 50: Ethyl 2-{2,3-difluoro-5-[4-(2-heptyl-3,5-dioxo-6-phenyl-2,5- dihydro-3H-[1,2,4]triazin-4-yl)butyl]phenoxy}-2-methylpropionate (50)

The compound 50 (oil) is prepared using the triazine 2g according to the method of synthesis 1 using the intermediate 6j for the first alkylation and bromoheptane for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 85-15, Rf = 0.44. Example 51: Ethyl 2-(3-{4-[2-(6-cyanohexyl)-3,5-dioxo-6-phenyl-2,5- dihydro-3H-[1 ,2,4]trϊazin-4-yl]-butyl}phenoxy)-2-methylpropionate (51 )

The compound 51 (oil) is prepared using the triazine 2g according to the method of synthesis 1 using the intermediate 6b for the first alkylation and 7-bromoheptanenitrile for the second. TLC Merck silica gel 60 F 254, CH₂CI₂-EtOAc: 90-10, Rf = 0.81.

Example 52: Ethyl 2-{3-[4-(2-benzyloxymethyl-3,5-dioxo-6-phenyl-2,5- dihydro-3H-[1 ,2,4]triazin-4-yl)butyl]phenoxy}-2-methylpropionate (52)

The compound 52 (oil) is prepared using the triazine 2g according to the method of synthesis 1 using the intermediate 6b for the first alkylation and chloromethoxymethylbenzene for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20,

Rf = 0.57. Example 53: Ethyl 2-(3-{4-[2-(3-cyclohexylpropyl)-3,5-dioxo-6-phenyl-

2,5-dihydro-3H-[1,2,4]triazin-4-yl]butyl}phenoxy)-2-methylpropionate

(53).

The compound 53 (oil) is prepared using the triazine 2g according to the method of synthesis 1 using the intermediate 6b for the first alkylation and (3-bromopropyl)cyclohexane for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.33.

Example 54: Ethyl 2-(3-f4-r6-benzyl-3,5-dioxo-2-(4A4-trifluorobutyl)-2,5- dihydro-3H-[1,2_s4]triazin-4-yl]butyl}phenoxy)-2-methylpropionate (54)

The compound 54 (oil) is prepared using the triazine 2d according to the method of synthesis 1 using the intermediate 6b for the first alkylation andl ,1 ,1-trifluoro-4-iodobutane for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.47. Example 55: Ethyl 2-{3-[4-(6-benzyl-2-heptyl-3,5-dioxo-2,5-dihydro-3H- [1 ,2,4]triazin-4-yl)butyl]phenoxy}-2-methylpropionate (55)

The compound 55 (oil) is prepared using the triazine 2d according to the method of synthesis 1 using the intermediate 6b for the first alkylation and bromoheptane for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.30.

Example 56: Ethyl 2-{3-[4-(6-bromo-2-heptyl-3,5-dioxo-2,5-dihydro-3H- [1 ,2,4]triazin-4-yl)butyl]phenoxy}-2-methylpropionate (56)

The compound 56 (oil) is prepared using the triazine 2i according to the method of synthesis 1 using the intermediate 6b for the first alkylation and bromoheptane for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.25. Example 57: Ethyl 2-(3-{4-[6-hexyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5- dihydro-3H-[1,2,4]triazin-2-yl]butyl}phenoxy)-2-methylpropionate (57)

The compound 57 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using 1 ,1 ,1-trifluoro-4-iodobutane for the first alkylation and the intermediate 6b for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.70.

Example 58: Ethyl 4-(2-{4-[3-(1 -ethoxycarbonyl-1 -methylethoxy)- phenyl]butyl}-6-hexyl-3,5-dioxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)- butyrate (58)

The compound 58 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using ethyl 4-bromobutanoate for the first alkylation and the intermediate 6b for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.34. Example 59: Ethyl 2-{3-[4-(4-heptyl-6-hexyl-3,5-dioxo-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)butyl]phenoxy}-2-methylpropionate (59)

The compound 59 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using bromoheptane for the first alkylation and the intermediate 6b for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.44.

Example 60: Ethyl 2-{3-[4-(4-Benzyl-6-hexyl-3,5-dioxo-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)butyl]phenoxy}-2-methylpropionate (60)

The compound 60 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using benzyl bromide for the first alkylation and the intermediate 6b for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.75. Example 61 : Ethyl 4-[2-(3-{6-hexyl-3,5-dioxo-4-(4oxo-4-thiophen-2-yl- butyl)-4,5-dihydro-3H-[1,2,4]triazin-2-yl]butyl}phenoxy)-2-methyl- propionate (61)

The compound 61 (oil) is prepared using the triazine 2j according to the method of synthesis 2 (Scheme 2). 0.21 g (5.3 mmol) of NaH (60% in paraffin) are placed in 10 ml of DMF at 0°C under nitrogen. A solution of 1g (4.4 mmol) of triazine 2j in 10 ml of DMF is run in dropwise. The reaction medium is then stirred for 30 min at this temperature, and a solution of 1.8 g (5.3 mmol) of intermediate 6b in 10 ml of DMF is then run in dropwise. Stirring is continued for 24 h at ambient temperature. After concentration to dryness, the residue obtained is taken up with H₂0 and extracted with ethyl acetate. After drying over MgSθ₄, the organic phases are evaporated and the light-coloured oil obtained is purified by flash chromatography on silica (CH₂CI₂-EtOAc: 90-10). 1.1 g of oil (yield = 51%) are isolated and are then placed in 15 ml of ethanol/2N HCl. This mixture is refluxed for 11 h and then concentrated to dryness. 0.84 g of oil (84% yield) is recovered. 0.08 g (2.14 mmol) of NaH (60% in paraffin) is placed in 5 ml of DMF at 0°C under nitrogen. A solution of 0.82 g (1.78 mmol) of oil isolated beforehand, in 10 ml of DMF, is run in dropwise. The reaction medium is stirred for 30 min at this temperature, and 4-chloro-1-thiophen-2-ylbutan-1-one (0.4 g, 2.14 mmol) is then added. Stirring is continued for 48 h at ambient temperature and the reaction medium is then concentrated to dryness. The residue is taken up with H₂0 and then extracted with ethyl acetate. After drying, the organic phases are evaporated. The light-coloured oil obtained is purified by flash chromatography on silica (petroleum ether-EtOAc: 70-30). 0.3 g of compound 61 is isolated in the form of an oil (yield = 30%). TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30,

Rf = 0.28.

Example 62: Ethyl 2-[3-(4-{4-[4-(3,5-bistrifluoromethylphenyl)butyl]- 6-hexyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl}butyl)phenoxy]- 2-methylpropionate (62)

The compound 62 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using 1-(4-bromobutyl)-3,5-bistrifluoromethyl- benzene for the first alkylation and the intermediate 6b for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.53.

Example 63: Ethyl 4-(6-cyclopentyl-2-{4-[3-(1-ethoxycarbonyl-1-methyl- ethoxy)phenyl]butyl}-3,5-dioxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)but-2- enoate (63)

The compound 63 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using ethyl 4-bromobut-2-enoate for the first alkylation and the intermediate 6b for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.28. Example 64: Ethyl 2-{3-[4-(4-benzyl-6-cyclopentyl-3,5-dioxo-4,5-dϊhydro- 3H-[1 ,2,4]triazin-2-yl)butyl]phenoxy}-2-methylpropionate (64)

The compound 64 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using benzyl bromide for the first alkylation and the intermediate 61 for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.60

Example 65: Ethyl 2-(3-{4-[6-cyclopentyl-3,5-dioxo-4-(2-oxo-2-phenyl- ethyl)-4,5-dihydro-3H-[1,2,4]triazin-2-yl]butyl}phenoxy)-2-methyl- propionate (65)

The compound 65 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using 2-chloro-1-phenylethanone for the first alkylation and the intermediate 61 for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.30. Example 66: Ethyl 2-[3-(4-{6-cyclopentyl-4-[(2,6-dimethylphenyl- carbamoyl)methyl]-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl}butyl)- phenoxy]-2-methylpropionate (66)

The compound 66 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using 2-chloro-N-(2,6-dimethylphenyl)acetamide for the first alkylation and the intermediate 61 for the second. TLC Merck silica gel 60 F 254, CH₂CI₂-EtOAc: 90-10, Rf = 0.40.

Example 67: Ethyl 2-(3-{4-[6-cyclopentyl-3,5-dioxo-4-(4-phenylbutyl)-4,5- dihydro-3H-[1,2,4]-triazin-2-yl]but-1-ynyl}phenoxy)-2-methylpropionate (67)

The compound 67 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using (4-bromobutyl)benzene for the first alkylation and the intermediate 6m for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.51. Example 68: Ethyl 2-(3-{4-[6-cyclopentyl-3,5-dioxo-4-(4-phenylbutyl)- 4,5-dihydro-3H-[1,2,4]triazin-2-yl]butyl}phenoxy)-2-methylpropionate (68)

The compound 68 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using (4-bromobutyl)benzene for the first alkylation and the intermediate 6b for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.25.

Example 69: 2-(3-{4-[6-Cyclopentyl-3,5-dioxo-4-(4-phenylbutyl)-4,5- dihydro-3H-[1,2,4]triazin-2-yl]butyl}phenoxy)-2-methylpropionic acid (69)

After saponification of the compound 68 (LiOH/THF/H₂0-reflux-

17h-66% yield), the compound 69 is isolated in the form of an oil. TLC Merck silica gel 60 F 254, EtOAc, Rf = 0.50. Example 70: Ethyl 2-{3-[4-(4-heptyl-3,5-dioxo-6-phenyl-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)butyl]phenoxy}-2-methylpropionate (70)

The compound 70 (oil) is prepared using the triazine 2g according to the method of synthesis 1 using bromoheptane for the first alkylation and the intermediate 6b for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.34.

Example 71 : Ethyl 2-(3-{4-[4-(3-cyclohexylpropyl)-3,5-dioxo-6-phenyl-

4,5-dihydrό-3H-[1,2,4]triazin-2-yl]butyl}phenoxy)-2-methylpropionate

(71)

The compound 71 (oil) is prepared using the triazine 2g according to the method of synthesis 1 using (3-bromopropyl)cyclohexane for the first alkylation and the intermediate 6b for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.33. Example 72: Example 2-(3-{4-[6-benzyl-3,5-dioxo-4-(4,4,4-trifluorobutyI)-

4,5-dihydro-3H-[1,2,4]triazin-2-yl]butyl}phenoxy)-2-methylpropionate

(72)

The compound 72 is prepared using the triazine 2k according to the method of synthesis 2 using the intermediate 6b for the first alkylation and 1 , ,1-trifluoro-4-iodobutane for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.57.

Example 73: Ethyl 2-{3-[4-(6-benzyl-4-heptyl-3,5-dioxo-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)butyl]phenoxy}-2-methylpropionate (73)

The compound 73 (oil) is prepared using the triazine 2k according to the method of synthesis 2 using the intermediate 6b for the first alkylation and bromoheptane for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.66. Example 74: 2-{3-[4-(6-Benzyl-4-heptyl-3,5-dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl)butyl]phenoxy}-2-methylpropionic acid (74)

After saponification of the compound 73 (LiOH/THF/H₂0-reflux- 12h-62% yield), the compound 74 is isolated in the form of an oil. TLC Merck silica gel 60 F 254, CH₂CI₂-EtOAc: 70-30, Rf = 0.45.

Example 75: Ethyl 2-{3-[4-(6-bromo-4-heptyl-3,5-dioxo-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)butyl]phenoxy}-2-methylpropϊonate (75)

The compound 75 (oil) is prepared using the triazine 2i according to the method of synthesis 1 using bromoheptane for the first alkylation and the intermediate 6b for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.30.

Example 76: Ethyl 2-(3-f5-r6-hexvl-3.5-dioxo-2-(4A4-trif⁾uorobutvl)-2.5- dihydro-3H-[1,2,4]triazin-4-yl]pentyl}phenoxy)-2-methylpropionate (76)

The compound 76 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using the intermediate 6c for the first alkylation and 1,1,1-trifluoro-4-iodobutane forthe second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 70-30, Rf = 0.58.

Example 77: Ethyl 4-(4-{5-[3-(1-ethoxycarbonyl-1-methylethoxy)phenyl]- pentyl}-6-hexyl-3,5-dioxo-4,5-dϊhydro-3H-[1,2,4]triazin-2-yl)but-2-enoate (77)

The compound 77 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using the intermediate 6c for the first alkylation and ethyl 4-bromobut-2-enoate for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.52. Example 78: Ethyl 2-{3-[5-(2-benzyl-6-hexyl-3,5-dioxo-2,5-dihydro-3H- [1 ,2,4]triazin-4-yl)pentyl]phenoxy}-2-methylpropionate (78)

The compound 78 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using the intermediate 6c for the first alkylation and benzyl bromide for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.54.

Example 79: Ethyl 4-(6-cyclopentyl-4-{5-[3-(1 -ethoxycarbonyl-1 -methyl- ethoxy)phenyl]pentyl}-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)but- 2-enoate (79)

The compound 79 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using the intermediate 6c for the first alkylation and ethyl 4-bromobut-2-enoate for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.53. Example 80: Ethyl 2-{3-[5-(2-heptyl-3,5-dioxo-6-phenyl-2,5-dihydro-3H- [1 ,2,4]triazin-4-yl)pentyl]phenoxy}-2-methylpropionate (80)

The compound 80 (oil) is prepared using the triazine 2g according to the method of synthesis 1 using the intermediate 6c for the first alkylation and bromoheptane for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.28.

Example 81: Ethyl 2-(3-(5-r6-hexvl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5- dihydro-3H-[1 ,2,4]triazin-2-yl]pentyl}phenoxy)-2-methylpropionate (81 )

The compound 81 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using 1 ,1 ,1-trifluoro-4-iodobutane for the first alkylation and the intermediate 6c for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 85-15, Rf = 0.51. Example 82: Ethyl 2-{3-[5-(4-benzyl-6-hexyl-3,5-dioxo-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)pentyl]phenoxy}-2-methylpropionate (82)

The compound 82 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using benzyl bromide for the first alkylation and the intermediate 6c for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 85-15, Rf = 0.41.

Example 83: Ethyl 2-(3-{5-[6-cyclopentyl-3,5-dioxo-4-(4,4,4-trifluoro- butyl)-4,5-dihydro-3H-[1,2,4]triazin-2-yl]pentyl}phenoxy)-2-methyl- propionate (83)

The compound 83 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using 1 ,1 ,1-trifluoro-4-iodobutane for the first alkylation and the intermediate 6c for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 85-15, Rf = 0.40. Example 84: Ethyl 4-(6-cyclopentyl-(2-{5-[3-(1 -ethoxycarbonyl-1 -methyl- ethoxy)phenyl]pentyl}-3,5-dioxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)but- 2-enoate (84)

The compound 84 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using ethyl 4-bromobut-2-enoate for the first alkylation and the intermediate 6c for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.36.

Example 85: Ethyl 2-(3-{5-[3,5-dioxo-6-phenyl-4-(4,4,4-trifluorobutyl)-4,5- dihydro-3H-[1,2,4]triazin-2-yl]pentyl}phenoxy)-2-methylpropionate (85)

The compound 85 (oil) is prepared using the triazine 2g according to the method of synthesis 1 using 1 ,1 ,1-trifluoro-4-iodobutane for the first alkylation and the intermediate 6b for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.25. Example 86: Ethyl 2-{3-[5-(4-heptyl-3,5-dioxo-6-phenyl-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)pentyl]phenoxy}-2-methylpropionate (86)

The compound 86 (oil) is prepared using the triazine 2g according to the method of synthesis 1 using bromoheptane for the first alkylation and the intermediate 6c for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.68.

Example 87: Ethyl 2-(3-{5-[6-benzyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5- dihydro-3H-[1,2,4]triazin-2-yl]pentyl}phenoxy)-2-methylpropionate (87)

The compound 87 (oil) is prepared using the triazine 2d according to the method of synthesis 1 using 1 ,1 ,1-trifluoro-4-iodobutane for the first alkylation and the intermediate 6c for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 85-15, Rf = 0.34. Example 88: Ethyl 2-{3-[5-(6-bromo-4-heptyl-3,5-dioxo-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)pentyl]phenoxy}-2-methylpropionate (88)

The compound 88 (oil) is prepared using the triazine 2i according to the method of synthesis 1 using bromoheptane for the first alkylation and the intermediate 6c for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 85-15, Rf = 0.41.

Example 89: Ethyl 2-{3-[6-(2-heptyl-3,5-dioxo-6-phenyl-2,5-dihydro-3H- [1 ,2,4]triazin-4-yl)hexyl]phenoxy}-2-methylpropionate (89)

The compound 89 (oil) is prepared using the triazine 2g according to the method of synthesis 1 using the intermediate 6d for the first alkylation and bromoheptane for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.56. Example 90: Ethyl 2-(3-(6-r6-hexvl-3.5-dioxo-4-(4A4-trifluorobutyl)-4.5- dihydro-3H-[1,2,4]triazin-2-yl]hexyl}phenoxy)-2-methylpropionate (90)

The compound 90 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using 1 ,1,1-trifluoro-4-iodobutane for the first alkylation and the intermediate 6d for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.35.

Example 91 : Ethyl 2-{3-[6-(4-benzyl-6-hexyl-3,5-dioxo-4,5-dihydro-3H- [1 ,2,4-triazin-2-yl)hexyl]phenoxy}-2-methylpropionate (91)

The compound 91 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using benzyl bromide for the first alkylation and the intermediate 6d for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 85-15, Rf = 0.41. Example 92: Ethyl 4-(6-cyclopentyl-2-{6-[3-(1 -ethoxycarbonyl-1 -methyl- ethoxy)phenyl]hexyl}-3,5-dioxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)but- 2-enoate (92)

The compound 92 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using ethyl 4-bromobut-2-enoate for the first alkylation and the intermediate 6d for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.47.

Example 93: Ethyl 2-{3-[6-(6-bromo-4-heptyl-3,5-dioxo-4,5-dihydro-3H- [1 ,2,4]triazϊn-2-yl)hexyl]phenoxy}-2-methylpropionate (93)

The compound 93 (oil) is prepared using the triazine 2i according to the method of synthesis 1 using bromoheptane for the first alkylation and the intermediate 6d for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 85-15, Rf = 0.45. Example 94: Ethyl 2-{3-[3-(4-benzyl-6-hexyl-3,5-dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl)propyl]phenylsulphanyl}-2-methylpropionate (94)

The compound 94 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using benzyl bromide for the first alkylation and the intermediate 6f for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.55.

Example 95: Ethyl 4-(6-cyclopentyl-2-{3-[3-(1 -ethoxycarbonyl-1 -methyl- ethylsulphanyl)phenyl]propyl}-3,5-dioxo-2,5-dihydro-3H-[1,2,4]triazin-4- yl)but-2-enoate (95)

The compound 95 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using ethyl 4-bromobut-2-enoate for the first alkylation and the intermediate 6f for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.27. Example 96: Ethyl 2-{3-[3-(4-benzyl-6-cyclopentyl-3,5-dioxo-4,5-dihydro- 3H-[1,2,4]triazin-2-yl)propyl]phenylsulphanyl}-2-methylpropionate (96)

The compound 96 (oil) is prepared using the triazine 2e according to the method of synthesis 1 using benzyl bromide for the first alkylation and the intermediate 6f for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.60.

Example 97: Ethyl 2-{3-[4-(2-heptyl-3,5-dioxo-6-phenyl-2,5-dihydro-3H- [1,2,4]triazin-4-yl)butyl]phenylsulphanyl}-2-methylpropionate (97)

The compound 97 (oil) is prepared using the triazine 2g according to the method of synthesis 1 using the intermediate 6e for the first alkylation and bromoheptane for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.62. Example 98: Ethyl 2-{3-[4-(6-benzyl-2-heptyl-3,5-dioxo-2,5-dihydro-3H- [1,2,4]triazin-4-yl)butyl]phenylsulphanyl}-2-methylpropionate (98)

The compound 98 (oil) is prepared using the triazine 2d according to the method of synthesis 1 using the intermediate 6e for the first alkylation and benzyl bromide for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 50-50, Rf = 0.77.

Example 99: Ethyl 2-(3-{4-[6-hexyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5- dihydro-3H-[1,2,4]triazin-2-yl]butyl}phenylsulphanyl)-2-methyl- propionate (99)

The compound 99 (oil) is prepared using the triazine 2c according to the method of synthesis 1 using 1 ,1 ,1-trifluoro-4-iodobutane for the first alkylation and the intermediate 6e for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 85-15, Rf = 0.42. Example 100: Ethyl 2-{3-[4-(6-bromo-4-heptyl-3,5-dioxo-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)butyl]phenylsulphanyl}-2-methylpropionate (100)

The compound 100 (oil) is prepared using the triazine 2i according to the method of synthesis 1 using bromoheptane for the first alkylation and the intermediate 6e for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.54.

Example 101 : Ethyl 2-{2-[4-(6-bromo-4-heptyl-3,5-dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl)butyl]phenoxy}-2-methylpropϊonate (101)

The compound 101 (oil) is prepared using the triazine 2i according to the method of synthesis 1 using bromoheptane for the first alkylation and the intermediate 6i for the second. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 90-10, Rf = 0.29. Example 102: Ethyl 2-(4-f2-r6-hexvl-3.5-dioxo-2-(4A4-trifluorobutvl)-2.5- dihydro-3H-[1,2,4]triazin-4-yl]ethoxy}phenoxy)-2-methylpropionate

(102)

The compound 102 is prepared according to the method of synthesis 4 presented in Scheme 4. 1.29 g (3.67 mmol) of triazine 2p, 0.75 g (3.34 mmol) of intermediaite 4i and 1.14 g (4.34 mmol) of triphenylphosphine are placed in 15 ml of THF at 40°C. A solution of DEAD (0.68 ml, 4.31 mmol) in 5 ml of THF is run in dropwise. The mixture is stirred at 40°C for 5 h. After concentration of the reaction medium to dryness, the oil obtained is purified by flash chromatography on silica (petroleum ether-EtOAc: 98-2). 0.71 g (40% yield) of compound 102 is isolated. TLC Merck silica gel 60 F 254, CH₂CI₂-EtOAc: 95-5, Rf = 0.72.

Example 103: Ethyl 2-(4-{2-[6-hexyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5- dihydro-3H-[1,2,4]triazin-2-yl]ethoxy}phenoxy)-2-methylpropionate (103)

The compound 103 (oil) is prepared according to the method of synthesis 4 using the triazine 2q and the intermediate 4i. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 80-20, Rf = 0.37. Example 104: Ethyl 2-(3- 2-r6-hexvl-3.5-dioxo-2-(4A4-trifluorobutvl)-2.5- dihydro-3H-[1,2,4]triazin-4-yl]ethoxy}phenoxy)-2-methylpropionate

(104)

The compound 104 (oil) is prepared according to the method of synthesis 4 using the triazine 2p and the intermediate 4j. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 50-50, Rf = 0.72.

Example 105: Ethyl 2-(3-{2-r6-hexyl-3,5-dioxo-4-(4A4-trifluorobutyl)-4,5- dihydro-3H-[1,2,4]triazin-2-yl]ethoxy}phenoxy)-2-methylpropionate

(105)

The compound 105 (oil) is prepared according to the method of synthesis 4 using the triazine 2q and the intermediate 4j. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 50-50, Rf = 0.69.

Example 106: Ethyl 2-{3-[4-(2-butyl-3,5-dioxo-6-pentyloxy-2,5-dihydro- 3H-[1 ,2,4]triazin-4-yl)butyl]phenoxy}-2-methylpropionate (106)

The compound prepared according to the method of synthesis 1 using the triazine 2i and using the intermediate 6b for the first alkylation and iodobutane for the second is placed in DMF in the presence of pentanol (1.5 eq) and of potassium carbonate (1.1 eq) for 7 h 30 min at 130°C. After treatment and purification on silica, the compound 106 is isolated in the form of an oil. TLC Merck silica gel 60 F 254, petroleum ether-EtOAc: 85-15, Rf = 0.35.

Example 107: Ethyl 2-(3-{5-[3,5-dioxo-6-pentyloxy-2-(4,4,4-trifluoro- butyl)-2,5-dihydro-3H-[1,2,4]triazin-4-yl]pentyl}phenoxy)-2-methyl- propionate (107)

The compound prepared according to the method of synthesis 1 using the triazine 2i and using the intermediate 6c for the first alkylation and 1 ,1 ,1-trifluoro-4-iodobutane for the second is placed in DMF in the presence of pentanol (1.5 eq) and of potassium carbonate (1.1 eq) for 7 h at 130°C. After treatment and purification on silica, the compound 107 is isolated in the form of an oil. TLC Merck silica gel 60 F 254, CH₂CI₂-EtOAc: 98-2, Rf = 0.54. The compounds of the invention were subjected to pharmacological trials which demonstrated their advantage as active substances in therapeutics.

PHARMACOLOGICAL EVALUATION

In vitro Activation of transcription (transactivation) of the reporter gene controlled by specific response elements after binding of the ligand to the receptor (reporter gene assay). These experiments were carried out according to J.M. Lehmann ef al. (J. Biol. Chem 1995, 270:12953-12956) with a few modifications. Subconfluent Cos-7 cells (ATCC, CRL-1651) are transfected with, firstly, (i) the chimeric receptors containing the human PPARα- PPARγ- or PPARδ-ligand-binding domain fused to the yeast galactosidase DNA-binding domain (Gal-4) and, secondly, (ii) the reporter plasmid containing five copies of the Gal-4 response element upstream of the thymidine kinase promoter adjacent to the luciferase gene (p5xUAS-tk-Luc). After 24 hours, these cells are treated for the following 24 hours with the compounds or their carrier, and the luciferase activity is evaluated after cell extraction according to the supplier's recommendations (Promega). The results have been reported in Table 5 below, in which the term "hit" denotes a compound for which the level of transactivation is significant without however allowing an EC₅₀ value to be defined.

Table 5: Reporter gene transactivation with the various PPAR subtypes of human origin

In vivo Normalization of metabolic parameters (plasma cholesterol and plasma triglycerides) in fasting (for 16-18 hours) male insulin-resistant rats (Ico: ZUCKER - fa/fa) after oral treatment, once a day for four days, with the compounds to be evaluated or their administration carrier. These metabolic parameters are measured for each animal by spectrophotometry at the start and at the end of treatment.

Table 6: Normalization of metabolic parameters

Thus, the present invention relates, as novel medicinal products that can be used in the treatment of diseases requiring PPAR-alpha and/or PPAR-gamma receptor agonists, to the compounds of formulae I and II defined above. These compounds are useful in the prevention and treatment of diseases such as diabetic dyslipidaemias, hypertriglyceridaemia, hypercholesterolaemia, hyperinsulinaemia, hyperglycaemia, the metabolic syndrome, obesity or atherosclerosis, or else in dermatology, in pathologies that have an inflammatory component or that result from abnormal cell differentiation, and also in the treatment of diseases such as psoriasis, acne, atopic dermatitis, skin ageing or photo-ageing. Finally, the invention relates to pharmaceutical compositions containing, as active principle, at least one compound of formulae I and II defined above, preferably in combination with any suitable excipient.

Claims

1) 3,5-Dioxo-(2H,4H)-1 ,2,4-triazine derivatives of general formulae

I or II

in which

-Ri represents hydrogen, a linear or branched C Cβ alkyl, alkoxy or alkenyl radical, a C₃ or C₅-C₆ cycloalkyl radical, a phenyl (C-ι-C₂) alkyl radical or a phenyl radical (the phenyl ring being optionally substituted with one or more groups such as C₁-C₄ alkyl, C₁-C₄ alkoxy, nitrile, nitro, halogen or trifluoromethyl), a thiophen-2-yl heterocycle, a secondary C₁-C7 alkylamine or a C₅-Cβ cycloalkylamine, or a halogen;

-R₂ represents hydrogen, a linear or branched C C alkyl or alkenyl radical, or one of the following radicals: Cι-C₆ alkyl substituted with groups such as trifluoromethyl, monofluoroethyl or polyfluoroethyl, C₅-C₆ cycloalkyl, nitrile, benzodioxan-2-yl, phthalimido, pyridinyl, 2,2,2-trifluoroacetylamino, C₁-C₄ alkoxy- carbonylvinyl, hydroxycarbonylvinyl, C C₄ alkoxycarbonyl, carboxylate, thiophen-2-carbonyl, indolyl, phenylcarbamoyl (for which the phenyl ring is optionally substituted with one or more groups such as C1_.-C₂ alkyl or nitro), C₁-C₄ alkoxy or alkoxyalkyl (C₁-C₄ for the alkoxy, C₂-C₄ for the alkyl), phenyloxy or benzyloxy or phenyl or benzhydryl or benzoyl (for which the phenyl ring is optionally substituted with one or more groups such as C₁-C₄ alkyl, C₁-C₄ alkoxy, nitro, halogen or trifluoromethyl); linker represents a C₂-C₆ alkyl chain, -(CH₂)_n-C ≡€-, -(CH₂)_n-C ≡€- or -(CH₂)_n-0-, where n = 1 to 5; R₃ represents a group of general formula below

for which X = O or S, linker can be connected to the ortho-, meta- or para- positions of the aromatic of the group R₃, R4 and Rs represent hydrogen, fluorine or a linear or branched C₅-C₁₀ alkenyl group, R₅, Re and R₇ represent hydrogen or fluorine, Rg, R₁₀ and Rn represent hydrogen or a linear or branched C₁-C₅ alkyl group, and also the addition salts with pharmaceutically acceptable bases, and the various enantiomers of the compounds having asymmetric carbons, and also mixtures thereof in any proportions, including in particular racemic mixtures.

2) 3,5-Dioxo-(2H,4H)-1 ,2,4-triazine derivatives of general formulae I or II, according to Claim 1 , in which:

-Ri represents hydrogen, a linear or branched C Cβ alkyl or alkoxy radical, a C₅-C-₆ cycloalkyl radical, a phenyl (CrC₂) alkyl radical or a phenyl radical, a thiophen-2-yl heterocycle or a Cs-Ce cycloalkylamine, or a halogen. - R₂ represents hydrogen, a linear or branched C₁-C₇ alkyl or alkenyl radical, or one of the following radicals: C-ι-C₆ alkyl substituted with groups such as trifluoromethyl, monofluoroethyl or polyfluoroethyl, C₅-C₆ cycloalkyl, nitrile, benzodioxan-2-yl, phthalimido, pyridinyl, 2,2,2-trifluoroacetylamino, C-₁-C₄ alkoxy- carbonylvinyl, hydroxycarbonylvinyl, C₁-C₄ alkoxycarbonyl, carboxylate, thiophen-2-carbonyl, indolyl, phenylcarbamoyl (for which the phenyl ring is optionally substituted with one or more groups such as C C₂ alkyl or nitro), C₁-C₄ alkoxy, or alkoxyalkyl (C₁-C4 for the alkoxy, C₂-C for the alkyl), phenyloxy or benzyloxy or phenyl or benzhydryl or benzoyl (for which the phenyl ring is optionally substituted with one or more groups such as C₁-C4 alkyl, C₁-C₄ alkoxy, nitro, halogen or trifluoromethyl); linker represents a C₂-C₆ alkyl chain or -(CH₂)_n-0- where n = 1 to 5; R₃ represents a group of general formula below

for which X = O, linker can be connected to the ortho-, meta- or para- positions of the aromatic of the group R3, R4, R5, Re, R7 and R₈ represent hydrogen or fluorine, Rg, R₁₀ and Rn represent hydrogen or a linear or branched C₁-C₅ alkyl group.

3) 3,5-Dioxo-(2H,4H)-1 ,2,4-triazine derivatives of general formulae I or II, according to either of Claims 1 and 2, in which: -Ri represents hydrogen, a linear or branched C C₆ alkyl or alkoxy radical, a C₅-C₆ cycloalkyl radical, a phenyl (C-i-C₂) alkyl radical or a phenyl radical; -R₂ represents hydrogen, a linear or branched C1-C7 alkyl radical, or a Cι-C₆ alkyl radical substituted with groups such as trifluoromethyl or phenyl;

- linker represents a C₂-C₆ alkyl chain or -(CH₂)_n-0- where n = 1 to 5;

- R₃ represents a group of general formula below

for which X = O, linker can be connected to the ortho-, meta- or para- positions of the aromatic of the group R₃, R₄, R₅, R₆, R₇ and Rs represent hydrogen or fluorine, Rg, R1₀ and Rn represent hydrogen or a linear or branched C₁-C₅ alkyl group, in particular R₉ and R-io represent the methyl group and R represents hydrogen or the ethyl group. 4) 3,5-Dioxo-(2H,4H)-1 ,2,4-triazine derivatives of formulae I or II according to one of Claims 1 to 3, in which: -Ri represents a linear or branched C Cβ alkyl or alkoxy radical or a phenyl radical;

Rs represents a group of general formula below:

for which: linker can be connected to the meta- or para-positions of the aromatic of the group R₃

X = 0

R₄ to R₈ represent hydrogen

Rg and R₁₀ represent a methyl radical Rn represents hydrogen or an ethyl radical.

5) Compounds of general formulae I or II according to Claim 1, characterized in that they are chosen from: 1. ethyl 2-(4-{3-[6-hexyl-3,5-dioxo-2-(4,4,4-trifluorobutyl)-2,5-dihydro-3H- [1 ,2,4]triazin-4-yl]propyl}phenoxy)-2-methylpropionate 2. ethyl 2-{4-[2-(2-benzyl-6-hexyl-3,5-dioxo-2,5-dihydro-3H-[1 ,2,4]triazin- 4-yl)ethyl]phenoxy}-2-methylpropionate

3. ethyl 2-(4-{2-[6-hexyl-3,5-dioxo-2-(3-phenylpropyl)-2,5-dihydro-3H- [1 ,2,4]triazin-4-yl]ethyl}phenoxy)-2-methylpropionate

4. 2-{4-[2-(2-benzyl-6-cyclopentyl-3,5-dioxo-2,5-dihydro-3H-[1 ,2,4]triazin- 4-yl)ethyl]phenoxy}-2-methylpropionic acid 5. ethyl 2-{4-[2-(4-benzyl-6-hexyl-3,5-dioxo-4,

5-dihydro-3H-[1 ,2,4]triazin- 2-yl)ethyl]phenoxy}-2-methylpropionate

6. ethyl 2-(4-{2-[6-hexyl-3, 5-dioxo-4-(3-phenylpropyl)-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl]ethyl}phenoxy)-2-methylpropionate

7. ethyl 2-{4-[2-(4-benzyl-6-cyclopentyl-3,5-dioxo-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)ethyl]phenoxy}-2-methylpropionate

8. ethyl 2-methyl-2-{4-[2-(4-methyl-3,5-dioxo-6-pyrrolidin-1 -yl-4,5- dihydro-3H-[1 ,2,4]triazin-2-yl)ethyl]phenoxy}propionate

9. ethyl 2-{4-[2-(6-bromo-4-methyl-3,5-dioxo-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)ethyl]phenoxy)-2-methylpropionate

10. ethyl 2-(4-{3-[6-hexyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl]propyl}phenoxy)-2-methylpropionate

11.2-(4-{3-[6-hexyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl]propyl}phenoxy)-2-methylpropionic acid

12. ethyl 2-[4-{3-[6-hexyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl]propyl}-2-(3-methylbut-2-enyl)phenoxy]-2-methyl- propionate

13. ethyl 2-{4-[3-(4-benzyl-6-cyclopentyl-3,5-dioxo-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)propyl]phenoxy}-2-methylpropionate

14. ethyl 2-{4-[3-(6-bromo-4-heptyl-3,5-dioxo-4,5-dihydro-3H-[1 ,2,4]triazin- 2-yl)propyl]phenoxy}-2-methylpropionate

15. ethyl 2-[4-[3-(6-bromo-4-heptyl-3,5-dioxo-4,5-dihydro-3H-[1 ,2,4]triazin- 2-yl)propyl]-2-(3-methylbut-2-enyl)phenoxy]-2-methylpropionate

16. ethyl 2-{3-[3-(2-benzyl-6-hexyl-3,5-dioxo-2,5-dihydro-3H-[1 ,2,4]triazin- 4-yl)propyl]phenoxy}-2-methylpropionate

17. ethyl 2-[3-(3-{6-hexyl-2-[2-(2-nitrophenyl)-2-oxoethyl]-3,5-dioxo-2,5- dihydro-3H-[1 ,2,4]triazin-4-yl}propyl)phenoxy]-2-methylpropionate

18. ethyl 2-(3-{3-[6-cyclopentyl-3,5-dioxo-2-(4,4,4-trifluorobutyl)-2,5- dihydro-3H-[1 ,2,4]triazin-4-yl]propyl}phenoxy)-2-methylpropionate

19. ethyl 4-(6-cyclopentyl-4-{3-[3-(1 -ethoxycarbonyl-1 -methylethoxy)- phenyl]propyl}-3,5-dioxo-2,5-dihydro-3H-[1 ,2,4]triazin-2-yl)but- 2-enoate

20. ethyl 2-{3-[3-(2-benzyl-6-cyclopentyl-3,5-dioxo-2,5-dihydro-3H- [1 ,2,4]triazin-4-yl)propyl]phenoxy}-2-methylpropionate

21. ethyl 2-(3-{3-[2-(3-cyclohexylpropyl)-6-cyclopentyl-3,5-dioxo-2,5- dihydro-3H-[1 ,2,4]triazin-4-yl]propyl}phenoxy)-2-methylpropionate

22.ethyl 2-[3-(3-{6-benzyl-2-[4-(4-methoxyphenyl)-4-oxobutyl]-3,5-dioxo- 2,5-dihydro-3H-[1 ,2,4]triazin-4-yl}propyl)phenoxy]-2-methylpropionate

23. ethyl 2-{3-[3-(4-benzyl-6-hexyl-3,5-dioxo-4,5-dihydro-3H-[1 ,2,4]triazin- 2-yl)propyl]phenoxy}-2-methylpropionate

24.2-{3-[3-(4-benzyl-6-hexyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)- propyl]phenoxy}-2-methylpropionic acid

25.ethyl 2-[3-(3-{6-hexyl-4-[2-(2-nitrophenyl)-2-oxoethyl]-3,5-dioxo-4,5- dihydro-3H-[1 ,2,4]triazin-2-yl}propyl)phenoxy]-2-methylpropionate

26. ethyl 2-(3-{3-[6-cyclopentyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5- dihydro-3H-[1 ,2,4]triazin-2-yl]propyl}phenoxy)-2-methylpropionate

27.2-(3-{3-[6-cyclopentyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl]propyl}phenoxy)-2-methylpropionic acid

28. ethy 2-[3-(3-{6-cyclopentyl-3,5-dioxo-4-[2-(2,2,2-trifluoroacetylamino)- ethyl]-4,5-dihydro-3H-[1 ,2,4]triazin-2-yl}propyl)phenoxy]-2-methyl- propionate

29. ethyl 4-(6-cyclopentyl-2-{3-[3-(1 -ethoxycarbonyl-1 -methylethoxy)- phenyl]propyl}-3,5-dioxo-2,5-dihydro-3H-[1 ,2,4]triazin-4-yl)but- 2-enoate

30.4-(2-{3-[3-(1-carboxy-1-methylethoxy)phenyl]propyl}-6-cyclopentyl-3,5- dioxo-2,5-dihydro-3H-[1 ,2,4]triazin-4-yl)but-2-enoic acid

31. ethyl 2-{3-[3-(4-benzyl-6-cyclopentyl-3,5-dioxo-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)propyl]phenoxy}-2-methylpropionate

32. ethyl 2-{3-[3-(4-benzyl-6-cyclopentyl-3,5-dioxo-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)propenyl]phenoxy}-2-methylpropionate

33. ethyl 2-{3-[3-(4-cyclohexylmethyl-6-cyclopentyl-3,5-dioxo-4,5-dihydro- 3H-[1 ,2,4]triazin-2-yl)propyl]phenoxy}-2-methylpropionate

34. ethyl 2-(3-{3-[6-cyclopentyl-3,5-dioxo-4-(4-oxo-4-thiophen-2-ylbutyl)- 4,5-dihydro-3H-[1 ,2,4]triazin-2-yl]propyl}phenoxy)-2-methylpropionate

35. ethyl 2-{3-[3-(4-benzyloxymethyl-6-cyclopentyl-3,5-dioxo-4,5-dihydro- 3H-[1 ,2,4]triazin-2-yl)propyl]phenoxy}-2-methylpropionate

36. ethyl 2-(3-{3-[4-(3-cyclohexylpropyl)-6-cyclopentyl-3,5-dioxo-4,5- dihydro-3H-[1 ,2,4]triazin-2-yl]propyl}phenoxy)-2-methylpropionate

37.2-(3-{3-[4-(3-cyclohexylpropyl)-6-cyclopentyl-3,5-dioxo-4,5-dihydro- 3H-[1 ,2,4]triazin-2-yl]propyl}phenoxy)-2-methylpropionic acid

38. ethyl 2-[3-(3-{6-cyclopentyl-4-[2-(1 H-indol-3-yl)ethyl]-3,5-dioxo-4,5- dihydro-3H-[1 ,2,4]triazin-2-yl}propyl)phenoxy]-2-methylpropionate

39. ethyl 2-[3-(3-{6-cyclopentyl-4-[4-(4-methoxyphenyl)-4-oxobutyl]-3,5- dioxo-4,5-dihydro-3H-[1 ,2,4]triazin-2-yl}propyl)phenoxy]- 2-methylpropionate

40. ethyl 2-(3-{3-[6-cyclopentyl-4-(3,3-diphenylpropyl)-3,5-dioxo-4,5- dihydro-3H-[1 ,2,4]triazin-2-yl]propyl}phenoxy)-2-methylpropionate

41.ethyl 2-{3-[3-(6-bromo-4-heptyl-3,5-dioxo-4,5-dihydro-3H-[1 ,2,4]triazin- 2-yl)propyl]phenoxy}-2-methylpropionate

42. ethyl 2-{3-[3-(4-benzyl-3,5-dioxo-6-thiophen-2-yl-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)propyl]phenoxy}-2-methylpropionate

43.ethyl 2-(3-{4-[6-hexyl-3,5-dioxo-2-(4,4,4-trifluorobutyl)-2,5-dihydro-3H- [1 ,2,4]triazin-4-yl]butyl}phenoxy)-2-methylpropionate

44. ethyl 4-(4-{4-[3-(1 -ethoxycarbonyl-1 -methylethoxy)phenyl]butyl}- 6-hexyl-3,5-dioxo-4,5-dihydro-3H-[1 ,2,4]triazin-2-yl)but-2-enoate

45. ethyl 2-{3-[4-(2-heptyl-6-hexyl-3,5-dioxo-2,5-dihydro-3H-[1 ,2,4]triazin- 4-yl)butyl]phenoxy}-2-methylpropionate

46. ethyl 2-(3-{4-[6-cyclopentyl-3,5-dioxo-2-(4-phenylbutyl)-2,5-dihydro- 3H-[1 ,2,4]triazin-4-yl]butyl}phenoxy)-2-methylpropionate

47.ethyl 2-(3-{4-[3,5-dioxo-6-phenyl-2-(4,4,4-trifluorobutyl)-2,5-dihydro- 3H-[1 ,2,4]triazin-4-yl]butyl}phenoxy)-2-methylpropionate

48. ethyl 2-{3-[4-(2-heptyl-3,5-dioxo-6-phenyl-2,5-dihydro-3H-[1 ,2,4]triazin- 4-yl)-butyl]phenoxy}-2-methylpropionate

49.2-{3-[4-(2-heptyl-3,5-dioxo-6-phenyl-2,5-dihydro-3H-[1 ,2,4]triazin-4-yl)- butyl]phenoxy}-2-methylpropionic acid

50. ethyl 2-{2,3-d ifluoro-5-[4-(2-heptyl-3,5-dioxo-6-phenyl-2,5-dihydro-3H- [1 ,2,4]triazin-4-yl)butyl]phenoxy}-2-methylpropionate

51. ethyl 2-(3-{4-[2-(6-cyanohexyl)-3,5-dioxo-6-phenyl-2,5-dihydro-3H- [1 ,2,4]triazin-4-yl]butyl}phenoxy)-2-methylpropionate

52. ethyl 2-{3-[4-(2-benzyloxymethyl-3,5-dioxo-6-phenyl-2,5-dihydro-3H- [1 ,2,4]triazin-4-yl)butyl]phenoxy}-2-methylpropionate

53.ethyl 2-(3-{4-[2-(3-cyclohexylpropyl)-3,5-dioxo-6-phenyl-2,5-dihydro- 3H-[1 ,2,4]triazin-4-yl]butyl}phenoxy)-2-methylpropionate

54. ethyl 2-(3-{4-[6-benzyl-3,5-dioxo-2-(4,4,4-trifluorobutyl)-2,5-dihydro- 3H-[1 ,2,4]triazin-4-yl]butyl}phenoxy)-2-methylpropionate

55. ethyl 2-{3-[4-(6-benzyl-2-heptyl-3,5-dioxo-2,5-dihydro-3H-[1 ,2,4]triazin- 4-yl)butyl]phenoxy}-2-methylpropionate

56. ethyl 2-{3-[4-(6-bromo-2-heptyl-3,5-dioxo-2,5-dihydro-3H-[1 ,2,4]triazin- 4-yl)butyl]phenoxy}-2-methylpropionate

57.ethyl 2-(3-{4-[6-hexyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl]butyl}phenoxy)-2-methylpropionate

58. ethyl 4-(2-{4-[3-(1 -ethoxycarbonyl-1 -methylethoxy)phenyl]butyl}- 6-hexyl-3,5-dioxo-2,5-dihydro-3H-[1 ,2,4]triazin-4-yl)butyrate

59. ethyl 2-{3-[4-(4-heptyl-6-hexyl-3,5-dioxo-4,5-dihydro-3H-[1 ,2,4]triazin- 2-yl)butyl]phenoxy}-2-methylpropionate

60. ethyl 2-{3-[4-(4-benzyl-6-hexyl-3,5-dioxo-4,5-dihydro-3H-[1 ,2,4]triazin- 2-yl)butyl]phenoxy}-2-methylpropionate

61. ethyl 4-[2-(3-{6-hexyl-3,5-dioxo-4-(4-oxo-4-thiophen-2-ylbutyl)-4,5- dihydro-3H-[1 ,2,4]triazin-2-yl]butyl}phenoxy)-2-methylpropionate

62. ethyl 2-[3-(4-{4-[4-(3,5-bistrifluoromethylphenyl)butyl]-6-hexyl-3,5- dioxo-4,5-dihydro-3H-[1 ,2,4]triazin-2-yl}butyl)phenoxy]-2-methyl- propionate

63. ethyl 4-(6-cyclopentyl-2-{4-[3-(1 -ethoxycarbonyl-1 -methylethoxy)- phenyl]butyl}-3,5-dioxo-2,5-dihydro-3H-[1 ,2,4]triazin-4-yl)but-2-enoate

64. ethyl 2-{3-[4-(4-benzyl-6-cyclopentyl-3, 5-dioxo-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)butyl]phenoxy}-2-methylpropionate

65. ethyl 2-(3-{4-[6-cyclopentyl-3,5-dioxo-4-(2-oxo-2-phenylethyl)-4,5- dihydro-3H-[1 ,2,4]triazin-2-yl]butyl}phenoxy)-2-methylpropionate

66. ethyl 2-[3-(4-{6-cyclopentyl-4-[(2,6-dimethylphenylcarbamoyl)methyl]- 3,5-dioxo-4,5-dihydro-3H-[1 ,2,4]triazin-2-yl}butyl)phenoxy]-2-methyl- propionate

67. ethyl 2-(3-{4-[6-cyclopentyl-3,5-dioxo-4-(4-phenylbutyl)-4,5-dihydro- 3H-[1 ,2,4]triazin-2-yl]but-1 -ynyl}phenoxy)-2-methylpropionate

68. ethyl 2-(3-{4-[6-cyclopentyl-3,5-dioxo-4-(4-phenylbutyl)-4,5-dihydro- 3H-[1 ,2,4]triazin-2-yl]butyl}phenoxy)-2-methylpropionate

69.2-(3-{4-[6-cyclopentyl-3,5-dioxo-4~(4-phenylbutyl)-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl]butyl}phenoxy)-2-methylpropionic acid

70. ethyl 2-{3-[4-(4-heptyl-3,5-dioxo-6-phenyl-4,5-dihydro-3H-[1 ,2,4]triazin- 2-yl)butyl]phenoxy}-2-methylpropionate

71. ethyl 2-(3-{4-[4-(3-cyclohexylpropyl)-3,5-dioxo-6-phenyl-4,5-dihydro- 3H-[1 ,2,4]triazin-2-yl]butyl}phenoxy)-2-methylpropionate

72.ethyl 2-(3-{4-[6-benzyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5-dihydro- 3H-[1 ,2,4]triazin-2-yl]butyl}phenoxy)-2-methylpropionate

73. ethyl 2-{3-[4-(6-benzyl-4-heptyl-3,5-dioxo-4,5-dihydro-3H-[1 ,2,4]triazin- 2-yl)butyl]phenoxy}-2-methylpropionate

74.2-{3-[4-(6-benzyl-4-heptyl-3,5-dioxo-4,5-dihydro-3H-[1 ,2,4]triazin-2-yl)- butyl]phenoxy}-2-methylpropionic acid

75. ethyl 2-{3-[4-(6-bromo-4-heptyl-3,5-dioxo-4,5-dihydro-3H-[1 ,2,4]triazin- 2-yl)butyl]phenoxy}-2-methylpropionate

76.ethyl 2-(3-{5-[6-hexyl-3,5-dioxo-2-(4,4,4-trifluorobutyl)-2,5-dihydro-3H- [1 ,2,4]triazin-4-yl]pentyl}phenoxy)-2-methylpropionate

77. ethyl 4-(4-{5-[3-(1 -ethoxycarbonyl-1 -methylethoxy)phenyl]pentyl}- 6-hexyl-3,5-dioxo-4,5-dihydro-3H-[1 ,2,4]triazin-2-yl)but-2-enoate

78. ethyl 2-{3-[5-(2-benzyl-6-hexyl-3,5-dioxo-2,5-dihydro-3H-[1 ,2,4]triazin- 4-yl)pentyl]phenoxy}-2-methylpropionate

79. ethyl 4-(6-cyclopentyl-4-{5-[3-(1 -ethoxycarbonyl-1 -methylethoxy)- phenyl]pentyl}-3,5-dioxo-4,5-dihydro-3H-[1 ,2,4]triazin-2-yl)but- 2-enoate

80. ethyl 2-{3-[5-(2-heptyl-3,5-dioxo-6-phenyl-2,5-dihydro-3H-[1 ,2,4]triazin- 4-yl)pentyl]phenoxy}-2-methylpropionate

81. ethyl 2-(3-{5-[6-hexyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl]pentyl}phenoxy)-2-methylpropionate

82. ethyl 2-{3-[5-(4-benzyl-6-hexyl-3,5-dioxo-4,5-dihydro-3H-[1 ,2,4]triazin- 2-yl)pentyl]phenoxy}-2-methylpropionate

83.ethyl 2-(3-{5-[6-cyclopentyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5- dihydro-3H-[1 ,2,4]triazin-2-yl]pentyl}phenoxy)-2-methylpropionate

84. ethyl 4-(6-cyclopentyl-(2-{5-[3-(1 -ethoxycarbonyl-1 -methylethoxy)- phenyl]pentyl}-3,5-dioxo-2,5-dihydro-3H-[1 ,2,4]triazin-4-yl)but- 2-enoate

85.ethyl 2-(3-{5-[3,5-dioxo-6-phenyl-4-(4,4,4-trifluorobutyl)-4,5-dihydro- 3H-[1 ,2,4]triazin-2-yl]pentyl}pherioxy)-2-methylpropionate

86. ethyl 2-{3-[5-(4-heptyl-3,5-dioxo-6-phenyl-4,5-dihydro-3H-[1 ,2,4]triazin- 2-yl)pentyl]phenoxy}-2-methylpropionate

87.ethyl 2-(3-{5-[6-benzyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5-dihydro- 3H-[1 ,2,4]triazin-2-yl]pentyl}phenoxy)-2-methylpropionate

88. ethyl 2-{3-[5-(6-bromo-4-heptyl-3,5-dioxo-4,5-dihydro-3H-[1 ,2,4]triazin- 2-yl)pentyl]phenoxy}-2-methylpropionate

89. ethyl 2-{3-[6-(2-heptyl-3,5-dioxo-6-phenyl-2,5-dihydro-3H-[1 ,2,4]triazin- 4-yl)hexyl]phenoxy}-2-methylpropionate

90.ethyl 2-(3-{6-[6-hexyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl]hexyl}phenoxy)-2-methylpropionate

91. ethyl 2-{3-[6-(4-benzyl-6-hexyl-3,5-dioxo-4,5-dihydro-3H-[1 ,2,4-triazin- 2-yl)hexyl]phenoxy}-2-methylpropionate

92. ethyl 4-(6-cyclopentyl-2-{6-[3-(1 -ethoxycarbonyl-1 -methylethoxy)- phenyl]hexyl}-3,5-dioxo-2,5-dihydro-3H-[1 ,2,4]triazin-4-yl)but-2-enoate

93. ethyl 2-{3-[6-(6-bromo-4-heptyl-3,5-dioxo-4,5-dihydro-3H-[1 ,2,4]triazin- 2-yl)hexyl]phenoxy}-2-methylpropionate

94. ethyl 2-{3-[3-(4-benzyl-6-hexyl-3,5-dioxo-4,5-dihydro-3H-[1 ,2,4]triazin- 2-yl)propyl]phenylsulphanyl}-2-methylpropionate

95. ethyl 4-(6-cyclopentyl-2-{3-[3-(1 -ethoxycarbonyl-1 -methyl- ethylsulphanyl)phenyl]propyl}-3,5-dioxo-2,5-dihydro-3H-[1 ,2,4]triazin- 4-yl)but-2-enoate

96.ethyl 2-{3-[3-(4-benzyl-6-cyclopentyl-3,5-dioxo-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)propyl]phenylsulphanyl}-2-methylpropionate

97. ethyl 2-{3-[4-(2-heptyl-3,5-dioxo-6-phenyl-2,5-dihydro-3H-[1 ,2,4]triazin- 4-yl)butyl]phenylsulphanyl}-2-methylpropionate

98. ethyl 2-{3-[4-(6-benzyl-2-heptyl-3,5-dioxo-2,5-dihydro-3H-[1 ,2,4]triazin- 4-yl)butyl]phenylsulphanyl}-2-methylpropionate

99. ethyl 2-(3-{4-[6-hexyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl]butyl}phenylsulphanyl)-2-methylpropionate

100. ethyl 2-{3-[4-(6-bromo-4-heptyl-3,5-dioxo-4,5-dihydro-3H- [1 ,2,4]triazin-2-yl)butyl]phenylsulphanyl}-2-methylpropionate 101.ethyl 2-{2-[4-(6-bromo-4-heptyl-3,5-dioxo-4,5-dihydro-3H- [1,2,4]triazin-2-yl)butyl]phenoxy}-2-methylpropionate 102. ethyl 2-(4-{2-[6-hexyl-3,5-dioxo-2-(4,4,4-trifluorobutyl)-2,5-dihydro- 3H-[1 ,2,4]triazin-4-yl]ethoxy}phenoxy)-2-methylpropionate 103. ethyl 2-(4-{2-[6-hexyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5-dihydro- 3H-[1 ,2,4]triazin-2-yl]ethoxy}phenoxy)-2-methylpropionate 104. ethyl 2-(3-{2-[6-hexyl-3,5-dioxo-2-(4,4,4-trifluorobutyl)-2,5-dihydro- 3H-[1 ,2,4]triazin-4-yl]ethoxy}phenoxy)-2-methylpropionate 105. ethyl 2-(3-{2-[6-hexyl-3,5-dioxo-4-(4,4,4-trifluorobutyl)-4,5-dihydro- 3H-[1 ,2,4]triazin-2-yl]ethoxy}phenoxy)-2-methylpropionate 106. ethyl 2-{3-[4-(2-butyl-3,5-dioxo-6-pentyloxy-2,5-dihydro- 3H-[1 ,2,4]triazin-4-yl)butyl]phenoxy}-2-methylpropionate 107. ethyl 2-(3-{5-[3,5-dioxo-6-pentyloxy-2-(4,4,4-trifluorobutyl)-2,5- dihydro-3H-[1 ,2,4]triazin-4-yl)pentyl}phenoxy})-2-methylpropionate

6) Process for preparing the chemical compounds according to one of Claims 1 to 5, characterized in that: a) a derivative of general formula III

in which Ri represents the groups as described above in formulae I and II is condensed with a halogenated derivative of formula R₂Y (for the compounds corresponding to formula II) and R₃-linker-(Y or OTs) (for the compounds corresponding to formula I) where R₂, R₃ and linker are as described above in formulae I and II, and Y represents a halogen such as chlorine, bromine or iodine. This reaction can be carried out in the presence of a base such as sodium hydride or potassium tert-butoxide in dimethylformamide; b) deacetylation is carried out in an acid medium such as para- toluenesulphonic acid in ethanol; c) the product is treated with halogenated derivative of formula R Y (for the compounds corresponding to formula I) and R3-linker-(Y or OTs) (for the compounds corresponding to formula II) where R₂, R3, linker and Y and the reaction conditions are as described in paragraph a) above.

7) Processs for preparing the chemical compounds according to one of Claims 1 to 5, characterized in that: a) a compound of general formula IV

in which Ri represents the groups as described above in formulae I and II is treated with a halogenated derivative R Y (for the compounds corresponding to formula I) and R₃-linker-(Y or OTs) (for the compounds corresponding to formula II) where R₂, R₃ and linker are as described for formulae I and II and Y represents a halogen such as chlorine, bromine or iodine. This reaction can be carried out in the presence of a base such as sodium hydride or potassium tert-butoxide in dimethylformamide; b) after acid hydrolysis in an alcoholic medium (such as HCl in ethanol), the product is treated with a halogenated derivative of formula R₂Y (for the compounds corresponding to formula II) and R₃-linker-(Y or OTs) (for the compounds corresponding to formula I) where R₂, R₃, linker and Y and the reaction conditions are as described in the paragraph above.

8) Process for preparing the chemical compounds only of general formula I according to one of Claims 1 to 5 characterized in that: a) a solid support of resin type, such as, for example, Wang resin or SASRIN resin, is treated with a compound V

in which R4, R5, Rε, R7, Rs, R9, R10, R11, X and linker are as described above in general formulae I and II, and Gp represents a protective group, among which is tetrahydropyran. The coupling reaction with the resin is carried out under conditions known to those skilled in the art, among which is the use of diisopropylcarbodiimide in THF in the presence of DMAP. b) After hydrolysis in acid medium such as para-toluenesulphonic acid in a methanol/dichloromethane mixture, the hydroxyl group thus liberated is activated in the form described in formula VI

in which R , R5, Re, R7, Re, R9, R10, Rn, X and linker are as described above in general formulae l and II, Y represents a halogen such as chlorine, bromine or iodine, and Z represents a sulphonyl group SO2R12 where R 2 represents groups such as methyl or 4-methylphenyl. For this, the resin is treated with a sulphonyl halide such as para-toluenesulphonyl chloride in the presence of a base such as triethylamine in dichloromethane. c) The resin is treated with a compound of formula VII

in which Ri is as defined for formulae I and II. The reaction is carried out in the presence of a base such as sodium hydride or potassium tert-butoxide in dimethylformamide. d) The resin thus obtained is fractionated and reacts with various alkylating agents R₂Y where R₂ is as defined above for formulae I or II, and Y represents a halogen such as chlorine, bromine or iodine. The reaction can be carried out in the presence of a base such as sodium hydride or potassium tert-butoxide in dimethylformamide. After cleavage of the resin in an acid medium such as trifluoroacetic acid in dichloromethane, the compounds obtained with this method of synthesis correspond only to formula I.

9) Process for preparing the chemical compounds according to one of claims 1 to 5, characterized in that: a) a compound of general formula III

in which Ri represents the groups as defined above in formulae I and II is treated with a halogenated derivative R₂Y (for the compounds corresponding to formula II) and Y-(CH₂)_n0₂C-Me (for the compounds corresponding to formula I) where R₂ and n are as described for formulae I and II, and Y represents a halogen such as chlorine, bromine or iodine. This reaction can be carried out in the presence of a base such as sodium hydride or potassium tert-butoxide in dimethylformamide; b) hydrolysis is carried out in an acid medium such as para- toluenesulphonic acid in ethanol; c) the product is treated with a halogenated derivative of formula R₂Y (for the compounds corresponding to formula I) and Y-(CH₂)_n0₂C-Me

(for the compounds corresponding to formula II) where R₂, n and Y and the reaction conditions are as described in paragraph a) above. d) in the case of the compounds of formula VIII,

an additional hydrolysis in a basic medium such as LiOH in a THF/H₂O mixture is necessary; e) the alcohols thus obtained are coupled with compounds of formula IX

for which the hydroxyl function can be in the ortho-, meta- or para-position of the aromatic of the compounds IX, and R4, R5, Re, R7, Rs, R9, R10, Rn and X are as defined in formulae I and II. The reaction conditions are those of the Mitsunobu reaction.

10) As novel medicinal products that can be used in the treatment of diseases requiring PPAR-alpha and/or PPAR-gamma receptor agonists, the compounds defined according to one of Claims 1 to 5.

11) As novel medicinal products that can be used in the prevention and treatment of diseases such as diabetic dyslipidaemias, hypertriglyceridaemia, hypercholesterolaemia, hyperinsulinaemia, hyper- glycaemia, the metabolic syndrome, obesity or atherosclerosis, the compounds defined according to one of Claims 1 to 5.

12) As novel medicinal products that can be used in dermatology, or in pathologies that have an inflammatory component or that result from abnormal cell differentiation, the compounds defined according to one of Claims 1 to 5. 13) As novel medicinal products that can be used in the treatment of diseases such as psoriasis, acne, atopic dermatitis, skin ageing or photo- ageing, the compounds defined according to one of Claims 1 to 5.

14) Pharmaceutical composition characterized in that it contains, as active principle, a compound defined according to one of Claims 1 to 5.

15) Pharmaceutical composition according to Claim 12, characterized in that it contains a compound defined according to one of

Claims 1 to 5, in combination with any suitable excipient.