HK1110863A - 1,2,4-triazine derivatives, preparation and use thereof in human therapy - Google Patents

Description

1, 2, 4-triazine derivatives, their preparation and their use in human therapy

Technical Field

The present invention relates to novel derivatives of 3, 5-dioxo- (2H, 4H) -1, 2, 4-triazine functionalized in the 2, 4 and 6 positions, which activate PPAR α and/or γ receptors, their preparation and their use in human therapy.

Background

The metabolic syndrome is the result of increased insulin resistance in the periphery and is characterized by hyperinsulinemia, glucose tolerance, altered lipid metabolism, and arterial hypertension (Grundy, s.m.: Hypertriglyceridemia, insulin resistance, and the metabolic syndrome am.j.diol.1999, 83, 25F-29F). Obesity is often associated with these metabolic diseases, and the association of these multiple risk factors contributes to the development of atheroma at the origin of arterial thrombosis, which is now the first cause of death in industrialized regions. Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily of transcription factors. Upon activation, it forms a heterodimer with the 9-cis retinoic acid receptor (RXR); this complex (PPAR-RXR) is linked specifically to DNA sequences located in the regulatory regions of genes involved in lipid and carbohydrate metabolism (Pineda Torra, I., Gervois, P. and Staels, B.: Peroxisome promoter-activated receptor alpha peptide disease, inflammation, atheriosis and imaging. curr. Opin. Lipidol.1999, 10, 151-doped 159; Vamecq, J. and Latruffe, N.: medical science of Peroxisome promoter-activated receptors. Lancet 1999, 354, 141-doped 148). PPAR activation restores, on the one hand, certain altered metabolic pathways which predispose a person to atherosclerosis, and, on the other hand, reduces inflammatory events which promote the development and rupture of atherosclerotic plaques.

The compounds of the invention are characterized by their novel structure, their affinity for alpha and/or gamma PPAR receptors and their pharmacological properties.

Disclosure of Invention

The compounds of the invention correspond to general formula I:

wherein the content of the first and second substances,

-R₁and R₂May be the same or different and represents a linear or branched C₁-C₇Alkyl or alkenyl radicals, e.g. by trifluoromethyl, C₅-C₆Cycloalkyl, nitrile, C₁-C₄Alkoxycarbonylvinyl, hydroxycarbonylvinyl, C₁-C₄Alkoxycarbonyl, carboxylate, benzyloxy or phenyl substituted C₁-C₆Alkyl (wherein the phenyl ring may be substituted by one or more groups such as C₁-C₄Alkyl radical, C₁-C₄Alkoxy, nitro, halogen or trifluoromethyl substitution),

-YR₃represents oxygen or NR₃Wherein R is₃Represents hydrogen, linear or branched C₁-C₇Alkyl or alkenyl, C substituted by, for example, trifluoromethyl or phenyl₁-C₆Alkyl (wherein the phenyl ring may be substituted by one or more groups such as C₁-C₄Alkyl radical, C₁-C₄Alkoxy, nitro, halogen or trifluoromethyl substitution),

-Z represents an oxygen or carbon atom capable of bonding to the ortho, meta or para position of the phenyl group of formula I,

n may be 0 to 5 when Z ═ C, or n may be 2 to 4 when Z ═ O,

x represents oxygen or sulphur,

-R₄、R₅、R₆、R₇and R₈Represents hydrogen or fluorine, and is selected from the group consisting of,

-R₉、R₁₀and R₁₁Represents hydrogen or linear or branched C₁-C₅An alkyl group, a carboxyl group,

and the various enantiomers of addition salts of pharmaceutically acceptable bases and compounds having an asymmetric carbon, and mixtures thereof in all proportions, including especially racemic mixtures.

The invention relates in particular to compounds of formula I, wherein:

-R₁and R₂Independently of one another, represents linear or branched C₁-C₇Alkyl or alkenyl radicals, e.g. by trifluoromethyl, C₆Cycloalkyl, nitrile or phenyl substitutionC of (A)₁-C₆Alkyl (wherein the phenyl ring may be substituted by one or more groups such as C₁-C₄Alkyl radical, C₁-C₄Alkoxy, nitro, halogen, trifluoromethyl substitution),

-YR₃represents oxygen or NR₃Wherein R is₃Represents hydrogen, linear or branched C₁-C₇Alkyl or alkenyl, C substituted by, for example, trifluoromethyl or phenyl₁-C₆An alkyl group, a carboxyl group,

-Z represents an oxygen or carbon atom capable of bonding to the ortho, meta or para position of the phenyl group of formula I,

n may be 0 to 5 when Z ═ C, or n may be 2 to 4 when Z ═ O,

x represents oxygen or sulphur,

-R₄、R₅、R₆、R₇and R₈Represents hydrogen or fluorine, and is selected from the group consisting of,

-R₉、R₁₀and R₁₁Represents hydrogen or linear or branched C₁-C₅An alkyl group.

The invention more particularly relates to compounds of formula I wherein:

-R₁and R₂Independently of one another, represents linear or branched C₁-C₇Alkyl or alkenyl, C substituted by, for example, trifluoromethyl or nitrile groups₁-C₆An alkyl group, a carboxyl group,

-YR₃represents oxygen or NR₃Wherein R is₃Represents hydrogen, or linear or branched C₁-C₇An alkyl group, a carboxyl group,

-Z represents a carbon atom capable of bonding to the ortho, meta or para position of the phenyl group of formula I,

n can vary from 0 to 5,

x represents oxygen or sulphur,

-R₄、R₅、R₆、R₇and R₈Represents hydrogen or fluorine, and is selected from the group consisting of,

-R₉、R₁₀and R₁₁Represents hydrogen or linear or branched C₁-C₅Alkyl, especially R₉And R₁₀Represents methyl, R₁₁Represents hydrogen or ethyl.

The invention also relates more particularly to derivatives of 3, 5-dioxo- (2H, 4H) -1, 2, 4-triazine of formula I, wherein:

-R₁and R₂Independently of one another, represents linear or branched C₁-C₇An alkyl or alkenyl group which may be substituted with a trifluoromethyl group at the end of the chain,

-YR₃represents oxygen or NR₃Wherein R is₃Represents hydrogen or linear or branched C₁-C₇An alkyl group, a carboxyl group,

-Z represents a carbon atom capable of bonding in the meta or para position of the phenyl group of formula I,

n can vary from 1 to 5,

x represents oxygen or sulphur,

-R₄to R₈Represents hydrogen, and is selected from the group consisting of,

-R₉and R₁₀Represents a methyl group, and a salt thereof,

-R₁₁represents hydrogen or ethyl.

The invention encompasses the salts of the compounds of the general formula I with pharmaceutically acceptable bases, and the various enantiomers of the compounds with asymmetric carbons, as well as mixtures thereof in all ratios, including especially racemic mixtures.

Synthesis of

The compounds of the present invention can be synthesized by using the synthetic routes described below or by using synthetic methods known to those of ordinary skill in the art.

Method 1

The synthesis of compounds of formula I (scheme 1) is characterized by the condensation of derivatives of formula II with derivatives of formula III:

wherein R is₁And R₂Represents a group as described in formula I above,

wherein YR₃、n、Z、X、R₄、R₅、R₆、R₇、R₈、R₉、R₁₀And R₁₁As described in formula I above. This reaction can be carried out in the presence of a base such as triethylamine in N-butanol (when Y ═ N) or potassium carbonate in dimethylformamide (when YR₃O ═ O);

route 1

Method 2

This synthesis of compounds of general formula I where Z ═ O (scheme 2) is characterized:

1) condensation of a derivative of formula II with a derivative of formula IV:

wherein R is₁And R₂Represents a group as described in formula I above,

wherein R is₃Y may be equal to NH or O, and n is as described in formula I above.

The reaction can be carried out in the absence of a solvent without the addition of a base (at R)₃In the case of Y ═ NH) or in a base such as K₂CO₃In the presence of (at R)₃Y ═ O).

2) The resulting derivative V

With compounds of the general formula VI

Condensation of which X, R₄、R₅、R₆、R₇、R₈、R₉、R₁₀And R₁₁As described in formula I above. This reaction can be carried out in THF in the presence of triphenylphosphine and diethyl azodicarboxylate under conditions such as the Mitsunobu reaction.

Route 2

Method 3

This synthesis of compounds of general formula I where Z ═ O (scheme 3) is characterized:

1) the alcohol functional derivative of formula VII is protected with a protecting group such as tert-butyldimethylsilane,

wherein R is₁、R₂And n is as previously described in formula I. This reaction can be carried out, for example, under THF conditions by using chloro-tert-butyldimethylsilane and imidazole.

2) By halogenation of derivatives R₃Alkylation of the nitrogen of the previously obtained compound VIII with Hal under operating conditions such as NaH or tBuOK in DMF, wherein the Hal group represents halogen such as Cl, Br or I, R₃As described in formula I above.

3) Compound IX thus obtained is deprotected under the operating conditions, e.g. tetrabutylammonium fluoride in THF.

4) The obtained derivative X

With compounds of the general formula VI

Condensation of which X, R₄、R₅、R₆、R₇、R₈、R₉、R₁₀And R₁₁As described in formula I above. This reaction can be carried out in THF in the presence of triphenylphosphine and diethyl azodicarboxylate under conditions such as the Mitsunobu reaction.

Route 3

Method 4

This approach is taken when Y ═ N and Z ═ C, and depicted (scheme 4), where:

1) reacting a derivative of the formula II

(wherein R is₁And R₂Represents a radical as described in formula I above)

With derivatives of the general formula XI

(wherein n, R₃、R₄、R₅、R₆、R₇And R₈As described in formula I above and A may be hydrogen or methyl)

And (3) condensation. This reaction can be carried out in the presence of a base, such as triethylamine in n-butanol.

2) BBr after demethylation (if A ═ Me in, for example, dichloromethane₃Under the conditions of (a) or (b) reacting said derivative XII with a base

By a halogenated derivative of formula XIII (used as a solvent in the presence of a base such as potassium carbonate)

Alkylation, wherein the Hal group represents halogen such as Cl, Br or I, and R₉、R₁₀And R₁₁As described previously in formula I.

Route 4

Method 5

This approach is taken when Y ═ N and Z ═ C, and depicted (scheme 5), where:

1) reacting a derivative of formula XIV

(wherein R is₁、R₂、R₄、R₅、R₆、R₇、R₈And n is as described in formula I) and formula R₃Derivatives of Hal (wherein Hal represents halogen such as Cl, Br or I, R₃As described in formula I) above under operating conditions such as tBuOK or NaH in DMF.

2) BBr in, for example, dichloromethane₃After demethylation under the conditions of (a) and (b) the derivative XII thus obtained

By a halogenated derivative of formula XIII (used as a solvent in the presence of a base such as potassium carbonate)

Alkylation, wherein the Hal group represents halogen such as Cl, Br or I, and R₉、R₁₀And R₁₁As described previously in formula I.

Route 5

Method 6

The method is depicted (route 6), in which:

1) reacting a derivative of formula XIV

(wherein R is₁＝(CH₂)₂CN and R₂、R₃、n、Z、X、R₄、R₅、R₆、R₇、R₈、R₉、R₁₀And R₁₁As described in formula I or R₂＝(CH₂)₂CN and R₁、R₃、n、Z、X、R₄、R₅、R₆、R₇、R₈、R₉、R₁₀And R₁₁As described in formula I above) under operating conditions, for example in the presence of the base NaH in DMF.

2) Then the triazine nitrogen of the derivative XIVa or XIVb thus obtained is reacted with

By the general formula R in the case of the intermediate XIVa₁Halogenated derivatives of Hal and the general formula R in the case of the intermediate XIVb₂Halogenated derivatives of Hal, alkylated under operating conditions such as tBuOK or NaH in DMF, wherein the Hal group represents a halogen such as Cl, Br or I, and R₁And R₂As described in formula I above.

Route 6

If desired, the intermediates and the final compounds can be purified according to one or more purification methods selected from extraction, filtration, silica gel chromatography, normal or reverse phase preparative HPLC and crystallization.

The starting materials used in the aforementioned processes are either commercially available or readily accessible to the skilled person according to the methods described in the literature.

The following examples illustrate the invention without limiting its scope.

Elemental analysis and IR and NMR spectroscopy confirmed the structure of the compound.

Intermediates

Intermediate 1:

a)6-bromo-2H- [1, 2, 4]Triazine-3, 5-dione (1a)

2H- [1, 2, 4] in the presence of 60ml bromine]Triazine-3, 5-dione (50g, 442mmol) was placed in 800ml of 60 ℃ water for 10 hours. The reaction medium is then slowly added to the ammonia solution until the pH is 5. It is then extracted in ethyl acetate and the organic phase is passed over MgSO₄And (5) drying. Filtration and dry concentration isolated 1a as a white solid (79.2g, 93% yield). TLC silica gel 60F254Merck, CH₂Cl₂∶MeOH 90∶10，Rf＝0.32。

b)6-bromo-2, 4-dimethyl-2H- [1, 2, 4 [ ]]Triazine-3, 5-dione (1b)

Under nitrogen, 11.8g (295mmol) of NaH(60% in paraffin) was suspended in 250ml DMF at 0 ℃. 25.80g (135mmol) of intermediate 1a diluted in 150ml of DMF are added dropwise. The solution was then left at ambient temperature and 18.4ml (296mmol) of methyl iodide were added dropwise. After stirring overnight and drying the concentrated reaction medium, the residue obtained is dissolved in water and extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, then dried and concentrated. The residue obtained is dissolved in ether and crystallized, the first crystalline fraction being isolated. The filtrate was dried, concentrated and purified by flash silica chromatography (heptane: AcOEt 50: 50). This isolated 24g of intermediate 1b (81% yield). TLC silica gel 60F254Merck, CH₂Cl₂∶AcOEt 80∶20，Rf＝0.59。

c)Intermediates (1c) - (1g)

The synthesis of intermediates 1c to 1g was carried out according to the procedure described for the synthesis of 1b starting from 1a by using various alkylating reagents RX.

Table 1: intermediates 1c-1g

TLC: silica gel 60F254Merck, PE Petroleum Ether

Intermediate 2:

a)6-bromo-4-methyl-2H- [1, 2, 4]Oxazine-3, 5-diones (2a)

20.3g (105.7mmol) of triazine 1a are placed under reflux in 150ml of acetic anhydride for 4.5 hours. After drying and concentration of the reaction medium, the precipitate is separated off and then recrystallized from ether: 24.3g of crystals were isolated (yield 98%). 4.5g (114.2mmol) NaH (60% in paraffin) are placed in 50ml DMF under nitrogen. A solution of 24.3g (103.8mmol) of the crystals isolated previously in 150ml of DMF is added dropwise. The reaction medium is stirred at ambient temperature for 45 minutes, then 7ml (114.2mmol) of methyl iodide are added; stirring was then continued at ambient temperature for 21 hours. After drying and concentration, the residue obtained is dissolved in H₂O and extracted with ethyl acetate. Over MgSO₄After drying, the organic phase is evaporated and chromatographed on flash silica (CH)₂Cl₂AcOEt 90: 10) was purified. 22.9g of crystals were isolated (yield 89%) and placed in 300ml of ethanol in the presence of 0.6g of p-toluenesulfonic acid. The mixture was heated at reflux for 4.5 hours, then dried and concentrated. The residue was dissolved in water and extracted with ethyl acetate. The organic phase was dried and evaporated and 17g of intermediate 2a were isolated as a solid (yield 89%). TLC silica gel 60F254Merck, CH₂Cl₂∶AcOEt 90∶10，Rf＝0.29。

b)Intermediates (2b) - (2f)

The synthesis of intermediates 2b-2f was carried out according to the procedure described for synthesis 2a, starting from 1a, by using various alkylating reagents RX.

Table 2: intermediates 2b-2f

TLC: silica gel 60F254Merck, PE Petroleum Ether

Intermediate 3:

a)3- (6-bromo-4-methyl-3, 5-dioxo-4, 5-dihydro-3H- [1, 2, 4)]Triazin-2-yl) -propionitrile (3a)

2.4g (11.6mmol) of triazine 2a and 7ml (106mmol) of acrylonitrile are placed in a solution of 24ml of pyridine and water (1: 1) and refluxed for 3 hours. After concentration, the reaction medium is extracted with AcOEt and MgSO₄After drying, the organic phase was concentrated by drying. 2.8g of solid 3a were isolated and then washed with ether (yield 93%). TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf ═ 0.18.

b) Intermediates 3b and 3c

The synthesis of intermediates 3b and 3c was carried out starting from intermediates 2d and 2e, respectively, according to the method described for the synthesis of 3 a.

Table 3: intermediates 3b and 3c

Starter molecule	Yield of	TLC	Status of state	Intermediates 3b-3c
					2d	91％	PE∶AcOEt 70∶30Rf＝0.34	Solid body	3 b: 3- [ 6-bromo-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -4, 5-dihydro-3H- [1, 2, 4]Triazin-2-yl radical]-propionitrile
2e	95％	CH2Cl2∶AcOEt70∶30Rf＝0.51	Solid body	3 c: 3- (6-bromo-4-heptyl-3, 5-dioxo-4, 5-dihydro-3H- [1, 2, 4)]Triazin-2-yl) -propionitrile

TLC: silica gel 60F254Merck, PE Petroleum Ether

Intermediate 4:

d)6-bromo-4-methyl-2- (4, 4, 4-trifluoro-butyl) -2H- [1, 2, 4]Triazine-3, 5-dione (4a)

0.85g (21.3mmol) NaH (60% in paraffin) was placed in 10ml DMF under nitrogen. A solution of 4g (19.4mmol) of intermediate 2a in 40ml DMF is added dropwise. The reaction medium is brought to ambient temperatureStirring for 1 hour, then 5g (21.3mmol)1, 1, 1-trifluoro-4-iodo-butane was added; stirring was then continued at ambient temperature for 3 hours. After drying and concentration, the residue obtained is dissolved in water and extracted with ethyl acetate. Over MgSO₄After drying, the organic phase is evaporated and the oil obtained is purified by flash chromatography on silica (petroleum ether: AcOEt 80: 20). 5.3g of crystals corresponding to compound 4a were isolated (yield 87%). TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf 0.58.

d)6-bromo-2-heptyl-4-methyl-2H- [1, 2, 4]Triazine-3, 5-dione (4b)

The synthesis of intermediate 4b was carried out according to the described method for the synthesis of 4a, starting with 2a, by using 1-bromoheptane for the alkylation step (yield 91%). TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf ═ 0.76.

Intermediate 5:

according to the described method for the synthesis of 4a, starting from intermediates 2b and 2c, by using various halogenated derivatives R₁X carries out the synthesis of intermediates 5a-5 d.

Table 4: intermediates 5a to 5d

TLC: silica gel 60F254Merck, PE Petroleum Ether

Intermediate 6:

the synthesis of intermediates 6a-6c was carried out according to the described method for the synthesis of 4a starting from intermediate 2d by using various halogenated derivatives RX.

Table 5: intermediates 6a to 6c

TLC: silica gel 60F254Merck, PE Petroleum Ether

Intermediate 7:

the synthesis of intermediates 7a to 7d was carried out according to the described method for the synthesis of 4a starting from intermediate 2e by using various halogenated derivatives RX.

Table 6: intermediates 7a to 7d

TLC: silica gel 60F254Merck, PE Petroleum Ether

Intermediate 8:

the synthesis of intermediates 8a-8b was carried out according to the described method for the synthesis of 4a starting from intermediate 2f by using various halogenated derivatives RX.

Table 7: intermediates 8a-8b

TLC: silica gel 60F254Merck, PE Petroleum Ether

Intermediate 9:

a)6- (2-hydroxy-ethylamino) -2, 4-di- (4, 4, 4-trifluorobutyl) -2H- [1, 2, 4]Triazine-3, 5-bis Ketones (9a)

3g (7.3mmol) of triazine 1d are placed in 1.3ml of ethanolamine at 130 ℃ for 5 hours. After cooling, 50ml of water are added to the reaction medium, which is then extracted with AcOEt. Over MgSO₄After drying, the organic phase is concentrated by drying and the residue obtained is purified by flash chromatography on silica (petroleum ether: AcOEt 70: 30). 1.9g of an oil corresponding to intermediate 9a were isolated (66% yield). TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf ═ 0.28.

b)Intermediates 9b-9l

The synthesis of intermediates 9b-9l was performed according to the described procedure for synthesis of 9a, starting from the starting compounds listed in table 8.

Table 8: intermediates 9b-9l

Starter molecule	Amino alcohols	Yield of	TLC	Status of state	Intermediates 9b-9k
						4b	Ethanol-amines	77％	CH2Cl2∶AcOEt60∶40Rf＝0.28	Solid body	9 b: 2-heptyl-6- (2-hydroxy-ethylamino) -4-methyl-2H- [1, 2, 4]Triazine-3, 5-diones
1e	Ethanol-amines	67％	PE∶AcOEt 70∶30Rf＝0.56	Oil	9 c: 2, 4-diheptyl-6- (2-hydroxy-ethyl)Amino) -2H- [1, 2, 4]Triazine-3, 5-diones
						1f	Ethanol-amines	56％	PE∶AcOEt 80∶20Rf＝0.18	Oil	9 d: 2, 4-bis (3-cyclohexyl-propyl) -6- (2-hydroxy-ethylamino) -2H- [1, 2, 4]Triazine-3, 5-diones
1b	Amino-propanol	18％	AcOEtRf＝0.42	Oil	9 e: 6- (3-hydroxy-propyl-amino) -2, 4-dimethyl-2H- [1, 2, 4]Triazine-3, 5-diones
						4a	Amino-propanol	44％	PE∶AcOEt70∶30Rf＝0.13	Solid body	9 f: 6- (3-hydroxy-propylamino) -4-methyl-2- (4, 4, 4-trifluoro-butyl) -2H- [1, 2, 4]Triazine-3, 5-diones
4b	Amino-propanol	67％	CH2Cl2∶AcOEt60∶40Rf＝0.32	Solid body	9 g: 2-heptyl-6- (3-hydroxy-propylamino) -4-methyl-2H- [1,2，4]triazine-3, 5-diones

6a	Amino-propanol	45％	PE∶AcOEt 80∶20Rf＝0.05	Solid body	9 h: 6- (3-hydroxy-propyl-amino) -2-methyl-4- (4, 4, 4-trifluoro-butyl) -2H- [1, 2, 4]Triazine-3, 5-diones
						7a	Amino-propanol	34％	CH2Cl2∶MeOH90∶10Rf＝0.47	Solid body	9 i: 4-heptyl-6- (3-hydroxy-propylamino) -2-methyl-2H- [1, 2, 4]Triazine-3, 5-diones
7b	Amino-propanol	64％	PE∶AcOEt70∶30Rf＝0.30	Solid body	9 j: 4-heptyl-6- (3-hydroxy-propylamino) -2- (4, 4, 4-trifluoro-butyl) -2H- [1, 2, 4]Triazine-3, 5-diones
						1b	Amino-butanols	50％	AcOEtRf＝0.35	Solid body	9 k: 6- (4-hydroxy-butyl-amino) -2, 4-dimethyl-2H- [1, 2, 4]Triazine-3, 5-diones
7a	Amino-butanols	21％	CH2Cl2∶MeOH90∶10Rf＝0.45	Solid body	9 l: 4-heptyl-6- (4-hydroxy-butylamino) -2-methyl-2H- [1, 2, 4]Triazine-3, 5-diones

TLC: silica gel 60F254Merck, PE Petroleum Ether

c)2-heptyl-6- [ 3-hydroxypropyl) - (4, 4, 4-trifluorobutyl) -amino]-4-methyl-2H- [1, 2, 4] Triazine-3, 5-dione (9m)

7.3g (24.2mmol) of triazine 9g are placed in 50ml of dichloromethane at ambient temperature in the presence of tert-butylchlorodimethylsilane (4g, 26.5mmol)And then the mixture is left overnight. The reaction medium is then washed with water followed by brine. Over MgSO₄After drying, the organic phase is concentrated by flash chromatography on silica (CH)₂Cl₂AcOEt 95: 5) purifying the residue obtained. 10g of oil were isolated (quantitative yield). 4.1g (10mmol) of this compound are placed in 40ml of DMF at 0 ℃ under nitrogen and 0.4g (10mmol) of NaH (60% in paraffin wax) are added in portions; the mixture was then stirred for 10 minutes. 2.4g (10mmol) of 1, 1, 1-trifluoro-4-iodobutane were added and the solution was stirred at ambient temperature for 3 hours. 0.5 equivalents of NaH and 1, 1, 1-trifluoro-4-iodobutane were again added and stirring was continued for 2 hours. After dry concentration, the residue was dissolved in water and extracted with AcOEt. Over MgSO₄After drying, the organic phase is concentrated by drying and the oil obtained is purified by flash chromatography on silica (petroleum ether: AcOEt 90: 10). 2g of the compound were thus isolated (yield 40%) and then diluted in 30ml of THF; 7.4ml of tetrabutylammonium fluoride solution (1M in THF) are then added dropwise. The mixture is stirred at ambient temperature for 2 hours, then 50ml of water are added and the medium is extracted with AcOEt. Over MgSO₄After drying, the organic phase is concentrated by drying and the oil obtained is purified by flash chromatography on silica (petroleum ether: AcOEt 70: 30). 1.5g of triazine 9m are isolated in the form of an oil (quantitative yield). TLC silica gel 60F254Merck, petroleum ether: AcOEt 90: 10, Rf ═ 0.38.

d)Intermediate 9n-9o

The synthesis of intermediates 9n and 9o was carried out according to the described procedure for the synthesis of 9m starting from intermediates 9e and 9k, respectively, using bromoheptane.

Table 9: intermediate 9n-9o

Starter molecule	Yield of	TLC	Status of state	Intermediate 9n-9o
					9e	59％	Heptane AcOEt 50: 50Rf 0.16	Oil	9 n: 6- [ heptyl- (3-hydroxy-propyl) -amino]-2, 4-dimethyl-2H- [1, 2, 4]Triazine-3, 5-diones
9k	59％	Heptane: AcOEt 50: 50Rf ═ 0.24	Oil	9 o: 6- [ heptyl- (4-hydroxy-butyl) -amino]-2, 4-dimethyl-2H- [1, 2, 4]Triazine-3, 5-diones

TLC: silica gel 60F254Merck, PE Petroleum Ether

e)2-heptyl-6- (2-hydroxyethoxy) -4-methyl-2H- [1, 2, 4]Triazine-3, 5-dione (9p)

1.5g (4.9mmol) of triazine 4b and 0.8g (5.8mmol) of K₂CO₃Placed in 1.5ml of ethylene glycol at 130 ℃ for 0.5 hour. To the reaction medium was added 50ml of water, and the reaction medium was then extracted with AcOEt. Over MgSO₄After drying, the organic phase is concentrated by flash chromatography on silica (CH)₂Cl₂AcOEt 70: 30) purifying the residue obtained. From this 0.5g of an oil corresponding to intermediate 9p was isolated (39% yield). TLC silica gel 60F254 Merek, heptane: AcOEt 50: 50, Rf ═ 0.08.

f)Intermediate 9q-9s

The synthesis of intermediates 9q-9s was carried out using various diols starting from starting compounds 4b and 1d according to the described method for the synthesis of 9 p.

Table 10: intermediate 9q-9s

TLC: silica gel 60F254Merck

Intermediate 10:

a)3- (2-hydroxy-ethyl) -phenol (10a)

11.3g of (3-hydroxyphenyl) -acetic acid (74.2mmol) are placed in 100ml of THF at 0 ℃ under nitrogen. At this temperature, 100ml of water are added dropwiseLiAlH₄Solution of (1M in THF). The mixture was then left at 60 ℃ for 2 hours. It was then slowly neutralized with 6N HCl solution and then extracted with diethyl ether. The organic phase was washed with water and MgSO₄Dried, then dried and concentrated. By silica flash Chromatography (CH)₂Cl₂AcOEt 70: 30) purifying the residue obtained. 9g of an oil corresponding to intermediate 10a were isolated therefrom (yield 88%). TLC silica gel 60F254Merck, CH₂Cl₂∶AcOEt 70∶30，Rf＝0.18。

b)2- (3-Hydroxyphenoxy) -2-methyl-propionic acid ethyl ester (10b)

15g of resorcinol (136mmol) were added to 120ml of a solution of sodium (6.3g, 274mmol) in ethanol. The mixture was left at reflux for 1 hour and then a solution of ethyl bromoisobutyrate (13.2ml, 90mmol) in 30ml of ethanol was added dropwise. Heating was continued for 3 hours and the reaction medium was then dried and concentrated. The resulting residue was dissolved in a solution of water and acetic acid and then extracted with AcOEt. The organic phase was washed with water and MgSO₄Dried, then dried and concentrated. By silica flash Chromatography (CH)₂Cl₂AcOEt 90: 10) purifying the residue obtained. 14.4g of an oil corresponding to intermediate 10b were isolated (yield 72%). TLC silica gel 60F254Merck, CH₂Cl₂∶AcOEt 70∶30，Rf＝0.66。

c)2- (4-Hydroxyphenoxy) -2-methyl-propionic acid ethyl ester (10c)

11g of hydroquinone (100mmol) in 100ml of DMF are left at 80 ℃ for 2 hours. The mixture was cooled at ambient temperature and then droppedA solution of ethyl bromoisobutyrate (14.7ml, 100mmol) in 30ml DMF was added. The mixture was stirred for 3 hours and then the reaction medium was dried and concentrated. The residue obtained is dissolved in 1N HCl solution and then extracted with AcOEt. The organic phase was washed with water and MgSO₄Dried, then dried and concentrated. The residue obtained is purified by flash chromatography on silica (petroleum ether: AcOEt 80: 20). 9g of an oil corresponding to intermediate 10c were isolated therefrom (yield 40%). TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf ═ 0.50.

d)2- (3-bromophenoxy) -2-methyl-propionic acid ethyl ester (10d)

At K₂CO₃(21g, 152mmol) 25g (144.5mmol) of 3-bromophenol were placed in 75ml of ethyl 2-bromoisobutyrate and heated at reflux for 7 hours. Removing K by filtration₂CO₃Thereafter, the reaction medium is dried and concentrated. After purification by flash chromatography on silica (petroleum ether: AcOEt 90: 10), 37g of intermediate 10d were collected as a clear oil (yield: 89%). TLC silica gel 60F254Merck, petroleum ether: AcOEt 90: 10, Rf ═ 0.40.

d)Intermediates 10e to 10i

The synthesis of intermediates 10e-10j was performed according to the described procedure for synthesis of 10d, starting from the various substituted phenols listed in table 8.

Table 11: intermediates 10e-10j

TLC: silica gel 60F254Merck, PE Petroleum Ether

Intermediate 11:

a)2- (3-bromo-phenylthio) -2-methyl-propionic acid ethyl ester (11a)

At 9.4ml (63.5mmol) ethyl bromoisobutyrate and 8g (57.9mmol) K₂CO₃In the presence of this, 10g (52.9mmol) of 3-bromobenzothiophenol were placed in 100ml of EtOH. The mixture was stirred at reflux for 4 hours, then dried and concentrated. The residue obtained is dissolved in water, extracted with AcOEt and then MgSO₄Drying, and concentrating the organic phase. The resulting oil was purified by flash chromatography on silica (petroleum ether: AcOEt 90: 10) and 11a was isolated as a clear oil (16.8g, quantitative yield). TLC silica gel 60F254Merck, petroleum ether: AcOEt 90: 10, Rf ═ 0.72.

c)Intermediates 11b to 11e

The synthesis of intermediates 11b-11e was carried out according to the described method for synthesis of 11a, starting with the various substituted thiophenols (G) listed in table 12, using ethyl bromoisobutyrate or tert-butyl bromoisobutyrate.

Table 12: intermediates 11b to 11e

TLC: silica gel 60F254Merck, PE Petroleum Ether

Intermediate 12:

a)2- [3- (3-hydroxypropyl) -phenoxy]-2-methyl-propionic acid ethyl ester (12a)

10d (50g, 175mmol) in the presence of 2-propanol (12ml, 210mmol) were placed under nitrogen in 400ml of diisopropylamine. Adding Pd (PPh)₃)₂Cl₂(3.5g) and CuI (500mg) and the reaction medium is stirred under reflux for 5 hours. The precipitate formed during the reaction was filtered through celite and the reaction medium was concentrated by drying. The resulting oil was purified by silica flash chromatography (petroleum ether: AcOEt 80: 20). It was then placed in a solution of 250ml THF and 150ml EtOH in the presence of Pd/C under 6 bar hydrogen. The mixture was stirred at ambient temperature for 24 hours. After filtration through celite, the reaction medium is concentrated by drying and 12a is isolated as a clear oil (32g, 69% yield). TLC silica gel 60F254Merck, heptane: AcOEt 80: 20, Rf 0.56.

b)Intermediates 12b-12e

The synthesis of intermediates 12b-12e was carried out according to the described procedure for synthesis of 12a, starting from the starting bromine compounds listed in table 13, using various alkynols. Note: in the case of sulfur derivatives, Wilkinson's catalyst is used in the hydrogenation step.

Table 13: intermediates 12b-12e

TLC: silica gel 60F254Merck, PE Petroleum Ether

Intermediate 13

a)2- [4- (2-aminoethyl) -phenoxy]-2-methyl-propionic acid ethyl ester (13a)

10.1g (73.6mmol) tyramine was placed in a mixture of 100ml water and 50ml acetone at 0 ℃ in the presence of sodium bicarbonate (6.1g, 72.6 mmol). 11.6ml (81.2mmol) of benzyl chloroformate are added dropwise at this temperature, and the reaction medium is then stirred at ambient temperature for 4 hours. After drying and concentration, the residue obtained is dissolved in water and extracted with AcOEt. Over MgSO₄After drying, the organic phase was concentrated by drying and the resulting solid was recrystallized from diethyl ether: this gave 17.2g of a solid (yield 86%). It is then placed in 37ml of ethyl bromoisobutyrate at 130 ℃ for 5 hours in the presence of 8.8g (63.7mmol) of potassium carbonate. After filtration, the reaction medium is dried and concentrated and the residue obtained is purified by flash chromatography on silica (petroleum ether: AcOEt 70: 30). 22.7g of clear oil were obtained (yield 93%). The oil was then placed in 200ml etoh under 3 bar of hydrogen in the presence of palladium on carbon and the solution was then stirred at ambient temperature for 3 hours. After filtration through celite, the reaction medium is concentrated by drying and 14.7g of intermediate 13a are isolated therefrom as an oil (quantitative yield). TLC silica gel 60F254Merck, CH₂Cl₂∶MeOH 90∶10，Rf＝0.11。

b)2- [3- (2-aminoethyl) -phenoxy]-2-methyl-propionic acid ethyl ester (13b)

10d (14g, 49mmol) were placed in 160ml of DMF in the presence of N-vinylphthalimide (11g, 63mmol) and 27ml (194mmol) of triethylamine. Addition of Pd (OAc)₂(0.3g) and P (oTol)₃(0.4g) and the reaction medium is stirred for 10 hours at 110 ℃. The reaction medium is concentrated by drying, the residue obtained is dissolved in water and extracted with AcOEt. Over MgSO₄After drying, the organic phase is concentrated by drying and the isolated oil is purified by flash chromatography on silica (heptane: AcOEt 90: 10). 11.5g of an oil (yield 62%) were obtained and then placed in a solution of 70ml of THF and 70ml of EtOH in the presence of Pd/C under 6 bar of hydrogen. The mixture was stirred at ambient temperature for 72 hours. After filtration through kieselguhr, the reaction medium is concentrated by drying and the residue obtained is purified by flash chromatography on silica (petroleum ether: AcOEt 80: 20). 10.9g of a clear oil were obtained (yield: 94%). This oil was then placed in 140ml EtOH in the presence of 3.5ml hydrazine hydrate and the solution was then heated at reflux for 4 hours. After insoluble matter was filtered off, the reaction medium was dried and concentrated and then subjected to flash chromatography on silica (CH)₂Cl₂∶MeOH∶NH₄OH 90: 9: 1) purifying the residue obtained. Thereby, 5.7g of intermediate 13b was isolated as an oil (yield 80%). TLC silica gel 60F254Merck, CH₂Cl₂∶MeOH∶NH₄OH 90∶9∶1，Rf＝0.28。

c)Intermediates 13c-13i

The synthesis of intermediates 13c-13i was performed according to the described procedure for synthesis of 13b, starting from the starting bromine compounds listed in table 14, using various N-alkylated phthalimides. Note: in the case of sulfur derivatives, Wilkinson's catalyst is used in the hydrogenation step.

Table 14: intermediates 13b-13i

Starter molecule	N-substituted phthalimides	Total yield	Form of TLC	Status of state	Intermediates 13c-13h
						10d	N-allylphthalimides	80％	CH2Cl2∶MeOH90∶10Rf＝0.12	Oil	13 c: 2- [3- (3-amino-propyl) -phenoxy]-2-methyl-propionic acid ethyl ester
11a	N-vinyl phthalimide	66％	CH2Cl2∶MeOH∶NH4OH90∶9∶1Rf＝0.20	Oil	13d：2-[3-(2-amino-ethyl) -phenylthio]-2-methyl-propionic acid ethyl ester
						11a	N-allylphthalimides	70％	CH2Cl2∶MeOH∶NH4OH90∶9∶1Rf＝0.30	Oil	13 e: 2- [3- (3-amino-propyl) -phenylthio]-2-methyl-propionic acid ethyl ester
11a	N-but-3-enylphthalimides	38％	CH2Cl2∶MeOH∶NH4OH90∶9∶1Rf＝0.27	Oil	13 f: 2- [3- (4-amino-butyl) -phenylthio]-2-methyl-propionic acid ethyl ester
						11b	N-vinyl phthalimide	41％	CH2Cl2∶MeOH∶NH4OH90∶9∶1Rf＝0.28	Oil	13 g: 2- [4- (2-amino-ethyl) -phenylthio]-2-methyl-propionic acid ethyl ester
11b	N-allylphthalimides	38％	CH2Cl2∶MeOH∶NH4OH90∶9∶1Rf＝0.23	Oil	13 h: 2- [4- (3-amino-propyl) -phenylthio]-2-methyl-propionic acid ethyl ester
						11e	N-vinyl phthalimide	63％	CH2Cl2∶MeOH90∶10Rf＝0.18	Oil	13 i: 2- [4- (2-amino-ethyl) -phenylthio]-2-methyl-propionic acid tert-butyl ester

TLC: silica gel 60F254Merck

d)Intermediates 13j-13n

The synthesis of intermediates 13j-13N was performed according to the described procedure for synthesis of 13b, starting from the starting bromine compounds listed in table 15, using various N-alkylated phthalimides.

Table 15: intermediates 13j-13n

TLC: silica gel 60F254Merck

Intermediate 14:

a)2- [4- (2-heptylamino-ethyl) -phenoxyBase of]-2-methyl-propionic acid ethyl ester (14a)

13a (4.1g, 5mmol) was placed in 42ml dichloromethane in the presence of heptanoic acid (2.3ml, 16.5 mmol). 2.3ml (16.5mmol) of triethylamine and 2.8ml (18.2mmol) of diethyl cyanophosphate were added successively. The mixture is stirred at ambient temperature for 24 hours and the reaction medium is then dried and concentrated. The residue was dissolved in water and extracted with ethyl acetate. Over MgSO₄After drying, the organic phase is concentrated by drying and flash chromatography on silica (CH)₂Cl₂MeOH 90: 10) purified the separated oil. 4.7g of oil were obtained (yield 78%). 13ml of BH₃The THF solution (1M) was placed at 0 ℃ under nitrogen and the oil obtained previously (diluted in 20ml of THF) was added dropwise. The mixture was left at reflux for 2 hours and then neutralized with 10ml EtOH/HCl (1.5N). The solution was again placed under reflux for 1 hour and then dried and concentrated. The resulting residue was dissolved in saturated sodium bicarbonate solution and then extracted with dichloromethane. Over MgSO₄After drying, the organic phase is concentrated by drying and flash chromatography on silica (CH)₂Cl₂MeOH 90: 10) purified the separated oil. From this 1.6g of intermediate 14a was isolated as an oil (73% yield). TLC silica gel 60F254Merck, CH₂Cl₂∶MeOH∶NH₄OH 90∶9∶1，Rf＝0.50。

b)Intermediates 14b-14c

The synthesis of intermediates 14b-14c was performed according to the described method for synthesis of 14a, starting with intermediate 13a, using various carboxylic acids.

Table 16: intermediates 14b-14c

TLC: silica gel 60F254Merck

Examples

Example 1: 2- {2- [2- (4-butyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-)]Triazin-6-yloxy) -ethyl]-phenoxy } -2-methyl-propionic acid ethyl ester (1)

Compound 1 was prepared according to synthesis method 1: at 0.5g (3.7mmol) K₂CO₃In the presence of 1g (4mmol) of the derivative 10g and 1g (3.8mmol) of triazine 5a are placed in 3ml DMF. The mixture was stirred at 120 ℃ for 7 hours. The reaction medium is filtered, dried and concentrated, and then subjected to silica flash Chromatography (CH)₂Cl₂AcOEt 98: 2) purifying the residue obtained. 1.2g of white crystals were isolated (yield 74%).

TLC silica gel 60F254Merck, CH₂Cl₂∶AcOEt 95∶5，Rf＝0.40，F＝76℃RMN ¹H(CDCl₃)：0.94ppm(t，3H，J＝7.4Hz)，1.20ppm(t，3H，J＝7.2Hz)，1.39ppm(m，2H，J＝7.5ppm)，1.63ppm(m，8H)，3.16ppm(t，2H，J＝7.6Hz)，3.50ppm(s，3H)，3.95ppm(t，2H，J＝7.6Hz)，4.22ppm(q，2H，J＝7.0Hz)，4.37ppm(t，2H，J＝7.6Hz)，7.00ppm(m，4H).

Example 2: 2- {3- [2- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] -c]Triazin-6-yloxy) -ethyl]-phenoxy } -2-methyl-propionic acid ethyl ester (2)

Compound 2 (oil) was prepared according to synthesis method 1 from triazine 4b and intermediate 10 h. TLC silica gel 60F254Merck, CH₂Cl₂∶AcOEt 90∶10，Rf＝0.62。

Example 3: 2-methyl-2- (3- {2- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-yloxy]-ethyl } -phenoxy) -propionic acid ethyl ester (3)

Compound 3 (oil) was prepared according to synthesis method 1 from triazine 6a and intermediate 10 h.

TLC silica gel 60F254Merck, CH₂Cl₂∶AcOEt 90∶10，Rf＝0.57。

Example 4: 2-methyl-2- (3- {3- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-yloxy]-propyl } -phenoxy) -propionic acid ethyl ester (4)

Compound 4 (oil) was prepared from triazine 4a and intermediate 12a according to synthesis method 1. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf ═ 0.30.

Example 5: 2- {3- [3- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazin-6-yloxy) -propyl]-phenoxy group} -2-methyl-propionic acid ethyl ester (5)

Compound 5 (oil) was prepared according to synthesis method 1 from triazine 4b and intermediate 12 a. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf 0.52.

Example 6: 2-methyl-2- (3- {3- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-yloxy]-propyl } -phenoxy) -propionic acid ethyl ester (6)

Compound 6 (oil) was prepared from triazine 6a and intermediate 12a according to synthesis method 1. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf ═ 0.46.

Example 7: 2- {3- [3- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-l]Triazin-6-yloxy) -propyl]-phenoxy } -2-methyl-propionic acid ethyl ester (7)

Compound 7 (oil) was prepared from triazine 7a and intermediate 12a according to synthesis method 1. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf 0.61.

Example 8: 2- (3- {3- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-]Triazin-6-yloxy]-propyl } -phenoxy) -2-methyl-propionic acid ethyl ester (8)

Compound 8 (oil) was prepared according to synthesis method 1 from triazine 7b and intermediate 12 a. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf 0.53.

Example 9: 2-methyl-2- (3- {5- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-yloxy]-pentyl } -phenoxy) -propionic acid ethyl ester (9)

Compound 9 (oil) was prepared according to synthesis method 1 from triazine 4a and intermediate 12 b. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.34.

Example 10: 2- {3- [5- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazin-6-yloxy) -pentyl]-phenoxy } -2-methyl-propionic acid ethyl ester (10)

Compound 10 (oil) was prepared according to synthesis method 1 from triazine 4b and intermediate 12 b. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf ═ 0.54.

Example 11: 2- {3- [5- (4-butyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-)]Triazin-6-yloxy) -pentyl]-phenoxy } -2-methyl-propionic acid ethyl ester (11)

Compound 11 (oil) was prepared according to synthesis method 1 from triazine 5a and intermediate 12 b. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.29.

Example 12: 2- {3- [5- (4-butyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-)]Triazin-6-yloxy) -pentyl]-phenoxy } -2-methyl-propionic acid (12)

Compound 12 (oil) was prepared by hydrolysis of compound 11 (HCl 12N, reflux, 16h, 62%).

TLC silica gel 60F254Merck, CH₂Cl₂∶MeOH 90∶10，Rf＝0.43。

Example 13: 2- {3- [5- (2, 4-dibutyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4)]Triazin-6-yloxy) -pentyl]-phenoxy } -2-methyl-propionic acid ethyl ester (13)

Compound 13 (oil) was prepared according to synthesis method 1 from triazine 1c and intermediate 12 b. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.63.

Example 14: 2- (3- {5- [ 4-butyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-]Triazin-6-yloxy]-pentyl } -phenoxy) -2-methylpropionic acid ethyl ester (14)

Compound 14 (oil) was prepared according to synthesis method 1 from triazine 5b and intermediate 12 b. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.35.

Example 15: 2- {3- [5- (4-butyl-2-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-)]Triazin-6-yloxy) -pentyl]-phenoxy } -2-methyl-propionic acid ethyl ester (15)

Compound 15 (oil) was prepared according to synthesis method 1 from triazine 5c and intermediate 12 b. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.53.

Example 16: 2-methyl-2- (3- {5- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-yloxy]-pentyl } -phenoxy) -propionic acid ethyl ester (16)

Compound 16 (oil) was prepared from triazine 6a and intermediate 12b according to synthesis method 1. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.33.

Example 17: 2- {3- [5- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-)]Triazine 6-yloxy) -pentyl]-phenoxy } -2-methyl-propionic acid ethyl ester (17)

Compound 17 (oil) was prepared according to synthesis method 1 from triazine 7a and intermediate 12 b. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.36.

Example 18: 2- (3- {5- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-]Triazin-6-yloxy]-pentyl } -phenoxy) -2-methyl-propionic acid ethyl ester (18)

Compound 18 (oil) was prepared according to synthesis method 1 from triazine 7b and intermediate 12 b. TLC silica gel 60F254Merck, heptane: AcOEt 70: 30, Rf ═ 0.35.

Example 19: 2- {3- [5- (2-benzyl-4-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazin-6-yloxy) -pentyl]-phenoxy } -2-methyl-propionic acid ethyl ester (19)

Compound 19 (oil) was prepared according to synthesis method 1 from triazine 7c and intermediate 12 b. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.51.

Example 20: 2- [4- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4)]Triazin-6-yloxymethyl) -phenoxy]-2-methyl-propionic acid ethyl ester (20)

Compound 20 (oil) was prepared according to synthesis method 1 from triazine 4b and intermediate 10 f. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.28.

Example 21: 2-methyl-2- {4- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-yloxymethyl]-phenoxy } -propionic acid ethyl ester (21)

Compound 21 (oil) was prepared according to synthesis method 1 from triazine 6a and intermediate 10 f. TLC silica gel 60F254Merck, petroleum ether: AcOEt 60: 40, Rf ═ 0.46.

Example 22: 2- [4- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-)]Triazin-6-yloxymethyl) -phenoxy]-2-methyl-propionic acid ethyl ester (22)

Compound 22 (oil) was prepared according to synthesis method 1 from triazine 7a and intermediate 10 f. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.34.

Example 23: 2- {4- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-yloxymethyl]-phenoxy } -2-methyl-propionic acid ethyl ester (23)

Compound 23 (oil) was prepared according to synthesis method 1 from triazine 7b and intermediate 10 f. TLC silica gel 60F254Merck, petroleum ether: AcOEt 90: 10, Rf 0.61.

Example 24: 2-methyl-2- (4- {2- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-yloxy]-ethyl } -phenoxy) -propionic acid ethyl ester (24)

Compound 24 (oil) was prepared according to synthesis method 1 from triazine 4a and intermediate 10 j. TLC silica gel 60F254Merck, CH₂Cl₂∶AcOEt 90∶10，Rf＝0.45。

Example 25: 2- {4- [2- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazin-6-yloxy) -ethyl]-phenoxy } -2-methyl-propionic acid ethyl ester (25)

Compound 25 (oil) was prepared according to synthesis method 1 from triazine 4b and intermediate 10 j. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.45.

Example 26: 2- {4- [2- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-)]Triazin-6-yloxy) -ethyl]-phenoxy } -2-methyl-propionic acid ethyl ester (26)

Compound 26 (oil) was prepared according to synthesis method 1 from triazine 7a and intermediate 10 j. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf ═ 0.46.

Example 27: 2- {4- [3- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazin-6-yloxy) -propyl]-phenoxy } -2-methyl-propionic acid ethyl ester (27)

Compound 27 (oil) was prepared according to synthesis method 1 from triazine 4b and intermediate 12 c. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf ═ 0.33.

Example 28: 2-methyl-2- (4- {4- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-yloxy]-butyl } -phenoxy) -propionic acid ethyl ester (28)

Compound 28 (oil) was prepared according to synthesis method 1 from triazine 4a and intermediate 12 d. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf ═ 0.31.

Example 29: 2- {4- [4- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-l-)]Triazin-6-yloxy) -butyl]-phenoxy } -2-methyl-propionic acid ethyl ester (29)

Compound 29 (oil) was prepared according to synthesis method 1 from triazine 4b and intermediate 12 d. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf ═ 0.49.

Example 30: 2-methyl-2- (4- {4- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-yloxy]-butyl } -phenoxy) -propionic acid ethyl ester (30)

Compound 30 (oil) was prepared according to synthesis method 1 from triazine 6a and intermediate 12 d. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf ═ 0.35.

Example 31: 2- (4- {4- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-]Triazin-6-yloxy]-butyl } -phenoxy) -2-methyl-propionic acid ethyl ester (31)

Compound 31 (oil) was prepared according to synthesis method 1 from triazine 7b and intermediate 12 d. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.51.

Example 32: 2- {3- [3- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazin-6-yloxy) -propyl]-phenylthio } -2-methyl-propionic acid ethyl ester (32)

Compound 32 (oil) was prepared according to synthesis method 1 from triazine 4b and intermediate 12 e. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.37.

Example 33: 2- {3- [3- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazin-6-yloxy) -propyl]-phenoxy } -2-methyl-propionic acid ethyl ester (33)

Preparation of compound 33 according to synthesis method 2: 1.1g (3.7mmol) of triazine 9q, 0.83g (3.7mmol) of ester 10b and 1.25g (4.7mmol) of PPh are reacted at 40 deg.C₃Placed in 30ml of THF. 0.74ml (4.7mmol) of DEAD diluted in 10ml of THF are added dropwise and the mixture is stirred at 40 ℃ for 1 hour. Subsequently, the reaction medium is dried, concentrated and the residue obtained is purified by neutral alumina flash chromatography (heptane: AcOEt 80: 20). 0.8g of compound 33 was isolated as a clear oil (yield 43%).

TLC silica gel 60F254Merck, heptane: AcOEt 50: 50, Rf 0.30.

Example 34: 2- {3- [3- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazin-6-yloxy) -propoxy]-phenylthio } -2-methyl-propionic acid ethyl ester (34)

Compound 34 (oil) was prepared according to synthesis method 2 from triazine 9q and intermediate 11 c. TLC silica gel 60F254Merck, heptane: AcOEt 50: 50, Rf 0.33.

Example 35: 2- (3- {3- [3, 5-dioxo-2, 4-di- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-]Triazin-6-yloxy]-propoxy } -phenoxy) -2-methyl-propionic acid ethyl ester (35)

Compound 35 (oil) was prepared according to synthesis method 2 from triazine 9r and intermediate 10 b. TLC silica gel 60F254Merck, heptane: AcOEt 50: 50, Rf 0.50.

Example 36: 2- {3- [4- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazin-6-yloxy) -butoxy]-phenoxy } -2-methyl-propionic acid ethyl ester (36)

Compound 36 (oil) was prepared according to synthesis method 2 from triazine 9s and intermediate 10 b. TLC silica gel 60F254Merck, heptane: AcOEt 50: 50, Rf 0.34.

Example 37: 2- {3- [4- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazin-6-yloxy) -butoxy]-phenylthio } -2-methyl-propionic acid ethyl ester (37)

Compound 37 (oil) was prepared according to synthesis method 2 from triazine 9s and intermediate 11 c. TLC silica gel 60F254Merck, heptane: AcOEt 50: 50, Rf ═ 0.37.

Example 38: 2- {4- [2- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazin-6-yloxy) -ethoxy]-phenylthio } -2-methyl-propionic acid ethyl ester (38)

Compound 38 (oil) was prepared according to synthesis method 2 from triazine 9p and intermediate 11 d. TLC silica gel 60F254Merck, heptane: AcOEt 50: 50, Rf 0.33.

Example 39: 2- (4- {3- [3, 5-dioxo-2, 4-di- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-yloxy]-propoxy } -phenoxy) -2-methyl-propionic acid ethyl ester (39)

Compound 39 (oil) was prepared according to synthesis method 2 from triazine 9r and intermediate 10 c. TLC silica gel 60F254Merck, heptane: AcOEt 50: 50, Rf 0.50.

Example 40: 2- {4- [2- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazin-6-ylamino) -ethoxy]-phenoxy } -2-methyl-propionic acid ethyl ester (40)

Compound 40 (oil) was prepared according to synthesis method 2 from triazine 9b and intermediate 10 c. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.29.

EXAMPLE 41: 2- (4- {2- [3, 5-dioxo-2, 4-di- (4, 4, 4-trifluorobutyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-d]Triazin-6-ylamino]-ethoxy } -phenoxy) -2-methyl-propionic acid ethyl ester (41)

Compound 41 (oil) was prepared according to synthesis method 2 from triazine 9a and intermediate 10 c. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.50.

Example 42: 2- {4- [2- (2, 4-diheptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino) -ethoxy]-phenoxy } -2-methyl-propionic acid ethyl ester (42)

Compound 42 (oil) was prepared according to synthesis method 2 from triazine 9c and intermediate 10 c. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.85.

Example 43: 2- (4- {2- [2, 4-bis- (3-cyclohexyl-propyl) -3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-tetrahydro-)]Triazin-6-ylamino]-ethoxy } -phenoxy) -2-methyl-propionic acid ethyl ester (43)

Compound 43 (oil) was prepared according to synthesis method 2 from triazine 9d and intermediate 10 c. TLC silica gel 60F254Merck, heptane: AcOEt 80: 20, Rf ═ 0.85.

Example 44: 2-methyl-2- (4- {3- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino]-propoxy } -phenoxy) -propionic acid ethyl ester (44)

Compound 44 (oil) was prepared according to synthesis method 2 from triazine 9f and intermediate 10 c. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf ═ 0.36.

Example 45: 2- {4- [3- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazin-6-ylamino) -propoxy groups]-phenoxy } -2-methyl-propionic acid ethyl ester (45)

Compound 45 (oil) was prepared according to synthesis method 2 from triazine 9g and intermediate 10 c. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf ═ 0.48.

Example 46: 2-methyl-2- (4- {3- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino]-propoxy } -phenoxy) -propionic acid ethyl ester (46)

Compound 46 (oil) was prepared according to synthesis method 2 from triazine 9h and intermediate 10 c. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf ═ 0.37. F116 deg.c

Example 47: 2- {4- [3- (4-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-l]Triazin-6-ylamino) -propoxy groups]-phenoxy } -2-methyl-propionic acid ethyl ester (47)

Compound 47 (oil) was prepared according to synthesis method 2 from triazine 9i and intermediate 10 c. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.30.

Example 48: 2- (4- {3- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-]Triazin-6-ylamino]-propoxy } -phenoxy) -2-methyl-propionic acid ethyl ester (48)

Compound 48 (oil) was prepared according to synthesis method 2 from triazine 9j and intermediate 10 c. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf 0-50.

Example 49: 2- {4- [3- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-l]Triazin-6-ylamino) -propoxy groups]-phenylthio } -2-methyl-propionic acid ethyl ester (49)

Compound 49 (oil) was prepared according to synthesis method 2 from triazine 9i and intermediate 11 d. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.46.

Example 50: 2- {4- [4- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-l]Triazin-6-ylamino) -butoxy]-phenoxy } -2-methyl-propionic acid ethyl ester (50)

Compound 50 (oil) was prepared according to synthesis method 2 from triazine 9l and intermediate 10 c. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.50.

Example 51: 2- (3- {3- [ 2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-)]Triazin-6-yl) - (4, 4, 4-trifluoro-butyl) -amino]-propoxy } -phenoxy) -2-methyl-propionic acid ethyl ester (51)

Compound 51 (oil) was prepared according to synthesis method 3 from triazine 9m and intermediate 10b using Mitsunobu coupling conditions as described in example 33.

TLC silica gel 60F254Merck, petroleum ether: AcOEt 90: 10, Rf ═ 0.56.

Example 52: 2- (3- {3- [2, 4-dimethyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4)]Triazin-6-yl) -heptyl-amino]-propoxy } -phenylthio) -2-methyl-propionic acid ethyl ester (52)

Compound 52 (oil) was prepared from triazine 9n and intermediate 11c according to synthesis method 3, using coupling conditions as described in example 33.

TLC silica gel 60F254Merck, heptane: AcOEt 70: 30, Rf ═ 0.22.

Example 53: 2- (4- {3- [2, 4-dimethyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4)]Triazin-6-yl) -heptyl-amino]-propoxy } -phenylthio) -2-methyl-propionic acid ethyl ester (53)

Compound 53 (oil) was prepared from triazine 9n and intermediate 11d according to synthesis method 3, using coupling conditions as described in example 33.

TLC silica gel 60F254Merck, heptane: AcOEt 80: 20, Rf 0.45.

Example 54: 2- (3- {4- [ (2, 4-dimethyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4)]Triazin-6-yl) -heptyl-amino]-butoxy } -phenylthio) -2-methyl-propionic acid ethyl ester (54)

Compound 54 (oil) was prepared from triazine 9o and intermediate 11c according to synthesis method 3, using coupling conditions as described in example 33.

TLC silica gel 60F254Merck, heptane: AcOEt 70: 30, Rf ═ 0.25.

Example 55: 2- (2- {2- [3, 5-dioxo-2, 4-di- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-]Triazin-6-ylamino]-ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester (55)

Preparation of compound 55 according to synthesis method 4: 6.6g (16.1mmol) of triazine 1d, 2g (13.4mmol) of 2 (2-methoxy-phenyl) -ethylamine and 4.7ml (33.9mmol) of triethylamine are placed in 20ml of n-butanol at 120 ℃ for 28 hours. After drying and concentrating the reaction medium, the residue obtained is dissolved in water and extracted with AcOEt. The organic phase is washed with MgSO 2₄Dried, then dried and concentrated. By fast twoThe resulting oil was purified by silica chromatography (petroleum ether: AcOEt 90: 10). 3.1g of the intermediate are isolated in the form of an oil (yield 48%) and then placed under nitrogen at 0 ℃ in 30ml of ch₂Cl₂In (1). Dropwise adding BBr₃(12.8ml in CH at 1M₂Cl₂Medium) and the reaction medium is stirred at ambient temperature for 3.5 hours. It was then left at 0 ℃ and acidified with 0.1N HCl solution until pH 1. The organic phase is decanted off and then washed with 100ml of water. Over MgSO₄After drying, it is dried, concentrated and chromatographed on flash silica (CH)₂Cl₂AcOEt 95: 5) purifying the residue obtained. 1.9g of the corresponding phenol were isolated (yield 65%) and then washed with 1.9ml (12.5mmol) of ethyl bromoisobutyrate and 0.6g (4.3mmol) of K₂CO₃It was placed in 2ml DMF in the presence of water. The reaction medium is heated at 130 ℃ for 22 hours and then filtered off and dried to concentrate. By flash silica Chromatography (CH)₂Cl₂AcOEt 98: 2) purifying the obtained oil. 0.8g of compound 55 is isolated in the form of an oil (yield: 34%). TLC silica gel 60F254Merck, CH₂Cl₂∶AcOEt 95∶5，Rf＝0.66。

Example 56: 2-methyl-2- (3- {2- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino]-ethyl } -phenoxy) -propionic acid ethyl ester (56)

Preparation of compound 56 according to synthesis method 1: in the presence of 1.3ml (9.3mmol) of triethylamine, 1.1g (4.4mmol) of derivative 13b and 1g (3.7mmol) of triazine 4a are placed in 10ml of nBuOH. The mixture was stirred at 120 ℃ for 24 hours. After drying and concentrating the reaction medium, the residue obtained is dissolved in water and extracted with AcOEt. The organic phase is washed with MgSO 2₄Dried, then dried and concentrated. The resulting oil was purified by flash silica chromatography (petroleum ether: AcOEt 90: 10). 0.4g of compound 56 was isolated as an oil (yield 27%)。

TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.19.

Example 57: 2- {3- [2- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] -c]Triazin-6-ylamino) -ethyl]-phenoxy } -2-methyl-propionic acid ethyl ester (57)

Compound 57 (oil) was prepared according to synthesis method 1 from triazine 4b and intermediate 13 b. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf ═ 0.44.

Example 58: 2-methyl-2- (3- {2- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino]-ethyl } -phenoxy) -propionic acid ethyl ester (58)

Compound 58 (oil) was prepared according to synthesis method 1 from triazine 6a and intermediate 13 b. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.33.

Example 59: 2- {3- [2- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] -tetrahydro]Triazin-6-ylamino) -ethyl]-phenoxy } -2-methyl-propionic acid ethyl ester (59)

Compound 59 (oil) was prepared according to synthesis method 1 from triazine 7a and intermediate 13 b. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.50.

Example 60: 2- (3- {2- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-]Triazin-6-ylamino]-ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester (60)

Compound 60 (oil) was prepared according to synthesis method 1 from triazine 7b and intermediate 13 b. TLC silica gel 60F254Merck, petroleum ether: AcOEt 90: 10, Rf ═ 0.22.

Example 61: 2- {3- [2- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] -tetrahydro]Triazin-6-ylamino) -ethyl]-phenylthio } -2-methyl-propionic acid ethyl ester (61)

Compound 61 (oil) was prepared according to synthesis method 1 from triazine 7a and intermediate 13 d. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf 0.61.

Example 62: 2-methyl-2- (3- {3- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino]-propyl } -phenoxy) -propionic acid ethyl ester (62)

Compound 62 (oil) was prepared according to synthesis method 4 from triazine 4a and intermediate 13 j. TLC silica gel 60F254Merck, CH₂Cl₂∶AcOEt 90∶10，Rf＝0.60。

Example 63: 2- (3- {3- [2- (2-cyano-ethyl) -4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-tetrahydro-)]Triazin-6-ylamino]-propyl } -phenoxy) -2-methyl-propionic acid ethyl ester (63)

Compound 63 (oil) was prepared according to synthesis method 4 from triazine 3a and intermediate 13 j. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.44.

Example 64: 2- {3- [3- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazin-6-ylamino) -propyl]-phenoxy } -2-methyl-propionic acid ethyl ester (64)

Compound 64 (oil) was prepared according to synthesis method 4 from triazine 4b and intermediate 13 j. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.20.

Example 65: 2-methyl-2- (3- {3- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino]-propyl } -phenoxy) -propionic acid ethyl ester (65)

Compound 65 (oil) was prepared according to synthesis method 4 from triazine 6a and intermediate 13 j. TLC silica gel 60F254Merck, CH₂Cl₂∶AcOEt 90∶10，Rf＝0.78。

Example 66: 2- (3- {3- [3, 5-dioxo-2, 4-di- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-]Triazin-6-ylamino]-propyl } -phenoxy) -2-methyl-propionic acid ethyl ester (66)

Compound 66 (oil) was prepared according to synthesis method 4 from triazine 1d and intermediate 13 l. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf ═ 0.49.

Example 67: 2- {3- [3- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-l]Triazin-6-ylamino) -propyl]-phenoxy } -2-methyl-propionic acid ethyl ester (67)

Compound 67 (oil) was prepared according to synthesis method 1 from triazine 7a and intermediate 13 c. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.50.

Example 68: 2- (3- {3- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-]Triazin-6-ylamino]-propyl } -phenoxy) -2-methyl-propionic acid ethyl ester (68)

Compound 68 (oil) was prepared according to synthesis method 4 from triazine 7b and intermediate 13 j. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.63.

Example 69: 2- {3- [3- (2, 4-diheptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino) -propyl]-phenoxy } -2-methyl-propionic acid ethyl ester (69)

Compound 69 (oil) was prepared according to synthesis method 4 from triazine 1e and intermediate 13 j. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.53.

Example 70: 2- {3- [3- (2-benzyl-4-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-tetrahydro-)]Triazin-6-ylamino) -propyl]-phenoxy } -2-methyl-propionic acid ethyl ester (70)

Compound 70 (oil) was prepared according to synthesis method 4 from triazine 7c and intermediate 13 j. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.47.

Example 71: 2- (3- {3- [ 4-benzyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-]Triazin-6-ylamino]-propyl } -phenoxy) -2-methyl-propionic acid ethyl ester (71)

Compound 71 (oil) was prepared from triazine 8a and intermediate 13j according to synthesis method 4. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.30.

Example 72: 2- {3- [3- (4-benzyl)-2-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino) -propyl]-phenoxy } -2-methyl-propionic acid ethyl ester (72)

Compound 72 (oil) was prepared according to synthesis method 4 from triazine 8b and intermediate 13 j. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.42.

Example 73: 2- {4- [3- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-l]Triazin-6-ylamino) -propyl]-phenylthio } -2-methyl-propionic acid ethyl ester (73)

Compound 73 (oil) was prepared according to synthesis method 1 from triazine 7a and intermediate 13 e. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.58.

Example 74: 2-methyl-2- (3- {4- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino]-butyl } -phenoxy) -propionic acid ethyl ester (74)

Compound 74 (oil) was prepared according to synthesis method 4 from triazine 4a and intermediate 13 m. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.21.

Example 75: 2- {3- [4- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazine-6-ylamino) -butyl]-phenoxy } -2-methyl-propionic acid ethyl ester (75)

Compound 75 (oil) was prepared from triazine 4b and intermediate 13m according to synthesis method 4. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.44.

Example 76: 2-methyl-2- (3- {4- [4- (3-methyl-but-2-enyl) -3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-tetrahydro-n-1-yl ] -2]Triazin-6-ylamino]-butyl } -phenoxy) -propionic acid ethyl ester (76)

Compound 76 (oil) was prepared according to synthesis method 4 from triazine 5d and intermediate 13 m. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.50.

Example 77: 2-methyl-2- (3- {4- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino]-butyl } -phenoxy) -propionic acid ethyl ester (77)

Compound 77 (oil) was prepared according to synthesis method 4 from triazine 6a and intermediate 13 k. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.35.

Example 78: 2-methyl-2- (3- {4- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazine-6-ylamino]-butyl } -phenoxy) -propionic acid tert-butyl ester (78)

Compound 78 (oil) was prepared from triazine 6a and intermediate 13m according to synthesis method 4 using tert-butyl bromoisobutyrate in the final step.

TLC silica gel 60F254Merck, heptane: AcOEt 60: 40, Rf ═ 0.35.

Example 79: 2-methyl-2- (3- {4- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino]-butyl } -phenoxy) -propionic acid (79)

Hydrolysis of Compound 78 (trifluoroacetic acid/CH)₂Cl₂Yield 61%), compound 79 was isolated as a solid.

TLC silica gel 60F254Merck, CH₂Cl₂∶MeOH 90∶10，Rf＝0.73。F＝116℃

Example 80: 2- (3- {4- [3, 5-dioxo-2, 4-di- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino]-butyl } -phenoxy) -2-methyl-propionic acid ethyl ester (80)

Compound 80 (oil) was prepared according to synthesis method 4 from triazine 1d and intermediate 13 m. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.32.

Example 81: 2- (3- {4- [2- (2-cyano-ethyl) -3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino]-butyl } -phenoxy) -2-methyl-propionic acid ethyl ester (81)

Compound 81 (oil) was prepared from triazine 3b and intermediate 13k according to synthesis method 4. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf ═ 0.20.

Example 82: 2- (3- {4- [ 2-heptyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-]Triazin-6-ylamino]-butyl } -phenoxy) -2-methyl-propionic acid ethyl ester (82)

Compound 82 (oil) was prepared according to synthesis method 4 from triazine 6b and intermediate 13 k. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.37.

Example 83: 2- (3- {4- [ 2-heptyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-]Triazin-6-ylamino]-butyl } -phenoxy) -2-methyl-propionic acid ethyl ester (83)

Compound 83 (oil) was prepared from triazine 6b and intermediate 13m according to synthesis method 4 using tert-butyl bromoisobutyrate in the final step.

TLC silica gel 60F254Merck, heptane: AcOEt 60: 40, Rf ═ 0.43.

Example 84: 2- (3- {4- [ 2-heptyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-]Triazin-6-ylamino]-butyl } -phenoxy) -2-methyl-propionic acid (84)

Hydrolysis of Compound 83 (trifluoroacetic acid/CH)₂Cl₂Yield 76%) compound 84 was isolated as an oil.

TLC silica gel 60F254Merck, CH₂Cl₂∶MeOH 95∶5，Rf＝0.39。

Example 85: 2- (3- {4- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-]Triazin-6-ylamino]-butyl } -phenoxy) -2-methyl-propionic acid ethyl ester (85)

Compound 85 (oil) was prepared according to synthesis method 4 from triazine 7b and intermediate 13 m. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.75.

Example 86: 2- (3- {4- [2- (2-cyano-ethyl) -4-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-tetrahydro-)]Triazin-6-ylamino]-butyl } -phenoxy) -2-methyl-propionic acid ethyl ester (86)

Compound 86 (oil) was prepared according to synthesis method 4 from triazine 3c and intermediate 13 m. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf 0.51.

Example 87: 4- (6- {4- [3- (1-ethoxycarbonyl-1-methyl-ethoxy) -phenyl]-butylamino } -4-heptyl-3, 5-dioxo-4, 5-dihydro-3H- [1, 2, 4]Triazin-2-yl) -but-2-enoic acid ethyl ester (87)

Preparation of compound 87 (oil) according to synthesis method 6: 0.2g (5mmol) NaH (60% in paraffin) was suspended in 10ml DMF at 0 ℃ under nitrogen. 1.4g (2.6mmol) of compound 86 diluted in 4ml of DMF are added dropwise. The mixture was stirred at ambient temperature for 4.5 hours and then dried and concentrated. The residue was dissolved in water and extracted with AcOEt. The organic phase is washed with MgSO 2₄Dried, then dried and concentrated. By flash silica Chromatography (CH)₂Cl₂AcOEt 90: 10) and 0.8g of solid was isolated (yield: 63%). 78mg (1.9mmol) NaH (60% in paraffin) are suspended in 15ml DMF at 0 ℃ under nitrogen. The previously isolated solid (0.8g, 1.6mmol) diluted in 5ml of DMF was added dropwise and the mixture was stirred at ambient temperature for 1 hour. 0.29ml (2.1mmol) of ethyl 4-bromo-but-2-enoate are added and stirring is continued for 9 hours. After drying and concentration, the residue obtained is dissolved in water and extracted with AcOEt. The organic phase is washed with MgSO 2₄Dried, then dried and concentrated. The resulting oil was purified by flash silica chromatography (petroleum ether: AcOEt 80: 20). 0.6g of compound 87 was isolated as an oil (56% yield).

TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.33.

Example 88: 2- {3- [4- (2, 4-diheptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro-, [2 ], [2, 4-tetrahydro- ]1，2，4]Triazin-6-ylamino) -butyl]-phenoxy } -2-methyl-propionic acid ethyl ester (88)

Compound 88 (oil) was prepared from triazine 1e and intermediate 13k according to synthesis method 4. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.53.

Example 89: 2- {3- [4- (2-benzyl-4-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-l]Triazin-6-ylamino) -butyl]-phenoxy } -2-methyl-propionic acid ethyl ester (89)

Compound 89 (oil) was prepared according to synthesis method 4 from triazine 7c and intermediate 13 k. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.37. F-58 ℃.

Example 90: 2- (3- {3- [ 4-benzyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-]Triazin-6-ylamino]-butyl } -phenoxy) -2-methyl-propionic acid ethyl ester (90)

Compound 90 (oil) was prepared according to synthesis method 4 from triazine 8a and intermediate 13 k. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.46.

Example 91: 2- {3- [4- (4-benzyl-2-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-l]Triazin-6-ylamino) -butyl]-phenoxy } -2-carboxylic acid methyl esterYl-propionic acid ethyl ester (91)

Compound 91 (oil) was prepared from triazine 8b and intermediate 13k according to synthesis method 4. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.60.

Example 92: 2- (3- {5- [3, 5-dioxo-2, 4-di- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-]Triazin-6-ylamino]-pentyl } -phenoxy) -2-methyl-propionic acid ethyl ester (92)

Compound 92 (oil) was prepared according to synthesis method 4 from triazine 1d and intermediate 13 n. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.45.

Example 93: 2-methyl-2- (3- {4- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino]-butyl } -phenylthio) -propionic acid ethyl ester (93)

Compound 93 (oil) was prepared according to synthesis method 1 from triazine 4a and intermediate 13 f. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.45.

Example 94: 2- {3- [4- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazin-6-ylamino) -butyl]-phenylthio } -2-methyl-propionic acid ethyl ester (94)

Compound 94 (oil) was prepared according to synthesis method 1 from triazine 4b and intermediate 13 f. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.26.

Example 95: 2-methyl-2- (3- {4- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino]-butyl } -phenylthio) -propionic acid ethyl ester (95)

Compound 95 (oil) was prepared according to synthesis method 1 from triazine 6a and intermediate 13 f. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.34.

Example 96: 2-methyl-2- (3- {4- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino]-butyl } -sulfanyl) -propionic acid (96)

Hydrolysis of Compound 95 (BBr)₃/CH₂Cl₂Yield 49%), compound 96 was isolated as a solid.

TLC silica gel 60F254Merck, CH₂Cl₂∶AcOEt 80∶20，Rf＝0.24。F＝106℃

Example 97: 2- (3- {4- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4,5-tetrahydro- [1, 2, 4]Triazin-6-ylamino]-butyl } -sulfanyl) -2-methyl-propionic acid ethyl ester (97)

Compound 97 (oil) was prepared according to synthesis method 1 from triazine 7b and intermediate 13 f. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.74.

Example 98: 2- {3- [4- (2, 4-diheptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino) -butyl]-phenylthio } -2-methyl-propionic acid ethyl ester (98)

Compound 98 (oil) was prepared according to synthesis method 1 from triazine 1e and intermediate 13 f. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.53.

Example 99: 2- {3- [4- (2-benzyl-4-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-l]Triazin-6-ylamino) -butyl]-phenylthio } -2-methyl-propionic acid ethyl ester (99)

Compound 99 (oil) was prepared according to synthesis method 1 from triazine 7c and intermediate 13 f. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.43.

Example 100: 2- (3- {4- [ 4-benzyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-]Triazin-6-ylamino]-butyl } -phenylsulfanyl) -2-methyl-ethyl propionate (100)

Compound 100 (oil) was prepared according to synthesis method 1 from triazine 8a and intermediate 13 f. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.27.

Example 101: 2- {3- [4- (4-benzyl-2-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-l]Triazin-6-ylamino) -butyl]-phenylthio } -2-methyl-propionic acid ethyl ester (101)

Compound 101 (oil) was prepared according to synthesis method 1 from triazine 8b and intermediate 13 f. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.39.

Example 102: 2-methyl-2- (4- {2- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino]-ethyl } -phenoxy) -propionic acid ethyl ester (102)

Compound 102 (oil) was prepared according to synthesis method 1 from triazine 4a and intermediate 13 a. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.22.

Example 103: 2- {4- [2- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazin-6-ylamino) -ethyl]-phenoxy } -2-methyl-propionic acid ethyl ester (103)

Compound 103 (oil) was prepared according to synthesis method 1 from triazine 4b and intermediate 13 a. TLC silica gel 60F254Merck, CH₂Cl₂∶AcOEt 90∶10，Rf＝0.54。

Example 104: 4- [6- {2- [4- (1-ethoxycarbonyl-1-methyl-ethoxy) -phenyl]-ethylamino } -3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -4, 5-dihydro-3H- [1, 2, 4]Triazin-2-yl radical]-ethyl but-2-enoate (104)

Compound 104 (oil) was prepared from triazine 3b and intermediate 13a according to synthesis method 6 using ethyl 4-bromo-but-2-enoate in the alkylation step.

TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.34.

Example 105: 2- (4- {2- [2- (3-cyclohexyl-propyl) -3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino]-ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester (105)

Compound 105 (oil) was prepared according to synthesis method 1 from triazine 6c and intermediate 13 a. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.44.

Example 106: 2- {4- [2- (4-heptyl-2-methyl-3, 5-dioxo-2, 3,4, 5-tetrahydro- [1, 2, 4-]Triazin-6-ylamino) -ethyl]-phenoxy } -2-methyl-propionic acid ethyl ester (106)

Compound 106 (solid) was prepared according to synthesis method 1 from triazine 7a and intermediate 13 a. TLC silica gel 60F254Merck, petroleum ether: AcOEt 70: 30, Rf ═ 0.60. F-54 ℃.

Example 107: 2- (4- {2- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-]Triazin-6-ylamino]-ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester (107)

Compound 107 (solid) was prepared according to synthesis method 1 from triazine 7b and intermediate 13 a. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.47. F-63 ℃.

Example 108: 2- {4- [2- (2, 4-diheptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino) -ethyl]-phenoxy } -2-methyl-propionic acid ethyl ester (108)

Compound 108 (oil) was prepared according to synthesis method 1 from triazine 1e and intermediate 13 a. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.57.

Example 109: 2- {4- [2- (4-benzyl-2-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-l]Triazin-6-ylamino) -ethyl]-phenoxy } -2-methyl-propionic acid ethyl ester (109)

Compound 109 (solid) was prepared according to synthesis method 1 from triazine 8b and intermediate 13 a. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.60. F ═ 65 ℃.

Example 110: 2- {4- [2- (2, 4-bis-benzyloxymethyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-tetrahydro-)]Triazin-6-ylamino) -ethyl]-phenoxy } -2-methyl-propionic acid ethyl ester (110)

Compound 110 (oil) was prepared according to synthesis method 1 from triazine 1g and intermediate 13 a. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.34.

Example 111: 2- (4- {2- [ (2, 4-dimethyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4)]Triazin-6-yl) - (4, 4, 4-trifluoro-butyl) -amino]-ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester (111)

Preparation of compound 111 according to synthesis method 5: in the presence of 5.1ml (36.8mmol) triethylamine 3.2g (14.7mmol) triazine 1b and 5.4ml (36.8mmol)2- (4-methoxy-phenyl) -ethylamine are placed in 30ml nBuOH for 10.5 h at 130 ℃. After drying and concentration, the residue obtained is dissolved in water and extracted with AcOEt. The organic phase is washed with MgSO 2₄Dried, then dried and concentrated. By passingFlash silica chromatography (heptane: AcOEt 50: 50) purified the oil and isolated 2.3g of a solid (54% yield). 0.48g (12mmol) NaH (60% in paraffin) was suspended in 15ml DMF at 0 ℃ under nitrogen. 2.3g (7.9mmol) of the previously isolated solid diluted in 5ml of DMF are added dropwise. The mixture was stirred at ambient temperature for 0.5 h, then 4.7g (19.8mmol) of 1, 1, 1-trifluoro-4-iodo-butane was added and stirring was continued for 6.5 h. After drying and concentration, the residue obtained is dissolved in water and extracted with AcOEt. The organic phase is washed with MgSO 2₄Dried, then dried and concentrated. By flash silica Chromatography (CH)₂Cl₂AcOEt 95: 5) and 0.82g of oil were isolated (yield: 26%). Then 0.4g of the latter is placed in 15ml of CH at-60 ℃ under nitrogen₂Cl₂In, BBr is dripped₃Solution (1M in CH)₂Cl) (0.24ml diluted in 2ml CH₂Cl₂Medium) and the reaction medium is stirred at ambient temperature for 2 hours. It was then left at 0 ℃ and neutralized with 1N HCl solution. The organic phase is decanted and then washed with 100ml of water. Over MgSO₄After drying, it is concentrated by drying and 0.38g of the corresponding phenol are isolated (quantitative yield). Then at 0.14g (1mmol) K₂CO₃It was placed in 0.5ml of ethyl bromoisobutyrate at 150 ℃ for 5 hours in the presence of water. After filtration and concentration by dry chromatography on silica (CH)₂Cl₂AcOEt 95: 5) and 0.25g of compound 111 was isolated as an oil (51% yield).

TLC silica gel 60F254Merck, CH₂Cl₂∶AcOEt 90∶10，Rf＝0.65。

Example 112: 2- (4- {2- [2, 4-dimethyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4)]Triazin-6-yl) -heptyl-amino]-ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester (112)

Compound 112 (oil) was prepared according to synthesis method 1 from triazine 1b and intermediate 14 a. TLC silica gel 60F254Merck, CH₂Cl₂∶AcOEt 70∶30，Rf＝0.70。

Example 113: 2- (4- {2- [2, 4-dimethyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4)]Triazin-6-yl) -heptyl-amino]-ethyl } -phenoxy) -2-methyl-propionic acid (113)

Compound 113 was prepared according to synthesis method 5 from triazine 1b and from 2- (4-methoxy-phenyl) -ethylamine by alkylating nitrogen with 1-bromoheptane and by using tert-butyl bromoisobutyrate. In the presence of trifluoroacetic acid in CH₂Cl₂After hydrolysis, compound 113 is isolated as an oil.

TLC silica gel 60F254Merck, CH₂Cl₂∶MeOH 90∶10，Rf＝0.43。

Example 114: 2- (4- {2- [ (2, 4-dimethyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4)]Triazin-6-yl) -phenethyl-amino]-ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester (114)

Compound 114 (oil) was prepared according to synthesis method 1 from triazine 1b and intermediate 14 b. TLC silica gel 60F254Merck, CH₂Cl₂∶AcOEt 90∶10，Rf＝0.74。

Example 115: 2- (4- {2- [ (2, 4-dimethyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4)]Triazin-6-yl) - (3-phenyl-propyl) -amino]-ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester (115)

Compound 115 (oil) was prepared according to synthesis method 1 from triazine 1b and intermediate 14 c. TLC silica gel 60F254Merck, CH₂Cl₂∶AcOEt 90∶10，Rf＝0.63。

Example 116: 2- (4- {2- [ (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-)]Triazin-6-yl) -phenethyl-amino]-ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester (116)

Compound 116 (oil) was prepared according to synthesis method 1 from triazine 7a and intermediate 14 b. TLC silica gel 60F254Merck, CH₂Cl₂，Rf＝0.52。

Example 117: 2- (4- {2- [ (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-)]Triazin-6-yl) - (3-phenyl-propyl) -amino]-ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester (117)

Compound 117 (oil) was prepared according to synthesis method 1 from triazine 7a and intermediate 14 c. TLC silica gel 60F254Merck, CH₂Cl₂，Rf＝0.46。

Example 118: 2-methyl-2- (4- {2- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4]Triazin-6-ylamino]-ethyl } -phenylthio) -propionic acid (118)

Compound 118 was prepared according to synthesis method 1 from triazine 4a and intermediate 13 i. In the presence of trifluoroacetic acid in CH₂Cl₂After hydrolysis, compound 118 is isolated as a solid.

TLC silica gel 60F254Merck, AcOEt, Rf ═ 0.42. F-128 ℃.

Example 119: 2- {4- [2- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazin-6-ylamino) -ethyl]-phenylthio } -2-methyl-propionic acid ethyl ester (119)

Compound 119 (oil) was prepared according to synthesis method 1 from triazine 4b and intermediate 13 g. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.60.

Example 120: 2- {4- [2- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazin-6-ylamino) -ethyl]-phenylthio } -2-methyl-propionic acid (120)

Compound 120 was prepared according to synthesis method 1 from triazine 4b and intermediate 13 i. In the presence of trifluoroacetic acid in CH₂Cl₂After hydrolysis, compound 120 is isolated as a solid.

TLC silica gel 60F254Merck, CH₂Cl₂∶MeOH 90∶10，Rf＝0.34。F＝70℃。

Example 121: 2- {4- [2- (4-butyl-2-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-)]Triazin-6-ylamino) -ethyl]-phenylthio } -2-methyl-propionic acid (121)

Compound 121 was prepared according to synthesis method 1 from triazine 5c and intermediate 13 i. In the presence of trifluoroacetic acid in CH₂Cl₂After hydrolysis, compound 121 is isolated as an oil.

TLC silica gel 60F254Merck, CH₂Cl₂∶MeOH 98∶2，Rf＝0.46。

Example 122: 2- {4- [2- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-)]Triazin-6-ylamino) -ethyl]-phenylthio } -2-methyl-propionic acid ethyl ester (122)

Compound 122 (solid) was prepared according to synthesis method 1 from triazine 7a and intermediate 13 g. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.67. F-49 ℃.

Example 123: 2- (4- {2- [ 4-heptyl-3, 5-dioxo 2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4-l]Triazin-6-ylamino]-ethyl } -phenylthio) -2-methyl-propionic acid (123)

According to the synthesis method 1, the synthesis method comprises the following steps,compound 123 was prepared from triazine 7b and intermediate 13 i. In the presence of trifluoroacetic acid in CH₂Cl₂After hydrolysis, compound 123 is isolated as a solid.

TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf 0-19. F-86 ℃.

Example 124: 2- {4- [3- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4-d-ydro-)]Triazin-6-ylamino) -propyl]-phenylthio } -2-methyl-propionic acid ethyl ester (124)

Compound 125 (oil) was prepared according to synthesis method 1 from triazine 4b and intermediate 13 h. TLC silica gel 60F254Merck, petroleum ether: AcOEt 80: 20, Rf ═ 0.20.

Pharmacological evaluation

In vitro

Transcriptional activation of reporter genes (reporter gene method) controlled by specific response elements upon ligand binding to receptor

These experiments were performed according to J.M.Lehmann et al (J.biol.chem 1995, 270: 12953-12956) with several modifications. Sub-fused Cos-7 cells (ATCC, CRL-1651) were transfected with: (i) a chimeric receptor (chimeric receptor) comprising a human PPAR α or PPAR γ or PPAR δ ligand bound to the binding domain of the yeast galactosidase (Gal-4) DNA binding domain, and (ii) the reporter plasmid, comprising five copies of a Gal-4 response element upstream of the thymidine kinase promoter adjacent to the luciferase gene (p5 xUAS-tk-Luc). After 24 hours, the cells were treated with the compound and its vehicle for another 24 hours and evaluated for luciferase activity after cell extraction according to the manufacturer's (Promega) recommendations.

The results are reported in Table 17 below, in whichDesignation of "hit" indicates that the level of transcriptional activation is significant but EC cannot be determined₅₀Wherein the designation "nd" indicates that no data was collected.

Table 17: transcriptional activation of reporter genes by various human PPAR subtypes

Examples	hPPAR-GAL4αEC50(μM)	hPPAR-GAL4γEC50(μM)	hPPAR-GAL4δEC50(μM)
				Fenofibric acid	16.9	65.2	＞100
Rosiglitazone	0	1.12	0
				Pioglitazone	＞10	4.77	0
1	3-10	0	0
				2	＞10	～10	0
3	～3	0	0
				4	＞10	0	0
5	～3	～10	0
				6	～0.3	0	0
7	0.3-1	1-3	0
				8	～0.3	3-10	0
9	3-10	～10	0
				10	0.3-1	～1	0
11	0.3-1	1-3	0
				12	～0.03	1-3	hit
13	0.01-0.03	0.1-0.3	～3
				14	0.01-0.03	～1	～10
15	0.001-0.003	0.1-0.3	hit
				16	～0.1	3-10	0
17	0.3-1	～0.3	0
				18	0.03-0.1	～1	0
19	～3	3-10	0
				20	hit	hit	0
21	3-10	0	0
				22	10	hit	0
23	1	hit	0
				24	＞10	0	0
25	hit	＞10	hit
				26	＞10	0	0
27	～3	3-10	3-10
				28	～10	hit	0
29	3-10	3-10	3-10
				30	0.03-0.1	＞10	hit
31	～0.1	～1	3-10
				32	1-3	hit	0
33	～3	～3	0
				34	＞10	＞10	0
35	0.03-0.1	3-10	～10

Examples	hPPAR-GAL4αEC50(μM)	hPPAR-GAL4γEC50(μM)	hPPAR-GAL4δEC50(μM)
				36	0.3-1	3-10	hit
37	＞10	～10	0
				38	＞10	＞10	0
39	0.1-0.3	3-10	～3
				40	3-10	～10	＞10
41	～0.1	～10	1-3
				42	～1	＞10	1-3
43	～3	hit	0
				44	＞10	3-10	0
45	1-3	～3	hit
				46	0.3-1	0	0
47	～0.3	～0.3	hit
				48	0.3-1	0.3-1	～3
49	＞10	＞10	0
				50	＞10	～10	0
51	3-10	＞10	0
				52	hit	0	0
53	1-3	0	0
				54	＞10	0	0
55	＞10	0	0
				56	hit	hit	0
57	～3	1-3	hit
				58	＞10	0	0
59	1-3	nd	0
				60	＞10	hit	0
61	～3	nd	0
				62	＞10	0	0
63	0	hit	0
				64	＞10	3-10	hit
65	0.1-0.3	＞10	0
				66	0.03-0.1	＞10	～10
67	～1	nd	0
				68	0.1-0.3	3-10	0
69	1-3	～10	0
				70	～1	～10	0
71	～1	hit	0
				72	3-10	3-10	0
73	0.1-0.3	nd	0
				74	～1	3-10	0
75	3-10	3-10	0
				76	0.01-0.03	1-3	3-10
77	～0.3	3-10	0
				78	＞10	0	0
79	～0.03	3-10	0
				80	0.01-0.03	0.3-1	＞10

Examples	hPPAR-GAL4αEC50(μM)	hPPAR-GAL4γEC50(μM)	hPPAR-GAL4δEC50(μM)
				81	0.3-1	＞10	0
82	～0.01	0.1-0.3	hit
				83	＞10	0	0
84	0.003-0.01	～0.3	1-3
				85	～0.03	1-3	hit
86	＞10	～1	hit
				87	～0.3	0.1-0.3	hit
88	～0.3	～10	0
				89	＞10	1-3	3-10
90	～0.1	～10	0
				91	0.3-1	3-10	0
92	0.003-0.01	3-10	0
				93	＞10	hit	0
94	3-10	3-10	0
				95	1-3	＞10	0
96	0.03-0.1	～10	＞10
				97	1-3	hit	0
98	＞10	0	0
				99	＞10	3-10	0
100	1-3	＞10	0
				101	1-3	0	0
102	＞10	hit	0
				104	1-3	＞10	0
105	1-3	～10	0
				106	～1	nd	＞10
107	～1	hit	0
				108	＞10	hit	0
109	～1	nd	3-10
				110	1-3	hit	＞10
111	0	hit	0
				112	1-3	～10	1-3
113	0.3-1	3-10	0.3-1
				114	～10	nd	0
115	～3	nd	＞10
				116	～10	nd	0
117	～10	nd	0
				118	1-3	～10	0
119	0.3	0.3	hit
				120	0.3-1	1-3	hit
121	0.03-0.1	1-3	hit
				122	～0.3	nd	＞10
123	0.1-0.3	～10	0
				124	0.3-1	＞10	0

In vivo

Normalization of metabolic parameters (cholesterol, plasma triglycerides) in insulin resistant male rats (Ico: ZUCKER-fa/fa) (fasting for 16-18 hours after treatment with the compound to be evaluated or its administered vehicle given to the male rats once daily for four days by oral route).

These metabolic parameters were determined by spectrophotometry at the beginning and end of each animal treatment.

Table 18: normalization of metabolic parameters

Examples	Plasma triglycerides	Plasma cholesterol
			11	2.5mg/kg inactivity 10 mg/kg-37%	2.5 mg/kg-25% and 10 mg/kg-25%
13	2.5mg/kg inactivity 10 mg/kg-28%	2.5 mg/kg-8% and 10 mg/kg-12%
			15	2.5 mg/kg-22% and 10 mg/kg-63%	2.5 mg/kg-4% and 10 mg/kg-8%
16	2.5mg/kg inactivity 10 mg/kg-15%	2.5 mg/kg-14% and 10 mg/kg-25%
			17	10 mg/kg-37%	Is active at 10mg/kg
41	No activity at 10mg/kg	10 mg/kg-28%
			45	No activity at 10mg/kg	10 mg/kg-16%
46	10 mg/kg-32%	10 mg/kg-13%
			47	10mg/kg is-45%	10 mg/kg-25%
53	No activity at 10mg/kg	2.5 mg/kg-7% and 10 mg/kg-28%
			59	2.5 mg/kg-13%	2.5 mg/kg-37%
65	2.5mg/kg inactivity 10 mg/kg-13%	2.5 mg/kg-13% and 10 mg/kg-23%
			66	No activity at 10mg/kg	10 mg/kg-9%
67	10 mg/kg-23%	10 mg/kg-14%

Examples	Plasma triglycerides	Plasma cholesterol
			68	Is active at 10mg/kg	10 mg/kg-21%
7.2	No activity at 10mg/kg	10 mg/kg-21%
			73	No activity at 10mg/kg	10 mg/kg-14%
74	2.5mg/kg inactivity 10 mg/kg-26%	2.5 mg/kg-18% and 10 mg/kg-29%
			75	Is active at 10mg/kg	2.5 mg/kg-19% and 10 mg/kg-13%
76	10 mg/kg-7%	2.5 mg/kg-16% and 10 mg/kg-22%
			77	Is active at 10mg/kg	2.5 mg/kg-29% and 10 mg/kg-35%
79	2.5 mg/kg-55%	2.5 mg/kg-32%
			80	No activity at 10mg/kg	10 mg/kg-16%
81	10 mg/kg-17%	10mg/kg is-12%
			82	Is active at 10mg/kg	10 mg/kg-13%
84	2.5mg/kg inactivity 10 mg/kg-7%	2.5mg/kg inactivity 10 mg/kg-13%
			85	Is active at 10mg/kg	10 mg/kg-21%
92	No activity at 10mg/kg	10 mg/kg-18%
			95	No activity at 10mg/kg	2.5 mg/kg-18% and 10 mg/kg-40%
96	2.5 mg/kg-26% and 10 mg/kg-60%	2.5 mg/kg-28% and 10 mg/kg-21%
			112	10 mg/kg-31%	10 mg/kg-43%
113	2.5mg/kg inactivity 10 mg/kg-26%	2.5 mg/kg-30% and 10 mg/kg-40%
			119	2.5 mg/kg-29% of the activity at 10mg/kg	2.5 mg/kg-21% and 10 mg/kg-32%
120	2.5 mg/kg-27% and 10 mg/kg-73%	2.5 mg/kg-32% and 10 mg/kg-33%
			121	2.5 mg/kg-24%	2.5 mg/kg-7%
122	10 mg/kg-35%	10 mg/kg-22%
			123	2.5 mg/kg-6% and 10 mg/kg-20%	2.5 mg/kg-8% and 10 mg/kg-14%

The invention therefore relates to the compounds of the formula I as defined above as novel medicaments for the treatment of diseases which require PPAR α and/or PPAR γ receptor agonists. These compounds are useful in the present invention and for the prevention and treatment of, for example: diabetic dyslipidemia, hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia, hyperglycemia, metabolic syndrome, obesity, atherosclerosis, and for pathological skin diseases with an inflammatory component or caused by abnormal cell differentiation, and for the treatment of, for example: psoriasis, acne, atopic dermatitis, skin aging, and photoaging.

Finally, the present invention relates to pharmaceutical compounds comprising as active ingredient at least one compound of formula I as defined above, preferably in combination with suitable excipients.

Claims (16)

1.3, 5-dioxo- (2H, 4H) -1, 2, 4-triazine derivatives of the general formula I, as well as the addition salts of pharmaceutically acceptable bases and the various enantiomers of compounds having an asymmetric carbon, and also mixtures thereof in all ratios, including in particular racemic mixtures,

wherein

-R₁And R₂May be the same or different and represents a linear or branched C₁-C₇Alkyl or alkenyl, by radicals such as trifluoromethyl, C₅-C₆Cycloalkyl, nitrile, C₁-C₄Alkoxycarbonylvinyl, hydroxycarbonylvinyl, C₁-C₄Alkoxycarbonyl, carboxylate, benzyloxy or phenyl substituted C₁-C₆Alkyl (wherein the phenyl ring may be substituted by one or more groups such as C₁-C₄Alkyl radical, C₁-C₄Alkoxy, nitro, halogen or trifluoromethyl substitution),

-YR₃represents oxygen or NR₃Wherein R is₃Represents hydrogen, linear or branched C₁-C₇Alkyl or alkenyl, C substituted by radicals such as trifluoromethyl or phenyl₁-C₆Alkyl (wherein the phenyl ring may be substituted by one or more groups such as C₁-C₄Alkyl radical, C₁-C₄Alkoxy, nitro, halogen or trifluoromethyl substitution),

-Z represents an oxygen or carbon atom capable of bonding to the ortho, meta or para position of the phenyl group in formula I,

n may be 0 to 5 when Z ═ C, or 2 to 4 when Z ═ O,

x represents oxygen or sulphur,

-R₄、R₅、R₆、R₇and R₈Represents hydrogen or fluorine, and is selected from the group consisting of,

-R₉、R₁₀and R₁₁Represents hydrogen or linear or branched C₁-C₅An alkyl group.

2.3, 5-dioxo- (2H, 4H) -1, 2, 4-triazine derivatives of the general formula I according to claim 1, wherein:

-R₁and R₂Independently of one another, represents linear or branched C₁-C₇Alkyl or alkenyl, by radicals such as trifluoromethyl, C₆Cycloalkyl, nitrile, or phenyl substituted C₁-C₆Alkyl (wherein the phenyl ring may be substituted by one or more groups such as C₁-C₄Alkyl radical, C₁-C₄Alkoxy, nitro, halogen or trifluoromethyl substitution),

-YR₃represents oxygen or NR₃Wherein R is₃Represents hydrogen, linear or branched C₁-C₇Alkyl or alkenyl, C substituted by radicals such as trifluoromethyl or phenyl₁-C₆An alkyl group, a carboxyl group,

-Z represents an oxygen or carbon atom capable of bonding to the ortho, meta or para position of the phenyl group in formula I,

n may be 0 to 5 when Z ═ C, or 2 to 4 when Z ═ O,

x represents oxygen or sulphur,

-R₄、R₅、R₆、R₇and R₈Represents hydrogen or fluorine, and is selected from the group consisting of,

-R₉、R₁₀and R₁₁Represents hydrogen or linear or branched C₁-C₅An alkyl group.

3. 3, 5-dioxo- (2H, 4H) -1, 2, 4-triazine derivatives of the general formula I according to any of claims 1 to 2, wherein:

-R₁and R₂Independently of one another, represents linear or branched C₁-C₇Alkyl or alkenyl, C substituted by radicals such as trifluoromethyl or nitrile₁-C₆An alkyl group, a carboxyl group,

-YR₃represents oxygen or NR₃Wherein R is₃Represents hydrogen or linear or branched C₁-C₇An alkyl group, a carboxyl group,

-Z represents a carbon atom capable of bonding to the ortho, meta or para position of the phenyl group in formula I,

n is 0 to 5,

x represents oxygen or sulphur,

-R₄、R₅、R₆、R₇and R₈Represents hydrogen or fluorine, and is selected from the group consisting of,

-R₉、R1₀and R₁₁Represents hydrogen or linear or branched C₁-C₅Alkyl, especially R₉And R₁₀Represents methyl, R₁₁RepresentsHydrogen or ethyl.

4.3, 5-dioxo- (2H, 4H) -1, 2, 4-triazine derivatives of the general formula I according to any of claims 13 to 3, in which:

-R₁and R₂Independently of one another, represents linear or branched C₁-C₇An alkyl or alkenyl group which may be substituted with a trifluoromethyl group at the end of the chain,

-YR₃represents oxygen or NR₃Wherein R is₃Represents hydrogen or linear or branched C₁-C₇An alkyl group, a carboxyl group,

-Z represents a carbon atom capable of bonding in the meta-or para-position of the phenyl group in formula I,

n is 1 to 5,

x represents oxygen or sulphur,

-R₄to R₈Represents hydrogen, and is selected from the group consisting of,

-R₉and R₁₀Represents a methyl group, and a salt thereof,

-R₁₁represents hydrogen or ethyl.

5. Compounds of general formula I according to claim 1, wherein the compounds are selected from:

1)2- {2- [2- (4-butyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -ethyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

2)2- {3- [2- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -ethyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

3) 2-methyl-2- (3- {2- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy ] -ethyl } -phenoxy) -propionic acid ethyl ester

4) 2-methyl-2- (3- {3- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy ] -ethyl } -phenoxy) -propionic acid ethyl ester

5)2- {3- [3- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -propyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

6) 2-methyl-2- (3- {3- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy ] -ethyl } -phenoxy) -propionic acid ethyl ester

7)2- {3- [3- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -propyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

8)2- (3- {3- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy ] -propyl } -phenoxy) -2-methyl-propionic acid ethyl ester

9) 2-methyl-2- (3- {5- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy ] -pentyl } -phenoxy) -propionic acid ethyl ester

10)2- {3- [5- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -pentyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

11)2- {3- [5- (4-butyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -pentyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

12)2- {3- [5- (4-butyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -pentyl ] -phenoxy } -2-methyl-propionic acid

13)2- {3- [5- (2, 4-dibutyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -pentyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

14)2- (3- {5- [ 4-butyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy ] -pentyl } -phenoxy) -2-methylpropionic acid ethyl ester

15)2- {3- [5- (4-butyl-2-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -pentyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

16) 2-methyl-2- (3- {5- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy ] -pentyl } -phenoxy) -propionic acid ethyl ester

17)2- {3- [5- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -pentyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

18)2- (3- {5- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy ] -pentyl } -phenoxy) -2-methyl-propionic acid ethyl ester

19)2- {3- [5- (2-benzyl-4-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -pentyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

20)2- [4- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxymethyl) -phenoxy ] -2-methyl-propionic acid ethyl ester

21) 2-methyl-2- {4- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxymethyl ] -phenoxy } -propionic acid ethyl ester

22)2- [4- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxymethyl) -phenoxy ] -2-methyl-propionic acid ethyl ester

23)2- {4- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxymethyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

24) 2-methyl-2- (4- {2- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy ] -ethyl } -phenoxy) -propionic acid ethyl ester

25)2- {4- [2- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -ethyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

26)2- {4- [2- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -ethyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

27)2- {4- [3- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -propyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

28) 2-methyl-2- (4- {4- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy ] -ethyl } -phenoxy) -propionic acid ethyl ester

29)2- {4- [4- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -ethyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

30) 2-methyl-2- (4- {4- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy ] -ethyl } -phenoxy) -propionic acid ethyl ester

31)2- (4- {4- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy ] -butyl } -phenoxy) -2-methyl-propionic acid ethyl ester

32)2- {3- [3- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -propoxy ] -phenylthio } -2-methyl-propionic acid ethyl ester

33)2- {3- [3- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -propoxy ] -phenoxy } -2-methyl-propionic acid ethyl ester

34)2- {3- [3- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -propoxy ] -phenylthio } -2-methyl-propionic acid ethyl ester

35)2- (3- {3- [3, 5-dioxo-2, 4-bis- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy ] -propoxy } -phenoxy) -2-methyl-propionic acid ethyl ester

36)2- {3- [4- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -butoxy ] -phenoxy } -2-methyl-propionic acid ethyl ester

37)2- {3- [4- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -butoxy ] -phenylthio } -2-methyl-propionic acid ethyl ester

38)2- {4- [2- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy) -ethoxy ] -phenylthio } -2-methyl-propionic acid ethyl ester

39)2- (4- {3- [3, 5-dioxo-2, 4-bis- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yloxy ] -propoxy } -phenoxy) -2-methyl-propionic acid ethyl ester

40)2- {4- [2- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -ethoxy ] -phenoxy } -2-methyl-propionic acid ethyl ester

41)2- (4- {2- [3, 5-dioxo-2, 4-di- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -ethoxy } -phenoxy) -2-methyl-propionic acid ethyl ester

42)2- {4- [2- (2, 4-diheptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -ethoxy ] -phenoxy } -2-methyl-propionic acid ethyl ester

43)2- (4- {2- [2, 4-bis- (3-cyclohexyl-propyl) -3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -ethoxy } -phenoxy) -2-methyl-propionic acid ethyl ester

44) 2-methyl-2- (4- {3- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -propoxy } -phenoxy) -propionic acid ethyl ester

45)2- {4- [3- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -propoxy ] -phenoxy } -2-methyl-propionic acid ethyl ester

46) 2-methyl-2- (4- {3- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -propoxy } -phenoxy) -propionic acid ethyl ester

47)2- {4- [3- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -propoxy ] -phenoxy } -2-methyl-propionic acid ethyl ester

48)2- (4- {3- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -propoxy } -phenoxy) -2-methyl-propionic acid ethyl ester

49)2- {4- [3- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -propoxy ] -phenylthio } -2-methyl-propionic acid ethyl ester

50)2- {4- [4- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -butoxy ] -phenoxy } -2-methyl-propionic acid ethyl ester

51)2- (3- {3- [ (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yl) - (4, 4, 4-trifluoro-butyl) -amino ] -propoxy } -phenoxy) -2-methyl-propionic acid ethyl ester

52)2- (3- {3- [ (2, 4-dimethyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yl) -heptyl-amino ] -propoxy } -phenylthio) -2-methyl-propionic acid ethyl ester

53)2- (4- {3- [ (2, 4-dimethyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yl) -heptyl-amino ] -propoxy } -phenylthio) -2-methyl-propionic acid ethyl ester

54)2- (3- {4- [ (2, 4-dimethyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yl) -heptyl-amino ] -butoxy } -phenylthio) -2-methyl-propionic acid ethyl ester

55)2- (2- {2- [3, 5-dioxo-2, 4-bis- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester

56) 2-methyl-2- (3- {2- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -ethyl } -phenoxy) -propionic acid ethyl ester

57)2- {3- [2- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -ethyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

58) 2-methyl-2- (3- {2- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -ethyl } -phenoxy) -propionic acid ethyl ester

59)2- {3- [2- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -ethyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

60)2- (3- {2- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester

61)2- {3- [2- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -ethyl ] -phenylthio } -2-methyl-propionic acid ethyl ester

62) 2-methyl-2- (3- {3- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -ethyl } -phenoxy) -propionic acid ethyl ester

63)2- (3- {3- [2- (2-cyano-ethyl) -4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -propyl } -phenoxy) -2-methyl-propionic acid ethyl ester

64)2- {3- [3- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -propyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

65) 2-methyl-2- (3- {3- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -ethyl } -phenoxy) -propionic acid ethyl ester

66)2- (3- {3- [3, 5-2-oxo-2, 4-bis- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -propyl } -phenoxy) -2-methyl-propionic acid ethyl ester

67)2- {3- [3- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -propyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

68)2- (3- {3- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -propyl } -phenoxy) -2-methyl-propionic acid ethyl ester

69)2- {3- [3- (2, 4-diheptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -propyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

70)2- {3- [3- (2-benzyl-4-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -propyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

71)2- (3- {3- [ 4-benzyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -propyl } -phenoxy) -2-methyl-propionic acid ethyl ester

72)2- {3- [3- (4-benzyl-2-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -propyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

73)2- {3- [3- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -propyl ] -phenylthio } -2-methyl-propionic acid ethyl ester

74) 2-methyl-2- (3- {4- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -butyl } -phenoxy) -propionic acid ethyl ester

75)2- {3- [4- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -butyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

76) 2-methyl-2- (3- {4- [4- (3-methyl-but-2-enyl) -3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -butyl } -phenoxy) -propionic acid ethyl ester

77) 2-methyl-2- (3- {4- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -butyl } -phenoxy) -propionic acid ethyl ester

78) 2-methyl-2- (3- {4- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -butyl } -phenoxy) -propionic acid tert-butyl ester

79) 2-methyl-2- (3- {4- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -butyl } -phenoxy) -propionic acid

80)2- (3- {4- [3, 5-dioxo-2, 4-di- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -butyl } -phenoxy) -2-methyl-propionic acid ethyl ester

81)2- (3- {4- [2- (2-cyano-ethyl) -3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -butyl } -phenoxy) -2-methyl-propionic acid ethyl ester

82)2- (3- {4- [ 2-heptyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -butyl } -phenoxy) -2-methyl-propionic acid ethyl ester

83)2- (3- {4- [ 2-heptyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -butyl } -phenoxy) -2-methyl-propionic acid tert-butyl ester

84)2- (3- {4- [ 2-heptyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -butyl } -phenoxy) -2-methyl-propionic acid

85)2- (3- {4- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -butyl } -phenoxy) -2-methyl-propionic acid ethyl ester

86)2- (3- {4- [2- (2-cyano-ethyl) -4-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -butyl } -phenoxy) -2-methyl-propionic acid ethyl ester

87)4- (6- {4- [3- (1-ethoxycarbonyl-1-methyl-ethoxy) -phenyl ] -butylamino } -4-heptyl-3, 5-dioxo-4, 5-dihydro-3H- [1, 2, 4] triazin-2-yl) -but-2-enoic acid ethyl ester

88)2- {3- [4- (2, 4-diheptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -butyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

89)2- {3- [4- (2-benzyl-4-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -butyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

90)2- (3- {4- [ 4-benzyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -butyl } -phenoxy) -2-methyl-propionic acid ethyl ester

91)2- {3- [4- (4-benzyl-2-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -butyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

92)2- (3- {5- [3, 5-dioxo-2, 4-di- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -pentyl } -phenoxy) -2-methyl-propionic acid ethyl ester

93) 2-methyl-2- (3- {4- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -butyl } -phenylthio) -propionic acid ethyl ester

94)2- {3- [4- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -butyl ] -phenylthio } -2-methyl-propionic acid ethyl ester

95) 2-methyl-2- (3- {4- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -butyl } -phenylthio) -propionic acid ethyl ester

96) 2-methyl-2- (3- {4- [ 2-methyl-3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -butyl } -phenylthio) -propionic acid

97)2- (3- {4- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -butyl } -phenylthio) -2-methyl-propionic acid ethyl ester

98)2- {3- [4- (2, 4-diheptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -butyl ] -phenylthio } -2-methyl-propionic acid ethyl ester

99)2- {3- [4- (2-benzyl-4-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -butyl ] -phenylthio } -2-methyl-propionic acid ethyl ester

100)2- (3- {4- [ 4-benzyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -butyl } -phenylthio) -2-methyl-propionic acid ethyl ester

101)2- {3- [4- (4-benzyl-2-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -butyl ] -phenylthio } -2-methyl-propionic acid ethyl ester

102) 2-methyl-2- (4- {2- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -ethyl } -phenoxy) -propionic acid ethyl ester

103)2- {4- [2- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -ethyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

104)4- [6- {2- [4- (1-ethoxycarbonyl-1-methyl-ethoxy) -phenyl ] -ethylamino } -3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -4, 5-dihydro-3H- [1, 2, 4] triazin-2-yl ] -but-2-enoic acid ethyl ester

105)2- (4- {2- [2- (3-cyclohexyl-propyl) -3, 5-dioxo-4- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester

106)2- {4- [2- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -ethyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

107)2- (4- {2- [ 4-heptyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester

108)2- {4- [2- (2, 4-diheptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -ethyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

109)2- {4- [2- (4-benzyl-2-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -ethyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

110)2- {4- [2- (2, 4-bis-benzyloxymethyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -ethyl ] -phenoxy } -2-methyl-propionic acid ethyl ester

111)2- (4- {2- [ (2, 4-dimethyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yl) - (4, 4, 4-trifluoro-butyl) -amino ] -ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester

112)2- (4- {2- [ (2, 4-dimethyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yl) -heptyl-amino ] -ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester

113)2- (4- {2- [ (2, 4-dimethyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yl) -heptyl-amino ] -ethyl } -phenoxy) -2-methyl-propionic acid

114)2- (4- {2- [ (2, 4-dimethyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yl) -phenethyl-amino ] -ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester

115)2- (4- {2- [ (2, 4-dimethyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yl) - (3-phenyl-propyl) -amino ] -ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester

116)2- (4- {2- [ 4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yl) -phenethyl-amino ] -ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester

117)2- (4- {2- [ (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-yl) - (3-phenyl-propyl) -amino ] -ethyl } -phenoxy) -2-methyl-propionic acid ethyl ester

118) 2-methyl-2- (4- {2- [ 4-methyl-3, 5-dioxo-2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -ethyl } -phenylthio) -propionic acid

119)2- {4- [2- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -ethyl ] -phenylthio } -2-methyl-propionic acid ethyl ester

120)2- {4- [2- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -ethyl ] -phenylthio } -2-methyl-propionic acid

121)2- {4- [2- (4-butyl-2-heptyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -ethyl ] -phenylthio } -2-methyl-propionic acid

122)2- {4- [2- (4-heptyl-2-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -ethyl ] -phenylthio } -2-methyl-propionic acid ethyl ester

123)2- (4- {2- [ 4-heptyl-3, 5-dioxo 2- (4, 4, 4-trifluoro-butyl) -2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino ] -ethyl } -phenylthio) -2-methyl-propionic acid

124)2- {4- [3- (2-heptyl-4-methyl-3, 5-dioxo-2, 3, 4, 5-tetrahydro- [1, 2, 4] triazin-6-ylamino) -propyl ] -phenylthio } -2-methyl-propionic acid ethyl ester.

6. A process for the preparation of a compound according to any one of claims 1 to 5,

wherein:

reacting a derivative of the formula II

Condensation with a derivative of the general formula III,

wherein R is₁And R₂Represents a group as described in formula I above, and wherein YR₃、n、Z、X、R₄、R₅、R₆、R₇、R₈、R₉、R₁₀And R₁₁As described in formula I aboveIn particular, the condensation is carried out in the presence of a base such as triethylamine (when Y ═ N) in N-butanol or potassium carbonate (when YR is present) in dimethylformamide₃When ═ O).

7. A process for the preparation of a compound of general formula I according to any one of claims 1 to 5, wherein Z ═ O, wherein:

a) reacting a derivative of the formula II

Condensation with a derivative of the general formula IV,

wherein R is₁And R₂Represents a group as described in formula I above, and wherein R₃Y may be equal to NH or O and n is as described in formula I above, in particular in the absence of solvent and without the addition of a base (at R)₃Y ═ NH) or in the presence of a base such as K₂CO₃Under the condition of (in R)₃Y ═ O) is performed,

b) the resulting derivative V

Condensation with a compound of the general formula VI,

x, R therein₄、R₅、R₆、R₇、R₈、R₉、R₁₀And R₁₁As described above for formula I, in particular, the condensation is carried outIn THF in the presence of triphenylphosphine and diethyl azodicarboxylate under the conditions of, for example, a Mitsunobu reaction.

8. A process for the preparation of a compound of general formula I according to any one of claims 1 to 5, wherein Z ═ O, wherein:

a) alcohol function of derivatives of formula VII

Protected by a protecting group, e.g. tert-butyldimethylsilane, in which R₁、R₂And n is as previously described for formula I, in particular, the protection is carried out using chloro-tert-butyldimethylsilane and imidazole, for example, under THF conditions,

b) by halogenation of the derivative R under operating conditions such as NaH or tBuOK in DMF₃Hal alkylates the nitrogen of the compound VIII obtained above, wherein the Hal group represents halogen such as Cl, Br or I, and R₃As described in the foregoing description of formula I,

c) deprotecting the compound of formula IX thus obtained under operating conditions, for example tetrabutylammonium fluoride in THF,

d) reacting the resulting derivative X

With compounds of the general formula VI

Condensation of which X, R₄、R₅、R₆、R₇、R₈、R₉、R₁₀And R₁₁As described in formula I above, in particular, the condensation is carried out in THF in the presence of triphenylphosphine and diethyl azodicarboxylate under reaction conditions such as Mitsunobu.

9. A process for the preparation of compounds of general formula I according to any one of claims 1 to 5, wherein Y ═ N and Z ═ C, wherein:

a) reacting a derivative of the formula II

With derivatives of the general formula XI

Condensation of wherein R₁And R₂Represents a group as described in formula I above, and wherein n, R₃、R₄、R₅、R₆、R₇And R₈As described in formula I above and a may be hydrogen or methyl, in particular, the condensation is carried out in the presence of a base, such as triethylamine in n-butanol;

b) BBr after demethylation (if A ═ Me in, for example, dichloromethane₃Under the conditions of (a) and (b) reacting the derivative XII

By a halogenated derivative of formula XIII (used as a solvent in the presence of a base such as potassium carbonate)

Alkylation, wherein the Hal group represents halogen such as Cl, Br or I, and R₉、R₁₀And R₁₁As described previously in formula I.

10. A process for the preparation of compounds of general formula I according to any one of claims 1 to 5, wherein Y ═ N and Z ═ C, wherein:

a) reacting a derivative of formula XIV

And formula R₃Derivatives of Hal are alkylated under operating conditions such as NaH or tBuOK in DMF, where R is₁、R₂、R₄、R₅、R₆、R₇、R₈And n is as described in formula I above, and wherein Hal represents halogen such as Cl, Br or I and R3 is as described in formula I above,

b) BBr in, for example, dichloromethane₃After demethylation under the conditions of (a) and (b) the derivative XII thus obtained

By a halogenated derivative of formula XIII (used as a solvent in the presence of a base such as potassium carbonate)

Alkylation wherein the Hal group represents halogen such as Cl, Br or I and R₉、R₁₀And R₁₁As described in formula I aboveThe above-mentioned processes are described.

11. A process for preparing a compound according to any one of claims 1 to 5, wherein:

a) the derivatives of the general formula I

Under the operating conditions, e.g. in the presence of a base NaH in DMF, wherein R₁＝(CH₂)₂CN and R₂、R₃、n、Z、X、R₄、R₅、R₆、R₇、R₈、R₉、R₁₀And R₁₁As described in formula I or R₂＝(CH₂)₂CN and R₁、R₃、n、Z、X、R₄、R₅、R₆、R₇、R₈、R₉、R₁₀And R₁₁As described in the foregoing description of formula I,

b) then the triazine nitrogen of the derivative XIVa or XIVb thus obtained is reacted with

By the general formula R in the case of the intermediate XIVa₁Halogenated derivatives of Hal and the general formula R in the case of the intermediate XIVb₂Halogenated derivatives of Hal, alkylated under operating conditions, for example in the presence of NaH or tBuOK in DMF, wherein the Hal group represents halogen such as Cl, Br or I and R₁And R₂As described in formula I above.

12. The use of compounds according to any one of claims 1 to 5 as new medicaments for the treatment of diseases which require PPAR α and/or PPAR γ receptor agonists.

13. The use of compounds according to any one of claims 1 to 5 as novel medicaments for the prophylaxis and treatment of diseases such as: diabetic dyslipidemia, hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia, hyperglycemia, metabolic syndrome, obesity and atherosclerosis.

14. Use of a compound according to any one of claims 1 to 5 as a novel medicament having an inflammatory component or a pathological skin disease caused by abnormal cell differentiation.

15. The use of compounds according to any one of claims 1 to 5 as new medicaments for the treatment of, for example: psoriasis, acne, atopic dermatitis, skin aging, and photoaging.

16. A pharmaceutical compound comprising as active ingredient a compound according to any one of claims 1 to 5 and a suitable excipient.