WO2010034212A1

WO2010034212A1 - Phenoxy acetic acid pyrazine ester derivatives, the preparation methods and uses thereof

Info

Publication number: WO2010034212A1
Application number: PCT/CN2009/072733
Authority: WO
Inventors: 李晓祥; 徐自奥; 李德刚
Original assignee: 安徽省新星药物开发有限责任公司
Priority date: 2008-09-28
Filing date: 2009-07-13
Publication date: 2010-04-01
Also published as: CN101684102B; CN101684102A

Abstract

Phenoxy acetic acid pyrazine ester derivatives represented by formula (I), the preparation methods and uses thereof, wherein R₁-R₁₂ have the prescribed meanings. The pharmaceutically acceptable salts, enantiomorphs, racemic mixtures, and diastereoisomer mixtures of the present compounds. The preparation methods of the present compounds and their pharmaceutically acceptable salts. The present compounds can lower the serum triglyceride level and serum cholesterol, elevate high density lipoprotein level, and improve blood rheology.

Description

Ethyl pyridyl Phenyl ester

3⁄4 surgery collar ^

This invention relates to a new class of phenoxyacetate pyrazine derivatives. The invention also relates to a process for the preparation of such compounds, and to the use of such compounds for the prevention and treatment of cardiovascular and cerebrovascular diseases. Background technique

Blood lipids are a general term for lipids contained in the blood. Lipids are composed of fats and lipids. Lipids in the blood mainly include free cholesterol, cholesterol lipids, triglycerides, free fatty acids and phospholipids. Blood lipids account for a small proportion of the total amount of lipids in the human body, but it is transported between tissues and can often reflect the level of lipid metabolism in the body. The blood lipid content is not constant. It fluctuates within a certain range. Lipids bind to apolipoproteins in plasma to form lipoproteins that are soluble in plasma for transport and metabolism. Lipoproteins are large spherical particles with a non-polar interior and a polar exterior. Lipoproteins mainly include chylomicrons (TG), very low density lipoprotein (VLDL-C), low density lipoprotein (LDL-C), medium density lipoprotein (IDL-C), high density lipoprotein (HDL-C). .

Hyperlipidemia often causes a range of diseases, including high-risk diseases such as atherosclerosis, coronary heart disease, stroke, and myocardial infarction. Since the 1990s, with the continuous increase of people's income and the rapid increase of living standards, obese people have experienced explosive growth, and the number of patients with hyperlipidemia has increased rapidly. According to a data released recently, the number of people with dyslipidemia in China over 18 years old reached 160 million: Among the people over 35 years old, 25 million people also suffer from hypertension and hyperlipidemia, and the rate of blood lipid compliance is less than 30%. It is believed that hyperlipidemia is one of the important factors in the mechanism of cardiovascular and cerebrovascular diseases, and cardiovascular and cerebrovascular diseases often have hyperviscosity. Therefore, it corrects dyslipidemia and reduces blood viscosity, and has the effect of preventing and treating cardiovascular and cerebrovascular diseases. Great value.

At present, the blood lipid-lowering drugs commonly used at home and abroad are: bile acid chelating agents, nicotinic acid, phenoxy derivatives, HMG-CoA reductase inhibitors, and the like. Although they all have certain effects, their efficacy is relatively simple, and it has a poor or no effect on lowering blood viscosity and improving blood rheology. Summary of the invention

The present invention provides a novel pyridyl phenoxyacetate derivative having the formula (I) and a salt thereof, the structural formula of which is as shown in (I): 〇z(CR ₈ R ₉ )n

• Ri R ₂ , R ₃ , R ₄ , which are the same or different from each other, independently represent hydrogen, an alkyl group having 1 to 6 carbon atoms, a nitro group, a halogen group, an amino group, an acyl group, a sulfonyl group, a carboxyl group, a hydroxyl group, a hydroxyalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, a carbamoyl group, a thiourea group, and 1 to 6 An alkyl sulfide of a carbon atom, an alkylsulfonate having 1 to 6 carbon atoms, an aminomethyl group, a cyano group, a group having an unsaturated double bond of 2 to 4 carbon atoms, and 2 to 4 carbons A group of an unsaturated oxime bond of an atom, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group, a substituted aryl group, an aralkyl group, a substituted aralkyl group, an aryloxy group, a substituted aryl group An oxy group, an arylcarbonyl group, a substituted arylcarbonyl group, an aryloxycarbonyl group, a substituted aryloxycarbonyl group or the like.

• R ₆ , R ₇ , R ₈ , which are the same or different from each other, each independently represent hydrogen, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and 1 to 6 A hydroxyalkyl group of a carbon atom, a cycloalkyl group having 3 to 6 carbon atoms. R ₂ and R ₃ may be the same substituent or different substituents.

• Rio Rn R ₁₂ is the same or different from each other and independently represents hydrogen, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and an alkoxy group having 2 to 6 carbon atoms. a carbonyl group, a carboxyl group, a hydroxyalkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group or a substituted aryl group.

• n is an integer from 1-6.

Preferred compounds in the present invention are such compounds, wherein:

Ri, , , , are the same or different from each other, and each independently may be hydrogen, nitro, halogen, amino, acyl, sulfonyl, carboxy, hydroxy, carbamoyl, thioureido, aminomethyl, cyano;

Rl, R2, R3, R4, and R5 are the same or different from each other, and each of them may independently contain 1 to 6 Alkyl of a carbon atom, especially methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-amyl, n-hexyl, Heterohexyl, tert-hexyl, etc.;

Rl, R2, R3, R4, and R5 are the same or different from each other, and each independently may have 1 to 6 hydroxyalkyl groups, particularly hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxy-n-butyl, hydroxy Isobutyl, hydroxy-n-pentyl, hydroxyisopentyl, hydroxyhexyl, hydroxyisohexyl, etc.;

R1, R2, R3, R4, and R5 are the same or different from each other, and each independently may be an alkoxy group having 1 to 6 carbon atoms, particularly a methoxy group, an ethoxy group, a n-propoxy group, or an isopropoxy group. Base, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, isopentyloxy, tert-pentyloxy, n-hexyloxy, isohexyloxy, tert-hexyloxy, etc.;

Rl, R2, R3, R4, and R5 are the same or different from each other, and each independently may be an alkoxycarbonyl group having 2 to 6 carbon atoms, particularly a methoxycarbonyl group, an ethoxycarbonyl group, a n-propoxycarbonyl group, or an isopropoxy group. a carbonyl group, a n-butoxycarbonyl group, an isobutoxycarbonyl group, a tert-butoxycarbonyl group, a n-pentyloxycarbonyl group, an isopentyloxycarbonyl group, a t-pentyloxycarbonyl group, or the like;

Rl, R2, R3, R4, and R5 are the same or different from each other, and each independently may be an alkyl sulfide having 1 to 6 carbon atoms, particularly methylthio, ethylthio, n-propylthio, isopropyl Sulfur, n-butylthio, isobutylthio, tert-butylthio, n-pentylthio, isopentylthio, tert-pentylthio, n-hexylthio, isohexylthio, tert-hexylthio;

Rl, R2, R3, R4, and R5 are the same or different from each other, and each independently may be an alkylsulfonate having 1 to 6 carbon atoms, particularly a methanesulfonate group, an ethylsulfonate group, or a n-propanesulfonate group. , isopropylsulfonate, n-butanesulfonate, isobutylsulfonate, t-butyrylsulfonate, n-pentanesulfonate, isovalerate, tert-pentanesulfonate, n-hexylsulfonate, isohexylsulfonate Acid group, tert-hexyl sulfonate group, etc.;

R1, R2, R3, R4, and R5 are the same or different from each other, and each independently may be a group having an unsaturated double bond of 2 to 4 carbon atoms, particularly a vinyl group, a propenyl group, an allyl group, and a butene group. Base, butadienyl group, etc.;

Rl, R2, R3, R4, and R5 are the same or different from each other, and each independently may be a group having an unsaturated hydrazone bond of 2 to 4 carbon atoms, particularly an ethyl group, a propyl group, a propyl group, Butyl group and the like; R1, R2, R3, R4, and R5 are the same or different from each other, and each independently may be a cycloalkyl group having 3 to 6 carbon atoms, particularly a cyclopropyl group, a methylcyclopropyl group, or a second group. Methylcyclopropyl, ethylcyclopropyl, methylcyclopentyl, cyclohexyl, etc.; R1, R2, R3, R4, and R5 are the same or different from each other, and each independently may be a substituted cycloalkyl group having 3 to 6 carbon atoms, and the substituent herein is especially an alkyl group, an alkoxy group, a nitro group, Halogen, amino, acyl, sulfonamide, carboxyl, hydroxy, etc.;

R1, R2, R3, R4 and R5 are the same or different from each other, and each independently may be an aryl group, in particular, a phenyl group, a naphthyl group and other aromatic heterocyclic rings;

R1, R2, R3, R4, and R5 are the same or different from each other, and each independently may be a substituted aryl group, and the substituents herein are, in particular, an alkyl group, an alkoxy group, a nitro group, a halogen group, an amino group, an acyl group, or a sulfonamide group. , carboxyl group, hydroxyl group, etc.;

Rl, R2, R3, R4, and R5 are the same or different from each other, and each independently may be an aralkyl group, particularly a benzyl group, a phenethyl group, a phenylpropyl group, a phenylisopropyl group, a naphthylmethyl group, a naphthylethyl group, Naphthylpropyl, naphthylisopropyl and other areheterocycloalkyl groups;

R1, R2, R3, R4, and R5 are the same or different from each other, and each independently may be a substituted aralkyl group, and the substituent herein is especially an alkyl group, an alkoxy group, a nitro group, a halogen group, an amino group, an acyl group, or a sulfonamide. Base, carboxyl group, hydroxyl group, etc.;

Rl, R2, R3, R4, and R5 are the same or different from each other, and each independently may be an aryloxy group, particularly a phenoxy group, a benzyloxy group, a phenethyloxy group, a phenylpropoxy group, a naphthylmethoxy group, Naphthylmethoxy, naphthylethoxy, naphthyloxy and other aromatic heterocyclic oxy groups;

Rl, R2, R3, R4, and R5 are the same or different from each other, and each independently may be a substituted aryloxy group, and the substituent herein is especially an alkyl group, an alkoxy group, a nitro group, a halogen group, an amino group, an acyl group, or a sulfonamide. Base, carboxyl group, hydroxyl group, etc.;

Rl, R2, R3, R4, and R5 are the same or different from each other, and each independently may be an arylcarbonyl group, particularly a benzoyl group, a naphthoyl group, a phenylacetyl group, a naphthylacetyl group, and other aromatic heterocyclic carbonyl groups;

Rl, R2, R3, R4, and R5 are the same or different from each other, and each independently may be a substituted arylcarbonyl group, and the substituent herein is especially an alkyl group, an alkoxy group, a nitro group, a halogen group, an amino group, an acyl group, or a sulfonamide. Base, carboxyl group, hydroxyl group, etc.;

Rl, R2, R3, R4, and R5 are the same or different from each other, and each independently may be an aryloxycarbonyl group, particularly a phenoxycarbonyl group, a benzyloxycarbonyl group, a phenethyloxycarbonyl group, a phenylpropoxycarbonyl group, a naphthylmethoxycarbonyl group. , naphthylmethoxycarbonyl, naphthylethoxycarbonyl, naphthyloxycarbonyl and other aromatic heterocyclic oxycarbonyl groups;

Rl, R2, R3, R4, R5 are the same or different from each other, and each independently may be substituted An aryloxycarbonyl group, the substituent herein being especially an alkyl group, an alkoxy group, a nitro group, a halogen, an amino group, an acyl group, a sulfonyl group, a carboxyl group, a hydroxyl group or the like;

• R ₆ , R ₇ , , are the same or different from each other, and each independently may be hydrogen;

R6, R7, R8, and R9 are the same or different from each other, and each independently may be an alkyl group having 1 to 6 carbon atoms, particularly methyl, ethyl, n-propyl, isopropyl, n-butyl, and iso- Butyl, tert-butyl, n-pentyl, isopentyl, tert-amyl, n-hexyl, isohexyl, tert-hexyl, etc.;

R6, R7, R8, and R9 are the same or different from each other, and each independently may be an alkoxy group having 1 to 6 carbon atoms, particularly a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, n-Butoxy, isobutoxy, tert-butoxy, n-pentyloxy, isopentyloxy, tert-pentyloxy, n-hexyloxy, isohexyloxy, tert-hexyloxy, etc.;

R6, R7, R8, and R9 are the same or different from each other, and each independently may be a hydroxyalkyl group having 1 to 6 carbon atoms, particularly a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxy-n-butyl group, Hydroxyisobutyl, hydroxy-n-pentyl, hydroxyisopentyl, hydroxyhexyl, hydroxyisohexyl, etc.;

R6, R7, R8, and R9 are the same or different from each other, and each independently may be a cycloalkyl group having 3 to 6 carbon atoms, particularly a cyclopropyl group, a methylcyclopropyl group, a dimethylcyclopropyl group, and a Cyclopropyl, methylcyclopentyl, cyclohexyl, etc.;

• Rio Rn R ₁₂ is the same or different from each other, and each independently may be hydrogen or a carboxyl group;

R10, R11, and R12 are the same or different from each other, and each independently may be an alkyl group having 1 to 6 carbon atoms, particularly methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl , tert-butyl, n-pentyl, isopentyl, tert-amyl, n-hexyl, isohexyl, tert-hexyl, etc.;

R10, R11, and R12 are the same or different from each other, and each independently may be an alkoxy group having 1 to 6 carbon atoms, particularly a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, and a n-butyl group. Oxyl, isobutoxy, tert-butoxy, n-pentyloxy, isopentyloxy, tert-pentyloxy, n-hexyloxy, isohexyloxy, tert-hexyloxy, etc.;

R10, R11, and R12 are the same or different from each other, and each independently may be an alkoxycarbonyl group having 2 to 6 carbon atoms, particularly a methoxycarbonyl group, an ethoxycarbonyl group, a n-propoxycarbonyl group, an isopropyloxycarbonyl group, or a n-butyl group. An oxycarbonyl group, an isobutoxycarbonyl group, a tert-butoxycarbonyl group, a n-pentyloxycarbonyl group, an isopentyloxycarbonyl group, a t-pentyloxycarbonyl group, or the like;

R10, R11, and R12 are the same or different from each other, and each independently may be a hydroxyalkyl group having 1 to 6 carbon atoms, particularly a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxy-n-butyl group, or a hydroxy group. Butyl, hydroxy-p-pentane Base, hydroxyisopentyl, hydroxyhexyl, hydroxyisohexyl, etc.;

R10, R11, and R12 are the same or different from each other, and each independently may be a cycloalkyl group having 3 to 6 carbon atoms, particularly a cyclopropyl group, a methylcyclopropyl group, a dimethylcyclopropyl group, an ethyl ring. Propyl, methylcyclopentyl, cyclohexyl, etc.;

R10, R11, and R12 are the same or different from each other, and each independently may be an aryl group or a substituted aryl group such as a phenyl group, a benzyl group, a nitrophenyl group, a phenyl group, a hydroxyphenyl group, an alkoxyphenyl group. Wait;

• n is an integer from 1-6.

More preferred compounds in the invention are such compounds, wherein:

• Ri R ₂ , R ₃ , , are the same or different from each other, and each independently may be hydrogen, nitro, halogen, amino, acyl, sulfonyl, carboxy, hydroxy, carbamoyl, thioureido, aminomethyl, Cyano group

Rl, R2, R3, R4, and R5 are the same or different from each other, and each independently may be an alkyl group, particularly a methyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a t-butyl group. ; may be hydroxyalkyl, especially hydroxymethyl, hydroxyethyl, hydroxypropyl; may be a decyloxy group, especially methoxy, ethoxy, n-propoxy; may be alkoxycarbonyl, especially Is methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl; may be cycloalkyl, especially cyclopropyl, cyclobutyl, cyclopentyl; may be substituted cycloalkyl, especially methylcyclopropyl, Dimethylcyclopropyl, ethylcyclopropyl, methylcyclopentyl, methoxycyclopropyl, nitrocyclopropyl, halogen cyclopropyl, aminocyclopropyl, acylcyclopropyl; may be benzene Alkyl, naphthyl, substituted phenyl and substituted naphthyl (especially phenyl and naphthyl substituted by alkyl, alkoxy, nitro, halogen, amino, acyl, sulfonyl, carboxy, hydroxy) ; may be an aralkyl group, especially benzyl, phenethyl, phenylpropyl, phenylisopropyl and a substituted phenylalkyl group (especially a benzyl group substituted with an alkyl group, an alkoxy group, a nitro group, a halogen, an amino group, an acyl group, a sulfonyl group, a carboxyl group, a hydroxyl group, etc., a phenethyl group, a phenylpropyl group, a phenylisopropyl group) A phenylcarbonyl group which may be substituted with an arylcarbonyl group, particularly a benzoyl group, a phenylacetyl group and a benzene ring (especially by an alkyl group, an alkoxy group, a nitro group, a halogen group, an amino group, an acyl group, a sulfoamino group, Carboxy, hydroxy, etc. substituted benzoyl, phenylacetyl);

• R ₆ , R ₇ , R ₈ , and R ₉ are the same or different from each other, and each independently may be hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy. , ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxy-n-butyl, hydroxyisobutylcyclopropyl, methyl Cyclopropyl, dimethylcyclopropyl, ethylcyclopropyl, methylcyclopentane Base, cyclohexyl, etc.;

• Rio Rn R ₁₂ is the same or different from each other and may independently be hydrogen, carboxy, methyl, ethyl, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, hydroxymethyl, hydroxyethyl.

• n is 2 - 3, more preferably 1.

For example, the compounds of the invention are the following compounds:

• 2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester;

• 2-[4-(2,2-Dichlorocyclopropyl)phenoxy]-2-methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester;

• 2-[α-(4-chlorophenyl)-4-methylphenyl]oxy]-2-methylbutyric acid 3,5,6-trimethylpyrazine-2-yl-methyl ester;

• 2-[4-(2,4-Dichlorophenoxy)phenoxy]propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester;

· [p--4-chlorobenzoyl-β-aminoethylphenoxy]isobutyric acid 3,5,6-trimethylpyrazine-2-yl-methyl ester;

• 2-(4-chlorophenoxy)-2-methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester;

• 2-(4-hydroxyphenoxy)propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester;

• 2-(4-methoxyphenoxy)propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester;

• 2-(4-Aminophenoxy)-2-methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester.

· 2-(4-Isopropylphenoxy)-2-methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester

• 2-[4-(4-Chloro-benzyloxy)-phenyloxy]-2-methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester

• 2-(4-biphenyloxy)-2-methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester

• 2-(4-Isobutyryl-phenyloxy)-2-methylpropionic acid isopropyl 3,5,6-trimethylpyrazine-2-yl-methyl ester

• 2-Methyl-2-(4-(4-chlorobenzoyl)phenoxy)propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester hydrochloride

The term "halogen" as used herein in the definition or partial definition includes fluorine, chlorine, bromine and iodine.

Those skilled in the art will appreciate that the compound of formula (I) may contain a chiral center. When a chiral center is present in a compound of formula (I), it may exist in enantiomeric form. The pure optical isomers, enantiomeric mixtures, diastereomeric mixtures, racemic mixtures, and the above-mentioned compounds, mixtures of pharmaceutically acceptable salts of the structures of formula (I) are all within the scope of the invention.

The compounds of the invention can be achieved according to the methods and procedures described below.

The compound of the formula (I) of the present invention can be produced by a person skilled in the art by esterification or ester substitution of the compounds (Π) and (III). The reaction formula of this reaction is as follows:

Wherein R1 to R12 are as defined above; R13 may be a hydroxyl group, a halogen atom, an alkoxy group having 1 to 6 carbon atoms, and the alkoxy group herein may be, for example, a methoxy group, an ethoxy group or a n-propoxy group. Base, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, isopentyloxy, tert-pentyloxy, n-hexyloxy, isohexyloxy, tert-hexyloxy, etc. ;

The reaction is carried out by esterification or transesterification under conventional conditions. The reaction can be carried out without a catalyst or by the action of a catalyst which can be a mineral acid (e.g., hydrogen chloride gas, concentrated sulfuric acid, phosphoric acid, perchloric acid, tetrafluoroboric acid, etc.), an organic acid ( Such as: benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic anhydride, etc., Lewis acid (such as: trifluoride, aluminum trichloride, ferric sulfate, Sc (0Tf) 3, etc.) A base (sodium alkoxide, sodium hydroxide, potassium hydroxide), a tetrachloroaluminum ether complex, a dicyclohexylcarbodiimide, a sulfonic acid type strongly acidic ion exchange resin, or the like. The reaction temperature is 0-100 ° C, preferably 20-60 ° C, sometimes in order to control the reaction rate, can be carried out at or above this temperature, and the protection by inert gas (N2) can sometimes reduce the side reaction. occur. The reaction is carried out in a suitable solvent which does not hinder the reaction. The solvent which is usually used is a solvent having a boiling point higher than the reaction temperature (e.g., diethyl ether, dichloromethane, chloroform, benzene, toluene, acetonitrile, tetrahydrofuran, 1). , 4-dioxane, etc.). If R7 is a halogen atom, an organic base may be added as an acid binding agent in the reaction, and the acid binding agent may preferably not interfere with the reaction, and may be triethylamine, pyridine, N, N-dimethylformamide, N, N. - an inert reagent such as dimethylaniline, N, N-dimethylaminopyridine or tetramethylethylenediamine.

The above compound (I) can be isolated by, for example, distillation, recrystallization, column layer The corresponding pharmacologically acceptable salts are also obtained by the above methods, and the salts of the present invention include their optical isomers.

The present invention relates to a pharmaceutically acceptable salt thereof in addition to the compound of the formula (I). The pharmaceutically acceptable salts are particularly suitable for pharmaceutical applications because they are more soluble in water than the starting or base compounds. The compound of the present invention has a basic nitrogen, and thus can be prepared by acid addition with a pharmaceutically acceptable inorganic acid and an organic acid, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid. And sulfuric acid, organic acids such as carbonic acid, acetic acid, oxalic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-bromobenzenesulfonic acid, succinic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, Glycolic acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, tartaric acid and trifluoroacetic acid, amino acids and the like. Thus, such pharmaceutically acceptable salts include sulfates, pyrosulfates, hydrogen sulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates. Salt, chloride, bromide, iodide, acetate, propionate, octoate, acrylate, formate, isobutyrate, acid salt, citrate, propyl citrate, oxalic acid Salt, malonate, succinate, suberate, sebacate, fumarate, maleate, 2-butane-1, 4-diate, 3-cyclohexene -2, 5-diacid salt, benzoate, chlorobenzoate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, hippurate, beta _hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, glutamine Acid salts, arginine salts, lysine salts, and the like. For the purpose of medicine, a chlorine salt is particularly preferably used.

The compounds of the invention may also exist in a variety of polymorphic forms, such as amorphous forms and crystalline forms. All crystal forms of the compounds of the invention are included within the scope of the invention.

The compound (I) in the present invention is a novel compound which increases blood rheology on the basis of hypolipidemic activity, thereby achieving blood lipid lowering and improving blood rheology uniformity, and preventing and treating cardiovascular and cerebrovascular diseases. The disease has important clinical value. The invention adopts the qualified first-class Kunming species (^ mouse model, and carries out preliminary screening of pharmacodynamics, the research shows that the compound of the invention can significantly reduce the TG, TC content, HDL-C in the serum of high-lipid mice induced by egg yolk milk, The LDL-C content, with the increase of the dose, the blood lipid lowering effect is gradually enhanced, wherein the compound (I) in the experimental group 80 mg/k _g group has a lower blood lipid lowering effect than the 40 mg/k _g group, suggesting that the compound of the present invention has a significant decrease. The effect of blood lipids on the blood rheology of experimental hyperlipidemia mice showed that the whole blood viscosity (high cut, low cut), plasma viscosity, red of the experimental group rats The cell aggregation index was significantly lower than that of the model group, indicating that the compound of the present invention has a markedly improved hemorheological effect.

The compound (I) of the present invention has significant hypolipidemic effects on mammals such as humans, rats, mice, guinea pigs, dogs and pigs, for example: it lowers serum triglyceride levels and lowers serum cholesterol, Increases high-density lipoprotein levels, improves blood flow and other cardiovascular and cerebrovascular diseases. It is an excellent lipid-lowering drug that is safe for oral or injection purposes and can be formulated into a variety of suitable dosage forms such as tablets, powders, capsules, injections and suppositories. Of course, what kind of dosage form to use depends on the specific conditions. The oral dose for conventional treatment is 40-300 mg/kg administered three times a day.

The results of the pharmacodynamic effects of the compounds of the present invention are illustrated below by taking only the compound of Example 1 as an example. 70 qualified Kunming species (^ mice) were randomly divided into 7 groups, 10 rats in each group, normal control group, model group, drugs (compound (I)) 20, 40, 80 mg/kg and simvastatin 12 5mg/kg, fenofibrate 37. 5mg/kg positive drug control group. Each drug-administered group ig corresponding test drug, normal group and model group i _g equal volume of normal saline, once a day, continuous 30 16 hours after the last administration of the drug, each experimental group (except the normal control group), the mice were intraperitoneally injected with 75% egg yolk milk, 0.5 mL / only, 20 h after blood collection by eyelid, serum TG, TG, HDL-C , LDL-C content, blood rheology index Determination of whole blood viscosity (Tib), plasma viscosity (ηρ), erythrocyte aggregation index (ΑΙ) index at high, medium and low shear rates by automatic viscosity fast tester Liver tissue was fixed in the right lobe of the liver, fixed in 10% formaldehyde, stained with HE, and histopathological examination was performed to observe the liver steatosis.

The levels of TG and TC in the serum of the model group were significantly higher than those in the normal mice. After the administration of compound ( I ), the TG and TC in the high dose group were significantly decreased, which was significantly different from the model group (P<0.05). There was no significant difference between the fenofibrate control group and the simvastatin control group (P>0.05). There was no significant difference between the middle and low dose groups and the high-fat control group (P>0.05). ), see Table 1.

Table 1 Compound ( I ) on TG and TC in experimental hyperlipidemia mice (x±s, n= 10) Dose TC

Group TG (mmol/L)

Mg Kg lower TG% lower TC%

(mmol/L)

- Normal group 1.11 soil 0.24 2.42 soil 0.65 - -

- Model group 10.12+2.53## 9.21+1.99## - - Compound ( I ) 80

7.96±2.04* 7.68±0.97* 21.3 % 16.6% Large dose

40

Medium dose 8.32 soil 5.64 8.16+4.36 17.8% 11.4%

20

Small dose 10.53 soil 5.81 9.13±3.92 0 0.9%

40

Fenofibrate group 8.42 soil 0.50* 7.99 soil 1.86 16.8% 13.2%

15

Simvastatin group 7.92 soil 2.61* 7.60+1.30* 21.7% 17.5%

#P<0.05, ##P<0.01 compared with the normal group; *P<0.05, **P<0.01 compared with the model group, the serum LDL level in the model group was significantly higher than that in the normal mice; The LDL in the high-dose group was significantly lower than that in the model group (P<0.05), and the LDL/HDL was significantly different from the model group (P<0.01). The median dose was different between the HDL and LDL and the model group. Significant significance (P>0.05), but LDL/HDL was significantly different from the model group (P<0.01). There was no significant difference between the low dose and the model group (P>0.05). See Table 2.

Effects of Compound (Table 2) on HDL and LDL in experimental hyperlipidemia mice (x±s, n=10)

Dose HDL

Group LDL (mmol/L) LDL/HDL mg Kg (mmol/L)

Normal group - 1.38 soil 0.37 0.82+0.33 0.59 soil 0.18 model group - 2.38 soil 0.51** 4.78 soil 1.07** 2.01±0.21** Compound (I)

80 2.35 soil 0.29 3.92+0.65* 1.67+0.23** large dose

Medium dose 40 2.48 soil 0.89 3.922+2.38 1.41 soil 0.47** low dose 20 2.61±0.79 4.82 soil 1.67 1.91 soil 0.56 fenofibrate group 40 2.76 soil 0.92 5.33+2.67 1.88±0.36 simvastatin group 15 2.91 soil 0.45* 3.81+0.76* 1.46+0.23**

#P<0.05, ##P<0.01 compared with the normal group; *P<0.05, **P<0.01 compared with the model group, liver pathological changes were observed under the microscope, as shown in Figure 1. The results showed that the liver tissue of the normal group was intact and clear, the structure of the hepatic lobule was normal, the central vein was large and the wall was thin, and the liver cells were arranged into hepatic cord. The cells were distributed radially around the central vein, and the cells were polygonal. The histopathological changes of the liver in the model group and the high-dose group were similar to those in the normal group. No staining, cytoplasmic loosening and steatosis, and inflammatory cell infiltration were observed.

The levels of η ηρ and ΑΙ in the model group were significantly higher than those in the normal mice. After compound ( I ), the η ηρ and ΑΙ in the high-dose and medium-dose groups were significantly lower than those in the model group (Ρ<0.05). .

See Table 3. Table 3 Effect of Compound ( I ) on Hemorheology in Experimental Hyperlipidemia Mice (x±s, n=10)

Dose

Group AI mg Kg 2S" 30S -" 200S"

Normal group - 8.41 soil 0.35 4.62 soil 0.14 4.21 ± 0.57 1.74 soil 0.24 0.38 soil 0.09 model group - 10.13 soil 0.21 ^## 5.23+0.11** 6.02 soil 0.42** 2.58 soil 0.21** 1.29 soil 0.14 compound

80 9.15+0.24** 4.32+0.20** 4.65+0.25** 1.87+0.21** 0.68 soil 0.12** large dose

Medium dose 40 9.58+0.39* 4.52+0.17* 4.78 soil 0.38* 1.90 soil 0.10** 1.09+0.15* low dose 20 9.92 soil 0.29 4.62 soil 0.15 4.90±0.37* 2.11±0.06* 1.25 soil 0.14 fenofibine

40 9.86+0.51 4.55 soil 0.22* 4.85 soil 0.47* 2.08 soil 0.21* 1.15±0.11* special group

Simvastat

15 9.75±0.27* 4.54+0.11* 4.81+0.36* 1.96 soil 0.17* 1.17+0.08* Ting group

#P<0.05, ##P<0.01 compared with the normal group; *P<0.05, **P<0.01 compared with the model group. The above results show that the compound (I) has a significant hypolipidemic effect, and fenofibrate Compared with simvastatin, it has a stronger effect on improving blood rheology. Outline

Figure 1: Microscopic observation of liver pathological changes

A: Normal group (X 100)

B: Model group (X 100)

C: Compound (I) High dose group (X 100) Specific embodiment:

The specific examples are included below to illustrate the preparation methods, and are not intended to limit the disclosure. The reagents and intermediates used may be either commercially available or may be those skilled in the art of organic synthesis. Cooked personnel are readily prepared according to standard literature methods. Other methods of preparing the compounds of the invention are known to those skilled in the art. Example 1

Preparation of 2-methyl-2-(·(4-chlorobenzoyl)phenoxy)propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester: 13.5 g (0.04 mol) 2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propanoyl chloride was added to 120 mL of dichloromethane, stirred and dissolved to 0 ° C, then 6.1 g (0.04 mol) 2 was added. -Hydroxymethyl-3,5,6-trimethylpyrazine and 10 mL of triethylamine. After stirring, the mixture was stirred at room temperature for 4 hours, filtered, and the filtrate was washed with water. The layer was washed with aq. EtOAc EtOAc EtOAc (EtOAc m. Confirmed by structure as 3,5,6-trimethylpyrazine-2-yl-methyl 2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propanoate, melting point: 145 -147 ° C, Elemental analysis: Theoretical value (%): C: 66.296, H: 5.564, N: 6.185; Measured value (%): C: 66.045, H: 5.570, N: 6.245; Infrared spectrum (KBr tablet) ): 3443cm- 1, 3093cm- 1, 2952cm- 1, 2920cm- 1, 1733cm - 1, 1648cm - 1, 1599cm - 1, 1417cm-l, 1277cm - 1, 1145cm - 1, 1012cm-l, 928cm-l, 856cm-l, 763cm-l; 1H-NMR (CDC13): 51.7122 (3H, s, -CH3), δ2·3937~2·4866(3Η, s, -CH3), 55.2863 (2H, s, -CH2-), 56.8499- 7.7110 (8H, multiplet, Ar-H); ESI mass spectrometry M+H]+: 452 m/z Example 2

Preparation of 2-methyl-2-(·(4-chlorobenzoyl)phenoxy)propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester: 13.5 g (0.04 mol) 2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propanoyl chloride was added to 100 mL of chloroform and stirred to dissolve at 0 ° C, then 6.1 g (0.04 mol) 2 was added. -Hydroxymethyl-3,5,6-trimethylpyrazine and 10 mL of N,N-dimethylformamide, after stirring, stirred at room temperature for 6 hours, filtered, filtrate Washing with water, the aqueous layer was extracted twice with chloroform. The mixture was combined with chloroform, and then washed with saturated aqueous sodium hydrogencarbonate. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated. The precipitated crystals were filtered off and dried to give 6.9 g of a yellow solid, which was confirmed by structure to be 2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propanoic acid 3,5,6- Trimethylpyrazine-2-yl-methyl ester, melting point: 146~147 °C. Example 3

Preparation of 2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2-methylpropanoic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester:

According to the preparation method of Example 1, 2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2-methylpropanoyl chloride and 2-hydroxymethyl-3,5,6-tri Methylpyrazine, according to the law can be obtained 2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2-methylpropanoic acid 3,5,6-trimethylpyrazine-2- Y-methyl ester. ESI mass spectrum [M+H]+: 424 m/z Example 4

Preparation of 2-[α-(4-chlorophenyl)-4-methylphenyl]oxy]-2-methylbutyric acid 3,5,6-trimethylpyrazine-2-yl-methyl ester: According to the implementation The preparation method of Example 1, using 2-[α-(4-chlorophenyl) 4-methylphenyl]oxy]-2-methylbutyryl chloride and 2-hydroxymethyl-3,5,6-trimethylpyridinium Oxazine, can be obtained according to the law to obtain 2-[α-(4-chlorophenyl)-4-methylphenyl]oxy]-2-methylbutyric acid 3,5,6-trimethylpyrazine-2-yl- ester. ESI mass spectrum [M+H]+: 454 m/z. Example 5

Preparation of 2-[4-(2,4-dichlorophenoxy)phenoxy]propanoic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester:

According to the preparation method of Example 1, 2-[4-(2,4-dichlorophenoxy)phenoxy]propionyl chloride and 2-hydroxymethyl-3,5,6-trimethylpyrazine, 2-[4-(2,4-Dichlorophenoxy)phenoxy]propionic acid can be obtained according to law 3,5,6-trimethylpyrazine-2-yl-methyl ester ESI mass spectrum [M+H]+: 462 m/zo

Example 6

Preparation of [p--4-chlorobenzoyl-p-aminoethylphenoxy]isobutyric acid 3,5,6-trimethylpyrazine-2-yl-methyl ester:

According to the preparation method of Example 1, using p--4-chlorobenzoyl-β-aminoethylphenoxy]isobutyryl chloride and 2-hydroxymethyl-3,5,6-trimethylpyrazine, according to the law [p--4-chlorobenzoyl-β-aminoethylphenoxy]isobutyric acid 3,5,6-trimethylpyrazine-2-yl-methyl ester can be obtained. ESI mass spectrum [M+H]+: 495 m/z.

Example 7

Preparation of 2-(4-chlorophenoxy)2-methylpropionic acid 3,5,6-trimethylpyrazine-2]yl-methyl ester:

According to the preparation method of Example 1, 2-(p-chlorophenoxy)-2-methylpropanoyl chloride and 2-hydroxymethyl-3,5,6-trimethylpyrazine can be obtained according to the law to obtain 2- (4-Chlorophenoxy)-2-methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester. ESI mass spectrum [M+H]+: 450 m/z.

Example 8

2-(4-hydroxyphenoxy)propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester

According to the preparation method of Example 1, 2-(4-hydroxyphenoxy)propionyl chloride and 2 3⁄4 methyl-3,5,6-trimethylpyrazine are used according to the law to obtain 2-(4-hydroxybenzene). Oxy)propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester. ESI mass spectrum [M+H]+: 317 m/z. Example 9

Preparation of 2-(4-methoxyphenoxy)propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester:

According to the preparation method of Example 1, 2-(4-methoxyphenoxy)-propionyl chloride and 2 3⁄4 methyl-3,5,6-trimethylpyrazine can be obtained according to the law to obtain 2-(4). -Methoxyphenoxy)propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester. ESI mass spectrum [M+H]+: 331 m/z.

Example 10

Preparation of 2-(4-aminophenoxy) 2-methylpropanoic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester:

According to the preparation method of Example 1, 2-(Φaminophenoxy)-2-methylpropionyl chloride and 2-hydroxymethyl group were used.

-3,5,6-trimethylpyrazine, according to the operation, can obtain 2-(Φaminophenoxy)-2-methylpropionic acid 3,5,6-trimethylpyrazine-2-yl- ester. ESI mass spectrum [M+H]+: 330 m/z.

Example 11

Preparation of 2-methyl-2-(·(4-chlorobenzoyl)phenoxy)propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester: 15.9 g (0.05 mol) 2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propionic acid, 7.6 g (0.05 mol) 2-hydroxymethyl-3,5,6-trimethylpyrazine 5g of p-toluenesulfonic acid and 150mL of toluene were added to the reaction flask, heated under reflux for 8 hours, filtered, and the filtrate was washed with water. The aqueous layer was extracted twice with toluene. The toluene layer was combined and washed with saturated aqueous sodium hydrogencarbonate to separate organic layer. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to dryness. Example 12

Preparation of 2-methyl-2-(·(4-chlorobenzoyl)phenoxy)propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester: In the above Example 11 The p-toluenesulfonic acid is replaced by sulfuric acid, and 2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propionic acid 3,5,6-trimethylpyrazine-2- can be obtained according to the law. Y-methyl ester. Example 13

Preparation of 2-(4-isopropylphenoxy)-2-methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester:

11. lg (0.05 mol) 2-(4-isopropylphenoxy)-2-methylpropionic acid 7.6 g (0.05 mol) 2-hydroxymethyl-3,5,6-trimethylpyrazine Adding 4.5 g of tetrafluoroboric acid and 150 mL of toluene to the reaction flask, heating and refluxing for 6 hours, filtering, washing the filtrate with water, extracting the aqueous layer twice with toluene, and combining the toluene layer, washing with saturated aqueous sodium hydrogencarbonate, and separating organic The layers were dried over anhydrous magnesium sulfate, filtered and evaporated. ESI mass spectrum [M+H]+: 357 m/z. Example 14

Preparation of 2-[4-(4-chloro-benzyloxy)phenyloxy]-2-methylpropanoic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester: 2-[ 4-(4-Chloro-benzyloxy)-phenyloxy]-2-methylpropanoic acid (21.0 g, 0.066 mmol), 2-hydroxymethyl-3,5,6-trimethylpyrazine (9.7 g , 0.064mmol), added to a 250ml three-neck bottle. Add 150ml

The mixture was dissolved in THF, and then the solution was cooled to 0 ° C to 5 ° C using an ice water bath. Under a magnetic stirring condition, a solution of DCC (0.13 g, 0.063 mmol) in THF (10 ml) was added dropwise to the reaction mixture (the reaction was exothermic). The progress of the reaction was monitored by TLC, and the reaction was carried out overnight under the conditions of magnetic stirring under normal temperature. On the next day, the reaction solution was spun dry, and 150 ml of ethyl acetate was added to dissolve the remaining solid, which was washed once with a sodium carbonate solution and three times with water. The organic phase separated by liquid separation was dried over anhydrous magnesium sulfate. Filter The ethyl acetate was spun dry and purified by column chromatography on silica gel to afford 12.7 g of a yellow solid. ESI mass spectrometry

Example 15

Preparation of 2-(4-biphenyloxy)2-2-propionic acid 3,5,6-trimethylpyrazine-2]yl-methyl ester

Add methyl 2-(4-biphenyloxy)-2-methylpropanoate (13.5 g, 0.05 mol) and 2-hydroxymethyl-3,5,6-trimethylpyrene in a 100 ml three-necked vial The oxazine (9.1 g, 0.061 mmol) was placed in an oil bath at 100 ° C, mechanically stirred, and the mixture was completely melted, then the catalyst was added with sodium alkoxide, and a small tube of methanol was collected by a condenser, and nitrogen gas was constantly supplied to facilitate the flow. Methanol gas overflow. The yield of the collected methanol was weighed every 15 minutes until constant weight to determine the degree of reaction of the transesterification. After the end of the reaction, the product was purified by column chromatography to yield 7.8 g of pale yellow. ESI mass spectrum [M+H]+: 391 m/z.

Example 16

Preparation of 2-(4-isobutyryl-phenyloxy)-2-methylpropionic acid isopropyl 3,5,6-trimethylpyrazine-2-yl-methyl ester: In Example 15 above The catalyst sodium methoxide was replaced by sodium isopropoxide, with 2-(Φ isobutyryl-phenyloxy)-2-methylpropionic acid isopropyl ester and 2-hydroxymethyl-3,5,6-trimethylpyridinium. As a starting material, 2-(4-isobutyryl-phenyloxy)-2-methylpropionic acid isopropyl 3,5,6-trimethylpyrazine-2-yl-A can be obtained according to the operation. Ester, pale yellow solid. ESI mass spectrum [M+H]+: 385 m/z.

Example 17

Preparation of 2-methyl-2-(·(4-chlorobenzoyl)phenoxy)propanoic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester hydrochloride:

The product obtained in Example 1 was 2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester with a little After dissolving in anhydrous ether, diethyl ether hydrochloride is added, and a large amount of white precipitate crystals are formed, which is 2-methyl-2-(4-(4-chlorobenzoyl)phenoxy)propionic acid 3,5,6. -trimethylpyrazine -2-yl-methyl ester hydrochloride.

The invention has been described in terms of a preferred embodiment. It is to be understood that the foregoing description and embodiments are merely illustrative of the invention. Various alternatives and modifications of the invention can be devised by those skilled in the art without departing from the spirit and scope of the invention.

Claims

Claims Formula (I) Compound:

Its towel:

• 1^~ are the same or different from each other, each independently representing hydrogen, an alkyl group having 1 to 6 carbon atoms, a nitro group, a halogen, an amino group, an acyl group, a sulfonyl group, a carboxyl group, a hydroxyl group, and having 1 to 6 carbon atoms. A hydroxyalkyl group, an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 6 carbon atoms, a carbamoyl group, a thiourea group, an alkyl sulfide having 1 to 6 carbon atoms An alkylsulfonate having 1 to 6 carbon atoms, an aminomethyl group, a cyano group, a group having an unsaturated double bond of 2 to 4 carbon atoms, and an unsaturated hydrazone bond having 2 to 4 carbon atoms. a group, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group, a substituted aryl group, an aralkyl group, a substituted aralkyl group, an aryloxy group, a substituted aryloxy group, an arylcarbonyl group, Substituted arylcarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl;

• R _{6 to} R ₉ are the same or different from each other, and each independently represents hydrogen, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a hydroxyl group having 1 to 6 carbon atoms. An alkyl group, a cycloalkyl group having 3 to 6 carbon atoms;

• R _{1( ) to} R ₁₂ are the same or different from each other, and each independently represents hydrogen, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and 2 to 6 carbon atoms. Alkoxycarbonyl group, carboxyl group, hydroxyalkyl group having 1 to 6 carbon atoms, cycloalkyl group having 3 to 6 carbon atoms, aryl group or substituted aryl group;

• n is an integer from 1-6;

And its enantiomers, racemates, diastereomeric mixtures, racemic mixtures, solvates or pharmaceutically acceptable salts.

2. A compound of formula (I) as claimed in claim 1 wherein: • 1^~ are the same or different from each other and represent each independently:

Hydrogen, nitro, halogen, amino, acyl, sulfonyl, carboxy, hydroxy, carbamoyl, thioureido, aminomethyl, cyano;

An alkyl group having 1 to 6 carbon atoms, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-amyl , n-hexyl, isohexyl or tert-hexyl; containing 1 to 6 hydroxyalkyl groups, preferably hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxy-n-butyl, hydroxyisobutyl, hydroxy-n-pentyl, hydroxy Isoamyl, hydroxyhexyl or hydroxyisohexyl;

An alkoxy group having 1 to 6 carbon atoms, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy Base, isopentyloxy, tert-pentyloxy, n-hexyloxy, isohexyloxy or tert-hexyloxy;

An alkoxycarbonyl group having 2 to 6 carbon atoms, preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, n-pentyloxy a carbonyl group, an isopentyloxycarbonyl group or a tert-pentyloxycarbonyl group;

An alkyl sulfide having 1 to 6 carbon atoms, preferably methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, n-pentyl Sulfur, isopentylthio, tert-pentylthio, n-hexylthio, isohexylthio or tert-hexylthio;

An alkyl sulfonate having 1 to 6 carbon atoms, preferably a mesylate group, an ethylsulfonate group, a n-propanesulfonate group, an isopropylsulfonate group, a n-butanesulfonate group, an isobutylsulfonate group, or a tertiary Butanesulfonate, n-pentanesulfonate, isovalerylsulfonate, tert-pentanesulfonate, n-hexylsulfonate, isohexylsulfonate or tert-hexylsulfonate;

a group having an unsaturated double bond of 2 to 4 carbon atoms, preferably a vinyl group, a propenyl group, an allyl group, a butenyl group or a butadienyl group;

a group having an unsaturated hydrazone bond of 2 to 4 carbon atoms, preferably an ethyl group, a propyl group, a propyl group or a butyl group;

a substituted or unsubstituted cycloalkyl group having 3 to 6 carbon atoms, wherein the cycloalkyl group having 3 to 6 carbon atoms is preferably a cyclopropyl group, a methylcyclopropyl group or a dimethylcyclopropane group a group, an ethylcyclopropyl group, a methylcyclopentyl group or a cyclohexyl group, the substituent when substituted is preferably an alkyl group, an alkoxy group, a nitro group, a halogen, an amino group, an acyl group, a sulfonyl group, a carboxyl group or a hydroxyl group; a substituted or unsubstituted aryl group, wherein the aryl group is preferably a phenyl group or a naphthyl group, and the substituent when substituted is preferably an alkyl group, an alkoxy group, a nitro group, a halogen group, an amino group, an acyl group, a sulfoamino group, Carboxyl or hydroxy;

a substituted or unsubstituted aralkyl group, wherein the aralkyl group is preferably a benzyl group, a phenethyl group, a phenylpropyl group, a phenylisopropyl group, a naphthylmethyl group, a naphthylethyl group, a naphthylpropyl group or a naphthylisopropyl group. The substituent, when substituted, is preferably an alkyl group, an alkoxy group, a nitro group, a halogen, an amino group, an acyl group, a sulfonyl group, a carboxyl group or a hydroxyl group; a substituted or unsubstituted aryloxy group, wherein the aryloxy group The group is preferably a phenoxy group, a benzyloxy group, a phenethyloxy group, a phenylpropoxy group, a naphthylmethoxy group, a naphthylmethoxy group, a naphthylethoxy group or a naphthylpropoxy group, and the substituent when substituted is preferably An alkyl group, an alkoxy group, a nitro group, a halogen, an amino group, an acyl group, a sulfonyl group, a carboxyl group or a hydroxyl group;

a substituted or unsubstituted arylcarbonyl group, wherein the arylcarbonyl group is preferably a benzoyl group, a naphthoyl group, a phenylacetyl group or a naphthylacetyl group, and the substituent when substituted is preferably an alkyl group or an alkoxy group. , nitro, halogen, amino, acyl, sulfonyl, carboxy or hydroxy;

a substituted or unsubstituted aryloxycarbonyl group, wherein the aryloxycarbonyl group is preferably a phenoxycarbonyl group, a benzyloxycarbonyl group, a phenethyloxycarbonyl group, a phenylpropoxycarbonyl group, a naphthylmethoxycarbonyl group, a naphthylmethoxycarbonyl group. , naphthalene ethoxycarbonyl or naphthyloxycarbonyl, the substituent when substituted is preferably an alkyl group, an alkoxy group, a nitro group, a halogen, an amino group, an acyl group, a sulfonyl group, a carboxyl group or a hydroxyl group;

» R ₆ ~ are the same or different from each other and represent each independently:

Hydrogen

An alkyl group having 1 to 6 carbon atoms, preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, tert-amyl , n-hexyl, isohexyl or tert-hexyl; alkoxy group having 1 to 6 carbon atoms, preferably methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy Base, tert-butoxy, n-pentyloxy, isopentyloxy, tert-pentyloxy, n-hexyloxy, isohexyloxy or tert-hexyloxy;

a hydroxyalkyl group having 1 to 6 carbon atoms, preferably a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxy-n-butyl group, a hydroxyisobutyl group, a hydroxy-n-pentyl group, a hydroxyisopentyl group, a hydroxyhexyl group or Hydroxylhexyl;

a cycloalkyl group having 3 to 6 carbon atoms, preferably a cyclopropyl group, a methylcyclopropyl group, a dimethylcyclopropyl group, an ethylcyclopropyl group, a methylcyclopentyl group or a cyclohexyl group; • R _{1Q to} R ₁₂ are the same or different from each other and each independently represents:

Hydrogen, carboxyl group;

An alkoxycarbonyl group having 2 to 6 carbon atoms, preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, n-pentyloxy a carbonyl group, an isopentyloxycarbonyl group or a tert-pentyloxycarbonyl group;

a cycloalkyl group having 3 to 6 carbon atoms, preferably a cyclopropyl group, a methylcyclopropyl group, a dimethylcyclopropyl group, an ethylcyclopropyl group, a methylcyclopentyl group or a cyclohexyl group;

An aryl group or a substituted aryl group, preferably a phenyl group, a benzyl group, a nitrophenyl group, a phenyl group, a hydroxyphenyl group or an alkoxyphenyl group;

• n is an integer from 1-6;

3. A compound of formula (I) as claimed in claim 1 wherein:

• 1^~ are the same or different from each other and independently represent: hydrogen, nitro, halogen, amino, acyl, sulfonyl, carboxy, hydroxy, carbamoyl, thioureido, aminomethyl, cyano; alkyl Preferred are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl; hydroxyalkyl, preferably hydroxymethyl, hydroxyethyl, hydroxypropyl; alkoxy Preferred is methoxy, ethoxy, n-propoxy; alkoxycarbonyl, preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl; cycloalkyl, preferably cyclopropyl, cyclobutyl, Cyclopentyl; substituted cycloalkyl, preferably methylcyclopropyl, dimethylcyclopropyl, ethylcyclopropyl, methylcyclopentyl, methoxycyclopropyl, nitrocyclopropyl, Halogen ring Alkyl, aminocyclopropyl, acylcyclopropyl; phenyl, naphthyl, substituted phenyl or substituted naphthyl, wherein the substituent is preferably alkyl, alkoxy, nitro, halogen, amino, acyl , sulfonyl, carboxy or hydroxy; aralkyl, preferably benzyl, phenethyl, phenylpropyl, phenylisopropyl or phenylcyclo substituted phenylalkyl, wherein the phenylalkyl is benzyl, benzene Ethyl, phenylpropyl or phenylisopropyl, the substituent is alkyl, alkoxy, nitro, halogen, amino, acyl, sulfonyl, carboxy or hydroxy; arylcarbonyl, preferably benzoyl, phenylacetyl a phenylcarbonyl group substituted with a phenyl ring, wherein the phenylcarbonyl group is a benzoyl group or a phenylacetyl group, and the substituent is an alkyl group, an alkoxy group, a nitro group, a halogen, an amino group, an acyl group, a sulfonyl group, a carboxyl group or Hydroxyl group;

• R _{6 to} R ₉ are the same or different from each other and independently represent: hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, methoxy, ethoxy, positive Propyloxy, isopropoxy, n-butoxy, isobutoxy, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxy-n-butyl, hydroxyisobutylcyclopropyl, methylcyclopropyl, dimethyl a cyclopropyl group, an ethylcyclopropyl group, a methylcyclopentyl group or a cyclohexyl group;

• R _{1Q to} R ₁₂ are the same or different from each other and independently represent: hydrogen, carboxyl, methyl, ethyl, methoxy, ethoxy, methoxycarbonyl, ethoxycarbonyl, hydroxymethyl or hydroxyethyl ;

• n is 1;

4. A compound of formula (I) as claimed in claim 1 which is selected from the group consisting of:

• [p--4-chlorobenzoyl-β-aminoethylphenoxy]isobutyric acid 3,5,6-trimethylpyrazine-2-yl-methyl ester;

• 2-(4-Aminophenoxy)-2-methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester; • 2-(4-isopropylphenoxy)-2-methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester;

• 2-[4-(4-Chloro-benzyloxy)-phenyloxy]-2-methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester;

• 2-(4-biphenyloxy)-2-methylpropionic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester;

• 2-(4-isobutyryl-phenyloxy)-2-methylpropionic acid isopropyl 3,5,6-trimethylpyrazine-2-yl-methyl ester;

• 2-Methyl-2-(4-(4-chlorobenzoyl)phenoxy)propanoic acid 3,5,6-trimethylpyrazine-2-yl-methyl ester hydrochloride.

A process for producing a compound (I) according to Claim 1 to 4, which comprises the step of obtaining a compound (I) by esterification from the following compounds (?) and (III):

Wherein, 1^~ ₂ is as defined above, and R _{13 is} selected from the group consisting of a hydroxyl group, a halogen, an alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a n-propoxy group, an isopropoxy group, n-Butoxy, isobutoxy, tert-butoxy, n-pentyloxy, isopentyloxy, tert-pentyloxy, n-hexyloxy, isohexyloxy or tert-hexyloxy.

The method according to claim 5, which further comprises the step of preparing a corresponding pharmaceutically acceptable salt from the compound (I) by reacting with a pharmaceutically acceptable inorganic or organic acid.

A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 and an enantiomer, a racemate, a mixture of diastereomers, a racemic mixture, a solvate or a pharmaceutically acceptable compound The salt is the active ingredient, as well as pharmaceutically acceptable excipients.

The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is a tablet, a capsule, an injection, an oral preparation, a dropping pill, an emulsion, a suspension, a lyophilized powder injection, and a sustained release agent. , controlled release agents, oral disintegration agents, effervescent agents, etc.

9. The compound of claim 1 to 4 and its enantiomers, racemates, diastereomeric mixtures, racemic mixtures, solvates or pharmaceutically acceptable salts, prepared for lowering blood fat or improving blood The application of rheological drugs.

10. The compound of claim 1 to 4 and an enantiomer, racemate, diastereomeric mixture, racemic mixture, solvate or pharmaceutically acceptable salt thereof, prepared for use in lowering serum triglycerides Use in drugs that lower serum cholesterol or raise high-density lipoprotein.