WO2010034212A1 - Dérivés esters d'acide phénoxyacétique et de pyrazine, leurs procédés de préparation et leurs utilisations - Google Patents

Dérivés esters d'acide phénoxyacétique et de pyrazine, leurs procédés de préparation et leurs utilisations Download PDF

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WO2010034212A1
WO2010034212A1 PCT/CN2009/072733 CN2009072733W WO2010034212A1 WO 2010034212 A1 WO2010034212 A1 WO 2010034212A1 CN 2009072733 W CN2009072733 W CN 2009072733W WO 2010034212 A1 WO2010034212 A1 WO 2010034212A1
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group
carbon atoms
tert
substituted
trimethylpyrazine
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PCT/CN2009/072733
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English (en)
Chinese (zh)
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李晓祥
徐自奥
李德刚
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安徽省新星药物开发有限责任公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/18—Oxygen or sulfur atoms

Definitions

  • 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). .
  • TG chylomi
  • 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.
  • 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): ⁇ 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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 2 - 3, more preferably 1.
  • the compounds of the invention are the following compounds:
  • halogen as used herein in the definition or partial definition includes fluorine, chlorine, bromine and iodine.
  • the compound of formula (I) may contain a chiral center.
  • 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 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 ( ⁇ ) and (III).
  • the reaction formula of this reaction is as follows:
  • 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 e.g., a tetrachloroaluminum ether complex
  • dicyclohexylcarbodiimide a sulfonic acid
  • 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.).
  • 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.
  • 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.
  • such pharmaceutically acceptable salts include sulfates, pyrosulfates, hydrogen sulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates.
  • 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 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.
  • 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 ( ⁇ ), erythrocyte aggregation index ( ⁇ ) 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.
  • 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.
  • 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 ⁇ ⁇ and ⁇ in the model group were significantly higher than those in the normal mice. After compound ( I ), the ⁇ ⁇ and ⁇ in the high-dose and medium-dose groups were significantly lower than those in the model group ( ⁇ 0.05). .
  • Example 1 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 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 Example 1
  • Example 1 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.

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Abstract

L'invention porte sur des dérivés esters d'acide phénoxyacétique et de pyrazine représentés par la formule (I), sur leurs procédés de préparation et sur leurs utilisations, dans laquelle formule R1-R12 ont des significations prescrites; sur les sels, énantiomorphes, mélanges racémiques et mélanges de diastéréoisomères pharmaceutiquement acceptables des présents composés; et sur les procédés de préparation des présents composés et de leurs sels pharmaceutiquement acceptables. Les présents composés peuvent abaisser le taux sérique de triglycérides et le cholestérol sérique, élever le taux de lipoprotéines de haute densité et améliorer la rhéologie du sang.
PCT/CN2009/072733 2008-09-28 2009-07-13 Dérivés esters d'acide phénoxyacétique et de pyrazine, leurs procédés de préparation et leurs utilisations WO2010034212A1 (fr)

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