CN101627030A

CN101627030A - Compounds with partial agonist activity of ppar gamma and application thereof

Info

Publication number: CN101627030A
Application number: CN200880007518A
Authority: CN
Inventors: 郭建辉; 姜勇
Original assignee: Shanghai Allist Pharmaceuticals Inc
Current assignee: Shanghai Allist Pharmaceuticals Inc
Priority date: 2007-03-09
Filing date: 2008-03-05
Publication date: 2010-01-13
Also published as: CN101260103A; WO2008110062A1

Abstract

The present invention discloses compounds with partial agonist activity of PPAR Gamma represented by formula I,pharmaceutical salts thereof, their preparation, pharmaceutical compositions containing the compounds or their pharmaceutical salts, and their application in the preparation of medicine used for the treatment and/or prevention of the diseases associated with PPAR Gamma, such as diabetes, diseases associated with blood sugar singularly rising, metabolic syndrome or adiposity.

Description

Compounds with partial agonist activity of ppar gamma and application thereof

Compound and its applied technical field with PPAR gamma portion agonist activities

The present invention relates to the compound with PPAR gamma portion agonist activities or its pharmaceutically acceptable salt, its preparation method, the pharmaceutical composition comprising the compound or its pharmaceutically acceptable salt and its application in the medicine for preparing the disease for being used to treat and/or preventing PPAR γ acceptors correlation, such as diabetes, pathoglycemia rise relevant disease, metabolic syndrome or obesity.Background technology

Diabetes are that it affects the health of the mankind in the world by the disorderly caused disease of several genes.Diabetes can be divided into two types：（1) type i diabetes or insulin-dependent diabetes mellitus（IDDM), its patient secretion is few or not excreting insulin, and patient must insulin injection daily；（2) type ii diabetes or Non-Insulin Dependent Diabetes Mellitus（MDDM), the concentration of type 2 diabetes patient's plasma insulin and normal person are essentially identical, mainly the sensitiveness reduction of insulin, act on it is abnormal cause insulin relative deficiency, this can further influence the metabolism in being muscle, liver and adipose tissue to the tissue of insulin sensitivity of sugar and fat.The Π patients with type Ⅰ DM incidence of disease is high, accounts for the 90% of diabetic.

Recently research is found, type ii diabetes have close relationship with peroxisome proliferator-activated receptors (peroxisome proliferators-activated receptor, PPAR).PPAR belongs to by a member in transcription factor-nuclear hormone receptor superfamily of ligand activation, it can and retinoic acid receptor X（RXR heterodimer) is formed, and is combined and activated gene expression with the hormone response element on target gene.PPAR/ RXR heterodimers play an important role in terms of control cytolipin dynamic equilibrium and Adipocyte Differentiation.The PPAR of mammal can be divided into 3 hypotypes, i.e. PPARa, PPAR γ and PPAR δ.Wherein PPAR γ mainly play important regulating and controlling effect in terms of the expression and differentiation of adipose tissue related gene, are also the important regulatory factor of glucose and lipid metabolism target gene.PPARa stimulates the propagation of peroxidase, accelerates the oxidation of aliphatic acid, so that the content of fatty acid in blood is reduced, PPARa activators such as fiber acid derivative（Fibrates it) can be used for treatment dyslipidemia.

Oral hypoglycemic thing in the market mainly include 5 major classes, i.e. sulfonylureas, biguanides, the fragrant preparation of α-glucose, | sit hole diones（Thiazolidinediones, TZD) and potassium channel antagonistses.The TZD class compounds of latest developments are the novel insulin sensitizers using PPAR γ as action target spot, it is possible to increase body, so as to correct abnormal carbohydrate metabolism, reduces high sugared toxicity to the sensitiveness of insulin.But this kind of medicine with complete PPARy agonist activities, Such as the Rosiglitazone listed（Rosiglitazone, Avandia, Avandia) and Pioglitazone (Pioglitazone, Ai Ting, Actos), in process of clinical application, the side effects such as patient body weight increase, oedema, adipose tissue surge, bone marrow fat acid change can be produced.Research shows that TZD class medicines are the differentiation that fat cell is adjusted by exciting PPARy and then the sensitiveness for improving insulin, and this can also aggravate internal fat and store and then produce the side effects such as increased weight simultaneously.

Application of the safety problem of complete PP AR gamma agonist clinical practices to PP AR gamma agonists in treating diabetes brings huge challenge.For this this area PPARy partial agonist new in the urgent need to finding a class, it should retain the beneficial effect that can make insulin sensitivity enhancing and have less side effect.Partial agonist（Partial agonist)-as there is certain affinity, but its intrinsic activity is low, and weaker effect can only be produced after being combined with acceptor, even if concentration increases, can not reach full agonist（Full agonist) as ceiling effect.But the presence of the partial agonist of high concentration can then capture acceptor, the effect of antagonism full agonist.

Metabolex companies have the chemical constitution parent nucleus different from Rosiglitazone in the oral hypoglycemic Metaglidasen ground.Research shows that MeUglidasen is PPARy partial agonists, and being selectively adjusted improves the gene of insulin sensitivity, the gene without activating increased weight and fluid retention.

W09402467 discloses a series of imidazoles ether compounds, and the compound has the activity of Angiotensin II (Angiotensin II, AT II) receptor antagonist.Summary of the invention

The technical problems to be solved by the invention are to provide the new compound that a class has P P A R gamma portion agonist activities（Such as following formula structure I) or its pharmaceutically acceptable salt, its preparation method, the composition comprising the compound or its pharmaceutically acceptable salt and its application in the disease for treating and/or preventing PPAR γ acceptors correlation, such as diabetes, pathoglycemia rise relevant disease, metabolic syndrome or obesity is prepared.

The invention provides following technical scheme：

1. general structure（I compound .' shown in)

Or its pharmaceutically acceptable salt,

Wherein, selected from halogen, d-C₄Alkyl, the d- C of halogen substitution₄Alkyl, d-C₄Alkoxy, C₃-C₇Cycloalkyl, hydroxyl, cyano group, C ,-C₄Alkoxy carbonyl group, aromatic rings and containing at least one be selected from N, S and 0 heteroatomic hetero-aromatic ring；With

N=1 ~ 5, and be integer.

2. the compound as described in technical scheme 1, wherein selected from halogen, C ,-C₄Alkyl, the d- C of halogen substitution₄Alkyl and cyano group.

3. the compound as described in technical scheme 1 or 2, wherein n=l or 2.

4. the compound as described in technical scheme 3, wherein n=l, and be 3 or 4 bit substituents

Compound as described in technical scheme 4, wherein 1, it is 4 bit substituents.

6. the compound as described in technical scheme 3, wherein n=2, and ^ is 2 and 5 bit substituents.

7. the compound as described in technical scheme 6, wherein R, selected from the substitution of halogen, base and halogen ,-C₄Alkyl.

8. the compound as described in technical scheme 1, wherein the compound is the compound being selected from the group：

1) the chloro- 1- of 2- butyl -4- { [2'- (1 〃-tetrazolium -5- bases）--biphenyl -4- bases] methyl } -5- [(4- fluorine benzyloxies）Methyl] -1 〃-imidazoles；

2) the chloro- 1- of 2- butyl-4- { [2'- (1-tetrazolium-5- bases）-：- biphenyl -4- bases] methyl } -5- [(4- bromo-benzyloxys）Methyl] imidazoles；

3) the chloro- 1- of 2- butyl -4- { [2'- tetrazolium -5- bases）-：- biphenyl -4- bases] Yue yls } -5- [(4- methylbenzyloxies）Yue yls]-imidazoles；

4) the chloro- 1- of 2- butyl -4- { [2'- tetrazolium -5- bases）- biphenyl -4- bases] methyl } -5- [(4- trifluoro Yue base benzyloxies）Methyl] -1 ^ imidazoles；

5) the chloro- 1- of 2- butyl -4- { [2'- tetrazolium -5- bases）Stupid -4- the bases of-- connection] methyl } -5- [(4- cyano benzyloxies）Methyl]-imidazoles；

6) 2- butyl-4-chloro- 1- { [2'- tetrazolium-5- bases） -：- biphenyl -4- bases] methyl } -5- [(3- fluorine benzyloxies）Methylimidazole；

7) 2- butyl-4-chloro- 1- { [2'- tetrazolium-5- bases）--biphenyl -4- bases] methyl } -5_ [(3- trifluoromethyl benzyloxies）Methyl] _ 1 ^ imidazoles；

8) the chloro- 1- of 2- butyl -4- { [2'- (1#-tetrazolium -5- bases）--biphenyl -4- bases] methyl } -5- [(2,5- difluoro benzyloxies）Yue yls]-imidazoles；With 9) the chloro- 1- of 2- butyl -4- { [2'- tetrazolium -5- bases）- 1,1'- biphenyl -4- bases] methyl } -5- { [2,5- bis-（Trifluoromethyl）Benzyloxy] methyl } -1 imidazoles.

9. a kind of method of compound any one of technology of preparing scheme 1-8, including step：

A) ：By trityl Losartan（Π Ι) it is dissolved in solvent, in the presence of a base, with corresponding benzyl br-derivatives（Π) occur into ether reaction and obtain corresponding intermediate（IV)；

B) ：By gained intermediate（IV) it is dissolved in solvent, in the presence of a base, heating deprotection base obtains target compound（I) ;

And optional step C):Base addition salts are formed by gained compound and suitable inorganic acid or organic acid formation acid-addition salts or with suitable inorganic base or organic base.

10. a kind of pharmaceutical composition, described pharmaceutical composition includes the compound or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier any one of technical scheme 1 to 8.

11. the pharmaceutical composition as described in technical scheme 10, it is also comprising other one or more hypoglycemic agents.

12. the pharmaceutical composition as described in technical scheme 11, other wherein described hypoglycemic agents are selected from sulfonylurea drugs, biguanides, α _ glucosidase inhibitor and diones medicine, and other preferably described hypoglycemic agents are selected from tolbutamide, glibenclamide, Glipizide, insoral, two Yue biguanides, buformin, acarbose, Miglitol, voglibose, Rosiglitazone and Pioglitazone.

13. the pharmaceutical composition as described in technical scheme 10, wherein described pharmaceutical composition is that the content of compound any one of technical scheme 1 to 8 or its pharmaceutically acceptable salt is 0.6mg-12g, preferably 0.6mg- 6g, more preferably 0.6mg- 3g unit dose medicine.

14. the pharmaceutical composition as any one of technical scheme 10 to 13, wherein described pharmaceutical composition are oral formulations, rectally preparation, parenteral formulations or local administration preparation. 15. the pharmaceutical composition any one of compound or its pharmaceutically acceptable salt or technical scheme 10 to 13 as any one of technical scheme 1-8 is preparing the application in being used to treat and/or preventing the medicine of the related disease of PPAR γ acceptors.

16. the application as described in technical scheme 15, wherein the disease is selected from diabetes, pathoglycemia rise relevant disease, lipid disorders, metabolic syndrome, angiocardiopathy, coronary artery disease, high blood cholesterol and obesity.

17. such as the application that technical scheme 16 is confused, wherein the disease is diabetes or pathoglycemia rise relevant disease.

18.-kind for the treatment of and/or the method for the related disease of prevention mammal PPAR γ acceptors, including will treat and/or the technical scheme 1-8 of prevention effective dose in any described compound or its pharmaceutically acceptable salt or the pharmaceutical composition any one of technical scheme 10 to 13 give the mammals of needs.

19. the method as described in technical scheme 18, wherein the disease is selected from diabetes, pathoglycemia rise relevant disease, lipid disorders, metabolic syndrome, angiocardiopathy, coronary artery disease, high blood cholesterol and obesity.

20. the method as described in technical scheme 19, wherein the disease is diabetes or pathoglycemia rise relevant disease.

21. the method as any one of technical scheme 18 to 20, wherein further comprising the mammal that the compound or its salt any one of other hypoglycemic drugs and technical scheme 1 to 8 or the pharmaceutical composition any one of technical scheme 10 to 13 are simultaneously or sequentially given to needs.Detailed description of the invention

There is provided a kind of formula for the first aspect of the present invention（I compound or its pharmaceutically acceptable salt shown in)：

Wherein, selected from halogen, C ,-C₄Alkyl, the d- C of halogen substitution₄Alkyl, C ,-C₄Alcoxyl C₃- (₇Cycloalkyl, hydroxyl, cyano group, _ (₄Alkoxy carbonyl group, aromatic rings and containing at least one It is individual to be selected from N, S and 0 heteroatomic hetero-aromatic ring, preferably halogen, C ,-^ alkyl, halogen substitution (₄Alkyl or cyano group;

N=1 ~ 5, and be integer, preferably 1 or 2.

In the preferred scheme that the present invention is provided, n=1, ^ is 3 or 4 bit substituents, wherein selected from halogen, C ,-C₄Alkyl, the C ,-C of halogen substitution₄Alkyl and cyano group.

In the scheme that one provided of the invention is more highly preferred to, n=l, 1^ is 4 bit substituents, wherein R, selected from halogen, d- C₄Alkyl, the d-C of halogen substitution₄Alkyl and cyano group.

In another preferred scheme that the present invention is provided, n=2 are 2 and 5 bit substituents, wherein selected from halogen, C ,-C₄Alkyl, the d-C of halogen substitution₄Alkyl and cyano group.

In another scheme being more highly preferred to that the present invention is provided, n=2 are 2 and 5 bit substituents, wherein selected from halogen, d- C₄Alkyl and the C ,-C of halogen substitution₄Alkyl.

In the present invention, halogen refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine； C,-C₄Alkyl refers to the straight or branched alkyl containing 1 ~ 4 carbon atom, such as methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group, it is preferred that methyl, ethyl, propyl group, isopropyl, most preferable, ethyl； d- (：₄Alkoxy refers to the alkoxy containing 1 ~ 4 carbon atom, such as methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy or tert-butoxy； C₃- C₇Cycloalkyl refers to the cycloalkyl containing 3 ~ 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl； C₄Alkoxy carbonyl group can be methoxycarbonyl group, carbethoxyl group, propylene carbonyl oxygen, butyloxycarbonyl, butoxy carbonyl, isobutyl boc, secondary butoxy carbonyl or tertbutyloxycarbonyl；Aromatic rings includes having monocyclic, bicyclic or multi-loop system armaticity ring, such as benzene, naphthalene；Refer to containing at least one selected from the heteroatomic hetero-aromatic rings of ^ S and 0 at least containing one selected from N, S and 0 hetero atom and with monocyclic, bicyclic or multi-loop system hetero-aromatic ring, such as pyrroles, thiophene, furans, oxazoles, pyridine, pyrimidine, piperidines, quinoline, thiazole, indoles.

In the present invention, pharmaceutically acceptable salt includes acid-addition salts and base addition salts.The acid-addition salts of representative include hydrobromate, hydrochloride, sulfate, sulphite, phosphate, acetate, a careless hydrochlorate, valerate, oleate, palmitate, stearate, laruate, borate, benzene Yue hydrochlorates, lactate, citrate, maleate, fumarate, succinate, tartrate, benzene Yue hydrochlorates, mesylate, gluconate, Lactobionate and lauryl sulfonate etc..The base addition salts of representative include alkali metal cation salt, the cationic salts of alkaline-earth metal and quaternary ammonium cation in more specific scheme, and compound of the present invention can be selected from The chloro- 1_ of 2-butyl-4- { [2'- tetrazolium-5- bases）--biphenyl -4- bases] Yue yls } -5- [(4- fluorine benzyloxies）Yue yls] -1#- imidazoles；

The chloro- 1- of 2-butyl-4- { [2'- tetrazolium-5- bases）--biphenyl -4- bases] methyl } -5- [(4- bromo-benzyloxys）Methyl]-imidazoles；

The chloro- 1- of 2_ butyl -4- { [2'- tetrazolium -5- bases）--biphenyl-4-yl] methyl }-5_ [(4- methylbenzyloxies）Methyl] -1 〃-imidazoles；

The chloro- 1- of 2-butyl-4- { [2'- (1 〃-tetrazolium-5- bases）--biphenyl -4- bases] methyl } -5- [(4- trifluoromethyl benzyloxies）Methyl] -1 〃-imidazoles；

2- butyl-4-chloro- 1- { [2'- tetrazolium-5- bases）--biphenyl -4- bases] methyl } -5- [(4- cyano benzyloxies）Methyl] -1 ^ " imidazoles；

The chloro- 1_ of 2-butyl-4- { [2'- tetrazolium-5- bases）--biphenyl -4- bases] Yue yls } -5- [(3- fluorine benzyloxies）Methyl] imidazoles；

The chloro- 1- of 2-butyl-4- { [2'- (I tetrazolium-5- bases）--biphenyl -4- bases] Yue yls } -5- [(3- trifluoromethyl benzyloxies）Methyl] -1 〃-imidazoles；

The chloro- 1- of 2-butyl-4- { [2'- (1#- tetrazolium-5- bases）--biphenyl -4- bases] Yue yls } -5- [(2,5- difluoro benzyloxies）Methyl]-imidazoles；With

The chloro- 1- of 2- butyl -4- { [2'- tetrazolium -5- bases）--biphenyl -4- bases] methyl } -5- { [2,5- bis-（Trifluoro Yue bases）Benzyloxy] Yue yls }-imidazoles the second aspect of the present invention is there is provided a kind of preparation method for preparing compound of the present invention, by following process route, using suitable benzyl bromine（Such as following formula structure I I) processing trityl Losartan（Chemistry is entitled：The chloro- 1- of 2- butyl -4- { [2'- (1- trityls-tetrazolium -5- bases）- 1,-biphenyl -4- base] Yue yls } -5_ hydroxy methylimidazoles, such as following formula structure III) corresponding intermediate is made（Such as following formula structure I V), then deprotection base obtains described compound, including step：

A) ：Trityl Losartan is dissolved in suitable solvent, in the presence of a base, occurs into ether reaction with corresponding benzyl br-derivatives and obtains corresponding intermediate；

B) ：Gained intermediate is dissolved in suitable solvent, in the presence of a base, heating deprotection base obtains target compound；

And optional step C)：Base addition salts are formed by gained compound and suitable inorganic acid or organic acid formation acid-addition salts or with suitable inorganic base or organic base.

In route shown in upper figure, R, n is as defined above described in text；Suitable solvent includes DMF, DMS 0, acetone or its mixed solvent in step A, and suitable alkali includes Na H, K0H, NaOH, Na NH₂Or its mixed base；Suitable solvent includes methanol, ethanol, isopropanol, tetrahydrofuran, DMF, acetone or its mixed solvent in step B, and suitable alkali is purified including NaOH, K0H, NaOE t methods, for example with the method for column chromatography.

In above-mentioned preparation process, the reaction shown in step A can be -1 0.C is carried out under reflux temperature, and preferably reaction temperature is 5 ~ 1 00 °C, more preferably 20 ~ 80 °C;Reaction shown in step B is generally carried out under conditions of heating, and preferably reaction temperature is 4 (TC to reflux temperature, more preferably 50 °C to reflux temperature；The reaction time respectively reacted usually not especially limits, and those skilled in the art are easy to determine the reaction time by this area conventional technology, for example, monitor reaction end by TLC.

In addition; pass through the description of the above; according to ordinary skill knowledge or customary means; can also there are the modification and replacement of diversified forms to the preparation method of above-mentioned offer; for example with corresponding benzyl chloride or benzyl iodo for benzyl bromine as in step A into etherifying reagent; after and for example the reaction shown in step A terminates, its intermediate can be purified without isolation and directly carries out deprotection reaction shown in follow-up step B.The third aspect of the present invention is there is provided a kind of pharmaceutical composition, and it contains compound of the present invention or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.

Described pharmaceutical composition can deliver medicine to mammal（Such as people）, can orally, rectum, parenteral（Intravenous, intramuscular is subcutaneous）, the mode such as local be administered, wherein especially optimal with oral way.During using pharmaceutical composition, the mammal that needs are treated and/or prevented will be applied to containing treatment and/or the compound of the present invention of prevention effective dose or the pharmaceutical composition of its pharmaceutically acceptable salt（Such as people）.Term " treatment and/or prevention effective dose " refers to being enough feeding Newborn animal（Such as people）The amount of the internal biology for causing animal doctor or clinician to be sought or the reactive compound of medical response.Common doctor, animal doctor and clinician can be readily determined treatment and/or prevention specify disease needed for compound of the present invention or its pharmaceutically acceptable salt effective dose.Typically, it is daily 0. 01 ~ 200mg/kg weight in patients, preferably daily 0. 01 ~ 1 00mg/kg weight in patients, most preferably daily 0. 01 ~ 5 0mg/kg weight in patients.More particularly, for the people of 60kg body weight, day dosage be usually 0. 6mg ~ 12 g, preferably 0. 6mg ~ 6g, most preferably 0. 6mg ~ 3g.Certainly, specific dosage is also contemplated that method of administration, age, sex, body weight and the health status of patient, and the factor such as treated particular condition, within the scope of these are all skilled practitioners technical ability.Terminology used in this article " mammal " includes but is not limited to cat, dog, rabbit, goat, sheep, rat, mouse and people etc., particularly preferred people.

Described pharmaceutical composition may be formulated for the solid dosage forms being administered orally, including glue Nang agent, tablet, pill, powder and granule etc..Usually contained in solid dosage forms 0. 5 ~ 50 °/.Active component, preferably comprise 1 ~ 2 5% active component.In these solid dosage forms, the compound that provides of the present invention or its pharmaceutically acceptable salt can be with least one conventional inert excipients (or carriers）Mixing, the inert excipient（Or carrier）Including but not limited to：（A) filler or solubilizer, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；（B) adhesive, for example, hydroxymethyl cellulose, alginates, gelatin, PVP, sucrose and Arabic gum；（C) NMF, for example, glycerine；（D) disintegrant, for example, agar, calcium carbonate, farina, tapioca, alginic acid, some composition silicates, polyvinyl polypyrrole alkanone and sodium carbonate；（E) Slow solvents, such as paraffin；（F) absorbsion accelerator, for example, quaternary ammonium compound；（G) wetting agent, Li such as Whale ceryl alcohols and glycerin monostearate；（H) adsorbent, for example, kaolin；With（I) lubricant, for example, talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl sodium sulfate, or its mixture.In glue Nang agent, tablet and pill, formulation can also include Slow electuaries.

Solid dosage forms such as tablet, glue Nang agent, pill and granule can be prepared using coating and shell material, such as casing and other materials well known in the art.The release that they can include reactive compound in opacifying agent, also, this composition can discharge in certain part in a delayed fashion in alimentary canal.If necessary, reactive compound can also form micro- glue Nang forms with the one or more in above-mentioned excipient.

Described pharmaceutical composition can also be formulated as liquid formulation for oral administration, including pharmaceutically acceptable emulsion, solution, suspension or tincture etc..In addition to the compound of the invention provided or its pharmaceutically acceptable salt are as active component, liquid dosage form can be included and routinely adopted in this area Inert diluent, such as water or other solvents, solubilizer and emulsifying agent, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propane diols, 1,3- butanediols, two Yue base Yue acid amides or vegetable oil, particularly cottonseed oil, peanut oil, maize germ, olive oil, castor oil or sesame oil, or these materials mixture etc..In addition to these inert diluents, composition can also include auxiliary agent, such as wetting agent, emulsifying agent, suspending agent, sweetener, flavouring or spices, or its suitable mixture etc..

In the presence of pharmaceutical composition of the present invention is with suspension, in addition to the compound of the invention provided or its pharmaceutically acceptable salt, suspension can include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar, or these materials mixture etc..

Described pharmaceutical composition may be formulated for the formulation of parenteral injection, including physiologically acceptable sterile, aqueous or non-aqueous solution, dispersion liquid, suspension or emulsion, and for being dissolved into the aseptic powdery of sterile Injectable solution or dispersion liquid again.Aqueous or nonaqueous carrier, diluent, solvent or excipient can be used for preparing the sterile, aqueous or non-aqueous solution, dispersion liquid, suspension or emulsion.Suitable aqueous or nonaqueous carrier, diluent, solvent or excipient includes water, ethanol, polyalcohol, or its suitable mixture etc..

Described pharmaceutical composition may be formulated for the formulation of local administration, including ointment, powder, patch, propellant and inhalant.The compound or its pharmaceutically acceptable salt that the present invention is provided aseptically can be mixed together with physiologically acceptable carrier and any preservative, Slow electuaries, or the propellant that may be needed if necessary.

Described pharmaceutical composition can also include other pharmaceutically acceptable therapeutic agents, especially other hypoglycemic agents.Other described hypoglycemic agents include but is not limited to：Sulfonylurea drugs are such as tolbutamide, glibenclamide, Glipizide；Biguanides are such as insoral, two Yue biguanides, buformin, alpha-glucosidase restrainer is such as acarbose, Miglitol, voglibose；Thiazolidinediones（Th i azo l i d ined i ones, TZD) medicine is such as Rosiglitazone, Pioglitazone.On the other hand, compound of the present invention or its pharmaceutically acceptable salt or medicine of the pharmaceutical composition available for preparation for treating and/or preventing the related diseases of PPAR γ containing described compound or its pharmaceutically acceptable salt, the particularly disease related to the regulation of RXR and PPAR nuclear receptors.It is preferred that the disease is selected from diabetes, pathoglycemia rise relevant disease, lipid disorders, metabolic syndrome, angiocardiopathy, coronary artery disease, high blood cholesterol and obesity, especially diabetes and pathoglycemia rise relevant disease. A kind of agonist activity of degree, preferred evaluation method is described below：

Using reporter gene（Reporter gene) method, using the principle of genetic transcription downstream can be activated after nuclear receptor activation, a kind of screening model of screening nuclear receptor coactivator agent in living cells is devised, for verifying that compound activates PPARy activity.Experimental method is as follows：Use RT- PCR methods（Reverse transcription（RT) and cDNA polymerase chain amplification（PCR the technology) being combined）PPARy full-length cDNAs are cloned into from adipose tissue, the PCR primer of amplification is inserted into sequencing identification after expression vector pcDNA3.1.Reporter gene detects that carrier pGL3-Promoter are built with the luciferase of Promega companies.Transfection experiment is carried out with U20S cells in 96 orifice plates, cotransfection RXR and PPARy gene while reporter gene is transfected, and transfection adds compound to be detected after 24 hours, and maintains solvent DMS0 final concentration of 0.1 %.Compound effects cell lysis and carry out the detection of uciferase activity after 24 hours.Intensity of activation of the compound to nuclear receptor can be learnt by the luminous intensity of observation.In order to correct transfection efficiency, the test error that causes of the cell inoculation factor such as quantity and toxicity of compound, also cotransfection GFP plasmids are as internal reference simultaneously, and in analysis of experimental results, the luminous value of all test holes is all corrected with GFP values.Result of the test represents that the value of solvent control is 1, and value shows that more greatly activation capability is higher with relative activation multiple.In model discrimination, observe activation situation of the sample to acceptor under the conditions of 6 kinds of various concentrations, the pharmacological property of compound is more fully reacted, and digital simulation is iterated according to formula below and goes out the concentration-response curve of compound effects, and calculates corresponding effective concentration 50 (EC₅₀ ) 。

On diabetes animal model, the compound that the present invention is provided has good hypoglycemic effect, and a kind of preferred experimental evaluation method is as follows：Healthy spontaneity type ii diabetes animal model, male GK rats（Goto- Kakizaki rats）, body weight 200g, animal fasting 12 hours, blood glucose meter measure fasting blood sugar, afterwards continuous gavage administration（20 mg/kg) or comparison liquid 0.5%CMC-Na (sodium carboxymethylcelluloses）（10mL/kg), successive administration determines fasting blood sugar again after 10 days, and the hypoglycemic effect of testing compound is evaluated by comparing the fasting blood sugar before and after being administered.Another further aspect, the invention further relates to treat and/or prevent the method for the related disease of mammal PPARY acceptors, including by treat and/or prevention effective dose compound of the present invention or its pharmaceutically acceptable salt or containing compound of the present invention or its is pharmaceutically acceptable Salt pharmaceutical composition give need this treatment and/or prevention mammal, it is preferred that the disease is selected from diabetes, pathoglycemia rise relevant disease, lipid disorders, metabolic syndrome, angiocardiopathy, coronary artery disease, high blood cholesterol and obesity, especially diabetes or pathoglycemia rise relevant disease.

Compound of the present invention or its pharmaceutically acceptable salt or pharmaceutical composition containing compound of the present invention or its pharmaceutically acceptable salt can be administered alone, or be administered with other pharmaceutically acceptable therapeutic agents, particularly combined with other treating diabetes and/or prophylactic agent.The therapeutic agent includes but is not limited to：Sulfonylurea drugs are such as tolbutamide, glibenclamide, Glipizide；Biguanides are such as insoral, two Yue biguanides, buformin, (X-glucosidase inhibitor is such as acarbose, Miglitol, voglibose；Thiazolidinediones (Thiazolidinediones, TZD) medicine is such as Rosiglitazone, Pioglitazone.Main advantages of the present invention are：It the experiment proved that the compound of the invention provided has the activity of PPAR Y portion activators, compared with existing complete PPARy activators, hypoglycemic beneficial effect is remained, and reduces the side effects such as the increased weight as caused by complete PPARy activators, oedema, adipose tissue surge, bone marrow fat acid change.The present invention is expanded on further with reference to embodiment.It should be understood that these embodiments are merely to illustrate the present invention rather than limited the scope of the invention.The experimental method of unreceipted actual conditions in the following example, generally according to normal condition, or according to the condition proposed by manufacturer.The raw material used is can be commercial buying or can be easily as those skilled in the art according to made from known references method.For involved abbreviation, DMF refers to DMF, and DMS0 refers to two Yue base sulfoxides, and PVPP refers to polyvinyl polypyrrole alkanone, and PVP refers to PVP.Unless otherwise stated, parts and percentages are parts by weight and percentage by weight.Embodiment

Embodiment 1:The chloro- 1- of 2- butyl -4- { [2'- (I tetrazolium -5- bases）- 1, the stupid -4- bases of-connection] Yue yls } -5- [(4- fluorine benzyloxies）Methyl]-imidazoles

Step A:The chloro- 1- of 2- butyl -4- { [2'- (1- triphens Yue bases-tetrazolium -5- bases）- 1,1'- biphenyl -4- bases] methyl } -5- [(4- fluorine benzyloxies）Methyl]-imidazoles

By triphen Yue base Losartans（Chemistry is entitled：The chloro- 1- of 2- butyl -4- { [2'- (1- triphen Yue base tetrazolium -5- bases）- 1,1'- biphenyl -4- bases] methyl } _ 5- hydroxy methylimidazoles）（Purchased from Zhejiang sky medication chemistry Co., Ltd）665mg (lmmol) is dissolved in 10mL DMF, plus NaH (silver gray solid particle, content>60%, active hydrogen amount（Purity）>97%) 44mg, reacts at room temperature half an hour, then adds 122 μ 4- fluorobenzyl bromides（ lmmol ) .Continue to react 12h.After reaction terminates, column chromatography purifies to obtain white powder 627mg, is intermediate product through differentiating（2- butyl-4-chloro- 1- { [2'- (1- trityls-tetrazolium-5- bases）- 1,-biphenyl -4- base] Yue yls } -5- [(4- fluorine benzyloxies）Yue yls]-imidazoles）, yield 81%.

Ή-NMR (400Mz, DMS0) δ：7.61-7.49 (m, 6H), 7.46 (s, 1H), 7.46-7.39 (m, 6H), 7.39-7.35 (t, 1H), 7.33-7.27 (d, 1H), 7.25-7.21 (d, 1H), 7.11 (t, 3 Η), 6.98-6.93 (d, 2H), 6.77-6.75 (d, 2H), 6.42 (d, 2 Η), 6.23 (d, 2H), 4.99 (s, 2H), 4.72 (s, 2 Η), 4.54 (s, 2 Η), 2.52 (t, 2H), 1.72 (m, 2 Η), 1.36 (m, 2H), 0.87 (t, 3 Η).Step B:The chloro- 1- of 2- butyl -4- { [2'- (1#- tetrazolium -5- bases）- 1,1'- biphenyl -4- bases] methyl } -5- [(4- fluorine benzyloxies）Methyl]-imidazoles

Intermediate 382mg (0.495mmol) obtained by step Α is dissolved in 10mL absolute methanols, add 45mg K0H, back flow reaction 2h, be concentrated under reduced pressure removing solvent, gained residue purifies to obtain white solid 188mg through column chromatography, is titled reference compound, yield 72% through differentiating.

. p.： 153.3-155.9°C;

'H-NMR(400Mz, DMS0) δ：10.80 (s, 1H), 8.73-8.71 (d, 1H), 7.65-7.58 (t, 1H), 7.51-7.46 (t, 1H), 7.45-7.39 (d, 1H), 7.37-7.33 (dd, 2H), 7.32-7.28 (dd, 2H), 7.27-7.21 (dd, 2H), 7.02-6.57 (dd, 2H), 4.97 (s, 2H), 4.76 (s, 2H), 4.59 (s, 2H), 2.67-2.54 (t, 2H), 1.80-1.71 (m, 2H), 1.37-1.32 (m, 2H), 0.89-0.86 (t, 3H)；

ESI— MS: (M+H) =531, (M-H)"=529₀Embodiment 2：The chloro- 1- of 2-butyl-4- { [2'- tetrazolium-5- bases）- 1,-biphenyl -4- base] Yue yls } -5- [(4- bromo-benzyloxys）Methyl]-imidazoles

Step A:The chloro- 1- of 2- butyl -4- { [2'- (1- trityls-tetrazolium -5- bases）- 1 ,-biphenyl-4- base] methyl }-5- [(4-bromo-benzyloxys）Methyl] imidazoles

According to the method shown in the step A of embodiment 1, using 250mg 4- bromobenzyl bromines（Lmmol) replace 122 4-fluorobenzyl bromides of L that intermediate 2- butyl-4- chloro- 1- { [2'- U- trityls-tetrazolium-5- bases are made）- 1,1'- biphenyl -4- bases] methyl } -5- [(4- bromo-benzyloxys）Yue yls] imidazoles 550mg (light yellow oils）, 66 ° of yield/..

' Η-beautiful R (400Mz, DMS0) δ：7.64-7.59 (m, 6H), 7.57-7.51 (d, 1H), 7.46-7.39 (m, 6H), 7.45-7.37 ", 1H), 7.36-7.31 (d, 1H), 7.27-7.23 (d, 1H), 7.21-7.12 (m, 3H), 6.98-6.93 (m, 2H), 6.77-6.75 (m, 2H), 6.42 (d, 2H), 6.23 (d, 2H), 4.87 (s, 2H), 4.69 (s, 2H), 4.54 (s, 2H), 2.52 (t, 2H), 1.71 (m, 2H), 1.35 (m, 2H), 0.86 (t, 3H).Step B:The chloro- 1_ of 2- butyl -4- { [2'- tetrazolium -5- bases）- 1,1'- biphenyl -4- bases] methyl } -5- [(4- bromo-benzyloxys）Methyl]-imidazoles

Intermediate 417mg (0.507mmol) obtained by step A is dissolved in lOmL absolute methanols, add 45mg K0H, back flow reaction 2h, be concentrated under reduced pressure removing solvent, gained residue purifies to obtain buff powder 201mg through column chromatography, it is titled reference compound, yield 68% through differentiating.

M. p.： 168.5-170°C;

Ή-NMR (400Mz, DMS0) δ：10.76 (s, 1H), 8.72-8.60 (d, 1H), 7.71-7.62 (m, 1H), 7.52-7.45 (m, 1H), 7.45-7.40 (d, 1H), 7.16 (d, 2H), 7.11-7.05 (d, 2H), 7.02-6.96 (m, 2H), 6.95-6.78 (d, 2H), 4.96 (s, 2H), 4.72 (s, 2H), 4.54 (s, 2H), 2.61-2.54 (t, 2H), 1.78-1.71 (m, 2H), 1.37-1.29 (m, 2H), 0.88-0.85 (t, 3H)；

ESI- MS:(Μ+Η Γ=591, (M-H) -=589.Embodiment 3:2- butyl-4-chloro- 1- { [2'- tetrazolium-5- bases）- 1,-biphenyl -4- base] first Base } -5- [(4- methylbenzyloxies）Methyl] imidazoles

Step A:The chloro- 1- of 2- butyl -4- { [2'- (1- trityl tetrazole -5- bases）- 1, V-biphenyl -4- bases] methyl } -5- [(4- methylbenzyloxies）Methyl]-I imidazoles

According to the method shown in the step A of embodiment 1, using 169 L 4- methyl benzyl bromines（Lmmol) replace 122 μ 4- fluorobenzyl bromides that intermediate 2- butyl -4- chloro- 1- { [2'- (1- trityls-tetrazolium -5- bases are made）- 1,1'- biphenyl -4- bases] Yue yls } -5- [(4- methylbenzyloxies）Yue yls]-imidazoles 415mg (white powders）, yield 54%.

'H-NMR(400Mz, DMS0) δ：7.79-7.66 (m, 6H), 7.61 (s, 1H), 7.59-7.44 (m, 6H), 7.39-7.33 (t, 1H), 7.31-7.27 (d, 1H), 7.24-7.21 (d, 1H), 7.19-7.11 (m, 3H), 6.98-6.93 (d, 2H), 6.77-6.75 (d, 2H), 6.42 (d, 2H), 6.23 (d, 2H), 4.99 (s, 2H), 4.72 (s, 2H), 4.54 (s, 2H), 2.54-2.51 (t, 2H), 2.15 (s, 3H), 1.75-1.68 (m, 2H), 1.41-1.32 (m, 2H), 0.88-0.85 (t, 3H).Step B:The chloro- 1- of 2- butyl -4- { [2'- tetrazolium -5- bases）- 1,-biphenyl -4- base] methyl } -5- [(4- Yue base benzyloxies）Methyl]-imidazoles

Intermediate 385mg (0.501mmol) obtained by step A is dissolved in the anhydrous Yue alcohol of 10mL, add 45mg K0H, back flow reaction 2h, be concentrated under reduced pressure removing solvent, gained residue purifies to obtain white solid 195mg through column chromatography, it is titled reference compound, yield 74% through differentiating.

. p.： 127.3°C;

Ή-NMR (400Mz, DMS0) δ：10.45 (s, 1H), 8.67-8.61 (d, 1H), 7.64-7.58 (t, 1H), 7.53-7.48 (m, 3H), 7.42-7.37 (dd, 1H), 7.34-7.29 (dd, 2H), 7.26-7.21 (dd, 2H), 7.06-6.95 (dd, 2H), 4.97 (s, 2H), 4.91 (s, 2H), 4.54 (s, 2H), 2.54 (t, 2H), 2.15 (s, 3H), 1.78-1.71 (m, 2H), 1.36-1.32 (m, 2H), 0.87-0.85 (t, 3H)；

ESI— MS: ( +H)⁺=527, (M—H)—=525。 Embodiment 4:The chloro- 1- of 2- butyl -4- { [2'- tetrazolium -5- bases）- 1,1'- biphenyl -4- bases] Yue yls } -5- [(4- trifluoromethyl benzyloxies）Yue yls]-imidazoles

Step Α:The chloro- 1- of 2- butyl -4- [2'- (1- trityls -;^- tetrazolium -5- bases）- 1, Γ-biphenyl -4- bases] Yue yls } -5_ [(4- trifluoromethyl benzyloxies）Methyl] imidazoles

According to the method shown in the step Α of embodiment 1, replace 122 4-fluorobenzyl bromides of μ that the chloro- 1- of intermediate 2- butyl-4- { [2'- (1- triphen Yue bases-1#-tetrazolium _ 5_ bases are made using 264mg 4- trifluoromethyl benzyls bromines (1. Immol)）- 1, Γ-biphenyl -4- bases] methyl } -5- [(4- trifluoro Yue base benzyloxies）Methyl] -1 〃-imidazoles 617mg (white powders）, yield 75%.

'H-NMR(400 z, DMS0) δ：7.91-7.79 (m, 6H), (the d of 7.73- 7.67, 1H), 7.64-7.47 (m, 6H), 7.45-7.41 (d, 2H), 7.38-7.32 (t, 1H), 7.25-7.21 (d, 1H), 7.14-7.05 (d, 1H), 6.98-6.91 (m, 3H), 6.79-6, 72 (d, 2H), 6.46 (d, 2H), 6.25 (d, 2H), 5.02 (s, 2H), 4.78 (s, 2H), 4.51 (s, 2H), .2.57-2.54 (t, 2H), 1.71-1.64 (m, 2H), 1.41-1.32 (m, 2H), 0.88-0.85 (t, 3H).Step B:The chloro- 1- of 2- butyl -4- { [2'- tetrazolium -5- bases）- 1,1'- biphenyl -4- bases] Yue yls } -5- [(4- trifluoromethyl benzyloxies）Yue yls]-imidazoles

Intermediate 412mg (0.501mmol) obtained by step A is dissolved in 10mL absolute methanols, add 45mg K0H, back flow reaction 2h, be concentrated under reduced pressure removing solvent, gained residue purifies to obtain white solid 195mg through column chromatography, it is titled reference compound, yield 67% through differentiating.

M. p.： 140.6-141.4°C;

Ή-NMR (400Mz, DMS0) δ：10.65 (s, 1H), 8.79-8.71 (d, 1 Η), 7.68-7.54 (t, 1H), 7.55-7.45 (m, 3H), 7.43-7.39 (d, 1H), 7.36-7.29 (dd, 2H), 7.28-7.21 (dd, 2H), 7.12-6.95 (dd, 2H), 4.96 (s, 2H), 4.76 (s, 2H), 4.59 (s, 2H), 2.67-2.54 (t, 2H), 1.80-1.71 (m, 2H), 1.37-1.32 (m, 2H), 0.87-0.85 (t, 3H)；

ESI-MS: (M+H)⁺=581, (M—H)—=579。 Embodiment 5:The chloro- 1- of 2- butyl -4- { [2'- tetrazolium -5- bases）- 1,-biphenyl -4- base] Yue yls } -5- [(4- cyano benzyloxies）Methyl]-imidazoles

Step Α:The chloro- 1- of 2- butyl -4- { [2'- (1- trityls-tetrazolium -5- bases）- 1, Γ-biphenyl -4- bases] Yue yls } -5_ [(4- cyano benzyloxies）Methyl]-imidazoles

According to the method shown in the step Α of embodiment 1, using 196mg 4- cyano group benzyl bromines（Lmmol) replace 122 μ 4- fluorobenzyl bromides that the chloro- 1- of intermediate 2- butyl -4- { [2'- (- 1 〃 of 1- trityls-tetrazolium -5- bases are made）- 1,1'- biphenyl -4- bases] methyl } -5- [(4_ cyano benzyloxies）Methyl] -1 ^ imidazoles 491mg (off-white powders）, yield 63%.

' Η-gangster R (400Mz, DMS0) δ：7.81-7.65 (m, 6H), (the d of 7.67- 7.56, 1H), 7.54-7.41 (m, 6H), 7.36-7.28 (t, 1H), 7.25-7.21 (d, 2H), 7.19-7.16 (t, 1H), 7.14-7.05 (d, 1H), 6.98-6.91 (m, 3H), 6.79-6.72 (d, 2H), 6.46-6.37 (d, 2H), 6.25-6.17 (d, 2H), 5.02 (s, 2H), 4.78 (s, 2H), 4.51 (s, 2H), 2.57-2.54 (t, 2H), 1.71-1.64 (m, 2H), 1.41-1.32 (m, 2H), 0.91-0.87 (t, 3H).Step B:The chloro- 1- of 2- butyl -4- { [2'- tetrazoliums _ 5- bases）- 1,1'- biphenyl -4- bases] methyl } _ 5_ [(4- cyano benzyloxies）Methyl]-imidazoles

Intermediate 390mg (0.500mmol) obtained by step A is dissolved in the anhydrous Yue alcohol of 10mL, add 45mg K0H, back flow reaction 2h, be concentrated under reduced pressure removing solvent, gained residue purifies to obtain Off-white solid 207mg through column chromatography, it is titled reference compound, yield 77% through differentiating.

M. ρ·： 142.3-143.8°C;

Ή-NMR (400 z, D S0) δ：10.58 (s, 1H), 8.72-8.69 (d, 1H), 7.65-7.54 (t, 1H), 7.52-7.45 (m, 3H), 7.44-7.39 (d, 1H), 7.35-7.29 (d, 2H), 7.27-7.21 (d, 2H), 7.02-6.95 (d, 2H), 4.99 (s, 2H), 4.76 (s, 2H), 4.59 (s, 2H), 2.67-2.54 (s, 2H), 1.80-1.71 (m, 2H), 1.37-1.32 (m, 2H), 0.91-0.87 (t, 3H)；

ESI- MS: (M+H)⁺=538, (M- H) 536。 Embodiment 6:The chloro- 1- of 2- butyl -4- { [2'- tetrazolium -5_ bases）- 1, _ biphenyl -4- base] Yue yls } -5- [(3- fluorine benzyloxies）Methyl]-imidazoles

Step Α:The chloro- 1- of 2- butyl -4- { [2'- (1- trityls-tetrazolium -5- bases）- 1, V-biphenyl-4- bases] methyl }-5- [(3-fluorine benzyloxies）Methyl] imidazoles

According to the method shown in the step Α of embodiment 1, using 122 μ 3- fluorobenzyl bromides（Lmmol) replace 122 L 4- fluorobenzyl bromides that intermediate 2- butyl -4- chloro- 1- { [2'- (1- triphen Yue base tetrazolium -5- bases are made）- 1,1'- biphenyl -4- bases] methyl } -5_ [(3- fluorine benzyloxies）Yue yls] -1#- imidazoles 620mg (white powders）, 80 ° of yield/..

Ή-N R (400Mz, CDC1₃) δ：7.94 (m, 1H), 7.52-7.46 (m, 2H), 7.36-7.30 (m, 4H), 7.28-7.21 (m, 8H), 7.09 (d, 2H), 7.00-6.89 (m, 8H), 6.70 (d, 2H), 5.04 (s, 2H), 4.35 (s, 2H), 4.21 (s, 2H), 2.48 (t, 2H), 1.70-1.61 (m, 2H), 1.36-1.20 (m, 2H), 0.85 (t, 3H).Step B:The chloro- 1- of 2- butyl -4- { [2'- (1#- tetrazolium -5- bases）- 1,1'- biphenyl -4- bases] methyl } -5- [(3- fluorine benzyloxies）Methyl] imidazoles

Intermediate 386mg (0.500mmol) obtained by step Α is dissolved in 10mL absolute methanols, add 45mg K0H, back flow reaction 2h, be concentrated under reduced pressure removing solvent, gained residue purifies to obtain white solid 180mg through column chromatography, it is titled reference compound, yield 68% through differentiating.

Ή-NMR (400 z, CDC1₃) δ：7.87 (d, 1H), 7.63-7.50 (m, 2H), 7.37 (d, 1H), 7.26-7.19 (m, 1H), 7.02 (d, 2H), 6.98-6.85 (m, 3H), 6.71 (d, 2H), 5.08 (s, 2H), 4.39 (s, 2H), 4.21 (s, 2H), 2.29 (t, 2H), 1.59-1.40 (m, 2H), 1.30-1.18 (m, 2H), 0.82 (t, 3H).Embodiment 7:The chloro- 1- of 2- butyl -4- { [2'- tetrazolium -5- bases）- 1,1'- biphenyl -4- bases] Yue yls } -5- [(3- trifluoromethyl benzyloxies）Methyl] imidazoles

Step A:The chloro- 1_ of 2- butyl -4- { [2'- (1- trityls-tetrazolium -5- bases）- 1, V-biphenyl -4- bases] Yue yls } -5- [(3- trifluoro Yue base benzyloxies）Methyl]-imidazoles

According to the method shown in the step A of embodiment 1, replace 122 4-fluorobenzyl bromides of μ Ι that 2-butyl of intermediate-4- chloro- 1- { [2'- (1- trityls-tetrazolium-5- bases are made using 264mg 3- trifluoromethyl benzyls bromines (1. Immol)）- 1,1'- biphenyl -4- bases] Yue yls } -5- [(3- trifluoro Yue base benzyloxies）Methyl]-imidazoles 594mg (white powders）, yield 71%.

' Η-beautiful R (400Mz, DMS0) δ：7.95-7.85 (m, 6H), 7.84-7.78 (t, 1H), 7.77-7.68 (m, 6 Η), 7.64-7.59 (t, 1H), 7.57-7.54 (d, 1H), 7.53-7.48 (t, 1H), 7.47-7.43 (t, 1H), 7.42-7.40 (d, 1H), 7.38-7.33 (d, 1H), 7.31-7.27 (t, 3H), 7.25-7.17 (d, 2H), 6.96-6.91 (d, 2H), 5.02 (s, 2H), 4.72 (s, 2H), 4.51 (s, 2H), 2.57-2.54 (d, 2H), 1.71-1.64 (m, 2H), 1.41-1.32 (m, 2H), 0.90-0.87 (t, 3H).Step B:The chloro- 1- of 2- butyl -4- { [2'- tetrazolium -5- bases）- 1,1'- biphenyl -4- bases] methyl } -5_ [(3- trifluoromethyl benzyloxies）Methyl] imidazoles

Intermediate 412mg (0. SOlmmol) obtained by step A is dissolved in 10mL absolute methanols, add 45mg K0H, back flow reaction 2h, be concentrated under reduced pressure removing solvent, gained residue purifies to obtain white solid 227mg through column chromatography, it is titled reference compound, yield 78% through differentiating.

M. p.： 128.3-129.3°C;

H-N R (400Mz, DMS0) δ：：10. 56 (s, 1 Η), 8.56 (s, 1H), 7.95

(s, 1H), 7.72-7.63 (d, 1H) 7., 62-7.56 (t, 1H), 7.54--7.48

(d, 1H), 7.51-7.46 (t, 1H) 7 .44-7.41 (d, 1H), 7.39--7.35

( t, 1H) , 7.34-7.30 ( d, 1H) 7. .28 -7.22 ( d, 2H ) , 7.07- -6.95

(d, 2H), 4.96 (s, 2H), 4. 72 (s, 2H), 4.54 (s, 2H), 2.57

(t, 2H), 1.74-1.68 (m, 2H), 1., 5-1.36 (m, 2H), 0.90--0.87

, 3H ) ;

ESI-MS: (M+H)⁺=581, (M- H)— =579。 Embodiment 8:The chloro- 1- of 2- butyl -4- { [2'- tetrazolium -5- bases）- 1, biphenyl -4- base] methyl } _ 5- [(2,5- difluoro benzyloxies）Yue yls]-imidazoles

Step Α:The chloro- 1- of 2- butyl -4- { [2'- (1- trityls-tetrazolium -5- bases）- 1,1'- join stupid -4- bases] methyl } -5- [(2,5- difluoro benzyloxies）Methyl]-imidazoles

According to the method shown in the step Α of embodiment 1, using 206mg 2, the fluorobenzyl bromides of 5- bis-（Lmmol) replace 122 L 4- fluorobenzyl bromides that intermediate 2- butyl -4- chloro- 1- { [2'- (1- trityl tetrazole -5- bases are made）- 1,1'- biphenyl -4- bases] methyl } -5- [(2,5- difluoro benzyloxies）Methyl] -1 〃-imidazoles 441mg (white powders）, 56 ° of yield/..

'H-NMR(400 z, DMS0) δ：7.90-7.79 (m, 6H), (the t of 7.73- 7.68, 1H), 7.65-7.59 (m, 6 Η), 7.57-7.52 (t, 1H), 7.51-7.46 (d, 1H), 7.43-7.40 (d, 1H), 7.37-7.34 (t, 3H), 7.27-7.21 (d, 1H), 7.11-7.04 (d, 2H), 7.02-6.96 (d, 2H), 6.84-6.82 (d, 1H), 6.81 (s, 1H), 4.99 (s, 2H), 4.72 (s, 2H), 4.51 (s, 2H), 2.57-2.54 (t, 2H), 1.71-1.64 (m, 2H), 1.41-1.32 (m, 2H), 0.90-0.87 (t, 3H).Step B:The chloro- 1- of 2- butyl -4- { [2'- tetrazolium -5- bases）- 1,-biphenyl -4- base] methyl } -5- [(2,5- difluoro benzyloxies）Yue yls]-1-imidazoles

Intermediate 396mg (0.501mmol) obtained by step A is dissolved in 10mL absolute methanols, add 45mg K0H, back flow reaction 2h, be concentrated under reduced pressure removing solvent, gained residue purifies to obtain white solid 168mg through column chromatography, it is titled reference compound, yield 61% through differentiating.

M. p.： 168.5-170°C;

' Η-leg (400Mz, DMS0) δ：8.56 (s, 1H), 7.72-7.64 (d, 1 Η), 7.62-7.56 (t, 1H), 7.45-7.39 (d, 1H), 7.36-7.27 (d, 1H), 7 22-7.15 (d, 2H), 7.12-7.05 (d, 2H), 6.95-6.87 (d, 1H), 6.81 (s, 1H), 4.99 (s, 2H), 4.72 (s, 2H), 4.60 (s, 2H), 2.57-2.54 (t, 2H), 1.71-1.64 (m, 2H), 1.41-1.32 (m, 2H), 0.90-0.87 (t, 3H)； ESI-MS: (Μ+ΗΓ-549, (M—H)— =547. Embodiment 9:The chloro- 1- of 2- butyl -4- { [2'- (1#- tetrazolium -5- bases）- 1,-biphenyl -4- base] methyl } -5- { [2,5- bis-（Trifluoromethyl）Benzyloxy] Yue yls }-imidazoles

Step Α:The chloro- 1- of 2- butyl -4- { [2'- (1- trityls-tetrazolium -5- bases）- 1, Γ-biphenyl -4- bases] Yue yls } -5- { [2,5- bis-（Trifluoromethyl）Benzyloxy] Yue yls }-imidazoles

According to the method shown in the step Α of embodiment 1, using 307mg 2,5- bis-（Trifluoromethyl）Benzyl bromine（1 Hidden ol) replace 122 4-fluorobenzyl bromides of L that-4-chlorine of intermediate 2- butyl _ 1_ { [2'- (1- trityls-tetrazolium-5- bases are made）- 1,1'- xenyl _ 4-yl] methyl }-5- { [2,5- bis-（Trifluoromethyl）Benzyloxy] Yue yls }-imidazoles 454mg (white powders）, yield 51%.

Ή-N R (400Mz, D S0) δ：8.10 ", 1H), (the d of 7.87- 7.81, 1H), 7.79-7.75 (d, 1H), 7.73-7.69 (m, 6H), 7.67-7.63 (d, 1H), 7.62-7.53 (m, 6 Η), 7.50-7.44 (t, 1 Η), 7.42-7.39 (d, 1H), 7.37-7.31 (d, 1H), 7.29-7.17 (m, 3H), 6.96-6.91 (d, 2H), 6.72-6.66 (d, 2H), 4.98 (s, 2H), 4.72 (s, 2H), 4.51 (s, 2H), 2.57-2.54 (t, 2H), 1.71-1.64 (m, 2H), 1.41-1.32 (m, 2H), 0.90-0.87 (t, 3H).Step B:The chloro- 1_ of 2- butyl -4- { [2'- (1#- tetrazolium -5- bases）- 1,1'- biphenyl -4- bases] methyl } -5- { [2,5- bis-（Trifluoromethyl）Benzyloxy] methyl } -1 〃-imidazoles

Intermediate 325mg (0.501mmol) obtained by step A is dissolved in the anhydrous Yue alcohol of 10mL, add 45mg K0H, back flow reaction 2h, be concentrated under reduced pressure removing solvent, gained residue purifies to obtain white solid 224mg through column chromatography, it is titled reference compound, yield 69% through differentiating.

M. p.： 118.6—120.4°C;

Ή-NMR (400 z, DMS0) δ：8.63 (s, 1H), 8.31 (s, 1H), 7.79-7.77 (d, 1H), 7.74-7.69 (d, 1H), 7.67-7.59 (d, 1H), 7.55-7.52 (t, 1H), 7.51-7.46 (d, 1H), 7.44-7.39 (d, 1H), 7.34-7.26 (t, 2H), 7.22-7.05 (m, 2H), 5.01 (s, 2H), 4.72 (s, 2H) 4.69 ", 2H), 2.54-2.37 (t, 2H), 1.71-1.64 (m, 2H), 1.41-1.32 (m, 2H), 0.90-0.87 (t, 3H)；

ESI— MS: ( +H) ⁺=649, (Μ—ΗΓ=647.Embodiment 10:PPAR Y agonist activities are determined

With RT- PCR methods（Reverse transcription（RT) and cDNA polymerase chain amplification（PCR the technology) being combined）PPAR Y full-length cDNAs are cloned into from adipose tissue, the PCR primer of amplification is inserted into sequencing identification after expression vector pcDNA3.1.Reporter gene detects that carrier pGL3-Promoter are built with the luciferase of Promega companies.Transfection experiment is carried out with U20S cells in 96 orifice plates, cotransfection RXR and PPARy gene while reporter gene is transfected, and transfection adds compound to be detected after 24 hours, and maintains solvent DMS0 final concentration of 0.1 %.Compound effects cell lysis and carry out the detection of uciferase activity after 24 hours.Intensity of activation of the compound to nuclear receptor can be learnt by the luminous intensity of observation.In order to correct transfection efficiency, the test error that causes of the cell inoculation factor such as quantity and toxicity of compound, also cotransfection GFP plasmids are as internal reference simultaneously, and in analysis of experimental results, the luminous value of all test holes is all corrected with GFP values.Result of the test represents that the value of solvent control is 1, and value shows that more greatly activation capability is higher with relative activation multiple.In model discrimination, observe activation situation of the sample to acceptor under the conditions of 6 kinds of various concentrations, the pharmacological property of compound has more fully been reacted, and digital simulation is iterated according to formula below and has gone out the concentration-response curve of compound effects, and has calculated corresponding effective concentration 50（EC₅.）. b

= « + - c + e

Concrete outcome refers to following table:

It is above-mentioned test result indicates that, under identical concentration, the activation multiple measured by 1-9 of embodiment of the present invention compound is respectively less than Rosiglitazone.Therefore, learnt from above-mentioned experimental result, compared with complete PPAR Y agonist rosiglitazones, 1-9 couple of PPAR y of compound of embodiment of the present invention agonist activity is weaker, is PPAR y partial agonist.Embodiment 11:To the antagonism of the PPAR y agonist activities of full agonist Rosiglitazone

With RT-PCR methods（Reverse transcription（RT) and cDNA polymerase chain amplification（PCR the technology) being combined）PPAR y full-length cDNAs are cloned into from adipose tissue, the PCR primer of amplification is inserted into sequencing identification after expression vector pcDNA3. 1.Reporter gene detects that carrier GL3-Promoter are built with the luciferase of Promega companies.Transfection experiment is carried out with U20S cells in 96 orifice plates, cotransfection RXR and PPAR γ genes while reporter gene is transfected, after transfecting 24 hours, random packet：One group is not added with compound as solvent blank control group, one group adds Ι Ο μ Μ Rosiglitazone as positive controls, other are respectively plus 0.001 μ Μ, 0. 01 μ Μ, 0. 1 μ Μ, 1 μ Μ, 5 μ Μ or the compound to be detected of 10 μ Μ concentration and 1. 0 μ Μ Rosiglitazone maintain each group solvent DMS0 final concentration of 0. 1 % as detection group.Cell lysis and the detection of uciferase activity is carried out after above each group is acted on 24 hours.Intensity of activation of the above each group to nuclear receptor can be learnt by the luminous intensity of observation.And then release power of the testing compound to the antagonism of the PPAR y agonist activities of full agonist Rosiglitazone.In order to correct transfection efficiency, the test error that causes of the cell inoculation factor such as quantity and toxicity of compound, also cotransfection GFP plasmids are as internal reference simultaneously, and in analysis of experimental results, the luminous value of all test holes is all used GFP values are corrected.Result of the test represents that the value of solvent control is 1, and value shows that more greatly activation capability is higher, and testing compound is weaker to the antagonism of the PPAR γ agonist activities of full agonist Rosiglitazone with relative activation multiple.Test result indicates that, add 1. Ο μ Μ Rosiglitazones and 0 001 μ Μ, the μ Μ of 0.01 μ Μ 0.1, 1 μ Μ, relative activation multiple measured by the compound of the embodiment 1 ~ 9 of 5 μ Μ or 10 six concentration of μ Μ is respectively less than 1 with only adding the ratio of the relative activation multiple measured by 1.0 μ Μ Rosiglitazones, this shows the compound of embodiment 1 ~ 9 in 0.001 μ Μ, the μ Μ of 0.01 μ 0.1, 1 μ Μ, there is antagonism to the PPAR γ agonist activities of full agonist Rosiglitazone under six concentration of 5 μ Μ and 10 μ Μ.

It is above-mentioned test result indicates that compound of the invention has antagonism to the PPAR γ agonist activities of complete PPAR gamma agonists Rosiglitazone.Embodiment 12:Hypoglycemic effect experiment

Healthy spontaneity type ii diabetes animal model, male GK rats（Goto- Kakizaki rats）, body weight 200g, animal fasting 12 hours, blood glucose meter measure fasting blood sugar, random packet, continuous gavage gives embodiment compound respectively（20 mg/kg), Rosiglitazone（20 mg/kg) or comparison liquid 0.5%CMC-Na (sodium carboxymethylcelluloses）（10mL/kg), successive administration determines fasting blood sugar again after 10 days.

Compare the blood glucose value before and after being administered and understand that the compound of embodiment 1 ~ 9 has the hypoglycemic effect suitable with positive control drug Rosiglitazone.Embodiment 13:Long term administration increased weight is tested Healthy spontaneity type ii diabetes animal model, male GK rats（Goto-Kakizaki rats）, body weight 200g, packet, continuously gives the feed containing embodiment compound 3,4,7 or Rosiglitazone respectively at random（20 mg/kg/ days）, to give normal Feeding material group as control, successive administration observes increased weight situation after 40 days.Experimental result：Blank control group the weight of animals increases by 23.2%;It is respectively 26. Vk, 26.2%, 25.5% to give the feed group body weight increase of embodiment compound 3,4,7, and sign, outward appearance, behavior, activity, excrement shape no abnormality seen, similar to blank control group；The feed group body weight increase for giving Rosiglitazone is 38.7%.Show that the long term administration of embodiment compound 3,4,7 influences smaller to increased weight, long term toxicity is low, is administered safe.Embodiment 14:Pharmaceutical composition

The glue Nang of compound containing embodiment 3 is prepared by following components：

Compound 3

Starch

Lactose

PVP

PVPP

Talcum powder

Lauryl sodium sulfate

According to a conventional method, compound 3 is mixed into sieving with starch, then after being well mixed with above-mentioned other components, loads common gelatin glue Nang, obtain 1000 glue Nang.

By similar approach, the glue Nang of the compound containing other embodiment can be made respectively.Embodiment 15:Pharmaceutical composition

The tablet of compound containing embodiment 3 is prepared by following components：

The 15g of compound 3

Starch 15g

Lactose 30g

PVP 2.5g

PVPP 2.5g

Talcum powder 1.5g

Lauryl sodium sulfate 4g

According to a conventional method, compound 3 was mixed with starch, then mixed with above-mentioned other components After uniform, direct tablet compressing obtains 1 000 tablets.

By similar approach, the tablet of the compound containing other embodiment can be made respectively.All documents that the present invention is referred to all are incorporated as reference in this application, are individually recited just as each document as with reference to such.In addition, it is to be understood that after the above-mentioned instruction content of the present invention has been read, those skilled in the art can make various changes or modifications to the present invention, and these equivalent form of values equally fall within the application appended claims limited range.

Claims

General structure（I compound shown in):

Or its pharmaceutically acceptable salt,

Wherein, ^ is selected from halogen, c ,-c₄What alkyl, halogen replaced（:The alkyl of ,-(4, c ,-c₄The wide C of alkoxy, C, cycloalkyl, hydroxyl, cyano group, d- c₄Alkoxy carbonyl group, aromatic rings and containing at least one be selected from N, S and 0 heteroatomic hetero-aromatic ring；With

N=1 ~ 5, and be integer.

2. compound as claimed in claim 1, wherein R, selected from halogen, C ,-C alkyl, the d- C of halogen substitution₄Alkyl and cyano group.

3. compound as claimed in claim 1 or 2, wherein n=1 or 2.

4. compound as claimed in claim 3, wherein n=l, and 1, it is 3 or 4 bit substituents.

5. compound as claimed in claim 4, wherein ^ are 4 bit substituents.

6. compound as claimed in claim 3, wherein n=2, and！, it is 2 and 5 bit substituents.

7. compound as claimed in claim 6, wherein R, selected from halogen, C ,-C₄Alkyl and the d- C of halogen substitution₄Alkyl.

8. the compound as described in claim 1, wherein the compound is the compound being selected from the group：

1) the chloro- 1- of 2- butyl-4- { [2'--5-bases of tetrazolium）- 1,1'- biphenyl -4- bases] methyl } -5- [(4- fluorine benzyloxies）Yue yls]-imidazoles；

2) the chloro- 1- of 2- butyl -4- { [2'- tetrazolium -5- bases）Stupid -4- the bases of -1, Γ-connection] Yue yls } -5- [(4- bromo-benzyloxys）Yue yls] imidazoles；

3) the chloro- 1- of 2- butyl -4- { [2'- tetrazolium -5_ bases）- 1, Γ-biphenyl -4- bases] methyl } -5- [(4- methylbenzyloxies）Methyl]-imidazoles；

4) the chloro- 1- of 2- butyl -4- { [2'- (1 〃-tetrazolium -5- bases）- 1,1'_ biphenyl -4- bases] Yue Base } -5- [(4- trifluoro Yue base benzyloxies）Yue yls] -1 〃-imidazoles；

5) the chloro- 1- of 2- butyl -4- { [2'- tetrazolium -5- bases）Biphenyl -4- bases] methyl } -5- [(4- cyano benzyloxies）Yue yls]-imidazoles;

6) the chloro- 1- of 2- butyl -4- { [2'- (1 〃-tetrazolium -5- bases）- 1,1 biphenyl -4- bases] methyl } -5- [(3- fluorine benzyloxies）Methyl]-imidazoles；

7) 2- butyl-4-chloro- 1- { [2'- tetrazolium-5- bases）Biphenyl -4- bases] Yue yls } -5- [(3- trifluoromethyl benzyloxies）Methyl]-lyy- imidazoles；

8) the chloro- 1- of 2- butyl -4- { [2'- (1 〃-tetrazolium -5- bases）- biphenyl -4- bases] methyl } -5- [(2,5- difluoro benzyloxies）Methyl] -1#- imidazoles；With

9) the chloro- 1_ of 2- butyl-4- { [2'- (1-tetrazolium-5- bases）- biphenyl -4- bases] methyl } -5- [2,⁵_ bis-（Trifluoromethyl）Benzyloxy] methyl }-imidazoles.

9. a kind of method for preparing compound any one of claim 1-8, including step： A ) ：By trityl Losartan（III) it is dissolved in solvent, it is in the presence of a base, and corresponding

、 B) ：By gained intermediate (ν) ' ^ in solvent ', in the presence of a base, heating deprotection base obtain target compound（I);

And optional step C)：Base addition salts are formed by gained compound and suitable inorganic acid or organic acid formation acid-addition salts or with suitable inorganic base or organic base.

10. a kind of pharmaceutical composition, described pharmaceutical composition includes the compound or its pharmaceutically acceptable salt and pharmaceutically acceptable carrier any one of claim 1 to 8.

11. the pharmaceutical composition as described in claim 10, it is also comprising other one or more hypoglycemic agents.

12. the pharmaceutical composition as described in claim 11, other wherein described hypoglycemic agents be selected from sulfonylurea drugs, biguanides, alpha-glucosidase restrainer and diones medicine, other preferably described hypoglycemic agents be selected from tolbutamide, glibenclamide, Glipizide, insoral, Two Yue biguanides, buformin, acarbose, Miglitol, voglibose, Rosiglitazone and Pioglitazone.

13. the pharmaceutical composition as described in claim 10, wherein described pharmaceutical composition is that the content of compound any one of claim 1 to 8 or its pharmaceutically acceptable salt is 0.6mg-12g, preferably 0.6mg- 6g, more preferably 0.6mg- 3g unit dose medicine.

14. the pharmaceutical composition as any one of claim 10 to 13, wherein described pharmaceutical composition are oral formulations, rectally preparation, parenteral formulations or local administration preparation.

15. the pharmaceutical composition any one of compound or its pharmaceutically acceptable salt or claim 10 to 13 as any one of claim 1-8 is preparing the application in being used to treat and/or preventing the medicine of the related disease of PPAR γ acceptors.

16. the application as described in claim 15, wherein the disease is selected from diabetes, pathoglycemia rise relevant disease, lipid disorders, metabolic syndrome, angiocardiopathy, coronary artery disease, high blood cholesterol and obesity.

17. the application as described in claim 16, wherein the disease is diabetes or pathoglycemia rise relevant disease.

18.-kind for the treatment of and/or the method for the related disease of prevention mammal PPAR γ acceptors, including will treat and/or the claim 1-8 of prevention effective dose in any described compound or its pharmaceutically acceptable salt or the pharmaceutical composition any one of claim 10 to 13 give the mammals of needs.

19. the method as described in claim 18, wherein the disease be selected from diabetes ', pathoglycemia rise relevant disease, lipid disorders, metabolic syndrome, angiocardiopathy, coronary artery disease, high blood cholesterol and obesity.

20. the method as described in claim 19, wherein the disease is diabetes or pathoglycemia rise relevant disease.

21. the method as any one of claim 18 to 20, wherein further comprising the mammal that the compound or its salt any one of other hypoglycemic drugs and claim 1 to 8 or the pharmaceutical composition any one of claim 10 to 13 are simultaneously or sequentially given to needs.