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CN1308618A - Oxazoaryl-carboxylic acids for the treatment of insulin resistance and hyperglycemia - Google Patents

Oxazoaryl-carboxylic acids for the treatment of insulin resistance and hyperglycemia Download PDF

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CN1308618A
CN1308618A CN99808363A CN99808363A CN1308618A CN 1308618 A CN1308618 A CN 1308618A CN 99808363 A CN99808363 A CN 99808363A CN 99808363 A CN99808363 A CN 99808363A CN 1308618 A CN1308618 A CN 1308618A
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carbon atoms
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phenyl
trifluoromethyl
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M·S·马拉马斯
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Wyeth LLC
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

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Abstract

The present invention provides compounds of formula OR a pharmaceutically acceptable salt thereof, wherein R is (a) OR (b) and A is OR, useful for the treatment of metabolic disorders associated with insulin resistance OR hyperglycemia5Or (c) R1Is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, thienyl, furyl, pyridyl, or (e)2Is hydrogen, alkyl of 1-6 carbon atoms, or aryl of 6-10 carbon atoms, R3And R4Independently halogen, hydrogen, alkyl of 1 to 12 carbon atoms, aryl of 6 to 10 carbon atoms, halogen, trifluoromethyl of 1 to 6 carbon atoms, alkoxyaryl of 7 to 14 carbon atoms, nitro, amino, alkoxycarbonyl, urea, carbamate, urea, alkylsulfonamide, -NR7(CH2)mCO2H. Arylsulfonamides, cycloalkyl of 3 to 8 carbon atoms, or heterocycles of 5 to 7 atomic rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur, R5Is hydrogen, alkyl of 1-6 carbon atoms, -CH 8)R9、－C(CH2)nCO2R10、－C(CH3)2CO2R10、－CH(R8)(CH2)nCO2R10、－CH(R8)C6H4CO2R10or-CH2-tetrazole, R6Is hydrogen, alkyl of 1 to 6 carbon atoms, halogen, alkoxy of 1 to 6 carbon atoms, trifluoroalkyl of 1 to 6 carbon atoms or trifluoroalkoxy of 1 to 6 carbon atoms.

Description

Be used for the treatment of insulin resistance and hyperglycemia De oxazole-aryl-carboxylic acid
Background of invention
People recognize that for a long time ubiquity insulin resistance in the patient of glucose intolerance.(American Journal of Medicine 1976 such as Reaven, 60,80) use to continue infusion glucose and Regular Insulin (Regular Insulin/glucose lock shape (clamp) technology) and oral glucose tolerance test confirmation, insulin resistance is present in not among non-obesity on the same group, the non-ketoacidosis patient.These patients' scope is from the extremely tangible fasting hyperglycemia of critical (borderline) glucose tolerance.In these researchs, diabetic groups comprises insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) two class patients.
Consistent with lasting insulin resistance is the hyperinsulinemia that is easier to measure, and this can measure by the circulation blood insulin concentration in the accurate mensuration patient blood plasma.Hyperinsulinemia can occur as the result of insulin resistance, for example, in the patient of obesity and/or diabetes (NIDDM) patient and/or glucose intolerance, perhaps in IDDM patient, occur as result with the excessive insulin injection of comparing through the hormone normal physiological release of endocrine pancreas.
(sum up by a large amount of experiments, clinical and epidemiological study by Stout, Metabolism, 1985,34,7 and by Pyorala etc., Diabetes/Metabolism Reviews1987,3,463 sum up in more detail), established well hyperinsulinemia and obesity and with the contact of the ischemic disease (for example atherosclerosis) of great vessels.In 1 to 2 hour, significance raises relevant with the risk of coronary heart disease increase on the statistics of plasma insulin after the oral glucose lifting capacity.
Because in fact most these researchs get rid of the diabetic subject, the data that the risk of atheromatosis is relevant with diabetic symptom are not a lot, but demonstrate the identical trend (Pyorala etc.) with the ND.Yet in diabetic population, the sickness rate of the atheromatosis on M ﹠ M statistics surpasses ND crowd (Pyorala etc., Jarrett Diabetes/Metabolism Reviews 1989,5,547; Harris etc., from the mortality ratio of diabetes, Diabetes in America 1985).
The independent risk factors of atheromatosis are fat also relevant with insulin resistance with hypertension.Use Regular Insulin/glucose clamp connexion method, tracer glucose infusion and indirect heat assay method, the insulin resistance that has confirmed essential hypertension is positioned at peripheral tissues's (mainly being muscle) and directly related (DeFronzo and Ferrannini with hypertensive seriousness, Diabetaes care 1991,14,173).In suffering from hypertensive obese person, insulin resistance produces hyperinsulinemia, this disease is recovered by the mechanism that thermogenesis restriction body weight further increases, and heavily absorbs and stimulates sympathetic nervous system at kidney, heart and vascular system but Regular Insulin also increases kidney sodium, thereby cause hypertension.
Have recognized that at present insulin resistance generally is the result who has defective in the insulin receptor signalling system on the site after Regular Insulin is incorporated into acceptor.The scientific evidence that confirms the accumulation of insulin resistance in responding to the main tissue of Regular Insulin (muscle, liver, fat) is pointed out strongly, commitment in this cascade, particularly when insulin receptor kinase activates, there is the defective in the insulin signaling conduction, as if it weakened (the summary of Haring, Diabetalogia1991,34,848).
Protein-tyrosine phosphatase (PTP enzyme) plays an important role in the regulation and control of proteinic phosphorylation.The interaction of Regular Insulin and its acceptor causes some the tyrosine molecular phosphorus acidifying in described receptor protein, activates described receptor kinase thus.The PTP enzyme makes activated insulin receptor dephosphorylation, and tyrosine kinase activity is weakened.The PTP enzyme also can be by the catalysis insulin receptor kinase cell substrate dephosphorylation to regulate (post-receptor) signal behind the acceptor.As if probably with insulin receptor closely related and regulate and control probably thus the active enzyme of insulin receptor kinase comprise PTP1B, LAR, PTP α and SH-PTP2 (B.J.Goldstein, J.Cellular Biochemistry 1992,48,33; B.J.Goldstein, Receptor 1993,3,1-15; F.Ahmad and B.J.Goldstein, Biochim.BiophysActa 1995,1248,57-69).
(Diabetes 1991 for McGuire etc.; 40; 939) confirm that non-diabetic glucose intolerance patient has the PTP enzyme activity level of obvious rising in muscle tissue, and infusion of insulin can not suppress the PTP enzymic activity as the patient of insulin sensitivity with respect to normal patient.
Meyerovitch etc. (J.Clinical Invest.1989,84,976) promptly observe the PTP enzymic activity of remarkable increase at the rodent model of two kinds of IDDM in the liver of heredity diabetes BioBreeding rat and STZ inductive diabetes rat.Sredy etc. (Metabolism, 44,1074,1995) observe the PTP enzymic activity of similar increase in liver obesity, diabetes ob/ob mouse (the hereditary rodent model of NIDDM).
The compounds of this invention is at external PTP enzyme and the people's derivatize reorganization PTP enzyme-1B (hPTP-1B) that suppresses to be derived from rat liver microsomes that shown.They are used for the treatment of and obesity, glucose intolerance, diabetes, the hypertension insulin resistance relevant with the big and small vessel ischemic disease.
Invention is described
The invention provides and be used for the treatment of the formula I compound with following structure of the Metabolic disorder relevant or their pharmacy acceptable salt with insulin resistance or hyperglycemia,
Figure A9980836300161
Wherein
R is
A is OR 5Or
Figure A9980836300171
R 1For the cycloalkyl of the alkyl of 1-6 carbon atom, a 3-8 carbon atom, thienyl, furyl, pyridyl,
R 2Be the alkyl of hydrogen, a 1-6 carbon atom or the aryl of 6-10 carbon atom;
R 3And R 4Independent be trifluoromethyl, a 7-14 carbon atom of aryl, halogen, a 1-6 carbon atom of alkyl, a 6-10 carbon atom of halogen, hydrogen, a 1-12 carbon atom alkoxy aryl, nitro, amino, carbalkoxy, urea, carbamate, urea, alkyl sulfonamide ,-NR 7(CH 2) mCO 2The cycloalkyl of H, aryl sulfonic acid amides, a 3-8 carbon atom or contain 1 to 3 heterocycle that is selected from heteroatomic 5 to 7 atoms of oxygen, nitrogen or sulphur;
R 5For the alkyl of hydrogen, a 1-6 carbon atom ,-CH (R 8) R 9,-C (CH 2) nCO 2R 10,-C (CH 3) 2CO 2R 10,-CH (R 8) (CH 2) nCO 2R 10,-CH (R 8) C 6H 4CO 2R 10Or-CH 2-tetrazolium;
R 6Alkyl, halogen, the alkoxyl group of a 1-6 carbon atom, the trifluoroalkyl of a 1-6 carbon atom or the thrihalothaneoxy of 1-6 carbon atom for hydrogen, a 1-6 carbon atom;
R 7Alkyl for hydrogen or 1-6 carbon atom;
R 8For the cycloalkyl of the aralkyl of the aryl of the alkyl of hydrogen, a 1-6 carbon atom, a 6-10 carbon atom, a 7-15 carbon atom, a 3-8 carbon atom, phthalic acid,
Figure A9980836300181
R 9Be CO 2R 12, CONHR 12, tetrazolium, PO 3R 12
R 10Be the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-12 carbon atom, the aralkyl of a 7-15 carbon atom;
R 11Alkylidene group for 1-3 carbon atom;
R 12Be the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-12 carbon atom, the aralkyl of a 7-15 carbon atom;
X is O or S;
Y is O, N or S;
Z is C or N;
Q is O, N or S;
m＝1-3；
n＝1-6。
When The compounds of this invention contains basic moiety, can for example acetate, propionic acid, lactic acid, Citric Acid, tartrate, succsinic acid, fumaric acid, toxilic acid, propanedioic acid, amygdalic acid, oxysuccinic acid, phthalic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, nitric acid, sulfuric acid, methylsulfonic acid, naphthene sulfonic acid, Phenylsulfonic acid, toluenesulphonic acids, camphorsulfonic acid and similar known acceptable acid form pharmacy acceptable salt from organic and mineral acid.When The compounds of this invention contains carboxylate salt or phenol moieties or similar can form the part of base addition salt the time, also can form salt from organic and mineral alkali, be preferably an alkali metal salt, for example the salt of sodium, lithium or potassium.
Alkyl comprises both of straight shape chain and branched chain part.Halogen means bromine, chlorine, fluorine and iodine.The substituent aryl moiety of aryl or aralkyl is preferably phenyl, naphthyl or 1,4-benzodioxan-5-base, and wherein phenyl is for most preferably.Aryl moiety can with single-, two-or three optional replacements of substituting groups that are selected from following group, comprising: each of the alkoxy carbonyl of the alkoxyl group of the alkyl of 1-6 carbon atom, a 1-6 carbon atom, trifluoromethyl, halogen, a 2-7 carbon atom, the alkylamino of a 1-6 carbon atom and wherein said alkyl for the dialkyl amido of 1-6 carbon atom, nitro, cyano group ,-CO 2The alkyl carbonyl oxy of H, a 2-7 carbon atom and the alkyl-carbonyl of 2-7 carbon atom.
The compounds of this invention can contain unsymmetrical carbon and some compounds of the present invention can contain one or more asymmetric centers, and can therefore produce optical isomer and diastereomer.Although do not show the stereochemistry of formula I, the present invention includes R and S steric isomer and the mixture of other R and S steric isomer and their pharmacy acceptable salt of the enantiomer-pure of such optical isomer and diastereomer and racemize and fractionation.
Preferred compound of the present invention is the formula I compound of oxygen for those X.The preferred compound of the present invention is those formulas I compound, wherein:
X is O;
R 1For using R 6The phenyl that replaces;
R 2For the alkyl of 1-6 carbon atom and
R 3And R 4Each independently is a hydrogen or halogen.
：4-（4′---4-）-5--2-（4--）-4-（4′---3-）-5--2-（4--）-4′-[5--2-（4--）--4-]--4-3′-[5--2-（4--）--4-]--4-{4′-[5--2-（4--）--4-]--4-}-{3′-[5--2-（4--）--4-]--4-}-2-{4′-[5--2-（4--）--4-]--4-}-3--2-{3′-[5--2-（4--）--4-]--4-}-3--3； 5-two bromo-4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-4-yl]-biphenyl-4-alcohol { 3; 5-two bromo-4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-4-yl]-biphenyl-4-base oxygen base }-acetic acid 2-{3; 5-two bromo-4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-4-yl]-biphenyl-4-base oxygen base }-3-phenyl-methyl propionate 2-{3; 5-two bromo-4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-4-yl]-biphenyl-4-base oxygen base }-3-phenyl-propionic acid 2-{4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-4-yl]-biphenyl-4-ylmethyl }-[1; 2; 4] oxadiazole alkane (oxadiazolidine)-3; 5-diketone 2-{4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-3-ylmethyl }-[1; 2; 4] oxadiazole alkane-3,5-diketone 5-{4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-base oxygen ylmethyl }-1H-TETRAZOLE or their pharmaceutically acceptable salt.
According to following flow process, can use the raw material of literature method preparation can prepare The compounds of this invention by raw material available on the market or its.These flow processs show the preparation of representative compounds of the present invention.
Flow process I
Figure A9980836300211
In flow process I, in the presence of sodium acetate, handle the ketone (1) of commercially available acquisition with azanol, generate oxime (2).According to the known formula science of law [reference Tet.Lett.1980,21,2359-2360], be oxazole with oxime (2) commentaries on classicsization, in the presence of pyridine, handle oxime (2) with Acetyl Chloride 98Min., give birth to into oxazole (3).Use Suzuki method [reference Syn.Comm.1981,11, the aryl boric acid (4 of 513-519] ， Shi oxazole (3) and formula; R 3, R 4For the carbocyclic ring of the aryl of alkyl, aryl, trifluoromethyl, replacement, nitro, 5 to 7 carbon atoms or have 1 to 3 heterocycle that is selected from heteroatomic 5 to 7 former subrings of oxygen, nitrogen and sulphur) coupling, generate biphenyl (5).Described aryl boric acid be commercially available acquisition or can prepare according to the known formula science of law [reference J.Org.Chem.1984,49,5237-5243].Handle [reference J.Org.Chem.1974,39,1427-1429] by the boron tribromide that is used in the methylene dichloride, biphenyl (5) is converted into phenol (6).In the presence of sodium hydride or salt of wormwood, use dimethyl formamide or acetonitrile as solvent, with bromo or chloro alkyl carboxylic acid ester [(Br or Cl) (CH 2) nCO 2R 12] with phenol (6) alkylation.Be used in sodium hydroxide in methyl alcohol and the tetrahydrofuran (THF) subsequently with its saponification, generate biphenyl (7).Use Mitsunobu method [reference Synthesis.1981,1-27], make biphenyl (6) and hydroxyl-alkyl-carboxylate [HOCH (R 8) CO 2R 12] coupling, be used in sodium hydroxide in methyl alcohol and the tetrahydrofuran (THF) subsequently with its saponification, generate biphenyl (8).Prepare tetrazolium (9) with two steps order from phenol (6).The first step uses the bromo acetonitrile phenol (6) alkylation in the presence of sodium hydride, and second step was converted into tetrazolium (9) with sodiumazide with nitrile.
Flow process II
Figure A9980836300221
In flow process II, in the presence of sodium acetate, with bromine with thiazole (10) bromination.Use Suzuki method [reference Syn.Comm.1981,11,513-519], make 4-bromo-thiazole (11) and 4,4 '-coupling of methoxyl biphenyl ylboronic acid, generation biphenyl (12).With with the essentially identical method of in flow process I, describing, biphenyl (12) further is converted into the product of requirement.
Flow process III
In flow process III, use bromine, potassium acetate and acetate, can be with the single bromo of biphenol compound (13) or two bromo.In the reaction mixture of high dilution and in 5-10 ℃ the low temperature range, use the bromine of monovalent to obtain prevailing single brominated product (14; R 3, R 4=H, Br).At room temperature, obtain dibrominated product (14 with two normal bromines; R 3, R 4=Br, Br).Use Suzuki couling process [reference Syn.Comm.1981,11,513-519], generate terphenyl 15 and 16.At mineral alkali K for example 2CO 3Or Ba (OH) 2And palladium (0 or II) catalyzer Pd (PPh for example 3) 4, Pd (OAc) 2Or (dppf) PdCl 2There is down single bromo compound (14; R 3, R 4=H is Br) with boric acid R 13-Ar-B (OH) 2(R 13=halogen, trifluoromethyl, alkoxyl group, alkyl, nitro, amino, carbalkoxy) coupling, generate terphenyl (15; R 3=H).Similarly, under high temperature (100 ℃),, can make two bromo compounds (14 by using 2 normal boric acid; R 3, R 4=Br Br) through the Suzuki coupled reaction, obtains two coupling product (16) or list-coupling-list-brominated product (15; R 3, R 4=Br, aryl-R 13).Single bromo can provide in identical synthetic method with two bromo compounds has for example boric acid product of thiophene, furans, oxazole, thiazole, pyridine of multiple heterocycle.
Flow process IV
In flow process IV, adopt Suzuki method [reference Syn.Comm.1981,11, the aryl boric acid (4 of 513-519] ， Shi oxazole (3) and formula; R 3, R 4For the carbocyclic ring of the aryl of alkyl, aryl, trifluoromethyl, replacement, nitro, 5 to 7 carbon atoms or have 1 to 3 heterocycle that is selected from heteroatomic 5 to 7 annular atomses of oxygen, nitrogen and sulphur) coupling, generate biphenyl (17).In the presence of sodium acetate, biphenyl (17) is converted into oxime (18) with azanol.Under acidic conditions, make oxime (18) reduction with sodium cyanoborohydride, generate azanol (19).Handle azanol (19), Sheng Cheng oxadiazole alkane diketone (20) with N-(chloro carbonyl) isocyanic ester.Use known methodology [reference J.Med.Chem.1992,35,1853-1864], from phenyl aldehyde (17) preparation thiazolidinedione.
The compounds of this invention is used for the treatment of and insulin resistance or relevant general and obesity or the relevant Metabolic disorder of glucose intolerance of hyperglycemia.Therefore The compounds of this invention is used in particular for treatment or suppresses type ii diabetes.The compounds of this invention also is used for regulating and control at the disease glucose level of type i diabetes for example.
In the two kind standard pharmacological experimental methods of following its measurement, determine the ability of The compounds of this invention treatment or inhibition and insulin resistance or hyperglycemia diseases associated with representative compounds of the present invention to the PTP enzyme inhibition.Inhibition is through the triphosphoric acid insulin receptor ten bisphosphate peptide dephosphorylation effects of rats'liver protein-tyrosine phosphatase (PTP enzyme)
This standard pharmacological experimental method uses the phosphoric acid tyrosyl dodecapeptide corresponding to the 1142-1153 insulin receptor kinase territory of phosphorylation on 1146,1150 and 1151 tyrosine residuess as substrate, estimates rat liver microsomes PTP enzymic activity.Method of using and the result who obtains summarize as follows.The preparation of microsomal fraction: by using CO 2Suffocating, (body weight 100-150g male Sprague-Dawley rat (Charles River, Kingston NY), keep with the rodent food (Purina) of standard) also carries out the wide otomy of Bilateral chest to the execution rat.Extract liver and wash and weigh with cold 0.85% salt solution (w/v).Stir evenly tissue on ice with the buffer A of 10 volumes and as by as described in Meyerovitch J, Rothenberg P, Shechter Y, Bonner-Weir S, the Kahn CR, basically the separating particles body.In two kinds of non-insulin-dependent diabetes mellitus mouse models, make hyperglycemia normalizing .J Clin Invest 1991 with vanadate; 87:1286-1294 and Alberts B, Bray D, Lewis J, Raff M, Roberts K, Watson JD editor. cellular elements biology. New York: Garland publishing company, 1989 (making an amendment slightly).Through silk goods filter liver homogenate with remove any residual fragment of tissue and then under 40 ℃ in 10, under the 000xg centrifugal 20 minutes.Supernatant decanted liquid and under 40 ℃ in 100, under the 000xg centrifugal 60 minutes.To precipitate, microsome and a small amount of carrier are at 20mM TRIS-HCl (pH7.4), the 50mM 2 mercapto ethanol, 250mM sucrose, 2mM EDTA, 10mM EGTA, 2mM AEBSF, 0.1mM TLCK, 0.1mM TPCK, 0.5mM benzamidine, the 25ug/ml leupeptin, 5ug/ml pepstatin A, 5ug/ml H5B protease inhibitor, the 5ug/ml chymotrypsin inhibitor, resuspending also slightly stirs evenly up to ultimate density and reaches about 850ug protein/ml in the 10ug/ml aprotinin (buffer A).(Pierce chemical company, Rockford IL), measure protein concn through Pierce coomassie eurymeric protein test as standard substance to use the crystallization bovine serum albumin.The measurement of PTP enzymic activity: adopt Victoria Green WPB-ammonium molybdate method of describing as Lanzetta PA, Alvarez LJ, Reinach PS, Candia OA to be used.Be suitable for nmole flow measurement (the Anal Biochem.1979 of inorganic phosphate; 100:95-97) the improved test of also suitable plate reader is used for measuring through the phosphatic nmole that rat liver microsomes PTP enzyme discharges.This test method use as substrate (San Jose CA) entrusts synthetic ten bisphosphate peptides by AnaSpec company.Peptide TRDIYETDYYRK corresponding to the 1142-1153 catalytic domain of insulin receptor is the tyrosine of phosphorylation on 1146,1150 and 1151 tyrosine residuess.37 the degree ℃ under, the microsomal fraction (83.25ul) that will contain or not contain the 81.83mM HEPES reaction buffer (pH 7.4) of test-compound (6.25ul) and 305.5ul was hatched 10 minutes in advance.Be equipped with on the LABLINE Multi-Blok well heater of titer plate colligator, making 10.5ul peptide substrates balance to 37 degree ℃ of ultimate density 50uM.Add the microsome that contains or do not contain medicine hatch in advance and prepare liquid (39.5ul) starting the dephosphorylation reaction, under 37 degree ℃, this reaction was carried out 30 minutes.Hold back agent (MG/AM/Tw) through adding 200ul Victoria Green WPB-ammonium molybdate-polysorbas20 stops this reaction.Hold back agent contains 3 part of 0.45% Victoria Green WPB hydrochloride in 4N HCl and 0.5% polysorbas20,1 part of 4.2% ammonium molybdate tetrahydrate.Prepare the sample blank group through 200ul MG/AM/Tw being joined the film liquid that contains or do not contain medicine of hatching in advance that also adds 39.5ul in the substrate subsequently.At room temperature, make color developing 30 minutes and under 650nm, use the optical density of plate reader (Molecular Devices) working sample.The operation of preparation sample and blank group repeats four times.Its microsome of activity rating PTP enzyme inhibition of screening 50uM (finally) medicine.Calculate: the PTP enzymic activity that with the potassiumphosphate typical curve is benchmark is represented with the phosphatic nmole number that the every min of every mg protein is discharged.Test compound is calculated as the percentage ratio of Phosphoric acid esterase contrast to the restraining effect of reorganization PTP1B.Use SAS to discharge 6.08 PROCNLIN, measure the IC of test-compound with four parametrical nonlinearity logistical regressions of PTP enzymic activity 50Value.All compounds give with the concentration of 50 μ M.Use representative compounds of the present invention, obtain following result.
Embodiment With the variation % of comparing
????4 ????-28
????6 ????-30
????7 ????-74
????8 ????-78
????9 ????-20
????10 ????-35
????12 ????-68
????15 ????-47
????16 ????-20
????17 ????-54
Phenylarsine (reference substance) ????-57
Restraining effect through the triphosphoric acid insulin receptor ten bisphosphate peptide dephosphorylations of hPTP1B
This standard pharmacological experimental method uses the phosphoric acid tyrosyl dodecapeptide corresponding to the 1142-1153 insulin receptor kinase territory of phosphorylation on 1146,1150 and 1151 tyrosine residuess as substrate, estimates the active restraining effect of recombinant rat Protein Tyrosine Phosphatases PTP1B.Following Short Description the method used and the result who obtains.
As by as described in the Goldstein (referring to .Mol.Cell.Biochem.109 such as Goldstein, 107,1992), the preparation people PTP1B that recombinates.Used enzyme is prepared liquid to be placed at and to contain in 33mM Tris-HCl, 2mM EDTA, 10% glycerine and the 10mM 2 mercapto ethanol in the proteinic microtubule of 500-700 μ g/ml.The measurement of PTP enzymic activity: (Anal Biochem.100:95,1979) that adopt as Lanzetta etc. described and the Victoria Green WPB-ammonium molybdate method that the is suitable for plate reader phosphatic nmole detection that PTP1B discharges of recombinating.This test method use as substrate (San Jose CA) entrusts synthetic ten bisphosphate peptides by AnaSpec company.Peptide TRDIYETDYYRK corresponding to the 1142-1153 catalytic domain of insulin receptor is the tyrosine of phosphorylation on 1146,1150 and 1151 tyrosine residuess.With damping fluid (pH 7.4, contain 33mM Tris-HCl, 2mM EDTA and 50mM b-mercaptoethanol) dilution reorganization rPTP1B, obtain activity and be approximately 1000-2000nmoles/min/mg protein.Under 37 ℃, with the enzyme (83.25ul) that diluted with or do not hatch in advance 10 minutes with the 81.83mMHEPES reaction buffer (pH 7.4) of test-compound (6.25mL) and 305.5mL, be equipped with on the LABLINE Multi-Blok well heater of titer plate colligator, making the 10.5ml peptide substrates balance to 37 ℃ under the ultimate density 50uM.Add the recombinase that contains or do not contain medicine of hatching in advance and prepare liquid (39.5ml), under 37 ℃, this reaction was carried out 30 minutes to start the dephosphorylation reaction.Through adding hold back agent (MG/AM/Tw) termination reaction of 200mL Victoria Green WPB-ammonium molybdate-polysorbas20.Hold back agent contains 3 part of 0.45% Victoria Green WPB hydrochloride in 4N HCl and 0.5% polysorbas20,1 part of 4.2% ammonium molybdate tetrahydrate.Prepare the sample blank group through 200mL MG/AM/Tw being joined in the substrate and add subsequently the recombinase that contains or do not contain medicine that 39.5ml hatches in advance.At room temperature, make color developing 30 minutes and under 650nm, use the optical density of plate reader (Molecular Devices) working sample.Each four parts of preparation sample and blank.Calculate: the PTP enzymic activity that with the potassiumphosphate typical curve is benchmark is represented with the phosphatic nmole number that the every min of every mg protein is discharged.Test-compound is calculated as the percentage ratio of Phosphoric acid esterase control group to the restraining effect of reorganization PTP1B.Use SAS to discharge 6.08 PROCNLIN, measure the IC of test-compound with four parametrical nonlinearity logistical regressions of PTP enzymic activity 50Value.Obtain following result.
Embodiment ????IC 50(μM)
????1 ????1.66
????2 ????-47(2.5uM)
????3 ????-56(2.5uM)
????5 ????0.85
????6 ????-47(2.5uM)
????7 ????1.29
????8 ????1.25
????9 ????0.65
????10 ????0.47
????11 ????-40(2.5uM)
????12 ????0.13
????13 ????1.15
????14 ????-65(2.5uM)
????15 ????0.93
????16 ????1.2
????17 ????0.98
Phenyl-arsine oxide (reference substance) ????39.7
Sodium vanadate (reference substance) ????244.8
Ammonium molybdate tetrahydrate (reference substance) ????8.7
Use diabetes (ob/ob) mouse, confirm the activity of the reduction blood glucose of representative compounds of the present invention with body internal standard method.Employed method and the Short Description as a result that obtains are as follows.
Its feature of non-insulin-dependent diabetes mellitus (NIDDM) (NIDDM) syndrome is generally obesity, hyperglycemia, unusual insulin secretion, hyperinsulinemia and insulin resistance.Genetic obesity-hyperglycemia ob/ob mouse presents this type of multiple metabolic disturbance and is considered to be used to study the useful model [Coleman, D.:Diabelogia14:141-148,1978] of the hypoglycemic drug of treatment NIDDM.
In each test method, the mouse at similar age [male or female ob/ob (C57B1/6J) and their lean litermates (ob/+ or+/+, the Jackson laboratory), the age 2 was to 5 months sizes (10-65g)] be divided into 4 groups at random according to body weight, every group of 10 mouse.Each cage is raised 5 mouse, arbitrarily drinks water, and feeds to raise with normal rodent food and keeps.Every day, mouse by gavage (being suspended in 0.5% methylcellulose gum of 0.5ml) accept to be dissolved in the tap water or with food blended test-compound.The dosage that gives compound is in 2.5 to 200mg/kg body weight/day scopes.Feed to raise based on body weight weekly and calculate dosage and be expressed as active part.Give positive control ciglitazone (5-(4-(1-methyl cyclohexane ylmethoxy) benzyl)-2 with 100mg/kg/ days dosage, the 4-diketone) (referring to Chang, A.Wyse, B., Gilchrist, B., Peterson, T. and Diani, A.Diabetes 32:830-838,1983.), this medicine produces significantly reduced plasma glucose.Control group mice is only accepted carrier.
In the 4th day, the 7th day or the 14th day morning, after tail vein or sacrificed by decapitation, two bleed (approximately 50uL) collected the test tube that contains Sodium Fluoride.For every day wherein giving these researchs of compound through gavage, give behind the compound two hours, collect blood sample.Through centrifugal separation plasma and on Abbott V.P. analyser enzyme process measure the concentration of glucose.
To every mouse, the per-cent with respect to the plasma glucose of the average blood plasma glucose of vehicle treated mouse that calculates the 4th day, the 7th day or the 14th day changes.Be used to estimate the significant difference (CMS SAS discharges 5.18) of the plasma glucose levels between control group and each the compounds for treating group according to the variable analysis of DunettShi comparative experiments (a tail method).
Result displayed shows that The compounds of this invention is the hyperglycemia medicine in following table, because they reduce the blood glucose level in the diabetic mice.
Embodiment Dosage (mg/Kg) Change % with carrier glucose relatively
????5 ????100 ????-40 a
Ciglitazone (reference substance) ????100 ????-43
A-significance,statistical (p＜0.05).
Based on the result who in described standard pharmacological experimental method, obtains, representative compounds of the present invention has demonstrated in diabetic mice and has suppressed the PTP enzymic activity and reduce the blood glucose level, and be used for the treatment of the Metabolic disorder relevant thus, normally relevant Metabolic disorder with obesity or glucose intolerance with insulin resistance or hyperglycemia.More particularly, The compounds of this invention is used for the treatment of or suppresses type ii diabetes, and is used for being adjusted in the glucose level as the disease of type i diabetes.As used herein, term is regulated to mean and is kept glucose level in clinical normal range.
To about 250mg/kg, can effectively give these compounds at the about 1mg/kg of dosage every day, and can single dose or give with twice or the dosage that repeatedly separates.That any way that can be used for directly will giving at this active compound recipient's blood flow comprises is oral, by implantation, non-enteron aisle (comprising vein, intraperitoneal and subcutaneous injection), rectum, vagina and the such dosage of transdermal administration.For the purpose of the disclosure, percutaneous dosing is understood to include the administration that all body passages that pass body surface and liner comprise epidermis and mucosal tissue.Use can be carried out such administration with the The compounds of this invention of lotion, creme, foaming agent, patch, suspensoid, solution and suppository (rectum and vagina) form existence or their pharmacy acceptable salt.
The oral preparations that contains active compound of the present invention can comprise any conventional oral form of using, and it comprises tablet, capsule, hypogloeeis form, lozenge, dragee and oral liquid, suspensoid or solution.Capsule can contain for example mixture of crystallization and Microcrystalline Cellulose, tinting material, gelatin, glue etc. of for example pharmaceutically acceptable starch of active compound and inert filler and/or thinner (for example corn, potato or tapioca (flour)), carbohydrate, artificial sweetening agent, powdered cellulose.Can be by conventional compacting; the method of wet granulation or dry granulation prepares useful tablet formulation and uses pharmaceutically acceptable thinner; tackiness agent; lubricant; disintegrating agent; suspension agent or stablizer include but is not limited to Magnesium Stearate; stearic acid; talcum powder; sodium lauryl sulphate; Microcrystalline Cellulose; calcium carboxymethylcellulose; polyvinylpyrrolidone; gelatin; alginic acid; gum arabic; xanthan gum; Sodium Citrate; composition silicate; lime carbonate; glycine; dextran; sucrose; sorbyl alcohol; Lin Suanergai; calcium sulfate; lactose; kaolin; mannitol; sodium-chlor; talcum powder; dry starch and powdered sugar.Can use standard delay or division of day and night delivery formulations at this oral preparations with the absorption that changes active compound.Can be from traditional material, comprise that the cocoa beans ester and the glycerine that add or do not add with the wax that changes the suppository fusing point prepare suppository formulations.Also can use for example polyoxyethylene glycol of various molecular weights of water soluble suppository bases.
People understand dosage, system and the mode of administration of these compounds will be according to the illness of being treated and individual and change and will determine scheme according to the judgement of the medical practitioner that participates in.Beginning gives one or more compound and increase dosage at this with low dosage and act as preferably up to meeting the requirements of.
Following method is described the preparation of representative compounds of the present invention.
Embodiment 14-(4 '-methoxyl group-biphenyl-4-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole step a) 1-(4-bromo-phenyl)-acetoxime
With sodium acetate (80.0g, 976mmol) join 1-(4-bromo-phenyl)-acetone (52.0g, 244mmol), hydroxylamine hydrochloride (50.8g, 732.3mmol), in the mixture of ethanol (500mL) and water (100mL).Under 60 ℃, this reaction mixture was stirred 1 hour, be poured in the water and use ether extraction.Through MgSO 4Dry organic extracting solution.The evaporation and from the ether/hexane crystallization, obtain white solid (49.6g, 89% yield); MS m/e 227 (M +); To C 9H 10The analytical calculation value of BrNO: C, 47.39; H, 4.42; N, 6.14 measured values: C, 47.42; H, 4.37; N, 5.99.Step b) 4-(4-bromo-phenyl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles
(3.55mL, (10.0g is 43.86mmol) and in the mixture of toluene (20mL) 43.86mmol) to join 1-(4-bromo-phenyl)-acetoxime with pyridine.This reaction mixture was stirred 30 minutes, and be added dropwise to then 4-trifluoromethyl-phenyl Acetyl Chloride 98Min. (16.27mL, 109.6mmol).Under 100 ℃, new mixture was stirred 24 hours, and then with in its impouring water and use ethyl acetate extraction.Through MgSO 4Dry organic extracting solution.Evaporation and flash chromatography method (hexane/EtAOc 40: the 1) purifying of warp on silica gel obtain white solid (7.3g, 43% yield): mp82.84 ℃; MS m/e 381 (M +); To C 17H 11BrF 3The analytical calculation value of NO: C, 53.43; H, 2.90; N, 3.67 measured values: C, 53.47; H, 2.62; N, 3.43.Step c) 4-(4 '-methoxyl group-biphenyl-4-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles
Will be at the 4-methoxyl group-phenylo boric acid (1.44g in the ethanol (5mL), 7.19mmol) join 4-(4-bromo-phenyl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (2.5g, 6.54mmol), yellow soda ash (2N, 6.5mL), (0.23g is 0.196mmol) and in the mixture of toluene (200mL) for tetrakis triphenylphosphine palladium (0).With this reaction mixture refluxed 12 hours, be cooled to room temperature, and with hydrogen peroxide (30%, 5mL) handled 1 hour.Then, be poured into this mixture in the water and use ethyl acetate extraction.Through MgSO 4Dry this organic extracting solution.The evaporation and from hexane/ether crystallization, obtain white solid (2.2g, 82% yield): mp 167-168 ℃; MS m/e 409 (M +); To C 24H 18BrF 3NO 2The analytical calculation value: C, 70.41; H, 4.43; N, 3.42 measured values: C, 70.14; H, 4.32; N, 3.30.
Embodiment 24-(4 '-methoxyl group-biphenyl-3-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles
With with the essentially identical method of in embodiment 1 step c, describing, prepare title compound from 4-(4-bromo-phenyl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles and 4-methoxyl group-phenylo boric acid, obtain white solid, mp 93-94 ℃; MS m/e 409 (M +); To C 24H 18F 3NO 2The analytical calculation value: C, 70.41; H, 4.43; N, 3.42 measured values: C, 70.25; H, 4.33; N, 3.34.
Embodiment 34 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-alcohol
((1.6g is 3.91mmol) and in the mixture of methylene dichloride (20mL) 3.91mmol) to be added dropwise to 4-(4 '-methoxyl group-biphenyl-4-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles of cold (78 ℃) for 1.0M, 3.91mL with boron tribromide.Make reaction mixture return to room temperature gradually and stirred 10 hours.Then, this mixture is cooled to 0 ℃ and drip methyl alcohol (5mL).Stir after 10 minutes, be poured into this mixture in the water and use ether extraction.Through MgSO 4Dry organic extracting solution.The evaporation and from the ether/hexane crystallization, obtain pale solid (1.4g, 90% yield): mp 189-191 ℃; MS m/e 396 (M+H) +To C 23H 16F 3NO 2* 0.3H 2The analytical calculation value of O: C, 68.92; H, 4.17; N, 3.50 measured values: C, 68.97; H, 4.23; N, 3.33.
Embodiment 43 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-alcohol
With with the essentially identical method of in embodiment 3, describing, prepare title compound, and obtain mp 133-135 ℃ as white solid from 4-(4 '-methoxyl group-biphenyl-3-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles; MS m/e 395 (M +); To C 23H 16F 3NO 2* 0.3H 2The analytical calculation value of O: C, 68.92; H, 4.17; N, 3.50 measured values: C, 68.98; H, 3.83; N, 3.47.
Embodiment 5{4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-base oxygen base }-acetate
With sodium hydride (0.05g, 1.26mmol) join 4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-alcohol (0.5g, 1.26mmol) and N, in the mixture of dinethylformamide (5.0mL).At room temperature, this reaction mixture was stirred 1 hour.(0.18mL 1.89mmol) is added drop-wise in the mixture with the monobromo-acetic acid methyl esters.Stir after 30 minutes, be poured into mixture in the water and use ethyl acetate extraction.Through MgSO 4Dry organic extracting solution.Evaporation obtains xanchromatic oil (0.61g).Handle this resistates with methyl alcohol (20mL) and tetrahydrofuran (THF) (20mL), and (2.5N handled 30 minutes 5.0mL) with NaOH.Then this new reaction mixture is poured in the water,, and uses ether extraction with HCl (2N) acidifying.Through MgSO 4Dry organic extracting solution.The evaporation and from hexane/ether crystallization, obtain pale solid (0.42g, 73% yield): mp 209-211; MS m/e 454 (M+H) +To C 25H 18F 3NO 4The analytical calculation value: C, 66.23; H, 4.00; N, 3.09 measured values: C, 65.97; H, 3.93; N, 3.04.Embodiment 6{3 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-base oxygen base }-acetate
With with the essentially identical method of in embodiment 6, describing, from 3 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-alcohol preparation title compound, and obtain mp 178-179 ℃ as faint yellow solid; MS m/e 453 (M +); To C 25H 18F 3NO 4* 0.3H 2The analytical calculation value of O: C, 65.44; H, 3.99; N, 3.05 measured values: C, 65.50; H, 3.93; N, 2.92.
Embodiment 72-{4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-base oxygen base }-3-phenyl-propionic acid
Will be at the azo-2-carboxylic acid's diisopropyl ester (0.42mL in the benzene (10mL), 2.52mmol) be added dropwise to cold (0 ℃) 4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-alcohol (0.5g, 1.26mmol), 3-phenyl-lactic acid methyl esters (0.45g, 2.52mmol), (0.66g is 2.52mmol) and in the mixture of benzene (20mL) for triphenylphosphine.At room temperature, this reaction mixture was stirred 30 minutes, be poured in the water, and use ether extraction.Through MgSO 4Dry organic extracting solution.Evaporation obtains xanchromatic oil (0.6g).Handle this resistates with methyl alcohol (15mL) and tetrahydrofuran (THF) (15mL), and (2N handles 3.0mL) with sodium hydroxide.This reaction mixture was stirred 30 minutes, be poured in the water,, and use ether extraction with HCl (2N) acidifying.Through MgSO 4Dry organic extracting solution.The evaporation and from the ether/hexane crystallization, obtain white solid (0.38g, 55% yield): mp 183-184; MS m/e 544 (M+H) +To C 32H 24F 3NO 4The analytical calculation value: C, 70.71; H, 4.45; N, 2.58 measured values: C, 70.50; H, 4.32; N, 2.53.
Embodiment 82-{3 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-base oxygen base }-3-phenyl-propionic acid
With with the essentially identical method of in embodiment 7, describing, from 3 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-alcohol preparation title compound, and obtain mp 148-149 ℃ as white solid; MS m/e 543 (M +); To C 32H 24F 3NO 4The analytical calculation value: C, 70.71; H, 4.45; N, 2.58 measured values: C, 70.72; H, 4.28; N, 2.50.
Embodiment 93,5-two bromo-4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-4-yl]-biphenyl-4-alcohol
During 30 minutes, will be at the bromine (0.73mL in the acetate (50mL), 14.18mmol) be added dropwise to cold (5 ℃) 4 '-(2-benzyl-benzo [b] thiene-3-yl-)-xenyl-4-alcohol (2.8g, 7.09mmol), (6.95g is 70.9mmol) and in the mixture of acetate (200mL) for potassium acetate.After the adding, this mixture is poured in the water.The solid of filtering-depositing washes with water and drying, obtains white solid (2.1g, 61% yield): mp 79-81 ℃; MS m/e 551 (M +); To C 23H 14Br 2F 3NO 2The analytical calculation value: C, 49.94; H, 2.55; N, 2.53 measured values: C, 49.78; H, 2.46; N, 2.49.
Embodiment 10{3,5-two bromo-4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-4-yl]-biphenyl-4-base oxygen base }-acetate
With with the essentially identical method of in embodiment 5, describing, from 3,5-two bromo-4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-4-yl]-pure and mild monobromo-acetic acid methyl esters of biphenyl-4-prepares title compound, and obtains mp 165-166 ℃ as pale solid; MS m/e 609 (M +); To C 25H 16Br 2F 3NO 4The analytical calculation value: C, 49.13; H, 2.64; N, 2.29 measured values: C, 49.24; H, 2.58; N, 2.16.Embodiment 112-{3,5-two bromo-4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-4-yl]-biphenyl-4-base oxygen base }-3-phenyl-methyl propionate
With with the essentially identical method of in embodiment 7, describing, from 3,5-two bromo-4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-4-yl]-pure and mild 3-phenyl-lactic acid of biphenyl-4-methyl esters prepares title compound, and obtains mp 70-72 ℃ as white solid; MS m/e 713 (M +); To C 33H 24Br 2F 3NO 4The analytical calculation value: C, 55.41; H, 3.38; N, 1.96 measured values: C, 55.01; H, 3.21; N, 1.99.
Embodiment 122-{3,5-two bromo-4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-4-yl]-biphenyl-4-base oxygen base }-3-phenyl-propionic acid
With with the essentially identical method of in embodiment 7, describing, from 2-{3,5-two bromo-4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole-4-yl]-biphenyl-4-base oxygen base }-3-phenyl-methyl propionate prepares title compound, and obtains mp 241-243 ℃ as white solid; MS m/e699 (M +); To C 32H 22Br 2F 3NO 4The analytical calculation value: C, 54.80; H, 3.16; N, 2.00 measured values: C, 54.54; H, 3.03; N, 2.00.
Embodiment 132-{4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-ylmethyl }-[1,2,4] oxadiazole alkane-3,5-diketone step a) 4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-formaldehyde
With with the essentially identical method of in embodiment 1 step c, describing, prepare this compound from 4-(4-bromo-phenyl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles and 4-formylphenylboronic acid, and obtain as pale solid; MS m/e 407 (M +); To C 24H 16F 3NO 2The analytical calculation value: C, 70.76; H, 3.96; N, 3.44 measured values: C, 70.83; H, 3.70; N, 3.42.Step b) 4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-formoxime
With with the essentially identical method of in embodiment 1 step a, describing, from 4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-formaldehyde and azanol prepare this compound, and obtain as pale solid; MS m/e 422 (M +); To C 24H 17F 3N 2O 2The analytical calculation value: C, 68.24; H, 4.06; N, 6.63 measured values: C, 68.10; H, 3.82; N, 6.45.Step c) N-{4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-ylmethyl }-azanol
With hydrochloric acid (in the 4N Zai diox, 10mL) be added dropwise to 4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-formoxime (1.5g, 3.56mmol), sodium cyanoborohydride (1.1g, 17.81mmol), in the mixture of methyl alcohol (100mL) and tetrahydrofuran (THF) (100mL).This reaction mixture was stirred 1 hour, be poured in the water,, and use ethyl acetate extraction with sodium hydroxide (2N) alkalization.Through MgSO 4Dry organic extracting solution.Evaporation and the flash chromatography method on silica gel (EtOAc/MeOH 20: 1) purifying obtain pale solid (1.21g, 80% yield); MS m/e 424 (M +); To C 24H 19F 3N 2O 2* H 2The analytical calculation value of O: C, 67.06; H, 4.60; N, 6.52 measured values: C, 67.10; H, 4.34; N, 6.69.Step d) 2-{4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-ylmethyl }-[1,2,4] oxadiazole alkane-3,5-diketone
With N-(chloro carbonyl) isocyanic ester (0.2mL, 2.6mmol) be added dropwise to N-{4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-ylmethyl of cold (5 ℃)-azanol (1.1,2.6mmol) and in the mixture of tetrahydrofuran (THF) (20.0mL).This reaction mixture was stirred 30 minutes, be poured in the water,, and use ethyl acetate extraction with HCl (2N) acidifying.Through MgSO 4Dry organic extracting solution.Evaporation and the flash chromatography method on acidic silica gel (hexane/EtOAc 2: 1) purifying obtain white solid (0.68g, 53% yield): mp 196-198; MS m/e493 (M +); To C 26H 18F 3N 3O 4The analytical calculation value: C, 63.29; H, 3.68; N, 8.52 measured values: C, 62.95; H, 3.51; N, 8.40.
Embodiment 142-{4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-3-ylmethyl }-[1,2,4] oxadiazole alkane-3,5-diketone
With with the essentially identical method of in embodiment 1 step a-d, describing, prepare this compound, and obtain mp 216-218 ℃ as white solid from 3-(4-bromo-phenyl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles; MS m/e 493 (M +); To C 26H 18F 3N 3O 4The analytical calculation value: C, 63.29; H, 3.68; N, 8.52 measured values: C, 63.23; H, 3.43; N, 8.48.
Embodiment 155-{4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-base oxygen ylmethyl }-the 1H-tetrazolium
With sodium hydride (0.1g, 2.52mmol) join 4 '-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-biphenyl-4-alcohol (1.0g, 2.52mmol) and N, in the mixture of dinethylformamide (5.0mL).At room temperature, this reaction mixture was stirred 1 hour.(0.17mL 2.52mmol) is added drop-wise in this mixture for acetonitrile with monobromomethane.Stir after 30 minutes, be poured into mixture in the water and use ethyl acetate extraction.Through MgSO 4Dry organic extracting solution.Evaporation obtains xanchromatic oil (1.1g).With resistates N, dinethylformamide (20mL) is handled, and 120 ℃ down with ammonium chlorides (0.67g, 12.6mmol) and sodium azide (0.82g, 12.6mmol) processing is 10 hours.Then this mixture is poured in the water,, and uses ether extraction with HCl (2N) acidifying.Through MgSO 4Dry organic extracting solution.The evaporation and from hexane/ether crystallization, obtain white solid (0.49g, 41% yield): mp 226-227; MS m/e 477 (M +); To C 25H 18F 3N 5O 2The analytical calculation value: C, 62.89; H, 3.80; N, 14.67 measured values: C, 62.54; H, 3.63; N, 14.76.Embodiment 16{1-bromo-6-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-naphthalene-2-base oxygen base }-acetate step a) 4 '-(6-methoxyl group-naphthalene-2-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles
With with the essentially identical method of in embodiment 1 step b, describing, prepare this compound from 1-(6-methoxyl group-naphthalene-2-yl) acetoxime and 4-trifluoromethyl-phenyl Acetyl Chloride 98Min., and obtain mp 138-139 as white solid; MS m/e 383 (M +); To C 22H 19F 3NO 2The analytical calculation value: C, 68.93; H, 4.21; N, 3.65 measured values: C, 68.83; H, 4.25; N, 3.70.Step b) 6-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-naphthalene-2-alcohol
With with the essentially identical method of in embodiment 3, describing, prepare this compound from 4 '-(6-methoxyl group-naphthalene-2-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles and boron tribromide, and obtain mp 188-191 as white solid; MS m/e 370 (M+H) +To C 21H 14F 3NO 2The analytical calculation value: C, 68.29; H, 3.82; N, 3.79 measured values: C, 67.81; H, 3.76; N, 3.66.Step c) 1-bromo-6-[5-ethyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-naphthalene-2-alcohol
With with the essentially identical method of in embodiment 9, describing, prepare this compound from 4 '-(6-hydroxyl-naphthalene-2-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles and bromine, and obtain as pale solid; MS m/e 447 (M +); To C 21H 13BrF 3NO 2The analytical calculation value: C, 56.27; H, 2.92; N, 3.12 measured values: C, 56.20; H, 2.66; N, 3.15.Step d) 1-bromo-6-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-naphthalene-2-base oxygen base }-acetate
With with the essentially identical method of in embodiment 5, describing, prepare this compound from 4 '-(5-bromo-6-hydroxyl-naphthalene-2-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles and monobromo-acetic acid methyl esters, and obtain mp 212-214 ℃ as white solid; MS m/e 506 (M+H) +To C 23H 15BrF 3NO 4The analytical calculation value: C, 54.57; H, 2.99; N, 2.77 measured values: C, 54.17; H, 2.69; N, 2.76.
Embodiment 172-{1-bromo-6-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles-4-yl]-naphthalene-2-base oxygen base }-3-phenyl-propionic acid
With with the essentially identical method of in embodiment 7, describing, prepare this compound from 4 '-(5-bromo-6-hydroxyl-naphthalene-2-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazoles and monobromo-acetic acid methyl esters, and obtain mp 195-197 ℃ as pale solid; MS m/e 596 (M+H) +To C 30H 21BrF 3NO 4The analytical calculation value: C, 60.42; H, 3.55; N, 2.35 measured values: C, 60.31; H, 3.35; N, 2.42.

Claims (22)

1.具有以下结构的式I化合物或者它们的药学上可接受的盐，
Figure A9980836300021
1. A compound of formula I having the following structure or a pharmaceutically acceptable salt thereof,
Figure A9980836300021
 其中in R为
Figure A9980836300022
R is
Figure A9980836300022
 A为OR5或
Figure A9980836300023
A is OR 5 or
Figure A9980836300023
 R1为1-6个碳原子的烷基、3-8个碳原子的环烷基、噻吩基、呋喃基、吡啶基、 R is an alkyl group of 1-6 carbon atoms, a cycloalkyl group of 3-8 carbon atoms, thienyl, furyl, pyridyl, R2为氢、1-6个碳原子的烷基、或6-10个碳原子的芳基；R is hydrogen , an alkyl group of 1-6 carbon atoms, or an aryl group of 6-10 carbon atoms; R3和R4独立为卤素、氢、1-12个碳原子的烷基、6-10个碳原子的芳基、卤素、1-6个碳原子的三氟甲基、7-14个碳原子的烷氧基芳基、硝基、氨基、烷氧羰基、脲、氨基甲酸酯、脲、烷基磺酰胺、-NR7(CH2)mCO2H、芳基磺酰胺、3-8个碳原子的环烷基、或含有1至3个选自氧、氮或硫的杂原子的5至7个原子环的杂环；R and R are independently halogen, hydrogen, alkyl of 1-12 carbon atoms, aryl of 6-10 carbon atoms, halogen, trifluoromethyl of 1-6 carbon atoms, 7-14 carbon Atomic alkoxyaryl, nitro, amino, alkoxycarbonyl, urea, carbamate, urea, alkylsulfonamide, -NR 7 (CH 2 ) m CO 2 H, arylsulfonamide, 3- Cycloalkyl groups of 8 carbon atoms, or heterocyclic rings of 5 to 7 atom rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur; R5为氢、1-6个碳原子的烷基、-CH(R8)R9、-C(CH2)nCO2R10、-C(CH3)2CO2R10、-CH(R8)(CH2)nCO2R10、-CH(R8)C6H4CO2R10或-CH2-四唑；R 5 is hydrogen, an alkyl group with 1-6 carbon atoms, -CH(R 8 )R 9 , -C(CH 2 ) n CO 2 R 10 , -C(CH 3 ) 2 CO 2 R 10 , -CH (R 8 )(CH 2 ) n CO 2 R 10 , -CH(R 8 )C 6 H 4 CO 2 R 10 or -CH 2 -tetrazole; R6为氢、1-6个碳原子的烷基、卤素、1-6个碳原子的烷氧基、1-6个碳原子的三氟烷基或1-6个碳原子的三氟烷氧基； R6 is hydrogen, alkyl of 1-6 carbon atoms, halogen, alkoxyl of 1-6 carbon atoms, trifluoroalkyl of 1-6 carbon atoms or trifluoroalkane of 1-6 carbon atoms Oxygen; R7为氢或1-6个碳原子的烷基；R 7 is hydrogen or an alkyl group of 1-6 carbon atoms; R8为氢、1-6个碳原子的烷基、6-10个碳原子的芳基、7-15个碳原子的芳烷基、3-8个碳原子的环烷基、苯二甲酸、 R is hydrogen , alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, aralkyl of 7-15 carbon atoms, cycloalkyl of 3-8 carbon atoms, phthalic acid , R9为CO2R12、CONHR12、四唑、PO3R12；R 9 is CO 2 R 12 , CONHR 12 , tetrazole, PO 3 R 12 ; R10为氢、1-6个碳原子的烷基、6-12个碳原子的芳基、7-15个碳原子的芳烷基；R 10 is hydrogen, an alkyl group of 1-6 carbon atoms, an aryl group of 6-12 carbon atoms, an aralkyl group of 7-15 carbon atoms; R11为1-3个碳原子的亚烷基；R 11 is an alkylene group of 1-3 carbon atoms; R12为氢、1-6个碳原子的烷基、6-12个碳原子的芳基、7-15个碳原子的芳烷基；R 12 is hydrogen, an alkyl group of 1-6 carbon atoms, an aryl group of 6-12 carbon atoms, an aralkyl group of 7-15 carbon atoms; X为O或S；X is O or S; Y为O、N或S；Y is O, N or S; Z为C或N；Z is C or N; Q为O、N或S；Q is O, N or S; m＝1-3；m=1-3; n＝1-6。n=1-6. 2.权利要求1的化合物或者它们的药学上可接受的盐，其中X为氧。2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is oxygen. 3.权利要求2的化合物或者它们的药学上可接受的盐，其中3. The compound of claim 2 or their pharmaceutically acceptable salts, wherein R1为用R6取代的苯基；R 1 is phenyl substituted with R 6 ; R2为1-6个碳原子的烷基；和R 2 is an alkyl group of 1-6 carbon atoms; and R3和R4每一个独立为氢或卤素。 R3 and R4 are each independently hydrogen or halogen. 4.权利要求1的化合物，其为4-(4′-甲氧基-联苯-4-基)-5-甲基-2-(4-三氟甲基-苯基)-噁唑或者它的药学上可接受的盐。4. The compound of claim 1 which is 4-(4'-methoxy-biphenyl-4-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole or Its pharmaceutically acceptable salts. 5.权利要求1的化合物，其为4-(4′-甲氧基-联苯-3-基)-5-甲基-2-(4-三氟甲基-苯基)-噁唑或者它的药学上可接受的盐。5. The compound of claim 1 which is 4-(4'-methoxy-biphenyl-3-yl)-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole or Its pharmaceutically acceptable salts. 6.权利要求1的化合物，其为4′-[5-甲基-2-(4-三氟甲基-苯基)-噁唑-4-基]-联苯-4-醇或者它的药学上可接受的盐。6. The compound of claim 1, which is 4'-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol or its Pharmaceutically acceptable salts. 7.权利要求1的化合物，其为3′-[5-甲基-2-(4-三氟甲基-苯基)-噁唑-4-基]-联苯-4-醇或者它的药学上可接受的盐。7. The compound of claim 1, which is 3'-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ol or its Pharmaceutically acceptable salts. 8.权利要求1的化合物，其为{4′-[5-甲基-2-(4-三氟甲基-苯基)-噁唑-4-基]-联苯-4-基氧基}-乙酸或者它的药学上可接受的盐。8. The compound of claim 1, which is {4'-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy }-acetic acid or a pharmaceutically acceptable salt thereof. 9.权利要求1的化合物，其为{3′-[5-甲基-2-(4-三氟甲基-苯基)-噁唑-4-基]-联苯-4-基氧基}-乙酸或者它的药学上可接受的盐。9. The compound of claim 1, which is {3'-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yloxy }-acetic acid or a pharmaceutically acceptable salt thereof. 10.权利要求1的化合物，其为2-{4′-[5-甲基-2-(4-三氟甲基-苯基)-噁唑-4-基]-联苯-4-基氧基}-3-苯基-丙酸或者它的药学上可接受的盐。10. The compound of claim 1, which is 2-{4'-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yl Oxy}-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof. 11.权利要求1的化合物，其为2-{3′-[5-甲基-2-(4-三氟甲基-苯基)-噁唑-4-基]-联苯-4-基氧基}-3-苯基-丙酸或者它的药学上可接受的盐。11. The compound of claim 1, which is 2-{3'-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yl Oxy}-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof. 12.权利要求1的化合物，其为3，5-二溴-4′-[5-甲基-2-(4-三氟甲基-苯基)-噁唑-4-基]-联苯-4-醇或者它的药学上可接受的盐。12. The compound of claim 1, which is 3,5-dibromo-4'-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl -4-ol or its pharmaceutically acceptable salt. 13.权利要求1的化合物，其为{3，5-二溴-4′-[5-甲基-2-(4-三氟甲基-苯基)-噁唑-4-基]-联苯-4-基氧基}-乙酸或者它的药学上可接受的盐。13. The compound of claim 1, which is {3,5-dibromo-4'-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-bis phen-4-yloxy}-acetic acid or a pharmaceutically acceptable salt thereof. 14.权利要求1的化合物，其为2-{3，5-二溴-4′-[5-甲基-2-(4-三氟甲基-苯基)-噁唑-4-基]-联苯-4-基氧基}-3-苯基-丙酸甲酯或者它的药学上可接受的盐。14. The compound of claim 1, which is 2-{3,5-dibromo-4'-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl] -Biphenyl-4-yloxy}-3-phenyl-propionic acid methyl ester or a pharmaceutically acceptable salt thereof. 15.权利要求1的化合物，其为2-{3，5-二溴-4′-[5-甲基-2-(4-三氟甲基-苯基)-噁唑-4-基]-联苯-4-基氧基}-3-苯基-丙酸或者它的药学上可接受的盐。15. The compound of claim 1, which is 2-{3,5-dibromo-4'-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl] - biphenyl-4-yloxy}-3-phenyl-propionic acid or a pharmaceutically acceptable salt thereof. 16.权利要求1的化合物，其为2-{4′-[5-甲基-2-(4-三氟甲基-苯基)-噁唑-4-基]-联苯-4-基甲基}-[1，2，4]噁二唑烷-3，5-二酮或者它的药学上可接受的盐。16. The compound of claim 1, which is 2-{4'-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yl Methyl}-[1,2,4]oxadiazolidine-3,5-dione or a pharmaceutically acceptable salt thereof. 17.权利要求1的化合物，其为2-{4′-[5-甲基-2-(4-三氟甲基-苯基)-噁唑-4-基]-联苯-3-基甲基}-[1，2，4]噁二唑烷-3，5-二酮或者它的药学上可接受的盐。17. The compound of claim 1, which is 2-{4'-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-3-yl Methyl}-[1,2,4]oxadiazolidine-3,5-dione or a pharmaceutically acceptable salt thereof. 18.权利要求1的化合物，其为5-{4′-[5-甲基-2-(4-三氟甲基-苯基)-噁唑-4-基]-联苯-4-基氧基甲基}-1H-四唑或者它的药学上可接受的盐。18. The compound of claim 1, which is 5-{4'-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-yl Oxymethyl}-1H-tetrazole or a pharmaceutically acceptable salt thereof. 19.在需要它们的哺乳动物上治疗由胰岛素抗性或高血糖介导的代谢失调的方法，该方法包括给予所述哺乳动物具有以下结构的式I化合物或者它们的药学上可接受的盐， 19. A method of treating metabolic disorders mediated by insulin resistance or hyperglycemia in a mammal in need thereof, the method comprising administering to said mammal a compound of formula I or a pharmaceutically acceptable salt thereof, 其中in R为
Figure A9980836300061
R is
Figure A9980836300061
 A为OR5或
Figure A9980836300062
A is OR 5 or
Figure A9980836300062
 R1为1-6个碳原子的烷基、3-8个碳原子的环烷基、噻吩基、呋喃基、吡啶基、
Figure A9980836300063
 R is an alkyl group of 1-6 carbon atoms, a cycloalkyl group of 3-8 carbon atoms, thienyl, furyl, pyridyl,
Figure A9980836300063
 R2为氢、1-6个碳原子的烷基、或6-10个碳原子的芳基；R is hydrogen , an alkyl group of 1-6 carbon atoms, or an aryl group of 6-10 carbon atoms; R3和R4独立为卤素、氢、1-12个碳原子的烷基、6-10个碳原子的芳基、卤素、1-6个碳原子的三氟甲基、7-14个碳原子的烷氧基芳基、硝基、氨基、烷氧羰基、脲、氨基甲酸酯、脲、烷基磺酰胺、-NR7(CH2)mCO2H、芳基磺酰胺、3-8个碳原子的环烷基、或含有1至3个选自氧、氮或硫的杂原子的5至7个原子环的杂环；R and R are independently halogen, hydrogen, alkyl of 1-12 carbon atoms, aryl of 6-10 carbon atoms, halogen, trifluoromethyl of 1-6 carbon atoms, 7-14 carbon Atomic alkoxyaryl, nitro, amino, alkoxycarbonyl, urea, carbamate, urea, alkylsulfonamide, -NR 7 (CH 2 ) m CO 2 H, arylsulfonamide, 3- Cycloalkyl groups of 8 carbon atoms, or heterocyclic rings of 5 to 7 atom rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur; R5为氢、1-6个碳原子的烷基、-CH(R8)R9、-C(CH2)nCO2R10、-C(CH3)2CO2R10、-CH(R8)(CH2)nCO2R10、-CH(R8)C6H4CO2R10或-CH2-四唑；R 5 is hydrogen, an alkyl group with 1-6 carbon atoms, -CH(R 8 )R 9 , -C(CH 2 ) n CO 2 R 10 , -C(CH 3 ) 2 CO 2 R 10 , -CH (R 8 )(CH 2 ) n CO 2 R 10 , -CH(R 8 )C 6 H 4 CO 2 R 10 or -CH 2 -tetrazole; R6为氢、1-6个碳原子的烷基、卤素、1-6个碳原子的烷氧基、1-6个碳原子的三氟烷基或1-6个碳原子的三氟烷氧基； R6 is hydrogen, alkyl of 1-6 carbon atoms, halogen, alkoxyl of 1-6 carbon atoms, trifluoroalkyl of 1-6 carbon atoms or trifluoroalkane of 1-6 carbon atoms Oxygen; R7为氢或1-6个碳原子的烷基；R 7 is hydrogen or an alkyl group of 1-6 carbon atoms; R8为氢、1-6个碳原子的烷基、6-10个碳原子的芳基、7-15个碳原子的芳烷基、3-8个碳原子的环烷基、苯二甲酸、
Figure A9980836300071
R is hydrogen , alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, aralkyl of 7-15 carbon atoms, cycloalkyl of 3-8 carbon atoms, phthalic acid ,
Figure A9980836300071
 R9为CO2R12、CONHR12、四唑、PO3R12；R 9 is CO 2 R 12 , CONHR 12 , tetrazole, PO 3 R 12 ; R10为氢、1-6个碳原子的烷基、6-12个碳原子的芳基、7-15个碳原子的芳烷基；R 10 is hydrogen, an alkyl group of 1-6 carbon atoms, an aryl group of 6-12 carbon atoms, an aralkyl group of 7-15 carbon atoms; R11为1-3个碳原子的亚烷基；R 11 is an alkylene group of 1-3 carbon atoms; R12为氢、1-6个碳原予的烷基、6-12个碳原子的芳基、7-15个碳原子的芳烷基；R is hydrogen , an alkyl group with 1-6 carbon atoms, an aryl group with 6-12 carbon atoms, and an aralkyl group with 7-15 carbon atoms; X为O或S；X is O or S; Y为O、N或S；Y is O, N or S; Z为C或N；Z is C or N; Q为O、N或S；Q is O, N or S; m＝1-3；m=1-3; n＝1-6。n=1-6. 20.在需要它们的哺乳动物上治疗或抑制II型糖尿病的方法，该方法包括给予所述哺乳动物具有以下结构的式I化合物或者它们的药学上可接受的盐，
Figure A9980836300072
20. A method of treating or inhibiting type II diabetes in a mammal in need thereof, the method comprising administering to said mammal a compound of formula I having the structure, or a pharmaceutically acceptable salt thereof,
Figure A9980836300072
 其中in R为
Figure A9980836300081
R is
Figure A9980836300081
 A为OR5或
Figure A9980836300082
A is OR 5 or
Figure A9980836300082
 R1为1-6个碳原子的烷基、3-8个碳原子的环烷基、噻吩基、呋喃基、吡啶基、
Figure A9980836300083
 R is an alkyl group of 1-6 carbon atoms, a cycloalkyl group of 3-8 carbon atoms, thienyl, furyl, pyridyl,
Figure A9980836300083
 R2为氢、1-6个碳原子的烷基、或6-10个碳原子的芳基；R is hydrogen , an alkyl group of 1-6 carbon atoms, or an aryl group of 6-10 carbon atoms; R3和R4独立为卤素、氢、1-12个碳原子的烷基、6-10个碳原子的芳基、卤素、1-6个碳原子的三氟甲基、7-14个碳原子的烷氧基芳基、硝基、氨基、烷氧羰基、脲、氨基甲酸酯、脲、烷基磺酰胺、-NR7(CH2)mCO2H、芳基磺酰胺、3-8个碳原子的环烷基、或含有1至3个选自氧、氮或硫的杂原子的5至7个原子环的杂环；R and R are independently halogen, hydrogen, alkyl of 1-12 carbon atoms, aryl of 6-10 carbon atoms, halogen, trifluoromethyl of 1-6 carbon atoms, 7-14 carbon Atomic alkoxyaryl, nitro, amino, alkoxycarbonyl, urea, carbamate, urea, alkylsulfonamide, -NR 7 (CH 2 ) m CO 2 H, arylsulfonamide, 3- Cycloalkyl groups of 8 carbon atoms, or heterocyclic rings of 5 to 7 atom rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur; R5为氢、1-6个碳原子的烷基、-CH(R8)R9、-C(CH2)nCO2R10、-C(CH3)2CO2R10、-CH(R8)(CH2)nCO2R10、-CH(R8)C6H4CO2R10或-CH2-四唑；R 5 is hydrogen, an alkyl group with 1-6 carbon atoms, -CH(R 8 )R 9 , -C(CH 2 ) n CO 2 R 10 , -C(CH 3 ) 2 CO 2 R 10 , -CH (R 8 )(CH 2 ) n CO 2 R 10 , -CH(R 8 )C 6 H 4 CO 2 R 10 or -CH 2 -tetrazole; R6为氢、1-6个碳原子的烷基、卤素、1-6个碳原子的烷氧基、1-6个碳原子的三氟烷基或1-6个碳原子的三氟烷氧基； R6 is hydrogen, alkyl of 1-6 carbon atoms, halogen, alkoxyl of 1-6 carbon atoms, trifluoroalkyl of 1-6 carbon atoms or trifluoroalkane of 1-6 carbon atoms Oxygen; R7为氢或1-6个碳原子的烷基；R 7 is hydrogen or an alkyl group of 1-6 carbon atoms; R8为氢、1-6个碳原子的烷基、6-10个碳原子的芳基、7-15个碳原子的芳烷基、3-8个碳原子的环烷基、苯二甲酸、
Figure A9980836300091
R is hydrogen , alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, aralkyl of 7-15 carbon atoms, cycloalkyl of 3-8 carbon atoms, phthalic acid ,
Figure A9980836300091
 R9为CO2R12、CONHR12、四唑、PO3R12；R 9 is CO 2 R 12 , CONHR 12 , tetrazole, PO 3 R 12 ; R10为氢、1-6个碳原子的烷基、6-12个碳原子的芳基、7-15个碳原子的芳烷基；R 10 is hydrogen, an alkyl group of 1-6 carbon atoms, an aryl group of 6-12 carbon atoms, an aralkyl group of 7-15 carbon atoms; R11为1-3个碳原子的亚烷基；R 11 is an alkylene group of 1-3 carbon atoms; R12为氢、1-6个碳原子的烷基、6-12个碳原子的芳基、7-15个碳原子的芳烷基；R 12 is hydrogen, an alkyl group of 1-6 carbon atoms, an aryl group of 6-12 carbon atoms, an aralkyl group of 7-15 carbon atoms; X为O或S；X is O or S; Y为O、N或S；Y is O, N or S; Z为C或N；Z is C or N; Q为O、N或S；Q is O, N or S; m＝1-3；m=1-3; n＝1-6。n=1-6. 21.在需要它们的哺乳动物上调控葡萄糖水平的方法，该方法包括给予所述哺乳动物具有以下结构的式I化合物或者它们的药学上可接受的盐， 21. A method of regulating glucose levels in a mammal in need thereof, the method comprising administering to said mammal a compound of formula I having the structure, or a pharmaceutically acceptable salt thereof, 其中in R为 R is A为OR5或 A is OR 5 or R1为1-6个碳原子的烷基、3-8个碳原子的环烷基、噻吩基、呋喃基、吡啶基、
Figure A9980836300103
 R is an alkyl group of 1-6 carbon atoms, a cycloalkyl group of 3-8 carbon atoms, thienyl, furyl, pyridyl,
Figure A9980836300103
 R2为氢、1-6个碳原子的烷基、或6-10个碳原子的芳基；R is hydrogen , an alkyl group of 1-6 carbon atoms, or an aryl group of 6-10 carbon atoms; R3和R4独立为卤素、氢、1-12个碳原子的烷基、6-10个碳原子的芳基、卤素、1-6个碳原子的三氟甲基、7-14个碳原子的烷氧基芳基、硝基、氨基、烷氧羰基、脲、氨基甲酸酯、脲、烷基磺酰胺、-NR7(CH2)mCO2H、芳基磺酰胺、3-8个碳原子的环烷基、或含有1至3个选自氧、氮或硫的杂原子的5至7个原子环的杂环；R and R are independently halogen, hydrogen, alkyl of 1-12 carbon atoms, aryl of 6-10 carbon atoms, halogen, trifluoromethyl of 1-6 carbon atoms, 7-14 carbon Atomic alkoxyaryl, nitro, amino, alkoxycarbonyl, urea, carbamate, urea, alkylsulfonamide, -NR 7 (CH 2 ) m CO 2 H, arylsulfonamide, 3- Cycloalkyl groups of 8 carbon atoms, or heterocyclic rings of 5 to 7 atom rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur; R5为氢、1-6个碳原子的烷基、-CH(R8)R9、-C(CH2)nCO2R10、-C(CH3)2CO2R10、-CH(R8)(CH2)nCO2R10、-CH(R8)C6H4CO2R10或-CH2-四唑；R 5 is hydrogen, an alkyl group with 1-6 carbon atoms, -CH(R 8 )R 9 , -C(CH 2 ) n CO 2 R 10 , -C(CH 3 ) 2 CO 2 R 10 , -CH (R 8 )(CH 2 ) n CO 2 R 10 , -CH(R 8 )C 6 H 4 CO 2 R 10 or -CH 2 -tetrazole; R6为氢、1-6个碳原子的烷基、卤素、1-6个碳原子的烷氧基、1-6个碳原子的三氟烷基或1-6个碳原子的三氟烷氧基； R6 is hydrogen, alkyl of 1-6 carbon atoms, halogen, alkoxyl of 1-6 carbon atoms, trifluoroalkyl of 1-6 carbon atoms or trifluoroalkane of 1-6 carbon atoms Oxygen; R7为氢或1-6个碳原子的烷基；R 7 is hydrogen or an alkyl group of 1-6 carbon atoms; R8为氢、1-6个碳原子的烷基、6-10个碳原子的芳基、7-15个碳原子的芳烷基、3-8个碳原子的环烷基、苯二甲酸、 R is hydrogen , alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, aralkyl of 7-15 carbon atoms, cycloalkyl of 3-8 carbon atoms, phthalic acid , R9为CO2R12、CONHR12、四唑、PO3R12；R 9 is CO 2 R 12 , CONHR 12 , tetrazole, PO 3 R 12 ; R10为氢、1-6个碳原子的烷基、6-12个碳原子的芳基、7-15个碳原子的芳烷基；R 10 is hydrogen, an alkyl group of 1-6 carbon atoms, an aryl group of 6-12 carbon atoms, an aralkyl group of 7-15 carbon atoms; R11为1-3个碳原子的亚烷基；R 11 is an alkylene group of 1-3 carbon atoms; R12为氢、1-6个碳原子的烷基、6-12个碳原子的芳基、7-15个碳原子的芳烷基；R 12 is hydrogen, an alkyl group of 1-6 carbon atoms, an aryl group of 6-12 carbon atoms, an aralkyl group of 7-15 carbon atoms; X为O或S；X is O or S; Y为O、N或S；Y is O, N or S; Z为C或N；Z is C or N; Q为O、N或S；Q is O, N or S; m＝1-3；m=1-3; n＝1-6。n=1-6. 22.药用组合物，其包括具有以下结构的式I化合物或者它们的药学上可接受的盐和药用载体， 22. A pharmaceutical composition comprising a compound of formula I having the following structure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, 其中in R为 R is A为OR5或
Figure A9980836300122
A is OR 5 or
Figure A9980836300122
 R1为1-6个碳原子的烷基、3-8个碳原子的环烷基、噻吩基、呋喃基、吡啶基、 R is an alkyl group of 1-6 carbon atoms, a cycloalkyl group of 3-8 carbon atoms, thienyl, furyl, pyridyl, R2为氢、1-6个碳原子的烷基、或6-10个碳原子的芳基；R is hydrogen , an alkyl group of 1-6 carbon atoms, or an aryl group of 6-10 carbon atoms; R3和R4独立为卤素、氢、1-12个碳原子的烷基、6-10个碳原子的芳基、卤素、1-6个碳原子的三氟甲基、7-14个碳原子的烷氧基芳基、硝基、氨基、烷氧羰基、脲、氨基甲酸酯、脲、烷基磺酰胺、-NR7(CH2)mCO2H、芳基磺酰胺、3-8个碳原子的环烷基、或含有1至3个选自氧、氮或硫的杂原子的5至7个原子环的杂环；R and R are independently halogen, hydrogen, alkyl of 1-12 carbon atoms, aryl of 6-10 carbon atoms, halogen, trifluoromethyl of 1-6 carbon atoms, 7-14 carbon Atomic alkoxyaryl, nitro, amino, alkoxycarbonyl, urea, carbamate, urea, alkylsulfonamide, -NR 7 (CH 2 ) m CO 2 H, arylsulfonamide, 3- Cycloalkyl groups of 8 carbon atoms, or heterocyclic rings of 5 to 7 atom rings containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulfur; R5为氢、1-6个碳原子的烷基、-CH(R8)R9、-C(CH2)nCO2R10、-C(CH3)2CO2R10、-CH(R8)(CH2)nCO2R10、-CH(R8)C6H4CO2R10或-CH2-四唑；R 5 is hydrogen, an alkyl group with 1-6 carbon atoms, -CH(R 8 )R 9 , -C(CH 2 ) n CO 2 R 10 , -C(CH 3 ) 2 CO 2 R 10 , -CH (R 8 )(CH 2 ) n CO 2 R 10 , -CH(R 8 )C 6 H 4 CO 2 R 10 or -CH 2 -tetrazole; R6为氢、1-6个碳原子的烷基、卤素、1-6个碳原子的烷氧基、1-6个碳原子的三氟烷基或1-6个碳原子的三氟烷氧基； R6 is hydrogen, alkyl of 1-6 carbon atoms, halogen, alkoxyl of 1-6 carbon atoms, trifluoroalkyl of 1-6 carbon atoms or trifluoroalkane of 1-6 carbon atoms Oxygen; R7为氢或1-6个碳原子的烷基；R 7 is hydrogen or an alkyl group of 1-6 carbon atoms; R8为氢、1-6个碳原子的烷基、6-10个碳原子的芳基、7-15个碳原子的芳烷基、3-8个碳原子的环烷基、苯二甲酸、
Figure A9980836300131
R is hydrogen , alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, aralkyl of 7-15 carbon atoms, cycloalkyl of 3-8 carbon atoms, phthalic acid ,
Figure A9980836300131
 R9为CO2R12、CONHR12、四唑、PO3R12；R 9 is CO 2 R 12 , CONHR 12 , tetrazole, PO 3 R 12 ; R10为氢、1-6个碳原子的烷基、6-12个碳原子的芳基、7-15个碳原子的芳烷基；R 10 is hydrogen, an alkyl group of 1-6 carbon atoms, an aryl group of 6-12 carbon atoms, an aralkyl group of 7-15 carbon atoms; R11为1-3个碳原子的亚烷基；R 11 is an alkylene group of 1-3 carbon atoms; R12为氢、1-6个碳原子的烷基、6-12个碳原子的芳基、7-15个碳原子的芳烷基；R 12 is hydrogen, an alkyl group of 1-6 carbon atoms, an aryl group of 6-12 carbon atoms, an aralkyl group of 7-15 carbon atoms; X为O或S；X is O or S; Y为O、N或S；Y is O, N or S; Z为C或N；Z is C or N; Q为O、N或S；Q is O, N or S; m＝1-3；m=1-3; n＝1-6。n=1-6.
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