CN1308621A - Phenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia - Google Patents

Phenyl oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia Download PDF

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CN1308621A
CN1308621A CN99808361A CN99808361A CN1308621A CN 1308621 A CN1308621 A CN 1308621A CN 99808361 A CN99808361 A CN 99808361A CN 99808361 A CN99808361 A CN 99808361A CN 1308621 A CN1308621 A CN 1308621A
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hydrogen
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M·S·马拉马斯
J·E·弗罗贝尔
A·J·迪特里希
李泽南
I·古纳旺
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Wyeth LLC
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    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
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    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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Abstract

This invention provides compounds of structural Formula (I) wherein A is O, S, or N; B is -(CH2)m-, -CH(OH)-, or carbonyl; R<1> is hydrogen, halogen, alkyl of 1-6 carbon atoms, alcoxy of 1-6 carbon atoms, or trifluoromethyl; R<2> is alkyl of 1-18 carbon atoms, aryl of 6-10 carbon atoms, arylalkyl of 7-15 carbon atoms, Het-alkyl wherein the alkyl moiety is 1-6 carbon atoms; Het is (a) or (b); R<2a> is alkylene of 1-3 carbon atoms; G is oxygen, sulfur, or nitrogen; R<3>, R<4> are each, independently, hydrogen, halogen, alkyl of 1-3 carbon atoms, aryl of 6-10 carbon atoms or a heterocyclic ring of 5 to 7 ring atom containing 1 to 3 heteroatoms selected from oxygen, nitrogen, sulfur; R<5> is hydrogen, alkyl of 1-6 carbon atoms, -CH(R<7>)R<8>-, -C(CH2)nCO2R<9>, -C(CH3)2CO2R<9>, -CH(R<7>)(CH2)nCO2R<9>, or CH(R<7>)C6H4CO2R<9>; R<6> is hydrogen, halogen, alkyl of 1-6 carbon atoms, or -OR<5>; m=1-6; n=1-6; R<7> is hydrogen, alkyl of 1-6 carbons atoms, aryl of 6-10 carbon atoms, or arylalkyl of 7-15 carbon atoms; R<8> is -CO2R<10>, -CONHR<10>, tetrazole, or -PO3; R<9> and R<10> are each, independently, hydrogen, alkyl of 1-6 carbon atoms, aryl of 6-10 carbon atoms, or arylalkyl of 7-15 carbon atoms; or a pharmaceutically acceptable salt thereof, which are useful in treating metabolic disorders related to insulin resistance or hyperglycemia.

Description

The phenyl oxo-acetic acids that is used for the treatment of insulin resistance and hyperglycemia
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 (IDDDM) 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).
(Diatetes 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.1 989,84,976) 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.
The open 3-benzoyl benzofuran derivative of Eur.Pat.Appl.425359 A1 is as the preparation of cardiovascular agent intermediate.Czech. patent 265559 B1 openly prepare 2-ethyl-3-(3,5-two bromo-4-hydroxy benzoyls) cumarone as the uricosuric agent method.Open 2-ethyl-3-(3, the 5-two bromo-4-hydroxy benzoyls) cumarone [HU 18236 (1980)] of Fodor
Invention is described
The invention provides it 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 and hyperglycemia,
Figure A9980836100131
Wherein:
A is O, S or N;
B is-(CH 2) m-,-CH (OH)-or carbonyl;
R 1Be the alkyl of hydrogen, nitro, halogen, a 1-6 carbon atom, the alkoxyl group or the trifluoromethyl of a 1-6 carbon atom;
R 2For the aralkyl of the aryl of the alkyl of 1-18 carbon atom, a 6-10 carbon atom, a 7-15 carbon atom, wherein moieties is the Het-alkyl of 1-6 carbon atom;
Het is
Figure A9980836100141
Or
Figure A9980836100142
R 2aAlkylidene group for 1-3 carbon atom;
G is oxygen, sulphur or nitrogen;
R 3, R 4Each is independently for the aryl of the alkyl of hydrogen, halogen, a 1-3 carbon atom, a 6-10 carbon atom or contain 1 to 3 heterocycle that is selected from heteroatomic 5 to 7 annular atomses of oxygen, nitrogen, sulphur;
R 5For the alkyl of hydrogen, a 1-6 carbon atom ,-CH (R 7) R 8,-C (CH 2) nCO 2R 9,-C (CH 3) 2CO 2R 9,-CH (R 7) (CH 2) nCO 2R 9Or CH (R 7) C 6H 4CO 2R 9
R 6For the alkyl of hydrogen, halogen, a 1-6 carbon atom or-OR 5
m＝1-6；
n＝1-6；
R 7Be the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom;
R 8For-CO 2R 10,-CONHR 10, tetrazolium or-PO 3H 2
R 9And R 10Each independently is the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom.
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 similarly known acceptable acid form pharmacy acceptable salt from organic and mineral acid.When The compounds of this invention contains carboxylate radical or phenol moieties or similarly can form the part of base addition salt, 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 comprise straight chain and the branch chain portion both.Halogen refers to bromine, chlorine, fluorine and iodine.The substituent aryl moiety of aryl or aralkyl is phenyl, naphthyl or 1, and 4-benzodioxan-5-base is preferred, and wherein phenyl is for most preferably.Aryl moiety can be selected from following substituting group optional one, two or three-replace: 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 each alkyl be 1-6 carbon atom dialkyl amido, nitro, cyano group ,-CO 2The alkyl-carbonyl oxygen base 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 optically active isomer and diastereomer.Although do not show the stereochemistry of formula I, the present invention includes the R and the S steric isomer of the enantiomer-pure of such optically active isomer and diastereomer and racemize and fractionation; And the mixture of other R and S steric isomer and their pharmacy acceptable salt.
Preferred compound of the present invention is those formulas I compound or their pharmacy acceptable salt, wherein R 1Be hydrogen or halogen; R 2Be the alkyl of 1-6 carbon atom or the aralkyl of 7-15 carbon atom; R 3And R 4Be halogen; With m be 1;
More preferably compound is following lists in the present invention: embodiment 1. (2-ethyl-cumarone-3-yl)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone embodiment 2.[2,6-two bromo-4-(2-ethyl-cumarone-3-carbonyl)-phenoxy group]-acetate embodiment 3.2,6-two bromo-4-(2-ethyl-cumarone-3-base-methyl)-phenol embodiment 4. (3,5-two bromo-2,4-dihydroxyl-phenyl)-(2-ethyl-cumarone-3-yl)-ketone embodiment 5.[2,6-two bromo-4-(2-butyl-cumarone-3-carbonyl)-phenoxy group]-acetate embodiment 6. (2-butyl-cumarone-3-yl)-(3,5-two bromo-4-dihydroxyl-phenyl)-ketone embodiment 7.[2,6-two bromo-4-(2-butyl-cumarone-3-ylmethyl)-phenoxy group]-acetate embodiment 8. (2-ethyl-cumarone-3-yl)-(2,4,6-three bromo-3-hydroxyl-phenyl)-ketone embodiment 9. (2-benzyl-cumarone-3-yl)-(4-hydroxyl-3,5-two iodo-phenyl)-ketone embodiment 10.[4-(2-benzyl-cumarone-3-carbonyl)-2,6-two bromo-phenoxy groups]-acetate embodiment 11. (2-benzyl-benzo [b] thiene-3-yl-)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone embodiment 12.[4-(2-benzyl-benzo [b] thiophene-3-carbonyl)-2,6-two bromo-phenoxy groups]-acetate embodiment 13. (5-chloro-2-ethyl-cumarone-3-yl)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone embodiment 14. (2-benzyl-cumarone-3-yl)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone embodiment 15. (3,5-two bromo-4-hydroxyl-phenyl)-(2-styroyl-cumarone-3-yl)-ketone embodiment 16. (2-butyl-cumarone-3-yl)-(4-hydroxyl-3,5-two iodo-phenyl)-ketone embodiment 17.[4-(2-benzyl-cumarone-3-carbonyl)-2,6-two iodo-phenoxy groups]-acetate embodiment 18. (2-ethyl-cumarone-3-yl)-(4-hydroxyl-3,5-two iodo-phenyl)-ketone embodiment 19.[2,6-two bromo-4-(2-styroyl-cumarone-3-carbonyl)-phenoxy group]-acetate embodiment 20.[2,6-two bromo-4-(5-chloro-2-ethyl-1-cumarone-3-carbonyl)-phenoxy group]-acetate embodiment 21.[4-(2-benzyl-benzo [b] thiophene-3-carbonyl)-2,6-two bromo-phenoxy group-methyl]-phosphoric acid embodiment 22. (R)-2-[2,6-two bromo-4-(2-butyl-cumarone-3-carbonyl)-phenoxy group]-3-phenyl-propionic acid embodiment 23. (R)-2-[2,6-two bromo-4-(2-butyl-cumarone-3-ylmethyl)-phenoxy group]-3-phenyl-propionic acid.
According to following flow process, by raw material available on the market or the feedstock production The compounds of this invention that uses literature method to prepare.Flow process I shows the preparation of representative compounds of the present invention.
Flow process I
Figure A9980836100171
In flow process 1, commercially available cumarone and thionaphthene (1) can be used the alkyl lithium reagents lithiumation in the 2-position, and it uses aldehyde R 2-CHO handles, and generates alcohol (2) [reference Org.React.1979, the 26th volume].Go back carbinol (2) with sodium borohydride and trifluoroacetic acid [reference Syn.Comm.1990,20,487-493], obtain compound (3).Use friedel-crafts method [friedel-crafts and correlated response, Wiely Interscience, New York .1963-1965], handle compound (3), generate ketone (4) with acyl chlorides.Use Wolf-Ke to vow the method for receiving [reference Org.Reactions.1948, the 4th volume], ketone can be reduced to compound (6).Use BBr 3[reference J.Org.Chem.1974,39,1427-1429] makes compound (4) and (6) demethylation, generates phenol (5) and (7).Can be with bromine and the potassium acetate in acetate or the iodine that is used in the presence of the sodium hydroxide with phenol (5) and (7) bromination or iodate, generate the compound (9) of bromo or iodo.In palladium catalyst [Suzuki method; Reference Syn.Comm.1981,11,513-519] exist down, compound (9) can with fragrance or assorted fragrant boric acid coupling, generate terphenyl (10).Compound (5), (7), (9) and (10) can be used in and generate the product (11-13) that requires.The first, in the presence of sodium hydride, the enough monobromo-acetic acid methyl esters of energy generate the oxo-acetic acids methyl esters with compound (5), (7) and (9) alkylation, and the enough sodium hydroxide saponification of its energy generate oxo-acetic acids (11).The second, the enough bromo acetonitriles of energy generate oxo-acetonitrile with compound (5), (7) and (9) alkylation, and it is handled with sodium azide and ammonium chloride, generates tetrazolium (12).The 3rd, use Mitsunobu method [reference Synthesis.1981,1-27], can handle compound (5), (7) and (9) by enough 2-hydroxycarboxylic acid esters (for example 3-phenylacetic acid), generate the oxo-acetic acids ester, the enough sodium hydroxide saponification of its energy obtain oxo-acetic acids (13).
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.Restraining effect through the triphosphoric acid insulin receptor ten bisphosphate peptide dephosphorylations 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 Kahm 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, RaffM, 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 850 ug 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.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 (pH7.4) 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 4 N 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.The activity rating of screening 50uM (finally) medicine its to microsome PTP enzyme inhibition.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 ??IC 50(μM) Under 50 μ M with the variation % of comparing
????1 ????70.1
????2 ????-25
????3 ????-34
????4 ????34.3
????5 ????31.2
????6 ????24.2
????7 ????22.7
????8 ????17.5
????9 ????22.7
????10 ????36
????11 ????33.9
????12 ????27.8
????13 ????27.1
????14 ????27.8
????15 ????20.5
????16 ????15.3
????17 ????28.4
????18 ????30.7
????19 ????26.3
????20 ????40.4
????21 ????34.5
????22 ????-77
????23 ????-85
Phenyl-arsine oxide (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 33mMTris-HCl, 2mM EDTA and 50mM b-mercaptoethanol) dilution reorganization rPTP1B, obtain activity and be approximately 1000-2000 nmoles/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 (pH7.4) 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 200mL Victoria Green WPB-ammonium molybdate-polysorbas20 hold back agent (MG/AM/Tw) termination reaction.Hold back agent contains 3 part of 0.45% Victoria Green WPB hydrochloride in 4NHCl 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 groups.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 Under 10 μ M with the variation % of comparing ??IC 50(μM)
????1 ??25.8(rPTP1B)
????2 ????-30(rPTP1B)
????3 ????-74(rPTP1B)
????4 ????-64(rPTP1B)
????5 ????-78(rPTP1B)
????6 ????-90(rPTP1B)
????7 ????-99(rPTP1B)
????7 ??1.4(hPTP1B)
????8 ????-61(rPTP1B)
????9 ????-99(rPTP1B)
????10 ????-75(rPTP1B)
????11 ??3.97(rPTP1B)
????11 ??1.94(hPTP1B)
????12 ????-88(rPTP1B)
????13 ????-64(rPTP1B)
????14 ????-81(rPTP1B)
????15 ?2.6(rPTP1B)
????16 ?0.19(rPTP1B)
????16 ?2.6(hPTP1B)
????17 ????-97(rPTP1B)
????18 ????-60(rPTP1B)
????19 ????-53(rPTP1B)
????20 ????-34(rPTP1B)
????21 ??-35(rPTP1B)
????22 ?1.15(hPTP1B)
????23 ?0.87(hPTP1B)
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.:Diabetologia14:141-148,1978] of the hypoglycemic drug of treatment NIDDM.
In each test method, agematched mouse [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) Glucose % from carrier changes Regular Insulin % from carrier changes
????1 ????100 ????-44.6 ????-89.5
????2 ????100 ????-48.1 ????-78.2
????3 ????100 ????-6.2a ????-56.6
????4 ????100 ????-19.8a ????-61.8
????5 ????100 ????-20.1 ????-54.8
????6 ????100 ????-40.6 ????-70.4
????7 ????100 ????-29.4 ????-13.1a
????8 ????100 ????-3.3a ????-31.2
????9 ????100 ????-37.1 ????-73.7
????10 ????100 ????-17.7a ????-70.0
????11 ????100 ????-30.3 ????-53.2
????12 ????100 ????-30.7 ????-60.7
????13 ????100 ????-12a ????-74.5
????14 ????100 ????-36.8 ????-40.7a
????15 ????100 ????-32.8 ????-10.3a
????16 ????100 ????51.8 ????-73.7
????18 ????100 ????39.6 ????-83.6
Ciglitazone (reference substance) ????100 ????-43 ????-39
A-does not have remarkable activity (p＜0.05) under this dosage.
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.
Effective administration per daily dose of these compounds is about 1-250mg/kg, and can be with single dose or with two or a plurality of divided dose administration.Can give these dosage and make active compound of the present invention directly enter receptor's blood in any useful mode, comprise oral, implantation, non-enteron aisle (comprising intravenously, intraperitoneal and subcutaneous injection), rectum, vagina and percutaneous dosing.Percutaneous dosing disclosed by the invention comprises the administration of (comprising epithelium and mucous tissue) of all endotheliums by body surface and body passageway.Available The compounds of this invention or its pharmacy acceptable salt carry out this class administration with lotion, ointment, foaming agent, patch, suspensoid, solution and suppository (rectum and vaginal suppository) form.
The oral preparations that contains active compound of the present invention can comprise any oral dosage form commonly used, comprises tablet, capsule, buccal form, lozenge, lozenge and liquid oral, suspension or solution.Capsule can contain this active compound and inert filler and/or thinner, as pharmaceutically acceptable starch (as corn, potato or tapioca (flour)), sugar, artificial sweetening agent, powdered Mierocrystalline cellulose, as the mixture of crystal and Microcrystalline Cellulose, flour, gelatin, natural gum etc.Used tablet can be by conventional compacting; the wet granulation or the preparation of dry granulation method; and can utilize pharmaceutically acceptable thinner; tackiness agent; lubricant; disintegrating agent; suspension agent or stablizer; include, but are not limited to Magnesium Stearate; stearic acid; talcum powder; sodium lauryl sulphate; Microcrystalline Cellulose; calcium carboxymethylcellulose; Polyvinylpyrolidone (PVP); gelatin; alginic acid; gum arabic; xanthan gum; Trisodium Citrate; silicate composite; lime carbonate; glycine; dextrin; sucrose; Sorbitol Powder; Lin Suanergai; calcium sulfate; lactose; kaolin; mannitol; sodium-chlor; talcum powder; dry starch and powdered sugar.Oral preparations of the present invention can utilize standard delay or time-delay release dosage form to change the absorption of this active compound.Can adopt traditional material, comprise theobroma oil, add or do not add the beeswax and the glycerine that can change this suppository fusing point and prepare suppository.Also can use water soluble suppository bases, as various molecular weight polyethylene glycol.
The dosage, dosage regimen and the administering mode that are clear that these compounds will change according to disease of being treated and individuality, and will obey the judgement of medical worker.Preferably begin to give one or more compound of the present invention, increase to the dosage that meets the requirements of effect then with low dosage.
The preparation process of following method explanation representative embodiment of the present invention.Embodiment 1 (2-ethyl-cumarone-3-yl)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone
Obtain this compound from Sigma Chemicals.Embodiment 2[2,6-two bromo-4-(2-ethyl-cumarone-3-carbonyl)-phenoxy group]-acetate
With the monobromo-acetic acid tert-butyl ester (0.57mL, 3.54mmol) be added drop-wise to (2-ethyl-cumarone-3-yl)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone (1.0g, 2.36mmol), salt of wormwood (0.98g, 7.08mmol) and N, in the mixture of dinethylformamide (10mL).Under 80 ℃, this mixture was stirred 3 hours, be poured in the water and use ethyl acetate extraction.Through MgSO 4Dry organic extracting solution.Evaporation obtains xanchromatic oil (1.4g), it is dissolved in the methylene dichloride (50mL) and with trifluoroacetic acid (5mL) handled 10 hours.Vacuum is removed volatile matter.And, obtain white solid (0.82g, 42% yield): mp 135-137 through flash chromatography method (hexane/EtoAc 1: 1) the purifying resistates on acidic silica gel; MSm/e480 M +To C 19H 14Br 2O 5The analytical calculation value: C, 47.33; H, 2.93; Measured value: C, 47.25; H, 2.91.Embodiment 32,6-two bromo-4-(2-ethyl-cumarone-3-base-methyl)-phenol
Tert-butyldimethylsilyl chloride is joined (2-ethyl-cumarone-3-yl)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone (10.0g, 23.58mmol), imidazoles (1.6g, 23.58mmol), 4-dimethylaminopyridine (100mg) and N, in the mixture of dinethylformamide (100mL).At room temperature, this mixture was stirred 10 hours, in the impouring water, and use ethyl acetate extraction.Through MgSO 4Dry organic extracting solution.Evaporation obtains oil (11.5g), and it is dissolved in the methyl alcohol (100mL) also with sodium borohydride (0.96g, 25.65mmol) processing.At room temperature, this mixture was stirred 3 hours, in the impouring water, and use ether extraction.Through MgSO 4Dry organic extracting solution.Evaporation obtains resistates (10.5g), its be dissolved in methylene dichloride (100mL) and 0 ℃ down with triethyl silicane (6.21mL, 38.9mmol) and trifluoroacetic acid (10mL) processing.Stir after 30 minutes, vacuum is removed volatile matter and the hydrofluoric acid (5.0mL) that is used under 80 ℃ in the acetonitrile (50ml) was handled resistates 5 hours.Vacuum is removed volatile matter and through flash chromatography method (hexane/ethyl acetate 10: 1) purifying resistates, is obtained white solid (6.5g, 37% yield): mp 87-88; MSm/e 408 M +Embodiment 4 (3,5-two bromo-2,4-dihydroxyl-phenyl)-(2-ethyl-cumarone-3-yl)-ketone
With bromine (0.73mL, 14.2mmol) solution in acetate (3mL) joins known compound (2,4-dihydroxyl-phenyl)-(2.0g is 7.08mmol) at 6: 1 acetate: in the solution in the water (14mL) for (2-ethyl-cumarone-3-yl)-ketone (CA registration number 90908-66-0 number).Join in the water (200mL) this reaction mixture and filtration, obtain title compound (2.7g, 87% yield): mp 150-151 into brown solid; MSm/e 438 M +To C 17H 12Br 2O 4The analytical calculation value: C, 46.39; H, 2.75; Measured value: C, 45.95; H, 2.66.Embodiment 5[2,6-two bromo-4-(2-butyl-cumarone-3-carbonyl)-phenoxy group]-acetate
With with the essentially identical method of in embodiment 2, describing, prepare this compound by (2-butyl-cumarone-3-yl)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone and the monobromo-acetic acid tert-butyl ester, and obtain pale solid, mp 92-94 ℃; MSm/e 508 (M +); To C 21H 18Br 2O 5The analytical calculation value: C, 49.44; H, 3.56; Measured value: C, 47.24; H, 3.59.Embodiment 6 (2-butyl-cumarone 3-yl)-(3,5-two bromo-4-dihydroxyl-phenyl)-ketone
With bromine (3.49mL) be added dropwise to 2-normal-butyl-3-(hydroxyl-benzoyl)-benzo [b] furans (10.0g, 34.0mmol), acetate (50mL) and H 2In the mixture of O (10mL).This reaction mixture was stirred 12 hours and was poured in the water.The solid of filtering-depositing is also dry, obtains white solid (11.2g, 71% yield): mp 95-97; MS m/e 450 M +To C 19H 16Br 2O 3* 0.8H 2The analytical calculation value of O: C, 48.89; H, 3.80; Measured value: C, 48.83; H, 3.37.Embodiment 7[2,6-two bromo-4-(2-butyl-cumarone-3-ylmethyl)-phenoxy group]-acetate
With with the basic identical method of in embodiment 2, describing, by 2,6-two bromo-4-(2-ethyl-cumarone-3-base-methyl)-phenol and the monobromo-acetic acid tert-butyl ester prepare this compound, and obtain pale solid, mp 118-119 ℃; MS m/e 494 (M +); To C 21H 20Br 2O 4The analytical calculation value: C, 50.83; H, 4.06; Measured value: C, 50.46; H, 3.94.Embodiment 8 (2-ethyl-cumarone-3-yl)-(2,4,6-three bromo-3-hydroxyl-phenyl)-ketone
With with as the essentially identical method of in embodiment 6, describing, prepare this compound by (2-ethyl-cumarone-3-yl)-(3-hydroxyl-phenyl)-ketone and bromine, and obtain white solid, mp 153-154 ℃; MS m/e 517 M-H) +To C 17H 11Br 3O 3The analytical calculation value: C, 40.52; H, 2.20; Measured value: C, 40.12; H, 2.07.Embodiment 9 (2-benzyl-cumarone-3-yl)-(4-hydroxyl-3,5-two iodo-phenyl)-ketone
(2.48g, 7.55mmol) drips of solution in sodium hydroxide (1.2g) and water (113mL) joins in the mixture of iodine (4.22g), sodium iodide (2.75g) and water (113mL) with (2-benzyl-cumarone-3-yl)-(4-hydroxyl-phenyl)-ketone.Under 65 ℃, new mixture was stirred 3 hours.Be poured into this mixture in the water and use ethyl acetate extraction.Through MgSO 4Dry organic extracting solution.The evaporation and through flash chromatography method (petrol ether/ethyl acetate 6: 4) purifying, obtain brown solid (1.92g, 4% yield): mp 153-154 ℃; MS m/e 580 (M +); To C 22H 14I 2O 3The analytical calculation value: C, 45.55; H, 2.43; Measured value: C, 46.23; H, 2.36.Embodiment 10[4-(2-benzyl-cumarone-3-carbonyl)-2,6-two bromo-phenoxy groups]-acetate
With with the essentially identical method of in embodiment 20, describing, prepare this compound by (2-benzyl-cumarone-3-yl)-(4-hydroxyl-phenyl)-ketone and monobromo-acetic acid methyl esters, and obtain pale solid, mp 165-167 ℃; MS m/e 544 (M) +To C 24H 16Br 2O 5The analytical calculation value: C, 52.97; H, 2.96; Measured value: C, 52.74; H, 2.94.Embodiment 11 (2-benzyl-benzo [b] thiene-3-yl-)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone
The 1 equivalent tin chloride (IV) of use in the dithiocarbonic anhydride solvent is as promotor; with 1 equivalent methoxybenzoyl chlorine acidylate known compound 2-benzyl-benzo [b] thiophene (CA registration number 3407-15-6 number), obtain (2-benzyl-benzo [b] thiene-3-yl-)-(4-methoxyl group-phenyl)-ketone (85% yield).Under 228 ℃, use 6 equivalent pyridine hydrochlorides, make this compound demethylation, obtain (2-benzyl-benzo [b] thiene-3-yl-)-(4-hydroxyl-phenyl)-ketone (90% yield).According to the method for embodiment 4, make this compound bromination, obtain title compound (95% yield): mp 155.5-156.5 ℃ into white solid; MS m/e 500 (M) +To C 22H 14Br 2O 2The analytical calculation value of S: C, 52.61; H, 2.80; Measured value: C, 52.43; H, 2.71.Embodiment 12[4-(2-benzyl-benzo [b] thiophene-3-carbonyl)-2,6-two bromo-phenoxy groups]-acetate
With with the essentially identical method of in embodiment 20, describing, prepare this compound by (2-benzyl-benzo [b] thiene-3-yl-)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone and monobromo-acetic acid methyl esters, and obtain pale solid, mp 162-163 ℃; MS m/e 558 (M) +To C 24H 16Br 2O 4The analytical calculation value of S: C, 51.45; H, 2.88; Measured value: C, 51.15; H, 2.71.Embodiment 13 (5-chloro-2-ethyl-cumarone-3-yl)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone
With with the essentially identical method of in embodiment 6, describing, prepare this compound by (5-chloro-2-ethyl-cumarone-3-yl)-(4-hydroxyl-phenyl)-ketone and bromine, and obtain white solid, mp 126-128 ℃; MS m/e 454.9 (M-H) +To C 17H 11Br 2ClO 3The analytical calculation value: C, 44.53; H, 2.42; Measured value: C, 44.35; H, 2.13.Embodiment 14 (2-benzyl-cumarone-3-yl)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone
With with the essentially identical method of in embodiment 6, describing, prepare this compound by (2-benzyl-cumarone-3-yl)-(4-hydroxyl-phenyl)-ketone and bromine, and obtain pale solid, mp 156-158 ℃; MS m/e 484 (M +); To C 22H 14Br 2O 3The analytical calculation value: C, 53.43; H, 2.74; Measured value: C, 53.73; H, 2.75.Embodiment 15 (3,5-two bromo-4-hydroxyl-phenyl)-(2-styroyl-cumarone-3-yl)-ketone
With with the essentially identical method of in embodiment 6, describing, prepare this compound by (2-styroyl-cumarone-3-yl)-(4-hydroxyl-phenyl)-ketone and bromine, and obtain yellow solid, mp 153-154 ℃; MS m/e 502 (M+H) +To C 23H 16Br 2O 3* 0.057C 2H 4O 2The analytical calculation value: C, 55.12; H, 3.25; Measured value: C, 54.72; H, 2.99.Embodiment 16 (2-butyl-cumarone 3-yl)-(4-hydroxyl-3,5-two iodo-phenyl)-ketone
Known compound (CA registration number 1951-26-4 number): mp 141.5-142.5 ℃; MS m/e545 (M+H) +To C 19H 16I 2O 3The analytical calculation value: C, 41.79; H, 2.95; Measured value: C, 41.97; H, 2.83.Embodiment 17[4-(2-benzyl-cumarone-3-carbonyl)-2,6-two iodo-phenoxy groups]-acetate
With with the essentially identical method of in embodiment 2, describing, prepare this compound by (2-benzyl-cumarone-3-yl)-(3,5-two iodo-4-hydroxyl-phenyl)-ketone and the monobromo-acetic acid tert-butyl ester.Use formic acid to substitute trifluoroacetic acid.Obtain product, mp 144-146 ℃ for pale solid; MS m/e 638 (M +); To C 24H 16I 2O 5The analytical calculation value: C, 45.17; H, 2.53; Measured value: C, 44.19; H, 2.42.Embodiment 18[4-(2-benzyl-benzo [b] thiophene-3-carbonyl)-2,6-two bromo-phenoxy groups]-acetate
Known compound (CA registration number 68-90-6 number).Embodiment 19[2,6-two bromo-4-(2-styroyl-cumarone-3-carbonyl)-phenoxy group]-acetate
With with the essentially identical method of in embodiment 20, describing, prepare this compound, and obtain pale solid, mp 163-164 ℃ by (2-styroyl-cumarone-3-yl)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone; MS m/e 556 (M +); To C 25H 18Br 2O 5The analytical calculation value: C, 53.79; H, 3.25; Measured value: C, 53.91; H, 3.14.Embodiment 20[2,6-two bromo-4-(5-chloro-2-ethyl-1-cumarone 3-carbonyl)-phenoxy group]-acetate step a) [2,6-two bromo-4-(5-chloro-2-ethyl-1-cumarone-3-carbonyl)-phenoxy group]-methyl acetate
The monobromo-acetic acid methyl esters is added drop-wise to (4-chloro-2-ethyl-cumarone-3-yl)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone (2.81g, 6.13mmol), salt of wormwood (0.93g) and N, in the mixture of dinethylformamide (28mL).This mixture was stirred 15 hours, be poured in the water and use ethyl acetate extraction.Through MgSO 4Dry organic extracting solution.The evaporation and through flash chromatography method (petrol ether/ethyl acetate 9: 1) purifying, obtain white solid (2.89g, 89% yield): mp 108-109 ℃; MS m/e 528 (M +); To C 20H 51Br 2ClO 5The analytical calculation value: C, 45.27; H, 2.89; Measured value: C, 45.08; H, 2.61.Step b) [2,6-two bromo-4-(5-chloro-2-ethyl-1-cumarone-3-carbonyl)-phenoxy group]-acetate
(15.9mL, (2.8g is 5.3mmol) in the solution in tetrahydrofuran (THF) (20mL) and methyl alcohol (20mL) 0.5N) to join [2,6-two bromo-4-(5-chloro-2-ethyl-1-cumarone-3-carbonyl)-phenoxy group]-methyl acetate with potassium hydroxide.This mixture was stirred 30 minutes, in the impouring water, with the HCl acidifying and be cooled to 0 ℃.The solid of filtering-depositing is also dry.Recrystallization crude product product from acetate and water obtains white solid (2.01g, 74% yield): mp 175-177 ℃; MS m/e514 (M +).To C 19H 13Br 2ClO 5The analytical calculation value: C, 44.18; H, 2.54; Measured value: C, 44.16; H, 2.46.Embodiment 21[4-(2-benzyl-benzo [b] thiophene-3-carbonyl)-2,6-two bromo-phenoxymethyls]-phosphoric acid
Sodium hydride (0.09g, 80% in mineral oil) is joined (2-benzyl-benzo [b] thiene-3-yl-)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone of cold (0 ℃), and (0.96g is 1.91mmol) and in the mixture of tetrahydrofuran (THF) (20mL).This mixture was stirred 1 hour and was added dropwise to then trifluoro-methanesulfonyl oxy methyl acid phosphate diethyl ester (0.63g).Make new mixture rise to room temperature, stirred 4 hours, and be warmed to 50 ℃ and stirred other 2 hours then.In the mixture impouring water and use ethyl acetate extraction.Through MgSO 4Dry organic extracting solution.Through flash chromatography method (methylene dichloride/acetonitrile 95: 5) purifying, obtain brown oil (0.79g, 63% yield).This product is dissolved in the methylene dichloride (18mL) and at 0 ℃ to be handled 6 hours with iodo trimethyl silane (0.45mL) down.With in this mixture impouring water and use ethyl acetate extraction.Through MgSO 4Dry organic extracting solution.The evaporation and through flash chromatography method (methylene dichloride/acetonitrile 85: 15) purifying, obtain yellow solid (1.1g, 77% yield): mp 210-212 ℃; MS m/e 595 (M+H) +Embodiment 22 (R)-2-[2,6-two bromo-4-(2-butyl-cumarone-3-carbonyl)-phenoxy group]-3-phenyl-propionic acid
Diethylazodicarboxylate (0.13mL) is added dropwise to (2-butyl-cumarone-3-yl)-(3,5-two bromo-4-hydroxyl-phenyl)-and ketone (0.24g, 0.54mmol), in the solution of triphenylphosphine (0.21g), (S)-(-)-3-phenyl-lactic acid methyl esters (0.14g) and benzene (2.4mL).Under 80 ℃, this mixture stirring was also at room temperature spent the night in 3 hours.Vacuum is removed volatile matter and through flash chromatography method purifying resistates, is obtained oil (0.13g).This product is dissolved in tetrahydrofuran (THF) (1.7mL) and the methyl alcohol (1.7mL) also with potassium hydroxide (1.0N, 0.5mL) processing.After stirring 4 hours, in this mixture impouring water, with HCl (1N) acidifying and use ether extraction.Through MgSO 4Dry organic extracting solution.Evaporation obtains faint yellow solid (0.23g, 84% yield): mp 56-58 ℃; MS m/e 597 (M-H) +To C 28H 24Br 2O 5* 0.8H 2The analytical calculation value of O: C, 54.69; H, 4.20; Measured value: C, 54.65; H, 3.88.Embodiment 23 (R)-2-[2,6-two bromo-4-(2-butyl-cumarone-3-ylmethyl)-phenoxy group]-3-phenyl-propionic acid
With with the essentially identical method of in embodiment 21, describing, by 2,6-two bromo-4-(2-ethyl-cumarone-3-base-methyl)-phenol and (S)-(-)-3-phenyl-lactic acid methyl esters prepares this compound, and obtains oil (0.11g, 91 yields).The 1N sodium hydroxide (0.19mL) that is used in the methyl alcohol was handled this product 30 minutes.Evaporation obtains white solid (0.1g, 84% yield), mp 225-226 ℃; MS m/e 583 (M-H) +To C 28H 25Br 2O 4Na * 0.3H 2The analytical calculation value of O: C, 54.78; H, 4.20; Measured value: C, 54.60; H, 3.79.

Claims (25)

1. have the formula I compound of following structure or their pharmacy acceptable salt,
Wherein:
A is O, S or N;
B is-(CH 2) m-,-CH (OH)-or carbonyl;
R 1Be the alkyl of hydrogen, nitro, halogen, a 1-6 carbon atom, the alkoxyl group or the trifluoromethyl of a 1-6 carbon atom;
R 2For the aralkyl of the aryl of the alkyl of 1-18 carbon atom, a 6-10 carbon atom, a 7-15 carbon atom, wherein moieties is the Het-alkyl of 1-6 carbon atom;
Het is Or
Figure A9980836100023
R 2aAlkylidene group for 1-3 carbon atom;
G is oxygen, sulphur or nitrogen;
R 3, R 4Each is independently for the aryl of the alkyl of hydrogen, halogen, a 1-3 carbon atom, a 6-10 carbon atom or contain 1 to 3 heterocycle that is selected from heteroatomic 5 to 7 annular atomses of oxygen, nitrogen, sulphur;
R 5For the alkyl of hydrogen, a 1-6 carbon atom ,-CH (R 7) R 8,-C (CH 2) nCO 2R 9,-C (CH 3) 2CO 2R 9,-CH (R 7) (CH 2) nCO 2R 9Or CH (R 7) C 6H 4CO 2R 9
R 6For the alkyl of hydrogen, halogen, a 1-6 carbon atom or-OR 5
m＝1-6；
n＝1-6；
R 7Be the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom;
R 8For-CO 2R 10,-CONHR 10, tetrazolium or-PO 3
R 9And R 10Each independently is the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom.
2. the compound of claim 1 or their pharmacy acceptable salt, wherein
R 1Be hydrogen or halogen;
R 2Be the alkyl of 1-6 carbon atom or the aralkyl of 7-15 carbon atom;
R 3And R 4Be halogen; With
m＝1。
4. the compound of claim 1, it is [2,6-two bromo-4-(2-ethyl-cumarone-3-carbonyl)-phenoxy group]-acetate or its pharmacy acceptable salt.
5. the compound of claim 1, it is 2,6-two bromo-4-(2-ethyl-cumarone-3-base-methyl)-phenol or its pharmacy acceptable salt.
6. the compound of claim 1, it is (3,5-two bromo-2,4-dihydroxyl-phenyl)-(2-ethyl-cumarone-3-yl)-ketone or its pharmacy acceptable salt.
7. the compound of claim 1, it is [2,6-two bromo-4-(2-butyl-cumarone-3-carbonyl)-phenoxy group]-acetate or its pharmacy acceptable salt.
8. the compound of claim 1, it is (2-butyl-cumarone-3-yl)-(3,5-two bromo-4-dihydroxyl-phenyl)-ketone or its pharmacy acceptable salt.
9. the compound of claim 1, it is [2,6-two bromo-4-(2-butyl-cumarone-3-ylmethyl)-phenoxy group]-acetate or its pharmacy acceptable salt.
10. the compound of claim 1, it is (2-ethyl-cumarone-3-yl)-(2,4,6-three bromo-3-hydroxyl-phenyl)-ketone or its pharmacy acceptable salt.
11. the compound of claim 1, it is (2-benzyl-cumarone-3-yl)-(4-hydroxyl-3,5-two iodo-phenyl)-ketone or its pharmacy acceptable salt.
12. the compound of claim 1, it is [4-(2-benzyl-cumarone-3-carbonyl)-2,6-two bromo-phenoxy groups]-acetate or its pharmacy acceptable salt.
13. the compound of claim 1, it is (2-benzyl-benzo [b] thiene-3-yl-)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone or its pharmacy acceptable salt.
14. the compound of claim 1, it is [4-(2-benzyl-benzo [b] thiophene-3-carbonyl)-2,6-two bromo-phenoxy groups]-acetate or its pharmacy acceptable salt.
15. the compound of claim 1, it is (5-chloro-2-ethyl-cumarone-3-yl)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone or its pharmacy acceptable salt.
16. the compound of claim 1, it is (2-benzyl-cumarone-3-yl)-(3,5-two bromo-4-hydroxyl-phenyl)-ketone or its pharmacy acceptable salt.
17. the compound of claim 1, it is [4-(2-benzyl-cumarone-3-carbonyl)-2,6-two iodo-phenoxy groups]-acetate or its pharmacy acceptable salt.
18. the compound of claim 1, it is [2,6-two bromo-4-(2-styroyl-cumarone-3-carbonyl)-phenoxy group]-acetate or its pharmacy acceptable salt.
19. the compound of claim 1, it is [2,6-two bromo-4-(5-chloro-2-ethyl-1-cumarone-3-carbonyl)-phenoxy group]-acetate or its pharmacy acceptable salt.
20. the compound of claim 1, it is [4-(2-benzyl-benzo [b] thiophene-3-carbonyl)-2,6-two bromo-phenoxymethyls]-phosphoric acid or its pharmacy acceptable salt.
21. the compound of claim 1, it is (R)-2-[2,6-two bromo-4-(2-butyl-cumarone-3-carbonyl)-phenoxy group]-3-phenyl-propionic acid or its pharmacy acceptable salt.
22. the compound of claim 1, it is (R)-2-[2,6-two bromo-4-(2-butyl-cumarone-3-ylmethyl)-phenoxy group]-3-phenyl-propionic acid or its pharmacy acceptable salt.
23. treatment is by the method for the Metabolic disorder of insulin resistance or hyperglycemia mediation in the Mammals that needs is arranged, this method comprises and gives formula I compound that described Mammals has following structure or their pharmacy acceptable salt,
Wherein:
A is O, S or N;
B is-(CH 2) m-,-CH (OH)-or carbonyl;
R 1Be the alkyl of hydrogen, halogen, a 1-6 carbon atom, the alkoxyl group or the trifluoromethyl of a 1-6 carbon atom;
R 2For the aralkyl of the aryl of the alkyl of 1-18 carbon atom, a 6-10 carbon atom, a 7-15 carbon atom, wherein moieties is the Het-alkyl of 1-6 carbon atom;
Het is
Figure A9980836100052
Or
Figure A9980836100053
R 2aAlkylidene group for 1-3 carbon atom;
G is oxygen, sulphur or nitrogen;
R 3, R 4Each is independently for the aryl of the alkyl of hydrogen, halogen, a 1-3 carbon atom, a 6-10 carbon atom or contain 1 to 3 heterocycle that is selected from heteroatomic 5 to 7 annular atomses of oxygen, nitrogen, sulphur;
R 5For the alkyl of hydrogen, a 1-6 carbon atom ,-CH (R 7) R 8,-C (CH 2) nCO 2R 9,-C (CH 3) 2CO 2R 9,-CH (R 7) (CH 2) nCO 2R 9Or CH (R 7) C 6H 4CO 2R 9
R 6For the alkyl of hydrogen, halogen, a 1-6 carbon atom or-OR 5
m＝1-6；
n＝1-6；
R 7Be the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom;
R 8For-CO 2R 10,-CONHR 10, tetrazolium or-PO 3
R 9And R 10Each independently is the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom.
24. comprising, treatment or suppress the method for type ii diabetes in the Mammals that needs is arranged, this method give formula I compound that described Mammals has following structure or their pharmacy acceptable salt,
Wherein:
A is O, S or N;
B is-(CH 2) m-,-CH (OH)-or carbonyl;
R 1Be the alkyl of hydrogen, halogen, a 1-6 carbon atom, the alkoxyl group or the trifluoromethyl of a 1-6 carbon atom;
R 2For the aralkyl of the aryl of the alkyl of 1-18 carbon atom, a 6-10 carbon atom, a 7-15 carbon atom, wherein moieties is the Het-alkyl of 1-6 carbon atom;
Het is
Figure A9980836100062
Or
Figure A9980836100063
R 2aAlkylidene group for 1-3 carbon atom;
G is oxygen, sulphur or nitrogen;
R 3, R 4Each is independently for the aryl of the alkyl of hydrogen, halogen, a 1-3 carbon atom, a 6-10 carbon atom or contain 1 to 3 heterocycle that is selected from heteroatomic 5 to 7 annular atomses of oxygen, nitrogen, sulphur;
R 5For the alkyl of hydrogen, a 1-6 carbon atom ,-CH (R 7) R 8,-C (CH 2) nCO 2R 9,-C (CH 3) 2CO 2R 9,-CH (R 7) (CH 2) nCO 2R 9Or CH (R 7) C 6H 4CO 2R 9
R 6For the alkyl of hydrogen, halogen, a 1-6 carbon atom or-OR 5
m＝1-6；
n＝1-6；
R 7Be the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom;
R 8For-CO 2R 10,-CONHR 10, tetrazolium or-PO 3
R 9And R 10Each independently is the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom.
25. regulate the method for glucose level in the Mammals that needs is arranged, this method comprises and gives formula I compound that described Mammals has following structure or their pharmacy acceptable salt, Wherein:
A is O, S or N;
B is-(CH 2) m-,-CH (OH)-or carbonyl;
R 1Be the alkyl of hydrogen, halogen, a 1-6 carbon atom, the alkoxyl group or the trifluoromethyl of a 1-6 carbon atom;
R 2For the aralkyl of the aryl of the alkyl of 1-18 carbon atom, a 6-10 carbon atom, a 7-15 carbon atom, wherein moieties is the Het-alkyl of 1-6 carbon atom;
Het is
Figure A9980836100081
Or
R 2aAlkylidene group for 1-3 carbon atom;
G is oxygen, sulphur or nitrogen;
R 3, R 4Each is independently for the aryl of the alkyl of hydrogen, halogen, a 1-3 carbon atom, a 6-10 carbon atom or contain 1 to 3 heterocycle that is selected from heteroatomic 5 to 7 annular atomses of oxygen, nitrogen, sulphur;
R 5For the alkyl of hydrogen, a 1-6 carbon atom ,-CH (R 7) R 8,-C (CH 2) nCO 2R 9,-C (CH 3) 2CO 2R 9,-CH (R 7) (CH 2) nCO 2R 9Or CH (R 7) C 6H 4CO 2R 9
R 6For the alkyl of hydrogen, halogen, a 1-6 carbon atom or-OR 5
m＝1-6；
n＝1-6；
R 7Be the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom;
R 8For-CO 2R 10,-CONHR 10, tetrazolium or-PO 3
R 9And R 10Each independently is the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom.
26. medicinal compositions, it comprises formula I compound or their pharmacy acceptable salt and the pharmaceutical carrier with following structure, Wherein:
A is O, S or N;
B is-(CH 2) m-,-CH (OH)-or carbonyl;
R 1Be the alkyl of hydrogen, halogen, a 1-6 carbon atom, the alkoxyl group or the trifluoromethyl of a 1-6 carbon atom;
R 2For the aralkyl of the aryl of the alkyl of 1-18 carbon atom, a 6-10 carbon atom, a 7-15 carbon atom, wherein moieties is the Het-alkyl of 1-6 carbon atom;
Het
Figure A9980836100092
Or
Figure A9980836100093
R 2aAlkylidene group for 1-3 carbon atom;
G is oxygen, sulphur or nitrogen;
R 3, R 4Each is independently for the aryl of the alkyl of hydrogen, halogen, a 1-3 carbon atom, a 6-10 carbon atom or contain 1 to 3 heterocycle that is selected from heteroatomic 5 to 7 annular atomses of oxygen, nitrogen, sulphur;
R 5For the alkyl of hydrogen, a 1-6 carbon atom ,-CH (R 7) R 8-,-C (CH 2) nCO 2R 9,-C (CH 3) 2CO 2R 9,-CH (R 7) (CH 2) nCO 2R 9Or CH (R 7) C 6H 4CO 2R 9
R 6For the alkyl of hydrogen, halogen, a 1-6 carbon atom or-OR 5
m＝1-6；
n＝1-6；
R 7Be the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom;
R 8For-CO 2R 10,-CONHR 10, tetrazolium or-PO 3
R 9And R 10Each independently is the alkyl of hydrogen, a 1-6 carbon atom, the aryl of a 6-10 carbon atom or the aralkyl of 7-15 carbon atom.
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