CN105566267A - Novel oxime ether derivative and preparation method thereof and application of derivative by serving as drug - Google Patents

Novel oxime ether derivative and preparation method thereof and application of derivative by serving as drug Download PDF

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Publication number
CN105566267A
CN105566267A CN201610064100.XA CN201610064100A CN105566267A CN 105566267 A CN105566267 A CN 105566267A CN 201610064100 A CN201610064100 A CN 201610064100A CN 105566267 A CN105566267 A CN 105566267A
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group
benzyloxy
cumarone
dihydro
bases
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黄文龙
钱海
李政
杨建勇
苏欣
潘渺博
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China Pharmaceutical University
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China Pharmaceutical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • 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
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/83—Oxygen atoms

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention relates to a novel oxime ether derivative shown as a general formula (I) (please see the formula in the description) and a preparation method thereof and application of a pharmaceutical composition containing the derivative in preparation of a drug for treating diabetes and a metabolic syndrome. The oxime ether derivative has the excellent in-vivo hypoglycemic activity and can be used for preventing or treating the diabetes.

Description

One class novel oxime ether derivant, its preparation method and the purposes as medicine thereof
Technical field
The present invention relates to the field of pharmacology relevant to diabetes, be specifically related to a kind of novel oxime ether derivatives, its preparation method and the pharmaceutical composition containing this derivative as the application in preparation treatment diabetes and Metabolic syndrome disease drug.The oxime ether derivatives structure related in the present invention has uniqueness and novelty on this compounds structure of modification.
Background technology
Diabetes are a kind of energy metabolism diseases, are divided into type 1 diabetes (insulin-dependent diabetes mellitus) and diabetes B (non-insulin-dependent diabetes).About there are 3.66 hundred million diabetic subjects in the current whole world, accounts for 6.4% of world population, and wherein diabetes B patient accounts for 90 ~ 95% of diabetic subject's sum.
Diabetes can by dietary adjustments and exercise treatment.When these can not relief of symptoms time, need to carry out pharmacological agent.The medicine of current diabetes comprises: biguanides, as N1,N1-Dimethylbiguanide, can reduce the formation of glucose in liver; Sulfonylurea, can the more Regular Insulin of stimulating pancreas β emiocytosis as Glyburide; Thiazolidinediones, as U-721017E, strengthens the Purificatiou of Regular Insulin by activating peroxisome proliferator activated receptor γ (PPAR-γ); Alpha-glucosidase inhibitor, as acarbose, can suppress the generation of glucose in enteron aisle; Glucagon-like-peptide-1 (GLP-1) analogue, as Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37], can promote the β cells secrete insulin of pancreas; DPP IV (DPP-IV) inhibitor, as Xi Gelieting, can suppress the degraded of GLP-1 in body.But the method for current existing treatment diabetes has certain defect.Such as injection of insulin agent and sulfonylurea, may cause hypoglycemia and body weight to increase side effect; N1,N1-Dimethylbiguanide class, alpha-glucosidase inhibitor and GLP-1 analogue may cause gastrointestinal side effect; PPAR-gamma agonist may cause body weight to increase and oedema side effect; DPP-IV inhibitor may cause epipharyngitis, headache and infection side effect.Research for multiple field is carried out, to bringing safer and more effective novel blood sugar lowing medicine for diabetic subject.
Free-fat acid acceptor (FFAR) is the g protein coupled receptor (GPCRs) going orphanization in recent years.Current fixed free fatty acid acceptor has g protein coupled receptor 40 (GPR40) family, comprise GPR40 and (also claim free-fat acid acceptor 1, FFA1), GPR41 (also claims also to claim free-fat acid acceptor 3, FFA3), GPR84, GPR120 of GPR43 (also claiming also to claim free-fat acid acceptor 2, FFA2) and other family.GPR40 is the orphan type GPCR found when finding new galanin-galanin receptors (GALR) hypotype, expresses at the clone camber of pancreatic beta cell and excreting insulin.GPR40 can in conjunction with such as Palmiticacid, and stearic acid, oleic acid, the lipid acid in the blood plasma such as linoleic acid plus linolenic acid realizes various physiological-function.Such as, activate after long-chain free fatty acids is combined with GPR40, in inducing cell, calcium ion level raises, and strengthens the secretion (GSIS) of the Regular Insulin that glucose stimulates.GPR40 conditioning agent play incretin be used for promotion GISI, in addition also can with multiple treatment diabetes medicament conbined usage.Based on more than, GPR40 agonist can treat diabetes and relevant indication, especially diabetes B, obese insulin resist, glucose intolerance, and other metabolism syndrome illnesss.With the therapy target that GPR40 is potential, find and transform the compound with GPR40 agonist activity and there is important researching value and application prospect.
Disclose the patent application of a series of GPR40 agonist at present, comprising WO2004041266, WO2005087710, WO2005051890, WO2006083781, WO2007013689, WO2008066097, WO2009054390, WO2010085525, WO2015024448, WO2015088868 etc.
The present invention relates to the oxime ether derivatives of novel structure, it has hypoglycemic activity in excellent GPR40 agonist activity and body.What therefore described oxime ether derivatives and pharmacologically acceptable salt thereof can be potential be used for the treatment of or prevent diabetes and relative disease, has wide DEVELOPMENT PROSPECT.
Summary of the invention
The object of the present invention is to provide the compound shown in a kind of general formula (I) or its pharmaceutically useful salt:
Wherein:
Ring A is selected from aryl or heteroaryl;
R 1and R 2independently be selected from hydrogen, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl separately, wherein said alkyl, cycloalkyl, alkoxyl group optionally further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl group replace;
R 3be selected from alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl;
R 4be selected from hydrogen, halogen, alkyl, alkoxyl group.
Preferred version of the present invention, the compound shown in preferred following general formula (I) or its pharmaceutically useful salt:
Wherein:
Ring A is preferably from phenyl ring or thiphene ring;
R 1and R 2independently be selected from hydrogen, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl separately, wherein said alkyl, cycloalkyl, alkoxyl group optionally further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl group replace;
R 3be selected from alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl;
R 4be selected from hydrogen, halogen, alkyl, alkoxyl group.
Preferred general formula (I) compound or its pharmaceutically useful salt:
Wherein:
Ring A is preferably from phenyl ring or thiphene ring;
R 1and R 2independently be selected from hydrogen, halogen, hydroxyl, cyano group, C separately 1-C 6alkyl, C 1-C 6alkoxyl group, cycloalkyl, wherein said alkyl, cycloalkyl, alkoxyl group optionally further by one or more be selected from halogen, hydroxyl, cyano group, alkyl, alkoxyl group group replace;
R 3preferably from C 1-C 6alkyl, C 1-C 6alkoxyl group, cycloalkyl, heterocyclic radical, aryl;
R 4preferably from hydrogen, fluorine, C 1-C 6alkyl, C 1-C 6alkoxyl group.
The salt of preferred general formula (I) compound or its pharmacist:
Wherein:
Ring A is preferably from phenyl ring or thiphene ring;
R 1and R 2independently be selected from hydrogen, F, Cl, C separately 1-C 6alkyl, C 1-C 6alkoxyl group, wherein said alkyl, alkoxyl group are optionally selected from F, hydroxyl, cyano group, C by one or more further 1-C 6the group of alkyl replaced;
R 3preferably from C 1-C 6alkyl, C 1-C 6alkoxyl group, aryl;
R 4preferably from hydrogen, fluorine, C 1-C 6alkyl, C 1-C 6alkoxyl group.
Preferred the present invention has the compound or pharmaceutically acceptable salt thereof of general formula (I), and described compound is selected from:
2-(6-(4-(2-methoxy imino-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-1);
2-(6-(4-(2-(2-fluorobenzene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-2);
2-(6-(4-(2-(3-fluorobenzene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-3);
2-(6-(4-(2-(4-fluorobenzene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-4);
2-(6-(4-(2-(2-toluene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-5);
2-(6-(4-(2-(3-toluene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-6);
2-(6-(4-(2-(4-toluene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-7);
2-(6-(4-(2-(3-chlorobenzene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-8);
2-(6-(4-(2-(4-chlorobenzene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-9);
2-(6-(4-(2-(3-phenylfluoroform)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-10);
2-(6-(4-(2-(4-phenylfluoroform)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-11);
2-(6-(4-(2-(4-methoxyphenyl)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-12);
2-(6-(4-(2-(3,4-difluorophenyl)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-13);
2-(6-(4-(2-(2,4 dichloro benzene base)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-14);
2-(6-(4-(2-methoxy imino-2-(thiophene-2-base) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-15);
2-(6-(4-(2-ethoxyimino-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-16);
2-(6-(4-(2-third oxygen imido grpup-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-17);
2-(6-(4-(2-isobutyl oxygen imido grpup-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-18);
2-(6-(4-(2-ring third methoxy imino-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-19);
2-(6-(4-(2-benzyloxy imido grpup-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-20);
2-(6-(the fluoro-4-of 3-(2-methoxy imino-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-21);
2-(6-(the fluoro-4-of 2-(2-methoxy imino-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-22);
2-(6-(3-methoxyl group-4-(2-methoxy imino-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-23).
Another aspect of the present invention relates to a kind of pharmaceutical composition, and it contains the described compound or its pharmaceutically useful salt and suitable carrier, thinner or vehicle for the treatment of effective dose.
The present invention relates to the application in preparation treatment diabetes and Metabolic syndrome disease drug of described compound or its pharmaceutically useful salt or its pharmaceutical composition simultaneously.
Detailed description of the invention
Unless otherwise stated, following use term in the specification and in the claims has following implication.
" alkyl " refers to saturated aliphatic hydrocarbon group, comprises straight chain and the branched group of 1 to 20 carbon atom.Alkyl preferably containing 1 to 10 carbon atom, the alkyl more preferably containing 1 to 6 carbon atom, the alkyl more preferably containing 1 to 3 carbon atom, most preferably is methyl.Non-limiting example comprises methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, neo-pentyl, hexyl etc., and various branched chain isomers etc.Alkyl can be replacement or unsubstituted, when substituted, substituting group can be substituted on any spendable tie point, be preferably one or more following group, the group of independent selected from halo, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl replaced.
" cycloalkyl " refers to the unsaturated monocycle of saturated or part or many rings cyclic hydrocarbon substituent, and it comprises 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, and more preferably cycloalkyl ring comprises 3 to 10 carbon atoms.The non-limiting example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc.
" aryl " refers to 6 to 14 yuan of the π-electron system with conjugation full carbon monocycles or fused polycycle (namely sharing the right ring of adjacent carbon atoms) group, is preferably 6 to 10 yuan, such as phenyl and naphthyl.Described aryl rings can condense on heteroaryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is aryl rings.
Aryl can be replacement or unsubstituted, when substituted, substituting group is preferably one or more following group, and the group independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio replaced.
" heteroaryl " refers to comprise 1 to 4 heteroatoms, the heteroaromatic system of 5 to 14 annular atomses, and wherein heteroatoms comprises oxygen, sulphur and nitrogen.Be preferably 5 to 10 yuan.Heteroaryl is preferably 5 yuan or 6 yuan, such as furyl, thienyl, pyridyl, pyrryl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, tetrazyl etc.Described heteroaryl ring can condense on aryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is heteroaryl ring.
Heteroaryl can be optional replacement or unsubstituted, when substituted, substituting group is preferably one or more following group, and the group independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio replaced.
" alkoxyl group " refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), and wherein the definition of alkyl is described above.Non-limiting example comprises methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.Alkoxyl group can be optional replacement or unsubstituted, when substituted, substituting group is preferably one or more following group, and the group independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio replaced.
" optionally " or " optionally " mean subsequently described ground event or environment can but need not occur, this explanation comprises this event or environment occurs or not spot occasion.Such as, " optionally by heterocyclic group that alkyl replaces " mean alkyl can but must not exist, this explanation comprises situation that heterocyclic group replaced by alkyl and heterocyclic group not by situation that alkyl replaces.
" replacement " refers to the one or more hydrogen atoms in group, is preferably maximum 5, is more preferably 1 ~ 3 hydrogen atom and is replaced by the substituting group of respective number independently of one another.Self-evident, substituting group is only in their possible chemical position, those skilled in the art can determine when not paying and too much making great efforts (by experiment or theoretical) may or impossible replacement.Such as, have the amino of free hydrogen or hydroxyl and the carbon atom with unsaturated (as olefinic) key in conjunction with time may be unstable.
" pharmaceutical composition " represents containing one or more compounds of the present invention or its pharmaceutically useful salt, or the mixture of its prodrug and other chemical compositions, and other chemical compositions are pharmaceutically useful carrier and vehicle such as.The object of pharmaceutical composition promotes that organism is to the absorption of activeconstituents, is beneficial to activeconstituents and plays biological activity in vivo.
General formula of the present invention (I) compound synthesizes by following steps:
The compound represented by general formula (II) obtains general formula compound (III) with leavings group replacement, and itself and compound IV are reacted in the presence of base and prepared general formula compound (I).
Wherein: W is leavings group; R 1~ R 4definition as described in general formula (I).
W represents leavings group, can mention the C of such as Cl, Br, I, optional halo 1-C 6alkyl sulphonyl oxygen base (such as, methylsulfonyl oxygen base, ethylsulfonyl oxygen base, three chloromethanesulfonyl), optionally there is substituent C 6-C 10aryl sulfonyl oxygen base (such as, phenyl sulfonyl oxygen base, p-toluenesulfonyl oxygen base, m-nitrobenzenesulfonyl oxygen base etc.) etc.
Comprise mineral alkali and organic bases as described alkali, described mineral alkali can be mentioned such as, and alkaline carbonate class is sodium carbonate, salt of wormwood, cesium carbonate etc. such as; Alkali metal hydrocarbonate class is as saleratus etc.; Alkali metal hydroxide is lithium hydroxide, sodium hydroxide, potassium hydroxide etc. such as; Described organic bases can mention such as triethylamine, pyridine, lutidine, n-Butyl Lithium, potassium tert.-butoxide etc.
In the present invention, in the GPR40 agonist activity of compound and body, hypoglycemic activity can measure by using Analytical system as described below.
Following biology testing example describes explains the present invention.
The condition that in test case of the present invention, the usual conditioned disjunction routinely of the experimental technique of actual conditions is advised according to commodity manufacturer.The reagent in unreceipted concrete source is the common agents that market is bought.
Test case 1 the compounds of this invention surely turns the agonist activity of cell to hGPR40-CHO
The present invention uses following methods to measure the GPR40 agonist activity of the compounds of this invention:
HGPR40-CHO surely turns cell with 3 × 10 4the density in/hole is seeded to 96 orifice plates, is placed in 37 DEG C, 5%CO 2cell culture incubator incubated overnight; Discard substratum, after every hole adds 100ulHBSS cleaning, add 100ul and hatch 90min containing the Fluo-4 dye solution 37 DEG C of Probenecid; After hatching end, sucking-off Fluo-4 dye solution, adds 100 μ lHBSS damping fluids, washes away dyestuff; Every hole adds the HBSS of 100 μ l containing Probenecid, hatches 10min for 37 DEG C; In 96 orifice plates, every hole adds the medicine of different concns, according to optimum configurations table FLIPR (MolecularDevices) reading.Analysis design mothod result.Agonist activity=(compound well fluorescent value-blank control wells fluorescent value)/(linolic acid hole fluorescent value-blank control wells fluorescent value) × 100%, the results are shown in Table 1.
Table 1:hGPR40 receptor agonist activity
Conclusion: all compounds of the present invention have obvious agonist activity to GPR40, wherein I-1, I-2, I-3, I-4 and I-12 have stronger GPR40 agonist activity.
In test case 2 the present invention compound body in hypoglycemic activity can measure by using Analytical system as described below:
Normal mouse oral glucose tolerance test (OGTT): 10 week age Kunming kind cleaning grade mouse, body weight 18 ~ 22g, male, be divided into 7 groups at random, blank group (blank solvent: the carboxymethylcellulose sodium solution of 0.5%), positive drug control group (TAK-875:20mg/kg), test-compound group (20mg/kg), often organize 8, before experiment, mouse fasting can't help water 12 hours, each group of equal oral administration gavage administration, blood is got in docking, measures blood glucose value (being designated as-30min).Then gavage gives blank solvent, TAK-875 and test-compound respectively, measures blood glucose value and be designated as 0min after 30min, gives the glucose solution that concentration is 2g/10ml immediately afterwards by 10ml/kg gavage, and measures blood glucose value in 15,30,60,120min.The results are shown in Table 2.
Table 2: preferred compound is on the impact of normal Mouse oral sugar tolerance
Note: * P≤0.05 is the Student'st assay relative to blank group.
The tolerance test of normal mouse oral glucose shows: I-1, I-2, I-3, I-4 and I-12 obviously can improve the oral glucose tolerance of normal mouse in vivo, show good hypoglycemic activity.
Embodiment
Below in conjunction with embodiment, the invention will be further described.It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.
Embodiment 1
(6-hydroxyl-1-cumarone-3-base) methyl acetate
4-chloroacetyl acetacetic ester (4.25ml, 31.43mmol) is dissolved in the 20ml vitriol oil of 0 DEG C, and the faint yellow viscous solution of formation is placed in ice bath and is cooled to about-5 DEG C, add Resorcinol (3.15g, 28.57mmol), in controlling, temperature is lower than 0 DEG C in batches, finish, stirring at room temperature 2h, reaction solution is poured in 50ml frozen water, and adularescent solid is separated out, suction filtration, washing (5ml × 2) filter cake, dry beige solid 5.6g, crude yield 82%.
Get above-mentioned crude product (2g, 9.50mmol) in the mono-neck bottle of 200ml, add 1NNaOH solution (100ml), solution becomes goldenrod immediately, above-mentioned solution is placed in oil bath reflux 2h, react, be cooled to room temperature, regulate PH to 2-3 with the vitriol oil, gained solution extracts with ethyl acetate (30ml × 4), merge organic phase, with saturated aqueous common salt (20ml × 2) washing, anhydrous sodium sulfate drying, filters, filtrate decompression is steamed and is desolventized to obtain beige column crystallization 1.3g, crude yield 71.2%.Get above-mentioned crude product (1g, 5.20mmol) be suspended in 10ml methyl alcohol, drip the 0.5ml vitriol oil, drip and finish, temperature rising reflux reacts about 4h, react, remove methyl alcohol under reduced pressure, in residual liquid impouring 30ml water, extract with ethyl acetate (20ml × 3), merge organic phase, wash with saturated sodium bicarbonate solution (15ml × 2) respectively, saturated aqueous common salt (15ml × 2) washs, anhydrous sodium sulfate drying, filter, filtrate decompression is steamed and is desolventized to obtain tan solid, column chromatography (petrol ether/ethyl acetate, 80: 20, v/v) purifying obtains faint yellow solid 0.75g, productive rate 70%.
1HNMR(300MHz，DMSO-d 6)δ：9.54(s，1H，ArOH)，7.69(s，1H，ArH)，7.33(d，J＝8.41Hz，1H，ArH)，6.87(d，J＝1.89Hz，1H，ArH)，6.75，6.72(dd，J＝2.01，8.40Hz，1H，ArH)，3.71(s，2H，ArCH 2CO)，3.63(s，3H，-OCH 3).
Embodiment 2
(6-hydroxyl-2,3-dihydro-1-cumarone-3-base) methyl acetate (IV)
Starting ester (2g, 9.71mmol) be dissolved in methyl alcohol, add catalytic amount palladium carbon 0.2g, with hydrogen exchange three times, pass into hydrogen in stirred at ambient temperature 24h, reacted, to lay the groundwork filtration with diatomite, washing leaching cake, filtrate decompression is steamed and is desolventized to obtain gray powdery solid 1.93g, productive rate 95%.
1HNMR(300MHz，CDCl 3)δ：6.97(d，J＝8.71Hz，1H，ArH)，6.31-6.34(m，2H，ArH)，4.82(brs，1H，ArOH)，4.75(t，J＝9.10Hz，1H，-OCH 2)，4.26，4.24(dd，J＝5.72，9.10Hz，1H，-OCH 2)，3.74-3.84(m，1H，ArCH)，3.72(s，3H，-OCH 3)，2.74，2.69(dd，J＝5.72，16.41Hz，1H，-COCH 2)，2.55，2.50(dd，J＝9.11，16.41Hz，1H，-COCH 2).
Embodiment 3
2-(6-(4-(2-methoxy imino-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-1)
The first step: 2-bromoacetophenone (0.7g, 3.52mmol) is dissolved in 15mlDMSO, adds methoxy amido hydrochloride (0.4g, 5.28mmol), finish, stirring at room temperature 5h, the 150ml that adds water dilutes, with ethyl acetate (30ml × 3) extraction, merge organic phase, wash with saturated aqueous common salt (15ml × 2), anhydrous sodium sulfate drying, filter, filtrate decompression is steamed and is desolventized to obtain tan solid 0.8g, is directly used in the next step.
Second step: get above-mentioned oil product (0.8g, 3.52mmol) and be dissolved in 25ml acetonitrile, add salt of wormwood (1.46g successively, 10.56mmol), 4-salicylic alcohol (0.44g, 3.52mmol), said mixture heats 65 DEG C of reaction 8h, suction filtration, filtrate decompression is steamed and is desolventized to obtain tan solid, through column chromatography (petrol ether/ethyl acetate, 70: 30, v/v) purifying obtains white solid II-10.85g, productive rate 88%.
1HNMR(300MHz，DMSO-d 6)δ：7.72-7.64(m，2H)，7.39-7.32(m，3H)，7.19(d，J＝8.5Hz，2H)，6.84(d，J＝8.5Hz，2H)，5.19(s，2H)，5.13(t，J＝5.4Hz，1H)，4.38(d，J＝5.1Hz，2H)，3.98(s，3H).
3rd step: get above-mentioned white solid product II-10.85g and be dissolved in 20ml methylene dichloride, sulfur oxychloride 1ml is dripped under ice bath, add a DMF catalysis, stir post-heating to 40 DEG C reaction 3h, reaction solution removes unnecessary sulfur oxychloride under reduced pressure, and gained brown oil III-10.92g is directly used in the next step.
4th step: above-mentioned brown oil III-1 (0.4g, 1.5mmol) be dissolved in 20ml acetonitrile, add IV (0.3g successively, 1.5mmol), salt of wormwood (0.6g, 4.5mmol), gained mixture heats 65 DEG C of reaction 10h, suction filtration, filtrate decompression is steamed and is desolventized to obtain brown oil, through column chromatography (petrol ether/ethyl acetate, 85: 15, v/v) purifying obtains white solid 0.55g, gained solid is dissolved in 4mL tetrahydrofuran (THF), in 6mL methyl alcohol and 2mL water, add LiOH (0.2g, 8mmol), room temperature reaction 4h, remove tetrahydrofuran (THF) and methyl alcohol under reduced pressure, drip 1N dilute hydrochloric acid under ice-water bath and regulate PH2-3, separate out white solid, suction filtration, dry white powdery solids 0.51g, fusing point 118-119 DEG C, productive rate 82%.
1HNMR(300MHz，DMSO-d 6)δ：12.21(brs，1H)，7.64，7.62(dd，J＝6.5，2.4Hz，2H)，7.46-7.36(m，3H)，7.32(d，J＝8.4Hz，2H)，7.08(d，J＝7.7Hz，1H)，6.91(d，J＝8.4Hz，2H)，6.41(d，J＝7.9Hz，2H)，5.22(s，2H)，4.93(s，2H)，4.66(t，J＝8.9Hz，1H)，4.20-4.09(m，1H)，3.99(s，3H)，3.72-3.55(m，1H)，2.57(d，J＝4.8Hz，1H)，2.28，2.23(dd，J＝15.6，9.4Hz，1H). 13CNMR(75MHz，DMSO-d 6)δ：171.24，161.09，159.34，157.85，154.42，133.59，130.22，129.92，129.85，128.83，127.16，125.04，123.33，114.73，107.03，97.07，78.20，69.43，62.72，59.73，40.69，37.85.ESI-MSm/z：446.1[M-H] -.Anal.calcd.ForC 26H 25NO 6：C，69.79；H，5.63；N，3.13；Found：C，69.74；H，5.62；N，3.14.
Embodiment 4
2-(6-(4-(2-(2-fluorobenzene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-2)
The same I-1 of synthetic method, obtains white solid 0.42g, fusing point 113-115 DEG C, productive rate 78%.
1HNMR(300MHz，DMSO-d 6)δ：12.47(brs，1H)，7.47-7.40(m，2H)，7.36-7.31(m，4H)，7.26，7.23(dd，J＝10.3，5.3Hz，1H)，6.91(d，J＝8.5Hz，2H)，6.39-6.37(m，2H)，5.25(s，2H)，4.95(s，2H)，4.67(t，J＝9.0Hz，1H)，4.28-4.10(m，1H)，4.03(s，3H)，3.75-3.54(m，1H)，2.68，2.63(dd，J＝16.5，5.4Hz，1H)，2.48-2.37(m，1H). 13CNMR(75MHz，DMSO-d 6)δ：173.51，164.63，161.61，159.79，157.45，152.83，135.62，129.87，125.21，124.53，122.21，118.23，117.97，116.37，107.25，97.13，77.54，73.26，69.43，62.92，40.74，37.86.ESI-MSm/z：464.1[M-H] -.Anal.calcd.ForC 26H 24FNO 6：C，67.09；H，5.20；N，3.01；Found：C，67.06；H，5.19；N，3.01.
Embodiment 5
2-(6-(4-(2-(3-fluorobenzene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-3)
The same I-1 of synthetic method, obtains white solid 0.36g, fusing point 107-108 DEG C, productive rate 73%.
1HNMR(300MHz，DMSO-d 6)δ：12.36(brs，1H)，7.52-7.38(m，3H)，7.32(d，J＝8.5Hz，2H)，7.26，7.23(dd，J＝10.1，5.8Hz，1H)，7.09(d，J＝7.8Hz，1H)，6.91(d，J＝8.6Hz，2H)，6.43(d，J＝7.9Hz，2H)，5.23(s，2H)，4.93(s，2H)，4.67(t，J＝9.0Hz，1H)，4.29-4.11(m，1H)，4.01(s，3H)，3.75-3.54(m，1H)，2.68，2.63(dd，J＝16.5，5.4Hz，1H)，2.48-2.37(m，1H). 13CNMR(75MHz，DMSO-d 6)δ：173.59，164.67，161.11，159.59，157.65，152.87，135.32，129.87，125.01，124.54，122.25，118.20，117.97，116.37，107.25，97.17，77.56，73.21，69.41，62.99，40.77，37.82.ESI-MSm/z：464.1[M-H] -.Anal.calcd.ForC 26H 24FNO 6：C，67.09；H，5.20；N，3.01；Found：C，67.04；H，5.21；N，3.02.
Embodiment 6
2-(6-(4-(2-(4-fluorobenzene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-4)
The same I-1 of synthetic method, obtains white solid 0.56g, fusing point 126-127 DEG C, productive rate 85%.
1HNMR(300MHz，DMSO-d 6)δ：12.36(brs，1H)，7.68(d，J＝8.9Hz，2H)，7.32(d，J＝8.6Hz，2H)，7.23(d，J＝8.9Hz，2H)，7.08(d，J＝7.8Hz，1H)，6.90(d，J＝8.6Hz，2H)，6.46-6.36(m，2H)，5.22(s，2H)，4.92(s，2H)，4.67(t，J＝9.0Hz，1H)，4.16，4.13(dd，J＝8.8，7.0Hz，1H)，3.99(s，3H)，3.68-3.62(m，1H)，2.64，2.59(dd，J＝16.4，5.5Hz，1H)，2.41，2.36(dd，J＝16.4，9.1Hz，1H). 13CNMR(75MHz，DMSO-d 6)δ：173.92，165.2，161.10，159.50，157.75，153.66，130.24，129.86，129.53，129.42，125.01，122.63，115.96，115.68，114.74，107.17，97.14，77.78，69.42，62.77，59.76，40.76，37.81.ESI-MSm/z：464.1[M-H] -.Anal.calcd.ForC 26H 24FNO 6：C，67.09；H，5.20；N，3.01；Found：C，67.03；H，5.21；N，3.02.
Embodiment 7
2-(6-(4-(2-(2-toluene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-5)
The same I-1 of synthetic method, obtains white solid 0.24g, fusing point 105-107 DEG C, productive rate 68%.
1HNMR(300MHz，DMSO-d 6)δ：12.47(brs，1H)，7.47(d，J＝7.1Hz，1H)，736-7.31(m，4H)，7.25(d，J＝7.8Hz，2H)，6.92(d，J＝7.8Hz，2H)，6.39-6.37(m，2H)，5.25(s，2H)，4.97(s，2H)，4.65(t，J＝9.2Hz，1H)，4.27-4.12(m，1H)，4.03(s，3H)，3.75-3.54(m，1H)，2.68，2.63(dd，J＝16.5，5.4Hz，1H)，2.54(s，3H)，2.43-2.36(m，1H). 13CNMR(75MHz，DMSO-d 6)δ：173.46，164.65，161.67，159.73，157.42，135.12，130.95，129.87，125.21，124.53，123.78，122.25，118.28，117.95，116.34，107.26，97.17，77.56，73.23，69.41，62.94，40.75，37.82，20.13.ESI-MSm/z：460.1[M-H] -.Anal.calcd.ForC 27H 27NO 6：C，70.27；H，5.90；N，3.04；Found：C，70.24；H，5.91；N，3.03.
Embodiment 8
2-(6-(4-(2-(3-toluene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-6)
The same I-1 of synthetic method, obtains white solid 0.35g, fusing point 108-109 DEG C, productive rate 73%.
1HNMR(300MHz，DMSO-d 6)δ：12.34(brs，1H)，7.45，7.40(dd，J＝17.1，9.3Hz，2H)，7.38-7.12(m，4H)，7.08(d，J＝8.0Hz，1H)，6.92(t，J＝9.0Hz，2H)，6.45-6.40(m，2H)，5.19(s，2H)，4.92(s，2H)，4.66(t，J＝8.9Hz，1H)，4.24-4.07(m，1H)，3.98(s，3H)，3.70-3.48(m，1H)，2.55，2.50(dd，J＝16.2，5.6Hz，1H)，2.31(d，J＝10.6Hz，1H)，2.29(s，3H). 13CNMR(75MHz，DMSO-d 6)δ：177.21，166.49，159.15，158.37，157.32，138.28，133.97，131.06，129.21，128.76，127.86，125.13，123.81，114.59，105.29，97.16，75.65，73.04，70.82，61.9，41.25，37.76，21.32.ESI-MSm/z：460.1[M-H] -.Anal.calcd.ForC 27H 27NO 6：C，70.27；H，5.90；N，3.04；Found：C，70.23；H，5.91；N，3.03.
Embodiment 9
2-(6-(4-(2-(4-toluene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-7)
The same I-1 of synthetic method, obtains white solid 0.43g, fusing point 114-116 DEG C, productive rate 76%.
1HNMR(300MHz，DMSO-d 6)δ：12.39(brs，1H)，7.53(d，J＝8.1Hz，2H)，7.32(d，J＝8.6Hz，2H)，7.20(d，J＝8.1Hz，2H)，7.09(d，J＝7.9Hz，1H)，6.90(d，J＝8.6Hz，2H)，6.49-6.37(m，2H)，5.19(s，2H)，4.93(s，2H)，4.68(t，J＝9.0Hz，1H)，4.18，4.15(dd，J＝8.9，6.9Hz，1H)，3.97(s，3H)，3.73-3.60(m，1H)，2.69，2.64(dd，J＝16.6，5.5Hz，1H)，2.45(d，J＝9.1Hz，1H)，2.30(s，3H). 13CNMR(75MHz，DMSO-d 6)δ：177.30，161.11，159.23，158.76，157.99，140.79，131.25，129.96，128.81，127.15，125.03，123.14，114.11，105.11，102.31，75.98，73.21，68.79，60.72，41.19，38.15，21.3.ESI-MSm/z：460.1[M-H] -.Anal.calcd.ForC 27H 27NO 6：C，70.27；H，5.90；N，3.04；Found：C，70.23；H，5.91；N，3.05.
Embodiment 10
2-(6-(4-(2-(3-chlorobenzene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-8)
The same I-1 of synthetic method, obtains white solid 0.22g, fusing point 103-105 DEG C, productive rate 67%.
1HNMR(300MHz，DMSO-d 6)δ：12.38(brs，1H)，7.77-7.54(m，2H)，7.54-7.37(m，2H)，7.32(d，J＝8.5Hz，2H)，7.09(d，J＝7.8Hz，1H)，6.92，6.88(dd，J＝12.5，8.8Hz，2H)，6.55-6.33(m，2H)，5.23(s，2H)，4.95(s，2H)，4.68(t，J＝9.1Hz，1H)，4.18，4.15(dd，J＝8.9，6.9Hz，1H)，4.01(s，3H)，3.78-3.59(m，1H)，2.70，2.65(dd，J＝16.6，5.5Hz，1H)，2.44(d，J＝7.5Hz，1H). 13CNMR(75MHz，DMSO-d 6)δ：173.44，161.09，159.34，157.85，154.42，135.59，134.57，130.22，129.92，129.85，128.83，127.16，125.04，123.33，114.73，105.03，97.07，78.20，69.43，62.72，59.75，40.66，37.75.ESI-MSm/z：480.1[M-H] -.Anal.calcd.ForC 26H 24ClNO 6：C，64.80；H，5.02；N，2.91；Found：C，64.84；H，5.01；N，2.92.
Embodiment 11
2-(6-(4-(2-(4-chlorobenzene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-9)
The same I-1 of synthetic method, obtains white solid 0.36g, fusing point 122-124 DEG C, productive rate 84%.
1HNMR(300MHz，DMSO-d 6)δ：12.34(brs，1H)，7.65(d，J＝8.6Hz，2H)，7.46(d，J＝8.6Hz，2H)，7.32(d，J＝8.6Hz，2H)，7.09(d，J＝7.9Hz，1H)，6.90(d，J＝8.6Hz，2H)，6.52-6.36(m，2H)，5.22(s，2H)，4.93(s，2H)，4.68(t，J＝9.1Hz，1H)，4.18，4.15(dd，J＝8.9，6.9Hz，1H)，4.00(s，3H)，3.76-3.61(m，1H)，2.69，2.64(dd，J＝16.6，5.5Hz，1H)，2.45(d，J＝9.0Hz，1H). 13CNMR(75MHz，DMSO-d 6)δ：173.55，165.78，161.11，159.77，157.72，136.15，132.62，129.84，128.98，128.90，125.00，122.26，114.76，107.26，97.18，77.55，73.88，70.67，61.91，40.51，37.54.ESI-MSm/z：480.1[M-H] -.Anal.calcd.ForC 26H 24ClNO 6：C，64.80；H，5.02；N，2.91；Found：C，64.84；H，5.01；N，2.91.
Embodiment 12
2-(6-(4-(2-(3-phenylfluoroform)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-10)
The same I-1 of synthetic method, obtains white solid 0.16g, fusing point 106-108 DEG C, productive rate 72%.
1HNMR(300MHz，DMSO-d 6)δ：12.37(brs，1H)，7.93(d，J＝11.7Hz，2H)，7.78(d，J＝7.6Hz，1H)，7.70-7.59(m，1H)，7.32(d，J＝7.7Hz，2H)，7.09(d，J＝8.0Hz，1H)，6.89(d，J＝7.4Hz，2H)，6.52-6.36(m，2H)，5.30(s，2H)，4.92(s，2H)，4.67(t，J＝9.1Hz，1H)，4.26-4.08(m，1H)，4.03(s，3H)，3.68-3.62(m，1H)，2.68，2.63(dd，J＝16.7，5.4Hz，1H)，2.43(d，J＝9.4Hz，1H). 13CNMR(75MHz，DMSO-d 6)δ：177.11，165.28，159.14，158.82，157.36，134.23，131.12，129.98，128.87，128.64，127.12，125.07，124.34，120.12，114.26，107.00，102.08，77.86，74.25，70.34，61.95，40.71，37.89.ESl-MSm/z：514.1[M-H] -.Anal.calcd.ForC 27H 24F 3NO 6：C，62.91；H，4.69；N，2.72；Found：C，62.94；H，4.68；N，2.73.
Embodiment 13
2-(6-(4-(2-(4-phenylfluoroform)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-11)
The same I-1 of synthetic method, obtains white solid 0.25g, fusing point 119-120 DEG C, productive rate 79%.
1HNMR(300MHz，DMSO-d 6)δ：12.40(brs，1H)，7.85(d，J＝8.1Hz，2H)，7.76(d，J＝8.2Hz，2H)，7.32(d，J＝8.3Hz，2H)，7.09(d，J＝7.8Hz，1H)，6.91(d，J＝8.3Hz，2H)，6.44(d，J＝8.1Hz，2H)，5.27(s，2H)，4.93(s，2H)，4.68(t，J＝9.0Hz，1H)，4.29-4.08(m，1H)，4.03(s，3H)，3.78-3.57(m，1H)，2.69，2.64(dd，J＝16.6，5.4Hz，1H)，2.45(d，J＝9.1Hz，1H). 13CNMR(75MHz，DMSO-d 6)δ：175.44，161.09，159.34，158.85，157.42，137.59，133.57，130.22，129.92，129.85，128.83，127.16，125.04，124.12，123.33，114.53，105.03，97.07，78.20，73.04，69.43，61.72，41.12，37.75.ESI-MSm/z：514.1[M-H] -.Anal.calcd.ForC 27H 24F 3NO 6：C，62.91；H，4.69；N，2.72；Found：C，62.95；H，4.68；N，2.72.
Embodiment 14
2-(6-(4-(2-(4-methoxyphenyl)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-12)
The same I-l of synthetic method, obtains white solid 0.13g, fusing point 117-118 DEG C, productive rate 64%.
1HNMR(300MHz，DMSO-d 6)δ：12.37(brs，1H)，7.61(d，J＝8.8Hz，2H)，7.32(d，J＝8.5Hz，2H)，7.08(d，J＝7.9Hz，1H)，7.00-6.87(m，4H)，6.49-6.36(m，2H)，5.18(s，2H)，4.92(s，2H)，4.66(t，J＝9.0Hz，1H)，4.16，4.13(dd，J＝8.8，7.0Hz，1H)，3.96(s，3H)，3.77(s，3H)，3.70-3.60(m，1H)，2.61，2.56(dd，J＝16.2，5.4Hz，1H)，2.36，2.31(dd，J＝16.2，9.2Hz，1H). 13CNMR(75MHz，DMSO-d 6)δ：173.58，168.01，159.01，158.97，157.43，155.24，153.39，148.54，130.57，129.68，129.36，128.10，124.52，114.71，114.25，113.78，113.47，106.64，96.65，75.44，73.45，70.83，62.04，55.14，40.52，37.51.ESI-MSm/z：476.1[M-H] -.Anal.calcd.ForC 27H 27NO 7：C，67.91；H，5.70；N，2.93；Found：C，67.93；H，5.71；N，2.92.
Embodiment 15
2-(6-(4-(2-(3,4-difluorophenyl)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-13)
The same I-1 of synthetic method, obtains white solid 0.25g, fusing point 120-122 DEG C, productive rate 69%.
1HNMR(300MHz，DMSO-d 6)δ：12.38(brs，1H)，7.77-7.58(m，1H)，7.57-7.40(m，2H)，7.33(d，J＝8.6Hz，2H)，7.09(d，J＝7.8Hz，1H)，6.91(d，J＝8.6Hz，2H)，6.59-6.31(m，2H)，5.23(s，2H)，4.93(s，2H)，4.68(t，J＝9.1Hz，1H)，4.29-4.06(m，1H)，4.01(s，3H)，3.76-3.54(m，1H)，2.70，2.65(dd，J＝16.6，5.5Hz，1H)，2.45(d，J＝9.1Hz，1H). 13CNMR(75MHz，DMSO-d 6)δ：173.59，164.6，161.11，159.59，157.65，152.87，149.6，130.32，129.87，125.01，124.54，122.25，118.20，117.97，116.37，116.13，114.78，107.25，97.17，77.56，73.21，69.41，62.99，40.77，37.82.ESI-MSm/z：482.1[M-H] -.Anal.calcd.ForC 26H 23F 2NO 6：C，64.59；H，4.80；N，2.90；Found：C，64.53；H，4.81；N，2.91.
Embodiment 16
2-(6-(4-(2-(2,4 dichloro benzene base)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-14)
The same I-1 of synthetic method, obtains white solid 0.18g, fusing point 104-106 DEG C, productive rate 60%.
1HNMR(300MHz，DMSO-d 6)δ：12.38(brs，1H)，7.77-7.54(m，1H)，7.54-7.37(m，2H)，7.32(d，J＝8.5Hz，2H)，7.09(d，J＝7.8Hz，1H)，6.92(d，J＝8.5Hz，2H)，6.55-6.33(m，2H)，5.23(s，2H)，4.95(s，2H)，4.68(t，J＝9.1Hz，1H)，4.18，4.15(dd，J＝8.9，6.9Hz，1H)，4.03(s，3H)，3.78-3.59(m，1H)，2.71，2.66(dd，J＝16.6，5.6Hz，1H)，2.45(d，J＝7.6Hz，1H). 13CNMR(75MHz，DMSO-d 6)δ：175.44，161.09，159.34，158.85，157.42，135.59，134.57，130.22，129.92，129.85，128.83，127.16，125.04，123.33，114.53，105.03，97.07，78.20，69.43，62.72，59.75，40.12，37.75.ESI-MSm/z：514.1[M-H] -.Anal.calcd.ForC 26H 23Cl 2NO 6：C，60.48；H，4.49；N，2.71；Found：C，60.45；H，4.48；N，2.71.
Embodiment 17
2-(6-(4-(2-methoxy imino-2-(thiophene-2-base) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-15)
The same I-1 of synthetic method, obtains white solid 0.26g, fusing point 108-110 DEG C, productive rate 74%.
1HNMR(300MHz，DMSO-d 6)δ：12.42(brs，1H)，7.85(d，J＝5.0Hz，1H)，7.64(d，J＝3.6Hz，1H)，7.36(d，J＝8.2Hz，2H)，7.23-7.16(m，1H)，7.10-7.02(m，3H)，6.44(d，J＝7.7Hz，2H)，5.05(s，2H)，4.95(s，2H)，4.67(t，J＝9.0Hz，1H)，4.25-4.12(m，1H)，4.03(s，3H)，3.67，3.63(dd，J＝13.9，7.5Hz，1H)，2.66，2.61(dd，J＝16.4，5.4Hz，1H)，2.43，2.38(dd，J＝16.4，9.1Hz，1H). 13CNMR(75MHz，DMSO-d 6)δ：173.91，167.45，161.12，159.56，158.01，129.21，128.76，127.86，126.81，125.02，124.56，123.57，114.59，105.19，97.16，77.74，73.75，68.69，62.86，40.20，37.76.ESI-MSm/z：452.1[M-H] -.Anal.calcd.ForC 24H 23NO 6S：C，63.56；H，5.11；N，3.09；Found：C，63.51；H，5.12；N，3.08.
Embodiment 18
2-(6-(4-(2-ethoxyimino-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-16)
The first step: 2-bromoacetophenone (3g, 15.07mmol), 4-salicylic alcohol (1.96g, 15.83mmol) is dissolved in 25ml acetonitrile, adds salt of wormwood (6.25g, 45.22mmol), gained mixture heats 65 DEG C of reaction 8h, suction filtration, and filtrate decompression is steamed and desolventized to obtain khaki color solid 3.2g, not purified, be directly used in the next step.
Second step: above-mentioned khaki color solid product (3.2g, 13.21mmol) be dissolved in 20mlDMSO, add oxammonium hydrochloride (1.84g in batches, 26.42mmol), room temperature reaction 10h, by in reaction solution impouring 200ml water, with ethyl acetate (30ml × 3) extraction, merge organic phase, wash with saturated aqueous common salt (15ml × 2), anhydrous sodium sulfate drying, filters, and filtrate decompression is steamed and desolventized to obtain tan solid, through column chromatography (petrol ether/ethyl acetate, 65: 35, v/v) purifying obtains white solid 3.1g, productive rate 91%.
1HNMR(300MHz，DMSO-d 6)δ：11.88(s，1H)，7.63(d，J＝3.6Hz，2H)，7.36-7.31(m，3H)，7.19(d，J＝8.2Hz，2H)，6.87(d，J＝8.2Hz，2H)，5.22(s，2H)，5.04(t，J＝5.6Hz，1H)，4.38(d，J＝5.6Hz，2H).
3rd step: get above-mentioned white solid product 0.6g and be dissolved in 20ml acetonitrile, add 0.4ml monobromethane and 1.5g salt of wormwood respectively, gained mixture heats 65 DEG C of reaction 6h, suction filtration, and filtrate decompression is steamed and desolventized to obtain faint yellow solid 0.8g, gained solid is dissolved in 20ml methylene dichloride, under ice bath, drip sulfur oxychloride 1ml, add a DMF catalysis, stir post-heating to 40 DEG C reaction 3h, reaction solution removes unnecessary sulfur oxychloride under reduced pressure, and gained brown oil 0.92g is directly used in the next step.
4th step: above-mentioned brown oil (0.46g, 1.5mmol) be dissolved in 20ml acetonitrile, add IV (0.3g successively, 1.5mmol), salt of wormwood (0.6g, 4.5mmol), gained mixture heats 65 DEG C of reaction 10h, suction filtration, filtrate decompression is steamed and is desolventized to obtain brown oil, through column chromatography (petrol ether/ethyl acetate, 85: 15, v/v) purifying obtains white solid 0.47g, gained solid is dissolved in 4mL tetrahydrofuran (THF), in 6mL methyl alcohol and 2mL water, add LiOH (0.2g, 8mmol), room temperature reaction 4h, remove tetrahydrofuran (THF) and methyl alcohol under reduced pressure, drip 1N dilute hydrochloric acid under ice-water bath and regulate PH2-3, separate out white solid, suction filtration, dry white powdery solids 0.43g, fusing point 118-120 DEG C, productive rate 78%.
1HNMR(300MHz，DMSO-d 6)δ：12.23(brs，1H)，7.65，7.63(dd，J＝6.5，2.5Hz，2H)，7.45-7.35(m，3H)，7.33(d，J＝8.4Hz，2H)，7.08(d，J＝7.7Hz，1H)，6.91(d，J＝8.4Hz，2H)，6.41(d，J＝7.9Hz，2H)，5.22(s，2H)，4.93(s，2H)，4.66(t，J＝8.9Hz，1H)，4.20-4.09(m，1H)，3.97(q，J＝7.1Hz，2H)，3.72-3.55(m，1H)，2.57(d，J＝4.8Hz，1H)，2.28，2.23(dd，J＝15.6，9.4Hz，1H)，1.15(t，J＝7.1Hz，3H). 13CNMR(75MHz，DMSO-d 6)δ：171.26，161.07，159.35，157.83，154.45，133.57，130.25，129.96，129.87，128.82，127.16，125.01，123.33，114.73，107.03，97.07，78.20，69.43，62.72，59.73，42.15，40.69，37.85，15.09.ESI-MSm/z：460.1[M-H] -.Anal.calcd.ForC 27H 27NO 6：C，70.27；H，5.90；N，3.04；Found：C，70.23；H，5.91；N，3.03.
Embodiment 19
2-(6-(4-(2-third oxygen imido grpup-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-17)
The same I-16 of synthetic method, obtains white solid 0.36g, fusing point 112-114 DEG C, productive rate 64%.
1HNMR(300MHz，DMSO-d 6)δ：12.34(brs，1H)，7.86-7.56(m，2H)，7.51-7.37(m，3H)，7.31(d，J＝6.7Hz，2H)，7.08(d，J＝7.9Hz，1H)，6.91(d，J＝8.2Hz，2H)，6.54-6.32(m，2H)，5.24(s，2H)，4.92(s，2H)，4.67(t，J＝9.1Hz，1H)，4.38-4.27(m，1H)，4.16(t，J＝6.4Hz，2H)，3.77-3.69(m，1H)，2.68，2.63(dd，J＝16.3，5.0Hz，1H)，2.50-2.35(m，1H)，1.91-1.59(m，2H)，0.94(t，J＝8.6Hz，3H). 13CNMR(75MHz，DMSO-d 6)δ：177.21，166.49，159.12，158.36，157.31，134.28，131.06，129.21，128.76，127.86，127.13，123.81，114.59，112.61，105.19，97.16，75.75，73.04，70.82，41.25，37.76，20.61，10.12.ESI-MSm/z：474.2[M-H] -.Anal.calcd.ForC 28H 29NO 6：C，70.72；H，6.15；N，2.95；Found：C，70.75；H，6.14；N，2.96.
Embodiment 20
2-(6-(4-(2-isobutyl oxygen imido grpup-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-18)
The same I-16 of synthetic method, obtains white solid 0.31g, fusing point 106-107 DEG C, productive rate 60%.
1HNMR(300MHz，DMSO-d 6)δ：12.38(brs，1H)，7.63，7.61(dd，J＝6.5，3.0Hz，2H)，7.50-7.36(m，3H)，7.31(d，J＝8.6Hz，2H)，7.09(d，J＝7.9Hz，1H)，6.92(d，J＝8.6Hz，2H)，6.52-6.33(m，2H)，5.25(s，2H)，4.94(s，2H)，4.67(t，J＝9.1Hz，1H)，4.17，4.14(dd，J＝8.9，6.9Hz，1H)，4.01(d，J＝6.7Hz，2H)，3.75-3.57(m，1H)，2.69，2.64(dd，J＝16.6，5.5Hz，1H)，2.45(d，J＝9.1Hz，1H)，2.11-1.93(m，1H)，0.94(d，J＝6.7Hz，6H). 13CNMR(75MHz，DMSO-d 6)δ：174.21，166.45，159.12，158.36，157.01，134.28，131.06，129.21，128.76，127.86，127.13，123.81，114.59，105.19，97.16，80.74，75.75，73.04，70.82，40.25，37.76，26.3，19.2.ESI-MSm/z：488.2[M-H] -.Anal.calcd.ForC 29H 31NO 6：C，71.15；H，6.38；N，2.86；Found：C，71.11；H，6.37；N，2.87.
Embodiment 21
2-(6-(4-(2-ring third methoxy imino-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-19)
The same I-16 of synthetic method, obtains white solid 0.36g, fusing point 113-115 DEG C, productive rate 69%.
1HNMR(300MHz，DMSO-d 6)δ：12.34(brs，1H)，7.86-7.56(m，2H)，7.51-7.37(m，3H)，7.31(d，J＝7.3Hz，2H)，7.09(d，J＝7.7Hz，1H)，6.93(d，J＝7.2Hz，2H)，6.57-6.25(m，2H)，5.26(s，2H)，4.92(s，2H)，4.67(t，J＝9.0Hz，1H)，4.17(t，J＝7.8Hz，1H)，4.05(d，J＝7.1Hz，2H)，3.68-3.65(m，1H)，2.69，2.64(dd，J＝16.6，5.3Hz，1H)，2.45-2.41(m，1H)，1.19-1.06(m，1H)，0.56(d，J＝8.0Hz，2H)，0.34(d，J＝4.6Hz，2H). 13CNMR(75MHz，DMSO-d 6)δ：177.21，166.49，159.12，158.36，157.31，134.28，131.06，129.21，128.76，127.86，127.13，123.81，114.59，105.29，97.16，80.67，75.75，73.04，70.82，41.25，37.76，8.61，2.32.ESI-MSm/z：486.2[M-H] -.Anal.calcd.ForC 29H 29NO 6：C，71.44；H，6.00；N，2.87；Found：C，71.41；H，6.01；N，2.86.
Embodiment 22
2-(6-(4-(2-benzyloxy imido grpup-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-20)
The same I-16 of synthetic method, obtains white solid 0.47g, fusing point 148-150 DEG C, productive rate 78%.
1HNMR(300MHz，DMSO-d 6)δ：12.37(brs，1H)，7.65(d，J＝11.4Hz，2H)，7.48-7.40(m，9H)，7.24(d，J＝7.0Hz，1H)，7.08(d，J＝7.9Hz，1H)，6.94-6.81(m，2H)，6.51-6.33(m，2H)，5.27(s，4H)，4.90(s，2H)，4.66(t，J＝9.0Hz，1H)，4.27-4.10(m，1H)，3.65-3.61(m，1H)，2.62，2.57(dd，J＝16.5，4.9Hz，1H)，2.38，2.33(dd，J＝16.4，9.3Hz，1H). 13CNMR(75MHz，DMSO-d 6)δ：177.31，165.38，159.61，158.42，157.33，137.53，134.02，131.23，129.98，128.87，128.64，127.12，126.56，125.07，124.34，123.72，114.26，107.00，102.08，77.86，74.25，73.82，70.34，40.71，37.89.ESI-MSm/z：522.2[M-H] -.Anal.calcd.ForC 32H 29NO 6：C，73.41；H，5.58；N，2.68；Found：C，73.45；H，5.57；N，2.67.
Embodiment 23
2-(6-(the fluoro-4-of 3-(2-methoxy imino-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-21)
The same I-1 of synthetic method, obtains white solid 0.38g, fusing point 126-128 DEG C, productive rate 73%.
1HNMR(300MHz，DMSO-d 6)δ：12.39(brs，1H)，7.65，7.63(dd，J＝6.6，2.9Hz，2H)，7.46-7.37(m，3H)，7.27-7.14(m，3H)，7.09(d，J＝7.8Hz，1H)，6.49-6.34(m，2H)，5.30(s，2H)，4.94(s，2H)，4.67(t，J＝9.0Hz，1H)，4.21-4.10(m，1H)，3.98(s，3H)，3.68-3.62(m，1H)，2.60，2.55(dd，J＝16.2，5.4Hz，1H)，2.35，2.30(dd，J＝16.1，9.2Hz，1H). 13CNMR(75MHz，DMSO-d 6)δ：174.30，161.11，159.23，153.99，152.34，148.79，135.43，134.23，131.25，129.96，128.81，127.15，125.03，123.14，116.11，115.27，107.11，97.17，77.98，73.21，68.79，60.72，41.19，38.05.ESI-MSm/z：464.1[M-H] -.Anal.calcd.ForC 26H 24FNO 6：C，67.09；H，5.20；N，3.01；Found：C，67.05；H，5.21；N，3.01.
Embodiment 24
2-(6-(the fluoro-4-of 2-(2-methoxy imino-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-22)
The same I-1 of synthetic method, obtains white solid 0.32g, fusing point 123-125 DEG C, productive rate 67%.
1HNMR(300MHz，DMSO-d 6)δ：12.34(brs，1H)，7.78-7.62(m，2H)，7.45-7.40(m，4H)，7.10(d，J＝8.7Hz，1H)，6.92-6.72(m，2H)，6.44(d，J＝6.1Hz，2H)，5.25(s，2H)，4.97(s，2H)，4.68(t，J＝9.0Hz，1H)，4.24-4.07(m，1H)，3.98(s，3H)，3.69-3.63(m，1H)，2.64，2.59(dd，J＝16.3，5.4Hz，1H)，2.44-2.27(m，1H). 13CNMR(75MHz，DMSO-d 6)δ：174.11，165.28，161.14，160.82，159.36，134.23，131.12，129.98，128.87，128.64，127.12，125.07，120.12，110.26，107.00，102.23，97.08，77.86，74.25，62.76，61.95，40.71，37.89.ESI-MSm/z：464.1[M-H] -.Anal.calcd.ForC 26H 24FNO 6：C，67.09；H，5.20；N，3.01；Found：C，67.06；H，5.21；N，3.02.
Embodiment 25
2-(6-(3-methoxyl group-4-(2-methoxy imino-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid (I-23)
The same I-1 of synthetic method, obtains white solid 0.23g, fusing point 117-119 DEG C, productive rate 60%.
1HNMR(300MHz，DMSO-d 6)δ：12.38(brs，1H)，7.69-7.66(m，2H)，7.45-7.40(m，3H)，7.09(d，J＝7.9Hz，1H)，6.97-6.91(m，3H)，6.43-6.38(m，2H)，5.17(s，2H)，4.92(s，2H)，4.66(t，J＝8.7Hz，1H)，4.32-4.07(m，1H)，3.96(s，3H)，3.77-3.72(m，1H)，3.67(s，3H)，2.69，2.64(dd，J＝16.6，5.5Hz，1H)，2.45(d，J＝9.1Hz，1H). 13CNMR(75MHz，DMSO-d 6)δ：174.21，166.49，159.12，158.36，150.31，148.91，134.28，131.06，129.21，128.76，127.86，127.13，123.81，121.24，114.59，112.61，105.19，97.16，75.75，73.04，70.82，61.23，56.12，41.25，37.76.ESI-MSm/z：476.1[M-H] -.Anal.calcd.ForC 27H 27NO 7：C，67.91；H，5.70；N，2.93；Found：C，67.93；H，5.71；N，2.93.
Embodiment 26
Tablet containing promoting agent I-2:
Activeconstituents, pregelatinized Starch and Microcrystalline Cellulose are sieved, fully mixes, add polyvinylpyrrolidonesolution solution, mixing, softwood processed, sieves, wet granular processed, in 50-60 DEG C of drying, sieves Sodium carboxymethyl starch, Magnesium Stearate and talcum powder and is added to compression molding in above-mentioned particle.
Empirical tests, above-mentioned composition also has hypoglycemic activity in excellent body.

Claims (7)

1. the compound shown in a general formula (I) or its pharmaceutically useful salt:
Wherein:
Ring A is selected from aryl or heteroaryl;
R 1and R 2independently be selected from hydrogen, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl separately, wherein said alkyl, cycloalkyl, alkoxyl group optionally further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl group replace;
R 3be selected from alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl;
R 4be selected from hydrogen, halogen, alkyl, alkoxyl group.
2. compound or its pharmaceutically useful salt of what claim 1 defined have general formula (I):
Wherein:
Ring A is preferably from phenyl ring or thiphene ring;
R 1and R 2independently be selected from hydrogen, halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl separately, wherein said alkyl, cycloalkyl, alkoxyl group optionally further by one or more be selected from halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl group replace;
R 3be selected from alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl;
R 4be selected from hydrogen, halogen, alkyl, alkoxyl group.
3. compound or its pharmaceutically useful salt of what claim 2 defined have general formula (I):
Wherein:
Ring A is preferably from phenyl ring or thiphene ring;
R 1and R 2independently be selected from hydrogen, halogen, hydroxyl, cyano group, C separately 1-C 6alkyl, C 1-C 6alkoxyl group, cycloalkyl, wherein said alkyl, cycloalkyl, alkoxyl group optionally further by one or more be selected from halogen, hydroxyl, cyano group, alkyl, alkoxyl group group replace;
R 3preferably from C 1-C 6alkyl, C 1-C 6alkoxyl group, cycloalkyl, heterocyclic radical, aryl;
R 4preferably from hydrogen, fluorine, C 1-C 6alkyl, C 1-C 6alkoxyl group.
4. compound or its pharmaceutically useful salt of what claim 3 defined have general formula (I):
Wherein:
Ring A is preferably from phenyl ring or thiphene ring;
R 1and R 2independently be selected from hydrogen, F, Cl, C separately 1-C 6alkyl, C 1-C 6alkoxyl group, wherein said alkyl, alkoxyl group are optionally selected from F, hydroxyl, cyano group, C by one or more further 1-C 6the group of alkyl replaced;
R 3preferably from C 1-C 6alkyl, C 1-C 6alkoxyl group, aryl;
R 4preferably from hydrogen, fluorine, C 1-C 6alkyl, C 1-C 6alkoxyl group.
5. general formula (I) compound that defines of claim 4 or its pharmaceutically useful salt, described compound is selected from:
2-(6-(4-(2-methoxy imino-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(4-(2-(2-fluorobenzene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(4-(2-(3-fluorobenzene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(4-(2-(4-fluorobenzene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(4-(2-(2-toluene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(4-(2-(3-toluene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(4-(2-(4-toluene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(4-(2-(3-chlorobenzene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(4-(2-(4-chlorobenzene)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(4-(2-(3-phenylfluoroform)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(4-(2-(4-phenylfluoroform)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(4-(2-(4-methoxyphenyl)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(4-(2-(3,4-difluorophenyl)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(4-(2-(2,4 dichloro benzene base)-2-(methoxy imino) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(4-(2-methoxy imino-2-(thiophene-2-base) oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(4-(2-ethoxyimino-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(4-(2-third oxygen imido grpup-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(4-(2-isobutyl oxygen imido grpup-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(4-(2-ring third methoxy imino-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(4-(2-benzyloxy imido grpup-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(the fluoro-4-of 3-(2-methoxy imino-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(the fluoro-4-of 2-(2-methoxy imino-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid;
2-(6-(3-methoxyl group-4-(2-methoxy imino-2-benzene oxyethyl group) benzyloxy)-2,3-dihydro-1-cumarone-3-bases) acetic acid.
6. a pharmaceutical composition, containing the compound or pharmaceutically acceptable salt thereof one of claim 1-5 Suo Shu and suitable carrier or vehicle.
7. the compound that defines of claim 1-5 any one or its pharmaceutically useful salt or the purposes of its pharmaceutical composition in preparation treatment diabetes and Metabolic syndrome disease drug.
CN201610064100.XA 2016-01-27 2016-01-27 Novel oxime ether derivative and preparation method thereof and application of derivative by serving as drug Pending CN105566267A (en)

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Citations (4)

* Cited by examiner, † Cited by third party
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Application publication date: 20160511