CN104910118A - Bishydroxycoumarin compound, preparation method and purpose thereof - Google Patents

Bishydroxycoumarin compound, preparation method and purpose thereof Download PDF

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CN104910118A
CN104910118A CN201410093055.1A CN201410093055A CN104910118A CN 104910118 A CN104910118 A CN 104910118A CN 201410093055 A CN201410093055 A CN 201410093055A CN 104910118 A CN104910118 A CN 104910118A
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alkylidene group
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alkyl
hydrogen
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CN104910118B (en
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南发俊
耿美玉
徐济民
艾菁
张仰明
彭霞
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Shanghai Institute of Materia Medica of CAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
    • C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
    • C07D311/16—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted in position 7

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Abstract

The invention relates to a bishydroxycoumarin compound, a preparation method and a purpose of a protein tyrosine kinase inhibitor for preparing an antitumor drug. The bishydroxycoumarin compound has a structure having a general formula I, and has wide spectrum kinases inhibition activity and has direct inhibition activity for c-Met kinases, and the compound of the present invention can be used for preparing the antitumor drug.

Description

One marcumar compounds and its production and use
Technical field
The invention belongs to medical compounds synthesis field, particularly, relate to a kind of Dicoumarin Derivatives, its preparation method and preparing the purposes in antitumor drug as protein tyrosine kinase inhibitor.
Background technology
The health and lives of tumour seriously harm humans, the research for oncotherapy more and more receives publicity.Since entering 21st century, along with the huge progress that the researchs such as oncological pathology, cytobiology, tumorigenicity obtain, the key enzyme of to breed using some to tumor cell differentiation and shift relevant intracellular signal transduction pathway as drug screening target spot, the important directions that exploitation is efficient, the novel targeted antitumor drug of low toxicity has become the research and development of current antitumor drug.
Protein tyrosine kinase occupies very consequence in intracellular signal transduction pathway, regulates a series of physiology processes such as cell growth in vivo, differentiation, death.The imbalance of protein tyrosine kinase function can cause a series of diseases in organism.Existing data shows, the proto-oncogene more than 50% and oncoprotein all have protein tyrosine kinase activity, and their unconventionality expression will cause cell proliferation adjustment to get muddled, and then cause tumour to occur.Therefore, the activity of Tyrosylprotein kinase is suppressed can to play antineoplastic action (Cepero, V; Sierra, J.R., Giordano, S.Tyrosine kinases as molecular targets to inhibit cancer progression and metastasis.Curr.Pharm.Des, 2010,16 (12), 1396-409).
At present, existing patent literature Dicoumarin Derivatives is as protein tyrosine kinase inhibitor, and its linking group is mainly alkyl chain or arylidene chain, wherein can also introduce the heteroatoms such as unsaturated link(age), O, N or carbonyl, amide group etc.And this connection chain is difficult to introduce side chain substituents again, the impact of connection portion on kinase inhibiting activity can not be investigated, and compound also not easily synthesizes (patent: CN102558049A) comprehensively.
Summary of the invention
Technical problem
Present inventor finds a class using amino acid as the Dicoumarin Derivatives of connection portion, and it has the inhibit activities of wide spectrum for protein tyrosine kinase.Wherein, for the inhibit activities IC of c-Met (hepatocyte growth factor receptor) 50value reaches 9nM.This marcumar compounds comprises and to connect with an amino acid and to contain two amido linkages connection chain.The amino acid that contriver finds connection portion is further connected with the activity that suitable side chain substituents can significantly improve compound.On this basis, contriver obtains a series of compound with further potentiality to be exploited.
Technical scheme
One object of the present invention is for providing a kind of Dicoumarin Derivatives, and it is represented by following general formula I:
General formula I
Wherein:
X 1and X 2be nitrogen (-NH-), C independently of one another 1-C 6alkylamino, C 6-C 12the C that aryl replaces 1-C 6alkylamino, fluoro C 1-C 6alkylamino or oxygen;
Preferably, X 1and X 2identical, be oxygen or nitrogen;
N is the integer of 1-5; When the integer of n=2-5, the R in different repeat units 11group can be identical or different, and the R in different repeat units 12group can be identical or different; Preferably, n is 1 or 2;
R 1-R 10be hydrogen, hydroxyl, C independently of one another 1-C 6alkyloyl, C 1-C 6alkoxyl group, C 1-C 6alkyl-carbonyl oxygen base, C 1-C 6alkyl siloxy, C 1-C 6alkyloxycarbonyl oxygen base or phenyl C 1-C 6alkylidene group oxygen base, or R 4and R 10common formation wherein m is the integer of 6-10; Or R 9and R 10connected carbon atom forms substituted or unsubstituted 3-6 unit heterocycle, and wherein, the substituting group on described 3-6 unit heterocycle is for being selected from C 1-C 6alkyl and phenyl C 1-C 61-3 in alkylidene group, and described 3-6 unit heterocycle contains 1-3 atom N;
Preferably, R 1-R 10be hydrogen, hydroxyl, formyl radical, ethanoyl, methoxyl group, oxyethyl group, tertiary butyl oxygen base, methanoyl, acetoxyl group, tertiary butyl dimethyl Si base, tertiary butyl diethyl siloxy, tertbutyloxycarbonyl oxygen base or benzyl oxygen base independently of one another, or, R 4and R 10common formation wherein m is 8-10; Or R 9and R 10connected carbon atom forms substituted or unsubstituted 5 yuan of heterocycles, and wherein, the substituting group on described 5 yuan of heterocycles is for being selected from C 1-C 3alkyl and phenyl C 1-C 32 in alkylidene group, and described 5 yuan of heterocycles contain 2 atom N;
More preferably, R 1-R 10be hydrogen, hydroxyl, formyl radical, ethanoyl, methoxyl group, oxyethyl group, tertiary butyl oxygen base, methanoyl, acetoxyl group, tertiary butyl dimethyl Si base, tertbutyloxycarbonyl oxygen base or benzyl oxygen base independently of one another, or, R 4and R 10common formation wherein m is 8; Or R 3and R 4or R 9and R 10connected carbon atom forms substituted or unsubstituted 5 yuan of heterocycles, and wherein, the substituting group on described 5 yuan of heterocycles is methyl and benzyl, and described 5 yuan of heterocycles contain 2 atom N;
R 11and R 12be hydrogen, C independently of one another 1-C 6straight or branched alkyl, C 3-C 6cycloalkyl C 1-C 6alkylidene group, phenyl C 1-C 6alkylidene group, C 1-C 6alkyl-S-C 1-C 6alkylidene group, C 1-C 6straight or branched alkoxy carbonyl C 1-C 6alkylidene group, hydroxycarbonyl group C 1-C 6alkylidene group, aminocarboxyl C 1-C 6alkylidene group, amino C 1-C 6alkylidene group, C 1-C 6the aminocarboxyl C that alkyl replaces 1-C 6alkylidene group, or R 11and R 12connected carbon atom forms 5-7 unit cycloalkyl;
Preferably, R 11and R 12be hydrogen, benzyl, C independently of one another 1-C 6straight or branched alkyl, C 3-C 6cycloalkyl C 1-C 3alkylidene group, C 1-C 3alkyl-S-C 1-C 3alkylidene group, C 1-C 4straight or branched alkoxy carbonyl C 1-C 4alkylidene group, hydroxycarbonyl group C 1-C 3alkylidene group, aminocarboxyl C 1-C 3alkylidene group, amino C 1-C 3alkylidene group or tert-butylamino carbonyl methylene radical, or R 11and R 12connected carbon atom forms cyclohexyl;
More preferably, R 11and R 12be hydrogen, benzyl, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, hexyl, cyclohexylmethylene, CH independently of one another 3-S-C 2h 4-, tertiary butyloxycarbonyl methylene, hydroxycarbonyl group methylene radical, aminocarboxyl methylene radical, Aminopropylidene or tert-butylamino carbonyl methylene radical, or R 11and R 12connected carbon atom forms cyclohexyl;
R 13for hydrogen, C 1-C 6alkyl or halogen, be preferably hydrogen.
Preferably, Dicoumarin Derivatives of the present invention is be selected from the one in following compound:
Another object of the present invention is for providing the preparation method of above-mentioned Dicoumarin Derivatives, and described preparation method is realized by following route: wherein, X 1, X 2, R 1~ R 13definition identical with substituent definition each in general formula I;
Specifically, compd A (is prepared by reference to literature method: Sivakumar, Krishnamoorthy, Xie, Fang, Cash, Brandon M., Long, Su, Barnhill, Hannah N., Wang, Qian.Organic Letters, 2004, vol.6, #24, p.4603-4606 or by reference to literature method prepare: Saari, Walfred S., Wai, John S., Fisher, Thorsten E., Thomas, Craig M., Hoffman, Jacob M., et al.Journal of Medicinal Chemistry, 1992, vol.35, #21p.3792-3802) with the compd B (amino acid that 9-fluorenylmethyloxycarbonyl (Fmoc) is protected, can be obtained by commercial goods approach) in pyridine (Py)/methylene dichloride (DCM), add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) reaction, the intermediate (Compound C) obtained adds piperidines (piperidine) again and takes off 9-fluorenylmethoxycarbonyl groups (Fmoc) protecting group in acetonitrile, generate Compound D (amine intermediate).Last again with compd E (3-formic acid tonka bean camphor or 3-formic acid quinolinone, both all prepare by reference to literature method: Leone-Bay, Andrea; Paton et al.Journal of Medicinal Chemistry, 1998, vol.41, #7p.1163 – 1171) in methylene dichloride (DCM), add DMAP (DMAP) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) reaction, obtain the compound of general formula I.
Another object of the present invention is for providing above-mentioned Dicoumarin Derivatives in preparation as the purposes in the medicine of protein tyrosine kinase inhibitor.
Another object of the present invention is preparing the purposes in antitumor drug for providing above-mentioned Dicoumarin Derivatives.
Another object of the present invention is to provide a kind of pharmaceutical composition, and it compound of Formula I comprising treatment significant quantity is as activeconstituents and pharmaceutically acceptable auxiliary material.Described pharmaceutically acceptable auxiliary material is such as dispersion agent, vehicle, disintegrating agent, antioxidant, sweeting agent, Drug coating etc.Present invention also offers described pharmaceutical composition in preparation as the purposes in the medicine of protein tyrosine kinase inhibitor, and described pharmaceutical composition is preparing the purposes in antitumor drug.
Another object of the present invention is to provide the purposes of above-mentioned Dicoumarin Derivatives treatment tumour.
Beneficial effect
The novel temparin of Design and synthesis of the present invention one class effectively can suppress the propagation of phosphorylation level as kinase whose in c-Met, ALK, EGFR etc. and the tumour cell as A549, EBC-1, BaF3/TPR-Met, therefore has and makes the possibility that kinase inhibitor is used as anti-tumor drug.And the compound structure that the present invention relates to is relatively simple, be easy to preparation.
Accompanying drawing explanation
Fig. 1 is the impact of part of compounds of the present invention on A549 and BaF3/TPR-Met cell levels c-Met phosphorylation.
Embodiment
Below in conjunction with specific embodiment, the present invention is further elaborated, but the present invention is not limited to these embodiments.
Preparation embodiment
In following preparation embodiment, the Mercury-Vx300M Instrument measuring that NMR produces with Varian, NMR calibrates: δ H7.26ppm (CDCl 3), 2.50ppm (DMSO-d 6); Mass spectrum Agilent1200Quadrupole LC/MS LC-MS instrument or SHIMADZU GCMS-QP5050A measure; Reagent provides primarily of Solution on Chemical Reagents in Shanghai company; TLC tlc silica gel plate is produced by Yantai, Shandong fellow member of an association or organization's silica gel development corporation, Ltd., model HSGF254; The normal phase column chromatography silica gel that compound purifying uses is the production of Qingdao subsidiary factory of marine chemical industry factory, model zcx-11,200-300 order.
Preparation embodiment 1
(R)-N-(N-(Daphnelin-3-)-4-methyl-valeramide-2-)-Daphnelin-3-acid amides (compound number: 510-1)
(prepared by reference method: Sivakumar, Krishnamoorthy for 7,8-bis-(methoxymethoxy)-tonka bean camphor-3-amine (120mg, 0.427mmol); Xie, Fang; Cash, Brandon M.; Long, Su; Barnhill, Hannah N.; Wang, Qian.Organic Letters, 2004, vol.6, #24, p.4603-4606) with N-(9-fluorenylmethyloxycarbonyl)-D-Leu (Fmoc-D-Leu-OH) (227mg, 0.641) 5mL30% pyridine/methylene dichloride is dissolved in, add 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), stirring at room temperature is after 24 hours, revolve desolventizing, column chromatography obtains intermediate 1 white solid 190mg, molar yield: 72%. 1H NMR(300MHz,CDCl 3)δ8.60(s,1H),8.57(br,1H),7.75(d,J=7.5Hz,2H),7.62-7.56(m2H),7.38(t,J=7.5Hz,2H),7.30((t,J=7.2Hz,2H),7.18(d,J=8.7Hz,1H),7.13(d,J=8.7Hz,1H),5.32-5.18(m,5H),4.48(d,J=6.0Hz,2H),4.38(s,1H),4.23(t,J=6.6Hz,1H),3.70(s,3H),3.52(s,3H),1.78-1.54(m,3H),0.96(s,6H).
Above-mentioned intermediate 1 (190mg, 0.308mmol) is dissolved in 10mL acetonitrile (CH 3cN), add piperidines (piperidine) (31 μ L, 0.308mmol), stirring at room temperature, after 6 hours, revolves desolventizing, and column chromatography obtains amine intermediate 2 white solid 85mg, molar yield: 70%. 1H NMR(300MHz,CDCl 3)δ10.10(s,1H),8.65(s,1H),7.18(d,J=8.7Hz,1H),7.11(d,J=8.7Hz,1H),5.26(s,2H),5.24(s,2H),3.70(s,3H),3.60-3.53(m,1H),3.51(s,3H),1.92-1.63(m,5H),1.06-0.88(m,6H).
Above-mentioned amine intermediate 2 (85mg, 0.216mmol), (prepared by reference method: Leone-Bay, Andrea for 7,8-bis-(methoxymethoxy)-coumarin-3-carboxy acid (80mg, 0.259mmol); Paton et al.Journal of Medicinal Chemistry, 1998, vol.41, #7p.1163 – 1171), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) (62mg, 0.324mmol) and DMAP (DMAP) (6mg, 0.049mmol) be dissolved in 10mL methylene dichloride (DCM), stirring at room temperature is after two hours, revolve desolventizing, column chromatography obtains temparin intermediate 3 (120mg, productive rate: 81%). 1H NMR(300MHz,CDCl 3)δ9.15(d,J=6.9Hz,1H),8.88(s,1H),8.87(s,1H),8.63(s,1H),7.40(d,J=9.0Hz,1H),7.21(d,J=9.0Hz,1H),7.17(d,J=8.7Hz,1H),7.11(d,J=8.7Hz,1H),5.33(s,2H),5.25(s,4H),5.22(s,2H),4.78-4.70(m,1H),3.71(s,3H),3.68(s,3H),3.52(s,3H),3.50(s,3H),1.95-1.75(m,3H),1.02(d,J=6.0Hz,3H),0.98(d,J=6.3Hz,3H).
Above-mentioned intermediate 3 is dissolved in 2mL methylene dichloride, adds the ethyl acetate solution of 2mL2N HCl, stirring at room temperature 2 as a child after, namely obtain target compound, yellow solid 96mg.Molar yield: 92%. 1H NMR(300MHz,DMSO-d 6)δ10.65(s,1H),9.90(s,2H),9.58(br s,1H),9.30(br s,1H),9.04(d,J=7.8Hz,1H),8.77(s,1H),8.46(s,1H),7.33(d,J=8.4Hz,1H),7.00(d,J=8.7Hz,1H),6.91(d,J=8.4Hz,1H),6.81(d,J=8.4Hz,1H),5.04-4.94(m,1H),1.74-1.60(m,3H),0.94(d,J=5.1Hz,6H). 13C NMR(75MHz,DMSO-d 6)δ171.8,161.4,161.0,157.7,152.3,149.1,148.1,144.2,140.3,132.0,131.9,127.7,121.6,120.2,118.1,113.6,113.0,112.7,112.1,111.8,52.0,41.4,24.5,23.1,21.8.
Preparation embodiment 2
N-(1-((Daphnelin-3-) formamyl) cyclohexyl)-Daphnelin-3-acid amides (compound number: 522C)
With reference to the method preparing embodiment 1, with 7,8-bis-(methoxymethoxy)-tonka bean camphor-3-amine, 1-(9-fluorenylmethyloxycarbonyl-amino) cyclohexane carboxylic and 7,8-bis-(methoxymethoxy)-coumarin-3-carboxy acid prepare target compound for starting raw material. 1h NMR (300MHz, DMSO-d 6) δ 10.73 (br s, 1H), 9.94 (br s, 1H), 9.61 (br s, 1H), 9.31 (br s, 1H), (9.09 s, 1H), 9.03 (s, 1H), 8.72 (s, 1H), (8.38 s, 1H), 7.32 (d, J=8.4Hz, 1H), 7.01 (d, J=9.0Hz, 1H), 6.93 (d, J=8.4Hz, 1H), 6.82 (d, J=8.1Hz, 1H), 2.28-2.18 (m, 2H), 1.88-1.74 (m, 2H), (1.72-1.56 m, 3H), 1.54-1.36 (m, 2H), 1.35-1.20 (m, 1H). 13c NMR (75MHz, DMSO-d 6) δ 173.0,161.5,161.4,158.0,152.4,148.9,148.0,144.2,140.0,132.1,131.9,126.4,121.6,120.3,118.0,113.8,113.2 (two carbon), 112.1,111.8,59.9,31.28 (two carbon), 24.71,20.92 (two carbon).
Preparation embodiment 3
(S)-N-(N-(Daphnelin-3-)-3-methyl-butyramide-2-)-Daphnelin-3-acid amides (compound number: 496)
With reference to the method preparing embodiment 1, with 7,8-bis-(methoxymethoxy)-tonka bean camphor-3-amine, N-(9-fluorenylmethyloxycarbonyl)-Valine and 7,8-bis-(methoxymethoxy)-coumarin-3-carboxy acid prepare target compound for starting raw material. 1H NMR(300MHz,DMSO-d 6)δ10.65(s,1H),9.94(s,1H),9.90(s,1H),9.60(s,1H),9.31(s,1H),9.13(d,J=8.7Hz,1H),8.78(s,1H),8.46(s,1H),7.34(d,J=8.7Hz,1H),7.00(d,J=8.7Hz,1H),6.91(d,J=8.7Hz,1H),6.81(d,J=8.4Hz,1H),4.97-4.90(m,1H),2.27-2.08(m,1H),1.05-0.85(m,6H). 13C NMR(75MHz,DMSO-d 6)δ170.89,161.5,161.2,157.7,152.3,149.1,148.1,144.2,140.3,132.0,131.9,127.9,121.5,120.1,118.1,113.6,113.0,112.8,112.1,111.9,57.7,31.3,19.2,17.4.
Preparation embodiment 4
N-(N-(Daphnelin-3-)-ethanamide-2-)-Daphnelin-3-acid amides (compound number: 454)
With reference to the method preparing embodiment 1, with 7,8-bis-(methoxymethoxy)-tonka bean camphor-3-amine, glycine and 7,8-bis-(methoxymethoxy)-coumarin-3-carboxy acid for starting raw material prepares target compound. 1HNMR(300MHz,DMSO-d 6)δ10.65(s,1H),9.94(s,1H),9.78(s,1H),9.60(s,1H),9.32(s,1H),9.15(t,J=5.4Hz,1H),8.78(s,1H),8.50(s,1H),7.35(d,J=8.7Hz,1H),6.99(d,J=8.7Hz,1H),6.91(d,J=8.7Hz,1H),6.81(d,J=8.4Hz,1H),4.28(d,J=5.1Hz,2H). 13C NMR(75MHz,DMSO-d 6)δ168.6,161.9,160.8,157.7,152.3,149.0,148.0,144.3,140.1,132.1,131.9,126.5,121.6,120.4,118.0,113.6,113.1,112.8,112.1,111.8,43.6.
Preparation embodiment 5
(S)-N-(N-(Daphnelin-3-)-3-phenylpropionamide-2-)-Daphnelin-3-acid amides (compound number: 544)
With reference to the method preparing embodiment 1, with 7,8-bis-(methoxymethoxy)-tonka bean camphor-3-amine, N-(9-fluorenylmethyloxycarbonyl)-L-Phe and 7,8-bis-(methoxymethoxy)-coumarin-3-carboxy acid prepare target compound for starting raw material. 1h NMR (300MHz, DMSO-d 6) δ 10.65 (br s, 1H), 9.99 (s, 1H), 9.09 (d, J=7.8Hz, 1H), 8.71 (s, 1H), 8.46 (s, 1H), (7.35-7.15 m, 6H), 6.99 (d, J=8.4Hz, 1H), 6.90 (d, J=8.7Hz, 1H), 6.82 (d, J=8.4Hz, 1H), 5.25-5.16 (m, 1H), 3.22 (dd, J=13.8,4.8Hz, 1H), 3.03 (dd, J=13.5,8.7Hz, 1H). 13c NMR (75MHz, DMSO-d 6) δ 170.6,161.3,160.9,157.7,152.4,149.1,148.1,144.2,140.2,136.8,132.1,131.9,129.3 (two carbon), 128.1 (two carbon), 127.3,126.5,121.6,120.2,118.1,113.7,113.1,112.4,112.1,111.8,54.6,38.0.
Preparation embodiment 6
N-(N-(Daphnelin-3-)-decoylamide-2-)-Daphnelin-3-acid amides (compound number: 538)
With reference to the method preparing embodiment 1, with 7, sad and 7,8-bis-(the methoxymethoxy)-coumarin-3-carboxy acid of 8-bis-(methoxymethoxy)-tonka bean camphor-3-amine, 2-(9-fluorenylmethyloxycarbonyl-amino) prepares target compound for starting raw material. 1H NMR(300MHz,DMSO-d 6)δ10.64(s,1H),9.94(s,1H),9.88(s,1H),9.59(s,1H),9.32(s,1H),9.11(d,J=8.1Hz,1H),8.77(s,1H),8.47(s,1H),7.34(d,J=8.4Hz,1H),7.00(d,J=8.1Hz,1H),6.91(d,J=7.8Hz,1H),6.81(d,J=8.4Hz,1H),4.98-4.90(m,1H),1.90-1.65(m,2H),1.40-1.15(m,8H),0.84(t,J=6.6Hz,3H). 13C NMR(75MHz,DMSO-d 6)δ171.5,161.3,161.1,157.7,152.3,149.0,148.1,144.2,140.3,132.0,131.9,127.6,121.6,120.1,118.1,113.6,113.0,112.8,112.1,111.8,53.2,32.7,31.0,28.3,24.8,21.9,13.8.
Preparation embodiment 7
(S)-N-(N-(Daphnelin-3-)-4-methylsulfanyl-butyramide-2-)-Daphnelin-3-acid amides (compound number: 528)
With reference to the method preparing embodiment 1, with 7,8-bis-(methoxymethoxy)-tonka bean camphor-3-amine, N-(9-fluorenylmethyloxycarbonyl)-METHIONINE and 7,8-bis-(methoxymethoxy)-coumarin-3-carboxy acid prepare target compound for starting raw material. 1H NMR(300MHz,DMSO-d 6)δ10.60(br s,1H),10.30-9.25(br s,3H),9.88(s,1H),9.18(d,J=7.8Hz,1H),8.76(s,1H),8.47(s,1H),7.34(d,J=9.0Hz,1H),7.01(d,J=9.0Hz,1H),6.91(d,J=8.7Hz,1H),6.81(d,J=8.1Hz,1H),5.05-4.95(m,1H),2.58-2.50(m,2H),2.21–2.10(m,1H),2.06(s,3H),2.04-1.93(m,1H). 13C NMR(75MHz,DMSO-d 6)δ170.7,161.6,161.0,157.7,152.3,149.0,148.2,144.2,140.3,132.1,131.9,127.8,121.6,120.1,118.1,113.6,113.1,112.8,112.1,111.8,52.8,32.6,29.3,14.7.
Preparation embodiment 8
(S)-N-(N-(Daphnelin-3-)-3-cyclohexyl-propionic acid amide-2-)-Daphnelin-3-acid amides (compound number: 550)
With reference to the method preparing embodiment 1, with 7,8-bis-(methoxymethoxy)-tonka bean camphor-3-amine, N-(9-fluorenylmethyloxycarbonyl)-3-cyclohexyl-ALANINE and 7,8-bis-(methoxymethoxy)-coumarin-3-carboxy acid prepare target compound for starting raw material. 1H NMR(300MHz,DMSO-d 6)δ9.89(s,1H),9.05(d,J=7.5Hz,1H),8.77(s,1H),8.45(s,1H),7.33(d,J=8.4Hz,1H),7.00(d,J=9.0Hz,1H),6.91(d,J=8.4Hz,1H),6.81(d,J=8.4Hz,1H),5.05-4.95(m,1H),1.85-1.55(m,6H),1.45-1.35(m,1H),1.24-1.04(m,4H),1.02-0.84(m,2H). 13C NMR(75MHz,DMSO-d 6)δ171.9,161.4,161.1,157.7,152.3,149.1,148.1,144.2,140.3,132.0,131.9,127.7,121.6,120.2,118.1,113.6,113.0,112.7,112.1,111.8,51.5,33.8,33.2,32.0,25.9,25.7,25.6.
Preparation embodiment 9
N-(N-(Daphnelin-3-)-2-methyl-malonamic-2-)-Daphnelin-3-acid amides (compound number: 482)
With reference to the method preparing embodiment 1, with 7,8-bis-(methoxymethoxy)-tonka bean camphor-3-amine, 2-(9-fluorenylmethyloxycarbonyl-amino) isopropylformic acid and 7,8-bis-(methoxymethoxy)-coumarin-3-carboxy acid prepare target compound for starting raw material. 1H NMR(300MHz,DMSO-d 6)δ10.70(br s,1H),9.97(br s,1H),9.61(br s,1H),9.33(br s,1H),9.12(s,1H),9.00(s,1H),8.71(s,1H),8.34(s,1H),7.31(d,J=8.4Hz,1H),7.01(d,J=8.4Hz,1H),6.91(d,J=8.7Hz,1H),6.82(d,J=8.1Hz,1H),1.60(s,6H). 13C NMR(75MHz,DMSO-d 6)δ174.0,162.4,161.7,158.9,152.9,149.5,148.7,144.7,140.8,132.6,132.5,128.5,122.3,120.7,118.9,114.3,113.8,113.7,112.7,112.4,57.8,25.3.
Preparation embodiment 10
N-(N-(Daphnelin-3-)-2,2-dimethvl-propionamide-3-)-Daphnelin-3-acid amides (compound number: 496B)
With reference to the method preparing embodiment 1, with 7,8-bis-(methoxymethoxy)-tonka bean camphor-3-amine, 2,2-dimethyl-3-(9-fluorenylmethyloxycarbonyl-amino) propionic acid and 7,8-bis-(methoxymethoxy)-coumarin-3-carboxy acid prepare target compound for starting raw material. 1H NMR(300MHz,DMSO-d 6)δ8.92(t,J=6.0Hz,1H),8.73(s,1H),8.29(s,1H),7.31(d,J=8.7Hz,1H),7.03(d,J=8.1Hz,1H),6.90(d,J=8.4Hz,1H),6.83(d,J=8.4Hz,1H),3.55(s,2H),1.27(s,6H).
Preparation embodiment 11
(S)-4-((Daphnelin-3-) is amino)-3-(Daphnelin-3-the amide group)-4-ketobutyric acid tert-butyl ester (compound number: 568)
With reference to the method preparing embodiment 1, with 7,8-bis-(methoxymethoxy)-tonka bean camphor-3-amine, N-(9-fluorenylmethyloxycarbonyl)-L-Aspartic acid-4-tert-butyl ester and 7,8-bis-(methoxymethoxy)-coumarin-3-carboxy acid prepare target compound for starting raw material. 1H NMR(300MHz,DMSO-d 6)δ9.63(s,1H),9.38(d,J=7.5Hz,1H),8.81(s,1H),8.46(s,1H),7.36(d,J=8.4Hz,1H),7.01(d,J=8.1Hz,1H),6.91(d,J=8.7Hz,1H),6.81(d,J=8.9Hz,1H),5.15-5.06(m,2H),2.84(d,J=5.7Hz,2H),1.37(s,9H). 13C NMR(75MHz,DMSO-d 6)δ169.6,169.2,161.8,160.9,157.7,152.6,149.4,148.2,144.3,140.2,132.1,131.9,126.8,121.8,120.2,118.2,113.7,113.2,112.4,112.1,111.8,80.7,50.5,37.5,27.6.
Preparation embodiment 12
(S)-4-((Daphnelin-3-) is amino)-3-(Daphnelin-3-amide group)-4-ketobutyric acid (compound number: 512)
By above-claimed cpd (S)-4-((7,8-dihydroxycoumarin-3-) amino)-3-(7,8-dihydroxycoumarin-3-amide group)-4-ketobutyric acid the tert-butyl ester (compound number: 568) (40mg, 0.0704mmol) be dissolved in 4mL formic acid (HCOOH), stirring at room temperature is after 6 hours, revolve desolventizing, column chromatography obtains target product yellow solid 13mg, molar yield: 36%. 1H NMR(300MHz,DMSO-d 6)δ9.70(s,1H),9.40(d,J=7.5Hz,1H),8.72(s,1H),8.47(s,1H),7.30(d,J=8.4Hz,1H),7.01(d,J=8.4Hz,1H),6.81(d,J=8.4Hz,2H),5.08-5.02(m,1H),2.84(d,J=6.0Hz,2H).
Preparation embodiment 13
(S)-N 1-(Daphnelin-3-)-2-(Daphnelin-3-amide group)-N 4-trityl succinic diamide (compound number: 753)
With reference to the method preparing embodiment 1, with 7,8-bis-(methoxymethoxy)-tonka bean camphor-3-amine, N α-(9-fluorenylmethyloxycarbonyl)-N γ-trityl-altheine-4-tert-butyl ester and 7,8-bis-(methoxymethoxy)-coumarin-3-carboxy acid prepare target compound for starting raw material. 1H NMR(300MHz,CD 3OD+CDCl 3)δ8.72(s,1H),8.48(s,1H),7.27-7.05(m,16H),6.89(d,J=8.4Hz,1H),6.88(d,J=8.4Hz,1H),6.80(d,J=8.4Hz,1H),5.13(t,J=6.3Hz,1H),3.08-3.00(m,2H).
Preparation embodiment 14
(S)-N 1-(Daphnelin-3-)-2-(Daphnelin-3-amide group) succinic diamide (compound number: 511)
By (S)-N 1-(Daphnelin-3-)-2-(Daphnelin-3-amide group)-N 4-trityl succinic diamide (compound number: 753) (46mg, 0.0704mmol) be dissolved in 3mL methylene dichloride (DCM), after adding 2mL trifluoracetic acid (TFA), stirring at room temperature is filtered after 2 hours and is obtained target compound 24mg, molar yield: 77%. 1H NMR(300MHz,DMSO-d 6)δ10.67(br s,1H),9.92(br s,1H),9.64(s,2H),9.43(d,J=7.5Hz,1H),9.32(br s,1H),8.80(s,1H),8.48(s,1H),7.52(s,1H),7.35(d,J=8.7Hz,1H),7.04(s,1H),7.00(d,J=8.4Hz,1H),6.91(d,J=8.1Hz,1H),6.81(d,J=8.7Hz,1H),5.08-4.99(m,1H),2.73(d,J=5.7Hz,2H). 13CNMR(75MHz,DMSO-d 6)δ171.6,170.1,161.7,160.8,157.7,152.4,149.2,148.0,144.3,140.0,132.1,131.9,126.0,121.7,120.3,118.0,113.6,113.1,112.5,112.1,111.8,50.6,37.0.
Preparation embodiment 15
(S)-N-(N-(Daphnelin-3-)-4-amino-valeramide-2-)-Daphnelin-3-acid amides (compound number: 548)
With reference to the method preparing embodiment 1, with 7,8-bis-(methoxymethoxy)-tonka bean camphor-3-amine, N α-fluorenylmethyloxycarbonyl-N δ-tertbutyloxycarbonyl-L-Orn and 7,8-bis-(methoxymethoxy)-coumarin-3-carboxy acid prepare target compound for starting raw material. 1H NMR(300MHz,CD 3OD)δ9.54(d,J=7.5Hz,1H),8.78(s,1H),8.51(s,1H),7.23(d,J=9.0Hz,1H),6.94(d,J=8.4Hz,1H),6.92(d,J=8.4Hz,1H),6.82(d,J=8.4Hz,1H),4.96-4.89(m,1H),3.03(t,J=6.9Hz,2H),2.18-2.06(m,1H),2.04-1.91(m,1H),1.90-1.78(m,2H). 13C NMR(75MHz,CD 3OD)δ172.4,164.8,163.2,160.0,154.1,151.1,149.8,145.8,141.8,133.6,133.5,129.6,123.1,121.5,119.8,115.0,114.4,113.9,113.7,113.6,54.9,40.6,30.7,25.0.
Preparation embodiment 16
(R)-1-phenyl-N-(N-(Daphnelin-3-)-4-methyl-valeramide-2-)-3-methyl-8-oxo-1,8-dihydropyrane also [3,2-g] indazole-7-acid amides (compound number: 622B)
With reference to the method preparing embodiment 1, with 7,8-bis-(methoxymethoxy)-tonka bean camphor-3-amine, (prepared by reference method: Sivakumar, Krishnamoorthy; Xie, Fang; Cash, Brandon M.; Long, Su; Barnhill, Hannah N.; Wang; Qian.Organic Letters; 2004; vol.6; #24, p.4603-4606), N-(9-fluorenylmethyloxycarbonyl)-D-Leu and 1-phenyl-3-methyl-8-oxo-1,8-dihydropyrane also [3; 2-g] (prepared by reference method: Leone-Bay, Andrea for indazole-7-carboxylic acid; Paton et al.Journal of Medicinal Chemistry, 1998, vol.41, #7p.1163 – 1171) prepare target compound for starting raw material. 1H NMR(300MHz,CD 3OD)δ8.78(s,1H),8.24(s,1H),7.36(d,J=9.0Hz,1H),7.30-7.21(m,5H),7.15(d,J=8.7Hz,1H),6.68(d,J=8.4Hz,1H),6.64(d,J=8.4Hz,1H),5.49(s,1H),5.44(s,1H),4.85-4.78(m,1H),2.57(s,3H),1.98-1.78(m,3H),1.06(d,J=6.3Hz,3H),1.02(d,J=5.7Hz,3H).
Preparation embodiment 17
(R)-N-(N-(7,8-dihydroxyl-1,2-dihydro-quinolinone-3-)-4-methyl-valeramide-2-)-7,8-dihydroxyl-1,2-dihydro-quinolinone-3-acid amides (compound number: 508A)
With reference to the method preparing embodiment 1, with 7,8-bis-(methoxymethoxy)-1,2-dihydro-quinolinone-3-amine, (prepared by reference method: Sivakumar, Krishnamoorthy; Xie, Fang; Cash, Brandon M.; Long, Su; Barnhill, Hannah N.; Wang; Qian.Organic Letters; 2004; vol.6; #24, p.4603-4606), N-(9-fluorenylmethyloxycarbonyl)-D-Leu and 7,8-bis-(methoxymethoxy)-1; (prepared by reference method: Leone-Bay, Andrea for 2-dihydro-quinolinone-3-carboxylic acid; Paton et al.Journal of Medicinal Chemistry, 1998, vol.41, #7p.1163 – 1171) prepare target compound for starting raw material. 1H NMR(300MHz,DMSO-d 6)δ11.16(s,1H),10.91(s,1H),10.24(d,J=8.1Hz,1H),9.47(s,1H),8.69(s,1H),8.49(s,1H),7.32(d,J=9.0Hz,1H),6.97(d,J=8.7Hz,1H),6.86(d,J=8.7Hz,1H),6.75(d,J=8.4Hz,1H),4.87-4.78(m,1H),1.75-1.65(m,3H),0.97-0.88(m,6H).
Preparation embodiment 18
(R)-N-(N-(Daphnelin-3-)-4-methyl-valeramide-2-)-5,7-dihydroxycoumarin-3-acid amides (compound number: 510C)
With reference to the method preparing embodiment 1, with 7,8-bis-(methoxymethoxy)-tonka bean camphor-3-amine, (prepared by reference method: Sivakumar, Krishnamoorthy; Xie, Fang; Cash, Brandon M.; Long, Su; Barnhill, Hannah N.; Wang; Qian.Organic Letters; 2004; vol.6; #24; p.4603-4606), N-(9-fluorenylmethyloxycarbonyl)-D-Leu and 5,7-bis-(methoxymethoxy)-coumarin-3-carboxy acid (reference method preparation: Leone-Bay, Andrea; Paton et al.Journal of Medicinal Chemistry, 1998, vol.41, #7p.1163 – 1171) prepare target compound for starting raw material. 1H NMR(300MHz,DMSO-d 6)δ9.92(s,1H),8.96(d,J=7.8Hz,1H),8.82(s,1H),8.45(s,1H),7.00(d,J=8.7Hz,1H),6.81(d,J=8.7Hz,1H),6.34(s,1H),6.31(s,1H),5.01-4.91(m,1H),1.71-1.60(m,3H),0.93(d,J=5.7Hz,6H).
Preparation embodiment 19
(R)-7-hydroxy-n-(N-(umbelliferone-3-)-4-methyl-valeramide-2-)-tonka bean camphor-3-acid amides (compound number: 478F)
With reference to the method preparing embodiment 1, with 7-methoxymethoxy tonka bean camphor-3-amine, (prepared by reference method: Sivakumar, Krishnamoorthy; Xie, Fang; Cash, Brandon M.; Long, Su; Barnhill, Hannah N.; Wang, Qian.Organic Letters, 2004, vol.6, #24, p.4603-4606), (prepared by reference method: Leone-Bay, Andrea for 7-methoxymethoxy coumarin-3-carboxy acid; Paton et al.Journal of Medicinal Chemistry, 1998, vol.41, #7p.1163 – 1171) and N-(9-fluorenylmethyloxycarbonyl)-D-Leu be that starting raw material prepares target compound. 1H NMR(300MHz,DMSO-d 6)δ11.10(s,1H),10.39(s,1H),9.92(s,1H),9.01(d,J=7.9Hz,1H),8.81(s,1H),8.50(s,1H),7.82(d,J=8.5Hz,1H),7.52(d,J=8.4Hz,1H),6.89(dd,J=8.4Hz,1.2Hz,1H),6.85–6.70(m,3H),5.03-4.98(m,1H),1.68-1.66(m,3H),0.94(d,J=5.1Hz,6H). 13C NMR(75MHz,DMSO-d 6)δ171.8,163.8,161.3,161.1,159.8,157.8,156.4,151.7,148.5,132.1,129.1,127.2,120.4,114.4,113.6,113.0,111.2,111.1,101.9,101.8,52.0,41.4,24.5,23.1,21.8.
Preparation embodiment 20
(R)-N-(N-(8-formyl radical-umbelliferone-3-)-4-methyl-valeramide-2)-8-formyl radical-umbelliferone-3-acid amides (compound number: 534)
By (R)-7-hydroxy-n-(N-(umbelliferone-3-)-4-methyl-valeramide-2-)-tonka bean camphor-3-acid amides (compound number: 478F) (40mg, 0.0837mmol) be dissolved in 4mL trifluoracetic acid (TFA), add six methylene tetramine (urotropin) (36mg, 0.256mmol) reflux is after 14 hours, add 3mL water, 60 DEG C are stirred 20 minutes.After extraction into ethyl acetate process, organic phase concentrates, and column chromatography obtains target compound 14mg.Molar yield: 31%. 1H NMR(300MHz,CDCl 3)δ12.49(s,1H),12.01(s,1H),10.61(s,1H),10.57(s,1H),8.97(d,J=7.2Hz,1H),8.88(s,2H),8.66(s,1H),7.80(d,J=9.3Hz,1H),7.59(d,J=8.9Hz,1H),7.00(d,J=9.0Hz,1H),6.91(d,J=8.7Hz,1H),4.82-4.72(m,1H),1.95-1.72(m,3H),1.03(d,J=6.3Hz,3H),0.99(d,J=6.3Hz,2H).
Preparation embodiment 21
(R)-N-(N-(Daphnelin-3-)-4-methyl-valeramide-2-)-umbelliferone-3-acid amides (compound number: 494)
With reference to the method preparing embodiment 1, with 7,8-bis-(methoxymethoxy)-tonka bean camphor-3-amine, (prepared by reference method: Sivakumar, Krishnamoorthy; Xie, Fang; Cash, Brandon M.; Long, Su; Barnhill, Hannah N.; Wang, Qian.Organic Letters, 2004; vol.6; #24, p.4603-4606), (prepared by reference method: Leone-Bay, Andrea for N-(9-fluorenylmethyloxycarbonyl)-D-Leu and 7-methoxymethoxy-coumarin-3-carboxy acid; Paton et al.Journal of Medicinal Chemistry, 1998, vol.41, #7p.1163 – 1171) prepare target compound for starting raw material. 1h NMR (300MHz, DMSO-d 6) δ 11.14 (s, 1H), 10.00 (s, 1H), 9.90 (s, 1H), 9.33 (s, 1H), 9.01 (d, J=7.8Hz, 1H), 8.80 (s, 1H), 8.44 (s, 1H), 7.82 (d, J=8.4Hz, 1H), 6.99 (d, J=8.4Hz, 1H), 6.88 (d, J=8.4Hz, 1H), 6.82-6.79 (m, 2H), 5.02-4.92 (m, 1H), 1.75-1.62 (m, 3H), 0.93 (d, J=4.8Hz, 6H). 13c NMR (75MHz, DMSO-d 6) δ 171.9,163.9,161.4,161.2,157.8,156.4,148.6,148.2,140.3,132.2,132.1,127.9,120.2,118.2,114.5,113.1 (two carbon), 112.1,111.2,101.9,52.0,41.4,24.6,23.2,21.8.
Preparation embodiment 22
(R)-N-(N-(umbelliferone-3-)-4-methyl-valeramide-2-)-Daphnelin-3-acid amides (compound number: 494A)
With reference to the method preparing embodiment 1, with 7-(methoxymethoxy)-tonka bean camphor-3-amine, (prepared by reference method: Sivakumar, Krishnamoorthy; Xie, Fang; Cash, Brandon M.; Long, Su; Barnhill, Hannah N.; Wang, Qian.Organic Letters, 2004; vol.6; #24, p.4603-4606), (prepared by reference method: Leone-Bay, Andrea for N-(9-fluorenylmethyloxycarbonyl)-D-Leu and 7-methoxymethoxy-coumarin-3-carboxy acid; Paton et al.Journal of Medicinal Chemistry, 1998, vol.41, #7p.1163 – 1171) prepare target compound for starting raw material. 1H NMR(300MHz,DMSO-d 6)δ9.94(s,1H),9.05(d,J=7.8Hz,1H),8.77(s,1H),8.50(s,1H),7.53(d,J=8.4Hz,1H),7.34(d,J=8.7Hz,1H),6.91(d,J=8.4Hz,1H),6.80(dd,J=8.1,2.1Hz,1H),6.74(d,J=2.1Hz,1H),5.04-4.94(s,1H),1.73-1.61(m,3H),0.93(d,J=5.7Hz,5H).
Preparation embodiment 23
(R)-N-(N-(umbelliferone-3-)-4-methyl-valeramide-2-)-5,7-dihydroxycoumarin-3-acid amides (compound number: 494F)
With reference to the method preparing embodiment 1, with 7-(methoxymethoxy)-tonka bean camphor-3-amine, (prepared by reference method: Sivakumar, Krishnamoorthy; Xie, Fang; Cash, Brandon M.; Long, Su; Barnhill, Hannah N.; Wang; Qian.Organic Letters; 2004; vol.6; #24; p.4603-4606), N-(9-fluorenylmethyloxycarbonyl)-D-Leu and 5,7-bis-(methoxymethoxy)-coumarin-3-carboxy acid (reference method preparation: Leone-Bay, Andrea; Paton et al.Journal of Medicinal Chemistry, 1998, vol.41, #7p.1163 – 1171) prepare target compound for starting raw material. 1H NMR(300MHz,DMSO-d 6)δ9.92(s,1H),8.96(d,J=8.1Hz,1H),8.82(s,1H),8.49(s,1H),7.53(d,J=8.7Hz,1H),6.79(dd,J=8.4,2.1Hz,1H),6.74(d,J=1.8Hz,1H),6.34(d,J=1.8Hz,1H),6.31(d,J=1.8Hz,1H),5.02-4.91(m,1H),1.71-1.60(m,3H),0.93(d,J=5.7Hz,6H).
Preparation embodiment 24
(R)-N-(N-(umbelliferone-3-)-4-methyl-valeramide-2-)-8-Hydroxycoumarin-3-acid amides (compound number: 478E)
With reference to the method preparing embodiment 1, with 7-(methoxymethoxy)-tonka bean camphor-3-amine, (prepared by reference method: Sivakumar, Krishnamoorthy; Xie, Fang; Cash, Brandon M.; Long, Su; Barnhill, Hannah N.; Wang, Qian.Organic Letters, 2004; vol.6; #24, p.4603-4606), (prepared by reference method: Leone-Bay, Andrea for N-(9-fluorenylmethyloxycarbonyl)-D-Leu and 8-(methoxymethoxy)-coumarin-3-carboxy acid; Paton et al.Journal of Medicinal Chemistry, 1998, vol.41, #7p.1163 – 1171) prepare target compound for starting raw material. 1H NMR(300MHz,DMSO-d 6)δ10.45(s,1H),10.38(s,1H),9.96(s,1H),9.09(d,J=8.1Hz,1H),8.84(s,1H),8.50(s,1H),7.53(d,J=8.4Hz,1H),7.44–7.35(m,1H),7.26-7.22(m,2H),6.79(d,J=8.4Hz,1H),6.74(s,1H),5.06-4.96(m,1H),1.74-1.62(m,3H),0.94(d,J=4.5Hz,6H). 13C NMR(75MHz,DMSO-d 6)δ171.7,160.9,160.4,159.8,157.8,151.8,148.4,144.4,142.6,129.1,127.3,125.1,120.4,120.3,120.1,119.3,118.1,113.6,111.2,101.9,52.0,41.4,24.5,23.1,21.8.
Preparation embodiment 25
(R)-N-(N-(Daphnelin-3-)-4-methyl-valeramide-2-)-7,8-escoparone-3-acid amides (compound number: 538A)
With reference to the method preparing embodiment 1, with 7,8-bis-(methoxymethoxy)-tonka bean camphor-3-amine, (prepared by reference method: Sivakumar, Krishnamoorthy; Xie, Fang; Cash, Brandon M.; Long, Su; Barnhill, Hannah N.; Wang, Qian.Organic Letters, 2004; vol.6, #24, p.4603-4606), N-(9-fluorenylmethyloxycarbonyl)-D-Leu and 7; (prepared by reference method: Leone-Bay, Andrea for 8-dimethoxy-coumarin-3-carboxy acid; Paton et al.Journal of Medicinal Chemistry, 1998, vol.41, #7p.1163 – 1171) prepare target compound for starting raw material. 1H NMR(300MHz,DMSO-d 6)δ9.95(s,1H),9.93(s,1H),9.32(s,1H),9.01(d,J=8.1Hz,1H),8.84(s,1H),8.46(s,1H),7.75(d,J=9.3Hz,1H),7.24(d,J=8.7Hz,1H),7.00(d,J=8.4Hz,1H),6.81(d,J=8.4Hz,1H),5.05-4.96(m,1H),3.96(s,3H),3.86(s,3H),1.75-1.60(s,3H),0.94(d,J=4.8Hz,6H). 13C NMR(75MHz,DMSO)δ171.8,161.1,160.6,157.7,157.2,148.5,148.1,147.8,140.3,134.8,132.0,127.8,126.1,120.2,118.1,114.6,113.1,113.0,112.1,110.3,60.8,56.6,52.0,41.3,24.5,23.2,21.8.
Preparation embodiment 26
(R)-N-(N-(7,8-diacetyl tonka bean camphor-3-)-4-methyl-valeramide-2-)-7,8-diacetyl tonka bean camphor-3-acid amides (compound number: 678-1)
By (R)-N-(N-(7,8-dihydroxycoumarin-3-)-4-methyl-valeramide-2-)-7,8-dihydroxycoumarin-3-acid amides (compound number: 510-1) (15mg, 0.0294mmol) be dissolved in and heavily steam tetrahydrofuran (THF) (THF), add triethylamine (Et 3and Acetyl Chloride 98Min. (CH N) 3cOCl), add rear stirring at room temperature after one hour, revolve desolventizing column chromatography for separation and obtain target compound 12mg, molar yield: 60%. 1H NMR(300MHz,CDCl 3)δ9.04(d,J=6.9Hz,1H),8.93(s,2H),8.67(s,1H),7.59(d,J=8.7Hz,1H),7.35(d,J=8.7Hz,1H),7.26(d,J=8.7Hz,1H),7.13(d,J=8.7Hz,1H),4.80-4.71(m,1H),2.42(s,3H),2.38(s,3H),2.35(s,3H),2.32(s,3H),1.95-1.74(m,3H),1.02(d,J=6.3Hz,3H),0.98(d,J=6.0Hz,3H).
Preparation embodiment 27
(R)-N-(N-(7,8-dibenzyl-tonka bean camphor-3-)-4-methyl-valeramide-2-)-7,8-dihydroxyl-tonka bean camphor-3-acid amides (compound number: 690)
With reference to the method preparing embodiment 1, with 7,8-dibenzyl-tonka bean camphor-3-amine, (prepared by reference method: Sivakumar, Krishnamoorthy; Xie, Fang; Cash, Brandon M.; Long, Su; Barnhill, Hannah N.; Wang; Qian.Organic Letters; 2004; vol.6; #24; p.4603-4606), (prepared by reference method: Leone-Bay, Andrea for N-(9-fluorenylmethyloxycarbonyl)-D-Leu and 7,8-bis-(methoxymethoxy)-tonka bean camphor-3-acid acid; Paton et al.Journal of Medicinal Chemistry, 1998, vol.41, #7p.1163 – 1171) prepare synthesis for starting raw material and obtain target compound. 1H NMR(300MHz,DMSO-d 6)δ9.06(d,J=7.8Hz,1H),8.78(s,1H),8.54(s,1H),7.56-7.26(m,12H),7.20(d,J=8.7Hz,1H),6.92(d,J=8.4Hz,1H),5.24(s,2H),5.09(s,2H),5.07-4.98(m,1H),1.74-1.60(m,3H),0.94(d,J=5.1Hz,6H).
Preparation embodiment 28
(R)-N-(N-(7-benzyl-8-hydroxyl-tonka bean camphor-3-)-4-methyl-valeramide-2-)-7-benzyl-8-hydroxyl-tonka bean camphor-3-acid amides (compound number: 690A)
With reference to the method preparing embodiment 1, with 7-benzyl-8-(methoxymethoxy)-tonka bean camphor-3-amine, (prepared by reference method: Sivakumar, Krishnamoorthy; Xie, Fang; Cash, Brandon M.; Long, Su; Barnhill, Hannah N.; Wang; Qian.Organic Letters; 2004; vol.6; #24; p.4603-4606), N-(9-fluorenylmethyloxycarbonyl)-D-Leu and 7-benzyl-8-(methoxymethoxy)-tonka bean camphor-3-acid acid (reference method preparation: Leone-Bay, Andrea; Paton et al.Journal of Medicinal Chemistry, 1998, vol.41, #7p.1163 – 1171) prepare synthesis for starting raw material and obtain target compound. 1H NMR(300MHz,CDCl 3)δ9.15(d,J=6.9Hz,1H),8.86(s,2H),8.63(s,1H),7.46-7.35(m,10H),7.20(d,J=9.0Hz,2H),7.00(d,J=8.4Hz,2H),6.95(d,J=8.7Hz,1H),6.90(d,J=8.7Hz,1H),5.92(s,1H),5.82(s,1H),5.26(s,2H),5.19(s,2H),4.80-4.71(m,1H),1.95-1.76(s,3H),1.02(d,J=6.3Hz,3H),0.98(d,J=6.0Hz,3H).
Preparation embodiment 29
(S)-N-(N-(Daphnelin-3-)-4-methyl-valeramide-2-)-7,8-bis-(tertiary butyl dimethyl Si base)-tonka bean camphor-3-acid amides (compound number: 739)
With reference to the method preparing embodiment 1, with 7,8-bis-(methoxymethoxy)-tonka bean camphor-3-amine, (prepared by reference method: Sivakumar, Krishnamoorthy; Xie, Fang; Cash, Brandon M.; Long, Su; Barnhill, Hannah N.; Wang; Qian.Organic Letters; 2004; vol.6; #24; p.4603-4606), N-(9-fluorenylmethyloxycarbonyl)-L-Leu and 7,8-bis-(tertiary butyl dimethyl Si base)-coumarin-3-carboxy acid (reference method preparation: Leone-Bay, Andrea; Paton et al.Journal of Medicinal Chemistry, 1998, vol.41, #7, p.1163 – 1171 and Carta F, Maresca A, Scozzafava A, et al.Bioorganic & Medicinal Chemistry, 2012, vol.20, #7, p.2266-2273) for starting raw material prepares target compound. 1H NMR(300MHz,CDCl 3)δ9.47(d,J=7.5Hz,1H),8.88(s,1H),8.85(s,1H),8.52(s,1H),7.54(s,1H),7.20(d,J=8.7Hz,1H),6.89(d,J=8.7Hz,1H),6.81(s,2H),6.71(s,1H),5.14-5.04(m,1H),1.90-1.70(m,3H),1.09-1.00(m,15H),0.99(s,6H),0.29(s,3H),0.28(s,3H),0.25(s,6H).
Preparation embodiment 30
(R)-N-(N-(7-hydroxyl-8-acetoxyl group tonka bean camphor-3-)-4-methyl-valeramide-2-)-7-hydroxyl-8-acetoxyl group tonka bean camphor-3-acid amides (compound number: 594)
By 690A (50mg, 0.0724mmol) be dissolved in 6mL methylene dichloride, add triethylamine (30 μ L, 0.22mmol) and under ice bath, add Acetyl Chloride 98Min. (150 μ L, 0.188mmol), stirring at room temperature, after one hour, is spin-dried for, column chromatography obtains intermediate 4 (41mg, 73%). 1H NMR(300MHz,CDCl 3)δ9.06(d,J=6.9Hz,1H),8.87(s,1H),8.86(s,1H),8.64(s,1H),7.51(d,J=8.7Hz,1H),7.44-7.32(m,10H),7.27(d,J=8.4Hz,1H),7.04(d,J=8.7Hz,1H),6.95(d,J=8.7Hz,1H),5.24(s,2H),5.16(s,2H),4.77-4.68(m,1H),2.40(s,3H),2.37(s,3H),1.93-1.74(m,3H),1.02(d,J=6.0Hz,3H),0.98(d,J=6.0Hz,3H).
Intermediate 4 (41mg, 0.053mmol) is dissolved in 10mL tetrahydrofuran (THF), after Ar displacement, adds 10mg10%Pd/C, Ar displacement again, then hydrogen displacement, stirring at room temperature is after 5 hours, and diatomite filtration, ethyl acetate is washed.Filtrate is spin-dried for, and column chromatography obtains target product 21mg.Productive rate: 75%. 1H NMR(300MHz,Acetone-d 6)δ9.20(s,1H),9.06(d,J=7.2Hz,1H),8.88(s,1H),8.65(s,1H),7.76(d,J=9.0Hz,1H),7.45(d,J=9.0Hz,1H),7.11(d,J=9.0Hz,1H),6.99(d,J=8.4Hz,1H),5.06-4.88(m,1H),2.40(s,3H),2.36(s,3H),1.88-1.75(m,3H),1.03-0.94(m,6H).
Preparation embodiment 31
Compound number: 676
With reference to preparing the method for embodiment 30, prepare target compound with 690A, sebacoyl chloride for starting raw material. 1H NMR(300MHz,Acetone-d 6)δ8.99(s,1H),8.89(d,J=9.6Hz,1H),8.77(s,1H),8.57(s,1H),7.74(d,J=8.7Hz,1H),7.45(d,J=8.7Hz,1H),7.10(d,J=8.7Hz,1H),6.98(d,J=8.7Hz,1H),4.98(td,J=9.8,4.8Hz,1H),2.75-2.62(m,3H),2.57-2.45(m,1H),1.99-1.72(m,8H),1.65-1.36(m,7H),1.02(d,J=6.3Hz,3H),0.98(d,J=6.6Hz,3H).
Preparation embodiment 32
Compound number: 710
With reference to preparing the method for embodiment 30, with 690, tert-Butyl dicarbonate prepares target compound for starting raw material. 1H NMR(300MHz,CDCl 3)δ9.29(d,J=7.8Hz,1H),8.92(s,1H),8.90(s,1H),8.47(s,1H),7.65(s,1H),7.60(d,J=8.7Hz,1H),7.32(d,J=8.7Hz,1H),6.78(s,2H),6.62(br s,1H),5.14-5.02(m,1H),1.94-1.73(m,3H),1.58(s,9H),1.56(s,9H),1.03(d,J=2.1Hz,3H),1.02(d,J=2.4Hz,3H).
5 EXPERIMENTAL EXAMPLE
EXPERIMENTAL EXAMPLE
EXPERIMENTAL EXAMPLE 1: the impact that molecular level compound is lived on multiple Tyrosylprotein kinase enzyme
1, experimental technique
(1) enzyme reaction substrate Poly (Glu, Tyr) PBS (10mM sodium phosphate buffer, 150mM NaCl, pH7.2-7.4) of 4:1 without potassium ion is diluted to 20 μ g/mL, 125 μ L/ hole coated elisa plates, put 37 DEG C of reaction 12-16 hour.Discard liquid in hole.Wash plate, wash plate three times, each 5 minutes with T-PBS (containing the PBS without potassium ion of 0.1%Tween-20,200 μ L/ holes).Dry enzyme plate 1-2 hour in 37 DEG C of baking ovens.
(2) every hole adds with reaction buffer (50mM HEPES pH7.4,50mM MgCl 2, 0.5mMMnCl 2, 0.2mM Na 3vO 41mM DTT) the ATP solution 49 μ L that dilutes, 1 μ L compound to be tested (compound well) or the DMSO (negative control hole) containing respective concentration is added in every hole, the kinases territory recombinant protein adding each Tyrosylprotein kinase that 50 μ L dilute with reaction buffer again starts reaction, and each experiment need be established without ATP control wells holes.Put 37 DEG C of shaking tables (100rpm) and react 1 hour.Discard liquid in hole, T-PBS washes plate three times.
(3) add antibody PY99 diluent (T-PBS1:500 of antibody containing BSA5mg/mL dilutes), 100 μ L/ holes, 37 DEG C of shaking tables react 0.5 hour.Discard liquid in hole, T-PBS washes plate three times.
(4) add the anti-diluent of sheep anti mouse two (T-PBS1:2000 of antibody containing BSA5mg/ml dilutes) of horseradish peroxidase-labeled, 100 μ L/ holes, 37 DEG C of shaking tables react 0.5 hour.Discard liquid in hole, T-PBS washes plate three times.
(5) the OPD nitrite ion 100 μ L/ hole of 2mg/ml is added [with containing 0.03%H 2o 20.1M citric acid-sodium citrate damping fluid (pH=5.4) dilution], 25 DEG C of lucifuges reaction 1-10 minute.
(6) 2M H is added 2sO 450 μl/ hole stopped reaction, to decline orifice plate microplate reader VERSAmax reading with wavelengthtunable, wavelength is 490nm.
(7) interpretation of result
2, experimental result
The enzymic activity test of molecular level shows, 510-1 lives to c-Met enzyme and has significant restraining effect, (comprises c-Met with family member RON to other tested Tyrosylprotein kinases; High homology kinases AxL; There is certain homology kinases IGF1R; And other kinases such as ALK, EGFR family, VEGFR family, PDGFR family) also have obvious enzyme to live restraining effect (table 1).
Table 1. compound is to the enzyme of Tyrosylprotein kinase inhibiting rate alive
C-Met: hepatocyte growth factor receptor
Ron: macrophage-stimulating protein receptor
AxL: adhere to associated kinase
ALK: a modification lymphom kinase
FGFR1: fibroblast growth factor acceptor 1
Flt-1: Vascular endothelial growth factor receptor-1
Flt-3: VEGF R3
PDGFR-α: Platelet-derived growth factor α-receptor
PDGFR-β: platelet derived growth factor B β
RET: orphan receptor Tyrosylprotein kinase
EGFR/T790M/L858R: two mutant epidermal growth factor acceptor (790 Threonines sport methionine(Met), and 858 leucines sport arginine)
ErbB2: epidermal growth factor acceptor 2
ErbB4: EGF-R ELISA 4
EPH-A2:EPH acceptor A2
IGF1R: insulin-like growth acceptor 1
EXPERIMENTAL EXAMPLE 2: compound molecule level is to receptor tyrosine kinase c-Met enzyme inhibition test alive
1, experimental technique
(1) enzyme reaction substrate Poly (Glu, Tyr) PBS (10mM sodium phosphate buffer, 150mM NaCl, pH7.2-7.4) of 4:1 without potassium ion is diluted to 20 μ g/mL, 125 μ L/ hole coated elisa plates, put 37 DEG C of reaction 12-16 hour.Discard liquid in hole.Wash plate, wash plate three times, each 5 minutes with T-PBS (containing the PBS without potassium ion of 0.1%Tween-20,200 μ L/ holes).Dry enzyme plate 1-2 hour in 37 DEG C of baking ovens.
(2) every hole adds with reaction buffer (50mM HEPES pH7.4,50mM MgCl 2, 0.5mMMnCl 2, 0.2mM Na 3vO 41mM DTT) the ATP solution 49 μ L that dilutes, 1 μ L compound to be tested (compound well) or the DMSO (negative control hole) containing respective concentration is added in every hole, add the Tyrosylprotein kinase c-Met kinases territory recombinant protein startup reaction that 50 μ L dilute with reaction buffer again, each experiment need be established without ATP control wells holes.Put 37 DEG C of shaking tables (100rpm) and react 1 hour.Discard liquid in hole, T-PBS washes plate three times.
(3) add antibody PY99 diluent (T-PBS1:500 of antibody containing BSA5mg/mL dilutes), 100 μ L/ holes, 37 DEG C of shaking tables react 0.5 hour.Discard liquid in hole, T-PBS washes plate three times.
(4) add the anti-diluent of sheep anti mouse two (T-PBS1:2000 of antibody containing BSA5mg/ml dilutes) of horseradish peroxidase-labeled, 100 μ L/ holes, 37 DEG C of shaking tables react 0.5 hour.Discard liquid in hole, T-PBS washes plate three times.
(5) the OPD nitrite ion 100 μ L/ hole of 2mg/ml is added [with containing 0.03%H 2o 20.1M citric acid-sodium citrate damping fluid (pH=5.4) dilution], 25 DEG C of lucifuges reaction 1-10 minute.
(6) 2M H is added 2sO 450 μ L/ hole stopped reactions, to decline orifice plate microplate reader VERSAmax reading with wavelengthtunable, wavelength is 490nm.
(7) interpretation of result
IC 50value adopts the random bundled software of microplate reader to return with four parameter methods and tries to achieve.
2, experimental result
The enzymic activity test of molecular level shows, this series compound is lived to c-Met enzyme and had significant restraining effect, and wherein 510-1 activity is obviously better than other compounds (table 2).
The c-Met inhibit activities of table 2. part of compounds
Compound name IC 50(μM) Compound name IC 50(μM)
454 3.60±0.44 482 0.039±0.006
494 1.37±0.21 496 0.072±0.001
510-1 0.009±0.002 511 0.063±0.005
512 0.090±0.002 544 0.024±0.001
522C 0.115±0.008 538 0.030±0.001
550 0.022±0.001 568 0.015±0.004
528 0.122±0.010 496B 0.132±0.044
The impact test of c-Met activation in EXPERIMENTAL EXAMPLE 3 compound on intracellular
1, experimental technique
1.1 cell strains:
A549 cell (source is U.S. ATCC cell bank, the moderate expression cell line of c-Met, and in cell, the activation of c-Met depends on the induction of HGF)
(BaF3 source is German DSMZ cell bank to BaF3/TPR-Met, BaF3/TPR-Met is the vehicles cells strain that the laboratory self built builds, in cell, TPR-Met fusion rotein stably express is in endochylema, can not relying on the stimulation of HGF and continuous activation, is the strain of Met dependency sensitive cells)
1.2 experimental procedures:
A549 cell is inoculated in (300,000/hole) in 12 orifice plates, cultivate and be changed to serum-free medium after 18-24 hour and cultivate 12 hours, add after 510-1,522C or PF-2341066 act on 4 hours, then add HGF (50ng/mL) and stimulate 15 minutes collecting cells.BaF3/TPR-Met cell is inoculated in (500,000/hole) in 12 orifice plates, cultivates and add test compounds effect after 4 hours after 18-24 hour, collecting cell.First wash once with cold PBS (containing 1mM vanadic acid sodium); Then 1 × sds gel sample loading buffer (50mM Tris-HCl (pH6.8), 100mM DTT, 2%SDS, 10% glycerine, 1mM vanadic acid sodium, 0.1% tetrabromophenol sulfonphthalein) lysing cell is added.After cell lysate heats 10 minutes in boiling water bath, in centrifugal 10 minutes of 4 DEG C of 12000rpm.
Get supernatant liquor and carry out SDS-PAGE electrophoresis, after electrophoresis terminates, by half-dried electrotransfer system by protein delivery to nitrocellulose filter (Amersham Life Sciences, Arlington Heights, IL, USA), nitrocellulose filter is placed in confining liquid (5% skim-milk is diluted in TBS-T) room temperature and closes 2 hours, then film correspondence is placed in anti-p-c-Met (Y1234/1235, Cell Sinaling Technology) (1:1000) or anti-GAPDH (Kangcheng Bio) (1:10000) antibody in, 4 DEG C of overnight incubation.Three times are washed, each 15 minutes with TBS-T.Film is placed in two anti-diluents, incubated at room 1-2 hour; The same wash film 3 times after, with ECL (Picece, Rockford, IL) reagent color development, development.
2, experimental result
Result shows, and under 10 μMs of concentration, in the A549 cell that test compounds is induced BaF3/TPR-Met and HGF, c-Met phosphorylation all has obvious restraining effect (see Fig. 1).
EXPERIMENTAL EXAMPLE 1 shows on a molecular scale, the kinase inhibiting activity of the wide spectrum that compound 510-1 has had, and also illustrates that compound of the present invention is the kinase inhibitor of a broad spectrum simultaneously.EXPERIMENTAL EXAMPLE 2 describes compound of the present invention and has direct inhibit activities for c-Met kinases enzyme is alive, and part of compounds shows extraordinary c-Met inhibit activities.It is inhibited that EXPERIMENTAL EXAMPLE 3 indicates c-Met activation in compound on intracellular of the present invention.Above data show that compound of the present invention has significant restraining effect to multiple with the closely-related kinases of tumor development process, and therefore compound of the present invention has good potentiality to be exploited as anti-tumor medicine.

Claims (10)

1. a Dicoumarin Derivatives, it has the structure represented by following general formula I:
General formula I
Wherein:
X 1and X 2be nitrogen, C independently of one another 1-C 6alkylamino, C 6-C 12the C that aryl replaces 1-C 6alkylamino, fluoro C 1-C 6alkylamino or oxygen;
N is the integer of 1-5; When the integer of n=2-5, the R in different repeat units 11group can be identical or different, and the R in different repeat units 12group can be identical or different;
R 1-R 10be hydrogen, hydroxyl, C independently of one another 1-C 6alkyloyl, C 1-C 6alkoxyl group, C 1-C 6alkyl-carbonyl oxygen base, C 1-C 6alkyl siloxy, C 1-C 6alkyloxycarbonyl oxygen base or phenyl C 1-C 6alkylidene group oxygen base, or R 4and R 10common formation wherein m is the integer of 6-10; Or R 9and R 10connected carbon atom forms substituted or unsubstituted 3-6 unit heterocycle, and wherein, the substituting group on described 3-6 unit heterocycle is for being selected from C 1-C 6alkyl and phenyl C 1-C 61-3 in alkylidene group, and described 3-6 unit heterocycle contains 1-3 atom N;
R 11and R 12be hydrogen, C independently of one another 1-C 6straight or branched alkyl, C 3-C 6cycloalkyl C 1-C 6alkylidene group, phenyl C 1-C 6alkylidene group, C 1-C 6alkyl-S-C 1-C 6alkylidene group, C 1-C 6straight or branched alkoxy carbonyl C 1-C 6alkylidene group, hydroxycarbonyl group C 1-C 6alkylidene group, aminocarboxyl C 1-C 6alkylidene group, amino C 1-C 6alkylidene group, C 1-C 6the aminocarboxyl C that alkyl replaces 1-C 6alkylidene group, or R 11and R 12connected carbon atom forms 5-7 unit cycloalkyl;
R 13for hydrogen, C 1-c 6alkyl or halogen.
2. Dicoumarin Derivatives according to claim 1, wherein,
X 1and X 2identical, be oxygen or nitrogen;
N is 1 or 2; As n=2, the R in different repeat units 11group can be identical or different, and the R in different repeat units 12group can be identical or different;
R 1-R 10be hydrogen, hydroxyl, formyl radical, ethanoyl, methoxyl group, oxyethyl group, tertiary butyl oxygen base, methanoyl, acetoxyl group, tertiary butyl dimethyl Si base, tertiary butyl diethyl siloxy, tertbutyloxycarbonyl oxygen base or benzyl oxygen base independently of one another, or, R 4and R 10common formation wherein m is 8-10; Or R 9and R 10connected carbon atom forms substituted or unsubstituted 5 yuan of heterocycles, and wherein, the substituting group on described 5 yuan of heterocycles is for being selected from C 1-C 3alkyl and phenyl C 1-C 32 in alkylidene group, and described 5 yuan of heterocycles contain 2 atom N;
Preferably, R 1-R 10be hydrogen, hydroxyl, formyl radical, ethanoyl, methoxyl group, oxyethyl group, tertiary butyl oxygen base, methanoyl, acetoxyl group, tertiary butyl dimethyl Si base, tertbutyloxycarbonyl oxygen base or benzyl oxygen base independently of one another, or, R 4and R 10common formation wherein m is 8; Or R 3and R 4or R 9and R 10connected carbon atom forms substituted or unsubstituted 5 yuan of heterocycles, and wherein, the substituting group on described 5 yuan of heterocycles is methyl and benzyl, and described 5 yuan of heterocycles contain 2 atom N;
R 11and R 12be hydrogen, benzyl, C independently of one another 1-C 6straight or branched alkyl, C 3-C 6cycloalkyl C 1-C 3alkylidene group, C 1-C 3alkyl-S-C 1-C3 alkylidene group, C 1-C 4straight or branched alkoxy carbonyl C 1-C 4alkylidene group, hydroxycarbonyl group C 1-C 3alkylidene group, aminocarboxyl C 1-C 3alkylidene group, amino C 1-C 3alkylidene group or tert-butylamino carbonyl methylene radical, or R 11and R 12connected carbon atom forms cyclohexyl;
Preferably, R 11and R 12be hydrogen, benzyl, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, hexyl, cyclohexylmethylene, CH independently of one another 3-S-C 2h 4-, tertiary butyloxycarbonyl methylene, hydroxycarbonyl group methylene radical, aminocarboxyl methylene radical, Aminopropylidene or tert-butylamino carbonyl methylene radical, or R 11and R 12connected carbon atom forms cyclohexyl;
R 13for hydrogen, C 1-C 6alkyl or halogen, preferred hydrogen.
3. Dicoumarin Derivatives according to claim 1 and 2, wherein, described Dicoumarin Derivatives is be selected from the one in following compound:
4. the preparation method of Dicoumarin Derivatives as claimed in claim 1, described preparation method is realized by following route, wherein, X 1, X 2, R 1~ R 13definition identical with the definition in general formula I:
Compd A and compd B, in Py/DCM, add EDCI reaction, the Compound C obtained; in acetonitrile, add the protecting group that piperidines takes off compd B again, generate Compound D, finally again with compd E in DCM; add DMAP and EDCI reaction, obtain the compound of general formula I.
5. a pharmaceutical composition, its compound of Formula I as claimed in claim 1 comprising treatment significant quantity is as activeconstituents and pharmaceutically acceptable auxiliary material.
6. pharmaceutical composition according to claim 5, wherein, described pharmaceutically acceptable auxiliary material is dispersion agent, vehicle, disintegrating agent, antioxidant, sweeting agent and/or Drug coating.
7. Dicoumarin Derivatives as claimed in claim 1 is being prepared as the purposes in the medicine of protein tyrosine kinase inhibitor.
8. Dicoumarin Derivatives as claimed in claim 1 is preparing the purposes in antitumor drug.
9. pharmaceutical composition as claimed in claim 5 is being prepared as the purposes in the medicine of protein tyrosine kinase inhibitor.
10. pharmaceutical composition as claimed in claim 5 is preparing the purposes in antitumor drug.
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