CN101307059B - Eriocalyxin B derivates, preparation method thereof and applications in antineoplastic drugs - Google Patents

Abstract

The invention relates to a derivate of eriocalyxin B of a structural formula (I), a method for preparing the same, a drug composition which uses the derivate as an active ingredient and an application of the derivate and the drug composition in the preparation of anti-neoplastic drugs.

Description

Eriocalyxin B derivates thing, its preparation method and the application in antitumor drug thereof

Technical field:

The present invention relates to the Eriocalyxin B derivates thing of structural formula (I), its preparation method is the pharmaceutical composition of activeconstituents with this analog derivative, and their application in the preparation antitumor drug.

Background technology:

Cancer is the major causes of death of various countries, the world today.Along with the growth in whole world population and life-span, owing to the lasting deterioration of environment, cancer morbidity and mortality ratio continue to rise always year by year simultaneously.Just there is a cancer patients in average per 90 families of China, and tumor mortality accounts for China city and the rural area cause of the death first and second respectively.The cancer therapy drug of present clinical use can only be that the state of an illness is necessarily alleviated mostly, and common malignancy such as stomach, liver, lung, oesophagus, colon, mammary gland, uterine neck are still lacked effective cancer therapy drug.Though chemotherapeutics has certain curative effect, because its bigger toxic side effect and brought the huge human body and spiritual misery, therefore be badly in need of the less relatively and antitumor drug of determined curative effect of toxic side effect clinically to the patient.Making full use of the Chinese medicinal herb resource, is that lead compound carries out structure of modification and composition optimizes with its effective constituent, and design is synthetic to have the more compound of strong biological activity, is an effective way seeking new type antineoplastic medicine.The eriocalyxin B that separation obtains in the natural product has demonstrated wider anti-tumor activity and (has seen Chinese patent application publication number CN1424028A, application number 02134163.X; Publication number CN1868468A, application number 200510110089.8).Bibliographical information (Euro.J Med.Chem., 42 (2007), 494-502) cross water-soluble transformation, but its activity reduces greatly to the eriocalyxin B structure.Therefore it is carried out fat-soluble structure of modification and composition optimizes, seeking more, the compound of powerful antitumor activity is very important.

So far, do not see the report that Eriocalyxin B derivates thing of the present invention is arranged in the technology now.

Summary of the invention:

The purpose of this invention is to provide a kind of Eriocalyxin B derivates thing, its preparation method, and the application of above-claimed cpd in the preparation antitumor drug with structural formula (I).

The objective of the invention is to realize by following technological method:

The Eriocalyxin B derivates thing of following structural formula (I):

(I) n=1-8 wherein, R=C ₂H ₅, isopropyl (sec.-propyl).

The preparation method of Eriocalyxin B derivates thing gets eriocalyxin B, halohydrocarbon, silver salt, is 1 with mol ratio: 1-16: 1-4, and in organic solvent, 0 ℃-room temperature, reacted 10 hours-7 days, get formula (I) compound, used halohydrocarbon is chlorine or bromine or idohydrocarbon; Silver salt is trifluoro-methane sulfonic acid silver (AgOTf) or trifluoro-methane sulfonic acid silver (AgOTf) or silver carbonate (Ag ₂CO ₃) or silver suboxide (Ag ₂O) and composition thereof; Organic solvent is methylene dichloride or benzene or toluene or normal hexane.

The another kind of preparation method of Eriocalyxin B derivates thing, in organic solvent, eriocalyxin B obtains the compound that structural formula is II with the acid effect, this compound again under the effect of silver salt with halohydrocarbons reaction, get formula (I) compound, used organic solvent is methylene dichloride or tetrahydrofuran (THF) or 1,3-dioxane or benzene or toluene or normal hexane; Acid is trifluoromethayl sulfonic acid or acetate or tosic acid or dilute hydrochloric acid; Silver salt is trifluoro-methane sulfonic acid silver (AgOTf) or silver carbonate (Ag ₂CO ₃) or silver suboxide (Ag ₂O) and composition thereof; Halohydrocarbon is chlorine or bromine or idohydrocarbon.

Another preparation method of Eriocalyxin B derivates thing, structural formula is compound, the alkali of (III), gets formula (I) compound with halohydrocarbons reaction under room temperature-reflux conditions; Described organic solvent is tetrahydrofuran (THF) or 1,3-dioxane or benzene or toluene or normal hexane; Alkali is sodium hydride or potassium hydride KH or sodium hydroxide or potassium hydroxide or potassium tert.-butoxide; Halohydrocarbon is chlorine or bromine or idohydrocarbon.

Among the above-mentioned preparation method, halohydrocarbon is an idohydrocarbon, and acid is trifluoromethayl sulfonic acid.

The pharmaceutical composition that is used for the treatment of cancer of the present invention wherein contains formula (I) compound and pharmaceutically acceptable carrier.

The application of The compounds of this invention in the preparation antitumor drug.

Pharmaceutically acceptable carrier is meant the pharmaceutical carrier of pharmaceutical field routine described in the pharmaceutical composition of the present invention, for example: thinner, vehicle such as water etc., weighting agent such as starch, sucrose etc.; Tamanori such as derivatived cellulose, alginate, gelatin and polyvinylpyrrolidone; Wetting agent such as glycerine; Disintegrating agent such as agar, lime carbonate and sodium bicarbonate; Absorption enhancer such as quaternary ammonium compound; Tensio-active agent such as cetyl alcohol; Absorption carrier such as kaolin and soap clay; Lubricant such as talcum powder, calcium stearate and magnesium and and polyoxyethylene glycol etc.Can also in composition, add other assistant agent such as flavouring agent, sweeting agent etc. in addition.

The compounds of this invention can composition form by oral, snuffing is gone into, the mode of rectum or administered parenterally is applied to the patient who needs this treatment.Be used for when oral, can be made into conventional solid preparation such as tablet, pulvis, granula, capsule etc., make liquid preparation such as water or oil-suspending agent or other liquid preparations such as syrup, elixir etc.; When being used for administered parenterally, can be made into solution, water or the oiliness suspension agent etc. of injection.Preferred form is tablet, capsule and injection.

The various formulations of pharmaceutical composition of the present invention can be according to the conventional production method preparation of pharmaceutical field.Activeconstituents is mixed with one or more carriers, be made into required formulation then.

It is 0.1%～99.5% activeconstituents that pharmaceutical composition of the present invention preferably contains weight ratio, most preferably contains weight ratio and be 0.5%～95% activeconstituents.

The amount of application of The compounds of this invention can be according to variations such as the type of route of administration, patient's age, body weight, the disease of being treated and severity, and its per daily dose can be 0.01～10mg/kg body weight, preferred 0.1～5mg/kg body weight.Can use by one or many.

Following three kinds of methods are adopted in preparation with Eriocalyxin B derivates thing of structural formula (I):

Method 1: in organic solvent, under room temperature and the lucifuge condition, eriocalyxin B, halohydrocarbon, silver salt are by 1: the molar ratio reaction of 1-16: 1-4 10 hours-7 days.Described organic solvent can be methylene dichloride, benzene, toluene, normal hexane etc.Halohydrocarbon can be chlorine, bromine, idohydrocarbon, preferentially adopts idohydrocarbon.Silver salt can be silver trifluoromethanesulfonate or silver trifluoromethanesulfonate (AgOTf) and silver carbonate (AgCO ₃), the mixture of silver suboxide (AgO).

Method 2: in organic solvent, eriocalyxin B obtains structural formula with the acid effect and is

Compound, this compound again under the silver salt effect with halohydrocarbons reaction.Described organic solvent can be a methylene dichloride, tetrahydrofuran (THF), 1,3-dioxane, benzene, toluene, normal hexane etc.Acid is trifluoromethayl sulfonic acid, acetate, and tosic acid, dilute hydrochloric acid etc. preferentially adopt trifluoromethayl sulfonic acid.Silver salt can be trifluoro-methane sulfonic acid silver (AgOTf), silver carbonate (Ag ₂CO ₃), silver suboxide (Ag ₂O) and composition thereof.Halohydrocarbon can be chlorine, bromine, idohydrocarbon, preferentially adopts idohydrocarbon.

Method 3: structural formula is

Compound under the effect of alkali with halohydrocarbons reaction.Described organic solvent can be a tetrahydrofuran (THF), 1, and the 3-dioxane, benzene, toluene, normal hexanes etc., alkali can be sodium hydrides, potassium hydride KH, sodium hydroxide, potassium hydroxide, potassium tert.-butoxides etc., halohydrocarbon can be chlorine, bromine, idohydrocarbon, preferentially adopt idohydrocarbon.

Embodiment:

The following example is illustrating rather than limiting it of the inventive method.The multiple condition that it will be apparent to those skilled in the art and other modifications and the adaptive change of parameter comprise within the spirit and scope of the present invention.

Embodiment 1:

Eriocalyxin?B Eriocalin?A

Get eriocalyxin B (Eriocalxin B) 0.05mmol, be dissolved in the 3mL tetrahydrofuran (THF), add the hydrochloric acid of 5mL 1N, the stirring at room reaction.TLC adds entry 10mL after following the tracks of the reaction raw materials disappearance, ethyl acetate (3 * 5mL) extractions.Merge organic phase, anhydrous sodium sulfate drying, filtration, concentrate crude product.Crude product is through silica gel column chromatography, and eluent is a sherwood oil: ethyl acetate=5: 1 (v/v)], get target product-Eriocalin A.

Relevant test data is as follows:

Eriocalin?A：

¹H-NMR(300MHz，CDCl ₃)：δ＝6.10(1H，s)，5.39(1H，s)，4.69(1H，d，J＝9.54Hz)，4.57(1H，d，J＝11.7Hz)，4.12(1H，d，J＝9.6Hz)，3.73(2H，br)，3.13(1H，br)，2.83(1H，d，J＝8.1Hz)，2.71-2.68(2H，m)，2.09(1H，d，J＝11.7Hz)，1.98-1.56(6H，m)，1.50(3H，s)，1.09(3H，s)ppm； ¹³C-NMR(75MHz，CDCl ₃)：δ＝207.66，206.83，200.11，146.99，117.46，77.00，71.34，61.50，59.20，51.96，50.68，41.83，38.69，37.70，36.96，36.80，31.35，29.26，23.01，20.51ppm；IR(KBr)：υmax＝3441.45，2926.88，2882.34，1748.40，1644.38，1454.49，1107.72，1065.01，936.10cm-1；UV(CHCl ₃)λmax(1ogε)＝241.60(3.85)nm；MS(EI)：m/z；344；MS(HR-ESI)：m/z：calcd?for?C ₂₀H ₂₄O ₅Na：367.1521；found：367.1525[M+Na] ⁺.

Embodiment 2:

Eriocalin?A Eriocalin?B-J

N=1-8 wherein, R=C ₂H ₅, isopropyl

Get embodiment 1 products therefrom (Eriocalin A) 0.03mmol, be dissolved in the 5mL tetrahydrofuran (THF), add sodium hydride (NaH) 0.045mmol, halohydrocarbon 0.06mmol, back flow reaction.TLC follows the tracks of the reaction raw materials back elimination solid that disappears, filtrate concentrate crude product.Crude product is through silica gel column chromatography [eluent is sherwood oil: ethyl acetate=20-5: 1 (v/v)], obtain nine target products (Eriocalin B, C, D, E, F, G, H, I, J).

Embodiment 3:

N=1-8 wherein, R=C ₂H ₅, isopropyl

Get embodiment 1 products therefrom (Eriocalin A) 0.03mmol, be dissolved in the 1mL methylene dichloride, add three fluosulfonic acid silver (AgOTf) 0.045mmol, silver carbonate (Ag ₂CO ₃) 0.06mmol, add the halohydrocarbon that is dissolved in the 2mL methylene dichloride in advance under the stirring at room, lucifuge reaction 10 hours-4 days.The TLC detection reaction is back elimination solid fully, filtrate concentrate crude product.Crude product is through silica gel column chromatography [eluent is sherwood oil: ethyl acetate=20-5: 1 (v/v)], obtain nine target products (Eriocalin B, C, D, E, F, G, H, I, J).

Embodiment 4:

Its first n=1-8, R=C ₂H ₅, isopropyl

Get eriocalyxin B (Eriocalyxin B) 0.05233mmol, be dissolved in the lmL methylene dichloride, add three fluosulfonic acid silver (AgOTf) 0.0785mmol, silver carbonate (Ag ₂CO ₃) 0.105mmol, add the halohydrocarbon that is dissolved in the 2mL methylene dichloride in advance under the stirring at room, lucifuge reaction 10 hours-4 days.The TLC detection reaction is back elimination solid fully, filtrate concentrate crude product.Crude product is through silica gel column chromatography [eluent is sherwood oil: ethyl acetate=20-5: 1 (v/v)], obtain nine target products (Eriocalin B, C, D, E, F, G, H, I, J).

Relevant test data is as follows:

Eriocalin?B：n＝1，R＝C ₂H ₅， ${\left[\mathrm{\α}\right]}_D^{21}=-266.89(C=0.148\mathrm{in\; CH}{\mathrm{Cl}}_3);$ ¹H-NMR(300MHz，CDCl ₃)：δ＝6.05(1H，s)，5.33(1H，s)，4.68(1H，d，J＝9.6Hz)，4.11(2H，d，J＝11.7Hz)，3.80(1H，dd，J＝8.1Hz)，3.69(1H，m)，3.30(1H，dd，J＝8.1Hz)，3.13(1H，br)，2.81(1H，d，J＝7.8Hz)，2.69-2.66(2H，m)，2.0(1H，d，J＝11.7Hz)，1.91-1.51(8H，m)，1.36(3H，s)，1.08(3H，s)，0.99(3H，t，J＝7.2Hz)ppm； ¹³C-NMR(75MHz，CDCl ₃)：δ＝207.75，204.34，200.29，147.27，116.75，78.65，77.43，72.41，61.79，60.07，52.04，48.67，41.71，38.56，37.86，36.80，36.65，31.42，29.33，23.29，22.75，20.60，10.74ppm；IR(KBr)：υmax＝3430.45，2958.48，2930.53，2879.98，1745.25，1726.26，1705.53，1645.22，1460.67，1122.06，1060.01，939.14cm-1；UV(CHCl ₃)λmax(logε)＝241.40(3.81)nm；MS(EI)：m/z：386；MS(HR-ESI)：m/z：calcdfor?C ₂₃H ₃₁O ₅：387.2171；found：387.2170[M+H] ⁺.

Eriocalin?C：n＝2，R＝C ₂H ₅， ${\left[\mathrm{\α}\right]}_D^{20}=-190.65(C=0.132\mathrm{inCHC}{l}_3);$ ¹H-NMR(300MHz，CDCl ₃)：δ＝6.05(1H，s)，5.33(1H，s)，4.68(1H，d，J＝9.6Hz)，4.11(2H，d，J＝11.8Hz)，3.83(1H，dd，J＝7.8Hz)，3.68(1H，m)，3.30(1H，dd，J＝7.8Hz)，3.10(1H，br)，2.81(1H，d，J＝7.5Hz)，2.69-2.66(2H，m)，2.03-1.36(11H，m)，1.36(3H，s)，1.08(3H，s)，0.95(3H，t，J＝7.5Hz)ppm； ¹³C-NMR(75MHz，CDCl ₃)：δ＝207.79，204.39，200.36，147.25，116.80，78.66，77.45，70.51，61.78，60.06，52.02，48.64，41.71，38.56，37.86，36.78，36.63，32.15，31.40，29.35，22.75，20.60，19.35，13.89ppm；IR(KBr)：υmax＝3432.26，2960.12，2933.02，2875.71，1746.06，1730.56，1707.07，1644.85，1459.54，1119.87，1062.17，936.39cm-1；UV(CHCl ₃)λmax(logε)＝241.20(3.72)nm；MS(EI)：m/z：400；MS(HR-ESI)：m/z：calcd?for?C ₂₄H ₃₂O ₅Na：423.2147；found：423.2141[M+Na] ⁺.

Eriocalin?D：n＝2，R＝isopropyl， ${\left[\mathrm{\α}\right]}_D^{21}=-208.12(C=0.197\mathrm{in\; CH}{\mathrm{Cl}}_3);$ ¹H-NMR(300MHz，CDCl ₃)：δ＝6.05(1H，s)，5.33(1H，s)，4.68(1H，d，J＝9.6Hz)，4.12(2H，d，J＝11.8Hz)，3.86(1H，dd，J＝7.8Hz)，3.69(1H，m)，3.30(1H，dd，J＝7.8Hz)，3.10(1H，br)，2.81(1H，d，J＝7.5Hz)，2.70(2H，m)，2.04-1.51(10H)，1.38(3H，s)，1.08(3H，s)，0.91(6H，d，d，J＝7.3Hz)ppm； ¹³C-NMR(75MHz，CDCl ₃)：δ＝207.73，204.38，200.33，147.28，116.74，78.72，77.44，69.22，61.80，60.07，52.03，48.68，41.72，39.01，38.57，37.85，36.81，36.66，31.90，31.42，29.36，24.94，22.67，22.66，20.60ppm；IR(KBr)：υmax＝3432.22，2956.07，2930.18，2871.82，1749.85，1729.35，1644.20，1459.35，1115.84，1063.74，935.25cm-1；UV(CHCl ₃)λmax(logε)＝241.60(3.69)nm；MS(EI)：m/z：414；MS(HR-ESI)：m/z：calcd?for?C ₂₅H ₃₄O ₅Na：437.2303；found：437.2303[M+Na] ⁺.

Eriocalin?E：n＝3，R＝C ₂H ₅， ${\left[\mathrm{\α}\right]}_D^{19}=-186.59(C=0.276\mathrm{in\; CH}{\mathrm{Cl}}_3);$ ¹H-NMR(300MHz，CDCl ₃)：δ＝6.05(1H，s)，5.33(1H，s)，4.68(1H，d，J＝9.6Hz)，4.10(2H，d，J＝11.8Hz)，3.83(1H，dd，J＝7.8Hz)，3.68(1H，m)，3.30(1H，dd，J＝7.8Hz)，3.10(1H，br)，2.81(1H，d，J＝7.5Hz)，2.70(2H，m)，2.03-1.57(13H，m)，1.37(3H，s)，1.09(3H，s)，0.87-0.85(3H，d，J＝7.5)ppm； ¹³C-NMR(75MHz，CDCl ₃)：δ＝207.70，204.30，200.25，147.30，116.68，78.67，77.42，70.81，61.80，60.08，52.05，48.69，41.71，38.56，37.86，36.82，36.66，31.43，29.67，29.34，28.29，22.75，22.44，20.60，14.05ppm；IR(KBr)：υmax＝3423.31，2954.84，2925.59，2855.33，1751.71，1728.01，1643.93，1459.47，1115.95，1063.35，935.58cm-1；UV(CHCl3)λmax(logε)＝241.00(3.67)nm；MS(EI)：m/z：414；MS(HR-ESI)：m/z：calcd?for?C ₂₅H ₃₄O ₅Na：437.2303；found：437.2312[M+Na] ⁺.

Eriocalin?F：n＝4，R＝C ₂H ₅， ${\left[\mathrm{\α}\right]}_D^{21}=-130.21(C=0.192\mathrm{in\; CH}{\mathrm{Cl}}_3);$ ¹H-NMR(300MHz，CDCl ₃)：δ＝6.05(1H，s)，5.33(1H，s)，4.68(1H，d，J＝9.6Hz)，4.10(2H，d，J＝11.6Hz)，3.83(1H，dd，J＝7.8Hz)，3.68(1H，m)，3.29(1H，dd，J＝7.8Hz)，3.10(1H，br)，2.81(1H，d，J＝7.3Hz)，2.69(2H，m)，2.02-1.46(15H)，1.36(3H，s)，1.08(3H，s)，0.89-0.84(3H，t，J＝7.5Hz)ppm； ¹³C-NMR(75MHz，CDCl ₃)：δ＝207.74，204.35，200.32，147.27，116.75，78.68，77.44，70.87，61.79，60.07，52.03，48.66，41.71，38.57，37.86，36.80，36.65，31.62，31.42，30.47，30.01，29.33，27.04，25.80，22.75，14.06ppm；IR(KBr)：υmax＝3432.53，2932.13，2870.13，1751.88，1729.82，1643.25，1459.85，1115.03，1064.07，935.91cm-1；UV(CHCl ₃)λmax(logε)＝242.80(3.33)nm；MS(EI)：m/z：428；MS(HR-ESI)：m/z：calcd?for?C ₂₆H ₃₆O ₅Na：451.2460；found：451.2468[M+Na] ⁺.

Eriocalin?G：n＝5，R＝C ₂H ₅， ${\left[\mathrm{\α}\right]}_D^{21}=-210.35(C=0.145\mathrm{in\; CH}{\mathrm{Cl}}_3);$ ¹H-NMR(300MHz，CDCl ₃)：δ＝6.05(1H，s)，5.33(1H，s)，4.68(1H，d，J＝9.6Hz)，4.10(2H，d，J＝11.6Hz)，3.83(1H，dd，J＝7.8Hz)，3.68(1H，m)，3.29(1H，dd，J＝7.8Hz)，3.10(1H，br)，2.81(1H，d，J＝7.3Hz)，2.69(2H，m)，2.02-1.46(11H，m)，1.36(3H，s)，1.31-1.27(6H，m)，1.08(3H，s)，0.89-0.84(3H，t，J＝7.5Hz)ppm； ¹³C-NMR(75MHz，CDCl ₃)：δ＝207.74，204.33，200.29，147.28，116.73，78.68，77.44，70.87，61.80，60.07，52.04，48.67，41.72，38.57，37.86，36.81，36.66，31.76，31.42，30.06，29.34，29.10，26.11，22.76，22.58，20.60，14.06ppm；IR(KBr)：υmax＝3432.43，2930.37，2857.33，1751.49，1728.82，1644.21，1457.93，1115.94，1064.17，935.55cm-1；UV(CHCl ₃)λmax(logε)＝241.40(3.76)nm；MS(EI)：m/z：442；MS(HR-ESI)：m/z：calcd?forC ₂₇H ₃₈O ₅Na：465.2616；found：465.2605[M+Na] ⁺.

Eriocalin?H：n＝6，R＝C ₂H ₅， ${\left[\mathrm{\α}\right]}_D^{20}=-184.07(C=0.182\mathrm{in\; CH}{\mathrm{Cl}}_3);$ ¹H-NMR(300MHz，CDCl ₃)：δ＝6.03(1H，s)，5.32(1H，s)，4.67(1H，d，J＝9.6Hz)，4.09(2H，d，J＝12Hz)，3.81(1H，dd，J＝7.8Hz)，3.67(1H，m)，3.30(1H，dd，J＝7.8Hz)，3.10(1H，br)，2.79(1H，d，J＝7.5Hz)，2.68(2H，m)，2.06-1.37(11H，m)，1.35(3H，s)，1.33-1.25(8H，m)，1.07(3H，m)，0.87-0.83(3H，t，J＝7.0Hz)ppm； ¹³C-NMR(75MHz，CDCl ₃)：δ＝207.80，204.39，200.38，147.26，116.77，78.67，77.39，70.86，61.76，60.05，52.01，48.63，41.70，38.57，37.85，36.77，36.62，31.80，31.39，30.04，29.37，29.21，29.20，26.13，22.75，22.63，20.60，14.09ppm；IR(KBr)：υmax＝3432.90，2928.95，2856.15，1751.67，1729.45，1643.25，1459.51，1115.82，1064.24，935.55cm-1；UV(CHCl ₃)λmax(logε)＝241.20(3.64)nm；MS(EI)：m/z：456；MS(HR-ESI)：m/z：calcd?forC ₂₈H ₄₀O ₅Na：479.2773；found：479.2772[M+Na] ⁺.

Eriocalin?I：n＝7，R＝C ₂H ₅， ${\left[\mathrm{\α}\right]}_D^{20}=-134.78(C=0.230\mathrm{in\; CH}{\mathrm{Cl}}_3);$ ¹H-NMR(300MHz，CDCl ₃)：δ＝6.04(1H，s)，5.32(1H，s)，4.67(1H，d，J＝9.6Hz)，4.09(2H，d，J＝12Hz)，3.81(1H，dd，J＝7.8Hz)，3.67(1H，m)，3.30(1H，dd，J＝7.8Hz)，3.10(1H，br)，2.79(1H，d，J＝7.5Hz)，2.68(2H，m)，2.06-1.37(10H，m)，1.35(3H，s)，1.33-1.25(11H，m)，1.07(3H，s)，0.87-0.83(3H，t，J＝7.0Hz)ppm； ¹³C-NMR(75MHz，CDCl ₃)：δ＝207.79，204.39，200.37，147.26，116.78，78.68，77.40，70.87，61.77，60.06，52.02，48.63，41.71，38.57，37.85，36.79，36.64，31.86，31.40，30.06，29.50，29.51，29.35，29.25，26.14，22.76，22.66，20.60，14.10PPm；IR(KBr)：υmax＝3432.58，2927.84，2855.63，1751.56，1730.44，1642.09，1460.09，1115.19，1064.26，935.91cm-1；UV(CHCl ₃)λmax(logε)＝241.60(3.39)nm；MS(EI)：m/z：470；MS(HR-ESI)：m/z：calcdfor?C ₂₉H ₄₂O ₅Na：493.2929；found：493.2917[M+Na] ⁺.

Eriocalin?J：n＝8，R＝C ₂H ₅， ${\left[\mathrm{\α}\right]}_D^{21}=-161.29(C=0.093\mathrm{in\; CH}{\mathrm{Cl}}_3);$ ¹H-NMR(300MHz，CDCl ₃)：δ＝6.05(1H，s)，5.33(1H，s)，4.68(1H，d，J＝9.6Hz)，4.10(2H，d，J＝11.6Hz)，3.82(1H，dd，J＝7.6Hz)，3.69(1H，m)，3.30(1H，dd，J＝7.6Hz)，3.10(1H，br)，2.80(1H，d，J＝7.5Hz)，2.69(2H，m)，2.06-1.37(11H，m)，1.36(3H，s)，1.33-1.25(12H，m)，1.08(3H，s)，0.87-0.84(3H，t，J＝7.5Hz)ppm； ¹³C-NMR(75MHz，CDCl ₃)：δ＝207.74，204.33，200.29，147.28，116.73，78.68，77.43，70.88，61.80，60.07，52.04，48.66，41.72，38.56，37.86，36.81，36.66，31.88，31.42，30.06，29.54(3C)，29.43，29.34，26.14，22.76，22.66，20.60，14.08ppm；IR(KBr)：υmax＝3432.91，2926.04，2854.53，1751.64，1688.81，1459.64，1116.20，1064.46，935.82cm-1；UV(CHCl ₃)λmax(logε)＝241.60(3.65)nm；MS(EI)：m/z：484；MS(HR-ESI)：m/z：calcd?forC ₃₀H ₄₄O ₅Na：507.3086；found：507.3092[M+Na] ⁺.

Embodiment 5:

Tablet: any compound of embodiment 1-4 gained 10mg, lactose 180mg, starch 55mg, Magnesium Stearate 5mg;

The preparation method: compound, lactose and starch are mixed, and water is evenly moistening, the mixture after moistening is sieved and drying, after sieve, adds Magnesium Stearate, then with the mixture compressing tablet, and every heavy 250mg, compounds content is 10mg.

Embodiment 6:

Ampulla: any compound of embodiment 1-4 gained 2mg, sodium-chlor 10mg;

Preparation method: compound and sodium-chlor are dissolved in the proper amount of water for injection, filter gained solution, in the ampoule of under aseptic condition, packing into.

Embodiment 7:

Capsule: embodiment 1-4 gained compound 10mg, lactose 187mg, Magnesium Stearate 3mg;

The preparation method: compound is mixed with auxiliary agent, sieve, uniform mixing, the mixture that the obtains hard gelatin capsule of packing into, the heavy 200mg of each capsule, active component content is 10mg.

Embodiment 8:

The anti tumor activity in vitro experiment of formula (I) Eriocalyxin B derivates thing:

Eriocalyxin B derivates thing with structural formula (I) is carried out the anti tumor activity in vitro experiment.Compound 1-10 according to the sulphonyl rhodamine B (sulforhodamine B, SRB) the protein staining method has been carried out the anti tumor activity in vitro screening to BEL-7402, A549, HT-29 JEG-3 respectively; Compound 1-10 is according to tetrazolium (microculture tetrazolium simultaneously, MTT) reduction method has also been carried out the external biological activity experiment to HT60, MOLT-4 human leukemia cell line, adopt VP-16 (to rely on the pool swill, Etoposide) positive contrast, the result shows (seeing Table 1): this type of fat-soluble derivant has a wider anti-tumor activity external.When the fatty carbon chain number that hydroxyl connect of B ring C-6 position between 3-5, liver cancer, lung cancer, colorectal carcinoma, leukemia are all had significant inhibitory effect, and along with the increase of carbochain number, activity weakens gradually.But compound 10 has demonstrated the anti-tumor activity strong than other compounds in the anti-leukocythemia liveness experiment.

Table 1: compound 1-10 is to the inhibiting rate % of growth of tumour cell

Claims (8)

1. the Eriocalyxin B derivates thing of following structural formula (I):

(I) n=1-8 wherein, R=C ₂H ₅, sec.-propyl.

2. the preparation method of claim 1 Eriocalyxin B derivates thing gets eriocalyxin B, halohydrocarbon, silver salt, is 1 with mol ratio: 1-16: 1-4, in organic solvent, 0 ℃-room temperature, reacted 10 hours-7 days, get formula (I) compound, used halohydrocarbon is chlorine or bromine or idohydrocarbon; Silver salt is trifluoro-methane sulfonic acid silver (AgOTf) or silver carbonate (Ag ₂CO ₃) and composition thereof; Organic solvent is methylene dichloride or benzene or toluene or normal hexane.

3. the preparation method of claim 1 Eriocalyxin B derivates thing, in organic solvent, eriocalyxin B obtains the compound that structural formula is an II with the acid effect, this compound again under the effect of silver salt with halohydrocarbons reaction, get formula (I) compound, used organic solvent is methylene dichloride or tetrahydrofuran (THF) or 1,3-dioxane or benzene or toluene or normal hexane; Acid is trifluoromethayl sulfonic acid or acetate or tosic acid or dilute hydrochloric acid; Silver salt is trifluoro-methane sulfonic acid silver (AgOTf) or silver carbonate (Ag ₂CO ₃) and composition thereof; Halohydrocarbon is chlorine or bromine or idohydrocarbon,

4. the preparation method of claim 1 Eriocalyxin B derivates thing, structural formula is compound, the alkali of (III), gets formula (I) compound with halohydrocarbons reaction under room temperature-reflux conditions; Organic solvent is tetrahydrofuran (THF) or 1,3-dioxane or benzene or toluene or normal hexane; Alkali is sodium hydride or potassium hydride KH or sodium hydroxide or potassium hydroxide or potassium tert.-butoxide; Halohydrocarbon is chlorine or bromine or idohydrocarbon,

5. according to the method for claim 2 or 4, wherein halohydrocarbon is an idohydrocarbon.

6. according to the method for claim 3, wherein acid is trifluoromethayl sulfonic acid.

7. the pharmaceutical composition that is used for the treatment of cancer wherein contains formula (I) compound and the pharmaceutically acceptable carrier of claim 1.

8. the application of the compound of claim 1 in the anti-liver cancer of preparation, lung cancer, colorectal carcinoma, leukemia medicament.