CN105131011A - Carbamate endocyclic xanthone derivative and preparation method and medicinal application thereof - Google Patents

Carbamate endocyclic xanthone derivative and preparation method and medicinal application thereof Download PDF

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CN105131011A
CN105131011A CN201510553154.8A CN201510553154A CN105131011A CN 105131011 A CN105131011 A CN 105131011A CN 201510553154 A CN201510553154 A CN 201510553154A CN 105131011 A CN105131011 A CN 105131011A
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methyl
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CN105131011B (en
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张晓进
尤启冬
胡明阳
李想
孙昊鹏
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China Pharmaceutical University
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China Pharmaceutical University
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
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Abstract

The invention relates to the field of medicinal chemistry, in particular to a carbamate endocyclic xanthone derivative (I) and a preparation method and medicinal application thereof. The derivative is a structural analogue of garcinia natural product gambogic acid, has an anti-tumor effect and can be used for preparing anti-tumor medicine, and the growth inhibition activity for kinds of tumor cells is at the micromole and sub-micromole level (the formula is as shown in specifications).

Description

Carbamate bridged ring Xanthone derivative, its preparation method and medicinal use
Technical field
The present invention relates to medicinal chemistry art.Be specifically related to class carbamate bridged ring Xanthone derivative and preparation method thereof and its application in pharmacy.This analog derivative is the analog of garcinia natural product morellic acid, has antitumor action, can be used for preparing antitumor drug.
Background technology
Gamboge is that the trunk of the garcinia plant of the torrid zone and subtropical zone draws the colloidal resin splitting rear secretion, has the history of centuries in Asia as drug use.Wherein the anti-tumor activity of natural product morellic acid (gambogicacid/GA) is the most remarkable.Research shows, morellic acid optionally can kill tumour cell, and has no significant effect normal hemopoietic system and white corpuscle.Research shows that morellic acid is by being increase cancer suppressor gene Bax and minimizing to lure oncogene Bcl-2 to express (CancerChemother.Pharmacol., 2006,58,434-443.).Further research also finds, morellic acid can make cell cycle arrest in the G2/M phase by the phosphorylation function of regulation and control CDK7 (cyclin-dependentkinase7), thus generation restraining effect (Carcinogenesis is bred to stomach cancer cell BGC-823,2007,28,632-638.).Morellic acid is by reducing protein kinase C (proteinkinaseC simultaneously, PKC) MMP2/9 (matrixmetalloproteinase2/9 that mediates of signal path, MMP2/9) expression, produce human breast cancer cell (MDA-MB-231, MDA-MB-435) restraining effect with concentration dependent infected, is embodied in T suppression cell and sticks, shifts and attack (J.Mol.Med., 2008,86,1367-1377.).The adhesion (Biochem.Pharmacol., 2011,82,1873-1883.) of morellic acid also by suppressing integrin β_1 (integrin β 1) the gathering integrin signaling path relevant with cell membrane lipid to carry out inhibition tumor cell.Morellic acid and the Phosphorylation events of class natural garcinia bridged ring xanthone by suppressing the catalytic activity of IKK β to suppress I κ B, and then retardance NF-κ B nuclear translocation, thus suppress the expression of relevant inhibitor of apoptosis protein, impel apoptosis of tumor cells (Eur.J.Med.Chem., 2012,51,110-123.).Morellic acid has Antineoplastic angiogenesis activity simultaneously, the generation of tumour cell VEGF (VEGF) can be reduced, thus suppress the increment of the huve cell (HUVECs) caused by VEGF, transfer in vitro and microvascularly form [CancerLett., 258 (2007), 80-89.].Morellic acid can as the effective kinds of tumor cells inhibitors of apoptosis of one and tumor neogenetic blood vessels inhibitor.
Morellic acid molecular weight is large, and in rigid structure, lack water soluble group, physico-chemical property and pharmacokinetic property are not good.These shortcomings seriously constrain the development research of morellic acid as new drug.The structure activity study of morellic acid shows, in morellic acid, D ring bridged ring region and B, C ring are the necessary skeleton of its anti-tumor activity.This seminar simplifies thing 1 based on obtaining the morellic acid with anti-tumor activity to the research of morellic acid skeleton, and it has certain anti-tumor activity, but its druggability is still poor.Be mainly manifested in compound 1 and lack necessary water-soluble of druggability, in its structure, hydrophilic phenolic hydroxyl group defines intramolecular hydrogen bond on the one hand, reduces water-soluble, on the other hand, lacks hydrophilic nitrogen-atoms in the structure of compound 1.The water-soluble not good anti-tumor in vivo activity (JournalofMedicinalChemistry56 (2013) 276-292) having had a strong impact on compound 1.
The structure that morellic acid and structure thereof simplify thing 1 is as follows:
Summary of the invention
The present invention has carried out structural modification to lead compound 1; a series of compound (I) with carbamate structures is obtained by a step acylation reaction or addition reaction; it has good anti-tumor activity, to the growth inhibitory activity of kinds of tumor cells all in micromole and sub-micromolar level.In addition, the water-soluble and cell-membrane permeable of compound (I) is all improved, and is obviously better than lead compound 1 and natural product morellic acid.Compound will change medicine into, and both biological activity and druggability are indispensable, and therefore the comprehensive anti-tumor activity of the compounds of this invention (I) and druggability, be obviously better than lead compound 1, be expected to be developed to antitumor drug.
The general structure of compound of the present invention is as follows:
Wherein R 1, R 2independently represent hydrogen, C separately 1-C 6alkyl, C 1-C 6hydroxyalkyl, C 1-C 6amine alkyl, 5 ~ 7 Yuans cyclosubstituted C of nitrogen-containing hetero 1-C 6alkyl or 5 ~ 7 Yuans nitrogen heterocyclic rings replace C 1-C 6alkyloyl; Or R 1, R 2be connected to form 5-7 person's nitrogen heterocyclic ring;
R 3represent hydrogen or methyl;
And R 1, R 2, R 3different times table hydrogen.
R 1, R 2preferably independently represent hydrogen, methyl, ethyl or propyl group separately.
R 1, R 2preferably be connected to form Pyrrolidine base, imidazolyl, piperidyl, 4-piperidinyl piperidine base, 4-methylpiperazine phenylpiperidines base, piperazinyl, homopiperazine base, morpholine base or N methyl piperazine base.
The invention also discloses the preparation method of compound of Formula I, comprise the following steps:
Wherein R 1, R 2, R 3definition is with claim 1.
Compound 1a, 1b react to obtain compound of Formula I from different urea chlorides, the optional methyl alcohol of reaction solvent, ethanol, acetone, acetonitrile, tetrahydrofuran (THF), Virahol, propyl carbinol, ether, isopropyl ether, n-butyl ether, tetrahydrofuran (THF), methylene dichloride, N, one in dinethylformamide, Isosorbide-5-Nitrae-dioxane or arbitrary combination.Catalyzer DMAP, mineral alkali or organic bases also should be added as salt of wormwood, sodium carbonate, cesium carbonate, triethylamine, pyridine, DBU, DIPEA etc. in reaction.
Compound of the present invention can add pharmaceutically acceptable carrier and make common medicinal preparation, as tablet, capsule, pulvis, syrup, liquor, suspension agent, injection, the common drug auxiliary materials such as spices, sweeting agent, liquid or solid filler or thinner can be added.
Compound of Formula I can adopt common separation method to carry out purifying, as recrystallization, column chromatography etc.
The present invention also comprises the hydrate of compound of Formula I, steric isomer, solvate and pharmacy acceptable salt etc.Compound of Formula I pharmacy acceptable salt by Compound I being dissolved in certain solvent as ethanol, ethyl acetate, methyl alcohol, the trimethyl carbinol, tetrahydrofuran (THF), methylene dichloride etc., can adding corresponding organic acid example hydrochloric acid, toxilic acid, tartrate, Citric Acid etc. and preparing.
Compound of the present invention administering mode clinically can adopt the modes such as oral, injection.
Compound Doses used in clinical practise of the present invention is 0.01mg-1000mg/ days, also can depart from this scope according to state of an illness weight and formulation difference.
The invention has the advantages that without the need to using natural product morellic acid to modify as raw material, can be obtained by synthesis; Also comparatively morellic acid is simple for resulting structures novelty simultaneously, its anti-tumor activity is suitable with morellic acid simultaneously, 1 C or 8-position double bond is introduced nitrogenous, oxygen heteroatom replacement side chain, there is good anti-tumor activity, to the growth inhibitory activity of kinds of tumor cells all in micromole and sub-micromolar level, simultaneously the druggability of the compounds of this invention is as water-soluble, permeable membrane etc., is obviously better than lead compound 1 and natural product morellic acid.Compound will change medicine into, and both biological activity and druggability are indispensable, and therefore the comprehensive anti-tumor activity of the compounds of this invention (I) and druggability, be obviously better than lead compound 1, be expected to be developed to antitumor drug.
Below the active testing result of part of compounds of the present invention:
Test method: adopt classical MTT staining (CancerResearch47 (1987) 936-942), incubation time is 48 hours.By microplate reader, under wavelength 570nm condition, detect optical density value (OD).With the tumour cell of solvent control process for control group, with the inhibiting rate of formulae discovery drug on tumor cell the following, with SigmaPlot computed in software IC 50value, in table 2.Inhibiting rate=[(control group mean OD value-administration group mean OD value)/control group mean OD value] * 100%
Table 1 part of compounds of the present invention inhibition tumor cell rises in value active IC 50
Note: HepG2: human liver cancer cell HCT116: human colon cancer cell A549: human lung carcinoma cell
From table 1, compound of the present invention has stronger anti-tumour cell proliferative activity, and it is active suitable with primer 1 with natural product morellic acid.
Below the film transmitance experimental result of part of compounds of the present invention:
Experimental technique: (one) Pharmaceutical formulations: accurate takes testing compound, adds appropriate auxiliary material ethanol solution, is mixed with 10mmol/L concentration, ultrasonic to dissolving completely, and vortex 1min makes it be evenly distributed, and is placed in 4 DEG C of preservations; (2) System Solution preparation two) System Solution preparation: 50mL System Solution storing solution ultrapure water is diluted to 2L, regulates pH to 7.4 with NaOH after mixing, and by 0.22 μM of membrane filtration, be placed in 4 DEG C of preservations.(3) measuring method: the PAMPAExplorerTM specification sheets provided in strict accordance with pION performs.1. set up Excel form: set up compound information form, and import PAMPAExplorerTM software, pH and 3 part of parallel sample number is set; 2. prepare blank plate and reference plate: blank plate, liquid-transfering gun pipettes 150 μ Lindenmayer system solution to each hole of UVPlate, covers plate lid to be measured; Reference plate: get System Solution to DeepWellPlate hole, every hole 2mL, adds each reagent solution 4 μ L respectively, respectively pipettes 150 μ L to UVPlate holes, cover plate lid to be measured after mixing; 3. transshipment model is set up: remove STIRWELLTMPAMPAsandwith, from DeepWellPlate, pipette 200 μ L pastille System Solution in DonorPlate, add a cover.5 μ LABS damping fluids (AcceptorSinkBuffer) and 200 μ LGIT lipoprotein solutions (GITlipidsolution) are added successively on the film in each hole of AcceptorPlate.After being assembled by Donor and Acceptor, be placed in 37 DEG C of 50rpm vibrators, take out after half an hour, it is to be measured that 150 μ L to UVPlate are got in each hole of every plate; 4. measure: respectively by blank plate, reference plate, and the UVPlate of Donor and Acceptor, put into microplate reader and carry out sweep measuring according to software prompt, wavelength region 200 ~ 500nm; (4) data processing: carry software according to PAMPAExplorerTM and carry out data analysis, automatically generate and obtain Pe value, after removing outlier, concrete transmitance is in table 3.
The film transmitance under physiological ph conditions of table 2 part of compounds of the present invention
Note: Ketoprofen (Ketoprofen) and Proprasylyte (Propranolol) be respectively film transmitance measure in negative control and positive control
From table 2, compound of the present invention has good permeable membrane, points out it to have good gastrointestinal absorption, and is obviously better than natural product morellic acid and lead compound 1.
Below the water-soluble experimental result of part of compounds of the present invention:
Experimental technique: adopt pION company to record based on the Gemini determinator of the Avdeef-Bucher potentiometric titration of classics, concrete operations are carried out in strict accordance with the specification sheets of Gemini determinator.Experimental data is by GeminipD software collection, and result adopts GeminipS software to carry out matching optimization.The results are shown in Table 3.
Table 3 part of compounds of the present invention water-soluble
As shown in Table 3, the good water solubility of compound of the present invention in primer 1, and is better than morellic acid far away, in addition, when the compounds of this invention exists with hydrochloride form, water-solublely significantly to promote.
Embodiment
Embodiment 1
8-N, N-formyl oxygen dimethylamino-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-1)
Compound 1a (80mg, 0.2mmol) is dissolved in acetone, adds N successively, N-dimethylaminoethyl chloride (34.24mg, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.
By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-175mg, productive rate 76.53%.m.p.133.2-135.7℃； 1HNMR(300MHz,CDCl 3):δ1.05(s,3H,C 14-H),1.27-1.34(m,4H,C 15-H,C 16-H a),1.48(s,3H,C 19-H),1.72(s,3H,C 20-H),2.29(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.34(d,J＝9.6,1H,C 17-H),2.52(d,J＝4.6Hz,2H,C 11-H),3.05(s，3H，N-CH 3),3.18(s，3H，N-CH 3),3.45(dd,J 1＝4.3Hz,J 2＝4.5Hz,1H,C 7-H),4.42-4.47(m,1H,C 12-H),6.77(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.96(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.28(t,J＝10.88Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)EI-MSm/z:451[M] +.；HRMS(ESI)：calcd.forC 26H 29NO 6[M+Na +]474.1887，found494.1892.
Embodiment 2
8-N, N-diethylin methanoyl-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-2)
Compound 1a (80mg, 0.2mmol) is dissolved in acetone, adds N successively, N-diethylin formyl chloride (43.24mg, 0.32mmol), triethylamine (0.044mL, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-279mg, productive rate 75.89%.m.p.144.6-146.4℃； 1HNMR(300MHz,CDCl 3):δ0.95(s,3H,C 14-H),1.18-1.25(m,4H,C 15-H,C 16-H a),1.30(s,3H,C 19-H),1.32-1.56(m,6H,N(CH 2 CH 3 ) 2)1.61(s,3H,C 20-H),2.26(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.37(d,J＝9.6,1H,C 17-H),2.54(d,J＝7.8Hz,2H,C 11-H),3.44(dd,J 1＝6.9Hz,J 2＝4.5Hz,1H,C 7-H),3.46-3.62(m,6H,N( CH 2 CH 3) 2),4.34-4.37(m,1H,C 12-H),6.43(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.45(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.32(t,J＝8.1Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)EI-MSm/z:479[M] +.；HRMS(ESI)：calcd.forC 28H 33NO 6[M+H +]480.2308，found480.2378
Embodiment 3
8-N-methyl-N ethyl methanoyl-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-3)
Compound 1a (80mg, 0.2mmol) is dissolved in methylene dichloride, adds N-methyl-N ethylcarbamoyl chlorine (29.76mg successively, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains white object product I-368mg, productive rate 73.11%.m.p.138-142℃； 1HNMR(300MHz,CDCl 3):δ0.95(s,3H,C 14-H),1.18-1.25(m,4H,C 15-H,C 16-H a),1.30(s,3H,C 19-H),1.38(m,3H,NCH 2 CH 3 )1.61(s,3H,C 20-H),2.26(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.37(d,J＝9.6,1H,C 17-H),2.54(d,J＝7.8Hz,2H,C 11-H),2.82-3.22(m,5H, CH 3 N CH 2 CH 3),3.44(dd,J 1＝6.9Hz,J 2＝4.5Hz,1H,C 7-H),4.34-4.37(m,1H,C 12-H),6.43(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.45(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.32(t,J＝8.1Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)EI-MSm/z:465[M] +.；HRMS(ESI)：calcd.forC 27H 30NO 6[M+H +]466.2224，found466.2229
Embodiment 4
8-N morpholine methanoyl-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-4)
Compound 1a (80mg, 0.2mmol) is dissolved in methylene dichloride, adds N-morpholine formyl chloride (47.68mg, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N successively 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains white object product I-465mg, productive rate 65.92%.m.p.163-166℃； 1HNMR(300MHz,CDCl 3):δ0.95(s,3H,C 14-H),1.18-1.25(m,4H,C 15-H,C 16-H a),1.30(s,3H,C 19-H),1.61(s,3H,C 20-H),2.26(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.37(d,J＝9.6,1H,C 17-H),2.54(d,J＝7.8Hz,2H,C 11-H),3.65(m,4H,O(CH2)2),3.75(m,4H,N(CH2)2),3.44(dd,J 1＝6.9Hz,J 2＝4.5Hz,1H,C 7-H),4.34-4.37(m,1H,C 12-H),6.43(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.45(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.32(t,J＝8.1Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)EI-MSm/z:493[M] +.；HRMS(ESI)：calcd.forC 28H 31NO 7[M+Na +]516.1993，found516.1995
Embodiment 5
8-N-Pyrrolidine methanoyl-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-5)
Compound 1a (80mg, 0.2mmol) is dissolved in methylene dichloride, adds N-Pyrrolidine formyl chloride (43.24mg successively, 0.32mmol), triethylamine (0.044mL, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains white object product I-564mg, productive rate 67.09%.m.p.142-144℃； 1HNMR(300MHz,CDCl 3):δ0.95(s,3H,C 14-H),1.18-1.25(m,4H,C 15-H,C 16-H a),1.30(s,3H,C 19-H),1.53-1.59(m,4H,Pyrrolidine),1.61(s,3H,C 20-H),2.26(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.37(d,J＝9.6,1H,C 17-H),2.54(d,J＝7.8Hz,2H,C 11-H),3.44(dd,J 1＝6.9Hz,J 2＝4.5Hz,1H,C 7-H),3.75(m,4H,N(CH 2) 2),4.34-4.37(m,1H,C 12-H),6.43(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.45(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.32(t,J＝8.1Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)EI-MSm/z:477[M] +.
Embodiment 6
8-N-piperidine formyl oxygen base-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-6)
Compound 1a (80mg, 0.2mmol) is dissolved in ethyl acetate, adds N-piperidine formyl chlorine (47.04mg, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N successively 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains white object product I-664mg, productive rate 65.17%.m.p.153-155℃； 1HNMR(300MHz,CDCl 3):δ0.95(s,3H,C 14-H),1.18-1.25(m,4H,C 15-H,C 16-H a),1.30(s,3H,C 19-H),1.61(s,3H,C 20-H),1.53-1.59(m,6H,piperidine),2.26(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.37(d,J＝9.6,1H,C 17-H),2.54(d,J＝7.8Hz,2H,C 11-H),3.44(dd,J 1＝6.9Hz,J 2＝4.5Hz,1H,C 7-H),3.75(m,4H,N(CH 2) 2),4.34-4.37(m,1H,C 12-H),6.43(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.45(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.32(t,J＝8.1Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)EI-MSm/z:491[M] +.；HRMS(ESI)：calcd.forC 26H 29NO 6[M+H +]492.2381，found492.2383
Embodiment 7
8-N-lupetidine methanoyl-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-7)
Compound 1a (80mg, 0.2mmol) is dissolved in ethyl acetate, adds N-lupetidine formyl chloride (51.52mg successively, 0.32mmol), triethylamine (0.044mL, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-759mg, productive rate 58.42%.m.p.146-148℃； 1HNMR(300MHz,CDCl 3):δ0.95(s,3H,C 14-H),1.18-1.25(m,4H,C 15-H,C 16-H a),1.30(s,3H,C 19-H),1.45(m,3H,piperidine-CH 3),1.61(s,3H,C 20-H),1.53-1.59(m,6H,piperidine),2.26(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.37(d,J＝9.6,1H,C 17-H),2.54(d,J＝7.8Hz,2H,C 11-H),3.44(dd,J 1＝6.9Hz,J 2＝4.5Hz,1H,C 7-H),3.75(m,3H,N CHCH 2 ),4.34-4.37(m,1H,C 12-H),6.43(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.45(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.32(t,J＝8.1Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)EI-MSm/z:505[M] +.HRMS(ESI)：calcd.forC 30H 36NO 6[M+H +]506.6099，found506.6073
Embodiment 8
8-N-3-pyrroline methanoyl-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-8)
Compound 1a (80mg, 0.2mmol) is dissolved in tetrahydrofuran (THF), adds N-3-pyrroline formyl chloride (41.92mg successively, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-862mg, productive rate 65.26%.m.p.146-148℃； 1HNMR(300MHz,CDCl 3):δ0.95(s,3H,C 14-H),1.18-1.25(m,4H,C 15-H,C 16-H a),1.30(s,3H,C 19-H),1.61(s,3H,C 20-H),2.26(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.37(d,J＝9.6,1H,C 17-H),2.54(d,J＝7.8Hz,2H,C 11-H),3.44(dd,J 1＝6.9Hz,J 2＝4.5Hz,1H,C 7-H),3.75(m,4H,N(CH 2) 2),4.34-4.37(m,1H,C 12-H),6.43(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),5.78(m,2H,pyrroline),6.45(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.32(t,J＝8.1Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)EI-MSm/z:475[M] +.；HRMS(ESI)：calcd.forC 28H 29NO 6[M+H +]476.2068，found476.2078
Embodiment 9
8-N-thiazolidine methanoyl-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-9)
Compound 1a (80mg, 0.2mmol) is dissolved in tetrahydrofuran (THF), adds N successively, N-dimethylaminoethyl chloride (48.32mg, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-967mg, productive rate 67.68%.m.p.152-154℃； 1HNMR(300MHz,CDCl 3):δ0.95(s,3H,C 14-H),1.18-1.25(m,4H,C 15-H,C 16-H a),1.30(s,3H,C 19-H),1.61(s,3H,C 20-H),2.26(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.37(d,J＝9.6,1H,C 17-H),2.54(d,J＝7.8Hz,2H,C 11-H),2.71(m,2H,SCH 2),3.44(dd,J 1＝6.9Hz,J 2＝4.5Hz,1H,C 7-H),3.75(m,4H,N(CH 2) 2),4.34-4.37(m,1H,C 12-H),6.43(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.45(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.32(t,J＝8.1Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)EI-MSm/z:495[M] +.；HRMS(ESI)：calcd.forC 27H 29NO 6S,[M+H +]496.1788，found496.1786
Embodiment 10
8-N, N-dihydroxy ethyl carbamoyloxy group-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-10)
Compound 1a (80mg, 0.2mmol) is dissolved in acetone, adds N successively, N-dihydroxy ethyl chloroformamide (53.44mg, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-1049mg, productive rate 47.94%.m.p.155-157℃； 1HNMR(300MHz,CDCl 3):δ0.95(s,3H,C 14-H),1.18-1.25(m,4H,C 15-H,C 16-H a),1.30(s,3H,C 19-H),1.61(s,3H,C 20-H),2.26(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.37(d,J＝9.6,1H,C 17-H),2.54(d,J＝7.8Hz,2H,C 11-H),3.15(m,4H, CH 2 N CH 2 )3.44(dd,J 1＝6.9Hz,J 2＝4.5Hz,1H,C 7-H),3.65(m,4H, CH 2 OH),4.34-4.37(m,1H,C 12-H),6.43(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.45(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.32(t,J＝8.1Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)EI-MSm/z:511[M] +.
Embodiment 11
8-N, N-diisopropylaminoethyl methanoyl-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-11)
Compound 1a (80mg, 0.2mmol) is dissolved in acetone, adds N successively, N-diisopropylaminoethyl formyl chloride (34.24mg, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-1178mg, productive rate 76.92%.m.p.158-160℃； 1HNMR(300MHz,CDCl 3):δ0.95(s,3H,C 14-H),1.18-1.25(m,4H,C 15-H,C 16-H a),1.27(m,12H,CH 3),1.30(s,3H,C 19-H),1.61(s,3H,C 20-H),2.26(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.37(d,J＝9.6,1H,C 17-H),2.54(d,J＝7.8Hz,2H,C 11-H),3.44(dd,J 1＝6.9Hz,J 2＝4.5Hz,1H,C 7-H),3.95(m,2H,N(CH) 2),4.34-4.37(m,1H,C 12-H),6.43(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.45(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.32(t,J＝8.1Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)EI-MSm/z:507[M] +.；HRMS(ESI)：calcd.forC 30H 38NO 6[M+H +]508.2694，found508.2702
Embodiment 12
8-(4-piperidinyl piperidine) methanoyl-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-12)
Compound 1a (80mg, 0.2mmol) is dissolved in methylene dichloride, adds 1-chlorocarbonyl-4-piperidinopiperidine (73.60mg successively, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-1274mg, productive rate 64.46%.m.p.184-186℃； 1HNMR(300MHz,CDCl 3):δ0.95(s,3H,C 14-H),1.18-1.25(m,4H,C 15-H,C 16-H a),1.30(s,3H,C 19-H),1.53-1.59(m,10H,piperidine),1.61(s,3H,C 20-H),2.26(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.37(d,J＝9.6,1H,C 17-H),2.54(d,J＝7.8Hz,2H,C 11-H),2.45-2.63(m,5H,N CH(CH 2 ) 2 )3.44(dd,J 1＝6.9Hz,J 2＝4.5Hz,1H,C 7-H),,3.75(m,4H,CON (CH 2 ) 2 )4.34-4.37(m,1H,C 12-H),6.43(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.45(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.32(t,J＝8.1Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)EI-MSm/z:574[M] +.；HRMS(ESI)：calcd.forC 34H 42N 2O 6[M+H +]575.3116，found575.3119
Embodiment 13
8-(4-methylpiperazine) methanoyl-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-13)
Compound 1a (80mg, 0.2mmol) is dissolved in methylene dichloride, adds 4-methylpiperazine formyl chloride (51.84mg successively, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-1359mg, productive rate 58.30%.m.p.158-160℃； 1HNMR(300MHz,CDCl 3):δ0.95(s,3H,C 14-H),1.18-1.25(m,4H,C 15-H,C 16-H a),1.30(s,3H,C 19-H),1.61(s,3H,C 20-H),2.21(m,7H,N CH 3 (CH 2 ) 2 )2.26(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.37(d,J＝9.6,1H,C 17-H),2.54(d,J＝7.8Hz,2H,C 11-H),3.20(m,4H,N(CH 2) 2)3.44(dd,J 1＝6.9Hz,J 2＝4.5Hz,1H,C 7-H),4.34-4.37(m,1H,C 12-H),6.43(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.45(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.32(t,J＝8.1Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)EI-MSm/z:506[M] +.HRMS(ESI)：calcd.forC 29H 34N 2O 6[M+H +]507.5980，found507.5989.
Embodiment 14
8-(2-morpholine ethylamino) methanoyl-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-14)
Compound 1a (80mg, 0.2mmol) is dissolved in acetone, adds 2-morpholine ethylcarbamoyl chlorine (52.48mg successively, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-1452mg, productive rate 48.51%.m.p.138.2-139.7℃； 1HNMR(300MHz,CDCl 3):δ1.05(s,3H,C 14-H),1.27-1.34(m,4H,C 15-H,C 16-H a),1.48(s,3H,C 19-H),1.72(s,3H,C 20-H),2.29(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.34(d,J＝9.6,1H,C 17-H),2.42(m,4H, N(CH 2 ) 2 ),2.52(d,J＝4.6Hz,2H,C 11-H),2.58(m,2H,NCH 2),3.26(m,2H, NHCH 2 ),3.45(dd,J 1＝4.3Hz,J 2＝4.5Hz,1H,C 7-H),3.65(m,4H,O (CH 2 ) 2 )4.42-4.47(m,1H,C 12-H),6.77(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.96(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.28(t,J＝10.88Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H),8.12(s,H,NH)EI-MSm/z:536.25[M] +.；HRMS(ESI)：calcd.forC 30H 37N 2O 7[M+H +]537.2601，found537.2624.
Embodiment 15
8-(3-pyrroles's propylcarbamic) methanoyl-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-15)
Compound 1a (80mg, 0.2mmol) is dissolved in acetone, adds 3-pyrroles's propylcarbamoyl chlorine (56.96mg successively, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-1562mg, productive rate 56.36%.m.p.133.2-135.7℃； 1HNMR(300MHz,CDCl 3):δ1.05(s,3H,C 14-H),1.27-1.34(m,4H,C 15-H,C 16-H a),1.48(s,3H,C 19-H),1.68,(m,2H, CH 2 (CH 2) 2),1.72(s,3H,C 20-H),1.78-1.86(m,4H,pyrroline),2.29(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.34(d,J＝9.6,1H,C 17-H),2.42(m,4H, N(CH 2 ) 2 ),2.52(d,J＝4.6Hz,2H,C 11-H),2.58(m,2H,NCH 2),3.26(m,2H, NHCH 2 ),3.45(dd,J 1＝4.3Hz,J 2＝4.5Hz,1H,C 7-H),4.42-4.47(m,1H,C 12-H),6.77(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.96(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.28(t,J＝10.88Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H),8.12(s,H,NH)EI-MSm/z:534[M] +.；HRMS(ESI)：calcd.forC 31H 39N 2O 6[M+H +]535.2808，found535.2819.
Embodiment 16
8-(2-morpholine ethylmethylamino) methanoyl-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-16)
Compound 1a (80mg, 0.2mmol) is dissolved in acetone, adds 2-morpholine ethylmethylamino formyl chloride (56.96mg successively, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-1662mg, productive rate 56.36%.m.p.135.2-137.7℃； 1HNMR(300MHz,CDCl 3):δ1.05(s,3H,C 14-H),1.27-1.34(m,4H,C 15-H,C 16-H a),1.48(s,3H,C 19-H),1.72(s,3H,C 20-H),2.29(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.34(d,J＝9.6,1H,C 17-H),2.42(m,4H, N(CH 2 ) 2 ),2.52(d,J＝4.6Hz,2H,C 11-H),2.58(m,2H,NCH 2),3.26(m,2H, NHCH 2 ),3.37(s,3H,NCH 3),3.45(dd,J 1＝4.3Hz,J 2＝4.5Hz,1H,C 7-H),3.65(m,4H,O (CH 2 ) 2 )4.42-4.47(m,1H,C 12-H),6.77(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.96(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.28(t,J＝10.88Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H),8.12(s,H,NH)EI-MSm/z:550[M] +.；HRMS(ESI)：calcd.forC 31H 39N 2O 7[M+H +]551.2757，found551.2734.
Embodiment 17
8-(2-piperidinoethyl is amino) methanoyl-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-17)
Compound 1a (80mg, 0.2mmol) is dissolved in acetone, adds 2-piperidinoethyl urea chloride (51.84mg successively, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-1762mg, productive rate 58.05%.m.p.141.2-143.7℃； 1HNMR(300MHz,CDCl 3):δ1.05(s,3H,C 14-H),1.27-1.34(m,4H,C 15-H,C 16-H a),1.48(s,3H,C 19-H),1.72(s,3H,C 20-H),1.89(m,6H,piperidyl),2.29(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.34(d,J＝9.6,1H,C 17-H),2.42(m,4H, N(CH 2 ) 2 ),2.52(d,J＝4.6Hz,2H,C 11-H),2.58(m,2H,NCH 2),3.26(m,2H, NHCH 2 ),3.45(dd,J 1＝4.3Hz,J 2＝4.5Hz,1H,C 7-H),4.42-4.47(m,1H,C 12-H),6.77(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.96(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.28(t,J＝10.88Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H),8.12(s,H,NH)EI-MSm/z:534[M] +.；HRMS(ESI)：calcd.forC 31H 39N 2O 6[M+H +]535.2808，found535.2786.
Embodiment 18
8-acetamido methanoyl-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-18)
Compound 1a (80mg, 0.2mmol) is dissolved in acetone, adds acetamido formyl chloride (39.04mg, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N successively 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-1854mg, productive rate 57.93%.m.p.135.7-137.7℃； 1HNMR(300MHz,CDCl 3):δ1.05(s,3H,C 14-H),1.27-1.34(m,4H,C 15-H,C 16-H a),1.48(s,3H,C 19-H),1.72(s,3H,C 20-H),2.29(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.34(d,J＝9.6,1H,C 17-H),2.52(d,J＝4.6Hz,2H,C 11-H),2.96,(s,3H,acetyl),3.45(dd,J 1＝4.3Hz,J 2＝4.5Hz,1H,C 7-H),4.42-4.47(m,1H,C 12-H),6.77(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.96(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.28(t,J＝10.88Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)8.07(s,H,NH)EI-MSm/z:466[M] +.；HRMS(ESI)：calcd.forC 26H 28NO 7[M+H +]466.1866，found466.1876.
Embodiment 19
8-(1-imidazoles) methanoyl-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-19)
Compound 1a (80mg, 0.2mmol) is dissolved in acetone, adds 1-imidazole carboxamide chlorine (34.24mg, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N successively 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-1975mg, productive rate 76.53%.m.p.133.2-135.7℃； 1HNMR(300MHz,CDCl 3):δ1.05(s,3H,C 14-H),1.27-1.34(m,4H,C 15-H,C 16-H a),1.48(s,3H,C 19-H),1.72(s,3H,C 20-H),2.29(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.34(d,J＝9.6,1H,C 17-H),2.52(d,J＝4.6Hz,2H,C 11-H),3.45(dd,J 1＝4.3Hz,J 2＝4.5Hz,1H,C 7-H),4.42-4.47(m,1H,C 12-H),6.77(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.96(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.28(t,J＝10.88Hz,1H,C 3-H),7.32(m,3H,imidazole)7.41(d,J＝9.6Hz,1H,C 8-H)EI-MSm/z:474[M] +.；HRMS(ESI)：calcd.forC 27H 27N 2O 6[M+H +]475.1869，found475.1848.
Embodiment 20
8-(4-methylhomopiperazin) methanoyl-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-20)
Compound 1a (80mg, 0.2mmol) is dissolved in acetone, adds 4-methylhomopiperazin formyl chloride (56.32mg successively, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-2052mg, productive rate 50%.m.p.159-161℃； 1HNMR(300MHz,CDCl 3):δ0.95(s,3H,C 14-H),1.18-1.25(m,4H,C 15-H,C 16-H a),1.30(s,3H,C 19-H),1.61(s,3H,C 20-H),1.72(m,2H, CH 2 (CH 2) 2),2.21(m,7H,N CH 3 (CH 2 ) 2 )2.26(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.37(d,J＝9.6,1H,C 17-H),2.54(d,J＝7.8Hz,2H,C 11-H),3.20(m,4H,N(CH 2) 2)3.44(dd,J 1＝6.9Hz,J 2＝4.5Hz,1H,C 7-H),4.34-4.37(m,1H,C 12-H),6.43(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.45(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.32(t,J＝8.1Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)EI-MSm/z:521[M] +.HRMS(ESI)：calcd.forC 30H 37N 2O 6[M+H +]521.2652，found521.2641
Embodiment 21
Piperazine methanoyl-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-21)
In being dissolved in by compound 1a (80mg, 0.2mmol), add piperazine formyl chloride (47.36mg, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N successively 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-2162mg, productive rate 62.88%.m.p.158-160℃； 1HNMR(300MHz,CDCl 3):δ0.95(s,3H,C 14-H),1.18-1.25(m,4H,C 15-H,C 16-H a),1.30(s,3H,C 19-H),1.61(s,3H,C 20-H),2.21(m,4H,NH (CH 2 ) 2 )2.26(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.37(d,J＝9.6,1H,C 17-H),2.54(d,J＝7.8Hz,2H,C 11-H),3.20(m,4H,N(CH 2) 2)3.44(dd,J 1＝6.9Hz,J 2＝4.5Hz,1H,C 7-H),4.34-4.37(m,1H,C 12-H),6.43(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.45(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.32(t,J＝8.1Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)8.05(s,H,NH),EI-MSm/z:506[M] +.HRMS(ESI)：calcd.forC 28H 33N 2O 6[M+H +]493.2339，found493.2356.
Embodiment 22
8-(4-(4 '-methylpiperazine base)) piperidine formyl oxygen base-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-22)
By compound 1a (80mg, in 0.2mmol) being dissolved in, add 4-(4 '-methylpiperazine base) successively) piperidine formyl chlorine (74.56mg, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-2256mg, productive rate 51.85%.m.p.186-188℃； 1HNMR(300MHz,CDCl 3):δ0.95(s,3H,C 14-H),1.18-1.25(m,4H,C 15-H,C 16-H a),1.30(s,3H,C 19-H),1.53-1.59(m,,4H,piperidine),1.61(s,3H,C 20-H),2.26(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.37(d,J＝9.6,1H,C 17-H),2.54(d,J＝7.8Hz,2H,C 11-H),2.45-2.63(m,5H,N CH(CH 2 ) 2 )，2.88-2.98(m,7H,N CH 3 (CH 2 ) 2 )3.44(dd,J 1＝6.9Hz,J 2＝4.5Hz,1H,C 7-H),,3.75(m,4H,CON (CH 2 ) 2 )4.34-4.37(m,1H,C 12-H),6.43(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.45(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.32(t,J＝8.1Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)EI-MSm/z:589[M] +.；HRMS(ESI)：calcd.forC 34H 44N 3O 6[M+H +]590.3230，found590.3218.
Embodiment 23
8-(N, N-dimethyl-penten diamino) methanoyl-3,3-dimethyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-23)
Compound 1a (80mg, 0.2mmol) is dissolved in acetone, adds N successively, N-dimethyl-penten dimethylcarbamyl chloride (51.84mg, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-2363mg, productive rate 59.15%.m.p.142.4-144.8℃； 1HNMR(300MHz,CDCl 3):δ1.05(s,3H,C 14-H),1.27-1.34(m,4H,C 15-H,C 16-H a),1.36(m,2H),1.48(s,3H,C 19-H),1.52(m,4H),1.72(s,3H,C 20-H),2.29(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.34(d,J＝9.6,1H,C 17-H),2.42-2.47(m,2H, N(CH 2 )),2.52(d,J＝4.6Hz,2H,C 11-H),2.58(m,2H,NCH 2),3.26(m,6H, N(CH 3 ) 2 ),3.45(dd,J 1＝4.3Hz,J 2＝4.5Hz,1H,C 7-H),4.42-4.47(m,1H,C 12-H),6.77(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.96(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.28(t,J＝10.88Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H),8.12(s,H,NH)EI-MSm/z:536[M] +.；HRMS(ESI)：calcd.forC 31H 39N 2O 6[M+H +]537.2965，found537.2986.
Embodiment 24
8-N, N-formyl oxygen dimethylamino-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-24)
Compound 1b (78mg, 0.2mmol) is dissolved in acetone, adds N successively, N-dimethylaminoethyl chloride (34.24mg, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-2467mg, productive rate 72.46%.m.p.131.2-133.1℃； 1HNMR(300MHz,CDCl 3):δ1.05(s,3H,C 14-H),1.27-1.34(m,4H,C 15-H,C 16-H a),2.29(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.34(d,J＝9.6,1H,C 17-H),2.52(d,J＝4.6Hz,2H,C 11-H),3.05(s，3H，N-CH 3),3.18(s，3H，N-CH 3),3.45(dd,J 1＝4.3Hz,J 2＝4.5Hz,1H,C 7-H),3.59-3.62(d,J＝3.6Hz,2H,C 3-H),4.42-4.47(m,1H,C 12-H),6.77(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.96(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.28(t,J＝10.88Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)EI-MSm/z:423[M] +.；HRMS(ESI)：calcd.forC 24H 26NO 6[M+H +]424.1760，found424.1782.
Embodiment 25
8-piperidine formyl Oxy-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-25)
Compound 1b (78mg, 0.2mmol) is dissolved in methylene dichloride, adds piperidine formyl chlorine (51.84mg, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N successively 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-2563mg, productive rate 62.30%.m.p.162-164℃； 1HNMR(300MHz,CDCl 3):δ0.95(s,3H,C 14-H),1.18-1.25(m,4H,C 15-H,C 16-H a),1.53-1.59(m,6H,piperidine),2.26(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.37(d,J＝9.6,1H,C 17-H),2.54(d,J＝7.8Hz,2H,C 11-H),3.20(m,4H,N(CH 2) 2)3.44(dd,J 1＝6.9Hz,J 2＝4.5Hz,1H,C 7-H),3.59-3.62(d,J＝3.6Hz,2H,C 3-H),4.34-4.37(m,1H,C 12-H),6.43(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.45(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.32(t,J＝8.1Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)EI-MSm/z:463[M] +.HRMS(ESI)：calcd.forC 27H 30NO 6[M+H +]464.2082，found464.2092.
Embodiment 26
8-(4-methylpiperazine) methanoyl-1-(3-methyl but-2-ene-1-base)-3,3a, 4,5-tetrahydrochysene-1,5-methyl bridge-1H, 7H-furans [3,4-d] the synthesis of xanthene-7,13-diketone (I-26)
Compound 1b (78mg, 0.2mmol) is dissolved in methylene dichloride, adds 4-methylpiperazine formyl chloride (51.84mg successively, 0.32mmol), salt of wormwood (43mg, 0.32mmol), DMAP (28mg, 0.24mmol), N 2protection, room temperature reaction spends the night.By reaction solution underpressure distillation except desolventizing, CH in residue 2cl 2dissolve, saturated aqueous ammonium chloride washing (20ml) 1 time, washing (20ml), saturated common salt water washing (20mL), anhydrous Na SO 4drying, suction filtration, filtrate concentrates to obtain solid crude product, with silica gel column chromatography (petrol ether/ethyl acetate system wash-out) separation and purification, obtains light yellow target product I-2659mg, productive rate 58.30%.m.p.161-163℃； 1HNMR(300MHz,CDCl 3):δ0.95(s,3H,C 14-H),1.18-1.25(m,4H,C 15-H,C 16-H a),2.21(m,7H,N CH 3 (CH 2 ) 2 )2.26(dd,J 1＝13.5Hz,J 2＝4.5Hz,1H,C 16-H b),2.37(d,J＝9.6,1H,C 17-H),2.54(d,J＝7.8Hz,2H,C 11-H),3.20(m,4H,N(CH 2) 2)3.44(dd,J 1＝6.9Hz,J 2＝4.5Hz,1H,C 7-H),3.59-3.62(d,J＝3.6Hz,2H,C 3-H),4.34-4.37(m,1H,C 12-H),6.43(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 2-H),6.45(dd,J 1＝8.1Hz,J 2＝0.9Hz,1H,C 4-H),7.32(t,J＝8.1Hz,1H,C 3-H),7.41(d,J＝9.6Hz,1H,C 8-H)EI-MSm/z:478[M] +.HRMS(ESI)：calcd.forC 29H 34N 2O 6[M+H +]479.2182，found479.2192。

Claims (6)

1. the compound shown in general formula I or its pharmacy acceptable salt:
Wherein R 1, R 2independently represent hydrogen, C separately 1-C 6alkyl, C 1-C 6hydroxyalkyl, C 1-C 6amine alkyl, 5 ~ 7 Yuans cyclosubstituted C of nitrogen-containing hetero 1-C 6alkyl or 5 ~ 7 Yuans nitrogen heterocyclic rings replace C 1-C 6alkyloyl; Or R 1, R 2be connected to form 5-7 person's nitrogen heterocyclic ring;
R 3represent hydrogen or methyl;
And R 1, R 2, R 3different times table hydrogen.
2. the compound of claim 1 or its pharmacy acceptable salt, wherein R 1, R 2independently represent hydrogen, methyl, ethyl or propyl group separately.
3. the compound of claim 1 or its pharmacy acceptable salt, wherein R 1, R 2be connected to form Pyrrolidine base, imidazolyl, piperidyl, 4-piperidinyl piperidine base, 4-methylpiperazine phenylpiperidines base, piperazinyl, homopiperazine base, morpholine base or N methyl piperazine base.
4. the compounds process for production thereof of claim 1, comprising:
Wherein R 1, R 2, R 3definition is with claim 1.
5. a pharmaceutical composition, wherein containing the compound of claim 1 or its pharmacy acceptable salt and pharmaceutically acceptable carrier.
6. the compound of claim 1 or its pharmacy acceptable salt are for the preparation of the purposes of the medicine for the treatment of malignant tumour.
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