CN104004013A - Indole andrographolide, ramification of indole andrographolide and preparing method and medical application of ramification - Google Patents
Indole andrographolide, ramification of indole andrographolide and preparing method and medical application of ramification Download PDFInfo
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- CN104004013A CN104004013A CN201410263842.6A CN201410263842A CN104004013A CN 104004013 A CN104004013 A CN 104004013A CN 201410263842 A CN201410263842 A CN 201410263842A CN 104004013 A CN104004013 A CN 104004013A
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- rographolide
- ethanoyl
- benzoyl
- butyldimethylsilyl
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Abstract
The invention discloses indole andrographolide, ramification of the indole andrographolide and a preparing method and medical application of the ramification, and belongs to the field of medicinal chemistry. The structure general formulas of the ramification of the indole andrographolide are shown in (I) and (II) in the specification, R1 represents hydrogen, substituent or non-substituent C1-8 aliphatic series acyl, substituent or non-substituent aromatic acyl and silylation, R2 and R4 represent hydrogen, substituent or non-substituent C1-8 aliphatic series acyl, substituent or non-substituent aromatic acyl and silylation or double bond delta 14, 15 generated through the elimination reaction of 14 bit or 15 bit, and R3 represents hydrogen, substituent or non-substituent C1-8 aliphatic series acyl and substituent or non-substituent aromatic acyl. The invention further discloses the preparing method of the indole andrographolide and medical application of the ramification in preparing antineoplastic drugs.
Description
Technical field
The present invention relates to indoles andrographolidume derivative, its synthetic method and medicinal use, specifically refer at 2 of rographolide and derivative thereof, a pair of horses going side by side is closed indole ring in 3-position, form indoles also [3,2-b] andrographolide compound synthetic method and in the purposes of preparing in antitumor drug, belong to pharmaceutical chemistry field.
Background technology
Due to factors such as human habitats, cause the sickness rate of malignant tumour to be in recent years ascendant trend year by year, become the common disease of serious harm human health.Although the antitumor drug a great variety of having gone on the market at present, but still can not meet clinical demand, therefore develops determined curative effect, the little new type antineoplastic medicine of side effect seems particularly urgent.
Rographolide (Andrographolide), for extracting the diterpene ginkgolide obtaining in acanthaceous plant Herba Andrographis Andrographis paniculata (Burm.f.) Nees, is one of main effective constituent of Herba Andrographis.Modern pharmacology research shows that rographolide has antibacterial, antiviral, antitumor, immunomodulatory, and hypoglycemic and anti-HIV etc. act on [S.Nanduri, et al.WO2001085709; J.X.Chen, et al.Biol.Pharm.Bull.2009,8:1385-1391; H.Y.Chung, et al.Planta.2005,71:1106-1111; S.Rajagopal, et al.J.Exp.Ther.Oncol.2003,3:147-158; T.G.Kim, et al.In Vivo.2005,19 (3): 551-557; R.Ajaya.Kumar, et al.J.Ethnopharmacol.2004,92:291-295; C.G.Jiang, et al.Anticancer Res.2007,27:2439-2447; Y.C.Lee, et al.Eur.J.Pharmaol.2010,63:23-32; Y.Ding, et al.J.Exp.Cell Res.2008,314 (3): 590-602; Nalamolu Koteswara Rao.Journal of Pharmacology & Therapeutics, Vol.5, No.1,2006, pp.47-50].
In view of rographolide is in the existing great potential of anti-tumor aspect, many investigators transform its structure, to obtaining the better compound of anti-tumor activity.India researchist Nanduri etc. has examined or check the antitumor structure activity relationship of rographolide first, finds that complete lactonic ring structure plays an important role to its anti-tumor activity, and after 8,17 double bond epoxidations, its activity is had no significant effect.This research group has synthesized a series of 3 on this basis, 14, the derivative of 19-OH esterification, pharmacological evaluation proves that these compounds are in vitro to various human cancer cells, as breast cancer cell MCF-7, nervus centralis cancer cells U251, colon cancer cell SW620, lung carcinoma cell H522, ovarian cancer cell SK OV3, prostate cancer cell DU145, kidney cancer cell A498 etc. have obvious restraining effect [S.Nanduri, et al.Bioorg Med Chem Lett.2004,14:4711-4717].Chowdhury and Saeeng Deng Liangge research group have also synthesized respectively a series of 3 on the basis that retains the complete lactonic ring of rographolide, 14, the derivative of 19-OH esterification, the improved antitumor activity of compound in cell in vitro poison test display section has obvious enhancing [C.Chowdhury, et al.Bioorg Med Chem Lett.2010,20:6947-6950; R.Saeeng, et al.Bioorg Med Chem Lett.2012,22:49-52].In addition, what auspicious research group of waiting so long of Wuhan University utilizes the method for bio-transformation to obtain a series of 3, the andrographolidume derivative that 19-OH is oxidized, cell in vitro poison test display section derivative has good anti-tumor activity [X.J.He, et al.Journal of Molecular Catalysis B:Enzymatic.2010,62:242-247; X.J.He, et al.Journal of Molecular Catalysis B:Enzymatic.2011,68:89-93].
Due to the unsettled physico-chemical property of rographolide, in for its antineoplastic structure of modification, existing research work mainly concentrates on 3,14, and the hydroxyl of 19 carries out acidylate, ester modify, structural change is little; Also there is part Study work to carry out larger change to the structure of rographolide, but often destroyed complete lactonic ring structure, thereby cause its active decline or disappearance.This seminar is oxidized for 19 hydroxyls of rographolide early stage, has synthesized a series of 19-carboxylates derivativess, wherein significantly [Xue Xiaowen etc., Chinese invention patent CN102964320 A of part of compounds anti-tumor activity; Chen, et al.Bioorganic & Medicinal Chemistry Letters23 (2013) 3166-3169].Then, we introduce nitrogen-atoms again, synthesize a series of rographolide-19-amide derivatives, found that part 19-amide derivatives has better anti-tumor activity [Xue Xiaowen etc., Chinese invention patent publication number CN103588738A] than corresponding 19-carboxylicesters.In view of the introducing of the nitrogen-atoms impact on rographolide compounds anti-tumor activity, consider again widely used many antitumor drugs clinically, as camptothecine, vinealeucoblastine(VLB) etc. all belong to the alkaloid that contains indole ring, in the time that searching has the rographolide novel derivative of better activity, the present invention combines these two kinds of factors, at 2 of rographolide, 3 a pair of horses going side by sides enter indole ring, in introducing indole ring like this on rographolide skeleton, again nitrogen-atoms is introduced together, thereby rographolide compounds is transformed into indole alkaloid by terpene, a series of indoles andrographolidume derivative are synthesized, and by measuring its activity, find the antitumor drug of high-efficiency low-toxicity.
Summary of the invention
The object of the present invention is to provide a kind of new indoles that has pharmaceutical use andrographolidume derivative.
The present invention also aims to provide a kind of new indoles that has pharmaceutical use the preparation method of andrographolidume derivative.
The present invention also aims to provide a kind of new indoles that has pharmaceutical use andrographolidume derivative in the application of preparing in antitumor drug.
Object of the present invention is achieved through the following technical solutions:
Two serial indoles andrographolidume derivative, have as general formula (I), the structure shown in (II):
Wherein, R
1for hydrogen, replacement or unsubstituted C
1～8aliphatic acyl radical, replacement or unsubstituted aromatic acyl, silylation.R
2and R
4for hydrogen, replacement or unsubstituted C
1～8aliphatic acyl radical, replacement or unsubstituted aromatic acyl, silylation or 14,15 generation elimination reactions form two key Δs
14,15.R
3for hydrogen, replacement or unsubstituted C
1～8aliphatic alkyl, replacement or unsubstituted aromatic base.
The substituting group of the aliphatic acyl radical described in preferred embodiment of the present invention is straight or branched formula alkoxyl group, replacement or the unsubstituted aromatic base of the straight or branched formula amido of 1～8 carbon, 1～8 carbon; The substituting group of alkyl is straight or branched formula alkoxyl group, replacement or the unsubstituted aromatic base of the straight or branched formula amido of 1～8 carbon, 1～8 carbon; In all descriptions, aromatic substituting group is halogen above, hydroxyl, the alkyl of 1～8 carbon, the alkoxyl group of 1～8 carbon, amino, 1～8 amino that carbon alkyl replaces, the amide group of 1～8 carbon, cyano group, carboxyl.
In most preferred embodiment of the present invention, described indoles also [3,2-b] andrographolidume derivative is:
Series I compound:
I
1: also [3,2-b] rographolide of 14,19-O-bis-(tertiary butyl dimethyl-silicon)-indoles
I
2: 14-O-t-Butyldimethylsilyl-indoles is [3,2-b] rographolide also
I
3: also [3,2-b] rographolide of 14-O-t-Butyldimethylsilyl-19-O-ethanoyl-indoles
I
4: also [3,2-b] rographolide of 14-O-t-Butyldimethylsilyl-19-O-benzoyl-indoles
I
5: indoles is [3,2-b] rographolide also
I
6: 19-O-ethanoyl-indoles is [3,2-b] rographolide also
I
7: 19-O-benzoyl-indoles is [3,2-b] rographolide also
I
8: 14,19-O-diacetyl-indoles is [3,2-b] rographolide also
I
9: 14,19-O-dibenzoyl-indoles is [3,2-b] rographolide also
I
10: also [3,2-b] rographolide of 14-O-(2,4-dichloro) benzoyl-19-O-ethanoyl-indoles
I
11: also [3,2-b] rographolide of 14-O-ethanoyl-19-O-benzoyl-indoles
I
12: 19-O-benzoyl-indoles is [3,2-b]-14-deoxidation-14 also, 15-bis-dehydrogenation rographolides
I
13: 19-O-ethanoyl-indoles is [3,2-b]-14-deoxidation-14 also, 15-bis-dehydrogenation rographolides
I
14: also [3,2-b]-14-deoxidation-14 of 19-O-(2,4-dichloro) benzoyl-indoles, 15-bis-dehydrogenation rographolides
Series II compound:
II
1: 14-O-t-Butyldimethylsilyl-indoles is [3,2-b] rographolide-19-carboxylate methyl ester also
II
2: indoles is [3,2-b] rographolide-19-carboxylate methyl ester also
II
3: 14-O-ethanoyl-indoles is [3,2-b] rographolide-19-carboxylate methyl ester also
II
4: also [3,2-b] rographolide-19-carboxylate methyl ester of 14-O-(2,4-dichloro) benzoyl-indoles
II
5: also [3,2-b] rographolide-19-carboxylate methyl ester of 14-O-(2,4 dichloro benzene oxygen) ethanoyl-indoles
II
6: 14-O-benzoyl-indoles is [3,2-b] rographolide-19-carboxylate methyl ester also
II
7: indoles is [3,2-b]-14-deoxidation-14 also, 15-bis-dehydrogenation rographolide-19-carboxylate methyl esters
II
8: 14-O-t-Butyldimethylsilyl-indoles is [3,2-b] rographolide-19-benzyl carboxylate also
II
9: indoles is [3,2-b] rographolide-19-benzyl carboxylate also
II
10: 14-O-ethanoyl-indoles is [3,2-b] rographolide-19-benzyl carboxylate also
II
11: also [3,2-b] rographolide-19-benzyl carboxylate of 14-O-(2,4-dichloro) benzoyl-indoles
II
12: also [3,2-b] rographolide-19-benzyl carboxylate of 14-O-(2,4 dichloro benzene oxygen) ethanoyl-indoles
II
13: indoles is [3,2-b]-14-deoxidation-14 also, 15-bis-dehydrogenation rographolide-19-benzyl carboxylates
Remarks: DC-Bz represents 2,4 dichloro benzene formyl radical; DCPO-Ac represents the ethanoyl that 2,4 dichloro benzene oxygen base replaces
General formula (I) compounds process for production thereof, method is as follows:
14-O-t-Butyldimethylsilyl-rographolide (1) is (according to the method for our previous exploitation; made through three-step reaction by rographolide; the Chinese invention patent that concrete grammar has just been applied for reference to us; publication number CN 103588738 A) first obtain compound 2 through 19 primary hydroxyls of selective protection; 3 hydroxyl oxygens are changed into carbonyl by compound 2 use PCC oxidations; make ketone 3, then compound 3 reacts with phenylhydrazine hydrochloride introduces indole ring, obtains target compound I
1, I
2and I
3.I
1, I
2and I
3obtain remaining target compound (I finally by a series of subsequent reactions
4-I
14).
General formula (II) compounds process for production thereof, method is as follows:
14-O-t-Butyldimethylsilyl-rographolide-19-aldehyde (4) is (according to the method for our previous exploitation, made through four-step reaction by rographolide, the Chinese invention patent that concrete grammar has just been applied for reference to us, patent publication No. CN 103588738 A) first by oxidizing reaction, aldehyde radical is oxidized to carboxyl, obtain compound 5, then compound 5 becomes ester to obtain compound 6 with methyl iodide or cylite, 3 hydroxyls of compound 6 are oxidized to carbonyl by PCC again, obtain compound 7, compound 7 reacts to obtain target compound II with phenylhydrazine hydrochloride
1and II
8.II
1and II
8desiliconization alkane protecting group obtains target compound II
2and II
9, II
2and II
9finally become ester or reaction occurs to eliminate and obtain remaining target compound (II
3-7and II
10-13).
By pharmacological evaluation, describe indoles rographolide and the inhibited proliferation of derivative to tumor cell line thereof in detail:
1. materials and methods
1.1 materials and instrument
(1)RPMI-1640(Hyclone，Cat#SH30809.01B)
(2)FBS(GIBCO，Cat#10099-141)
(3)Pen?Strep(P/S)(GIBCO，Cat#15140)
(4)DMEM/F12(Hyclone，Cat#SH30023.01B)
(5)0.25％Trypsin-EDTA(GIBCO，Cat#25200-056)
(6)Cell?counting?Kit-8(Dojindo，Cat#CK04)
(7)100mm?TC-Treated?Culture?Dish(Corning?Incorporated，Cat#430167)
(8)384-well?culture?plates(Coming?Incorporated，Cat#3701)
(9) the multi-functional microplate reader of NOVOSTAR (BMG)
1.2 control samples and given the test agent
Positive control and given the test agent are first dissolved in 100%DMSO, are configured to the stock solution of 20mM, and in 4 DEG C of preservations.Experiment before be the solution of 200 times of each experimental concentrations by gradient dilution by above-mentioned stock solution with DMSO, then with contain 10%FBS substratum dilute 20 times.
1.3 experimental technique
(1) DU145 cell cultures is in the RPMI-1640 substratum that contains 10%FBS and 1%P/S.HCT116 and MCF7 cell cultures are in the DMEM/F12 substratum that contains 10%FBS and 1%P/S.
(2) in experiment time,, digest cell with 0.25%Trypsin-EDTA from culture dish surface, inoculate 45ul DU145, HCT116 or MCF7 cell in 384 orifice plates, and density is 1000 cells/well, at 5%CO
237 DEG C of incubators in cultivate.
(1) after cell attachment, every hole adds the sample after the dilution of 5ul different concns, and the plank that vibrates gently, makes it to mix, and control wells adds the DMSO after 5ul dilution, DMSO content≤0.5% in every hole.
(2) cell is at 5%CO
237 DEG C of incubators in cultivate after 72 hours, every hole adds 5ul CCK8, continue at 5%CO
237 DEG C of incubators in hatch 2～4 hours.
(1) 450nm measures absorption value.
1.4 data analysis
Data are carried out to Treatment Analysis with Graphpad Prism5.
2. pharmacologically active data
Table one. indoles rographolide and derivative thereof the inhibited proliferation to tumor cell line
By the screening active ingredients discovery of above compound, it is I that three kinds of tumor cell lines are all had to better inhibiting compound
8, I
12, I
13, II
3and II
9, have the potentiality of further exploitation.
Embodiment
Embodiment 1
The preparation of 14,19-O-bis-(t-Butyldimethylsilyl)-rographolide (2):
By 14-O-t-Butyldimethylsilyl-rographolide (1.37g, 2.95mmol) be dissolved in 10mlDMF, TBSCl (0.89g, 5.90mmol) and imidazoles (0.24g, 3.54mmol) be dissolved in 10ml DMF, under ice bath, slowly be added dropwise to reaction solution, dropwise rear reaction 20min, after reaction finishes, add EA (60ml) dilution, use the aqueous solution that contains sodium bicarbonate to wash (3x60ml), massive laundering (3x60ml), saturated common salt washing (3x60ml), anhydrous sodium sulfate drying organic layer.To be dried organic layer concentrated, column chromatography purification (PE: EA=6: 1).Finally must be dried white solid 14,19-O-bis-(t-Butyldimethylsilyl)-rographolide (1.09g, 1.88mmol, productive rate 76%), reclaim 14-O-t-Butyldimethylsilyl-rographolide (0.22g, 0.47mmol).Mp：110-112℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：6.83(t，1H，J＝5.7Hz)，5.06-5.07(m，1H)，4.86(s，1H)，4.57(s，1H)，4.43(dd，1H，J＝6.4Hz，9.8Hz)，4.40(s，1H)，4.21(d，1H，J＝9.9Hz)，4.10(dd，1H，J＝3.0Hz，9.8Hz)，3.42(d，1H，J＝9.9Hz)，3.31-3.38(m，1H)，2.47-2.56(m，1H)，2.39-2.47(m，2H)，1.69-2.10(m，7H)，1.24(s，3H)，0.71(s，3H)，0.92(s，9H)，0.89(s，9H)，0.17(s，3H)，0.13(s，3H)，0.08(s，6H).
13C-NMR(75MHz，CDCl
3，ppm)δ：169.5，147.4，149.9，126.8，109.0，79.5，73.3，66.4，64.6，55.6，54.6，42.0，38.2，37.1，36.8，28.0，25.2，25.1，24.0，23.2，22.5，17.5，17.2，15.1，-4.7，-5.2，-6.2，-6.3.HRMS(ESI)m/zcalcd?for?C
32H
59O
5Si
2[M+H]
+579.3901，found579.3903.
Embodiment 2
The preparation of 14,19-O-bis-(t-Butyldimethylsilyl)-3-oxygen-rographolide (3):
By 14,19-O-bis-(t-Butyldimethylsilyl)-rographolide (0.60g, 1.04mmol) be dissolved in 14ml methylene dichloride, under room temperature, stir, add PCC (0.45g, 2.07mmol) and sodium-acetate (0.34g, 4.15mmol), finally add 0.45g silica gel, room temperature reaction.Stopped reaction after 24h, add filtered through silica gel, filtrate is concentrated, column chromatography purification (PE: EA=5: 1) obtain transparent thick liquid, placement for some time becomes white solid 14,19-O-bis-(t-Butyldimethylsilyl)-3-oxygen-rographolide (0.53g, 0.92mmol, productive rate 88%).Mp：90-92℃.1H-NMR(300MHz，CDCl
3，ppm)δ：6.84(t，1H，J＝5.7Hz)，5.06-5.08(m，1H)，4.94(s，1H)，4.65(s，1H)，4.43(dd，1H，J＝6.5Hz，9.8Hz)，4.10(dd，1H，J＝3.1Hz，9.8Hz)，3.87(d，1H，J＝9.9Hz)，3.54(d，1H，J＝9.9Hz)，2.61-3.64(m，2H)，1.97-2.02(m，3H)，1.70-1.80(m，1H)，1.59-1.64(m，3H)，1.12(s，3H)，1.00(s，3H)，0.93(s，9H)，0.85(s，9H)，0.18(s，3H)，0.13(s，3H)，0.01(6H，s).?
13C-NMR(75MHz，CDCl
3，ppm)δ：213.6，169.8，147.6，146.1，127.5，110.3，73.8，67.0，66.1，56.4，55.4，53.8，38.7，38.0，37.6，36.1，25.7，25.6，24.8，21.5，18.1，17.8，14.8，-4.1，-4.6，-5.6，-5.7.HRMS(ESI)m/z?calcd?for?C
32H
57O
5Si
2[M+H]
+577.3745，found577.3740.
Embodiment 3
Also [3,2-b] rographolide (I of 14,19-O-bis-(tertiary butyl dimethyl-silicon)-indoles
1), also [3,2-b] rographolide (I of 14-O-t-Butyldimethylsilyl-indoles
2) and also [3,2-b] rographolide (I of 14-O-t-Butyldimethylsilyl-19-O-ethanoyl-indoles
3) preparation:
Phenylhydrazine hydrochloride (0.60g, 4.15mmol) is added in reaction flask, be dissolved in 5ml acetic acid, 14,19-O-bis-(t-Butyldimethylsilyl)-3-oxygen-rographolide is dissolved in 22ml acetic acid and adds in dropping funnel, N
2protection; 90～100 DEG C of backflow oil baths; slowly drip F in reaction solution; stopped reaction after 3.5h; reaction solution is added in frozen water; EA (3x50ml) extraction; saturated sodium bicarbonate is washed (3x60ml); final saturation salt washing (3x60ml), anhydrous sodium sulfate drying, will be dried organic layer concentrated; column chromatography purification (PE: EA=6: 1); obtain yellow solid 14, also [3,2-b] rographolide (I of 19-O-bis-(tertiary butyl dimethyl-silicon)-indoles
1) (0.96g, 1.48mmol).Mp：202-205℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：8.61(s，1H)，7.48(d，1H，J＝7.5Hz)，7.33(d，1H，J＝7.7Hz)，7.09-7.15(m，2H)，6.96(t，1H，J＝5.7Hz)，?5.19(s，1H)，4.96(s，1H)，4.67(s，1H)，4.49(dd，1H，J＝6.4Hz，9.8Hz)，4.15(dd，1H，J＝3.0Hz，9.8Hz)，3.84(d，1H，J＝9.1Hz)，3.58(d，1H，J＝9.0Hz)，2.49-2.92(m，4H)，1.86-2.13(m，4H)，1.55-1.72(m，1H)，1.44(s，3H)，1.25-1.31(m，1H)，0.98(s，9H)，0.94(s，9H)，0.78(s，3H)，0.26(s，3H)，0.19(s，3H)，0.12(s，3H)，0.09(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：169.9，147.9，146.4，139.1，136.3，127.7，127.3，121.1，118.7，117.6，110.6，109.2，106.6，73.9，67.4，67.1，54.7，53.0，40.4，39.1，37.7，35.4，26.0，25.6，24.8，18.2，17.8，15.0，-4.1，-4.4，-5.5，-5.6.HRMS(ESI)m/z?calcd?for?C
38H
60NO
4Si
2[M+H]
+650.4061，found?650.4064.
Also separate and obtain also [3,2-b] rographolide (I of 14-O-t-Butyldimethylsilyl-indoles simultaneously
2) and also [3,2-b] rographolide (I of 14-O-t-Butyldimethylsilyl-19-O-ethanoyl-indoles
3).
I
2：(0.82g，1.53mmol)。Mp：130-133℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：8.62(s，1H)，7.49(m，1H)，7.25-7.31(m，1H)，7.07-7.18(m，2H)，6.96(t，1H，J＝5.9Hz)，5.18(s，1H)，4.96(s，1H)，4.67(s，1H)，4.48(dd，1H，J＝6.4Hz，9.7Hz)，4.14(dd，1H，J＝2.7Hz，J＝9.7Hz)，3.84(d，1H，J＝9.0Hz)，3.58(d，1H，J＝9.1Hz)，2.89-2.93(d，2H)，2.70-2.82(m，2H)，2.49-2.54(m，2H)，1.88-2.15(m，5H)，1.68(s，3H)，0.98(s，9H)，0.94(s，9H)，0.78(s，3H)，0.26(s，3H)，0.19(s，3H)，0.12(s，3H)，0.09(s，3H).?
13C-NMR(75MHz，CDCl
3，ppm)δ：170.4，148.0，146.4，138.6，136.4，127.7，127.3，121.2，118.8，117.6，110.8，109.3，106.8，74.0，67.0，66.8，54.8，53.2，40.3，39.2，37.7，35.4，29.9，26.0，25.6，25.6，24.9，24.8，17.8，15.0，-4.1，-4.4.HRMS(ESI)m/z?calcd?for?C
32H
46NO
4Si[M+H]
+536.3196，found536.3195.
I
3：(0.26g，0.45mmol)。Mp：170-172℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：8.14(s，1H)，7.48(d，1H，J＝7.8Hz)，7.36(d，1H，J＝7.8Hz)，7.09-7.27(m，2H)，6.95(t，1H，J＝6.42Hz)，5.18(s，1H)，4.99(s，1H)，4.70(s，1H)，4.49(dd，1H，J＝6.4Hz，9.8Hz)，4.24(s，1H)，4.15(dd，1H，J＝3.09Hz，9.75Hz)，2.90-2.95(m，2H)，2.60-2.90(m，2H)，2.48-2.55(m，2H)，2.18(s，3H)，1.90-2.13(m，3H)，1.59-1.69(m，2H)，1.44(s，3H)，0.95(s，9H)，0.84(s，3H)，0.26(s，3H)，0.19(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：169.9，169.0，147.2，145.2，136.3.，135.8，127.2，126.7，121.2，118.6，117.64，110.2，109.1，107.3，73.4，68.2，66.6，59.8，54.3，52.8，39.6，37.1，37.0，34.8，25.4，25.1，24.5，?24.3，20.6，17.3，14.5，13.6，-4.6，-5.0.HRMS(ESI)m/z?calcd?for?C
34H
48NO
5Si[M+H]
+578.3302，found578.3304.
Embodiment 4
14-O-t-Butyldimethylsilyl-19-O-benzoyl-indoles is [3,2-b] rographolide (I also
4) preparation:
By phenylformic acid (1.37g, 2.55mmol) and EDCI (1.17g, 6.12mmol) be dissolved in the methylene dichloride of 12ml, add the DMAP of catalytic amount, reaction 0.5h, 14-O-t-Butyldimethylsilyl-indoles also [3, 2-b] rographolide (1.37g, 2.55mmol) be dissolved in 8ml methylene dichloride, slowly be added dropwise to reaction solution, stopped reaction after 24h, (40ml) dilution adds methylene chloride, ammonium chloride solution is washed (3x50ml), saturated sodium bicarbonate solution (3x50ml) is washed, saturated aqueous common salt (3x50ml) is washed, anhydrous sodium sulfate drying.Organic layer is concentrated, and thin-layer chromatography (PE: EA=3: 1) purifying, and then recrystallization (EA) obtains faint yellow sterling (1.00g, 1.56mmol, productive rate 61%).Mp：244-246℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：8.14(s，1H)，8.08(d，1H，J＝7.3Hz)，7.48-7.66(m，4H)，7.11-7.25(m，3H)，6.97(t，1H，J＝6.4Hz)，5.20(1H，m)，5.01(s，1H)，4.72(s，1H)，4.47-4.62(3H，m)，4.16(dd，1H，J＝3.1Hz，J＝9.7Hz)，2.93-2.98(m，2H)，2.53-2.98(m，4H)，1.60-2.20(m，5H)，1.54(s，3H)，0.95(s，9H)，0.87(s，3H)，0.27(s，3H)，0.19(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：169.4，165.8，147.2，145.5，136.2，135.8，132.8，129.7，128.8，128.3，127.2，126.7，121.2，118.6，117.4，110.1，109.1，107.4，73.4，68.3，66.6，54.3，52.8，39.7，37.7，37.1，34.9，25.4，25.1，24.6，17.3，14.5，-4.6，-5.0.HRMS(ESI)m/z?calcd?for?C
39H
50NO
5Si[M+H]
+640.3458，found640.3466.
Embodiment 5
Indoles is [3,2-b] rographolide (I also
5) preparation:
By 14,19-O-bis-(tertiary butyl dimethyl-silicon)-indoles also [3,2-b] rographolide (0.49g, 0.75mmol) is dissolved in 5ml tetrahydrofuran (THF), by TBAF (0.31g, 1.19mmol) be dissolved in the tetrahydrofuran (THF) of 5ml, under ice bath, be added dropwise to reaction solution, stopped reaction after 1h, add ethyl acetate dilution (40ml), washing (3x40ml), saturated common salt washing (3x40ml), anhydrous sodium sulfate drying.Organic layer is concentrated to obtain to also [3,2-b] rographolide (I of indoles
5) (0.30g, 0.71mmol, thick productive rate 94%).Mp：255-258℃.?
1H-NMR(300MHz，DMSO-d
6，ppm)δ：10.25(s，1H)，7.36(d，1H，J＝7.5Hz)，7.30(d，?1H，J＝7.7Hz)，6.86-6.98(m，2H)，6.70(t，1H，J＝6.4Hz)，5.79(d，1H，J＝5.8Hz)，5.03(m，1H)，4.89(s，1H)，4.77(m，1H)，4.70(s，1H)，4.40-4.45(m，1H)，4.05-4.09(m，1H)，3.53-3.60(m，2H)，2.85-2.90(m，1H)，2.67-2.72(m，2H)，1.45-2.48(5m，H)，1.32(s，3H)，0.74(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：169.9，147.6，146.3，138.8，136.3，129.1，126.9，119.9，117.5，117.1，110.9，107.9，105.5，74.3，64.7，64.5，54.3，52.7，37.3，34.8，25.8，24.7，24.1，14.8.HRMS(ESI)m/z?calcd?for?C
26H
32NO
4[M+H]
+422.2331，found422.2328.
Embodiment 6
19-O-ethanoyl-indoles is [3,2-b] rographolide (I also
6) preparation:
With reference to the preparation method of embodiment 5, by 14-O-t-Butyldimethylsilyl-19-O-ethanoyl-indoles also [3,2-b] rographolide make, productive rate 91%.Mp：256-258℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：8.09(s，1H)，7.48(d，1H，J＝7.9Hz)，7.34(d，1H，J＝8.0Hz)，7.03-7.20(m，3H)，5.16(d，1H，J＝4.8Hz)，4.99(s，1H)，4.69(s，1H)，4.48-4.54(m，1H，J＝6.1Hz，J＝10.5Hz)，4.28-4.32(m，1H，J＝2.0Hz，J＝10.5Hz)，4.22(s，2H)，2.92-2.97(d，2H)，2.74-2.79(m，2H)，2.48-2.56(m，2H)，2.16(s，3H)，1.88-2.12(m，4H)，1.42(s，3H)，1.25(s，1H)，0.83(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：170.2，169.9，147.3，146.2，136.6，136.4，129.1，126.8，120.5，117.8，117.5，110.8，108.2，106.6，74.3，66.9，64.6，54.2，52.4，37.8，37.1，34.5，25.8，24.6，24.1，20.8，14.6.HRMS(ESI)m/z?calcd?for?C
28H
34NO
5[M+H]
+464.2437，found464.2429.
Embodiment 7
19-O-benzoyl-indoles is [3,2-b] rographolide (I also
7) preparation:
With reference to the preparation method of embodiment 5, by 14-O-t-Butyldimethylsilyl-19-O-benzoyl-indoles also [3,2-b] rographolide make (productive rate 95%).Mp：256-258℃.
1H-NMR(300MHz，DMSO-d
6，ppm)δ：10.74(s，1H)，7.98-8.00(m，2H)，7.64-7.69(m，1H)，7.51-7.56(m，2H)，7.42-7.44(m，1H)，7.27-7.29(m，2H)，6.92-7.06(m，2H)，6.71(t，1H，J＝6.4Hz)，5.81(d，1H，J＝5.76Hz)，5.06(m，1H)，4.90(s，1H)，4.73(s，1H)，4.42-4.55(m，3H)，4.08(d，1H，J＝9.6Hz)，2.92-2.97(m，2H)，2.74-2.79(m，2H)，2.40-2.49(m，2H)，1.92-2.26(m，5H)，1.50(s，3H)，0.81(s，3H).
13C-NMR(75MHz，DMSO-d
6，ppm)δ：?169.9，165.6，147.3，146.2，136.5，133.2，129.7，129.2，129.1，128.7，127.0，120.7，118.0，117.6，110.8，108.2，107.0，74.3，67.8，64.6，54.2，52.3，38.2，37.1，34.5，25.6，25.1，24.1，14.5.HRMS(ESI)m/z?calcd?for?C
33H
36NO
5[M+H]
+526.2593，found526.2585.
Embodiment 8
14,19-O-diacetyl-indoles is [3,2-b] rographolide (I also
8) preparation:
By 19-O-ethanoyl-indoles also [3; 2-b] rographolide (0.10g, 0.22mmol) is dissolved in 2ml acetic anhydride, 120 DEG C of backflows; stopped reaction after 1h; the 10ml that adds water, adds sodium carbonate solid, until without Bubble formation under ice bath; EA extracts (3x15ml); saturated sodium bicarbonate solution (3x45ml) is washed, and saturated aqueous common salt (3x45ml) is washed, anhydrous sodium sulfate drying.Organic layer is concentrated, the yellow solid (20mg, productive rate 18%) of column chromatography purification.
Mp：204-207℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：8.12(s，1H)，7.52(d，1H，J＝6.8Hz)，7.34(d，1H，J＝7.6Hz)，7.11-7.19(m，3H)，6.07(s，1H)，4.98(s，1H)，4.78(s，1H)，4.58-4.78(m，2H)，4.23-4.31(m，3H)，2.91-2.96(m，2H)，2.74-2.79(m，2H)，2.40-2.84(m，3H)，2.18(s，6H)，1.89-2.18(m，3H)，1.55-1.65(m，2H)，1.43(s，3H)，1.28(m，1H)，0.82(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：170.4，169.0，150.2，146.4，136.6，136.3，127.2，124.1，121.8，119.2，118.1，110.6，108.6，107.8，71.6，68.7，67.8，4.8，53.4，40.2，37.6，37.5，35.2，25.8，25.3，25.0，21.1，20.7，14.7.HRMS(ESI)m/z?calcd?for?C
30H
36NO
6[M+H]
+506.2543，found506.2544.
Embodiment 9
14-O-ethanoyl-19-O-benzoyl-indoles is [3,2-b] rographolide (I also
11) preparation:
With reference to the preparation method of embodiment 8, by 19-O-benzoyl-indoles also [3,2-b] rographolide make (productive rate 48%).Mp：150-152℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：8.30(s，1H)，8.08(d，2H，J＝7.2Hz)，7.50-7.66(m，4H)，7.08-7.28(m，4H)，6.07(d，1H，J＝5.6Hz))，5.00(s，1H)，4.47-4.64(m，4H)，4.30(dd，1H，J＝1.4Hz，J＝11.2Hz)，2.94-2.99(m，1H)，2.51-2.77(m，4H)，2.19(s，3H)，1.93-2.15(m，4H)，1.63-1.72(m，1H)，1.53(s，3H)，0.88(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：170.5，169.5，166.4，150.3，146.5，136.5，136.4，133.3，130.2，129.3，128.8，127.2，124.2，121.8，119.2，118.1，110.6，?108.7，107.9，71.7，68.8，67.8，54.8，53.3，40.3，38.2，37.6，35.2，25.9，25.3，25.2，20.7，14.8.HRMS(ESI)m/z?calcd?for?C
35H
38NO
6[M+H]
+568.2699，found568.2699.
Embodiment 10
14,19-O-dibenzoyl-indoles is [3,2-b] rographolide (I also
9) and also [3,2-b]-14-deoxidation-14 of 19-O-benzoyl-indoles, 15-bis-dehydrogenation rographolide (I
12) preparation:
With reference to the preparation method of embodiment 4, by indoles also [3,2-b] rographolide make.
I
9：Mp198-200℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：8.13(s，1H)，8.02-8.10(m，7H)，7.05-7.21(m，5H)，6.31(m，1H)，4.96(s，1H)，4.73(dd，1H，J＝3.1Hz，5.6Hz)，4.65(s，1H)，4.39-4.52(m，3H)，2.88-2.93(m，1H)，2.47-2.90(m，4H)，1.52-2.19(m，5H)，1.49(s，3H)，0.78(s，3H).
13C-NMR(75MHz，CDCL3，ppm)δ：169.2，166.3，166.1，150.7，146.3，136.5，136.3，133.9，133.3，130.2，129.8，129.3，128.8，128.7，127.2，124.3，121.7，119.2，118.1，110.5，108.8，107.9，71.7，68.8，68.3，54.9，53.3，40.3，38.2，37.5，35.2，29.7，25.9，25.2，25.1，14.7.HRMS(ESI)m/z?calcd?for?C
40H
40NO
6[M+H]
+630.2856，found630.2851.
I
12：Mp205-207℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：8.23(s，1H)，8.08-8.11(m，2H)，7.53-7.67(m，4H)，7.07-7.30(m，4H)，6.82(m，1H)，6.32(m，1H)，4.99(s，1H)，4.49-4.99(m，3H)，2.99-3.03(m，1H)，2.56-2.82(m，4H)，1.66-2.55(m，5H)，1.55(s，3H)，0.94(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：168.0，166.4，146.5，145.5，144.2，136.6，136.4，133.3，130.2，129.3，128.8，127.2，126.0，121.8，119.2，118.1，110.6，108.6，107.9，105.1，68.8，54.9，53.4，40.5，38.2，37.6，35.2，29.7，26.2，25.9，25.2，14.9.HRMS(ESI)m/z?calcd?for?C
33H
34NO
4[M+H]
+508.2488，found508.2485.
Embodiment 11
Also [3,2-b] rographolide (I of 14-O-(2,4-dichloro) benzoyl-19-O-ethanoyl-indoles
10) preparation:
With reference to the preparation method of embodiment 4, by 19-O-ethanoyl-indoles also [3,2-b] rographolide make (productive rate 17%).Mp：100-102℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：8.11(s，1H)，7.83-7.85(m，1H)，7.32-7.52(m，4H)，7.06-7.23(m，3H)，6.33(d，1H，J＝5.9Hz)，4.92(s，1H)，4.72(dd，?1H，J＝6.2Hz，11.4Hz)，4.56(s，1H)，4.46(dd，1H，J＝3.4Hz，11.4Hz)，4.19(s，2H)，2.91-2.96(1H，m)，2.47-2.88(4H，m)，2.16(s，3H)，1.87-2.12(m，3H)，1.47-1.56(1H，m)，1.41(s，3H)，1.23-1.28(m，1H)，0.77(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：170.5，168.8，164.2，151.0，146.2，139.4，136.6，136.2，135.4，132.6，131.4，127.3，127.1，126.8，123.9，121.8，119.2，118.2，110.5，108.7，107.7，71.4，68.8，68.7，54.8，53.3，40.3，37.6，37.5，35.2，25.9，25.5，24.9，21.2，14.8.HRMS(ESI)m/z?calcd?for?C
35H
36Cl
2NO
6[M+H]
+636.1920，found636.1916.
Embodiment 12
19-O-ethanoyl-indoles is [3,2-b]-14-deoxidation-14 also, 15-bis-dehydrogenation rographolide (I
13) preparation:
By indoles also [3,2-b] rographolide (0.15g, 0.36mmol) be dissolved in 2ml tetrahydrofuran (THF), add 3ml diacetyl oxide, the DMAP of catalytic amount, room temperature reaction, 12h stopped reaction, the 5ml that adds water, adds sodium carbonate solid, until without Bubble formation under ice bath, extraction (3x20ml) adds methylene chloride, saturated sodium bicarbonate solution (3x60ml) is washed, saturated common salt washing (3x60ml), anhydrous sodium sulfate drying.Organic layer is concentrated, and column chromatography purification obtains faint yellow solid (90mg, 0.20mmol, productive rate 57%).Mp：235-238℃.?
1H-NMR(300MHz，CDCl
3，ppm)δ：8.20(1H，s)，7.51-7.53(m，1H)，7.36-7.38(m，1H)，7.06-7.20(m，3H)，6.80(t，1H，J＝6.4Hz)，6.30-6.31(m，1H)，4.97(s，1H)，4.54(s，1H)，4.25(s，2H)，2.95-3.00(m，1H)，2.51-2.58(m，4H)，2.19(s，3H)，1.90-2.09(m，3H)，1.50-1.71(m，2H)，1.44(s，3H)，0.86(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：170.2，167.7，147.5，145.9，144.9，136.5，136.4，126.9，125.5，120.5，117.8，117.6，110.8，107.7，106.6，105.8，66.9，54.1，52.4，37.8，37.0，34.4，25.9，25.7，24.6，20.8，14.7.HRMS(ESI)m/z?calcd?for?C
28H
32NO
4[M+H]
+446.2331，found446.2331.
Embodiment 13
Also [3,2-b]-14-deoxidation-14 of 19-O-(2,4-dichloro) benzoyl-indoles, 15-bis-dehydrogenation rographolide (I
14) preparation:
With reference to the preparation method of embodiment 4, by indoles also [3,2-b] rographolide make (productive rate 16%).Mp：222-224℃.
1H-NMR(300MHz，DMSO-d
6，ppm)δ：10.68(s，1H)，7.75-7.79(m，2H)，7.54(d，1H，J＝8.3Hz)，7.43-7.45(m，2H)，7.28(d，1H，J＝7.8Hz)，6.91-7.05(m，?2H)，6.64-6.73(m，2H)，4.88(s，1H)，4.44-4.54(m，3H)，2.92-2.97(d，1H)，2.71-2.77(m，2H)，1.91-2.45(m，6H)，1.45(s，3H)，0.77(s，3H).
13C-NMR(75MHz，DMSO-d
6，ppm)δ：167.7，164.0，147.5，145.9，145.0，137.0，136.5，136.2，133.1，132.3，130.3，128.8，127.6，126.9，125.4，120.6，117.9，117.7，110.7，107.7，107.1，105.8，68.4，54.1，52.3，38.0，37.0，34.4，25.9，25.7，24.9，14.4.HRMS(ESI)m/z?calcd?for?C
33H
32Cl
2NO
4[M+H]
+576.1708，found576.1699.
Series II compound
Embodiment 14
The preparation of 14-O-t-Butyldimethylsilyl-rographolide-19-carboxylic acid (5):
By 14-O-t-Butyldimethylsilyl-rographolide-19-aldehyde (1.5g, 3.24mmol), isopentene (4.13ml, 38.88mmol) add in t-BuOH/THF (45ml/22ml), under ice bath, drip the NaClO of fresh preparation
2-NaH
2pO
4damping fluid (1.76g/3.03g, 15mlH
2o), after half an hour, rise to room temperature, stopped reaction after 7 hours.Reaction solution adds ethyl acetate (50ml) dilution, separates organic layer, and ethyl acetate (2X20ml) aqueous layer extracted merges organic layer and uses saturated aqueous common salt (2X90ml) washing, anhydrous sodium sulfate drying.Dry organic phase is concentrated, and column chromatography purification (sherwood oil: ethyl acetate=3: 1), final white powder solid (1.33g, 2.78mmol, productive rate 86%) that must be dry.Mp：104-106℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：6.70(t，1H，J＝6.0Hz)，4.96(s，1H)，4.77(s，1H)，4.46(s，1H)，4.39(dd，1H，J＝6.4Hz，9.8Hz)，3.95-4.05(m，1H)，3.13(d，1H，J＝8.1Hz)，2.25-2.42(m，3H)，1.68-1.98(m，5H)，1.32(s，3H)，1.12-1.21(m，2H)，0.79(s，9H)，0.58(s，3H)，0.04(s，3H)，0.01(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：180.6，170.3，148.3，146.3，127.3，109.4，77.6，74.1，66.8，55.3，48.9，39.5，37.8，28.3，25.5，25.3，24.6，23.9，17.7，13.1，-4.2，-4.7.HRMS(ESI)m/z?calcd?for?C
26H
43O
6Si[M+H]
+479.2829，found479.2829.
Embodiment 15
The preparation of 14-O-t-Butyldimethylsilyl-rographolide-19-carboxylate methyl ester (6a):
By 14-O-t-Butyldimethylsilyl-rographolide-19-carboxylic acid (3.20g, 6.68mol) be dissolved in 60mlDMF, add salt of wormwood (1.38g, 9.99mmol), methyl iodide (0.50ml, 8.02mmol), stopped reaction after 5 hours.Reaction solution (120ml) dilution that adds water, adds EA extraction (3X120ml), merges organic layer and with saturated aqueous common salt (3X360ml) washing, anhydrous sodium sulfate drying.By concentrated dry organic phase, column chromatography pure (sherwood oil: ethyl acetate=3: 1), final white powder solid (2.31g, 2.78mmol, productive rate 70%) that must be dry.Mp：115-117℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：6.79(t，1H，J＝5.4Hz)，5.03(t，1H，J＝3.3Hz)，4.87(s，1H)，4.55(s，1H)，4.40(dd，1H，J＝6.4Hz，9.8Hz)，4.05(d，1H，J＝3.1，9.8Hz)，3.64(s，3H)，3.12(dd，1H，J＝4.2，12.0Hz)，1.73-2.11(m，8H)，1.39(s，3H)，1.25-1.29(m，1H)，0.88(s，9H)，0.56(s，3H)，0.13(s，3H)，0.09(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：177.8，170.0，148.0，146.3，127.3，109.5，78.0，73.8，67.0，55.4，51.2，49.5，39.4，38.0，37.8，28.5，25.6，24.6，23.7，17.8，12.7，-4.2，-4.6.HRMS(ESI)m/z?calcd?for?C
27H
45O
6Si[M+H]
+493.2985，found493.2984.
Embodiment 16
The preparation of 14-O-t-Butyldimethylsilyl-3-oxygen-rographolide-19-carboxylate methyl ester (7a):
With reference to the preparation method of embodiment 2, make (productive rate 86%) by 14-O-t-Butyldimethylsilyl-rographolide-19-carboxylate methyl ester.Mp：133-135℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：6.77(t，1H，J＝5.4Hz)，5.04(t，1H，J＝2.0Hz)，4.92(s，1H)，4.62(s，1H)，4.40(dd，1H，J＝6.5Hz，9.8Hz)，4.05(d，1H，J＝3.2，9.8Hz)，3.64(s，3H)，2.91-3.20(m，1H)，2.58-2.72(m，1H)，2.40-2.51(m，3H)，1.86-2.18(m，5H)，1.47-1.61(m，2H)，1.35(m，3H)，0.89(s，9H)，0.83(m，3H)，0.14(s，3H)，0.09(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：207.8，173.6，169.7，147.3，145.5，127.5，110.4，73.7，67.0，57.4，56.9，54.8，52.0，39.3，38.9，37.5，36.9，25.8，25.6，24.6，21.1，17.8，12.6，-4.2，-4.6.HRMS(ESI)m/z?calcd?for?C
27H
43O
6Si[M+H]
+491.2829，found491.2823.
Embodiment 17
14-O-t-Butyldimethylsilyl-indoles is [3,2-b] rographolide-19-carboxylate methyl ester (II also
1) and also [3,2-b] rographolide-19-carboxylate methyl ester (II of indoles
2) preparation:
With reference to the preparation method of embodiment 3, made by 14-O-t-Butyldimethylsilyl-3-oxygen-rographolide-19-carboxylate methyl ester.
II
1：Mp123-126℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：7.95(s，1H)，7.47-7.50(m，1H)，7.31-7.34(m，1H)，7.08-7.20(m，2H)，6.92(t，1H，J＝6.0Hz)，5.16(s，1H)，4.96(s，1H)，4.67(s，1H)，4.47(dd，1H，J＝6.4Hz，9.8Hz)，4.13(dd，1H，J＝3.1Hz，9.6Hz)，3.64(s，3H)，2.91-2.96(m，1H)，2.49-2.82(4H，m)，1.69-2.20(5H，m)，1.64(3H，s)，0.93(6H，s)，0.78(s，3H)，0.23(s，3H)，0.17(s，3H).
13C-NMR(75MHz，CDCL3，ppm)δ：174.1，169.6，147.4，145.6，136.4，134.1，127.2，126.9，121.5，118.7，117.5，110.4，109.0，108.3，73.4，66.6，54.4，53.5，51.4，45.4，39.6，37.0，35.0，29.3，27.0，25.5，25.1，24.4，17.5，17.3，13.1，-4.6，-5.0.HRMS(ESI)m/z?calcd?for?C
33H
46NO
5Si[M+H]
+564.3145，found564.3144.
II
2：Mp140-142℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：7.96(s，1H)，7.49-7.51(m，1H)，7.30-7.32(m，1H)，7.07-7.20(m，2H)，7.01(t，1H，J＝6.0Hz)，5.05-5.07(m，1H)，4.96(s，1H)，4.67(s，1H)，4.72(dd，1H，J＝6.1Hz，J＝10.4Hz)，4.46(dd，1H，J＝1.7Hz，J＝10.4Hz)，3.61(s，3H)，2.95-3.05(m，1H)，2.72-2.77(2H，m)，2.48-2.51(2H，m)，1.86-2.15(m，5H)，1.65(3H，s)，0.78(s，3H).
13C-NMR(75MHz，CDCL3，ppm)δ：174.5，170.2，148.8，146.5，136.7，134.4，128.1，127.3，122.0，119.2，118.1，110.9，108.8，108.8，74.4，66.2，54.9，54.1，51.9，46.0，40.2，37.5，35.3，29.6，27.4，26.1，25.0，13.4.HRMS(ESI)m/z?calcd?for?C
27H
32NO
5[M+H]
+450.2280，found450.2282.
Embodiment 18
14-O-ethanoyl-indoles is [3,2-b] rographolide-19-carboxylate methyl ester (II also
3) preparation:
With reference to the preparation method of embodiment 8, by indoles also [3,2-b] rographolide-19-carboxylate methyl ester make (productive rate 86%).Mp：122-124℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：7.77(s，1H)，7.52(d，1H，J＝7.7Hz)，7.33(d，1H，J＝7.7Hz)，7.09-7.21(m，3H)，7.06-7.21(m，3H)，6.06(d，1H，J＝6.1Hz)，4.96(s，1H)，4.57-4.63(m，2H)，4.29(d，1H，J＝1.9，J＝11.2Hz)，3.61(s，3H)，2.95(d，1H，J＝15.1Hz)，2.48-2.72(m，6H)，2.16(s，3H)，1.86-2.13(m，3H)，1.65(3H，s)，0.86-1.37(m，2H)，0.76(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：173.9，170.0，168.6，159.9，146.1，136.2，133.9，126.8，123.6，121.5，118.7，117.7，110.3，108.2，108.1，71.1，67.3，54.4，53.6，51.3，45.4，39.7，37.0，34.9，26.9，25.5，24.9，20.2，12.9.HRMS(ESI)m/z?calcd?for?C
29H
34NO
6[M+H]
+492.2386，found492.2384.
Embodiment 19
Also [3,2-b] rographolide-19-carboxylate methyl ester (II of 14-O-(2,4-dichloro) benzoyl-indoles
4) preparation:
With reference to the preparation method of embodiment 4, by indoles also [3,2-b] rographolide-19-carboxylate methyl ester make (productive rate 26%).Mp：123-126℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：7.84(s，1H)，7.81(s，1H)，7.47-7.51(m，2H)，7.30-7.32(m，1H)，7.29-7.34(m，2H)，7.06-7.22(m，3H)，6.32(d，1H，J＝5.8Hz)，4.91(s，1H)，4.71(dd，1H，J＝6.1Hz，J＝11.4Hz)，4.55(s，1H)，4.46(dd，1H，J＝1.7Hz，J＝10.4Hz)，3.61(d，3H，J＝10.7Hz)，2.93-2.98(m，1H)，2.48-2.85(m，4H)，1.85-2.26(m，4H)，1.86-2.15(m，5H)，1.65(3H，s)，0.85-0.91(m，1H)，0.71(s，3H).?
13C-NMR(75MHz，CDCl
3，ppm)δ：174.7，169.2，164.7，151.6，151.1，149.9，146.4，139.6，136.7，135.4，134.0，132.6，131.4，127.3，123.9，122.0，119.3，118.3，110.8，108.8，108.6，71.5，68.9，54.9，54.0，51.9，45.9，45.9，40.2，37.4，35.4，27.4，26.0，25.6，13.4.HRMS(ESI)m/z?calcd?for?C
34H
34Cl
2NO
6[M+H]
+622.1763，found622.1746.
Embodiment 20
Also [3,2-b] rographolide-19-carboxylate methyl ester (II of 14-O-(2,4 dichloro benzene oxygen) ethanoyl-indoles
5) preparation:
With reference to the preparation method of embodiment 4, by indoles also [3,2-b] rographolide-19-carboxylate methyl ester make (productive rate 37%).Mp：108-110℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：8.03(s，1H)，7.49-7.52(m，1H)，7.29-7.38(m，2H)，7.07-7.20(m，4H)，6.79(d，1H，J＝8.8Hz)，6.19(d，1H，J＝5.5Hz)，4.95(s，1H)，4.77(s，2H)，4.60(dd，1H，J＝5.9Hz，J＝11.5Hz)，4.52(s，1H)，4.32(d，1H，J＝11.3Hz)，3.63(d，3H，J＝7.2Hz)，2.90-2.95(m，1H)，2.47-2.72(m，4H)，1.85-2.27(m，4H)，1.65(3H，s)，0.85-0.91(m，1H)，0.73(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：174.4，168.8，167.8，152.1，151.4，146.6，136.7，134.3，130.5，127.7，127.3，124.7，123.6，122.0，119.3，118.2，118.0，114.9，110.8，108.7，108.6，71.3，68.9，66.3，54.9，54.0，51.9，45.9，40.2，37.4，35.4，27.4，26.0，25.6，13.4.HRMS(ESI)m/z?calcd?for?C
35H
36Cl
2NO
7[M+H]
+652.1869，found652.1860.
Embodiment 21
14-O-benzoyl-indoles is [3,2-b] rographolide-19-carboxylate methyl ester (II also
6) and also [3,2-b]-14-deoxidation-14 of indoles, 15-bis-dehydrogenation rographolide-19-carboxylate methyl ester (II
7) preparation:
With reference to the preparation method of embodiment 4, by indoles also [3,2-b] rographolide-19-carboxylate methyl ester make.
II
6：Mp126-128℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：8.08(d，2H，J＝7.5Hz)，7.91(s，1H)，7.27-7.61(m，5H)，7.06-7.21(m，3H)，6.31(d，1H，J＝6.0Hz)，4.93(s，1H)，4.72(dd，1H，J＝6.2Hz，11.3Hz)，4.62(s，2H)，4.32(d，1H，J＝1.7，11.3Hz)，3.59(s，3H)，2.46-2.92(m，5H)，1.83-2.15(m，3H)，1.64(3H，s)，0.86-1.37(m，2H)，0.67(s，3H).?
13C-NMR(75MHz，CDCL3，ppm)δ：173.8，168.7，165.6，150.2，146.0，136.2，133.8，133.3，129.3，128.3，128.2，126.8，123.8，121.5，118.7，117.7，110.2，108.3，108.2，71.2，67.8，54.5，53.5，51.3，45.4，39.7，36.9，34.8，26.9，25.5，24.8，12.8.HRMS(ESI)m/z?calcd?for?C
34H
36NO
6[M+H]
+554.2543，found554.2544.
II
7：Mp156-158℃.
1H-NMR(300MHz，DMSO-d
6，ppm)δ：10.74(s，1H)，6.29-7.49(m，7H)，4.88(s，1H)，4.50(s，1H)，3.53(s，3H)，2.92(d，1H，J＝13.2Hz)，1.90-2.81(m，7H)，1.56(3H，s)，1.23-1.36(m，2H)，0.76(s，3H).
13C-NMR(75MHz，DMSO-d
6，ppm)δ：173.8，167.6，149.1，147.3，145.9，144.8，136.5，135.1，126.8，125.4，120.7，117.8，110.7，107.8，107.0，105.7，79.1，54.6，53.9，51.4，45.5，36.8，34.5，26.7，25.9，13.0.HRMS(ESI)m/z?calcd?for?C
27H
30NO
4[M+H]
+432.2175，found432.2169.
Embodiment 22
The preparation of 14-O-t-Butyldimethylsilyl-rographolide-19-benzyl carboxylate (6b):
With reference to the preparation method of embodiment 15, make (58%) by 14-O-t-Butyldimethylsilyl-rographolide-19-carboxylic acid.Mp：47-48℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：7.29-7.35(m，5H)，6.78(t，1H，J＝6.0Hz)，4.98-5.19(m，4H)，4.84(s，1H)，4.53(s，1H)，4.39-4.52(m，3H)，4.40(dd，1H，J＝6.4Hz，9.8Hz)，4.06(dd，1H，J＝3.1Hz，9.8Hz)，3.16(s，1H)，2.32-2.61(m，2H)，1.62-2.17(m，6H)，1.42(s，3H)，1.18-1.32(m，2H)，0.89(s，9H)，0.50(s，3H)，0.12(s，3H)，0.10(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：176.9，169.8，148.0，146.2，135.2，128.6，128.5，128.4，128.3，128.2，127.3，109.6，78.1，73.8，67.0，66.6，66.2，55.5，55.3，49.7，39.4，38.0，37.8，28.5，25.7，25.6，24.6，23.9，17.8，14.0，?12.8，-4.1，-4.7.HRMS(ESI)m/z?calcd?for?C
33H
49O
6Si[M+H]
+569.3298，found569.3298.
Embodiment 23
The preparation of 14-O-t-Butyldimethylsilyl-3-oxygen-rographolide-19-benzyl carboxylate (7b):
With reference to the preparation method of embodiment 2, make (productive rate 84%) by 14-O-t-Butyldimethylsilyl-rographolide-19-benzyl carboxylate.Mp：47-50℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：7.26-7.33(m，5H)，6.75(t，1H，J＝6.0Hz)，5.00-5.16(m，3H)，4.90(s，1H)，4.60(s，1H)，4.39(dd，1H，J＝6.5Hz，9.8Hz)，4.05(dd，1H，J＝3.2，J＝9.8Hz)，2.84-2.96(m，1H)，2.52-2.68(m，1H)，2.39-2.48(m，3H)，1.86-2.07(m，5H)，1.47-1.61(m，2H)，1.37(m，3H)，0.89(s，9H)，0.71(s，3H)，0.13(s，3H)，0.10(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：207.6，172.8，169.7，147.3，145.5，134.9，128.7，128.5，128.4，128.3，127.5，110.4，73.7，67.0，66.9，57.5，57.1，54.7，39.3，38.9，37.5，37.0，25.8，25.6，24.6，21.1，17.8，12.7，-4.1，-4.6.HRMS(ESI)m/z?calcd?for?C
33H
47O
6Si[M+H]
+567.3142，found567.3141.
Embodiment 24
14-O-t-Butyldimethylsilyl-indoles is [3,2-b] rographolide-19-benzyl carboxylate (II also
8) and also [3,2-b] rographolide-19-benzyl carboxylate (II of indoles
9) preparation:
With reference to the preparation method of embodiment 3, made by 14-O-t-Butyldimethylsilyl-3-oxygen-rographolide-19-benzyl carboxylate.
II
8：Mp101-103℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：7.79(s，1H)，7.47(d，1H，J＝7.6Hz)，7.09-7.30(m，8H)，6.99(t，1H，J＝5.7Hz)，5.00-5.20(m，3H)，4.92(s，1H)，4.64(s，1H)，4.45(dd，1H，J＝6.5Hz，9.8Hz)，4.11(dd，1H，J＝3.0Hz，9.7Hz)，2.91(d，1H，J＝15.0Hz)，2.42-2.81(m，4H)，1.76-2.15(m，5H)，1.62(3H，s)，0.92(s，9H)，0.72(s，0.72)，0.22(s，3H)，0.15(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：173.0，169.4，147.4，145.6，136.2，133.9，128.0，127.8，127.7，127.1，126.8，121.5，118.7，117.5，110.3，109.0，108.5，73.4，66.5，66.1，54.3，53.6，45.7，39.6，37.0，35.0，27.0，25.6，25.3，25.1，24.4，17.5，15.2，13.4，-4.6，-5.0.HRMS(ESI)m/z?calcd?for?C
39H
50NO
5Si[M+H]
+640.3458，found640.3462.
II
9：Mp88-91℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：8.04(s，1H)，7.55(d，1H，J＝7.5Hz)，7.27-7.34(m，4H)，7.10-7.22(m，4H)，6.99(t，1H，J＝5.7Hz)，5.05-5.16(m，2H)，4.95-4.97(m，2H)，4.67(s，1H)，4.39(dd，1H，J＝6.1Hz，10.4Hz)，4.20(dd，1H，J＝1.7Hz，10.4Hz)，3.21-3.27(m，1H)，2.01(d，1H，J＝15.1Hz)，2.73(t，2H，J＝6.7Hz)，2.45-2.54(m，2H)，1.88-2.17(m，4H)，1.66(3H，s)，0.91(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：173.4，170.1，148.5，145.9，136.2，135.0，134.0，128.0，127.8，127.7，127.6，126.8，121.5，118.7，117.6，110.4，108.4，74.1，66.3，65.5，54.3，53.6，45.8，39.8，37.0，34.8，26.9，25.7，24.4，13.2.HRMS(ESI)m/z?calcd?for?C
33H
36NO
5[M+H]
+526.2593，found526.2596.
Embodiment 25
14-O-ethanoyl-indoles is [3,2-b] rographolide-19-benzyl carboxylate (II also
10) preparation:
With reference to the preparation method of embodiment 8, by indoles also [3,2-b] rographolide-19-benzyl carboxylate make (productive rate 79%) .Mp:103-105 DEG C.
1h-NMR (300MHz, CDCl
3, ppm) and δ: 7.97 (s, 1H), 7.82 (d, 1H, J=7.2Hz), 7.13-738 (m, 9H), 6.06 (s, 1H), 5.04-5.17 (m, 2H), 4.97 (s, 1H), 4.55-4.61 (m, 2H), 4.30 (d, 1H, J=11.1Hz), 2.98 (d, 1H, J=15.0Hz), 2.45-2.77 (m, 4H), 2.19 (s, 3H), 1.88-2.16 (m, 3H), 1.66 (3H, s), 1.28-1.32 (m, 1H), 0.85-0.99 (m, 1H), 0.76 (s, 3H).
13c-NMR (75MHz, CDCl
3, ppm) and δ: 173.5,170.5,169.2,150.5,146.6,136.7,135.5,134.3,128.5,128.2,128.2,127.3,124.1,122.0,119.2,118.2,110.8,108.8,108.6,71.7,67.8,66.6,54.8,54.2,46.2,40.2,37.5,35.4,27.5,26.1,25.4,20.7,13.6.HRMS (ESI) m/z calcd for C
35h
38nO
6[M+H]
+568.2699, found568.2698.
Embodiment 26
Also [3,2-b] rographolide-19-carboxylate methyl ester (II of 14-O-(2,4-dichloro) benzoyl-indoles
11) preparation:
With reference to the preparation method of embodiment 4, by indoles also [3,2-b] rographolide-19-benzyl carboxylate make.
Mp：101-104℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：7.84(s，1H)，7.82(d，1H，J＝3.6Hz)，7.47-7.51(m，2H)，7.06-7.34(m，10H)，6.31(d，1H，J＝5.4Hz)，5.00-5.13(m，2H)，4.89(s，1H)，4.69(dd，1H，J＝5.8Hz，11.2Hz)，4.53(s，1H)，4.43(d，1H，J＝1.7Hz，11.3Hz)，2.95(d，1H，J＝15.0Hz)，2.42-2.81(m，4H)，1.85-2.15(m，4H)，1.62(3H，s)，0.80-0.92(m，?1H)，0.68(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：173.5，169.1，164.2，151.2，146.4，139.3，136.7，135.5，134.3，132.6，131.4，128.6，128.5，128.3，128.2，127.3，123.8，122.0，119.2，118.3，110.8，108.9，108.6，71.5，68.9，66.6，54.8，54.1，46.1，40.3，37.5，35.4，27.5，26.0，25.6，13.6，13.2.HRMS(ESI)m/z?calcd?for?C
40H
38Cl
2NO
6[M+H]
+698.2076，found698.2060.
Embodiment 27
Also [3,2-b] rographolide-19-benzyl carboxylate (II of 14-O-(2,4 dichloro benzene oxygen) ethanoyl-indoles
12) and also [3,2-b]-14-deoxidation-14 of indoles, 15-bis-dehydrogenation rographolide-19-benzyl carboxylate (II
13) preparation:
With reference to the preparation method of embodiment 4, by indoles also [3,2-b] rographolide-19-benzyl carboxylate make.
II
12: productive rate 35.86%.Mp:98-100 DEG C.
1h-NMR (300MHz, CDCl
3, ppm) δ: 7.78 (s, 1H), 7.81 (s, 1H), 7.06-7.49 (m, 11H), 6.79 (d, 1H, J=8.8Hz), 6.17 (d, 1H, J=5.5Hz), 5.00-5.15 (m, 2H), 4.93 (s, 1H), 4.76 (s, 2H), 4.59 (dd, 1H, J=5.9Hz, 11.5Hz), 4.50 (s, 1H), 4.31 (d, 1H, J=11.4Hz), 2.91 (d, 1H, J=15.0Hz), 2.44-2.72 (m, 4H), 1.85-2.13 (m, 4H), 1.64 (3H, s), 0.82-0.95 (m, 1H), 0.69 (s, 3H).
13c-NMR (75MHz, CDCl
3, ppm) and δ: 173.4,168.7,167.8,152.1,151.3,146.4,136.7,135.5,134.2,130.6,128.5,128.4,128.3,128.2,127.6,127.3,124.6,123.5,122.0,119.3,118.2,114.9,110.7,108.8,108.5,71.2,68.9,66.7,66.3,54.8,54.1,46.1,40.2,37.5,35.4,27.5,26.0,25.6,13.6.HRMS (ESI) m/z calcd for C
41h
40cl
2nO
7[M+H]
+728.2182, found728.2178.
II
13：Mp：72-74℃.
1H-NMR(300MHz，CDCl
3，ppm)δ：7.78(s，1H)，7.49(d，1H，J＝7.7Hz)，7.02-731(m，10H)，6.77(t，1H，J＝7.1Hz)，6.06(s，1H)，5.01-5.14(m，2H)，4.91(s，1H)，4.47(s，1H)，2.96(d，1H，J＝15.0Hz)，2.44-2.81(m，4H)，1.88-2.12(m，3H)，1.66(3H，s)，0.80-0.92(m，1H)，0.76(s，3H).
13C-NMR(75MHz，CDCl
3，ppm)δ：173.5，168.2，150.5，146.6，145.4，144.3，136.7，135.5，134.3，128.5，128.3，128.2，127.3，125.9，122.0，119.2，118.1，110.8，109.0，108.5，105.1，66.7，54.9，54.2，46.2，40.4，37.6，35.4，29.7，27.5，26.3，26.1，13.7.HRMS(ESI)m/z?calcd?for?C
33H
34NO
4[M+H]
+508.2488，found508.2491。
Claims (4)
1. two serial indoles andrographolidume derivative, have as general formula (I), the structure shown in (II):
Wherein, R
1for hydrogen, replacement or unsubstituted C
1～8aliphatic acyl radical, replacement or unsubstituted aromatic acyl, silylation.R
2and R
4for hydrogen, replacement or unsubstituted C
1～8aliphatic acyl radical, replacement or unsubstituted aromatic acyl, silylation or 14,15 generation elimination reactions form two key Δs
14,15.R
3for hydrogen, replacement or unsubstituted C
1～8aliphatic alkyl, replacement or unsubstituted aromatic base.
2. the derivative of a kind of indoles according to claim 1 rographolide, is characterized in that: the substituting group of aliphatic acyl radical is straight or branched formula alkoxyl group, replacement or the unsubstituted aromatic base of the straight or branched formula amido of 1～8 carbon, 1～8 carbon; The substituting group of alkyl is straight or branched formula alkoxyl group, replacement or the unsubstituted aromatic base of the straight or branched formula amido of 1～8 carbon, 1～8 carbon; In all descriptions, aromatic substituting group is halogen above, hydroxyl, the alkyl of 1～8 carbon, the alkoxyl group of 1～8 carbon, amino, 1～8 amino that carbon alkyl replaces, the amide group of 1～8 carbon, cyano group, carboxyl.
According to the indoles described in claim 1 to 2 also [3,2-b] andrographolidume derivative be:
Series I compound:
I
1: also [3,2-b] rographolide of 14,19-O-bis-(tertiary butyl dimethyl-silicon)-indoles
I
2: 14-O-t-Butyldimethylsilyl-indoles is [3,2-b] rographolide also
I
3: also [3,2-b] rographolide of 14-O-t-Butyldimethylsilyl-19-O-ethanoyl-indoles
I
4: also [3,2-b] rographolide of 14-O-t-Butyldimethylsilyl-19-O-benzoyl-indoles
I
5: indoles is [3,2-b] rographolide also
I
6: 19-O-ethanoyl-indoles is [3,2-b] rographolide also
I
7: 19-O-benzoyl-indoles is [3,2-b] rographolide also
I
8: 14,19-O-diacetyl-indoles is [3,2-b] rographolide also
I
9: 14,19-O-dibenzoyl-indoles is [3,2-b] rographolide also
I
10: also [3,2-b] rographolide of 14-O-(2,4-dichloro) benzoyl-19-O-ethanoyl-indoles
I
11: also [3,2-b] rographolide of 14-O-ethanoyl-19-O-benzoyl-indoles
I
12: 19-O-benzoyl-indoles is [3,2-b]-14-deoxidation-14 also, 15-bis-dehydrogenation rographolides
I
13: 19-O-ethanoyl-indoles is [3,2-b]-14-deoxidation-14 also, 15-bis-dehydrogenation rographolides
I
14: also [3,2-b]-14-deoxidation-14 of 19-O-(2,4-dichloro) benzoyl-indoles, 15-bis-dehydrogenation rographolide series II compounds:
II
1: 14-O-t-Butyldimethylsilyl-indoles is [3,2-b] rographolide-19-carboxylate methyl ester also
II
2: indoles is [3,2-b] rographolide-19-carboxylate methyl ester also
II
3: 14-O-ethanoyl-indoles is [3,2-b] rographolide-19-carboxylate methyl ester also
II
4: also [3,2-b] rographolide-19-carboxylate methyl ester of 14-O-(2,4-dichloro) benzoyl-indoles
II
5: also [3,2-b] rographolide-19-carboxylate methyl ester of 14-O-(2,4 dichloro benzene oxygen) ethanoyl-indoles
II
6: 14-O-benzoyl-indoles is [3,2-b] rographolide-19-carboxylate methyl ester also
II
7: indoles is [3,2-b]-14-deoxidation-14 also, 15-bis-dehydrogenation rographolide-19-carboxylate methyl esters
II
8: 14-O-t-Butyldimethylsilyl-indoles is [3,2-b] rographolide-19-benzyl carboxylate also
II
9: indoles is [3,2-b] rographolide-19-benzyl carboxylate also
II
10: 14-O-ethanoyl-indoles is [3,2-b] rographolide-19-benzyl carboxylate also
II
11: also [3,2-b] rographolide-19-benzyl carboxylate of 14-O-(2,4-dichloro) benzoyl-indoles
II
12: also [3,2-b] rographolide-19-benzyl carboxylate of 14-O-(2,4 dichloro benzene oxygen) ethanoyl-indoles
II
13: indoles is [3,2-b]-14-deoxidation-14 also, 15-bis-dehydrogenation rographolide-19-benzyl carboxylates.
4. a kind of indoles according to claim 1 andrographolidume derivative are in the purposes of preparing in antitumor drug.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964320A (en) * | 2012-11-27 | 2013-03-13 | 中国药科大学 | 19-carboxyl andrographolide derivative, preparation method and medicinal application thereof |
| CN103224492A (en) * | 2013-04-15 | 2013-07-31 | 南京工业大学 | 14-aryl ether andrographolide derivatives and preparation method and application thereof |
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2014
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102964320A (en) * | 2012-11-27 | 2013-03-13 | 中国药科大学 | 19-carboxyl andrographolide derivative, preparation method and medicinal application thereof |
| CN103224492A (en) * | 2013-04-15 | 2013-07-31 | 南京工业大学 | 14-aryl ether andrographolide derivatives and preparation method and application thereof |
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| Title |
|---|
| CLAAS LÜDER DIEDRICH ET AL.: "Linear versus Angular Fischer Indole Annulation: Relative Configuration Determines Regioselectivity", 《EUROPEAN JOURNAL OF ORGANIC CHEMISTRY》 * |
| F. M. MILLER ET AL.: "Fischer Indole Synthesis from cis- and trans-9-Methyl-3-decalone", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| 戴桂馥等: "穿心莲内酯衍生物体外抗肿瘤作用及构效关系研究", 《中国新药杂志》 * |
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