WO2016150207A1 - 蓝萼甲素衍生物及其制备方法和应用 - Google Patents

蓝萼甲素衍生物及其制备方法和应用 Download PDF

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WO2016150207A1
WO2016150207A1 PCT/CN2015/097692 CN2015097692W WO2016150207A1 WO 2016150207 A1 WO2016150207 A1 WO 2016150207A1 CN 2015097692 W CN2015097692 W CN 2015097692W WO 2016150207 A1 WO2016150207 A1 WO 2016150207A1
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acid
solution
hydrogen chloride
following
cancer
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PCT/CN2015/097692
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French (fr)
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李云森
陈子珺
邓世平
冯海梅
魏中元
李勇
刘乾
陈祥
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苏州沪云肿瘤研究中心股份有限公司
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Priority claimed from CN201510138028.6A external-priority patent/CN104817464B/zh
Priority claimed from CN201510138029.0A external-priority patent/CN104761460B/zh
Priority claimed from CN201510243692.7A external-priority patent/CN104887652A/zh
Application filed by 苏州沪云肿瘤研究中心股份有限公司 filed Critical 苏州沪云肿瘤研究中心股份有限公司
Priority to US15/561,685 priority Critical patent/US10196344B2/en
Priority to EP15886129.4A priority patent/EP3275859B1/en
Priority to JP2017550599A priority patent/JP6694894B2/ja
Publication of WO2016150207A1 publication Critical patent/WO2016150207A1/zh

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    • C—CHEMISTRY; METALLURGY
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    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/04—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated
    • C07C225/08—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and containing rings
    • C07C225/12—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being saturated and containing rings with doubly-bound oxygen atoms bound to carbon atoms being part of rings
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/112—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C07D295/116—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings with the doubly bound oxygen or sulfur atoms directly attached to a carbocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/86—Ring systems containing bridged rings containing four rings

Definitions

  • the invention belongs to the field of chemical medicine, in particular to a blue scorpion A derivative and a preparation method and application thereof.
  • Glaucocalyxin A also known as the king's date, is from the ground of the labyrinth plant Rabdosia japonica (Burm.f.) Hara var.glaucocalyx (Maxim.) Hara Extracted from the whole grass.
  • Lanthanine A whose chemical name is Kauri-16-ene-3,15-dione, (7 ⁇ ,14R)-, has the formula: C 20 H 28 O 4 , molecular weight: 332.43, and the structural formula is as follows:
  • the content of scutellarin in dried leaves of blue musk tea is as high as 1.03% [Zhang Yuan Barrel, Sha Dongxu, Sha Ming et al. Chinese Journal of Traditional Chinese Medicine, 1991, 16 (11): 679]. Its structure is similar to Rubescensine A, belonging to the enantiomer-kaurane diterpenoid, and also has an antitumor pharmacophore group similar to Rubescensine A, ⁇ -unsaturated cyclopentanone structural unit. .
  • scutellarin has low polarity and poor water solubility, and is not suitable for direct administration as a drug; it has strong anti-autoimmune and anti-tumor effects in vitro, but it takes a large dose for a long time to produce a drug effect.
  • the drug is fast in the body, has a short half-life, and has low bioavailability, and cannot be directly used as a drug. Therefore, under the premise of retaining the pharmacophore ⁇ , ⁇ -unsaturated cyclopentanone, structural modification of its outer double bond, synthesis of anti-autoimmune and anti-tumor drug derivatives, is a solution to its An effective route to the defects of the drug.
  • the present invention provides a cerulein derivative, and a preparation method and use thereof.
  • the present invention provides a leucomycin derivative represented by formula (I) or a salt thereof:
  • R is any one of the following groups: dimethylamino, diethylamino, piperidine, piperazine, cycloheximide, morpholine, N-methylpiperazine, methylaniline, dibenzyl Base amine, imidazole, 2-methylimidazole, 4-phenylamino group Butanone, 3-(phenylamino)cyclohexanone, p-chlorophenylamino-butanone, o-chlorophenylamino-butanone, benzylamine, hydrazine, 2-amino-6-hydroxyindole, pyrrole, pyrrole- 2-carboxylic acid, 2-methylpyrrolidine, 3-methylpyrrole, 2-pyrrolidone, 3-aminobenzamide, p-aminobenzamide and amino acids.
  • the scutellarin derivative provided by the present invention has high specificity against autoimmune and antitumor effects, and can be used as an active compound to further develop a new pharmaceutical preparation for chemotherapeutic autoimmune diseases and cancer diseases.
  • the scutellarin derivative of the present invention is expected to fill a drug blank for the treatment of systemic lupus erythematosus, psoriasis and triple-negative breast cancer.
  • the R group is a dimethylamino group
  • the leucotriene derivative is dimethylaminoblue hydrazone hydrochloride, and the structural formula is as shown in the following formula II:
  • the 1 H NMR spectrum and the 13 C NMR spectrum of the dimethylaminoblue hydrazone hydrochloride shown in Formula II are shown in Fig. 1 and Fig. 2, respectively, and the LC-MS spectrum thereof is shown in Fig. 3. 1 to 3, the molecular formula of dimethylaminoblue hydrazone hydrochloride is: C 22 H 36 ClNO 4 ⁇ HCl.
  • the dimethylaminoblue hydrazone hydrochloride salt of the formula II has good water solubility, and has high oral bioavailability when used as a drug; and, its anti-autoimmune and anti-tumor effects Targeted, it is expected to fill the gap in the treatment of systemic lupus erythematosus, psoriasis and triple-negative breast cancer.
  • the present invention provides a process for the preparation of a scutellarin derivative according to the first aspect, which comprises: subjecting a donor compound of cyanoin and an R group to an addition reaction under the action of a catalyst And got it.
  • the catalyst is sodium methoxide, sodium ethoxide, pyridine, sodium carbonate, carbon. Any one or more of potassium acid.
  • the ratio of the number of moles of the R group to the scutellarin is (1 to 10):1;
  • the ratio of the number of moles of the catalyst to the cyanidin is (1 to 10):1.
  • the reaction is carried out at -30 to 60 ° C;
  • the reaction is carried out in a solvent
  • the solvent comprises any one or more of the following: an alcohol, a ketone, an ether, an ester, and an alkyl halide; and still more preferably, the alcohol includes any one or more of the following: methanol, ethanol , isopropanol, isobutanol, tert-butanol; the ketone comprises one or more of the following: acetone, 2-butanone; the ether includes any one or more of the following: diethyl ether, two Oxycyclohexane, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran; the ester includes any one or more of the following: methyl acetate, ethyl acetate and butyl acetate; the halogenated hydrocarbon includes two Methyl chloride, chloroform;
  • the preparation method further comprises the steps of evaporating the solvent after the reaction and/or detecting by TLC and/or HPLC.
  • the present invention provides a method for producing a salt of a scutellarin derivative according to the first aspect, which comprises:
  • the cerulein derivative is dissolved in an organic solvent to form a solution, and the resulting solution is subjected to a salt formation reaction with an acid to control the pH of the solution to obtain a scutellarin derivative salt.
  • the acid includes an organic acid and a mineral acid
  • the inorganic acid comprises any one of the following: hypoiodic acid, hypochlorous acid, hypobromous acid, iodic acid, perchloric acid, peroxodisulfuric acid, peroxydicarbonic acid, percarbonic acid, pyrophosphoric acid, coke Sulfuric acid, pyrosulfite, tetrathiosulfate, phosphoric acid, thiosulfuric acid, sulfuric acid, chloric acid, metaphosphoric acid, hydroiodic acid, hydrogen azide acid, hydrofluoric acid, hydrosulfuric acid, hydrochloric acid, hydrobromic acid, tetraboric acid , carbonic acid, nitric acid, bromic acid, sulfurous acid, phosphorous acid, chlorous acid, hydrochloric acid, nitrous acid, orthophosphoric acid, crude sulfuric acid and raw carbonic acid;
  • the organic acid comprises any one of the following: tartaric acid, oxalic acid, malic acid, citric acid, ascorbic acid, benzoic acid, salicylic acid, caffeic acid, lactic acid, sorbic acid, fumaric acid, formic acid, acetic acid, Benzoic acid, oxalic acid, succinic acid, pyruvic acid, ⁇ -ketosuccinic acid, benzenesulfonic acid, ethanesulfonic acid, resin acid, trifluoroacetic acid, maleic acid, tetrasulfonic acid, methanesulfonic acid, Fuma Acids and amino acids.
  • the organic solvent comprises any one or more of the following: an alcohol, a ketone, an ether, an ester, and an alkyl halide;
  • the alcohol comprises any one or more of the following: methanol, ethanol, isopropanol, isobutanol, tert-butanol;
  • the ketone comprises one or more of the following: acetone, 2 Butanone;
  • the ether includes any one or more of the following: diethyl ether, dioxane, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran;
  • the ester includes any one or more of the following Species: methyl acetate, ethyl acetate and butyl acetate;
  • the halogenated hydrocarbons include dichloromethane, chloroform.
  • the pH of the solution is controlled using a hydrogen chloride solution
  • the hydrogen chloride solution comprises an aqueous solution of hydrogen chloride, a methanol solution of hydrogen chloride, an ethanol solution of hydrogen chloride, an isopropanol solution of hydrogen chloride, a n-propanol solution of hydrogen chloride, an isobutanol solution of hydrogen chloride, and an ethyl acetate solution of hydrogen chloride. Any one of a solution of hydrogen chloride in acetone, a solution of hydrogen chloride in diethyl ether, and a hydrogen chloride in dioxane solution;
  • the pH of the control solution is 6.0 to 8.0;
  • the reaction is carried out at a temperature of from -30 to 60 °C.
  • the present invention provides the use of a scutellarin derivative or a salt thereof according to the first aspect for the preparation of a medicament for the treatment of an autoimmune disease and/or for the treatment of cancer;
  • the autoimmune disease is systemic lupus erythematosus or psoriasis;
  • the cancer comprises any one or more of the following: triple negative breast cancer, glioma, cervical cancer, esophageal cancer, lung cancer, liver cancer, choriocarcinoma, oral epidermoid carcinoma, prostate cancer, rectal cancer.
  • the scutellarin derivative of the present invention is highly targeted against autoimmune and anti-tumor effects, and can be used as an active compound to further develop new chemotherapeutic drugs for autoimmune diseases and cancer diseases. preparation.
  • the leucomycin derivative of the present invention is expected to fill a drug blank for the treatment of diseases such as systemic lupus erythematosus, psoriasis and triple-negative breast cancer.
  • Fig. 1 is a 1 H NMR spectrum of a cerulein derivative of the present invention.
  • Figure 2 is a 13 C NMR spectrum of a scutellarin derivative of the present invention.
  • Figure 3 is a LC-MS spectrum of a scutellarin derivative salt of the present invention.
  • Figure 4 is a graph showing the IC 50 (i.e., half effective inhibitory concentration) of a blue mitin derivative for inhibiting proliferation of five cell lines of the present invention.
  • FIG. 5 is GLA proliferation inhibition IC 50 of FIG. 5 cell lines.
  • Fig. 6 is a comparison diagram of IC 50 of a blue scorpion A derivative of the present invention, and GLA inhibiting proliferation of various cells.
  • Figure 7 is an XY scatter plot of the concentration and inhibition rate of a scutellarin derivative of the present invention.
  • Figure 8 is an XY scatter plot of GLA concentration and inhibition rate.
  • a preparation method of a cyanidin derivative is disclosed, that is, a cyanosine nitrogen derivative obtained by modifying blue scutella A, and then a cyanosine nitrogen derivative is reacted with an acid to form a water-soluble substance.
  • a good blue arule nitrogen derivative salt is disclosed, that is, a cyanosine nitrogen derivative obtained by modifying blue scutella A, and then a cyanosine nitrogen derivative is reacted with an acid to form a water-soluble substance.
  • reaction formula of the blue indole A derivative obtained by modification of scutellarin is as follows:
  • the ruthenium-methyl GLA is used as a raw material, and the catalyst dosage is as follows: the molar ratio of the catalyst to the raw material blue saponin is 1 to 10, and the temperature control range is -30 to 60 °C.
  • R in RH is a nitrogen source donor, and R in RH and R in the scutellarin derivative have the same structure.
  • R may be any of the following groups: dimethylamino, diethylamino, piperidine, piperazine, cycloheximide, morpholine, N-methylpiperazine, aniline, methyl-aniline, 2-benzylamine, imidazole, 2-methylimidazole, 4-phenylaminobutanone, 3-(phenylamino)cyclohexanone, p-chlorophenylamino-butanone, o-chlorophenylamino-butyl Ketone, benzylamine, hydrazine, 2-amino-6-hydroxyindole, pyrrole, 2-carboxypyrrole, 2-carboxy-4-hydro-pyrrole, 3-methylpyrrole, 3-aminobenzamide, p-aminobenzoic acid Amides and various amino acids.
  • R in the above structural formula may be any one of the group structures in Table 1:
  • a method for preparing dimethylaminoblue hydrazone hydrochloride which mainly comprises the following steps:
  • the first step the preparation of dimethylaminoblue
  • the second step is to prepare dimethylaminoblue hydrazone hydrochloride.
  • the organic solvent in the above first and second steps may be one or more of the following solvents: alcohols, ketones, ethers, esters and alkyl halides.
  • the organic solvent in the first step is methanol
  • the organic solvent in the second step is isopropanol.
  • the hydrogen chloride solution in the above second step may be any one of the following: aqueous hydrogen chloride solution, hydrogen chloride methanol solution, hydrogen chloride ethanol solution, hydrogen chloride isopropanol solution, hydrogen chloride n-propanol solution, hydrogen chloride isobutanol solution, ethyl hydrogen chloride ethyl acetate. Solution, hydrogen chloride acetone solution, hydrogen chloride diethyl ether solution and hydrogen chloride dioxane solution.
  • the hydrogen chloride solution is preferably a hydrogen chloride isopropanol solution.
  • dimethylaminoblue hydrazone hydrochloride was characterized by a hydrogen spectroscopy method using a nuclear magnetic resonance method, and the results are shown in Fig. 1-2.
  • dimethylaminoblue hydrazone hydrochloride has the formula: C 22 H 36 ClNO 4 ⁇ HCl, 1 H NMR (DMSO) ⁇ : 0.98 (6H, d, 2 ⁇ CH 3 ), 1.05 (3H , m, CH 3 ), 1.74 (6H, m, 2 ⁇ CH 3 ), 3.91 (1H, s, CH), 6.20 (1H, s, CH), 4.83 (1H, s, CH), 5.86 (1H, s, CH), 6.20 (1H, s, CH), 10.58 (1H, s, OH).
  • dimethylaminoblue hydrazone hydrochloride has the formula: C 22 H 36 ClNO 4 ⁇ HCl, 13 C NMR (DMSO) ⁇ :
  • the obtained dimethylaminoblue hydrazone hydrochloride was subjected to LC-MS detection, and the results of the detection are shown in FIG.
  • dimethylaminoblue hydrazone hydrochloride has the formula: C 22 H 36 ClNO 4 ⁇ HCl, MS m/e: 378.6 (M+).
  • Example 3 The respective steps in Example 3 are the same as those in Example 2.
  • the difference between the two examples is that the reaction temperature and the pH value controlled in the preparation of the dimethylaminoblue hydrazone hydrochloride in the second step are different.
  • the reaction temperature was controlled at -30 ° C and the pH was adjusted to 6.
  • Example 4 The respective steps in Example 4 are the same as those in Example 2.
  • the difference between the two examples is that the reaction temperature and the pH value controlled in the preparation of the dimethylaminoblue hydrazone hydrochloride in the second step are different.
  • the reaction temperature was controlled at 60 ° C and the pH was adjusted to 8.
  • Example 5 The procedure of Example 5 was different from that of Example 2 in that the reaction temperature was controlled to -10 ° C and the pH was adjusted to 7 in the preparation of the dimethylaminoblue hydrazone hydrochloride salt in the second step.
  • Example 6 In the second step, the reaction temperature was controlled to 20 ° C and the pH was adjusted to 7 when the dimethylaminoblue hydrazone hydrochloride was prepared.
  • the reaction solvent to be applied is the organic solvent exemplified in the examples
  • the hydrogen chloride solution is preferably the hydrogen chloride isopropanol solution and the hydrogen chloride ethanol solution
  • the reaction temperature in the second step is -10
  • Optimum at ⁇ 20 °C, pH is adjusted to 7 is optimal.
  • the sphingosine derivative obtained by the present invention was subjected to a pharmacodynamic test, and it was found by experiments that the scutellarin derivative can be used for the preparation of an anti-autoimmune disease and an antitumor drug.
  • drugs against the following cancers Sanyin breast cancer, glioma, cervical cancer, esophageal cancer, lung cancer, liver cancer, choriocarcinoma, oral epidermoid cancer, prostate cancer, rectal cancer.
  • triple-negative breast cancer and glioma which have good anti-cancer targeting, are applied to the treatment of triple-negative breast cancer, filling the drug blank of triple-negative breast cancer.
  • the immune diseases are systemic lupus erythematosus and psoriasis.
  • GH02 dimethylaminoblue hydrazone hydrochloride
  • GLA scutellarin
  • Cell proliferation inhibition rate [(control group absorbance - blank absorbance) - (dosing group absorbance - blank absorbance)] / (pair Photo group absorbance value - blank absorbance value)%.
  • MDA-MB-231 and MCF-7 are breast cancer cell lines
  • SGC-7901 is a gastric cancer cell line
  • U251 is a glioma cell line
  • A549 is a lung cancer cell line.
  • Figure 4 shows the IC 50 of GH02 against the above five cell lines.
  • GH02 has the lowest IC 50 for MDA-MB-231 breast cancer cell lines, i.e., GH02 is the best for breast cancer.
  • FIG 5 is a GLA above the IC 50 of the five cell lines, can be seen from the figure, the lowest of GLA IC 50 MDA-MB-231 breast cancer cell lines; and by comparison of FIG. 6, GH02 and GLA Breast Cancer The medicine works best.
  • GH02 and GLA have the lowest IC 50 for the MDA-MB-231 breast cancer cell line and the highest inhibition rate for the MDA-MB-231 breast cancer cell line, therefore, the blue of the present invention
  • a retinoid derivatives have the best inhibitory effect on breast cancer.

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Abstract

一种如式(I)所示的蓝萼甲素衍生物或其盐，其制备方法和在制备抗自身免疫性疾病和抗肿瘤药物的用途，如红斑狼疮、银屑病和三阴乳腺癌等疑难病。

Description

蓝萼甲素衍生物及其制备方法和应用 技术领域
本发明属于化学医药领域，具体地涉及蓝萼甲素衍生物及其制备方法和应用。
背景技术
蓝萼甲素(Glaucocalyxin A，以下简称GLA)，又名王枣子乙素，是从唇形科植物蓝萼香茶菜Rabdosia japonica(Burm.f.)Hara var.glaucocalyx(Maxim.)Hara的地上全草中提取得到的。蓝萼甲素，其化学名为贝壳杉-16-烯-3，15-二酮，(7α，14R)-，分子式为：C20H28O4，分子量为：332.43，结构式如下所示：
Figure PCTCN2015097692-appb-000001
蓝萼甲素在蓝萼香茶菜的干燥叶子中含量高达1.03％[张元桶，沙东旭，沙明等.中国中药杂志，1991，16(11)：679]。其结构与冬凌草甲素类似，属于对映-贝壳杉烷类二萜，且结构中也具有类似冬凌草甲素的抗肿瘤药效基团α，β-不饱和环戊酮结构单元。体内外抗肿瘤实验表明，其对多种人癌瘤细胞株(CE-1、U87、A549、MCF-7、Hela、K562、HepG2、NCI-H460、KB、JEG-3、K562、HL-60等具有显著的抑制增殖作用，特别对非激素依赖性前列腺癌(DU-145)、直肠癌(Lovo)细胞最为敏感，抗瘤谱广；能抑制Lewis肺癌、S180实体型以及HCA实体型等实体瘤的生长，明显增加荷腹水型S180腹水型和荷HCA腹水型小鼠的生命延长率，其抗肿瘤的强弱呈剂量依赖关系。2011年最新文献[Li WenGao，Jian Zhang，Wen Hua Yang，Bin Wang，Jian Wen Wang.Toxicology in Vitro 2011，25：51-63]报道了蓝萼甲素通过线粒体-调节死亡途径诱导凋亡，抑制人早幼粒白血病细胞增殖，是一种很有前景的具有抗肿瘤活性的先 导化合物。
另外，作为一种抗自身免疫性疾病药物，蓝萼甲素在系统性红斑狼疮和银屑病等病症的治疗中也取得突破性进展，获得良好的疗效。在文献药香茶菜研究进展[宿玉，崔佳，施务务等.亚太传统医药，2011，06]中指出，从香茶菜中获得的蓝萼甲素除了在抗癌、抗菌、保肝以及心血管的作用，还在自身免疫抑制方面具有活性作用。
但是，蓝萼甲素极性小，水溶性差，不适合直接作为药物给药；体外具有较强的抗自身免疫和抗肿瘤作用，但体内需要大剂量长时间才能产生药效。药物在体内消除快、半衰期短、生物利用度低，尚不能直接作为药物使用。因此在保留药效基团α，β-不饱和环戊酮的前提下，对其环外双键进行结构修饰，合成抗自身免疫和抗肿瘤药效更强的衍生物，是一条解决其作为药物存在的缺陷的有效途径。
发明内容
为解决上述技术问题，本发明提供了一种蓝萼甲素衍生物，以及它们的制备方法和用途。
具体地，第一方面，本发明提供了一种如式(I)所示的蓝萼甲素衍生物或其盐：
Figure PCTCN2015097692-appb-000002
其中，R为以下基团中的任何一种：二甲基氨基、二乙基氨基、哌啶、哌嗪、环己亚胺、吗啉、N-甲基哌嗪、甲基苯胺、二苄基胺、咪唑、2-甲基咪唑、4-苯基胺基 丁酮、3-(苯基氨基)环己酮、对氯苯基氨基-丁酮、邻氯苯基氨基-丁酮、苄胺、嘌呤、2-氨基-6-羟基嘌呤、吡咯、吡咯-2-羧酸、2-甲基吡咯烷、3-甲基吡咯、2-吡咯烷酮、3-氨基苯甲酰胺、对氨基苯甲酰胺和氨基酸。
本发明所提供的蓝萼甲素衍生物抗自身免疫和抗肿瘤作用的针对性好，可以作为活性化合物，进一步开发新的化学治疗自身免疫性疾病和治疗癌症疾病的药物制剂。特别是，本发明的蓝萼甲素衍生物有望填补治疗系统性红斑狼疮、银屑病和三阴乳腺癌的药物空白。
在一个优选的实施方案中，R基团为二甲基氨基，所述蓝萼甲素衍生物为二甲氨基蓝萼甲素盐酸盐，结构式如以下式II所示：
Figure PCTCN2015097692-appb-000003
式II所示的二甲氨基蓝萼甲素盐酸盐的1H NMR谱图和13C NMR谱图分别如图1和图2所示，其LC-MS谱图如图3所示。由图1～图3可知，二甲氨基蓝萼甲素盐酸盐的分子式为：C22H36ClNO4·HCl。
发明人通过实验发现，式II所示的二甲氨基蓝萼甲素盐酸盐具有很好的水溶性，并且作为药物使用时，口服生物利用度高；并且，其抗自身免疫和抗肿瘤作用的针对性好，有望填补治疗系统性红斑狼疮、银屑病和三阴乳腺癌等疾病的药物空白。
第二方面，本发明提供了如第一方面所述的蓝萼甲素衍生物的制备方法，其包括：使蓝萼甲素与R基团的供体化合物在催化剂的作用下发生加成反应而得。
上述制备方法中，作为优选，所述催化剂为甲醇钠、乙醇钠、吡啶、碳酸钠、碳 酸钾中的任何一种或几种。
优选地，R基团与蓝萼甲素的摩尔数之比为(1～10)∶1；
优选地，所述催化剂与蓝萼甲素的摩尔数之比为(1～10)∶1。
优选地，所述反应在-30～60℃下进行；
优选地，所述反应在溶剂中进行；
进一步优选地，所述溶剂包括以下中的任何一种或几种：醇、酮、醚、酯和卤代烷；更进一步优选地，所述醇包括以下中的任意一种或几种：甲醇、乙醇、异丙醇、异丁醇、叔丁醇；所述酮包括以下中的一种或几种：丙酮、2-丁酮；所述醚包括以下中的任意一种或几种：乙醚、二氧六环、异丙醚、甲基叔丁基醚、四氢呋喃；所述酯包括以下中的任意一种或几种：乙酸甲酯、乙酸乙酯和乙酸丁酯；所述卤代烃包括二氯甲烷、氯仿；
进一步优选地，所述制备方法还包括在反应后蒸干溶剂和/或用TLC和/或HPLC检测的步骤。
第三方面，本发明提供了如第一方面所述的蓝萼甲素衍生物的盐的制备方法，其包括：
将所述蓝萼甲素衍生物溶于有机溶剂中形成溶液，所得溶液与酸进行成盐反应，控制溶液pH值，得到蓝萼甲素衍生物盐。
所述制备方法中，优选地，所述酸包括有机酸和无机酸；
进一步优选地，所述无机酸包括以下中的任意一种：次碘酸、次氯酸、次溴酸、碘酸、高氯酸、过二硫酸、过二碳酸、过碳酸、焦磷酸、焦硫酸、焦亚硫酸、连四硫酸、磷酸、硫代硫酸、硫酸、氯酸、偏磷酸、氢碘酸、氢叠氮酸、氢氟酸、氢硫酸、氢氯酸、氢溴酸、四硼酸、碳酸、硝酸、溴酸、亚硫酸、亚磷酸、亚氯酸、盐酸、亚硝酸、原磷酸、原硫酸和原碳酸；
进一步优选地，所述有机酸包括以下中的任意一种：酒石酸、草酸、苹果酸、枸橼酸、抗坏血酸、苯甲酸、水杨酸、咖啡酸、乳酸、山梨酸、延胡索酸、甲酸、乙酸、苯甲酸、乙二酸、丁二酸、丙酮酸、α-酮丁二酸、苯磺酸、乙磺酸、树脂酸、三氟乙酸、马来酸、四磺酸、甲磺酸、富马酸和氨基酸。
优选地，所述有机溶剂包括以下中的任何一种或几种：醇、酮、醚、酯和卤代烷；
进一步优选地，所述醇包括以下中的任意一种或几种：甲醇、乙醇、异丙醇、异丁醇、叔丁醇；所述酮包括以下中的一种或几种：丙酮、2-丁酮；所述醚包括以下中的任意一种或几种：乙醚、二氧六环、异丙醚、甲基叔丁基醚、四氢呋喃；所述酯包括以下中的任意一种或几种：乙酸甲酯、乙酸乙酯和乙酸丁酯；所述卤代烃包括二氯甲烷、氯仿。
优选地，使用氯化氢溶液控制溶液的pH值；
进一步优选地，所述氯化氢溶液包括氯化氢的水溶液、氯化氢的甲醇溶液、氯化氢的乙醇溶液、氯化氢的异丙醇溶液、氯化氢的正丙醇溶液、氯化氢的异丁醇溶液、氯化氢的乙酸乙酯溶液、氯化氢的丙酮溶液、氯化氢的乙醚溶液、氯化氢的二氧六环溶液中的任意一种；
优选地，控制溶液的pH值为6.0～8.0；
优选地，所述反应在-30～60℃的温度下进行。
第四方面，本发明提供了如第一方面所述的蓝萼甲素衍生物或其盐在制备用于治疗自身免疫性疾病和/或治疗癌症的药物中的用途；
优选地，所述自身免疫性疾病为系统性红斑狼疮或银屑病；
优选地，所述癌症包括以下任意一种或几种：三阴乳腺癌、脑胶质瘤、宫颈癌、食管癌、肺癌、肝癌、绒毛膜癌、口腔表皮样癌、前列腺癌、直肠癌。
有益效果
相比于蓝萼甲素，本发明的蓝萼甲素衍生物抗自身免疫和抗肿瘤作用的针对性好，可以作为活性化合物，进一步开发新的化学治疗自身免疫性疾病和治疗癌症疾病的药物制剂。特别是，本发明的蓝萼甲素衍生物有望填补治疗系统性红斑狼疮、银屑病和三阴乳腺癌等疾病的药物空白。
附图说明
为了更清楚地说明本发明实施例中的技术方案，下面将对实施例描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为本发明的一种蓝萼甲素衍生物的1H NMR谱图。
图2为本发明的一种蓝萼甲素衍生物的13C NMR谱图。
图3为本发明的一种蓝萼甲素衍生物盐的LC-MS谱图。
图4为本发明的一种蓝萼甲素衍生物对五种细胞系增殖抑制的IC50(即半数有效抑制浓度)图。
图5为GLA对5种细胞系增殖抑制的IC50图。
图6为本发明的一种蓝萼甲素衍生物，GLA对各种细胞作用增殖抑制的IC50比较图。
图7为本发明的一种蓝萼甲素衍生物浓度和抑制率的XY散点图。
图8为GLA浓度和抑制率的XY散点图。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的 所有其他实施例，都属于本发明保护的范围。
实施例1
本实施例中公开了蓝萼甲素衍生物的制备方法，即蓝萼甲素经过修饰获得的蓝萼甲素氮代衍生物，然后蓝萼甲素氮代衍生物在与酸反应生成水溶性好的蓝萼甲素氮代衍生物盐。
其中，蓝萼甲素经过修饰获得的蓝萼甲素氮代衍生物反应式如下：
Figure PCTCN2015097692-appb-000004
以蓝萼甲素GLA为原料，催化剂用量为：催化剂与原料蓝萼甲素的摩尔比为1～10，温度控制范围为-30～60℃。
RH中的R为氮源供体，RH中的R和蓝萼甲素衍生物中的R的结构相同。R可以为以下基团中的任意一种：二甲基氨基、二乙基氨基、哌啶、哌嗪、环己亚胺、吗啉、N-甲基哌嗪、苯胺、甲基-苯胺、2-苄基胺、咪唑、2-甲基咪唑、4-苯基胺基丁酮、3-(苯基氨基)环己酮、对氯苯基氨基-丁酮、邻氯苯基氨基-丁酮、苄胺、嘌呤、2-氨基-6-羟基嘌呤、吡咯、2-羧基吡咯、2-羧基-4-氢-吡咯、3-甲基吡咯、3-氨基苯甲酰胺、对氨基苯甲酰胺和各种氨基酸。
获得的蓝萼甲素衍生物的结构式如下：
Figure PCTCN2015097692-appb-000005
上述结构式中的R的结构可以是表1中基团结构中的任意一种：
表1、R基团名称及其结构
Figure PCTCN2015097692-appb-000006
Figure PCTCN2015097692-appb-000007
上述的蓝萼甲素衍生物再与酸反应，生成水溶性好的蓝萼甲素衍生物盐，能与蓝萼甲素衍生物反应的酸的种类如表2中所示：
表2与蓝萼甲素衍生物反应的酸
Figure PCTCN2015097692-appb-000008
Figure PCTCN2015097692-appb-000009
实施例2
本实施例中公开了一种制备二甲氨基蓝萼甲素盐酸盐的方法，主要包括以下几步骤：
第一步、制备二甲氨基蓝萼甲素
1、将蓝萼甲素1.00g与有机溶剂20ml混合于室温下搅拌，直至蓝萼甲素完全溶解。
2、过滤后，在搅拌状态下逐滴加入33％的二甲胺溶液0.68ml，混合液室温搅拌1～2h，TLC监测。
3、反应完毕后，体系在40～50℃减压蒸馏，得二甲氨基蓝萼甲素粉末1.05g，二甲氨基蓝萼甲素的收率93.0％，HPLC纯度为99.2％。
第二步、制备二甲氨基蓝萼甲素盐酸盐
1、在冰浴条件下，将1.00g二甲氨基蓝萼甲素置于10ml有机溶剂中，充分搅拌至溶解。
2、过滤，控制温度0℃，向其中滴加氯化氢溶液，调pH值至7，搅拌30min，有 白色固体产生。
3、将沉淀过滤，得到类白色二甲氨基蓝萼甲素盐酸盐固体1.00g，收率92.0％，HPLC纯度为99.5％。
实际上，上述第一步和第二步中的有机溶剂可以是以下溶剂中的一种或几种：醇、酮、醚、酯和卤代烷。在本实施例中，第一步中的有机溶剂为甲醇，第二步中的有机溶剂为异丙醇。
在其它实施例中，上述醇可以是以下中的任意一种或者几种混合物：甲醇、乙醇、异丙醇、异丁醇和叔丁醇；上述酮为丙酮或2-丁酮；上述醚可以是以下中的任意一种或者几种混合物：乙醚、二氧六环、异丙醚、甲基叔丁基醚和四氢呋喃；上述酯可以是以下中的任意一种或者几种混合物：乙酸甲酯、乙酸乙酯和乙酸丁酯；上述卤代烃为二氯甲烷或氯仿。
上述第二步中的氯化氢溶液可以是以下中的任意一种：氯化氢水溶液、氯化氢甲醇溶液、氯化氢乙醇溶液、氯化氢异丙醇溶液、氯化氢正丙醇溶液、氯化氢异丁醇溶液、氯化氢乙酸乙酯溶液、氯化氢丙酮溶液、氯化氢乙醚溶液和氯化氢二氧六环溶液。
在本实施例中，上述氯化氢溶液优选氯化氢异丙醇溶液。
在本实施例中，使用核磁共振法，用氢谱对二甲氨基蓝萼甲素盐酸盐进行表征，其结果如图1-2所示。
由图1中可知，二甲氨基蓝萼甲素盐酸盐分子式：C22H36ClNO4·HCl，1H NMR(DMSO)δ：0.98(6H，d，2×CH3)，1.05(3H，m，CH3)，1.74(6H，m，2×CH3)，3.91(1H，s，C-H)，6.20(1H，s，C-H)，4.83(1H，s，C-H)，5.86(1H，s，C-H)，6.20(1H，s，C-H)，10.58(1H，s，O-H)。
由图2中可知，二甲氨基蓝萼甲素盐酸盐分子式：C22H36ClNO4·HCl，13C NMR(DMSO)δ：
Figure PCTCN2015097692-appb-000010
在本实施例中，对得到的二甲氨基蓝萼甲素盐酸盐进行LC-MS检测，其检测结果如图3所示。
通过图3中的图谱可知，二甲氨基蓝萼甲素盐酸盐分子式：C22H36ClNO4·HCl，MS m/e：378.6(M+)。
实施例3
实施例3中的各个步骤与实施例2中的一致，两个实施例的区别点在于，第二步中制备二甲氨基蓝萼甲素盐酸盐时控制的反应温度以及pH值不一样，在本实施例中，反应温度控制在-30℃，pH值调节到6。
实施例4
实施例4中的各个步骤与实施例2中的一致，两个实施例的区别点在于，第二步中制备二甲氨基蓝萼甲素盐酸盐时控制的反应温度以及pH值不一样，在本实施例中，反应温度控制在60℃，pH值调节到8。
实施例5
实施例5与实施例2的步骤区别为：第二步中制备二甲氨基蓝萼甲素盐酸盐时反应温度控制为-10℃，pH值调节到7。
实施例6
实施例6中与实施例2的区别：第二步中制备二甲氨基蓝萼甲素盐酸盐时反应温度控制为20℃，pH值调节到7。
上述实施例2-实施例6中，应用到的反应溶剂为实施例中所列举的有机溶剂，氯化氢溶液以氯化氢异丙醇溶液和氯化氢乙醇溶液最佳，并且第二步中反应温度在-10～20℃最佳，pH值调节到7为最佳。
在以下实施例中，对本发明获得的蓝萼甲素衍生物进行药效实验，通过实验可知，所述的蓝萼甲素衍生物可以应用于制备抗自身免疫性疾病和抗肿瘤药物中。例如抗以下癌症的药物：三阴乳腺癌、脑胶质瘤、宫颈癌、食管癌、肺癌、肝癌、绒毛膜癌、口腔表皮样癌、前列腺癌、直肠癌。尤其是三阴乳腺癌和脑胶质瘤，其抗癌针对性好，应用到治疗三阴乳腺癌的药物中，填补了三阴乳腺癌的药物空白。身免疫性疾病为系统性红斑狼疮、银屑病。
实施例7
细胞增殖实验(MTT)：
二甲氨基蓝萼甲素盐酸盐(以下称为GH02)和蓝萼甲素(即GLA)对肿瘤细胞系的细胞增殖抑制实验：调整肿瘤细胞系的细胞密度至104/100μl，每孔100μl种96孔板，培养过夜。待细胞完全贴壁，长至70-80％，用完全培养基稀释GH02和GLA母液(浓度都是100mM)，使其终浓度为1、3.125、6.25、12.5、25、50、100μmol/L，加至96孔板，每个浓度4个复孔，同时设立空白对照组(即无细胞组)，于37℃含5％CO2的培养箱中培养，48h后，每孔加入MTT至终浓度为0.5mg/ml，继续在37℃含5％CO2的培养箱中培养4h，弃去上清，每孔加入150μl DMSO，摇床10min，用酶标仪检测490nm处吸光值。
细胞增殖抑制率＝[(对照组吸光值-空白吸光值)-(加药组吸光值-空白吸光值)]/(对 照组吸光值-空白吸光值)％。
如图4-6所示，其中，MDA-MB-231、MCF-7是乳腺癌细胞系，SGC-7901是胃癌细胞系，U251是脑胶质瘤细胞系，A549是肺癌细胞系。
图4为GH02对上述的五种细胞系的IC50，从图中可以看出，GH02对MDA-MB-231乳腺癌细胞系的IC50最低，即GH02对乳腺癌的药效最好。
图5是GLA对上述五种细胞系的IC50，从图中可以看出，GLA对MDA-MB-231乳腺癌细胞系的IC50最低；并且通过图6的对比，GH02和GLA对乳腺癌的药效最好。
如图7所示，随着GH02浓度的增大，GH02对上述五种细胞系的抑制作用均提高，即能够抑制肿瘤细胞增殖。
如图8所示，随着GLA浓度的增大，GH02对上述五种细胞系的抑制作用均提高，即能够抑制肿瘤细胞增殖。
并且从图7和图8中可知，GH02和GLA对MDA-MB-231乳腺癌细胞系的IC50最低，并且对MDA-MB-231乳腺癌细胞系的抑制率最高，因此，本发明的蓝萼甲素衍生物对乳腺癌的抑制效果最好。
对所公开的实施例的上述说明，使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下，在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。

Claims (10)

  1. 如式(I)所示的蓝萼甲素衍生物或其盐：
    Figure PCTCN2015097692-appb-100001
    其中，R为以下基团中的任何一种：二甲基氨基、二乙基氨基、哌啶、哌嗪、环己亚胺、吗啉、N-甲基哌嗪、甲基苯胺、二苄基胺、咪唑、2-甲基咪唑、4-苯基胺基丁酮、3-(苯基氨基)环己酮、对氯苯基氨基-丁酮、邻氯苯基氨基-丁酮、苄胺、嘌呤、2-氨基-6-羟基嘌呤、吡咯、吡咯-2-羧酸、2-甲基吡咯烷、3-甲基吡咯、2-吡咯烷酮、3-氨基苯甲酰胺、对氨基苯甲酰胺和氨基酸。
  2. 如权利要求1所述的蓝萼甲素衍生物的制备方法，其包括：使蓝萼甲素与R基团的供体化合物在催化剂的作用下发生加成反应而得。
  3. 如权利要求2所述的制备方法，其特征在于，所述催化剂为甲醇钠、乙醇钠、吡啶、碳酸钠、碳酸钾中的任何一种或几种。
  4. 如权利要求2或3所述的制备方法，其特征在于，R基团与蓝萼甲素的摩尔数之比为(1～10)∶1；
    优选地，所述催化剂与蓝萼甲素的摩尔数之比为(1～10)∶1。
  5. 如权利要求2-4任一项所述的制备方法，其特征在于，所述反应在-30～60℃下进行；
    优选地，所述反应在溶剂中进行；
    进一步优选地，所述溶剂包括以下中的任何一种或几种：醇、酮、醚、酯和卤代烷；更进一步优选地，所述醇包括以下中的任意一种或几种：甲醇、乙醇、异丙醇、异丁醇、叔丁醇；所述酮包括以下中的一种或几种：丙酮、2-丁酮；所述醚包括以下中的任意一种或几种：乙醚、二氧六环、异丙醚、甲基叔丁基醚、四氢呋喃；所述酯包括以下中的任意一种或几种：乙酸甲酯、乙酸乙酯和乙酸丁酯；所述卤代烃包括二氯甲烷、氯仿；
    进一步优选地，所述制备方法还包括在反应后蒸干溶剂和/或用TLC和/或HPLC检测的步骤。
  6. 如权利要求1所述的蓝萼甲素衍生物的盐的制备方法，其包括：
    将所述蓝萼甲素衍生物溶于有机溶剂中形成溶液，所得溶液与酸进行成盐反应，控制溶液pH值，得到蓝萼甲素衍生物盐。
  7. 如权利要求6所述的制备方法，其特征在于：所述酸包括有机酸和无机酸；
    优选地，所述无机酸包括以下中的任意一种：次碘酸、次氯酸、次溴酸、碘酸、高氯酸、过二硫酸、过二碳酸、过碳酸、焦磷酸、焦硫酸、焦亚硫酸、连四硫酸、磷酸、硫代硫酸、硫酸、氯酸、偏磷酸、氢碘酸、氢叠氮酸、氢氟酸、氢硫酸、氢氯酸、氢溴酸、四硼酸、碳酸、硝酸、溴酸、亚硫酸、亚磷酸、亚氯酸、盐酸、亚硝酸、原磷酸、原硫酸和原碳酸；
    优选地，所述有机酸包括以下中的任意一种：酒石酸、草酸、苹果酸、枸橼酸、抗坏血酸、苯甲酸、水杨酸、咖啡酸、乳酸、山梨酸、延胡索酸、甲酸、乙酸、苯甲酸、乙二酸、丁二酸、丙酮酸、α-酮丁二酸、苯磺酸、乙磺酸、树脂酸、三氟乙酸、马来酸、四磺酸、甲磺酸、富马酸和氨基酸。
  8. 如权利要求6或7所述的制备方法，其特征在于，所述有机溶剂包括以下中的任何一种或几种：醇、酮、醚、酯和卤代烷；
    优选地，所述醇包括以下中的任意一种或几种：甲醇、乙醇、异丙醇、异丁醇、叔丁醇；所述酮包括以下中的一种或几种：丙酮、2-丁酮；所述醚包括以下中的任意一种或几种：乙醚、二氧六环、异丙醚、甲基叔丁基醚、四氢呋喃；所述酯包括以下中的任意一种或几种：乙酸甲酯、乙酸乙酯和乙酸丁酯；所述卤代烃包括二氯甲烷、氯仿。
  9. 如权利要求6-8任一项所述的制备方法，其特征在于，使用氯化氢溶液控制溶液的pH值；
    优选地，所述氯化氢溶液包括氯化氢的水溶液、氯化氢的甲醇溶液、氯化氢的乙醇溶液、氯化氢的异丙醇溶液、氯化氢的正丙醇溶液、氯化氢的异丁醇溶液、氯化氢的乙酸乙酯溶液、氯化氢的丙酮溶液、氯化氢的乙醚溶液、氯化氢的二氧六环溶液中的任意一种；
    优选地，控制溶液的pH值为6.0～8.0；
    优选地，所述反应在-30～60℃的温度下进行。
  10. 如权利要求1所述的蓝萼甲素衍生物或其盐在制备用于治疗自身免疫性疾病和/或治疗癌症的药物中的用途；
    优选地，所述自身免疫性疾病为系统性红斑狼疮或银屑病；
    优选地，所述癌症包括以下任意一种或几种：三阴乳腺癌、脑胶质瘤、宫颈癌、食管癌、肺癌、肝癌、绒毛膜癌、口腔表皮样癌、前列腺癌、直肠癌。
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