CN104761460B - Glaucocalyxin A derivative and preparation method and application thereof - Google Patents
Glaucocalyxin A derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to a glaucocalyxin A derivative, a salt thereof obtained by acidifying the glaucocalyxin A derivative and a synthesis method thereof. The modified glaucocalyxin A derivative salt can be used for preparing a medicinal preparation, and can better play the treatment effect on tumors and autoimmune diseases.
Description
Technical field
The invention belongs to chemical medicine, more particularly to glaucocalyxin A, the system of glaucocalyxin A derivative is specifically related to
Preparation Method and application.
Background technology
Glaucocalyxin A, also known as common rabdosia leaf B prime, are from labiate rabdosia japonica Rabdosia japonica
(Burm.f.) extract what is obtained in the ground herb of Hara var.glaucocalyx (Maxim.) Hara.Glaucocalyxin A
(GlaucocalyxinA, structural formula as shown in formula I, hereinafter referred to as GLA), chemical entitled Kaur-16-ene-3,15-dione,
(7 α, 14R)-, molecular formula：C20H28O4, molecular weight 332.43.
Glaucocalyxin A rabdosia japonica dry leaf in the content [such as first bucket, Sha Dongxu, Sha Ming that is up to 1.03%
CHINA JOURNAL OF CHINESE MATERIA MEDICA, 1991,16 (11)：679].Its structure is similar with Oridonin, belongs to ent-kaurane diterpenoids,
And also there is the antitumor pharmacophoric group α, β-unsaturation ring pentanone construction unit of similar Oridonin in structure.Inside and outside resists
Tumor experiment shows that it is to the strain of various people's cancer cells (CE-1, U87, A549, MCF-7, Hela, K562, HepG2, NCI-
H460, KB, JEG-3, K562, HL-60 etc. are acted on significant Inhibit proliferaton, especially to non-hormone dependence prostate cancer
(DU-145), the carcinoma of the rectum (Lovo) cell is most sensitive, and antitumor spectra is wide；Lewis lung cancer, S180 solid types and HCA can be suppressed
The growth of the solid tumors such as solid type, hence it is evident that increase the increase in life span of lotus ascitic type S180 ascitic types and lotus HCA ascitic type mouse,
Its is antineoplastic strong and weak in dose-dependence.Current paper [Li WenGao, Jian Zhang, Wen Hua in 2011
Yang, Bin Wang, JianWenWang.Toxicology in Vitro 2011,25：51-63] report glaucocalyxin A lead to
Cross mitochondria-regulation apoptotic pathway apoptosis-induced, suppress people in loop propagation, be a kind of very promising have
The lead compound of antitumor activity.
In addition, used as a kind of anti-autoimmune disease medicine, glaucocalyxin A is in systemic loupus erythematosus and psoriasis etc.
Also made a breakthrough in the treatment of illness, obtain good curative effect.Document medicine Rabdosia amethystoides progress [Su Yu, Cui Jia,
Apply business business etc. Asia-Pacific traditional medicine, 2011,06] in point out, the glaucocalyxin A obtained from Rabdosia amethystoides except anticancer, antibacterial,
Liver protection and cardiovascular effect, the active effect also in terms of autoimmunity depression.
But, glaucocalyxin A polarity is small, and poorly water-soluble is not suitable for directly as drug administration；It is external to resist with stronger
Autoimmunity and antitumor action, but the heavy dose of long-time of needs could produce drug effect in vivo.Medicine is eliminated soon, partly decline in vivo
Phase is short, bioavilability is low, can not still be used directly as medicine.Therefore pharmacophoric group α is being retained, β-unsaturation ring pentanone
Under the premise of, structural modification is carried out to its exocyclic double bond, synthesize anti-autoimmunity and the stronger derivative of antitumor drug effect, it is one
Solve the effective way of its defect existed as medicine.
The research of this seminar finds derivative --- dimethylamino glaucocalyxin A hydrochloride (the structural formula such as formula of glaucocalyxin A
II), with the anti-autoimmunity and antitumor tumor activity suitable with glaucocalyxin A, and its good water solubility, therefore, with diformazan ammonia
Base glaucocalyxin A hydrochloride is reactive compound, is developed further into the anti-autoimmunity of new chemotherapy and antineoplastic
Preparation.
Therefore, the research direction now for glaucocalyxin A turns to the diformazan for obtaining good water solubility as raw material with glaucocalyxin A
Amino glaucocalyxin A hydrochloride (hereinafter referred to as GH02).
The content of the invention
In order to solve the above technical problems, the present invention is with glaucocalyxin A as raw material, glaucocalyxin A derivative is obtained by modification,
The salt of good water solubility is obtained with acid reaction again, the specific aim of its anti-autoimmunity of tool and antitumor action is good, is expected to fill up system
Property lupus erythematosus, psoriasis and three cloudy breast cancer medicine blank.
To reach above-mentioned purpose, technical scheme is as follows：
A kind of glaucocalyxin A derivative, structural formula is (I),
Wherein, R can be any one of following group：Dimethylamino, diethylamino, piperidines, piperazine, hexamethylene
Imines, morpholine, N methyl piperazine, methylaniline, dibenzyl amine, imidazoles, 2-methylimidazole, 4- phenyl amidos butanone, 3- (phenyl
Amino) cyclohexanone, rubigan amino-butanone, Chloro-O-Phenyl amino-butanone, benzylamine, purine, 2- amino-hypoxanthine,
Pyrroles, pyrroles -2- carboxylic acids, 2- crassitudes, 3- methylpyrroles, 2-Pyrrolidone, 3-AB, p-aminophenyl first
Acid amides, amino acid.
In a preferred embodiment of the invention, further include, it is a kind of by above-described glaucocalyxin A derivative
The preparation method of its salt is obtained after acidified, glaucocalyxin A derivative is dissolved in organic solvent and is formed solution, then entered with acid
Row salt-forming reaction, controls solution ph, obtains glaucocalyxin A derivative salt, and described acid includes organic acid and inorganic acid, described
Inorganic acid includes any one in following acid：Hypoiodous acid, hypochlorous acid, hypobromous acid, acid iodide, perchloric acid, excessively peroxy-disulfuric acid, two carbon
Acid, percarbonic acid, pyrophosphoric acid, pyrosulfuric acid, pyrosulfurous acid, tetrathionic acid, phosphoric acid, thiosulfuric acid, sulfuric acid, chloric acid, metaphosphoric acid, hydrogen iodine
Acid, hydronitric acid, hydrofluoric acid, hydrosulphuric acid, hydrochloric acid, hydrobromic acid, tetraboric acid, carbonic acid, nitric acid, bromic acid, sulfurous acid, phosphorous acid,
Chlorous acid, hydrochloric acid, nitrous acid, former phosphoric acid, ortho-sulfuric acid, orthocarbonic acid；The organic acid includes any one in following acid：Winestone
Acid, oxalic acid, malic acid, citric acid, ascorbic acid, benzoic acid, salicylic acid, caffeic acid, lactic acid, sorbic acid, fumaric acid, first
Acid, acetic acid, benzoic acid, ethanedioic acid, succinic acid, pyruvic acid, α -one succinic acid, benzene sulfonic acid, ethyl sulfonic acid, resin acid, trifluoroacetic acid,
Maleic acid, tetrasulfonic acid, methanesulfonic acid, fumaric acid, amino acid.
In a preferred embodiment of the invention, further include, above-described glaucocalyxin A derivative and its salt
Application in medicine, the application of the glaucocalyxin A derivative and its salt in antineoplastic, the tumour includes following
Any one or a few：Three cloudy breast cancer, glioma, cervical carcinoma, the cancer of the esophagus, lung cancer, liver cancer, choriocarcinoma, oral cavity epidermis
Sample cancer, prostate cancer, the carcinoma of the rectum；The application of the glaucocalyxin A derivative and its salt in autoimmune disease medicine, institute
Autoimmune disease is stated for systemic loupus erythematosus, psoriasis.
In a preferred embodiment of the invention, further include, prepare above-described glaucocalyxin A derivative
Method is comprised the following steps：
(1) glaucocalyxin A and R are weighed, the wherein molal quantity of R is at least a times of glaucocalyxin A, separately weighs catalyst and fit
Amount, three's mixing, is dissolved in appropriate solvent, stirring reaction；
(2) reacted solvent system solvent evaporated, TLC, HPLC detection, obtains final product.
In a preferred embodiment of the invention, further include, the catalyst be sodium methoxide, caustic alcohol, pyridine,
Any one of sodium carbonate, potassium carbonate.
In a preferred embodiment of the invention, further include, the ratio between the molal quantity of R and the molal quantity of glaucocalyxin A
It is 1~10：1, the ratio between molal quantity of the catalyst and glaucocalyxin A is 1~10, and its reaction temperature is -30~60 DEG C.
In a preferred embodiment of the invention, further include, the solvent include it is following in one or more：
Alcohol, ketone, ether, ester and alkyl halide；The alcohol include it is following in one or more：Methyl alcohol, ethanol, isopropanol, isobutanol, tertiary fourth
Alcohol；The ketone include it is following in one or more：Acetone, 2- butanone；The ether include it is following in one or more：Second
Ether, dioxane, isopropyl ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran；The ester include it is following in one or more：Acetic acid first
Ester, ethyl acetate and butyl acetate；The halogenated hydrocarbons includes dichloromethane, chloroform.
In a preferred embodiment of the invention, further include, the hydrogen chloride solution includes the water-soluble of hydrogen chloride
Liquid, methanol solution, ethanol solution, aqueous isopropanol, normal propyl alcohol solution, isobutanol solution, ethyl acetate solution, acetone soln,
Any one in diethyl ether solution, hydrogen dioxane solution, the pH value of the solution is 6.0~8.0, the temperature is -30~
60℃。
In a preferred embodiment of the invention, further include, dissolving glaucocalyxin A and its derivative it is organic molten
Agent include it is following in one or more：Alcohol, ketone, ether, ester and alkyl halide；The alcohol include it is following in one or more：First
Alcohol, ethanol, isopropanol, isobutanol, the tert-butyl alcohol；The ketone include it is following in one or more：Acetone, 2- butanone；The ether
Including one or more in following：Ether, dioxane, isopropyl ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran；The ester includes
One or more in below：Methyl acetate, ethyl acetate and butyl acetate；The halogenated hydrocarbons includes dichloromethane, chloroform.
The beneficial effects of the invention are as follows:
The glaucocalyxin A derivative salt that one, the present invention are obtained have it is water-soluble well, in applying it to medicine, mouth
Take bioavilability good.
Secondly, the specific aim of glaucocalyxin A derivative of the invention and its anti-autoimmunity of salt and antitumor action it is good, have
The medicine blank of systemic loupus erythematosus, psoriasis and three cloudy breast cancer is filled up in prestige.
Thirdly, the process is simple for preparing glaucocalyxin A derivative and its salt of the invention, raw material is easy to get, purity is high, cost
It is low, it is adapted to industrialized production.
Brief description of the drawings
Technical scheme in technology in order to illustrate more clearly the embodiments of the present invention, in being described to embodiment technology below
The required accompanying drawing for using is briefly described, it should be apparent that, drawings in the following description are only some realities of the invention
Example is applied, for those of ordinary skill in the art, on the premise of not paying creative work, can also be according to these accompanying drawings
Obtain other accompanying drawings.
Fig. 1 is glaucocalyxin A derivative of the invention1H NMR spectras.
Fig. 2 is glaucocalyxin A derivative of the invention13C NMR spectras.
Fig. 3 is the LC-MS spectrograms of glaucocalyxin A derivative of the present invention.
Fig. 4 is the LC-MS spectrograms of glaucocalyxin A derivative of the present invention.
Fig. 5 is GH02 of the invention to five kinds of IC of cell line50Figure.
Fig. 6 is GLA to 5 kinds of IC50 figures of cell line.
Fig. 7 is GH02, and GLA compares figure to the IC50 mono- of each cytosis.
Fig. 8 is the XY scatter diagrams of GH02 concentration and inhibiting rate.
Fig. 9 is the XY scatter diagrams of GLA concentration and inhibiting rate.
Specific embodiment
Below in conjunction with the accompanying drawing in the embodiment of the present invention, the technical scheme in the embodiment of the present invention is carried out clear, complete
Site preparation is described, it is clear that described embodiment is only a part of embodiment of the invention, rather than whole embodiments.It is based on
Embodiment in the present invention, it is every other that those of ordinary skill in the art are obtained under the premise of creative work is not made
Embodiment, belongs to the scope of protection of the invention.
Embodiment 1
Glaucocalyxin A derivative and preparation method thereof is disclosed in the present embodiment, is the indigo plant that glaucocalyxin A is obtained by modification
Calyx A prime nitrogen spreads out for derivative for derivative, then glaucocalyxin A nitrogen in the glaucocalyxin A nitrogen generation with acid reaction generation good water solubility
Biogenic salt.
Wherein, glaucocalyxin A is as follows for derivatives reaction formula by the glaucocalyxin A nitrogen of modification acquisition：
With glaucocalyxin A GLA as raw material, catalyst amount is：Catalyst is 1~10 with the mol ratio of raw material glaucocalyxin A,
Temperature controlling range is -30~60 DEG C.
R in RH is nitrogen source donor, and the R in RH is identical with the structure of the R in glaucocalyxin A derivative.R can following base
Any one in group：Dimethylamino, diethylamino, piperidines, piperazine, cycloheximide, morpholine, N methyl piperazine, methyl
Aniline, dibenzyl amine, imidazoles, 2-methylimidazole, 4- phenyl amidos butanone, 3- (phenyl amino) cyclohexanone, rubigan amino-
Butanone, Chloro-O-Phenyl amino-butanone, benzylamine, purine, 2- amino-hypoxanthine, pyrroles, pyrroles -2- carboxylic acids, 2- methyl pyrroles
Cough up alkane, 3- methylpyrroles, 2-Pyrrolidone, 3-AB, Para Amino Benzamide, amino acid.
The structural formula of the glaucocalyxin A derivative of acquisition is as follows：
The structure of the R in structure above can be any one in unit structure in table 1：
The R group title of table 1 and its structure
Above-mentioned glaucocalyxin A derivative again with acid reaction, generate good water solubility glaucocalyxin A derivative salt, can be with indigo plant
The sour species of calyx A prime derivatives reaction is as shown in table 2：
The acid of table 2 and glaucocalyxin A derivatives reaction
Embodiment 2
In embodiment 2 as a example by preparing dimethylamino glaucocalyxin A hydrochloride.
The first step：Prepare dimethylamino glaucocalyxin A
1st, glaucocalyxin A 1.00g is mixed with organic solvent 20ml and is stirred at room temperature, until glaucocalyxin A is completely dissolved.
2nd, after filtering, it is added dropwise over 33% dimethylamine solution 0.68ml under stirring, mixed liquor is stirred at room temperature 1~
2h, TLC are monitored.
3rd, after completion of the reaction, system obtains dimethylamino glaucocalyxin A powder 1.05g, diformazan in 40~50 DEG C of vacuum distillations
The yield 93.0% of amino glaucocalyxin A, HPLC purity is 99.2%.
Second step：Prepare dimethylamino glaucocalyxin A hydrochloride
1st, under condition of ice bath, 1.00g dimethylamino glaucocalyxin As are placed in 10ml organic solvents, are stirred well to molten
Solution.
2nd, filter, control 0 DEG C of temperature, hydrogen chloride solution is added dropwise thereto, adjust pH value to 7, stir 30min, have white solid
Body is produced.
3rd, will precipitation filtering, obtain off-white color dimethylamino glaucocalyxin A HCl, solid 1.00g, yield 92.0%,
HPLC purity is 99.5%.
In fact, the organic solvent in the above-mentioned first step and second step can be one or more in following solvent：Alcohol,
Ketone, ether, ester and alkyl halide.In the present embodiment, the organic solvent in the first step is methyl alcohol, and the organic solvent in second step is different
Propyl alcohol.
In other embodiments, above-mentioned alcohol can be it is following in any one or several mixtures：Methyl alcohol, ethanol,
Isopropanol, isobutanol and the tert-butyl alcohol；Above-mentioned ketone is acetone or 2- butanone；Above-mentioned ether can be it is following in any one or it is several
Plant mixture：Ether, dioxane, isopropyl ether, methyl tertiary butyl ether(MTBE) and tetrahydrofuran；Above-mentioned ester can be it is following in it is any
One or several mixtures：Methyl acetate, ethyl acetate and butyl acetate；Above-mentioned halogenated hydrocarbons is dichloromethane or chloroform.
Hydrogen chloride solution in above-mentioned second step can be it is following in any one：Hydrochloride aqueous solution, hydrogen chloride first
Alcoholic solution, ethanol solution of hydrogen chloride, isopropanol solution of hydrogen chloride, hydrogen chloride normal propyl alcohol solution, hydrogen chloride isobutanol solution, chlorination
Hydroacetic acid ethyl ester solution, hydrogen chloride acetone soln, ether solution of hydrogen chloride and hydrogen chloride dioxane solution.
In the present embodiment, the preferred isopropanol solution of hydrogen chloride of above-mentioned hydrogen chloride solution.
In the present embodiment, using nuclear magnetic resonance method, composed with hydrogen and dimethylamino glaucocalyxin A hydrochloride is characterized, its
Result is as shown in Figure 1-2.
From in Fig. 1, dimethylamino glaucocalyxin A hydrochloride molecular formula：C22H36ClNO4HCl,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).
From in Fig. 2, dimethylamino glaucocalyxin A hydrochloride molecular formula：C22H36ClNO4HCl,13C NMR(DMSO)
δ:
In the present embodiment, LC-MS detections are carried out to the dimethylamino glaucocalyxin A hydrochloride for obtaining, its testing result is such as
Shown in Fig. 3-4.
By the collection of illustrative plates in Fig. 3-4, dimethylamino glaucocalyxin A hydrochloride GLA-DMA molecular formula：C22H35NO4, MS
m/e:378.6(M+)。
Embodiment 3
Each step in embodiment 3 with it is consistent in embodiment 2, the distinctive points of two embodiments are, in second step
Prepare the reaction temperature that is controlled during dimethylamino glaucocalyxin A hydrochloride and pH value is different, in the present embodiment, reaction temperature
Degree control is in -30 DEG C, pH value regulation to 6.
Embodiment 4
Each step in embodiment 4 with it is consistent in embodiment 2, the distinctive points of two embodiments are, in second step
Prepare the reaction temperature that is controlled during dimethylamino glaucocalyxin A hydrochloride and pH value is different, in the present embodiment, reaction temperature
Degree control is in 60 DEG C, pH value regulation to 8.
Embodiment 5
In embodiment 5 with embodiment 2 in be distinguished as：Reacted when dimethylamino glaucocalyxin A hydrochloride is prepared in second step
Temperature control is -10 DEG C, pH value regulation to 7.
Embodiment 6
With the difference of embodiment 2 in embodiment 6：Reaction temperature when dimethylamino glaucocalyxin A hydrochloride is prepared in second step
It is controlled to 20 DEG C, pH value regulation to 7.
Wherein in above-described embodiment 2- embodiments 6, the reaction dissolvent being applied to is organic solvent cited in embodiment,
Hydrogen chloride solution is optimal with isopropanol solution of hydrogen chloride and ethanol solution of hydrogen chloride, and in second step reaction temperature -10~
20 DEG C optimal, and it is optimal that pH value is adjusted to 7.
In the present embodiment, effect experiment is carried out to the glaucocalyxin A derivative that the present invention is obtained, by experiment, institute
The glaucocalyxin A derivative stated can apply to prepare in anti-autoimmune disease and antineoplastic.For example resist following cancer
Medicine：Three cloudy breast cancer, glioma, cervical carcinoma, the cancer of the esophagus, lung cancer, liver cancer, choriocarcinoma, oral cavity epidermoid carcinoma, prostatitis
Gland cancer, the carcinoma of the rectum.Especially three cloudy breast cancer and glioma, its anticancer specific aim are good, are applied to the cloudy breast cancer for the treatment of three
In medicine, the medicine blank of three cloudy breast cancer has been filled up.Body immunity disease is systemic loupus erythematosus, psoriasis.
Cell proliferation experiment (MTT)：
Cell growth inhibition assays of the GH02 and GLA (glaucocalyxin A) to tumor cell line：Adjust the thin of tumor cell line
Born of the same parents' density to 104/100ul, per the orifice plate of hole 100ul kind 96, overnight incubation.Treat that cell is completely adherent, it is long to 70-80%, it is finished
Full culture medium dilutes GH02 and GLA mother liquors (concentration is all 100mM), make its final concentration of 1,3.125,6.25,12.5,25,50,
100umol/L, adds to 96 orifice plates, 4 multiple holes of each concentration, while setting up blank control group (i.e. acellular group), contains in 37 DEG C
Cultivated in the incubator of 5%CO2, after 48h, MTT to final concentration of 0.5mg/ml is added per hole, continue to contain 5%CO2's at 37 DEG C
4h is cultivated in incubator, supernatant discarded adds 150ul DMSO, shaking table 10min per hole, extinction at 490nm is detected with ELIASA
Value.
Cell proliferation inhibition rate=[(control group light absorption value-blank absorbency)-(dosing group light absorption value-Blank absorbance
Value)]/(control group light absorption value-blank absorbency) %.
As illustrated in figs. 5-7, wherein, MDA-MB-231, MCF-7 are breast cancer cell lines, and SGC-7901 is gastric carcinoma cell lines,
U251 is brain glioblastoma cell system, and A549 is lung cancer cell line.
Fig. 5 be GH02 to five kinds of above-mentioned IC50 of cell line, it can be seen that GH02 is to MDA-MB-231 mammary gland
The IC50 of cancerous cell line is minimum, i.e. GH02 is best to the drug effect of breast cancer.
Fig. 6 is IC50s of the GLA to above-mentioned five kinds of cell line, it can be seen that GLA is thin to MDA-MB-231 breast cancer
The IC50 of born of the same parents system is minimum；And the contrast for passing through Fig. 7, GH02 and GLA are best to the drug effect of breast cancer.
As shown in figure 8, with the increase of GH02 concentration, GH02 is improved to the inhibition of above-mentioned five kinds of cell lines, can
Enough suppress cell propagation.
As shown in figure 9, with the increase of GLA concentration, GH02 is improved to the inhibition of above-mentioned five kinds of cell lines, i.e., can
Suppress cell propagation.
And knowable to from Fig. 8 and Fig. 9, GH02 and GLA is minimum to the IC50 of MDA-MB-231 breast cancer cell lines, and
To the inhibiting rate highest of MDA-MB-231 breast cancer cell lines, therefore, suppression of the glaucocalyxin A derivative of the invention to breast cancer
Effect processed is best.
The foregoing description of the disclosed embodiments, enables professional and technical personnel in the field to realize or uses the present invention.
Various modifications to these embodiments will be apparent for those skilled in the art, as defined herein
General Principle can be realized in other embodiments without departing from the spirit or scope of the present invention.Therefore, the present invention
The embodiments shown herein is not intended to be limited to, and is to fit to and principles disclosed herein and features of novelty phase one
The scope most wide for causing.
Claims (9)
1. a kind of glaucocalyxin A derivative, it is characterised in that structural formula is (I),
Wherein, R is dimethylamino or diethylamino；
The method for preparing the glaucocalyxin A derivative is comprised the following steps：
1) glaucocalyxin A and dimethylamine or diethylamine are weighed, the molal quantity of wherein dimethylamine or diethylamine is at least glaucocalyxin A
One times, separately weigh catalyst in right amount, three's mixing is dissolved in appropriate solvent, stirring reaction；
(2) reacted solvent system solvent evaporated, TLC, HPLC detection, obtains final product.
2. a kind of glaucocalyxin A derivative according to claim 1, it is characterised in that the catalyst is sodium methoxide, second
Any one of sodium alkoxide, pyridine, sodium carbonate, potassium carbonate.
3. a kind of glaucocalyxin A derivative according to claim 1, it is characterised in that the molal quantity of dimethylamine or diethylamine
It is 1~10 with the ratio between the molal quantity of glaucocalyxin A：1, the ratio between molal quantity of the catalyst and glaucocalyxin A is 1~10, and its is anti-
It is -30~60 DEG C to answer temperature.
4. a kind of glaucocalyxin A derivative according to claim 1, it is characterised in that the solvent include it is following in one
Plant or several：Methyl alcohol, ethanol, isopropanol, isobutanol, the tert-butyl alcohol, acetone, 2- butanone, ether, dioxane, isopropyl ether, methyl
Tertbutyl ether, tetrahydrofuran, methyl acetate, ethyl acetate, butyl acetate, dichloromethane, chloroform.
5. a kind of preparation method that glaucocalyxin A derivative described in claim 1 is obtained its salt after acidified, its feature exists
In, glaucocalyxin A derivative is dissolved in solution is formed in organic solvent, salt-forming reaction is then carried out with acid, solution ph is controlled,
Glaucocalyxin A derivative salt is obtained, described acid includes any one in following acid：Hypoiodous acid, hypochlorous acid, hypobromous acid, iodine
Acid, perchloric acid, peroxy-disulfuric acid, cross two carbonic acid, percarbonic acid, pyrophosphoric acid, pyrosulfuric acid, pyrosulfurous acid, tetrathionic acid, phosphoric acid, thio
Sulfuric acid, sulfuric acid, chloric acid, metaphosphoric acid, hydroiodic acid, hydronitric acid, hydrofluoric acid, hydrosulphuric acid, hydrochloric acid, hydrobromic acid, tetraboric acid, carbon
Acid, nitric acid, bromic acid, sulfurous acid, phosphorous acid, chlorous acid, hydrochloric acid, nitrous acid, former phosphoric acid, ortho-sulfuric acid, orthocarbonic acid；Tartaric acid, grass
Acid, malic acid, citric acid, ascorbic acid, benzoic acid, salicylic acid, caffeic acid, lactic acid, sorbic acid, fumaric acid, formic acid, second
Acid, benzoic acid, ethanedioic acid, succinic acid, pyruvic acid, α -one succinic acid, benzene sulfonic acid, ethyl sulfonic acid, resin acid, trifluoroacetic acid, Malaysia
Acid, tetrasulfonic acid, methanesulfonic acid, fumaric acid, amino acid.
6. application of the glaucocalyxin A derivative salt in pharmacy, it is by the glaucocalyxin A derivative described in claim 5 through acid
The preparation method that its salt is obtained after change is obtained, it is characterised in that the glaucocalyxin A derivative salt answering in antineoplastic
With application of the glaucocalyxin A derivative salt in autoimmune disease medicine.
7. application of the glaucocalyxin A derivative salt according to claim 6 in pharmacy, it is characterised in that the tumour bag
Include it is following any one or a few：Three cloudy breast cancer, glioma, cervical carcinoma, the cancer of the esophagus, lung cancer, liver cancer, choriocarcinoma, mouth
Chamber epidermoid carcinoma, prostate cancer, the carcinoma of the rectum；The autoimmune disease is systemic loupus erythematosus, psoriasis.
8. the preparation method that the glaucocalyxin A derivative is obtained its salt after acidified according to claim 5, it is special
Levy and be, the hydrochloric acid is hydrogen chloride solution, the aqueous solution of the hydrogen chloride solution including hydrogen chloride, methanol solution, ethanol are molten
Liquid, aqueous isopropanol, normal propyl alcohol solution, isobutanol solution, ethyl acetate solution, acetone soln, diethyl ether solution, dioxane are molten
Any one in liquid, the pH value of the solution is 6.0~8.0, and the temperature is -30~60 DEG C.
9. the preparation method that the glaucocalyxin A derivative is obtained its salt after acidified according to claim 8, it is special
Levy and be, dissolve glaucocalyxin A derivative organic solvent include it is following in one or more：It is methyl alcohol, ethanol, isopropanol, different
Butanol, the tert-butyl alcohol, acetone, 2- butanone, ether, dioxane, isopropyl ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, methyl acetate,
Ethyl acetate, butyl acetate, dichloromethane, chloroform.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510138029.0A CN104761460B (en) | 2015-03-26 | 2015-03-26 | Glaucocalyxin A derivative and preparation method and application thereof |
| JP2017550599A JP6694894B2 (en) | 2015-03-26 | 2015-12-17 | Glococalixin A derivative, its preparation method and application |
| PCT/CN2015/097693 WO2016150208A1 (en) | 2015-03-26 | 2015-12-17 | Pharmaceutical composition and dosage form containing glaucocalyxin a derivative or salt thereof |
| US15/561,685 US10196344B2 (en) | 2015-03-26 | 2015-12-17 | Glaucocalyxin a derivative and preparation method and application thereof |
| EP15886129.4A EP3275859B1 (en) | 2015-03-26 | 2015-12-17 | Glaucocalyxin a derivative and preparation method and application thereof |
| PCT/CN2015/097692 WO2016150207A1 (en) | 2015-03-26 | 2015-12-17 | Glaucocalyxin a derivative and preparation method and application thereof |
| PCT/CN2015/097691 WO2016150206A1 (en) | 2015-03-26 | 2015-12-17 | Dimethylamino glaucocalyxin a hydrochloride salt and crystalline form thereof |
Applications Claiming Priority (1)
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| WO2016150208A1 (en) * | 2015-03-26 | 2016-09-29 | 苏州沪云肿瘤研究中心股份有限公司 | Pharmaceutical composition and dosage form containing glaucocalyxin a derivative or salt thereof |
| US11406622B2 (en) | 2017-02-23 | 2022-08-09 | Suzhou Pharmavan Co., Ltd. | Glaucocalyxin a derivative, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof and uses thereof in preparation of drugs for treating psoriasis |
| CN109651331A (en) * | 2019-01-02 | 2019-04-19 | 中国人民解放军军事科学院军事医学研究院 | A kind of glaucocalyxin A derivative and its preparation method and application |
| CN114191423B (en) * | 2020-09-17 | 2023-03-14 | 苏州沪云新药研发股份有限公司 | Application of small-molecule diterpene compound or salt thereof in preparation of medicine for preventing and treating acute lung injury |
| CN116966179A (en) * | 2022-04-22 | 2023-10-31 | 苏州沪云新药研发股份有限公司 | Application of diterpenoid derivative or salt thereof in preparation of medicine for preventing and treating atopic dermatitis |
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| CN1158566A (en) * | 1994-06-20 | 1997-09-03 | 库特·伯格 | Pharmaceutical compsn. for the prevention and/or treatment of viral infections and optionally inflammations as well as a method for treatment thereof |
| WO2006133395A2 (en) * | 2005-06-08 | 2006-12-14 | Regents Of The University Of Minnesota | Stereoselective reduction of triterpenones |
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| CN1158566A (en) * | 1994-06-20 | 1997-09-03 | 库特·伯格 | Pharmaceutical compsn. for the prevention and/or treatment of viral infections and optionally inflammations as well as a method for treatment thereof |
| WO2006133395A2 (en) * | 2005-06-08 | 2006-12-14 | Regents Of The University Of Minnesota | Stereoselective reduction of triterpenones |
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