CN104860949A - Substituted-amino dithiocarbamic acid ester matrine derivative and preparation method and application - Google Patents
Substituted-amino dithiocarbamic acid ester matrine derivative and preparation method and application Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
Abstract
The invention relates to a substituted-amino dithiocarbamic acid ester matrine derivative. Please see the general molecular formula of the matrine derivative in the specifications, wherein, the R is selected from fat amino or a cyclic amine group or benzyl. The invention further provides salts capable of being accepted by the matrine derivative in pharmacy, and the preparation method and application of the matrine derivative. According to preliminary cell tests, the substituted-amino dithiocarbamic acid ester matrine derivative and the salts capable of being accepted by the same in pharmacy have the advantages of being capable of remarkably inhibiting the human hepatocarcinoma cell line Hun-7, having the remarkable anti-hepatoma activity, having great potential in preparation of anti-hepatic fibrosis and anti-hepatoma drugs, being low in toxicity, and being capable of being used for preparing the drugs for treating relative inflammation diseases involving cell factors and the nuclear transcription factor NFkappaB.
Description
Technical field
The present invention relates to medical art, specifically, be the matrine derivative and pharmacy acceptable salt class thereof that a class is new, its preparation method and application, compound has anti-tumor activity, can be used for the medicine of the associated cancers such as Hepatoma therapy.
Background technology
In the material that the dry root such as cassia leguminous plant kuh-seng, Herba Sophorae alopecuroidis, root of subprostrate sophora and ground segment thereof extract, isolate and comprised matrine (Matrine), sophocarpine (sophocarpine) etc. more than 20 and plant alkaloid (cloudy strong, Guo Li bow, kuh-seng, Chinese medicine modern study and clinical application, p424).
Matrine has pharmacotoxicological effect widely, as anti-inflammatory, antiviral, rheumatism, anti-hepatic fibrosis, antitumor, antibacterial, antianaphylaxis, parasiticide, anti-arrhythmia, the swelling diuretic, (Jiang Hezhong such as immunity and biological respinse regulating effect, matrine and Oxymatyine pharmacological action and Advances in preparation, the practical combination of Chinese tradiational and Western medicine is clinical, 2007,7 (1): 89).Report that matrine and sophocarpine have antitumor emaciation effect in recent years, it acts on Zhang Y relevant to inflammation-inhibiting cytokine, et al.Sophocarpineand matrine inhibit the production of TNF-alpha and IL-6 in murine macrophagesand prevent cachexia-related symptoms induced by colon26 adenocarcinoma inmice, Int Immunopharmacol.2008; 8 (13-14): 1767-72).Matrine is used widely in treatment chronic hepatitis and hepatic fibrosis etc. clinically, day by day to come into one's own (village selected works, Sun Lihua in recent years in effect that is antitumor and control tumor cachexia.The clinical application of matrine, Chinese clinical medicine and nursing, 2005,2 & 3:89).
China Patent Publication No. CN 103933038A discloses the application of one group of matrine compound for the preparation of anti-hepatic fibrosis and medicines resistant to liver cancer, but research and development possess good antitumous effect more, productive rate is high and the matrine compound that toxicity is little is still very necessary.
Summary of the invention
The object of the invention is for deficiency of the prior art, a kind of substituted-amino dithio formate class matrine derivative is provided.
Second object of the present invention is, provides a kind of preparation method of substituted-amino dithio formate class matrine derivative.
3rd object of the present invention is, provides a kind of pharmacy acceptable salt class of substituted-amino dithio formate class matrine derivative.
4th object of the present invention is, provides a kind of preparation method of pharmacy acceptable salt class of substituted-amino dithio formate class matrine derivative.
5th object of the present invention provides the application of a kind of substituted-amino dithio formate class matrine derivative and pharmacy acceptable salt class thereof.
For realizing above-mentioned first object, the technical scheme that the present invention takes is: a kind of substituted-amino dithio formate class matrine derivative, and it is characterized in that, the general structure of described matrine derivative is as follows:
Wherein R is selected from i or ii or iii:
I. fat amido, the substituting group of described amino is selected from saturated or unsaturated alkyl, and saturated hydrocarbyl is methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, n-pentyl, cyclopentyl, n-hexyl or cyclohexyl; Unsaturated alkyl is benzyl or substituted benzyl, styroyl or substituted benzene ethyl, substituting group be positioned at phenyl ring neighbour, or contraposition, monosubstituted or polysubstituted;
Ii. cyclammonium base, is selected from piperidines, Pyrrolidine and piperazine, morpholine, sulfydryl morpholine; It is methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, n-pentyl, cyclopentyl, n-hexyl or cyclohexyl that substituting group on cyclammonium is selected from saturated hydrocarbyl; Saturated hydrocarbyl is benzyl or substituted benzyl, styroyl or substituted benzene ethyl, substituting group be positioned at phenyl ring neighbour, or contraposition, monosubstituted or polysubstituted;
Iii. benzyl, the substituting group of described benzyl is selected from halogen, nitro, itrile group, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, carbonyl, propoxy-or isopropoxy.
Preferably, described R is n-propylamine base.
Preferably, described R is piperidines.
Preferably, described R is fluorine substituted benzyl.
For realizing above-mentioned second object, the technical scheme that the present invention takes is: the preparation method of described matrine derivative, comprises the following steps: compound sophocarpine and dithiocarbonic anhydride and amine in water 80 DEG C react and within 12 hours, obtain described substituted-amino dithio formate class matrine derivative;
The structural formula of described compound sophocarpine is
For realizing above-mentioned 3rd object, the technical scheme that the present invention takes is: the pharmacy acceptable salt class of described matrine derivative.
Preferably, the pharmacy acceptable salt class of described matrine derivative is hydrochloride, vitriol, hydrosulfate, hydrobromate, oxalate, Citrate trianion or mesylate.
For realizing above-mentioned 4th object, the technical scheme that the present invention takes is: the preparation method of the pharmacy acceptable salt class of described matrine derivative, comprise the following steps: described substituted-amino dithio formate class matrine derivative is obtained by reacting its corresponding salt to sour HA, and described sour HA is hydrochloric acid, sulfuric acid, hydrogen sulfate, Hydrogen bromide, oxalic acid, citric acid or methylsulfonic acid.
For realizing above-mentioned 5th object, the technical scheme that the present invention takes is: described matrine derivative and the application of pharmacy acceptable salt class in the anti-liver cancer of preparation or anti-inflammatory drug thereof.
Preferably, described matrine derivative and pharmacy acceptable salt class thereof suppress the application in the medicine of human hepatoma cell strain Hun-7 in preparation.
The invention has the advantages that:
1, the invention provides a kind of substituted-amino dithio formate class matrine derivative and pharmacy acceptable salt class thereof of new sulfur-bearing, preliminary test cell line confirms that it has significant restraining effect for human hepatoma cell strain Hun-7, there is the active function of remarkable anti-liver cancer, there are great potentiality preparing in anti-hepatic fibrosis and medicines resistant to liver cancer;
2, substituted-amino dithio formate class matrine derivative of the present invention and pharmacy acceptable salt class thereof have low toxin, can be used for the relevant diseases associated with inflammation preparing drug treated cells Summing Factor nuclear factor NF κ B participation;
3, preparation method's step of the compounds of this invention is simple, productive rate is high.
Embodiment
Below in conjunction with embodiment, embodiment provided by the invention is elaborated.
The invention provides a kind of substituted-amino dithio formate class matrine derivative and pharmacy acceptable salt class thereof, the general structure of described matrine derivative is as follows:
Wherein R is selected from i or ii or iii:
I. fat amido, the substituting group of described amino is selected from saturated or unsaturated alkyl, and saturated hydrocarbyl is methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, n-pentyl, cyclopentyl, n-hexyl or cyclohexyl; Unsaturated alkyl is benzyl or substituted benzyl, styroyl or substituted benzene ethyl, substituting group be positioned at phenyl ring neighbour, or contraposition, monosubstituted or polysubstituted; Preferably n-propylamine base;
Ii. cyclammonium base, is selected from piperidines, Pyrrolidine and piperazine, morpholine, sulfydryl morpholine; It is methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, n-pentyl, cyclopentyl, n-hexyl or cyclohexyl that substituting group on cyclammonium is selected from saturated hydrocarbyl; Saturated hydrocarbyl is benzyl or substituted benzyl, styroyl or substituted benzene ethyl, substituting group be positioned at phenyl ring neighbour, or contraposition, monosubstituted or polysubstituted; Preferably piperidines;
Iii. benzyl, the substituting group of described benzyl is selected from halogen, nitro, itrile group, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, carbonyl, propoxy-or isopropoxy; It is preferably fluorine substituted benzyl.
The substituted-amino dithio formate class matrine derivative pharmacy acceptable salt class of above-mentioned general formula is hydrochloride, vitriol, hydrosulfate, hydrobromate, oxalate, Citrate trianion, mesylate etc.
Present invention also offers the preparation method of above-mentioned substituted-amino dithio formate class matrine derivative, the method is as follows:
The synthesis of matrine derivative pharmacy acceptable salt class of the present invention is on the basis of above-mentioned reaction, does following reaction further:
Being prepared as follows of the particular compound related in above-mentioned preparation method:
Prepare compound (II):
Compound (I) sophocarpine and dithiocarbonic anhydride and amine in water 80 DEG C react and within 12 hours, obtain compound (II).
The preparation of compound salt:
Compound (II) and sour HA are obtained by reacting its corresponding salt, and HA is hydrochloric acid, sulfuric acid, hydrogen sulfate, Hydrogen bromide, oxalic acid, citric acid, methylsulfonic acid etc.
The chemical structure of part preferred compound of the present invention's synthesis, productive rate, nuclear-magnetism and mass-spectrometric data are as shown in table 1.
The structure of table 1 part preferred compound, productive rate, mass spectrum and molecular formula
Note: the mensuration of C, H, N tri-kinds of ultimate analyses differ 0.3% with calculated value.
Through biological activity test, these compounds have the activity suppressing human hepatocyte's strain, can be used for the medicine preparing Hepatoma therapy associated cancer.
The preparation of embodiment 1:13-(N, N-Methyl disulfide subtituted acid ester) matrine (in table compd A-2)
Dithiocarbonic anhydride 80mg (1mmol) and dimethylamine 36mg (0.8mmol) is placed in 25ml reaction flask, adds H
2o 2ml; add sophocarpine 120mg (0.5mmol) under stirring, nitrogen protection, 60 DEG C are reacted 12 hours; after completion of the reaction; add extraction into ethyl acetate, saturated nacl aqueous solution washs, organic layer anhydrous sodium sulfate drying; silica gel column chromatography after concentrating under reduced pressure; eluant dichloromethane: methyl alcohol (50:1), obtains white solid 160mg, productive rate 86.9%.
1H NMR(300MHz,CDCl
3)δ4.36(dd,J＝12.6,4.1Hz,2H),4.01–3.88(m,1H),3.51(s,3H),3.32(s,3H),3.09(t,J＝12.6Hz,1H),2.80(dd,J＝17.2,5.4Hz,3H),2.64(dd,J＝17.3,6.7Hz,1H),2.29–1.85(m,8H),1.80–1.19(m,12H).
13C NMR(75MHz,CDCl
3)δ195.10,166.58,63.92,57.29,57.27,57.21,51.94,45.07,43.15,42.43,41.81,41.55,37.53,37.49,35.60,31.63,27.71,26.59,21.19,21.09,20.76,20.69.
MS(ESI):m/z 368.31[M+H]
+.。
The preparation of embodiment 2:13-(piperidines dithio formate) matrine (in table compd A-4)
Dithiocarbonic anhydride 80mg (1mmol) and piperidines 65mg (0.8mmol) is placed in 25ml reaction flask; add water 2ml; sophocarpine 120mg (0.5mmol) is added under stirring; nitrogen protection; 60 DEG C are reacted 12 hours; after completion of the reaction; add extraction into ethyl acetate; saturated nacl aqueous solution washs; organic layer anhydrous sodium sulfate drying, silica gel column chromatography after concentrating under reduced pressure, eluant dichloromethane: methyl alcohol (50:1); obtain white solid 147mg, productive rate 72.1%.
1H NMR(300MHz,CDCl
3)δ4.53–4.25(m,2H),4.19(s,1H),4.06–3.70(m,2H),3.44(ddd,J＝24.5,12.5,6.4Hz,1H),3.12(s,1H),2.80(dd,J＝17.2,5.3Hz,2H),2.63(dd,J＝17.3,7.2Hz,1H),2.29–1.81(m,6H),1.81–1.37(m,13H).
13C NMR(75MHz,CDCl
3)δ193.36,166.68,77.50,77.28,77.07,76.65,64.12,63.52,57.18,52.67,51.95,51.49,42.51,41.74,41.06,37.53,35.52,35.27,34.86,31.71,31.42,24.55,24.24.
MS(ESI):m/z 408.45[M+H]
+.。
The preparation of embodiment 313-(4-benzyl piepridine dithio formate) matrine (in table compd A-6)
Dithiocarbonic anhydride 80mg (1mmol) and 4-benzyl piepridine 140mg (0.8mmol) is placed in 25ml reaction flask; add water 2ml; sophocarpine 120mg (0.5mmol) is added under stirring; nitrogen protection; 60 DEG C are reacted 12 hours; after completion of the reaction; add extraction into ethyl acetate; saturated nacl aqueous solution washs; organic layer anhydrous sodium sulfate drying, silica gel column chromatography after concentrating under reduced pressure, eluant dichloromethane: methyl alcohol (50:1); obtain white solid 186mg, productive rate 74.7%.
1H NMR(300MHz,CDCl
3)δ7.32–6.98(m,6H),5.47(s,1H),4.62–4.24(m,3H),4.01–3.83(m,1H),3.06(dd,J＝16.8,8.3Hz,3H),2.76(d,J＝11.0Hz,4H),2.47(t,J＝21.6Hz,4H),2.28–1.12(m,24H).
13C NMR(75MHz,CDCl
3)δ193.46,193.23,166.58,139.61,129.01,128.36,126.16,77.69,77.47,77.27,76.84,63.88,63.45,57.29,57.26,57.10,42.67,42.50,42.37,41.80,38.02,37.62,35.60,31.95,31.74,31.53,26.62,26.36,21.19,21.10,20.77.
MS(ESI):m/z 498.63[M+H]
+.。
The preparation of embodiment 4:13-(N-is to benzyl dithio formate) matrine (in table compd A-10)
25ml reaction flask is placed in by dithiocarbonic anhydride 80mg (1mmol) with to fluorobenzene methylamine 100mg (0.8mmol); add water 2ml; sophocarpine 120mg (0.5mmol) is added under stirring; nitrogen protection; 60 DEG C are reacted 12 hours; after completion of the reaction; add extraction into ethyl acetate; saturated nacl aqueous solution washs; organic layer anhydrous sodium sulfate drying, silica gel column chromatography after concentrating under reduced pressure, eluant dichloromethane: methyl alcohol (50: methyl alcohol (50:1); obtain white solid 155mg, productive rate 69.2%.
1H NMR(300MHz,CDCl
3)δ7.42–7.18(m,3H),7.01(dd,J＝11.0,6.2Hz,1H),4.85(d,J＝5.4Hz,1H),4.39(s,1H),4.11(d,J＝5.2Hz,1H),3.11(dt,J＝10.8,5.4Hz,3H),2.64(ddd,J＝23.6,17.0,5.7Hz,2H),2.41–1.39(m,11H),1.36–1.18(m,3H).
13C NMR(75MHz,CDCl
3)δ195.86,166.86,132.25,132.21,130.10,130.00,115.52,115.40,64.21,63.59,56.86,49.89,45.64,41.00,37.26,31.61.
MS(ESI):m/z 448.49[M+H]
+.。
Above embodiment describes the preparation method of substituted-amino dithio formate class matrine derivative of the present invention for compd A-2 in table 1, A-4, A-6 and A-10.Enforcement of the present invention is not limited to above embodiment, and other compounds for Material synthesis, repeat the step in above embodiment with different primary amine, secondary amine, just can synthesize required substituted-amino dithio formate class matrine derivative.In embodiment, agents useful for same is commercially available analytical pure.
Embodiment 5: biological activity test:
5.1 plant and instrument
CO
2cell culture incubator, enzyme-linked immunosorbent assay instrument, the double Bechtop of vertical one side, inverted biologic microscope.
5.2 experiment materials and preparation
5.2.1 test medicine:
Matrine derivative, matrine
Proterties: powder
Content: 99%
Compound method: DMSO dissolves, and is desired concn sample with PBS dilution;
5.2.2 cell strain:
Human hepatoma cell strain (Huh-7), is provided by east liver and gall hospital of The 2nd Army Medical College.
5.2.3 reagent:
5.2.3.1 cell culture medium: DMEM, foetal calf serum, 0.25% trypsin solution (Trypsin) (GIBCO company); DMSO, Sigma company, MTT, AMRESCO company.
5.2.3.2 phosphoric acid buffer (PBS): NaCl 8.0g, KCl 0.2g, Na
2hPO
412H
2o 3.6g, KH
2pO
40.27g, is dissolved in 1L distilled water, 121 DEG C of autoclave sterilization 20min, 4 DEG C of preservations.
5.2.3.3MTT (AMRESCO) solution: be made into 5mg/ml solution with PBS.
5.2.3.4 cytolysate: containing 10% sodium lauryl sulphate (SDS), 5% isopropylcarbinol, the hydrochloric acid of 0.02M/L.
5.2.4 test consumptive material: 96 porocyte culture plates, 50ml Tissue Culture Flask, purchased from Corning company.
5.3 experimental procedure
5.3.1 sample preparation: be dissolved in respectively by sample in methyl-sulphoxide (DMSO), obtains the solution that concentration is 10mg/ml.Make gradient dilution with PBS again, obtain the dilute sample that concentration is 10 μ g/ml, 9 μ g/ml, 8 μ g/ml, 7 μ g/ml, 6 μ g/ml, 5 μ g/ml, 4 μ g/ml, 3g/ml, 2 μ g/ml.
5.3.2 added by the sample diluted in flat 96 orifice plates, every hole 10 μ l, each concentration does 3 parallel testings.Blank adds in plate after using DMSO to do corresponding gradient dilution.
5.3.3 get the cell being in logarithmic phase, be suspended in after trysinization also washing in the cell culture medium containing 10% calf serum, through trypan-blue exclusion assay living cell counting number, and adjust cell suspension density to 2 × 10
5/ ml.
5.3.4 added in flat 96 orifice plates of liquid above-mentioned, every hole adds 90 μ l cell suspensions, in 37 DEG C, 5%CO
2cultivate 48 hours in cell culture incubator.
5.3.5 add 20 μ l MTT solution (5mg/ml) in every hole, continue to place 3 ~ 4 hours in incubator.
5.3.6 every hole adds 100 μ l cytolysates, continues to place in incubator to spend the night.
5.3.7 492nm absorbance value (OD) is measured.
5.3.8 according to comparative survival rate of cells after the process of absorbance value calculation sample.
5.3.9 do straight-line regression according to the inhibiting rate of different concns, calculate IC
50(μ g/ml).
5.4 experimental results: sample is to the IC of each cell strain
50see the following form.
Table 2 sample is to the inhibiting rate of each concentration of Huh-7 cell and IC
50value
Compound of the present invention has the active function of remarkable anti-liver cancer, and in addition, the compounds of this invention also has low toxin, can be used for the relevant diseases associated with inflammation preparing drug treated cells Summing Factor nuclear factor NF κ B participation.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the prerequisite not departing from the inventive method; can also make some improvement and supplement, these improve and supplement and also should be considered as protection scope of the present invention.
Claims (10)
1. a substituted-amino dithio formate class matrine derivative, is characterized in that, the general structure of described matrine derivative is as follows:
Wherein R is selected from i or ii or iii:
I. fat amido, the substituting group of described amino is selected from saturated or unsaturated alkyl, and saturated hydrocarbyl is methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, n-pentyl, cyclopentyl, n-hexyl or cyclohexyl; Unsaturated alkyl is benzyl or substituted benzyl, styroyl or substituted benzene ethyl, substituting group be positioned at phenyl ring neighbour, or contraposition, monosubstituted or polysubstituted;
Ii. cyclammonium base, is selected from piperidines, Pyrrolidine and piperazine, morpholine, sulfydryl morpholine; It is methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, n-pentyl, cyclopentyl, n-hexyl or cyclohexyl that substituting group on cyclammonium is selected from saturated hydrocarbyl; Saturated hydrocarbyl is benzyl or substituted benzyl, styroyl or substituted benzene ethyl, substituting group be positioned at phenyl ring neighbour, or contraposition, monosubstituted or polysubstituted;
Iii. benzyl, the substituting group of described benzyl is selected from halogen, nitro, itrile group, methyl, ethyl, n-propyl, sec.-propyl, methoxyl group, oxyethyl group, carbonyl, propoxy-or isopropoxy.
2. matrine derivative according to claim 1, is characterized in that, described R is n-propylamine base.
3. matrine derivative according to claim 1, is characterized in that, described R is piperidines.
4. matrine derivative according to claim 1, is characterized in that, described R is fluorine substituted benzyl.
5. the preparation method of matrine derivative according to claim 1, it is characterized in that, comprise the following steps: compound sophocarpine and dithiocarbonic anhydride and amine in water 80 DEG C react and within 12 hours, obtain described substituted-amino dithio formate class matrine derivative;
The structural formula of described compound sophocarpine is
6. the pharmacy acceptable salt class of the arbitrary described matrine derivative of claim 1-4.
7. the pharmacy acceptable salt class of matrine derivative according to claim 6, it is characterized in that, the pharmacy acceptable salt class of described matrine derivative is hydrochloride, vitriol, hydrosulfate, hydrobromate, oxalate, Citrate trianion or mesylate.
8. the preparation method of the pharmacy acceptable salt class of matrine derivative according to claim 6, it is characterized in that, comprise the following steps: described matrine derivative and sour HA are obtained by reacting its corresponding salt, described sour HA is hydrochloric acid, sulfuric acid, hydrogen sulfate, Hydrogen bromide, oxalic acid, citric acid or methylsulfonic acid.
9. the application of pharmacy acceptable salt class in the anti-liver cancer of preparation or anti-inflammatory drug of the arbitrary described matrine derivative of claim 1-4 or the arbitrary described matrine derivative of claim 6 or 7.
10. the pharmacy acceptable salt class of the arbitrary described matrine derivative of claim 1-4 or the arbitrary described matrine derivative of claim 6 or 7 suppresses the application in the medicine of human hepatoma cell strain Hun-7 in preparation.
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| CN107814801A (en) * | 2017-10-20 | 2018-03-20 | 上海长海医院 | New matrine compound and preparation method and application |
| CN108440529A (en) * | 2018-04-17 | 2018-08-24 | 华东理工大学 | Double thick piperidines, preparation method, purposes and its intermediate |
| CN109928978A (en) * | 2019-05-05 | 2019-06-25 | 湖南科技大学 | Tetra- aryl -3- sulphur -2- nitrogen -21- carbon chlorophyll compound of 5,10,15,20- and preparation method |
| CN111440169A (en) * | 2020-04-03 | 2020-07-24 | 南方科技大学 | Alkaloid nitrogen nitride derivative and preparation method thereof |
| CN114891001A (en) * | 2022-05-20 | 2022-08-12 | 哈尔滨商业大学 | Sophocarpine derivative and preparation method and application thereof |
| CN114891001B (en) * | 2022-05-20 | 2023-12-05 | 哈尔滨商业大学 | Sophocarpine derivative, and preparation method and application thereof |
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| CN104860949B (en) | 2017-07-11 |
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