CN115010642B - Beta-elemene imide derivative and application thereof - Google Patents

Beta-elemene imide derivative and application thereof Download PDF

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CN115010642B
CN115010642B CN202210685337.5A CN202210685337A CN115010642B CN 115010642 B CN115010642 B CN 115010642B CN 202210685337 A CN202210685337 A CN 202210685337A CN 115010642 B CN115010642 B CN 115010642B
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elemene
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董金华
刘德志
景永奎
苏浩尘
张美慧
徐莉英
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Shenyang Pharmaceutical University
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Abstract

The invention discloses a beta-elemene imide derivative and application thereof, belonging to the technical field of medicines, and aiming at introducing an imide structure into a beta-elemene parent nucleus to synthesize the beta-elemene imide derivative with novel structure so as to obtain the beta-elemene imide derivative with good water solubility and high antitumor activity and create a novel beta-elemene anticancer drug. The invention also relates to a preparation method of the compound and the medicinal salt thereof and application of the compound-containing composition in preparing anticancer drugs.

Description

Beta-elemene imide derivative and application thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a novel beta-elemene imide derivative and application of the beta-elemene imide derivative or a medicinal salt thereof in preparing an anti-tumor medicament.
Background
The elemene emulsion is a broad-spectrum antitumor drug, and the main anticancer component is beta-elemene, and has dual antitumor effects of inhibiting tumor cell proliferation and improving organism immunity. However, due to poor water solubility, beta-elemene is only applied to clinical injection, emulsion injection, oral emulsion, freeze-dried powder injection and aerosol at present.
To improve the antitumor activity and water solubility of beta-elemene, a series of structural modifications have been made (Xu L Y, tao S J, wang X M, et al, the synthesis and anti-proliferative effects of beta-elemene derivatives with mTOR inhibition activity [ J ]. Bioorg Med Chem,2006,14 (15): 5351-5356; zhang Xingzhong, xu Liying, tao Shujuan, et al, beta-elemene enol ester compounds synthesis and anticancer activity studies [ J ]. J. Chinese journal of pharmaceutical chemistry, 2007, 17 (1): 13-17; xu Liying, wang Xianming, yu Zhiying, et al, beta-elemene amine derivatives synthesis and anticancer activity studies [ J ]. Chinese journal of pharmaceutical chemistry, 2009, 19 (4): 247-260; zhang Xingzhong. Elemene derivatives synthesis and anticancer activity studies [ D ]. Shenyang: shenyang university of medicine 2005). Wherein, the 13-position of the beta-elemene is introduced with nitrogen, oxygen and other polar groups to show higher in vitro anti-tumor activity, wherein, the in vitro anti-tumor activity of the fluorouracil derivative of the beta-elemene and the 1, 2-benzisothiazole-3- (2H) -thioketone-1, 1-dioxide derivative is higher than that of the parent compound beta-elemene, and the IC50 value of the beta-2-4 times lower than that of the beta-elemene on human HeLa cells, human gastric cancer SGC-7901 cells and human promyelocytic leukemia HL-60 cells (Xu Liying, tao Shujuan, zhang Xingzhong, and the like. The synthesis of the beta-elemene aromatic heterocyclic derivative and the in vitro anti-tumor activity are researched [ J ]. J. Chinese journal of pharmaceutical chemistry, 2006, 16 (5): 277-280). Fluorouracil and 1, 2-benzisothiazole-3- (2H) -thione-1, 1-dioxide both contain imide structures, and it is presumed that the introduction of imide structure fragments into the beta-elemene structure may be advantageous for improving the antitumor activity thereof. And a great deal of research at home and abroad also shows that the imide structure has an anti-tumor effect: such as Edotecarin, 5-FU, etc. In view of the antitumor activity of both the elemene and the imide compound, the invention provides a segment with imide group introduced at the 13 position of the beta-elemene based on the maintenance of the sesquiterpene skeleton of the beta-elemene for the first time, synthesizes the beta-elemene imide derivative, and is expected to enhance the antitumor activity while improving the water solubility of the beta-elemene, thereby discovering a novel antitumor drug with the characteristic of elemene effect.
Disclosure of Invention
The invention aims to introduce an imide structure into a beta-elemene parent nucleus to synthesize a beta-elemene imide derivative with novel structure so as to obtain the beta-elemene imide derivative with good water solubility and high antitumor activity and create a novel beta-elemene antitumor drug.
The invention provides a beta-elemene imide derivative or a medicinal salt thereof, wherein the beta-elemene imide derivative is any one of the following 13 structures:
Figure BDA0003699731480000021
the beta-elemene imide derivative "medicinal salt" refers to conventional acid addition salt, which maintains the biological effectiveness and characteristics of the beta-elemene imide derivative and is formed by the beta-elemene imide derivative and proper non-toxic organic acid or inorganic acid. The inorganic and organic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, tartaric acid, salicylic acid, methanesulfonic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, maleic acid. In the present invention, preferred pharmaceutically acceptable salts are halogen acid, fumaric acid, maleic acid, methanesulfonic acid, citric acid addition salts.
The invention also provides a pharmaceutical composition containing the beta-elemene imide derivative or the pharmaceutical salt thereof and pharmaceutically acceptable excipients.
The invention also provides application of the beta-elemene imide derivative or the medicinal salt thereof or the pharmaceutical composition containing the derivative in preparing antitumor drugs.
The invention also provides application of the beta-elemene imide derivative or the medicinal salt thereof or the pharmaceutical composition containing the derivative in preparing proliferation inhibitors of Raji tumor cells.
The invention also provides a preparation method of the beta-elemene imide derivative, which comprises the following steps: obtaining a monochloroelemene intermediate through chloro-beta-elemene, reacting the intermediate with a fragment with an imide structure to obtain a corresponding beta-elemene imide derivative, wherein the monochloroelemene intermediate has the structural formula:
Figure BDA0003699731480000031
the invention has the beneficial effects that:
the invention introduces an imide structure into beta-elemene to synthesize beta-elemene imide derivatives with novel structures, and the beta-elemene imide derivatives are used for improving the anticancer activity of beta-elemene and improving the water solubility.
The beta-elemene imide derivative and the medicinal salt thereof have better anticancer activity, and the preparation method is simple and feasible and is easy to operate, thereby providing a thinking for creating new beta-elemene anticancer drugs.
Detailed Description
Example 1
Preparation of monochloro beta-elemene
Figure BDA0003699731480000032
51.0g (0.25 mol) of beta-elemene and 35mL (0.61 mol) of glacial acetic acid are added into a three-necked flask equipped with a mechanical stirrer, the flask is cooled to 5 ℃ by an ice water bath, 180mL (1.41 mol/L,0.254 mol) of sodium hypochlorite solution is dropwise added under stirring, and the reaction is continued for 1h after the completion of the dropwise addition for 4 h. Then the reaction solution is transferred to a separating funnel, extracted twice by 50mL petroleum ether (60-90 ℃), the organic phases are combined, washed to be neutral by water, dried by anhydrous sodium sulfate and concentrated to obtain 52.5g light yellow green oily substance, and GC shows that the oily substance contains 41.4 percent of unreacted elemene and 44.5 percent of monochloroelemene mixture (13-chloro-beta-elemene (1) and 14-chloro-beta-elemene (2)). Separating by silica gel column chromatography and petroleum ether.
Example 2
Figure BDA0003699731480000033
2.0g of the monochloro beta-elemene mixture prepared in the example 1 and 3.90g (20.9 mmol,2.5 eq) of 1-t-butoxycarbonyl piperazine are dissolved in 20mL of absolute ethyl alcohol and reacted for 10-12h at 50 ℃, after the reaction is finished, the solvent is distilled off, water is added, ethyl acetate is used for extraction, the organic phases are combined, saturated sodium bicarbonate solution and saturated sodium chloride solution are used for washing the organic phases, anhydrous sodium sulfate is dried and concentrated to obtain 2.44g of crude product, the yield is 75%, and the crude product is separated and purified by silica gel column chromatography to obtain yellow oily substance which is 1-Boc protected elemene piperazine (YD-10-a) for standby.
The purified YD-10-a was put into a 100mL eggplant-shaped bottle, and a 5% hydrogen chloride-diethyl ether solution was added at a ratio of 1g/10mL, followed by stirring at room temperature for 5 hours. Adding water and sodium bicarbonate solution, and regulating pH value to 8-9. The organic layers were washed three times with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated to give a yellow oil, which was separated and purified by column chromatography to give compound YD-10.
Example 3
Figure BDA0003699731480000041
0.29g (1 mmol,1 eq) YD-10 and 0.25g (2.5 mmol,2.5 eq) maleimide are dissolved in acetone solution and added to 0.35g K 2 CO 3 (2.5 mmol,2.5 eq) and refluxing for 8-10h, after the reaction, evaporating the solvent, adding water, extracting with ethyl acetate, combining the organic phases, washing with saturated sodium chloride aqueous solution, drying, concentrating to obtain crude product of white oil 0.35g, yield 90.7%. And (3) separating and purifying by silica gel column chromatography to obtain the target compound. 1 H NMR(600MHz,CDCl 3 )δ5.83–5.76(m,1H),4.96–4.80(m,6H),3.88–3.87(m,1H),2.97–2.88(m,2H),2.83(dd,J＝8.9,4.8Hz,2H),2.74(dt,J＝18.5,4.6Hz,1H),2.57(s,3H),2.46(s,3H),2.14(dd,J＝12.6,3.5Hz,1H),2.09–1.96(m,2H),1.80–1.72(s,3H),1.62(td,J＝12.6,4.7Hz,2H),1.56(tt,J＝13.7,2.2Hz,2H),1.47–1.41(m,2H),1.01(s,3H)；ESI-MS，m/z 397.0[M+K] + 。
Example 4
Figure BDA0003699731480000042
1, 3-Dioxisoindoline-5-carboxylic acid (2.0 mmol) was dissolved in N, N-Dimethylformamide (DMF), N-carbonyldiimidazole (2.2 mmol, CDI) was added thereto, and the reaction was carried out at 30℃for 2 hours, and YD-10 (2.0 mmol) prepared in example 2 was added to the reaction mixture, followed by stirring. After 8 hours, the reaction is finished, 10mL of water is added, extraction is carried out for three times by ethyl acetate, the organic phases are combined, the organic phases are washed by saturated sodium chloride and dried by anhydrous sodium sulfate, the crude product of the target compound is obtained after concentration, and the colorless transparent oily target compound is obtained after separation and purification by silica gel column chromatography or preparative thin layer chromatography, and the yield is 92.2%. 1 H NMR(600MHz,CDCl 3 )δ7.92(d,J＝7.6Hz,1H),7.86(s,1H),7.79(d,J＝7.5Hz,1H),5.82(dd,J＝17.4,10.9Hz,1H),4.95(s,2H),4.92(d,J＝7.0Hz,1H),4.89(s,1H),4.82(s,1H),4.58(s,1H),3.81(s,2H),3.37(s,2H),3.00–2.93(m,2H),2.43(d,J＝93.2Hz,4H),2.10–1.99(m,2H),1.71(s,3H),1.54–1.42(m,3H),1.26(d,J＝3.1Hz,3H),1.01(s,3H)；ESI-MS，m/z 462.3[M+H] + 。
Example 5
Figure BDA0003699731480000051
The preparation of example 4 was followed using YD-10 and 2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxylic acid as starting materials to give the title compound as a white solid in 88.3% yield. 1 H NMR(600MHz,CDCl 3 )δ7.87(d,J＝3.2Hz,1H),5.83(dd,J＝17.3,11.0Hz,1H),4.97(s,2H),4.93–4.91(m,1H),4.90(s,1H),4.83(p,J＝1.6Hz,1H),4.59–4.58(m,1H),3.66–3.55(m,5H),2.98(q,J＝13.3Hz,2H),2.47(d,J＝5.2Hz,4H),2.08(tt,J＝8.2,4.0Hz,1H),2.03(dd,J＝11.7,4.4Hz,1H),1.73–1.70(s,3H),1.66–1.60(m,1H),1.60–1.55(m,2H),1.52–1.41(m,3H),1.01(s,3H)；ESI-MS，m/z 428.3[M+H] + ,450.3[M+Na] + 。
Example 6
Figure BDA0003699731480000052
The preparation method of example 2 is followed to obtain a yellow-green solid target compound with a yield of 45.2% by using the monochloro beta-elemene mixture and pomalidomide prepared in example 1 as raw materials. 1 H NMR(600MHz,CDCl 3 )δ7.46–7.37(m,1H),7.16(d,J＝7.1Hz,1H),6.86(d,J＝8.3Hz,1H),5.84–5.78(dd,1H),5.23(s,2H),4.97(dd,J＝12.6,5.3Hz,1H),4.92–4.87(m,3H),4.81(dq,J＝3.2,1.6Hz,1H),4.73–4.69(m,1H),4.58(t,J＝2.5Hz,1H),4.49–4.34(m,2H),3.03–2.99(m,1H),2.86–2.75(m,2H),2.15–2.08(m,1H),2.05–1.95(m,2H),1.70–1.69(s,3H),1.59–1.57(m,3H),1.56–1.42(m,3H),1.00–0.99(s,3H)；ESI-MS，m/z 476.1[M+H] + 498.1[M+Na] + 。
Example 7
Figure BDA0003699731480000061
The procedure of example 6 was followed using as starting materials a mixture of monochloro- β -elemene and 5-aminopyrimidine-2, 4 (1 h,3 h) -dione to give the title compound as a yellow oil in 42.1% yield. 1 H NMR(600MHz,CDCl 3 )δ8.26–7.98(m,0H),5.81(ddt,J＝21.2,15.2,7.6Hz,1H),4.93–4.88(m,2H),4.86–4.74(m,2H),4.74–4.66(m,1H),4.59–4.53(m,2H),4.46(dd,J＝16.8,9.4Hz,1H),2.09–1.86(m,2H),1.70(s,3H),1.67–1.56(m,2H),1.54–1.22(m,4H),1.01(s,3H)；ESI-MS，m/z 330.2[M+H]+352.1[M+Na] + 。
Example 8
Figure BDA0003699731480000062
Preparation according to example 6 using a mixture of monochloro beta-elemene and 3-amino-2, 6-piperidinedione as starting materialsThe procedure produced the title compound as a blue oil in 32.1% yield. 1 H NMR(600MHz,CDCl 3 )δ5.82(dd,J＝17.5,10.8Hz,1H),4.99(s,1H),4.96(s,1H),4.93–4.91(m,1H),4.89(s,1H),4.83(t,J＝1.9Hz,1H),4.59(s,1H),3.42–3.37(m,2H),3.31(d,J＝14.4Hz,1H),2.79(dt,J＝17.8,4.1Hz,1H),2.56(ddd,J＝17.8,12.6,5.2Hz,1H),2.23(dt,J＝13.7,4.7Hz,1H),2.04–2.00(m,2H),1.91–1.81(m,1H),1.71(s,3H),1.67–1.54(m,2H),1.51–1.40(m,3H),1.26(d,J＝6.6Hz,1H),1.01(s,3H)；ESI-MS，m/z 331.3[M+H] + 。
Example 9
Figure BDA0003699731480000063
The preparation method of example 6 is followed by taking a monochloro beta-elemene mixture and 5-amino isoindoline-1, 3-dione as raw materials to prepare a yellowish green oily target compound, wherein the yield is 38.2%. 1 H NMR(600MHz,CDCl 3 )δ7.61(d,J＝8.1Hz,1H),7.06(d,J＝2.0Hz,1H),6.83(dd,J＝8.0,2.1Hz,1H),5.81(dd,J＝17.5,10.8Hz,1H),4.91(d,J＝7.4Hz,2H),4.89(d,J＝1.5Hz,1H),4.83–4.81(m,1H),4.78(s,1H),4.59(s,1H),4.26–4.15(m,2H),2.01(td,J＝12.1,11.7,3.5Hz,2H),1.71(s,3H),1.69–1.21(m,6H),1.01(s,3H)；ESI-MS，m/z 365.3[M+H] + 。
Example 10
Figure BDA0003699731480000071
The procedure of example 6 was followed using as starting materials a mixture of monochloro- β -elemene and 4-amino-N- (1, 3-dioxoisoindolin-5-yl) butyramide to give the title compound as a yellow oil in 44.3% yield. 1 H NMR(600MHz,CDCl 3 )δ7.62(d,J＝8.2Hz,1H),7.06(d,J＝2.1Hz,1H),6.83(dd,J＝4.7,2.1Hz,1H),5.82(dd,J＝17.4,10.9Hz,1H),5.02–4.97(m,1H),4.93–4.88(m,3H),4.70(d,J＝7.2Hz,1H),4.59(d,J＝2.0Hz,1H),4.22(d,J＝5.1Hz,2H),3.49(s,1H),2.05(s,5H),1.73(s,1H),1.71(s,3H),1.65–1.58(m,2H),1.51–1.45(m,3H),1.26(t,J＝7.1Hz,5H),1.01(s,3H)；ESI-MS，m/z 365.3[M+K] + 。
Example 11
Figure BDA0003699731480000072
Dissolving 2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidine-5-carboxylic acid (5.0 mmol) in absolute ethyl alcohol, adding potassium carbonate (5.5 mmol), stirring, refluxing for 2h, adding a monochloro beta-elemene mixture (2.5 mmol), continuously refluxing for 6-8h, evaporating ethanol after the reaction is finished, adding 10mL of water, extracting with ethyl acetate, washing an organic phase with saturated sodium chloride solution, drying with absolute sodium sulfate, concentrating to obtain a crude product of a target compound, and separating and purifying by silica gel column chromatography or preparative thin layer chromatography to obtain a colorless transparent oily target compound, wherein the yield is 32.5%. 1 H NMR(600MHz,DMSO-d 6 )δ8.47(s,1H),5.81(dd,J＝18.4,9.6Hz,1H),4.90–4.86(m,2H),4.79(d,J＝10.0Hz,2H),4.71(s,1H),4.62–4.52(m,2H),4.43(d,J＝16.9Hz,1H),2.04–1.94(m,2H),1.67(s,J＝7.4Hz,3H),1.63–1.30(m,4H),1.24(s,2H),0.96(s,3H)；ESI-MS，m/z 359.3[M+H] + ,381.3[M+Na] + ,397.0[M+K] + 。
Example 12
Figure BDA0003699731480000073
The preparation method of example 11 was followed using a mixture of monochloro beta-elemene and 1, 3-dioxoisoindoline-5-carboxylic acid as starting materials to give the title compound as a colorless oil in a yield of 47.3%. 1 H NMR(600MHz,CDCl 3 )δ8.53(q,J＝2.0,1.5Hz,1H),8.47(ddd,J＝7.8,4.2,1.4Hz,1H),7.96(dt,J＝7.9,1.8Hz,1H),5.85–5.78(dd,1H),5.18(d,J＝1.3Hz,1H),5.12(s,1H),4.94–4.91(m,1H),4.90(d,J＝2.8Hz,3H),4.84(p,J＝1.6Hz,1H),4.61–4.55(m,1H),2.12(td,J＝11.5,9.7,5.6Hz,1H),2.04(dd,J＝12.2,3.9Hz,1H),1.72(s,J＝1.1Hz,3H),1.63–1.50(m,6H),1.02(s,3H)；ESI-MS，m/z 359.3[M+H] + 。
Example 13
Figure BDA0003699731480000081
3- (1, 3-dioxoisoindoline-5-formamido) propionic acid (5.0 mmol) is dissolved in N, N-Dimethylacetamide (DMAC), potassium carbonate (5.5 mmol) is added, stirring is carried out, reaction is carried out for 2h at 80 ℃, a monochloro beta-elemene mixture (2.5 mmol) is added, reaction is continued for 6-8h, 10mL of water is added after the reaction is finished, ethyl acetate extraction is carried out, a large amount of water is used for washing the organic phase, saturated sodium chloride solution is used for washing the organic phase, anhydrous sodium sulfate is used for drying, concentration is carried out to obtain a crude product of the target compound, and the colorless oily target compound is obtained through separation and purification by silica gel column chromatography or preparative thin layer chromatography, and the yield is 45.3%. 1 H NMR(600MHz,CDCl 3 )δ8.51(d,J＝10.5Hz,1H),8.44(d,J＝7.2Hz,1H),7.94(dd,J＝11.1,7.9Hz,1H),5.82(dd,J＝17.4,10.9Hz,1H),5.14(d,J＝35.8Hz,1H),4.97(d,J＝14.6Hz,1H),4.94–4.87(m,3H),4.83(s,1H),4.79(s,1H),4.74–4.68(m,1H),4.60(s,1H),4.35–4.26(m,1H),2.24–1.95(m,4H),1.78–1.39(m,9H),1.02(s,3H)；ESI-MS，m/z 487.44[M+Na] + 。
Example 14
Figure BDA0003699731480000082
The preparation method of example 13 was followed using a mixture of monochloro beta-elemene and 4- (1, 3-dioxoisoindoline-5-carboxamide) butyric acid as starting materials to give the title compound as a colourless oil in 42.5% yield. 1 H NMR(600MHz,CDCl 3 )δ8.51(d,J＝10.8Hz,1H),8.44(dd,J＝8.1,4.7Hz,1H),7.94(dd,J＝11.3,7.6Hz,1H),5.82(dd,J＝17.4,10.8Hz,1H),5.14(d,J＝35.8Hz,1H),4.97(d,J＝15.1Hz,1H),4.92(dd,J＝6.9,3.1Hz,1H),4.90(d,J＝4.0Hz,2H),4.83(s,1H),4.79(s,1H),4.71(dd,J＝14.9,5.3Hz,1H),4.60(s,1H),4.31(d,J＝4.9Hz,1H),2.16–1.95(m,3H),1.74(d,J＝12.8Hz,1H),1.71(s,3H),1.63(ddd,J＝25.0,12.2,8.1Hz,1H),1.49(dd,J＝15.1,7.3Hz,4H),1.26(d,J＝6.1Hz,3H),1.02(s,3H)；ESI-MS，m/z 502.9[M+Na] + 。
Example 15
Figure BDA0003699731480000091
The preparation method of example 13 was followed using a mixture of monochloro beta-elemene and 6- (1, 3-dioxoisoindoline-5-carboxamide) hexanoic acid as starting materials to give the title compound as a colourless oil in 40.3% yield. 1 H NMR(600MHz,CDCl 3 )δ8.51(d,J＝10.1Hz,1H),8.43(d,J＝6.4Hz,1H),7.94(dd,J＝10.5,7.3Hz,1H),5.82(dd,J＝17.5,10.9Hz,1H),5.36–5.24(m,1H),5.14(d,J＝35.9Hz,1H),5.01–4.94(m,1H),4.94–4.91(m,1H),4.90(d,J＝4.0Hz,1H),4.83(s,1H),4.79(s,1H),4.74–4.67(m,1H),4.60(s,1H),4.35–4.24(m,1H),2.25–1.96(m,5H),1.71(s,3H),1.68–1.36(m,5H),1.28–1.24(m,11H),1.02(s,3H)；ESI-MS，m/z 506.9[M+H] + 。
Example 16
The proliferation inhibition effect of the target compound prepared in the above examples on human burkitt's lymphoma cell line (Raji tumor cells) was measured by the SRB method. Taking cells with good growth state in logarithmic phase, counting and diluting to 10 5 Cell density of individual/mL, 2mL per well, were cultured in 24 well plates. Storing the medicine in dimethyl sulfoxide (DMSO) with storage concentration of 20mMol, taking 1 μL mother liquor, diluting with chromatographic pure ethanol to promote medicine dissolution, diluting the medicine with culture medium to required concentration, and adding into 24-well plate, wherein DMSO content is required<0.1% ethanol content<1%, and culturing in an incubator for 72 hours. Mixing cells, adding equal volume of trypan blue dye solution, mixing, incubating for 30s, counting normal and blue-stained cells with blood cell counting plate, calculating cell survival rate and growth inhibition rate, and calculating drug IC with EXCEL software 50 Values.
The proliferation inhibition effect of the target compounds of examples 3 to 15 on Raji tumor cells was measured by the above method using ibuteinib (Ibrutinib) as a positive control, and the half Inhibition Concentration (IC) of the drug was calculated 50 ) As shown in Table 1. Wherein, most of the compounds have higher activity than the lead compound beta-elemene, and the result shows that the in vitro anticancer activity of the beta-elemene can be enhanced by introducing an imide structure into the beta-elemene structure.
TABLE 1 half-Inhibitory Concentration (IC) of target compounds on cancer cells 50 )
Figure BDA0003699731480000092
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Figure BDA0003699731480000101
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Figure BDA0003699731480000111
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Claims (7)

1. The beta-elemene imide derivative or the pharmaceutical salt thereof is characterized in that the beta-elemene imide derivative is any one of the following structures:
Figure FDA0003699731470000011
2. the β -elemene imide derivative or a pharmaceutically acceptable salt thereof according to claim 1 wherein the pharmaceutically acceptable salt is the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, acetate, tartrate, salicylate, methanesulfonate, succinate, citrate, malate, lactate, fumarate or maleate salt of the β -elemene imide derivative.
3. The use of the beta-elemene imide derivative or the pharmaceutical salt thereof as claimed in claim 1 in the preparation of antitumor drugs.
4. The use of the beta-elemene imide derivative or the pharmaceutically acceptable salt thereof as claimed in claim 1 in the preparation of proliferation inhibitors of Raji tumor cells.
5. A pharmaceutical composition comprising the β -elemene imide derivative of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
6. The use of the pharmaceutical composition of claim 5 for the preparation of an antitumor drug.
7. The use of the pharmaceutical composition of claim 5 for the preparation of proliferation inhibitors of Raji tumor cells.
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CN107216283A (en) * 2017-07-12 2017-09-29 钱春发 A kind of beta-elemene derivatives containing dihydropyridine structure and its production and use
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1844084A (en) * 2006-05-10 2006-10-11 沈阳药科大学 Beta-elemene amino acid or carboxylic acid derivatives and preparation process and use thereof
CN1850779A (en) * 2006-05-10 2006-10-25 沈阳药科大学 Beta-element nitrogenous derivative, and its preparing method and use
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