CN104945336B - 紫苏酸甲酯含氮衍生物及其制备和应用 - Google Patents
紫苏酸甲酯含氮衍生物及其制备和应用 Download PDFInfo
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- CN104945336B CN104945336B CN201410120191.5A CN201410120191A CN104945336B CN 104945336 B CN104945336 B CN 104945336B CN 201410120191 A CN201410120191 A CN 201410120191A CN 104945336 B CN104945336 B CN 104945336B
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- CDSMSBUVCWHORP-UHFFFAOYSA-N R-perillic acid Natural products CC(=C)C1CCC(C(O)=O)=CC1 CDSMSBUVCWHORP-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 26
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 7
- 201000011510 cancer Diseases 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- -1 phenyl Chemical group 0.000 claims description 17
- 125000001424 substituent group Chemical group 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
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- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
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- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
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- 230000001093 anti-cancer Effects 0.000 abstract description 4
- 239000012453 solvate Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
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- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 6
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药技术领域,涉及一系列紫苏酸甲酯含氮衍生物及其制备和应用,具有如式Ⅰ结构特征。本发明还包括所述紫苏酸甲酯含氮衍生物药学上可接受的盐和溶剂化物,以及含有所述紫苏酸甲酯含氮衍生物或其药学上可接受的盐作为活性成分的药物组合物,并可用于治疗癌症。本发明所述的紫苏酸甲酯含氮衍生物及其药用盐类具有较好的抗癌活性,其制备方法简单可行,易操作。
Description
技术领域:
本发明涉及一系列新的紫苏酸甲酯含氮衍生物,该化合物的盐类和以该化合物或其盐类为活性成分的药物组合物及其制备和应用。本发明还涉及紫苏酸甲酯含氮衍生物的合成中所述的中间体的制备方法。
背景技术:
单萜类化合物柠檬烯和紫苏醇具有良好的抗肿瘤作用,在国外已进入临床研究阶段(Vigushin D M,Poon G K.,Boddy A,et al.Phase I and pharmacokinetic study ofd-limonene in patient with advanced cancer.Cancer Chemother Pharmacol,1998,42(2):111-117.Bailey H H,Attia S,Love R R,et al.Phase II trial of daily oralperillyl alcohol(NSC641066)in treatment-refractory metastatic breast cancer[J].Cancer Chemother Pharmacol,2008,62(1):149-157.da Fonseca C O,SchwartsmannG,Fischer J,et al.Preliminary results from a phase I/II study of perillylalcohol intranasal administration in adults with recurrent maligant gliomas[J].Surgical Neurology,2008,70(3):259-266.)。紫苏酸甲酯作为柠檬烯的代谢产物,对法尼基转移酶和香叶酰香叶基转移酶的抑制活性均明显强于柠檬烯和紫苏醇(Gelb M H,Tamanoib F,Yokoyama K,et al.The inhibition of protein prenyltransferases byoxygenated metabolites of limonene and perillyl alcohol.Cancer Letters1995,91(2):169-175.)。
紫苏酸甲酯水溶性差,借鉴本课题组前期对榄香烯、柠檬烯衍生物抗癌构效关系的研究结果,认为增强化合物的极性和水溶性有利于提高抗肿瘤活性(陈娇娇,董金华,景永奎,等.柠檬烯类似物及其制备方法和用途[P].中国专利,200610081622.7,公开号CN101070300.董金华,徐莉英,景永奎,等.一种β-榄香烯含氮衍生物的制备及应用[P].中国专利,200610080037.5,公开号CN1844105.徐莉英,董金华,景永奎,等.β-榄香烯含氮衍生物及其制备方法和用途[P].中国专利,200610081625.0,公开号CN1850779.)。因此,本发明首次明确提出保持紫苏酸甲酯的含双键的单环单萜骨架,在环外烯丙位引入亲水性的含氮基团,从而改善水溶性,提高抗肿瘤活性,合成了本发明所述紫苏酸甲酯含氮衍生物,并经药理试验研究了其抗肿瘤活性。
发明内容:
本发明以紫苏酸甲酯为先导化合物,为提高化合物的极性或亲水性、增强其抗癌活性,在环外烯丙位引入亲水性的胺类基团,合成了紫苏酸甲酯含氮衍生物,并经药理试验证明可抑制多种肿瘤细胞增殖,它们的主要作用为抗肿瘤。
本发明提供紫苏酸甲酯含氮衍生物结构如下式I:
其中,R1、R2选自:C1-C6烷基,C1-C6烷氧基;或NR1R2为5-10元含氮杂环;或NR1R2为带有取代基的哌嗪基,所述取代基为C1-C6烷基、C1-C6烷氧基苯基、含有烯键的C1-C6烷基、含有炔键的C1-C6烷基、含有羟基的C1-C6烷基、含有苯基的C1-C6烷基;带有取代基的氨基,所述取代基选自:C1-C6烷基、C3-C7环烷基。
优选地,R1、R2选自:C1-C4烷基,C1-C4烷氧基;或NR1R2为5-10元含氮杂环;或NR1R2为带有取代基的哌嗪基,所述取代基为C1-C4烷基、C1-C4烷氧基苯基、含有烯键的C1-C4烷基、含有炔键的C1-C4烷基、含有羟基的C1-C4烷基、含有苯基的C1-C4烷基;带有取代基的氨基,所述取代基选自:C1-C4烷基、C3-C6环烷基。
更为优选地,R1、R2选自:甲基、乙基;或NR1R2为5元含氮杂环;或NR1R2为带有取代基的哌嗪基,所述取代基为甲基、乙基、丙基、异丙基、丁基、烯丙基、羟基乙基、苯基甲基、苯基乙基、甲氧基苯基、乙氧基苯基。
最为优选的,本发明的化合物选自:
本发明还提供了紫苏酸甲酯含氮衍生物及其药用盐的制备方法,其合成路线如下:
NR1R2如权利要求书所述,
优选:
本发明上述紫苏酸甲酯含氮衍生物及其药用盐类的制备过程中所用溶剂为常用的反应溶剂,无特殊要求。
本发明提供了含上述紫苏酸甲酯含氮衍生物及其药用盐类,其特征在于,所述的药用盐指常规的酸加成盐。
所述的药用盐为与与合适的非毒性有机酸或无机酸成的盐。如盐酸,氢溴酸,氢碘酸,硫酸,磷酸,硝酸,乙酸,酒石酸,水杨酸,甲磺酸,丁二酸,柠檬酸,苹果酸,乳酸,富马酸,马来酸等。
本发明提供了一种药物组合物,所述组合物由上述的紫苏酸甲酯含氮衍生物及其药用盐类和药学上可被接受的赋形剂组成。提供了紫苏酸甲酯含氮衍生物及其药用盐类及其组合物在制备抗癌药物中的用途。
本发明所描述的紫苏酸甲酯含氮衍生物,是为改善紫苏醇的水溶性和提高抗癌活性,而在其分子中引入含氮基团所合成的化合物,这些衍生物可能具有更强的生理活性和较大极性,其氨基便于和酸成盐来达到改善水溶性的目的。
本发明的紫苏酸甲酯含氮衍生物及其药用盐类具有较好的抗癌活性,其制备方法简单可行,易操作。
具体实施方式:
下面通过实施例来说明本发明的可实施性,本领域的技术人员应当理解,根据现有技术的教导,对相应的技术特征进行修改或替换,仍然属于本发明要求保护的范围。
实施例1紫苏酸的合成
在1000mL茄形瓶中加入0.1mol紫苏醛,58mL2-甲基-2-丁烯(含量90%),100mL叔丁醇,冰浴下滴加0.1mol亚氯酸钠(含量80%)、0.39mol二水合磷酸二氢钠和130mL水的混合溶液。加毕后室温搅拌2h。加入50mL乙醚,分离有机相和水相,水相用乙醚萃取,合并有机相,无水硫酸钠干燥。浓缩,得白色固体,用乙酸乙酯重结晶得白色片状结晶,收率52.9%,熔点,130-131℃。
实施例2紫苏酸甲酯的合成
将0.05mol实施例1产物,0.07mol碳酸钾溶于100mLDMF中,室温搅拌下滴加0.06mol碘甲烷的DMF(20mL)溶液,加毕后室温反应5h,加入50mL饱和盐水溶液,水层用乙醚萃取,合并有机相,用饱和盐水溶液洗涤有机相,无水硫酸钠干燥。浓缩后得无色液体,收率95.3%。
实施例3氯代紫苏酸甲酯的合成
在100mL茄形瓶中加入25.8mmol实施例2产物、20mL二氯甲烷和38.7mmol冰醋酸,冰浴下缓慢滴加77.3mmol次氯酸钠水溶液(含有效氯8%)。加毕继续反应30min。加10mLNa2SO3水溶液,分出有机层,水层用二氯甲烷萃取,合并有机相,用水和饱和NaCl溶液洗涤,无水硫酸钠干燥。浓缩得淡黄色液体,收率85.9%。
实施例4紫苏酸甲酯含氮衍生物的合成通法
将3.50mmol实施例3产物和5.25mmol碳酸钾溶于10mL丙酮中。搅拌下滴加4.20mmol胺类化合物,加热回流反应6-8h。减压蒸除丙酮,加入10mL饱和盐水,转移至分液漏斗中,用二氯甲烷萃取,合并有机相,无水硫酸钠干燥。浓缩后得化合物1-11。
按此合成方法得到:
化合物1:淡黄色固体。熔点161-164℃。MS(EI)[M+H]+m/z:279.2068.1H NMR(300MHz,CDCl3)δ(ppm):6.98(1H,br s),4.99,4.94(2H,s,s),3.74(3H,s),3.41-3.21(2H,m),3.17–2.72(5H,m),2.66–2.02(7H,m),1.98–1.76(1H,m),1.61–1.36(4H,m).
化合物2:淡黄色固体。熔点165-168℃。MS(EI)[M+H]+m/z:293.2224.1H NMR(300MHz,CDCl3)δ(ppm):6.98(1H,br s),4.98,4.90(2H,s,s),3.73(3H,s),3.17-2.71(6H,m),2.52–2.05(5H,m),1.99–1.80(3H,m),1.56–1.41(1H,m),1.27(6H,d,J=6.3Hz).
化合物3:白色固体。熔点83-85℃。MS(EI)[M+H]+m/z:371.2329.1H NMR(300MHz,CDCl3)δ(ppm):7.01(1H,br s),6.95-6.76(4H,m),5.03,4.92(2H,s,s),3.78(3H,s),3.74(3H,s),3.28–2.84(6H,m),2.67–2.50(4H,m),2.50–2.01(5H,m),2.01–1.87(1H,m),1.60–1.47(1H,m).
化合物4:白色固体。熔点45-46℃。MS(EI)[M+H]+m/z:279.2068.1H NMR(300MHz,CDCl3)δ(ppm):7.00(1H,br s),4.98,4.88(2H,s,s),3.73(3H,s),2.94(2H,s),2.54–2.33(9H,m),2.30(3H,s),2.30–2.03(4H,m),1.96–1.83(1H,m),1.58–1.44(1H,m).
化合物5:淡黄色油状物。MS(EI)[M+H]+m/z:307.2380.1H NMR(300MHz,CDCl3)δ(ppm):7.00(1H,br s),4.98,4.87(2H,s,s),3.73(3H,s,),2.93(2H,s),2.73-2.54(1H,m),2.59–2.41(8H,m),2.41–2.03(5H,m),1.93–1.85(1H,m),1.56–1.43(1H,m),1.06(6H,d,J=6.5Hz).
化合物6:淡黄色油状物。MS(EI)[M+H]+m/z:321.2536.1H NMR(300MHz,CDCl3)δ(ppm):6.99(1H,br s),4.99,4.90(2H,s,s),3.73(3H,s),2.98(2H,s),2.76-2.45(10H,m),2.42–2.35(1H,m),2.35–2.03(4H,m),1.96–1.85(1H,m),1.66–1.29(5H,m),0.93(3H,t,J=7.3Hz).
化合物7:白色固体。熔点33-34℃。MS(EI)[M+H]+m/z:305.2223.1H NMR(300MHz,CDCl3)δ(ppm):6.99(1H,br s),5.96–5.80(1H,m),5.26–5.10(2H,m),4.98,4.87(2H,s,s),3.73(3H,s),3.01(2H,d,J=6.6Hz),2.94(2H,s),2.65–2.40(8H,m),2.40–2.04(5H,m),1.95–1.83(1H,m),1.58–1.43(1H,m).
化合物8:淡黄色固体。熔点55-57℃。MS(EI)[M+H]+m/z:309.2174.1H NMR(300MHz,CDCl3)δ(ppm):7.00(1H,br s),4.98,4.89(2H,s,s),3.73(3H,s),3.66–3.53(2H,m),2.95(2H,s),2.60–2.36(10H,m),2.36–1.87(6H,m),1.58–1.42(1H,m).
化合物9:白色固体。熔点53-55℃。MS(EI)[M+H]+m/z:355.2381.1H NMR(300MHz,CDCl3)δ(ppm):7.33-7.28(5H,m),7.01(1H,br s),4.99,4.88(2H,s,s),3.74(3H,s),2.95(2H,s),2.62-2.40(10H,m),2.40-2.05(5H,m),1.94-1.85(1H,m),1.57-1.43(1H,m).
化合物10:淡黄色油状物。MS(EI)[M+H]+m/z:250.1801.1H NMR(300MHz,CDCl3)δ(ppm):6.99(1H,br s),5.00,4.84(2H,s,s),3.73(3H,s),3.07(2H,s),2.55-2.43(4H,m),2.43-2.04(5H,m,),1.95-1.85(1H,m),1.81-1.67(4H,m),1.56-1.44(1H,m).
化合物11:淡黄色油状物。MS(EI)[M+H]+m/z:224.1645.1H NMR(300MHz,CDCl3)δ(ppm):7.00(1H,br s),4.98,4.88(2H,s,s),3.73(3H,s),2.87(2H,s),2.51–2.24(4H,m),2.19(6H,s),2.14-2.15(1H,m),1.95–1.84(1H,m),1.54–1.45(1H,m).
实施例5
用MTT法测定了目标化合物对人宫颈癌细胞HeLa,人肝癌细胞HepG2,人结肠癌细胞HCT116,人肺癌细胞A549,人黑色素瘤细胞A375-S2,人纤维肉瘤细胞HT1080和人原髓细胞白血病细胞HL60七类肿瘤细胞的增殖抑制作用。
1)贴壁细胞选用对数生长期的贴壁肿瘤细胞,用胰酶消化后,用含10%小牛血清的RPMI l640培养基配成5×104/ml的细胞悬液,接种在96孔培养板中,每孔100μl,37℃,5%CO2培养24h。实验组更换新的含不同浓度被测样品(10~100μmol·L-1)的培养液,对照组则更换含等体积溶剂的培养液,每组设3个平行孔,37℃,5%CO2培养48h。弃去上清液,用PBS小心洗2次,每孔加入100μl新鲜配制的含0.5mg/ml MTT的培养基,37℃继续培养4h。小心弃去上清,并加入150μl DMSO,用微型振荡器混匀10min后,用酶标仪在492nm处测定光密度值(OD)。
2)悬浮细胞选用对数生长期的细胞,用含10%小牛血清的RPMI l640培养基配成1×104/ml的细胞悬液,接种在96孔培养板中,每孔50μl,37℃,5%CO2培养24h。实验组加入含不同浓度被测样品(10~100μmol·L-1)的培养液50μl,对照组则加入含等体积溶剂的培养液,每组设3个平行孔,37℃,5%CO2培养48h,每孔加入10μl新鲜配制的含5mg/ml MTT的培养基,37℃继续培养4h。用三联液(SDS10g,10M HCl0.1mL,异丁醇5mL,用蒸馏水稀释至100mL)100μl溶解结晶,37℃孵育12h。用酶标仪在492nm处测定光密度值(OD)。
按以下公式计算药物对肿瘤细胞体外增殖的抑制率(Inhibition Rate,IR%):
IR%=(1-ODsample/ODcontrol)×100%
用ICP1.0.0软件计算药物的半数抑制浓度(IC50)。
结果见下表,所有目标化合物抑制七种肿瘤细胞株的IC50值均小于紫苏酸甲酯,因此,在紫苏酸甲酯结构中引入含氮基团可提高化合物的体外抗肿瘤活性。
表1式Ⅰ化合物和紫苏酸甲酯对肿瘤细胞的IC50值
。
Claims (10)
1.一种紫苏酸甲酯含氮衍生物及其盐,具有式I的结构:
其中,NR1R2为带有取代基的哌嗪基,所述取代基为C1-C6烷基、C1-C6烷氧基苯基、含有羟基的C1-C6烷基、含有苯基的C1-C6烷基。
2.如权利要求1所述的紫苏酸甲酯含氮衍生物及其盐,其特征在于,NR1R2为带有取代基的哌嗪基,所述取代基为C1-C4烷基、C1-C4烷氧基苯基、含有羟基的C1-C4烷基、含有苯基的C1-C4烷基。
3.如权利要求1所述的紫苏酸甲酯含氮衍生物及其盐,其特征在于,NR1R2为带有取代基的哌嗪基,所述取代基为甲基、乙基、丙基、异丙基、丁基、羟基乙基、苯基甲基、苯基乙基、甲氧基苯基、乙氧基苯基。
4.如下的紫苏酸甲酯含氮衍生物及其盐,其特征在于,选自
。
5.如权利要求1所述的紫苏酸甲酯含氮衍生物及其药用盐,其特征在于,所述的盐指常规的酸加成盐。
6.如权利要求5所述的紫苏酸甲酯含氮衍生物及其药用盐,其特征在于,所述的酸为有机酸或无机酸,为盐酸,溴酸,氢碘酸,硫酸,磷酸,硝酸,乙酸,酒石酸,水杨酸,甲磺酸,丁二酸,柠檬酸,苹果酸,乳酸,富马酸或马来酸。
7.一种药物组合物,其特征在于,包含权利要求1-6任何一项所述的紫苏酸甲酯含氮衍生物及其药用盐和药学上可被接受的赋形剂。
8.一种如权利要求1所述的紫苏酸甲酯含氮衍生物及其盐的制备方法,其特征在于:合成路线如下:
NR1R2如权利要求1所述。
9.权利要求1-6任何一项所述紫苏酸甲酯含氮衍生物及其盐或权利要求7所述的药物组合物在制备抗肿瘤药物中的应用。
10.根据权利要求9所述的应用,其特征在于:所述的肿瘤为宫颈癌、肝癌、纤维肉瘤、结肠癌、黑色素瘤、乳腺癌、肺癌、淋巴癌、原髓细胞白血病。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1733683A (zh) * | 2005-08-05 | 2006-02-15 | 中国科学院广州化学研究所 | 一种制备4-异丙基环己烷甲酸的方法 |
CN1850779A (zh) * | 2006-05-10 | 2006-10-25 | 沈阳药科大学 | β-榄香烯含氮衍生物及其制备方法和用途 |
CN101429175A (zh) * | 2008-12-12 | 2009-05-13 | 天津工业大学 | 一种具有抗肿瘤活性的紫苏醇衍生物及其用途 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1733683A (zh) * | 2005-08-05 | 2006-02-15 | 中国科学院广州化学研究所 | 一种制备4-异丙基环己烷甲酸的方法 |
CN1850779A (zh) * | 2006-05-10 | 2006-10-25 | 沈阳药科大学 | β-榄香烯含氮衍生物及其制备方法和用途 |
CN101429175A (zh) * | 2008-12-12 | 2009-05-13 | 天津工业大学 | 一种具有抗肿瘤活性的紫苏醇衍生物及其用途 |
Non-Patent Citations (1)
Title |
---|
食物来源单萜类物质紫苏醇的抗癌作用;胡东等;《临床血液学杂志》;20010430;第14卷(第3期);141-143 * |
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