CN107501380A - 23‑羟基白桦酸23位修饰衍生物、其制备方法及用途 - Google Patents
23‑羟基白桦酸23位修饰衍生物、其制备方法及用途 Download PDFInfo
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
- C07J63/008—Expansion of ring D by one atom, e.g. D homo steroids
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及天然药物及药物化学领域,具体涉及23‑羟基白桦酸衍生物(I),该衍生物为23‑羟基白桦酸的C23位进行结构改造所获得的产物。本发明还公开了这些23‑羟基白桦酸衍生物的制备方法以及这些新型衍生物用于抗肿瘤的用途。
Description
技术领域
本发明涉及天然药物及药物化学领域,具体涉及23-羟基白桦酸衍生物(I),该衍生物为23-羟基白桦酸的C23位进行结构改造所获得的产物。本发明还公开了这些23-羟基白桦酸衍生物的制备方法以及这些新型衍生物用于抗肿瘤的用途。
背景技术
中药白头翁是毛茛科白头翁属多年生草本植物,我国分布广泛,具有清热解毒、凉血止痢等功效。23-羟基白桦酸(23-hydroxybetulinic acid,23-HBA)最初是从中药白头翁[Pulsatilla chinensis(Bunge)Regel]中发现的五环三萜类化合物,可以看作是白桦酸的衍生物。1962年有其提取分离报道,1983年证实其结构,1984年报道了晶体结构。1990年后叶文才等详细研究了白头翁的化学成分,还发现23-羟基白桦酮酸等成分。
23-HBA具有抑制多种肿瘤细胞增殖的活性。研究表明,23-HBA对于HL-60, BEL-7402,SF-763,Hela和B16的IC50分别为45.15μM,39.67μM,43.40μM,52.39μM和29.87μM。BinYe等人(见李学汤,张覃沐。药学学报,1985,20,243;王绵英,张覃沐。中国药理学报,1985,6,195)研究发现23-HBA通过上调凋亡基因beclin-1的表达,促进了HL-60的自噬凋亡。在K562细胞株中,23-HBA 能显著影响线粒体膜电位,并且能选择性下调Bcl-2,生物素等抗凋亡基因,上调Bax,细胞色素C,caspase-9和caspase-3等促凋亡基因。Wing-Keung Liu等人(见CN101139350;Jinyi Xu,JingYi Yang,et al.Bioorg.Med.Chem.Lett.,2008, 18:4741)发现23-HBA也能产生大量的活性自由基而导致B16细胞株的凋亡。
白桦酸是五环三萜类天然产物中一种研究较为深入的化合物,因其优秀的抗 HIV活性和抗肿瘤活性而备受瞩目。23-HBA可以看作是白桦酸C-23位羟基化的衍生物,比白桦酸多了一个特殊的可供结构修饰的位点。前人的研究主要参照白桦酸的成功经验,而对23位羟基的研究颇为少见,故目前C-23位的构效关系仍然不明。
我们立足于天然产物的结构改造寻找新药分子,通过对23位羟基的酰化,引入不同大小的脂肪族侧链、不同位置不同基团取代的苯环、杂环取代基,得到了活性较好的抗肿瘤化合物。
发明内容
本发明的目的旨在寻找研发活性好,毒性小,对耐药肿瘤有效的23-HBA衍生新药候选化合物,并进一步提供一种治疗肿瘤及其它疾病或病症的药物组合物。
为解决上述技术问题,本发明提供如下技术方案:
通式(I)的23-HBA衍生物或其药学上可接受的盐:
其中:R1代表环己基、4-甲基环己基、4-羰基环己基、2-氧代环己基、3,5- 二氧代环己基、3-甲氧基环己基、3-甲基环己基、螺[2.5]辛烷基、环丙基、反式 -2-氟环丙烷基、双环[2.2.1]庚烷基、邻甲基苯基、间甲基苯基、对甲基苯基、邻羟基苯基、间羟基苯基、4-羟基-2-甲基苯、2-甲基-3-羟基苯基、2-羟基-6- 甲基苯基、2,5-二甲基苯基、2,3-二甲基苯基、2,4-二甲基苯基、对羟基苯基、 4-乙炔基苯基、3-乙炔基苯基、2-乙烯基苯、3-乙烯基苯、4-乙烯基苯、对甲氧基取代苯基、邻甲氧基取代苯基、间甲氧基取代苯基、对氨基取代苯基、邻氨基取代苯基、3,4-二氨基苯基、2,3-二氨基苯基、5-氨基-2-甲基苯基、3-氨基-5-甲基苯基、4-氨基-2-甲基苯基、2-氨基-3-甲基苯基、2-氨基-6-甲基苯、3-甲氨基苯基、3-羟基-2-氨基苯基、邻硝基取代苯基、间硝基取代苯基、对硝基取代苯基、 2,4-二硝基苯基、4-(N,N-二(2-氯乙基)氨基)苯基、邻氟苯基、3-氟-4-甲基苯基、3-氟-5-甲基苯基、4-氟-3-羟基苯基、2-氟-5-羟基苯基、对氟苯基、间氟苯基、多氟取代苯基、3-氟-4-氨基苯基、对氯苯基、间氯苯基、对三氟甲基苯基、邻三氟甲基苯基、对醛基苯、邻醛基苯、间醛基苯、3-吡啶基、1-萘甲基、苯乙烯基、对氟苯基乙烯基、邻氟苯基乙烯基、间氟苯基乙烯基、对硝基苯基乙烯基、间硝基苯基乙烯基、对甲氧基苯基乙烯基、多甲氧基取代苯基乙烯基、3-(4-(N,N-二(2-氯乙基)氨基)苯基)丙基;
R2代表氢或苄基。
本发明通式I的23-羟基白桦酸衍生物,其中
R1优选代表环己烷、对甲氧基取代苯基、对氨基取代苯基、邻硝基取代苯基、间硝基取代苯基、对硝基取代苯基、2,4-二硝基苯基、4-(N,N-二(2-氯乙基)氨基)苯基、对氟苯基、间氟苯基、多氟取代苯基、对氯苯基、间氯苯基、对三氟甲基苯基、邻三氟甲基苯基、3-吡啶基、1-萘甲基、苯乙烯基、对氟苯基乙烯基、对硝基苯基乙烯基、对甲氧基苯基乙烯基、多甲氧基取代苯基乙烯基、 3-(4-(N,N-二(2-氯乙基)氨基)苯基)丙基;
R2优选代表氢或苄基。
通式(I)的化合物或其药学上可接受的盐更为理想的是:其中
R1代表环己烷、间硝基取代苯基、4-(N,N-二(2-氯乙基)氨基)苯基、对甲氧基取代苯基、间氯苯基、对三氟甲基苯基、邻三氟甲基苯基、2,3,4,5-四氟苯基、3-吡啶、1-萘甲基、苯乙烯基、对氟苯基乙烯基、对硝基苯基乙烯基、3-(4- (N,N-二(2-氯乙基)氨基)苯基)丙基;
R2代表氢。
本发明的部分优选化合物为:
3-羟基-23-环己甲酰氧基-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-间硝基苯甲酰氧基-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-氮芥苯甲酰氧基-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-对氟苯甲酰氧基-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-间氯苯甲酰氧基-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-邻三氟甲基苯甲酰氧基-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-对三氟甲基苯甲酰氧基-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-(2,3,4,5-四氟苯甲酰氧基)-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-(3-吡啶甲酰氧基)-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-氮芥苯丁酰氧基-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-对甲氧基苯甲酰氧基-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-对氟肉桂酰氧基-羽扇豆-20(29)-烯-28-酸。
发明内容
本发明通式I的衍生物可用下列方法制备得到:
a、将23-HBA或28-苄基23-HBA溶解于二氯甲烷/吡啶中;
b、加入相应的酸、DMAP和EDCI/DCC,室温搅拌反应8-24h;
c、将步骤b产物经水洗,柱层析纯化,得到通式为I的化合物。
药理试验证明,本发明的23-HBA衍生物具有更好的抗肿瘤作用,可以用于进一步制备抗肿瘤药物。优选治疗的肿瘤疾病是肝癌、黑色素瘤、乳腺癌以及卵巢癌。
下面是本发明部分化合物的体外抗人类多种肿瘤增殖活性的药理实验结果:
实验设备与试剂
仪器 超净工作台(苏州艾可林净化设备有限公司)
恒温CO2培养箱(日本SANYO)
酶联免疫检测仪(美国BIO-RAD)
倒置生物显微镜(日本OLYMPUS)
试剂 青、链霉素混合液(南京凯基生物科技发展有限公司)
胰蛋白酶消化液(南京凯基生物科技发展有限公司)
PBS(南京凯基生物科技发展有限公司)
MTT(BIOSHARP)
DMSO(SIGMA)
细胞株 人卵巢癌细胞A2780、人恶性黑色素瘤细胞A375、小
鼠黑色素瘤细胞B16、人乳腺癌细胞MCF-7、人肝癌细
胞HepG2。
实验方法
1.细胞消化、计数、制成浓度为5×104个/mL的细胞悬液,96孔板中每孔加入100μl细胞悬液(每孔5×103个细胞);
2.96孔板置于37℃,5%CO2培养箱中培养24小时;
3.用完全培养基稀释药物至所需浓度,每孔加入100μL相应的含药培养基;
4.96孔板置于37℃,5%CO2培养箱中培养72小时;
5.MTT法:
1)将96孔板进行MTT染色,λ=490nm,测定OD值。
2)每孔加入20μL MTT(5mg/mL),在培养箱继续培养4小时;
3)弃去培养基,每孔加入150μL DMSO溶解,摇床10分钟轻轻混匀;λ=490nm,酶标仪读出每孔的OD值。
6.计算抑制率。
实验结果
表1.实施例对5种细胞株抗增殖活性的IC50值(μM)
具体实施方式
以下通过实施例形式展示具体的实施方式,对本发明内容进行进一步的详细说明,但不应当将此理解为本发明上述主题的范围仅限于以下的实施例,凡是基于本发明上述内容在本领域内所能实现的技术均应属于本发明的内容。
实施例1
3-羟基-23-环己甲酰氧基-羽扇豆-20(29)-烯-28-酸
将23-HBA(100mg,0.21mmol)溶于无水吡啶(3mL)中,加入DMAP(25mg, 0.21mmol)、DCC(44mg,0.21mmol)和环己烷羧酸(1eq)。室温搅拌反应6-12 h。乙酸乙酯(50mL)稀释,10%盐酸洗至酸性,水洗两次,饱和食盐水洗两次,无水硫酸钠干燥,过滤,浓缩,柱层析,得目标产物(均为白色固体)。 60.3%。1H NMR(CDCl3,300MHz)δ:0.67(3H,s),0.79(3H,s),0.86(3H,s), 0.89(3H,s),1.62(3H,s),2.08-2.32(3H,m),2.95(1H,m,H-19),3.32(1H,t,J=8.2Hz,H-3),3.74,4.08(each 1H,d,J=11.4Hz,H-23),4.54,4.67(each 1H, s,H-29);13C NMR(CDCl3,75MHz)δ:11.7,14.5,16.0,16.5,18.1,19.4,20.9, 24.7,25.4,25.8,26.2,29.1,29.3,29.7,30.6,32.2,34.0,37.0,38.4,38.7,40.7,42.3,42.4,43.4,46.9,48.1,49.3,50.8,56.4,66.2,72.6,109.6,150.4,176.2,182.0; ESI-MS m/z:581.4[M-H]-,617.4[M+Cl]-。
实施例2
3-羟基-23-间硝基苯甲酰氧基-羽扇豆-20(29)-烯-28-酸
合成方法参照实施例1的合成,60.8%。1H NMR(CDCl3,300MHz)δ:0.84 (3H,s),0.91(3H,s),0.96(3H,s),0.97(3H,s),1.69(3H,s),2.15-2.33(2H, m),3.02(1H,m,H-19),3.50(1H,m,H-3),4.05(1H,d,J=11.4Hz,H-23a), 4.58(1H,d,J=11.4Hz,H-23b),4.61,4.74(each 1H,s,H-29),7.70(1H,t,J= 8.0Hz),8.39(1H,d,J=7.8Hz),8.46(1H,d,J=8.2Hz),8.86(1H,s);ESI-MS m/z:622.4[M+H]+.
实施例3
3-羟基-23-氮芥苯甲酰氧基-羽扇豆-20(29)-烯-28-酸
将28-苄基23-HBA(200mg,0.35mmol)溶于无水二氯甲烷(10mL)中,加入 DMAP(42mg,0.35mmol)、DCC(73mg,0.35mmol)和相应羧酸(1eq)。室温搅拌反应6-12h。乙酸乙酯(50mL)稀释,10%盐酸洗至酸性,水洗两次,饱和食盐水洗两次,无水硫酸钠干燥,过滤,浓缩,柱层析(石油醚∶乙酸乙酯=8∶1-5∶1),得苄基产物。将得到的苄基产物溶于四氢呋喃(15mL)中,加入 10%钯碳(苄基产物质量20%量),室温常压氢化,TLC跟踪反应至原料大部分反应但不完全反应,过滤,浓缩,柱层析得目标产物(均为白色固体) 55.2%。1H NMR(CDCl3,300MHz)δ:0.77(s,3H),0.80(s,3H),0.85(s,3H), 0.92(s,3H),1.67(3H,s,Me-30),2.18(1H,m),2.27(1H,m),3.00(1H,m, H-19),3.41(1H,m,H-3),3.62-3.68(m,4H),3.75-3.83(m,4H),3.89(1H,d,J =11.4Hz,H-23a),4.47(1H,d,J=11.4Hz,H-23b),4.59(1H,s,H-29a),4.72(1 H,s,H-29b),6.67(d,J=9.1Hz,2H),7.92(d,J=9.1Hz,2H);13C NMR(CDCl3,75MHz)δ:11.9,14.6,15.8,16.7,18.2,19.4,20.9,25.5,26.1,29.5,30.6, 32.1,34.1,36.9,37.1,38.2,38.7,40.1,40.7,42.4,42.7,46.9,48.6,49.4,50.9, 53.3,56.5,65.7,72.4,109.6,110.9,128.5,131.8,149.8,166.8,181.2;ESI-MS m/z:758.4[M-H]-.
实施例4
3-羟基-23-对氟苯甲酰氧基-羽扇豆-20(29)-烯-28-酸
合成方法参照实施例1的合成,66.0%。1H NMR(CDCl3,300MHz)δ:0.82(3 H,s),0.89(3H,s),0.95(6H,s),1.68(3H,s),1.93-2.12(2H,m),2.14-2.31(2 H,m),3.03(1H,m,H-19),3.47(1H,t,J=7.4Hz,H-3),3.99,4.48(each 1H,d, J=11.5Hz,H-23),4.61,4.74(each 1H,s,H-29),7.14(2H,m),8.06(2H,dd,J =8.7,5.6Hz);ESI-MS m/z:758.4[M-H]-.
实施例5
3-羟基-23-间氯苯甲酰氧基-羽扇豆-20(29)-烯-28-酸
合成方法参照实施例1的合成,45.7%。1H NMR(CDCl3,300MHz)δ:0.82(3 H,s),0.89(3H,s),0.95(3H,s),0.98(3H,s),1.67(3H,s),2.11-2.28(2H,m), 3.00(1H,m,H-19),3.48(1H,m,H-3),4.03(1H,d,J=11.4Hz,H-23a),4.50(1 H,d,J=11.4Hz,H-23b),4.59,4.72(each 1H,s,H-29),7.41(1H,d,J=7.8 Hz),7.55(1H,d,J=8.7Hz),7.91(1H,d,J=7.8Hz),7.98(1H,s);ESI-MS m/z: 609.3[M-H]-.
实施例6
3-羟基-23-邻三氟甲基苯甲酰氧基-羽扇豆-20(29)-烯-28-酸
合成方法参照实施例1的合成,56.6%。1H NMR(CDCl3,300MHz)δ:0.82(3 H,s),0.89(3H,s),0.96(6H,s),1.69(3H,s),2.18-2.31(2H,m),3.01(1H,m, H-19),3.52(1H,m,H-3),4.14(1H,d,J=11.5Hz,H-23a),4.43(1H,d,J= 11.5Hz,H-23b),4.61,4.74(each1H,s,H-29),7.63(2H,m),7.78(1H,m),7.83 (1H,m);ESI-MS m/z:643.4[M-H]-.
实施例7
3-羟基-23-对三氟甲基苯甲酰氧基-羽扇豆-20(29)-烯-28-酸
合成方法参照实施例1的合成,63.5%。1H NMR(CDCl3,300MHz)δ:0.75(3 H,s),0.82(3H,s),0.89(6H,s),1.61(3H,s),1.81-1.98(3H,m),2.07-2.24(2 H,m),2.93(1H,m,H-19),3.45(1H,t,J=7.7Hz,H-3),3.98,4.42(each 1H,d, J=11.5Hz,H-23),4.53,4.66(each 1H,s,H-29),7.65(2H,d,J=8.2Hz),8.08 (2H,d,J=8.2Hz);ESI-MS m/z:643.4[M-H]-,679.4[M+Cl]-;ESI-MS m/z: 643.4[M-H]-.
实施例8
3-羟基-23-(2,3,4,5-四氟苯甲酰氧基)-羽扇豆-20(29)-烯-28-酸
合成方法参照实施例1的合成,60.3%。1H NMR(CDCl3,300MHz)δ:0.74(3 H,s),0.81(3H,s),0.88(3H,s),0.90(3H,s),1.62(3H,s),1.83-1.97(3H,m),2.08-2.24(2H,m),2.94(1H,m,H-19),3.44(1H,t,J=7.7Hz,H-3),3.98,4.42 (each 1H,d,J=11.4Hz,H-23),4.54,4.67(each 1H,s,H-29),7.56(1H,dd,J =14.1,7.9Hz);ESI-MS m/z:647.3[M-H]-.
实施例9
3-羟基-23-(3-吡啶甲酰氧基)-羽扇豆-20(29)-烯-28-酸
合成方法参照实施例1的合成,42.1%。1H NMR(CDCl3,300MHz)δ:0.75(3 H,s),0.82(3H,s),0.86(3H,s),0.88(3H,s),1.61(3H,s),1.82-1.98(3H,m), 2.10-2.22(2H,m),2.94(1H,m,H-19),3.45(1H,t,J=7.3Hz,H-3),4.02,4.40 (each 1H,d,J=11.4Hz,H-23),4.53,4.66(each 1H,s,H-29),7.36(1H,dd,J =7.7,5.1Hz),8.25(1H,d,J=7.9Hz),8.75(1H,d,J=3.7Hz),9.16(1H,s);ESI-MS m/z:576.4[M-H]-.
实施例10
3-羟基-23-氮芥苯丁酰氧基-羽扇豆-20(29)-烯-28-酸
合成方法参照实施例3的合成,41.0%。1H NMR(CDCl3,300MHz)δ:0.74(s, 6H),0.83(s,3H),0.90(s,3H),1.67(3H,s,Me-30),2.18(1H,m),2.24(1H,m),2.32(t,J=7.4Hz,2H),2.57(t,J=7.4Hz,2H),3.01(1H,m,H-19),3.38(1 H,m,H-3),3.62(m,4H),3.68(m,4H),3.79(1H,d,J=11.4Hz,H-23a),4.17 (1H,d,J=11.4Hz,H-23b),4.59(1H,s,H-29a),4.72(1H,s,H-29b),6.62(d,J =8.4Hz,2H),7.07(d,J=8.3Hz,2H);13C NMR(CDCl3,75MHz)δ:11.9,14.6, 15.8,16.7,18.2,19.4,20.9,25.5,26.1,29.5,30.6,32.1,34.1,34.3,36.9,37.1, 38.2,38.7,40.1,40.5,40.7,42.4,42.7,46.9,47.0,48.6,49.4,50.9,53.6,56.5, 65.7,72.4,109.6,112.3,129.5,130.8,144.1,167.8,181.1.
实施例11
3-羟基-23-对甲氧基苯甲酰氧基-羽扇豆-20(29)-烯-28-酸
合成方法参照实施例1的合成,56.9%。1H NMR(CDCl3,300MHz)δ:0.81(3 H,s),0.88(3H,s),0.95(6H,s),1.68(3H,s),1.88-2.02(2H,m),2.13-2.32(2H, m),3.00(1H,m,H-19),3.88(3H,s),3.93(1H,m,H-3),3.69(1H,d,J=11.6 Hz,H-23a),4.49(1H,d,J=11.6Hz,H-23b),4.60,4.73(each 1H,s,H-29),6.94 (2H,d,J=8.8Hz),8.00(2H,d,J=8.8Hz);ESI-MS m/z:607.4[M+H]+.
实施例12
3-羟基-23-对氟肉桂酰氧基-羽扇豆-20(29)-烯-28-酸
合成方法参照实施例1的合成,46.6%。1H NMR(CDCl3,300MHz)δ:0.80(3 H,s),0.89(3H,s),0.96(3H,s),0.98(3H,s),1.69(3H,s),1.88-2.05(3H,m), 2.16-2.33(2H,m),3.02(1H,m,H-19),3.46(1H,t,J=7.2Hz,H-3),3.92,4.36 (each 1H,d,J=11.6Hz,H-23),4.61,4.74(each 1H,s,H-29),6.39(1H,d,J= 15.9Hz),7.10(3H,t,J=8.5Hz),7.55(2H,dd,J=8.2,5.5Hz),7.67(1H,d,J =16.0Hz);ESI-MS m/z:621.2[M+H]+,619.4[M-H]-,655.3[M+Cl]-.
实施例13
取上述配方,用常规方法制备成片剂。
Claims (7)
1.通式(I)的23-羟基白桦酸衍生物或其药学上可接受的盐:
其中:R1代表环己基、4-甲基环己基、4-羰基环己基、2-氧代环己基、3,5-二氧代环己基、3-甲氧基环己基、3-甲基环己基、螺[2.5]辛烷基、环丙基、反式-2-氟环丙烷基、双环[2.2.1]庚烷基、邻甲基苯基、间甲基苯基、对甲基苯基、邻羟基苯基、间羟基苯基、4-羟基-2-甲基苯、2-甲基-3-羟基苯基、2-羟基-6-甲基苯基、2,5-二甲基苯基、2,3-二甲基苯基、2,4-二甲基苯基、对羟基苯基、4-乙炔基苯基、3-乙炔基苯基、2-乙烯基苯、3-乙烯基苯、4-乙烯基苯、对甲氧基取代苯基、邻甲氧基取代苯基、间甲氧基取代苯基、对氨基取代苯基、邻氨基取代苯基、3,4-二氨基苯基、2,3-二氨基苯基、5-氨基-2-甲基苯基、3-氨基-5-甲基苯基、4-氨基-2-甲基苯基、2-氨基-3-甲基苯基、2-氨基-6-甲基苯、3-甲氨基苯基、3-羟基-2-氨基苯基、邻硝基取代苯基、间硝基取代苯基、对硝基取代苯基、2,4-二硝基苯基、4-(N,N-二(2-氯乙基)氨基)苯基、邻氟苯基、3-氟-4-甲基苯基、3-氟-5-甲基苯基、4-氟-3-羟基苯基、2-氟-5-羟基苯基、对氟苯基、间氟苯基、多氟取代苯基、3-氟-4-氨基苯基、对氯苯基、间氯苯基、对三氟甲基苯基、邻三氟甲基苯基、对醛基苯、邻醛基苯、间醛基苯、3-吡啶基、1-萘甲基、苯乙烯基、对氟苯基乙烯基、邻氟苯基乙烯基、间氟苯基乙烯基、对硝基苯基乙烯基、间硝基苯基乙烯基、对甲氧基苯基乙烯基、多甲氧基取代苯基乙烯基、3-(4-(N,N-二(2-氯乙基)氨基)苯基)丙基;
R2代表氢或苄基。
2.权利要求1中的23-羟基白桦酸衍生物或其药学上可接受的盐:
R1代表环己烷、对甲氧基取代苯基、对氨基取代苯基、邻硝基取代苯基、间硝基取代苯基、对硝基取代苯基、2,4-二硝基苯基、4-(N,N-二(2-氯乙基)氨基)苯基、对氟苯基、间氟苯基、多氟取代苯基、对氯苯基、间氯苯基、对三氟甲基苯基、邻三氟甲基苯基、3-吡啶基、1-萘甲基、苯乙烯基、对氟苯基乙烯基、对硝基苯基乙烯基、对甲氧基苯基乙烯基、多甲氧基取代苯基乙烯基、3-(4-(N,N-二(2-氯乙基)氨基)苯基)丙基;
R2代表氢或苄基。
3.权利要求2中的23-羟基白桦酸衍生物或其药学上可接受的盐:
R1为环己烷、间硝基取代苯基、4-(N,N-二(2-氯乙基)氨基)苯基、对甲氧基取代苯基、间氯苯基、对三氟甲基苯基、邻三氟甲基苯基、2,3,4,5-四氟苯基、3-吡啶、1-萘甲基、苯乙烯基、对氟苯基乙烯基、对硝基苯基乙烯基、3-(4-(N,N-二(2-氯乙基)氨基)苯基)丙基;
R2为氢。
4.本发明的部分化合物为:
3-羟基-23-环己甲酰氧基-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-间硝基苯甲酰氧基-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-氮芥苯甲酰氧基-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-对氟苯甲酰氧基-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-间氯苯甲酰氧基-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-邻三氟甲基苯甲酰氧基-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-对三氟甲基苯甲酰氧基-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-(2,3,4,5-四氟苯甲酰氧基)-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-(3-吡啶甲酰氧基)-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-氮芥苯丁酰氧基-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-对甲氧基苯甲酰氧基-羽扇豆-20(29)-烯-28-酸;
3-羟基-23-对氟肉桂酰氧基-羽扇豆-20(29)-烯-28-酸。
5.药物组合物,其中含有治疗有效量的权利要求1的通式(I)的化合物及药学上可接受的载体。
6.权利要求1的化合物或其盐在制备治疗肿瘤疾病药物中的应用。
7.权利要求6的用途,其中肿瘤疾病是肝癌、黑色素瘤、乳腺癌以及卵巢癌。
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