CN104003998A - 冬凌草甲素14-o-取代氮芥衍生物、制备方法及用途 - Google Patents
冬凌草甲素14-o-取代氮芥衍生物、制备方法及用途 Download PDFInfo
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Abstract
本发明涉及药物化学领域,具体涉及一类具有抗肿瘤活性的新型冬凌草甲素14-O-取代氮芥类衍生物,本发明还公开了这些冬凌草甲素氮芥衍生物的制备方法以及含有所述化合物的药物组合物和所述化合物在***疾病以及相关其它疾病或病症中的应用。
Description
技术领域
本发明涉及药物化学领域,具体涉及一类新型的冬凌草甲素14-O-取代氮芥类衍生物,特别涉及通过拼合原理在冬凌草甲素母核上引入氮芥类侧链的冬凌草甲素14-O-取代氮芥衍生物。本发明还公开了这些冬凌草甲素氮芥衍生物的制备方法和这些新型衍生物用于抗肿瘤的用途。
背景技术
冬凌草甲素(oridonin)是从唇形科香茶菜属(Rabdosia)植物中分离出的一种贝壳杉烯二萜类(ent-kaurene diterpenoid)天然有机化合物,主要植物来源有:香茶菜(Rabdosia amethystoides),显脉叶香茶菜(Rabdosia nervosa),毛叶香茶菜(Rabdosia jabdsia),道孚香茶菜(Rabdosia downsis),冬凌草或碎米亚(Rabdosiarubescens)和延命草(Isodon japonicus)。
冬凌草甲素具有抗细胞增殖、抑制癌细胞DNA、RNA和蛋白质的合成、诱导细胞调亡、抗突变以及β-受体阻断等作用。30年来随着对其研究的深入,国内外学者发现它对食管癌、胃癌、肝癌、肺癌、鼻咽癌、结肠癌、膀胱癌、***和白血病均具有一定治疗作用,其药理活性研究倍受关注,然而其抗肿瘤活性尚不突出,存在很大的改善优化空间。
拼合原理(combination principles)是药物设计中一种常用的手段,越来越成为设计和开发新药先导化合物的重要途径之一。拼合原理主要是指将两种药物的结构拼合在一个分子内,或将两者的药效基团兼容在一个分子中,称之为杂交分子(Hybrid molecules),新形成的杂交分子或兼具两者的性质,增强药理作用,减小各自相应的毒副作用;或使两者取长补短,更好地发挥各自的药理活性,协同完成治疗过程。如苯丁酸氮芥(Chlorambucil)是临床应用的抗肿瘤药物,但其毒性较大,副作用较多,严重影响了其广泛应用。罗氏公司设计以甾体为其载体,增加其靶向性,来减少它的毒副作用,在这种思路指导下将***龙(Prednisolone)和苯丁酸氮芥拼合形成抗肿瘤药泼尼莫司汀(Prednimustine),其对***癌的选择性显著提高,降低了苯丁酸氮芥的毒性。
目前临床上所使用的抗肿瘤治疗药物通常为细胞毒类药物,存在毒副作用大,严重伤害人体免疫***等缺点。研究发现,化疗中所用的许多药物都是通过干扰细胞生长,代谢和增殖过程,诱导肿瘤细胞凋亡而达到治疗目的,但往往由于肿瘤产生了抑癌基因P53突变,出现对药物的耐药性而失败。而针对细胞毒药物的结构修饰来增加选择性、减少毒性,改善理化性质的报道已有不少。其中一个常用的策略就是与天然产物进行拼合,一方面提高活性,减少毒性,另一方面也能改善多药耐药性。
发明内容
本发明的目的旨在寻找研发活性好,毒性小,对耐药肿瘤有效的冬凌草甲素新药候选化合物,并进一步提供一种***及其它疾病或病症的药物组合物。
本发明立足天然产物的结构改造,依据药物化学中的拼合原理,根据多活性基团拼合可以得到更高活性目标化合物的设计思想,将各种有抗肿瘤活性的药物或者分子片段拼合到一起,设计获得新型冬凌草甲素14-O-取代氮芥类衍生物,为解决上述技术问题,本发明提供如下技术方案:
通式(I)所示冬凌草甲素衍生物或其可药用盐:
其中R1代表羟基、氧代、乙酰氧基、丙酰氧基、正丙磺酰氧基、甲氧基、乙氧基、苄氧基;
R2代表(CH2)m,CHR3(CH2)m;
R3代表Boc-NH,HCONH,ArCH2NH;
m=0-8;
Ar代表取代苯基。
本发明通式I的冬凌草甲素衍生物,其中
R1优选羟基、氧代、乙酰氧基;
R2优选(CH2)m,CHR3(CH2)m,m=0-3;
R3优选Boc-NH,HCONH。
本发明的部分优选化合物为:
ent-1,6,7-三羟基-(14-O-(4-(双(2-氯乙基)氨基)苯甲酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯;
ent-1,6,7-三羟基-(14-O-(4-(双(2-氯乙基)氨基)苯乙酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯;
ent-1,6,7-三羟基-(14-O-(4-(双(2-氯乙基)氨基)苯丁酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯;
ent-1,6,7-三羟基-(14-O-(4-(双(2-氯乙基)氨基)-S-2-(Boc-氨基)苯丙酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯;
ent-1,6,7-三羟基-(14-O-(4-(双(2-氯乙基)氨基)-S-2-(甲酰氨基)苯丙酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯;
ent-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)苯甲酰基))-1,15-二氧代-7,20-氧桥-16-贝壳杉烯;
ent-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)苯乙酰基))-1,15-二氧代-7,20-氧桥-16-贝壳杉烯;
ent-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)苯丁酰基))-1,15-二氧代-7,20-氧桥-16-贝壳杉烯;
ent-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)-S-2-(Boc-氨基)苯丙酰基))-1,15-二氧代-7,20-氧桥-16-贝壳杉烯;
ent-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)-S-2-(甲酰氨基)苯丙酰基))-1,15-二氧代-7,20-氧桥-16-贝壳杉烯;
ent-(1-O-乙酰基)-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)苯甲酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯;
ent-(1-O-乙酰基)-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)苯乙酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯;
ent-(1-O-乙酰基)-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)苯丁酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯;
ent-(1-O-乙酰基)-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)-S-2-(Boc-氨基)苯丙酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯;
ent-(1-O-乙酰基)-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)-S-2-(甲酰氨基)苯丙酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯。
本发明通式I的衍生物可在本课题组已有研究基础上用下列方法制备得到:
反应图解1起始物1的合成方法见CN102002051A,通式为I的化合物合成步骤如下:
a、将14位为羟基的冬凌草甲素或其衍生物溶解于二氯甲烷中;
b、加入相应的酸、DMAP和EDCI,室温搅拌反应12-36h;
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,本发明的冬凌草甲素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、白血病、胃癌、乳腺癌、对顺铂耐药的肝癌。
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)
细胞株人肝癌细胞Bel-7402、人白血病细胞K562、
人胃癌细胞MGC-803、人乳腺癌细胞MCF-7和人肝癌
顺铂耐药细胞Bel-7404/CP20。
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种人类癌细胞株抗增殖活性的IC50值(μM)
样品 | K562 | MCF-7 | Bel-7402 | MGC-803 | Bel-7404/CP20 |
冬凌草甲素 | 4.76 | 14.60 | 7.48 | 5.69 | 17.17 |
实施例1 | 1.12 | 0.68 | 0.50 | 1.09 | 2.01 |
实施例2 | 1.54 | 0.89 | 0.76 | 1.21 | 3.78 |
实施例3 | 2.28 | 1.32 | 1.43 | 2.02 | 5.21 |
实施例4 | 1.41 | 3.22 | 2.36 | 6.72 | 7.98 |
实施例5 | 7.03 | 14.58 | 3.84 | 7.10 | 14.23 |
实施例6 | 1.10 | 0.79 | 1.37 | 2.25 | 2.18 |
实施例7 | 1.21 | 0.84 | 1.53 | 2.21 | 2.09 |
实施例8 | 1.35 | 0.91 | 2.41 | 3.76 | 1.90 |
实施例9 | 2.42 | 4.10 | 3.09 | 5.24 | 6.47 |
实施例10 | 6.09 | 12.11 | 7.73 | 8.90 | 12.65 |
实施例11 | 1.17 | 0.67 | 0.90 | 1.60 | 1.85 |
实施例12 | 1.34 | 0.98 | 0.96 | 1.52 | 1.60 |
实施例13 | 2.37 | 2.25 | 2.53 | 3.95 | 5.32 |
实施例14 | 3.42 | 6.54 | 4.33 | 5.82 | 4.69 |
实施例15 | 10.84 | 7.99 | 6.20 | 11.04 | 14.09 |
下面是本发明部分化合物的体内抗肿瘤活性的药理实验结果:
实验方法
由上海斯莱克实验动物有限责任公司提供,周龄为3周,体重12-16g的雌性Balb/c裸鼠70只。收集培养的肝癌Bel-7402细胞,计数、调整使细胞悬液浓度为1.5×107个/ml,于裸小鼠右侧腋窝皮下每只接种0.1ml。用游标卡尺测量裸鼠移植瘤的直径,接种肿瘤细胞7天后,肿瘤长至50-75mm3时,每组10只将裸鼠随机分为7组。衍生物溶于DMSO,再滴入poloxamer母液,最后加生理盐水至所需剂量。DMSO终浓度为1%,poloxamer终浓度为2%。各组裸鼠给药,模型组腹腔注射等量溶媒,每天注射1次,持续25天;阳性对照组尾静脉注射10mg/kg紫杉醇,隔天注射1次;冬凌草甲素组腹腔注射10mg/kg冬凌草甲素,每天注射1次,持续25天;衍生物组腹腔注射10mg/kg的衍生物,每天1次,持续注射25天。给药25天结束后处死裸鼠,通过手术剥取瘤块,称重。计算肿瘤生长抑制率(%),用SPSS17.0对结果进行分析,组间用t检验进行统计学分析处理,其计算公式如下:
实验结果
表2部分实施例的体内抗肿瘤活性
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
将冬凌草甲素(0.2mmol)溶于15ml二氯甲烷中,加入苯甲酸氮芥(0.22mmol),室温搅拌18小时,加入适量水(约15ml),乙酸乙酯萃取(10ml×3次),饱和食盐水洗,无水硫酸钠干燥,过滤,浓缩,柱层析(二氯甲烷∶甲醇=300∶1),得白色粉末状固体。
ent-1,6,7-三羟基-(14-O-(4-(双(2-氯乙基)氨基)苯甲酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯。1H NMR(CDCl3,300MHz):δ(ppm)7.78(d,J=9.0Hz,2H,Ar-H),6.62(d,J=9.0Hz,2H,Ar-H),6.17(m,2H),6.03(s,1H),5.47(s,1H),4.30(s,1H),4.08,4.33(dd,JA=JB=10.2Hz,each1H),3.78(m,4H),3.65(m,4H),3.57(m,1H),3.28(d,J=9.6Hz,1H),2.67(m,1H),2.39(m,1H),2.04(m,1H),1.78(m,2H),1.68(m,3H),1.49(m,2H),1.36(m,2H),1.13(s,3H),1.12(s,3H);ESI-MS m/z608.4[M+H]+.
实施例2
ent-1,6,7-三羟基-(14-O-(4-(双(2-氯乙基)氨基)苯乙酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯。参照实施例1的合成方法。1H NMR(CDCl3,300MHz):δ(ppm)7.78(d,J=9.0Hz,2H,Ar-H),6.62(d,J=9.0Hz,2H,Ar-H),6.17(m,2H),6.03(s,1H),5.47(s,1H),4.30(s,1H),4.08,4.33(dd,JA=JB=10.2Hz,each1H),4.12(s,2H),3.78(m,4H),3.65(m,4H),3.57(m,1H),3.28(d,J=9.6Hz,1H),2.67(m,1H),2.39(m,1H),2.04(m,1II),1.78(m,2H),1.68(m,3H),1.49(m,2H),1.36(m,2H),1.13(s,3H),1.12(s,3H);ESI-MS m/z622.2[M+H]+.
实施例3
ent-1,6,7-三羟基-(14-O-(4-(双(2-氯乙基)氨基)苯丁酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯。参照实施例1的合成方法。1H NMR(CDCl3,300M Hz),δ(ppm):6.92(d,J=8.4Hz,2H,Ar-H),6.53(d,J=8.4Hz,2H,Ar-H),6.07(s,1H),6.06(d,J=6.0Hz,1H),5.75(s,1H),5.41(s,1H),4.25(s,1H),4.23,4.01(dd,JA=JB=10.2Hz,each1H,20-CH2),3.69(m,1H),3.63(m,4H),3.55(m,4H),3.43(m,1H),3.12(d,J=9.6Hz,1H),2.65(m,1H),2.43(t,J=7.2Hz,2H),2.20(t,J=7.2Hz,2H),1.91(m,1H),1.81(m,2H),1.73(m,2H),1.70(m,2H),1.65(m,3H),1.37(m,2H),1.18(s,3H,-CH3),1.05(s,3H,-CH3);ESI-MS m/z650.5[M+H]+.
实施例4
ent-1,6,7-三羟基-(14-O-(4-(双(2-氯乙基)氨基)-S-2-(Boc-氨基)苯丙酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯。参照实施例1的合成方法。1H NMR(CDCl3,300M Hz),δ(ppm):6.99(d,J=8.4Hz,2H,Ar-H),6.57(d,J=8.4Hz,2H,Ar-H),6.11(m,1H),6.06(d,J=10.5Hz,1H),5.88(s,1H),5.45(s,1H),4.93(d,J=7.2Hz,1H),4.38(m,1H),4.33,4.07(dd,JA=JB=10.2Hz,each1H,20-CH2),3.98(br,1H),3.70(m,4H),3.62(m,4H),3.48(m,1H),3.10(m,1H),2.92(m,2H),2.61(m,1H),2.25(m,1H),1.99(m,1H),1.62(m,7H),1.42(m,2H),1.38(s,9H),1.11(s,6H,-CH3);ESI-MSm/z751.6[M+H]+.
实施例5
ent-1,6,7-三羟基-(14-O-(4-(双(2-氯乙基)氨基)-S-2-(甲酰氨基)苯丙酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯。参照实施例1的合成方法。1H NMR(CDCl3,300M Hz),δ(ppm):7.40(s,1H),6.99(d,J=8.4Hz,2H,Ar-H),6.55(d,J=8.4Hz,2H,Ar-H),6.14(m,2H),5.83(s,1H),5.51(s,1H),4.37(m,2H),4.28,4.09(dd,JA=JB=10.2Hz,each1H,20-CH2),3.80(m,1H),3.69(m,4H),3.63(m,4H),3.50(m,1H),3.20(m,1H),2.63(m,2H),2.26(m,1H),2.12(m,2H),2.06(m,3H),1.65(m,3H),1.28(s,3H),1.12(s,6H,-CH3);ESI-MS m/z679.3[M+H]+.
实施例6
ent-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)苯甲酰基))-1,15-二氧代-7,20-氧桥-16-贝壳杉烯。参照实施例1的合成方法。1H NMR(CDCl3,300MHz):δ(ppm)7.79(d,J=9.0Hz,2H,Ar-H),6.63(d,J=9.0Hz,2H,Ar-H),6.27(s,1H),6.00(s,1H),5.59(s,1H),5.45(d,J=11.4Hz,1H),4.35(m,1H),4.03,4.33(dd,JA=JB=10.2Hz,each1H),3.78(m,5H),3.63(m,4H),3.27(d,J=9.6Hz,1H),2.67(m,1H),2.41(m,3H),2.04(m,3H),1.80(m,1H),1.71(m,1H),1.36(m,1H),1.21(s,3H),1.01(s,3H);ESI-MS m/z606.3[M+H]+.
实施例7
ent-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)苯乙酰基))-1,15-二氧代-7,20-氧桥-16-贝壳杉烯。参照实施例1的合成方法。1H NMR(CDCl3,300MHz):δ(ppm)7.79(d,J=9.0Hz,2H,Ar-H),6.63(d,J=9.0Hz,2H,Ar-H),6.27(s,1H),6.00(s,1H),5.59(s,1H),5.45(d,J=11.4Hz,1H),4.35(m,1H),4.03,4.33(dd,JA=JB=10.2Hz,each1H),4.10(s,2H),3.78(m,5H),3.63(m,4H),3.27(d,J=9.6Hz,1H),2.67(m,1H),2.41(m,3H),2.04(m,3H),1.80(m,1H),1.71(m,1H),1.36(m,1H),1.21(s,3H),1.01(s,3H);ESI-MS m/z620.2[M+H]+.
实施例8
ent-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)苯丁酰基))-1,15-二氧代-7,20-氧桥-16-贝壳杉烯。参照实施例1的合成方法。1H NMR(CDCl3,300M Hz),δ(ppm):7.01(d,J=8.7Hz,2H,Ar-H),6.60(d,J=8.7Hz,2H,Ar-H),6.25(s,1H),5.85(s,1H),5.60(s,1H),5.40(d,J=11.7Hz,1H),4.22(s,1H),4.29,4.03(dd,JA=JB=10.2Hz,each1H,20-CH2),3.72(m,1H),3.71(m,4H),3.60(m,4H),3.13(d,J=9.3Hz,1H),2.60(m,1H),2.50(t,J=7.2Hz,2H),2.35(m,2H),2.26(t,J=7.2Hz,2H),1.96(m,2H),1.84(m,2H),1.73(m,2H),1.68(m,1H),1.25(m,2H),1.19(s,3H,-CH3),1.00(s,3H,-CH3);ESI-MS m/z648.4[M+H]+.
实施例9
ent-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)-S-2-(Boc-氨基)苯丙酰基))-1,15-二氧代-7,20-氧桥-16-贝壳杉烯。参照实施例1的合成方法。1H NMR(CDCl3,300MHz),δ(ppm):6.98(d,J=8.4Hz,2H,Ar-H),6.59(d,J=8.4Hz,2H,Ar-H),6.13(m,1H),6.04(d,J=10.5Hz,1H),5.88(s,1H),5.45(s,1H),4.32,4.06(dd,JA=JB=10.2Hz,each1H,20-CH2),3.99(br,1H),3.75(m,4H),3.64(m,4H),3.49(m,1H),3.11(m,1H),2.94(m,2H),2.64(m,1H),2.24(m,1H),1.98(m,1H),1.63(m,7H),1.45(m,2H),1.39(s,9H),1.12(s,6H,-CH3);ESI-MS m/z749.3[M+H]+.
实施例10
ent-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)-S-2-(甲酰氨基)苯丙酰基))-1,15-二氧代-7,20-氧桥-16-贝壳杉烯。参照实施例1的合成方法。1H NMR(CDCl3,300M Hz),δ(ppm):7.41(s,1H),6.98(d,J=8.4Hz,2H,Ar-H),6.55(d,J=8.4Hz,2H,Ar-H),6.12(m,2H),5.81(s,1H),4.87(m,1H),4.18,4.07(dd,JA=JB=10.2Hz,each1H,20-CH2),3.81(m,1H),3.70(m,4H),3.66(m,4H),3.51(m,1H),3.25(m,1H),2.68(m,2H),2.21(m,1H),2.15(m,2H),2.02(m,3H),1.64(m,3H),1.29(s,3H),1.11(s,6H,-CH3);ESI-MS m/z677.3[M+H]+.
实施例11
ent-(1-O-乙酰基)-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)苯甲酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯。参照实施例1的合成方法。1H NMR(CDCl3,300MHz):δ(ppm)7.78(d,J=9.0Hz,2H,Ar-H),6.62(d,J=9.0Hz,2H,Ar-H),6.17(m,2H),6.00(s,1H),5.47(s,1H),4.65(m,1H),4.32(s,1H),4.18,4.33(dd,JA=JB=10.5Hz,each1H),3.79(m,4H),3.65(m,4H),3.29(d,J=10.2Hz,1H),2.61(m,1H),2.09(m,1H),2.05(s,3H),1.78(m,1H),1.58(m,3H),1.49(m,2H),1.36(m,3H),1.14(s,3H),1.12(s,3H);ESI-MS m/z650.1[M+H]+.
实施例12
ent-(1-O-乙酰基)-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)苯乙酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯。参照实施例1的合成方法。1H NMR(CDCl3,300MHz):δ(ppm)7.78(d,J=9.0Hz,2H,Ar-H),6.62(d,J=9.0Hz,2H,Ar-H),6.17(m,2H),6.00(s,1H),5.47(s,1H),4.65(m,1H),4.32(s,1H),4.18,4.33(dd,JA=JB=10.5Hz,each1H),4.11(s,2H),3.79(m,4H),3.65(m,4H),3.29(d,J=10.2Hz,1H),2.61(m,1H),2.09(m,1H),2.05(s,3H),1.78(m,1H),1.58(m,3H),1.49(m,2H),1.36(m,3H),1.14(s,3H),1.12(s,3H);ESI-MS m/z663.2[M+H]+.
实施例13
ent-(1-O-乙酰基)-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)苯丁酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯。参照实施例1的合成方法。1H NMR(CDCl3,300M Hz),δ(ppm):7.01(d,J=8.4Hz,2H,Ar-H),6.61(d,J=8.4Hz,2H,Ar-H),6.14(s,1H),6.10(d,J=10.5Hz,1H),5.80(s,1H),5.49(s,1H),4.62(m,1H),4.26(m,1H),4.26,4.18(dd,JA=JB=10.5Hz,each1H,20-CH2),3.81(m,1H),3.78(m,4H),3.61(m,4H),3.18(d,J=9.9Hz,1H),2.60(m,1H),2.50(t,J=7.2Hz,2H),2.28(t,J=7.2Hz,2H),2.03(m,2H),1.97(s,3H),1.91(m,4H),1.55(m,5H),1.12(s,6H);ESI-MSm/z692.5[M+H]+.
实施例14
ent-(1-O-乙酰基)-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)-S-2-(Boc-氨基)苯丙酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯。参照实施例1的合成方法。1H NMR(CDCl3,300M Hz),δ(ppm):6.98(d,J=8.4Hz,2H,Ar-H),6.56(d,J=8.4Hz,2H,Ar-H),6.15(m,1H),6.02(d,J=10.5Hz,1H),5.86(s,1H),5.45(s,1H),4.39(m,1H),4.31,4.04(dd,JA=JB=10.2Hz,each1H,20-CH2),3.98(br,1H),3.79(m,4H),3.62(m,4H),3.44(m,1H),3.15(m,1H),2.97(m,2H),2.67(m,1H),2.27(m,1H),2.03(s,3H),1.97(m,1H),1.65(m,7H),1.48(m,2H),1.39(s,9H),1.13(s,6H,-CH3);ESI-MS m/z793.3[M+H]+.
实施例15
ent-(1-O-乙酰基)-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)-S-2-(甲酰氨基)苯丙酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯。参照实施例1的合成方法。1H NMR(CDCl3,300M Hz),δ(ppm):7.49(s,1H),6.98(d,J=8.4Hz,2H,Ar-H),6.52(d,J=8.4Hz,2H,Ar-H),6.12(m,2H),5.81(s,1H),4.87(m,1H),4..45(m,1H),4.18,4.07(dd,JA=JB=10.2Hz,each1H,20-CH2),3.82(m,1H),3.70(m,4H),3.66(m,4H),3.49(m,1H),3.25(m,1H),2.65(m,2H),2.21(m,1H),2.15(m,2H),2.01(s,3H),2.02(m,3H),1.63(m,3H),1.19(s,3H),1.01(s,6H,-CH3);ESI-MS m/z721.3[M+H]+.
实施例16
取上述配方,用常规方法制备成片剂。
Claims (5)
1.通式(I)所示冬凌草甲素衍生物或其可药用盐:
R1代表羟基、氧代、乙酰氧基、丙酰氧基、正丙磺酰氧基、甲氧基、乙氧基、苄氧基;
R2代表(CH2)m,CHR3(CH2)m;
R3代表Boc-NH,HCONH,ArCH2NH;
m=0-8;
Ar代表取代苯基。
2.权利要求1的冬凌草甲素衍生物或其药学上可接受的盐,
R1代表羟基、氧代、乙酰氧基;
R2代表(CH2)m,CHR3(CH2)m,m=0-3;
R3代表Boc-NH,HCONH。
3.权利要求2的化合物或其可药用盐,其中有
ent-1,6,7-三羟基-(14-O-(4-(双(2-氯乙基)氨基)苯甲酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯;
ent-1,6,7-三羟基-(14-O-(4-(双(2-氯乙基)氨基)苯乙酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯;
ent-1,6,7-三羟基-(14-O-(4-(双(2-氯乙基)氨基)苯丁酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯;
ent-1,6,7-三羟基-(14-O-(4-(双(2-氯乙基)氨基)-S-2-(Boc-氨基)苯丙酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯;
ent-1,6,7-三羟基-(14-O-(4-(双(2-氯乙基)氨基)-S-2-(甲酰氨基)苯丙酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯;
ent-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)苯甲酰基))-1,15-二氧代-7,20-氧桥-16-贝壳杉烯;
ent-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)苯乙酰基))-1,15-二氧代-7,20-氧桥-16-贝壳杉烯;
ent-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)苯丁酰基))-1,15-二氧代-7,20-氧桥-16-贝壳杉烯;
ent-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)-S-2-(Boc-氨基)苯丙酰基))-1,15-二氧代-7,20-氧桥-16-贝壳杉烯;
ent-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)-S-2-(甲酰氨基)苯丙酰基))-1,15-二氧代-7,20-氧桥-16-贝壳杉烯;
ent-(1-O-乙酰基)-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)苯甲酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯;
ent-(1-O-乙酰基)-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)苯乙酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯;
ent-(1-O-乙酰基)-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)苯丁酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯;
ent-(1-O-乙酰基)-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)-S-2-(Boc-氨基)苯丙酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯;
ent-(1-O-乙酰基)-6,7-二羟基-(14-O-(4-(双(2-氯乙基)氨基)-S-2-(甲酰氨基)苯丙酰基))-15-氧代-7,20-氧桥-16-贝壳杉烯。
4.一种药物组合物,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。
5.权利要求1的化合物或其盐在制备***疾病以及相关其它疾病或病症中的应用。
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