CN109485688A - 三萜衍生物及其药物组合物和应用 - Google Patents
三萜衍生物及其药物组合物和应用 Download PDFInfo
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Abstract
本发明公开了一种新型三萜衍生物及其药物组合物和应用。新型三萜衍生物为具有结构通式(Ⅰ)的化合物或其可药用盐。本发明的三萜衍生物与现有技术中的肿瘤药物相比,具有多种靶点且活性效果显著更优。
Description
技术领域
本发明属于药物学领域,具体地涉及一种三萜衍生物及其药物组合物和应用。
背景技术
肿瘤作为人类健康的一大威胁一直受到广泛的关注,寻找新的抗肿瘤药物是全世界药物化学家研究的重点和热点。从天然产物(Natural products)中寻找新的抗肿瘤药物是抗肿瘤药物发现的主要途径之一。三萜是一类具有30个碳原子构成基本碳架的结构独特的化合物,广泛存在于自然界,已经被分离、鉴定的化合物超过了20000种,具有抗炎、抗氧化、抗增殖、抗病毒等多种生物活性。
现阶段药物开发策略多为国际上大的制药公司践行的“单一化合物,单一靶点”的研究思路,然而根据此思路研发的肿瘤药物,其耐受性逐渐成为一个不可避免的问题,Michael B.Sporn曾撰文指出,肿瘤是一种多种致病因素和多种基因参与的病理过程,因此如若有能够作用于多种靶点的多功能肿瘤药物,则将有助于克服肿瘤药物的耐受性问题,并可适用于预防和治疗肿瘤。
发明内容
本发明的目的是针对上述缺陷,提供一种具有抗肿瘤活性且能够作用于多靶点的三萜衍生物。
为实现上述目的,本发明采用的技术方案是:
一种三萜衍生物,其特征在于:所述三萜衍生物为具有结构通式(Ⅰ)的化合物或其可药用盐,
式(I)中,
R1为H,C1-6烷基羰基,C1-6卤代烷基羰基,未被取代或为选自卤素、硝基、C1-6烷基、C1-6烷氧基中的一个或多个取代基所取代的苄基,未被取代或为选自卤素、硝基、C1-6烷基、C1-6烷氧基中的一个或多个取代基所取代的苯甲酰基,或HOOCC(CH3)2CH2C=O;
R2为H,OH,C1-6酰基羰基,C1-6卤代酰基羰基,未被取代或为选自卤素、硝基、C1-6烷基、C1-6烷氧基中的一个或多个取代基所取代的苄氧基或苯甲酰氧基;
X为CH2、C=O、CH-OH,Y为CH;或X-Y为CH=C;
Z为NH或-NR4(C=O)n(CH2)m(C=O)pNR5-,其中,n、p独立地为0或1,m为1-10之间的整数,R4,R5均为H或二者连接使所述NR4(C=O)n(CH2)m(C=O)pNR5形成5-10元环;
R3为(a)-(CH2)qCOOR6,其中q为1-10的整数,R6为H、C1-12烃基或卤代烃基、被一个或二个羰基和/或氧所间隔的C1-12烃基或卤代烃基;(b)碳数2-8的含氮杂环,所述含氮杂环未被取代或为选自卤素、硝基、C1-6烷基、C1-6烷氧基、C1-6烷基酰基中的一个或多个取代基所取代;(c)(d)苄基或苯环为选自卤素、硝基、C1-6烷基、C1-6烷氧基中的一个或多个取代基所取代的苄基;
或者,Z-R3为OH;
当X-Y为CH=C时,Z,R1,R2不同时满足如下条件:Z为NH,R1为H或乙酰基,R2为H。
进一步地,所述-NR4(C=O)n(CH2)m(C=O)pNR5-中,n、p为0,m为1-10之间的整数,R4,R5均为H;或者,n、p中的一个为0、另一个为1,m为1或2,R4,R5均为H;或者,n、p为0,m为1-3之间的整数,R4,R5二者连接使所述NR4(C=O)n(CH2)mNR5形成6-8元环。
优选地,Z为NH;NH(CH2)rNH,其中r为1-6之间的整数;
进一步地,所述(a)中,R6为H、C1-C6烷基或卤代烷基,C1-C6烷基羰基,C1-C6卤代烷基羰基,苯基,苯环为选自卤素、硝基、C1-6烷基、C1-6烷氧基中的一个或多个取代基所取代的苯基,苄基或或苯环为选自卤素、硝基、C1-6烷基、C1-6烷氧基中的一个或多个取代基所取代的苄基,所述卤代为氟代或氯代,所述卤素为氟或氯。
优选地,所述(a)中,R6为H、甲基、乙基、异丙基、CF3C=O、苯基或苄基。
优选地,所述(a)中,q为1-6之间的整数。
优选地,所述(b)中,所述含氮杂环为饱和或不饱和5-6元单杂环,所述含氮杂环中氮原子数为1-2个,氧原子数为0-1个,所述含氮杂环上与Z连接的原子为氮原子或碳原子;或者,所述含氮杂环为双环,所述双环中一个为苯环,另一个为不饱和5-6元单杂环。
进一步优选地,所述(b)中,所述含氮杂环为
根据本发明的一个具体且优选方面,通式(I)中,Z-R3为
根据本发明的又一具体且优选方面,通式(I)中,R1为H、CH3C=O、CF3C=O、苄基、苯甲酰基或HOOCC(CH3)2CH2C=O;R2为H、OH、CH3(C=O)O、CF3C=O、苄氧基或苯甲酰氧基。
优选地,本发明的三萜衍生物为选自如下化合物或如下化合物的可药用盐:
根据本发明,所述的结构通式(I)的化合物,其不仅包括单一的某种化合物形式,还包括多种结构满足通式(I)要求的化合物的混合物形式,以及同一化合物的不同异构体形式例如外消旋体、对映异构体、非对映异构体等。所述的可药用盐包括但不限于盐酸盐、磷酸盐、硫酸盐、醋酸盐、马来酸盐、甲磺酸盐、苯磺酸盐、苯酸盐、甲基苯磺酸盐、琥珀酸盐、延胡索酸盐、富马酸盐、酒石酸盐、没食子酸盐、柠檬酸盐等。
根据本发明的第二方面,提供一种用于抗肿瘤的药物组合物,该药物组合物包含本发明上述的三萜衍生物。
进一步地,三萜衍生物在所述药物组合物中作为活性成分使用。
上述药物组合物的活性成分可以仅包含上述的三萜衍生物,此时,三萜衍生物在药物组合物中含量优选为有效量的;或者活性成分还可以为上述三萜衍生物与其他抗肿瘤活性成分的组合。
根据本发明的第三方面,提供根据以上所述的三萜衍生物在制备抗肿瘤药物组合物中的应用。
由于以上技术方案的实施,本发明与现有技术相比具有如下优点:
与现有技术中的肿瘤药物相比,本发明的化合物具有多种靶点且活性效果显著更优。
具体实施方式
本发明述及的结构通式(Ⅰ)的化合物可利用本领域常规的化学反应来制备,根据具体的目标化合物结构,可相应设计合成路线。举例如下:
本专利所列化合物,分别以齐墩果酸(Oleanolic acid,化合物1),二氢齐墩果酸(Dihydrooleanolic acid,化合物2),12-羰基齐墩果酸(12-Carbonyl oleanolic acid,化合物3),常春藤苷元(Hederagenin,化合物4)为起始原料,参照以下路线所示方法,经乙酰化,继续与草酰氯反应制备酰氯中间体,与不同的取代胺反应,制备成酰胺,经不同的条件水解,制备产物化合物5-30。
合成路线如下所示:
路线1:
路线2:
路线3:
路线4:
路线5:
路线6:
以下将通过具体实施例进一步阐述本发明,但并不用于限制本发明的保护范围。
本发明的实施例中,1H-NMR与13C-NMR用Varian Mercury 400核磁共振仪记录,化学位移以δ(ppm)表示;分离用硅胶未作特别说明时均为200-300目,洗脱液的配比均为体积比。
实施例1:制备3-乙酰基齐墩果酸-28-[(E)-3’-(苯[d]二氧戊烷)-1’-哌嗪基丙
烷-2’-烯-1’-酮]酰胺(化合物5)
原料齐墩果酸(化合物1)(4.56g,10mmol)溶于无水吡啶(50mL)中,搅拌下加入乙酸酐(4.08g,40mmol),DMAP(123mg,1mmol)室温下搅拌4h。反应结束,加入乙酸乙酯(200mL),用10%HCl调节pH4-5;有机层用饱和食盐水洗(50mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=2:1),得白色中间产物(3-乙酰基齐墩果酸)4.59g,产率92%。
所得白色中间产物的核磁数据为:
1H NMR(400MHz,CDCl3,δ)5.28(s,1H,H-12),4.47-4.51(m,1H,H-3),2.81(d,J=6.0Hz,1H),2.04(s,3H,CH3CO),1.13(s,3H),0.94(S,3H),0.93(S,3H),0.90(s,3H),0.86(S,3H),0.85(S,3H),0.75(s,3H)。
将3-乙酰基齐墩果酸(1.50g,3mmol)溶于无水二氯甲烷(20mL)中,冰浴冷却下加入草酰氯(1.27mL),室温下搅拌6h。反应结束,减压除去溶剂及过量的草酰氯,得黄色固体,即酰氯中间体,用无水二氯甲烷(5mL)溶解备用。将(937mg,3.6mmol)溶于无水二氯甲烷(20mL)中,加入三乙胺(364mg,3.6mmol),冰浴下逐滴加入酰氯中间体,恢复室温,搅拌过夜。反应结束,加入二氯甲烷(150mL),用饱和食盐水洗(50mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=1:1),得白色固体2.00g,即化合物5,产率90%。
所得白色固体核磁数据如下:
1H NMR(400MHz,CDCl3,δ)7.62(d,J=8.0Hz,1H,CH=),7.03(s,1H,2”-H-Ph),7.01(d,J=4.0Hz,1H,6”-H-Ph),6.81(d,J=4.0Hz,1H,5”-H-Ph),6.70(d,J=8.0Hz,1H,=CH),6.00(s,2H,OCH2O),5.28(brs,1H,H-12),4.49(t,J=8.0Hz,H-3),3.70(brs,8H,N(CH2CH2)2N),3.09(d,J=6.0,1H),2.04(s,3H),1.14(s,3H),0.94(s,3H),0.93(s,3H),0.91(s,3H),0.86(s,3H),0.85(s,3H),0.73(s,3H);
13C NMR(100MHz,CDCl3,δ)171.12,166.06,149.32,148.35,144.69,143.31,129.64,124.11,121.79,114.62,108.68,106.44,101.42,77.48,77.16,76.84,60.53,55.54,47.84,47.73,46.47,42.03,39.33,38.24,37.86,37.16,34.09,33.20,32.91,30.57,30.25,28.19,28.06,26.12,23.68,23.55,21.46,18.34,17.10,16.82,15.55,14.36。
实施例2:制备齐墩果酸-28-[(E)-3’-(苯[d]二氧戊烷)-1’-哌嗪基丙烷-2’-烯-
1’-酮]酰胺(化合物6)
将化合物5(1.90g,2.57mmol)溶解于CH3OH-THF-H2O(1:2:1,40mL)中,加入NaOH(326mg,8.16mmol),室温搅拌过夜。反应结束,加入乙酸乙酯(150mL),用10%HCl调节pH 4-5;有机层用饱和食盐水洗(50mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=1:1),得白色固体1.38g,即化合物6,产率77%。
所得白色固体核磁数据如下:
1H NMR(400MHz,CDCl3,δ)7.61(d,J=8.0Hz,1H,CH=),7.02(s,1H,2”-H-Ph),7.00(d,J=4.0Hz,1H,6”-H-Ph),6.80(d,J=4.0Hz,1H,5”-H-Ph),6.67(d,J=8.0Hz,1H,=CH),5.99(s,2H,OCH2O,),5.27(brs,1H,H-12),3.70(brs,8H,N(CH2CH2)2N),3.18-3.22(m,1H,H-3),3.09(d,J=6.0,1H),1.14(s,3H),0.98(s,3H),0.94(s,3H),0.90(s,3H),0.90(s,3H),0.77(s,3H),0.73(s,3H);
13C NMR(100MHz,CDCl3,δ)175.59(28-CO),166.05(CO-CH=),149.34,148.42,144.66,143.34,129.61,124.10,121.92,114.59,108.69,106.49,101.63,79.14,55.44,47.90,47.71,46.48,43.68,42.02,39.30,38.90,38.54,37.24,34.09,33.19,32.98,30.56,30.23,28.24,28.06,27.35,26.14,24.18,23.50,18.44,17.08,15.70,15.47。
实施例3:制备3-苄基醚齐墩果酸-28-[(E)-3’-(苯[d]二氧戊烷)-1’-哌嗪基丙
烷-2’-烯-1’-酮]酰胺(化合物7)
将化合物6(140mg,0.2mmol)溶于DMF(2mL)中,冰浴搅拌下加入NaH(38mg,1mmol),溴化苄(121μL,1mmol),室温下搅拌4h。反应结束,倾入冰水中,加入乙酸乙酯(50mL),用10%HCl调节pH 4-5;有机层用饱和食盐水洗(20mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=2:1),得白色固体158mg,即化合物7,产率82%。
所得白色固体核磁数据如下:
1H NMR(400MHz,CDCl3,δ)7.62(d,J=8.0Hz,1H,CH=),7.25-7.36(m,5H,-Ph),7.03(s,1H,2”-H-Ph),7.01(d,J=4.0Hz,1H,6”-H-Ph),6.80(d,J=4.0Hz,1H,5”-H-Ph),6.68(d,J=8.0Hz,1H,=CH),6.00(s,2H,OCH2O),5.28(brs,1H,H-12),4.66(d,J=6.0,1H,PhCH2),(d,J=6.0,1H,PhCH2),3.70(brs,8H,N(CH2CH2)2N),3.09(d,J=6.0,1H),2.92(dd,J=6.0,2.0,1H,H-3),1.14(s,3H),0.99(s,3H),0.94(s,3H),0.91(s,3H),0.91(s,3H),0.83(s,3H),0.73(s,3H);
13C NMR(100MHz,CDCl3,δ)166.07,149.35,148.43,144.68,143.36,139.65,129.62,128.31,127.57,127.32,124.11,121.98,114.60,108.70,106.51,101.63,86.66,71.48,55.96,47.91,47.72,46.49,43.70,42.03,39.36,39.05,38.49,37.23,34.10,33.21,33.01,30.57,30.22,28.45,28.06,26.17,24.25,23.60,22.86,18.39,17.11,16.76,15.50。
实施例4:制备3-苯甲酰基齐墩果酸-28-[(E)-3’-(苯[d]二氧戊烷)-1’-哌嗪基丙
烷-2’-烯-1’-酮]酰胺(化合物8)
将化合物6(140mg,0.2mmol)溶于无水吡啶(2mL)中,搅拌下加入三氟乙酸酐(140μL,1mmol),DMAP(24mg,0.2mmol)室温下搅拌4h。反应结束,加入乙酸乙酯(50mL),用10%HCl调节pH 4-5;有机层用饱和食盐水洗(20mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=2:1),得白色固体100mg,即为化合物8,产率63%。
所得白色固体核磁数据如下:
1H NMR(400MHz,CDCl3)δ7.62(d,J=8.0Hz,1H,CH=),7.03(s,1H,2”-H-Ph),7.00(d,J=4.0Hz,1H,6”-H-Ph),6.80(d,J=4.0Hz,1H,5”-H-Ph),6.67(d,J=8.0Hz,1H,=CH),6.00(s,2H,OCH2O),5.27(brs,1H,H-12),4.67-4.70(m,H-3),3.70(brs,8H,N(CH2CH2)2N),3.09(d,J=6.0,1H),1.14(s,3H),0.94(s,3H),0.94(s,3H),0.90(s,3H),0.90(s,3H),0.90(s,3H),0.73(s,3H);
13C NMR(100MHz,CDCl3)δ175.54,166.11,149.37,148.43,144.75,143.43,129.58,124.13,121.63,114.52,108.70,106.48,101.64,86.43,55.40,47.82,47.70,46.46,43.68,42.02,39.30,38.11,38.04,37.11,34.09,33.18,32.84,30.56,30.20,28.02,26.10,24.21,23.52,23.24,18.27,17.06,16.56,15.51。
实施例5:制备3-(3”,3”-二甲基丁二酰基)齐墩果酸-28-[(E)-3’-(苯[d]二氧戊 烷)-1’-哌嗪基丙烷-2’-烯-1’-酮]酰胺(化合物9)
将化合物6(349mg,0.5mmol)溶解于无水吡啶(8mL)中,加入2,2-二甲基丁二酸酐(320mg,2.5mmol),DMAP(61mg,0.5mmol),完全溶解后,微波反应器加热至160℃,反应3h。反应结束,加入乙酸乙酯(50mL),用10%HCl调节pH 4-5;有机层用饱和食盐水洗(25mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=1:1),得白色固体302g,即为化合物9,产率73%。
所得白色固体核磁数据如下:
1H NMR(400MHz,CDCl3,δ)7.62(d,J=8.0Hz,1H,CH=),7.03(s,1H,H-Ph),7.00(d,J=4.0Hz,1H,H-Ph),6.80(d,J=4.0Hz,1H,H-Ph),6.67(d,J=8.0Hz,1H,=CH),5.99(s,2H,OCH2O),5.26(brs,1H,H-12),4.48-4.52(m,1H,H-3),3.70(brs,8H,N(CH2CH2)2N),3.08(d,J=6.0Hz,1H),2.66(d,J=8.0Hz,1H,H-2’),2.56(d,J=8.0Hz,1H,H-2’),1.30(s,3H,CH3-3’),1.28(s,3H,CH3-3’),1.13(s,3H),0.93(s,3H),0.90(s,3H),0.90(s,3H),0.84(s,3H),0.81(s,3H),0.72(s,3H);
13C NMR(100MHz,CDCl3,δ)181.53(4’-COOH),175.58(28-CO),171.12(CO-1’),166.09(CO-CH=),149.34(OCH2),148.43(OCH2),144.65(C-13),143.48(CO-CH=),129.60(=CH-C),124.14(Ar-C),121.94(C-12),114.51(CO-CH=CH),108.69(Ar-C),106.5(Ar-C)1,101.63(OCH2O),81.60(C-3),55.55,55.45,47.90,47.80,47.72,46.45,44.83,43.70,42.02,40.55,39.31,38.90,38.55,38.22,37.77,37.25,37.11,34.10,33.19,32.92,31.73,30.56,30.22,28.24,28.16,28.04,25.76,25.25,24.22,23.50,18.32,17.08,16.84,15.71,15.50。
实施例6:制备3-乙酰基齐墩果酸-28-[(3’-哌嗪基-1’-丙酸甲酯]酰胺(化合物
10)
将3-乙酰基齐墩果酸(1.00g,2mmol)溶于无水二氯甲烷(20mL)中,冰浴冷却下加入草酰氯(2mL),室温下搅拌6h。反应结束,减压除去溶剂及过量的草酰氯,得黄色固体,即酰氯中间体,用无水二氯甲烷(5mL)溶解备用。将1-哌嗪基-3-丙酸甲酯盐酸盐(540mg,2.2mmol)溶于无水二氯甲烷(20mL)中,加入三乙胺(445mg,4.4mmol),冰浴下逐滴加入酰氯中间体,恢复室温,搅拌过夜。反应结束,加入二氯甲烷(150mL),用饱和食盐水洗(50mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=1:1),得白色固体1.15g,即为化合物10,产率88%。
所得白色固体核磁数据如下:
1H NMR(400MHz,CDCl3,δ)5.25(brs,1H,H-12),4.47-4.50(m,1H,H-3),3.68(s,OCH3,3H),3.61(brs,4H,H-1’),3.07(d,J=8.0Hz,1H,H-3),3.05(d,J=8.0Hz,1H),2.68(t,J=8.0Hz,2H,H-4’),2.50(t,J=8.0Hz,2H,H-3’),2.34-2.46(brs,4H,H-2’),1.12(s,3H),0.92(s,3H),0.92(s,3H),0.89(s,3H),0.86(s,3H),0.84(s,3H),0.72(s,3H);
13C NMR(100MHz,CDCl3,δ)174.95,172.75,170.96,144.84,121.43,80.97,55.44,53.50,53.15,51.70,47.76,47.42,46.44,45.29,43.61,41.88,39.18,38.13,37.73,37.04,34.07,33.12,32.86,32.11,30.43,30.01,28.09,27.96,25.97,24.13,23.58,23.43,22.78,21.34,18.27,16.98,16.72,15.45。
实施例7:制备齐墩果酸-28-[(3’-哌嗪基-1’-丙酸甲酯]酰胺(化合物11)
将化合物10(0.74g,1.13mmol)溶解于无水CH3OH-DCM(4:1,25mL)中,加入NaOCH3(61mg,1.13mmol),室温搅拌过夜。反应结束,加入2g硅胶,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=1:1),得白色固体518mg,即为化合物11,产率75%。
所得白色固体核磁数据如下:
1H NMR(400MHz,CDCl3,δ)5.23(brs,1H,H-12),3.66(s,OCH3,3H),3.59(brs,4H,H-1’),3.18(d,J=4.0Hz,1H,H-3),3.05(d,J=8.0Hz,1H),2.67(t,J=8.0,2H,H-4’),2.48(t,J=8.0,2H,H-3’),2.39(brs,4H,H-2’),1.11(s,3H),0.96(s,3H),0.90(s,3H),0.88(s,3H),0.87(s,3H),0.75(s,3H),0.70(s,3H);
13C NMR(100MHz,CDCl3,δ)175.01,172.83,144.84,121.59,79.04,55.42,53.53,53.18,51.77,47.88,47.47,46.50,45.36,43.64,41.93,39.21,38.84,38.51,37.18,34.11,33.17,32.97,32.12,30.48,30.05,28.22,28.02,27.31,26.07,24.18,23.47,22.85,18.44,17.03,15.68,15.43。
实施例8:制备齐墩果酸-28-[(3’-哌嗪基-1’-丙酸]酰胺(化合物12)
将化合物10(500mg,0.77mmol)溶解于CH3OH-THF-H2O(1:2:1,20mL)中,加入NaOH(184mg,4.6mmol),室温搅拌过夜。反应结束,加入100mL乙酸乙酯,用10%HCl调节pH 4-5;有机层用饱和食盐水洗(50mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(二氯甲烷:甲醇=10:1),得白色固体262mg,即为化合物12,产率82%。
所得白色固体核磁数据如下:
1H NMR(400MHz,Pyridine-d5,δ)5.47(brs,1H,H-12),3.78(brs,4H,H-1’),3.43-3.49(m,2H),2.90(d,J=8.0Hz,2H,H-4’),2.80(t,J=8.0Hz,2H,H-3’),2.56(brs,4H,H-2’),2.17(t,J=12.0Hz,1H),1.28(s,3H),1.28(s,3H),1.08(s,3H),0.99(s,3H),0.99(s,3H),0.99(s,3H),0.99(s,3H);
13C NMR(100MHz,Pyridine-d5,δ)175.28,175.12,145.77,122.27,78.51,56.32,54.79,54.02,48.60,47.97,47.13,46.05,44.51,42.62,40.03,39.80,39.36,37.84,34.63,33.83,33.58,33.54,30.95,30.54,29.19,28.72,28.51,26.57,24.56,24.19,19.25,17.75,16.95,16.06。
实施例9:制备3-(3”,3”-二甲基丁二酰基)齐墩果酸-28-[(3’-哌嗪基-1’-丙酸]
酰胺(化合物13)
将化合物12(350mg,0.59mmol)溶解于无水吡啶(8mL)中,加入2,2-二甲基丁二酸酐(378mg,2.95mmol),DMAP(72mg,0.59mmol),完全溶解后,微波反应器加热至160℃,反应3h。反应结束,加入乙酸乙酯(50mL),用10%HCl调节pH 4-5;有机层用饱和食盐水洗(25mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=1:1),得白色固体304g,即为化合物13,产率71%。
所得白色固体核磁数据如下:
1H NMR(400MHz,Pyridine-d5,δ)5.44(brs,1H,H-12),4.79(d,J=8.0Hz,1H,H-3),3.83(brs,4H),3.43(d,J=8.0Hz,1H),3.00(brs,4H),2.92(d,J=12.0Hz,2H),1.56(s,6H),1.25(s,3H),1.02(s,3H),0.98(s,3H),0.98(s,3H),0.97(s,3H),0.93(s,3H),0.88(s,3H);
13C NMR(100MHz,pyridine-d5,δ)179.68,175.22,171.83,162.12,145.71,122.03,81.28,56.04,48.33,47.96,47.09,46.94,46.68,45.57,45.18,44.49,42.57,41.25,39.93,38.60,38.51,38.31,37.59,34.62,33.54,30.93,30.46,28.66,28.59,26.62,26.52,26.32,24.54,24.32,24.08,23.15,18.90,17.60,17.50,15.84。
实施例10:制备3-乙酰基-12,13-二氢齐墩果酸-28-[(E)-3’-(苯[d]二氧戊烷)-
1’-哌嗪基丙烷-2’-烯-1’-酮]酰胺(化合物14)
将3-乙酰基-12,13-二氢齐墩果酸(0.21g,0.42mmol)溶于无水二氯甲烷(6mL)中,加入DMF 3滴,冰浴冷却下加入草酰氯(1.0mL),室温下搅拌6h。反应结束,减压除去溶剂及过量的草酰氯,得黄色固体,即酰氯中间体,用无水二氯甲烷(3mL)溶解备用。将(164mg,0.63mmol)溶于无水二氯甲烷(8mL)中,加入三乙胺(64mg,0.63mmol),冰浴下逐滴加入酰氯中间体,恢复室温,搅拌过夜。反应结束,加入二氯甲烷(50mL),用饱和食盐水洗(20mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=1:1),得白色固体243mg,即为化合物14,产率78%。
所得白色固体核磁数据如下:
1H NMR(400MHz,CDCl3,δ)7.59(d,J=8.0Hz,1H,CH=),7.00(s,1H,2”-H-Ph),6.97(d,J=4.0Hz,1H,6”-H-Ph),6.77(d,J=4.0Hz,1H,5”-H-Ph),6.66(d,J=8.0Hz,1H,=CH),5.97(s,2H,OCH2O),4.93(t,J=8.0Hz,1H),4.42-4.45(m,1H,H-3),3.69(brs,8H,N(CH2CH2)2N),2.67(d,J=6.0Hz,1H),2.30(s,1H),2.01(s,3H,CH3CO),0.98(s,3H),0.87(s,3H),0.84(s,3H),0.80(s,3H),0.79(s,3H),0.79(s,3H),0.79(s,3H);
13C NMR(100MHz,CDCl3,δ)176.22,170.90,165.98,149.29,148.34,143.36,129.47,124.06,114.41,108.61,106.38,101.56,80.63,77.48,77.16,76.84,71.98,60.42,55.36,48.86,47.95,41.48,40.69,38.27,37.84,37.05,36.43,34.17,32.40,30.76,30.26,29.25,28.02,27.55,24.07,23.60,21.37,21.33,18.14,16.55,16.45,15.93。
实施例11:制备12,13-二氢齐墩果酸-28-[(E)-3’-(苯[d]二氧戊烷)-1’-哌嗪基
丙烷-2’-烯-1’-酮]酰胺(化合物15)
将化合物14(300mg,0.53mmol)溶解于CH3OH-THF-H2O(1:2:1,12mL)中,加入NaOH(84mg,2.12mmol),室温搅拌过夜。反应结束,加入乙酸乙酯(50mL),用10%HCl调节pH 4-5;有机层用饱和食盐水洗(20mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=1:1),得白色固体267mg,即为化合物15,产率72%。
所得白色固体核磁数据如下:
1H NMR(400MHz,CDCl3,δ)7.61(d,J=8.0Hz,1H,CH=),7.02(s,1H,2”-Ph),7.00(d,J=4.0Hz,1H,6”-Ph),6.80(d,J=4.0Hz,1H,5”-Ph),6.67(d,J=8.0Hz,1H,=CH),5.99(s,2H),3.68-3.74(m,8H),3.15-3.19(m,3H),1.00(s,3H),0.95(s,3H),0.89(s,3H),0.86(s,3H),0.81(s,3H),0.79(s,3H),0.74(s,3H);
13C NMR(100MHz,CDCl3,δ)170.88,165.87,149.18,148.23,143.27,129.36,123.95,114.28,108.50,106.28,101.45,78.66,77.30,76.98,76.67,71.97,60.33,55.22,48.88,47.85,41.37,40.62,39.15,38.78,38.50,37.04,36.35,34.06,32.99,32.37,30.66,30.16,29.17,27.95,27.44,27.17,23.98,23.46,21.28,20.99,18.15,17.78,16.35,15.79,15.31,14.14。
实施例12:制备3-(3”,3”-二甲基丁二酰基)-12,13-二氢齐墩果酸-28-[(E)-3’-
(苯[d]二氧戊烷)-1’-哌嗪基丙烷-2’-烯-1’-酮]酰胺(化合物16)
将化合物15(200mg,0.29mmol)溶解于无水吡啶(3mL)中,加入2,2-二甲基丁二酸酐(186mg,1.45mmol),DMAP(35mg,0.29mmol),完全溶解后,微波反应器加热至160℃,反应3h。反应结束,加入乙酸乙酯(50mL),用10%HCl调节pH 4-5;有机层用饱和食盐水洗(25mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=1:1),得白色固体171mg,即为化合物16,产率71%。
所得白色固体核磁数据如下:
1H NMR(400MHz,CDCl3,δ)7.62(d,J=8.0Hz,1H,CH=),7.02(s,1H,2”-Ph),7.00(d,J=4.0Hz,1H,6”-Ph),6.79(d,J=4.0Hz,1H,5”-Ph),6.67(d,J=8.0Hz,1H,=CH),5.99(s,2H,OCH2O),4.92-4.98(m,1H),4.45-4.49(m,1H,H-3),3.68-3.75(m,,8H),2.64(d,J=8.0Hz,1H,H-2’),2.54(d,J=8.0Hz,1H,H-2’),1.28(s,3H,CH3-3’),1.26(s,3H,CH3-3’),0.99(s,3H),0.89(s,3H),0.85(s,3H),0.81(s,3H),0.81(s,3H),0.79(s,3H),0.77(s,3H);
13C NMR(100MHz,CDCl3,δ)182.14(COOH),176.39(COO),171.00(CONH),166.21(CONH),149.39,148.40,143.66,129.50,124.18,114.32,108.68,106.47,101.62,81.27,72.07,60.53,55.43,48.88,48.04,44.81,41.53,40.74,40.54,40.33,38.31,37.84,37.09,36.49,34.21,30.80,30.32,29.30,28.04,27.59,25.71,25.42,25.18,24.11,23.57,21.43,18.17,16.61,16.51,15.93,14.30。
实施例13:制备3-(3’,3’-二甲基丁二酰基)-12-羰基齐墩果酸(化合物17)
将原料12-羰基齐墩果酸(189mg,0.40mmol)溶解于无水吡啶(3mL)中,加入2,2-二甲基丁二酸酐(256mg,2mmol),DMAP(49mg,0.40mmol),完全溶解后,微波反应器加热至160℃,反应3h。反应结束,加入乙酸乙酯(50mL),用10%HCl调节pH 4-5;有机层用饱和食盐水洗(25mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=1:1),得白色固体202mg,即为化合物17,产率68%。
所得白色固体核磁数据如下:
1H NMR(400MHz,CDCl3,δ)4.52(brs,1H,H-3),2.86(d,J=8.0Hz,1H,H-2’),2.74(d,J=6.0Hz,1H),2.69(s,1H),2.47(d,J=8.0Hz,1H,H-2’),1.29(s,3H,,CH3-3’),1.24(s,3H,CH3-3’),1.03(s,3H),0.97(s,3H),0.94(s,3H),0.90(s,3H),0.90(s,3H),0.87(s,3H),0.81(s,3H);
13C NMR(100MHz,CDCl3,δ)211.5,185.0,183.5,170.5,81.0,54.9,51.8,49.3,47.6,45.5,41.9,41.3,40.8,38.5,37.8,37.2,37.1,36.1,34.6,33.5,31.8,31.6,30.7,28.5,27.8,27.0,24.3,23.4,23.3,22.4,20.3,18.6,17.9,17.0,15.9。
实施例14:制备3-乙酰基-12-羰基齐墩果酸-28-[(E)-3’-(苯[d]二氧戊烷)-1’-
哌嗪基丙烷-2’-烯-1’-酮]酰胺(化合物18)
将原料12-羰基齐墩果酸(1.30g,2.74mmol)溶解于无水吡啶(15mL)中,搅拌下加入乙酸酐(1.29mL,13.7mmol),DMAP(67mg,0.55mmol)室温下搅拌过夜。反应结束,加入乙酸乙酯(100mL),用10%HCl调节pH 4-5;有机层用饱和食盐水洗(50mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,得白色中间产物3-乙酰基-12羰基齐墩果酸(1.28g)。取上述中间产物(392mg,0.76mmol)溶于无水二氯甲烷(6mL)中,加入DMF 3滴,冰浴冷却下加入草酰氯(1.0mL),室温下搅拌6h。反应结束,减压除去溶剂及过量的草酰氯,得黄色固体,即酰氯中间体,用无水二氯甲烷(3mL)溶解备用。将(164mg,0.63mmol)溶于无水二氯甲烷(8mL)中,加入三乙胺(84μL,0.63mmol),冰浴下逐滴加入酰氯中间体,恢复室温,搅拌过夜。反应结束,加入二氯甲烷(50mL),用饱和食盐水洗(20mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=1:1),得白色固体506mg,即为化合物18,产率88%。
所得白色固体核磁数据如下:
1H NMR(400MHz,CDCl3,δ)7.60(d,J=15.3Hz,1H,CH=),7.01(s,1H,2”-Ph),6.99(d,J=8.1Hz,1H,6”-Ph),6.79(d,J=7.9Hz,1H,5”-Ph),6.66(d,J=15.3Hz,1H,=CH),5.98(s,2H,OCH2O),4.42–4.48(m,1H,H-3),3.68(brs,8H),2.02(s,3H,CH3CO),0.97(s,3H),0.93(s,3H),0.90(s,3H),0.88(s,3H),0.84(s,3H),0.84(s,3H),0.82(s,3H);
13C NMR(101MHz,CDCl3,δ)211.72,176.15,171.01,166.05,149.37,148.40,143.48,131.62,129.51,124.13,114.40,108.67,106.46,101.62,80.54,55.32,51.71,49.91,47.86,47.49,47.09,42.04,41.42,39.60,38.58,37.86,37.79,37.08,36.96,36.58,34.41,33.37,32.95,31.88,30.68,30.49,30.36,28.02,24.91,24.09,23.51,21.39,18.26,16.76,16.56,16.35,15.61,15.38。
实施例15:制备12-羰基齐墩果酸-28-[(E)-3’-(苯[d]二氧戊烷)-1’-哌嗪基丙
烷-2’-烯-1’-酮]酰胺(化合物19)
将化合物18(479mg,0.67mmol)溶解于CH3OH-THF-H2O(1:2:1,20mL)中,加入NaOH(107mg,2.68mmol),室温搅拌过夜。反应结束,加入乙酸乙酯(50mL),用10%HCl调节pH 4-5;有机层用饱和食盐水洗(30mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=1:1),得白色固体345mg,即为化合物19,产率72%。
所得白色固体核磁数据如下:
1H NMR(400MHz,CDCl3,δ)7.62(d,J=8.0Hz,1H,CH=),7.03(s,1H,2”-Ph),7.00(d,J=4.0Hz,1H,6”-Ph),6.80(d,J=4.0Hz,1H,5”-Ph),6.67(d,J=8.0Hz,1H,=CH),6.00(s,2H,OCH2O),3.72(brs,8H),3.16-3.20(m,1H,H-3),2.99(s,1H),2.90(d,J=6.0Hz,1H),0.99(s,3H),0.98(s,3H),0.95(s,3H),0.95(s,3H),0.91(s,3H),0.84(s,3H),0.77(s,3H);
13C NMR(100MHz,CDCl3,δ)211.92,176.18,166.08,149.40,148.43,143.52,129.54,124.15,114.42,108.70,106.49,101.65,78.76,60.52,55.27,51.77,50.08,47.90,42.14,41.43,38.95,38.66,38.07,37.09,36.63,34.44,33.41,31.97,30.72,30.52,28.10,27.21,24.12,23.34,20.72,18.41,16.39,15.48,15.35,14.34。
实施例16:制备3-(3”,3”-二甲基丁二酰基)-12-羰基齐墩果酸-28-[(E)-3’-(苯
[d]二氧戊烷)-1’-哌嗪基丙烷-2’-烯-1’-酮]酰胺(化合物20)
将化合物19(186mg,0.2mmol)溶解于无水吡啶(3mL)中,加入2,2-二甲基丁二酸酐(167mg,1.30mmol),DMAP(32mg,0.26mmol),完全溶解后,微波反应器加热至160℃,反应3h。反应结束,加入乙酸乙酯(50mL),用10%HCl调节pH 4-5;有机层用饱和食盐水洗(25mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=1:1),得白色固体149mg,即为化合物20,产率68%。
所得白色固体核磁数据如下:
1H NMR(400MHz,CDCl3,δ)7.61(d,J=8.0Hz,1H,CH=),7.02(s,1H,2”-Ph),6.99(d,J=4.0Hz,1H,6”-Ph),6.79(d,J=4.0Hz,1H,5”-Ph),6.66(d,J=8.0Hz,1H,=CH),5.98(s,2H,OCH2O),4.43-4.47(m,1H,H-3),3.72(brs,8H),2.96(s,1H),2.88(d,J=8.0Hz,1H),2.64(d,J=8.0Hz,1H,H-2’),2.54(d,J=8.0Hz,1H,H-2’),1.28(s,3H,CH3-3’),1.26(s,3H,CH3-3’),0.97(s,3H),0.93(s,3H),0.93(s,3H),0.89(s,3H),0.83(s,3H),0.83(s,3H),0.80(s,3H);
13C NMR(100MHz,CDCl3,δ)211.8,182.2,176.2,171.0,166.2,149.4,148.4,143.7,129.5,124.2,114.3,108.6,106.5,101.6,81.1,60.5,55.3,51.7,49.9,47.9,44.8,42.0,41.4,40.5,38.5,37.7,36.9,36.6,34.4,33.4,30.6,30.5,28.0,27.9,25.8,25.2,24.1,23.4,21.1,20.6,18.3,16.6,16.3,15.3,14.3。
实施例17:3-乙酰基-12-羰基齐墩果酸-28-(4’-氨基丁酸乙酯)酰胺(化合物21)
将3-乙酰基-12羰基齐墩果酸(501mg,1.2mmol)溶于无水二氯甲烷(10mL)中,加入DMF 3滴,冰浴冷却下加入草酰氯(1.0mL),室温下搅拌6h。反应结束,减压除去溶剂及过量的草酰氯,得黄色固体,即酰氯中间体,用无水二氯甲烷(5mL)溶解备用。将4-氨基丁酸乙酯盐酸盐(201mg,0.63mmol)溶于无水二氯甲烷(8mL)中,加入三乙胺(293μL,2.0mmol),冰浴下逐滴加入酰氯中间体,恢复室温,搅拌过夜。反应结束,加入二氯甲烷(50mL),用饱和食盐水洗(20mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=1:1),得白色固体490mg,即为化合物21,产率78%。
所得白色固体核磁数据如下:
1H NMR(400MHz,CDCl3,δ)6.02(s,1H),4.44-4.48(m,1H,H-3),3.29(q,J=8.0Hz,2H,OCH2CH3),2.69-2.73(m,2H),2.34(t,J=8.0Hz,2H),1.83(t,J=8.0Hz,2H),1.25(t,J=8.0Hz,3H,OCH2CH3),0.96(s,3H),0.96(s,3H),0.93(s,3H),0.89(s,3H),0.86(s,3H),0.85(s,3H),0.84(s,3H);
13C NMR(100MHz,CDCl3,δ)211.76,177.56,173.67,171.03,80.57,60.76,55.31,51.67,49.78,46.74,42.04,41.50,39.39,38.61,37.88,37.77,36.97,36.57,34.82,34.47,33.56,32.24,32.09,31.92,30.77,28.04,27.52,24.70,23.53,23.41,23.33,21.40,20.75,18.30,16.58,16.42,15.38,14.36。
实施例18:制备3,23-二乙酰基常春藤苷元-28-[二甘氨肽乙酯]酰胺(化合物22)
原料常春藤皂苷元(化合物4)(0.94g,2mmol)溶于无水吡啶(20mL)中,搅拌下加入乙酸酐(0.92g,8mmol),室温下搅拌4h。反应结束,加入100mL乙酸乙酯,用10%HCl调节pH4-5;有机层用饱和食盐水洗(50mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=2:1),得白色中间产物(3,23,-二乙酰基常春藤皂苷元)1.08g,产率90.0%。
所得白色中间产物的熔点(mp)为163-164℃;所得白色中间产物的核磁数据如下:
1H NMR(400MHz,CDCl3,δ)5.28(s,1H,H-12),4.77–4.81(m,1H),3.88(d,J=8.0Hz,1H),3.70(d,J=8.0Hz,1H),2.07(s,3H),2.02(s,3H),1.12,0.97,0.93,0.91,0.83,0.75(s,CH3×6);
HRMS-ESI:(m/z)calcd for C34H51O6[M-H]-555.3691,found 555.3682。
将上述中间体(415mg,0.75mmol)溶于无水二氯甲烷(10mL)中,冰浴冷却下加入草酰氯(1.0mL),室温下搅拌6h。反应结束,减压除去溶剂及过量的草酰氯,得黄色固体,即酰氯中间体,用无水二氯甲烷(4mL)溶解备用。将二甘氨肽乙酯盐酸盐(221mg,1.12mmol)溶于无水二氯甲烷(10mL)中,加入三乙胺(340mg,3.36mmol),冰浴下逐滴加入酰氯中间体,恢复室温,搅拌过夜。反应结束,加入100mL二氯甲烷,用饱和食盐水洗(50mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=1:1),得白色固体377mg,即为化合物22,产率72%。
所得白色固体核磁数据如下:
1H NMR(400MHz,CDCl3,δ)6.76(s,1H,NH),6.67(s,1H,NH),5.45(brs,1H,H-12),4.76-4.80(m,1H,H-3),3.86(d,J=6.0Hz,1H,H-23),3.69(d,J=6.0Hz,1H,H-23),4.20(q,J=8.0Hz,2H,OCH2CH3),4.01(t,J=4.0Hz,2H),2.06(s,1H,CH3CO),2.02(s,1H,CH3CO),1.28(t,J=8.0Hz,3H,OCH2CH3),1.15(s,3H),0.95(s,3H),0.92(s,3H),0.92(s,3H),0.83(s,3H),0.70(s,3H);
13C NMR(100MHz,CDCl3,δ)179.21,171.07,170.82,169.51,169.41,144.39,123.39,74.60,65.56,61.70,47.91,47.79,46.70,46.53,43.69,42.24,42.02,41.47,40.67,39.51,37.94,36.82,34.22,33.13,32.57,32.11,30.86,27.37,25.84,23.97,23.71,23.69,23.09,21.38,21.07,18.05,16.65,16.01,14.30,13.23。
实施例19:制备常春藤苷元-28-[二甘氨肽]酰胺(化合物23)
将化合物22(150mg,0.21mmol)溶解于CH3OH-THF-H2O(1:2:1,8mL)中,加入NaOH(76mg,1.89mmol),室温搅拌过夜。反应结束,加入100mL乙酸乙酯,用10%HCl调节pH 4-5;有机层用饱和食盐水洗(50mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(二氯甲烷:甲醇=10:1),得白色固体99mg,即为化合物23,产率80%。
所得白色固体核磁数据如下:
1H NMR(400MHz,pyridine-d5,δ)9.12(s,1H,NH),7.99(s,1H,NH),5.57(brs,1H,H-12),3.73(d,J=4.0Hz 1H,H-3),4.54(d,J=8.0Hz,1H,H-23),4.38(d,J=8.0Hz,1H,H-23),4.48(d,J=2.0Hz,2H),4.21(t,J=8.0Hz,2H),1.22(s,3H),1.07(s,3H),1.02(s,3H),1.02(s,3H),0.92(s,3H),0.90(s,3H);
13C NMR(100MHz,pyridine-d5,δ)178.55,173.17,170.60,144.83,123.72,73.74,68.21,48.87,48.50,47.08,46.90,44.04,43.23,42.59,42.51,40.17,39.18,37.51,34.69,33.83,33.50,33.03,31.20,28.24,27.99,26.49,24.27,24.24,24.05,18.91,17.45,16.40,13.45。
实施例20:制备常春藤苷元-28-[二甘氨肽甲酯]酰胺(化合物24)
将化合物22(150mg,0.21mmol)溶解于无水CH3OH(8mL)中,加入NaOCH3(40mg),室温搅拌过夜。反应结束,加入2g硅胶,减压浓缩除去溶剂,硅胶柱层析(二氯甲烷:甲醇=10:1),得白色固体101mg,即为化合物24,产率80%。
所得固体核磁数据如下:
1H NMR(400MHz,Pyridine-d5,δ)8.88(s,1H,NH),8.06(s,1H,NH),5.58(brs,1H,H-12),4.48-4.54(m,1H),4.35(brs,3H),4.21(d,J=4.0Hz,2H),3.76(d,J=6.5Hz,1H),3.62(s,3H,OCH3),3.13(d,J=8.0Hz,1H),1.25(s,3H),1.11(s,3H),1.07(s,3H),1.02(s,3H),0.96(s,3H),0.93(s,3H);
13C NMR(100MHz,pyridine-d5,δ)178.52,170.29,144.51,123.00,73.43,67.86,49.67,48.56,48.18,46.79,46.54,43.73,43.51,42.91,42.16,42.06,39.84,38.88,34.40,33.42,33.22,32.72,30.89,27.91,27.66,26.19,23.96,23.81,18.63,17.15,16.13,13.16。
化合物25-27的制备通法
将3,23-二乙酰基常春藤苷元(2mmol)溶于无水二氯甲烷(20mL)中,冰浴冷却下加入草酰氯(2mL),室温下搅拌6h。反应结束,减压除去溶剂及过量的草酰氯,得黄色固体,即酰氯中间体,用无水二氯甲烷(8mL)溶解备用。将氨基酸盐酸盐(NH2(CH2)nCOOC2H5·HCL,n为1、3或5,2.2mmol)溶于无水二氯甲烷(20mL)中,加入三乙胺(4.4mmol),冰浴下逐滴加入酰氯中间体,恢复室温,搅拌过夜。反应结束,加入二氯甲烷(150mL),用饱和食盐水洗(50mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=2:1),得白色产物,即为化合物25-27。
实施例21:制备3,23-二乙酰基常春藤苷元-28-[甘氨酸乙酯]酰胺(化合物25)
制备中使用的氨基酸盐酸盐为NH2(CH2)nCOOC2H5·HCL,n为1;
所得白色产物的核磁数据如下:
1H NMR(600MHz,CDCl3,δ)6.55–6.45(m,1H,CONH),5.45(s,1H,H-12),4.78(dd,J=11.7,4.7Hz,1H),4.21(q,J=7.1Hz,2H,NHCH2COO),4.11(dd,J=18.6,5.5Hz,2H,C-23),3.86(d,J=11.6Hz,1H,OCH2)3.92–3.76(m,2H,H-3),3.70(d,J=11.7Hz,1H,OCH2),2.06(s,3H,CH3COO-),2.02(s,3H,CH3COO-),1.28(t,J=7.1Hz,3H,CH3CH2),1.15(s,3H,CH3),0.95(s,3H,CH3),0.92(s,3H,CH3),0.91(s,3H,CH3),0.83(s,3H,CH3),0.71(s,3H,CH3);
13C NMR(151MHz,CDCl3,δ)178.28(CH2COO),171.06(C-28),170.80(Ac-),170.23(Ac-),144.48(C-13),123.22(C-12),74.59(C-3),65.54(C-23),61.58(OOCH2CH3),47.91,47.80,46.70,46.43,42.31(NHCH2),42.01,41.83,40.66,39.52,37.94,36.82,34.23,33.14,32.50,32.15,30.87,27.38,25.82,23.93,23.74,23.70(CH3CO),23.09(CH3CO),21.38,21.07,18.05,16.55,16.00,14.30(CH2CH3),13.22。
实施例22:3,23-二乙酰基常春藤苷元-28-[4’氨基-丁酸乙酯]酰胺(化合物26)
制备中使用的氨基酸盐酸盐为NH2(CH2)nCOOC2H5·HCL,n为3;
所得白色产物的核磁数据如下:
1H NMR(600MHz,CDCl3,δ)6.04(t,J=5.3Hz,1H,CONH),5.38(s,1H,H-12),4.77(dd,J=11.5,4.5Hz,1H),4.13(q,J=7.1Hz,2H,NHCH2),3.86(d,J=11.6Hz,1H,H-23),3.70(d,J=11.6Hz,1H,H-23),3.40(td,J=13.7,6.8Hz,1H,H-3),3.08–2.98(m,1H,OCH2),2.56–2.50(m,1H,OCH2),2.33(td,J=7.2,2.3Hz,2H,CH2COOCH2CH3),2.05(s,2H,CH3COO-),2.02(s,2H,CH3COO-),1.25(td,J=7.1,0.9Hz,3H,CH3),1.14(s,3H,CH3),0.97(s,3H,CH3),0.90(s,6H,2×CH3),0.83(s,3H,CH3),0.75(s,3H,CH3);
13C NMR(151MHz,CDCl3,δ)178.36(CH2COO),173.51(C-28),171.06(Ac-),170.81(Ac-),145.05(C-13),122.72(C-12),74.59(C-3),65.54(C-23),60.65(OOCH2CH3),47.92,47.78,46.82,46.41,42.25,42.10,40.66,39.49,39.13(NHCH2),37.91,36.84,34.26,33.14(CH2),32.80,32.15,32.02,30.87,27.40,25.80,24.64(CH2),23.82,23.73(CH3CO),23.64,23.07(CH3CO),21.38,21.07,18.05,17.05,15.98,14.38(CH2CH3),13.23。
实施例23:制备3,23-二乙酰基常春藤苷元-28-[6’-氨基己酸乙酯]酰胺(化合物
27)
制备中使用的氨基酸盐酸盐为NH2(CH2)nCOOC2H5·HCL,n为5;
所得白色产物的核磁数据如下:
1H NMR(600MHz,CDCl3,δ)5.94–5.86(m,1H,CONH),5.37(s,1H,H-12),4.77(dd,J=11.4,4.7Hz,1H),4.11(q,J=7.1Hz,2H,NHCH2),3.86(d,J=11.6Hz,1H,H-23,H-23),3.70(d,J=11.7Hz,1H,H-23),3.35(dt,J=20.4,7.0Hz,1H,H-3),2.99(dt,J=12.1,6.9Hz,1H,OCH2),2.51(dd,J=12.5,2.8Hz,1H,OCH2),2.29(t,J=7.4Hz,2H,CH2COOCH2CH3),2.05(s,3H,CH3COO-),2.02(s,3H,CH3COO-),1.25(t,J=7.1Hz,3H,CH3),1.14(s,3H,CH3),0.97(s,3H,CH3),0.90(s,6H,2×CH3),0.83(s,3H,CH3),0.76(s,3H,CH3);
13C NMR(151MHz,CDCl3,δ)178.17(CH2COO),173.69(C-28),171.05(Ac-),170.82(Ac-),145.29(C-13),122.58(C-13),74.58(C-3),65.54(C-23),60.39(OOCH2CH3),47.92,47.76,46.86,46.38,42.43,42.16,40.65,39.49(NHCH2),39.36,37.92,36.83,34.32,34.27(CH2),33.13,32.70,32.16,30.87,29.25(CH2),27.38,26.73(CH2),25.76,24.70(CH2),23.86,23.73(CH3CO),23.66,23.07(CH3CO),21.38,21.06,18.05,17.07,15.99,14.40(CH2CH3),13.23。
化合物28-30的制备通法
分别将化合物25-27(1mmol)溶解于CH3OH-THF-H2O(1:2:1,20mL)中,加入NaOH(6mmol),室温搅拌过夜。反应结束,加入乙酸乙酯(100mL),用10%HCl调节pH 4-5;有机层用饱和食盐水洗(50mL×3),无水硫酸钠干燥,滤过,减压浓缩除去溶剂,硅胶柱层析(正己烷:乙酸乙酯=1:1),得白色产物,即为化合物28-30。
实施例24:制备常春藤苷元-28-(甘氨酸)酰胺(化合物28)
以化合物25为原料制备化合物28;
所得白色产物的核磁数据如下:
1H NMR(600MHz,pyridine-d5,δ)7.93(s,1H,CONH),5.70(s,1H,H-12),5.55(s,2H,CH2COOH),4.62~4.58,4.37~4.33,4.23,4.22,4.21,4.19,4.14,4.13,4.12,4.10,4.09,4.08,3.75,3.73,3.62,1.24,1.08,1.04,1.01,0.94,0.91(s each,3H each,6×CH3);
13C NMR(150MHz,pyridine-d5,δ)178.30(C-28),173.60(COOH),145.08(C-13),123.51(C-12),73.74(C-3),68.23(C-23),48.91,48.52,47.17,46.83,43.27(CH2COOH),42.76,42.57,42.46,40.20,39.20,37.56,34.76,33.89,33.52,33.12,31.25,28.25,28.03,26.50,24.30,24.07,18.94,17.57,16.39,13.48。
实施例25:制备常春藤苷元-28-(4’-氨基丁酸)酰胺(化合物29)
以化合物26为原料制备化合物29;
所得白色产物的核磁数据如下:
1H NMR(600MHz,pyridine-d5,δ)7.52(s,1H,CONH),5.50(t,1H,H-12),4.23~4.20,4.19,3.74,3.73,3.72,3.71,3.69,3.68,3.67,3.56,3.55,3.54,3.53,3.14,3.13,3.12,3.11,2.66,2.65,2.63,1.22,1.08,1.05,1.03,0.94,0.91(s each,3H each,6×CH3);
13C NMR(150MHz,d5-pyridine,δ)178.03(C-28),176.28(COOH),145.27(C-13),123.26(C-12),73.78(C-3),68.30(C-23),48.94,48.50,47.19,46.73,43.27,42.58,42.28,40.20(NHCH2),40.12,39.19,37.59,34.76,34.20(CH2COOH),33.58,33.21,33.05,31.27,28.33,28.05,26.53,26.06(CH2),24.27,24.15,24.07,18.97,18.00,16.40,13.51。
实施例26:制备常春藤苷元-28-(6’-氨基己酸)酰胺(化合物30)
以化合物27为原料制备化合物30;
所得白色产物的核磁数据如下:
1H NMR(600MHz,CDCl3,δ)7.57(m,1H,NHCH2),5.94(t,1H,H-12),5.36(t,1H,H-3),2.50,2.49,2.48,2.47,2.35,2.34,2.32,2.32,2.31,2.31,2.29,2.04,1.75,1.73,1.70,1.68,1.64,1.63,1.62,1.61,1.60,1.58,1.26,1.25,1.24,1.24,1.14,0.95,0.89,0.88,0.75;
13C NMR(150MHz,CDCl3,δ)178.41(C-28),174.14(COOH),145.19(C-13),122.77(C-12),76.79(C-3),72.05(C-23),51.66,49.77,47.65,46.92,46.40,42.45,42.25,41.94,39.61,39.56,39.49,39.39,38.31,36.98,34.27,34.04,33.97,33.67,33.12,32.64,32.27,30.86,29.18,29.02,28.97,27.42,26.72,26.43,26.33,25.90,24.66,24.59,24.37,23.88,23.72,23.65,18.57,17.07,15.86,11.58。
实施例27:细胞毒实验
实验目的:
通过体外培养人肺癌细胞A549,人乳腺癌细胞MDA-MB-231,人表皮癌细胞KB,耐药的人表皮癌细胞KB-VIN,人乳腺癌细胞MCF-7,采用SRB法检测细胞增殖活性,筛选受试化合物的体外抗肿瘤活性。
实验材料:
1.受试细胞株:人肺癌细胞A549、人乳腺癌细胞MDA-MB-231,人表皮癌细胞KB,耐药的人表皮癌细胞KB-VIN,人乳腺癌细胞MCF-7,购自中国科学院上海生命科学研究院细胞资源中心。
2.SRB,购自上海国药集团。
3.受试药物:本发明合成的三萜衍生物。
4.阳性对照物:紫杉醇(Paclitaxel)
实验方法:
1.受试药物的配制:准确称取受试样品各2mg,用DMSO配置成10m M 100μM的母液,用相应培养基配制成不同的浓度,0.22μM滤膜过滤备用。
2.细胞增殖抑制实验:取对数生长期细胞,调整密度为5×104加入不同浓度含药培养基100μL,对照组每孔加培养基100μL,对照组与药物组均设3个复孔,另设空白对照组,不加细胞只加培养基的作为对照组调零。将96孔板置5%CO2培养箱(37℃)培养48h,加入0.04%SRB 20μL,继续培养4h后,弃上清,加入DMSO 150μL,振荡溶解10min,酶标仪于515nm处测定OD值。
3.观察指标
按公式计算抑制率,计算三次平行试验的IC50平均值,结果参见表1。
抑制率(%)=[(1-用药组平均OD值/对照组平均OD值)]×100%。
表1:化合物的细胞毒性
a72小时暴露试验样品的50%细胞生长抑制浓度。数据代表三次独立实验的平均值和标准差。
bA-549是人肺癌细胞株。
cMDA-MB-231是乳腺癌细胞株。
dKB是人表皮癌细胞株。
ekb-vin是过表达P-糖蛋白耐药的人表皮癌细胞株。
fMCF-7是人乳腺癌株。
上述实施例只为说明本发明的技术构思及特点,其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰,都应涵盖在本发明的保护范围之内。
Claims (12)
1.一种三萜衍生物,其特征在于:所述三萜衍生物为具有结构通式(Ⅰ)的化合物或其可药用盐,
式(I)中,
R1为H,C1-6烷基羰基,C1-6卤代烷基羰基,未被取代或为选自卤素、硝基、C1-6烷基、C1-6烷氧基中的一个或多个取代基所取代的苄基,未被取代或为选自卤素、硝基、C1-6烷基、C1-6烷氧基中的一个或多个取代基所取代的苯甲酰基,或HOOCC(CH3)2CH2C=O;
R2为H,OH,C1-6酰基羰基,C1-6卤代酰基羰基,未被取代或为选自卤素、硝基、C1-6烷基、C1-6烷氧基中的一个或多个取代基所取代的苄氧基或苯甲酰氧基;
X为CH2、C=O、CH-OH,Y为CH;或X-Y为CH=C;
Z为NH或-NR4(C=O)n(CH2)m(C=O)pNR5-,其中,n、p独立地为0或1,m为1-10之间的整数,R4,R5均为H或二者连接使所述NR4(C=O)n(CH2)m(C=O)pNR5形成5-10元环;
R3为(a)-(CH2)qCOOR6,其中q为1-10的整数,R6为H、C1-12烃基或卤代烃基、被一个或二个羰基和/或氧所间隔的C1-12烃基或卤代烃基;(b)碳数2-8的含氮杂环,所述含氮杂环未被取代或为选自卤素、硝基、C1-6烷基、C1-6烷氧基、C1-6烷基酰基中的一个或多个取代基所取代;(c)(d)苄基或苯环为选自卤素、硝基、C1-6烷基、C1-6烷氧基中的一个或多个取代基所取代的苄基;
或者,Z-R3为OH;
当X-Y为CH=C时,Z,R1,R2不同时满足如下条件:Z为NH,R1为H或乙酰基,R2为H。
2.根据权利要求1所述的三萜衍生物,其特征在于:所述-NR4(C=O)n(CH2)m(C=O)pNR5-中,n、p为0,m为1-10之间的整数,R4,R5均为H;或者,n、p中的一个为0、另一个为1,m为1或2,R4,R5均为H;或者,n、p为0,m为1-3之间的整数,R4,R5二者连接使所述NR4(C=O)n(CH2)mNR5形成6-8元环。
3.根据权利要求1或2所述的三萜衍生物,其特征在于:Z为NH;NH(CH2)rNH,其中r为1-6之间的整数;
4.根据权利要求1所述的三萜衍生物,其特征在于:所述(a)中,R6为H、C1-C6烷基或卤代烷基,C1-C6烷基羰基,C1-C6卤代烷基羰基,苯基,苯环为选自卤素、硝基、C1-6烷基、C1-6烷氧基中的一个或多个取代基所取代的苯基,苄基或或苯环为选自卤素、硝基、C1-6烷基、C1-6烷氧基中的一个或多个取代基所取代的苄基,所述卤代为氟代或氯代,所述卤素为氟或氯。
5.根据权利要求1或4所述的三萜衍生物,其特征在于:所述(a)中,R6为H、甲基、乙基、异丙基、CF3C=O、苯基或苄基。
6.根据权利要求1或4或5所述的三萜衍生物,其特征在于:所述(a)中,q为1-6之间的整数。
7.根据权利要求1所述的三萜衍生物,其特征在于:所述(b)中,所述含氮杂环为饱和或不饱和5-6元单杂环,所述含氮杂环中氮原子数为1-2个,氧原子数为0-1个,所述含氮杂环上与Z连接的原子为氮原子或碳原子;或者,所述含氮杂环为双环,所述双环中一个为苯环,另一个为不饱和5-6元单杂环。
8.根据权利要求1或7所述的三萜衍生物,其特征在于:所述(b)中,所述含氮杂环为
9.根据权利要求1所述的三萜衍生物,其特征在于:通式(I)中,根据权利要求1所述的三萜衍生物,其特征在于:通式(I)中,R1为H、CH3C=O、CF3C=O、苄基、苯甲酰基或HOOCC(CH3)2CH2C=O;R2为H、OH、CH3(C=O)O、CF3C=O、苄氧基或苯甲酰氧基,Z-R3为
10.根据权利要求1所述的三萜衍生物,其特征在于:其选自如下化合物或如下化合物的可药用盐:
11.一种用于抗肿瘤的药物组合物,其特征在于,所述药物组合物包含如权利要求1至10中任一项权利要求所述的三萜衍生物。
12.如权利要求1至10中任一项权利要求所述的三萜衍生物在制备抗肿瘤药物组合物中的应用。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112142818A (zh) * | 2019-06-27 | 2020-12-29 | 中国药科大学 | 齐墩果酸和δ-齐墩果酸的衍生物及其医药用途 |
CN114874281A (zh) * | 2022-01-27 | 2022-08-09 | 贵州医科大学 | 一种齐墩果酸衍生物及其制备方法与应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104761610A (zh) * | 2015-02-10 | 2015-07-08 | 江西本草天工科技有限责任公司 | 一类新型的α-常春藤皂苷衍生物及其制备方法和用途 |
CN105418721A (zh) * | 2015-11-05 | 2016-03-23 | 沈阳化工大学 | 一种具有抗肿瘤活性的齐墩果酸化学修饰物及其制备方法 |
CN106749486A (zh) * | 2016-11-30 | 2017-05-31 | 沈阳化工大学 | 一种以乙二胺为连接臂的齐墩果酸衍生物及其应用 |
-
2017
- 2017-09-13 CN CN201710821120.1A patent/CN109485688B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104761610A (zh) * | 2015-02-10 | 2015-07-08 | 江西本草天工科技有限责任公司 | 一类新型的α-常春藤皂苷衍生物及其制备方法和用途 |
CN105418721A (zh) * | 2015-11-05 | 2016-03-23 | 沈阳化工大学 | 一种具有抗肿瘤活性的齐墩果酸化学修饰物及其制备方法 |
CN106749486A (zh) * | 2016-11-30 | 2017-05-31 | 沈阳化工大学 | 一种以乙二胺为连接臂的齐墩果酸衍生物及其应用 |
Non-Patent Citations (6)
Title |
---|
AHMED ASHOUR: "《Rational design and synthesis of topoisomerase I and II inhibitors based on oleanolic acid moiety for new anti-cancer drugs》", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
DIEGO RODRÍGUEZ-HERN_ANDEZ: "《Hederagenin as a triterpene template for the development of new antitumor compounds 》", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
STN: "《Butanoic acid,4-[[(3β,4α)-3,23-dihydroxy-28-oxoolean-12-en-28-yl]amino]-(CA INDEX NAME)》", 《REGISTRY数据库》 * |
STN: "《Glycine, N-[(3β,4α)-3,23-bis(acetyloxy)-28-oxoolean-12-en-28-yl]-, ethyl ester (CA INDEX NAME)》", 《REGISTRY数据库》 * |
STN: "《Glycine, N-[(3β,4α)-3,23-dihydroxy-28-oxoolean-12-en-28-yl]-(CA INDEX NAME)》", 《REGISTRY数据库》 * |
TONG, XIAOHANG: "《The derivatives of Pulsatilla saponin A, a bioactive compound from Pulsatilla chinensis: Their synthesis, cytotoxicity, haemolytic toxicity and mechanism of action》", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 》 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112142818A (zh) * | 2019-06-27 | 2020-12-29 | 中国药科大学 | 齐墩果酸和δ-齐墩果酸的衍生物及其医药用途 |
WO2020259205A1 (zh) * | 2019-06-27 | 2020-12-30 | 中国药科大学 | 齐墩果酸和δ-齐墩果酸的衍生物及其医药用途 |
CN112142818B (zh) * | 2019-06-27 | 2023-07-21 | 中国药科大学 | 齐墩果酸和δ-齐墩果酸的衍生物及其医药用途 |
CN114874281A (zh) * | 2022-01-27 | 2022-08-09 | 贵州医科大学 | 一种齐墩果酸衍生物及其制备方法与应用 |
CN114874281B (zh) * | 2022-01-27 | 2023-09-26 | 贵州医科大学 | 一种齐墩果酸衍生物及其制备方法与应用 |
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