CN104098645B - 一类熊果酸吲哚衍生物、制备方法及其用途 - Google Patents
一类熊果酸吲哚衍生物、制备方法及其用途 Download PDFInfo
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- CN104098645B CN104098645B CN201410335117.5A CN201410335117A CN104098645B CN 104098645 B CN104098645 B CN 104098645B CN 201410335117 A CN201410335117 A CN 201410335117A CN 104098645 B CN104098645 B CN 104098645B
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- Prior art keywords
- ursolic acid
- indole
- indole derivatives
- reaction
- acid indole
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- 229940096998 ursolic acid Drugs 0.000 title claims abstract description 47
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Abstract
本发明涉及有机合成和药物化学领域，具体涉及一类具有人体肿瘤细胞毒活性的熊果酸吲哚衍生物的制备方法，含有它们的药物组合物及其抗肿瘤用途。药理学实验表明，本发明的熊果酸吲哚衍生物对2株肿瘤细胞，如人肝癌细胞(SMMC‑7721、HepG2)具有显著的抑制作用，具有开发抗肿瘤药物的价值。
Description
技术领域
本发明涉及有机合成和药物化学领域，具体涉及一类具有人体肿瘤细胞毒活性的熊果酸吲哚衍生物的制备方法，含有它们的药物组合物及其抗肿瘤用途。
背景技术
肿瘤是全世界死亡率最高的重大恶性疾病之一。据统计，我国每年死于癌症人数达150万，已居死因第一位。目前，化疗仍是治疗肿瘤的基本手段之一。然而现有的化疗药物仍存在较多的不足。这主要是因为绝大多数抗肿瘤药都属于抗细胞增殖剂，如烷化剂、DNA结合剂等，其治疗依据是肿瘤细胞具有更高的增殖率，因此并不是真正地选择性作用于癌细胞。这导致大多数药物存在选择性低，对正常细胞毒性过大的问题；肿瘤细胞在治疗过程中易产生多药耐药性，造成化疗失败。因此，寻找疗效强、选择性高、安全性好的新型抗肿瘤药物仍是现代癌症研究一个重要的研究方向。
熊果酸(Ursolic acid)又名乌索酸、乌苏酸，属于A-香树脂醇(A-Amyrin)型五环三萜类化合物，普遍存在于白花蛇舌草、女贞子、乌梅、夏枯草等植物中，是在自然界中分布较广的天然活性化合物，为许多中药复方的主要有效成分之一。1990年，日本将熊果酸列为最有希望的癌化学预防药物之一。熊果酸的药理活性引起药物专家的广泛关注，其活性研究的报道越来越多。
熊果酸的化学结构式为
近年来国内外已有不少以熊果酸或类似物为母体，合成具有抗肿瘤活性的衍生物的报道。目前对于熊果酸分子的修饰大部分都是对C-3和C-28位置羧基和羟基进行衍生化反应，如Ohigashi小组在1986年研究了熊果酸及其衍生物对人淋巴瘤细胞株Raji的细胞抑制作用。熊果酸显示出与已知的肿瘤生长抑制剂-维甲酸(Retinoic acid)相当的抑制活性，同时研究表明，3-羰基熊果酸的抑制活性要明显高于熊果酸母体。
吲哚是一类非常重要的杂环化合物，在分子设计和合成中一直备受人们的关注，吲哚及其衍生物在抗炎、杀虫、杀菌以及抗肿瘤等方面表现出广谱生物活性，因此，对吲哚的研究具有重大的意义。尤其在抗肿瘤方面已有许多上市药品，如靛玉红是一种吲哚的缩合产物，该化合物对慢粒白血病具有明显的抑制作用，且具有临床疗效可靠，毒副作用小，对骨髓无明显抑制作用等特点。褪黑素(melatonin，M LT)是由松果体分泌的吲哚类激素，化学名为5-甲氧基-N-乙酰吲哚乙胺，是一种重要的生理性肿瘤抑制剂。体内外实验和临床应用均表明，M LT能有效抑制乳腺癌、前列腺癌、结肠癌等多种肿瘤，在预防、治疗和延缓肿瘤方面具有显著效果。2006年，由Sugen公司上市的SU11248(商品名:舒尼替尼)是用高通量筛选的方法得到的3位接有吡唑的吲哚醌类抗癌化合物，它是一种多靶点抑制剂，主要用于临床治疗恶性间质瘤或转移性肾细胞癌。从夹竹桃科长春花植物(Vinca rosea)中提出的具有抗癌作用的生物碱，现已正式用于临床的有主要为长春碱(vinblastine，VLB)、长春新碱(vincristine，VCR)及半合成的长春酰胺(长春地辛,(vindesine，VDS)和长春瑞宾(vinorelbine，VBR)。此类化合物的化学结构相似，母核是catharanthine环和vindoline环以碳桥相连的二聚吲哚结构。其作用机制都是通过抑制微管蛋白来影响细胞有丝分裂，从而起到抗癌作用。因此吲哚类衍生物很有潜力成为优秀的抗癌药物，所以我选择合成吲哚类衍生物作为我的课题，探讨其在药物研发领域可能的应用价值，如有进展，将对人们开发治疗疑难病症的新药做出贡献。
为了更深入研究熊果酸杂环衍生物的构效关系，本发明提供一种具有抗肿瘤活性的熊果酸吲哚衍生物的制备方法，对A环进行衍生化，通过骈合的方式引入吲哚杂环。并在此基础上将羧基酯化和酰胺化，衍生物的结构较为新颖，国内外未见报道。
发明内容
本发明公开了一类熊果酸衍生物，其结构式为下列通式(I)：
其中，R1为H时，R2为OMe，R3为羟基、甲氧基或3-二甲胺基丙胺基；
或者R2为H时，R1为Me、OMe、OEt、F、Cl或Br，R3为羟基、甲氧基或3-二甲胺基丙胺基。
本发明通式I化合物可通过下面方法制备：
其中，a.Jones试剂,丙酮，0℃；
b.取代基苯肼盐酸盐，乙醇，盐酸，回流；
c.i)SOCl2,苯，回流；ii)甲醇，回流；
d.3-二甲氨基丙胺，N,N'-二环己基碳酰亚胺(DCC),1-羟基苯并三氮唑(HoBt),二氯甲烷，室温反应；
本发明的优点在于，本发明对天然产物熊果酸进行结构改造，得到一系列熊果酸吲哚衍生物，体外细胞增殖抑制实验表明，它们对两种肝癌细胞株包括SMMC-7721细胞、HepG2细胞均具有明显的体外增殖抑制作用。其中化合物I-c1的体外抗肿瘤效果最好。
本发明的药学上可接受的盐与其化合物具有同样的药效。
具体实施方式
以下通过本发明的具体实施例进一步说明本发明，但不作为对本发明的限制。
实施例1 氧化熊果酸(III)的合成
将熊果酸(1g，2mmol)溶于150ml丙酮，反应置于冰水中搅拌15min后缓慢滴加Jones试剂(将26.72克三氧化铬溶于23毫升浓硫酸中，然后以水稀释至100毫升即得)1ml，反应在室温下搅拌反应5h，加入45ml异丙醇搅拌30min后过滤掉沉淀，溶液减压浓缩去除溶剂。甲醇重结晶得白色结晶3-氧化熊果酸III(0.56g，64％)。
m.p.276-278℃；1H NMR(CDCl3,300MHz):δ0.88(s,3H),0.91(d,J＝6.3Hz,3H),0.96(s,3H),0.95(m,2H),0.99(d,J＝6.0Hz,3H),1.07(s,3H),1.11(s,3H),1.13(s,3H),1.36(m,5H),1.52(m,5H),1.64(td,J＝14.3,7.0Hz,1H),1.76(dd,J＝13.6,7.0Hz,1H),1.94(m,2H),2.24(d,J＝11.2Hz,1H),5.31(m,1H)；IR(KBr,cm-1):2930,1718,1657,1456,1378,751.HRMS(ESI):m/z[M+H]+calcd forC30H48O3:456.7003；found:456.7009.
实施例2 对甲基取代基的苯肼盐酸盐的合成
将对甲基苯胺(0.32g，3mmol)溶于3ml20％盐酸中，亚硝酸钠(0.28g，4mmol)溶于0.7ml水中在冰浴的条件下缓慢滴加到上述溶液中，混合液冰浴条件下搅拌反应1h后，再将溶于1.8ml35％盐酸中的氯化亚锡(1.354g,6mmol)溶液缓慢滴入上述反应中反应2h，抽滤除去滤液后得到苯肼盐酸盐固体(0.34g，70％)。
实施例3 对甲氧基取代基的苯肼盐酸盐的合成
将对甲氧基苯胺(0.37g，3mmol)溶于3ml20％盐酸中，亚硝酸钠(0.28g，4mmol)溶于0.7ml水中在冰浴的条件下缓慢滴加到上述溶液中，混合液冰浴条件下搅拌反应1h后，再将溶于1.8ml35％盐酸中的氯化亚锡(1.354g,6mmol)溶液缓慢滴入上述反应中反应2h，抽滤除去滤液后得到苯肼盐酸盐固体(0.38g，69％)。
实施例4 对乙氧基取代基的苯肼盐酸盐的合成
将对乙氧基苯胺(0.42g，3mmol)溶于3ml20％盐酸中，亚硝酸钠(0.28g，4mmol)溶于0.7ml水中在冰浴的条件下缓慢滴加到上述溶液中，混合液冰浴条件下搅拌反应1h后，再将溶于1.8ml35％盐酸中的氯化亚锡(1.354g,6mmol)溶液缓慢滴入上述反应中反应2h，抽滤除去滤液后得到苯肼盐酸盐固体(0.42g，68％)。
实施例5 对氟取代基的苯肼盐酸盐的合成
将对氟苯胺(2.25ml，3mmol)溶于3ml20％盐酸中，亚硝酸钠(0.28g，4mmol)溶于0.7ml水中在冰浴的条件下缓慢滴加到上述溶液中，混合液冰浴条件下搅拌反应1h后，再将溶于1.8ml35％盐酸中的氯化亚锡(1.354g,6mmol)溶液缓慢滴入上述反应中反应2h，抽滤除去滤液后得到苯肼盐酸盐固体(0.32g，70％)。
实施例6 对氯取代基的苯肼盐酸盐的合成
将对氯苯胺(0.38g，3mmol)溶于3ml20％盐酸中，亚硝酸钠(0.28g，4mmol)溶于0.7ml水中在冰浴的条件下缓慢滴加到上述溶液中，混合液冰浴条件下搅拌反应1h后，再将溶于1.8ml35％盐酸中的氯化亚锡(1.354g,6mmol)溶液缓慢滴入上述反应中反应2h，抽滤除去滤液后得到苯肼盐酸盐固体(0.40g，70％)。
实施例7 对溴取代基的苯肼盐酸盐的合成
将对溴苯胺(0.52g，3mmol)溶于3ml20％盐酸中，亚硝酸钠(0.28g，4mmol)溶于0.7ml水中在冰浴的条件下缓慢滴加到上述溶液中，混合液冰浴条件下搅拌反应1h后，再将溶于1.8ml35％盐酸中的氯化亚锡(1.354g,6mmol)溶液缓慢滴入上述反应中反应2h，抽滤除去滤液后得到苯肼盐酸盐固体(0.54g，70％)。
实施例8 邻甲氧基取代基的苯肼盐酸盐的合成
将邻甲氧基苯胺(0.37g，3mmol)溶于3ml20％盐酸中，亚硝酸钠(0.28g，4mmol)溶于0.7ml水中在冰浴的条件下缓慢滴加到上述溶液中，混合液冰浴条件下搅拌反应1h后，再将溶于1.8ml35％盐酸中的氯化亚锡(1.354g,6mmol)溶液缓慢滴入上述反应中反应2h，抽滤除去滤液后得到苯肼盐酸盐固体(0.39g，70％)。
实施例9 对甲基吲哚熊果酸衍生物(I-a1)的合成
将氧化熊果酸(0.4407g，1mmol)溶于10ml无水乙醇，对甲苯肼(0.34g，2.1mmol)加入体系中，滴加0.5ml浓盐酸后85℃回流3h。反应结束后将反应液倒入20ml冷水中，用二氯甲烷萃取三次，合并有机相，依次用水和饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩去除溶剂。产物用硅胶柱层析纯化(石油醚/丙酮15:1，v/v)，得到化合物I-a1的淡黄色固体(0.38g,70％)。
m.p.216～219℃；1H NMR(300MHz,CDCl3):δ0.88(s,3H),0.91(d,J＝6.5Hz,3H),0.96(s,3H),0.98(d,J＝6.3Hz,3H),1.05～1.09(m,1H),1.14(s,6H),1.27(s,3H),1.32～1.90(m,14H),2.03(m,1H),2.10～2.16(m,2H),2.20(d,J＝16.3Hz,1H),2.25(d,J＝12.8Hz,1H),2.43(s,3H),2.78(d,J＝14.9Hz,1H),5.37(t,J＝3.3Hz,1H),6.94(d,J＝8.0Hz,1H),7.18(d,J＝8.1Hz,1H),7.21(s,1H),7.60(brs,1H)；IR(KBr,cm-1):3427,3416,2947,2924,2869,1695,1457,1382,1303,1237,961；HRMS(ESI):m/z[M+H]+calcd for C37H52NO2:542.8143；found:542.8137.
实施例10 对甲氧基吲哚熊果酸衍生物(I-a2)的合成
参照实施例2的合成方法，以化合物III和对甲氧苯肼为原料，在相同条件下反应3h，产物经硅胶柱层析纯化(石油醚/丙酮15:1，v/v)，得到化合物I-a2的淡黄色固体(0.36g，65％)。
m.p.288～291℃；1H NMR(300MHz,CDCl3):δ0.88(s,3H),0.90(d,J＝6.5Hz,3H),0.93(d,J＝10.9Hz,3H),0.97(s,3H),1.05～1.09(m,1H),1.13(s,3H),1.15(s,3H),1.27(s,3H),1.32～1.90(m,14H),1.98(m,1H),2.10～2.17(m,2H),2.19(d,J＝14.9Hz,1H),2.25(d,J＝10.3Hz,1H),2.76(d,J＝14.9Hz,1H),3.84(s,3H,OCH3),5.37(t,J＝3.3Hz,1H),6.77(d,J＝8.6Hz,1H),6.89(s,1H),7.17(d,J＝8.6Hz,1H),7.58(brs,1H)；IR(KBr,cm-1):3427,3367,2946,2923,2868,1695,1482,1456,1382,1284,1218,1173；HRMS(ESI):m/z[M+H]+calcd for C37H52NO3:558.8137；found:558.8141.
实施例11 对乙氧基吲哚熊果酸衍生物(I-a3)的合成
参照实施例2的合成方法，以化合物III和对乙氧苯肼为原料，在相同条件下反应3h，产物经硅胶柱层析纯化(石油醚/丙酮15:1，v/v)，得到化合物I-a3的淡黄色固体(0.35g，61％)。
m.p.255～258℃；1H NMR(300MHz,CDCl3):δ0.88(s,3H),0.91(d,J＝6.5Hz,3H),0.93(d,J＝6.5Hz,3H),0.97(s,3H),1.05～1.09(m,1H),1.13(s,3H),1.16(s,3H),1.26(s,3H),1.29～1.40(m,6H),1.42(t,J＝7.0Hz,3H),1.45～1.90(m,8H),1.99(m,1H),2.10～2.17(m,2H),2.20(d,J＝18.1Hz,1H),2.25(d,J＝12.7Hz,1H),2.75(d,J＝14.8Hz,1H),4.07(q,J＝6.8Hz,2H,OCH2),5.37(t,J＝3.3Hz,1H),6.77(d,J＝8.6Hz,1H),6.89(s,1H),7.17(d,J＝8.6Hz,1H),7.57(brs,1H)；IR(KBr,cm-1):3427,3418,2947,2924,2854,1694,1510,1459,1383,1311,1192,1086,965；HRMS(ESI):m/z[M+H]+calcd for C38H54NO3:572.8403；found:572.8408.
实施例12 对氟吲哚熊果酸衍生物(I-a4)的合成
参照实施例2的合成方法，以化合物III和对氟苯肼为原料，在相同条件下反应3h，产物经硅胶柱层析纯化(石油醚/丙酮5:1，v/v)，得到化合物I-a4的淡黄色固体(0.30g，55％)。
m.p.178～181℃；1H NMR(300MHz,CDCl3):δ0.87(s,3H),0.94(d,J＝6.4Hz,3H),0.94(s,3H),0.99(d,J＝6.4Hz,3H),1.05～1.09(m,1H),1.16(s,3H),1.24(s,3H),1.33(s,3H),1.37～1.90(m,14H),2.05(m,1H),2.12～2.18(m,2H),2.22(d,J＝15.0Hz,1H),2.32(d,J＝11.3Hz,1H),2.75(d,J＝14.9Hz,1H),5.39(t,J＝3.3Hz,1H),6.86(ddd,J＝2.3,9.05,9.05Hz,1H),7.07(dd,J＝2.1,9.5,Hz,1H),7.21(dd,J＝4.3,8.6,Hz,1H),7.71(brs,1H)；IR(KBr,cm-1):3427,3385,2948,2925,2856,1692,1459,1381,1275,971；HRMS(ESI):m/z[M+H]+calcd for C36H49FNO2:546.7782；found:546.7777.
实施例13 对氯吲哚熊果酸衍生物(I-a5)的合成
参照实施例2的合成方法，以化合物III和对氯苯肼为原料，在相同条件下反应3h，产物经硅胶柱层析纯化(石油醚/丙酮10:1，v/v)，得到化合物I-a5的淡黄色固体(0.32g，57％)。
m.p.225～228℃；1H NMR(300MHz,CDCl3):δ0.87(s,3H),0.91(d,J＝6.4Hz,3H),0.96(d,J＝7.2Hz,3H),1.05～1.09(m,1H),1.13(s,3H),1.16(s,3H),1.28(s,3H),1.32～1.90(m,14H),2.01(m,1H),2.10～2.16(m,2H),2.20(d,J＝13.1Hz,1H),2.25(d,J＝11.5Hz,1H),2.74(d,J＝15.1Hz,1H),5.37(t,J＝3.3Hz,1H),7.05(d,J＝8.5Hz,1H),7.19(d,J＝8.5Hz,1H),7.37(s,1H),7.73(brs,1H)；IR(KBr,cm-1):3430,3382,2946,2923,2870,1696,1458,1385,1302,1234,793；HRMS(ESI):m/z[M+H]+calcd for C36H49ClNO2:563.2325；found:563.2329.
实施例14 对溴吲哚熊果酸衍生物(I-a6)的合成
参照实施例2的合成方法，以化合物III和对溴苯肼为原料，在相同条件下反应3h，产物经硅胶柱层析纯化(石油醚/丙酮10:1，v/v)，得到化合物I-a6的淡黄色固体(0.35g，58％)。
m.p.298～301℃；1H NMR(300MHz,CDCl3):δ0.87(s,3H),0.91(d,J＝6.5Hz,3H),0.94(s,3H),0.96(d,J＝8.5Hz,3H),1.05～1.09(m,1H),1.13(s,3H),1.15(s,3H),1.28(s,3H),1.32～1.90(m,14H),2.00(m,1H),2.10～2.16(m,2H),2.19(d,J＝11.8Hz,1H),2.26(d,J＝11.5Hz,1H),2.74(d,J＝15.1Hz,1H),5.37(t,J＝3.3Hz,1H),7.10～7.20(m,2H),7.53(s,1H),7.74(brs,1H)；IR(KBr,cm-1):3427,3356,2947,2924,2866,1696,1459,1382,1304,1233,1047,790；HRMS(ESI):m/z[M+H]+calcd for C36H49BrNO2:607.6838；found:607.6842.
实施例15 邻甲氧基吲哚熊果酸衍生物(I-a7)的合成
参照实施例2的合成方法，以化合物III和邻甲氧基苯肼为原料，在相同条件下反应3h，产物经硅胶柱层析纯化(石油醚/丙酮10:1，v/v)，得到化合物I-a7的淡黄色固体(0.37g，65％)。
m.p.238～241℃；1H NMR(300MHz,CDCl3):δ0.89(s,3H),0.91(d,J＝6.6Hz,3H),0.94(d,J＝6.6Hz,3H),0.97(s,3H),1.05～1.09(m,1H),1.14(s,3H),1.18(s,3H),1.30(s,3H),1.32～1.90(m,14H),1.98(m,1H),2.10～2.17(m,2H),2.22(d,J＝15.0Hz,1H),2.26(d,J＝10.8Hz,1H),2.78(d,J＝14.9Hz,1H),3.96(s,3H,OCH3),5.37(t,J＝3.3Hz,1H),6.61(d,J＝7.3Hz,1H),6.99(d,J＝7.4Hz,1H),7.03(t,J＝7.5Hz,1H),7.90(brs,1H)；IR(KBr,cm-1):3483,2947,2924,2866,1696,1456,1386,1253,1077,768；HRMS(ESI):m/z[M+H]+calcd for C37H52NO3:558.8137；found:558.8140.
实施例16 对甲基吲哚熊果酸酯类衍生物(I-b1)的合成
在50mL的三口圆底烧瓶中将50mg(0.09mmol)对甲基吲哚熊果酸衍生物溶于5mL苯，缓慢加入0.1mL的氯化亚砜(0.16g,1.34mmol)，加热回流3h。反应结束后蒸去苯和多余的氯化亚砜得到黄色油状的对甲基吲哚熊果酸酰氯。向瓶中加入5mL甲醇，加热回流2h。反应结束后蒸去溶剂，产物经硅胶柱层析纯化(石油醚/丙酮50:1，v/v)，得到化合物I-b1的淡黄色固体(42mg，84％)。
m.p.169～173℃；1H NMR(300MHz,CDCl3):δ0.87(s,3H),0.94(d,J＝6.4Hz,3H),0.98(s,3H),0.99(d,J＝5.8Hz,3H),1.05～1.09(m,1H),1.13(s,3H),1.23(s,3H),1.32(s,3H),1.32～1.90(m,14H),2.05(m,1H),2.10～2.18(m,2H),2.23(d,J＝14.9Hz,1H),2.32(d,J＝11.5Hz,1H),2.45(s,3H),2.80(d,J＝14.9Hz,1H),3.65(s,3H,COOCH3),5.39(t,J＝3.3Hz,1H),6.95(d,J＝8.2Hz,1H),7.20(d,J＝8.1Hz,1H),7.23(s,1H),7.62(brs,1H)；IR(KBr,cm-1):3392,2946,2923,2870,1721,1456,1382,1305,1201,1049,792；HRMS(ESI):m/z[M+H]+calcd forC38H54NO2:556.8409；found:556.8402.
实施例17 对甲氧基吲哚熊果酸酯类衍生物(I-b2)的合成
参照实施例9的合成方法，以对甲氧基吲哚熊果酸衍生物为原料，在相同条件下反应，产物经硅胶柱层析纯化(石油醚/丙酮50:1，v/v)，得到化合物I-b2的淡黄色固体(43mg，83％)。
m.p.162～165℃；1H NMR(300MHz,CDCl3):δ0.85(s,3H),0.89(d,J＝6.3Hz,3H),0.93(d,J＝9.3Hz,3H),0.97(s,3H),1.05～1.09(m,1H),1.14(s,3H),1.21(s,3H),1.30(s,3H),1.32～1.90(m,14H),2.03(m,1H),2.10～2.18(m,2H),2.21(d,J＝19.8Hz,1H),2.30(d,J＝11.1Hz,1H),2.76(d,J＝14.8Hz,1H),3.63(s,3H,COOCH3),3.84(s,3H,OCH3),5.37(d,J＝3.3Hz,1H),6.76(d,J＝8.4Hz,1H),6.89(s,1H),7.18(d,J＝8.7Hz,1H),7.61(brs,1H)；IR(KBr,cm-1):3394,2946,2924,2871,1723,1594,1483,1457,1381,1283,1203,1086,794；HRMS(ESI):m/z[M+H]+calcd for C38H54NO3:572.8403；found:572.8408.
实施例18 对乙氧基吲哚熊果酸酯类衍生物(I-b3)的合成
参照实施例9的合成方法，以对乙氧基吲哚熊果酸衍生物为原料，在相同条件下反应，产物经硅胶柱层析纯化(石油醚/丙酮50:1，v/v)，得到化合物I-b3的淡黄色固体(45mg，85％)。
m.p.162～165℃；1H NMR(300MHz,CDCl3):δ0.87(s,3H),0.93(d,J＝6.4Hz,3H),0.98(d,J＝6.3Hz,3H),0.99(s,3H),1.05～1.09(m,1H),1.16(s,3H),1.23(s,3H),1.32(s,3H),1.33～1.42(m,6H),1.44(t,J＝7.0Hz,3H),1.46～1.90(m,8H),2.03(m,1H),2.10～2.19(m,2H),2.23(d,J＝14.5Hz,1H),2.30(d,J＝11.4Hz,1H),2.77(d,J＝14.9Hz,1H),3.65(s,3H,COOCH3),3.84(s,3H,OCH3),4.09(q,J＝6.4Hz,2H,OCH2),5.39(d,J＝3.3Hz,1H),6.79(dd,J＝2.2,8.4Hz,1H),6.91(d,J＝2.1Hz,1H),7.19(d,J＝8.6Hz,1H),7.59(brs,1H)；IR(KBr,cm-1):3389,2946,2924,2870,1723,1593,1457,1383,1281,1197,1087,790；HRMS(ESI):m/z[M+H]+calcd for C39H56NO3:586.8669；found:586.8672.
实施例19 对氟吲哚熊果酸酯类衍生物(I-b4)的合成
参照实施例9的合成方法，以对氟吲哚熊果酸衍生物为原料，在相同条件下反应，产物经硅胶柱层析纯化(石油醚/丙酮50:1，v/v)，得到化合物I-b4的淡黄色固体(39mg，77％)。
m.p.315～318℃；1H NMR(300MHz,CDCl3):δ0.87(s,3H),0.94(d,J＝6.4Hz,3H),0.94(s,3H),0.99(d,J＝6.4Hz,3H),1.05～1.09(m,1H),1.16(s,3H),1.24(s,3H),1.33(s,3H),1.37～1.90(m,14H),2.05(m,1H),2.12～2.18(m,2H),2.22(d,J＝15.0Hz,1H),2.32(d,J＝11.3Hz,1H),2.75(d,J＝14.9Hz,1H),3.65(s,3H,COOCH3),5.39(t,J＝3.3Hz,1H),6.86(ddd,J＝2.3,9.05,9.05Hz,1H),7.07(dd,J＝2.1,9.5,Hz,1H),7.21(dd,J＝4.3,8.6,Hz,1H),7.71(brs,1H)；IR(KBr,cm-1):3381,2947,2924,2871,1711,1592,1484,1456,1382,1308,1230,1170,792；HRMS(ESI):m/z[M+H]+calcd for C37H51FNO2:560.8048；found:560.8041.
实施例20 对氯吲哚熊果酸酯类衍生物(I-b5)的合成
参照实施例9的合成方法，以对氯吲哚熊果酸衍生物为原料，在相同条件下反应，产物经硅胶柱层析纯化(石油醚/丙酮50:1，v/v)，得到化合物I-b5的淡黄色固体(41mg，79％)。
m.p.143～147℃；1H NMR(300MHz,CDCl3):δ0.85(s,3H),0.92(d,J＝6.2Hz,3H),0.95(s,3H),0.96(d,J＝6.7Hz,3H),1.05～1.09(m,1H),1.14(s,3H),1.21(s,3H),1.30(s,3H),1.32～1.90(m,14H),2.01(m,1H),2.10～2.16(m,2H),2.19(d,J＝15.6Hz,1H),2.30(d,J＝11.2Hz,1H),2.74(d,J＝15.1Hz,1H),3.63(s,3H,COOCH3),5.37(t,J＝3.3Hz,1H),7.05(d,J＝8.6Hz,1H),7.19(d,J＝8.4Hz,1H),7.37(s,1H),7.73(brs,1H)；IR(KBr,cm-1):3378,2947,2924,2855,1710,1459,1381,1305,1201,1146,793；HRMS(ESI):m/z[M+H]+calcd for C37H51ClNO2:577.2591；found:577.2595.
实施例21 对溴吲哚熊果酸酯类衍生物(I-b6)的合成
参照实施例9的合成方法，以对溴吲哚熊果酸衍生物为原料，在相同条件下反应，产物经硅胶柱层析纯化(石油醚/丙酮50:1，v/v)，得到化合物I-b6的淡黄色固体(47mg，84％)。
m.p.148～151℃；1H NMR(300MHz,CDCl3):δ0.84(s,3H),0.91(d,J＝6.4Hz,3H),0.95(d,J＝7.7Hz,3H),1.05～1.09(m,1H),1.13(s,3H),1.21(s,3H),1.26(s,3H),1.30(s,3H),1.32～1.90(m,14H),2.02(m,1H),2.10～2.16(m,2H),2.19(d,J＝13.8Hz,1H),2.29(d,J＝11.7Hz,1H),2.74(d,J＝15.0Hz,1H),3.63(s,3H,COOCH3),5.36(t,J＝3.3Hz,1H),7.16(d,J＝8.6Hz,1H),7.26(d,J＝8.4Hz,1H),7.52(s,1H),7.78(brs,1H)；IR(KBr,cm-1):3376,2947,2924,2856,1711,1458,1382,1304,1201,1146,792；HRMS(ESI):m/z[M+H]+calcd for C37H51BrNO2:621.7104；found:621.7109.
实施例22 邻甲氧基吲哚熊果酸酯类衍生物(I-b7)的合成
参照实施例9的合成方法，以邻甲氧基吲哚熊果酸衍生物为原料，在相同条件下反应，产物经硅胶柱层析纯化(石油醚/丙酮50:1，v/v)，得到化合物I-b7的淡黄色固体(43mg，83％)。
m.p.101～103℃；1H NMR(300MHz,CDCl3):δ0.87(s,3H),0.93(d,J＝6.2Hz,3H),0.98(d,J＝6.2Hz,3H),0.98(s,3H),1.05～1.09(m,1H),1.16(s,3H),1.25(s,3H),1.33(s,3H),1.34～1.90(m,14H),2.05(m,1H),2.10～2.19(m,2H),2.25(d,J＝15.6Hz,1H),2.32(d,J＝11.4Hz,1H),2.81(d,J＝14.8Hz,1H),3.65(s,3H,COOCH3),3.98(s,3H,OCH3),5.39(d,J＝3.3Hz,1H),6.63(d,J＝7.6Hz,1H),7.01(t,J＝7.6Hz,1H),7.07(d,J＝7.9Hz,1H),7.92(brs,1H)；IR(KBr,cm-1):3380,2946,2923,2854,1723,1458,1378,1252,1076,724；HRMS(ESI):m/z[M+H]+calcd for C38H54NO3:572.8403；found:572.8401.
实施例23 对甲基吲哚熊果酸酰胺类衍生物(I-c1)的合成
将对甲基吲哚熊果酸衍生物(49mg，0.1mmol)溶于2ml二氯甲烷，HoBt(18mg，0.12mmol)和DCC(24mg，0.12mmol)加入反应体系中室温搅拌反应30min后将3-二甲氨基丙胺0.02ml(0.12mmol)添加进去。室温搅拌过夜。反应结束后过滤掉DCU，滤液减压浓缩后用乙腈溶解4℃放置过夜，进一步过滤掉DCU，再减压浓缩后经硅胶柱层析纯化(石油醚/丙酮30:1，v/v)，得到化合物I-c1的淡黄色固体(51mg，81％)。
m.p.184～188℃；1H NMR(300MHz,CDCl3):δ0.88(s,3H),0.93(d,J＝6.5Hz,3H),0.95(d,J＝6.5Hz,3H),0.96(s,3H),1.05～1.09(m,1H),1.15(s,3H),1.21(s,3H),1.29(s,3H),1.34～2.30(m,21H),2.36(s,6H),2.43(s,3H),2.48(t,J＝6.9Hz,2H),2.77(d,J＝14.9Hz,1H),3.09(m,1H),3.47(m,1H),5.41(t,J＝3.3Hz,1H),6.92(brs,1H),6.94(s,1H),7.18(d,J＝9.5Hz,1H),7.23(d,J＝9.1Hz,1H),7.63(brs,1H)；IR(KBr,cm-1):3411,3298,2946,2924,2866,1636,1522,1459,1380,1305,1185,1050,794；HRMS(ESI):m/z[M+H]+calcd for C42H64N3O:626.9772；found:626.9778.
实施例24 对甲氧基吲哚熊果酸酰胺类衍生物(I-c2)的合成
参照实施例16的合成方法，以对甲氧基吲哚熊果酸衍生物为原料，在相同条件下反应，产物经硅胶柱层析纯化(石油醚/丙酮30:1，v/v)，得到化合物I-c2的淡黄色固体(49mg，76％)。
m.p.169～172℃；1H NMR(300MHz,CDCl3):δ0.88(s,3H),0.91(d,J＝6.3Hz,3H),0.95(d,J＝6.3Hz,3H),0.97(s,3H),1.05～1.09(m,1H),1.14(s,3H),1.21(s,3H),1.29(s,3H),1.34～2.30(m,21H),2.32(s,6H),2.43(t,J＝6.9Hz,2H),2.75(d,J＝14.9Hz,1H),3.09(m,1H),3.47(m,1H),3.84(s,3H,OCH3),5.41(t,J＝3.3Hz,1H),6.76(d,J＝8.6Hz,1H),6.88(s,1H),6.92(brs,1H),7.18(d,J＝8.6Hz,1H),7.66(brs,1H)；IR(KBr,cm-1):3411,3305,2948,2925,2869,1633,1526,1459,1381,1285,1204,1050,796；HRMS(ESI):m/z[M+H]+calcd for C42H64N3O2:642.9766；found:642.9760.
实施例25 对乙氧基吲哚熊果酸酰胺类衍生物(I-c3)的合成
参照实施例16的合成方法，以对乙氧基吲哚熊果酸衍生物为原料，在相同条件下反应，产物经硅胶柱层析纯化(石油醚/丙酮30:1，v/v)，得到化合物I-c3的淡黄色固体(53mg，81％)。
m.p.174～176℃；1H NMR(300MHz,CDCl3):δ0.88(s,3H),0.93(d,J＝6.3Hz,3H),0.95(d,J＝6.3Hz,3H),0.97(s,3H),1.05～1.09(m,1H),1.15(s,3H),1.21(s,3H),1.30(s,3H),1.42(t,J＝7.0Hz,3H),1.43～2.30(m,21H),2.38(s,6H),2.51(t,J＝6.9Hz,2H),2.74(d,J＝14.7Hz,1H),3.13(m,1H),3.47(m,1H),4.07(q,J＝7.0Hz,2H,OCH2),5.42(t,J＝3.3Hz,1H),6.77(d,J＝8.7Hz,1H),6.89(s,1H),6.92(brs,1H),7.17(d,J＝8.7Hz,1H),7.60(brs,1H)；IR(KBr,cm-1):3411,3298,2966,2925,2869,1634,1512,1461,1383,1283,1192,1049,790；HRMS(ESI):m/z[M+H]+calcd for C43H66N3O2:657.0032；found:657.0028.
实施例26对氟吲哚熊果酸酰胺类衍生物(I-c4)的合成
参照实施例16的合成方法，以对氟吲哚熊果酸衍生物为原料，在相同条件下反应，产物经硅胶柱层析纯化(石油醚/丙酮30:1，v/v)，得到化合物I-c4的淡黄色固体(51mg，81％)。
m.p.129～132℃；1H NMR(300MHz,CDCl3):δ0.83(s,3H),0.94(d,J＝6.4Hz,3H),0.94(s,3H),0.99(d,J＝6.4Hz,3H),1.05～1.09(m,1H),1.16(s,3H),1.24(s,3H),1.33(s,3H),1.34～2.30(m,21H),2.34(s,6H),2.48(t,J＝6.9Hz,2H),2.74(d,J＝15.0Hz,1H),3.11(m,1H),3.48(m,1H),5.31(t,J＝3.3Hz,1H),6.94(brs,1H),6.86(ddd,J＝2.3,9.05,9.05Hz,1H),7.07(dd,J＝2.1,9.5,Hz,1H),7.21(dd,J＝4.3,8.6,Hz,1H),7.71(brs,1H)；IR(KBr,cm-1):3411,3355,2958,2928,2866,1704,1633,1528,1458,1381,1310,1170,1050,793；HRMS(ESI):m/z[M+H]+calcd for C41H61FN3O:630.9411；found:630.9403.
实施例27 对氯吲哚熊果酸酰胺类衍生物(I-c5)的合成
参照实施例16的合成方法，以对氯吲哚熊果酸衍生物为原料，在相同条件下反应，产物经硅胶柱层析纯化(石油醚/丙酮30:1，v/v)，得到化合物I-c5的淡黄色固体(55mg，85％)。
m.p.264～267℃；1H NMR(300MHz,CDCl3):δ0.87(s,3H),0.93(d,J＝7.6Hz,3H),0.95(s,3H),0.96(d,J＝7.6Hz,3H),1.05～1.09(m,1H),1.14(s,3H),1.22(s,3H),1.30(s,3H),1.34～2.30(m,21H),2.36(s,6H),2.49(t,J＝6.9Hz,2H),2.74(d,J＝15.0Hz,1H),3.11(m,1H),3.48(m,1H),5.41(t,J＝3.3Hz,1H),6.94(brs,1H),7.05(d,J＝8.5Hz,1H),7.20(d,J＝8.5Hz,1H),7.37(s,1H),7.78(brs,1H)；IR(KBr,cm-1):3411,3280,2949,2925,2867,1634,1523,1460,1380,1305,1089,1051,794；HRMS(ESI):m/z[M+H]+calcd for C41H61ClN3O:647.3954；found:647.3949.
实施例28 对溴吲哚熊果酸酰胺类衍生物(I-c6)的合成
参照实施例16的合成方法，以对溴吲哚熊果酸衍生物为原料，在相同条件下反应，产物经硅胶柱层析纯化(石油醚/丙酮30:1，v/v)，得到化合物I-c6的淡黄色固体(56mg，81％)。
m.p.240～245℃；1H NMR(300MHz,CDCl3):δ0.87(s,3H),0.93(d,J＝7.6Hz,3H),0.94(s,3H),0.96(d,J＝7.6Hz,3H),1.05～1.09(m,1H),1.14(s,3H),1.22(s,3H),1.30(s,3H),1.34～2.30(m,21H),2.35(s,6H),2.48(t,J＝6.9Hz,2H),2.74(d,J＝15.0Hz,1H),3.11(m,1H),3.48(m,1H),5.41(t,J＝3.3Hz,1H),6.94(brs,1H),7.15(d,J＝8.7Hz,1H),7.19(d,J＝10.8Hz,1H),7.53(s,1H),7.81(brs,1H)；IR(KBr,cm-1):3411,3269,2948,2924,2868,1634,1524,1459,1381,1304,1265,1048,967,793；HRMS(ESI):m/z[M+H]+calcd for C41H61BrN3O:691.8467；found:691.8461.
实施例29 邻甲氧基吲哚熊果酸酰胺类衍生物(I-c7)的合成
参照实施例16的合成方法，以邻甲氧基吲哚熊果酸衍生物为原料，在相同条件下反应，产物经硅胶柱层析纯化(石油醚/丙酮30:1，v/v)，得到化合物I-c7的淡黄色固体(49mg，76％)。
m.p.294～298℃；1H NMR(300MHz,CDCl3):δ0.88(s,3H),0.93(d,J＝6.3Hz,3H),0.95(d,J＝6.3Hz,3H),0.96(s,3H),1.05～1.09(m,1H),1.15(s,3H),1.22(s,3H),1.31(s,3H),1.34～2.30(m,21H),2.34(s,6H),2.46(t,J＝6.9Hz,2H),2.78(d,J＝15.0Hz,1H),3.10(m,1H),3.48(m,1H),3.96(s,3H,OCH3),5.41(t,J＝3.3Hz,1H),6.61(d,J＝7.3Hz,1H),6.95(brs,1H),6.97(d,J＝8.1Hz,1H),7.03(t,J＝8.1Hz,1H),7.91(brs,1H)；IR(KBr,cm-1):3411,3289,2949,2924,2868,1635,1522,1458,1379,1302,1255,1078,1053,774,731；HRMS(ESI):m/z[M+H]+calcdfor C42H64N3O2:642.9766；found:642.9761.
实施例30 体外抗肿瘤活性筛选
筛选细胞株为SMMC-7721、HepG2(人肝癌细胞)。
实验方法：
取对数生长期状态良好的细胞，胰蛋白酶消化，制成5×104细胞/mL的悬液。将细胞悬液移入96孔培养板，每孔100μL，置37℃、5％CO2条件下培养24h。
将受试衍生物用DMSO配制成一定浓度的母液，再用RPMI1640培养基将衍生物母液稀释成不同作用浓度的稀释液。移去旧培养基，加入不同浓度的含药培养基，每孔100μL。另设空白对照组和阳性对照多柔比星对照组。药物作用24h后，吸弃含药培养基，于每孔加入无血清、无酚红1640培养基100μL，再加入MTT溶液(5mg/mL)10μL，继续温育4h。
吸去各孔内上清液，每孔加入DMSO150μL，振荡10min，使结晶物充分溶解，酶标仪测定490nm处各孔的光吸收值(OD值)，计算细胞的增殖抑制率：抑制率(％)＝(1-用药组平均OD值/空白对照组平均OD值)×100％。应用SPSS16.0软件进行数据处理并计算癌细胞增殖的半数抑制浓度(IC50)，结果见表1。
表1 熊果酸吲哚衍生物对2种癌细胞的体外增殖抑制作用
如表1结果所示，所合成的熊果酸衍生物对这两种肿瘤细胞均具有一定的增殖抑制作用，其中化合物I-c1,I-c2,I-c4和I-c5均显示出较强的抑制活性，与阳性对照多柔比星相当，尤其是熊果酸吲哚酰胺衍生物I-c1对肝癌细胞SMMC-7721和HepG2的IC50值分别为1.1和1.3μM，优于阳性对照多柔比星。说明此类熊果酸吲哚衍生物表现出较好的抗癌活性，具有开发抗癌药物的潜力。
实施例31 本发明所涉及化合物I-a1～I-a7、I-b1～I-b7和I-c1～I-c7片剂的制备
取20克化合物I-a1～I-a7、I-b1～I-b7或者I-c1～I-c7或者其药学上可接受的盐当中的一种，加入制备片剂的常规辅料180克，混匀，常规压片机制成1000片。
实施例32 本发明所涉及化合物I-a1～I-a7、I-b1～I-b7和I-c1～I-c7胶囊的制备：
取20克化合物I-a1～I-a7、I-b1～I-b7或者I-c1～I-c7或者其药学上可接受的盐当中的一种，加入制备胶囊剂的常规辅料如淀粉180克，混匀，装胶囊制成1000粒。
Claims (4)
1.一种具有式I所示结构的熊果酸吲哚衍生物及其药学上可接受的盐，
其中，R1为H时，R2为OMe，R3为3-二甲胺基丙胺基；
或者R2为H时，R1为Me、OMe、OEt、F、Cl或Br，R3为3-二甲胺基丙胺基。
2.根据权利要求1所述的熊果酸吲哚衍生物及其药学上可接受的盐在制备抗肿瘤药物中应用。
3.根据权利要求2所述的熊果酸吲哚衍生物及其药学上可接受的盐在制备抗肿瘤药物中应用，其特征为：所述肿瘤为肝癌。
4.一种制备如权利要求1所述的熊果酸吲哚衍生物的方法，其特征在于：熊果酸吲哚衍生物I-a1～I-a7任意一个化合物经过DCC和HOBt的活化后，再与3-二甲氨基丙胺反应制得熊果酸吲哚酰胺类衍生物，结构式如式I-c1～I-c7所示：
I-c1:R1为甲基，R2为氢；
I-c2:R1为甲氧基，R2为氢；
I-c3:R1为乙氧基，R2为氢；
I-c4:R1为氟，R2为氢；
I-c5:R1为氯，R2为氢；
I-c6:R1为溴，R2为氢；
I-c7:R1为氢，R2为甲氧基。
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