CN102702147B - 穿心莲内酯类似物及其治疗的应用 - Google Patents
穿心莲内酯类似物及其治疗的应用 Download PDFInfo
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- CN102702147B CN102702147B CN201210200037.XA CN201210200037A CN102702147B CN 102702147 B CN102702147 B CN 102702147B CN 201210200037 A CN201210200037 A CN 201210200037A CN 102702147 B CN102702147 B CN 102702147B
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Abstract
本发明公开一种新的穿心莲内酯衍生物和类似物及其制备方法和用于治疗,预防和缓解人类病毒和肿瘤疾病。本发明还涉及该类化合物的药物组成和作为抗病毒和抗癌疾病药物及应用。经化学合成与制备,获得半合成多系列穿心莲内酯类似物,具下列结构通式I。
Description
技术领域
本发明涉及新的穿心莲内酯类似物,用于治疗、预防和缓解人类病毒和肿瘤疾病是非常有效的。本发明还涉及该类化合物的药物组成和作为抗病毒和抗癌疾病药物及应用。
背景技术
穿心莲内酯(andrographolide)是穿心莲的主要活性成分,穿心莲为爵床科植物穿心莲(Andrographis)的全草或叶。又名春莲秋柳、一见喜、榄核莲、苦胆草、金香草、金耳钩、印度草和苦草。有清热解毒、消炎、消肿止痛作用。主治细菌性痢疾、尿路感染、急性扁桃体炎、肠炎、咽喉炎、肺炎和流行性感冒,外用可治疗疮疖肿毒和外伤感染。在亚洲许多国家广泛用于治疗病毒感染、糖尿病、风湿关节炎、咽喉炎和腹泻(Purietal.,J.Nat.Prod.1993,56,995-999;ZhangandTan,Clin.Exp.Pharmacol.Physiol.1996,23,675-678;ZhangandTan,Clin.Exp.Pharmacol.Physiol.2000,27,358-363)。一份研究表明,穿心莲表现出良好的癌症(Satyanarayanaetal.,Science2003,299,363-370)治疗效果。
由于穿心莲及类似物的抗肿瘤和抗病毒的活性,近年来的在治疗或预防艾滋病、阿尔茨海默氏病和肝炎取得了进展,世界专利WO96/17605,美国专利US6486196B、US20060106098A1、US6576,662B2、US6486,196B2、US2006/0106098A1、US2011/0077295A1、US2002/0016363A1、US2002/0016324A1、US7625945B2和US20020032229A1发现了穿心莲内酯类似物的抗癌活性;US20110077295A1的报道穿心莲内酯衍生物用于治疗癌症、糖尿病、炎症、细菌和病毒感染;US2005/0215628A1、US2012/0015923A1和US20120015923报道了穿心莲内酯衍生物治疗炎症;US2006/0223785报道了穿心莲内酯衍生物抗病毒活性。到目前为止,检索全部对穿心莲内酯的结构改造文献,还没有在C15位引进取代基形成新的内酯类似物的具有抗病毒和抗癌活性文献报道;同时也没有同时在C7和C15位引进取代基形成新的类似物及其新的类似物抗病毒活性和抗癌活性的文献报道。
发明内容
本发明的目的是提供了一种新的穿心莲内酯类似物,作为抗病毒和抗癌药物的使用,含有这些化合物的药物组合物和制备方法,其结构通式为结构式I
或立体异构体,前药,药学上可接受的盐,复盐或溶剂化物,其中:
虚线为不存在或选至下列之一:-C-C-、-C=C-、-C-杂键、 X1andX2为不存在或独立的选至,但不局限于:氢、卤素、-C-、-S-、-O-、-NH-、-NR-、-NRR、-NHC(O)-、-NRC(O)-、-NHSO2-、-NRSO2-、-SO2NH-、-SO2NR-、-C(O)-、-C(O)NH-、-C(O)NR-、-C(O)R-、-CO2-、-C(O)H、-C(O)NH2-、-CO2H、-C(NH)NH-、-C(NH)NR-、-C(S)-、-C(S)NH-、-C(S)NR-、-C(S)R-、-C(NH)NH-、-C(NH)NR-、=CH-、=CH2、=CH-O-、=CH-S-、=CH-Se-、=CH-NR-、=CH-NH-、=CH-PR-,
其中R是选至,但不局限于:-C1-6烷基、-CO2H、-CO2C1-6烷基、COC1-6烷基、苯、-CH2苯、杂烷基和杂芳基;Y为不存在或独立的选至,但不局限于:-CH2-、-CH2-CH2-、-CH2-CH2-CH2-、-CHF-、和-CF2-,其中每个CH2和CHF为无取代或含有1或2个取代基,其取代基选至于Ra;
Z为不存在或独立的选至,但不局限于:氢、卤素、-C1-6烷基、-C2-6烯基、-C2-6炔基、-C3-10环烷基、-C3-10环烯基、芳基、-C3-10杂环、-C3-10杂芳环、-CN、-CF3、-OH、-OC1-6烷基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、胍、脒、-S-C1-6烷基、-SOC1-6烷基、-SO2C1-6烷基、-NHSO2C1-6烷基、-NHC(O)C1-6烷基、-SO2NHC1-6烷基、-C(O)OH、-C(O)OC1-6烷基、-C(O)NHC1-6烷基、P(O)(OH)2、P(O)(OR)2、-(CH2)mP(O)(OH)2、-(CH2)mP(O)(OC1-6烷基)2、-(CH2)mP(O)(NRbC(Rc))2、C3-8氨基酸和C3-10(OH)0-10羟基;
每个R1、R2和R3为不存在或独立的选至,但不局限于::氢、卤素、-C1-10烷基、-C2-6烯基、-C2-6炔基、-(CH2)pC3-10氰烷基、-(CH2)pC3-7环烷芳基、-(CH2)pC3-7环烷基、杂芳基、-(CH2)pC4-10环烯、-(CH2)pC4-7环烯芳基、-(CH2)pC4-7环烯杂芳基、-(CH2)p杂芳基、-C2-6烯烷基、-C2-6烯芳基、-C2-6烯杂芳基、-C2-6烯基-C3-7环烷基、-C2-6炔烷基、-C2-6炔芳基、-C2-6炔杂芳基、-C2-6炔基-C3-7环烷基、-C2-6炔-C3-7环烯、-C2-6炔-C2-7环杂烷基、-C2-6-C2-7环杂烯、-C(O)(CH2)0-3苯基、-(CH2)PC(O)苯基、-C(NH)(CH2)0-3苯基、-(CH2)mP(O)(NRbC(Rc))2、C3-8氨基酸基、C3-10(OH)0-10多羟基、芳基、双苯基、-C3-10杂环基、-C3-10杂芳基、-CN、-CF3、-OH、-OC1-6烷基、-NH2、-NHC1-6烷基、-N(C1-6烷基)2、-NHC(O)C1-6烷基、胍、脒-SC1-6烷基、-SOC1-6烷基、-SO2C1-6烷基、-NHSO2C1-6烷基、-SO2NHC1-6烷基、-C(O)OH、-C(O)OC1-6烷基、-C(O)NHC1-6烷基、P(O)(OH)2、P(O)(OR)2、-(CH2)mP(O)(OH)2、-(CH2)mP(O)(OC1-6烷基)2、-(CH2)mP(O)(NRbC(Rc))2、C3-8氨基酸基和C3-10(OH)0-10多羟基;
其中每个CH2为无取代或含有1或2个取代基,其取代基选至于:氢、-CF3、-OH、-NH2、-C1-6烷基、-OC1-5烷基、-NHC1-6烷基和-N(C1-6烷基)2,每个烷基、烯和炔为无取代或含有1或2个取代基,其取代基选至于:氢、CF3、-OH、-NH2、C1-6烷基、-OC1-6烷基、-NHC1-6烷基和-N(C1-6烷基)2,并且每个环烷基、环烯基、环杂烷基、环杂烯基、苯基、芳基和杂芳基为无取代或含有1,2,3或4个独立取代基,其取代基选至于Ra;
A环选择:C3-14烷基环基、C3-14芳环基、C3-14杂环基和C3-14杂环基;
所述C3-14烷基环基、C3-14芳环基、C3-14杂环基和C3-14杂环基是选至,但不局限于:吖啶基、氮杂环丁烷基、氮杂环辛烷基、氮杂环庚烷基、氮杂环庚烷基、氮丙啶基、氮丙啶基、氮杂环丁二烯基、苯并呋喃基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并噻喃基、苯并噻唑基、苯并四唑基、苯并异唑基、苯并异噻唑基、苯并咪唑啉基、苯并吡唑基、苯并三唑基、苯并噻吩基、苯并恶唑基、苯并-1H-四唑基、苯并-2H-四唑基、苯并-3H-四唑基、苯并-4H-四唑基、苯并-5H-四唑基、苯并噻吩基、苯并呋吖基、苯并二氮杂基、咔唑基、咔啉基、噌嗪基、咔唑基、咔啉基、苯并二氢吡喃基、苯并哌喃基、香豆素基、十氢喹啉基、4H-咔唑基、1,4-二氧己环基、2,6-二氢-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢硫代吡喃基、呋吖基、六氢氮杂庚烷基、咪唑基、二氢吲哚基、吲嗪基、吲唑基、异吲哚基异喹啉基烷基咪唑基、咪唑啉基、吲哚基、吲嗪基、吲唑基、1H-吲唑基、吲哚基、二氢吲哚基、吲嗪基、3H-吲哚基、异苯并呋喃基、异喹啉基、1,2-异恶唑基、1,3-异恶唑基、异恶唑基、异苯并二氢吡喃基、异二氢吲哚基、异噻唑基、异恶唑啉、异喹啉基、亚甲二氧苯基、亚甲二氧苯基、吗啉基、萘啶基、环氧丙烷基、恶二唑基、恶唑基、唑啉基、八氢异喹啉基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、唑烷基、四氢呋喃基、环氧乙基、环氧乙烷基、氧丙环基、氧杂环丁烷基、环氧己烷基、氧杂环庚烷基、唑啉基、吡唑基、2(1H)嘧啶酮基、哌啶基、环硫乙烷基、菲啶基、菲咯啉基、吩嗪基、吩噻嗪、吩恶噻基、吩恶嗪基、2,3-二氮杂萘基、哌啶基、2H-吡咯基、吡啶-2-酮基、哌嗪基、哌啶基、4-哌嗪基、胡椒基、蝶啶基、嘌呤基、吡嗪基、吡唑烷基、哒嗪基、吡唑啉基、哒嗪基、吡啶并咪唑基、吡啶并噻唑基、吡啶基、嘧啶基、吡啶并嘧啶基、吡唑基、唑啉基、吡唑基、吡咯基、吡喃基、吡嗪基、吡咯烷基、喹唑啉基、喹啉基、喹喔啉基、4H-喹啉基、奎宁环基、喹啉2(1H)酮基、喹啉基、噻二唑基、6H-1,2,5-噻二嗪基、1,2,3-噻噻二唑基、1,2,4-噻二嗪基、1,2,5-噻二嗪基、1,3,4-三唑基、1,3,4-噻二嗪基、硫代吗啉基、噻吩基、硫代吗啉基、硫杂丙烯基、硫杂环基、噻丁环基、四氢噻吩基、噻吩基、硫化环戊烷基、塞喃基、塞庚环基、硫杂卓基、噻唑基、苯并噻吩基、2,4,6-三羟基嘌呤基,1,2-噻唑基、1,3-噻唑基和占吨基;其中A环,包括上述表示杂芳基,以及二氢和四氢类似物,是未取代的或任选取代的1,2或3个相同或不同的取代基,每个取代基选至于,但不仅限于:氢、-OH、-OR、-SH-、-SR-、-O-、-NO2、-NH2、-NH-、-NR-、-NRR、-CF3、-CN、-C(O)-、-NHC(O)-、-NRC(O)-、-C(O)NH-、-C(O)NR-、-NHSO2-、-NRSO2-、-SO2NH-、-SO2NR-、-C(O)R-、-CO2-、-C(NH)NH-和-C(NH)NR-,其中R选至于:-C1-6烷基、-CH2F、-CHF2、-CF3、-CO2H、-CO2C1-6烷基、COC1-6烷基、苯基、-CH2苯基、杂烷基和杂芳基、氧基、-(CH2)0-3OH、-CN、-NH2、-NH(C1-6烷基)、-N(C1-6烷基)2、-C1-6烷基、-OC1-6烷基、卤素、-CH2F、-CHF2、-CF3、-CO2H、-CO2C1-6烷基、-C3-7环烷基、苯基、CH2苯基、杂芳基和-CH2杂芳基;
Ra,RbandRc为相同或不同选至,但不局限于:氢、卤素、-C-、-S-、-O-、-NH-、-NR-、-NRR、-NHC(O)-、-NRC(O)-、-NHSO2-、-NRSO2-、-SO2NH-、-SO2NR-、-C(O)-、-C(O)NH-、-C(O)NR-、-C(O)R-、-CO2-、-C(O)H、-C(O)NH2-、-CO2H、-C(NH)NH-、-C(NH)NR-、-C(S)-、-C(S)NH-、-C(S)NR-、-C(S)R-、-C(NH)NH-和-C(NH)NR-,其中R为选至,但不局限于:-C1-6烷基、-CO2H、-CO2C1-6烷基、COC1-6烷基、苯基、-CH2苯基、杂烷基和杂芳基;m为0、1、2、3或4;p为0、1、2或3;
本发明提供的穿心莲内酯、其衍生物和类似物的一种化合物的实例选至于,但不局限于所选实例或立体异构体,异构体,制药可接受的盐,无机酸盐,有机酸盐,有机碱盐,复盐,前药或溶剂化物及其在关联制药可接受的赋形剂或载体。
本发明提供了制备一种化合物通式I的工艺,以穿心莲内酯为原料,从四氢呋喃,二氧六环,N,N-二甲基酰胺,N,N-二甲基,甲苯,乙醇或甲醇中,选用其中一种溶剂;从有机碱,无机碱,分子筛或氧化铝催化剂中,选用其中一种;在-78℃到90℃温度下,修饰穿心莲内酯的7-位、12-位或15-位,并且形成新的C-C、C-O、C-S、C-N或C-P键,获得制成穿心莲内酯衍生物和类似物。
本发明提供的穿心莲内酯衍生物和类似物的一种化合物的实例用于治疗,预防或减缓病毒,癌症,细菌,真菌和其他疾病的进展,包括炎症,炎性疾病和免疫系统疾病,病毒,癌症,细菌和真菌,其实例选至于,但不局限于所选实例的单独或与已知药品联合用药,用药剂量在0.02mg/kg-2.0克/公斤(静脉注射,肌肉注射,口服,外用和其它给药途径)采用各种方法所治疗和抑制的病毒选至于,但不局限于:托加病毒、手足口病毒、逆转录病毒、腺病毒、单纯疱疹病毒1型、单纯疱疹病毒、水痘带状疱疹病毒、EB病毒、人类巨细胞病毒、人类疱疹病毒8型、人类乳头状瘤病毒、BK病毒、JC病毒、天花病毒、人类II型博卡病毒、细小病毒、人类星状病毒、诺瓦克病毒、柯萨奇病毒、肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、脊髓灰质炎病毒、鼻病毒、急性呼吸道综合征病毒、黄热病病毒、登革热病毒、西尼罗河病毒、风疹病毒、戊型肝炎病毒、B19病毒、人类免疫缺陷病毒、流感病毒、胡宁病毒、拉沙病毒、萨比亚病毒、克里米亚病毒、刚果出血热病毒、埃博拉病毒、马尔堡病毒、麻疹病毒、腮腺炎病毒、副流感病毒、呼吸道合胞病毒、人类偏肺病毒、狂犬病毒和丁型肝炎轮状病毒。
本发明提供的穿心莲内酯衍生物和类似物的一种化合物的实例,但不局限于实例,用于治疗、预防或减缓疾病病毒、癌症、细菌、真菌和其他感染进展,包括炎症、炎性疾病和免疫系统综合征,这些疾病由病毒感染呼吸道、尿道、皮肤、软组织、骨和关节、腹部、盆腔或心内膜所致免疫系统综合征疾病,所述疾病选至,但不局限于:艾滋病、与艾滋病相关的恶性肿瘤的皮肤损伤、甲病毒引起脑炎、沙粒、节肢动物传播的病毒性脑炎、玻利维亚出血热、禽流感病毒感染、柯萨奇病毒感染、巨细胞病毒感染克里米亚、刚果出血热、登革热、东部马脑炎、感染埃博拉病毒感染、埃可病毒感染、EB病毒感染、EB病毒感染、病毒相关恶性肿瘤、丝状黄病毒感染、德国麻疹、出血热、肾综合征、疱疹病毒感染、单纯疱疹病毒感染、带状疱疹病毒感染、人类乳头状瘤病毒相关的表皮病变、子宫颈癌的人类乳头状瘤病毒感染、日本脑炎、卡波济氏肉瘤、朝鲜出血热、疾病拉沙热、淋巴细胞性脉络丛脑膜炎、传染性软疣、墨累河谷脑炎、诺沃克病毒有关的腹泻、鄂木斯克出血热、正粘病毒感染、副流感病毒感染、副粘病毒感染、细小病毒B19感染、小核糖核酸病毒感染、轮状病毒腹泻、痘病毒感染、狂犬病、呼吸道合胞病毒感染、麻疹、天花、圣路易斯脑炎、蜱传脑炎、天花、委内瑞拉马脑炎、病毒性出血热、白血病和淋巴瘤的病毒感染、西部马脑炎、西尼罗河病毒病败血症、感染性心内膜炎、腺病毒血清型14、T细胞白血病、淋巴瘤、丝状病毒、亚天花、安第斯山脉的病毒感染、阿根廷出血热、星状病毒感染、禽脑脊髓炎病毒感染、禽流感病毒感染肾炎、禽流正呼肠孤病毒的感染、禽流的肺病毒感染、迪布焦埃博拉病毒感染、昌迪普尔病毒、奎瓦病毒感染、德尔日的病、博尔纳病、博恩霍尔姆疾病、腺病毒感染牛、冠状病毒的感染、牛流行发热、疹病毒感染牛4、牛细小病毒感染、牛病毒性腹泻、巴西出血热、支气管炎、本迪布焦病毒感染、猫流感、宫颈上皮内瘤样病变、病毒感染鸡传染性贫血病毒感染、水痘、流行基孔肯雅热、普通感冒、牛痘、柯萨奇病毒感染、蟋蟀麻痹病毒感染、巨细胞病毒感染、巨细胞病毒性结肠炎、巨细胞病毒性视网膜炎、埃博拉病毒感染、疫情关节炎、疣状表皮发育不良、猫白血病病毒感染、丝状病毒感染、手足口疾病、生殖器疣、感染汉坦、甲型肝炎、乙型肝炎、丙型肝炎、生殖器疱疹、单纯疱疹、带状疱疹、疹病毒性脑炎、疹病毒性脑膜炎、疱疹性角结膜炎、人乳头状瘤病毒、阳性口咽癌、人类巨细胞病毒感染、人类呼吸道合胞病毒感染、全身性鼻炎、传染性单核细胞增多症、传染性胰脏坏死、锦鲤疱疹病毒感染、库京病毒感染、喉乳头状瘤、白血病、单核细胞增多症、腮腺炎、流行性乙型脑炎病毒感染、多发性粘液瘤、细小病毒B19的足底疣、猪腺病毒感染、统淋巴瘤、视网膜坏死、风疹全脑炎、兔出血性疾病、罗斯河热、轮状病毒感染、舒普乳头状瘤病毒感染、猴泡沫病毒感染、苏丹病毒感染、猪水泡病、热带痉挛性截瘫、水痘带状疱疹病毒感染、委内瑞拉出血热、扁平疣、病毒性关节炎、病毒性关节炎、病毒性出血性败血症、辛农布雷病毒感染、土拨鼠肝炎病毒感染、病毒黄热病、兹卡发烧、模板、由腺病毒引起的人畜共患的病毒感染、艾普斯坦巴尔二氏病毒感染、博卡病毒感染、卢约病毒感染、马尔堡病毒感染、马尔堡病毒病、马亚罗病毒病、猴痘、单股反链病毒感染、流行性肾病、奥罗普切病毒发烧、致植物退化病毒感染、夸尔亚病毒感染、兔出血性疾病、莱斯顿埃波拉病毒感染、莱斯顿病毒感染、鼻病毒感染、病毒性脑炎罗西奥、蔷薇疹感染、苏丹埃波拉病毒感染、塔伊森林埃波拉病毒感染、热带痉挛性截瘫、土耳其冠状病毒感染和土耳其痘病毒性感染。
本发明所述穿心莲内酯衍生物或类似物或可药用盐的抗病毒和抗肿瘤的应用,包括与其它治疗剂配伍联合用药。至少一种或多种组合已知的抗病毒剂或抗炎剂与穿心莲内酯衍生物或类似物或可药用盐配伍一起施用,选自胞苷类似物、尿苷模拟、腺苷模拟、鸟苷类似物、胸苷类似物或肌苷类似物的一种(但不局限于以下治疗剂),包括:脱氧胞苷2′,3′-双脱氧胞苷、2“碳环3′-马帝德-氢化胞苷的,2′,3′-脱氢-2′,3′-双脱氧胞苷氨酸、2′,3′-脱氢-2′,3′-脱氧-5-甲基胞苷、氟-2′,3′-双脱氧胞苷、3-(4-羟基-1′,2′-丁二烯)胞嘧啶、3′-叠氮2′,3′-脱氧-5-甲基胞嘧啶、3′-叠氮-2′,3′-脱氧-5-甲基胞嘧啶、3′-叠氮-2′,3′-脱氧-5-甲基-胞嘧啶、3′-叠氮-2′,3′-双脱氧胞苷、3′-叠氮-2′,3′-双脱氧-5-氟胞嘧啶、2′,3′-脱氧-2,3′-双去氢胞苷、β-L-5-氟-2′,3′-脱氧-2′,3′-二脱氢拉米呋啶、阿立他滨、恩曲他滨、阿立他滨、脱氧-5-甲基尿苷、3′-叠氮-2′,3′-脱氧-5-氯尿嘧啶核苷、3′-叠氮-2′,3′-脱氧-5-乙基尿苷、3′-叠氮-2′3′-氟3′-二脱氧尿苷、2′,3′-脱氧-5-溴尿苷、3′-氟-2′,3′-脱氧-5-乙基尿苷、3′-叠氮-2′,3′-脱氧-5-溴尿苷、3′-叠氮-2′,3′-二脱氧尿苷、3′-氟-2′,3′-脱氧-5-氯尿苷、3′-氟-2′,3′-二脱氧尿苷、2′,3′-脱氧-3′-叠氮尿苷、2,3′-二脱氧-3′-3′-氟-5-氯尿苷、2,3′-二脱氧腺苷、2′,3′-脱氧-2′-氟-ARA-腺苷、2-氯脱氧腺苷、9-(4-羟基-1′,2′-丁二烯)腺嘌呤、9-(2-膦酰甲氧乙基)腺嘌呤、2′,3′-脱氢-2“3′-二脱氧腺苷、二脱氧腺苷、5-甲基-2′,3′-二脱氧腺苷、3′-氟-2′,3′-二脱氧腺苷、2,3′-二脱氧-2′,3′-脱氢的N6-(O-甲基)腺苷、2′,3′-二脱氧-2′,3′-脱氢-N6-(2-甲基)腺苷、2′,3′-双脱氧-3′-氟腺苷、2,3′-双脱氧鸟苷、2′,3′-二去氢鸟苷、3′-叠氮-3′-脱氧鸟苷、3′-氟-2′,3′-双脱氧鸟苷、双脱氧鸟苷、3′-曡氮-2′,3′-双脱氧鸟苷、3′-氟-2′,3′-双脱氧鸟苷、2,3′-双脱氧-3′-叠氮鸟苷、3′-脱氧胸苷、2′,3′-双脱氧胸苷、2′,3′-双脱氧胸苷、3′-叠氮-3′-脱氧胸苷、3′-氟-3′-脱氧胸苷、3′-氟-2′,3′-双脱氧胸苷、3′-脱氧-2′,3′-双脱氧胸苷、2′,3′-脱氢-2′,3′-双脱氧胸苷、2′,3′-双脱氧肌苷、2,6-二胺嘌呤、2′,3′-二去氧核糖苷、2,6-二氨基-3-叠氮-2′,3′-二去氧核糖苷、2,6-氨基嘌呤、3′-氟-2′,3′-二去氧核糖苷、3-膦酰甲氧乙基-2,6-二氨基,2,6-二氨基嘌呤、-2′,3′-二去氧核糖苷、叠氮-2′,3′-脱氧-二氨基嘌呤、3′-氟-2′,3′-双脱氧二氨基嘌呤、2′,3′-二脱氧-3′-氟-2,6-二氨基腺嘌呤核苷、阿巴卡韦、阿昔洛韦阿昔洛韦、阿德福韦、阿洛夫定、金刚烷胺、双链聚核糖核苷酸、阿比朵尔、安普那韦、阿扎那韦、阿托伐他汀钙、波普瑞韦、西多福韦、双汰芝、阿糖胞苷、地瑞那韦的、地拉韦啶、地达诺新、地昔洛韦、去羟肌苷、替诺福韦、二十二醇、依度尿苷、依非韦伦、恩夫韦、恩替卡韦、进入抑制剂、艾夫他滨、恩曲他滨、泛昔洛韦、福米韦生、福沙那伟、膦甲酸钠、膦乙醇、融合抑制剂、更昔洛韦、伊巴他滨、异丙肌苷、疱疹净、咪喹莫特、茚肌苷、奥斯他韦、喷昔洛韦、帕拉米韦、金刚乙胺、利巴韦林、利托那韦、沙奎那韦、司他夫定、替诺福韦、替诺福韦、地西他滨、非阿尿苷、碘苷、膦甲酸钠、洛布卡韦、索立夫定、曲氟胸苷、曲金刚烷、利巴韦林、司他夫定、替拉那韦、三协唯、恩曲他滨替诺福韦、万乃洛韦、缬更昔洛韦、马拉维若、阿糖腺昔、他立韦林、扎西他滨、扎那米韦、齐多夫定、增强协同剂、整合酶抑制剂、III型干扰素、干扰素II型、I型干扰素、干扰素、洛匹那韦、洛韦胺、马拉韦罗、吗啉胍、甲吲噻腙、奈非那韦、奈韦拉平、聚乙二醇干扰素α-2a、普可那利、逆转录酶抑制剂、蛋白酶抑制剂和拉替拉韦。
本发明提供的穿心莲内酯衍生物和类似物的一种化合物的实例用于治疗、预防或减缓疾病进展的癌症和与肿瘤相关的疾病及综合征,所述疾病选至,但不局限于:多发性骨髓瘤、白血病、淋巴瘤、急性白血病、急性淋巴细胞性白血病、星细胞瘤、慢性淋巴细胞性白血病、慢性粒细胞性白血病、急性髓细胞白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、多发性骨髓瘤、血液癌症低脑癌、头部和颈部癌症、肺癌、乳腺癌、生殖系统的癌症、消化系统癌症、胰腺癌上消化道癌症、结肠癌、直肠癌、膀胱癌、肾细胞癌、前列腺癌、口腔和咽部的癌症、呼吸系统癌症、骨骼和关节癌症、软组织癌、皮肤癌、生殖系统的癌症、神经系统的淋巴癌症、舌,口,咽,或其他口腔癌、食道癌、胃癌、小肠癌、结肠癌或直肠癌、肛门或直肠肛门癌、喉癌、支气管和其他癌症、呼吸器官癌症、心脏,肝脏,肝内胆管,胆囊,胰腺,或其他胆道或消化器官癌症、黑色素瘤、基底细胞癌、鳞状,其他非上皮皮肤癌细胞癌、子宫或子宫颈癌、子宫体癌、卵巢癌、外阴癌、阴道,或其他女性生殖器官癌、前列腺、睾丸、阴茎或其他男性生殖器癌、膀胱癌、抗癌肾、肾,盆腔或尿道癌、泌尿生殖器官癌、甲状腺癌、其他内分泌癌、皮肤T细胞淋巴瘤、粒细胞和单核细胞、腺癌、肉瘤、听神经瘤、间变性星形细胞瘤、基底细胞癌、软骨肉瘤、绒毛膜上皮癌、脊索瘤、颅咽管瘤、皮肤黑色素瘤、囊腺癌、胚胎瘤、室管膜瘤、尤文氏瘤、上皮癌、肉瘤、胃癌、泌尿生殖道癌、胶质母细胞瘤、血管母细胞瘤、肝癌、卡波西氏肉瘤、大细胞癌、平滑肌肉瘤、脂肪肉瘤、髓样甲状腺、髓母细胞瘤、脑膜瘤间皮瘤、粘液肉瘤神经母细胞瘤、神经纤维、骨肉瘤、卵巢上皮癌、乳头状癌、乳头状腺癌、甲状腺瘤、嗜铬细胞瘤、松果体瘤、视网膜母细胞瘤、横纹肌肉瘤、滑膜瘤、甲状腺癌症、葡萄膜黑色素瘤、肾母细胞瘤的乳腺腺体、髓质癌、胶质癌、管状癌和炎性乳腺癌、管组织性管腺瘤、卵巢癌、卵巢腺癌、上皮卵巢肿瘤子宫癌、子宫颈上皮,包括鳞状细胞癌、腺癌的腺癌、宫颈癌、卵巢腺癌前列腺癌、前列腺癌、腺癌、膀胱癌、鳞状细胞癌、腺癌、小细胞癌、骨髓增生性疾病、骨肿瘤、非小细胞肺癌、鳞状细胞癌、腺癌、大细胞未分化癌、小细胞肺癌癌、基底细胞癌、黑色素瘤、鳞状细胞癌的光化性角化病、眼视网膜母细胞瘤、皮肤或眼内黑色素瘤、原发性肝癌、肾细胞癌、如乳头状、滤泡状、髓和未分化甲状腺癌、艾滋病有关的、如弥漫性大B淋巴瘤、细胞淋巴瘤、B细胞免疫母细胞淋巴瘤、小无裂细胞淋巴瘤、卡波西氏肉瘤、病毒诱导的癌症、乙型肝炎病毒、丙型肝炎病毒、肝胆细胞癌、-细胞白血病、淋巴瘤、人类乳头状瘤病毒、宫颈癌、原发性脑肿瘤、脑胶质瘤、少枝胶质细胞、室管膜瘤、脑膜瘤、淋巴瘤、髓母细胞瘤、听神经瘤、恶性神经鞘肿瘤、神经鞘瘤、恶性纤维组织细胞瘤、恶性纤维组织细胞瘤、恶性脑膜瘤、恶性间皮瘤、恶性混合苗勒管肿瘤、口咽癌、下咽癌、喉癌、鼻咽癌、口咽的癌症、生殖细胞肿瘤、精原细胞瘤、性腺间质肿瘤、睾丸间质细胞瘤、睾丸细胞瘤、睾丸癌、胸腺肿瘤、胃癌、如淋巴瘤、胃间质瘤、类癌;胸腺瘤、胸腺癌、直肠癌和结肠癌。
本发明提供一种穿心莲内酯衍生物或类似物或可药用盐的抗肿瘤的应用,包括与其它治疗剂配伍联合用药。至少一种或多种组合已知的抗肿瘤剂或抗炎剂与穿心莲内酯衍生物或类似物或可药用盐配伍一起施用选自以下(但不局限于以下治疗剂),包括:长春新碱、白消安、长春新碱、顺铂、卡铂、丝裂霉素C、阿霉素、秋水仙碱、依托泊苷、紫杉醇、多西紫杉醇、喜树碱、拓扑替康、三氧化二砷、5-氮胞苷、5-氟尿嘧啶、甲氨喋呤、5-氟-2-脱氧尿嘧啶核苷、羟基脲、硫代鸟嘌呤、马法兰、苯丁酸氮芥、环磷酰胺、丙脒腙、表阿霉素、阿克拉霉素、博莱霉素、依利碘铵的醋酸、氟达拉滨、奥曲肽、维甲酸、鬼臼毒素、他莫昔芬、多沙唑嗪、坦索罗辛盐酸特拉唑嗪、坦索罗辛、氟吡啶、洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、阿托伐他汀、安普那韦、阿巴卡韦、利托那韦、沙奎那韦、罗非昔布、亚硝基羟丙氨酸、托可维A酸、13-顺式维甲酸、9-顺式维甲酸、α-二氟甲基鸟氨酸、芬维A胺的、维甲酰酚胺、染料木素、阿糖胞苷、硼替佐米、格列卫、吉非替尼赫赛汀、利妥昔单抗、吉西他滨、洛匹那韦、西仑吉肽、洛那法尼、抑激酶素和伐地考昔。
本发明所述穿心莲内酯衍生物和类似物,在穿心莲内酯的3,7,8,12,15和/或19位引入取代基形成穿心莲内酯衍生物和类似物,具体结构见表1实施例1至实施例436,但不局限于实施例。
本发明所述穿心莲内酯衍生物和类似物的应用:在制备治疗抗病毒和抗癌疾病的药物的应用及制备药理上可接受的盐和前药的应用,包括与其它已知的抗病毒和抗癌药物配伍使用的给药方式包括且不局限于:口服、非胃肠道、皮下、静脉内、肌内、腹膜内、透皮、颊、鞘内、颅内、鼻内或局部途径。
本发明的组成是有效的抑制病毒复制,治疗由DNA病毒引起的感染,如单纯疱疹病毒、巨细胞病毒、乳头多瘤空泡、水痘带状疱疹病毒、EB病毒;治疗由RNA病毒引起的感染,如披膜病毒或逆转录病毒;治疗由人类亲T细胞病毒I和II引起的感染;治疗由慢病毒引起的感染;治疗由HIV-1和HIV-2引起的感染。
此外,本发明组成引入酸或碱基增大了其制备工艺的溶解度、简便、稳定性增强或因其他原因,制药可接受的碱基的例子包括:氨基酸、氨基酸酯、氢氧化铵、氢氧化钾、氢氧化钠、碳酸氢钠、氢氧化铝、碳酸钙、氢氧化镁、铝硅酸盐、硅酸铝、镁、氢氧化铝、二异丙基乙胺、乙醇胺、乙二胺、三乙醇胺、三乙胺、三异丙胺、三甲胺和三羟甲基氨基甲烷;与制药可接受的可与碱基成盐的酸、如盐酸、氢溴酸、碘化氢、硫酸、硝酸、硼酸、磷酸、醋酸、丙烯酸、己二酸、褐藻酸、烷基磺酸、氨基酸、抗坏血酸、苯甲酸、硼酸、丁酸、碳酸、柠檬酸、脂肪酸、甲酸、富马酸、延胡索酸、葡萄糖酸、氢醌磺酸、异抗坏血酸、乳酸、马来酸、甲磺酸、草酸、对溴苯磺酸、丙酸、甲苯磺酸、水杨酸、硬脂酸、琥珀酸、酒石酸、巯基乙酸、甲苯磺酸、尿酸;多元酸的盐类、如磷酸钠、磷酸氢二钠、磷酸二氢钠;当该碱基是盐、阳离子可以是任何制药可接受的阳离子如铵、碱金属、碱土金属钠、钾、锂、镁、钙和铵。
具体实施方式
化学合成
下面将通过实施例对本发明结构通式I所述的化合物的合成做进一步说明,但下述的实施例仅是本发明其中的例子而已,并不限定本发明权利要求的保护范围,该权利要求的保护范围以权利要求书为准。除非另有定义以外,全部取代基定义为如上所述。基于有机合成文献已知的合成路线和设计制备下述化合物。
穿心莲内酯溶于甲苯中,在Al2O3催化剂的存在下,回流反应获得脱水穿心莲内酯,一个关键的中间产物A,见反应式II;化合物B溶于四氢呋喃在碱催化剂存在下,和含有醛基的试剂反应在C15位形成C=C双键的化合物C,见反应式III;化合物D与过氧化氢试剂反应,在C8-C17双键位形成过氧化物E,见反应式IV;化合物F与亲核试剂反应在C12位形成C-杂键化合物G,见反应式V;化合物H与亲核试剂反应在C7位形成C-杂键化合物I,见反应式VI;化合物J在4-二甲氨基吡啶(DMAP)和三乙胺催化剂存在下,和含有酸、酸衍生物或卤代试剂反应,在C3位或C19位形成酯或醚化合物K,见反应式VII。
实施例
合成与制备举例(实例化学结构见1-436表1)
穿心莲内酯是从中国华泰生物科技有限公司购买,核磁共振氢谱测定除了特殊注明条件外均采用1HNMR(600MHz,DMSO-d6)。
通式反应A(羟基酯化)
穿心莲内酯3.00克(10mmol)和DMAP1.2克(10mmol),三乙胺1.5克(15mmol)混合在20毫升的二氯甲烷中,分别加入4-O葡萄糖基苯甲酰氯4.8克(15mmol),搅拌,直到反应完成,将反应液过滤,经硅胶柱层析分离,得到目标化合物。
通式反应B(羟基脱保护)
乙酰化保护的穿心莲内酯4.30克(10mmol)混合乙醇20毫升和水5毫升混合溶液,加入碳酸钾1.50克,混合物加热回流2小时,将反应液过滤,经硅胶柱层析分离,得到目标化合物。
通式反应C(15位C=C键形成)
乙酰化保护的穿心莲内酯2.1克(6mmol)溶于甲醇20毫升中,加2-甲酰呋喃0.80克(8.34mmol)和Na2CO30.50克(4.72mmol),50℃反应4小时,反应液用乙酸乙酯提取,经硅胶柱层析分离,得到目标化合物。
通式反应D(12位的C-C键形成)
乙酰化保护的穿心莲内酯2.1克(6mmol)溶于甲醇10毫升中,加入硝基甲烷4ml和NaOCH31.04克(18.27mmol),50℃反应4小时,反应液用乙酸乙酯提取,经硅胶柱层析分离,得到目标化合物。
通式反应E(7位C-杂键形成)
混合7-氯代穿心莲内酯2.2克(6mmol)溶于四氢呋喃(THF)10毫升中,加入吗啉4毫升和NaOCH35.0204克(9.14mmol),50℃反应4小时,反应液用乙酸乙酯提取,经硅胶柱层析分离,得到目标化合物。实施例1.11,12-二脱氢-14-去氧穿心莲内酯的制备:穿心莲内酯3.00g(8.6mmol)溶于20ml吡啶中,加入氧化铝6.00g(5.9mmol),混合物回流5h,反应液用乙酸乙酯提取,经硅胶柱色谱分离得到目标化合物;IR(KBr,cm-1):3295-3081,2969,1744,1637,1451,1273,1086,1026;1HNMR:δ7.65(m,1H),6.74(m,1H),6.12(d,J=15.6Hz,1H),5.02(m,1H),4.89(d,J=12Hz,2H),4.73(d,J=1.2Hz,1H),4.42(d,J=1.2Hz,1H),4.13(m,1H),3.85(d,J=3.0Hz,1H),3.29(m,1H),3.23(m,1H),2.36(d,J=10.8Hz,2H),1.98(m,1H),1.72(d,J=2.4Hz,1H),1.55(m,2H),1.41(m,1H),1.33(m,1H),1.19(m,1H),1.14(m,1H),1.09(s,3H),0.76(s,3H)。
实施例2.3,14,19-三乙酰基穿心莲内酯的制备:穿心莲内酯3.00g(8.6mmol)溶于20ml醋酸酐中,加氯化锌2.0g(0.3mmol),混合物80℃反应5h,反应液用乙酸乙酯提取,经硅胶柱层析分离得目标产物;IR(KBr,cm-1):3436-3078,1753,1736,1728,1247,1132,1095,1077;1HNMR(CDCl3):δ6.89(t,1H),5.93(d,J=6Hz,1H),4.74(br,2H),4.56(m,2H),4.33(d,J=11.7Hz,1H)4.25(d,J=1.8Hz,1H),4.17(d,J=11.7Hz,1H),3.04(d,J=6.3Hz,1H),2.94(d,J=7.8Hz,1H),2.25(s,3H),2.12(s,3H),2.08(s,3H),2.06(m,1H),2.04(m,1H),1.87(d,J=2.4Hz,2H),1.85(d,J=3.6Hz,2H),1.54(d,J=3.9Hz,1H),1.36(d,J=2Hz,2H),1.18(s,3H),1.08(s,3H)。
实施例3.7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂7-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基-8-环氧乙烷基-12-(吡啶-2-基)氨基-14-脱氧穿心莲内酯和2-(4-(二甲氨基)苯基)-2-氧乙酸,采用通式反应法C,获得目标化合物;1HNMR:δ7.65(s,1H),7.74(m,2H),7.58(d,J=9.0Hz,2H),7.04(m,3H),6.31(m,1H),6.06(d,J=15.6Hz,1H),5.80(s,1H),5.02(s,1H),4.85(d,J=1.8Hz,2H),4.15(m,1H),3.85(m,1H),3.74(m,1H),3.33(m,2H),3.31(m,1H),2.98(s,6H),2.90(m,1H),2.63(d,J=3.0Hz,1H),2.16(d,J=10.2Hz,1H),1.74(m,3H),1.58(m,2H),1.52(dd,J=3.6Hz,4.2Hz,1H),1.49(m,2H),1.32(m,2H),1.28(s,3H),1.08(s,3H),1.07(m,2H),0.89(s,3H)。
实施例4.3,19-二乙酰基-11,12-二去氢-14-去氧穿心莲内酯的制备:14-脱氧-11,12-去二氢穿心莲内酯3.00g(10.0mmol)溶于在二氯甲烷20ml中,加乙酰氯3.50g(45.2mmol)和三乙胺3ml,室温反应混合物3h,反应液用乙酸乙酯提取,经硅胶柱层析分离得到目标化合物;IR(KBr,cm-1):3436-3078,2983,1748,1728,1642,1440,1376,1132,1095,1077,1037;1HNMR(300MHz,CDCl3):δ7.00(d,J=1.8Hz,1H),6.69(d,J=0.9Hz,1H),6.16(d,J=12Hz,1H),4.88(m,1H),4.61(m,1H),4.45(m,1H),4.38(d,J=11.7Hz,1H),4.41(t,J=13.0Hz,1H),4.12(d,J=12.0Hz,1H),2.45(m,3H),2.05(s,6H),1.87(d,J=2.4Hz,2H),1.85(d,J=3.6Hz,2H),1.79(m,1H),1.54(d,J=3.9Hz,1H),1.36(d,J=2.1Hz,2H),1.04(s,3H),0.78(s,3H)。
实施例5.11,12-二去氢-14-去氧-(E)-15-(4-羟基-3-甲基-5-硝基苯亚甲基)穿心莲内酯的制备:反应试剂为14-去氧-11,12-去二氢穿心莲内酯和3-硝基-4-羟基-5-甲氧基苯甲醛,用通式反应法C,得目标产物;1HNMR:δ7.62(s,1H),7.69(s,1H),7.55(s,1H),6.72(m,1H),6.21(s,1H),6.19(s,1H),5.03(br,1H),4.73(m,1H),4.43(m,1H),4.13(br,1H),3.84(d,J=9.6Hz,1H),3.84(s,3H),3.27(m,1H),3.22(m,1H),2.38(t,J=10.8Hz,2H),1.97(m,1H),1.72(d,J=13.2Hz,1H),1.58(m,2H),1.40(d,J=4.2Hz,3.6Hz,1H),1.34(d,J=13.2Hz,1H),1.17(m,2H),1.08(s,3H),0.77(s,3H)。
实施例6.(E)-2-(1,2-二羟乙基)-4-(6羟基-5-(羟甲基)-5,8a-二甲基-2-亚甲基十氢萘-1-基)丁-2-烯酰基肼的制备:穿心莲内酯3.00g(8.6mmol)溶于20mlTHF中,加入水合肼2ml(40%),室温反应2h,反应混合物用乙酸乙酯提取,经硅胶柱色谱分离得到目标化合物;IR(KBr,cm-1):3398-3325,3092,2978,2957,2849,1727,1674,1649,1456,1366,1221,1074。
实施例7.7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(Z)-15-(羧基(4-(二甲氨基)苯基)亚甲基)穿心莲内酯的制备:反应试剂7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-脱二氢-14-脱氧穿心莲内酯和2-(4-(二甲氨基)苯基)-2-氧乙酸,采用通式反应法C得目标产物;1HNMR:δ11.0(s,1H),7.61(s,1H),7.21(d,J=9.0Hz,2H),7.02(d,J=7.0Hz,2H),6.75(d,J=9.0Hz,2H),6.31(m,1H),6.24(s,1H),6.16(d,J=15.6Hz,1H),5.20(m,2H),5.05(s,1H),4.73(m,1H),4.43(m,1H),4.15(m,1H),3.84(d,J=10.8Hz,1H),3.74(m,3H),3.29(m,1H),3.27-3.22(m,2H),3.06(s,6H),2.42-2.35(m,2H),1.60-1.56(m,2H),1.39(q,J=4.2Hz,1H),1.33(d,J=13.8Hz,1H),1.27(s,3H),1.08(s,3H),0.77(s,3H)。
实施例8.(E)-4-羟基-3-(2-(3,3,6a,10b-四甲基-8-亚甲基十氢-1H-萘并[2,1-d][1,3二氧芑-7.基)亚乙基)二氢呋喃-2(3H)-酮的制备:穿心莲内酯3.00g(10.0mmol)加入苯300ml,二甲基亚砜40ml,对甲苯磺酸0.7g(4.07mmol)和2,2-二甲氧基丙烷4g(38.5mmol),80℃反应12h,反应液用乙酸乙酯提取,经硅胶柱色谱分离得目标产物;IR(KBr,cm-1):3351-3076,2970,1760,1640,1199,1077,1047,1034,913;1HNMR(600MHz,DMSO-d6):δ6.60(m,1H),5.72(d,J=6.0Hz,1H),5.06(d,J=4.8Hz,1H),4.89(d,J=12Hz,2H),4.73(d,J=1.2Hz,1H),4.60(m,1H),4.42(d,J=1.2Hz,1H),4.37(m,1H),4.13(m,1H),3.85(d,J=3.0Hz,1H),3.29(m,1H),3.23(m,1H),2.36(d,J=10.8Hz,2H),1.98(m,1H),1.72(d,J=2.4Hz,1H),1.54(s,3H),1.53(s,3H),1.41(m,1H),1.33(m,1H),1.19(m,1H),1.14(m,1H),1.12(s,3H),1.01(s,3H)。
实施例9.7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-8,17-环氧穿心莲内酯的制备:反应试剂为8-环氧乙烷基-11,12-二脱氢-14-脱氧穿心莲内酯和2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-胺,采用通式反应法E,获得目标化合物;1HNMR:δ7.65(m,1H),7.04(m,3H),6.31(m,1H),6.06(d,J=15.6Hz,1H),5.02(s,1H),4.89(d,J=12Hz,2H),4.15(m,1H),3.96(br,1H),3.74(m,1H),3.33(m,2H),3.31(d,J=10.2Hz,1H),2.90(m,1H),2.63(d,J=3.0Hz,1H),3.86(s,3H),2.16(d,J=10.2Hz,1H),1.74(m,2H),1.52(dd,J=3.6Hz,4.2Hz,1H),1.43-1.30(m,2H),1.32(m,2H),1.08(s,3H),1.07(m,2H),0.89(s,3H)。
实施例10.(E)-3-(2-(3,3,6a,10b-四甲基-8-亚甲基十氢-1H-萘并[2,1-d][1,3]二氧芑-7-基)乙烯基)呋喃-2(5H)-酮的制备:14-脱氧-11,12-去二氢穿心莲内酯3.00g(10.0mmol)溶于300ml苯和40ml二甲基亚砜中,加对甲苯磺酸0.7g(4.07mmol)和2,2-二甲氧基丙烷4g(38.5mmol),80℃反应7h,反应液用乙酸乙酯提取,经硅胶柱色谱分离得到目标化合物;IR(KBr,cm-1):3068-2996,1760,1637,1248,1093,1076,1042;1HNMR:δ7.12(m,1H),6.91(m,1H),6.12(d,J=15.6Hz,1H),4.80(d,J=12Hz,2H),4.73(d,J=1.2Hz,1H),4.55(m,1H),4.09(d,J=12Hz,1H),3.47(d,J=3.0Hz,1H),3.24(m,1H),2.40(m,2H),2.05(m,2H),1.74(m,2H),1.53(m,1H),1.44(s,3H),1.38(s,3H),1.35(m,2H),1.28(m,1H),1.22(m,2H),1.13(m,1H),1.01(s,3H)。
实施例11.12-硝甲基-14-去氧穿心莲内酯的制备:反应试剂为穿心莲内酯和硝基甲烷,采用通式反应法D,获得目标化合物;IR(KBr,cm-1):3418-3018,2927,1770,1643,1556,1260,1165,1082,1036;1HNMR:δ7.65(m,1H),4.87(m,2H),4.82(m,2H),4.75(m,2H),4.58(m,1H),3.78(d,J=10.8Hz,1H),3.22(m,1H),3.19(m,1H),3.17(t,J=6Hz,1H),2.29(d,J=12.6Hz,1H),1.75(m,3H),1.57(m,4H),1.39(d,J=9.6Hz,1H),1.28(m,1H),1.06(d,J=1.8Hz,1H),1.03(s,3H),0.56(s,3H)。
实施例12.7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)亚甲基)穿心莲内酯的制备:反应试剂为7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-脱二氢-14-脱氧穿心莲内酯和4-(甲基吡嗪基)苯甲醛,采用通式反应法C,得目标产物;1HNMR:δ8.05(s,2H),7.61(s,1H),7.02(d,J=7.0Hz,2H),6.31(m,1H),6.24(s,1H),6.16(d,J=15.6Hz,1H),5.20(m,2H),5.05(s,1H),4.73(m,1H),4.43(m,1H),4.15(m,1H),3.84(d,J=10.8Hz,1H),3.74(m,3H),3.29(m,1H),3.27-3.22(m,2H),3.21(m,4H),2.50(m,4H),2.42-2.35(m,2H),2.27(s,3H),1.60-1.56(m,2H),1.39(q,J=4.2Hz,1H),1.33(d,J=13.8Hz,1H),1.27(s,3H),1.08(s,3H),0.77(s,3H)。
实施例13.11,12-二去氢-14-去氧-8,17-环氧穿心莲内酯的制备:14-脱氧-11,12-去二氢穿心莲内酯1.50g(5.0mmol)溶于30ml氯仿中,加3-氯过氧苯甲酸15ml和2,2-二甲氧基丙烷2.0g(19.2mmol),室温反应3h,反应液用乙酸乙酯提取,经硅胶柱色谱分离得目标产物;IR(KBr,cm-1):3369-3079,2969,1753,1350,1273,1086;1HNMR:δ7.61(m,1H),6.30(m,1H),6.06(d,J=15.6Hz,1H),5.73(s,1H),5.02(br,1H),4.85(d,J=1.8Hz,2H),4.15(m,1H),3.85(m,1H),3.33(m,2H),3.31(d,J=10.2Hz,1H),2.63(d,J=3.0Hz,1H),2.16(d,J=10.2Hz,1H),1.74(m,2H),1.58(m,2H),1.52(dd,J=3.6Hz,4.2Hz,1H),1.32(m,2H),1.08(s,3H),1.07(m,1H),0.89(s,3H)。
实施例14.3,19-二乙酰基-7-羟基-11,12-二去氢-14-去氧穿心莲内酯的制备:3,19-二乙酰-14-脱氧-11,12-去二氢穿心莲内酯2.0g(4.81mmol)溶于二氯甲烷20ml中,加叔丁基过氧化氢0.87g(9.67mmol),SeO20.53g(4.81mmol),3-氯过氧苯甲酸15ml和2,2-二甲氧基丙烷2.0g(19.2mmol),室温反应3h,反应液用乙酸乙酯提取,经硅胶柱色谱分离得目标产物;IR(KBr,cm-1):3469-3080,2947,1756,1732,1649,1443,1374,1245,1083,1034;1HNMR(300MHz,CDCl3):δ7.00(m,1H),6.65(m,1H)6.16(d,J=12Hz,1H),4.88(m,1H),4.61(m,1H),4.45(m,1H),4.38(d,J=11.7Hz,1H),4.41(t,J=13.0Hz,1H),4.12(d,J=12.0Hz,1H),2.45(m,3H),2.05(s,6H),1.87(m,2H),1.85(m,2H),1.79(m,1H),1.54(d,J=3.9Hz,1H),1.36(m,2H),1.04(s,3H),0.78(s,3H)。
实施例15.7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-8-环氧乙烷基-12-((吡啶-2-基)氨基)-14-脱氧穿心莲内酯和4-(甲基吡嗪基)苯甲醛,用通式反应法C,得目标产物;1HNMR:8.07(m,3H),7.74(m,2H),7.02(m,3H),6.75(m,2H),6.22(s,1H),4.73(m,1H),4.43(m,1H),4.15(m,1H),3.84(d,J=10.8Hz,1H),3.74(m,2H),2.41(m,1H),3.27-3.22(m,7H),2.52-2.35(m,8H),2.20(s,3H),1.60-1.50(m,4H),1.39(q,J=4.2Hz,1H),1.33(d,J=13.8Hz,1H),1.27(s,3H),1.17(m,2H),1.08(s,3H),0.77(s,3H)。
实施例16.7-羟基-11,12-二去氢-14-去氧穿心莲内酯的制备:反应试剂为14-去氧-11,12-去二氢穿心莲内酯,采用通式反应E法,获得目标化合物;IR(KBr,cm-1):3443-3080,2947,1753,1649,1443,1374,1245,1083,1034。
实施例17.(E)-4-羟基-3-(2-(9-羟基3,3,6a,10b-四甲基-8-亚甲基十氢-1H-萘并[2,1-d][1,3]二氧芑-7-基)亚乙基)二氢呋喃-2(3H)-酮的制备:反应试剂为(E)-4-羟基-3-(2-(3,3,6a,10b-四甲基-8-甲烯基十氢-1H-萘并[2,1-D][1,3]二恶英-7-基)乙基)二氢呋喃-2-(3H)酮,采用通式反应法E,获得目标化合物;IR(KBr,cm-1):3346-3079,2972,2931,2868,1753,1640,1440,1383,1350,1199,1076,1047,1021。
实施例18.(E)-4-羟基-3-(2-(3,3,6a,10b-四甲基十氢化螺[萘并[2,1-d][1,3]二氧芑-8,2′-环氧乙烷]-7-基)亚乙基)二氢呋喃-2(3H)-酮的制备:(E)-4-羟基-3-(2-(3,3,6a,10b-四甲基-8-甲烯基十氢-1H-萘并[2,1-D][1,3]二恶英-7-基)乙基)二氢呋喃-2-(3H)酮,1.50g(3.85mmol)溶于氯仿20ml,加入间氯过氧化苯甲酸0.8g(4.64mmol),室温反应3h,反应液用乙酸乙酯提取,经硅胶柱色谱分离得目标化合物;IR(KBr,cm-1):3369-3079,2972,2931,2855,1760,1640,1440,1384,1350,1220,1202,1199,1077,1047,1034,913。
实施例19.3,19-二乙酰基-7-氯-11,12-二去氢-14-去氧穿心莲内酯的制备:3,19-二乙酰基-14-去氧-11,12-去二氢穿心莲内酯4g(9.3mmol)溶于40ml氯仿,加吡啶3.7g(46.9mmol)和氯化亚砜5.5g(46.2mmol),室温反应3h,反应液用乙酸乙酯提取,硅胶柱色谱分离得目标产物;IR(KBr,cm-1):3436-3078,2983,1748,1728,1642,1220,1132,1095,1077;1HNMR:δ7.54(m,1H),6.74(dd,J=10.0Hz,15.8Hz,1H),6.11(d,J=15.8Hz,1H),5.05(d,J=1.5Hz,1H),4.93(d,J=1.5Hz,1H),4.22(d,J=11.1Hz,1H),3.50(dd,J=11.4Hz,J=4.7Hz,1H),3.35(d,J=11.0Hz,1H),2.47(m,1H),2.33(d,J=9.8Hz,1H),2.05(m,1H),2.01(s,3H),1.93(s,3H),1.82(m,1H)1.78(m,2H),1.53(m,3H),1.34(m,1H),1.26(s,3H),1.20(m,1H),0.82(s,3H)。
实施例20.7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)穿心莲内酯的制备:反应试剂为7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二脱氢-14-脱氧穿心莲内酯和4-(二甲氨基)苯甲醛,采用通式反应法C,得目标产物;1HNMR:δ7.61(s,1H),7.58(d,J=9.0Hz,2H),7.02(d,J=7.0Hz,2H),6.75(d,J=9.0Hz,2H),6.31(m,1H),6.24(s,1H),6.16(d,J=15.6Hz,1H),5.20(m,2H),5.05(s,1H),4.73(m,1H),4.43(m,1H),4.15(m,1H),3.84(d,J=10.8Hz,1H),3.74(m,3H),3.29(m,1H),3.27-3.22(m,2H),3.06(s,6H),2.42-2.35(m,2H),1.60-1.56(m,2H),1.39(q,J=4.2Hz,1H),1.33(d,J=13.8Hz,1H),1.27(s,3H),1.08(s,3H),0.77(s,3H)。
实施例21.3,19-二乙酰基-7-氧基-11,12-二去氢-14-去氧穿心莲内酯的制备:3,19-二乙酰基-7-羟基-14-去氧-11,12-去二氢穿心莲内酯1.5g(3.9mmol)溶于15ml二甲基甲酰胺(DMF)中,加0.75g(3.5mmol)PDC,混合物60℃反应3h,反应液用乙酸乙酯提取,经硅胶柱色谱分离得目标产物;IR(KBr,cm-1):3453-2944,1755,1736,1688,1247,1083,1040;1HNMR:δ6.88(m,1H),6.58(m,1H),6.18(d,J=15.6,1H),4.81(m,2H),4.62(dd,J=4.8Hz,4.2Hz,1H),4.43(d,J=12.0Hz,1H),4.29(d,J=12.0Hz,1H),2.80(dd,J=1.8Hz,3.0Hz,1H)2.54(m,2H),2.09(s,3H),2.06(s,3H),1.87(m,1H),1.72(m,3H),1.49(m,1H),1.36(m,1H),1.25(m,1H),1.04(s,3H),0.91(s,3H)。
实施例22.3,19-二乙酰基-7-(4-吗啉基)-11,12-二去氢-14-去氧穿心莲内酯的制备:反应试剂为3,19-二乙酰基-7-氯代-14-去氧-11,12-去二氢穿心莲内酯和吗啉,采用通式反应法E,获得目标化合物;IR(KBr,cm-1):3430-3078,1748,1728,1642,1347,1272,1222,1132,1083,1036;1HNMR:δ7.65(m,1H),7.59(m,1H),7.09(s,1H),5.12(d,J=15.6Hz,1H),5.02(d,J=4.8Hz,1H),4.42(m,1H),3.67(m,4H),3.29(m,1H),3.23(m,1H),2.86(m,4H),2.36(d,J=10.8Hz,2H),3.09(m,3H),2.06(s,6H),1.98(m,1H),1.72(d,J=2.4Hz,1H),1.41(m,2H),1.33(m,1H),1.14(m,1H),1.09(s,3H),0.76(s,3H)。
实施例23.7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-8-环氧乙烷基-14-脱氧穿心莲内酯和4-(甲基吡嗪基)苯甲醛,采用通式反应法C,得目标产物;1HNMR:8.07(s,2H),7.64(s,1H),7.02(s,2H),6.75(m,1H),6.22(s,1H),6.16(d,J=15.6Hz,1H),4.73(s,1H),4.43(m,1H),4.15(m,1H),3.84(d,J=10.8Hz,1H),3.74(m,3H),2.41(m,1H),3.27-3.22(m,6H),2.52-2.35(m,8H),2.20(s,3H),1.60-1.56(m,2H),1.39(q,J=4.2Hz,1H),1.33(d,J=13.8Hz,1H),1.27(s,3H),1.17(m,2H),1.08(s,3H),0.77(s,3H)。
实施例24.11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂为8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯和2-(4-(二甲氨基)苯基)-2-氧乙酸,采用通式反应法C,获得目标产物;IR(KBr,cm-1):3430-3087,2931,1744,1640,1599,1559,1525,1445,1384,1367,1311,1187,1167,1128,1082,1038;1HNMR:δ7.61(s,1H),7.58(d,J=9.0Hz,2H),6.75(d,J=9.0Hz,2H),6.31(m,1H),6.24(s,1H),6.16(d,J=15.6Hz,1H),5.01(d,J=4.8Hz,1H),4.14(q,J=2.4Hz,1H),3.85(d,J=2.4Hz,1H),3.21(m,1H),2.98(s,6H),2.97(s,1H),2.67(d,J=2.4Hz,1H),2.51(d,J=4.2Hz,1H),2.21(d,J=9.6Hz,1H),1.78(m,2H),1.62(m,2H),1.33(m,2H),1.09(s,3H),0.91(s,3H)。
实施例25.12-(4-吗啉基)-14-去氧穿心莲内酯的制备:反应试剂为穿心莲内酯和吗啉,采用通式反应法E,获得目标化合物;IR(KBr,cm-1):3399-2926,1755,1711,1635,1607,1509,1448,1385,1273,1247,1171,1115,1077,1038;1HNMR:δ7.67(m,1H),4.84(s,2H),4.43(d,J=12.0Hz,1H),4.37(d,J=11.4Hz,1H),3.94(m,1H),3.75(m,1H),3.45(m,4H),3.32(m,4H),3.21(m,1H),3.16(d,J=3.0Hz,2H),2.86(t,J=9.6Hz,4H),2.23(m,1H),2.05(m,2H),1.71-1.52(m,4H),1.32(m,2H),1.21(s,3H),0.62(s,3H)。
实施例26.(E)-5-氧基-4-(2-(3,3,6a,10b-四甲基-8-亚甲基十氢-1H-萘并[2,1-d][1,3]二氧芑-7-基)亚乙基)四氢呋喃-3-基甲磺酸酯的制备:(E)-4-羟基-3-(2-(3,3,6a,10b-四甲基-8-甲烯基十氢-1H-萘并[2,1-D][1,3]二恶英-7-基)乙基)二氢呋喃-2-(3H)酮,1.50g(3.85mmol)溶于氯仿20ml加甲基磺酰氯0.60g(5.24mmol)和三乙胺1.30g(12.82mmol),室温反应3h,反应液用乙酸乙酯提取,经硅胶柱色谱分离得到目标化合物,作为下步反应试剂。
实施例27.12-((5-氨基-4H-1,2,4-三唑-3-基)硫)-14-去氧穿心莲内酯的制备:反应试剂穿心莲内酯和3-氨基-5-巯基-1,2,4-三唑,用通式反应法E,得目标产物;IR(KBr,cm-1):3432-3362,3079,2947,2927,2875,1753,1643,1593,1497,1452,1383,1260,1165,1082,1036;1HNMR:1HNMR(600MHz,DMSO-d6):δ6.54(m,1H),5.71(m,1H),5.05(br,1H),4.83(s,1H),4.62(m,1H),4.41(q,J=4.2Hz,1H),4.06(d,J=8.4Hz,1H),3.85(d,J=5.4Hz,1H),3.26(m,2H),2.50(m,2H),2.34(m,1H),1.94(m,1H),1.76-1.63(m,4H),1.34(m,1H),1.23(m,2H),1.09(s,3H),0.66(s,3H)。
实施例28.12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂为8-环氧乙烷基-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-脱氧穿心莲内酯和和4-二甲氨基苯甲醛,用通式反应法C,得目标产物;1HNMR:δ7.61(s,1H),7.58(d,J=9.0Hz,2H),7.03(d,J=7.0Hz,2H),6.75(d,J=9.0Hz,2H),5.01(s,1H),4.14(q,J=2.4Hz,1H),3.85(d,J=2.4Hz,1H),3.21(m,1H),3.75(m,4H),2.98(s,6H),2.97(s,1H),2.67(m,3H),2.51(d,J=4.2Hz,1H),2.21(m,3H),1.78(m,3H),1.62(m,2H),1.33(m,5H),1.09(s,3H),0.91(s,3H)。
实施例29.12-((4,6-二甲基嘧啶-2-基)硫)-14-去氧穿心莲内酯的制备:反应试剂为穿心莲内酯和2,4-二甲基-6-巯基嘧啶,采用通式反应法E,获得目标化合物;IR(KBr,cm-1):3436-3080,2927,2857,1754,1644,1603,1514,1452,1384,1260,1173,1151,1079,1038,967,919;1HNMR:δ7.56(m,1H),6.96(m,1H),5.02(m,1H),4.98(m,1H),4.90(m,1H),4.61(m,1H),4.46(m,1H),4.26(m,1H),4.04(d,J=11.2Hz,1H),3.48(m,1H),3.41(d,J=11.2Hz,1H),2.57(m,1H),2.42(m,1H),2.27(m,1H),1.88-1.78(m,3H),1.65-1.75(m,3H),1.37(s,3H),1.35(m,1H),1.29(s,3H),1.28(s,3H),1.25-1.18(m,1H),0.87(m,1H),0.81(s,3H)。
实施例30.7-(4-吗啉基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧穿心莲内酯的制备:反应试剂为7-吗啉基-8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯和(2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)2-胺,采用通式反应法D,获得目标化合物;1HNMR:δ7.65(m,1H),7.59(m,1H),7.09(s,1H),7.02(d,J=7.0Hz,2H),5.12(d,J=15.6Hz,1H),5.02(d,J=4.8Hz,1H),4.42(m,1H),3.74(m,1H),3.67(m,5H),3.29(m,2H),3.23(m,3H),2.86(m,4H),2.36(d,J=10.8Hz,2H),3.09(s,3H),1.98(m,1H),1.72(q,J=2.4Hz,1H),1.41(m,3H),1.33(m,1H),1.28(s,3H),1.14(m,1H),1.09(s,3H),0.76(s,3H)。
实施例31.12-((2-氨基苯基)硫)-14-去氧穿心莲内酯的制备:反应试剂为穿心莲内酯和2-氨基巯酚,采用通式反应法E,获得目标产物;IR(KBr,cm-1):3436-3362,3076,1749,1642,1609,1478,1446,1384,1201,1080,1036;1HNMR:δ8.24(m,2H),7.86(m,1H),7.70(t,J=8.1Hz,1H),7.55(s,1H),6.0(s,1H),4.83(m,3H),4.66(m,1H),4.31(m,1H),4.23(d,J=11.4Hz,1H),3.63(d,J=12Hz,1H),3.49(d,J=11.4Hz,1H),3.44(m,2H),2.49(m,1H),2.36(m,1H),1.96-1.85(m,3H),1.78-1.69(m,2H),1.63(m,1H),1.57(d,J=9.6Hz,1H),1.35(m,3H),1.28-1.08(m,4H),0.75(s,3H)。实施例32.11,12-二去氢-14-去氧-15-(丙烷-2-亚基)穿心莲内酯的制备:反应试剂为14-去氧-11,12-去二氢穿心莲内酯和丙酮,采用通式反应法C,获得目标化合物;IR(KBr,cm-1):3337-3080,2928,2855,1746,1642,1445,1175,1073,1034;1HNMR:δ7.26(m,1H),6.83(dd,J=10.0Hz,15.8Hz,1H),6.15(d,J=15.8Hz,1H),4.78(d,J=1.5Hz,1H),4.54(d,J=1.48Hz,1H),4.22(d,J=11.1Hz,1H),3.50(dd,J=11.4Hz,4.7Hz,1H),3.35(d,J=11.0Hz,1H),2.47(m,1H),2.33(d,J=9.8Hz,1H),2.05(m,1H),2.01(s,3H),1.93(s,3H),1.82(m,1H),1.78(m,2H),1.53(m,1H),1.34(m,1H),1.26(s,3H),1.25(m,1H),1.20(m,1H),0.82(s,3H)。
实施例33.11,12-二去氢-14-去氧-(E)-15-(1,3-二羟基丙烷-2-亚基)穿心莲内酯的制备:反应试剂14-去氧-11,12-去二氢穿心莲内酯和多聚甲醛,采用通式反应法C,获得目标产物;IR(KBr,cm-1):3394-2934,2873,1753,1654,1451,1388,1106,1080,1035;1HNMR:δ7.35(m,1H),6.90(dd,J=10.8Hz,15.8Hz,1H),6.15(d,J=15.8Hz,1H),4.76(d,J=1.7Hz,1H),4.66(d,J=4.5Hz,1H),4.51(d,J=1.7Hz,1H),4.30(br,1H),4.13(m,1H),3.80(m,4H),3.42(m,1H),3.33(m,1H),3.0(m,1H),2.41(m,2H),2.06(m,1H),1.80(m,1H),1.73(m,2H),1.47(m,1H),1.45(m,1H),1.31(dd,J=2.0Hz,12.3Hz,1H),1.23(s,3H),1.25(m,1H),1.20(m,1H),0.83(s,3H)。
实施例34.7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)15-((2-氨基-9-甲基-6-氧基-6,9-二氢-1H-嘌呤-8-基)亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂7-吗啉基-8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯和2-氨基-9-甲基-6-氧-6,9-二氢-1H-嘌呤甲醛,采用通式反应法C得目标产物;IR(KBr,cm-1):3440-3078,2983,1745,1724,1642,1450,1347,1222,1122,1083;1HNMR:δ8.90(s,1H),6.72(m,1H),6.31(m,2H),6.06(d,J=15.6Hz,1H),4.73(s,1H),4.43(m,1H),4.13(br,1H),3.84(d,J=9.6Hz,1H),3.67(m,4H),3.22(m,1H),3.70(s,3H),3.31(d,J=10.2Hz,1H),3.22(m,1H),2.86(m,4H),2.16(d,J=10.2Hz,1H),2.38(t,J=10.8Hz,2H),1.97(m,1H),1.72(d,J=13.2Hz,1H),1.40(dd,J=4.2Hz,3.6Hz,1H),1.34(d,J=13.2Hz,1H),1.17(m,2H),1.09(s,3H),0.76(s,3H)。
实施例35.11,12-二去氢-14-去氧-(E)-15-(2,4-二氯苯基亚基)穿心莲内酯的制备:反应试剂14-去氧-11,12-去二氢穿心莲内酯和2,4-二氯苯甲醛,用通式反应法C得目标产物;IR(KBr,cm-1):3390-3080,2923,1750,1646,1601,1508,1221,1201,1173,1037;1HNMR:δ8.03(d,J=8.4Hz,1H),7.83(s,1H),7.69(s,1H),7.53(d,J=8.4Hz,1H),6.83(m,1H),6.48(s,1H),6.26(d,J=15.6Hz,1H),5.03(s,1H),4.73(m,1H),4.42(m,1H),4.13(d,J=4.8Hz,1H),3.84(d,J=10.8Hz,1H),3.28(d,J=7.2Hz,1H),3.21(d,J=9.6Hz,1H),3.16(d,J=3.0Hz,1H),2.43(d,J=10.2Hz,1H),2.36(d,J=13.2Hz,1H),1.98(d,J=10.2Hz,1H),1.71(d,J=12.0Hz,1H),1.60(m,1H),1.57(d,J=11.4Hz,1H),1.39(dd,J=3.0Hz,3.6Hz,1H),1.32(d,J=13.2Hz,1H),1.16(m,3H),1.08(s,3H),0.77(m,1H)。
实施例36.11,12-二去氢-14-去氧-(E)-15-(2,4-二氟苯基亚甲基)穿心莲内酯的制备:反应试剂为14-去氧-11,12-去二氢穿心莲内酯和2,4-二氟苯甲醛,用通式反应法C得目标产物;IR(KBr,cm-1):3390-3080,2923,1750,1646,1605,1555,1224,1201,1173,1053;1HNMR:δ8.03(d,J=8.4Hz,1H),7.83(s,1H),7.69(s,1H),7.53(d,J=8.4Hz,1H),6.83(m,1H),6.48(s,1H),6.26(d,J=15.6Hz,1H),5.03(s,1H),4.73(m,1H),4.42(m,1H),4.13(d,J=4.8Hz,1H),3.84(d,J=10.8Hz,1H),3.28(d,J=7.2Hz,1H),3.21(d,J=9.6Hz,1H),3.16(d,J=3.0Hz,1H),2.43(d,J=10.2Hz,1H),.36(d,J=13.2Hz,1H),1.98(d,J=10.2Hz,1H),1.71(d,J=12.0Hz,1H),1.60(m,1H),1.57(d,J=11.4Hz,1H),1.39(dd,J=3.0Hz,3.6Hz,1H),1.32(d,J=13.2Hz,1H),1.16(m,3H),1.08(s,3H),0.77(m,1H)。
实施例37.11,12-二去氢-14-去氧基-(E)-15-(4-(二甲氨基)苯亚甲基)穿心莲内酯的制备:反应试剂14-去氧-11,12-去二氢穿心莲内酯和4-(二甲氨基)苯甲醛,用通式反应法C得目标产物;IR(KBr,cm-1):3446-3080,2927,1750,1646,1384,1201,1173,1053;1HNMR:δ7.62(m,1H),7.59(d,J=9.0Hz,2H),6.75(d,J=9.0Hz,2H),6.72(m,1H),6.21(s,1H),6.15(d,J=15.8Hz,1H),5.03(br,1H),4.73(m,1H),4.43(m,1H),4.13(br,1H),3.84(d,J=9.6Hz,1H),3.27(m,1H),3.22(m,1H),2.98(s,6H),2.38(t,J=10.8Hz,2H),1.97(m,1H),1.72(d,J=13.2Hz,1H),1.58(m,2H),1.40(dd,J=4.2Hz,3.6Hz,1H),1.34(d,J=13.2Hz,1H),1.17(m,2H),1.08(s,3H),0.77(s,3H)。
实施例38.11,12-二去氢-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂为8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯和2-氨基-7-甲基-7H-吡咯[2,3-d]嘧啶-5-甲醛,采用通式反应法C,得目标产物;1HNMR:δ8.42(br,2H),7.62(s,1H),6.72(m,1H),6.21(m,1H),6.06(d,J=15.6Hz,1H),4.85(d,J=1.8Hz,2H),4.15(m,1H),3.85(m,1H),3.33(m,2H),3.22(m,1H),2.63(d,J=3.0Hz,1H),2.16(d,J=10.2Hz,1H),1.97(m,1H),1.74(m,2H),1.58(m,2H),1.52(dd,J=3.6Hz,4.2Hz,1H),1.32(m,2H),1.08(s,3H),1.07(m,2H),0.89(s,3H)。
实施例39.11,12-二去氢-14-去氧-(E)-15-(呋喃-3-基亚甲基)穿心莲内酯的制备:反应试剂14-去氧-11,12-去二氢穿心莲内酯和和呋喃-2-甲醛,采用通式反应法C,获得目标产物;IR(KBr,cm-1):3390-3076,2923,2857,1750,1646,1555,1037,1017,952,880,803,753;1HNMR:δ7.77(d,J=4.2Hz,1H),7.59(s,1H),6.86(d,J=3.0Hz,1H),6.77(d,J=3.0Hz,1H),6.74(m,1H),6.21(d,J=3.6Hz,1H),6.12(d,J=15.6Hz,1H),4.91(m,2H),4.38(m,1H),3.23(m,1H),2.36(m,2H),1.94(m,1H),1.68(d,J=10.8Hz,1H),1.55(m,2H),1.32(m,3H),1.14(m,4H),1.05(s,3H),0.75(s,3H)。
实施例40.11,12-二去氢-14-去氧-(E)-15-(4-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)苯亚甲基)穿心莲内酯的制备:反应试剂为14-去氧-11,12-去二氢穿心莲内酯和和4-((3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)氧)苯甲醛,采用通式反应法C,得目标产物;IR(KBr,cm-1):3428-3079,2923,2857,1750,1646,1601,1511,1447,1384,1228,1088,1037,1017,952;1HNMR:δ7.70(d,J=9.0Hz,2H),7.07(d,J=9.0Hz,2H),6.81(m,1H),6.28(s,1H),6.24(d,J=15.6Hz,1H),5.16(d,J=8.4Hz,1H),5.03-4.96(m,2H),4.74(m,1H),4.66(m,1H),4.49(m,1H),4.44(m,1H),4.13(m,1H),3.92(m,1H),3.84(d,J=10.8Hz,1H),3.72-3.65(m,2H),3.30-3.21(m,3H),3.28(m,2H),3.16(m,1H),2.41(m,2H),1.98(m,1H),1.72(d,J=12.6Hz,1H),1.65-1.56(m,2H),1.45-1.30(m,1H),1.18(m,3H),1.11(s,3H),0.77(s,3H)。
实施例41.11,12-二去氢-14-去氧-(E)-15-(4-羟基-3-甲基-5-硝基苯亚甲基-8,17-环氧穿心莲内酯的制备:反应试剂为8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯和4-羟基-3甲氧基-5-硝基苯甲醛,采用通式反应法C,得目标产物;1HNMR:δ7.61(s,1H),7.65(s,1H),7.55(s,1H),6.31(m,1H),6.24(s,1H),6.16(d,J=15.6Hz,1H),5.01(d,J=4.8Hz,1H),4.14(q,J=2.4Hz,1H),3.85(d,J=2.4Hz,1H),3.80(s,3H),3.21(m,2H),2.97(s,1H),2.67(d,J=2.4Hz,1H),2.51(d,J=4.2Hz,1H),2.21(d,J=9.6Hz,1H),1.78(m,2H),1.62(m,2H),1.52(m,1H),1.33(m,2H),1.09(s,3H),0.94(d,J=4.2Hz,1H),0.91(s,3H)。
实施例42.3-(4-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)苯甲酰基)-11,12-二去氢-14-去氧穿心莲内酯的制备:反应试剂为14-去氧-11,12-去二氢穿心莲内酯和和4-((3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)氧)苯甲酸醛,采用通式反应法A,得目标产物;IR(KBr,cm-1):3414-2929,1741,1667,1232,1076,1040;1HNMR:δ7.90(d,J=8.4Hz,2H),7.67(m,1H),7.11(d,J=8.4Hz,2H),6.15(m,1H),5.88(m,1H),5.22(d,J=7.8Hz,1H),5.10(s,1H),5.02(s,1H),4.74(m,1H),4.66(d,J=7.2Hz,1H),4.49(m,1H),4.44(m,1H),4.13(m,1H),3.92(m,1H),3.84(d,J=10.8Hz,1H),3.69(m,2H),3.43(m,3H),3.28(m,2H),3.11(d,J=15.0Hz,1H),2.41(d,J=9.6Hz,1H),2.37(d,J=13.2Hz,1H),1.98(m,1H),1.72(d,J=12.6Hz,1H),1.58(m,2H),1.41(d,J=9.6Hz,1H),1.34(d,J=13.2Hz,1H),1.18(m,3H),1.11(s,3H),0.77(s,3H)。
实施例43.3-(4-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)苯甲酰基)-12-(4-吗啉基)-14-去氧穿心莲内酯的制备:反应试剂为14-去氧-12-吗啉基穿心莲内酯和4-((3,4,5-三羟基-6-羟甲基)四氢-2H-吡喃-2-基)氧)苯甲酸,采用通式反应法A,得目标产物;IR(KBr,cm-1):3430-3079,2926,2853,1741,1667,1614,1513,1474,1384,1304,1271,1232,1076,1036,891;1HNMR:δ7.91(d,J=9.0Hz,2H),7.56(m,1H),7.11(d,J=9.0Hz,2H),5.88(m,1H),5.22(m,2H),5.15(s,1H),5.08(s,1H),4.84(m,2H),4.43(d,J=12.0Hz,2H),4.37(d,J=11.4Hz,2H),3.94(m,1H),3.75(m,1H),3.72(q,J=7.8Hz,1H),3.67(d,J=10.8Hz,1H),3.6-3.44(m,6H),3.32(m,4H),3.22(m,2H),2.37(d,J=11.4Hz,1H),2.32(d,J=3.0Hz,2H),2.05(m,1H),2.02(m,1H),1.71-1.52(m,5H),1.23(m,2H),1.16(s,3H),1.08(m,1H),0.76(s,3H)。
实施例44.11,12-二去氢-14-去氧-(E)-55-(4-(二甲氨基)-2-羟基苯亚甲基)穿心莲内酯的制备:反应试剂为14-去氧-11,12-去二氢穿心莲内酯和4-(二甲氨基)-2-羟基苯甲醛,采用通式反应法C,获得目标化合物;1HNMR:δ7.62(s,1H),7.09(d,J=7.5Hz,1H),6.27(d,J=9.0Hz,2H),6.72(m,1H),6.21(s,1H),6.19(s,1H),5.03(br,1H),4.73(m,1H),4.43(m,1H),4.13(br,1H),3.84(d,J=9.6Hz,1H),3.27(m,1H),3.22(m,1H),3.06(s,6H),2.38(t,J=10.8Hz,2H),1.97(m,1H),1.72(d,J=13.2Hz,1H),1.62(m,2H),1.40(dd,J=4.2Hz,3.6Hz,1H),1.34(d,J=13.2Hz,1H),1.17(m,2H),1.08(s,3H),0.77(s,3H)。
实施例45.(E)-3-(2-(6a,10b-二甲基-8-亚甲基-3-(4-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)苯基)十氢-1H-萘并[2,1-d][1,3]二氧芑-7-基)亚乙基)-4-羟基二氢呋喃-2(3H)-酮的制备:穿心莲内酯1.0g(3mmol)溶于20ml甲苯中,加入4-((3,4,5-三乙氧-6-(乙氧甲基)四氢-2H-吡喃-2-基)氧基)苯甲醛1.3g(3mmol)回流反应7h,反应液用乙酸乙酯提取,经硅胶柱色谱分离得到目标产物;IR(KBr,cm-1):3428-2929,1741,1667,1615,1232,1076,1040;1HNMR:δ7.33(d,J=8.4Hz,2H),6.97(d,J=8.4Hz,2H),6.82(t,J=6.6Hz,1H),5.77(m,1H),5.48(m,1H),5.05(m,1H),4.93(d,J=7.2Hz,2H),4.62(d,J=7.2Hz,1H),4.43(m,2H),4.27(d,J=11.4Hz,1H),4.05(dd,J=2.4Hz,4.2Hz,1H),3.92(m,1H),3.66(m,2H),3.55(m,2H),3.44(m,4H),3.17(m,1H),2.02(m,3H),1.73(m,1H),1.61(m,2H),1.55(m,1H),1.37(m,1H),1.34(s,3H),1.20(m,2H),1.07(m,1H),0.86(s,3H)。
实施例46.11,12-二去氢-14-去氧-(E)-15-((2-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)亚甲基)穿心莲内酯的制备:反应试剂为14-去氧-11,12-去二氢穿心莲内酯和2-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-醛,用通式反应法C,得目标产物;1HNMR:δ8.90(s,1H),7.62(s,1H),7.08(s,1H),7.0(br,2H),6.72(m,1H),6.21(s,1H),6.19(s,1H),5.03(br,1H),4.73(s,1H),4.43(m,1H),4.13(br,1H),3.84(d,J=9.6Hz,1H),3.22(m,1H),3.60(s,3H),3.22(m,1H),2.38(t,J=10.8Hz,2H),1.97(m,1H),1.72(d,J=13.2Hz,1H),1.58(m,2H),1.40(dd,J=4.2Hz,3.6Hz,1H),1.34(d,J=13.2Hz,1H),1.17(m,2H),1.08(s,3H),0.77(s,3H)。
实施例47.3-(4-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)苯甲酰基)-12-硝甲基-14-去氧穿心莲内酯的制备:反应试剂为12-硝基亚甲基-14-去氧穿心莲内酯和4-((3,4,5-三乙氧-6-(乙氧甲基)四氢-2H-吡喃-2-基)氧基)苯甲酸,采用通式反应法A,获得目标化合物;IR(KBr,cm-1):3430-3081,2924,1754,1690,1607,1554,1511,1427,1374,1228,1088,1045;1HNMR:δ7.99(d,J=9.0Hz,2H),7.41(m,1H),7.12(d,J=9.0Hz,2H),5.68(m,1H),5.22(m,1H),4.75(m,1H),4.52(d,J=1.2Hz,1H),4.13(m,1H),3.85(d,J=3.0Hz,1H),3.44(m,4H),3.29(m,1H),3.23(m,1H),2.72(d,J=9.6Hz,2H),2.49(d,J=10.8Hz,2H),2.36(d,J=10.8Hz,2H),2.27(m,4H),2.26(s,3H),1.98(m,1H),1.72(d,J=2.4Hz,1H),1.52(m,3H),1.41(m,1H),1.33(m,1H),1.23(m,1H),1.16(s,3H),0.76(s,3H)。
实施例48.3-(4-(4-甲基哌嗪-1-基)-4-氧代丁酰基)-12-硝甲基-14-去氧穿心莲内酯的制备:反应试剂为12-硝基亚甲基-14-去氧穿心莲内酯和4-(4-甲基哌嗪-1-基)-4-氧代丁酸,采用通式反应法A,获得目标产物;IR(KBr,cm-1):3430-3078,2928,1795,1754,1739,1627,1445,1385,1291,1223,1174,1144,1086,1050;1HNMR:δ7.65(m,1H),4.87(m,2H),4.82(m,2H),4.75(m,2H),4.58(m,1H),3.78(d,J=10.8Hz,1H),3.44(m,4H),3.22(m,1H),3.19(m,1H),3.17(t,J=6Hz,1H),2.72(d,J=9.6Hz,2H),2.49(d,J=10.8Hz,2H),2.29(d,J=12.6Hz,1H),2.27(m,4H),2.16(s,3H),1.75(m,3H),1.57(m,4H),1.39(d,J=9.6Hz,1H),1.28(m,1H),1.06(m,1H),1.03(s,3H),0.87(m,1H),0.56(s,3H)。
实施例49.3-(4-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)苯甲酰基)-12-((2-氨基苯基)硫)-14-去氧穿心莲内酯的制备:反应试剂12-((2-氨基苯基)巯基)-14-去氧穿心莲内酯和4-((3,4,5-三乙氧-6-(乙氧甲基)四氢-2H-吡喃-2-基)氧基)苯甲酸,用通式反应法A,获得目标产物;IR(KBr,cm-1):3436-3362,3079,2929,2846,1741,1667,1614,1513,1473,1384,1304,1265,1130,1076,1040;1HNMR:δ9.56(s,1H),7.64(s,1H),7.53(d,J=9.0Hz,2H),7.09(d,J=9.0Hz,2H),7.04(s,1H),4.95-5.20(br,5H),4.75(m,1H),4.71(m,1H),4.51(m,1H),4.41(m,1H),4.19(m,1H),4.13(m,1H),3.93(m,2H),3.69(m,5H),2.50(m,3H),1.99-1.23(m,10H),1.18-0.87(m,7H),0.45(s,3H)。
实施例50.11,12-二去氢-14-去氧-(E)-15-(2-氨基-4-氧基-3H-嘧啶-5-基亚甲基)穿心莲内酯的制备:反应试剂14-去氧-11,12-去二氢穿心莲内酯和2-氨基-6-氧-1,6二氢嘧啶-5-醛,用通式反应法C得目标产物;1HNMR:δ8.42(br,2H),7.62(s,1H),6.72(m,1H),6.26(d,J=15.6Hz,1H),6.21(s,1H),6.19(s,1H),5.03(br,1H),4.73(m,1H),4.43(m,1H),4.13(br,1H),3.84(d,J=9.6Hz,1H),3.27(m,1H),3.22(m,1H),2.38(t,J=10.8Hz,2H),1.97(m,1H),1.72(d,J=13.2Hz,1H),1.58(m,2H),1.40(dd,J=4.2Hz,3.6Hz,1H),1.34(d,J=13.2Hz,1H),1.17(m,2H),1.08(s,3H),0.77(s,3H)。
实施例51.12-(二乙氧磷酰基)-14-去氧穿心莲内酯的制备:反应试剂为14-去氧穿心莲内酯和磷酸二乙酯,用通式反应法E,得目标产物;IR(KBr,cm-1):3436-3085,2951,2851,1734,1644,1445,1349,1296,1219,1069,1056,1011,990,837;1HNMR:δ6.65(m,1H),4.97(s,1H),4.94(m,1H),4.89(m,1H),4.54(m,1H),4.10(d,J=7.2Hz,1H),4.07(m,4H),3.80(d,J=6Hz,1H),3.22(d,J=4.8Hz,1H),3.17(d,J=5.4Hz,Hz,1H),2.33(d,J=13.2Hz,1H),1.96(m,1H),1.76(m,3H),1.61(m,3H),1.48(d,J=10.8Hz,1H),1.31(m,2H),1.29(s,3H),1.18(s,3H),1.08(m,2H),1.06(s,3H),0.61(s,3H)。
实施例52.(E)-3-(2-(6a,10b-二甲基-8-亚甲基-3-(3-硝基苯)十氢-1H-萘并[2,1-d][1,3]二氧芑-7-基)亚乙基)-4-羟基二氢呋喃-2(3H)-酮的制备:穿心莲内酯1.50g(4.7mmol)溶于20ml甲苯中,加入对甲苯磺酸0.27g(1.4mmol)和间硝基苯甲醛4.31g(28.5mmol),60℃反应10h,反应液用乙酸乙酯提取,经硅胶柱色谱分离得到目标产物;IR(KBr,cm-1):3449-3080,2922,2855,1755,1732,1670,1640,1527,1448,1382,1352,1217,1112,1019,998;1HNMR:δ8.24(d,J=7.8Hz,2H),7.87(d,J=7.8Hz,1H),6.70(t,J=7.2Hz,1H),6.66(s,1H),6.02(s,1H),4.95(s,1H),4.87(s,1H),4.68(m,1H),4.41(t,J=6.6Hz,1H),4.27(d,J=10.8Hz,1H),4.06(d,J=9.6Hz,1H),3.65(m,2H),2.37(d,J=12.6Hz,1H),2.01(m,1H),1.94(d,J=9.6Hz,2H),1.85(d,J=12.6Hz,1H),1.78(d,J=10.2Hz,2H),1.34(s,3H),1.28(m,5H),0.86(s,3H)。
实施例53.12-((3-氯苯基)氨基)-14-去氧穿心莲内酯的制备:反应试剂为(E)-5-氧-4-(2-(3,3,6a,10b-四甲基-8-甲烯基十氢-1H-萘并[2,1-d][1,3]二恶英-7-基)乙烯基)四氢呋喃-3-基甲磺酸酯和间氯苯胺,用通式反应法E,得目标产物;IR(KBr,cm-1):3394-3080,2970,2931,2868,1760,1640,1450,1384,1350,1221,1199,1077,1047,1034,945;1HNMR:δ7.65(m,1H),7.01(t,J=8.1Hz,1H),6.51(d,J=2.4Hz,1H),6.50(d,J=8.4Hz,1H),6.44(d,J=8.4Hz,1H),4.97(s,1H),4.94(s,1H),4.89(m,1H),4.54(m,1H),4.10(d,J=7.2Hz,1H),3.80(d,J=6Hz,1H),3.22(d,J=4.8Hz,1H),3.17(d,J=5.4Hz,1H),2.33(d,J=13.2Hz,1H),1.96(m,1H),1.76(m,3H),1.61(m,3H),1.48(d,J=10.8Hz,1H),1.31(m,2H),1.08(m,2H),1.06(s,3H),0.61(s,3H)。
实施例54.7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(Z)-15-(羧基(1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯和2-(4-(二甲氨基)苯基)-2-氧乙酸,采用通式反应法C,得目标产物;1HNMR:δ13.2(br,1H),11.1(s,1H),9.17(br,1H),8.05(s,1H),7.46(s,1H),7.41(m,1H),7.31(s,1H),7.04(m,3H),6.31(m,1H),6.06(d,J=15.6Hz,1H),5.02(s,1H),4.15(m,1H),3.96(br,3H),3.74(m,1H),3.33(m,2H),3.31(d,J=10.2Hz,1H),2.90(m,1H),2.63(d,J=3.0Hz,1H),3.86(s,3H),2.16(d,J=10.2Hz,1H),1.74(m,2H),1.52(dd,J=3.6Hz,4.2Hz,1H),1.43-1.30(m,2H),1.32(m,2H),1.08(s,3H),1.07(m,2H),0.89(s,3H)。
实施例55.12-((1r,3s,5R,7S)-3-羟基金刚烷-1-基)氨基)-14-去氧穿心莲内酯的制备:反应试剂为(E)-5-氧-4-(2-(3,3,6a,10b-四甲基-8-甲烯基十氢-1H-萘并[2,1-d][1,3]二恶英-7-基)乙烯基)四氢呋喃-3-基甲磺酸酯和3-氨基-1-金刚烷醇,采用通式反应法E,获得目标产物;IR(KBr,cm-1):3432-2947,2875,1753,1643,1452,1383,1260,1165,1082,1036,1021,917;1HNMR:δ7.70(m,1H),6.81(m,1H),5.15(m,1H),5.10(m,1H),5.05(m,1H),4.96(s,1H),4.74(m,1H),4.66(d,J=6.6Hz,1H),4.49(m,1H),4.43(m,1H),4.13(m,1H),3.92(m,1H),3.85(d,J=10.8Hz,1H),3.72-3.64(m,2H),3.43(m,4H),3.29(m,2H),3.22(d,J=10.2Hz,1H),3.16(m,1H),2.43(d,J=3.0Hz,1H),2.37(d,J=13.2Hz,1H),1.97(m,1H),1.72(d,J=12.6Hz,1H),1.60(m,2H),1.41(d,J=3.6Hz,1H),1.34(d,J=13.2Hz,2H),1.25-1.12(m,3H),1.08(s,3H),0.78(s,3H)。
实施例56.12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)穿心莲内酯的制备:反应试剂为14-去氧-12-(1-((4H咪唑-2-基)氨基)-1-氧代丙烷-2-基)氨基)穿心莲内酯和4-(二甲氨基)苯甲醛,采用通式反应法C,得目标产物;1HNMR:7.62(s,1H),7.59(d,J=9.0Hz,2H),7.04(d,J=7.5Hz,2H),6.75(d,J=9.0Hz,2H),6.72(m,1H),6.21(s,1H),6.19(s,1H),5.03(br,1H),4.73(s,1H),4.43(m,1H),4.13(br,1H),3.84(d,J=9.6Hz,1H),3.27(m,1H)3.74(m,1H),3.22(m,1H),2.98(m,7H),2.38(t,J=10.8Hz,2H),1.97(m,1H),1.72(d,J=13.2Hz,1H),1.58(m,2H),1.40(dd,J=4.2Hz,3.6Hz,1H),1.34(d,J=13.2Hz,1H),1.17(m,5H),1.08(s,3H),0.77(s,3H)。
实施例57.12-((1s,3s,5s)-1,3,5-三氮杂金刚烷-7-基氨基)-14-去氧穿心莲内酯的制备:反应试剂(E)-5-氧-4-(2-(3,3,6a,10b-四甲基-8-甲烯基十氢-1H-萘并[2,1-d][1,3]二恶英-7-基)乙烯基)四氢呋喃-3-基甲磺酸酯和7-氨基-1,3,5-三氮杂金刚烷,用通式反应法E得目标产物;IR(KBr,cm-1):3428-2933,1754,1644,1173,1151,1079,1038;1HNMR:δ7.75(m,1H),4.93(m,1H),4.85(m,1H),4.79(m,1H),4.51(d,J=10.8Hz,1H),4.13(d,J=4.8Hz,1H),3.81(m,2H),3.21(m,4H),3.09(m,3H),3.01(m,1H),2.95(m,2H),2.31(s,3H),1.97(m,3H),1.75-1.60(m,6H),1.33(m,2H),1.19(m,1H),1.16(m,1H),1.12(s,3H),1.09(s,3H),1.03(m,1H)。
实施例58.12-((1-(((1r,3s,5R,7S)-3-羟基金刚烷-1-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧穿心莲内酯的制备:反应试剂为(E)-5-氧-4-(2-(3,3,6a,10b-四甲基-8-甲烯基十氢-1H-萘并[2,1-d][1,3]二恶英-7-基)乙烯基)四氢呋喃-3-基甲磺酸酯和2-氨基-N-((1,3,5,7)-3-羟基金刚烷-1-基丙胺,用通式反应法E,得目标产物;IR(KBr,cm-1):3436-3421,2933,2871,1754,1677,1647,1450,1384,1331,1173,1151,1034cm-1;1HNMR:δ7.87(m,1H),6.74(s,1H),6.12(d,J=10.8Hz,1H),4.93(m,2H),4.78(d,J=12.6Hz,1H),4.73(d,J=10.8Hz,1H),3.82(m,2H),3.60(d,J=6.6Hz,2H),3.36(m,3H),3.10(m,4H),2.36(m,4H),1.97-1.21(m,16H),1.07(s,3H),0.93(m,1H),0.81(m,1H),0.77(m,1H),0.61(s,3H)。
实施例59.11,12-二去氢-14-去氧-(E)-15-((2-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯和2-氨基-7-甲基-7H-吡咯[2,3-d]嘧啶-5-甲醛,用通式反应法C,得目标产物;1HNMR:δ8.90(s,1H),7.62(s,1H),7.08(s,1H),7.0(m,1H),6.72(m,1H),6.06(d,J=15.6Hz,1H),5.03(br,1H),4.73(m,1H),4.43(m,1H),4.13(br,1H),3.84(d,J=9.6Hz,1H),3.22(m,1H),3.60(s,3H),3.31(d,J=10.2Hz,1H),3.22(m,1H),2.16(d,J=10.2Hz,1H),2.38(t,J=10.8Hz,2H),1.97(m,1H),1.72(d,J=13.2Hz,1H),1.58(m,2H),1.40(dd,J=4.2Hz,3.6Hz,1H),1.34(d,J=13.2Hz,1H),1.17(m,2H),1.08(s,3H),0.77(s,3H)。
实施例60.11,12-二去氢-14-去氧-(E)-15-(4-(二乙氨基)-2-羟基苯亚甲基)穿心莲内酯的制备:反应试剂为14-去氧-11,12-去二氢穿心莲内酯和4-(二乙胺基)水杨醛,用通式反应法C得目标产物;IR(KBr,cm-1):3426-2969,2931,2871,1721,1603,1557,1525,1452,1410,1376,1355,1272,1230,1147,1104,1078,1035,939;1HNMR:δ9.86(s,1H),7.77(d,J=9.0Hz,1H),7.62(s,1H),6.67(m,1H),6.45(s,1H),6.33(dd,J=2.4Hz,1.8Hz,1H),6.17(s,1H),6.14(s,1H),6.12(d,J=15.6Hz,1H),5,04(d,J=4.8Hz,1H),4.72(m,1H),4.43(m,1H),4.15(d,J=5.4Hz,1H),3.85(d,J=9.6Hz,1H),3.32(m,4H),3.27(m,1H),3.22(m,1H),2.36(t,J=9.6Hz,2H),1.97(m,1H),1.71(d,J=13.2Hz,1H),1.52(m,2H),1.38(dd,J=3.6Hz,4.2Hz,1H),1.34(d,J=13.8Hz,1H),1.17(d,J=13.8Hz,1H),1.09(m,6H),0.75(s,3H)。
实施例61.11,12-二去氢-14-去氧-(E)-15-(4-(4-甲基哌嗪-1-基)苯亚甲基)穿心莲内酯的制备:反应试剂为14-去氧-11,12-去二氢穿心莲内酯和4-(甲基吡嗪基)苯甲醛,用通式反应法C,得目标产物;IR(KBr,cm-1):A3411-3096,2936,2849,1748,1641,1577,1515,1448,1379,1344,1246,1188,1145,1038;1HNMR:δ7.64(s,1H),7.59(d,J=4.5Hz,2H),6.97(d,J=9.0Hz,2H),6.75(m,1H),6.22(s,1H),6.20(d,J=l5.6Hz,1H),5.05(m,2H),4.73(m,1H),4.43(m,1H),4.15(m,1H),3.84(d,J=10.8Hz,1H),3.29-3.22(m,6H),2.42-2.35(m,6H),2.20(s,3H),1.96(d,J=8.4Hz,1H),1.72(d,J=13.2Hz,1H),1.60-1.56(m,1H),1.39(d,J=4.2Hz,1H),1.33(d,J=13.8Hz,1H),1.17(m,2H),1.08(s,3H),0.77(s,3H)。
实施例62.12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯的制备:反应试剂为14-去氧-11,12-去二氢穿心莲内酯和2-(4-(二甲氨基)苯基)-2-氧乙酸,采用通式反应法C,得目标产物;IR(KBr,cm-1):3546-3210,2923,1750,1705,1647,1385,1205,1176,1053,1037;1HNMR:δ10.22(br,1H)7.22(s,1H),7.28(d,J=9.0Hz,2H),6.72(m,1H),6.26(d,J=15.6Hz,1H),6.19(s,1H),5.03(br,1H),4.85(d,J=1.8Hz,2H),3.85(m,1H),3.33(m,1H),3.27(m,1H),3.22(m,1H),3.02(s,6H),2.63(d,J=3.0Hz,1H),2.16(d,J=10.2Hz,1H),1.74(m,2H),1.58(m,2H),1.52(q,J=3.6Hz,1H),1.32(m,2H),1.08(s,3H),0.89(s,3H)。
实施例63.11,12-二去氢-14-去氧-(E)-15-((1-甲基-2-氧基-1,2,3,8a-四氢咪唑并[1,2-a]吡啶-6-基)亚甲基)穿心莲内酯的制备:反应试剂为14-去氧-11,12-去二氢穿心莲内酯和1-甲基-2-氧-1,2,3,8a-四氢咪唑并[1,2-a]吡啶-6-醛,用通式反应法C得目标产物;IR(KBr,cm-1):3435-3067,2923,1740,1705,1660,1647,1385,1205,1176,1053,1037;1HNMR:δ7.62(s,1H),7.22(s,1H),6.72(m,1H),6.41(d,J=11Hz,1H),6.26(d,J=15.6Hz,1H),6.19(s,1H),5.78(d,J=11Hz,1H),4.85(m,2H),4.73(m,1H),4.43(m,1H),4.13(br,1H),3.84(d,J=9.6Hz,1H),3.27(m,1H),3.51(s,3H),3.42(m,2H),3.22(m,1H),2.38(t,J=10.8Hz,2H),1.97(m,1H),1.72(d,J=13.2Hz,1H),1.58(m,2H),1.40(dd,J=4.2Hz,3.6Hz,1H),1.34(d,J=13.2Hz,1H),1.17(m,2H),1.08(s,3H),0.77(s,3H)。
实施例64.7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂为7-吗啉基-8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯和4-(甲基吡嗪基)苯甲醛,采用通式反应法C,获得目标化合物;1HNMR:8.07(s,2H),7.64(s,1H),6.75(m,1H),6.31(m,1H),6.06(d,J=15.6Hz,1H),4.73(m,1H),4.43(m,1H),4.15(m,1H),3.84(d,J=10.8Hz,1H),3.67(m,3H),2.41(m,1H),3.27-3.22(m,6H),2.86(m,4H),2.52-2.35(m,8H),2.20(s,3H),1.60-1.56(m,2H),1.39(q,J=4.2Hz,1H),1.33(d,J=13.8Hz,1H),1.17(m,2H),1.08(s,3H),0.77(s,3H)。
实施例65.11,12-二去氢-14-去氧-(E)-15-((2-(2-(羟甲基)吡咯烷-1-基)嘧啶-5-基)亚甲基)穿心莲内酯的制备:反应试剂为14-去氧-11,12-去二氢穿心莲内酯和2-(2-(羟甲基)吡咯-1-基)嘧啶-5-醛,采用通式反应法C,获得目标化合物;IR(KBr,cm-1):3392,2934,1754,1654,1558,1451,1376,1357,1211,1106,1080,1035,1043;1HNMR:δ7.62(s,1H),8.09(s,2H),6.72(m,1H),6.26(d,J=15.6Hz,1H),6.19(s,1H),5.03(br,1H),4.73(m,1H),4.43(m,1H),4.13(br,1H),3.84(d,J=9.6Hz,1H),3.45(m,2H),3.27(m,1H),3.22(m,1H),2.98(s,6H),2.85(m,2H),2.38(t,J=10.8Hz,2H),1.97(m,1H),1.72(d,J=13.2Hz,1H),1.58(m,6H),1.40(dd,J=4.2Hz,3.6Hz,1H),1.34(d,J=13.2Hz,1H),1.17(m,2H),1.08(s,3H),0.77(s,3H)。
实施例66.11,12-二去氢-14-去氧-(E)-15-(4-(二乙氨基(-2-羟基苯亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂为8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯和4-(二甲氨基)-2-羟基苯甲醛,采用通式反应法C,获得目标产物;IR(KBr,cm-1):3322-2934,1654,1558,1451,1350,1273,1100,1060,1035;1HNMR:δ9.86(s,1H),7.77(d,J=9.0Hz,1H),7.62(s,1H),6.67(m,1H),6.45(s,1H),6.33(m,1H),6.20(d,J=15.6Hz,1H),6.17(s,1H),6.14(s,1H),4.43(m,1H),4.15(d,J=5.4Hz,1H),3.85(d,J=9.6Hz,1H),3.32(m,5H),3.27(m,1H),2.63(m,1H),2.36(t,J=9.6Hz,2H),1.71(d,J=13.2Hz,2H),1.52(m,3H),1.38(dd,J=3.6Hz,4.2Hz,1H),1.34(d,J=13.8Hz,1H),1.17(d,J=13.8Hz,1H),1.09(m,9H),0.75(s,3H)。
实施例67.7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)15-(4-(二甲氨基-2-羟基苯亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂7-吗啉基-8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯和4-二甲氨基-2-羟基苯甲醛,采用通式反应法C,获得目标产物;1HNMR:δ7.61(s,1H),7.08(d,J=7.2Hz,1H),6.31(m,1H),6.28(d,J=7.2Hz,1H),6.24(s,1H),6.21(s,1H),6.16(d,J=15.6Hz,1H),5.01(d,J=4.8Hz,1H),4.14(q,J=2.4Hz,1H),3.85(d,J=2.4Hz,1H),3.67(m,4H),3.21(m,2H),2.98(s,6H),2.97(s,1H),2.88(m,1H),2.86(m,4H),2.67(d,J=2.4Hz,1H),2.51(d,J=4.2Hz,1H),2.21(d,J=9.6Hz,1H),1.78(m,2H),1.62(m,1H),1.33(m,2H),1.09(s,3H),0.94(d,J=4.2Hz,1H),0.91(s,3H)。
实施例68.11,12-二去氢-14-去氧-(E)-15-((1-甲基-2-氧基-1,2,3,8a-四氢咪唑并[1,2-a]吡啶-6-基)亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂为8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯和1-甲基-2-氧-1,2,3,8a-四氢咪唑[,2-a]-6-甲醛,用通式反应法C,获得目标产物;IR(KBr,cm-1):3435-3067,2923,1740,1660,1647,1385,1205,1176,1105,1037;1HNMR:δ7.22(s,1H),6.42(m,1H),6.41(d,J=11Hz,1H),6.31(m,1H),6.06(d,J=15.6Hz,1H),6.90(m,1H),5.78(d,J=11Hz,1H),5.02(br,1H),4.15(m,1H),3.85(m,1H),3.48(s,3H),3.41(m,4H),3.31(d,J=10.2Hz,1H),2.63(d,J=3.0Hz,1H),2.16(d,J=10.2Hz,1H),1.74(m,2H),1.58(m,2H),1.52(dd,J=3.6Hz,4.2Hz,1H),1.32(m,2H),1.08(s,3H),1.07(m,2H),0.89(s,3H)。
实施例69.11,12-二去氢-14-去氧-(E)-15-((2-(2-(羟甲基)吡咯烷-1-基)嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯和2-(2-(羟甲基)吡咯-1-基)嘧啶-5-甲醛,采用通式反应法C,得目标产物;IR(KBr,cm-1):3392,2934,1754,1644,1558,1451,1376,1357,1211,1116,1080,1043;1HNMR:δ8.05(s,2H),7.61(s,1H),6.72(m,1H),6.21(m,1H),6.19(s,1H),6.06(d,J=15.6,5.02(br,1H),4.85(d,J=1.8Hz,2H),4.15(m,1H),3.85(m,1H),3.33(m,2H),3.45(m,2H),3.31(d,J=10.2Hz,1H),2.85(m,2H),2.63(d,J=3.0Hz,1H),38(t,J=10.8Hz,2H),2.20(m,1H),2.16(d,J=10.2Hz,1H),1.74(m,2H),1.58(m,6H),1.52(dd,J=3.6Hz,4.2Hz,1H),1.40(dd,J=4.2Hz,3.6Hz,1H),1.34(m,1H),1.08(s,3H),1.07(m,2H),0.89(s,3H)。
实施例70.12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯的制备:反应试剂为8-环氧乙烷基-14-去氧-11,12-去二氢穿心莲内酯和2-(4-(二甲氨基)苯基)-2-氧乙酸,采用通式反应法C,获得目标化合物;IR(KBr,cm-1)3650-2900,2968-2810,1753,1720,1350,1273,1086;1HNMR:δ10.22(br,1H),7.28(d,J=9.0Hz,2H),7.22(s,1H),6.80(d,J=9.0Hz,2H),6.21(m,1H),6.19(d,J=15.6Hz,1H),5.03(br,1H),4.85(d,J=1.8Hz,2H),4.15(br,1H),3.85(m,1H),3.33(m,2H),3.27(m,1H),3.22(m,1H),3.02(s,6H),2.63(d,J=3.0Hz,1H),2.38(t,J=10.2Hz,2H),2.16(d,J=10.2Hz,1H),1.97(m,1H),1.52(dd,J=3.6Hz,4.2Hz,1H),1.08(s,3H),1.07(m,2H),0.89(s,3H)。
实施例71.11,12-二去氢-14-去氧-(E)-15-(4-(4-甲基哌嗪-1-基)苯亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂为8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯和4-(甲基吡嗪基)苯甲醛,采用通式反应法C得目标产物;IR(KBr,cm-1):3417-3083,2925,1745,1600,1452,1380,1324,1296,1242,1185,1145,1078,1038,1008,976,923,815;1HNMR:δ7.63(s,1H),7.60(d,J=9.0Hz,2H),6.98(d,J=9.0Hz,2H),6.33(m,1H),6.20(s,1H),6.17(d,J=15.6Hz,1H),5.01(d,J=4.8Hz,1H),4.14(q,J=3.0Hz,1H),3.85(q,J=2.4Hz,1H),3.21(m,4H),2.67(d,J=4.2Hz,1H),2.50(m,4H),2.27-2.20(m,4H),1.76(m,2H),1.59(m,3H),1.53(m,2H),1.33(dd,J=3.6Hz,2.4Hz,3H),1.14(s,1H),1.09(s,3H),0.92(s,3H)。
实施例72.7-(4-吗啉基)-11,12-二去氢-14-去氧-8,17-环氧穿心莲内酯的制备:反应试剂为7-吗啉基-8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯,通过脱水反应,得目标产物;IR(KBr,cm-1):3369,3079,2968-2810,1753,1454,1350,1336,1273,1120,1086,1009;1HNMR:δ7.61(m,1H),6.31(m,1H),6.06(d,J=15.6Hz,1H),5.02(s,1H),4.85(d,J=1.8Hz,2H),4.15(m,1H),3.85(m,1H),3.67(m,4H),3.33(m,2H),3.31(d,J=10.2Hz,1H),2.63(d,J=3.0Hz,1H),2.86(m,5H),2.16(d,J=10.2Hz,1H),1.74(m,2H),1.58(m,1H),1.52(dd,J=3.6Hz,4.2Hz,1H),1.32(m,1H),1.08(s,3H),1.07(m,2H),0.89(s,3H)。
实施例73.7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-((2-(2-(羟甲基)吡咯烷-1-基)嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂7-吗啉基-8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯和2-(2-(羟甲基)吡咯-1-基)嘧啶-5-甲醛,采用通式反应法C,得目标产物;1HNMR:δ8.08(s,2H),7.61(m,1H),6.31(m,1H),6.06(d,J=15.6Hz,1H),5.81(s,1H),5.02(s,1H),4.85(d,J=1.8Hz,2H),4.15(m,1H),3.85(m,1H),3.67(m,4H),3.33(m,2H),3.31(d,J=10.2Hz,1H),2.63(d,J=3.0Hz,1H),2.86-2.7(m,8H),2.16(d,J=10.2Hz,1H),1.74-1.63(m,4H),1.58-1.42(m,3H),1.52(dd,J=3.6Hz,4.2Hz,1H),1.32(m,1H),1.08(s,3H),1.07(m,2H),0.89(s,3H)。
实施例74.7-(4-吗啉基)-11,12-二去氢-14-去氧-(Z)-15-(羧基(4-(二甲氨基)苯基)亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂为7-吗啉基-8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯和2-(4-(二甲氨基)苯基)-2-氧乙酸,采用通式反应法C,得目标产物;IR(KBr,cm-1):3650-2900,2968-2810,1753,1720,1454,1350,1283,1273,1120,1086,1009;1HNMR:δ10.22(br,1H)7.22(s,1H),7.28(d,J=9.0Hz,2H),6.80(d,J=9.0Hz,2H),6.21(m,1H),6.19(d,J=15.6Hz,1H),5.03(br,1H),4.85(d,J=1.8Hz,2H),3.85(m,1H),3.67(m,4H),3.33(m,2H),3.27(m,1H),3.22(m,1H),3.02(s,6H),2.90(m,1H),2.86(m,4H),2.63(d,J=3.0Hz,1H),2.16(d,J=10.2Hz,1H),1.74(m,2H),1.52(dd,J=3.6Hz,4.2Hz,1H),1.32(m,2H),1.08(s,3H),0.89(s,3H)。
实施例75.7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-(4-(N-(2-(二甲氨基)乙基)甲脒基)苯亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂为7-吗啉基-8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯和N-(2-(二甲氨基)乙基)-4-甲脒基苯甲醛,采用通式反应法C,获得目标产物;IR(KBr,cm-1)3450-2910,2968-2810,2230,1753,1680,1454,1350,1283,1273,1120,1086,1009;1HNMR:δ10.22(br,1H),7.22(s,1H),7.28(d,J=9.0Hz,2H),6.80(d,J=9.0Hz,2H),6.21(m,1H),6.19(m,1H),6.19(d,J=15.6Hz,1H),5.81(m,1H),5.03(br,1H),4.85(d,J=1.8Hz,2H),3.85(m,1H),3.67(m,4H),3.33(m,2H),3.27(m,1H),3.22(m,1H),3.02(s,6H),2.98(t,J=7.2Hz,2H),2.90(m,1H),2.86(m,4H),2.63(d,J=3.0Hz,1H),2.51(t,J=7.2Hz,2H),2.16(d,J=10.2Hz,1H),1.74(m,2H),1.52(dd,J=3.6Hz,4.2Hz,1H),1.32(m,2H),1.08(s,3H),0.89(s,3H)。
实施例76.7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂为7-吗啉基-8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯和4-二甲氨基苯甲醛,用通式反应法C,得目标产物;IR(KBr,cm-1):3100-2750,1750,1646,1454,1384,1283,1201,1173,1120,1053,1009;1HNMR:δ7.62(s,1H),7.59(d,J=9.0Hz,2H),6.75(d,J=9.0Hz,2H),6.72(m,1H),6.31(m,1H),6.19(d,J=15.6Hz,1H),5.02(s,1H),4.85(d,J=1.8Hz,2H),4.15(m,1H),3.85(m,1H),3.67(m,4H),3.33(m,2H),3.31(d,J=10.2Hz,1H),3.02(d,6H),2.63(d,J=3.0Hz,1H),2.86(m,5H),2.16(d,J=10.2Hz,1H),1.74(m,2H),1.58(m,1H),1.52(dd,J=3.6Hz,4.2Hz,1H),1.32(m,1H),1.08(s,3H),0.89(s,3H)。
实施例77.11,12-二去氢-14-去氧-(E)-15-(4-(1H-咪唑-1-基)苯亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂为8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯和4-(1H-咪唑-1-基)苯甲醛,采用通式反应法C,获得目标化合物;IR(KBr,cm-1):370069-2800,1753,1640,1520,1450,1350,1233,1086;1HNMR:δ7.61(s,1H),7.57(d,J=9.0Hz,2H),7.47(d,J=7.0Hz,1H),7.32(d,J=9.0Hz,2H),7.17(d,J=7.0Hz,1H),7.15(s,1H),6.31(m,1H),6.24(s,1H),6.16(d,J=15.6Hz,1H),5.01(d,J=4.8Hz,1H),4.14(q,J=2.4Hz,1H),3.85(d,J=2.4Hz,1H),3.21(m,1H),2.97(s,1H),2.67(d,J=2.4Hz,1H),2.51(d,J=4.2Hz,1H),2.21(d,J=9.6Hz,1H),1.78(m,2H),1.62(m,2H),1.52(m,1H),1.33(m,2H),1.09(s,3H),0.94(d,J=4.2Hz,1H),0.91(s,3H)。
实施例78.11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)-8,17-环氧穿心莲内酯的制备:反应试剂为8-环氧乙烷基-14-脱氧-11,12-去二氢穿心莲内酯和4-二甲氨基-2-羟基苯甲醛,采用通式反应法C,获得目标产物;IR(KBr,cm-1):3369-3079,3021,2969,2831,1753,1350,1273,1604,1086;1HNMR:δ7.61(s,1H),7.08(d,J=7.2Hz,1H),6.31(m,1H),6.28(d,J=7.2Hz,1H),6.24(s,1H),6.21(s,1H),6.16(d,J=15.6Hz,1H),5.01(d,J=4.8Hz,1H),4.14(q,J=2.4Hz,1H),3.85(d,J=2.4Hz,1H),3.21(m,3H),2.98(s,6H),2.97(s,1H),2.67(d,J=2.4Hz,1H),2.51(d,J=4.2Hz,1H),2.21(d,J=9.6Hz,1H),1.78(m,2H),1.62(m,2H),1.52(m,1H),1.33(m,2H),1.09(s,3H),0.94(d,J=4.2Hz,1H),0.91(s,3H)。
实施例79.11,12-二去氢-14-去氧-(E)-15-(4-(1H-咪唑-1-基)苯亚甲基)穿心莲内酯的制备:反应试剂为14-脱氧-11,12-去二氢穿心莲内酯和4-(1H-咪唑-1-基)苯甲醛,采用通式反应法C得目标产物;IR(KBr,cm-1):3414,3082,1763,1640,1606,262,1187,1116,1080,1057;1HNMR:δ7.59(d,J=8.4Hz,1H),7.81(s,1H),7.76(d,J=8.4Hz,1H),7.71(m,2H),7.65(m,2H),7.12(s,1H),6.85(m,1H),6.28(d,J=15.6Hz,1H),5.08(s,1H),4.47(s,1H),4.43(s,1H),4.20(s,1H),3.84(d,J=10.8Hz,1H),1.96(d,J=10.8Hz,1H),1.98(s,1H),1.70(s,1H),1.63(m,2H),1.56(s,2H),1.36(m,2H),1.21(m,2H),1.09(s,3H),1.06(s,1H),0.92(s,1H),0.90(s,3H)。
实施例1-436见表1
表1实施例1-436
实施例437.注射液I(5毫克/5毫升)的制备
实施例待测物5.0克,乙醇(95%)600毫升,1,2-丙二醇600毫升和吐温(80)100毫升溶解,注射用水加至5000毫升的总量,与0.22微米膜过滤器过滤的解决方案和30分钟消毒,在100℃获得1000注射5毫克/5毫升的准备。
实施例438.注射液II(8毫克/5毫升)的制备
实施例待测物8.0克,二甲基亚砜50毫升,1,2-丙二醇100毫升和吐温80,100毫升溶解,注射用水加至5000毫升的总量,解决方案与0.22微米膜过滤过滤和消毒30分钟,在100℃获得1000准备注射8毫克/5毫升。
活性测定
实施例439.体外抗病毒实验
测试样品:实施例23,35,37,38,40,41,44,45,46,50,53,55,57,58,59,62,63,65,66,68,69,70,71,76,77,78,79,83,95,124和188
病毒株:由美国过敏和感染病研究所提供
方法:所测实施例,分别稀释至20毫克/毫升DMSO中,然后用含有50μg/ml的庆大霉素和2%胎牛血清(FBS)的培养基(MEM)溶液,按照LOG10倍数将100μg/ml浓度逐一稀释到0.1μg/ml,制成稀释液,将不同稀释浓度的稀释液分别添加到含有80-100%融合细胞的96孔板中的5孔中。每个稀释度的三个孔加感染病毒,其余两孔未受感染作为毒性对照。在3-5天培养期间内,感染复数(MOl),即感染时病毒与细胞数量的比值要尽可能的低,以便获得最大的细胞病变效应(CPE),取一个已知活性实施例作为阳性对照。当未经处理的病毒空白对照组达到最大的细胞病变效应(CPE)时,每孔进行显微镜读取数据。然后用中性红染料染色约2小时,然后除去每孔中上浮染料部分,然后用柠檬酸∶乙醇(50∶50)索伦森缓冲液提取已被均匀染色部分,然后用分光光度计测定光密度。用归一化法将病毒空白对照和测定数值光密度值转换为百分数(%)。经回归分析,得出所测实施例最大的细胞病变半数抑制浓度50%(EC50)。
测试结果:体外抗病毒测试结果见表2;测试结果表明本发明的实施例具有广泛地的抗病毒活性,实施例37,53,57和83分别对病毒B、E和F显示的EC50值为小于1微克/毫升;实施例23,35,38,40,41,44,45,46,50,55,58,59,62,63,65,66,68,69,70,71,76,77,78,79,95,124和188显示分别对多种病毒的EC50值为小于50微克/毫升。
表2.体外抗病毒测试结果(EC50值)
注:所有空白对照为二甲基亚砜;所有实施例的EC50浓度范围:0.1~100微克/毫升;-为浓度大于100微克/毫升,+为浓度小于100微克/毫升,++为浓度小于50微克/毫升,+++为浓度小于1微克/毫升;
A:登革热病毒,II型,NewGuineaC;B:Entrovirus-71病毒,Tainan/4643/98C:日本脑炎病毒,SA-14/V1;D:呼吸道合胞病毒,A2;E:裂谷热病病毒,MP-12;F:SARS冠状病毒,Urbani;G:风疹病毒,TO-336.;H:流感A病毒,H1N1,Califomia/07/2009;
I:乙型肝炎病毒,ayw1;J:丙型肝炎病毒CON1;K:人类副流感病毒I,H5N1;L:单纯疱疹病毒,II;M:人类乳头状瘤病,VIII;
N:单纯疱疹病毒,II;O:HIV-1病毒,B;P:人类鼻病毒,C;Q:人类疱疹病毒,II;
实施例440.体内抗肿瘤实验
测试样品:实施例1,6,11,14,22,25,31,35,36,37,39,40,45,46,55,57,58,71,76,95,108,124,184,188,210和246。
试验动物:昆明种健康小鼠,体重19~21g,雌雄各半分组,每组16只,其它组单性别使用,由北京军事医学科学院药物研究所动物中心提供。
瘤株:小鼠肉瘤S180为腹水型传代,来源于北京军事医学科学院药物研究所。
肿瘤动物模型的制备:无菌吸取生长7天的肉瘤S180传代小鼠腹水,用生理盐水分别稀释成密度为4×107cell/ml-1的肿瘤细胞悬液,每只小鼠0.2ml接种于右前肢腋窝皮下,接种后7天,在造模小鼠右腋下长出大小较为一致的肿瘤,即为造模成功,为保证接种细胞的活力,实验过程中,将细胞悬液置于含冰的烧杯中,整个造模过程于230分钟内完成。
方法:将接种后24h的小鼠随机分组,模型对照组和阳性药对照组,环磷酰胺(CTX)25mg/kg,各组动物每日给药1次,连续给药7天,停药次日处死瘤鼠,剥取瘤块,称量小鼠及瘤块重量,计算抑瘤率及体重变化。
结果:与空白组比较p<0.05为有显著性差异,因此具有明显抗肿瘤活性的是实施例6,31,36和124,p<0.00为有更显著性差异,上述实验数据表明:实施例71,188,210,108,39,1,11和57与对照组相比,具有非常显著差异,试验结果见表3。
表3对肉瘤S180生长的抑制作用(n=16)
注:空白对照:生理盐水;阳性对照:环磷酰胺;溶剂:二甲基亚砜;剂量范围:4-100毫克/公斤;P<0.01:相对于对照组显着差异;**P<0.001,与对照组相比,差异是非常显着,抑制率超过40%的样本有统计学显着优于对照组。
Claims (10)
1.选自下列的穿心莲内酯衍生物或类似物:3-(7-羟基-6-(羟甲基)-6,9a-二甲基-3a,4,5,5a,6,7,8,9,9a,9b-十氢-1H-环戊[a]萘-2-基)呋喃-2(5H)-酮、11,12-二去氢-14-去氧-8,17-环氧穿心莲内酯、7-羟基-11,12-二去氢-14-去氧穿心莲内酯、(E)-3-(2-(3,3,6a,10b-四甲基-8-亚甲基十氢-1H-萘并[2,1-d][1,3]二氧芑-7-基)乙烯基)呋喃-2(5H)-酮;(E)-2-(1,2-二羟乙基)-4-(6-羟基-5-(羟甲基)-5,8a-二甲基-2-亚甲基十氢萘-1-基)丁-2-烯酰基肼、15,15-二羟甲基-11,12-二去氢-14-去氧穿心莲内酯、12-硝甲基-14-去氧穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(1,3-二羟基丙烷-2-亚基)穿心莲内酯、(E)-4-羟基-3-(2-(9-羟基-3,3,6a,10b-四甲基-8-亚甲基十氢-1H-萘并[2,1-d][1,3]二氧芑-7-基)亚乙基)二氢呋喃-2(3H)-酮、(E)-4-羟基-3-(2-(3,3,6a,10b-四甲基十氢化螺[萘并[2,1-d][1,3]二氧芑-8,2′-环氧乙烷]-7-基)亚乙基)二氢呋喃-2(3H)-酮、11,12-二去氢-14-去氧-(E)-15-(呋喃-3-基亚甲基)穿心莲内酯、3,19-二乙酰基-11,12-二去氢-14-去氧穿心莲内酯、3,19-二甲酰基-11,12-去氢-14-去氧穿心莲内酯、7-(4-吗啉基)-11,12-二脱氢-14-去氧穿心莲内酯、12-(4-吗啉基)-14-去氧穿心莲内酯、3,19-二乙酰基-7-氧基-11,12-二去氢-14-去氧穿心莲内酯、3,19-二乙酰基-7-羟基-11,12-二去氢-14-去氧穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-8,17-环氧穿心莲内酯、(E)-(4-(2-(6-羟基-5-(羟甲基)-5,8a-二甲基-2-亚甲基十氢萘-1-基)乙烯基)-5-氧代四氢呋喃-3-基)磷酸二甲酯、12-((5-氨基-4H-1,2,4-三唑-3-基)硫)-14-去氧穿心莲内酯、3,19-二乙酰基-7-氯-11,12-二去氢-14-去氧穿心莲内酯、12-((2-氨基苯基)硫)-14-去氧穿心莲内酯、12-((3-氯苯基)氨基)-14-去氧穿心莲内酯、(E)-5-氧基-4-(2-(3,3,6a,10b-四甲基-8-亚甲基十氢-1H-萘并[2,1-d][1,3]二氧芑-7-基)亚乙基)四氢呋喃-3-基甲磺酸酯、12-(二乙氧磷酰基)-14-去氧穿心莲内酯、12-((4,6-二甲基嘧啶-2-基)硫)-14-去氧穿心莲内酯、12-((2-氨基苯基)硫)穿心莲内酯、3,14,19-三甲酰基-11,12-去氢-14-去氧穿心莲内酯、(E)-3-(2-(4b,10a-二甲基-2-亚甲基-7-(3-硝基苯)十四氢菲-1-基)亚乙基)-4-羟基二氢呋喃-2(3H)-酮、(E)-3-(2-(6a,10b-二甲基-8-亚甲基-3-(3-硝基苯)十氢-1H-萘并[2,1-d][1,3]二氧芑-7-基)亚乙基)-4-羟基二氢呋喃-2(3H)-酮、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧穿心莲内酯、12-((1s,3s,5s)-1,3,5-三氮杂金刚烷-7-基氨基)-14-去氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(4-胍基苯亚甲基)-8,17-环氧穿心莲内酯、3-(1-((1H-咪唑-2-基)氨基)-2-((6aR,9R,10R)-9-羟基-10-(羟甲基)-6a,10-二甲基-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙基)呋喃-2(5H)-酮、12-((1r,3s,5R,7S)-3-羟基金刚烷-1-基)氨基)-14-去氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-8,17-环氧穿心莲内酯、3,19-二乙酰基-7-(4-吗啉基)-11,12-二去氢-14-去氧穿心莲内酯、6-(羟甲基)-6,9a-二甲基-2-(2-氧基-2,5-d二氢呋喃-3-基)-2,4,5,5a,6,7,8,9,9a,9b-十氢-1H-环戊[a]萘-7-基-4-吗啉基-4-氧代丁酸酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-8,17-环氧穿心莲内酯、11,12-二去氢-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧穿心莲内酯、6-(羟甲基)-6,9a-二甲基-2-(2-氧基-2,5-d二氢呋喃-3-基)-2,4,5,5a,6,7,8,9,9a,9b-十氢-1H-环戊[a]萘-7-基-4-(4-甲基哌嗪-1-基)-4-氧代丁酸酯、(E)-5-((2-氨基嘧啶-5-基)亚甲基)-3-((E)-2-((6aR,9R,10R)-9-羟基-10-(羟甲基)-6a,10-二甲基-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)呋喃-2(5H)-酮、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)穿心莲内酯、11,12-二去氢-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-8,17-环氧穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)穿心莲内酯、2-氨基-5-((E)-(4-((E)-2-((6aR,9R,10R)-9-羟基-10-(羟甲基)-6a,10-二甲基-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)-6-基)乙烯基)-5-氧代呋喃-2(5H)-亚基)甲基)嘧啶-4(3H)-酮、12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、(E)-5-(4-(二甲氨基)苯亚甲基)-3-((E)-2-((6aR,9R,10R)-9-羟基-10-(羟甲基)-6a,10-二甲基-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)呋喃-2(5H)-酮、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(4-(N-(2-(二甲氨基)乙基)甲脒基)苯亚甲基)-8,17-环氧穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、(E)-3-((E)-2-((6aR,9R,10R)-9-羟基-10-(羟甲基)-6a,10-二甲基-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)-5-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)呋喃-2(5H)-酮、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)-8,17-环氧穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧基-(E)-15-(4-(二甲氨基)苯亚甲基)穿心莲内酯、(E)-5-(4-(二甲氨基)-2-羟基苯亚甲基)-3-((E)-2-((6aR,9R,10R)-9-羟基-10-(羟甲基)-6a,10-二甲基-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)呋喃-2(5H)-酮、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-(4-胍基苯亚甲基)穿心莲内酯、12-(2-吡啶-2-基)氨基)-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)穿心莲内酯、(E)-5-(4-(4H-咪唑-2-基)苯亚甲基)-3-((E)-2-((6aR,9R,10R)-9-羟基-10-(羟甲基)-6a,10-二甲基-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)呋喃-2(5H)-酮、2-((2-((6aR,9R,10R)-9-羟基-10-(羟甲基)-6a,10-二甲基-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)-1-(2-氧基-2,5-二氢呋喃-3-基)乙基)氨基)-N-(4H-咪唑-2-基)丙酰胺、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)穿心莲内酯、12-((1-(((1r,3s,5R,7S)-3-羟基金刚烷-1-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-胍基苯亚甲基)穿心莲内酯、7-(4-吗啉基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧穿心莲内酯、3-((E)-2-((6aR,9R,10R)-10-(羟甲基)-6a,10-二甲基-9-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)呋喃-2(5H)-酮、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)亚甲基)穿心莲内酯、3-(4-(4-甲基哌嗪-1-基)-4-氧代丁酰基)-12-硝甲基-14-去氧穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-(4-胍基苯亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧基穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)-8,17-环氧穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)亚甲基)穿心莲内酯、(E)-5-((2-氨基-4-羟基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)亚甲基)-3-((E)-2-((6aR,9R,10R)-9-羟基-10-(羟甲基)-6a,10-二甲基-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)呋喃-2(5H)-酮、(E)-5-((2-氨基-6-羟基-9-甲基-9H-嘌呤-8-基)亚甲基)-3-((E)-2-((6aR,9R,10R)-9-羟基-10-(羟甲基)-6a,10-二甲基-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)呋喃-2(5H)-酮、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-胍基苯亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基-9-甲基-6-氧基-6,9-二氢-1H-嘌呤-8-基)亚甲基)穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-((4-亚氨基-1-甲基-6-氧基-4,5,6,7-四氢-1H-吡唑并[3,4-d]吡啶-3-基)亚甲基)穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-(2-吗啉基嘧啶-5-基亚甲基)穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-8,17-环氧穿心莲内酯、(E)-3-((E)-2-((6aR,9R,10R)-9-羟基-10-(羟甲基)-6a,10-二甲基-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)-5-(4-(4-甲基哌嗪-1-基)苯亚甲基)呋喃-2(5H)-酮、(E)-3-((E)-2-((6aR,9R,10R)-9-羟基-10-(羟甲基)-6a,10-二甲基-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)-5-(4-(2-(羟甲基)吡咯烷-1-基)苯亚甲基)呋喃-2(5H)-酮、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-8,17-环氧穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基-9-甲基-6-氧基-6,9-二氢-1H-嘌呤-8-基)亚甲基)穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((4-亚氨基-1-甲基-6-氧基-4,5,6,7-四氢-1H-吡唑并[3,4-d]吡啶-3-基)亚甲基)穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(2-吗啉基嘧啶-5-基亚甲基)穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-((2-(2-(羟甲基)吡咯烷-1-基)嘧啶-5-基)亚甲基)穿心莲内酯、12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)穿心莲内酯、12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基-9-甲基-6-氧基-6,9-二氢-1H-嘌呤-8-基)亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-((4-亚氨基-1-甲基-6-氧基-4,5,6,7-四氢-1H-吡唑并[3,4-d]吡啶-3-基)亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-(2-吗啉基嘧啶-5-基亚甲基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、3-(4-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)苯甲酰基)-11,12-二去氢-14-去氧穿心莲内酯、6-(羟甲基)-6,9a-二甲基-2-(2-氧基-2,5d-二氢呋喃-3-基)-2,4,5,5a,6,7,8,9,9a,9b-十氢-1H-环戊[a]萘-7-基-4-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)苯甲酸酯、(Z)-2-(4-(二甲氨基)苯基)-2-(4-((E)-2-((6aR,9R,10R)-9-羟基-10-(羟甲基)-6a,10-二甲基-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)呋喃-2(5H)-亚基)醋酸乙酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基-6-氧基-1,6-二氢嘧啶-5-基)亚甲基)穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-(2-(羟甲基)吡咯烷-1-基)嘧啶-5-基)亚甲基)穿心莲内酯、(E)-3-(2-(6a,10b-二甲基-8-亚甲基-3-(4-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)苯基)十氢-1H-萘并[2,1-d][1,3]二氧芑-7-基)亚乙基)-4-羟基二氢呋喃-2(3H)-酮、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基-9-甲基-6-氧基-6,9-二氢-1H-嘌呤-8-基)亚甲基)-8,17-环氧穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((4-亚氨基-1-甲基-6-氧基-4,5,6,7-四氢-1H-吡唑并[3,4-d]吡啶-3-基)亚甲基)-8,17-环氧穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(2-吗啉基嘧啶-5-基亚甲基)-8,17-环氧穿心莲内酯、12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-(4-(N-(2-(二甲氨基)乙基)甲脒基)苯亚甲基)穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-((2-(2-(羟甲基)吡咯烷-1-基)嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)-8,17-环氧穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(N-(2-(二甲氨基)乙基)甲脒基)苯亚甲基)穿心莲内酯、12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(4-胍基苯亚甲基)穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-((E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基-6-氧基-1,6-二氢嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-(2-(羟甲基)吡咯烷-1-基)嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)穿心莲内酯、12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-(4-(N-(2-(二甲氨基)乙基)甲脒基)苯亚甲基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、7,12-双((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧穿心莲内酯、3-(4-(4-甲基哌嗪-1-基)-4-氧代丁酰基)-12-((2-氨基苯基)硫)-14-去氧穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)亚甲基)穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧基-(E)-15-(4-(二甲氨基)苯亚甲基)穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(N-(2-(二甲氨基)乙基)甲脒基)苯亚甲基)-8,17-环氧穿心莲内酯、12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(4-胍基苯亚甲基)-8,17-环氧穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-((E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)-8,17-环氧穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-(4-(4H-咪唑-2-基)苯亚甲基)穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)-8,17-环氧穿心莲内酯、12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)-8,17-环氧穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)穿心莲内酯、7,12-双((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-8,17-环氧穿心莲内酯、3-(1-((1H-咪唑-2-基)氨基)-2-((6aR,9R,10R)-10-(羟甲基)-6a,10-二甲基-9-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙基)呋喃-2(5H)-酮、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-胍基苯亚甲基)穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)-8,17-环氧穿心莲内酯、3-(4-(4-甲基哌嗪-1-基)-4-氧代丁酰基)-12-((2-氨基苯基)硫)穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基-9-甲基-6-氧基-6,9-二氢-1H-嘌呤-8-基)亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-((4-亚氨基-1-甲基-6-氧基-4,5,6,7-四氢-1H-吡唑并[3,4-d]吡啶-3-基)亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(2-吗啉基嘧啶-5-基亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-(4-(4H-咪唑-2-基)苯亚甲基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基-4-羟基-7-甲基-7H-吡咯[2,3-d]嘧啶-5-基)亚甲基)穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基-6-羟基-9-甲基-9H-嘌呤-8-基)亚甲基)穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((4-亚氨基-1-甲基-6-氧基-4,5,6,7-四氢-1H-吡唑并[3,4-d]吡啶-3-基)亚甲基)穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-胍基苯亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-((2-(2-(羟甲基)吡咯烷-1-基)嘧啶-5-基)亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)-8,17-环氧穿心莲内酯、3-(4-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)苯甲酰基)-12-硝甲基-14-去氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基-9-甲基-6-氧基-6,9-二氢-1H-嘌呤-8-基)亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-((4-亚氨基-1-甲基-6-氧基-4,5,6,7-四氢-1H-吡唑并[3,4-d]吡啶-3-基)亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(2-吗啉基嘧啶-5-基亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、(E)-5-((2-氨基嘧啶-5-基)亚甲基)-3-((E)-2-((6aR,9R,10R)-10-(羟甲基)-6a,10-二甲基-9-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)呋喃-2(5H)-酮、12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-(4-(4-甲基哌嗪-1-基)苯亚甲基)穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-(4-(2-(羟甲基)吡咯烷-1-基)苯亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基-4-羟基-7-甲基-7H-吡咯[2,3-d]嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-((2-氨基-6-羟基-9-甲基-9H-嘌呤-8-基)亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(4-(N-(2-(二甲氨基)乙基)甲脒基)苯亚甲基)穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基-9-甲基-6-氧基-6,9-二氢-1H-嘌呤-8-基)亚甲基)穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(2-吗啉基嘧啶-5-基亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-((2-(2-(羟甲基)吡咯烷-1-基)嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、7-(4-吗啉基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)穿心莲内酯、2-氨基-5-((E)-(4-((E)-2-((6aR,9R,10R)-10-(羟甲基)-6a,10-二甲基-9-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)-5-氧代呋喃-2(5H)-亚基)甲基)嘧啶-4(3H)-酮、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-(4-(4-甲基哌嗪-1-基)苯亚甲基)-8,17-环氧穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-(4-(2-(羟甲基)吡咯烷-1-基)苯亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(4-(N-(2-(二甲氨基)乙基)甲脒基)苯亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-(2-(羟甲基)吡咯烷-1-基)嘧啶-5-基)亚甲基)穿心莲内酯、3-(4-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)苯甲酰基)-12-(4-吗啉基)-14-去氧穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基-9-甲基-6-氧基-6,9-二氢-1H-嘌呤-8-基)亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((4-亚氨基-1-甲基-6-氧基-4,5,6,7-四氢-1H-吡唑并[3,4-d]吡啶-3-基)亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(2-吗啉基嘧啶-5-基亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、(E)-5-(4-(二甲氨基)苯亚甲基)-3-((E)-2-((6aR,9R,10R)-10-(羟甲基)-6a,10-二甲基-9-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)呋喃-2(5H)-酮、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(N-(2-(二甲氨基)乙基)甲脒基)苯亚甲基)穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧基-(E)-15-(4-(二甲氨基)苯亚甲基)穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、(E)-3-((E)-2-((6aR,9R,10R)-10-(羟甲基)-6a,10-二甲基-9-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)-5-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)呋喃-2(5H)-酮、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-(2-(羟甲基)吡咯烷-1-基)嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)穿心莲内酯、7-(4-吗啉基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)穿心莲内酯、7-(4-吗啉基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)-8,17-环氧穿心莲内酯、(E)-5-(4-(二甲氨基)-2-羟基苯亚甲基)-3-((E)-2-((6aR,9R,10R)-10-(羟甲基)-6a,10-二甲基-9-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)呋喃-2(5H)-酮、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-胍基苯亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)穿心莲内酯、(E)-5-(4-(4H-咪唑-2-基)苯亚甲基)-3-((E)-2-((6aR,9R,10R)-10-(羟甲基)-6a,10-二甲基-9-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)呋喃-2(5H)-酮、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(N-(2-(二甲氨基)乙基)甲脒基)苯亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)穿心莲内酯、7-(4-吗啉基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)-8,17-环氧穿心莲内酯、N1-((5R,7R)-1,3-二氮杂金刚烷-6-基)-N3-(4-((E)-(4-((E)-2-((6aR,9R,10R)-9-羟基-10-(羟甲基)-6a,10-二甲基-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)-5-氧代呋喃-2(5H)-亚基)甲基)苯基)丙二酰胺、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)穿心莲内酯、3-(4-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)苯甲酰基)-12-((2-氨基苯基)硫)-14-去氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-胍基苯亚甲基)-8,17-环氧穿心莲内酯、12-((1-((1H-咪唑-2-基)氨基)-14-去氧-(E)-15-(4-(3-((5S,7S)-1,3-二氮杂金刚烷-6-基氨基)-3-氧代丙酰氨基)苯亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-(4-(3-((5S,7S)-1,3-二氮杂金刚烷-6-基氨基)-3-氧代丙酰氨基)苯亚甲基)穿心莲内酯、7,12-双((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)-8,17-环氧穿心莲内酯、(E)-5-((2-氨基-4-羟基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)亚甲基)-3-((E)-2-((6aR,9R,10R)-10-(羟甲基)-6a,10-二甲基-9-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)呋喃-2(5H)-酮、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)穿心莲内酯、(E)-5-((2-氨基-6-羟基-9-甲基-9H-嘌呤-8-基)亚甲基)-3-((E)-2-((6aR,9R,10R)-10-(羟甲基)-6a,10-二甲基-9-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)呋喃-2(5H)-酮、7-(4-吗啉基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基-9-甲基-6-氧基-6,9-二氢-1H-嘌呤-8-基)亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((4-亚氨基-1-甲基-6-氧基-4,5,6,7-四氢-1H-吡唑并[3,4-d]吡啶-3-基)亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(2-吗啉基嘧啶-5-基亚甲基)穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、12-((1-((1H-咪唑-2-基)氨基)-14-去氧-(E)-15-(4-(3-((5S,7S)-1,3-二氮杂金刚烷-6-基氨基)-3-氧代丙酰氨基)苯亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-(4-(3-((5S,7S)-1,3-二氮杂金刚烷-6-基氨基)-3-氧代丙酰氨基)苯亚甲基)-8,17-环氧穿心莲内酯、7,12-双((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)穿心莲内酯、(E)-3-((E)-2-((6aR,9R,10R)-10-(羟甲基)-6a,10-二甲基-9-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)-5-(4-(4-甲基哌嗪-1-基)苯亚甲基)呋喃-2(5H)-酮、7,12-双((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、(E)-3-((E)-2-((6aR,9R,10R)-10-(羟甲基)-6a,10-二甲基-9-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)-5-(4-(2-(羟甲基)吡咯烷-1-基)苯亚甲基)呋喃-2(5H)-酮、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-(2-(羟甲基)吡咯烷-1-基)嘧啶-5-基)亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-氨基-9-甲基-6-氧基-6,9-二氢-1H-嘌呤-8-基)亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((4-亚氨基-1-甲基-6-氧基-4,5,6,7-四氢-1H-吡唑并[3,4-d]吡啶-3-基)亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(2-吗啉基嘧啶-5-基亚甲基)-8,17-环氧穿心莲内酯、7,12-双((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)穿心莲内酯、7-(4-吗啉基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、7,12-双((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、(Z)-2-(4-(二甲氨基)苯基)-2-(4-((E)-2-((6aR,9R,10R)-10-(羟甲基)-6a,10-二甲基-9-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙烯基)-5-氧代呋喃-2(5H)-亚基)醋酸乙酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(N-(2-(二甲氨基)乙基)甲脒基)苯亚甲基)穿心莲内酯、7,12-双((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-(2-(羟甲基)吡咯烷-1-基)嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)穿心莲内酯、7,12-双((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(4-(N-(2-(二甲氨基)乙基)甲脒基)苯亚甲基)-8,17-环氧穿心莲内酯、7,12-双((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(4-(3-((5S,7S)-1,3-二氮杂金刚烷-6-基氨基)-3-氧代丙酰氨基)苯亚甲基)穿心莲内酯、12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(4-(3-((5S,7S)-1,3-二氮杂金刚烷-6-基氨基)-3-氧代丙酰氨基)苯亚甲基)穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(4-(3-((5S,7S)-1,3-二氮杂金刚烷-6-基氨基)-3-氧代丙酰氨基)苯亚甲基)穿心莲内酯、7,12-双((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-(4-(3-((5S,7S)-1,3-二氮杂金刚烷-6-基氨基)-3-氧代丙酰氨基)苯亚甲基)穿心莲内酯、N1-(4-((E)-(4-(1-((1H-咪唑-2-基)氨基)-2-((6aR,9R,10R)-9-羟基-10-(羟甲基)-6a,10-二甲基-5,5a,6,6a,7,8,9,10,10a,11-十氢苯并[g]咪唑[2,1-b]喹唑啉-6-基)乙基)-5-氧代呋喃-2(5H)-亚基)甲基)苯基)-N3-((1s,5R,7S)-1,3-三氮杂金刚烷-6-基)丙二酰胺、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(4-(3-((5S,7S)-1,3-二氮杂金刚烷-6-基氨基)-3-氧代丙酰氨基)苯亚甲基)-8,17-环氧穿心莲内酯、12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(E)-15-(4-(3-((5S,7S)-1,3-二氮杂金刚烷-6-基氨基)-3-氧代丙酰氨基)苯亚甲基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-(4-(3-((5S,7S)-1,3-二氮杂金刚烷-6-基氨基)-3-氧代丙酰氨基)苯亚甲基)-8,17-环氧穿心莲内酯、7,12-双((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、3-(3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)-11,12-二去氢-14-去氧-(E)-15-(4-(3-((5S,7S)-1,3-二氮杂金刚烷-6-基氨基)-3-氧代丙酰氨基)苯亚甲基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(Z)-15-(1-(2-氨基嘧啶-5-基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)穿心莲内酯、7-(N-(1-吗啉基-1-氧代丙-2-基)氨基)-12-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-14-去氧-(Z)-15-(1-(4-二甲氨基)苯基)-2-乙氧基-2-氧代亚乙基)-8,17-环氧穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(4-(二乙氨基)-2-羟基苯亚甲基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(4-(4-甲基哌嗪-1-基)苯亚甲基)穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(Z)-15-(羧基(4-(二甲氨基)苯基)亚甲基)-8,17-环氧穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(Z)-15-(羧基(4-(二甲氨基)苯基)亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)亚甲基)穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(Z)-15-(羧基(1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)-8,17-环氧穿心莲内酯、7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-11,12-二去氢-14-去氧-(E)-15-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯和7-((2-((4H-咪唑-2-基)氨基)-1-氧代丙-2-基)氨基)-12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-((2-(4-甲基哌嗪-1-基)嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯,或立体异构体、其制药可接受的盐。
2.根据权利要求1的穿心莲内酯衍生物和类似物,为其无机酸盐、有机酸盐或复盐。
3.一种药物组合物,包含根据权利了要求1或2的穿心莲内酯衍生物和类似物,及其制药可接受的赋形剂或载体。
4.根据权利要求1或2所述的穿心莲内酯衍生物和类似物在制备治疗、预防或减缓病毒、癌症的药物中的用途。
5.选自下列的穿心莲内酯衍生物和类似物在制备治疗、预防或减缓病毒的药物中的应用:11,12-二去氢-14-去氧-15-(丙烷-2-亚基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(2-氨基-4-氧基-3H-嘧啶-5-基亚甲基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-((2-氨基嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(2,4-二氟苯基亚甲基)穿心莲内酯、11,12-二去氢-14-去氧基-(E)-15-(4-(二甲氨基)苯亚甲基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)-8,17-环氧穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)穿心莲内酯、7-(4-吗啉基)-11,12-二去氢-14-去氧-(E)-15-(2-氨基-5-氧基-3H-嘧啶-5-基亚甲基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(4-胍基苯亚甲基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)苯亚甲基)-8,17-环氧穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(2,4-二氯苯基亚基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-((1-甲基-1H-苯并[d]咪唑-5-基)亚甲基)-8,17-环氧穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-((2-氨基-7-甲基-7H-吡咯并[2,3-d]嘧啶-5-基)亚甲基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(4-(二甲氨基)-2-羟基苯亚甲基)-8,17-环氧穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-((2-氨基-9-甲基-6-氧基-6,9-二氢-1H-嘌呤-8-基)亚甲基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-((4-亚氨基-1-甲基-6-氧基-4,5,6,7-四氢-1H-吡唑并[3,4-d]吡啶-3-基)亚甲基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15(2-吗啉基嘧啶-5-基亚甲基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-((2-(2-(羟甲基)吡咯烷-1-基)嘧啶-5-基)亚甲基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-((2-氨基-9-甲基-6-氧基-6,9-二氢-1H-嘌呤-8-基)亚甲基)-8,17-环氧穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-((4-亚氨基-1-甲基-6-氧基-4,5,6,7-四氢-1H-吡唑并[3,4-d]吡啶-3-基)亚甲基)-8,17-环氧穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(2-吗啉基嘧啶-5-基亚甲基)-8,17-环氧穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(4-(N-(2-(二甲氨基)乙基)甲脒基)苯亚甲基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-((2-(2-(羟甲基)吡咯烷-1-基)嘧啶-5-基)亚甲基)-8,17-环氧穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(4-((3,4,5-三羟基-6-(羟甲基)四氢-2H-吡喃-2-基)氧基)苯亚甲基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(4-(3-((5S,7S)-1,3-二氮杂金刚烷-6-基氨基)-3-氧代丙酰氨基)苯亚甲基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(4-(3-((5S,7S)-1,3-二氮杂金刚烷-6-基氨基)-3-氧代丙酰氨基)苯亚甲基)-8,17-环氧穿心莲内酯、12-(2-(吡啶-2-基)氨基)-14-去氧-(E)-15-(1-甲基-2-(乙氧羰基)-3-氧基-1,2,3,8a-四氢咪唑并[1,2-a]吡啶)-8,17-环氧穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(4-(1H-咪唑-1-基)苯亚甲基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(4-(1H-咪唑-1-基)苯亚甲基)-8,17-环氧穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-((1-甲基-2-氧基-1,2,3,8a-四氢咪唑并[1,2-a]吡啶-6-基)亚甲基)-8,17-环氧穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(4-羟基-3-甲基-5-硝基苯亚甲基)穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(4-(二乙氨基)-2-羟基苯亚甲基)-8,17-环氧穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(4-羟基-3-甲基-5-硝基苯亚甲基)-8,17-环氧穿心莲内酯、11,12-二去氢-14-去氧-(E)-15-(4-(4-甲基哌嗪-1-基)苯亚甲基)-8,17-环氧穿心莲内酯。
6.根据权利要求4或5的用途,其中病毒选自:托加病毒、逆转录病毒、腺病毒、单纯疱疹病毒、水痘带状疱疹病毒、手足口病毒、EB病毒、人类巨细胞病毒、人类疱疹病毒8型、人类乳头状瘤病毒、BK病毒、JC病毒、天花病毒、人类II型博卡病毒、细小病毒、人类星状病毒、诺瓦克病毒、柯萨奇病毒、肝炎病毒、脊髓灰质炎病毒、鼻病毒、急性呼吸道综合征病毒、黄热病病毒、登革热病毒、西尼罗河病毒、风疹病毒、流感病毒、胡宁病毒、拉沙病毒、萨比亚病毒、克里米亚病毒、刚果出血热病毒、埃博拉病毒、马尔堡病毒、麻疹病毒、腮腺炎病毒、副流感病毒、呼吸道合胞病毒、人类偏肺病毒、狂犬病毒;
所述病毒导致的疾病选自:艾滋病、与艾滋病、艾滋病相关的恶性肿瘤的皮肤损伤、甲病毒引起脑炎、节肢动物传播的病毒性脑炎、登革热、东部马脑炎、感染埃博拉病毒感染、埃可病毒感染、病毒相关恶性肿瘤、丝状病毒感染、黄病毒感染、德国麻疹、出血热、肾综合征、疱疹病毒感染、人类乳头状瘤病毒感染、日本脑炎、卡波济氏肉瘤、拉沙热、淋巴细胞性脉络丛脑膜炎、传染性软疣、墨累河谷脑炎、诺沃克病毒有关的腹泻、正粘病毒感染、副流感病毒感染、副粘病毒感染、细小病毒B19感染、小核糖核酸病毒感染、轮状病毒腹泻、痘病毒感染、狂犬病、呼吸道病毒感染、麻疹、花、圣路易斯脑炎、蜱传脑炎、天花、委内瑞拉马脑炎、白血病和淋巴瘤的病毒感染、西部马脑炎、西尼罗河病毒病败血症、感染性心内膜炎、T细胞白血病、淋巴瘤、亚天花、安第斯山脉的病毒感染、星状病毒感染、禽脑脊髓炎病毒感染、禽流感病毒感染、迪布焦埃博拉病毒感染、昌迪普尔病毒感染、奎瓦病毒感染、德尔日的病、博尔纳病、博恩霍尔姆疾病、牛腺病毒感染、冠状病毒的感染、牛流行发热、牛细小病毒感染、牛病毒性腹泻、猫流感、宫颈上皮内瘤样病变病毒感染、鸡传染性贫血病毒感染、水痘、普通感冒、牛痘、柯萨奇病毒感染、蟋蟀麻痹病毒感染、埃博拉病毒感染、疫情关节炎、疣状表皮发育不良、猫白血病病毒感染、手足口疾病、生殖器疣、甲型肝炎、乙型肝炎、丙型肝炎、疹病毒性脑炎、疹病毒性脑膜炎、疱疹性角结膜炎、HPV阳性口咽癌、人类巨细胞病毒感染、人类呼吸道合胞病毒感染、传染性胰脏坏死、库京病毒感染、白血病、单核细胞增多症、腮腺炎、流行性乙型脑炎病毒感染、多发性粘液瘤、猪腺病毒感染、统淋巴瘤、视网膜坏死、风疹全脑炎、罗斯河热、轮状病毒感染、舒普乳头状瘤病毒感染、猴泡沫病毒感染、苏丹病毒感染、猪水泡病、热带痉挛性截瘫、水痘带状疱疹病毒感染、扁平疣、病毒性关节炎、病毒性出血性败血症、土拨鼠肝炎病毒感染、病毒黄热病、腺病毒引起的人畜共患的病毒感染、艾普斯坦-巴尔二氏病毒感染、博卡病毒感染、利贝迈斯特病毒感染、卢约病毒感染、马尔堡病毒感染、马尔堡病毒病、马亚罗病毒病、猴痘、单股反链病毒、流行性肾病、奥罗普切病毒发烧、致植物退化病毒感染、夸尔亚病毒、兔出血性疾病、莱斯顿埃波拉病毒感染、莱斯顿病毒感染、鼻病毒感染、罗西奥病毒性脑炎、蔷薇疹感染、苏丹埃波拉病毒感染、塔伊森林埃波拉病毒感染和土耳其火鸡痘病毒性感染。
7.根据权利要求6所述的用途,包括至少一种或多种组合选自下列的已知的抗病毒剂或抗炎剂与穿心莲内酯衍生物或类似物联合使用:胞苷类似物、尿苷模拟、腺苷模拟、鸟苷类似物、胸苷类似物或肌苷类似物的一种、包括:脱氧胞苷2′,3′-双脱氧胞苷、2“碳环3′-马帝德-氢化胞苷的,2′,3′-脱氢-2′,3′-双脱氧胞苷氨酸、2′,3′-脱氢-2′,3′-脱氧-5-甲基胞苷、氟-2′,3′-双脱氧胞苷、3′-叠氮2′,3′-脱氧-5-甲基胞嘧啶、3′-叠氮-2′,3′-脱氧-5-甲基胞嘧啶、3′-叠氮-2′,3′-脱氧-5-甲基-胞嘧啶、3′-叠氮-2′,3′-双脱氧胞苷、3′-叠氮-2′,3′-双脱氧-5-氟胞嘧啶、2′,3′-脱氧-2,3′-双去氢胞苷、β-L-5-氟-2′,3′-脱氧-2′,3′-二脱氢拉米呋啶、、恩曲他滨、阿立他滨、脱氧-5-甲基尿苷、3′-叠氮-2′,3′-脱氧-5-氯尿嘧啶核苷、3′-叠氮-2′,3′-脱氧-5-乙基尿苷、3′-叠氮-2′3′-氟3′-二脱氧尿苷、2′,3′-脱氧-5-溴尿苷、3′-氟-2′,3′-脱氧-5-乙基尿苷、3′-叠氮-2′,3′-脱氧-5-溴尿苷、3′-叠氮-2′,3′-二脱氧尿苷、3′-氟-2′,3′-脱氧-5-氯尿苷、3′-氟-2′,3′-二脱氧尿苷、2′,3′-脱氧-3′-叠氮尿苷、2,3′-二脱氧-3′-3′-氟-5-氯尿苷、2,3′-二脱氧腺苷、2′,3′-脱氧-2′-氟-ARA-腺苷、2-氯脱氧腺苷、9-(4-羟基-1′,2′-丁二烯)腺嘌呤、9-(2-膦酰甲氧乙基)腺嘌呤、2′,3′-脱氢-2“3′-二脱氧腺苷、二脱氧腺苷、5-甲基-2′,3′-二脱氧腺苷、3′-氟-2′,3′-二脱氧腺苷、2′,3′-双脱氧-3′-氟腺苷、2,3′-双脱氧鸟苷、2′,3′-二去氢鸟苷、3′-叠氮-3′-脱氧鸟苷、3′-氟-2′,3′-双脱氧鸟苷、双脱氧鸟苷、3′-曡氮-2′,3′-双脱氧鸟苷、3′-氟-2′,3′-双脱氧鸟苷、2,3′-双脱氧-3′-叠氮鸟苷、3′-脱氧胸苷、2′,3′-双脱氧胸苷、3′-叠氮-3′-脱氧胸苷、3′-氟-3′-脱氧胸苷、3′-氟-2′,3′-双脱氧胸苷、3′-脱氧-2′,3′-双脱氧胸苷、2′,3′-脱氢-2′,3′双脱氧胸苷、2′,3′-双脱氧肌苷、2,6-二胺嘌呤、2′,3′-二去氧核糖苷、2,6-二氨基-3-叠氮-2′,3′-二去氧核糖苷、2,6-氨基嘌呤、3′-氟-2′,3′-二去氧核糖苷、3-膦酰甲氧乙基-2,6-二氨基-2,6-二氨基嘌呤、-2′,3′-二去氧核糖苷、3′-氟-2′,3′-双脱氧二氨基嘌呤、2′,3′-二脱氧-3′-氟-2,6-二氨基腺嘌呤核苷、阿巴卡韦、阿昔洛韦、阿德福韦、阿洛夫定、金刚烷胺、双链聚核糖核苷酸、阿比朵尔、安普那韦、阿扎那韦、阿托伐他汀钙、波普瑞韦、西多福韦、双汰芝、阿糖胞苷、地瑞那韦的、地拉韦啶、地达诺新、地昔洛韦、去羟肌苷、替诺福韦、二十二醇、依度尿苷、依非韦伦、恩夫韦、恩替卡韦、进入抑制剂、艾夫他滨、恩曲他滨、泛昔洛韦、福米韦生、福沙那伟、膦甲酸钠、膦乙醇、融合抑制剂、更昔洛韦、伊巴他滨、异丙肌苷、疱疹净、咪喹莫特、茚肌苷、奥斯他韦、喷昔洛韦、帕拉米韦、金刚乙胺、利巴韦林、利托那韦、沙奎那韦、司他夫定、替诺福韦、替诺福韦、地西他滨、非阿尿苷、碘苷、膦甲酸钠、洛布卡韦、索立夫定、曲氟胸苷、曲金刚烷、利巴韦林、司他夫定、替拉那韦、三协唯、恩曲他滨替诺福韦、万乃洛韦、缬更昔洛韦、马拉维若、阿糖腺昔、他立韦林、扎西他滨、扎那米韦、齐多夫定、增强协同剂、整合酶抑制剂、III型干扰素、干扰素II型、I型干扰素、洛匹那韦、洛韦胺、马拉韦罗、吗啉胍、甲吲噻腙、奈非那韦、奈韦拉平、聚乙二醇干扰素α-2a、普可那利、逆转录酶抑制剂、蛋白酶抑制剂和拉替拉韦。
8.根据权利要求1所述的穿心莲内酯衍生物和类似物在制备预防或减缓癌症的药物中的用途。
9.根据权利要求8所述的应用,包括至少一种或多种组合的选自下列的已知的抗肿瘤剂与穿心莲内酯衍生物或类似物配伍联合用药:长春新碱、白消安、长春新碱、顺铂、卡铂、丝裂霉素C、阿霉素、秋水仙碱、依托泊苷、紫杉醇、多西紫杉醇、喜树碱、拓扑替康、三氧化二砷、5-氮胞苷、5-氟尿嘧啶、甲氨喋呤、5-氟-2-脱氧尿嘧啶核苷、羟基脲、硫代鸟嘌呤、马法兰、苯丁酸氮芥、环磷酰胺、丙脒腙、表阿霉素、阿克拉霉素、博莱霉素、依利碘铵的醋酸、氟达拉滨、奥曲肽、维甲酸、鬼臼毒素、他莫昔芬、多沙唑嗪、坦索罗辛盐酸特拉唑嗪、坦索罗辛、氟吡啶、洛伐他汀、辛伐他汀、普伐他汀、氟伐他汀、阿托伐他汀、安普那韦、阿巴卡韦、利托那韦、沙奎那韦、罗非昔布、亚硝基羟丙氨酸、托可维A酸、13-顺式维甲酸、9-顺式维甲酸、α-二氟甲基鸟氨酸、芬维A胺、维甲酰酚胺、染料木素、阿糖胞苷、硼替佐米、格列卫、吉非替尼赫赛汀、利妥昔单抗、吉西他滨、洛匹那韦、西仑吉肽、洛那法尼、抑激酶素和伐地考昔。
10.根据权利要求3的药物组合物,其给药方式为口服、非胃肠道、皮下、静脉内、肌内、腹膜内、透皮、颊、鞘内、颅内、鼻内或局部途径。
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