CN116265474A - 新型喜树碱类化合物及其药物组合物和用途 - Google Patents
新型喜树碱类化合物及其药物组合物和用途 Download PDFInfo
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- CN116265474A CN116265474A CN202111551928.5A CN202111551928A CN116265474A CN 116265474 A CN116265474 A CN 116265474A CN 202111551928 A CN202111551928 A CN 202111551928A CN 116265474 A CN116265474 A CN 116265474A
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Abstract
本发明提供了具有式Ⅰ结构的新型喜树碱类化合物及其药物组合物和用途，具体而言所述用途为在制备抗肿瘤药物中的用途，所述肿瘤包括肝癌、肺癌、乳腺癌、胃癌、肠癌、宫颈癌、头颈部癌、胰腺癌、肾癌、卵巢癌或前列腺癌。
Description
技术领域
本发明属于医药化学领域，具体涉及一种新型喜树碱类化合物及其衍生物，包括此类化合物的组合物及其在恶性肿瘤治疗方面的应用。
背景技术
喜树碱(CPT)为一种吡咯喹啉细胞毒性生物碱，是除紫杉醇之外，研究最多的天然抗肿瘤药物之一。主要来源于我国特有的植物珙桐科植物喜树(Camptotheca acuminateDecne)，1966年由Wall等人首次从我国引种的喜树杆中分离得到。1967-1970年，研究者发现该生物碱在体外对Hela细胞、L1210细胞及啮齿类动物显示出较强的抗肿瘤活性，引起人们的极大关注。研究表明其对胃癌、直肠癌和白血病等多种恶性肿瘤均有一定的疗效。但是由于该生物碱易产生恶心、呕吐、腹泻、脱发等副作用，并且其水溶性差，制成水溶性的钠盐后抗肿瘤活性降低等原因，使得喜树碱的临床研究于20世纪70年代中后期几乎停滞不前。直至1985年，Hsiang等人发现喜树碱及衍生物是以拓朴异构酶(topoⅠ)为作用靶点抑制DNA的合成而发挥抗癌作用的机理后，才又一次引起人们的广泛关注，许多衍生物应运而生，成为抗癌领域研究的新热点。已批准上市的喜树碱类抗肿瘤药物如下所示：
DNA拓扑异构酶是广泛存在于生物体内的一类必需酶，通过调节超螺旋、连锁、去连锁以及核酸解离作用，影响DNA拓扑结构，其主要分为拓扑异构酶Ⅰ(TopoisomeraseⅠ，TopoⅠ)与拓扑异构酶Ⅱ(TopoisomeraseⅡ，TopoⅡ)。相比TopoⅡ抑制剂，TopoⅠ抑制剂疗效高，抗瘤谱广，已成为设计新型抗肿瘤药物的重要靶酶。
喜树碱分子由A、B、C、D、E五个环骈合而成，A、B环为喹啉环，C环为吡咯环，D环为吡啶酮，E环为一个具有S型手性碳的α-羟基内酯。分子结构呈高度不饱和态，五环之间有连续的共轭体系，使得喜树碱具有强烈的天然荧光。室温下经稀碱处理，容易开环成水溶性羧酸盐，酸化则又重新内酯化成环。通过对A、B环的结构改造，可得到抗肿瘤活性更好的、毒副作用更低的喜树碱类抗肿瘤药物。喜树碱A/B/C环标记如下：
本发明致力于喜树碱的结构改造，发现了一系列喜树碱类新型衍生物，抗肿瘤活性显著提高。
发明内容
发明要解决的问题
本发明的目的是提供具有优异的抗肿瘤作用且副作用低的喜树碱类化合物及其药学可接受的盐或溶剂化物，包括此类化合物的药物组合物，及其在制备抗肿瘤药物方面的应用。
用于解决问题的方案
本发明第一方面提供结构新颖的喜树碱化合物，具体为式Ⅰ所示的喜树碱化合物，或其药学可接受的盐或溶剂化物：
R1、R2各自为氢、芳香基或取代的芳香基。其中R1、R2不可同时为氢。
所述芳香基为C6-C12芳香基，芳香基为苯基、萘基，更优选苯基。芳香基的取代基选自C1-C4烷基、C1-C4烷氧基、C1-C4烷硫基、C1-C4烷胺基、卤素、三氟甲基、C1-C4烷基酰基、C1-C4烷氧酰基、硝基、氰基。取代基的位置选自苯环的邻位、间位、对位，更优选对位。
本发明第二方面在于提供单晶或者多晶型物形式的喜树碱类化合物。
本发明第三方面在于提供一种药物组合物，其含有以上所述的化合物或其药学可接受的盐或溶剂化物，和药学可接受的载体、赋形剂、稀释剂、辅剂、媒介物中的一种或组合。
本发明第四方面在于提供一种喜树碱类化合物，或其药学可接受的盐、溶剂化物以及其药物组合物在制备抗肿瘤药物中的应用，所述肿瘤包括肝癌、肺癌、乳腺癌、胃癌、肠癌、宫颈癌、头颈部癌、胰腺癌、肾癌、卵巢癌或前列腺癌。
发明的效果
本发明提供的喜树碱类化合物及其药学可接受的盐或溶剂化物，其对于人肝癌BEL-7402细胞增殖有显著的抑制作用。MTT法体外抑制实验结果表明，化合物HCPT-05,HCPT-07,HCPT-08在25μg/mL浓度下人肝癌BEL-7402细胞增殖抑制率依次为35.13％、38.42％、36.92％，均高于10-羟基喜树碱相应浓度的肿瘤抑制率(30.23％)。化合物HCPT-05,HCPT-07,HCPT-08在50μg/mL浓度下肿瘤抑制率依次为50.73％、51.84％、55.69％，均高于10-羟基喜树碱相应浓度的肿瘤抑制率(43.78％)。化合物HCPT-05,HCPT-07,HCPT-08在100μg/mL浓度下肿瘤抑制率依次为70.44％、69.74％、68.91％，均高于10-羟基喜树碱相应浓度的肿瘤抑制率(55.01％)。HCPT-09、HCPT-10在25、50、100μg/mL浓度下显示出较10-羟基喜树碱弱的抗肿瘤活性。其他化合物表现出10-羟基喜树碱基本相当或稍强的细胞毒性作用，数据详见表1。
表1.新型喜树碱衍生物对人肝癌BEL-7402细胞毒性作用(x平均值±s,n＝8)
注明：HCPT为10-羟基喜树碱；**代表P<0.01.
附图说明
附图1.HCPT-01的合成路线。
附图2.HCPT-01的1H NMR图谱。
附图3.HCPT-02的1H NMR图谱。
附图4.HCPT-03的1H NMR图谱。
附图5.HCPT-04的1H NMR图谱。
附图6.HCPT-05的1H NMR图谱。
附图7.HCPT-06的1H NMR图谱。
附图8.HCPT-07的1H NMR图谱。
附图9.HCPT-08的1H NMR图谱。
附图10.HCPT-09的1H NMR图谱。
附图11.HCPT-10的1H NMR图谱。
附图12.新型喜树碱类化合物结构式。
具体实施方式
本发明涉及新型的喜树碱类化合物，具体提供式Ⅰ所示的喜树碱类化合物：
R1、R2各自为氢、芳香基或取代的芳香基。其中R1、R2不可同时为氢；所述芳香基为C6-C12芳香基，所述芳香基为苯基、萘基，更优选苯基；所述芳香基的取代基选自C1-C4烷基、C1-C4烷氧基、C1-C4烷硫基、C1-C4烷胺基、卤素、三氟甲基、C1-C4烷基酰基、C1-C4烷氧酰基、硝基、氰基；所述取代基的位置选自苯环的邻位、间位、对位，更优选对位；所述卤素选自F、Cl、Br、I，更优选F；所述C1-C4烷基酰基中的C1-C4烷基选自甲基、乙基、丙基、丁基，更优选甲基。
本发明的式Ⅰ化合物还包括单晶或多晶型物形式及其所有的异构体形式和异构体混合物形式。
本发明还涉及其通式Ⅰ化合物的药学可接受的药用盐，以及其药学可接受的溶剂化物，如水合物。
优选的，上述化合物选自以下10种：
本发明所述的化合物或其药学可接受的盐或溶剂化物及其药物组合物，可用于肿瘤包括肝癌、肺癌、乳腺癌、胃癌、肠癌、宫颈癌、头颈部癌、胰腺癌、肾癌、卵巢癌或前列腺癌等的治疗。
在本发明的药物组合物中，作为活性成分的通式Ⅰ的化合物、其药学可接受的盐或溶剂化物在所述药物组合物中的重量比为0.01％-99.99％，其余为药物可接受的载体。药物组合物以适合药用的制剂形式存在。所述药用的制剂可以为片剂、胶囊剂、颗粒剂、丸剂、散剂、膏剂、混悬剂、注射剂、粉针剂、栓剂、霜剂、滴剂等。其中，所述片剂为糖衣片剂、薄膜片剂、肠溶片剂或缓释片剂；所述胶囊剂为硬胶囊剂、软胶囊剂、缓释胶囊剂；所述粉针剂为冻干粉针剂。
本发明的药物组合物在制备成粉剂、片剂、可分散粉剂、胶囊、扁囊剂、栓剂和软膏形式的固体或半固体药物制剂时，可使用固体载体。可使用的固体载体优选为选自于稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、膨胀剂等中的一种或多种物质，或可为包封物质。在粉状制剂中，在载体中含有5-90wt％的微粒化活性成分。适宜的固体载体包括碳酸镁、硬脂酸镁、滑石粉、蔗糖、乳糖、果胶、糊精、淀粉、明胶、甲基纤维素、羧甲基纤维素钠、低沸点蜡、可可脂等。
本发明的液体制剂包括溶液、悬液和乳液。例如，非胃肠道给药的注射剂可为水或水-丙二醇溶液形式，用于调节其等渗度，pH等，使之适于活体的生理条件。液体制剂还可制成在聚乙二醇、水溶液中的溶液形式。可通过将活性成分溶解在水中，再加入适量的着色剂、调味剂、稳定剂和增稠剂来制备口服水溶液。可将微粒化的活性成分分赛在粘性物质如天然和合成胶、甲基纤维素、羧甲基纤维素钠和其它已知悬浮剂中制备适于口服的水悬液。
本发明的药物组合物，作为制剂形式，每剂中含有的本发明化合物的有效量为0.1mg-1000mg，所述每剂指的是，每一制剂单位，如片剂的每片、胶囊的每粒、也可以指每次服用剂量。
本发明的所述药物组合物还可以是指药物组合物可以进行常规制药操作，例如灭菌。
本发明所述化合物可以单独给药，或者与其他药学可接受的化合物联合给药。
使用药物组合物或制剂时，是将安全有效量的本发明所述化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，例如，日给药剂量通常为0.1-1000mg/kg，优选1-1000mg/kg。当然具体剂量还应考虑给药途径、病人健康状况等因素。
本发明化合物可以通过任何本领域已知的合适方法给予患者，给药方式的部分实例可包括：口服、静脉内注射、肌肉注射、皮下注射、局部给药等。
本发明所涉及的术语“芳香基”是指由至少6个碳原子组成的芳香体系形成的基团，该体系可以由单环、双环、多环，其中环的连接方式可以以碳碳单键或者稠合的方式形成。作为芳香基团的实例，可以包括以下基团：苯基、萘基、联苯基、蒽基、芘基、茚基、苝基、芴基等。
本发明所涉及的术语“杂芳基”是指由碳原子和独立选自N、O或S的杂原子组成的芳香族化合物形成的基团。所述芳香族化合物可以是单环、双环、多环。其中双环和多环可以由单环通过单键连接方式或稠合方式形成。作为杂芳基的实例，可以包括以下基团：吡啶基、吡咯基、噻吩基、呋喃基、嘧啶基、哒嗪基、吡嗪基、吡唑基、咪唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、吲哚基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、喹唑啉基、喹喔啉基、噌啉基、吲唑基、嘌呤基等。
本发明所涉及的术语“取代的芳香基”是指具有取代基的上述定义的芳香基，所涉及的取代基可以是烷基、环烷基、不饱和烃基、烷氧基、烷巯基、烷胺基、卤素、三氟甲基、苯氧基、烷基酰基、烷基磺酰基、硝基、叠氮基、酯基、氰基、酰胺基等。所述取代可以为单取代或多取代，例如：对于苯基而言，在单取代的情况下，取代基的位置可以是邻位、间位或对位其中之一；在多取代的情况下，取代基的位置可以是邻位、间位、对位的任意组合。
本发明所涉及的术语“烷基”是指由碳原子和氢原子组成的基团，且不含不饱和度的基团(如：双键，三键或环等)，其涵盖了各种可能的异构体基团。该基团通过单键与分子的其余部分相连。本发明所涉及的术语“C1-C4烷基”是指碳原子数目为1-4的上述定义的烷烃，作为C1-C4烷基的实例，可包括下列基团：甲基、乙基、正丙基、异丙基、正丁基及其同分异构体。
本发明涉及的术语“立体异构体”包括所有对映异构/立体异构纯的和对映异构/立体异构富集的本发明的化合物。
本发明所涉及的术语“溶剂化物”表示本发明化合物与一种或多种溶剂分子的物理缔合。该物理缔合包括各种程度的离子和共价结合，包括氢键合。在某些情况中，例如当一种或多种溶剂分子掺入结晶固体的晶格中时，能够分离溶剂化物。“溶剂化物”包括溶液相和可分离的溶剂化物。溶剂化物的非限制实例包括乙醇化物、甲醇化物、丙酮化物等。“水合物”是其中溶剂分子是H2O的溶剂化物。溶剂化物的制备通常是已知的。典型的非限制方法包括在高于环境温度下将本发明化合物溶解于需要量的所需溶剂中(有机物或水或其混合物)，以足以形成结晶的速度冷却溶液，然后通过标准方法分离结晶。分析技术例如红外光谱可以证实作为溶剂化物(或水合物)的结晶溶剂(水)的存在。
本发明所述的“药物组合物”，其含有本发明化合物及其药学可接受的盐或溶剂化物，以及药学可接受的载体、赋形剂、稀释剂、辅剂、媒介物中的一种或它们组合。
为了使本技术领域的技术人员能够更好地理解本发明的技术方案，下面结合实施例，进一步阐述本发明。
实施例1 HCPT-01的制备
按照附图1化合物HCPT-01的合成路线进行制备具有下述结构的HCPT-01。
步骤1:3-三甲基硅基-1-丙醛的制备
向干燥洁净反应瓶加入3-三甲基硅基-1-丙醇(20.00g,1.0eq)，二氯甲烷(200mL)，抽真空氮气保护，冰水浴降温至0～5℃，加入戴斯马丁试剂(76.80g,1.2eq)，加完室温搅拌1小时后点板监控反应完全(展开剂正己烷：乙酸乙酯-20:1)，过滤，滤液用碳酸氢钠水溶液(200mL)和硫代硫酸钠水溶液(200mL)洗涤2次，有机相40℃下减压浓缩干。过柱，正己烷：乙酸乙酯＝20:1，得到3-三甲基硅基-1-丙醛15.50g，直接用于下一步反应。
步骤2:中间体HCPT-I的制备
向干燥洁净反应瓶加入30％硫酸(39mL)，硫酸亚铁七水合物(6.30g)，室温搅拌溶解，溶清后加入3-三甲基硅基-1-丙醛(15.00g)，乙二醇二甲醚溶液(156mL)。另取干燥洁净单口瓶，加入30％硫酸(430mL)，30％双氧水(2.5mL)，缓慢加入10-羟基喜树碱(7.80g)室温搅拌直至溶清后，加此溶液滴加至上述溶液中，滴完室温搅拌1小时后，加入30％双氧水(7.5mL)，加完室温搅拌过夜。反应液用正己烷(300ml×3)洗涤，氯仿萃取(500ml×3)，合并有机相，无水硫酸钠干燥，过滤，减压浓缩至500mL，室温静置1小时，过滤，减压干燥得到HTCP-I 3.00g。1HNMR(300M,DMSO-d6)7.648(d,J＝9.0Hz,1H),7.308(d,J＝1.8Hz,1H),,7.275-7.239(m,1H),7.012(s,1H),5.794(s,1H),5.673(s,1H),5.040(s,1H),4.958(s,2H),3.474(s,1H),3.289(t,J1＝J2＝10.5Hz,2H),2.256-2.174(m,1H),2.023-1.941(m,1H),0.959(t,J1＝J2＝10.5Hz,2H),0.889(t,J1＝J2＝10.5Hz,3H),0.060(s,9H).TOF-MS:calcd for C25H29N2O5Si 465.1840[M+H+],found 465.1846。
步骤3:中间体HCPT-01的制备
向100ml反应瓶依次加入HCPT-I(100.0mg)，对二甲氨基吡啶(20.0mg)，苯基异氰酸酯(52.0mg)，DMF(10mL)，加完抽真空氮气保护，升温50℃反应过夜。将反应液温度降至室温，加入饮用水50ml搅拌1小时后，将析出固体抽滤。固体用饮用水10ml洗涤两次，固体40℃真空干燥2小时。固体加入氯仿溶解，滤过不溶物，滤液40℃减压浓缩，制备分离,得21.3mgHCPT-01。1HNMR(300M,DMSO-d6)7.647(d,J＝8.7Hz,1H),7.475-7.433(m,3H),7.396(d,J＝1.8Hz,1H),7.373-7.337(m,1H),7.276(t,J1＝J2＝9.0Hz,2H),7.100-7.056(m,1H),7.028(s,1H),5.783(s,1H),5.681(s,1H),4.972(s,2H),3.426(s,1H),3.288(t,J1＝J2＝10.5Hz,2H),2.238-2.156(m,1H),2.127-2.045(m,1H),0.959(t,J1＝J2＝10.5Hz,2H),0.889(t,J1＝J2＝10.5Hz,3H),0.06(s,9H).TOF-MS:calcd for C32H33N3O6Si 584.2211[M+H+],found 584.2216。
实施例2 HCPT-02的制备
向100ml反应瓶依次加入HCPT-I(100.0mg)，对二甲氨基吡啶(20.0mg)，对甲基苯基异氰酸酯(57.2mg)，DMF(10mL)，加完抽真空氮气保护，升温50℃反应过夜。将反应液温度降至室温，加入饮用水50ml搅拌1小时后，将析出固体抽滤。固体用饮用水10ml洗涤两次，固体40℃真空干燥2小时。固体加入氯仿溶解，滤过不溶物，滤液40℃减压浓缩，制备分离,得20.7mg HCPT-02。1H NMR(300M,DMSO-d6)7.648(d,J＝8.7Hz,1H),7.480(d,J＝9.0Hz,2H),7.409-7.338(m,5H),7.035(s,1H),5.827(s,1H),5.678(s,1H),4.965(s,2H),3.474(s,1H),3.289(t,J1＝J2＝10.5Hz,2H),2.319(s,3H),2.262-2.180(m,1H),2.037-1.956(m,1H),0.959(t,J1＝J2＝10.5Hz,2H),0.889(t,J1＝J2＝10.5Hz,3H),0.060(s,9H).TOF-MS:calcd for C33H35N3O6Si 598.2368[M+H+],found 598.2363。
实施例3 HCPT-03的制备
向100ml反应瓶依次加入HCPT-I(100.0mg)，对二甲氨基吡啶(20.0mg)，4-甲氧基苯基异氰酸酯(64.1mg)，DMF(10mL)，加完抽真空氮气保护，升温50℃反应过夜。将反应液温度降至室温，加入饮用水50ml搅拌1小时后，将析出固体抽滤。固体用饮用水10ml洗涤两次，固体40℃真空干燥2小时。固体加入氯仿溶解，滤过不溶物，滤液40℃减压浓缩，制备分离,得25.8mg HCPT-03。1H NMR(300M,DMSO-d6)7.650(d,J＝9.0Hz,1H),7.43(d,J＝2.1Hz,2H),7.408-7.397(m,1H),7.376-7.341(m,1H),7.315(s,1H),7.038(s,1H),6.909(d,J＝9.0Hz,1H)5.790(s,1H),5.712(s,1H),4.966(s,2H),3.790(s,3H),3.475(s,1H),3.290(t,J1＝J2＝10.2Hz,2H),2.263-2.182(m,1H),2.039-1.957(m,1H),0.960(t,J1＝J2＝10.2Hz,2H),0.890(J1＝J2＝10.2Hz,3H),0.060(s,9H).TOF-MS:calcd for C33H35N3O7Si614.2317[M+H+],found 614.2320。
实施例4 HCPT-04的制备
向100ml反应瓶依次加入HCPT-I(100.0mg)，对二甲氨基吡啶(20.0mg)，4-甲硫基苯基异氰酸酯(71.0mg)，DMF(10mL)，加完抽真空氮气保护，升温50℃反应过夜。将反应液温度降至室温，加入饮用水50ml搅拌1小时后，将析出固体抽滤。固体用饮用水10ml洗涤两次，固体40℃真空干燥2小时。固体加入氯仿溶解，滤过不溶物，滤液40℃减压浓缩，制备分离,得27.9mg HCPT-04。1H NMR(300M,DMSO-d6)7.961(d,J＝9.0Hz,2H),7.666-7.607(m,3H),7.425(s,1H),7.400(d,J＝1.8Hz,1H),7.377-7.341(m,1H),7.040(s,1H),5.785(s,1H),5.705(s,1H),4.967(s,2H),3.475(s,1H),3.290(t,J1＝J2＝10.5Hz,2H),2.380(s,3H),2.263-2.182(m,1H),2.039-1.958(m,1H),0.960(t,J1＝J2＝10.2Hz,2H),0.890(t,J1＝J2＝10.2Hz,3H),0.060(s,9H).TOF-MS:calcd for C33H36N3O7Si 630.2089[M+H+],found630.2078。
实施例5 HCPT-05的制备
向100ml反应瓶依次加入HCPT-I(100.0mg)，对二甲氨基吡啶(20.0mg)，4-氟苯基异氰酸酯(58.9mg)，DMF(10mL)，加完抽真空氮气保护，升温50℃反应过夜。将反应液温度降至室温，加入饮用水50ml搅拌1小时后，将析出固体抽滤。固体用饮用水10ml洗涤两次，固体40℃真空干燥2小时。固体加入氯仿溶解，滤过不溶物，滤液40℃减压浓缩，制备分离,得27.6mg HCPT-05。1HNMR(300M,DMSO-d6)7.637(d,J＝9.0Hz,1H),7.612-7.562(m,2H),7.387(d,J＝1.8Hz,1H),7.364-7.3328(m，2H),7.168-7.106(m,1H),7.017(s,1H),5.783(s,1H),5.700(s,1H),4.967(s,2H),3.416(s,1H),3.284(t,J1＝J2＝10.5Hz,2H),2.232-2.151(m,1H),2.139-2.058(m,1H),0.958(t,J1＝J2＝10.2Hz,2H),0.89(t,J1＝J2＝10.2Hz,3H),0.060(s,9H).TOF-MS:calcd for C32H32FN3O7Si 602.2117[M+H+],found602.2107。
实施例6 HCPT-06的制备
向100ml反应瓶依次加入HCPT-I(100.0mg)，对二甲氨基吡啶(20.0mg)，1-萘基异氰酸酯(72.3mg)，DMF(10mL)，加完抽真空氮气保护，升温50℃反应过夜。将反应液温度降至室温，加入饮用水50ml搅拌1小时后，将析出固体抽滤。固体用饮用水10ml洗涤两次，固体40℃真空干燥2小时。固体加入氯仿溶解，滤过不溶物，滤液40℃减压浓缩，制备分离,得15.8mg HCPT-06。1H NMR(300M,DMSO-d6)8.336(s,1H),8.064-7.996(m,1H),7.791-7.750(m,1H),7.651(d,J＝9.0Hz,1H),7.482-7.397(m,4H),7.377-7.341(m,1H),7.309-7.267(m,1H),7.057-7.021(m,2H),5.796(s,1H),5.721(s,1H),4.969(s,2H),3.479(s,1H),3.29(t,J1＝J2＝10.5Hz,2H),2.266-2.184(m,1H),2.044-1.962(m,1H),0.96(t,J1＝J2＝10.2Hz,2H),0.89(t,J1＝J2＝10.2Hz,3H),0.060(s,9H).TOF-MS:calcd for C36H35N3O6Si634.2368[M+H+],found 634.2359。
实施例7 HCPT-07的制备
向100ml反应瓶依次加入HCPT-I(100.0mg)，对二甲氨基吡啶(20.0mg)，4-乙酰苯基异氰酸酯(69.2mg)，DMF(10mL)，加完抽真空氮气保护，升温50℃反应过夜。将反应液温度降至室温，加入饮用水50ml搅拌1小时后，将析出固体抽滤。固体用饮用水10ml洗涤两次，固体40℃真空干燥2小时。固体加入氯仿溶解，滤过不溶物，滤液40℃减压浓缩，制备分离,得30.1mg HCPT-07。1H NMR(300M,DMSO-d6)8.071(d,J＝9.0Hz,2H),7.749(d,J＝9.0Hz,2H)，7.651(d,J＝9.0Hz,1H),7.576(s,1H),7.403-7.341(m，2H),7.037(s,1H),5.830(s,1H),5.681(s,1H),4.967(s,2H),3.477(s,1H),3.290(t,J1＝J2＝10.5Hz,2H),2.500(s,3H),2.264-2.182(m,1H),2.037-1.956(m,1H),0.960(t,J1＝J2＝10.2Hz,2H),0.89(t,J1＝J2＝10.2Hz,3H),0.060(s,9H).TOF-MS:calcd for C34H35N3O7Si 626.2317[M+H+],found626.2302。
实施例8 HCPT-08的制备
向100ml反应瓶依次加入HCPT-I(100.0mg)，对二甲氨基吡啶(20.0mg)，4-氰基苯基异氰酸酯(61.9mg)，DMF(10mL)，加完抽真空氮气保护，升温50℃反应过夜。将反应液温度降至室温，加入饮用水50ml搅拌1小时后，将析出固体抽滤。固体用饮用水10ml洗涤两次，固体40℃真空干燥2小时。固体加入氯仿溶解，滤过不溶物，滤液40℃减压浓缩，制备分离,得27.4mg HCPT-08。1H NMR(300M,DMSO-d6)7.832(d,J＝9.0Hz,2H),7.708(d,J＝9.0Hz,2H)，7.650(d,J＝8.7Hz,1H),7.605(s,1H),7.403-7.341(m，2H),7.029(s,1H),5.795(s,1H),5.711(s,1H),4.977(s,2H),3.423(s,1H),3.290(t,J1＝J2＝10.5Hz,2H),2.237-2.155(m,1H),2.144-2.062(m,1H),0.960(t,J1＝J2＝10.2Hz,2H),0.89(t,J1＝J2＝10.2Hz,3H),0.060(s,9H).TOF-MS:calcd for C33H32N4O6Si 609.2164[M+H+],found 609.2170。
实施例9 HCPT-09的制备
向100ml反应瓶依次加入HCPT-I(100.0mg)，对二甲氨基吡啶(20.0mg)，4-硝基苯基异氰酸酯(70.5mg)，DMF(10mL)，加完抽真空氮气保护，升温50℃反应过夜。将反应液温度降至室温，加入饮用水50ml搅拌1小时后，将析出固体抽滤。固体用饮用水10ml洗涤两次，固体40℃真空干燥2小时。固体加入氯仿溶解，滤过不溶物，滤液40℃减压浓缩，制备分离,得23.5mg HCPT-09。1H NMR(300M,DMSO-d6)8.157(d,J＝9.3Hz,2H),7.806(d,J＝9.0Hz,2H)，7.688(s,1H),7.638(d,J＝8.7Hz,1H),7.388(d,J＝1.8Hz,1H),7.364-7.329(m,1H),7.014(s,2H),5.828(s,1H),5.673(s,1H),4.967(s,1H),3.423(s,1H),3.285(t,J1＝J2＝10.5Hz,2H),2.232-2.150(m,1H),2.141-2.059(m,1H),0.958(t,J1＝J2＝10.2Hz,2H),0.888(t,J1＝J2＝10.2Hz,3H),0.060(s,9H).TOF-MS:calcd for C32H32N4O8Si 629.2062[M+H+],found 629.2056。
实施例10 HCPT-10的制备
向100ml反应瓶依次加入HCPT-I(100.0mg)，对二甲氨基吡啶(20.0mg)，4-异氰酸酯苯甲酸甲酯(76.1mg)，DMF(10mL)，加完抽真空氮气保护，升温50℃反应过夜。将反应液温度降至室温，加入饮用水50ml搅拌1小时后，将析出固体抽滤。固体用饮用水10ml洗涤两次，固体40℃真空干燥2小时。固体加入氯仿溶解，滤过不溶物，滤液40℃减压浓缩，制备分离,得26.6mg HCPT-10。1H NMR(300M,DMSO-d6)7.829(d,J＝9.0Hz,2H),7.734(d,J＝9.0Hz,2H)，7.638(d,J＝8.7Hz,1H),7.532(s,1H),7.387(d,J＝1.8Hz,1H),7.364-7.328(m,1H),7.027(s,1H),5.781(s,1H),5.705(s,1H),4.958(s,2H),3.893(s,3H),3.471(s,1H),3.284(t,J1＝J2＝10.5Hz,2H),2.260-2.179(m,1H),2.035-1.954(m,1H),0.958(t,J1＝J2＝10.2Hz,2H),0.888(t,J1＝J2＝10.2Hz,3H),0.060(s,9H).TOF-MS:calcd for C34H35N3O8Si642.2266[M+H+],found 642.2261。
上述实施例仅为本发明的优选技术方案，而不应视为对于本发明的限制，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种如式Ⅰ所示的喜树碱类化合物或其药学可接受的盐或溶剂化物：
其特征在于，
R1、R2各自为氢、芳香基或取代的芳香基。
2.根据权利要求1所述的化合物或其药学可接受的盐或溶剂化物，其特征在于，R1、R2不可同时为氢；所述芳香基为C6-C12芳香基中的一种；所述芳香基的取代基选自C1-C4烷基、C1-C4烷氧基、C1-C4烷硫基、C1-C4烷胺基、卤素、三氟甲基、C1-C4烷基酰基、C1-C4烷氧酰基、硝基、氰基中的一种。
3.根据权利要求1所述的化合物或其药学可接受的盐或溶剂化物，其特征在于，所述芳香基的取代基的位置选自苯环的邻位、间位、对位的其中一个。
4.根据权利要求2所述的化合物或其药学可接受的盐或溶剂化物，其特征在于，所述卤素选自F、Cl、Br、I中的一种。
5.根据权利要求2所述的化合物或其药学可接受的盐或溶剂化物，其特征在于，所述C1-C4烷基、C1-C4烷氧基、C1-C4烷硫基、C1-C4烷胺基、C1-C4烷基酰基中的C1-C4烷基选自甲基、乙基、丙基、丁基中的一种。
6.根据权利要求1任一项所述的化合物或其药学可接受的盐或溶剂化物，其特征在于，所述化合物为单晶或多晶型物形式。
7.根据权利要求1-6任一项所述的化合物或其药学可接受的盐或溶剂化物，其特征在于，所述化合物有如下结构中的一种：
8.一种药物组合物，其特征在于，含有如权利要求1-6任一项所述的化合物或其药学可接受的盐或溶剂化物，和药学可接受的载体、赋形剂、稀释剂、辅剂、媒介物中的一种或组合。
9.根据权利要求1-6任一项所述的化合物或其药学可接受的盐或溶剂化物，其特征在于，在制备抗肿瘤药物中的应用，所述肿瘤包括肝癌、肺癌、乳腺癌、胃癌、肠癌、宫颈癌、头颈部癌、胰腺癌、肾癌、卵巢癌或前列腺癌。
10.根据权利要求8所述的药物组合物，其特征在于，在制备抗肿瘤药物中的应用，所述肿瘤包括肝癌、肺癌、乳腺癌、胃癌、肠癌、宫颈癌、头颈部癌、胰腺癌、肾癌、卵巢癌或前列腺癌。
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