CN116375668B - 一种新型紫杉烷类化合物的制备方法、应用 - Google Patents
一种新型紫杉烷类化合物的制备方法、应用 Download PDFInfo
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- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
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- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
本发明提供了具有式Ⅰ结构的新型紫杉烷类化合物的用途和制备方法。所述新型紫杉烷类化合物如(I)所示：本发明提供了具有式(Ⅰ)结构的新型紫杉烷类化合物和在制备抗肿瘤药物中的用途。
Description
技术领域
本发明提供了具有式I结构的新型紫杉烷类化合物的用途及制备方法。
背景技术
多烯紫杉醇(商品名：泰索帝或Taxotere)，其通过抑制微管解聚、促进微管二聚体合成达到抗肿瘤的作用。体外抗肿瘤试验结果表明，多烯紫杉醇抑制细胞分裂的能力是紫杉醇的2倍，IC50为4～35mg/mL，肿瘤增殖抑制率达到紫杉醇的10倍。此外，相比与紫杉醇，多烯紫杉醇具有更好的水溶性，从而提高了其细胞内浓度和生物利用度，并延长了细胞内潴留时间(元进英等，抗癌新药紫杉醇和多烯紫杉醇[M]，北京：化学工业出版社)，)。多烯紫杉醇结构式如下
自1995年批准上市以来，多烯紫杉醇陆续在美国等60多个国家上市，用于治疗乳腺癌和非小细胞肺癌等。临床结果表明，多烯紫杉醇对晚期乳腺癌、非小细胞肺癌、卵巢癌、胰腺癌、肝癌、头颈部癌等有效，对晚期乳腺癌有效率为60％，对治疗晚期非小细胞肺癌有效率达31％，对晚期卵巢癌有效率达30％。
本发明人致力于多烯紫杉醇的结构改造，式(I)是在多烯紫杉醇的结构基础上，进行了结构改造，经初步药效筛选得到新型紫杉烷类药物，根据药效研究结果显示，裸鼠模型药效显著提高，且毒副作用明显下降，能够消除肿瘤(抑瘤率达到99％以上)，停药后观察期内未发现肿瘤复发，该结果在肺癌A549、肝癌HepG2和胰腺癌Panc-1模型上得以验证，预计将广泛应用于相关疾病的临床治疗中。
发明内容
本发明第一方面提供结构新颖的紫杉烷类化合物，具体为式I所示的紫杉烷化合物，或其药学可接受的盐或溶剂化物：
本发明第二方面提供了如上所述新型紫杉烷类化合物的制备方法，具体步骤为以式V所示的多烯紫杉醇为原料经三乙基硅烷保护制得式VI所示化合物DTX1，DTX1经4-乙酰苯基异氰酸酯缩合制得式III所示化合物DTX2，DTX2经盐酸水解制得式II化合物(参考专利CN111196790A)，式Ⅱ经与还原试剂反应和/或经与氘代试剂反应后、经后处理制得如式I所示的紫杉烷类化合物：
进一步地，所述还原试剂为硼氢化钠、硼氢化钾、硼氢化锂、氰基硼氢化钠或三乙酰氧基硼氢化钠中的任一种或几种；
再进一步地，为硼氢化钠。
进一步地，所述还原试剂与式II化合物摩尔比为1-2:1；
再进一步地，为1:1。
进一步地，所述醇类溶剂为甲醇、乙醇、正丙醇或异丙醇中的一种或任几种；
再进一步地，为甲醇。
进一步地，反应温度为-10～0℃，反应时间为2～3小时；
再进一步地，所述反应温度为-10～-5℃。
进一步地，所述后处理为经过柱层析分离或经过制备色谱分离；
进一步地，所述柱层析为硅胶柱层析分离，洗脱剂为乙酸乙酯和正己烷的混合物、二氯甲烷和甲醇的混合物或乙酸乙酯与石油醚的混合物；
再进一步地，所述柱层析分离使用100-400目硅胶，洗脱剂为乙酸乙酯与正己烷的体积比为1:1～6的混合物。
本发明还提供了一种药物组合物，含有如上所示的式Ⅲ化合物以及药学上可接受的辅料和/或载体。
本发明还提供了如上所述的新型紫杉烷类化合物如上所述的药物组合物在制备抗肿瘤药物中的应用；
优选地，所述肿瘤包括眼癌、直肠癌、结肠癌、宫颈癌、前列腺癌、乳腺癌、膀胱癌、口腔癌、胃癌、肝癌、胰腺癌、肺癌、子宫癌、卵巢癌、睾丸癌、肾癌、脑癌、中枢神经系统癌、咽喉癌、皮肤黑色素瘤、急性淋巴细胞白血病、急性髓系白血病、尤因肉瘤、卡波西肉瘤、基底细胞癌和鳞状细胞癌、小细胞肺癌、绒膜癌、横纹肌肉瘤、血管肉瘤、血管内皮瘤、肾母细胞瘤、神经母细胞瘤、食道癌、喉癌、淋巴瘤、神经纤维瘤、结节性脑硬化、血管瘤或淋巴癌。
有益效果
由于采用了上述技术方案，本发明的有益效果是：
1)本发明提供的紫杉烷类化合物，该化合物对各肿瘤细胞株的增殖抑制作用，其自身的药理和毒理性质均优于多烯紫杉醇，相对于多烯紫杉醇具有显著地抑制肿瘤细胞增殖的活性，并且在药代动力学方面也具有很大优势；
2)本发明合成的新型紫杉烷类化合物制备方法，制备方法具有成本低、收率和纯度高的优点。
附图说明
图1为式I所示结构的1H-NMR谱图；
图2为式I所示结构的ESI低分辨质谱。
具体实施例
下面将结合本发明实施例，对本发明实施例中的技术方案进行清楚、完整地描述。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
通过对所合成的化合物的经济性、多样性以及生物活性进行综合考量，优选了部分化合物列于下表中。具体的化合物结构如表1所示。表1中的化合物只是为了更好的说明本发明，并不会对本发明产生限定，本领域的技术人员不应将此理解为本发明上述主题的范围仅限于以下化合物。
| 序号 | R1 | R2 | R3 | R4 | R5 | R6 | R7 | R8 | R9 | R10 |
| 1 | H | H | H | H | H | H | H | H | H | H |
| 2 | H | H | H | H | H | H | H | H | H | D |
| 3 | D | D | D | D | D | D | D | D | D | D |
| 4 | D | D | D | D | D | D | D | D | D | H |
| 5 | D | D | D | H | H | H | H | H | H | H |
| 6 | D | D | D | D | D | D | H | H | H | H |
| 7 | D | D | D | H | H | H | H | H | H | D |
| 8 | D | D | D | D | D | D | H | H | H | D |
制备本发明化合物的方法在以下技术方案和实施例中进行了说明。原料可以经市场购买到或者可以通过文献中已知的方法或者如详解所示进行制备。本领域技术人员应当理解，也可以利用其它合成路线合成本发明的化合物。尽管在下文中已经对合成路线中的具体原料和条件进行了说明，但是，可以很容易地将其替换为其它类似的原料及条件，这些对本发明制备方法的变型或者变体而产生的诸如化合物的各种异构体等都包括在本发明范围内。另外，如下所述制备方法可以按照本发明公开内容、使用本领域技术人员熟知的常规化学方法进行进一步修饰。例如，在反应过程中对适当的基团进行保护等等。
实施例1
在室温条件下，向500mL三口圆底烧瓶中依次加入20.0g多烯紫杉醇(DTX)、100mL吡啶后搅拌溶解。在氮气保护下，滴加12.0g三乙基氯硅烷(TESCl)，温度保持在20～30℃之间，加料完毕后搅拌3小时。加入100mL水搅拌0.5小时。用乙酸乙酯(200mL×3)萃取，水洗，饱和食盐水洗涤，无水硫酸钠干燥3.0小时过滤，减压浓缩至干得36.4g粗品。用30.0mL乙酸乙酯将上述粗品溶解，然后室温条件下滴加180mL正己烷搅拌打浆，然后减压抽滤，减压干燥后得21.3gDTX1(白色粉末状固体)收率89％。1H NMR(CDCl3,400MHz)δ：8.12(d,J＝7.2Hz,2H),7.59(t,J1＝7.2Hz,J2＝7.6Hz,1H),7.48(t,J＝8.0Hz,J2＝8.8Hz,2H),7.37(t,J1＝J2＝7.2Hz,2H),7.31-7.27(m,3H),6.33(t,J1＝J2＝8.8Hz,1H),5.67(d,J＝7.2Hz,1H),5.48(d,J＝8.8Hz,1H),5.28(d,J＝8.4Hz,1H),5.13(s,1H),4.95(d,J＝8.0Hz,1H),4.55(s,1H),4.41(dd,J1＝6.4Hz,J2＝10.4Hz,1H),4.32(d,J＝8.4Hz,1H),4.27(s,1H),4.20(d,J＝8.8Hz,1H),3.90(d,J＝7.02Hz,1H),2.53(s,3H),2.50-2.44(m,1H),2.38-2.32(m,1H),2.18-2.12(m,1H),1.97-1.90(m,4H),1.75(s,3H),1.61(s,1H),1.31(s,9H),1.27(s,3H),1.16(s,3H),0.94(t,J＝8.0Hz,9H),0.79(t,J＝8.0Hz,9H),0.59-0.54(m,6H),0.45-0.31(m,6H).
实施例2
在室温条件下，向250m三口圆底烧瓶中依次加入20.0g DTX1、2.4g对二甲氨基吡啶(DMAP)、6.8g 4-乙酰苯基异氰酸酯，然后加入200mL无水四氢呋喃。在氮气保护条件下，升温至50℃并保温搅拌反应5小时。经TLC监控反应结束后，将反应液降温冷却后直接减压浓缩至干得粗品，粗品经柱层析分离得23.5g白色固体DTX2，收率87％。柱层析条件：石油醚：乙酸乙酯＝4:1→2:1。1H NMR(400MHz,CDCl3):8.12(d,J＝7.6Hz,2H),7.95(d,J＝8.8Hz,2H),7.60-7.53(m,4H),7.48(t,J1＝J2＝7.6Hz,2H),7.38(t,J1＝J2＝7.6Hz,2H),7.31-7.28(m,3H),6.48(s,1H),6.32(t,J1＝J2＝8.8Hz,1H),5.72(d,J＝6.8Hz,1H),5.52(d,J＝9.6Hz,1H),5.31(d,J＝7.2Hz,1H),4.98(d,J＝8.8Hz,1H),4.58(s,1H),4.55-4.51(dd,J1＝10.4Hz,J2＝6.4Hz,1H),4.33(d,J＝8.4Hz,1H),4.21(d,J＝8.4Hz,1H),3.82(d,J＝6.8Hz,1H),2.58(s,3H),2.55(s,3H),2.43-2.37(m,1H),2.23-2.17(m,1H),2.11(s,3H),1.96-1.90(m,3H),1.73(s,3H),1.33(s,9H),1.24(s,3H),1.20(s,3H),0.92(t,J1＝J2＝8.0Hz,9H),0.78(t,J1＝J2＝8.0Hz,9H),0.64-0.58(m,6H),0.48-0.32(m,6H).TOF-MS:calcd for C64H88N2O16Si21197.5751[M+H+],found 1197.5739；calcd forC64H88N2O16Si21219.5570[M+Na+],found 1219.5587
实施例3
在室温条件下，向5000mL三口圆底烧瓶中依次加入20.0g DTX2、50mL二氯甲烷、100mL甲醇搅拌溶解至澄清，然后降温至5～10℃后滴加35mL浓盐酸并保温搅拌反应3小时。经TLC监控反应结束后，加入饱和碳酸氢钠溶液调节pH至7.0～8.0左右。后续依次用乙酸乙酯(10.0mL×3)萃取，水洗，饱和食盐水洗涤，无水硫酸钠干燥后减压过滤及减压浓缩至干得粗品。该粗品经柱层析得11.8mg式II(白色固体)，收率57％。柱层析洗脱条件：石油醚：乙酸乙酯＝2:1→1:1。1HNMR(400MHz,CDCl3):δ8.09(d,J＝7.6Hz,2H),7.91(d,J＝8.8Hz,2H),7.61(t,J1＝J2＝7.6Hz,2H),7.62-7.59(m,4H),7.39-7.36(m,4H),7.33-7.29(m,1H),6.34(s,1H),6.23(t,J1＝9.2Hz,J2＝5.6Hz,1H),5.47(d,J＝8.4Hz,1H),5.27-5.24(m,1H),4.96(d,J＝9.6Hz,1H),4.63(br,1H),4.47-4.42(m,1H),4.30(d,J＝8.8Hz,1H),4.17(d,J＝8.4Hz,1H),3.80(d,J＝7.2Hz,1H),3.57(br,1H),3.46(s,1H),2.88(br,1H),2.60-2.52(m,4H),2.38(s,3H),2.29-2.27(m,2H),2.00(m,1H),1.90(s,3H),1.87-1.82(m,4H),1.33(s,9H),1.24(s,3H),1.16(s,3H).TOF-MS:calcd for C52H60N2O16969.4021[M+H+],found969.3995。
实施例4
室温条件下，称取500mg式II加入到100mL三口瓶中，然后加入5mL甲醇，搅拌溶解后降温至0℃，加入硼氢化钠20mg，保温搅拌至TLC监控反应结束。向反应液加入20mL乙酸乙酯，20ml饮用水萃取，有机相经适量无水硫酸钠干燥后，过滤。滤液减压浓缩，经柱层析分离(200～300目硅胶)，洗脱剂乙酸乙酯/正己烷(1:6～1:1)。将所需洗脱液减压浓缩至干，得式I-1330mg白色粉末，收率66％。1H NMR(CDCl3,500MHz)δ：8.10(d,J＝6.5Hz,2H),7.61(t,J1＝6.5Hz,J2＝6.0Hz,1H),7.50(t,J1＝6.5Hz,J2＝6.0Hz,2H),7.41-7.35(m,6H),7.33-7.30(m,1H),7.28(d,J＝7.0Hz,2H),7.06(bra,1H),6.32(s,1H),6.24(m,1H),5.67(d,J＝5.5Hz,1H),5.42(d,J＝6.0Hz,1H),5.26(m,1H),4.96(d,J＝8.0Hz,1H),4.62(s,1H),4.56(t,J1＝5.0Hz,J2＝5.5Hz,1H),4.45-4.42(m,1H),4.30(d,J＝7.0Hz,1H),4.18(d,J＝7.0Hz,1H),3.80(d,J＝5.0Hz,1H),3.45(d,J＝4.5Hz,1H),2.95(s,1H),2.57-2.52(m,1H),2.37(s,3H),2.31-2.45(m,2H),1.91-1.87(m,4H),1.68(m,6H),1.33(s,9H),1.26(s,3H),1.17(s,3H).LR-ESI:calcd for C52H62N2O161009.4[M+K+],found 1009.4。
实施例5
室温条件下，称取500mg式II加入到100mL三口瓶中，然后加入5mL的甲醇，搅拌溶解后降温至-5℃，加入硼氢化钠20mg，保温搅拌至TLC监控反应结束。将反应液加入20mL乙酸乙酯，20ml饮用水萃取，有机相经适量无水硫酸钠干燥后，过滤。滤液减压浓缩，经柱层析分离(目硅胶)，洗脱剂乙酸乙酯/正己烷/>将所需洗脱液减压浓缩至干，得I-1360mg白色粉末，收率72％。
实施例6
室温条件下，称取500mg式II加入到100mL三口瓶中，然后加入5mL的甲醇，搅拌溶解后降温至-10℃，加入硼氢化钠20mg，保温搅拌至TLC监控反应结束。将反应液加入20mL乙酸乙酯，20ml饮用水萃取，有机相经适量无水硫酸钠干燥后，过滤。滤液减压浓缩，经柱层析分离(目硅胶)，洗脱剂乙酸乙酯/正己烷/>将所需洗脱液减压浓缩至干，得I-1420mg白色粉末，收率84％。
实施例7
室温条件下，称取500mg式II加入到100mL三口瓶中，然后加入5mL的甲醇，搅拌溶解后降温至-5℃，加入硼氘化钠20mg，保温搅拌至TLC监控反应结束。将反应液加入20mL乙酸乙酯，20ml饮用水萃取，有机相经适量无水硫酸钠干燥后，过滤。滤液减压浓缩，经柱层析分离(目硅胶)，洗脱剂乙酸乙酯/正己烷/>将所需洗脱液减压浓缩至干，得式I-2280mg白色粉末，收率55％。
实施例8
室温条件下，称取500mg式II加入到100mL三口瓶中，然后加入5mL的甲醇，搅拌溶解后降温至-10℃，加入氰基硼氘化钠32mg，保温搅拌至TLC监控反应结束。将反应液加入20mL乙酸乙酯，20ml饮用水萃取，有机相经适量无水硫酸钠干燥后，过滤。滤液减压浓缩，经柱层析分离(目硅胶)，洗脱剂乙酸乙酯/正己烷/>将所需洗脱液减压浓缩至干，得式I-2320mg白色粉末，收率65％。
实施例9
室温条件下，称取500mg式II加入到100mL三口瓶中，然后加入5mL的甲醇，搅拌溶解后降温至-10℃，加入硼氘化锂12mg，保温搅拌至TLC监控反应结束。将反应液加入20mL乙酸乙酯，20ml饮用水萃取，有机相经适量无水硫酸钠干燥后，过滤。滤液减压浓缩，经柱层析分离(目硅胶)，洗脱剂乙酸乙酯/正己烷/>将所需洗脱液减压浓缩至干，得式I-2250mg白色粉末，收率41％。
实施例10
室温条件下，称取2g氘代叔丁醇(式VII)加入到250mL三口瓶中，冰水浴降温，搅拌溶解后，加入4.3g三光气，加完升至室温搅拌至TLC监控反应结束。将反应液减压浓缩至干得化合物式VI液体2.8g收率72％。
实施例11
室温条件下，称取5g式Ⅱ加入到500mL三口瓶中，然后加入50ml甲酸，室温搅拌搅拌至TLC监控反应结束。降温至0℃缓慢加入碳酸钠溶液200ml，加入200mL乙酸乙酯，萃取，有机相经适量无水硫酸钠干燥后，过滤。滤液减压浓缩，经乙酸乙酯/正己烷(1:6)得3.5g化合物式II’白色粉末，收率58％。
实施例12
室温条件下，称取3g化合物式II’加入到250mL三口瓶中，然后加入20mL二氯甲烷和5ml三乙胺，搅拌溶解后，加入2g化合物式VI，室温搅拌至TLC监控反应结束。将反应液加入200mL乙酸乙酯，100ml饮用水萃取，有机相经适量无水硫酸钠干燥后，过滤。滤液减压浓缩，经乙酸乙酯/正己烷(1:6)得1.6g化合物式II”白色粉末，收率46％。
实施例13
室温条件下，称取500mg化合物式II”加入到100mL三口瓶中，然后加入5mL的甲醇，搅拌溶解后降温至-5℃，加入硼氘化钠20mg，保温搅拌至TLC监控反应结束。将反应液加入20mL乙酸乙酯，20ml饮用水萃取，有机相经适量无水硫酸钠干燥后，过滤。滤液减压浓缩，经柱层析分离(目硅胶)，洗脱剂乙酸乙酯/正己烷/>将所需洗脱液减压浓缩至干，得式I-3240mg白色粉末，收率50％。
实施例14
CTG法检测式I及式II化合物对各肿瘤细胞株的增殖抑制作用：
采用CellTiter-Glo Luminescent Cell Viability Assay(简称CTG)法检测供试品式I及式II化合物对各肿瘤细胞株的增殖抑制作用，并计算IC50值。肿瘤细胞系包括有：人胰腺癌细胞株：SW1990、PANC-1、HPAF-II；人胃癌细胞株：NCI-N87、MGC-803；人食管癌细胞株：KYSE-150、KYSE-410；人头颈癌细胞株：C666-1、Fadu；人乳腺癌细胞株：MDA-MB-231；人肺癌细胞株：A549；人肾上腺皮质癌细胞株：SW-13；人膀胱癌/尿路上皮癌株：BIU-87。共计13种肿瘤细胞株。
试验方法：收集对数生长期细胞，在96孔板中每孔添加细胞悬液，置37℃培养箱中孵育过夜。用各肿瘤细胞系对应的完全培养基稀释供试品式I及式II化合物，按照下表对药物进行梯度稀释。在96孔板，加入含待测药物培养基，每个浓度做三个复孔，并设置不加待测药物的阴性对照孔。将96孔板置于培养箱中孵育72h。再加入CTG试剂，并设置空白对照孔，再混匀裂解并室温孵育10min，用酶标仪测定荧光信号值(Lum)。
表1各肿瘤细胞系的供试品式I及式II化合物的梯度稀释浓度设置
数据处理与分析：采用GraphPad Prism 8.0软件对数据进行图形化处理，计算IC50，对数据进行四参数非线性回归分析，匹配相适应的剂量-效应曲线。细胞存活率的计算公式如下：
试验结果：供试品化合物对各肿瘤细胞株的增殖抑制作用的IC50值如下表所示，由此可见，式I化合物相对于式II化合物具有显著地抑制肿瘤细胞增殖的活性。
表2供试品化合物对各肿瘤细胞株的IC50(nM)
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进或润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (5)
1.一种新型紫杉烷类化合物，其特征在于，其结构式如式(I)所示：
式(I)中，R1、R2、R3、R4、R5、R6、R7、R8、R9、R10各自独立地为氢或者氘。
2.如权利要求1所述的一种新型紫杉烷类化合物，其特征在于，式(I)中，R1、R2、R3、R4、R5、R6、R7、R8、R9、R10中一个或者多个为氘。
3.如权利要求1所述的一种新型紫杉烷类化合物，其特征在于，式(I)中，R1、R2、R3、R4、R5、R6、R7、R8、R9、R10均为氘。
4.一种药物组合物，含有如权利要求1所示的式I化合物以及药学上可接受的辅料和/或载体。
5.如权利要求1所述的新型紫杉烷类化合物如或权利要求4所述的药物组合物在制备抗肿瘤药物中的应用，其特征在于，所述肿瘤包括胰腺癌、胃癌、食管癌、头颈癌、乳腺癌、肺癌、肾上腺皮质癌或膀胱癌。
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