CN109485636A - 一种新型btk激酶抑制剂的盐酸盐及其制备方法与用途 - Google Patents
一种新型btk激酶抑制剂的盐酸盐及其制备方法与用途 Download PDFInfo
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Abstract
本发明属于药物化学领域，涉及一种新型BTK激酶抑制剂的盐酸盐及其制备方法，具体地，本发明涉及[2(1H)‑丙烯酰基‑3,4‑二氢异喹啉‑5‑基]‑氨基甲酸‑4‑[8‑甲氧基‑(2H)‑酞嗪‑1‑酮基]苯酯的盐酸盐及其制备方法与用途，所述[2(1H)‑丙烯酰基‑3,4‑二氢异喹啉‑5‑基]‑氨基甲酸‑4‑[8‑甲氧基‑(2H)‑酞嗪‑1‑酮基]苯酯的结构式如式(a)所示，其盐酸盐稳定性高，引湿性低，溶解度好，生物利用度高。
Description
技术领域
本发明属于药物化学领域，涉及一种新型BTK激酶抑制剂的盐酸盐及其制备方法，具体地，本发明涉及[2(1H)-丙烯酰基-3,4-二氢异喹啉-5-基]-氨基甲酸-4-[8-甲氧基-(2H)-酞嗪-1-酮基]苯酯的盐酸盐及其制备方法与用途。
背景技术
布鲁顿氨酸激酶(Bruton's tyrosine kinase，BTK)属于Tec家族的成员。它由独特的N-端结构域即PH(pleckstrin homology)结构域、TH(Tec homology)同源区、SH3(Srchomology3)结构域、SH2(Src homology2)结构域和催化结构域，也称SH1/TK(Srchomologyl/Tyrosine kinase)结构域或者激酶结构域组成(Akinleye et al：Ibrutiniband novel BTK inhibitors in clinical development.Journal of Hematology&Oncology2013，6：59)。在B淋巴细胞正常发育过程中，BTK基因不同蛋白区域的正确表达在B细胞的功能及多种转导途径中具有关键性作用。
基于BTK信号传导通路开发小分子靶向药物为B细胞类肿瘤如白血病、发性骨髓瘤及B细胞类免疫疾病的治疗提供一条全新的途径。BTK在自身免疫疾病中的作用的证据已经由BTK-缺失型小鼠和BTK-充足型小鼠模型试验提供(Kil LP，et al：Bruton's tyrosinekinase mediated signaling enhances leukemogenesis in a mouse model forchronic lymphocytic leukemia.Am J Blood Res2013，3(1)：71-83.)。在慢性淋巴细胞白血病(CLL)小鼠模型中，BTK-缺失型小鼠完全废止慢性淋巴细胞白血病，BTK过度表达会加速白血病发病，增加死亡率。
目前已知BTK抑制剂的选择性不理想，除了抑制BTK，还抑制其他多种激酶(如ETK，EGF，BLK，FGR，HCK，YES，BRK和JAK3等)，从而产生较多的副作用；同时，BTK结合位点发生突变后往往会导致耐药性的产生。因此临床上需要更多的BTK抑制剂，用于治疗肿瘤等疾病，同时可以克服此类不良事件。
化合物(a)的[2(1H)-丙烯酰基-3,4-二氢异喹啉-5-基]-氨基甲酸-4-[8-甲氧基-(2H)-酞嗪-1-酮基]苯酯，体外激酶活性检测发现其对BTK激酶具有良好的抑制活性，IC50值为5.5nM，贫血、血小板减少和中性粒细胞减少等副作用小，具有良好的应用前景。但在化合物(a)的成药性研究过程中，本发明的发明人发现不同的化合物(a)药用盐在水溶性、生物利用度等方面有较大的差异。因此，深入研究找到适合药用的[2(1H)-丙烯酰基-3,4-二氢异喹啉-5-基]-氨基甲酸-4-[8-甲氧基-(2H)-酞嗪-1-酮基]苯酯盐型，十分必要。
发明内容
一方面，本发明提供[2(1H)-丙烯酰基-3,4-二氢异喹啉-5-基]-氨基甲酸-4-[8-甲氧基-(2H)-酞嗪-1-酮基]苯酯的盐酸盐，[2(1H)-丙烯酰基-3,4-二氢异喹啉-5-基]-氨基甲酸-4-[8-甲氧基-(2H)-酞嗪-1-酮基]苯酯的结构式如式(a)所示，其盐酸盐稳定性高，引湿性低，溶解度好，生物利用度高，
另一方面，本发明提供[2(1H)-丙烯酰基-3,4-二氢异喹啉-5-基]-氨基甲酸-4-[8-甲氧基-(2H)-酞嗪-1-酮基]苯酯盐酸盐的制备方法，包括以下步骤：
步骤A：式(1)的化合物与式(2)的化合物缩合得到式(3)的化合物；
步骤B：式(3)的化合物与式(4)的化合物反应得到式(5)的化合物；
步骤C：式(5)的化合物脱去保护基得到式(6)的化合物；
步骤D：式(6)的化合物与丙烯酰氯反应得到式a化合物；
步骤E：式(a)化合物与HCl反应制得式(a)化合物盐酸盐，反应路线如下：
在一些优选的实施方案中，步骤E中式(a)化合物与HCl反应的溶剂选自乙酸乙酯和二氯甲烷。
在一些优选的实施方案中，步骤E中溶剂的使用量为3-10倍式(a)化合物质量；优选地，步骤E中溶剂的使用量为3-5倍式(a)化合物质量。
在一些具体的实施方案中，室温下，将式(a)化合物溶于5倍于式(a)化合物质量的乙酸乙酯溶剂中，加入饱和氯化氢乙酸乙酯至上清液无沉淀生成，室温下继续搅拌10-30min即得。
第三方面，本发明提供了一种药物组合物，其含有[2(1H)-丙烯酰基-3,4-二氢异喹啉-5-基]-氨基甲酸-4-[8-甲氧基-(2H)-酞嗪-1-酮基]苯酯的盐酸盐及药学上可接受的载体。
第四方面，本发明提供了[2(1H)-丙烯酰基-3,4-二氢异喹啉-5-基]-氨基甲酸-4-[8-甲氧基-(2H)-酞嗪-1-酮基]苯酯盐酸盐或包含所述[2(1H)-丙烯酰基-3,4-二氢异喹啉-5-基]-氨基甲酸-4-[8-甲氧基-(2H)-酞嗪-1-酮基]苯酯盐酸盐的药物组合物在制备用于治疗和/或预防肿瘤的药物中的应用，所述肿瘤包括但不限于实体瘤，优选为肺癌、头颈部肿瘤、结直肠癌、膀胱癌、胰腺癌、乳腺癌、前列腺癌、胃癌、口腔癌、肝癌、卵巢癌。更优选地，所述肿瘤为非小细胞肺癌。
具体实施方式
以下结合实施例更详细的解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的范围。
实施例1[2(1H)-丙烯酰基-3,4-二氢异喹啉-5-基]-氨基甲酸-4-[8-甲氧基-(2H)-酞嗪-1-酮基]苯酯的制备
步骤1：称取5-氨基-3,4-二氢异喹啉-2(1H)-甲酸叔丁酯(50mmol)和DIPEA(100mmol)于反应瓶中，加入二氯甲烷300ml，室温搅拌下缓慢滴加和氯甲酸对氯苯酯(51mmol)，滴毕，室温下继续搅拌1h，停止反应，浓缩反应混合物，加入乙酸乙酯70ml，稀盐酸水溶液(0.2-0.3N)和饱和食盐水洗涤，无水硫酸钠干燥，过滤，浓缩得(3,4-二氢异喹啉-2(1H)-甲酸叔丁酯-5-基)-氨基甲酸对氯苯酯，直接用于下一步，ESI–MS:[M+H]+m/z 403。
步骤2：称取3-甲氧基-1-二甲氧基甲基苯(500mmol)于反应瓶中，加入四氢呋喃(800ml)溶解，60℃、氮气保护下，加入s-BuLi(565mmol)，将反应液在-60℃下搅拌1h；称取干冰(50mmol)于另一反应瓶中，加入四氢呋喃(200ml)，加入n-BuLi(5ml)，氮气保护下搅拌2h后，加入上述混合物，继续搅拌30min，停止反应，加入水1000ml，用浓盐酸调节pH至2，分离有机相，水相用乙酸乙酯萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥，重结晶得到6-甲氧基-2-二甲氧基甲基苯甲酸；称取6-甲氧基-2-二甲氧基甲基苯甲酸(400mmol)、乙酸(93mmol)、肼(600mmol)于反应瓶中，加入异丙醇300ml，氮气保护下，100℃回流反应2h，停止反应，加入乙酸乙酯300ml，水500ml，萃取，合并有机相，无水硫酸钠干燥，悬干，柱层析纯化得8-甲氧基-2H-酞嗪-1-酮，ESI–MS:[M+H]+m/z 177。
步骤3：称取8-甲氧基-2H-酞嗪-1-酮(150mmol)、(3,4-二氢异喹啉-2(1H)-甲酸叔丁酯-5-基)-氨基甲酸对氯苯酯(195mmol)于反应瓶中，加入DMF100ml，55℃下反应过夜，停止反应，加入水100ml，二氯甲烷200ml，萃取，分离有机相，水相继续用二氯甲烷萃取(3*50ml)，合并有机相，无水硫酸钠干燥，柱层析纯化得(3,4-二氢异喹啉-2(1H)-甲酸叔丁酯-5-基)-氨基甲酸-4-[8-甲氧基-(2H)-酞嗪-1-酮基]苯酯。
步骤4：称取(3,4-二氢异喹啉-2(1H)-甲酸叔丁酯-5-基)-氨基甲酸-4-[8-甲氧基-(2H)-酞嗪-1-酮基]苯酯(50mmol)于反应瓶中，加入三氟乙酸20ml，室温下搅拌1h，减压浓缩至干，加入乙酸乙酯80ml，依次用1.5M磷酸氢二钠水溶液和饱和食盐水洗涤，无水硫酸钠干燥，过滤，减压浓缩得中间体(1,2,3,4-四氢异喹啉-5-基)氨基甲酸-8-甲氧基-2-(2H)-酞嗪-1-酮基苯酯；称取所得中间体(1,2,3,4-四氢异喹啉-5-基)氨基甲酸-8-甲氧基-2-(2H)-酞嗪-1-酮基苯酯(20mmol)于反应瓶中，加入二氯甲烷100ml溶解，0℃下加入DIEA(40mmol)，搅拌30min后，继续在0℃下滴加丙烯酰氯(20mmol)，滴毕，室温搅拌3h，停止反应，加水100ml，二氯甲烷萃取(3*50ml)，合并有机相，无水硫酸钠干燥，柱层析纯化得[2(1H)-丙烯酰基-3,4-二氢异喹啉-5-基]-氨基甲酸-4-[8-甲氧基-(2H)-酞嗪-1-酮基]苯酯。
1H NMR(600MHz,CDCl3)(δ,ppm):9.50(s,1H),8.10(s,1H),7.80～7.78(m,2H),7.58～7.55(m,2H),7.44～7.43(m,1H),7.28～7.26(m,3H),7.18～7.15(m,2H),6.62～6.60(m,1H),5.96～5.94(m,1H),5.36～5.3(m,1H),4.22(s,2H),3.84(s,2H),3.61～3.59(m,2H),3.13～3.11(m,2H)。
ESI–MS:[M+H]+m/z 497。
实施例2：[2(1H)-丙烯酰基-3,4-二氢异喹啉-5-基]-氨基甲酸-4-[8-甲氧基-(2H)-酞嗪-1-酮基]苯酯盐酸盐的制备
称取实施例1化合物(0.5mmol)于反应瓶中，加乙酸乙酯2mL，室温下加入饱和氯化氢乙酸乙酯溶液至不再有沉淀生成，室温下继续搅拌10min，减压蒸除溶剂，室温下真空干燥获得标题化合物。
1H NMR(600MHz,CDCl3)(δ,ppm):9.50(s,1H,重水交换后消失),8.10(s,1H),7.80～7.78(m,2H),7.58～7.55(m,2H),7.44～7.43(m,1H),7.28～7.26(m,3H),7.18～7.15(m,2H),6.62～6.60(m,1H),5.96～5.94(m,1H),5.36～5.3(m,1H),4.22(s,2H),3.84(s,2H),3.61～3.59(m,2H),3.13～3.11(m,2H)。
实验例1：体外激酶活性评价
将实施例1和2制备的化合物，用DMSO稀释至10mM后，依次稀释至1uM、100nM、10nM、1nM、0.1nM、0.01nM。
取每个浓度的化合物溶液10μl至96孔板中，加入90μl1×激酶缓冲液(50mMHEPES,pH7.5,0.0015％Brij-35,10mMMgCl2,2mM DTT，临用前配制)；同时设立DMSO对照组和无酶活对照组，均仅含10μlDMSO和90μl1×激酶缓冲液。各组在室温下混匀10min，然后分别转移5μl至384孔板中；将激酶BTK溶于1×激酶缓冲液，配制成2.5×激酶溶液，然后转移10μl2.5×激酶溶液至上述含各浓度化合物的384孔板中；DMSO对照组加入10μl2.5×激酶溶液；无酶活对照组加入10μl不含激酶的1×激酶缓冲液。室温下孵育10min；将FAM标记的多肽和ATP溶于1×激酶缓冲液，配制成2.5×底物溶液，然后转移10μl2.5×底物溶液至上述384孔板中，28℃孵育1hr；各孔中加入25μl(100mMHEPES,pH7.5,0.015％Brij-35,0.2％CoatingReagent#3，50mMEDTA临用前配制)，终止液终止反应；置于LabChipEZReader上读取转化率数据，并计算抑制率I％，计算公式为I％＝(Max-Conversion)/(Max-Min)×100，其中Max为DMSO对照组的转化率，Min为无酶活对照组的转化率，Conversion为化合物处理组的转化率，数据经XLfit处理，拟合得IC50。IC50值表示与未加化合物处理组相比，化合物抑制50％酶活力时对应的化合物浓度。IC50结果见表1。
表1
| 受试化合物 | IC <sub>50</sub>(nM) | 受试化合物 | IC <sub>50</sub>(nM) |
| 实施例1 | 5.5 | 实施例2 | 5.2 |
实验例2体外Romas细胞活性评价
取处于指数生长期状态良好的Raji细胞一瓶，收集细胞，低速台式离心机，1500转/min，离心3min。弃上清，用移液器加入5mL完全培养基进行细胞重悬。使用细胞计数仪计数，完全培养基进行稀释，调整细胞密度至5×104个/mL。使用排枪接种于96孔板上，100μL/孔，置恒温CO2培养箱中培养24小时。使用纳升加样仪进行化合物加样，72小时后，加CCK-8，10μL/孔，2小时后Envision酶标仪450nm处检测其吸光值，计算抑制率，并计算IC50，结果见表2.
表2
| 受试化合物 | IC <sub>50</sub>(μM) | 受试化合物 | IC <sub>50</sub>(μM) |
| 实施例1 | 7 | 实施例2 | 5 |
上述实验结果表明实施例2化合物具有良好的体外Romas细胞抑制活性。
实验例3溶解性评价
按2015年药典四部溶解度实验法实验，实验结果见表3.
表3
| 化合物 | 实施例2化合物 |
| 水溶性 | 易溶 |
| pH1.8的人工胃液 | 易溶 |
| pH5.0的人工肠液 | 易溶 |
注：易溶是指溶质1g(ml)能在水1～不到10ml中溶解；
pH1.8的人工胃液的配制方法为：取浓盐酸0.765mL，加水约80mL、胃蛋白酶1.0g、氯化钠0.2g，摇匀后，加水稀释成100mL，用盐酸水溶液调pH至1.8；
pH5.0的人工肠液的配制方法为：取0.865g冰乙酸、0.831g牛胆酸钠、0.288g卵磷脂、1.520g氯化钾置于100mL容量瓶中，用水溶解并定容至100mL，用氢氧化钠水溶液调pH至5.0。
实施例4引湿性评价
称取实施例2化合物10mg，采用动态水分吸附(DVS)仪在25℃下于0％RH～80％RH相对湿度范围内测试该晶型的引湿性，实验结果表明，实施例2化合物在0％RH至80％RH范围内的重量变化为0.5％，几乎不吸湿。
Claims (8)
1.[2(1H)-丙烯酰基-3,4-二氢异喹啉-5-基]-氨基甲酸-4-[8-甲氧基-(2H)-酞嗪-1-酮基]苯酯的盐酸盐，所述[2(1H)-丙烯酰基-3,4-二氢异喹啉-5-基]-氨基甲酸-4-[8-甲氧基-(2H)-酞嗪-1-酮基]苯酯的结构式如式(a)所示，
2.权利要求1所述的盐酸盐的的制备方法，包括以下步骤：
步骤A：式(1)的化合物与式(2)的化合物缩合得到式(3)的化合物；
步骤B：式(3)的化合物与式(4)的化合物反应得到式(5)的化合物；
步骤C：式(5)的化合物脱去保护基得到式(6)的化合物；
步骤D：式(6)的化合物与丙烯酰氯反应得到式a化合物；
步骤E：式(a)化合物与HCl反应制得式(a)化合物盐酸盐，反应路线如下：
3.如权利要求2所述的制备方法，其特征在于：式(a)化合物与HCl反应的溶剂选自乙酸乙酯和二氯甲烷。
4.如权利要求2所述的制备方法，其特征在于：步骤E中溶剂的使用量为3-10倍式(a)化合物质量。
5.如权利要求2所述的制备方法，其特征在于：步骤E中溶剂的使用量为3-5倍式(a)化合物质量。
6.包含权利要求1所述盐酸盐及药学上可接受的载体的药物组合物。
7.权利要求1所述的盐酸盐及权利要求6所述的药物组合物在制备用于治疗和/或预防肿瘤的药物中的应用。
8.如权利要求7所述的在制备用于治疗和/或预防肿瘤的药物中的应用，其特征在于：所述肿瘤为非小细胞肺癌。
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