CN115850242B - 喹啉-2(1h)-酮衍生物及其制备方法和用途 - Google Patents
喹啉-2(1h)-酮衍生物及其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及一类喹啉‑2(1H)‑酮衍生物及其制备方法和用途。所述喹啉‑2(1H)‑酮结构是一类全新的CGRP和5‑HT1F双靶点分子，同时具有CGRP受体抑制活性和5‑HT1F受体激动活性，可用于制备治疗/预防CGRP和5‑HT1F受体相关疾病的药物的应用。
Description
技术领域
本发明涉及医药技术领域，具体涉及喹啉-2(1H)-酮衍生物及其制备方法和用途，更具体地涉及式(I)化合物及其在制备用于预防或治疗急性和慢性偏头痛药物中的应用。
背景技术
舒马曲坦是一种不能穿越血-脑屏障的吸水性5-HT1激动剂，能使头部血管平滑肌收缩，并能有效治疗偏头痛。目前未知的疼痛触发器刺激了三叉神经节(三叉神经节使头部组织内的脉管系统受神经支配)，导致脉管系统上的轴索释放血管活性神经肽。然后，这些释放的神经肽激活了一系列事件并最终导致疼痛。这种神经原性炎症被舒马曲坦阻断，阻断机制涉及5-HT受体。
血清素5-HT显示出被至少7种受体类型介导的不同生理活性，其中最异源的是5-HT1。5-HT1F受体显示出的药理学轮廓明显不同于已公开的任何血清素受体。研究显示，舒马曲坦除了对5-HT1B和5-HT1D受体具有上述强亲和力外，对5-HT1F亚型也具有较强的亲和力。这表明5-HT1F受体在偏头痛中可能发挥重要作用。随后开发出对5-HT1F受体亚类具有相对选择性的受体激动剂，研究表明这种选择性通常会降低用于治疗偏头痛及相关疾病潜药的其它化合物所特有的血管收缩活性。
CGRP抑制剂可用于已发生CGRP受体过度活化的病理生理病症。这些病症包括神经性血管舒张、神经性炎症、偏头痛、丛集性头痛及其它头痛、热损伤、循环性休克、绝经期潮红及哮喘。CGRP受体活化已牵涉于偏头痛的发病机制中。在偏头痛期间，CGRP的血清含量升高且用抗偏头痛药物进行治疗使CGRP含量恢复正常，同时减轻头痛。
发明内容
本发明提供了一种全新的喹啉-2(1H)-酮衍生物及其制备方法和用途，以及喹啉-2(1H)-酮衍生物在制备用于预防或治疗偏头痛和其它CGRP/5-HT1F受体相关疾病的药物中的应用。
本发明的技术方案如下：
本发明提供了式(I)所示的喹啉-2(1H)-酮衍生物或其立体异构体、药学可接受的盐或溶剂合物：
本发明还提供了式(I)化合物的制备方法，其中包括以下步骤：
本发明还提供了包含治疗有效量的式(I)化合物和药用辅料的组合物。
进一步的，所述的药物所述药物组合物可以制成口服制剂、注射剂。
进一步的，所述口服制剂为片剂、胶囊或口服乳剂。
本发明还提供了式(I)化合物制备用于预防或治疗与异常水平CGRP/5-HT1F或CGRP/5-HT1F受体信号相关的病症的用途。
进一步的，所述病症为偏头痛。
进一步的，所述病症为神经性疼痛。
本发明得到了一类CGRP/5-HT1F双靶点分子化合物，所述化合物是全新化合物并且同时具备CGRP抑制活性和5-HT1F受体激动活性。另外，所述化合物提供新技术特征和医学用途的优势，例如，其具有不同的化学和受体结合特性，因此可用于治疗偏头痛和其它CGRP/5-HT1F受体相关疾病。
具体实施方式
下面将结合具体实施例对本发明进行清楚、完整的描述，本领域技术人员将会理解，下述实施例是本发明部分实施方式，而不是全部实施方式，仅用于说明本发明，而不应视为对本发明保护范围的限制。
实施例1式(I)化合物的合成
步骤1：化合物2的合成
将250mL无水四氢呋喃、化合物1(25.0g)及DMF(25.0mg)依次加入500mL单口瓶，氮气保护下降温至0℃，将草酰氯(17.2g)逐滴加入至反应液中，加毕后，室温搅拌2小时。将反应液浓缩干，向粗品中加入100mL无水二氯甲烷，浓缩干，重复操作三次，除去多余的草酰氯，得到化合物2(黄色油状物)。
步骤2：化合物3的合成
将120mL无水二氯甲烷、化合物2A(25.0g)及吡啶(10.0g)依次加入500mL三口瓶，氮气保护下将溶于120mL无水二氯甲烷的化合物2(26.6g)逐滴加入到反应液中，加毕后，室温搅拌12小时。向反应液中加入200mL的饱和氯化铵水溶液，分液，水相用二氯甲烷萃取三次，每次200mL。合并有机相，干燥，过滤，滤液浓缩干得到粗品。粗品经制备色谱纯化得到化合物3。MS(ESI)m/z＝368[M-56+1]+。
步骤3：化合物4的合成
将120mL无水DMF、化合物3(22.3g)及碳酸铯(85.6g)依次加入500mL三口瓶，反应液升温至85℃，保温搅拌12小时。向反应液中加入200mL水，分液，水相用乙酸乙酯萃取三次，每次700mL。合并有机相，用1000mL饱和食盐水洗涤，干燥，过滤，滤液浓缩干，得到粗品化合物4。MS(ESI)m/z＝351[M-56+H]+。
步骤4：化合物5的合成
将60mL无水DMF、36mL甲醇、化合物4(6.00g)、碳酸铯(85.6g)、Pd(dppf)Cl2(1.08g)及三乙胺(4.47g)依次加入250mL氢化瓶，用一氧化碳置换三次，50Psi，80℃保温搅拌16小时。两个批次合并处理。将反应液过滤，滤液浓缩干,得到粗品。向粗品中加入100mL水，过滤，滤饼真空干燥得到化合物5。MS(ESI)m/z＝287[M-100]。
步骤5：化合物6的合成
将280mL甲醇和化合物5(28.0g)依次加入500mL三口瓶，氮气保护下缓慢滴加LiOH水溶液(5M)，加毕后，室温搅拌12小时，升温至50℃，保温搅拌4小时。反应液浓缩干，得到粗品。向粗品中加入50mL水，用二氯甲烷萃取三次，每次50mL，弃去有机相。水相用1MHCl调节pH约等于4。过滤，滤饼真空干燥得到化合物6。MS(ESI)m/z＝316[M-56]。
步骤6：化合物7的合成
将150mL无水DMF、化合物6(15.0g)及DIEA(10.4g)依次加入500mL三口瓶，氮气保护下降温至0℃。将HATU(19.9g)加入至反应液，0℃保温搅拌半小时后，将化合物6A(9.24g)加入反应液，室温搅拌12小时后，升温至50℃保温搅拌3小时。向反应液中加入300mL水，过滤，滤饼经柱层析纯化得到化合物7。MS(ESI)m/z＝584[M+H]+。
步骤7：化合物8的合成
将30mL乙酸乙酯和7(6.00g)依次加入到250mL三口瓶，缓慢将HCl/EtOAc(4M,60mL)滴加到反应液中，氮气保护下，室温搅拌3小时。将反应液浓缩干，得到化合物8。MS(ESI)m/z＝484[M+H]+。
步骤8：化合物9的合成
将30mL无水DMF、化合物8A(2.30g)及DIEA(1.38g)依次加入至100mL三口瓶，室温搅拌15分钟后，氮气保护下将反应液降温至0℃。将CDI(1.27g)加入至反应液，0℃保温搅拌1小时。将化合物8(3.70g)和DIEA(1.38g)溶于10mLDMF后，加入至反应液中，升温至55℃，保温搅拌4小时。向反应液中加入100mL水,过滤，滤液用乙酸乙酯萃取三次，每次10mL。有机相用10mL水洗涤，干燥，过滤。滤液和之前滤饼合并浓缩干，得到化合物9。MS(ESI)m/z＝327[M+H]+。
步骤9：化合物10的合成
将50mL无水四氢呋喃、化合物9(5.00g)依次加入到250mL三口瓶，室温下缓慢滴加LiOH水溶液(3M,6.73mL),加毕后，室温搅拌12小时。反应液浓缩干，得到粗品。向粗品中加入20mL水，用二氯甲烷萃取三次，每次10mL。弃去有机相，水相用1MHCl调节pH约等于4。过滤，滤饼真空干燥得到化合物10。MS(ESI)m/z＝729[M+H]+。
步骤10：化合物(I)的合成
将5mL无水DMF、化合物10(300mg)、DIEA(106mg)及HATU(203mg)依次加入到50mL三口瓶，20℃搅拌半小时后，将化合物10A(75.4mg)加入到反应液中，20℃保温搅拌4小时。向反应液中加入50mL水，过滤，滤饼经制备色谱分离纯化得到化合物(I)。MS(ESI)m/z＝894[M+H]+；1HNMR(400MHz,DMSO-d6):δ13.03(brs,1H),12.02(brs,1H),10.74(d,J＝1.5Hz,1H),10.07(s,1H),8.32(d,J＝1.1Hz,1H),8.05(brd,J＝8.5Hz,1H),8.01-7.96(m,2H),7.72(s,1H),7.47(dd,J＝1.3,8.8Hz,1H),7.39-7.33(m,2H),7.30(d,J＝8.6Hz,1H),7.08(d,J＝2.0Hz,1H),7.01(s,1H),6.72(brd,J＝7.9Hz,1H),4.80(q,J＝7.7Hz,1H),4.16(brd,J＝6.0Hz,2H),3.60-3.51(m,1H),3.29-3.20(m,1H),3.12(brt,J＝9.1Hz,1H),3.03-2.82(m,5H),2.80-2.62(m,5H),2.47(s,3H),2.38-2.27(m,1H),2.20(s,4H),2.09-1.63(m,16H),1.51(brt,J＝8.1Hz,1H),1.45-1.30(m,4H),1.16(quin,J＝11.5Hz,2H)；13CNMR(101MHz,DMSO-d6):δ170.50,164.35,161.74,156.62,139.33,137.77,134.00,133.56,130.49,129.84,128.74,128.57,127.86,127.43,126.01,122.83,121.38,119.55,118.70,117.87,115.77,114.44,111.08,110.77,60.65,55.99,54.80,51.50,48.29(brd,J＝24.0Hz,1C),46.38,45.84,45.40(brs,1C),44.09(brd,J＝12.4Hz,1C),41.79,38.09,35.65,32.87,32.61,30.79-30.30(m,1C),27.32(d,J＝5.8Hz,1C),16.87。
生物学评价
实施例2化合物(I)的体外功能活性
2.1化合物(I)对人CGRP受体拮抗活性测定
细胞：稳定表达人源CGRP的SK-N-MC细胞。
试剂：cAMPKit，PerkinElmer；完全培养基：MEM+10％胎牛血清+1*青霉素链霉素；实验缓冲液：1*HBSS+20mMHEPES+0.1％BSA+500mMIBMX。
设备：Envision系统，PerkinElmer。
TrypLE消化处理后将细胞重悬于实验缓冲液中，种到384细胞培养板中，接种密度为20,000每孔。参照药Rimegepant/Vazegepant和化合物(I)用DMSO溶解，设置10个浓度梯度，然后用实验缓冲液3倍稀释，每个梯度设置3个平行组。每孔加入2.5μl的化合物，37℃培养10min。用实验缓冲液将人α-CGRP稀释到8*α-CGRP(16nM)，加入2.5μl稀释好的8*α-CGRP，于37℃孵育30min。冻融Eu-cAMPtracer和Ulight-anti-cAMP，用lysisbuffer将其稀释。加入10μlEu-cAMPtracer至试验孔，然后加入10μlUlight-anti-cAMP至试验孔中。化合物最终起始测试浓度为1μM。将反应版于室温200g离心30s，25℃静置1h后，采用Envision收集数据。化合物拮抗IC50使用Prism计算得到，结果见表1。
表1Rimegepant、Vazegepant和式I化合物的人CGRP受体拮抗活性
| 化合物名称 | 人CGRP受体拮抗活性IC50(nM) |
| Rimegepant | 1.72 |
| Vazegepant | 0.31 |
| 化合物(I) | 1.01 |
2.2化合物(I)对人5-HT1F受体的激动活性测定
细胞：稳定表达人源5-HT1F的Flpin-CHO-5-HT1F细胞。
试剂：cAMPKit，PerkinElmer；完全培养基：F12K+10％胎牛血清；实验缓冲液：1*HBSS+20mMHEPES+0.1％BSA+500μMIBMX。
设备：Envision系统，PerkinElmer。
将Flpin-CHO-5-HT1F细胞用完全培养基种到6cm细胞培养皿中培养过夜，接种密度为0.8*10^6。将Gi3质粒转染至Flpin-CHO-GNAI3细胞中孵育过夜。将细胞消化，重悬到实验缓冲液中，种到384细胞培养板中，接种密度为8,000每孔，接种体积为15μl每孔。参照药Lasmiditan/LY334370和化合物(I)用DMSO溶解，设置10个浓度梯度，然后用实验缓冲液3倍稀释，每个梯度设置3个平行组。每孔加入2.5μl的化合物，37℃培养5min。用实验缓冲液将forkskolin稀释至4μM(8*)，加入2.5μl稀释好的8*forkskolin，于37℃孵育10min。冻融Eu-cAMPtracer和Ulight-anti-cAMP，用lysisbuffer将其稀释。加入10μlEu-cAMPtracer至试验孔，然后加入10μlUlight-anti-cAMP至试验孔中。化合物最终起始测试浓度为1μM。将反应版于室温200g离心30s，25℃静置1h后，采用Envision收集数据。化合物激动EC50使用Prism计算得到，结果见表2。其中LY334370的结构式如下：
表2Lasmiditan、LY334370和式I化合物的人5-HT1F受体激动活性
| 化合物名称 | 人5-HT1F受体激动活性EC50(nM) |
| Lasmiditan | 19.11 |
| LY334370 | 1.358 |
| 化合物(I) | 77.9 |
本发明以稳定表达人源CGRP的SK-N-MC细胞和人源5-HT1F的Flpin-CHO-5-HT1F细胞为模型，分别研究化合物(I)的体外CGRP受体抑制活性和5-HT1F受体激动活性。结果显示，与单靶点调节剂相比，化合物(I)同时具有CGRP受体抑制活性(IC50＝1.72nM)和5-HT1F受体激动活性(EC50＝77.9nM)，即本发明获得了CGRP/5-HT1F双靶点分子化合物，所述化合物是全新化合物并且同时具备CGRP抑制活性和5-HT1F受体激动活性。化合物(I)除保持与CGRP靶点在T122、D94、D72的关键氢键外，通过在喹啉-2(1H)-酮的6位引入5-HT1F的药效基团(即取代吲哚氨基甲酰基)，即提升分子与5-HT1F靶点EBP区域的结合，制得结构新颖的CGRP和5-HT1F双靶点分子，可用于治疗/预防CGRP和5-HT1F受体相关疾病，所述化合物(I)提供新技术特征和医学用途的优势。
以上详细描述了本发明的优选实施方式，但是，本发明并不限于上述实施方式中的具体细节，在本发明的技术构思范围内，可以对本发明的技术方案进行多种等同变换，这些等同变换均属于本发明的保护范围。另外需要说明的是，在上述具体实施方式中所描述的各个具体技术特征，在不矛盾的情况下，可以通过任何合适的方式进行组合。为了避免不必要的重复，本发明对各种可能的组合方式不再另行说明。此外，本发明的各种不同的实施方式之间也可以进行任意组合，只要其不违背本发明的思想，其同样应当视为本发明所公开的内容。
Claims (8)
1.式(I)所示的化合物、或其药学上可接受的盐，
2.权利要求1所述式(I)所示的化合物的制备方法，其特征在于包括以下步骤：
3.一种药物组合物，其特征在于包含治疗有效量的权利要求1所述式(I)化合物和药用辅料。
4.根据权利要求3所述的药物组合物，其特征在于所述药物组合物制成口服制剂、注射剂。
5.根据权利要求4所述的药物组合物，其特征在于所述口服制剂为片剂、胶囊或口服乳剂。
6.权利要求1所述的式(I)所示的化合物、或其药学上可接受的盐用于制备与CGRP受体抑制和5-HT1F受体激动的受体信号相关病症的药物的用途。
7.根据权利要求6所述的用途，其特征为所述病症为偏头痛。
8.根据权利要求6所述的用途，其特征为所述病症为神经性疼痛。
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