CN103483275B - Nsaid类抗炎止痛药物和egfr激酶抑制剂的偶联化合物及其合成方法和应用 - Google Patents
Nsaid类抗炎止痛药物和egfr激酶抑制剂的偶联化合物及其合成方法和应用 Download PDFInfo
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- CN103483275B CN103483275B CN201310424904.2A CN201310424904A CN103483275B CN 103483275 B CN103483275 B CN 103483275B CN 201310424904 A CN201310424904 A CN 201310424904A CN 103483275 B CN103483275 B CN 103483275B
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- quinazoline
- acetylenylaniline
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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- C07—ORGANIC CHEMISTRY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
本发明公开了通过酯键连接的NSAID类抗炎止痛药物和EGFR抑制剂的具有式Ⅰ，Ⅱ，或Ⅲ所示结构的偶联化合物或者其药学上可接受的盐或立体异构体或其前药分子：
Description
技术领域
本发明属于化学医药领域，具体地涉及一类NSAID类抗炎止痛药物和EGFR激酶抑制剂的偶联化合物或其药学上可接受的盐或立体异构体及其前药分子及其合成方法和在合成药物中的应用。
背景技术
肿瘤是现代社会中常见的一种高死亡率的疾病。传统的***的方法主要是以根治性手术切除为主，辅以术前术后化疗，然而疗效难尽如人意。靶向药物因特异性强、毒性低而备受关注。
近年来的研究显示，表皮生长因子受体(epidermal growth factor,EGFR)在多数肿瘤中的高表达与肿瘤的发生、发展和预后密切相关，因此,针对EGFR的靶向药物已陆续开发并逐步应用于肿瘤治疗的临床实践。包括单克隆抗体（如西妥昔单抗、Matuzumab等）和小分子络氨酸激酶抑制剂（如吉非替尼、埃罗替尼、拉帕替尼等）。尽管EGFR抑制剂以其高选择性和低毒性的优势在肿瘤临床治疗中取得了令人鼓舞的疗效，但是有些患者对这类治疗并不敏感，并且有些患者对该类药物最终产生耐药。
除了EGFR外，COX-2也被认为是肿瘤治疗中的一个非常具有前景的靶点。近年来国内外研究发现，在多种恶性肿瘤组织中，COX-2表达水平均明显增高。COX是***素合成过程中的关键酶，而环氧化酶-2(cyclooxygenase-2,COX-2)是一种诱导型酶，可在多种因子刺激下产生，对肿瘤的发生、发展和转移有重要影响，其主要通过抑制凋亡、抑制机体的抗肿瘤免疫、促进肿瘤新血管生成、增强侵袭力等机制发挥作用。
实际上EGFR和COX-2表达之间存在着非常多的联系。目前已有小组提出，COX-2的激活和过度表达是由于EGFR的激活。EGFR由它的一种配体-双调蛋白（AR）刺激，诱导在极化的结肠上皮细胞中COX-2的胞核靶向，PG的释放和随后的有丝***。COX-2抑制剂已经显示出能阻止这一系列的行为。
非甾体类抗炎药（Nonsteroidal Antiinflammatory Drugs，NSAIDs）为环氧酶（COX）的抑制剂，作为抗炎、退热和镇痛药在临床上被广泛地使用，有一些药物已经作为OTC药无须处方即可直接在药店购买。多年来的国内外临床显示，NSAID类抗炎止痛药物能延缓多种类型的肿瘤的发生和发展。应用NSAID类抗炎止痛药物***研究得最多的是结肠癌，无论是动物模型、体外药理实验、治疗试验和流行病学调查都发现，NSAIDs在早期即能阻止结肠癌的发生。
发明内容
本发明的目的之一是提供一类对肿瘤（特别是肺癌类）的具有良好治疗效果的NSAID类抗炎止痛药物和EGFR激酶抑制剂的偶联化合物或其药学上可接受的盐或立体异构体及其前药分子。
实现上述目的的技术方案如下：
通过酯键连接的NSAID类抗炎止痛药物和EGFR抑制剂的具有式Ⅰ，Ⅱ，或Ⅲ所示结构的偶联化合物或者其药学上可接受的盐或立体异构体或其前药分子：
R为NSAID类抗炎止痛药物；优选地，NSAID类抗炎止痛药物的化学结构可不同，包括，但不局限于，酮洛芬（2-(4-苯甲酰苯)丙酸，C16H14O3），布洛芬（2-(4-异丁基苯)丙酸，C13H18O2），SC-75416（7-叔丁基-6-氯-2-(三氟甲基)-2H-苯并吡喃-3-羧酸，C15H14ClF3O3），阿司匹林2-（（乙酰氧基）苯甲酸，C9H8O4），萘普生（（+）-α-甲基-6-甲氧基-2-萘乙酸，C14H14O3），吲哚美辛（2-甲基-1-（4-氯苯甲酰基）-5-甲氧基-1H-吲哚-3-羧酸，C19H16ClNO4），舒林酸（（Z)-5-氟-2-甲基-1-[（4-甲亚硫酰苯基)亚甲基]-1H-茚-3-羧酸，C20H17FO3S），他米巴罗汀（4-(5,5,8,8-四甲基-5,6,7,8-四氢萘-2-烯氨基甲酰)苯甲酸，C22H25NO3）。
本发明的另一目的是提供上述偶联化合物的合成方法。
实现上述目的技术方案如下：
通过酯键连接NSAID类抗炎止痛药物和EGFR抑制剂的偶联化合物的合成，所述方法为：1）在适当的条件下，NSAID类抗炎止痛类药物先和卤代烷或醇发生酯化反应，得到酯化产物中间体，所述适当条件包括酰氯或羧酸活化酯与醇酯化的条件、酸与醇直接缩合的条件、羧酸或其盐与溴代物酯化的条件；然后制备的酯化产物中间体再与具有式Ⅳ，Ⅴ或Ⅵ所示结构的EGFR抑制剂所含的酚羟基或其盐发生醚化反应，得到偶联化合物；
或2）、NSAID类抗炎止痛类药物与具有式Ⅶ，Ⅷ或Ⅸ所示结构的EGFR抑制剂所含的羟基或其盐发生酯化反应，得到偶联化合物。
所述NSAID类抗炎止痛类药物包括所述NSAID类抗炎止痛类药物及其酸、羧酸盐、酰氯和羧酸活化酯中的任一种。
所述醇为2-溴乙醇，2-氯乙醇，2-碘乙醇；所述卤代烷为1,2-二溴乙烷，1-溴-2-氯乙烷，1,2-二氯乙烷。
本发明的另一目的是提供一种***的药用组合物。
实现上述目的技术方案如下：
一种***的药用组合物，其药学活性成份是上述的通过酯键连接NSAID类抗炎止痛药物和EGFR抑制剂的化合物或者其药学上可接受的盐或立体异构体或其前药分子。
本发明的另一目的是提供上述通过酯键连接NSAID类抗炎止痛药物和EGFR抑制剂的偶联化合物或者其药学上可接受的盐或立体异构体或其前药分子的应用。
所述肿瘤包括非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、***癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌、结肠直肠癌等等。
实现上述目的技术方案如下：
上述通过酯键连接NSAID类抗炎止痛药物和EGFR抑制剂的偶联化合物或者其药学上可接受的盐或立体异构体或其前药分子在制备肿瘤药物中的应用。
本发明通过将NSAID类抗炎止痛药物和EGFR抑制剂偶联，得到新的化学实体，得到的偶联化合物具有良好的***（特别是肺癌类）的效果，为临床治疗选择提供了新的药物。
具体实施方式
通过以下实施例对本发明具体实施方法进行描述，但该实施例并非用于限制本发明的保护范围。
实施例1
2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙基-2-(4-苯甲酰苯)丙酸的合成
步骤1
3-羟基-4-(2-甲氧基乙氧基)苯甲酸乙酯的合成
将10.9g3,4-二羟基苯甲酸乙酯溶于40ml干燥的DMF（二甲基甲酰胺）中，冰浴下缓慢加入3.6gNaH，氩气保护下，10min后缓慢滴入8.34g2-溴乙基甲基醚与100mgKI溶于10ml干燥的DMF的溶液，3h内滴完，期间维持反应温度为0℃。滴加完毕后使反应温度自然升至室温，反应过夜，TLC跟踪至反应结束。将反应液用水稀释，乙酸乙酯萃取，依次饱和氯化钠溶液洗涤，无水硫酸钠干燥。粗产品柱色谱分离得产物3-羟基-4-(2-甲氧基乙氧基)苯甲酸乙酯7.2g（50%）。
1H NMR(400MHz,CDCl3)δ7.59(dd,J=8.4,1.6Hz,1H),7.53(d,J=1.2Hz,1H),6.87(d,J=8.4Hz,1H),4.28(q,J=7.2Hz,2H),4.13(t,J=4.4Hz,2H),3.66(t,J=4.4Hz,2H),3.35(s,3H),1.31(t,J=7.2Hz,3H)
步骤2
3-(2-乙酰氧基乙氧基)-4-(2-甲氧基乙氧基)苯甲酸乙酯的合成
将7.2g步骤1所制得的产物3-羟基-4-(2-甲氧基乙氧基)苯甲酸乙酯溶于10ml干燥的DMF中，加入4.6g2-溴乙基乙酸酯以及1.2g无水K2CO3，60℃反应过夜。TLC跟踪至反应结束后，将反应液用水稀释，乙酸乙酯萃取，依次饱和氯化钠溶液洗涤，无水硫酸钠干燥后减压浓缩得产物3-(2-乙酰氧基乙氧基)-4-(2-甲氧基乙氧基)苯甲酸乙酯7.5g（77%）。
1H NMR(400MHz,CDCl3)δ7.59(d,J=8.4Hz,1H),7.52(s,1H),6.85(d,J=8.4Hz,1H),4.39(t,J=4.4Hz,2H),4.29(q,J=6.8Hz,2H),4.20(t,J=4.4Hz,2H),4.13(t,J=4.4Hz,2H),3.72(t,J=4.4Hz,2H),3.79(s,3H),2.01(s,3H),1.32(t,J=6.8Hz,3H).
步骤3
5-(2-乙酰氧基乙氧基)-4-(2-甲氧基乙氧基)-2-硝基苯甲酸乙酯的合成
将8g步骤2所制得的产物3-(2-乙酰氧基乙氧基)-4-(2-甲氧基乙氧基)苯甲酸乙酯溶于24ml冰乙酸中，冰盐浴下缓慢滴加2.4ml浓硝酸，维持0℃下搅拌一小时后再缓慢滴加2.4ml浓硫酸，使其自然升至室温反应过夜。将反应液用水稀释，DCM（二氯甲烷）萃取，依次饱和氯化钠溶液洗涤，无水硫酸钠干燥后减压浓缩得产物5-(2-乙酰氧基乙氧基)-4-(2-甲氧基乙氧基)-2-硝基苯甲酸乙酯6.8g（75%）。
1H NMR(400MHz,CDCl3)δ7.46(s,1H),7.09(s,1H),4.44(t,J=4.4Hz,2H),4.35(q,J=6.8Hz,2H),4.28(t,J=4.4Hz,2H),4.22(t,J=4.4Hz,2H),3.77(t,J=4.4Hz,2H),3.41(s,3H),2.06(s,3H),1.32(t,J=6.8Hz,3H).
ESI+m/z372.0(M+H)+.
步骤4
5-(2-乙酰氧基乙氧基)-4-(2-甲氧基乙氧基)-2-氨基苯甲酸乙酯的合成
将6.8g步骤3所制得的产物5-(2-乙酰氧基乙氧基)-4-(2-甲氧基乙氧基)-2-硝基苯甲酸乙酯溶于81ml乙醇中，依次加入27.1ml水和2.7ml浓盐酸，油浴加热下剧烈搅拌，分批缓慢加入10.3g铁粉后升温回流0.5h，TLC跟踪至反应结束。将反应液抽滤，滤饼用DCM洗涤。滤液用水稀释后，DCM萃取，依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥后减压浓缩得产物5-(2-乙酰氧基乙氧基)-4-(2-甲氧基乙氧基)-2-氨基苯甲酸乙酯6.2g（100%）。
ESI+m/z342.0(M+H)+.
步骤5
2-(7-(2-甲氧基乙氧基)-4-氧杂-3,4-二羟基喹唑啉-6-氧基)乙酸乙酯的合成
将6g步骤4所制得的产物5-(2-乙酰氧基乙氧基)-4-(2-甲氧基乙氧基)-2-氨基苯甲酸乙酯溶于28ml甲酰胺中，加入1g甲酸铵，加热至180℃反应3h，TLC跟踪反应结束。将反应液用水稀释后，DCM萃取，依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥后减压浓缩得产物2-(7-(2-甲氧基乙氧基)-4-氧杂-3,4-二羟基喹唑啉-6-氧基)乙酸乙酯4g（70%）。
ESI+m/z323.0(M+H)+.
步骤6
2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙酸乙酯的合成
冰浴下，在3g步骤5所制得的产物2-(7-(2-甲氧基乙氧基)-4-氧杂-3,4-二羟基喹唑啉-6-氧基)乙酸乙酯中缓慢滴加20mlPOCl3，加热至110℃回流反应1h，TLC跟踪至反应结束。将反应液减压浓缩后用水稀释，乙酸乙酯萃取，依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥后减压浓缩得中间产物2-(4-氯-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙酸乙酯3g。将该中间产物悬浮于30ml异丙醇中，加入1ml3-胺基苯乙炔，80℃回流反应过夜。TLC跟踪至反应结束，将反应液减压浓缩得产物2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙酸乙酯3.1g(79%)。
ESI+m/z422.1(M+H)+.
步骤7
2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙醇的合成
将3.1g步骤6所制得的产物2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙酸乙酯溶于20ml甲醇中，加入1gKOH搅拌过夜，TLC跟踪至反应结束。反应液减压浓缩后柱色谱分离得产物2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙醇2.3g(82%)。
1H NMR(400MHz,MeOD)δ8.43(s,1H),7.93(s,1H),7.79-7.74(m,2H),7.40(t,J=8.0Hz,1H),7.28(d,J=7.6Hz,1H),7.17(s,1H),4.36(t,J=4.4Hz,2H),4.25(t,J=4.4Hz,2H),4.00(t,J=4.4Hz,2H),3.90(t,J=4.4Hz,2H),3.53(s,1H),3.50(s,3H).
ESI+m/z380.0(M+H)+.
步骤8
2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙基-2-(4-苯甲酰苯)丙酸的合成
将400mg酮洛芬溶于2ml干燥的DCM中，冰浴下加入0.16ml草酰氯，再加入1滴DMF，0℃→rt反应2h后减压浓缩制得酰氯备用。
将130mg步骤7所制得的产物2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙醇用6ml干燥的THF溶解，冰浴下加入0.23ml干燥的Et3N，搅拌10min后加入上述酰氯溶于2ml干燥的THF的溶液，自然升至室温反应过夜，TLC跟踪至反应结束。将反应液用水稀释，乙酸乙酯萃取，依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥后减压浓缩，粗产品柱色谱分离得产物2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙基-2-(4-苯甲酰苯)丙酸210mg(95%)。
1HNMR(400MHz,CDCl3)δ8.64(s,1H),8.28(br.,1H),7.98(s,1H),7.91(d,J=8.0Hz,1H),7.62(s,1H),7.30-7.03(m,7H),4.45-4.35(m,2H),4.20-4.18(m,4H),3.79-3.74(m,3H),3.40(s,3H),3.08(s,1H),2.40(d,J=6.8Hz,2H),1.82-1.75(m,1H),1.53(d,J=7.2Hz,3H),0.86(d,J=6.4Hz,6H);13CNMR(125MHz,CDCl3)δ196.6,173.6,156.3,153.7,153.2,148.3,146.7,140.5,138.9,137.5,137.0,132.4,131.5,129.8,128.85,128.78,128.6,128.3,128.1,127.3,125.1,122.4,106.3,108.2,102.9,83.3,77.34,77.26,77.0,76.7,70.6,68.6,62.4,58.9,45.0,18.3.
ESI+m/z616.3(M+H)+.
实施例2
2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙基-2-(4-异丁基苯)丙酸的合成
合成方法如实施例1。
1H NMR(400MHz,CDCl3)δ8.59(s,1H),7.83(s,1H),7.73(d,J=8.0Hz,1H),7.31-7.00(m,8H),4.52-4.46(m,1H),4.42-4.36(m,1H),4.16-4.14(m,4H),3.73-3.68(m,3H),3.40(s,3H),3.06(s,1H),2.39(d,J=7.2Hz,2H),1.81(m,1H),1.47(d,J=7.2Hz,3H),0.85(d,J=6.4Hz,6H);13C NMR(125MHz,CDCl3)δ174.5,156.4,154.1,153.4,148.6,147.1,140.5,138.8,137.3,129.4,129.2,128.8,127.6,127.0,125.1,122.6,122.4,109.3,108.5,103.4,83.3,77.4,77.3,76.7,70.8,69.2,66.5,62.3,59.2,44.9,29.6,22.3,18.5,13.9;
ESI+m/z568.3(M+H)+.
实施例3
2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙基-2-乙酰氧基苯甲酸的合成
合成方法如实施例1，其中步骤8中所用酰氯为购买的成品，非自制。
1H NMR(400MHz,CDCl3)δ8.61(s,1H),8.08(br.,1H),7.96(d,J=8.0Hz,1H),7.83-7.80(m,1H),7.72(d,J=8.0Hz,1H),7.51(dt,J=1.6,8.0Hz,1H),7.29-7.16(m,5H),7.06(d,J=8.0Hz,1H),4.62(t,J=4.0Hz,2H),4.31(t,J=4.0Hz,2H),4.12(t,J=4.0Hz,2H),3.70(t,J=4.4Hz,2H),3.34(s,3H),3.09(s,1H),2.31(s,3H);13CNMR(125MHz,CDCl3)δ169.8,164.0,156.3,153.9,153.4,150.6,148.6,133.9,131.7,129.9,128.8,127.5,125.9,123.6,122.5,122.3,119.1,117.4,109.4,108.6,103.0,83.3,77.4,77.3,77.0,76.7,70.6,68.9,66.5,62.8,20.8.
ESI+m/z542.0(M+H)+.
实施例4
2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙基-2-(6-甲氧基萘-2-烯)丙酸的合成
合成方法如实施例1。
1HNMR(400MHz,CDCl3)δ8.62(s,1H),7.89-7.05(m,9H),5.71-5.70(m,1H),4.68(m,2H),4.37-4.28(m,4H),3.82(m,2H),3.45(s,3H),3.11(s,1H),1.47(s,9H);13CNMR(125MHz,CDCl3)δ163.4,156.3,154.2,152.4,151.6,148.8,138.7,136.3,131.8,129.0,127.9,126.9,125.1,122.8,122.4,117.5,116.2,115.5,109.2,103.0,87.3,77.5,77.3,77.0,76.7,70.9,69.3,66.5,63.2,59.2,29.7,29.6,29.3,29.2.
实施例5
2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙基-2-(6-甲氧基萘-2-烯)丙酸的合成
合成方法如实施例1。
1H NMR(400MHz,CDCl3)δ8.66(s,1H),7.89(s,1H),7.79(d,J=8.0Hz,1H),7.62-7.59(m,3H),7.39-7.02(m,8H),4.54-4.52(m,2H),4.27(t,J=4.4Hz,2H),4.10(t,J=4.4Hz,2H),3.91-3.87(m,4H),3.68(t,J=4.4Hz,2H),3.42(s,3H),3.12(s,1H),1.59(d,J=6.8Hz,3H);13CNMR(125MHz,CDCl3)δ174.4,157.6,157.4,156.3,154.0,153.4,148.3,147.1,138.8,135.2,133.6,133.5,132.1,130.8,129.1,128.8,128.7,127.5,127.3,127.1,126.9,126.0,125.8,125.7,125.1,124.6,122.5,122.3,121.8,118.9,118.7,109.2,108.3,105.4,103.2,83.3,77.4,77.3,77.0,76.7,70.6,69.0,66.4,62.3,59.0,55.1,45.1,18.4.
ESI+m/z592.3(M+H)+.
实施例6
3-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙基-2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1H-吲哚-3-烯)乙酸的合成
合成方法如实施例1。
1H NMR(400MHz,CDCl3)δ8.64(s,1H),7.86(s,1H),7.76(t,J=8.4Hz,1H),7.61(d,J=8.4Hz,2H),7.42(d,J=8.4Hz,2H),7.36(t,J=8.0Hz,1H),7.27(d,J=5.2Hz,1H),7.21(dd,J=2.4,10.0Hz,2H),6.94(s,1H),6.84(d,J=8.8Hz,1H),6.63(dd,J=2.4,8.8Hz,1H),4.54(m,2H),4.50(m,2H),4.17(m,2H),3.75-3.68(m,6H),3.42(s,3H),3.09(s,1H),2.33(s,1H),1.56(d,J=7.2Hz,3H);13C NMR(125MHz,CDCl3)δ171.8,170.6,168.3,156.3,156.0,154.3,154.1,154.0,153.6,148.7,147.3,139.2,138.8,136.0,133.8,131.1,130.7,130.5,129.0,128.9,127.7,125.0,122.8,122.3,114.9,112.2,111.5,110.9,110.7,109.4,108.9,102.9,101.3,83.3,77.3,77.0,76.7,70.9,69.2,66.7,62.7,59.2,55.6,30.8,13.3.
ESI+m/z719.2M+.
实施例7
(E)-2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙基-2-(5-氟-2-甲基-1-(4-(甲亚硫酰基)苯亚甲基)-1H-茚-3-烯)乙酸的合成
步骤1,2,3,4,5,6,7同实施例1中步骤1,2,3,4,5,6,7。
步骤8
(E)-2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙基-2-(5-氟-2-甲基-1-(4-(甲亚硫酰基)苯亚甲基)-1H-茚-3-烯)乙酸的合成
将159mg舒林酸溶于2ml干燥的THF中，冰浴下加入184mgDCC（N,N'-二环己基碳二亚胺），使其自然升至室温反应1h合成活性酯。取100mg实施例1步骤7中所制得的产物2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙醇溶于6ml干燥的THF（四氢呋喃）中，加入11mgDMAP（4-二甲氨基吡啶），氩气保护，冰浴下加入上述活性酯。使其自然升至室温反应过夜，TLC跟踪至反应结束。将反应液抽滤，DCM洗涤，所得滤液减压浓缩后柱色谱分离得产物(E)-2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙基-2-(5-氟-2-甲基-1-(4-(甲亚硫酰基)苯亚甲基)-1H-茚-3-烯)乙酸189mg（88%）。
1H NMR(400MHz,CDCl3)δ8.73(s,1H),7.87(s,1H),7.78-7.07(m,12H),6.86-6.83(m,1H),6.51-6.47(m,1H),4.56(t,J=4.4Hz,2H),4.31(t,J=4.8Hz,2H),4.23(t,J=4.4Hz,2H),3.77(t,J=4.8Hz,2H),3.60-3.56(m,2H),3.43(s,3H),3.08(s,1H),2.79(s,3H),2.18(s,3H);13CNMR(125MHz,CDCl3)δ
ESI+m/z718.4(M+H)+.
实施例8
2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙基-4-(5,5,8,8-四甲基-5,6,7,8-四氢萘-2-烯氨基甲酰)苯甲酸的合成
合成方法如实施例6。
1H NMR(400MHz,CDCl3)δ8.81(s,1H),8.54(s,1H),7.95(d,J=8.4Hz,2H),7.82(d,J=8.8Hz,3H),7.72(d,J=8.0Hz,1H),7.57(s,1H),7.48-7.44(m,2H),7.23-7.15(m,4H),4.63(s,2H),4.31(s,2H),3.59(s,2H),3.24(s,3H),3.04(s,1H),1.63(s,4H),1.24-1.24(m,12H);13CNMR(125MHz,CDCl3)δ165.4,165.3,156.5,153.9,153.5,148.6,147.0,145.7,141.7,139.2,138.8,135.1,132.0,129.7,128.8,127.6,127.1,127.0,125.2,122.54,122.49,118.4,118.3,109.5,108.7,103.1,83.3,77.5,77.3,77.0,76.7,70.6,68.9,66.6,63.0,59.0,34.9,34.3,33.9,31.7;
ESI+m/z713.5(M+H)+.
实施例9
2-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-2-(4-苯甲酰苯)丙酸的合成
步骤1
6,7-二甲氧基喹唑酮的合成
称取30g2-氨基-4,5-二甲氧基苯甲酸甲酯悬浮于240ml甲酰胺中，加热至140℃反应24h，瓶中出现大量固体。冷却后过滤，滤饼用少量水洗涤后干燥得产物29.3g（87%）。
1H NMR(400MHz,DMSO)δ12.01(br.,1H),7.99(s,1H),7.44(s,1H),7.13(s,1H),3.90(s,3H),3.87(s,3H).
步骤2
6,7-二羟基喹唑酮的合成
在10g步骤1所合成的产物中加入85ml40%HBr溶液，水浴下缓慢加入30ml乙酸酐，撤去水浴，油浴加热至110℃反应1h后升至140℃反应36h，可看见瓶中出现大量白色固体。冷却后过滤，滤饼溶于75ml水中，加氨水调pH值至9，过滤，滤饼用75ml1MNaHCO3溶液洗涤，干燥得产物6.5g（75%）。1H NMR(400MHz,DMSO)δ7.78(s,1H),7.29(s,1H),6.84(s,1H).
步骤3
6,7-二乙酰氧基喹唑酮的合成
在7.6g步骤2所合成的产物6,7-二羟基喹唑酮中加入40ml乙酸酐及1ml吡啶，加热至130℃回流反应6h后冷却至室温，将反应液倒入100ml水中搅拌，析出大量灰白色固体，过滤，滤饼用少量水洗涤，干燥得产物6,7-二乙酰氧基喹唑酮9g（80%）。
1H NMR(400MHz,DMSO)δ12.41(s,1H),8.13(s,1H),7.97(s,1H),7.60(s,1H),2.34(s,3H),2.32(s,3H).
步骤4
6,7-二乙酰氧基-4-苯胺基喹唑啉的合成
将4g步骤3所合成的产物6,7-二乙酰氧基喹唑酮悬浮于100ml氯仿中，冰浴下缓慢滴入10ml三氯氧磷，完毕后撤去冰浴，加热至70℃反应2h后将反应液冷至室温，冰浴下加入15ml三乙胺后再继续加热至70℃反应12h。将反应液减压浓缩后用水稀释，乙酸乙酯萃取，依次饱和氯化钠水溶液洗涤，无水硫酸钠干燥后减压浓缩得中间氯代产物6,7-二乙酰氧基-4-氯喹唑啉3.4g。在上述氯代产物中加入60ml异丙醇和1.34g3-乙炔基苯胺，加热至70℃反应过夜，可见体系中出现大量固体，冷却后抽滤，滤饼用少量异丙醇洗涤得产物6,7-二乙酰氧基-4-苯胺基喹唑啉3g（55%）。
1H NMR(400MHz,DMSO)δ11.53(br.,1H),8.96-8.93(m,2H),7.94-7.93(m,2H),7.80(d,J=8.4Hz,1H),7.53(t,J=8.0Hz,1H),7.43(d,J=8.0Hz,1H),4.30(s,1H),2.43(s,3H),2.40(s,3H).
步骤5
6,7-二羟基-4-苯胺基喹唑啉的合成
将3g步骤4所制得的产物6,7-二乙酰氧基-4-苯胺基喹唑啉溶于40ml甲醇中，加入5ml氨水，室温反应。TLC跟踪至反应结束，将反应液减压浓缩得产物6,7-二羟基-4-苯胺基喹唑啉2.3g（100%）。
1H NMR(400MHz,DMSO)δ9.87(br.,1H),8.52(s,1H),8.00(s,1H),7.85(s,1H),7.41-7.19(m,4H),4.27(s,1H);
ESI+m/z278.0(M+H)+.
步骤6
4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-醇的合成
将1g步骤5所制得的产物6,7-二羟基-4-苯胺基喹唑啉溶于10ml干燥的DMF中，加入1g无水碳酸钾以及486mg2-溴乙基甲基醚，维持20℃反应2d。将反应液用水稀释，乙酸乙酯萃取，依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥后减压浓缩，粗产品柱色谱分离得产物4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-醇620mg(62%)。
1H NMR(400MHz,MeOD)δ8.42(s,1H),7.93(s,1H),7.79-7.75(m,1H),7.71(s,1H),7.40(t,J=8.0Hz,1H),7.29-7.26(m,1H),7.21(m,1H),4.39(t,J=4.4Hz,2H),3.93(t,J=4.4Hz,2H),3.51(s,4H).
步骤7
4-(4-苯甲酰苯)-1-溴-3-戊酮的合成
在2g酮洛芬中加入3ml2-溴乙醇，冰浴下缓慢滴加1.2ml二氯亚砜。将反应液升温至80℃反应，TLC跟踪至反应结束。将反应液用水稀释，乙酸乙酯萃取，依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥后减压浓缩，粗产品柱色谱分离得产物4-(4-苯甲酰苯)-1-溴-3-戊酮1.9g(70%)。
1H NMR(400MHz,CDCl3)δ7.81-7.76(m,3H),7.69(d,J=8.0Hz,1H),7.61-7.55(m,2H),7.50-7.43(m,3H),4.40(dt,J=2.4,6.0,8.4Hz,2H),3.87(q,J=7.2Hz,1H),3.47(t,J=6.0Hz,2H),1.57(d,J=7.2Hz,3H).
ESI+m/z362.2(M+H)+.
步骤8
2-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-2-(4-苯甲酰苯)丙酸的合成
在100mg步骤6所制得的产物4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-醇中，加入150mg步骤7所制得的产物4-(4-苯甲酰苯)-1-溴-3-戊酮，124mg无水碳酸钾，25mg碘化钾以及3ml干燥的DMF，40℃反应。TLC跟踪至反应结束。将反应液用水稀释，乙酸乙酯萃取，依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥后减压浓缩，粗产品柱色谱分离得产物2-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-2-(4-苯甲酰苯)丙酸152mg(83%)。
1H NMR(400MHz,CDCl3)δ8.13(s,1H),7.93-7.20(m,14H),4.53-4.44(m,2H),4.28-4.18(m,4H),3.91(q,J=7.2Hz,1H),3.82(t,J=4.8Hz,2H),3.43(s,3H),3.04(s,1H),1.60(d,J=7.2Hz,3H);13CNMR(125MHz,CDCl3)δ196.9,174.7,156.4,154.3,153.8,147.9,147.7,140.6,139.1,137.9,137.2,132.6,131.5,129.9,129.3,128.9,128.8,128.6,128.2,127.4,124.8,122.6,122.0,109.3,109.0,103.5,83.5,77.3,77.0,76.7,70.4,68.3,66.6,61.9,59.2,45.4,18.3.
ESI+m/z616.3(M+H)+.
实施例10
2-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-2-(4-异丁基苯)丙酸的合成
步骤1,2,3,4,5,6同实施例9的步骤1,2,3,4,5,6。
步骤7
2-溴乙基-2-(4-异丁基苯)丙酸的合成
合成方法同实施例9步骤7。
1HNMR(400MHz,CDCl3)δ7.24(d,J=8.0Hz,2H),7.12(d,J=8.0Hz,2H),4.42-4.30(m,2H),3.78(q,J=7.2Hz,1H),3.47(dt,J=0.8,6.0,6.4Hz,2H),2.47(d,J=7.2Hz,2H),1.91-1.80(m,1H),1.53(d,J=7.2Hz,3H),0.92(d,J=6.8Hz,6H).
ESI+m/z313.8(M+H)+.
步骤8
2-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-2-(4-异丁基苯)丙酸的合成
1H NMR(400MHz,CDCl3)δ8.64(s,1H),8.28(br.,1H),7.98(s,1H),7.91(d,J=8.0Hz,1H),7.62(s,1H),7.30-7.03(m,7H),4.45-4.35(m,2H),4.20-4.18(m,4H),3.79-3.74(m,3H),3.40(s,3H),3.08(s,1H),2.40(d,J=6.8Hz,2H),1.82-1.75(m,1H),1.53(d,J=7.2Hz,3H),0.86(d,J=6.4Hz,6H);13CNMR(125MHz,CDCl3)δ175.3,156.3,153.9,153.4,147.8,146.9,140.5,139.1,137.0,129.2,128.6,127.1,126.9,124.5,122.4,121.7,109.1,108.2,102.5,83.3,77.26,77.23,77.0,76.7,70.2,68.1,66.0,61.4,58.9,44.8,44.7,29.9,29.5,22.1,18.3.
实施例11
2-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-2-乙酰氧基苯甲酸的合成
步骤1,2,3,4,5,6同实施例9的步骤1,2,3,4,5,6。
步骤7
4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-醇的合成
在400mg实施例9步骤6所制得的产物4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-醇中，加入240mg2-溴乙基乙酸酯，307mg无水碳酸钾，20mg碘化钾以及4ml干燥的DMF,40℃反应。TLC跟踪至反应结束。将反应液用水稀释，乙酸乙酯萃取，依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥后减压浓缩，粗产品未经分离直接投入下一步反应。
将上述反应粗产物溶于5ml甲醇中，加入200mgKOH，室温反应过夜。TLC跟踪至反应结束。将反应液直接减压浓缩后柱色谱分离得产物389mg(86%)。
步骤8
2-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-2-乙酰氧基苯甲酸的合成
将300mg步骤7所制得的产物4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-醇溶于10ml干燥的THF中，冰浴下加入0.25ml干燥的Et3N，搅拌10min后加入344mg邻乙酰基苯甲酰氯，使其自然升至室温反应过夜，TLC跟踪至反应结束。将反应液用水稀释，乙酸乙酯萃取，依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥后减压浓缩，粗产品柱色谱分离得产物2-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-2-乙酰氧基苯甲酸240mg（56%）。
1H NMR(400MHz,CDCl3)δ8.55(s,1H),8.51(br.,1H),7.79-6.68(m,10H),4.49(m,2H),4.15-4.08(m,4H),3.67(m,2H),3.30(s,3H),3.08(s,1H),2.26(s,3H);13CNMR(125MHz,CDCl3)δ170.2,164.0,156.3,154.0,153.2,150.1,147.8,138.8,135.6,133.8,131.3,129.6,128.4,127.1,125.7,124.9,124.8,123.3,122.3,122.1,118.9,117.1,109.0,107.9,83.23,83.19,77.3,77.0,76.7,70.0,68.0,62.8,58.7,20.7.
实施例12
2-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-7-叔丁基-6-氯-2-(三氟甲基)-2H-吡喃-3-羧酸的合成
步骤1,2,3,4,5,6同实施例9的步骤1,2,3,4,5,6。
步骤7
2-溴乙基-7-叔丁基-6-氯-2-(三氟甲基)-2H-苯并吡喃-3-羧酸的合成
合成方法同实施例9步骤7。
1H NMR(400MHz,CDCl3)δ7.69(s,1H),7.22(s,1H),7.06(s,1H),5.74(q,J=6.8Hz,1H),4.63-4.53(m,2H),3.63(t,J=6.4Hz,2H),1.48(s,9H).
步骤8
2-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-7-叔丁基-6-氯-2-(三氟甲基)-2H-吡喃-3-羧酸的合成
合成方法同实施例9步骤8。
1H NMR(400MHz,CDCl3)δ8.67(s,1H),7.92-7.02(m,10H),5.72-5.70(m,1H),4.70-4.65(m,2H),4.42-4.39(m,2H),4.28-4.26(m,2H),4.14-4.11(m,2H),3.45(s,3H),3.11(s,1H),1.46(s,9H).
实施例13
2-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-2-(6-甲氧基萘-2-烯)丙酸的合成
步骤1,2,3,4,5,6同实施例9的步骤1,2,3,4,5,6。
步骤7
2-溴乙基-2-(6-甲氧基萘-2-烯)丙酸的合成
合成方法同实施例9步骤7。
1H NMR(400MHz,CDCl3)δ7.72-7.69(m,3H),7.43(dd,J=1.6,8.4Hz,1H),7.16-7.12(m,2H),4.44-4.32(m,2H),3.95-3.86(m,4H),3.47(dt,J=1.2,6.0,7.2Hz,2H),1.62(d,J=7.2Hz,3H).
步骤8
2-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-2-(6-甲氧基萘-2-烯)丙酸的合成
合成方法同实施例9步骤8。
1H NMR(400MHz,CDCl3)δ8.12(s,1H),8.01-7.04(m,13H),4.44(m,2H),4.19(m,4H),3.88(m,4H),3.76(m,2H),3.40(s,3H),3.10(s,1H),1.63(d,J=7.2Hz,3H);13CNMR(125MHz,CDCl3)δ175.3,157.5,156.2,153.9,153.5,147.8,147.1,139.1,134.9,133.5,129.0,128.7,127.2,127.1,124.5,122.5,121.7,118.9,109.1,108.5,105.4,102.5,83.4,77.29,77.25,77.0,76.7,70.2,68.1,66.0,65.5,61.5,59.0,45.2,18.3.
ESI+m/z591.7M+.
实施例14
3-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1H-吲哚-3-烯)乙酸的合成
步骤1,2,3,4,5,6同实施例9的步骤1,2,3,4,5,6。
步骤7
2-溴乙基-2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1H-吲哚-3-烯)乙酸的合成
合成方法同实施例9步骤7。
1H NMR(400MHz,CDCl3)δ7.67(d,J=8.4Hz,2H),7.48(d,J=8.4Hz,2H),6.98(d,J=2.4Hz,1H),6.89(d,J=9.2Hz,1H),6.69(dd,J=2.8,9.2Hz,1H),4.43(t,J=6.0Hz,2H),3.84(s,3H),3.71(s,2H),3.52(t,J=6.0Hz,2H),2.40(s,3H).
ESI+m/z464.2M+.
步骤8
3-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1H-吲哚-3-烯)乙酸的合成
合成方法同实施例9步骤8。
1H NMR(400MHz,CDCl3)δ8.59(s,1H),8.20(s,1H),7.89(s,1H),7.63-7.12(m,9H),6.90(s,1H),6.77(d,J=8.8Hz,1H),6.58(d,J=8.8Hz,1H),4.39(m,2H),3.78-3.66(m,7H),3.37(s,3H),3.05(s,1H),2.30(s,3H);13CNMR(125MHz,CDCl3)δ171.1,168.1,156.3,155.7,154.1,153.5,147.8,147.2,139.1,138.8,135.9,133.4,130.9,130.6,130.3,128.9,128.6,127.3,124.8,122.4,122.0,114.7,112.0,111.1,109.1,108.4,103.2,101.4,83.3,77.3,77.0,76.7,70.2,68.0,66.7,62.2,58.9,55.4,29.9,13.1.
实施例15
(E)-2-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-2-(5-氟-2-甲基-1-(4-(甲亚硫酰基)苯亚甲基)-1H-茚-3-烯)乙酸的合成
步骤1,2,3,4,5,6,7同实施例11的步骤1,2,3,4,5,6,7。
步骤
8(E)-2-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-2-(5-氟-2-甲基-1-(4-(甲亚硫酰基)苯亚甲基)-1H-茚-3-烯)乙酸的合成。
合成方法同实施例7步骤8
1H NMR(400MHz,CDCl3)δ8.66(s,1H),7.98(s,1H),7.71-7.10(m,11H),6.87(dd,J=2.0,8.8Hz,1H),6.58-6.47(m,1H),4.55(t,J=5.6Hz,2H),4.34(t,J=5.6Hz,2H),4.26(t,J=4.4Hz,2H),3.83(t,J=4.4Hz,2H),3.63(s,2H),3.44(s,3H),3.07(s,1H),2.79(s,3H),2.16(s,3H);
ESI+m/z718.1(M+H)+.
实施例16
2-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-4-(5,5,8,8-四甲基-5,6,7,8-四氢萘-2-烯氨基甲酰)苯甲酸的合成
步骤1,2,3,4,5,6同实施例9的步骤1,2,3,4,5,6。
步骤7
2-溴乙基-4-(5,5,8,8-四甲基-5,6,7,8-四氢萘-2-烯氨基甲酰)苯甲酸的合成
合成方法同实施例9步骤7。
1H NMR(400MHz,CDCl3)δ8.16(d,J=8.0Hz,2H),7.94(d,J=8.4Hz,2H),7.54(s,1H),7.45(d,J=8.0Hz,1H),7.32(d,J=8.8Hz,1H),4.67(t,J=6.0Hz,2H),3.68(t,J=6.0Hz,2H),1.69(s,4H),1.29-1.28(m,12H).
ESI+m/z459.1(M+H)+.
步骤8
2-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-4-(5,5,8,8-四甲基-5,6,7,8-四氢萘-2-烯氨基甲酰)苯甲酸的合成。
合成方法同实施例9步骤8
1H NMR(400MHz,CDCl3)δ8.52(s,1H),8.30(s,1H),8.02(d,J=8.4Hz,2H),7.91-7.82(m,4H),7.59(d,J=12.4Hz,2H),7.45(d,J=8.4Hz,1H),7.32-7.21(m,4H),4.69(t,J=5.6Hz,2H),4.23(t,J=5.6Hz,1H),4.15(t,J=4.4Hz,2H),3.75(d,J=4.4Hz,2H),3.36(s,3H),3.09(s,1H),1.67(s,4H),1.26(s,12H);13CNMR(125MHz,CDCl3)δ175.9,166.1,164.9,156.5,154.5,152.8,148.3,145.8,145.7,141.9,139.6,138.8,135.0,131.9,130.0,129.0,128.8,127.7,127.2,124.8,122.7,122.0,118.4,118.3,108.9,107.5,103.3,83.4,77.5,77.3,77.0,76.7,70.3,68.4,66.7,65.6,62.7,59.1,35.0,34.9,34.4,34.0,31.81,31.78,30.6,29.7,21.0.
ESI+m/z713.9(M+H)+.
实施例17
2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)双(乙基-2,1-二烯)-双(2-(4-苯甲酰苯)丙酸)的合成
步骤1,2,3,4,5,6同实施例9的步骤1,2,3,4,5,6。
步骤7
2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)双(乙基-2,1-二烯)-双(2-(4-苯甲酰苯)丙酸)的合成
在150mg实施例9步骤5所制得的产物6,7-二羟基-4-苯胺基喹唑啉中加入565mg实施例9步骤7所制得的产物4-(4-苯甲酰苯)-1-溴-3-戊酮，497mg无水碳酸钾，24mg碘化钾以及5ml干燥的DMF，40℃反应过夜，TLC跟踪至反应结束。将反应液用水稀释后，乙酸乙酯萃取，依次饱和氯化钠溶液洗涤，无水硫酸钠干燥后减压浓缩，粗产品柱色谱分离得产物2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)双(乙基-2,1-二烯)-双(2-(4-苯甲酰苯)丙酸)320mg（71%）。
1H NMR(400MHz,CDCl3)δ8.64(s,1H),8.27(br.,1H),7.94(s,1H),7.83-7.14(m,23H),4.52(t,J=4.4Hz,2H),4.47-4.37(m,2H),4.24-4.18(m,4H),3.90-3.80(m,2H),3.06(s,1H),1.58(d,J=7.2Hz,3H),1.55(dd,J=3.2,6.8Hz,3H);13CNMR(125MHz,CDCl3)δ186.0,187.0,174.4,173.7,156.4,153.8,147.8,140.6,140.5,139.0,137.8,137.7,137.2,137.0,132.5,132.4,131.5,131.4,129.8,129.2,128.93,128.92,128.90,128.86,128.74,128.70,128.5,128.4,128.3,128.19,128.16,128.12,128.09,127.3,124.9,121.5,122.0,109.5,109.0,103.8,83.4,77.3,77.2,77.0,76.7,66.65,66.60,62.5,62.0,45.2,45.1,18.4,18.3.
ESI+m/z838.2(M+H)+.
实施例18
2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)双(乙基-2,1-二烯)-双(2-(4-异丁基苯)丙酸)的合成
合成方法同实施例17。
1H NMR(400MHz,CDCl3)δ8.65(s,1H),8.29(br.,1H),7.99(s,1H),7.93(d,J=8.0Hz,1H),7.63(s,1H),7.31-7.03(m,11H),4.52-4.41(m,4H),4.20-4.18(m,4H),3.78-3.73(m,2H),3.09(s,1H),2.41(d,J=7.2Hz,4H),1.83-1.78(m,2H),1.55(d,J=6.4Hz,3H),1.50(d,J=7.2Hz,3H),0.88(d,J=6.8Hz,12H);13CNMR(125MHz,CDCl3)δ175.3,174.4,156.2,153.6,153.4,147.7,146.9,140.5,140.3,139.0,137.2,137.0,129.2,129.1,128.6,127.1,126.9,124.5,122.4,121.7,109.2,108.6,103.2,83.3,77.3,77.25,77.0,76.7,66.5,66.3,62.2,61.5,44.8,44.74,44.71,29.9,22.13,22.11,18.4,18.3.
实施例19
2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)双(乙基-2,1-二烯)-双(2-乙酰氧基苯甲酸)的合成
步骤1,2,3,4,5,6同实施例9的合成步骤1,2,3,4,5,6。
步骤7
2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)二乙醇的合成
在500mg实施例9步骤5所制得的产物6,7-二羟基-4-苯胺基喹唑啉中加入903mg2-溴乙基乙酸酯，1.24g无水碳酸钾，150mg碘化钾，10ml干燥的DMF，50℃反应过夜，TLC跟踪至反应结束。将反应液用水稀释后，乙酸乙酯萃取，依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥后减压浓缩，所得粗产品未经分离直接投入下一步反应。
将上述反应所制得的粗产物溶于20ml甲醇中，加入500mgKOH，室温搅拌反应过夜，TLC跟踪至反应结束。将反应液直接减压弄死后柱色谱分离得产物2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)二乙醇520mg（79%）。
ESI+m/z366.0(M+H)+.
步骤8
2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)双(乙基-2,1-二烯)-双(2-乙酰氧基苯甲酸)的合成
将260mg步骤7所制得的产物2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)二乙醇溶于1ml干燥的THF中，冰浴下加入0.65mldryEt3N，搅拌10min后缓慢加入430mg邻乙酰基苯甲酰氯溶于3ml干燥的THF的溶液，使其自然升至室温反应，TLC跟踪至反应结束。将反应液用水稀释，乙酸乙酯萃取，依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥后减压浓缩，粗产品柱色谱分离得产物2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)双(乙基-2,1-二烯)-双(2-乙酰氧基苯甲酸)270mg(54%)。
1H NMR(400MHz,CDCl3)δ8.58(s,1H),8.39(br.,1H),7.91-6.95(m,14H),4.56-4.67(m,4H),4.24-4.17(m,4H),3.11(s,1H),2.27(s,6H);13CNMR(125MHz,CDCl3)δ169.42,169.39,164.1,163.8,156.2,153.8,153.3,150.4,150.3,150.1,147.9,146.8,138.7,135.6,133.9,133.8,131.43,131.36,129.7,129.6,128.4,127.2,125.8,124.8,123.5,123.3,122.3,122.1,118.9,111.7,109.2,108.3,83.2,77.35,77.26,77.0,76.7,67.4,66.4,62.9,62.6,20.7,20.6.
实施例20
3,3'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)双(乙基-2,1-二烯)-双(丙基-3,1-二烯)双(2-(6-甲氧基萘-2-烯)丙酸)的合成
合成方法同实施例17。
1H NMR(400MHz,CDCl3)δ8.69(s,1H),8.05-6.98(m,19H),4.50(m,2H),4.36(t,J=6.0Hz,2H),4.22(m,2H),4.08(t,J=6.0Hz,2H),3.94-3.69(m,8H),3.13(s,1H),1.66(d,J=6.8Hz,3H),1.57(d,J=7.2Hz,3H);13CNMR(125MHz,CDCl3)δ175.5,174.4,157.7,157.5,156.1,153.7,153.6,147.6,147.1,139.1,135.3,135.0,133.7,133.5,129.08,129.07,128.84,128.78,128.7,127.2,127.0,126.0,125.9,125.7,124.3,122.6,121.5,119.1,118.7,109.2,108.8,105.5,105.4,102.9,83.5,77.33,77.25,77.0,76.7,66.5,66.1,62.4,61.3,55.2,55.1,45.34,45.32,45.2,18.44,18.40.
实施例21
2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)双(乙基-2,1-二烯)-双(7-7-叔丁基-6-氯-2-(三氟甲基)-2H-吡喃-3-羧酸)的合成
合成方法同实施例17。
1H NMR(400MHz,MeOD)δ8.38(s,1H),7.94(s,1H),7.83(s,1H),7.75(d,J=8.0Hz,1H),7.62(d,J=2.0Hz,1H),7.53(d,J=4.0Hz,1H),7.36(t,J=8.0Hz,1H),7.25-7.23(m,2H),7.17(s,1H),7.06(s,1H),6.98(s,1H),5.73(dt,J=6.8,12.0,18.8Hz,1H),4.77-4.74(m,2H),4.65-4.61(m,2H),4.53-4.52(m,2H),3.51(s,1H),1.44(s,9H),1.41(s,9H);13CNMR(125MHz,CDCl3)δ164.2,163.4,156.3,154.0,152.8,152.4,151.6,151.6,148.0,147.5,138.9,137.1,136.4,131.9,131.8,129.0,127.6,127.0,126.9,124.5,124.4,122.7,122.1,121.8,117.5,117.3,116.1,115.8,115.6,115.5,109.5,109.4,103.3,83.4,77.3,77.0,76.7,71.1,70.8,70.6,70.3,66.7,66.5,63.2,62.3,36.6,29.2.
实施例22
2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)双(乙基-2,1-二烯)-双(2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1H-吲哚-3-烯)乙酸)的合成
合成方法同实施例17。
实施例23
(E)-2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)双(乙基-2,1-二烯)-双(2-((E)-5-氟-2-甲基-1-(4-(甲亚硫酰基)苯亚甲基)-1H-茚-3-烯)乙酸)的合成
步骤1,2,3,4,5,6,7同实施例19的步骤1,2,3,4,5,6,7。
步骤8
(E)-2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)双(乙基-2,1-二烯)-双(2-((E)-5-氟-2-甲基-1-(4-(甲亚硫酰基)苯亚甲基)-1H-茚-3-烯)乙酸)的合成
将741mg舒林酸溶于5ml干燥的THF中，冰浴下加入430mgDCC搅拌，维持0℃反应2h制成活化酯待用。
取185mg实施例19步骤7所制得的产物2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)二乙醇溶于6ml干燥的THF中，加入30mgDMAP，冰浴下缓慢加入上述活化酯，使其自然升至室温反应过夜，TLC跟踪至反应结束。将反应液用水稀释后，乙酸乙酯萃取，依次用饱和氯化钠溶液洗涤，无水硫酸钠干燥后减压浓缩，粗产品柱色谱分离得产物(E)-2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)双(乙基-2,1-二烯)-双(2-((E)-5-氟-2-甲基-1-(4-(甲亚硫酰基)苯亚甲基)-1H-茚-3-烯)乙酸)250mg(46%）。
1H NMR(400MHz,CDCl3)δ8.64(d,J=4.0Hz,1H),7.68-7.08(m,18H),6.86-6.83(m,2H),6.50(t,J=8.8Hz,2H),4.55-4.49(m,4H),4.31-4.30(m,4H),3.61-3.59(m,4H),3.08(s,1H),2.79-2.77(m,6H),2.15-2.14(m,6H);13C NMR(125MHz,CDCl3)δ170.7,170.0,164.1,162.20,162.16,156.4,153.8,153.7,148.0,147.4,146.6,146.5,146.4,145.3,145.2,141.4,141.3,139.6,139.4,139.0,138.5,138.4,131.41,131.4,129.39,129.37,128.8,128.5,128.2,127.4,124.9,123.78,123.77,123.63,123.55,123.5,122.5,122.1,110.8,110.7,110.65,110.55,109.4,109.0,106.1,106.0,105.8,103.4,83.5,77.3,77.0,76.7,66.9,66.6,62.7,43.71,43.66,31.6,31.5,10.4.
ESI+m/z1042.7(M+H)+.
实施例24
2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)双(乙基-2,1-二烯)-双(4-(5,5,8,8-四甲基-5,6,7,8-四氢萘-2-烯氨基甲酰)苯甲酸)的合成
合成方法同实施例17。
1H NMR(400MHz,CDCl3)δ8.69-8.56(m,3H),7.93-7.21(m,19H),4.69(s,2H),4.54(s,2H),4.39(s,2H),4.31(s,2H),3.05(s,1H),1.66-1.65(m,8H),1.28-1.24(m,24H);13C NMR(125MHz,CDCl3)δ165.7,165.5,156.6,153.84,153.78,148.2,147.2,145.8,145.7,141.8,139.6,139.3,138.9,135.2,135.1,132.1,131.7,129.9,129.8,129.7,128.9,127.6,127.25,127.16,127.1,125.1,122.6,122.3,118.41,118.37,109.6,108.9,103.4,83.4,77.3,77.0,76.7,66.9,66.7,63.0,62.8,38.7,34.98,34.96,34.3,34.0,31.8,31.74,31.72.
ESI+m/z1033.2(M+H)+.
下面为本发明化合物生物活性测定结果
实验材料：
H1975/HCC827：人非小细胞肺癌细胞，PBS，MTT，DMEM培养基，胰酶，多通道移液器，涡旋振荡器，多孔酶标仪，生物安全柜，5%CO2细胞培养箱，细胞计数仪，显微镜，恒温水浴锅，96孔板
实验方法：
1.H1975/HCC827细胞用PBS清洗后使用胰酶消化，室温1000rpm离心5分钟，用适量的培养基重悬，使用细胞计数板进行计数，按照1000-2000个/孔/100μl，使用多通道移液器，接种到96孔板中，每个浓度设6个复孔，共计6个浓度梯度。细胞数目的依据：最终检测OD570在0.2-0.8之间（朗伯-比尔定律）。
2.将化合物用DMSO配成10mol/l的母液。将10μl母液加入到90μlDMSO中，使用涡旋振荡器混匀，依次逐级稀释5次，配制成DMSO储存液，放置于4℃待用。使用前再次混匀并按照1:500将储存液加入到完全培养基中作为工作液，使用涡旋振荡器混匀。工作液需要现用现配，以防止长时间放置导致析出。
3.96孔板在细胞培养箱中培养24小时后，将100μl化合物工作液加入，继续共培养72小时。
4.小心吸去上层培养基，重新加入100μl含MTT（0.5mg/ml）的培养基，培养箱中放置4小时。培养基去除干净，加入100μlDMSO，震荡混匀。MTT的配制：1.25gMTT加入到250mlPBS中，混匀，4℃避光保存。
5.使用多孔板酶标仪检测570nm或者490nm的吸光值。使用Graphpad进行EC50的计算及对增值曲线进行做图。
下表为部分化合物的生物活性数据：
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (7)
1.通过酯键连接的NSAID类抗炎止痛药物和EGFR抑制剂的偶联化合物或者其药学上可接受的盐：
所述偶联化合物选自以下：
2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙基-2-乙酰氧基苯甲酸、
2-(4-(3-乙炔基苯胺)-7-(2-甲氧基乙氧基)喹唑啉-6-氧基)乙基-7-叔丁基-6-氯-2-(三氟甲基)-2H-吡喃-3-羧酸、
2-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-2-(4-异丁基苯)丙酸、
2-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-2-乙酰氧基苯甲酸、
2-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-2-(6-甲氧基萘-2-烯)丙酸、
3-(4-(3-乙炔基苯胺)-6-(2-甲氧基乙氧基)喹唑啉-7-氧基)乙基-2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1H-吲哚-3-烯)乙酸、
2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)双(乙基-2,1-二烯)-双(2-(4-苯甲酰苯)丙酸)、
2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)双(乙基-2,1-二烯)-双(2-乙酰氧基苯甲酸)、
2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)双(乙基-2,1-二烯)-双(7-7-叔丁基-6-氯-2-(三氟甲基)-2H-吡喃-3-羧酸)、
2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)双(乙基-2,1-二烯)-双(2-(1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1H-吲哚-3-烯)乙酸)
2,2'-(4-(3-乙炔基苯胺)喹唑啉-6,7-二烯)双(氧)双(乙基-2,1-二烯)-双(4-(5,5,8,8-四甲基-5,6,7,8-四氢萘-2-烯氨基甲酰)苯甲酸)。
2.权利要求1所述的通过酯键连接NSAID类抗炎止痛药物和EGFR抑制剂的偶联化合物的合成方法，其特征是，该合成方法为：
1)、在适当的条件下，NSAID类抗炎止痛类药物先和卤代烷或醇发生酯化反应，得到酯化产物中间体，所述适当条件包括酰氯或羧酸活化酯与醇酯化的条件、酸与醇直接缩合的条件、或羧酸或其盐与卤代物酯化的条件；制备的酯化产物中间体再与具有式Ⅳ，Ⅴ或Ⅵ所示结构的EGFR抑制剂所含的酚羟基或其盐发生醚化反应，得到偶联化合物；
或2)、NSAID类抗炎止痛类药物与具有式Ⅶ，Ⅷ或Ⅸ所示结构的EGFR抑制剂所含的羟基或其盐发生酯化反应，得到偶联化合物；
上述NSAID类抗炎止痛类药物包括所述NSAID类抗炎止痛类药物及其酸、羧酸盐、酰氯和羧酸活化酯中的任一种。
3.根据权利要求2所述的合成方法，其特征是，所述醇为2-溴乙醇，2-氯乙醇，或2-碘乙醇；所述卤代烷为1,2-二溴乙烷，1-溴-2-氯乙烷，或1,2-二氯乙烷。
4.一种***的药用组合物，其药学活性成份包括有权利要求1所述的通过酯键连接NSAID类抗炎止痛药物和EGFR抑制剂的化合物或者其药学上可接受的盐。
5.权利要求1所述的通过酯键连接NSAID类抗炎止痛药物和EGFR抑制剂的偶联化合物或者其药学上可接受的盐在制备肿瘤药物中的应用。
6.根据权利要求5所述的应用，所述肿瘤为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌。
7.根据权利要求5所述的应用，所述所述肿瘤为胰腺癌、乳腺癌、***癌、肝癌、皮肤癌、上皮细胞癌、胃肠间质瘤、白血病、组织细胞性淋巴癌、鼻咽癌、结肠直肠癌。
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