CN110498796A - 一种含磺酰氟基团的他达那非类似物及其合成方法 - Google Patents
一种含磺酰氟基团的他达那非类似物及其合成方法 Download PDFInfo
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Abstract
本发明公开一种其通式如式1至所示含磺酰氟基团的他达那非类似物,及其制备方法和用途。本发明的化合物物可以在制备抗肿瘤药物中应用,具有一定的体外抗肿瘤活性,可用于制备抗肿瘤药物。本发明的制备合成工艺操作简单、不使用金属试剂、环境污染少、条件温和。
Description
技术领域
本发明涉及一种含磺酰氟基团的他达那非类似物及其合成方法。
背景技术
他达那非(Tadalafil)是一种5型磷酸二酯酶(PDE5)抑制剂,由lilly-Icos公司研发,2003年经FDA批准,作为治疗男性勃起功能障碍的药物在美国上市。而且发现该药物另外一种临床应用是治疗肺动脉高压。与同类药物相比,其具有选择性高,半衰期长,患者有更大的自主性等优点。
发明内容
本发明的第一个目的是:用磺酰氟气体对含有氨基以及羟基的药物进行磺酰氟化,得到一种含磺酰氟基团的他达那非类似物,预期这些类似物可对药物的药效产生积极的影响;本发明的第二个目的是提供用于制备这类化合物的中间化合物;本发明的第三个目的是提供制备本发明化合物的方法。
本发明的一种含磺酰氟基团的他达那非类似物,其结构式如式1所示。
其中,R1是(C1-C6)烷氧基、(C1-C6)烷基氨基;R2是自由氢、(C1-C6)酰氧基、(C1-C6)烷基、2-卤代乙酰氧基。
优选地,本发明的含磺酰氟基团的他达那非类似物,其结构式如式2所示
优选地,本发明的含磺酰氟基团的他达那非类似物,其结构式如式53所示
优选地,本发明的含磺酰氟基团的他达那非类似物,其结构式如式4
所示,其中:R3是(C1-C6)酰氧基、(C1-C6)烷基。
优选地,本发明的含磺酰氟基团的他达那非类似物,其结构式如式5所示
优选地,本发明的含磺酰氟基团的他达那非类似物,其结构式如式6所示
本发明用于制备前述的含磺酰氟基团的他达那非类似物的中间化合物是1-(苯并[d][1,3]二氧杂环戊烯-5-基)-6-((氟磺酰基)氧基)-2,3,4,9-四氢-1H-吡
啶并[3,4-b]吲哚--3-羧酸甲酯的一对对映异构体(+/-)-TDA-05,其结构式如式7所示。
本发明用于制备前述的的含磺酰氟基团的他达那非类似物的中间化合物是1-(苯并[d][1,3]二氧杂环戊烯-5-基)-6-((氟磺酰基)氧基)-2,3,4,9-四氢-1H-
吡啶并[3,4-b]吲哚--3-羧酸甲酯的一对对映异构体(+/-)-TDA-06,其结构式如式3所示。
本发明用于制备前述的的含磺酰氟基团的他达那非类似物的中间化合物是
1-(苯并[D][1,3]二氧基-5-基)-2-(2-氯乙酰基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-甲酸酯的一对对映异构体的(+/-)-TDA-07,其结构式如式X3所示:
本发明用于制备前述的的含磺酰氟基团的他达那非类似物的中间化合物是
1-(苯并[D][1,3]二氧基-5-基)-2-(2-氯乙酰基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-甲酸酯的一对对映异构体的(+/-)-TDA-08,其结构式如式X4所示。
上述的每两个化合物一组形成一个外消旋结构,检测活性的时候是检测外消旋化合物。
本发明的1-(苯并[D][1,3]二氧杂环戊烯-5-基)-2-(2-氯乙酰基)-6-((氟磺酰基)氧基)-2,3,4,9-四氢-1H-吡啶基甲基并[3,4-b]吲哚-3-羧酸甲酯的两对互
为差向异构体的对映异构体的(+/-)-TDA-09或(+/-)-TDA-10的制备方法如式11,即:分别将1-(苯并[d][1,3]二氧杂环戊烯-5-基)-6-((氟磺酰基)氧基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯的两对互为差向异构体的对映异构体(+/-)-TDA-05或(+/-)-TDA-06与氯乙酰氯在三乙胺存在下发生酰化反应得到目标产物。
本发明所述中间化合物1-(苯并[d][1,3]二氧杂环戊烯-5-基)-6-((氟磺酰基)氧基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯的两对互为差向异构体的对映异构体(+/-)-TDA-05或(+/-)-TDA-06的制备方法如式12所示,即:分别将1-(苯并[D][1,3]二氧基-5-基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯的两对互为差向异构体的对映异构体(+/-)-TDA-03或(+/-)-TDA-04与磺酰氟气体在三乙胺催化下发生磺酰氟化反应得到中间化合物
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-6-((氟磺酰基)氧基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯的两对互为差向异构体的对映异构体(+/-)-TDA-05或(+/-)-TDA-06。
本发明的含磺酰氟基团的他达那非类似物的制备方法如式13所示,即:
将6-(苯并[1,3]二氧基-5-基)-10-羟基-2-甲基-2-3,6-,7-,12-,12-六氢吡嗪-[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮的两对互为差向异构体的对映异构体(+/-)-TDA-11或(+/-)-TDA-12与磺酰氟气体在三乙胺催化下发生磺酰氟化反应得到目标产物(+/-)-TDA-13与(+/-)-TDA-14。
本发明的含磺酰氟基团的他达那非类似物的制备方法如式14所示,即:分
别将1-(苯并[D][1,3]二氧基-5-基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯的两对互为差向异构体的对映异构体(+/-)-TDA-03或(+/-)-TDA-04与氯乙酰氯发生酰化反应得到1-(苯并[D][1,3]二氧基-5-基)-2-(2-氯乙酰基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-甲酸酯的两对互为差向异构体的对映异构体的(+/-)-TDA-07或(+/-)-TDA-08,然后再将1-(苯并[D][1,3]二氧基-5-基)-2-(2-氯乙酰基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-甲酸酯的两对互为差向异构体的对映异构体的(+/-)-TDA-07或(+/-)-TDA-08与甲胺发生氨解环合反应得到6-(苯并[1,3]二氧基-5-基)-10-羟基-2-甲基-2-3,6-,7-,12-,12-六氢吡嗪-[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮的两对互为差向异构体的对映异构体的(+/-)-TDA-11或(+/-)-TDA-12,再依权利要求13的方法制备出目标产物。
本发明的中间化合物1-(苯并[D][1,3]二氧基-5-基)-2-(2-氯乙酰基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-甲酸酯的两对互为差向异构体的对映异构体的(+/-)-TDA-07或(+/-)-TDA-08的制备方法如式15所示,即:分别将1-(苯并[D][1,3]二氧基-5-基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯的两对互为差向异构体的对映异构体(+/-)-TDA-03或(+/-)-TDA-04与氯
乙酰氯发生酰化反应得到1-(苯并[D][1,3]二氧基-5-基)-2-(2-氯乙酰基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-甲酸酯的两对互为差向异构体的对映异构体的(+/-)-TDA-07或(+/-)-TDA-08。
本发明所述的任一化合物,包括中间化合物,在抗肿瘤药物中的应用。
本发明所述的任一种化合物,包括中间化合物,的组合在抗肿瘤药物中的应用。
相应试验表明,本发明所述的任一化合物或其组合可在抗肿瘤药物中的应用。
本发明的含磺酰氟基团的他达那非类似物可以在制备抗肿瘤药物中应用,经PD1/PD-L1蛋白分子生物结合抑制作用测试,具有一定的体外抗肿瘤活性,因此本发明的化合物可用于制备抗肿瘤药物。本发明所述的含磺酰氟基团的他达那非类似物结构新颖,对肿瘤细胞表现出比较强的抑制作用,具有优良的应用前景。本发明的制备合成工艺操作简单、不使用金属试剂、环境污染少、条件温和。
具体实施方式
本发明将通过下面的实施例加以说明。
本发明化合物通过核磁,高分辨质谱,红外,紫外测定结构。
实施例1:5-羟基色氨酸甲酯盐酸盐((+/-)-TDA-02)制备方法
5-羟基色氨酸甲酯盐酸盐((+/-)-TDA-02)结构式如式9所示,其制备方法如下:
氩气保护下将2g(9.08mmol)5羟基色氨酸溶于20ml(493.7mmol)甲醇中,再在冰水浴搅拌下滴加1.22ml(18.16mmol)氯化亚砜,搅拌10分钟后,升温至50℃反应7小时。旋蒸,将甲醇旋干,得到墨绿色固体。风干过夜,次日将固体碾碎,加入乙酸乙酯搅拌打浆4小时,再抽滤洗涤,得到2.4293g灰色固体(产率为99.2%),参见式10。
实施例2:1-(苯并[D][1,3]二氧基-5-基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯((+/-)-TDA-03与(+/-)-TDA-04制备方法
1-(苯并[D][1,3]二氧基-5-基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯((+/-)-TDA-03与(+/-)-TDA-04)结构式如式18示,制备方法如下:
氩气保护下,将2.7g(10mmol)5-羟基色氨酸甲酯盐酸盐与1.65g(11mmol)胡椒醛搅拌下溶于25ml异丙醇中,升温至110℃反应6小时,再降至室温搅拌过夜。加入饱和碳酸钠溶液搅拌中和,再用乙酸乙酯萃取三次,饱和食盐水洗涤一次。浓缩,柱层析(H60硅胶,石油醚:乙酸乙酯=1:1)分别得到互为差向异构体的灰白色的固体(+/-)-TDA-03366.9mg(产率为10%)与(+/-)-TDA-04353.5mg(产率为9.7%)。
(+/-)-TDA-03表征数据如下:熔点:164-166℃,核磁分析:1H NMR(400MHz,CDCl3)δ9.81(s,1H),7.33(d,J=11.4Hz,1H),7.07(d,J=8.6Hz,1H),7.07(d,J=8.6Hz,1H),6.96–6.84(m,2H),6.83–6.76(m,2H),6.70(dd,J=8.6,2.3Hz,1H),5.94(s,2H),5.14(s,1H),3.93(dd,J=11.1,4.2Hz,1H),3.81(s,3H),3.12(dd,J=15.0,2.6Hz,1H),3.00–2.81(m,1H);13C NMR(101MHz,DMSO)δ173.00,150.41,147.19,146.79,136.06,130.86,127.27,121.97,111.56,110.77,108.79,108.01,106.10,101.87,100.92,57.67,56.36,51.76,25.48,14.09.高分辨质谱分析:HRMS-ESI(m/z):367.1436[M-H]-,红外光谱分析:IR(cm-1):3397.3,3214.4,3036.8,2995.8,2949.4,2904.2,2850.7,2596.4,2035.0,1847.3,1737.3,1626.4,1588.6,1543.4,1503.0,1487.5,1444.3,1359.4,1324.8,855.6,835.3,810.3,744.1,718.2,699.5,685.9,624.6.紫外光谱分析:UVmax(CH2Cl2)nm:202,206,210,214,218,228,246.。(+/-)-TDA-04:熔点:169-172℃,核磁分析:1H NMR(400MHz,CDCl3)δ9.79(s,1H),7.63(s,1H),7.00(dd,J=8.6,3.8Hz,1H),6.85(d,J=2.3Hz,1H),6.75–6.63(m,4H),5.92–5.85(m,2H),5.25(s,1H),3.91(dt,J=11.0,5.5Hz,1H),3.69(d,J=5.7Hz,3H),3.09(dd,J=15.4,5.1Hz,1H),2.95(dd,J=15.3,7.2Hz,1H);13C NMR(101MHz,CDCl3)δ174.08,149.87,148.01,147.47,135.70,131.40,127.59,121.89,111.89,111.57,108.79,108.22,107.93,103.36,101.22,60.59,54.84,52.28,29.62,14.28.高分辨质谱分析:HRMS-ESI(m/z):367.1439[M-H]-,红外光谱分析:IR(cm-1):3395.2,3068.8,3028.1,2952.1,2897.9,2850.4,2780.6,2622.5,2037.3,1847.7,1732.4,1629.4,1599.4,1573.6,1501.8,1487.0,1448.7,1358.3,834.1,811.0,800.1,734.9,718.5,702.2,654.8,624.2.紫外光谱分析:UVmax(CH2Cl2)nm:202,206,210,216,220,228,246.。
实施例3:1-(苯并[D][1,3]二氧基-5-基)-2-(2-氯乙酰基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-甲酸酯(+/-)-TDA-07的制备方法
1-(苯并[D][1,3]二氧基-5-基)-2-(2-氯乙酰基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-甲酸酯((+/-)-TDA-07结构式如式9所示,其制备方法如下:
将338.7mg(0.9254mmol)的底物(1-(苯并[D][1,3]二氧基-5-基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯的对映异构体)溶于含0.3ml(2.1583mmol)三乙胺的10ml乙酸乙酯溶液中,搅拌及冰水浴下缓慢滴加含0.13ml(1.6332mmol)氯乙酰氯的乙酸乙酯溶液。搅拌10分钟后,转至33℃反应7小时后,加入水搅拌,再用乙酸乙酯萃取三次,饱和食盐水洗涤一次。浓缩,柱层析(H60硅胶,石油醚:乙酸乙酯=1:1)得到281.6mg淡红色固体(产率为68.7%)。(+/-)-TDA-07:熔点:253-256℃,核磁分析:1H NMR(400MHz,DMSO)δ11.05(s,1H),7.78–7.62(m,1H),7.34(dd,J=19.5,5.2Hz,2H),6.90(dd,J=8.7,2.2Hz,1H),6.84–6.75(m,2H),6.68(s,1H),6.45(d,J=8.1Hz,1H),5.98(d,J=7.4Hz,2H),5.21(d,J=6.5Hz,1H),4.84(d,J=13.9Hz,1H),4.45(d,J=13.9Hz,1H),3.43(t,J=13.5Hz,1H),3.13–2.97(m,4H);13C NMR(101MHz,DMSO)δ170.34,167.70,146.83,143.34,134.30,133.33,131.69,131.50,128.64,122.40,115.36,111.80,110.31,109.11,107.59,106.69,101.07,65.02,51.81,29.80,18.64,13.53.高分辨质谱分析:HRMS-ESI(m/z):443.1105[M-H]-,红外光谱分析:IR(cm-1):3347.2,3094.8,3060.4,3028.1,3011.7,2951.4,2933.1,2875.7,2851.6,2774.1,2608.8,2363.5,2118.5,1862.4,1765.7,1742.0,1667.1,1631.4,1611.7,1593.8,1505.0,1489.3,1457.0,1441.2,1411.4,1383.2,1355.4,1312.3,895.3,877.1,829.4,803.0,789.6,757.8,746.6,737.5,719.7,707.1,676.1,663.8,651.7,636.3,617.2.紫外光谱分析:UVmax(CH2Cl2)nm:206,210,218,228,246.。
实施例4:1-(苯并[D][1,3]二氧基-5-基)-2-(2-氯乙酰基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-甲酸酯的差向异构体的对映异构体(+/-)-TDA-08的制备方法:
1-(苯并[D][1,3]二氧基-5-基)-2-(2-氯乙酰基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-甲酸酯的差向异构体的对映异构体((+/-)-TDA-08结构式如式10所示,其制备方法如下:
将580.1mg(1.5850mmol)的底物(1-(苯并[D][1,3]二氧基-5-基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯的差向异构体的对映异构体)溶于含0.51ml(3.6691mmol)三乙胺的10ml乙酸乙酯溶液中,搅拌及冰水浴下缓慢滴加含0.22ml(2.7639mmol)氯乙酰氯的5ml乙酸乙酯溶液。搅拌10分钟后,转至33℃反应8小时后,加入水搅拌,再用乙酸乙酯萃取三次,饱和食盐水洗涤一次。浓缩,柱层析(H60硅胶,石油醚:乙酸乙酯=1:1)得到387.3mg淡黄色固体(产率为55.1%)。(+/-)-TDA-08:熔点:206-208℃,核磁分析:1H NMR(400MHz,DMSO)δ7.77–7.69(m,1H),7.69–7.63(m,1H),7.31(dd,J=28.8,8.5Hz,2H),7.00–6.71(m,3H),6.06–5.84(m,2H),4.76–4.64(m,2H),4.26–4.18(m,2H),3.50(dd,J=39.2,18.9Hz,4H);13C NMR(101MHz,CDCl3)δ167.90,167.02,144.25,134.88,132.43,131.06,128.97,126.67,119.99,115.84,111.94,110.62,106.74,65.73,41.14,32.06,30.70,29.82,22.82,19.31,14.32,13.85.高分辨质谱分析:HRMS-ESI(m/z):443.1009[M-H]-,红外光谱分析:IR(cm-1):3305.6,3112.1,3079.1,2997.5,2951.6,2933.9,2918.3,2850.3,2781.6,2703.5,2055.9,1862.7,1746.4,1725.1,166.5,1584.6,1566.6,1503.7,1489.9,1453.9,1437.5,1368.9,1330.1,1311.3,884.6,865.4,837.5,808.8,787.4,765.1,751.4,741.0,725,6,692.1,682.2,652.1,628.5,607.2.紫外光谱分析:UVmax(CH2Cl2)nm:204,210,214,220,228,246.。
实施例5:6-(苯并[1,3]二氧基-5-基)-10-羟基-2-甲基-2-3,6-,7-,12-,12-六氢吡嗪-[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮((+/-)-TDA-11与(+/-)-TDA-12)的制备
6-(苯并[1,3]二氧基-5-基)-10-羟基-2-甲基-2-3,6-,7-,12-,12-六氢吡嗪-[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮((+/-)-TDA-11与(+/-)-TDA-12)结构式如式13和式14所示,(+/-)-TDA-11的制备方法如下(参见式14):
氩气保护下,将281.6mg(0.636mmol)底物溶于12ml甲醇中,再加入290mg25%甲胺水溶液(9.337mmol)。升温至72℃回流反应12小时,加入水搅拌,再用乙酸乙酯萃取三次,饱和食盐水洗涤一次。浓缩,柱层析(H60硅胶,乙酸乙酯)得到57mg淡黄色固体(产率为22.1%)。(+/-)-TDA-11:熔点:270-273℃,核磁分析:1H NMR(400MHz,DMSO)δ10.72(s,1H),8.70(s,1H),7.08(d,J=8.6Hz,1H),6.86–6.70(m,4H),6.56(dd,J=8.6,2.1Hz,1H),6.08(s,1H),5.92(s,2H),4.36(dd,J=11.6,4.2Hz,1H),4.23–4.11(m,1H),3.94(d,J=17.1Hz,1H),3.43–3.36(m,1H),2.96–2.82(m,4H);13C NMR(101MHz,DMSO)δ164.71,162.25,150.70,147.60,147.21,133.02,130.73,130.67,126.62,121.66,111.69,108.31,108.14,106.63,102.20,101.25,54.93,52.04,50.88,50.68,32.61,26.74.高分辨质谱分析:HRMS-ESI(m/z):406.1663[M-H]-,红外光谱分析:IR(cm-1):3339.4,3278.4,2960.4,2899.7,2785.5,2615.2,1840.7,1736.6,1653.9,1606.2,1573.4,1502.7,1487.7,1454.5,1435.7,1401.9,1371.7,1344.7,1325.4,876.7,855.2,834.0,821.2,794.3,774.0,750.3,731.5,715.3,691.8,661.2,647.8,616.6.紫外光谱分析:UVmax(CH2Cl2)nm:206,210,214,228,246.。
实施例6:6-(苯并[1,3]二氧基-5-基)-10-羟基-2-甲基-2-3,6-,7-,12-,12-六氢吡嗪-[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮(+/-)-TDA-12的制备方法(参见式X8)
氩气保护下,将283mg(0.636mmol)底物溶于11ml甲醇中,再加入1.22g25%甲胺水溶液(38.635mmol)。升温至70℃回流反应7小时,加入水搅拌,再用乙酸乙酯萃取三次,饱和食盐水洗涤一次。浓缩,柱层析(H60硅胶,乙酸乙酯)得到134.6mg淡黄色固体(产率为52.3%)。(+/-)-TDA-12:熔点:208-211℃,核磁分析:1H NMR(400MHz,DMSO)δ10.71(d,J=10.7Hz,1H),8.68(d,J=13.3Hz,1H),7.09(t,J=9.1Hz,1H),6.86(dt,J=12.0,6.0Hz,1H),6.76(d,J=14.9Hz,3H),6.65–6.53(m,2H),6.11–5.87(m,2H),5.75(d,J=1.8Hz,1H),4.24(d,J=17.6Hz,1H),4.08–3.97(m,2H),3.14(dd,J=15.2,4.1Hz,1H),2.95–2.77(m,4H);13C NMR(101MHz,DMSO)δ164.95,162.47,150.79,147.75,147.37,133.09,131.00,130.86,126.74,121.84,111.93,108.43,108.33,106.77,102.41,101.48,53.37,52.19,51.07,50.87,32.81,26.98.高分辨质谱分析:HRMS-ESI(m/z):406.1482[M-H]-,红外光谱分析:IR(cm-1):3289.6,2916.4,2898.2,2849.0,2781.2,2597.1,1854.2,1730.2,1652.9,1598.1,1501.8,1486.7,1456.6,1441.5,1405.5,1371.9,1334.6,875.7,836.5,798.6,785.5,756.6,711.2,670.5,624.9,611.7.紫外光谱分析:UVmax(CH2Cl2)nm:202,206,210,214,218,228,246.。
实施例7:6-(苯并[d][1,3]二氧醇-5-基)-2-甲基-1,4-二氧基-1,2,3,4,4,6,7,12,12a-八氢吡嗪[1',2':1,6]吡啶[3,4-b]吲哚-10-基硫脲酸盐((+/-)-TDA-13与(+/-)-TDA-14)的制备
6-(苯并[d][1,3]二氧醇-5-基)-2-甲基-1,4-二氧基-1,2,3,4,4,6,7,12,12a-八氢吡嗪[1',2':1,6]吡啶[3,4-b]吲哚-10-基硫脲酸盐((+/-)-TDA-13与(+/-)-TDA-14)结构式分别为式5和式6。(+/-)-TDA-13的制备方法为:
用二氯甲烷将85.9mg(0.213mmol)底物恰好溶解,再加入0.15ml(1.095mmol)三乙胺,再用气球通入磺酰氟气体室温下反应5小时,旋蒸浓缩,加入水搅拌,再用乙酸乙酯萃取三次,饱和食盐水洗涤一次。浓缩,柱层析(H60硅胶,石油醚:乙酸乙酯=1:2)得到48.3mg白色固体(产率为46.6%)。(+/-)-TDA-13:熔点:275-278℃,比旋光度:[α]26.4=-0.001(C=0.14875,CHCl3),核磁分析:1H NMR(400MHz,DMSO)δ11.49(s,1H),7.85(d,J=2.3Hz,1H),7.45(d,J=8.9Hz,1H),7.20(dd,J=8.8,2.4Hz,1H),6.88(s,1H),6.78(d,J=7.9Hz,2H),6.14(s,1H),5.93(s,2H),4.41(dd,J=11.7,3.9Hz,1H),4.25–4.12(m,1H),3.96(d,J=17.2Hz,1H),3.64–3.56(m,1H),3.04–2.89(m,4H);13C NMR(101MHz,DMSO)δ166.95,166.33,147.10,146.20,143.67,137.15,136.49,135.25,131.71,128.65,125.89,108.22,107.28,106.79,106.01,100.94,65.01,55.47,55.14,29.99,18.63,13.48;19F NMR(376MHz,DMSO)δ-100.01(s).高分辨质谱分析:HRMS-ESI(m/z):488.1111[M-H]-,红外光谱分析:IR(cm-1):3299.1,3102.0,3087.5,2904.2,2869.6,2770.8,1865.7,1853.2,1678.1,1657.3,1630.8,1591.7,1502.4,1487.4,1445.7,1426.3,1402.8,1369.4,1326.5,890.6,848.9,827.5,801.9,789.6,750.5,720.7,695.8,639.0.紫外光谱分析:UVmax(CH2Cl2)nm:208,212,218,228,246.。
实施例8:6-(苯并[d][1,3]二氧醇-5-基)-2-甲基-1,4-二氧基-1,2,3,4,4,6,7,12,12a-八氢吡嗪[1',2':1,6]吡啶[3,4-b]吲哚-10-基硫脲酸盐差向异构体的对映异构体(+/-)-TDA-14的制备方法为(参见式13):
用二氯甲烷将127.6mg(0.315mmol)底物溶解,再加入0.2ml(0.146mmol)三乙胺,再用气球通入磺酰氟气体室温下反应5小时,旋蒸浓缩,加入水搅拌,再用乙酸乙酯萃取三次,饱和食盐水洗涤一次。浓缩,柱层析(H60硅胶,石油醚:乙酸乙酯=1:2)得到37.3mg白色固体(产率为24.3%)。(+/-)-TDA-14:熔点:271-274℃比旋光度:[α]26.6=-0.026(C=0.18,CHCl3),核磁分析:1H NMR(400MHz,DMSO)δ11.53(s,1H),7.83–7.75(m,1H),7.48(d,J=8.9Hz,1H),7.25(dt,J=15.2,7.6Hz,1H),6.90–6.83(m,2H),6.80(d,J=1.7Hz,1H),6.62(dd,J=8.1,1.4Hz,1H),6.11–5.88(m,2H),4.29–4.20(m,1H),4.11(dd,J=11.8,4.1Hz,1H),4.07–3.99(m,1H),3.35(d,J=4.3Hz,1H),3.03–2.92(m,1H),2.85(d,J=6.0Hz,3H);13C NMR(101MHz,DMSO)δ164.87,162.77,148.13,147.80,144.04,135.75,134.04,132.91,126.51,122.28,113.20,111.08,109.23,108.88,108.64,101.75,52.32,51.27,51.11,33.07,26.99;19F NMR(376MHz,CDCl3)δ-100.01.高分辨质谱分析:HRMS-ESI(m/z):488.1282[M-H]-,红外光谱分析:IR(cm-1):3185.4,3106.0,2923.4,2873.2,2773.1,2031.7,1853.4,1735.4,1663.4,1580.6,1503.1,1487.7,1450.1,1412.1,1400.9,1377.2,1358.0,1328.1,861.4,820.7,812.7,799.5,792.4,778.6,753.6,716.9,692.4,649.4,636.3,611.0.紫外光谱分析:UVmax(CH2Cl2)nm:206,210,214,220,228,246.。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-6-((氟磺酰基)氧基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯((+/-)-TDA-05与(+/-)-TDA-06)结构式分别为式7和式8。
实施例9:1-(苯并[d][1,3]二氧杂环戊烯-5-基)-6-((氟磺酰基)氧基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚--3-羧酸甲酯(+/-)-TDA-05的制备方法
参见式12,用二氯甲烷将1.14g(3.115mmol)底物(1-(苯并[D][1,3]二氧基-5-基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯的对映异构体)溶解,再加入0.6ml(0.438mmol)三乙胺,再用气球通入磺酰氟气体室温下反应6小时,旋蒸浓缩,加入水搅拌,再用乙酸乙酯萃取三次,饱和食盐水洗涤一次。浓缩,柱层析(H60硅胶,石油醚:乙酸乙酯=2:1)得到236.7mg固体(产率为15.6%)。(+/-)-TDA-05:熔点:176-177℃比旋光度:[α]26.2=0.008(C=0.5,CHCl3),核磁分析:1H NMR(400MHz,CDCl3)δ7.72(d,J=16.9Hz,1H),7.46(t,J=6.2Hz,1H),7.23(d,J=8.8Hz,1H),7.11–7.04(m,1H),6.87(dd,J=7.9,1.5Hz,1H),6.80(d,J=8.0Hz,2H),5.95(s,2H),5.15(s,1H),3.94(dd,J=11.1,4.2Hz,1H),3.82(d,J=5.1Hz,3H),3.17(ddd,J=20.9,11.2,4.9Hz,1H),3.03–2.92(m,1H);13C NMR(101MHz,DMSO)δ172.71,147.26,146.95,143.47,138.90,135.44,126.66,122.10,113.12,112.47,109.84,108.82,108.10,100.98,100.98,57.48,56.09,51.79,30.02,25.18;19F NMR(376MHz,DMSO)δ-166.77.高分辨质谱分析:HRMS-ESI(m/z):449.1768[M-H]-,红外光谱分析:IR(cm-1):3452.3,3435.8,3331.4,3100.3,3083.0,3011.1,2955.1,2894.5,2851.0,2827.8,2787.6,1849.3,1729.8,1627.8,1607.0,1580.5,1500.1,1485.3,1430.9,1373.2,1344.5,1324.3,1309.8,888.1,874.3,845.6,815.6,804.1,795.9,769.2,745.4,725.8,711.1,678.4,652.0,632.1,615.7.紫外光谱分析:UVmax(CH2Cl2)nm:206,210,216,228,238,246.。
实施例10:1-(苯并[d][1,3]二氧杂环戊烯-5-基)-6-((氟磺酰基)氧基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯(+/-)-TDA-06的制备方法
用二氯甲烷将1.14g(3.115mmol)底物(1-(苯并[d][1,3]二氧杂环戊烯-5-基)-6-((氟磺酰基)氧基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯的差向异构体的对映异构体)恰好溶解,再加入0.6ml(0.438mmol)三乙胺,再用气球通入磺酰氟气体室温下反应6小时,旋蒸浓缩,加入水搅拌,再用乙酸乙酯萃取三次,饱和食盐水洗涤一次。浓缩,柱层析(H60硅胶,石油醚:乙酸乙酯=2:1)得到251.7mg固体(产率为16.6%)。(+/-)-TDA-06:熔点:159-161℃比旋光度:[α]26.3=-0.022(C=0.5,CHCl3),核磁分析:1H NMR(400MHz,DMSO)δ11.06(s,1H),7.66(dd,J=8.7,2.9Hz,1H),7.39(d,J=8.8Hz,1H),7.17(dd,J=8.8,2.4Hz,1H),6.85(dd,J=4.7,3.1Hz,2H),6.70(dd,J=8.0,1.4Hz,1H),5.99(d,J=1.8Hz,2H),5.30(s,1H),3.85(t,J=6.1Hz,1H),3.64(s,3H),3.10(dd,J=15.2,5.2Hz,1H),2.93(dd,J=15.2,7.0Hz,1H).;13C NMR(101MHz,DMSO)δ173.69,147.42,146.68,143.40,137.84,136.68,135.10,126.64,121.52,113.22,112.29,109.88,108.61,107.76,100.91,53.75,51.75,30.14,24.37,18.69;19F NMR(376MHz,DMSO)δ-100.01.高分辨质谱分析:HRMS-ESI(m/z):449.1600[M-H]-,红外光谱分析:IR(cm-1):3303.7,3271.8,3070.3,3032.7,2998.7,2955.5,2919.8,2851.0,2780.5,2039.3,1848.6,1740.7,1630.7,1610.0,1582.5,1504.2,1488.2,1460.4,1442.8,1400.2,1370.5,1356.7,1341.7,1323.5.紫外光谱分析:UVmax(CH2Cl2)nm:206,210,216,228,234,246.。
实施例11:1-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-氯乙酰基)-6-((氟磺酰基)氧基)-2,3,4,9-四氢-1H-吡啶基甲基并[3,4-b]吲哚-3-羧酸甲酯的对映异构体(+/-)-TDA-09的制备方法
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-氯乙酰基)-6-((氟磺酰基)氧基)-2,3,4,9-四氢-1H-吡啶基甲基并[3,4-b]吲哚-3-羧酸甲酯((+/-)-TDA-09结构式如式4所示。1-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-氯乙酰基)-6-((氟磺酰基)氧基)-2,3,4,9-四氢-1H-吡啶基甲基并[3,4-b]吲哚-3-羧酸甲酯对映异构体(+/-)-TDA-09的制备方法为:
用15ml乙酸乙酯将236.7mg(0.5283mmol)底物溶解,再加入0.15ml(1.0566mmol)三乙胺,冰浴下加入0.63ml(0.7925mmol)氯乙酰氯,升至室温反应17小时,加入水搅拌,再用乙酸乙酯萃取三次,饱和食盐水洗涤一次。浓缩,柱层析(H60硅胶,石油醚:乙酸乙酯=2:1)得到175.2mg固体(产率为63.2%)。(+/-)-TDA-09:熔点:109-112℃,比旋光度:[α]26.6=0.048(C=0.5,CHCl3),核磁分析:1H NMR(400MHz,CDCl3)δ8.41(s,1H),7.54(d,J=2.1Hz,1H),7.33(d,J=8.8Hz,1H),7.16(dd,J=8.8,2.2Hz,1H),6.84(s,2H),5.88(d,J=8.3Hz,2H),4.94(s,1H),4.36(d,J=12.3Hz,1H),4.21(d,J=12.5Hz,1H),3.65(d,J=15.7Hz,1H),3.27–3.10(m,4H).;13C NMR(101MHz,CDCl3)δ171.52,169.89,167.34,147.53,144.30,135.59,132.68,132.33,126.58,122.89,115.03,112.43,110.66,109.91,108.07,107.71,101.28,60.56,53.71,42.25,21.25,14.18;19F(376MHz,CDCl3)δ-75.87.红外光谱分析:IR(cm-1):3296.9,3075.9,2952.3,2904.9,2850.2,2778.8,2663.2,2604.8,2253.9,2047.6,1852.7,1744.4,1655.7,1632.3,1597.2,1503.6,1443.1,1383.0,1369.2,1326.0,1309.5,872.0,848.8,818.7,787.3,758.9,729.8,678.9,648.0,631.7.紫外光谱分析:UVmax(CH2Cl2)nm:206,212,222,228,234,246.。
实施例12:1-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-氯乙酰基)-6-((氟磺酰基)氧基)-2,3,4,9-四氢-1H-吡啶基甲基并[3,4-b]吲哚-3-羧酸甲酯的差向异构体的对映异构体(+/-)-TDA-10的制备方法
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-2-(2-氯乙酰基)-6-((氟磺酰基)氧基)-2,3,4,9-四氢-1H-吡啶基甲基并[3,4-b]吲哚-3-羧酸甲酯的差向异构体的对映异构体(+/-)-TDA-10)结构式如式式5所示
用15ml乙酸乙酯将251.7mg(0.5618mmol)底物溶解,再加入0.16ml(1.1236mmol)三乙胺,冰浴下加入0.64ml(0.8427mmol)氯乙酰氯,升至室温反应17小时,加入水搅拌,再用乙酸乙酯萃取三次,饱和食盐水洗涤一次。浓缩,柱层析(H60硅胶,石油醚:乙酸乙酯=2:1)得到133.4mg固体(产率为45.3%)。(+/-)-TDA-10:熔点:97-101℃,比旋光度:[α]26.7=-0.015(C=0.5,CHCl3),核磁分析:1H NMR(400MHz,CDCl3)δ8.76(s,1H),7.44(s,1H),7.23(d,J=8.8Hz,1H),7.07(dd,J=8.8,2.2Hz,1H),6.91–6.67(m,3H),6.12(s,1H),5.92(s,3H),5.27(s,1H),4.20(d,J=13.3Hz,1H),4.01(s,1H),3.69–3.53(m,4H);13C NMR(101MHz,CDCl3)δ171.57,171.38,169.21,144.39,135.75,131.25,129.04,126.45,120.02,114.94,112.62,110.54,108.75,106.79,101.52,60.61,54.07,42.59,29.74,21.11,19.66,14.21;19F NMR(376MHz,CDCl3)δ-75.72.高分辨质谱分析:HRMS-ESI(m/z):525.1124[M-H]-,红外光谱分析:IR(cm-1):3307.7,3073.1,2954.2,2916.0,2855.9,2779.8,2695.9,2605.8,2253.7,2037.7,1850.9,1740.2,1659.1,1589.9,1503.9,1489.0,1443.1,1368.3,1322.6,863.6,817.1,785.5,754.7,729.8,696.3,639.7.紫外光谱分析:UVmax(CH2Cl2)nm:206,210,214,226,228,234,246.。
以上所述(+/-)-TDA-01、(+/-)-TDA-02、(+/-)-TDA-03、(+/-)-TDA-04、(+/-)-TDA-11和(+/-)-TDA-12均为已经公开的化合物,其中:(+/-)-TDA-01和(+/-)-TDA-02是商业销售的化合物,(+/-)-TDA-03、(+/-)-TDA-04、(+/-)-TDA-11和(+/-)-TDA-12公开于PCT专利WO 0194345A2。
本发明通过本发明的化合物通过PD1/PD-L1蛋白分子生物结合抑制作用测试,(+/-)-TDA-13、(+/-)-TDA-14、(+/-)-TDA-09、(+/-)-TDA-10、(+/-)-TDA-05和(+/-)-TDA-06均具有一定的体外抗肿瘤活性。含磺酰氟基团的化合物(+/-)-TDA-13、(+/-)-TDA-14、(+/-)-TDA-09和(+/-)-TDA-10活性高于相对应的不含磺酰氟基团的化合物(+/-)-TDA-11、(+/-)-TDA-12、(+/-)-TDA-07和(+/-)-TDA-08。测试结果如表1:
表1Cisbio人体PD1/PD-L1生物化学相互作用实验(Cisbio Human PD1/PD-L1biochemical interaction assay)
备注:试验化合物浓度:50μM。
Claims (19)
1.一种含磺酰氟基团的他达那非类似物,其结构式如式1所示,
其中,R1是(C1-C6)烷氧基、(C1-C6)烷基氨基;R2是自由氢、(C1-C6)酰氧基、(C1-C6)烷基、2-卤代乙酰氧基。
2.根据权利要求1所述的含磺酰氟基团的他达那非类似物,其结构式如式
2所示。
3.根据权利要求1所述的含磺酰氟基团的他达那非类似物,其结构式如式3
所示。
4.根据权利要求1所述的含磺酰氟基团的他达那非类似物,其结构式如式4
示,其中:R3是(C1-C6)酰氧基、(C1-C6)烷基。
5.根据权利要求4所述的含磺酰氟基团的他达那非类似物,其结构式如式5
所示。
6.根据权利要求4所述的含磺酰氟基团的他达那非类似物,其结构式如式6
所示。
7.用于制备权利要求2或3所述的含磺酰氟基团的他达那非类似物的中间化
合物(+/-)-TDA-05,其结构式如式7所示。
8.用于制备权利要求2或3所述的含磺酰氟基团的他达那非类似物的中间
化合物(+/-)-TDA-06,其结构式如式8所示。
9.用于制备权利要求5或6所述的含磺酰氟基团的他达那非类似物的中间
化合物(+/-)-TDA-07,其结构式如式9所示。
10.用于制备权利要求5或6所述的含磺酰氟基团的他达那非类似物的中间
化合物(+/-)-TDA-08,其结构式如式10所示。
11.权利要求2或3所述含磺酰氟基团的他达那非类似物的制备方法,其特
征在于如式11,即:分别将1-(苯并[d][1,3]二氧杂环戊烯-5-基)-6-((氟磺酰基)氧基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯的两对互为差向异构体的对映异构体(+/-)-TDA-05或(+/-)-TDA-06与氯乙酰氯在三乙胺存在下发生酰化反应得到目标产物1-(苯并[D][1,3]二氧杂环戊烯-5-基)-2-(2-氯乙酰基)-6-((氟磺酰基)氧基)-2,3,4,9-四氢-1H-吡啶基甲基并[3,4-b]吲哚-3-羧酸甲酯(+/-)-TDA-09或(+/-)-TDA-10。
12.权利要求7或8所述中间化合物的制备方法,其特征在于如式12所示,
即:分别将1-(苯并[D][1,3]二氧基-5-基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯的两对互为差向异构体的对映异构体(+/-)-TDA-03或(+/-)-TDA-04与磺酰氟气体在三乙胺催化下发生磺酰氟化反应得到目标产物1-(苯并[d][1,3]二氧杂环戊烯-5-基)-6-((氟磺酰基)氧基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚--3-羧酸甲酯((+/-)-TDA-05与(+/-)-TDA-06)。
13.权利要求5或6所述含磺酰氟基团的他达那非类似物的制备方法,其
特征在于如式13所示,即:将6-(苯并[1,3]二氧基-5-基)-10-羟基-2-甲基-2-3,6-,7-,12-,12-六氢吡嗪-[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮的两对互为差向异构体的对映异构体(+/-)-TDA-11或(+/-)-TDA-12与磺酰氟气体在三乙胺催化下发生磺酰氟化反应得到目标产物(+/-)-TDA-13与(+/-)-TDA-14。
14.权利要求5或6所述含磺酰氟基团的他达那非类似物的制备方法,其
特征在于如式14所示,即:分别将1-(苯并[D][1,3]二氧基-5-基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯的两对互为差向异构体的对映异构体(+/-)-TDA-03或(+/-)-TDA-04与氯乙酰氯发生酰化反应得到1-(苯并[D][1,3]二氧基-5-基)-2-(2-氯乙酰基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-甲酸酯的两对互为差向异构体的对映异构体的(+/-)-TDA-07或(+/-)-TDA-08,然后再将1-(苯并[D][1,3]二氧基-5-基)-2-(2-氯乙酰基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-甲酸酯的两对互为差向异构体的对映异构体的(+/-)-TDA-07或(+/-)-TDA-08与甲胺发生氨解环合反应得到6-(苯并[1,3]二氧基-5-基)-10-羟基-2-甲基-2-3,6-,7-,12-,12-六氢吡嗪-[1’,2’:1,6]吡啶并[3,4-b]吲哚-1,4-二酮的两对互为差向异构体的对映异构体的(+/-)-TDA-11或(+/-)-TDA-12,再依权利要求13的方法制备出目标产物。
15.权利要求9或10所述中间化合物的制备方法如式15所示,即:分别
将1-(苯并[D][1,3]二氧基-5-基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯的两对互为差向异构体的对映异构体(+/-)-TDA-03或(+/-)-TDA-04与氯乙酰氯发生酰化反应得到1-(苯并[D][1,3]二氧基-5-基)-2-(2-氯乙酰基)-6-羟基-2,3,4-,9-四氢-1H-吡啶并[3,4-b]吲哚-3-甲酸酯的两对互为差向异构体的对映异构体的(+/-)-TDA-07或(+/-)-TDA-08。
16.权利要求1至6所述的任一化合物在抗肿瘤药物中的应用。
17.权利要求1至6的任一种化合物的组合在抗肿瘤药物中的应用。
18.权利要求7或8所述化合物在抗肿瘤药物中的应用。
19.权利要求7或8所述化合物的组合在抗肿瘤药物中的应用。
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