CN105198824B - 一种二氢异噁唑啉化合物及其制备方法和应用 - Google Patents

一种二氢异噁唑啉化合物及其制备方法和应用 Download PDF

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CN105198824B
CN105198824B CN201510646163.1A CN201510646163A CN105198824B CN 105198824 B CN105198824 B CN 105198824B CN 201510646163 A CN201510646163 A CN 201510646163A CN 105198824 B CN105198824 B CN 105198824B
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CN105198824A (zh
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刘峰
藤昕辰
董奎勇
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Jiangsu Guanyu Biotechnology Co ltd
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Suzhou University
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Abstract

本发明公开了一种二氢异噁唑啉化合物及其制备方法和应用，其中，制备方法是，将底物肟、硝酸银和氟化剂混合，抽真空然后在反应体系中充入氮气，随后加入水和氯化苯的混合溶剂，加热反应混合物至85℃，TLC跟踪反应至底物消耗完全，恢复至室温，乙酸乙酯萃取反应混合物，合并有机相，无水硫酸钠干燥，过滤，浓缩，随后柱层析分离纯化即可得目标产物。本发明所合成的5‑氟甲基二氢异噁唑啉类化合物对组蛋白去乙酰化酶具有一定抑制效果，具有潜在的抗肿瘤活性。

Description

一种二氢异噁唑啉化合物及其制备方法和应用
技术领域
本发明涉及化学药物技术领域，具体来说，涉及一种具有组蛋白去乙酰化酶抑制活性的二氢异噁唑啉化合物及其制备方法和应用。
背景技术
HDACs的过度表达不利于某些特定基因的表达，包括一些肿瘤抑制基因，从而导致各种疾病，包括多种恶性肿瘤。HDAC抑制剂按结构主要可分为三类：羟肟酸类、苯甲酰胺类及环肽类，都是通过占据HDACs的乙酰化赖氨酸(底物)通道来实现酶活性抑制。除了上市已久的Vorinostat(SAHA，羟肟酸类)、Romidepsin(环肽类)及刚上市的Belinostat(羟肟酸类)、Panobinostat(羟肟酸类)外，正处于各期临床研究的HDAC抑制剂超过10个，以包含羟肟酸或苯甲酰胺药效团的小分子化合物为主。
现有技术中存在的问题和不足：现有药物和正处于临床研究的药物基本上都是非选择性组蛋白去乙酰化酶抑制剂，以羟肟酸类为主，具有毒副作用较强等问题。发现含有新颖结构的HDAC抑制剂有望解决抗药性和毒副作用较强等问题。
发明内容
本部分的目的在于概述本发明的实施例的一些方面以及简要介绍一些较佳实施例。在本部分以及本申请的说明书摘要和发明名称中可能会做些简化或省略以避免使本部分、说明书摘要和发明名称的目的模糊，而这种简化或省略不能用于限制本发明的范围。
鉴于上述现有HDAC抑制剂和/或二氢异噁唑啉化合物中存在的问题，提出了本发明。
因此，本发明其中一个目的是提供一种具有组蛋白去乙酰化酶抑制活性的二氢异噁唑啉化合物。
为解决上述技术问题，根据本发明的一个方面，本发明提供了如下技术方案：一种二氢异噁唑啉化合物，其化学结构简式为:
其中，R1为芳基；R2和R3为烷基或氢原子；R4为烷基或氢原子；R5为氢原子、烷基或芳基。
本发明其中另一个目的是提供一种具有组蛋白去乙酰化酶抑制活性的二氢异噁唑啉化合物的制备方法。
为解决上述技术问题，根据本发明的一个方面，本发明提供了如下技术方案：一种二氢异噁唑啉化合物的制备方法，其是将底物肟、硝酸银和氟化剂混合，抽真空然后在反应体系中充入氮气，随后加入水和氯化苯的混合溶剂，加热反应混合物至85℃，TLC跟踪反应至底物消耗完全，恢复至室温，乙酸乙酯萃取反应混合物，合并有机相，无水硫酸钠干燥，过滤，浓缩，随后柱层析分离纯化即可得目标产物。
作为本发明所述二氢异噁唑啉化合物的制备方法的一种优选方案，其中：所述底物肟的化学结构简式为：
其中，其中，R1为芳基；R2和R3为烷基或氢原子；R4为烷基或氢原子；R5为氢原子、烷基或芳基。
作为本发明所述二氢异噁唑啉化合物的制备方法的一种优选方案，其中：所述水和氯化苯的混合溶剂体积比为1:1。
本发明再一个目的是提供一种具有组蛋白去乙酰化酶抑制活性的二氢异噁唑啉化合物在抗肿瘤活性领域的应用。
本发明所合成的5-氟甲基二氢异噁唑啉类化合物对组蛋白去乙酰化酶具有一定抑制效果，具有潜在的抗肿瘤活性。
具体实施方式
为使本发明的上述目的、特征和优点能够更加明显易懂，下面结合具体实施方式做详细的说明。
在下面的描述中阐述了很多具体细节以便于充分理解本发明，但是本发明还可以采用其他不同于在此描述的其它方式来实施，本领域技术人员可以在不违背本发明内涵的情况下做类似推广，因此本发明不受下面公开的具体实施例的限制。
本发明的反应原理为：
具体的，将底物肟1(0.15mmol,1.0equiv)、硝酸银(0.03mmol,0.2equiv)和Selectfluor(0.3mmol,2.0equiv)置于25mL反应瓶中；抽空-充氮气，重复三次，随后加入溶剂PhCl-H2O(3mL,v/v＝1:1)。油浴加热反应混合物至85℃，TLC跟踪反应至底物消耗完全。恢复至室温，乙酸乙酯萃取反应混合物(3×15mL)，合并有机相，无水硫酸钠干燥，过滤，浓缩，随后柱层析分离纯化即可得目标产物2。
其中，所述的目标产物2，其化合物结构表征为：
MHz,CDCl3)δ155.75,129.82,128.65,128.29,126.26,82.41(d,JC-F＝174.8Hz),78.29(d,JC-F＝20.3Hz),35.64(d,JC-F＝6.2Hz)；19F NMR(376MHz,CDCl3)δ-228.58–-233.20(m,1F)；IR(thin film,KBr):ν(cm-1)2952,1147,1357,690；HRMS[CI]calcd for C10H10FNO[M+H]+180.0825,found 180.0823.
3.25(dd,J＝16.6,7.3Hz,1H)；13C NMR(100MHz,CDCl3)δ161.20,155.85,128.28,121.62,114.16,82.98(d,JC-F＝174.5Hz),78.51(d,JC-F＝20.2Hz),55.36,36.34(d,JC-F＝6.2Hz)；19F NMR(376MHz,CDCl3)δ-228.23–-232.13(m,1F)；IR(thin film,KBr):ν(cm-1)2922,1603,1245,1111,821；HRMS[CI]calcd for C11H12FNO2[M+H]+210.0930,found 210.0934.
1H),4.61–4.48(m,1H),3.68(dd,J＝16.6,11.0Hz,1H),3.49(dd,J＝16.6,7.2Hz,1H)；13CNMR(100 MHz,CDCl3)δ156.30,133.50,130.54,130.14,128.09,127.25,127.15,126.50,125.98,125.70,124.26,82.51(d,JC-F＝175.0Hz),77.16(d,JC-F＝20.3Hz),38.70(d,JC-F＝6.0Hz)；19F NMR(376 MHz,CDCl3)δ-230.00–-232.84(m,1F)；IR(thin film,KBr):ν(cm-1)2922,1509,1057,799,638；HRMS[CI]calcd for C14H12FNO[M+H]+230.0981,found230.0991.
1H),4.69–4.57(m,1H),4.56–4.46(m,1H),3.51(dd,J＝16.6,11.0Hz,1H),3.33(dd,J＝16.6,7.4Hz,1H)；13C NMR(100 MHz,CDCl3)δ155.96,143.05,140.11,128.93,127.98,127.89,127.41,127.22,127.08,82.85(d,JC-F＝174.9Hz),78.78(d,JC-F＝20.4Hz),36.23(d,JC-F＝6.0Hz)；19F NMR(376 MHz,CDCl3)δ-227.61–-234.17(m,1F)；IR(thin film,KBr):ν(cm-1)2946,1489,1019,879,763；HRMS[CI]calcd for C16H14FNO[M+H]+256.1138,found256.1142.
16.7,7.4Hz,1H),2.38(s,3H)；13C NMR(100 MHz,CDCl3)δ156.18,140.60,129.47,126.70,126.29,82.89(d,JC-F＝174.7Hz),78.55(d,JC-F＝20.4Hz),36.32(d,JC-F＝6.0Hz),21.46；19F NMR(376 MHz,CDCl3)δ-228.23–-232.13(m,1F)；IR(thin film,KBr):ν(cm-1)2920,1409,1008,896,813；HRMS[CI]calcd for C11H12FNO[M+H]+194.0981,found 194.0986.
7.4Hz,1H)；13C NMR(100 MHz,CDCl3)δ157.57,155.88,131.52,129.49,120.86,118.30,111.42,83.08(d,JC-F＝174.3Hz),78.67(d,JC-F＝20.3Hz),55.50,38.85(d,JC-F＝6.0Hz)；19F NMR(376MHz,CDCl3)δ-227.61–-232.13(m,1F)；IR(thin film,KBr):ν(cm-1)2946,1519,1248,1016,753；HRMS[CI]calcd for C11H12FNO2[M+H]+210.0930,found 210.0926.
4.55–4.42(m,1H),3.44(dd,J＝16.6,11.1Hz,1H),3.27(dd,J＝16.7,7.4Hz,1H)；13C NMR(100 MHz,CDCl3)δ163.87(d,JC-F＝251.0Hz),155.25,128.71(d,JC-F＝8.5Hz),125.41(d,JC-F＝3.4Hz),115.93(d,JC-F＝22.0Hz),82.80(d,JC-F＝175.0Hz),78.86(d,JC-F＝20.3Hz),36.20(d,JC-F＝6.2Hz)；19F NMR(376 MHz,CDCl3)δ-107.27–-111.17(m,1F),-228.58–-233.46(m,1F)；IR(thin film,KBr):ν(cm-1)2952,1512,1238,835,633；HRMS[CI]calcd forC10H9F2NO[M+H]+198.0730,found 198.0735.
7.5Hz,1H)；13C NMR(100 MHz,CDCl3)δ155.31,136.29,129.06,127.97,127.64,82.76(d,JC-F＝175.1Hz),79.02(d,JC-F＝20.3Hz),35.98(d,JC-F＝6.2Hz)；19F NMR(376 MHz,CDCl3)δ-228.58–-235.95(m,1F)；IR(thin film,KBr):ν(cm-1)2922,1597,1355,1276,821；HRMS[CI]calcd for C10H9ClFNO[M+H]+214.04035,found 214.0436.
16.7,7.5Hz,1H).13C NMR(100 MHz,CDCl3)δ154.73,134.30,130.42,129.76,129.57,126.26,124.32,82.30(d,JC-F＝175.2Hz),78.65(d,JC-F＝20.2Hz),35.33(d,JC-F＝6.3Hz)；19F NMR(376 MHz,CDCl3)δ-226.90–-235.24(m,1F)；IR(thin film,KBr):ν(cm-1)2952,1301,1014,907,683；HRMS[CI]calcd for C10H9ClFNO[M+H]+214.0435,found 214.0440.
NMR(100 MHz,CDCl3)δ155.41,132.01,128.18,128.08,124.60,82.77(d,JC-F＝175.1Hz),79.06(d,JC-F＝20.3Hz),35.89(d,JC-F＝6.2Hz)；19F NMR(376 MHz,CDCl3)δ-229.65–-233.46(m,1F)；IR(thin film,KBr):ν(cm-1)2922,1952,1351,1002,817；HRMS[CI]calcdfor C10H9BrFNO[M+H]+259.9930,found 259.9937.
16.7,7.5Hz,1H).13C NMR(100 MHz,CDCl3)δ154.69,130.82(q,JC-F＝32.7Hz),129.57,129.30,128.87,126.29(q,JC-F＝3.7Hz),123.24(q,JC-F＝272.5Hz),123.00(q,JC-F＝3.9Hz),82.26(d,JC-F＝175.3Hz),78.82(d,JC-F＝20.2Hz),35.24(d,JC-F＝6.3Hz)；19F NMR(376 MHz,CDCl3)δ-62.90(s,3F),-228.94–-234.88(m,1F)；IR(thin film,KBr):ν(cm-1)2955,1182,1098,824,693；HRMS[CI]calcd for C11H9F4NO[M+H]+248.0699,found248.0702.
4.42(m,1H),3.48(dd,J＝16.5,11.0Hz,1H),3.31(dd,J＝16.6,7.4Hz,1H)；13C NMR(100MHz,CDCl3)δ151.98,131.53,128.62,128.56,127.35,82.65(d,JC-F＝175.1Hz),78.91(d,JC-F＝20.5Hz),36.99(d,JC-F＝6.0Hz)；19F NMR(376 MHz,CDCl3)δ-227.61–-234.53(m,1F)；IR(thin film,KBr):ν(cm-1)2951,1437,1012,810,707；HRMS[CI]calcd for C8H8FNOS[M+H]+186.0389,found 186.0398.
5H)；13C NMR(100 MHz,CDCl3)δ162.35,83.06(d,JC-F＝174.3Hz),77.10(d,JC-F＝20.2Hz),37.20,36.61(d,JC-F＝5.9Hz),30.39,30.34,25.84,25.71；19F NMR(376 MHz,CDCl3)δ-228.94–-233.46(m,1F)；IR(thin film,KBr):ν(cm-1)2927,2853,1449,1013,826；HRMS[CI]calcd for C10H16FNO[M+H]+186.1294,found 186.1302.
CDCl3)δ161.33&160.01,129.75&129.70,128.39,127.89&127.80,126.65&126.61,85.35(d,JC-F＝20.2Hz)&81.00(d,JC-F＝21.3Hz),81.92(d,JC-F＝174.2Hz)&80.03(d,JC-F＝170.5Hz),43.19(d,JC-F＝4.6Hz)&42.61(d,JC-F＝4.0Hz),17.95&17.24；19F NMR(376 MHz,CDCl3)δ-228.77–-229.23&-229.54–-230.10(m,1F)；IR(thin film,KBr):ν(cm-1)2935,1313,885,767,694；HRMS[CI]calcd for C11H12FNO[M+H]+194.0981,found 194.0987.
128.74,128.67,127.56,87.77(d,JC-F＝20.0Hz),80.86(d,JC-F＝171.5Hz),51.07(d,JC-F＝3.6Hz),25.68,19.22(d,JC-F＝1.2Hz)；19F NMR(376 MHz,CDCl3)δ-226.54–-235.95(m,1F)；IR(thin film,KBr):ν(cm-1)2972,1558,1002,764,694；HRMS[CI]calcd for C12H14FNO[M+H]+208.1138,found 208.1144.
16.8Hz,1H),3.08(d,J＝16.7Hz,1H),1.51(s,3H).13C NMR(100 MHz,CDCl3)δ155.74,129.67,129.09,128.25,126.11,85.01(d,JC-F＝177.9Hz),84.67(d,JC-F＝18.6Hz),41.74(d,JC-F＝3.8Hz),21.56(d,JC-F＝3.3Hz)；19F NMR(376 MHz,CDCl3)δ-225.25(t,J＝47.2Hz,1F)；IR(thin film,KBr):ν(cm-1)3029,1446,1359,758,691；HRMS[CI]calcd for C11H12FNO[M+H]+194.0981,found 194.0983.
(150 MHz,CDCl3)δ156.19,140.14(d,JC-F＝3.5Hz),130.25,129.27,128.73,128.71,128.36,126.67,125.49,88.88(d,JC-F＝18.3Hz),85.53(d,JC-F＝183.5Hz),42.90(d,JC-F＝3.6Hz)；19F NMR(600MHz,CDCl3)δ-221.41(t,J＝47.6Hz,1F)；IR(thin film,KBr):ν(cm-1)3028,1447,1367,757,690；HRMS[CI]calcd for C16H14FNO[M+H]+256.1138,found256.1139.
3.84(m,1H),3.83(s,3H),3.53–3.46(m,1H)；13C NMR(100 MHz,CDCl3)δ160.69,155.30,139.87,128.23,127.82,127.75,125.06,121.34,113.65,88.03(d,JC-F＝18.3Hz),85.06(d,JC-F＝183.3Hz),54.88,42.69(d,JC-F＝3.5Hz)；19F NMR(376 MHz,CDCl3)δ-221.38(t,J＝47.4Hz,1F)；IR(thin film,KBr):ν(cm-1)2921,1454,1257,821,698；HRMS[CI]calcd forC17H16FNO2[M+H]+286.1243,found 286.1252.
＝4.2Hz),16.95(d,JC-F＝21.9Hz)；19F NMR(376 MHz,CDCl3)δ-182.79–-189.45(m,1F)；IR(thin film,KBr):ν(cm-1)2932,1720,1337,882,690；HRMS[CI]calcd for C11H12FNO[M+H]+194.0981,found 194.0983.
J＝16.7,11.1Hz,1H),3.29(dd,J＝16.7,7.5Hz,1H),1.45(dd,J＝23.9,6.1Hz,3H)；13C NMR(100 MHz,CDCl3)δ155.81,129.74,128.70,128.25,126.23,89.19(d,JC-F＝174.1Hz),81.24(d,JC-F＝21.4Hz),35.62(d,JC-F＝5.2Hz),15.79(d,JC-F＝22.8Hz)；19F NMR(376 MHz,CDCl3)δ-186.96–-189.80(m,1F)；IR(thin film,KBr):ν(cm-1)2958,1599,1294,889,738；HRMS[CI]calcd for C11H12FNO[M+H]+194.0981,found 194.0984.
(d,JC-F＝8Hz)128.25,126.30,125.21(d,JC-F＝7.7Hz),92.03(d,JC-F＝179.9Hz),82.40(d,JC-F＝25.0Hz),34.87(d,JC-F＝5.0Hz)；19F NMR(376 MHz,CDCl3)δ-194.30(dd,J＝47.2,18.2Hz,1F)；IR(thin film,KBr):ν(cm-1)2927,1356,885,745,690；HRMS[CI]calcd forC16H14FNO[M+H]+256.1138,found 256.1134.
128.80(d,JC-F＝1.9Hz),128.53,128.24(d,JC-F＝2.6Hz),126.29(d,JC-F＝6.4Hz),126.21,93.36(d,JC-F＝178.1Hz),81.85(d,JC-F＝25.0Hz),36.22(d,JC-F＝4.9Hz)；19F NMR(376MHz,CDCl3)δ-182.75(dd,J＝46.4,15.9Hz,1F)；IR(thin film,KBr):ν(cm-1)2919,1447,988,757,690；HRMS[CI]calcd for C16H14FNO[M+H]+256.1138,found 256.1145.
(d,JC-F＝32.0Hz),43.28,26.39(d,JC-F＝20.7Hz),24.81,16.05(d,JC-F＝2.8Hz)；19F NMR(376MHz,CDCl3)δ-184.27–-184.67(m,1F)；IR(thin film,KBr):ν(cm-1)2936,1309,951,890,689；HRMS[CI]calcd for C13H14FNO[M+H]+220.1138,found 220.1131.
4.64(m,1H),3.66–3.48(m,1H),2.12–1.75(m,4H),1.49–1.17(m,2H)；13C NMR(100MHz,CDCl3)δ161.83,129.82,128.39,128.09,126.54,89.33(d,JC-F＝179.4Hz),79.84(d,JC-F＝16.3Hz),46.35(d,JC-F＝5.5Hz),25.12(d,JC-F＝19.0Hz),24.44,20.05(d,JC-F＝9.3Hz)；19FNMR(376MHz,CDCl3)δ-182.79–-186.96(m,1F)；IR(thin film,KBr):ν(cm-1)2927,1356,1193,792,678；HRMS[CI]calcd for C13H14FNO[M+H]+220.1138,found 220.1143.
实验证明：化合物浓度为10μM,对组蛋白去乙酰化酶(从HeLa细胞核中提取)活性的抑制百分比从5％到41％不等。即，本发明所合成的5-氟甲基二氢异噁唑啉类化合物对组蛋白去乙酰化酶具有一定抑制效果，具有潜在的抗肿瘤活性。
应说明的是，以上实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的精神和范围，其均应涵盖在本发明的权利要求范围当中。

Claims (3)

1.一种二氢异噁唑啉化合物，其特征在于：其化学结构如下:
2.一种如权利要求1所述的二氢异噁唑啉化合物的制备方法，其特征在于：将底物肟、硝酸银和selectflour混合，抽真空然后在反应体系中充入氮气，随后加入水和氯化苯的混合溶剂，加热反应混合物至85℃，TLC跟踪反应至底物消耗完全，恢复至室温，乙酸乙酯萃取反应混合物，合并有机相，无水硫酸钠干燥，
过滤，浓缩，随后柱层析分离纯化即可得目标产物，
所述底物肟的化学结构简式为：
3.如权利要求2所述的二氢异噁唑啉化合物的制备方法，其特征在于：所述水和氯化苯的混合溶剂体积比为1:1。
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