CN114292269A - 一种邻氨基嘌呤苯甲酰胺类衍生物及其制备方法和应用 - Google Patents
一种邻氨基嘌呤苯甲酰胺类衍生物及其制备方法和应用 Download PDFInfo
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Abstract
Description
技术领域
本发明属于生物医药领域,特别涉及一类新型邻氨基嘌呤苯甲酰胺类衍生物、制备方法及其医疗应用。
背景技术
组蛋白去乙酰化酶(Histone Deacetylases,HDACs)是一类十分重要的翻译后修饰酶,其与肿瘤的发生发展密切相关,是抗肿瘤药物研究的重要靶酶之一。目前有多种具有不同类型化学结构的小分子组蛋白去乙酰化酶抑制剂(HDACi)被发现和研究,其中异羟肟酸类化合物为开发最广泛的一类HDACi,但异羟肟酸类是一种HDACs的泛抑制剂,具有无法预知的临床药物毒性,临床用药后常见的3级及4级不良反应包括血小板减少,中性粒细胞减少,贫血,疲劳和腹泻;临床使用常用的异羟酸类抑制剂伏立诺他(SAHA)后也有死亡病例的报道,因此目前研发应用小分子HDACi所面临的挑战是缺乏亚型特异性;亚型选择性高的HDACi能减少非靶标蛋白结合活性,减少毒副作用,带来更高的临床治愈率和安全性。近年来有一类苯甲酰胺类HDACi能够选择性结合I类HDAC,包括HDAC1、HDAC2、HDAC3等,由于本类化合物的芳香环能够与HDAC亚型的底部口袋结合,产生慢键合-慢释放或强键合-慢释放的靶蛋白结合动力学特性,因而比异羟肟酸类HDACi有更好的亚型选择性和更长的靶标驻留时间。
将经典的抗肿瘤药效团嘌呤母核与苯甲酰氨药效团结合成新颖结构的邻氨基嘌呤苯甲酰胺类衍生物,能够获得具有HDAC亚型特异性、毒副作用小的抗肿瘤活性物质。
发明内容
本发明提供了一类邻氨基嘌呤苯甲酰胺类衍生物,或可药用盐、前药、水合物及以任何形式代谢形成的产物;本发明同时还提供了所述化合物的制备方法及其在药物学上的应用,所述化合物结构新颖,不仅能有效抑制组蛋白去乙酰化酶(HDACs)活性还能抑制I类亚型HDAC(HDAC1/3)的活性,因而可用于与HDAC酶有关的疾病的治疗,对相关癌症有明显治疗效果。
本发明的目的是这样来实现的,一种结构为下列通式(I)的化合物,或其可药用盐、前药、水合物及以任何形式代谢形成的产物:
通式(I)中Y为烃基;R1为卤素或烃氨基;R2为氢、烷基、卤素、烷氧基、羟基、氰基或硝基;上述烷基或烷氧基可进一步被一个或多个取代基所取代,所述取代基为卤素、羟基、氰基或硝基。
优选地,本发明具有通式(I)的化合物,其代表性化合物选自以下的一种:
N-(2-氨基-4-氟-苯基)-4-(2,6-二氯-嘌呤-9-基甲基)-苯甲酰胺(I-1)、
N-(2-氨基苯基)-4-(2-氯-6-甲胺基-嘌呤-9-基甲基)-苯甲酰胺(I-2)、
N-(2-氨基苯基)-4-(2-氯-6-乙胺基-嘌呤-9-基甲基)-苯甲酰胺(I-3)、
N-(2-氨基苯基)-4-(2-氯-6-丙胺基-嘌呤-9-基甲基)-苯甲酰胺(I-4)、
N-(2-氨基苯基)-4-(2-氯-6-丁胺基-嘌呤-9-基甲基)-苯甲酰胺(I-5)、
N-(2-氨基-4-氟-苯基)-4-(2-氯-6-乙氨基-嘌呤-9-基甲基)-苯甲酰胺(I-6)、
N-(2-氨基-4-溴-苯基)-4-(2-氯-6-丙氨基-嘌呤-9-基甲基)-苯甲酰胺(I-7)、
N-(2-氨基-4-氟-苯基)-4-(2-氯-6-丁氨基-嘌呤-9-基甲基)-苯甲酰胺(I-8)、
N-(2-氨基-4-氟-苯基)-4-(2-氯-6-二乙基氨基-嘌呤-9-基甲基)-苯甲酰胺(I-9)。
本发明提供的化合物是新型嘌呤异羟肟酸衍生物,其具有组蛋白去乙酰化酶(HDACs)及I类组蛋白去乙酰化酶亚型的抑制作用,因此所述化合物可用于与这种酶有关的疾病的治疗,为此,本发明尤其涉及所述的具有通式(I)的化合物,或其可药用盐、前药、水合物及以任何形式代谢形成的产物在制备治疗由组蛋白乙酰化酶介导疾病中的应用。
本发明采取的又一技术方案是:一种用于治疗由组蛋白乙酰化酶介导疾病的药物组合物,所述药物组合物的有效成分含有通式(I)的化合物或其可药用盐、前药、水合物和以以任何形式代谢形成的产物。
所述的组蛋白乙酰化酶介导的疾病包括恶性肿瘤,恶性肿瘤包括但不限于乳腺癌、白血病、肝癌、结肠癌、胃癌、肾癌、肺癌、胰腺癌、神经胶质瘤、淋巴瘤、纤维肉瘤、卵巢癌、宫颈癌、黑色素瘤和前列腺癌等。
本发明同时涉及所述的化合物在制备治疗肿瘤药物中的应用。
本发明所述通式(I)的化合物可由通式(II)的化合物与通式(III)的化合物反应来制备:
其中,Y、R1、R2如通式(I)中所述。
该反应在一种溶剂中进行,所述溶剂可为正丁醇、乙酸乙酯、二氯甲烷、三氯甲烷、N,N-二甲基甲酰胺、四氢呋喃、丙酮或二甲亚砜等,反应温度为0℃至溶剂的回流温度,反应采用等摩尔量的通式(II)和通式(III)的化合物;反应在碱存在的条件下进行,所述的碱包括无机碱和有机碱,所述的无机碱可为碱金属碳酸盐类(例如,碳酸钠、碳酸钾、碳酸銫等)、碱金属碳酸氢盐类(碳酸氢钾等)和碱金属氢氧化物(例如,氢氧化钠、氢氧化钾、氢氧化锂等);所述的有机碱可为三乙胺、吡啶、二甲基吡啶、甲醇钠、正丁基锂或叔丁醇钾等。
式(Ⅲ)的化合物是公知的,或者可按照公知方法制备,大多数是可商购的。
式(Ⅱ)的化合物可通过式(Ⅳ)的化合物来制备:
其中,Y、R1如前定义。
该反应在一种溶剂中进行,所述溶剂可为乙醇、甲醇、丙醇、N-甲基吡咯烷酮,反应在碱存在的条件下进行,所述的碱包括无机碱和有机碱,所述的无机碱可为碱金属碳酸盐类(例如,碳酸钠、碳酸钾、碳酸銫等)、碱金属碳酸氢盐类(碳酸氢钾等)和碱金属氢氧化物(例如,氢氧化钠、氢氧化钾、氢氧化锂等);所述的有机碱可为三乙胺、吡啶、二甲基吡啶、甲醇钠、正丁基锂或叔丁醇钾等,反应温度为0℃至溶剂的回流温度。
式(Ⅳ)的化合物可通过式(V)的化合物与式(VI)的化合物反应来制备:
该反应在一种溶剂中进行,所述溶剂为乙酸乙酯、二氯甲烷、三氯甲烷、四氢呋喃及N,N-二甲基甲酰胺等,反应在碱金属碳酸盐类(例如,碳酸钠、碳酸钾、碳酸銫等)存在下进行,反应温度为0℃至溶剂的回流温度,反应通常采用等摩尔量的式(V)的化合物与式(VI)的化合物。
本发明的有益效果为:本发明的化合物不仅能有效抑制组蛋白去乙酰化酶(HDACs)活性还能抑制I类亚型HDAC(HDAC1/3)的活性,因而可用于与HDAC酶有关的疾病的治疗,对相关癌症有明显治疗效果。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整的描述,以充分地理解本发明的目的、方案和效果。
制备例1:4-(2,6-二氯-9H-嘌呤基)甲基-苯甲酸甲酯的制备:
称取2,6-二氯嘌呤18.8g(0.1mol)溶解在300mL无水DMF中,加入无水碳酸钾13.8g,搅拌的同时加入4-溴甲基苯甲酸甲酯22.8g,隔绝空气,室温反应过夜,TLC跟踪反应过程直至反应完全。反应完成后缓慢加入稀HCl或者稀H2SO4(0.1mol/L)调节pH至中性,用乙酸乙酯和饱和食盐水充分萃取反应液三次,将三次有机相合并,然后用无水MgSO4干燥有机相,过柱分离,减压蒸干得白色固体27.9g。
其检测结果为:m.p.162~164℃;IR(KBr)cm-1:3066,2951,1708,1596,1558,1500,1438,1238,1191,1114,1014,960,879,628;1H-NMR(600MHz,DMSO-d6)δ8.87(s,1H),7.95-7.93(m,2H),7.45(d,J=8.4Hz,2H),5.62(s,2H),3.85(s,3H)。
按上述方法,由适宜的嘌呤环6位被取代的2-氯-6-烃氨基嘌呤和4-溴甲基苯甲酸甲酯制备下述化合物:
(1)4-[2-氯-6-(甲胺基)-9H-嘌呤基]甲基-苯甲酸甲酯
白色固体;其检测结果为:mp:196-198℃;IR:(KBr,cm-1)3749,3286,2950,1735,1578,1543,1431,1362,1230,1188,1111,1018,926,752,691,567;1H-NMR(600MHz,DMSO-d6)δ8.27(d,J=8.4Hz,2H),7.94(s,1H),7.93(d,J=1.7Hz,1H),7.36(s,1H),7.35(s,1H),5.45(s,2H),3.84(s,3H),2.92(d,J=4.6Hz,3H)。
(2)4-[2-氯-6-(乙胺基)-9H-嘌呤基]甲基-苯甲酸甲酯
白色固体;其检测结果为:mp:175-176℃;IR:(KBr,cm-1)3749,3251,2955,2866,1720,1581,1577,1434,1288,1234,1111,1015,961,856,802,748,652,625;1H-NMR(600MHz,DMSO-d6)δ8.37(t,J=5.4Hz,1H),8.28(s,1H),7.94(d,J=8.3Hz,2H),7.36(d,J=8.0Hz,2H),5.45(s,2H),3.84(s,3H),3.48–3.43(m,2H),1.17(t,J=7.1Hz,3H)。
(3)4-[2-氯-6-(丙胺基)-9H-嘌呤基]甲基-苯甲酸甲酯
白色固体;其检测结果为:mp:145-147℃;IR:(KBr,cm-1)3745,3260,3078,2955,1720,1578,1435,1335,1230,1180,1015,961,922,853,752,694,548;1H-NMR(600MHz,DMSO-d6)δ8.38(t,J=5.7Hz,1H),8.28(s,1H),7.97–7.92(m,2H),7.37(d,J=8.2Hz,2H),5.45(s,2H),3.84(s,3H),3.38(dd,J=13.7,6.5Hz,2H),1.63–1.57(m,2H),0.90(t,J=7.4Hz,3H)。
(4)4-[2-氯-6-(丁胺基)-9H-嘌呤基]甲基-苯甲酸甲酯
白色固体;其检测结果为:mp:86-87℃;IR:(KBr,cm-1)3748,3395,3256,3076,2951,2869,1724,1582,1508,1435,1180,1111,1015,845,748,694,579;1H-NMR(600MHz,DMSO-d6)δ8.37(t,J=5.7Hz,1H),8.28(s,1H),7.96–7.93(m,2H),7.37(d,J=8.2Hz,2H),5.45(s,2H),3.84(s,3H),3.43(dd,J=13.2,6.8Hz,2H),1.61–1.54(m,2H),1.34(dt,J=14.8,7.3Hz,2H),0.90(t,J=7.3Hz,3H)。
(5)4-[2-氯-6-(二乙胺基)-9H-嘌呤基]甲基-苯甲酸甲酯
白色固体;其检测结果为:mp:110-111℃;IR:(KBr,cm-1)3113,2936,1713,1520,1454,1200,1057,1022,841,783,721,675,648,629,575;1H-NMR(600MHz,DMSO-d6)δ8.31(s,1H),7.96-7.93(m,2H),7.39-7.36(m,2H),5.45(s,2H),4.18(s,2H),3.84(s,3H),3.65(s,2H),1.27-1.16(s,6H)。
制备例2:4-(2,6-二氯-9H-嘌呤基)甲基-苯甲酸的制备
称取4-(2,6-二氯-9H-嘌呤基)甲基-苯甲酸甲酯16.8g溶解于200mL甲醇中,缓慢加热使其完全溶解,然后边搅拌边缓慢滴加0.5mol/L的NaOH水溶液,TLC跟踪反应进程至水解完全,加入适量水,搅拌的同时用稀HCl或稀H2SO4(1mol/L)调节pH至酸性,析出白色沉淀,抽滤,适量乙酸乙酯和石油醚冲洗滤饼并烘干,得得白色固体13.2g。
其检测结果为:mp:236-238℃;IR:(KBr,cm-1)3394,2561,2295,1692,1296,1184,1110,1049,925,875,783,590,543;1H-NMR(600MHz,DMSO-d6)δ12.99(s,1H),8.28(s,1H),7.92(d,J=8.2Hz,2H),7.34(d,J=8.0Hz,2H),5.44(s,2H);HRMS(ESI)m/z calcd forC13H8Cl2N4O2[M-H]-320.9946,found:320.9952。
按上述方法,由适宜的嘌呤环6位被取代的4-(2-氯-6-烃氨基-9H-嘌呤基)甲基-苯甲酸甲酯制备下述化合物:
(1)4-[2-氯-6-(甲胺基)-9H-嘌呤基]甲基-苯甲酸
白色固体;其检测结果为:mp:238-239℃;IR:(KBr,cm-1)3749,2924,2469,2365,1697,1659,1512,1280,1231,1196,1114,1018,984,930,780,629,528;1H-NMR(600MHz,DMSO-d6)δ12.98(s,1H),8.27(d,J=6.7Hz,2H),7.94-7.90(m,2H),7.33(d,J=8.3Hz,2H),5.44(s,2H),2.93(d,J=4.6Hz,3H);HRMS(ESI)m/z calcd for C14H12ClN5O2[M-H]-316.0601,found:316.0577。
(2)4-[2-氯-6-(乙胺基)-9H-嘌呤基]甲基-苯甲酸
白色固体;其检测结果为:mp:243-244℃;IR:(KBr,cm-1)3733,2889,2550,1686,1624,1474,1423,1308,1180,1018,930,752,621,540;1H-NMR(600MHz,DMSO-d6)δ12.99(s,1H),8.37(t,J=5.5Hz,1H),8.28(s,1H),7.92(d,J=8.2Hz,2H),7.34(d,J=8.0Hz,2H),5.44(s,2H),3.49-3.43(m,2H),1.17(t,J=7.1Hz,3H);HRMS(ESI)m/z calcd forC15H14ClN5O2[M-H]-330.0758,found:330.0738。
(3)4-[2-氯-6-(丙胺基)-9H-嘌呤基]甲基-苯甲酸
白色固体;其检测结果为:mp:253-254℃;IR:(KBr,cm-1)3749,3275,3202,2519,1697,1628,1481,1354,1230,1165,1119,1018,937,756,714,540;1H-NMR(600MHz,DMSO-d6)δ12.97(s,1H),8.36(t,J=5.6Hz,1H),8.27(s,1H),7.92(d,J=8.3Hz,2H),7.34(d,J=8.2Hz,2H),5.43(s,2H),3.38(dd,J=13.4,6.5Hz,2H),1.64-1.56(m,2H),0.89(t,J=7.3Hz,3H);HRMS(ESI)m/z calcd for C16H16ClN5O2[M-H]-344.0914,found:344.0898。
(4)4-[2-氯-6-(丁胺基)-9H-嘌呤基]甲基-苯甲酸
白色固体;其检测结果为:mp:260-261℃;IR:(KBr,cm-1)3349,3275,3206,2932,2519,1698,1628,1585,1481,1416,1358,1285,1169,1119,1018,926,621,583;1H-NMR(600MHz,DMSO-d6)δ12.97(s,1H),8.33(t,J=5.2Hz,1H),8.26(s,1H),7.93(dd,J=13.4,8.3Hz,2H),7.36(dd,J=13.9,8.3Hz,2H),5.43(s,2H),3.42(dd,J=13.0,6.6Hz,2H),1.61–1.53(m,2H),1.32(dt,J=14.7,7.3Hz,2H),0.90(t,J=7.3Hz,3H);HRMS(ESI)m/zcalcd for C17H18ClN5O2[M-H]-358.1071,found:358.1066。
(5)4-[2-氯-6-(二乙胺基)-9H-嘌呤基]甲基-苯甲酸
白色固体;其检测结果为:mp:215-217℃;IR:(KBr,cm-1)3749,3460,2936,2808,2287,1701,1589,1485,1269,1188,1161,1061,818,756,625,571;1H-NMR(600MHz,DMSO-d6)δ12.99(s,1H),8.30(s,1H),7.94–7.90(m,2H),7.35(d,J=8.2Hz,2H),5.44(s,2H),4.18(s,2H),3.65(s,2H),1.21(s,6H);HRMS(ESI)m/z calcd for C17H18ClN5O2[M-H]-358.1071,found:358.1066。
实施例1:
N-(2-氨基-4-氟-苯基)-4-(2,6-二氯-嘌呤-9-基甲基)-苯甲酰胺(I-1)的制备:
称取4-(2,6-二氯-9H-嘌呤基)甲基-苯甲酸9.7g,加300mL无水四氢呋喃溶解,冰浴下加入EDCI(1.5eq)、三乙胺(2.5eq),N2保护,冰浴搅拌30min备用。另取一反应瓶,将邻苯二胺用无水四氢呋喃溶解,将4-(2,6-二氯-9H-嘌呤基)甲基-苯甲酸溶液缓慢滴加入邻苯二胺溶液中,N2保护,室温条件反应,采用TLC监测反应完全后,用水和乙酸乙酯萃取,合并有机相并用饱和NaCl水洗涤一次后,用无水MgSO4干燥有机相。减压旋转蒸发有机相,用硅胶柱纯化,洗脱液浓缩后析出黄色固体7.0g。
其检测结果为:mp:218-220℃;IR:(KBr,cm-1)3240,2958,1596,1512,1473,1315,1284,1230,1164,1122,1060,976,921,844,748,648,524,466;1H-NMR(600MHz,DMSO-d6)δ9.58(s,1H),8.58(s,1H),7.94(d,J=8.4Hz,2H),7.39(d,J=8.4Hz,2H),7.08(dd,J=8.4,6.0Hz,1H),6.51(dd,J=11.4,3.0Hz,1H),6.34(td,J=11.4,3.0Hz,1H),5.54(s,2H),5.24(s,2H);13C-NMR(151MHz,DMSO-d6)δ165.62,162.31,160.72,153.61,145.10,142.61,139.88,134.63,129.05,128.98,127.66,119.54,102.49,102.34,101.91,101.74,46.94;HRMS(ESI)m/zcalcd for C19H13Cl2FN6O[M+Na]+453.0410,found:453.0409。
实施例2:
N-(2-氨基苯基)-4-(2-氯-6-甲胺基-嘌呤-9-基甲基)-苯甲酰胺(I-2)的制备:
采用4-[2-氯-6-(甲胺基)-9H-嘌呤基]甲基-苯甲酸9.5g,通过与实施例1相似的实验方法,制得白色固体5.5g。
其检测结果为:mp:217-219℃;IR:(KBr,cm-1)3328,3035,2943,2360,1639,1519,1488,1454,1342,1303,1253,1226,1153,1095,918,752,713,651;1H-NMR(600MHz,DMSO-d6)δ9.61(s,1H),8.28(s,1H),8.25(d,J=4.3Hz,1H),7.94(d,J=8.0Hz,2H),7.37(d,J=8.1Hz,2H),7.15(d,J=7.7Hz,1H),6.96(t,J=7.5Hz,1H),6.76(d,J=7.8Hz,1H),6.58(t,J=7.4Hz,1H),5.44(s,2H),4.88(s,2H),2.93(d,J=4.2Hz,3H);13C-NMR(151MHz,DMSO-d6)δ165.40,156.03,149.93,143.53,141.65,140.36,134.62,128.66,127.60,127.09,126.96,123.62,116.67,116.52,46.50,27.63;HRMS(ESI)m/z calcd for C20H18ClN7O[M+H]+408.1340,found:408.1324。
实施例3:
N-(2-氨基苯基)-4-(2-氯-6-乙胺基-嘌呤-9-基甲基)-苯甲酰胺(I-3)的制备:
采用4-[2-氯-6-(乙胺基)-9H-嘌呤基]甲基-苯甲酸9.9g,通过与实施例1相似的实验方法,制得白色固体5.2g。
其检测结果为:mp:226-228℃;IR:(KBr,cm-1)3290,1627,1523,1488,1454,1292,1253,1226,1114,759,713,655;1H-NMR(600MHz,DMSO-d6)δ9.63(s,1H),8.35(t,J=5.3Hz,1H),8.29(s,1H),7.95(d,J=8.0Hz,2H),7.38(d,J=7.8Hz,2H),7.15(d,J=7.7Hz,1H),6.96(m,1H),6.77(dd,J=8.0,1.3Hz,1H),6.58(dd,J=11.6,4.4Hz,1H),5.44(s,2H),4.89(s,2H),3.45-3.47(m,2H),1.17(t,J=7.1Hz,3H);13C-NMR(151MHz,DMSO-d6)δ165.42,155.40,153.92,150.12,143.62,141.66,140.41,134.65,128.72,127.64,127.16,127.00,123.63,118.66,116.67,116.53,46.52,35.37,15.00;HRMS(ESI)m/z calcd forC21H20ClN7O[M+H]+422.1496,found:422.1497。
实施例4:
N-(2-氨基苯基)-4-(2-氯-6-丙胺基-嘌呤-9-基甲基)-苯甲酰胺(I-4)的制备:
采用4-[2-氯-6-(丙胺基)-9H-嘌呤基]甲基-苯甲酸10.3g,通过与实施例1相似的实验方法,制得白色固体5.1g。
其检测结果为:mp:215-217℃;IR:(KBr,cm-1)3305,2935,2873,1624,1523,1488,1454,1303,1249,1226,1153,1118,756,713,651,601;1H-NMR(600MHz,DMSO-d6)δ9.62(s,1H),8.35(t,J=5.5Hz,1H),8.30(d,J=12.6Hz,1H),7.95(d,J=8.1Hz,2H),7.38(d,J=8.0Hz,2H),7.15(d,J=7.6Hz,1H),7.00-6.93(m,1H),6.77(dd,J=7.9,0.9Hz,1H),6.58(t,J=7.3Hz,1H),5.44(s,2H),4.89(s,2H),3.38(dd,J=13.4,6.6Hz,2H),1.68-1.54(m,2H),0.89(t,J=7.3Hz,3H);13C-NMR(151MHz,DMSO-d6)δ165.41,155.62,153.88,150.12,143.62,141.64,140.41,134.64,128.71,127.65,127.15,126.99,123.62,118.61,116.65,116.51,46.52,42.26,22.49,11.82;HRMS(ESI)m/z calcd for C22H22ClN7O[M+H]+436.1653,found:436.1644。
实施例5:
N-(2-氨基苯基)-4-(2-氯-6-丁胺基-嘌呤-9-基甲基)-苯甲酰胺(I-5)的制备:
采用4-[2-氯-6-(丁胺基)-9H-嘌呤基]甲基-苯甲酸10.7g,通过与实施例1相似的实验方法,制得白色固体4.7g。
其检测结果为:mp:197-199℃;IR:(KBr,cm-1)3217,2935,2869,1658,1620,1573,1508,1458,1350,1311,1257,1222,1157,1091,929,817,748,705;1H-NMR(600MHz,DMSO-d6)δ9.62(s,1H),8.38-8.30(m,1H),8.29(s,1H),7.95(d,J=8.1Hz,2H),7.39(d,J=8.0Hz,2H),7.15(d,J=7.6Hz,1H),7.00-6.91(m,1H),6.77(dd,J=8.0,1.2Hz,1H),6.59(t,J=7.5Hz,1H),5.44(s,2H),4.89(s,2H),3.43(dd,J=13.0,6.6Hz,2H),1.64-1.51(p,2H),1.33(m,2H),0.90(t,J=7.3Hz,3H);13C-NMR(151MHz,DMSO-d6)δ165.43,155.61,153.92,150.12,143.61,141.60,140.41,134.66,128.72,127.67,127.15,127.00,123.66,118.62,116.68,116.55,46.54,31.35,20.02,19.88,14.17;HRMS(ESI)m/z calcd for C23H24ClN7O[M+H]+450.1809,found:450.1821。
实施例6:
N-(2-氨基-4-氟-苯基)-4-(2-氯-6-乙氨基-嘌呤-9-基甲基)-苯甲酰胺(I-6)的制备:
采用4-[2-氯-6-(乙胺基)-9H-嘌呤基]甲基-苯甲酸9.9g,通过与实施例1相似的实验方法,制得黄色固体5.3g。
其检测结果为:mp:232-234℃;IR:(KBr,cm-1)3218,3220,2939,2885,1620,1523,1438,1307,1226,1164,1022,975,929,864,786,732,624,540,466;1H-NMR(600MHz,DMSO-d6)δ9.57(s,1H),8.36(dd,J=6.0,5.4Hz,1H),8.29(s,1H),7.94(d,J=8.4Hz,2H),7.37(d,J=8.4Hz,2H),7.08(dd,J=8.4,6.0Hz,1H),6.52(dd,J=10.8,3.0Hz,1H),6.34(td,J=10.8,3.0Hz,1H),5.43(s,2H),5.23(s,2H),3.45(m,2H),1.16(t,J=7.2Hz,3H);13C-NMR(151MHz,DMSO-d6)δ165.67,162.30,160.72,153.89,145.91,141.65,140.43,134.48,129.00,128.72,127.58,119.53,118.63,102.50,102.35,101.90,101.74,46.53,35.35,14.98;HRMS(ESI)m/z calcd for C21H19ClFN7O[M+H]+440.1402,found:440.1393。
实施例7:
N-(2-氨基-4-溴-苯基)-4-(2-氯-6-丙氨基-嘌呤-9-基甲基)-苯甲酰胺(I-7)的制备:
采用4-[2-氯-6-(丙胺基)-9H-嘌呤基]甲基-苯甲酸10.3g,通过与实施例1相似的实验方法,制得白色固体5.4g。
其检测结果为:mp:228-230℃;IR:(KBr,cm-1)3286,2935,2873,1620,1500,1419,1342,1307,1157,1095,929,894,740,682,594,455。1H-NMR(600MHz,DMSO-d6)δ9.58(s,1H),8.34(dd,J=6.0,5.4Hz,1H),8.28(s,1H),7.94(d,J=7.8Hz,2H),7.38(d,J=7.8Hz,2H),7.09(d,J=7.8Hz,1H),6.93(d,J=2.4Hz,1H),6.70(dd,J=8.4,2.4Hz,1H),5.43(s,2H),5.23(s,2H),3.37(dd,J=13.2,6.0Hz,2H),1.60(m,2H),0.89(t,J=7.2Hz,3H);13C-NMR(151MHz,DMSO-d6)δ165.37,155.60,153.88,150.10,143.41,141.62,140.33,136.00,134.67,128.67,127.62,127.30,127.06,121.19,118.59,117.50,116.91,46.51,39.55,22.49,11.81;HRMS(ESI)m/z calcd for C22H21BrClN7O[M-H]-512.0601,found:512.0632.
实施例8:
N-(2-氨基-4-氟-苯基)-4-(2-氯-6-丁氨基-嘌呤-9-基甲基)-苯甲酰胺(I-8)的制备:
采用4-[2-氯-6-(丁胺基)-9H-嘌呤基]甲基-苯甲酸10.7g,通过与实施例1相似的实验方法,制得黄色固体6.2g。
其检测结果为:mp:196-198℃;IR:(KBr,cm-1)3290,2935,2873,1620,1515,1438,1307,1253,1226,1168,1095,975,925,864,744,651,524,536,470;1H-NMR(600MHz,DMSO-d6)δ9.57(s,1H),8.36(m,2H),8.29(s,2H),7.94(d,J=8.4Hz,2H),7.08(dd,J=8.6,6.0Hz,1H),6.52(dd,J=10.8,3.0Hz,1H),6.34(td,J=10.8,3.0Hz,1H),5.43(s,2H),5.23(s,2H),3.41(dd,J=13.1,6.8Hz,2H),1.56(m,2H),1.32(dq,J=14.7,7.3Hz,2H),0.90(t,J=7.2Hz,3H);13C-NMR(151MHz,DMSO-d6)δ165.68,162.31,160.73,153.89,145.97,141.58,140.41,134.51,129.03,128.96,127.62,119.58,118.60,102.52,102.37,101.94,101.78,46.53,31.34,20.00,19.87,14.15;HRMS(ESI)m/z calcd for C23H23ClFN7O[M+H]+468.1715,found:468.1704。
实施例9:
N-(2-氨基-4-氟-苯基)-4-(2-氯-6-二乙基氨基-嘌呤-9-基甲基)-苯甲酰胺(I-9)的制备:
采用4-[2-氯-6-(二乙胺基)-9H-嘌呤基]甲基-苯甲酸10.7g,通过与实施例1相似的实验方法,制得黄色固体5.9g。
其检测结果为:mp:190-192℃;IR:(KBr,cm-1)3448,3363,3224,2935,2873,1639,1589,1512,1442,1319,1284,1222,1164,975,918,837,783,640,524,460;1H-NMR(600MHz,DMSO-d6)δ9.57(s,1H),8.32(s,1H),7.94(d,J=8.4Hz,2H),7.37(d,J=8.4Hz,2H),7.08(dd,J=8.6,6.0Hz,1H),6.52(dd,J=11.4.8,3.0Hz,1H),6.34(td,J=11.4,3.0Hz,1H),5.43(s,2H),5.23(s,2H),4.18(s,2H),3.64(s,2H),1.19(m,6H);13C-NMR(151MHz,DMSO-d6)δ165.66,162.30,160.72,153.94,145.91,141.09,140.38,134.49,129.06,128.98,127.63,119.54,118.26,102.49,102.34,101.90,101.74,46.48,14.46,12.98;HRMS(ESI)m/z calcd for C23H23ClFN7O[M+H]+468.1715,found:468.1699。
实施例10:
对本发明化合物的HDACs抑制活性进行测定,测定方法如下:
将HeLa细胞提取物与Buffer按照1:2的体积比进行稀释,用Buffer将所述化合物稀释成5×的终浓度,用Buffer将底物稀释50倍(1mM,2×终浓度);
在使用前30min内配置Color de LysTM Developer检测试剂:首先用预冷的Buffer将Color de LysTM Developer稀释20倍(如,50μL加950μL的Buffer),然后用新鲜配制的Developer溶液将TSA稀释100倍;
取96孔板,每孔分别加入15μL稀释后的HeLa细胞提取物和10μL所述化合物或SAHA(临床用抗肿瘤药物),37℃孵育5min,加入25μL的底物(空白组孔内不加酶及化合物,用Buffer代替;对照组孔内化合物用Buffer代替),将96孔板置于37℃摇床中孵育30min;
每孔加入50μL所配制的Color de LysTM Developer,继续孵育30min;
孵育完成后,在酶标仪上测定405nm条件下的各孔紫外吸光度值,通过测定对照组和实验组的405nm下的紫外吸光度,可计算化合物的抑制率并求得IC50值,结果见表1。
表1:HDACs抑制活性
由表1的实验结果可知,阳性对照药物MS-275的IC50为0.524μΜ,在参考范围,结果可信,受试化合物IC50低于对照组,表明其抑制活性均强于对照药物,对HDACs均具有良好的抑制活性。
实施例11:
对本发明化合物的HDAC1/3亚型酶抑制活性进行测定,测定方法如下:
将底物(5mM)用Assay buffer稀释25倍,使其浓度为200mM,BSA稀释至1mg/mL,HDAC1/3稀释至0.4ng/μL(每个反应体系中含2ng),置于冰上备用;
将各化合物及TSA、MS-275用Assay buffer稀释至相应浓度,最大浓度中DMSO含量不得超过1%;
在空白组、阳性对照组、样品组中依次加入30μL Assay buffer、5μL稀释后的BSA溶液和5μL稀释后的底物;在空白组加入10μLbuffer,阴性对照组加入5μL buffer和5μL酶溶液,在阳性对照组中和化合物组加入5μL化合物浓度及5μL酶溶液,使每个反应体系的终体积为50μL,加毕,于37℃下孵育30min;
孵育后,每孔加入显色剂50μL,再于室温下孵育15min;
在酶标仪360nm为激发光波长、460nm为检测波长下测定每孔的荧光强度,计算抑制率及IC50值,结果见表2。
表2 HDAC1/3抑制活性
由表1的实验结果可知,受试化合物IC50均低于对照组MS-275,其抑制活性均强于MS-275,表明受试化合物对HDAC1及HDAC3亚型有明显抑制作用,具有优异的I类HDAC酶亚型选择性。
实施例12:
对本发明化合物的抗肿瘤活性进行测定,测定方法如下:
所述化合物或MS-275、SAHA在使用前溶于DMSO中,然后用含1%DMSO与5%新鲜小牛血清的RPMI-1640稀释为5~6个浓度梯度;
将处于对数生长期的肿瘤细胞,调整至适宜细胞密度,接种于96孔培养板内,同时加入稀释药液或阴性对照液10μL/孔,均设五复孔,每块培养板上另设两个调零孔;
将96孔板移入37℃、5%CO2、饱和湿度的培养箱内,培养2d后,加入5mg/ml MTT试液20μL/孔,于37℃、5%CO2、饱和湿度条件下继续培养4h后,终止培养,然后加入三联溶解液100μL/孔,于37℃放置过夜;
用空白对照组调零,在酶标仪上于570nm波长处测定各孔吸光度OD值,根据结果计算IC50,结果见表3。
表3化合物对肿瘤细胞的抑制活性(n=3)
由表2的实验结果可知,受试化合物对六种癌细胞均表现出优异的抑制活性,其IC50值均小于5.5μΜ,与对照组药物MS-275与SAHA相比,受试化合物对结肠癌细胞、乳腺癌细胞、肝癌细胞、非小细胞肺癌细胞、胃癌细胞及白血病细胞均有明显的抑制活性。
实施例13:
对本发明化合物的对正常LO2肝细胞的毒性进行测定,测定方法如下:
培养至对数生长期的LO2肝细胞细胞用胰酶消化后,配制成浓度约为5×104个/mL的细胞悬浮液,每孔取100μL接种于96孔板,接种好板后置于37℃、5%的CO2培养箱培养,使其贴壁;
加入含有不同浓度化合物的培养基100μL,每个浓度设五个复孔,对照组加入不含药物的培养基100μL,同样也设五个复孔。空白对照组只加入培养基,不加细胞。加毕后放入37℃、5%的CO2培养箱培养48h;
弃除孔内培养液,加入新的空白培养液后,每孔加入5mg/mL的MTT溶液20μL,放置于培养箱中继续培养4h;
弃去上层清液,每孔加入DMSO 150μL,在492nm处用酶标仪检测吸光度,以空白组数据校正,计算细胞存活率,结果见表4。
表4化合物对正常肝细胞的毒性(n=3)
当化合物浓度为50μM,化合物对LO2细胞的存活率均显著高于MS-275(P<0.001),表明化合物的肝毒性均低于阳性对照药物MS-275。当化合物浓度为100μM,化合物对LO2细胞的存活率均显著高于MS-275(P<0.001),表明在20倍IC50值浓度下4种活性化合物的肝毒性均低于MS-275。
以上所述,只是本发明的较佳实施例而已,本发明并不局限于上述实施方式,只要其以相同的手段达到本发明的技术效果,都应属于本发明的保护范围。在本发明的保护范围内其技术方案和/或实施方式可以有各种不同的修改和变化。
Claims (9)
2.根据权利要求1所述的结构为通式(I)的化合物,或其可药用盐、前药、水合物及以任何形式代谢形成的产物,其特征在于,所述化合物选自以下的一种:
N-(2-氨基-4-氟-苯基)-4-(2,6-二氯-嘌呤-9-基甲基)-苯甲酰胺、
N-(2-氨基苯基)-4-(2-氯-6-甲胺基-嘌呤-9-基甲基)-苯甲酰胺、
N-(2-氨基苯基)-4-(2-氯-6-乙胺基-嘌呤-9-基甲基)-苯甲酰胺、
N-(2-氨基苯基)-4-(2-氯-6-丙胺基-嘌呤-9-基甲基)-苯甲酰胺、
N-(2-氨基苯基)-4-(2-氯-6-丁胺基-嘌呤-9-基甲基)-苯甲酰胺、
N-(2-氨基-4-氟-苯基)-4-(2-氯-6-乙氨基-嘌呤-9-基甲基)-苯甲酰胺、
N-(2-氨基-4-溴-苯基)-4-(2-氯-6-丙氨基-嘌呤-9-基甲基)-苯甲酰胺、
N-(2-氨基-4-氟-苯基)-4-(2-氯-6-丁氨基-嘌呤-9-基甲基)-苯甲酰胺、
N-(2-氨基-4-氟-苯基)-4-(2-氯-6-二乙基氨基-嘌呤-9-基甲基)-苯甲酰胺。
4.根据权利要求3所述的方法,其特征在于,式(II)的化合物与式(III)的化合物在碱存在的溶剂中进行反应,反应温度为0℃至溶剂的沸点,式(II)的化合物与式(III)的化合物的摩尔比为1:1;溶剂为正丁醇、乙酸乙酯、二氯甲烷、三氯甲烷、N,N-二甲基甲酰胺、四氢呋喃、丙酮或二甲亚砜;碱为无机碱或有机碱,无机碱为碱金属碳酸盐、碱金属碳酸氢盐或碱金属氢氧化物,有机碱为三乙胺、吡啶、二甲基吡啶、甲醇钠、正丁基锂或叔丁醇钾。
5.据权利要求3所述的方法,其特征在于,式(Ⅳ)的化合物在碱存在的溶剂中进行反应,反应温度为0℃至溶剂的沸点;溶剂为乙醇、甲醇、丙醇或N-甲基吡咯烷酮;碱为无机碱或有机碱,无机碱为碱金属碳酸盐、碱金属碳酸氢盐或碱金属氢氧化物,有机碱为三乙胺、吡啶、二甲基吡啶、甲醇钠、正丁基锂或叔丁醇钾。
6.据权利要求3所述的方法,其特征在于,式(V)的化合物与式(VI)的化合物在碱存在的碱金属碳酸盐溶液中进行反应,反应温度为0℃至溶剂的沸点,式(V)的化合物与式(VI)的化合物的摩尔比为1:1;溶剂为乙酸乙酯、二氯甲烷、三氯甲烷、四氢呋喃或N,N-二甲基甲酰胺。
7.权利要求1-2任一项所述的化合物或其可药用盐、前药、水合物和以任何形式代谢形成的产物在制备治疗组蛋白乙酰化酶介导疾病的药物中的应用。
8.根据权利要求7所述的应用,其特征在于,组蛋白乙酰化酶介导疾病包括恶性肿瘤,恶性肿瘤为乳腺癌、白血病、肝癌、结肠癌、胃癌、肾癌、肺癌、胰腺癌、神经胶质瘤、淋巴瘤、纤维肉瘤、卵巢癌、宫颈癌、黑色素瘤或前列腺癌。
9.一种用于治疗由组蛋白乙酰化酶介导疾病的药物组合物,其特征在于:所述药物组合物的有效成分含有权利要求1-2任一项所述的化合物或其可药用盐、前药、水合物和以以任何形式代谢形成的产物。
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FAN YUN: "Design, synthesis and biological evaluation of novel histone deacetylase1/2 (HDAC1/2) and cyclin-dependent Kinase2 (CDK2) dual inhibitors against malignant cancer", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》, vol. 198, pages 2 - 3 * |
WEI-SHENG HUANG: "9-(Arenethenyl)purines as Dual Src/Abl Kinase Inhibitors Targeting the Inactive Conformation:Design, Synthesis, and Biological Evaluation", 《JOURNAL OF MEDICINAL CHEMISTRY》, vol. 52, no. 15, pages 4743 - 4756 * |
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