CN116768902A - 一种取代酚羟基苯基吡咯并嘧啶化合物及其制备方法和应用 - Google Patents
一种取代酚羟基苯基吡咯并嘧啶化合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于化药技术领域,具体涉及一种取代酚羟基苯基吡咯并嘧啶化合物及其制备方法和应用。该取代酚羟基苯基吡咯并嘧啶化合物如式I所示,本发明制备过程简单易行,制备得到的喹唑啉类化合物或其在药学上可接受的盐具有高效抑制去泛素化酶USP51的效果,且具有较高选择性,并且安全性良好、溶解性和生物利用度高,为拓宽对USP家族的认知、去泛素化酶USP51参与蛋白去泛素化的过程相关机制研究以及新型抗肿瘤小分子药物的开发提供了新的视野和思路。
Description
技术领域
本发明属于化药技术领域,具体涉及一种取代酚羟基苯基吡咯并嘧啶化合物及其制备方法和应用。
背景技术
恶性肿瘤是威胁人类生命安全的重大疾病之一。目前,恶性肿瘤的治疗手段主要有:手术,放射治疗以及化学治疗等。传统抗肿瘤药物由于毒副作用大等缺点阻碍了其在临床的进一步应用。大量研究表明,去泛素化酶通过调节蛋白质相互作用、定位和酶活性,从而影响细胞过程,包括转录、DNA 损伤信号和DNA修复、细胞周期进展、氧化应激、凋亡等,发挥极其重要的生理功能。其与肿瘤发生发展关系之密切。去泛素化酶抑制剂也被发现在多种肿瘤临床前研究中发挥出显著的抗肿瘤作用,已成为新型抗肿瘤药物领域研发热点。
上皮-间充质转化(EMT)及其逆转过程和间充质-上皮转化(MET)在肿瘤转移中发挥关键作用。在EMT过程中,上皮细胞失去了与邻近细胞保持密切联系的粘附连接和紧密连接。多种转录因子激活EMT可诱导肿瘤细胞的迁移、侵袭和转移。而ZEB1作为是一种掌控EMT诱导转录因子,它可以促进肿瘤侵袭、转移和治疗耐药性。在多种癌症类型中,ZEB1的异常表达与侵袭性行为、高肿瘤指数、耐药、高代谢可塑性和转移有关。例如,在乳腺癌患者中,发现三阴性/基底样乳腺癌乳腺癌的肿瘤细胞中出现ZEB1高表达。
USP51是一种ZEB1(Zinc Finger E-Box Binding Homeobox 1)的去泛素酶,靶向USP51也可能作为一种靶向促癌转录因子ZEB1的替代途径。通过对人类去泛素酶文库筛选发现USP51是一种可以结合、去泛素化和稳定ZEB1的泛素化酶。间质样乳腺癌细胞中USP51的缺失会导致了ZEB1蛋白和间质标记物的下调,钙黏蛋白-E的上调和细胞侵袭的抑制。相反,USP51在上皮细胞中过表达导致ZEB1和间叶细胞标记物上调。此外,USP51能够调控ZEB1靶基因的表达。重要的是,USP51在乳腺癌患者中过表达,并与生存不良相关。
目前USP家族抑制剂的开发主要针对于热点的USP7、USP1、USP9等靶点。USP51作为较为新颖的去泛素酶对其蛋白酶本身及其抑制剂的研究和报道均较少见。且目前开发的去泛素化酶选择性抑制剂仍存在诸多问题:①对于去泛素化酶的相关研究集中在USP 家族成员,尤其是 USP7,但大多数对其报道的抑制剂表现出的抑制活性较弱,或包含不良的化学特征,或对目前已知的去泛素化酶家族的选择性较差。②目前,人们对于去泛素化酶蛋白结构及功能底物的了解不充分、不均衡,对于去泛素化酶与肿瘤发生相关的内在机制仍缺少探索认知。这也导致了目前大多数去泛素化酶的小分子抑制剂存在特异性差等缺陷。此外,原有的抑制剂筛选方法与技术也存在与实际生理环境相容性差、易出现假阳性等缺陷。因此,研究并设计合成出结构新颖的、高抑制活性、高选择性、高安全性的靶向USP51小分子抑制剂具有重要的科研意义。
发明内容
本发明的目的是解决现有技术的不足,一种取代酚羟基苯基吡咯并嘧啶化合物及其制备方法和应用,具体采用以下的技术方案:
一种取代酚羟基苯基吡咯并嘧啶化合物,其结构式如式I所示:
式I,其中NR2R3为3-9元饱和杂环氨基、二烷基氨基中的一种;所述杂环氨基含有至少一个N原子和O原子作为环原子,并且,所述杂环氨基通过氨基部分与分子其余部分连接;所述二烷基氨基为二甲基氨基、二乙基氨基、二丙基氨基中的一种;n取自0-4任一整数。
本发明的发明人在大量研究中发现,上述取代酚羟基苯基吡咯并嘧啶化合物或其在药学上可接受的盐具有高效选择抑制去泛素化酶USP51的效果,可以应用在制备和治疗预防癌症药物中,可以作为治疗癌症的药物组合物的活性成分,该药物组合物包含一种或多种药学上可接受的赋形剂,上述药物组合物的剂型为药学上可接受的任一剂型,还可以应用在去泛素化酶USP51抑制剂中。
上述癌症包括:妇科癌类,例如:卵巢癌、子宫颈癌、阴道癌、阴部癌、子宫/子宫内膜癌、妊娠滋养细胞肿瘤、输卵管癌、子宫肉瘤;内分泌癌类,例如:肾上腺皮质癌、脑垂体癌、胰癌、甲状腺癌、副甲状腺癌、胸腺癌、多发性内分泌肿瘤;骨癌类,例如:骨肉瘤、尤因肉瘤、软骨肉瘤等;肺癌类,例如:小细胞肺癌、非小细胞肺癌;脑和CNS肿瘤,例如:神经母细胞瘤、听神经瘤、神经胶瘤和其他脑肿瘤,脊髓肿瘤、乳癌、结肠直肠癌、晚期结肠直肠腺癌;胃肠癌类,例如:肝癌、肝外胆管癌、胃肠类癌性肿瘤、胆囊癌、胃癌、食道癌、小肠癌;泌尿生殖器癌类,例如:阴茎癌、翠丸癌、前列腺癌;头和颈部肿瘤类,例如:鼻癌、鼻窦癌、鼻咽癌、口腔癌、唇癌、唾腺癌、喉头癌、下咽癌、正咽癌;血癌类,例如:急性骨髓性白血病、急性淋巴性白血病、儿童白血病、慢性淋巴性白血病、慢性骨髓性白血病、发状细胞性白血病、急性早幼粒细胞白血病、血浆细胞性白血病;骨髓癌血液病症,例如:骨髓分化不良症候群、骨髓增生性病症、范禾尼贫血、再生障碍性贫血、特发性巨球蛋白血症;淋巴癌类,例如:霍奇金病、非霍奇金氏淋巴瘤、周围T-细胞林巴瘤、皮肤型T-细胞淋巴瘤、AIDS相关性淋巴瘤;眼癌类,包括:视网膜母细胞瘤、葡萄膜黑色素瘤;皮肤癌类,例如:黑色素瘤、非黑色素瘤皮肤癌、梅克尔细胞癌;软组织肉瘤类,例如:卡波希肉瘤、儿童软组织肉瘤、成人软组织肉瘤、泌尿系统癌症,例如:肾癌维尔姆斯肿瘤、膀肤癌、尿道癌和转移性细胞癌。优选用于乳腺癌、卵巢癌、淋巴瘤、肺癌、结直肠癌、前列腺癌、膀胱癌、肝癌、口味癌、神经母细胞瘤或白血病或其他与去泛素化酶USP51相关的癌症。
作为进一步优选的实施方式,上述取代酚羟基苯基吡咯并嘧啶化合物选自以下化合物1-8中的任意一种:
。
作为进一步优选的实施方式,上述取代酚羟基苯基吡咯并嘧啶化合物结构如下:
。
本发明的化合物1-8均显示出出色且远超阳性对照DHI和EPI的抑制USP51的活性,且其中化合物5活性强于其他类似物,化合物5心脏毒IC50为12.23 μM,显示出较高安全性,并且化合物5具有较高的Cmax和AUC,口服半衰期达到5.03 h,口服生物利用度为41.3%,具有较高的生物利用度。
本发明还提供了一种上述取代酚羟基苯基吡咯并嘧啶化合物选自以下化合物或其药学上可接受的盐的制备方法,其制备路线如下:
;首先,吡咯并嘧啶A1与4-碘苯甲醚A2在碘化亚铜作用下发生芳香C-N偶联反应获得中间体A,随后4-炔基苯胺B1与4-腈基碘苯B2发生薗头偶联反应得到大平面结构B3,随后与中间体A偶联获得中间体B,B在碳酸铯、碘化钾作用下与不同氨基卤代烷发生取代反应获得一系列目标分子。
本发明还提供了一种药物组合物,药物组合物包含一种或多种药学上可接受的赋形剂,上述赋形剂包括碳水化合物、聚合物、脂质或矿物中的至少一种。
本发明的有益效果为:本发明制备过程简单易行,制备得到的喹唑啉类化合物或其在药学上可接受的盐具有高效抑制去泛素化酶USP51的效果,且具有较高选择性,并且安全性良好、溶解性和生物利用度高,为拓宽对USP家族的认知、去泛素化酶USP51参与蛋白去泛素化的过程相关机制研究以及新型抗肿瘤小分子药物的开发提供了新的视野和思路。
具体实施方式
以下将结合实施例对本发明的构思、具体结构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。
实施例1
取代酚羟基苯基吡咯并嘧啶化合物
化合物1的制备:
化合物1的结构如下:
,其制备过程如下:
步骤1:化合物A的制备:
化合物A的结构如下:
;
将化合物A1(300 mg, 1.03 mmol)溶解在1,4-二氧六环(5 mL)中, 加入 化合物A2(285 mg,0.49 mmol),加入碘化亚铜(18 mg, 0.08 mmol)、反式-1,2-环己二胺(120 mg,0.70 mmol)和磷酸钾(500 mg, 3.01 mmol)。放入油浴中,加热至110℃,回流3小时后,用硅藻土过滤,将瓶内的液体用旋转蒸发仪浓缩将得到的粗品用硅胶柱层析进行纯化(石油醚:乙酸乙酯=5:1至3:1)得化合物1(白色固体,303 mg,产率:70%)。
化合物A的核磁测试结果为:
1H NMR (400 MHz, DMSO-d 6) δ 9.82 (d,J= 2.5 Hz, 1H), 9.02 (d,J= 2.5 Hz,1H), 7.90 (t,J= 3.0 Hz, 1H), 7.51 (dd,J= 8.9, 2.5 Hz, 2H), 6.95 (dd,J= 8.9,2.5 Hz, 2H), 6.86 (t,J= 3.0 Hz, 1H).13C NMR (100 MHz, Chloroform-d) δ 157.33,153.18, 152.41, 151.45, 132.06, 128.29, 126.23, 118.74, 116.27, 101.41.HRMS(ESI): m/z calcd for C33H33N6O3 +[M+H]+: 246.0429 ; found 246.0429。
上述步骤中化合物A1的化学式如下:
;
上述步骤中化合物A2的化学式如下:
。
步骤2:化合物B3的制备
化合物B3的结构如下:
;
在氩气保护的环境下,将化合物B1(对炔基苯胺,100 mg, 0.785 mmol)溶解在四氢呋喃(5 mL)中,加入化合物B2(4-腈基碘苯,170 mg, 0.776 mmol),碘化亚铜(14.9 mg,0.0785 mmol)、三乙胺(0.313 mL)和双三苯基膦二氯化钯(55.8 mg, 0.0785 mmol)。回流过夜后,将瓶内的液体用旋转蒸发仪浓缩,用饱和 NaCl 溶液洗反应液,乙酸乙酯萃取(3×100 mL),有机相使用无水硫酸钠进行干燥,浓缩,将得到的粗品用硅胶柱层析进行纯化(石油醚 :乙酸乙酯 = 7:1)得化合物 B3(白色固体,112 mg,产率:66%)。
化合物B3的核磁测试结果为:
1H NMR (400 MHz, Chloroform-d) δ 8.30 – 8.13 (m, 1H), 7.82 (dd,J=7.6, 1.8 Hz, 1H), 7.78 – 7.64 (m, 2H), 7.17 (dt,J= 6.7, 3.2 Hz, 1H), 6.85 –6.64 (m, 3H), 3.87 (s, 2H)。
上述步骤中化合物B1的化学式如下:
;
上述步骤中化合物B2的化学式如下:
。
步骤3:化合物B的制备:
化合物B的结构如下:
;
将化合物A(130 mg, 0.41 mmol)溶解在1,4-二氧六环(4 mL)中,加入化合物B3(130 mg, 0.62 mmol),加入醋酸钯(6 mg, 0.02 mmol),加入1,1'-联萘-2,2'-双二苯膦(35 mg, 0.02 mmol)和碳酸铯(260 mg, 0.73 mmol)。放入油浴中,加热至110 ℃,回流8小时后,用硅藻土过滤,将瓶内的液体用旋转蒸发仪浓缩将得到的粗品,直接用于下一步。
步骤4:化合物1的制备:
将化合物A(60 mg, 0.14 mmol)、碘化钾(5.25 mg, 0.035 mmol)、碳酸铯(114mg, 0.35 mmol)溶于乙腈(1 mL)中,随后加入N,N-二甲胺基溴乙烷氢溴酸盐(65 mg, 0.28mmol),回流过夜后,加水淬灭反应,旋干乙腈后,加水(10 mL)和乙酸乙酯(3×10 mL)萃取,有机相使用无水硫酸钠进行干燥,浓缩,将得到的粗品用硅胶柱层析进行纯化(二氯甲烷 :甲醇 = 18 : 1)得化合物 1(白色固体,53 mg,产率:77%)。
化合物1的核磁测试结果为:
1H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 7.74 (d, J = 8.4 Hz,2H), 7.65 (dd, J = 9.3, 2.4 Hz, 2H), 7.63 – 7.54 (m, 4H), 7.48 (d, J = 8.4Hz, 2H), 7.43 (s, 1H), 7.24 (d, J = 3.7 Hz, 1H), 7.13 – 7.06 (m, 2H), 6.58(d, J = 3.7 Hz, 1H), 4.19 (t, J = 5.6 Hz, 2H), 2.85 (t, J = 5.6 Hz, 2H), 2.43(s, 6H).13C NMR (100 MHz, Chloroform-d) δ 157.5, 155.5, 151.5, 151.0, 141.3,132.7, 132.0, 131.9, 130.9, 128.8 , 126.6 , 125.0 , 118.7 , 117.8 , 115.1 ,114.4 , 113.9 , 110.9 , 101.4 , 94.8 , 87.0 , 66.2 , 58.2 , 45.9 .HRMS (ESI):m/z calcd for C31H27N6O+[M+H]+: 499.2241 ; found 499.2244。
上述步骤中N,N-二甲胺基溴乙烷氢溴酸盐的化学式如下:
实施例2
化合物2的制备:
化合物2的结构如下:
,其制备过程如下:
将实施例1中N,N-二甲胺基溴乙烷氢溴酸盐替换为4-(2-溴乙基)吗啉氢溴酸盐其他条件保持不变获得化合物2。
化合物2的核磁测试结果为:
1H NMR (400 MHz, Chloroform-d) δ 8.73 (s, 1H), 7.76 – 7.72 (m, 2H),7.67 – 7.64 (m, 2H), 7.63 – 7.57 (m, 4H), 7.50 – 7.43 (m, 3H), 7.24 (d, J =3.7 Hz, 1H), 7.12 – 7.04 (m, 2H), 6.58 (d, J = 3.7 Hz, 1H), 4.21 (t, J = 5.7Hz, 2H), 3.81 – 3.72 (m, 4H), 2.87 (t, J = 5.7 Hz, 2H), 2.63 (dd, J = 5.7,3.8 Hz, 4H).13C NMR (100 MHz, Chloroform-d) δ 157.5 , 155.5 , 151.5 , 151.0 ,141.3 , 132.7 , 132.0 , 131.8 , 130.9 , 128.8 , 126.6 , 125.1 , 118.7 , 117.8, 115.2 , 114.4 , 113.9 ,110.9 , 101.4 , 94.7 , 87.0 , 66.9 , 66.2 , 57.7 ,54.2.HRMS (ESI): m/z calcd for C33H29N6O2 +[M+H]+: 541.2347 ; found 541.2349。
上述步骤中4-(2-溴乙基)吗啉氢溴酸盐的化学式如下:
;
实施例3
化合物3的制备:
化合物3的结构如下:
,其制备过程如下:
将实施例1中N,N-二甲胺基溴乙烷氢溴酸盐替换为4-(2-溴乙基)哌嗪氢溴酸盐其他条件保持不变获得化合物3。
化合物3的核磁测试结果为:
1H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 7.74 (d,J= 8.4 Hz,2H), 7.68 – 7.56 (m, 6H), 7.48 (t,J= 7.4 Hz, 3H), 7.24 (d,J= 3.7 Hz, 1H),7.11 – 7.03 (m, 2H), 6.58 (d,J= 3.7 Hz, 1H), 4.20 (t,J= 5.7 Hz, 2H), 2.90 (t,J= 5.7 Hz, 2H), 2.82 – 2.54 (m, 8H), 2.38 (s, 3H).13C NMR (101 MHz, CDCl3) δ157.4, 155.5, 151.5, 151.0, 141.3, 132.7, 132.0, 131.9, 130.9, 128.8, 126.6,125.0, 118.7, 117.8, 115.1, 114.4, 113.9, 110.9, 101.4, 94.8, 87.0, 66.3,57.1, 54.9, 53.1, 45.7. HRMS (ESI): m/z calcd for C34H32N7O+[M+H]+: 554.2663 ;found 554.2665。
上述步骤中4-(2-溴乙基)哌嗪氢溴酸盐的化学式如下:
实施例4
化合物4的制备:
化合物4的结构如下:
,其制备过程如下:
将实施例1中N,N-二甲胺基溴乙烷氢溴酸盐替换为4-(2-溴乙基)四氢吡咯氢溴酸盐其他条件保持不变获得化合物4。
化合物4的核磁测试结果为:
1H NMR (400 MHz, Chloroform-d) δ 8.73 (d, J = 2.4 Hz, 1H), 7.74 (dd,J = 8.7, 2.4 Hz, 2H), 7.67 – 7.58 (m, 6H), 7.47 (dd, J = 8.7, 2.4 Hz, 2H),7.36 (s, 1H), 7.24 (s, 1H), 7.11 – 7.06 (m, 2H), 6.57 (t, J = 3.1 Hz, 1H),4.23 (t, J = 4.8 Hz, 2H), 3.01 (t, J = 4.8 Hz, 2H), 2.73 (d, J = 5.9 Hz, 4H),1.89 – 1.85 (m, 4H).13C NMR (100 MHz, Chloroform-d) δ 157.5 , 151.0 , 141.3 ,132.7 , 132.0 , 131.9 , 130.8 , 128.8 , 126.6 , 125.1 , 118.7 , 117.8 , 115.2, 113.9 , 112.8 , 110.9 , 101.4 , 87.0 , 67.2 , 55.0 , 54.8 , 23.5 .HRMS(ESI): m/z calcd for C33H29N6O+[M+H]+: 525.2397 ; found 525.2399。
上述步骤中4-(2-溴乙基)四氢吡咯氢溴酸盐的化学式如下:
实施例5
化合物5的制备:
化合物5的结构如下:
,其制备过程如下:
将实施例1中N,N-二甲胺基溴乙烷氢溴酸盐替换为4-(2-溴乙基)四氢吡咯氢溴酸盐其他条件保持不变获得化合物5。
化合物5的核磁测试结果为:
1H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 7.75 (d, J = 8.4 Hz,2H), 7.69 – 7.58 (m, 4H), 7.58 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.6 Hz, 3H),7.24 (d, J = 3.7 Hz, 1H), 7.06 (d, J = 8.8 Hz, 2H), 6.58 (d, J = 3.7 Hz, 1H),4.12 (t, J = 6.2 Hz, 2H), 2.69 (t, J = 7.4 Hz, 2H), 2.42 (s, 6H), 2.12 (p, J= 6.6 Hz, 2H).13C NMR (100 MHz, Chloroform-d) δ 157.6 , 155.5 , 151.5 , 151.0, 141.4 , 132.7 , 132.0 , 131.8 , 130.8 , 128.8 , 126.6 , 125.0 , 118.7 ,117.8 , 115.0 , 114.3 , 113.9 , 110.9 , 101.4 , 94.8 , 87.0 , 66.3 , 56.3 ,45.1 , 27.0 . HRMS (ESI): m/z calcd for C32H29N6O+[M+H]+: 513.2397 ; found513.2399。
上述步骤中4-(2-溴乙基)四氢吡咯氢溴酸盐的化学式如下:
;
实施例6
化合物6的制备:
化合物6的结构如下:
,其制备过程如下:
将实施例1中N,N-二甲胺基溴乙烷氢溴酸盐替换为4-(2-溴丙基)吗啉氢溴酸盐其他条件保持不变获得化合物6。
化合物6的核磁测试结果为:
1H NMR (400 MHz, Chloroform-d) δ 8.63 (s, 1H), 7.64 – 7.54 (m, 4H),7.50 (d, J = 7.9 Hz, 4H), 7.34 (dd, J = 8.5, 2.8 Hz, 2H), 7.16 (d, J = 3.7Hz, 1H), 6.83 (dd, J = 8.7, 2.9 Hz, 2H), 6.49 (d, J = 3.7 Hz, 1H), 4.07 (d, J= 7.7 Hz, 2H), 3.68 (d, J = 4.5 Hz, 4H), 2.42 (d, J = 16.4 Hz, 6H), 1.94 (t,J = 7.8 Hz, 2H).13C NMR (100 MHz, Chloroform-d) δ 157.9 , 154.5 , 151.9 ,150.6 , 146.1 , 132.5 , 132.0 , 132.0 , 130.6 , 128.5 , 126.1 , 125.9 , 124.7, 118.6 , 118.0 , 115.9 , 113.1 , 111.2 , 101.1 , 87.5 , 66.7 , 56.4 , 53.5 ,49.0 , 24.7 . HRMS (ESI): m/z calcd for C34H31N6O2 +[M+H]+: 555.2503 ; found555.2505。
上述步骤中4-(2-溴丙基)吗啉氢溴酸盐的化学式如下:
;/>
实施例7
化合物7的制备:
化合物7的结构如下:
,其制备过程如下:
将实施例1中N,N-二甲胺基溴乙烷氢溴酸盐替换为4-(2-溴丙基)哌嗪氢溴酸盐其他条件保持不变获得化合物7。
化合物7的核磁测试结果为:
1H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H), 7.74 (d, J = 8.4 Hz,2H), 7.66 – 7.60 (m, 4H), 7.58 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H),7.39 (s, 1H), 7.24 (d, J = 3.7 Hz, 1H), 7.09 – 7.03 (m, 2H), 6.58 (d, J = 3.7Hz, 1H), 4.10 (t, J = 6.3 Hz, 2H), 2.76 – 2.52 (m, 8H), 2.33 (s, 3H), 2.06 –2.02 (m, 2H).13C NMR (100 MHz, Chloroform-d) δ 157.8 , 155.5 , 151.5 , 151.0 ,141.3 , 132.7 , 132.0 , 131.8 , 130.6 , 128.8 , 126.7 , 125.0 , 118.7 , 117.8, 115.1 , 114.3 , 113.9 , 110.9 , 101.3 , 94.8 , 86.9 , 66.6 , 55.1 , 55.0 ,53.0 , 45.9 , 26.7. HRMS (ESI): m/z calcd for C34H32N7O+[M+H]+: 568.2819 ;found 568.2820。
上述步骤中4-(2-溴丙基)哌嗪氢溴酸盐的化学式如下:
;
实施例8
化合物8的制备:
化合物8的结构如下:
,其制备过程如下:
将实施例1中N,N-二甲胺基溴乙烷氢溴酸盐替换为4-(2-溴丙基)四氢吡咯氢溴酸盐其他条件保持不变获得化合物8。
化合物8的核磁测试结果为:
1H NMR (400 MHz, DMSO-d6) δ 9.91 (s, 1H), 8.86 (s, 1H), 7.99 – 7.93(m, 2H), 7.91 – 7.85 (m, 2H), 7.82 – 7.76 (m, 2H), 7.73 – 7.68 (m, 2H), 7.64(d, J = 3.7 Hz, 1H), 7.55 – 7.49 (m, 2H), 7.24 – 7.16 (m, 2H), 6.70 (d, J =3.7 Hz, 1H), 4.19 (t, J = 6.1 Hz, 2H), 3.39 – 3.23 (m, 6H), 2.21 (dt, J =13.2, 6.0 Hz, 2H), 1.98 – 1.89 (m, 4H).13C NMR (100 MHz, DMSO-d6) δ 157.2 ,156.0 , 151.7 , 151.2 , 142.9 , 133.0 , 132.8 , 132.3 , 131.1 , 128.3 , 127.4, 125.2 , 119.0 , 118.2 , 115.5 , 113.7 , 113.0 , 110.8 , 101.9 , 95.3 , 87.4, 65.8 , 53.4 , 51.8 , 25.9 , 23.2 .HRMS (ESI): m/z calcd for C34H31N6O+[M+H]+:539.2554 ; found 539.2557.
上述步骤中4-(2-溴丙基)四氢吡咯氢溴酸盐的化学式如下:
;
实施例9
激酶活性筛选
利用Ub-AMC(C-末端-7-酰氨基标记泛素蛋白-4-甲基香豆素标记)法进行USP体外激酶活性测试,检测上述药物小分子与蛋白激酶的直接作用能力,这些底物被各种去泛素化酶有效裂解或水解,释放出高度荧光的部分。荧光底物AMC与泛素链结合不发射荧光,当USP将荧光底物AMC从泛素链上切割下来后,AMC 发射荧光,通过检测荧光强度分析USP的抑制程度。同时,选择化合物二氢杨梅(Dihydromyricetin,DIH)和表没食子儿茶素(Epigallocatechin, EPI )作为阳性对照,分别将荧光底物AMC和各药物分子加入buffer中,随后加入USP51蛋白,并在4 ℃、12000 rmp条件下离心混匀样品,上机检测荧光强度。为了较为直观比较化合物酶活差异,将IC50分为四类:100 nM<IC50<1 μM (A),10 nM<IC50<100 nM (B),1 nM<IC50<10 nM (C)。检测结果见下表:具体测试结果如下列所示:
从上图结果可知,化合物1-8均显示出出色且远超阳性对照DHI和EPI的抑制USP51的活性,且其中化合物5活性强于其他类似物,有望开发成为潜在的USP51小分子抑制剂。
实施例10
化合物5选择性评价
进一步对优选化合物5的选择性进行了评价,对207个去泛素化酶靶标、激酶、蛋白酶进行了酶活性分析,评价结果显示,化合物5对USP51具有强烈抑制作用,IC50<10 nM;对USP1、USP5、OTUB1、USP7、USP9X、USP24、USP14、USP15等其余DUBs和其他靶点不具有明显选择性(IC50>1 μM)。结果表明,化合物5是一种USP51选择性抑制剂。
实施例11
化合物5安全性评价
对优选的化合物5进行了hERG心脏毒性评价,使用稳定转染并表达人源心肌HERG离子通道的HEK293细胞,将培养好的细胞放置在倒置显微镜下,通过微操作仪使记录电极接触细胞表面,随后进行膜电容补偿和串联电阻补偿,使电流线平滑,用于后续测试。采用磁阀控制8道灌流给药系统,通过给药电极灌流给药,将配好的化合物5母液分别按照比例稀释至30 μM、10 μM、3 μM、1 μM、0.3 μM,加入灌流给药系统中,通过重力作用控制流速对细胞进行持续灌流,连接给药电极,调节位置于细胞左上,当细胞进行电流记录后卖给与对照组(不含化合物5)灌流,待电流稳定后,换成化合物2灌流,观察其作用。通过Clampfit软件分析,化合物5心脏毒IC50为12.23 μM,显示出较高安全性。
实施例11
化合物5的口服生物利用度
对优选的化合物5进行了小鼠体内生物利用度评价,小鼠禁食过夜后,三只灌胃给药(50 mg/kg),三只尾静脉给药(10 mg/kg),随后在5 min, 15 min, 30 min, 1 h, 2 h,4 h, 6 h, 8 h分别采全血0.1-0.2 mL,置于预肝素钠化管中,轻弹数下使血液与肝素钠充分混匀后离心(4 ℃, 3000 rpm, 12 min)得到血浆,取50 μL血浆样品,加入50 μL稀释液(50%甲醇/水)和250 μL甲醇沉淀剂,涡旋后离心(4℃, 12000 rpm, 12 min),将上清液过膜封存送LC-MS/MS检测。并通过WinNonlin软件分析参数,结合下表结果显示化合物5具有较高的Cmax和AUC,口服半衰期达到5.03 h,口服生物利用度为41.3%,具有较高的生物利用度。
尽管本发明的描述已经相当详尽且特别对几个所述实施例进行了描述,但其并非旨在局限于任何这些细节或实施例或任何特殊实施例,而是应当将其视作是通过参考所附权利要求考虑到现有技术为这些权利要求提供广义的可能性解释,从而有效地涵盖本发明的预定范围。此外,上文以发明人可预见的实施例对本发明进行描述,其目的是为了提供有用的描述,而那些目前尚未预见的对本发明的非实质性改动仍可代表本发明的等效改动。
Claims (10)
1.一种取代酚羟基苯基吡咯并嘧啶化合物,其特征在于,其结构式如式I所示:
式I,其中NR2R3为3-9元饱和杂环氨基、二烷基氨基中的一种;所述杂环氨基含有至少一个N原子和O原子作为环原子,并且,所述杂环氨基通过氨基部分与分子其余部分连接;所述二烷基氨基为二甲基氨基、二乙基氨基、二丙基氨基中的一种;n取自0-4任一整数。
2.根据权利要求1所述的取代酚羟基苯基吡咯并嘧啶化合物,其特征在于,所述取代酚羟基苯基吡咯并嘧啶化合物的结构如以下化合物1-8中的任意一种:
。
3.一种权利要求2所述的取代酚羟基苯基吡咯并嘧啶化合物,其特征在于,所述取代酚羟基苯基吡咯并嘧啶化合物结构如下:
。
4.一种权利要求1-3任一项所述的取代酚羟基苯基吡咯并嘧啶化合物,其特征在于,其制备路线为路线如下:
。
5.一种权利要求1-4任一项所述的取代酚羟基苯基吡咯并嘧啶化合物或其在药学上可接受的盐在制备治疗和/或预防癌药物中的应用。
6.根据权利要求5所述的应用,其特征在于,癌症为乳腺癌、卵巢癌、淋巴瘤、肺癌、结直肠癌、前列腺癌、膀胱癌、肝癌、口味癌、神经母细胞瘤或白血病。
7.一种权利要求1-4任一项所述的喹唑啉化合物在制备作为去泛素化酶USP51抑制剂中的应用。
8.一种药物组合物,其特征在于,以权利要求1-3任一项所述的喹唑啉类化合物或其在药学上可接受的盐为主要活性成分。
9.根据权利要求8所述的药物组合物,其特征在于,所述药物组合物包含一种或多种药学上可接受的赋形剂。
10.根据权利要求9所述的药物组合物,其特征在于,所述赋形剂包括碳水化合物、聚合物、脂质或矿物中的至少一种。
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