CN114989147B - 一种苯并嘧啶类化合物或其药学上可接受的盐及其制备方法和应用 - Google Patents
一种苯并嘧啶类化合物或其药学上可接受的盐及其制备方法和应用 Download PDFInfo
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Abstract
本申请公开了一种苯并嘧啶类化合物或其药学上可接受的盐及其制备方法和应用。所述苯并嘧啶类化合物结构式如式(Ⅰ)所示，本发明的苯并嘧啶类化合物能够对KRASG12C突变的肿瘤细胞增殖产生抑制作用。
Description
技术领域
本发明属于有机合成技术领域，尤其涉及一种苯并嘧啶类化合物或其药学上可接受的盐及其制备方法和应用。
背景技术
鼠类肉瘤病毒癌基因(RAS)蛋白是GTP酶家族中的一个重要成员，包括NRAS，HRAS和KRAS。这些酶在细胞外信号转导，增殖，凋亡和分化中起重要作用。KRAS与鸟嘌呤三核苷酸磷酸(GTP)结合为活性构象，与鸟嘌呤二核苷酸磷酸(GDP)结合为无活性构象。突变的KRAS蛋白和GTP紧密结合使KRAS蛋白处于异常的持续激活构象，导致下游信号通路持续性激活。KRAS抑制剂通过识别突变KRAS，阻断KRAS/GEF相互作用，抑制KRAS下游效应因子从而产生抗肿瘤活性。然而，由于体内高水平的GTP和KRAS与GTP强有力的结合作用力，导致靶向KRAS变得非常困难。此外，KRAS蛋白是一个狭长的平坦口袋，这导致了基于KRAS药物的设计变得困难。KRAS被称为“不可成药靶点”。
KRAS G12C抑制剂通过占据蛋白构象变化时的SWII口袋，并且与突变的半胱氨酸共价结合，使突变的KRAS G12C停留在无活性构象，抑制下游信号通路，包括RAS-MEK-ERK信号通路，从而产生抗肿瘤作用。
发明内容
本发明旨在至少解决现有技术中存在的上述技术问题之一。为此，本发明提供了一种苯并嘧啶类化合物。
本发明还提供了所述苯并嘧啶类化合物的制备方法。
本发明还提供了所述苯并嘧啶类化合物的应用。
本发明的第一方面提供了一种苯并嘧啶类化合物，所述苯并嘧啶类化合物的结构式如式(Ⅰ)所示：
本发明关于苯并嘧啶类化合物或其药学上可接受的盐的技术方案，至少具有以下有益效果：
1、本发明的苯并嘧啶类化合物能够对KRAS G12C突变的肿瘤增殖产生抑制作用。抗肿瘤活性效果好。
2、根据权利要求1所述苯并嘧啶类化合物的制备方法，其特征在于，包括如下步骤：
S1.将化合物1在氯化亚砜溶液中进行反应得到化合物2；
S2.在第一有机溶剂中加入化合物2和Boc-哌嗪，在碱性条件下进行反应得到化合物3；
S3.化合物3和5-氯-2-甲氧基苯硼酸在钯催化条件下进行铃木反应得到化合物4；
S4.化合物4在酸性条件下脱Boc得到化合物5；
S5.化合物5与5-硝基-2-糠酸进行缩合反应得到目标产物。
所述化合物1～5的结构式如下：
5、根据权利要求2所述苯并嘧啶类化合物或其药学上可接受的盐的制备方法，其特征在于，步骤S2所述第一有机溶剂分别独立地选自N,N-二甲基甲酰、甲苯或1,4二氧六环。
6、根据权利要求2所述苯并嘧啶类化合物或其药学上可接受的盐的制备方法，其特征在于，步骤S2中所述有机碱为三乙胺、N,N-二异丙基乙胺。
6、根据权利要求2所述苯并嘧啶类化合物或其药学上可接受的盐的制备方法，其特征在于，步骤S3中的所述钯催化剂为四三苯基膦钯或[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物。
7、根据权利要求2所述苯并嘧啶类化合物或其药学上可接受的盐的制备方法，其特征在于，步骤S4中所述缩合剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1-羟基苯并三唑、卡特缩合剂。
8、一种药物组合物，其特征在于，包含权利要求1所述苯并嘧啶类化合物或其药学上可接受的赋形剂。
9、权利要求1所述的苯并嘧啶类化合物或其药学上可接受的盐在制备用于治疗或预防癌症的药物中的应用。
一般术语
本发明中所述“药学上可接受的”是指在施用于动物或人类时不产生不良反应、过敏反应或其他不利反应的分子实体和组合物，如本发明中的“药学上可接受的赋形剂”包括任何和所有溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等，此类赋形剂用于药学活性物质的使用是本领域所熟知的。
含有本发明所述的药物组合物能以常规方式来制造，例如通过常规混合、溶解、造粒、糖衣丸制备、磨细、乳化、囊封、捕集或冻干方法。适当的配制品取决于所选的施用途径。
附图说明
图1是实施例1制备的苯并嘧啶类化合物的核磁共振氢谱图；
图2是实施例1制备的苯并嘧啶类化合物的核磁共振碳谱图；
图3是实施例1制备的苯并嘧啶类化合物的质谱图。
具体实施方式
如无特殊说明，本发明所用原料、试剂及溶剂，均为商业购买未经任何处理或者可通过文献方法制得的说明。本领域技术人员应当理解，下面所具体描述的内容是说明性的而非限制性的，不应以此限制本发明的保护范围。
RPMI-1640培养基购自Gibco；胎牛血清购自Gibco；二甲基亚砜(DMSO)、四甲基偶氮唑蓝(MTT)均购自Sigma。细胞购买自长沙优泽生物科技有限公司，所购细胞均经STR鉴定。ARS-1620购买于MCE。为了更清楚地说明本发明，下面结合优选实施例对本发明做进一步说明。
实施例1
实施例1提供了一种苯并嘧啶类化合物，所述苯并嘧啶类化合物的结构式如式(Ⅰ)所示：
其制备方法包括如下步骤：
S1.向化合物1(275.9mg,1mmol)的亚硫酰氯(8mL)溶液中，加入一滴N，N-二甲基甲酰胺并将所得混合物回流搅拌8小时。反应结束将混合物冷却至室温并真空浓缩，得到化合物2。
S2.将化合物2(293.8mg,1mmol)在N,N-二甲基甲酰胺(1mL)中加入DIPEA(130mg,1mmol)和哌嗪-1-甲酸叔丁酯(186mg,1mmol)，并将所得混合物在50℃搅拌2小时。反应结束加入水析出化合物3。
S3.将Pd(PPh3)4(40mg,0.35mmol)和Na 2CO3(111mg，1mmol)加入含化合物3(444.3mg,1mmol)的N,N-二甲基甲酰胺和水的混合溶液中(1mL水+3mL N,N-二甲基甲酰胺)，再加入2-甲氧基-5氯-苯硼酸(186.4mg，1mmol)，并将所得混合物在100℃搅拌24小时。反应结束后用水和乙酸乙酯萃取，有机层真空浓缩，并通过硅胶快速柱色谱法纯化，得到化合物4。
S4.将化合物4(506.1mg，1mmol)在盐酸-1,4-二氧六环溶液中搅拌半小时后，真空浓缩得到化合物5.
S5.将化合物5(406.0mg，1mmol)和5-硝基-2-糠酸(157.0mg，1mmol)溶于二氯甲烷中，加入卡特缩合剂(442.2mg，1mmol)、N,N-二异丙基乙胺(130mg，1mmol)后搅拌过夜，将所得溶液旋干，通过柱层析得到目标产物。
所述化合物1～5的结构式如下：
将所得到产物用核磁共振和质谱确认结构：
(4-(6-chloro-7-(5-chloro-2-methoxyphenyl)-8-fluoroquinazolin-4-yl)piperazin-1-yl)(5-nitrofuran-2-yl)methanone(KS-19)1H NMR(400MHz,CDCl3)δ8.84(s,1H),7.84(s,1H),7.44(dd,J＝8.8,2.5Hz,1H),7.40(d,J＝3.8Hz,1H),7.30(d,J＝3.8Hz,1H),7.25(d,J＝2.5Hz,1H),7.00(d,J＝8.9Hz,1H),4.22–3.79(m,8H),3.71(s,3H).13C NMR(101MHz,DMSO)δ161.96,157.38,155.92,154.69,153.53,151.71,147.84,130.86,130.71,129.80,126.63,126.45,124.53,122.50,121.00,117.74,116.97,113.89,113.30,56.52.MS(ESI)m/z 546.0750(M+H)+.
性能测试
应用例1
本申请实施例1制备的苯并嘧啶类化合物对人NIC-H358、NIC-H23肺癌细胞进行抗肿瘤活性研究，采用MTT法检测化合物对肿瘤细胞增殖的抑制效果。
实验原理：MTT比色法是一种检测细胞存活和生长的方法，其原理为活细胞线粒体中的琥珀酸脱氢酶能使外源性MTT还原为水不溶性蓝紫色结晶甲瓒，并沉积在细胞中，而死细胞缺少这一功能。二甲基亚砜(DMSO)可以溶解活细胞中的甲瓒，用酶联免疫检测仪检测570nM下的吸光度值(OD值)，可以根据吸光度值反应活细胞的数量，在一定范围内，OD值越小，则表明细胞活性越弱，药物的抑制增殖效果越好。
试剂配制
1、MTT
将50mL的离心管用锡箔纸包裹避光，精密称取MTT粉末(Methylthiazolyldiphenyl-tetrazolium bromide，又名Thiazolyl Blue)250mg，加入到离心管中，加入50ml的PBS，使MTT粉末完全溶解，用0.22μm孔径的滤膜过滤除菌并分装，在-20℃条件下避光保存。
2、实施例1化合物配置
取高压好的EP管用于称取化合物，向EP管中加入对应量的DMSO，使液体成20mM的母液，使用时用相应量的培养基稀释1配成浓度为0.625μM，1.25μM，2.5μM，5μM，10μM工作液。
实验步骤：
(1)取对数生长期的细胞，消化，调整细胞数浓度为2.5×104/mL，按100μL/孔接种到96孔板中。在37℃，5％CO2细胞培养箱中培养过夜，待细胞贴壁。
(2)吸出原有培养基，每组加入不同浓度的实施例1化合物，化合物浓度分别为为0.625μM，1.25μM，2.5μM，5μM，10μM。以0.1％的DMSO设为对照组，在细胞培养箱中继续培养48h。
(3)每孔加入10μL MTT液，在培养箱中孵育4h。
(4)弃去培养基，每孔加入100μL DMSO，振荡15min充分溶解甲瓒结晶。
(5)用酶联免疫检测仪测定570nm下的吸光度值。
(6)按以下公式计算细胞生长抑制率：
抑制率＝[(As-Ab)/(Ac-Ab)]×100％；
As：实验孔的吸光度(含细胞、MTT、实施例1化合物)；
Ac：对照孔的吸光度(含细胞、MTT，无实施例1化合物)；
Ab：空白孔的吸光度(不含细胞和实施例1化合物，含MTT)；
根据上述试验，得出来的数据如表1所示：
表1实施例(I)的数据
根据上述体外实验结果，实施例1化合物能有效抑制抑制NCI-H358和NCI-H23细胞生长，IC50分别为0.46μM±0.02,0.87μM±0.04并且优于阳性对照ARS-1620。我们可以得出本申请所述的实施例1化合物能够抑制KRAS G12C突变的NCI-H358和NCI-H23肿瘤细胞生长。
Claims (8)
1.一种苯并嘧啶类化合物或其药学上可接受的盐，其特征在于，所述苯并嘧啶类化合物的结构式如式（Ⅰ）所示：
式（Ⅰ）。
2.根据权利要求1所述苯并嘧啶类化合物或其药学上可接受的盐的制备方法，其特征在于，包括如下步骤：
S1. 将化合物1在氯化亚砜溶液中进行反应得到化合物2；
S2. 在第一有机溶剂中加入化合物2和Boc-哌嗪，在碱性条件下进行反应得到化合物3；
S3. 化合物3和5-氯-2-甲氧基苯硼酸在钯催化条件下进行铃木反应得到化合物4；
S4. 化合物4在酸性条件下脱Boc得到化合物5；
S5. 化合物5与5-硝基-2-糠酸进行缩合反应得到目标产物；
所述化合物1~5的结构式如下：
。
3.根据权利要求2所述苯并嘧啶类化合物或其药学上可接受的盐的制备方法，其特征在于，步骤S1所述第一有机溶剂分别独立地选自N,N-二甲基甲酰胺、甲苯或1,4二氧六环。
4.根据权利要求2所述苯并嘧啶类化合物或其药学上可接受的盐的制备方法，其特征在于，步骤S2中所述碱性条件为有机碱存在的条件；所述有机碱为三乙胺或N,N-二异丙基乙胺。
5.根据权利要求2所述苯并嘧啶类化合物或其药学上可接受的盐的制备方法，其特征在于，步骤S3中的钯催化条件为钯催化剂存在的条件；所述钯催化剂为四三苯基膦钯或[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物。
6.根据权利要求2所述苯并嘧啶类化合物或其药学上可接受的盐的制备方法，其特征在于，步骤S5中缩合反应中的缩合剂为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1-羟基苯并三唑、或卡特缩合剂。
7.一种药物组合物，其特征在于，包含权利要求1所述苯并嘧啶类化合物或其药学上可接受的赋形剂。
8.权利要求1所述的苯并嘧啶类化合物或其药学上可接受的盐在制备用于抑制KRASG12C突变的肺癌细胞生长的药物中的应用。
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| WO2010146173A1 (en) * | 2009-06-18 | 2010-12-23 | Vereniging Voor Christelijk Hoger Onderwijs, Wetenschappelijk Onderzoek En Patientenzorg | Quinazoline derivatives as histamine h4-recept0r inhibitors for use in the treatment of inflammatory disorders |
| CN114222743A (zh) * | 2019-08-16 | 2022-03-22 | 劲方医药科技(上海)有限公司 | 氧代六元环并嘧啶类化合物，其制法与医药上的用途 |
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| WO2010146173A1 (en) * | 2009-06-18 | 2010-12-23 | Vereniging Voor Christelijk Hoger Onderwijs, Wetenschappelijk Onderzoek En Patientenzorg | Quinazoline derivatives as histamine h4-recept0r inhibitors for use in the treatment of inflammatory disorders |
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