CN114989195A - 一种噻吩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
一种噻吩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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- CN114989195A CN114989195A CN202210583947.4A CN202210583947A CN114989195A CN 114989195 A CN114989195 A CN 114989195A CN 202210583947 A CN202210583947 A CN 202210583947A CN 114989195 A CN114989195 A CN 114989195A
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- Prior art keywords
- compound
- pharmaceutically acceptable
- acceptable salt
- thienopyrimidine
- acid
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 229940125898 compound 5 Drugs 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
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Abstract
Description
技术领域
本发明属于有机合成技术领域,尤其涉及一种噻吩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”。
近年来,针对KRAS突变的研究主要集中在KRAS G12C,针对KRAS G12D的研究较少。KRAS G12D抑制剂通过使突变的KRASG12D停留在无活性KRAS-GDP构象从而抑制下游蛋白,包括RAS-MEK-ERK信号通路,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,本发明提供了一种噻吩并嘧啶类化合物或其药学上可接受的盐。
本发明还提供了所述噻吩并嘧啶类化合物或其药学上可接受的盐的制备方法。
本发明还提供了所述噻吩并嘧啶类化合物或其药学上可接受的盐的应用。
本发明的第一方面提供了一种噻吩并嘧啶类化合物或其药学上可接受的盐,所述噻吩并嘧啶类化合物的结构式如式(Ⅰ)所示:
本发明关于噻吩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:
本发明的噻吩并嘧啶类化合物能够结合KRAS G12D,对KRAS G12D突变的肿瘤增殖产生抑制作用。抗肿瘤活性效果好。
本发明的第二方面提供了一种噻吩并嘧啶类化合物或其药学上可接受的盐的制备方法,包括如下步骤:
S1.将化合物1、2和N,N-二异丙基乙胺加入到第一有机溶剂中进行反应得到化合物3;
S2.将化合物3、4和叔丁醇钠在第二有机溶剂中进行反应得到化合物5;
S3.在第三有机溶剂中加入化合物5和1-萘硼酸,在钯催化剂和无机碱的条件下进行反应得到化合物6;化合物6在酸性条件下得到式(Ⅰ)化合物;
所述化合物1~6的结构式如下:
根据权利要求2所述噻吩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,所述第一有机溶剂、第二有机溶剂、第三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。
根据权利要求2所述噻吩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。
根据权利要求2所述噻吩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中所述无机碱为碳酸钠、碳酸钾或磷酸钾。
一种药物组合物,其特征在于,包含权利要求1所述噻吩并嘧啶类化合物或其药学上可接受的盐;和药学上可接受的赋形剂。
权利要求1所述的噻吩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。
本发明的第四方面还提供了一种药物组合物,所述组合物含有本发明的噻吩并嘧啶类化合物或其药学上可接受的盐,和药学上可接受的赋形剂。
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。
本发明中所述“药学上可接受的盐”包括碱加成盐和酸加成盐。
药学上可接受的碱加成盐可以用金属或胺(例如碱金属和碱土金属或有机胺)来形成。化合物的药学上可接受的盐也可以用药学上可接受的阳离子来制备。适合的药学上可接受的阳离子是本领域技术人员所熟知的并且包括碱金属阳离子、碱土金属阳离子、铵阳离子和季铵阳离子。碳酸盐或碳酸氢盐也是可能的。用作阳离子的金属的是钠、钾、镁、铵、钙或三价铁等。适合的胺的包括异丙胺、三甲胺、组氨酸、N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、二环己胺、乙二胺、N-甲基葡糖胺和普鲁卡因。
药学上可接受的酸加成盐包括无机酸盐或有机酸盐。适合的酸盐包括盐酸盐、甲酸盐、乙酸盐、柠檬酸盐、水杨酸盐、硝酸盐、磷酸盐。其他适合的药学上可接受的盐是本领域技术人员所熟知的并且包括例如甲酸、乙酸、柠檬酸、草酸、酒石酸或扁桃酸、盐酸、氢溴酸、硫酸或磷酸;与有机羧酸、磺酸、磺酸基酸或磷酸基酸或N-取代的氨基磺酸,例如乙酸、三氟乙酸(TFA)、丙酸、乙醇酸、琥珀酸、马来酸、羟基马来酸、甲基马来酸、富马酸、苹果酸、酒石酸、乳酸、草酸、葡糖酸、葡糖二酸、葡糖醛酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、水杨酸、4-氨基水杨酸、2-苯氧基苯甲酸、2-乙酰氧基苯甲酸、扑酸、烟酸或异烟酸的盐;以及与氨基酸,例如在自然界中参与蛋白质合成的20种α氨基酸,例如谷氨酸或天冬氨酸,以及与苯乙酸、甲磺酸、乙磺酸、2-羟基乙磺酸、乙烷1,2-二磺酸、苯磺酸、4-甲基苯磺酸、萘2-磺酸、萘1,5-二磺酸、2-磷酸甘油酸或3-磷酸甘油酸、葡萄糖6-磷酸、N-环己基氨基磺酸(用于环己氨磺酸盐的形成),或与其他酸性有机化合物,例如抗坏血酸的盐。
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为本发明所述含噻吩并嘧啶类化合物式(I)核磁共振的氢谱图。
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。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。
实施例1
实施例1提供了一种噻吩并嘧啶类化合物,所述噻吩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:
将化合物1(281.84mg)、化合物2(212.15mg)和N,N-二异丙基乙胺(90mg)加入到N,N- 二甲基甲酰胺中(2mL)进行反应得到化合物3,化合物3和4在碱性条件下生成化合物5,化合物5进行Suzuki反应得到化合物6,化合物6在盐酸条件下脱除BOC,旋干溶剂得到化合物(I);
化合物5的制备:
将化合物3(458.02mg)、化合物4(141.12mg)和叔丁醇钠(90mg)加入到甲苯(2mL)进行反应得到化合物5.
化合物6的制备:
在N,N-二甲基甲酰胺中加入化合物5(463.10mg)和1-萘硼酸(258.00mg),在四三苯基膦钯7mg和碳酸钠300mg的条件下进行反应,通过柱层析法得到化合物6。
所述化合物1~6的结构式如下:
将所得到产物用核磁共振确认结构:
1H NMR(400MHz,DMSO)δ11.37(s,1H),10.43(d,J=8.7Hz,1H),10.08(s,1H),8.17–8.09(m,3H),7.77 (d,J=6.5Hz,1H),7.70–7.63(m,4H),4.68(d,J=16.0Hz,4H),4.24(s,8H),4.01(d,J=13.1Hz,2H),3.56 (s,2H),3.20(s,2H),2.20(s,2H),1.90(d,J=7.4Hz,2H).
性能测试
应用例1
本申请实施例1制备的噻吩并嘧啶类化合物对人SW1990、Panc1胰腺癌细胞和小鼠CT26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(噻唑蓝)粉末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5μM,10μM,25μM,50μM,100μM 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5μM, 10μM,25μM,50μM,100μM。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
SW1990(IC<sub>50</sub>) | CT26(IC<sub>50</sub>) | Panc1(IC<sub>50</sub>) | |
本申请实施例I制备的化合物 | 2.5μM±0.11 | 2.1μM±0.21 | 1.8μM±0.09 |
根据上述体外实验结果,实施例1化合物能有效抑制抑制SW1990,Panc1和CT26 细胞生长,IC50分别为2.5μM±0.11,2.1μM±0.21,1.8μM±0.09。我们可以得出本申请所述的实施例1化合物能够抑制KRAS G12D突变的SW1990,Panc1和CT26肿瘤细胞生长。
上面结合实施例对本发明作了详细说明,但是本发明不限于上述实施例,在所属技术领域普通技术人员所具备的知识范围内,还可以在不脱离本发明宗旨的前提下作出各种变化。
Claims (7)
3.根据权利要求2所述噻吩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,所述第一有机溶剂、第二有机溶剂、第三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。
4.根据权利要求2所述噻吩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。
5.根据权利要求2所述噻吩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中所述无机碱为碳酸钠、碳酸钾或磷酸钾。
6.一种药物组合物,其特征在于,包含权利要求1所述噻吩并嘧啶类化合物或其药学上可接受的盐;和药学上可接受的赋形剂。
7.权利要求1所述的噻吩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。
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CN112047948A (zh) * | 2019-06-06 | 2020-12-08 | 山东轩竹医药科技有限公司 | Kras突变体抑制剂 |
WO2021106231A1 (en) * | 2019-11-29 | 2021-06-03 | Taiho Pharmaceutical Co., Ltd. | A compound having inhibitory activity against kras g12d mutation |
WO2022068921A1 (zh) * | 2020-09-30 | 2022-04-07 | 上海医药集团股份有限公司 | 一种喹唑啉类化合物及其应用 |
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WO2021106231A1 (en) * | 2019-11-29 | 2021-06-03 | Taiho Pharmaceutical Co., Ltd. | A compound having inhibitory activity against kras g12d mutation |
WO2022068921A1 (zh) * | 2020-09-30 | 2022-04-07 | 上海医药集团股份有限公司 | 一种喹唑啉类化合物及其应用 |
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