CN111808108A - 取代2,6-二氨基嘌呤类衍生物及其制备方法和在抗肿瘤药物中的应用 - Google Patents
取代2,6-二氨基嘌呤类衍生物及其制备方法和在抗肿瘤药物中的应用 Download PDFInfo
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药技术领域，提供了一种如式Ⅰ所示的取代2,6‑二氨基嘌呤类衍生物及其制备方法，本发明还公开了所述取代2,6‑二氨基嘌呤类衍生物能够抑制ALK活性，具有明显肿瘤细胞抑制活性。
Description
技术领域
本发明属药物合成领域，涉及取代2,6-二氨基嘌呤类衍生物，以及所述化合物的药学可接受的盐、水合物、溶剂化物或前药，它们的制备方法及其作为治疗剂特别是作为ALK抑制剂的用途。
背景技术
恶性肿瘤严重威胁人类健康，现已成为全球最大的公共卫生问题之一。中国作为一个发展中大国，由于工业化、城镇化、人口老龄化进程的加快，不良的生活方式以及环境污染等因素，恶性肿瘤形势也愈发严峻。世界癌症报告统计，2012年中国癌症发病人数为306.5万，约占全球发病的五分之一；癌症死亡人数为220.5万，约占全球癌症死亡人数的四分之一。肿瘤治疗是世界性的难题，传统的化学治疗手段，较易产生严重的毒副作用，严重降低患者的生活质量。目前，靶向药物的开发相对而言具有更好的安全性及耐受性，已成为抗肿瘤药物开发的主要方向。
研究表明，间变性淋巴瘤激酶(ALK)融合基因的形成导致ALK基因活化，异常的ALK活性可以抑制细胞凋亡，对恶性肿瘤的发生和发展起了重要作用，因此ALK已成为抗肿瘤药物设计开发的重要靶点。克唑替尼(Crizotinib)作为第一个上市的ALK抑制剂，对ALK阳性的非小细胞肺癌有着良好的疗效。然而，克唑替尼在使用一段时间后出现耐药性问题，导致肿瘤细胞对药物的脱敏。
因此，研究开发新型ALK抑制剂从而提高药物与靶蛋白的结合亲和力具有重要的科学意义。
发明内容
本发明的目的在于提供一种通式为(I)的取代2,6-二氨基嘌呤类衍生物，及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药。
为了实现上述目的，本发明提供的取代2,6-二氨基嘌呤类衍生物结构通式如下：
所述的R1选自氢、C1-C6烷基、被卤素取代的C1-C6烷基、C3-C6环烷基；所述的R1优选C1-C6烷基。
所述的R2选自氢、卤素、C1-C6烷基，C1-C6烷氧基，N-烷基酰胺基、二甲基氧磷基；所述的R2优选C1-C6烷氧基，N-烷基酰胺基或二甲基氧磷基。
本发明所述的取代2,6-二氨基嘌呤类衍生物，选自：
此外，按照本发明所属领域的一些通常方法，本发明中通式(I)的部分化合物具有碱性基团，可以与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有机酸加成盐，与下列酸加成的盐是特别优选的：盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。最优选为盐酸。
本发明的“水合物”是指溶剂分子是水所形成的缔合物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。
本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式(I)的衍生物，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
通式(I)所示的化合物可以以非溶剂化形式和含有药学上可接受的溶剂(如水、乙醇等)的溶剂化形式。通式(I)所示的化合物可以含有不对称或手性中心，因此可以以不同立体异构形式存在。本发明的所有立体异构形式，包括但不限于非对映异构体、对映异构体和阻转异构体以及它们的混合物(如外消旋混合物)，均包括在本发明的范围内。
通式(I)所示的化合物可以以不同的互变异构体形式存在，所有这些形式均包括在本发明的范围内。术语“互变异构体”或“互变异构形式”是指经由低能垒互相转化的不同能量的结构异构体。
本发明中“烷基”是指直链或支链的烷基，其中C1-C6基团是指该部分中具有1-6个碳原子，即基团包含1、2、3、4、5或6个碳原子。
本发明的“烷氧基”是指烷基醚基烷基，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基等。
本发明中的术语“环烷基”是指任选取代的一价饱和烃环，其包含3-6个成环碳原子，也可包括作为取代基的其他非成环原子(例如：甲基环丙基)。
本发明中所述的“卤素”是指氟、氯、溴或碘代。
本发明可以含有通式(I)的衍生物，及其药学上可接受的盐、水合物、溶剂化物或前药作为活性成份，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型，上述药学上可接受的赋型剂是指任何可用于药学领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成份组合使用，只要它们不产生其他不利的作用，例如过敏反应。
本发明含有通式(I)的衍生物可以通过包括化学领域众所周知的方法来合成，尤其根据本发明的说明来合成。本发明所述衍生物的制备方法，均可按照路线1的方法进行合成，具体为：以2,6-二氯-7-甲基/异丙基嘌呤(1)为原料与不同取代的苯胺在碱性条件下进行亲核取代反应得到中间体(2)，接着再与5-氨基-1,3-二甲基吡唑发生在醋酸钯催化下的偶联反应，得到目标化合物，合成路线如下。
路线中试剂和条件：(a)DIPEA,n-BuOH,100℃；(b)1,3-Dimethyl-1H-pyrazol-5-amine，Pd(AcO)2,X-phos,Cs2CO3,dioxane,90℃.
本发明所述的抗肿瘤具体为肺癌、胃癌或神经胶质瘤。
在采用本发明化合物进行治疗或预防过程中，假如需要分开的剂量，通常会给药以使得获得的日剂量为0.1mg/kg-50mg/kg。当采用肠胃外路径时将给予较低剂量。例如，就静脉或腹腔给药而言，通常使用的剂量为0.1mg/kg-30mg/kg。同样，就吸入给药而言，将采用的剂量为0.05mg/kg–20mg/kg。口服给药也是合适的，特别是以片剂形式。通常，单位剂型将包含约0.5mg-0.5g本发明化合物且单位剂型可每日给药一次、二次、三次或四次或如果需要的话，以更高频率给药。
本发明显著的技术效果。
本发明人在文献调研的基础上，借助计算机辅助药物设计手段，设计并合成了一系列取代2,6-二氨基嘌呤类衍生物。此类化合物具有明显的ALK抑制活性，骨架新颖，能够明显抑制肿瘤细胞生长。本发明实验结果显示，本实验室合成的取代2,6-二氨基嘌呤类具有较强的抗肿瘤活性优点，可用于制备抗肿瘤药物，具有临床开发抗肿瘤药物的前景。
具体实施方法
下述实施例旨在阐述而不是限制本发明的范围。
化合物的核磁共振氢谱用Bruker ARX-400测定，质谱用Agilent 1100LC/MS测定；原料一般可以从商业来源获得或者使用本领域技术人员所熟知的方法来制备，或根据本发明所述的方法制备。未经特殊说明，所用试剂均为分析纯或化学纯。
实施例1。
步骤1中间体2的合成
将2,6-二氯-7-甲基嘌呤(2.00g,9.85mmol)溶于20mL正丁醇中，然后加入2-氨基-N-甲基苯甲酰胺(1.63g,10.84mmol)和N,N-二异丙基乙胺(2.73g,11.82mmol)，加毕升温至100℃，反应5h后TLC检测反应完成。将反应液降至室温，然后加入100mL水，100mL乙酸乙酯萃取，饱和食盐水洗涤有机层，Na2SO4干燥过夜。滤除干燥剂，减压蒸除溶剂，残余物经硅胶柱层析纯化，得2.20g白色固体，收率70.51％。
步骤2目标化合物的合成
将中间体2(500mg,1.58mmol)，5-氨基-1,3-二甲基吡唑(193mg,1.74mmol)、X-Phos(112mg,0.16mmol)和碳酸铯(1.54g,4.74mmol)溶于25mL的1,4-二氧六环中，然后在氮气保护下加入醋酸钯(35mg,0.16mmol)，加毕升温至90℃，反应8h后TLC检测反应完成。将反应液降至室温，减压浓缩除去溶剂，然后加入100mL乙酸乙酯萃取，分别用水和饱和食盐水洗涤有机层，Na2SO4干燥过夜。滤除干燥剂，减压蒸除溶剂，残余物经硅胶柱层析纯化，得0.31g白色固体，收率50.17％。
1H-NMR(400MHz,DMSO-d6)δ11.61(s,1H),9.35(s,1H),8.73(d,J＝4.4Hz,1H),8.01(s,1H),7.96(d,J＝8.4Hz,1H),7.74(d,J＝7.8Hz,1H),7.53(t,J＝8.4Hz,1H),6.95(dd,J＝7.8,2.4Hz,1H),6.02(s,1H),3.72(s,3H),3.62(s,3H),2.83(d,J＝4.6Hz,3H),2.07(s,3H).ESI-MS m/z:392.2[M+H]+.
按照实施例1的方法，分别以取代2,6-二氯-嘌呤为原料依次与取代苯胺和5-氨基-1,3-二甲基吡唑发生取代反应得到实施例2-6。
实施例2。
1H-NMR(400MHz,DMSO-d6)δ11.62(s,1H),9.31(s,1H),8.03(s,1H),7.21(d,J＝8.0Hz,1H),7.02-6.98(m,3H),6.01(s,1H),3.86(s,3H),3.71(s,3H),3.61(s,3H),2.05(s,3H).ESI-MS m/z:365.2[M+H]+.
实施例3。
1H-NMR(400MHz,DMSO-d6)δ11.61(s,1H),9.35(s,1H),8.02(s,1H),7.53(t,J＝7.8Hz,1H),7.20-7.17(m,2H),6.97(dd,J＝7.8,2.2Hz,1H),6.04(s,1H),3.71(s,3H),3.61(s,3H),2.06(s,3H),1.83(d,J＝13.5Hz,6H).ESI-MS m/z:411.2[M+H]+.
实施例4。
1H-NMR(400MHz,DMSO-d6)δ11.60(s,1H),9.34(s,1H),8.74(d,J＝4.5Hz,1H),8.01(s,1H),7.95(d,J＝8.4Hz,1H),7.72(d,J＝8.0Hz,1H),7.53(t,J＝8.4Hz,1H),6.95(dd,J＝7.8,2.4Hz,1H),6.02(s,1H),5.21(m,1H),3.62(s,3H),2.04(s,3H),1.62(d,J＝6.2Hz,6H).ESI-MS m/z:420.2[M+H]+.
实施例5。
1H-NMR(400MHz,DMSO-d6)δ11.60(s,1H),9.31(s,1H),8.03(s,1H),7.22(d,J＝8.0Hz,1H),7.02-6.98(m,3H),6.04(s,1H),5.20(m,1H),3.86(s,3H),3.62(s,3H),2.04(s,3H),1.61(d,J＝6.1Hz,6H).ESI-MS m/z:493.1[M+H]+.
实施例6。
1H-NMR(400MHz,DMSO-d6)δ11.62(s,1H),9.34(s,1H),8.02(s,1H),7.53(t,J＝7.8Hz,1H),7.20-7.17(m,2H),6.97(dd,J＝7.8,2.2Hz,1H),6.04(s,1H),5.22(m,1H),3.62(s,3H),2.05(s,3H),1.84(d,J＝13.0Hz,6H),1.62(d,J＝6.2Hz,6H).ESI-MS m/z:439.2[M+H]+.
药理活性测试。
一、体外ALK抑制活性测试。
HTRF均相时间分辨荧光技术：激酶ALKWT和ALKL196M购自Sigma Aldrich,检测试剂盒HTRF KinEASE-TK购自Cisbio公司，按照说明书操作进行测试。将实施例化合物配置成一系列梯度浓度，在室温下与激酶共同孵育5min，之后加入适量的酶反应底物、ATP，启动酶反应过程，30min后，向酶反应体系中加入适量的反应终止液和检测液，孵育1h后，最后在酶标仪中进行读数，同时拟合IC50值。测试结果见表1。
表1体外ALK抑制活性测试结果。
如上表所示，本发明通式(I)中的实施例化合物对ALK及ALKL196M具有明显的抑制活性。
二、MTT法测试细胞增殖抑制活性。
细胞株：人非小细胞肺癌NCI-H2228(EML4-ALK阳性细胞株)、SK-N-BE2(ALIC基因扩增细胞株)、SH-SY5Y(ALK FI 174突变细胞株)购于中国科学院细胞库。
测试方法：将上述肿瘤细胞按5000-10000个每孔接种至96孔板，置于37℃，5％CO2细胞培养箱中培养24h，然后加入不同浓度的待测化合物，每个浓度设定3个复孔，加毕继续培养48h，弃培养液，MTT试剂测定细胞活力。每孔加入15μL预先配制好的MTT反应液，继续培养4h，吸弃上清，100μL/孔加入DMSO溶解还原产物，避光5min，490nm波长处读取吸光度值，计算细胞活力。IC50指细胞生长被抑制一半时抑制剂的浓度。结果见表2。
表2 MTT法测试细胞增殖抑制结果。
结果表明：本发明合成的化合物对三种癌细胞NCI-H2228、SK-N-BE2和SH-SY5Y具有明显的抑制活性。
Claims (6)
1.一种取代2,6-二氨基嘌呤类衍生物及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于，所述的衍生物结构式如下：
其中，
R1选自氢、C1-C6烷基、被卤素取代的C1-C6烷基、C3-C6环烷基
R2选自氢、卤素、C1-C6烷基，C1-C6烷氧基，N-烷基酰胺基或二甲基氧磷基。
2.如权利要求1所述的取代2,6-二氨基嘌呤类衍生物及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于，所述的R1选自C1-C6烷基；R2选自C1-C6烷氧基，N-烷基酰胺基、二甲基氧磷基。
3.如权利要求1所述的取代2,6-二氨基嘌呤类衍生物及其几何异构体或其药学上可接受的盐、水合物、溶剂化物或前药，其特征在于，所述的衍生物选自：
4.如权利要求1-3中任一所述的取代2,6-二氨基嘌呤类衍生物在制备抗肿瘤药物中的应用。
5.如权利要求1-3中任一所述的化合物在制备用于抑制ALK介导的病症或疾病的药物中的应用。
6.权利要求1-3中任一所述的取代2,6-二氨基嘌呤类衍生物用于制备抗肿瘤药物，其特征在于，所述的抗肿瘤具体为肺癌、胃癌或神经胶质瘤。
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