CN106831790B - 7H-吡咯并[2,3-d]嘧啶衍生物 - Google Patents
7H-吡咯并[2,3-d]嘧啶衍生物 Download PDFInfo
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- JJTNLWSCFYERCK-UHFFFAOYSA-N 7h-pyrrolo[2,3-d]pyrimidine Chemical class N1=CN=C2NC=CC2=C1 JJTNLWSCFYERCK-UHFFFAOYSA-N 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims abstract description 11
- 201000005202 lung cancer Diseases 0.000 claims abstract description 11
- 208000020816 lung neoplasm Diseases 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
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- 239000000470 constituent Substances 0.000 claims description 2
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了式(Ⅰ)所示的7H‑吡咯并[2,3‑d]嘧啶衍生物。本发明提供的化合物对肿瘤细胞具有显著的抑制作用,可以用于预防和/或治疗肿瘤相关疾病,尤其是肺癌,具有广泛的应用前景。
Description
技术领域
本发明涉及7H-吡咯并[2,3-d]嘧啶衍生物。
背景技术
目前,肺癌是发病率和死亡率增长最快,对人群健康和生命威胁最大的恶性肿瘤之一。
然而,尽管市场上已经存在多种治疗肺癌的药物,但是都存在着各种缺陷,例如生物利用度不高、专属性不强、毒副作用大等问题。而这些缺陷,往往是由于化合物本身的结构特点及其作用靶标所带来的,难以在进一步的研究开发中克服。
因此,本领域人员都希望合成出结构各异的多种化合物以及探索到新的作用靶标以克服前述缺陷。
发明内容
为解决上述问题,本发明提供了一种全新结构的7H-吡咯并[2,3-d]嘧啶衍生物。
式(Ⅰ)所示的化合物或其药学上可接受的盐、或其溶剂合物:
其中,
R1表示-NH2、-NH(C1-C4烷基)或者-N(C1-C4烷基)2;
R2表示氢或C1-C6烷基;
R3表示氢或C1-C6烷基;
R4表示氢或C1-C6烷基;
R5表示无或苯环上的一个或多个取代基,所述取代基分别独立地选自羟基或-o-(R6O)n-R7-x;
n表示1~10的正整数;
R6和R7分别独立地选自亚甲基、亚乙基、亚丙基、亚丁基、亚戊基、亚己基、亚庚基、亚辛基、亚壬基或亚癸基;
X表示卤原子、-OH或-OSO2-R7,R7表示苯基或被1个或多个C1-C6烷基取代的苯基。
进一步地,R1为-NH2。
进一步地,R2为氢。
进一步地,R3表示C1-C6烷基,优选正丁基或叔丁基。
进一步地,R4为氢。
进一步地,R1为-NH2,且R2为氢,且R3表示C1-C6烷基,优选正丁基或叔丁基。
进一步地,n为3、4或5。
进一步地,R6和R7均为亚乙基。
进一步地,X为对甲苯磺酰基。
进一步地,所述化合物为如下化合物之一:
Ts表示对甲苯磺酰基。
本发明还提供了前述的化合物、或其溶剂合物、或其药学上可接受的盐在制备抗肿瘤药物中的用途;优选的,所述药物是预防和/或治疗肺癌的药物;更优选的,所述肺癌是非小细胞肺癌。
本发明还提供了一种药物组合物,它是以前述的化合物、或其溶剂合物、或其药学上可接受的盐为活性成分,加上药学上可接受的辅料制备而成的制剂。
本发明中,所述C1-C4的烷基是指C1、C2、C3、C4的烷基,即具有1~4个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基等等。类似的,所述C1~C6的烷基是指C1、C2、C3、C4、C5、C6的烷基,即具有1~6个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、仲丁基、戊基、己基等等。
本发明中,“治疗”也包括复发性(relapse)预防或阶段性(phase)预防,以及急性或慢性体征、症状和/或功能失常的治疗。治疗可以是对症治疗,例如抑制症状。它可以在短期内实现,在中期内调整,或者可以说是长期治疗,例如在维持疗法里面。
所述“预防”包括延迟和/或阻止病症、疾病或病况和/或其伴发症状的发作;防止对象染上病症、疾病或病况;或降低对象染上病症、疾病或病况的风险的方法。
本发明中,“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
本发明中,“盐”是将化合物或其立体异构体,与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
试验结果显示,本发明的化合物对肺癌细胞株A549具有明显的抑制作用,具有广阔的市场前景。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
下述附图中,编号HYCZ01对应本发明化合物1,编号HYCZ02为对应本发明化合物2,PP1为阳性对照药。
图1:在48h和72h,HYCZ01、HYCZ02及PP1为不同浓度(12.5um、25um、50um、80um、100um)时,A549的生长曲线。
图2:在48h和72h,HYCZ01、HYCZ02及PP1对A549在不同高浓度(50um,80um,100um)的抑制率。
具体实施方式
下述实施例中,关键中间体产物可通过自制得到,其余所有参与合成的试剂在商业中均可从国药、长征公司购买得到。
实施例1本发明关键中间体的制备
(1)制备5-碘-4-氨基-7H-吡咯并[2,3-d]嘧啶
称取4-氨基-7H-吡咯并[2,3-d]嘧啶(0.60g,4.47mmol)和N-碘代琥珀酰亚胺(1.51g,6.71mmol)溶于100ml乙腈中,并于120℃回流加热24h。反应完成后蒸发溶剂,用二氯甲烷与水混合萃取,有机相用无水硫酸钠干燥后减压蒸发,并用柱层析分离纯化得到黄色固体0.96g(产率为82.51%)。
1H NMR(500MHz,DMSO-d6)δ13.78(s,1H),8.17(s,1H),7.09(bs,2H).HR-MS(ESI+):Calc.for[C6H5IN4]:260.9592[M+H]+,found:260.9638[M+H]+,282.9458[M+Na]+.
(2)制备5-碘-7-正丁基-7H-吡咯并[2,3-d]嘧啶4-氨基
称取5-碘-4-氨基-7H-吡咯并[2,3-d]嘧啶(2g,0.0077mol)和碳酸钾(4.2g,0.0310mol),加入DMF(50mL)溶解后加热到90℃回流后,正丁基碘(2mL)用分液漏斗滴加到溶液中。反应3小时后,蒸发溶剂,用乙酸乙酯萃取,有机相用无水硫酸钠干燥后减压蒸发,并用柱层析分离纯化得到白色固体1.80g(产率为74%)。
1H NMR(600MHz,Chloroform-d)δ8.26(s,1H),7.07(s,1H),5.99(s,2H),4.16(t,J=7.2Hz,2H),1.83–1.75(m,2H),1.33–1.26(m,2H),0.96-0.92(t,J=7.4Hz,3H).HR-MS(ESI+):Calc.for[C10H13IN4]:317.0218[M+H]+;Found 317.0261[M+H]+,339.0090[M+Na]+.
实施例2制备4-(4-氨基-7-正丁基-7H-吡咯并[2,3-d]嘧啶-5-)苯酚(化合物1)
将4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)苯酚(660mg,3.0mmol)加入到5-碘-7-正丁基-7H-吡咯并[2,3-d]嘧啶4-氨基(177mg,0.56mmol)的1,4-二氧乙烷/水(5:1,25mL:5mL)溶液中后,继续加入碳酸钾(41.4mg,3.0mmol)和PdCl2(dppf)(4mg,0.05mmol)。然后在油浴90℃中加热24小时。加入水和乙酸乙酯萃取,有机层用无水硫酸镁干燥并减压蒸发得到白色固体100mg(产率为75%)。
1H NMR(600MHz,Chloroform-d)δ8.25(s,1H),7.55-7.05(d,J=7.4Hz,4H),7.01(s,1H),6.99(s,1H),5.36(s,2H),4.26-4.23(t,J=7.2Hz,2H),1.89–1.83(m,2H),1.41–1.36(m,2H),0.89-0.87(d,3H).HR-MS(ESI+):Calc.for[C16H18N4O]:283.1514[M+H]+;Found283.1552[M+H]+,305.1386[M+Na]+。
实施例3制备2-(2-(2-(2-(4-(4-氨基-7-正丁基-7H-吡咯并[2,3-d]嘧啶-5-)苯氧基)乙氧基)乙氧基)乙氧基)乙基4-甲基苯磺酸(化合物2)
四甘醇双(对甲苯盐酸盐)(164mg,3.46mmol),4-(4-氨基-7-正丁基-7H-吡咯并[2,3-d]嘧啶-5-)苯酚(100mg,3.46mmol),和无水碳酸钾(100mg,3.46mol)于50mL苯溶液中回流加热4h,1N HCl的中和后,将反应混合物用二氯甲烷萃取。然后将溶液减压干燥,得到固体后进行柱色谱分离得到棕黄色糖浆状产物160mg(产率为76%)。
1H NMR(600MHz,Chloroform-d)δ8.29(s,1H),δ7.84-6.97(m,8H,arom-H),6.95(s,1H),5.52(s,2H),4.23-4.21(t,J=7.2Hz,2H),4.23-3.59(t,J=7.2Hz,16H),δ2.44(s,3H),1.87–1.80(m,2H),1.44–1.35(m,2H),0.97-0.95(t,J=7.4Hz,3H).HR-MS(ESI+):Calc.for[C31H40N4O7S]:613.2618[M+H]+;Found 613.2694[M+H]+,635.2521[M+Na]+.
实施例4本发明化合物的药效试验
采用MTT检测法,其为黄色化合物,是一种接受氢离子的染料,可作用于活细胞线粒体中的呼吸
肺癌细胞株:A549链,在琥珀酸脱氢酶和细胞色素C的作用下tetrazolium环开裂,生成蓝色的formanzan结晶,formazan结晶的生成量仅与活细胞数目成正比,还原生成的formanzan结晶可在二甲亚砜(DMSO)中溶解,利用酶标仪测定490nm处的光密度值(OD)值,即可反应出活细胞数量。
一、实验步骤
实验用品:肺癌细胞株、细胞培养所需工具、MTT以及化合物母液为10mmol/L,阳性对照药Src抑制剂PP1。
1、具体方法
(1)复苏A549,待状态良好时,即传代一次后细胞长到80%左右(即对数生长期)进行铺板(96孔板)。
(2)首先,收集细胞,通过计数板调整细胞悬液浓度,以每孔1000—10000个细胞接种到96孔板,具体每孔的细胞数依据不同细胞的生长速度和药物作用时间来确定,549铺5000和1299铺5000,每孔200ul(100ul的细胞悬液+100ul的不同浓度梯度的药物稀释液),边孔(36个)加200ul的双无培养基(为了防止边缘效应)。
(3)铺板加药后,根据48h、72h处理,然后呈色,每孔加含20ulMTT溶液(5mg/mL)的培养液200ul,继续培养1-4h,终止培养,小心吸弃孔内培养上清液,对于悬浮细胞需要离心后再吸弃孔内的培养上清液。每孔加150ulDMSO,在摇床上震荡15~20min,使结晶物充分溶解。
(4)比色:在酶标仪上测定,选择490或者570nm波长,从而测定各孔的光吸收值,记录结果。
(5)计算
抑制率=(对照-给药)/对照×100%
IC50(半数抑制浓度)时可根据不同浓度的抑制率用spass软件求算。
二、实验结果
A549细胞作用48h和72h,药物剂量分为12.5um、25um、50um、80um、100um,分别铺板6000和5000细胞进行实验,结果如下表1~3以及图1~2所示:
表1本发明化合物对A549的抑制作用(48h)
表2本发明化合物对A549的抑制作用(72h)
表3对照药PP1对A549的抑制作用(48h、72h)
综上所述,本发明提供的化合物对肿瘤细胞具有显著的抑制作用,可以用于预防和/或治疗肿瘤相关疾病,尤其是肺癌,具有广泛的应用前景。
Claims (4)
1.如下所示的化合物或其药学上可接受的盐:
Ts表示对甲苯磺酰基。
2.权利要求1所述的化合物或其药学上可接受的盐在制备抗肿瘤药物中的用途;其中,所述药物是预防和/或治疗肺癌的药物。
3.根据权利要求2所述的用途,其特征在于:所述肺癌是非小细胞肺癌。
4.一种药物组合物,其特征在于:它是以权利要求1所述的化合物或其药学上可接受的盐为活性成分,加上药学上可接受的辅料制备而成的制剂。
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---|
Synthesis of 4-Amino-5-cyanopyrrolo[2,3-d]pyrimidine,the Aglycone of Toyocamycin;Taylor, Edward C. et al.;《Journal of the American Chemical Society》;19640331;第86卷(第5期);第951-952页,第951页化合物Ib * |
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