WO2018149231A1 - 7H-吡咯并[2,3-d]嘧啶衍生物及抗肿瘤的应用 - Google Patents

7H-吡咯并[2,3-d]嘧啶衍生物及抗肿瘤的应用 Download PDF

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WO2018149231A1
WO2018149231A1 PCT/CN2017/118484 CN2017118484W WO2018149231A1 WO 2018149231 A1 WO2018149231 A1 WO 2018149231A1 CN 2017118484 W CN2017118484 W CN 2017118484W WO 2018149231 A1 WO2018149231 A1 WO 2018149231A1
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compound according
alkyl
compound
butyl
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PCT/CN2017/118484
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French (fr)
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陈勃江
何杨
柴莹莹
李为民
周兴龙
陈海
李长富
黄日东
沈珍
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四川大学华西医院
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    • 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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  • the present invention relates to 7H-pyrrolo[2,3-d]pyrimidine derivatives.
  • lung cancer is one of the most malignant tumors with the fastest growth in morbidity and mortality and the greatest threat to population health and life.
  • the present invention provides a novel structure of 7H-pyrrolo[2,3-d]pyrimidine derivatives.
  • R 1 represents -NH 2 , -NH(C 1 -C 4 alkyl) or -N(C 1 -C 4 alkyl) 2 ;
  • R 2 represents hydrogen or a C 1 -C 6 alkyl group
  • R 3 represents hydrogen or C 1 -C 6 alkyl
  • R 4 represents hydrogen or a C 1 -C 6 alkyl group
  • R 5 represents no or one or more substituents on the phenyl ring, the substituents are each independently selected from a hydroxyl group or -O-(R 6 O) n -R 7 -X;
  • n a positive integer of 1 to 10;
  • R 6 and R 7 are each independently selected from a methylene group, an ethylene group, a propylene group, a butylene group, a pentylene group, a hexylene group, a heptylene group, an octylene group, an anthranylene group or an anthranylene group;
  • X represents a halogen atom, -OH or -OSO 2 -R 7
  • R 7 represents a phenyl group or a phenyl group substituted by one or more C 1 -C 6 alkyl groups.
  • R 1 is -NH 2 .
  • R 2 is hydrogen
  • R 3 represents a C 1 -C 6 alkyl group, preferably n-butyl or t-butyl.
  • R 4 is hydrogen
  • R 1 is -NH 2 and R 2 is hydrogen
  • R 3 represents a C 1 -C 6 alkyl group, preferably n-butyl or t-butyl.
  • n 3, 4 or 5.
  • R 6 and R 7 are both ethylene groups.
  • X is p-toluenesulfonyl.
  • the compound is one of the following compounds:
  • Ts represents p-toluenesulfonyl.
  • the present invention also provides the use of the aforementioned compound, or a solvate thereof, or a pharmaceutically acceptable salt thereof, for the preparation of an antitumor drug; preferably, the drug is a drug for preventing and/or treating lung cancer; more preferably The lung cancer is non-small cell lung cancer.
  • the present invention also provides a pharmaceutical composition which is prepared by using the aforementioned compound, or a solvate thereof, or a pharmaceutically acceptable salt thereof as an active ingredient, together with a pharmaceutically acceptable adjuvant.
  • the present invention also provides a method for antitumor, which comprises administering to a patient a compound as described above, or a solvate thereof, or a pharmaceutically acceptable salt thereof.
  • the patient is a patient with liver cancer, lung cancer and kidney cancer.
  • the C 1 -C 4 alkyl group means a C 1 , C 2 , C 3 , C 4 alkyl group, that is, a linear or branched alkyl group having 1 to 4 carbon atoms, for example.
  • the C 1 -C 6 alkyl group means a C 1 , C 2 , C 3 , C 4 , C 5 , C 6 alkyl group, that is, a straight or branched chain having 1 to 6 carbon atoms.
  • Alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, hexyl and the like.
  • treatment also includes relapse prevention or phase prevention, as well as treatment of acute or chronic signs, symptoms and/or dysfunction.
  • Treatment can be symptomatic treatment, such as inhibition of symptoms. It can be achieved in the short term, adjusted in the medium term, or ideally long-term treatment, for example in maintenance therapy.
  • prevention includes delaying and/or preventing the onset of a condition, disease or condition and/or its associated symptoms; preventing the subject from contracting the condition, disease or condition; or reducing the risk of the subject being infected with the condition, disease or condition. .
  • pharmaceutically acceptable means that a carrier, carrier, diluent, adjuvant, and/or salt formed is generally chemically or physically compatible with the other ingredients which comprise a pharmaceutical dosage form, and It is physiologically compatible with the receptor.
  • the "salt" is an acid form and/or a base salt which forms a compound or a stereoisomer thereof with an inorganic and/or organic acid and a base, and also includes a zwitter ion salt (internal salt), and also includes a season.
  • An ammonium salt such as an alkylammonium salt.
  • the salt in the present invention may be a hydrochloride, a sulfate, a citrate, a besylate, a hydrobromide, a hydrofluoride, a phosphate, an acetate, a propionate or a dibutyl compound.
  • test results show that the compound of the present invention has a significant inhibitory effect on lung cancer cell line A549 and has broad market prospects.
  • the number HYCZ01 corresponds to the compound 1 of the present invention
  • the number HYCZ02 corresponds to the compound 2 of the present invention
  • PP1 is a positive control drug.
  • Figure 1 Growth curves of A549 at different concentrations (12.5um, 25um, 50um, 80um, 100um) at 48h and 72h, HYCZ01, HYCZ02 and PP1.
  • FIG. 2 At 48h and 72h, HYCZ01, HYCZ02 and PP1 inhibited A549 at different high concentrations (50um, 80um, 100um).
  • Tetraethylene glycol bis(p-toluene hydrochloride) (164 mg, 3.46 mmol), 4-(4-amino-7-n-butyl-7H-pyrrolo[2,3-d]pyrimidin-5-)phenol (100 mg , 3.46 mmol), and anhydrous potassium carbonate (100 mg, 3.46 mol) were heated under reflux for 4 h in 50 mL of benzene solution. After neutralization of 1N HCl, the reaction mixture was extracted with dichloromethane. Then, the solution was dried under reduced pressure to give a solid, which was then subjected to column chromatography to yield 160 mg (yield: 76%) of brown brown syrup.
  • MTT assay which is a yellow compound, is a dye that accepts hydrogen ions and acts on the mitochondria of living cells.
  • Lung cancer cell line A549 chain
  • succinate dehydrogenase and cytochrome C under the action of succinate dehydrogenase and cytochrome C, the tetrazolium ring is cracked, and blue foranzan crystal is formed.
  • the amount of formazan crystal is only proportional to the number of living cells, and the formazan crystal formed by reduction can be Dissolved in dimethyl sulfoxide (DMSO), the optical density value (OD) at 490 nm was measured by a microplate reader to reflect the number of viable cells.
  • DMSO dimethyl sulfoxide
  • lung cancer cell strain lung cancer cell strain, tools required for cell culture, MTT and compound mother liquor were 10 mmol/L, and positive control drug Src inhibitor PP1.
  • Resuscitation A549 when the state is good, that is, after the passage, the cells are grown to about 80% (ie, logarithmic growth phase) and plated (96-well plate).
  • the cells are collected, and the concentration of the cell suspension is adjusted by a counting plate, and 1000-10000 cells per well are inoculated into a 96-well plate, and the number of cells per well is determined according to the growth rate of different cells and the time of drug action. 549 5,000 and 1299 5,000, 200 ul per well (100 ul of cell suspension + 100 ul of different concentration gradients of drug dilution), side holes (36) plus 200 ul of double medium (to prevent edge effects).
  • Inhibition rate (control - administration) / control ⁇ 100%
  • IC 50 half the inhibitory concentration
  • A549 cells were treated for 48h and 72h, and the drug dose was divided into 12.5um, 25um, 50um, 80um, 100um, and 6000 and 5000 cells were plated respectively.
  • the results are shown in Tables 1 to 3 and Figure 1-2 below:
  • the compounds provided by the present invention have significant inhibitory effects on tumor cells and can be used for the prevention and/or treatment of tumor-related diseases, especially lung cancer, and have broad application prospects.

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  • 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

7H-吡咯并[2,3-d]嘧啶衍生物及抗肿瘤的应用 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：
Figure PCTCN2017118484-appb-000001
其中，
R 1表示-NH 2、-NH(C 1-C 4烷基)或者-N(C 1-C 4烷基) 2；
R 2表示氢或C 1-C 6烷基；
R 3表示氢或C 1-C 6烷基；
R 4表示氢或C 1-C 6烷基；
R 5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-(R 6O) n-R 7-X；
n表示1～10的正整数；
R 6和R 7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-OSO 2-R 7，R 7表示苯基或被1个或多个C 1-C 6烷基取代的苯基。
进一步地，R 1为-NH 2。
进一步地，R 2为氢。
进一步地，R 3表示C 1-C 6烷基，优选正丁基或叔丁基。
进一步地，R 4为氢。
进一步地，R 1为-NH 2，且R 2为氢，且R 3表示C 1-C 6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，R 6和R 7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：
Figure PCTCN2017118484-appb-000002
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。
本发明还提供了一种抗肿瘤的方法，它是对患者给予前述的化合物、或其溶剂合物、或其药学上可接受的盐。
其中，所述患者是肝癌、肺癌和肾癌患者。
本发明中，所述C 1-C 4的烷基是指C 1、C 2、C 3、C 4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C 1～C 6的烷基是指C 1、C 2、C 3、C 4、C 5、C 6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
Figure PCTCN2017118484-appb-000003
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[C 6H 5IN 4]: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
Figure PCTCN2017118484-appb-000004
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[C 10H 13IN 4]: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)
Figure PCTCN2017118484-appb-000005
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PdCl 2(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[C 16H 18N 4O]:283.1514[M+H]+；Found 283.1552[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)
Figure PCTCN2017118484-appb-000006
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[C 31H 40N 4O 7S]: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％
IC 50(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)
Figure PCTCN2017118484-appb-000007
表2 本发明化合物对A549的抑制作用(72h)
Figure PCTCN2017118484-appb-000008
表3 对照药PP1对A549的抑制作用(48h、72h)
Figure PCTCN2017118484-appb-000009
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 (14)

  1. 式(Ⅰ)所示的化合物或其药学上可接受的盐、或其溶剂合物：
    Figure PCTCN2017118484-appb-100001
    其中，
    R 1表示-NH 2、-NH(C 1-C 4烷基)或者-N(C 1-C 4烷基) 2；
    R 2表示氢或C 1-C 6烷基；
    R 3表示氢或C 1-C 6烷基；
    R 4表示氢或C 1-C 6烷基；
    R 5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-(R 6O) n-R 7-X；
    n表示1～10的正整数；
    R 6和R 7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-OSO 2-R 7，R 7表示苯基或被1个或多个C 1-C 6烷基取代的苯基。
  2. 根据权利要求1所述的化合物，其特征在于：R 1为-NH 2。
  3. 根据权利要求1所述的化合物，其特征在于：R 2为氢。
  4. 根据权利要求1所述的化合物，其特征在于：R 3表示C 1-C 6烷基，优选正丁基或叔丁基。
  5. 根据权利要求1所述的化合物，其特征在于：R 4为氢。
  6. 根据权利要求1-5任一项所述的化合物，其特征在于：R 1为-NH 2，且R 2为氢，且R 3表示C 1-C 6烷基，优选正丁基或叔丁基。
  7. 根据权利要求1-6任一项所述的化合物，其特征在于：n为3、4或5。
  8. 根据权利要求1-7任一项所述的化合物，其特征在于：R 6和R 7均为亚乙基。
  9. 根据权利要求1-8任一项所述的化合物，其特征在于：X为对甲苯磺酰基。
  10. 根据权利要求1所述的化合物，所述化合物为如下化合物之一：
    Figure PCTCN2017118484-appb-100002
    Ts表示对甲苯磺酰基。
  11. [根据细则26改正30.01.2018]　　
    权利要求1-9任一项所述的化合物、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。
  12. [根据细则26改正30.01.2018]　
    一种药物组合物，其特征在于：它是以权利要求1-9任一项所述的化合物、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。
  13. [根据细则26改正30.01.2018]　
    一种抗肿瘤的方法，其特征在于：它是对患者给予权利要求1-9任一项所述的化合物、或其溶剂合物、或其药学上可接受的盐。
  14. [根据细则26改正30.01.2018]　
    根据权利要求12所述的方法，其特征在于：所述患者是肝癌、肺癌和肾癌患者。
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005007085A2 (en) * 2003-06-20 2005-01-27 The Regents Of The University Of California Pyrazolo pyrimidine derivatives and methods of use thereof
CN104395315A (zh) * 2012-06-29 2015-03-04 辉瑞大药厂 作为LRRK2抑制剂的新的4-(取代的氨基)-7H-吡咯并〔2,3-d〕嘧啶类
CN106831790A (zh) * 2017-02-17 2017-06-13 四川大学华西医院 7H‑吡咯并[2,3‑d]嘧啶衍生物

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106008527B (zh) * 2016-06-29 2018-05-15 四川大学华西医院 吡唑并[3,4-d]嘧啶衍生物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005007085A2 (en) * 2003-06-20 2005-01-27 The Regents Of The University Of California Pyrazolo pyrimidine derivatives and methods of use thereof
CN104395315A (zh) * 2012-06-29 2015-03-04 辉瑞大药厂 作为LRRK2抑制剂的新的4-(取代的氨基)-7H-吡咯并〔2,3-d〕嘧啶类
CN106831790A (zh) * 2017-02-17 2017-06-13 四川大学华西医院 7H‑吡咯并[2,3‑d]嘧啶衍生物

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
BURCHAT, A. F.: "Pyrrolo[2, 3-d]pyrimidines containing an extended 5-su- bstituent as potent and selective inhibitors of lck II", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 10, no. 19, October 2000 (2000-10-01), pages 2171 - 2174, XP004211996 *
JOERGENSEN, ANKER.: "Phosphorus pentoxide in organic synthesis, XII. Synthesis of 7H-pyrrolo[2, 3-d]pyrimidin-4-amines", LIEBIGS ANNALEN DER CHEMIE, vol. 1, 14 January 1985 (1985-01-14), pages 142 - 148, XP002712719 *
MULVIHILL, MARK J.: "1, 3-Disubstituted-imidazo[1, 5-a]pyrazines as insu- lin-like growth-factor-I receptor (IGF-IR) inhibitors", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 17, no. 4, 10 November 2006 (2006-11-10), pages 1091 - 1097, XP005868844 *
SABAT, NAZARII.: "Synthesis of 2, 6-Substituted 7-(Het)aryl-7-deazapurin Nucleobases (2, 4-Disubstituted 5-(Het)aryl-pyrrolo[2, 3-d]pyrimidines", SYNTHESIS, vol. 49, no. 20, 20 June 2017 (2017-06-20), pages 4623 - 4650, XP002784101 *
TAYLOR, EDWARD C.: "Synthesis of pyrrolo[2, 3-d]pyrimidines. The aglycon of toyocamycin", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 87, 5 May 1965 (1965-05-05), pages 1995 - 2003 *
WIDLER, L.: "7-Alkyl- and 7-cycloalkyl-5-arylpyrrolo[2, 3-d]pyrimidines, potent inhibitors of the tyrosine kinase c-sr", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 11, no. 6, 31 December 2001 (2001-12-31), pages 49 - 852, XP004230947 *

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