CN102002044A - 嘌呤-8-酮类及噻唑并嘧啶类衍生物及其制备方法和医药用途 - Google Patents
嘌呤-8-酮类及噻唑并嘧啶类衍生物及其制备方法和医药用途 Download PDFInfo
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Abstract
本发明涉及药物化学领域,具体涉及嘌呤-8-酮类及噻唑并嘧啶类与抑制肿瘤新生血管生成相关的衍生物的制备方法和医药用途。制备方法操作简便,反应时间短,原料及反应试剂经济易得,各步产率均较高。这两类化合物主要应用于抑制肿瘤新生血管生成以及用于治疗肿瘤疾病的用途。
Description
技术领域
本发明涉及药物化学领域,具体涉及嘌呤-8-酮类及噻唑并嘧啶类两类受体酪氨酸激酶抑制剂,本发明还公开了其制备方法,含其的药物组合物,及用于抑制肿瘤血管生成和治疗肿瘤疾病的用途。
背景技术
细胞信号转导的基本方式是蛋白磷酸化,磷酸化过程在胞内多种蛋白激酶的催化作用下进行。细胞内一类主要的蛋白激酶是酪氨酸蛋白激酶(Tyrosine Protein Kinases,TPKs),其磷酸化作用位点为蛋白质的酪氨酸残基。TPKs是信号转导中一类与受体及多种信号蛋白活化有关的信号酶,对细胞的增殖、分化及功能具有重要的调节作用,为一个大的结构多样的酶家族,分为受体依赖型TPKs(Receptor Tyrosine Kinases,RTKs)和非受体依赖型TPKs。受体酪氨酸激酶(Receptor Tyrosine Kinases,RTKs)是最大的一类酶联受体,它既是受体,又是酶,能够同配体结合,并将靶蛋白的酪氨酸残基磷酸化。所有的RTKs都是由三个部分组成:含有配体结合位点的细胞外结构域、单次跨膜的疏水a螺旋区和含有酪氨酸蛋白激酶活性的细胞内结构域。受体酪氨酸激酶在没有同生长因子配体结合时是以单体存在的,并且没有活性;一旦有生长因子配体与受体的细胞外结构域结合,激活胞内结构域的酶活性区启动信号转导,大多数生长因子如表皮生长因子(Epidermal Growth Factor,EGF)、血管内皮生长因子(Vascular endothelial growth factor,VEGF)、血小板衍生生长因子(Platelet-derived growth factor,PDGF)、成纤维细胞生长因子(Fibroblast growth factor,FGF)、胰岛素和胰岛素样生长因子-1(Insulin and insulin-like growth factor-1,IGF-1)和神经生长因子(Nerve growth factor,NGF)等的受体均有RTK活性。具有RTK活性的受体是外界刺激信息传递至细胞核,转化成细胞效应的信号通路的关键组成部分。然而,它们的异常表达导致细胞增殖调节发生紊乱,是肿瘤发生的重要机制,还与肿瘤的侵袭和转移、肿瘤新生血管的生成和肿瘤的化疗抗性密切相关。
发明内容
1.本发明内容之一公开了嘌呤-8-酮类及噻唑并嘧啶类两类衍生物的制备方法,克服了文献报道的收率低,反应时间长等缺点。提供了合成上述两类化合物的制备方法,同时提供了一种应用微波辅助技术合成6,9-二取代嘌呤酮的制备方法。
嘌呤-8-酮类及噻唑并嘧啶类化合物具有抑制表达和过多激活的VEGFR的功能,能治疗由此调控失常引起的肿瘤,是潜在的抗肿瘤药物。
本发明的嘌呤-8-酮类及噻唑并嘧啶类两类化合物的结构通式(I和II)如下:
其中Z代表O、S或NH;
R1代表5元或6元芳环或脂环,所述芳环包括苯环或含有1个杂原子O、S或N的芳香杂环,芳环可被1至2个下列取代基取代:卤素、卤代甲基、三氟甲基、三氟甲氧基、腈基、硝基或烷氧基。
R2、R4代表5元或6元芳环或脂环,所述芳环包括苯环或含有1至3个独立选自N、O和S等杂原子的芳香杂环,芳环可被1至4个下列取代基取代:卤素、1至3个碳原子的烷基、卤代甲基、羟基、三氟甲基、三氟甲氧基、腈基、硝基、氨基、烷氧基、苯氧基、巯基、苯甲酰基、取代或无取代的苯甲酰胺基或N-苯基取代的脲基;或R2代表8至10个原子的双环芳香杂环,所述芳香杂环含有1至4个独立选自N、O和S等杂原子,它们可被1至4个下列取代基取代:卤素、1至3个碳原子的烷基、卤代甲基、羟基、三氟甲基、三氟甲氧基、腈基、硝基、烷氧基、羧基或苯甲酰基。即R2和R4可以代表上述相同或不同的基团。
R3代表6元芳环,所述芳环包括苯环或含有1至3个独立选自N、O和S等杂原子的芳香杂环,芳环可被1至4个下列取代基取代:卤素、1至3个碳原子的烷基、卤代甲基、羟基、三氟甲基、三氟甲氧基、腈基、硝基、氨基、烷氧基、苯甲酰胺基或含卤素取代的苯甲酰胺基。
n代表0、1或2。
通式I和II化合物较优选的是:
Z代表O或NH。
R1代表5元或6元芳环或脂环,所述芳环包括苯环或含有1个杂原子O或S的芳香杂环,芳环可被1至2个下列取代基取代:卤素、卤代甲基、三氟甲基、三氟甲氧基或烷氧基。
R2、R4代表6元芳环或脂环,所述芳环包括苯环或含有1至3个独立选自N、O和S等杂原子的芳香杂环,芳环可被1至4个下列取代基取代:卤素、1至3个碳原子的烷基、卤代甲基、羟基、三氟甲基、三氟甲氧基、腈基、硝基、氨基、烷氧基、苯氧基、巯基、苯甲酰基、取代或无取代的苯甲酰胺基或N-苯基取代的脲基。
R3代表苯环,苯环可被1至4个下列取代基取代:卤素、1至3个碳原子的烷基、卤代甲基、三氟甲基、三氟甲氧基、腈基、硝基或烷氧基。
n代表0、1或2。
更优选的化合物是:
Z代表O或NH。
R1代表苄基、β-苯乙基或2-呋哺甲基。
R2、R3、R4代表苯环,苯环可被1至2个下列取代基取代:卤素、甲基、三氟甲基、三氟甲氧基、硝基、烷氧基或取代或无取代的苯甲酰胺基。
n代表0。
本发明部分优选的化合物如下:
9-苄基-6-[(4-甲基苯基)氨基]-7H-嘌呤-8(9H)-酮(I-01);
9-苄基-6-[(4-三氟甲基苯基)氨基]-7H-嘌呤-8(9H)-酮(I-02);
9-苄基-6-[(2-三氟甲氧基苯基)氨基]-7H-嘌呤-8(9H)-酮(I-03);
9-苄基-6-[(2,4-二氟苯基)氨基]-7H-嘌呤-8(9H)-酮(I-04);
9-苄基-6-[(2-氯苯基)氨基]-7H-嘌呤-8(9H)-酮(I-05);
9-苄基-6-[(2-甲氧基苯基)氨基]-7H-嘌呤-8(9H)-酮(I-05-01);
9-苄基-6-[(4-氯苯基)氨基]-7H-嘌呤-8(9H)-酮(I-06);
9-(苯乙基)-6-[(2-甲基苯基)氨基]-7H-嘌呤-8(9H)-酮(I-07);
9-(苯乙基)-6-[(4-三氟甲基苯基)氨基]-7H-嘌呤-8(9H)-酮(I-08);
9-(苯乙基)-6-[(4-甲氧基苯基)氨基]-7H-嘌呤-8(9H)-酮(I-09);
9-(苯乙基)-6-[(3-氯苯基)氨基]-7H-嘌呤-8(9H)-酮(I-10);
9-(苯乙基)-6-[(4-氟-3-氯苯基)氨基]-7H-嘌呤-8(9H)-酮(I-11);
9-(2-呋喃甲基)-6-(苯基氨基)-7H-嘌呤-8(9H)-酮(I-12);
9-(2-呋喃甲基)-6-[(2-甲氧基苯基)氨基]-7H-嘌呤-8(9H)-酮(I-13);
9-(2-呋喃甲基)-6-[(4-甲氧基苯基)氨基]-7H-嘌呤-8(9H)-酮(I-14);
9-(2-呋喃甲基)-6-[(2-三氟甲氧基苯基)氨基]-7H-嘌呤-8(9H)-酮(I-15);
9-(2-呋喃甲基)-6-[(4-氟苯基)氨基]-7H-嘌呤-8(9H)-酮(I-16);
9-(2-呋喃甲基)-6-[(2,4-二氟苯基)氨基]-7H-嘌呤-8(9H)-酮(I-17);
9-(2-呋喃甲基)-6-[(3-氯苯基)氨基]-7H-嘌呤-8(9H)-酮(I-18);
9-(2-呋喃甲基)-6-[(4-硝基苯基)氨基]-7H-嘌呤-8(9H)-酮(I-19);
9-苄基-6-(苯氧基)-7H-嘌呤-8(9H)-酮(I-20);
9-苄基-6-(4-溴苯氧基)-7H-嘌呤-8(9H)-酮(I-21);
9-(2-呋喃甲基)-6-(2-甲氧基苯氧基)-7H-嘌呤-8(9H)-酮(I-22);
N,2-二苯基噻唑并[5,4-d]嘧啶-7-胺(II-01);
2-苯基-N-(4-甲基苯基)噻唑并[5,4-d]嘧啶-7-胺(II-02);
2-苯基-N-(2-甲氧基苯基)噻唑并[5,4-d]嘧啶-7-胺(II-03);
2-苯基-N-(4-氟苯基)噻唑并[5,4-d]嘧啶-7-胺(II-04);
2-苯基-N-(2-氯苯基)噻唑并[5,4-d]嘧啶-7-胺(II-05);
2-苯基-N-(3-氯苯基)噻唑并[5,4-d]嘧啶-7-胺(II-06);
2-苯基-N-(4-硝基苯基)噻唑并[5,4-d]嘧啶-7-胺(II-07);
N-[4-[(2-苯基噻唑并[5,4-d]嘧啶-7-基)氨基]苯基]苯甲酰胺(II-08);
3-氯-N-[4-[(2-苯基噻唑并[5,4-d]嘧啶-7-基)氨基]苯基]苯甲酰胺(II-09);
N-苯基-2-(4-甲氧基苯基)噻唑并[5,4-d]嘧啶-7-胺(II-10);
N-(2-甲基苯基)-2-(4-甲氧基苯基)噻唑并[5,4-d]嘧啶-7-胺(II-11);
2-(4-甲氧基苯基)-N-(4-氟苯基)噻唑并[5,4-d]嘧啶-7-胺(II-12);
2-(4-甲氧基苯基)-N-(3-氯苯基)噻唑并[5,4-d]嘧啶-7-胺(II-13);
N-(2-甲氧基苯基)-2-(3-氯苯基)噻唑并[5,4-d]嘧啶-7-胺(II-14);
N-(4-氟苯基)-2-(3-氯苯基)噻唑并[5,4-d]嘧啶-7-胺(II-15);
N-苯基-2-(4-硝基苯基)噻唑并[5,4-d]嘧啶-7-胺(II-16);
N-(4-氟-3-氯苯基)-2-(4-硝基苯基)噻唑并[5,4-d]嘧啶-7-胺(II-17);
N-[4-[7-[(4-氯苯基)氨基]噻唑并[5,4-d]嘧啶-2-基]苯基]苯甲酰胺(II-18);
根据本发明,药学上可接受的盐包括通式I和II化合物与下列酸形成的酸加成盐:盐酸、氢溴酸、硫酸、磷酸、碳酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸或对甲苯磺酸。
本发明通式I化合物的制备方法提供如下(合成示意图见图1):
1)将化合物6与伯胺、氯化亚铜、反式-4-羟基-L-脯氨酸、碳酸钾在二甲基亚砜中反应生成化合物7;
2)在微波辐射条件下,将化合物7与伯胺、浓盐酸在乙醇中加热反应得到通式Ia的产物;
3)将化合物6与醇或硫醇反应生成化合物8;
4)将化合物8与与伯胺、氯化亚铜、反式-4-羟基-L-脯氨酸、碳酸钾在二甲基亚砜中反应生成Ib的化合物;
图1
5)中间体6以氨基丙二酸二乙酯盐酸盐为原料,制备方法如下(合成示意图见图2):
i.氨基丙二酸二乙酯与氯甲酸甲酯、三乙胺在二氯甲烷中反应生成化合物3;
ii.化合物3与甲脒醋酸盐咋NaOMe/MeOH中反应生成化合物5;
iii.化合物5与三氯氧磷反应生成化合物6;
图2
本发明通式II化合物的制备方法如下(合成示意图见图2):
1)氨基丙二酸二乙酯与酰氯反应生成式8化合物;
2)式8化合物与路易斯试剂反应生成化合物9;
3)式9化合物与醋酸甲脒反应生成式10化合物;
4)式10化合物与三氯氧磷反应生成式11化合物;
图2
2.本发明的另一内容是在化合物式I和式II中,探索发现具有抑制肿瘤细胞新生血管生成的苗头化合物,药理实验结果显示,(1)化合物式I和式II大多对于肿瘤新生血管生长密切相关的VEGF-HUVEC细胞(内皮细胞生长因子诱导的人脐静脉内皮细胞)有较强的增值抑制作用(见表一),从而阻止了依赖血管供应的肿瘤生长,阻止转移瘤的形成;(2)本发明的化合物式I和式II对体外人肺癌细胞(A549)、人乳腺癌细胞(MCF-7)、人肝癌细胞(HepG2)有较显著的细胞毒作用(见表二),可以与药用载体混合,是潜在的抗肿瘤药物。
表1部分化合物VEGF-HUVEC增殖的抑制结果
其中Sunitinib malate是公开报道的活性较好的阳性对照药。由以上数据可以看出,本专利所包含的部分化合物的生物活性已达到阳性药的活性数量级。
表2部分化合物体外抗肿瘤细胞活性筛选结果
体外抗肿瘤细胞的抑制活性筛选结果如表二所示,I-03,II-01,II-02对A549有好的抑制作用,I-05-01对MCF-2和HepG2均由较强的抑制活性,与Sunitinib malate阳性对照物的活性相当。
本发明的化合物以数项标准药理学检验规程进行评价,结果表明本发明的化合物作为血管生成抑制剂具有显著活性并且可作为抗肿瘤药物。可以用于治疗或抑制那些病因学上至少部分由RTKs功能失调引起的疾病。基于所述标准药理学检验程序评价中所显示的活性,本发明的化合物因而可以用于抗肿瘤领域,适用范围包括乳腺癌、肾癌、膀胱癌、口腔癌、喉癌、食管癌、胃癌、结肠癌、卵巢癌、子宫癌、肺癌、胰腺癌、前列腺癌、肝癌、皮肤癌和白血病。
具体实施方式
本发明部分活性化合物的制备实例如下:
熔点采用北京泰克显微熔点测定仪测定(温度计未经校正);IR用Nicolet Impact 410型傅立叶变换红外光谱仪测定(KBr压片);1H-NMR核磁共振由BrukerAV-300型(300MHz)核磁共振仪测定(TMS为内标物);质谱由岛津GC-MS 2050型气质联用仪(EI-MS)测定;元素分析由中国药科大学分析测试中心完成测定,误差均在±0.5%以内。
实施例1
4,6-二氯嘧啶-5-氨基甲酸甲酯(6)
将4,6-二羟基嘧啶-5-氨基甲酸甲酯10.35g(56mmol)缓慢加至盛有105mL三氯氧磷的250mL圆底烧瓶中,毕后,滴加N,N-二乙苯胺21mL,加热至110℃,回流,反应12h;然后50℃,搅拌过夜。待反应液自然冷却至室温后,缓慢分次的将反应液倾注于600mL冰-水混合液中,微微振摇。待三氯氧磷完全水解后,将此水解液用二氯甲烷萃取,饱和氯化铵溶液洗涤(600mL),分出有机相,减压浓缩,柱层析(乙酸乙酯∶石油醚=1∶8)分离,干燥得9.40g白色固体,即产品6,收率为76%。Mp 92-93℃;IR(KBr):3213,1701,1536,1513,1415,1390cm-1;1H NMR(300MHz,CDCl3):d 3.84(s,3H),6.38(s,1H),8.69(s,1H)ppm;MS(EI)m/z221(M+)。
实施例2
9-苄基-6-氯-7H-嘌呤-8(9H)-酮(7a)
在N2保护下,将4,6-二氯嘧啶-5-氨基甲酸甲酯(6)110mg(0.50mmol),CuCl 10mg(0.10mmol),trans-4-hydroxy-L-proline 26mg(0.20mmol),K2CO3 138mg(1.0mmol)和DMSO 2.5mL加至25mL双颈烧瓶中,后缓慢滴加苄胺60μL(0.55mmol),加热至75℃,反应1h;然后升高温度至130℃,反应3h。加乙酸乙酯(20mL)萃取,分别用饱和氯化铵溶液(20mL)和饱和氯化钠溶液(20mL)洗涤,分出有机相,无水硫酸钠干燥。减压浓缩,柱层析(乙酸乙酯∶石油醚=1∶3)分离,干燥得105mg浅黄色固体,即产品7a,收率为81%。Mp 250-251℃;IR(KBr):3407,1712,1634,1587,1495,733,696cm-1;1H NMR(300MHz,DMSO-d6):d 5.02(s,2H),7.28-7.34(m,5H),8.44(s,1H),12.22(br s,1H)ppm;MS(EI)m/z 260(M+)。
实施例3
9-(苯乙基)-6-氯-7H-嘌呤-8(9H)-酮(7b)
采用与合成7a相同的方法,以中间体6110mg(0.50mmol)和β-苯乙胺70μL(0.55mmol)为原料,得105mg浅黄色固体,即产品7b,收率为77%。Mp 204-205℃;IR(KBr):3381,1712,1633,1583,1491,733,698cm-1;1H NMR(300MHz,DMSO-d6):d 3.04(t,J=7.2Hz,2H),4.06(t,J=7.2Hz,2H),7.16-7.28(m,5H),8.42(s,1H),12.04(br s,1H)ppm;MS(EI)m/z 274(M+)。
实施例4
9-苄基-6-[(4-甲基苯基)氨基]-7H-嘌呤-8(9H)-酮(I-01)
将9-苄基-6-氯-7H-嘌呤-8(9H)酮(7a)130mg(0.50mmol),3mL乙醇加至10mL的微波反应管中,搅拌;然后分别滴加4-甲基苯胺64mg(0.60mmol)和浓盐酸50μL。微波辐射加热至120℃,反应40min。冷却至室温,析出大量浅黄色固体。抽滤,加少量的冷乙醇洗涤,干燥得137mg白色固体,即产品I-01,收率为83%。Mp 309-310℃;IR(KBr):3356,3141,1700,1646,1623,1604,1584,1511,1461,1430,1410,697cm-1;1H NMR(300MHz,DMSO-d6):d 2.27(s,3H),4.98(s,2H),7.14(d,J=8.4Hz,2H),7.26-7.33(m,5H),7.59(d,J=8.4Hz,2H),8.23(s,1H),8.87(s,1H),10.59(s,1H)ppm;MS(EI)m/z 331(M+).Anal.Calcd for C19H17ON5:C,68.87;H,5.17;N,21.13.Found:C,68.80;H,5.43;N,21.08。
实施例5
9-苄基-6-[(4-氯苯基)氨基]-7H-嘌呤-8(9H)-酮(I-06)
采用与合成I-01相同的方法,以7a 130mg(0.50mmol)和4-氯苯胺76mg(0.60mmol)为原料,得137mg灰白色固体,即产品I-06,收率为78%。Mp 323-324℃;IR(KBr):3343,1693,1647,1619,1583,1492,1461,1400,1350,777,721,698cm-1;1H NMR(300MHz,DMSO-d6):d4.99(s,2H),7.30-7.34(m,5H),7.39(d,J=8.7Hz,2H),7.71(d,J=8.7Hz,2H),8.28(s,1H),8.89(s,1H),10.43(s,1H)ppm;MS(EI)m/z 351(M+).Anal.Calcd for C18H14ON5Cl·0.2H2O:C,60.83;H,4.08;N,19.71.Found:C,60.74;H,4.20;N,19.74。
实施例6
9-(苯乙基)-6-[(3-氯苯基)氨基]-7H-嘌呤-8(9H)-酮(I-10)
采用与合成I-01相同的方法,以7b 137mg(0.50mmol)和3-氯苯胺63μL(0.60mmol)为原料,得153mg赤色固体,即产品I-10,收率为84%。Mp 297-298℃;IR(KBr):3363,3222,1709,1627,1590,1468,1400,777cm-1;1H NMR(300MHz,DMSO-d6):d 3.05(t,J=7.2Hz,2H),4.03(t,J=7.2Hz,2H),7.05(d,J=7.8Hz,1H),7.19-7.29(m,5H),7.36(t,J=7.8Hz,J=8.1Hz,1H),7.45(d,J=8.1Hz,1H),8.01(s,1H),8.32(s,1H),8.89(s,1H),10.32(s,1H)ppm;MS(EI)m/z 365(M+).Anal.Calcd for C19H16ON5Cl:C,62.38;H,4.41;N,19.14.Found:C,62.34;H,4.48;N,18.98。
实施例7
9-(2-呋喃甲基)-6-[(2-甲氧基苯基)氨基]-7H-嘌呤-8(9H)-酮(I-13)
采用与合成I-01相同的方法,以9-(2-呋喃甲基)-6-氯-7H-嘌呤-8(9H)-酮125mg(0.50mmol)和2-甲氧基苯胺67μL(0.60mmol)为原料,得51mg赤色固体,即产品I-13,收率为30%。Mp 273-274℃;IR(KBr):3338,3141,1712,1663,1624,1588,1488,1452,1431,1403,1387,743cm-1;1H NMR(300MHz,DMSO-d6):d 3.88(s,3H),4.98(s,2H),6.36-6.41(m,2H),6.94-7.09(m,3H),7.58(s,1H),8.07(s,1H),8.15(d,J=7.8Hz,1H),8.23(s,1H),11.06(s,1H)ppm;MS(EI)m/z 337(M+).Anal.Calcd for C17H15O3N5:C,60.53;H,4.48;N,20.76.Found:C,60.40;H,4.50;N,20.50。
实施例8
9-(2-呋喃甲基)-6-[(4-氟苯基)氨基]-7H-嘌呤-8(9H)-酮(I-16)
采用与合成I-01相同的方法,以9-(2-呋喃甲基)-6-氯-7H-嘌呤-8(9H)-酮125mg(0.50mmol)和4-氟苯胺60μL(0.60mmol)为原料,得100mg赤色固体,即产品I-16,收率为62%。Mp 307-309℃;IR(KBr):3338,3141,1711,1663,1625,1588,1488,1452,1431,781cm-1;1H NMR(300MHz,DMSO-d6):d 4.98(s,2H),6.36-6.40(m,2H),7.18(t,J=9.0Hz,2H),7.57(s,1H),7.64-7.69(m,2H),8.25(s,1H),8.72(s,1H),10.34(s,1H)ppm;MS(EI)m/z 325(M+).Anal.Calcd for C16H12O2N5F:C,59.08;H,3.72;N,21.53.Found:C,58.86;H,3.89;N,21.28。
实施例9
4-苯氧基-6-氯嘧啶-5-氨基甲酸甲酯(8a)
将4,6-二氯嘧啶-5-氨基甲酸甲酯(6)332mg(1.5mmol),苯酚212mg(2.25mmol),K2CO3 621mg(4.50mmol)和丙酮12mL加入50mL圆底烧瓶中,加热至50℃,反应1h。抽滤,滤去K2CO3残渣,用少量乙酸乙酯洗涤滤饼,后将滤液减压浓缩。加约20mL乙酸乙酯萃取,分别加1N NaOH溶液(20mL)和饱和氯化铵溶液(20mL)洗涤,分出有机相;无水硫酸钠干燥,抽滤,将滤液加压浓缩,干燥得389mg白色固体,即产品8a,产率为93%。Mp 89-90℃;IR(KBr):3248,1707,1550,1509,1445,1389,1264,1182,1164,1064,765,690cm-1;1H NMR(300MHz,CDCl3):d 3.82(s,3H),6.62(s,1H),7.14-7.44(m,5H),8.40(s,1H)ppm;MS(EI)m/z 279(M+)。
实施例10
9-苄基-6-(苯氧基)-7H-嘌呤-8(9H)-酮(I-20)
在N2保护下,将4-苯氧基-6-氯嘧啶-5-氨基甲酸甲酯(8a)167mg(0.60mmol),CuCl 12mg(0.12mmol),trans-4-hydroxy-L-proline 31mg(0.24mmol),K2CO3 166mg(1.2mmol)和DMSO 2.0mL加至25mL双颈烧瓶中,后缓慢滴加苄胺80μL(0.72mmol),加热至75℃,反应3h;然后升高温度至130℃,反应4h。将反应液用乙酸乙酯(20mL)稀释,抽滤,除去固体残渣;后将滤液萃取,用饱和氯化铵溶液(20mL)洗涤,分出有机相,无水硫酸钠干燥。减压浓缩,柱层析(乙酸乙酯∶石油醚=1∶3)分离,干燥得141mg浅黄色固体,即产品I-20,收率为74%。Mp 227-228℃;IR(KBr):3132,1703,1642,1596,1489,1454,1384,1301,1247,1198,727,689cm-1;1H NMR(300MHz,DMSO-d6):d 5.03(s,2H),7.23-7.47(m,10H),8.21(s,1H),11.90(br s,1H)ppm;MS(EI)m/z 318(M+).Anal.Calcd for C18H14O2N4:C,67.91;H,4.43;N,17.60.Found:C,67.90;H,4.57;N,17.58。
实施例11
9-(2-呋喃甲基)-6-(2-甲氧基苯氧基)-7H-嘌呤-8(9H)-酮(I-22)
采用与合成I-20相同的方法,以4-(2-甲氧基苯氧基)-6-氯嘧啶-5-氨基甲酸甲酯185mg(0.60mmol)和2-呋喃甲胺72μL(0.72mmol)为原料,75℃,反应4h;130℃,反应4h。得160mg浅黄色固体,即产品I-22,收率为79%。Mp 200-201℃;IR(KBr):3331,3132,1717,1645,1596,1502,1486,1374,1312,1264,1109,743cm-1;1H NMR(300MHz,DMSO-d6):d 3.70(s,3H),5.03(s,2H),6.41(s,2H),7.00(t,J=7.5Hz,1H),7.16-7.30(m,3H),7.60(s,1H),8.17(s,1H),11.88(s,1H)ppm;MS(EI)m/z 338(M+).Anal.Calcd for C17H14O4N4:C,60.35;H,4.17;N,16.56.Found:C,60.28;H,4.13;N,16.62。
实施例12
N-(4,6-二羟基-嘧啶-5-基)硫代苯甲酰胺(10a)
将切好的Na丝0.99g(42.9mmol)缓慢加入盛有50mL无水甲醇的100mL的圆底烧瓶中,待完全反应后,即得NaOMe/MeOH反应体系。将醋酸甲脒(4)1.49g(14.3mmol)加入上述制得的反应体系中,搅拌约10min后,缓慢加入2-硫代苯甲酰胺基丙二酸二乙酯3.84g(13.0mmol),加热至75℃,回流,反应4h。将反应液自然冷却一段时间,再于冰浴条件下冷却至室温。然后缓慢滴加浓盐酸直至析出大量黄色固体(约需10mL浓盐酸),后加约10mL冰水,微微振摇。抽滤,分别加冰水(20mL)和乙酸乙酯(20mL)洗涤滤饼固体,干燥得2.03g黄色固体,即产品10a,产率为63%。Mp 208-209℃;IR(KBr):3529,3173,1649,1556,1448,1370,1310,1242,774,693cm-1;1H NMR(300MHz,DMSO-d6):d 7.41-7.53(m,3H),7.86(d,J=7.5Hz,2H),8.13(s,1H),10.75(s,1H),12.22(br s,2H)ppm;MS(EI)m/z 247(M+)。
实施例13
2-苯基-7-氯噻唑并[5,4-d]嘧啶(11a)
将中间体10a 2.72g(11mmol)和三氯氧磷30mL加入100mL圆底烧瓶中,然后滴加N,N-二乙苯胺5mL,加热至110℃,回流,反应12h;然后rt,搅拌过夜。待反应液自然冷却至室温后,缓慢分次的将反应液倾注于300mL冰-水混合液中,微微振摇,析出大量黄色固体。静置,抽滤,得2.01g粗品;后在二氯甲烷和石油醚混合溶剂中重结晶,干燥得1.12g深黄色固体,即产品11a,收率为41%。Mp 144-145℃;IR(KBr):3416,1561,1553,1499,1470,1442,1425,764,698cm-1;1H NMR(300MHz,CDCl3):d 7.44-7.54(m,3H),8.05-8.08(m,2H),8.79(s,1H)ppm;MS(EI)m/z 247(M+)。
实施例14
N,2-二苯基噻唑并[5,4-d]嘧啶-7-胺(II-01)
将2-苯基-7-氯噻唑并[5,4-d]嘧啶(11a)99mg(0.40mmol),3mL乙醇和水混合(V/V=1∶1)溶剂加至10mL的微波反应管中,搅拌;然后分别滴加苯胺55μL(0.60mmol)和浓盐酸50μL。微波辐射加热至120℃,反应30min。冷却至室温,析出大量黄色固体。抽滤,加少量的冷乙醇洗涤,干燥得112mg深黄色固体,即产品II-01,收率为92%。Mp 168-170℃;IR(KBr):3416,3256,1609,1581,1570,1534,1496,1468,1458,1442,758,734,692,684cm-1;1HNMR(300MHz,DMSO-d6):d 7.13(t,J=7.2Hz,1H),7.40(t,J=7.8Hz,2H),7.60-7.62(m,3H),7.93(d,J=7.8Hz,2H),8.16-8.19(m,2H),8.54(s,1H),9.98(s,1H)ppm;MS(EI)m/z 303((M-1)+).Anal.Calcd for C17H12N4S:C,67.08;H,3.97;N,18.41.Found:C,66.80;H,3.84;N,18.38。
实施例15
N-[4-[(2-苯基噻唑并[5,4-d]嘧啶-7-基)氨基]苯基]苯甲酰胺(II-08)
采用与合成II-01相同的方法,以中间体11a 99mg(0.40mmol)和N-(4-氨基苯基)苯甲酰胺85mg(0.40mmol)为原料,得142mg黄绿色固体,即产品II-08,收率为84%。Mp237-239℃;IR(KBr):3454,3283,1643,1615,1578,1530,1513,1466,765,691cm-1;1H NMR(300MHz,DMSO-d6):d 7.53-7.63(m,6H),7.80(d,J=9.0Hz,2H),7.91(d,J=9.0Hz,2H),7.99(d,J=6.9Hz,2H),8.18-8.20(m,2H),8.54(s,1H),10.00(s,1H),10.30(s,1H)ppm;MS(EI)m/z 423(M+).Anal.Calcd for C24H17N5OS:C,68.07;H,4.05;N,16.54.Found:C,67.88;H,4.16;N,16.44。
实施例16
实施例中目标化合物的药理学试验:
VEGF-HUVEC抑制活性的测试方法:MTT法
将HUVEC原代细胞稀释至3×105细胞/mL,铺96孔细胞培养板,100μL/孔,置于37℃,5%CO2培养。细胞贴壁后换含有5%FCS的M199细胞培养液饥饿24h,加入VEGF至终浓度为10ng/mL,同时分别加入系列稀释的化合物至终浓度为10-5,10-6,10-7,10-8和10-9mol/L,每个浓度设3个复孔,同时设不加化合物的对照组。培养72h后MTT法测OD570-630,计算化合物对细胞增殖的抑制率:细胞生长抑制率(%)=(1-OD实验组/OD对照组)×100%。
细胞毒活性试验测试方法:MMT法
用胰酶消化肿瘤细胞,以含10%小牛血清的RPMI1640培养液配制细胞悬液,浓度为10000细胞/ml,取对数生长期细胞培养于96孔培养板内,每孔100μl(含1000~1200个肿瘤细胞)。次日,给药组加入含有不同浓度化合物,每药设4~5个剂量组,每组至少设3个平行孔。对照组加入与化合物等体积的溶剂。置5%CO2温箱中于37℃培养,4天后弃去培养液,每孔加入200μl 0.2% MTT溶液(RPMI1640配制)。37℃保温4小时,弃去上清,每孔加入DMSO 150μl溶解甲簪颗粒,轻度振荡后,用酶标仪,在参考波长450nm、检测波长570nm条件下测定光密度值(OD)。以溶剂对照处理的肿瘤细胞为对照组,用下面公式计算药物对肿瘤细胞的抑制率,并计算IC50。细胞生长抑制率(%)=(1-OD实验组/OD对照组)×100%。
Claims (10)
1.通式I和II的化合物的制备方法;
其中Z代表O、S或NH;
R1代表5元或6元芳环或脂环,所述芳环包括苯环或含有1个杂原子O、S或N的芳香杂环,芳环可被1至2个下列取代基取代:卤素、卤代甲基、三氟甲基、三氟甲氧基、腈基、硝基或烷氧基;
R2、R4代表5元或6元芳环或脂环,所述芳环包括苯环或含有1至3个独立选自N、O和S等杂原子的芳香杂环,芳环可被1至4个下列取代基取代:卤素、1至3个碳原子的烷基、卤代甲基、羟基、三氟甲基、三氟甲氧基、腈基、硝基、氨基、烷氧基、苯氧基、巯基、苯甲酰基、取代或无取代的苯甲酰胺基或N-苯基取代的脲基;或R2代表8至10个原子的双环芳香杂环,所述芳香杂环含有1至4个独立选自N、O和S等杂原子,它们可被1至4个下列取代基取代:卤素、1至3个碳原子的烷基、卤代甲基、羟基、三氟甲基、三氟甲氧基、腈基、硝基、烷氧基、羧基或苯甲酰基。即R2和R4可以代表上述相同或不同的基团;
R3代表6元芳环及五元杂环,所述芳环包括苯环或含有1至3个独立选自N、O和S等杂原子的芳香杂环,芳环可被1至4个下列取代基取代:卤素、1至3个碳原子的烷基、卤代甲基、羟基、三氟甲基、三氟甲氧基、腈基、硝基、氨基、烷氧基、苯甲酰胺基或含卤素取代的苯甲酰胺基;
n代表0、1或2。
2.权利要求1的化合物,其中R1代表苄基、β-苯乙基或2-呋喃甲基,n代表0。
3.权利要求1的化合物,其中Z代表O或NH。
4.权利要求1的化合物,其中R2、R4代表6元芳环或脂环,所述芳环包括苯环或含有1至3个独立选自N、O和S等杂原子的芳香杂环,芳环可被1至4个下列取代基取代:卤素、1至3个碳原子的烷基、卤代甲基、羟基、三氟甲基、三氟甲氧基、腈基、硝基、氨基、烷氧基、苯氧基、巯基、苯甲酰基、取代或无取代的苯甲酰胺基或N-苯基取代的脲基;
R3代表苯环,苯环可被1至4个下列取代基取代:卤素、1至3个碳原子的烷基、卤代甲基、三氟甲基、三氟甲氧基、腈基、硝基或烷氧基。
5.权利要求1的化合物,其中药学上可接受的盐为化合物I或II与下列酸形成的酸加成盐:盐酸、氢溴酸、硫酸、磷酸、碳酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸或对甲苯磺酸。
8.权利要求I中的通式I和II的化合物和药学上可接受的载体在制备肿瘤新生血管生成作用药物中的用途。
9.权利要求1至4中任一项的化合物在制备用于治疗肿瘤疾病的药物的用途。
10.权利要求9的用途,其中肿瘤疾病是乳腺癌、肾癌、膀胱癌、口腔癌、喉癌、食管癌、胃癌、结肠癌、卵巢癌、子宫癌、肺癌、胰腺癌、前列腺癌、肝癌、皮肤癌和白血病。
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103012440A (zh) * | 2013-01-17 | 2013-04-03 | 齐齐哈尔大学 | 一锅法合成噻唑并[3,2-a]嘧啶类衍生物的方法 |
CN108495855A (zh) * | 2015-11-20 | 2018-09-04 | 生命弧度公司 | 作为mnk抑制剂的稠合噻唑并嘧啶衍生物 |
CN110172067A (zh) * | 2019-04-11 | 2019-08-27 | 河南科技大学第一附属医院 | 一种具有杀菌活性的噻唑类药物分子及其制备方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080269238A1 (en) * | 2004-04-01 | 2008-10-30 | Takeda Pharmaceutical Company Limited | Thiazolopyrimidine Derivative |
WO2010009207A1 (en) * | 2008-07-16 | 2010-01-21 | Schering Corporation | Bicyclic heterocycle derivatives and their use as gpcr modulators |
-
2010
- 2010-09-29 CN CN 201010296189 patent/CN102002044A/zh active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080269238A1 (en) * | 2004-04-01 | 2008-10-30 | Takeda Pharmaceutical Company Limited | Thiazolopyrimidine Derivative |
WO2010009207A1 (en) * | 2008-07-16 | 2010-01-21 | Schering Corporation | Bicyclic heterocycle derivatives and their use as gpcr modulators |
Non-Patent Citations (2)
Title |
---|
《J. Org. Chem. 》 20010726 Gergely M. Makara等 Synthesis of Bicyclic Pyrimidine Derivatives as ATP Analogues 5783-5789 1,3,4 第66卷, 第17期 * |
《Tetrahedron》 20100528 Qi-Fei Zhong等 n efficient synthesisof6,9-disubstitutedpurin-8-onesviacopper-catalyzed coupling/cyclization 表3,历程1-2 1-4,6,9 第66卷, 第27-28期 * |
Cited By (6)
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CN108495855B (zh) * | 2015-11-20 | 2022-05-31 | 生命弧度公司 | 作为mnk抑制剂的稠合噻唑并嘧啶衍生物 |
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