CN114573581B - 5-取代氨基-1,3-二取代苯基吡啶并[2,3-d]嘧啶类化合物及其制备与应用 - Google Patents
5-取代氨基-1,3-二取代苯基吡啶并[2,3-d]嘧啶类化合物及其制备与应用 Download PDFInfo
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- CN114573581B CN114573581B CN202210322190.3A CN202210322190A CN114573581B CN 114573581 B CN114573581 B CN 114573581B CN 202210322190 A CN202210322190 A CN 202210322190A CN 114573581 B CN114573581 B CN 114573581B
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- pyrimidine
- trione
- fluorophenyl
- methyl
- bis
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Abstract
本发明的5‑取代氨基‑1,3‑二取代苯基吡啶并[2,3‑d]嘧啶类化合物及其制备与应用，属于医药技术领域。所述的5‑取代氨基‑1,3‑二取代苯基吡啶并[2,3‑d]嘧啶类化合物结构通式如式(I)所示：R1独立地选自氢、氟；R2独立地选自氢、甲基、苄基；R3、R4独立地选自氢、甲基、环丙基、2‑二甲氨基乙基、3‑吗啉丙基、3‑三氟甲基苯基、4‑三氟甲基苯基、4‑三氟甲氧基苯基、3‑氯‑4‑氟苯基、3‑氯‑4‑三氟甲基苯基、2‑呋喃甲基，或R3、R4与它们相连的氮原子一起组成吗啉基。该化合物合成方法简便，适于工业化生产，生物活性测试显示此类化合物具有抗肿瘤活性，可应用于制备抗肿瘤药物。
Description
技术领域
本发明属于医药技术领域，具体涉及5-取代氨基-1,3-二取代苯基吡啶并[2,3-d]嘧啶类化合物及其制备与应用。
背景技术
恶性肿瘤作为一种重大疾病，严重威胁人类健康，已经困扰人类多年，也是阻碍人类寿命增长的一大因素。随着癌基因和抑癌基因的发现、细胞信号转导通路的阐明，极大地丰富了人类对细胞癌变机制的认识，通过对癌基因产物功能的分析，发现许多癌蛋白位于正常细胞信号转导通路的不同部位，对促进细胞分裂增殖起着重要的作用(KleinG.Science,1987(4833):1539-1545)。
丝裂原活化蛋白激酶MAPK信号途径是细胞中非常重要的信息传递链。MAPK通路有三级的信号传递过程：MAPK，MAPK激酶(MEK或MKK)以及MAPK激酶的激酶(MEKK或MKKK)。这三种激酶能依次激活，共同调节着细胞的生长、分化、应激、炎症反应等多种重要的生理/病理效应，是诱发肿瘤产生的重灾区(Orton RJ,Sturm OE,Vyshemirsky V,Calder M,GilbertDR,Kolch W.The Biochemical Journal.2005,392(2):249-61)。人体内常见的MAPK信号通路主要有细胞信号外激酶(ERK1/2)信号通路、c-Jun-N端激酶(JNK)/应激活化蛋白(SAPK)信号通路、p38MAPK信号通路和丝裂原活化的细胞外信号调节激酶(MEK)等，目前已上市的MAPK通路抑制剂小分子药物主要有：
曲美替尼(Trametinib)是一种具有抗癌活性的MEK抑制剂药物，它可以抑制MEK1和MEK2激酶的活性。Trametinib在III期临床试验中对携带BRAF V600E突变的转移性黑色素瘤取得了良好的效果。在该突变中，BRAF蛋白第600位的氨基酸缬氨酸已被谷氨酸取代，从而使突变的BRAF蛋白具有组成性活性(Flaherty KT,Infante JR,Daud A,Gonzalez R,Kefford RF,Sosman J,et al.The New England Journal of Medicine.2012,367(18):1694-703)。
比美替尼(Binimetinib)是一种MEK的选择性抑制剂，由Array Biopharma开发用于治疗多种癌症。Binimetinib是，MEK是促肿瘤MAPK通路中的一种中心激酶。已证明该途径的不当激活发生在许多癌症中。2018年6月，它被FDA批准与encorafenib联合用于治疗不可切除或转移性BRAF V600E或V600K突变阳性黑色素瘤患者(Koelblinger P,Dornbierer J,Dummer R.Future Oncology.2017,13(20):1755-1766)。
索拉非尼(Sorafenib)是一种可以口服的Raf激酶抑制剂，可直接抑制Raf激酶活性，阻断Ras通路的信号传递，也可作用于血小板衍生生长因子受体和血管内皮生长因子受体，下调p-MEK的表达水平，从而阻断下游Ras-Raf-MEK-ERK通路。索拉非尼引发的致死性不良反应如胃肠道不适、皮肤毒性等发生率极低(Wilhelm SM,Carter C,Tang L,etal.Cancer Research.2004,64(19):7099-7109)。
达拉非尼(Dabrafenib)是一款用于治疗不可手术或转移性黑色素瘤的药物，可特异性的作用于B-RafV600E结构域，阻断MAPK通路，抑制肿瘤细胞生长增殖，促进其凋亡。且研究表明B-Raf激酶抑制剂与MEK抑制剂合用可以调控引起B-Raf抑制剂不良反应的平行通路，两者合用可以提高响应速度，降低毒性。患者常较快对达拉非尼产生耐药性，因此，可以通过与MEK抑制剂曲美替尼联合用药解决这一问题(Khoja L,Hogg D.Expert Review ofAnticancer Therapy.2015,112(6):536-545)。
发明内容
本发明的目的是提供一种5-取代氨基-1,3-二取代苯基吡啶并[2,3-d]嘧啶类化合物及其制备与应用，所述的化合物具体为5-取代氨基-1,3-二取代苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮类化合物，相应为在制备治疗或/和预防与B-Raf激酶，Ras/Raf/MEK/ERK信号通路、p38MAPK信号通路和JNK-SAPK信号通路等MAPK通路相关的肿瘤疾病药物方面的应用，包括作为多靶点抑制剂在抗肿瘤方面的应用。
如式I所示的一种5-取代氨基-1,3-二取代苯基吡啶并[2,3-d]嘧啶类化合物、其前体药物和药物活性代谢物，及其药学上可接受的盐：
R1独立地选自氢、卤素；
R2独立地选自氢、C1-C4烷基、苄基；
R3、R4独立地选自氢、C1-C4烷基、C3-C6环烷基、2-二甲氨基乙基、3-吗啉丙基、C1-C3烷基取代的苯基、卤素取代的苯基、卤素取代的C1-C3烷基取代苯基，或R3、R4与它们相连的氮原子一起组成吗啉基。
进一步地，本发明所述的如式I所示化合物、其前体药物和药物活性代谢物以及其药学上可接受的盐：
R1独立地选自氢、氟；
R2独立地选自氢、甲基、苄基；
R3、R4独立地选自氢、甲基、环丙基、2-二甲氨基乙基、3-吗啉丙基、3-三氟甲基苯基、4-三氟甲基苯基、4-三氟甲氧基苯基、3-氯-4-氟苯基、3-氯-4-三氟甲基苯基、2-呋喃甲基，或R3、R4与它们相连的氮原子一起组成吗啉基。
进一步地，本发明优选为如下化合物：
6-苄基-1,3-双(4-氟苯基)-8-甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T01)，其结构式如下式I-1所示：
6-苄基-5-{[2-(二甲氨基)乙基]氨基}-1,3-双(4-氟苯基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T02)，其结构式如下式I-2所示：
6-苄基-1,3-双(4-氟苯基)-8-甲基-5-(甲氨基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T03)，其结构式如下式I-3所示：
5-{[3-氯-4-(三氟甲基)苯基]氨基}-1,3-双(4-氟苯基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T04)，其结构式如下式I-4所示：
1,3-双(4-氟苯基)-8-甲基-5-{[3-(三氟甲基)苯基]氨基}吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T05)，其结构式如下式I-5所示：
1,3-双(4-氟苯基)-8-甲基-5-{[4-(三氟甲基)苯基]氨基}吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T06)，其结构式如下式I-6所示：
5-[(3-氯-4-氟苯基)氨基]-1,3-双(4-氟苯基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T07)，其结构式如下式I-7所示：
1,3-双(4-氟苯基)-8-甲基-5-{[4-(三氟甲氧基)苯基]氨基}吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T08)，其结构式如下式I-8所示：
1,3-双(4-氟苯基)-5-[(呋喃-2-基甲基)氨基]-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T09)，其结构式如下式I-9所示：
1,3-双(4-氟苯基)-8-甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T10)，其结构式如下式I-10所示：
6-苄基-8-甲基-5-[(3-吗啉丙基)氨基]-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T11)，其结构式如下式I-11所示：
6-苄基-5-(环丙基氨基)-8-甲基-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T12)，其结构式如下式I-12所示：
6-苄基-8-甲基-5-吗啉基-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T13)，其结构式如下式I-13所示：
6-苄基-5-{[2-(二甲氨基)乙基]氨基}-8-甲基-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T14)，其结构式如下式I-14所示：
6,8-二甲基-5-[(3-吗啉丙基)氨基]-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T15)，其结构式如下式I-15所示：
一种药物组合物，包括作为活性成分的本发明所述的化合物，其前体药物和药物活性代谢物，以及其在药学上可接受的盐中任何一个的化合物和药学上可接受的载体或稀释剂。
“药学上可接受的盐”指保留了式I所示化合物的生物效力和性质，并与非毒性有机或无机酸或有机或无机碱形成的常规酸加成盐或碱加成盐。酸加成盐包括盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、磷酸盐、硫酸盐、高氯酸盐、硫氰酸盐、硫酸氢盐、过硫酸盐、硼酸盐、甲酸盐、乙酸盐、丙酸盐、戊酸盐、新戊酸盐、己酸盐、庚酸盐、辛酸盐、异辛酸盐、十一烷酸盐、月桂酸盐、棕榈酸盐、硬脂酸盐、油酸盐、环丙酸盐、草酸盐、丙二酸盐、琥珀酸盐、马来酸盐、富马酸盐、己二酸盐、壬二酸盐、丙烯酸盐、草莓盐、巴豆酸盐、惕格酸盐、衣康酸盐、山梨酸盐、肉桂酸盐、乙醇酸盐、乳酸盐、苹果酸盐、酒石酸盐、柠檬酸盐、亚酒石酸盐、扁桃酸盐、二苯乙醇酸盐、托品酸盐、抗坏血酸盐、葡萄糖酸盐、葡庚糖酸盐、葡萄糖二酸盐、甘露糖酸盐、乳糖酸盐、苯甲酸盐、酞酸盐、对酞酸盐、糠酸盐、烟酸盐、异烟酸盐、水杨酸盐、乙酰水杨酸盐、酪酸盐、没食子酸盐、咖啡酸盐、阿魏酸盐、苦味酸盐、樟脑酸盐、樟脑磺酸盐、甲磺酸盐、乙磺酸盐、丙磺酸盐、苯磺酸盐、对甲苯磺酸盐、对氨基苯磺酸盐、氨基磺酸盐、牛磺酸盐、2-羟基乙磺酸盐、甘氨酸盐、丙氨酸盐、缬氨酸盐、亮氨酸盐、异亮氨酸盐、苯丙氨酸盐、色氨酸盐、酪氨酸盐、天冬氨酸盐、天冬酰胺盐、谷氨酸盐、赖氨酸盐、谷氨酰胺盐、甲硫氨酸盐、丝氨酸盐、苏氨酸盐、半胱氨酸盐、脯氨酸盐、组氨酸盐、精氨酸盐、依地酸盐、丙酮酸盐、α-酮戊二酸盐、藻酸盐、环戊烷丙酸盐、3-苯基丙酸盐、3-环己基丙酸、2-萘甲酸盐、2-萘磺酸盐、双羟萘酸盐、月桂基硫酸盐、甘油磷酸盐、月桂基硫酸盐、果胶脂酸盐。优选用于生成酸加成盐的酸包括盐酸、对甲苯磺酸、甲磺酸、顺丁烯二酸、苹果酸、苦味酸、柠檬酸、对氨基苯磺酸。碱加成盐包括铵盐，碱金属盐，例如钠和钾盐，碱土金属盐，例如钙和镁盐，有机碱的盐，例如二环己胺盐，N-甲基-D-葡糖胺盐，而且，碱性含氮基团可以用这样的试剂季铵化，例如低级烷基卤化物，如甲基，乙基，丙基和丁基的氯、溴和碘化物；硫酸二烷基酯，如硫酸二甲酯，二乙酯，二丁酯和二戊酯；长链卤化物，如癸基，月桂基，肉豆蔻基和硬脂酰基的氯、溴和碘化物；芳烷基卤化物，如苄基和苯乙基的溴化物。
本发明也涉及抑制MEK激酶和B-RAF激酶的药用组合物，该组合物含有式I所示化合物或其衍生物或其药学上可接受的酸加成盐以及药学上可接受的载体。
“药学上可接受的”如药学上可接受的载体、赋形剂、前体药物，指药理学上可接受的、并对给药具体化合物的患者基本上无毒性。
“药学活性代谢物”指药学上可接受并有效的式I所示化合物的代谢产物。
本发明中应用的术语“卤素”包括氟、氯、溴及碘。
本发明化合物可以通过不同的方法给患者服用，包括以胶囊剂或片剂口服，以无菌溶液剂或混悬剂给药，并且在某些情况下，可以以溶液剂形式静脉注射。可以将本发明的游离碱化合物以其药学上可接受的酸加成盐形式进行配制和服用。
本发明所述化合物作为全新结构类型的与B-Raf激酶，Ras/Raf/MEK/ERK信号通路、p38MAPK信号通路和JNK-SAPK信号通路等MAPK信号通路相关小分子抑制剂，具有结构类型新颖，且能够作用于多个靶点等特点，可用于制备治疗或预防与B-Raf激酶，Ras/Raf/MEK/ERK信号通路、p38MAPK信号通路和JNK-SAPK信号通路等MAPK通路相关的肿瘤疾病如肺癌、肝癌、黑色素瘤、结肠癌、直肠癌、乳腺癌、卵巢癌、宫颈癌及肾癌的药物，具有良好的应用价值和开发应用前景。
本发明化合物的制备路线：
本发明所述化合物T01-T15及药学上可接受的盐、以及其前体药物，具有能够作用于Ras/Raf/MEK/ERK信号通路，抑制ERK1/2的磷酸化作用，从而达到抑制肿瘤细胞增殖的目的。
本发明有益效果：
本发明提供了一类全新抗肿瘤化合物的结构，具有潜在的成药价值，且化合物制备路线简便，易于合成且成本低廉。与已上市药物相比，具有更加显著的抗肿瘤细胞增殖活性。
具体实施方式
以下述实例详细叙述本发明。但是，应当明白，本发明不限于具体叙述的下述实例。实施例1：6-苄基-1,3-双(4-氟苯基)-8-甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T01)的制备
步骤I：称量40mL二氯甲烷溶解固体光气(9.5g,32mmol)于500mL圆底烧瓶内，称量对氟苯胺(8.89g 80mmol)溶于40mL二氯甲烷中，室温下将其用滴液漏斗在30min内滴入瓶内，再称量三乙胺(20.24g,0.2mol)溶于50mL二氯甲烷中，并在30min内滴入瓶内，再次称量对氟苯胺(8.89g 80mmol)溶于40mL二氯甲烷中，按上述再次滴入瓶内。滴完后搅拌反应30min监测对氟苯胺反应完全。减压蒸馏除去约3/4体积的二氯甲烷，再用5％HCl溶液搅拌5-10min后产生大量固体，滤出固体，用乙醚反复洗涤，干燥后即为1,3-二对氟苯脲，白色固体，产量18.5g，产率93.16％。
步骤II：称量1,3-二对氟苯脲(4.96g,20mmol)、丙二酸(2.7g,26mmol)、三氯氧磷(3.4g,22mmol)和15ml乙腈置于35mL密封管内。密封加热至120℃后反应1h，监测原料反应完全后，将封管内的反应液倒入茄形瓶内，减压蒸馏除去所有溶剂，加入50mL 2mol/L NaOH和20mL乙酸乙酯搅拌溶解。再用2mol/L NaOH水溶液萃取有机相三次，合并水层，再用少量乙酸乙酯萃取水层一次，留下的水层用盐酸调pH至产生大量固体。滤出固体，用水洗涤滤饼，干燥后得黄白色固体1,3-双(4-氟基苯基)嘧啶-2,4,6(1H,3H,5H)-三酮3.87g，产率61.18％。
步骤III：称量1,3-双(4-氟基苯基)嘧啶-2,4,6(1H,3H,5H)-三酮(5.12g,16.2mmol)、三氯氧磷(4.92g,32.4mmol)和20ml乙腈置于125mL密封管内。密封加热至120℃后反应3h，监测原料反应完全后，将封管内的反应液倒入茄形瓶内，减压蒸馏除去所有溶剂，加入少量乙醇溶解混合物，再加水以析出固体，滤出固体，用水洗涤滤饼，干燥后得黄色固体6-氯-1,3-双(4-氟基苯基)嘧啶-2,4(1H,3H)-二酮5.12g，产率94.43％。
步骤IV：称量6-氯-1,3-双(4-氟基苯基)嘧啶-2,4(1H,3H)-二酮(3.34g,10mmol)、40％甲胺水溶液(1.28g,15mmol)、三乙胺(2.22g,20mmol)和20mL乙醇于50mL圆底烧瓶内，搅拌回流反应8小时后反应完全。减压蒸馏除去大部分乙醇，加入乙醚搅拌出固体。滤出固体，用乙醚洗涤固体，干燥后得黄色固体6-甲胺基-1,3-双(4-氟基苯基)嘧啶-2,4(1H,3H)-二酮，产量3.16g，产率95.96％。
步骤V：称量6-甲胺基-1,3-双(4-氟基苯基)嘧啶-2,4(1H,3H)-二酮(1.65g,5mmol)、苄基丙二酸二乙酯(1.50g,6mmol)和15g二苯醚于100mL三颈圆底烧瓶内，于加热套上加热至256℃后回流反应40min，TLC监测原料反应完全后，将反应液倒入30mL石油醚中，析出大量固体，抽滤，干燥后经柱层析纯化得纯品6-苄基-5-羟基-1,3-双(4-氟基苯基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，白色固体，产量2.00g，产率82.07％。
步骤VI：称量6-苄基-5-羟基-1,3-双(4-氟基苯基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(3.39g,6.95mmol)、三乙胺(1.06g,10.44mmol)、0.1g DMAP和15mL乙腈于100mL圆底烧瓶内，量取5mL乙腈溶解对甲基苯磺酰氯(2.54g,10.17mmol)于锥形瓶内，再将该溶液慢滴入烧瓶内，室温搅拌10min后加热回流5h，TLC监测反应完全。减压蒸馏除去溶剂，加入乙酸乙酯搅拌出大量固体，抽滤，干燥即得产物6-苄基-1,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯，黄白色固体，产量4.22g，产率94.63％。
步骤VII：称量6-苄基-1,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯(0.91g,1.41mmol)、N-氨丙基吗啉(0.28g,1.95mmol)、三乙胺(0.23g,2.25mmol)和15mL正丁醇于50mL圆底烧瓶内，加热至120℃回流反应8h，TLC监测反应完全。待反应液冷却至室温后有大量结晶析出，滤出结晶，用甲醇反复洗涤，干燥后即得6-苄基-1,3-双(4-氟苯基)-8-甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T01)，白色固体，产量0.33g，产率38.13％；m.p.：112.4-116.2℃℃；MS:614.4[M+H]+；1HNMR(400MHz,DMSO-d6)δ9.03(t,J＝5.2Hz,1H),7.53(dd,J＝8.9,4.9Hz,2H),7.40–7.23(m,8H),7.15(dd,J＝7.4,4.1Hz,3H),4.01(s,2H),3.46(s,4H),3.26–3.30(m,2H),2.75(s,3H),2.18(s,6H),1.56(s,2H)。
实施例2：6-苄基-5-{[2-(二甲氨基)乙基]氨基}-1,3-双(4-氟苯基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T02)的制备
采用实施例1的方法制得化合物6-苄基-1,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯。
步骤VII：称量6-苄基-1,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯(0.91g,1.41mmol)、N,N-二甲基乙二胺(0.17g,1.95mmol)、三乙胺(0.23g,2.25mmol)和15mL正丁醇于50mL圆底烧瓶内，加热至120℃回流反应8h，TLC监测反应完全。待反应液冷却至室温后有大量结晶析出，滤出结晶，用甲醇反复洗涤，干燥后即得6-苄基-5-{[2-(二甲氨基)乙基]氨基}-1,3-双(4-氟苯基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T02)，白色固体，产量0.31g，产率39.43％；m.p.：85.7-95.3℃；MS:558.22992[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.11(t,J＝4.6Hz,1H),7.55–7.50(m,2H),7.41–7.36(m,4H),7.35–7.31(m,2H),7.27–7.23(m,2H),7.16–7.11(m,3H),4.05(s,2H),3.37–3.27(m,2H),2.75(s,3H),2.25(t,J＝6.1Hz,2H),1.95(s,6H)。
实施例3：6-苄基-1,3-双(4-氟苯基)-8-甲基-5-(甲氨基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T03)的制备
采用实施例1的方法制得化合物6-苄基-1,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯。
步骤VII：称量6-苄基-1,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯(0.91g,1.41mmol)、40％甲胺水溶液(0.17g,1.95mmol)、三乙胺(0.23g,2.25mmol)和15mL正丁醇于50mL圆底烧瓶内，加热至120℃回流反应8h，TLC监测反应完全。待反应液冷却至室温后有大量结晶析出，滤出结晶，用甲醇反复洗涤，干燥后即得6-苄基-1,3-双(4-氟苯基)-8-甲基-5-(甲氨基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T03)，白色固体，产量0.52g，产率73.68％；m.p.：257.9-262.0℃；MS:501.17163[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.03(q,J＝5.3Hz,1H),7.58–7.49(m,2H),7.41–7.24(m,8H),7.18–7.11(m,3H),4.07(s,2H),2.90(d,J＝5.3Hz,3H),2.75(s,3H)。
实施例4：5-{[3-氯-4-(三氟甲基)苯基]氨基}-1,3-双(4-氟苯基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T04)的制备
采用实施例1的方法制得化合物6-甲胺基-1,3-双(4-氟基苯基)嘧啶-2,4(1H,3H)-二酮。
步骤V：称量6-甲胺基-1,3-双(4-氟基苯基)嘧啶-2,4(1H,3H)-二酮(1.65g,5mmol)、丙二酸二乙酯(0.96g,6mmol)和15g二苯醚于100mL三颈圆底烧瓶内，于加热套上加热至256℃后回流反应40min，TLC监测原料反应完全后，将反应液倒入30mL石油醚中，析出大量固体，抽滤，干燥后经柱层析纯化得纯品1,3-双(4-氟苯基)-5-羟基-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQA20)，白色固体，产量1.39g，产率69.97％；m.p.：246.3-253.6℃；MS:398.09290[M+H]+；1H NMR(400MHz,DMSO-d6)δ12.00(s,1H),7.60–7.54(m,2H),7.43–7.34(m,6H),5.63(s,1H),2.73(s,3H)。
步骤VI：称量1,3-双(4-氟苯基)-5-羟基-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(2.66g,6.69mmol)、三乙胺(1.06g,10.44mmol)、0.1g DMAP和15mL乙腈于100mL圆底烧瓶内，量取5mL乙腈溶解对甲基苯磺酰氯(2.54g,10.17mmol)于锥形瓶内，再将该溶液慢滴入烧瓶内，室温搅拌10min后加热回流5h，TLC监测反应完全。减压蒸馏除去溶剂，加入乙酸乙酯搅拌出大量固体，抽滤，干燥即得产物1,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯，黄白色固体，产量3.49g，产率94.62％。
步骤VII：称量,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯(0.83g,1.5mmol)、3-氯-4-三氟甲基苯胺(0.38g,1.95mmol)、三乙胺(0.23g,2.25mmol)和15mL正丁醇于50mL圆底烧瓶内，加热至120℃回流反应8h，TLC监测反应完全。待反应液冷却至室温后有大量结晶析出，滤出结晶，用甲醇反复洗涤，干燥后即得5-{[3-氯-4-(三氟甲基)苯基]氨基}-1,3-双(4-氟苯基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T04)，白色固体，产量0.56g，产率64.94％；m.p.：265.2-269.7℃；MS:575.08948[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),7.78–7.65(m,3H),7.61–7.53(m,2H),7.46–7.31(m,6H),5.65(s,1H),2.74(s,3H)。
实施例5：1,3-双(4-氟苯基)-8-甲基-5-{[3-(三氟甲基)苯基]氨基}吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T05)的制备
采用实施例4的方法制得化合物1,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯。
步骤VII：称量1,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯(0.83g,1.5mmol)、3-三氟甲基苯胺(0.31g,1.95mmol)、三乙胺(0.23g,2.25mmol)和15mL正丁醇于50mL圆底烧瓶内，加热至120℃回流反应8h，TLC监测反应完全。待反应液冷却至室温后有大量结晶析出，滤出结晶，用甲醇反复洗涤，干燥后即得1,3-双(4-氟苯基)-8-甲基-5-{[3-(三氟甲基)苯基]氨基}吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T05)，白色固体，产量0.62g，产率76.48％；m.p.：197.2-201.3℃；MS:541.12878[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),7.70–7.53(m,6H),7.46–7.32(m,6H),5.60(s,1H),2.74(s,3H)。
实施例6：1,3-双(4-氟苯基)-8-甲基-5-{[4-(三氟甲基)苯基]氨基}吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T06)的制备
采用实施例4的方法制得化合物1,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯。
步骤VII：称量1,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯(0.83g,1.5mmol)、4-三氟甲基苯胺(0.31g,1.95mmol)、三乙胺(0.23g,2.25mmol)和15mL正丁醇于50mL圆底烧瓶内，加热至120℃回流反应8h，TLC监测反应完全。待反应液冷却至室温后有大量结晶析出，滤出结晶，用甲醇反复洗涤，干燥后即得1,3-双(4-氟苯基)-8-甲基-5-{[4-(三氟甲基)苯基]氨基}吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T06)，白色固体，产量0.65g，产率80.18％；m.p.：199.0-201.7℃；MS:541.12787[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.74(s,1H),7.77–7.73(m,2H),7.61–7.51(m,4H),7.45–7.32(m,6H),5.81(s,1H),2.74(s,3H)。
实施例7：5-[(3-氯-4-氟苯基)氨基]-1,3-双(4-氟苯基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T07)：
采用实施例4的方法制得化合物1,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯。
步骤VII：称量1,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯(0.83g,1.5mmol)、3-氯-4-氟苯胺(0.29g,1.95mmol)、三乙胺(0.23g,2.25mmol)和15mL正丁醇于50mL圆底烧瓶内，加热至120℃回流反应8h，TLC监测反应完全。待反应液冷却至室温后有大量结晶析出，滤出结晶，用甲醇反复洗涤，干燥后即得5-[(3-氯-4-氟苯基)氨基]-1,3-双(4-氟苯基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T07)，白色固体，产量0.56g，产率71.13％；m.p.：250.3-254.2℃；MS:525.09283[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.36(s,1H),7.60–7.52(m,3H),7.49–7.31(m,8H),5.47(s,1H),2.73(s,3H)。
实施例8：1,3-双(4-氟苯基)-8-甲基-5-{[4-(三氟甲氧基)苯基]氨基}吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T08)：
采用实施例4的方法制得化合物1,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯。
步骤VII：称量1,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯(0.83g,1.5mmol)、4-三氟甲氧基苯胺(0.35g,1.95mmol)、三乙胺(0.23g,2.25mmol)和15mL正丁醇于50mL圆底烧瓶内，加热至120℃回流反应8h，TLC监测反应完全。待反应液冷却至室温后有大量结晶析出，滤出结晶，用甲醇反复洗涤，干燥后即得1,3-双(4-氟苯基)-8-甲基-5-{[4-(三氟甲氧基)苯基]氨基}吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T08)，白色固体，产量0.62g，产率74.28％；m.p.：212.7-220.2℃；MS:557.12305[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),7.60–7.52(m,2H),7.47–7.30(m,10H),5.56(s,1H),2.73(s,3H)。
实施例9：1,3-双(4-氟苯基)-5-[(呋喃-2-基甲基)氨基]-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T09)的制备
采用实施例4的方法制得化合物1,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯。
步骤VII：称量1,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯(0.83g,1.5mmol)、2-呋喃甲胺(0.19g,1.95mmol)、三乙胺(0.23g,2.25mmol)和15mL正丁醇于50mL圆底烧瓶内，加热至120℃回流反应8h，TLC监测反应完全。待反应液冷却至室温后有大量结晶析出，滤出结晶，用甲醇反复洗涤，干燥后即得1,3-双(4-氟苯基)-5-[(呋喃-2-基甲基)氨基]-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T09)，白色固体，产量0.43g，产率60.17％；m.p.：195.2-198.4℃；MS:477.13617[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.96(t,J＝5.6Hz,1H),7.62–7.48(m,3H),7.41–7.26(m,6H),6.43–6.36(m,2H),5.40(s,1H),4.41(d,J＝5.5Hz,2H),2.68(s,3H)。
实施例10：1,3-双(4-氟苯基)-8-甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T10)的制备
采用实施例4的方法制得化合物1,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯。
步骤VII：称量1,3-双(4-氟苯基)-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯(0.83g,1.5mmol)、N-氨丙基吗啉(0.28g,1.95mmol)、三乙胺(0.23g,2.25mmol)和15mL正丁醇于50mL圆底烧瓶内，加热至120℃回流反应8h，TLC监测反应完全。待反应液冷却至室温后有大量结晶析出，滤出结晶，用甲醇反复洗涤，干燥后即得1,3-双(4-氟苯基)-8-甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T29)，白色固体，产量0.41g，产率52.21％；m.p.：91.8-93.6℃℃；MS:524.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.69(t,J＝5.3Hz,1H),7.51(dd,J＝8.9,4.8Hz,2H),7.38(dd,J＝8.7,4.5Hz,4H),7.32(d,J＝9.2Hz,2H),5.25(s,1H),3.56(t,J＝4.6Hz,4H),3.18(q,J＝6.4Hz,2H),2.68(s,3H),2.35(s,6H),1.73(p,J＝6.8Hz,2H)。
实施例11：6-苄基-8-甲基-5-[(3-吗啉丙基)氨基]-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T11)的制备
步骤I：称量40mL二氯甲烷溶解固体光气(9.5g,32mmol)于500mL圆底烧瓶内，称量苯胺(7.45g,80mmol)溶于40mL二氯甲烷中，室温下将其用滴液漏斗在30min内滴入瓶内，再称量三乙胺(20.24g,0.2mol)溶于50mL二氯甲烷中，并在30min内滴入瓶内，再次称量苯胺(7.4g,80mmol)溶于40mL二氯甲烷中，按上述再次滴入瓶内。滴完后搅拌反应30min监测对氟苯胺反应完全。减压蒸馏除去约3/4体积的二氯甲烷，再用5％HCl溶液搅拌5-10min后产生大量固体，滤出固体，用乙醚反复洗涤，干燥后即为1,3-二苯基脲，白色固体，产量16.17g，产率93.25％。
步骤II：称量1,3-二苯基脲(4.25g,20mmol)、丙二酸(2.7g,26mmol)、三氯氧磷(3.4g,22mmol)和15ml乙腈置于35mL密封管内。密封加热至120℃后反应1h，监测原料反应完全后，将封管内的反应液倒入茄形瓶内，减压蒸馏除去所有溶剂，加入50mL 2mol/L NaOH和20mL乙酸乙酯搅拌溶解。再用2mol/L NaOH水溶液萃取有机相三次，合并水层，再用少量乙酸乙酯萃取水层一次，留下的水层用盐酸调pH至产生大量固体。滤出固体，用水洗涤滤饼，干燥后得黄白色固体1,3-二苯基嘧啶-2,4,6(1H,3H,5H)-三酮3.75g，产率66.90％。
步骤III：称量1,3-二苯基嘧啶-2,4,6(1H,3H,5H)-三酮(4.54g,16.2mmol)、三氯氧磷(4.92g,32.4mmol)和20ml乙腈置于125mL密封管内。密封加热至120℃后反应3h，监测原料反应完全后，将封管内的反应液倒入茄形瓶内，减压蒸馏除去所有溶剂，加入少量乙醇溶解混合物，再加水以析出固体，滤出固体，用水洗涤滤饼，干燥后得黄色固体6-氯-1,3-二苯基嘧啶-2,4(1H,3H)-二酮4.58g，产率94.64％。
步骤IV：称量6-氯-1,3-二苯基嘧啶-2,4(1H,3H)-二酮(2.99g,10mmol)、40％甲胺水溶液(1.28g,15mmol)、三乙胺(2.22g,20mmol)和20mL乙醇于50mL圆底烧瓶内，搅拌回流反应8小时后反应完全。减压蒸馏除去大部分乙醇，加入乙醚搅拌出固体。滤出固体，用乙醚洗涤固体，干燥后得黄色固体6-甲胺基-1,3-二苯基嘧啶-2,4(1H,3H)-二酮，产量2.76g，产率94.09％。
步骤V：称量6-甲胺基-1,3-二苯基嘧啶-2,4(1H,3H)-二酮(1.47g,5mmol)、苄基丙二酸二乙酯(1.50g,6mmol)和15g二苯醚于100mL三颈圆底烧瓶内，于加热套上加热至256℃后回流反应40min，TLC监测原料反应完全后，将反应液倒入30mL石油醚中，析出大量固体，抽滤，干燥后经柱层析纯化得纯品6-苄基-5-羟基-1,3-二苯基-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，白色固体，产量1.39g，产率61.57％。
步骤VI：称量6-苄基-5-羟基-1,3-二苯基-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(2.42g,5.36mmol)、三乙胺(1.06g,10.44mmol)、0.1g DMAP和15mL乙腈于100mL圆底烧瓶内，量取5mL乙腈溶解对甲基苯磺酰氯(2.54g,10.17mmol)于锥形瓶内，再将该溶液慢滴入烧瓶内，室温搅拌10min后加热回流5h，TLC监测反应完全。减压蒸馏除去溶剂，加入乙酸乙酯搅拌出大量固体，抽滤，干燥即得产物6-苄基-1,3-二苯基-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯，黄白色固体，产量3.07g，产率94.62％。
步骤VII：称量6-苄基-1,3-二苯基-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯(0.91g,1.5mmol)、N-氨丙基吗啉(0.28g,1.95mmol)、三乙胺(0.23g,2.25mmol)和15mL正丁醇于50mL圆底烧瓶内，加热至120℃回流反应8h，TLC监测反应完全。待反应液冷却至室温后有大量结晶析出，滤出结晶，用甲醇反复洗涤，干燥后即得6-苄基-8-甲基-5-[(3-吗啉丙基)氨基]-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T11)，白色固体，产量0.4g，产率46.16％；m.p.：180.6-185.1℃；MS:578.27502[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.06(t,J＝5.2Hz,1H),7.57–7.37(m,8H),7.36–7.23(m,4H),7.20–7.10(m,3H),4.01(s,2H),3.44(t,J＝4.5Hz,4H),3.35–3.26(m,3H),2.71(s,3H),2.18(t,J＝4.5Hz,4H),2.13(t,J＝6.8Hz,2H),1.54(p,J＝6.9Hz,2H)。
实施例12：6-苄基-5-(环丙基氨基)-8-甲基-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T12)的制备
采用实施例11的方法制得化合物6-苄基-1,3-二苯基-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯。
步骤VII：称量6-苄基-1,3-二苯基-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯(0.91g,1.5mmol)、环丙胺(0.12g,1.95mmol)、三乙胺(0.23g,2.25mmol)和15mL正丁醇于50mL圆底烧瓶内，加热至120℃回流反应8h，TLC监测反应完全。待反应液冷却至室温后有大量结晶析出，滤出结晶，用甲醇反复洗涤，干燥后即得6-苄基-5-(环丙基氨基)-8-甲基-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T12)，白色固体，产量0.29g，产率39.41％；m.p.：152.7-159.4℃；MS:491.20706[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.32(d,J＝3.5Hz,1H),7.57–7.37(m,8H),7.35–7.23(m,4H),7.20–7.10(m,3H),4.33(s,2H),2.71(s,3H),2.66–2.58(m,1H),0.63(d,J＝6.7Hz,2H),0.56–0.46(m,2H)。
实施例13：6-苄基-8-甲基-5-吗啉基-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T13)的制备
采用实施例11的方法制得化合物6-苄基-1,3-二苯基-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯。
步骤VII：称量6-苄基-1,3-二苯基-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯(0.91g,1.5mmol)、吗啉(0.17g,1.95mmol)、三乙胺(0.23g,2.25mmol)和15mL正丁醇于50mL圆底烧瓶内，加热至120℃回流反应8h，TLC监测反应完全。待反应液冷却至室温后有大量结晶析出，滤出结晶，用甲醇反复洗涤，干燥后即得6-苄基-8-甲基-5-吗啉基-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T13)，白色固体，产量0.29g，产率37.14％；m.p.：85.3-89.7℃；MS:521.21753[M+H]+；1H NMR(400MHz,DMSO-d6)δ7.48(d,J＝8.1Hz,2H),7.42–7.22(m,8H),7.18(dd,J＝12.5,6.9Hz,4H),7.09–6.98(m,1H),4.06(d,J＝15.5Hz,1H),3.95(d,J＝15.5Hz,1H),3.30(s,3H),3.08–2.87(m,4H)。
实施例14：6-苄基-5-{[2-(二甲氨基)乙基]氨基}-8-甲基-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T14)的制备
采用实施例11的方法制得化合物6-苄基-1,3-二苯基-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯。
步骤VII：称量6-苄基-1,3-二苯基-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯(0.91g,1.5mmol)、N,N-二甲基乙二胺(0.17g,1.95mmol)、三乙胺(0.23g,2.25mmol)和15mL正丁醇于50mL圆底烧瓶内，加热至120℃回流反应8h，TLC监测反应完全。待反应液冷却至室温后有大量结晶析出，滤出结晶，用甲醇反复洗涤，干燥后即得6-苄基-5-{[2-(二甲氨基)乙基]氨基}-8-甲基-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T14)，白色固体，产量0.34g，产率43.45％；m.p.：181.4-186.4℃；MS:522.24884[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.16(t,J＝4.7Hz,1H),7.56–7.41(m,8H),7.36–7.26(m,4H),7.19–7.12(m,3H),4.07(s,2H),3.38–3.33(m,2H),2.73(s,3H),2.28(t,J＝6.2Hz,2H),1.97(s,6H)。
实施例15：6,8-二甲基-5-[(3-吗啉丙基)氨基]-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T15)的制备
采用实施例11的方法制得化合物6-甲胺基-1,3-双(4-氟基苯基)嘧啶-2,4(1H,3H)-二酮。
步骤V：称量6-甲胺基-1,3-二苯基嘧啶-2,4(1H,3H)-二酮(1.47g,5mmol)、甲基丙二酸二乙酯(1.04g,6mmol)和15g二苯醚于100mL三颈圆底烧瓶内，于加热套上加热至256℃后回流反应40min，TLC监测原料反应完全后，将反应液倒入30mL石油醚中，析出大量固体，抽滤，干燥后经柱层析纯化得纯品6-甲基-5-羟基-1,3-二苯基-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，白色固体，产量1.05g，产率55.94％。
步骤VI：称量6-甲基-5-羟基-1,3-二苯基-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(2.51g,6.66mmol)、三乙胺(1.06g,10.44mmol)、0.1g DMAP和15mL乙腈于100mL圆底烧瓶内，量取5mL乙腈溶解对甲基苯磺酰氯(2.54g,10.17mmol)于锥形瓶内，再将该溶液慢滴入烧瓶内，室温搅拌10min后加热回流5h，TLC监测反应完全。减压蒸馏除去溶剂，加入乙酸乙酯搅拌出大量固体，抽滤，干燥即得产物6-苄基-1,3-二苯基-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯，黄白色固体，产量3.34g，产率94.62％。
步骤VII：称量6-甲基-1,3-二苯基-8-甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲基苯磺酸酯(0.79g,1.5mmol)、N-氨丙基吗啉(0.28g,1.95mmol)、三乙胺(0.23g,2.25mmol)和15mL正丁醇于50mL圆底烧瓶内，加热至120℃回流反应8h，TLC监测反应完全。待反应液冷却至室温后有大量结晶析出，滤出结晶，用甲醇反复洗涤，干燥后即得6,8-二甲基-5-[(3-吗啉丙基)氨基]-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(T15)，白色固体，产量0.29g，产率38.54％；m.p.：82.4-84.3℃；MS:502.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.62–8.64(m 1H),7.51–7.41(m,8H),7.34–7.28(m,2H),3.52(t,J＝4.6Hz,4H),3.43(q,J＝6.5Hz,2H),2.68(s,3H),2.36–2.24(m,6H),2.06(s,3H),1.65(p,J＝7.0Hz,2H)。
药理实施例
实施例16：受试化合物对MCF7、A375、SK-Mel-2细胞增殖的抑制活性
(1)实验材料
细胞系：MCF7、A375、SK-Mel-2细胞分别以4000、5000、4000个/孔的密度铺于96孔板，每孔200ul，24h后使用。
编号T01-T15目标化合物：以DMSO溶解，用培养液稀释配制为100μM、50μM、25μM、12.5μM、6.25μM、3.125μM六个不同浓度保存于-20℃待用，DMSO在培养液中的终浓度低于0.1％。
阳性对照药：5-氟尿嘧啶(5-Fu,Fluorouracil)。
MTT：以PBS溶解为2mg/mL，保存于-20℃。
(2)实验方法
利用MTT方法，选取MCF7、A375、SK-Mel-2细胞来评价供试样品的抗肿瘤增值活性。MCF7、A375、SK-Mel-2细胞株在DMEM培养基上进行培养，该培养基包含10％小牛血清(FBS)。当细胞增殖至80-90％时使其合并随后进行不超过20代的传代培养，然后在下一步处置前使它们适应环境达到24h。将这些细胞置于96孔板上，然后在含有5％CO2、恒温37℃的孵箱中培养至细胞贴壁完全。24h过后加入不同浓度的发明代表性化合物。再经过24h的培养，向其中加入MTT(2mg/mL)并继续培养4h。移除培养基质，将晶体溶解于DMSO中，利用酶标仪(Thermo Multiskan GO,Thermo Fisher,美国)在570nm波长下测量吸光度。根据公式：细胞生长抑制率＝(1-药物组OD值/对照组OD值)×100％，计算相应浓度下的细胞生长抑制率，以受试化合物的不同浓度及对细胞的抑制率作对数曲线，计算受试化合物相对应的IC50值。按照上述方法测定本发明代表性化合物。
在上述制得的15个化合物中，大多数对MCF-7、A375和SK-MEL-2细胞株呈现出了中等的肿瘤细胞增殖抑制活性，其中T06对MCF7、A375和SK-MEL-2均表现出了较强的抑制增殖活性，IC50低至24.02±0.45μM、25.81±0.69μM和29.28±0.53μM。
制剂实施例
下列制剂实施例仅举例说明本发明的保护范围，但不以任何方式构成限定。以下实施例中所述的活性化合物即指上述实施例中制得的化合物T01～T15。
实施例17：片剂配方
活性化合物25-1000mg，淀粉45mg，微晶纤维素35mg，聚乙烯吡咯烷酮(为10％水溶液)4mL，羧甲基纤维素钠4.5mg，硬脂酸镁0.5mg，滑石1mg。
实施例18：悬浮剂配方
活性化合物0.1-1000mg，羧甲基纤维素钠50mg，糖浆1.25mg，苯甲酸钠0.1mg，矫味剂25mg，着色剂5mg，加纯水至5mL。
实施例19：气溶胶配方
活性化合物0.25mg，乙醇25-75mL，抛射剂22(氯二氟甲烷)70mg。
实施例20：栓剂配方
活性化合物250mg，饱和脂肪酸甘油酯类2000mL。
实施例21：可注射制剂配方
活性化合物50mg，等渗盐溶液1000mL。
实施例22：软膏配方
微粉化活性化合物0.025g，液体石蜡10g，加软白蜡至100g。
实施例23：软膏配方
活性化合物0.025g，丙二醇5g，脱水山梨醇倍半油酸酯5g，液体石蜡10g，加软白蜡至100g。
实施例24：水包油霜剂配方
活性化合物0.025g，十六醇5g，单硬脂酸甘油酯5g，液体石蜡10g，鲸蜡醇聚氧乙烯醚2g，柠檬酸0.1g，柠檬酸钠0.2g，丙二醇35g，加水至100g。
实施例25：水包油霜剂配方
微粉化活性化合物0.025g，软白蜡15g，液体石蜡5g，十六醇5g，Sorbimacrogolstearate(特定药用辅料级的吐温65)2g，脱水山梨醇单硬脂酸酯0.5g，山梨酸0.2g，柠檬酸0.1g，柠檬酸钠0.2g，加水至100g。
实施例26：油包水霜剂配方
活性化合物0.025g，软白蜡35g，液体石蜡5g，脱水山梨醉倍半油酸酯5g，山梨酸0.2g，柠檬酸0.1g，柠檬酸钠0.2g，加水至100g。
实施例27：洗剂配方
活性化合物0.25g，异丙醇0.5mL，羧基乙烯基聚合物3mg，NaOH 2mg，加水至1g。
实施例28：注射用悬浮液配方
活性化合物10mg，羧甲基纤维素钠7mg，NaCl 7mg，聚氧乙烯(20)脱水山梨醇单油酸酯0.5mg，苯甲醇8mg，加无菌水至1mL。
实施例29：用于口腔和鼻吸入的气雾剂配方
活性化合物0.1％w/w，脱水山梨醇三油酸酯0.7％w/w，三氯氟甲烷24.8％w/w，二氯四氟乙烷24.8％w/w，二氯二氟甲烷49.6％w/w。
实施例30：雾化溶液配方
活性化合物7mg，丙二醇5mg，加水至10g。
实施例31：用于吸入的粉剂配方
用下述成份的混合物填充明质胶囊，微粉化活性化合物0.1mg，乳糖20mg，借助于吸入装置吸入该粉末。
实施例32：用于吸入的粉剂配方
球化的粉剂装入多剂粉末吸入器，每剂含有微粉化活性化合物0.1mg。
实施例33：用于吸入的粉剂配方
将球化的粉剂装入多剂粉末吸入器，每剂含有微粉化活性化合物0.1mg，微粉化乳糖1mg。
实施例34：胶囊剂配方
活性化合物1.0mg，小糖球321mg，Aquacoat ECD 30 6.6mg，乙酰柠檬酸三丁酯0.5mg，吐温-80 0.1mg，Eudragit L 100-55 17.5mg，柠檬酸三乙酯1.8mg，滑石粉8.8mg，消泡剂MMS0.lmg。
实施例35：胶囊剂苗体配方
活性化合物2.0mg，小糖球305mg，Aquocoat ECD 30 5.0mg，乙酰柠檬三丁酯0.4mg，吐温-80 0.14mg，Eudragit NE30 D 12.6mg，Eudragit S 100 12.6mg，滑石粉0.l6mg。
实施例36：灌肠剂配方
活性化合物2mg，羧甲基纤维素钠25mg，乙二胺四乙酸二钠0.5mg，对羟基苯甲酸甲酯0.8mg，对羟基苯甲酸丙酯0.2mg，氯化钠7mg，柠檬酸1.8mg，吐温-80 0.01mg，加纯水至1mL。
实施例37：含有脂质体的配方
A.滴注配方的制备
将二棕榈酰基卵磷脂(45mg)，二肉豆蔻酰基卵磷脂(7mg)，二棕榈酰基磷脂酰甘油(1mg)和活性化合物(5mg)放入玻璃管中，将所有组份溶解在氯仿中，用N2蒸发掉大部分溶剂，然后减压，由此，在玻璃管表面形成脂质薄膜.在该脂质中加入水溶液(0.9％NaCl)，在高于脂质的转相温度下形成脂质体，所得悬液含有大小范围为极小囊泡至2μm的脂质体。
B.吸入用配方的制备
按实施例A制备脂质体，其中的水溶液含有10％乳糖，乳糖与脂质之比为7:3。将该脂质体悬液用干冰冷冻，并且进行冷冻干燥，将干燥产物微粉化，所得颗粒的质均空气动力学直径(MMAD)约为2μm。
以上所述，仅是本发明的较佳实施例而已，并非是对本发明作其他形式的限制，任何熟悉本专业的技术人员可能利用上述揭示的技术内容加以变更或改型为等同变化的等效实施例。凡是未脱离本发明技术方案内容，依据本发明的技术实质对以上实施例所作的任何简单修改、等同变化与改型，仍属于本发明技术方案的保护范围。
Claims (5)
1.5-取代氨基-1,3-二取代苯基吡啶并[2,3-d]嘧啶类化合物或其药学上可接受的盐，其特征在于，所述化合物为如下化合物中任一个：
6-苄基-1,3-双(4-氟苯基)-8-甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
6-苄基-5-{[2-(二甲氨基)乙基]氨基}-1,3-双(4-氟苯基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
6-苄基-1,3-双(4-氟苯基)-8-甲基-5-(甲氨基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
5-{[3-氯-4-(三氟甲基)苯基]氨基}-1,3-双(4-氟苯基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
1,3-双(4-氟苯基)-8-甲基-5-{[3-(三氟甲基)苯基]氨基}吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
1,3-双(4-氟苯基)-8-甲基-5-{[4-(三氟甲基)苯基]氨基}吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
5-[(3-氯-4-氟苯基)氨基]-1,3-双(4-氟苯基)-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
1,3-双(4-氟苯基)-8-甲基-5-{[4-(三氟甲氧基)苯基]氨基}吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
1,3-双(4-氟苯基)-5-[(呋喃-2-基甲基)氨基]-8-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
1,3-双(4-氟苯基)-8-甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
6-苄基-8-甲基-5-[(3-吗啉丙基)氨基]-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
6-苄基-5-(环丙基氨基)-8-甲基-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
6-苄基-8-甲基-5-吗啉基-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
6-苄基-5-{[2-(二甲氨基)乙基]氨基}-8-甲基-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
6,8-二甲基-5-[(3-吗啉丙基)氨基]-1,3-二苯基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮。
2.一种药物组合物，其特征在于，所述药物组合物包括作为活性成分的权利要求1所述的5-取代氨基-1,3-二取代苯基吡啶并[2,3-d]嘧啶类化合物及其药学上可接受的盐中任一个的化合物和药学上可接受的载体或稀释剂。
3.一种权利要求1所述的5-取代氨基-1,3-二取代苯基吡啶并[2,3-d]嘧啶类化合物或其药学上可接受的盐的应用，其特征在于，应用于制备抑制MCF-7、A375、SK-MEL-2肿瘤细胞增长的药物。
4.一种权利要求2所述的药物组合物的应用，其特征在于，应用于制备抑制MCF-7、A375、SK-MEL-2肿瘤细胞增长的药物。
5.一种权利要求1所述的5-取代氨基-1,3-二取代苯基吡啶并[2,3-d]嘧啶类化合物或其药学上可接受的盐或权利要求2所述的药物组合物的应用，其特征在于，应用于制备治疗癌症药物，所述的癌症为黑色素瘤、乳腺癌。
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| WO2006124874A2 (en) * | 2005-05-12 | 2006-11-23 | Kalypsys, Inc. | Inhibitors of b-raf kinase |
| CN101006086A (zh) * | 2004-06-11 | 2007-07-25 | 日本烟草产业株式会社 | 用于治疗癌症的5－氨基－2,4,7－三氧代－3,4,7,8－四氢－2H－吡啶并[2,3－d]嘧啶衍生物和相关化合物 |
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| CN101006086A (zh) * | 2004-06-11 | 2007-07-25 | 日本烟草产业株式会社 | 用于治疗癌症的5－氨基－2,4,7－三氧代－3,4,7,8－四氢－2H－吡啶并[2,3－d]嘧啶衍生物和相关化合物 |
| WO2006124874A2 (en) * | 2005-05-12 | 2006-11-23 | Kalypsys, Inc. | Inhibitors of b-raf kinase |
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