CN114456166B - 5-取代氨基-3-甲基吡啶并[2,3-d]嘧啶类化合物及其制备与应用 - Google Patents
5-取代氨基-3-甲基吡啶并[2,3-d]嘧啶类化合物及其制备与应用 Download PDFInfo
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- CN114456166B CN114456166B CN202210330914.9A CN202210330914A CN114456166B CN 114456166 B CN114456166 B CN 114456166B CN 202210330914 A CN202210330914 A CN 202210330914A CN 114456166 B CN114456166 B CN 114456166B
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- pyrimidine
- amino
- trione
- ethyl
- pyrido
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明的5‑取代氨基‑3‑甲基吡啶并[2,3‑d]嘧啶类化合物及其制备与应用，属于医药技术领域。化合物具体为5‑取代氨基‑3‑甲基吡啶并[2,3‑d]嘧啶‑2,4,7(1H,3H,8H)‑三酮类化合物，其结构通式如式(I)所示：R1为氢、甲基或乙基；R2为氢、甲基、苄基、2‑甲基苄基；R3为异丙基、环丙基、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、吡啶‑2‑基、4‑甲基吡啶‑2‑基、2‑(甲氧羰基)苯基、3‑羧基苯基、2‑氧代‑2‑(对甲苯氨基)乙基、2‑氧代‑2‑(邻甲苯氨基)乙基或3‑[(3‑吗啉丙基)氨甲酰]苯基。本发明化合物的合成方法简便，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，可应用于抗肿瘤药物中。
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-3-甲基吡啶并[2,3-d]嘧啶类化合物及其制备与应用。
背景技术
MAPK(mitogen-activated protein kinase,MAPK)是丝氨酸/苏氨酸激酶家族，在将细胞外信号传导到细胞内的各种反应中起着核心作用。MAPK家族被分为两大类：典型性MAPK和非典型性MAPK。典型性MAPK包括细胞外信号调节激酶1/2(ERK1/2)、c-Jun氨基(N)-末端激酶1/2/3(JNK1/2/3)、p38亚型和ERK5。非典型性MAPK包括ERK3/4、ERK7/8和Nemo样激酶(NLK)。所有的真核生物均有多种MAPK通路，一种三级激酶模式，包括MAPK激酶激酶(MKKK)、MAPK激酶(MKK)和MAPK，它们协同调控基因的表达、有丝分裂、代谢生长、运动、存活、凋亡和分化(Coulombe P,Rodier G,et al.Mol Cell Biol,2003,23:4542-4558)。
已有研究报道MAPK家族参与了不同状态下癌症细胞的增殖生长。如：MAPK途径已被证明在血管生成和转移中起关键作用；MAPK通路与ROS调节的血管炎症反正有关；p38和ERK1/2活性升高可能与内皮细胞凋亡有关；p38或ERK1/2的抑制已被证明可防止TNF-α诱导的人肺微血管内皮细胞通透性的增加。(Perander M,Aberg E,et al.Biochem J,2008,411:613-622)
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)是一种口服小分子ATP非竞争性选择性MEK1和MEK2抑制剂。在临床前研究中，有效抑制磷酸化细胞外信号调节激酶(Perk)-1/2。对V600E和V600K突变患者同样有效，于2013年5月被FDA批准用于治疗BRAF突变转移性黑色素瘤(Grimaldi.AM.Simeone E.Ascierto P A.Current Opinion in Oncology.2014,26(2):196-203.)。
司美替尼(Selumetinib)是阿斯利康开发的一种丝裂原活化蛋白激酶1和2(MEK1/2)抑制剂，用于治疗与神经纤维瘤病和各种癌症相关的肿瘤。批准用于有症状、无法手术的2岁以上患有Ⅰ型神经纤维瘤病的儿科患者。MEK1/2是细胞外信号相关激酶(ERK)路的上游调节器，MEK和ERK都是RAS调节的RAF-MEK-ERK通路的组成部分，该通路在许多癌症中被激活(Markham A,Keam SJ.Drugs.2020,80(8):931-937.)。
发明内容
本发明的目的是提供一种5-取代氨基-3-甲基吡啶并[2,3-d]嘧啶类化合物及其制备与应用，具体为5-取代氨基-3-甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮类化合物，相应在制备治疗或/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5-取代氨基-3-甲基吡啶并[2,3-d]嘧啶类化合物、其前体药物和药物活性代谢物以及其药学上可接受的盐；
R1为氢、C1-C4烷基；
R2为氢、C1-C4烷基、苄基、C1-C4烷基取代苄基；
R3为C1-C6烷基、C1-C4烷基取代的苯基、卤素取代的苯基、卤素取代的C1-C4烷基取代的苯基、羧基取代的苯基、氨基取代的C1-C4烷基取代的苯基、吡啶基、C1-C4烷基取代吡啶基、氨基取代的C1-C6烷基、C1-C4烷氧基取代的C1-C4烷基、氨基取代的C1-C4酰基；
R1、R2和R3可以为一个或多个。
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为氢、甲基或乙基；
R2为氢、甲基、苄基或2-甲基苄基；
R3为异丙基、环丙基、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、吡啶-2-基、4-甲基吡啶-2-基、2-(甲氧羰基)苯基、3-羧基苯基、2-氧代-2-(对甲苯氨基)乙基、2-氧代-2-(邻甲苯氨基)乙基或3-[(3-吗啉丙基)氨甲酰]苯基。
进一步的，本发明优选如下化合物：
6-苄基-5-(异丙基氨基)-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM01)，其结构式如下式I-1所示：
6-苄基-5-(环丙基氨基)-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM02)，其结构式如下式I-2所示：
6-苄基-5-{[2-(二甲氨基)乙基]氨基}-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM03)，其结构式如下式I-3所示：
6-苄基-1,3,8-三甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM04)，其结构式如下式I-4所示：
5-{[3-氯-4-(三氟甲基)苯基]氨基}-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM05)，其结构式如下式I-5所示：
1,3,8-三甲基-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(XQM06)，其结构式如下式I-6所示：
5-[(3-氯-4-氟苯基)氨基]-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM07)，其结构式如下式I-7所示：
1,3,8-三甲基-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(XQM08)，其结构式如下式I-8所示：
1,3,8-三甲基-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(XQM09)，其结构式如下式I-9所示：
1,3,8-三甲基-5-(吡啶-2-基氨基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM10)，其结构式如下式I-10所示：
1,3,8-三甲基-5-[(4-甲基吡啶-2-基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM11)，其结构式如下式I-11所示：
2-[(1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]苯甲酸甲酯(XQM12)，其结构式如下式I-12所示：
N-(对甲苯基)-2-[(1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]乙酰胺(XQM13)，其结构式如下式I-13所示：
N-(邻甲苯基)-2-[(1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]乙酰胺(XQM14)，其结构式如下式I-14所示：
1,3,6,8-四甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM15)，其结构式如下式I-15所示：
3-[(1,3,6,8-四甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]苯甲酸(XQM16)，其结构式如下式I-16所示：
N-(3-吗啉丙基)-3-[(1,3,6,8-四甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]苯甲酰胺(XQM17)，其结构式如下式I-17所示：
5-{[3-氯-4-(三氟甲基)苯基]氨基}-1-乙基-3,8-二甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM18)，其结构式如下式I-18所示：
1-乙基-3,8-二甲基-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(XQM19)，其结构式如下式I-19所示：
5-[(3-氯-4-氟苯基)氨基]-1-乙基-3,8-二甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM20)，其结构式如下式I-20所示：
1-乙基-3,8-二甲基-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(XQM21)，其结构式如下式I-21所示：
1-乙基-3,8-二甲基-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(XQM22)，其结构式如下式I-22所示：
1-乙基-3,8-二甲基-5-(吡啶-2-基氨基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM23)，其结构式如下式I-23所示：
2-[(1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]苯甲酸甲酯(XQM24)，其结构式如下式I-24所示：
1-乙基-3,8-二甲基-5-[(4-甲基吡啶-2-基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM25)，其结构式如下式I-25所示：
6-苄基-1-乙基-3,8-二甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM26)，其结构式如下式I-26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，其中：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/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通路相关的癌症疾病如肺癌、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XQM01-XQM26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，相应的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-5-(异丙基氨基)-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM01)的制备
步骤I：称量6-氯-3-甲基尿嘧啶(4.80g,30mmol)、碳酸钾(4.98g,36mmol)、TBAB(0.2g,0.6mmol)、3mL水和50mL丙酮于250mL圆底烧瓶内，室温搅拌至固体先溶解后又析出固体，再将溶于10mL丙酮的硫酸二甲酯(4.16g,33mmol)溶液慢滴入烧瓶内，稍作搅拌后回流2h。TLC监测反应完全后，滤出固体，母液经减压蒸馏后得白色固体，用乙醚打浆，再次滤出固体，即得产物6-氯-1,3-二甲基尿嘧啶，白色固体，产量5.10g，产率91.70％。
步骤II：称量6-氯-1,3-二甲基尿嘧啶(2.61g,15.00mmol)、甲胺(40％)水溶液(1.51g,19.50mmol)、TEA(3.04g,30.00mmol)和15mL乙醇于100mL圆底烧瓶内，搅拌回流过夜反应。TLC监测反应完全，减压蒸馏出乙醇后，加入10mL乙醚打浆，滤出固体，干燥后得1,3-二甲基-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮，淡黄色固体，产量2.33g，产率91.67％。
步骤III：称量1,3-二甲基-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮(1.69g,10mmol)、苄基丙二酸二乙酯(3.25g,13mmol)和10.00g二苯醚于50mL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20mL石油醚中，析出固体，抽滤，干燥后经柱层析纯化得纯品6-苄基-5-羟基-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，白色固体，产量1.05g，产率44.29％。
步骤IV：称量6-苄基-5-羟基-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(5.79g,17.71mmol)、三乙胺(2.51g,24.8mmol)、0.11g DMAP和15mL乙腈于100mL圆底烧瓶内，量取5mL乙腈溶解对甲苯磺酰氯(4.04g,21.26mmol)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-1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯，黄白色固体，产量4.42g，产率94.62％。
步骤V：称量6-苄基-1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.81g,10mmol)，异丙胺(0.65g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品6-苄基-5-(异丙基氨基)-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，白色固体，产量0.81g，产率35.43％；M.p:171.4-176.0℃；MS:369.19052[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.13(d,J＝9.0Hz,1H),7.20–7.28(m,2H),7.17–7.08(m,3H),3.92(s,2H),3.77–3.66(m,1H),3.41(s,6H),3.20(s,3H),1.01(d,J＝6.2Hz,6H)。
实施例2：6-苄基-5-(环丙基氨基)-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM02)的制备
采用实施例1的方法制得化合物6-苄基-1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯；
步骤V：称量6-苄基-1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.81g,10mmol)，环丙基甲胺(0.63g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品6-苄基-5-(环丙基氨基)-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，白色固体，产量0.79g，产率35.22％；M.p:177.2-178.0℃；MS:367.17505[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.42(d,J＝3.4Hz,1H),7.18–7.27(m,2H),7.07–7.16(m,3H),4.30(s,2H),3.41(s,6H),3.18(s,3H),2.60–2.63(m,1H),0.69–0.60(m,2H),0.45–0.55(m,2H)。
实施例3：6-苄基-5-{[2-(二甲氨基)乙基]氨基}-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM03)的制备
采用实施例1的方法制得化合物6-苄基-1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯；
步骤V：称量6-苄基-1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.81g,10mmol)，N1，N1-二甲基乙烷-1,2-二胺(0.97g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品6-苄基-5-{[2-(二甲氨基)乙基]氨基}-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，白色固体，产量0.91g，产率37.09％；M.p:140.8-142.1℃；MS:398.31[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.24(t,J＝4.6Hz,1H),7.19–7.28(m,2H),7.07–7.17(m,3H),4.01(s,2H),3.41(s,6H),3.25–3.34(m,2H),3.19(s,3H),2.27(t,J＝6.1Hz,2H),2.01(s,6H)。
实施例4：6-苄基-1,3,8-三甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM04)的制备
采用实施例1的方法制得化合物6-苄基-1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯；
步骤V：称量6-苄基-1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.81g,10mmol)，N-氨丙基吗啉(1.58g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品6-苄基-1,3,8-三甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，白色固体，产量1.03g，产率39.21％；M.p:168.3-174.4℃；MS:454.24268[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.17(t,J＝5.2Hz,1H),7.19–7.28(m,2H),7.07–7.17(m,3H),3.98(s,2H),3.47(t,J＝4.5Hz,4H),3.41(s,6H),3.27(q,J＝6.4Hz,2H),3.20(s,3H),2.21(t,J＝4.5Hz,4H),2.17(t,J＝6.9Hz,2H),1.56(p,J＝6.8Hz,2H)。
实施例5：
5-{[3-氯-4-(三氟甲基)苯基]氨基}-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM05)的制备
采用实施例1的方法制得化合物1,3-二甲基-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮；
步骤III：称量1,3-二甲基-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮(3.38g,20mmol)、丙二酸二乙酯(4.16g,26mmol)和20.00g二苯醚于50mL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20mL石油醚中，析出大量固体，抽滤，干燥后得5-羟基-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，白色固体，产量3.89g，产率88.29％。
步骤IV：称量5-羟基-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(4.20g,17.71mmol)、三乙胺(2.51g,24.8mmol)、0.11g DMAP和15mL乙腈于100mL圆底烧瓶内，量取5mL乙腈溶解对甲苯磺酰氯(4.04g,21.26mmol)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1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯，黄白色固体，产量4.28g，产率95.82％
步骤V：称量1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(3.91g,10mmol)，3-氯-4-三氟甲基苯胺(2.15g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品5-{[3-氯-4-(三氟甲基)苯基]氨基}-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，白色固体，产量1.11g，产率35.81％；M.p:266.5-268.8℃；MS:.415.07635[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),7.73(d,J＝10.4Hz,2H),7.65(d,J＝8.8Hz,1H),5.54(s,1H),3.45(s,3H),3.42(s,3H),3.24(s,3H)。
实施例6：1,3,8-三甲基-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(XQM06)的制备
采用实施例5的方法制得化合物1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯；
步骤V：称量1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.20g,10mmol)，4-三氟甲基苯胺(1.77g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品1,3,8-三甲基-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，白色固体，产量0.87g，产率31.35％；M.p:206.2-213.2℃；MS:381.11520[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.90(s,1H),7.76(d,J＝8.4Hz,2H),7.51(d,J＝8.3Hz,2H),5.72(s,1H),3.45(s,3H),3.42(s,3H),3.24(s,3H)。
实施例7：5-[(3-氯-4-氟苯基)氨基]-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM07)的制备
采用实施例5的方法制得化合物1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯；
步骤V：称量1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.20g,10mmol)，3-氯-4-氟苯胺(1.60g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品5-[(3-氯-4-氟苯基)氨基]-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，白色固体，产量0.92g，产率36.31％；M.p:194.5-197.9℃；MS:365.07977[M+H]+；1HNMR(400MHz,DMSO-d6)δ10.47(s,1H),7.55–7.41(m,2H),7.27–7.34(m,1H),5.36(s,1H),3.45(s,3H),3.40(s,3H),3.23(s,3H)。
实施例8：1,3,8-三甲基-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(XQM08)的制备
采用实施例5的方法制得化合物1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯；
步骤V：称量1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.20g,10mmol)，3-三氟甲基苯胺(1.77g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品1,3,8-三甲基-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，白色固体，产量1.11g，产率39.45％；M.p:213.6-216.4℃；MS:381.11514[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.72(s,1H),7.70–7.54(m,4H),5.50(s,1H),3.45(s,3H),3.41(s,3H),3.24(s,3H)。
实施例9：1,3,8-三甲基-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(XQM09)的制备
采用实施例5的方法制得化合物1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯；
步骤V：称量1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.20g,10mmol)，4-三氟甲氧基苯胺(1.95g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品1,3,8-三甲基-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，白色固体，产量0.87，产率30.91％；M.p:210.9-213.2℃；MS:397.10986[M+H]+；1HNMR(400MHz,DMSO-d6)δ10.62(s,1H),7.38–7.45(m,4H),5.46(s,1H),3.45(s,3H),3.41(s,3H),3.23(s,3H)。
实施例10：1,3,8-三甲基-5-(吡啶-2-基氨基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM10)的制备
采用实施例5的方法制得化合物1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯；
步骤V：称量1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.20g,10mmol)，2-氨基吡啶(1.03g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品1,3,8-三甲基-5-(吡啶-2-基氨基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，白色固体，产量0.81g，产率32.11％；M.p:252.6-256.2℃；MS:314.12317[M+H]+；1H NMR(400MHz,DMSO-d6)δ11.67(s,1H),8.35(d,J＝4.9Hz,1H),7.73–7.75(m,1H),7.44(s,1H),7.03(d,J＝8.0Hz,2H),3.45(s,3H),3.42(s,3H),3.23(s,3H)。
实施例11：1,3,8-三甲基-5-[(4-甲基吡啶-2-基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM11)的制备
采用实施例5的方法制得化合物1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯；
步骤V：称量1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.20g,10mmol)，4-甲基-2-氨基吡啶(1.19g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品1,3,8-三甲基-5-[(4-甲基吡啶-2-基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，白色固体，产量1.12g，产率38.12％；M.p:248.6-250.2℃；MS:328.13882[M+H]+；1H NMR(400MHz,DMSO-d6)δ11.61(s,1H),8.19(d,J＝5.1Hz,1H),7.43(s,1H),6.90–6.83(m,2H),3.45(s,3H),3.42(s,3H),3.22(s,3H),2.30(s,3H)。
实施例12：2-[(1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]苯甲酸甲酯(XQM12)的制备
采用实施例5的方法制得化合物1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯；
步骤V：称量1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.20g,10mmol)，2-氨基苯甲酸甲酯(1.67g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品2-[(1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]苯甲酸甲酯，白色固体，产量0.79g，产率31.15％；M.p:237.1-240.2℃；MS:371.13315[M+H]+；1H NMR(400MHz,DMSO-d6)δ11.39(s,1H),7.94(d,J＝7.7Hz,1H),7.63(s,2H),7.26(s,1H),5.75(s,1H),3.84(s,3H),3.43(s,3H),3.40(s,3H),3.24(s,3H)。
实施例13：N-(对甲苯基)-2-[(1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]乙酰胺(XQM13)的制备
采用实施例5的方法制得化合物1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯；
步骤V：称量1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.20g,10mmol)，2-氨基-N-(对甲苯基)乙酰胺(1.80g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品，白色固体N-(对甲苯基)-2-[(1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]乙酰胺，产量1.12g，产率36.51％；M.p:271.7-275.4℃；MS:384.16632[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.10(s,1H),9.61(t,J＝5.3Hz,1H),7.47(d,J＝8.0Hz,2H),7.12(d,J＝8.0Hz,2H),6.38(s,1H),4.19(d,J＝5.3Hz,2H),3.43(s,3H),3.26(s,3H),2.25(s,3H)。
实施例14：N-(邻甲苯基)-2-[(1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]乙酰胺(XQM14)的制备
采用实施例5的方法制得化合物1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯；
步骤V：称量1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.20g,10mmol)，2-氨基-N-(邻甲苯基)乙酰胺(1.80g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品，白色固体N-(邻甲苯基)-2-[(1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]乙酰胺，产量1.04g，产率35.71％；M.p:279.6-284.3℃；MS:384.16611[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.63(s,1H),9.54(s,1H),7.95(s,3H),7.44(s,1H),7.16(dd,J＝37.2,12.7Hz,3H),6.44(s,1H),4.40–4.19(m,2H),3.44(s,3H),3.26(s,3H),2.89(s,9H),2.73(s,9H),2.22(s,3H)。
实施例15：1,3,6,8-四甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM15)的制备
采用实施例1的方法制得化合物1,3-二甲基-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮；
步骤III：称量1,3-二甲基-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮(3.38g,20mmol)、2-甲基丙二酸二乙酯(4.52g,26mmol)和20.00g二苯醚于50mL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20mL石油醚中，析出大量固体，抽滤，干燥后得5-羟基-1,3,6,8-四甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，白色固体，产量3.69g，产率86.15％。
步骤IV：称量5-羟基-1,3,6,8-四甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(4.45g,17.71mmol)、三乙胺(2.51g,24.8mmol)、0.11g DMAP和15mL乙腈于100mL圆底烧瓶内，量取5mL乙腈溶解对甲苯磺酰氯(4.04g,21.26mmol)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1,3,6,8-四甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基4-甲基苯磺酸酯，黄白色固体，产量4.57g，产率97.73％。
步骤V：称量1,3,6,8-四甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基4-甲基苯磺酸酯(4.05g,10mmol)，N-氨丙基吗啉(1.58g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品1,3,6,8-四甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，白色固体，产量0.88g，产率32.51％；M.p:176.0-177.6℃；MS:378.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ8.77–8.72(m,1H),3.55(t,J＝4.6Hz,4H),3.44–3.39(m,3H),3.38(s,3H),3.37(s,2H),3.18(d,J＝1.9Hz,3H),2.34(s,2H),2.32(s,2H),2.31(s,2H),2.01(d,J＝2.4Hz,3H),1.66(p,J＝7.0Hz,2H)。
实施例16：3-[(1,3,6,8-四甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]苯甲酸(XQM16)的制备
采用实施例15的方法制得化合物1,3,6,8-四甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基4-甲基苯磺酸酯；
步骤V：称量1,3,6,8-四甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基4-甲基苯磺酸酯(4.05g,10mmol)，3-氨基苯甲酸(1.51g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品，白色固体3-[(1,3,6,8-四甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]苯甲酸，产量0.91g，产率31.25％；M.p:254.5-256.1℃；MS:371.1[M+H]+；1H NMR(400MHz,DMSO-d6)δ12.46(s,1H),10.28(s,1H),7.56(d,J＝7.6Hz,1H),7.39 7.42(m,1H),7.34(s,1H),7.16(dd,J＝8.0,2.1Hz,1H),3.50(s,3H),3.47(s,3H),1.91(s,3H),1.53(s,3H)。
实施例17：N-(3-吗啉丙基)-3-[(1,3,6,8-四甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]苯甲酰胺(XQM17)的制备
采用实施例15的方法制得化合物1,3,6,8-四甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基4-甲基苯磺酸酯；
步骤V：称量1,3,6,8-四甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基4-甲基苯磺酸酯(4.05g,10mmol)，3-氨基-N-(3-吗啉丙基)苯甲酰胺(2.90g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品，白色固体N-(3-吗啉丙基)-3-[(1,3,6,8-四甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]苯甲酰胺，产量1.21g，产率32.13％；M.p:106.2-107.3℃；MS:497.3[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.30(s,1H),8.44–8.46(m,1H),7.45(d,J＝7.7Hz,1H),7.35–7.37(m,1H),7.30–7.32(m,1H),7.03(dd,J＝7.9,2.2Hz,1H),3.56(t,J＝4.6Hz,4H),3.50(s,3H),3.47(s,3H),3.28(d,J＝6.4Hz,2H),3.22(s,3H),2.37–2.33(m,4H),2.31(d,J＝7.2Hz,2H),1.66(q,J＝7.0Hz,2H),1.52(s,3H)。
实施例18：5-{[3-氯-4-(三氟甲基)苯基]氨基}-1-乙基-3,8-二甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM18)的制备
步骤I：称量6-氯-3-甲基尿嘧啶(4.80g,30mmol)、碳酸钾(4.98g,36mmol)、TBAB(0.2g,0.6mmol)、3mL水和50mL丙酮于250mL圆底烧瓶内，室温搅拌至固体先溶解后又析出固体，再将溶于10mL丙酮的硫酸二乙酯(5.09g,33mmol)溶液慢滴入烧瓶内，搅拌后回流2h。TLC监测反应完全后，滤出固体，母液经减压蒸馏后得白色固体，用乙醚打浆，再次滤出固体，得6-氯-1-乙基-3-甲基嘧啶-2,4(1H,3H)-二酮，白色固体，产量4.69g，产率87.73％。
步骤II：称量6-氯-1-乙基-3-甲基嘧啶-2,4(1H,3H)-二酮(4.70g,25.00mmol)、甲胺(40％)水溶液(2.52g,32.50mmol)、TEA(5.06g,50.00mmol)和40mL乙醇于250mL圆底烧瓶内，搅拌回流过夜反应。TLC监测反应完全，减压蒸馏出乙醇后，加入约20mL乙醚打浆，滤出固体，干燥后得1-乙基-3-甲基-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮，淡黄色固体，产量3.66g，产率88.79％。
步骤III：称量1-乙基-3-甲基-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮(3.66g,20mmol)、丙二酸二乙酯(4.16g,26mmol)和30.00g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，析出固体，抽滤，干燥后得1-乙基-5-羟基-3,8-二甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，白色固体，产量4.54g，产率93.77％。
步骤IV：称量1-乙基-5-羟基-3,8-二甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(4.27g,17.71mmol)、三乙胺(2.51g,24.8mmol)、0.11g DMAP和15mL乙腈于100mL圆底烧瓶内，量取5mL乙腈溶解对甲苯磺酰氯(4.04g,21.26mmol)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固体，抽滤，干燥即得产物1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯，黄白色固体，产量4.66g，产率95.12％。
步骤V：称量1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.05g,10mmol)，3-氯-4-三氟甲基苯胺(2.15g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品，白色固体5-{[3-氯-4-(三氟甲基)苯基]氨基}-1-乙基-3,8-二甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，产量1.01g，产率33.01％；M.p:198.1-201.1℃；MS:428.09195[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.67(s,1H),7.81–7.58(m,3H),5.53(s,1H),4.00(q,J＝6.9Hz,2H),3.42(s,3H),3.23(s,3H),1.30(t,J＝6.9Hz,3H)。
实施例19：1-乙基-3,8-二甲基-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(XQM19)的制备
采用实施例18的方法制得化合物1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯；
步骤V：称量1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.05g,10mmol)，4-三氟甲基苯胺(1.77g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品，白色固体1-乙基-3,8-二甲基-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，产量0.89g，产率31.23％；M.p:183.3-186.1℃；MS:395.13086[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),7.75(d,J＝8.6Hz,2H),7.50(d,J＝8.3Hz,2H),5.72(s,1H),4.00(q,J＝6.9Hz,2H),3.43(s,3H),3.23(s,3H),1.31(t,J＝6.9Hz,3H)。
实施例20：5-[(3-氯-4-氟苯基)氨基]-1-乙基-3,8-二甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM20)的制备
采用实施例18的方法制得化合物1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯；
步骤V：称量1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.05g,10mmol)，3-氯-4-氟苯胺(1.59g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品，白色固体5-[(3-氯-4-氟苯基)氨基]-1-乙基-3,8-二甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，产量0.91g，产率33.51％；M.p:229.1-231.3℃；MS:379.09543[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.45(s,1H),7.53(dd,J1＝6.6,J2＝2.6Hz,1H),7.44–7.46(m,1H),7.29-7.33(m,1H),5.35(s,1H),3.99(q,J＝6.9Hz,2H),3.40(s,3H),3.22(s,3H),1.29(t,J＝6.9Hz,3H)。
实施例21：1-乙基-3,8-二甲基-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(XQM21)的制备
采用实施例18的方法制得化合物1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯；
步骤V：称量1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.05g,10mmol)，3-三氟甲基苯胺(1.77g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品，白色固体1-乙基-3,8-二甲基-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，产量0.93g，产率32.15％；M.p:209.5-212.0℃；MS:395.13174[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.69(s,1H),7.79–7.45(m,4H),5.49(s,1H),4.00(q,J＝6.9Hz,2H),3.42(s,3H),3.23(s,3H),1.30(t,J＝6.9Hz,3H)。
实施例22：1-乙基-3,8-二甲基-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(XQM22)的制备
采用实施例18的方法制得化合物1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯；
步骤V：称量1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.05g,10mmol)，4-三氟甲氧基苯胺(1.95g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品，白色固体1-乙基-3,8-二甲基-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，产量1.03g，产率31.27％；M.p:172.4-175.6℃；MS:411.12637[M+H]+；1H NMR(400MHz,DMSO-d6)δ10.59(s,1H),7.41(s,4H),5.46(s,1H),3.99(q,J＝6.9Hz,2H),3.41(s,3H),3.22(s,3H),1.30(t,J＝6.9Hz,3H)。
实施例23：1-乙基-3,8-二甲基-5-(吡啶-2-基氨基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM23)的制备
采用实施例18的方法制得化合物1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯；
步骤V：称量1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.05g,10mmol)，2-氨基吡啶(1.03g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品，白色固体1-乙基-3,8-二甲基-5-(吡啶-2-基氨基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，产量1.11g，产率35.67％；M.p:261.8-263.5℃；MS:328.13977[M+H]+；1H NMR(400MHz,DMSO-d6)δ11.65(s,1H),8.36(s,1H),7.75(s,1H),7.46(s,1H),7.05(d,J＝8.5Hz,2H),4.00(s,2H),3.44(s,3H),3.25(s,3H),1.51–1.02(m,3H)。
实施例24：2-[(1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]苯甲酸甲酯(XQM24)的制备
采用实施例18的方法制得化合物1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯；
步骤V：称量1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.05g,10mmol)，邻氨基苯甲酸甲酯(1.66g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品，白色固体2-[(1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]苯甲酸甲酯，产量1.08g，产率32.31％；M.p:196.2-198.4℃；MS:385.14984[M+H]+；1H NMR(400MHz,DMSO-d6)δ11.38(s,1H),7.93(d,J＝7.9Hz,1H),7.70–7.59(m,2H),7.23–7.26(m,1H),5.67(s,1H),3.99(q,J＝6.9Hz,2H),3.84(s,3H),3.41(s,3H),3.24(s,3H),1.30(t,J＝6.9Hz,3H)。
实施例25：1-乙基-3,8-二甲基-5-[(4-甲基吡啶-2-基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM25)的制备
采用实施例18的方法制得化合物1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯；
步骤V：称量1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.05g,10mmol)，4-甲基-2-氨基吡啶(1.19g,11mmol，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品，白色固体1-乙基-3,8-二甲基-5-[(4-甲基吡啶-2-基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，产量0,88g，产率31.24％；M.p:249.5-251.9℃；MS:342.15543[M+H]+；1H NMR(400MHz,DMSO-d6)δ11.60(s,1H),8.21(d,J＝5.1Hz,1H),7.45(s,1H),6.88(s,2H),3.99(q,J＝6.9Hz,2H),3.43(s,3H),3.24(s,3H),2.31(s,3H),1.30(t,J＝6.9Hz,3H)。
实施例26：6-苄基-1-乙基-3,8-二甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(XQM26)的制备
采用实施例18的方法制得化合物1-乙基-3-甲基-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮；
步骤III：称量1-乙基-3-甲基-6-(甲氨基)嘧啶-2,4(1H,3H)-二酮(3.66g,20mmol)、苄基丙二酸二乙酯(6.50g,26mmol)和30.00g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，干燥后得6-苄基-1-乙基-5-羟基-3,8-二甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，白色固体，产量4.62g，产率91.09％。
步骤IV：称量6-苄基-1-乙基-5-羟基-3,8-二甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮(6.04g,17.71mmol)、三乙胺(2.51g,24.8mmol)、0.11g DMAP和15mL乙腈于100mL圆底烧瓶内，量取5mL乙腈溶解对甲苯磺酰氯(4.04g,21.26mmol)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-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯，黄白色固体，产量4.68g，产率94.66％。
步骤V：称量6-苄基-1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基对甲苯磺酸酯(4.95g,10mmol)，N-氨丙基吗啉(1.58g,11mmol)，15mL正丁醇于50mL圆底烧瓶内，加热回流8h，有固体生成，TLC监测反应完全。抽滤，干燥后经柱层析纯化得纯品6-苄基-1-乙基-3,8-二甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮，白色固体，产量0.98g，产率32.14％；M.p:34.1-135.1℃；MS:468.3[M+H]+；1H NMR(400MHz,DMSO-d6)δ9.14(t,J＝5.2Hz,1H),7.23–7.25(m,2H),7.11–7.13(m,3H),3.97(d,J＝7.4Hz,4H),3.47(t,J＝4.6Hz,4H),3.42(s,3H),3.26(q,J＝6.5Hz,2H),3.19(s,3H),2.21(t,J＝4.6Hz,4H),2.17(t,J＝6.9Hz,2H),1.56(q,J＝6.8Hz,2H),1.27(t,J＝6.9Hz,3H)。
药理实施例
实施例27
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XQM01-XQM26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26个化合物中，多数化合物对A549、A375和SK-MEL-2肿瘤细胞增殖均有抑制作用，其中XQM01和XQM10对MCF7细胞株的IC50值分别为9.97±0.59μM和10.25±0.39μM，这一结果明显优于阳性对照药5-F尿嘧啶(IC50＝13.42±0.54μM)，此外XQM01和XQM10对两株恶性黑色素瘤细胞A375和SK-MEL-2均表现出了中等抑制增殖活性。
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XQM01～XQM26。
实施例28：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29：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30：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31：栓剂配方
活性化合物250mg，饱和脂肪酸甘油酯类2000mL。
实施例32：可注射制剂配方
活性化合物50mg，等渗盐溶液1000mL。
实施例33：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34：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35：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36：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37：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38：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39：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40：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41：雾化溶液配方
活性化合物7mg，丙二醇5mg，加水至10g。
实施例42：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43：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44：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45：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46：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47：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48：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 (6)
1.5-取代氨基-3-甲基吡啶并[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-5-(异丙基氨基)-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
6-苄基-5-(环丙基氨基)-1,3,8-三甲基吡啶并[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}-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
6-苄基-1,3,8-三甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
5-{[3-氯-4-(三氟甲基)苯基]氨基}-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
1,3,8-三甲基-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]-1,3,8-三甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
1,3,8-三甲基-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；
1,3,8-三甲基-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；
1,3,8-三甲基-5-(吡啶-2-基氨基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
1,3,8-三甲基-5-[(4-甲基吡啶-2-基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
2-[(1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]苯甲酸甲酯；
N-(对甲苯基)-2-[(1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]乙酰胺；
N-(邻甲苯基)-2-[(1,3,8-三甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]乙酰胺；
1,3,6,8-四甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
3-[(1,3,6,8-四甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]苯甲酸；
N-(3-吗啉丙基)-3-[(1,3,6,8-四甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]苯甲酰胺；
5-{[3-氯-4-(三氟甲基)苯基]氨基}-1-乙基-3,8-二甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
1-乙基-3,8-二甲基-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-乙基-3,8-二甲基吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
1-乙基-3,8-二甲基-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-乙基-3,8-二甲基-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-乙基-3,8-二甲基-5-(吡啶-2-基氨基)吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
2-[(1-乙基-3,8-二甲基-2,4,7-三氧代-1,2,3,4,7,8-六氢吡啶并[2,3-d]嘧啶-5-基)氨基]苯甲酸甲酯；
1-乙基-3,8-二甲基-5-[(4-甲基吡啶-2-基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮；
6-苄基-1-乙基-3,8-二甲基-5-[(3-吗啉丙基)氨基]吡啶并[2,3-d]嘧啶-2,4,7(1H,3H,8H)-三酮。
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-3-甲基吡啶并[2,3-d]嘧啶类化合物及其药学上可接受的盐中任何一个的化合物和药学上可接受的载体或稀释剂。
3.权利要求1所述的5-取代氨基-3-甲基吡啶并[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，用于制备抑制MCF7、A375以及SK-MEL-2肿瘤细胞增长的药物。
4.权利要求2所述的药物组合物的应用，其特征在于，用于制备抑制MCF7、A375以及SK-MEL-2肿瘤细胞增长的药物。
5.权利要求1所述的5-取代氨基-3-甲基吡啶并[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，用于制备治疗癌症药物，所述的癌症为黑色素瘤、乳腺癌。
6.权利要求2所述的药物组合物的应用，其特征在于，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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