CN107721937A - 含有嘧啶酮骨架的化合物的制备方法和用途 - Google Patents
含有嘧啶酮骨架的化合物的制备方法和用途 Download PDFInfo
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- CN107721937A CN107721937A CN201711012200.9A CN201711012200A CN107721937A CN 107721937 A CN107721937 A CN 107721937A CN 201711012200 A CN201711012200 A CN 201711012200A CN 107721937 A CN107721937 A CN 107721937A
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- Prior art keywords
- phenyl
- methyl
- pyrimidinyl
- morpholinyl
- dihydro
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical group OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 title abstract 2
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Abstract
本发明涉及通式Ⅰ所示的嘧啶酮化合物、其几何异构体及其药学上可接受的盐、溶剂化物或前药，它们的制备方法以及含有所述化合物的药物组合物，取代基R1具有在说明书中给出的含义。本发明还涉及通式Ⅰ的化合物在制备治疗和/或预防癌症和其他增生性疾病的药物中的用途。
Description
技术领域
本发明涉及新的吗啉嘧啶酮类化合物、其几何异构体及其药学上可接受的 盐、溶剂化物或前药，他们的制备方法以及含有所述化合物的药物组合物。本发 明还涉及该类化合物用于制备和/或预防癌症和其他增生性疾病的药物中的用 途。
背景技术
癌症(cancer)即恶性肿瘤，是一种严重危害人类健康的致命性疾病。从全 世界范围来看，目前全世界有1400万新癌症病例，癌症死亡人数达820万。其 中新增肺癌病例180万，死亡人数159万。因此，恶性肿瘤已成为仅次于心血管 疾病的人类第二类杀手。
磷酯酰肌醇-3-激酶(Phosphoinositide-3-kinase,PI3K)及其下游的蛋白激酶 B(Protein kinase B，Akt/PKB)、雷帕霉素靶体蛋白(Mammalian target of rapamycin，mTOR)组成的PI3K-Akt-mTOR信号通路简称PI3K通路，在肿瘤 细胞生物学过程中发挥着重要作用，与细胞周期、血管形成、肿瘤发生和侵袭的 关系密切。该信号通路的过度表达会导致细胞的增殖、转录、翻译和代谢过程异 常，引起肿瘤的发生。因此，以PI3K/Akt信号通路中关键分子为靶点的小分子 抑制剂已成为当前抗肿瘤药物的研究热点。
磷脂酰肌醇-3激酶是一类特异性受体酪氨酸激酶(RTKs)，PI3K是由调节 亚基p85和催化亚基p110组成的异源二聚体，根据其底物和催化亚基p110结构 的不同分为I、II、III型，Ⅰ型又可近一步分为ⅠA类和ⅠB类，成为PI3Ks家族， 包括数个磷脂酰肌醇激酶和DNA依赖的蛋白激酶如ATM、ATR和DNA-PK等， 它能使磷脂酰肌醇的第三位羟基磷酸化，产生具有第二信使作用的肌醇酯物质— 磷脂酰肌醇-3-磷酸酯(PIP3)。第二信使PIP3可以使PI3K与下游的效应物(特 别是AKt)配对结合，从而导致膜募集和磷酸化。研究表明：PI3K家族与细胞 增殖、抗凋亡、细胞迁移、冒泡转运、细胞癌性转化等众多过程相关，这些生物 效应主要是通过PI3K催化形成的“锚”分子3-磷酰肌醇酯(PIP,PIP2,PIP3)介导 的。研究发现，在广泛人类肿瘤谱中PI3K通路普遍失调，该通路中某些基因突 变所致的功能异常或缺失会引起正常细胞转化、促进肿瘤细胞增殖和存活并介导 肿瘤细胞的侵袭和迁移，因此是小分子抑制剂的较佳作用靶点，为癌症的治疗提 供了机会。
哺乳动物雷帕霉素靶蛋白(mammal target of rapamycin，mTOR)是丝氨酸/ 苏氨酸磷脂酰肌醇-3-激酶相关激酶家族成员(phosphatidylinositol-3-kinases associatedkinase，PIKK)唯一的磷酸化蛋白底物，具有抑制细胞凋亡作用，在 肿瘤细胞中常过度表达。根据功能和结构的不同分为两种蛋白复合物：mTORC1 和mTORC2。其中，mTORC1对雷帕霉素敏感，可促进核糖体合成、mRNA翻 译以及细胞自噬；mTORC2对雷帕霉素不敏感，可促进细胞进入细胞周期、细 胞的存活、细胞骨架的重塑和代谢。mTOR是AKt的下游效应分子，活化的AKt 可间接激活mTORC1，进而磷酸化核糖体蛋白p和翻译抑制分子e结合蛋白。 同时，mTORC2通过磷酸化Akt的Ser473位点上调PI3K/AKt/mTOR信号通路 的活性，进一步刺激肿瘤细胞的生长。
目前，许多靶向Ⅰ型PI3K(Pi3Kα)的化合物已进入临床研究阶段，如：天然 产物渥曼青霉素、Buparlisib、Alpelisib、PI-103、BEZ-235、PKI-587等。
文献报道的GDC-0941是由基因泰克研究开发,属于吗啉嘧啶酮类化合物， 是从化合物虚拟筛选出得到的选择性I类磷脂酰肌醇3-激酶(PI3K)抑制剂，体 外抑制PI3K P110α亚型的IC50是为3nM。
本发明人在参考文献的基础上，设计合成了一系列吗啉嘧啶酮类衍生物，经 体外对多种肿瘤细胞株进行抗肿瘤活性筛选，结果表明具有抗肿瘤活性。
本发明涉及通式(Ⅰ)所示的吗啉嘧啶酮类化合物及其药学上可接受的盐、溶 剂化物或其前药，
其中，
R1的结构式选自：
优选
R2为苯基、(C3-C6)环烷基、5-10元杂芳基、5-10元饱和或部分饱和的杂 环基，所述杂芳基和杂环基含有1-3个任选自O、N和S的杂原子，且R2任选 1-3个R3取代；
R3为1-3个相同或不同的选自氢、羟基、卤素、硝基、氨基、氰基、叠氮基、 巯基、(C1-C6)烷基、(C1-C6)烷氧基、任选被羟基、氨基或卤代的(C1-C6)烷 基或(C1-C6)烷氧基、(C1-C6)烷巯基、烯丙基、被单或二(C1-C6烷基)取代 的氨基、(C1-C6)烷基酰胺基、游离的、成盐的、酯化的和酰胺化的羧基、(C1-C6) 烷基亚磺酰基、(C1-C6)烷基磺酰基、(C1-C6)烷基酰基、氨基甲酰基、被单或 二(C1-C6烷基)取代的氨基甲酰基的取代基。
本发明还优选涉及通式(Ⅰ)所示的吗啉嘧啶酮类化合物及其几何异构体、药 学上可接受的盐、溶剂化物或其前药，
其中，R2为苯基、5-10元杂芳基，所述杂芳基含有1-3个任选自O,N和S 的杂原子，且R2任选1-3个R3取代；
R3为1-3个相同或不同的选自氢、羟基、卤素、硝基、氨基、氰基、(C1-C4) 烷基、乙烯基、丙烯基、2-甲基丙烯基、乙炔基、(C1-C4)烷氧基、三氟甲基、 三氟甲氧基、烯丙基、被单或二(C1-C4烷基)取代的氨基、(C1-C4)烷基酰胺 基、羧基、(C1-C4)烷基亚磺酰基、磺酰基、(C1-C4)烷基酰基、氨基甲酰基、 4-(二甲基氨基)-1-哌啶基羰基的取代基；
本发明特别优选涉及通式(Ⅰ)所示的吗啉嘧啶酮类化合物及其几何异构体、 药学上可接受的盐、溶剂化物或其前药，其中，
R2为苯基、苯并噻唑基、苯并噁唑基、吡啶基、呋喃基、噻吩基、吡咯基、 吡嗪基、嘧啶基、哒嗪基、吲哚基、咪唑基、三氮唑基，且R2任选1-3个R3取 代；
R3为1-3个相同或不同的选自氢、羟基、氟、氯、溴、碘、硝基、氨基、氰 基、甲基、乙基、正丙基、异丙基、叔丁基、乙烯基、丙烯基、2-甲基丙烯基、 乙炔基、甲氧基、乙氧基、环丙氧基、叔丁氧基、三氟甲基、三氟甲氧基、烯丙 基、甲氨基、乙胺基、二甲氨基、甲酰氨基、乙酰氨基、丙酰氨基、环丙酰氨基、 羧基、甲基亚磺酰基、磺酰基、甲磺酰基、甲酰基、乙酰基、丙酰基、环丙酰基、 氨基甲酰基、4-(二甲基氨基)-1-哌啶基羰基的取代基。
本发明通式(Ⅰ)所示的吗啉嘧啶酮类化合物及其几何异构体、药学上可接受 的盐、溶剂化物或其前药优选一下化合物，但这些化合物并不意味着对本发明的 任何限制：
1-苯基-3-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(2-氯苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(3-氯苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(4-氯苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(对甲苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-[4-(三氟甲基)苯基]-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯 基]脲
N-(4-溴苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(4-氟苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(2,4-二甲氧基苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯 基]脲
N-(4-硝基苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(4-乙酰基苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(2,4-二氯苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(2,4-二甲基苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基] 脲
N-[3-(三氟甲基)苯基]-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯 基]脲
N-[2-(三氟甲基)苯基]-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯 基]脲
N-[4-(三氟甲氧基)苯基]-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基) 苯基]脲
(E)-2-(4-甲氧基亚苄基)-N-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯 基]氨基-1-甲酰肼
(E)-2-[4-(三氟甲氧基)亚苄基]-N-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧 啶基)苯基]氨基-1-甲酰肼
(E)-2-(3-甲氧基亚苄基)-N-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯 基]氨基-1-甲酰肼
而且，按照本发明所属领域的一些通常方法，本发明中上式I的含有吗啉嘧 啶酮骨架化合物可以与酸生成药学上可接受的盐。可药用加成盐包括无机酸和有 机酸加成盐，与下列酸加成的盐是特别优选的：盐酸、氢溴酸、硫酸、磷酸、甲 磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、 马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。
此外，本发明还包括本发明衍生物的前药。本发明衍生物的前药是通式I的 衍生物，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条 件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
本发明中“卤素”是指氟、氯、溴或碘代；“烷基”是指直链或支链的烷基；“环 烷基”是指取代或未取代的环烷基；“芳基”是指无取代基或连有取代基的苯基； “杂芳基”是指含有一个或多个选自N、O、S杂原子的单环或多环的环状体系， 环状体系是芳香性的，如咪唑基、吡啶基、吡唑基、(1,2,3)-和(1,2,4)-三唑基、 呋喃基、噻吩基、吡咯基，噻唑基，苯并噻唑基，噁唑基，异噁唑基，萘基，喹 啉基，异喹啉基，苯并咪唑基，苯并噁唑基等；“饱和或部分饱和的杂环基”是指 含有一个或多个选自N、O、S的杂原子的单环或多环的环状体系，如吡咯烷基、 吗啉基、哌嗪基、哌啶基、吡唑烷基、咪唑烷基和噻唑啉基等。
本发明可以含有上式I的含有吗啉嘧啶酮骨架的化合物，及其药学上可接受 的盐、溶剂化物作为活性成份，与药学上可接受的载体或赋型剂混合制备成组合 物，并制备成临床上可接受的剂型，上述药学上可接受的赋型剂是指任何可用于 药学领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成份组 合使用，只要它们不产生其他不利的作用，例如过敏反应。
本发明上式Ⅰ的含有吗啉嘧啶酮骨架的化合物用于患者的临床剂量可以根 据：活性成分在体内的治疗功效和生物利用度、它们的代谢和排泄速率和患者的 年龄、性别、疾病期来进行适当调整，不过成人的每日剂量一般应当为10-500mg， 优选为50-300mg。因此，当本发明的药物组合物被制成单位剂型时，考虑到上 述有效剂量，每单位制剂应当含有10-500mg上式Ⅰ的含有吗啉嘧啶酮骨架的化 合物，优选为50-300mg。按照医生或药师的指导，这些制剂可以以一定间隔分 若干次给药(优选为一至六次)。
本发明的药用组合物可配制成若干种剂型，其中含有药物领域中一些常用的 赋形剂。如上所述的若干种剂型可以采用注射剂、片剂、胶囊剂、气雾剂、栓剂、 膜剂、滴丸剂、外用搽剂、软膏剂等剂型药物。
用于本发明药物组合物的载体是药物领域中可得到的常见类型，包括：粘合 剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、无色素、矫味剂、防 腐剂、加溶剂和基质等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、 腹膜内或局部)给药，如果某些药物在胃部条件下不稳定的，可将其配制成肠衣 片剂。
通过体外抑制肺癌细胞H460、结肠癌细胞HT-29、人乳腺癌细胞MDA- MB-231、人胃癌细胞MKN-45和人肺腺癌细胞A549活性试验，我们发现本发 明化合物具有显著的抗肿瘤活性，因此本发明化合物可以用于制备治疗和/或预 防各种癌症的药物，如乳腺、肺、肝脏、肾脏、结肠、直肠、胃、前列腺、膀胱、 子宫、胰腺、骨髓、睾丸、卵巢、淋巴、软组织、头颈、甲状腺、食道的癌和白 血病、成神经细胞瘤等。特别用于制备治疗和/或预防肺癌和肝癌的药物。
本发明的活性化合物或其可药用盐及其溶剂化物可作为唯一的抗肿瘤药物 单独使用，或者可以与现已上市的抗肿瘤药物(如铂类药物顺铂、喜树碱类药物 伊立替康、长春花碱类药物诺维本、脱氧胞昔类药物吉西他滨、足叶乙甙、紫杉 醇等)联合使用。联合治疗通过将各个治疗组分同时、顺序或隔开给药来实现。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制 备方法。应当理解，下述实施例和制备例的范围并不以任何方式限制本发明的范 围。
下面的合成路线描述了本发明的通式Ⅰ衍生物的制备，所有的原料都是通过 这些路线中描述的方法、通过有机化学领域普通技术人员熟知的方法制备的或者 可商购。本发明的全部最终化合物都是通过这些路线中描述的方法或通过与其类 似的方法制备的，这些方法是有机化学领域普通技术人员熟知的。这些路线中应 用的全部可变因数如下文的定义或如权利要求中的定义。
按照本发明的通式Ⅰ衍生物，可按照路线一、路线二方法，其中化合物T1 由化合物Ⅰ与不同取代异氰酸酯制得，化合物T2由化合物Ⅰ、氯甲酸苄酯、水 合肼和不同取代的醛经一系列反应制得，其中T1～T2的取代基的定义同通式Ⅰ 化合物。
路线一:
路线二:
具体实施方式：
以下实施例旨在阐述而不是限制本发明的范围。化合物的核磁共振氢谱用Bruker ARX-300测定，质谱用Agilent 1100LC/M(S)D测定；所用试剂均为分析 纯或化学纯。
实施例1 1-苯基-3-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲的制 备
1.1 4-硝基苯甲腈的合成(M2)
将100g(0.66mol)对硝基苯甲醛、60g(0.86mol)盐酸羟胺、100mL DMSO 加三颈瓶中，回流反应4h。反应液冷却至室温，倒入500mL的冰水中，抽滤， 得黄色固体，干燥得淡黄色固体88.91g，收率90.7％。
1.2 4-硝基苄基亚氨酸乙酯的合成(M3)
在干燥的HCl气体存在下，将80g(0.54mol)对硝基苯甲腈溶于86mL(1.62 mol)无水乙醇和800mL干燥的1,4-二氧六环，室温反应12h。溶剂蒸干，得黄 色粘稠状固体，倒入52mL2.5％NaOH溶液，调pH至中性，抽滤，干燥得黄色 固体43.48g，收率为71.4％。
1.3 N-甲基-4-硝基苯甲脒的合成(M4)
将5g 4-硝基苄基亚氨酸乙酯(0.026mol)和2g(0.030mol)甲胺盐酸盐 溶于50mL甲醇/水(9:1)混合溶剂，升温至45℃搅拌5h。溶剂蒸干，得黄色 固体。加入20mL水溶解，用3.4mL2.5％NaOH溶液调pH至12，抽滤，干燥 得暗白色固体2.6g，收率为57％。
1.4 6-羟基-3-甲基-2-(4-硝基苯基)-4(3H)-嘧啶酮的合成(M5)
将2.6g N-甲基-4-硝基苯甲脒(0.016mol)和3.5mL(0.033mol)丙二酸 二甲酯溶于6mL苯甲醚，升温至130℃反应12h，抽滤，干燥得黄色固体2.6g， 收率为57％。
1.5 6-氯-3-甲基-2-(4-硝基苯基)-4(3H)-嘧啶酮的合成(M6)
将8.8g(0.036mol)6-羟基-3-甲基-2-(4-硝基苯基)-4(3H)-嘧啶酮溶于44mL 三氯氧磷，升温至80℃搅拌5h。蒸除三氯氧磷，将所得固体缓慢加入到冰水中，， 用15％NaOH溶液调pH至12，抽滤，干燥得黄色固体7.6g，收率为80.8％。
1.6 3-甲基-6-吗啉基-2-(4-硝基苯基)-4(3H)-嘧啶酮的合成(M7)
将4g(0.015mol)6-氯-3-甲基-2-(4-硝基苯基)-4(3H)-嘧啶酮加入4mL(0.045mol)吗啉和40mLDMF中，升温至80℃搅拌3.5h。将反应液倒入20mL冰水 中，用3.0mL15％NaOH溶液调pH至12，抽滤，干燥得黄色固体3.9g，收率 为87.9％。
1.7 2-(4-氨基苯基)-3-甲基-6-吗啉基-4(3H)-嘧啶酮的合成(I)
将5g(0.089mol)铁粉加入到0.9mL浓盐酸和60mL90％乙醇中，室温 搅拌30min。升温至60℃，加入4g(0.013mol)3-甲基-6-吗啉基-2-(4-硝基苯 基)-4(3H)-嘧啶酮。80℃回流反应5h。稍冷，加入0.2g(0.017mol)活性炭脱 色，升温至回流搅拌30min。趁热抽滤，冷却，用3.6mL 10％NaOH溶液调节 pH至10，用3×30mL二氯甲烷萃取，合并有机相，干燥。蒸除有机溶剂，得浅 黄色粉末，收率为55.25％。
1.8 1-苯基-3-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲的的合成
将0.05mol苯基异氰酸酯溶于5mL二氯甲烷中，加入0.05mol中间体I， 室温反应5h左右。反应完毕，抽滤得类白色固体0.13g，收率为75.6％。
MS(ESI)m/z(％):406.3[M+H]+；1H-NMR(400MHz,Chloroform-d)δ8.77(s, 1H),8.46(s,1H),7.56(d,J＝8.2Hz,2H),7.42(d,J＝7.7Hz,4H),7.25(s,1H),7.02 (d,J＝7.7Hz,1H),5.47(s,1H),3.70(s,4H),3.49(s,4H),3.42(s,3H)
按照实施例1的方法，以中间体I为原料与各种苯基异氰酸酯反应制备得到 实施例1-16的化合物(见表1)
实施例17(E)-2-(4-甲氧基亚苄基)-N-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶 基)苯基]氨基-1-甲酰肼的合成
17.1 中间体苯基N-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]氨基-1- 甲酸苯酯的合成(Ⅱ)
将1.4g(0.0049mol)2-(4-氨基苯基)-3-甲基-6-吗啉基-4(3H)-嘧啶酮溶于5 mL二氯甲烷中，冰浴条件下，缓慢滴加8.2mL(0.015mol)氯甲酸苯酯，滴毕， 加入5mL氯仿，升温35℃反应3h。将反应液冷却至室温，静置过夜，抽滤， 得白色固体1.92g，收率为90.14％。
17.2 N-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]氨基-1-甲酰肼的合 成(Ⅲ)
将1.0g(0.0025mol)苯基[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基) 苯基]氨基甲酸苯酯溶于1.5mL(0.025mol)水合肼和10mL甲苯80℃反应5h。 将反应液冷却至室温，浓缩溶剂，加入15mL异丙醇-异丙醚(1:5)搅拌，抽 滤，干燥得白色固体0.4g，收率为47.6％。
17.3 (E)-2-(4-甲氧基亚苄基)-N-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基) 苯基]氨基-1-甲酰肼的合成
将0.05mol4-甲氧基苯甲醛溶于5mL无水乙醇中，加入0.05mol中间体 (Ⅲ)，升温回流反应。反应完毕，冷却至室温，抽滤得类白色固体0.13g，收 率为76.8％。
MS(ESI)m/z(％):463.2[M+H]+(见Figure 37)；1H-NMR(400MHz, DMSO-d6)δ10.77(s,1H),9.15(s,1H),7.93(s,1H),7.81(t,J＝8.3Hz,4H), 7.63-7.54(m,2H),7.05-6.96(m,2H),5.44(s,1H),3.81(s,3H),3.64(t,J＝4.8Hz, 4H),3.46(t,J＝4.8Hz,4H),3.28(s,3H)
按照实施例17的方法，以中间体Ⅲ为原料与各种取代苯甲醛反应制备得到 实施例17-19的化合物(见表1)
表1
本发明产物的体外抗肿瘤细胞活性
对按照本发明的上式Ⅰ的吗啉嘧啶酮骨架的化合物进行了体外抑制人肺癌 细胞H460、人结肠癌细胞HT-29、人乳腺癌细胞MDA-MB-231、人胃癌细胞 MKN-45和人肺腺癌细胞A549活性筛选。对照品GDC-0941按照文献(J.Med. Chem.2008,51(18),pp5522-5532)所述方法制备得到。
(1)细胞复苏并传代2-3次稳定后，用胰蛋白酶溶液(0.25％)使其从培 养瓶底部消化下来。将细胞消化液倒入离心管中后，之后加入培养液以终止消化。 将离心管在800r/min下离心10min，弃去上清液后加入5mL培养液，吹打混 匀细胞，吸取10μL细胞混悬液加入细胞计数板中计数，调整细胞浓度为104个 /孔。96孔板中除A1孔为空白孔不加细胞外，其余皆加入100μL细胞混悬液。 将96孔板放入培养箱中培养24h。
(2)用50μL二甲基亚砜溶解受试样品，然后加入适量培养液，使样品溶 解成2mg/mL药液，然后在24孔板中将样品稀释为20、4、0.8、0.16、0.032μg/mL。
每个浓度加入3孔，其中周围两行两列细胞长势受环境影响较大，只和为空 白细胞孔使用。将96孔板放入培养箱中培养72h。
(3)将96孔板中带药培养液弃去，用磷酸缓冲溶液(PBS)将细胞冲洗两 遍，在每孔中加入MTT(0.5mg/mL)100μL放入培养箱中4h后，弃去MTT 溶液，加入二甲基亚砜100μL。在磁力振荡器上振荡使存活细胞与MTT反应产 物甲臜充分溶解，放入酶标仪中测定结果。通过Bliss法可求出药物IC50值。
部分化合物的抑制人肺癌细胞H460、人结肠癌细胞HT-29、人乳腺癌细胞 MDA-MB-231、人胃癌细胞MKN-45和人肺腺癌细胞A549活性结果见表2。
表2
从上述实验结果可以清楚的看出，本发明所要保护的通式I的化合物，具有 良好的体外抗肿瘤活性，相当或由于阳性对照药GDC-0941。
Claims (9)
1.通式(Ⅰ)的化合物及其药学上可接受的盐、溶剂化物或其前药，
其中，
R1的结构式选自：
R2为苯基、(C3-C6)环烷基、5-10元杂芳基、5-10元饱和或部分饱和的杂环基，所述杂芳基和杂环基含有1-3个任选自O、N和S的杂原子，且R2任选1-3个R3取代；
R3为1-3个相同或不同的选自氢、羟基、卤素、硝基、氨基、氰基、叠氮基、巯基、(C1-C6)烷基、(C1-C6)烷氧基、任选被羟基、氨基或卤代的(C1-C6)烷基或(C1-C6)烷氧基、(C1-C6)烷巯基、烯丙基、被单或二(C1-C6烷基)取代的氨基、(C1-C6)烷基酰胺基、游离的、成盐的、酯化的和酰胺化的羧基、(C1-C6)烷基亚磺酰基、(C1-C6)烷基磺酰基、(C1-C6)烷基酰基、氨基甲酰基、被单或二(C1-C6烷基)取代的氨基甲酰基的取代基。
2.权利要求1的通式(Ⅰ)的化合物及其药学上可接受的盐、溶剂化物或其前药，
其中，
R1的结构式选自：
3.权利要求2的通式(Ⅰ)的化合物及其药学上可接受的盐、溶剂化物或其前药，
其中，
R2为苯基、5-10元杂芳基，所述杂芳基含有1-3个任选自O,N和S的杂原子，且R2任选1-3个R3取代；
R3为1-3个相同或不同的选自氢、羟基、卤素、硝基、氨基、氰基、(C1-C4)烷基、乙烯基、丙烯基、2-甲基丙烯基、乙炔基、(C1-C4)烷氧基、三氟甲基、三氟甲氧基、烯丙基、被单或二(C1-C4烷基)取代的氨基、(C1-C4)烷基酰胺基、羧基、(C1-C4)烷基亚磺酰基、磺酰基、(C1-C4)烷基酰基、氨基甲酰基、4-(二甲基氨基)-1-哌啶基羰基的取代基。
4.权利要求3的通式(Ⅰ)的化合物及其药学上可接受的盐、溶剂化物或其前药，其中，
R2为苯基、苯并噻唑基、苯并噁唑基、吡啶基、呋喃基、噻吩基、吡咯基、吡嗪基、嘧啶基、哒嗪基、吲哚基、咪唑基、三氮唑基，且R2任选1-3个R3取代；
R3为1-3个相同或不同的选自氢、羟基、氟、氯、溴、碘、硝基、氨基、氰基、甲基、乙基、正丙基、异丙基、叔丁基、乙烯基、丙烯基、2-甲基丙烯基、乙炔基、甲氧基、乙氧基、环丙氧基、叔丁氧基、三氟甲基、三氟甲氧基、烯丙基、甲氨基、乙氨基、二甲氨基、甲酰氨基、乙酰氨基、丙酰氨基、环丙酰氨基、羧基、甲基亚磺酰基、磺酰基、甲磺酰基、甲酰基、乙酰基、丙酰基、环丙酰基、氨基甲酰基、4-(二甲基氨基)-1-哌啶基羰基的取代基。
5.下列通式(Ⅰ)的化合物及其药学上可接受的盐、溶剂化物或其前药，
1-苯基-3-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(2-氯苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(3-氯苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(4-氯苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(对甲苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-[4-(三氟甲基)苯基]-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(4-溴苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(4-氟苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(2,4-二甲氧基苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(4-硝基苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(4-乙酰基苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(2,4-二氯苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-(2,4-二甲基苯基)-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-[3-(三氟甲基)苯基]-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-[2-(三氟甲基)苯基]-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
N-[4-(三氟甲氧基)苯基]-N`-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]脲
(E)-2-(4-甲氧基亚苄基)-N-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]氨基-1-甲酰肼
(E)-2-[4-(三氟甲氧基)亚苄基]-N-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]氨基-1-甲酰肼
(E)-2-(3-甲氧基亚苄基)-N-[4-(1-甲基-4-吗啉基-6-氧代-1,6-二氢-2-嘧啶基)苯基]氨基-1-甲酰肼。
6.一种药用组合物，包含权利要求1-5中任何一项的化合物及其药学上可接受的盐、溶剂化物或前药作为活性成分以及药学上可接受的赋形剂。
7.权利要求1-5中任何一项的化合物及其药学上可接受的盐、溶剂化物或前药在制备治疗和/或预防增生性疾病药物中的应用。
8.权利要求1-5中任何一项的化合物及其药学上可接受的盐、溶剂化物或前药在制备治疗和/或预防癌症的药物中的应用。
9.权利要求1-5中任何一项的化合物及其药学上可接受的盐、溶剂化物或前药在制备治疗和/或预防肺癌、肝癌、胃癌、结肠癌、乳腺癌的药物中的应用。
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010120994A2 (en) * | 2009-04-17 | 2010-10-21 | Wyeth Llc | Ureidoaryl-and carbamoylaryl-morpholino- pyrimidine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their synthesis |
| CN103172577A (zh) * | 2012-01-13 | 2013-06-26 | 沈阳药科大学 | 4-氨基喹唑啉及4-氨基喹啉类化合物及其用途 |
| CN104230952A (zh) * | 2014-08-16 | 2014-12-24 | 沈阳药科大学 | 含有嘧啶骨架的化合物及其制备方法和用途 |
-
2017
- 2017-10-26 CN CN201711012200.9A patent/CN107721937B/zh active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010120994A2 (en) * | 2009-04-17 | 2010-10-21 | Wyeth Llc | Ureidoaryl-and carbamoylaryl-morpholino- pyrimidine compounds, their use as mtor kinase and pi3 kinase inhibitors, and their synthesis |
| CN103172577A (zh) * | 2012-01-13 | 2013-06-26 | 沈阳药科大学 | 4-氨基喹唑啉及4-氨基喹啉类化合物及其用途 |
| CN104230952A (zh) * | 2014-08-16 | 2014-12-24 | 沈阳药科大学 | 含有嘧啶骨架的化合物及其制备方法和用途 |
Non-Patent Citations (2)
| Title |
|---|
| CHRISTOPH M. DEHNHARDT等: "Identification of 2-oxatriazines as highly potent pan-PI3K/mTOR dual inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
| 孙铁民: "PI3K抑制剂的研究进展专题", 《中南药学》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116874496A (zh) * | 2023-07-10 | 2023-10-13 | 东南大学 | 三环类化合物及其制备方法、药物组合物和应用 |
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