CN112979659B - 一类HIF-2α小分子抑制剂的制备及用途 - Google Patents
一类HIF-2α小分子抑制剂的制备及用途 Download PDFInfo
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- CN112979659B CN112979659B CN202110197296.0A CN202110197296A CN112979659B CN 112979659 B CN112979659 B CN 112979659B CN 202110197296 A CN202110197296 A CN 202110197296A CN 112979659 B CN112979659 B CN 112979659B
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- Prior art keywords
- triazolo
- pyrazin
- methyl
- methylamine
- ylmethyl
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Abstract
本发明属于医药技术领域，涉及一类HIF‑2α小分子抑制剂及其制备方法和用途。所述的HIF‑2α小分子抑制剂为如结构通式Ⅰ
所示的化合物及其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药，本发明利用分子模拟药物设计软件MOE进行药效团的筛选和分子对接，根据最后对接的优势结构及电子等排原理，设计并合成了一系列化合物，体外抗肿瘤活性筛选试验表明，该类化合物具有抗肿瘤活性。本发明提供的HIF‑2α小分子抑制剂在预防或治疗癌症，特别是胶质瘤方面，具有较好的应用前景。
Description
技术领域
本发明属于医药技术领域，涉及一类HIF-2α小分子抑制剂及其制备方法和用途。
背景技术
癌症(cancer)即恶性肿瘤，一般是机体内正常的细胞因外界的刺激而发生细胞分化和增殖异常、生长失去控制并具有浸润性和转移性。胶质瘤是神经胶质瘤(Gliomas)的简称，也称为胶质细胞瘤，是颅内最常见的原发性中枢神经系统肿瘤，其恶性程度高，约占所有颅内原发肿瘤的一半。替莫唑胺(Temozolomide，TMZ)是一种口服烷化剂，能穿过血脑屏障直达病灶，是临床上治疗胶质瘤的一线化疗药物之一。但是有研究表明，用TMZ治疗人脑胶质瘤的有效率约为45％。其中，脑胶质瘤对TMZ产生耐药性是导致化疗失败的最主要原因。因此，寻找新的治疗胶质瘤的化疗药物迫在眉睫。
大气层中的氧气，是动物赖以生存的必要元素，低氧环境与肿瘤的发生发展密不可分，肿瘤的快速增殖和血液供应的减少/不足都会引起低氧环境。胶质瘤等实体瘤存在于低氧微环境中，低氧微环境可通过促进肿瘤血管新生、诱导肿瘤干细胞样表型转化等介导肿瘤细胞产生放化疗抵抗。
人类的低氧诱导因子(Hypoxia inducible factor，HIFs)家族是由三个受调控的HIF-α(HIF-1α，HIF-2α/EPAS-1，和HIF-3α)亚单位和组成型ARNT(也称为HIF-β)亚单位组成的异二聚体。常氧时低氧诱导因子氧含量敏感的α亚单位异构体HIF-1/2α通过泛素化途径降解；而低氧条件下，HIF-1/2α稳定并入核启动下游靶基因的转录表达，使肿瘤细胞能够耐受低氧环境。
研究发现HIF-2α在维持肿瘤细胞生长方面发挥重要作用，因此开发HIF-2α的靶点抑制药物具有重要意义。目前尚无已上市的HIF-2α抑制剂，仅见可靶向抑制pVHL缺失的肾癌细胞的小分子P2977，目前处于临床Ⅱ期试验阶段，而未见对于胶质瘤等其它肿瘤作用的HIF-2α抑制剂报道。在课题组前期的研究中，小分子HWM-1表现出优异的抑制HIF-2α蛋白的作用，且对胶质瘤有很好的抑制作用。
本发明在课题组前期研究的小分子HWM-1的结构骨架基础上，保留其与HIF-2α蛋白形成氢键和π-π共轭的相互作用不变，利用分子模拟药物设计软件MOE进行药效团的筛选和分子对接，根据最后对接的优势结构及电子等排原理，设计并合成了一系列化合物，体外抗肿瘤活性筛选试验表明，该类化合物具有抗肿瘤活性。因此，研发新的可靶向肿瘤干细胞特异高表达的HIF-2α的抑制剂，对于抑制肿瘤的发生、转移和复发具有十分重要的临床意义。
发明内容
鉴于现有技术存在的问题，本发明的目的在于提供一类HIF-2α小分子抑制剂及其制备方法和用途。本发明利用分子模拟药物设计软件MOE进行药效团的筛选和分子对接，根据最后对接的优势结构及电子等排原理，设计并合成了一系列化合物，体外抗肿瘤活性筛选试验表明，该类化合物具有抗肿瘤活性。本发明提供的HIF-2α小分子抑制剂在预防或治疗癌症，特别是胶质瘤方面，具有较好的应用前景。
为实现上述目的，本发明采用以下技术方案。
一类HIF-2α小分子抑制剂，所述的HIF-2α小分子抑制剂为如结构通式Ⅰ所示的化合物及其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药，
其中：
m代表0、1、2或3；n代表0、1、2或3；x代表0、1、2或3；
R1、R2相同或者不同，分别独立地选自氢、三氟甲基、(C1～C4)烷基；
R3选自1～4个相同或不同的氢、卤素；
X为CH或N；
Y为五元或六元(芳)杂环，所述杂环分别含有1～3个任选自N、O、S的杂原子，且还任选被1～3个相同或不同的R4取代；
R4分别独立地选自为1～4个相同或不同的氢、卤素、羟基、三氟甲基、三幅甲氧基、氨基、叠氮基、硝基、氰基、巯基、(C1-C4)烷基、(C3-C6)环烷基、(C1-C4)烯基、(C1-C4)炔基、(C1-C4)烷氧基、(C1-C4)烷硫基、烯丙基、(2-甲基)烯丙基、(C1-C4)烷氧基甲基、(C1-C4)烷基酰基、(C1-C3)亚烷基二氧基的取代基。
进一步地，所述的HIF-2α小分子抑制剂为如结构通式Ⅰ所示的化合物及其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药，
其中：
m代表0、1、2或3；n代表0、1、2或3；x代表0、1、2或3；
R1、R2相同或者不同，分别独立地选自氢、三氟甲基、甲基；
R3选自1～4个相同或不同的氢、氟、溴；
X为CH或N；
Y为
R4独立地选自为1～4个相同或不同的氢、氟、氯、溴、羟基、三氟甲基、三幅甲氧基、氨基、叠氮基、硝基、氰基、巯基、甲基、乙基、正丙基、环丙基、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、甲硫基、乙硫基、烯丙基、(2-甲基)烯丙基、甲氧基甲基、乙氧基甲基、异丙氧基甲基、甲酰基、乙酰基、丙酰基、环丙酰基、丁酰基、2,3-亚甲基二氧基、2,3-亚乙基二氧基的取代基。
所述通式为I的化合物及其立体异构体，及其药学上可接受的盐和/或水合物，结构选自下述任意一种：
(1)1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-苄基-N-呋喃-2-基甲基)甲胺；
(2)1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(4-氟苄基)-N-(呋喃-2-基甲基)甲胺；
(3)1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(3-溴苯基)-N-(呋喃-2-基甲基)甲胺；
(4)N-苄基-1-(呋喃-2-基)-N-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲基)甲胺；
(5)N-(4-氟苄基)-1-(呋喃-2-基)-N-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲基)甲胺；
(6)N-(2-溴-4-氟苄基)-1-(呋喃-2-基)-N-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲基)甲胺；
(7)1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-苄基-N-(异恶唑-5-基甲基)甲胺；
(8)1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(2-溴-4-氟苄基)-N-(异恶唑-5-基甲基)甲胺；
(9)1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(3-溴苯基)-N-(异恶唑-5-基甲基)甲胺；
(10)N-苄基-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(恶唑-5-基甲基)甲胺；
(11)N-(4-氟苄基)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(恶唑-5-基甲基)甲胺；
(12)N-(3-溴苯)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(恶唑-5-基甲基)甲胺；
(13)1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(4-氟苄基)-N-(噻唑-5-基甲基)甲胺；
(14)1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(2-溴-4-氟苄基)-N-(噻唑-5-基甲基)甲胺；
(15)1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(3-溴苯基)-N-(噻唑-5-基甲基)甲胺；
(16)N-苄基-1-(异噻唑-5-基)-N-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲基)甲胺；
(17)N-(2-溴-4-氟苄基)-1-(异噻唑-5-基)-N-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲基)甲胺；
(18)N-(3-溴苯)-1-(异噻唑-5-基)-N-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲基)甲胺；
(19)1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-苄基-N-(吡啶-2-基甲基)甲胺；
(20)1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(4-氟苄基)-N-(吡啶-2-基甲基)甲胺；
(21)1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(3-溴苯基)-N-(吡啶-2-基甲基)甲胺；
(22)N-(4-氟苄基)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(吡啶-3-基甲基)甲胺；
(23)N-(2-溴-4-氟苄基)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(嘧啶-4-基甲基)甲胺；
(24)N-(3-溴苯)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(嘧啶-5-基甲基)甲胺；
(25)N-((1H-吡唑-3-基)甲基)-1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-苄基甲胺；
(26)N-((1H-吡唑-3-基)甲基)-1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(2-溴-4-氟苄基)甲胺；
(27)N-((1H-吡唑-5-基)甲基)-1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(3-溴苯基)甲胺；
(28)N-((1H-吡唑基-5-基)甲基)-N-苄基-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲胺；
(29)N-((1H-吡唑基-4-基)甲基)-N-(4-氟苄基)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲胺；
(30)N-((1H-吡唑-4-基)甲基)-N-(3-溴苯基)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲胺。
一种药物组合物，包括上述的HIF-2α小分子抑制剂及其立体异构体、其药学上可接受的盐、水合物或溶剂化物和药学上可接受的载体和赋形剂。
所述的HIF-2α小分子抑制剂及其立体异构体或其药学上可接受的盐、水合物、溶剂化物或药物组合物在制备预防或治疗肿瘤药物中的应用。
进一步地，所述的肿瘤为胶质瘤。
进一步地，所述药物的剂型为药物治疗学上可接受的剂型。
进一步地，所述药物的剂量为药物治疗学上可接受的剂量。
下面的合成路线描述了本发明的通式Ⅰ化合物的合成工艺路线，所有的原料都是通过这些示意式中描述的方法、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示意式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。这些示意式中应用的全部可变因素如下文的定义或如权利要求中的定义。
以1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-苄基-N-(呋喃-2-基甲基)甲胺(A1)为例，合成方法如下所示，所有原料均为市售分析纯。
本发明可以含有上述通式Ⅰ的化合物的立体异构体及其药学上可接受的盐、水合物或溶剂化物作为活性成分，与药学上可接受的载体或赋形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形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分组合使用，只要它们不产生其他不利的作用，比如过敏反应。
除非另外指出，本发明所用的术语“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；“烯基”是指直链或支链的烯基；“炔基”是指直链或支链的炔基；“芳基”是指除去芳烃中的一个氢原子而得的有机基团，如苯基、萘基；5-10元杂芳基包括含有一个或多个选择N、O和S的杂原子，其中每个杂芳基的环状体系可以是单环或多环的，环状体系是芳香性，一共含有5-10个原子，可以举出例如咪唑基、吡啶基、嘧啶基、(1,2,3)-和(1,2,4)-三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噁唑基、吡唑基、吡咯基、噻唑基、苯并噻吩基、苯并呋喃基、苯并咪唑基、苯并噻唑基、吲哚基、喹啉基等；5-10元杂环基包括含有一个或多个选自N、O和S的杂原子，其中每个杂芳基的环状体系可以是单环或多环的，但是是非芳香性的，环状体系一共含有5-10个原子，可以任选包括1或2个碳碳双键或碳碳三键，可以举出例如吡咯烷基、吗啉基、哌嗪基、哌啶基、噻唑啉基等。
发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上课接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，而葡萄糖盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月硅酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N+(Cl-4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，Cl-8磺酸化物和芳香磺酸化物。
本发明的“溶剂合物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂合物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
当所述溶剂为水时，可以使用术语“水合物”。根据本发明的一个实施例，一个本发明化合物分子可以与一个水分子相结合，比如一水合物；根据本发明的一个实施例，一个本发明化合物分子可以与多于一个的水分子相结合，比如二水合物；根据本发明的一个实施例，一个本发明化合物分子可以与少于一个的水分子相结合，比如半水合物。应注意，本发明所述的水合物保留有非水合形式的所述化合物的生物有效性。
本发明化合物或其药物组合物可以单位剂量形式给药，给药途径可为倡导或非常道，如口入、静脉注射、肌肉注射、皮下注射、鼻腔，口腔黏膜、眼、肺和呼吸道、皮肤、阴道、直肠等，优选注射剂。
本发明化合物可以制成普通制剂，也可制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、润湿剂、黏合剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；黏合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各种稀释剂、润湿剂、黏合剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为了本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其他添加剂。
本发明还涉及通式Ⅰ的化合物具有强的抑制HIF-2α蛋白的作用，并且还涉及该类化合物及其药学上可接受的盐、水合物在由于HIF-2α高表达CSCs的生长所引起疾病的药物中的用途，特别是在制备治疗胶质瘤的药物中的用途。
本发明所述的“疾病”，包括但不限于以下疾病：癌，包括乳腺癌、卵巢癌、膀胱癌、脑癌、结肠癌、直肠癌、肾癌、肝癌、肺癌、胰腺癌、肾上腺癌、前列腺癌、胃癌、阴道癌、宫颈癌、子宫内膜癌、甲状腺癌和皮肤癌等。巴造血系统瘤，包括急性淋巴细胞白血病、B细胞淋巴瘤和Burketts淋巴瘤等；髓造血系统瘤，包括急性和慢性粒细胞性白血病和早幼粒细胞白血病；间质来源的瘤，包括纤维肉瘤及横纹肌肉瘤；其它肿瘤，包括黑色素瘤、精原细胞瘤、畸胎瘤、成神经细胞瘤、神经胶质瘤等。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明说使用的术语“预防”指获病或障碍的风险的减少(即：使疾病的至少一种临床症状在主体内停止发展，该主题可能面对或预先倾向面对这种疾病，但还没有经历或表现出疾病的症状)。
本发明说使用的术语“治疗“任何疾病或病症，在其中一些实施例中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施例中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施例中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施例中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
与现有技术相比，本发明的有益效果如下。
(1)本发明通过实验研究首次提出本发明如结构通式I所示的一类小分子抑制剂，主要通过抑制HIF-2α蛋白进而抑制肿瘤细胞的增殖，可作为一种新的抗肿瘤药物来彻底清除肿瘤。
(2)本发明提红的HIF-2α小分子抑制剂以三唑并吡嗪为母核，属于芳香胺类，与脂肪胺相比，毒性降低。
(3)本发明提供的小分子抑制剂对HIF-1α的表达无明显的抑制作用，证实是HIF-2α的特异性的抑制剂，具有靶向的专一性。
(4)现有的HIF-2α抑制剂主要用于肾癌，本发明提供的HIF-2α小分子抑制剂的抗癌谱较广，对多种癌症细胞具有生长抑制作用，尤其对于星形胶质瘤细胞具有良好的抑制作用。
附图说明
图1为本发明提供的一类HIF-2α小分子抑制剂的结构通式。
具体实施方式
为了更好地解释本发明，以下结合具体实施例对本发明作进一步的详细说明，但它们不对本发明构成限定。实施例旨在阐述而不是限制本发明的范围。所述的化合物经高效液相色谱(HPLC)、薄层色谱(TLC)进行检测。随后可以采用诸如红外光谱(IR)、核磁共振波谱(1H NMR，13C NMR)，高分辨质谱(HRMS)等确证其结构。所用试剂均为分析纯或化学纯。
一类HIF-2α小分子抑制剂，所述的HIF-2α小分子抑制剂为如结构通式Ⅰ所示的化合物及其立体异构体、药学上可接受的盐、水合物、溶剂化物或前药，
其中：
m代表0、1、2或3；n代表0、1、2或3；x代表0、1、2或3；
R1、R2相同或者不同，分别独立地选自氢、三氟甲基、(C1～C4)烷基；
R3选自1～4个相同或不同的氢、卤素；
X为CH或N；
Y为五元或六元(芳)杂环，所述杂环分别含有1～3个任选自N、O、S的杂原子，且还任选被1～3个相同或不同的R4取代；
R4分别独立地选自为1～4个相同或不同的氢、卤素、羟基、三氟甲基、三幅甲氧基、氨基、叠氮基、硝基、氰基、巯基、(C1-C4)烷基、(C3-C6)环烷基、(C1-C4)烯基、(C1-C4)炔基、(C1-C4)烷氧基、(C1-C4)烷硫基、烯丙基、(2-甲基)烯丙基、(C1-C4)烷氧基甲基、(C1-C4)烷基酰基、(C1-C3)亚烷基二氧基的取代基。
实施例1 1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-苄基-N-(呋喃-2-基甲基)甲胺(A1)的制备。
步骤1、将3-溴-2-氯嘧啶(10g，0.052mol)溶于甲苯(200ml)中，降温至-65℃，逐滴加入DMF(二甲基甲酰胺)(6.2ml，0.08mol)，滴毕，滴加正丁基锂(1.57M溶于正己烷的溶液；51mL，0.08mol)。搅拌20分钟后，用1N盐酸终止反应，然后用乙酸乙酯萃取反应液，水洗有几层，无水硫酸镁干燥、过滤，浓缩至尽干，得产物(中间体a)无需进一步纯化即可用于下一步。
步骤2、在室温下，向溶于乙醇(30mL)的中间体a的溶液中缓慢分批加入硼氢化钠(2g，0.052mol)，加毕后搅拌30分钟。用36％冰醋酸溶液终止反应后，用乙酸乙酯萃取，无水硫酸镁干燥、过滤，浓缩有机层至干。残留物通过柱色谱法提纯得到黄色粉末(中间体b)(5.6g，75％)。
步骤3、将步骤2制得的中间体b(10g，0.07mol)溶于DMF(50mL)，降温至0℃，搅拌下逐滴滴加二氯亚砜(9.2g，0.77mol)。滴毕，室温反应1小时，TLC监测。用乙酸乙酯(40mL)稀释反应液，然后添加水终止反应，有机层用无水硫酸镁干燥、过滤，浓缩至干以得到中间体c，该产物无需进一步纯化即可用于下一步。
步骤4、将步骤3制得的中间体c的溶液(10g)，用水合肼(10.5g，0.21mol)少量多次加入其中，并于85℃回流，TLC监测反应完全。反应液冷却后，加入冰水中搅拌，析出固体抽滤，滤饼干燥得黄色粉末(中间体d)(9.66g，87％)。
步骤5、将步骤4制得的中间体d(5g，0.063mol)加至原甲酸三乙酯(50ml)中，80℃下反应，TLC监测反应完全。反应液冷却后直接抽滤，用石油醚洗涤滤饼，滤饼干燥后得黄色粉末(中间体e)(9.6g，90％)。
步骤6、于250ml的茄形瓶加入糠醛(9.6g,0.1mol)和甲醇(90ml)，后置于冰浴中搅拌，待温度下降至0℃后搅拌中少量多次加入硼氢化钠(3.78g,0.1mol)待无气泡后，加入苄胺(10.71g,0.1mol)，撤去冰浴，室温搅拌6小时，蒸干溶剂，得油状物(中间体f，17.8g，95.0％)。该产物无需进一步纯化即可用于下一步。
步骤7于250ml的茄形瓶加入步骤5制得的中间体e(2g,0.01mol)，碳酸钾(1.38g，0.01mol)，碘化钾(0.166g,0.001mol)和N,N-二甲基甲酰胺90ml，室温搅拌15min后加入步骤6制得的中间体f(1.87g,0.01mol)，置于油浴加热至85℃搅拌1h后，撤油浴，冷却至室温，加水溶解，用乙酸乙酯萃取水层2次后合并有机相，饱和食盐水洗涤后收集有机层，无水硫酸钠干燥有机层，得乳白色固体A1(2.65g，83.0％)。ESI-MS m/z：319.37；1H-NMR(400MHz，DMSO-d6)δ9.15(s,1H),8.36(d,J＝2.7Hz,1H),7.69(d,J＝2.7Hz,1H),7.36(d,J＝4.2Hz,1H),7.21-7.25(m,5H),6.65(d,J＝1.3Hz,1H),6.32(t,J＝1.3Hz,J＝4.2Hz,1H),4.19(s,1H),3.96(s,1H),3.74(s,2H),3.58(s,2H)。
实施例2 1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(4-氟苄基)-N-(呋喃-2-基甲基)甲胺(A2)的制备。
制备方法同实施例1，ESI-MS m/z：337.36；1H-NMR(400MHz，DMSO-d6)δ9.13(s,1H),8.36(d,J＝2.7Hz,1H),7.68(d,J＝2.7Hz,1H),7.44(dd,J＝0.32Hz,2H),7.36(d,J＝4.3Hz,1H),7.07(t,2H),6.52(d,J＝0.88Hz,1H),6.30(t,J＝0.88Hz,J＝4.3Hz,1H),3.99(s,2H),3.82(s,2H),3.54(s,2H)。
实施例3 1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(3-溴苯基)-N-(呋喃-2-基甲基)甲胺(A3)的制备。
制备方法同实施例1，ESI-MS m/z：398.26。
实施例4N-苄基-1-(呋喃-2-基)-N-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲基)甲胺(A4)的制备。
制备方法同实施例1，ESI-MS m/z：333.4。
实施例5N-(4-氟苄基)-1-(呋喃-2-基)-N-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲基)甲胺(A5)的制备。
制备方法同实施例1，ESI-MS m/z：351.39。
实施例6N-(2-溴-4-氟苄基)-1-(呋喃-2-基)-N-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲基)甲胺(A6)的制备。
制备方法同实施例1，ESI-MS m/z：430.28。
实施例7 1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-苄基-N-(异恶唑-5-基甲基)甲胺(A7)的制备。
制备方法同实施例1，ESI-MS m/z：320.36。
实施例8 1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(2-溴-4-氟苄基)-N-(异恶唑-5-基甲基)甲胺(A8)的制备。
制备方法同实施例1，ESI-MS m/z：417.24。
实施例9 1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(3-溴苯基)-N-(异恶唑-5-基甲基)甲胺(A9)的制备。
制备方法同实施例1，ESI-MS m/z：399.25。
实施例10N-苄基-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(恶唑-5-基甲基)甲胺(A10)的制备。
制备方法同实施例1，ESI-MS m/z：334.38。
实施例11N-(4-氟苄基)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(恶唑-5-基甲基)甲胺(A11)的制备。
制备方法同实施例1，ESI-MS m/z：352.37。
实施例12N-(3-溴苯)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(恶唑-5-基甲基)甲胺(A12)的制备。
制备方法同实施例1，ESI-MS m/z：413.28。
实施例13 1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(4-氟苄基)-N-(噻唑-5-基甲基)甲胺(A13)的制备。
制备方法同实施例1，ESI-MS m/z：354.41。
实施例14 1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(2-溴-4-氟苄基)-N-(噻唑-5-基甲基)甲胺(A14)的制备。
制备方法同实施例1，ESI-MS m/z：433.3。
实施例15 1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(3-溴苯基)-N-(噻唑-5-基甲基)甲胺(A15)的制备。
制备方法同实施例1，ESI-MS m/z：415.31。
实施例16 N-苄基-1-(异噻唑-5-基)-N-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲基)甲胺(A16)的制备。
制备方法同实施例1，ESI-MS m/z：350.44。
实施例17 N-(2-溴-4-氟苄基)-1-(异噻唑-5-基)-N-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲基)甲胺(A17)的制备。
制备方法同实施例1，ESI-MS m/z：447.33。
实施例18 N-(3-溴苯)-1-(异噻唑-5-基)-N-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲基)甲胺(A18)的制备。
制备方法同实施例1，ESI-MS m/z：429.34。
实施例19 1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-苄基-N-(吡啶-2-基甲基)甲胺(A19)的制备。
制备方法同实施例1，ESI-MS m/z：330.4。
实施例20 1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(4-氟苄基)-N-(吡啶-2-基甲基)甲胺(A20)的制备。
制备方法同实施例1，ESI-MS m/z：348.39。
实施例21 1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(3-溴苯基)-N-(吡啶-2-基甲基)甲胺(A21)的制备。
制备方法同实施例1，ESI-MS m/z：409.29。
实施例22 N-(4-氟苄基)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(吡啶-3-基甲基)甲胺(A22)的制备。
制备方法同实施例1，ESI-MS m/z：462.41。
实施例23 N-(2-溴-4-氟苄基)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(嘧啶-4-基甲基)甲胺(A23)的制备。
制备方法同实施例1，ESI-MS m/z：442.3。
实施例24 N-(3-溴苯)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(嘧啶-5-基甲基)甲胺(A24)的制备。
制备方法同实施例1，ESI-MS m/z：424.31。
实施例25 N-((1H-吡唑-3-基)甲基)-1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-苄基甲胺(A25)的制备。
制备方法同实施例1，ESI-MS m/z：319.37。
实施例26 N-((1H-吡唑-3-基)甲基)-1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(2-溴-4-氟苄基)甲胺(A26)的制备。
制备方法同实施例1，ESI-MS m/z：416.26。
实施例27 N-((1H-吡唑-5-基)甲基)-1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(3-溴苯基)甲胺(A27)的制备。
制备方法同实施例1，ESI-MS m/z：398.27。
实施例28 N-((1H-吡唑基-5-基)甲基)-N-苄基-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲胺(A28)的制备。
制备方法同实施例1，ESI-MS m/z：333.4。
实施例29 N-((1H-吡唑基-4-基)甲基)-N-(4-氟苄基)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲胺(A29)的制备。
制备方法同实施例1，ESI-MS m/z：351.39。
实施例30 N-((1H-吡唑-4-基)甲基)-N-(3-溴苯基)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲胺(A30)的制备。
制备方法同实施例1，ESI-MS m/z：412.3。
本发明实施例1～30制备的HIF-2α小分子抑制剂的化合物的结构式如表1所示。
表1.实施例1～30制备的HIF-2α小分子抑制剂的化合物的结构式。
实施例31实施例1-30制备的HIF-2α小分子抑制剂体外抗肿瘤细胞活性研究实验。
对按照本发明的所述结构通式Ⅰ的化合物(实施例1-30制备的HIF-2α小分子抑制剂)进行了体外抑制人脑星形胶质细胞瘤U118-MG、U-87MG和U251-MG活性筛选。
1实验材料。
1.1细胞与试剂。
人脑星形胶质瘤细胞U118-MG、人脑星形胶质瘤细胞U87-MG和人脑星形胶质瘤细胞U251-MG，DMEM培养基，Trypsin-EDTA(0.05％)，胎牛血清(FBS)，二甲基亚砜(DMSO)，噻唑蓝(MTT)。
2实验方法。
2.1细胞培养。
自液氮中取出U118-MG,U87-MG和U251-MG细胞，37℃的水浴融化，1000rpm离心5min，去除上清，分别加入10％胎牛血清的DMEM培养基1mL，将细胞悬液移入25cm2细胞培养瓶中，再加入10％胎牛血清的培养基4mL培养。
2.2MTT细胞增殖分析。
取对数生长期的人脑星形胶质瘤细胞(U118-MG、U87-MG和U251-MG)，消化，用含10％胎牛血清的DMEM培养基(购自美国Hyclone公司)调整细胞浓度为2×104个/mL的单细胞悬液，接种于96孔板，每孔细胞数为2×103个，细胞过夜培养，使之贴壁，弃培养液，每孔给予100μL含不同浓度的受试样品(分别为0.1μM、0.3μM、1μM、3μM、10μM、30μM、100μM、300μM、1000μM、3000μM)或不同浓度的阳性药(分别为0.1μM、0.3μM、1μM、3μM、10μM、30μM、100μM、300μM、1000μM、3000μM)的培养基，每个浓度设3个复孔，实验设空白组、溶剂对照组、阳性对照组和实验组。96孔板置于37℃，5％CO2培养箱培养48h；每孔加入5mg/mL的MTT溶液20μL，继续培养2h，小心吸取弃各孔溶液，再每孔加入DMSO溶液100μL，避光，摇床摇晃10min；用酶标仪在波长570nm(检测MTT)处测量吸光度，计算药物的半数毒性浓度(IC50)。按下列公式计算生长抑制率：生长抑制率(％)＝[1-(加药孔-调零孔)/(对照孔-调零孔)]*100％；用SPSS22.0软件计算IC50，实验重复三次。
实施例1-30制备的HIF-2α小分子抑制剂对人脑星形胶质瘤细胞(U118、U87和U251)的半数抑制浓度(IC50)结果见表2。
表2.实施例1-30制备的HIF-2α小分子抑制剂对人脑星形胶质瘤细胞(U118、U87和U251)的半数抑制浓度(IC50)结果。
从上述试验结果可以清楚地看出，本发明提供的如结构通式Ⅰ所示的化合物具有良好的体外抗肿瘤活性，部分活性较好的化合物相当或优于阳性对照药TMZ，因此为深入研究和开发新的抗肿瘤药物开辟了新的途径。
以上所述为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (4)
1.一类化合物及其药学上可接受的盐，结构选自下述任意一种：
1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-苄基-N-呋喃-2-基甲基)甲胺；
1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(4-氟苄基)-N-(呋喃-2-基甲基)甲胺；
1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(3-溴苄基)-N-(呋喃-2-基甲基)甲胺；
N-苄基-1-(呋喃-2-基)-N-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲基)甲胺；
N-(4-氟苄基)-1-(呋喃-2-基)-N-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲基)甲胺；
N-(2-溴-4-氟苄基)-1-(呋喃-2-基)-N-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲基)甲胺；
1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-苄基-N-(异恶唑-5-基甲基)甲胺；
1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(2-溴-4-氟苄基)-N-(异恶唑-5-基甲基)甲胺；
1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(3-溴苄基)-N-(异恶唑-5-基甲基)甲胺；
N-苄基-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(恶唑-5-基甲基)甲胺；
N-(4-氟苄基)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(恶唑-5-基甲基)甲胺；
N-(3-溴苄基)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(恶唑-5-基甲基)甲胺；
1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(4-氟苄基)-N-(噻唑-5-基甲基)甲胺；
1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(2-溴-4-氟苄基)-N-(噻唑-5-基甲基)甲胺；
1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(3-溴苄基)-N-(噻唑-5-基甲基)甲胺；
N-苄基-1-(异噻唑-5-基)-N-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲基)甲胺；
N-(2-溴-4-氟苄基)-1-(异噻唑-5-基)-N-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲基)甲胺；
N-(3-溴苄基)-1-(异噻唑-5-基)-N-((3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲基)甲胺；
1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-苄基-N-(吡啶-2-基甲基)甲胺；
1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(4-氟苄基)-N-(吡啶-2-基甲基)甲胺；
1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(3-溴苄基)-N-(吡啶-2-基甲基)甲胺；
N-(4-氟苄基)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(吡啶-3-基甲基)甲胺；
N-(2-溴-4-氟苄基)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(嘧啶-4-基甲基)甲胺；
N-(3-溴苄基)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(嘧啶-5-基甲基)甲胺；
N-((1H-吡唑-3-基)甲基)-1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-苄基甲胺；
N-((1H-吡唑-3-基)甲基)-1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(2-溴-4-氟苄基)甲胺；
N-((1H-吡唑-5-基)甲基)-1-([1,2,4]三唑并[4,3-a]吡嗪-8-基)-N-(3-溴苄基)甲胺；
N-((1H-吡唑-5-基)甲基)-N-苄基-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲胺；
N-((1H-吡唑-4-基)甲基)-N-(4-氟苄基)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲胺；
N-((1H-吡唑-4-基)甲基)-N-(3-溴苄基)-1-(3-甲基-[1,2,4]三唑并[4,3-a]吡嗪-8-基)甲胺。
2.如权利要求1所述的化合物及其药学上可接受的盐，其特征在于，所述化合物在制备预防或治疗胶质瘤药物中的应用。
3.如权利要求2所述的化合物及其药学上可接受的盐，所述药物的剂型为药物治疗学上可接受的剂型。
4.如权利要求2所述的化合物及其药学上可接受的盐，所述药物的剂量为药物治疗学上可接受的剂量。
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