CN106279045A - 环丙烷衍生物及其制备方法和在医药上的应用 - Google Patents
环丙烷衍生物及其制备方法和在医药上的应用 Download PDFInfo
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- CN106279045A CN106279045A CN201510237458.3A CN201510237458A CN106279045A CN 106279045 A CN106279045 A CN 106279045A CN 201510237458 A CN201510237458 A CN 201510237458A CN 106279045 A CN106279045 A CN 106279045A
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- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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Abstract
本发明涉及一种环丙烷衍生物及其制备方法和在医药上的应用，具体而言本发明涉及通式(I)所示的化合物或者其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或者前药、它们的制备方法、包括其药物组合物以及本发明的化合物药物组合物在医药上的用途，特别作为EGFR靶点抑制剂的用途，
Description
技术领域
本发明涉及一种环丙烷衍生物及其制备方法和在医药上的应用，具体是一种具有EGFR靶点抑制作用的新颖环丙烷衍生物或其立体异构体、水合物、溶剂化物、代谢产物、药学上可接受的盐、共晶或前药、其药物组合物以及其在医药上的应用。
背景技术
细胞表面受体中的受体酪氨酸激酶超家族通过细胞外生长因子对细胞信号的调节起重要的作用。受体酪氨酸激酶能够催化磷酸基团从ATP转移至底物的酪氨酸基团上。当没有配体激活受体酪氨酸激酶时，这些激酶处于未磷酸化的单体状态，其激酶域呈非活性的结构。当配体与受体酪氨酸激酶的胞外段结合时，受体发生寡聚化，并且自磷酸化，增加激酶的催化活性的同时形成了信号蛋白的结合位点，信号蛋白与其结合，从而激活多条信号通路。这些信号通路相互联系，调控细胞的增殖、生存、分化、功能、迁移和凋亡。当受体酪氨酸激酶失去调控，异常激活时，细胞会发生转化成肿瘤细胞，增殖、生长能力和耐药能力提高，具有较强的成血管能力、侵袭力和转移能力(Yarden和Sliwkowski,2001,Nat Rev Mol Cell Biol,2,127-137)。
ErbB家族属于受体酪氨酸激酶，包含四个成员：表皮生长因子受体(EGFR/HER1/ErbB1)、HER2(neu/ErbB2)、HER3(ErbB3)和HER4(ErbB4)(Olayioye,Neve等,2000,EMBO J,19,3159-3167；Yarden和Sliwkowski,2001,Nat Rev Mol Cell Biol,2,127-137)。它们都含有胞外配体结合域、单跨膜域和胞内酪氨酸激酶和调节域。其功能是催化ATP的磷酸基转移至底物蛋白的酪氨酸基团上。配体依赖的受体寡聚化导致受体调节域的自磷酸化，从而发生胞内信号转导，最终引起细胞增殖。该信号通路与肿瘤的发生和发展密切相关。在多种肿瘤中，超活化的ErbB受体，尤其是EGFR，会导致生长因子信号的失调控。EGFR的激活通常是由于过表达或突变引起的持续活化或配体的自分泌表达。因此抑制EGFR是一个备受关注的抗肿瘤策略。许多靶向EGFR的小分子抑制剂相继被开发，其中一些已经运用于临床治疗。
第一代的EGFR激酶抑制剂如吉非替尼、厄罗替尼在临床上能有效治疗非小细胞 肺癌，尤其是那些含有EGFR激酶域发生激活突变的非小细胞肺癌(Mok,Wu等,2009,N Engl J Med,361,947-957；Rosell,Moran等,2009,N Engl J Med,361,958-967)。最常见的EGFR激活突变是L858R和delE746_A750，相对于野生型的EGFR，这些突变能够增加受体对吉非替尼和厄罗替尼的亲和力，而降低受体对ATP的亲和力(Carey,Garton等,2006,Cancer Res,66,8163-8171；Yun,Boggon等,2007,Cancer Cell,11,217-227)。
第二代的EGFR激酶抑制剂普遍具有喹啉结构，是不可逆的EGFR抑制剂。不同于吉非替尼，它们含有亲电子能力，能够与EGFR中保守的半胱氨酸基团(Cys 797)发生迈克尔加成反应。这些化合物的共价性质使它们相较于可逆的抑制剂，具有更强的占据ATP位点的能力，因此，尽管T790M突变能够增加ATP的亲和力，这类抑制剂在临床前模型中还是足以抑制EGFR T790M(Engelman,Zejnullahu等,2007,Cancer Res,67,11924-11932；Li,Ambrogio等,2008,Oncogene,27,4702-4711)。第二代的EGFR激酶抑制剂以阿法替尼(Afatinib)，Dacomitinib(PF-00299804)和来那替尼(Neratinib)为代表。三者均为EGFR和HER2的不可逆抑制剂，治疗机理除竞争性地占据EGFR上ATP结合位点外，还能与EGFR结合口袋开口处附近所特有氨基酸残基发生烷基化作用或共价键结合，进而实现对EGFR的不可逆抑制。
随着第一代EGFR激酶抑制剂的持续使用，日益凸显的耐药性成为不可回避的问题。由于获得性耐药的出现，吉非替尼和厄罗替尼的运用最终受到了限制。超过50％的肺癌患者都会出现获得性耐药，其中超过90％都含有EGFR的T790M看门残基突变(Kobayashi,Boggon等,2005,N Engl J Med,352,786-792；Pao,Miller等,2005,PLoS Med,2,e73)。T790M突变并非从空间构象上阻碍药物的结合，而是恢复受体对ATP的亲和力，与野生型相当(Yun,Mengwasser等,2008,Proc Natl Acad Sci U S A,105,2070-2075)。第二代的EGFR激酶抑制剂可通过共价结合克服上述突变带来的问题，大幅升高药物浓度并提供持续的封闭效应，增强对肿瘤细胞的持久抑制。另外，明显的皮肤毒性(如痤疮样皮疹)也是第一代EGFR激酶抑制剂所面临的难题。第二代EGFR激酶抑制剂(如Afatinib)在这方面有了较好的改善。为了满足临床需求，需要继续研发新的能够有效克服T790M突变的EGFR抑制剂。
目前已有多篇文献报道了蛋白激酶抑制剂及其抗肿瘤的用途。如：
CN102731485公开了可作为EGFR抑制剂的喹唑啉衍生物及其制备方法、药物 组合物和用途。结构如下所示：
其中R1选自苯环或取代的苯环，R2选自氢或N，N-二甲氨基甲基，R3选自甲氧乙基、四氢呋喃-3-基、(S)-四氢呋喃-3-基或(R)-四氢呋喃-3-基。
WO2012159457公开了一种喹唑啉衍生物类酪氨酸激酶抑制剂及其制备方法与应用。结构如下所示：
其中R1选自未被取代或被1-3个相同或不同的取代的以下一组基团：C1-6烷基、C3-6烯基、C3-6炔基、C3-8环烷基C0-6烷基、6-10元并环基C6烷基、7-10元螺环基C0-6烷基和7-10元桥环基C0-6烷基等；R2选自未被取代或被1～2个相同或不同的Q2取代的以下一组基团：C3-4环烷基C0-6烷基、6-10元并环基C0-6烷基、7-10元螺环基C0-6烷基和7-10元桥环基C6烷基，且所述环烷基、并环基、螺环基和桥环基中的碳原子可以被1-3个相同或不同的O、S(O)m、N(H)n和/或C(O)替换，但经替换后的环中不存在"-O-C(O)-"酯结构，而且当R2为7-10元桥环基CQ-6烷基时，R1不为C3-4环烷基C0-6烷基或C1-6烷基；Q2选自下列一组基团：卤素原子，羟基，氨基，羧基，氰基，硝基，三氟甲基，d.6烷基，C1-6烷氧基，C1-6烷基氨基，二(C1-6烷基)氨基，C1-6烷基羰氧基，C1-6烷氧基羰基，C1-6烷基酰氨基，C1-6烷基磺酰基，C1-6烷基亚磺酰基和C1-6烷基磺酰氨基。
CN102898386公开了一种喹唑啉衍生物、其制备方法、中间体、组合物及其应用。结构如下所示：
其中R1为取代或未取代的C6～C10芳基或取代或未取代的C3～C12杂芳基，R2为氢、卤素、羟基、氨基、C1～C6烷基或C1～C6卤代烷基、C2～C6链烯基、C2～C6炔基、C1～C6烷氧基、C1～C6烷氧基取代的C1～C6烷氧基、3-8元环烷基氧基、C2～C6链烯基氧基、C2～C6炔基氧基、2-7个碳原子的烷氧基甲基、C1～C6烷硫基、C1～C6烷基亚磺酰基、C1～C6烷基磺酰基、C1～C6烷基亚磺酰胺基、氰基、羧基、2-7个碳原子的烷氧羰基烷基、2-7个碳原子的烷氧羰基烷氧基、C1～C6烷基氨基、2-12个碳原子的二烷基氨基、1-6个碳原子的N-烷基氨基甲酰基、2-12个碳原子的N，N-二烷基氨基甲酰基、R5-(CH2)a-Y-、R5-(CH2)b-Z-(CH2)a-Y-或Het-W-(CH2)a-Y-；X为卤素原子，R3和R4各自独立地为氢、C1～C6烷基、R6R7N-(CH2)c-、R6R7N-(CH2)c-Y-(CH2)b-或Het-W-(CH2)d-。
发明内容
本发明的目的在于提供一种新颖的具有EGFR抑制剂活性的取代环丙烷衍生物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药及其在制备治疗癌症相关药物中的用途。
本发明提供一种通式(I)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中：
R1 独立选自选自F、Cl、Br、三氟甲基、甲基、乙基、乙炔基、-OCH2-苯环、-OCH2-噻唑或-OCH2-吡啶，优选F、Cl、Br、三氟甲基或乙炔基，更优选F或Cl，所述的苯环、噻唑或吡啶任选进一步被0、1、2、3或4个选自F、Cl、Br、甲基或三氟甲基的取代基所取代；
R2选自选自H、F、Cl、Br、甲氧基、乙氧基、甲氧乙氧基或优选H、甲氧基、乙氧基或更优选
n选自0、1、2、3、4或5，优选1、2或3。
本发明优选方案，一种通式(I)所述的化合物，其中该化合物选自如下结构之一：
根据本发明的具体实施方案，本发明的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中所述的盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、醋酸盐、三氟乙酸盐、硫氰酸盐、马来酸盐、羟基马来酸盐、戊二酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、苯甲酸盐、水杨酸盐、苯乙酸盐、肉桂酸盐、乳酸盐、丙二酸盐、特戊酸盐、琥珀酸盐、富马酸盐、苹果酸盐、扁桃酸盐、酒石酸盐、没食子酸盐、葡萄糖酸盐、月桂酸盐、棕榈酸盐、果胶酸盐、苦味酸盐、柠檬酸盐或者它们的组合；优选的，所述的盐选自盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、醋酸盐、马来酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、苯甲酸盐、水杨酸盐、肉桂酸盐、乳酸盐、丙二酸盐、琥珀酸盐、富马酸盐、苹果酸盐、酒石酸盐、柠檬酸盐或者它们的组合。
本发明还提供了一种药物组合物，所述的组合物包括：有效剂量的本发明所述的 化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，以及药学上可接受的载体、稀释剂、佐剂、媒介物或赋形剂；所述的组合物还可进一步包括一种或多种其他治疗剂。
根据本发明的具体实施方案，本发明的药物组合物中所述的其他治疗剂包括：顺铂(cisplatin)、卡铂(carboplatin)、奥沙利铂(oxaliplatin)、达卡巴嗪(dacarbazine)、替莫唑胺(temozolomide)、丙卡巴肼(procarbazine)、甲氨蝶呤(methotrexate)、氟尿嘧啶(fluorouracil)、阿糖胞苷(cytarabine)、吉西他滨(gemcitabine)、巯基嘌呤(mercaptopurine)、氟达拉滨(fludarabine)、长春碱(vinblastine)、长春新碱(vincristine)、长春瑞滨(vinorelbine)、紫杉醇(paclitaxel)、多西紫杉醇(docetaxel)、拓扑替康(topotecan)、伊立替康(irinotecan)、依托泊苷(etoposide)、曲贝替定(trabectedin)、更生霉素(dactinomycin)、多柔比星(doxorubicin)、表柔比星(epirubicin)、道诺霉素(daunorubicin)、米托蒽醌(mitoxantrone)、博来霉素(bleomycin)、丝裂霉素C(mitomycin)、伊沙匹隆(ixabepilone)、他莫昔芬(tamoxifen)、氟他胺(flutamide)、西罗莫司(sirolimus)、阿法替尼(afatinib)、alisertib、amuvatinib、阿帕替尼(apatinib)、阿西替尼(axitinib)、硼替佐米(bortezomib)、波舒替尼(bosutinib)、布立尼布(brivanib)、卡博替尼(cabozantinib)、西地尼布(cediranib)、crenolanib、克卓替尼(crizotinib)、达拉非尼(dabrafenib)、达可替尼(dacomitinib)、达鲁舍替(danusertib)、达沙替尼(dasatinib)、多韦替尼(dovitinib)、厄洛替尼(erlotinib)、foretinib、ganetespib、吉非替尼(gefitinib)、依鲁替尼(ibrutinib)、埃克替尼(icotinib)、伊马替尼(imatinib)、iniparib、拉帕替尼(lapatinib)、lenvatinib、linifanib、linsitinib、马赛替尼(masitinib)、momelotinib、莫替沙尼(motesanib)、来那替尼(neratinib)、尼罗替尼(nilotinib)、尼拉帕尼(niraparib)、oprozomib、奥拉帕尼(olaparib)、帕唑帕尼(pazopanib)、pictilisib、帕纳替尼(ponatinib)、奎扎替尼(quizartinib)、瑞格非尼(regorafenib)、氯构色替(rigosertib)、rucaparib、鲁索替尼(ruxolitinib)、塞卡替尼(saracatinib)、saridegib、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、替拉替尼(telatinib)、tivantinib、替肟扎尼(tivozanib)、托法替尼(tofacitinib)、曲美替尼(trametinib)、凡德他尼(vandetanib)、维利帕尼(veliparib)、威罗菲尼(vemurafenib)、维莫德吉(vismodegib)、volasertib、阿仑单抗(alemtuzumab)、贝伐单抗(bevacizumab)、布妥昔单抗(brentuximab vedotin)、卡妥索单抗(catumaxomab)、西 妥昔单抗(cetuximab)、地诺单抗(denosumab)、吉妥珠单抗(gemtuzumab)、伊匹单抗(ipilimumab)、尼妥珠单抗(nimotuzumab)、奥法木单抗(ofatumumab)、帕尼单抗(panitumumab)、利妥昔单抗(rituximab)、托西莫单抗(tositumomab)、曲妥珠单抗(trastuzumab)或它们的组合。
本发明还提供了所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药或者所述的药物组合物在作为一种EGFR受体酪氨酸激酶抑制剂在制备药物制剂的应用，特别是在用于制备用于治疗和/或预防过度增殖性疾病的药物制剂中的应用。
根据本发明的具体实施方案，本发明的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药或者所述的药物组合物的应用中，所述过度增殖性疾病包括脑瘤、非小细胞肺癌、表皮鳞癌、膀胱癌、胰腺癌、结肠癌、乳腺癌、卵巢癌、子宫颈癌、子宫内膜癌、结直肠癌、肾癌、食管腺癌、食管鳞状细胞癌、实体瘤、非霍奇金淋巴瘤、肝癌、肺癌，胃癌、皮肤癌、甲状腺癌、头颈癌、前列腺癌、神经胶质瘤和鼻咽癌中的一种或多种；优选非小细胞肺癌、乳腺癌、表皮鳞癌、胃癌和结肠癌的一种或多种。
具体实施方式
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果，旨在帮助阅读者更好地理解本发明的实质和特点，不作为对本案可实施范围的限定。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。
NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18100×4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.20mm，薄层层析分离纯化产品采用 的规格是0.4mm～0.5mm。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。
氮气氛是指反应瓶连接一个约1L容积的氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
氢化反应通常抽真空，充入氢气，反复操作3次。
实施例中无特殊说明，反应在氮气氛下进行。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温。
室温为最适宜的反应温度，为20℃～30℃。
M为摩尔每升。
实施例1：N-[4-(3-氯-4-氟-苯氨基)-7-[(3S)-四氢呋喃-3-基]氧基-喹唑啉-6-基]-2-环丙基-丙-2-烯酰胺(化合物1)
N-[4-(3-chloro-4-fluoro-anilino)-7-[(3S)-tetrahydrofuran-3-yl]oxy-quinazolin-6-yl]-2-cyclopropyl-prop-2-enamide
第一步：2-(三氟甲磺酸基)丙-2-烯酸甲酯(1B)
methyl 2-(trifluoromethylsulfonyloxy)prop-2-enoate
将2-羰基丙酸甲酯(1A)(5.0g,4.9mmol)溶于二氯甲烷(50mL)中，氮气保护。0℃加入三氟甲磺酸酐(13.8g,4.9mmol)，再加入N,N-二异丙基乙基胺(6.3g,4.9mmol)，室温反应2小时。反应液加入水(50mL)，萃取分层。水相用二氯甲烷(50mL×1)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。残留物用硅胶柱色谱分离提纯(乙酸乙酯：石油醚(v/v)＝0:1～1:99)，得到标题化合物2-(三氟甲磺酸基)丙-2-烯酸甲酯(1B)，无色油状(4g，产率35％)。
1H NMR(400MHz,CDCl3)δ6.33(d,1H),5.85(d,1H),3.90(s,3H).
第二步：2-环丙基丙-2-烯酸甲酯(1C)
methyl 2-cyclopropylprop-2-enoate
将2-(三氟甲磺酸基)丙-2-烯酸甲酯(1B)(2g,8.5mmol)、环丙基硼酸(1.1g,12.8mmol)、磷酸钾(2.72g,12.8mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(0.62g, 0.85mmol)加入到四氢呋喃(10mL)中，80℃微波反应2小时。反应液浓缩，加入水(20mL)，萃取分层。水相用(20mL×1)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。残留物用硅胶柱色谱分离提纯(乙酸乙酯：石油醚(v/v)＝1:19～1:5)，得到标题化合物2-环丙基丙-2-烯酸甲酯(1C)，无色液体(0.60g，产率55.6％)。
1H NMR(400MHz,CDCl3)δ6.02(d,1H),5.31(t,1H),3.78(s,3H),1.75(m,1H),0.82–0.76(m,2H),0.54–0.45(m,2H).
第三步：2-环丙基丙-2-烯酸(1D)
2-cyclopropylprop-2-enoic acid
将2-环丙基丙-2-烯酸甲酯(1C)(1.0g,7.9mmol)溶于四氢呋喃(5mL)和水(5mL)中，加入氢氧化锂一水合物(0.95g,40mmol)，60℃反应3小时。反应液加入二氯甲烷(10mL)和水(10mL)，萃取。水相用4M盐酸调节pH至2～3，用二氯甲烷(10mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到标题化合物2-环丙基丙-2-烯酸(1D)，无色液体(0.50g，产率56％)。
1H NMR(400MHz,CDCl3)δ10.50(s,1H),6.19(d,1H),5.43(s,1H),1.75(m,1H),0.86–0.77(m,2H),0.57–0.49(m,2H).
第四步：N-[4-(3-氯-4-氟-苯氨基)-7-[(3S)-四氢呋喃-3-基]氧基-喹唑啉-6-基]-2-环丙基-丙-2-烯酰胺(化合物1)
N-[4-(3-chloro-4-fluoro-anilino)-7-[(3S)-tetrahydrofuran-3-yl]oxy-quinazolin-6-yl]-2-cyclopropyl-prop-2-enamide
将2-环丙基丙-2-烯酸(1D)(0.132g,1.17mmol)溶于吡啶(8mL)中，加入N4-(3- 氯-4-氟-苯基)-7-[(3S)-四氢呋喃-3-基]氧基-喹唑啉-4,6–二胺(1E)(0.200g,0.534mmol)，加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.511g,2.67mmol)，室温反应4小时。反应液浓缩，残留物用硅胶柱色谱分离提纯(乙酸乙酯：石油醚(v/v)＝2:3～9:1)，得到标题化合物N-[4-(3-氯-4-氟-苯氨基)-7-[(3S)-四氢呋喃-3-基]氧基-喹唑啉-6-基]-2-环丙基-丙-2-烯酰胺(化合物1)，黄色固体(0.15g，产率60％)。
1H NMR(400MHz,CDCl3)δ9.20(s,1H),9.05(s,1H),8.58(s,1H),8.34(s,1H),7.81(d,1H),7.49(s,1H),7.16(s,1H),6.99(t,1H),6.26(s,1H),5.48(s,1H),5.16(s,1H),4.19–3.88(m,4H),2.39(dd,1H),2.30–2.17(m,1H),1.62(s,1H),1.00(d,2H),0.69(s,2H)；
19F NMR(376MHz,CDCl3)δ-119.84；
LCMS m/z＝469.0[M+1]。
生物测试例
测试例1：测试癌细胞生长抑制
连续传代肿瘤细胞经胰蛋白酶消化，悬于培养基，计数后种入96孔细胞培养板。非小细胞肺癌细胞NCI-H1975每孔10000个细胞，人上皮细胞癌细胞A431细胞系每孔10000个细胞，在37℃，5％CO2孵箱中，培养过夜。第二天每种细胞取6个孔加入30μl 50％三氯乙酸固定；其余各孔分别加入得自实施例的化合物。待测化合物以DMSO配置成溶液，最高浓度10μM，按下述方法5倍稀释10个待测浓度。对于NCI-H1975、A431细胞系，用含0.1％FBS的培养基梯度稀释待测，并使其为终浓度2倍。将种植NCI-H1975、A431细胞的96孔细胞培养板培养基换为新鲜含0.1％FBS的培养基(每孔100μl)，再加入100μl含2倍终浓度的待测化合物。各96孔细胞培养板在37℃，5％CO2细胞培养箱孵育72小时。然后每孔加入50μl 50％三氯乙酸，置于4℃冰箱中固定1小时。
将各孔中的三氯乙酸弃去，用300μl双蒸水洗5次。室温下干燥后，每孔加入50μl0.4％SRB(Sulforhodamine-B)染料溶液(1％乙酸/0.4％SRB)，反应15min。弃去各孔的染料溶液，用1％乙酸洗6-7次，室温干燥。各孔加入200μl 10mM Tris溶液(pH＝10.5)，振荡溶解。用酶标仪测定各孔490nm吸光度。以待测化合物浓度为0的孔的读数为对照，使用origin7.5计算和分析实施例化合物的半效抑制浓度(IC50)。
本发明化合物的抗肿瘤细胞增殖活性通过以上的试验进行测定，测得的IC50值见 表 1。
表 1 抗肿瘤细胞增殖活性试验结果
生物测试例2：药代动力学评价
雄性SD大鼠(购自维通利华实验动物有限公司)180-240g，禁食给水过夜，3只大鼠口服灌胃5mg/kg，3只大鼠静脉注射1mg/kg。口服给药组，化合物以0.5％甲基纤维素(MC)溶液(含0.4％吐温80)配制成0.5mg/mL的混悬液，在给药前和在给药后30分钟以及1、2、4、6、8、12和24小时采血；静脉给药组，化合物以10％的DMA，20％Solutol HS-15(30％，w/v)和70％生理盐水配制成0.2mg/mL的溶液，在给药前和在给药后5、15和30分钟以及1、2、4、8、12和24小时采血。血液样品5500转/分钟离心10分钟，收集血浆，于-30℃保存。取各时间点大鼠血浆10μL，加入含内标的乙腈溶液500μL混合后，涡旋混合4分钟，3700转/分钟离心18分钟，取上清液70μL与70μL水混合，取混和液5μL进行LC-MS/MS分析。主要药代动力学参数用WinNonlin 6.3软件非房室模型分析，药代动力学评价试验结果见表 2。
表 2 药代动力学评价试验结果
结论：本发明化合物表现出明显优于对照药物Afatinib的药代动力学特征。
Claims (9)
1.一种通式(I)所示的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中：
R1独立选自选自F、Cl、Br、三氟甲基、甲基、乙基、乙炔基、-OCH2-苯环、-OCH2-噻唑或-OCH2-吡啶，所述的苯环、噻唑或吡啶任选进一步被0至4个F、Cl、Br、甲基或三氟甲基的取代基所取代；
n选自0、1、2、3、4或5；
R2选自选自H、F、Cl、Br、甲氧基、乙氧基、甲氧乙氧基或
2.根据权利要求1所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中：
R1独立选自选自F、Cl、Br、三氟甲基或乙炔基；
R2选自选自H、甲氧基、乙氧基或
n选自1、2或3。
3.根据权利要求2所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中所述化合物选自：
4.根据权利要求1-3所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，其中其药学上可接受的盐中所述的盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、磷酸盐、醋酸盐、三氟乙酸盐、硫氰酸盐、马来酸盐、羟基马来酸盐、戊二酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、苯甲酸盐、水杨酸盐、苯乙酸盐、肉桂酸盐、乳酸盐、丙二酸盐、特戊酸盐、琥珀酸盐、富马酸盐、苹果酸盐、扁桃酸盐、酒石酸盐、没食子酸盐、葡萄糖酸盐、月桂酸盐、棕榈酸盐、果胶酸盐、苦味酸盐、柠檬酸盐或者它们的组合。
5.一种药物组合物，所述的组合物包括：有效剂量的根据权利要求1-4中任一项所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药，以及药学上可接受的载体、稀释剂、佐剂、媒介物或赋形剂；所述的组合物还可进一步包括一种或多种其他治疗剂。
6.根据权利要求5所述的组合物，所述的其他治疗剂选自顺铂(cisplatin)、卡铂(carboplatin)、奥沙利铂(oxaliplatin)、达卡巴嗪(dacarbazine)、替莫唑胺(temozolomide)、丙卡巴肼(procarbazine)、甲氨蝶呤(methotrexate)、氟尿嘧啶(fluorouracil)、阿糖胞苷(cytarabine)、吉西他滨(gemcitabine)、巯基嘌呤(mercaptopurine)、氟达拉滨(fludarabine)、长春碱(vinblastine)、长春新碱(vincristine)、长春瑞滨(vinorelbine)、紫杉醇(paclitaxel)、多西紫杉醇(docetaxel)、拓扑替康(topotecan)、伊立替康(irinotecan)、依托泊苷(etoposide)、曲贝替定(trabectedin)、更生霉素(dactinomycin)、多柔比星(doxorubicin)、表柔比星(epirubicin)、道诺霉素(daunorubicin)、米托蒽醌(mitoxantrone)、博来霉素(bleomycin)、丝裂霉素C(mitomycin)、伊沙匹隆(ixabepilone)、他莫昔芬(tamoxifen)、氟他胺(flutamide)、西罗莫司(sirolimus)、阿法替尼(afatinib)、alisertib、amuvatinib、阿帕替尼(apatinib)、阿西替尼(axitinib)、硼替佐米(bortezomib)、波舒替尼(bosutinib)、布立尼布(brivanib)、卡博替尼(cabozantinib)、西地尼布(cediranib)、crenolanib、克卓替尼(crizotinib)、达拉非尼(dabrafenib)、达可替尼(dacomitinib)、达鲁舍替(danusertib)、达沙替尼(dasatinib)、多韦替尼(dovitinib)、厄洛替尼(erlotinib)、foretinib、ganetespib、吉非替尼(gefitinib)、依鲁替尼(ibrutinib)、埃克替尼(icotinib)、伊马替尼(imatinib)、iniparib、拉帕替尼(lapatinib)、lenvatinib、linifanib、linsitinib、马赛替尼(masitinib)、momelotinib、莫替沙尼(motesanib)、来那替尼(neratinib)、尼罗替尼(nilotinib)、尼拉帕尼(niraparib)、oprozomib、奥拉帕尼(olaparib)、帕唑帕尼(pazopanib)、pictilisib、帕纳替尼(ponatinib)、奎扎替尼(quizartinib)、瑞格非尼(regorafenib)、氯构色替(rigosertib)、rucaparib、鲁索替尼(ruxolitinib)、塞卡替尼(saracatinib)、saridegib、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、替拉替尼(telatinib)、tivantinib、替肟扎尼(tivozanib)、托法替尼(tofacitinib)、曲美替尼(trametinib)、凡德他尼(vandetanib)、维利帕尼(veliparib)、威罗菲尼(vemurafenib)、维莫德吉(vismodegib)、volasertib、阿仑单抗(alemtuzumab)、贝伐单抗(bevacizumab)、布妥昔单抗(brentuximab vedotin)、卡妥索单抗(catumaxomab)、西妥昔单抗(cetuximab)、地诺单抗(denosumab)、吉妥珠单抗(gemtuzumab)、伊匹单抗(ipilimumab)、尼妥珠单抗(nimotuzumab)、奥法木单抗(ofatumumab)、帕尼单抗(panitumumab)、利妥昔单抗(rituximab)、托西莫单抗(tositumomab)、曲妥珠单抗(trastuzumab)或它们的组合。
7.权利要求1-4中任一项所述的化合物或其立体异构体、水合物、代谢产物、溶剂化物、药学上可接受的盐、共晶或前药或者权利要求5或6所述的药物组合物，在作为EGFR受体酪氨酸激酶抑制剂在制备药物制剂中的应用，特别是在制备用于治疗和/或预防过度增殖性疾病的药物制剂中的应用。
8.根据权利要求7中所述的应用，其中所述的过度增殖性疾病包括脑瘤、非小细胞肺癌、表皮鳞癌、膀胱癌、胰腺癌、结肠癌、乳腺癌、卵巢癌、子宫颈癌、子宫内膜癌、结直肠癌、肾癌、食管腺癌、食管鳞状细胞癌、实体瘤、非霍奇金淋巴瘤、肝癌、肺癌，皮肤癌、甲状腺癌、头颈癌、前列腺癌、神经胶质瘤及鼻咽癌中的一种或多种。
9.根据权利要求7中所述的应用，其中所述的过度增殖性疾病包括非小细胞肺癌、乳腺癌、表皮鳞癌、胃癌及结肠癌中的一种或多种。
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| CN101304978A (zh) * | 2005-11-08 | 2008-11-12 | 韩美药品株式会社 | 作为多元抑制剂的喹唑啉衍生物及其制备方法 |
| CN102731485A (zh) * | 2011-04-02 | 2012-10-17 | 齐鲁制药有限公司 | 4-(取代苯氨基)喹唑啉衍生物及其制备方法、药物组合物和用途 |
| CN102898386A (zh) * | 2011-07-27 | 2013-01-30 | 上海医药集团股份有限公司 | 喹唑啉衍生物、其制备方法、中间体、组合物及其应用 |
| CN103965120A (zh) * | 2013-01-25 | 2014-08-06 | 上海医药集团股份有限公司 | 喹啉及喹唑啉衍生物、制备方法、中间体、组合物及应用 |
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| CN102731485A (zh) * | 2011-04-02 | 2012-10-17 | 齐鲁制药有限公司 | 4-(取代苯氨基)喹唑啉衍生物及其制备方法、药物组合物和用途 |
| CN102898386A (zh) * | 2011-07-27 | 2013-01-30 | 上海医药集团股份有限公司 | 喹唑啉衍生物、其制备方法、中间体、组合物及其应用 |
| CN103965120A (zh) * | 2013-01-25 | 2014-08-06 | 上海医药集团股份有限公司 | 喹啉及喹唑啉衍生物、制备方法、中间体、组合物及应用 |
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