CN108822127B - 4-羟亚胺基噻吩并[2,3-b]噻喃-2-甲酰胺类化合物及其用途 - Google Patents
4-羟亚胺基噻吩并[2,3-b]噻喃-2-甲酰胺类化合物及其用途 Download PDFInfo
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- CN108822127B CN108822127B CN201810537992.XA CN201810537992A CN108822127B CN 108822127 B CN108822127 B CN 108822127B CN 201810537992 A CN201810537992 A CN 201810537992A CN 108822127 B CN108822127 B CN 108822127B
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- thiopyran
- thieno
- dihydro
- hydroxyimino
- carboxamide
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Abstract
本发明属于医药技术领域，涉及4‑羟亚胺基噻吩并[2,3‑b]噻喃‑2‑甲酰胺类化合物及其医药用途。所述的4‑羟亚胺基噻吩并[2,3‑b]噻喃‑2‑甲酰胺类化合物的结构如下，其中R＇、R〞R＇、R〞独立地选自氢，苯基，C1‑C6烷基取代的苯基，C1‑C6烷氧基取代的苯基，卤素取代的苯基，卤代C1‑C6烷氧基取代的苯基，取代的C1‑C6烷基，所述取代基为苯基或吗啉基，或R＇、R〞与相连的N原子一起组成吗啉基或哌啶基。本发明所述的4‑羟亚胺基噻吩并[2,3‑b]噻喃‑2‑甲酰胺类化合物、其立体异构体、药学上可接受的盐、前体药物或药物活性代谢物可以与现有药物合并或单独使用用于制备治疗表皮生长因子受体信号转到失调的相关疾病药物。
Description
技术领域
本发明属于医药技术领域，涉及4-羟亚胺基噻吩并[2,3-b]噻喃-2-甲酰胺类化合物及其制备方法和作为表皮生长因子受体酪氨酸激酶抑制剂的应用。
背景技术
近几年来我国各类肿瘤的发病和死亡出现显著上升的趋势，目前男性发病率和死亡率最高的肿瘤为肺癌，女性则为乳腺癌和肺癌。吸烟、过量饮酒、身体活动不足等不健康生活习惯，雾霾，以及经济社会快速发展和社会转型给人们带来的工作、生活压力，对健康造成的影响不容忽视，与环境、生活方式有关的肺癌、肝癌、结直肠癌、乳腺癌死亡率上升趋势更加明显，其中肺癌和乳腺癌上升幅度最大，过去30年分别上升了465％和96％(StewartBW,Wild CP.WHO:World Cancer Report 2014.Lyon:International Agency forResearch on Cancer,2014.)，因此，对肺癌和乳腺癌的预防与治疗是目前研究的热点。
根据癌细胞的分化程度和形态特征研究发现，众多肿瘤患者中存在着大量的表皮生长因子信号传导的失调和表皮生长因子受体酪氨酸激酶的过度表达。已知表皮生长因子受体(epidermal growth factor receptor,EGFR)作为受体型酪氨酸激酶家族的一员，是一种跨膜糖蛋白，其由细胞外的表皮生长因子结合区(包含621个氨基酸残基)、疏水跨膜结构域(23个氨基酸残基)、细胞内的激酶区(542个氨基酸残基)和羧基末端四部分所组成。EGFR有4种类型HER-1、HER-2、HER-3和HER-4，当小分子配体与EGFR结合，使EGFR活化，进而EGFR的酪氨酸激酶区激活，识别蛋白的底物酶,就会将信号传入细胞内，同时EGFR活化后还可激活许多下游信号传导通路，刺激细胞生长增殖(Zhang H,Berezov A,Wang Q,Zhang G,Drebin J,Murali R,Greene MI.ErbB receptors:from oncogenes to targeted cancertreatment.The Journal of Clinical Investigation,2007,117(8):2051–2058.)。由于受体型酪氨酸激酶主要差异为胞外配体结合区，而胞内的酪氨酸激酶结构域具有较高的同源性，本发明旨在合成胞外配体结合区结合良好的小分子配体，从而抑制胞内酪氨酸激酶活性区，抑制酶的催化活性和酪氨酸自磷酸化，进而抑制细胞周期进程、血管生成和肿瘤的转移等。
现有的表皮生长因子受体酪氨酸激酶抑制剂，如吉非替尼、厄洛替尼、拉帕替尼等，均存在着腹泻、皮疹、瘙痒等皮肤反应，及可能的头痛、心脏QT间期延长和生物利用度降低等(李莹,田驰,王磊,谢蒙蒙,程泽能.小分子表皮生长因子受体酪氨酸激酶抑制剂的研究进展.肿瘤药学,2016,6(2):81-88.)。
本发明所述的4-羟亚胺基噻吩并[2,3-b]噻喃-2-甲酰胺类化合物作为全新结构类型的表皮生长因子受体酪氨酸激酶抑制剂，具有结构类型新颖，药效作用与现有药物相当或优于现有药物的特点，可用于治疗或预防与表皮生长因子受体信号传导失调引起的相关疾病如非小细胞肺癌、胃癌、乳腺癌、卵巢癌、肾细胞癌、结肠直肠癌、膀胱癌和头颈部鳞癌，具有良好的应用价值和开发应用前景。
发明内容
本发明所解决的技术问题是提供一种如式I所示的化合物、其前体药物和药物活性代谢物以及其药学上可接受的盐，并提供了其在制备预防和治疗EGFR信号传导失调相关的疾病的药物中的应用。
其中，
R＇、R〞独立地选自氢，苯基，C1-C6烷基取代的苯基，C1-C6烷氧基取代的苯基，卤素取代的苯基，卤代C1-C6烷氧基取代的苯基，取代的C1-C6烷基，所述取代基为苯基或吗啉基，或R＇、R〞与相连的N原子一起组成吗啉基或哌啶基；
进一步地，
R＇、R〞独立地选自氢，苯基，C1-C4烷基取代的苯基，C1-C4烷氧基取代的苯基，卤素取代的苯基，卤代C1-C4烷氧基取代的苯基，取代的C1-C4烷基，所述取代基为苯基或吗啉基，或R＇、R〞与相连的N原子一起组成吗啉基或哌啶基。
更进一步地，
R＇、R〞独立地选自氢，乙基，丙基，异丙基，丁基，叔丁基，4-甲基苯基，4-三氟甲氧基苯基，3-(4-吗啉基)丙基，2-(2-甲氧基苯氧基)乙基，2-(3,4-二甲氧基苯基)乙基，或与它们相连的氮原子一起组成吗啉基或哌啶基。
“药学上可接受的盐”指保留了式I化合物的生物效力和性质，并与合适的非毒性有机酸或无机酸或有机碱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、果胶脂酸盐等。碱盐包括铵盐，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-葡糖胺盐等，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等。优选用于生成酸加成盐的酸包括盐酸和醋酸。
“药学活性代谢物”指药学上可接受并有效的式I化合物的代谢产物。
本发明还涉及抑制表皮生长因子受体酪氨酸激酶的药用组合物，该组合物含有式I化合物或衍生物或其药学上适用的酸加成盐以及药学上适用的载体。
本发明中应用的术语“卤素”包括氟、氯或溴。
“取代的”，除非另外说明，指取代基可以在一个或多个位置存在，取代基独立地选自具体的选项。
“药学上可接受的”如药学上可接受地载体、赋形剂、前体药物等，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。
本发明化合物可以通过不同的方法给患者服用，例如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适用的酸加成盐形式进行配制和服用。
本发明涉及4-羟亚胺基噻吩并[2,3-b]噻喃-2-甲酰胺类化合物、其前体药物和药物活性代谢物及其药学上可接受的盐可以与现有药物合并或单独使用，用于制备治疗表皮生长因子受体信号传导失调的相关疾病药物。
本发明所述的药用组合物可以与现有药物合并或单独使用用于制备治疗表皮生长因子受体信号传导失调的相关疾病的药物。
其中所述的表皮生长因子受体为HER-1、HER-2、HER-3或HER-4，其中其中所述的表皮生长因子受体信号传导失调的相关疾病为非小细胞肺癌，胃癌、乳腺癌、卵巢癌，肾细胞癌，结肠直肠癌、膀胱癌和头颈部鳞癌。
使用的治疗方法和剂量
本发明描述的待治疗的各种疾病和病症是本领域技术人员熟知的和清楚的。也应理解本领域技术人员可以用治疗有效量的化合物治疗目前正为疾病或病症而痛苦的患者，或者通过预防性的治疗为疾病或病症而痛苦的患者从而影响有关的疾病和病症。
本发明使用的术语“患者”是指患有肿瘤的温血动物，例如哺乳动物。应理解豚鼠、狗、猫、大鼠、小鼠马、牛、羊和人是在本术语含义范围内的动物的实例。
这里使用的术语“治疗有效量”是指对控制与肿瘤有关的疾病和病症有效的量。术语“控制”是用来指所有可以减缓、中断、阻止或停止本文描述的疾病和病症的发展的过程，而未必是需要完全消除全部的疾病和病症的症状。
治疗有效量可以通过主治诊断医师作为本领域技术人员使用常规的技术和观察类似情况下得到的结果容易地确定。在确定治疗有效量的剂量过程中，主治诊断医师考虑许多因素，包括但不限于：哺乳动物的种类；其大小、年龄和大体的健康情况；涉及的具体疾病；疾病的程度或复杂情况或严重程度；个体患者的反应；给药的特定化合物；给药方式；给药的制剂的生物利用率特性；选择的配药方案；伴随的药物治疗的使用及其他相关的情况。
活性化合物的治疗有效量预计从大约0.001毫克每公斤体重每天(mg/kg/天)至大约100mg/kg/天不等。优选的量可以由本领域技术人员确定。
在有效治疗患有上述的疾病和病症的患者时，此类化合物可以以使化合物生物可利用的任何形式或方式按治疗有效量给药，包括口服、吸入和肠胃外的路径。例如，化合物可以通过口服、吸入气雾剂或干燥粉、皮下注射、肌内注射、静脉注射、透皮给药、鼻内给药、直肠给药、局部给药等等方式给药。口服或吸入给药通常优选用于治疗呼吸系统疾病，例如哮喘。配制配方的本领域技术人员可以根据选择的化合物的具体特性，要治疗的疾病或病症的情况，疾病或病症的阶段及其他相关的情况容易地选择恰当的给药形式和方式。
本发明的化合物可以单独给药或与药学上可接受的载体或赋形剂结合以药物组合物的形式给药，载体或赋形剂的比例和性质由选择的化合物的溶解度和化学性质，选择的给药途径，和标准制药准则确定。本发明的化合物虽然本身是有效的，但可以以其药学上可接受的盐例如酸加成盐或碱加成盐的形式配制配方和给药，这是为了稳定、方便结晶、提高溶解度等等目的。
本发明提供了含有治疗有效量的化合物与一种或多种药学上可接受的载体或赋形剂混合或以其他方式结合的药物组合物。
药物组合物按药物领域众所周知的方法制备。可以作为活性成分的运载体或介质的载体或赋形剂可以是固体、半固体或液体原料。合适的载体或赋形剂是本领域众所周知的。可使药物组合物适于口服、吸入、肠胃外使用或局部使用，可以以片剂、胶囊、气雾剂、吸入剂、栓剂、溶液、悬浮液等等形式给患者用药。
本发明的化合物可以例如与一种惰性稀释剂或与一种可食用的载体口服给药.它们可以包在胶囊中或压成药片。为了口服治疗给药，化合物可以与赋形剂混合，并以片剂、锭剂、胶囊、酏剂、悬浮液、糖浆、糯米纸囊剂、咀嚼胶等等形式使用。这些制剂应该含有至少4％的本发明化合物，即活性成分，但是可以根据具体形式而变化，在单元重量的4％至大约70％之间方便地变化。存在于组合物的化合物的量应可以得到合适的剂量。本发明优选的组合物和制剂可以由本领域技术人员确定。
片剂、丸剂、胶囊、锭剂等等可以还含有一种或多种下列的助剂：粘合剂例如微晶纤维素、黄着树胶或明胶；赋形剂例如淀粉或乳糖，崩解剂例如海藻酸、Primogel、玉米淀粉等等；润滑剂例如硬脂酸镁或Sterotex；助流剂例如胶体二氧化硅；并可以加入甜味剂例如蔗糖或糖精或调味剂例如薄荷、水杨酸甲酯或橙子香料。当药剂单位形式是胶囊时，除了含有上述类型的原料之外，可以含有液体载体例如聚乙二醇或脂肪油。其它的药剂单位形式可以含有修饰药剂单位物理形式的其它的不同的原料，例如作为涂层。这样，片剂或丸剂可以涂有糖、片胶或其它的肠溶衣试剂.糖浆除了含有本化合物，可以含有蔗糖作为甜味剂和一定的防腐剂、染料和着色剂和食用香料。制备这些不同的组合物使用的材料应该是药学纯的和使用量下是无毒的。
为了肠胃外治疗给药，本发明的化合物可以加入到一种溶液或悬浮液中。这些制剂应该含有至少0.1％的本发明化合物，但是可以在制剂重量的0.1和大约50％之间改变。存在于这种组合物中的化合物的量应当可以得到合适的剂量。优选的组合物和制荆能够由本领域技术人员确定。
本发明的化合物也可以通过吸入，例如用气雾剂或干燥粉给药。可以用一种液化的或压缩的气体或用一种分配本发明化合物或其配方的合适的泵送系统释放。通过吸入化合物给药的配方可以以单相、双相的或三相的系统输送。对于用化合物的气雾剂给药，许多系统是可用的。干粉配方是通过将化合物制粒或碾磨至合适的粒径制备的，或者是通过混合已制粒的或碾磨的化合物与合适的载体例如乳糖等等制备的。通过吸入的释放系统包括必要的容器、活化剂、阀门、亚容器等等。优选的通过吸入给药的气雾剂和干粉配方能够由本领域技术人员确定。
本发明的化合物还可以局部给药，这样做时裁体适当地含有溶液、软膏或者凝胶基剂。基剂例如可以舍有一种或多种下列物质：矿脂、羊毛脂、聚乙二醇、蜂蜡、矿物油、例如水和醇的稀释剂，和乳化剂和稳定剂.局部配方含钙化合物或其药学上可接受的盐的浓度可以从约0.1到约10％w/v(重量每单位体积)。
该溶液或者悬浮液还可以含有一种或多种下列助剂：无菌稀释剂例如注射用水，盐水溶液，固定油类，聚乙二醇，甘油，丙二醇或者其它的合成溶剂；抗菌剂例如苄醇或者羟苯甲酸甲酯；抗氧化剂例如维生素C或者亚硫酸氢钠；鳌合剂例如乙二胺四乙酸；缓冲剂例如醋酸盐、柠檬酸盐或者磷酸盐和调节渗透压的试剂例如氯化钠或者葡萄糖。肠胃外制剂可以装在玻璃或塑料制成的安瓿、一次性注射器或多剂量小瓶中。
具体实施方式
如下反应流程概括了制备本发明化合物的制备步骤。
反应流程
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施例。
实施例1：N-乙基-4-羟亚胺基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-甲酰胺的制备
步骤A：3-(噻吩-2-硫基)丙酸的制备
在250mL圆底烧瓶中加入0.04mol 2-巯基噻吩、0.04mol丙烯酸、80mL四氢呋喃，搅拌下滴加11mL三乙胺，加热回流反应12h，反应完毕，稍冷后蒸去四氢呋喃。冷却后，加入40mL乙酸乙酯和20mL水，用18％盐酸调节溶液的pH值至2，收集有机层，水层用乙酸乙酯萃取，合并有机层，用无水硫酸镁干燥。抽滤，滤液蒸去溶剂，冷却后析出棕色固体，以石油醚重结晶得白色固体，产量5.82g，收率77.4％。m.p.:43-45℃。
步骤B：5,6-二氢-4H-噻吩并[2,3-b]噻喃-4-酮的制备
在250mL三颈瓶中加入0.02mol 3-(噻吩-2-硫基)丙酸、20mL二氯甲烷和2滴DMF，氮气保护下，边搅拌边滴加含有草酰氯的二氯甲烷溶液(草酰氯2.2mL，二氯甲烷15mL)，室温搅拌2h。将反应液用冰盐浴冷却至-10℃以下，边搅拌边滴加含有四氯化锡的二氯甲烷溶液(四氯化锡1.15mL，二氯甲烷10mL)。滴毕，0℃下搅拌2h。向三颈瓶中加入30mL水，提取有机层，水层用二氯甲烷萃取，合并有机层。有机层依次用饱和碳酸钠溶液、水和饱和氯化钠溶液洗涤，无水硫酸镁干燥。抽滤，滤液蒸去溶剂，冷却后得棕色粗品，经石油醚重结晶，得淡黄色固体，产量2.75g，收率80.9％。m.p.:59.0-60.5℃。1H-NMR(300MHz,DMSO-d6):δ2.77(t,2H,J＝6.6Hz),3.47(t,2H,J＝6.6Hz),7.35(d,1H,J＝5.4Hz),7.38(d,1H,J＝5.4Hz)。MS(m/z):171.0([M+H]+)。
步骤C：2-三氯乙酰基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-4-酮的制备
将0.06mol三氯化铝和20mL二氯甲烷混合，加入到250mL圆底烧瓶中，冰浴冷却。搅拌下滴加含有三氯乙酰氯的二氯甲烷溶液(三氯乙酰氯0.026mol，二氯甲烷25mL)，约20min滴毕，搅拌30min，继续冰浴下滴加含有0.02mol 5,6-二氢-4H-噻吩并[2,3-b]噻喃-4-酮的二氯甲烷溶液20mL，滴毕室温搅拌24h，将反应混合物倾入100mL水中，提取有机层，水层用二氯甲烷萃取，合并有机层，用无水硫酸镁干燥。抽滤，滤液蒸去溶剂，以乙醇重结晶。得浅黄色晶体，产量2.95g，收率47.0％。m.p.:152.5-154.0℃。1H-NMR(600MHz,CDCl3)δ:2.92(t,2H,J＝6.6Hz),3.45(t,2H,J＝6.6Hz),8.45(s,1H)；ESI-MS(m/z):312.9([M-H]-)。
步骤D：4-氧代-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-羧酸的制备
在250mL圆底烧瓶中加入0.01mol 2-三氯乙酰基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-4-酮，0.013mol碳酸钠和150mL水，于60℃反应15h，反应完毕，冷却至室温，抽滤，滤液用盐酸调节pH值至2，抽滤，用水洗涤固体，得淡黄色粉末状固体，产量1.89g，收率88.3％，m.p.:201-203℃。1H-NMR(400MHz,DMSO-d6)δ:2.81(t,2H,J＝6.4Hz),3.45(t,2H,J＝6.4Hz),7.80(s,1H),13.43(s,1H)；ESI-MS(m/z):212.8([M-H]-)。
步骤E：N-乙基-4-氧代-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-甲酰胺的制备
在50mL圆底烧瓶中，加入1.5mmol 4-氧代-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-羧酸、1.5mmol乙胺、1.9mmol 1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、0.3mmol 1-羟基苯并三唑、1mL三乙胺和15mL干燥的二氯甲烷，室温搅拌48h，过滤，滤液依次用18％的盐酸、饱和碳酸钠、水和饱和氯化钠洗涤，提取有机层，用无水硫酸镁干燥。抽滤，滤液蒸去溶剂，得到粗品，经硅胶柱层析分离，得到白色固体0.26g，收率72.2％；mp 215～217℃；IR(KBr,cm-1):3352.7,3080.6,3019.0,2969.7,2924.8,2899.6,2866.1,1659.8,1630.0,1555.1,1517.5,1417.6,1398.5,1282.7,1248.0,1184.6,1045.0,892.0,701.5,629.1；1H-NMR(600MHz,CDCl3)δ：7.78(s,1H),6.28(s,1H),3.43～3.48(m,2H),3.39(t,J＝6.6Hz,2H),2.86(t,J＝6.6Hz,2H),1.23(t,J＝7.2Hz,3H)；ESI-MS m/z:242.1([M+H]+),264.0([M+Na]+),482.9([2M+H]+),482.9([2M+Na]+)。
步骤F：N-乙基-4-羟亚胺基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-甲酰胺的制备
将0.3mmol N-乙基-4-氧代-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-甲酰胺溶于20mL无水乙醇，加入0.025g(0.3mmol)醋酸钠、0.021g(0.3mmol)盐酸羟胺，回流12h，冷却析出固体，抽滤洗涤，用乙醇重结晶得到白色粉末0.06g，收率81.8％。m.p.:254～256℃；IR(KBr,cm-1):3270.2,3075.6,3032.3,2973.5,2933.5,2891.1,1608.6,1548.9,1516.4,1385.0,1291.0,1251.3,974.8,871.6,836.6；1H-NMR(600MHz,CDCl3)δ：11.14(s,1H),8.60(s,1H),7.98(s,1H),3.19～3.24(m,2H),3.17(t,J＝6.0Hz,2H),2.92(t,J＝6.0Hz,2H),1.09(t,J＝7.2Hz,3H)；ESI-MS m/z:255.2([M-H]-)。
实施例2：N-异丙基-4-羟亚胺基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-甲酰胺的制备
按照实施例1的合成方法，得到白色晶体，收率82.4％。m.p.:191～194℃；IR(KBr,cm-1):3423.0,2923.2,2853.0,1615.9,1384.3,1115.7,977.1；1H-NMR(400MHz,CDCl3)δ：8.05(s,1H),7.76(s,1H),5.75(d,J＝7.2Hz,1H),4.18～4.27(m,1H),3.07～3.13(m,4H),1.23(d,J＝6.4Hz,6H)；ESI-MS m/z:271.1([M+H]+),293.1([M+Na]+),541.0([2M+H]+),563.0([2M+Na]+)。
实施例3：N-丁基-4-羟亚胺基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-甲酰胺的制备
按照实施例1的合成方法，得到白色粉末，收率23.8％。m.p.:164～166℃；IR(KBr,cm-1):3326.1,3093.2,3020.7,2957.4,2929.4,2869.6,1593.0,1561.2,1455.2,1390.2,1304.1,989.5,863.2；1H-NMR(600MHz,CDCl3)δ：7.81(s,1H),7.74(s,1H),5.92(s,1H),3.39～3.42(m,2H),3.09～3.13(m,4H),1.54～1.59(m,2H),1.36～1.42(m,2H),0.94(t,J＝7.2Hz,3H)；ESI-MS m/z:283.6([M-H]-)。
实施例4：N-(4-甲基苯基)-4-羟亚胺基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-甲酰胺的制备
按照实施例1的合成方法，得到白色粉末，收率47.6％。m.p.:209～211℃；IR(KBr,cm-1):3342.1,3076.5,3028.0,2918.4,2853.8,1601.5,1537.1,1518.0,1460.6,1406.8,1392.9,1315.8,1249.4,987.1,804.6；1H-NMR(600MHz,DMSO-d6)δ：11.20(s,1H),10.30(s,1H),8.27(s,1H),7.59(d,J＝7.8Hz,2H),7.15(d,J＝7.8Hz,2H),3.21(t,J＝6.0Hz,2H),2.96(t,J＝6.0Hz,2H),2.27(s,3H)；ESI-MS m/z:316.8([M-H]-)。
实施例5：N-(4-三氟甲氧基苯基)-4-羟亚胺基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-甲酰胺的制备
按照实施例1的合成方法，得到白色粉末，收率96.2％。m.p.:231～232℃；IR(KBr,cm-1):3316.2,3096.4,2928.3,1713.3,1647.8,1606.6,1520.6,1408.2,1278.2,1250.2,1204.2,1153.5,986.1,845.9,811.3；1H-NMR(600MHz,DMSO-d6)δ：11.24(s,1H),10.58(s,1H),8.32(s,1H),7.86(d,J＝8.4Hz,2H),7.35(d,J＝7.8Hz,2H),3.17～3.25(m,2H),2.92～3.01(m,2H)；ESI-MS m/z:386.9([M-H]-)。
实施例6：N-[3-(4-吗啉基)丙基]-4-羟亚胺基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-甲酰胺的制备
按照实施例1的合成方法，得到白色晶体，收率31.9％。m.p.:255～257℃；IR(KBr,cm-1):3232.4,3067.3,2955.8,2933.4,2867.8,2740.7,2605.2,1625.6,1545.3,1519.9,1447.1,1390.7,1305.7,1268.2,1250.0,1188.6,1134.5,1102.7,1087.0,970.7,864.9；1H-NMR(600MHz,DMSO-d6)δ：11.19(s,1H),8.81(s,1H),8.00(s,1H),3.93(t,J＝7.2Hz,2H),3.78(t,J＝7.2Hz,2H),3.38(m,2H),3.28(t,J＝6.0Hz,2H),3.16～3.20(m,2H),3.02～3.12(m,4H),2.91～2.94(m,2H),1.90～1.96(m,2H)；ESI-MS m/z:356.1([M+H]+),394.1([M+K]+)。
实施例7：N-[2-(2-甲氧基苯氧基)乙基]-4-羟亚胺基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-甲酰胺的制备
按照实施例1的合成方法，得到白色晶体，收率86.5％。m.p.:185～188℃；IR(KBr,cm-1):3481.7,3361.8,3080.8,2919.8,2882.6,1639.0,1547.4,1507.4,1454.5,1301.5,1253.8,1224.2,1126.8,1019.6,974.8,744.9,736.0；1H-NMR(600MHz,CDCl3)δ：7.73(s,1H),6.85(s,1H),6.90～7.00(m,5H),4.18(t,J＝5.4Hz,2H),3.90(s,3H),3.79(q,J＝5.4Hz,2H),3.08～3.12(m,4H)；ESI-MS m/z:379.1([M+H]+),401.1([M+Na]+),779.2([2M+Na]+)。
实施例8：N-[2-(3,4-二甲氧基苯基)乙基]-4-羟亚胺基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-甲酰胺的制备
按照实施例1的合成方法，得到白色粉末，收率38.5％。m.p.:226～227℃；IR(KBr,cm-1):3359.3,3071.8,3004.7,2957.8,2927.1,2850.7,1623.7,1554.7,1512.1,1461.9,1305.4,1261.1,1234.5,1139.9,1026.4,988.9,858.1,817.5；1H-NMR(600MHz,DMSO-d6)δ：11.14(s,1H),8.67(t,J＝5.4Hz,1H),7.97(s,1H),6.85(d,J＝8.4Hz,1H),6.81(s,1H),6.72(d,J＝7.8Hz,1H),3.71(s,3H),3.70(s,3H),3.38～3.41(m,2H),3.17(t,J＝6.0Hz,2H),2.92(t,J＝6.0Hz,2H),2.74(t,J＝7.2Hz,2H)；ESI-MS m/z:391.0([M-H]-)。
实施例9：2-(4-吗啉甲酰基)-4-羟亚胺基-5,6-二氢-4H-噻吩并[2,3-b]噻喃的制备
按照实施例1的合成方法，得到浅黄色粉末，收率47.6％。m.p.:140～142℃；IR(KBr,cm-1):3251.9,3024.0,2960.8,2919.2,2857.2,1595.4,1388.6,1258.0,1109.0,979.9,868.6；1H-NMR(600MHz,CDCl3)δ：7.84(s,1H),7.55(s,1H),3.74～3.80(m,4H),3.69～3.73(m,4H),3.08～3.12(m,4H)；ESI-MS m/z:299.1([M+H]+),321.0([M+Na]+),619.0([2M+Na]+)。
药理实施例
实施例10：人源肺腺癌细胞A549和人源大细胞肺癌细胞NCI-H460的抑制作用
阳性药物：吉非替尼，购自大连美仑生物技术有限公司。
细胞株：人肺腺癌细胞A549；人大细胞肺癌细胞NCI-H460(中科院上海细胞库)。
细胞培养条件：RMPI1640培养基：胎牛血清＝1:9，青霉素：100单位/mL；链霉素：100单位/mL。于37℃、5％CO2恒温培养箱中培养传代。
试验用主要试剂：RMPI1640培养基(美国GIBCO公司)；胎牛血清(美国Hyclone公司)；胰酶(美国Sigma公司)；噻唑蓝(MTT，美国Sigma公司)；
试验用主要仪器：高压灭菌锅SN510C(日本YAMATO)；CO2培养箱(日本SANYO)、倒置显微镜(CKX31，日本OLYMPUS)、酶标光度计(MULTISKAN MC，England)。
试验方法：首先用RM1640将受试药物(原液浓度为4mM)配制成浓度为80μM的溶液。待细胞培养至对数生长期后，贴壁细胞用0.25％的胰酶消化液消化约5min，加入10％胎牛血清RMPI1640培养基终止消化，吹打成细胞悬液，移入15mL离心管，1000转，离心5min(悬浮生长细胞无需消化，直接将细胞悬液移入15mL离心管，1000转，离心5min)弃上清，加入10％胎牛血清RMPI1640培养基，吹打混匀，制备成单细胞悬液，调整细胞悬液浓度为3.0×104个/mL，将上述细胞悬液铺于96孔板中，每孔200μL，每组设3个孔；另留3个孔，各加入10％胎牛血清RMPI1640培养基200μL作为空白对照孔。继续培养24h后，实验组各组加入浓度为80μM的受试药物2μL；对照组加入RMPI1640 2μL；继续培养24h，结束培养前4h取出培养板，每孔加入5mg/ml的MTT 20μL(避光)，继续培养，结束后，吸弃培养基，每孔加入DMSO 150μL，震荡摇匀，在酶标仪上以562nm的波长测定吸光度值。重复3次。
细胞生长抑制率计算公式：生长抑制率＝[1-(实验组吸光度平均值-空白对照吸光度平均值)/(对照组吸光度平均值-空白对照吸光度平均值)]×100％。
对本发明的化合物进行该实验，表明对EGFR高表达的人源肺腺癌细胞A549和人源大细胞肺癌细胞NCI-H460的细胞增殖有抑制作用，抑制率列表如下：
实施例11：对人乳腺癌细胞MCF-7的抑制作用
实验方法：以人乳腺癌细胞MCF-7为测试细胞株，培养于含有10％(w)胎牛血清的RPM I-1640培养液中，于37℃，在体积分数为5％的CO2培养箱中培养24h。取对数生长期细胞(1.5×104个/mL)接种于96孔板中，每孔100μL，加入浓度为100μmol·L-1的目标化合物和阳性对照药他莫昔芬，用酶标仪在490nm处测吸光值。根据公式：细胞生长抑制率＝1-(加药孔细胞数/对照孔细胞数)×100％，计算100μM浓度下的细胞生长抑制率。
部分样品的抑制率如下：
实验结果表明所筛选的部分化合物在100μM浓度时对人乳腺癌细胞MCF-7的生长有抑制作用。
在实施例12-32中，“活性化合物”是指式I化合物，或其盐或溶剂化物。下述非限定性实施例说明用于不同局部给药方式的配方。在经皮给药的配方中，活性化合物的用量一般为0.001–0.2％w/w)，优选0.01–0.1％w/w)。
实施例12：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13：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，矫味剂适量，着色剂适量，加纯水至5mL。
实施例14：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15：栓剂配方
活性化合物250mg，饱和脂肪酸甘油酯类2000mL。
实施例16：可注射制剂配方
活性化合物50mg，等渗盐溶液1000mL。
实施例17：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18：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19：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，Ce tomacrogol1 000 2g，柠檬酸0.1g，柠檬酸钠0.2g，丙二醇35g，加水至100g。
实施例20：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 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21：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22：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适量，加水至1g。
实施例23：注射用悬浮液配方
活性化合物0.05-10mg，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24：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25：雾化溶液配方
活性化合物7mg，丙二醇5mg，加水至10g。
实施例26：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27：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28：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29：胶囊剂配方
活性化合物1.0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MMS 0.lmg。
实施例30：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31：灌肠剂配方
活性化合物0.2mg，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32：含有脂质体的配方配方
A.滴注配方的制备
在一玻璃管中混合合成的二棕榈酰基卵磷脂(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)，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它形式的限制，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。但是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 (8)
1.式(I)所示的化合物及其药学上可接受的盐：
其中，
R＇、R〞独立地选自氢，苯基，C1-C6烷基取代的苯基，C1-C6烷氧基取代的苯基，卤代C1-C6烷氧基取代的苯基，取代的C1-C6烷基，所述取代基为苯基或吗啉基，或R＇、R〞与相连的N原子一起组成吗啉基。
2.权利要求1所述的化合物及其药学上可接受的盐：
其中，
R＇、R〞独立地选自氢，苯基，C1-C4烷基取代的苯基，C1-C4烷氧基取代的苯基，卤代C1-C4烷氧基取代的苯基，取代的C1-C4烷基，所述取代基为苯基或吗啉基，或R＇、R〞与相连的N原子一起组成吗啉基。
3.权利要求1所述的化合物及其药学上可接受的盐：
其中，
R＇、R〞独立地选自氢，4-甲基苯基，4-三氟甲氧基苯基，3-(4-吗啉基)丙基，或与它们相连的氮原子一起组成吗啉基。
4.如下的化合物及其药学上可接受的盐，选自：
N-乙基-4-羟亚胺基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-甲酰胺；
N-异丙基-4-羟亚胺基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-甲酰胺；
N-丁基-4-羟亚胺基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-甲酰胺；
N-(4-甲基苯基)-4-羟亚胺基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-甲酰胺；
N-(4-三氟甲氧基苯基)-4-羟亚胺基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-甲酰胺；
N-[3-(4-吗啉基)丙基]-4-羟亚胺基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-甲酰胺；
N-[2-(2-甲氧基苯氧基)乙基]-4-羟亚胺基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-甲酰胺；
N-[2-(3,4-二甲氧基苯基)乙基]-4-羟亚胺基-5,6-二氢-4H-噻吩并[2,3-b]噻喃-2-甲酰胺；
2-(4-吗啉甲酰基)-4-羟亚胺基-5,6-二氢-4H-噻吩并[2,3-b]噻喃。
5.如权利要求1所述的化合物及其药学上可接受的盐的制备方法，其特征在于，反应流程如下：
其中，R＇、R〞如权利要求1所述。
6.一种药物组合物，包括作为活性成分的权利要求1-4中任何一项的化合物及其药学上可接受的盐和药学上可接受的载体。
7.权利要求1-4任何一项所述的化合物及其药学上可接受的盐在制备治疗表皮生长因子受体信号转导失调的相关疾病药物中的应用，所述的表皮生长因子受体信号转导失调的相关疾病为非小细胞肺癌、胃癌、乳腺癌、卵巢癌、肾细胞癌、结肠直肠癌、膀胱癌或头颈部鳞癌。
8.权利要求6所述的药物组合物在制备治疗表皮生长因子受体信号转导失调的相关疾病药物中的应用，所述的表皮生长因子受体信号转导失调的相关疾病为非小细胞肺癌、胃癌、乳腺癌、卵巢癌、肾细胞癌、结肠直肠癌、膀胱癌或头颈部鳞癌。
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| TW432067B (en) * | 1995-08-29 | 2001-05-01 | Merck & Co Inc | Synthesis of hydroxysulfone and related compounds |
| US8183391B2 (en) * | 2006-04-21 | 2012-05-22 | Zach Systems S.P.A. | Process for preparing dorzolamide |
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