CN105061460B - 含有硫醚结构的四氢苯并[4,5]噻吩并[2,3‑d]嘧啶类化合物及其应用 - Google Patents
含有硫醚结构的四氢苯并[4,5]噻吩并[2,3‑d]嘧啶类化合物及其应用 Download PDFInfo
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- CN105061460B CN105061460B CN201510506949.3A CN201510506949A CN105061460B CN 105061460 B CN105061460 B CN 105061460B CN 201510506949 A CN201510506949 A CN 201510506949A CN 105061460 B CN105061460 B CN 105061460B
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- thieno
- pyrimidine
- tetrahydro benzos
- hydroxy phenyls
- compound
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明属于医药技术领域,涉及含有硫醚结构的四氢苯并[4,5]噻吩并[2,3‑d]嘧啶类化合物及其作为表皮生长因子受体酪氨酸激酶抑制剂应用,及其制备方法。含有硫醚结构的四氢苯并[4,5]噻吩并[2,3‑d]嘧啶类化合物和药学上可接受的盐,及其药学上配伍可接受的载体或稀释剂作为表皮生长因子受体酪氨酸激酶抑制剂。其结构通式如下所示:R1、R2如权利要求和说明书所述。本发明的这类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抑制表皮生长因子、人类肺癌细胞株A549、人类卵巢癌细胞株SKOV3及人类骨肉瘤细胞U2OS‑EGFP‑4A12G的活性,是一种具有抗肿瘤作用的表皮生长因子受体酪氨酸激酶抑制剂。
Description
技术领域
本发明属于医药技术领域,涉及含有硫醚结构的四氢苯并[4,5]噻吩并[2,3-d]嘧啶类化合物及其制备方法,还涉及其作为表皮生长因子受体酪氨酸激酶抑制剂应用。
背景技术
根据癌细胞的分化程度和形态特征,肺癌可分为非小细胞肺癌和小细胞肺癌。研究发现,肺癌患者中存在着大量的表皮生长因子信号转导的失调和表皮生长因子受体酪氨酸激酶的过度表达。
表皮生长因子受体(EGFR)是具有膜外配体受体结合域和细胞内酪氨酸激酶活性域的一种跨膜蛋白。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分子的磷酸化,启动信号转导通路,最终影响细胞存活和细胞增殖。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。
本发明所述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,药效作用明显的特点。可用于治疗或预防与表皮生长因子受体信号转导失调引起的相关疾病如小细胞肺癌,鳞癌,腺癌,大细胞癌,结肠直肠癌、乳腺癌,卵巢癌,肾细胞癌,支气管哮喘,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信号转导失调相关的疾病的药物中的应用。
其中
其中
R1为H或C1-C4烷基;
R2独立的选自H、卤素、C1-C4烷基、羟基、C1-C4烷氧基。
优选地,
R1为H或乙基;
R2独立的选自H、氟、氯、溴、甲基、羟基、甲氧基、2,4-二甲基。
“药物可接受的盐”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。酸加成盐的实例包括醋酸盐,己二酸盐,藻酸盐,天冬氨酸盐,苯甲酸盐,苯磺酸盐,硫酸氢盐,丁酸盐,柠檬酸盐,樟脑酸盐,樟脑磺酸盐,环戊丙酸盐,二葡萄糖酸盐,十二烷基硫酸盐,乙磺酸盐,富马酸盐,葡庚糖酸盐,甘油磷酸盐,半硫酸盐,庚酸盐,己酸盐,氢氯酸盐,氢溴酸盐,氢碘酸盐,2-羟基乙磺酸盐,乳酸盐,马来酸盐,甲磺酸盐,2-萘磺酸盐,烟酸盐,硝酸盐,草酸盐,扑酸盐,果胶酯酸盐,过硫酸盐,3-苯基丙酸盐,苦味酸盐,新戊酸盐,丙酸盐,琥珀酸盐,硫酸盐,酒石酸盐,硫氰酸盐,甲苯磺酸盐和十一酸盐。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,和氨基酸的盐,例如精氨酸,赖氨酸等,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。
“药学上可接受的”如药学上可接受地载体、赋性剂、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。
“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。
本发明也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。
具体实施方式
反应流程1概括了制备本发明化合物的合成步骤。
以下述实例详细叙述本发明。但是,应当明确,本发明不限于具体叙述的下述实例。
实施例1:7-(4-乙氧基苯基)-4-苯硫基-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号01)的制备
步骤A:4-(4-乙氧基苯基)环己酮的制备
依次将4-(4-羟基苯基)环己酮15.0g(79.0mmol),无水碳酸钾109.0g(789.5mmol),丙酮200mL,硫酸二乙酯24.4g(157.9mmol)放入500mL茄型瓶中,加热回流搅拌6h后,减压蒸干溶剂,向剩余物中加入水500mL,于室温下搅拌2h,抽滤,水洗2次,干燥后得白色固体16.6g,收率96.5%,m.p.:70-72℃。
步骤B:2-氨基-6-(4-乙氧基苯基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺的制备
向100mL三颈瓶中依次加入4-(4-乙氧基苯基)环己酮2.0g(9.2mmol),氰乙酰胺0.8g(9.2mmol)、硫粉(升华)0.3g(9.2mmol),无水乙醇6.0mL,然逐滴滴加哌啶0.8g(9.2mmol),并控温45-50℃,滴加完后于上述温度下搅拌反应5h。反应完毕后,将反应液冰冻2h,抽滤析出的固体,乙醇洗涤2次,石油醚洗涤1次,自然风干后得橙红色固体1.6g,收率56.1%。m.p.:219-221℃;IR:(KBr,cm-1)3458(m),3291(d),2912(m),1632(s),1559(s),1510(s),1474(s),1414(s),1234(s),1179(s),1114(s),1043(s),824(s);1H-NMR(400MHz,DMSO-d6):δ1.31(t,3H,CH3),1.73-1.84(m,1H,CH2),1.91-1.95(m,1H,CH2),2.53-2.58(m,1H,CH2),2.63-2.80(m,3H,CH2),2.81-2.90(m,1H,CH),3.99(m,2H,CH2-O),6.53(brs,2H,NH2),6.85(d,2H,Ar-H,J=8.8Hz),6.94(s,2H,NH2),7.19(d,2H,Ar-H,J=8.8Hz);ESI-MS(m/z):317.3([M+H]+)。
步骤C:7-(4-乙氧基苯基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶-4(3H)-酮的制备
向50mL茄形瓶中加入2-氨基-6-(4-乙氧基苯基)-4,5,6,7-四氢苯并[b]噻吩-3-甲酰胺1.0g(3.2mmol)和甲酰胺5.7g(126.4mmol),于165℃下搅拌反应6h后,冷却至室温,待其析出大量固体后加入异丙醇5mL,于室温下搅拌1h,抽滤,异丙醇洗涤1次,自然风干后得棕色固体0.7g,收率66.0%。m.p.:239-240℃;IR:(KBr,cm-1)3430(m),2925(s),2880(s),1657(s),1592(s),1511(s),1370(s),1247(d),1175(s),834(s);1H-NMR(400MHz,DMSO-d6):δ1.31(t,3H,CH3),1.87-1.94(m,1H,CH2),1.97-2.03(m,1H,CH2),2.78-2.86(m,2H,CH2),2.96-3.01(m,2H,CH2),3.12-3.18(m,1H,CH2),4.00(m,2H,CH2-O),6.87(d,2H,Ar-H,J=8.8Hz),7.23(d,2H,Ar-H,J=8.8Hz),8.02(s,1H,Ar-H),12.34(brs,1H,NH);ESI-MS(m/z):327.4([M+H]+)。
步骤D:4-氯-7-(4-乙氧基苯基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶的制备
向100mL茄形瓶中依次加入7-(4-乙氧基苯基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶-4(3H)-酮10.0g(31.0mmol)和三氯氧磷30mL(315.3mmol),加热回流搅拌,待固体全部溶解后,再回流10min,减压蒸干溶剂,得棕黑色油状粗品。经柱层析分离(石油醚∶乙酸乙酯=2:1)得到淡黄色晶体9.4g,收率88.3%。m.p.:166-169℃;IR:(KBr,cm-1)3442(m),2974(s),2924(d),2875(s),1515(s),1493(s),1428(s),1383(s),1253(s),1122(s),1046(s),838(s);1H-NMR(400MHz,CDCl3):δ1.42(t,3H,CH3),1.96-2.06(m,1H,CH2),2.23-2.29(m,1H,CH2),2.98-8.15(m,4H,CH2),3.36-3.42(m,1H,CH),4.04(m,2H,CH2-O),6.89(d,2H,Ar-H,J=8.4Hz),7.19(d,2H,Ar-H,J=8.4Hz),8.74(s,1H,Ar-H);ESI-MS(m/z):345.3([M+H]+)。
步骤E:7-(4-乙氧基苯基)-4-苯硫基-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号01)的制备
将4-氯-7-(4-乙氧基苯基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶0.5g(1.5mmol)与苯硫酚0.2g(1.6mmol)投入50mL茄形瓶,加入正丁醇4.8mL,加入三乙胺0.4g(4.4mmol),加热回流反应1h,冷却析出固体,抽滤,用水10mL和乙醇30mL各洗涤1次,自然风干后即得到淡黄色固体0.5g,收率77.0%。m.p.:153-155℃;IR:(KBr,cm-1)3454(m),2919(s),2851(s),1643(m),1512(s),1493(s),1384(s),1246(s),1117(m),825(s),750(s),620(s);1H-NMR(400MHz,CDCl3):δ1.42(t,3H,CH3),2.01-2.09(m,1H,CH2),2.26-2.31(m,1H,CH2),2.94-3.01(m,1H,CH2),3.07-3.23(m,3H,CH2),3.45-3.50(m,1H,CH),4.04(m,2H,CH2),6.89(d,2H,Ar-H,J=8.8Hz),7.21(d,2H,Ar-H,J=8.8Hz),7.47(brs,3H,Ar-H),7.59-7.61(m,2H,Ar-H),8.55(s,1H,Ar-H);ESI-MS(m/z):419.4([M+H]+)。
实施例2:7-(4-乙氧基苯基)-4-(2-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号02)的制备
参照实例1的方法,制得7-(4-乙氧基苯基)-4-(2-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号02)0.4g,收率58.5%。m.p.:140-142℃;IR:(KBr,cm-1)3452(m),2921(s),2851(s),1612(m),1512(s),1495(s),1383(s),1246(s),1115(m),828(s),752(s),620(s);1H-NMR(400MHz,CDCl3):δ1.42(t,3H,CH3),1.99-2.09(m,1H,CH2),2.25-2.30(m,1H,CH2),2.94-3.01(m,1H,CH2),3.06-3.26(m,3H,CH2),3.50-3.56(m,1H,CH),3.80(s,3H,CH3),4.04(m,2H,CH2),6.89(d,2H,Ar-H,J=8.4Hz),7.02-7.07(m,2H,Ar-H),7.21(d,2H,Ar-H,J=8.4Hz),7.47-7.51(m,1H,Ar-H),7.56(dd,1H,J1=7.2Hz,J2=2.0Hz),8.53(s,1H,Ar-H);ESI-MS(m/z):449.2([M+H]+)。
实施例3:7-(4-乙氧基苯基)-4-(3-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号03)的制备
参照实例1的方法,制得7-(4-乙氧基苯基)-4-(3-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号03)0.4g,收率58.5%。m.p.:146-148℃;IR:(KBr,cm-1)3450(m),2921(s),2851(s),1641(m),1512(s),1492(s),1411(s),1383(s),1246(s),1114(s),828(s),779(s),620(s);1H-NMR(400MHz,CDCl3):δ1.42(t,3H,CH3),1.99-2.09(m,1H,CH2),2.26-2.31(m,1H,CH2),2.95-3.01(m,1H,CH2),3.06-3.21(m,3H,CH2),3.44-3.49(m,1H,CH),3.83(s,3H,CH3-O),4.04(m,2H,CH2),6.89(d,2H,Ar-H,J=8.8Hz),7.01(dd,1H,Ar-H,J1=8.4Hz,J2=2.4Hz),7.14(t,1H,Ar-H),7.17-7.22(m,3H,Ar-H),7.38(t,1H,Ar-H),8.58(s,1H,Ar-H);ESI-MS(m/z):449.3([M+H]+)。
实施例4:7-(4-乙氧基苯基)-4-(4-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号04)的制备
参照实例1的方法,制得7-(4-乙氧基苯基)-4-(4-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号04)0.4g,收率58.5%。m.p.:158-160℃;IR:(KBr,cm-1)3449(m),2923(s),2677(s),1592(s),1512(s),1494(s),1383(s),1245(s),1175(s),1115(s),1034(s),827(s),621(s);1H-NMR(400MHz,CDCl3):δ1.42(t,3H,CH3),2.00-2.09(m,1H,CH2),2.26-2.30(m,1H,CH2),2.94-3.02(m,1H,CH2),3.07-3.25(m,3H,CH2),3.46-3.50(m,1H,CH),3.87(s,3H,CH3-O),4.04(m,2H,CH2),6.89(d,2H,Ar-H,J=8.0Hz),7.00(d,2H,Ar-H,J=8.0Hz),7.20(d,2H,Ar-H,J=8.0Hz),7.50(d,2H,Ar-H,J=8.0Hz),8.56(s,1H,Ar-H);ESI-MS(m/z):449.2([M+H]+)。
实施例5:7-(4-乙氧基苯基)-4-(4-甲基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号05)的制备
参照实例1的方法,制得7-(4-乙氧基苯基)-4-(4-甲基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号05)0.5g,收率81.0%。m.p.:158-159℃;IR:(KBr,cm-1)3453(m),2920(s),2851(s),1640(s),1512(s),1495(s),1384(s),1244(s),1116(s),827(s),778(s),620(s);1H-NMR(400MHz,CDCl3):δ1.42(t,3H,CH3),1.99-2.09(m,1H,CH2),2.26-2.30(m,1H,CH2),2.42(s,3H,CH3),2.94-3.01(m,1H,CH2),3.06-3.24(m,3H,CH2),3.45-3.51(m,1H,CH),4.04(m,2H,CH2),6.89(d,2H,Ar-H,J=8.4Hz),7.21(d,2H,Ar-H,J=8.4Hz),7.28(d,2H,Ar-H,J=7.6Hz),7.48(d,2H,Ar-H,J=7.6Hz),8.56(s,1H,Ar-H);ESI-MS(m/z):433.2([M+H]+)。
实施例6:7-(4-乙氧基苯基)-4-(2,4-二甲基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号06)的制备
参照实例1的方法,制得7-(4-乙氧基苯基)-4-(2,4-二甲基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号06)0.6g,收率87.7%。m.p.:150-152℃;IR:(KBr,cm-1)3454(m),2921(s),2851(s),1642(m),1512(s),1494(s),1383(s),1247(s),1115(s),826(s),779(s),620(s);1H-NMR(400MHz,CDCl3):δ1.42(t,3H,CH3),2.00-2.10(m,1H,CH2),2.26-2.31(m,1H,CH2),2.34(s,3H,CH3),2.39(s,3H,CH3),2.94-3.01(m,1H,CH2),3.07-3.25(m,3H,CH2),3.49-3.55(m,1H,CH),4.05(m,2H,CH2),6.89(d,2H,Ar-H,J=8.8Hz),7.10(d,1H,Ar-H,J=8.0Hz),7.20-7.22(m,3H,Ar-H),7.45(d,1H,Ar-H,J=8.0Hz),8.53(s,1H,Ar-H);ESI-MS(m/z):447.3([M+H]+)。
实施例7:7-(4-乙氧基苯基)-4-(2-氟苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号07)的制备
参照实例1的方法,制得7-(4-乙氧基苯基)-4-(2-氟苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号07)0.6g,收率93.7%。m.p.:136-138℃;IR:(KBr,cm-1)3454(m),2919(s),2851(s),1641(m),1513(s),1494(s),1384(s),1248(s),1116(m),826(s),772(s),620(s);1H-NMR(400MHz,CDCl3):δ1.42(t,3H,CH3),2.00-2.10(m,1H,CH2),2.27-2.32(m,1H,CH2),2.94-3.01(m,1H,CH2),3.07-3.24(m,3H,CH2),3.46-3.52(m,1H,CH),4.05(m,2H,CH2),6.89(d,2H,Ar-H,J=8.4Hz),7.20-7.27(m,4H,Ar-H),7.48-7.54(m,1H,Ar-H),7.57-7.61(m,1H,Ar-H),8.53(s,1H,Ar-H);ESI-MS(m/z):437.3([M+H]+)。
实施例8:7-(4-乙氧基苯基)-4-(4-氟苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号08)的制备
参照实例1的方法,7-(4-乙氧基苯基)-4-(4-氟苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号08)0.2g,收率34.9%。m.p.:147-149℃;IR:(KBr,cm-1)3452(m),2921(s),1612(s),1513(s),1491(s),1384(s),1250(s),1119(s),828(s),777(s),621(s);1H-NMR(400MHz,CDCl3):δ1.42(t,3H,CH3),2.00-2.06(m,1H,CH2),2.28-2.30(m,1H,CH2),2.97-3.01(m,1H,CH2),3.08-3.21(m,3H,CH2),3.44-3.47(m,1H,CH),4.04(m,2H,CH2),6.89(d,2H,Ar-H,J=8.4Hz),7.16-7.21(m,4H,Ar-H),7.56-7.58(m,2H,Ar-H),8.57(s,1H,Ar-H);ESI-MS(m/z):437.0([M+H]+)。
实施例9:7-(4-乙氧基苯基)-4-(4-氯苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号09)的制备
参照实例1的方法,制得7-(4-乙氧基苯基)-4-(4-氯苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号09)0.6g,收率89.4%。m.p.:161-163℃;IR:(KBr,cm-1)3454(m),2921(s),2852(s),1640(s),1513(s),1496(s),1474(s),1383(s),1245(s),1116(m),822(s),746(s),621(s);1H-NMR(400MHz,CDCl3):δ1.42(t,3H,CH3),1.99-2.09(m,1H,CH2),2.26-2.30(m,1H,CH2),2.95-3.02(m,1H,CH2),3.06-3.21(m,3H,CH2),3.42-3.48(m,1H,CH),4.04(m,2H,CH2),6.89(d,2H,Ar-H,J=8.4Hz),7.20(d,2H,Ar-H,J=8.4Hz),7.44(d,2H,Ar-H,J=8.4Hz),7.52(d,2H,Ar-H,J=8.4Hz),8.55(s,1H,Ar-H);ESI-MS(m/z):453.0([M+H]+)。
实施例10:7-(4-乙氧基苯基)-4-(4-溴苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号10)的制备
参照实例1的方法,制得7-(4-乙氧基苯基)-4-(4-溴苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号10)0.6g,收率78%。m.p.:165-167℃;IR:(KBr,cm-1)3454(m),2920(s),2852(s),1640(m),1512(s),1496(s),1472(s),1384(s),1243(s),1115(m),826(s),779(s),620(s);1H-NMR(400MHz,CDCl3):δ1.42(t,3H,CH3),1.99-2.09(m,1H,CH2),2.26-2.30(m,1H,CH2),2.94-3.01(m,1H,CH2),3.06-3.19(m,3H,CH2),3.42-3.47(m,1H,CH),4.04(m,2H,CH2),6.89(d,2H,Ar-H,J=8.4Hz),7.20(d,2H,Ar-H,J=8.4Hz),7.45(d,2H,Ar-H,J=8.4Hz),7.59(d,2H,Ar-H,J=8.4Hz),8.55(s,1H,Ar-H);ESI-MS(m/z):496.8([M+H]+)。
实施例11:7-(4-羟基苯基)-4-苯硫基-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号11)的制备
将7-(4-乙氧基苯基)-4-苯硫基-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号01)0.6g(1.5mmol)和无水三氯化铝0.6g(4.5mmol)投入100mL茄形瓶,加入甲苯10mL,加热回流搅拌,反应1h后,停止反应,向反应体系中加入水30mL,室温下搅拌3h,抽滤,自然风干,产物经柱层析(甲醇:二氯甲烷=1:30)得到黄色固体0.3g,收率45.8%。m.p.:195-197℃;IR:(KBr,cm-1)3453(m),2920(s),2851(s),1641(m),1384(s),1115(m),829(s),780(s),620(s);1H-NMR(400MHz,CDCl3):δ1.42(t,3H,CH3),1.99-2.09(m,1H,CH2),2.25-2.31(m,1H,CH2),2.94-3.00(m,1H,CH2),3.06-3.24(m,3H,CH2),3.45-3.51(m,1H,CH),5.30(s,1H,Ar-OH),6.83(d,2H,Ar-H,J=8.4Hz),7.17(d,2H,Ar-H,J=8.4Hz),7.46-7.48(m,3H,Ar-H),7.59-7.61(m,2H,Ar-H),8.55(s,1H,Ar-H);ESI-MS(m/z):391.1([M+H]+)。
实施例12:7-(4-羟基苯基)-4-(4-甲基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号12)的制备
参照实例11的方法,制得7-(4-羟基苯基)-4-(4-甲基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号12)0.4g,收率58.3%。m.p.:227-229℃;IR:(KBr,cm-1)3443(m),2918(s),2850(s),1644(m),1516(s),1493(s),1412(s),1384(s),1112(s),829(s),781(s),620(s);1H-NMR(400MHz,CDCl3):δ2.01-2.08(m,1H,CH2),2.25-2.29(m,1H,CH2),2.42(s,3H,CH3),2.93-2.99(m,1H,CH2),3.05-3.21(m,3H,CH2),3.45-3.49(m,1H,CH),4.97(s,1H,Ar-OH),6.82(d,2H,Ar-H,J=7.2Hz),7.16(d,2H,Ar-H,J=7.2Hz),7.28(d,2H,Ar-H,J=7.2Hz),7.47(d,2H,Ar-H,J=7.2Hz),8.56(s,1H,Ar-H);ESI-MS(m/z):405.2([M+H]+)。
实施例13:7-(4-羟基苯基)-4-(2,4-二甲基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号13)的制备
参照实例11的方法,制得7-(4-羟基苯基)-4-(2,4-二甲基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号13)0.4g,收率54.7%。m.p.:250-252℃;IR:(KBr,cm-1)3453(m),2919(s),2851(s),1641(m),1513(s),1494(s),1410(s),1384(s),1108(m),829(s),782(s),620(s);1H-NMR(400MHz,CDCl3):δ1.99-2.10(m,1H,CH2),2.26-2.31(m,1H,CH2),2.34(s,3H,CH3),2.39(s,3H,CH3),2.93-3.00(m,1H,CH2),3.06-3.25(m,3H,CH2),3.49-3.54(m,1H,CH),4.75(s,1H,Ar-OH),6.83(d,2H,Ar-H,J=7.6Hz),7.09(d,1H,Ar-H,J=7.2Hz),7.18(t,3H,Ar-H),7.45(d,1H,Ar-H,J=7.2Hz),8.53(s,1H,Ar-H);ESI-MS(m/z):419.1([M+H]+)。
实施例14:7-(4-羟基苯基)-4-(2-氟苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号14)的制备
参照实例11的方法,制得7-(4-羟基苯基)-4-(2-氟苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号14)0.4g,收率62.7%。m.p.:111-113℃;IR:(KBr,cm-1)3449(m),2919(s),2851(s),1640(m),1515(s),1475(s),1413(s),1384(s),1111(m),827(s),758(s),619(s);1H-NMR(400MHz,CDCl3):δ1.99-2.10(m,1H,CH2),2.26-2.31(m,1H,CH2),2.94-3.01(m,1H,CH2),3.07-3.26(m,3H,CH2),3.46-3.51(m,1H,CH),4.80(s,1H,Ar-OH),6.83(d,2H,Ar-H,J=7.6Hz),7.17(d,2H,Ar-H,J=7.6Hz),7.21-7.23(m,1H,Ar-H),7.26(brs,1H,Ar-H),7.49-7.54(m,1H,Ar-H),7.59(t,1H,Ar-H),8.54(s,1H,Ar-H);ESI-MS(m/z):409.2([M+H]+)。
实施例15:7-(4-羟基苯基)-4-(4-氯苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号15)的制备
参照实例11的方法,制得7-(4-羟基苯基)-4-(4-氯苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号15)0.4g,收率66.1%。m.p.:209-211℃;IR:(KBr,cm-1)3452(m),2920(s),2851(s),1640(m),1515(s),1495(s),1414(s),1384(s),1110(s),826(s),780(s),620(s);1H-NMR(400MHz,CDCl3):δ2.02-2.06(m,1H,CH2),2.26-2.30(m,1H,CH2),2.94-3.00(m,1H,CH2),3.06-3.22(m,3H,CH2),3.42-3.47(m,1H,CH),4.78(s,1H,Ar-OH),6.83(d,2H,Ar-H,J=7.6Hz),7.16(d,2H,Ar-H,J=7.6Hz),7.43(d,2H,Ar-H,J=8.4Hz),7.52(d,2H,Ar-H,J=8.4Hz),8.55(s,1H,Ar-H);ESI-MS(m/z):425.2([M+H]+)。
实施例16:7-(4-羟基苯基)-4-(4-溴苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号16)的制备
参照实例11的方法,制得7-(4-羟基苯基)-4-(4-溴苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号16)0.4g,收率56.9%。m.p.:224-225℃;IR:(KBr,cm-1)3454(m),2920(s),2851(s),1640(m),1516(s),1496(s),1469(s),1413(s),1384(s),1113(s),828(s),781(s),620(s);1H-NMR(400MHz,CDCl3):δ2.04(brs,1H,CH2),2.25-2.30(m,1H,CH2),2.94-3.00(m,1H,CH2),3.06-3.16(m,3H,CH2),3.41-3.47(m,1H,CH),4.71(brs,1H,Ar-OH),6.82(d,2H,Ar-H,J=8.4Hz),7.16(d,2H,Ar-H,J=8.4Hz),7.45(d,2H,Ar-H,J=8.0Hz),7.59(d,2H,Ar-H,J=8.0Hz),8.55(s,1H,Ar-H);ESI-MS(m/z):469.0([M+H]+)。
实施例17:7-(4-羟基苯基)-4-(2-羟基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号17)的制备
将7-(4-乙氧基苯基)-4-(2-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号02)0.7g(1.5mmol)和无水三氯化铝1.2g(9.0mmol)投入100mL茄形瓶,加入甲苯11mL,加热回流搅拌,反应15min后,停止反应,向反应体系中加入水30mL,室温下搅拌3h,抽滤,自然风干,产物经柱层析(甲醇:二氯甲烷=1:30)得到黄色固体0.5g,收率72.6%。m.p.:116-118℃;IR:(KBr,cm-1)3452(m),2919(s),2851(s),1641(m),1515(s),1472(s),1414(s),1384(s),1111(m),830(s),755(s),620(s);1H-NMR(400MHz,DMSO):δ1.95-2.04(m,1H,CH2),2.13-2.17(m,1H,CH2),2.91-3.03(m,2H,CH2),3.09-3.17(m,2H,CH2),3.36-3.41(m,1H,CH),6.73(d,2H,Ar-H,J=8.0Hz),6.89(t,1H,Ar-H),6.98(d,1H,Ar-H,J=7.6Hz),7.15(d,2H,Ar-H,J=8.0Hz),7.35(t,1H,Ar-H),7.44(d,1H,Ar-H,J=7.6Hz),8.52(s,1H,Ar-H),9.22(s,1H,Ar-OH),9.93(s,1H,Ar-OH);ESI-MS(m/z):407.1([M+H]+)。
实施例18:7-(4-羟基苯基)-4-(3-羟基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号18)的制备
参照实例17的方法,制得7-(4-羟基苯基)-4-(3-羟基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号18)0.4g,收率63.6%。m.p.:214-216℃;IR:(KBr,cm-1)3450(m),2919(s),2850(s),1640(m),1515(s),1413(s),1384(s),1109(m),831(s),781(s),620(s);1H-NMR(400MHz,DMSO):δ1.95-2.04(m,1H,CH2),2.11-2.16(m,1H,CH2),2.91-3.14(m,5H,2×CH2,CH),6.73(d,2H,Ar-H,J=8.4Hz),6.90(d,1H,Ar-H,J=8.8Hz),6.99-7.02(m,2H,Ar-H),7.15(d,2H,Ar-H,J=8.4Hz),7.29(t,1H,Ar-H),8.58(s,1H,Ar-H),9.22(s,1H,Ar-OH),9.76(s,1H,Ar-OH);ESI-MS(m/z):407.2([M+H]+)。
实施例19:7-(4-羟基苯基)-4-(4-羟基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号19)的制备
参照实例17的方法,制得7-(4-羟基苯基)-4-(4-羟基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号19)0.3g,收率76.7%。m.p.:277-279℃;IR:(KBr,cm-1)3435(m),2919(s),2851(s),1643(m),1492(s),1412(s),1384(s),1111(m),829(s),782(s),620(s);1H-NMR(400MHz,DMSO):δ1.92-2.03(m,1H,CH2),2.12-2.16(m,1H,CH2),2.90-3.16(m,4H,2×CH2),3.36(brs,1H,CH),6.73(d,2H,Ar-H,J=7.6Hz),6.88(d,2H,Ar-H,J=8.0Hz),7.15(d,2H,Ar-H,J=7.6Hz),7.38(d,2H,Ar-H,J=8.0Hz),8.54(s,1H,Ar-H),9.22(s,1H,Ar-OH),9.95(s,1H,Ar-OH);ESI-MS(m/z):407.2([M+H]+)。
实施例20:7-(4-羟基苯基)-4-(2-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号20)的制备
步骤A:4-氯-7-(4-羟基苯基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶的制备
将4-氯-7-(4-乙氧基苯基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶2.5g(7.2mmol)和无水三氯化铝2.9g(21.6mmol)投入100mL茄形瓶,加入甲苯50mL,加热回流搅拌,反应30min后,停止反应,向反应体系中加入水100mL,室温下搅拌3h,抽滤,自然风干,经柱层析(甲醇:二氯甲烷=1:40)分离得到黄色固体1.1g,收率48.5%。m.p.:202-204℃;IR:(KBr,cm-1)3261(m),2907(m),1561(s),1540(s),1513(s),1487(s),1384(s),1221(s),1171(s),1131(s),845(s);1H-NMR(400MHz,DMSO):δ1.91-2.00(m,1H,CH2),2.09-2.14(m,1H,CH2),2.93-3.08(m,3H,CH2),3.13-3.17(m,1H,CH2),3.25(brs,1H,CH),6.72(d,2H,Ar-H,J=8.4Hz),7.14(d,2H,Ar-H,J=8.4Hz),8.84(s,1H,Ar-H),9.22(s,1H,Ar-OH);ESI-MS(m/z):317.2([M+H]+)。
步骤B:7-(4-羟基苯基)-4-(2-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号20)的制备
将4-氯-7-(4-羟基苯基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶0.5g(1.6mmol)和2-甲氧基苯硫酚0.2g(1.7mmol)投入50mL茄形瓶中,加入三乙胺0.5g(4.8mmol),加入正丁醇4mL,加热搅拌回流1h,反应结束后冷却析出晶体,抽滤,用水10mL和乙醇10mL各洗涤1次,自然风干后得到黄色固体0.5g,收率77.3%。m.p.:161-163℃;IR:(KBr,cm-1)3444(m),2921(s),2851(s),1585(s),1515(s),1412(s),1383(s),1247(s),1129(s),830(s),753(s),621(s);1H-NMR(400MHz,CDCl3):δ1.98-2.08(m,1H,CH2),2.25-2.29(m,1H,CH2),2.93-2.99(m,1H,CH2),3.05-3.25(m,3H,CH2),3.49-3.55(m,1H,CH),3.80(s,3H,CH3-O),4.93(s,1H,Ar-OH),6.82(d,2H,Ar-H,J=7.2Hz),7.02-7.07(m,2H,Ar-H),7.16(d,2H,Ar-H,J=7.2Hz),7.49(t,1H,Ar-H),7.55(d,1H,Ar-H,J=7.6Hz),8.51(s,1H,Ar-H);ESI-MS(m/z):420.9([M+H]+)。
实施例21:7-(4-羟基苯基)-4-(3-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号21)的制备
参照实例20的方法,制得7-(4-羟基苯基)-4-(3-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号21)0.5g,收率72.7%。m.p.:176-178℃;IR:(KBr,cm-1)3457(m),2920(s),2851(s),1640(m),1515(s),1383(s),1111(s),829(s),781(s),620(s);1H-NMR(400MHz,CDCl3):δ1.98-2.09(m,1H,CH2),2.26-2.29(m,1H,CH2),2.93-3.00(m,1H,CH2),3.06-3.21(m,3H,CH2),3.44-3.49(m,1H,CH),3.83(s,3H,CH3-O),4.78(s,1H,Ar-OH),6.83(d,2H,Ar-H,J=8.4Hz),7.01(d,1H,Ar-H,J=8.4Hz),7.14-7.19(m,4H,Ar-H),7.38(t,1H,Ar-H),8.58(s,1H,Ar-H);ESI-MS(m/z):421.2([M+H]+)。
实施例22:7-(4-羟基苯基)-4-(4-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号22)的制备
参照实例20的方法,制得7-(4-羟基苯基)-4-(4-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶(化合物编号22)0.6g,收率87.9%。m.p.:231-233℃;IR:(KBr,cm-1)3450(m),2920(s),2851(s),1642(m),1514(s),1494(s),1384(s),1250(s),1173(m),1110(s),827(s),621(s);1H-NMR(400MHz,CDCl3):δ2.02-2.10(m,1H,CH2),2.26-2.30(m,1H,CH2),2.95-3.00(m,1H,CH2),3.09-3.16(m,3H,CH2),3.45-3.50(m,1H,CH),3.87(s,3H,CH3-O),4.71(s,1H,Ar-OH),6.83(d,2H,Ar-H,J=8.4Hz),7.00(d,2H,Ar-H,J=8.8Hz),7.17(d,2H,Ar-H,J=8.4Hz),7.50(d,2H,Ar-H,J=8.8Hz),8.56(s,1H,Ar-H);ESI-MS(m/z):421.2([M+H]+)。
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。
药理实施例
实施例23:
表皮生长因子(EGFR)体外活性测定
按照Mowafy等(Eur.J.Med.Chem,2013,61,132-145)介绍的方法,进行本项测定。
本测定使用的是Kinase-Glo Plus发光激酶检测试剂盒。它通过测量激酶反应后溶剂中ATP的量来评定激酶活性。发光信号强弱与ATP的量成正比而与激酶活性成反比。将测试化合物在10%DMSO中稀释至100μM,然后取出5μl的稀释液加入到50μl的反应中以保证所有反应中DMSO的最终浓度均为1%。所有的酶促反应均在30℃下反应40min。在50μl的反应混合物中包含40mM的三羟甲基氨基甲烷(Tris),10mM的MgCl2,0.1mg/mL的牛血清白蛋白(BSA),0.2mg/mL的复合基质(Glu,Tyr),10μM的ATP和EGFR,并控制pH保持在7.4。在酶促反应结束后,向每个反应中加入50μl的Kinase-Glo Plus发光激酶检测溶剂并随后在室温下培育5min。发光信号通过Tecan公司的无限M1000型酶标仪来测定。
IC50值的测定通过使用ADP-GloTM检测试剂盒来完成。它通过蛋白激酶来测定ADP的生成,在上述试剂盒中伴随激酶反应而生成的ADP会导致发光信号增强。首先,将反应混合物置于96孔板中于30℃下培育30min,随后向其中加入25μl的ADP-GloTM试剂。摇晃该96孔板,然后于室温下继续培育40min。最后加入50μl的激酶检测试剂,随后96孔板的结果通过GloMax酶标仪来读取。空白组的试验方法与样品组完全平行一致。最终,蛋白激酶的活性数值通过减除空白组的数值来进行校正。
按照上述方法,测试本发明代表性化合物与EGFR的结合,IC50值的结果示于表1。
表1
实施例24:A-549细胞增殖测定
按照Stockert等(Acta Histochemica,2012,114(8),785-796)介绍的方法,进行本项测定。
本测定使用MTT法并利用人类肺癌细胞株A549来评价发明代表性化合物的抗肿瘤增值活性。A549细胞株在Dulbecco氏改进的Eagle培养基(DMEM)上进行培养,该培养基包含10%小牛血清(FBS),100U/mL的青霉素以及100g/mL的链霉素。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(8×104/mL),然后在含有5%CO2的湿润环境中培养过夜并控温在37℃。24h过后加入20μM/50μM的发明代表性化合物。再经过24h的培养,向其中加入MTT(5mg/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(TECAN SPECTRA,Wetzlar,德国)在490nm波长下测量吸光度。抑制作用通过抑制率和IC50值来表示。
按照上述方法测定本发明代表性化合物,结果示于表2。
表2
实施例25:对卵巢癌细胞SKOV3增殖的作用
对数生长期细胞用胰酶消化后,以6×103个/孔细胞数加人96孔培养板,置37℃、5%CO2培养箱中培养,第2天待大部分细胞贴壁后置人4℃恒温箱1h,以促成细胞同步化生长。吸去上清液,加人含10%新生小牛血清(FCS)RPMI 1640培养液,200μL/孔,按实验设计分组。把无菌生理盐水配制的化合物注射液加入96孔中,每孔中加入200μL,使每孔的药物浓度分别为1mg/mL、2mg/mL和5mg/mI,以0mg/mL为阴性对照组。继续培养24、48、72h后,各孔分别加人20μL MTT溶液(浓度为5mg/mL),轻轻震荡培养板,放回培养箱内再孵育4h,然后吸尽上清液,于各孔中加二甲亚砜200μL,置震荡器上震荡5-10min,用酶标光度计测出每孔中波长为580nm的吸光值(A=580),A=580值与活细胞数量成正比。
按照上述方法测定本发明代表性化合物,结果示于表3。
表3
实施例26:对骨肉瘤细胞U2OS-EGFP-4A12G增殖的作用
对数生长期细胞用胰酶消化后,台盼蓝计数,配制成细胞密度为1×l04个/mL的细胞悬液,接种于96孔板中,每孔200μL,每孔约2×103个细胞,预培养24h,把无菌生理盐水配制的化合物注射液加入96孔中,每孔中加入200μL,使每孔的药物浓度分别为1mg/mL、2mg/mL和5mg/mI,以0mg/mL为阴性对照组。在分别培养0h、12h、24h和48h后每孔加入MTT溶液(5mg/mL)20μL,继续孵育4h,终止培养。小心吸弃培养孔中的上清液,每孔加入150μL的二甲基亚砜(DMSO),震荡10min,使甲腊充分溶解,选择490nm波长,在酶联免疫检测仪上测定各孔光吸收值(A值),重复检测5次。
按照上述方法测定本发明代表性化合物,结果示于表4。
表4
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。
实施例27:明胶胶囊
硬明胶胶囊的制备采用:
可以根据所提供的合理变化来改进上述制剂。
实施例28:片剂
片剂的制备采用
将上述组分混合并压制成片剂。
实施例29:片剂
每片中含有2.5-1000mg活性组分的片剂制备如下:
使活性成分、淀粉和纤维素通过45号目筛并彻底混合。将聚乙烯吡咯烷酮溶液与所得粉末混合,随后经14号目筛。将生成的颗粒在50-60℃下干燥并经18号目筛。将预先经过60号目筛的羧甲基纤维素钠、硬脂酸镁和滑石粉加入到上述颗粒中,随后混合,在压片机上压制得到片剂。
实施例30:混悬液
每5ml含有0.1-1000mg药物的混悬液制备如下:
令药物经45号目筛并与羧甲基纤维素钠和糖浆混合形成平滑的糊剂。将苯甲酸溶液、矫味剂和着色剂用一些水稀释并在搅拌下加入上述糊剂。随后加入足量的水以达到所需的体积。
实施例31:组合片剂
使活性成分、淀粉和纤维素通过45号目筛并彻底混合。将聚乙烯吡咯烷酮溶液与所得粉末混合,随后经14号目筛。将生成的颗粒在50-60℃下干燥并经18号目筛。将预先经过60号目筛的羧甲基纤维素钠、硬脂酸镁和滑石粉加入到上述颗粒中,随后混合,在压片机上压制得到片剂。
对于上述说明,本领域技术人员可容易地理解本发明的必要特征,不背离本发明的精神和范围,本发明可进行各种改变和改进以适应不同的应用和条件。
Claims (9)
1.一种式Ⅰ的化合物或其药学上可接受的盐,所述式I化合物结构如下所示:
其中
R1为H或C1-C4烷基;
R2独立的选自H、卤素、C1-C4烷基、羟基、C1-C4烷氧基。
2.如权利要求1所述的式I的化合物或其药学上可接受的盐:
其中,R1为H或乙基。
3.如权利要求1或2所述的式I的化合物或其药学上可接受的盐:
R2独立的选自H、氟、氯、溴、甲基、羟基、甲氧基、2,4-二甲基。
4.如权利要求1所述的式I的化合物或其药学上可接受的盐,选自:
7-(4-乙氧基苯基)-4-苯硫基-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-乙氧基苯基)-4-(2-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-乙氧基苯基)-4-(3-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-乙氧基苯基)-4-(4-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-乙氧基苯基)-4-(4-甲基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-乙氧基苯基)-4-(2,4-二甲基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-乙氧基苯基)-4-(2-氟苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-乙氧基苯基)-4-(4-氟苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-乙氧基苯基)-4-(4-氯苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-乙氧基苯基)-4-(4-溴苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-羟基苯基)-4-苯硫基-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-羟基苯基)-4-(2-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-羟基苯基)-4-(3-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-羟基苯基)-4-(4-甲氧基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-羟基苯基)-4-(2-羟基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-羟基苯基)-4-(3-羟基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-羟基苯基)-4-(4-羟基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-羟基苯基)-4-(4-甲基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-羟基苯基)-4-(2,4-二甲基苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-羟基苯基)-4-(2-氟苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-羟基苯基)-4-(4-氯苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶;
7-(4-羟基苯基)-4-(4-溴苯硫基)-5,6,7,8-四氢苯并[4,5]噻吩并[2,3-d]嘧啶。
5.一种药物组合物,包含权利要求1-4任何一项所述的式Ⅰ的化合物或其药学上可接受的盐作为活性成分和药物可接受的载体。
6.权利要求1-4任何一项所述的式Ⅰ化合物或其药学上可接受的盐或权利要求5所述的药物组合物在制备治疗非小细胞肺癌药物中的应用。
7.权利要求1-4任何一项所述的式Ⅰ化合物或其药学上可接受的盐或权利要求5所述的药物组合物在制备预防和治疗与表皮生长因子受体信号转导失调相关的疾病药物中的应用。
8.根据权利要求7所述的应用,其特征在于:所述表皮生长因子受体为HER-1、HER-2、HER-3或HER-4。
9.根据权利要求7所述的应用,其特征在于:其中所述的表皮生长因子受体信号转导失调的相关疾病为鳞癌,腺癌,大细胞癌,结肠直肠癌、乳腺癌,卵巢癌,肾细胞癌或支气管哮喘。
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