CN113801094A - 一种2-羰基苯并噻吩类化合物及其制备方法和用途 - Google Patents
一种2-羰基苯并噻吩类化合物及其制备方法和用途 Download PDFInfo
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- CN113801094A CN113801094A CN202111280281.7A CN202111280281A CN113801094A CN 113801094 A CN113801094 A CN 113801094A CN 202111280281 A CN202111280281 A CN 202111280281A CN 113801094 A CN113801094 A CN 113801094A
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Abstract
Description
技术领域
本发明涉及一种化合物及制备方法和用途,具体涉及一种2-羰基苯并噻吩类化合物或其可药用的盐及其制备方法和用途。
背景技术
雌激素受体(ER)与其内源性的配体17β-雌二醇(E2)发生特异性结合后,可通过激发雌激素受体介导的相关信号通路来调控乳腺上皮细胞的增殖、分化和凋亡。ERα已被证实与乳腺癌细胞的增长和繁殖密切相关,其作为有效的乳腺癌治疗靶点,一直被广泛研究。基于ERα的内分泌治疗是目前临床中治疗乳腺癌的一种重要方法。然而,目前多数内分泌治疗药物在长期用药当中,不可避免存在耐药性,部分药物具有诱发子宫内膜癌的风险。因此,急需开发新型的ERα调节剂。
发明内容
发明目的:本发明目的是提供一种2-羰基苯并噻吩类化合物或其可药用的盐,作为ERα调节剂治疗乳腺癌。本发明的另一目的是提供上述化合物或其可药用的盐的制备方法。本发明的最后一个目的是提供所述的化合物或其可药用的盐在制备治疗人乳腺癌、子宫内膜癌的药物中的用途。
技术方案:本发明提供的2-羰基苯并噻吩类化合物或其可药用的盐,包含结构如通式(I)或(II)所示的化合物:
其中,
R1选自NHCH3、N(CH3)2、NHCH2CH2OH、OCH2CH3、碳数为3~5的N杂环、吗啡啉基;
R2选自氢、C1-C3烷基;
R3选自氢、C1-C3烷基。
所述的2-羰基苯并噻吩类化合物或其可药用的盐,所述化合物选自如下结构:
药物组合物,包含一种或多种所述的2-羰基苯并噻吩类化合物或其可药用的盐,及药学上可接受的载体。
所述的2-羰基苯并噻吩类化合物或其可药用的盐的制备方法,包括以下步骤:
对甲氧基苯甲醛(1)与丙二酸发生反应得到中间体(2),然后通过二氯亚砜酰化反应得中间体(3),接着通过Weinreb酰胺化反应得化合物(4),冰浴下通过格氏反应得中间体(5),然后依次脱掉甲基保护基(6)、通过苄基保护反应得中间体(7);
中间体(7)再与中间体(8)发生亲核取代反应得中间体(9),脱Boc保护基(10)后与侧链发生亲核取代或通过与不同类型的酰氯进行缩合得化合物(11-16),最后通过三溴化硼脱掉苄基保护基得通式(I)所述2-羰基苯并噻吩类化合物或其可药用的盐;
或,中间体(7)与中间体(19)发生亲核取代反应,得中间体(20),然后通过脱Boc保护基,再与侧链发生亲核取代或通过与不同类型的酰氯进行缩合得化合物(22-31),最后通过三溴化硼脱掉保护基得通式(II)所述2-羰基苯并噻吩类化合物或其可药用的盐。
所述的2-羰基苯并噻吩类化合物或其可药用的盐的制备方法,所述中间体(8)是通过以下步骤制备所得:
对苄氧基苯酚通过亲核反应得化合物(18),Pd/C催化下通过氢化反应得化合物(8)。
所述的2-羰基苯并噻吩类化合物或其可药用的盐的制备方法,所述中间体(19)是通过以下步骤制备所得:
对苄氧基苯酚通过亲核反应得化合物(32),Pd/C催化下通过氢化反应得化合物(19)。
所述的2-羰基苯并噻吩类化合物或其可药用的盐或者所述的药物组合物在制备治疗乳腺癌药物中的用途。
所述的2-羰基苯并噻吩类化合物或其可药用的盐或者所述的药物组合物在制备治疗子宫内膜癌药物中的用途。
有益效果:本发明的2-羰基苯并噻吩类化合物或其可药用的盐对MCF-7细胞以及Ishikawa细胞具有抗增殖作用,可用于制备治疗人乳腺癌、子宫内膜癌的药物,具有良好的市场应用前景。
附图说明
图1为裸鼠移植瘤实验的结果(他莫昔芬p.o 100mg/kg/day,XH07 i.v 30mg/kg/day,给药18天)。图1 A为给药后的肿瘤图片;图1 B为肿瘤体积抑制图,x轴为以天为单位的治疗时间,y轴为以mm3为单位的平均肿瘤体积;图1 C为给药后的肿瘤平均重量图;图1 D为给药后的子宫平均湿重图。
具体实施方式
以下实施例中的终产物以及中间体的核磁谱图数据是以DMSO-d6或者CDCl3或Methanol-d4为溶剂,TMS为内标,由Bruker公司的300MHz或者400MHz核磁共振仪测定;高分辨质谱(HRMS)均是由安捷伦公司的型号为Q-TOF 6520的质谱仪测定。
化合物的合成、纯化、分离中所使用的试剂有:(1)柱层析硅胶:200或者300目硅胶均购自青岛海洋化工;(2)HSGF254型TLC薄层色谱板:购自烟台化工研究所;(3)柱层析洗脱系统中所使用的常规溶剂如石油醚、二氯甲烷、乙酸乙酯、甲醇等以及反应所需的化学试剂,除特殊说明外,均为市售化学纯或分析纯产品。
实施例1:对甲氧基肉桂酸(2)的制备
将4-甲氧基苯甲醛(6.5g,47.8mmol),丙二酸(9.9g,95.6mmol)在吡啶(60ml)和哌啶(3.2ml)中的溶液回流90分钟。将得到的溶液倒入冰水中,然后加入浓HCl(40ml)。产物沉淀并通过过滤分离,用水洗涤并干燥,从乙醇中重结晶,得到白色针状固体(7.8g,92%)。1HNMR(300MHz,DMSO-d6)δ7.68-7.50(m,3H),6.98-6.95(m,2H),6.38(d,1H).。
实施例2:2-氯甲酰基-3-氯-6-甲氧基苯并噻吩(3)的制备
将对甲氧基肉桂酸(10g,56.18mmol)加入到60ml氯苯中,加入SOCl2(40mL,561.8mmol),吡啶(0.45mL,5.618mmol)。将反应液加热到130℃,搅拌5小时,反应液呈亮黄色。待反应结束后,减压蒸馏除去过量的二氯亚砜和氯苯,并将剩余的半固体反应液加入到正己烷中,60℃下搅拌半小时。然后过滤,得黄色固体7g,产率为40%,该固体可不经纯化直接用于下一步反应。
实施例3:2-(N-甲基-N-甲氧基甲酰胺)-3-氯-6-甲氧基苯并噻吩(4)的制备
在氮气保护下,将2-氯甲酰基-3-氯-6-甲氧基苯并噻吩(2g,7.7mmol)溶于15mL无水二氯甲烷中,将N,O-二甲基羟胺盐酸盐(0.83g,8.5mmol)加入其中,然后滴加三乙胺(5.4mL,38.8mmol)。将所得溶液在室温搅拌18h,将反应液用水淬灭,并用乙酸乙酯萃取,用水,盐水洗涤,并用Na2SO4干燥,减压蒸馏浓缩,柱层析纯化,得到黄色固体(13.8g,62.4%)。1HNMR(300MHz,CDCl3)δ7.82(d,J=8.9Hz,1H),7.23-7.21(m,1H),7.09-7.07(m,1H),3.90(s,3H),3.73(s,3H),3.39(s,3H).
实施例4:2-苯甲酰基-3-氯-6-甲氧基苯并噻吩(5)的制备
在0℃中,N2保护下,2-(N-甲基-N-甲氧基甲酰胺)-3-氯-6-甲氧基苯并噻吩(2g,7.0mmol)溶解在15ml无水THF中的溶液中,苯基溴化镁(8.4ml,8.4mmol)逐滴加入混合物中。将该溶液在0℃搅拌5h。将所得溶液用水淬灭,并用EA(50ml×3)萃取,干燥并浓缩至干,并通过柱层析纯化,得到所需化合物,黄色固体(1.5g,65%)。1H NMR(300MHz,CDCl3)δ7.88-7.79(m,3H),7.63-7.54(m,1H),7.50-7.45(m,2H),7.25-7.24(m,1H),7.10-7.05(m,1H),3.90(s,3H).
实施例5:2-苯甲酰基-3-氯-6-羟基苯并噻吩(6)的制备
在0℃和N2保护下,将2-苯甲酰基-3-氯-6-甲氧基苯并噻吩(2g,6.6mmol)溶于10ml DCM的溶液中,将BBr3(26.4ml,1M)滴加到混合物中。将所得溶液在0℃下搅拌2h。TLC监测反应结束后,加入水淬灭反应液,DCM萃取,合并有机相,干燥并浓缩至干,通过柱层析纯化,得到目标化合物,为黄色固体(1.62g,85%)。1H NMR(300MHz,CDCl3)δ7.91-7.80(m,3H),7.65-7.59(m,1H),7.52-7.47(m,2H),7.26-7.25(s,1H),7.08-7.05(m,1H).
实施例6:2-苯甲酰基-3-氯-6-苄氧基苯并噻吩(7)的制备
在氮气保护下,0℃中将2-苯甲酰基-3-氯-6-羟基苯并噻吩(2g,6.94mmol)溶解于10mlDMF中,NaH(77mg,3.23mmol)和溴化苄(1.19g)缓慢加入。将溶液在室温下搅拌1h。将所得溶液用NH4Cl水溶液淬灭并用DCM萃取,用无水Na2SO4干燥,过滤并浓缩,通过柱层析纯化,得到期望的化合物,为黄色固体(2.13g,81%)。1H NMR(300MHz,DMSO-d6)δ7.89-7.81(m,4H),7.74-7.66(m,1H),7.57-7.50(m,2H),7.53-7.47(m,2H),7.46-7.29(m,4H),5.24(s,2H).
实施例7:2-苯甲酰基-3-氧-(4-(2-(叔丁氧基羰基氨基)乙氧基)苯基)-6-苄氧基苯并噻吩(9)的制备
化合物2-苯甲酰基-3-氯-6-苄氧基苯并噻吩(2g,5.29mmol)溶解在10ml DMF中,将侧链化合物8(1.47g,5.82mmol)和Cs2CO3(3.45g,10.6mmol)加入到反应液中。该溶液在50℃下搅拌18h。将所得溶液用水淬灭并用DCM萃取,干燥并浓缩至干,通过柱色层析纯化,得到所需化合物,为黄色固体(2.2g,70%)。1H NMR(300MHz,CDCl3)δ7.70-7.67(m,2H),7.50-7.30(m,10H),7.02-6.98(m,1H),6.64-6.58(m,2H),6.54-6.47(m,2H),5.16(s,2H),4.99-4.96(m,1H),3.89-3.85(m,2H),3.47-3.44(m,2H),1.44(s,9H).
实施例8:2-苯甲酰基-3-氧-(4-(2-氨基乙氧基)苯基)-6-苄氧基苯并噻吩(10)的制备
将2-苯甲酰基-3-氧-(4-(2-(叔丁氧基羰基氨基)乙氧基)苯基)-6-苄氧基苯并噻吩(2g,3.36mmol)溶解在5ml DCM中,加入5ml浓盐酸。反应液在室温搅拌2h。完成后,浓缩混合物以除去大部分HCl,用NaHCO3水溶液将PH调节至7-8,用DCM萃取,将合并的有机层浓缩至干,直接用于下一步。1H NMR(300MHz,CDCl3)δ7.79-7.71(m,2H),7.58-7.34(m,10H),7.06-7.01(m,1H),6.72-6.64(m,2H),6.61-6.53(m,2H),5.20(s,2H),3.92(t,J=5.1Hz,2H),3.08(t,J=5.1Hz,2H).
实施例9:(E)-4-((2-(4-((2-苯甲酰基-6-苄氧基苯并噻吩-3-基)氧基)苯氧基)乙基)氨基)-N-甲基-丁-2-烯酰胺(11)的制备
将2-苯甲酰基-3-氧-(4-(2-氨基乙氧基)苯基)-6-苄氧基苯并噻吩(500mg,1.0mmol)溶于5mlDMF的溶液中,加入(E)-4-溴-N-甲基-2-丁烯酰胺(161mg,0.9mmol)和DIPEA(1.29g,10mmol)。将最终溶液在室温搅拌18h。将所得溶液用DCM萃取,并用LiCl水溶液洗涤,将合并的有机层浓缩至干,并通过柱层析法纯化,得到目标化合物,为黄色固体(323mg,54%)。1H NMR(300MHz,CDCl3)δ7.73-7.67(m,2H),7.50-7.30(m,11H),7.05-6.80(m,2H),6.65-6.47(m,4H),5.95-5.91(m,1H),5.15(s,2H),3.94-3.91(m,2H),3.43-3.39(m,2H),2.95(t,J=5.0Hz,2H),2.85(d,J=4.9Hz,3H).
实施例10:(E)-4-((2-(4-((2-苯甲酰基-6-羟基苯并噻吩-3-基)氧基)苯氧基)乙基)氨基)-N-甲基-2-丁烯酰胺(XH01)的制备
在冰水浴、氮气保护下,将化合物11(500mg,0.84mmol)溶解到5mL的二氯甲烷溶液中,冰水浴下加入BBr3(2.49mL,1M的二氯甲烷溶液),将该溶液在冰水浴下搅拌1.5小时,TLC监测反应直到结束。待反应结束后,用MeOH淬灭反应,浓缩至干,并通过柱层析纯化(DCM∶MeOH=30∶1-10∶1),得黄色固体(218mg,产率52%)。1H NMR(300MHz,MeOD)δ7.66-7.61(m,2H),7.52-7.46(m,1H),7.36-7.31(m,3H),7.23-7.22(m,1H),6.89-6.67(m,4H),6.54-6.47(m,2H),6.09-6.03(m,1H),3.97(t,J=5.2Hz,2H),3.44-3.42(m,2H),2.95-2.91(t,J=5.2Hz,2H),2.77(s,3H).MS ESI m/z 503.3[M+H]+.
实施例11:(E)-4-((2-(4-((2-苯甲酰基-6-羟基苯并噻吩-3-基)氧基)苯氧基)乙基)氨基)-N,N-二甲基-丁-2-烯酰胺(XH02)的制备
将化合物XH02的合成方法与上述XH01合成方法类似。1H NMR(300MHz,MeOD)δ7.65-7.63(m,2H),7.54-7.46(m,1H),7.37-7.34(m,3H),7.24-7.21(m,1H),6.92-6.68(m,4H),6.63-6.57(m,1H),6.53-6.46(m,2H),3.99-3.94(t,2H),3.50-3.48(m,2H),3.11(s,3H),3.11-2.95(m,5H).MS ESI m/z 517.3[M+H]+.
实施例12:(E)-4-((2-(4-((2-苯甲酰基-6-羟基苯并噻吩-3-基)氧基)苯氧基)乙基)氨基)-1-(4-吗啉基)-丁-2-烯-1-酮(XH03)的制备
将化合物XH03的合成方法与上述XH01合成方法类似。1H NMR(300MHz,MeOD)δ7.65-7.62(m,2H),7.53-7.47(m,1H),7.38-7.32(m,3H),7.24-7.23(m,1H),6.90-6.77(m,2H),6.76-6.66(m,2H),6.64-6.47(m,3H),3.99(t,J=5.1Hz,2H),3.63(m,8H),3.49-3.47(m,2H),2.96(t,J=5.2Hz,2H).MS ESI m/z 559.3[M+H]+.
实施例13:N-(2-(4-((2-苯甲酰基-6-苄氧基苯并噻吩-3-基)氧基)苯氧基)乙基)丙烯酰胺(14)的制备
在冰水浴、氮气保护下,将化合物2-苯甲酰基-3-氧-(4-(2-氨基乙氧基)苯基)-6-苄氧基苯并噻吩(495mg,1mmol)溶于5mL二氯甲烷溶液中,随之加入丙烯酰氯(99mg,1.1mmol)和DIPEA(258mg,2mmol),所得反应液在0℃下搅拌2h直至反应完成。待反应结束后,将反应液用20mL H2O淬灭,并用二氯甲烷萃取,合并有机层并用无水Na2SO4干燥、减压浓缩至干,所得固体无需进一步纯化即可用于下一步反应。。1H NMR(400MHz,CDCl3)δ7.77-7.68(m,2H),7.52-7.32(m,11H),7.09-7.03(m,1H),6.67-6.52(m,4H),6.33-6.29(m,1H),6.18-6.05(m,2H),5.68-5.61(m,1H),5.18(s,2H),3.97(t,J=5.1Hz,2H),3.78-3.70(m,2H).
实施例14:N-(2-(4-((2-苯甲酰基-6-羟基苯并噻吩-3-基)氧基)苯氧基)乙基)丙烯酰胺(XH04)的制备
将化合物14(100mg,0.18mmol)溶于在10mlDCM中。0℃,N2保护下滴加BBr3(0.9ml,0.9mmol)。将该溶液在0℃下搅拌1.5h。TLC监测反应结束后,加入水淬灭反应液,用DCM萃取,收集有机相减压浓缩,然后通过柱层析纯化,得到黄色固体(62mg,74%)。1H NMR(300MHz,MeOD)δ7.64-7.58(m,2H),7.52-7.44(m,1H),7.37-7.29(m,3H),7.23-7.22(m,1H),6.86-6.82(m,1H),6.70-6.62(m,2H),6.51-6.43(m,2H),6.28-6.22(m,2H),5.66-5.62(m,1H),3.94(t,J=5.4Hz,2H),3.57(t,J=5.4Hz,2H).MS ESI m/z 482.2[M+Na]+.
实施例15:(E)-N-(2-(4-((2-苯甲酰基-6-苄氧基苯并噻吩-3-基)氧基)苯氧基)乙基)-丁-2-烯酰胺(XH05)的制备
化合物XH05的合成方法与上述化合物XH04的合成方法类似。1H NMR(300MHz,MeOD)δ7.64-7.58(m,2H),7.51-7.44(m,1H),7.36-7.29(m,3H),7.23-7.22(m,1H),6.86-6.72(m,2H),6.71-6.62(m,2H),6.54-6.44(m,2H),5.98-5.92(m,1H),3.92(t,J=5.4Hz,2H),3.55(t,J=5.4Hz,2H),1.83-1.79(m,3H).MS ESI m/z 496.3[M+Na]+.
实施例16:N-(2-(4-((2-苯甲酰基-6-羟基苯并噻吩-3-基)氧基)苯氧基)乙基)甲基丙烯酰胺(XH06)的制备
化合物XH06的合成方法与上述化合物XH04的合成方法类似。1H NMR(300MHz,MeOD)δ7.63-7.60(m,2H),7.51-7.46(m,1H),7.36-7.31(m,3H),7.23(m,1H),6.85-6.81(m,1H),6.73-6.65(m,2H),6.50-6.47(m,2H),5.71-5.66(m,1H),5.37-5.35(m,1H),3.95(t,J=5.6Hz,2H),3.56(t,J=5.6Hz,2H),1.92(s,3H).MS ESI m/z 496.3[M+Na]+.
实施例17:(2-(4-(苄氧基)苯氧基)乙基)氨基甲酸叔丁酯(18)的制备
4-苄氧基苯酚(2g,10mmol)溶于15mlDMF中,依次加入2-溴乙基氨基甲酸叔丁酯(2.24g,10mmmol),K2CO3(4.14g,30mmol),Cs2CO3(3.25g,10mmol),室温搅拌48h。用DCM萃取反应液,并用LiCl水溶液洗涤,将有机相合并浓缩,通过柱层析纯化,得到目标化合物,为白色固体(2.91g,85%)。
实施例18:(2-(4-羟基苯氧基)乙基)氨基甲酸叔丁酯(8)的制备
(2-(4-(苄氧基)苯氧基)乙基)氨基甲酸叔丁酯(2g,5.8mmol)溶于20ml甲醇中,加入Pd/C(200mg),室温搅拌18h。过滤反应液,减压浓缩至干,通过柱层析纯化,到目标化合物,为白色固体(1.3g,88%)。1H NMR(300MHz,CDCl3)δ6.95-6.80(m,4H),4.03(t,J=5.1Hz,2H),3.60-3.57(m,3H),1.58(s,9H).
实施例19:3-(4-((2-苯甲酰基-6-苄氧基苯并噻吩-3-基)氧基)苯氧基)氮杂环丁烷-1-甲酸叔丁酯(20)的制备
2-苯甲酰基-3-氯-6-苄氧基苯并噻吩(2g,5.27mmol)溶于10mlDMF中,将3-(4-羟基苯氧基)氮杂环丁烷-1-甲酸叔丁酯(1.54g,5.80mmol)和Cs2Co3(3.43g,10.6mmol)加入反应液,反应液70℃加热搅拌18h。将所得反应液加入水淬灭,用DCM萃取,将有机层浓缩至干,并通过柱层析法纯化,得到目标化合物,为黄色固体(1.8g,56%)。1H NMR(400MHz,DMSO-d6)δ7.79-7.75(m,1H),7.71-7.65(m,2H),7.59-7.54(m,1H),7.50-7.48(m,2H),7.45-7.35(m,6H),7.11-7.04(m,1H),6.62-6.47(m,4H),5.23(s,2H),4.86-4.81(m,1H),4.23-4.19(m,2H),3.74-3.68(m,2H),1.38(s,9H).
实施例20:(3-(4-(3-氧基-氮杂环丁烷基)苯氧基)-6-苄氧基苯并噻吩-2-基)(苯基)甲酮(21)的制备
3-(4-((2-苯甲酰基-6-苄氧基苯并噻吩-3-基)氧基)苯氧基)氮杂环丁烷-1-甲酸叔丁酯(2g,3.29mmol)溶解在5mlDCM中,加入5ml浓盐酸。反应液在室温搅拌2h。完成后,浓缩混合物以除去大部分HCl,用NaHCO3水溶液将PH调节至7-8,用DCM萃取,将合并的有机层浓缩至干,无需进一步纯化即可用于下一步。1H NMR(300MHz,CDCl3)δ7.68-7.62(m,2H),7.52-7.31(m,10H),7.02-6.99(m,1H),6.53-6.37(m,4H),5.15(s,2H),4.91-4.81(m,1H),3.93-3.81(m,2H),3.76-3.67(m,2H).
实施例21:(E)-4-(3-(4-((2-苯甲酰基-6-苄氧基苯并噻吩-3-基)氧基)苯氧基)氮杂环丁烷-1-基)-N-甲基-丁-2-烯酰胺(22)的制备
(3-(4-(3-氧基-氮杂环丁烷基)苯氧基)-6-苄氧基苯并噻吩-2-基)(苯基)甲酮(500mg,0.99mol)溶于5mlDMF的溶液中,加入(E)-4-溴-N-甲基-丁-2-烯酰胺(158mg,0.89mmol)和DIPEA(1.27g,9.9mmol)。将最终溶液在室温搅拌18h。将所得溶液用DCM萃取,并用LiCl水溶液洗涤,将合并的有机层浓缩至干,并通过柱层析法纯化,得到目标化合物,为黄色固体(333mg,56%)。1H NMR(300MHz,CDCl3)δ7.77-7.71(m,2H),7.57-7.38(m,10H),7.07-7.05(m,1H),6.78-6.73(m,1H),6.53-6.48(m,4H),5.99-5.94(m,1H),5.21(s,2H),4.71(t,J=5.7Hz,1H),3.91-3.77(m,2H),3.34-3.29(m,2H),3.17-3.13(m,2H),2.92(d,J=4.9Hz,3H).
实施例22:(E)-4-(3-(4-((2-苯甲酰基-6-羟基苯并噻吩-3-基)氧基)苯氧基)氮杂环丁烷-1-基)-N-甲基-丁-2-烯酰胺(XH07)的制备
将化合物22(100mg,0.16mmol)溶于在10ml DCM中。0℃,N2保护下滴加BBr3(0.8ml,0.8mmol)。将该溶液在0℃下搅拌1.5h。TLC监测反应结束后,加入水淬灭反应液,用DCM萃取,收集有机相减压浓缩,然后通过柱层析纯化,得到黄色固体(59mg,70%)。1H NMR(400MHz,MeOD)δ7.64-7.61(m,2H),7.52-7.49(m,1H),7.40-7.30(m,3H),7.24(d,J=2.4Hz,1H),6.87-6.85(m,1H),6.67-6.62(m,1H),6.58-6.47(m,4H),6.04-5.99(m,1H),4.73-4.69(m,1H),3.83-3.71(m,2H),3.21-3.13(m,2H),2.77(m,3H).MS ESI m/z 537.2[M+Na]+.
实施例23:(E)-4-(3-(4-((2-苯甲酰基-6-羟基苯并噻吩-3-基)氧基)苯氧基)氮杂环丁烷-1-基)-N,N二甲基-丁-2-烯酰胺(XH08)的制备
化合物XH08的合成方法与上述化合物XH07的合成方法类似。1H NMR(300MHz,MeOD)δ7.64-7.60(m,2H),7.52-7.44(m,1H),7.38-7.32(m,1H),7.24-7.23(m,1H),6.88-6.85(m,1H),6.69-6.61(m,1H),6.57-6.43(m,5H),4.88-4.71(m,1H),3.85-3.73(m,2H),3.36-3.32(m,2H),3.23-3.18(m,2H),3.12(s,3H),2.98(s,3H).MS ESI m/z 551.2[M+Na]+.
实施例24:(E)-4-(3-(4-((2-苯甲酰基-6-羟基苯并噻吩-3-基)氧基)苯氧基)氮杂环丁烷-1-基)-1-(1-吡咯烷基)-丁-2-烯-1-酮(XH09)的制备
化合物XH09的合成方法与上述化合物XH07的合成方法类似。1H NMR(300MHz,MeOD)δ7.64-7.56(m,2H),7.52-7.43(m,1H),7.35-7.29(m,3H),7.23-7.22(m,1H),6.84(m,1H),6.73-6.65(m,1H),6.54-6.33(m,5H),4.70-4.66(m,1H),3.78-3.73(m,2H),3.58-3.53(m,2H),3.47-3.42(m,2H),3.35-3.32(m,2H),3.20-3.18(m,2H),2.02-1.77(m,4H).MS ESIm/z577.2[M+Na]+.
实施例25:(E)-4-(3-(4-((2-苯甲酰基-6-羟基苯并噻吩-3-基)氧基)苯氧基)氮杂环丁烷-1-基)-1-(1-哌啶基)-丁-2-烯-1-酮(XH10)的制备
化合物XH10的合成方法与上述化合物XH07的合成方法类似。1H NMR(300MHz,MeOD)δ7.63-7.57(m,2H),7.51-7.42(m,1H),7.37-7.28(m,3H),7.24-7.23(m,1H),6.84(m,1H),6.68-6.43(m,6H),4.71-4.63(m,1H),3.80-3.70(m,2H),3.59-3.53(m,4H),3.36-3.31(m,2H),3.23-3.14(m,2H),1.69-1.63(m,2H),1.57-1.52(m,4H).MS ESI m/z 491.3[M+Na]+.
实施例26:(E)-4-(3-(4-((2-苯甲酰基-6-羟基苯并噻吩-3-基)氧基)苯氧基)氮杂环丁烷-1-基)-1-(4-吗啉基)-2-丁烯-1-酮(XH11)的制备
化合物XH11的合成方法与上述化合物XH07的合成方法类似。1H NMR(300MHz,MeOD)δ7.61-7.58(m,2H),7.51-7.47(m,1H),7.37-7.31(m,3H),7.24-7.23(m,1H),6.88-6.84(m,1H),6.67-6.63(m,1H),6.59-6.45(m,5H),4.72-4.66(m,1H),3.78-3.75(m,2H),3.66-3.60(m,8H),3.35-3.30(m,2H),3.23-3.18(m,2H).MS ESI m/z 571.2[M+H]+.
实施例27:(E)-4-(3-(4-((2-苯甲酰基-6-羟基苯并噻吩-3-基)氧基)苯氧基)氮杂环丁烷-1-基)-N-(2-羟基乙基)-丁-2-烯酰胺(XH12)的制备
化合物XH12的合成方法与上述化合物XH07的合成方法类似。1H NMR(300MHz,MeOD)δ7.62-7.60(m,2H),7.52-7.47(m,1H),7.37-7.31(m,3H),7.24-7.22(m,1H),6.88-6.84(m,1H),6.70-6.61(m,1H),6.57-6.47(m,3H),6.14-6.09(m,1H),4.74-4.72(m,1H),3.89-3.84(m,2H),3.62(t,J=5.6Hz,2H),3.47-3.31(m,6H).MS ESI m/z 545.2[M+H]+.
实施例28:(E)-4-(3-(4-((2-苯甲酰基-6-羟基苯并噻吩-3-基)氧基)苯氧基)氮杂环丁烷-1-基)-丁-2-烯酸乙酯(XH13)的制备
化合物XH13的合成方法与上述化合物XH07的合成方法类似.1H NMR(300MHz,MeOD)δ7.62-7.59(m,2H),7.48(t,J=7.4Hz,1H),7.33(m,3H),7.23-7.21(m,1H),6.89-6.76(m,2H),6.54-6.45(m,4H),5.99-5.96(m,1H),4.69-4.66(m,1H),4.20-4.12(m,2H),3.78-3.73(m,2H),3.33-3.21(m,2H),3.18-3.15(m,2H),1.28-1.23(m,3H).MS ESI m/z530.2[M+H]+.
实施例29:1-(3-(4-((2-苯甲酰基-6-苄氧基苯并噻吩-3-基)氧基)苯氧基)氮杂环丁烷-1-基)-2-丙烯-1-酮(24)的制备
在冰水浴、氮气保护下,将(3-(4-(3-氧基-氮杂环丁烷基)苯氧基)-6-苄氧基苯并噻吩-2-基)(苯基)甲酮(507mg,1mmol)溶于5mL二氯甲烷溶液中,随之加入丙烯酰氯(99mg,1.1mmol)和DIPEA(258mg,2mmol)。最终反应液在0℃下搅拌2h直至反应完成,待反应结束后,将反应液用20mL H2O淬灭,并用二氯甲烷萃取,合并有机层、并用无水Na2SO4干燥、减压浓缩至干,所得固体无需进一步纯化即可用于下一步反应。1H NMR(400MHz,CDCl3)δ7.71-7.67(m,2H),7.51-7.34(m,10H),7.08-7.02(m,1H),6.53-6.45(m,4H),6.23-6.14(m,2H),5.72-5.67(m,1H),5.16(s,2H),4.86-4.81(m,1H),4.52-4.33(m,2H),4.22-4.00(m,2H).
实施例30:1-(3-(4-((2-苯甲酰基-6-羟基苯并噻吩-3-基)氧基)苯氧基)氮杂环丁烷-1-基)-2-丙烯-1-酮(XH14)的制备
在冰水浴、氮气保护下,将化合物24(200mg,0.35mmol)溶解到5mL的二氯甲烷溶液中,冰水浴下加入BBr3(1.75mL,在1M的二氯甲烷溶液)。将该溶液在冰水浴下搅拌1.5h,TLC监测反应直到结束。待反应结束后,用MeOH淬灭反应,浓缩至干,并通过柱层析纯化(DCM∶MeOH=30∶1-10∶1),得黄色固体(84mg,产率51%)。1H NMR(400MHz,CDCl3)δ7.64-7.61(m,2H),7.52-7.49(m,1H),7.39-7.33(m,3H),7.25-7.22(m,1H),6.89-6.86(m,1H),6.74-6.50(m,4H),6.38-6.22(m,2H),5.76-5.72(m,1H),4.93-4.91(m,1H),4.65-4.60(m,1H),4.41-4.36(m,1H),4.21-4.17(m,1H),3.95-3.92(m,1H).MS ESI m/z 494.1[M+Na]+.
实施例31:(E)-1-(3-(4-((2-苯甲酰基-6-羟基苯并噻吩-3-基)氧基)苯氧基)氮杂环丁烷-1-基)-2-丁烯-1-酮(XH15)的制备
化合物XH15的合成方法与上述化合物XH14的合成方法类似。1H NMR(300MHz,MeOD)δ7.63-7.60(m,2H),7.52-7.47(m,1H),7.40-7.30(m,3H),7.24-7.23(m,1H),6.90-6.77(m,2H),6.61-6.45(m,4H),6.04-5.97(m,1H),4.92-4.82(m,1H),4.61-4.55(m,1H),4.38-4.32(m,1H),4.16-4.11(m,1H),3.90-3.87(m,1H),1.89-1.86(m,3H).MS ESI m/z508.2[M+Na]+.
实施例32:1-(3-(4-((2-苯甲酰基-6-羟基苯并噻吩-3-基)氧基)苯氧基)氮杂环丁烷-1-基)-2-甲基-2-丙烯-1-酮(XH16)的制备
化合物XH16的合成方法与上述化合物XH14的合成方法类似。1H NMR(300MHz,MeOD)δ7.65-7.58(m,2H),7.53-7.45(m,1H),7.40-7.31(m,3H),7.24-7.23(m,2H),6.86-6.84(m,1H),6.57-6.46(m,4H),5.47-5.45(m,1H),5.37-5.35(m,1H),4.89-4.85(m,1H),4.64-4.58(m,1H),4.38-4.33(m,1H),4.21-4.16(m,1H),3.94-3.89(m,1H),1.90-1.89(m,3H).MS ESI m/z 508.2[M+Na]+.
实施例33:3-(4-苄氧基苯氧基)氮杂环丁烷-1-甲酸叔丁酯(32)的制备
4-苄氧基苯酚(2g,10mmol)溶于15mlDMF中,将3-碘代氮杂环丁烷-1-甲酸叔丁酯(3.4g,12mmol)和Cs2CO3(9.77g,30mmol)加入反应液,反应液140℃加热搅拌3h。TLC监测反应结束后,将反应液加入水淬灭,用DCM萃取,将有机层浓缩至干,并通过柱层析法纯化,得到目标化合物,为白色固体(2.70g,76%)。
实施例34:3-(4-羟基苯氧基)氮杂环丁烷-1-甲酸叔丁酯(19)的制备
3-(4-苄氧基苯氧基)氮杂环丁烷-1-甲酸叔丁酯(2g,5.63mmol)溶于20ml甲醇中,加入Pd/C(200mg),室温搅拌18h。过滤反应液,减压浓缩至干,通过柱层析纯化,到目标化合物,为白色固体(1.27g,85%)。1H NMR(300MHz,CDCl3)δ6.81-6.73(m,2H),6.62-6.54(m,2H),4.77-4.74(m,1H),4.30-4.16(m,2H),3.97-3.94(m,2H).
实施例35:活性测试
表1是以下活性测试所用到的试剂来源。
表1 试剂来源
试剂名称 | 生产厂家 |
不完全DMEM(高糖)培养基(含双抗) | 江苏凯基生物技术股份有限公司 |
不完全L-15培养基(含双抗) | 江苏凯基生物技术股份有限公司 |
南美胎牛血清(FBS) | GIBCO |
人乳腺癌MCF-7细胞株 | 南京厉行生物技术股份有限公司 |
人子宫内膜癌Ishikawa细胞株 | 南京厉行生物技术股份有限公司 |
人乳腺癌细胞株MDA-MB-231 | 南京厉行生物技术股份有限公司 |
CCK-8 | 上海碧云天生物技术有限公司 |
胰蛋白酶 | Biosharp |
PBS | 自制 |
无血清冻存液 | Bambanker |
阳性对照(Fulvestrant) | MedChemExpress |
DMSO | 南京化学试剂股份有限公司 |
阳性药(Raloxifene) | 阿拉丁 |
戊酸雌二醇 | 上海通用药业股份有限公司 |
表2是以下活性测试所用到的仪器来源。
表2 仪器来源
(一)人乳腺癌细胞株MCF-7的抗增殖活性实验
由于MCF-7细胞抗增殖实验可以用来初步评价化合物在体外对ER阳性乳腺癌的抑制作用,所以本文对合成的部分化合物进行了体外MCF-7抗增殖实验。
1、实验方法
取对数生长期的人乳腺癌MCF-7细胞用于生物活性测试,用完全培养基将消化下来的细胞团的密度稀释至3×104个/ml,并用排枪将此细胞悬液接种至96孔板中。每块96孔板各设一组空白阴性对照和一组空白阳性对照,阴性对照不加药也不加细胞悬液,用同体积的完全培养基替代,阳性对照只加细胞悬液不加药,给药时用同体积的含有0.1%的DMSO的完全培养基替代。另外,外周的36个孔为防止96孔板中央待测区的细胞悬液因长期置于细胞培养箱内而引起的溶剂挥发,需加入200μl的PBS缓冲溶液。铺完细胞后,放入细胞培养箱内孵育24h。然后取出96孔板,每孔加入100μl含样品的完全培养基,使得待测样品的最终浓度依次为80μM、40μM、20μM、10μM、1μM,每个浓度各设置3个复孔。放入培养箱内培养48h后,避光的条件下每孔加入20μl的CCK-8溶液,于培养箱中培养1-2h。取出96孔板,于酶标仪中检测其光吸收值(OD),检测波长设置为450nm。按照如下公式算出各浓度的抑制率,并用GraphPad Prism 7.0绘制出浓度-抑制率曲线,最后给出化合物的IC50值(抑制率=OD阳性-OD待测/OD阳性-OD阴性)。
2、实验结果
表3为化合物的药理(抗增殖)实验结果。
表3 化合物对MCF-7细胞株抗增殖实验结果
Compound | IC<sub>50</sub>(μM) | Compound | IC<sub>50</sub>(μM) |
XH01 | 19.75 | XH09 | 4.78 |
XH02 | 17.53 | XH10 | 0.98 |
XH03 | 14.93 | XH11 | 17.71 |
XH04 | 19.13 | XH12 | 12.23 |
XH05 | 20.31 | XH13 | 9.75 |
XH06 | 18.35 | XH14 | 22.44 |
XH07 | 8.00 | XH15 | 14.57 |
XH08 | 15.2 | XH16 | 15.35 |
Tamoxifen | 22.32 | Raloxifene | 28.71 |
上述人乳腺癌MCF-7细胞株来自南京厉行生物技术股份有限公司,他莫昔芬、雷洛昔芬实施例作对照组。
研究结果表明,本发明化合物对MCF-7细胞表现出较好的抑制活性。
(二)人子宫内膜癌细胞株Ishikawa的抗增殖活性实验
1、实验方法
操作以及给药浓度设置均与MCF-7相同,但调整了细胞孵育时间,Ishikawa细胞株的孵育时间为18h。
2、实验结果
表4为人子宫内膜癌细胞株Ishikawa的抗增殖活性实验结果。
表4 化合物对Ishikawa细胞株的抗增殖活性实验结果
上述人子宫内膜癌细胞株Ishikawa来自南京厉行生物技术股份有限公司,他莫昔芬、雷洛昔芬实施例作对照组。
研究结果表明,本发明化合物对Ishikawa细胞表现出较好的抑制活性,且构效趋势与其在MCF-7中相一致。
(三)人乳腺癌细胞株MDA-MB-231的抗增殖活性实验
由于MDA-MB-231细胞抗增殖实验可以用来初步评价化合物在体外对ER阴性乳腺癌的抑制作用,所以本文对合成的部分化合物进行了体外MDA-MB-231抗增殖实验。
1、实验方法
操作以及给药浓度设置均与MCF-7相同。
2、实验结果
化合物对人乳腺癌细胞株MDA-MB-231的抗增殖活性实验结果见表5。
表5 化合物对人乳腺癌细胞株MDA-MB-231的抗增殖活性实验结果
Compound | IC<sub>50</sub>(μM) | Compound | IC<sub>50</sub>(μM) |
XH01 | >25 | XH09 | >25 |
XH02 | >25 | XH10 | >25 |
XH03 | >25 | XH11 | >25 |
XH04 | >25 | XH12 | >25 |
XH05 | >25 | XH13 | >25 |
XH06 | >25 | XH14 | >25 |
XH07 | >25 | XH15 | >25 |
XH08 | >25 | XH16 | >25 |
Raloxifene | >25 |
上述人乳腺癌细胞株MDA-MB-231来自南京厉行生物技术股份有限公司,雷洛昔芬实施例作对照组。
研究结果表明,本发明化合物对ER阴性的细胞株MDA-MB-231没有明显的抑制作用,具有良好的靶标选择性。
(四)裸鼠移植瘤实验
1、实验方法
裸鼠接种细胞前4天腹腔注射戊酸雌二醇,注射剂量为1.5mg/kg。细胞接种注射部位统一为裸鼠右前乳房脂肪垫处,碘伏棉球消毒后,使用1ml注射器抽取混匀的MCF-7细胞悬液(6×106/ml)0.1ml,注射器针头刺透裸鼠皮肤后,略上挑针头,移至注射部位,缓慢注射细胞悬液。注射完毕后,无菌棉球按压进针处,将实验器械及废弃物无害化处理。刚建模的裸鼠放入更换新垫料的笼具,于次日观察裸鼠的精神状态及活动进食情况,注射部位是否有红肿。
待肿瘤长到80mm3左右进行分组给药18天,期间测量肿瘤体积,18天后处理取材。给药情况为:Control组:10%HPCD∶PEG-400(9∶1)灌胃给药;他莫昔芬组:称取50mg的药物,加入10%的HPCD进行溶解,然后加入PEG-400至5ml进行溶解,每只鼠每天灌胃给药0.2ml;XH10组:称取XH10 15mg,加入0.5ml的DMSO,再加入0.5ml的无水乙醇进行溶解,再贴壁加入4ml的CMCNA溶解,每只鼠每天尾静脉注射0.2ml。
2、实验结果
裸鼠移植瘤实验结果见图1。
实验结果表明,XH10(i.v 30mg/kg/day)可以明显抑制移植瘤的生长,且效果与他莫昔芬(p.o 100mg/kg/day)相当(图1 A、B、C);未发现XH10具有增加子宫湿重的作用,其在子宫中没有表现出激动活性(图1 D)。
Claims (8)
3.一种药物组合物,其特征在于,包含一种或多种如权利要求1或2所述的2-羰基苯并噻吩类化合物或其可药用的盐,及药学上可接受的载体。
4.一种如权利要求1所述的2-羰基苯并噻吩类化合物或其可药用的盐的制备方法,其特征在于,包括以下步骤:
对甲氧基苯甲醛(1)与丙二酸发生反应得到中间体(2),然后通过二氯亚砜酰化反应得中间体(3),接着通过Weinreb酰胺化反应得化合物(4),冰浴下通过格氏反应得中间体(5),然后依次脱掉甲基保护基(6)、通过苄基保护反应得中间体(7);
中间体(7)再与中间体(8)发生亲核取代反应得中间体(9),脱Boc保护基(10)后与侧链发生亲核取代或通过与不同类型的酰氯进行缩合得化合物(11-16),最后通过三溴化硼脱掉苄基保护基得通式(I)所述2-羰基苯并噻吩类化合物或其可药用的盐;
或,中间体(7)与中间体(19)发生亲核取代反应,得中间体(20),然后通过脱Boc保护基,再与侧链发生亲核取代或通过与不同类型的酰氯进行缩合得化合物(22-31),最后通过三溴化硼脱掉保护基得通式(II)所述2-羰基苯并噻吩类化合物或其可药用的盐。
7.权利要求1或2任一项所述的2-羰基苯并噻吩类化合物或其可药用的盐或者权利要求3所述的药物组合物在制备治疗乳腺癌药物中的用途。
8.权利要求1或2任一项所述的2-羰基苯并噻吩类化合物或其可药用的盐或者权利要求3所述的药物组合物在制备治疗子宫内膜癌药物中的用途。
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