CN117209483A - 苯并呋喃类衍生物及其制备方法和应用 - Google Patents
苯并呋喃类衍生物及其制备方法和应用 Download PDFInfo
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- CN117209483A CN117209483A CN202211333650.9A CN202211333650A CN117209483A CN 117209483 A CN117209483 A CN 117209483A CN 202211333650 A CN202211333650 A CN 202211333650A CN 117209483 A CN117209483 A CN 117209483A
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- benzofuran
- propyl
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Abstract
本申请公开了一种苯并呋喃类衍生物及其制备方法。本发明进一步公开了上述化合物或以上述化合物为主要活性成分的组合物在制备用于抗心律失常的药物中的应用。
Description
技术领域
本发明属于医药领域,具体而言,本发明涉及到一种新的心房选择性的苯并呋喃类衍生物及其制备方法和应用。
背景技术
心房颤动,简称房颤(AF),是最常见的持续性心律失常之一,总患病率约为2%,其患病率随着年龄的增加而增加,75岁以上人群可达10%。房颤发生的主要原因是心房电重构,其基本特征是心房肌动作电位时程(APD)与心房有效不应期(ERP)的缩短。临床上将房颤分为阵发性房颤、持续性房颤和永久性房颤。目前临床应用治疗房颤药物的作用机制分为钠通道阻滞剂、β肾上腺素受体阻滞剂、钙通道阻滞剂和钾通道阻滞剂。
钾离子通道在人类基因组中有80多个基因,是最大、结构最多样化的离子通道家族之一,其电流是心肌细胞动作电位形成中除0相去极化外的动作电位复极过程的主要电流。钾离子通道的抑制可以降低膜的兴奋性,延长心脏的的动作电位和有效不应期,降低心率失常的易感性。乙酰胆碱(Ach)激活的钾离子通道(KAch)是内向整流钾通道家族中的一员,是由Kir3.1和Kir3.4蛋白以2:2组成的异四聚体。通道活性受Ach 等配体激活的G蛋白、细胞外Na+、细胞内PH值等调节,Ach激活的钾电流(IKAch) 在维持细胞膜静息电位和动作电位3期复极中起重要作用。该通道在传导系统和心房肌细胞膜表达丰富,在心室组织中有少量表达,且沿心肌细胞T管分布,理论上抑制 KAch通道可以延长动作电位时程和有效不应期来治疗房颤,并且不会有致心率失常的风险。
随着经济社会的发展,人口的老龄化问题日益凸显,房颤的患病率及发病率不断增长,但目前临床上常用得药物胺碘酮、心律平、多非利特因选择性差,存在严重不良反应,可引起更严重的室性心律失常,无法满足临床房颤患者的治疗需求,所以开发安全、高效的心房选择性治疗药物有重要的科学意义和经济价值。
CN105753822A公开了一种苯并呋喃类衍生物及其制备方法和应用,其结构式为:
CN106432159A公开了一种新型苯并呋喃类衍生物其制备方法和应用,其结构通式式为:
但仍需开发新型的用于制备抗心律失常的相关药物。
发明内容
本发明的第一个目的在于提供所示的化合物Ⅰ。
化合物Ⅰ结构如下:
本发明所述式Ⅰ结构的化合物为(4-(2-羟基-3-(吡啶-4-基氨基)丙氧基)苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3-基)甲酮。
本发明的第二个目的在于提供式Ⅰ所代表的苯并呋喃类衍生物的制备方法。
本发明描述的式Ⅰ化合物的合成路线如下:
(1)使式II化合物在碱作用下与甲基磺酰氯反应生成式III所示化合物:
(2)使式III所示化合物与四氢吡咯反应生成式IV所示化合物:
(3)将式IV所示化合物和对羟基苯甲酰氯与三氯化铝反应,生成式V所示化合物:
(4)将式V所示化合物与环氧氯丙烷在碱性条件下反应生成式VI所示化合物;
(5)将式VI所示化合物与四氨基吡啶、异丙醇和三氯化铝搅拌后在80~100℃反应,反应完成后冷却减压旋蒸,得到黄色油状物,柱层析得到目标化合物:
具体地,包括如下步骤:
(1)式Ⅲ化合物3-(苯并呋喃-2-基)丙基甲磺酸酯的制备:
将式Ⅱ3-(苯并呋喃-2-基)丙-1-醇加入二氯甲烷溶解,三乙胺作碱,冰盐浴至0度,氮气保护,滴加甲磺酰氯。反应完加水,依次用稀盐酸,碳酸氢钠溶液洗涤,有机相干燥,减压旋蒸得到固体。
(2)式Ⅳ化合物1-(3-(苯并呋喃-2-基)丙基)吡咯烷的制备:
将适量的四氢吡咯加入到乙腈中,氮气保护下再将3-(苯并呋喃-2-基)丙基甲磺酸酯的乙腈溶液滴进反应瓶中,加热回流,反应完成后柱层析,得到白色固体。
(3)式Ⅴ化合物(4-羟基苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3-基)甲酮的制备:
将1-(3-(苯并呋喃-2-基)丙基)吡咯烷和对羟基苯甲酰氯投入到甲苯溶液中去,冰水浴冷却至0度,分批投入三氯化铝,保温反应,反应完成后将反应液导入稀盐酸中淬灭,分相,水相用甲苯萃取,收集有机相干燥,减压旋蒸得到浅黄色固体。
(4)式Ⅵ化合物(4-(环氧乙烷-2-基甲氧基)苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3- 基)甲酮的制备:
在反应瓶中加入适量的氢氧化钠水溶液,再加入(4-羟基苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3-基)甲酮和适量的四丁基溴化铵,滴加适量环氧氯丙烷,滴加完毕后加热至回流,反应完后冷却至室温,用乙酸乙酯萃取三次,水洗至中性,有机相干燥,减压旋蒸,得到目标化合物。
(5)式Ⅰ化合物(4-(2-羟基-3-(吡啶-4-基氨基)丙氧基)苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3-基)甲酮的制备:
在反应瓶中加入加入(4-羟基苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3-基)甲酮,四氨基吡啶和异丙醇,搅拌溶解,边搅拌边加入三氯化铝,然后升温至90度反应,反应完成后冷却减压旋蒸,得到黄色油状物,柱层析得到目标化合物。
本发明的第三个目的在于提供一种药物组合物,含有至少一种式Ⅰ所代表的苯并呋喃类衍生物,或其在药学上可接受的盐,溶剂化物,水合物,药学上可接受的前药作为药物活性成分。根据需要,本发明的药物组合还可以加入一种或多种可接受的载体或赋形剂。
本发明的化合物可与药学上各种常用添加剂制成药物组合物。根据治疗目的,可将药物组合物制成各种类型的给药单位剂型,如片剂、丸剂、粉剂、液体、悬浮液乳液、颗粒剂、胶囊、栓剂和针剂(溶液及悬浮液)等。
为了使片剂形式的药物组合物成形,可使用本领域任何已知的并广泛使用的赋形剂。例如,载体,如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭士、结晶纤维素和硅酸等;粘合剂,如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明教溶液,羧甲基纤维素、紫胶、甲基纤维素和磷酸钟、聚乙烯吡咯烷酮等:崩解剂,如干淀粉、藻酸钠、琼脂粉和海带粉,碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯十二烷基硫酸钠、硬脂酸单甘酯、淀粉和乳糖等;崩解抑制剂,如白糖、甘油三硬脂酸国定子油和氢化油吸附促进剂,如季胺碱和十二烷硫酸钠等;润湿剂,如甘油、淀粉等;吸附剂,如淀粉、乳糖、高岭土、膨润士和胶体硅酸等:以及润滑剂,如纯净的滑石.硬脂酸盐、硼酸粉和聚乙二醇等。如果需要的话还可以用通常的涂渍材料使片剂作为糖衣片剂、涂明胶膜片剂、肠衣片剂、涂膜片剂、双层膜片剂及多层片剂。
为了使丸剂形式的药物组合物成形,可使用本领域任何已知的并广泛使用的赋性剂,例如,载体,如乳糖,淀粉,椰子油,硬化植物油,高岭士和滑石等等;粘合剂,如阿拉伯树胶粉,黄著胶粉,明胶和乙醇等等;崩解剂,如琼脂和海带粉等。
为了使栓剂形式的药物组合物成形,可使用本领域任何已知并广泛使用的赋性剂,例如,聚乙二醇,椰子油,高级醇,高级醇的酯,明胶和半合成的甘油酯等。
为了制备针剂形式的药物组合物.可将溶液和悬浮液消毒,并最好加入适量的氯化钠,葡萄糖或甘油等,制成与血液等渗压的针剂。在制备针剂时,也可使用本领域内任何常用的载体。例如,水,乙醇,丙二醇,乙氧基化的异硬脂醇,聚氧基化的异硬脂醇和聚乙烯脫水山梨醇的脂肪酸酯等。此外,还可加入通常的溶解剂、缓冲剂和止痛剂等。
本发明中,所述的药物组合物的给药方法没有特殊限制。可根据病人年龄性别和其它条件及症状,选择各种剂型的制剂给药。例如,片剂、丸剂、溶液悬浮液乳液、颗粒剂和胶囊是口服给药;针剂可以单独给药或者和注射用输送液(如葡萄糖溶液及氨基酸溶液)混合进行静脉注射,如有必要可以单纯用针剂进行肌肉皮内、皮下或腹内注射;栓剂为给药到直肠。本发现的施用量可根据用药途径、患者的年龄、体重、疾病的类型和严重程度等进行变化,通常的给药剂量可为:日剂量0.1~10mg/kg体重。
本发明的第四个目的在于提供式Ⅰ所代表的苯并呋喃类衍生物在制备抗心律失常的药物中的应用。
本发明相对于现有产品而言,提高了抗心律失常的治疗效果,降低了药物的不良反应,降低了诱发室性心律失常的风险,增强了药物的稳定性,而且合成过程操作也更加简单,大大降低成本,适合大规模生产。
附图说明
图1为式Ⅰ化合物对IKAch离子通道电流的抑制作用结果图;
图2为式Ⅰ化合物的1H NMR;
图3为式Ⅰ化合物的13C NMR;
图4为式Ⅰ化合物的高分辨率质谱HRMS。
具体实施方式
下面通过具体的实施方式对本发明的技术方案做进一步的说明,其中列举的实施例是对本发明的说明,而不以任何方式限制其保护范围。
实施例1 3-(苯并呋喃-2-基)丙基甲磺酸酯的制备。
将3-(苯并呋喃-2-基)丙-1-醇(5g,28.4mmol)溶于100mL二氯甲烷中,加入三乙胺(3.5g,34.1mmol),磁力搅拌,冰盐浴冷却至-5~0℃,氮气保护下滴加甲基磺酰氯 (3.6g,31.2mmol)的二氯甲烷溶液,反应1h,薄层色谱监测反应完毕,加入1M稀盐酸100mL洗涤三次,再碳酸氢钠饱和溶液100mL洗涤三次,收集有机相,减压旋蒸,得到固体6.8g,即3-(苯并呋喃-2-基)丙基甲磺酸酯,为收率94.7%。1H NMR(500MHz, CDCl3)δ7.49–7.42(m,2H),7.28(td,J=7.4,1.6Hz,1H),7.22(td,J=7.4,1.6Hz,1H), 6.23(d,J=1.3Hz,1H),3.51(t,J=5.0Hz,2H),3.00(s,3H),2.38(t,J=5.7Hz,2H),1.91 (p,J=5.3Hz,2H).
实施例2 1-(3-(苯并呋喃-2-基)丙基)吡咯烷的制备。
将3-(苯并呋喃-2-基)丙基甲磺酸酯(6g,23.6mmol)溶于100mL乙腈中,加入四氢吡咯(3.4g,47.2mmol),加热回流,薄层色谱监测反应完毕,冷却完毕加入硅胶制砂,柱层析,得到目标化合物4.1g,收率75.6%。1H NMR(500MHz,CDCl3)δ7.45(ddd,J= 10.6,6.5,1.6Hz,1H),7.25(dtd,J=30.9,7.5,1.6Hz,1H),2.66–2.60(m,1H),2.63(s,1H), 2.48(t,J=5.3Hz,1H),2.38(t,J=7.9Hz,1H),1.89(tt,J=5.9,4.3Hz,1H),1.84(td,J= 7.5,6.7,4.2Hz,2H).
实施例3(4-羟基苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3-基)甲酮的制备。
将1-(3-(苯并呋喃-2-基)丙基)吡咯烷(4g,17.4mmol)融入到100mL甲苯中,加入对羟基苯甲酰氯(3.55g,22.6mmol),磁力搅拌,冰水浴降温至0℃,分批加入三氯化铝(3.0g,22.6mmol),保持内温在0~15℃,添加完毕后搅拌1h,薄层色谱监测反应完毕,将反应液缓慢倒入10%稀盐酸中,内温上升,趁热分相,用甲苯萃取水相三次(50mL×3),有机相用饱和食盐水洗涤三次(100mL×3),干燥,减压旋蒸,得到浅黄色固体4.76g,收率78.1%。1H NMR(500MHz,CDCl3)δ9.95(s,1H),7.74–7.63(m,3H),7.47(dd,J= 7.2,1.9Hz,1H),7.37–7.26(m,2H),6.82–6.76(m,2H),2.66–2.60(m,4H),2.48(t,J= 7.6Hz,2H),2.38(t,J=7.9Hz,2H),1.94–1.78(m,6H).
实施例4(4-(环氧乙烷-2-基甲氧基)苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3-基)甲酮的制备。
将(4-羟基苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3-基)甲酮(4g,11.4mmol)投入到 10%氢氧化钠水50mL溶液中去,加入四丁基溴化铵(0.4g,1mmol),滴加环氧氯丙烷(3mL,30.8mmol),滴加完毕后加热至80℃,反应2h,薄层色谱监测反应完毕,停止加热,冷却至室温,反应液用乙酸乙酯(50mL×3)萃取,合并有机相,干燥,减压旋蒸得4.3g油状物,收率92.3%。1H NMR(500MHz,CDCl3)δ7.86–7.80(m,2H),7.66(dd, J=7.1,1.8Hz,1H),7.47(dd,J=7.2,1.9Hz,1H),7.37–7.26(m,2H),7.13–7.06(m,2H), 4.36(dd,J=12.5,6.9Hz,1H),3.93(dd,J=12.5,6.9Hz,1H),3.01(p,J=7.0Hz,1H), 2.72(dd,J=7.0,5.1Hz,1H),2.68–2.58(m,4H),2.51–2.42(m,3H),2.38(t,J=7.9Hz, 2H),1.94–1.78(m,6H).
实施例5(4-(2-羟基-3-(吡啶-4-基氨基)丙氧基)苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3- 基)甲酮的制备。
将(4-(环氧乙烷-2-基甲氧基)苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3-基)甲酮(4.3 g,10.6mmol)投入到50mL异丙醇中,加入四氨基吡啶(5g,53mmol),磁力搅拌,分批加入三氯化铝(1g,7.4mmol),升温至90℃,反应5h,薄层色谱监测反应完毕,冷却至室温,减压旋蒸,得到油状物7g,加入二氯甲烷复溶,加入硅胶制砂,柱层析,得到白色固体3.1g,收率59.7%。
1H NMR(500MHz,CDCl3):δ=8.18–8.17(d,J=5.0Hz,2H),7.84–7.82(d,J=10.0Hz, 2H),7.67(d,J=5.0Hz,1H),7.48-7.46(d,J=5.0Hz,1H),7.33-7.30(m,2H),7.12–7.10(d,J =10.0Hz,2H),6.63–6.62(d,J=5.0Hz,2H),4.65(s,1H),4.44–4.40(m,1H),4.10–3.86 (m,3H),3.57–3.54(m,1H),3.44–3.41(m,1H),3.29–3.26(m,2H),2.58-2.57(d,J=5.0Hz, 1H),2.41-2.20(m,3H),2.22-1.90(m,3H),1.85-1.67(m,2H),1.43–1.32(m,1H).13C NMR (125MHz,CDCl3)δ190.63,168.85,159.92,153.88,152.63,150.88,133.02,132.35,129.73, 124.60,123.46,122.61,118.89,114.69,111.39,109.95,70.11,69.12,54.30,54.16,46.35, 25.15,24.74,23.56.ESI-HRMS:m/z calcd for C33H33N3O4[(M+H)+],499.6110,found 500.6093。
实施例6式Ⅰ化合物和胺碘酮对人体内GIRK1/4离子通道的影响。
用胶原酶处理(30mg胶原酶在15mLND96溶液中,室温1h)分离出爪蟾卵母细胞,在添加100units/mL青霉素、100g/mL链霉素和2.5mM丙酮酸钠的ND96溶液中17℃孵育1天。ND溶液的组成为96mM NaCl、2mM KCl、1mM MgCl2、1.8mM CaCl2和 5mM HEPES(pH7.5)。然后给卵母细胞注射GIRK1和GIRK4的cRNA(每个卵母细胞每个cRNA 10ng),再孵育2~4天,直到电生理检测。使用OC-725放大器(Warner instruments, Inc.,Hamden,CT,USA)和填充3M KCl(0.5-2.0M)的玻璃微电极进行两电极电压钳位。卵母细胞置于灌注ND96溶液的记录室中,膜电位保持在80mV。灌流液变为高钾溶液 (96mM KCl,2mM NaCl,1mM MgCl2,1.8mM CaCl2,5mM HEPES,pH 7.5)诱导向内电流,3mM Ba+可抑制90%以上。Ba+敏感电流被认为是IKAch。利用500ms内120~ +50mV的电压斜坡脉冲记录电流-电压关系。所有实验都是在室温下进行的。使用pClamp软件(Axon Instruments,Foster,City,CA,USA)进行数据采集和分析。实验结果如图1。
实验结果表明:式Ⅰ化合物能够剂量依赖性地阻断IKAch离子通道的电流,并且对IKAch电流的抑制程度强于胺碘酮。
实验例7式Ⅰ化合物应用于乌头碱诱发的家兔房颤模型。
家兔以1g/kg体重的剂量静脉注射乌拉坦麻醉。行气管插管接人工呼吸机给予人工呼吸,开胸。双极电极置于右低心房及右心室游离壁记录。将浸透0.05mL乌头碱溶液(0.05%) 的棉球放置在心房上;或将少量的乌头碱结晶直接放置在心房上,即可引起房颤。房颤发生两分钟后,静脉推注给药。式Ⅰ化合物的剂量分别为10、20、50μg/kg/min,胺碘酮的剂量为10、20、50μg/kg/min,多非利特给药剂量为50μg/kg/min。实验结果见表一。
表一:式Ⅰ化合物对乌头碱诱发的家兔房颤模型的影响
由上表可以看出式Ⅰ化合物表现出了良好的治疗房颤的效果,治疗效果优于胺碘酮,明显强于多非利特。
实验例8式Ⅰ化合物对比格犬心房细胞动作电位的影响。
从体重8~11kg的比格犬中分离出左心房肌,并悬浮在含有Krebs-Henseleit溶液的器官浴中。由外部以恒定频率(1Hz)电刺激驱动,双极铂电极和矩形电流脉冲(持续时间为3毫秒。填充有3M KCl的常规微电极。微电极放大器传导到分析系统。在动作电位参数的基线测量(0相去极化的最大速率[Vmax]和APD在50%和90%复极化)之前,将心房肌稳定约45分钟。然后将待测试药物和空白组(0.1% DMSO)加入到灌注介质中, 30分钟以达到稳态效果。实验结果见表二。
表二:不同浓度式Ⅰ化合物对比格犬心房细胞动作电位的影响
实验结果显示,10μM的式Ⅰ化合物能够显著延长比格犬心房的动作电位时程,对于折返性心律失常有良好的治疗效果。
实验例9式Ⅰ化合物对比格犬心室动作电位的影响。
从体重8~11kg的比格犬中分离出右心室肌,并悬浮在含有Krebs-Henseleit溶液的器官浴中。由外部以恒定频率(1Hz)电刺激驱动,双极铂电极和矩形电流脉冲(持续时间为3毫秒。填充有3M KCl的常规微电极。微电极放大器传导到分析系统。在动作电位参数的基线测量(0相去极化的最大速率[Vmax]和APD在50%和90%复极化)之前,将心室肌稳定约45分钟。然后将待测试药物和空白组(0.1% DMSO)加入到灌注介质中, 30分钟以达到稳态效果。实验结果见表三。
表三:式Ⅰ化合物和胺碘酮对比格犬心室肌动作电位的影响
实验结果显示,10μM的式Ⅰ化合物对比格犬的心室肌动作电位参数没有显著影响,10μM的胺碘酮显著延长心室肌的动作电位时程,使APD50和APD90分别增加了7.3%和 17%,有致心率失常的风险。式Ⅰ化合物相比胺碘酮更加安全有效。
实验例10式Ⅰ化合物对致心律失常的兔模型的应用。
选用32只体重2.5~3.5kg的雌性新西兰大白兔,肌肉注射氯胺酮(35mg/kg)和甲苯噻嗪(5mg/kg)麻醉,并在试验过程中根据需要补充。使用测谎仪系统连续监测心电,并使用心电处理器进行分析。尖端心动过速扭转(TdP)连续6次以上的定义为多态性室性心动过速。基线测量后,开始静脉滴注甲氧胺(15mg/kg/min)。10分钟后给予式Ⅰ化合物(500 μg/kg/min)、胺碘酮(500μg/kg/min)、多非利特(5、10μg/kg/min)连续静脉滴注。实验结果见表四。
表四:式Ⅰ化合物、胺碘酮和多非利特对致心律失常的兔模型的影响
实验结果显示,大剂量的式Ⅰ化合物只是小概率地引起室性早搏(PVC),不会诱发尖端扭转心动过速(TdP)和室颤(VF),同等剂量的胺碘酮会诱发TdP,有致心律失常的风险,多非利特在10μg/kg/min的剂量下诱发75%的兔子TdP和25%的兔子室颤,致心律失常的风险很大,对比之下,式Ⅰ化合物比胺碘酮和多非利特更加安全有效。
综上,本发明提供了式Ⅰ所示化合物及其在制备低毒性的抗心律失常药物中的用途。实验结果表明,本发明提供的化合物具有优异的抗心律失常活性,主要通过抑制乙酰胆碱影响的钾离子电流来延长心肌细胞的动作电位,并且不影响心室肌的动作电位时程。化合物的抗房颤作用甚至优于胺碘酮和多非利特。更重要的是,与胺碘酮和多非利特相比,本发明化合物的致心律失常风险明显降低,安全性更高。本发明为制备低毒性的抗心律失常药物提供了一种新的选择。
Claims (10)
1.一种苯并呋喃类衍生物,所述苯并呋喃类衍生物结构式如式Ⅰ所示:
2.权利要求1所述的苯并呋喃类衍生物的制备方法,其特征在于,其合成路线如下:
(1)使式II化合物在碱作用下与甲基磺酰氯反应生成式III所示化合物:
(2)使式III所示化合物与四氢吡咯反应生成式IV所示化合物:
(3)将式IV所示化合物和对羟基苯甲酰氯与三氯化铝反应,生成式V所示化合物:
(4)将式V所示化合物与环氧氯丙烷在碱性条件下反应生成式VI所示化合物;
(5)将式VI所示化合物与四氨基吡啶、异丙醇和三氯化铝搅拌后在80~100℃反应,反应完成后冷却减压旋蒸,得到黄色油状物,柱层析得到目标化合物:
3.根据权利要求2所述的制备方法,其特征在于,包括如下步骤:
(1)3-(苯并呋喃-2-基)丙基甲磺酸酯的制备:
将式Ⅱ所示3-(苯并呋喃-2-基)丙-1-醇用有机溶剂溶解,以三乙胺或N,N-二异丙基乙胺作碱,冰盐浴至-5~0度,氮气保护,缓慢滴加甲磺酰氯,反应完加水,依次用稀盐酸、碳酸氢钠溶液洗涤,有机相干燥,减压旋蒸得到固体3-(苯并呋喃-2-基)丙基甲磺酸酯;
(2)1-(3-(苯并呋喃-2-基)丙基)吡咯烷的制备:
将四氢吡咯加入到乙腈中,氮气保护下再将3-(苯并呋喃-2-基)丙基甲磺酸酯的乙腈溶液缓慢滴进反应瓶中,加热回流,反应完成后柱层析,得到白色固体1-(3-(苯并呋喃-2-基)丙基)吡咯烷;
(3)(4-羟基苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3-基)甲酮的制备:
将1-(3-(苯并呋喃-2-基)丙基)吡咯烷和对羟基苯甲酰氯投入到甲苯溶液中去,冰水浴冷却至-5~0℃,分批投入三氯化铝,保温反应,反应完成后将反应液倒入5%~10%稀盐酸中淬灭,分相,水相用甲苯萃取,收集有机相干燥,减压旋蒸得到浅黄色固体(4-羟基苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3-基)甲酮;
(4)(4-(环氧乙烷-2-基甲氧基)苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3-基)甲酮的制备:
在反应瓶中加入氢氧化钠水溶液,再加入(4-羟基苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3-基)甲酮和适量的四丁基溴化铵,滴加环氧氯丙烷,滴加完毕后加热至回流,反应完后冷却至室温,用乙酸乙酯萃取三次,水洗至中性,有机相干燥,减压旋蒸,得到(4-(环氧乙烷-2-基甲氧基)苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3-基)甲酮;
5)(4-(2-羟基-3-(吡啶-4-基氨基)丙氧基)苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3-基)甲酮的制备:
在反应瓶中加入加入(4-羟基苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3-基)甲酮,四氨基吡啶和异丙醇,搅拌溶解,边搅拌边加入三氯化铝,然后升温至80~100℃反应,反应完成后冷却减压旋蒸,得到黄色油状物,柱层析得到目标化合物。
4.根据权利要求3所述的制备方法,其特征在于,步骤(1)中,3-(苯并呋喃-2-基)丙-1-醇、三乙胺或N,N-二异丙基乙胺、甲基磺酰氯的摩尔用量比为:25~30:30~36:30~35,所述有机溶剂为二氯甲烷。
5.根据权利要求3所述的制备方法,其特征在于,步骤(2)中,3-(苯并呋喃-2-基)丙基甲磺酸酯与四氢吡咯的摩尔比为20~25:45~50。
6.根据权利要求3所述的制备方法,其特征在于,步骤(3)中,1-(3-(苯并呋喃-2-基)丙基)吡咯烷、对羟基苯甲酰氯、三氯化铝的摩尔比为15~18:20~25:20~25。
7.根据权利要求3所述的制备方法,其特征在于,步骤(4)中,(4-羟基苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3-基)甲酮、四丁基溴化铵、环氧氯丙烷的摩尔比为10~12:1:30~32;步骤(5)中,(4-(环氧乙烷-2-基甲氧基)苯基)(2-(3-(吡咯烷-1-基)丙基)苯并呋喃-3-基)甲酮、四氨基吡啶、三氯化铝的摩尔比为10~12:50~55:5~8。
8.一种药物组合物,其特征在于,以权利要求1所述的苯并呋喃类衍生物作为药物活性成分。
9.权利要求1所述的苯并呋喃类衍生物或权利要求8所述的药物组合物在制备用于抗心律失常的药物中的应用。
10.根据权利要求9所述的应用,其特征在于,所述心律失常对应的相关适应症包括阵发性或持续性心房颤动或心房扑动、窦房心律或心律可复律症或上述的组合。
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