CN115677577A - 靶向srsf6蛋白的小分子化合物及其制备方法和用途 - Google Patents
靶向srsf6蛋白的小分子化合物及其制备方法和用途 Download PDFInfo
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- CN115677577A CN115677577A CN202111293452.XA CN202111293452A CN115677577A CN 115677577 A CN115677577 A CN 115677577A CN 202111293452 A CN202111293452 A CN 202111293452A CN 115677577 A CN115677577 A CN 115677577A
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Abstract
本发明公开了一种靶向SRSF6蛋白的小分子化合物及其制备方法和用途。化合物如式(I)所示。分子能够选择性抑制SRSF6高表达的异常细胞,从而减少异常可变剪接事件的发生,抑制肿瘤的发生与发展,特别是结直肠肿瘤,可作为抗结直肠癌的候选新药。
Description
技术领域
本发明涉及药物化学和药物治疗学领域,具体涉及一种靶向SRSF6蛋白的小分子化合物及其制备方法和用途。
背景技术
研究表明,异常的可变剪接(AS)在肿瘤的发生与发展中普遍存在,大部分肿瘤相关基因由于异常剪接而产生异常的生理学功能。SR(serine/arginine-rich)蛋白是一类富含丝氨酸/精氨酸的剪接因子,其蛋白家族共存在12个SRSF成员,它们共同的结构包括位于N末端的RNA识别结构域(RNA recognition motif,RRM结构域)和位于C末端含有高度磷酸化的丝氨酸/精氨酸的结构域(arginine/serine-rich domain,RS结构域),SR蛋白通过RRM结构域特异性地结合pre-RNA来确定剪接的部位;RS结构域则募集其他剪接因子参与RNA的剪接。SR蛋白的表达失调,会导致各种剪接过程出现异常,进而促进恶性肿瘤的发生。SRSF6(serine/arginine-rich splicing factor 6)蛋白是SR蛋白家族的成员之一,研究表明其在结直肠癌、肺癌等癌症中表达上调。SRSF6可与细胞黏附因子ZO-1的外显子23(exon23)的基序结合,激活了ZO-1exon23的剪接,导致了异常可变剪接的发生,进而促进了结直肠癌的发生与发展。
结直肠癌(Colorectal cancer,CRC)是由结肠或直肠内壁上形成的常见消化道恶性肿瘤,是当今世界对人类生存和健康构成极大威胁的恶性肿瘤之一,列西方发达国家癌症死亡谱的第三位。随着居民生活方式和饮食结构的改变,结直肠癌在我国的发病率呈明显上升趋势,已位列我国新发癌症的第二位。结直肠癌病因复杂,可以发生在结肠或直肠的任何部位。茚达特罗是用于成人慢性阻塞性肺疾病(COPD)患者的药物,而有研究表明,其可用于肿瘤的治疗,特别是结直肠肿瘤;它是通过调控细胞中的可变剪接,从而达到抑制细胞增殖、迁移、侵袭的效果。
发明内容
发明目的:本发明提供靶向SRSF6蛋白的小分子化合物及其制备方法和用途。分子能够选择性抑制SRSF6高表达的异常细胞,从而减少异常可变剪接事件的发生,抑制肿瘤的发生与发展,特别是结直肠肿瘤,可作为抗结直肠癌的候选新药。
技术方案:本发明提供了如通式如式(I)所示的化合物:
其中:
R1选自取代或者非取代的C1-C3直链烷基、取代或者非取代的C1-C3烯基、取代或者非取代的C6-C10芳基、取代或者非取代的C6-C10芳烷基、C6-C10卤代芳烷基或C6-C10杂芳环基,其中,杂芳基的杂原子各自独立地选自N、O、S;
R2选自C1-C3烷氧基、取代氨基、C1-C8脂肪胺基、饱和或不饱和的取代或者非取代的C6-C10芳基、取代或者非取代的C6-C10杂芳基、卤代芳香族的碳环胺基或取代或者非取代的5-7元杂环基,其中,杂芳基或者杂环基中的杂原子各自独立地选自N、O、S,卤代的卤原子指氟、氯、溴或者碘;所述取代氨基被以下1-3个取代基分别取代:C1-C4烷基、5,6-二乙基茚满基、取代或者非取代苯基、茚满基、吲哚基、甲磺酰基取代的哌啶基、苯并噻唑基、苯并咪唑基;
X选自羟基或者卤素,所述卤素选自氟、氯、溴和碘;
手性中心*为S构型或R构型。
优选地,R1选自甲基、烯丙基、取代或者非取代的苄基、取代或者非取代的吡啶基或者三氮唑;所述取代或者非取代的苄基被以下1-3个基团独立取代:卤素或者C1-C3烷基;
R2选自R2选自甲氧基、5,6-二乙基-2,3-二氢-1H-茚-2-胺基、2-氨基茚满基、苯胺基、溴苯胺基、杂芳胺基、C1-C4脂肪胺基、吗啉基、哌啶基、吡咯基、取代或者非取代的哌嗪基、取代或者非取代的高哌嗪基、吲哚基、2,3-二氢茚基,其中,取代或者非取代的哌嗪基或者取代或者非取代的高哌嗪基被下列的1-3个独立的取代基所取代:C1-C4烷基、取代或非取代的苯基或者取代或者非取代的苄基,其中苯基或者苄基被以下取代基团取代:卤素或者C1-C3烷基。
优选地,R1选自选自苄基、3-取代苄基、4-取代苄基或者多取代苄基,所述苄基的取代基为甲基或者卤素;
R2选自5,6-二乙基-2,3-二氢-1H-茚-2-胺基、N-苯代哌嗪基、N-苯代高哌嗪基、溴苯胺基、2,3-二氢吲哚基或者为2,3-二氢茚基;所述N-苯代哌嗪基选自:苄基取代哌嗪基、甲基苄基取代哌嗪基或者苄基溴取代哌嗪基;N-苯代高哌嗪基选自:苄基取代高哌嗪基、甲基苄基取代高哌嗪基或者苄基溴取代高哌嗪基。
优选地,所述多取代苄基为3,5位卤代苄基、3,4-卤代苄基或者全卤代苄基。
优选地,所述R1选自苄基、4-甲基苄基、3-氟苄基、4-氟苄基、3,5-二氟苄基、3,4-二氟苄基、全氟代苄基;
R2选自5,6-二乙基-2,3-二氢-1H-茚-2-胺基、2-溴苯胺基、2,3-二氢吲哚基、2,3-二氢茚基、苄基取代哌嗪基、4-甲基苄基取代哌嗪基、4-溴苄基取代哌嗪基、苄基取代高哌嗪基、4-甲基苄基取代高哌嗪基。
在一些实施例中,所述化合物优选自下列化合物:
发明第二方面提供了上述化合物的制备方法,包括以下步骤:
5-乙酰基-2,8-二羟基喹啉与R1X反应后溴化得到化合物II,溴化选用的溴化剂可选自溴水、N-溴代琥珀酰亚胺或者四丁基三溴化铵;化合物II通过(R)/(S)-2-甲基-CBS-噁唑硼烷配合硼烷被立体选择性地还原为化合物III,化合物III在碱性条件下分子内环合,后与亲核试剂R2H反应得到目标化合物I,合成路线如下:
或化合物I进一步卤化,得到化合物I’:
优选地,从化合物II制备化合物III的反应中,溶剂选自无水乙腈,无水二氯甲烷,氯仿,无水四氢呋喃,无水N,N′-二甲基甲酰胺、二甲亚砜中的一种或多种;根据其手性要求,分别选择(R)或(S)-CBS类手性催化剂,搭配硼烷进行不对称还原;反应温度为-20℃至25℃。
从化合物III制备化合物IV的反应中:溶剂选自乙腈,二氯甲烷、氯仿、丙酮、四氢呋喃、甲醇、N,N-二甲基甲酰胺、二甲亚砜或二氧六环中的一种或多种;碱选自碳酸钾、碳酸钠、碳酸氢钠、氢氧化钠、氢氧化钾或三乙胺;反应温度为25℃至加热回流;
从化合物IV制备化合物I的反应中:溶剂选自乙腈、N,N-二甲基甲酰胺、二甲亚砜、正丁醇或二乙二醇二甲醚;反应温度为60℃至150℃;
从化合物I制备化合物I’的反应中:溶剂选自乙腈、二氯甲烷、氯仿或四氢呋喃中的一种或多种,在惰性气体保护的条件下与卤化试剂反应,反应温度为-20℃至0℃。
优选地,
作为更优选,所述化合物的制备方法,从化合物II制备化合物III的反应中,溶剂选择无水四氢呋喃,催化剂根据需要选择(R)-2-甲基-CBS-噁唑硼烷或(S)-2-甲基-CBS-噁唑硼烷,反应温度为-20℃至0℃;
从化合物III制备化合物IV的反应中:溶剂选择为丙酮,碱选择为碳酸钾或三乙胺,反应温度为55℃至65℃。
从化合物IV制备化合物I的反应中:溶剂选择为正丁醇,反应温度为110℃至120℃。
这些化合物可按照常规分离技术加以纯化。
优选地,从化合物I制备化合物I’的反应中:溶剂选择为二氯甲烷,在氮气保护下反应,反应温度为-20℃至0℃。
本发明第三方面提供了上述化合物在制备治疗与恶性肿瘤有关疾病药物中的应用。
优选地,所述是与恶性肿瘤有关疾病为SRSF6蛋白过表达介导的各类肿瘤,包括结直肠肿瘤(SRSF6蛋白过表达介导的结直肠肿瘤)。
在本发明的一些实施例中,以茚达特罗及其中间体作为阳性对照,通过体外细胞实验,证明了本发明化合物对RKO、HT-29、SW620等结直肠癌细胞系均具有明显抑制作用。
在本发明的一些实施例中,通过SPR亲和力实验及蛋白热迁移实验,证明了化合物I1与SRSF6蛋白具有较好的结合作用。
在本发明的一些实施例中,通过大鼠体内药物代谢动力学实验,证明了化合物I1、I5、I7具有很好的体内药物代谢动力学数据。
有益效果:本发明的化合物用于靶向治疗SRSF6高表达的结直肠肿瘤和其他肿瘤,为结直肠癌的化学治疗提供潜在药物分子。
附图说明
图1是对本发明代表化合物I1与SRSF6蛋白片段的结合作用的验证;
图2是本发明代表化合物I1(LYW2)、I5(LYW3)、I7(LYW4)与对照品茚达特罗中间体(LYW1)经静脉注射与灌胃给药后SPF大鼠体内血药浓度-时间曲线(n=3)。
具体实施方式
为了进一步阐明本发明,下面给出一系列实施例,这些实施例完全是例证性的,它们仅用来对本发明具体描述,不应当理解为对本发明的限制。
一、化合物合成
实施例1:制备(S)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)-8-((4-氟苄基)氧基)喹啉-2(1H)-酮(I1)
1.1中间体II1的合成
将5-乙酰基-2,8-二羟基喹啉(1g,4.92mmol)和无水碳酸钾(816mg,5.91mmol)加入反应瓶后,加入丙酮(20mL)并升温至回流,在回流条件下滴加4-氟溴苄(727uL,5.91mmol),充分搅拌后收集滤饼1.3g。
将滤饼(1.3g,4.18mmol)加入反应瓶后,加入无水THF(26mL)和无水甲醇(10mL)并升温至40℃并充分搅拌,再分批次缓慢加入四丁基三溴化铵(2.82g,5.85mmol),对末端伯碳进行溴化,得到代表性中间体5-(2-溴乙酰基)-8-4-(氟苄基)氧喹啉-2(1H)-酮(化合物Ⅱ1)。
1H NMR(300MHz,DMSO-d6)δ11.14(s,1H),8.50(d,J=10.1Hz,1H),7.88(d,J=8.6Hz,1H),7.71–7.65(m,2H),7.32(d,J=8.6Hz,1H),7.25(d,J=8.9Hz,2H),6.68(d,J=10.0Hz,1H),5.41(s,2H),4.94(s,2H).MS(ESI)m/z=390.0[M+H]+(C18H13BrFNO3).
1.2中间体III1的合成
氮气保护条件下,将化合物II1(500mg,1.27mmol)加入到100mL双颈反应瓶中,加入无水THF(15mL)和催化量的(S)-2-甲基-CBS-噁唑硼烷(1M,128μL,0.13mmol),置于-10℃冷阱中充分搅拌。10min后,量取硼烷-四氢呋喃络合物(1M,1.54mL,1.54mmol),在半小时内缓慢滴入反应体系,在此温度下继续搅拌15min,TLC监测反应完成,用甲醇(5mL)淬灭反应。通过减压浓缩除去溶剂后,向瓶中加入1M盐酸溶液(50mL),室温搅拌过夜后过滤,收集滤饼,真空干燥后得白色固体III1 455mg,收率为90.53%。
1H NMR(400MHz,DMSO-d6)δ10.79(s,1H),8.19(d,J=10.0Hz,1H),7.69–7.62(m,2H),7.27–7.17(m,4H),6.57(d,J=9.9Hz,1H),5.97(s,1H),5.28(s,2H),5.26–5.18(m,1H),3.69(dd,J=10.4,4.8Hz,1H),3.65–3.60(m,1H).MS(ESI)m/z=392.0[M+H]+(C18H15BrFNO3).
1.3中间体IV1的合成
将化合物III1(400mg,1.02mmol)加入到100mL单口反应瓶中,加入重蒸丙酮(40mL)和无水碳酸钾(211mg,1.53mmol),加热至回流,充分搅拌。4h后TLC监测反应完成,过滤,用丙酮洗涤滤饼,收集合并滤液。滤液减压浓缩除去溶剂后,加入乙酸乙酯进行重结晶,得到淡黄色固体IV1 272mg,收率为85.67%。
1H NMR(400MHz,Chloroform-d)δ9.23(s,1H),8.11(d,J=9.8Hz,1H),7.47–7.39(m,2H),7.16–7.08(m,3H),7.02(d,J=8.3Hz,1H),6.75(d,J=9.8Hz,1H),5.16(s,2H),4.26–4.21(m,1H),3.23(dd,J=5.6,4.0Hz,1H),2.80(dd,J=5.6,2.6Hz,1H).MS(ESI)m/z=312.1[M+H]+(C18H14FNO3).
1.4目标产物I1的合成
将化合物IV1(250mg,0.80mmol)与5,6-二乙基-2,3-二氢-1H-茚-2-胺(167mg,0.88mmol)加入到单口反应瓶中,加入15mL正丁醇将其溶解后升温至110℃,在此温度下充分搅拌5h,TLC监测反应完成。将反应液浓缩后通过硅胶柱层析纯化,得到目标产物I181mg,收率为20.15%。
1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.28(d,J=10.0Hz,1H),7.69–7.63(m,2H),7.27–7.18(m,4H),6.98(s,2H),6.58(d,J=9.9Hz,1H),5.34(d,J=8.9Hz,1H),3.82(p,J=7.4Hz,1H),3.12(ddd,J=15.6,11.7,7.6Hz,2H),3.02–2.82(m,4H),2.57(d,J=7.5Hz,2H),2.53(d,J=7.4Hz,2H),1.12(t,J=7.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ161.37,143.93,140.07,138.41,138.36,136.91,132.02,130.67,130.59,129.91,124.64,122.81,119.88,115.69,115.48,112.63,69.48,67.19,58.75,54.18,37.28,25.33,16.10.MS(ESI)m/z=501.3[M+H]+(C31H33FN2O3).
实施例2:制备(R)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)-8-((4-氟苄基)氧基)喹啉-2(1H)-酮(I2)
(1)中间体III2的合成
由化合物II制备化合物III时,将反应中的催化剂变更为(R)-2-甲基-CBS-噁唑硼烷即得实施例1中的中间体III1的对映异构体III2,步骤如下:
氮气保护条件下,将化合物II1(500mg,1.27mmol)加入到100mL双颈反应瓶中,加入无水THF(15mL)和催化量的(R)-2-甲基-CBS-噁唑硼烷(1M,128μL,0.13mmol),置于-10℃冷阱中充分搅拌。10min后,量取硼烷-四氢呋喃络合物(1M,1.54mL,1.54mmol),在半小时内缓慢滴入反应体系,在此温度下继续搅拌15min,TLC监测反应完成,用甲醇(5mL)淬灭反应。通过减压浓缩除去溶剂后,向瓶中加入1M盐酸溶液(50mL),室温搅拌过夜后过滤,收集滤饼,真空干燥后得白色固体III2 461mg,收率为91.73%。
1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),8.19(d,J=10.0Hz,1H),7.67–7.63(m,2H),7.24–7.19(m,4H),6.57(d,J=9.9Hz,1H),5.97(d,J=4.7Hz,1H),5.29(s,2H),5.23(dt,J=7.3,4.8Hz,1H),3.69(dd,J=10.4,4.8Hz,1H),3.62(dd,J=10.4,7.2Hz,1H).MS(ESI)m/z=392.0[M+H]+(C18H15BrFNO3).
(2)目标产物I2的合成
将得到的中间体III2的合成参照实施例1中步骤1.3的方法,合成中间体IV2,参照实施例1中步骤1.4的方法,将中间体IV2(300mg,0.96mmol)和5,6-二乙基-2,3-二氢-1H-茚-2-胺(200mg,1.06mmol)反应,经硅胶柱层析纯化后,得到目标产物I2 103mg,收率为21.35%。
1H NMR(400MHz,DMSO-d6)δ10.85(s,1H),8.32(t,J=11.1Hz,1H),7.65(t,J=6.9Hz,2H),7.33–7.12(m,4H),6.96(d,J=14.3Hz,2H),6.59(t,J=7.8Hz,1H),5.48(s,1H),5.29(s,2H),4.04–3.82(m,2H),3.06(ddd,J=35.7,20.1,9.8Hz,6H),2.54(d,J=7.4Hz,3H),1.10(t,J=6.7Hz,6H).13C NMR(101MHz,DMSO-d6)δ161.41,144.09,140.30,137.78,133.26,131.28,130.66,130.58,129.91,124.56,122.96,119.93,117.08,115.69,115.48,112.60,69.46,58.42,36.11,25.31,16.04.MS(ESI)m/z=501.3[M+H]+(C31H33FN2O3).
实施例3:制备(S)-8-((4-氟苄基)氧基)-5-(1-羟基-2-甲氧基乙基)喹啉-2(1H)-酮(I3)
参照实施例1中步骤1.4的方法,将中间体Ⅳ1(200mg)和无水甲醇(2mL)反应,经硅胶柱层析纯化后,得到目标产物I3 128mg,收率为58.03%。
1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.21(d,J=9.9Hz,1H),7.66(dd,J=8.5,5.7Hz,2H),7.26–7.19(m,3H),7.06(d,J=8.3Hz,1H),6.56(d,J=9.9Hz,1H),5.27(s,2H),4.89(t,J=5.9Hz,1H),4.65(dd,J=7.0,4.6Hz,1H),3.65–3.57(m,1H),3.50–3.42(m,1H),3.19(s,3H).13C NMR(101MHz,DMSO-d6)δ161.35,144.05,137.22,133.34,133.31,130.69,130.60,129.95,128.99,122.55,121.02,118.22,115.70,115.49,112.46,82.59,69.56,66.08,56.88.MS(ESI)m/z=344.1[M+H]+(C19H18FNO4).
实施例4:制备(S)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)-8-((4-甲苄基)氧基)喹啉-2(1H)-酮(I4)
以4-甲基溴苄替换实施例1中4-氟溴苄,参照实施例1中的方法及反应条件,可得到目标产物I4。
1H NMR(300MHz,Chloroform-d)δ9.38(s,1H),8.48(s,1H),8.08(d,J=10.0Hz,1H),7.34–7.28(m,4H),7.21(d,J=7.7Hz,2H),6.96(d,J=5.1Hz,2H),6.57(d,J=9.6Hz,1H),5.62(d,J=9.5Hz,1H),5.12(d,J=5.1Hz,2H),3.97–3.83(m,1H),3.29–3.05(m,6H),2.59(q,J=7.5Hz,4H),2.39(s,3H),1.18(t,J=7.5Hz,6H).13C NMR(75MHz,Chloroform-d)δ169.64,161.33,141.06,138.51,136.59,136.17,132.46,129.50,128.90,128.01,124.41,122.64,119.96,111.04,77.26,70.89,66.23,58.97,53.74,36.54,25.45,21.28,15.48.MS(ESI)m/z=497.3[M+H]+(C32H36N2O3)
实施例5:制备(R)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)-8-((4-甲苄基)氧基)喹啉-2(1H)-酮(I5/LYW3)
以4-甲基溴苄替换实施例1中4-氟溴苄,参照实施例2中的方法及反应条件,可得到目标产物I5。
1H NMR(300MHz,DMSO-d6)δ8.20(d,J=10.0Hz,1H),7.45(d,J=8.0Hz,2H),7.18(d,J=7.9Hz,4H),6.93(d,J=2.1Hz,2H),6.54(d,J=9.9Hz,1H),5.24(s,2H),5.04(t,J=6.1Hz,1H),3.54-3.49(m,1H),2.98(m,2H),2.73(d,J=6.4Hz,2H),2.64-2.57(m,2H),2.53(m,4H),2.28(s,3H),1.12(t,J=7.5Hz,6H).13C NMR(75MHz,DMSO)δ161.29,143.59,139.73,139.67,139.44,137.57,134.12,133.47,129.78,129.36,128.37,124.63,122.31,119.84,117.26,112.59,70.12,69.41,59.67,56.03,40.26,25.34,21.24,16.15.MS(ESI)m/z=497.3[M+H]+(C32H36N2O3).
实施例6:制备(S)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)-8-((3-氟苄基)氧基)喹啉-2(1H)-酮(I6)
以3-氟溴苄替换实施例1中4-氟溴苄,参照实施例1中的方法及反应条件,可得到目标产物I6。
1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),8.32(s,1H),8.24(d,J=9.9Hz,1H),7.54(d,J=8.7Hz,1H),7.42(t,J=5.6Hz,2H),7.23(s,2H),7.14(ddt,J=9.0,6.2,2.7Hz,1H),6.97(s,2H),6.59(d,J=9.9Hz,1H),5.32(s,2H),5.25(dd,J=9.2,3.6Hz,1H),3.77(p,J=7.3Hz,1H),3.09(ddd,J=15.7,10.8,7.5Hz,2H),2.95(td,J=13.7,12.9,6.2Hz,2H),2.83(dt,J=16.2,8.0Hz,2H),2.59–2.52(m,4H),1.12(t,J=7.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ165.46,161.43,143.83,139.95,138.66,138.62,136.96,132.48,130.76,130.68,129.87,124.64,124.62,124.14,124.11,122.75,119.91,117.22,115.17,114.98,114.95,112.54,69.43,67.61,58.88,54.45,37.75,37.68,25.33,16.09.MS(ESI)m/z=501.3[M+H]+(C31H33FN2O3).
实施例7:制备(R)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)-8-((3-氟苄基)氧基)喹啉-2(1H)-酮(I7/LYW4)
以3-氟溴苄替换实施例1中4-氟溴苄,参照实施例2中的方法及反应条件,可得到目标产物I7。
1H NMR(400MHz,DMSO-d6)δ10.77(s,1H),8.21(d,J=10.0Hz,1H),7.57–7.52(m,1H),7.45–7.39(m,2H),7.19(d,J=2.0Hz,2H),7.14(ddd,J=9.0,6.6,2.6Hz,1H),6.93(d,J=3.5Hz,2H),6.56(d,J=9.9Hz,1H),5.42(s,1H),5.31(s,2H),5.05(t,J=6.1Hz,1H),3.52(q,J=6.6Hz,1H),2.98(ddd,J=15.5,11.6,6.9Hz,2H),2.77–2.72(m,2H),2.60(t,J=5.6Hz,1H),2.54(t,J=7.5Hz,5H),1.12(t,J=7.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ161.46,143.52,139.80,139.75,139.42,137.29,133.84,130.75,130.66,129.77,124.68,124.64,124.12,124.09,122.40,119.86,117.37,115.17,114.95,112.48,69.52,69.43,59.72,56.13,25.34,16.14.MS(ESI)m/z=501.3[M+H]+(C31H33FN2O3).
实施例8:制备(R)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)-8-((2-氟苄基)氧基)喹啉-2(1H)-酮(I8)
以2-氟溴苄替换实施例1中4-氟溴苄,参照实施例2中的方法及反应条件,可得到目标产物I8。
1H NMR(300MHz,DMSO-d6)δ10.62(s,1H),8.42(d,J=10.0Hz,1H),7.72(t,J=7.6Hz,1H),7.46–7.34(m,2H),7.26(dd,J=14.3,7.7Hz,3H),6.91(d,J=5.8Hz,2H),6.59(d,J=9.9Hz,1H),5.31(s,2H),5.06(s,1H),4.48(s,1H),3.68–3.49(m,4H),2.86(dp,J=20.5,6.9Hz,3H),2.54(d,J=7.9Hz,4H),1.09(t,J=7.5Hz,6H).13C NMR(75MHz,DMSO-d6)δ161.33,143.86,139.67,136.95,131.34,131.29,130.88,130.77,129.80,124.97,124.92,124.71,124.48,123.98,123.79,122.57,121.50,118.68,115.88,115.60,112.59,64.80,57.65,25.30,16.08.MS(ESI)m/z=501.3[M+H]+(C31H33FN2O3).
实施例9:制备(S)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)-8-((3,5-二氟苄基)氧基)喹啉-2(1H)-酮(I9)
以3,5-二氟溴苄替换实施例1中4-氟溴苄,参照实施例1中的方法及反应条件,可得到目标产物I9。
1H NMR(400MHz,DMSO-d6)δ11.01(s,1H),8.34–8.30(m,1H),8.24(d,J=9.7Hz,1H),7.44(d,J=6.8Hz,2H),7.23(s,2H),7.17(dt,J=9.1,2.4Hz,1H),6.97(s,2H),6.59(d,J=9.9Hz,1H),5.31(s,2H),5.22(s,1H),3.77–3.67(m,1H),3.07(ddd,J=15.3,11.2,7.3Hz,2H),2.89(p,J=11.5Hz,2H),2.78(dt,J=15.2,7.0Hz,2H),2.55(t,J=7.5Hz,4H),1.12(t,J=7.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ161.52,143.64,139.84,138.85,136.98,129.80,124.64,122.76,119.89,117.28,112.45,111.39,111.14,103.63,68.92,67.92,59.04,54.74,25.33,16.12.MS(ESI)m/z=519.3[M+H]+(C31H32F2N2O3).
实施例10:制备(S)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)-8-((3,4-二氟苄基)氧基)喹啉-2(1H)-酮(I10)
以3,4-二氟溴苄替换实施例1中4-氟溴苄,参照实施例1中的方法及反应条件,可得到目标产物I10。
1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),8.23(d,J=10.0Hz,1H),7.85–7.79(m,1H),7.44(q,J=4.5Hz,2H),7.27–7.19(m,2H),6.95(d,J=2.0Hz,2H),6.57(d,J=9.9Hz,1H),5.27(s,2H),5.17(dd,J=8.1,4.4Hz,1H),3.64(q,J=7.0Hz,1H),3.04(ddd,J=15.3,11.3,7.2Hz,2H),2.85(q,J=7.2,6.2Hz,2H),2.72(ddd,J=15.7,6.9,3.8Hz,2H),2.55(t,J=7.5Hz,4H),1.12(t,J=7.5Hz,6H).13C NMR(101MHz,DMSO-d6)δ161.49,143.62,139.71,139.16,139.12,137.09,134.91,133.15,125.20,124.67,124.63,122.62,119.86,117.79,117.62,112.50,68.94,68.40,59.23,55.21,38.64,38.52,25.33,16.13.MS(ESI)m/z=519.3[M+H]+(C31H32F2N2O3).
实施例11:制备(S)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)-8-((全氟苄基)氧基)喹啉-2(1H)-酮(I11)
以全氟代溴苄替换实施例1中4-氟溴苄,参照实施例1中的方法及反应条件,可得到目标产物I11。
1H NMR(400MHz,DMSO-d6)δ10.84(s,1H),8.21(d,J=10.0Hz,1H),7.32(d,J=8.4Hz,1H),7.25(d,J=8.4Hz,1H),6.95(d,J=3.8Hz,2H),6.54(d,J=9.9Hz,1H),5.28(s,2H),5.08(t,J=6.1Hz,1H),3.54(q,J=6.7Hz,1H),2.99(ddd,J=15.4,11.7,7.0Hz,2H),2.76(d,J=6.2Hz,2H),2.65–2.57(m,2H),2.54(d,J=7.5Hz,4H),1.12(t,J=7.5Hz,6H).13CNMR(101MHz,DMSO-d6)δ161.54,143.71,139.77,139.45,137.19,134.41,129.52,124.71,124.66,122.57,119.87,117.31,112.21,69.44,59.71,58.48,56.13,25.34,16.16.(ESI)m/z=573.3[M+H]+(C31H29F5N2O3).
实施例12:制备(R)-8-(苄氧基)-5-(2-(4-丁基哌嗪-1-基)-1-羟乙基)喹啉-2(1H)-酮(I12)
参照实施例1中步骤1.4的方法,将茚达特罗中间体5-(2R)-2-环氧乙烷基-8-苄氧基-2(1H)-喹啉酮(200mg,0.68mmol)和1-丁基哌嗪(116mg,0.82mmol)反应,经硅胶柱层析纯化后,得到目标产物82mg,收率为27.61%。
1H NMR(300MHz,DMSO-d6)δ10.64(s,1H),8.18(d,J=9.9Hz,1H),7.63–7.51(m,2H),7.36(dt,J=14.4,7.0Hz,3H),7.23–7.11(m,2H),6.54(d,J=9.9Hz,1H),5.29(s,2H),5.16(d,J=3.9Hz,1H),2.63–2.46(m,4H),2.44–2.30(m,4H),2.21(t,J=7.2Hz,4H),1.37(dq,J=14.6,6.8Hz,2H),1.22(dq,J=19.9,7.2Hz,2H),0.86(t,J=7.1Hz,3H).MS(ESI)m/z=436.3[M+H]+(C26H33N3O3).
实施例13:制备(R)-8-(苄氧基)-5-(2-(4-苄基哌嗪-1-基)-1-羟乙基)喹啉-2(1H)-酮(I13)
参照实施例1中步骤1.4的方法,将茚达特罗中间体5-(2R)-2-环氧乙烷基-8-苄氧基-2(1H)-喹啉酮(200mg,0.68mmol)和1-苄基哌嗪(145mg,0.82mmol)反应,经硅胶柱层析纯化后,得到目标产物105mg,收率为32.79%。
1H NMR(300MHz,DMSO-d6)δ10.58(s,1H),8.12(d,J=10.0Hz,1H),7.52(d,J=8.2Hz,2H),7.37-7.06(m,10H),6.49(d,J=9.9Hz,1H),5.24(s,2H),5.08(m,1H),3.38(s,2H),2.57-2.46(m,2H),2.45-2.08(m,8H).13C NMR(75MHz,DMSO)δ161.35,143.57,138.71,137.54,137.16,133.91,129.70,129.23,128.78,128.59,128.31,128.25,127.32,122.17,119.91,117.35,112.54,70.21,67.50,66.35,62.54,53.70,53.10.MS(ESI)m/z=470.2[M+H]+(C29H31N3O3).
实施例14:制备(R)-8-(苄氧基)-5-(1-羟基-2-(4-(4-甲基苄基)哌嗪-1-基)乙基)喹啉-2(1H)-酮(I14)
参照实施例1中步骤1.4的方法,将茚达特罗中间体5-(2R)-2-环氧乙烷基-8-苄氧基-2(1H)-喹啉酮(200mg,0.68mmol)和1-(4-甲基苄基)哌嗪(156mg,0.82mmol)反应,经硅胶柱层析纯化后,得到目标产物125mg,收率为37.91%。
1H NMR(300MHz,DMSO-d6)δ10.58(s,1H),8.12(d,J=10.0Hz,1H),7.52(d,J=6.8Hz,2H),7.30(m,3H),7.17-6.99(m,6H),6.49(d,J=9.9Hz,1H),5.24(s,2H),5.07(m,1H),3.35(s,2H),2.39(m,10H),2.22(s,3H).13C NMR(75MHz,DMSO)δ161.35,143.57,137.54,137.16,136.30,135.59,133.92,129.70,129.22,129.15,128.78,128.31,128.25,122.16,119.90,117.35,112.52,70.21,67.53,66.36,62.29,53.71,53.07,21.16.MS(ESI)m/z=484.3[M+H]+(C30H33N3O3)
实施例15:制备(R)-8-(苄氧基)-5-(2-(4-(4-溴苄基)哌嗪-1-基)-1-羟乙基)喹啉-2(1H)-酮(I15)
参照实施例1中步骤1.4的方法,将茚达特罗中间体5-(2R)-2-环氧乙烷基-8-苄氧基-2(1H)-喹啉酮(200mg,0.68mmol)和1-(4-溴苄基)哌嗪(209mg,0.82mmol)反应,经硅胶柱层析纯化后,得到目标产物133mg,收率为35.56%
1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.17(d,J=9.9Hz,1H),7.57(d,J=7.5Hz,2H),7.50(d,J=8.2Hz,2H),7.38(t,J=7.5Hz,2H),7.31(d,J=7.1Hz,1H),7.24(d,J=8.2Hz,2H),7.16(q,J=8.4Hz,2H),6.53(d,J=9.8Hz,1H),5.29(s,2H),5.15(s,1H),5.11(s,1H),3.40(s,2H),2.60-2.52(m,2H),2.49-2.18(m,8H).MS(ESI)m/z 548.2[M+H]+(C29H30BrN3O3).
实施例16:制备(R)-8-(苄氧基)-5-(2-(4-(4-氟苯基)哌嗪-1-基)-1-羟乙基)喹啉-2(1H)-酮(I16)
参照实施例1中步骤1.4的方法,将茚达特罗中间体5-(2R)-2-环氧乙烷基-8-苄氧基-2(1H)-喹啉酮(200mg,0.68mmol)和1-(4-氟苯基)哌嗪(148mg,0.82mmol)反应,经硅胶柱层析纯化后,得到目标产物221mg,收率为68.45%。
1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.23(d,J=9.9Hz,1H),7.58(d,J=7.4Hz,2H),7.38(t,J=7.4Hz,2H),7.34–7.29(m,1H),7.19(s,2H),7.03(t,J=8.7Hz,2H),6.92(dd,J=9.1,4.7Hz,2H),6.56(d,J=9.9Hz,1H),5.30(s,2H),5.20(dd,J=8.1,4.3Hz,1H),3.04(t,J=5.1Hz,4H),2.64(qd,J=11.2,9.7,5.0Hz,5H),2.48(d,J=4.1Hz,1H).13CNMR(101MHz,DMSO-d6)δ161.37,143.64,137.58,137.17,133.87,129.76,128.80,128.33,128.27,122.22,119.99,117.52,117.44,117.38,115.79,115.58,112.58,70.26,67.70,66.14,53.61,49.42.MS(ESI)m/z 474.3[M+H]+(C28H28FN3O3).
实施例17:制备(R)-8-(苄氧基)-5-(2-(4-苄基-1,4-二氮杂-1-基)-1-羟乙基)喹啉-2(1H)-酮(I17)
参照实施例1中步骤1.4的方法,将茚达特罗中间体5-(2R)-2-环氧乙烷基-8-苄氧基-2(1H)-喹啉酮(200mg,0.68mmol)和1-苄基高哌嗪(130mg,0.82mmol)反应,经硅胶柱层析纯化后,得到目标产物101mg,收率为30.63%。
1H NMR(300MHz,DMSO-d6)δ10.60(s,1H),8.15(d,J=10.0Hz,1H),7.52(d,J=8.2Hz,2H),7.36-7.26(m,3H),7.24(m,5H),7.12(d,J=4.0Hz,2H),6.49(d,J=9.9Hz,1H),5.24(s,2H),5.02(t,J=6.2Hz,1H),3.50(s,2H),2.79-2.60(m,6H),2.55-2.48(m,3H),1.59(m,2H).13C NMR(75MHz,DMSO)δ160.77,142.95,139.35,136.97,136.58,133.22,129.10,128.34,128.19,127.99,127.71,127.65,126.60,121.55,119.45,116.87,111.98,69.63,67.57,65.09,61.58,54.91,54.57,54.03,53.64,27.21.MS(ESI)m/z=484.3[M+H]+(C30H33N3O3).
实施例18:制备(R)-8-(苄氧基)-5-(1-羟基-2-(4-(4-甲基苄基)-1,4-二氮杂-1-基)乙基)喹啉-2(1H)-酮(I18)
参照实施例1中步骤1.4的方法,将茚达特罗中间体5-(2R)-2-环氧乙烷基-8-苄氧基-2(1H)-喹啉酮(200mg,0.68mmol)和1-(4-甲基苄基)高哌嗪(167mg,0.82mmol)反应,经硅胶柱层析纯化后,得到目标产物98mg,收率为28.88%。
1H NMR(300MHz,DMSO-d6)δ10.59(s,1H),8.16(d,J=10.0Hz,1H),7.53(d,J=6.8Hz,2H),7.31(m,3H),7.16-7.04(m,6H),6.50(d,J=9.9Hz,1H),5.26(s,2H),5.02(t,J=6.3Hz,1H),3.46(s,2H),2.76-2.60(m,6H),2.52(m,4H),2.23(s,3H),1.61(m,2H).13CNMR(75MHz,DMSO)δ161.35,143.53,137.57,137.17,136.79,136.16,133.83,129.69,129.16,128.93,128.78,128.31,128.24,122.14,120.03,117.45,112.56,70.22,68.16,65.68,61.92,55.51,55.07,54.60,54.17,27.81,21.16.MS(ESI)m/z=498.3[M+H]+(C31H35N3O3)
实施例19:制备(R)-8-(苄氧基)-5-(1-羟基-2-吗啉代乙基)喹啉-2(1H)-酮(I19)
参照实施例1中步骤1.4的方法,将茚达特罗中间体5-(2R)-2-环氧乙烷基-8-苄氧基-2(1H)-喹啉酮(200mg,0.68mmol)和吗啉(72mg,0.82mmol)反应,经硅胶柱层析纯化后,得到目标产物63mg,收率为24.29%。
1H NMR(400MHz,DMSO-d6)δ10.62(s,1H),8.19(d,J=11.7Hz,1H),7.57(d,J=7.2Hz,2H),7.42-7.35(m,2H),7.32(d,J=7.6Hz,1H),7.25-7.13(m,2H),6.55(d,J=9.9Hz,1H),5.29(s,2H),5.15(s,1H),3.53(s,4H),2.56(m,2H),2.42(m,4H).13C NMR(101MHz,DMSO)δ161.34,143.59,137.53,137.16,133.84,129.73,128.79,128.34,128.26,122.21,119.95,117.33,112.56,70.24,67.46,66.72,66.69,54.23.MS(ESI)m/z=381.2[M+H]+(C22H24N2O4).
实施例20:制备(R)-8-(苄氧基)-5-(1-羟基-2-(哌啶-1-基)乙基)喹啉-2(1H)-酮(I20)
参照实施例1中步骤1.4的方法,将茚达特罗中间体5-(2R)-2-环氧乙烷基-8-苄氧基-2(1H)-喹啉酮(200mg,0.68mmol)和哌啶(70mg,0.82mmol)反应,经硅胶柱层析纯化后,得到目标产物87mg,收率为33.71%。
1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.19(d,J=9.9Hz,1H),7.57(d,J=7.0Hz,2H),7.38(t,J=7.2Hz,2H),7.31(t,J=7.3Hz,1H),7.24-7.12(m,2H),6.54(d,J=9.9Hz,1H),5.29(s,2H),5.16(s,1H),2.56(m,2H),2.42(s,4H),1.53-1.43(m,4H),1.39-1.33(m,2H).13C NMR(101MHz,DMSO)δ161.35,143.60,137.51,137.16,133.74,129.69,128.79,128.32,128.25,122.17,119.87,117.33,112.56,70.22,67.14,54.82,25.78,24.19.MS(ESI)m/z=379.2[M+H]+(C23H26N2O3).
实施例21:制备(R)-8-(苄氧基)-5-(1-羟基-2-(吡咯烷基-1-基)乙基)喹啉-2(1H)-酮(I21)
参照实施例1中步骤1.4的方法,将茚达特罗中间体5-(2R)-2-环氧乙烷基-8-苄氧基-2(1H)-喹啉酮(200mg,0.68mmol)和四氢吡咯(58mg,0.82mmol)反应,经硅胶柱层析纯化后,得到目标产物85mg,收率为34.21%。
1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),8.21(d,J=10.0Hz,1H),7.57(d,J=8.3Hz,2H),7.37(t,J=7.3Hz,2H),7.31(t,J=7.3Hz,1H),7.16(q,J=8.4Hz,2H),6.54(d,J=9.9Hz,1H),5.29(s,2H),5.11-5.04(m,1H),2.73(dd,J=12.5,8.0Hz,1H),2.62(dd,J=12.5,4.6Hz,1H),2.55(d,J=6.5Hz,4H),1.65(s,4H).13C NMR(101MHz,DMSO)δ161.33,143.67,137.43,137.16,133.59,129.78,128.80,128.32,128.25,122.28,120.08,117.37,112.49,70.21,68.83,63.83,54.47,23.57.MS(ESI)m/z=365.2[M+H]+(C22H24N2O3).
实施例22:制备(R)-8-(苄氧基)-5-(1-羟基2-(苯氨基)乙基)-1-羟乙基)喹啉-2(1H)-酮(I22)
参照实施例1中步骤1.4的方法,将茚达特罗中间体5-(2R)-2-环氧乙烷基-8-苄氧基-2(1H)-喹啉酮(200mg,0.68mmol)和苯胺(76mg,0.82mmol)反应,经硅胶柱层析纯化后,得到目标产物60mg,收率为22.77%。
1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.35(d,J=10.0Hz,1H),7.57(dt,J=6.2,1.4Hz,2H),7.38(t,J=7.3Hz,2H),7.31(t,J=7.3Hz,1H),7.15(s,2H),6.96(t,J=7.8Hz,2H),6.62(d,J=9.9Hz,1H),6.47(d,J=6.4Hz,2H),6.46(d,J=1.2Hz,1H),6.05(d,J=6.1Hz,1H),5.25(s,2H),4.97(t,J=5.9Hz,1H),4.89(q,J=6.4Hz,1H),3.68–3.55(m,2H).13C NMR(101MHz,DMSO-d6)δ161.33,148.33,143.66,137.19,136.66,130.85,129.79,129.21,128.81,128.35,128.32,122.62,120.09,118.11,116.33,113.17,112.64,70.26,66.05,55.62.MS(ESI)m/z=387.2[M+H]+(C24H22N2O3).
实施例23:制备(R)-8-(苄氧基)-5-(2-((2-溴苯基)氨基)-1-羟乙基)喹啉-2(1H)-酮(I23)
参照实施例1中步骤1.4的方法,将茚达特罗中间体5-(2R)-2-环氧乙烷基-8-苄氧基-2(1H)-喹啉酮(200mg,0.68mmol)和2-溴苯胺(141mg,0.82mmol)反应,经硅胶柱层析纯化后,得到目标产物85mg,收率为26.79%。
1H NMR(400MHz,DMSO-d6)δ10.68(s,1H,NH),8.35(d,J=10.0Hz,1H),7.56(d,J=6.4Hz,2H),7.42(d,J=7.9Hz,1H),7.39-7.35(d,J=8.4Hz,1H),7.31(d,J=6.0Hz,1H),7.16(d,J=8.4Hz,1H),6.98(m,2H),6.63(d,J=9.8Hz,1H),6.49(t,J=7.6Hz,1H),6.25(d,J=8.2Hz,1H),5.24(s,2H),5.03(s,1H),3.79(m,1H),3.68-3.49(m,1H).13C NMR(101MHz,DMSO)δ161.29,144.36,143.90,143.87,137.09,136.29,132.61,129.98,129.23,128.97,128.80,128.35,122.90,119.88,118.35,117.70,113.24,112.60,109.68,70.23,65.40,55.31.MS(ESI)m/z=465.1[M+H]+(C24H21BrN2O3).
实施例24:制备(R)-8-(苄氧基)-5-(1-羟基-2-(异丁基氨基)乙基)喹啉-2(1H)-酮(I24)
参照实施例1中步骤1.4的方法,将茚达特罗中间体5-(2R)-2-环氧乙烷基-8-苄氧基-2(1H)-喹啉酮(200mg,0.68mmol)和异丁胺(123mg,0.82mmol)反应,经硅胶柱层析纯化后,得到目标产物73mg,收率为29.22%。
1H NMR(400MHz,DMSO-d6)δ8.23(d,J=10.0Hz,1H),7.57(d,J=7.1Hz,2H),7.38(t,J=7.3Hz,2H),7.31(t,J=7.3Hz,1H),7.21–7.15(m,2H),6.56(d,J=9.8Hz,1H),5.30(s,2H),5.18–5.13(m,1H),2.76(s,1H),2.74(s,1H),2.45(dd,J=6.8,1.9Hz,2H),1.72(hept,J=6.7Hz,1H),0.87(dd,J=6.7,4.1Hz,6H).13C NMR(101MHz,DMSO-d6)δ161.31,143.74,137.16,128.82,128.77,128.27,128.22,119.88,112.57,70.22,68.21,56.89,27.76,20.95.MS(ESI)m/z=367.2[M+H]+(C22H26N2O3).
实施例25:制备(R)-8-(苄氧基)-5-(2-(3,4-二氢异喹啉-2(1H)-基)-1-羟乙基)喹啉-2(1H)-酮(I25)
参照实施例1中步骤1.4的方法,将茚达特罗中间体5-(2R)-2-环氧乙烷基-8-苄氧基-2(1H)-喹啉酮(200mg,0.68mmol)和(S)-2,3-二氢-1H-茚满-1-胺(109mg,0.82mmol)反应,经硅胶柱层析纯化后,得到目标产物112mg,收率为38.51%。
1H NMR(300MHz,DMSO-d6)δ10.67(s,1H),8.18(d,J=9.9Hz,1H),7.58(d,J=7.4Hz,2H),7.39(t,J=7.3Hz,2H),7.33(d,J=7.1Hz,1H),7.28(d,J=7.6Hz,1H),7.23-7.12(m,5H),6.54(d,J=9.9Hz,1H),5.30(s,2H),5.05(d,J=5.0Hz,1H),4.19(t,J=6.6Hz,1H),2.98-2.62(m,5H),2.27(m,1H),1.78-1.66(m,1H).MS(ESI)m/z=427.2[M+H]+(C27H26N2O3).
实施例26:制备(R)-8-(苄氧基)-5-(1-羟基-2-(吲哚-1-基)乙基)喹啉-2(1H)-酮(I26)
参照实施例1中步骤1.4的方法,将茚达特罗中间体5-(2R)-2-环氧乙烷基-8-苄氧基-2(1H)-喹啉酮(200mg,0.68mmol)和吲哚啉(98mg,0.82mmol)反应,经硅胶柱层析纯化后,得到目标产物103mg,收率为36.62%。
1H NMR(300MHz,DMSO-d6)δ10.64(s,1H),8.04(d,J=9.9Hz,1H),7.58(d,J=7.3Hz,2H),7.37(m,3H),7.18(s,2H),6.97(d,J=6.2Hz,1H),6.89(t,J=7.6Hz,1H),6.56(d,J=9.9Hz,1H),6.47(t,J=7.2Hz,1H),6.33(d,J=7.6Hz,1H),5.29(s,2H),4.97(t,J=5.6Hz,1H),4.88(s,1H),3.90(dt,J=11.4,5.4Hz,2H),3.52(q,J=9.5,8.9Hz,1H),3.28-3.21(m,1H),2.85(dt,J=17.1,8.0Hz,2H).MS(ESI)m/z=413.2[M+H]+(C26H24N2O3).
实施例27:制备(R)-8-(苄氧基)-5-(1-羟基-2-((1-(甲磺酰基)哌啶-4-基)氨基)乙基)喹啉-2(1H)-酮(I27)
参照实施例1中步骤1.4的方法,将茚达特罗中间体5-(2R)-2-环氧乙烷基-8-苄氧基-2(1H)-喹啉酮(200mg,0.68mmol)和1-甲磺酰基-4-氨基哌啶(146mg,0.82mmol)反应,经硅胶柱层析纯化后,得到目标产物52mg,收率为16.17%。
1H NMR(400MHz,DMSO-d6)1H NMR(400MHz,DMSO-d6)δ10.66(s,1H),8.31(s,1H),8.22(d,J=9.9Hz,1H),7.57(d,J=6.9Hz,2H),7.38(t,J=7.3Hz,2H),7.34–7.29(m,1H),7.23–7.16(m,2H),6.57(d,J=9.9Hz,1H),5.31(s,2H),5.13(dd,J=7.7,4.7Hz,1H),3.47(dd,J=11.8,4.6Hz,2H),2.84(s,5H),2.79–2.70(m,3H),1.97–1.89(m,2H),1.46–1.35(m,2H).13C NMR(101MHz,DMSO-d6)δ165.37,161.34,143.81,137.19,137.15,132.81,129.82,128.82,128.35,128.26,122.50,119.93,117.27,112.57,70.21,68.42,53.61,53.45,44.44,34.66,30.62,30.41.MS(ESI)m/z=472.2[M+H]+(C24H29N3O5S).
实施例28:制备(R)-8-(苄氧基)-5-(2-(苯并[d]噻唑-5-基氨基)-1-羟乙基)喹啉-2(1H)-酮(I28)
参照实施例1中步骤1.4的方法,将茚达特罗中间体5-(2R)-2-环氧乙烷基-8-苄氧基-2(1H)-喹啉酮(200mg,0.68mmol)和1,3-苯并噻唑-5-胺(123mg,0.82mmol)反应,经硅胶柱层析纯化后,得到目标产物84mg,收率为27.78%。
1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),10.10(s,1H),9.12(s,1H),8.43(d,J=9.9Hz,1H),7.72(d,J=8.6Hz,1H),7.56(d,J=7.5Hz,2H),7.37(t,J=7.5Hz,2H),7.32(s,1H),7.16(d,J=4.9Hz,2H),6.93(d,J=8.6Hz,1H),6.87(s,1H),6.64(d,J=9.6Hz,1H),5.23(s,2H),4.99(t,J=5.9Hz,1H),3.70(d,J=10.7Hz,1H),3.66(d,J=6.9Hz,1H).MS(ESI)m/z=444.1[M+H]+(C25H21N3O3S).
实施例29:制备(R)-8-(苄氧基)-5-(2-((1H苯并[d]咪唑-2-基)氨基)-1-羟乙基)喹啉-2(1H)-酮(I2)
参照实施例1中步骤1.4的方法,将茚达特罗中间体5-(2R)-2-环氧乙烷基-8-苄氧基-2(1H)-喹啉酮(200mg,0.68mmol)和2-氨基苯并咪唑(109mg,0.82mmol)反应,经硅胶柱层析纯化后,得到目标产物68mg,收率为23.38%。
1H NMR(400MHz,DMSO-d6)δ10.70(s,1H),8.26(s,1H),7.56(d,J=7.3Hz,2H),7.38(t,J=7.3Hz,2H),7.32(d,J=7.2Hz,1H),7.25–7.16(m,2H),7.15–7.09(m,2H),6.91(dd,J=6.0,3.2Hz,2H),6.82(d,J=8.2Hz,1H),6.54(d,J=9.9Hz,1H),5.34(d,J=3.6Hz,1H),5.30(s,2H),4.25(dd,J=15.0,8.1Hz,1H),4.15(dd,J=14.9,4.1Hz,1H).13C NMR(101MHz,DMSO-d6)δ165.06,161.32,155.49,144.05,141.84,137.60,137.11,137.08,134.92,131.72,129.88,128.81,128.33,128.21,122.54,120.86,120.65,120.10,118.82,117.62,114.87,112.58,111.88,108.50,70.21,68.77,49.41.MS(ESI)m/z=427.2[M+H]+(C25H22N4O3).
实施例30:制备(R)-8-(苄氧基)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-氟乙基)喹啉-2(1H)-酮(I’1)
将茚达特罗中间体(R)-8-苄氧基-5-(-2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)喹啉-2(1H)-酮,即LYW1(100mg)溶于二氯甲烷(5mL)中,氮气置换后降温至-20℃左右,搅拌10min后缓慢滴入氟化试剂DAST(41mg,0.25mmol),维持温度搅拌至反应完全;反应结束后,加入饱和碳酸氢钠溶液淬灭DAST,二氯甲烷萃取后合并有机层,浓缩后经硅胶柱层析纯化,得到目标化合物60mg,收率约为59.75%。
1H NMR(300MHz,DMSO-d6)δ8.13(d,J=9.9Hz,1H),7.63–7.59(m,2H),7.45–7.38(m,3H),7.25(s,1H),7.20(d,J=8.5Hz,1H),6.99–6.95(m,2H),6.62(d,J=9.9Hz,1H),5.35(s,2H),3.59(p,J=6.7,6.2Hz,1H),3.26–3.16(m,1H),3.02(dt,J=15.5,6.4Hz,3H),2.69–2.62(m,2H),2.59(d,J=7.7Hz,4H),1.13(d,J=7.5Hz,6H).MS(ESI)m/z=485.3[M+H]+(C31H33FN2O2).
实施例31:制备(S)-8-(苄氧基)-5-(2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-氟乙基)喹啉-2(1H)-酮(I’2)
将LYW1的对映异构体(S)-8-苄氧基-5-(-2-((5,6-二乙基-2,3-二氢-1H-茚-2-基)氨基)-1-羟乙基)喹啉-2(1H)-酮(100mg)溶于二氯甲烷(5ml)中,氮气置换后降温至-20℃左右,搅拌10min后缓慢滴入氟化试剂DAST(41mg,0.25mmol),维持温度搅拌至反应完全;反应结束后,加入饱和碳酸氢钠溶液淬灭DAST,二氯甲烷萃取后合并有机层,浓缩后经硅胶柱层析纯化,得到目标化合物63mg,收率约为62.74%。
1H NMR(300MHz,DMSO-d6)δ8.14(d,J=9.9Hz,1H),7.62(d,J=6.9Hz,2H),7.43(t,J=7.1Hz,3H),7.28(d,J=8.4Hz,1H),7.22(d,J=8.4Hz,1H),6.99(d,J=1.7Hz,2H),6.64(d,J=9.9Hz,1H),5.37(s,2H),3.68–3.62(m,1H),3.11–2.99(m,3H),2.79–2.65(m,3H),2.61(d,J=7.5Hz,4H),1.17(d,J=7.5Hz,6H).MS(ESI)m/z=485.3[M+H]+(C31H33FN2O2).
二、化合物I对结直肠癌细胞系的抑制作用
根据茚达特罗的治疗作用,我们筛选了其中间体LYW1为先导化合物,研究了系列化合物I对结直肠癌细胞系的体外抑制作用。发现其对RKO、HT29、SW620均具有较强的抑制作用,具体实验过程及结果如下所示:
1、化合物I对SW620细胞的抑制作用:
以茚达特罗为阳性对照,配制10、20、30、40μM的浓度梯度,将其对SW620的IC50固定在20-25μM之间。化合物I以同样浓度梯度配制后进行初筛,具有相较茚达特罗更低IC50的化合物进行二次筛选,二次筛选时化合物的浓度梯度为1、2、4、8μM。
两轮筛选均作用于结直肠癌细胞系SW620,初始细胞数为每孔5000个,直接测定第48h的细胞存活率,最终确定化合物的IC50。
细胞存活率=[(实验组读数-空白组读数)/(对照组读数-空白组读数)]×100%。
表1化合物I对SW620抑制作用
化合物 | IC<sub>50</sub>(μM) | 化合物 | IC<sub>50</sub>(μM) |
茚达特罗 | 23.05 | I<sub>11</sub> | 6.093 |
LYW1 | 3.542 | I<sub>13</sub> | 36.31 |
I<sub>1</sub>(LYW2) | 3.121 | I<sub>14</sub> | 22.33 |
I<sub>2</sub> | 8.624 | I<sub>15</sub> | 11.02 |
I<sub>4</sub> | 2.899 | I<sub>17</sub> | 22.22 |
I<sub>5</sub>(LYW3) | 2.975 | I<sub>18</sub> | 19.35 |
I<sub>6</sub> | 3.055 | I<sub>23</sub> | 25.61 |
I<sub>7</sub>(LYW4) | 2.734 | I<sub>25</sub> | 24.76 |
I<sub>9</sub> | 3.154 | I<sub>26</sub> | 20.34 |
I<sub>10</sub> | 4.184 |
2、化合物I对RKO(人结肠腺癌细胞)、HT29(人结肠癌细胞)的抑制作用:
以茚达特罗为阳性对照,将其对RKO、HT29的IC50固定在10-15μM,其他过程同SW620细胞系。
表2化合物对RKO抑制作用
化合物 | IC<sub>50</sub>(μM) |
茚达特罗 | 12.79 |
LYW1 | 2.033 |
I<sub>1</sub>(LYW2) | 1.422 |
I<sub>2</sub> | 5.563 |
I<sub>7</sub>(LYW4) | 3.107 |
表3化合物对HT29抑制作用
化合物 | IC<sub>50</sub>(μM) |
茚达特罗 | 12.71 |
LYW1 | 2.425 |
I<sub>1</sub>(LYW2) | 1.422 |
I<sub>2</sub> | 4.687 |
I<sub>7</sub>(LYW4) | 2.663 |
三、化合物I1与SRSF6蛋白结合作用的研究
SRSF蛋白在mRNA前体的组成性剪接、选择性剪接、mRNA出核以及翻译等基因表达调控过程中发挥着重要作用。SRSF蛋白根据含有RRM结构域的数目不同分为两组,其中SRSF6具有RRM1和RRM2两个结构域。RRM1结构域含有RNP-1和RNP-2保守序列,其能与相关RNA结合;而RRM2结构域中含有进化保守的SWQDLKD七肽序列。在选择性剪接位点的特异性识别中,RRM1和RRM2结构域发挥着不可替代的作用。过表达的SRSF6与细胞黏附因子ZO-1结合诱导了结直肠癌的发生,而茚达特罗被验证可抑制肿瘤的发生发展。因此,我们提取了SRSF6蛋白的RRM1、RRM2结构域片段,通过表面离子共振(surface plasmon resonance,SPR)实验,证实了茚达特罗及其中间体(LYW1)与SRSF6具有显著的结合;接着,我们以LYW1为参照,通过蛋白热迁移实验考察了化合物I1(LYW2)与SRSF6蛋白的结合能力。
我们以DMSO作为空白组,用56.5μM的SRSF6蛋白分别与LYW1、LYW2按1:10的浓度加入到PCR管中,再避光加入TS染料后,进行热迁移实验。实验结果如下:
表4 SRSF6蛋白热迁移实验结果
# | Well | Protein | Ligand | Task | ΔTm B | ΔTm D |
1 | A01 | SRSF6 | DMSO | R | 0.01 | -0.07 |
2 | B01 | SRSF6 | DMSO | R | -0.01 | 0.07 |
3 | C01 | SRSF6 | LYW1 | S | -14.11 | -13.66 |
4 | D01 | SRSF6 | LYW1 | S | -13.12 | -12.82 |
5 | E01 | SRSF6 | LYW2 | S | -10.35 | -10.16 |
6 | F01 | SRSF6 | LYW2 | S | -11.58 | -10.86 |
实验结果显示,LYW1、I1(LYW2)与DMSO相比,两个化合物均使SRSF6蛋白发生了不同程度的负迁移,但LYW1自身具有较强的荧光性,因此,I1(LYW2)与SRSF6蛋白具有更优异的结合作用(图1)。
四、I1、I5、I7在大鼠体内药物代谢动力学研究
为研究本发明系列化合物I的构效关系和成药性,我们考察了系列化合物给药后在大鼠体内的药代动力学特征与口服绝对生物利用度,为后续候选化合物的体内药效等研究提供了药动学数据支撑。我们以LYW1作为对照,选择了细胞活性实验中结果较好的化合物I1(LYW2)、I5(LYW3)、I7(LYW4),按5mg/kg静脉注射、100mg/kg灌胃两种方式给药大鼠(n=3),在既定时间收集血浆,分别建立HPLC-MS/MS方法测定化合物在大鼠血浆中的浓度,利用WinNonlin软件计算药动学参数,得到数据结果如下:
LYW1:静脉注射给予LYW1(5mg/kg)后,AUC0-t为626.82±17.46h·μg/L,AUC0-∞为646.42±19.69h·μg/L,t1/2约为4.07±0.74h,表观分布容积V约为45.58±9.55L/kg,清除率CL约为7.74±0.24L/h/kg;灌胃给予LYW1(100mg/kg)后,AUC0-t为323.75±78.04h·μg/L,AUC0-∞为352.78±72.78h·μg/L,达峰浓度Cmax值为212.58±45.86μg/L,达峰时间Tmax为0.14±0.05h,口服绝对生物利用度为2.73%(图2中A图所示)。LYW2:静脉注射给予LYW2(5mg/kg)后,AUC0-t为1986.59±312.69h·μg/L,AUC0-∞为2117.28±322.75h·μg/L,t1/2约为6.02±0.37h,表观分布容积V约为20.88±3.84L/kg,清除率CL约为2.40±0.35L/h/kg;灌胃给予LYW2(100mg/kg)后,AUC0-t为5223.36±395.51h·μg/L,AUC0-∞为5287.25±386.25h·μg/L,达峰浓度Cmax值为357.75±43.49μg/L,达峰时间Tmax为9.33±2.31h,口服绝对生物利用度为12.49%(图2中B图所示)。
LYW3:静脉注射给予LYW3(5mg/kg)后,AUC0-t为859.95±11.40h·μg/L,AUC0-∞为875.48±11.30h·μg/L,t1/2约为3.94±0.09h,表观分布容积V约为32.47±0.64L/kg,清除率CL约为5.71±0.07L/h/kg;灌胃给予LYW3(100mg/kg)后,AUC0-t为3168.54±280.72h·μg/L,AUC0-∞为3195.56±250.81h·μg/L,达峰浓度Cmax值为277.72±48.87μg/L,达峰时间Tmax为6.00±0.00h,口服绝对生物利用度为18.25%(图2中C图所示)。
LYW4:静脉注射给予LYW4(5mg/kg)后,AUC0-t为1172.54±19.18h·μg/L,AUC0-∞为1194.06±21.48h·μg/L,t1/2约为4.10±0.34h,表观分布容积V约为24.75±1.92L/kg,清除率CL约为4.19±0.07L/h/kg;灌胃给予LYW4(100mg/kg)后,AUC0-t为4856.18±370.32h·μg/L,AUC0-∞为4896.71±363.75h·μg/L,达峰浓度Cmax值为188.21±27.61μg/L,达峰时间Tmax为16.00±6.93h,口服绝对生物利用度为20.50%(图2中D图所示)。
根据数据结果及图2所示,静脉注射(5mg/kg)与灌胃给药(100mg/kg)(图2中E图和图2中的F图所示)后血浆中药物浓度均较低,静脉注射LYW1、LYW2、LYW3、LYW4的C2min分别为604.18±61.50、979.86±162.90、601.66±40.37、722.16±60.39μg/L,化合物进入体内后可能存在迅速分布,且表观分布容积较大,可能存在广泛分布或特异性组织分布;灌胃给药后,与对照品相比,系列化合物在大鼠的体内吸收速度缓慢,对照品LYW1吸收迅速,Tmax值为0.14±0.05h,而其余Tmax值分别为为9.33±2.31、6.00±0.00、16.00±6.93h,系列化合物口服生物利用度较对照品有明显提高;静脉注射后,从4-6h血药浓度数据看,LYW2、LYW3、LYW4代谢变缓,而对照无此现象,推测系列化合物可能存在胆汁排泄与肝肠循环现象。
以上数据表明,本发明系列化合物具有更好的药物代谢动力学参数。
综上所述,基于茚达特罗对结直肠癌的抑制作用,我们筛选了先导化合物LYW-1并对结构进行了设计优化,合成了新的系列化合物I。体外研究发现其可显著抑制SRSF6过表达而诱导的结直肠癌细胞的发生发展;体内药物代谢动力学实验结果进一步证明了该系列化合物优于先导化合物LYW-1的体内药物代谢数据,为后续药效、毒理研究提供数据支撑,为以SRSF6为新靶点的小分子抗肿瘤药的成药提供了可能,具有良好的应用前景。
Claims (10)
1.一种通式如式(I)所示的化合物:
其中:
R1选自取代或者非取代的C1-C3直链烷基、取代或者非取代的C1-C3烯基、取代或者非取代的C6-C10芳基、取代或者非取代的C6-C10芳烷基、C6-C10卤代芳烷基或C6-C10杂芳环基,其中,杂芳基的杂原子各自独立地选自N、O、S;
R2选自C1-C3烷氧基、取代氨基、C1-C8脂肪胺基、饱和或不饱和的取代或者非取代的C6-C10芳基、取代或者非取代的C6-C10杂芳基、卤代芳香族的碳环胺基或取代或者非取代的5-7元杂环基,其中,杂芳基或者杂环基中的杂原子各自独立地选自N、O、S,卤代的卤原子指氟、氯、溴或者碘;所述取代氨基被以下1-3个取代基分别取代:C1-C4烷基、5,6-二乙基茚满基、取代或者非取代苯基、茚满基、吲哚基、甲磺酰基取代的哌啶基、苯并噻唑基、苯并咪唑基;
X选自羟基或者卤素,所述卤素选自氟、氯、溴和碘;
手性中心*为S构型或R构型。
2.根据权利要求1所述的化合物,其特征在于,R1选自甲基、烯丙基、取代或者非取代的苄基、取代或者非取代的吡啶基或者三氮唑;所述取代或者非取代的苄基被以下1-3个基团独立取代:卤素或者C1-C3烷基;
R2选自甲氧基、5,6-二乙基-2,3-二氢-1H-茚-2-胺基、2-氨基茚满基、苯胺基、溴苯胺基、杂芳胺基、C1-C4脂肪胺基、吗啉基、哌啶基、吡咯基、取代或者非取代的哌嗪基、取代或者非取代的高哌嗪基、吲哚基、2,3-二氢茚基,其中,取代或者非取代的哌嗪基或者取代或者非取代的高哌嗪基被下列的1-3个独立的取代基所取代:C1-C4烷基、取代或非取代的苯基或者取代或者非取代的苄基,其中苯基或者苄基被以下取代基团取代:卤素或者C1-C3烷基。
3.根据权利要求1所述的化合物,其特征在于,R1选自选自苄基、3-取代苄基、4-取代苄基或者多取代苄基,所述苄基的取代基为甲基或者卤素;
R2选自5,6-二乙基-2,3-二氢-1H-茚-2-胺基、N-苯代哌嗪基、N-苯代高哌嗪基、溴苯胺基、2,3-二氢吲哚基或者为2,3-二氢茚基;所述N-苯代哌嗪基选自:苄基取代哌嗪基、甲基苄基取代哌嗪基或者苄基溴取代哌嗪基;N-苯代高哌嗪基选自:苄基取代高哌嗪基、甲基苄基取代高哌嗪基或者苄基溴取代高哌嗪基。
4.根据权利要求1所述的化合物,其特征在于,所述R1选自苄基、4-甲基苄基、3-氟苄基、4-氟苄基、3,5-二氟苄基、3,4-二氟苄基、全氟代苄基;
R2选自5,6-二乙基-2,3-二氢-1H-茚-2-胺基、2-溴苯胺基、2,3-二氢吲哚基、2,3-二氢茚基、苄基取代哌嗪基、4-甲基苄基取代哌嗪基、4-溴苄基取代哌嗪基、苄基取代高哌嗪基、4-甲基苄基取代高哌嗪基。
7.根据权利要求6所述化合物的制备方法,其特征在于,
化合物II制备化合物III的反应中:溶剂选自乙腈、二氯甲烷、氯仿、四氢呋喃、N,N′-二甲基甲酰胺、二甲亚砜中的一种或多种;反应温度为-20℃至25℃;
从化合物III制备化合物IV的反应中:溶剂选自乙腈,二氯甲烷、氯仿、丙酮、四氢呋喃、甲醇、N,N-二甲基甲酰胺、二甲亚砜或二氧六环中的一种或多种;碱选自碳酸钾、碳酸钠、碳酸氢钠、氢氧化钠、氢氧化钾或三乙胺;反应温度为25℃至加热回流;
从化合物IV制备化合物I的反应中:溶剂选自乙腈、N,N-二甲基甲酰胺、二甲亚砜、正丁醇或二乙二醇二甲醚;反应温度为60℃至150℃;
从化合物I制备化合物I’的反应中:溶剂选自乙腈、二氯甲烷、氯仿或四氢呋喃中的一种或多种,在惰性气体保护的条件下与卤化试剂反应,反应温度为-20℃至0℃。
8.根据权利要求7所述化合物的制备方法,其特征在于:
从化合物II制备化合物III的反应中:溶剂选择无水四氢呋喃,反应温度为-20℃至0℃;
从化合物III制备化合物IV的反应中:溶剂选择为丙酮,碱选择为碳酸钾或三乙胺,反应温度为55℃至65℃;
从化合物IV制备化合物I的反应中:溶剂选择为正丁醇,反应温度为110℃至120℃。
从化合物I制备化合物I’的反应中:溶剂选择为二氯甲烷,在氮气保护下反应,反应温度为-20℃至0℃。
9.如权利要求1-5任一项所述的化合物在制备治疗与恶性肿瘤有关疾病药物中的应用。
10.如权利要求9所述的应用,其特征在于,所述是与恶性肿瘤有关疾病为SRSF6蛋白过表达介导的肿瘤,包括结直肠肿瘤。
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