CN117700376A - N-苄基苯甲酰胺类化合物及其药物组合物和应用 - Google Patents
N-苄基苯甲酰胺类化合物及其药物组合物和应用 Download PDFInfo
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- CN117700376A CN117700376A CN202311813841.XA CN202311813841A CN117700376A CN 117700376 A CN117700376 A CN 117700376A CN 202311813841 A CN202311813841 A CN 202311813841A CN 117700376 A CN117700376 A CN 117700376A
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Abstract
本发明公开了一种N‑苄基苯甲酰胺类化合物及其药物组合物和应用。该类化合物的结构如式I,还包含其药学上可接受的盐,其在体内外可有效释放母药,肿瘤抑制活性优异,并且通过前药策略显著降低母药的毒性,安全性良好,具有成药前景。
Description
技术领域
本发明涉及一种N-苄基苯甲酰胺类化合物及其药物组合物和应用,尤其涉及一种可制备为微管蛋白抑制剂前药的N-苄基苯甲酰胺类化合物及其药物组合物和应用。
背景技术
微管是细胞骨架的主要组成部分,在维持细胞形态、细胞分裂、信号转导等过程中起着重要作用,因此,微管蛋白是一个非常有前景的新型化疗药物的靶标。微管蛋白抑制剂能阻止肿瘤细胞的过度增殖,是一类重要的抗肿瘤治疗药物。目前,临床上应用的微管抑制剂主要有以紫杉醇为代表的抑制微管蛋白解聚药物及以长春碱类为代表的抑制微管蛋白聚集药物。秋水仙碱结合位点是目前对微管蛋白研究较多的一个位点,作用于该位点的抑制剂通常结构较简单,如秋水仙碱、Combretastatin A-4等。此外,作用于该位点的抑制剂还能破坏肿瘤组织的血管,因此,作用于秋水仙碱位点的微管蛋白抑制剂的研究已成为当今抗肿瘤研究的热点。但这些药物存在毒副作用大、水溶性差、易产生耐药性等缺点。
发明内容
发明目的:本发明的第一目的是提供一种N-苄基苯甲酰胺类化合物,第二目的是提供一种包含所述化合物的药物组合物,第三目的是提供所述化合物及其药物组合物在制备微管蛋白抑制剂药物中的应用。
技术方案:本发明所述的N-苄基苯甲酰胺类化合物有式I的结构,还包含其药学上可接受的盐:
其中:
R1选自氢、羟基、巯基、卤素、氰基、羧基、C1-C3的酯基、C1-C3的酰胺基、羟甲基、醛基、硝基、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、C1-C6烷氨基、C6-C10芳基、C3-C10含有一个氮、氧、硫的杂芳基、C4-C8含有一个氮、氧、硫的杂环基;
R2选自氢、羟基、巯基、卤素、氰基、羧基、C1-C3的酯基、C1-C3的酰胺基、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、C3-C10含有一个氮、氧、硫的杂芳基、C4-C8含有一个氮、氧、硫的杂环基;
R3选自氢、C1-C8烷基、C1-C8含有一个双键或三键的不饱和烷基、C3-C8环烷基、C6-C10芳基、C3-C10含有一个氮、氧、硫的杂芳基、C4-C8含有一个氮、氧、硫的杂环基;
X选自CH2、NH、O、S、C4-C8的氮杂螺环、C4-C6的氮杂芳螺环、C1-C8链状烷基、C1-C3链状醚基、C1-C3链状酯基。
优选,所述结构中:
R1选自氢、卤素、硝基、C1-C8烷氧基、C1-C6烷氨基、C6-C10芳基、C3-C10含有一个氮、氧、硫的杂芳基;
R2选自氢、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、C3-C10含有一个氮、氧、硫的杂芳基、C4-C8含有一个氮、氧、硫的杂环基;
R3选自氢、C1-C8烷基、C1-C8含有一个双键或三键的不饱和烷基、C3-C8环烷基、C6-C10芳基、C3-C10含有一个氮、氧、硫的杂芳基、C4-C8含有一个氮、氧、硫的杂环基;
X选自CH2、NH、O、S、C4-C8的氮杂螺环、C4-C6的氮杂芳螺环、C1-C8链状烷基。
进一步优选,所述结构中:
R1选自氢、卤素、硝基、C1-C8烷氧基、C1-C6烷氨基;
R2选自氢、C1-C8烷基、C1-C8烷氧基、C4-C8含有一个氮、氧、硫的杂环基;
R3选自氢、C1-C8烷基、C1-C8含有一个双键或三键的不饱和烷基、C6-C10芳基;
X选自CH2、NH、O、S、C4-C8的氮杂螺环、C4-C6的氮杂芳螺环。
再进一步优选,所述结构中:
R1选自氢、氟、氯、溴、硝基、甲氧基、乙氧基、乙胺基、N,N-二甲氨基;
R2选自氢、甲基、乙基、甲氧基、乙氧基、哌嗪、吗啉、哌啶;
R3选自氢、甲基、乙基、烯丙基、炔丙基、1-丁炔-3-基、3-甲基-1-丁炔-3-基、1-丁烯-3-基、苄基、4-炔丙氧基苄基、3-炔丙氧基苄基、2-炔丙氧基苄基、4-烯丙氧基苄基、3-烯丙氧基苄基、2-烯丙氧基苄基;
X选自NH、O、S。
具体地,本发明所述的N-苄基苯甲酰胺类化合物选自以下任一的化合物:
生物正交反应是指能够在生物体系中进行、且不会与天然生物化学过程相互干扰的一类化学反应。传统的生物正交反应以新化学键生成的连接反应为主,近年来,一类新兴的反应类型——以化学键断裂为基础的生物正交剪切反应逐渐发展起来,并在分子的“释放”、“激活”和“操控”等方面得到了越来越广泛的应用。聚焦于药物化学范畴,生物正交化学被广泛用于减少药物毒副作用、改善类药性质、提高治疗效果。
本发明首次将秋水仙碱结合位点的微管蛋白抑制剂与过渡金属催化的生物正交剪切策略进行结合,提供了一种毒副作用低、对肿瘤的选择性杀伤力高、安全性好的微管蛋白抑制剂前药分子,有望实现肿瘤的精准治疗。
本发明所述的前药自身具有较弱的活性甚至没有活性,但是在给药后,在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。通式I所示的化合物可以以非溶剂化形式和含有药学上可接受的溶剂(如水、乙醇等)的溶剂化形式;通式I所示的化合物可以含有不对称或手性中心,因此可以以不同立体异构形式存在;本发明的所有立体异构形式,包括但不限于非对映异构体、对映异构体和阻转异构体以及它们的混合物(如外消旋混合物),均包括在本发明的范围内。
其中,本发明所述的药学上可接受的盐为所述化合物与选自以下任一的酸形成的盐:盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸、阿魏酸。
“药学上可接受的盐”是指化合物的盐,由具有特定取代基的化合物与相对无毒的酸或碱制备。当化合物中含有相对酸性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的游离体形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的游离体形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐,所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸(形成碳酸盐或碳酸氢盐)、磷酸(形成磷酸盐、磷酸一氢盐、磷酸二氢盐、硫酸(形成硫酸盐或硫酸氢盐)、氢碘酸、亚磷酸等;以及有机酸盐,所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸;有机酸盐还包括氨基酸(如精氨酸等)、葡糖醛酸等有机酸的盐。当某些特定的化合物含有碱性和酸性的官能团,从而可以被转换成任一碱或酸加成盐。优选地,以常规方式使盐与碱或酸接触,再分离母体化合物,由此再生化合物的游离体形式。化合物的游离体形式与其各种盐的形式的不同之处在于某些物理性质,例如在极性溶剂中的溶解度不同。
“药学上可接受的盐”可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下,这样的盐的制备方法是:在水或有机溶剂或两者的混合物中,经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地,优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
本发明所述的化合物也可作为溶剂化物使用。
本发明包括所述化合物的各种氘代形式。与碳原子相连的每个可用氢原子可以独立的被氘原子取代。
本发明通式Ⅰ的化合物可用下列方法制备得到:
其中,R1、R2、R3的定义同前所述。
具体合成步骤如下:
以5位不同取代的2-氟苯甲酸为原料,在浓硫酸和乙醇条件下发生酯化反应,随后与哌嗪/吗啉/硫代吗啉进行亲核取代反应,而后碱性条件下酯解得到中间体4。将4位不同取代的3-羟基苯腈与溴苄反应对羟基进行保护,而后再用硼烷-四氢呋喃还原氰基得到中间体7。中间体4和7经酰胺缩合得到中间体8,而后经氢化反应脱去苄基保护基得到母药化合物9,最后与不同取代基的溴代烃进行亲核取代反应得到生物正交前药化合物10。
本发明所述的药物组合物本发明所述的N-苄基苯甲酰胺类化合物以及药学上可接受的载体。
优选,所述药物组合物的剂型选自胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂、贴剂。可任意混合的载体根据剂型、给药形式等可以改变。载体的例子包括赋形剂、粘合剂、崩解剂、润滑剂、矫味剂、香味剂、着色剂或甜味剂等。
“药学上可接受的载体”可为药物生产领域中广泛采用的辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物,还可以提供方法,使受试者接受给药后活性成分以所期望的速率溶出,或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂,或者提供某种功能,例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种:粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
本发明所述的药物组合物可根据公开的内容使用本领域技术人员已知的任何方法来制备。例如,常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
本发明所述的药物组合物可以任何形式给药,包括注射(静脉内)、粘膜、口服(固体和液体制剂)、吸入、眼部、直肠、局部或胃肠外(输注、注射、植入、皮下、静脉内、动脉内、肌内)给药。本发明的药物组合物还可以是控释或缓释剂型(例如脂质体或微球)。固体口服制剂的实例包括但不限于粉末、胶囊、囊片、软胶囊剂和片剂。口服或粘膜给药的液体制剂实例包括但不限于悬浮液、乳液、酏剂和溶液。局部用制剂的实例包括但不限于乳剂、凝胶剂、软膏剂、乳膏剂、贴剂、糊剂、泡沫剂、洗剂、滴剂或血清制剂。胃肠外给药的制剂实例包括但不限于注射用溶液、可以溶解或悬浮在药学上可接受载体中的干粉制剂、注射用悬浮液和注射用乳剂。所述的药物组合物的其它合适制剂的实例包括但不限于滴眼液和其他眼科制剂;气雾剂,如鼻腔喷雾剂或吸入剂;适于胃肠外给药的液体剂型;栓剂以及锭剂。
本发明所述的N-苄基苯甲酰胺类化合物或药物组合物应用在制备抑制微管蛋白活性的药物中。
优选,所述药物为抗肿瘤药物,用于结肠癌、白血病、肝癌、乳腺癌等。
有益效果:与现有技术相比,本发明具有如下显著优点:
该类化合物在体内外可有效释放母药并显著抑制微管蛋白抑制活性,肿瘤抑制活性优异(细胞水平抑制活性达到纳摩尔浓度水平,动物水平抑瘤率达到50%以上),并且通过前药策略显著降低母药的毒性,安全性良好,具有成药前景。
附图说明
图1为本发明的部分化合物对小鼠体重影响的结果(*P<0.05,**P<0.01与空白组比较)。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例1
5-氟-N-(4-甲氧基-3-(丙-2-炔-1-氧基)苄基)-2-吗啉苯甲酰胺
步骤1:将2,5-二氟苯甲酸(1)(3.0g,19.0mmol)混合于20mL乙醇中,加入催化量的浓硫酸,回流反应12h。旋蒸除去溶剂,加水稀释残余物,用DCM(3×50mL)萃取。随后用饱和食盐水洗涤有机相,无水硫酸钠干燥,真空浓缩得到中间体2(2.82g,80%)。
步骤2:将中间体2(2.82g,15.2mmol)混合于20mL DMSO中加入吗啉(6.63mL,75.7mmol),于120℃下搅拌6h。降温后用200mL水稀释反应液,用乙酸乙酯(3×50mL)萃取。随后用饱和食盐水洗涤有机相,无水硫酸钠干燥,真空浓缩得到中间体3(2.80g,73%)。
步骤3:中间体3(2.80g,11.06mmol)混合于10mL甲醇,加入10mL 10%NaOH水溶液,80℃搅拌反应30min,旋蒸除去甲醇,而后用10%盐酸调节pH=3。固体经减压抽滤收集,用水洗涤滤饼,干燥得到中间体4(2.21g,90%)。
步骤4:将3-羟基-4-甲氧基苯腈(2.5g,16.8mmol)溶于乙腈(25.0mL)中。然后加入碳酸钾(4.65g,33.5mmol)和溴苄(3.35mL,29.4mmol)。所得混合物回流1.5h,冷却并过滤。滤液浓缩,用乙酸乙酯稀释,而后用水洗涤。有机相用无水硫酸钠干燥,蒸发得到残余物,通过柱层析纯化得到中间体6(3.73g,93%)。
步骤5:中间体6(2g,8.36mmol)混合于四氢呋喃硼烷溶液中,氩气保护下回流搅拌反应10小时。旋蒸除去溶剂,通过柱层析纯化得到中间体7(1.18g,58%)。
步骤6:向10mL无水乙腈溶液中加入中间体4(370mg,1.64mmol)和中间体7(800mg,3.29mmol)、HATU(633.45mg,1.97mmol)、三乙胺(274μL,1.97mmol)。混合物搅拌反应3小时,用DCM(3×25mL)萃取。随后用饱和食盐水洗涤有机相,无水硫酸钠干燥,真空浓缩得到残余物,经柱层析纯化得到中间体8(533.3mg,72%)。
步骤7:将中间体8(500mg,1.11mmol)溶解于20mL乙醇中,加入钯碳(125mg)。在氢气气氛下搅拌反应2h,过滤后滤液真空浓缩得到残余物,经柱层析纯化得到中间体9(328mg,82%)。
步骤8:将中间体9(150mg,416.22μmol)、溴丙炔(297.08mg,2.5mmol)、无水碳酸钾(517.71mg,3.75mmol)溶解于丙酮中,加热回流反应12小时,旋蒸除去溶剂,用乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥后,真空浓缩得到残余物,经柱层析纯化得到目标产物,白色固体,收率为72.7%。
1H NMR(300MHz,DMSO-d6)δ9.92(t,J=5.7Hz,1H),7.63–7.52(m,1H),7.42–7.27(m,2H),7.09(d,J=1.6Hz,1H),7.00(d,J=2.3Hz,2H),4.77(d,J=2.4Hz,2H),4.44(d,J=5.6Hz,2H),3.77(s,3H),3.54(t,J=2.4Hz,1H),3.49–3.40(m,4H),2.83(dd,J=5.6,3.3Hz,4H).13C NMR(100MHz,DMSO-d6)δ164.89,149.07,147.55,147.52,146.96,131.53,131.37,123.58,123.50,121.95,118.67,118.45,116.90,116.67,114.84,112.67,79.76,78.64,66.46,56.56,56.13,53.32,43.02.ESI-MS m/z:399.2[M+H]+。
实施例2
N-(3-(丁-3-炔-2-氧基)-4-甲氧苄基)-5-氟-2-吗啉苯甲酰胺
将中间体9(150mg,416.22μmol)、3-丁炔-2-醇(35.01mg,499.47μmol)、三苯基膦(218.34mg,832.44μmol)溶解于无水二氯甲烷中,冷却至0℃,氮气保护,滴加偶氮二甲酸二异丙酯(126.25mg,624.33μmol),常温反应3小时,用乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥后,真空浓缩得到残余物,经柱层析纯化得到目标产物,白色固体,收率为34.3%。
1H NMR(400MHz,DMSO-d6)δ9.89(t,J=5.7Hz,1H),7.56(dd,J=9.5,2.8Hz,1H),7.41–7.27(m,2H),7.10(d,J=1.8Hz,1H),7.04–6.88(m,2H),5.00(qd,J=6.5,2.0Hz,1H),4.43(t,J=5.8Hz,2H),3.76(s,3H),3.44(p,J=3.0,2.6Hz,5H),2.85–2.78(m,4H),1.54(d,J=6.5Hz,3H).13C NMR(100MHz,DMSO-d6)δ164.90,149.47,147.54,147.51,146.50,131.51,123.55,123.47,122.18,118.66,118.45,116.90,116.66,116.54,112.77,83.73,76.95,66.46,64.32,56.14,53.33,42.96,22.53.ESI-MS m/z:413.2[M+H]+。
实施例3
5-氟-N-(4-甲氧基-3-((2-甲基丁-3-炔-2-基)氧代)苄基)-2-吗啉苯甲酰胺
将中间体9(100mg,277.48μmol)、3-氯-3-甲基-1-丁炔(170.75mg,1.66mmol)、无水碳酸铯(362.86mg,1.66mmol)溶解于丙酮中,加热回流反应12小时,旋蒸除去溶剂,用乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥后,真空浓缩得到残余物,经柱层析纯化得到目标产物,黄色固体,收率为68.4%。
1H NMR(400MHz,DMSO-d6)δ9.87(t,J=5.7Hz,1H),7.59–7.49(m,1H),7.40–7.25(m,3H),7.09(dd,J=8.3,2.1Hz,1H),6.99(d,J=8.4Hz,1H),4.42(d,J=5.7Hz,2H),3.73(s,3H),3.53–3.42(m,5H),2.84–2.78(m,4H),1.55(s,6H).13CNMR(100MHz,DMSO-d6)δ164.91,152.29,147.47,144.37,131.14,124.07,123.46,123.38,123.10,118.64,118.42,116.90,116.66,113.03,86.50,76.57,73.73,66.46,56.08,53.28,42.84,29.57.ESI-MSm/z:427.2[M+H]+。
实施例4
N-(3-(烯丙氧基)-4-甲氧苄基)-5-氟-2-吗啉苯甲酰胺
将中间体9(150mg,416.22μmol)、溴丙烯(302.12mg,2.50mmol)、无水碳酸钾(517.71mg,3.75mmol)溶解于丙酮中,加热回流反应12小时,旋蒸除去溶剂,用乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥后,真空浓缩得到残余物,经柱层析纯化得到目标产物,黄褐色固体,收率为82.1%。
1H NMR(300MHz,DMSO-d6)δ9.95(t,J=5.7Hz,1H),7.64(ddd,J=9.5,2.7,0.9Hz,1H),7.49–7.34(m,2H),7.12(s,1H),7.03(d,J=1.2Hz,2H),6.13(ddt,J=17.3,10.5,5.3Hz,1H),5.47(dq,J=17.3,1.7Hz,1H),5.32(dq,J=10.5,1.5Hz,1H),4.62(dt,J=5.4,1.5Hz,2H),4.51(d,J=5.7Hz,2H),3.85(s,3H),3.57–3.48(m,4H),2.95–2.85(m,4H).13CNMR(100MHz,DMSO-d6)δ164.91,148.89,148.06,147.51,134.29,131.69,131.43,131.36,123.51,123.43,121.14,118.63,118.41,117.91,116.88,116.64,114.29,112.59,69.48,66.44,56.12,53.31,43.06,38.70.ESI-MS m/z:401.2[M+H]+。
实施例5
N-(3-(丁-3-烯-2-氧基)-4-甲氧苄基)-5-氟-2-吗啉苯甲酰胺
将中间体9(100mg,277.48μmol)、3-氯-1-丁烯(150.76mg,1.66mmol)、无水碳酸钾(230.09mg,1.66mmol)溶解于丙酮中,加热回流反应12小时,旋蒸除去溶剂,用乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥后,真空浓缩得到残余物,经柱层析纯化得到目标产物,黄色液体,收率为69.4%。
1H NMR(300MHz,DMSO-d6)δ9.86(t,J=5.7Hz,1H),7.62–7.51(m,1H),7.40–7.26(m,2H),7.01(s,1H),6.94(d,J=1.1Hz,2H),5.88(ddd,J=17.0,10.5,6.1Hz,1H),5.23(dt,J=17.3,1.5Hz,1H),5.09(dt,J=10.5,1.4Hz,1H),4.84(p,J=6.3Hz,1H),4.41(dd,J=5.7,3.9Hz,2H),3.76(s,3H),3.48–3.40(m,4H),2.85–2.76(m,4H),1.35(d,J=6.3Hz,3H).13C NMR(100MHz,DMSO-d6)δ164.54,148.25,148.12,147.66,134.62,131.89,131.25,131.01,125.54,124.52,122.47,119.28,118.84,117.55,116.97,116.54,114.25,112.64,68.44,66.32,56.75 53.43,42.52,38.62.20.65.ESI-MS m/z:415.2[M+H]+。
实施例6
N-(3-(苄氧基)-4-甲氧苄基)-5-氟-2-吗啉苯甲酰胺
按照实施例1的操作,得目标化合物即中间体8,白色固体,收率为87.3%。
1H NMR(300MHz,DMSO-d6)δ9.89(t,J=5.6Hz,1H),7.57(dd,J=8.9,2.2Hz,1H),7.50–7.26(m,7H),7.13(s,1H),6.97(s,2H),5.07(s,2H),4.44(d,J=5.6Hz,2H),3.78(s,3H),3.43(t,J=4.5Hz,4H),2.79(t,J=4.5Hz,4H).13C NMR(100MHz,DMSO-d6)δ167.84,152.55,149.71,148.12,147.83,144.71,136.62,130.42,128.65,128.39,127.64,124.16,122.87,119.42,118.85,117.25,116.52,116.04,109.15,71.24,66.32,56.15 52.93,44.41.ESI-MS m/z:451.2[M+H]+。
实施例7
5-氟-N-(4-甲氧基-3-((4-(丙-2-炔-1-氧基)苄基)氧代)苄基)-2-吗啉苯甲酰胺
将中间体9(70mg,194.24μmol)、1-(溴甲基)-4-(丙-2-炔-1-氧基)苯(264.67mg,1.17mmol)、无水碳酸铯(254mg,1.17mmol)溶解于丙酮中,加热回流反应12小时,旋蒸除去溶剂,用乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥后,真空浓缩得到残余物,经柱层析纯化得到目标产物,黄色固体,收率为71.6%。
1H NMR(300MHz,Chloroform-d)δ10.19(d,J=6.2Hz,1H),7.88(dd,J=9.7,2.7Hz,1H),7.26(d,J=8.5Hz,2H),7.14–6.98(m,2H),6.86(d,J=1.9Hz,1H),6.86–6.72(m,3H),6.74(s,1H),4.98(s,2H),4.48(d,J=2.4Hz,2H),4.43(d,J=5.5Hz,2H),3.79(s,3H),3.27(d,J=4.9Hz,3H),2.61(t,J=4.5Hz,4H),2.40(t,J=2.4Hz,1H).13C NMR(100MHz,Chloroform-d)δ167.54,156.71,152.59,149.94,148.67,147.72,144.63,136.62,130.42,129.36,122.53,119.58,117.71,116.37,114.28,109.78,78.21,76.91,71.14,66.41,56.18 52.87,44.48.ESI-MS m/z:505.2[M+H]+。
实施例8
5-氟-N-(4-甲氧基-3-((3-(丙-2-炔-1-氧基)苄基)氧代)苄基)-2-吗啉苯甲酰胺
将中间体9(70mg,194.24μmol)、1-(溴甲基)-3-(丙-2-炔-1-氧基)苯(264.67mg,1.17mmol)、无水碳酸铯(254mg,1.17mmol)溶解于丙酮中,加热回流反应12小时,旋蒸除去溶剂,用乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥后,真空浓缩得到残余物,经柱层析纯化得到目标产物,白色固体,收率为68.5%。
1H NMR(400MHz,Chloroform-d)δ10.28(t,J=5.4Hz,1H),7.97(dd,J=9.7,2.9Hz,1H),7.24–7.10(m,3H),7.05(dd,J=7.0,1.5Hz,2H),6.97–6.90(m,2H),6.88(d,J=7.9Hz,1H),6.83(dt,J=8.2,1.4Hz,1H),5.14(s,2H),4.66(d,J=2.4Hz,2H),4.53(d,J=5.5Hz,2H),3.91(s,3H),3.39(t,J=4.6Hz,4H),2.74(t,J=4.6Hz,4H),2.51(t,J=2.4Hz,1H).13C NMR(100MHz,Chloroform-d)δ167.81,160.43,152.85,149.46,148.74,147.58,144.74,136.72,130.17,129.63,122.58,119.43,117.52,115.85,114.61,109.42,79.41,76.32,70.42,66.54,55.86 52.37,44.26.ESI-MS m/z:505.2[M+H]+。
实施例9
5-氟-N-(4-甲氧基-3-((2-(丙-2-炔-1-氧基)苄基)氧代)苄基)-2-吗啉苯甲酰胺
将中间体9(70mg,194.24μmol)、1-(溴甲基)-2-(丙-2-炔-1-氧基)苯(264.67mg,1.17mmol)、无水碳酸铯(254mg,1.17mmol)溶解于丙酮中,加热回流反应12小时,旋蒸除去溶剂,用乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥后,真空浓缩得到残余物,经柱层析纯化得到目标产物,粉色固体,收率为74.1%。
1H NMR(400MHz,Chloroform-d)δ10.28(d,J=6.0Hz,1H),7.98(dd,J=9.7,3.0Hz,1H),7.54–7.47(m,1H),7.27–7.10(m,3H),7.02–6.90(m,4H),6.89(d,J=8.1Hz,1H),5.23(s,2H),4.76(d,J=2.4Hz,2H),4.53(d,J=5.3Hz,2H),3.92(s,3H),3.40(t,J=4.5Hz,4H),2.78(t,J=4.6Hz,4H),2.51(t,J=2.4Hz,1H).13C NMR(100MHz,Chloroform-d)δ167.47,156.74,152.36,149.75,148.45,147.26,144.59,136.21,130.52,129.47,122.49,119.24,117.48,115.13,114.94,109.43,79.66,76.27,70.28,66.87,55.3252.57,44.51.ESI-MS m/z:505.2[M+H]+。
实施例10
N-(3-((4-(烯丙氧基)苄基)氧代)-4-甲氧苄基)-5-氟-2-吗啉苯甲酰胺
将中间体9(100mg,277.48μmol)、1-(烯丙氧基)-4-(溴甲基)苯(378.10mg,1.66mmol)、无水碳酸铯(362.86mg,1.66mmol)溶解于丙酮中,加热回流反应12小时,旋蒸除去溶剂,用乙酸乙酯萃取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥后,真空浓缩得到残余物,经柱层析纯化得到目标产物,粉色固体,收率为66.4%。
1H NMR(300MHz,Chloroform-d)δ10.28(d,J=6.4Hz,1H),8.28–6.51(m,10H),6.03(ddt,J=17.2,10.5,5.2Hz,1H),5.40(dq,J=17.3,1.7Hz,1H),5.29(dt,J=10.5,1.5Hz,1H),5.09(s,2H),4.55(d,J=5.5Hz,2H),4.43(dt,J=5.2,1.6Hz,2H),3.90(s,3H),3.43–3.34(m,4H),2.73(t,J=4.5Hz,4H).13C NMR(100MHz,Chloroform-d)δ167.82,157.42,152.66,149.34,148.37,147.82,145.53,134.25,130.74,128.58,123.65,119.73,118.26,115.58,114.62,111.68,82.58,76.27,72.69,66.34,55.64 52.92,44.51.ESI-MSm/z:507.2[M+H]+。
实施例11:片剂
取上述配方,用常规方法制备成片剂。
实施例12:抗增殖活性评价
1、实验方法
(1)细胞消化、计数、制成浓度为3.5×104个/mL的细胞悬液,96孔板中每孔加入100μl细胞悬液;
(2)96孔板置于37℃,5% CO2培养箱中培养24小时;
(3)用完全培养基稀释药物至所需浓度,每孔加入100μL相应的含药培养基,同时设立阴性对照组;
(4)96孔板置于37℃,5% CO2培养箱中培养72小时;
(5)CCK-8法:
①将96孔板进行CCK-8染色,λ=450nm,测定OD值。
②每孔加入10μL CCK-8,在培养箱继续培养2-3小时;
③摇床10分钟轻轻混匀;λ=450nm,酶标仪读出每孔的OD值,计算抑制率。
2、实验结果
表1.本发明部分化合物对4种人类癌细胞株和1种人类正常细胞株抗增殖活性的IC50值(nM)及化合物与母药IC50之比值
由表1可以看出,本发明的部分生物正交前药化合物对4种癌细胞株和1种正常细胞株的细胞毒性较母药大幅降低,表明这些生物正交前药化合物具有较好的安全性,在治疗过程中毒副作用较小。
实施例13:部分生物正交前药化合物被钯树脂催化释放后对K562细胞的生长抑制活性评价
1、实验方法
化合物按照相应要求配置成母液,按照倍数稀释成终浓度后用于后续试验。将不同浓度的生物正交前药化合物与不同剂量的钯树脂在96孔板中与K562细胞共孵育72h,随后利用CCK-8法测量并计算抑制率。
2、实验结果
表2.本发明部分化合物被钯树脂催化释放后对K562细胞的生长抑制实验结果
由表2可以看出,本发明的部分生物正交前药化合物在与钯树脂共孵育后,其细胞毒性得到有效恢复,表明这些生物正交前药化合物在被钯树脂激活释放后能够有效抑制肿瘤细胞的生长,起到高效低毒的治疗作用。
实施例14:部分生物正交前药化合物在释放前后对微管蛋白聚集的抑制活性评价
1、实验方法
化合物按照相应要求配置成母液,按照倍数稀释成终浓度后用于后续试验。浓度设置为5个,每个浓度重复3次。将2mg/mL微管蛋白(细胞骨架)的量重新悬浮于PEM缓冲液[80mM PIPES(pH 6.9),0.5mM EGTA,2mM MgCl2和15%甘油]中,然后在冰上与化合物或溶剂DMSO预孵育5分钟。在检测微管蛋白聚合反应之前,加入含有GTP的PEG至终浓度为3mg/mL。通过Berthold LB941微孔板式多功能酶标仪,30分钟后在340nm检测吸光度。通过设置空白对照组,Graphpad计算得出不同化合物的IC50,结果以μM为单位。
2、实验结果
表3本发明部分化合物被钯树脂催化释放前后对微管蛋白聚集的抑制实验结果
实施例 | 释放前IC50 | 释放后IC50 | IC50(释放前)/IC50(释放后) |
1 | 275 | 2.53 | 109 |
2 | 361 | 3.03 | 119 |
3 | 251 | 2.56 | 98 |
4 | 284 | 2.22 | 128 |
5 | 289 | 1.87 | 155 |
6 | 301 | 2.45 | 123 |
7 | 233 | 2.49 | 94 |
8 | 201 | 1.88 | 107 |
9 | 249 | 2.58 | 97 |
10 | 219 | 2.09 | 105 |
由表3可以看出,本发明的部分生物正交前药化合物对微管蛋白聚集的抑制活性较低,而当化合物与钯树脂共孵育后,对微管蛋白聚集的抑制活性得以恢复,进而抑制细胞的增殖,具有较好的安全性。
实施例15:部分化合物的体内安全性评价
1、实验方法
由上海斯莱克实验动物有限责任公司提供,周龄为4周的雌性ICR小鼠21只。将动物随机分组,每组3只,分别为空白对照组,母药组,前药组。空白对照组注射溶媒DMF:吐温80:9%生理盐水=10:2:88(V:V:V),母药组和前药组尾静脉给药剂量分别为40mg/kg、80mg/kg、160mg/kg溶媒为DMF:吐温80:9%生理盐水=10:2:88(V:V:V),连续给药21天,每两天测量一次体重。
2、实验结果
由图1可以看出,本发明的代表实施例化合物在高剂量下对小鼠的体重不会产生显著性影响,而母药在高剂量下会使小鼠体重显著性降低。表明本发明的生物正交前药化合物具有更优的体内安全性。
实施例16:部分化合物的体内抗肿瘤活性评价
1、实验方法
由上海斯莱克实验动物有限责任公司提供,周龄为4周的雌性ICR小鼠24只。收集培养的小鼠肝癌细胞H22细胞悬液,浓度为1×107个/ml,以每只0.1ml接种于小鼠右前肢腋窝皮下。小鼠移植瘤用游标卡尺测量移植瘤直径,肿瘤生长至100mm3左右时将动物随机分组,每组6只,分别为空白对照组,钯树脂对照组,母药组,前药+钯树脂组。空白对照注射溶媒DMF:吐温80:9%生理盐水=10:2:88(V:V:V),钯树脂对照组和前药+钯树脂组均在给药前瘤内注射Pd树脂(1mg in 50μL of PBS)。空白对照组,钯树脂对照组不给药。母药组,前药+钯树脂组尾静脉给药剂量为20mg/kg,溶媒为DMF:吐温80:9%生理盐水=10:2:88(V:V:V),连续给药21天。给药21天结束后处死小鼠,通过手术剥取瘤块,称重。计算肿瘤生长抑制率(%),用SPSS17.0对结果进行分析,组间用t检验进行统计学分析处理,其计算公式如下:
2、实验结果
表4.部分化合物的体内抗肿瘤活性
由表4可以看出,本发明的部分生物正交前药化合物可在肿瘤部位原位释放,产生浓度更高的母药,因此其体内肿瘤生长抑制效果较母药更强,治疗效果更优。
Claims (10)
1.一种N-苄基苯甲酰胺类化合物,其特征在于,有式I的结构,还包含其药学上可接受的盐:
其中:
R1选自氢、羟基、巯基、卤素、氰基、羧基、C1-C3的酯基、C1-C3的酰胺基、羟甲基、醛基、硝基、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、C1-C6烷氨基、C6-C10芳基、C3-C10含有一个氮、氧、硫的杂芳基、C4-C8含有一个氮、氧、硫的杂环基;
R2选自氢、羟基、巯基、卤素、氰基、羧基、C1-C3的酯基、C1-C3的酰胺基、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、C3-C10含有一个氮、氧、硫的杂芳基、C4-C8含有一个氮、氧、硫的杂环基;
R3选自氢、C1-C8烷基、C1-C8含有一个双键或三键的不饱和烷基、C3-C8环烷基、C6-C10芳基、C3-C10含有一个氮、氧、硫的杂芳基、C4-C8含有一个氮、氧、硫的杂环基;
X选自CH2、NH、O、S、C4-C8的氮杂螺环、C4-C6的氮杂芳螺环、C1-C8链状烷基、C1-C3链状醚基、C1-C3链状酯基。
2.根据权利要求1所述的N-苄基苯甲酰胺类化合物,其特征在于,所述结构中:
R1选自氢、卤素、硝基、C1-C8烷氧基、C1-C6烷氨基、C6-C10芳基、C3-C10含有一个氮、氧、硫的杂芳基;
R2选自氢、C1-C8烷基、C1-C8烷氧基、C3-C8环烷基、C3-C10含有一个氮、氧、硫的杂芳基、C4-C8含有一个氮、氧、硫的杂环基;
R3选自氢、C1-C8烷基、C1-C8含有一个双键或三键的不饱和烷基、C3-C8环烷基、C6-C10芳基、C3-C10含有一个氮、氧、硫的杂芳基、C4-C8含有一个氮、氧、硫的杂环基;
X选自CH2、NH、O、S、C4-C8的氮杂螺环、C4-C6的氮杂芳螺环、C1-C8链状烷基。
3.根据权利要求1所述的N-苄基苯甲酰胺类化合物,其特征在于,所述结构中:
R1选自氢、卤素、硝基、C1-C8烷氧基、C1-C6烷氨基;
R2选自氢、C1-C8烷基、C1-C8烷氧基、C4-C8含有一个氮、氧、硫的杂环基;
R3选自氢、C1-C8烷基、C1-C8含有一个双键或三键的不饱和烷基、C6-C10芳基;
X选自CH2、NH、O、S、C4-C8的氮杂螺环、C4-C6的氮杂芳螺环。
4.根据权利要求1所述的N-苄基苯甲酰胺类化合物,其特征在于,所述结构中:
R1选自氢、氟、氯、溴、硝基、甲氧基、乙氧基、乙胺基、N,N-二甲氨基;
R2选自氢、甲基、乙基、甲氧基、乙氧基、哌嗪、吗啉、哌啶;
R3选自氢、甲基、乙基、烯丙基、炔丙基、1-丁炔-3-基、3-甲基-1-丁炔-3-基、1-丁烯-3-基、苄基、4-炔丙氧基苄基、3-炔丙氧基苄基、2-炔丙氧基苄基、4-烯丙氧基苄基、3-烯丙氧基苄基、2-烯丙氧基苄基;
X选自NH、O、S。
5.根据权利要求1所述的N-苄基苯甲酰胺类化合物,其特征在于,选自以下任一的化合物:
6.根据权利要求1所述的N-苄基苯甲酰胺类化合物,其特征在于,所述药学上可接受的盐为所述化合物与选自以下任一的酸形成的盐:盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸、阿魏酸。
7.一种药物组合物,其特征在于,所述药物组合物包含权利要求1~6任一所述N-苄基苯甲酰胺类化合物以及药学上可接受的载体。
8.一种权利要求1~6任一所述的N-苄基苯甲酰胺类化合物或权利要求7所述的药物组合物在制备抑制微管蛋白活性的药物中的应用。
9.根据权利要求8所述的应用,其特征在于,所述药物为抗肿瘤药物。
10.根据权利要求9所述的应用,其特征在于,所述肿瘤为结肠癌、白血病、肝癌、乳腺癌。
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