CN110041180B - 含氮杂侧链的紫草素肟衍生物及其制备方法和医药用途 - Google Patents
含氮杂侧链的紫草素肟衍生物及其制备方法和医药用途 Download PDFInfo
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Abstract
Description
技术领域
本发明属于医药领域,涉及一种含氮杂侧链的紫草素肟衍生物及其制备方法和医药用途,尤其涉及一种含氮杂侧链的紫草素、阿卡宁及其外消旋体肟衍生物及其制备方法和医药用途。
背景技术
紫草为《中华人民共和国药典》收载的临床常用中药。紫草可分为硬紫草(又名东北紫草,Lithospermum erythrohizon)和软紫草(又名新疆紫草,A.euchroma Johnst)。硬紫草中的主要有效成分为紫草素及其衍生物,软紫草中含有阿卡宁及其衍生物。紫草素和阿卡宁互为对映异构体,已经被证实均具有抗炎、促进伤口愈合、抗菌、抗病毒、抗血栓、抗甲状腺亢进、抗免疫低下、降血糖、保肝护肝等多种生物活性。近年来,紫草素、阿卡宁及其消旋体衍生物的抗肿瘤活性研究引人关注,以其为先导化合物开发抗肿瘤新药的研究具有重要意义。
在前期研究中,我们发明了一系列萘茜母核氧烷基化羰基肟化的紫草素衍生物(中国发明专利:ZL201310044118,ZL201310044877)。这些化合物在体外表现出非常强的抗肿瘤活性,然而该类化合物表现出较差的水溶性;其溶解性影响了该类化合物的应用。在本专利研究工作前,没有任何水溶性好的萘茜母核氧烷基化羰基肟化的紫草素衍生物被文献报道。
许多含碱性氮的杂环类化合物都具有较强的生理活性,同时,含氮杂环也是抗肿瘤药物的基本骨架。因此,在目标化合物结构中引入含氮杂环,将含氮杂环与酸成盐,可以改善目标化合物的溶解性,可能提高其抗肿瘤活性。在前期的工作中,我们在萘茜母核氧烷基化羰基肟化的紫草素衍生物的肟羟基上引入了含氮杂环,化合物的水溶性改善但是抗肿瘤活性显著降低,这一结果表明引入含氮杂环的位置对该类化合物的抗肿瘤活性影响很大。
发明内容
本发明的目的在于克服现有技术的不足,提供一种含氮杂侧链的紫草素肟衍生物及其制备方法和医药用途;更具体来说,是提供了一种含氮杂侧链的紫草素、阿卡宁及其外消旋体肟衍生物及其制备方法和医药用途。本发明以1,4,5,8-O-四甲基紫草素,1,4,5,8-O-四甲基阿卡宁及其消旋体为原料,在侧链引入含氮杂环,再通过氧化脱甲基化羰基肟化方法,提供了一种含氮杂侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物的制备方法和医药用途。药理结果显示,本发明含氮杂侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物具有良好的抗肿瘤活性。
本发明的目的是通过以下技术方案实现的:
第一方面,本发明涉及一种含氮杂侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物,所述衍生物的结构式如式(Ⅰ)所示:
其中,R代表含氮杂环;所述含氮杂环包括含取代基的吡啶、嘧啶、吡嗪、哒嗪、噻唑、吲哚、吗啉、哌啶、哌嗪、N-亚甲基-N-羟乙基哌嗪、N-亚甲基-N-羟丁基哌嗪及其生理可接受的盐;所述取代基包括烷基或卤素;n为1~4中的任一正整数。
优选的,所述衍生物结构式如式(Ⅱ)所示:
其中,吡啶环以氮原子的邻位、对位或间位与羧酸酯连接;R1为氢、烷基或卤素;n为1~4中的任一正整数。
更优选,所述衍生物为含吡啶侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物,化学名为6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟吡啶羧酸酯衍生物,其结构式如下所示:
其中,吡啶环以氮原子的邻位、对位或间位与羧酸酯连接;R1为氢、烷基或卤素。
优选的,所述衍生物结构式如式(Ⅲ)所示:
其中,R2为1-4个碳的直链烷基、羟乙基及羟丁基;n为1~4中的任一正整数。
更优选,所述衍生物为含哌嗪侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物,化学名为6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟烷基哌嗪乙酸酯衍生物,其结构式如下所示:
其中,R2为1-4个碳的直链烷基、羟乙基及羟丁基。
优选的,所述衍生物结构式如式(Ⅳ)所示:
更优选,所述衍生物为含N-甲基哌啶侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物,化学名为6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟N-甲基哌啶甲酸酯衍生物,其结构式如下所示:
优选的,所述衍生物结构式如式(Ⅴ)、(Ⅵ)、(Ⅶ)、(Ⅷ)或(Ⅸ)所示:
其中,n为1~4中的任一正整数。
更优选,所述衍生物为含吡嗪侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物,化学名为6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟吡嗪-2-甲酸酯,其结构式如下所示:
更优选的,所述衍生物为含嘧啶侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物,化学名为6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟嘧啶-5-甲酸酯,其结构式如下所示:
更优选的,所述衍生物为含哒嗪侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物,化学名为6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟哒嗪-4-甲酸酯,其结构式如下所示:
更优选的,所述衍生物为含吗啉侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物,化学名为6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟吗啉-N-乙酸酯,其结构式如下所示:
更优选的,所述衍生物为含噻唑侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物,化学名为6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟噻唑-4-甲酸酯,其结构式如下所示:
第二方面,本发明涉及一种所述含氮杂侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物的制备方法,所述方法包括如下步骤:
S3、所述化合物ⅩⅢ经硝酸铈胺氧化及羰基肟化反应,得所述含氮杂侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物。
优选的,步骤S1中,2-(1-羟基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘(Ⅹ)与含3,4-二氢吡喃(THP)保护基的溴代烷基醇的摩尔比为1:1.2-1:2.5。所述亲核取代反应的反应温度为45-55℃,反应时间为20-48小时。
优选的,步骤S2中,所述酯化反应是在催化量的对二甲氨基吡啶及1.2倍当量的缩合剂N,N’-二环己基碳二亚胺存在的条件下进行的;酯化反应的温度为20-40℃,反应时间为20-48小时。
优选的,步骤S3中,硝酸铈胺氧化具体是在3-20℃条件下,在化合物ⅩⅢ中滴入含2-2.5倍当量硝酸铈铵的水溶液进行反应。
优选的,步骤S3中,羰基肟化反应具体是将硝酸铈胺氧化产物加入2-2.5倍当量的盐酸羟胺,35-45℃反应20-48小时。
更优选,所述方法包括如下步骤:
A1、在钠氢的存在下,2-(1-羟基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘(Ⅹ)与2-(8-溴辛氧基)-3,4-二氢吡喃发生亲核取代反应,得到侧链羟基醚化的衍生物
A2、所述侧链羟基醚化的衍生物烷基醇末端的3,4-二氢吡喃保护基团在酸性下脱除,得2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘;进一步与含氮杂环羧酸酯发生酯化反应得化合物
A3、步骤A2所得化合物经硝酸铈胺氧化及羰基肟化反应,得所述含氮杂侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物。
第三方面,本发明涉及一种所述含氮杂侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物在制备抗肿瘤药物中的用途。
与现有技术相比,本发明具有如下的有益效果:
1)本发明化合物的制备方法简便,收率较高且原料易得。
2)所制备的含氮杂侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟化衍生物,结构新颖,水溶性好。
3)体内外抗肿瘤活性实验研究表明,该类化合物抗肿瘤活性较强。
附图说明
通过阅读以下附图对非限制性实施例所作的详细描述,本发明的其它特征、目的和优点将会变得更明显:
图1为含氮杂侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物(结构式Ⅰ)的制备过程示意图。
图2为实施例21化合物(Ⅲ-1)对HCT-15移植瘤的抑瘤效果示意图。
图3为实施例21化合物(Ⅲ-1)在血浆中的不同时间点的降解曲线。
具体实施方式
下面结合附图和具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明,但不以任何形式限制本发明。应当指出的是,对本领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干调整和改进。这些都属于本发明的保护范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。
实施例1
本实施例涉及一种具有上述结构式(Ⅻ-1)的2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘的制备方法,如图1所示,包括以下步骤:
将2-(1-羟基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘(Ⅹ)溶于无水N,N’-二甲基甲酰胺中,冷却至0℃,加入2倍当量的氢化钠,搅拌30分钟后再加入2倍当量的2-(8-溴辛氧基)-四氢吡喃,反应液升温至50℃搅拌反应24小时。加入冰水淬灭反应,乙酸乙酯萃取,硅胶柱层析后得淡棕色油状物。油状物溶于甲醇,滴加浓盐酸1毫升,室温搅拌过夜。反应液减压浓缩至小体积,用乙酸乙酯萃取。有机层经饱和碳酸氢钠洗涤、无水硫酸钠干燥、减压浓缩及硅胶柱层析柱后,得2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘(Ⅻ-1)。产物呈棕色油状物,收率78%。1H NMR(400MHz,CDCl3)δ6.89(s,1H),6.72–6.66(m,2H),5.21–5.15(m,1H),4.82–4.74(m,1H),3.82(s,3H),3.79(s,3H),3.75(s,3H),3.63(s,3H),3.46–3.40(m,2H),3.25–3.16(m,2H),2.80–2.71(m,1H),2.44–2.35(m,2H),1.55(s,3H),1.43(s,3H),1.40–1.34(m,2H),1.31–1.08(m,10H)。
实施例2
本实施例涉及一种具有上述结构式((R)-Ⅻ-1)的(R)-2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例1步骤相同,在步骤一中以(R)-2-(1-羟基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘((R)-Ⅹ)代替2-(1-羟基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘(Ⅹ)。产物呈棕色油状物,收率71%。1H NMR(400MHz,CDCl3)δ6.95(s,1H),6.76–6.66(m,2H),5.21–5.13(m,1H),4.87–4.76(m,1H),3.88(s,3H),3.71(s,3H),3.79(s,3H),3.65(s,3H),3.49–3.41(m,2H),3.28–3.16(m,2H),2.82–2.75(m,1H),2.48–2.33(m,2H),1.56(s,3H),1.45(s,3H),1.46–1.34(m,2H),1.30–1.10(m,10H)。
实施例3
本实施例涉及一种具有上述结构式((S)-Ⅻ-1)的(S)-2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例1步骤相同,在步骤一中以(S)-2-(1-羟基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘((S)-Ⅹ)代替2-(1-羟基-4-甲基-3-戊烯基)-1,4,5,8-四甲氧基萘(Ⅹ)。产物呈棕色油状物,收率75%。1H NMR(400MHz,CDCl3)δ6.91(s,1H),6.76–6.66(m,2H),5.21–5.13(m,1H),4.85–4.76(m,1H),3.89(s,3H),3.71(s,3H),3.79(s,3H),3.65(s,3H),3.49–3.41(m,2H),3.26–3.16(m,2H),2.81–2.75(m,1H),2.48–2.33(m,2H),1.56(s,3H),1.45(s,3H),1.45–1.34(m,2H),1.28–1.10(m,10H)。
实施例4
本实施例涉及一种具有结构式(Ⅱ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟吡啶-2-甲酸酯(Ⅱ-1)的制备方法,如图1所示,包括以下步骤:
将2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘(Ⅻ)溶于无水二氯甲烷中,加入催化量的对二甲氨基吡啶及1.2倍当量的缩合剂N,N’-二环己基碳二亚胺。反应液室温搅拌10min后,加入等当量的吡啶-2-甲酸。反应液室温搅拌24小时后,用二氯甲烷稀释并抽滤。滤液经水、饱和食盐水清洗,减压浓缩至干后得淡黄色油状物。油状物用二氯甲烷-乙腈(3:1,V/V)溶解;溶液冷却至5℃左右,搅拌下滴入含2.5倍当量硝酸铈铵的水溶液,继续搅拌至反应原料消失,二氯甲烷萃取。有机层经饱和氯化钠溶液清洗,无水硫酸钠干燥后蒸干。硅胶柱层析纯化,收集6位产物的黄色带,回收洗脱剂至干并得橙色的油状物。油状物用无水乙醇溶解,加入2.5倍当量的盐酸羟胺,40℃反应过夜;反应液放冷,抽滤后得6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟吡啶-2-甲酸酯(Ⅱ-1)。产物呈橙红色粉末,收率22.6%。1H NMR(400MHz,DMSO-d6)δ12.03(s,2H),8.72(d,J=4.8Hz,1H),8.20(d,J=8.0Hz,1H),7.66(d,J=4.8Hz,1H),7.54(dd,J=7.9,4.7Hz,1H),7.36(d,J=2.0Hz,2H),7.03(s,1H),5.18(s,1H),4.61(dd,J=7.5,5.1Hz,1H),4.25(t,J=6.4Hz,2H),3.73(s,3H),3.56(s,3H),3.28–3.22(m,2H),2.35–2.22(m,2H),1.68–1.65(m,2H),1.59(s,3H),1.44(s,3H),1.33–1.16(m,10H)。
实施例5
本实施例涉及一种具有结构式(Ⅱ)的(R)-6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟吡啶-2-甲酸酯((R)-Ⅱ-1)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以(R)-2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘((R)-Ⅻ)代替2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘(Ⅻ)。产物呈橙红色粉末,收率25.1%。1H NMR(400MHz,DMSO-d6)δ11.88(s,2H),8.76(d,J=4.8Hz,1H),8.23(d,J=8.0Hz,1H),7.67(d,J=4.8Hz,1H),7.52(dd,J=7.9,4.7Hz,1H),7.36(d,J=2.0Hz,2H),7.02(s,1H),5.19(s,1H),4.61(dd,J=7.5,5.1Hz,1H),4.26(t,J=6.4Hz,2H),3.78(s,3H),3.51(s,3H),3.29–3.22(m,2H),2.39–2.21(m,2H),1.73–1.67(m,2H),1.64(s,3H),1.45(s,3H),1.33–1.16(m,10H)。
实施例6
本实施例涉及一种具有结构式(Ⅱ)的(S)-6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟吡啶-2-甲酸酯((S)-Ⅱ-1)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以(S)-2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘((S)-Ⅻ)代替2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘(Ⅻ)。产物呈橙红色粉末,收率18.5%。1H NMR(400MHz,DMSO-d6)δ11.92(s,2H),8.75(d,J=4.8Hz,1H),8.21(d,J=8.0Hz,1H),7.67(d,J=4.8Hz,1H),7.56(dd,J=7.9,4.7Hz,1H),7.35(d,J=2.0Hz,2H),7.02(s,1H),5.19(s,1H),4.60(dd,J=7.5,5.1Hz,1H),4.25(t,J=6.4Hz,2H),3.78(s,3H),3.51(s,3H),3.29–3.22(m,2H),2.40–2.21(m,2H),1.72–1.67(m,2H),1.64(s,3H),1.45(s,3H),1.32–1.16(m,10H)。
实施例7
本实施例涉及一种具有结构式(Ⅱ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-4-氯-吡啶-2-甲酸酯(Ⅱ-2)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,以4-氯-吡啶-2-甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率20.5%。黄色固体126mg。1H NMR(400MHz,DMSO-d6)δ12.02(s,2H),8.65(d,J=5.2Hz,1H),8.02(d,J=2.2Hz,1H),7.77(dd,J=5.2,2.2Hz,1H),7.36–7.30(m,2H),7.03(s,1H),5.17(s,1H),4.64–4.58(m,1H),4.28–4.23(m,2H),3.73(s,3H),3.55(s,3H),3.25–3.20(m,2H),2.32–2.25(m,2H),1.67–1.62(m,2H),1.59(s,3H),1.46(s,3H),1.32–1.18(m,10H)
实施例8
本实施例涉及一种具有结构式(Ⅱ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-5-氯-吡啶-2-甲酸酯(Ⅱ-3)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以5-氯-吡啶-2-甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率21.5%。1H NMR(400MHz,DMSO-d6)δ12.00(s,2H),8.71(s,1H),8.14–7.93(m,2H),7.36–7.30(m,2H),7.04(s,1H),5.16(t,J=7.5Hz,1H),4.65–4.55(m,2H),4.23(t,J=6.3Hz,2H),3.72(s,3H),3.56(s,3H),3.25–3.18(m,2H),2.39–2.21(m,2H),1.67–1.60(m,2H),1.58(s,3H),1.44(s,3H),1.39–1.01(m,10H)。
实施例9
本实施例涉及一种具有结构式(Ⅱ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-6-氯-吡啶-2-甲酸酯(Ⅱ-4)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以6-氯-吡啶-2-甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率19.4%。1H NMR(400MHz,DMSO-d6)δ11.99(s,2H),8.00(s,2H),7.72(d,J=6.7Hz,1H),7.33(d,J=14.1Hz,2H),7.02(d,J=19.5Hz,1H),5.17(s,1H),4.61(s,1H),4.25(s,2H),3.75(s,3H),3.55(s,3H),3.25–3.20(m,2H),2.32–2.25(m,2H),1.68–1.62(m,2H),1.58(s,3H),1.46(s,3H),1.41–1.03(m,10H)。
实施例10
本实施例涉及一种具有结构式(Ⅱ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-6-甲基-吡啶-2-甲酸酯(Ⅱ-5)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以6-甲基-吡啶-2-甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率18.7%。1H NMR(400MHz,DMSO-d6)δ12.01(s,2H),7.91–7.69(m,2H),7.45(s,1H),7.39–7.25(s,2H),7.05(s,1H),5.17(s,1H),4.60(s,1H),4.30–4.12(m,2H),3.74(s,3H),3.55(s,3H),3.28–3.18(m,2H),2.45(s,3H),2.30(s,2H),1.72–1.63(m,2H),1.59(s,3H),1.46(s,3H),1.35–1.11(m,10H)。
实施例11
本实施例涉及一种具有结构式(Ⅱ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-6-氟-吡啶-2-甲酸酯(Ⅱ-6)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以6-氟-吡啶-2-甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率21.4%。1H NMR(400MHz,DMSO-d6)δ12.02(s,2H),8.14(q,J=7.8Hz,1H),7.96(d,J=7.4Hz,1H),7.39(d,J=33.3Hz,2H),7.05(s,1H),5.18(d,J=7.3Hz,1H),4.61(d,J=6.4Hz,1H),4.28–4.22(m,2H),3.74(s,3H),3.55(s,3H),3.25–3.20(m,2H),2.32–2.26(m,2H),1.70–1.61(m,2H),1.59(s,3H),1.46(s,3H),1.35–1.10(m,10H)。
实施例12
本实施例涉及一种具有结构式(Ⅱ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-吡啶-4-甲酸酯(Ⅱ-7)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以吡啶-4-甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率22.6%。1H NMR(400MHz,DMSO-d6)δ12.02(s,2H),8.76(d,J=5.3Hz,2H),7.78(d,J=5.0Hz,2H),7.34(d,J=2.0Hz,2H),7.04(s,1H),5.17(s,1H),4.60(dd,J=7.5,5.1Hz,1H),4.25(t,J=6.4Hz,2H),3.74(s,3H),3.55(s,3H),3.28–3.20(m,2H),2.35–2.24(m,2H),1.68–1.64(m,2H),1.59(s,3H),1.46(s,3H),1.36–1.16(m,10H)。
实施例13
本实施例涉及一种具有结构式(Ⅱ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-2-氟-吡啶-4-甲酸酯(Ⅱ-8)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以2-氟-吡啶-4-甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率20.4%。1H NMR(400MHz,DMSO-d6)δ12.02(s,2H),8.41(d,J=5.0Hz,1H),7.73(d,J=5.0Hz,1H),7.51(s,1H),7.34(s,2H),7.04(s,1H),5.16(d,J=7.3Hz,1H),4.60(t,J=6.2Hz,1H),4.25(t,J=6.4Hz,2H),3.74(s,3H),3.51(s,3H),3.23(t,J=6.4Hz,2H),2.32–2.26(m,2H),1.67–1.62(m,2H),1.58(s,3H),1.46(s,3H),1.32–1.18(m,10H)。
实施例14
本实施例涉及一种具有结构式(Ⅱ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-2-氯-吡啶-4-甲酸酯(Ⅱ-9)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以2-氯-吡啶-4-甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率19.4%。1H NMR(400MHz,DMSO-d6)δ12.02(s,2H),8.58(d,J=5.0Hz,1H),7.79(d,J=5.4Hz,2H),7.34(s,2H),7.04(s,1H),5.16(d,J=7.3Hz,1H),4.60(t,J=6.3Hz,1H),4.28–4.22(m,2H),3.74(s,3H),3.55(s,3H),3.23(t,J=6.4Hz,2H),2.32–2.24(m,2H),1.65(q,J=6.9Hz,2H),1.58(s,3H),1.46(s,3H),1.34–1.13(m,10H)。
实施例15
本实施例涉及一种具有结构式(Ⅱ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-2-溴-吡啶-4-甲酸酯(Ⅱ-10)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以2-溴-吡啶-4-甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率20.0%。1H NMR(400MHz,DMSO-d6)δ12.02(s,2H),8.56(d,J=5.0Hz,1H),7.92(s,1H),7.81(d,J=5.0Hz,1H),7.38–7.32(m,2H),7.04(s,1H),5.17(s,1H),4.60(t,J=6.3Hz,1H),4.24(t,J=6.5Hz,2H),3.74(s,3H),3.55(s,3H),3.23(t,J=6.4Hz,2H),2.35–2.25(m,2H),1.70–1.62(m,2H),1.58(s,3H),1.46(s,3H),1.34–1.12(m,10H)。
实施例16
本实施例涉及一种具有结构式(Ⅱ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟吡啶-3-甲酸酯(Ⅱ-11)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以吡啶-3-甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率21.9%。1H NMR(400MHz,DMSO-d6)δ12.02(s,2H),9.04(s,1H),8.77(d,J=4.8Hz,1H),8.23(d,J=8.0Hz,1H),7.52(dd,J=7.9,4.7Hz,1H),7.38–7.30(m,2H),7.04(s,1H),5.18(d,J=7.2Hz,1H),4.60(t,J=6.3Hz,1H),4.24(t,J=6.5Hz,2H),3.74(s,3H),3.55(s,3H),3.23(t,J=6.1Hz,2H),2.29(d,J=7.0Hz,2H),1.67–1.63(m,2H),1.59(s,3H),1.46(s,3H),1.38–1.00(m,10H)。
实施例17
本实施例涉及一种具有结构式(Ⅱ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-2-溴-吡啶-3-甲酸酯(Ⅱ-12)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以2-溴-吡啶-3-甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率20.8%。1H NMR(400MHz,DMSO-d6)δ12.02(s,2H),8.50(s,1H),8.09(d,J=7.4Hz,1H),7.54(t,J=6.3Hz,1H),7.35(s,2H),7.02(s,1H),5.17(s,1H),4.60(s,1H),4.37–4.16(m,2H),3.72(s,3H),3.55(s,3H),3.25–3.21(m,2H),2.30(s,2H),1.72–1.62(m,2H),1.59(s,3H),1.46(s,3H),1.38–1.07(m,10H)。
实施例18
本实施例涉及一种具有结构式(Ⅱ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-5-氟-吡啶-3-甲酸酯(Ⅱ-13)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以5-氟-吡啶-3-甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率23.1%。1H NMR(400MHz,DMSO-d6)δ12.02(s,2H),8.96–8.74(m,2H),8.07(d,J=9.0Hz,1H),7.36–7.30(m,2H),7.04(s,1H),5.17(s,1H),4.60(t,J=6.2Hz,1H),4.24(t,J=6.4Hz,2H),3.72(s,3H),3.55(s,3H),3.22(t,J=6.3Hz,2H),2.32–2.26(m,2H),1.68–1.62(m,2H),1.58(s,3H),1.45(s,3H),1.43–1.05(m,10H)。
实施例19
本实施例涉及一种具有结构式(Ⅱ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-5-甲基-吡啶-3-甲酸酯(Ⅱ-14)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以5-甲基-吡啶-3-甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率20.4%。1H NMR(400MHz,DMSO-d6)δ12.03(s,2H),8.85(s,1H),8.61(s,1H),8.04(s,1H),7.36–7.32(m,2H),7.03(s,1H),5.17(s,1H),4.60(s,1H),4.25–4.20(m,2H),3.74(s,3H),3.55(s,3H),3.25–3.21(m,2H),2.36–2.29(m,5H),1.74–1.70(m,2H),1.59(s,3H),1.46(s,3H),1.32–1.18(m,10H)。
实施例20
本实施例涉及一种具有结构式(Ⅱ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-5-溴-吡啶-3-甲酸酯(Ⅱ-15)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以5-溴-吡啶-3-甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率20.2%。1H NMR(400MHz,DMSO-d6)δ12.00(s,2H),9.11–8.91(m,2H),8.37(s,1H),7.36–7.32(m,2H),7.05(s,3H),5.25–5.08(m,1H),4.60(t,J=6.3Hz,1H),4.24(t,J=6.5Hz,2H),3.76(s,3H),3.54(s,3H),3.26–3.15(m,2H),2.38–2.12(m,2H),1.75–1.62(m,2H),1.59(s,3H),1.50–1.44(m,2H),1.42(s,3H),1.35–1.18(m,8H)。
实施例21
本实施例涉及一种具有结构式(Ⅲ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-4-甲基-1-哌嗪乙酸酯(Ⅲ-1)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以4-甲基-1-哌嗪乙酸代替吡啶-2-甲酸。产物呈黄色固体,收率19.7%。1H NMR(400MHz,DMSO-d6)δ11.99(s,2H),7.35(d,J=2.6Hz,2H),7.05(s,1H),5.18(t,J=6.7Hz,1H),4.62(t,J=6.6Hz,1H),3.99(d,J=7.1Hz,2H),3.75(s,3H),3.56(s,3H),3.25–3.21(m,4H),2.82–2.73(s,4H),2.64(s,3H),2.48–2.44(m,4H),2.31(s,2H),1.61(s,3H),1.53–1.50(m,2H),1.48(s,3H),1.35–1.10(m,10H)。
实施例22
本实施例涉及一种具有结构式(Ⅲ)的(R)-6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-4-甲基-1-哌嗪乙酸酯((R)-Ⅲ-1)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例21步骤相同,在步骤一中以(R)-2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘((R)-Ⅻ)代替2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘(Ⅻ)。产物呈黄色固体,收率25.2%。1H NMR(400MHz,DMSO-d6)δ12.03(s,1H),10.59(s,1H),7.41–7.36(m,2H),7.08(s,1H),5.22(t,J=7.1Hz,1H),4.65(t,J=6.4Hz,1H),4.06(t,J=6.6Hz,2H),3.78(s,3H),3.59(s,3H),3.44(d,J=11.8Hz,2H),3.28(q,J=6.4,6.0Hz,2H),3.17(s,6H),2.93(s,2H),2.77(s,3H),2.35(s,2H),1.64(s,3H),1.60–1.53(m,2H),1.51(s,5H),1.25(s,8H).
实施例23
本实施例涉及一种具有结构式(Ⅲ)的(S)-6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-4-甲基-1-哌嗪乙酸酯((S)-Ⅲ-1)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例21步骤相同,在步骤一中以(S)-2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘((S)-Ⅻ)代替2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘(Ⅻ)。产物呈黄色固体,收率17.2%。1H NMR(400MHz,DMSO-d6)δ12.04(s,1H),10.58(s,1H),7.39(s,2H),7.08(s,1H),5.28–5.17(m,1H),4.65(t,J=6.3Hz,1H),4.06(t,J=6.7Hz,2H),3.79(s,3H),3.59(s,3H),3.44(d,J=12.1Hz,2H),3.34–3.23(m,2H),3.19–3.14(m,6H),2.93(s,2H),2.77(s,3H),2.42–2.28(m,2H),1.64(s,3H),1.56(t,J=6.8Hz,2H),1.51(s,3H),1.38–1.20(m,8H)。
实施例24
本实施例涉及一种具有结构式(Ⅲ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-4-羟乙基-1-哌嗪乙酸酯(Ⅲ-2)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以THP保护的4-羟乙基-1-哌嗪乙酸代替吡啶-2-甲酸。产物呈黄色固体,收率21.3%。1H NMR(400MHz,DMSO-d6)δ12.04(s,2H),7.38–7.32(m,2H),7.05(s,1H),5.19(t,J=6.4Hz,1H),4.62(t,J=6.4Hz,1H),3.98(t,J=6.6Hz,2H),3.75(s,3H),3.56(s,3H),3.54–3.51(m,2H),3.27–3.22(m,2H),3.16(s,2H),2.68–2.52(m,10H),2.31(d,J=6.2Hz,2H),1.61(s,3H),1.55–1.51(m,2H),1.48(s,3H),1.46–1.40(m,2H),1.25–1.18(s,8H)。
实施例25
本实施例涉及一种具有结构式(Ⅲ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-4-羟丁基-1-哌嗪乙酸酯(Ⅲ-3)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以THP保护的4-羟丁基-1-哌嗪乙酸代替吡啶-2-甲酸。产物呈黄色固体,收率20.6%。1H NMR(400MHz,DMSO-d6)δ12.18(s,2H),7.38–7.32(m,2H),7.04(s,1H),5.18(t,J=8.0Hz,1H),4.62(t,J=6.8Hz,1H),3.97(t,J=6.7Hz,2H),3.75(s,3H),3.56(s,3H),3.27–3.21(m,4H),3.13(d,J=1.9Hz,2H),2.44(s,4H),2.30(t,J=6.9Hz,4H),2.23–2.17(m,2H),1.66(s,3H),1.61(s,3H),1.51(d,J=6.2Hz,2H),1.48(s,2H),1.39–1.35(m,4H),1.26–1.17(m,8H)。
实施例26
本实施例涉及一种具有结构式(Ⅳ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-1-甲基-4-哌啶甲酸酯(Ⅳ-1)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以1-甲基-4-哌啶甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率25.0%。1H NMR(400MHz,DMSO-d6)δ12.04(s,2H),7.34(d,J=1.7Hz,2H),7.16(s,1H),5.08(t,J=7.2Hz,1H),4.31(t,J=7.5Hz,1H),3.96(dd,J=9.3,4.1Hz,2H),3.74(s,3H),3.53(s,3H),2.91(d,J=12.5Hz,2H),2.59(s,3H),2.52(t,J=7.6Hz,2H),2.46(s,1H),2.40–2.25(m,2H),1.94(s,2H),1.89–1.78(m,2H),1.53(s,6H),1.45(d,J=7.1Hz,2H),1.36(t,J=8.6Hz,2H),1.27–0.99(m,10H)。
实施例27
本实施例涉及一种具有结构式(Ⅳ)的(R)-6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-1-甲基-4-哌啶甲酸酯((R)-Ⅳ-1)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例26步骤相同,在步骤一中以(R)-2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘((R)-Ⅻ)代替2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘(Ⅻ)。产物呈黄色固体,收率22.0%。1H NMR(400MHz,DMSO-d6)δ12.10(s,2H),7.39(d,J=1.7Hz,2H),7.18(s,1H),5.08(t,J=7.2Hz,1H),4.31(t,J=7.5Hz,1H),3.99(dd,J=9.3,4.1Hz,2H),3.77(s,3H),3.53(s,3H),2.91(d,J=12.5Hz,2H),2.61(s,3H),2.52(t,J=7.6Hz,2H),2.48(s,1H),2.40–2.25(m,2H),1.96(s,2H),1.89–1.78(m,2H),1.55(s,6H),1.45(d,J=7.1Hz,2H),1.37(t,J=8.6Hz,2H),1.29–0.99(m,10H)。
实施例28
本实施例涉及一种具有结构式(Ⅳ)的(S)-6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-1-甲基-4-哌啶甲酸酯((S)-Ⅳ-1)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例26步骤相同,在步骤一中以(S)-2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘((S)-Ⅻ)代替2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘(Ⅻ)。产物呈黄色固体,收率27.0%。1H NMR(400MHz,DMSO-d6)δ12.01(s,2H),7.38–7.31(m,2H),7.04(s,1H),5.21–5.14(m,1H),4.62(t,J=6.8Hz,1H),3.98(d,J=6.7Hz,2H),3.74(s,3H),3.55(s,3H),3.25–3.18(m,2H),2.96–2.83(m,2H),2.65(s,3H),2.62–2.51(m,2H),2.47(s,1H),2.35–2.23(m,2H),2.02–1.93(m,2H),1.90–1.77(m,2H),1.60(s,3H),1.56–1.51(m,2H),1.47(s,3H),1.38–1.11(m,10H)。
实施例29
本实施例涉及一种具有结构式(Ⅳ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟-1-甲基-3-哌啶甲酸酯(Ⅳ-2)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以1-甲基-3-哌啶甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率22.5%。1H NMR(400MHz,DMSO-d6)δ12.04(s,2H),7.34(d,J=2.2Hz,2H),7.04(s,1H),5.18(t,J=6.6Hz,1H),4.62(d,J=7.6Hz,1H),3.96(d,J=6.9Hz,2H),3.74(s,3H),3.55(s,3H),3.26–3.22(m,2H),2.83(d,J=9.0Hz,1H),2.68–2.60(m,1H),2.57–2.52(m,1H),2.30(s,2H),2.19(s,3H),2.06–1.98(m,2H),1.75(d,J=12.4Hz,1H),1.60(s,3H),1.50(s,3H),1.46–1.42(m,2H),1.41–0.99(m,12H)。
实施例30
本实施例涉及一种具有结构式(Ⅴ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟吡嗪-2-甲酸酯(Ⅴ-1)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以吡嗪-2-甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率22.9%。1H NMR(400MHz,DMSO-d6)δ11.99(s,2H),9.16(s,1H),8.81(d,J=31.1Hz,2H),7.38–7.32(m,2H),7.04(s,1H),5.17(s,1H),4.61(t,J=6.6Hz,1H),4.29(t,J=6.6Hz,2H),3.75(s,3H),3.55(s,3H),3.28–3.20(m,2H),2.36–2.28(m,2H),1.73–1.63(m,2H),1.59(s,3H),1.46(s,3H),1.35–1.15(m,8H)。
实施例31
本实施例涉及一种具有结构式(Ⅵ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟嘧啶-5-甲酸酯(Ⅵ-1)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以嘧啶-5-甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率21.9%。1H NMR(400MHz,DMSO-d6)δ11.99(s,2H),7.95(s,1H),7.69–7.63(m,2H),7.38–7.30(m,2H),7.05(s,1H),5.20–5.15(m,1H),4.63–4.58(m,1H),4.29–4.15(m,2H),3.77(s,3H),3.57(s,3H),3.24–3.20(m,2H),2.33–2.28(m,2H),1.61(s,3H),1.48(s,3H),1.36–1.30(m,2H),1.28–1.16(m,10H)。
实施例32
本实施例涉及一种具有结构式(Ⅶ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟哒嗪-4-甲酸酯(Ⅶ-1)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以哒嗪-4-甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率21.2%。1H NMR(400MHz,DMSO-d6)δ12.00(s,2H),9.52(s,2H),8.02(s,1H),7.37–7.32(m,2H),7.04(s,1H),5.17(s,1H),4.61(t,J=7.6Hz,1H),4.31(t,J=6.7Hz,2H),3.74(s,3H),3.56(s,3H),3.25–3.21(m,2H),2.38–2.26(m,2H),1.70–1.64(m,2H),1.58(s,3H),1.46(s,3H),1.35–1.16(m,8H)。
实施例33
本实施例涉及一种具有结构式(Ⅷ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟吗啉-4-乙酸酯(Ⅷ-1)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以吗啉-4-乙酸代替吡啶-2-甲酸。产物呈黄色固体,收率18.8%。1H NMR(400MHz,DMSO-d6)δ12.02(s,2H),7.34(d,J=2.2Hz,2H),7.04(s,1H),5.17(t,J=6.7Hz,1H),4.61(d,J=6.6Hz,1H),3.97(t,J=6.6Hz,2H),3.74(s,3H),3.55(s,3H),3.51(t,J=4.4Hz,4H),3.24(d,J=6.4Hz,2H),3.15(s,2H),2.43(t,J=4.4Hz,4H),2.35–2.25(m,2H),1.60(s,3H),1.54–1.50(m,2H),1.47(s,3H),1.44–1.05(m,10H)。
实施例34
本实施例涉及一种具有结构式(Ⅸ)的6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟噻唑-4-甲酸酯(Ⅸ-1)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例4步骤相同,在步骤一中以噻唑-4-甲酸代替吡啶-2-甲酸。产物呈黄色固体,收率21.2%。1H NMR(400MHz,DMSO-d6)δ12.00(s,2H),9.13(s,1H),8.51(s,1H),7.37–7.32(m,2H),7.05(s,1H),5.17(t,J=8.0Hz,1H),4.61(t,J=8.0Hz,1H),4.23(t,J=6.9Hz,2H),3.75(s,3H),3.53(s,3H),3.26–3.20(m,2H),2.32–2.28(m,2H),1.74–1.61(m,2H),1.59(s,3H),1.46(s,3H),1.35–1.15(m,10H)。
实施例35
本实施例涉及一种具有结构式(Ⅸ)的(R)-6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟噻唑-4-甲酸酯((R)-Ⅸ-1)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例34步骤相同,在步骤一中以(R)-2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘(R-Ⅻ)代替2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘(Ⅻ)。产物呈黄色固体,收率20.6%。1H NMR(400MHz,DMSO-d6)δ12.02(s,2H),9.18(s,1H),8.55(s,1H),7.36–7.30(m,2H),7.02(s,1H),5.19(t,J=8.0Hz,1H),4.64(t,J=8.0Hz,1H),4.26(t,J=6.9Hz,2H),3.77(s,3H),3.53(s,3H),3.26–3.20(m,2H),2.35–2.28(m,2H),1.72–1.60(m,2H),1.59(s,3H),1.44(s,3H),1.33–1.16(m,10H)。
实施例36
本实施例涉及一种具有结构式(Ⅸ)的(S)-6-[1’-(8"-羟基辛氧基)-4’-甲基-3’-戊烯基]-5,8-二甲氧基-1,4-萘二酮二肟噻唑-4-甲酸酯((S)-Ⅸ-1)的制备方法,如图1所示,包括以下步骤:
本实施例步骤同实施例34步骤相同,在步骤一中以(S)-2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘(S-Ⅻ)代替2-[1-(8-羟基辛氧基)-4-甲基-3-戊烯基]-1,4,5,8-四甲氧基萘(Ⅻ)。产物呈黄色固体,收率22.9%。1H NMR(400MHz,DMSO-d6)δ12.07(s,2H),9.18(s,1H),8.55(s,1H),7.39–7.30(m,2H),7.02(s,1H),5.19(t,J=8.0Hz,1H),4.64(t,J=8.0Hz,1H),4.25(t,J=6.9Hz,2H),3.77(s,3H),3.53(s,3H),3.26–3.20(m,2H),2.35–2.28(m,2H),1.72–1.60(m,2H),1.59(s,3H),1.44(s,3H),1.33–1.14(m,10H)。
实施例37
对实施例2至实施例36所述含氮杂侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟化衍生物进行体外肿瘤细胞生长抑制实验。
实验方法:本实施例按照常规溴化四氮唑蓝(MTT)法进行,测定目标化合物对肿瘤细胞生长的抑制作用,阳性对照物选用专利ZL201310044118《外消旋体紫草素萘茜母核羟基甲基化羰基肟衍生物及其制备和用途》中的化合物Ⅱ-4。。
肿瘤细胞株:选用人结肠癌细胞株(HCT-15,HCT-116)、人乳腺癌细胞株(MDA-MB-231)、人肝癌细胞株(BEL-7402)和人卵巢癌细胞株(A2780)进行生长抑制试验;所述细胞株均可以从公开的市售渠道获得。
细胞抑制率计算:
抑制率=(对照组平均OD值-给药组平均OD值)/对照组平均OD值。
生物统计:使用SPSS软件,根据目标化合物在不同浓度下对细胞生长的抑制率,以非线性最小平方误差回归分析计算IC50值,测定结果如表1所示。
表1 目标化合物抑制肿瘤细胞生长的IC50值
**:阳性对照物为专利ZL201310044118中的化合物Ⅱ-4。
由表1可知,本发明所述含氮杂侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟化衍生物,对人结肠癌细胞株(HCT-15,HCT-116)、人乳腺癌细胞株(MDA-MB-231)、人肝癌细胞株(BEL-7402)和人卵巢癌细胞株(A2780)均具有较强的生长抑制作用,能够用于制备抗肿瘤的相关药物。
实施例38
本实施例对实施例2至实施例36所述含氮杂侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟化衍生物的水溶解性进行了测定。
测定方法:将定量化合物溶于纯水(pH=7.4,T=25℃)中,将该溶液逐级稀释;稀释后的溶液进样20μL,用HPLC法测定目标化合物在318nm检测波长下的峰面积,绘制化合物浓度与色谱面积的标准曲线,建立用于含量测定的高效液相色谱法。后将过量的待测物溶于纯水中,搅拌至达到溶解平衡。将饱和溶液稍静置,取上清液用微孔滤膜过滤,取续滤液稀释若干倍后进样20μL,用HPLC法测定其在318nm检测波长下的峰面积。根据标准曲线,计算待测物在该条件下的溶解度。在溶解度测定中,专利ZL201310044118的化合物Ⅱ-4选为阳性对照物。部分化合物的溶解度测定结果如表2所示。
表2 部分目标化合物在水中的溶解度
*注:阳性对照物选用专利ZL201310044118的化合物Ⅱ-4。
实施例39
选择实施例21所述含氮杂侧链的外消旋体紫草素萘茜母核羟基甲基化羰基肟化衍生物(Ⅲ-1)进行体内抗肿瘤活性实验。
实验方法:
将HCT-15细胞正常传代培养至所需数目,用PBS调整细胞浓度(1×107个/mL)后接种于小鼠右前肢腋窝皮下(0.2mL/只)。接种24h后,将小鼠按5-8只/组依次分组为给药组、阳性对照组(5-Fu及专利ZL201310044118的化合物Ⅱ-4)和阴性对照组(Control),称重记录。用已配好的化合物溶液对小鼠进行腹腔注射或尾静脉注射(0.2mL/只),空白对照组用不含化合物的溶液进行注射,隔天给药,给药7次,末次给药24h后,小鼠称重后颈椎脱臼处死,取出移植瘤称重。
肿瘤抑制率计算公式:
肿瘤抑制率(%)=(阴性对照组的瘤重-给药组的瘤重)/阴性对照组瘤重×100%
表3 化合物对裸鼠HCT-15结肠癌移植瘤的影响
由表3和附图2可知,当阳性对照组和给药组的剂量都为30mg/kg且给药方式都为尾静脉给药时,与阴性对照组相比,专利ZL201310044118的化合物Ⅱ-4的抑瘤率为50.33%,本专利中化合物Ⅲ-1的抑瘤率强于阳性对照物Ⅱ-4,达到了74.67%,具有显著的优越性。
实施例40
选择实施例21所述含氮杂侧链的外消旋体紫草素萘茜母核羟基甲基化羰基肟化衍生物(Ⅲ-1)进行血浆代谢稳定性测定。
实验方法:
将含有10μg/mLⅢ-1的血浆溶液置于37℃水浴振荡孵育,反应时间设置从0min至6h(0min,5min,10min,20min,30min,1h,2h,4h,6h),不同时间点的样品终止反应后处理进样,HPLC分析结果,并通过绘制标准曲线定量。每组设置平行3份样品,结果如附图3所示。
实验结果表明,由于化合物Ⅲ-1含有酯键,其在37℃的血浆中,快速发生水解,计算得到Ⅲ-1在血浆中的半衰期(t1/2)为0.35h,其水解后的产物确证为具有羟基烷基醇侧链结构的外消旋体紫草素肟衍生物ⅩⅤ(表1)。该化合物与专利(ZL201310044118,ZL201310044877)中的化合物相比较,显示了更强的抗肿瘤活性(表1)。化合物Ⅲ-1为化合物ⅩⅤ的前药,在血浆中水解为化合物ⅩⅤ发挥抗肿瘤作用。本发明发现,在化合物ⅩⅤ的末端羟基上引入适当的水溶性基团并制备前药,可解决专利(ZL201310044118,ZL201310044877)中紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物的溶解性。
综上所述,为改善紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物的水溶性而不影响其抗肿瘤活性,本发明通过在萘茜母核氧烷基化羰基肟化的紫草素衍生物侧链羟基上引入烷基醇后,制备其含氮杂环羧酸酯。与专利(中国发明专利:ZL201310044118,ZL201310044877)中紫草素萘茜母核氧烷基化羰基肟化系列化合物相比,本专利所涉及的含氮杂侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物显示了较强的水溶性。与此同时,体内抗肿瘤活性研究结果显示,该类化合物具有更好的抑制肿瘤生长作用,具有良好的新药开发前景。本发明采用的结构修饰方法解决了紫草素、阿卡宁及其外消旋体萘茜母核氧烷基化羰基肟化衍生物水溶性差的问题,同时不影响其抗肿瘤活性;这一结构修饰方法产生了意想不到的技术效果,具有显著的创新性。
本发明化合物的制备方法简便,收率较高且原料易得。所制备含氮杂侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟化衍生物,结构新颖,水溶性好。体外抗肿瘤活性实验研究表明,该类化合物抗肿瘤活性较强。
以上对本发明的具体实施例进行了描述。需要理解的是,本发明并不局限于上述特定实施方式,本领域技术人员可以在权利要求的范围内做出各种变形或修改,这并不影响本发明的实质内容。
Claims (6)
6.一种如权利要求1~5中任一项所述的含氮杂侧链的紫草素、阿卡宁及其外消旋体萘茜母核羟基甲基化羰基肟衍生物在制备抗肿瘤药物中的用途。
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