CN116283643A - 氯硝柳胺氨基酸酯衍生物或其可药用盐及其制备方法 - Google Patents
氯硝柳胺氨基酸酯衍生物或其可药用盐及其制备方法 Download PDFInfo
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- CN116283643A CN116283643A CN202310062730.3A CN202310062730A CN116283643A CN 116283643 A CN116283643 A CN 116283643A CN 202310062730 A CN202310062730 A CN 202310062730A CN 116283643 A CN116283643 A CN 116283643A
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- amino acid
- niclosamide
- pharmaceutically acceptable
- acid ester
- acceptable salt
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Abstract
本发明涉及氯硝柳胺氨基酸酯衍生物或其可药用盐及其制备方法,该类氯硝柳胺氨基酸酯和其药学上可接受的盐具有良好的水溶性和生物利用度,经摄入体内后可以代谢转化为具有药理活性的氯硝柳胺原药。本合成方法原料易得、成本低、收率高,得到的氯硝柳胺氨基酸酯盐纯度高,适用于工业化大规模生产应用。可为新型抗肿瘤药物的开发提供参考,也可用于杀螺及抗绦虫。
Description
技术领域
本发明涉及药物合成技术领域,具体是指氯硝柳胺氨基酸酯衍生物或其可药用盐及其制备方法。
背景技术
氯硝柳胺于1953年在德国拜耳化学研究实验室被发现。它最初是作为杀灭钉螺(血吸虫病的中间宿主)的杀螺剂而开发的,并于1959年以Bayluscide名称上市。该药灭螺效率高,对非靶生物毒性较低,对螺卵、幼螺和血吸虫尾蚴亦均有较强的杀灭作用。1960年,拜耳的科学家发现它对人类绦虫感染有效,并于1962年将其命名为Yomesan供人类使用。
在过去的几年里,越来越多的证据表明氯硝柳胺是一种多功能药物,能够抑制或调节多个信号通路和生物学过程,这表明它可能被开发为一种新的治疗方法,而不仅仅是抗蠕虫疾病。近些年,在氯硝柳胺的研究中,对其抗肿瘤作用的研究居多。到目前为止氯硝柳胺已被证明对结肠癌、乳腺癌、前列腺、胶质母细胞瘤、骨肉瘤、卵巢癌、白血病、肾上腺皮质癌、肺癌和口腔癌有良好的抗癌活性。
但是氯硝柳胺在水中溶解度极低,在胃肠道溶出缓慢,进而限制了药物的吸收。如何改善氯硝柳胺在水中的溶解度,提高其生物利用度,成为了氯硝柳胺研究的热点及难点。
目前,已报道的提高氯硝柳胺水溶性的方法主要有两大类:一是物理方法,通过制成氯硝硫胺的固体分散体或包合物等制剂,但是这类剂型溶解速度缓慢,溶出度小,改善效果不明显。二是化学方法,目前主要采用前药策略将氯硝柳胺制成前药,主要有氯硝柳胺磷酸酯及其药学上可接受的盐,其可以将氯硝柳胺水溶性提高到较高程度,但也存在生产条件苛刻,精制困难,收率不高,生物利用度不佳的问题。
发明内容
本发明的目的在于提供氯硝柳胺氨基酸酯衍生物或其可药用盐及其制备方法,以解决上述背景技术中提出的问题。
为解决上述技术问题,本发明提供的技术方案为:一种氯硝柳胺氨基酸酯衍生物或其可药用盐,具有如图1所示的化合物:
其中R为L-氨基酸侧链基团,所述L-氨基酸为赖氨酸、缬氨酸、色氨酸、苯丙氨酸、甲硫氨酸、苏氨酸、异亮氨酸、亮氨酸或组氨酸。
作为优选,所述的氯硝柳胺氨基酸酯衍生物或其可药用盐,可药用盐是盐酸盐、氢溴酸盐、三氟乙酸盐、硫酸盐、硫酸氢盐、草酸盐、酒石酸盐、苹果酸盐或甲磺酸盐。
所述的氯硝柳胺氨基酸酯衍生物或其药用盐在制备抗肿瘤药物,杀螺及抗绦虫的应用。
所述的氯硝柳胺氨基酸酯衍生物或其药用盐的制备方法,具体步骤如图2所示:
其中R为L-氨基酸侧链基团,所述L-氨基酸为赖氨酸、缬氨酸、色氨酸、苯丙氨酸、甲硫氨酸、苏氨酸、异亮氨酸、亮氨酸或组氨酸。
所述的氯硝柳胺氨基酸酯衍生物或其药用盐的制备方法,具体步骤如下:
(1)将缩合剂、三乙胺溶于无水有机溶剂中,后加入4-二甲氨基吡啶和保护氨基酸,0℃冰水浴中加底物氯硝柳胺于体系中,再缓慢升温至25-100℃,搅拌反应4~24h;
(2)过滤,滤液加乙酸乙酯,用饱和碳酸氢钠水溶液洗涤3次,饱和氯化钠水溶液洗涤至中性,分出有机相,用无水硫酸镁干燥;
(3)过滤,旋蒸得图3所示化合物粗品,柱层析纯化得图3所示化合物精品;
(4)将图3所示化合物加入2~6M HCl/乙醇溶液中搅拌反应0.5~6h脱除保护基,浓缩后重结晶,得到图1所示的化合物盐酸盐。
作为优选,步骤(1)中缩合剂为N,N'-二环己基碳酰亚胺、1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐或二异丙基碳二亚胺;溶剂为N,N-二甲基甲酰胺、四氢呋喃、二甲基亚砜、乙酸乙酯、乙腈、二氯甲烷、苯或甲苯。
作为优选,步骤(1)中投料比为:氯硝柳胺:保护氨基酸:缩合剂:三乙胺
=1:1.1~1.5:1.3~1.8:1.3~2.0,4-二甲氨基吡啶为氯硝柳胺质量的5%-10%。
作为优选,步骤(4)中的重结晶溶剂为乙醇或甲醇。
本发明优点在于:发明提供了氯硝柳胺氨基酸酯衍生物或其可接受的盐及其制备方法,采用的制备方法原料易得、成本低、收率高,得到的氯硝柳胺氨基酸酯盐纯度高,适用于工业化大规模生产应用。相较于氯硝柳胺,具有更好的水溶性和生物利用度。
附图说明
图1是氯硝柳胺氨基酸酯化合物可药用盐的结构式图。
图2是氯硝柳胺氨基酸酯衍生物或其药用盐的制备化学方程式图。
图3是氯硝柳胺氨基酸酯化合物的结构式图。
具体实施方式
下面用具体实施例说明本发明,并不是对本发明的限制。
实施例
实施例1:2-O-(N-BOC-L-缬氨酰)-4′-硝基-2′,5-二氯水杨酰苯胺的合成
将EDCI 0.917g(4.8mmol)、三乙胺0.526g(5.2mmol)溶于30ml干燥DMF中,后加入4-二甲氨基吡啶(DMAP)0.065g和BOC-缬氨酸0.956g(4.4mmol),0℃冰水浴加底物氯硝柳胺1.308g(4mmol)于体系中,再缓慢升温至室温,搅拌反应6h,薄层色谱观察反应完全。过滤,滤液加乙酸乙酯50ml,用饱和碳酸氢钠水溶液50ml洗涤3次,饱和氯化钠水溶液洗涤至中性,分出有机相,用无水硫酸镁干燥,过滤,旋蒸,得粗品。柱层析得化合物1 1.737g,收率为82.60%。
实施例2:2-O-(L-缬氨酰)-4′-硝基-2′,5-二氯水杨酰苯胺盐酸盐的合成
将1.737g(3.3mmol)产物1加于50ml圆底烧瓶中,加20ml 2M HCl/乙醇溶液中常温搅拌4h,薄层色谱观察反应完全。过滤,滤液浓缩后用乙醇重结晶,过滤,烘箱干燥,得到化合物2,2-O-(L-缬氨酰)-4′-硝基-2′,5-二氯水杨酰苯胺盐酸盐1.391g,收率为90.91%。
1H-NMR(300MHz,DMSO-d6)δ10.11(s,1H),δ8.90(s,2H),δ8.00(d,1H),δ8.10(d,1H),δ7.69(s,1H),δ7.85(d,1H),δ8.05(d,1H),δ8.33(s,1H),δ4.25(d,1H),δ2.39(m,1H),δ0.96(d,6H)。
实施例3:2-O-(N-BOC-L-赖氨酰)-4′-硝基-2′,5-二氯水杨酰苯胺的合成
将DCC 0.990g(4.8mmol)、三乙胺0.526g(5.2mmol)溶于30ml干燥DMF中,后加入4-二甲氨基吡啶(DMAP)0.065g和BOC-赖氨酸1.157g(4.4mmol)0℃冰水浴中加底物氯硝柳胺1.308g(4mmol)于体系中,再缓慢升温至室温,搅拌反应6h,薄层色谱观察反应完全。过滤,滤液加乙酸乙酯50ml,用饱和碳酸氢钠水溶液50ml洗涤3次,饱和氯化钠水溶液洗涤至中性,分出有机相,用无水硫酸镁干燥,过滤,旋蒸,得粗品。柱层析得化合物3,1.776g,收率为80.01%。
实施例4:2-O-(L-赖氨酰)-4′-硝基-2′,5-二氯水杨酰苯胺盐酸盐的合成
将1.776g(3.2mmol)产物3加于50ml圆底烧瓶中,加20ml 2M HCl/乙醇溶液中常温搅拌5h,薄层色谱观察反应完全。过滤,滤液浓缩后用乙酸乙酯重结晶,过滤,烘箱干燥,得到化合物4,2-O-(L-赖氨酰)-4′-硝基-2′,5-二氯水杨酰苯胺盐酸盐1.279g,收率为87.62%。
1H-NMR(300MHz,DMSO-d6)δ10.13(s,1H),δ8.1(d,1H),δ8.23(d,1H),δ7.72(s,1H),δ7.93(d,1H),δ8.13(d,1H),δ8.41(s,1H),δ8.76(s,2H),δ1.88(m,2H),δ1.25(m,2H),δ1.53(m,2H),δ2.69(m,2H),δ1.51(s,2H)。
实施例5:2-O-(N-BOC-L-苯丙氨酰)-4′-硝基-2′,5-二氯水杨酰苯胺的合成。
将DCC 0.990g(4.8mmol)、三乙胺0.526g(5.2mmol)溶于30ml干燥DMF中,后加入4-二甲氨基吡啶(DMAP)0.065g和BOC-苯丙氨酸1.167g(4.4mmol)0℃冰水浴中加底物氯硝柳胺1.308g(4mmol)于体系中,再缓慢升温至室温,搅拌反应6h,薄层色谱观察反应完全。过滤,滤液加乙酸乙酯50ml,用饱和碳酸氢钠水溶液50ml洗涤3次,饱和氯化钠水溶液洗涤至中性,分出有机相,用无水硫酸镁干燥,过滤,旋蒸,得粗品。柱层析得氯硝柳胺化合物5,1.797g,收率为78.26%。
实施例6:2-O-(L-苯丙氨酰)-4′-硝基-2′,5-二氯水杨酰苯胺醋酸盐的合成
将1.797g(3.1mmol)产物5加于50ml圆底烧瓶中,加20ml 2M HCl/乙醇溶液中常温搅拌5h,薄层色谱观察反应完全。滴加0.5ml醋酸于体系中,搅拌2h。过滤,滤液浓缩后用乙酸乙酯重结晶,过滤,烘箱干燥,得到化合物6,2-O-(L-苯丙氨酰)-4′-硝基-2′,5-二氯水杨酰苯胺醋酸盐1.337g,收率为86.51%。
1H-NMR(300MHz,DMSO-d6)δ10.10(s,2H),δ8.02(d,1H),δ8.19(d,1H),δ7.80(s,1H),δ7.85(d,2H),δ8.05(d,1H),δ8.32(s,1H),δ8.71(s,2H),δ4.14(t,3H),δ3.29(d,2H),δ7.14(s,4H),δ7.19(s,1H)。
实施例7:2-O-(N-BOC-L-异亮氨酰)-4′-硝基-2′,5-二氯水杨酰苯胺的合成
将EDCI 0.917g(4.8mmol)、三乙胺0.526g(5.2mmol)溶于30ml干燥DMF中,后加入4-二甲氨基吡啶(DMAP)0.065g和BOC-异亮氨酸1.017g(4.4mmol)0℃冰水浴下加底物氯硝柳胺1.308g(4mmol)于体系中,再缓慢升温至室温,搅拌反应6h,薄层色谱观察反应完全。过滤,滤液加乙酸乙酯50ml,用饱和碳酸氢钠水溶液50ml洗涤3次,饱和氯化钠水溶液洗涤至中性,分出有机相,用无水硫酸镁干燥,过滤,旋蒸,得粗品。柱层析得化合物7,1.653g,收率为76.52%。
实施例8:2-O-(L-异亮氨酰)-4′-硝基-2′,5-二氯水杨酰苯胺氢溴酸盐的合成
将1.653g(3.1mmol)产物7加于50ml圆底烧瓶中,加20ml 2M HCl/乙醇溶液中常温搅拌6h,薄层色谱观察反应完全。过滤,滤液浓缩后用乙酸乙酯重结晶,过滤,烘箱干燥,得到化合物8,2-O-(L-异亮氨酰)-4′-硝基-2′,5-二氯水杨酰苯胺氢溴酸盐1.300g,收率为86.32%。
1H-NMR(300MHz,DMSO-d6)δ10.09(s,1H),δ8.12(d,1H),δ8.20(d,1H),δ7.91(s,1H),δ7.90(d,1H),δ8.15(d,1H),δ8.25(s,1H),δ4.25(d,1H),δ8.90(s,1H),δ2.14(m,1H),δ1.11(d,3H),δ1.55(m,2H),δ0.99(t,3H)。
实施例9:2-O-(N-BOC-L-色氨酰)-4′-硝基-2′,5-二氯水杨酰苯胺的合成
将DCC 0.990g(4.8mmol)、三乙胺0.526g(5.2mmol)溶于30ml干燥DMF中,后加入4-二甲氨基吡啶(DMAP)0.065g和BOC-色氨酸1.335(4.4mmol)0℃冰水浴下加底物氯硝柳胺1.308g(4mmol)于体系中,再缓慢升温至室温,搅拌反应6h,薄层色谱观察反应完全。过滤,滤液加乙酸乙酯50ml,用饱和碳酸氢钠水溶液50ml洗涤3次,饱和氯化钠水溶液洗涤至中性,分出有机相,用无水硫酸镁干燥,过滤,旋蒸,得粗品。柱层析得化合物9,1.921g,收率为78.47%。
实施例10:2-O-(L-色氨酰)-4′-硝基-2′,5-二氯水杨酰苯胺三氟乙酸盐的合成
将1.921g(3.1mmol)产物9加于50ml圆底烧瓶中,加20ml 2M HCl/乙醇溶液中常温搅拌6h,薄层色谱观察反应完全。滴加1ml三氟乙酸酸于体系中,搅拌2h。过滤,滤液浓缩后用乙酸乙酯重结晶,过滤,烘箱干燥,得到化合物10,2-O-(L-色氨酰)-4′-硝基-2′,5-二氯水杨酰苯胺三氟乙酸盐1.638g,收率为84.32%。
1H-NMR(300MHz,DMSO-d6)δ10.11(s,1H),δ8.09(d,1H),δ8.17(d,1H),δ7.89(s,1H),δ7.88(d,1H),δ8.20(d,1H),δ8.25(s,1H),δ4.14(t,1H),δ3.42(d,1H),δ8.71(s,2H),
δ7.20(s,1H),δ10.79(s,1H),δ7.58(d,1H),δ6.98(t,3H),δ7.06(t,1H),δ7.33(d,1H)。
实施例11:氯硝柳胺对不同肿瘤细胞的体外抑制作用
1.实验材料:
细胞株:人乳腺癌细胞:MCF-7,MDA-MB-231
培养基:含10%FBS的DMEM(MCF-7),10%FBS的L-15(MDA-MB-231)。
药物及配置:药物为上述合成的氯硝柳胺衍生物,药物首先溶于DMSO,然后用培养基稀释后加入细胞中。
2.实验方法
(1)肿瘤细胞体外培养
(2)MTT法测定氯硝柳胺衍生物对不同肿瘤细胞的体外抑制作用。
细胞抑制率%=(对照组OD值-用药组OD值)/对照组OD值×100%
(3)实验结果
氯硝柳胺衍生物作用于肿瘤细胞72h后,测定OD值,计算IC50值。实验结果参见表1,结果表明,这些化合物大部分都有良好的抗肿瘤活性,其中活性最好的化合物是化合物2,对MDA-MB-231细胞,该化合物表现出比氯硝柳胺更强的抑制作用。
表1氯硝柳胺衍生物72小时对肿瘤细胞的体外抑制作用
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,根据本发明的技术方案及其发明构思加以等同替换或改变,都应涵盖在本发明的保护范围之内。
Claims (8)
1.一种氯硝柳胺氨基酸酯衍生物或其可药用盐,其特征在于,具有如图1所示的化合物:
其中R为L-氨基酸侧链基团,所述L-氨基酸为赖氨酸、缬氨酸、色氨酸、苯丙氨酸、甲硫氨酸、苏氨酸、异亮氨酸、亮氨酸或组氨酸。
2.根据权利要求1所述的氯硝柳胺氨基酸酯衍生物或其可药用盐,其特征在于:可药用盐是盐酸盐、氢溴酸盐、三氟乙酸盐、硫酸盐、硫酸氢盐、草酸盐、酒石酸盐、苹果酸盐或甲磺酸盐。
3.权利要求1-2所述的氯硝柳胺氨基酸酯衍生物或其药用盐在制备抗肿瘤药物,杀螺及抗绦虫的应用。
4.根据权利要求1所述的氯硝柳胺氨基酸酯衍生物或其药用盐的制备方法,其特征在于,具体步骤如图2所示:
其中R为L-氨基酸侧链基团,所述L-氨基酸为赖氨酸、缬氨酸、色氨酸、苯丙氨酸、甲硫氨酸、苏氨酸、异亮氨酸、亮氨酸或组氨酸。
5.根据权利要求4所述的制备方法,其特征在于,具体步骤如下:
(1)将缩合剂、三乙胺溶于无水有机溶剂中,后加入4-二甲氨基吡啶和保护氨基酸,0℃冰水浴中加底物氯硝柳胺于体系中,再缓慢升温至25-100℃,搅拌反应4~24h;
(2)过滤,滤液加乙酸乙酯,用饱和碳酸氢钠水溶液洗涤3次,饱和氯化钠水溶液洗涤至中性,分出有机相,用无水硫酸镁干燥;
(3)过滤,旋蒸得图3所示化合物粗品,柱层析纯化得图3所示化合物精品;
(4)将图3所示化合物加入2~6M HCl/乙醇溶液中搅拌反应0.5~6h脱除保护基,浓缩后重结晶,得到图1所示的化合物盐酸盐。
6.根据权利要求5所述的制备方法,其特征在于,步骤(1)中缩合剂为N,N'-二环己基碳酰亚胺、1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐或二异丙基碳二亚胺;溶剂为N,N-二甲基甲酰胺、四氢呋喃、二甲基亚砜、乙酸乙酯、乙腈、二氯甲烷、苯或甲苯。
7.根据权利要求5所述的制备方法,其特征在于,步骤(1)中投料比为:氯硝柳胺:保护氨基酸:缩合剂:三乙胺=1:1.1~1.5:1.3~1.8:1.3~2.0,4-二甲氨基吡啶为氯硝柳胺质量的5%-10%。
8.根据权利要求5所述的制备方法,其特征在于,步骤(4)中的重结晶溶剂为乙醇或甲醇。
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