CN114656413B - 一种阿法骨化醇杂环酯类衍生物及其制备方法 - Google Patents
一种阿法骨化醇杂环酯类衍生物及其制备方法 Download PDFInfo
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- OFHCOWSQAMBJIW-AVJTYSNKSA-N alfacalcidol Chemical class C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C OFHCOWSQAMBJIW-AVJTYSNKSA-N 0.000 claims abstract description 19
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
本发明属于药物化学和药理学技术领域，具体涉及一种阿法骨化醇杂环酯类衍生物及其制备方法。该阿法骨化醇衍生物具有式(I)所示结构，由阿法骨化醇与DMAP，EDCI和相应的杂环酸在二氯甲烷中反应得到相应的阿法骨化醇杂环酯类衍生物。本发明得到的阿法骨化醇杂环酯类衍生物具有较强的抗肿瘤活性，可用于制备抗肿瘤药物。
Description
技术领域
本发明属于药物化学和药理学技术领域，具体涉及一种阿法骨化醇杂环酯类衍生物及其制备方法。
背景技术
阿法骨化醇(alfacalcidol)是维生素D类化合物中的脂溶性甾醇，是一类参与钙、磷的内环境稳定和骨的矿化过程的物质。阿法骨化醇最早由美国骨保健国际公司(BoneCare International)研制，并先后在以色列、德国、日本、意大利获得批准上市。用于治疗因维生素D代谢障碍而引起的钙代谢紊乱，临床用于骨质疏松症、慢性肾功能不全、甲状旁腺功能减退症、抗维生素D佝偻症、骨软化症等。近些年来，阿法骨化醇的类似物骨化三醇和度骨化醇被发现具有抗肿瘤活性，抗肿瘤作用机制与抑制Hh信号通路有关，其中骨化三醇正在临床研究中。阿法骨化醇衍生物的抗肿瘤活性报道较少，因此通过结构修饰来发现新的阿法骨化醇衍生物来开发新型抗肿瘤药物具有较高的研究价值。由于阿法骨化醇结构中不含有氮原子，我们希望通过化学修饰引入含氮基团，从而提高药物分子的水溶性，而且容易成盐有利于临床给药，因此本发明提供了含氮杂环酸与阿法骨化醇形成的酯类衍生物。
发明内容
发明目的：有鉴于此，本发明的目的在于提供一种阿法骨化醇杂环酯类衍生物，这些衍生物具有与依托泊甙相当或更优的抑制肿瘤细胞增殖活性，可用于制备抗肿瘤药物。
技术方案：本发明提供了一种阿法骨化醇杂环酯类衍生物，该阿法骨化醇衍生物具有式(I)所示结构：
其中，R表示H或C1-7烃基，X表示N或C。
进一步的，所述阿法骨化醇杂环酯类衍生物具有如式2a～2d中任意一项所示的结构：
其中，
R为氢，X为N时，该阿法骨化醇杂环酯类衍生物为式2a所示结构的化合物；
R为氢，X为C时，该阿法骨化醇杂环酯类衍生物为式2b所示结构的化合物；
R为甲基，X为N时，该阿法骨化醇杂环酯类衍生物为式2c所示结构的化合物；
R为乙基，X为C时，该阿法骨化醇杂环酯类衍生物为式2d所示结构的化合物。
本发明还提供了一种阿法骨化醇杂环酯类衍生物的制备方法，包括以下步骤：
由阿法骨化醇与DMAP，EDCI和相应的6-取代2-吡啶甲酸或6-取代2-吡嗪甲酸在二氯甲烷中反应得到，其中，所述反应的反应式为：
其中，R表示H或C1-7烃基，X表示N或C；
所述的制备方法具体操作如下：将阿法骨化醇溶于二氯甲烷中，依次加入杂环酸、DMAP、EDCI，进行反应，得到第一反应液，将第一反应液用有机溶剂稀释，依次水洗、饱和食盐水洗，MgSO4干燥，减压干燥，然后柱层析得到白色固体，所述白色固体为阿法骨化醇杂环酯类衍生物，其中阿法骨化醇、杂环酸、DMAP、EDCI的摩尔比为：1:5:1.6：6。
优选的，上述制备方法中，所述的DMAP为4-二甲氨基吡啶，EDCI名称为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。
优选的，所述的杂环酸为6-取代2-吡啶甲酸或6-取代2-吡嗪甲酸中的一种。
优选的，所述的制备方法中，反应温度为25℃，反应时间为12h。
优选的，所述的有机溶剂为二氯甲烷、乙酸乙酯和苯中的至少一种。
有益效果：与现有技术相比，本发明中提供的阿法骨化醇杂环酯类衍生物。并且通过体外肿瘤细胞增殖抑制实验发现此类细胞毒活性超过或与阳性对照依托泊甙相当，可应用于防治乳腺癌、结肠癌、肝癌的药物的制备。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1为本发明实施例1提供的阿法骨化醇杂环酯类衍生物(2a)的核磁共振1H谱图；
图2为本发明实施例1提供的阿法骨化醇杂环酯类衍生物(2a)的核磁共振13C谱图；
图3为本发明实施例1提供的阿法骨化醇杂环酯类衍生物(2b)的核磁共振1H谱图；
图4为本发明实施例1提供的阿法骨化醇杂环酯类衍生物(2b)的核磁共振13C谱图。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，以使本领域的技术人员能够更好的理解本发明的优点和特征，从而对本发明的保护范围做出更为清楚的界定。本发明所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例，基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
将20mg(0.05mmol)的阿法骨化醇溶于1mL的二氯甲烷中，依次加入2-吡啶甲酸30mg(0.25mmol)，DMAP 10mg(0.08mmol)和EDCI 65mg(0.3mmol)，TLC检测反应结束，加入20ml二氯甲烷稀释，饱和碳酸氢钠溶液洗一次，然后依次水洗、饱和食盐水洗，MgSO4干燥，减压干燥，柱层析(石油醚:乙酸乙酯＝2:1)得到阿法骨化醇二(吡啶2-甲酸)酯(2b)30mg，产率98％。
1H NMR(400MHz,CDCl3)δ8.78(d,J＝2.8Hz,2H),8.07(dd,J＝34.7,7.9Hz,2H),7.89-7.72(m,2H),7.47-7.46(m,2H),6.46(d,J＝11.2Hz,1H),6.02-5.89(m,2H),5.60-5.59(m,1H),5.51(s,1H),5.16(d,J＝1.8Hz,1H),2.92(dd,J＝13.0,4.2Hz,1H),2.80(dd,J＝12.3,4.1Hz,1H),2.65(dd,J＝13.0,8.9Hz,1H),2.54-2.53(m,1H),2.34-2.33(m,1H),1.99-1.89(m,2H),1.65-1.64(mz,2H),1.56-1.45(m,2H),1.34-1.01(m,12H),0.90-0.83(m,10H),0.28(s,3H).13C NMR(100MHz,CDCl3)δ164.4,163.7,150.1,150.0,148.0,148.0,144.0,141.6,137.0,136.9,131.0,126.9,126.8,125.7,125.3,125.2,116.8,116.3,74.5,71.1,56.4,56.2,45.9,41.6,40.4,39.4,36.8,36.0,29.1,28.0,27.5,23.8,23.6,22.8,22.5,22.0,18.8,11.5.
实施例2
将20mg(0.05mmol)的阿法骨化醇溶于1mL的二氯甲烷中，依次加入2-吡嗪甲酸30mg(0.25mmol)，DMAP 10mg(0.08mmol)和EDCI 65mg(0.3mmol)，TLC检测反应结束，加入20ml二氯甲烷稀释，饱和碳酸氢钠溶液洗一次，然后依次水洗、饱和食盐水洗，MgSO4干燥，减压干燥，柱层析(石油醚:乙酸乙酯＝2:1)得到阿法骨化醇二吡嗪甲酸酯(2a)25mg，产率81％。
1H NMR(400MHz,CDCl3)δ9.28(dd,J＝26.4,1.3Hz,2H),8.80-8.72(m,4H),6.49(d,J＝11.5Hz,1H),5.95-5.89(m,2H),5.66-5.65(m,1H),5.55(s,1H),5.23-5.19(m,1H),2.94(dd,J＝13.0,4.0Hz,1H),2.83-2.77(m,1H),2.66(dd,J＝12.8,9.1Hz,1H),2.56-2.55(m,1H),2.36-2.34(m,J＝13.2,9.2,3.6Hz,1H),1.98-1.89(m,2H),1.66(t,J＝11.1Hz,2H),1.51-1.50(m,2H),1.27-1.26(m,12H),0.96-0.80(m,10H),0.24(s,2H).13C NMR(100MHz,CDCl3)δ163.1,162.7,147.7,147.6,146.3,146.2,144.7,144.6,144.5,143.5,143.4,141.0,130.2,126.1,116.8,116.5,75.0,71.6,56.4,56.2,45.9,41.5,40.3,39.4,36.7,36.0,29.2,28.0,27.5,23.8,23.6,22.8,22.5,22.0,18.8,11.4.
为了更好地理解本发明的实质，下面分别用本发明提供的阿法骨化醇杂环酯类衍生物对三种肿瘤细胞株的生长的抑制作用的药理实验结果，说明其在抗肿瘤药物研究领域中的新用途。药理实施例给出了代表性化合物的部分活性数据。必须说明，本发明的药理实施例是用于说明本发明而不是对本发明的限制。根据本发明的实质对本发明进行的简单改进都属于本发明要求保护的范围。
药物实验例1：化合物2a～2d和依托泊甙对人结肠癌细胞(HT-29)细胞毒活性测试
人结肠癌细胞HT-29用RPMI1640培养基培养，培养基中含有10％的胎牛血清，100U/mL青霉素和100U/mL的链霉素。细胞以每孔5×103的浓度加入到96孔板中，在37℃含有5％CO2的潮湿空气的培养箱中培养24小时。
将化合物2a～2d溶于DMSO中，配制1×10-2mol/L的母液，用完全培养基将母液稀释到相应浓度取对数生长期细胞接种于96孔板，24h贴壁后加入不同浓度的化合物溶液，每个浓度设4个平行孔，培养68h后加入四甲基偶氮唑盐(MTT)溶液，继续培养4h，弃去培养液，加入二甲亚砜150μL，振荡10min，用酶标仪测定570nm吸收度(A)值，计算半数抑制浓度(IC50)，具体如表1所示。根据表1可知，化合物2a的IC50为1.2×10-6M，而阳性对照依托泊甙对HT-29细胞的IC50为3.4×10-6M。
药物实验例2-3：化合物2a～2d和依托泊甙对人乳腺癌细胞(MCF-7)，人肝癌细胞(HepG2)细胞毒活性测试。
采用药物实验例1所示方法，对人乳腺癌细胞(MCF-7)，人肝癌细胞(HepG2)的生长抑制作用进行药理实验，计算半数抑制浓度(IC50)，具体如表1所示。
表1 化合物2a～2d和依托泊甙的细胞毒活性IC50(μM)
| 化合物 | HT-29 | MCF-7 | HepG2 |
| 2a | 1.2 | 3.2 | 0.4 |
| 2b | 1.1 | 5.0 | 5.1 |
| 2c | 0.9 | 1.7 | 1.5 |
| 2d | 7.5 | 4.1 | 7.9 |
| 依托泊甙 | 3.4 | 5.5 | 6.3 |
根据表1可知，本发明提供的阿法骨化醇杂环酯类衍生物具有重要的生物活性，体外对人结肠癌细胞(HT-29)、人乳腺癌细胞(MCF-7)，人肝癌细胞(HepG2)共三种肿瘤细胞的细胞毒活性试验表明：此类式(1)所示结构的阿法骨化醇杂环酯类衍生物对肿瘤细胞生长具有抑制作用，有可能发展成为新的防治肿瘤药物。从以上药理实施例中我们可以看出这些化合物对这三种肿瘤细胞都显示了较强的细胞毒活性，细胞毒活性超过或与阳性对照依托泊甙相当，具有开发成抗肿瘤药物的潜力。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (6)
1.一种阿法骨化醇杂环酯类衍生物，其特征在于：所述的阿法骨化醇杂环酯类衍生物具有式(I)所示结构：
其中，R表示H或C1-7烃基，X均同时表示N或X均同时表示C。
2.根据权利要求1所述的阿法骨化醇杂环酯类衍生物，其特征在于，所述的阿法骨化醇杂环酯类衍生物具有如式2a～2d中任意一项所示的结构：
其中，
R为氢，X为N时，该阿法骨化醇杂环酯类衍生物为式2a所示结构的化合物；
R为氢，X为C时，该阿法骨化醇杂环酯类衍生物为式2b所示结构的化合物；
R为甲基，X为N时，该阿法骨化醇杂环酯类衍生物为式2c所示结构的化合物；
R为乙基，X为C时，该阿法骨化醇杂环酯类衍生物为式2d所示结构的化合物。
3.一种如权利要求1所述的阿法骨化醇杂环酯类衍生物的制备方法，其特征在于：包括以下步骤：由阿法骨化醇与DMAP，EDCI和相应的杂环酸在二氯甲烷中反应得到；
所述的制备方法具体操作如下：将阿法骨化醇溶于二氯甲烷中，依次加入杂环酸、DMAP、EDCI，进行反应，得到第一反应液，将第一反应液用有机溶剂稀释，依次水洗、饱和食盐水洗，MgSO4干燥，减压干燥，然后柱层析得到白色固体，所述白色固体为阿法骨化醇杂环酯类衍生物，其中阿法骨化醇、杂环酸、DMAP、EDCI的摩尔比为：1:5:1.6：6。
4.根据权利要求3所述的阿法骨化醇杂环酯类衍生物的制备方法，其特征在于：所述的DMAP为4-二甲氨基吡啶，EDCI名称为1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐。
5.根据权利要求3所述的阿法骨化醇杂环酯类衍生物的制备方法，其特征在于：所述的杂环酸为6-取代2-吡啶甲酸或6-取代2-吡嗪甲酸中的一种。
6.根据权利要求3所述的阿法骨化醇杂环酯类衍生物的制备方法，其特征在于：所述的制备方法中，反应温度为25℃，反应时间为12h。
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