CN117224529A - 一种佛司可林四环类似物在制备抗炎药物中的应用 - Google Patents
一种佛司可林四环类似物在制备抗炎药物中的应用 Download PDFInfo
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Abstract
本发明属于药物化学和药理学技术领域,涉及一种佛司可林四环类似物在制备抗炎药物中的应用,该佛司可林四环类似物具有式(I)所示化学结构式,由佛司可林与甲醇钠在甲醇中反应得到7‑脱乙酰佛司可林1,然后7‑脱乙酰佛司可林1与高碘酸钠在DCM‑H2O混合溶液中反应得到佛司可林重排产物2,佛司可林重排产物2与DMP、吡啶在乙腈中反应得到佛司可林重排产物3,最后佛司可林重排产物3在无水醋酸银、无水醋酸铜和醋酸钯催化下与芳基碘化物在无水二氯乙烷中反应得到佛司可林四环类似物。本发明得到的佛司可林四环类似物具有较强的抗炎活性,可用于制备抗炎药物。
Description
技术领域
本发明涉及药物化学和药理学技术领域,具体涉及一种佛司可林四环类似物在制备抗炎药物中的应用。
背景技术
佛司可林是一种二萜类化合物,在抗癌、抗哮喘、抗高血压和正性肌力等方面都具有重要的药用价值。另外,佛司可林还可以与其他某些蛋白发生相互作用,如作用于葡萄糖转运蛋白和离子通道等。药效学研究结果表明,佛司可林可以有效促进中枢及周围神经***中神经元的分化及神经突起生长,从而对心脑血管***、呼吸***及肿瘤等产生重要影响,具有强心、平喘、抗肿瘤、抗血栓及降低眼内压等药理作用。现临床上开始用于心脑血管病、肿瘤和老年常患疾病等的治疗,药理作用明显,临床应用前景广阔。以价廉易得的佛司可林为原料,通过化学方法进行结构转化,对其进行化学骨架的改造,得到新的化合物,并开发其在药物化学和药理学技术领域的应用,具有重要意义。
发明内容
有鉴于此,本发明的目的在于提供一种佛司可林四环类似物在制备抗炎药物中的应用,此类化合物结构中具有独特的四环结构,并且具有较强的抗炎活性,可用于制备抗炎药物。
本发明提供了一种佛司可林四环类似物,该佛司可林四环类似物具有式(I)所示结构:
其中,R表示苯基、对三氟甲氧基苯基、对叔丁基苯基、对氯苯基、对甲基苯基、对甲氧基苯基、对硝基苯基和对氰基苯基中的一种。
进一步的,所述佛司可林四环类似物具有如式4a~4c中任意一项所示的结构:
其中,
R为苯基时,该佛司可林四环类似物为式4a所示结构的化合物;
R为对三氟甲氧基苯基时,该佛司可林四环类似物为式4b所示结构的化合物;
R为对叔丁基苯基时,该佛司可林四环类似物为式4c所示结构的化合物;
本发明还提供了佛司可林四环类似物的制备方法,包括以下步骤:
将佛司可林与甲醇钠在甲醇中反应得到7-脱乙酰佛司可林1,然后7-脱乙酰佛司可林1与高碘酸钠在DCM-H2O混合溶液中反应得到佛司可林重排产物2,佛司可林重排产物2与DMP、吡啶在乙腈中反应得到佛司可林重排产物3,最后佛司可林重排产物3在无水醋酸银、无水醋酸铜和醋酸钯催化下与芳基碘化物在无水二氯乙烷中反应得到佛司可林四环类似物4。
其中,所述反应的反应式为:
其中,R表示苯基、对三氟甲氧基苯基、对叔丁基苯基、对氯苯基、对甲基苯基、对甲氧基苯基、对硝基苯基和对氰基苯基中的一种。
具体的,该制备方法包括以下步骤:
(1)将佛司可林溶于甲醇中,加入甲醇钠,40℃反应2h,得第一反应液,将所述第一反应液冷却后,减压浓缩,用有机溶剂稀释,依次经过水洗,饱和食盐水洗,无水MgSO4干燥,减压浓缩,然后通过闪过柱层析得到白色固体7-脱乙酰佛司可林1,其中,佛司可林、甲醇钠的摩尔比为1:2;
(2)将7-脱乙酰佛司可林1溶于二氯甲烷-水的混合溶液中,加入硅胶和高碘酸钠,40℃反应24h,得到第二反应液,将所述第二反应液冷却后,减压浓缩,用有机溶剂稀释,过滤,有机相依次经过水洗、饱和食盐水洗,无水MgSO4干燥,减压浓缩,然后通过闪过柱层析得到白色固体佛司可林重排产物2,其中,二氯甲烷和水的体积比为4:1,硅胶和7-脱乙酰佛司可林1的质量比为1:1,7-脱乙酰佛司可林1和高碘酸钠的摩尔比为1:10;
(3)将佛司可林重排产物2溶于乙腈中,加入戴斯马丁氧化剂、吡啶,20℃反应12h,得到第三反应液,将所述第三反应液用有机溶剂稀释,依次经过饱和碳酸钠水溶液洗,饱和硫代硫酸钠水溶液洗,饱和食盐水洗,无水MgSO4干燥,减压浓缩,然后通过闪过柱层析得到白色固体佛司可林骨架重排产物3,其中,佛司可林重排产物2、戴斯马丁氧化剂、吡啶的摩尔比为1:3:2;
(4)将佛司可林重排产物3溶于无水二氯乙烷中,依次加入无水醋酸银、无水醋酸铜、醋酸钯、芳基碘化物,80℃反应18h,得到第四反应液,将所述第四反应液冷却后,用有机溶剂稀释,过滤,滤液减压浓缩,通过闪过柱层析得到白色固体,所述白色固体为佛司可林四环类似物4,其中佛司可林重排产物3、无水醋酸银、无水醋酸铜、醋酸钯、芳基碘化物的摩尔比为1:1.2:2:0.05:2;
其中,所述芳基碘化物为碘苯、对三氟甲氧基碘苯、对叔丁基碘苯、对氯碘苯、对甲基碘苯、对甲氧基碘苯、对硝基碘苯、对氰基碘苯中的一种
进一步的,上述制备方法中,所述有机溶剂为甲醇、二氯甲烷、乙酸乙酯和二氯乙烷中的至少一种。
进一步的,所述抗炎药物为抑制促炎因子的药物。
进一步的,所述促炎因子包括肿瘤坏死因子、白细胞介素、***素、一氧化氮和活性氧中的一种或多种。
进一步的,所述促炎因子为一氧化氮。
进一步的,所述药物的剂型为口服制剂。
进一步的,所述药物的剂型为片剂、胶囊剂、丸剂、颗粒剂、汤剂、膏剂、露剂、口服液剂、滴丸剂和糖浆剂中的一种。
进一步的,所述药物还包括药学上可接受的辅料。
进一步的,所述药学上可接受的辅料包括水果粉、食用香精、甜味剂、酸味剂、填充剂、润滑剂、防腐剂、助悬剂、食用色素、稀释剂、乳化剂、崩解剂和增塑剂中的一种或多种。
与现有技术相比,本申请提供了一类新的化合物佛司可林四环类似物在制备抗炎药物中的应用,该化合物含有独特的四环结构,这种新的结构赋予这类衍生物优异的抗炎活性,可应用于抗炎药物的制备。
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2提供的佛司可林重排产物(3)的核磁共振1H谱图;
图2为本发明实施例2提供的佛司可林重排产物(3)的核磁共振13C谱图;
图3为本发明实施例2提供的佛司可林重排产物(3)的X-射线单晶衍射结构图;
图4为本发明实施例3提供的佛司可林四环类似物(4a)的核磁共振1H谱图;
图5为本发明实施例3提供的佛司可林四环类似物(4a)的核磁共振13C谱图;
图6为本发明实施例3提供的佛司可林四环类似物(4b)的核磁共振1H谱图;
图7为本发明实施例3提供的佛司可林四环类似物(4b)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,显然,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410mg(1.0mmol)的佛司可林溶于甲醇(10ml),加入360mg甲醇钠(30wt%inMeOH,2.0mmol),40℃反应2小时。反应液减压浓缩,加入乙酸乙酯(10ml)稀释,然后依次水洗、饱和食盐水洗,无水MgSO4干燥,减压浓缩,通过闪过柱层析(石油醚:乙酸乙酯=8:1)得到360mg白色固体,即7-脱乙酰佛司可林1(产率98%)。
1H NMR(400MHz,Chloroform-d)δ6.60(m,1H,9-OH),6.13(dd,J=17.4,10.7Hz,1H,H-14),5.20(d,J=
17.4Hz,1H,H-15),4.99(d,J=10.6Hz,1H,H-15),4.62(s,1H,H-1),4.48(s,1H,H-6),4.13(t,J=3.5Hz,1H,H-7),3.18(d,J=17.2Hz,1H,H-12),2.93(dt,J=9.4,3.1Hz,1H,1-OH),2.70(q,J=3.7Hz,1H,7-OH),2.50(d,J=17.2Hz,1H,H-12),2.42–2.36(m,1H,H-2e),2.09(d,J=2.7Hz,1H,H-5),1.84–1.79(m,1H,6-OH),1.73(td,J=13.9,3.6Hz,1H,H-3a),1.65(s,3H,CH3),1.42(s,3H,CH3),1.42-1.41(m,1H,H-2a),1.41(s,3H,CH3),1.27(s,3H,CH3),1.12(dt,J=13.4,3.5Hz,1H,H-3e),1.06(s,3H,CH3).
实施例2
将368mg(1.0mmol)的7-脱乙酰佛司可林1溶于二氯甲烷-水(10ml,v:v=4:1)的混合溶液中,加入368mg硅胶、2.14g(10.0mmol)高碘酸钠,40℃反应24小时。反应液减压浓缩,加入乙酸乙酯(10ml)稀释,过滤,有机相依次水洗、饱和食盐水洗,无水MgSO4干燥,减压浓缩,通过闪过柱层析(石油醚:乙酸乙酯=10:1)得到340mg白色固体,即佛司可林重排产物2(产率98%);接着将366mg(1.0mmol)重排产物2溶于乙腈(10ml)中,加入158μL(2.0mmol)吡啶、1.27g(3.0mmol)戴斯-马丁氧化剂,20℃反应12小时。反应液减压浓缩,然后加入乙酸乙酯(10ml)稀释,依次经过饱和碳酸钠水溶液洗,饱和硫代硫酸钠水溶液洗,饱和食盐水洗,无水MgSO4干燥,减压浓缩,通过闪过柱层析得到122mg白色固体,即佛司可林重排产物3(产率35%)。
1H NMR(400MHz,DMSO-d6)δ9.58(s,1H,H-16),5.91(dd,J=17.4,10.6Hz,1H,H-13),5.40(s,1H,H-11),5.20(dd,J=17.4,1.3Hz,1H,H-14),4.98(dd,J=10.5,1.2Hz,1H,H-14),4.26(dd,J=6.0,3.4Hz,1H,H-1),2.73(s,1H,H-5),2.06(ddt,J=15.6,6.8,5.1Hz,1H),1.75(dddd,J=15.2,8.9,5.0,3.4Hz,1H),1.57(ddd,J=14.5,9.7,4.9Hz,1H),1.37(s,3H,CH3),1.32(ddd,J=12.6,5.2,2.0Hz,1H),1.28(s,3H,CH3),1.21(s,3H,CH3),1.10(s,3H,CH3),1.08(s,3H,CH3).13C NMR(100MHz,DMSO)δ200.8,172.1,151.1,144.0,112.2,106.8,90.3,81.7,81.6,76.7,52.6,51.1,34.8,31.2,30.4,28.1,24.1,23.5,20.1,13.7.
实施例3
将346mg(1.0mmol)佛司可林重排产物3溶于无水二氯乙烷(10ml)中,依次加入200mg(1.2mmol)无水醋酸银、363mg(2.0mmol)无水醋酸铜、12mg(0.05mmol)醋酸钯、408mg(2.0mmol)碘苯,80℃下反应18小时。反应液加入乙酸乙酯(10ml)稀释,过滤,滤液依次经过水洗、饱和食盐水洗,无水MgSO4干燥,减压浓缩,通过闪过柱层析(石油醚:乙酸乙酯=30:1)得到238mg白色固体,即佛司可林四环类似物4a(产率69%)。
1H NMR(400MHz,Chloroform-d)δ9.67(s,1H,CHO),7.45–7.10(m,5H,ArH),6.48(d,J=16.1Hz,1H,H-14),6.26(d,J=16.2Hz,1H,H-13),5.25(s,1H,H-11),4.06(dd,J=6.2,3.5Hz,1H,H-1),2.72(s,1H,H-5),1.98(dq,J=18.1,6.0Hz,1H),1.84–1.73(m,1H),1.53(td,J=9.8,5.0Hz,1H),1.46(s,3H,CH3),1.37–1.30(m,1H),1.29(s,3H,CH3),1.21(s,3H,CH3),1.11(s,3H,CH3),1.08(s,3H,CH3).13C NMR(100MHz,CDCl3)δ201.07,171.83,151.30,136.84,134.89,128.51,127.53,127.36,126.67,107.20,90.12,81.95,81.73,76.40,52.84,51.28,34.95,31.21,30.33,28.07,24.36,23.40,20.14,13.69.HRMS(ESI):m/z calcd for C26H30O5Na:445.1991;found:445.1989[M+Na]+.
实施例4-5
根据以上实施例3的方法,将碘苯分别换为对三氟甲氧基碘苯和对叔丁基碘苯,制备化合物4b和4c。
下面列出是4b-4c各化合物的理化数据:
4b:产率63%。1H NMR(400MHz,Chloroform-d)δ9.67(s,1H,CHO),7.45–7.29(m,2H,ArH),7.14–7.02(m,2H,ArH),6.48(d,J=16.1Hz,1H,H-14),6.24(d,J=16.1Hz,1H,H-13),5.24(s,1H,H-11),4.08(dd,J=6.1,3.5Hz,1H,H-1),2.71(s,1H,H-5),1.99(dtd,J=15.6,6.6,5.0Hz,1H),1.79(dddd,J=15.5,10.0,5.2,3.5Hz,1H),1.54(tt,J=10.0,5.0Hz,1H),1.46(s,3H,CH3),1.38–1.31(m,1H),1.29(s,3H,CH3),1.22(s,3H,CH3),1.11(s,3H,CH3),1.09(s,3H,CH3).13C NMR(100MHz,CDCl3)δ200.8,171.8,151.5,148.4,135.9,135.7,127.9,125.9,121.7,121.0,119.2,106.8,90.1,82.0,81.8,76.3,52.8,51.3,34.9,31.2,30.3,28.2,24.4,23.4,20.1,13.7.HRMS(ESI):m/z calcd for C27H29O6NaF3:529.1814;found:529.1815[M+Na]+.
4c:产率24%。1H NMR(400MHz,)δ9.66(d,J=0.8Hz,1H,CHO),7.36–7.21(m,4H,ArH),6.46(d,J=16.1Hz,1H,H-14),6.22(d,J=16.1Hz,1H,H-13),5.24(s,1H,H-11),4.05(dd,J=6.1,3.4Hz,1H,H-1),2.70(s,1H,H-5),2.08-1.90(m,1H),1.78(dddd,J=15.7,9.6,5.4,3.7Hz,1H),1.55–1.47(m,1H),1.45(s,3H,CH3),1.40–1.32(m,1H),1.29–1.26(m,3H,CH3),1.22(s,9H,C(CH3)3),1.21(s,3H,CH3),1.11(s,3H,CH3),1.08(s,3H,CH3).13C NMR(100MHz,CDCl3)δ201.1,171.8,151.2,150.6,134.2,134.1,127.1,126.3,125.4,107.3,90.1,81.9,81.7,76.5,52.8,51.3,35.0,34.6,31.3,31.2,30.3,28.2,24.3,23.4,20.1,13.7.HRMS(ESI):m/z calcd for C30H38O5Na:501.2617;found:501.2625[M+Na]+.
为了更好地理解本发明的实质,下面分别用本发明提供的佛司可林四环类似物对LPS诱导的RAW264.7细胞NO释放的抑制作用的药理实验结果,说明其在抗炎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。
药物实施例1:化合物4a-4c、佛司可林和***对LPS诱导的RAW264.7巨噬细胞NO释放的抑制活性
将RAW264.7巨噬细胞以1×105个/m L的密度接种于96孔板上,在37℃、5%CO2培养箱中孵育24h。本实验设置对照组、LPS诱导组、阳性对照***(dexamethasone,DEX)组和实验组,阳性对照组和实验组以0.2、1.0、5.0、25.0μM待测化合物4a-4c或DEX加入到处理好的RAW264.7巨噬细胞中。放置4h后在对照组加入10μL培养基,其余组加入LPS(1.0μg/mL)用以诱导细胞,培养孵育24h,离心,收集细胞上层清液,通过一氧化氮试剂盒测定NO的释放量,并用Graphpad5软件计算IC50。应用四甲基偶氮唑盐微量酶反应比色(MTT)法检测化合物在20μM对RAW264.7巨噬细胞生长的影响。
表1化合物4a-4c、佛司可林和***对LPS诱导的RAW264.7巨噬细胞NO释放的抑制活性
化合物 | IC50(μM) | 细胞存活率/% |
4a | 1.7 | 99.43±2.10 |
4b | 0.8 | 99.76±3.11 |
4c | 0.3 | 99.24±1.46 |
佛司可林 | 25.1 | 100.33±1.88 |
DEX | 8.6 | 99.27±2.43 |
根据表1可知,本发明提供的佛司可林四环类似物具有重要的生物活性,LPS诱导的RAW 264.7巨噬细胞NO释放的抑制活性试验表明:此类式(1)所示结构的佛司可林四环类似物对LPS诱导的RAW 264.7巨噬细胞NO释放具有较好的抑制活性,实施例中化合物4a-4c抑制效果明显优于阳性对照药***和佛司可林,并且没有明显的细胞毒性,有可能发展成为新的抗炎药物。
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 (9)
1.一种式I所示结构的佛司可林四环类似物在制备抗炎药物中的应用,
其中,R表示苯基、对三氟甲氧基苯基、对叔丁基苯基、对氯苯基、对甲基苯基、对甲氧基苯基、对硝基苯基和对氰基苯基中的一种。
2.根据权利要求1所述的应用,其特征在于,所述佛司可林四环类似物具有如式4a~4c中任意一项所示的结构:
3.根据权利要求1所述的应用,其特征在于,所述抗炎药物为抑制促炎因子的药物。
4.根据权利要求3所述的应用,其特征在于,所述促炎因子包括肿瘤坏死因子、白细胞介素、***素、一氧化氮和活性氧中的一种或多种。
5.根据权利要求3所述的应用,其特征在于,所述促炎因子为一氧化氮。
6.如权利要求1-5任一项所述的应用,其特征在于,所述药物的剂型为口服制剂。
7.如权利要求1-5任一项所述的应用,其特征在于,所述药物的剂型为片剂、胶囊剂、丸剂、颗粒剂、汤剂、膏剂、露剂、口服液剂、滴丸剂和糖浆剂中的一种。
8.如权利要求1-5任一项所述的应用,其特征在于,所述药物还包括药学上可接受的辅料。
9.如权利要求8所述的应用,其特征在于,所述药学上可接受的辅料包括水果粉、食用香精、甜味剂、酸味剂、填充剂、润滑剂、防腐剂、助悬剂、食用色素、稀释剂、乳化剂、崩解剂和增塑剂中的一种或多种。
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