CN103588616B - 一种垫状卷柏提取物及其制备方法和应用 - Google Patents
一种垫状卷柏提取物及其制备方法和应用 Download PDFInfo
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- C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
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- C07C65/19—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups having unsaturation outside the aromatic ring
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Abstract
本发明对垫状卷柏提取物进行了深入的研究,发现垫状卷柏提取物具有显著的抗炎活性。运用多种柱色谱分离技术和半制备高效液相色谱分离方法,提取分离到一类具有9,9-二苯基-1-(苯乙炔基)-9H-芴新骨架结构的化合物(DZJB 1-6),命名为selaginpulvilins A-F(结构式(Ⅰ)如下)。对从垫状卷柏中分离提取的这6个化合物进行结构修饰,进而得到一系列化合物。这些化合物能显著抑制4型磷酸二酯酶(PDE4)的活性,可用于制备PDE4抑制剂,治疗哮喘,慢性阻塞性肺炎,炎症等。本发明对PDE4抑制剂的开发提供一种新结构。
Description
技术领域
本发明涉及天然提取物及其修饰,更具体地,涉及一种垫状卷柏提取物及其制备方法和应用。
背景技术
环核苷酸磷酸二酯酶(Cyclic nucleotide phosphodiesterases,PDEs)是一类重要的超级酶家族,通过对cAMP和cGMP的水解,有效控制细胞内的cAMP和cGMP浓度,从而调节体内第二信使所传导的生化作用。PDEs在哺乳动物组织中分布广泛,其多样性致使不同的PDE酶在细胞和亚细胞水平有着特定的分布,可选择性调节多种细胞功能,是良好的药物设计与治疗靶点。
4型磷酸二酯酶(PDE4)作为特异性催化水解cAMP的PDE家族酶,在人体内主要分布于炎症细胞内。在炎症反应中,cAMP对细胞因子的释放等生理过程起着关键的负调节作用,因此通过抑制PDE4提高细胞内cAMP浓度将有助于减轻炎症反应对机体的伤害。目前,PDE4抑制剂已被开发成抗炎的药物,如罗氟司特(Roflumilast)等,临床上主要用于治疗肺部的炎症,尤其是针对于哮喘和慢性阻塞性肺病的治疗上。但服用此类药物会引起腹泻、恶心等不良反应,因此如何克服这些PDE4抑制剂存在的不良反应,研究新型的特异性抑制剂就成为研究的热点之一。天然产物是寻找具有新型PDE4抑制剂的重要来源之一,对于开发新一代疗效强、副作用小的PDE4抑制剂具有重要的意义。
目前垫状卷柏中只报道过炔酚selaginellin类化合物,且多用于抗菌及抗氧化,对于作为PDE4抑制剂尚无研究。本发明所述从垫状卷柏中发现的新颖的炔酚类化合物为首次应用在抑制PDE4方面。
发明内容
本发明为一种垫状卷柏提取物,所述的垫状卷柏提取物如结构式Ⅰ所示:
其中:
R1,R4为H,烷基或酰基;
R2,R3,R5,R7分别代表卤素,醛基,羧基,磺酸基,硝基,亚硝基或氢;
R6代表H,-CH3,-CH2OH,-CHO或-COOH。
所述的R1和R4为氢、甲基、乙基或乙酰基。
所述的R2,R3,R5,R7为氢。
所述的化合物优选为:
DZJB-1:4,4'-(7-羟基-2-羟甲基-1-(4-羟基苯)乙炔基-9H-芴-9,9-二取代)联苯酚、
DZJB-2:7-羟基-9,9-二(4-羟基苯)-1-((4-羟基苯)乙炔基)-9H-芴-2-醛、
DZJB-3:4,4'-(7-羟基-1-((4-羟基苯)乙炔基)-2-甲基-9H-芴-9,9-二取代)联苯酚、
DZJB-4:4,4'-(7-羟基-1-((4-羟基苯)乙炔基)-9H-芴-9,9-二取代)联苯酚、
DZJB-5:8-((4-羟基苯)乙炔基)-9,9-二(4-甲氧基苯)-9H-芴-2-醇、
DZJB-6:7-羟基-1-((4-羟基苯)乙炔基)-9,9-二(4-甲氧基苯)-9H-芴-2-醛、
DZJB-7:(7-甲氧基-9,9-二(4-甲氧基苯)-1-((4-甲氧基苯)乙炔基)-9H-芴-2-基)甲醇、
DJB-8:7-甲氧基-9,9-二(4-甲氧基苯)-1-((4-甲氧基苯)乙炔基)-9H-芴-2-醛、
DZJB-9:7-甲氧基-9,9-二(4-甲氧基苯)-1-((4-甲氧基苯)乙炔基)-2-甲基-9H-芴、
DZJB-10:7-甲氧基-9,9-二(4-甲氧基苯)-1-((4-甲氧基苯)乙炔基)-9H-芴、
DZJB-11:7-羟基-9,9-二(4-羟基苯)-1-((4-羟基苯)乙炔基)-9H-芴-2-羧酸、
DZJB-12:7-甲氧基-9,9-二(4-甲氧基苯)-1-((4-甲氧基苯)乙炔基)-9H-芴-2-羧酸、
DZJB-13:(7-乙酰氧基-2-(乙酰氧基甲基)-1-((4-乙酰氧基苯)乙炔基)-9H-芴-9,9-二取代)二(4,1-亚苯基)二乙酸酯、
DZJB-14:(7-乙酰氧基-1-((4-乙酰氧基苯)乙炔基)-2-甲酰基-9H-芴-9,9-二取代)二(4,1-亚苯基)二乙酸酯、
DZJB-15:(7-乙酰氧基-1-((4-乙酰氧基苯)乙炔基)-9H-芴-9,9-二取代)二(4,1-亚苯基)二乙酸酯、
DZJB-16:(7-乙酰氧基-1-((4-乙酰氧基苯)乙炔基)-2-甲基-9H-芴-9,9-二取代)二(4,1-亚苯基)二乙酸酯、
DZJB-17:4-((7-乙酰氧基-9,9-二(4-甲氧基苯)-9H-芴-1-基)乙炔基)乙酸苯酯、
或DZJB-18:4-((7-乙酰氧基-2-甲酰基-9,9-二(4-甲氧基苯)-9H-芴-1-基)乙炔基)乙酸苯酯。
更进一步提供一种制备上述的垫状卷柏提取物的方法,如图1所示,
S1.将垫状卷柏全草粉粹,用95%乙醇超声提取3次,回收溶剂,得提取浸膏;
S2.将步骤S1得到的提取浸膏依次用石油醚和乙酸乙酯萃取,分别得到两个部分,随后乙酸乙酯萃取物经MCI柱层析,分别用30%、50%、70%、90%、100%甲醇-水梯度洗脱,得各种阶段的洗脱液;
S3.分别将取步骤S2所得洗脱液,通过硅胶柱层析、凝胶柱层析、ODS柱层析以及高效液相色谱等分离手段,即得。
更进一步提供一种上述的垫状卷柏提取物在制备PDE4抑制剂中的应用。
本发明有以下优点:
1.从天然产物中发现了一类新骨架化合物,丰富了天然产物的种类。
2.垫状卷柏提取物首次应用在抑制PDE4活性方面,且表现出非常好的抑制活性以及选择性。有望成为治疗炎症例如哮喘的新药物。
附图说明
图1为本发明所涉及的化合物的分离流程图。
具体实施方式
下面结合具体实施例进一步详细说明本发明。除非特别说明,本发明采用的试剂、设备和方法为本技术领域常规市购的试剂、设备和常规使用的方法。
现在参考下列说明性的实施例,进一步解释本发明,其中NMR波谱采用Bruker AM-400 spectrometer记录,TMS内标。柱色谱硅胶(300~400目):青岛海洋化工厂;GF254硅胶薄层色谱预制板:青岛海洋化工厂;MCI填料(CHP20P,75~150μm):日本Mitsubishi公司;葡聚糖凝胶(SephadexLH-20):美国GE公司;ODS填料(12nm,S-50μm):日本YMC公司;其余溶剂和试剂:分析纯(AR),天津市百世化工有限公司。
实施例1
垫状卷柏萃取物的制备
取垫状卷柏全草1kg,粉碎成粗粉。加入8倍体积量的95%乙醇,浸泡7天,减压抽滤,减压回收乙醇,余液浓缩至相对密度为1.25的稠膏。重复两次以上浸泡提取步骤,最终得垫状卷柏乙醇提取物50g。垫状卷柏乙醇提取物用1L水溶解,依次用等量的石油醚、乙酸乙酯各萃取三次。合并乙酸乙酯萃取液,减压浓缩,得到乙酸乙酯萃取物39g。
实施例2
单体化合物的分离
按照实施例1,得到乙酸乙酯萃取物39g,乙酸乙酯萃取物应用MCI柱初步分段,以甲醇∶水=3∶7~10∶0洗脱;然后采用200–300目柱色谱硅胶以石油醚:乙酸乙酯或石油醚:丙酮或氯仿:甲醇等溶剂体系梯度洗脱,再反复采用凝胶柱LH-20、ODS柱纯化,最后经半制备高效液相色谱手段在(乙腈∶水)或(甲醇∶水)条件下进一步纯化,最终得到6个单体化合物,具体分离流程参考图1。
实施例3
DZJB-1:4,4'-(7-羟基-2-羟甲基-1-(4-羟基苯)乙炔基-9H-芴-9,9-二取代)联苯酚的制备
按照实施例2的方法,最后通过凝胶(LH-20氯仿:甲醇=1:1)纯化,重结晶,得到题述化合物,黄色块状晶体,其结构如下:
UV(MeOH)λmax(log ε)204(4.84)nm,300(4.47)nm。
IR(KBr)νmax3312,2207,1607,1510,1449,1357,1241,1174and833cm-1。
Negative ESIMSm/z511.2[M-H]-,546.9[M+Cl]-,556.7[M+HCOO]-;HRESIMS m/z511.1543[M+H]+(calcd for C34H24O5,511.1551)。
4,4'-(7-羟基-2-羟甲基-1-(4-羟基苯)乙炔基-9H-芴-9,9-二取代)联苯酚波谱数据(400MHz,Methanol-d4)
实施例4
DZJB-2:7-羟基-9,9-二(4-羟基苯)-1-((4-羟基苯)乙炔基)-9H-芴-2-醛的制备
按照实施例2的方法,最后通过凝胶(LH-20)洗脱剂为无水乙醇,纯化得到题述化合物。其结构如下:
UV(MeOH)λmax(log ε)208(4.70)nm,294(4.24)nm,305(4.26)nm,314(4.28)nm,360(4.21)nm。
IR(KBr)νmax3284,2202,1679,1604,1557and1507cm-1。
positive ESIMS m/z 511.1[M+H]+,negativeESIMSm/z509.1[M-H]-;HRESIMS m/z509.1386[M-H]-(calcd for C34H22O5,509.1394)。
7-羟基-9,9-二(4-羟基苯)-1-((4-羟基苯)乙炔基)-9H-芴-2-醛波谱数据(400MHz,Methanol-d4)
实施例5
DZJB-3:4,4'-(7-羟基-1-((4-羟基苯)乙炔基)-2-甲基-9H-芴-9,9-二取代)联苯酚的制备
按照实施例2的方法,最后通过半制备高效液相,洗脱剂乙腈:水6:4,保留时间为10.8min,纯化得到题述化合物。其结构如下:
UV(MeOH)λmax(log ε)208(4.76)nm,288(4.36)nm,299(4.41)nm,315(4.18)nm。
IR(KBr)νmax3375,2193,1604,1508and1447cm-1。
positive ESIMS m/z 497.2[M+H]+,negative ESIMS m/z495.2[M-H]-;HRESIMSm/z495.1594[M-H]-(calcd for C34H24O4,495.1602)。
4,4'-(7-羟基-1-((4-羟基苯)乙炔基)-2-甲基-9H-芴-9,9-二取代)联苯酚波谱数据(400MHz,Methanol-d4)
实施例6
DZJB-4:4,4'-(7-羟基-1-((4-羟基苯)乙炔基)-9H-芴-9,9-二取代)联苯酚的制备
按照实施例5的方法,保留时间为9.2min,制备得到提述化合物。结构如下:
UV(MeOH)λmax(log ε)205(4.89)nm,288(4.52)nm,298(4.53)nm,316(4.35)nm。
IR(KBr)νmax3367,2203,1563,1509,1468cm-1。
Positive ESIMS m/z 483.2[M+H]+,negative ESIMS m/z 481.2[M-H]-;HRESIMS m/z505.1417[M+Na]+(calcd for C33H22O4,505.1410).
4,4'-(7-羟基-1-((4-羟基苯)乙炔基)-9H-芴-9,9-二取代)联苯酚波谱数据(400MHz,Methanol-d4)
实施例7
DZJB-5:8-((4-羟基苯)乙炔基)-9,9-二(4-甲氧基苯)-9H-芴-2-醇的制备
按照实施例2的方法,最后通过半制备高效液相,洗脱剂乙腈:水8:2,保留时间为8.0min,纯化得到题述化合物。其结构如下:
UV(MeOH)λmax(log ε)209(4.76)nm,291(4.47)nm,298(4.49)nm,314(4.30)nm。
IR(KBr)νmax3691,2207,1601,1503and1455cm-1。
positive ESIMS m/z 511.2[M+H]+,negative ESIMS m/z509.2[M-H]-;HRESIMS m/z509.1729[M-H]-(calcd for C35H26O4,509.1758)。
8-((4-羟基苯)乙炔基)-9,9-二(4-甲氧基苯)-9H-芴-2-醇波谱数据(400MHz,Methanol-d4)
实施例8
DZJB-6:7-羟基-1-((4-羟基苯)乙炔基)-9,9-二(4-甲氧基苯)-9H-芴-2-醛的制备
按照实施例2的方法,最后通过半制备高效液相,洗脱剂乙腈:水7:3,保留时间为8.5min,纯化得到题述化合物。其结构如下:
UV(MeOH)λmax(log ε)208(4.77)nm,302(4.30)nm,315(4.33)nm,358(4.29)nm。
IR(KBr)νmax3436,2204,1669,1607,1555and1509cm-1。
Positive ESIMS m/z539.0[M+H]+,negative ESIMS m/z 537.3[M-H]-;HRESIMS m/z537.1720[M-H]-(calcd for C36H26O5,537.1707)。
7-羟基-1-((4-羟基苯)乙炔基)-9,9-二(4-甲氧基苯)-9H-芴-2-醛波谱数据(400MHz,Methanol-d4)
实施例9
DZJB-7:(7-甲氧基-9,9-二(4-甲氧基苯)-1-((4-甲氧基苯)乙炔基)-9H-芴-2-基)甲醇的制备
按照实施例3的方法,得到4,4'-(7-羟基-2-羟甲基-1-(4-羟基苯)乙炔基-9H-芴-9,9-二取代)联苯酚,用丙酮溶解,加入适量无水K2CO3,搅拌1min后加入CH3I,室温搅拌10h,得到题述化合物,其结构和核磁数据如下:
1HNMR(400MHz,Methanol-d4)δ7.73(d,J=7.8Hz,1H),7.69(d,J=8.4Hz,1H),7.52(d,J=7.7Hz,1H),7.19(d,J=8.7Hz,4H),6.95(d,J=8.7Hz,2H),6.91(dd,J=8.4,2.3Hz,1H),6.84(d,J=8.7Hz,2H),6.78(d,J=2.3Hz,1H),6.68(d,J=8.7Hz,4H),3.79(s,3H),3.72(s,6H),3.70(s,3H).
实施例10
DZJB-8:7-甲氧基-9,9-二(4-甲氧基苯)-1-((4-甲氧基苯)乙炔基)-9H-芴-2-醛的制备
按照实施例4的方法,得到7-羟基-9,9-二(4-羟基苯)-1-((4-羟基苯)乙炔基)-9H-芴-2-醛,用丙酮溶解,加入适量无水K2CO3,搅拌1min后加入CH3I,室温搅拌10h,得到题述化合物,其结构和核磁数据如下:
1HNMR(400MHz,Methanol-d4)δ7.90(d,J=8.0Hz,1H),7.75(d,J=8.0Hz,1H),7.69(d,J=8.4Hz,1H),7.19(d,J=8.7Hz,4H),6.95(d,J=8.7Hz,2H),6.91(dd,J=8.4,2.3Hz,1H),6.84(d,J=8.7Hz,2H),6.78(d,J=2.3Hz,1H),6.68(d,J=8.7Hz,4H),3.80(s,3H),3.70(s,6H),3.69(s,3H).
实施例11
DZJB-9:7-甲氧基-9,9-二(4-甲氧基苯)-1-((4-甲氧基苯)乙炔基)-2-甲基-9H-芴,以及DZJB-10:7-甲氧基-9,9-二(4-甲氧基苯)-1-((4-甲氧基苯)乙炔基)-9H-芴的制备
按照实施例5、实施例6以及实施例10的方法可制备题述化合物。
实施例12
DZJB-12:7-甲氧基-9,9-二(4-甲氧基苯)-1-((4-甲氧基苯)乙炔基)-9H-芴-2-羧酸的制备
按照实施例10的方法,得到7-甲氧基-9,9-二(4-甲氧基苯)-1-((4-甲氧基苯)乙炔基)-9H-芴-2-醛,加入二甲基亚砜溶解,在冰浴中加入1.2eq碱性高锰酸钾,室温下搅拌2~3h,反应得到题述化合物,其结构和核磁数据如下:
1HNMR(400MHz,Methanol-d4)δ8.21(d,J=8.4Hz,1H),8.01,(d,J=8.4Hz,1H),7.76(d,J=8.2Hz,1H),7.48(d,J=8.7Hz,2H),7.12(d,J=8.6Hz,4H),7.06(s,1H),6.95(d,J=8.7Hz,2H),6.89(d,J=8.2Hz,1H),6.87(d,J=8.6Hz,4H),3.85(s,3H),3.83(s,6H),3.82(s,3H).
实施例13
DZJB-11:7-羟基-9,9-二(4-羟基苯)-1-((4-羟基苯)乙炔基)-9H-芴-2-羧酸的制备
按照实施例12的方法,得到7-甲氧基-9,9-二(4-甲氧基苯)-1-((4-甲氧基苯)乙炔基)-9H-芴-2-羧酸,加入二氯甲烷溶解,在-40℃环境下中加入三溴化硼,搅拌20~30h,反应得到题述化合物,其结构和核磁数据如下:
1HNMR(400MHz,Methanol-d4)δ8.21(d,J=8.0Hz,1H),8.01(d,J=8.0Hz,1H),7.67(d,J=8.3Hz,1H),7.15(d,J=8.7Hz,4H),6.89(d,J=8.6Hz,2H),6.82(dd,J=8.3,2.1Hz,1H),6.77(d,J=2.1Hz,1H),6.72(d,J=8.6Hz,2H),6.64(d,J=8.7Hz,4H).
实施例14
DZJB-15:(7-乙酰氧基-1-((4-乙酰氧基苯)乙炔基)-9H-芴-9,9-二取代)二(4,1-亚苯基)二乙酸酯的制备
按照实施例6的方法,得到4,4'-(7-羟基-1-((4-羟基苯)乙炔基)-9H-芴-9,9-二取代)联苯酚,加入吡啶溶解,加入1.1eq乙酸酐,室温下搅拌反应10~15h,得到题述化合物,其结构和核磁数据如下:
1HNMR(400MHz,Methanol-d4)δ7.84(d,J=8.5Hz,1H),7.80(d,J=8.0Hz,1H),7.56(d,J=8.6Hz,2H)),7.48(d,J=8.0Hz,1H),7.36(s,1H),7.34(t,J=8.0Hz,1H),7.25(d,J=8.6Hz,2H),7.20(d,J=8.7Hz,4H),7.19(d,J=8.5Hz,1H),7.17(d,J=8.7Hz,4H),2.30(s,3H),2.28(s,6H),2.27(s,3H).
实施例15
DZJB-13:(7-乙酰氧基-2-(乙酰氧基甲基)-1-((4-乙酰氧基苯)乙炔基)-9H-芴-9,9-二取代)二(4,1-亚苯基)二乙酸酯、DZJB-14:(7-乙酰氧基-1-((4-乙酰氧基苯)乙炔基)-2-甲酰基-9H-芴-9,9-二取代)二(4,1-亚苯基)二乙酸酯以及DZJB-16:(7-乙酰氧基-1-((4-乙酰氧基苯)乙炔基)-2-甲基-9H-芴-9,9-二取代)二(4,1-亚苯基)二乙酸酯的制备
按照实施例3、实施例4、实施例5以及实施例14的方法可制备题述化合物。
实施例16
DZJB-17:4-((7-乙酰氧基-9,9-二(4-甲氧基苯)-9H-芴-1-基)乙炔基)乙酸苯酯的制备
按照实施例7的方法,得到8-((4-羟基苯)乙炔基)-9,9-二(4-甲氧基苯)-9H-芴-2-醇,加入吡啶溶解,加入1.1eq乙酸酐,室温下搅拌反应10~15h,得到题述化合物,其结构和核磁数据如下:
1HNMR(400MHz,Methanol-d4)δ7.84(d,J=8.5Hz,1H),7.80(d,J=8.0Hz,1H),7.56(d,J=8.6Hz,2H)),7.48(d,J=8.0Hz,1H),7.36(s,1H),7.34(t,J=8.0Hz,1H),7.25(d,J=8.6Hz,2H),7.19(d,J=8.5Hz,1H),7.12(d,J=8.7Hz,4H),6.87(d,J=8.7Hz,4H),3.83(s,6H),2.28(s,6H).
实施例17
垫状卷柏提取物对PDE4酶的抑制作用及对PDE酶家族的选择性
待测分子与含有重组PDE4D2蛋白(该重组蛋白是我们制备得到,详细制备方法可参考我们已发表且含有制备该重组蛋白的文献:Bioorganic & MedicinalChemistry Letters,2012年,22卷,页码:3261–3264),20mM Tris-HCl,pH7.5,2mM二硫苏糖醇(dithiothreitol),10mMMgCl2以及20,000–30,000cpm的3H-cAMP在室温下孵育15分钟,然后分别用0.2M ZnSO4and Ba(OH)2中止反应,然后利用PerkinElmer2910计数仪测量上清液中未反应的3H-cGMP,每个分子至少测量三次,对PDE4D2蛋白活性抑制的IC50值通过浓度测试及非线性回归,计算获得。
同时也测试了垫状卷柏提取物对PDE4酶、PDE5酶、PDE9酶的选择性.
本发明化合物对PDE4、PDE5、PDE9的抑制活性测试数据如表1(IC50值为抑制率达到50%时的抑制剂浓度)。
Claims (4)
1.一种垫状卷柏提取物及其衍生物,其特征在于,结构式如Ⅰ所示:
其中:
R6为H,-CH3,-CH2OH,-CHO或-COOH;
所述的R1和R4为氢、甲基、乙基或乙酰基;
所述的R2,R3,R5,R7为氢。
2.一种垫状卷柏提取物及其衍生物,其特征在于,所述提取物及其衍生物为
DZJB-1的结构式为:
DZJB-2:7-羟基-9,9-二(4-羟基苯)-1-((4-羟基苯)乙炔基)-9H-芴-2-醛、
DZJB-3的结构式为:
DZJB-4的结构式为:
DZJB-5:8-((4-羟基苯)乙炔基)-9,9-二(4-甲氧基苯)-9H-芴-2-醇、
DZJB-6:7-羟基-1-((4-羟基苯)乙炔基)-9,9-二(4-甲氧基苯)-9H-芴-2-醛、
DZJB-7:(7-甲氧基-9,9-二(4-甲氧基苯)-1-((4-甲氧基苯)乙炔基)-9H-芴-2-基)甲醇、
DJB-8:7-甲氧基-9,9-二(4-甲氧基苯)-1-((4-甲氧基苯)乙炔基)-9H-芴-2-醛、
DZJB-9:7-甲氧基-9,9-二(4-甲氧基苯)-1-((4-甲氧基苯)乙炔基)-2-甲基-9H-芴、
DZJB-10:7-甲氧基-9,9-二(4-甲氧基苯)-1-((4-甲氧基苯)乙炔基)-9H-芴、
DZJB-11:7-羟基-9,9-二(4-羟基苯)-1-((4-羟基苯)乙炔基)-9H-芴-2-羧酸、
DZJB-12:7-甲氧基-9,9-二(4-甲氧基苯)-1-((4-甲氧基苯)乙炔基)-9H-芴-2-羧酸、
DZJB-13:(7-乙酰氧基-2-(乙酰氧基甲基)-1-((4-乙酰氧基苯)乙炔基)-9H-芴-9,9-二取代)二(4,1-亚苯基)二乙酸酯、
DZJB-14:(7-乙酰氧基-1-((4-乙酰氧基苯)乙炔基)-2-甲酰基-9H-芴-9,9-二取代)二(4,1-亚苯基)二乙酸酯、
DZJB-15:(7-乙酰氧基-1-((4-乙酰氧基苯)乙炔基)-9H-芴-9,9-二取代)二(4,1-亚苯基)二乙酸酯、
DZJB-16:(7-乙酰氧基-1-((4-乙酰氧基苯)乙炔基)-2-甲基-9H-芴-9,9-二取代)二(4,1-亚苯基)二乙酸酯、
DZJB-17:4-((7-乙酰氧基-9,9-二(4-甲氧基苯)-9H-芴-1-基)乙炔基)乙酸苯酯、
或DZJB-18:4-((7-乙酰氧基-2-甲酰基-9,9-二(4-甲氧基苯)-9H-芴-1-基)乙炔基)乙酸苯酯。
3.一种制备权利要求1所述的垫状卷柏提取物的方法,其特征在于,
S1.将垫状卷柏全草粉粹,用95%乙醇超声提取3次,回收溶剂,得提取浸膏;
S2.将步骤S1得到的提取浸膏依次用石油醚和乙酸乙酯萃取,分别得到两个部分,随后乙酸乙酯萃取物经MCI柱层析,分别用30%、50%、70%、90%、100%甲醇-水梯度洗脱,得各种阶段的洗脱液;
S3.分别将取步骤S2所得洗脱液,通过硅胶柱层析、凝胶柱层析、ODS柱层析以及高效液相色谱分离手段,即得。
4.一种根据权利要求1所述的垫状卷柏提取物及其衍生物在制备PDE4抑制剂中的应用。
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