CN103494806B - 苯骈α-吡喃酮类化合物的应用及其制备方法 - Google Patents
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Abstract
本发明公开苯骈α‑吡喃酮类化合物(结构如下)的应用及其制备方法:将飞龙掌血(Toddalia asiatica)根粉粹,用95%乙醇提取,提取物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硅胶柱层析、凝胶柱层析、MCI柱层析、ODS柱层析以及高效液相色谱等分离手段,从该部分分离得到一系列苯骈α‑吡喃酮类单体化合物;本发明所得的化合物是4型磷酸二酯酶(PDE4)抑制剂,为研制抗炎抗哮喘药物提供先导化合物,可制备治疗哮喘或变应性鼻炎等炎性疾病的药物。
Description
技术领域
本发明涉及苯骈α-吡喃酮类化合物,在治疗4型磷酸二酯酶相关疾病的药物中的应用及其制备方法,属于中药有效成分用途领域。
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。目前苯骈α-吡喃酮类化合物多用于制备抗凝血药,本发明所述苯骈α-吡喃酮类化合物对于作为PDE4抑制剂尚无研究。
发明内容
本发明要解决的技术问题是,为了克服现有技术中苯骈α-吡喃酮类化合物应用不足,苯骈α-吡喃酮类化合物在治疗4型磷酸二酯酶相关疾病的药物中的应用。
本发明另一目的是从天然产物中寻找具有新型PDE4抑制剂,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。
本发明中涉及的苯骈α-吡喃酮类化合物首次发现可用于制备治疗和/或预防4型磷酸二酯酶相关疾病的药物。
作为一种优选的方案,本发明发现了苯骈α-吡喃酮类化合物在制备治疗和/或预防哮喘或炎症的药物中的应用。优选地,所述的炎症为哮喘。
作为一种优选的方案,本发明发现了苯骈α-吡喃酮类化合物在制备PDE4酶抑制剂上的应用。
优选地,所述的苯骈α-吡喃酮类化合物结构式如式1所示:
(I)
其中,R1,R2,R3和R4选自如下基团或片段:
-OCH3,-OH,-CH2CH=C(CH3)2,-CH2CH(OH)C(OH)(CH3)2,-CH2CH(OH)C(OCH3)=CH2,-CH2CH(OH)C(OCH3)(CH3)2,-CH=CHCO(CH3),-CH=CHC(CH3)=CH2,-CH2CH=C(CH3)2,-CH2COCH(CH3)2,-CH2CH(OH)C(OCH2CH3)(CH3)2,-CH2CH2CH(CH3)2,6,7-二甲氧基香豆素,6-二甲基-3,6二氢-2H-吡喃,2,2-二甲基四氢-2H-吡喃,2,2-二甲基-3-丙基噁丙环,(E)-1-甲基-3-(3-甲基丁-2-烯-1-亚基)喹啉-2,4(1H,3H)-二酮,2,2,6-三甲基-2H-吡喃并[3,2-c]喹啉-5(6H)-酮,4-(1-乙氧基乙基)-1,3,5,5-四甲基环己-1-烯,1-(2,4,6,6-四甲基环己-3-烯-1-基)乙醇,(E)-3-(6-羟基-2,4-二甲氧基-3-(3-甲基丁-2-烯-1-基)苯基)败脂酸,(E)-3-(6-羟基-2,4-二甲氧基-3-(3甲基-2-羰基丁基)苯基)败脂酸,(E)-3-(3-(2,3-二羟基-3甲基丁基)-6-羟基-2,4-二甲基氧苯基)败脂酸,葡萄糖,阿魏酰奎宁酸,萘喹酮,绿原酸,喹诺酮;这些取代基位置发生变化,其对应的化合物也可能有PDE4酶抑制剂活性。
优选地,所述的苯骈α-吡喃酮类化合物可以为:
FLZX-1,其中R1=-OCH3R2=-CH2CH=C(CH3)2R3=-OCH3R4=H或FLZX-2,其中R1=-OCH3R2=HR3+R4=6-二甲基-3,6二氢-2H-吡喃或FLZX-3,其中R1=-OCH3R2=H R3=-OCH3R4=-CH2CH=C(CH3)2或FLZX-11,其中R1=H R2=-OCH3R3+R4=6-二甲基-3,6二氢-2H-吡喃或FLZX-16,其中R1=H R2=-OH R3+R4=或6-二甲基-3,6二氢-2H-吡喃或FLZX-17,其中R1=-OCH3R2=-CH2CHCH(CH3)2R3=-OCH3R4=H或FLZX-18,其中R1=-OCH3R2=H R3+R4=2,2-二甲基四氢-2H-吡喃或FLZX-19,其中R1=-OCH3R2=H R3=-OCH3R4=-CH2CHCH(CH3)2或FLZX-20,其中R1=H R2=-OCH3R3+R4=2,2-二甲基四氢-2H-吡喃或FLZX-21,其中R1=OCH3R2=H R3=-OCH3R4=喹诺酮或2,2,6-三甲基-2H-吡喃并[3,2-c]喹啉-5(6H)-酮片段。这些化合物对PDE4酶10uM抑制率均大于50%。显示比较好的PDE4酶抑制剂活性。
发明同时提供了一种治疗和/或预防4型磷酸二酯酶相关疾病的药物,其特征在于含有苯骈α-吡喃酮类化合物。所述的药物还可以含有药学上可接受的辅料。述药物的剂型可以为口服型片剂、丸剂、胶囊、注射用注射液、粉剂、经皮或皮下吸收的剂型.
本发明同时还提供苯骈α-吡喃酮类化合物的制备方法。包括以下操作步骤:取飞龙掌血根,粉粹,加入乙醇浸泡,超声提取,滤过,减压回收乙醇,余液浓缩至稠膏,得飞龙掌血乙醇提取物。
所述飞龙掌血乙醇提取物依次用4倍体积量石油醚、乙酸乙酯各萃取3次,合并乙酸乙酯萃取液,减压蒸发干,得乙酸乙酯萃取物。
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)、(氯仿:甲醇)、(石油醚:乙酸乙酯)等多种洗脱体系洗脱,再反复采用凝胶柱、ODS柱纯化以及高效液相色谱分析纯化,最后得到24个单体化合物。
本发明所述的另外四个化合物是在分离单体化合物的基础上再通过合成的方法得到,四个单体化合物分别在钯碳催化下,干燥甲醇作为溶剂进行氢化反应,即得到另外四个对应的还原产物。
与现有技术相比,本发明具有以下有益效果:
本发明提供了苯骈α-吡喃酮化合物类化合物新的用途,即作为4型磷酸二酯酶抑制剂的应用。所述的苯骈α-吡喃酮化合物类化合物可用于抑PDE4酶。进而用于治疗哮喘或变应性鼻炎等炎性疾病等与PDE4相关的疾病。
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
以下结合实例进一步说明本发明,但实施例并不对本发明做任何形式的限定。以下实施例3-26所获得化合物为已知化合物,它们也可以通过商业途径购买获得,用于实现同样的功能。
实施例1:飞龙掌血提取物的制备
取飞龙掌血根1kg,粉粹成粗粉,加8倍体积量的95%乙醇浸泡,超声提取3次,每次7天,滤过,合并滤液,减压回收乙醇,余液浓缩至相对密度为1.25的稠膏,得飞龙掌血乙醇提取物85g。
实施例2:飞龙掌血萃取物的制备
飞龙掌血乙醇提取物依次用4倍体积量石油醚、乙酸乙酯各萃取3次,合并乙酸乙酯萃取液,减压蒸发干,得乙酸乙酯萃取物63g。
实施例3:苯骈α-吡喃酮类已知单体化合物的制备
(1)取飞龙掌血根1kg,粉粹成粗粉,加8倍体积量的95%乙醇浸泡,超声提取3次,每次7天,滤过,合并滤液,减压回收乙醇,余液浓缩至相对密度为1.25的稠膏,得飞龙掌血乙醇提取物85g。
(2)飞龙掌血乙醇提取物依次用4倍体积量石油醚、乙酸乙酯各萃取3次,合并乙酸乙酯萃取液,减压蒸发干,得乙酸乙酯萃取物63g。
(3)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、ODS柱纯化,最后经高效液相色谱在(乙睛∶水)和(甲醇∶水)条件下进一步纯化,即得到19个已知苯骈α-吡喃酮类单体化合物,具体分离流程参考图1。参考文献:Journal of the Pharmaceutical Society of Japan,1991年,111(7)卷,页码376-385。
实施例4:
按照实施例3的方法,最后通过凝胶(氯仿:甲醇=1:1)纯化得到FLZX-1,其结构和核磁数据如下:
1H NMR(400MHz,CDCl3)δ1.67,1.77(each3H,s),3.34(2H,d,J=7.0Hz),3.81,3.87(each3H,s),5.13(1H,t,J=7.0Hz),6.22(1H,d,J=9.6Hz),6.61(1H,s),7.86(1H,d,J=9.6Hz)
实施例5:
按照实施例3的方法,最后通过凝胶(无水乙醇)纯化得到FLZX-2,其结构和核磁数据如下:
1H NMR(400MHz,CDCl3)δ1.46(6H,s),3.88(3H,s),5.57(1H,d,J=10.0Hz),6.12(1H,d,J=9.6Hz),6.23(1H,s),6.79(1H,d,J=10.0Hz),7.95(1H,d,J=9.6Hz)
实施例6:
按照实施例3的方法,经正相硅胶柱以石油醚∶乙酸乙酯=10∶1等度洗脱后,最后通过凝胶(无水乙醇)纯化得到FLZX-3,其结构和核磁数据如下:
1H NMR(400MHz,CDCl3)δ1.66,1.82(each3H,s),3.44(2H,d,J=7.2Hz),3.91,3.92(each3H,s),5.20(1H,t,J=7.1Hz),6.13(1H,d,J=9.6Hz),6.32(1H,s),7.79(1H,d,J=9.6Hz)
实施例7:
按照实施例3的方法,最后通过正相硅胶柱以石油醚∶乙酸乙酯=1∶1等度洗脱得到FLZX-4,其结构和核磁数据如下:
1H NMR(400MHz,CDCl3)δ1.28,1.29(each3H,s),2.32,2.57(OH,s),2.74(1H,m),2.91(1H,m),3.59(1H,d,J=9.5Hz),3.87,3.89(each3H,s),6.24(1H,d,J=9.6Hz),6.64(1H,s),7.84(1H,d,J=9.6Hz)
实施例8:
按照实施例3的方法,最后用半制备HPLC以MeOH/H2O(70/30;3mL/min)等度洗脱,得到FLZX-5,其结构和核磁数据如下:
1H NMR(400MHz,MeOD)δ1.80(3H,s),2.90(1H,m),2.92(1H,m),3.88,3.90(each3H,s),4.35(1H,t,J=7.0Hz),4.68(2H,s),6.23(1H,d,J=9.6Hz),6.74(1H,s),8.02(1H,d,J=9.6Hz)
实施例9:
按照实施例3的方法,最后用半制备HPLC以MeOH/H2O(70/30;3mL/min)等度洗脱,得到FLZX-6,其结构和核磁数据如下:
1H NMR(400MHz,MeOD)δ1.23,1.25(each3H,s),2.82(1H,m),2.84(1H,m),3.29(3H,s),3.81(1H,m),3.88,3.90(each3H,s),6.24(1H,d,J=9.6Hz),6.76(1H,s),8.03(1H,d,J=9.6Hz)
实施例10:
按照实施例3的方法,最后通过正相硅胶柱以氯仿∶甲醇=60∶1梯度洗脱得到FLZX-7,其结构和核磁数据如下:
1H NMR(400MHz,CDCl3)δ2.40(3H,s),3.99,4.00(each3H,s),6.20(1H,d,J=9.6Hz),6.34(1H,s),7.25(1H,d,J=16.0Hz),7.94(1H,d,J=16.0Hz),7.99(1H,d,J=9.6Hz)
实施例11:
按照实施例3的方法,最后用半制备HPLC以MeOH/H2O(90/10;3mL/min)等度洗脱得到FLZX-8,其结构和核磁数据如下:
1H NMR(400MHz,CDCl3)δ2.01(3H,s),3.94,3.96(each3H,s),5.06,5.13(each1H,s),6.16(1H,d,J=9.6Hz),6.31(1H,s),6.80(1H,d,J=16.0Hz),7.37(1H,d,J=16.0Hz),7.97(1H,d,J=9.6Hz)
实施例12:
按照实施例3的方法,最后用半制备HPLC以MeOH/H2O(70/30;3mL/min)等度洗脱得到FLZX-9,其结构和核磁数据如下:
1H NMR(400MHz,CDCl3)δ3.91,3.91(each3H,s),3.96(3H,s),6.16(1H,d,J=9.6Hz),6.34(1H,s),7.97(1H,d,J=9.6Hz)
实施例13:
按照实施例3的方法,最后用半制备HPLC以MeOH/H2O(80/20;3mL/min)等度洗脱得到FLZX-10,其结构和核磁数据如下:
1H NMR(400MHz,CDCL3)δ1.72,1.81(each3H,s),3.82(3H,s),3.41(2H,d,J=6.8Hz),5.22(1H,t,J=6.8Hz),6.22(1H,d,J=9.6Hz),6.84(1H,s),7.90(1H,d,J=9.6Hz)
实施例14:
按照实施例3的方法,最后通过正相硅胶柱以石油醚∶氯仿=4∶1梯度洗脱得到FLZX-11,其结构和核磁数据如下:
1H NMR(400MHz,CDCl3)δ1.48(6H,s),3.84(3H,s),6.20(1H,d,J=9.6Hz),6.74(1H,s),6.82(1H,d,J=10.0Hz),7.55(1H,d,J=9.6Hz)
实施例15:
按照实施例3的方法,最后用半制备HPLC以MeOH/H2O(80/20;3mL/min)等度洗脱得到FLZX-12,其结构和核磁数据如下:
1H NMR(400MHz,CDCl3)δ1.61(3H,s),3.91,3.95(each3H,s),4.83,4.85(each1H,s),6.13(1H,d,J=9.6Hz),6.15(1H,d,J=12.0Hz),6.31(1H,s),6.39(1H,d,J=12.0Hz),7.97(1H,d,J=9.6Hz)
实施例16:
按照实施例3的方法,最后用半制备HPLC以MeOH/H2O(65/35;3mL/min)等度洗脱得到FLZX-13,其结构和核磁数据如下:
1H NMR(400MHz,CDCl3)δ1.17,1.19(each3H,s),2.78(1H,m),3.80(2H,s),3.77,3.81(each3H,s),6.24(1H,d,J=9.6Hz),6.61(1H,s),7.85(1H,d,J=9.6Hz)
实施例17:
按照实施例3的方法,最后用半制备HPLC以MeOH/H2O(65/35;3mL/min)等度洗脱得到FLZX-14,其结构和核磁数据如下:
1H NMR(400MHz,CDCl3)δ1.30,1.42(each3H,s),2.89(1H,m),2.95(1H,m),3.80(1H,m),3.87,3.90(each3H,s),6.25(1H,d,J=9.6Hz),6.65(1H,s),7.86(1H,d,J=9.6Hz)
实施例18:
按照实施例3的方法,最后通过正相硅胶柱以氯仿∶甲醇=60∶1梯度洗脱得到FLZX-15,其结构和核磁数据如下:
1H NMR(400MHz,CDCl3)δ1.15(3H,t,J=6.9Hz),1.22(6H,s),2.78(1H,m),2.79(1H,m),3.46(2H,q,J=6.9Hz),3.70(1H,m),3.86,3.87(each3H,s),6.20(1H,d,J=9.6Hz),6.60(1H,s),7.84(1H,d,J=9.6)
实施例19:
按照实施例3的方法,最后通过凝胶(氯仿∶甲醇=1:1)纯化得到FLZX-16,其结构和核磁数据如下:
1H NMR(400MHz,CDCL3)δ1.51(6H,s),3.49(1H,s),5.74(1H,d,J=10Hz),6.26(1H,d,J=9.6Hz),6.86(1H,s),6.88(1H,d,J=10Hz),7.56(1H,d,J=9.6Hz)
实施例20:
按照实施例4的方法,得到FLZX-1单体化合物,化合物在钯碳催化下,干燥甲醇作为溶剂进行氢化反应,即得到对应的还原产物FLZX-17,其结构和核磁数据如下:
1H NMR(400MHz,CDCl3)δ0.94,0.96(each3H,s),1.38(2H,m),1.60(1H,m),2.62(2H,m),3.91,3.92(each3H,s),6.22(1H,d,J=9.6Hz),6.60(1H,s),7.86(1H,d,J=9.6Hz)
实施例21:
按照实施例5的方法,得到FLZX-2单体化合物,化合物在钯碳催化下,干燥甲醇作为溶剂进行氢化反应,即得到对应的还原产物FLZX-18,其结构和核磁数据如下:
1H NMR(400MHz,CDCl3)δ1.34(3H,s),1.82(2H,t,J=6.7Hz),2.80(2H,t,J=6.7Hz),3.84(3H,s),6.11(1H,d,J=9.6Hz),6.19(1H,s),7.97(1H,d,J=9.6Hz)
实施例22:
按照实施例6的方法,得到FLZX-3单体化合物,化合物在钯碳催化下,干燥甲醇作为溶剂进行氢化反应,即得到对应的还原产物FLZX-19,其结构和核磁数据如下:
1H NMR(400MHz,CDCl3)δ0.94,0.96(each3H,s),1.38(2H,m),1.59(1H,m),3.91,3.95(each3H,s),2.74(2H,m),6.14(1H,d,J=9.6Hz),6.31(1H,s),7.99(1H,d,J=9.6Hz)
实施例23:
按照实施例14的方法,得到FLZX-11单体化合物,化合物在钯碳催化下,干燥甲醇作为溶剂进行氢化反应,即得到对应的还原产物FLZX-20,其结构和核磁数据如下:
1H NMR(400MHz,CDCl3)δ1.42(6H,s),1.87(2H,m),2.93(2H,m),3.88(3H,s),6.24(1H,d,J=9.6Hz),6.72(1H,s),7.59(1H,d,J=9.6Hz)
实施例24:
按照实施例3的方法,然后通过正相硅胶柱以石油醚∶丙酮=6∶1梯度洗脱,最后经凝胶柱(氯仿∶甲醇=1∶1)进一步纯化得到FLZX-21,其结构和核磁数据如下:
1H NMR(400MHz,CDCl3)δ1.61(3H,s),1.64(3H,s),1.84(3H,s),2.09(1H,dd,J=13.7,4.9Hz),2.18(1H,dd,J=13.7,6.6Hz),3.66(3H,s),3.78(1H,m),3.82(3H,s),3.91(3H,s),5.11(1H,d,J=8.5Hz),6.12(1H,d,J=9.6Hz),6.26(1H,s),6.93(1H,s),6.93(1H,s),6.93(1H,s),7.29(1H,m),7.30(1H,m),7.54(1H,t,J=7.7Hz),7.95(1H,d,J=9.6Hz),8.22(1H,d,J=7.8Hz);13CNMR(CDCl3,100MHz)δ40.35(C-13),26.87(C-12),78.77(C-11),137.48(C-10),115.71(C-9),153.75(C-8a),106.35(C-8),161.29(C-7),90.37(C-6),155.93(C-5),103.84(C-4a),138.73(C-4),11.07(C-3),160.96(C-2),18.05(C-13′),25.98(C-12′),131.19(C--11′),127.77(C-10′),29.52(C-9′),138.91(C--8′a),113.69(C-8′),130.23(C-7′),121.60(C-6′),123.38(C-5′),116.76(C-4′a),155.41(C-4′),109.91(C-3′),162.98(C-2′),29.29(N-CH3),56.01(5-OCH3),56.11(7-OCH3);ESIMS m/z514[M+H]+.
实施例25:
按照实施例3的方法,最后用半制备HPLC以CH3CN/H2O(90/10;3mL/min)等度洗脱得到FLZX-22,其结构和核磁数据如下:
1H NMR(400MHz,CDCl3)δ1.13,1.15(each3H,s),1.57(1H,m),1.58(3H,s),2.26(1H,d,J=16.1Hz),2.90(1H,d,J=10.9Hz),3.13(1H,t,J=9.2Hz),3.53(1H,d,J=10.0Hz),3.75,3.78,3.92,4.02(each3H,s),4.76(1H,s),5.34(1H,t,J=8.5Hz),5.73,5.87(each1H,d,J=9.6Hz),6.05,6.06(each1H,s),7.55,7.69(each1H,d,J=9.6Hz).
实施例26:
按照实施例3的方法,最后通过正相硅胶柱以氯仿∶甲醇=60∶1梯度洗脱得到FLZX-23,其结构和核磁数据如下:
1H NMR(400MHz,CDCl3)δ2.49(3H,s),3.77,3.80,3.99(each3H,s),6.10(1H,s),6.10(1H,d,J=9.5Hz),6.10(1H,s),6.41(1H,s),7.29(1H,s),8.03(1H,d,J=9.7Hz).
实施例27:五个苯骈α-吡喃酮类新单体化合物的制备
(1)取飞龙掌血根1kg,粉粹成粗粉,加8倍体积量的95%乙醇浸泡,超声提取3次,每次7天,滤过,合并滤液,减压回收乙醇,余液浓缩至相对密度为1.25的稠膏,得飞龙掌血乙醇提取物85g。
(2)飞龙掌血乙醇提取物依次用4倍体积量石油醚、乙酸乙酯各萃取3次,合并乙酸乙酯萃取液,减压蒸发干,得乙酸乙酯萃取物63g。
(3)乙酸乙酯萃取物应用MCI柱初步分段,以甲醇∶水=3∶7~10∶0洗脱得到四个组分(I-III);组分I(20.5g)通过ODS柱以甲醇∶水=5∶5~10∶0洗脱得到四个组分(Ia–Id);组分Ic(4.1g)采用200–300目柱色谱硅胶以氯仿:甲醇=40:1梯度洗脱,再采用凝胶柱纯化得到FLZX-24(52mg);组分Id(2.2g)采用200–300目柱色谱硅胶以氯仿∶甲醇=60:1梯度洗脱,然后用半制备HPLC以MeOH/H2O(45/55;3mL/min)等度洗脱,最后得到FLZX-25(83mg)。组分II(16.5g)采用硅胶柱以石油醚∶乙酸乙酯=10:1开始梯度洗脱得到四部分(IIa-IId);IIb再次采用硅胶柱以石油醚∶乙酸乙酯=12:1开始梯度洗脱得到四部分(IIb1-IIb4),IIb1通过ODS柱以甲醇∶水=5∶2~10∶0洗脱得到FLZX-26(56mg),IIb2通过ODS柱以甲醇∶水=5∶2~10∶0洗脱,再次硅胶柱以石油醚∶丙酮=6:1梯度洗脱得到FLZX-27(5mg);IIb3再次采用硅胶柱以二氯甲烷∶甲醇=60:1开始梯度洗脱得到FLZX-28(20mg)。
实施例28:五个苯骈α-吡喃酮类新单体化合物的核磁数据及质谱数据
本发明中五个苯骈α-吡喃酮类新单体化合物采用ESIMS,HRMS,1HNMR,13CNMR,HMBC,HMBC等现代波谱技术进行结构鉴定,并结合查阅文献,确定化合物结构。
五个苯骈α-吡喃酮类新单体化合物质谱数据:
FLZX-24:ESIMS m/z657.2[M-H]-,HRESIMS m/z681.2102[M+Na]+;(calcd forC33H38O14Na,681.2127).
FLZX-25:ESIMS m/z643.2[M-H]-,HRESIMS m/z639.2432[M+Na]+;(calcd forC32H36O14Na,639.2412).
FLZX-26:ESIMS m/z581.3[M-H]-,HRESIMS m/z605.2341[M+Na]+;(calcd forC32H38O10Na,605.2357).
FLZX-27:ESIMS m/z597.2[M-H]-,HRESIMS m/z621.2303[M+Na]+;(calcd forC32H38O11Na,621.2306).
FLZX-28:ESIMS m/z:613.2[M+Na]+,HRESIMS m/z613.2433[M+Na]+;(calcd forC32H38O11Na,613.2408).
实施例28:苯骈α-吡喃酮类单体化合物对PDE4酶的抑制作用
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&Medicinal ChemistryLetters,2012年,22卷,页码:3261–3264),20mM Tris-HCl,pH7.5,2mM二硫苏糖醇(dithiothreitol),10mM MgCl2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。
本发明化合物对PDE4酶的抑制活性测试数据如表6(同等条件下,阳性对照物rolipram对PDE4酶的抑制活性IC50为570nM,IC50值为抑制率达到50%时的抑制剂浓度)。
Claims (1)
1.苯骈α-吡喃酮类化合物在制备PDE4抑制剂中的应用,其特征在于,所述苯骈α-吡喃酮类化合物的结构如式(Ⅰ)所示:
。
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