CN110368383A - 二氢青蒿素衍生物在制备降血脂药物中的应用 - Google Patents
二氢青蒿素衍生物在制备降血脂药物中的应用 Download PDFInfo
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- 229960002521 artenimol Drugs 0.000 title claims abstract description 16
- 239000008280 blood Substances 0.000 title claims abstract description 13
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- -1 amino, hydroxyl Chemical group 0.000 claims description 25
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- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 6
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- ZPOLNCDBPYJDSE-UHFFFAOYSA-N 3-[4-[bis(2-chloroethyl)amino]phenyl]-2-formamidopropanoic acid Chemical compound O=CNC(C(=O)O)CC1=CC=C(N(CCCl)CCCl)C=C1 ZPOLNCDBPYJDSE-UHFFFAOYSA-N 0.000 description 1
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 1
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- YZTJYBJCZXZGCT-UHFFFAOYSA-N phenylpiperazine Chemical compound C1CNCCN1C1=CC=CC=C1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract
本发明公开了式I所示的二氢青蒿素衍生物在制备降血脂药物中的应用，拓宽了二氢青蒿素衍生物的制药用途。
Description
技术领域
本发明属于化合物的医药用途技术领域，涉及一类二氢青蒿素衍生物在制备降血脂药物中的应用。
背景技术
青蒿素及其衍生物具有高效、快速和低毒的抗疟活性，在全世界范围内得到广泛应用。近年来研究表明，青蒿素及其衍生物还具有抗炎、抗细菌脓毒症、抗组织纤维化和降血脂等多种生物活性。目前对青蒿素的研究主要集中在提高活性、拓宽药效、增加稳定性和溶解性等方面。
发明人所在课题组在过去的研究中，将一些活性小分子或药物引入到二氢青蒿素结构中，设计了多种结构类型的二氢青蒿素衍生物，通过条件的探索，简易、高收率地实现了这些目标化合物的合成，并发现其中部分化合物虽然本身不具备抗菌作用，但其可以作为β-内酰胺类抗生素的抗菌增效剂。
前蛋白转化酶枯草杆菌蛋白酶9(PCSK9)是由肝脏合成的蛋白酶，该酶经分子内自身催化切开后分泌入血，与肝细胞表面低密度脂蛋白受体(LDL-R)结合，促进LDL-R降解,致使低密度脂蛋白胆固醇(LDL-C)水平升高。PCSK9抑制剂被认为是继他汀类药物后的新一代降脂药物,其中获益最大的是在强化降脂治疗后LDL-C仍无法达标的高风险冠心病患者和无法耐受大剂量他汀类药物治疗的高胆固醇血症患者。
发明内容
本发明的目的在于考察二氢青蒿素衍生物在降血脂方面的活性，以拓宽二氢青蒿素衍生物的制药用途。
经研究，本发明提供如下技术方案：
式I所示的二氢青蒿素衍生物或其消旋体、立体异构体、互变异构体、氮氧化物、药学上可接受的盐在制备降血脂药物中的应用：
式I中，n为1或2；
Y为-NR1R2、
R1和R2独立地为H、C1-C3烷基或C1-C3羟烷基；
R3为H、C1-C3烷基、C1-C3羟烷基、取代或未取代苯基、叔丁氧羰基、苄氧羰基或脂肪酰基；所述苯基上的取代基为一个或多个，独立选自卤素、羟基、氨基或C1-C3烷基；
R4和R5独立地为H或C1-C3烷基；
R6和R7独立地为H、氨基、羟基或C1-C3烷基；
R8为H、C1-C3烷基、C1-C3烷硫基、取代或未取代苯基；所述苯基上的取代基为一个或多个，独立选自卤素、羟基、氨基或C1-C3烷基。
进一步，式I中，
R1和R2独立地为H、C1-C2烷基或C1-C2羟烷基；
R3为H、C1-C2烷基、C1-C2羟烷基、取代或未取代苯基、叔丁氧羰基、苄氧羰基或烷酰基；
所述苯基上的取代基为一个或多个，独立选自卤素、羟基、氨基或C1-C2烷基；
R4和R5独立地为H或C1-C2烷基；
R6和R7独立地为H、氨基、羟基或C1-C2烷基；
R8为H、C1-C2烷基、C1-C2烷硫基、取代或未取代苯基；所述苯基上的取代基为一个或多个，独立选自卤素、羟基、氨基或C1-C2烷基。
进一步，式I中，
R1和R2独立地为H、C1-C2烷基或C1-C2羟烷基；
R3为H、C1-C2烷基、C1-C2羟烷基、苯基、叔丁氧羰基、苄氧羰基或乙酰基；
R4和R5独立地为H或C1-C2烷基；
R6和R7独立地为H、氨基、羟基或C1-C2烷基；
R8为H、C1-C2烷基、C1-C2烷硫基或苯基。
进一步，式I中，
R1和R2独立地为H、甲基、乙基或羟乙基；
R3为H、甲基、羟乙基、苯基或叔丁氧羰基；
R4和R5独立地为H或甲基；
R6和R7独立地为H或氨基；
R8为H、甲基、甲硫基或苯基。
进一步，式I所示的二氢青蒿素衍生物为以下化合物中的任一种：
进一步，式I所示的二氢青蒿素衍生物为以下化合物中的任一种：2a-5,2b-2,2b-3,2b-4,3a-1,3a-2,3b-5,3b-6,4b-5～4b-8,5a-1,5a-6,5b-6。
进一步，所述降血脂药物为PCSK9抑制剂。
除另有说明外，本发明中的术语“消旋体”是指由等量对映体构成的光学不活性的有机物。“立体异构体”是指原子组成及键接相同而原子在三维空间排列上不同的分子。“互变异构体”是指因分子中某一原子在两个位置迅速移动而产生的官能团异构体。“氮氧化物”是指三级氮连接氧原子形成+N-O-结构单元的有机物。“药学上可接受的盐”可以是酸性盐，也可以是碱性盐，例如无机酸盐、有机酸盐、无机碱盐或有机碱盐。
本发明的有益效果在于：本发明公开了式I所示的二氢青蒿素衍生物在制备降血脂药物中的应用，拓宽了二氢青蒿素衍生物的制药用途。
具体实施方式
为了使本发明的目的、技术方案和有益效果更加清楚，下面将对本发明的优选实施例进行详细的描述。
为了使本发明的目的、技术方案和有益效果更加清楚，下面将对本发明的优选实施例进行详细的描述。
优选实施例中使用的主要试剂及规格:二甲胺、二乙胺、乙醇胺、氮甲基乙醇胺、二乙醇胺、吡咯烷、哌啶、吗啉、乙腈、二氯甲烷(重庆化学试剂总厂,AR)；无水哌嗪、N-甲基哌嗪、N-羟乙基哌嗪、N-Boc-哌嗪、N-苯基哌嗪、3-溴-1-丙醇、咪唑、2-甲基咪唑、4-甲基咪唑、吡唑、3,5-二甲基吡唑、苯并咪唑、1,2,3-三氮唑、1,2,4-三氮唑、苯并三氮唑、3-氨基-1,2,4-三氮唑、3-氨基-5-巯基-1,2,4-三氮唑、1-H-四氮唑、5-甲基四氮唑、5-苯基四氮唑、5-甲巯基四氮唑(上海达瑞精细化工有限公司,＞98％)；1-羟基-苯并三氮唑(上海共价化学科技公司,工业级)；二氢青蒿素(重庆华立武陵山制药有限公司,AR)；溴乙醇(上海达瑞精细化工有限公司,AR)；46.5％BF3.Et2O(上海晶纯试剂有限公司,AR)；其余试剂均为市售化学纯或分析纯产品,未经纯化直接使用。
优选实施例中使用的主要仪器及型号:精密显微熔点测定仪(X-6,北京福凯仪器有限公司)；数字式自动旋光仪(WZZ-2S,上海精密科学仪器有限公司)；超导核磁共振波谱仪(AV-300,Bruker,瑞士)；高分辨质谱仪(HR ESI MS)(Varian7.0T,Varian,USA)。
实施例1、DHA胺类衍生物的合成
1、DHA脂肪胺类衍生物1的合成
DHA脂肪胺类衍生物1a-1h按照文献(Chong Wu,et al.Design,Synthesis andEvaluation of the Antibacterial Enhancement Activities of AminoDihydroartemisinin Derivatives.Molecules,2013,18,6866-6882)中所述化合物4a-4u的制备方法进行制备。
2、DHA哌嗪类衍生物2的合成
1)中间体M1的合成
中间体M1按照中国专利104418864B(双氢青蒿素与喹诺酮类化合物的偶联物及其制备方法和应用)中所述中间体IM1和IM2的制备方法进行制备。
2)DHA哌嗪类衍生物2a-1～2a-5及2b-1～2b-5的合成
在100mL圆底烧瓶中依次加入M1、CH3CN、K2CO3及哌嗪或取代哌嗪,控温搅拌反应,TLC监测反应进程。反应结束后,加入CH2Cl2 15mL和饱和NaCl水溶液20mL,静置分层,水层用CH2Cl2(10mL×2)萃取,合并有机相,饱和食盐水20mL洗涤,无水Na2SO4干燥,减压旋蒸除去CH2Cl2得粗品或纯品,必要时柱层析,干燥,即得目标化合物2。具体合成条件及结果见表1。
表1目标化合物2的合成条件及结果
目标化合物2表征数据如下:
2a-1:1H NMR(300MHz,CDCl3)δ:0.90(3H,d,J＝7.5Hz,H-13),0.95(3H,d,J＝6.6Hz,H-14),1.43(3H,s,H-15),1.22-2.06(10H,m,H-2,H-3,H-7～H-10),2.37-2.60(12H,m,H-1,H-11,H-17～H-19),3.52-3.59(1H,m,H-16),3.91-3.98(1H,m,H-16),4.80(1H,s,H-12),5.45(1H,s,H-5).
2a-2:1H NMR(300MHz,CDCl3)δ:0.90(3H,d,J＝7.5Hz,H-13),0.96(3H,d,J＝6.6Hz,H-14),1.43(3H,s,H-15),1.46(9H,s,H-22),1.22-2.06(10H,m,H-2,H-3,H-7～H-10),2.30(3H,s,H-20),2.37-2.60(12H,m,H-1,H-11,H-17～H-19),3.52-3.59(1H,m,H-16),3.91-3.98(1H,m,H-16),4.80(1H,s,H-12),5.45(1H,s,H-5).
2a-3:黄色油状物； 1H NMR(300MHz,CDCl3)δ:0.89(3H,d,J＝7.3Hz,H-13),0.95(3H,d,J＝6.0Hz,H-14),1.42(3H,s,H-15),1.15-2.06(10H,m,H-2,H-3,H-7～H-10),2.28-2.59(14H,m,H-1,H-11,H-17～H-20),3.36-4.43(1H,m,H-16),3.62(2H,t,J＝5.3Hz,H-21),3.84-3.91(1H,m,H-16),4.77(1H,d,J＝3.3Hz,H-12),5.30(1H,s,H-22),5.38(1H,s,H-5)；13C NMR(75MHz,CDCl3)δ:103.98(C-4),101.90(C-12),87.84(C-5),81.07(C-6),68.54(C-16),59.36(C-22),57.72(C-20),55.52(C-17),53.26(C-19),52.45(C-1),46.76(C-18),44.31(C-7),37.39(C-11),36.32(C-10),34.57(C-3),30.76(C-9),26.12(C-8),24.63(C-15),24.30(C-2),20.29(C-14),13.01(C-13).HRMS:C23H40N2O6[M+H]+计算值441.2959,测定值441.2954.
2a-4:m.p.:107.8-109.1℃； 1H NMR(300MHz,CDCl3)δ:0.90(3H,d,J＝7.2Hz,H-13),0.96(3H,d,J＝6.0Hz,H-14),1.43(3H,s,H-15),1.46(9H,s,H-22),1.22-2.06(10H,m,H-2,H-3,H-7～H-10),2.32-2.65(8H,m,H-1,H-11,H-17and H-18),3.40-3.44(4H,m,H-19),3.52-3.58(1H,m,H-16),3.92-4.00(1H,m,H-16),4.80(1H,s,H-12),5.46(1H,s,H-5)；13C NMR(75MHz,CDCl3)δ:154.6(C-21),104.0(C-4),101.9(C-12),87.8(C-5),81.0(C-6),79.7(C-22),66.0(C-16),57.9(C-17),53.5(C-19),52.0(C-1),49.2(C-18),44.4(C-7),37.4(C-11),36.4(C-10),34.6(C-3),30.8(C-9),28.4(C-23),26.4(C-17),26.1(C-8),24.6(C-15),24.4(C-2),20.4(C-14),13.0(C-13).HR MS:C27H40N2O5[M+H]+计算值497.3221,测定值497.3222.
2a-5:m.p.:90.0-91.7℃； 1H NMR(300MHz,CDCl3)δ:0.90(3H,d,J＝7.2Hz,H-13),0.95(3H,d,J＝6.0Hz,H-14),1.44(3H,s,H-15),1.23-2.06(10H,m,H-2,H-3,H-7～H-10),2.32-2.42(1H,m,H-1),2.59-2.70(7H,m,H-11,H-17and H-18),3.21(4H,t,J＝7.5Hz,H-19),3.58-3.65(1H,m,H-16),3.98-4.05(1H,m,H-16),4.83(1H,d,J＝2.7Hz,H-12),5.48(1H,s,H-5),6.89(1H,t,J＝7.2Hz,H-23),6.94(2H,d,J＝7.8Hz,H-21),7.25-7.30(2H,m,H-22)；13C NMR(75MHz,CDCl3)δ:151.3(C-20),129.1(C-22),120.0(C-23),116.0(C-21),104.0(C-4),102.0(C-12),87.9(C-5),81.1(C-6),66.0(C-16),57.9(C-17),53.5(C-19),52.6(C-1),49.2(C-18),44.4(C-7),37.5(C-11),36.4(C-10),34.7(C-3),30.9(C-9),26.2(C-8),24.7(C-15),24.4(C-2),20.3(C-14),13.1(C-13).HR MS:C27H40N2O5(M+H)+计算值473.3010,测定值473.3014.
2b-1:黄色油状物； 1H NMR(300MHz,CDCl3)δ:0.89(3H,d,J＝7.2Hz,H-13),0.96(3H,d,J＝6.0Hz,H-14),1.44(3H,s,H-15),1.26-2.06(12H,m,H-2,H-3,H-7～H-10and H-17),2.37-2.62(12H,m,H-1,H-11,H-18～H-20),3.37-3.44(1H,m,H-16),3.84-3.92(1H,m,H-16),4.77(1H,s,H-12),5.39(1H,s,H-5).
2b-2:黄色油状物； 1H NMR(300MHz,CDCl3)δ:0.89(3H,d,J＝7.2Hz,H-13),0.96(3H,d,J＝6.0Hz,H-14),1.44(3H,s,H-15),1.26-2.06(12H,m,H-2,H-3,H-7～H-10and H-17),2.30(3H,s,H-20),2.37-2.62(12H,m,H-1,H-11,H-18～H-20),3.37-3.44(1H,m,H-16),3.84-3.92(1H,m,H-16),4.77(1H,s,H-12),5.39(1H,s,H-5)；13C NMR(75MHz,CDCl3)δ:104.1(C-4),101.9(C-12),87.8(C-5),81.0(C-6),66.5(C-16),55.5(C-18),55.0(C-19),53.1(C-20),52.5(C-21),46.0(C-1),44.4(C-7),37.1(C-11),36.4(C-10),34.6(C-3),30.9(C-9),27.0(C-17),26.2(C-8),24.6(C-15),24.4(C-2),20.3(C-14),13.0(C-13).HR MS:C23H40N2O5[M+H]+计算值425.3010,测定值425.3010.
2b-3:黄色油状物； 1H NMR(300MHz,CDCl3)δ:0.89(3H,d,J＝7.3Hz,H-13),0.95(3H,d,J＝6.0Hz,H-14),1.42(3H,s,H-15),1.15-2.06(12H,m,H-2,H-3,H-7～H-10and H-17),2.28-2.59(14H,m,H-1,H-11,H-17～H-20),3.36-3.43(1H,m,H-16),3.62(2H,t,J＝5.3Hz,H-21),3.84-3.91(1H,m,H-16),4.77(1H,d,J＝3.3Hz,H-12),5.30(1H,s,H-23),5.38(1H,s,H-5)；13C NMR(75MHz,CDCl3)δ:104.00(C-4),101.90(C-12),87.81(C-5),81.04(C-6),66.43(C-16),59.31(C-22),57.68(C-20),55.42(C-17),53.06(C-19),52.76(C-18),52.49(C-1),44.35(C-7),37.42(C-11),36.35(C-10),34.56(C-3),30.84(C-9),26.97(C-17),26.12(C-8),24.61(C-15),24.40(C-2),20.30(C-14),12.97(C-13).HR MS:C24H42N2O6[M+H]+计算值455.3116,测定值455.3115.
2b-4:黄色油状物； 1H NMR(300MHz,CDCl3)δ:0.90(3H,d,J＝7.5Hz,H-13),0.96(3H,d,J＝6.0Hz,H-14),1.43(3H,s,H-15),1.47(9H,s,H-23),1.26-2.06(12H,m,H-2,H-3,H-7～H-10and H-17),2.32-2.43(1H,m,H-1),2.61-2.64(1H,m,H-11),3.40-3.46(11H,m,H-16,H-18～H-20),3.92-4.00(1H,m,H-16),4.19(2H,t,J＝6.3Hz,H-14),4.76(1H,s,H-12),5.37(1H,s,H-5)；13C NMR(75MHz,CDCl3)δ:154.6(C-21),104.0(C-4),101.9(C-12),87.8(C-5),81.0(C-6),79.7(C-22),66.5(C-16),55.3(C-18),52.6(C-20),52.5(C-19),52.0(C-1),44.4(C-7),37.4(C-11),36.4(C-10),34.6(C-3),30.8(C-9),28.4(C-23),26.4(C-17),26.1(C-8),24.6(C-15),24.4(C-2),20.4(C-14),13.0(C-13).HR MS:C27H46N2O7[M+H]+计算值511.3378,测定值511.3370.
2b-5:1H NMR(300MHz,CDCl3)δ:0.92(3H,d,J＝7.5Hz,H-13),0.96(3H,d,J＝5.7Hz,H-14),1.44(3H,s,H-15),1.23-2.06(12H,m,H-2,H-3,H-7～H-10and H-17),2.32-2.42(1H,m,H-1),2.49-2.65(7H,m,H-11,H-18and H-19),3.22-3.25(4H,m,H-20),3.40-3.48(1H,m,H-16),3.88-3.96(1H,m,H-16),4.80(1H,d,J＝2.4Hz,H-12),5.41(1H,s,H-5),6.87(1H,t,J＝7.2Hz,H-23),6.94(2H,d,J＝7.8Hz,H-21),7.25-7.30(2H,m,H-22)；13C NMR(75MHz,CDCl3)δ:151.2(C-21),129.1(C-23),119.7(C-24),116.0(C-22),104.0(C-4),102.0(C-12),87.9(C-5),81.1(C-6),66.5(C-16),55.6(C-18),53.2(C-20),52.6(C-1),49.1(C-19),44.4(C-7),37.5(C-11),36.4(C-10),34.6(C-3),30.9(C-9),28.4(C-17),26.2(C-8),24.7(C-15),24.5(C-2),20.4(C-14),13.0(C-13).HR MS:C28H42N2O5[M+H]+计算值487.3167,测定值487.3162.
实施例2、DHA唑类衍生物的合成
在100mL圆底烧瓶中依次加入唑类化合物YH、N,N-二甲基甲酰胺(DMF)和碱(NaH或K2CO3),搅拌15min后,加入M1,控温搅拌反应,TLC监测反应进程。反应完成后,加入乙酸乙酯(EtOAc)15mL和饱和NaCl水溶液20mL,静置分层,水层用EtOAc(10mL×2)萃取,合并有机相,饱和食盐水20mL洗涤,无水Na2SO4干燥,减压旋蒸除去EtOAc得粗品或纯品,必要时柱层析,干燥,即得目标化合物3,4,5。具体合成条件及结果见表2,3,4。
表2目标化合物3的合成条件及结果
表3目标化合物4的合成条件及结果
表4目标化合物5的合成条件及结果
目标化合物3-5的表征数据如下：
3a-1:m.p.:93.7-95.1℃； 1H NMR(300MHz,CDCl3)δ:0.80(3H,d,J＝7.4Hz,H-14),0.93(3H,d,J＝5.5Hz,H-13),1.42(3H,s,H-15),1.17-2.08(10H,m,H-2,H-3,H-7～H-10),2.34(1H,td,J＝14.0,3.9Hz,H-1),2.51-2.65(1H,m,H-11),3.68-3.81(1H,m,H-16),4.19-4.41(3H,m,H-16and H-17),4.75(1H,d,J＝3.4Hz,H-12),5.13(1H,s,H-5),6.23(s,1H,H-19),7.42(1H,s,H-20),7.51(1H,s,H-20)；13CNMR(75MHz,CDCl3)δ:139.29(C-20),129.67(C-19),105.16(C-18),103.98(C-4),101.87(C-12),87.70(C-5),80.89(C-6),66.66(C-16),52.37(C-1),51.99(C-17),44.10(C-7),37.11(C-11),36.29(C-10),34.46(C-3),30.62(C-9),26.08(C-8),24.57(C-15),24.14(C-2),20.29(C-14),12.81(C-13).HR MS:C20H30N2O5(M+Na)+计算值401.2047,测定值401.2050.
3a-2:黄色油状物； 1H NMR(300MHz,CDCl3)δ:0.85(3H,d,J＝7.2Hz,H-14),0.94(3H,d,J＝6.1Hz,H-13),1.44(3H,s,H-15),1.22-2.07(10H,m,H-2,H-3,H-7～H-10),2.32-2.38(1H,m,H-1),2.61-2.63(1H,m,H-11),3.62-3.68(1H,m,H-16),4.15-4.21(3H,m,H-16and H-17),4.76(1H,s,H-12),5.11(1H,s,H-5),7.00(1H,s,H-19),7.09(1H,s,H-18),7.62(1H,s,H-20)；13C NMR(75MHz,CDCl3)δ:128.7(C-20),123.1(C-19),118.9(C-18),104.1(C-4),102.0(C-12),87.8(C-5),80.8(C-6),67.0(C-16),52.3(C-1),47.2(C-17),44.0(C-7),37.2(C-11),36.3(C-10),34.4(C-3),30.6(C-9),26.1(C-8),24.6(C-15),24.3(C-2),20.3(C-14),13.0(C-13).HR MS:C20H30N2O5(M+H)+计算值379.2228,测定值379.2221.
3a-3:黄色油状物； 1H NMR(300MHz,CDCl3)δ:0.91(3H,d,J＝6.9Hz,H-14),0.95(3H,d,J＝6.3Hz,H-13),1.45(3H,s,H-15),1.19-2.06(10H,m,H-2,H-3,H-7～H-10),2.12(3H,s,H-21),2.32-2.43(1H,m,H-1),2.59-2.66(1H,m,H-11),3.40-3.52(4H,m,H-16and H-17),4.69(1H,d,J＝2.7Hz,H-12),5.39(1H,s,H-5)；13CNMR(75MHz,CDCl3)δ:127.8(C-18),127.2(C-20),118.8(C-19),104.2(C-4),102.0(C-12),87.8(C-5),80.9(C-6),66.9(C-16),52.4(C-1),47.8(C-17),44.0(C-7),37.2(C-11),36.3(C-10),34.4(C-3),30.6(C-9),26.1(C-8),24.6(C-15),24.2(C-2),20.3(C-14),13.0(C-13),12.7(C-21).HR MS:C21H32N2O5(M+H)+计算值393.2384,测定值393.2382.
3a-4:黄色油状物； 1H NMR(300MHz,CDCl3)δ:0.85(3H,d,J＝7.2Hz,H-14),0.94(3H,d,J＝4.8Hz,H-13),1.43(3H,s,H-15),1.22-2.07(10H,m,H-2,H-3,H-7～H-10),2.29-2.34(1H,m,H-1),2.41(3H,s,H-21),2.61-2.63(1H,m,H-11),3.58-3.63(1H,m,H-16),3.99-4.16(3H,m,H-16and H-17),4.76(1H,d,J＝3.3Hz,H-12),5.08(1H,s,H-5).6.88(1H,s,H-19),6.92(1H,s,H-18)；13C NMR(75MHz,CDCl3)δ:126.7(C-20and C-19),118.9(C-18),104.2(C-4),102.0(C-12),87.8(C-5),80.9(C-6),66.8(C-16),52.4(C-1),45.8(C-17),44.0(C-7),37.2(C-11),36.3(C-10),34.4(C-3),30.6(C-9),26.1(C-8),24.6(C-15),24.2(C-2),20.3(C-14),13.0(C-13),12.9(C-21).HR MS:C21H32N2O5(M+H)+计算值393.2384,测定值393.2386.
3a-5:黄色油状物； 1H NMR(300MHz,CDCl3)δ:0.81(3H,d,J＝7.2Hz,H-14),0.87(3H,d,J＝6.3Hz,H-13),1.42(3H,s,H-15),1.26-2.08(10H,m,H-2,H-3,H-7～H-10),2.29-2.37(1H,m,H-1),2.21(3H,s,H-21),2.28(3H,s,H-22),2.51-2.59(1H,m,H-11),3.64-3.69(1H,m,H-16),4.12-4.28(3H,m,H-16and H-17),4.75(1H,d,J＝2.7Hz,H-12),5.07(1H,s,H-5).5.86(1H,s,H-19)；13C NMR(75MHz,CDCl3)δ:147.4(C-20),139.4(C-19),104.6(C-4),103.9(C-19),101.7(C-12),87.6(C-5),80.9(C-6),66.4(C-16),52.3(C-1),47.9(C-17),44.2(C-7),37.0(C-11),36.3(C-10),34.6(C-3),30.7(C-9),26.1(C-8),24.5(C-15),24.0(C-2),20.2(C-14),13.0(C-13),12.8(C-21),11.1(C-22)；HR MS:C22H34N2O5(M+Na)+计算值429.2360,测定值429.2356.
3a-6:黄色油状物； 1H NMR(300MHz,CDCl3)δ:0.76(3H,d,J＝7.5Hz,H-14),0.83(3H,d,J＝6.0Hz,H-13),1.39(3H,s,H-15),1.15-1.99(10H,m,H-2,H-3,H-7～H-10),2.24-2.35(H,m,H-1),2.52-2.59(H,m,H-11),3.70-3.76(1H,m,H-16),4.28-4.43(3H,m,H-16and H-17),4.73(1H,d,J＝2.7Hz,H-12),4.91(1H,s,H-5),7.30(2H,t,J＝2.4Hz,H-21and H-22),7.42(1H,d,J＝7.5Hz,H-23),7.80(1H,d,J＝7.5Hz,H-20),7.95(1H,s,H-18).
3b-1:m.p.:109.3-110.2℃； 1H NMR(300MHz,CDCl3)δ:0.94(3H,d,J＝6.9Hz,H-14),0.96(3H,d,J＝5.6Hz,H-13),1.44(3H,s,H-15),1.17-2.22(12H,m,H-2,H-3,H-7～H-10and H-17),2.37(1H,m,H-1),2.59-2.72(1H,m,H-11),3.28-3.36(1H,m,H-16),3.82-3.89(1H,m,H-16),4.23(2H,t,J＝7.0Hz,H-18),4.78(1H,d,J＝3.3Hz,H-12),5.40(1H,s,H-5),6.25(1H,s,H-20),7.37(1H,s,H-19),7.52(1H,s,H-21)；13C NMR(75MHz,CDCl3)δ:139.31(C-21),129.09(C-20),105.25(C-19),104.06(C-4),102.01(C-12),87.84(C-5),81.00(C-6),64.96(C-16),52.47(C-1),49.00,44.29(C-7),37.38(C-11),36.33(C-10),34.54(C-3),30.82(C-17),30.49(C-9),26.13(C-8),24.62(C-15),24.46(C-2),20.33(C-14),13.09(C-13).HR MS:C21H32N2O5(M+Na)+计算值415.2203,测定值415.2202.
3b-2:黄色浆状物； 1H NMR(300MHz,CDCl3)δ:0.94-0.98(6H,m,H-13and H-14),1.43(3H,s,H-15),1.25-2.06(12H,m,H-2,H-3,H-7～H-10and H-17),2.33-2.42(1H,m,H-1),2.60-2.71(1H,m,H-11),3.33-3.40(1H,m,H-16),3.83-3.90(1H,m,H-16),4.04(2H,t,J＝7.2Hz,H-18),4.78(1H,s,H-12),5.37(1H,s,H-5),6.91(1H,s,H-20),7.07(1H,s,H-19),7.47(1H,s,H-21)；13C NMR(75MHz,CDCl3)δ:137.1(21),129.5(C-20),118.8(C-19),104.1(C-4),102.0(C-12),87.9(C-5),80.9(C-6),64.4(C-16),52.5(C-1),44.2(C-7),43.8(C-18),37.5(C-11),36.3(C-10),34.5(C-3),31.2(C-17),30.8(C-9),26.1(C-8),24.6(C-15),24.5(C-2),20.3(C-14),13.1(C-13).HR MS:C21H32N2O5[M+H]+计算值393.2384,测定值393.2386.
3b-3:黄色油状物； 1H NMR(300MHz,CDCl3)δ:0.91(3H,d,J＝6.9Hz,H-14),0.95(3H,d,J＝6.3Hz,H-13),1.45(3H,s,H-15),1.19-2.06(12H,m,H-2,H-3,H-7～H-10and H-17),2.13(3H,s,H-22),2.32-2.43(1H,m,H-1),2.59-2.66(1H,m,H-11),3.40-3.52(4H,m,H-16and H-18),4.69(1H,d,J＝2.7Hz,H-12),5.39(1H,s,H-5)；13C NMR(75MHz,CDCl3)δ:127.9(C-19),127.2(C-21),118.9(C-20),104.2(C-4),102.0(C-12),87.8(C-5),80.9(C-6),66.9(C-16),52.4(C-1),47.8(C-18),44.0(C-7),37.2(C-11),36.3(C-10),34.4(C-3),30.6(C-9),29.7(C-17),26.1(C-8),24.6(C-15),24.2(C-2),20.3(C-14),13.0(C-13),12.7(C-21).HR MS:C22H34N2O5[M+H]+计算值407.2540,测定值407.2542.
3b-4:黄色油状物； 1H NMR(300MHz,CDCl3)δ:0.85(3H,d,J＝7.2Hz,H-14),0.94(3H,d,J＝4.8Hz,H-13),1.43(3H,s,H-15),1.22-2.07(12H,m,H-2,H-3,H-7～H-10and H-17),2.29-2.34(1H,m,H-1),2.41(3H,s,H-21),2.61-2.63(1H,m,H-11),3.58-3.63(1H,m,H-16),3.99-4.16(3H,m,H-16and H-17),4.76(1H,d,J＝3.3Hz,H-12),5.08(1H,s,H-5).6.88(1H,s,H-20),6.92(1H,s,H-19)；13C NMR(75MHz,CDCl3)δ:126.7(C-20and C-19),118.9(C-18),104.2(C-4),102.0(C-12),87.8(C-5),80.9(C-6),66.8(C-16),52.4(C-1),45.8(C-17),44.0(C-7),37.2(C-11),36.3(C-10),34.4(C-3),30.6(C-9),29.6(C-17),26.1(C-8),24.6(C-15),24.2(C-2),20.3(C-14),13.0(C-13),12.9(C-21).HR MS:C22H34N2O5[M+H]+计算值407.2540,测定值407.2537.
3b-5:黄色油状物； 1H NMR(400MHz,CDCl3)δ:0.93(3H,d,J＝7.4Hz,H-13),0.96(3H,d,J＝7.4Hz,H-14),1.44(3H,s,H-15),1.37-2.12(12H,m,H-2,H-3,H-7～H-10and H-17),2.21(3H,s,H-21),2.29(3H,s,H-22),2.39(1H,m,H-1),2.61-2.68(1H,m,H-11),3.36-3.41(1H,m,H-16),3.85-3.90(1H,m,H-16),4.03(2H,t,J＝7.1Hz,H-18),4.80(1H,d,J＝2.4Hz,H-12),5.45(1H,s,H-5),5.77(1H,s,H-19)；13C NMR(75MHz,CDCl3)δ:147.18(C-21and C-23),138.39(C-20),104.77(C-4),103.98(C-20),101.79(C-12),87.81(C-5),80.97(C-6),65.07(C-16),52.44(C-1),45.56(C-17),44.30(C-7),37.30(C-11),36.31(C-10),34.54(C-3),30.79(C-9),30.53(C-18),26.07(C-8),24.59(C-15),24.43(C-2),20.27(C-14),13.39(C-13),13.02(C-13),10.85(C-22and C-23).HR MS:C23H36N2O5[M+Na]+计算值443.2516,测定值443.2518.
3b-6:黄色浆状物； 1H NMR(300MHz,CDCl3)δ:0.87(3H,d,J＝6.9Hz,H-13),0.98(3H,d,J＝7.5Hz,H-14),1.44(3H,s,H-15),1.26-2.16(12H,m,H-2,H-3,H-7～H-10and H-17),2.33-2.43(1H,m,H-1),2.68-2.71(1H,m,H-11),3.39-3.47(1H,m,H-16),3.88-3.95(1H,m,H-16),4.30(2H,t,J＝7.2Hz,H-18),4.82(1H,d,J＝2.4Hz,H-12),5.40(1H,s,H-5),7.30-7.33(2H,m,H-22and H-23),7.41(1H,d,J＝4.8Hz,H-21),7.82-7.85(1H,m,H-24),7.98(1H,s,H-19)；13C NMR(75MHz,CDCl3)δ:129.1(C-21and C-24),116.1(C-22and C-23),104.0(C-4),102.0(C-12),87.8(C-5),81.0(C-6),66.4(C-16),52.5(C-1),49.0(C-18),44.0(C-7),37.5(C-11),36.4(C-10),34.6(C-3),30.7(C-9),29.7(C-17),26.2(C-8),24.7(C-15),24.5(C-2),20.4(C-14),13.0(C-13).HRMS:C25H34N2O5[M+H]+计算值443.2541,测定值443.2538.
4a-1:m.p.:100.8-102.4℃； 1H NMR(300MHz,CDCl3)δ:0.74(3H,d,J＝7.2Hz,H-14),0.93(3H,d,J＝5.4Hz,H-13),1.42(3H,s,H-15),1.12-2.11(10H,m,H-2,H-3,H-7～H-10),2.34(1H,m,H-1),2.47-2.63(1H,m,H-11),3.89-3.96(1H,m,H-16),4.33-4.40(1H,m,H-16),4.64(2H,m,H-17),4.77(1H,s,H-12),5.21(1H,s,H-5),7.60(2H,s,H-18)；13C NMR(75MHz,CDCl3)δ:133.96(C-18),103.97(C-4),102.10(C-12),87.79(C-5),80.92(C-6),66.12(C-16),54.73(C-17),52.37(C-1),44.12(C-7),37.13(C-11),36.29(C-10),34.47(C-3),30.58(C-9),26.08(C-8),24.58(C-15),23.93(C-2),20.31(C-14),12.67(C-13).HR MS:C19H29N3O5[M+Na]+计算值402.1999,测定值402.1997.
4a-2:m.p.:128.4-129.7℃； 1H NMR(300MHz,CDCl3)δ:0.81(3H,d,J＝7.2Hz,H-14),0.95(3H,d,J＝5.4Hz,H-13),1.42(3H,s,H-15),1.16-2.08(10H,m,H-2,H-3,H-7～H-10),2.35(1H,m,H-1),2.56-2.65(1H,m,H-11),3.77-3.84(1H,m,H-16),4.26-4.33(1H,m,H-16),4.52-4.60(1H,m,H-17),4.63-4.72(1H,m,H-17),4.78(1H,d,J＝3.2Hz,H-12),5.16(1H,s,H-5),7.62(1H,s,H-18),7.72(1H,s,H-19)；13C NMR(75MHz,CDCl3)δ:133.62(C-19),123.94(C-18),104.11(C-4),102.06(C-12),87.77(C-5),80.78(C-6),66.46(C-16),52.33(C-1),50.12(C-17),43.97(C-7),37.18(C-11),36.23(C-10),34.35(C-3),30.54(C-9),26.04(C-8),24.51(C-15),24.19(C-2),20.30(C-14),12.80(C-13).HR MS:C19H29N3O5[M+Na]+计算值402.1999,测定值402.1993.
4a-3:m.p.:93.5-95.2℃； 1H NMR(300MHz,CDCl3)δ:0.78(3H,d,J＝7.2Hz,H-14),0.94(3H,d,J＝4.5Hz,H-13),1.42(3H,s,H-15),1.19-2.08(10H,m,H-2,H-3,H-7～H-10),2.31-2.39(1H,m,H-1),2.58-2.62(1H,m,H-11),3.74-3.81(1H,m,H-16),4.09-4.17(1H,m,H-16),4.36-4.38(2H,m,H-17),4.78(1H,s,H-12),5.17(1H,s,H-5),7.96(1H,s,H-19),8.12(1H,s,H-18).
4a-4:m.p.:100.5～104.3℃； 1H NMR(300MHz,CDCl3)δ:0.89(3H,d,J＝7.4Hz,H-14),0.96(3H,d,J＝5.6Hz,H-13),1.44(3H,s,H-15),1.27-2.10(10H,m,H-2,H-3,H-7～H-10),2.37(1H,td,J＝14.2,3.7Hz,H-1),2.63-2.74(1H,m,H-11),3.61-3.70(1H,m,H-16),4.08-4.23(3H,m,H-16and H-17),4.81(1H,d,J＝3.5Hz,H-12),5.27(1H,s,H-5),7.80(1H,s,H-18)；13C NMR(75MHz,CDCl3)δ:154.04,140.14,104.17,102.24,87.74,80.72,66.47,52.25,43.91,43.51,37.23,36.18,34.25,30.49,25.95,24.47,24.40,20.21,12.83.HR MS:C19H30N4O5[M+Na]+计算值417.2108,测定值417.2105.
4a-5:m.p.:97.3-98.5℃； 1H NMR(300MHz,CDCl3)δ:0.91(3H,d,J＝7.4Hz,H-14),0.94(3H,d,J＝6.3Hz,H-13),1.41(3H,s,H-15),1.21-2.09(10H,m,H-2,H-3,H-7～H-10),2.37(1H,td,J＝14.1,3.6Hz,H-1),2.54-2.69(1H,m,H-11),3.23(2H,t,J＝5.8Hz,H-17),3.82-3.66(1H,m,H-16),3.98-4.06(1H,m,H-16),4.83(1H,d,J＝3.2Hz,H-12),5.06(2H,s,H-20),5.57(1H,s,H-5)；13C NMR(75MHz,CDCl3)δ:163.32,148.19,104.35,101.96,88.16,81.26,67.28,52.40,44.26,37.28,36.30,34.52,32.05,30.87,25.94,24.52,24.33,20.33,12.93.HR MS:C19H30N4O5S[M-H]-计算值425.1864,测定值425.1866.
4a-6:m.p.:139.3-140.5℃； 1H NMR(300MHz,CDCl3)δ:0.63(3H,d,J＝7.5Hz,H-13),0.85(3H,d,J＝6.0Hz,H-14),1.39(3H,s,H-15),0.97-1.99(10H,m,H-2,H-3,H-7～H-10),2.23-2.34(1H,m,H-1),2.47-2.50(1H,m,H-11),3.88-3.93(1H,m,H-16),4.45-4.52(1H,m,H-16),4.73(1H,d,J＝3.0Hz,H-12),4.80-4.93(3H,m,H-5and H-17),7.37(1H,t,J＝7.5Hz,H-21),7.49(1H,t,J＝7.2Hz,H-20),7.57(1H,d,J＝8.1Hz,H-19),7.86(2H,d,J＝8.4Hz,H-22)；13C NMR(75MHz,CDCl3)δ:145.8(C-23),133.5(C-18),127.1(C-21),123.8(C-20),119.8(C-22),109.6(C-19),104.0(C-4),102.0(C-12),87.6(C-5),80.7(C-6),66.1(C-16),52.2(C-1),48.0(C-17),43.9(C-7),36.9(C-11),36.2(C-10),34.3(C-3),30.5(C-9),26.0(C-8),24.4(C-15),24.0(C-2),20.2(C-14),12.6(C-13).HR MS:C23H31N3O5[M+Na]+计算值452.2156,测定值452.2151.
4a-7:m.p.:65.6-67.3℃； 1H NMR(300MHz,CDCl3)δ:0.73(3H,d,J＝6.9Hz,H-13),0.87(3H,d,J＝7.5Hz,H-14),1.42(3H,s,H-15),1.01-1.99(10H,m,H-2,H-3,H-7～H-10),2.25-2.33(1H,m,H-1),2.49-2.55(1H,m,H-11),4.00-4.04(1H,m,H-16),4.62-4.68(1H,m,H-16),4.81(1H,s,H-12),4.89-5.03(3H,m,H-5and H-17),7.38(1H,d,J＝9.0Hz,H-20),7.86(2H,d,J＝9.3Hz,H-19)；13C NMR(75MHz,CDCl3)δ:143.5(C-18),126.2(C-20),117.9(C-19),103.9(C-4),101.7(C-12),87.7(C-5),80.8(C-6),65.5(C-16),56.5(C-17),52.2(C-1),44.0(C-7),36.7(C-11),36.3(C-10),34.3(C-3),30.6(C-9),26.1(C-8),24.5(C-15),23.9(C-2),20.1(C-14),12.7(C-13).HRMS:C23H31N3O5[M+Na]+计算值452.2156,测定值452.2159.
4a-8:m.p.:131.2-132.7℃； 1H NMR(300MHz,CDCl3)δ:0.91(3H,d,J＝7.2Hz,H-14),0.95(3H,d,J＝6.0Hz,H-13),1.44(3H,s,H-15),1.26-2.06(10H,m,H-2,H-3,H-7～H-10),2.32-2.43(H,m,H-1),2.65-2.72(H,m,H-11),3.83～3.90(1H,m,H-16),4.22-4.29(1H,m,H-16),4.75(2H,t,J＝3.6Hz,H-17),4.87(1H,s,H-12),5.45(1H,s,H-5),7.40(1H,t,J＝7.5Hz,H-21),7.52(1H,t,J＝7.5Hz,H-20),7.62(1H,d,J＝8.4Hz,H-22),8.03(1H,d,J＝8.4Hz,H-19)；13C NMR(75MHz,CDCl3)δ:143.5(C-23),127.9(C-18),127.4(C-19),124.6(C-21),120.3(C-20),108.6(C-22),104.1(C-4),102.3(C-12),88.0(C-5),81.0(C-6),79.7(C-17),65.5(C-16),52.5(C-1),44.3(C-7),37.3(C-11),36.3(C-10),34.5(C-3),30.7(C-9),26.1(C-8),24.6(C-15),24.3(C-2),20.3(C-14),12.9(C-13).HR MS:C23H31N3O6[M+Na]+计算值468.2105,测定值468.2098.
4b-1:m.p.:100.8-102.4℃； 1H NMR(300MHz,CDCl3)δ:0.94(3H,d,J＝7.2Hz,H-14).,0.96(3H,d,J＝6.2Hz,H-13),1.43(3H,s,H-15),1.17-2.10(10H,m,H-2,H-3,H-7～H-10),2.16-2.28(2H,m,H-17),2.37(1H,m,H-1),2.56-2.72(1H,m,H-11),3.26-3.43(1H,m,H-16),3.81-3.88(1H,m,H-16),4.54(2H,m,H-18),4.79(1H,d,J＝3.2Hz,H-12),5.44(1H,s,H-5),7.59(2H,s,H-18)；13C NMR(75MHz,CDCl3)δ:133.98(C-19),104.00(C-4),102.09(C-12),87.85(C-5),81.05(C-6),64.78(C-16),52.51(C-17),51.86(C-1),44.34(C-7),37.29(C-11),36.36(C-10),34.59(C-3),30.84(C-9),29.88(C-18),26.15(C-8),24.64(C-15),24.43(C-2),20.35(C-14),13.01(C-13).HR MS:C20H31N3O5[M+Na]+计算值416.2156,测定值416.2155.
4b-2:m.p.:100.8-102.4℃； 1H NMR(300MHz,CDCl3)δ:0.94(3H,d,J＝7.2Hz,H-14),0.96(3H,d,J＝6.1Hz,H-13),1.43(3H,s,H-15),1.21-2.25(12H,m,H-2,H-3,H-7～H-10and H-17),2.28-2.43(1H,m,H-1),2.65(1H,m,H-11),3.31-3.43(1H,m,H-16),3.83-3.94(1H,m,H-16),4.46-4.52(2H,m,H-17),4.78(1H,d,J＝3.2Hz,H-12),5.40(1H,s,H-5),7.56(1H,s,H-18),7.72(1H,s,H-19)；13C NMR(75MHz,CDCl3)δ:133.77(C-20),123.48(C-19),104.10(C-4),102.04(C-12),87.84(C-5),80.94(C-6),64.52(C-16),52.41(C-1),47.19(C-17),44.18(C-7),37.34(C-11),36.27(C-10),34.46(C-3),30.75(C-9),30.41(C-18),26.08(C-8),24.56(C-15),24.45(C-2),20.31(C-14),13.04(C-13).HR MS:C20H31N3O5[M+Na]+计算值416.2156,测定值416.2157.
4b-3:黄色油状物； 1H NMR(300MHz,CDCl3)δ:0.92-0.97(6H,m,H-14and H-13),1.43(3H,s,H-15),1.19-2.08(10H,m,H-2,H-3,H-7～H-10),2.16-2.19(2H,m,H-17),2.32-2.36(1H,m,H-1),2.64-2.67(1H,m,H-11),3.32-3.40(1H,m,H-16),3.84-3.91(1H,m,H-16),4.28(2H,t,J＝6.9Hz,H-18),4.77(1H,s,H-12),5.39(1H,s,H-5),7.96(1H,s,H-20),8.09(1H,s,H-19)；13C NMR(75MHz,CDCl3)δ:151.9(C-20),143.0(19),104.1(C-4),102.0(C-12),87.8(C-5),80.9(C-6),64.5(C-16),52.4(C-1),46.7(C-18),44.2(C-7),37.4(C-11),36.3(C-10),34.5(C-3),30.7(C-9),29.9(C-18),26.1(C-8),24.6(C-15),24.5(C-2),20.3(C-14),13.0(C-13).HR MS:C20H31N3O5[M+Na]+计算值416.2156,测定值416.2155.
4b-4:黄色浆状物； 1H NMR(300MHz,CDCl3)δ:0.93(3H,d,J＝7.4Hz,H-14),0.96(3H,d,J＝5.1Hz,H-13),1.43(3H,s,H-15),1.25-2.15(12H,m,H-2,H-3,H-7～H-10and H-17),2.37(1H,td,J＝14.0,3.8Hz,H-1),2.62-2.71(1H,m,H-11),3.55-3.62(1H,m,H-16),3.84-3.92(1H,m,H-16),3.97-4.08(2H,m,H-18),4.81(1H,d,J＝3.3Hz,H-12),5.44(1H,s,H-5),7.65(1H,s,H-19)；13C NMR(75MHz,CDCl3)δ:153.99,142.09,104.21,101.97,87.84,80.88,64.67,52.43,46.28,44.22,37.41,36.26,34.45,30.77,29.32,26.04,24.59,24.46,20.28,13.06.HR MS:C20H32N4O5[M+Na]+计算值431.2265,测定值431.2266.
4b-5:黄色浆状物； 1H NMR(300MHz,CDCl3)δ:0.91(3H,d,J＝7.4Hz,H-14),0.94(3H,d,J＝6.3Hz,H-13),1.41(3H,s,H-15),1.21-2.09(12H,m,H-2,H-3,H-7～H-10and H-17),2.37(1H,td,J＝14.1,3.6Hz,H-1),2.54-2.69(1H,m,H-11),3.23(2H,t,J＝5.8Hz,H-18),3.66-3.82(1H,m,H-16),3.98-4.06(1H,m,H-16),4.80(1H,d,J＝3.2Hz,H-12),5.44(2H,s,H-21),5.57(1H,s,H-5)；13C NMR(75MHz,CDCl3)δ:163.55,148.20,104.21,101.97,87.93,80.93,64.67,52.43,44.22,37.40,36.31,34.50,30.87,29.65,26.11,24.59,24.46,20.31,13.06.HR MS:C20H32N4O5S[M+Na]+计算值463.1986,测定值463.1986.
4b-6:黄色浆状物； 1H NMR(300MHz,CDCl3)δ:0.94(3H,d,J＝7.5Hz,H-13),0.97(3H,d,J＝6.9Hz,H-14),1.42(3H,s,H-15),1.21-2.06(10H,m,H-2,H-3,H-7～H-10),2.31-2.44(3H,m,H-1and H-17),2.60-2.70(1H,m,H-11),3.37-3.45(1H,m,H-16),3.86-3.93(1H,m,H-16),4.79-4.87(3H,m,H-12and H-18),5.50(1H,s,H-5),7.37-7.41(2H,m,H-21),7.84-7.88(2H,m,H-20)；13C NMR(75MHz,CDCl3)δ:144.3(C-19),126.3(C-21),117.9(C-20),104.0(C-4),102.1(C-12),87.9(C-5),81.1(C-6),64.8(C-16),53.7(C-18),52.6(C-1),44.4(C-7),37.3(C-11),36.4(C-10),34.6(C-3),30.7(C-9),26.2(C-8),24.7(C-15),24.5(C-2),22.7(C-17),20.4(C-14),13.0(C-13).HRMS:C24H33N3O5[M+Na]+计算值466.2312,测定值466.2309.
4b-7:黄色浆状物； 1H NMR(300MHz,CDCl3)δ:0.95-0.98(6H,m,H-13and H-14),1.43(3H,s,H-15),1.26-2.09(10H,m,H-2,H-3,H-7～H-10),2.28-2.42(3H,m,H-1and H-17),2.65-2.70(1H,m,H-11),3.41-3.48(1H,m,H-16),3.88-3.95(1H,m,H-16),4.72-4.78(2H,m,H-18),4.81(1H,d,J＝3.3Hz,H-12),5.44(3H,s,H-5),7.38(1H,t,J＝7.5Hz,H-21),7.46-7.55(2H,m,H-22and H-23),8.08(1H,d,J＝7.8Hz,H-20)；13C NMR(75MHz,CDCl3)δ:145.9(C-19),133.0(C-24),127.3(C-21),123.9(C-22),120.0(C-20),109.2(C-23),104.2(C-4),102.1(C-12),87.9(C-5),81.0(C-6),64.8(C-16),52.5(C-1),45.3(C-18),44.3(C-7),37.4(C-11),36.3(C-10),34.6(C-3),30.6(C-9),29.9(C-17),26.1(C-8),24.6(C-15),24.5(C-2),20.3(C-14),13.1(C-13).HR MS:C24H33N3O5[M+Na]+计算值466.2312,测定值466.2310.
4b-8:m.p.:106.3-108.1℃； 1H NMR(300MHz,CDCl3)δ:0.88(3H,d,J＝9.3Hz,H-14),0.93(3H,d,J＝7.2Hz,H-13),1.45(3H,s,H-15),1.22-2.03(10H,m,H-2,H-3,H-7～H-10),2.13-2.17(2H,m,H-17),2.32-2.42(H,m,H-1),2.64-2.71(H,m,H-11),3.62-3.67(1H,m,H-16),4.10～4.18(1H,m,H-16),4.66(2H,t,J＝6.0Hz,H-18),4.85(1H,s,H-12),5.43(1H,s,H-5),7.40(1H,t,J＝7.2Hz,H-21),7.52(1H,t,J＝7.2Hz,H-22),7.59(1H,d,J＝7.8Hz,H-23),8.02(1H,d,J＝8.7Hz,H-20)；13C NMR(75MHz,CDCl3)δ:143.5(C-24),127.9(C-19),127.3(C-20),124.5(C-22),120.3(C-21),108.5(C-23),104.1(C-4),102.1(C-12),87.9(C-5),81.0(C-6),77.4(C-18),64.1(C-16),52.5(C-1),44.3(C-7),37.3(C-11),36.4(C-10),34.5(C-3),30.8(C-9),28.6(C-17),26.1(C-8),24.6(C-15),24.5(C-2),20.3(C-14),13.0(C-13).HR MS:C24H33N3O6[M+Na]+计算值482.2262,测定值482.2260.
5a-1:m.p.:135.2-136.5℃； 1H NMR(300MHz,CDCl3)δ:0.72(3H,d,J＝7.8Hz,H-13),0.95(3H,d,J＝5.1Hz,H-14),1.43(3H,s,H-15),1.25-2.06(10H,m,H-2,H-3,H-7～H-10),2.31-2.40(1H,m,H-1),2.63-2.65(1H,m,H-11),3.80-3.86(1H,m,H-16),4.28-4.35(1H,m,H-16),4.63(2H,t,J＝4.8Hz,H-18),4.79(1H,s,H-12),5.19(1H,s,H-5),8.64(1H,s,H-18)；13C NMR(75MHz,CDCl3)δ:143.0(C-18),104.2(C-4),102.3(C-12),87.9(C-5),80.7(C-6),65.7(C-16),52.3(C-1),48.4(C-17),43.9(C-7),37.3(C-11),36.3(C-10),34.3(C-3),30.5(C-9),26.0(C-8),24.5(C-15),24.3(C-2),20.3(C-14),12.8(C-13).HR MS:C18H28N4O5[M+Na]+计算值403.1952,测定值403.1951.
5a-2:m.p.:123.2-124.6℃； 1H NMR(300MHz,CDCl3)δ:0.72(3H,d,J＝7.5Hz,H-13),0.95(3H,d,J＝4.8Hz,H-14),1.43(3H,s,H-15),1.24-2.05(10H,m,H-2,H-3,H-7～H-10),2.31-2.39(1H,m,H-1),2.54-2.61(1H,m,H-11),3.96-4.03(1H,m,H-16),4.38-4.45(1H,m,H-16),4.78(1H,s,H-12),4.87(2H,t,J＝4.8Hz,H-17),5.22(1H,s,H-5),8.52(1H,s,H-18)；13C NMR(75MHz,CDCl3)δ:152.8(C-18),104.1(C-4),102.2(C-12),87.9(C-5),80.9(C-6),65.5(C-16),53.1(C-17),52.4(C-1),44.1(C-7),37.3(C-11),36.3(C-10),34.4(C-3),30.6(C-9),26.1(C-8),24.6(C-15),24.0(C-2),20.3(C-14),12.6(C-13).HR MS:C18H28N4O5[M+Na]+计算值403.1952,测定值403.1949.
5a-3:m.p.:117.4-119.1℃； 1H NMR(300MHz,CDCl3)δ:0.93(3H,d,J＝7.5Hz,H-13),0.95(3H,d,J＝5.7Hz,H-13),1.43(3H,s,H-15),1.26-2.07(10H,m,H-2,H-3,H-7～H-10),2.32-2.42(1H,m,H-1),2.56(1H,s,H-20),2.62-2.73(1H,m,H-11),3.41-3.49(1H,m,H-16),3.87-3.94(1H,m,H-16),4.33-4.38(2H,m,H-18),4.80(1H,s,H-12),5.40(1H,s,H-5)；13C NMR(75MHz,CDCl3)δ:162.75,103.96,102.03,87.79,80.89,64.22,52.46,49.83,44.24,37.22,36.29,34.53,30.73,26.03,24.58,24.39,20.27,12.90,10.76.HR MS:C19H30N4O5[M+Na]+计算值417.2108,测定值417.2106.
5a-4:m.p.:114.2-115.7℃； 1H NMR(300MHz,CDCl3)δ:0.75(3H,d,J＝7.2Hz,H-14),0.94(3H,d,J＝4.5Hz,H-13),1.42(3H,s,H-15),1.21-2.04(10H,m,H-2,H-3,H-7～H-10),2.29-2.38(1H,m,H-1),2.57(3H,s,H-19),2.58-2.61(1H,m,H-11),3.80-3.87(1H,m,H-16),4.34-4.37(1H,m,H-16),4.46-4.48(2H,m,H-17),4.76(1H,s,H-12),5.11(1H,s,H-5)；13C NMR(75MHz,CDCl3)δ:152.1(C-18),104.2(C-4),102.3(C-12),87.7(C-5),80.7(C-6),65.8(C-16),52.3(C-1),47.0(C-17),43.9(C-7),37.2(C-11),36.2(C-10),34.3(C-3),30.5(C-9),26.0(C-8),24.5(C-15),24.2(C-2),20.3(C-14),13.0(C-13),8.9(C-19).HR MS:C19H30N4O5[M+Na]+计算值417.2108,测定值417.2106.
5a-5:m.p.:121.7-123.3℃； 1H NMR(300MHz,CDCl3)δ:0.90(3H,d,J＝7.5Hz,H-14),0.96(3H,d,J＝6.3Hz,H-13),1.43(3H,s,H-15),1.21-2.04(10H,m,H-2,H-3,H-7～H-10),2.32-2.43(H,m,H-1),2.61-2.66(H,m,H-11),3.63(2H,t,J＝5.7Hz,H-17),3.75-3.83(1H,m,H-16),3.93(3H,s,H-19),4.12-4.19(H,m,H-16),4.83(1H,d,J＝2.7Hz,H-12),5.43(1H,s,H-5)；13C NMR(75MHz,CDCl3)δ:154.0(C-18),104.1(C-4),102.2(C-12),87.9(C-5),80.9(C-6),66.5(C-16),52.4(C-1),44.2(C-7),37.4(C-11),36.3(C-10),34.5(C-3),33.6(C-17),33.4(C-19),30.7(C-9),26.1(C-8),24.6(C-15),24.3(C-2),20.3(C-14),12.9(C-13).HR MS:C19H30N4O5S[M+Na]+计算值449.1829,测定值449.1821.
5a-6:m.p.:129.8-130.8℃； 1H NMR(300MHz,CDCl3)δ:0.87(3H,d,J＝6.9Hz,H-13),0.98(3H,d,J＝7.5Hz,H-14),1.44(3H,s,H-15),1.26-2.12(10H,m,H-2,H-3,H-7～H-10),2.33-2.43(1H,m,H-1),2.68-2.71(1H,m,H-11),3.94-4.00(1H,m,H-16),4.52-4.59(1H,m,H-16),4.78-4.82(1H,m,H-17),4.83(1H,d,J＝2.7Hz,H-12),4.91-4.99(1H,m,H-17),5.15(1H,s,H-5),7.47-7.50(3H,m,H-21and H-22),8.17(1H,d,J＝5.4Hz,H-20)；13C NMR(75MHz,CDCl3)δ:165.1(C-18),130.3(C-22),128.8(C-21),127.3(C-19),126.7(C-20),104.0(C-4),102.0(C-12),87.8(C-5),80.8(C-6),64.9(C-16),52.1(C-1),52.3(C-17),44.0(C-7),37.1(C-11),36.3(C-10),34.2(C-3),30.6(C-9),26.1(C-8),24.4(C-15),24.0(C-2),20.0(C-14),12.87(C-13).HR MS:C24H32N4O5[M+Na]+计算值479.2265,测定值479.2268.
5b-1:黄色油状物； 1H NMR(300MHz,CDCl3)δ:0.94(3H,d,J＝7.8Hz,H-13),0.97(3H,d,J＝6.6Hz,H-14),1.44(3H,s,H-15),1.26-2.06(10H,m,H-2,H-3,H-7～H-10),2.22-2.28(2H,m,H-17),2.33-2.42(1H,m,H-1),2.63-2.70(1H,m,H-11),3.39-3.46(1H,m,H-16),3.87-3.94(1H,m,H-16),4.54(2H,t,J＝6.9Hz,H-18),4.79(H,s,H-12),5.39(1H,s,H-5),8.62(1H,s,H-19)；13C NMR(75MHz,CDCl3)δ:142.6(C-19),104.2(C-4),102.2(C-12),87.9(C-5),80.9(C-6),64.3(C-16),52.4(C-1),45.5(C-18),44.2(C-7),37.4(C-11),36.3(C-10),34.5(C-3),30.7(C-9),30.0(C-17),26.1(C-8),24.6(C-15),24.5(C-2),20.3(C-14),13.0(C-13).HR MS:C19H30N4O5[M+Na]+计算值417.2108,测定值417.2111.
5b-2:黄色油状物； 1H NMR(300MHz,CDCl3)δ:0.93-0.98(6H,m,H-13and H-14),1.43(3H,s,H-15),1.26-2.06(10H,m,H-2,H-3,H-7～H-10),2.28-2.32(2H,m,H-17),2.37-2.43(1H,m,H-1),2.61-2.68(1H,m,H-11),3.35-3.42(1H,m,H-16),3.86-3.92(1H,m,H-16),4.74-4.79(3H,m,H-12and H-18),5.41(1H,s,H-5),8.51(1H,s,H-19)；13C NMR(75MHz,CDCl3)δ:152.8(C-19),104.1(C-4),102.2(C-12),87.9(C-5),81.0(C-6),64.4(C-16),52.5(C-1),50.2(C-18),44.3(C-7),37.4(C-11),36.4(C-10),34.6(C-3),30.8(C-9),29.5(C-17),26.1(C-8),24.6(C-15),24.5(C-2),20.3(C-14),13.0(C-13).HR MS:C19H30N4O5[M+Na]+计算值417.2108,测定值417.2114.
5b-3:黄色油状物； 1H NMR(300MHz,CDCl3)δ:0.93(3H,d,J＝7.5Hz,H-13),0.95(3H,d,J＝5.7Hz,H-13),1.43(3H,s,H-15),1.26-2.07(10H,m,H-2,H-3,H-7～H-10),2.16-2.22(2H,m,H-17),2.32-2.42(1H,m,H-1),2.56(1H,s,H-20),2.62-2.73(1H,m,H-11),3.41-3.49(1H,m,H-16),3.87-3.94(1H,m,H-16),4.33-4.38(2H,m,H-18),4.80(1H,s,H-12),5.40(1H,s,H-5)；13C NMR(75MHz,CDCl3)δ:162.75(C-19),103.96(C-4),102.03(C-12),87.79(C-5),80.89(C-6),64.22(C-16),52.46(C-1),49.83(C-18),44.24(C-7),37.22(C-11),36.29(C-10),34.53(C-3),30.73(C-9),29.38(C-17),26.03(C-8),24.58(C-15),24.39(C-2),20.27(C-14),12.90(C-13),10.76(C-20).HRMS:C20H32N4O5[M+Na]+计算值431.2265,测定值431.2272.
5b-4:黄色油状物； 1H NMR(300MHz,CDCl3)δ:0.93(3H,d,J＝7.5Hz,H-13),0.97(3H,d,J＝6.1Hz,H-13),1.44(3H,s,H-15),1.19-2.10(10H,m,H-2,H-3,H-7～H-10),2.14-2.27(2H,m,H-17),2.32-2.47(1H,m,H-1),2.57(3H,s,H-20),2.64-2.73(1H,m,H-11),3.39-3.59(1H,m,H-16),3.88-3.95(1H,m,H-16),4.33-4.43(2H,m,H-18),4.81(1H,d,J＝3.3Hz,H-12),5.41(1H,s,H-5)；13C NMR(75MHz,CDCl3)δ:104.16(C-4),102.01(C-12),87.87(C-5),80.86(C-6),64.31(C-16),52.42(C-1),44.27(C-18),44.17(C-7),37.41(C-11),36.30(C-10),34.48(C-3),30.71(C-9),29.72(C-17),26.04(C-8),24.59(C-15),24.48(C-2),20.26(C-14),12.99(C-13),8.70(C-20).HR MS:C20H32N4O5[M+Na]+计算值431.2265,测定值431.2273.
5b-5:黄色浆状物； 1H NMR(300MHz,CDCl3)δ:0.91(3H,d,J＝7.5Hz,H-13),0.95(3H,d,J＝6.3Hz,H-13),1.43(3H,s,H-15),1.25-2.06(12H,m,H-2,H-3,H-7～H-10and H-17),2.32-2.41(1H,m,H-1),2.62-2.67(1H,m,H-11),3.42-3.55(3H,m,H-16and H-18),3.92(1H,s,H-20),3.97-4.04(1H,m,H-16),4.80(1H,d,J＝3.0Hz,H-12),5.39(1H,s,H-5)；13C NMR(75MHz,CDCl3)δ:154.2(C-19),104.1(C-4),102.1(C-12),87.9(C-5),81.0(C-6),66.0(C-16),52.4(C-1),44.2(C-7),37.4(C-11),36.3(C-10),34.5(C-3),33.3(C-18),30.8(C-9),30.3(C-17),29.1(C-20),26.1(C-8),24.6(C-15),24.5(C-2),20.3(C-14),13.0(C-13).HR MS:C20H32N4O5S[M+Na]+计算值463.1986,测定值463.1985.
5b-6:白色浆状物； 1H NMR(300MHz,CDCl3)δ:0.87(3H,d,J＝7.2Hz,H-13).0.96(3H,d,J＝6.7Hz,H-14),1.43(3H,s,H-15),1.12-2.11(10H,m,H-2,H-3,H-7～H-10),2.31-2.37(3H,m,H-1,H-17),2.62-2.72(1H,m,H-11),3.36-3.54(1H,m,H-16),3.97-4.01(1H,m,H-16),4.73-4.81(2H,m,H-18),4.82(1H,d,J＝2.7Hz,H-12),5.46(1H,s,H-5),7.42-7.58(3H,m,H-22and H-23),8.27-8.07(2H,d,J＝5.4Hz,H-21)；13C NMR(75MHz,CDCl3)δ:165.11(C-19),130.21(C-23),128.80(C-22),127.40(C-20),126.81(C-21),104.07(C-4),102.21(C-12),87.87(C-5),80.98(C-6),64.51(C-16),52.52(C-1),50.28(C-17),44.31(C-7),37.37(C-11),36.37(C-10),34.55(C-3),30.82(C-9),29.67(C-18),26.12(C-8),24.61(C-15),24.53(C-2),20.31(C-14),12.99(C-13).HR MS:C25H34N4O5[M+Na]+计算值493.2427,测定值493.2421.
实施例3、DHA胺类衍生物和DHA唑类衍生物的PCSK9抑制活性测试
DHA胺类衍生物和DHA唑类衍生物的PCSK9抑制活性委托美国礼来公司OpenInnovation Drug Discovery(OIDD)program进行测试，首先进行单浓度初筛(PrimarySP)，然后对初步筛选出的潜力分子进行多浓度测试(Primary CRC)。部分化合物的PCSK9抑制活性测试结果见表5。
表5 PCSK9 Inhibition(Eff-1)抑制活性测试结果
表5测试了部分目标化合物对人肝癌细胞HepG2分泌PCSK9的抑制率以及对HepG2细胞的毒性。Primary SP测试结果显示，在2μM或5μM测试浓度下，部分化合物能够抑制HepG2细胞分泌PCSK9，其中2b-2,2b-3,3a-1,5a-1,5b-6活性更好；测试化合物在2μM或5μM测试浓度下都几乎没有细胞毒性。Primary CRC测试结果显示，2b-3对PCSK9的IC50值低(表明活性强)，对HepG2细胞的Cell Health IC50值高(表明毒性低)，有很好的研究潜力。
表6 TEST PCSK9 Translation Inh Mult活性测试结果
从表6可以看出,在hPCSK9 Huh7 TT抑制活性测试中，DHA胺类衍生物和DHA唑类衍生物具有一定的抑制活性，其中2a-5,2b-4,3a-2,3b-5,3b-6,4b-5～4b-8,5a-6,5b-6的抑制活性超过60％，5a-6甚至超过90％，具有进一步开发为降血脂药物的潜力。
最后说明的是，以上优选实施例仅用以说明本发明的技术方案而非限制，尽管通过上述优选实施例已经对本发明进行了详细的描述，但本领域技术人员应当理解，可以在形式上和细节上对其作出各种各样的改变，而不偏离本发明权利要求书所限定的范围。
Claims (7)
1.式I所示的二氢青蒿素衍生物或其消旋体、立体异构体、互变异构体、氮氧化物、药学上可接受的盐在制备降血脂药物中的应用：
式I中，n为1或2；
Y为-NR1R2、
R1和R2独立地为H、C1-C3烷基或C1-C3羟烷基；
R3为H、C1-C3烷基、C1-C3羟烷基、取代或未取代苯基、叔丁氧羰基、苄氧羰基或脂肪酰基；所述苯基上的取代基为一个或多个，独立选自卤素、羟基、氨基或C1-C3烷基；
R4和R5独立地为H或C1-C3烷基；
R6和R7独立地为H、氨基、羟基或C1-C3烷基；
R8为H、C1-C3烷基、C1-C3烷硫基、取代或未取代苯基；所述苯基上的取代基为一个或多个，独立选自卤素、羟基、氨基或C1-C3烷基。
2.如权利要求1所述的应用，其特征在于：式I中，
R1和R2独立地为H、C1-C2烷基或C1-C2羟烷基；
R3为H、C1-C2烷基、C1-C2羟烷基、取代或未取代苯基、叔丁氧羰基、苄氧羰基或烷酰基；所述苯基上的取代基为一个或多个，独立选自卤素、羟基、氨基或C1-C2烷基；
R4和R5独立地为H或C1-C2烷基；
R6和R7独立地为H、氨基、羟基或C1-C2烷基；
R8为H、C1-C2烷基、C1-C2烷硫基、取代或未取代苯基；所述苯基上的取代基为一个或多个，独立选自卤素、羟基、氨基或C1-C2烷基。
3.如权利要求2所述的应用，其特征在于：式I中，
R1和R2独立地为H、C1-C2烷基或C1-C2羟烷基；
R3为H、C1-C2烷基、C1-C2羟烷基、苯基、叔丁氧羰基、苄氧羰基或乙酰基；
R4和R5独立地为H或C1-C2烷基；
R6和R7独立地为H、氨基、羟基或C1-C2烷基；
R8为H、C1-C2烷基、C1-C2烷硫基或苯基。
4.如权利要求3所述的应用，其特征在于：式I中，
R1和R2独立地为H、甲基、乙基或羟乙基；
R3为H、甲基、羟乙基、苯基或叔丁氧羰基；
R4和R5独立地为H或甲基；
R6和R7独立地为H或氨基；
R8为H、甲基、甲硫基或苯基。
5.如权利要求4所述的应用，其特征在于：式I所示的二氢青蒿素衍生物为以下化合物中的任一种：
6.如权利要求5所述的应用，其特征在于：式I所示的二氢青蒿素衍生物为以下化合物中的任一种：2a-5,2b-2,2b-3,2b-4,3a-1,3a-2,3b-5,3b-6,4b-5～4b-8,5a-1,5a-6,5b-6。
7.如权利要求1所述的应用，其特征在于：所述降血脂药物为前蛋白转化酶枯草杆菌蛋白酶9即PCSK9抑制剂。
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Application publication date: 20191025 |