CN107405330B - 具有降血脂活性的竹柏內酯类化合物,其制备方法及用途 - Google Patents
具有降血脂活性的竹柏內酯类化合物,其制备方法及用途 Download PDFInfo
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Classifications
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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
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/06—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/16—Peri-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一类具有降血脂活性的竹柏內酯类化合物,其制备方法及用途,具体地,所述的化合物具有如式I所示的结构,其中,各基团的定义如说明书中所述。本发明的化合物具有体内或体外增加低密度脂蛋白摄取的活性,具有作为新型降血脂药物的潜力。
Description
技术领域
本发明属于药物化学领域,更具体而言,涉及一类新的具有降血脂活性的竹柏內酯类化合物,其制备方法及用于降血脂\动脉粥样硬化的药物中的用途。
背景技术
动脉粥样硬化是因为炎症细胞与动脉壁之间的炎症反应不断恶化而形成的慢性炎症性的疾病,是当今西方社会上致死量最高的因素之一。降血脂疗法是针对动脉粥样硬化最有效的治疗手段,其中他汀类作为降脂药中的明星药物在降脂市场中占据了很大的份额,非常有效的降低了高血脂病人心血管疾病的发生和致死率。然而,他汀类并非对所有的高血脂,和高动脉粥样硬化硬化风险的病人有效果,很大一部分患者对他汀类反应不敏感,不能靠他汀类阻止其动脉粥样硬化的发展进程,发展新型的降血脂药物的任务迫在眉睫。
综上所述,本领域迫切需要提供新的具有降血脂活性的化合物。
发明内容
本发明的目的是提供一类具有降血脂活性的化合物。
本发明的第一方面,提供了一种如下式I所示的化合物,或其药学上可接受的盐的用途:
其中,A选自下组:N-R、O;其中,R选自下组:H、C1-C4的酰基、C1-C4的烷基、C1-C4的卤代烷基、取代或未取代的C6-C10芳基、取代或未取代的C1-C10杂芳基;
R1选自下组:H、取代或未取代的C1-C4的烷基、C1-C4的卤代烷基、取代或未取代的C1-C4烷基(如2-羟基乙基,2-羟甲基乙基)、取代或未取代的乙烯基;
R2选自下组:无、H、氧原子、羟基;
R3选自下组:H、卤素、C1-C4的烷基、C1-C4的卤代烷基、-OH、-NH-R;其中,R选自下组:H、C1-C4的酰基、取代或未取代的C1-C4的烷基;
R4选自下组:H、卤素、氧原子、氰基、羟基、羧基、C1-C4的烷基、C1-C4的卤代烷基、-NH-R、-O-单糖基、-O-二糖基,或-O-三糖基;其中,R选自下组:H、C1-C4的酰基、取代或未取代的C1-C4的烷基;
R5选自下组:H、卤素、氰基、羟基、-COOR、取代或未取代C1-C10烷基、取代或未取代的C1-C10卤代烷基、取代或未取代(优选为取代)的C7-C11芳基-酰基、-NH-R、-O-单糖基、-O-二糖基,或-O-三糖基;其中,R选自下组:H、C1-C4的酰基、取代或未取代的C1-C4的烷基;
或R4和R5共同构成-R”-O-R”-,其中,所述的R”为无,或取代或未取代的C1-C4的亚烷基:
R6选自下组:H、卤素、氧原子、氰基、羧基、羟基、-COOR、取代或未取代C1-C10烷基、取代或未取代的C1-C10卤代烷基、取代或未取代(优选为取代)的C7-C11芳基酰基、-NH-R、-O-单糖基、-O-二糖基,或-O-三糖基;其中,R选自下组:H、C1-C4的酰基、取代或未取代的C1-C4的烷基;
或R5和R6共同构成-R”-O-R”-,其中,所述的R”为无,或取代或未取代的C1-C4的亚烷基;
R7选自下组:H、C1-C4的烷基、C1-C4的卤代烷基;
R8为无,H、或R8与R2共同构成-R”-O-R”-,其中,所述的R”为无或C1-C4的亚烷基:
R9为无,H、或R9为-OH:
所述的为双键或单键;
所述的“取代”指基团上的一个或多个氢原子被选自下组的取代基取代:羧基、苯基、C3-C6的环烷基、卤素、C1-C10烷基-氧基、C2-C10酰基、羟基、羟基-C1-C10的亚烷基,或单糖基-O-、二糖基-O-,或-O-三糖基-O-;
其特征在于,所述的化合物被用于选自下组的一种或多种用途:
a)制备用于降血脂的药物组合物;
b)制备用于降低低密度脂蛋白(LDL)含量的药物组合物;
c)制备用于稳定LDLR基因稳定性的药物组合物;
d)制备用于上调LDLR基因表达的药物组合物;
e)制备用于增加肝细胞表面LDLR受体数量的药物组合物;
f)制备用于减少LDLR受体降解的药物组合物;
g)制备用于降低血液中TC和/或TG浓度的药物组合物;
h)制备用于增加血液中高密度脂蛋白(HDL)浓度的药物组合物;
i)制备用于改善肝功能损伤的药物组合物。
在另一优选例中,在所述化合物中,各手性碳原子可以任选地为R构型或S构型。
在另一优选例中,所述的R3为C1-C4的烷基。
在另一优选例中,所述的肝功能损伤为高脂诱导的肝功能损伤。
在另一优选例中,所述的改善肝功能损伤为降低ALT\AST指标。
在另一优选例中,所述的式I化合物具有以下式Ia所示的结构:
式中,
R1选自下组:取代或未取代的C1-C4的烷基、C1-C4的卤代烷基、乙烯基;其中,所述的取代指基团上的一个或多个氢原子被羟基、C1-C4的酰基或单糖基-O-取代;
R2为H或-OH;
R7选自下组:C1-C4的烷基、C1-C4的卤代烷基;
其余各基团的定义如权利要求1中所述。
在另一优选例中,所述的式I化合物具有以下式Ib所示的结构:
式中,
R1选自下组:取代或未取代的C1-C4的烷基、C1-C4的卤代烷基;
R2与R8共同构成-O-;
R7选自下组:C1-C4的烷基、C1-C4的卤代烷基;
其余各基团的定义如权利要求1中所述。
在另一优选例中,R5选自下组:卤素、氰基、羟基、-COOR、取代或未取代C1-C10烷基、取代或未取代的C1-C10卤代烷基、-NH-R;其中,R选自下组:H、C1-C4的酰基、C1-C4的烷基、C1-C4的卤代烷基、取代或未取代(优选为取代)的C7-C11芳基-酰基。
在另一优选例中,R6选自下组:卤素、氰基、羧基、羟基、取代或未取代C1-C10烷基、取代或未取代的C1-C10卤代烷基、-NH-R;其中,R选自下组:H、C1-C4的酰基、C1-C4的烷基、C1-C4的卤代烷基。
在另一优选例中,R2选自下组:羟基;
R4选自下组:H、卤素、氰基、羧基、羟基、;
R5选自下组:H、卤素、氰基、羟基、-COOR、取代或未取代C1-C10烷基、取代或未取代的C1-C10卤代烷基、-NH-R;其中,R选自下组:H、C1-C4的酰基、C1-C4的烷基、C1-C4的卤代烷基、取代或未取代(优选为取代)的C7-C11芳基-酰基;
R6选自下组:H、卤素、氰基、羧基、羟基、取代或未取代C1-C10烷基、取代或未取代的C1-C10卤代烷基、取代或未取代(优选为取代)的C7-C11芳基-酰基、-NH-R;其中,R选自下组:H、C1-C4的酰基、C1-C4的烷基、C1-C4的卤代烷基;
所述的“取代”指基团上的一个或多个氢原子被选自下组的取代基取代:羧基、苯基、C3-C6的环烷基、卤素、C1-C10烷基-氧基、羟基、羟基-C1-C10的亚烷基,或单糖基-O-。
在另一优选例中,所述的A、R1、R2、R3、R4、R5、R6、R7、R8和R9为如实施例中各具体化合物所对应的基团。
在另一优选例中,所述的药物组合物还用于选自下组的用途:
j)(体外非治疗性地)增加肝细胞对LDL的摄取率;
k)(体外非治疗性地)上调肝细胞LDLR基因表达水平。
在另一优选例中,所述的药物组合物中,所述式I化合物的有效剂量为0.1-50mg/kg体重,较佳地为1-20mg/kg体重。
在另一优选例中,所述的药物组合物为选自下组的剂型:口服剂型、注射剂型。
在另一优选例中,所述的剂型包括片剂、颗粒剂、胶囊剂、丸剂等。
本发明的第二方面,提供了一种药盒,所述药盒含有:
(i)第一容器,以及装于该第一容器中的活性成分(a)式I化合物;或含有活性成分(a)的药物;
(ii)第二容器,以及装于该第二容器中的活性成分(b)他汀类药物,或其药学上可接受的盐;或含有活性成分(b)的药物;以及
(iii)说明书,所述说明书中记载了联合给予活性成分(a)和活性成分(b)从而降低使用对象体内低密度脂蛋白含量的说明。
在另一优选例中,所述的式I化合物如本发明第一方面中所述。
在另一优选例中,所述的使用对象为哺乳动物,较佳地为人。
在另一优选例中,所述的他汀类药物选自下组:普伐他汀、阿伐他汀,或其组合。
本发明的第三方面,提供了一种如下式I所示的化合物:
其中,所述的化合物选自下组:
本发明的第四方面,提供了一种如下式I所示的化合物,或其药学上可接受的盐的用途:
其中,A、R1、R2、R3、R4、R5、R6、R7、R8和R9等定义如本发明第一方面中所述,并且所述的为双键或单键;其中,所述的化合物被用于选自下组的用途:
a)降低施用对象的血脂水平;
b)降低施用对象低密度脂蛋白(LDL)含量;
c)稳定施用对象LDLR基因稳定性;
d)上调施用对象LDLR基因表达;
e)增加施用对象肝细胞表面LDLR受体数量;
f)减少施用对象LDLR受体降解;
g)降低施用对象血液中TC和/或TG浓度;
h)增加施用对象血液中高密度脂蛋白(HDL)浓度;
i)改善施用对象肝功能损伤。
在另一优选例中,所述的施用对象为哺乳动物,较佳地为人。
在另一优选例中,所述的肝功能损伤为高脂诱导的肝功能损伤。
在另一优选例中,所述的改善肝功能损伤为降低ALT\AST指标。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1化合物2-8对低密度脂蛋白基因表达水平的影响;
图2化合物3腹腔给药对高脂模型金黄地鼠血脂指标的影响;
图3化合物3腹腔给药对高脂模型金黄地鼠高密度脂蛋白在总胆固醇中比例的影响;
图4化合物3腹腔给药对高脂模型金黄地鼠肝功能指标的影响;
图5化合物3口服给药对高脂模型金黄地鼠总胆固醇水平的影响;
图6化合物3口服给药对高脂模型金黄地鼠甘油三酯水平的影响;
图7化合物3口服给药对高脂模型金黄地鼠低密度脂蛋白水平的影响;
图8化合物3口服给药对高脂模型金黄地鼠高密度脂蛋白在总胆固醇中比例的影响。
具体实施方式
本发明人经过长期而深入的研究,意外地发现,竹柏内酯类化合物具有良好的降血脂活性,且活性优于现有通用的降血脂化合物他汀类药物。所述的化合物可以时间依赖性及剂量依赖性地在体内或体外降低总胆固醇、甘油三酯、低密度脂蛋白浓度,并增加高密度脂蛋白浓度。基于上述发现,发明人完成了本发明。
术语
如本文所用,术语“C1-C4烷基”或“C1-C10烷基”指具有1~4个或1-10个碳原子的直链或支链烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基,或类似基团。
术语“C3-C6环烷基”指具有3~6个碳原子的环烷基,例如环丙基、环丁基、甲基环丁基、环戊基,或类似基团。
如本文所用,术语“C1-C4酰基”指形如“具有0-3个碳原子的直链或支链烷基/环烷基/芳基/杂芳基-羰基”结构的取代基,如乙酰基、丙酰基、丁酰基,或类似基团。
术语“C1-C4亚烷基”指如上文所述的C1~C4烷基失去一个氢原子之后形成的基团,例如-CH2-、-CH2-CH2-,或类似基团。
术语“卤素”指F、Cl、Br和I。
术语“C6-C10芳基”指具有6-10个碳原子的芳基,例如苯基、萘基等,所述的芳基可以是取代或未取代的。
术语“C1-C10杂芳基”指具有1-10个碳原子和一个或多个选自O、S和/或N的杂原子的杂芳基,优选C2-C8杂芳基。所述的杂芳基可以是取代或未取代的。
本发明中,术语“含有”、“包含”或“包括”表示各种成分可一起应用于本发明的混合物或组合物中。因此,术语“主要由...组成”和“由...组成”包含在术语“含有”中。
本发明中,术语“药学上可接受的”成分是指适用于人和/或动物而无过度不良副反应(如毒性、刺激和变态反应),即有合理的效益/风险比的物质。
本发明中,术语“有效量”指治疗剂治疗、缓解或预防目标疾病或状况的量,或是表现出可检测的治疗或预防效果的量。对于某一对象的精确有效量取决于该对象的体型和健康状况、病症的性质和程度、以及选择给予的治疗剂和/或治疗剂的组合。因此,预先指定准确的有效量是没用的。然而,对于某给定的状况而言,可以用常规实验来确定该有效量,临床医师是能够判断出来的。
在本文中,除特别说明之处,术语“取代”指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、未取代或卤代的C1-C6烷基、未取代或卤代的C2-C6酰基、未取代或卤代的C1-C6烷基-羟基。
除非特别说明,本发明中,所有出现的化合物均意在包括所有可能的光学异构体,如单一手性的化合物,或各种不同手性化合物的混合物(即外消旋体)。本发明的所有化合物之中,各手性碳原子可以任选地为R构型或S构型,或R构型和S构型的混合物。
如本文所用,术语“本发明化合物”指式I所示的化合物。该术语还包括及式I化合物的各种晶型形式、药学上可接受的盐、水合物或溶剂合物。
如本文所用,术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸,甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯甲磺酸,苯磺酸等有机酸;以及天冬氨酸、谷氨酸等酸性氨基酸。
竹柏内酯类化合物
竹柏(Podocarpus nagi)为罗汉松科(Podocarpaceae)罗汉松属植物,主要化学成分为降二萜双内酯,具有抗肿瘤、抗菌、杀虫、生长调节抑制等作用。本发明人首次发现,竹柏内酯类化合物可以增强肝细胞摄取低密度脂蛋白的能力。体内药效学评价发现所述的化合物可以非常显著的降低高脂诱导脂质代谢紊乱的金黄地鼠的总胆固醇,甘油三酯,低密度脂蛋白等血脂指标,提高高密度脂蛋白在总胆固醇中的比例,改善其肝功能,同时可以缓解高脂饮食引起的脂肪肝形成,因此是一种潜在的降脂化合物。
具体地,本发明人从竹柏树皮、树枝、树叶和果实中,分离得到了以下的降二萜内酯类化合物1-25和N1-N20,其中1-25为已知化合物,N1-N20为新化合物:
竹柏内酯类化合物降低LDL浓度的用途
低密度脂蛋白受体(LDLR)是肝脏回收摄取低密度脂蛋白LDL的主要受体,于1974年被发现,并开始广泛开始其结构和功能方面的相关研究。LDLR由839个氨基酸残基构成,合成于粗面内质网,经过剪接和糖基化修饰后转运至细胞膜上的大小约160KD胞膜糖蛋白。LDLR基因突变是遗传性高血脂症的主要原因之一。
LDLR基因的表达水平和血浆胆固醇水平密切相关,位于LDLR基因启动子部位的SRE调节位点受细胞内SREBP1/2的调节,而后者是与胞内胆固醇水平密切相关。但细胞内胆固醇水平高时,SREBP被固定于ER膜上,不能进入高尔基体激活;当细胞内胆固醇水平降低时,SREBP在胆固醇的作用下被释放,随后转移到高尔基体内被剪接成活化蛋白,进入细胞核内,作为转录因子调节含有SRE的基因转录,包括LDLR,HMG-CoA R等胆固醇和脂肪酸代谢相关的基因。除了胆固醇水平调节,LDLR基因还受许多细胞因子和生长因子和激素的调节,如雌激素,肿瘤坏死因子,佛波酯,胰岛素等。他汀类药物是HMG-CoA R的抑制剂,本类药物通过抑制胆固醇的合成,降低细胞内胆固醇的含量,从而负反馈型上调LDLR的细胞内水平,达到进一步增强其降脂功能的作用。调节LDLR水平和功能是调节机体血脂水平的一个重要途径。
LDLR基因另外一个特点是其基因具有不稳定的特性,基因合成后在很短的时间内即降解。这个过程可能与LDLR基因本身的3′端序列有关。LDLR基因3′端含有AU富集区,此区被看做是基因不稳定的一个特征性序列,很多RNA结合蛋白可以与此序列结合,从而引起mRNA的迅速降解。小檗碱被报道可以增加LDLR基因的稳定性,提高其基因和蛋白水平,从而增加LDLR的功能,降低血浆LDL水平,经过临床试验已证实小檗碱是一个有效的通过调节LDLR水平发挥降脂效果的化合物。
本申请中,所述的竹柏内酯类化合物可以在体内或体外上调LDLR蛋白的基因表达水平,同时增加LDLR蛋白本身的稳定性,从而使得LDLR蛋白水平上调,进而促进肝细胞对于低密度脂蛋白的摄取。在体内实验中,所述的竹柏内酯类化合物对LDLR蛋白水平有上调作用,进而促进肝细胞对于低密度脂蛋白的摄取,从而降低血液中LDL浓度,达到清除LDL的目的。
除此之外,本发明人发现,在体内实验中,除了LDL水平得到下降之外,受试动物的血清总胆固醇(TC)水平,甘油三酯(TG)水平也同样得到下调。同时,高密度脂蛋白在总胆固醇中的比例显著提高。这说明竹柏内酯类化合物对于高脂诱导的脂肪肝形成具有减缓作用。
另外,在体内实验中,给予竹柏内酯类化合物对于高脂饮食导致的肝功能损伤也产生了一定的改善,具体表现为血液中天冬氨酸氨基转移酶、丙氨酸氨基转移酶指标水平的改善。
药物组合物和施用方法
由于本发明化合物具有优异的降低血液中LDL含量的活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解由于血液中LDL含量过高导致的疾病,如脂肪肝等。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-3000(活性剂量范围3-30mg/kg)mg本发明化合物/剂,更佳地,含有10-2000mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选6~600mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
与现有技术相比,本发明的主要优点包括:
1.首次发现竹柏内酯类化合物具有良好的降血脂活性,体外活性优于现有技术中已知的药物普伐他汀和阿伐他汀;
2.本发明的竹柏内酯化合物的降血脂活性具有明显的时间依赖性和剂量依赖性;
3.本发明的竹柏内酯化合物可以有效降低血液中LDL浓度作用机制:通过稳定LDLR基因的稳定性上调LDLR基因的表达,从而增加肝细胞表面LDLR受体数量,达到清除LDL的目的;
4.本发明化合物的体外、体内活性均有效,活性剂量低,可以在低达3mg/kg的剂量下就表现出降血脂效果,远低于与已报道的普伐他汀和小檗碱类药物起效剂量;
5.除了降低LDL外,还能降低血液中TC、TG浓度,并增加HDL(高密度脂蛋白,对机体有利的一种蛋白)浓度;
6.除了降低血脂指标外,对高脂诱导的肝功能损伤有明显的改善功能,能够显著降低ALT\AST(衡量肝功能指标)。
仪器和器材
此外光谱UV:SHIMADIU UV-2550和Beckman DU-7紫外可见光光谱仪;
红外光谱IR:Perkin-Elmer 577型红外分光光度仪;
低分辨质谱LR-EIMS:Finnigan MAT-95;
高分辨质谱HR-EIMS:Kratos 1H spectrometer;
核磁共振谱:Varian INOVA 600型核磁共振仪,Bruker AM-500,AM-400,AM-300型核磁共振仪,δ(ppm),以TMS为内标;
LC-MS:Agilent 1100液相偶联Bruker esquire质谱仪;
分析型HPLC:Waters 2690 Separate Model,Waters PDA 996检测器偶联AlltchELSD 2000检测器,Millennium 2000操作系统,Waters RP18 column(5.0×125mm,5μm,Waters),流速1.0ml/min,CH3CN(Merck,Germany),H2O(乐百氏);Jasco HPLC(ChiralcelIA column,5μm,150×4.6mm),流速0.6ml/min,hexane/ethanol(7:3).
HPLC-MS:Waters 2695 Separate Model,Waters PDA 2998检测器偶联AlltchELSD 2424检测器,3100 Ms detector,SunFireTM C-18 column(4.6×100mm,3.5μm,Waters),流速1.0ml/min,CH3CN(Merck,Germany),H2O(乐百氏);Jasco HPLC(ChiralcelIA column,5μm,150×4.6mm),流速0.6ml/min,hexane/ethanol(7:3).
制备型HPLC:Varian SD1 instrument,Varians 320单波长检测器,C18 column(220×25nm,10μm,Waters),流速15ml/min,CH3CN(Merck,Germany),H2O(乐百氏);
SpectraMax M2e多功能酶标仪(美国分子仪器公司);
电泳仪和半干电转印槽(Bio-Rad Laboratories,Hercules,CA);
PCR仪(Bio-Rad Laboratories,Hercules,CA);
台式冷冻离心机(德国Hettich公司);
752C紫外可见分光光度计(上海第三分析仪器);
DK-8B电热恒温水槽(上海精宏实验设备有限公司);
REVCO二氧化碳培养箱(美国REVCO公司);
试剂与材料
柱层析硅胶:100-200目,200-300目硅胶和硅胶H均为青岛海洋化工厂生产;
TLC薄层制备板:HSGF254为烟台化工厂生产。
MCI树脂:CHP20P(75-150μm)为三菱公司生产;
葡聚糖凝胶Sephadex LH-20:Pharmacia Biotech AB,Uppsala,Sweden。
显色剂:10%硫酸-香兰醛溶液,碘;
植物材料:竹柏枝叶采于广西田林,竹柏树皮采于海南琼中,由上海药物研究所标本室沈金贵副教授采集并鉴定,标本保存于本所标本室。
DMEM、胎牛血清(fetal bovine serum,FBS)购自Gibco-BRL(Grand Island,NY);DiI购自biotuim(Hayward,CA);β-actin抗体购自Cell Signaling Technology(Beverly,MA);LDLR,PCSK9抗体购自Abcam(Cambridge,UnitedKingdom);PCR引物在上海生工合成。蛋白酶抑制剂Cocktail购自Calbiochem(San Diego,CA);Immobilon-P transfer转移膜(PVDF)购自Millipore Corporation(Bedford,MA);增强化学发光试剂(Enhancedchemiluminescence reagents,ECL)购自Pierce(Rockford,IL);医用X-光胶片购自中国碧云天公司;TRIzol reagent购自Invitrogen(Carlsbad,CA);M-MLV反转录酶购自Promega(Madison,WI);Real time PCR反应试剂购自Bio-Rad Laboratories;金黄地鼠高脂饲料(0.12%胆固醇,10%椰子油)购自上海斯莱克斯公司。蛋白测定试剂盒购自中国碧云天公司;肝脏组织甘油三酯TG,总胆固醇TC含量测定试剂盒购自上海荣盛生物科技公司。血液指标(总胆固醇TC,甘油三酯TG,高密度脂蛋白HDL,低密度脂蛋白LDL,丙氨酸氨基转移酶ALT,天冬氨酸氨基转移酶AST)测定试剂盒购自四川迈克生物公司。其他试剂除特殊说明外均购自上海国药集团。
实验动物为雄性叙利亚金黄地鼠,体重100±10g,购自中国科学院上海实验动物中心。动物放置于中国科学院上海药物研究所SPF动物房(温度23±1℃;湿度60%),自然昼/夜循环,用标准的食物和水饲养。(实验批准号:SIMM-AE-2010-10-WYP-01)
实施例1化合物1-12的提取分离方法
竹柏树皮(16.2kg)打粉后用95%乙醇浸泡,室温提取三次,合并提取液并浓缩至无醇味,然后转移至龙头瓶中,分别用石油醚、氯仿、乙酸乙酯、正丁醇与水分配,得到石油醚部位(95g)、氯仿部位(15g)、乙酸乙酯部位(255g),氯仿部位和乙酸乙酯部位合并,硅胶柱纯化(200-300目,青岛海洋化工生产),用氯仿:甲醇系统200∶1,100∶1,50∶1,30∶1,20∶1,10∶1,5∶1,丙酮洗脱,TLC检测后合并得到12个馏分,馏分2通过凝胶柱层析(氯仿/甲醇1∶1),再通过硅胶柱层析(氯仿/丙酮50∶1-10∶1)得到化合物2(188mg),12(209mg)和一个组分(78mg),该组分通过Pre-HPLC制备分离得到化合物1(12mg)。馏分4和5分别经凝胶和硅胶柱层析分别得到化合物10(304mg)和11(99mg),馏分6经过硅胶和凝胶柱层析以及Pre-HPLC制备分离分别得到化合物3(1.2g)和4(2.1g),馏分7和8合并经MCI和硅胶柱层析得到化合物7(380mg)。
竹柏枝叶(11.3kg)粉碎,用95%乙醇浸泡三次,浓缩提取液至无醇味,然后依次用石油醚、二氯甲烷、乙酸乙酯和正丁醇分别与水分配,得到二氯甲烷部位(175g)和乙酸乙酯部位(105g),氯仿和乙酸乙酯部位分别经硅胶、凝胶、MCI、Pre-HPLC等柱层析得到化合物2(470mg),3(3.6g),4(36mg),5(78mg),6(17mg),7(1.1g),8(2mg),9(15mg)。
每种化合物的特性如下:
1-Deoxynagilactone A(1)
白色粉末,MF:C19H24O5,ESIMS m/z 333.1[M+H]+.377.1[M+HCOO]-;1H NMR(300MHz,CDCl3):δ5.94(s,1H,H-11),5.30(d,J=9.0Hz,1H,H-7),5.00(dd,8.7,5.9,1H,H-6),3.26(m,1H,H-15),2.74(s,1H),2.37-2.23(m,1H),1.82(d,J=5.7Hz,1H,H-5),1.60(s,3H),1.52(m,2H),1.34(3H×2),1.25(d,J=6.9Hz,3H,H-16).13C NMR(400MHz,CDCl3):δ28.2(t,C-1),17.4(t,C-2),32.4(t,C-3),43.2(s,C-4),50.0(d,C-5),73.3(d,C-6),60.6(d,C-7),109.5(s,C-8),171.2(s,C-9),35.7(s,C-10),105.2(d,C-11),162.4(s,C-12),165.4(s,C-14),29.4(d,C-15),20.1(q,C-16),20.7(q,C-17),23.3(q,C-18),179.9(s,C-19),25.0(q,C-20).
3-Deoxynagilactone(2)
白色粉末,MF:C19H22O6,ESIMS m/z 347.1[M+H]+,391.3[M+HCOO]-;1H NMR(300MHz,CDCl3):δ5.90(s,1H,H-11),5.29(d,J=8.9Hz,1H,H-7),4.98(dd,J=8.7,6.0Hz,1H,H-6),3.50(m,1H,H-2),3.25(d,J=6.8Hz,1H,H-15),3.23(d,J=2.3Hz,1H,H-1),2.44(d,J=14.5,2.3Hz,1H,H-3a),1.85(d,J=14.4Hz,1H,H-3b),1.71(d,J=5.7Hz,1H,H-5),1.55(s,3H,H-20),1.51(s,3H,H-18),1.32(d,J=6.6Hz,3H,H-16),1.25(d,J=6.6Hz,3H,H-17).
Nagilactone A(3)
白色粉末,MF:C19H24O6.ESIMS m/z:349.2[M+H]+,719.3[2M+Na]+.393.2[M+HCOO]-,1H NMR(300MHz,Pyr):δ1.26(d,J=6.6Hz,3H),1.30(d,J=6.6Hz,3H),1.33(s,3H,H-18),1.55(m,1H),1.81(d,J=5.9Hz,1H,H-5),2.01(s,3H,H-17),2.55(m,1H),3.50(m,1H,H-15),4.18(m,1H,H-1),5.17(dd,J=5.7,8.6Hz,1H,H-6),5.67(d,J=8.2Hz,1H,H-7),7.38(s,1H,H-11).
1-Deoxy-2-hydroxy-nagilactone A(4)
白色粉末,MF:C19H24O6.ESIMS m/z:349.2[M+H]+,719.3[2M+Na]+,393.7[M+HCOO]-,1H NMR(300MHz,Pyr):δ1.26(d,J=6.7Hz,3H,H-17),1.33(d,J=6.7Hz,3H,H-16),1.45(s,3H,H-18),1.84(s,3H,H-20),1.82(d,J=5.3Hz,H-5),2.05(dd,J=13.3,6.5Hz,1H),2.24(dd,J=13.7,4.9Hz,1H),2.53(m,1H),2.69(t,J=13.1Hz,1H),3.48(m,1H,H-15),4.35(br m,1H,H-2),5.11(dd,J=6.5,8.5Hz,1H,H-6),5.63(d,J=8.4Hz,1H,H-7),6.33(s,1H,H-11),7.80(brs,1H).
Episellowin C(5)
白色粉末,MF:C19H24O6.ESIMS m/z:349.2[M+H]+,719.3[2M+Na]+,393.2[M+HCOO]-,.1H NMR(300MHz,Pyr):δ1.23(d,J=6.8Hz,3H,H-16),1.31(d,J=6.8Hz,3H,H-17),1.64(s,3H,H-20),1.74(s,3H,H-18),1.82(d,J=4.8Hz,1H,H-5),2.20-2.00(m,2H,H-2),3.50(m,1H,H-15),3.82(dd,J=6.3,10.9Hz,1H,H-3),5.21(dd,J=4.7,8.8Hz,1H,H-6),5.65(d,J=8.9Hz,1H,H-7),6.15(s,1H,H-11).
Nagilactone C(6)
白色粉末,MF:C19H22O7.ESIMS m/z:363.1[M+H]+,747.3[2M+Na]+,407.0[M+HCOO]-,1H NMR(300MHz,Pyr):δ3.71(d,J=4.3Hz,1H,H-1),3.56(dd,J=6.2,4.5Hz,1H,H-2),4.71(d,J=6.2Hz,1H,H-3),2.12(d,J=6.7Hz,1H,H-5),4.98(dd,J=8.0,6.5Hz,1H,H-6),5.66(d,J=8.0Hz,1H,H-7),6.71(s,1H,H-11),3.47(q,J=6.8Hz,1H,H-15),1.25(d,J=6.8Hz,3H,H-16),1.33(d,J=6.8Hz,3H,H-17),1.49(s,1H,H-18),2.12(s,3H,H-20).
Nagilactone B(7)
白色粉末,MF:C19H24O7,ESIMS m/z:365.2[M+H]+,751.4[2M+Na]+,363.3[M-H]-,727.5[2M-H]-,1H NMR(300MHz,Pyr):δ7.04(s,1H,H-11),5.66(d,J=8.7Hz,1H,H-7),5.18(m,1H,H-6),4.33(m,2H),3.50(m,1H,H-15),2.76(t,J=12.5Hz,1H),2.13(d,J=17.1Hz,1H),2.03(s,3H,H-20),1.92(d,J=6.8Hz,1H,H-5),1.48(s,3H,H-18),1.33(d,J=6.8Hz,3H,H-16),1.27(d,J=6.7Hz,3H,H-17).
Urbalactone(8)
白色粉末,MF:C19H24O7,ESIMS m/z:365.2[M+H]+,751.3[2M+Na]+,409.2[M+HCOO]-,727.3[2M-H]-,1H NMR(300MHz,Pyr):δ7.48(s,1H,H-11),5.72(d,J=8.7Hz,1H,H-7),5.25(m,1H,H-6),4.50(m,1H),4.50(d,J=6.1Hz,1H),3.53(m,1H,H-15),3.04(ddd,J=12.5,4.5,1.5Hz,1H),2.24(d,J=6.1,1.5Hz,1H),2.06(s,3H,H-20),1.98(d,J=6.8Hz,1H,H-5),1.58(s,3H,H-18),1.33(d,J=6.8Hz,3H,H-16),1.27(d,J=6.7Hz,3H,H-17).
3β-hydroxy-nagilactone A(9)
白色粉末,MF:C19H24O7,ESIMS m/z:365.1[M+H]+,751.3[2M+Na]+,409.0[M+HCOO]-,727.1[2M-H]-,1H NMR(300MHz,Pyr):δ7.49(s,1H,H-11),5.74(d,J=8.7Hz,1H,H-7),5.25(dd,J=8.7,4.7Hz,1H,H-6),4.19(dd,1H),4.04(dd,1H),3.53(m,1H,H-15),2.67(m,1H),2.52(m,1H),2.15(s,3H,H-20),1.94(d,J=4.9Hz,1H,H-5),1.72(s,3H,H-18),1.33(d,J=6.8Hz,3H,H-16),1.27(d,J=6.7Hz,3H,H-17)
15-Methoxycarbonyl-nagilactone D(10)
白色粉末,MF:C20H22O8,ESIMS m/z:391.1[M+H]+,413.1[M+Na]+,389.3[M-H]-,1HNMR(300MHz,Pyr):δ6.77(s,1H,H-11),5.00(dd,J=16.1,6.8Hz,1H,H-6),4.69(d,J=5.8Hz,1H,H-3),4.34(q,J=7.0Hz,1H,H-15),3.73(t,J=5.8Hz,1H,H-1),3.68(s,2H,H-7a),3.58(dd,J=9.4,5.0Hz,1H,H-2),2.95(dd,J=16.4,6.5Hz,1H,H-7),1.87(d,J=6.7Hz,1H,H-5),1.58(s,3H),1.56(s,3H),1.42(s,3H).
2,3-Dihydro-2-hydroxypodolide(11)
白色粉末,MF:C19H24O6,ESIMS m/z:349.1[M+H]+,393.2[M+HCOO]-,1H NMR(300MHz,CDCl3):δ6.03(s,1H,H-11),4.93(d,J=4.8Hz,1H,H-6),4.42(d,J=3.3Hz,1H,H-14),4.06(m,1H,H-2),3.96(s,1H,H-7),3.49(s,1H),2.36(m,1H,H-3),2.17(t,J=13.3Hz,1H,H-1),1.91(m,1H,H-15),1.85(d,J=5Hz,1H,H-5),1.80-1.74(m,1H),1.51(m,1H,H-3),1.38(s,3H,H-18),1.28(s,3H,H-20),1.10(d,J=6.7Hz,6H,H-16 and H-17).
Nagilactone E(12)
白色粉末,MF:C19H24O6,ESIMS m/z:349.1[M+H]+,719.3[2M+Na]+,347.0[M-H]-.1HNMR(300MHz,CDCl3):δ5.97(s,1H,H-11),4.99(d,J=3.7Hz,1H,H-6),4.42(d,J=3.8Hz,1H,H-14),3.97(s,1H,H-7),3.67(m,1H,H-3),3.47(d,J=10.0Hz,1H),2.17(m,1H),1.93-1.72(m,3H),1.59(s,3H),1.52(s,3H),1.24(d,J=8.1Hz,3H),1.11(dd,J=6.7,4.5Hz,6H).
实施例2化合物13-25、N1-N20的提取分离方法
竹柏树枝和果实(24kg)粉碎后,用95%工业乙醇室温浸泡三天,反复三次,合并提取液,减压浓缩至无醇味,将总浸膏悬浮于5L水中,用石油醚、乙酸乙酯依次萃取,每种溶剂反复三次,减压浓缩萃取液,得石油醚部位(215g),乙酸乙酯部位(675g)和水部位(1.2kg)。乙酸乙酯部位分别经MCI树脂、聚酰胺柱色谱、正相硅胶柱色谱、Sephadex LH-20柱色谱、制备型高效液相进行分离纯化,共得到10个化合物:2(110mg)、3(48mg)、4(150mg)、13(23mg)、14(15mg)、15(8mg)、N1(34mg)、N2(26mg)、N3(18mg)、N4(9mg)、N5(12mg)、N20(5mg);水部位经过大孔树脂柱层析后,40%的乙醇洗脱部位分别经硅胶柱层析、凝胶柱层析、制备型高效液相进行分离纯化,共分离得到32个化合物:2(30mg)、4(180mg)、5(11mg)、6(57mg)、7(68mg)、8(9mg)、9(6mg)、16(6mg)、17(12mg)、18(26mg)、19(13mg)、20(11mg)、21(13mg)、22(17mg)、23(5mg)、24(9mg)、25(13mg)、N6(18mg)、N7(36mg)、N8(14mg)、N9(19mg)、N10(12mg)、N11(15mg)、N12(46mg)、N13(54mg)、N14(29mg)、N15(63mg)、N16(33mg)、N17(24mg)、N18(39mg)、N19(41mg)。经过理化性质、波谱数据和质谱分析鉴定,化合物2、3-9、13-25为已知化合物,N1-N20为新化合物。
已知化合物的特性如下:
2、4-9的理化性质及波谱数据与实施例1中的数据一致。化合物13-25的理化性质及波谱学数据如下:
16-hydroxy nagilactone E(13)
白色粉末,MF:C19H24O7,EIMS m/z:364[M]+.13C NMR(125MHz,Py-d5):δ178.4(C-19),164.4(C-12),159.9(C-9),117.3(C-11),82.9(C-14),73.4(C-3),73.0(C-6),62.9(C-16),59.4(C-8),55.4(C-7),46.2(C-4),45.8(C-5),37.1(C-10),35.1(C-15),29.8(C-1),29.0(C-2),24.4(C-19),22.5(C-20),16.6(C-17).
sellowin A(14)
白色粉末,MF:C19H24O8,EIMS m/z 362[M]+,13C NMR(100MHz,Py-d5):δ30.9(C-1),52.4(C-2),53.2(C-3),43.6(C-4),43.6(C-5),73.8(C-6),55.2(C-7),58.8(C-8),159.1(C-9),36.1(C-10),117.6(C-11),164.2(C-12),82.9(C-14),35.0(C-15),62.9(C-16),16.5(C-17),21.6(C-18),177.6(C-19),21.6(C-20).
2β-hydroxy nagilatone F(15)
白色粉末,MF:C19H24O5,EIMS m/z:332[M]+.13C NMR(125MHz,MeOH-d4):δ183.6(C-19),165.6(C-12),161.2(C-9),134.6(C-8),123.8(C-7),113.0(C-11),84.8(C-14),74.0(C-6),65.1(C-2),46.4(C-5),43.9(C-4),41.2(C-1),37.2(C-10),31.3(C-15),28.5(C-20),23.5(C-18),19.9(C-17),15.5(C-16).
2β,16-dihydroxy nagilactone F(16)
白色粉末,MF:C19H24O6,EIMS m/z:348[M]+.1H NMR(400MHz,Py-d5):δ6.52(brs,1H,H-7),6.10(s,1H,H-11),5.15(dd,J=3.0,1.8Hz,1H,H-14),5.09(d,J=1.8,H-6),4.32(m,1H,H-2β),4.17(dd,J=10.7,4.3Hz,1H,H-16b),3.95(dd,J=10.7,7.9Hz,1H,H-16a),2.61(m,overlap,1H,H-15),2.57(m,overlap,1H,H-3β),2.52(dd,J=13.6,9.1Hz,1H,H-1α),2.21(dd,J=13.5,5.1Hz,1H,H-3α),1.87(dd,J=13.5,7.1Hz,1H,H-1β),1.83(d,J=5.2Hz,1H,H-5),1.41(d,J=6.8Hz,3H,H-17),1.39(s,3H,H-18),1.32(s,3H,H-20).
Nagilactone I(17)
白色粉末,MF:C19H24O6,EIMS m/z:376[M]+.1H NMR(400MHz,Py-d5):δ6.16(brs,1H,H-7),5.83(d,J=1.6Hz,1H,H-11),5.22(brs,1H,H-14),5.02(t-like,1H,H-6),4.10(m,1H,H-2β),3.71(s,3H,H-OMe),3.18(dq,J=6.8,3.6Hz,1H,H-15),2.41(dd,J=9.1,12.6Hz,1H,H-3α),2.21(t,J=12.6Hz,1H,H-1β),1.93(dd,J=9.1,4.0Hz,1H,H-1α),1.92(d,J=5.2Hz,1H,H-5),1.60(dd,1H,J=13.5,7.1Hz,1H,H-3β),1.39(s,3H,H-20),1.38(d,J=7.4Hz,1H,H-17),1.28(s,3H,H-18).
Nagilactone D(18)
白色粉末,MF:C19H24O5,EIMS m/z:332[M]+.1H NMR(400MHz,Py-d5):δ6.70(s,1H,H-11),4.94(dt,1H,J=3.0Hz,H-6),4.70(m,J=3.2Hz,1H,H-3),3.76(d,J=4.2Hz,1H,H-1),3.58(dd,J=5.8,4.2Hz,1H,H-2),3.32(dd,J=16.5,7.6Hz,1H,H-7a),2.78(dd,J=16.6,6.7Hz,1H,H-7b),2.48(q,J=7.8,6.8Hz,2H,H-15),1.93(d,J=6.8Hz,1H,H-5),1.57(s,3H,H-18),1.46(s,3H,H-19),1.11(t,J=7.5Hz,3H,H-16).
3β-hydroxy-7-deoxy-17-nor-nagilactone(19)
白色粉末,MF:C19H24O8,EIMS m/z 364[M]+,13C NMR(125MHz,Py-d5):δ179.1(C-17),164.4(C-9),163.3(C-14),163.0(C-12),108.6(C-11),108.4(C-8),79.2(C-1),75.6(C-3),75.3(C-2),74.4(C-6),50.6(C-5),46.4(C-4),43.2(C-10),26.2(C-7),25.1(C-15),23.7(C-18),15.6(C-20),12.2(C-16).
3-epinagilactone C(20)
白色粉末,MF:C19H22O7.EIMS m/z:362[M]+.1H NMR(400MHz,Py-d5):δ3.68(br d,J=3.6Hz,1H,H-1),3.58(dd,J=6.0,4.1Hz,1H,H-2),4.83(br s,H-3),2.27(d,J=6.2Hz,1H,H-5),5.14(dd,J=7.7,6.2Hz,1H,H-6),5.66(d,J=7.7Hz,1H,H-7),6.71(s,1H,H-11),3.47(q,J=6.6Hz,1H,H-15),1.27(d,J=6.6Hz,3H,H-16),1.33(d,J=6.6Hz,3H,H-17),1.70(s,1H,H-18),1.60(s,3H,H-20).
nagilactoside B(21)
白色固体,MF:C25H34O11,ESIMS m/z:511.1[M+H]+.13C NMR(125MHz,CD3OD):δ183.6(C-19),170.9(C-14),167.5(C-9),166.4(C-12),112.7(C-8),108.8(C-11),101.8(C-1’),78.8(C-3’),78.0(C-5’),77.2(C-2’),75.8(C-6),74.9(C-1),71.6(C-4’),63.9(C-6’),60.8(C-7),50.2(C-5),44.6(C-4),31.3(C-10),30.4(C-15),27.4(C-2),26.0(C-3),24.1(C-20),20.7(C-16),20.6(C-17),18.0(C-18).
nagilactoside A(22)
白色固体,MF:C25H34O11,ESIMS m/z:511.1[M+H]+.13C NMR(125MHz,CD3OD):δ182.3(C-19),170.4(C-14),166.9(C-9),162.7(C-12),112.1(C-8),107.3(C-11),104.0(C-1’),79.2(C-3’),79.1(C-5’),75.8(C-2’),75.5(C-6),72.5(C-2),72.3(C-4’),63.4(C-6’),60.5(C-7),48.8(C-5),43.1(C-4),42.3(C-1),37.7(C-10),32.4(C-3),30.2(C-15),27.8(C-20),24.4(C-16),21.2(C-17),20.8(C-18).
nagilactoside D(23)
白色粉末,MF:C37H54O21,ESIMS m/z 673.2[M+H]+.13C NMR(125MHz,CD3OD):δ183.8(C-19),171.7(C-14),168.8(C-9),165.1(C-12),112.6(C-8),106.9(C-11),105.1(C-1”),103.7(C-1’),78.2(C-5”),78.0 and 77.9(C-5’and C-3”),77.2(C-3’),76.0(C-2),75.0(C-6),73.7(C-2”),71.7(C-2’),71.5(C-4’),70.2(C-4”),62.8(C-6’),60.9(C-7),60.8(C-6”),43.8(C-4),42.4(C-1),38.2(C-10),34.4(C-3),30.4(C-15),27.7(C-20),24.2(C-18),20.8(C-16),20.5(C-17).
nagilactoside C(24)
白色粉末,MF:C37H54O21,ESIMS m/z 673.2[M+H]+.13C NMR(125MHz,CD3OD):δ183.7(C-19),171.6(C-14),168.8(C-9),164.9(C-12),112.6(C-8),106.8(C-11),105.2(C-1”),103.1(C-1’),87.8(C-3’),78.2(C-5”),77.8 and 77.6(C-5’and C-3”),76.0(C-2),75.8(C-6),74.4(C-2”),73.5(C-2’),71.6(C-4’),7O.2(C-4”),62.8(C-6’),62.7(C-6”),60.8(C-7),43.7(C-4),42.3(C-1),38.2(C-10),34.1(C-3),30.4(C-15),27.8(C-20),24.1(C-18),20.8(C-16),20.5(C-17).
nagilactoside F(25)
白色粉末,MF:C37H54O21,ESIMS m/z 835.3[M+H]+.13C NMR(125MHz,CD3OD):δ183.7(C-19),171.6(C-14),168.8(C-9),164.9(C-12),112.6(C-8),106.8(C-11),105.3 and104.3(C-1”and C-1”’),102.9(C-1’),89.6(C-3”),77.8(C-1),75.1(C-6),62.6 and 62.5(C-6”and C-6’”),60.8(C-7),49.3(C-5),43.7(C-4),42.3(C-1),38.2(C-10),34.2(C-3),30.4(C-15),27.7(C-20),24.1(C-18),20.8(C-16),20.5(C-17).
新化合物的特性如下:
N1:
白色固体,MF:C19H24O5,MW=332.1H NMR(400MHz,Pyr-d5):δ6.29(s,1H,H-11),5.02(m,1H,H-6),4.36(dddt,J=11.8,9.0,5.6Hz,1H,H-2),3.47(dd,J=16.7,9.9Hz,1H,H-7a),3.06(m,1H,H-15),2.77(dd,J=16.7,6.1Hz,1H,H-7b),2.57(dd,J=13.8,12.4Hz,1H,H-3a),2.50(m,1H,H-1a),2.23(dd,J=13.6,5.2Hz,1H,H-3b),2.00(dd,J=13.6,6.4Hz,1H,H-1b),1.64(d,J=6.4Hz,1H,H-5),1.39(s,3H,H-18),1.30(s,3H,H-20),1.20(d,J=6.5Hz,3H,H-16),1.13(d,J=6.5Hz,3H,H-17)
13C NMR(100MHz,Pyr-d5):δ182.4(C-19),166.3(C-9),165.6(C-14),163.0(C-12),107.1(C-11),106.9(C-18),74.7(C-6),64.2(C-2),47,9(C-4),43.8(C-1),42.6(C-4),38.4(C-10),38.3(C-3),26.0(C-7),25.9(C-20),24.8(C-18),20.4(C-16),20.3(C-17).
N2:
白色固体,MF:C18H18O5,MW=330.1H NMR(400MHz,Pyr-d5):δ6.79(s,1H,H-11),6.78(dd,1H,J=16.7,11.0Hz,H-15),6.24(d,J=16.7Hz,1H,H-16a),5.56(d,J=11.2Hz,1H,H-16b),4.91(dt,J=9.7,6.6Hz,1H,H-6),4.71(d,J=5.9Hz,1H,H-3),3.74(d,J=4.2Hz,1H,H-1),3.60(dd,J=16.5,9.3Hz,1H,H-7α),3.58(m,1H,H-2),2.78(dd,1H,J=16.6,9.3Hz,H-7β),1.97(d,J=6.7Hz,1H,H-5),1.55(s,3H,H-19),1.47(s,3H,H-17).
13C NMR(100MHz,Pyr-d5):δ177.9(C-18),164.4(C-9),161.5(C-12),154.9(C-14),126.1(C-15),122.1(C-16),110.3(C-8),109.8(C-11),72.9(C-6),68.0(C-3),57.9(C-1),52.2(C-2),50.8(C-5),50.1(C-4),38.7(C-10),26.6(C-17),25.8(C-7),18.2(C-19).
N3:
白色固体,MF:C19H24O8,MW=364.1H NMR(400MHz,Pyr-d5):δ6.73(s,1H,H-11),5.74(d,J=8.9Hz,1H,H-7),5.42(dd,J=8.9,4.9Hz,1H,H-6),4.82(m,1H,H-2α),4.79(m,1H,H-1α),4.56(d,J=3.0Hz,1H,H-3α),3.55(m,1H,H-15),2.89(d,J=4.9Hz,1H,H-5),2.37(s,3H,H-20),1.80(s,3H,H-18),1.37(d,J=6.7Hz,3H,H-17),1.25(d,J=6.8Hz,3H,H-16).
13C NMR(100MHz,Pyr-d5):δ180.3(C-19),170.9(C-14),164.9(C-9),163.1(C-12),113.1(C-8),106.8(C-11),75.3(C-6),74.5(C-1),74.1(C-2),73.3(C-3),61.6(C-7),47.4(C-5),46.5(C-4),41.9(C-10),30.1(C-15),23.6(C-20),23.5(C-18),21.4(C-17),20.4(C-16).
N4:
白色固体,MF:C19H22O6,MW=362.1H NMR(400MHz,Pyr-d5):δ6.16(s,1H,H-11),5.56(d,J=3.4Hz,1H,H-7),5.26(dd,J=6.1,3.4Hz,1H,H-6),3.46(td,J=2.4,1.1Hz,1H,H-2),3.33(d,J=3.8Hz,1H,H-3),2.28(dd,/=14.5,2.4Hz,1H,H-1a),1.83(d,J=6.5Hz,3H,H-16),1.83(d,J=6.5Hz,3H,H-17),1.78(m,1H,H-1b),1.74(d,J=6.9Hz,1H,H-5),1.49(s,3H,H-18),1.29(3,3H,H-20).
13C NMR(100MHz,Pyr-d5):δ178.2(C-19),168.4(C-14),165.7(C-9),161.3(C-12),114.2(C-8),105.6(C-11),85.1(C-6),74.6(C-15),68.2(C-7),53.4(C-3),52.8(C-2),47.2(C-5),43.9(C-4),36.2(C-10),33.5(C-1),30.7(C-16),30.1(C-17),25.0(C-20),22.3(C-18).
N5:
白色固体,MF:C19H24O7,MW=364.1H NMR(400MHz,Pyr-d5):δ6.31(s,1H,H-11),5.91(d,J=8.30Hz,1H,H-7),5.06(m,1H,H-6),4.30(m,1H,H-2),4.23(t,J=9.7Hz,1H,H-16b),3.95(m,1H,H-16a),3.84(m,1H,H-15),2.66(d,J=13.1Hz,1H,H-3β),2.44(dd,J=13.3,8.2Hz,1H,H-1α),2.22(dd,J=14.5,5.0Hz,1H,H-3α),2.01(dd,J=13.4,6.7Hz,1H,H-1β),1.84(s,3H,H-20),1.62(d,J=6.5Hz,1H,H-5),1.38(s,3H,H-18),1.36(s,3H,H-17).
13C NMR(100MHz,Pyr-d5):δ182.6(C-19),168.7(C-14),167.1(C-9),163.7(C-12),114.0(C-8),107.2(C-11),75.6(C-6),65.6(C-16),64.5(C-2),60.7(C-7),48.7(C-5),44.4(C-1),43.5(C-4),39.0(C-15),38.1(C-3),37.9(C-10),28.1(C-20),24.7(C-18),15.7(C-17)
N6:
白色固体,MF:C19H24O7,WM=364.1H NMR(400MHz,Pyr-d5):δ6.13(s,1H,H-11),5.96(d,J=8.9Hz,1H,H-7),5.16(dd,J=8.8,4.7Hz,1H,H-6),4.25(t,J=9.7Hz,1H,H-3),3.97(dd,J=10.2,5.4Hz,1H,H-16a),3.89(m,1H,H-5),3.77(dd,J=11.2,6.3Hz,1H,H-16b),1.79(s,3H,H-18),1.63(d,J=4.8Hz,1H,H-5),1.61(s,3H,H-20),1.36(d,J=6.8Hz,3H,H-16).
13C NMR(100MHz,Pyr-d5):δ179.6(C-19),168.9(C-14),166.6(C-9),162.9(C-12),115.1(C-8),105.1(C-11),75.0(C-6),74.2(C-3),65.5(C-16),61.6(C-7),52.6(C-5),47.0(C-4),39.1(C-15),36.8(C-10),32.4(C-1),29.4(C-2),23.1 and 23.0(C-18 andC-20),15.7(C-17).
N7:
白色固体,MF:C19H24O6,MW=348.1H NMR(400MHz,Pyr-d5):δ6.18(s,1H,H-11),5.66(d,J=8.7Hz,1H,H-7),5.17(dd,J=8.5,5.8Hz,1H,H-6),3.46(m,1H,H-3),3.50(t,J=6.7Hz,1H,H-15),2.03(d,J=5.9Hz,1H,H-5),1.70(3,3H,H-20),1.65(s,1H,H-18),1.34(d,J=6.8Hz,1H,H-16),1.27(d,J=6.8Hz,1H,H-17).
13CNMR(100MHz,Pyr-d5):δ182.0(C-19),170.5(C-14),167.6(C-9),162.9(C-12),112.3(C-8),106.1(C-11),75.7(C-6),65.8(C-3),61.0(C-7),50.5(C-5),49.2(C-4),36.5(C-10),31.3(C-1),30.1(C-15),28.3(C-2),26.2(C-20),21.3(C-16),20.6(C-17),19.0(C-18).
N8:
白色固体,MF:C19H22O6,MW=346.1H NMR(400MHz,Pyr-d5):δ6.67(d,J=3.3Hz,1H,H-1),6.66(s,1H,H-11),6.22(dd,J=10.0,1.7Hz,1H,H-2),5.71(d,J=8.5Hz,1H,H-7),5.36(m,1H,H-3),5.27(dd,J=8.4,6.2Hz,1H,H-6),3.54(m,1H,H-15),2.03(d,J=6.2Hz,1H,H-5),1.74(s,3H,H-20),1.68(s,3H,H-18),1.33(d,J=6.5Hz,3H,H-16),1.27(d,J=6.5Hz,3H,H-17).
13C NMR(100MHz,Pyr-d5):δ183.3(C-19),170.9(C-14),163.1(C-9),162.7(C-12),135.4(C-2),133.3(C-1),112.5(C-8),106.6(C-11),76.5(C-6),66.6(C-3),60.9(C-7),52.3(C-5),52.0(C-4),38.8(C-10),30.1(C-15),23.5(C-20),21.2(C-16),20.6(C-17),19.7(C-18).
N9:
白色固体,MF:C25H34O12,WM=526.1H NMR(400MHz,CD3OD):δ6.61(dd,J=10.2,3.1Hz,H-16a),6.34(s,1H,H-11),6.02(dd,J=10.1,1.6Hz,H-2),5.40(d,J=8.6Hz,1H,H-7),5.19(dd,J=8.4,6.1Hz,1H,H-6),4.81(brs,1H,H-3),4.59(d,J=7.8Hz,1H,H-1’),3.89(dd,J=11.7,2.4Hz,H-6’a),3.66(dd,J=11.7,7.0Hz,1H,H-6’b),3.35(m,1H,H-15),3.25-3.30(overlap,3H,H-3’,4’and 5’),3.20(m,1H,H-2’),2.01(d,J=6.0Hz,1H,H-5),1.47(s,3H,H-18),1.40(s,3H,H-20),1.32(d,J=6.8Hz,3H,H-16),1.28(d,J=6.8Hz,3H,H-17).
13C NMR(100MHz,CD3OD):δ183.7(C-19),172.1(C-14),164.5(C-12),164.4(C-9),134.0(C-1),132.0(C-2),112.7(C-8),106.2(C-11),105.3(C-1’),78.2 and 78.1(C-3’and 5’),76.5(C-6),75.6(C-2’),75.1(C-3),72.0(C-4’),63.4(C-6’),61.1(C-7),52.4(C-5),51.9(C-4),38.9(C-10),30.5(C-15),23.6(C-20),20.8(C-17),20.5(C-16),19.7(C-18).
N10:
白色固体,MF:C25H34O11,WM=516.1H NMR(400MHz,CD3OD):δ5.97(s,1H,H-11),5.35(d,J=8.7Hz,1H,H-7),5.10(dd,J=8.7,5.1Hz,1H,H-6),4.44(d,J=7.8Hz,1H,H-1’),4.32(d,J=4.5Hz,1H,H-3),3.88(dd,J=12.0,1.4Hz,1H,H-6’a),3.70(m,1H,H-6’b),3.35-3.32(overlap,3H,H-2’,3’,and 4’),3.19(dd,J=9.2,7.8Hz,1H,H-2’),2.11(d,J=5.1Hz,1H,H-5),1.99(m,1H,H-2a),1.96(m,1H,H-1a),1.82(m,1H,H-1a),1.74(dd,J=11.3,5.84Hz,1H,H-1b),1.44(s,3H,H-18),1.42(m,1H,H-2b),1.41(s,3H,H-20),1.31(d,J=6.8Hz,3H,H-16),1.27(d,J=6.8Hz,3H,H-17).
13C NMR(100MHz,CD3OD):δ181.8(C-19),171.7(C-14),169.1(C-9),164.9(C-12),112.9(C-8),105.1(C-11),102.2(C-1’),78.2(C-3’),78.0(C-5’),76.2(C-6),75.0(C-2’),73.8(C-3),71.7(C-4’),62.9(C-6’),61.5(C-7),50.8(C-5),49.1(C-4),37.1(C-10),30.5(C-15),30.4(C-1),24.7(C-20),24.4(C-2),20.8(C-17),20.4(C-16),19.9(C-18).
N11:
白色固体,MF:C19H24O7,MW=364.1H NMR(600MHz,Pyr-d5):δ6.32(s,1H,H-11),5.16(dd,J=5.2,1.4Hz,1H,H-6),4.89(d,J=5.3Hz,1H,H-14),4.40(d,J=1.4Hz,1H,H-7),4.33(dd,J=10.5,3.8Hz,1H,H-16b),4.25(m,1H,H-2),4.09(dd,J=10.5,7.2Hz,1H,H-16a),2.50(t,J=13.1Hz,1H,H-3β),2.46(dd,J=13.5,8.7Hz,1H,H-1α),2.31(m,1H,H-15),2.18(dd,J=13.6,4.9Hz,1H,H-3α),1.98(d,J=5.0Hz,1H,H-5),1.82(dd,J=13.5,7.4Hz,1H,H-1β),1.36(d,J=6.7Hz,3H,H-17),1.34(s,3H,H-18),1.33(s,3H,H-20).
13C NMR(125MHz,Pyr-d5):δ181.7(C-19),164.2(C-12),159.9(C-9),118.5(C-11),82.8(C-14),73.4(C-6),64.0(C-2),62.8(C-6),58.2(C-8),55.3(C-7),42.8(C-5),42.7(C-4),40.9(C-1),38.9(C-3),37.4(C-10),35.1(C-15),28.9(C-19),23.3(C-20),16.5(C-17).
N12:
白色固体,MF:C25H34O12,WM=526.1H NMR(400MHz,CD3OD):δ6.00(s,1H,H-11),5.09(dd,J=4.1,1.5Hz,1H,H-6),4.71(d,J=4.8Hz,1H,H-14),4.37(d,J=7.8Hz,1H,H-1’),4.16(d,J=1.5Hz,1H,H-7),3.89(m,1H,H-6’a),3.85(d,J=12.1Hz,1H,H-16a),3.77(dd,J=10.2,5.7Hz,1H,H-3),3.65(dd,J=11.8,4.5Hz,1H,H-16b),3.53(dd,J=10.9,7.4Hz,1H,H-6’b),3.34(m,H-5’),3.30(overlap,3H,H-2’,3’and 4’),2.25(d,J=11.1Hz,1H,H-2a),1.96(d,J=4.1Hz,1H,H-5),1.91(m,1H,H-2b),1.82(m,1H,H-1a),1.61(m,1H,H-1b),1.51(s,3H,H-18),1.24(s,3H,H-20),1.15(d,J=6.8Hz,3H,H-17).
13C NMR(100MHz,CD3OD):δ179.2(C-19),165.7(C-12),161.2(C-9),117.3(C-11),107.6(C-1’),83.7(C-3),83.6(C-14),78.1(C-3’),77.8(C-5’),75.3(C-2’),73.7(C-6),71.5(C-4’),63.5(C-6’),62.8(C-6),59.4(C-8),55.4(C-7),47.4(C-4),46.4(C-3),37.3(C-10),35.0(C-15),29.8(C-1),28.0(C-2),24.6(C-20),21.9(C-18),16.1(C-17).
N13:
白色固体,MF:C25H34O11,WM=510.1H NMR(400MHz,CD3OD):δ5.98(s,1H,H-11),5.05(dd,J=4.4,1.2Hz,1H,H-6),4.77(d,J=4.5Hz,1H,H-14),4.26(d,J=6.8Hz,H-1’),4.25(s,1H,H-7),4.18(dd,J=10.2,3.4Hz,1H,H-16b),3.87(dd,J=11.8,1.7Hz,1H,H-6’b),3.65(dd,J=11.7,5.2Hz,1H,H-6’a),3.62(dd,J=10.2,7.9Hz,1H,H-16a),3.25-3.30(m,3H,H-3’,H-4’and H-5’),3.14(dd,J=9.2,7.8Hz,1H,H-2’),2.19(t-1ike,1H,H-15),2.12(m,1H,H-3β),1.89(d,J=4.4Hz,1H,H-5),1.73(m,1H,H-1β),1.69(m,2H,H-2),1.50(m,1H,H-1α),1.48(m,1H,H-3α),1.25(s,3H,H-18),1.19(d,J=6.8Hz,3H,H-17),1.12(s,3H,H-20).
13CNMR(100MHz,CD3OD):δ182.6(C-19),165.9(C-12),161.7(C-9),117.3(C-11),105.5(C-1’),83.3(C-14),78.0 and 78.1(C-3’and 4’),75.2(C-2’),74.1(C-6),72.3(C-16),71.7(C-5’),62.8(C-6’),59.2(C-8),55.4(C-7),44.8(C-5),43.2(C-4),37.3(C-10),33.8(C-15),30.5(C-1),29.5(C-3),25.1(C-20),24.4(C-18),18.6(C-2),16.3(C-17)
N14:
白色固体,MF:C25H34O12,WM=526.1H NMR(400MHz,CD3OD):δ6.01(s,1H,H-11),5.09(dd,J=4.0,1.2Hz,1H,H-6),4.81(d,J=4.5Hz,1H,H-14),4.29(d,J=1.8Hz,1H,H-1’),4.28(d,J=1.8Hz,1H,H-7),4.22(dd,J=10.1,3.5Hz,H-16a),3.91(dd,J=11.9,1.9Hz,1H,H-6’a),3.69(dd,J=7.6,4.2Hz,1H,H-6’b),3.67(m,1H,H-3),3.63(dd,J=10.2,8.0Hz,1H,H-6b),3.36(t,J=8.8Hz,1H,H-3’),3.30(d,J=2.0Hz,1H,H-5’),3.26(d,J=9.7Hz,1H,H-4’),3.18(dd,J=9.1,7.9Hz,1H,H-2’),2.21(s,1H,H-15),2.04(m,1H,H-2a),1.94(d,J=4.2Hz,1H,H-5),1.85(d,J=16.2Hz,1H,H-1a),1.79(d,J=11.5Hz,1H,H-2b),1.57(d,J=10.6Hz,1H,H-1b),1.49(s,3H,H-18),1.25(s,3H,H-20),1.22(d,J=6.8Hz,3H,H-17).
13C NMR(100MHz,CD3OD):δ179.5(C-19),165.8(C-12),161.1(C-9),117.1(C-11),105.5(C-1’),83.3(C-14),78.0 and 77.9(C-3’and 5’),75.2(C-2’),74.0(C-3),73.8(C-6),72.3(C-16),71.7(C-4’),62.8(C-6’),59.5(C-8),55.4(C-7),46.4(C-5),46.2(C-4),37.7(C-10),33.8(C-15),30.1(C-1),29.0(C-2),24.2(C-20),22.0(C-18),16.3(C-17).
N15:
白色固体,MF:C25H32O12,WM=524.1H NMR(400MHz,CD3OD):δ6.02(s,1H,H-11),5.08(dd,J=4.0,1.2Hz,1H,H-6),4.79(d,J=4.6Hz,1H,H-14),4.29(d,J=1.8Hz,1H,H-1’),4.27(m,1H,H-7),4.20(dd,J=10.2,3.5Hz,H-16a),3.91(dd,J=11.9,2.0Hz,1H,H-6’a),3.69(dd,J=11.8,5.4Hz,1H,H-6’b),3.63(dd,J=10.2,7.8Hz,1H,H-16b),3.46(dt,J=3.8,1.9Hz,1H,H-2),3.36(t,J=8.8Hz,1H,H-3’),3.25-3.32(over1ap,3H,H-3’,H-4’andH-5’),3.18(m,1H,H-2’),2.33(dd,J=14.8,2.2Hz,1H,H-1a),2.20(d,J=3.7Hz,1H,H-15),1.94(d,J=14.6Hz,1H,H-1b),1.85(d,J=4.6Hz,1H,H-5),1.51(s,3H,H-18),1.28(s,3H,H-20),1.21(d,J=6.8Hz,3H,H-17).
13C NMR(100MHz,CD3OD):δ177,8(C-19),164.3(C-12),159.4(C-9),115.9(C-11),104.1(C-1’),81.9(C-14),76.6 and 76.7(C-3’and 5’),73.8(C-2’),73.1(C-6),70.8(C-16),70.3(C-4’),61.4(C-6’),57.5(C-8),53.9(C-7),52.2(C-3),51.6(C-2),42.7(C-5),42.8(C-4),35.3(C-10),32.4(C-15),29.9(C-1),24.8(C-20),22.0(C-18),14.9(C-17).
N16:
白色固体,MF:C25H34O10,MW=494.1H NMR(400MHz,CD3OD):δ5.76(d,J=1.7Hz,1H,H-11),5.25(m,1H,H-6),5.13(d,J=2.2Hz,1H,H-14),4.25(d,J=7.8Hz,1H,H-1’),4.05(dd,J=10.1,4.7Hz,1H,H-16b),3.88(dd,J=11.8,1.5Hz,1H,H-6,b),3.65(dt,J=5.7,4.1,1.7Hz,1H,H-6’a),3.50(dd,J=10.1,1.9Hz,1H,H-16a),3.25-3.35(m,3H,H-3’,H-4’and H-5’),3.17(dd,J=7.9,9.7Hz,1H,H-2’),2.63(m,1H,H-15),2.17(m,1H,H-3β),2.08(d,J=4.8Hz,1H,H-5),1.74(m,1H,H-1β),1.70(m,2H,H-2),1.55(m,1H,H-3α),1.34(s,3H,H-18),1.30(m,1H,H-1α),1.25(d,J=6.8Hz,3H,H-17),1.15(s,3H,H-20).
13C NMR(100MHz,CD3OD):δ183.7(C-19),166.5(C-12),161.7(C-9),134.4(C-8),124.3(C-7),112.2(C-11),105.1(C-1’),83.3(C-14),78.0 and 78.1(C-3’and 4’),75.2(C-2’),73.8(C-6),71.6(C-5’),71.4(C-16),62.7(C-6’),48.3(C-5),44.3(C-4),37.6(C-15),36.4(C-10),31.0(C-1),28.9(C-3),25.7(C-20),24.4(C-18),18.5(C-2),15.3(C-17).
N17:
白色固体,MF:C25H32O10,MW=492.1H NMR(400MHz,CD3OD):δ6.55(m,1H,H-7),5.98(m,1H,H-2),5.84(d,J=10.0Hz,1H,H-3),5.80(d,J=1.7Hz,1H,H-11),5.29(m,1H,H-6),5.20(d,J=2.1Hz,1H,H-14),4.28(d,J=7.8Hz,1H,H-1’),4.08(dd,J=10.1,4.7Hz,1H,H-16b),3.90(dd,J=11.7,1.2Hz,1H,H-6’b),3.67(dt,J=5.5,11.8Hz,1H,H-6’a),3.50(dd,J=10.0,8.1Hz,1H,H-16a),3.27-3.35(m,3H,H-3’,H-4’and H-5’),3.18(dd,J=9.2,7.9Hz,1H,H-2’),2.66(m,1H,H-15),2.29(d,J=5.0Hz,1H,H-5),2.25(m,1H,H-1β),1.42(s,3H,H-18),1.30(m,1H,H-1α),1.28(d,J=6.8Hz,3H,H-17),1.17(s,3H,H-20).
13C NMR(100MHz,CD3OD):δ181.1(C-19),166.3(C-12),160.2(C-9),134.5(C-8),129.0(C-3),128.0(C-2),124.1(C-7),112.2(C-11),105.1(C-1’),83.3(C-14),78.0(C-3’and 4’),75.0(C-2’),73.1(C-6),71.7(C-5’),71.5(C-16),62.7(C-6’),47.9(C-5),46.1(C-4),37.4(C-15),36.0(C-10),34.1(C-1),23.5(C-20),23.1(C-18),15.4(C-17)
N18:
白色固体,MF:C31H44O16,WM=672.1H NMR(400MHz,CD3OD):δ7.44(s,1H,H-11),5.31(d,J=8.7Hz,1H,H-7),5.04(dd,J=8.5,6.3Hz,1H,H-6),4.60(d,J=8.2Hz,1H,H-1’),4.58(d,J=7.4Hz,1H,H-1”),4.27(dd,J=6.5,3.8Hz,1H,H-1),3.94(dd,J=12.3,2.2Hz,1H,H-6’a),3.86(dd,J=11.7,2.3Hz,1H,H-6”a),3.76(dd,J=12,2,5.8Hz,1H,H-6’b),3.63(m,1H,H-6”b),3.58(m,1H,H-3’),3.46(m,1H,H-4”),3.42(m,1H,H-2’),3.25-3.36(m,6H,H-2”,3”,5”,4’,5’and H-15),2.32(ddd,J=15.2,10.8,5.0Hz,1H,H-2a),1.93-1.95(m,2H,H-1),1.53(m,1H,H-2b),1.47(s,3H,H-20),1.31(s,3H,H-18),1.28(d,J=6.8Hz,3H,H-16),1.23(d,J=6.8Hz,3H,H-17).
13C NMR(100MHz,CD3OD):δ180.6(C-19),170.9(C-14),167.4(C-9),166.3(C-12),112.7(C-8),108.8(C-11),105.2(C-1”),101.4(C-1’),87.5(C-3’),78.2(C-5”),77.9 and77.8(C-5’and C-3”),77.2(C-1),75.8(C-6),75.5(C-2”),74.4(C-2’),71.6(C-4’),70.0(C-4”),63.1(C-6’),62.7(C-6”),60.9(C-7),50.2(C-5),44.5(C-4),41.4(C-10),30.4(C-15),27.4(C-3),25.9(C-2),24.1(C-18),20.7(C-17),20.6(C-16),18.0(C-20)
N19:
White power,MF:C37H54O21,WM=834.1H NMR(400MHz,CD3OD):δ7.41(s,1H,H-11),5.32(d,J=8.6Hz,1H,H-7),5.04(dd,J=8.5,6.2Hz,1H,H-6),4.58(d,J=7.9Hz,1H,H-1’),4.39(d,J=7.9Hz,1H,H-1”),4.30(d,J=7.9Hz,1H,H-1”’),4.28(m,2H,H-1),2.30(m,1H,H-2a),1.93-1.95(m,2H,H-1),1.91(d,J=6.3Hz,1H,H-5),1.48(m,1H,H-2b),1.47(s,3H,H-20),1.30(s,3H,H-18),1.28(d,J=6.8Hz,3H,H-16),1.22(d,J=6.8Hz,3H,H-17).
13C NMR(100MHz,CD3OD):δ183.6(C-19),170.9(C-14),167.5(C-9),166.3(C-12),112.7(C-8),108.7(C-11),104.9 and 104.4(C-1”and C-1”’),101.4(C-1’),82.4(C-3”),77.2(C-1),75.8(C-6),70.1(C-6’),62.7 and 62.5(C-6”and C-6”’),60.9(C-7),50.2(C-5),44.6(C-4),41.4(C-10),30.4(C-15),27.4(C-3),25.6(C-2),24.1(C-18),20.7(C-17),20.6(C-16),18.0(C-20).
N20:
白色固体,MF:C18H20O6,MW=332.1H NMR(400MHz,Pyr-d):δ6.70(s,1H,H-11),5.05(d,1H,J=3.0Hz,H-6),4.70(d,J=3.2Hz,1H,H-3),3.74(d,J=1.6Hz,1H,H-1),3.59(dd,J=3.2,3.1Hz,1H,H-2),3.38(dd,J=16.6,9.8Hz,1H,H-7a),2.69(dd,J=16.5,6.5Hz,1H,H-7b),2.49(m,2H,H-15),2.10(d,J=6.7Hz,1H,H-5),1.67(s,3H,H-18),1.11(t,J
=7.6Hz,3H,H-16),1.04(s,3H,H-20).
实施例4化合物活性测试
1.1竹柏内酯类化合物活性测试
前述分离以及化学合成的各化合物(终浓度为5μM)处理脱脂血清饥饿12小时的HepG2细胞24小时,加入荧光标记的低密度脂蛋白(DiI-LDL)20μg/ml,37℃孵育4小时,用磷酸盐缓冲液(PBS)轻轻洗细胞5次后用异丙醇提取脂质,于酶标仪上测定荧光读数(激发光:520nm;发射光570nm)。然后用0.2M氢氧化钠裂解细胞,测定蛋白含量,计算出荧光/蛋白的数值。实验结果见表1,多个化合物中在5μM浓度下对低密度脂蛋白LDL摄取起到显著增强作用。对结构改造得的新化合物,也表现出HepG2肝细胞低密度脂蛋白摄取有增强作用(表1)。
表1.部分化合物对肝细胞低密度脂蛋白摄取的增强作用
作用强度+:101%-120%;++:121%-140%;+++:141%-160%;++++:161%-180%;
1.2竹柏内酯类化合物促进肝细胞低密度脂蛋白(LDL)摄取活性机制研究化合物上调低密度脂蛋白受体(LDLR)基因表达水平
LDLR蛋白水平上调可能是由两方面原因引起的:LDLR基因水平上升或LDLR蛋白本身的稳定性增加。基于以上的条件,检测了LDLR基因的表达水平。用化合物2-7,9在5μM浓度下处理肝细胞24小时,TRIzol试剂提取细胞总RNA,取3μg RNA用M-MLV(逆转录酶)反转录成cDNA,再用LDLR的特异性引物进行real-time PCR(实时定量PCR),以GAPDH作为内参照基因比对化合物对LDLR基因的调节作用。实验结果参见图1,化合物3,4,7显著性提高了LDLR基因的表达水平。与LDL摄取实验一致,促进LDL摄取率提高比较多的化合物3,4,7,同样在增加LDLR基因表达方面效果非常显著,分别达到了对照组基因表达水平的2倍(P<0.05,与对照组相比),4.5倍(P<0.001,与对照组相比)和3倍(P<0.001,与对照组相比)的表达水平。
实验中用到的基因引物序列及PCR条件见表2。
表2.引物序列及PCR反应条件
1.3化合物3腹腔给药体内降脂药效研究
实验动物
雄性叙利亚金黄地鼠,体重100±10g,购自中国科学院上海实验动物中心。
药物配制
化合物3用5%DMSO,2%Tween80及93%的生理盐水配制成15mg/ml的混悬药液,使用前超声混匀。每只动物给予200μl/100g的给药体积,给药剂量为30mg/kg.
实验方法
金黄地鼠适应性饲养一周后按照其初始血脂和体重水平随机平均分组。高脂模型组和给药组给予高脂饲料,给药组给予30mg/kg的化合物3,高脂模型组腹腔注射给予同等体积的溶剂(5%DMS,2%Tween80,93%生理盐水),正常饲料对照组给予正常饲料。实验开始两周后每周禁食16小时后自眼眶下静脉采血一次,测定血脂指标。四周后断颈处死金黄地鼠,肝脏称重,保存于-80℃待用。
血脂测定:血液4℃放置两小时使其分层,3000rpm,15min离心后吸取上层血清,用生理盐水稀释5倍后,用全自动生化分析仪测定血脂指标。
肝脏脂质测定:取200mg肝脏冰上于甲醇氯仿(v/v=8/1)溶液中匀浆,用氯仿萃取出有机相,氮气吹干,重新溶于乙酸乙酯中,用TG,TC测定试剂盒测定肝脏脂质含量。
统计方法:每组至少6只动物,应用Prism软件进行统计分析。对多组间差异比较采用ANOVA分析;两组间比较采用t检验。
实验结果
血脂测定实验结果参见图2。腹腔给予高脂喂养金黄地鼠化合物3(30mg/kg/day)两周后,金黄地鼠血液指标:总胆固醇TC,甘油三酯TG,低密度脂蛋白LDL明显改善,与高脂模型组相比,其水平显著下降(P<0.05,与高脂饮食组相比)。
高密度脂蛋白HDL在总胆固醇中的比例却显著提高(P<0.05,与高脂饮食组相比),结果参见图3。
由于高脂喂养造成的脂肪肝的影响,高脂模型组金黄地鼠肝功能损伤,血液中天冬氨酸氨基转移酶AST,丙氨酸氨基转移酶ALT水平上升,而给药组明显改善了这一症状,降低了两个肝功能指标水平。其中AST水平差异显著(P<0.05,与高脂饮食组相比)。说明化合物3具有改善肝功能的作用(图4)。
金黄地鼠肝脏脂质含量测定实验表明(表3):高脂喂养显著增加了金黄地鼠肝脏中甘油三酯和总胆固醇的含量,而给药组(化合物3,30mg/kg)的肝脏脂肪含量包括甘油三酯和总胆固醇明显下降。化合物3不仅可以改善血液中胆固醇指标,同时还可以减缓高脂诱导的脂肪肝形成。
表3.金黄地鼠肝脏脂质测定
(###P<0.001高脂饮食组vs正常饮食组,**P<0.01高脂饮食组vs高脂饮食+化合物组,*P<0.05高脂饮食组vs高脂饮食+化合物组)
1.4化合物3口服给药体内降脂药效研究
实验动物
雄性叙利亚金黄地鼠,体重100±10g,购自中国科学院上海实验动物中心。
药物配制
化合物3用5%CMC(羧甲基纤维素钠)配制成5mg/ml的混悬药液,使用前超声混匀。每只动物给予200μl/100g的给药体积,给药剂量为10mg/kg.
实验方法
金黄地鼠适应性饲养一周后按照其初始血脂和体重水平随机平均分组。高脂模型组和给药组给予高脂饲料,给药组口服给予10mg/kg的化合物3,高脂模型组口服给予同等体积的溶剂(5%CMC),正常饲料对照组给予正常饲料。实验开始每周禁食16小时后自眼眶下静脉采血一次,测定血脂指标。四周后断颈处死金黄地鼠,肝脏称重,保存于-80℃待用。
血脂测定:血液4℃放置两小时使其分层,3000rpm,15min离心后吸取上层血清,用生理盐水稀释5倍后,用全自动生化分析仪测定血脂指标。
统计方法:每组至少6只动物,应用Prism软件进行统计分析。对多组间差异比较采用ANOVA分析;两组间比较采用t检验。
实验结果
给药组与对照组在0周开始实验时其血脂指标非常接近,实验开始一周后,给药组即表现出了比较明显的降脂趋势,其总胆固醇TC(参见图5),甘油三酯TG(参见图6),低密度脂蛋白LDL水平(参见图7)较对照组相比明显降低,而高密度脂蛋白在总胆固醇中的比例
HDL/TC(参见图8)却有所上升(*P<0.05,#P<0.01,与高脂饮食组相比)。随着给药时间的延长,化合物3改善血液血脂指标的效果逐渐增强,其作用持续至四周实验结束。
综上所述,竹柏内酯类化合物在体外的LDL摄取实验中发挥了出乎意料的增强LDL摄取的效果。其中化合物3,4,7效果非常显著。在进一步的实验中,发现竹柏内酯类化合物是通过上调LDLR基因水平来实现其最终上调LDLR蛋白水平的效果的。选取了化合物3进行高脂诱导脂质代谢紊乱的金黄地鼠模型体内降脂的药效学评价。实验证实30mg/kg化合物3腹腔给药可以显著的降低金黄地鼠的总胆固醇,甘油三酯,低密度脂蛋白水平,同时升高“好胆固醇”高密度脂蛋白在总胆固醇中的比例。另外,化合物3改善了由于高脂饮食引起的脂肪肝的症状,降低了肝脏中总胆固醇和甘油三酯的含量,还可以改善肝功能。口服10mg/kg化合物3同样可以降低高脂诱导脂质代谢紊乱的金黄地鼠模型的总胆固醇,甘油三酯,低密度脂蛋白水平,同时升高“好胆固醇”高密度脂蛋白在总胆固醇中的比例。因此,实验证实,基于新的降脂靶点的竹柏内酯类化合物具有极高的临床应用价值和新药开发潜力。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (12)
1.一种如下式I所示的化合物,或其药学上可接受的盐的用途:
其中,
所述的式I化合物具有以下式Ia、Ib、化合物10或化合物17所示的结构:
且当所述的式I化合物为Ia结构时,R1选自下组:C1-C4的烷基;
R2选自下组:H、羟基;
R3选自下组:C1-C4的烷基;
R4选自下组:H、羟基;
R5选自下组:H、羟基、-O-单糖基、-O-二糖基,或-O-三糖基;
R6选自下组:H、羟基、-O-单糖基;
R7选自下组:C1-C4的烷基;
当所述的式I化合物为Ib结构时,R1选自下组:C1-C4的烷基;
R3选自下组:C1-C4的烷基;
R4选自下组:H、羟基;
R5选自下组:H、羟基;
R6选自下组:H;
R7选自下组:C1-C4的烷基;
R8与R2共同构成-O-;
其特征在于,所述的化合物被用于制备用于降血脂的药物组合物;或用于制备用于降低低密度脂蛋白(LDL)含量的药物组合物。
2.如权利要求1所述的用途,其特征在于,所述的式I化合物具有以下式Ia所示的结构:
式中,
各基团的定义如权利要求1中所述。
3.如权利要求1所述的用途,其特征在于,所述的式I化合物具有以下式Ib所示的结构:
式中各基团的定义如权利要求1中所述。
4.如权利要求1所述的用途,其特征在于,R5选自下组:羟基。
5.如权利要求1所述的用途,其特征在于,所述的式I化合物为Ia结构,且R6选自下组:羟基。
6.如权利要求1所述的用途,其特征在于,所述的式I化合物具有如下式所示的结构:
7.如权利要求1所述的用途,其特征在于,所述的药物组合物中,所述式I化合物的有效剂量为0.1-50mg/kg体重。
8.如权利要求1所述的用途,其特征在于,所述的药物组合物为选自下组的剂型:口服剂型、注射剂型。
9.如权利要求1所述的用途,其特征在于,所述的剂型选自片剂、颗粒剂、胶囊剂、或丸剂。
10.一种药盒,其特征在于,所述药盒含有:
(i)第一容器,以及装于该第一容器中的活性成分(a);或含有活性成分(a)的药物;
(ii)第二容器,以及装于该第二容器中的活性成分(b)他汀类药物,或其药学上可接受的盐;或含有活性成分(b)的药物,所述的他汀类药物选自下组:普伐他汀、阿伐他汀,或其组合;以及
(iii)说明书,所述说明书中记载了联合给予活性成分(a)和活性成分(b)从而降低使用对象体内低密度脂蛋白含量的说明;
其中,所述的活性成分(a)为如权利要求1所示的式I化合物。
11.一种化合物3的用途,
其特征在于,所述的化合物用于选自下组的任一用途:
制备用于降低血液中TC和/或TG浓度的药物组合物;
制备用于增加血液中高密度脂蛋白(HDL)浓度的药物组合物;或
制备用于改善肝功能损伤的药物组合物,且所述的肝功能损伤为高脂诱导的肝功能损伤。
12.如权利要求11所述的用途,其特征在于,所述的改善肝功能损伤为降低ALT\AST指标。
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