CN107362159A - 呫酮类化合物及其衍生物在制备降血脂药物中的应用 - Google Patents
呫酮类化合物及其衍生物在制备降血脂药物中的应用 Download PDFInfo
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- CN107362159A CN107362159A CN201610318173.7A CN201610318173A CN107362159A CN 107362159 A CN107362159 A CN 107362159A CN 201610318173 A CN201610318173 A CN 201610318173A CN 107362159 A CN107362159 A CN 107362159A
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- 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
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- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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Abstract
本发明涉及一类通式(Ⅰ)的,呫酮类化合物及其衍生物、对映异构体、非对映异构体、外消旋体和它们的混合物及其药学上可接受的盐及其组合物在制备具有预防和/或治疗高血脂症或者制备抑制前蛋白转化酶枯草溶菌素9(PCSK9)的产品中的新用途。
Description
技术领域
本发明涉及呫酮类化合物及其衍生物在制备降血脂产品中的新用途。
背景技术
现代社会中,肥胖、高血压、高血脂等健康问题日益严峻。高血脂是一种常见的多发性代谢性疾病,常表现为血清总胆固醇(TC)或甘油三酯(TAG)水平过高,常见于中老年人,但随着饮食结构的改变及饮酒量上升,青年患病率也逐年增高。高血脂症引起的动脉粥样硬化是诱发冠心病、高血压、心脑血管疾病的主要原因,并与糖尿病密切相关。对血脂异常进行干预是心血管疾病初级及二级预防的基础,因此,研究和开发新型降血脂药物具有重要的现实意义。
目前临床常使用的降血脂药物主要有他汀类、贝特类、烟酸类、胆酸螯合剂、胆固醇吸收抑制剂等。其中,他汀类药物因其药效和安全性的优势而居一线治疗地位,能有效降低血清中的LDL-C和TAG。贝特类降低TAG效果明显,烟酸缓释剂是最有效的升高HDL-C的药物,胆酸螯合剂和胆固醇抑制剂与他汀类联用,降低血清低密度脂蛋白胆固醇(LDL-C)作用明显。上述降脂药物虽然疗效确切,但大多数作用单一,具有易引起肝损伤、器质性病变、易反弹、复发率高、需长期服药等缺点,为临床用药带来了较大局限。此外,前蛋白转化酶枯草溶菌素9(PCSK9)作为与常染色体显性高胆固醇血症相关的新基因而成为新的治疗靶点。PCSK9的单克隆抗体(Evolocumab、Alirocumab等)、反义寡核苷酸、干扰小核糖核酸(siRNA)、模拟抗体蛋白药和小分子抑制剂等均能够抑制PCSK9,显著降低血清LDL-C,为难以接受大剂量他汀类药物治疗的患者提供了新选择。
山竹果壳作为东南亚国家和地区的传统药物一直用于腹痛、腹泻、痢疾、霍乱、感染性创伤、化脓、慢性溃疡等疾病的治疗。山竹果壳中含有多种药理活性成分,包括呫酮类、黄酮类、蒽醌类、脂肪酸、糖类、蛋白质、无机元素等。其中,呫酮类化合物是山竹果壳化学成分研究的重点,也是山竹果壳提取物中主要药理活性物质的来源基础。
发明内容
本发明的目的在于呫酮类化合物及其衍生物在制备降血脂产品以及在制备PCSK9抑制剂中的新用途。
本发明的一方面,提供了一种通式为(Ⅰ)的呫酮类化合物及其衍生物、对映异构体、非对映异构体、外消旋体和它们的混合物及其药学上可接受的盐在制备具有预防和/或治疗高血脂症或者制备抑制前蛋白转化酶枯草溶菌素9(PCSK9)的产品中的应用:
其中:
R1~R8各自独立地选自氢原子、羟基、卤素原子、氰基、硝基、砜基、亚砜基、C1~C10直链或支链饱和脂肪烷基或不饱和脂肪烷基、C1~C10直链或支链饱和脂肪羟烷基或不饱和脂肪羟烷基、C1~C10直链或支链饱和脂肪烃或不饱和脂肪烷氧基、C1~C10直链或支链饱和脂肪烃硫基或不饱和脂肪烃硫基、未取代或一取代或二取代含C1~C10的直链或支链饱和脂肪烃胺基、或未取代、取代的五~六元环烷胺基、含C1~C10的直链或支链饱和脂肪烃或不饱和脂肪烃基的低级烃酰基,低级烃酯基,低级烃酰胺基、含五~六元环的芳香烃酯基、酰胺基或杂环芳香烃酯基、酰胺基、C1~C10烷硫基或卤代C1~C10烷基、C2~C5烯基、C2~C5炔基、C3~C6环烷烃基、未取代、单取代或多取代五~六元单环芳香烃基、含1~3个N、O、S等杂原子的取代或未取代五~六元杂环芳香烃基、或稠环芳香烃基、稠环芳香杂环烃基。其中,R6为氢原子,或R1~R8均为氢原子或羟基,或R5为3-甲基-2-丁烯基的情况除外。
优选地,所述的化合物为R1~R8的取代基独立地选自氢原子、羟基、卤素原子、氰基、硝基、砜基、亚砜基、C1~C10直链或支链饱和脂肪烷基或不饱和脂肪烷基、C1~C10直链或支链饱和脂肪羟烷基或不饱和脂肪羟烷基、C1~C10直链或支链饱和脂肪烃或不饱和脂肪烷氧基、C1~C10直链或支链饱和脂肪烃硫基或不饱和脂肪烷硫基、未取代或一取代或二取代含C1~C10的直链或支链饱和脂肪烃胺基或未取代、取代的五~六元环烷胺基、含C1~C10的直链或支链饱和脂肪烃或不饱和脂肪烃基的低级烃酰基,低级烃酯基,低级烃酰胺基、含五~六元环的芳香烃酯基、酰胺基或杂环芳香烃酯基、酰胺基、C1~C10烷硫基或卤代C1~C10烷基、C2~C5烯基、C2~C5炔基、C3~C6环烷烃基、未取代、单取代或多取代五~六元单环芳香烃基、含1~3个N、O、S等杂原子的取代或未取代五~六元杂环芳香烃基、或稠环芳香烃基、稠环芳香杂环烃基。
更优选地,所述的化合物为R5为氢原子或羟基或甲氧基,R1和R6同时为羟基,其余取代基至少一个为不饱和烃基。
在上述任一优选例中,所述的化合物为R5为氢原子或羟基或甲氧基,R1和R6同时为羟基,其余取代基至少一个为烯基。
在上述任一优选例中,所述的化合物为R5为氢原子或羟基或甲氧基,R1和R6同时为羟基,其余取代基至少一个为碳原子个数大于或等于3的烯基。
在上述任一优选例中,所述的化合物为R5为氢原子或羟基或甲氧基,R1和R6同时为羟基,其余取代基至少一个为1,1-二甲基-2-丙烯基,或3-甲基-2-丁烯基,或3,7-二甲基-2,6-辛二烯基。
在上述任一优选例中,所述的化合物为1,3,6-三羟基-7-甲氧基-2,8-双(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,6-二羟基-3,7-二甲氧基-2,8-双(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,3,6,7-四羟基-2,8-双(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,3,5,6-四羟基-4-(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,3,6,7-四羟基-8-(3-羟基-3-甲基丁基)-2-(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,4,6,8-四羟基-7-(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,3,6-三羟基-7-甲氧基-4-(1,1-二甲基-2-丙烯基)-8-(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,3,6-三羟基-7-甲氧基-2-[(2E)-3,7-二甲基-2,6-辛二烯基]-9H-呫吨-9-酮、1,3,5,6-四羟基-2-(1,1-二甲基-2-丙烯基)-4,8-双(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,3,6-三羟基-7-甲氧基-8-[(2E)-3,7-二甲基-2,6-辛二烯基]-2-(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,5,6-三羟基-7-甲氧基-8-(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,3,6-三羟基-5-甲氧基-2-(1,1-二甲基-2-丙烯基)-7-(3-甲基-2-丁烯基)-9H-呫吨-9-酮。
本发明的另一方面,提供了所述的化合物包括作为活性成分的权利要求1-7项之化合物及其药用盐及药用载体在制备具有预防和/或治疗高血脂症或者制备抑制前蛋白转化酶枯草溶菌素9(PCSK9)的产品中的应用。
本发明的另一方面,提供了权利要求1中所述产品作为药物和/或保健品的应用。
本发明的其它方面由于本文的公开内容,对本领域的技术人员而言是显而易见的。
附图说明
图1.呫酮类化合物的结构通式。
图2.蛋白质印迹法检测呫酮类化合物对PCSK9蛋白表达水平的影响。
图3.呫酮类化合物给药前后对PCSK9蛋白表达水平影响的统计结果。
图4.呫酮类化合物给药前后SAMP8小鼠血浆甘油三酯比值。
图5.呫酮类化合物给药前后昆明小鼠血浆甘油三酯相对含量。
具体实施方式
呫酮类化合物及其衍生物
本发明中的呫酮类化合物也可称呫吨酮类化合物。此类化合物可以包括α-倒捻子素(α-mangostin,α-M,αM),它是山竹果皮分离得到的含量较高的呫酮类化合物,此外还包括β-及γ-倒捻子素等。它们的化学结构见式(Ⅱ)。
其中,α-倒捻子素对应式中R1=H,R2=CH3的化合物,
化学名称:1,3,6-三羟基-7-甲氧基-2,8-双(3-甲基-2-丁烯基)-9H-呫吨-9-酮。
β-倒捻子素对应式中R1=R2=CH3的化合物,
化学名称:1,6-二羟基-3,7-二甲氧基-2,8-双(3-甲基-2-丁烯基)-9H-呫吨-9-酮。
γ-倒捻子素对应式中R1=R2=H的化合物,
化学名称:1,3,6,7-四羟基-2,8-双(3-甲基-2-丁烯基)-9H-呫吨-9-酮。
此外,α-倒捻子素的结构类似物的CAS号及其结构式如下:
CAS号:13179-11-8
化学名称:1,3,5,6-四羟基-4-(3-甲基-2-丁烯基)-9H-呫吨-9-酮。
CAS号:76996-27-5
化学名称:1,3,6,7-四羟基-8-(3-羟基-3-甲基丁基)-2-(3-甲基-2-丁烯基)-9H-呫吨-9-酮。
CAS号:20245-38-9
化学名称:1,3,5–三羟基-2-(3-甲基-2-丁烯基)-9H-呫吨-9-酮
CAS号:112649-21-5
化学名称:1,3,6,7-四羟基-2,5,8-三(3-甲基-2-丁烯基)-9H-呫吨-9-酮
CAS号:3542-72-1
化学名称:1,3,6,7-四羟基氧杂蒽酮
CAS号:127716-76-1
化学名称:1,4,6,8-四羟基-7-(3-甲基-2-丁烯基)-9H-呫吨-9-酮
CAS号:84955-04-4
化学名称:1,3,6-三羟基-7-甲氧基-4-(1,1-二甲基-2-丙烯基)-8-(3-甲基-2-丁烯基)-9H-呫吨-9-酮
CAS号:21044-78-0
化学名称:1,3,6-三羟基-7-甲氧基-2-[(2E)-3,7-二甲基-2,6-辛二烯基]-9H-呫吨-9-酮
CAS号:105742-86-7
化学名称:1,3,5,6-四羟基-2-(1,1-二甲基-2-丙烯基)-4,8-双(3-甲基-2-丁烯基)-9H-呫吨-9-酮
CAS号:21044-85-9
化学名称:1,3,6-三羟基-7-甲氧基-8-[(2E)-3,7-二甲基-2,6-辛二烯基]-2-(3-甲基-2-丁烯基)-9H-呫吨-9-酮
CAS号:19274-65-8
化学名称:1,5,6-三羟基-7-甲氧基-8-(3-甲基-2-丁烯基)-9H-呫吨-9-酮
CAS号:130774-33-3
化学名称:1,3,6-三羟基-5-甲氧基-2-(1,1-二甲基-2-丙烯基)-7-(3-甲基-2-丁烯基)-9H-呫吨-9-酮
呫酮类化合物还可以包括上述化合物的结构类似物、衍生物、对映异构体、非对映异构体、外消旋体等。
药物组合物及药盒
为了便于临床应用,本发明的药物组合物可以包含在注射用给药器(如注射用针)中,所述的注射用给药器中,可以包含一次给药量的所述的药物组合物。所述的注射用给药器可以被包含在药盒中,以方便储存、使用。
本发明所述的药盒或试剂盒中,还可包括使用说明书,以利于本领域技术人员按照正确的方式使用。
本发明所述的呫酮类化合物及其衍生物可以与下列酸形成加成盐:硫酸、硝酸、盐酸、氢溴酸、氢碘酸、磷酸、甲酸、乙酸、丙酸、丁酸、丙二酸、己二酸、马来酸、柠檬酸、酒石酸、乳酸、甲磺酸、苯磺酸、对甲苯磺酸、门冬氨酸、萘二磺酸、草酸、苯甲酸、琥珀酸、樟脑磺酸、谷氨酸、天冬氨酸、苹果酸、水杨酸、抗坏血酸、异烟酸、扁桃酸、丙酮酸或富马酸等。
所述的呫酮类化合物或其药学上可接受的盐,还可以包括呫酮类化合物及其衍生物中的酸性基团和碱成的盐,所成的盐包括碱金属盐、季铵盐,如钠盐、钾盐、钙盐。季铵盐包括NR1R2,R1、R2选自C1~C10的烷烃。药学上可接受的盐的制备方法其特征在于:惰性碱为有机或无机碱,无机碱选自碳酸钾、碳酸钠、碳酸氢钠、醋酸钠、醋酸钾,有机碱选自三乙胺、吡咯、浓氨水、吡叮,惰性催化剂为N,N-二环己基碳二亚胺、N,N-二异丙基碳二亚胺、4-二甲胺基吡啶等。
药学上可接受的溶剂合物非限制性地包括化合物与水、乙醇、异丙醇、乙醚或丙酮的溶剂合物。
如本文所用,“药用”或“药学上可接受的”成分是适用于人和/或哺乳动物而无过度不良副反应(如毒性)的,即具有合理的效益/风险比的物质。术语“药学上可接受的载体”指用于治疗剂给药的载体,包括各种赋形剂和稀释剂。该术语指这样一些药剂载体:它们本身并不是必要的活性成分,且施用后没有过分的毒性。
合适的药学上可接受的载体或药用载体是本领域普通技术人员所熟知的。在Remington’s Pharmaceutical Sciences(Mack Pub.Co.,N.J.1991)中可找到关于药学上可接受的载体的充分说明。在组合物中药学上可接受的载体可含有液体,如水、BSS(Balanced Salt Solution)磷酸盐缓冲液、ringer溶液、生理盐水、平衡盐溶液、甘油或山梨醇等。另外,这些载体中还可能存在辅助性的物质,如润滑剂、助流剂、润湿剂或乳化剂、pH缓冲物质和稳定剂等。
所述药物的给药方式可以但不局限于口服、静注、肌注、喷射、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮内、皮下、静脉、粘膜组织;或是被其他物质混合或包裹后导入机体。所述的呫酮类化合物及其衍生物的药物组合物,其中含有有效量本发明化合物、其药学上可接受的盐或药学上可接受的溶剂合物,剂型可以是片剂、胶囊剂、散剂、颗粒剂、丸剂、栓剂、口服液、混悬剂、注射剂等药学上常见的剂型。
含有本发明化合物、其药学上可接受的药用盐或药学上可接受的载体的药物治疗剂量随病种、年龄、体重不同而变化,剂量范围为每天0.001-100mg/kg的任选范围,优选剂量范围为每天0.01-20mg/kg,更优选每天0.1-10mg/kg,可根据疾病程度的不同和剂型的不同偏离此剂量范围。
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。
本发明中的实施例如无特别说明,所用的实验动物、试剂、仪器、主要实验方法如下:
实验动物:正常昆明小鼠购自上海斯莱克实验动物有限责任公司;SAMP8小鼠购自天津中医药大学附属第一人民医院实验动物中心。光照周期:12h光照-12h黑暗,自由采食,自由饮水。
细胞:Hep G2人肝癌细胞来源于中国科学院细胞库(上海),目录号为TCHu 72;抗体:PCSK9一抗(Origin Rabbit)(货号ab31762,abcam,艾博抗贸易有限公司),二抗Donkey anti-Rabbit(货号#7074,Anti-rabbit IgG,HRP-linked Antibody,Cell Signaling Technology);脂质标准品:Avanti PolarLipidsinc(Alabama,USA)。
脂质组学方法:
1.1脂质提取方法:血浆样品采用甲基叔丁基醚进行两次萃取。首先,采用异丙醇/乙腈/水(体积比为75:20:5)混合溶剂配制混合内标溶液,混合内标为一系列机体内源性缺乏的脂质(其中包括TAG 17:0/17:0/17:0,DG 14:0/14:0,PE 17:0/17:0,PC 19:0/19:0,LPE 14:0,LPC 17:0,SM(d18:1/17:0),Cer(d18:1/17:0)和氘代花生四烯酸),内标的作用为校正分析物的提取回收率和质谱的响应。每种内标的终浓度均为10μg/mL。50μL血浆加入上述50μL混合内标溶液和0.75mL甲醇,并涡旋2min,使蛋白结合的脂质游离出,并使蛋白变性沉淀。然后加入2.5mL甲基叔丁基醚涡旋萃取10min,随后加入0.625mL水涡旋并离心使有机相和水相分层,其中含有脂质的上层有机相被转移至另外一个玻璃管中。下层用2mL的混合溶剂(为甲基叔丁基醚/甲醇/水(体积比为10:3:2.5)充分混合静置后的上层有机相)进行二次萃取,合并两次萃取的有机相于真空离心浓缩仪挥发浓缩,挥干后的样品重新用200μL异丙醇/乙腈/水(体积比为75:20:5)的混合溶剂进行复溶,并转移至进样小瓶中待LC-MS测定。
1.2色谱条件:色谱柱为Waters公司charged surface hybrid(CSHTM)C18色谱柱,2.1*100mm,1.7μm,流速为0.4mL/min,柱温维持在55℃。色谱洗脱采用梯度洗脱的方式对分析物进行洗脱,梯度洗脱的流动相变化如表1,样品进样量1μL。
表1.梯度洗脱时间表
流动相A:含异丙醇和乙腈(体积比90:10),含10mM的甲酸铵
流动相B:含乙腈和水(体积比60:40),含10mM的甲酸铵
1.3质谱条件:经3.1色谱条件洗脱后的洗脱液分别在正离子和负离子模式下进行电喷雾电离,质谱扫描模式选择TOF MS/MS模式,其中一个扫描循环包含一次母离子扫描(survey)和十次信息依赖的(information-dependentacquisition,IDA)子离子扫描,一次循环的总扫描时间为0.83s。离子源参数如下:离子源干燥气温度600℃,雾化气压力(GAS1)60psi,辅助干燥气压力(GAS2)60psi,气帘气压力35psi,喷雾电压5500V,碰撞气(CAD)压力10psi,碰撞气能量(CE)40±20V,去簇化电压(DP)80V。
1.4脂质鉴定和定量:由LipidviewTM软件的脂质库生成所有脂质的准分子离子峰列表(Na+,NH4 +和H+等加和物的分子质量),并导入获得的分子质量列表到总离子流色谱图(TIC)中提取得到相应的提取离子流色谱图(EIC);EIC中如未发现明显色谱峰,则认为该样品中不含该种脂质或者低于方法的检测限。EIC中如有一个或者多个色谱峰,则需要对峰进行筛选甄别,筛选的标准有四个:精确质量数(<5ppm),特异性的碎片离子(SM,PC和LPC具有质荷比为184.1的子离子;PE和LPE具有质荷比141的特异中性丢失(即母离子和子离子质荷比差值为141);TAG和DG的碎片离子跟其对应的脂肪酸相关;FFA在负离子模式有质荷比为18的特异中性丢失);保留时间(同类脂质中不同脂质分子保留时间应符合规律——双键越多和脂肪链越短对应越短的保留时间);同位素分布(和理论同位素分布模式比对);符合第二步筛选标准的色谱峰的峰面积用其对应的内标峰面积进行校正,两者的峰面积比作为脂质定量的相对浓度。
α-倒捻子素纳米粒制备方法:称取9mg MePEG3000-PLA4000和1mgMal-PEG3000-PLA4000至5mL EP管中,加入1mL的5mg/mLα-M二氯甲烷溶液,2mL 1%胆酸钠溶液,200w探头超声1s/s,超声2min,通风橱中搅拌挥发5min,然后旋转蒸发至无气泡产生,12500rpm/min离心45min,加入1mL去离子水,过Sepharose CL-4B柱,除去未包载的α-M。
实施例1.呫酮类化合物对前蛋白转化酶枯草溶菌素9(PCSK9)蛋白表达的影响
采用肝脏HepG2细胞,种于6孔板内,每孔细胞数约为6万,分为溶剂组,α-倒捻子素组,13179-11-8、76996-27-5、β-倒捻子素、γ-倒捻子素、CAS号为127716-76-1、84955-04-4、21044-78-0、105742-86-7、21044-85-9、19274-65-8、130774-33-3、20245-38-9、112649-21-5及3542-72-1组。药物给药剂量均为1000ng/mL,作用24h后,弃置培养基,加入100μL细胞裂解液后进行WesternBlot实验,一抗稀释浓度为PCSK9(Origin Rabbit)1:1000,4℃孵育过夜后,TBST清洗3次,二抗为Donkey anti-Rabbit1:3000室温孵育2h,TBST清洗3次后显色。实验结果表明,α-倒捻子素、13179-11-8和76996-27-5能够显著抑制PCSK9表达(图2),α-倒捻子素、13179-11-8和76996-27-5减少肝脏HepG2细胞中PCSK9表达比例分别为24.4%、25.4%和27.0%(图3A);呫酮类化合物β-倒捻子素、γ-倒捻子素、CAS号为127716-76-1、84955-04-4、21044-78-0、105742-86-7、21044-85-9、19274-65-8、130774-33-3的化合物也起到了抑制肝脏HepG2细胞PCSK9表达的作用;而呫酮类化合物20245-38-9、112649-21-5及3542-72-1对PCSK9水平无显著影响(图3B)。
实施例2.呫酮类化合物对血浆甘油三酯水平的影响
将7月龄SAMP8小鼠分为生理盐水组,载α-M纳米粒组,每组9只。SAMR小鼠作为正常对照,给予生理盐水。小鼠按照1mg/kgα-M的剂量尾静脉注射给药,每只注射0.2mL,连续给药4周。给药前后分别取血,采用脂质组学方法检测血浆甘油三酯水平。给予生理盐水的动物,随着月龄从7月龄增大至8月龄,血浆甘油三酯水平上升,给药后/给药前血浆甘油三酯比值为1.5左右,升高50%;而给予载α-M纳米粒组,随着月龄从7月龄增大至8月龄,血浆甘油三酯水平未发生明显上升,部分种类甚至有所下降,如图4所示,具有不同双键个数和脂肪链长度的血浆甘油三酯给药后/给药前比值等于或小于1。β-倒捻子素、γ-倒捻子素、CAS号为13179-11-8、76996-27-5、127716-76-1、84955-04-4、21044-78-0、105742-86-7、21044-85-9、19274-65-8、130774-33-3的化合物与α-倒捻子素类似,给药后,小鼠血浆甘油三酯水平亦未随月龄增大发生明显上升。
实施例3.呫酮类化合物对血浆甘油三酯水平的影响
昆明小鼠按照20mg/kgα-M的剂量口服给药,连续给药2周。在给药前和连续给药2周后分别取空腹血浆样品,采用脂质组学方法测定血浆中甘油三酯水平。如图5所示,具有不同双键个数和脂肪链长度的血浆甘油三酯水平在给药2周后发生明显下降。β-倒捻子素、γ-倒捻子素、CAS号为13179-11-8、76996-27-5、127716-76-1、84955-04-4、21044-78-0、105742-86-7、21044-85-9、19274-65-8、130774-33-3的化合物与α-倒捻子素类似,给药2周后小鼠血浆甘油三酯亦呈下降趋势。
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 (9)
1.一种通式为(Ⅰ)的呫酮类化合物及其衍生物、对映异构体、非对映异构体、外消旋体和它们的混合物及其药学上可接受的盐在制备具有预防和/或治疗高血脂症或者制备抑制前蛋白转化酶枯草溶菌素9(PCSK9)的产品中的应用:
其中:
R1~R8各自独立地选自氢原子、羟基、卤素原子、氰基、硝基、砜基、亚砜基、C1~C10直链或支链饱和脂肪烷基或不饱和脂肪烷基、C1~C10直链或支链饱和脂肪羟烷基或不饱和脂肪羟烷基、C1~C10直链或支链饱和脂肪烃或不饱和脂肪烷氧基、C1~C10直链或支链饱和脂肪烃硫基或不饱和脂肪烃硫基、未取代或一取代或二取代含C1~C10的直链或支链饱和脂肪烃胺基、或未取代、取代的五~六元环烷胺基、含C1~C10的直链或支链饱和脂肪烃或不饱和脂肪烃基的低级烃酰基,低级烃酯基,低级烃酰胺基、含五~六元环的芳香烃酯基、酰胺基或杂环芳香烃酯基、酰胺基、C1~C10烷硫基或卤代C1~C10烷基、C2~C5烯基、C2~C5炔基、C3~C6环烷烃基、未取代、单取代或多取代五~六元单环芳香烃基、含1~3个N、O、S等杂原子的取代或未取代五~六元杂环芳香烃基、或稠环芳香烃基、稠环芳香杂环烃基。其中,R6为氢原子,或R1~R8均为氢原子或羟基,或R5为3-甲基-2-丁烯基的情况除外。
2.根据权利要求1所述的应用,其特征在于,所述的化合物为R1~R8的取代基独立地选自氢原子、羟基、卤素原子、氰基、硝基、砜基、亚砜基、C1~C10直链或支链饱和脂肪烷基或不饱和脂肪烷基、C1~C10直链或支链饱和脂肪羟烷基或不饱和脂肪羟烷基、C1~C10直链或支链饱和脂肪烃或不饱和脂肪烷氧基、C1~C10直链或支链饱和脂肪烃硫基或不饱和脂肪烷硫基、未取代或一取代或二取代含C1~C10的直链或支链饱和脂肪烃胺基或未取代、取代的五~六元环烷胺基、含C1~C10的直链或支链饱和脂肪烃或不饱和脂肪烃基的低级烃酰基,低级烃酯基,低级烃酰胺基、含五~六元环的芳香烃酯基、酰胺基或杂环芳香烃酯基、酰胺基、C1~C10烷硫基或卤代C1~C10烷基、C2~C5烯基、C2~C5炔基、C3~C6环烷烃基、未取代、单取代或多取代五~六元单环芳香烃基、含1~3个N、O、S等杂原子的取代或未取代五~六元杂环芳香烃基、或稠环芳香烃基、稠环芳香杂环烃基。
3.根据权利要求1-2任一权利要求所述的应用,其特征在于,所述的化合物为R5为氢原子或羟基或甲氧基,R1和R6同时为羟基,其余取代基至少一个为不饱和烃基。
4.根据权利要求1-3任一权利要求所述的应用,其特征在于,所述的化合物为R5为氢原子或羟基或甲氧基,R1和R6同时为羟基,其余取代基至少一个为烯基。
5.根据权利要求1-4任一权利要求所述的应用,其特征在于,所述的化合物为R5为氢原子或羟基或甲氧基,R1和R6同时为羟基,其余取代基至少一个为碳原子个数大于或等于3的烯基。
6.根据权利要求1-5任一权利要求所述的应用,其特征在于,所述的化合物为R5为氢原子或羟基或甲氧基,R1和R6同时为羟基,其余取代基至少一个为1,1-二甲基-2-丙烯基,或3-甲基-2-丁烯基,或3,7-二甲基-2,6-辛二烯基。
7.根据权利要求1-6任一权利要求所述的应用,其特征在于,所述的化合物为1,3,6-三羟基-7-甲氧基-2,8-双(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,6-二羟基-3,7-二甲氧基-2,8-双(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,3,6,7-四羟基-2,8-双(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,3,5,6-四羟基-4-(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,3,6,7-四羟基-8-(3-羟基-3-甲基丁基)-2-(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,4,6,8-四羟基-7-(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,3,6-三羟基-7-甲氧基-4-(1,1-二甲基-2-丙烯基)-8-(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,3,6-三羟基-7-甲氧基-2-[(2E)-3,7-二甲基-2,6-辛二烯基]-9H-呫吨-9-酮、1,3,5,6-四羟基-2-(1,1-二甲基-2-丙烯基)-4,8-双(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,3,6-三羟基-7-甲氧基-8-[(2E)-3,7-二甲基-2,6-辛二烯基]-2-(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,5,6-三羟基-7-甲氧基-8-(3-甲基-2-丁烯基)-9H-呫吨-9-酮、1,3,6-三羟基-5-甲氧基-2-(1,1-二甲基-2-丙烯基)-7-(3-甲基-2-丁烯基)-9H-呫吨-9-酮。
8.根据权利要求1-7任一权利要求所述的应用,其特征在于,所述的化合物包括作为活性成分的权利要求1-7项之化合物及其药用盐及药用载体在制备具有预防和/或治疗高血脂症或者制备抑制前蛋白转化酶枯草溶菌素9(PCSK9)的产品中的应用。
9.根据权利要求1中所述产品,其特征在于,所述产品为药物和/或保健品。
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