WO2015176539A1 - 异喹啉生物碱衍生物用于制备促进ampk活性的药物的用途 - Google Patents

异喹啉生物碱衍生物用于制备促进ampk活性的药物的用途 Download PDF

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WO2015176539A1
WO2015176539A1 PCT/CN2015/000252 CN2015000252W WO2015176539A1 WO 2015176539 A1 WO2015176539 A1 WO 2015176539A1 CN 2015000252 W CN2015000252 W CN 2015000252W WO 2015176539 A1 WO2015176539 A1 WO 2015176539A1
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isoquinoline alkaloid
alkaloid derivative
ampk
formula
medicament
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PCT/CN2015/000252
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French (fr)
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李水盛
苏铭嘉
叶集焕
蔡胜发
蔡政谚
阮琪惇
徐兆民
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资元堂生物科技股份有限公司
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Priority to EP15796582.3A priority Critical patent/EP3146967B1/en
Priority to JP2016568445A priority patent/JP6386590B2/ja
Priority to KR1020167032252A priority patent/KR101888779B1/ko
Publication of WO2015176539A1 publication Critical patent/WO2015176539A1/zh

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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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines

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  • the present invention discloses the use of an isoquinoline alkaloid derivative for the preparation of a medicament having the efficacy of activating adenosine-dependent protein kinase (AMPK).
  • AMPK adenosine-dependent protein kinase
  • Isoquinoline alkaloid derivatives are a class of nitrogen-containing basic organic compounds present in nature and plants, most of which have complex cyclic structures, and their nitrogen atoms are contained in the ring and have significant biological activity.
  • the isoquinoline alkaloid derivative comprises nosorlinol or reticuline.
  • Norraline is known to be used primarily to raise normal blood pressure.
  • the retinoid is mainly used as an active ingredient for the treatment of malaria, and can also be used as a component of an analgesic.
  • AMPK AMP-dependent protein kinase
  • AMPK Phosphorylation of AMP-dependent protein kinase
  • AMPK can also regulate cell growth and proliferation, establish and stabilize cell polarity, regulate animal life, and regulate circadian rhythm.
  • the activation of AMPK has become one of the key points of drug development. Therefore, the new AMPK activator is a direction for the pharmaceutical industry to actively develop.
  • the present invention unanticipated the discovery that an isoquinoline alkaloid derivative, such as salsolinol and reticuline, has novel uses for promoting AMPK activity.
  • the present invention provides the use of an isoquinoline alkaloid derivative for the preparation of a medicament having the effect of activating a phosphorylated adenylate-dependent protein kinase (AMPK), wherein the isoquinoline alkaloid derivative has the following formula I :
  • R, R 1 and R 2 are each independently H, an alkyl group or an acyl group (R a CO), and R 3 is an alkyl group or a substituted benzyl group; wherein R a is H or an alkyl group.
  • X and Y are each independently H, OH, methoxy (OMe) or acyloxy (R a CO-O-); wherein R a is H or alkyl.
  • the isoquinoline alkaloid derivative of formula I is samelinol.
  • the invention provides the use of an isoquinoline alkaloid derivative of the invention of formula I for the preparation of a medicament having hypoglycemic efficacy.
  • the invention provides the use of an isoquinoline alkaloid derivative of the invention of formula I for the manufacture of a medicament for the treatment of diabetes.
  • the present invention provides the use of an isoquinoline alkaloid derivative of the present invention for the preparation of a medicament for the treatment of an AMPK-related disease, wherein the medicament is therapeutically effective by promoting AMPK activity.
  • the AMPK-related diseases include cancer, cardiovascular diseases, metabolic diseases, and have anti-inflammatory or wound healing effects.
  • Figure 1 shows the effect of norepinephrine on AMPK phosphorylation, in which AMPK activity was detected in C2C12 cells at different concentrations (1, 3 and 10 (M) of norpinephrine, respectively.
  • Figure 2 shows the effect of norepinephrine on rapid hypoglycemic effect.
  • Each ICR mouse was fed with high-fat food and high fructose for 2 weeks, and then administered with norraline (10 mg/day) on the first day. After 30 minutes of kg/day) and Glibenclamide (10 mg/kg), oral glucose (1 g/kg) was taken and blood was taken immediately. This time was set to 0 minutes and taken 30, 60, 90, 120 and 150 minutes later. The blood is tested for serum blood sugar levels.
  • Figure 3 shows the effect of norepinephrine on long-term hypoglycemic effect.
  • Each ICR mouse was fed with high-fat food and high fructose for 2 weeks, and was administered with norraline for 10 consecutive days (10 mg/ After kg/day) and Glibenclamide (10 mg/kg), respectively, add norborne salicin (10 mg/kg/day) and Glibenclamide (10 mg/kg), and after 30 minutes, take oral glucose (1 g/kg) and immediately Blood was collected, and the time was set to the 0th minute, and the blood was measured at 30, 60, 90, 120, and 150 minutes after the blood glucose level.
  • AMPK AMP-dependent protein kinase
  • the message pathway of AMPK contains glucose and lipid metabolism, and affects the expression of related genes and proteins.
  • drugs that promote AMPK activity can be used as potential drugs for various metabolic diseases such as diabetes, cancer, cardiovascular diseases such as atherosclerosis and ischemic heart disease, and can also be used for anti-inflammatory reaction or promoting wound healing. .
  • alkyl refers to a straight or branched chain monovalent hydrocarbon having from 1 to 20 carbon atoms, for example an alkyl group having from 1 to 10 carbons, preferably from 1 to 6 carbons.
  • the alkyl group is more preferably an alkyl group having 1 to 3 carbons. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.
  • the present invention provides a use of an isoquinoline alkaloid derivative for the preparation of a medicament having the effect of activating a phosphorylated adenylate-dependent protein kinase (AMPK), wherein the isoquinoline alkaloid derivative has the following formula I:
  • R, R 1 and R 2 are each independently H, alkyl or acyl (R a CO), and R 3 is alkyl or substituted benzyl; wherein R a is H or alkyl.
  • X and Y are each independently H, OH, methoxy (OMe) or acyloxy (R a CO-O-); wherein R a is H or alkyl.
  • the isoquinoline alkaloid derivative is salsolinol, which Has the following chemical formula:
  • the isoquinoline alkaloid derivative of the formula I of the present invention is exemplified by desalinol or reticuline with activated phosphorylation adenosine dependence.
  • the efficacy of protein kinase (AMPK), and further validated with hypoglycemic efficacy, can be used to treat diabetes.
  • the present invention provides the use of the isoquinoline alkaloid derivative of the formula I for the preparation of a medicament having hypoglycemic efficacy, further providing the use of a medicament for the preparation of a medicament for the treatment of diabetes.
  • the isoquinoline alkaloid derivative of formula I is salsolinol or reticuline.
  • the isoquinoline alkaloid derivative of the formula I of the present invention has an effect of promoting AMPK activity up to a therapeutic effect, it has a use for a medicament for preparing an AMPK-related disease, for example, for treating cancer, cardiovascular disease, metabolic disease Etc., and has the effect of resisting inflammation or promoting wound healing.
  • carrier or “pharmaceutically acceptable carrier” as used herein, includes, but is not limited to, pharmaceutically acceptable excipients, fillers, diluents or the like, including those of the pharmaceutical industry. Well known.
  • the analysis data of noriline is the following:
  • Example 2 Evaluation of norepinephrine and retinoids in promoting AMPK activity
  • the C 2 C 12 skeletal muscle progenitor cell line was purchased from the Taiwan Food Industry Development Institute.
  • the C 2 C 12 cell strain is a cell strain cultured from a leg skeletal muscle of an adult C3H mouse in a 95% oxygen, 5% carbon dioxide, and 37 ° C cell culture incubator, and the cell is cultured in a solution containing 4.5 mg/mL glucose, 10 % fetal bovine serum (FBS; Gibco/Invitrogen, Carlsbad, CA), and antibiotic solution (final concentration penicillin 100 IU/mL, streptomycin 100 ⁇ g/mL) in DMEM (Gibco/Invitrogen, Carlsbad, CA) in the medium.
  • FBS fetal bovine serum
  • antibiotic solution final concentration penicillin 100 IU/mL, streptomycin 100 ⁇ g/mL
  • DMEM Gibco/Invitrogen, Carlsbad, CA
  • C 2 C 12 myoblasts were propagated to the Petri dish for seven minutes, fetal bovine serum was replaced with 2% horse serum (Gibco/Invitrogen, Carlsbad, CA) to induce C 2 C 12 myoblasts. A muscle cell with multiple nuclei. Four days later, C 2 C 12 myoblasts were differentiated into myocytes, and the cells were replaced with serum-free DMEM 24 hours before the experiment to reduce the metabolic activity of the cells.
  • C 2 C 12 myocytes were treated with 1 ⁇ M, 3 ⁇ M and 10 ⁇ M of norpinephrine and retinoid for 5 min and 15 min, respectively, then C 2 C 12 myocytes were washed with PBS buffer and added with protease inhibition.
  • RIPA buffer (20 mM Tris-HCl pH 7.4, 100 mM NaCl, 1 mM EDTA, 1 mM EGTA, 0.1% SDS, 0.5% sodium deoxycholate, 1% NP-40 and 100X protease inhibitor cocktail (protease) Inhibitor cocktail)).
  • the cells were collected and centrifuged on ice, and then the supernatant of the sample was adjusted to the same concentration.
  • the hypoglycemic effect was evaluated by the Oral Glucose Tolerance Test (OGTT).
  • OGTT Oral Glucose Tolerance Test
  • mice After the first day of administration and continuous administration for 14 days, the mice were anesthetized separately, followed by norepinephrine (10 mg/kg/day) and Glibenclamide (10 mg/kg), respectively, and 30 minutes later, oral glucose ( 1 g/kg) and blood was taken immediately, and the time was set to the 0th minute, and the blood was taken 30, 60, 90, 120, and 150 minutes later, and the blood glucose level was measured after centrifugation.
  • norepinephrine 10 mg/kg/day
  • Glibenclamide 10 mg/kg
  • mice fed type II diabetes with high-sugar and high-fat foods had no hypoglycemic effect similar to Glibenclamide in rapid hypoglycemic action.
  • norpinephrine has a blood sugar lowering effect similar to that of Glibenclamide in the long-term effect of lowering blood sugar.
  • norpinephrine has an excellent effect in promoting AMPK activity.
  • norepinephrine has a hypoglycemic effect similar to that of Glibenclamide, and Glibenclamide affects insulin secretion, but relative to Glibenclamide, norepinephrine has a lower effect on insulin secretion.
  • the retinoic acid also has excellent effects in enhancing AMPK activity, and the 10 ⁇ M retinoid has a very good effect.

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Abstract

本发明公开一种异喹啉生物碱衍生物用于制备具有活化磷酸化腺苷酸依赖蛋白激酶（AMPK）功效的药物的用途，其中该异喹啉生物碱衍生物可为去甲猪毛菜碱（salsolinol）或网脉碱（reticuline）。其中该药物可以活化AMPK，因而可用于调节细胞生长及代谢，及治疗AMPK相关疾病。

Description

异喹啉生物碱衍生物用于制备促进AMPK活性的药物的用途 技术领域
本发明公开一种异喹啉生物碱衍生物用于制备具有活化磷酸化腺苷酸依赖蛋白激酶(AMPK)功效的药物的用途。
背景技术
异喹啉生物碱衍生物是存在于自然界动植物中的一类含氮的碱性有机化合物,大多数有复杂的环状结构,其氮原子多包含在环内,具有显著的生物活性,其中该异喹啉生物碱衍生物包含去甲猪毛菜碱(salsolinol)或网脉碱(reticuline)。去甲猪毛菜碱已知主要用于升高正常血压。而网脉碱主要为用于治疗疟疾的活性成分,亦可作为止痛剂的组成分。
磷酸化腺苷酸依赖蛋白激酶(AMP-dependent protein kinase,AMPK)是一种在细胞内维持能量代谢调节的蛋白激酶,其特征是能与磷酸化腺苷酸(AMP)结合,透过AMP维持ATP生成和消耗的平衡,维持能量代谢平衡。同时,AMPK亦可调控细胞生长和增殖、建立和稳定细胞极性、调节动物寿命、调控生理节律等。近几年以AMPK活化作用作为标的已成为药物开发的重点之一,因此新的AMPK活化剂为医药产业积极努力开发的方向。
发明内容
本发明非可预期的发现一种异喹啉生物碱衍生物,例如去甲猪毛菜碱(salsolinol)及网脉碱(reticuline),具有促进AMPK活性的新颖用途。
一方面,本发明提供一种异喹啉生物碱衍生物用于制备具有活化磷酸化腺苷酸依赖蛋白激酶(AMPK)功效的药物的用途,其中该异喹啉生物碱衍生物具下式I:
Figure PCTCN2015000252-appb-000001
其中R、R1及R2各独立为H、烷基或酰基(RaCO),R3为烷基或经取代的苄基(benzyl)；其 中Ra为H或烷基。
在本发明一实施态样,其中该经取代的苄基具有下式II:
Figure PCTCN2015000252-appb-000002
其中X及Y各独立为H、OH、甲氧基(OMe)或酰氧基(RaCO-O-)；其中Ra为H或烷基。
在本发明一实施例,该具式I的异喹啉生物碱衍生物为去甲猪毛菜碱(salsolinol)。
在本发明另一实施例,该具式I的异喹啉生物碱衍生物为网脉碱(reticuline)。
另一方面,本发明提供本发明具式I的异喹啉生物碱衍生物用于制备具有降血糖功效的药物的用途。
再一方面,本发明提供本发明具式I的异喹啉生物碱衍生物用于制备治疗糖尿病的药物的用途。
又一方面,本发明提供本发明具式I的异喹啉生物碱衍生物用于制备治疗AMPK相关疾病的药物的用途,其中该药物系透过促进AMPK活性达治疗之效。其中该AMPK相关疾病包括癌症、心血管疾病、新陈代谢疾病,并具抗发炎或促进伤口愈合之效。
本发明之该等及其它方面,可通过以下的较佳具体实施例的描述以及图式,得以更为明晰；即便其中可能会有变化或修饰,但不背离本发明所揭露的新颖观念的精神及范畴。
附图说明
本发明所呈现的较佳具体实施例图式是以阐述本发明为目的。应被理解的是,本发明并不局限于所示的较佳具体实施例。图中及实施例中的数据是以平均值±标准偏差(Mean+SD)表示,其中以成对t检定(paired t-test)检测,显著差异表示为*:P<0.05、**:P<0.01、#:P＝0.067。
图1显示去甲猪毛菜碱对于AMPK磷酸化的影响,其中分别以不同浓度(1、3及10(M)的去甲猪毛菜碱在C2C12细胞中进行AMPK活性检测。
图2显示去甲猪毛菜碱对于快速降血糖作用之影响,每只ICR小鼠以高脂食物及高果糖喂食2周后,在第1天分别投予去甲猪毛菜碱(10mg/kg/day)及Glibenclamide(10mg/kg)30分钟后,接着口服葡萄糖(1g/kg)并立即采血,将此时间定为第0分钟,并采取之后第30,60、90、120及150分钟的血液,检测血清血糖含量。
图3显示去甲猪毛菜碱对于长期降血糖作用的影响,每只ICR小鼠以高脂食物及高果糖喂食2周后,在连续14天分别投予去甲猪毛菜碱(10mg/kg/day)及Glibenclamide(10mg/kg)后,分别再给予去甲猪毛菜碱(10mg/kg/day)及Glibenclamide(10mg/kg),30分钟之后,口服葡萄糖(1g/kg)并立即采血,将此时间定为第0分钟,并采取之后第30,60、90、120及150分钟的血液,检测血清血糖含量。
图4显示网脉碱对于AMPK磷酸化的影响,其中分别以不同浓度(1、3及10(M)的去甲猪毛菜碱在C2C12细胞中进行AMPK活性检测。
具体实施方式
除非另有定义,所有本文所用的技术性及科学性术语,对于属于本发明领域的具有通常知识者而言,皆具有与其所习知者相同意义。
除非文中有清楚指明者，于本文中所使用的单数形式「一」、「一种」、及「该」的涵义均为包括「至少一种」的复数形式。因此，例如，当提及「一成分」时，包括复数个该等成分及本领域技术人员所知的同等物。
本文中所使用的「AMPK」一词,是磷酸化腺苷酸依赖蛋白激酶(AMP-dependent protein kinase)的缩写,是指一种调节细胞内能量代谢的蛋白激酶,为许多生物过程的主要调控因子。AMPK的讯息路径包含葡萄糖及脂质代谢,及影响相关基因与蛋白质的表达。当AMPK活化后会激发其活性,进一步调节其AMPK讯息路径下游的物质,调节肝脏、骨骼肌、心脏、脂肪组织及胰腺代谢。因此,具促进AMPK活性的药物可做为新陈代谢疾病如糖尿病、癌症、心血管疾病如动脉粥样硬化和缺血性心脏病等多种疾病的潜在药物,亦可用于抗发炎反应或促进伤口愈合。
本文中所使用的「烷基」一词,是指含1-20个碳原子的直链或支链单价烃,例如具有1-10个碳的烷基,较佳为具有1-6个碳的烷基,更佳为具有1-3个碳的烷基。烷基的实施例包括,但不局限于甲基、乙基、正丙基、异丙基、正丁基、异丁基,和第三丁基。
本发明提供一种异喹啉生物碱衍生物用于制备具有活化磷酸化腺苷酸依赖蛋白激酶(AMPK)功效的药物的用途,其中该异喹啉生物碱衍生物具下式I:
Figure PCTCN2015000252-appb-000003
其中R、R1及R2各独立为H、烷基或酰基(RaCO),R3为烷基或经取代的苄基(benzyl)；其中Ra为H或烷基。
在本发明一实施态样,其中该经取代的苄基具有下式II:
Figure PCTCN2015000252-appb-000004
其中X及Y各独立为H、OH、甲氧基(OMe)或酰氧基(RaCO-O-)；其中Ra为H或烷基。
根据本发明的一具体实施例,其中式I取代基R＝R1＝R2＝H,R3＝Me时,该异喹啉生物碱衍生物为去甲猪毛菜碱(salsolinol),其具有下列化学式:
Figure PCTCN2015000252-appb-000005
根据本发明的另一具体实施例,其中式I取代基R＝R2＝Me(甲基)、R1＝H、R3为一经取代的苄基(式II),其中X＝OH、Y＝OMe时,该异喹啉生物碱衍生物为网脉碱(reticuline),其具有下列化学式:
Figure PCTCN2015000252-appb-000006
如本发明实施例所示,本发明具式I的异喹啉生物碱衍生物,以去甲猪毛菜碱(salsolinol)或网脉碱(reticuline)为例,具活化磷酸化腺苷酸依赖蛋白激酶(AMPK)的功效,并进一步验证具有降血糖功效,故可用以治疗糖尿病。
因此,本发明提供该具式I的异喹啉生物碱衍生物用于制备具有降血糖功效的药物的用途,进一步提供制备治疗糖尿病的药物的用途。在一具体实施例中,该具式I的异喹啉生物碱衍生物为去甲猪毛菜碱(salsolinol)或网脉碱(reticuline)。
此外,因本发明具式I的异喹啉生物碱衍生物具有促进AMPK活性达治疗的功效,遂具有用于制备AMPK相关疾病的药物的用途,例如可用于治疗癌症、心血管疾病、新陈代谢疾病等,并具有抗发炎或促进伤口愈合之效。
根据本发明,该具式I的异喹啉生物碱衍生物可调制成任何一般制药技术所知或习用的药品型式,并可依任何制药习知技术配合常用的载剂或医药上可接受的载剂制成含有医疗有效量的组成物。
本文所使用的「载剂」或「医药上可接受的载剂」一词是指包括但不限于制药上可接受的赋形剂、填充剂、稀释剂或类似物,包括制药业一般知识者所熟知者。
以上述发明说明以及下列实施例说明本发明,但并非用以限制本发明的范围。
实施例1:本发明具式I的异喹啉生物碱衍生物的制备
依序加入1.6g多巴胺(dopamine)、10mL甲醇、1mL 1N盐酸、及2mL 99％乙醛于50毫升的圆底瓶中,在室温下搅拌六小时,经减压浓缩所得的浓缩物通入Lobar RP-18管柱(type B,Merck)进行纯化。以0.05％甲酸水溶液冲提后,所得冲提液经NMR核磁共振光谱分析鉴定,确认该化合物为去甲猪毛菜碱(salsolinol)。
依据ESI-TOF质谱仪、NMR核磁共振光谱等分析结果,去甲猪毛菜碱分析数据如下:
1H NMR(CD3OD,400MHz)δ6.63(1H,s)，6.57(1H,s)，4.30(1H,q,J＝6.8Hz,H-1)，3.40(1H,dt,J＝12.6,5.6Hz,Ha-3)，3.20(1H,ddd,J＝12.6,8.2,5.6Hz,Hb-3)，2.92(1H,ddd,J＝16.8,8.2,5.8Hz,Ha-4)，2.80(1H,dt,J＝16.8,5.6Hz,Hb-4)，1.55(3H,d,J＝6.8Hz,Me-1)；ESIMS:m/z.180([M+H]+)。
网脉碱(reticuline)可依习知方法自樟科植物五掌楠(Neolitsea konioshii(H.)K.&S.)木部分离而得(J.Chin.Chem.Soc.Taip.1992,39,189-194)。
实施例2:去甲猪毛菜碱及网脉碱于促进AMPK活性的评估
C2C12骨骼肌原母細胞株係購自台湾財團法人食品工業發展研究所。C2C12細胞株為由成年C3H小鼠的腿骨骼肌於95％氧氣、5％二氧化碳及37℃細胞培養箱中所培養出來的細胞株,該細胞培養於含4.5mg/mL葡萄糖、10％胎牛血清(fetal bovine serum,FBS；Gibco/Invitrogen,Carlsbad,CA)、及抗生素溶液(終濃度penicillin 100IU/mL，链霉素(streptomycin)100μg/mL)的DMEM(Gibco/Invitrogen,Carlsbad,CA)培養基中。當C2C12肌母細胞增殖至培養皿的七分滿後，以2％馬血清(horse serum；Gibco/Invitrogen,Carlsbad,CA)取代胎牛血清，以將C2C12肌母細胞誘導成具多細胞核的肌細胞。四天後C2C12肌母細胞分化成肌細胞，細胞於實驗前24小時將培養液換成不具血清的DMEM以降低細胞的代謝活動。
将C2C12肌细胞分别以1μM、3μM及10μM的去甲猪毛菜碱及网脉碱处理5分钟及15 分钟,然后将C2C12肌细胞用PBS缓冲液清洗并加入含有蛋白酶抑制剂的RIPA缓冲液(20mM Tris-HCl pH7.4,100mM NaCl,1mM EDTA,1mM EGTA,0.1％SDS,0.5％脱氧胆酸钠(sodium deoxycholate),1％NP-40及100X蛋白酶抑制剂混合物(protease inhibitor cocktail))。收集细胞并置于冰上离心,然后将样本的上清液调整为相同浓度。
结果
如图1所示,以10μM的去甲猪毛菜碱处理C2C12细胞5分钟后,其增进AMPK磷酸化的功效可为对照组的1.66倍,显示去甲猪毛菜碱在促进AMPK活性上具有优异的功效。
此外,如图2所示,分别以3μM及10μM的网脉碱处理C2C12细胞5分钟后,其增进AMPK磷酸化的功效分别为对照组的1.52及2.05倍,而在处理C2C12细胞15分钟后,其亦可增进AMPK磷酸化的功效分别达对照组的1.04及2.07倍,显示网脉碱在促进AMPK活性上具有优异的功效。
实施例3、去甲猪毛菜碱于降血糖作用的评估
以口服葡萄糖耐受试验(Oral Glucose Tolerance Test,OGTT)进行降血糖作用的评估。每只ICR小鼠以高脂食物及高果糖喂食2周后,分别以去甲猪毛菜碱(10mg/kg/day)及Glibenclamide(10mg/kg)连续14天投予小鼠,每组各以8只小鼠进行动物实验。在第1天投予及连续投予14天后,分别将小鼠麻醉,接着分别给予去甲猪毛菜碱(10mg/kg/day)及Glibenclamide(10mg/kg),30分钟后,口服葡萄糖(1g/kg)并立即采血,将此时间定为第0分钟,并采取之后第30,60、90、120及150分钟的血液,离心后测血清血糖含量。
结果
如图3所示,显示以高糖高脂食物喂食诱导第II型糖尿病的小鼠,去甲猪毛菜碱在快速降血糖作用上,具有与Glibenclamide相近的降血糖功效。如图4所示,进一步发现去甲猪毛菜碱在长期降低血糖的作用上,亦具与Glibenclamide相近的降血糖功效。
由实施例结果可知,去甲猪毛菜碱在促进AMPK活性上具有优异的功效。此外,去甲猪毛菜碱具有与Glibenclamide相近的降血糖功效,且因Glibenclamide会影响胰岛素分泌,但相对于Glibenclamide,去甲猪毛菜碱对胰岛素分泌量具有较低的影响性。网脉碱于增进AMPK活性亦具有优异功效,10μM之网脉碱即具有相当佳的功效。

Claims (10)

  1. 一种异喹啉生物碱衍生物用于制备具有活化磷酸化腺苷酸依赖蛋白激酶(AMPK)功效的药物的用途,其中该异喹啉生物碱衍生物具有下式I：
    Figure PCTCN2015000252-appb-100001
    其中R、R1及R2各独立为H、烷基或酰基(RaCO),R3为烷基或经取代的苄基；其中Ra为H或烷基。
  2. 如权利要求1所述的用途,其中该经取代的苄基具有下式II:
    Figure PCTCN2015000252-appb-100002
    其中X及Y各独立为H、OH、甲氧基(OMe)或酰氧基(RaCO-O-)；其中Ra为H或烷基。
  3. 如权利要求1所述的用途,其中该具式I的异喹啉生物碱衍生物为去甲猪毛菜碱(salsolinol)或网脉碱(reticuline)。
  4. 如权利要求3所述的用途,其中该具式I的异喹啉生物碱衍生物为去甲猪毛菜碱(salsolinol)。
  5. 如权利要求3所述的用途,其中该具式I的异喹啉生物碱衍生物为网脉碱(reticuline)。
  6. 一种异喹啉生物碱衍生物用于制备具有降血糖功效的药物的用途,其中该具式I的异喹啉生物碱衍生物为权利要求1至5中任一项的定义。
  7. 一种异喹啉生物碱衍生物用于制备治疗糖尿病的药物的用途,其中该具式I的异喹啉生物碱衍生物为权利要求1至5中任一项的定义。
  8. 一种异喹啉生物碱衍生物用于制备治疗AMPK相关疾病的药物的用途,其中该具式I的异喹啉生物碱衍生物为权利要求1至5中任一项的定义。
  9. 如权利要求8所述的用途,其中该AMPK相关疾病为癌症、心血管疾病、或新陈代谢疾病。
  10. 如权利要求8所述的用途,其中该药物具有抗发炎或促进伤口愈合的功效。
PCT/CN2015/000252 2014-05-23 2015-04-10 异喹啉生物碱衍生物用于制备促进ampk活性的药物的用途 WO2015176539A1 (zh)

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