CN112272668B - 新的被取代的n9-腺嘌呤衍生物，包含其的药物组合物及其用途 - Google Patents
新的被取代的n9-腺嘌呤衍生物，包含其的药物组合物及其用途 Download PDFInfo
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- CN112272668B CN112272668B CN201880094067.2A CN201880094067A CN112272668B CN 112272668 B CN112272668 B CN 112272668B CN 201880094067 A CN201880094067 A CN 201880094067A CN 112272668 B CN112272668 B CN 112272668B
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Landscapes
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- Life Sciences & Earth Sciences (AREA)
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了新的被取代的N9‑腺嘌呤衍生物，含有这些衍生物的药物组合物以及所述新衍生物和含有所述新衍生物的药物组合物作为AMPK激活剂的用途，所述AMPK激活剂适于制备用于治疗其中AMPK激活起相关作用的病症和疾病的药物。
Description
技术领域
本发明涉及新的被取代的N9-腺嘌呤衍生物，含有这些衍生物的药物组合物，以及所述新衍生物和含有所述新衍生物的药物组合物作为AMPK(AMP激活的蛋白激酶)激活剂的用途。因此，本发明的衍生物和含有所述衍生物的组合物适于制造旨在用于治疗其中AMPK激活起相关作用的病症和疾病的药物。
发明背景
大多数消耗能量的细胞过程都是由ATP向ADP的转化驱动的。当给定的应力导致这种关系降低时，AMP的细胞内含量增加，这会激活AMPK，例如在运动、局部缺血期间以及在糖尿病中，其中尽管存在血糖，但它无法进入细胞并且因此细胞讨厌能量缺乏。一旦激活，AMPK就会使大量蛋白质磷酸化，从而使某些耗能的合成代谢途径(例如大分子生物合成、细胞生长和增殖)失活，同时激活ATP产生途径(例如糖酵解和脂肪酸氧化)。这可以通过直接参与相应途径调节的酶的磷酸化，或通过调节细胞的基因表达来实现(S.Fragoso等人,"AMPK AND ENERGY HOMEOSTASIS",REB 27(1):3-8,2008)。
AMPK激活可以调节细胞中的不同过程。特别是在代谢水平上，它作用于脂肪酸、葡萄糖的代谢和蛋白质合成等。在脂肪酸代谢水平上，AMPK通过增加脂质的氧化并抑制其从头合成来进行干预。脂质氧化增加的发生在某种程度上是由于AMPK增加了PPAR-α的水平，而PPAR-α的水平与编码参与β-氧化的蛋白质的基因的转录有关(Barish GD等人,2006.PPAR delta:a dagger in the heart of the metabolic syndrome.J ClinInvest.116:590-7)。同样，据报道，AMPK可以直接磷酸化PPAR-α，尽管这种磷酸化的生理相关性尚不清楚。但AMPK还通过在转录和翻译后水平上抑制脂肪酸和脂质的从头合成来起作用。因此，它通过调节转录因子SREBP和ChREBP来减少参与脂肪生成的酶的合成来起作用(Kawaguchi T等人,2002,Mechanism for fatty acid"sparing"effect on glucose-induced transcription:regulation of carbohydrateresponsive element-bindingprotein by AMP activated protein kinase.J Biol Chem.277:3829-35)。它也可以直接作用于脂肪酸合成酶。它通过抑制而使Ser77和Ser79上的ACC1，Ser219和Ser221上的ACC2以及可能的FASN磷酸化(An Z等人,2007,Nicotine-induced activation of AMP-activated protein kinase inhibits fatty acid synthase in 3T3L1 adipocytes:arole for oxidant stress.J Biol Chem.282:26793-801)。以这种方式，发生脂肪生成的减少以及β-氧化的增加。在葡萄糖代谢水平上，AMPK通过增加糖酵解和抑制葡糖异生而起作用。据报道，它通过作用于例如参与Glut-4转录的GEF来调节糖酵解。AMPK可以增加其对Glut-4启动子的亲和力并提高其转录水平的方式使GEF磷酸化(Holmes BF等人,2005,Regulation of muscle GLUT4 enhancer factor and myocyte enhancer factor 2 byAMP-activated protein kinase.Am J Physiol Endocrinol Metab.289:E1071-6；Screaton RA等人,2004,The CREB coactivator TORC2 functions as a calcium-andcAMP sensitive coincidence detector.Cell.119:61-74；
SB等人,2007,Roleof AMPKalpha2 in basal,training-,and AICAR-induced GLUT4 hexokinase II,andmitochondrial protein expression in mouse muscle.Am J Physiol EndocrinolMetab.292:E331-9)。同样，AMPK还调节线粒体代谢，其主要效应子是转录因子PGC1α。AMPK直接磷酸化并激活该转录因子，该转录因子参与与氧化磷酸化和线粒体生物发生有关的基因的转录。
近年来，将AMPK鉴定为众所周知的抗糖尿病药物的间接靶标已导致更有效和更具特异性的AMPK激活剂的开发增加。
因此，寻找新的AMPK激活剂已在众多研究中得到反映，描述了被认为是AMPK的间接激活剂的药物，其抑制线粒体ATP的产生并改变细胞中的AMP:ATP比率，从而影响了代谢紊乱的治疗(Hawley SA等人,Use of cells expressing gamma subunit variants toidentify diverse mechanisms of AMPK activation.Cell Metab 2010；11(6):554-65)。这些包括双胍衍生物(例如二甲双胍)、噻唑烷二酮和植物化学物质。还研究了直接结合到AMPK全酶的三个亚基(α、β或γ)的直接激活剂。
因此，例如US20060287356 A1描述了作为直接AMPK激活剂的噻吩并吡啶酮衍生物，特别是经由变构机制并通过抑制苏氨酸的去磷酸化来激活AMPK。在这种情况下，在用这些衍生物治疗的小鼠中观察到的对葡萄糖和脂质代谢的影响主要是由肝脏中的AMPK刺激产生的。
WO2010103040 A1描述了作为AMPK激活剂的化合物5-氨基咪唑-4-羧酰胺核糖苷(AICAR)，其通过腺苷激酶(AK)代谢为AMP类似物ZMP。ZMP与AMPKγ亚基结合并模拟AMP对AMPK激酶的变构激活的作用，在动物模型中具有抗糖尿病作用。然而，AICAR的生物利用度低并且其有效施用需要高剂量的静脉内施用，这主要是由于其低胃肠道吸收及其快速转化为对AMPK无活性的多种代谢物。
在已知的活性成分二甲双胍(一种双胍衍生物，如上所述的AMPK的间接激活剂)的情况下，其施用涉及使用高剂量的活性成分和不希望的副作用，例如乳酸性酸中毒。
鉴于前述内容，仍然需要可用于治疗或预防与AMPK激活有关的病症，例如与年龄有关的赘生性、神经退行性或代谢性病变的新AMPK激活剂，特别是作为与AMPKγ亚基串联的巴特曼结构域(bateman domain)(结构由两个CBS基序-胱硫醚-β-合酶形成)的激动剂。
本发明的化合物被设计为与γ亚基的核苷酸结合位点结合的AMP模拟物。AMPK具有许多下游靶标，这些靶标会影响葡萄糖和糖原代谢以及脂质和胆固醇的生物合成，使这些化合物成为治疗和/或预防代谢疾病(例如高胆固醇血症、肥胖症、2型糖尿病或代谢综合征(也称为X综合征))的良好候选者。因此，本发明的化合物尤其适于以低有效剂量治疗和/或预防此类病症，其EC50(最大有效平均浓度)远低于从现有技术已知的AICAR衍生物或双胍衍生物的EC50。
发明内容
根据第一方面，本发明涉及以下通式(I)的作为AMPK激活剂的腺嘌呤N9-[芳基，杂芳基)膦酸酯衍生物
其中
·R为5或6元环芳基或5或6元环杂芳基，所述芳基或杂芳基在其自由位置可能被一个或多个选自氘、卤素原子、-OH、-CH3、-CN、-OCH3、OCH2CH3、-CH2COOH、-CH2COOCH3、-COOH、-COCH3、-COH的相同或不同的取代基取代，
·R1和R2彼此独立地选自H，直链或支链(C1-22)烷基，(C2-22)烯基，(C2-22)炔基，(C3-7)环烷基，(C3-22)-COOH烷基，(C5-6)-COOH芳基，氨基酸，优选丙氨酸、丝氨酸或精氨酸，甘油，胆碱或鞘磷脂基团；或者它们彼此独立地选自碱金属或碱土金属阳离子，特别是钠或镁，并且还可以是过渡金属阳离子或任何可接受的阳离子；
并且其中
—“芳基”是5或6元环芳族烃基，所述芳基可能是未被取代的或被相同或不同的取代基单取代或多取代的，所述取代基独立地选自由卤素原子、甲基、乙基、丙基、异丙基和环丙基、氘和羟基组成的组。
—“杂芳基”是5或6元环芳族烃基，其中至少一个环碳已被N、O、S、P或Se代替。
—膦酰基
可与未被另一个取代基取代的芳基或杂芳基环的任何碳原子连接，例如在6元杂芳基的情况下在相对于腺嘌呤的邻、间或对位。
在本发明的上下文中，术语烷基(C1-22)、烯基(C2-22)或炔基(C2-22)应理解为，在分别包含至少一个C＝C或C≡C键的烯基或炔基的情况下，具有1至22个或可能2至22个碳原子的脂族烃基。
优选的式(I)化合物是以下式(Ia-d)中R是选自苯基或环戊二烯基的芳基的那些化合物，R1和R2如上文所定义：
同样优选的是下式(Ie-p)的式(I)化合物，其中R是选自吡啶、嘧啶、吡咯基、吡唑基、吡喃基、呋喃基、噻吩基、磷酰基或硒苯基的杂芳基，R1和R2如上文所定义：
在本发明的化合物中，特别优选的那些是N9-苯基-3-膦酰基-腺嘌呤，其中R1和R2都是氢的化合物(Ia)的特定情况；N9-(2-呋喃基)-5-膦酰基-腺嘌呤，其中R1和R2都是氢的化合物(Il)和(Im)的特定情况；和N9-(3-二乙基膦酰基)苯基-腺嘌呤，其中R1和R2都是乙基的化合物(Ia)的特定情况。
本发明还涉及含有治疗有效量的上述化合物与一种或几种药学上可接受的赋形剂的药物组合物，以及所述药物组合物用于制造药物的用途，所述药物可用于治疗和/或预防其中AMPK激活起相关作用的病症和疾病，例如在代谢疾病如高胆固醇血症、肥胖症、2型糖尿病或代谢综合征(也称为X综合征)中，但也用于肌肉骨骼功能、内分泌功能、细胞稳态、对环境应力的适应，以及用于治疗或预防可以由AMPK全酶激活来控制和/或逆转的皮肤病变。
在根据本发明的药物组合物中，特别指出适合于经口、肠胃外、肌内和静脉内、经皮或透皮、经鼻、经直肠、经舌、经眼、经呼吸施用的那些，并且更具体地是呈简单片剂、舌下片剂、硬胶囊、经舌片剂、胶囊、糖锭、注射剂、喷雾剂、栓剂、皮肤乳膏、软膏或凝胶形式的那些。
在一个优选的实施方案中，本发明的组合物是经口施用的。
除了本发明的化合物之外，根据本发明的药物组合物还含有一种或多种选自稀释剂、润滑剂、粘合剂、崩解剂、稳定剂、防腐剂、吸收剂、着色剂、甜味剂、调味剂等的赋形剂或载体，这些赋形剂是基于药物组合物的最终剂型来选择。
作为非限制性实例，可以引用以下：
—作为稀释剂：乳糖、右旋糖、蔗糖、甘露糖醇、山梨糖醇、微晶纤维素、甘油；
—作为润滑剂：二氧化硅、滑石粉、硬脂酸及其镁盐和钙盐、聚乙二醇；
—作为粘合剂：硅酸铝镁、淀粉、明胶、黄芪胶、甲基纤维素、羧甲基纤维素钠和聚乙烯吡咯烷酮；
—作为崩解剂：琼脂、海藻酸及其钠盐、泡腾混合物；
—作为增溶剂：环糊精、聚乙烯己内酰胺、聚乙酸乙烯酯和聚乙二醇。
有用的剂量根据患者的性别、年龄和体重、施用途径、病症的性质和任何相关治疗而变化，范围为每公斤待治疗受试者的体重1μg至1,000mg的根据本发明的化合物，优选每公斤体重1mg至300mg，每天一个或多个剂量。
在本发明的上下文中，待治疗的受试者是人类或动物哺乳动物受试者。
例如，在包含腺嘌呤衍生物N9-(3-二乙基膦酰基)苯基-腺嘌呤(其中R是苯基并且R1和R2都是乙基的式(I)化合物的特定情况)的根据本发明的药物组合物的情况下，特别是与适当的赋形剂一起成形，压缩成片剂或填充在胶囊中，用于口服施用，所述本发明化合物以上述剂量施用，本发明的化合物经由在胃的酸性pH中进行酸水解而释放，除了被前药吸收并经由酯酶在细胞内被激活和在小肠中在细胞外被激活，以及在生理水性介质中水解，尽管程度较小。
在以软膏形式局部施用的药物组合物的另一个实例中，例如用于治疗可通过AMPK全酶激活控制和/或逆转的皮肤病变，本发明化合物以0.1mg/g软膏至2.0mg/g软膏的重量浓度范围包含在所述药物组合物中，所述药物组合物包括鲸蜡醇、蒸馏水、硬脂酸甘油酯、液体石蜡、聚山梨酸酯60、聚山梨酸酯80、丙二醇和抗坏血酸钠作为合适的赋形剂。在用于局部施用的药物组合物的另一个实例中，本发明的化合物将溶解在聚乙二醇300、1500和4000与抗坏血酸钠的混合物中。
在本发明中，可以通过AMPK全酶激活来控制和/或逆转的皮肤病变涵盖例如色素干性皮肤病和皮肤癌，包括但不限于黑素瘤和基底细胞癌(Wu,CL等人,Role of AMPK inUVB-induced DNA damage repair and growth control.Oncogene 32,2682-9(2013))。
具体实施方式
实施例
在下面的实施例中，其进一步说明了本发明，而不应理解为对本发明的限制，描述了式(I)化合物、特别是N9-(3-二乙基膦酰基)苯基-腺嘌呤的一个优选实施方案的实施例的合成程序，其中R是苯基并且R1和R2都是乙基的式(I)化合物的特定情况。
式(I)化合物的一般合成
一般合成机理由中性腺嘌呤与卤代-芳基硼酸(例如3-溴苯基硼酸或4-溴苯基硼酸)之间的Chan-Lam偶联控制，该偶联由化学计量量的铜(II)盐介导，如Yue,Y.等人,Copper-catalyzed cross-coupling reactions of nucleobases with arylboronicacids:An efficient access to N-arylnucleobases,European J.Org.Chem.5154-5157(2005)中所述。在类似于Negishi偶联的条件下，以四(三苯基膦)-钯(0)作为催化剂，三乙胺作为碱并且无水二甲基甲酰胺作为溶剂，将二烷基膦与通过柱色谱法纯化的偶联产物(例如9-(3-溴苯基)腺嘌呤和9-(4-溴苯基)腺嘌呤)偶联。随后，膦酸酯的两个酯键可以在酸性介质中与盐酸水溶液一起水解以获得相应的膦酸衍生物，随后又转化为盐，例如二钠，使其与氢氧化钠在水性介质中反应。
或者，如Morellato,L.等人,Synthesis of novel 9-aryl andheteroarylpurine derivatives via copper mediated coupling reaction,Tetrahedron Lett(2014)中所述，6-氯嘌呤和相应的卤代-杂芳基硼酸是用于产生非苄基杂芳基衍生物的基础，然后，在类似于Negishi偶联的条件下，以四(三苯基膦)-钯(0)作为催化剂，三乙胺作为碱并且无水二甲基甲酰胺作为溶剂，与所需的二烷基膦偶联。
N9-(3-二乙基膦酰基)苯基-腺嘌呤的合成
化合物N9-(3-二乙基膦酰基)苯基-腺嘌呤遵循两步过程从腺嘌呤获得：
步骤1：3-溴苯基-N9-腺嘌呤
该阶段改编自Yue,Y.等人,Copper-catalyzed cross-coupling reactions ofnucleobases with arylboronic acids:An efficient access to N-arylnucleobases,European J.Org.Chem.5154-5157(2005)。
简而言之，将5mmol腺嘌呤加入500ml 4:1甲醇-水混合物中，该混合物含有5mmol单水合乙酸铜(II)、10mmol N,N,N',N'-四甲基乙二胺和10mmol 3-溴苯基-硼酸。将混合物于1L烧瓶中在空气气氛下在室温下搅拌一小时。将甲醇加入烧瓶内的溶液中，将混合物通过硅藻土过滤，并蒸发溶剂。通过快速色谱法使用硅胶和负载物CH2Cl2:MeOH 20:1和CH2Cl2:MeOH 10:1作为洗脱剂，纯化所得固体。获得呈白色结晶固体状的具有r＝0.25的标题产物。产率50％。纯度>98％。
阶段2：N9-(3-二乙基膦酰基)苯基-腺嘌呤
将2mmol的3-溴苯基-N9-腺嘌呤、3mmol的三乙胺、0.1mmol的四(三苯基膦)钯(0)和3mmol的亚磷酸二乙酯装入50ml圆形烧瓶中。然后加入10ml无水二甲基甲酰胺，并将混合物在100℃下搅拌一小时。蒸发二甲基甲酰胺，并将所得固体通过使用硅胶和CH2Cl2:MeOH10:1作为洗脱剂的色谱法纯化。获得呈白色/米色结晶固体状的具有r＝0.20的所需产物N9-(3-二乙基膦酰基)苯基-腺嘌呤。产率90％。纯度>98％。熔点104℃。
光谱分析：
IR(KBr),cm-1:3297ms,3102ms,1676s,1599s,1487ms,1307s,1050ms,1022s,656m,562m.(ms＝中强，s＝强,m＝中等)
1H-NMR(300MHz,dmso-d6):δ(ppm)＝8.67s(1H,H8腺嘌呤),8.30dd(1H,H1,JPH＝16.6Hz,Jm＝1.2Hz),8.23s(1H2腺嘌呤CH),8.17-8.14m(1H,H2),7.79-7.75m(2H,H3+H4),7.43bs(2H,NH2),4.08dq(4H,CH2,JP-H＝15.3Hz,JH-H＝7.2Hz),1.29-1.25t(6H CH3,JH-H＝7.2Hz)ppm。
HRMS(ESI)[M+H]+[C15H18N5 PO3+H]+:计算值m/z＝348.1218；实验值m/z＝348.1220。
AMPK激活测定
将来自小鼠肌肉成肌细胞瘤细胞系(来自Sigma-Aldrich)的C2C12细胞以10,000个细胞/孔的细胞密度接种到96孔板中的200μl生长培养基(高葡萄糖DMEM、10％胎牛血清(PBS)、青霉素和链霉亲和素)中。使细胞生长直至汇合，并在测定当天将它们与目标化合物在培养箱中在37℃和5％CO2下在100μl生长培养基中温育1至24小时。所有条件均一式四份进行测试。所述化合物以不同浓度溶于无菌无水二甲基亚砜中施用。作为AMPK激活的阳性对照，使用最终浓度为100μl的单磷酸腺苷(AMP)溶液。在相应的时间之后，除去培养基，并在室温下用PBS小心洗涤细胞三次，并使用Abcam Elisa试剂盒定量磷酸化的α-AMPK:总α-AMPK的比率。遵循制造商的说明，并使用Licor
扫描仪对信号进行量化。温育4小时后，化合物N9-(3-二乙基膦酰基)苯基-腺嘌呤在低至30纳摩尔的浓度下显示出比AMP阳性对照更高的AMPK活性。
具体而言，在温育4小时后，化合物N9-(3-二乙基膦酰基)苯基-腺嘌呤在低至30纳摩尔的浓度下显示出AMPK活性大于用AMP阳性对照获得的AMPK活性的500％。EC50低于1微摩尔且相对于AMP对照的激活高于80％的那些化合物被视为所需的活性化合物。根据上述标准选择作为AMPK激活剂的化合物用于葡萄糖消耗测试和MTT细胞活力测试。
葡萄糖消耗测试
将小鼠肌肉成肌细胞瘤细胞系(来自Sigma-Aldrich)的C2C12细胞以每孔10,000个细胞的细胞密度接种在与光度计的使用兼容的白色96孔板上。使细胞在培养箱中在37℃和5％CO2下在200μl/孔的生长培养基(高葡萄糖DMEM、10％胎牛血清(PBS)、青霉素和链霉亲和素)中生长5天。每两天更换培养基。然后将培养基替换为分化培养基(低葡萄糖DMEM、2％N-羟基琥珀酰亚胺、青霉素和链霉亲和素)，使细胞分化为肌管持续三天。每天更换培养基。在测试前一天，将细胞血清饥饿(低葡萄糖DMEM、青霉素和链霉亲和素)。然后用不含葡萄糖的DMEM培养基替换所述培养基，并将化合物N9-(3-二乙基膦酰基)苯基-腺嘌呤在不同浓度下温育一小时，一式四份地重复所述条件。阳性对照由100纳摩尔人胰岛素溶液(来自Sigma)组成。按照制造商的说明使用Promega葡萄糖消耗试剂盒。所述试剂盒是基于作为葡萄糖的化学类似物的2-脱氧葡萄糖的细胞内吸收，并与荧光素发光酶测定法相结合，这与以下事实有关，即所得结果与所述葡萄糖类似物的细胞内浓度成比例。
在Biotek MX发光测定读板器上测量总发光。化合物N9-(3-二乙基膦酰基)苯基-腺嘌呤在低至30纳摩尔的浓度下显示出葡萄糖消耗活性类似于或高于胰岛素对照的葡萄糖消耗活性。N9-(3-二乙基膦酰基)苯基-腺嘌呤(30纳摩尔)的相对于对照的发光度(％)：125±9％。
MTT细胞活力/增殖测定
MTT氧化还原测定是基于线粒体酶琥珀酸脱氢酶产生的3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑(MTT)中溴化物的代谢还原，将其用甲臜染料染成蓝色，从而确定处理过的细胞的线粒体功能。
将C2C12细胞以每孔10,000个细胞的密度接种在与光度计的使用兼容的白色96孔板中。细胞在200μl/孔的生长培养基(高葡萄糖DMEM、10％FBS、青霉素和链霉亲和素)中生长5天，每两天更换培养基。随后，将培养基替换为分化培养基(低葡萄糖DMEM、2％NHS、青霉素和链霉亲和素)，并使细胞分化为肌管持续三天，每天更换培养基。在所有过程中，将细胞在细胞培养箱中于37℃和5％CO2下温育。将化合物N9-(3-二乙基膦酰基)苯基-腺嘌呤在无血清的低葡萄糖DMEM中温育24和48小时。温育化合物的浓度范围为10纳摩尔至1毫摩尔。作为AMP激活的阳性对照，使用最终浓度为100μl的AMP溶液。温育后，将10μl MTT试剂(Abcam)加入每个孔中，并在温育30分钟、45分钟和60分钟后，使用Biotek TX读板器在光度计中测量490nm下的吸光度。读数是取决于细胞氧化酶还原酶的NAD(P)H酶的间接量度。
与纳摩尔浓度的对照相比，化合物N9-(3-二乙基膦酰基)苯基-腺嘌呤显示出显著更高的信号。N9-(3-二乙基膦酰基)苯基-腺嘌呤(30纳摩尔和48小时温育)的相对于对照的发光度(％)：157±5％。
根据本发明的药物组合物的实例
用于成年人的每日口服剂量的药物制剂的药物组合物的实例包括20mg压缩颗粒形式的根据本发明的化合物以及以下赋形剂：微晶纤维素、羧甲基淀粉钠A型(源自马铃薯)、无水胶体二氧化硅和硬脂酸镁。
Claims (9)
1.一种具有以下通式(I)的化合物
其中
●R为苯基；
●R1和R2均为乙基；
其中应理解：
—膦酰基
可与苯环的任何碳原子连接。
2.根据权利要求1所述的化合物，其为N9-(3-二乙基膦酰基)苯基-腺嘌呤。
3.一种药物组合物，其含有一种根据权利要求1或2所述的化合物以及一种或几种药学上可接受的赋形剂。
4.根据权利要求3所述的药物组合物，其中根据权利要求1或2所述的化合物以每公斤待治疗受试者的体重1μg至1,000mg所述化合物的有效剂量存在。
5.根据权利要求4所述的药物组合物，其中根据权利要求1或2所述的化合物以每公斤体重1mg至300mg的有效剂量存在。
6.根据权利要求3-5任一项所述的药物组合物，其中所述药物组合物用于制造AMPK激活剂药物。
7.根据权利要求6所述的药物组合物，其用于制造药物，用于治疗和/或预防选自代谢疾病的病症和疾病，用于肌肉骨骼功能、内分泌功能、细胞稳态、对环境应力的适应，以及用于治疗或预防可以通过AMPK全酶激活来控制和/或逆转的皮肤病变。
8.根据权利要求7所述的药物组合物，所述代谢疾病为高胆固醇血症、肥胖症或2型糖尿病。
9.根据权利要求7所述的药物组合物，所述代谢疾病为代谢综合征。
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| CN101381379A (zh) * | 2003-04-25 | 2009-03-11 | 吉里德科学公司 | 激酶抑制性膦酸酯类似物 |
| WO2010108051A2 (en) * | 2009-03-20 | 2010-09-23 | Ligand Pharmaceuticals | Inhibitors of diacylglycerol o-acyltransferase 1(dgat-1) and uses thereof |
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| WO2016087665A2 (en) * | 2014-12-05 | 2016-06-09 | Centre National De La Recherche Scientifique (Cnrs) | Compounds for treating cystic fibrosis |
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| US7119205B2 (en) | 2003-05-16 | 2006-10-10 | Abbott Laboratories | Thienopyridones as AMPK activators for the treatment of diabetes and obesity |
| WO2010103040A1 (en) | 2009-03-10 | 2010-09-16 | INSERM (Institut National de la Santé et de la Recherche Médicale) | 5'-adenosine monophosphate-activated protein kinase (ampk) activators for treating pulmonary hypertension |
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| CN101381379A (zh) * | 2003-04-25 | 2009-03-11 | 吉里德科学公司 | 激酶抑制性膦酸酯类似物 |
| WO2010108051A2 (en) * | 2009-03-20 | 2010-09-23 | Ligand Pharmaceuticals | Inhibitors of diacylglycerol o-acyltransferase 1(dgat-1) and uses thereof |
| US20140303112A1 (en) * | 2013-04-09 | 2014-10-09 | Han-min Chen | Method for treating disease or condition susceptible to amelioration by AMPK activators and compounds of formula which are useful to activate AMP-activated protein kinase (AMPK) |
| WO2016087665A2 (en) * | 2014-12-05 | 2016-06-09 | Centre National De La Recherche Scientifique (Cnrs) | Compounds for treating cystic fibrosis |
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