CN106176776A - 葡萄糖激酶激动活性化合物的医药用途 - Google Patents
葡萄糖激酶激动活性化合物的医药用途 Download PDFInfo
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- CN106176776A CN106176776A CN201610510334.2A CN201610510334A CN106176776A CN 106176776 A CN106176776 A CN 106176776A CN 201610510334 A CN201610510334 A CN 201610510334A CN 106176776 A CN106176776 A CN 106176776A
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- glucokinase
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- agonist activity
- diabetes
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Abstract
本发明属于药物化学技术领域，具体地说涉及一类具有葡萄糖激酶激动活性化合物的医药用途。该类化合物以及包含这些化合物可用盐或组合物可以单独或联合其他抗糖尿病治疗药物，用于预防或治疗葡萄糖激酶介导的肥胖、糖尿病及其相关疾病。
Description
技术领域
本发明属于药物化学技术领域，具体涉及一类具有葡萄糖激酶激动活性化合物的医药用途。
背景技术
糖尿病是胰岛素绝对或相对缺乏引起的一种常见代谢性疾病，并因其引起的多种急、慢性并发症而严重危害人类健康（Hansen et al. Diabetes Metab Syndr Obes,2010, 3: 155-163）。葡萄糖激酶（GK）是糖酵解途径中的第一个关键酶，它可以在ATP存在的条件下，将葡萄糖磷酸化成为6-磷酸葡萄糖，进入下游的代谢过程。因此，此步是整个糖代谢过程的第1个限速步骤，GK作为糖代谢过程中的第1个限速酶，具有重要的生物学作用。GK主要存在于肝脏和胰腺中，在肝脏中，GK受到胰岛素的影响调节肝糖代谢，当血糖升高时，血浆胰岛素水平相应升高，GK活性增强，促进葡萄糖-6-磷酸的生成，从而促进肝糖原合成增加，抑制肝糖异生；当血糖水平较低时，则反之，使血糖浓度升高，从而维持血糖平衡；在胰岛β细胞中，胰岛素的分泌主要受胞内葡萄糖代谢的调节，而GK的活性可影响胞内葡萄糖代谢，则间接影响到胰岛素的分泌，所以GK在胰岛β细胞中充当了一个刺激胰岛素分泌的“葡萄糖感受器”，从而起到维持体内血糖稳态的作用（Postic et al. Recent Prog HormRes, 2001, 56: 195-217）。
葡萄糖激酶激动剂(GKA)可通过调节胰岛素释放和促进肝脏葡萄糖代谢的双重机制达到有效控制血糖和治疗糖尿病、肥胖症及其并发症的目的（Tahrani et al. Lancet,2011, 378(9786): 182-197）。GKA已被证实可在不同2型糖尿病动物模型中，剂量依赖性地降低血糖含量，如在ob/ob小鼠、db/db小鼠及Zucker大鼠模型口服耐糖试验中，GKA能够有效地改善葡萄糖耐受（Matschinsky et al，F1000 Med Rep，2010, 2: pii 43）。截止到目前，已有近二十种GKA进入临床试验，其中包括华领医药的sinogliatin，辉瑞的PF-04937319，罗氏的R-1440等。
具有式（Ⅰ）结构的化合物
其中R1为D-甘露糖，R2为D-甘露醇或D-阿拉伯醇
（Ⅰ）
是一类从真菌中分离得到的次级代谢产物 [Kohno et al. Tetrahedron, 1999, 55(25): 7771 – 7786; Omura et al. Journal of Antibiotics, 1999, 52(6): 586 –589; Kohno et al. Journal of Antibiotics, 1999, 52(12): 1114 – 1123]，该类化合物由三个结构片段构成：一个多甲基、多羟基取代的20碳不饱和脂肪酸、一个D-甘露糖和一个D-甘露醇或阿拉伯醇，具有抑制二酰基甘油酰基转移酶（Omura et al. Patent:US2002/193315）、拮抗趋化因子受体CXCR3 （Ondeyka et al. Molecular Diversity,2005, 9(1-3): 123 – 129）、抑制白色念珠菌生物膜的形成（Wang et al. Journal ofNatural Products, 2014, 77 (10): 2273 – 2279）的作用。
发明内容
本发明的目的就是要提供具有葡萄糖激酶激动活性化合物的医药用途。
本发明人经研究发现，结构如式（Ⅰ）的一类化合物
其中R1为D-甘露糖，R2为D-甘露醇或D-阿拉伯醇
（Ⅰ），
具有良好的葡萄糖激酶激动活性，因此，可作为葡萄糖激酶激动剂用于预防或治疗葡萄糖激酶介导的相关疾病，特别是肥胖、糖尿病及其并发症。
根据本发明之优选化合物包括但不限于：
其中R1为D-甘露糖，R2为
（Ⅱ），
其中R1为D-甘露糖，R2为
（Ⅲ）。
为此，本发明完成了前述葡萄糖激酶激动活性化合物在制备预防或治疗葡萄糖激酶介导的疾病的药物中的应用。
所述的应用，其中葡萄糖激酶介导的疾病为肥胖症。
所述的应用，其中葡萄糖激酶介导的疾病为糖尿病。
所述的应用，其中葡萄糖激酶介导的疾病为糖耐量异常、妊娠糖尿病、糖尿病慢性并发症。
本发明化合物能够增强葡萄糖激酶的活性。因此，本发明化合物可用于治疗与葡萄糖激酶不足相关的多种疾病，如肥胖症、糖尿病、糖耐量异常、妊娠糖尿病、糖尿病慢性并发症 (包括糖尿病性周围神经障碍、糖尿病性肾病、糖尿病性视网膜病、 糖尿病性大血管病)。
本发明结构式代表的化合物，在式（Ⅱ）中，R1为D-甘露糖，R2为时，简称化合物1，其结构式为
R1为D-甘露糖，R2为时，简称化合物2，其结构式为；
R1为D-甘露糖，R2为时，
简称化合物3，其结构式为；
在式（Ⅲ）中，R1为D-甘露糖，R2为时，简称化合物4，其结构式为；
R1为D-甘露糖，R2为时，简称化合物5，其结构式为：。
本发明的药物组合物，其含有所述的任一化合物作为活性成分和可药用载体。药物组合物的制备方法为本领域常用方法。
本文所述的化合物或其药学上可接受的加成盐或水合物可以利用各种给药途径或方式释放至患者。适合的给药途径包括但不限于吸入、透皮、口服、直肠、经粘膜、肠内和肠胃外给药，肠胃外给药包括肌内、皮下和静脉内注射。
本文所用的术语“给药”可涵盖所有直接与间接释放化合物到其预期作用部位的手段。
本发明的活性化合物可以本身形式给药，或者以药物组合物形式给药，其中活性化合物是与一种或多种药学上可接受的载体、赋形剂或稀释剂混合的。按照本发明使用的药物组合物通常是按常规方式配制的，使用一种或多种生理学上可接受的载体，包含赋形剂和助剂，它们有利于将活性化合物加工成可以在药学上使用的制剂。适当的制剂取决于所选择的给药途径。
关于口服给药，化合物可以是容易这样配制的，将活性化合物与本领域熟知的药学上可接受的载体结合。这类载体使本发明化合物能够配制成片剂、丸剂、锭剂、胶囊剂、液体、凝胶、糖浆剂、浆液、悬液等，用于被所要治疗的患者口服。口用药物制剂可以这样得到，与固体赋形剂混合，可选地研磨所得混合物，加工颗粒的混合物，如果需要的话加入适合的助剂，得到片剂或锭剂芯。适合的赋形剂确切地是填充剂，例如糖，包括乳糖、蔗糖或甘露糖醇；纤维素制备物，例如玉米淀粉、小麦淀粉、稻米淀粉、马铃薯淀粉、明胶、黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮。如果需要的话，可以加入崩解剂，例如交联聚乙烯吡咯烷酮、琼脂或藻酸或其盐，例如藻酸钠。
可以口服的药物制剂包括推入配合的胶囊剂，由明胶制成，以及软的密封胶囊剂，由明胶和一种增塑剂制成，例如甘油。推入配合的胶囊剂可以含有活性成分与下列成分的混合物：填充剂，例如乳糖；粘合剂，例如淀粉；和/或润滑剂，例如滑石粉或硬脂酸镁或微粉硅胶；和可选的稳定剂。在软胶囊剂中，活性化合物可以是溶解或悬浮在适合的液体中的，例如脂肪油、液体石蜡或液体聚乙二醇。另外，可以加入稳定剂。所有口服给药制剂都应当是适合于这类给药的剂量。
关于通过吸入给药，按照本发明使用的化合物适宜以气雾剂的形式从加压包装或雾化器中释放出来，其中利用适合的推进剂，例如二氯二氟甲烷、三氯氟代甲烷、二氯四氟乙烷、二氧化碳或其他适合的气体。在加压气雾剂的情况下，通过提供计量释放的阀门可以确定剂量单位。用在吸入器或吹入器内的明胶胶囊和药筒可以配制成含有化合物与适合的粉末基质的粉末混合物，例如乳糖或淀粉。
化合物可以配制用于肠胃外给药，通过注射，例如急推注射或连续输注。注射用制剂可以是单位剂型，例如在安瓿或多剂量容器内，其中加入防腐剂。组合物可以采取在油性或水性载体中的悬液、溶液或乳液的形式，并且可以含有配制用试剂，例如悬浮剂、稳定剂和/或分散剂，例如交联聚乙烯吡咯烷酮、琼脂或藻酸或其盐，例如藻酸钠。
肠胃外给药用药物制剂包括水溶性活性化合物的水溶液。可以酌情制备活性化合物的油性注射悬液。适合的亲脂性溶剂或载体包括脂肪油，例如芝麻油，或合成的脂肪酸酯，例如油酸乙酯或甘油三酯，或脂质体，水性注射悬液可以含有增加悬液粘性的物质，例如羧甲基纤维素钠葡聚糖。可选地，悬液还可以含有适合的稳定剂或增加化合物溶解度的试剂，以便制备高浓缩的溶液。
或者，活性成分可以是粉末形式，在使用前用适合的载体再生，例如无菌无热原的水。
化合物还可以配制成直肠组合物，例如栓剂或保留灌肠剂，例如含有常规的栓剂基质，例如可可脂或其他甘油酯。
除了前述制剂以外，化合物还可以配制成药库制剂。这类长效制剂可以通过植入或经皮释放（例如皮下或肌内）、肌内注射或透皮贴剂给药。因而，例如，化合物可以与适合的聚合或疏水性材料（例如在可接受的油中的乳液）或离子交换树脂一起配制，或者配制成微溶性衍生物，例如微溶性盐。
药物组合物还可以包含适合的固体或凝胶相载体或赋形剂。这类载体或赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖、淀粉、纤维素衍生物，明胶、和聚合物，例如聚乙二醇。
优选地，组合物是单位剂型，例如片剂或胶囊剂。
给药方式以及有效剂量的选择将尤其根据所治疗的疾病而异。给药方式和剂量的选择在本领域技术人员的能力范围内。
本文所述的化合物或其药学上可接受的盐和/或水合物可以单独给药，与其他本发明化合物联合给药，和/或以与其他已知治疗剂联合的形式给药。
本发明化合物可与其它葡萄糖激酶活性激动剂或一种或多种其它可用于治疗前文所提及病症的适当治疗药物合并使用，包括：抗糖尿病药物、抗视网膜病药物、抗神经病药物、抗肾病药物、抗动脉粥样硬化药物、抗感染药物、抗缺血药物、抗高血压药物、抗肥胖药物、抗脂血症障碍药物、抗血脂异常药物、食欲抑制药物。
与本发明化合物合并使用的适当抗糖尿病剂实例，包括胰岛素与胰岛素类似物；胰高血糖素样肽；磺酰基脲类及类似物：氯磺丙脲、格列本脲、甲苯磺丁脲、甲磺氮草脲、醋磺己脲、格列吡嗪、格列美脲、瑞格列奈、美格列奈；双胍类：二甲双胍、苯乙双胍、丁福明；α2受体与咪唑啉受体拮抗剂：咪格列唑、伊格列哚、德格列哚、咪唑克生、依法克生、氟洛克生；其它胰岛素促分泌剂：利诺格列、毒蜥外泌肽(exendin)-4、BTS-67582、A-4166；噻唑烷二酮(PPARγ激动剂：环格列酮、吡格列酮、曲格列酮、罗格列酮；非噻唑烷二酮PPARγ激动剂；选择性PPARγ调节剂：间格列达山(metaglidasen)；PPARα激动剂；PPARα/γ双重激动剂；PPARδ激动剂、PPARα/γ/δ泛激动剂；SGLT2抑制剂；二肽基肽酶-IV(DPP4)抑制剂；醛糖还原酶抑制剂；RXR激动剂：JTT-501、MX-6054、DRF2593、LG100268；脂肪酸氧化抑制剂：氯莫克舍、乙莫克舍；α-葡萄糖酶抑制剂：阿卡玻糖、米格列醇、乙格列酯、伏格列波糖、MDL-25，637、卡格列波糖、MDL-73，945；β-激动剂：BRL 35135、BRL 37344、Ro 16-8714、ICI D7114、CL 316，243、TAK-667、AZ40140；磷酸二酯酶抑制剂，两种cAMP与cGMP类型：昔多芬，L686398：L-386，398；糊精拮抗剂：普兰林肽、AC-137；脂肪加氧酶抑制剂：马索普洛卡；生长激素释放抑制激素类似物：BM-23014、司格列肽、奥曲肽；胰高血糖素拮抗剂：BAY 276-9955；胰岛素信号传导激动剂、胰岛素类似物、PTP1B抑制剂：L-783281、TER17411、TER17529；糖异生抑制剂：GP3034；生长激素释放抑制激素类似物与拮抗剂；抗脂肪分解剂：烟碱酸、阿昔莫司、WAG994；葡萄糖输送激动剂：BM-130795；葡萄糖合成酶激酶抑制剂：氯化锂、CT98014、CT98023；及甘丙肽受体激动剂。
其它适当的噻唑烷二酮包括Mitsubishi的MCC-555(公开于美国专利5,594,016中)、Glaxo-Wellcome的法格立他扎(farglitazar) (GI-262570)、恩格列酮(englitazone)(CP-68722，Pfizer)或达格列酮(darglitazone)(CP-86325，Pfizer)、爱沙格列酮(isaglitazone) (MIT/J&J)、JTT-501(JPNT/P&U)、L-895645(Merck)、R-119702(Sankyo/WL)、NN-2344或巴格列酮(balaglitazone) (Dr.Reddy/NN)。
具体实施方式
下面用具体实施例来进一步说明本发明的内容，但并不以任何方式意味着对本发明进行限制。下列实施例中所用方法如无特别说明均为常规方法。
下列实施例所涉及的仪器设备及部分原材料的规格型号如下：
紫外光谱仪：Pharmacia公司Ultrospec 2100 Pro型。
核磁共振仪： Bruker 公司AV-500 NMR。
高分辨质谱仪：Thermo Scientific公司LTQ Orbitrap Discovery (Bremen,Germany)。
高压液相系统（分析）：Waters公司，2个515型泵，996 检测器。
高压液相系统（制备）：Waters公司，600型泵，2487检测器
北京创新通恒公司，LC3000型半制备。
酶标仪：Perkin Elmer公司 Victor2 1420 Multilabel Counter。
分析型色谱柱：YMC-Pack Pro C18 (4.6×250 mm, 5 µm)。
制备色谱柱：YMC-Pack Pro C18 (50×500 mm, 5 µm )；北京创新通恒公司 C18(30×250 mm, 10 µm )
层析硅胶：300~400目，青岛海洋化工厂。
HPLC所用甲醇和乙腈为色谱级，购自德国Merck公司，其他试剂均为分析纯，购自北京化学试剂厂。
下面实施例中化合物1- 5可以采用任何现有技术制备，制备方法在Kohno et al.Journal of Antibiotics, 1999, 52(12): 1114 – 1123 和Omura et al. Patent:US2002/193315等文献中有详尽描述。
发明人利用如下方法制备了化合物1-5, 真菌NCC4047和NCC4056从采自河北保定冉庄的土壤中分离得到，保藏于华北制药集团新药研究开发有限责任公司菌种保藏中心，公众可从华北制药集团新药研究开发有限责任公司获得。
实施例1 化合物1-3的制备
将真菌NCC4047斜面菌株接种于种子培养基（各成分的质量分数分别为：淀粉2%，葡萄糖1%，黄豆饼粉0.2%，麦芽粉0.6%，酵母粉0.5% ，CaCO3 0.2%，MgSO4·7H2O 0.2%，NaCl0.2%，pH为7.0），于27℃、220 rpm摇瓶培养72 h后，接种于装量为100 g大米培养基（大米浸泡3 d，加入质量分数为2.5%的热榨黄豆饼粉，搅拌均匀后，120℃消毒30 min）的750 mL三角瓶中，27℃静置培养14 d。
发酵产物（固体发酵）约1Kg，使用2L 70%丙酮浸泡并搅拌，2h后过滤，滤液减压蒸馏至无丙酮后，用等体积乙酸乙酯萃取两次，合并萃取液，无水硫酸钠干燥，蒸干得深棕色膏状物6.0g。
用少量甲醇溶解油膏，过硅胶柱粗分（500 mL漏斗，G5孔径，装100g硅胶），洗脱溶剂依次为正己烷、氯仿、氯仿-甲醇（10:1, V:V）、氯仿-甲醇（1:1, V:V）和甲醇各400 mL，HPLC检测，前三部分无目的化合物，含有目标物的后两部分合并，减压蒸干得到粗组分3.0g。取其中1.0g利用制备型HPLC分离，色谱柱：50*500 mm，流动相：CH3CN-H2O(55:45, V:V)，流速：100 mL/min，检测波长210 nm，得到化合物1(56.7mg，Rt:18.5min)、2(278.5mg,Rt:25.0min )和3(155.8mg, Rt:30.6min )。
化合物1-3通过MS和NMR数据分析分别鉴定为TMC-171A（CAS No. 259258-91-8,化合物1）、TMC-171B（CAS No. 259258- 92-9，化合物2）、TMC-171C（CAS No. 259258-93-0，化合物3）。其理化性质和核磁数据如下：
化合物1（TMC-171A）：白色固体，易溶于甲醇、乙醇、乙酸乙酯，不溶于水、正己烷；UV(MeOH) λmax (log ε) 202 (4.43), 220 (sh, 4.12) nm；HRESI-MS m/z 803.4806 [M-H]-，分子式：C41H72O15。1H-NMR (DMSO-d6, 500 MHz) δ 6.69(1H, dd, J=10.0, 1.0 Hz, H-3), 5.25 (1H, brd, J=8.5 Hz, H-11), 5.19 (1H, d, J=9.0 Hz, H-7), 5.11 (1H, d,J=9.5 Hz, H-15), 5.02 (1H, dd, J=8.0, 1.0 Hz, H-3'), 4.84(1H, d, J=6.0, 2'-OH), 4.65(1H, d, J=5.5, 4"-OH ), 4.63(1H, d, J=6.0, 4'-OH ), 4.59(1H, d, J=4.0,5-OH ), 4.49(1H, d, J=6.5, 3"-OH ), 4.42(1H, d, J=5.5, 1'-OH ), 4.34(1H, d, J=6.0, 6"-OH ), 4.27(2H, m, J=6.0, 5'-OH, 6'-OH ), 4.16 (1H, dd, J=11.0, 2.5Hz, H-1"), 4.06(1H, d, J=3.5, 9-OH ), 3.90 (1H, d, J=8.5, H-13), 3.87(1H, d,J=4.5, 2"-OH ), 3.78 (1H, m, H-2’), 3.73 (1H, m, H-4'), 3.67 (2H, m, H-5, H-6"), 3.60 (1H, m, H-6'), 3.54 (2H, m, H-9, H-2"), 3.46 (1H, m, H-6"), 3.39(1H, m, H-1'), 3.27 (1H, m, H-4"), 3.21 (1H, m, H-5'), 3.16 (1H, m, H-3"),2.86 (1H, ddd, J=9.0, 6.0, 2.0, H-5"), 2.56 (2H, m, H-4 and H-12), 2.50 (H-16), 2.44(1H, m, H-8), 1.79 (3H, d, J=1.0 Hz, H-21), 1.56 (3H, brs, H-23),1.55 (3H, brs, H-25), 1.51 (3H, brs, H-27), 0.92 (3H, d, J=7.0 Hz, H-28),0.81(3H, t, J=7.0 Hz, H-20), 0.80 (3H, d, J=7.0 Hz, H-29), 0.77 (3H, d, J=6.5Hz, H-26), 0.70 (3H, d, =7.0 Hz, H-24); 13C-NMR (DMSO-d6, 125 MHz) δ 167.2(C-1), 146.7(C-3), 137.5(C-15), 136.0 (C-6), 135.5 (C-10), 131.3 (C-7), 130.7(C-11), 129.8 (C-14), 126.5 (C-2), 96.1 (C-1"), 85.6 (C-13), 81.1 (C- 9),80.8(C-5), 77.6 (C-5"), 74.1 (C-3"), 72.5(C-3'), 70.9(C-2"), 70.7(C-5'), 70.3(C-2'), 69.3(C-4'), 67.3 (C-4"), 63.5(C-6'), 63.0(C-1'), 61.3 (C-6"), 44.0(C-17), 36.9 (C-4), 36.0 (C-8), 33.7 (C-12), 32.0 (C-18), 29.8 (C-19), 29.4(C-16), 21.7 (C-28), 18.7 (C-29), 17.4 (C-24), 17.1 (C-26), 16.5 (C-22), 12.6(C-21), 11.2(C-20, C-27), 11.0(C-23, C-25)。
化合物2（TMC-171B）：白色固体，溶于甲醇、乙醇、乙酸乙酯，不溶于水、正己烷；UV(MeOH) λmax (log ε) 202 (4.43), 220 (sh, 4.12) nm; HRESI-MS m/z 803.4798 [M-H]-，分子式：C41H72O15。1H-NMR (DMSO-d6, 500 MHz) δ 6.63(1H, dd, J=10.0, 1.0 Hz, H-3), 5.24 (1H, brd, J=8.5 Hz, H-11), 5.19 (1H, d, J=9.0 Hz, H-7), 5.12 (1H,brd, J=9.0 Hz, H-15), 4.78 (1H, m, H-2'), 4.65(1H, d, J=5.5, 4"-OH ), 4.59(1H, d, J=4.0, 5-OH ), 4.49(1H, d, J=6.5, 3"-OH ), 4.53(1H, d, J=5.5, 1'-OH), 4.45(1H, d, J=8.0, 3'-OH), 4.44(1H, d, J=5.0, 5'-OH), 4.35(1H, d, J=6.0,6"-OH ), 4.30(1H, t J=5.5, 6'-OH ), 4.25(1H, d, J=7.5, 4'-OH ), 4.16 (1H,brs, H-1"), 4.07(1H, d, J=3.5, 9-OH ), 3.97 (1H, t, J=8.0Hz, H-3'), 3.90 (1H,d, J=8.5, H-13), 3.88(1H, d, J=4.5, 2"-OH ), 3.76 (1H, m, H-1'), 3.67 (2H, m,H-5, H-6"), 3.59 (1H, m, H-6'), 3.54 (2H, m, H-9, H-2"), 3.48 (1H, m, H-5'),3.46 (1H, m, H-6"), 3.61 (1H, m, H-1'), 3.38 (1H, m, H-6'), 3.27 (2H, m, H-4', H-4"), 3.16 (1H, m, H-3"), 2.86 (1H, ddd, J=9.0, 6.0, 2.0, H-5"), 2.56(2H, m, H-4 and H-12), 2.50 (H-16), 2.44(1H, m, H-8), 1.79 (3H, d, J=1.0 Hz,H-21), 1.56 (3H, brs, H-23), 1.55 (3H, brs, H-25), 1.51 (3H, brs, H-27), 0.92(3H, d, J=7.0 Hz, H-28), 0.81(3H, t, J=7.0 Hz, H-20), 0.80 (3H, d, J=7.0 Hz,H-29), 0.77 (3H, d, J=6.5 Hz, H-26), 0.70 (3H, d, =7.0 Hz, H-24); 13C-NMR(DMSO-d6, 125 MHz) δ 166.8(C-1), 146.3(C-3), 137.5(C-15), 136.0 (C-6), 135.5(C-10), 131.4 (C-7), 130.7 (C-11), 129.8 (C-14), 126.8 (C-2), 96.1 (C-1"),85.6 (C-13), 81.1 (C- 9), 80.8(C-5), 77.6 (C-5"), 74.1 (C-3"), 74.4(C-2'),70.9(C-2"), 70.8(C-5'), 69.9(C-4'), 67.1(C-3'), 67.3 (C-4"), 63.6(C-6'), 59.8(C-1'), 61.3 (C-6"), 44.0 (C-17), 36.9 (C-4), 36.0 (C-8), 33.7 (C-12), 32.0(C-18), 29.8 (C-19), 29.3 (C-16), 21.7 (C-28), 18.7 (C-29), 17.4 (C-24), 17.1(C-26), 16.4 (C-22), 12.6 (C-21), 11.2(C-20, C-27), 11.0(C-23, C-25)。
化合物3（TMC-171C）：白色固体，溶于甲醇、乙醇、乙酸乙酯。UV (MeOH) λmax (logε) 202 (4.43), 220 (sh, 4.12) nm; HRESI-MS(m/z ): 803.4778 [M-H]-，分子式：C41H72O15。1H-NMR (DMSO-d6, 500 MHz) δ 6.67(1H, dd, J=10.0, 1.0 Hz, H-3), 5.24(1H, brd, J=10 Hz, H-11), 5.19 (1H, d, J=10.0 Hz, H-7), 5.12 (1H, brd, J=10.0Hz, H-15), 4.77 (1H, d, J=6.0, 2'-OH), 4.65(1H, d, J=5.5, 4"-OH ), 4.58(1H,d, J=4.0, 5-OH ), 4.49(1H, d, J=6.0, 3"-OH ), 4.49(1H, d, J=8.0, 3"-OH), 4.41(1H, d, J=5.5, 5'-OH), 4.33(1H, d, J=6.0, 6"-OH ), 4.27(1H, t J=5.5, 3'-OH ),4.13(1H, d, J=7.5, 4'-OH ), 4.16 (1H, brs, H-1"), 4.07(1H, d, J=3.5, 9-OH ),3.90 (1H, d, J=8.5, H-13), 3.84(1H, d, J=4.5, 2"-OH ), 4.34 (1H, dd, H-1'),4.00 (1H, dd, H-1'), 3.72 (1H, m, H-2'), 3.67 (1H, m, H-6"), 3.62 (1H, m, H-6'), 3.59 (1H, m, H-3'), 3.58 (1H, m, H-4'), 3.54 (2H, m, H-9, H-2"), 3.48(1H, m, H-5'), 3.45 (1H, m, H-6"), 3.41 (1H, m, H-6'), 3.27 (1H, dt, J=5.5,9.5, H-4"), 3.16 (1H, m, H-3"), 2.86 (1H, ddd, J=9.5, 6.5, 2.0, H-5"), 2.56(2H, m, H-4 and H-12), 2.50 (H-16), 2.44(1H, m, H-8), 1.79 (3H, d, J=1.0, H-21), 1.56 (3H, brs, H-23), 1.55 (3H, brs, H-25), 1.51 (3H, brs, H-27), 0.92(3H, d, J=6.5, H-28), 0.81(3H, t, J=7.0 Hz, H-20), 0.80 (3H, d, J=7.0 Hz, H-29), 0.77 (3H, d, J=6.5 Hz, H-26), 0.70 (3H, d, =7.0 Hz, H-24); 13C-NMR (DMSO-d6, 125 MHz) δ 167.6(C-1), 146.4(C-3), 137.5(C-15), 136.0 (C-6), 135.5 (C-10), 131.3 (C-7), 130.7 (C-11), 129.8 (C-14), 126.5 (C-2), 96.1 (C-1"), 85.6(C-13), 81.1 (C- 9), 80.8(C-5), 77.6 (C-5"), 74.1 (C-3"), 68.5(C-2'), 70.9(C-2"), 71.1(C-5'), 69.3(C-4'), 69.5(C-3'), 67.3 (C-4"), 63.8(C-6'), 67.2(C-1'),61.3 (C-6"), 44.0 (C-17), 36.9 (C-4), 36.0 (C-8), 33.8 (C-12), 32.0 (C-18),29.8 (C-19), 29.3 (C-16), 21.7 (C-28), 18.7 (C-29), 17.4 (C-24), 17.1 (C-26),16.5 (C-22), 12.5 (C-21), 11.2(C-20, C-27), 11.1(C-23, C-25)。
实施例2 化合物4-5的制备
将真菌NCC4056斜面菌株接种于种子培养基（各成分的质量分数分别为：葡萄糖2%，黄豆饼粉0.2%，麦芽粉0.6%，酵母粉0.2% ，CaCO3 0.1%，MgSO4·7H2O 0.05%，NaCl 0.2%，pH为6.0），于27℃、220rpm摇瓶培养72 h后，以2%的接种量接种于装量为200mL/1L摇瓶的发酵培养基中（蛋白胨0.1% 可溶性淀粉1.0% 海水素2.0%），27℃静置培养16 d。
发酵培养物约3L，加入3L丙酮浸泡并搅拌，2h后过滤，滤液减压蒸馏至无丙酮后，用等体积乙酸乙酯萃取两次，合并萃取液，蒸干得棕色粘稠物2.5g。该粘稠物用100ml水分散，等体积正己烷萃取，萃余液用等体积乙酸乙酯萃取，萃取液蒸干得到1.1g 固体物。
上述固体物用少量甲醇溶解，硅胶柱色谱（2.6*50cm，300-400目硅胶），氯仿-甲醇(100:0---0:100)梯度洗脱, 20ml/管收集，GKA活性跟踪检测，将含有活性物质的部分合并，减压蒸干得到活性组分360mg。利用制备型HPLC分离，色谱柱：30*250mm，流动相：CH3CN-H2O(50:50, V:V)，流速：35mL/min，检测波长210nm，得到化合物4(36.8mg，Rt:32.0min)、5(25.3mg, Rt:36.5min )。
化合物4和5通过HRMS和NMR数据分析鉴定为roselipin 1A（CA No. 232258-17-2）和 roselipin 1B（CA No. 232258-18-3）。其理化性质和核磁数据如下：
化合物4（CA No. 232258-17-2，roselipin 1A）：白色固体，易溶于甲醇、乙醇、丙酮和乙酸乙酯，不溶于水、正己烷和石油醚。UV (MeOH) λmax (log ε) 202 (4.45), 222(3.36) nm; HRESI-MS m/z 775.4856 [M-H]-，分子式：C40H72O14。 1H-NMR (CD3OD, 500MHz) δ 6.80(1H, dd, J=10.0, 1.0 Hz, H-3), 5.56 (1H, dd, J=9.5, 1.0 Hz, H-11),5.33 (1H, dd, J=9.0, 1.0Hz, H-7), 4.49 (1H, brs, H-1"), 4.41 (1H, dd, J=12.0,3.0 Hz, H-1'), 4.41 (1H, dd, J=12.0, 6.5 Hz, H-1'), 3.94 (1H, ddd, J=9.0,6.5, 3.0 Hz, H-2'), 3.92 (1H, ddd, J=6.5, 6.5, 3.0 Hz, H-4'), 3.90 (1H, d, J=3.0 Hz, H-2"), 3.89 (1H, dd, J=11.5, 2.0 Hz, H-6"), 3.82 (1H, d, J=8.5, H-5),3.76 (1H, dd, J=11.5, 5.0 Hz, H-6"), 3.72 (1H, d, J=9.5, H-9), 3.65 (1H, ddd,J=7.0, 6.5, 6.5 Hz, H-5'), 3.58 (1H, dd, J=9.0, 2.0 Hz, H-3'), 3.57 (1H, dd,J=9.5, 9.0 Hz, H-4"), 3.49 (1H, dd, J=7.0, 3.5 Hz, H-13), 3.38 (1H, dd, J=9.0, 3.0 Hz, H-3"), 3.16 (1H, ddd, J=9.5, 5.0, 2.0 Hz, H-5"), 2.75 (1H, m, H-12), 2.73 (1H, m, H-4), 2.62 (1H, m, H-8), 1.90 (3H, d, J=1.5 Hz, H-21), 1.87(1H, m, H-14), 1.68 (3H, d, J=1.5 Hz, H-23), 1.64 (3H, d, J=1.0 Hz, H-25),1.62 (1H, m, H-16), 1.45 (1H, m, H-18), 1.42 (1H, m, H-19), 1.37 (1H, m, H-15), 1.24 (1H, m, H-17), 1.08 (1H, m, H-19), 0.99 (3H, d, J=7.0 Hz, H-26),0.95 (1H, m, H-15), 0.94 (3H, d, J=7.0 Hz, H-27), 0.90 (6H, d, J=6.5 Hz, H-28, 29), 0.89 (3H, d, J=7.0 Hz, H-20), 0.88 (1H, m, H-17),0.86 (3H, d, J=7.0Hz, H-22), 0.78 (3H, d, J=7.0 Hz, H-24)；13C-NMR (CD3OD, 125 MHz) δ 170.0(C-1),147.6(C-3), 137.1(C-6), 134.8 (C-10), 134.7 (C-11), 134.3 (C-7), 128.8 (C-2),102.6 (C-1"), 87.3 (C-13), 84.3 (C- 9), 83.7(C-5), 78.2 (C-5〞), 75.6 (C-3〞),72.7(C-2〞), 71.9(C-3´), 71.6(C-4´), 70.6(C-2´), 68.5 (C-4〞), 67.9(C-1´), 64.8(C-5´), 63.9 (C-6〞), 46.0 (C-17), 43.9 (C-15), 38.0 (C-4), 37.0 (C-8), 36.2(C-12), 34.3 (C-14), 32.9 (C-18), 29.9 (C-19), 28.9 (C-16), 21.3 (C-28), 20.7(C-29), 18.6 (C-26), 17.8 (C-24), 16.8(C-22), 15.6(C-27), 11.5(C-20), 11.3(C-23)。
化合物5（CA No. 232258-18-3, roselipin 1B）：白色固体，易溶于甲醇、乙醇、丙酮和乙酸乙酯，不溶于水、正己烷和石油醚。UV (MeOH) λmax (log ε) 202 (4.45), 222(3.36) nm; HRESI-MS m/z 775.4812 [M-H]- , 分子式：C40H72O14。1H-NMR (CD3OD, 500MHz) δ 6.78(1H, dd, J=10.0, 1.5 Hz, H-3), 5.57(1H, dd, J=9.5, 1.0 Hz, H-11),5.33 (1H, dd, J=9.0, 1.0Hz, H-7), 4.49 (1H, brs, H-1"), 4.20 (1H, dd, J=11.0,5.5 Hz, H-1'), 4.27(1H, dd, J=11.0, 7.0 Hz, H-1'), 4.14 (1H, ddd, J=9.0, 6.5,3.0 Hz, H-2'), 3.90 (1H, d, J=3.0 Hz, H-2"), 3.89 (1H, dd, J=11.5, 2.0 Hz, H-6"), 3.82 (1H, d, J=9.0, H-5), 3.81 (1H, d, J=8.5, H-5'), 3.76 (1H, dd, J=11.5, 5.0 Hz, H-6"), 3.73 (1H, ddd, J=8.0, 6.0, 3.5 Hz, H-6"), 3.72 (1H, d, J=9.5, H-9), 3.64 (1H, dd, J=11.0, 6.0Hz, H-5'), 3.57 (1H, dd, J=9.0,9.0 Hz,H-3"), 3.53 (1H, dd, J=8.0, 2.0 Hz, H-3'), 3.49 (1H, dd, J=7.0, 3.5 Hz, H-13), 3.38 (1H, dd, J=9.0, 3.0 Hz, H-3"), 3.16 (1H, ddd, J=9.5, 5.0, 2.0 Hz,H-5"), 2.76 (1H, m, H-12), 2.75 (1H, m, H-4), 2.63 (1H, m, H-8), 1.90 (3H, d,J=1.5 Hz, H-21), 1.87 (1H, m, H-14), 1.68 (3H, d, J=1.5 Hz, H-23), 1.64 (3H,d, J=1.0 Hz, H-25), 1.62 (1H, m, H-16), 1.45 (2H, m, H-18, H-19), 1.42 (1H,m, H-15), 1.27 (1H, m, H-17), 1.22 (1H, m, H-19), 1.02 (1H, m, H-15), 0.99(3H, d, J=7.0 Hz, H-26), 0.95 (3H, d, J=7.0 Hz, H-27), 0.94 (1H, m, H-17),0.90 (6H, d, J=6.5 Hz, H-28, 29), 0.89 (3H, d, J=7.0 Hz, H-20), 0.85 (3H, d,J=7.0 Hz, H-22), 0.78 (3H, d, J=7.0 Hz, H-24); 13C-NMR (CD3OD, 125 MHz) δ169.8(C-1), 147.7(C-3), 137.1(C-6), 134.8 (C-10), 134.7 (C-11), 134.3 (C-7),128.7 (C-2), 102.6 (C-1"), 87.3 (C-13), 84.3 (C- 9), 83.7(C-5), 78.2 (C-5"),75.6 (C-3"), 72.74(C-2"), 72.71(C-4'), 72.3(C-3'), 69.4(C-2'), 68.6 (C-4"),67.9(C-1'), 64.8(C-5'), 63.9 (C-6"), 46.0 (C-17), 43.9 (C-15), 38.0 (C-4),37.0 (C-8), 36.2 (C-12), 34.3 (C-14), 32.9 (C-18), 29.9 (C-19), 28.9 (C-16),21.3 (C-28), 20.7 (C-29), 18.6 (C-26), 17.8 (C-24), 16.8(C-22), 15.6(C-27),11.5(C-20), 11.3(C-23)。
实施例3 葡萄糖激酶活性测定
实验原理：葡萄糖激酶可以将底物葡萄糖和ATP转化为6-磷酸葡萄糖和ADP，6-磷酸葡萄糖和NADP则在 6-磷酸葡萄糖脱氢酶作用下生成 6-磷酸葡萄糖酸内脂和NADPH，而在340nm波长下，NADPH有最大吸收值，可通过检测NADPH的光吸收值来检测葡萄糖激酶活性的大小。
检测方法：基于上述原理，设计反应体系100µl，包括100 mM Tris-HCl (PH 7.4)、1 mM NADP、2 mM MgCl2、25 mM KCl、5mM葡萄糖、2 U/mL 6-磷酸葡萄糖脱氢酶、5µg/mL GK。将试验化合物溶于二甲亚砜，然后加入到反应体系中，37℃下孵育15分钟后，加入终浓度为2 mM ATP启动酶活反应。37℃下孵育30分钟后，通过测定340 nm处吸光值的变化来测定酶活反应的速度，并计算EC50值评价化合物的激动活性。
EC50值指酶促反应速率提高50%的化合物浓度。
葡萄糖激酶制备
将含有人类葡萄糖激酶全长序列的原核表达质粒转化到大肠杆菌中，构建葡萄糖激酶表达工程菌株。对表达菌株的培养、诱导后，收集菌体，超声破碎，使用镍亲和层析进行蛋白纯化，从而获得高纯度的葡萄糖激酶。
实施例4 口服葡萄糖耐量试验(OGTT)
取雄性C57BL/6J小鼠，进行15周自有饮水、高脂饮食饲养，定期检测体重以及皮下脂肪堆积程度。使用0.5%甲基纤维素水溶液溶解受试化合物1，以50 mg/kg剂量对模型小鼠进行灌胃给药。给药至第7天，当日禁食2h给药，给药后2 h取血，随即灌胃葡萄糖 (2g/kg)，糖负荷之后30min、60 min、90min、120 min取血。检测各时间段血糖浓度，制作血糖-时间曲线，计算0-120分钟内血糖值曲线下面积（AUC）。结果表明，与对照组比较，化合物1处理组AUC明显降低，达到36%。
Claims (4)
1.式（Ⅰ）化合物
其中R1为D-甘露糖，R2为D-甘露醇或D-阿拉伯醇
（Ⅰ）
在制备预防或治疗葡萄糖激酶介导的疾病的药物中的应用。
2.权利要求1所述的应用，其中葡萄糖激酶介导的疾病为肥胖症。
3.权利要求1所述的应用，其中葡萄糖激酶介导的疾病为糖尿病。
4.权利要求3所述的应用，其中葡萄糖激酶介导的疾病为糖耐量异常、妊娠糖尿病、糖尿病慢性并发症。
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| RU2775603C2 (ru) * | 2018-05-31 | 2022-07-05 | Хуа Медсин (Шанхай) Лтд. | Фармацевтическая комбинация, композиция и состав, содержащие активатор глюкокиназы и ингибитор альфа-глюкозидазы, способы приготовления и их применение |
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