CN118063291A - 一类四聚苄类化合物治疗和预防糖尿病的用途 - Google Patents
一类四聚苄类化合物治疗和预防糖尿病的用途 Download PDFInfo
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Abstract
本发明属于医药技术领域，公开了化合物(I)和(II)及其药学上可接受的盐，以及其药物组合物在制备治疗糖尿病药物中的应用。
Description
技术领域
本发明涉及一种四聚苄类化合物及其药学上可接受的盐、含有这类化合物的药物组合物，以及这类化合物在治疗糖尿病和糖耐量受损方面的应用，属于医药技术领域。
背景技术
传统名贵中药天麻为兰科(Orchidaceae)天麻属(Gastrodia R.Br.)植物天麻(Gastrodiaelata Blume)的干燥块茎，应用历史悠久。天麻作为传统名贵中药，用于治疗各种神经痛症和神经紊乱等相关疾病，同时还具有强身健体、增强记忆力和促进血液循环等作用[1,2]，医药和食品行业应用广泛。经过国内外学者对天麻及其炮制品的化学成分及药理活性的长期研究，目前已从天麻中分离并鉴定了以对羟基苄醇衍生物或对羟基苄基取代衍生物为主的100余个化学成分[3-7]，其中对羟基苄醇和天麻素被认为是天麻的特征性有效成分。《中国药典》中将天麻素作为天麻药材的质量控制成分[8]。同时，药理学研究还发现对羟基苄醇衍生物和天麻素具有多种体内外药理活性，并且天麻素还对心脏肥大和纤维化以及肿瘤免疫反应具有一定的药效[9-12]。然而，研究也表明，去除天麻素后的天麻提取物依然保持抗缺氧、镇静、催眠和抗炎作用，而更高剂量的天麻素确无以上作用[3]。基于此，本课题组前期已对天麻水提取物的化学成分及其药理活性开展了较为系统的研究，获得了具有强镇静催眠作用的微量成分N6-(4-羟基苄基)-腺苷(NHBA)[13,14]和可明显改善学习记忆作用的派利辛[38]等，证明了天麻中确实存在其它新型强药效成分。
糖尿病是以血葡萄糖水平慢性增高为特征的代谢疾病群。常用的口服降糖药物主要包括促胰岛素分泌剂类、二甲双胍类、α-糖苷酶(α-glucosidase)抑制剂类、噻唑烷二酮类、DPP-4酶抑制剂等；其中，α-糖苷酶抑制剂类的作用机制是抑制碳水化合物在小肠上部的吸收，可降低餐后血糖、改善空腹血糖。上市的α-糖苷酶抑制剂主要包括阿卡波糖、伏格列波糖，通常会有胃肠道反应等副作用。新型有效降糖药物的临床需求依然巨大，从天然药物中寻找具有降血糖的有效药物，一直是国内外学者研究的热点，并且取得了一定的成果，比如中国原创降血糖天然药物桑枝总生物碱片。
参考文献：
[1]江苏大学医学院.中药大辞典[M].上海：上海科学技术出版社,1977:315-317.
[2]国家中医药管理局《中华本草编委会》.中华本草[M].上海：上海科学技术出版社,1999:716-722.
[3]Zhan H.D.；Zhou H.Y.；Sui Y.P.The rhizome of Gastrodia elata Blume-anethnopharmacological review[J].J.Ethnopharmacol,2016,189:361-385.
[4]Wang Z.W.；Li Y.；Liu D.H.；et al.Chemical constituents from therhizomes of Gastrodia elata f.glauca and their potential neuroprotectiveeffects[J].Phytochem.Lett.2018；24:167-171.
[5]Wang Z.W.；Li Y.；Liu D.H.；et al.Four new phenolic constituents fromthe rhizomes of Gastrodia elata Blume[J].Nat.Prod.Res.2019,33:1140-1146.
[6]Chen S.Y.；Geng C.A.；Ma Y.B.；et al.Melatonin receptors agonisticactivities of phenols from Gastrodia elata[J].Nat.Prod.Bioprospect,2019,9:297-302.
[7]Chen S.Y.；Geng C.A.；Ma Y.B.；et al.Polybenzyls from Gastrodiaelata,their agonistic effects on melatonin receptors and structure-activityrelationships[J].Bioorg.Med.Chem.；2019,27:3299-306.
[8]乙酰天麻素临床验证协作组.乙酰天麻素治疗神经衰弱和血管性头痛近期疗效观察[J].中国神经精神病杂志,1986,12:269-270.
[9]Liu J.；Mori A.Antioxidant and pro-oxidant activities of p-hydroxybenzyl alcohol and vanillin:effects on free radicals,brainperoxidation and degradation of benzoate,deoxyribose,amino acids and DNA[J].Neuropharm.；1993,32:659-669.
[10]Lee Y.S.；Ha J.H.；Yong C.S.；et al.Inhibitory effects ofconstituents of Gastrodia elata BI.On glutamate-induced apoptosis in IMR-32Human neuroblastoma cells.[J].Arch.Pharm.Res.；1999,22:404-409.
[11]Hsieh C.L.；Chang C.H.；Chiang S.Y.；et al.Anticonvulsive and freeradical scavenging activities of vanillyl alcohol in ferric chloride-inducedepileptic seizures in Sprague-Dawley rats[J].Life Sci.2000,67:1185-1195.
[12]Yu S.J.；Kim J.R.；Lee C.K.；et al.Gastrodia elata Blume and anActive component,p-hydroxybenzyl alcohol reduce focal ischemic brain injurythrough antioxidant related gene expressions[J].Biol.Pharm.Bull.；2005,28:1016-1020.
[13]Zhang Y.；Li M.；Kang R.X.；at al.NHBA isolated from Gastrodia elataexerts sedative and hypnotic effects in sodium pentobarbital-treated mice[J].Pharm.Biochem.Behav.2012,102:450-457.
[14]He J.；Luo Z.；Huang L.；et al.Ambient mass spectrometry imagingmetabolomics method provides novel insights into the action mechanism of drugcandidates[J].Anal.Chem.2015,87:5372-5379.
发明内容
本发明要解决的技术问题是，提供一类具有治疗糖尿病作用的四聚苄类化合物及其药效学上可接受的盐，以及其药物组合物。
为解决本发明的技术问题，本发明提供如下技术方案：
本发明技术方案的第一方面是提供了一种如通式(I)和(Ⅱ)所示的四聚苄类化合物及其药学上可接受的盐。
具体而言，提供了如通式(I)所示的化合物及其药学上可接受的盐：
提供了如通式(Ⅱ)所示的化合物及其药学上可接受的盐：
本发明技术方案的第二方面是提供了第一方面所述化合物的制备方法。
取对羟基苄醇(CAS:623-05-2)，放入圆底烧瓶中，然后加入蒸馏水(与对羟基苯甲醇的重量比为30:1～50:1)中，加热回流30～50个小时，然后浓缩成浸膏。用反相ODS柱色谱分离，ODS干法拌样，湿法装柱后上样，依次用5％乙腈/水、10％-20％乙腈/水、25％乙腈/水、30％乙腈/水、50％乙腈/水、100％乙腈/水进行洗脱。30％乙腈/水洗脱部位，经硅胶制备薄层色谱(正己烷-乙酸乙酯-甲醇，6:2.5:1)分离，TLC检测合并相同组分得到a～d组分；其中，b经反相半制备HPLC(MG-II C18色谱柱，甲醇-水59:41，2.0mL/min)分离得到化合物(I)。d经硅胶制备薄层色谱(氯仿-甲醇，10:1)分离，TLC检测合并相同组分得到d2a～d2d。其中，d2c经反相半制备HPLC(MG-II C18色谱柱，甲醇-水62:38，2.5mL/min)分离得到化合物(Ⅱ)。
本发明技术方案的第三方面是提供含有式(I)和(Ⅱ)所示的化合物及其药学上可接受的盐的药物组合物。该药物组合物含有治疗有效量的本发明的四聚苄类衍生物及其药学上可接受的盐，以及任选的含有药用载体。
通常本发明药物组合物含有0.1-95％重量的本发明化合物。
本发明化合物的药物组合物可根据本领域公知的方法制备。用于此目的时，如果需要，可将本发明的化合物与一种或多种固体或液体药物赋形剂和/或辅剂结合，制成可作为人药或兽药使用的适当的施用形式或剂量形式。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、肌肉、皮下、鼻腔、口腔粘膜、皮肤、腹膜或直肠等，优选口服。
本发明化合物或含有它的药物组合物的给药途径可为注射给药。注射包括静脉注射、肌肉注射、皮下注射和皮内注射等。
给药剂型可以是液体剂型、固体剂型。如液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混悬剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂等。
本发明提取物或化合物可以制成普通制剂、也可以是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将单位给药剂型制成片剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如淀粉、糊精、硫酸钙、乳糖、甘露醇、蔗糖、氯化钠、葡萄糖、尿素、碳酸钙、白陶土、微晶纤维素、硅酸铝等；湿润剂与粘合剂，如水、甘油、聚乙二醇、乙醇、丙醇、淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、紫胶、甲基纤维素、磷酸钾、聚乙烯吡咯烷酮等；崩解剂，例如干燥淀粉、海藻酸盐、琼脂粉、褐藻淀粉、碳酸氢钠与枸橼酸、碳酸钙、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠、甲基纤维素、乙基纤维素等；崩解抑制剂，例如蔗糖、三硬脂酸甘油酯、可可脂、氢化油等；吸收促进剂，例如季铵盐、十二烷基硫酸钠等；润滑剂，例如滑石粉、二氧化硅、玉米淀粉、硬脂酸盐、硼酸、液体石蜡、聚乙二醇等。还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
例如为了将给药单元制成丸剂，可以广泛使用本领域公知的各种载体。关于载体的例子是，例如稀释剂与吸收剂，如葡萄糖、乳糖、淀粉、可可脂、氢化植物油、聚乙烯吡咯烷酮、Gelucire、高岭土、滑石粉等；粘合剂，如阿拉伯胶、黄蓍胶、明胶、乙醇、蜂蜜、液糖、米糊或面糊等；崩解剂，如琼脂粉、干燥淀粉、海藻酸盐、十二烷基磺酸钠、甲基纤维素、乙基纤维素等。
例如为了将给药单元制成胶囊，将有效成分本发明提取物或化合物与上述的各种载体混合，并将由此得到的混合物置于硬的明胶胶囊或软胶囊中。也可将有效成分本发明化合物制成微囊剂，混悬于水性介质中形成混悬剂，亦可装入硬胶囊中或制成注射剂应用。
例如，将本发明提取物或化合物制成注射用制剂，如溶液剂、混悬剂溶液剂、乳剂、冻干粉针剂，这种制剂可以是含水或非水的，可含一种和/或多种药效学上可接受的载体、稀释剂、粘合剂、润滑剂、防腐剂、表面活性剂或分散剂。如稀释剂可选自水、乙醇、聚乙二醇、1,3-丙二醇、乙氧基化的异硬脂醇、多氧化的异硬脂醇、聚氧乙烯山梨醇脂肪酸酯等。另外，为了制备等渗注射液，可以向注射用制剂中添加适量的氯化钠、葡萄糖或甘油，此外，还可以添加常规的助溶剂、缓冲剂、pH调节剂等。这些辅料是本领域常用的。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂、甜味剂或其它材料。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物、药物组合物的给药剂量取决于许多因素，例如所要预防或治疗疾病的性质和严重程度，患者或动物的性别、年龄、体重、性格及个体反应，给药途径、给药次数、治疗目的，因此本发明的治疗剂量可以有大范围的变化。一般来讲，本发明中药学成分的使用剂量是本领域技术人员公知的。可以根据本发明化合物组合物中最后的制剂中所含有的实际药物数量，加以适当的调整，以达到其治疗有效量的要求，完成本发明的预防或治疗目的。本发明化合物的每天的合适剂量范围本发明的提取物或化合物的用量为0.001-150mg/kg体重，优选为0.01-100mg/kg体重，更优选为0.01-60mg/kg体重，最优选为0.1-10mg/kg体重。上述剂量可以单一剂量形式或分成几个，例如二、三或四个剂量形式给药这受限于给药医生的临床经验以及包括运用其它治疗手段的给药方案。
每一种治疗所需总剂量可分成多次或按一次剂量给药。本发明的化合物、组合物可单独服用，或与其他治疗药物或对症药物合并使用并调整剂量。
本发明技术方案的第四方面是提供含有式(I)、(Ⅱ)所示的化合物及其药学上可接受的盐制备预防和/或治疗糖尿病药物中的应用，以及在制备预防和/或治疗前糖尿病药物中的应用
化合物(I)和(Ⅱ)或药学上可接受的盐在治疗或预防糖尿病的应用未见公开报道。
有益技术效果
本发明的发明人在对传统中药天麻的活性成分研究过程中，通过PTP1B抑制和α-葡萄糖苷酶抑制实验，对该类化合物进行了活性评价，结果显示化合物(I)和(Ⅱ)在具有一定的α-葡萄糖苷酶抑制作用，且灌胃给予样品(I)100mg/kg可明显延缓ICR小鼠口服蔗糖后的糖吸收作用。属于降血糖药物研发过程中具有价值的先导化合物。
附图说明
图1、化合物(I)对ICR小鼠口服蔗糖耐量的影响A.蔗糖负荷后血糖水平的变化；B.AUC值.**，***,p<0.01,0.001vs Model.n＝8.
具体实施方式
下面的实验实施例可进一步说明本发明，但不以任何方式限制本发明。
实施例1、化合物(I)和(Ⅱ)的制备过程如下：
取10克对羟基苄醇(CAS:623-05-2)，放入圆底烧瓶中，然后加入250毫升蒸馏水中，加热回流40个小时，然后浓缩成浸膏。用反相ODS柱色谱分离，ODS干法拌样，湿法装柱后上样，依次用5％乙腈/水(1.0L)、10％-20％乙腈/水(0.5L)、25％乙腈/水(0.5L)、30％乙腈/水(0.5L)、50％乙腈/水(0.5L)、100％乙腈/水(0.3L)进行洗脱，指定为相应的组分A-F。
30％乙腈/水洗脱部位D组分，经TLC检测，合并成分相似的流分得到Da1、Da2、D-b1～D-b8、D-c1～D-c6、D-d1～D-d7、D-e1～D-e15。D-b4(71mg)，经硅胶制备薄层色谱(正己烷-乙酸乙酯-甲醇，6:2.5:1)分离得到D-b4a～D-b4d；其中，D-b4b(27mg)经反相半制备HPLC(MG-II C18色谱柱，甲醇-水59:41，2.0mL/min)分离得到化合物(I)(9.0mg，tR＝86.0min)。D-d2(80mg)经硅胶制备薄层色谱(氯仿-甲醇，10:1)分离得到D-d2a～D-d2d。其中，D-d2c(50mg)经反相半制备HPLC(MG-II C18色谱柱，甲醇-水62:38，2.5mL/min)分离得到化合物(Ⅱ)(2.0mg，tR＝52.0min)。
化合物(I):白色无定形粉末，易溶于丙酮、甲醇，难溶于水；UV(MeOH)λmax(logε)205(4.13),224(3.55),280(3.32)nm；IRνmax 3277,3016,2917,2849,1890,1651,1612,1511,1437,1365,1245,1172,1107,1006,948,910,822,773,708cm-1；(-)-HRESIMS:m/z411.1603[M-H]-(calcd.for C27H23O4,411.1602)。
化合物(Ⅱ):白色无定形粉末，易溶于丙酮、甲醇，难溶于水；UV(MeOH)λmax(logε)204(4.82),227(4.46),283(3.88)；IRνmax3306,3019,2962,2921,2851,2705,2602,18881,1696,1612,1598,1510,1441,1366,1255,1233,1173,1110,1017,913,817,773cm-1；(+)-HRESIMS:m/z435.1570[M+Na]+(calcd.for C27H24O4Na,435.1567)。
实验例1、化合物(I)和(Ⅱ)的α-葡萄糖苷酶抑制活性实施例
实验方法：
以对硝基苯-α-D-吡喃葡萄糖苷(p-nitrophenyl-α-D-glucopyranoside，pNPG)为底物，在α-葡萄糖苷酶的催化作用下，生成对硝基苯酚(p-nitrophenol,pNP)，该产物在405nm波长处有吸收峰。以一定时间内生成pNP量表示α-葡萄糖苷酶的活性。将受试样品与α-葡萄糖苷酶预孵后，加入底物，检测受试样品对生成pNP的影响；并计算受试样品的半数抑制浓度IC50。
实验结果：
四聚苄类化合物(I)和(Ⅱ)对α-葡萄糖苷酶具有明显抑制作用，在终浓度10μM浓度下其对α-葡萄糖苷酶活性的抑制率分别为94.9％和91.4％；阳性药阿卡波糖在终浓度200μM时对α-葡萄糖苷酶的抑制率为75.2％。进一步测得化合物(I)和(Ⅱ)抑制α-葡萄糖苷酶的IC50分别为4.48×10-7M和8.37×10-7M。
实验例2、化合物(I)对正常小鼠口服蔗糖耐量的影响实验方法：正常雄性ICR小鼠，体重18-22g。禁食过夜，随机分为对照组、阿卡波糖组和化合物(I)组，分别口服水、阳性对照药阿卡波糖10mg/kg、和化合物(I)100mg/kg。在给药的同时口服双糖蔗糖4g/kg。分别于蔗糖负荷后0、30、60、120min取血，检测各时间点血葡萄糖浓度，并计算血糖-时间曲线下面积(area under the curve,AUC)。实验结果：
与对照组比较，阳性药阿卡波糖能够明显减小给予蔗糖负荷后血糖的升高幅度，血糖峰值下降21％，其AUC值降低19％；化合物(I)组蔗糖负荷后血糖峰值下降27％；AUC值降低12％。说明灌胃给予化合物(I)100mg/kg具有明显延缓ICR小鼠口服蔗糖后的糖吸收作用。见图1。
Claims (6)
1.一种如式(I)所示的四聚苄类化合物及其药学上可接受的盐：
2.一种如式(Ⅱ)所示的四聚苄类化合物及其药学上可接受的盐：
3.根据权利要求1和2任一项所述的化合物及其药学上可接受的盐，其特征在于，所述药学上可接受的盐选自通式化合物(I)和(Ⅱ)与有机酸或无机酸所成的盐。
4.一种药物组合物，其特征在于，所述的药物组合物包括权利要求1-3任一项所述的化合物及其药学上可接受的盐以及药学上可接受的载体或赋形剂。
5.权利要求1-3任一项所述的化合物及其药学上可接受的盐或权利要求4所述的药物组合物在制备治疗和预防糖尿病的药物中的应用。
6.权利要求1-3任一项所述的化合物及其药学上可接受的盐或权利要求4所述的药物组合物在制备治疗和预防糖耐量受损药物中的应用。
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