CN104125958A - 从茑萝属分离的新型化合物以及作为有效成分包含该新型化合物的用于预防或治疗糖尿病的组合物 - Google Patents
从茑萝属分离的新型化合物以及作为有效成分包含该新型化合物的用于预防或治疗糖尿病的组合物 Download PDFInfo
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Abstract
本发明涉及一种从茑萝属分离的新型化合物以及作为有效成分包含该新型化合物的组合物,更具体地说,涉及一种从茑萝属分离的新型化合物以及作为有效成分含有该新型化合物的用于预防或治疗糖尿病或糖尿病并发症的组合物。本发明的来自茑萝属的新型化合物具有优异的降低血糖、促进胰岛素分泌、抑制VEGF表达等效果,因此不仅具有预防或治疗糖尿病和因其引发的各种并发症的功效,而且与现有糖尿病治疗制剂联合用药时还能促进治疗效果。
Description
技术领域
本发明涉及一种从茑萝属分离的新型化合物以及作为有效成分包含该新型化合物的组合物,更具体地说,涉及一种从茑萝属分离的新型化合物以及作为有效成分包含该新型化合物的用于预防或治疗糖尿病及糖尿病并发症的组合物。
背景技术
糖尿病(diabetes)是指由多种病因引起的代谢紊乱,临床特征为因胰岛素分泌缺陷或胰岛素作用缺陷所导致的慢性高血糖症(hyperglycemia),当血液中的葡萄糖浓度长期持续异常高的状态时,由于慢性代谢紊乱和因其引发的慢性血管损伤,导致发生各种并发症。
糖尿病为典型的成人代谢性疾病,全世界人口中约5%患此疾病,由此导致的生命和经济损失巨大。大部分糖尿病患者服用口服药治疗制剂,但目前的现状是,尚未开发出安全的治疗药物。虽然胰岛素抵抗性(insulin resistance)被视为最重要的原因,但准确的机制尚不明确,只知道由于遗传因素和环境的复合原因所导致。
糖尿病是世界第三大疾病,预计到2010年会有约2亿5千万的糖尿病患者,预计韩国国内的患病率也会持续上升。在韩国国内的死亡原因中,糖尿病死因排名第7,占糖尿病患者总人数的90%以上的非胰岛素依赖型糖尿病(non-insulin dependent diabetes,NIDDM),主要发生在四十岁以上的中年人身上,因此,称为成人型糖尿病,是患者无法充分生成胰岛素或不能适当利用胰岛素而引起的代谢紊乱(DeFronzo RA et al.,Diabetes Care,15:318,1992)。非胰岛素依赖型糖尿病(NIDDM)的发病原因尚未明确,但是,西洋化的饮食生活和生活方式等环境因素、以及肥胖和缺乏运动等遗传因素都认为是其原因。通常,首先以饮食疗法和运动疗法治疗非胰岛素依赖型糖尿病(NIDDM),若此疗法效果不佳时,通常采用药物治疗,大多数情况下都使用胰岛素。胰岛素适用于通过饮食疗法和口服降糖药无法调节血糖的患者,但是,由于胰岛素是蛋白质,会在消化道被水解成非活性化,因此,存在着不能口服吸取,只能通过静脉注射或皮下注射来吸取的缺点。
口服降糖药能够提高细胞的胰岛素受体的敏感度,并刺激胰腺而促进胰岛素的分泌,因此,用于调节非胰岛素依赖型糖尿病(NIDDM)患者的血糖。但是,用于治疗非胰岛素依赖型糖尿病(NIDDM)的口服疗法有可能导致低血糖症、恶心、呕吐、腹泻、皮疹等,特别是,会导致致命的乳酸酸中毒等严重的副作用。此外,长期使用口服降糖药会引起心血管系统障碍或胃肠及肝的障碍,因此,建议不要长期使用。因上述缺陷和副作用,在目前的治疗剂中,还几乎没有既具有令人满意的效果,且安全性高并在副作用方面也令人放心而适用于所有糖尿病患者的药物,因此,迫切需要开发出治疗糖尿病、特别是对非胰岛素依赖型糖尿病(NIDDM)有更显著效果的药物。
通常,患糖尿病10年后,体内大部分器官均受到损伤而引发并发症。在这些并发症中,作为急性并发症,有低血糖症、酮症酸中毒、高渗性非酮症高血糖、高血糖性昏迷、糖尿病酸中毒、低血糖症等;作为慢性并发症,有糖尿病性视网膜病变、糖尿病性白内障、糖尿病肾病、糖尿病性神经障碍、心血管系统并发症、病毒感染等。慢性糖尿病肾病是血液透析治疗和末期肾功能衰竭的最重要原因,而糖尿病性白内障会导致失明,最终导致死亡。
引发上述糖尿病并发症的机制,大体分为蛋白质的非酶糖化反应(nonenzymatic glycation of proein)和多元醇代谢通路(polyol pathway)等。蛋白质的非酶糖化反应(nonenzymatic glycation of protein)是指,蛋白质的赖氨酸残基等氨基酸基团与还原糖在没有酶的作用下发生的缩合反应即美拉德反应,作为该反应的结果,产生糖化终产物。蛋白质的非酶糖化反应分为以下两个阶段:(1)蛋白质的赖氨酸残基等氨基酸基团和还原糖的醛基或酮基在没有酶的作用下发生亲核加成反应而形成初产物即锡夫氏碱(Schiffbase),该锡夫氏碱与相邻的酮胺加成物(ketoamine adduct)相互缩合而生成可逆性阿马多里(amadori)型初期糖基化产物;(2)由于持续高血糖状态,可逆性阿马多里(amadori)初期糖基化产物不发生分解而被重排(rearrangement)并与蛋白质发生交联(cross-linking),由此生成非可逆性的糖化终产物。
不同于可逆性的阿马多里型初期糖基化产物,糖化终产物是非可逆性的反应产物,一旦被生成,即使血糖恢复正常也不会被分解,并在蛋白质的生存期间蓄积在组织内,从而使组织结构和功能发生异常变化,在组织各处引起并发症(Vinson,J.A.et al.,J.Nutritinal Biochemistry,7:559,1996;Smith,P.R.et al.,Eur.J.Biochem.,210:729,1992)。
例如,由葡萄糖和各种蛋白质反应而生成的糖化终产物之一的糖化白蛋白,是引起慢性糖尿性肾病的重要因素。与未糖化的正常白蛋白相比,糖化白蛋白更容易导入到肾小球细胞内,而高浓度的葡萄糖将刺激肾小球系膜细胞,从而加大细胞外基质(extracellular matrix)的合成。因过度导入的糖化白蛋白和增加的细胞外基质,引起肾小球的纤维化。由于上述原因,肾小球持续受到破损,最终只能采用血液透析或器官移植等极端治疗方法。另外,有报告称,由于慢性糖尿,糖化终产物在动脉壁与胶原蛋白相结合,而在肾小球与基底膜蛋白相结合,从而堆积在组织中(Brownlee,M.et al.,Sciences,232:1629:1986)。
如上所述,由于蛋白质非酶糖化反应,在基底膜、血浆白蛋白、水晶体蛋白质、纤维蛋白、胶原蛋白等蛋白质中发生糖化,生成的糖化终产物使组织结构和功能发生异常变化,从而引发糖尿病视网膜病变(diabeticretinopathy)、糖尿病白内障(diabetic cataract)、糖尿肾病(diabetic nephropath)、糖尿病神经病变(diabetic neuropathy)等慢性糖尿病并发症(Yokozawa,T.etal.,J.of Trad.Med.,18:107,2001)。因此,为了延迟、预防或治疗糖尿病并发症的发病,抑制糖化终产物的形成是非常重要的(Brownlee,M.et al.,N.Engl.Med.,318:1315,1988)。
另外,糖化终产物导致血管内皮细胞生长因子VEGF mRNA和蛋白质的过度表达,从而引发非增殖性或增殖性的糖尿病视网膜病变。非正常的新生血管形成或病理性(pathogenic)新生血管的生长与多数状态有关。此状态包括糖尿病视网膜病变、牛皮癣、渗出型或湿型(wet)老年黄斑变性(ARMD)、风湿关节炎和其他炎症疾病以及大部分癌症(Aiello etal.,New Engl.J.Med,331:1480,1994;Peer et al.Lab.Invest.,72:638,1995)。在患有与此类状态有关的疾病的组织或肿瘤中,VEGF表达为异常高的水平,提高了血管新生或血管透过性。特别是,ARMD在临床上是重要的血管新生疾病。此疾病的特征在于,在老年人的一只或两只眼睛的脉络膜形成新生血管,在产业化国家中成为失明的主要因素。在各种治疗疗法中使用的抗-新生血管形成制剂只能引导VEGF或VEGF受体的化学量的减少,此类制剂的效果根据在患疾组织中以异常高的浓度形成的VEGF减弱(Lopez et al.,Invest.Opththalmol.Vis.Sci.,37:855,1996)。
为此,本发明人等为了寻求用于治疗糖尿病及其并发症且副作用小的天然生药材进行了悉心的研究,结果发现:从茑萝属分离的新型化合物具有能够使糖尿病小鼠的血糖、糖化血红蛋白(血色素)及尿蛋白等糖尿病指标好转的效果,从而完成了本发明。
发明内容
本发明的目的在于,提供一种用于治疗糖尿病及其并发症且副作用小的来自天然生药材的新型化合物。
本发明的另一目的在于,提供一种作为有效成分包含所述新型化合物的用于预防或治疗糖尿病及糖尿病并发症的药物组合物或者保健功能食品。
为了达到上述目的,本发明提供一种具有以下述化学式1表示的结构的化合物。
化学式1:
其中,R1以及R2分别独立地表示H、碳原子数为1至20的烷基、碳原子数为6至30的芳基、碳原子数为1至20的烯丙基、碳原子数为6至30的芳烷基或者酰基。
本发明还提供一种以下述化学式2表示的化合物的制备方法,包括:(a)通过由水、醇、有机溶剂和它们的混合物所组成的组中选出的溶剂提取茑萝属,制备茑萝属提取物的步骤;(b)在所述茑萝属提取物中加入水而进行悬浮,并依次以正己烷、乙酸乙酯和丁醇进行分离(fractionating)而得到水分离物的步骤;以及(c)分离提纯上述水分离物而得到以下述化学式2表示的化合物的步骤。
化学式2:
本发明还提供一种用于预防或治疗糖尿病或糖尿病并发症的药物组合物,其作为有效成分包含:以化学式1表示的化合物;以化学式1表示的化合物的盐;或者,含有以化学式1表示的化合物或以化学式1表示的化合物的盐的提取物。
本发明还提供一种用于预防糖尿病及糖尿病并发症的保健功能食品,其作为有效成分包含:以化学式1表示的化合物;以化学式1表示的化合物的盐;或者,含有以化学式1表示的化合物或其以化学式1表示的化合物的盐的提取物。
附图说明
图1是来自圆叶茑萝的新型化合物的HPLC(高效液相色谱法)光谱。
图2是来自圆叶茑萝的新型化合物的LC-MS(液相色谱-质谱联用)光谱。
图3是以D2O作为溶剂的来自圆叶茑萝的新型化合物的H-NMR(氢核磁共振)光谱。
图4是以D2O作为溶剂的来自圆叶茑萝的新型化合物的C-NMR(碳核磁共振)光谱。
图5是表示来自圆叶茑萝的新型化合物在人视网膜色素上皮细胞株中抑制VEGF(vascular endothelial growth factor)的蛋白合成的图表。
图6是表示来自圆叶茑萝的新型化合物在小鼠的胰腺β细胞株中促进胰岛素蛋白合成的图表。
图7是表示来自圆叶茑萝的新型化合物降低小鼠水晶体浑浊度效果的图。
图8是表示来自圆叶茑萝的新型化合物对糖尿模型动物血糖的抑制效果的图。
图9表示来自圆叶茑萝的新型化合物的葡萄糖耐受试验的图,显示血糖降低效果。
图10是表示来自圆叶茑萝的新型化合物对糖尿模型动物的糖化血红蛋白的抑制效果的图。
图11是表示来自圆叶茑萝的新型化合物对糖尿模型动物的肌氨酸酐尿排出正常的图。
图12是表示来自圆叶茑萝的新型化合物在糖尿模型动物中没有肝毒性的图。
图13是表示来自圆叶茑萝的新型化合物在糖尿模型动物中没有肝功能障碍的图。
图14是表示来自圆叶茑萝的新型化合物提高糖尿模型动物的β功能性并减少胰岛素葡萄糖耐量效果的图。
图15是表示来自圆叶茑萝的新型化合物增加糖尿模型动物的脂肪细胞因子表达效果的图。
图16是表示来自圆叶茑萝的新型化合物减少糖尿模型动物的胰高血糖素表达效果的图。
图17是表示来自圆叶茑萝的新型化合物对糖尿模型动物的DPP-IV活性抑制效果的图。
图18是表示来自圆叶茑萝的新型化合物对糖尿模型动物的α-葡萄糖苷酶活性抑制效果的图。
图19是表示来自圆叶茑萝的新型化合物减少糖尿模型动物的肿瘤坏死因子-α的表达的效果的图。
图20是表示来自圆叶茑萝的新型化合物在糖尿模型动物中的抗白内障效果的图。
具体实施方式
本发明的一实施方式涉及具有以下述化学式1表示的结构的化合物。
化学式1:
其中,R1及R2分别独立地表示H、碳原子数为1至20的烷基、碳原子数为6至30的芳基、碳原子数为1至20的烯丙基、碳原子数为6至30的芳烷基或者酰基。
优选上述化学式1中R1及R2分别独立地表示H或碳原子数为1至20的烷基。
进一步优选上述化学式1的化合物具有以下述化学式2表示的结构。
化学式2:
另外,上述化学式1的化合物可以从茑萝属中分离,优选从圆叶茑萝中分离。
本发明的实施例中使用的圆叶茑萝(Quamoclit angulata)为管花目旋花科属的一年生草质缠绕藤本,又称圆叶留红草。其原产地为热带美洲,主要作为观赏植物来栽培,其特征是,藤的生长类似于牵牛花,且向左缠绕。全草的长度为3m左右。叶互生,叶柄长,并呈心形的圆状。而且,叶顶端突然变尖,叶底部分的两侧端部呈尖角。通常,是在8~9月开花,花颜色是带黄的红色,在长长的花茎顶端生3~5朵花。其花朵模样类似于缩小版的牵牛花,花萼和雄蕊各5个,雌蕊1个。其果实为蒴果近球形,且在9月成熟,保留花萼。与留红草相似,但叶子没有裂。
本发明的具有化学式2结构的化合物为从茑萝属中分离的新型化合物,具有分子式C49H88O24,其作为具有化学式1结构的树脂糖苷的一种,连接有β-D-岩藻吡喃糖苷(beta-D-fucopyranose)等糖结构。
本发明中,将具有上述化学式2的结构的化合物命名为KRIBB-BH-P,上述新型化合物为米黄色粉末,通过LC-MS能够得到分子离子m/z1059.4,916.4(1052.4-145),786.9(916.4-136),514.8(786.9-136),378.9(514.8-136),232.9(378.9-146),其与分子式(elemental formula)C49H88O24一致。另外,通过1D-NMR(H NMR,C NMR)完成了明确的NMR指认(NMR assignment)。
本发明的新型化合物可通过公知的方法来制造。例如,可使用水、醇、醇水溶液、有机溶剂或它们的混合物等溶剂从茑萝中提取,优选使用水或醇提取,另外,还可以利用活性炭进行分离提纯。
以上述化学式2表示的化合物可通过如下方法制备。即,作为另一实施方式,本发明涉及一种以化学式2表示的化合物的制备方法,包括:(a)通过由水、醇、有机溶剂和它们的混合物所组成的组中选出的溶剂提取茑萝,制备茑萝提取物的步骤;(b)在所述茑萝提取物中加入水而进行悬浮,并依次以正己烷、乙酸乙酯和丁醇进行分离而得到水分离物的步骤;以及(c)分离提纯所述水分离物而得到以上述化学式2表示的化合物的步骤。
上述(a)步骤中,优选使用干燥的茑萝,优选通过填充有活性炭的柱(column)对茑萝提取物进行一次分离提纯。对于上述(c)步骤的分离提纯方法并非特别限定,但例如可以使用色谱法。
在本发明的一实施方式中,通过如下方法由圆叶茑萝制备化学式2的化合物。对破碎的圆叶茑萝,利用溶剂在常温下使用超声波提取器每2小时提取15分钟并持续进行2-3天,或者以水为溶剂在50℃下热水提取,其中,所述溶剂是由水、醇、有机溶剂和它们的混合溶液所组成的组中选择的溶剂。然后,在常温下利用真空旋转浓缩机对上述提取的提取物进行减压浓缩,之后用真空冷冻干燥机对所提取的残留物进行干燥后用水溶解,从而获得圆叶茑萝提取物。
使上述得到的圆叶茑萝提取物通过填充有活性炭的柱子,从而吸附圆叶茑萝的有效成分,再用蒸馏水洗涤填充有活性炭的柱子而去除非吸附成分。对上述去除了非吸附成分的填充有活性炭的柱子,以连续或阶段性地、并以提高浓度的方式供给10~50%(v/v)乙醇等有机溶剂,从而洗脱吸附在活性炭上的圆叶茑萝的有效成分,并进行分离提纯之后得到圆叶茑萝提取物。对如此提纯过的圆叶茑萝提取物,利用真空旋转浓缩机在常温下进行减压浓缩,再对该浓缩的提取物进行真空冷冻干燥后用水溶解,从而得到溶解于水的圆叶茑萝提取物。
将上述溶解于水的圆叶茑萝提取物悬浮于蒸馏水之后,依次以正己烷(nhexane)、乙酸乙酯(EtOAc)和丁醇(BuOH)进行溶剂分离,从而分别得到正己烷(nhexane)分离物、乙酸乙酯(EtOAc)分离物、丁醇(BuOH)分离物以及水分离物。
利用上述溶剂分离物分别实施抑制VEGF生成试验,将其中显示出最佳效果的水分离物通过以C18反相硅胶(silica gel)为固定相、以乙腈(Acetonitril)-水混合溶剂(1:9→9:1v/v)为流动相的柱色谱分离,从而分成十个分离组,对其中分离物ACN20[以乙腈(Aetonitril)-DW(2:8v/v)洗脱]实施交联葡聚糖柱色谱法[Sephadex column chromatography(5.0×65cm,甲醇:MeOH)],从而提纯了新型化合物。
本发明的一实施例中,对糖尿病小鼠上给予来自圆叶茑萝的新型化合物KRIBB-BH-P时,确认了作为糖尿病指标的血糖、糖化血红蛋白(血色素)及尿蛋白的构成有好转的现象。
另外,在给予本发明的来自圆叶茑萝的新型化合物KRIBB-BH-P的小鼠中没有发现肝毒性以及肝功能障碍,由此确认了在体内(in vivo)施用本发明的KRIBB-BH-P时的安全性。
本发明的另一实施例中,在给予来自圆叶茑萝的新型化合物KRIBB-BH-P的糖尿病小鼠中,确认到增加脂肪细胞因子的数值从而改善了胰岛素抵抗性,还确认到:在糖尿病小鼠中异常增加的胰高血糖素浓度,在给予来自圆叶茑萝的新型化合物KRIBB-BH-P的群中变为正常化。
另一实施方式中,本发明涉及一种用于预防或治疗糖尿病或糖尿病并发症的药物组合物及其保健功能食品,其作为有效成分包含:以所述化学式1表示的化合物;以所述化学式1表示的化合物的盐;或者,含有以化学式1表示的化合物或其盐的提取物。
本发明中,在所述化合物的化学式1中,优选R1以及R2分别独立地表示H或者碳原子数为1至20的烷基,进一步优选具有所述化学式2的结构。
本发明中,上述组合物和保健功能食品中还可添加通过茑萝的植物培养或组织培养获得的提取物。
本发明的新型化合物不仅具有预防或治疗糖尿病的效果,还具有预防或治疗糖尿病并发症的效果,作为所述并发症并非特别限定,可例举有:高血糖症(hyperglycemia)、高胰岛素血症(hyperinsulinemia)、高甘油三酯血症(hypertriglyceridemia)、抗胰岛素性(insulin resistance)、血脂障碍(dyslipidemia)、空腹血糖受损(impaired fasting glucose)、内糖耐量异常(impaired glucose tolerance)、肥胖、动脉硬化症、微细血管病、肾病、心脏病、足部溃疡、关节炎、骨质疏松症、糖尿病视网膜病变和除此以外的一个以上眼科疾病等。
在此,糖尿病包括:I型糖尿病、II型糖尿病、年轻人中发病的成人型糖尿病、隐匿性自身免疫性糖尿病、胰腺糖尿病等所有种类的糖尿病,糖尿病并发症除上面所举例的以外还包含有:肾小球硬化症、阳痿、糖尿病神经病变、经前期综合征、血管再狭窄、溃疡性结肠炎、冠状动脉心脏病、高血压、心绞痛、心肌梗塞、中风、皮肤以及结缔组织疾病、代谢性酸中毒、受损的葡萄糖耐量引发的症状等。
另外,所述的眼科疾病除了糖尿病性视网膜病变以外,还包括:白内障、黄斑变性、眼外肌麻痹、虹膜睫状体炎、视神经炎、青光眼、视网膜衰退、眼底出血、异常折射、结膜下出血、玻璃体积血等因糖尿病引发的所有眼科疾病。
本发明的药物组合物将从茑萝中分离的新型化合物作为必要成分,可单独包含该新型化合物,也可以包含一种以上的药物学上可接受的载体、赋形剂或稀释剂而作为药物组合物提供。
进一步地,本发明的药物组合物也可以与已知的糖尿病或者其并发症的治疗药物加以混合而提供。即,本发明的药物组合物可与具有预防或治疗糖尿病或者其并发症效果的公知的化合物联合用药。
因此,本发明的用于预防或治疗糖尿病或者糖尿病并发症的药物组合物还可包含已知的抗糖尿病化合物。
作为如上所述的抗糖尿病化合物:可例举有:那格列胺、瑞格列奈、格列酮类、磺脲类、甲福明、格列美脲、噻唑烷二酮类、双胍类、作为α-葡萄糖苷酶抑制剂的阿卡波糖、美格列奈(meglitinide)类的瑞格列奈等,但并非限定于这些。
一方面,本发明中,药物组合物的给药途径包括:口腔、静脉内、肌肉内、动脉内、骨髓内、鞘内、心脏内、经皮、皮下、腹腔内、鼻腔内、肠道、局部、舌下或直肠,但并非限定于此。
优选口服或非口服给药。本申请使用的用语“非口服”包括:在皮下、皮内、静脉内、肌肉内、关节内、粘液囊内、胸骨内、鞘内、病灶内以及颅骨内注射或者注入的技术。
药物组合物作为灭菌注射用水性或者油性悬浊液可以是灭菌注射用制剂的形态。此悬浊液可通过使用适合的分散剂或者润湿剂(如,吐温80)以及悬浮剂,根据本领域的公知技术制备成制剂。灭菌注射用制剂可以是无毒性且以非口服方式可接受的稀释剂或者溶剂之中的灭菌注射溶液或者悬浊液(如,1,3-丁二醇中的溶液)。作为以可接受的方式使用的赋形剂以及溶剂有:甘露醇、水、林格(Ringer)溶液以及等渗性氯化钠溶液。另外,灭菌非挥发性油通常作为溶剂或者悬浊化介质使用。为了达到这些目的,可以使用包括合成单-或二-甘油酯(synthetic mono-or di-glyceride)的刺激性小的任意非挥发性油。如油酸及其甘油酯衍生物等脂肪酸,相同于药学上可接受的天然油(如,橄榄油或者蓖麻油),特别相同于它们的聚氧乙烯化物质,能够用于注射制剂。
本发明的药物组合物可通过包括胶囊、片剂和水性悬浊液以及溶液的能够以口服方式接受的任何容量形式口服给药,但并非限定于此。口服用片剂的情况下,通常使用的载体包括乳糖以及玉米淀粉。典型地还添加如硬脂酸镁等的润滑剂。当以胶囊方式口服给药时,作为实用的稀释剂包括:乳糖以及干燥的玉米淀粉。当水性悬浊液口服给药时,活性成分与乳化剂以及悬浮剂混合。必要时,可添加甜味剂和/或调味剂和/或着色剂。
本发明的药物组合物还可以是用于直肠给药的栓剂的形态。这些组合物通过将本发明的化合物与适宜的非刺激性赋形剂混合制备,其中,该适宜的非刺激性赋形剂在室温下为固态,但在直肠温度下为液态。作为这些物质包括:可可、蜂蜡以及聚乙二醇,但并非限定于此。
本发明的药物组合物的口服给药方式,在目标治疗与通过局部用药方式易接近的部位或者器官相关时,特别实用。在皮肤上局部用药时,药物组合物应当以适宜的软膏剂型制成,该软膏剂型含有悬浮或溶解于载体中的活性成分。作为用于将本发明的化合物局部给药的载体有:矿物油、液体石蜡、白凡士林、丙二醇、聚氧乙烯、聚氧丙烯(polyoxypropylene)化合物、乳化蜡以及水,但并非限定于此。作为另一种方法,药物组合物可制成适宜的洗剂(lotion)或乳膏剂型,其含有悬浮或溶解于载体的活性化合物。作为适宜的载体有:矿物油、脱水山梨醇单硬脂酸酯、聚山梨酸酯60、十六烷基酯蜡(cetyl ester wax)、鲸蜡硬脂醇(cetearyl alcohol)、2-辛基十二烷醇、苯甲醇以及水,但并非限定于此。本发明的药物组合物还可通过直肠栓剂,以适宜的灌肠剂方式向下部肠道局部用药。局部用药的透皮贴剂也包括于本发明之中。
本发明的药物组合物可通过鼻内喷雾或吸入方式给药。这些组合物可通过药剂领域公知的技术制备,可使用苯甲醇或其他适宜的防腐剂、用于提高生物利用度的吸收促进剂、碳氟化合物和/或其他本领域公知的增溶剂或分散剂而制备为盐水中的溶液。
本发明的药物组合物以治疗有效量或者预防有效量含有所述新型化合物。
但是,对于特定患者的特定有效量根据如下各种因素发生变化,该因素包括:所使用的特定化合物的活性、年龄、体重、一般性健康、性别、规定饮食(diet)、给药时间、给药途径、排出率、药物组合以及需要预防或治疗的特定疾病的重症。本发明的药物组合物可制备成丸剂、糖衣丸、胶囊、液体制剂、凝胶、糖浆、浆液、悬浊剂。
当向鱼类的皮下细胞注入本发明的药物组合物时,可以向鳃囊或消化道给药。注射可以向肌肉组织内的肌肉细胞或其他细胞注射,也可以向腹腔内的内脏细胞注射。
作为优选形式,用于口腔内给药的药物组合物可以混合固体状的赋形剂和活性成分而制备,为了制备成片剂或者糖衣丸形态而可制备为颗粒状。作为适宜的赋形剂可以使用如乳糖、蔗糖、甘露醇以及山梨醇等糖类,或者来自玉米、面粉、米、土豆或其他植物的淀粉,甲基纤维素、羟丙基甲基纤维素或羧甲基纤维素钠等纤维素,如包括阿拉伯胶、黄蓍胶(tragacanth gum)的胶类等碳水化合物,或者如明胶、胶原蛋白等蛋白填充剂。根据需要,还可以添加交联结合的聚乙烯吡咯烷酮、琼脂以及褐藻酸(alginic acid)或者褐藻酸钠等分别为盐形式的崩解剂或者溶解剂。
作为优选方式,当非口服式给药时,本发明的药物组合物可制成水溶性溶液。优选为,Hank's液(Hank's solution)、林格氏液(Ringer's solution)或者如以物理方式缓冲的盐水等的适于物理形式的缓冲溶液。水溶性注入(injection)悬浊夜中,可添加如羧甲基纤维素钠、山梨醇或者右旋糖酐等的能够增加悬浊夜粘度的底物。进一步,活性成分的悬浊液可制备成适宜的油性注射悬浊夜(oily injection suspensions)。适宜的亲油性溶剂或载体有:如香油等的脂肪酸或油酸乙酯、甘油三酯,或者如脂质体等的合成脂肪酸酯。聚阳离子氨基酸聚合物(polycationic amino polymers)也可用于载体。为了增加化合物的溶解度并制造高浓度的溶液,悬浊液还可以任意使用适宜的稳定剂或药剂。
另外,本发明的来自茑萝的新型化合物可制备成用于预防或改善糖尿病及其并发症的食品的形式。
本发明的保健功能食品作为食品组合物包括功能食品(functionalfood)、营养补充剂(nutritional supplement)、保健食品(health food)以及食品添加剂(food additives)等所有形态。基于本领域公知的常规方法,所述类型的保健功能食品可制备成各种形态。例如,作为保健食品,将本发明的来自茑萝的新型化合物制备成茶、汁以及饮料形态用于饮用,或者对其进行颗粒化、胶囊化以及粉末化而摄取。另外,作为功能食品,可将本发明的来自茑萝的新型化合物添加于饮料(包括酒精饮料)、果实及其加工食品(例如:水果罐头、瓶装食品、果酱(jam)、果冻(marmalade)等)、鱼类、肉类及其加工食品(例如:火腿、香肠、咸牛肉等)、面包类以及面类(例如:乌冬面、荞麦面、拉面、意大利面、通心粉等)、果汁、各种饮料、曲奇饼、饴糖、乳制品(例如:黄奶油、干酪等)、食用植物油脂、人造奶油、植物蛋白质、蒸煮袋食品(retort food)、冷冻食品、各种调味料(例如:酱、酱油、沙司(sauce)等)等之中而制备。
实施例
下面,通过实施例更详细地说明本发明。但只要是本领域技术人员,应该明白以下实施例仅用于例示本发明,本发明的范围并不局限于下述的实施例。
实施例1:从茑萝中分离新型化合物
从济州南郡安德面西光里采集的圆叶茑萝51g,以水为溶剂在50℃下热水提取,或者,利用由水、醇、有机溶剂和它们的混合溶液所组成的组中选择的溶剂在室温下利用超声波提取器每2小时提取15分钟持续2~3天。提取后,对提取物用真空旋转浓缩机在常温下进行减压浓缩后,对所提取的残留物用真空冷冻干燥机进行干燥,从而得到了干燥的圆叶茑萝提取物。将上述浓缩液悬浮于水中,使其通过填充有活性炭的色谱柱而使圆叶茑萝的有效成分吸附,并通过蒸馏水洗涤填充有活性炭的柱子而去除了非吸附成分。对于去除了所述非吸附成分的活性碳填充柱,以连续或阶段性地、并以提高浓度的方式供给10~50%(v/v)乙醇等有机溶剂,从而洗脱吸附在活性炭的圆叶茑萝有效成分并进行分离提纯之后,得到了圆叶茑萝提取物。对所述分离提纯过的圆叶茑萝提取物进行减压浓缩,在5g所述浓缩的圆叶茑萝提取物中加水溶解至圆叶茑萝提取物的浓度达到20mg/ml。
将此水提取物悬浮于蒸馏水之后依次以正己烷(nhexane)、乙酸乙酯(EtOAc)和丁醇(BuOH)进行溶剂分离,而分别得到了正己烷(nhexane)分离物、乙酸乙酯分离物(EtOAc)、丁醇(BuOH)分离物以及水分离物。
对于所述溶剂分离物分别实施抑制VEGF生成试验,并对于其中显示出最佳效果的水分离物,实施以C18反相硅胶(silica gel)为固定相、以乙腈(Acetonitril)-水混合溶剂(1:9→9:1v/v)为流动相的柱色谱(columnchromatography)法,从而分成十个分离组。对于其中的分离物ACN20[以甲醇(MeOH)-水(1:9v/v)洗脱],实施交联葡聚糖柱色谱法[Sephadex columnchromatography(5.0×65cm,甲醇:MeOH)],从而提纯了新型化合物(图1)。所使用的条件和结果如下:
高效液相色谱(HPLC)分析(岛津:shimadzu模型)
柱:C18反相柱
流动溶剂:90%甲醇
流速:1ml/min
滞留时间:1.29分钟
实施例2:确认来自茑萝的新型化合物的结构
从实施例1分离的新型化合物为米黄色粉末,通过LC-MS能够得到分子离子m/z1059.4,916.4(1052.4-145),786.9(916.4-136),514.8(786.9-136),378.9(514.8-136),232.9(378.9-146)(图2),这与分子式(elementalformula)C49H88O24一致。
通过1D-NMR(H NMR,C NMR)完成了明确的NMR指认(NMRassignment)。
图3表示了以由氘(D2O)取代的水为溶剂,以四甲基硅烷(TMS)为标准物质测定的氢核磁共振光谱(H-NMR)结果。
图4表示了由氘(D2O)取代的水为溶剂,以四甲基硅烷(TMS)为标准物质测定的碳核磁共振光谱(C-NMR)结果。
根据上述结果,确认到实施例1中分离的来自圆叶茑萝的新型化合物为具有C49H88O24分子式、且具有化学式2结构的新型化合物。
化学式2:
所述化合物作为一种糖苷(配糖体,glycoside),在β-D-岩藻吡喃糖苷(beta-D-fucopyranose)上连接有糖结构,并命名为KRIBB-BH-P。
实施例3:确认来自茑萝的新型化合物的VEGF抑制能力
为了确认实施例1中制备的从圆叶茑萝分离的新型化合物对血管内皮细胞生长因子(VEGF)的抑制能力,在作为人视网膜色素上皮细胞株的ARPE19细胞株上处理所述新型化合物,确认了引发糖尿病视网膜病变等糖尿并发症的血管内皮细胞生长因子(VEGF)蛋白的表达。
ARPE19细胞株(ATCC,USA)是在DMEM;F12培养基(media)中添加10%FBS(Fetal bovine serum)而培养。为了在ARPE19细胞株中诱导VEGF蛋白质的表达,在60Φ的板(plate)上以1×105细胞(cell)/板的浓度涂布细胞,并在DMEM低葡萄糖培养基中添加10%FBS无血清而培养24小时后,替换为在DMEM葡萄糖培养基(low glucosemedia)中添加了30mM葡萄糖(glucose)的培养液,添加至新型化合物KRIBB-BH-P的最终浓度达到0.5μg/ml,之后为了确认VEGF蛋白质生成,培养了72小时。此时,作为对照群,以通过5.5mM葡萄糖(glucose)进行处理而VEGF未表达的细胞本身(-对照群)作为基准,确认通过30mM葡萄糖(glucose)进行处理时的VEGF表达程度(+对照群),比较来自圆叶茑萝提取物的化合物对VEGF表达的抑制能力。本实验中使用的30mM葡萄糖(glucose)浓度,是在各实验中使诱发VEGF的表达达到最佳的条件的浓度。
获取通过上述方法培养的ARPE19细胞的培养液,并利用VEGF ELISA试剂盒(R&D,UK)测定所分泌的VEGF量。
其结果,如图5所示,确认了由新型化合物KRIBB-BH-P处理的实验群中VEGF表达减少。
实施例4:确认来自茑萝的新型化合物的对胰岛素分泌的促进。
在小鼠胰腺β细胞株Min6细胞株中,确认从圆叶茑萝中分离的新型化合物KRIBB-BH-P的胰岛素分泌促进能力。
Min6(ATCC,USA)是在HDMEM培养基(media)中添加15%FBS(fetal bovine serum)而培养。为了在Min6细胞株中诱导胰岛素表达,在96孔(well)板上以1×104细胞(cell)/板的浓度涂布细胞,并在DMEM高葡萄糖(high glucose)培养基中添加15%FBS无血清培养72小时后,用PBS缓冲溶液洗涤,并在HBSS缓冲溶液中培养2小时后,换成添加了25mM葡萄糖(glucose)的HBSS缓冲溶液,添加至新型化合物KRIBB-BH-P的最终浓度达到0.5ng/ml,之后为了确认是否促进了胰岛素表达,培养了2个小时。此时,作为对照群,以通过5.5mM葡萄糖(glucose)进行处理而胰岛素未表达的细胞本身的胰岛素表达量作为基准点,作为阳性对照群,添加至1μM氨基胍、1μM阿卡波糖、1mM格列美脲。作为阴性对照群,确认通过25mM葡萄糖(glucose)进行处理时的胰岛素表达的程度,比较分析来自圆叶茑萝的新型化合物对胰岛素表达的促进。获取通过如上所述的方法培养的Min6细胞的培养液,利用胰岛素ELISA试剂盒(R&D,UK),测定所分泌的胰岛素的量。
其结果,如图6所示,在由新型化合物KRIBB-BH-P处理的胰腺β细胞株中能够确认到胰岛素表达的增加。
实施例5:小鼠的晶状体培养实验
在糖尿病患者身上,早期就出现白内障,且恶化速度迅速,导致视力急剧下降。患糖尿病会促进水晶体不透明现象。因此,通过晶状体培养实验,调查对糖尿病白内障生成的抑制功效。
摘取小鼠的眼球并放在碘溶液中消毒后只摘取晶状体。放在M199培养基中,并在细胞培养器里进行培养。在培养基中添加20mM xylose(木糖)培养时,可以引发水晶体的浑浊度,利用CCD摄像机,测定水晶体的浑浊度。
其结果,如图7所示,确认到:相比于通过公知为抑制白内障诱发的物质-槲皮素(quercetin)处理的阳性对照群,本发明的新型化合物KRIBB-BH-P的给药群中抑制水晶体浑浊度的效果更优异。
实施例6:通过来自茑萝的新型化合物处理的糖尿病小鼠的糖尿病指标分析。
6-1:血糖分析
通过来自圆叶茑萝的新型化合物处理正常小鼠和实际糖尿病小鼠,确认作为糖尿病指标的血糖、糖化血红蛋白(血色素)及尿蛋白的变化。
购买6周龄的小鼠(Male C57BL/6J mouse,20g,中央实验动物,首尔)和6周龄的糖尿病小鼠(Male C57BL/Ks DB/DB mouse,20g,中央实验动物,首尔),并在规定温度(25℃)和湿度(50%)下适应1周后,用于试验。
小鼠按各群组5只分组,分为正常小鼠对照群、糖尿病小鼠对照群、糖尿病小鼠药物处理(格列美脲:glimepride,阿卡波糖:acarbose)群、来自圆叶茑萝的新型化合物和药物的联合用药群,对于来自圆叶茑萝的新型化合物的给药群,分别以0.1mg/kg、1mg/kg、10mg/kg浓度对各个群口服给药,并饲养12周。对于各个群的小鼠每2周测定血糖的变化,另外,每6周采取尿样测定尿蛋白浓度,饲养12周后采取血液测定糖化血红蛋白浓度。
其结果,在血糖变化上,如图8所示,与正常小鼠对照群相比,糖尿病小鼠对照群的血糖上升,而在糖尿病小鼠的联合用药群和以0.1mg/kg、1mg/kg、10mg/kg浓度将来自圆叶茑萝的新型化合物口服给药的各个群中,显示出显著的下降效果。
6-2:葡萄糖耐受试验
购买5周龄的小鼠(Male C57BL/6J,19g,Core Tech Corp.,平泽),在规定的温度(25℃)和湿度(50%)下适应1周后,将其用于葡萄糖耐受试验。小鼠按各群组5只分组,作为对照群,分为喂普通饲料的普通饮食群和喂高脂肪饲料的高脂肪饮食群,并饲养2周。高脂肪饮食饲养第2周时,将实验动物禁食16小时之后,空腹时测定血糖,在24小时、16小时、8小时、4小时、2小时、1小时前以口服方式试样给药后,将葡萄糖(glucose)2g/kg(体重:body weight)以口服方式给药,之后以30分为间隔测定了血糖。
其结果,如图9所示,将试样口服给药24小时之后,显示出最高效果。
6-3:糖化血红蛋白(血色素)(HbA1c)分析
为了减少接受糖尿治疗的患者身上引发的并发症,最为重要的是维持适当的血糖值。由于在某个时间点测定的血糖值有可能因各种因素产生变化,因此,为了掌握长期的血糖控制趋势,最广泛使用的检查为糖化血红蛋白(HbA1c)检测。糖化血红蛋白是红细胞中正常存在的血红蛋白与糖结合的形态,当血糖保持高水平时,糖化血红蛋白值也升高。因糖化血红蛋白反映2~4个月期间的平均血糖值,所以对掌握长期的血糖控制程度方面有用。
为了确定来自圆叶茑萝的新型化合物对糖化血红蛋白的影响,对于正常小鼠对照群、糖尿病小鼠对照群、以及以0.1mg/kg、1mg/kg、10mg/kg浓度口服给药来自圆叶茑萝的新型化合物的群,每6周采取一次血液,并利用ELISA试剂盒(Cusabio biotech,Japan)进行测定。
其结果,如图10所示,在糖化血红蛋白的数值上,相比于正常小鼠对照群,在糖尿病小鼠上以10mg/kg浓度口服给药来自圆叶茑萝的新型化合物的群中显示出显著的下降效果。
6-4:肌氨酸酐的测定
糖尿病患者中出现肾脏和心脏并发症的情况常见。糖尿病可能会对过滤并排出我们身上的废物的肾脏产生损伤。肌氨酸酐检查通过测定血液中的肌氨酸酐浓度而评价肾脏功能。肌氨酸酐是蛋白质在肌肉中使用之后形成的肌酸的脱水物质,在血液中以非常少的量存在。肾脏的功能减弱时无法排泄肌氨酸酐。对于各群的糖尿模型小鼠口服给药12周之后采取小鼠的尿和血液,并利用ELISA试剂盒(R&D,USA)进行测定。
其结果,如图11表示,确认了在联合用药群、来自圆叶茑萝的新型化合物的给药群中,血液的肌氨酸酐浓度减少,而尿肌氨酸酐浓度提高,这说明肌氨酸酐的排泄顺畅。
实施例7:通过来自茑萝的新型化合物处理的糖尿病小鼠的肝毒性以及肝功能检查
7-1:丙氨酸转氨酶浓度分析
将在实施例5中使用的小鼠相同的6周龄小鼠和6周龄糖尿病小鼠,在规定温度(25℃)和湿度(50%)下适应1周后,用于肝毒性检查。
小鼠按每群组5只分组,分为正常小鼠对照群、糖尿病小鼠对照群、分别以0.1mg/kg、1mg/kg、10mg/kg浓度口服给药来自圆叶茑萝的新型化合物的群,并饲养12周。饲养12周以后,采取血液,测定丙氨酸转氨酶浓度。
丙氨酸转氨酶是氨基酸的代谢酶,用作诊断和观察过程的代表性检查项目。保持丙氨酸转氨酶的浓度,说明没有肝损伤。
为了确定来自圆叶茑萝的新型化合物对肝的影响,饲养12周之后,对于正常小鼠对照群、糖尿病小鼠对照群、分别以0.1mg/kg、1mg/kg、10mg/kg浓度口服给药来自圆叶茑萝的新型化合物的群,采取血液,利用ELISA试剂盒(Cusabio biotech,Japan)测定了丙氨酸转氨酶浓度变化。
其结果,如图12表示,糖尿病小鼠上分别以0.1mg/kg、1mg/kg、10mg/kg浓度口服给药来自圆叶茑萝的新型化合物的群,显示出相似于正常小鼠对照群的数值,从而确定了没有因此化合物引起肝毒性。
7-2:胆红素分析
为了确定来自圆叶茑萝的新型化合物给药群中是否引起了肝功能异常,利用所述实施例中采取的血液,并通过ELISA试剂盒(Cusabio biotech,Japan)测定了胆红素数值。胆红素数值的分析结果如图13所示,来自圆叶茑萝的新型化合物给药群的胆红素数值显示为正常范围之内的数值。由此,能够确认本发明的组合物是不会引发肝功能异常的安全的组合物。
实施例8:通过来自圆叶茑萝的新型化合物处理的糖尿病小鼠的胰岛素抵抗性以及β细胞的功能性分析
通过对在实施例7的条件下饲养的糖尿病小鼠群进行的空腹血液检测或者葡萄糖耐受试验,测定胰岛素和血糖,从而计算出胰岛素敏感指数。
作为胰岛素敏感指数利用了HOMA(Homeostasis assessment)-IR,通过胰岛素敏感指数评价了胰岛素抵抗性,通过HOMA-beta评价了β细胞的功能性。
其结果,如图14所示,来自圆叶茑萝的新型化合物的给药群中显示出了显著的结果。
HOMA-IR=(空腹胰岛素(Fastinginsulin)(μIU/mL)×空腹血糖(Fastingglucose)(nmol/L))/22.5
HOMA-beta=20×空腹胰岛素(Fastinginsulin)(U/mL)/空腹血糖(Fasting glucose)(mmol/L)-3.5
实施例9:通过来自圆叶茑萝的新型化合物处理的糖尿病小鼠血液中脂肪细胞因子(adiponectin)浓度分析
脂肪细胞因子(adiponectin)是由脂肪细胞中分泌出并富含在血液内中,而在肥胖或II型糖尿病患者身上一致证明为其减少。另外,低脂联素血症正发展为动脉硬化疾病的新的危险因素,在糖尿病患者中、特别是伴有大血管并发症的患者中脂肪细胞因子浓度减少。即脂肪细胞因子具有抗肥胖作用、抗糖尿作用、抗动脉硬化作用以及活性氧生成的抑制作用等。通过ELISA试剂盒(R&D,USA)测定了实施例7的条件下饲养的糖尿病小鼠群血液中的脂肪细胞因子浓度。
其结果,如图15所示,虽然在糖尿小鼠对照群中脂肪细胞因子的表达减少,但是其之外的群,特别是来自圆叶茑萝的新型化合物的给药群中确认到脂肪细胞因子的表达增加,该脂肪细胞因子是显示胰岛素抵抗性的改善的数值。
实施例10:通过来自茑萝的新型化合物处理的糖尿病小鼠的胰高血糖素(glucagon)浓度分析
对于维持适当的血糖数值起到重要作用的不仅仅是去除糖的胰岛素(insulin),还有增加糖的称为胰高血糖素(glucagon)的激素。
在II型糖尿病患者中,血糖增加,并对葡萄糖摄取的胰岛素分泌延迟,且胰高血糖素(glucagon)增加。根据一般公知,相对于血浆胰高血糖素的胰岛素比率的减少,与糖尿病病情的恶化有关。因此,确认了实施例7条件下饲养的糖尿病小鼠的胰高血糖素浓度。
其结果,如图16所示,与正常群相比,糖尿对照群的血浆胰高血糖素浓度显著高,但是,通过本发明化合物的给药,相比糖尿对照群显著降低,显示出比药物给药群更低。糖尿对照群中相对于血浆胰高血糖素的胰岛素比率,相比正常群显著小。由此可知,通过来自茑萝的单一化合物给药,与糖尿对照群相比,相对于血浆胰高血糖素浓度的胰岛素比率显著增加,来自茑萝的单一化合物能够使因糖尿病引起的异常胰岛素以及胰高血糖素浓度正常化,从而能够抑制糖尿病的恶化。
实施例11:通过来自圆叶茑萝的新型化合物处理的糖尿病小鼠的二肽基肽酶Ⅳ(dipeptidyl peptidase IV,DPP-IV)抑制效果分析。
肠促胰岛素有GIP(glucose dependent insulinotropic eptide)和GLP-1(glucagon like peptide)两种,两种激素都是由小肠的上皮细胞层内的内分泌细胞(endocrine cell)分泌,是在小肠内的血糖增加时分泌,并刺激胰腺的β细胞,从而促进胰岛素分泌并抑制α细胞中的胰高血糖素分泌。
因此,肠促胰岛素根据口服摄取的葡萄糖浓度降低血糖,几乎不引发低血糖。GIP和GLP-1均被丝氨酸蛋白酶(serine protease)系列的二肽基肽酶(dipeptidyl peptidase,DPP)-Ⅳ迅速分解。基于如上所述的事实,确认了实施例7条件下饲养的糖尿病小鼠群的DPP-4抑制效果。
其结果,如图17所示,来自圆叶茑萝的新型化合物给药群中能够确认到DPPⅣ活性的抑制。DPP-Ⅳ被关注为糖尿病治疗新靶标,通过DPP-Ⅳ活性的抑制,能够抑制血糖和糖化血红蛋白的上升,其对于预防或治疗糖尿病具有显著效果。
实施例12:通过来自茑萝的新型化合物处理的糖尿病小鼠的α-葡萄糖苷酶(alpha-glucosidase)的活性阻碍率测定
α-葡萄糖苷酶抑制剂通过抑制分布于小肠黏膜的α-葡萄糖苷酶的功能,从而抑制饮食后的血糖上升。即,α-葡萄糖苷酶(Alpha-glucosidase)将多糖类分解为单糖类,起到促进小肠内吸收的作用,通过抑制其而妨碍单糖类吸收的方法,延迟所摄取的食物中的碳水化合物的消化和吸收,从而减少饮食后血糖以及血液中的胰岛素的上升,并显示出糖尿病的治疗效果。α-葡萄糖苷酶抑制剂具有如下优点:不引发高胰岛素血症或低血糖,促进胰岛素分泌,促进了用于抑制胰高血糖素分泌的胰高血糖素样肽-1(glucagon-likepeptide-1)在小肠内的分泌。
基于如上所述的事实,测定了实施例7的条件下饲养的糖尿病小鼠群的α-葡萄糖苷酶活性。
其结果,如图18所示,本发明的新型化合物给药群中能够确认到α-葡萄糖苷酶的活性抑制。
实施例13:通过来自茑萝的新型化合物处理的糖尿病小鼠的肿瘤坏死因子α(tumor necrosis factor,TNF-alpha)
肿瘤坏死因子α(TNF-α)主要由脂肪细胞表达,此细胞因子(cytokine)的上升水平关系到肥胖以及胰岛素抵抗性。脂肪组织生成肿瘤坏死因子α、抵抗素和白细胞介素-6(IL-6)等细胞因子,已确认这些细胞因子具有抑制胰岛素的作用。肥胖患者的交感神经活性会增加,其使脂肪分解增加并使肌肉的血流(葡萄糖搬运)减少,从而直接影响胰岛素作用。α-肿瘤坏死因子提高血糖引发糖尿病,或者抑制脂肪细胞因子的分泌,从而阻碍了血管内皮细胞的NF-kB信号传递,并抑制巨噬细胞的吞噬作用的活性,其中,所述脂肪细胞因子进入血液中阻碍炎症的形成并抑制胆固醇的堆积。
基于如上所述的事实,测定了实施例7的条件下饲养的糖尿病小鼠群的TNF-α浓度。
其结果,如图19所示,来自茑萝的新型化合物的给药群中确认了TNF-α浓度减少。
实施例14:通过来自茑萝的新型化合物处理的糖尿病小鼠的抗白内障效果
从实施例7条件下饲养的糖尿病小鼠群中摘取的眼球分离水晶体,并移至孔板之后,通过LAS3000图像分析装置拍照。混浊程度是利用LAS300图像分析程序,对所拍摄的照片进行分析而测定了水晶体混浊度。
其结果,如图20所示,来自茑萝的新型化合物给药群中确认到混浊度减少。
以上,详细叙述了本发明的特征部分,但对本领域技术人员来讲,这种具体的技术仅仅是优选的实施方式而已,本发明的范围并不限定于此。因此,本发明的实质范围,是依照权利要求及其等价物来定义。
工业实用性
本发明的来自茑萝属的新型化合物具有优异的降血糖、促进胰岛素分泌、抑制VEGF表达等效果,因此,不仅对预防或治疗糖尿病及其并发症有显著的功效,并且与现有糖尿病治疗制剂联合用药时,还能够促进治疗效果。
Claims (20)
1.一种化合物,具有以下述化学式1表示的结构,
化学式1:
化学式1中,R1和R2分别独立地表示H、碳原子数为1至20的烷基、碳原子数为6至30的芳基、碳原子数为1至20的烯丙基、碳原子数为6至30的芳烷基或者酰基。
2.如权利要求1所述的化合物,其特征在于,
所述R1和R2分别独立地表示H或者碳原子数为1至20的烷基。
3.如权利要求1所述的化合物,其特征在于,具有以下述化学式2表示的结构,
化学式2:
4.如权利要求1所述的化合物,其特征在于,来自茑萝属。
5.如权利要求4所述的化合物,其特征在于,所述茑萝属为圆叶茑萝。
6.一种制备方法,是以下述化学式2表示的化合物的制备方法,包括:
(a)通过由水、醇、有机溶剂和它们的混合物所组成的组中选出的溶剂提取茑萝属,从而制备茑萝属提取物的步骤;
(b)在所述茑萝属提取物中加入水而进行悬浮,并依次用正己烷、乙酸乙酯和丁醇进行分离,从而得到水分离物的步骤;以及
(c)分离提纯所述水分离物,从而获得以下述化学式2表示的化合物的步骤,
化学式2:
7.如权利要求6所述的制备方法,其特征在于,所述茑萝属为圆叶茑萝。
8.一种用于预防或治疗糖尿病或糖尿病并发症的药物组合物,其作为有效成分包含:
以下述化学式1表示的化合物;
以下述化学式1表示的化合物的盐;或者,
含有以下述化学式1表示的化合物或以下述化学式1表示的化合物的盐的提取物,
化学式1:
化学式1中,R1和R2分别独立地表示H、碳原子数为1至20的烷基、碳原子数为6至30的芳基、碳原子数为1至20的烯丙基、碳原子数为6至30的芳烷基或者酰基。
9.如权利要求8所述的用于预防或治疗糖尿病或糖尿病并发症的药物组合物,其特征在于,
所述R1以及R2分别独立地表示H或者碳原子数为1至20的烷基。
10.如权利要求8所述的用于预防或治疗糖尿病或糖尿病并发症的药物组合物,其特征在于,
还含有通过茑萝的植物培养或组织培养获得的提取物和由该提取物获得的化合物。
11.如权利要求8所述的用于预防或治疗糖尿病或糖尿病并发症的药物组合物,其特征在于,所述化合物具有以下述化学式2表示的结构,
化学式2:
12.如权利要求8所述的用于预防或治疗糖尿病或糖尿病并发症的药物组合物,其特征在于,
所述糖尿病并发症由高血糖症、高胰岛素血症、高甘油三酯血症、抗胰岛素性、血脂障碍、空腹血糖受损、内糖耐量异常、肥胖、动脉硬化症、微细血管病、肾病、心脏病、足部溃疡、关节炎、骨质疏松症以及因糖尿引发的眼科疾病所组成的组中选出。
13.如权利要求12所述的用于预防或治疗糖尿病或糖尿病并发症的药物组合物,其特征在于,
所述因糖尿引发的眼科疾病是由糖尿病性视网膜病变、白内障、黄斑变性症、眼外肌麻痹、虹膜睫状体炎、视神经炎、青光眼、视网膜衰退、眼底出血、异常折射、结膜下出血以及玻璃体积血所组成的组中选出。
14.如权利要求8所述的用于预防或治疗糖尿病或糖尿病并发症的药物组合物,其特征在于,还包含抗糖尿病化合物。
15.如权利要求14所述的用于预防或治疗糖尿病或糖尿病并发症的药物组合物,其特征在于,
所述抗糖尿病化合物是由那格列胺、瑞格列奈、格列酮类、磺脲类、甲福明、格列美脲、噻唑烷二酮类、双胍类、作为α-葡萄糖苷酶抑制剂的阿卡波糖、美格列奈类的瑞格列奈所组成的组中选出。
16.一种用于预防糖尿病及糖尿病并发症的保健功能食品,其作为有效成分包含:
以下述化学式1表示的化合物;
以下述化学式1表示的化合物的盐;或者,
含有以下述化学式1表示的化合物或以下述化学式1表示的化合物的盐的提取物,
化学式1:
化学式1中,R1以及R2分别独立地表示H、碳原子数为1至20的烷基、碳原子数为6至30的芳基、碳原子数为1至20的烯丙基、碳原子数为6至30的芳烷基或者酰基。
17.如权利要求16所述的用于预防糖尿病及糖尿病并发症的保健功能食品,其特征在于,所述化合物具有以下述化学式2表示的结构,
化学式2:
18.如权利要求16所述的用于预防糖尿病及糖尿病并发症的保健功能食品,其特征在于,
所述糖尿病并发症由高血糖症、高胰岛素血症、高甘油三酯血症、抗胰岛素性、血脂障碍、空腹血糖受损、内糖耐量异常、肥胖、动脉硬化症、微细血管病、肾病、心脏病、足部溃疡、关节炎、骨质疏松症以及因糖尿引发的眼科疾病所组成的组中选出。
19.如权利要求18所述的用于预防糖尿病及糖尿病并发症的保健功能食品,其特征在于,
所述因糖尿引发的眼科疾病由糖尿病性视网膜病变、白内障、黄斑变性症、眼外肌麻痹、虹膜睫状体炎、视神经炎、青光眼、视网膜衰退、眼底出血、异常折射、结膜下出血以及玻璃体积血所组成的组中选出。
20.如权利要求16所述的用于预防糖尿病及糖尿病并发症的保健功能食品,其特征在于,
还含有通过茑萝的植物培养或组织培养获得的提取物和由该提取物获得的化合物。
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