CN115887460A - 川芎嗪硝酮衍生物在预防和治疗糖尿病并发症疾病中的应用 - Google Patents
川芎嗪硝酮衍生物在预防和治疗糖尿病并发症疾病中的应用 Download PDFInfo
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Abstract
本发明属于药物技术领域，公开了一种川芎嗪硝酮衍生物及其药物组合物在制备用于预防和/或治疗糖尿病并发症药物中的应用。实验结果显示川芎嗪硝酮衍生物能显著降低STZ诱导的糖尿病肾病模型大鼠的血糖、血清肌酐、尿素氮和尿液尿蛋白水平，降低肾脏指数。
Description
本申请是申请日为2017年05月27日，申请号为201710392539.X，发明名称为“川芎嗪硝酮衍生物在预防和治疗糖尿病并发症疾病中的应用”的中国发明专利申请的分案申请。
技术领域
本发明属于药物技术领域，具体涉及一种川芎嗪硝酮衍生物及其药物组合物在预防和治疗糖尿病并发症疾病中的应用。
背景技术
糖尿病是一种由于胰岛素分泌缺陷或胰岛素作用障碍所致的以高血糖为特征的代谢性疾病。持续高血糖与长期代谢紊乱等可导致全身组织器官，特别是眼、肾、心血管及神经系统的损害及其功能障碍和衰竭，严重者可引起失水，电解质紊乱和酸碱平衡失调等急性并发症酮症酸中毒和高渗昏迷。
糖尿病肾病(Diabetic Kidney Disease,DKD)是糖尿病最主要的微血管并发症之一，临床特征为蛋白尿，渐进性肾功能损害，高血压，水肿，晚期出现严重肾功能衰竭。DKD是目前引起终末期肾病的首要原因，约有30％～40％的糖尿病患者患有肾病。据IDF报道，2013年全球糖尿病患病率3.82亿人，25年内将增长到5.92亿人。
川芎嗪(Tetramethylpyrazine)是传统中药川芎的主要活性成分之一，临床上广泛用于治疗心脑血管、肾脏、视网膜、视神经缺血性眼病等疾病。既往研究证实，川芎嗪具有抗血栓、抗缺血再灌注、保护心脑血管系统、保肝、肾等多方面药理活性[中国现代中药,2016,18(10):1364-1370]。川芎嗪结构如下：
临床研究显示川芎嗪对糖尿病肾病有一定的治疗作用。杨林等[Chinese Journalof Information on TCM,2011,18(8):26-29]对川芎嗪注射液治疗糖尿病肾病的临床研究进行系统评价，结果显示，在与常规治疗组对比时，联合应用川芎嗪可降低糖尿病肾病患者24h尿清蛋白排泄率、24h尿蛋白总量以及24h尿蛋白定量，但其对血尿素氮、舒张压及收缩压等降低不明显。
发明内容
本发明公开了一种川芎嗪硝酮衍生物及其药物组合物的新用途，即川芎嗪硝酮衍生物及其药物组合物在制备用于预防和治疗糖尿病并发症疾病的药物中的应用。所述衍生物具有如下通式(I)的结构：
其中，R1和R3各自独立的为C1-C6烷基；R2为C1-C6烷基或
R4和R5各自独立的为仲丁基、异丁基、叔丁基、环戊基或环己基。
优选地，所述C1-C6烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基或正戊基。
进一步优选地，所述川芎嗪硝酮衍生物，具有下面的结构式：
本发明提供了所述川芎嗪硝酮衍生物及其药物组合物在预防和治疗糖尿病并发症疾病中的应用。
所述糖尿病并发症优选为糖尿病肾病和糖尿病性眼病。进一步优选的，所述糖尿病性眼病为视网膜病变、青光眼和白内障。
本发明还提供了所述川芎嗪硝酮衍生物及其药物组合物在制备药物中的应用，其中所述药物可用于预防和治疗糖尿病肾病及其并发症疾病。所述药物组合物包括治疗有效剂量的所述衍生物或其药学上可接受的盐，以及药学上可接受的载体。
包含所述川芎嗪硝酮衍生物的药物可以单独使用或者与其它药物组合使用，用来预防和治疗糖尿病并发症。可以联合使用的其它药物主要有临床常用口服抗糖尿病药，包括双胍类、磺脲类、葡萄糖苷酶抑制剂、噻唑烷二酮类、非磺脲类促胰岛素分泌药和二肽基肽酶抑制剂等；高血压药物，包括血管紧张素受体阻断剂(如losartan，氯沙坦)、血管紧张素转化酶抑制剂；和治疗糖尿病肾病的药物(如叶酸)。
本发明提供的川芎嗪衍生物TBN和TN-2可与临床上现有的糖尿病和糖尿病肾病治疗药物联合使用，通过协同作用提高疗效，降低现有临床药物的副作用，提高临床用药收益/风险比。
所述川芎嗪硝酮衍生物可与可用药物载体制成各种剂型，包括片剂、颗粒剂、针剂、粉剂、胶囊剂、悬浮剂。
优选地，所述川芎嗪硝酮衍生物的治疗有效剂量为0.001-2g/kg。
附图说明
图1为川芎嗪衍生物对STZ诱导DKD大鼠体重(图1a)、饮水量(图1b)和饮食量(图1c)的影响。###P<0.001,##P<0.01与对照组(Control)比较；***P<0.001,
*P<0.05与模型组(Model)比较。
图2为川芎嗪衍生物对STZ诱导DKD尿蛋白(图2a)和大鼠血糖(图2b)的影响。###P<0.001与对照组(Control)比较；***P<0.001,**P<0.05,*P<0.01与模型组(Model)比较。
图3为川芎嗪衍生物对STZ诱导DKD大鼠血清中肌酐(图3a)、尿素氮(图3b)、胆固醇(图3c)和甘油三酯(图3d)水平的影响。###P<0.001,##P<0.01与对照组(Control)比较；**P<0.05,*P<0.01与模型组(Model)比较。
图4为川芎嗪衍生物对STZ诱导DKD大鼠肾脏指数的影响。###P<0.001与对照组(Control)比较；**P<0.05,*P<0.01与模型组(Model)比较。
图5列出了糖尿病肾病模型大鼠视网膜病变出现的例数和出现时间。
具体实施方式
下面将结合本发明具体实施例对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例只是本发明一部分实施例，而不是全部的实施例。本领域技术人员应当理解，对本发明的具体实施例进行修改或者对部分技术特征进行同等替换，而不脱离本发明技术方案的精神，均应涵盖在本发明保护的范围中。
实施例1.STZ诱导糖尿病肾病大鼠模型的制作及分组
1.模型制作
选用SD大鼠(200±10g)作为造模动物，注射前禁食12h，注射时用柠檬酸缓冲液以1％的浓度溶解STZ，禁食大鼠称重后腹腔注射55mg/kg STZ放于笼内，确保大鼠24h充足饮水。STZ注射需要快速，在10min内注射完成。正常对照组注射等体积pH 4.5的柠檬酸-柠檬酸钠缓冲液。观察动物状态(出现多饮多尿)，STZ注射3周后尾静脉采血，测空腹血糖≥16.7mmol/L作为大鼠糖尿病肾病成模标准。
2.分组
DKD大鼠随机分配成6组，分别给予不同药物，给药6周后终止实验，观察药物对DKD大鼠的保护作用。
实施例2.川芎嗪衍生物对STZ诱导DKD大鼠体重、饮食和饮水的影响
每周观察大鼠造模后的一般情况和体重变化，一般情况包括大鼠的活动情况、精神状态、毛色、饮食、饮水量及尿量等。每周记录饮水量和饲料量。
川芎嗪衍生物对STZ诱导的糖尿病肾病大鼠的体重影响如图1a所示，TBN和TN-2对糖尿病肾病大鼠的体重基本没有影响；糖尿病肾病大鼠饮水量和饲料量变化分别如图1b和图1c所示，给予TBN和TN-2治疗组的DKD大鼠饮水量和饮食显著低于模型组，表明TBN和TN-2能够减缓DKD大鼠糖尿病疾病进程，从而改善DKD大鼠多饮多食的糖尿病症状。
实施例3.川芎嗪衍生物对STZ诱导的DKD大鼠视网膜病变的影响
实验过程中，每日给药时观察大鼠视网膜病变情况，记录不同组别大鼠发生视网膜病变的日期。
视网膜病变是糖尿病肾病的常见并发症之一，与糖尿病肾病的相关性较高。川芎嗪衍生物对STZ诱导的DKD大鼠视网膜病变的影响如图5所示，给予TBN和TN-2治疗后DKD大鼠出现视网膜病变的例数减少，出现视网膜病变的时间点相对延迟，研究结果表明川芎嗪衍生物TBN和TN-2能够减少并且延缓视网膜病变的发生。
实施例4.川芎嗪衍生物对STZ诱导DKD大鼠血糖和尿蛋白的影响
实验过程中，分别于造模完成后和给药完成后监测大鼠血糖，并收集一次24h尿液检测尿蛋白。
川芎嗪衍生物对STZ诱导的DKD大鼠血糖的影响如图2a所示，大鼠经STZ诱导3周后血糖显著升高，给予TBN和TN-2治疗6周后血糖显著下降。TBN和TN-2对STZ诱导的DKD大鼠尿蛋白的影响如图2b所示，给予TBN和TN-2治疗后的DKD大鼠尿液中的尿蛋白含量显著降低，且TBN与氯沙坦合用优于单独给予TBN治疗和单独给予氯沙坦治疗。
实施例5.川芎嗪衍生物对STZ诱导DKD大鼠血清生化指标的影响
给药6周后，大鼠麻醉后腹主动脉取血，静置1h后，3000rmp离心10min、-70℃保存。使用全自动生化分析仪检测血清中肌酐、尿素氮、胆固醇和甘油三酯的水平。
血清肌酐、尿素氮、胆固醇和甘油三酯水平能够反应机体脂质代谢、糖类代谢和肾脏功能等情况。川芎嗪衍生物对STZ诱导DKD大鼠血清中肌酐、尿素氮、胆固醇和甘油三酯的影响如图3所示，TBN和TN-2能够显著降低血清中的肌酐(图3a)、尿素氮(图3b)、胆固醇(图3c)和甘油三酯(图3d)的水平，且呈剂量依赖性，显示出对STZ诱导糖尿病肾病大鼠脂质代谢、糖类代谢和肾脏功能的改善作用。
实施例6.川芎嗪衍生物对STZ诱导DKD大鼠肾脏指数的影响
给药6周后，用高压灭菌手术器械开腹腔统一分离肾脏组织，生理盐水清洗，滤纸吸干后精细天平称重，然后置于-80℃冰箱保存备用。肾脏指数(相对肾重)即肾重(mg)/体重(g)＝BW/KW。
肾脏指数能够在一定程度上反应糖尿病肾病的病理情况。川芎嗪衍生物对STZ诱导的DKD大鼠肾脏指数的影响如图4所示，TBN和TN-2能够显著降低DKD大鼠的肾脏指数，表明TBN和TN-2能够延缓糖尿病肾病的疾病进程。
Claims (7)
1.川芎嗪硝酮衍生物或其药物组合物在制备用于预防和/或治疗糖尿病并发症疾病药物中的应用；所述糖尿病并发症疾病为糖尿病肾病；所述川芎嗪硝酮衍生物具有如下结构式：
2.根据权利要求1所述的应用，其中所述药物组合物包括治疗有效剂量的所述衍生物或其药学上可接受的盐，以及药学上可接受的载体。
3.根据权利要求1所述的应用，其中包含所述衍生物的药物单独使用或者与其它药物组合使用。
4.根据权利要求3所述的应用，其中所述其它组合药物为口服抗糖尿病药、降血压药或叶酸。
5.根据权利要求4所述的应用，其中所述口服抗糖尿病药为双胍类、磺脲类、葡萄糖苷酶抑制剂、噻唑烷二酮类、非磺脲类促胰岛素分泌药或二肽基肽酶抑制剂中的一种或几种组合；所述降血压药为血管紧张素受体阻断剂或血管紧张素转化酶抑制剂。
6.根据权利要求5所述的应用，其中所述衍生物可与药学上可接受的载体制成各种剂型，所述剂型为片剂、颗粒剂、针剂、粉剂、胶囊剂或悬浮剂。
7.根据权利要求1-6任一项所述的应用，其中所述川芎嗪硝酮衍生物的治疗有效剂量为0.001～2g/kg。
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| CA3064976A1 (en) | 2018-12-06 |
| CN107157999A (zh) | 2017-09-15 |
| JP2020521002A (ja) | 2020-07-16 |
| EP3632440A4 (en) | 2021-02-17 |
| AU2018276686B2 (en) | 2021-01-21 |
| US20200155548A1 (en) | 2020-05-21 |
| WO2018218961A1 (zh) | 2018-12-06 |
| CA3064976C (en) | 2022-06-28 |
| EP3632440A1 (en) | 2020-04-08 |
| US11197855B2 (en) | 2021-12-14 |
| JP6954698B2 (ja) | 2021-10-27 |
| AU2018276686A1 (en) | 2019-12-19 |
| CN116637115A (zh) | 2023-08-25 |
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