CN107157999A - 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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- CN107157999A CN107157999A CN201710392539.XA CN201710392539A CN107157999A CN 107157999 A CN107157999 A CN 107157999A CN 201710392539 A CN201710392539 A CN 201710392539A CN 107157999 A CN107157999 A CN 107157999A
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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药物以及用于预防和治疗糖尿病并发症中的应用。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，降低血清肌酐、尿素氮水平和尿液尿蛋白水平，降低肾脏指数，并且显著降低糖尿病肾病模型大鼠出现视网膜病变的机率。因此所述川芎嗪硝酮衍生物可与药物载体制成各种剂型。
Description
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。
迄今为止，DKD发生发展的机制尚未完全明确。但目前认为，DKD的发病机制与糖代谢紊乱及由此所致的非酶糖化、多元醇通路激活、蛋白激酶C激活，脂代谢紊乱、高血压所致的肾血流动力学改变、氧化应激、血管活性物质及细胞因子、遗传等因素有关。文献报道线粒体是细胞内活性氧自由基(ROS)的主要来源和内源性凋亡途径的重要参与者，其ROS过度合成可能是糖尿病及其并发症发病机制中的始动环节，阻断或清除ROS能够减轻糖尿病肾病导致的尿蛋白排泄率增加、肾小球硬化及肾小管间质纤维化等(Michael Brownlee，Nature,2001,414:813-820)。
糖尿病性眼病也是常见的糖尿病并发症之一。在糖尿病患病过程中，糖尿病患者的眼睛的大部分组织都受到影响，从而产生不同程度的和不同症状的眼部病变。糖尿病所致的眼病，主要有视网膜病变、白内障和青光眼等。
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：
川芎嗪可以通过抗细胞凋亡、抗炎、抗氧化等途径发挥肾脏组织细胞保护作用，从而减轻肾脏的功能性损伤。Yang等[Phytomedicine,2011,18(13):1148-1152]通过链脲霉素诱导的大鼠糖尿病肾病模型研究显示，川芎嗪能够显著改善肾功能，下调糖尿病肾病大鼠的血糖和尿蛋白排除率，其作用机理可能与川芎嗪下调肾脏组织中的VEGF有关。Gong等[Archives of Toxicology,2015,89(7):1057-1070]证明川芎嗪对亚砷酸钠诱导的人肾脏近曲小管细胞损伤同样具有保护活性，其机制与抑制ROS的产生，增加GSH水平，提高细胞色素C氧化酶活性，恢复线粒体膜电位，改善线粒体功能紊乱及降低β-catenin、NF-κB、p38MAPK、TNF-α、COX-2的蛋白表达，从而阻断细胞凋亡有关。同时，Gong的另外一篇关于川芎嗪的研究中[Am J Nephrol,2013,37(3):199-207]，同样证实川芎嗪能够通过抑制p38MAPK蛋白表达，发挥对造影剂诱导的肾脏损伤模型的保护作用。
临床研究显示川芎嗪对糖尿病肾病有一定的治疗作用，且具有较高的安全性。杨林等[Chinese Journal of 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。同时，使用过程中，未出现严重不良反应，提示川芎嗪注射液对糖尿病肾病患者具有一定的疗效。陈应军等[中国实用医药,2013,8(23):178-179]在对2型糖尿病伴随周围神经病变患者的治疗过程中发现，大剂量的川芎嗪注射液(360～400mg/d)静脉滴注，12d为一个疗程治疗患者时，其治疗结果总有效率高达95％，而同期采用常规剂量的川芎嗪注射液组(80mg/d)为82.93％，大剂量组的总有效率要高于常规剂量组，而不良反应并没有增加。
川芎嗪在眼科疾病治疗中亦有广泛应用。目前川芎嗪在临床上应用于糖尿病视网膜病变、视网膜血管阻塞、缺血性视网膜病变、青光眼等眼病。邓新国等采用腹腔注射盐酸川芎嗪观察兔眼视网膜组织中的药代动力学，研究表明腹腔注射川芎嗪后，该药能透过血一视网膜屏障进入视网膜组织.这一结果为川芎嗪全身用药治疗眼底病提供了实验依据。有研究者将糖尿病视网膜病变患者40例分成治疗组20例和对照组20例。治疗组用葛根素注射液静脉滴注，内服滋肾健脾化瘀方，同时应用电控川芎嗪离子导人。对照组用葛根素注射液静脉滴注，内服滋肾健脾化瘀方。观察2组治疗前后及眼底的变化。结果显示治疗组总有效率86.84％，对照组67.50％，治疗组的疗效明显优于对照组，2组疗效比较差异有统计学意义[王燕，中国中医眼科杂志，2004]。川芎嗪治疗眼底疾病的作用机制一般认为与改善血液流变学，抑制细胞内皮增生，清除自由基，抑制细胞凋亡和拮抗钙离子等作用有关。
综上所述，川芎嗪能够通过抗凋亡、抗炎、抗氧化等多种途径改善糖尿病肾病及其眼底疾病，并在临床研究中对糖尿病肾病显示出一定的治疗效果，但其对自由基的清除能力不足，治疗效果不能满足临床需要。
硝酮类化合物是一类具有强大自由基清除能力的化合物，对多种活性自由基均具有较强的清除作用，研究发现硝酮化合物对各种自由基导致疾病(如癌症、脑中风、帕金森病等)具有一定的治疗作用。基于川芎嗪在临床上在糖尿病肾病及眼底疾病治疗方面的应用，以及硝酮基团化合物强大的自由基清除作用，我们创造性的合成了川芎嗪硝酮衍生物TBN和TN-2。研究发现，川芎嗪硝酮衍生物对糖尿病肾病大鼠模型具有显著的保护作用，显著降低STZ诱导的糖尿病肾病模型大鼠的血糖，降低血清肌酐、尿素氮水平和尿液尿蛋白水平，降低肾脏指数。同时，川芎嗪硝酮衍生物可明显降低糖尿病并发症视网膜病变的发生机率。
本发明发现了川芎嗪硝酮衍生物的新用途，即在制备预防和治疗糖尿病并发症疾病药物中的应用。本发明提供的化合物TBN和TN-2是川芎嗪和硝酮基团的耦合物，兼有川芎嗪抗氧化、抗凋亡、抗炎等活性和硝酮基团的强自由基清除活性，在保留川芎嗪对糖尿病肾病疗效的基础上改善了高血糖或自由基诱导的氧化损伤。另一方面，TBN和TN-2对糖尿病视网膜病变也显示出一定的疗效，能够延缓糖尿病肾病及糖尿病视网膜病变的进展，为患者带来更高的获益比。
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。
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药物以及用于预防和治疗糖尿病并发症疾病中的应用。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，其中所书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，主要包括双胍类、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。优选的组合药物为血管紧张素受体阻断剂、血管紧张素转化酶抑制剂和叶酸。研究证明叶酸可通过降低同型半胱氨酸而保护糖尿病肾病。
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中的表1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表1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。
随着糖尿病肾病病理过程的进展，肾小球基底膜逐渐增厚，系膜进一步增宽，最终发展为灶性肾小管萎缩及间质纤维化，并进入肾衰竭期，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 (12)
1.川芎嗪硝酮衍生物在制备药物中的应用，其中所述药物包括所述衍生物或其药物组合物，用于预防和治疗糖尿病并发症疾病；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。
2.根据权利要求1所述的应用，其中所述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。
3.根据权利要求1所述的应用，其中所述衍生物具有如下结构式：
4.根据权利要求1所述的应用，其中所述糖尿病并发症为糖尿病肾病。
5.根据权利要求1所述的应用，其中所述糖尿病并发症为糖尿病性眼病、肾脏病变或神经病变。
6.根据权利要求5所述的应用，其中所述糖尿病性眼病为视网膜病变、青光眼或白内障。
7.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。
8.根据权利要求1所述的应用，其中包含所述衍生物的药物可以单独使用或者与其它药物组合使用。
9.根据权利要求8所述的应用，其中所述其它组合药物为降血压药。
10.根据权利要求9所述的应用，其中所述降血压药为血管紧张素受体阻断剂、血管紧张素转化酶抑制剂或叶酸。
11.根据权利要求7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。
12.根据权利要求7所述的应用，其中所述有效剂量为0.001～2g/kg。
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| JP2020515801A JP6954698B2 (ja) | 2017-05-27 | 2018-05-25 | テトラメチルピラジンニトロン誘導体の糖尿病合併症疾患の予防と治療における応用 |
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| WO2023165479A1 (zh) * | 2022-03-02 | 2023-09-07 | 广州喜鹊医药有限公司 | 硝酮化合物或其在药学上可接受的盐与sglt-2抑制剂联合应用 |
| CN116850188A (zh) * | 2023-05-29 | 2023-10-10 | 广州喜鹊医药有限公司 | 川芎嗪硝酮衍生物在制备预防或治疗2型糖尿病药物中的应用 |
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| AU2018276686B2 (en) | 2021-01-21 |
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