CN115381837A - 一类双环吗啉类化合物在预防或治疗糖尿病中的应用 - Google Patents
一类双环吗啉类化合物在预防或治疗糖尿病中的应用 Download PDFInfo
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- CN115381837A CN115381837A CN202110570017.0A CN202110570017A CN115381837A CN 115381837 A CN115381837 A CN 115381837A CN 202110570017 A CN202110570017 A CN 202110570017A CN 115381837 A CN115381837 A CN 115381837A
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及医药技术领域，公开一类双环吗啉类化合物、含有其的药物组合物在制备预防和/或治疗糖尿病及其相关病症的药物中的应用，发明人在对该化合物药理活性评价过程中发现：该化合物有抗糖尿病活性，其在1型糖尿病和2型糖尿病均表现显著的降血糖活性。
Description
技术领域
本发明涉及医药技术领域，一类双环吗啉类化合物在制备预防或治疗糖尿病的药物中的用途。
背景技术
糖尿病是由遗传、环境、免疫等因素相互作用而引起的代谢失调性内分泌疾病，以高血糖为主要标志，分为1型糖尿病和2型糖尿病。1型糖尿病又名胰岛素依赖型糖尿病，是由于自身免疫损伤等原因引起体内胰岛β细胞损害，导致胰岛素绝对缺乏而引起的高血糖病症，“三多一少”症状明显。2型糖尿病是由于体内对胰岛素的敏感性下降(相对缺乏)而导致的糖脂代谢紊乱，以高血糖高血脂为显著特点，往往伴有胰岛素抵抗。糖尿病作为一种代谢紊乱性疾病，可引发肾衰竭、失明、酮症酸中毒及心脑血管疾病等严重并发症，已成为继恶性肿瘤和心脑血管病之后严重威胁人类健康的第三大非传染性疾病。近年来我国糖尿病的患病率呈显著递增趋势迅速增加，给社会和家庭带来巨大压力和沉重负担，研发更多可用于临床的安全有效的降糖药物显得尤其重要。
目前糖尿病的治疗主要集中在多种降血糖药和胰岛素治疗，但均存在严重的毒副作用，且均不能有效预防并发症的发生。这些药物主要分为如下几类：(1)胰岛素，降糖效果明显，但易发生低血糖反应，皮下注射可出现皮肤病变。(2)促胰岛素分泌剂：磺酰脲类，如格列本脲、格列吡嗪、格列齐特等；非磺酰脲类，如瑞格列耐和那格列耐，此类药物较易发生低血糖反应，有肝肾毒性。(3)双胍类：如二甲双胍，有降低体重的作用，并可能出现乳酸血症。(4)α-葡萄糖苷酶抑制剂：阿卡波糖和伏格列波糖，常见肠道多气、腹胀等不良反应。(5)胰岛素增敏剂，即噻啶烷二酮类药物：曲格列酮、罗格列酮，常见有水肿、体重增加、肝损害等不良反应。
双环吗啉类化合物(代号WLP-S-17)已获得我国独立知识产权，具有肝脏病治疗作用。我们最近的研究发现，WLP-S-17在经典的STZ诱导的1型糖尿病小鼠模型和经典的高脂饮食联合STZ诱导的2型糖尿病小鼠模型，均表现显著的降血糖活性，且改善胰岛素抵抗，降低系统炎症水平，且对糖尿病肝肾损伤并发症有阻抑作用。特申请本专利。
发明内容
本发明要解决的技术问题是，提供一类双环吗啉类化合物、含有其的药物组合物在制备预防和/或治疗糖尿病药物中的应用。
为解决本发明的技术问题，本发明采用如下技术方案：
本发明技术方案的第一方面提供了一类双环吗啉类化合物在制备预防和/或治疗糖尿病药物中的应用，该类化合物结构如下：
其中，X选自无机酸、有机酸。
所述双环吗啉类化合物中无机酸选自氢氟酸、盐酸、氢溴酸、氢碘酸、醋酸、硫酸、磷酸；所述的有机酸选自乙酸、三氟乙酸、丙酸、草酸、苹果酸、丙二酸、琥珀酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸。
优选地，所述双环吗啉类化合物具有如下所示结构：
本发明技术方案的第二方面提供含有第一方面所述的双环吗啉类化合物的药物组合物在制备预防和/或治疗糖尿病药物中的应用，该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量％。
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、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也制成是缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、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。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
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依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有大范围的变化。一般来讲，本发明化合物的每天的合适剂量范围为0.001-150mg/Kg体重，优选为0.1-100mg/Kg体重，更优选为1-60mg/Kg体重，最优选为2-30mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整它的剂量。
有益技术效果：
1，本发明提供一类双环吗啉类化合物在预防或治疗糖尿病方面的新用途。
2，实验证明本发明所述的化合物在药理上具有以下两方面显著活性：对STZ诱导的1型糖尿病小鼠具有显著的降低空腹血糖活性；对高脂饮食联合STZ诱导的2型糖尿病小鼠具有显著的降低空腹血糖活性；对糖尿病相关系统炎症、肝脏损伤和肾脏损伤均有防治活性。
附图说明
图1.双环吗啉类化合物(代号：WLP-S-17)对链脲霉素(STZ)诱导的糖尿病小鼠进食量进水量的影响(n＝8-10)(*P＜0.05，**P＜0.01，***P＜0.001与空白对照组比较；#P＜0.05，##P＜0.01，###P＜0.001与模型组比较)。
图2双环吗啉类化合物(代号：WLP-S-17)对链脲霉素(STZ)诱导糖尿病小鼠空腹血糖的影响(n＝8-10)(*P＜0.05，**P＜0.01，***P＜0.001与空白对照组比较；#P＜0.05，##P＜0.01，###P＜0.001与模型组比较)。
图3.双环吗啉类化合物(代号：WLP-S-17)对链脲霉素(STZ)诱导糖尿病小鼠相关肝肾损伤的作用(n＝8-10)(*P＜0.05，**P＜0.01，***P＜0.001与空白对照组比较；#P＜0.05，##P＜0.01，###P＜0.001与模型组比较)。
图4双环吗啉类化合物(代号：WLP-S-17)对高脂饮食联合链脲霉素(HFD/STZ)诱导的2型糖尿病小鼠空腹血糖的影响(n＝14)。(##P<0.001与空白对照组比较；*P<0.05,**P<0.01与HFD/STZ模型组比较)。
图5双吗啉类化合物(代号：WLP-S-17)对高脂饮食联合链脲霉素(HFD/STZ)诱导的2型糖尿病小鼠口服糖耐量实验(OGTT)的折线图。
图6双吗啉类化合物(代号：WLP-S-17)对高脂饮食联合链脲霉素(HFD/STZ)诱导的2型糖尿病小鼠口服糖耐量实验(OGTT)的曲线下面积(n＝14)。(###P<0.001与空白对照组比较；*P<0.05,**P<0.01与HFD/STZ模型组比较)。
图7双吗啉类化合物(代号：WLP-S-17)对高脂饮食联合链脲霉素(HFD/STZ)诱导的2型糖尿病小鼠血清炎症因子肿瘤坏死因子-α(TNF-α)水平的影响(n＝14)。(##P<0.01与空白对照组比较；*P<0.05,***P<0.001与HFD/STZ模型组比较)。
图8双吗啉类化合物(代号：WLP-S-17)对高脂饮食联合链脲霉素(HFD/STZ)诱导的2型糖尿病小鼠胰腺组织病理的影响。
具体实施方式
下面的实施例及药理活性实验用于进一步说明本发明，但这并不意味着对本发明的任何限制。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
下述实施例中，部分物质相应的中文名称如下：
Control：空白对照
Model：模型对照
STZ：链脲霉素
HFD：高脂饲料
OGTT：口服葡萄糖耐量实验
ALT：谷丙转氨酶
AST：谷草转氨酶
BUN：尿素氮
AUC：曲线下面积
Glu：葡萄糖
TNF-α：肿瘤坏死因子α
metformin：二甲双胍
Rosiglitazone：罗格列酮
Fasting blood glucose：空腹血糖
下述实施例中所述室温如本领域常规所述，一般指15～25℃。
药理实验：双环吗啉类化合物(代号：WLP-S-17)的药理活性实验
实验例1双环吗啉类化合物(代号：WLP-S-17)在1型糖尿病降糖活性测试
实验方法：
SPF级雄性ICR小鼠(20～22g)，适应环境后按体重随机分为2组，空白对照组和糖尿病模型组，小鼠禁食不禁水18h，糖尿病模型组小鼠单次腹腔注射链脲霉素(STZ)180mg/kg(柠檬酸钠缓冲液配置)，空白对照组腹腔注射等量的柠檬酸钠缓冲液。注射后3天用罗氏血糖仪检测空腹血糖值，血糖值大于11.1mmol/L的小鼠为造模成功小鼠。将造模成功小鼠按照血糖值随机分为3组：模型组9只、二甲双胍200mg/kg组9只、WLP-S-17 10mg/kg组9只，各给药组小鼠每天灌胃给予相应剂量的药物，空白对照组和模型对照组小鼠每天灌胃给予相同量的0.5％CMC-Na溶液。每天给药1次。根据实验情况，在给药11天，各药物给药剂量加倍，继续给药5天，共给药16天。给药期间定期尾静脉采血，罗氏血糖仪监测记录动物空腹血糖情况，同时记录动物一般状态、进食量、进水量。在末次给药后，动物禁食不禁水过夜，摘眼球取血，室温静置2小时后3500r，20min离心，分离上层获得血清，全自动生化分析仪检测血清生化指标。
实验结果：
进食量、饮水量：
与空白对照组比较，STZ模型组小鼠进食量及饮水量均显著增加，结合模型组动物体重显著降低现象，动物表现出糖尿病典型的“三多一少”症状。WLP-S-1710mg/kg在给药过程中表现出显著的降低进食量和饮水量的作用，增加剂量到20mg/kg作用更加显著。阳性对照药二甲双胍(metformin)200mg/kg连续给药11天后400mg/kg再连续给药5天，亦表现显著降低饮水量的作用，对进食量无显著降低作用(图1)。
空腹血糖水平：
给药期间定期监测动物血糖变化。与空白对照组比较，单次注射180mg/kg STZ的模型小鼠空腹血糖值在各个监测点均显著升高。WLP-S-17 10mg/kg连续给药11天有降低空腹血糖趋势(模型组血糖值30.36±3.11，WLP-S-17血糖值25.73±7.28)，增加剂量为20mg/kg后连续给药2天和连续给药5天，均表现显著的降低血糖活性，与模型组比较有统计学差异(表1，图2)。阳性对照药二甲双胍200mg/kg，连续给药11天，未表现出明显的降血糖作用(模型组血糖值30.36±3.11，二甲双胍血糖值31.87±1.32)，增加剂量为400mg/kg给药2天和给药5天，表现显著的降血糖活性(表1、图2)。
表1双环吗啉类化合物(代号：WLP-S-17)对STZ诱导糖尿病小鼠空腹血糖的影响(n＝8-10)
*P＜0.05，**P＜0.01，***P＜0.001与空白对照组比较；#P＜0.05，##P＜0.01，###P＜0.001与模型组比较。
糖尿病相关肝肾损伤：
STZ诱导1型糖尿病小鼠，不仅血糖显著升高，亦表现显著的糖尿病相关肝肾损伤，血清ALT、AST、BUN水平较空白对照组均显著升高。在目前的给药剂量和给药方案下，WLP-S-17可显著改善糖尿病相关肝肾损伤，表现在显著降低血清ALT、AST、BUN水平。在糖尿病相关肝肾损伤方面，WLP-S-17活性优于二甲双胍(图3)
实验例2双环吗啉类化合物(代号：WLP-S-17)在2型糖尿病降糖活性测试
实验方法：
SPF级C57BL/6J小鼠适应环境后，随机分为空白对照组和模型组。空白对照组给予普通饲料，模型组给予60％高脂饲料，喂养10周。在动物出现胰岛素抵抗症状后，所有动物禁食不禁水12h，模型组小鼠给予链脲霉素(STZ)一次性腹腔注射(100mg/kg)，空白对照组注射等剂量的柠檬酸缓冲液(PH＝4.4)。1周后，尾静脉采血，葡萄糖氧化酶试剂盒测空腹4h血糖，空腹血糖值大于11.1mmol/L者符合模型筛选条件。将造模成功的2型糖尿病小鼠按血糖值随机分为3组，即HFD/STZ模型组、WLP-S-17 50mg/kg剂量组、罗格列酮(Rosiglitazone)10mg/kg剂量组，每组14只。分组后第2天按10mL/kg给药，空白对照组和模型组给予等剂量的0.5％CMC-Na溶液，每天给药一次，给药周期6周。实验过程中继续用不同的饲料分别喂养，保证充足的水和食物，定期尾尖取血，葡萄糖氧化酶试剂盒测定空腹血糖值。
口服葡萄糖耐量实验(OGTT)测定：给药第30天进行OGTT实验，动物禁食不禁水4h后，按2g/kg口服给予葡萄糖，分别测定给予葡萄糖后0、30、60、120min时的空腹血糖，绘制血糖趋势图，计算趋势图曲线下面积(Area under curve，AUC)，AUC越大，表明胰岛素利用越不敏感。
炎症因子检测：取血，制备血清，按照ELISA试剂盒说明书检测血清TNF-α水平。
胰腺组织病理：取胰腺组织，10％福尔马林溶液固定后，经过梯度乙醇脱水，二甲苯透明，然后放入溶解的石蜡中浸透3次，每次30min，石蜡块包埋好后进行连续切片(厚约4nm)，常规苏木紫-伊红(H.E.)染色。光镜检查胰腺组织病理状态并照相。
实验结果：
空腹血糖水平：
高脂饲料(HFD)诱导10周的C57BL/6J小鼠腹腔注射STZ后，HFD/STZ模型组小鼠空腹血糖显著升高，随着时间的延长，血糖一直处于显著升高的稳定状态。WLP-S-17 50mg/kg灌胃给药6周，能降低HFD/STZ小鼠空腹血糖水平，且在第3周、4周和6周显著降低空腹血糖值，与模型组比较有统计学差异。随着给药时间延长，罗格列酮逐渐减低小鼠空腹血糖值，于第6周显著降低2型糖尿病小鼠空腹血糖值(图5)。在该模型，WLP-S-17 50mg/kg降空腹血糖活性优于或与罗格列酮相当。
胰岛素抵抗情况：
口服葡萄糖耐量实验(OGTT)，是诊断糖尿病的金指标，能够了解胰岛β细胞功能及胰岛素抵抗情况。结果显示(图5，图6)，HFD/STZ模型组小鼠30min时血糖明显升高，曲线下面积较空白对照组显著增加，胰岛素利用不敏感。WLP-S-17 50mg/kg剂量组可显著降低OGTT曲线下面积，提高胰岛素的敏感性。罗格列酮亦可降低AUC，WLP-S-17 50mg/kg在该模型升高胰岛素敏感性，改善胰岛β细胞功能的作用优于罗格列酮。
炎症水平：
在炎症反应中，肿瘤坏死因子(Tumour necrosis factor-α，TNF-α)主要由单核巨噬细胞合成、分泌。其反过来又以自分泌和旁分泌的方式激活单核巨噬细胞，使后者产生释放大量的IL-1、IL-6、IL-8等炎症介质，激发炎症的连锁反应。大量研究证实，炎症参与了糖尿病的发生。血清中TNF-α检测结果见图7，HFD/STZ模型组小鼠血清TNF-α含量显著升高，体内炎症反应明显。WLP-S-17给药后，显著降低血清TNF-α，减轻体内的炎症程度，罗格列酮10mg/kg亦可显著降低血清TNF-α含量。在该模型中，WLP-S-17 50mg/kg抗炎活性优于罗格列酮10mg/kg。
胰腺组织病理结果：
胰腺组织病理结果如图8所示，空白对照组小鼠胰腺组织结构清晰，胰岛结构正常，形态规则整齐，与周围腺体界限清楚，胰岛内细胞密度较高，形态正常，排列规整，胰岛毛细血管未见扩张。HFD/STZ模型组小鼠胰岛结构不清，胰岛内细胞密度减少，排列紊乱，局部细胞缺失、塌陷，可见散在空泡样变性细胞，部分胰岛细胞胞膜皱缩，胞浆深染，细胞核固缩，呈现“凋亡征象”。胰岛毛细血管扩张明显，局部胰岛内可见散在淋巴细胞浸润。WLP-S-17 50mg/kg和罗格列酮10mg/kg给药后，可明显降低HFD/STZ小鼠胰腺病理组织评分，改善小鼠胰腺病理损伤，胰腺轮廓清晰，胰岛内细胞密度增加，无空泡样变性细胞，凋亡征象减少，炎症反应减轻。胰腺病理组织评分见表2。
表2双吗啉类化合物(代号：WLP-S-17)对HFD/STZ诱导的2型糖尿病小鼠胰腺组织病理评分的影响(n＝14)
###P<0.001与空白对照组比较；***P<0.001与HFD/STZ模型组比较。
Claims (6)
1.如通式I所示的双环吗啉类化合物在制备预防和/或治疗糖尿病及其相关病症的药物中的应用；
其中，X选自无机酸、有机酸。
2.根据权利要求1所述的应用，其特征在于，所述的无机酸选自氢氟酸、盐酸、氢溴酸、氢碘酸、醋酸、硫酸、磷酸；所述的有机酸选自乙酸、三氟乙酸、丙酸、草酸、苹果酸、丙二酸、琥珀酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸。
3.根据权利要求1所述的应用，其特征在于，所述双环吗啉类化合物选自如下所示结构：
4.根据权利要求1所述的应用，其特征在于，所述糖尿病包括1型糖尿病、2型糖尿病，及糖尿病并发症。
5.一种药物组合物在制备预防和/或治疗糖尿病的药物中的应用，其特征在于：所述的药物组合物含有有效剂量权利要求1-3所述的双环吗啉类化合物和药学上可接受的载体。
6.根据权利要求5的应用，其特征在于：所述药物组合物的剂型选自片剂、胶囊剂、丸剂、颗粒剂、口服液和混悬剂。
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| CN107488162A (zh) * | 2015-10-19 | 2017-12-19 | 中国医学科学院药物研究所 | 一类双环醇类衍生物及其制备和应用 |
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| CN107115338A (zh) * | 2016-03-01 | 2017-09-01 | 中国医学科学院药物研究所 | 双环醇在制备糖尿病药物中的应用 |
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