CN103381167A - Chukrasone A在预防胰腺纤维化的药物中的应用 - Google Patents
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Abstract
本发明公开了Chukrasone A在制备预防或治疗胰腺纤维化药物中的应用。本发明涉及的Chukrasone A在制备抗胰腺纤维化药物中的用途属于首次公开，由于骨架类型属于全新的骨架类型，而且其对于胰腺纤维化抑制活性强得意想不到，不存在由其他化合物给出任何启示的可能，具备突出的实质性特点，同时用于抗胰腺纤维化显然具有显著的进步。
Description
技术领域
本发明涉及Chukrasone A在制药中的应用，尤其涉及Chukrasone A在制备预防或治疗胰腺纤维化的药物中的应用。
背景技术
胰腺纤维化目前发病率愈来愈高，急需研发高效低毒的抗胰腺纤维化药物。
本发明涉及的化合物Chukrasone A是一个2012年发表（Liu, H. B. et al., 2012. Chukrasones A and B: Potential Kv1.2 Potassium Channel Blockers with New Skeletons from Chukrasia tabularis. Organic Letters 14 (17), 4438–4441.）的新骨架化合物，该化合物拥有全新的骨架类型，目前的用途仅仅涉及钾离子通道抑制活性（Liu, H. B. et al., 2012. Chukrasones A and B: Potential Kv1.2 Potassium Channel Blockers with New Skeletons from Chukrasia tabularis. Organic Letters 14 (17), 4438–4441.），对于本发明涉及的Chukrasone A在制备抗胰腺纤维化药物中的用途属于首次公开，由于骨架类型属于全新的骨架类型，而且其对于胰腺纤维化抑制活性强得意想不到，不存在由其他化合物给出任何启示的可能，具备突出的实质性特点，同时用于抗胰腺纤维化显然具有显著的进步。
发明内容
本发明所要解决的技术问题在于通过设计动物实验方法，研究Chukrasone A的抗胰腺纤维化作用。
所述化合物Chukrasone A结构如式（Ⅰ）所示：
式（Ⅰ）
因此，本发明的目的是提供Chukrasone A在制备预防或治疗胰腺纤维化的药物中的应用。
本发明的积极进步效果在于：Chukrasone A具有抗胰腺纤维化的作用，所以Chukrasone A的应用有很好的开发前景。
本发明涉及的Chukrasone A在制备抗胰腺纤维化药物中的用途属于首次公开，由于骨架类型属于全新的骨架类型，而且其对于胰腺纤维化抑制活性强得意想不到，不存在由其他化合物给出任何启示的可能，具备突出的实质性特点，同时用于抗胰腺纤维化显然具有显著的进步。
具体实施方式
本发明所涉及化合物Chukrasone A的制备方法参见文献（Liu, H. B. et al., 2012. Chukrasones A and B: Potential Kv1.2 Potassium Channel Blockers with New Skeletons from Chukrasia tabularis. Organic Letters 14 (17), 4438–4441.）。
以下通过实施例对本发明作进一步详细的说明，但本发明的保护范围不受具体实施例的任何限制，而是由权利要求加以限定。
实施例1：本发明所涉及化合物Chukrasone A片剂的制备：
取20克化合物Chukrasone A，加入制备片剂的常规辅料180克，混匀，常规压片机制成1000片。
实施例2：本发明所涉及化合物Chukrasone A胶囊剂的制备：
取20克化合物Chukrasone A，加入制备胶囊剂的常规辅料如淀粉180克，混匀，装胶囊制成1000片。
下面通过药效学实验来进一步说明其药物活性。
实验例:
1 材料
1.1 动物Wistar大鼠，雄性，体重180-200g。
1.2 Chukrasone A剂量：0.3mg/kg、0.9mg/kg、2.7mg/kg三个剂量。
2 实验方法
2.1 造模方法Wistar大鼠以腹腔注射dl-乙硫氨酸250 mg/天，连续2个月，可出现胰脏腺细胞减少，间质内脂肪及结缔组织的增生。
2.2 分组及给药方法
模型大鼠随机分为模型组，Chukrasone A 0.3mg/kg、0.9mg/kg、2.7mg/kg三个剂量组，另设空白对照组，于造模开始后给药，口服连续30天；60天时解剖动物。
2.3 检测指标
2.3.1 实验结束时取胰脏称重，计算脏器系数。
2.3.2 胰脏羟脯氨酸含量测定取100mg样本在水中匀浆，110℃ 10 N HCl 中水解20小时。HCl用氮气挥发，水解产物用双蒸水溶解后过滤。取0.5ml液体与3ml枸橼酸磷酸缓冲液（0.15M枸橼酸加0.6M磷酸氢二钠）和0.5ml溶于9M磷酸的1M过碘酸混合。加1.75ml提取缓冲液（5份甲苯：5份2-甲基-1-丙醇：2份1-丙醇），震荡30min，离心。组织相（0.6ml）与Ehrlich,s试剂混合放置15min。在565nm测定吸收度，用4-羟-1-脯氨酸制作标准曲线计算浓度，含量以ug/g组织表示。
2.3.3 组织学检查胰脏组织用10%福尔马林固定，石蜡包埋，染色后镜检。对炎症细胞浸润、间质水肿，纤维化、胰房细胞坏死，和出血情况评分（0-3分）。
3 结果
3.1 Chukrasone A对大鼠胰脏重量和脏器系数的影响
实验结束时，将大鼠处死、解剖，称量体重和胰脏重并计算其与体重的比值，结果见表 1。Chukrasone A对胰脏脏器系数的影响，与模型组比较有显著性差异。
表1
*表示p<0.05，与模型组比较
3.2 胰脏羟脯氨酸含量测定
实验结果时，对各组大鼠进行肺部羟脯氨酸含量测定，结果如表2。Chukrasone A对羟脯氨酸含量的影响，与模型组比较有显著性差异。
表2
*表示p<0.05，与模型组比较
3.3 组织学检查
实验结束时，将大鼠处死、解剖；标本常规包埋、固定、HE染色，镜检。
结果：模型组第60天可见胰导管周围严重炎症反应；嗜中粒细胞核淋巴细胞浸润，间质水肿，出血以及偶见胰泡细胞坏死；胰泡细胞消失位置及胰泡间出现纤维化。
Chukrasone A可剂量依赖性减少炎症反应，组织水肿和纤维化。评分结果见表3。Chukrasone A对评分的影响，与模型组比较有显著性差异。
表3
*表示p<0.05，与模型组比较
结论：本发明通过Chukrasone A对大鼠胰腺纤维化的影响，证实了Chukrasone A具有抗胰腺纤维化的作用。因此，Chukrasone A可作为活性成分用于制备抗胰腺纤维化的药物。
Claims (1)
1.Chukrasone A在治疗胰腺纤维化药物中的应用，所述化合物Chukrasone A结构如式（Ⅰ）所示：
式（Ⅰ）。
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| CN201310280929.XA CN103381167B (zh) | 2013-07-04 | 2013-07-04 | Chukrasone A在制备预防胰腺纤维化的药物中的应用 |
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Non-Patent Citations (1)
| Title |
|---|
| LIU, H. B. ET AL.: "Chukrasones A and B: Potential Kv1.2 Potassium Channel Blockers with New Skeletons from Chukrasia tabularis", 《ORGANIC LETTERS》 * |
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Effective date of registration: 20170111 Address after: 261000 Kuiwei District of Shandong city in Weifang province people''s livelihood Street No. 198 building 21, unit 1, No. 302 Patentee after: Shao Xiaohong Address before: 266000 Licang, Qingdao, No. nine East water road, No. 320, No. Patentee before: Gu Xiangmao |
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Inventor after: Song Huali Inventor after: Wang Guoping Inventor after: Fu Hongjuan Inventor before: Shao Xiaohong Inventor before: Wang Junmei |
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Effective date of registration: 20170815 Address after: 261100, No. 5, unit 7, building 75, 302, square street, Weifang, Hanting, Shandong Patentee after: Song Huali Address before: 261000 Kuiwei District of Shandong city in Weifang province people's livelihood Street No. 198 building 21, unit 1, No. 302 Patentee before: Shao Xiaohong |
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Granted publication date: 20151125 Termination date: 20180704 |