CN114432324B - 一种三萜皂苷类化合物治疗高尿酸血症和痛风的用途 - Google Patents
一种三萜皂苷类化合物治疗高尿酸血症和痛风的用途 Download PDFInfo
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- CN114432324B CN114432324B CN202111519928.7A CN202111519928A CN114432324B CN 114432324 B CN114432324 B CN 114432324B CN 202111519928 A CN202111519928 A CN 202111519928A CN 114432324 B CN114432324 B CN 114432324B
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- hyperuricemia
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- xanthine oxidase
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Abstract
本发明属于医药技术领域，具体涉及一种三萜皂苷类化合物治疗高尿酸血症和痛风的新用途。三萜皂苷类化合物根据结构不同可分为四环三萜皂苷和五环三萜皂苷，及其药学上可接受的盐、酯、前药、溶剂合物、多晶型物、水合物或衍生物在制备治疗高尿酸血症和痛风的用途。所述三萜皂苷类化合物，可起到与现有技术中高尿酸血症药物相当，甚至更好的降尿酸效果，但可以明显降低现有产品中高尿酸血症药物的毒副作用，提高安全性，可用于高尿酸血症和高尿酸血症引起的痛风或痛风并发症的治疗。
Description
技术领域
本发明属于医药技术领域，具体涉及一种三萜皂苷类化合物治疗高尿酸血症和痛风的新用途。
背景技术
随着人民生活水平提高，越来越多的摄入高蛋白与高嘌呤类食物，导致体内嘌呤代谢系统紊乱尿酸合成增多或排泄减少的一种代谢类疾病，其临床表现为血尿酸盐男性高于420μmol/L、女性高于360μmol/L。当尿酸含量超过人体内最大溶解度时，会以尿酸盐晶体的形式沉积在关节及其周围组织，从而诱发急性痛风性关节炎、痛风石，甚至导致关节畸形等。因此，高尿酸血症与急性痛风性关节炎是痛风发生、发展的不同阶段。据2013年《高尿酸血症和痛风治疗中国专家共识》指出，我国高尿酸发病率逐年升高，患病率高达10％，沿海和经济发达地区甚至高达20％。并且高尿酸血症的发病愈趋向年轻化，男性的发病率普遍高于女性。高尿酸血症与高血压、血脂紊乱、Ⅱ型糖尿病、代谢综合征、肾脏和心血管疾病密切相关。高尿酸血症和痛风已成为次于糖尿病的第二大代谢性疾病，危害着人体的身体健康。
高尿酸血症具有病期长、难以根治等特点。临床长期服用的别嘌呤醇和非布司他等产品具有降尿酸作用，用于长期治疗伴随痛风的高尿酸血症，但这些药物存在着肝肾损伤、白细胞减低、皮疹等毒副作用的问题。因此亟需寻找安全有效且性价比高的治疗高尿酸血症和痛风的天然产物。
三萜皂苷是由三萜类苷元和一个或多个糖基和/或其他化学基团缩合而成的化合物，是一种天然来源的具有多种生理功能的活性物质，存在于五加科、豆科、远志科及葫芦科等植物中，及日常生活中食用的豆类、番茄和土豆等。其中，在五加科植物中分离出来的富含各种药理作用的三萜皂苷，如人参、西洋参、三七、绞股蓝等植物，含有达玛烷型四环三萜皂苷，另外尚含有齐墩果烷型五环三萜皂苷。目前已发现30余种三萜皂苷类型，除了个别是单环三萜、二环三萜及三环三萜外，常见的皂苷元主要分为四环三萜和五环三萜两大类。三萜皂苷作为天然活性成分，具有抗癌、抗炎、抗过敏、抗菌、治疗白血病、抗病毒、降血糖、防治心脑血管疾病等广泛药理作用。
本发明旨在提供一种治疗和改善高尿酸血症和痛风的三萜皂苷类化合物的新用途。
发明内容
本发明解决的技术问题是提供了一种三萜皂苷类化合物包括但不限于药学上可接受的盐、酯、前药、溶剂合物、多晶型物、水合物或衍生物在治疗高尿酸血症和痛风疾病的中的用途。
本发明解决的技术问题在于克服现有技术中治疗高尿酸血症的药物具有毒副作用的缺陷，从而提供一种在保持理想的降尿酸效果的同时，降低毒副作用治疗高尿酸血症的药物。
本发明还涉及一种含有药物有效剂量的三萜皂苷类化合物包括但不限于药学上可接受的盐、酯、前药、溶剂合物、多晶型物、水合物或衍生物具有降低尿酸效果，治疗高尿酸血症与痛风疾病的用途。
本发明解决了三萜皂苷类化合物包括但不限于生理上可接受的盐酯、前药、溶剂合物、多晶型物、水合物或衍生物在制备黄嘌呤氧化酶抑制剂治疗高尿酸血症与痛风疾病中的用途。
本发明还涉及一种含有药物有效剂量的三萜皂苷类化合物和药学上可接受的载体的药物组合物。
本发明所述三萜皂苷类化合物可用于但不限于口服、经鼻、胃肠外、局部、经皮或直肠的施用途径。口服用药包括但不限于片剂、胶囊剂、颗粒剂、散剂、口服液等。非经肠用药剂型包括但不限于注射剂、栓剂和透皮吸收剂等。
附图说明
图1为三萜皂苷类化合物的基本结构图
具体实施方式
结合以下实施例对发明作进一步的说明，但这些实施例并不限制本发明的范围。
本实施1提供了化合物1人参皂苷Ra1，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施2提供了化合物2人参皂苷Rb1，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施3提供了化合物3人参皂苷Rc，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施4提供了化合物4人参皂苷Rs1，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施5提供了化合物5人参皂苷Rd，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施6提供了化合物6西洋参皂苷R1，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施7提供了化合物7人参皂苷F2，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施8提供了化合物8人参皂苷Re，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施9提供了化合物9拟人参皂苷F11，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施10提供了化合物10人参皂苷Rg3，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施11提供了化合物11人参皂苷Rg5，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施12提供了化合物12人参皂苷Rg6，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施13提供了化合物13人参皂苷Rg11，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施14提供了化合物14人参皂苷Rg12，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施15提供了化合物15人参皂苷Rf，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施16提供了化合物16人参皂苷Rg1，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施17提供了化合物17人参皂苷Rg2，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施18提供了化合物18人参皂苷Rs4，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施19提供了化合物19人参皂苷Rk1，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施20提供了化合物20人参皂苷Rk2，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施21提供了化合物21人参皂苷Rk3，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施22提供了化合物22三七皂苷R1，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施23提供了化合物23三七皂苷R2，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施24提供了化合物24三七皂苷R4，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施25提供了化合物25三人参皂苷S3，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施26提供了化合物26人参皂苷Rz1，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施27提供了化合物27三七皂苷A，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施28提供了化合物28人参皂苷Ro，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施29提供了化合物29人参皂苷Rm1，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
本实施30提供了化合物30竹节参苷F1，对黄嘌呤氧化酶性抑制率和高尿酸血症小鼠的作用。
实施例结果如下：化合物1-30黄嘌呤氧化酶性抑制率的影响
实验材料
黄嘌呤和别嘌醇购自西格玛奥德里奇(上海)贸易有限公司，黄嘌呤氧化酶购自北京世纪山水科技有限公司，二甲基亚砜购自Amresco公司，PBS缓冲液购自Gibco公司。
实验仪器
紫外分光光度计购自上海仪电分析仪器有限公司；电子分析天平购自瑞士Mettler Toledo公司。
实验方法
将样品和别嘌醇用DMSO溶解，PBS稀释成终浓度为10μM的贮备液。XOD用PBS溶解成2U/mL酶贮备液。在黄嘌呤氧化酶的催化下底物黄嘌呤被氧化成尿酸。10μM黄嘌呤底物分别加入2U/mL XOD和10μM不同样品，在294nm波长下记录1min内吸光度增长的数值，即产物尿酸的吸收。根据OD值计算反应速率，得出样品对黄嘌呤氧化酶的抑制率。
结果
三萜皂苷类化合物对黄嘌呤氧化酶抑制作用的实验结果见表2。
表2化合物对黄嘌呤氧化酶的抑制作用
实施例
药理实验：化合物1-30对高尿酸血症小鼠的血尿酸水平的影响
实验材料
氧嗪酸钾盐购自西格玛奥德里奇(上海)贸易有限公司；别嘌醇购自西格玛奥德里奇(上海)贸易有限公司；尿酸测定试剂盒购自南京建成生物工程研究所；化合物1-30购自上海源叶生物有限公司。
实验仪器
Epoch2型酶标仪购自美国博腾仪器有限公司；DHG-9123A电热恒温鼓风干燥箱购自上海精宏实验设备有限公司；MS204S电子分析天平购自瑞士Mettler Toledo公司；超低温离心机购自赛默飞世尔科技有限公司。
动物分组
选取健康雄性昆明小鼠18-20g，购自辽宁长生生物技术股份有限公司。随机分组，每组8只，分别为对照组、模型组、别嘌醇组(阳性药，5mg/kg)、受试化合物1-30组(15mg/kg)。
高尿酸血症模型的建立
将别嘌醇和化合物对照组用0.5％羧甲基纤维素钠(CMC-Na)溶液分别进行混悬。对照组灌胃给予生理盐水，其他组小鼠灌胃给予别嘌醇和15mg/kg化合物1-30，连续用药7d。末次给药后腹腔注射300mg/kg氧嗪酸钾盐，注射6h后，每组小鼠眼球取血，颈椎脱位处死小鼠。全血静止30min后，3000r/min离心10min，分离血清。使用生化分析仪检测血清中尿酸(UA)水平。
实验结果以表示，采用SAS 9.2软件GLM过程进行单因素方差分析，两两比较利用Duncan法进行显著性分析，p<0.05为差异显著，p<0.01为差异极显著。
结果
三萜皂苷类化合物对高尿酸血症小鼠血尿酸水平(UA)的实验结果见表3。
表3化合物1-30对高尿酸血症小鼠血尿酸水平(UA)的影响
注：与正常组相比，###P<0.05为显著差异；与模型组比较，*P<0.05为显著差异，**P<0.01和***P<0.001为差异极显著。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
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