CN110938025B - 一种儿茶醛缩苯基氨基硫脲化合物在防治痛风和高尿酸血症中的应用 - Google Patents
一种儿茶醛缩苯基氨基硫脲化合物在防治痛风和高尿酸血症中的应用 Download PDFInfo
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Abstract
本发明属于新药开发与应用领域，特别涉及一种儿茶醛缩苯基氨基硫脲化合物在防治痛风和高尿酸血症的应用。该发明提供了一种如式I所示的儿茶醛缩苯基氨基硫脲化合物用于制备降低血尿酸水平药物的应用。本发明提供的应用主要是通过抑制黄嘌呤氧化酶活性作用，从而降低血尿酸水平，能有效预防、治疗痛风和高尿酸血症，为临床治疗痛风和高尿酸血症提供了一种新的药物选择。
Description
技术领域
本发明属于新药开发与应用领域，特别涉及一种儿茶醛缩苯基氨基硫脲化合物在防治痛风和高尿酸血症的应用。
背景技术
痛风是一种单钠尿酸盐（MSU）沉积所致的晶体相关性关节病，与嘌呤代谢紊乱或尿酸排泄减少所致的高尿酸血症（hyperuricemia，HUA）直接相关。中国HUA的患病率呈逐年上升趋势，发病年龄越趋低龄化，现已成为仅次于糖尿病的第二大代谢性疾病，给社会和家庭带来了巨大的经济和精神负担。近十年的流行病学研究显示，中国不同地区HUA患病率存在较大的差别，为5.46%~19.30%，其中男性为9.2%~26.2%，女性为0.7%~10.5%，总体男性高于女性。痛风是长期嘌呤代谢障碍（或）尿酸排泄减少，血尿酸增高引起组织损伤的一组临床综合征，高尿酸血症是痛风最重要的生化基础。尿酸由饮食摄入和体内分解的嘌呤化合物在肝脏中产生，约2/3尿酸通过肾脏排泄，其余由消化道排泄。痛风包括急性痛风性关节炎和慢性痛风石疾病，血尿酸升高除可引起痛风之外，还与肾脏、内分泌代谢和心脑血管等系统疾病的发生和发展有关。
目前治疗痛风的常规药物主要有秋水仙碱、非甾体类抗炎药、别嘌呤醇、非布索坦和苯溴马隆等。这些药物以抑制尿酸的形成或（和）促进尿酸的排泄达到缓解和治疗痛风与高尿酸血症的目的。体内尿酸的合成与嘌呤代谢有关，黄嘌呤氧化酶（XOD）是体内尿酸生成的关键酶，它能催化次黄嘌呤和黄嘌呤转化为尿酸。体内尿酸过多可导高尿酸血症，进而导致痛风。别嘌呤醇和非布索坦是XOD的抑制剂，这两种药物通过抑制XOD，减少体内尿酸合成，从而有效治疗痛风。但它们在临床使用中都具有一定的副作用，如别嘌呤醇可引起皮肤过敏反应及肝肾功能损伤，严重者可发生致死性剥脱性皮炎等超敏反应综合征；非布索坦可引起肝功能损害、恶心、皮疹等。服用苯溴马隆的不良反应有胃肠不适、腹泻、皮疹和肝功能损害等；秋水仙碱不良反应常见有恶心、呕吐、腹泻、腹痛、肝功能障碍和肾功能损伤等。可见目前预防和治疗痛风与高尿酸血症的药物虽然较多，但是大多数的药物副作用较大，影响生活质量。因此，开发新型的治疗高尿酸血症和痛风的药物仍然是目前医药界研究的热点。
儿茶醛，亦称原儿茶醛，其化学名称为3，4-二羟基苯甲醛。来源于唇形科植物丹参的根或冬青科植物的叶中。儿茶醛药理作用非常广泛。但尚未有儿茶醛及其衍生物抑制XOD的研究文献报道。据有关文献报道缩氨基（硫）脲类物质有一定抑制酶的作用，本发明基于儿茶醛缩氨基(硫)脲可能有抑制XOD的基础下，合成一系列儿茶醛缩氨基(硫)脲类化合物，进行XOD活力抑制的筛选实验，并进行体内实验，从而获得安全高效的儿茶醛衍生物儿茶醛缩苯基氨基硫脲，实现本发明。
发明内容
鉴于以上背景，本发明提供了一种如式I所示的儿茶醛缩苯基氨基硫脲化合物在降低血尿酸水平药物的应用。本发明提供的应用是通过抑制黄嘌呤氧化酶活性作用，从而降低血尿酸水平，能有效预防、治疗痛风和高尿酸血症，为临床治疗痛风和高尿酸血症提供了一种新的药物选择。
为达到上述目的，本发明采用的技术方案如下。
一种化学合成药物儿茶醛缩苯基氨基硫脲，如结构式I所示：
式Ⅰ。
上述化学合成药物儿茶醛缩苯基氨基硫脲的制备方法，按照传统方法合成希夫碱：以3，4-二羟基苯甲醛（儿茶醛）为原料，以冰醋酸为催化剂，在溶剂甲醇中与4-苯基-3-氨基硫脲经醛胺进行缩合反应，合成结构式Ⅰ所示的儿茶醛缩苯基氨基硫脲。
上述化学合成药物儿茶醛缩苯基氨基硫脲预防、治疗痛风和高尿酸血症的用途在于，所述儿茶醛缩苯基氨基硫脲作为药物活性成分制备成片剂、胶囊、粒剂、注射剂、脂质体或缓释控释制剂。
所述儿茶醛缩苯基氨基硫脲还能够与别嘌醇、非布索坦、秋水仙碱或其它抗痛风中药联合应用于预防、治疗痛风和高尿酸血症。
所述儿茶醛缩苯基氨基硫脲还能够与金属离子螯合形成相应的金属配合物应用于应用于预防、治疗痛风和高尿酸血症。
上述化学合成药物儿茶醛缩苯基氨基硫脲预防、治疗痛风和高尿酸血症的用途，作为添加剂应用于保健食品或饲料中。
本发明成果的优点：与现有技术相比，本发明得到的儿茶醛缩苯基氨基硫脲化合物比别嘌醇更高效，更安全。
附图说明
图1为儿茶醛缩苯基氨基硫脲对不同浓度的XOD催化黄嘌呤的作用。
图2 为儿茶醛缩苯基氨基硫脲抑制XOD催化的Lineweaver-Burk曲线。
图3 儿茶醛缩苯基氨基硫脲对高尿酸模型小鼠血清XOD活力的抑制作用结果。
图4为儿茶醛缩苯基氨基硫脲对高尿酸模型小鼠血尿酸的作用结果
具体实施方式
以下结合附图对本发明的具体实施例做详细说明。
儿茶醛缩苯基氨基硫脲的制备：按传统方法进行醛胺缩合反应，4-苯基氨基硫脲和儿茶醛以等摩尔量分别用甲醇等溶剂溶解，混合，加冰乙酸作催化剂回流4 h制备。儿茶醛缩苯基氨基硫脲化合物的分离和纯化：儿茶醛缩苯基氨基硫脲反应液，减压蒸馏浓缩，冷却放4℃冰箱析晶，抽滤，冰丙酮洗涤，真空烘箱中烘干得灰白色粉末。
儿茶醛缩苯基氨基硫脲对XOD的体外抑制作用
2.1实验材料 儿茶醛缩苯基氨基硫脲、磷酸盐缓冲液、黄嘌呤、黄嘌呤氧化酶XOD、别嘌醇等。
2.2实验方法
2.2.1 酶活力检测及样品抑制XOD测定：反应温度25℃，总反应体系0.3mL（包括含1 mM EDTA 的0.05M pH 7.5PBS缓冲溶液、0.15mM黄嘌呤底物溶液、1 IU·mL-1 XOD酶溶液），以缓冲液调零,用含酶动力学软件的多功能酶标仪测定。实验设置正常组(不加样品)、样品组，将黄嘌呤底物溶液150 uL,样品溶液依次加入96孔板，其它用PBS代替，保持整个体系的体积（300 uL）一致，最后加入XOD溶液5 uL启动反应，测定290 nm处的吸光度值，间隔10 s记录一次，共测2 min内吸光度变化值，以时间为自变量，吸光度值为因变量，可以得到一条吸光度-时间的直线，计算直线的斜率Rate(dmA/min)。每个样品需要平行操作3次，取平均值计算样品的抑制率。以样品浓度为自变量X,抑制率为因变量Y，采用SPSS22.0统计软件包计算回归方程。再根据回归方程计算抑制率为50%时的样品浓度，即半数抑制浓度IC50。
2.2.2儿茶醛缩苯基氨基硫脲对XOD抑制机理 在测活体系中，固定底物黄嘌呤浓度，加入不同浓度的儿茶醛缩苯基氨基硫脲，改变XOD的质量浓度，测定不同浓度的抑制剂儿茶醛缩苯基氨基硫脲对XOD催化氧化黄嘌呤能力的影响。以酶促反应的速度对酶浓度作图，若得到一系列通过原点的直线，则为可逆抑制；若得到一组平行线，则为不可逆抑制。
2.2.3 儿茶醛缩苯基氨基硫脲对XOD抑制类型 固定XOD的质量浓度，改变底物黄嘌呤的浓度，测定不同浓度的抑制剂对酶活力的影响。通过Lineweaver-Burk方程：1/v =Km/Vmax*1/[S] +1/Vmax作图可以得出抑制类型。
2.3实验结果
2.3.1儿茶醛缩苯基氨基硫脲对XOD的抑制率和IC50
酶活测定实验发现儿茶醛缩苯基氨基硫脲对XOD有明显的抑制效果，抑制效果强于别嘌呤醇和儿茶醛。结果见表1。将样品浓度C为自变量与平均抑制率I%为因变量进行线性回归,根据线性回归方程计算抑制率I%=50%时C的值得IC50，各样品IC50见表2。
表1 儿茶醛缩苯基氨基硫脲对XOD的抑制活性。
| 浓度/(μg/mL) | 0.05 | 0.07 | 0.1 | 0.2 | 0.3 |
| 抑制率/%（均值） | 26.31 | 31.58 | 50 | 58.82 | 70 |
| XOD相对活性/% | 73.69 | 68.42 | 50 | 41.18 | 30 |
表2 各样品的IC50（n = 3, X±s）
| 样品 | IC<sub>50</sub>(μM) |
| 儿茶醛 | 438.63±2.8 |
| 儿茶醛缩苯基氨基硫脲 | 0.04±0.008 |
| 别嘌呤醇 | 7.05±0.24 |
2.3.2儿茶醛缩苯基氨基硫脲对XOD抑制机理
以酶促反应的速度对酶浓度作图，四个不同浓度的儿茶醛缩苯基氨基硫脲对XOD的抑制结果如图1所示，四条直线并没有平行，而是相交于一点，表明儿茶醛缩苯基氨基硫脲是XOD的可逆抑制剂。
2.3.3儿茶醛缩苯基氨基硫脲对XOD抑制类型 在XOD测活体系中，在相同的XOD浓度条件下，改变底物黄嘌呤在总体系300 μL中的浓度，测定290nm处不同浓度（0 μg/mL、0.05 μg/mL、0.1 μg/mL 、0.15 μg/mL）的抑制剂儿茶醛缩苯基氨基硫脲对XOD的抑制作用。儿茶醛缩苯基氨基硫脲对XOD的抑制类型如图2所示。双倒数作图的各直线在第二象限有共同交点，而交点并没有落在坐标轴上，在同一个底物浓度下，反应速率随抑制剂浓度增大而减小，米氏常数Km与最大反应速率Vm均随抑制剂浓度的改变而发生变化，说明儿茶醛缩苯基氨基硫脲对XOD的抑制机制既不是竞争性也不是反竞争性的，因此可以初步判断儿茶醛缩苯基氨基硫脲对XOD抑制机制可能是混合型的。
儿茶醛缩苯基氨基硫脲对高尿酸模型小鼠的影响 3.1实验动物 选取健康雄性昆明种小鼠40只，体重18-22g，由江西中医药大学实验动物科技中心提供[实验动物生产许可证号:SCXK(赣)2018-003]。实验前饲养一周，以适应环境。饲养条件：室温25±2℃，相对湿度60%-70%。
药液制备 各组灌胃给药药物及动物造模物质均用0.9%CMC-Na液配成含药混悬液。
实验方法
3.3.1动物造模 参照文献方法用氧嗪酸钾和尿酸ip小鼠，增加血清尿酸水平，造成小鼠高尿酸血症模型。雄性昆明种小鼠适应性饲养一周后随机分成生理盐水组、高尿酸模型组、儿茶醛缩苯基氨基硫脲组和别嘌呤醇组共4组，每组10只。除生理盐水组外，其他各组均以氧嗪酸钾和尿酸ip小鼠，连续3 d进行造模以增加血清尿酸水平，造成小鼠高尿酸血症模型。
实验操作 生理盐水组和高尿酸模型组每天均按20 mL/kg剂量ig生理盐水,连续6d,别嘌呤醇组（10 mg/kg）每天ig给药1次，持续6 d，儿茶醛缩苯基氨基硫脲组以10 mg/kg剂量灌喂6 d,从给药第4天开始，除生理盐水组外，其他各组每天ig给药前1h 均要ip氧嗪酸钾和尿酸，氧嗪酸钾和尿酸的剂量分别为0.3 g/kg和0.25 g/kg，每天1次，连续3 d进行造模。在第6天ig给药1 h后从小鼠股动脉进行采血，血样分别置于1.5 mL 离心管中，在4℃冰箱中凝固2h,在3000 r/min低温离心5 min。每份血样血清进行血清尿酸水平和血清XOD活力测定。
生化指标检测 分别测定小鼠血尿酸水平和血XOD活性。采用磷钨酸法检测各组小鼠血尿酸，酶比色法检测XOD活性。具体操作按试剂盒说明书进行。
实验结果
3.4.1儿茶醛缩苯基氨基硫脲对高尿酸模型小鼠血清XOD活力的抑制作用
采用磷钨酸法检测生理盐水组、高尿酸模型组、儿茶醛缩氨基硫脲组和别嘌呤醇组小鼠血清XOD活力，如图3所示，模型组XOD的活力与生理盐水对照组呈现出极显著差异，表明实验造模成功。造模后，儿茶醛缩苯基氨基硫脲和阳性药别嘌呤醇均能抑制小鼠血清XOD活力，且与模型组相比均呈现显著性差异。此外，儿茶醛缩苯基氨基硫脲对XOD的抑制作用与别嘌醇相当，且无显著性差异。以上结果表明，儿茶醛缩苯基氨基硫脲对XOD活力具有较好的抑制作用。
儿茶醛缩苯基氨基硫脲对高尿酸模型小鼠血尿酸的作用
小鼠经高尿酸造模后，检测生理盐水组、高尿酸模型组、儿茶醛缩氨基硫脲组和别嘌呤醇组小鼠血清尿酸水平。如图4所示，模型组小鼠血清含量与生理盐水对照组呈现出极显著性差异，表明实验造模成功。儿茶醛缩苯基氨基硫脲和阳性药别嘌呤醇均能降低小鼠血清尿酸水平，且与模型组相比具有显著性差异。与阳性药别嘌呤醇相比，小鼠血清尿酸在儿茶醛缩苯基氨基硫脲给药具有更好的降低作用，且两者之间呈现出显著性差异。
儿茶醛缩苯基氨基硫脲对动物急性毒性研究 选取健康昆明种小鼠20只（22±2g），雌雄各半，分两组，儿茶醛缩苯基氨基硫脲组，别嘌醇组，每组10只，雌雄各半，按体重质量500mg/kg剂量灌胃（ig）一次给药，给药后观察小鼠行为，死亡情况。结果，儿茶醛缩苯基氨基硫脲组给药一周内小鼠无毒性反应，无一死亡，状态良好；而别嘌醇组10只小鼠，死了4只，其中雌鼠2只，雄性小白鼠2只。初步毒性试验说明儿茶醛缩苯基氨基硫脲毒性极低，或者无毒。
上述实施例仅是本发明的较优实施方式，儿茶醛缩苯基氨基硫脲仅是本发明的药效活性较优化合物, 其他的儿茶醛缩氨基（硫）脲类化合物用于防治痛风和高尿酸血症的应用实施方案均属于本发明技术方案的范围内。
Claims (2)
1.一种如式I所示化合物儿茶醛缩苯基氨基硫脲在制备治疗高尿酸血症和痛风药物中
的应用：
式I 。
2.根据权利要求1所述的药物儿茶醛缩苯基氨基硫脲的用途，其特征在于，儿茶醛缩苯基氨基硫脲作为化学活性成分配制成片剂、胶囊、粒剂、注射液、脂质体、缓释控释制剂。
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| inhibition of Xanthine Oxidase by Thiosemicarbazones, Hydrazones and Dithiocarbazates Derived from Hydroxy-Substituted Benzaldehydes;Leigh, Maria等;《Chem.Med.Chem.》;20111231;第6卷(第6期);P1107-1117 * |
| Investigation of the interaction between benzaldehyde thiosemicarbazone compounds and xanthine oxidase;Mengrong Li等;《Journal of Molecular Structure》;20181231;P23-32 * |
| Synthesis, Activity Testing and Molybdenum(VI) Complexation of Schiff Bases Derived from 2,4,6-Trihydroxybenzaldehyde Investigated as Xanthine Oxidase Inhibitors;Maria Leigh等;《Chem.Med.Chem》;20111231;第6卷;P612-616 * |
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