CN111529526B - 一种化合物在制备治疗急性胰腺炎的药物中的用途 - Google Patents
一种化合物在制备治疗急性胰腺炎的药物中的用途 Download PDFInfo
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Abstract
本发明公开了一种化合物在制备治疗急性胰腺炎的药物中的用途，所述化合物能显著降低血清淀粉酶的含量，对治疗急性胰腺炎具有明显作用，且其疗效优于或者不劣于现有治疗药物——乌司他丁。所述化合物可用于开发治疗急性胰腺炎的新型药物，具有重要的医用前景和经济价值。
Description
技术领域
本发明属于医药领域，涉及一种化合物在制备治疗急性胰腺炎的药物中的用途。
背景技术
急性胰腺炎主要是由于胰酶对胰腺的自我消化和对其周围组织的消化，从而继发一系列的器官的功能障碍，临床以急性上腹痛、恶心、呕吐、发热和血胰酶增高等为特点。其病因甚多，常见的病因有胆石症、大量饮酒和暴饮暴食。急性胰腺炎的病死率约10％，几乎所有死亡病例均为首次发作。出现呼吸功能不全或低钙血症提示预后不良。重症坏死性胰腺炎的病死率达50％或更高，手术治疗可使其降至20％左右。
大多数急性胰腺炎属于轻症急性胰腺炎，经3～5天积极治疗多可治愈。其中一个关键的步骤为减少胰腺等各组酶类的分泌。乌司他丁是从新鲜人尿中提取的一种能抑制多种蛋白水解酶活力的糖蛋白，属蛋白酶抑制剂，研究发现用于治疗急性胰腺炎具有较好的效果。但乌司他丁在临床使用时存在常见粒细胞减少、腹泻、皮肤发红及瘙痒感、血管痛、丙氨酸氨基转移酶和冬氨酸氨基转移酶升高等副作用。目前对新的治疗急性胰腺炎的药物存在迫切需要。
发明内容
针对上述问题，本发明的目的是提供一种新的可用于治疗急性胰腺炎的药物。
为实现上述目的，本发明采取的技术方案为：
本发明提供了一种化合物在制备下调血清淀粉酶的药物中的用途，所述化合物的结构如通式(I)所示：
其中，
R1是C1-4-烷基、C3-7-环烷基、C3-7-环烷基-C1-4-烷基或R11取代的C2-7-烷基，
其中R11是-N(R111)R112或卤素，其中R111是氢、C1-4-烷基、C2-4-烯基、C2-4-炔基、C3-7-环烷基、C3-7-环烷基-C1-4-烷基、羟基-C2-4-烷基、C1-4-烷氧基-C2-4-烷基、1N-(C1-4-烷基)-吡唑基、1N-(H)-吡唑基、异噁唑基或被氟全部或部分取代的C1-4-烷基，
R112是氢、C1-4-烷基、C3-7-环烷基或C3-7-环烷基-C1-4-烷基，
或者R111和R112一起，包括与它们结合的氮原子形成Het环，
其中Het是哌啶-1-基、吗啉-4-基、硫代吗啉-4-基、S-氧代-硫代吗啉-4-基、S，S-二氧代-硫代吗啉-4-基、吡咯烷-1-基、氮杂环丁烷-1-基、高哌啶-1-基、4N-(R113)-哌嗪-1-基、2，5-二氢-吡咯-1-基、1，2，3，6-四氢吡啶-1-基、吡唑-1-基或咪唑-1-基，
其中R113是C1-4-烷基、C3-7-环烷基、C3-7-环烷基-C1-4-烷基或C1-4-烷基羰基，其中所述Het可由一个或两个独立地选自氟或C1-4-烷基的取代基任选取代，
R2是氢，
R3是氢，
R4是C1-4-烷基、C3-7-环烷基或C3-7-环烷基-C1-4-烷基，
R5是C1-4-烷基、卤素、C1-4-烷氧基、三氟甲基、氰基、羟基、苯基-C1-4-烷氧基、C1-4-烷氧基-C2-4-烷氧基、羟基-C2-4-烷氧基、C3-7-环烷氧基、C3-7-环烷基-C1-4-烷氧基或被氟全部或大部分取代的C1-4-烷氧基，
R6是氢或卤素。
所述化合物在专利ZL200780006529(申请号：CN200780006529.2，发明名称：作为EG5驱动蛋白调节剂的吲哚并吡啶)中公开，为驱动蛋白Eg5的抑制剂，可用于细胞增殖性疾病如肿瘤的治疗。
作为本发明的优选实施方式，所述化合物的结构如式(II)所示，命名为LH031：
作为本发明的优选实施方式，所述药物用于治疗急性胰腺炎。
作为本发明的优选实施方式，所述药物的剂型为口服剂。
作为本发明的优选实施方式，所述口服剂的溶剂为含5％的PEG400的生理盐水溶液。
作为本发明的优选实施方式，所述口服剂的用量为10～40mg/kg。
可根据不同的用药对象，按经验进行剂量调整。
更优选地，所述口服剂的用量为40mg/kg。
本发明首次发现了所述化合物可有效下调血清淀粉酶的含量，对急性胰腺炎具有明显的治疗作用，且其效果优于或者不劣于与现有治疗药物——乌司他丁，可用于开发为治疗急性胰腺炎的新型药物；此外，本发明化合物可制备成口服剂，用药更简单、方便，具有重要的医用前景和经济价值。
附图说明
图1为治疗24h后各组大鼠的体重。
图2为治疗24h后各组大鼠的死亡情况。
图3为治疗24h后各组大鼠的胰腺系数。
图4为治疗24h后各组大鼠的血清淀粉酶含量。
图5为治疗24h后各组大鼠的病理评分。
具体实施方式
为更好的说明本发明的目的、技术方案和优点，下面将结合附图和具体实施例对本发明作进一步说明。
实施例1本发明化合物对大鼠急性胰腺炎的治疗作用
(一)实验方法
造模：取SPF级雄性SD大鼠50只(212～236g)，经麻醉，备皮，消毒，上腹正中剑突下1～2cm处切2～3cm横向切口入腹。确定肝脏、胃、脾，顺胃下找到十二指肠，在胃后部十二指肠肠系膜与脾之间找到胰腺，并沿十二指肠内侧找到透明胆胰管开口以及开口处十二指肠大乳头。在近肝门处用动脉夹结扎肝总管，之后从十二指肠旁斜行进针并调整针头方向使其能够进入胆胰管中，逆行缓慢注射2.5％牛磺胆酸钠1mL/kg，注射速度为0.1mL/min，缝合伤口。此外，另取SPF级雄性SD大鼠10只(212～236g)作为假手术对照组，动物造模时仅开腹后取出胰腺轻轻翻动几次而后放回，不注射牛磺胆酸钠。
将50只造模成功的SD大鼠按体重随机分为5组(模型对照组、LH031低剂量组、LH031中剂量组、LH031高剂量组、阳性对照组)，每组10只，还包括假手术对照组10只SD大鼠。分组后0h、4h、22h分别按表1给予各组动物相应受试物。
表1各组大鼠治疗急性胰腺炎的给药方案
| 组别 | 受试物 | 给药途径 | 给药剂量 | 给药体积 | 给药频率 |
| 假手术对照组 | 生理盐水 | 灌胃口服 | / | 5mL/kg | 3次/日 |
| 模型对照组 | 生理盐水 | 灌胃口服 | / | 5mL/kg | 3次/日 |
| LH031低剂量组 | LH031 | 灌胃口服 | 10mg/kg | 5mL/kg | 3次/日 |
| LH031中剂量组 | LH031 | 灌胃口服 | 20mg/kg | 5mL/kg | 3次/日 |
| LH031高剂量组 | LH031 | 灌胃口服 | 40mg/kg | 5mL/kg | 3次/日 |
| 阳性对照组 | 乌司他丁 | 静脉注射 | 50000U/kg | 5mL/kg | 3次/日 |
注：乌司他丁用生理盐水稀释；LH031各剂量组的溶剂为含5％的PEG400的生理盐水溶液。
分别于造模前、造模并首次给药24h后对大鼠一般状态、体重、动物死亡情况进行观察记录。在首次给药24h后称重、取血并处死大鼠，全血于4℃，3000rpm离心15分钟，取血清检测血清淀粉酶(AMY)。待动物处死后，迅速外科手术开腹，游离出完整的胰腺组织，并称重以计算胰腺系数。肉眼进行大体观察后，取部分胰腺组织进行多聚甲醛固定，HE染色后按病理改变程度评价胰腺损伤。
胰腺系数的计算方法为：胰腺系数＝胰腺重量/体重*100％。
HE染色分别从炎症程度、胰腺腺泡坏死分别考虑病理变化，并按病理改变程度评价胰腺损伤：根据病变由轻到重的程度，依次半定量为极少量或无病变为阴性“-”记0分，轻度或少量“+”记1分，中度或中等量“++”记2分，重度或多量“+++”记3分，极重度或大量“++++”记4分，将每个指标分数统计总分后进行分析。
实验数据由GraphPad Prism 7.0生物统计学软件进行统计学处理：计量数据以Mean±SD表示，采用方差分析结合Dunnett’s多重比较法进行分析。
(二)实验结果
(1)一般状态、体重变化：造模前动物的精神状态均良好，毛色光洁，活动自如，呼吸均匀，摄食量，粪便未见明显异常。造模并首次给药24h后动物精神状态欠佳，毛发竖起，部分大鼠精神萎靡。治疗后，各组小鼠体重如图1所示(正常对照即假手术对照组，下同)，与模型对照组相比，首次给药24h后LH031各剂量组体重均无明显统计学差异(P>0.05，见图1)；
(2)死亡率：造模并首次给药24h后，模型对照组有3只动物死亡，LH031低剂量组有1只动物死亡，LH031中剂量组有1只动物死亡，其余各组没有动物死亡。使用本发明药物治疗显示出降低急性胰腺炎动物的死亡率的趋势，且具有明显的量效关系(见图2)。
(3)胰腺系数：与模型对照组(6.87±0.85)相比，LH031各剂量组胰腺系数均有下降的趋势，其中高剂量组(5.13±0.78)胰腺系数降低最多，且有显著的统计学差异(P＜0.01，见图3)；且高剂量组比阳性对照组降低更多。说明使用本发明药物能有效降低胰腺系数。
(4)血清淀粉酶(AMY)测定：与假手术对照组相比，模型对照组24h的血清淀粉酶含量明显升高(P<0.01)，表明造模成功；与模型对照组(5625.26±1783.35)相比，LH031各剂量组在首次给药24h后的血清淀粉酶均有下降的趋势，且中剂量组(4441.25±1287.09)、高剂量组(4051.8±1298.95)具有统计学差异(P＜0.05，见图4)，且高剂量组与阳性对照组基本一致。说明本发明药物能有效降低血清淀粉酶含量。
(5)病理评分：与假手术对照组相比，模型对照组胰腺HE染色病理评分显著升高(P<0.05)，表明造模成功；与模型对照组(2.56±1.38)相比，LH031各治疗组胰腺HE染色病理评分均有下降的趋势，且中剂量组(1.63±0.6)、高剂量组(1.11±0.67)具有显著的统计学差异(P＜0.01，见图5)。另外，高剂量组与阳性对照组相似。
综上，各实验数据显示，本发明的化合物能显著降低血清淀粉酶的含量，其治疗急性胰腺炎效果与现有药物乌司他丁相似，说明本发明药物能有效治疗急性胰腺炎。
最后应当说明的是，以上实施例仅用以说明本发明的技术方案，而非对本发明保护范围的限制，尽管参照较佳实施例对本发明作了详细地说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而不脱离本发明技术方案的实质和范围。
Claims (5)
1.一种化合物在制备治疗急性胰腺炎的药物中的用途，其特征在于，所述化合物的结构式如式(II)所示：
2.如权利要求1所述的用途，其特征在于，所述药物的剂型为口服剂。
3.如权利要求2所述的用途，其特征在于，所述口服剂的溶剂为含5％的PEG400的生理盐水溶液。
4.如权利要求3所述的用途，其特征在于，所述口服剂的用量为10～40mg/kg。
5.如权利要求4所述的用途，其特征在于，所述口服剂的用量为40mg/kg。
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