CN111671745A - 化合物在治疗溃疡性结肠炎药物制备中的应用 - Google Patents
化合物在治疗溃疡性结肠炎药物制备中的应用 Download PDFInfo
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Abstract
本发明涉及式(I)所示化合物或其药学上可接受的盐在制备治疗肠炎的药物中的应用，
式(I)中，每个R各自独立地为H、C1～C6的烷基、C1～C8的酰基。
Description
技术领域
本发明涉及一种化合物的医药新用途，具体涉及该化合物在治疗溃疡性结肠炎药物制备中的应用。
背景技术
溃疡性结肠炎(ulcerative colitis，UC)是一种主要累及直肠、结肠黏膜和黏膜下层的慢性非特异性炎症性肠病，临床主要表现为腹痛、腹泻、黏液脓血便等。因UC治愈难度大，常易复发，发病率呈逐年升高趋势，有癌变倾向，已被世界卫生组织(WHO)列为现代难治性疾病之一。
关于溃疡性结肠炎的发病机理，医学界存在遗传学说、感染学说、免疫学说等多种争论和猜测，尚无共识和定论，也为如何筛选研发治疗该疾病的药物带来了非常大的困难。一直以来，临床上对于溃疡性结肠炎的药物大多只能提供部分的保护作用，疗效并不显著，且伴随着不同程度的副作用。因此，开发具有治疗溃疡性结肠炎的新型药物具有十分重大的意义。然而，现状是尚没有理想的治疗溃疡性结肠炎的药物。
如式(II)所示结构化合物俗名为苏木酮A，其最初是中药材苏木中提取的化合物，但其在天然的药材中含量非常低，在干燥药材中含量仅仅为0.46ppm左右(参见非专利文献1),并非天然药材公知的活性成分。
由于天然含量太低，上述化合物并未发现其与中药材苏木传统的活血化瘀、消肿止痛的效果有明显关联，但曾作为神经保护剂被广泛报道，有报道称其神经保护作用可能与苏木酮A下调miR-15a表达，从而激活Wnt/β-catenin和PI3K/AKT信号通路有关(参见非专利文献2)。此外，还报道了苏木酮A对顺铂所致的肾损伤有保护作用，可能是通过提高Nrf2表达，从而调控其下游相关基因而发挥抗氧化作用和抗细胞凋亡作用而实现的(参见非专利文献3)。还有报道苏木酮A能抑制AKT/GSK-3β信号通路抑制破骨细胞生成，并对LPS诱导的炎性骨流失具有抑制作用(参见非专利文献4)。
非专利文献1：
Chemical constituents from Sappan Lignum，Y.P.Chen et al.Journal ofChinese Pharmaceutical Sciences.2008，17：82–86
非专利文献2：
Sappanone A prevents hypoxia-induced injury in PC-12 cells by down-regulation of miR-15a.Int J Biol Macromol.2019，15：35-41.
非专利文献3：
Sappanone A Protects Mice Against Cisplatin-Induced Kidney Injury.IntImmunopharmacol.2016，38：246-51.
非专利文献4：
Sappanone A Inhibits RANKL-induced Osteoclastogenesis in BMMs andPrevents Inflammation-Mediated Bone Loss.Int Immunopharmacol.2017，52：230-237.
发明内容
本发明的发明人一直致力研发溃疡性结肠炎治疗药物。在筛选活性化合物时，意外的发现了苏木酮A化合物能够明显的降低由DSS(葡聚糖硫酸钠，dextran sulfatesodium)诱导的肠炎模型中小鼠的肠炎发病程度。
具体而言，所谓DSS诱导肠炎模型，是利用小鼠进行肠炎治疗药物研究的公认模型，其是一个急性的溃疡性肠炎模型，该模型中让小鼠饮用溶解有葡聚糖硫酸钠的饮用水，再换正常饮用水饮用，小鼠会有肠道有溃疡性病变，包括水肿、腹泻和便血，模拟人类溃疡性肠炎。
本发明人进行的药理试验表明，式(II)所示化合物能够显著抑制DSS诱导的小鼠肠道炎症，且活性作用呈剂量依赖性关系。式(II)所示化合物能够减轻肠炎小鼠的便血情况，减轻小鼠结肠受到的损伤，维持结肠长度并保护结肠组织免受炎症损伤。提示了上述式(II)所示化合物的新医药用途，从而为临床治疗结肠炎症提供了新的选择。
本发明的下述式(I)所示化合物可认为是式(II)所示化合物的前药，其在生物体内可以转化为式(II)所示化合物发挥生理活性。具体而言，本发明提供了如下的技术方案：
本发明提供式(I)所示化合物或其药学上可接受的盐在制备治疗肠炎的药物中的应用，
式(I)中，每个R各自独立地为H、C1～C6的烷基、C1～C8的酰基。
Ca～Cb的表达方式代表该基团具有的碳原子数为a～b，除非特殊说明，一般而言该碳原子数不包括取代基的碳原子数。本发明中，对于化学元素的表述，若无特别说明，通常包含化学性质相同的同位素的概念，例如“氢”的表述，也包括化学性质相同的“氘”、“氚”的概念，碳(C)则包括12C、13C等，不再赘述。
具体而言，所谓的C1～C6的烷基，可举出甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、叔戊基、己基、环己基等。优选可以为甲基、乙基等。所谓C1～C8的酰基，可举出甲酰基、乙酰基、丙酰基、苯甲酰基等。
本发明中，R优选为H。从前药的观点看R优选为甲基、乙基、乙酰基、苯甲酰基等。
本发明的发明人，经由药理实验直接证明了式(II)的化合物在溃疡性肠炎治疗方面的有效性，该效果也可以扩展至对一般的肠炎也有治疗作用。
本发明的上述式(I)的化合物可以与其他现有治疗肠炎的化合物共用起到更好的效果，这些现有的化合物，例如可举出柳氮磺胺吡啶、诺氟沙星、氟哌酸、甲硝唑、巴西苏木素、原苏木素A、原苏木素B等。
根据药理实验结果，可以推测本发明的式(I)所示化合物在所述治疗肠炎引起的腹痛、便血、里急后重、肠炎引起的呕吐方面有用，可以起到缓解或治疗的作用。
本发明的式(I)所述化合物可以通过常规的制剂方法给药，例如制成选自片剂、胶囊剂、滴丸剂、颗粒剂、粉剂、口腔膜剂和口服液，或者制成注射剂、膏剂、霜剂、栓剂等，但并不限于这些。从治疗目的和简便程度看，优选将本发明的化合物制成口服制剂。
本发明的化合物制成制剂时，可以配合药学上可以接受的辅料一起使用，这些辅料可例举包括药学领域常规的溶剂(如水、乙醇、丙二醇、注射用油等)、稀释剂(如淀粉、糖粉、糊精、乳糖、预胶化淀粉、微晶纤维、无机钙盐(如硫酸钙、磷酸氢钙、药用碳酸钙等)、甘露醇等、植物油、聚乙二醇等)、粘合剂(如水、乙醇、淀粉浆、羧甲基纤维素钠、羟丙基纤维素、甲基纤维素和乙基纤维素、羟丙甲纤维素等)、崩解剂(如干淀粉、羧甲基淀粉钠、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等)、润滑剂(如硬脂酸镁、微粉硅胶、滑石粉、氢化植物油、聚乙二醇类、月桂醇硫酸镁等)、吸收促进剂(如表面活性剂、Azone(月桂氮卓酮)、EDTA、水杨酸、氨基酸乙胺衍生物、乙酰醋酸酯类、β-二羧酸酯、芳香族酸性化合物、脂肪族酸等)、防腐剂(如苯甲酸、羟丙丁酯、羟丙甲酯、苯酚、间甲酚等)、矫味剂(如蔗糖、甜菊素等)等。但并不限于这些。
在用于治疗肠道炎症时，本发明所述的药物的施用对象为人或哺乳动物。出于此目的，本发明所述药物的摄入的质量或给予的质量，以苏木酮A计，按照成人体重60～70kg计算，通常每人每天摄入120～700mg，更优选的每人每天摄入300～400mg。
本发明提供一种肠炎治疗用组合物，其特征在于，含有上述式(I)所示的化合物和药学上可接受的载体，优选使用式(II)所示化合物直接作为活性成分。本发明的肠炎治疗用组合物的各项说明，可以参照上述本发明式(I)所示化合物在制备治疗肠炎的药物中的应用中的各项说明。
附图说明
图1为示出了DSS诱导的肠炎模型中小鼠DAI各项评分及总评分随时间的变化图。
图2为示出了DSS诱导的肠炎模型中给药最后一天小鼠DAI总评分及结肠长度统计图。
图3为示出了DSS诱导的肠炎模型中各组小鼠结肠照片及HE染色图。
具体实施方式
以下记载证实本发明式(I)所示化合物在治疗肠炎方面的前景的具体实施例。下述实施例中的实验方法，如无特殊说明，均为常规方法。下述实施例中所用的原料、试剂材料等，如无特殊说明，均为市售购买产品。
合成例式(II)所示化合物的获得
由实验室合成所得，其合成方法参见Highly selective inhibition of IMPDH2provides the basis of antineuroinflammation therapy.PNAS.2017:E5986.
经UV、MS、NMR等方法确定其结构，纯度在95％以上。式(II)化合物的波谱学数据如下：
1H NMR(DMSO-d6,500MHz)δH 10.58(brs,1H),9.57(brs,1H),9.21(brs,1H),8.24(s,1H),7.72(d,J＝8.7Hz,1H),7.52(s,1H),6.83(m,2H),6.76(dd,J＝8.3,1.7Hz,1H),6.54(dd,J＝8.7,2.2Hz,1H),6.31(d,J＝2.2Hz,1H),5.35(d,J＝1.6Hz,2H)；and(-)-ESIMSm/z 283.4[M-H]-.
实施例1式(II)所示化合物抑制葡聚糖硫酸钠诱导的小鼠肠道炎症
超纯水(18MΩ·cm-1)由Milli-Q水处理系统处理(美国Millipore公司)；其他试剂均为分析纯，购于北京化工厂。
1.1受试动物：BAL b/c小鼠，6-8周，雄性，
购自北京维通利华实验动物技术有限公司。
1.2受试药物：
5％DSS溶液：称取20g DSS至玻璃瓶中，加入400mL双蒸水，超声混匀。
低剂量式(II)所示化合物(本发明中，有时也简称为SA)溶液(25mg/kg)：称取5mgSA，加入10mL生理盐水，使用前超声混匀，使用时每只小鼠灌胃剂量0.2mL/20g。
高剂量SA溶液(50mg/kg)：称取10mg SA，加入10mL生理盐水，使用前超声混匀，使用时每只小鼠灌胃剂量0.2mL/20g。
1.3动物分组及处理：
Bal b/c小鼠适应性喂养一周后分为四组，每组8只，分别为对照组，DSS组，SA低剂量组(25mg/kg)和SA高剂量组(50mg/kg)。
除对照组外其他三组的喂养用水更换为5％DSS溶液，并每天分别对SA低剂量组和SA高剂量组小鼠灌胃给药，另外两组则给药等体积的0.5％CMC-Na溶液。
每天称量小鼠体重，观察小鼠粪便状态和便血情况，并根据具体现象每项在0～4分范围按DAI评分细则对每只小鼠评分，记录并计算DAI总评分(总分最高12分)，DAI评分规则如表1所示。
表1 DAI评分细则
连续喂养，直至模型组小鼠出现明显便血，禁食12小时，处死小鼠并解剖，取出小鼠结肠，测量其长度，记录，并将部分结肠浸泡在4％多聚甲醛固定，进行HE染色。具体步骤如下：
1)把固定好的各组脑组织脱水、石蜡包埋并切片，每张切片厚4～5μm。
2)双蒸水漂洗3次，每次5min，最后把残余水分除去。
3)用苏木精染色35s，1％HCl酸化5s，此时切片颜色由红变蓝。
4)用水漂洗切片10min，切片颜色变蓝。
5)用0.5％伊红染料染色30s。
6)脱水，再用二甲苯透明，最后用中性树胶封片，用显微镜观察具体组织形态。
1.4试验结果
以下结合附图，对本发明做进一步说明。
图1示出了DSS诱导的肠炎模型中小鼠DAI各项评分及总评分随时间的变化图，其中a图为DAI总分；b图为体重项目评分；c图为便血项目评分；d图为粪便状态评分。每组实验动物数量n＝8，每组实验设置三个重复并取平均值，数据以平均数±标准平均误差(Means±SD)表示。
图2示出了DSS诱导的肠炎模型中给药最后一天小鼠DAI总评分及结肠长度统计图，其中a图为最后一天DAI评分；b图为解剖后小鼠结肠长度统计图。每组实验动物数量n＝8，每组实验设置三个重复并取平均值，数据以平均数±标准平均误差(Means±SD)表示。##：模型组对比对照组，P<0.01；*：给药组对比模型组，P<0.05；**：给药组对比模型组，P<0.01。
图3为示出了DSS诱导的肠炎模型中各组小鼠结肠照片及HE染色图。其中a图为结肠照片(标尺＝2cm)；b图为HE染色(标尺＝0.5mm)。每组实验动物数量n＝8。
肠炎动物实验中，通过每天对饲喂DSS的Bal b/c小鼠进行观察，我们发现如DAI评分所示(图1)，小鼠在喂养7天时粪便上有明显血迹，第8天时，个别小鼠肛门处有明显血迹，而在第13天时，模型组所有小鼠都有明显的便血情况，而且有小鼠状态十分虚弱，因此，实验在第13天结束并解剖所有小鼠。在整个肠炎实验过程中，给予SA对小鼠的体重变化情况影响不大(图1b)，但可以改善小鼠便血和血便情况，而且随着SA给药的剂量增加，小鼠的便血和血便严重程度减弱。
而最后一天DAI综合评分也表明，高浓度的SA能够降低DSS诱导的小鼠肠炎的严重程度(图2a)。将实验小鼠解剖并对其结肠进行详细研究发现，实验小鼠的结肠长度受到肠炎的影响(图2b)。对照组小鼠结肠长度均值最高；模型组因受到肠炎损伤，结肠长度均值最小；SA低剂量组结肠长度均值比模型组大，但没有显著性差异；SA高剂量组结肠长度均值则比模型组明显增大且有显著性差异。
同时，通过观察结肠的外观，我们发现(图3a)，对照组的结肠是皱缩的，颜色较浅；模型组的结肠由于损伤肠壁变薄，形状比较圆润，颜色也因为出血而变深，甚至颜色变黑；而SA高剂量组结肠状态与相近，颜色较浅而且皱缩。最后HE染色结果显示(图3b)，SA高剂量组结肠组织状态与DSS处理组肠壁薄，皱褶消失的状态不同，肠壁仍能保持良好的状态，肠壁较厚，皱褶保持完整，与对照组结肠组织状态相似。
本实施例的结果充分说明：
1)式(II)所示化合物能够有效降低肠炎发病程度；
2)式(II)所示化合物能够显著抑制肠道炎症损伤。
总之，本发明提供了式(II)所示化合物的新医药用途，从而为临床治疗结肠炎症提供了新的选择。
Claims (10)
1.式(I)所示化合物或其药学上可接受的盐在制备治疗肠炎的药物或保健食品中的应用，
式(I)中，每个R各自独立地为H、C1～C6的烷基、C1～C8的酰基。
2.根据权利要求1所述的应用，其特征在于，式(I)所示化合物为下述式(II)所示化合物，
3.根据权利要求1或2所述的应用，其特征在于，所述治疗肠炎的药物还包含选自柳氮磺胺吡啶、诺氟沙星、氟哌酸、甲硝唑、巴西苏木素、原苏木素A、原苏木素B中的一种或多种物质。
4.根据权利要求1或2所述的应用，其特征在于，所述治疗肠炎的药物用于溃疡性结肠炎的治疗。
5.根据权利要求1或2所述的应用，其特征在于，所述治疗肠炎的药物用于治疗或缓解腹痛、便血、里急后重、肠炎引起的呕吐。
6.根据权利要求1或2所述的应用，其特征在于，所述药物是选自片剂、胶囊剂、滴丸剂、颗粒剂、粉剂、口腔膜剂和口服液中的口服制剂；或者为选自注射剂、膏剂、霜剂和栓剂中的非口服制剂。
7.根据权利要求1或2所述的应用，其特征在于，每剂所述药物中包含120～700mg的式(I)所示的化合物。
8.一种肠炎治疗用组合物或保健食品，其特征在于，含有下述式(I)所示的化合物和药学上可接受的载体，
式(I)中，每个R各自独立地为H、C1～C6的烷基、C1～C8的酰基。
9.根据权利要求8所述的组合物，式(I)所示化合物为下述式(II)所示化合物，
10.根据权利要求8所述的组合物，其还包含选自柳氮磺胺吡啶、诺氟沙星、氟哌酸、甲硝唑、巴西苏木素、原苏木素A、原苏木素B中的一种或多种物质。
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1074681A (zh) * | 1992-01-23 | 1993-07-28 | 美国辉瑞有限公司 | 苯并吡喃及有关的白三烯b4拮抗剂 |
| KR101669759B1 (ko) * | 2015-06-03 | 2016-10-26 | 영남대학교 산학협력단 | 히드록시벤질리덴 크로마논계 화합물을 유효성분으로 함유하는 염증성 장질환의 예방 또는 치료용 조성물 |
| CN107050016A (zh) * | 2017-05-22 | 2017-08-18 | 北京大学 | 原苏木素a的医药用途 |
| CN107362160A (zh) * | 2017-08-29 | 2017-11-21 | 湖南源绿科技有限公司 | 苏木酮a在治疗神经退行性疾病中的应用 |
| CN111388460A (zh) * | 2020-01-10 | 2020-07-10 | 北京大学 | 苏木酮a的抗衰老用途 |
-
2020
- 2020-07-29 CN CN202010745465.5A patent/CN111671745A/zh active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1074681A (zh) * | 1992-01-23 | 1993-07-28 | 美国辉瑞有限公司 | 苯并吡喃及有关的白三烯b4拮抗剂 |
| KR101669759B1 (ko) * | 2015-06-03 | 2016-10-26 | 영남대학교 산학협력단 | 히드록시벤질리덴 크로마논계 화합물을 유효성분으로 함유하는 염증성 장질환의 예방 또는 치료용 조성물 |
| CN107050016A (zh) * | 2017-05-22 | 2017-08-18 | 北京大学 | 原苏木素a的医药用途 |
| CN107362160A (zh) * | 2017-08-29 | 2017-11-21 | 湖南源绿科技有限公司 | 苏木酮a在治疗神经退行性疾病中的应用 |
| CN111388460A (zh) * | 2020-01-10 | 2020-07-10 | 北京大学 | 苏木酮a的抗衰老用途 |
Non-Patent Citations (2)
| Title |
|---|
| SUHYUNLEE ET AL.: "Sappanone A exhibits anti-inflammatory effects via modulation of Nrf2 and NF-κB", 《INTERNATIONAL IMMUNOPHARMACOLOGY》 * |
| 沈洪 主编: "《溃疡性结肠炎 中西医的过去、现在与未来》", 30 November 2012 * |
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