CN111973599A - 用于眼部疾病治疗的化合物 - Google Patents
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Abstract
本发明提供式(I)的化合物或其盐在制备用于预防或治疗眼部疾病，尤其是葡萄膜炎中的用途。特别是当式(I)中X为N，R为乙基时的化合物(Ia)，在葡萄膜炎模型中，安全性和耐受性良好，表现出较好的疗效。
Description
技术领域
本发明涉及一种药物的新用途，特别涉及式(I)化合物、其盐或组合物在制备预防和/或治疗眼部疾病，尤其是葡萄膜炎的药物中的用途。
背景技术
葡萄膜炎(uveitis)又称色素膜炎，是虹膜、睫状体及脉络膜组织炎症的总称，常累及视网膜和前房及玻璃体内的液体。葡萄膜炎的症状包括眼部发红、视力模糊、畏光、视觉中漂浮的黑斑和眼部疼痛。葡萄膜炎可引起严重的并发症，如白内障、青光眼、带状角膜病变、视网膜水肿、永久性视力丧失等，是主要的致盲原因之一。近年来的研究表明其发病率在不断上升。
滴眼剂，尤其是糖皮质类固醇(例如，醋酸泼尼松龙)和扩瞳剂，或采用泼尼松龙片的口服治疗是用于减轻葡萄膜炎中的炎症和疼痛的药物疗法。此外可以使用局部睫状肌麻痹剂，诸如阿托品或后马托品。对于较深的炎症，使用类固醇或免疫抑制剂的口服用药或眼周注射。还经常使用抗代谢物药物疗法，诸如甲氨蝶呤，用于葡萄膜炎的顽固病例或侵袭性较强的病例。葡萄膜炎的发病机制尚不完全清楚，目前的治疗效果不够理想。为更好地预防或治疗该疾病，需要进一步研究开发新的药物。
发明内容
本发明的目的在于提供式(I)化合物在制备用于预防或治疗眼部疾病，特别是葡萄膜炎的药物中的用途。葡萄膜炎临床前药效评价结果表明，式(I)化合物可安全有效地降低疾病严重程度，为葡萄膜炎的预防或治疗提供了新的潜在治疗途径，增加葡萄膜炎的治疗选择。
本发明的目的可以通过以下技术方案实现：
本发明提供式(I)的化合物或其盐在制备用于预防和/或治疗眼部疾病的药物中的用途：
其中，X选自CH或N；R选自乙基、乙烯基或环丙基。
作为一个实施方式，本发明提供的用途包括向受试者施用含有下式(Ia)所示的药物：
本申请发明人发现，包含(Ia)化合物的药物在用于治疗眼部疾病，尤其是治疗葡萄膜炎时，表现出较好的药效和安全性。(Ia)化合物在牛IRBP R16诱导的Lewis大鼠实验性自身免疫型葡萄膜炎模型中，30mg/kg和90mg/kg剂量组对大鼠体重无明显影响，表现出良好的安全性和耐受性。同时，(Ia)化合物两个剂量组早期临床评分显著低于溶媒组，表现出较好的治疗效果。
作为一个实施方式，向受试者施用式(I)化合物的磷酸盐以实现本发明提供的用途。
在本发明的一些实施方案中，眼部疾病选自结膜炎、虹膜炎、眼色素层炎、角膜炎、巩膜炎、视神经炎和视网膜血管炎。
在具体的实施方案中，眼部疾病选自葡萄膜炎。所述的葡萄膜炎包括全葡萄膜炎、前部葡萄膜炎、中间葡萄膜炎和后部葡萄膜炎。
本发明同时提供一种用于治疗葡萄膜炎的组合物，该组合物包含有效量的式(I)化合物或其盐。
本发明用途中使用的化合物可单独被给用，或它们可在药物组合物中被给用。药物组合物除式(I)化合物及其盐外，还包括一种或多种可药用的载体、稀释剂或赋形剂。载体、稀释剂或赋形剂必须与制剂中的其它组分是相容的，并且对其接受者是无害的。
本发明提供的组合物为胶囊、滴眼剂或注射液，其中滴眼剂包括眼用乳剂或溶液。
本发明的用途还可与其它的眼部疾病的治疗组合使用。当采用组合治疗时，治疗剂可以一起给用或分开给用。组合治疗中的多于一种的治疗剂可采用相同或不同的给药方式。当治疗剂分开给用时，它们可以同时地或以任何顺序给用。式(I)的化合物和/或其它的一种或多种药学活性剂和给用的相对时间可以为了实现所需的组合疗效而进行选择。
术语“治疗”是指与疾病相关的一种或多种症状可被有利改变所采用的任何方式。因此，该术语包括治愈、预防或改善疾病的症状或副作用，或降低疾病进展速率。
附图说明
图1为大鼠体重变化结果图；
图2为大鼠葡萄膜炎临床评分结果图。
具体实施方式
为了更好地理解本发明的内容，下面结合具体实施例对本发明的技术方案做进一步的说明，但具体的实施方式并不意味着对本发明有任何限制。
Ia为参照专利CN201710055590.1中制备方法制得，其他试剂或材料市售购得。
实施例
1、试剂与动物信息
试剂：牛感光素类视黄醇结合蛋白(IRBP)肽R16、肺结核菌株H37Ra、不完全弗氏佐剂；
溶媒：0.5％甲基纤维素(MC)；
动物：SPF雌性Lewis大鼠，6-8周龄。
2、葡萄膜炎模型构建
将100mg肺结核菌株H37Ra用研钵压成细粉，与40mL不完全弗氏佐剂混合，得到含2.5mg/mL肺结核菌株H37Ra的弗氏完全佐剂(CFA)，分别取等体积的600μg/mL牛IRBP多肽R16和CFA进行充分混合，得到300μg/mL的多组分乳剂。使用1mL玻璃注射器将0.2mL乳剂对大鼠两只大腿(各50μL)及大鼠尾部(100μL)分三次进行皮下注射，从而诱导葡萄膜炎。根据每日的临床疾病评分判断造模成功。IRBP免疫大鼠自诱导后第3天开始给药，免疫的这一天被定义为第0天。
3、样品溶液配制
配制Ia化合物的0.5％MC溶液，使之呈白色均一混悬液。随后进行梯度稀释，得到低浓度样品溶液。
4、给药及记录
按表1对大鼠随机分组及给药，给药后每周记录体重三次。
表1动物分组及给药
5、临床评价
免疫后，从第3天开始，每天用眼底镜检查大鼠的眼睛，从发病到研究结束。临床症状以双盲的方式进行评分，评分标准如表2。将大鼠两眼临床评分相加，取各组平均值得到每组评分结果。
表2大鼠葡萄膜炎临床评分标准
| 级别 | 评分标准 |
| 0 | 无疾病症状；眼组织呈现正常的透明度和光反射(红光反射) |
| 0.5(轻微) | 虹膜上血管增粗 |
| 1 | 虹膜上遍布血管；瞳孔反射异常 |
| 2 | 前房模糊；红光反射降低 |
| 3 | 前房水呈现严重浑浊，但是瞳孔可见；红光反射迟钝 |
| 4 | 前房水严重浑浊且遮蔽瞳孔；红光反射消失；眼球突出 |
实验结果
1、大鼠体重变化结果，见表3和图1。
表3大鼠体重变化
结果显示，大鼠体重未见明显异常，给药期间未发生严重不良反应，表明本发明化合物Ia在低剂量和高剂量下均具有较好的安全性和耐受性。
2、大鼠葡萄膜炎临床评分结果见表4和图2。
表4大鼠葡萄膜炎临床评分
结果显示，低剂量和高剂量的(Ia)化合物临床评分显著低于溶媒组，在疾病初期疗效尤为明显，表现出较好的疗效。
需要指出的是，以上实施例是对本发明技术方案作的进一步非限制的详细说明，仅为说明本发明的技术构思和特点。其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡如本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。
Claims (8)
1.式(I)的化合物或其盐在制备预防和/或治疗眼部疾病的药物中的用途：
其中，X选自CH或N；R选自乙基、乙烯基或环丙基。
2.如权利要求1所述的用途，其特征在于：所述化合物为下式(Ia)的结构：
3.如权利要求1所述的用途，其特征在于：所述的盐为磷酸盐。
4.如权利要求1所述的用途，其特征在于：所述的眼部疾病选自结膜炎、虹膜炎、眼色素层炎、角膜炎、巩膜炎、视神经炎和视网膜血管炎。
5.如权利要求1所述的用途，其特征在于：所述的眼部疾病选自葡萄膜炎。
6.如权利要求1所述的用途，其特征在于：所述的葡萄膜炎包括全葡萄膜炎、前部葡萄膜炎、中间葡萄膜炎和后部葡萄膜炎。
7.一种用于治疗葡萄膜炎的组合物，其特征在于：包含有效量的式(I)化合物或其盐。
8.如权利要求7所述的组合物，其特征在于：所述组合物为胶囊、滴眼剂或注射液，其中滴眼剂包括眼用乳剂或溶液。
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| CN114767685A (zh) * | 2022-04-25 | 2022-07-22 | 北京大学第三医院（北京大学第三临床医学院） | 四氢叶酸在抑菌或者预防或治疗眼部疾病中的用途 |
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| CN106905322A (zh) * | 2016-01-26 | 2017-06-30 | 杭州华东医药集团新药研究院有限公司 | 吡咯嘧啶五元氮杂环衍生物及其应用 |
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| CN114767685A (zh) * | 2022-04-25 | 2022-07-22 | 北京大学第三医院（北京大学第三临床医学院） | 四氢叶酸在抑菌或者预防或治疗眼部疾病中的用途 |
| CN114767685B (zh) * | 2022-04-25 | 2023-10-20 | 北京大学第三医院（北京大学第三临床医学院） | 四氢叶酸在抑菌或者预防或治疗眼部疾病中的用途 |
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