CN109666053A - 一种a3腺苷受体激动剂及其用途 - Google Patents
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Abstract
本发明提供式(I)化合物，一种A3腺苷受体激动剂，其立体异构体、互变异构体或药学上可接受的盐，其作为A3腺苷受体激动剂及其在制备治疗由A3腺苷受体所致疾病的药物或药物组合物中的应用，本发明公开的化合物，在肿瘤治疗领域具有广泛的应用前景。
Description
技术领域
本发明涉及治疗领域，并且尤其涉及用于诱导肝细胞分化和肝再生的方法。
背景技术
近年来，肝切除术已变得安全，这是由于术前诊断、手术技术以及术后护理的改善。术后死亡率直接与术前肝功能和切除的肝体积有关。在具有正常肝实质的患者中，残余肝脏的功能快速恢复，因为肝细胞会增殖以恢复体积的损失。然而，在存在实质性肝病的条件下，如在患有肝硬化、严重肝脂肪变性或结肠直肠肝转移、在肝切除术以前由于新辅助化学疗法而导致虚弱的患者中，肝细胞增殖会受损，这使患者暴露于肝功能障碍和有关的并发症，以肝切除术后肝衰竭为终结，其具有高死亡率(60-90％)。
除脑以外，肝是仅有的重要器官，对其没有药理、机械、或体外方式来支持衰退的器官，如针对肺、肾以及心脏所发现的。肝还是独特的，因为它是仅有的哺乳动物器官，在切除或损伤以后其可以再生它的生物功能实质质量(薄壁组织质量)，而不是借助于生物上无功能的瘢痕组织加以愈合。
在再生肝方面，已鉴定了多种途径，包括细胞因子途径，其很大程度上负责肝细胞进入细胞周期(从G0过渡到G1)，一种称作引发的过程；以及生长因子途径，其负责细胞周期进展(G1期到S期)。
此外，肝的局部缺血-再灌注损伤是另一种已知的、外科手术的临床意义的表现，如肝移植和部分肝切除。在局部缺血再灌注损伤以后，存在肝损伤的两个不同时期。初期(再灌注以后＜2h)的特征在于氧化应激，其中活性氧物质(ROS)的生产和释放似乎直接导致肝细胞损伤。后期(再灌注以后6-48h)是由征集的中性白细胞(嗜中性粒细胞)所介导的炎性障碍。活化的肝巨噬细胞(枯否细胞，Kupffer cell)与中性白细胞的产物之间的相互关系，如肿瘤坏死因子(TNF-α)、白细胞介素(IL)-1、一氧化氮(NO)以及白三烯，与肝局部缺血再灌注损伤的发病机制有关。TNF-α的生物效应从诱导细胞死亡延伸到促进细胞再生。
确实，最近的研究已表明，在部分肝IR损伤的鼠科动物模型中，在随后的局部缺血再灌注的2h内，局部缺血预处理可以伴随肝细胞进入细胞周期。
腺苷，通过其与选择性G蛋白相关的膜受体的结合，命名为A1、A2A、A2B以及A3，在局部缺血以后能细胞外积累，并且已知能提供细胞保护。尤其是，已发现A3AR涉及介导心脏神经和化疗保护。
已提出A3腺苷受体，一种Gi蛋白相关的细胞表面受体，作为对抗癌症和炎症的标靶。该受体在各种肿瘤细胞类型中被高度表达，而在相邻的正常组织中则呈现低表达。体内研究已表明，A3AR激动剂会抑制结肠、***和胰腺癌以及黑色素瘤和肝细胞癌的发展。
A3AR激动剂还表明可以作为抗炎剂，其中通过在不同实验性自身免疫性模型中改善炎症过程，如类风湿性关节炎、多发性硬化以及克罗恩氏病。
此外，A3AR激动剂已经显示出对肿瘤和正常细胞生长具有不同的效应。虽然A 3AR的激活会抑制各种肿瘤细胞系的生长，但它会刺激正常细胞如骨髓细胞的增殖。
目前，在这种重要器官的急性或慢性损伤以后，没有药物干预被证明减弱肝细胞损伤或增加肝的组织再生。Can-Fite生物制药公司宣布治疗肝细胞癌(HCC)新药CF102的II期临床试验正式开始首例患者的治疗。该随机，双盲，安慰剂对照的II期临床研究将在美国，欧洲和以色列共招募78名HCC患者。该研究将评估索拉非尼一线治疗失败后，Child-Pugh B级晚期HCC患者接受CF102治疗的有效性和安全性，主要研究终点是总体生存期。这项II期临床试验是基于Can-Fite公司之前一项I/II期临床试验的有利数据。该I/II期临床试验中，18名晚期原发性HCC患者口服CF102，总生存期为7.8个月(67％之前接受过索拉非尼治疗)，Child-Pugh B级患者(28％)为8.1个月。4例患者疾病稳定超过4个月，1例HCC引起的转移性皮肤结节在3个月治疗期间完全消退。
CF102是一个口服有效的，高选择性和高亲和力的A3腺苷受体(A3AR)激动剂。但是该临床研究药物还存在诸多的缺点，为了克服CF102的缺点，本发明设计了一种如通式化合物I的A3AR激动剂。
发明内容
本发明提供一种式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，
其中，R1为选自氢，卤素，氰基，氨基，酰胺基，羟基，酯基，酰基，酰氧基，磺酰基，亚磺酰基，烷基，烷氧基，芳基，环烷基，杂芳基，杂环基，杂环基烷基；
R2，R3独立地为卤素。
本发明所述的式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，其中包括通式(II)化合物
其中，R1为C1～C6烷基，环烷基。
本发明所述化合物，其立体异构体，互变异构体或药学上可接受的盐，作为A3腺苷受体激动剂，在制备治疗由A3腺苷受体介导疾病的药物或药物组合物中的应用。
本发明所述的药物或药物组合物，其用于各种癌症的治疗。
本发明所述，治疗的各种癌症包括：肝癌，肺癌，食管癌，胃癌，肾细胞癌，肉瘤，胆管癌，结肠癌，***癌，卵巢癌，乳腺癌。
具体实施方式：
下面用实施例来进一步说明本发明，但本发明并不受其限制。
实施例1：
本发明按照文献WO2013111132提供类似试验方案，制备到化合物1，ESI-MS：m/z：571.3[M+H]+。
生物测试结果：按照文献WO2013111132提供的生物测试方法，本发明化合物1与文献中的活性比较如下：(IC50，nM)
| 化合物名称 | A3 | A1 | A2A | A2B |
| 化合物1 | 0.11 | 无活性 | 无活性 | 无活性 |
| IB-MECA | 0.68 | >1000 | 685 | 47600 |
| CI-IB-MECA | 0.717 | 5390 | 2090 | 无活性 |
可以看出，本发明化合物1对A3受体的活性极高，分别为IB-MECA和CI-IB-MECA的6倍和7倍左右，并且对另外三个亚型均没有活性。
Claims (5)
1.一种式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，
其中，R1为选自氢，卤素，氰基，氨基，酰胺基，羟基，酯基，酰基，酰氧基，磺酰基，亚磺酰基，烷基，烷氧基，芳基，环烷基，杂芳基，杂环基，杂环基烷基；
R2，R3独立地为卤素。
2.如权利要求1所述的式(I)化合物，其立体异构体，互变异构体或药学上可接受的盐，其中包括通式(II)化合物
其中，R1为C1～C6烷基，环烷基。
3.如权利要求1至2中任一项所述化合物，其立体异构体，互变异构体或药学上可接受的盐，作为A3腺苷受体激动剂，在制备治疗由A3腺苷受体介导疾病的药物或药物组合物中的应用。
4.如权利要求3所述的药物或药物组合物，其用于各种癌症的治疗。
5.如权利要求4所述，治疗的各种癌症包括：肝癌，肺癌，食管癌，胃癌，肾细胞癌，肉瘤，胆管癌，结肠癌，***癌，卵巢癌，乳腺癌。
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