CN104311442B - 卤代萘环的丁二酸酰胺衍生物、其制备方法及用途 - Google Patents
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Abstract
本发明涉及与高尿酸血症和痛风相关的药物领域。具体而言，本发明涉及一类卤代萘环的丁二酸酰胺结构的尿酸转运体1抑制剂、其制备方法、及含有它们的药物组合物以及它们在制备糖尿病药物中的应用。
Description
技术领域
本发明涉及治疗高尿酸血症和痛风相关的药物领域。具体而言，本发明涉及对高尿酸血症和痛风有治疗作用的一类含卤代萘环的丁二酸酰胺衍生物的尿酸转运体1(uratetransporter1,URAT1)抑制剂、制备方法、含有它们的药物组合物以及在医药上的用途。
背景技术
痛风是一种慢性代谢性疾病，以高尿酸血症和尿酸单钠盐(MSU)沉积在关节等部位而引起的痛疼为主要特征，主要原因为嘌呤代谢紊乱和/或尿酸排泄障碍。据估计，目前全球痛风患者有2000多万。目前用于治疗痛风的药物包括用于缓解疼痛的抗炎药物(如秋水仙碱等)、抑制尿酸生成药物(以别嘌醇和非布索坦为代表的黄嘌呤氧化酶抑制剂)、粗尿酸排泄药物(以丙磺舒、苯磺唑酮、苯溴马隆和氯沙坦为代表的尿酸排泄药物)和尿酸酶(以pegloticase为代表)。这些药物存在不同的程度的毒副作用，如苯溴马隆有引起爆发性肝炎的危险，别嘌醇有肝脏及骨髓毒性和变态反应等不良反应，等等。
Lesinurad(RDEA594)是一种由Ardea公司研制的可以抑制肾脏中尿酸转运体(uratetransporter1,URAT1)而通过尿液的途径来排出血液中尿酸的口服药物，目前处于III期临床阶段。Lesinurad最早由Valeant公司研发的抗病毒药物RDEA806发展而来。现在Lesinurad的所有权目前由于Ardea公司被收购而属于AstraZeneca。
本发明公开了一类卤代萘环的丁二酸酰胺衍生物的URAT1抑制剂，这些化合物可用于制备治疗高尿酸血症和痛风的药物。
发明内容
本发明的一个目的是提供一种具有良好活性，具有通式I的一类化合物。
本发明的另一个目的是提供制备具有通式I的化合物的方法。
本发明的再一个目的是提供含有通式I的化合物作为有效成分，以及一种或多种药学上可接受的载体、赋形剂或稀释剂的药用组合物，及其在治疗痛风方面的应用。
现结合本发明的目的对本发明内容进行具体描述。
本发明具有通式I的化合物及其药学上可以接受的前药酯具有下述结构式：
(I)
其中，R1选自卤素取代基；
R2选自H，C1-C5的烷基，C3-C6环烷基。
优选：R1选自F、Cl、Br、I取代基；
R2选自C1-C4的烷基，C3-C4环烷基。
优选通式I的化合物具有以下结构，
。
更优选通式I的化合物具有以下结构，
。
进一步选自下列化合物，
。
本发明所述通式I化合物通过以下路线合成：
。
化合物II用与丁二酸单甲酯III在缩合剂存在下缩合，得到化合物IV；化合物IV在碱存在下水解得到化合物V；化合物V与化合物R2NH(VI)在缩合剂存在下缩合，得到产物I。所述缩合剂选自DCC、EDC、TBTU和HATU等。所述R1、R2的定义如前所述。
本发明所述通式I化合物具有URAT1的抑制作用，可作为有效成分用于制备高尿酸血症和痛风的治疗药物。本发明所述通式I化合物的活性是通过受体结合试验来验证。
本发明的通式I化合物在相当宽的剂量范围内是有效的。例如每天服用的剂量约在1mg-500mg/人范围内，分为一次或数次给药。实际服用本发明通式I化合物的剂量可由医生根据有关的情况来决定。
具体实施方式
下面结合实施例对本发明作进一步的说明。需要说明的是，下述实施例仅是用于说明，而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。
实施例1
。
A.化合物IV-1的合成
3.54g(20mmol)化合物II-1和2.64g(20mmol)化合物III溶于50mL干燥的THF中，冰水浴冷却下搅拌，加入二环己基碳化二亚胺(DCC)4.13g(20mmol)和4-二甲氨基吡啶(DMAP)0.61g(5mmol)，而后室温下搅拌，直到TLC检测反应完成(12h以内)。反应混合物倾倒到300mL冰水中，搅拌，使用100mL×3的CH2Cl2萃取，合并萃取相，依次使用100mL1%的稀盐酸和100mL5%的盐水洗涤，无水硫酸钠干燥。抽滤除去干燥剂，滤液在旋转蒸发仪上蒸干，得到的残余物使用柱层析纯化，得到化合物IV-1，白色固体，ESI-MS,m/z=314([M+Na]+)。
B.化合物V-1的合成
化合物IV-14.36g(15mmol)溶于30mL无水甲醇中，室温下搅拌，加入3mL10%的LiOH溶液，而后室温下继续搅拌，直到TLC检测反应完成(5h以内)。
反应混合物倾倒到200mL冰水中，搅拌，用浓盐酸调节pH=2-3。使用100mL×3的CH2Cl2萃取，合并萃取相，使用100mL5%的盐水洗涤，无水硫酸钠干燥。抽滤除去干燥剂，滤液在旋转蒸发仪上蒸干，得到的残余物使用柱层析纯化(短柱)，得到化合物V-1,白色固体，ESI-MS,m/z=276([M-H]-)。
C.化合物I-1的合成
2.77g(10mmol)化合物V-1和0.73g(10mmol)化合物VI-1溶于30mL干燥的THF中，冰水浴冷却下搅拌，加入二环己基碳化二亚胺(DCC)2.06g(10mmol)和4-二甲氨基吡啶(DMAP)0.61g(5mmol)，而后室温下搅拌，直到TLC检测反应完成(12h以内)。反应混合物倾倒到200mL冰水中，搅拌，使用70mL×3的CH2Cl2萃取，合并萃取相，依次使用100mL1%的稀盐酸和100mL5%的盐水洗涤，无水硫酸钠干燥。抽滤除去干燥剂，滤液在旋转蒸发仪上蒸干，得到的残余物使用柱层析纯化，得到化合物I-1,黄白色固体。ESI-MS,m/z=350([M+NH4]+)。
实施例2-13
参照实施例1的操作步骤，制备了下表所列化合物。
实施例14
本发明所述的化合物及相关化合物对URAT1抑制的IC50值按照文献记载的类似的方法测定(US2014/0005136中实施例12)。结果如下列表所示。
构建稳定表达人源化URAT1转运体的细胞株：将人源化URAT1基因(SLC22A112)从质粒pCMV6-XL-5(Origene)亚克隆到真核表达的质粒pCMV6/neo(Origene)上。基因测序证实了人源化URAT1与基因库中记录的信息一致(NM_144585.2)。HEK293人胚胎肾细胞(ATCC#CRL-1573)在EMEM组织培养液中在5%的CO2和95%的空气气氛中培养。使用L2000型转染剂(Invitrogene)将pCMV6/Neo/URAT1转染到HEK293细胞上。24小时后，将被转染的细胞分到直径为10cm的组织培养皿中，继续生长一天，而后将培养基更换为含有0.5mg/mLG418(Gibco)的新鲜的培养基。8天后，选择并收集耐药性菌落，并用其测试对14C-标记的尿酸的转运活性。将HEK293/URAT1细胞以75,000/孔的密度种植于聚D-赖氨酸覆盖的96孔板上。
这些细胞在培养箱中37°C下生长过夜，而后冷却到室温下，其中的培养液使用250μL/孔的清洗液洗涤一次(125mM葡萄糖酸钠、pH=7.3的10mMHEPES)。将待测化合物或者空白对照加到含有40μM的14C-标记尿酸(54mCi/mmol)的缓冲液中，所述缓冲液含有125mM葡萄糖酸钠、4.8mM葡萄糖酸钾、1.2mM磷酸二氢钾、1.2mM硫酸镁、1.3mM葡萄糖酸钙、5.6mM葡萄糖、25mMHEPES，最终pH=7.3。96孔板在室温下培养10分钟，接着依次用50μL/孔和250μL/孔的上述清洗液各清洗三次。在96孔板上加入Microscint20型液闪剂，板子在45°C下培养过夜，而后在TopCountPlateReader上读数，并据此计算IC50。结果如下列表所示：
。
上述IC50的测定结果表明，本发明的化合物均表现出较好的URAT1抑制剂，可以用来制备治疗高尿酸血症和痛风的药物。
Claims (6)
1.具有通式I结构的化合物，
其中，R1选自卤素取代基；
R2选自H，C1-C5的烷基，C3-C6环烷基。
2.权利要求1所定义的具有通式I的化合物，
其中，R1选自F、Cl、Br、I取代基；
R2选自C1-C4的烷基，C3-C4环烷基。
3.权利要求2所定义的通式I化合物，选自下列化合物，
4.权利要求3所定义的通式I化合物，进一步选自下列化合物，
5.权利要求4所定义的通式I化合物，进一步选自下列化合物，
6.权利要求1-5任一项所定义的通式I化合物在制备治疗高尿酸血症和痛风药物方面的应用。
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| WO2014065413A1 (ja) * | 2012-10-26 | 2014-05-01 | 日本たばこ産業株式会社 | トリアゾール・イソオキサゾール化合物およびその医薬用途 |
| WO2014131374A1 (es) * | 2013-02-28 | 2014-09-04 | Centro De Neurociencias De Cuba (Neuronic) | Chaperoninas químicas como nuevos moduladores moleculares de la beta agregación proteica presente en las enfermedades conformacionales |
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| WO2014065413A1 (ja) * | 2012-10-26 | 2014-05-01 | 日本たばこ産業株式会社 | トリアゾール・イソオキサゾール化合物およびその医薬用途 |
| WO2014131374A1 (es) * | 2013-02-28 | 2014-09-04 | Centro De Neurociencias De Cuba (Neuronic) | Chaperoninas químicas como nuevos moduladores moleculares de la beta agregación proteica presente en las enfermedades conformacionales |
| CN103588660A (zh) * | 2013-11-18 | 2014-02-19 | 中国医学科学院生物医学工程研究所 | 一种新型的酰基苯胺化合物及用途 |
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