CN106045898A - 一种吲哚类化合物及其制备方法和用途 - Google Patents
一种吲哚类化合物及其制备方法和用途 Download PDFInfo
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- CN106045898A CN106045898A CN201610503306.8A CN201610503306A CN106045898A CN 106045898 A CN106045898 A CN 106045898A CN 201610503306 A CN201610503306 A CN 201610503306A CN 106045898 A CN106045898 A CN 106045898A
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- hyperuricemia
- pharmaceutical composition
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- uric acid
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明涉及一种吲哚类化合物，以及包含该化合物的药物组合物。所述化合物或药物组合物可用于抑制尿酸盐阴离子转运体1。本发明还涉及制备这类化合物和药物组合物的方法，以及它们在治疗或预防哺乳动物，特别是人类的与血液中尿酸值偏高有关的疾病的用途。
Description
技术领域
本发明属于药物技术领域，具体涉及一类化合物、组合物及其制备方法和用途，其中所述的化合物或组合物具有抑制尿酸盐阴离子转运体1活性的用途，并可用于预防或治疗与血液中尿酸值偏高有关的疾病。
背景技术
尿酸是人类嘌呤化合物的终末代谢产物。在人类中，尿酸主要经肾脏排泄，其排泄量占总排泄量的近三分之二。当尿酸产生过多或者排泄障碍，使尿酸蓄积引发人体内血液中尿酸浓度升高，进而导致高尿酸血症。在正常嘌呤饮食状态下，非同日两次空腹血尿酸水平男性高于420μmol/L，女性高于360μmol/L，即为高尿酸血症。
随着血液中尿酸浓度过饱和，尿酸钠盐开始形成结晶并沉积在关节滑膜、滑囊、软骨及其他组织中，当体内尿酸水平发生快速变化、局部创伤引起微小晶体释放或尿酸盐晶体蛋白包衣发生改变时，引起反复发作性炎性反应，继而诱发痛风。痛风特指急性特征关节炎和慢性痛风石疾病，主要包括急性发作性关节炎、痛风石形成、痛风石性慢性关节炎、尿酸盐肾病和尿酸性尿路结石，重者可出现关节残疾和肾功能不全。此外，痛风还与高血压、代谢综合征、高脂血症、糖尿病和胰岛素抵抗等多种病症相关(Terkeltaub RA.Clinicalpractice.Gout[J].N Engl J Med.2003,349:1647-1655)(Schlesinger N,Schumacher HRJr.Gort:can management be improved？[J].Curr Opin Rheumatol.2001,13:240-244)。
高尿酸血症和痛风是危害人类健康的严重的代谢性疾病；有数据表明，约5％-12％的高尿酸血症患者最终发展为痛风。尿酸是高尿酸血症及痛风发生的物质基础，因此，降低血液中尿酸浓度可用于预防或治疗高尿酸血症和痛风，并降低罹患其他高尿酸血症及通风并发症的风险。
研究表明，约90％的高尿酸血症是由尿酸排泄减少引起，尿酸在肾脏的排泄主要包括4个过程：肾小球的虑过、肾小管和集合管的重吸收、肾小管和集合管分泌以及分泌后的重吸收，每个过程都是由相应的蛋白参与完成，最后仅有8％-12％的尿酸排出体外(刘若霞，臧路平，吴新荣，山东医药[J]，2012年第52卷第28期)。尿酸盐阴离子转运体1(URAT1)是由Enomoto等发现的位于肾近曲小管上皮细胞刷状缘侧，参与尿酸在肾近曲小管的重吸收的一种跨膜转运蛋白。hURAT1由染色体11q13上的SLC22A12基因编码，含有10个外显子和9个内含子，由555个氨基酸残基，12个跨膜结构以及位于细胞内部的-NH2和-COOH末端组成。研究发现肾性低尿酸血症患者携带的SLC22A12基因发生突变，丧失编码URAT1成熟蛋白的能力，由此确定URAT1是肾性低尿酸血症的致病基因(Enomoto,Kimura H,Chairoungdua A,et al.Molecular identification of a renal urate anion exchanger thatregulates blood urate levels[J].Nature,2002,417(6887):447-452)，其对肾脏的尿酸重吸收功能具有重要意义且与血液中尿酸值的调控密切相关。
因此，具有URAT1抑制活性的物质可促进血中尿酸的排泄，用于治疗和预防与血液中尿酸值偏高有关的疾病，包括高尿酸血症、痛风、痛风石、痛风性关节炎、高尿酸血症相关性肾障碍、尿路结石等等。
这类药物已经成为治疗高尿酸血症、痛风及与高尿酸血症相关的疾病的研发热点。
发明内容
本发明提供了一类具有URAT1抑制活性的化合物，用于制备预防或治疗与血液中尿酸值偏高有关的疾病，比如高尿酸血症、痛风石、痛风性关节炎、与高尿酸血症有关的肾脏障碍和尿石症等；本发明化合物能够很好地抑制URAT1，同时具有优良的理化性质以及药代动力学性质。
本发明也提供了这些化合物的制备方法。
具体地说：
一方面，本发明涉及一种如式(I)所示的化合物或式(I)所示化合物的立体异构体，几何异构体，互变异构体，氮氧化物，水合物，溶剂化物，代谢产物，酯，药学上可接受的盐或它的前药，
其中，
Q为氰基、硝基、三氟甲基或羧酸；
Ra、Rb、Rc、Rd和Re各自独立地为H、氘、氟、氯、溴、碘、甲基、乙基、异丙基、甲氧基、三氟甲基、羟基、氨基、甲氨基、二甲氨基、硝基或氰基；
R1和R2各自独立地为H、氘、氟、氯、溴、甲基、乙基、三氟甲基、甲氧基、氨基、甲氨基、二甲氨基、硝基、氰基或羟基；和
R3和R4各自独立地为H、氘、氟、氯、溴或甲基。
另一方面，本发明涉及一种药物组合物，该药物组合物包含上述公开的化合物及其药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物或它们的组合。
在一些实施例中，本发明所述的药物组合物，进一步地包含其他预防或治疗高尿酸血症、痛风石、痛风性关节炎、与高尿酸血症有关的肾脏障碍和尿石症的药物，所述药物为秋水仙碱、非甾体抗炎药、糖皮质激素、抑制尿酸生成药、促尿酸排泄药、尿碱化剂或它们的任意组合。
在另一些实施例中，本发明所述的药物组合物，进一步地包含其他预防或治疗高尿酸血症、痛风石、痛风性关节炎、与高尿酸血症有关的肾脏障碍和尿石症的药物，所述药物秋水仙碱、吲哚美辛、依托考昔、双氯芬酸、布洛芬、罗非昔布、塞来昔布、美洛昔康、强的松、琥珀酸氢化考的松、别嘌醇、丙磺舒、苯磺唑酮、苯溴马隆、奥昔嘌醇、非布索坦、重组黄曲霉菌尿酸氧化酶、聚乙二醇化重组尿酸氧化酶、碳酸氢钠片、枸橼酸钾钠合剂或它们的任意组合。
另一方面，本发明涉及上述公开的化合物或其药物组合物在制备药物中的用途，所述药物用于预防或治疗哺乳动物，包括人类的高尿酸血症、痛风石、痛风性关节炎、与高尿酸血症有关的肾脏障碍和尿石症。
另一方面，本发明涉及上述公开的化合物或其药物组合物在制备药物中的用途，所述药物用于降低血液中尿酸水平。
另一方面，本发明涉及上述公开的化合物或其药物组合物在制备药物中的用途，所述药物用于在受试对象内抑制尿酸盐阴离子转运体1。
另一方面，本发明涉及上述公开的化合物的制备、分离和纯化的方法。
生物试验结果表明，本发明提供的化合物可作为较好的尿酸盐阴离子转运体1抑制剂。
本发明的任一方面的任一实施方案，可以与其它实施方案进行组合，只要它们不会出现矛盾。此外，在本发明任一方面的任一实施方案中，任一技术特征可以适用于其它实施方案中的该技术特征，只要它们不会出现矛盾。
定义和一般术语
在本发明中，各术语具有如下含义，除非另有说明。
术语“药学上可接受的盐”是指本发明的化合物的有机盐或无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describepharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐有盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过适当的碱得到的盐包括碱金属，碱土金属，铵和N+(C1-4烷基)4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C1-8磺酸化物和芳香磺酸化物。
术语“组合物”是指包含规定量的规定成分的产物，以及规定量的规定成分的组合所直接或间接地产生的任何产物。与药物组合物相关的这种术语的含义包括包含活性成分(单个或者多个)和组成载体的惰性成分(单个或者多个)的产物，以及由任何两种或多种成分混合、复合或聚集，或者由一种或多种成分分解，或者由一种或多种成分的其他类型的反应或相互作用而直接或间接产生的任何产物。因此，本发明药物组合物包括通过将本发明化合物与可药用载体混合而制备的任何组合物。
另外，本发明公开的化合物、包括它们的盐，也可以以它们的水合物形式或包含其溶剂(例如乙醇、DMSO，等等)的形式得到，用于它们的结晶。本发明公开化合物可以与药学上可接受的溶剂(包括水)固有地或通过设计形成溶剂化物；因此，本发明旨在包括本发明公开化合物溶剂化的和未溶剂化的形式。
具体实施方式
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的方法。
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式(I)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。
所属领域的专业人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company andAlfa ChemicalCompany，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，天津市福晨化学试剂厂，武汉鑫华远科技发展有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。
无水四氢呋喃，二氧六环，甲苯，乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，石油醚，正己烷，N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿都是干燥过的。
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。
核磁共振光谱使用Bruker 400MHz或600MHz核磁共振谱仪记录，以CDC13、DMSO-d6、CD3OD或丙酮-d6为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)、d(doublet，双峰)、t(triplet，三重峰)、m(multiplet，多重峰)、br(broadened，宽峰)、dd(doublet of doublets，双二重峰)、dt(doublet of triplets，双三重峰)。偶合常数，用赫兹(Hz)表示。
低分辨率质谱(MS)数据的测定条件是：Agilent 6120四级杆HPLC-M(柱子型号：Zorbax SB-C18,2.1x30mm,3.5微米,6min,流速为0.6mL/min。流动相：5％-95％(含0.1％甲酸的CH3CN)在(含0.1％甲酸的H2O)中的比例)，采用电喷雾电离(ESI)，在210nm/254nm下，用UV检测。
化合物纯度采用高效液相色谱法(HPLC)测定，使用Agilent 1260HPLC(柱子型号：Agilent zorbax Eclipse Plus C18)，并用DAD检测器检测，最终采用面积归一化法计算得到化合物纯度。
下面简写词的使用贯穿本发明：
HATU 2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
DMSO-d6 氘代二甲基亚砜
g 克
h 小时
min 分钟
mmol 毫摩尔
℃ 摄氏度
mL、ml 毫升
RT、rt、r.t. 室温
rpm 转每分钟
Rt 保留时间
制备本发明公开化合物的典型合成步骤如下面的合成方案所示。除非另外说明，Q、Ra、Rb、Rc、Rd、Re、R1、R2、R3和R4具有如本发明所述的定义。
合成方案1
羧酸化合物(1)与吲哚类化合物(2)在缩合剂的作用下反应生成化合物(I)。
下面的实施例可以对本发明做进一步的描述，然而，这些实施例不应作为对本发明的范围的限制。
实施例
实施例1:1-(3,5-二氯-4-羟基苯甲酰基)-1H-吲哚-3-甲腈的合成
将3,5-二氯-4-羟基苯甲酸(414mg,2.0mmol)，3-氰基吲哚(370mg,2.6mmol)，HATU(798mg,2.1mmol)和干燥的N,N-二甲基甲酰胺(10mL)加入50mL两口瓶中，向反应瓶中加入N,N-二异丙基乙胺(775mg,6.0mmol)，加完后，反应混合物在室温下搅拌24h。向反应混合物中加入饱和氯化铵水溶液(80mL)，水相用乙酸乙酯(60mL×2)萃取，合并有机相。有机相用饱和食盐水(60mL)洗涤，无水硫酸钠干燥，过滤，减压浓缩。残留物经硅胶柱层析(乙酸乙酯/二氯甲烷(v/v)＝1/100)，得到标题化合物为白色固体(93mg,14％)。
MS(ES-API,neg.ion)m/z:329.0[M-H]-；
1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.24(d,J＝7.9Hz,1H),7.85(s,2H),7.76(d,J＝7.1Hz,1H),7.54–7.49(m,2H)。
生物活性测试
试验例URAT1(尿酸阴离子转运体1)抑制活性测定
1)试验方法
a.人URAT1(hURAT1)稳定表达细胞株的构建
将hURAT1质粒转染至HEK-293T细胞中，使用G418(Geneticin，遗传霉素)获取hURAT1稳定表达细胞株。
b.尿酸吸收抑制
将hURAT1表达细胞接种至96孔板中，至少孵育12h后除去培养基，并用(Cl-)-freeHBSS缓冲液洗涤细胞；化合物用缓冲液四倍稀释得到一系列从200μM至0.8nM浓度的化合物溶液，将上述配制的5μL化合物溶液与45μL含[8-14C]尿酸的缓冲液混匀后添加至含有稳定转染细胞的96孔板中(即化合物终浓度为20μM至0.08nM)，同时设置缓冲液孔(转染细胞，不加入药物)及阴性孔(非转染细胞，不加入药物)；37℃孵育5min后去除缓冲液，并用缓冲液洗涤细胞，每孔加入50μL裂解缓冲液(100mM NaOH溶液)，将细胞进行裂解，600rpm震摇10min。1000rpm离心5min，移取45μL上清液至Isoplate-96微孔板，每孔加入150μL UltimaGoldTM XR，并600rpm震摇10min。使用MicroBeta Trilux闪烁/发光计数仪(PerkinElmer)计数，读[8-14C]尿酸剩余量，通过下列公式计算化合物抑制[8-14C]尿酸吸收的抑制率后通过XLfit软件计算IC50值，测得的IC50值见表1。
抑制率(％)＝[1-(药物孔14C摄取-阴性孔14C摄取)/(缓冲液孔14C摄取-阴性孔14C摄取)]×100；
其中，阴性孔为未接种转染细胞孔。
2)试验结果
表1本发明化合物hURAT1抑制活性的测试结果
| 编号 | IC50(nM) |
| 实施例1 | 20 |
上述试验结果表明，本发明化合物对hURAT1具有较好的抑制活性。
最后，需要注意的是，还有其他方式用来实施本发明。相应地，本发明的实施例是将作为例证进行说明，但并不限于本发明所描述的内容，还可能是在本发明范围内所作的修改或在权利要求中所添加的等同内容。本发明所引用的所有出版物或专利都将作为本发明的参考文献。
Claims (7)
1.一种化合物，其为式(I)所示的化合物或其药学上可接受的盐，
其中，
Q为氰基、硝基、三氟甲基或羧酸；
Ra、Rb、Rc、Rd和Re各自独立地为H、氘、氟、甲基、羟基、氨基、硝基或氰基；
R1和R2各自独立地为H、氘、氟、氯、溴、甲基、乙基、三氟甲基、甲氧基、氨基、甲氨基、二甲氨基、硝基、氰基或羟基；和
R3和R4各自独立地为H、氘、氟、氯、溴或甲基。
2.一种药物组合物，其包含权利要求1所述的化合物，其进一步包含药学上可接受的赋形剂、载体、佐剂、溶媒或它们的组合。
3.根据权利要求2所述的药物组合物，其进一步包含其他预防或治疗高尿酸血症、痛风石、痛风性关节炎、与高尿酸血症有关的肾脏障碍和尿石症的药物，所述药物为秋水仙碱、非甾体抗炎药、糖皮质激素、抑制尿酸生成药、促尿酸排泄药、尿碱化剂或它们的任意组合。
4.根据权利要求3所述的药物组合物，所述的其他预防或治疗高尿酸血症、痛风石、痛风性关节炎、与高尿酸血症有关的肾脏障碍和尿石症的药物为秋水仙碱、吲哚美辛、依托考昔、双氯芬酸、布洛芬、罗非昔布、塞来昔布、美洛昔康、强的松、琥珀酸氢化考的松、别嘌醇、丙磺舒、苯磺唑酮、苯溴马隆、奥昔嘌醇、非布索坦、重组黄曲霉菌尿酸氧化酶、聚乙二醇化重组尿酸氧化酶、碳酸氢钠片、枸橼酸钾钠合剂或它们的任意组合。
5.权利要求1所述的化合物或权利要求2-4任意一项所述的药物组合物在制备药物中的用途，所述药物用于预防或治疗哺乳动物，包括人类的高尿酸血症、痛风石、痛风性关节炎、与高尿酸血症有关的肾脏障碍和尿石症。
6.权利要求1所述的化合物或权利要求2-4任意一项所述的药物组合物在制备药物中的用途，所述药物用于降低血液中尿酸水平。
7.权利要求1所述的化合物或权利要求2-4任意一项所述的药物组合物在制备药物中的用途，所述药物用于抑制尿酸盐阴离子转运体1。
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| WO2019141259A1 (zh) | 2018-01-19 | 2019-07-25 | 苏州信诺维医药科技有限公司 | 杂环化合物、制备方法及其在医药上的应用 |
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