CN117586179A - 一种gpr183拮抗剂及其合成方法和应用 - Google Patents
一种gpr183拮抗剂及其合成方法和应用 Download PDFInfo
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- CN117586179A CN117586179A CN202311569726.2A CN202311569726A CN117586179A CN 117586179 A CN117586179 A CN 117586179A CN 202311569726 A CN202311569726 A CN 202311569726A CN 117586179 A CN117586179 A CN 117586179A
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- Prior art keywords
- compound
- acid
- piperazine
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- chlorophenyl
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- 229910052736 halogen Inorganic materials 0.000 claims description 10
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
本发明公开了一种化合物,其结构如式I所示,其中各基团和取代基的定义如说明书中所述。本发明还公开了上述化合物的合成方法,上述化合物可作为GPR183拮抗剂,用于治疗骨关节炎。
Description
技术领域
本发明涉及药物化学和药物治疗学技术领域,尤其涉及一种GPR183拮抗剂及其合成方法和应用,上述GPR183拮抗剂可用于治疗骨关节炎。
背景技术
维持软骨细胞的正常代谢对于改善骨关节炎的发生发展至关重要,软骨细胞中胆固醇代谢的CH25H-CYP7B1-RORα轴在骨关节炎发病机制中发挥重要作用。不同类型的胆固醇羟化酶通过将细胞内胆固醇转化为循环的氧甾醇,参与肝外组织的胆固醇代谢,调节多种生理过程。其中胆固醇羟化酶CH25H和CYP7B1会将胆固醇转化为7α,25-OHC。最新的实验数据显示CH25H和CYP7B1在骨关节炎的软骨细胞中表达上调,关节内注射CH25H和CYP7B1会导致软骨糖胺聚糖减少并引起滑膜炎,敲除CH25H的小鼠在DMM诱导的或代谢相关的创伤后骨关节炎(OA)中具有较轻的骨关节炎病理症状。因此,针对CH25H和CYP7B1参与的代谢轴可能为治疗骨关节炎提供新的治疗途径。
CH25H和CYP7B1参与将胆固醇转化为7α,25-OHC的生理过程,CH25H和CYP7B1的上调也会导致软骨细胞中7α,25-OHC水平显著上升。如上文所述,7α,25-OHC被鉴定为GPR183的内源性配体,鉴于CH25H和CYP7B1在骨关节炎中的重要作用及与7α,25-OHC的密切相关性,7α,25-OHC和GPR183构成的氧甾醇信号通路参与调控骨关节炎的发生发展。前期实验证实GPR183在软骨细胞中表达,且敲除GPR183的小鼠在DMM中的OA症状指标低于野生型小鼠。因此,GPR183可能是一个参与调控骨关节炎发生机制的新靶点,GPR183小分子拮抗剂也很可能是一类可以治疗骨关节炎的新型小分子候选药物。
发明内容
本发明的目的在于提供一种GPR183拮抗剂,其制备工艺简单,可用于制备治疗和缓解骨关节炎的药物。
为实现上述目的,本发明采用如下技术方案:
本发明的第一个方面是提供式(Ⅰ)所示的化合物、其水合物或其药学上可接受的盐,
其中,Linker不存在或选自下组:-O-、-SO-、-SO2-、-CONH-、-NHCO-、-NH-、-CO-、-NHCONH-、-CH2-;
R1、R2各自独立地选自下组:氢、C1-8烷基及其异构体、卤素、硝基、氨基、氰基、二氟甲基、三氟甲基、甲氧基、乙氧基、异丙氧基、二氟甲氧基、三氟甲氧基、羟基;
环M选自下组:苯基、含一个或多个杂原子的五元或六元杂环芳香基、取代的苯基及取代的五元或六元杂环芳香基、C3-8环烷基及其异构体;所述取代是指被选自下组的一个或多个基团取代:-OH、C1-8烷基、C1-8烷氧基、C6-14芳基、C3-8环烷基、、卤素、羧基、氨基;上述取代基任选被选自下组的一个或多个基团进一步取代:C6-14芳基、卤素、C1-8烷基、C1-8烷氧基、C3-8环烷基、氨基。
在另一优选例中,环M选自下组:
在另一优选例中,Linker选自下组:-SO2-、-NHCO-、-CO-、-CH2-。
在另一优选例中,R1、R2各自独立地选自下组:氢、C1-8烷基及其异构体、卤素、甲氧基。
在另一优选例中,所述化合物包括:[4-(4-氯苯基)吡啶-2-哌嗪]-(4-甲氧基苯基)甲酮;4-(4-甲氧基苄基)-[4-(4-氯苯基)吡啶]-2-哌嗪;1-{2-[4-(4-氯苯基)吡啶-]}-(4-甲氧基苯基)-1-甲酰胺哌嗪;1-{[4-(4-氯苯基)]-2-吡啶}-4-[(4-甲氧基苯基)磺酰基]哌嗪;1-{[4-(4-氯苯基)]-2-吡啶}-4-[(4-氟苯基)磺酰基]哌嗪;1-{[4-(4-氯苯基)]-2-吡啶}-4-甲苯磺酰基哌嗪;1-{[4-(4-氯苯基)]-2吡啶}-4-[(4-氯苯基)磺酰基]哌嗪;1-{[4-(4-氯苯基)]-2-吡啶}-4-[(3-甲氧基苯基)磺酰基]哌嗪;1-{[4-(4-氯苯基)]-2-吡啶}-4-[(3-氟苯基)磺酰基]哌嗪;[6-(4-氯苯基)吡啶-2-哌嗪}-(4-甲氧基苯基)甲酮;[5-(4-氯苯基)吡啶-3-哌嗪]-(4-甲氧基苯基)甲酮;[6-(4-氯苯基)嘧啶-4-哌嗪]-(4-甲氧基苯基)甲酮;1-{[6-(4-氯苯基)]-4-嘧啶}-4-(4-甲氧基苄基)哌嗪;4-[6-(4-氯苯基)嘧啶-4-基]-(4-甲氧基苯基)哌嗪-1-甲酰胺;4-(4-氯苯基)-6-{4-[(4-甲氧基苯基)磺酰基]哌嗪}嘧啶;[2-(4-氯苯基)嘧啶-4-哌嗪]-(4-甲氧基苯基)甲酮;[6-(4-氯苯基)-2-甲基嘧啶-4-哌嗪]-(4-甲氧基苯基)甲酮;[2-(4-氯苯基)-5-甲基嘧啶-4-哌嗪]-(4-甲氧基苯基)甲酮;{[2-(4-氯苯基)-6-甲基嘧啶]-4-哌嗪}-(4-甲氧基苯基)甲酮;{[2-(4-氯苯基)-5-甲氧基嘧啶]-4-哌嗪}-(4-甲氧基苯基)甲酮;[2-氨基-6-(4-氯苯基)嘧啶-4-哌嗪]-(4-甲氧基苯基)甲酮;[2-(4-氯苯基)-6-(三氟甲基)嘧啶-4-哌嗪]-(4-甲氧基苯基)甲酮;[2-(4-氯苯基)-5-(三氟甲基)嘧啶-4-哌嗪]-(4-甲氧基苯基)甲酮;{[2-三氟甲基-6-(4-氯苯基)]嘧啶-4-哌嗪}-(4-甲氧基苯基)甲酮;1-{[2-三氟甲基-4-(4-氯苯基)]-2-嘧啶}-4-(4-甲氧基苄基)哌嗪;1-{2-(三氟甲基)-6-[4-(4-氯苯基)]-2-嘧啶}-4-[(4-甲氧基苯基)磺酰基]哌嗪;{4-[4-(4-氯苯基)-1,3,5-三嗪-2-哌嗪]}-(4-甲氧基苯基)甲酮;{4-[2-(4-氯苯基)喹唑啉-4-哌嗪]}-(4-甲氧基苯基)甲酮;{4-[(1,1’-联苯基)-3-哌嗪]}-(4-甲氧基苯基)甲酮;{4-[5-(4-氯苯基)-1,3,4-噁二唑]-2-哌啶}-(4-甲氧基苯基)甲酮;{[4-(4-氯苯基)噻唑]-2-哌嗪}-(4-甲氧基苯基)甲酮;1-[4-(4-甲氧基苯甲酰基)哌嗪]-[(2R)-2-(4-氯苯基)环丙基]甲酮。上述化合物对应的结构式选自下组:
在水的存在下(例如使用含水溶剂的反应)制造时,可制得式(Ⅰ)化合物的水合物;在无水反应体系中,则可制得式(Ⅰ)化合物。上述“水合物”可通过加热处理或脱水处理而形成式(Ⅰ)化合物。
上述“药学上可接受的盐”为化合物与酸形成的酸加成盐,或为化合物与碱形成的碱加成盐;其中,所述酸包括但不限于:盐酸、氢溴酸、硫酸、磷酸、乙酸、酒石酸、水杨酸、柠檬酸、苹果酸、甲磺酸、对甲苯磺酸、乳酸、丙酮酸、马来酸、琥珀酸;所述碱加成盐包括从无机碱衍生的盐和从有机无毒碱衍生的盐,所述从无机碱衍生的盐包括但不限于:铝、铵、钾、钠、铁、铜、钙、亚铁、镁、锂、锰,所述从有机无毒碱衍生的盐包括但不限于:一级、二级和三级胺盐、取代胺包括天然取代胺、环胺、乙醇胺、N-乙基吗啉、N-乙基哌啶、葡萄胺。
本发明的第二个方面是提供一种药物组合物,其包含药学上可接受的载体和一种或多种安全有效量的如本发明的第一个方面中任一所述的化合物、其水合物或其药学上可接受的盐。可理解的是,上述药物组合物被配制成可注射流体、气雾剂、乳膏、凝胶剂、丸剂、胶囊剂、糖浆剂、透皮贴剂或赋形剂等。
“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,其适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的第三个方面是提供一种本发明的第一个方面中任一的化合物、其水合物或其药学上可接受的盐作为GPR183拮抗剂的用途。
本发明的第四个方面是提供一种本发明的第一个方面中任一的化合物、其水合物或其药学上可接受的盐的用途,其用于制备治疗或缓解骨关节炎的药物。
上述化合物抑制MMP-3和MMP-13的表达,具有软骨组织修复能力,促进软骨细胞分化。
本发明的第五个方面是提供式(Ⅰ)化合物的合成方法,包括如下步骤:
首先由各类含氯杂环在碱性条件下与N-Boc-哌嗪进行取代反应生成相应的连环化合物,然后在盐酸二氧六环溶液脱去Boc基团;该中间体可与苯甲酸衍生物进行酰胺反应、与苄溴衍生物和苯磺酰氯衍生物进行取代反应、和苯异氰酸酯衍生物进行加成反应生成目标化合物;反应完毕后一般用冰水淬灭,用乙酸乙酯或二氯甲烷等溶剂萃取,分别用水和饱和食盐水洗涤,用无水硫酸钠干燥后,减压蒸馏除去溶剂,经柱层析得到最终产物;得到的产物用核磁共振、质谱、高效液相色谱等方法证明化合物结构和纯度。
在一优选例中,上述某些式(Ⅰ)化合物的合成化学式如下所示:
试剂和条件:(a)N-Boc-哌嗪,DIPEA,DMF,r.t.;(a*)-Boc-哌嗪,t-BuONa,Xantphos,Pd2(dba)3,甲苯,Ar,80℃;(b)4-氯苯基硼酸,Pd(PPh3)4,2N aq Na2CO3,甲苯,Ar,80℃,12h;(c)3N HCl-1,4-二氧六环,r.t.。
与现有技术相比,本发明采用上述技术方案具有以下有益效果:
本发明制得的化合物能够用于治疗骨关节炎,具有促软骨分化效果,并对基质金属蛋白酶MMP-13和MMP-3的表达具有一定的抑制作用;且其合成方法为成熟路线,对小试、中试及放大具有重大的指导价值。
附图说明
此处所说明的附图用来提供对本发明的进一步理解,构成本发明的一部分,本发明的示意性实施例及其说明仅用于解释本发明,并不构成对本发明的不当限定。在附图中:
图1为本发明一实施例中式(Ⅰ)化合物对基质金属蛋白酶的抑制作用的结果示意图;
图2为本发明一实施例中式(Ⅰ)化合物促进软骨细胞分化的结果示意图。
具体实施方式
本发明人经过广泛而深入的研究,发现了式(Ⅰ)化合物,其为GPR183拮抗剂,可用于治疗骨关节炎。
术语(在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含义。)
在本发明中,所述卤素为F、Cl、Br或I。
在本发明中,术语“C1-8”是指具有1、2、3、4、5、6、7或8个碳原子,依此类推。
在本发明中,术语“烷基”表示饱和的线性或支链烃部分,例如术语“C1-8烷基”是指具有1至8个碳原子的直链或支链烷基,非限制性地包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、已基、庚基、辛基等。
在本发明中,术语“环烷基”表示饱和的环状烃基部分,例如术语“C3-8环烷基”是指在环上具有3至8个碳原子的环状烷基,非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
在本发明中,术语“杂环芳香基”表示包含至少一个(如1、2、3或4个)环杂原子(例如N,O或S)的芳香性的环状基团,例如吡啶、喹啉、吡嗪、呋喃、噻吩等。
在本发明中,术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如:卤素、羟基、羧基、氨基、C1-8烷基、C1--8烷氧基、C6-14芳基、C3-8环烷基等。
化合物
本发明提供式(Ⅰ)所示的化合物、其水合物或其药学上可接受的盐,
其中,各基团如上文所定义。
在另一优选例中,所述的化合物中,Linker、R1、R2、环M中任一个分别为本发明所述具体化合物中所对应的基团。
在另一优选例中,所述化合物优选为实施例中所制备的化合物。
制备方法
下述实施例更具体地描述本发明式(Ⅰ)结构化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。
药物组合物和施用方法
由于本发明部分化合物具有良好的GPR183拮抗活性,因此本发明化合物及其各种晶型,水合物或药学上可接受的无机或有机盐,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗骨关节炎。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药学上可接受的盐及药学上可接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。“药学上可接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。所述药物组合物剂型可为注射流体、气雾剂、乳膏、凝胶剂、丸剂、胶囊剂、糖浆剂、透皮贴剂或赋形剂等。
本发明化合物可以单独给药,或者与其他治疗药物联合给药。
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有作出创造性劳动的前提下所获得的所有其他实施例,都属于本发明保护的范围。下列实施例中未注明具体条件的实验方法,通常按照国家标准测定。下述实施例中未注明出处的实验材料,均为市售原料。下述实施例中的各步骤中采用的设备均为常规设备。若没有相应的国家标准,,则按照通用的国际标准、常规条件、或按照制造厂商所建议的条件进行。除非另外说明,,否则所有的份数为重量份,所有的百分比为质量百分比。除非另有定义或说明,本发明中所使用的所有专业与科学用语与本领域技术熟练人员所熟悉的意义相同。此外任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。
需要说明的是,在不冲突的情况下,本发明中的实施例及实施例中的特征可以相互组合。下面结合附图和具体实施例对本发明作进一步说明,但不作为本发明的限定。
下述实施例中,1H-NMR用Bruker 500MHz型仪和Bruker 400MHz型仪测定;MS用Bruker MicroTOF-Q LCMS型仪测定,除注明外均为ESI方式;所有溶剂在使用前均经过重新蒸馏,所使用的无水溶剂均是按标准方法干燥处理获得;除特别说明外,所有反应均是在氩气保护下进行并用TLC跟踪,后处理时均经饱和食盐水洗和无水硫酸镁干燥过程;产品的纯化除特别说明外均使用硅胶(200-300目)的柱色谱法;所使用的硅胶,包括200-300目和GF254为青岛海洋化工厂或烟台缘博硅胶公司生产。
一、制备实施例
实施例1、[4-(4-氯苯基)吡啶-2-哌嗪]-(4-甲氧基苯基)甲酮(1A)的制备
第一步:将2-溴-4-氯吡啶(963mg,5.00mmol)与N-Boc-哌嗪(1025mg,5.50mmol),叔丁醇钠(720mg,7.50mmol),Xantphos(146mg,0.25mmol)、三(二亚苄基丙酮)二钯(46mg,0.05mmol)一同溶于15mL的甲苯中,在80℃下加热反应并进行氩气保护,反应12h。随后冷却至室温,除去溶剂,分别三次加入乙酸乙酯溶液和饱和食盐水进行萃取,取有机相蒸干,通过硅胶柱层析得到中间体4-(4-氯吡啶-2-基)哌嗪-1-羧酸叔丁酯(920mg,3.10mmol)。
第二步:将4-(4-氯吡啶-2-基)哌嗪-1-羧酸叔丁酯(920mg,3.10mmol)与4-氯苯硼酸(725mg,4.65mmol)、四(三苯基膦)钯(36mg,0.03mmol)一同溶于18mL甲苯中,加入3.5mL2N的碳酸钠溶液,在氩气的保护下搅拌回流加热至85℃反应12h。反应结束后冷却至室温,减压蒸馏除去绝大部分溶剂,加入20mL的乙酸乙酯溶液后依次用水和饱和食盐水进行萃取,取有机相蒸干溶剂,通过硅胶柱层析得到中间体4-[4-(4-氯苯基)吡啶-2-基]哌嗪-1-羧酸叔丁酯(532mg,1.40mmol)。
第三步:将4-[4-(4-氯苯基)吡啶-2-基]哌嗪-1-羧酸叔丁酯(532mg,1.40mmol)溶于5mL的二氧六环溶液中,加入2mL 3N的盐酸二氧六环溶液,室温下进行搅拌反应6h。反应结束后减压蒸馏除去溶剂,得到盐酸化的中间体1-[4-(4-氯苯基)吡啶-2-基]哌嗪(390mg,1.26mmol)。
第四步:将1-[4-(4-氯苯基)吡啶-2-基]哌嗪(100mg,0.32mmol)与4-甲氧基苯甲酸(54mg,0.35mmol),HATU(146mg,0.38mmol),DIPEA(0.2mL,0.8mmol)一同溶于5mL的二氯甲烷中,在常温下搅拌3h。反应结束后加压蒸馏除去溶剂,加入10mL的乙酸乙酯溶液后依次用水和饱和食盐水进行萃取,取有机相经无水硫酸钠干燥后抽滤,取滤液减压蒸馏除去溶剂,通过硅胶柱层析得到目标化合物1A。1H NMR(600MHz,DMSO)δ8.29(d,J=6.4Hz,1H),8.08–8.03(m,2H),7.62–7.55(m,2H),7.48–7.43(m,2H),7.39(d,J=2.5Hz,1H),7.05–7.00(m,2H),6.94(dd,J=6..4,2.5Hz,1H),3.82(s,3H),3.74–3.56(m,8H).
实施例2、4-(4-甲氧基苄基)-[4-(4-氯苯基)吡啶]-2-哌嗪(1B)的制备
前三步与1A合成路线相同,得到中间体1-[4-(4-氯苯基)吡啶-2-基]哌嗪(100mg,0.32mmol),将以上中间体与4-甲氧基苄溴(71mg,0.35mmol),碳酸铯(160mg,0.50mmol),溶于5mL的乙腈中,在常温下搅拌3h。反应结束后加压蒸馏除去溶剂,三次用乙酸乙酯与饱和食盐水萃取,取有机相经无水硫酸钠干燥后抽滤,取滤液减压蒸馏除去溶剂,通过硅胶柱层析得到目标化合物1B。1H NMR(500MHz,CDCl3)δ8.36(d,J=6.0Hz,1H),7.92–7.84(m,2H),7.46–7.40(m,2H),7.32–7.25(m,2H),7.04(d,J=2.4Hz,1H),6.94–6.88(m,2H),6.65(dd,J=6.0,2.5Hz,1H),3.84(s,3H),3.54(s,2H),3.47–3.41(m,4H),2.67–2.55(m,4H).
实施例3、1-{2-[4-(4-氯苯基)吡啶-]}-(4-甲氧基苯基)-1-甲酰胺哌嗪(1C)的制备
前三步与1A合成路线相同,得到中间体1-[4-(4-氯苯基)吡啶-2-基]哌嗪(100mg,0.32mmol),将以上中间体与4-甲氧基苯异氰酸酯(48mg,0.32mmol),溶于5mL的二氯甲烷中,在常温下搅拌3h。反应结束后加压蒸馏除去溶剂,三次用乙酸乙酯与饱和食盐水萃取,取有机相经无水硫酸钠干燥后抽滤,取滤液减压蒸馏除去溶剂通过硅胶柱层析得到目标化合物1C。1H NMR(600MHz,DMSO)δ8.46(s,1H),8.29(d,J=5.9Hz,1H),8.15–8.11(m,2H),7.54–7.49(m,2H),7.39(d,J=2.4Hz,1H),7.38–7.34(m,2H),6..87(dd,J=5.9,2.4Hz,1H),6.85–6.80(m,2H),3.72(s,3H),3.63–3.57(m,4H),3.53–3.46(m,4H).
实施例4、1-{[4-(4-氯苯基)]-2-吡啶}-4-[(4-甲氧基苯基)磺酰基]哌嗪(1D)的制备
前三步与1A合成路线相同,得到中间体1-[4-(4-氯苯基)吡啶-2-基]哌嗪(100mg,0.32mmol),将以上中间体与4-甲氧基苯磺酰氯(73mg,0.35mmol),DIPEA(0.15mL,0.87mmol)溶于5mL的二氯甲烷中,在常温下搅拌3h。反应结束后加压蒸馏除去溶剂,三次用乙酸乙酯与饱和食盐水萃取,取有机相经无水硫酸钠干燥后抽滤,取滤液减压蒸馏除去溶剂,通过硅胶柱层析得到目标化合物1D。1H NMR(500MHz,CDCl3)δ8..36(d,J=6.0Hz,1H),7.88–7.84(m,2H),7.73–7.69(m,2H),7.42–7.38(m,2H),7.03–7.01(m,2H),6.99(d,J=2.2Hz,1H),6.63(dd,J=6.0,2.3Hz,1H),3.89(s,3H),3.60–3.47(m,4H),3.22–3.10(m,4H).
实施例5、1-{[4-(4-氯苯基)]-2-吡啶}-4-[(4-氟苯基)磺酰基]哌嗪(1E)的制备
采用与化合物1D相同方法,将4-甲氧基苯磺酰氯替换为4-甲基苯磺酰氯,最后得到1E。1H NMR(600MHz,DMSO)δ8.25(d,J=6.0Hz,1H),8..09–8.05(m,2H),7.89–7.83(m,2H),7.53–7.47(m,4H),7.33(d,J=2.4Hz,1H),6.80(dd,J=6.0,2.4Hz,1H),3.60–3.54(m,4H),3.07–3.00(m,4H).
实施例6、1-{[4-(4-氯苯基)]-2-吡啶}-4-甲苯磺酰基哌嗪(1F)的制备
采用与化合物1D相同方法,将4-甲氧基苯磺酰氯替换为4-甲基苯磺酰氯,最后得到1F。1H NMR(600MHz,DMSO)δ8.24(d,J=5.9Hz,1H),8..10–8.05(m,2H),7.66(d,J=8.3Hz,2H),7.53–7.48(m,2H),7.48–7.45(m,2H),7.32(d,J=2.4Hz,1H),6.78(dd,J=6.0,2.4Hz,1H),3.59–3.53(m,4H),3.02–2.95(m,4H),2.40(s,3H)..
实施例7、1-{[4-(4-氯苯基)]-2吡啶}-4-[(4-氯苯基)磺酰基]哌嗪(1G)的制备
采用与化合物1D相同方法,将4-甲氧基苯磺酰氯替换为4-甲基苯磺酰氯,最后得到1G。1H NMR(600MHz,CDCl3)δ8.31(d,J=6.6Hz,1H),7.94–7.89(m,2H),7.77–7.72(m,2H),7.59–7.54(m,2H),7.46–7.41(m,2H),6.99(d,J=2.5Hz,1H),6..75(dd,J=6.5,2.3Hz,1H),3.75–3.65(m,4H),3.28–3.20(m,4H).
实施例8、1-{[4-(4-氯苯基)]-2-吡啶}-4-[(3-甲氧基苯基)磺酰基]哌嗪(1H)的制备
采用与化合物1D相同方法,将4-甲氧基苯磺酰氯替换为4-甲基苯磺酰氯,最后得到1H。1H NMR(600MHz,CDCl3)δ8.30(d,J=7.0Hz,1H),7..97–7.93(m,2H),7.51–7.48(m,1H),7.47–7.44(m,2H),7.37(d,J=7.8Hz,1H),7.31–7.29(m,1H),7..17(dd,J=8.3,2.4Hz,1H),3.89(s,2H),3.79–3.74(m,4H),3.30–3.24(m,4H).
实施例9、1-{[4-(4-氯苯基)]-2-吡啶}-4-[(3-氟苯基)磺酰基]哌嗪(1I)的制备
采用与化合物1D相同方法,将4-甲氧基苯磺酰氯替换为4-甲基苯磺酰氯,最后得到1I。1H NMR(600MHz,DMSO)δ8.25(d,J=5.9Hz,1H),8..10–8.06(m,2H),7.74–7.70(m,1H),7.66–7.59(m,3H),7.52–7.47(m,2H),7.33(d,J=2.4Hz,1H),6..79(dd,J=5.9,2.5Hz,1H),3.58–3.53(m,4H),3.10–3.05(m,4H).
实施例10、[6-(4-氯苯基)吡啶-2-哌嗪}-(4-甲氧基苯基)甲酮(2A)的制备
第一步:取2,6-二氯吡啶(740mg,5.00mmol),N-Boc-哌嗪(930mg,5.00mmol),DIPEA(1.5mL,7.50mmol)溶于10mL无水DMF中,在常温下搅拌6h。待反应结束,加入20mL的EA溶液后依次用水和饱和食盐水进行萃取,取有机相减压蒸馏除去溶剂,通过硅胶柱层析得到中间体化合物4-(6-氯吡啶-2-基)哌嗪-1-羧酸叔丁酯(1158mg,3.90mmol)。
第二步:取上述中间体化合物4-(6-氯吡啶-2-基)哌嗪-1-羧酸叔丁酯(1158mg,3.90mmol),4-氯苯硼酸(910mg,5.85mmol)、四(三苯基膦)钯(45mg,0.04mmol)溶于15mL甲苯中,加入7mL 2N的碳酸钠溶液,在氩气的保护下搅拌回流加热至85℃反应12h。反应结束后冷却至室温,减压蒸馏除去绝大部分溶剂,三次用乙酸乙酯与饱和食盐水萃取,取有机相经无水硫酸钠干燥后抽滤,取滤液减压蒸馏除去溶剂,通过硅胶柱层析得到中间体4-(6-(4-氯苯基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(741mg,1.90mmol)。。
第三步:取上述中间体4-(6-(4-氯苯基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(741mg,1.90mmol),溶于5mL的二氧六环溶液中,加入2.5mL 3N的盐酸二氧六环溶液,室温下进行搅拌反应6h。反应结束后减压蒸馏除去溶剂,得到盐酸化的中间体1-(6-(4-氯苯基)吡啶-2-基)哌嗪(470mg,1.51mmol)。
第四步:取上述中间体1-(6-(4-氯苯基)吡啶-2-基)哌嗪(100mg,0.32mmol),4-甲氧基苯甲酸(54mg,0.35mmol),HATU(146mg,0.38mmol),DIPEA(0.2mL,0.8mmol)溶于5mL的二氯甲烷中,在常温下搅拌3h。反应结束后加压蒸馏除去溶剂,三次用乙酸乙酯与饱和食盐水萃取,取有机相经无水硫酸钠干燥后抽滤,,取滤液减压蒸馏除去溶剂,通过硅胶柱层析得到目标化合物2A。1H NMR(500MHz,CDCl3)δ7.96–7.91(m,2H),7.62(t,J=7.9Hz,1H),7.47–7.44(m,2H),7.44–7.38(m,2H),7.14(d,J=7.4Hz,1H),6.98–6.94(m,2H),6.68(d,J=8.4Hz,1H),3.87(s,3H),3.75–3.67(m,8H).
实施例11、[5-(4-氯苯基)吡啶-3-哌嗪]-(4-甲氧基苯基)甲酮(3A)的制备
采用与化合物2A相同方法,将2,6-二氯吡啶替换为3,5-二氯吡啶,最后得到3A。1HNMR(600MHz,DMSO)δ8.29(s,1H),8.10–8.06(m,2H),7.61–7.54(m,2H),7.45–7.43(m,2H),7.39(s,1H),7.10–7.06(m,2H),6.99(dd,J=6.4,2.5Hz,1H),3.80(s,3H),3.79–3.52(m,8H).
实施例12、[6-(4-氯苯基)嘧啶-4-哌嗪]-(4-甲氧基苯基)甲酮(4A)的制备
采用与化合物2A相同方法,将2,6-二氯吡啶替换为4,6-二氯嘧啶,最后得到4A。1HNMR(500MHz,CDCl3)δ8.71(s,1H),8.02–7.95(m,2H),7.51–7.45(m,2H),7.33–7.29(m,2H),6.91–6.84(m,2H),6.53(s,1H),3.95–3.85(m,4H),3.80(s,3H),3.76–3.65(m,4H).
实施例13、[2-(4-氯苯基)嘧啶-4-哌嗪]-(4-甲氧基苯基)甲酮(5A)的制备
采用与化合物2A相同方法,将2,6-二氯吡啶替换为4,6-二氯嘧啶。最后得到5A。1HNMR(500MHz,CDCl3)δ8.42(d,J=5.3Hz,1H),8.04–7.99(m,2H),7.51–7.42(m,4H),7.02(d,J=5.2Hz,1H),6.99–6.94(m,2H),4.10–3.97(m,4H),3.88(s,3H),3.85–3.63(m,4H).
实施例14、[6-(4-氯苯基)-2-甲基嘧啶-4-哌嗪]-(4-甲氧基苯基)甲酮(6A)的制备
采用与化合物2A相同方法,将2,6-二氯吡啶替换为4,6-二氯-2-甲基嘧啶,最后得到6A。1H NMR(500MHz,CDCl3)δ8.02–7.94(m,2H),7.51–7.41(m,4H),6.99–6.94(m,2H),6.71(s,1H),3.88(s,3H),3.87–3.73(m,8H),2.70(s,3H).
实施例15、[2-(4-氯苯基)-5-甲基嘧啶-4-哌嗪]-(4-甲氧基苯基)甲酮(7A)的制备
采用与化合物2A相同方法,将2,6-二氯吡啶替换为2,4-二氯-5-甲基嘧啶,最后得到7A。1H NMR(500MHz,DMSO)δ8.36–8.32(m,2H),8.31(s,1H),7.56–7.51(m,2H),7.46–7.41(m,2H),7.04–6.99(m,2H),3.81(s,3H),3.65–3.56(m,4H),2.72–2.66(m,4H),2.26(s,3H).
实施例16、{[2-(4-氯苯基)-6-甲基嘧啶]-4-哌嗪}-(4-甲氧基苯基)甲酮(8A)的制备
采用与化合物2A相同方法,将2,6-二氯吡啶替换为2,4-二氯-6-甲基嘧啶,最后得到8A。1H NMR(500MHz,CDCl3)δ8.47–8.41(m,2H),7.50–7.43(m,4H),7.00–6.94(m,2H),6.39(s,1H),4.02–3.69(m,11H),2.62(s,3H).
实施例17、{[2-(4-氯苯基)-5-甲氧基嘧啶]-4-哌嗪}-(4-甲氧基苯基)甲酮(9A)的制备
采用与化合物2A相同方法,将2,6-二氯吡啶替换为2,4-二氯-5-甲氧基嘧啶,最后得到9A。1H NMR(500MHz,DMSO)δ8.34–8.31(m,2H),7.54–7.51(m,2H),7.40–7.38(m,2H),7.01–6.98(m,2H),6.91(s,1H),3.84(s,3H),3.81(s,3H),3.78–3.71(m,4H),2.91–2.86(m,4H).
实施例18、[2-氨基-6-(4-氯苯基)嘧啶-4-哌嗪]-(4-甲氧基苯基)甲酮(10A)的制备
采用与化合物2A相同方法,将2,6-二氯吡啶替换为2-氨基-4,6-二氯嘧啶,最后得到10A。1H NMR(500MHz,CDCl3)δ7.92–7.85(m,2H),7.47–7.39(m,4H),6.99–6.92(m,2H),6.33(s,1H),5.24(s,2H),3.87(s,3H),3..82–3.63(m,8H).
实施例19、[2-(4-氯苯基)-6-(三氟甲基)嘧啶-4-哌嗪]-(4-甲氧基苯基)甲酮(11A)的制备
采用与化合物2A相同方法,将2,6-二氯吡啶替换为2,4-二氯-6-三氟甲基嘧啶,最后得到11A。1H NMR(500MHz,CDCl3)δ8.41–8.35(m,2H),7.56–7.40(m,4H),7.02–6.94(m,2H),6.78(s,1H),3.88(s,3H),3.94–3.69(m,8H).
实施例20、[2-(4-氯苯基)-5-(三氟甲基)嘧啶-4-哌嗪]-(4-甲氧基苯基)甲酮(12A)的制备
采用与化合物2A相同方法,将2,6-二氯吡啶替换为2,4-二氯-5-三氟甲基嘧啶,最后得到12A。1H NMR(500MHz,CDCl3)δ8.76(s,1H),8.55–8.45(m,2H),8.33–8.23(m,2H),7.52–7.44(m,4H),7.11–7.05(m,2H),4.12–4.02(m,4H),3.96(s,3H),3.94–3.82(m,4H).
实施例21、{[2-三氟甲基-6-(4-氯苯基)]嘧啶-4-哌嗪}-(4-甲氧基苯基)甲酮(13A)的制备
采用与化合物2A相同方法,将2,6-二氯吡啶替换为4,6-二氯-2-三氟甲基嘧啶,最后得到13A。1H NMR(500MHz,CDCl3)δ8.03–7.98(m,2H),7.74(s 1H),7.51–7.43(m,4H),6.99–6.94(m,2H),3.88(s,3H),3.88–3.66(m,8H).
实施例22、{4-[4-(4-氯苯基)-1,3,5-三嗪-2-哌嗪]}-(4-甲氧基苯基)甲酮(14A)的制备
采用与化合物2A相同方法,将2,6-二氯吡啶替换为2,4-二氯-1,3,5-三嗪,最后得到14A。1H NMR(500MHz,CDCl3)δ8.69(s,1H),8.42–8.36(m,2H),7.51–7.44(m,4H),7.02–6.93(m,2H),4.17–3.95(m,4H),3.88(s,3H),3.86–3.57(m,4H).
实施例23、{4-[2-(4-氯苯基)喹唑啉-4-哌嗪]}-(4-甲氧基苯基)甲酮(15A)的制备
采用与化合物2A相同方法,将2,6-二氯吡啶替换为2,,4-二氯喹唑啉,最后得到15A。1H NMR(500MHz,DMSO)δ8.54–8.47(m,2H),8.08(d,J=8.3Hz,1H),7.91(dd,J=8.4,1.0Hz,1H),7.88–7.83(m,1H),7.66–7.60(m,1H),7.60–7.56(m,2H),7.49–7.44(m,2H),7.06–6.99(m,2H),4.00–3.86(m,4H),3.82(s,3H),3.82–3.73(m,4H).
实施例24、{4-[(1,1’-联苯基)-3-哌嗪]}-(4-甲氧基苯基)甲酮(16A)的制备
第一步:将3-氯联苯(566mg,3.00mmol),N-Boc-哌嗪(164mg,3.30mmol),HATU(1368mg,3.6mmol),DIPEA(1.5mL,7.50mmol)溶于10mL二氯甲烷中,在常温下反应4h,随后蒸馏去除溶剂,三次用乙酸乙酯与饱和食盐水萃取,取有机相经无水硫酸钠干燥后抽滤,取滤液减压蒸馏除去溶剂,通过硅胶柱层析得到中间体化合物4-[(1,1’-联苯基)-3-哌嗪]-1-羧酸叔丁酯(862mg,2.50mmol)。
第二步:将4-[(1,1’-联苯基)-3-哌嗪]-1-羧酸叔丁酯(862mg,2.50mmol)溶于5mL二氧六环溶液中,加入1.5mL 3N的盐酸二氧六环溶液,室温下进行搅拌反应6h。反应结束后减压蒸馏除去溶剂,得到盐酸化的中间体1-(3-联苯)哌嗪(515mg,1.90mmol)。
第三步:将中间体1-(3-联苯)哌嗪盐酸盐(515mg,1.90mmol)与4-甲氧基苯甲酸(52mg,0.40mmol),HATU(168mg,0.40mmol),DIPEA(0.15mL,0.90mmol)一同溶于5mL的二氯甲烷中,在常温下搅拌3h。反应结束后加压蒸馏除去溶剂,三次用乙酸乙酯与饱和食盐水萃取,取有机相经无水硫酸钠干燥后抽滤,取滤液减压蒸馏除去溶剂,通过硅胶柱层析得到目标化合物16A。1H NMR(500MHz,CDCl3)δ7.64–7.57(m,2H),7.50–7.43(m,4H),7.42–7.35(m,2H),7.27–7.12(m,2H),7.09–6.99(m,1H),6.99–6.93(m,2H),4.05–3.68(m,7H),3.44–3.15(m,4H).
实施例25、{4-[5-(4-氯苯基)-1,3,4-噁二唑]-2-哌啶}-(4-甲氧基苯基)甲酮(17A)的制备
第一步:将4-氯-苯甲酰肼(544mg,4.00mmol)与1-Boc-4-哌啶甲酸(1007mg,4.4mmol),HATU(1824mg,4.80mmol),DIPEA(1.80mL,10.00mmol)一同溶于10mL的二氯甲烷中,在常温下搅拌3h。反应结束后加压蒸馏除去溶剂,三次用乙酸乙酯与饱和食盐水萃取,取有机相经无水硫酸钠干燥后抽滤,取滤液减压蒸馏除去溶剂,通过硅胶柱层析得到中间体化合物4-[2-(4-氯苯甲酰肼)-1-羰基]哌啶-1-羧酸叔丁酯(1318mg,3.80mmol)。
第二步:将4-(2-苯甲酰肼-1-羰基)哌啶-1-羧酸叔丁酯(1318mg,3.80mmol)与4-苯磺酰氯(866mg,4.60mmol),三乙胺(575mg,5.70mmol)溶于15mL的二氯甲烷中,在常温下搅拌6h。反应结束后加压蒸馏除去溶剂,三次用乙酸乙酯与饱和食盐水萃取,取有机相经无水硫酸钠干燥后抽滤,取滤液减压蒸馏除去溶剂,通过硅胶柱层析得到中间体化合物(694mg,2.10mmol)。
后续操作参照1A合成路线中的第三步、第四步,最后得到17A。。1H NMR(500MHz,CDCl3)δ7.95–7.89(m,2H),7.69–7.65(m,2H),7.45–7.40(m,2H),6.97–6.92(m,2H),3.86(s,3H),3.31(tt,J=10.7,3.9Hz,1H),3.23(t,J=11.5Hz,2H),2.24–2.15(m,2H),2.13–1.88(m,4H).
实施例26、{[4-(4-氯苯基)噻唑]-2-哌嗪}-(4-甲氧基苯基)甲酮(18A)的制备
第一步:取2'-溴-4-氯苯乙酮(684mg,3.00mmol),4-Boc-哌嗪-1-硫酰胺(808mg,3.30mmol)溶于10mL二氧六环中,滴入(0.6mL,4.50mmol)三乙胺,加热回流搅拌反应12h。待反应结束后减压蒸馏出去溶剂,三次用乙酸乙酯与饱和食盐水萃取,取有机相经无水硫酸钠干燥后抽滤,取滤液减压蒸馏除去溶剂,通过硅胶柱层析得到中间体化合物2-溴-4-(4-氯苯基)噻唑(653mg,1.50mmol)。
第二步:将上述中间体化合物2-溴-4-(4-氯苯基)噻唑(653mg,1.60mmol)与N-Boc-哌嗪(319mg,1.70mmol),叔丁醇钠(225mg,2.30mmol),Xantphos(45mg,0.10mmol)、三(二亚苄基丙酮)二钯(10mg,0.01mmol)一同溶于15mL的甲苯中,在氩气的保护下搅拌加热至80℃回流反应12h。反应结束后冷却至室温,减压蒸馏除去溶剂,三次用乙酸乙酯与饱和食盐水萃取,取有机相经无水硫酸钠干燥后抽滤,,取滤液减压蒸馏除去溶剂,通过硅胶柱层析得到中间体4-[4-(4-氯苯基)噻唑-2-基]哌嗪-1-羧酸叔丁酯(801mg,1.90mmol)。
第三一步:将上述中间体(801mg,1.90mmol)溶于7mL的二氧六环溶液中,加入1mL3N的盐酸二氧六环溶液,室温下进行搅拌反应6h。反应结束后减压蒸馏除去溶剂,得到盐酸化的中间体2-哌嗪-4-(4-氯苯基)噻唑(680mg,1.90mmol)。
第四步:将上述盐酸化的中间体2-哌嗪-4-(4-氯苯基)噻唑(118mg,0.40mmol)与4-甲氧基苯甲酸(52mg,0.40mmol),HATU(168mg,0.40mmol),DIPEA(0.15mL,0.90mmol)溶于5mL的二氯甲烷中,在常温下搅拌3h。反应结束后加压蒸馏除去溶剂,三次用乙酸乙酯与饱和食盐水萃取,取有机相经无水硫酸钠干燥后抽滤,取滤液减压蒸馏除去溶剂,通过硅胶柱层析得到目标化合物18A。1H NMR(500MHz,CDCl3)δ7.74–7.70(M,2H),7.55–7.50(m,2H),7.47–7.42(m,2H),6.99–6.93(m,2H),6.83(s,1H),3..87(s,3H),3.88–3.73(m,4H),3.70–3.61(m,4H).
二、药效评价
实施例27、钙流实验检测式(Ⅰ)化合物对GPR183的拮抗活性
本实施例采用钙流实验验证了式(Ⅰ)化合物对GPR183的拮抗活性,包括如下实验步骤:在含有潮霉素的培养基中选择稳定表现在含有潮霉素的培养基中选择稳定表现GPR183和Gα16的CHO-K1细胞。细胞以每孔20000个细胞的浓度接种于黑色边缘96孔透明底细胞培养板。细胞于37℃湿化5%CO2空气环境培养24小时。次日,由孔移除培养基后,以每孔100μL添加Fluo-4(Invitrogen;货号10471)且细胞于37℃培养45min后再于室温孵育15min。所有测试化合物于HBSS缓冲液中稀释成相应浓度。然后将培养板于FlexStation 3多功能酶标仪自动加样于孔中并以间隔2s测试2min。计算本发明化合物对GPR183受体的钙流抑制活性,所有测试化合物于HBSS缓冲液中稀释,其实验结果如表1和表2所示。
表1
*阳性对照组:NIBR189(hGPR183 Ca+IC50=11nM),相对抑制率100%;测试组:实验测试浓度:10μM。
表2
*阳性对照组:NIBR189(hGPR183 Ca+IC50=11nM),相对抑制率100%;测试组:实验测试浓度:10μM和1μM。
由上述结果可知,在一定浓度的条件下,本发明部分化合物具有良好的GPR183拮抗活性,其中化合物1A、1B、1C、1D、4A、4C、13A均具有良好的GPR183拮抗活性。
实施例28、检测式(Ⅰ)化合物对基质金属蛋白酶的抑制作用
基质金属蛋白酶(MMPs)的过度表达破坏Ⅱ型胶原是骨关节炎(OA)发生和发展的关键因素,其中,MMP-3和MMP-13被认为是主要的胶原降解酶,MMP-13不可逆转地降解软骨胶原基质,在骨关节炎的进展中起重要作用。
本实施例验证了式(Ⅰ)化合物对基质金属蛋白酶的抑制作用,包括如下实验步骤:将乳鼠的膝关节软骨组织剥离进行体外培养1周后,将p1代细胞接入24孔板,培养至第二天。加入待测小分子化合物(浓度分别为300nM、3μM的NIBR189、4C、5A),2h后用1ng/mL的IL-1β进行刺激,24h后用1mL的Trizol提取RNA。经离心处理后取上层清液,加入异丙醇,离心弃上清液,经75%酒精清洗后离心,弃上清,在干净且无RNA酶的环境中进行酒精自然风干。后经反转录得到cDNA,经q-RTPCR扩增后检测MMP-13及MMP-3的表达水平变化情况。
实验结果如图1所示,其纵坐标为mRNA水平上MMP-13及MMP-3表达情况的变化倍数,第一列数据为加入IL-1β刺激的对照组。实验结果表明,化合物4C在3μM的浓度下对MMP-3和MMP-13的表达具有一定的抑制作用,效果显著优于对照组,初步证明了该化合物具有一定软骨组织修复能力。
实施例29、检测式(Ⅰ)化合物对软骨细胞分化的促进作用
本实施例验证了式(Ⅰ)化合物对软骨细胞分化的促进作用,包括如下实验步骤:将前三天出生的WT小鼠的膝关节软骨组织剥离,用PBS清洗,剪碎,在37℃下用胰酶消化处理30min,离心除去胰酶,加入0.1%的Ⅱ型胶原酶消化处理,过夜后离心除去胶原酶,加DMEM-F12培养基在培养皿中培养2-3天。将培养好的软骨细胞系滴入24孔板,在培养箱中培养2-3h,加入软骨分化培养基(软骨分化终浓度如下:ITS100X 1×;TGFβ3 10ng/mL;***100nM;2-磷酸-坏血酸钠50μg/ml;脯氨酸40μg/ml;丙酮酸钠1mM),并以依次加入浓度为300nM、3μM的待测试小分子化合物(NIBR189、1B、1D、2A、4A、4B、4C、4D、5A、13A、18A)进行培养。一周后用4%的PFA固定15-30min,再用阿尔新蓝染色过夜,第二天拍照。
本实验通过在原代小鼠软骨细胞的分化培养基中加入不同浓度的小分子化合物,检测其对小鼠软骨细胞分化的促进效果。其中DM作为空白对照不做任何处理,将300nM和3μM的阳性化合物NIBR189及待测化合物加入到分化培养基中培养,经染色后观察软骨细胞分化程度。实验结果如图2所示,待测小分子化合物在3μM浓度下对软骨细胞分化普遍具有一定的促进作用,其中1B、1D、4B、4C、5A、18A的促进效果较优;且4C、5A在300nM的浓度下也可以继续维持较好的促分化效果。
以上对本发明的具体实施例进行了详细描述,但其只作为范例,本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言,任何对本发明进行的等同修改和替代也都在本发明的范畴之中。因此,在不脱离本发明的精神和范围下所作的均等变换和修改,都应涵盖在本发明的范围内。
Claims (10)
1.式(Ⅰ)所示的化合物、其水合物或其药学上可接受的盐,其特征在于,所述化合物的结构式为:
其中,Linker不存在或选自下组:-O-、-SO-、-SO2-、-CONH-、-NHCO-、-NH-、-CO-、-NHCONH-、-CH2-;
R1、R2各自独立地选自下组:氢、C1-8烷基及其异构体、卤素、硝基、氨基、氰基、二氟甲基、三氟甲基、甲氧基、乙氧基、异丙氧基、二氟甲氧基、三氟甲氧基、羟基;
环M选自下组:苯基、含一个或多个杂原子的五元或六元杂环芳香基、取代的苯基及取代的五元或六元杂环芳香基、C3-8环烷基及其异构体;所述取代是指被选自下组的一个或多个基团取代:-OH、C1-8烷基、C1-8烷氧基、C6-14芳基、C3-8环烷基、卤素、羧基、氨基;上述取代基任选被选自下组的一个或多个基团进一步取代:C6-14芳基、卤素、C1-8烷基、C1-8烷氧基、C3-8环烷基、氨基。
2.根据权利要求1所述的化合物,其特征在于,环M选自下组:
3.根据权利要求1所述的化合物,其特征在于,Linker选自下组:-SO2-、-NHCO-、-CO-、-CH2-。
4.根据权利要求1所述的化合物,其特征在于,R1、R2各自独立地选自下组:氢、C1-8烷基及其异构体、卤素、甲氧基。
5.根据权利要求1所述的化合物,其特征在于,所述化合物选自下组:
6.根据权利要求1所述的化合物,其特征在于,所述化合物药学上可接受的盐为化合物与酸形成的酸加成盐,或为化合物与碱形成的碱加成盐;其中,所述酸包括盐酸、氢溴酸、硫酸、磷酸、乙酸、酒石酸、水杨酸、柠檬酸、苹果酸、甲磺酸、对甲苯磺酸、乳酸、丙酮酸、马来酸、琥珀酸;所述碱加成盐包括从无机碱衍生的盐和从有机无毒碱衍生的盐,所述从无机碱衍生的盐包括铝、铵、钾、钠、铁、铜、钙、亚铁、镁、锂、锰,所述从有机无毒碱衍生的盐包括一级、二级和三级胺盐、取代胺包括天然取代胺、环胺、乙醇胺、N-乙基吗啉、N-乙基哌啶、葡萄胺。
7.一种药物组合物,其特征在于,所述药物组合物包含药学上可接受的载体和一种或多种安全有效量的权利要求1所述的化合物、其水合物或其药学上可接受的盐。
8.一种如权利要求1所述的化合物、其水合物或其药学上可接受的盐作为GPR183拮抗剂的用途。
9.一种如权利要求1所述的化合物、其水合物或其药学上可接受的盐的用途,其特征在于,
用于制备治疗或缓解骨关节炎的药物。
10.根据权利要求8或9所述的用途,其特征在于,所述化合物抑制MMP-3和MMP-13的表达,具有软骨组织修复能力,促进软骨细胞分化。
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