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CN1846699A - 1－(取代苯基)－5－甲基－2－(1h) 吡啶酮(i)化合物用于制备抗除肾间质纤维化外其他器官纤维化或组织纤维化药物的应用 - Google Patents

1－(取代苯基)－5－甲基－2－(1h) 吡啶酮(i)化合物用于制备抗除肾间质纤维化外其他器官纤维化或组织纤维化药物的应用 Download PDF

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CN1846699A
CN1846699A CNA2005100314457A CN200510031445A CN1846699A CN 1846699 A CN1846699 A CN 1846699A CN A2005100314457 A CNA2005100314457 A CN A2005100314457A CN 200510031445 A CN200510031445 A CN 200510031445A CN 1846699 A CN1846699 A CN 1846699A
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fibrosis
akf
methyl
pyridone
cells
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陶立坚
胡高云
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Xiangya Hospital of Central South University
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Xiangya Hospital of Central South University
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Priority to CNA2005100314457A priority Critical patent/CN1846699A/zh
Priority to RU2007141892/15A priority patent/RU2007141892A/ru
Priority to EP06722303A priority patent/EP1878428A4/en
Priority to CA002603763A priority patent/CA2603763A1/en
Priority to JP2008505716A priority patent/JP2008535871A/ja
Priority to KR1020077018590A priority patent/KR20080018857A/ko
Priority to PCT/CN2006/000651 priority patent/WO2006108354A1/zh
Priority to CN2006800002161A priority patent/CN1953749B/zh
Priority to AU2006233433A priority patent/AU2006233433A1/en
Priority to TW095128659A priority patent/TW200808315A/zh
Publication of CN1846699A publication Critical patent/CN1846699A/zh
Priority to US11/742,664 priority patent/US20090005424A9/en
Priority to US12/204,629 priority patent/US20080319027A1/en
Priority to US12/491,506 priority patent/US20090258911A1/en
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Abstract

本发明涉及1－(取代苯基)－5－甲基－2－(1H)吡啶酮化合物的用途，具体地是在制备抗纤维化药物中的用途。本发明对各种导致器官或组织纤维化的ECM产生细胞进行的细胞实验表明，1－(取代苯基)－5－甲基－2－(1H)吡啶酮对各种ECM产生细胞具有抑制作用，且其作用强于吡非尼酮。因此，该类化合物可作为制备抗除肾间质纤维化外其他器官纤维化或组织纤维化药物的活性成分。

Description

1-(取代苯基)-5-甲基-2-(1H)吡啶酮(I)化合物 用于制备抗除肾间质纤维化外其他器官纤维化或组织纤维化药物的应用
技术领域
本发明涉及1-(取代苯基)-5-甲基-2-(1H)吡啶酮化合物的用途，具体地是在制备抗纤维化药物中的用途。
技术背景
纤维化(fibrosis)可发生于多种器官或组织，引起器官或组织内实质细胞减少，纤维结缔组织增多，最终可导致器官或组织结构破坏和功能减退，甚至器官衰竭。目前对器官或组织纤维化的发生机制、诊断方法和防治措施已进行了广泛的研究，现有技术中，在某些方面已取得了长足的进步，但仍有一些关键问题没有解决。
现已知，器官或组织纤维化是由于多种原因(如炎症、免疫、毒物、缺血及血流动力学改变等)引起实质细胞损伤，然后导致实质细胞的炎症变性、坏死、并激活相应的巨噬细胞释放多种细胞因子和生长因子，这些因子激活静息状态的细胞外基质(extracellular martrix，ECM)产生细胞，使之转化为肌成纤维细胞；肌成纤维细胞增殖，并分泌细胞因子，通过旁分泌方式再作用于巨噬细胞。肌成纤维细胞可合成大量胶原等ECM成分，同时ECM降解减少，从而造成器官或组织纤维化。因此，器官或组织纤维化的发生和发展是细胞、细胞因子和ECM等相互作用、多因素参加的结果。鉴于ECM产生细胞在器官或组织纤维化形成中的重要作用，目前治疗器官或组织纤维化的重要靶标之一是抑制ECM产生细胞的增殖、活化和诱导其凋亡。
由于各器官或组织功能、形态的不同，以及各器官或组织主要组成细胞的不同，使得不同器官或组织的纤维化在其发病机理中既有共性、也有个性；因此，在不同器官或组织纤维化的发病机制和治疗靶点上也存在一定的差异。以ECM主要产生细胞为例，肝脏中是肝星状细胞，肾小球中为肾小球系膜细胞，肾间质中为肾间质成纤维细胞，肺脏中为肺成纤维细胞，心脏中为心成纤维细胞，腹膜中为腹膜间皮细胞。
吡啶酮类化合物在现有技术中已有公开。
美国专利US3839346A公开了下式结构的吡啶酮类化合物。
其中，取代基R数目为0或1，R取代基的种类代表硝基、氯原子、烷基、甲氧基。并公开了此类吡啶酮具有抗炎、解热、降低血清尿酸水平、止痛等作用。
美国专利US4052509A也公开了式(O)结构的化合物，其中具体公开了苯环上的取代基为硝基、甲氧基、对甲基、三氟甲基、氯原子，还具体公开了苯环上没有取代基的化合物，即1-苯基-5-甲基-2-(1H)吡啶酮。这些化合物具有良好的抗炎和镇痛活性，并且毒性低。。
中国专利申请公开CN 1386737A提供了一类吡啶酮化合物，具有如下的结构。
当n＝1时，所述的取代基R表示F、Br、I。
当n＝2时，所述的取代基R表示F、Cl、Br、I，饱和直链烃基、氧代饱和直链烃基、卤代饱和直链烃基。
所述的取代基团R在苯环上的位置具有邻位、间位、对位等方式。
现有技术中(EP1138329A)，已知的一种有效的抗纤维化的药物是吡非尼酮(pirfenidone，PFD 5-甲基1-苯基2(1氢)吡啶酮)。实验表明，在肾纤维化、肺纤维化动物实验和特异性肺纤维化病人的临床治疗中，PFD均具有阻止甚至逆转ECM聚积的作用(Shimizu T，Fukagawa M，Kuroda T，et al.Pirfenidone prevents collagen accumulation in the remnant kidney in rats with partialnephrectomy.Kidney Int，1997，52(Suppl 63)：S239-243；Raghu G，Johnson WC，LockhartD，et al.Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent，pirfenidone.Am J Respir Crit Care Med，1999，159：1061-1069)，能够防止甚至逆转纤维化发生和瘢痕形成，这已经在大量的体外和动物实验中得到证实。PFD抗纤维化作用的机制尚处于研究之中，但大量的研究已经证明PFD是一种有效的细胞因子抑制剂，能够通过参与调节某些因子，抑制成纤维细胞的生物学活性，导致细胞增殖受抑，基质胶原合成减少。
本申请发明人曾在《中南大学学报》(医学版)(2004，29(2))上公开了化合物1-(3-氟苯基)-5-甲基-2-(1H)吡啶酮对肾间质细胞抗纤维化作用的细胞实验，结果显示其具有良好的抗纤维化效果。
发明内容
本发明是在上述现有技术基础上，进一步公开吡啶酮类化合物对除肾间质纤维化外其他器官纤维化或组织纤维化的作用。
本发明提供如式(I)所示化合物用于制备抗除肾间质纤维化外其他器官或组织纤维化药物的应用；
当n＝1时，所述的取代基R表示F、Cl、Br、I、硝基、烷基、氧代烷基、卤代烷基；
当n＝2时，所述的取代基R表示F、Cl、Br、I，烷基、氧代烷基、卤代烷基。
其中，优选n＝1时，R为氟原子、硝基、甲氧基、甲基、三氟甲基、氯原子。
最优选氟原子的位置为间位(即3-氟取代)。
本发明所涉及的烷基是指直链或支链的具有1-6个碳原子数的烷基，优选1-4个碳原子，更优选直链烷基。
本发明对各种导致器官或组织纤维化的ECM产生细胞进行的细胞实验表明，1-(取代苯基)-5-甲基-2-(1H)吡啶酮对各种ECM产生细胞具有抑制作用，且其作用强于吡非尼酮。因此，该类化合物可作为制备抗除肾间质纤维化外其他器官纤维化或组织纤维化药物的活性成分。
具体实施例
本发明中以1-(3-氟苯基)-5-甲基-2-(1H)吡啶酮为例说明1-(取代基苯基)-5-甲基-2-(1H)吡啶酮化合物在制备抗纤维化药物中的应用。1-(3-氟苯基)-5-甲基-2-(1H)吡啶酮可按中国专利申请CN 1386737中公开的方法制备。
实施例1
1-(3-氟苯基)-5-甲基-2-(1H)吡啶酮(AKF-PD)与吡非尼酮(pirfenidone，PD)抑制小鼠肾小球系膜细胞增殖的作用比较，用噻唑蓝(MTT)方法检测。细胞用含10％小牛血清的DMEM培养基常规培养，将细胞制成1×105/ml的细胞悬液，每孔100ul接种于96孔板中。待细胞贴壁后换无血清DMEM培养基，24小时后弃去无血清培养基，换含不同浓度AKF-PD和PD的含10％小牛血清的培养基，每个浓度设5个复孔。分别于加药后8、20、44小时后，每孔加MTT10ul，4小时后将MTT吸出，每孔加MTT溶解液100ul，15min后待MTT完全溶解，酶标仪570nm测OD值。结果见表1。
表1  AKF-P与PD对小鼠肾小球系膜细胞的影响
  组别                            各时间点光密度值
  12h   24h   48h
  对照组   0.363±0.002   0.591±0.002   0.851±0.009
  AKF-PD 100μg/ml   0.368±0.003   0.594±0.003   0.812±0.002*
  AKF-PD 500μg/ml   0.363±0.002   0.579±0.001*   0.675±0.006**
  AKF-PD 1000μg/ml   0.361±0.002   0.557±0.002**   0.583±0.005***
  AKF-PD 2500μg/ml   0.355±0.002   0.541±0.002***   0.552±0.004***
  PD 100μg/ml   0.362±0.003   0.591±0.002   0.830±0.003*+
  PD 500μg/ml   0.360±0.003   0.590±0.001+++   0.707±0.002**++
  PD 1000μg/ml   0.362±0.002   0.565±0.001***++   0.599±0.004***+
  PD 2500μg/ml   0.362±0.002+   0.548±0.002***+   0.559±0.002***
*p＜0.05vs对照组     **p＜0.01vs对照组     ***p＜0.001vs对照组
+p＜0.05vsAKF-PD     ++p＜0.01vsAKF-PD     +++p＜0.001vsAKF-PD
在24小时，AKF-PD 500μg/ml能抑制小鼠肾小球系膜细胞的增殖，而PD 500μg/ml不能抑制小鼠肾小球系膜细胞的增殖；1000μg/ml、2500μg/ml的AKF-PD和PD均能抑制小鼠肾小球系膜细胞的增殖，但AKF-PD1000μg/ml、2500μg/ml的作用强于同等剂量的pirfenidone。在48小时，100μg/ml、500μg/ml、1000μg/ml、2500μg/ml AKF-PD和PD均能抑制小鼠肾小球系膜细胞的增殖，但AKF-PD在100μg/ml、500μg/ml、1000μg/ml的作用强于同等剂量的pirfenidone。
结论：AKF-PD能抑制小鼠肾小球系膜细胞的增殖，且其作用强于pirfenidone。
实施例2
1-(3-氟苯基)-5-甲基-2-(1H)吡啶酮(AKF-PD)与吡非尼酮(pirfenidone，PD)抑制大鼠心肌成纤维细胞增殖的作用比较，用噻唑蓝(MTT)方法检测。细胞用含10％小牛血清的DMEM培养基常规培养，将细胞制成1×105/ml的细胞悬液，每孔100ul接种于96孔板中。待细胞贴壁后换无血清DMEM培养基，24小时后弃去无血清培养基，换含不同浓度AKF-PD和PD的含10％小牛血清的培养基，每个浓度设5个复孔。分别于加药后8、20、44小时后，每孔加MTT10ul，4小时后将MTT吸出，每孔加MTT溶解液100ul，15min后待MTT完全溶解，酶标仪570nm测OD值。结果见
表2。
表2  AKF-PD与PD对大鼠心肌成纤维细胞的影响
  组别                     各时间点光密度值
  12h   24h   48h
  对照组   0.330±0.002   0.445±0.016   0.684±0.008
  AKF-PD 100ug/ml   0.328±0.010   0.426±0.006*   0.620±0.018***
  AKF-PD 500ug/ml   0.326±0.003   0.408±0.009**   0.580±0.014***
  AKF-PD 1000ug/ml   0.332±0.006   0.392±0.008**   0.538±0.009***
  AKF-PD 2500ug/ml   0.325±0.008   0.377±0.013***   0.514±0.005***
  PD 100ug/ml   0.330±0.014   0.429±0.009*   0.654±0.007*+
  PD 500ug/ml   0.329±0.013   0.411±0.006*   0.612±0.014***++
  PD 1000ug/ml   0.331±0.009   0.403±0.010**+   0.597±0.013***+++
  PD 2500ug/ml   0.329±0.008   0.392±0.009**+   0.566±0.027**
*p＜0.05vs对照组     **p＜0.01vs对照组     ***p＜0.001vs对照组
+p＜0.05vsAKF-PD     ++p＜0.01vsAKF-PD     +++p＜0.001vsAKF-PD
在24小时，100μg/ml、500μg/ml、1000μg/ml、2500μg/ml AKF-PD和PD均能抑制大鼠心肌成纤维细胞的增殖，但AKF-PD 1000μg/ml、2500μg/ml的作用强于同等剂量的pirfenidone；在48小时，100μg/ml、500μg/ml、1000μg/ml、2500μg/ml AKF-PD和PD均能抑制大鼠心肌成纤维细胞的增殖，但AKF-PD100μg/ml、500μg/ml、1000μg/ml的作用强于同等剂量的pirfenidone。
结论：AKF-PD能抑制大鼠心肌成纤维细胞的增殖，且其作用强于pirfenidone。
实施例3
1-(3-氟苯基)-5-甲基-2-(1H)吡啶酮(AKF-PD)与吡非尼酮(pirfenidone，PD)抑制人肝星状细胞增殖的作用比较，用噻唑蓝(MTT)方法检测。细胞用含10％小牛血清的DMEM培养基常规培养，将细胞制成1×105/ml的细胞悬液，每孔100ul接种于96孔板中。待细胞贴壁后换无血清DMEM培养基，24小时后弃去无血清培养基，换含不同浓度AKF-PD和PD的含10％小牛血清的培养基，每个浓度设5个复孔。分别于加药后8、20、44小时后，每孔加MTT10ul，4小时后将MTT吸出，每孔加MTT溶解液100ul，15min后待MTT完全溶解，酶标仪570nm测OD值。结果见表3。
表3  AKF-PD与PD对人肝星状细胞的影响
  组别                         各时间点光密度值
  12h   24h   48h
  对照组   0.207±0.001   0.370±0.002   0.455±0.002
  AKF-PD 100μg/ml   0.202±0.001   0.366±0.002   0.442±0.006
  AKF-PD 500μg/ml   0.202±0.001*   0.341±0.003**   0.406±0.002***
  AKF-PD 1000μg/ml   0.198±0.001**   0.312±0.003***   0.385±0.004***
  AKF-PD 2500μg/ml   0.195±0.002**   0.273±0.005***   0.246±0.001***
  PD 100μg/ml   0.206±0.003   0.371±0.001   0.447±0.003
  PD 500μg/ml   0.202±0.001*   0.345±0.002**   0.413±0.001***++
  PD 1000μg/ml   0.201±0.001*   0.330±0.001***++   0.402±0.001***++
  PD 2500μg/ml   0.198±0.001**   0.278±0.001***+   0.306±0.002***+++
*p＜0.05vs对照组     **p＜0.01vs对照组     ***p＜0.001vs对照组
+p＜0.05vsAKF-PD     ++p＜0.01vsAKF-PD     +++p＜0.001vsAKF-PD
从12小时开始，500μg/ml、1000μg/ml、2500μg/ml的AKF-PD和PD均能抑制人肝星状细胞的增殖；但24小时AKF-PD 1000μg/ml、2500μg/ml的作用强于同等剂量的pirfenidone，48小时AKF-PD 500μg/ml、1000μg/ml、2500μg/ml的作用强于同等剂量的pirfenidone。
结论：AKF-PD能抑制人肝星状细胞的增殖，且其作用强于pirfenidone。
实施例4
1-(3-氟苯基)-5-甲基-2-(1H)吡啶酮(AKF-PD)与吡非尼酮(pirfenidone，PD)抑制大鼠肺成纤维细胞增殖作用的比较，用噻唑蓝(MTT)方法检测。细胞用含10％小牛血清的DMEM培养基常规培养，将细胞制成1×105/ml的细胞悬液，每孔100ul接种于96孔板中。待细胞贴壁后换无血清DMEM培养基，24小时后弃去无血清培养基，换含不同浓度AKF-PD和PD的含10％小牛血清的培养基，每个浓度设5个复孔。分别于加药后8、20、44小时后，每孔加MTT10ul，4小时后将MTT吸出，每孔加MTT溶解液100ul，15min后待MTT完全溶解，酶标仪570nm测OD值。结果见表4。
表4  AKF-PD与PD对大鼠肺成纤维细胞的影响
  组别                   各时间点光密度值
  12h   24h   48h
  对照组   0.235±0.003   0.302±0.008   0.402±0.015
  AKF-PD 100ug/ml   0.235±0.009   0.301±0.013   0.399±0.008
  AKF-PD 500ug/ml   0.237±0.016   0.295±0.017   0.376±0.006*
  AKF-PD 1000ug/ml   0.233±0.011   0.267±0.016**   0.369±0.009**
  AKF-PD 2500ug/ml   0.235±0.005   0.173±0.015***   0.241±0.008***
  PD 100ug/ml   0.234±0.012   0.304±0.021   0.400±0.011
  PD 500ug/ml   0.231±0.012   0.294±0.020   0.386±0.009**++
  PD 1000ug/ml   0.233±0.005   0.291±0.024++   0.379±0.010**+++
  PD 2500ug/ml   0.236±0.008   0.278±0.005**+++   0.245±0.008***
*p＜0.05vs对照组     **p＜0.01vs对照组    ***p＜0.001vs对照组
+p＜0.05vsAKF-PD     ++p＜0.01vsAKF-PD    +++p＜0.001vsAKF-PD
在24小时，AKF-PD 1000μg/ml能抑制大鼠肺成纤维细胞的增殖，AKF-PD 2500μg/ml和PD2500μg/ml均能抑制大鼠肺成纤维细胞的增殖，但AKF-PD 2500μg/ml的作用强于同等剂量的pirfenidone。在48小时，500μg/ml、1000μg/ml、2500μg/ml的AKF-PD和PD均能抑制大鼠肺成纤维细胞的增殖，但AKF-PD 500μg/ml、1000μg/ml的作用强于同等剂量的pirfenidone。
结论：AKF-PD能够抑制肺成纤维细胞的增殖，且其作用强于pirfenidone。
实施例5
1-(3-氟苯基)-5-甲基-2-(1H)吡啶酮(AKF-PD)与吡非尼酮(pirfenidone，PD)抑制人皮肤疤痕成纤维细胞增殖作用的比较，用噻唑蓝(MTT)方法检测。细胞用含10％小牛血清的DMEM培养基常规培养，将细胞制成1×105/ml的细胞悬液，每孔100ul接种于96孔板中。待细胞贴壁后换无血清DMEM培养基，24小时后弃去无血清培养基，换含不同浓度AKF-PD和PD的含10％小牛血清的培养基，每个浓度设5个复孔。分别于加药后8、20、44小时后，每孔加MTT10ul，4小时后将MTT吸出，每孔加MTT溶解液100ul，15min后待MTT完全溶解，酶标仪570nm测OD值。结果见表5。
表5  AKF-PD与PD对人皮肤疤痕成纤维细胞的影响
  组别                       各时间点光密度值
  12h   24h   48h
  对照组   0.195±0.008   0.263±0.005   0.381±0.001
  AKF-PD 100μg/ml   0.192±0.010   0.245±0.002*   0.366±0.006*
  AKF-PD 500μg/ml   0.192±0.006   0.238±0.004*   0.345±0.007*
  AKF-PD 1000μg/ml   0.192±0.009   0.221±0.004**   0.323±0.009***
  AKF-PD 2500μg/ml   0.190±0.002   0.198±0.008***   0.267±0.001***
  PD 100μg/ml   0.194±0.004   0.250±0.003*   0.366±0.006*
  PD 500μg/ml   0.191±0.008   0.245±0.004*+   0.350±0.003***++
  PD 1000μg/ml   0.190±0.008   0.330±0.001*++   0.328±0.004***++
  PD 2500μg/ml   0.193±0.004   0.278±0.001***+++   0.264±0.005***
*p＜0.05vs对照组    **p＜0.01vs对照组    ***p＜0.001vs对照组
+p＜0.05vsAKF-PD    ++p＜0.01vsAKF-PD    +++p＜0.001vsAKF-PD
在24小时，100μg/ml、500μg/ml、1000μg/ml、2500μg/ml的AKF-PD和PD均能抑制人皮肤疤痕成纤维细胞的增殖，但AKF-PD 500μg/ml、1000μg/ml、2500μg/ml的作用强于同等剂量的pirfenidone。在48小时，AKF-PD 500μg/ml、1000μg/ml的作用强于同等剂量的pirfenidone。
结论：AKF-PD能抑制人皮肤疤痕成纤维细胞的增殖，且其作用强于pirfenidone。
实施例6
1-(3-氟苯基)-5-甲基-2-(1H)吡啶酮(AKF-PD)与吡非尼酮(pirfenidone，PD)抑制人腹膜间皮细胞增殖作用的比较，用噻唑蓝(MTT)方法检测。细胞用含10％小牛血清的DMEM培养基常规培养，将细胞制成1×105/ml的细胞悬液，每孔100ul接种于96孔板中。待细胞贴壁后换无血清DMEM培养基，24小时后弃去无血清培养基，换含不同浓度AKF-PD和PD的含10％小牛血清的培养基，每个浓度设5个复孔。分别于加药后8、20、44小时后，每孔加MTT10ul，4小时后将MTT吸出，每孔加MTT溶解液100ul，15min后待MTT完全溶解，酶标仪570nm测OD值。结果见表6。
表6  AKF-PD)与PD对人腹膜间皮细胞的影响
  组别                     各时间点光密度值
  12h   24h   48h
  对照组   0.347±0.006   0.585±0.002   0.814±0.003
  AKF-PD 100ug/ml   0.344±0.004   0.583±0.004   0.807±0.007
  AKF-PD 500ug/ml   0.344±0.005   0.573±0.004*   0.758±0.010*
  AKF-PD 1000ug/ml   0.343±0.004   0.553±0.004***   0.704±0.003***
  AKF-PD 2500ug/ml   0.346±0.005   0.502±0.003***   0.646±0.006***
  PD 100ug/ml   0.346±0.006   0.584±0.005   0.810±0.006
  PD 500ug/ml   0.343±0.004   0.577±0.003*   0.766±0.004***
  PD 1000ug/ml   0.363±0.003   0.563±0.003***+   0.714±0.002***+++
  PD 2500ug/ml   0.345±0.005   0.512±0.006***+   0.648±0.009***
*p＜0.05vs对照组     **p＜0.01vs对照组    ***p＜0.001vs对照组
+p＜0.05vsAKF-PD     ++p＜0.01vsAKF-PD    +++p＜0.001vsAKF-PD
在24小时，500μg/ml、1000μg/ml、2500μg/ml的AKF-PD和PD均能抑制人腹膜间皮细胞的增殖，AKF-PD 1000μg/ml、2500μg/ml的作用强于同等剂量的pirfenidone；在48小时，AKF-PD 1000μg/ml抑制人腹膜间皮细胞增殖的作用强于同等剂量的pirfenidone。
结论：AKF-PD能够抑制人腹膜间皮细胞的增殖，且其作用强于pirfenidone。
注：上述实验所用细胞除心肌成纤维细胞、皮肤疤痕成纤维细胞和腹膜间皮细胞是用已知的方法进行原代培养获得外，其他细胞均有商品化产品可供购买。

Claims (3)

1.1-(取代苯基)-5-甲基-2-(1H)吡啶酮(I)化合物用于制备抗除肾间质纤维化外其他纤维化器官或组织纤维化的药物的应用；
Figure A2005100314450002C1
当n＝1时，所述的取代基R表示F、Cl、Br、I、硝基、烷基、氧代烷基、卤代烷基；
当n＝2时，所述的取代基R表示F、Cl、Br、I，烷基、氧代烷基、卤代烷基。
2、根据权利要求1所述的化合物在制备抗除肾间质纤维化外其他纤维化器官或组织纤维化药物的应用，其特征在于n＝1时，R选自氟原子、硝基、甲氧基、甲基、三氟甲基、氯原子。
3、根据权利要求2所述的化合物在制备抗除肾间质纤维化外其他纤维化器官或组织纤维化药物的应用，其特征在于R为3-氟。
CNA2005100314457A 2005-04-13 2005-04-13 1－(取代苯基)－5－甲基－2－(1h) 吡啶酮(i)化合物用于制备抗除肾间质纤维化外其他器官纤维化或组织纤维化药物的应用 Pending CN1846699A (zh)

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WO2009039773A1 (fr) * 2007-09-19 2009-04-02 Central South University Nouvelle utilisation thérapeutique d'une aryl-2(1h)-pyridone substituée en position 1
CN101652138B (zh) * 2007-09-19 2011-07-06 中南大学 1-取代芳基-2（1h）-吡啶酮化合物的新医药用途
CN101986781B (zh) * 2008-03-10 2013-08-28 广东东阳光药业有限公司 结晶型1-(3-氟苯基)-5-甲基-2-(1h)吡啶酮、其制备方法、及其组合物和应用
WO2009111947A1 (zh) 2008-03-10 2009-09-17 广东东阳关药业有限公司 结晶型1-（3-氟苯基）-5-甲基-2-（1h）吡啶酮、其制备方法、及其组合物和应用
WO2010045871A1 (en) * 2008-10-21 2010-04-29 Dieretech Investment Limited Composition and method for treating proteinuria
CN101921225A (zh) * 2009-06-11 2010-12-22 北京凯得尔森生物技术有限公司 吡啡尼酮类化合物、其制备方法和应用
CN101921225B (zh) * 2009-06-11 2013-04-03 北京凯得尔森生物技术有限公司 吡啡尼酮类化合物、其制备方法和应用
CN113456636A (zh) * 2021-07-09 2021-10-01 中南大学 一种氟非尼酮在制备急性肝损伤药物中的应用
CN114716365A (zh) * 2022-01-04 2022-07-08 大连理工大学 一类n-取代苯基-2-吡啶酮化合物或其可药用盐在治疗肺纤维化中的应用
CN114716365B (zh) * 2022-01-04 2024-03-01 大连理工大学 一类n-取代苯基-2-吡啶酮化合物或其可药用盐在治疗肺纤维化中的应用
WO2024235145A1 (zh) * 2023-05-12 2024-11-21 大连理工大学 一类n-取代苯基-2-吡啶酮及内过氧化物的制备和应用
CN118526493A (zh) * 2023-10-30 2024-08-23 大连理工大学 一类n-取代苯基-2-吡啶酮化合物在治疗癌症和缓解纤维化中的应用
CN120053452A (zh) * 2023-11-30 2025-05-30 长沙晶易医药科技股份有限公司 一种2,4-二取代-5-氟嘧啶衍生物的新用途
CN120053452B (zh) * 2023-11-30 2025-12-05 长沙晶易医药科技股份有限公司 一种2,4-二取代-5-氟嘧啶衍生物的新用途

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