CN114539237A - Ido抑制剂、制备方法、药物组合物和应用 - Google Patents
Ido抑制剂、制备方法、药物组合物和应用 Download PDFInfo
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- CN114539237A CN114539237A CN202210186978.6A CN202210186978A CN114539237A CN 114539237 A CN114539237 A CN 114539237A CN 202210186978 A CN202210186978 A CN 202210186978A CN 114539237 A CN114539237 A CN 114539237A
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- acid
- ido inhibitor
- compound
- inhibitor according
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Abstract
本发明公开了一类IDO抑制剂、制备方法、药物组合物和应用。该类抑制剂的结构如式(I)，包含其异构体、药学上可接受的盐或它们的混合物。该类IDO抑制剂及其药物组合物对IDO具有高效的抑制作用，可作为治疗类风湿性关节炎等炎症性疾病的药物；所制备药物在分子水平和动物水平均可以发挥药效，抗炎活性优于萘普生，并且该类化合物合成方法简便，易操作。
Description
技术领域
本发明涉及一类IDO抑制剂、制备方法、药物组合物和应用，尤其涉及一类可制备为治疗类风湿性关节炎等炎症性疾病药物的IDO抑制剂、制备方法、药物组合物和应用。
背景技术
类风湿性关节炎(Rheumatoid Arthritis,RA)是一种慢性、以炎性滑膜炎为主的自身免疫性疾病，其临床主要表现为外周关节的非特异性炎症，患病关节及其周围组织呈现进行性破坏，滑膜炎长久反复发作，引起关节内骨和软骨的破坏，继而导致关节功能障碍，甚至功能丧失。并且随着老龄化加剧而呈现上升趋势，其中，老年群体(年龄＞65岁)的患病率最高，女性发病率高于男性。相当比例的RA患者可见骨质破坏，关节严重破坏的患者几乎丧失劳动力。
目前治疗RA的主要药物包括非甾体抗炎药、糖皮质激素、免疫抑制剂、生物制剂和小分子靶向药等，这些药物有效地改善了患者的病情，但也存在各自的局限性。因此，寻找新的治疗方法、特别是作用于新靶点的药物备受关注。
吲哚胺2,3-双加氧酶(Indoleamine 2,3-dioxygenase,IDO)是介导Trp-Kyn途径的关键限速酶，其存在三种亚型，即吲哚胺2,3-双加氧酶1(indoleamine 2,3-dioxygenase1,IDO1)、吲哚胺2,3-双加氧酶2(indoleamine 2,3-dioxygenase 2,IDO2)以及色氨酸2,3-双加氧酶(Tryptophan 2,3-dioxygenase,TDO)。近年来，IDO2与肿瘤和机体自身免疫相关方面的作用逐渐被揭示，研究表明IDO2可以直接作用于B细胞或通过B-T细胞之间的相互作用介导自身免疫性关节炎的病理机制，使得IDO2成为治疗RA的一个潜在靶点，目前尚未有针对IDO2靶点的药物成功上市。
发明内容
发明目的：针对现有化合物对IDO2的抑制活性较弱，且选择性不高等不足，本发明旨在提供一类具有优异的抗炎活性的IDO抑制剂、制备方法、药物组合物和应用。
技术方案：作为本发明涉及的第一方面，本发明的IDO抑制剂具有式(I)的结构，所述IDO抑制剂包含其异构体、药学上可接受的盐或它们的混合物：
其中：
m选自1、2或3；n选自0、1、2、3或4；X选自O或NH；
R1选自五元或六元芳杂环基；
R2选自H、F、Cl、Br、I、CF3、CHF2、CN、OCH3、OH或CH3，R2为单取代或多取代。
优选，上述结构中：
m选自1；n选自1或2；X选自NH。
优选，上述结构中：
R1选自：
其中，R3选自H、F、Cl、Br、I、CF3、CHF2、CN、OCH3、OH或CH3，R3为单取代或多取代；Y选自NH或O。
优选，上述结构中：
R2选自H、F、Cl、Br、CF3或CN，R2为单取代或双取代。
进一步优选，上述结构中：
R1选自：
其中，R3选自H、F、Cl、Br、CF3、CN或OCH3，R3为单取代或双取代。
更具体地，上述IDO抑制剂选自以下任一化合物：
作为本发明涉及的第二方面，上述IDO抑制剂的制备方法为：
化合物(II)与化合物(III)，经取代、环合、氧化、还原-偶联、叠氮化、开环、环合反应得到化合物(I)；
其中，R1、R2、m、n、X的定义如前所述。
具体地，由化合物II与取代苄胺III反应制备化合物IV，所用碱选自三乙胺、吡啶、N,N-二异丙基乙胺(DIPEA)、4-二甲氨基吡啶(DMAP)、碳酸钾、碳酸钠、碳酸铯或醋酸钠，优选碳酸钠；所用溶剂选自甲醇、乙醇、四氢呋喃或上述溶剂与水组成的混合溶剂，优选乙醇和水的混合溶剂。
由化合物IV与N,N'-羰基二咪唑(CDI)反应制备化合物V，所用溶剂选自二氯甲烷、乙酸乙酯、四氢呋喃、1,4-二氧六环、N,N-二甲基甲酰胺或任意两者组成的混合溶剂，优选乙酸乙酯。
由化合物V与过氧化氢(H2O2)反应制备化合物VI，所用酸选自盐酸、乙酸或三氟乙酸，优选三氟乙酸。
由化合物VI与化合物VII反应制备化合物VIII，所用碱选自氢氧化锂、氢氧化钠或氢氧化钾，优选氢氧化钠；所用溶剂选自二氯甲烷、乙酸乙酯、四氢呋喃、1,4-二氧六环、N,N-二甲基甲酰胺或上述溶剂与水组成的混合溶剂，优选四氢呋喃和水的混合溶剂。
由化合物VIII制备化合物IX，所用叠氮试剂选自叠氮钠和叠氮基三甲基硅烷，优选叠氮钠；所用溶剂选自四氢呋喃、1,4-二氧六环、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或任意两者组成的混合溶剂，优选N,N-二甲基甲酰胺。
由化合物IX经水解制备化合物X，所用碱选自氢氧化锂、氢氧化钠、氢氧化钾、碳酸钾或碳酸钠，优选氢氧化钠；所用溶剂选自甲醇、四氢呋喃、1,4-二氧六环、乙腈或N,N-二甲基甲酰胺与水的混合溶剂，优选甲醇与水或四氢呋喃与水的混合溶剂。
由化合物X与相应炔类化合物XI反应制备化合物I，所用的催化剂选自硫酸铜/抗坏血酸钠、氯化铜、溴化铜、氯化亚铜、溴化亚铜、碘化亚铜或铜粉，优选硫酸铜/抗坏血酸钠；所用的惰性气体选自氮气或氩气；所用溶剂选自四氢呋喃、1,4-二氧六环、乙腈、乙醇、甲醇、乙二醇二甲醚、二氯甲烷、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或上述溶剂与水组成的混合溶剂，优选四氢呋喃与水的混合溶剂。
将相应的酸与以上方法制备的化合物(I)成盐，即得上述IDO抑制剂的药学上可接受的盐。
作为本发明涉及的第三方面，本发明的药物组合物包含上述IDO抑制剂以及药学上可接受的载体。
上述IDO抑制剂可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、糖浆、悬浮剂或注射剂，制剂可以加入香料、甜味剂、液体/固体填料、稀释剂等常用药用辅料。
作为本发明涉及的第四方面，上述IDO抑制剂及其药物组合物作为IDO抑制剂药物，可用于治疗类风湿性关节炎等炎症性疾病。
有益效果：与现有技术相比，本发明具有如下显著优点：
(1)该类IDO抑制剂及其药物组合物可在纳摩尔浓度水平有效抑制IDO2，抑制率最优达到40％以上；
(2)该类IDO抑制剂及其药物组合物应用广泛，可作为治疗类风湿性关节炎等炎症性疾病的药物；所述药物在分子水平和动物水平均可以发挥药效，并且在相同的给药剂量下，抗炎活性显著优于萘普生；
(3)化合物制备方法简便、易操作。
附图说明
图1为化合物I-1对角叉菜胶诱导的小鼠足肿胀度结果；
图2为化合物I-1对角叉菜胶诱导的小鼠足肿胀抑制效果。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例1：(Z)-N-((1-(2-((4-(N-(3-溴苄基)-N'-羟基甲脒)-1,2,5-噁二唑-3-基)氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)吡啶甲酰胺(I-1)的合成
(Z)-4-氨基-N-(3-溴苄基)-N'-羟基-1,2,5-噁二唑-3-甲脒(IV-1)的合成
向2L三颈瓶中依次加入原料(Z)-4-氨基-N'-羟基-1,2,5-噁二唑-3-碳亚胺酰氯(II-1,21.0g,129.7mmol)、3-溴苄胺(III-1,20.0g,108.1mmol)和95％乙醇(500mL)搅拌，向反应液中加入200mLNa2CO3溶液(17.2g,162.0mmol)，升温至60℃加热搅拌5小时，TLC监测(石油醚:乙酸乙酯＝5:1)反应完全；将反应液转移至2L茄型瓶中，减压蒸除乙醇，再加入500mL水，于25℃搅拌1小时，抽滤，滤饼用水(100×3mL)洗涤，45℃烘干；所得粗品经乙酸乙酯/正己烷(V:V＝1:5)精制，抽滤，45℃烘干，得25.7g浅黄色固体IV-1，收率76.6％，m.p.100.0–102.0℃。1H-NMR(300MHz,DMSO-d6),δ(ppm):10.86(s,1H),7.43–7.38(m,1H),7.40–7.36(m,1H),7.24(t,J＝7.6Hz,1H),7.22–7.17(m,1H),7.03(t,J＝7.2Hz,1H),6.28(s,2H),4.61(d,J＝7.2Hz,2H).
3-(4-氨基-1,2,5-噁二唑-3-基)-4-(3-溴苄基)-1,2,4-噁二唑-5(4H)-酮(V-1)的合成
在1L三颈瓶中加入化合物IV-1(25.5g,81.7mmol)和乙酸乙酯(300mL)，搅拌下加入CDI(20.0g,122.5mmol)，50℃搅拌反应6小时，TLC监测(石油醚:乙酸乙酯＝5:1)反应完全后，加入水(300mL)进行洗涤，有机相依次用2mol/L盐酸水溶液(100mL×2)和饱和氯化钠溶液(300mL×2)洗涤，无水硫酸钠干燥；抽滤，滤液减压蒸除溶剂，粗品经甲醇重结晶，得22.4g类白色固体V-1，收率81.1％，m.p.152.0–154.0℃。1H-NMR(300MHz,DMSO-d6),δ(ppm):7.66–7.61(m,1H,-ArH),7.55(dt,J＝7.2,1.9Hz,1H),7.43–7.32(m,2H),6.65(s,2H),5.13(s,2H).
4-(3-溴苄基)-3-(4-硝基-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(VI-1)的合成
在2L三颈瓶中依次加入化合物V-1(22.5g,66.5mmol)和三氟乙酸(300mL)，搅拌，反应液冷却至0℃，缓慢滴加30％H2O2溶液(100mL)，滴加完毕，升温至45℃反应24小时，TLC监测(石油醚:乙酸乙酯＝10:1)反应基本完全后，将反应液冷却至0℃，缓慢滴加500mL亚硫酸钠溶液(126.0g,1.0mol)淬灭反应，并维持内温不超过5℃。向反应液中加入乙酸乙酯(500mL)进行萃取，有机相用水(300mL×3)洗涤，无水硫酸钠干燥，抽滤，滤液减压蒸除溶剂，粗品经硅胶柱层析纯化(洗脱剂：石油醚:乙酸乙酯＝25:1～5:1)，得11.1g黄色固体VI-1，收率45.5％，m.p.99.0–100.0℃。1H-NMR(300MHz,CDCl3),δ(ppm):7.52(dt,J＝7.5,1.8Hz,1H),7.46–7.41(m,1H),7.34–7.19(m,2H),5.08(s,2H).
4-(3-溴苄基)-3-(4-((2-溴乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(VIII-1)的合成
向250mL的三颈瓶中加入化合物VI-1(11.1g,30.1mmol)和THF(100mL)，搅拌溶解，冷却至0～5℃，缓慢加入溴乙胺溴化氢盐(VII-1,12.3g,60.2mmol)，再缓慢滴加2mol/L氢氧化钠溶液(45mL,90.0mmol)，维持0～5℃反应1.5小时，TLC监测(石油醚:乙酸乙酯＝10:1)反应基本完全后，将反应液转移至500mL茄型瓶，减压蒸除溶剂，加入乙酸乙酯(120mL)与水(120mL)进行萃取，有机相用饱和氯化钠溶液(100mL×2)洗涤，无水硫酸钠干燥；抽滤，滤液减压蒸除溶剂，粗品经硅胶柱层析纯化(洗脱剂：石油醚:乙酸乙酯＝50:1～15:1)，得7.4g黄色油状物VIII-1，收率54.9％。1H-NMR(300MHz,CDCl3),δ(ppm):7.64(t,J＝1.9Hz,1H),7.52–7.49(m,1H),7.45–7.41(m,1H),7.32–7.26(m,1H),5.80(t,J＝6.0Hz,1H),5.27(s,2H),3.86(q,J＝6.0Hz,2H),3.66(t,J＝6.0Hz,2H).
3-(4-((2-叠氮乙基)氨基)-1,2,5-噁二唑-3-基)-4-(3-溴苄基)-1,2,4-噁二唑-5(4H)-酮(IX-1)的合成
向250mL三颈瓶中加入化合物VIII-1(7.4g,16.63mmol)和DMF(50mL)，搅拌溶解，冷却至0～5℃，缓慢加入叠氮化钠(1.3g,20.0mmol)，加毕，于50℃反应4小时，TLC监测(石油醚:乙酸乙酯＝10:1)反应完全后，冷却至0～5℃，缓慢滴加水(60mL)，有固体析出，抽滤，滤饼用水(15mL×3)洗涤,滤液用次氯酸钠溶液处理，40℃烘干，得5.5g淡黄色固体IX-1，收率81.1％，m.p.80.0–81.0℃。1H-NMR(300MHz,CDCl3),δ(ppm):7.63–7.58(m,1H),7.50–7.46(m,1H),7.42–7.38(m,1H),7.24(t,J＝7.9Hz,1H),5.64(t,J＝6.4Hz,1H),5.24(s,2H),3.68–3.60(m,4H).
(Z)-4-((2-叠氮乙基)氨基)-N-(3-溴苄基)-N'-羟基-1,2,5-噁二唑-3-甲脒(X-1)的合成
向100mL三颈瓶中加入化合物IX-1(5.50g,13.5mmol)和THF(40mL)，搅拌溶解并冷却至0～5℃，缓慢滴加2mol/L氢氧化钠溶液(20mL,40.0mmol)，滴毕后于50℃搅拌反应4小时，TLC监测(石油醚:乙酸乙酯＝5:1)反应完毕，将反应液转移至250mL茄型瓶中，减压蒸除溶剂，残余物加水(50mL)，二氯甲烷萃取(40mL×3)，合并有机层，用饱和氯化钠溶液(50mL×2)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩，得4.40g黄色油状物X-1，收率85.7％。1H-NMR(300MHz,DMSO-d6),δ(ppm):10.94(s,1H),7.44(t,J＝1.7Hz,1H),7.41(m,1H),7.27(t,J＝7.6Hz,1H),7.23–7.18(m,1H),7.14(t,J＝7.2Hz,1H),6.47(t,J＝5.9Hz,1H),4.63(d,J＝7.2Hz,2H,3.55(q,J＝5.8Hz,2H),3.43(t,J＝5.8Hz,2H).
(Z)-N-((1-(2-((4-(N-(3-溴苄基)-N'-羟基甲脒)-1,2,5-噁二唑-3-基)氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)吡啶甲酰胺(I-1)的合成
向100mL三颈瓶中依次加入化合物X-1(2.20g,5.77mmol)、N-(丙基-2-炔-1-基)-吡啶甲酰胺(XI-1,1.10g,6.92mmol)和乙腈(24mL)，搅拌溶解，将6mL现配制的硫酸铜(183mg,1.15mmol)/抗坏血酸钠(445mg,2.30mmol)水溶液滴加入反应液，抽真空氮气保护，25℃搅拌反应8小时，TLC监测(二氯甲烷:甲醇＝25:1)原料基本反应完全后，将反应液转移至50mL茄型瓶，减压蒸除溶剂，快速硅胶柱层析纯化(洗脱剂：二氯甲烷:甲醇＝1:0～50:1)，得到的粗品经正己烷/乙酸乙酯精制(V:V＝1:1)，40℃烘干，得1.55g白色固体I-1，收率49.7％，m.p.127.0–128.0℃。1H-NMR(300MHz,DMSO-d6),δ(ppm):10.86(s,1H),9.27(t,J＝6.0Hz,1H),8.67(d,J＝4.7Hz,1H),8.10–7.97(m,3H),7.65–7.61(m,1H),7.43–7.39(m,2H),7.27(t,J＝7.6Hz,1H),7.19(d,J＝7.7Hz,1H),7.11(t,J＝7.2Hz,1H),6.44(t,J＝5.9Hz,1H),4.59–4.52(m,6H),3.67(q,J＝6.1Hz,2H).
实施例2：(Z)-N-((1-(2-((4-(N-(3-溴苄基)-N'-羟基甲脒)-1,2,5-噁二唑-3-基)氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-1H-吡咯-2-甲酰胺(I-2)的合成
以化合物X-1(0.10g,0.26mmol)、N-(丙基-2-炔-1-基)-1H-吡咯-2-甲酰胺中(XI-2,45mg,0.31mmol)和硫酸铜(8mg,0.05mmol)/抗坏血酸钠(20mg,0.10mmol)为原料，操作同I-1，得60mg白色固体I-2，收率43.8％，m.p.156.0–158.0℃。1H-NMR(300MHz,DMSO-d6),δ(ppm):11.46(s,1H),10.85(s,1H),8.52(s,1H),7.96(s,1H),7.49–7.38(m,2H),7.28(t,J＝7.6Hz,1H),7.21(d,J＝7.8Hz,1H),7.08(t,J＝7.1Hz,1H),6.88–6.81(m,2H),6.43(s,1H),6.10(s,1H),4.66–4.53(m,4H),4.48(d,J＝5.7Hz,2H),3.68(d,J＝6.1Hz,2H).
实施例3：(Z)-N-((1-(2-((4-(N-(3-氯苄基)-N'-羟基甲脒)-1,2,5-噁二唑-3-基)氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-1H-吡咯-2-甲酰胺(I-3)的合成
(Z)-4-氨基-N-(3-氯苄基)-N'-羟基-1,2,5-噁二唑-3-甲脒(IV-2)的合成
以化合物II-1(6.9g,42.5mol)、3-氯苄胺(III-2,5.0g,35.4mmol)和Na2CO3(5.6g,53.1mmol)为原料，操作同IV-1，得4.8g类白色固体IV-2，收率50.7％，m.p.106.0–108.0℃。1H-NMR(400MHz,DMSO-d6),δ(ppm):10.84(s,1H,),7.31(t,J＝7.7Hz,1H),7.29–7.23(m,2H),7.15(d,J＝7.6Hz,1H),7.04(t,J＝7.2Hz,1H),6.29(s,2H),4.62(d,J＝7.2Hz,2H).
3-(4-氨基-1,2,5-噁二唑-3-基)-4-(3-氯苄基)-1,2,4-噁二唑-5(4H)-酮(V-2)的合成
以化合物IV-2(4.5g,16.8mmol)和CDI(4.0g,25.2mol)为原料，操作同V-1，得4.0g白色固体V-2，收率82.2％，m.p.134.0–136.0℃。1H-NMR(300MHz,CDCl3),δ(ppm):7.49(s),7.42–7.32(m,3H),5.28(s,2H),5.17(s,2H).
4-(3-氯苄基)-3-(4-硝基-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(VI-2)的合成
以化合物V-2(3.7g,12.6mmol)、三氟乙酸(57mL)和30％H2O2溶液(19mL)为原料，操作同VI-1，得1.9g淡黄色固体VI-2，收率47.7％，m.p.84.0–86.0℃。1H-NMR(300MHz,CDCl3),δ(ppm):7.43(dd,J＝6.8,2.2Hz,1H),7.29–7.21(m,1H),7.17(t,J＝8.5Hz,1H),5.10(s,2H).
3-(4-((2-溴乙基)氨基-1,2,5-噁二唑-3-基)-4-(3-氯苄基)-1,2,4-噁二唑-5(4H)-酮(VIII-2)的合成
以化合物VI-2(1.0g,3.1mmol)、VII-1(1.2g,6.1mmol)和2mol/L氢氧化钠溶液(4.6mL,9.2mmol)为原料，操作同VIII-1，得490mg类白色固体VIII-2，收率39.6％，m.p.64.0–66.0℃。1H-NMR(300MHz,DMSO-d6),δ(ppm):7.51(s,1H),7.44–7.40(m,2H),7.38–7.33(m,1H),6.83(t,J＝5.6Hz,1H),5.14(s,2H),3.71–3.68(m,4H).
3-(4-((2-叠氮乙基)氨基-1,2,5-噁二唑-3-基)-4-(3-氯苄基)-1,2,4-噁二唑-5(4H)-酮(IX-2)的合成
以化合物VIII-2(450mg,1.12mmol)和叠氮化钠(80mg,1.23mmol)为原料，操作同IX-1，得368mg油状物IX-2，收率90.8％。1H-NMR(300MHz,CDCl3),δ(ppm):7.48(s,1H),7.41–7.36(m,1H),7.36–7.31(m,2H),5.65(t,J＝4.9Hz,1H),5.27(s,2H),3.67–3.59(m,4H).
(Z)-4-((2-叠氮乙基)氨基)-N-(3-氯苄基)-N'-羟基-1,2,5-噁二唑-3-甲脒(X-2)的合成
以化合物IX(320mg,0.88mmol)和2mol/L氢氧化钠溶液(1.3mL,2.64mmol)为原料，操作同X-1，得206mg油状物X-2，收率69.7％。1H-NMR(300MHz,DMSO-d6),δ(ppm):10.92(s,1H),7.33(t,J＝7.6Hz,1H),7.30–7.26(m,2H),7.18–7.09(m,2H),6.46(t,J＝5.9Hz,1H),4.64(d,J＝7.2Hz,2H),3.56(t,J＝5.7Hz,2H),3.43(q,J＝5.8Hz,2H).
(Z)-N-((1-(2-((4-(N-(3-氯苄基)-N'-羟基甲脒)-1,2,5-噁二唑-3-基)氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-1H-吡咯-2-甲酰胺(I-3)的合成
以化合物X-2(0.10g,0.29mmol)、XI-2(52mg,0.35mmol)和硫酸铜(9mg,0.06mmol)/抗坏血酸钠(22mg,0.11mmol)为原料，操作同I-1，得72mg类白色固体I-3，收率51.4％，m.p.220.0–222.0℃。1H-NMR(300MHz,DMSO-d6),δ(ppm):11.46(s,1H),10.85(s,1H),8.52(t,J＝5.8Hz,1H),7.96(s,1H),7.36–7.26(m,3H),7.17(d,J＝7.3Hz,1H),7.08(t,J＝7.2Hz,1H),6.88–6.78(m,2H),6.43(t,J＝5.9Hz,1H),6.10(q,J＝2.6Hz,1H),4.64–4.52(m,4H),4.48(d,J＝5.8Hz,2H),3.68(q,J＝6.0Hz,2H).
实施例4：(Z)-N-((1-(2-((4-(N-(3-溴-4-氟苄基)-N'-羟基甲脒)-1,2,5-噁二唑-3-基)氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-1H-吡咯-2-甲酰胺(I-4)的合成
(Z)-4-氨基-N-(3-溴-4-氟苄基)-N'-羟基-1,2,5-噁二唑-3-甲脒(IV-3)的合成
以化合物II-1(4.7g,29.36mol)、3-溴-4-氟苄胺(III-3,5.0g,24.4mmol)和Na2CO3(3.9g,36.6mmol)为原料，操作同IV-1，经硅胶柱层析纯化(洗脱剂:石油醚:乙酸乙酯＝20:1～5:1)，得5.5g油状物IV-3，收率68.8％。1H-NMR(300MHz,DMSO-d6+D2O),δ(ppm):7.70–7.60(m,1H,-ArH),7.45–7.38(m,2H),6.60(s,2H),5.11(s,2H).
3-(4-氨基-1,2,5-噁二唑-3-基)-4-(3-溴-4-氟苄基)-1,2,4-噁二唑-5(4H)-酮(V-3)的合成
以化合物IV-3(5.0g,15.1mmol)和CDI(3.7g,22.7mol)为原料，操作同V-1，得4.3g白色固体V-3，收率80.5％，m.p.144.0–146.0℃。1H-NMR(300MHz,DMSO-d6),δ(ppm):7.79(d,J＝6.5Hz,1H),7.45(s,1H),7.39(t,J＝8.6Hz,1H),6.64(s,2H),5.11(s,2H).
4-(3-溴-4-氟苄基)-3-(4-硝基-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(VI-3)的合成
以化合物V-3(4.0g,11.2mmol)、三氟乙酸(50mL)和30％H2O2溶液(17mL)为原料，操作同VI-1，经硅胶柱层析纯化(洗脱剂：石油醚:乙酸乙酯＝40:1～10:1)，得1.7g油状物VI-3，收率40.6％。1H-NMR(300MHz,CDCl3),δ(ppm):7.59–7.52(m,1H),7.37–7.32(m,1H),7.21–7.18(m,1H),5.17(s,2H).
4-(3-溴-4-氟苄基)-3-(4-((2-溴乙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(VIII-3)的合成
以化合物VI-3(1.5g,3.9mmol)、VII-1(1.6g,7.8mmol)和2mol/L氢氧化钠溶液(VII-1,5.9mL,11.7mmol)为原料，操作同VIII-1，经硅胶柱层析纯化(洗脱剂：石油醚:乙酸乙酯＝30:1～5:1)，得1.0g油状物VIII-3，收率61.2％。1H-NMR(300MHz,CDCl3),δ(ppm):7.74(dd,J＝6.4,2.2Hz,1H),7.50–7.45(m,1H),7.15–7.10(m,1H),5.79(t,J＝6.0Hz,1H),5.25(s,2H),3.86(q,J＝6.0Hz,2H),3.67(t,J＝5.9Hz,2H).
3-(4-((2-叠氮乙基)氨基)-1,2,5-噁二唑-3-基)-4-(3-溴-4-氟苄基)-1,2,4-噁二唑-5(4H)-酮(IX-3)的合成
以化合物VIII-3(0.9g,1.94mmol)和叠氮化钠(138mg,2.13mmol)为原料，操作同IX-1，得707mg油状物IX-3，收率85.8％。1H-NMR(300MHz,CDCl3),δ(ppm):7.71(dd,J＝6.4,2.2Hz,1H),7.51–7.42(m,1H),7.12(t,J＝8.4Hz,1H),5.70(t,J＝6.5Hz,1H),5.23(s,2H),3.65–3.58(m,4H).
(Z)-4-((2-叠氮乙基)氨基)-N-(3-溴-4-氟苄基)-N'-羟基-1,2,5-噁二唑-3-甲脒(X-3)的合成
以化合物IX-3(650mg,1.40mmol)和2mol/L氢氧化钠溶液(2.1mL,4.20mmol)为原料，操作同IX-1，经硅胶柱层析纯化(洗脱剂：石油醚:乙酸乙酯＝15:1～3:1)，得321mg油状物IX-3，收率57.6％。1H-NMR(300MHz,DMSO-d6),δ(ppm):10.94(s,1H),7.56(dd,J＝6.8,2.0Hz,1H),7.32(t,J＝8.6Hz,1H),7.26–7.23(m,1H),7.14(t,J＝7.2Hz,1H),6.45(t,J＝5.9Hz,1H),4.60(d,J＝7.2Hz,2H),3.55(t,J＝5.7Hz,2H),3.43(q,J＝5.8Hz,2H).
(Z)-N-((1-(2-((4-(N-(3-溴-4-氟苄基)-N'-羟基甲脒)-1,2,5-噁二唑-3-基)氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-1H-吡咯-2-甲酰胺(I-4)的合成
以化合物X-3(0.10g,0.25mmol)、XI-2(44mg,0.30mmol)和硫酸铜(7mg,0.05mmol)/抗坏血酸钠(20mg,0.10mmol)为原料，操作同I-1，得73mg类白色固体I-4，收率53.2％，m.p.174.0–176.0℃。1H-NMR(300MHz,DMSO-d6),δ(ppm):11.46(s,1H),10.86(s,1H),8.53(t,J＝5.9Hz,1H),7.96(s,1H),7.56(dd,J＝6.8,2.1Hz,1H),7.32(t,J＝8.6Hz,1H),7.28–7.20(m,1H),7.09(t,J＝7.2Hz,1H),6.87–6.80(m,2H),6.42(t,J＝5.9Hz,1H),6.09(q,J＝2.7Hz,1H),4.56–4.45(m,4H),4.46(d,J＝5.8Hz,2H),3.67(q,J＝6.1Hz,2H).
实施例5：(Z)-N-((1-(2-((4-(N-(3-溴苄基)-N'-羟基甲脒)-1,2,5-噁二唑-3-基)氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)呋喃-2-甲酰胺(I-5)的合成
以化合物X-1(0.10g,0.25mmol)、N-(丙基-2-炔-1-基)呋喃-2-甲酰胺(XI-3,70mg,01.47mmol)和硫酸铜(7mg,0.05mmol)/抗坏血酸钠(20mg,0.10mmol)为原料，操作同I-1，得95mg类白色固体I-5，收率45.9％，m.p.194.0–196.0℃。1H-NMR(300MHz,DMSO-d6),δ(ppm):10.85(s,1H),8.92(t,J＝5.9Hz,1H),7.99(s,1H),7.86(s,1H),7.44–7.39(m,2H),7.27(t,J＝7.6Hz,1H),7.20(d,J＝7.7Hz,1H),7.15(d,J＝3.5Hz,1H),7.10(t,J＝7.2Hz,1H),6.65(dd,J＝3.5,1.8Hz,1H),6.43(t,J＝5.9Hz,1H),4.64–4.54(m,4H),4.47(d,J＝5.9Hz,2H),3.68(q,J＝6.0Hz,2H).
实施例6：(Z)-(1-(2-((4-(N-(3-溴苄基)-N'-羟基甲脒)-1,2,5-噁二唑-3-基)氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-1H-吡咯-2-甲酸酯(I-6)的合成
以化合物X-1(0.15g,0.39mmol)、丙基-2-炔-1-基1H-吡咯-2-甲酰胺(XI-4,70mg,0.47mmol)和硫酸铜(13mg,0.08mmol)/抗坏血酸钠(30mg,0.15mmol)为原料，操作同I-1，得87mg类白色固体I-6，收率42.0％，m.p.>250℃。1H-NMR(300MHz,DMSO-d6),δ(ppm):11.95(s,1H),10.84(s,1H),8.21(s,1H),7.44–7.38(m,2H),7.27(t,J＝7.6Hz,1H),7.20(d,J＝7.7Hz,1H),7.10(t,J＝7.2Hz,1H),7.05(q,J＝2.5Hz,1H),6.81–6.78(m,1H),6.46(t,J＝5.9Hz,1H),6.21–6.17(m,1H),5.31(s,2H),4.67–4.52(m,4H),3.71(q,J＝5.9Hz,2H).
实施例7：(Z)-N-((1-(2-((4-(N-(3-溴苄基)-N'-羟基甲脒)-1,2,5-噁二唑-3-基)氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)异烟酰胺(I-7)的合成
以化合物X-1(0.15g,0.39mmol)、N-(丙基-2-炔-1-基)异烟酰胺(XI-5,75mg,0.47mmol)和硫酸铜(13mg,0.08mmol)/抗坏血酸钠(30mg,0.15mmol)为原料，操作同I-1，得97mg类白色固体I-7，收率45.7％，m.p.147.0–149.0℃。1H-NMR(300MHz,DMSO-d6),δ(ppm):10.84(s,1H),9.36(t,J＝5.7Hz,1H),8.79–8.71(m,2H),8.03(s,1H),7.84–7.75(m,2H),7.47–7.36(m,2H),7.33–7.16(m,2H),7.08(t,J＝7.2Hz,1H),6.44(t,J＝5.9Hz,1H),4.63–4.50(m,6H),3.69(q,J＝6.0Hz,2H).
实施例8：(Z)-N-((1-(2-((4-(N-(3-溴苄基)-N'-羟甲脒)-1,2,5-噁二唑-3-基)氨基)乙基)-1H-1,2,3-三氮唑-4-基)乙基)吡啶甲酰胺(I-8)的合成
以化合物X-1(0.15g,0.39mmol)、N-(丁基-3-炔-1-基)吡啶甲酰胺(XI-6,81mg,0.47mmol)和硫酸铜(12mg,0.08mmol)/抗坏血酸钠(30mg,0.15mmol)为原料，操作同I-1，得110mg类白色固体I-8，收率50.6％。m.p.127–129℃。1H-NMR(300MHz,DMSO-d6),δ(ppm):10.84(s,1H),8.97(t,J＝6.0Hz,1H),8.65(d,J＝4.8,1H),8.08–7.98(m,2H),7.92(s,1H),7.64–7.59(m 1H),7.46–7.38(m,2H),7.27(t,J＝7.6Hz,1H),7.20(d,J＝7.8Hz,1H),7.07(t,J＝7.2Hz,1H),6.43(t,J＝6.0Hz,1H),4.62–4.53(m,4H),3.67(q,J＝6.0Hz,2H),3.59(q,J＝7.0Hz,2H),2.92(d,J＝7.4Hz,2H).
实施例9：(Z)-N-((1-(2-((4-(N-(3-溴苄基)-N'-羟基甲脒)-1,2,5-噁二唑-3-基)氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-5-氟吡啶甲酰胺(I-9)的合成
以化合物X-1(0.1g,0.26mmol)、5-氟-N-(丙基-2-炔-1-基)吡啶甲酰胺(XI-7,55mg,0.31mmol)和硫酸铜(8mg,0.05mmol)/抗坏血酸钠(20mg,0.10mmol)为原料，操作同I-1，得49mg白色固体I-9，收率33.9％，m.p.139.0–140.0℃。1H-NMR(300MHz,DMSO-d6),δ(ppm):10.82(s,1H),9.19(t,J＝6.1Hz,1H),8.65(d,J＝2.8Hz,1H),8.12(dd,J＝8.7,4.7Hz,1H),7.96(s,1H),7.94–7.88(m,1H),7.43–7.36(m,2H),7.25(t,J＝7.6Hz,1H),7.18(d,J＝7.8Hz,1H),7.05(t,J＝7.2Hz,1H),6.41(t,J＝5.9Hz,1H),4.58–4.50(m,6H),3.65(q,J＝6.0Hz,2H).
实施例10：(Z)-4-溴-N-((1-(2-((4-(N-(3-溴苄基)-N'-羟基甲脒)-1,2,5-噁二唑-3-基)氨基)乙基)-1H-1,2,3-三氮唑-4-基)甲基)-1H-吡咯-2-甲酰胺(I-10)的合成
以化合物X-1(0.1g,0.26mmol)、4-溴-N-(丙基-2-炔-1-基)-1H-吡咯-2-甲酰胺(XI-8,70mg,0.31mmol)和硫酸铜(8mg,0.05mmol)/抗坏血酸钠(20mg,0.10mmol)为原料，操作同I-1，得47mg白色固体I-10，收率29.9％，m.p.161.0–162.0℃。1H-NMR(400MHz,DMSO-d6),δ(ppm):11.85(s,1H),10.83(s,1H),8.64(t,J＝5.8Hz,1H),7.95(s,1H),7.42–7.37(m,2H),7.25(t,J＝7.7Hz,1H),7.18(d,J＝7.8Hz,1H),7.06(t,J＝7.1Hz,1H),6.99–6.98(m,1H),6.90–6.85(m,1H),6.41(t,J＝6.0Hz,1H),4.58–4.51(m,4H),4.45(d,J＝5.6Hz,2H),3.66(q,J＝6.0Hz,2H).
实施例11：(Z)-N-((1-(3-((4-(N-(3-溴苄基)-N'-羟基甲脒)-1,2,5-噁二唑-3-基)氨基)丙基)-1H-1,2,3-三氮唑-4-基)甲基)吡咯甲酰胺(I-11)的合成
3-(3-溴苄基)-3-(4-((3-溴丙基)氨基)-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮(VIII-4)的合成
以化合物VI-1(736mg,2.0mmol)、3-溴丙胺氢溴酸盐(VII-2,875mg,4.0mmol)和2mol/L氢氧化钠溶液(2.0mL,4.0mmol)为原料，操作同VIII-1，得到450mg油状物VIII-4，收率49.0％。
3-(4-(4-叠氮丙基)氨基)-1,2,5-噁二唑-3-基)-4-(3-溴苄基)-1,2,4-噁二唑-5(4H)-酮(IX-4)的合成
以化合物VIII-4(400mg,0.87mmol)和叠氮化钠(61mg,0.96mmol)为原料，操作同IX-1，未经进一步纯化处理，得330mg油状物IX-4，收率90.9％。1H-NMR(300MHz,DMSO-d6),δ(ppm):7.62(s,1H),7.57–7.51(m,1H),7.40–7.31(m,2H),6.64(t,J＝5.8Hz,1H),5.11(s,2H),3.59(t,J＝6.6Hz,2H),3.41(q,J＝6.5Hz,2H),2.17(p,J＝6.7Hz,2H).
(Z)-4-((4-叠氮丙基)氨基)-N-(3-溴苄基)-N'-羟基-1,2,5-噁二唑-3-甲脒(X-4)的合成
以化合物IX-4(300mg,0.65mmol)和2mol/L氢氧化钠溶液(0.7mL,1.30mmol)为原料，操作同X-1，得195mg黄色固体X-4，收率75.8％，m.p.68.0–70.0℃。1H-NMR(300MHz,CDCl3),δ(ppm):10.86(s,1H),7.42(d,J＝9.1Hz,2H),7.27–7.21(m,2H),7.10(t,J＝7.1Hz,1H),6.32(t,J＝5.9Hz,1H),4.61(d,J＝7.1Hz,2H),3.40(s,2H),3.28(q,J＝6.5Hz,2H),1.83(p,J＝6.7Hz,2H).
(Z)-N-((1-(3-((4-(N-(3-溴苄基)-N'-羟基甲脒)-1,2,5-噁二唑-3-基)氨基)丙基)-1H-1,2,3-三氮唑-4-基)甲基)吡咯甲酰胺(I-11)的合成
以化合物X-4(0.10g,0.25mmol)、XI-1(48mg,0.30mmol)和硫酸铜(8mg,0.05mmol)/抗坏血酸钠(20mg,0.10mmol)为原料，操作同I-1，得40mg浅棕色固体I-11，收率29.6％，m.p.56.0–58.0℃。1H-NMR(300MHz,DMSO-d6),δ(ppm):10.86(s,1H),9.23(t,J＝6.0Hz,1H),8.67(d,J＝4.7Hz,1H),8.09(d,J＝7.6Hz,1H),8.04(dd,J＝7.3,1.7Hz,1H),8.00(s,1H),7.65–7.61(m,1H),7.43(s,1H),7.39(d,J＝7.7Hz,1H),7.30–7.18(m,2H),7.09(t,J＝7.1Hz,1H),6.34(t,J＝5.8Hz,1H),4.61–4.57(m,4H),4.38(t,J＝7.0Hz,2H),3.20(q,J＝6.6Hz,2H),2.10(p,J＝6.9Hz,2H).
实施例12：本发明化合物在酶水平抑制IDO2的活性实验
(1)实验方法
建立IDO2酶活性抑制分子筛选模型，如下方法进行测定：IDO酶可以催化色氨酸上的吡咯环氧化裂解产生N'-甲酰犬尿氨酸(N'-formylkynurenine)。在室温环境下，将40nM的IDO酶及900μM的L-色氨酸混合，并加入反应缓冲液(20mM ascorbate，3.5mΜmethyleneblue and 0.2mg/mL catalase in 50mM potassium phosphate buffer pH 6.5)，在室温反应3小时，然后在酶标仪上进行紫外测定，检测波长为321nm。实验结果见表1。
(2)实验结果
表1.目标化合物在酶水平对IDO2的抑制活性
表1结果显示，在100nM浓度下，本发明化合物对IDO2均有一定的抑制活性，其中化合物I-1对IDO2的抑制活性最优。
实施例13：基于二甲苯致小鼠耳肿胀模型评价化合物I-1和I-2的抗炎效果实验
(1)实验方法
将ICR小鼠随机分为模型组和各受试药组，每组8只。阳性对照组予萘普生(150mg·kg-1)，目标化合物给药剂量为100mg·kg-1，各受试药物配组以5％CMC-Na溶液：聚氧乙烯蓖麻油(EL40)＝95:5制成10mg/mL，并按0.2mL/10g灌胃给药。给药1小时后，将小鼠右耳两面用25μL二甲苯均匀涂布致炎，1小时后采用颈椎脱臼法处死，剪下双耳后脱毛打孔称重，计算肿胀率及肿胀抑制率。实验结果见表2。
肿胀率(％)＝(右耳重量-左耳重量)/左耳重量×100％；
肿胀抑制率(％)＝(模型组肿胀率-受试组肿胀率)/模型组肿胀率。
(2)实验结果
表2.目标化合物I-1和I-2对二甲苯诱导的小鼠耳肿胀影响
表2结果显示，目标化合物I-1和I-2对二甲苯诱导的小鼠耳肿胀表现出一定的抑制活性，作用要强于对照药萘普生。这些结果提示，化合物I-1和I-2具有较好的抗炎活性。
实施例14：基于角叉菜胶模型评价化合物I-1的抗炎效果实验
(1)实验方法
将ICR小鼠随机分为模型组和各受试药组，每组8只。阳性对照组予萘普生(100mg·kg-1)，目标化合物I-1给药剂量为100mg·kg-1、200mg·kg-1和400mg·kg-1，用5％CMC-Na溶液：聚氧乙烯蓖麻油(EL40)＝95:5配制。连续灌胃给药三天，每天一次按0.2mL/10g给药。第三天灌胃给药1小时后，测定小鼠右后足趾厚度，然后每只小鼠右脚趾底部注射25μL的1％角叉菜胶致炎，每隔1小时测定一次右后足趾厚度，连续测定5次。最终评价小鼠的足肿胀程度。实验结果见表3、图1和表4、图2。
肿胀度(mm)＝致炎右后足厚度-致炎前右后足厚度；
肿胀率(％)＝(致炎右后足厚度-致炎前右后足厚度)/致炎前右后足厚度×100％；
肿胀抑制率(％)＝(模型组肿胀率-受试组肿胀率)/模型组肿胀率。
(2)实验结果
表3.化合物I-1对角叉菜胶诱导小鼠足肿胀度
aThe results are expressed as mean±SD(n＝8).
表4.化合物I-1对角叉菜胶诱导小鼠足肿胀的抑制率
表3和表4结果显示，化合物I-1在角叉菜胶诱导小鼠足肿胀模型中表现出较好的抗炎效果。
Claims (11)
1.一种IDO抑制剂，其特征在于，具有式(I)的结构，所述IDO抑制剂包含其异构体、药学上可接受的盐或它们的混合物：
其中
m选自1、2或3；n选自0、1、2、3或4；X选自O或NH；
R1选自五元或六元芳杂环基；
R2选自H、F、Cl、Br、I、CF3、CHF2、CN、OCH3、OH或CH3，R2为单取代或多取代。
2.根据权利要求1所述的IDO抑制剂，其特征在于，所述结构中：
m选自1；n选自1或2；X选自NH。
3.根据权利要求1所述的IDO抑制剂，其特征在于，所述结构中：
R1选自：
其中，R3选自H、F、Cl、Br、I、CF3、CHF2、CN、OCH3、OH或CH3，R3为单取代或多取代；Y选自NH或O。
4.根据权利要求1所述的IDO抑制剂，其特征在于，所述结构中：
R2选自H、F、Cl、Br、CF3或CN，R2为单取代或双取代。
5.根据权利要求3所述的IDO抑制剂，其特征在于，所述结构中：
R1选自：
其中，R3选自H、F、Cl、Br、CF3、CN或OCH3，R3为单取代或双取代。
6.根据权利要求1所述的IDO抑制剂，其特征在于，选自以下任一化合物：
7.根据权利要求1～6任一所述的IDO抑制剂，其特征在于，所述药学上可接受的盐为所述IDO抑制剂与酸形成的盐，所述酸为盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸或阿魏酸。
8.一种权利要求1～7任一所述的IDO抑制剂的制备方法，其特征在于，所述制备方法为：
化合物(II)与化合物(III)，经取代、环合、氧化、还原-偶联、叠氮化、开环、环合反应得到化合物(I)；
其中，R1、R2、m、n、X的定义如权利要求1～6任一所述；
将相应的酸与以上方法制备的化合物(I)成盐，即得所述IDO抑制剂的药学上可接受的盐。
9.一种药物组合物，其特征在于，包含权利要求1～7任一所述的IDO抑制剂以及药学上可接受的载体。
10.一种权利要求1～7任一所述的IDO抑制剂或者权利要求9所述的药物组合物在制备IDO抑制剂药物中的应用。
11.根据权利要求10所述的应用，其特征在于，所述药物用于治疗类风湿性关节炎或炎症性疾病。
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| CN116444454A (zh) * | 2023-06-16 | 2023-07-18 | 中国医学科学院医药生物技术研究所 | N-羟基脒衍生物及制备方法和应用、肿瘤免疫治疗药物 |
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| CN116444454A (zh) * | 2023-06-16 | 2023-07-18 | 中国医学科学院医药生物技术研究所 | N-羟基脒衍生物及制备方法和应用、肿瘤免疫治疗药物 |
| CN116444454B (zh) * | 2023-06-16 | 2023-09-12 | 中国医学科学院医药生物技术研究所 | N-羟基脒衍生物及制备方法和应用、肿瘤免疫治疗药物 |
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