CN116514710A - 环取代炔基吡啶甲酰甘氨酸衍生物、制备方法、药物组合物和应用 - Google Patents
环取代炔基吡啶甲酰甘氨酸衍生物、制备方法、药物组合物和应用 Download PDFInfo
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract
本发明公开了一类环取代炔基吡啶甲酰甘氨酸衍生物、制备方法、药物组合物和应用。该化合物结构如式(I),该衍生物包含其药学上可接受的盐。该类衍生物对PHD2和FIH均具有高效的抑制作用,可以稳定细胞内缺氧诱导因子HIF,增加内源性促红细胞生成素的生成和分泌,促进红细胞生成;用于制备治疗和/或预防慢性疾病性相关的贫血、缺血性疾病及造血系统相关疾病药物。所制备药物在分子水平、细胞水平和动物水平均可以发挥药效,应用广泛,并且该类化合物合成方法简便易行。
Description
技术领域
本发明涉及一类环取代炔基吡啶甲酰甘氨酸衍生物、制备方法、药物组合物和应用,尤其涉及一类可制备为治疗和/或预防因红细胞生成素下降或不足所引起的贫血药物的环取代炔基吡啶甲酰甘氨酸衍生物、制备方法、药物组合物和应用。
背景技术
肾性贫血是慢性肾脏病(chronic kidney disease,CKD)患者最常见的并发症之一,严重影响患者的生活质量,也是导致心血管发生率及死亡率增高的重要因素。肾脏是人体产生分泌促红细胞生成素(erythropoietin,EPO)的主要器官,CKD患者由于肾功能衰退或损伤进而导致EPO分泌严重不足,直接造成造血(形成红细胞)能力受损,引发贫血症状。近年来肾性贫血治疗常用药物为注射用重组人EPO(rhEPO),rhEPO在疗效和安全性方面具有局限性:1)免疫原性问题;2)不可控高血压副作用;3)注射给药方式降低了治疗依从性;4)需要与铁剂联合用药。鉴于此,人们一直在寻找能够代替生物药rhEPO的更为安全、有效、便捷的治疗方法。
随着对EPO生物学研究的深入,科学家们发现内源性EPO主要受缺氧诱导因子(hypoxia inducible factor,HIF)的调控,HIF是人类对氧气的适应性调节、诱导低氧应激反应相关基因表达最重要的转录因子。近年来,科学家进一步揭示了氧感知HIF信号通路的生物学功能,证明了氧感应机制在机体生理学研究上具有重要意义。HIF通常由对氧气敏感的α亚基和稳定的β亚基两部分组成。低氧气情况下,胞质中的HIF-α进入细胞核与HIF-β结合形成异源二聚体HIF-α/β后,从而启动相关靶基因表达,比如EPO、VEGF、糖酵解相关基因等。常氧气情况下,HIF-α的氧依赖降解结构域中特定的脯氨酸残基可以被脯氨酰羟化酶(prolyl hydrolase domain,PHD)羟基化,羟基化的HIF-α可迅速被VHL(Von Hippel-Lindau)蛋白精准识别,招募形成E3连接酶复合体,继而被泛素化降解。PHD2亚型为体内调控HIF的最主要亚型。因此,抑制PHD2酶的活性可稳定细胞的HIF水平,促进HIF下游相关基因如EPO、转铁蛋白等表达,可促进红细胞生成及铁吸收,从而在针对肾性贫血等多种疾病具有治疗用途。PHD2抑制剂的药物研发近年取得一定的研究进展,特别是Fibrogen的Roxadustat(罗沙司他)、Akebia的Vadadustat、Bayer的Molidustat、GSK的Daprodustat、JTZ的Enarodustat已先后在中国及日本获批上市,并在治疗慢性肾性贫血取得较好疗效。
值得注意的是,HIF除了受脯氨酰羟化酶PHD2负调控之外,HIF的转录活性还受另一种羟化酶FIH(factor inhibiting HIF)负调控。FIH与PHD2同属于Fe(II)、O2、2-OG依赖型羟化酶家族,两者具有同源性。但不同于PHD2,FIH是一种天冬酰胺羟化酶,可羟基化HIF-α碳末端转录激活结构域(C-terminaltransactivation domain,C-TAD)特定的天冬酰胺残基。当C-TAD结构域中的Asn残基被羟基化后,HIF-α与转录增强子p300/CBP的结合能力将大幅度下降。目前,FIH抑制剂领域研究还比较少,缺乏高亲和力高活性分子。
另外,现有已上市的PHD2药物虽然在治疗慢性肾性贫血方面表现出了不错的潜力,但是同时具有一些不可控的心血管风险和其他不可忽视的副作用,如血栓、癫痫、以及严重/致命的感染等。同时,上述已上市的PHD2小分子抑制剂活性普遍一般,临床使用剂量较大,这也是造成上述副作用的原因之一。基于此,本项目开发一类环取代炔基吡啶甲酰甘氨酸PHD2/FIH双靶点小分子抑制剂。通过PHD2/FIH双重抑制,使得HIF-α以最原始的状态的入核,大大提高HIF的转录活性,达到更有效的提升EPO的目的,维持药效的同时降低药物使用剂量,进一步用于治疗慢性肾性贫血等疾病。
发明内容
发明目的:针对现有化合物存在的临床使用剂量过大、副作用大等不足,本发明旨在提供一类针对PHD2及FIH具有双重抑制活性的环取代炔基吡啶甲酰甘氨酸衍生物、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,本发明的环取代炔基吡啶甲酰甘氨酸衍生物具有式(I)的结构,所述环取代炔基吡啶甲酰甘氨酸衍生物包含其药学上可接受的盐:
其中:
A选自3~8元饱和单碳环,含氧或氮原子的3~8元饱和单杂环或者上述单环构成的螺环及桥环;
Ar选自5~6元单环芳基或杂芳基或者8~10元双环芳基或杂芳基,其中杂芳基为环上含有1~2个相同或不同的氮或氧原子的芳基;
R1选自位于Ar上任意位置取代的一个或多个C1-C4烷基、C1-C4烷氧基、C1-C4烷胺基、C1-C4酰胺基、C1-C4卤代烷基、卤素、苯基、苄基、三氟甲基、三氟甲氧基、氰基、硝基、羟基、氨基或羧基;
R2选自氢、甲基或卤素;
R3选自位于A上任意位置代基的一个或多个C1-C2烷基、卤素、苯基、苄基、氰基或羟基;
R4、R5各自独立地选自氢或甲基。
鉴于PHD2及FIH对HIF通路均具有负调控作用,因此本发明通过小分子化合物来双重抑制PHD2及FIH的活性,不仅可抑制HIF-α的Pro残基的羟基化,逃离被VHL识别降解的命运,还可以抑制Asn残基的羟基化,保留对增强子p300/CBP的结合力,使得HIF-α保留未被修饰过的原始状态入核,有望发挥更为有效的转录活性,促进内源性EPO以及铁吸收蛋白等表达,从而提高血液中血红蛋白和红细胞的形成,达到更为有效的肾性贫血治疗目的。本发明设计的环取代炔基吡啶甲酰甘氨酸类PHD2/FIH双靶点小分子抑制剂,用于治疗慢性肾性贫血等疾病。
优选,所述结构中A选自以下任一结构:
优选,所述结构中:
Ar为苯基。
更具体地,上述环取代炔基吡啶甲酰甘氨酸衍生物选自以下任一化合物:
上述环取代炔基吡啶甲酰甘氨酸衍生物药学上可接受的盐为所述衍生物与酸或碱形成的盐,所述酸为盐酸、氢溴酸、硫酸、磷酸、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、苯基乙酸或杏仁酸,所述碱为含有碱性金属阳离子、碱土金属阳离子或铵阳离子盐的无机碱,胆碱、二乙醇胺或吗啉。
作为本发明涉及的第二方面,本发明的环取代炔基吡啶甲酰甘氨酸衍生物的制备方法为:
化合物(II)与化合物(III),经偶联反应得到化合物(I);
化合物(II)与化合物(III)在碱和催化剂的条件下偶联得到通式(I)化合物,其中,碱选自三乙胺,二乙胺,N,N-二异丙基乙胺,催化剂选择双三苯基磷二氯化钯,反应溶剂为乙腈,反应温度优选为80℃,反应时间6-24小时。
其中,A、Ar、R1、R2、R3、R4、R5的定义如前所述;
将相应的酸或碱与以上方法制备的化合物(I)成盐,即得所述环取代炔基吡啶甲酰甘氨酸衍生物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环取代炔基吡啶甲酰甘氨酸衍生物以及药学上可接受的载体。
上述环取代炔基吡啶甲酰甘氨酸衍生物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,本发明的环取代炔基吡啶甲酰甘氨酸衍生物及其药物组合物可制备为脯氨酰羟化酶和/或天冬酰胺羟化酶抑制剂药物。所述药物用于治疗贫血症或缺血性疾病;其中,所述贫血症是由肾炎、肾损伤、类风湿性关节炎、风湿热、炎症性肠道疾病或肿瘤化疗引起的贫血症,所述缺血性疾病是缺血性脑卒中或心肌缺血相关疾病。
有益效果:与现有技术相比,本发明具有如下显著优点:
(1)该类衍生物和药物组合物可有效抑制PHD2和FIH活性,IC50值均达到纳摩尔浓度级别,IC50值最优小于10nM;
(2)该类衍生物和药物组合物应用广泛,可制备为治疗和/或预防慢性疾病性相关的贫血、缺血性疾病及造血系统相关疾病药物;所述药物在分子水平、细胞水平和动物水平均可以发挥药效,并且治疗效果更优异,显著提升血浆EPO和全血网织红细胞比率;
(3)化合物制备方法简便易行。
附图说明
图1为部分化合物细胞水平的荧光素酶报告试验结果(Hep3B细胞:人肝癌细胞;化合物浓度0.4μM、1.2μM、3.7μM、11.1μM、33.3μM、100.0μM,给药24小时);
图2为化合物I-21、I-22、阳性药FG-4592在10mg/kg、20mg/kg、50mg/kg剂量下,连续给药3天,取小鼠血样,小鼠血浆EPO水平;
图3为化合物I-21、I-22、阳性药FG-4592在5mg/kg、10mg/kg、20mg/kg剂量下,连续给药3天,取小鼠血样,小鼠全血网织红比率(%RBC)。
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
I-1的制备
(5-溴-3-羟基吡啶甲酰基)甘氨酸(0.546g,2.0mmol),(1-氯-4-(1-乙炔基环丙氧基)苯(0.384g,2.0mmol),四三苯基膦二氯化钯(0.070g,0.1mmol),碘化亚铜(0.019g,0.1mmol)和N,N-二异丙基乙胺(1.0mL)溶于CH3CN(8mL)中,在N2保护下将混合物在80℃搅拌5.0小时,硅藻土抽滤反应混合物并浓缩。通过硅胶柱色谱(洗脱液:在石油醚中10-80%EtOAc)纯化产物,得到目标产物白色固体(5-((1-(4-氯苯氧基)环丙基)乙炔基)-3-羟基吡啶甲酰基)甘氨酸0.610g;收率:82.4%,Rf:0.35(甲醇:乙酸乙酯=1:1),m.p.134.1-136.0℃,该化合物的1HNMR(500MHz,DMSO-d6)δ8.84(d,J=1.4Hz,1H),8.40(t,J=10.2Hz,1H),7.99(dd,J=7.5,1.5Hz,1H),7.94(d,J=7.5Hz,1H),7.33–7.27(m,2H),6.96–6.91(m,2H),4.06(d,J=10.3Hz,2H),2.39–2.22(m,4H).EI-MS m/z:387[M+H]+。
实施例2
I-2的制备
2-(5-溴-3-羟基吡啶甲酰胺基)-2甲基丙酸(0.602g,2.0mmol),1-氯-4-(1-乙炔基环丁氧基)苯(0.384g,2.0mmol),四三苯基膦二氯化钯(0.070g,0.1mmol),碘化亚铜(0.019g,0.1mmol)和N,N-二异丙基乙胺(1.0mL)溶于CH3CN(8mL)中,在N2保护下将混合物在80℃搅拌5.0小时,硅藻土抽滤反应混合物并浓缩。通过硅胶柱色谱(洗脱液:在石油醚中10-80%EtOAc)纯化产物,得到目标产物白色固体2-(5-((1-(4-氯苯氧基)环丁基)乙炔基)-3-羟基吡啶甲酰胺基)-2-甲基丙酸0.692g;收率:81.2%,Rf:0.32(甲醇:乙酸乙酯=1:1),m.p.146.0-149.5℃,该化合物的1H NMR(500MHz,DMSO-d6)δ8.51–8.46(m,2H),7.64(d,J=1.5Hz,1H),7.33–7.27(m,2H),6.98–6.92(m,2H),2.33(td,J=7.1,1.2Hz,5H),1.81(p,J=7.1Hz,2H),1.67(s,5H).EI-MS m/z:429[M+H]+。
实施例3
I-3的制备
(5-溴-3-羟基-6-甲基吡啶甲酰基)甘氨酸(0.575g,2.0mmol),1-氯-4-(1-乙炔基环丁氧基)苯(0.440g,2.0mmol),四三苯基膦二氯化钯(0.070g,0.1mmol),碘化亚铜(0.019g,0.1mmol)和N,N-二异丙基乙胺(1.0mL)溶于CH3CN(8mL)中,在N2保护下将混合物在80℃搅拌5.0小时,硅藻土抽滤反应混合物并浓缩。通过硅胶柱色谱(洗脱液:在石油醚中10-80%EtOAc)纯化产物,得到目标产物白色固体(5-((1-(4-氯苯氧基)环戊基)乙炔基)-3-羟基-6-甲基吡啶甲酰基)甘氨酸0.587g;收率:68.5%,Rf:0.30(甲醇:乙酸乙酯=1:1),m.p.151.1-152.3℃,该化合物的1H NMR(500MHz,DMSO-d6)δ9.48(t,J=10.2Hz,1H),7.59(s,1H),7.33–7.27(m,2H),6.98–6.92(m,2H),4.07(d,J=10.1Hz,2H),2.62(s,3H),2.15–2.04(m,6H),2.04–1.94(m,6H).EI-MS m/z:429[M+H]+。
实施例4
I-4的制备
制备方法同实施例1,用(1-氯-4-((1-乙炔基环己基)氧基)苯(0.470g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(5-((1-(4-氯苯氧基)环己基)乙炔基)-3-羟基吡啶甲酰基)甘氨酸0.593g,收率:68.9%,Rf:0.30(甲醇:乙酸乙酯=1:1),m.p.158.3-159.8℃,该化合物的1H NMR(500MHz,DMSO-d6)12.81(s,1H),12.45(s,1H),9.40(s,1H),8.20(s,1H),7.55(s,1H),7.34(d,J=29.6Hz,4H),3.99(s,2H),1.99(d,J=46.0Hz,4H),1.48(d,J=59.3Hz,6H).EI-MS m/z:429[M+H]+。
实施例5
I-5的制备
制备方法同实施例1,用1-(4-氯苯氧基)-1-乙炔基环庚烷(0.496g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(5-((1-(4-氯苯氧基)环庚基)乙炔基)-3-羟基吡啶甲酰基)甘氨酸0.413g,收率:46.7%,Rf:0.28(甲醇:乙酸乙酯=1:2),m.p.150.3-153.6℃,该化合物的1H NMR(500MHz,DMSO-d6)δ9.39(d,J=1.5Hz,1H),8.40(t,J=10.2Hz,1H),7.65(d,J=1.5Hz,1H),7.33–7.27(m,2H),6.97–6.91(m,2H),4.07(d,J=10.3Hz,2H),2.01–1.88(m,4H),1.60–1.48(m,4H),1.48–1.40(m,4H).EI-MS m/z:443[M+H]+。
实施例6
I-6的制备
制备方法同实施例1,用3-(4-氯苯氧基)-3-乙炔基双环[3.1.0]己烷(0.464g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(5-((3-(4-氯苯氧基)双环[3.1.0]己-3-基)乙炔基)-3-羟基吡啶甲酰0.531g,收率:62.3%,Rf:0.27(甲醇:乙酸乙酯=1:2),m.p.155.9-156.2℃,该化合物的1H NMR(500MHz,DMSO-d6)δ8.49(d,J=1.5Hz,1H),8.40(t,J=10.2Hz,1H),7.64(d,J=1.5Hz,1H),7.33–7.27(m,2H),6.98–6.92(m,2H),4.07(d,J=10.3Hz,2H),2.24–2.14(m,4H),1.99–1.85(m,4H).EI-MS m/z:427[M+H]+。
实施例7
I-7的制备
制备方法同实施例1,用6-(4-氯苯氧基)-6-乙炔基螺[2.5]辛烷(0.520g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(5-((6-(4-氯苯氧基)螺[2.5]辛烷-6-基)乙炔基)-3-羟基吡啶甲酰基)甘氨酸0.562g,收率:61.9%,Rf:0.30(甲醇:乙酸乙酯=1:2),m.p.158.0-159.6℃,该化合物的1H NMR(500MHz,DMSO-d6)δ8.49(d,J=1.5Hz,1H),8.41(t,J=10.3Hz,1H),7.65(d,J=1.5Hz,1H),7.33–7.27(m,2H),6.95–6.89(m,2H),4.07(d,J=10.3Hz,2H),2.11–1.98(m,4H),1.69–1.54(m,8H).EI-MS m/z:455[M+H]+。
实施例8
I-8的制备
制备方法同实施例1,用1-氯-4-((1-乙炔基-2-甲基环己基)氧基)苯(0.496g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(5-((1-(4-氯苯氧基)-2-甲基环己基)乙炔基)-3-羟基吡啶甲酰基)甘氨酸0.585g,收率:66.2%,Rf:0.33(甲醇:乙酸乙酯=1:2),m.p.135.0-138.1℃,该化合物的1H NMR(500MHz,DMSO-d6)δ8.49(d,J=1.5Hz,1H),8.40(t,J=10.2Hz,1H),7.65(d,J=1.5Hz,1H),7.33–7.27(m,2H),6.96–6.91(m,2H),4.07(d,J=10.3Hz,2H),2.13–2.00(m,2H),1.96(h,J=6.8Hz,1H),1.76–1.55(m,4H),1.54–1.43(m,2H),1.01(d,J=6.8Hz,3H).EI-MS m/z:443[M+H]+。
实施例9
I-9的制备
制备方法同实施例1,用1-氯-4-((1-乙炔基-3-甲基环己基)氧基)苯(0.496g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(5-((1-(4-氯苯氧基)-3-甲基环己基)乙炔基)-3-羟基吡啶甲酰基)甘氨酸0.588g,收率:66.5%,Rf:0.33(甲醇:乙酸乙酯=1:2),m.p.134.3-137.1℃,该化合物的1H NMR(500MHz,DMSO-d6)δ8.49(d,J=1.5Hz,1H),8.40(t,J=10.2Hz,1H),7.65(d,J=1.5Hz,1H),7.33–7.27(m,2H),6.96–6.91(m,2H),4.07(d,J=10.3Hz,2H),2.13–2.00(m,2H),1.96(h,J=6.8Hz,1H),1.76–1.55(m,4H),1.54–1.43(m,2H),1.13(d,J=6.8Hz,3H).EI-MS m/z:443[M+H]+。
实施例10
I-10的制备
制备方法同实施例1,用1-氯-4-((1-乙炔基-3-甲基环己基)氧基)苯(0.590g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(5-((1-(4-氯苯氧基)-4-甲基环己基)乙炔基)-3-羟基吡啶甲酰基)甘氨酸0.552g,收率:52.3%,Rf:0.34(甲醇:乙酸乙酯=1:2),m.p.137.1-139.8℃,该化合物的1H NMR(500MHz,DMSO-d6)δ9.39(d,J=1.5Hz,1H),8.40(t,J=10.2Hz,1H),7.65(d,J=1.5Hz,1H),7.33–7.27(m,2H),6.96–6.91(m,2H),4.07(d,J=10.3Hz,2H),2.13–2.00(m,2H),1.96(h,J=6.8Hz,1H),1.76–1.55(m,4H),1.54–1.43(m,2H),1.18(d,J=6.8Hz,3H).EI-MS m/z:443[M+H]+。
实施例11
I-11的制备
制备方法同实施例1,用4-((1-乙炔基-4-羟基环己基)氧基)苄腈(0.482g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(5-((1-(4-氰基苯氧基)-4-羟基环己基)乙炔基)-3-羟基吡啶甲酰基)甘氨酸0.513g,收率:58.9%,Rf:0.25(甲醇:乙酸乙酯=1:2),m.p.142.6-144.2℃,该化合物的1H NMR(500MHz,DMSO-d6)δ8.41–8.34(m,2H),7.75–7.69(m,2H),7.52(d,J=2.0Hz,1H),7.26–7.20(m,2H),4.07(d,J=10.3Hz,2H),3.72–3.61(m,1H),3.34(d,J=6.4Hz,1H),2.20(ddd,J=13.0,9.7,7.4Hz,2H),2.07(ddd,J=13.0,9.4,7.6Hz,2H),1.84–1.69(m,4H).EI-MS m/z:436[M+H]+。
实施例12
I-12的制备
制备方法同实施例1,用1-苄基-4-((1-乙炔基-4-氟环己基)氧基)苯(0.616g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(5-((1-(4-苄基苯氧基)-4-氟环己基)乙炔基)-3-羟基吡啶甲酰基)甘氨酸0.478g,收率:47.6%,Rf:0.31(甲醇:乙酸乙酯=1:2),m.p.161.5-163.7℃,该化合物的1H NMR(500MHz,DMSO-d6)δ9.41(d,J=1.5Hz,1H),8.41(t,J=10.3Hz,1H),7.60(d,J=1.5Hz,1H),7.31–7.15(m,5H),7.08(dt,J=7.4,0.9Hz,2H),6.95–6.89(m,2H),4.10–4.04(m,4H),2.11-2.20(m,4H),1.96–1.73(m,4H).EI-MS m/z:503[M+H]+。
实施例13
I-13的制备
制备方法同实施例1,用4-((4-氯-1-乙炔基环己基)氧基)苯甲酸(0.556g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体4-((1-((6-((羧甲基)氨基甲酰基)-5-羟基吡啶-3-基)乙炔基)-4-氯环己基)氧基)苯甲酸0.535g,收率:56.7%,Rf:0.34(甲醇:乙酸乙酯=1:2),m.p.156.0-158.9℃,该化合物的1H NMR(500MHz,DMSO-d6)δ8.49(d,J=1.5Hz,1H),8.41(t,J=10.3Hz,1H),7.92–7.86(m,2H),7.65(d,J=1.5Hz,1H),7.19–7.13(m,2H),4.38(p,J=6.9Hz,1H),4.07(d,J=10.3Hz,2H),2.23–2.11(m,4H),2.09–1.97(m,4H).EI-MS m/z:473[M+H]+。
实施例14
I-14的制备
制备方法同实施例1,用4-((4-溴-1-乙炔基环己基)氧基)苯胺(0.592g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(5-((1-(4-氨基苯氧基)-4-溴环己基)乙炔基)-3-羟基吡啶甲酰基)甘氨酸0.416g,收率:42.4%,Rf:0.38(甲醇:乙酸乙酯=1:2),m.p.156.0-158.9℃,该化合物的1H NMR(500MHz,DMSO-d6)δ9.39(d,J=1.5Hz,1H),8.41(t,J=10.3Hz,1H),7.65(d,J=1.5Hz,1H),6.86–6.81(m,2H),6.55–6.50(m,2H),4.11–4.02(m,3H),2.20–2.11(m,4H),2.11–2.01(m,4H).EI-MS m/z:488[M+H]+。
实施例15
I-15的制备
制备方法同实施例1,用4-([1,1'-联苯]-4-基氧基)-4-乙炔基环己烷-1-甲腈(0.602g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(5-((1-([1,1'-联苯基]-4-基氧基)-4-氰基环己基)乙炔基)吡啶甲酰基)甘氨酸0.453g,收率:47.3%,Rf:0.36(甲醇:乙酸乙酯=1:2),m.p.151.9-153.2℃,该化合物的1H NMR(500MHz,DMSO-d6)δ9.34(d,J=1.4Hz,1H),8.41(t,J=10.2Hz,1H),7.98(dd,J=7.5,1.5Hz,1H),7.91(d,J=7.5Hz,1H),7.61–7.56(m,2H),7.56–7.50(m,2H),7.50–7.43(m,2H),7.34(ddt,J=9.0,7.2,1.5Hz,1H),7.06–7.01(m,2H),4.07(d,J=10.1Hz,2H),3.00(q,J=6.7Hz,1H),2.03–1.86(m,8H).EI-MS m/z:480[M+H]+。
实施例16
I-16的制备
制备方法同实施例1,用1-((1-乙炔基-4-苯基环己基)氧基)-4-硝基苯(0.642g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(3-羟基-5-((1-(4-硝基苯氧基)-4-苯基环己基)乙炔基)吡啶甲酰基)甘氨酸0.523g,收率:50.6%,Rf:0.26(甲醇:乙酸乙酯=1:2),m.p.150.0-152.5℃,该化合物的1H NMR(500MHz,DMSO-d6)δ9.50(d,J=1.5Hz,1H),8.41(t,J=10.3Hz,1H),8.22–8.16(m,2H),7.60(d,J=1.5Hz,1H),7.32–7.18(m,5H),7.14–7.08(m,2H),4.07(d,J=10.3Hz,2H),2.84(m,1H),2.21–2.08(m,8H).EI-MSm/z:516[M+H]+。
实施例17
I-17的制备
制备方法同实施例1,用4-((4-苄基-1-乙炔基环己基)氧基)苯酚(0.612g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(5-((4-苄基-1-(4-羟基苯氧基)环己基)乙炔基)-3-羟基吡啶甲酰基)甘氨酸0.584g,收率:58.4%,Rf:0.29(甲醇:乙酸乙酯=1:2),m.p.156.0-158.9℃,该化合物的1H NMR(500MHz,DMSO-d6)δ8.81(s,1H),8.51(d,J=1.5Hz,1H),8.41(t,J=10.3Hz,1H),7.60(d,J=1.5Hz,1H),7.29–7.22(m,2H),7.21–7.18(m,1H),7.18–7.09(m,2H),6.92–6.86(m,2H),6.86–6.81(m,2H),4.07(d,J=10.3Hz,2H),2.54(dt,J=7.0,0.9Hz,2H),2.03–1.98(m,4H),1.90–1.78(m,1H),1.77–1.66(m,4H)..EI-MS m/z:501[M+H]+。
实施例18
I-18的制备
制备方法同实施例1,用3-(4-氯苯氧基)-3-乙炔氧杂环丁烷(0.416g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(5-((3-(4-氯苯氧基)氧杂环丁烷-3-基)乙炔基)-3-羟基吡啶甲酰基)甘氨酸0.385g,收率:47.9%,Rf:0.25(甲醇:乙酸乙酯=1:2),m.p.135.6-136.8℃,该化合物的1H NMR(500MHz,DMSO-d6)δ9.25(s,1H),8.06(s,1H),7.41(d,J=8.9Hz,3H),6.97(d,J=8.8Hz,2H),5.07(d,J=7.2Hz,2H),4.89(d,J=7.2Hz,2H).EI-MS m/z:403[M+H]+。
实施例19
I-19的制备
制备方法同实施例1,用4-(4-氯苯氧基)-4-乙炔基四氢-2H-吡喃(0.472g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(5-((4-(4-氯苯氧基)四氢-2H-吡喃-4-基)乙炔基)-3-羟基吡啶甲酰基)甘氨酸0.393g,收率:45.7%,Rf:0.26(甲醇:乙酸乙酯=1:2),m.p.137.3-139.7℃,该化合物的1H NMR(500MHz,DMSO-d6)δ12.45(s,1H),9.39(s,1H),8.23(s,1H),7.58(s,1H),7.35(d,J=23.9Hz,4H),3.94(d,J=29.0Hz,4H),3.67(s,2H),2.10(s,4H).EI-MS m/z:431[M+H]+。
实施例20
I-20的制备
制备方法同实施例1,用4-((3-乙炔基氮杂环丁烷-3-基)氧基)-N-甲基苯甲酰胺(0.460g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(3-羟基-5-((3-(4-(甲基氨基甲酰基)苯氧基)氮杂环丁烷-3-基)乙炔基)吡啶甲酰基)甘氨酸0.316g,收率:37.2%,Rf:0.20(甲醇:乙酸乙酯=1:2),m.p.162.1-164.5℃,该化合物的1H NMR(500MHz,DMSO-d6)δ9.30(d,J=1.5Hz,1H),8.40(t,J=10.2Hz,1H),7.83(q,J=3.7Hz,1H),7.80–7.74(m,2H),7.64(d,J=1.5Hz,1H),7.15–7.09(m,2H),4.07(d,J=10.1Hz,2H),3.99(d,J=4.3Hz,2H),3.93(d,J=4.4Hz,2H),2.92(d,J=3.7Hz,3H).EI-MS m/z:425[M+H]+。
实施例21
I-21的制备
制备方法同实施例1,用4-(4-溴苯氧基)-4-乙炔基四氢-2H-吡喃(0.562g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(5-((4-(4-溴苯氧基)四氢-2H-吡喃-4-基)乙炔基)-3-羟基吡啶甲酰基)甘氨酸0.467g,收率:49.3%,Rf:0.28(甲醇:乙酸乙酯=1:2),m.p.102.6-105.4℃,该化合物的1H NMR(500MHz,DMSO-d6)δ12.45(s,1H),9.37(t,J=6.1Hz,1H),8.23(s,1H),7.58(s,1H),7.53(d,J=8.4Hz,2H),7.25(d,J=8.4Hz,2H),3.98(d,J=6.1Hz,2H),3.91–3.86(m,2H),3.66(t,J=10.3Hz,2H),2.13(d,J=13.1Hz,2H),2.06–2.00(m,2H).EI-MS m/z:475[M+H]+。
实施例22
I-22的制备
制备方法同实施例1,用4-乙炔基-4-(4-氟苯氧基)四氢-2H-吡喃(0.440g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(5-((4-(4-氟苯氧基)四氢-2H-吡喃-4-基)乙炔基)-3-羟基吡啶甲酰基)甘氨酸0.351g,收率:42.4%,Rf:0.30(甲醇:乙酸乙酯=1:2),m.p.166.5-167.6℃,该化合物的1H NMR(500MHz,DMSO-d6)δ12.42(s,1H),9.35(s,1H),8.21(s,1H),7.56(s,1H),7.30(s,2H),7.18(s,2H),3.96(s,2H),3.90(s,2H),3.65(s,2H),2.09–2.00(m,4H).EI-MS m/z:415[M+H]+。
实施例23
I-23的制备
制备方法同实施例1,用4-乙炔基-4-(4-(三氟甲基)苯氧基)四氢-2H-吡喃(0.540g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(3-羟基-5-((4-(4-(三氟甲基)苯氧基)四氢-2H-吡喃-4-基)乙炔基)吡啶甲酰基)甘氨酸0.485g,收率:52.3%,Rf:0.31(甲醇:乙酸乙酯=1:2),m.p.53.9-54.6℃,该化合物的1H NMR(500MHz,DMSO-d6)δ12.43(s,1H),9.38(t,J=6.2Hz,1H),8.25(s,1H),7.73(d,J=8.4Hz,2H),7.61(s,1H),7.48(d,J=8.4Hz,2H),3.98(d,J=6.1Hz,2H),3.91–3.86(m,2H),3.69(d,J=9.0Hz,2H),2.27–2.20(m,2H),2.09(td,J=9.1,4.5Hz,2H).EI-MS m/z:465[M+H]+。
实施例24
I-24的制备
制备方法同实施例1,用4-乙炔基-4-(4-(三氟甲氧基)苯氧基)四氢-2H-吡喃(0.572g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(3-羟基-5-((4-(4-(三氟甲氧基)苯氧基)四氢-2H-吡喃-4-基)乙炔基)吡啶甲酰基)甘氨酸0.412g,收率:42.9%,Rf:0.32(甲醇:乙酸乙酯=1:2),m.p.98.6-99.8℃,该化合物的1H NMR(500MHz,DMSO-d6)δ12.43(s,1H),9.38(t,J=6.2Hz,1H),8.25(s,1H),7.70(d,J=8.4Hz,2H),7.59(s,1H),7.40(d,J=8.4Hz,2H),3.98(d,J=6.1Hz,2H),3.91–3.86(m,2H),3.69(d,J=9.0Hz,2H),2.27–2.20(m,2H),2.09(td,J=9.1,4.5Hz,2H).EI-MS m/z:481[M+H]+。
实施例25
I-25的制备
制备方法同实施例1,用4-乙炔基-4-(4-甲氧基苯氧基)四氢-2H-吡喃(0.464g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(3-羟基-5-((4-(4-甲氧基苯氧基)四氢-2H-吡喃-4-基)乙炔基)吡啶甲酰基)甘氨酸0.328g,收率:38.5%,Rf:0.35(甲醇:乙酸乙酯=1:2),m.p.109.1-112.3℃,该化合物的1H NMR(500MHz,DMSO-d6)δ12.41(s,1H),9.36(t,J=6.0Hz,1H),8.21(s,1H),7.54(s,1H),7.20(d,J=8.4Hz,2H),6.90(d,J=8.4Hz,2H),3.97(d,J=6.0Hz,2H),3.90(d,J=11.5Hz,2H),3.72(s,3H),3.64(t,J=9.0Hz,2H),2.06–1.98(m,4H).EI-MS m/z:427[M+H]+。
实施例26
I-26的制备
制备方法同实施例1,用4-乙炔基-4-(对甲苯氧基)四氢-2H-吡喃(0.432g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(3-羟基-5-((4-(对甲苯氧基)四氢-2H-吡喃-4-基)乙炔基)吡啶甲酰基)甘氨酸0.314g,收率:38.3%,Rf:0.38(甲醇:乙酸乙酯=1:2),m.p.125.6-126.4℃,该化合物的1H NMR(500MHz,DMSO-d6)δ12.45(s,1H),9.37(s,1H),8.21(s,1H),7.54(s,1H),7.15(s,4H),3.97(s,2H),3.88(s,2H),3.65(s,2H),2.26(s,3H),2.09–1.99(m,4H).EI-MS m/z:411[M+H]+。
实施例27
I-27的制备
制备方法同实施例1,用4-(4-(氯甲基)苯氧基)-4-乙炔基四氢-2H-吡喃(0.500g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(5-((4-(4-(氯甲基)苯氧基)四氢-2H-吡喃-4-基)乙炔基)-3-羟基吡啶甲酰基)甘氨酸0.421g,收率:47.4%,Rf:0.36(甲醇:乙酸乙酯=1:2),m.p.152.2-155.8℃,该化合物的1H NMR(500MHz,DMSO-d6)9.36(d,J=1.5Hz,1H),8.40(t,J=10.2Hz,1H),7.65(d,J=1.5Hz,1H),7.40(dt,J=7.5,1.0Hz,2H),7.03–6.97(m,2H),4.53(t,J=1.0Hz,2H),4.07(d,J=10.3Hz,2H),3.74(t,J=7.1Hz,4H),2.22(dt,J=12.3,7.1Hz,2H),2.13(dt,J=12.5,7.1Hz,2H).EI-MS m/z:445[M+H]+。
实施例28
I-28的制备
制备方法同实施例1,用4-乙炔基-4-(萘-2-基氧基)四氢-2H-吡喃(0.504g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(3-羟基-5-((4-(萘-2-基氧基)四氢-2H-吡喃-4-基)乙炔基)吡啶甲酰基)甘氨酸0.382g,收率:42.8%,Rf:0.34(甲醇:乙酸乙酯=1:2),m.p.169.9-171.1℃,该化合物的1H NMR(500MHz,DMSO-d6)12.41(s,1H),9.38(t,J=6.1Hz,1H),8.21(d,J=1.7Hz,1H),7.91(d,J=3.1Hz,1H),7.88(d,J=7.5Hz,2H),7.81(d,J=2.4Hz,1H),7.57(d,J=1.7Hz,1H),7.49(t,J=7.8Hz,1H),7.44(s,1H),7.41(d,J=6.9Hz,1H),3.98(d,J=6.2Hz,2H),3.93(d,J=5.5Hz,2H),3.71(t,J=9.0Hz,2H),2.24(d,J=13.4Hz,2H),2.16–2.10(m,2H).EI-MS m/z:447[M+H]+。
实施例29
I-29的制备
制备方法同实施例1,用8-((4-乙炔基四氢-2H-吡喃-4-基)氧基)喹啉(0.504g,2.0mmol)替换(1-氯-4-(1-乙炔基环丙氧基)苯,得黄色固体(3-羟基-5-((4-(喹啉-8-基氧基)四氢-2H-吡喃-4-基)乙炔基)吡啶甲酰基)甘氨酸0.461g,收率:51.8%,Rf:0.30(甲醇:乙酸乙酯=1:2),m.p.173.0-175.6℃,该化合物的1H NMR(500MHz,DMSO-d6)δ8.82(dd,J=7.5,1.6Hz,1H),8.49(d,J=1.5Hz,1H),8.42(t,J=10.2Hz,1H),8.32(dq,J=7.5,1.0Hz,1H),7.65(d,J=1.5Hz,1H),7.50(t,J=7.5Hz,1H),7.38(t,J=7.4Hz,1H),7.30(dt,J=7.5,1.4Hz,1H),7.25(dd,J=7.4,1.5Hz,1H),4.07(d,J=10.3Hz,2H),3.77(td,J=7.1,1.9Hz,4H),2.35–2.22(m,4H).EI-MS m/z:448[M+H]+。
实施例30:本发明中通式I的部分化合物的生物学实验
1、半数抑制浓度(IC50)检测
(1)PHD2
本发明将脯氨酰羟化酶蛋白与异硫氰酸荧光素(FITC)标记的荧光分子(CN109293673A),不同浓度的化合物溶液共同孵育,考察化合物与蛋白竞争性结合的能力。化合物能够占据关键辅因子2-0G的位点,导致荧光分子无法与蛋白结合,未结合脯氨酰羟化酶的荧光分子在溶液中旋转速度快,荧光偏振值低。依据这一特点,本发明通过测定化合物的荧光偏振值间接反映其脯氨酰羟化酶抑制活性。化合物三倍稀释成12个浓度梯度,取20μL加入384孔板(型号Corning#3575),再依次加入等体积的蛋白和荧光分子,使终浓度分别为20nM和5nM,摇床孵育1h,采用Tecan spark多功能酶标仪检测,激发波长485nm,发射波长535nm,测试结果用Graphpad Prism 8分析。代表性化合物的测试结果见表1。测试中采用的空白对照为20μL荧光分子+40μL缓冲液,阴性对照为20μL荧光分子+20μL蛋白+20μL缓冲液,阳性对照为上市药物FG-4592(Roxadustat)。缓冲液配方为10mM Hepes,150mM NaCl,0.05%Tween-20,pH 7.40。
计算公式:%抑制率=100*(1-(实测值-空白)/(阴性值-空白)),得出具体浓度所对应的抑制率。将所得数据导入Graphpad prism 8.0分析拟合得IC50值。
(2)FIH
本发明将天冬酰胺羟化酶蛋白与异硫氰酸荧光素(FITC)标记的荧光分子(CN109293673A),不同浓度的化合物溶液共同孵育,考察化合物与蛋白竞争性结合的能力。化合物能够占据关键辅因子2-0G的位点,导致荧光分子无法与蛋白结合,未结合脯氨酰羟化酶的荧光分子在溶液中旋转速度快,荧光偏振值低。依据这一特点,本发明通过测定化合物的荧光偏振值间接反映其脯氨酰羟化酶抑制活性。化合物三倍稀释成12个浓度梯度,取20μL加入384孔板(型号Corning#3575),再依次加入等体积的蛋白和荧光分子,使终浓度分别为15nM和5nM,摇床孵育1h,采用Tecan spark多功能酶标仪检测,激发波长485nm,发射波长535nm,测试结果用Graphpad Prism 8分析。代表性化合物的测试结果见表1。测试中采用的空白对照为20μL荧光分子+40μL缓冲液,阴性对照为20μL荧光分子+20μL蛋白+20μL缓冲液,阳性对照为上市药物FG-4592(Roxadustat)。缓冲液配方为10mM Hepes,150mM NaCl,0.05%Tween-20,pH 7.40。
计算公式:%抑制率=100*(1-(实测值-空白)/(阴性值-空白)),得出具体浓度所对应的抑制率。将所得数据导入Graphpad prism 8.0分析拟合得IC50值。
2、EPO基因检测
EPO为体内HIF升高后的标志物(J.Med.Chem.2012,55(7):2945-2959),当PHD2及FIH活性受到抑制后,促使体内EPO等蛋白表达含量升高,通过检测EPO的表达来验证化合物在细胞水平是否具有提高EPO的能力。
本试验采用人肝癌细胞Hep3B细胞,孵育给药10h后,按照RNA提取试剂盒操作,提取RNA。根据Prime ScriptTMRT reagent Kit with gDNA Eraser(Perfect Real Time)说明书进行反转录。在qPCR反应板中依次加入7μL DEPC水,0.5μL Sense Primer,0.5μLAntisense Primer,2μL cDNA,10μL SYBR Premix Ex TaqII,在Thermo Step One&StepOne Plus Real-Time PCR Systems完成扩增及定量过程。以HPRT作为内参基因,使用ΔΔCT方法分析EPO相对表达水平。
引物序列:
HPRT-forward 5′-GACCAGTCAACAGGGGACAT-3′,
reverse 5′-AACACTTCGTGGGGTCCTTTTC-3′,
EPO-forward 5′-GAGCCCAGAAGGAAGCCATC-3′,
reverse 5′-CGGAAAGTGTCAGCAGTGATTG-3′。
FG-4592(Roxadustat)是全球首创作为抗贫血药物的PHD2抑制剂,目前已经相继在中国,日本,智利,韩国和欧洲获批上市,本发明以FG-4592作为阳性对照化合物。FG-4592的结构为:
表1列出实施例I-1~I-29化合物的PHD2和FIH的结合活性,以IC50(nM)表示。
+=≤10nM
++=>10至≤100nM
+++=>100至≤1000nM
++++=>1000至≤10000nM
+++++=>10000至≤100000nM
表1本发明中部分化合物的脯氨酰羟化酶抑制活性及其相关生物学活性
由表1可见,本发明的化合物具有较强的PHD2及FIH抑制活性,8个化合物PHD2 IC50小于10nM,且FIH IC50可以很好的保持在100~1000nM,PHD2和FIH活性都维持在纳摩尔水平。
此外,专利CN107848976B公开了一系列脯氨酰羟化酶抑制剂,其中活性较好的化合物结构:
该类化合物为较强的PHD2抑制剂,而对FIH的抑制活性很弱。本发明化合物的特征在于炔基的α位亚甲基引入环烷类取代基,可以较大幅度地提升化合物对PHD2抑制活性和FIH抑制活性,为了对比本发明化合物与CN107848976B化合物的活性,我们合成了CN107848976B专利中的部分化合物,并采用本发明中相同的活性测试方法、同一批次进行PHD2抑制活性和FIH抑制活性测定。本发明中部分化合物与CN107848976B专利中化合物的IC50对比结果如下:
+=≤10nM
++=>10至≤100nM
+++=>100至≤1000nM
++++=>1000至≤10000nM
表2本发明中部分化合物与专利CN107848976B中化合物的PHD2活性对比情况
由表2化合物的数据对比可以看出,在其他基团基本相同的情况下,本发明中四氢吡喃环的引入,可以显著提升化合物对PHD2的抑制活性。
表3本发明中部分化合物与专利CN107848976B中化合物的FIH活性对比情况
由表3化合物的数据对比可以看出,专利CN107848976B中的化合物对FIH酶的抑制活性较弱。在其他基团基本相同的情况下,本发明中四氢吡喃环的引入,可以显著提升化合物对FIH的抑制活性,IC50值提升约2个数量级。
对表1部分化合物进行了细胞水平的荧光素酶基因报告试验,方法参照(Toxicol.Sci.2013,132(2),379-389.),给药24h后通过荧光素酶基因试剂盒检测细胞活性。图1说明此类化合物具有优于阳性药的细胞活性。
对表1部分化合物进行了动物水平的EPO试验,方法参照(J.Med.Chem.2018,61(12),5332-5349)。由图2可见,本发明的化合物在动物水平可以明显提升血浆EPO。
对表1部分化合物进行了动物水平的网织红细胞试验,方法参照(J.Med.Chem.2018,61(12),5332-5349)。由图3可见,本发明的化合物在动物水平可以明显提升全血网织红细胞比率。
本发明的环取代炔基吡啶甲酰甘氨酸类化合物无论在分子水平、细胞水平以及动物水平都具有良好的生物学活性。本发明的化合物可以在动物水平提升血液中红细胞生成素(EPO)和网织红细胞比率(%RBC)的水平,可用于治疗或预防慢性疾病性相关的贫血、缺血性疾病及造血系统相关疾病。
Claims (10)
1.一种环取代炔基吡啶甲酰甘氨酸衍生物,其特征在于,具有式(I)的结构,所述环取代炔基吡啶甲酰甘氨酸衍生物包含其药学上可接受的盐:
其中:
A选自3~8元饱和单碳环,含氧或氮原子的3~8元饱和单杂环或者上述单环构成的螺环及桥环;
Ar选自5~6元单环芳基或杂芳基或者8~10元双环芳基或杂芳基,其中杂芳基为环上含有1~2个相同或不同的氮或氧原子的芳基;
R1选自位于Ar上任意位置取代的一个或多个C1-C4烷基、C1-C4烷氧基、C1-C4烷胺基、C1-C4酰胺基、C1-C4卤代烷基、卤素、苯基、苄基、三氟甲基、三氟甲氧基、氰基、硝基、羟基、氨基或羧基;
R2选自氢、甲基或卤素;
R3选自位于A上任意位置代基的一个或多个C1-C2烷基、卤素、苯基、苄基、氰基或羟基;
R4、R5各自独立地选自氢或甲基。
2.根据权利要求1所述的环取代炔基吡啶甲酰甘氨酸衍生物,其特征在于,所述结构中A选自以下任一结构:
3.根据权利要求1所述的环取代炔基吡啶甲酰甘氨酸衍生物,其特征在于,所述结构中:
Ar为苯基。
4.根据权利要求1所述的环取代炔基吡啶甲酰甘氨酸衍生物,其特征在于,选自以下任一化合物:
5.根据权利要求1~4任一所述的环取代炔基吡啶甲酰甘氨酸衍生物,其特征在于,所述药学上可接受的盐为所述衍生物与酸或碱形成的盐,所述酸为盐酸、氢溴酸、硫酸、磷酸、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、苯基乙酸或杏仁酸,所述碱为含有碱性金属阳离子、碱土金属阳离子或铵阳离子盐的无机碱,胆碱、二乙醇胺或吗啉。
6.一种权利要求1~5任一所述的环取代炔基吡啶甲酰甘氨酸衍生物的制备方法,其特征在于,所述制备方法为:
化合物(II)与化合物(III),经偶联反应得到化合物(I);
其中,A、Ar、R1、R2、R3、R4、R5的定义如权利要求1~4任一所述;
将相应的酸或碱与以上方法制备的化合物(I)成盐,即得所述环取代炔基吡啶甲酰甘氨酸衍生物的药学上可接受的盐。
7.一种药物组合物,其特征在于,包含权利要求1~5任一所述的环取代炔基吡啶甲酰甘氨酸衍生物以及药学上可接受的载体。
8.一种权利要求1~5任一所述的环取代炔基吡啶甲酰甘氨酸衍生物或者权利要求7所述的药物组合物在制备脯氨酰羟化酶和/或天冬酰胺羟化酶抑制剂药物中的应用。
9.根据权利要8所述的应用,其特征在于,所述药物用于治疗贫血症或缺血性疾病。
10.根据权利要9所述的应用,其特征在于,所述贫血症是由肾炎、肾损伤、类风湿性关节炎、风湿热、炎症性肠道疾病或肿瘤化疗引起的贫血症;所述缺血性疾病是缺血性脑卒中或心肌缺血相关疾病。
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WO2019200120A1 (en) * | 2018-04-11 | 2019-10-17 | Lycera Corporation | Dihydroisoquinoline-2(1h)-carboxamide and related compounds and their use in treating medical conditions |
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CN107848976A (zh) * | 2015-10-09 | 2018-03-27 | 江苏恒瑞医药股份有限公司 | 炔基吡啶类脯氨酰羟化酶抑制剂、其制备方法和医药用途 |
WO2019200120A1 (en) * | 2018-04-11 | 2019-10-17 | Lycera Corporation | Dihydroisoquinoline-2(1h)-carboxamide and related compounds and their use in treating medical conditions |
US20210139484A1 (en) * | 2018-04-11 | 2021-05-13 | Gossamer Bio Services, Inc. | Dihydroisoquinoline-2(1h)-carboxamide and related compounds and their use in treating medical conditions |
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