CN115872947B - 苯并异噻唑苯甲酰胺类化合物或其药学上可接受的盐、制备方法和用途 - Google Patents
苯并异噻唑苯甲酰胺类化合物或其药学上可接受的盐、制备方法和用途 Download PDFInfo
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- CN115872947B CN115872947B CN202211621921.0A CN202211621921A CN115872947B CN 115872947 B CN115872947 B CN 115872947B CN 202211621921 A CN202211621921 A CN 202211621921A CN 115872947 B CN115872947 B CN 115872947B
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- pharmaceutically acceptable
- acceptable salt
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- benzisothiazole
- hif
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Abstract
本发明公开了一类苯并异噻唑苯甲酰胺类化合物或其药学上可接受的盐,其为式(I)所示的化合物或其药学上可接受的盐以及含有该类化合物的药物组合物。该类化合物能激动缺氧诱导因子2转录活性,增强促红细胞生成素的生成和分泌,从而促进红细胞的生成;本发明还涉及该类化合物的制备方法,含有所述化合物或其药学上可接受的盐的药物组合物。本发明所制备的HIF‑2α激动剂的杂环衍生物类化合物或其药学上可接受的盐可与脯氨酰羟化酶抑制剂联合使用在提升HIF‑2转录活性中起协同作用,其可用于治疗缺氧诱导因子2相关或EPO相关疾病,在缺血性疾病中有良好的应用前景。
Description
技术领域
本发明涉及药物化学领域,具体涉及苯并异噻唑苯甲酰胺类化合物或其药学上可接受的盐,还涉及所述化合物的制备方法和应用。该类化合物具有良好的缺氧诱导因子2转录激动活性,可以明显增加促红细胞生成素的生成和分泌,从而促进红细胞生成,可应用于治疗或预防贫血症如慢性肾性贫血以及缺血性疾病如缺血性脑卒中、心肌缺血、血管疾病等相关疾病。
背景技术
肾性贫血是慢性肾病(Chronic kidney disease,CKD)患者的常见并发症。早期诊断及治疗,对于降低心血管事件发生率及全因死亡率有着重要的意义。肾性贫血的发生机制复杂,促红细胞生成素(erythropoietin,EPO)的不足、铁缺乏、缺氧诱导因子氧传感通路均参与其中。
缺氧诱导因子(hypoxia inducible factor,HIF)是人体内一类重要的响应缺氧的核转录因子,可通过调节与红细胞生成、血管新生以及无氧代谢相关基因的转录,协助机体应对缺氧造成的压力。因此HIF通路的活性异常,与癌症和贫血等多种疾病紧密相关。
HIF由氧敏感性的HIF-α亚基以及与稳定表达的芳香烃受体核转位因子(arylhydrocarbon receptor nuclear translocator,ARNT)两个亚基异源二聚组成,其主要有3种亚型,分别为HIF-1、HIF-2和HIF-3。HIF作为在细胞水平检测和适应氧的中央调节因子,在人体胚胎发育、生理适应和疾病发病机制中起着关键作用。当氧分压正常时,HIF-α迅速被降解;当氧分压下降时,HIF-α脯氨酰羟基化减少,得以转运至细胞核内与HIF-β结合,发挥其促EPO基因转录的作用。HIF不仅参与调节EPO的生成,还可以调控十二指肠对铁的吸收,且可直接调控转铁蛋白及受体基因,促进游离铁释放入血液。在CKD患者体内,肾血流量减少,导致了结构和功能的改变,严重干扰缺氧诱导的REPs信号传导,耗氧量失调,肾脏处于一种“伪常氧”的状态。这种状态下,PHD酶保持活跃,HIF-α不会积累,无法形成二聚体,肾源EPO无法被激活和表达,间接升高的铁调素水平导致用于红细胞生成的循环铁含量减少,最终导致肾性贫血的发生。
由于HIF严格地受到脯氨酰羟化酶(prolyl hydroxylase,PHD)的调控,PHD是稳定HIF的良好治疗靶点。近年来,缺氧诱导因子脯氨酰羟化酶抑制剂(HIF-prolylhydroxylase inhibitors,HIF-PHIs)已有五种相关的新药上市用于肾性贫血的治疗,分别是罗沙司他(roxadustat)、达普司他(daprodustat)、伐度司他(vadadustat)、依那度他(enarodustat)、莫立司他(molidustat)和德度司他(Desidustat)。但在后期的临床研究中,罗沙司他与伐度司他表现出了不可控的心血管风险,以及血栓、癫痫等副作用。PHD抑制剂具有治疗潜力,其不足之处在于HIF下游靶基因众多,超出了红细胞生成的调节范围,不利于对HIF-2的特异性激活,其安全性仍需要进一步临床验证。
不同于PHD抑制剂机制,HIF-2α是EPO、VEGFA等血液新生和血管新生的最直接转录因子,具有功能专一、组织特异性等特点,是副作用小的理想的治疗肾性贫血等缺血性疾病的靶点。HIF-2α激动剂能特异性地与HIF-2α的PASB结构域结合,提升细胞内HIF-2复合物的含量,特异性激活HIF-2通路,诱导肾脏合成促红细胞生成素,从而达到治疗由于慢性肾脏疾病导致的贫血。然而目前报道的HIF-2α激动剂在HIF-2激动方面活性较弱,在使用时难以达到预期效果。
发明内容
发明目的:本发明针对现有HIF-2α激动剂在激动HIF-2时活性弱的问题,提供一种苯并异噻唑苯甲酰胺类化合物或其药学上可接受的盐用于增强缺氧诱导因子HIF-2α转录活性;还提供了上述化合物的制备方法及应用。
技术方案:本发明提供了苯并异噻唑苯甲酰胺类化合物或其药学上可接受的盐,所述化合物如式(I)所示:
Ar代表苯环或芳香杂环,包括五元和六元芳杂环;
R代表单取代、相同或不同的双取代或多取代的R取代基;R取代基任选自氢、C1-C4的烷基、C1-C4的烷氧基、C1-C4卤素取代的烷基、卤素、氨基、羟基、羧基、氰基、氨基甲酰基、C1-C4烷基取代的氨基甲酰基。
所述的苯并异噻唑苯甲酰胺类化合物或其药学上可接受的盐,选自如下化合物:
所述的苯并异噻唑苯甲酰胺类化合物或其药学上可接受的盐,所述的盐包括可药用金属盐如钠、钾、锂、钙、镁、铝或锌盐;可药用金属阳离子如钠、钾、锂、钙、镁、铝和锌的碳酸盐或碳酸氢盐;可药用有机伯胺、仲胺和叔胺,包括脂肪胺、芳香胺、脂肪二胺或羟基烷基胺,如甲胺、乙胺、2-羟基乙基胺、二乙胺、三乙胺、乙二胺、乙醇胺或二乙醇。
所述的苯并异噻唑苯甲酰胺类化合物或其药学上可接受的盐的制备方法:
药物组合物,其包含所述的苯并异噻唑苯甲酰胺类化合物或其药学上可接受的盐及其药学上可接受的辅料或它们的组合。
所述的苯并异噻唑苯甲酰胺类化合物或其药学上可接受的盐或所述的药物组合物在制备预防和/或治疗缺血性疾病药物中的用途。
所述的应用,所述缺血性疾病包括缺血引起的贫血症、缺血、血管疾病、脑卒、心绞痛、中风和心肌缺血。
所述的苯并异噻唑苯甲酰胺类化合物或其药学上可接受的盐或所述的药物组合物与脯氨酰羟化酶抑制剂联合使用在制备在预防和/或治疗缺血性疾病药物中的用途。
所述的用途,所述脯氨酰羟化酶抑制剂包括罗沙司他、伐度司他、达度司他、恩那司他与莫立司他。
所述的用途,所述缺血性疾病包括缺血引起的贫血症、缺血、血管疾病、脑卒、心绞痛、中风和心肌缺血。
化合物4与取代羧酸缩合得到通式(I)化合物。反应温度为20~60℃。反应所用溶剂可选二氯甲烷、三氯甲烷、丙酮、乙腈、二氧六环等。反应中还应加入有机碱或无机碱,如碳酸钾、碳酸钠、碳酸铯、三乙胺、吡啶等。反应中还应加入缩合剂,如二环己基碳二亚胺(DCC)、二异丙基碳二亚胺(DIC)、1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDCI)、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU)等。
本发明公开了上述苯并异噻唑苯甲酰胺类缺氧诱导因子2激动剂类化合物或其药学上可接受的盐在制备用于防护、处理、治疗或减轻缺血性疾病药物中的用途。
所述的药物用于防护、处理、治疗或减轻缺血性疾病药物中的用途。进一步的,所述缺血性疾病包括缺血引起的贫血症、缺血、血管疾病、脑卒、心绞痛、中风、心肌缺血和心肌梗塞等,本发明的化合物临床所用剂量为0.01mg-1000mg/天,也可根据病情轻重或剂型不同偏离此范围。
本发明涉及与脯氨酰羟化酶抑制剂联合使用制备治疗缺血性疾病药物在防护、处理、治疗或减轻缺血性疾病药物中的用途,其包含第一方面所述的化合物或第二方面所述药物用途中的化合物或第三方面所述的药物组合物和。所述脯氨酰羟化酶抑制剂包括罗沙司他(Roxadustat,FG-4592)
伐度司他(Vadadustat,AKB-6548)
达度司他(Daprodustat,GSK1278863)
恩那司他(Enarodustat,JTZ-951)
莫立司他(Molidustat,BAY 85-3934)
本发明的杂环衍生物类HIF-2α激动剂或其药学上可接受的盐与PHD抑制剂联合使用时,两者的使用剂量分别独立为0.01mg-1000mg/天,也可以根据病情轻重或剂型的不同偏离此范围;化合物与PHD抑制剂可以分别给药、同时给药或制备成复合物同时给药。在体内外药效学实验中,该类化合物可与PHD抑制剂联合使用在促进HIF-2激活上起协同作用。PHD抑制剂与HIF-2α激动剂在提升HIF-2转录活性中有着不同的机制:PHD抑制剂通过抑制PHD对HIF-2α的羟基化修饰活性以阻止细胞中的HIF-2α降解,最终提升HIF-2复合物的含量以增强HIF-2转录活性;HIF-2α激动剂通过与HIF-2α-PASB结构域的结合以加强HIF-2α与ARNT两个亚基二聚化作用,最终提升HIF-2水平以加强HIF-2转录活性。将两者联用既可稳定HIF-2α水平,又可提升HIF-2α与ARNT二聚能力,协同地提升HIF-2复合物含量。
有益效果:与现有技术相比,本发明所制备的苯并异噻唑苯甲酰胺类缺氧诱导因子2激动剂类化合物,在细胞水平具有良好的HIF-2激动活性,代表化合物1、15和20分别可将HIF-2转录活性提升至284%以上,远优于现有报道最优的M1002的转录活性141%;本发明的化合物与PHD抑制剂联用能够显著提升EPO,具有协同增效的作用。
附图说明
图1:荧光素酶报告基因实验测试化合物1的EC50。
具体实施方式
为了使本领域的技术人员更好地理解本发明的技术方案,下面进一步披露一些非限制实施例以对本发明作进一步的详细说明。
实施例1
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-苯基苯甲酰胺(1)
(1)1-(2-氯苯基)乙烷-1-亚胺的制备
在冰浴条件下,于2-氯苯甲腈(5g,0.036mol)的乙醚(60mL)溶液中缓慢滴加二(三甲基硅基)氨基锂(1M in THF,60mL,0.06mol)。滴加完毕后,反应液逐渐恢复室温,保持室温反应12小时。反应结束后,将反应液缓慢倒入冰水(200mL)中淬灭,悬浊液依次使用乙酸乙酯(3×100mL)萃取,饱和食盐水(50mL)洗涤。合并有机相,无水硫酸钠干燥,减压蒸除溶剂后得红色油状产物,其无需进一步纯化直接进行下一步反应。
(2)苯并[d]异噻唑-3-胺的制备
于1-(2-氯苯基)乙烷-1-亚胺(278.3mg,1.8mmol)的二甲亚砜和甲苯的混合溶液(10mL.v:v=1:1)中加入单质硫(256mg,8mmol)、K3PO4(764.1mg,3.6mmol)。在氮气保护下135℃反应36小时。反应结束后,抽滤除去硫,随后滤液减压蒸除甲苯。残余液加入水(20mL)后依次使用乙酸乙酯萃取(3×20mL),饱和食盐水(10mL)洗涤。合并有机相,无水硫酸钠干燥,减压蒸除溶剂后经柱层析纯化(石油醚:乙酸乙酯=5:1)后得目标产物为棕色固体(247.1mg,91.5%)。mp144.6-146.1℃.1H NMR(300MHz,DMSO-d6)δ8.15–8.05(m,1H),7.98–7.86(m,1H),7.50(dd,J=8.1,1.2Hz,1H),7.42–7.34(m,1H),6.81(s,2H).
(3)N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-苯基苯甲酰胺的合成
于4-苯基苯甲酸(199mg,1.0mmol)的二氯甲烷(5mL)溶液中,加入1-羟基苯并三唑(136mg,1.0mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(192mg,1.0mmol)、三乙胺(202mg,2.0mmol)和苯并[d]异噻唑-3-胺(100mg,0.67mmol),室温搅拌反应12h。反应结束后,反应液加水(5mL)淬灭,使用乙酸乙酯(3×10mL)萃取。合并有机相,饱和盐水(10mL)洗涤有机相,无水硫酸钠干燥,减压蒸馏除去溶剂后经柱层析(石油醚:乙酸乙酯=3:1)纯化得到目标化合物为白色固体(90mg,65%)。mp 196.8-200.0℃.1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),8.20(dd,J=14.2,8.3Hz,3H),8.01(d,J=8.1Hz,1H),7.89(d,J=8.4Hz,2H),7.80(d,J=7.0Hz,2H),7.65(t,J=7.0Hz,1H),7.53(t,J=7.5Hz,3H),7.45(t,J=7.3Hz,1H).EI-MS m/z:331[M+H]+.tR=7.017min,HPLC purity:96.0%.
实施例2
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-(吡啶-4-基)苯甲酰胺(2)
将氯化亚砜(5mL)加入4-(吡啶-4-基)苯甲酸(50mg,0.25mmol),回流反应3小时。反应结束后,减压蒸馏除去氯化亚砜后溶于二氯甲烷(1mL)中,在冰浴条件下滴加入苯并[d]异恶唑-3-胺(37mg,0.25mmol)的二氯甲烷(2mL)和吡啶(0.15mL)的混合溶液中。滴加完毕后,反应液逐渐恢复室温,保持室温反应3小时。反应结束后,减压蒸馏除去溶剂后经柱层析(石油醚:乙酸乙酯=2:1)纯化得到目标化合物为白色固体(20mg,35%)。mp 184.1-185.6℃.1H NMR(400MHz,DMSO-d6)δ11.31(s,1H),8.74–8.69(m,2H),8.27–8.17(m,3H),8.08–7.99(m,3H),7.89–7.80(m,2H),7.65(ddd,J=8.2,6.9,1.1Hz,1H),7.51(ddd,J=8.1,6.9,1.0Hz,1H).EI-MS m/z:332[M+H]+.tR=2.407min,HPLC purity:99.6%.
实施例3
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-(嘧啶-4-基)苯甲酰胺(3)
按照实施例1的方法,用3-(嘧啶-4-基)苯甲酸替换4-吡啶-3-基苯甲酸得到目标化合物为白色固体(51mg,60%)。mp>300℃.1H NMR(400MHz,Chloroform-d)δ9.21(t,J=1.5Hz,1H),8.77(dd,J=4.6,1.6Hz,1H),8.12(dd,J=8.6,1.4Hz,1H),8.05–7.99(m,2H),7.91(dd,J=4.6,1.5Hz,1H),7.89–7.84(m,2H),7.79(dd,J=7.4,1.5Hz,1H),7.44(td,J=7.2,1.3Hz,1H),7.33(ddd,J=8.6,7.1,1.6Hz,1H),6.98(s,1H).EI-MS m/z:333[M+H]+.tR=3.609min,HPLC purity:99.0%.
实施例4
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-(噻吩-2-基)苯甲酰胺(4)
按照实施例1的方法,用4-(2-噻吩基)苯甲酸替换4-吡啶-3-基苯甲酸得到目标化合物为白色固体(20mg,36%)。mp>300℃.1H NMR(400MHz,Chloroform-d)δ8.12(dd,J=8.6,1.4Hz,1H),8.04–7.98(m,2H),7.89–7.83(m,2H),7.79(dd,J=7.5,1.5Hz,1H),7.63(dd,J=6.1,1.7Hz,1H),7.59(dd,J=5.0,1.7Hz,1H),7.44(td,J=7.2,1.3Hz,1H),7.33(ddd,J=8.4,7.1,1.3Hz,1H),7.17(dd,J=6.1,5.0Hz,1H),6.98(s,1H).EI-MS m/z:337[M+H]+.tR=3.267min,HPLC purity:99.8%.
实施例5
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-(1H-吡咯-2-基)苯甲酰胺(5)
按照实施例1的方法,用4-(1H-吡咯-2-基)苯甲酸替换4-吡啶-3-基苯甲酸得到目标化合物为白色固体(50mg,72%)。mp>300℃.1H NMR(400MHz,Chloroform-d)δ9.11(d,J=6.4Hz,1H),8.12(dd,J=8.6,1.4Hz,1H),8.02–7.96(m,2H),7.79(dd,J=7.5,1.5Hz,1H),7.66–7.60(m,2H),7.44(td,J=7.2,1.3Hz,1H),7.40(dd,J=6.3,1.7Hz,1H),7.33(ddd,J=8.4,7.1,1.3Hz,1H),7.04(ddd,J=6.4,3.2,1.6Hz,1H),6.98(s,1H),6.54(dd,J=6.3,3.2Hz,1H).EI-MS m/z:320[M+H]+.tR=3.667min,HPLC purity:99.8%.
实施例6
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-(呋喃-2-基)苯甲酰胺(6)
按照实施例1的方法,用4-(呋喃-2-基)苯甲酸替换4-吡啶-3-基苯甲酸得到目标化合物为白色固体(51mg,70%)。mp>300℃.1H NMR(400MHz,Chloroform-d)δ8.12(dd,J=8.6,1.4Hz,1H),8.02–7.91(m,4H),7.79(dd,J=7.5,1.5Hz,1H),7.76–7.72(m,1H),7.44(td,J=7.2,1.3Hz,1H),7.33(ddd,J=8.4,7.1,1.3Hz,1H),6.98(s,1H),6.89(dd,J=4.9,1.7Hz,1H),6.65(dd,J=4.9,1.2Hz,1H).EI-MS m/z:321[M+H]+.tR=3.213min,HPLCpurity:99.8%.
实施例7
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-(3H-咪唑-2-基)苯甲酰胺(7)
按照实施例1的方法,用4-(2-咪唑基)苯甲酸替换4-吡啶-3-基苯甲酸得到目标化合物为白色固体(35mg,65%)。mp>300℃.1H NMR(400MHz,Chloroform-d)δ8.14–8.08(m,3H),8.03–7.97(m,2H),7.79(dd,J=7.6,1.5Hz,1H),7.44(td,J=7.2,1.3Hz,1H),7.39(dd,J=4.9,2.6Hz,1H),7.36–7.29(m,2H),6.98(s,1H).EI-MS m/z:321[M+H]+.tR=3.613min,HPLC purity:99.6%.
实施例8
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-[4-(三氟甲基)苯基]苯甲酰胺(8)
(1)4-[4-(三氟甲基)苯基]苯甲酸的制备
于1-溴-4-(三氟甲基)苯(200mg,0.89mmol)的乙二醇二甲醚和水的混合溶液(8mL,v:v=1:1)中加入4-羧基苯硼酸(147.5mg,0.89mmol)、碳酸铯(580mg,1.78mmol)和双三苯基磷二氯化钯(7mg,1%),N2保护,回流搅拌反应3小时。反应结束后,反应液加水(5mL)淬灭,硅藻土过滤除去钯试剂。使用稀盐酸将反应液调至酸性,使用乙酸乙酯(3×10mL)萃取。合并有机相,无水硫酸钠干燥,减压蒸馏除去溶剂后经柱层析(石油醚:乙酸乙酯=1:1)纯化得到目标化合物为白色固体(162mg,75%),mp288.2-288.4℃。
(2)N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-[4-(三氟甲基)苯基]苯甲酰胺的合成
于4-[4-(三氟甲基)苯基]苯甲酸(100mg,0.38mmol)的二氯甲烷(5mL)溶液中,加入1-羟基苯并三唑(51mg,0.38mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(73mg,0.38mmol)、4-二甲氨基吡啶(91mg,0.75mmol)和苯并[d]异噻唑-3-胺(38mg,0.25mmol),室温搅拌反应12h。反应结束后,反应液加水(5mL)淬灭,使用二氯甲烷(3×10mL)萃取。合并有机相,饱和盐水(10mL)洗涤有机相,无水硫酸钠干燥,减压蒸馏除去溶剂后经柱层析(石油醚:乙酸乙酯=5:1)纯化得到目标化合物为白色固体(30mg,75%)。mp 220.7-221.7℃.1HNMR(400MHz,DMSO-d6)δ11.30(s,1H),8.22(d,J=8.5Hz,3H),8.02(dd,J=8.1,4.0Hz,3H),7.97(d,J=8.5Hz,2H),7.89(d,J=8.2Hz,2H),7.65(ddd,J=8.2,6.9,1.1Hz,1H),7.51(ddd,J=8.1,7.0,1.0Hz,1H).EI-MS m/z:399[M+H]+.tR=2.709min,HPLC purity:98.3%.
实施例9
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-(4-氯苯基)苯甲酰胺(9)
按照实施例8的方法,用1-溴-4-氯苯替换1-溴-4-(三氟甲基)苯得到目标化合物为白色固体(20mg,40%)。mp 216.4-217.5℃.1H NMR(400MHz,DMSO-d6)δ11.26(s,1H),8.24–8.15(m,3H),8.01(dt,J=8.2,1.0Hz,1H),7.93–7.87(m,2H),7.87–7.81(m,2H),7.65(ddd,J=8.2,7.0,1.1Hz,1H),7.62–7.56(m,2H),7.51(ddd,J=8.0,6.9,1.0Hz,1H).EI-MSm/z:365[M+H]+.tR=2.780min,HPLC purity:99.3%.
实施例10
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-(4-氟苯基)苯甲酰胺(10)
按照实施例8的方法,用1-溴-4-氟苯替换1-溴-4-(三氟甲基)苯得到目标化合物为白色固体(50mg,40%)。mp 176.1-177.9℃.1H NMR(400MHz,DMSO-d6)δ11.24(s,1H),8.19(dd,J=17.8,8.3Hz,3H),8.03–7.99(m,1H),7.93–7.81(m,4H),7.65(ddd,J=8.1,6.9,1.1Hz,1H),7.53–7.48(m,1H),7.36(t,J=8.8Hz,2H).EI-MS m/z:349[M+H]+.tR=2.540min,HPLC purity:100.0%.
实施例11
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-(4-甲氧基苯基)苯甲酰胺(11)
按照实施例8的方法,用1-溴-4-甲氧基苯替换1-溴-4-(三氟甲基)苯得到目标化合物为白色固体(40mg,40%)。mp 191.2-192.3℃.1H NMR(400MHz,Chloroform-d)δ8.40–8.31(m,2H),8.14(d,J=8.5Hz,1H),7.85–7.77(m,2H),7.71–7.64(m,2H),7.62–7.57(m,1H),7.54–7.46(m,2H),7.11–7.04(m,2H),3.91(s,3H).EI-MS m/z:361[M+H]+.tR=3.007min,HPLC purity:96.1%.
实施例12
4-{4-[(苯并[d][1,2]硫杂氮杂环戊熳-3-基氨基)羰基]苯基}苯甲酸(12)
按照实施例8的方法,用4-溴苯甲酸替换1-溴-4-(三氟甲基)苯得到目标化合物为白色固体(60mg,50%)。mp>300℃.1H NMR(400MHz,Chloroform-d)δ
9.77(s,1H),8.12(dd,J=8.6,1.4Hz,1H),8.06–7.99(m,4H),7.82–7.74(m,3H),7.56–7.50(m,2H),7.44(td,J=7.2,1.3Hz,1H),7.36–7.29(m,1H),6.98(s,1H).EI-MS m/z:375[M+H]+.tR=2.107min,HPLC purity:99.1%.
实施例13
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-[3-(三氟甲基)苯基]苯甲酰胺(13)
按照实施例8的方法,用1-溴-3-(三氟甲基)苯替换1-溴-4-(三氟甲基)苯得到目标化合物为白色固体(60mg,62%)。mp 143.0-143.8℃.1H NMR(400MHz,DMSO-d6)δ13.09(s,1H),8.09–8.03(m,4H),8.01–7.97(m,1H),7.93–7.88(m,2H),7.81–7.71(m,3H),7.55(ddd,J=8.2,6.9,1.0Hz,1H),7.45–7.39(m,1H).EI-MS m/z:399[M+H]+.tR=2.670min,HPLCpurity:100.0%.
实施例14
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-(3-氯苯基)苯甲酰胺(14)
按照实施例8的方法,用1-溴-3-氯苯替换1-溴-4-(三氟甲基)苯得到目标化合物为白色固体(35mg,42%)。mp153.5-154.7℃.1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),8.20(dd,J=13.0,8.3Hz,3H),8.01(d,J=8.2Hz,1H),7.93(d,J=8.4Hz,2H),7.87(t,J=1.9Hz,1H),7.78(dt,J=7.6,1.5Hz,1H),7.68–7.63(m,1H),7.59–7.48(m,3H).EI-MS m/z:365[M+H]+.tR=2.840min,HPLC purity:99.4%.
实施例15
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-(3-氟苯基)苯甲酰胺(15)
按照实施例8的方法,用1-溴-3-氟苯替换1-溴-4-(三氟甲基)苯得到目标化合物为白色固体(46mg,20%)。mp 166.6-168.0℃.1H NMR(400MHz,DMSO-d6)δ11.27(s,1H),8.25–8.15(m,3H),8.02(dt,J=8.1,1.0Hz,1H),7.97–7.90(m,2H),7.71–7.62(m,3H),7.57(td,J=8.2,6.3Hz,1H),7.51(ddd,J=8.0,6.9,1.0Hz,1H),7.32–7.25(m,1H).EI-MS m/z:349[M+H]+.tR=2.605min,HPLC purity:99.8%.
实施例16
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-(3-甲基苯基)苯甲酰胺(16)
按照实施例8的方法,用1-溴-3-甲基苯替换1-溴-4-(三氟甲基)苯得到目标化合物为白色固体(50mg,32%)。mp 130.6-131.0℃.1H NMR(500MHz,Chloroform-d)δ8.12(dd,J=8.6,1.4Hz,1H),8.06–8.00(m,2H),7.79(dd,J=7.5,1.5Hz,1H),7.66–7.60(m,2H),7.48–7.39(m,4H),7.33(ddd,J=8.4,7.1,1.3Hz,1H),7.23(dtd,J=7.9,1.5,0.7Hz,1H),6.98(s,1H).EI-MS m/z:345[M+H]+.tR=3.805min,HPLC purity:99.2%.
实施例17
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-(3-甲氧基苯基)苯甲酰胺(17)
按照实施例8的方法,用1-溴-3-甲氧基苯替换1-溴-4-(三氟甲基)苯得到目标化合物为白色固体(48mg,20%)。mp 159.7-160.3℃.1H NMR(400MHz,DMSO-d6)δ11.25(s,1H),8.19(dd,J=19.1,8.3Hz,3H),8.01(dt,J=8.2,1.0Hz,1H),7.92–7.87(m,2H),7.65(ddd,J=8.2,7.0,1.1Hz,1H),7.51(ddd,J=8.0,6.9,1.0Hz,1H),7.43(d,J=7.9Hz,1H),7.39–7.29(m,2H),7.02(ddd,J=8.2,2.5,1.0Hz,1H),3.87(s,3H).EI-MS m/z:361[M+H]+.tR=2.670min,HPLC purity:100.0%.
实施例18
4-(3-氨基苯基)-N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)苯甲酰胺(18)
按照实施例8的方法,用1-溴-3-氨基苯替换1-溴-4-(三氟甲基)苯得到目标化合物为白色固体(32mg,22%)。mp>300℃.1H NMR(400MHz,Chloroform-d)δ8.12(dd,J=8.6,1.4Hz,1H),8.05–7.99(m,2H),7.79(dd,J=7.5,1.5Hz,1H),7.62–7.56(m,2H),7.44(td,J=7.2,1.3Hz,1H),7.36–7.30(m,1H),7.33–7.26(m,1H),7.29–7.23(m,1H),7.00–6.96(m,2H),6.67–6.61(m,1H),4.38(d,J=5.3Hz,1H),4.29(d,J=5.5Hz,1H).EI-MS m/z:346[M+H]+.tR=2.070min,HPLC purity:100.0%.
实施例19
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-(3-羟基苯基)苯甲酰胺(19)
按照实施例8的方法,用1-溴-3-羟基苯替换1-溴-4-(三氟甲基)苯得到目标化合物为白色固体(26mg,20%)。mp>300℃.1H NMR(400MHz,Chloroform-d)δ8.55(s,1H),8.12(dd,J=8.6,1.4Hz,1H),8.06–8.00(m,2H),7.79(dd,J=7.5,1.5Hz,1H),7.69–7.63(m,2H),7.44(td,J=7.2,1.3Hz,1H),7.33(ddd,J=8.4,7.1,1.3Hz,1H),7.22(dd,J=8.3,7.6Hz,1H),7.08(ddd,J=7.5,2.2,1.2Hz,1H),7.04(t,J=2.2Hz,1H),6.98(s,1H),6.79(ddd,J=8.4,2.2,1.2Hz,1H).EI-MS m/z:347[M+H]+.tR=3.100min,HPLC purity:100.0%.
实施例20
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-{3-[(甲基氨基)羰基]苯基}苯甲酰胺(20)
(1)3-溴-N-甲基苯甲酰胺的制备
于3-溴苯甲酸(500mg,2.49mmol)的二氯甲烷(5mL)溶液中,加入1-羟基苯并三唑(337mg,2.49mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(477mg,2.49mmol)、三乙胺(503mg,4.98mmol)和甲胺(116mg,3.73mmol),室温搅拌反应12h。反应结束后,反应液加水(5mL)淬灭,稀盐酸洗涤反应液,使用二氯甲烷(3×10mL)萃取。合并有机相,饱和盐水(10mL)洗涤有机相,无水硫酸钠干燥,减压蒸除溶剂后得淡黄色固体即为产物(432mg,80%),其直接用于下一步反应无需进一步纯化。
(2)4-{3-[(甲基氨基)羰基]苯基}苯甲酸的制备
于3-溴-N-甲基苯甲酰胺(170mg,0.79mmol)的乙二醇二甲醚和水的混合溶液(8mL,v:v=1:1)中加入4-羧基苯硼酸(130mg,0.79mmol)、碳酸铯(518mg,1.59mmol)和双三苯基磷二氯化钯(6mg,1%),N2保护,回流搅拌反应3小时。反应结束后,反应液加水(5mL)淬灭,硅藻土过滤除去钯试剂。使用稀盐酸将反应液调至酸性,使用乙酸乙酯(3×10mL)萃取。合并有机相,无水硫酸钠干燥,减压蒸馏除去溶剂后经柱层析(石油醚:乙酸乙酯=1:1)纯化得到产物为白色固体(157mg,85%),投入下一步。
(3)N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-{4-[(甲基氨基)羰基]苯基}苯甲酰胺的合成
于4-{3-[(甲基氨基)羰基]苯基}苯甲酸(80mg,0.31mmol)的二氯甲烷(5mL)溶液中,加入1-羟基苯并三唑(53mg,0.40mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(76mg,0.40mmol)、4-二甲氨基吡啶(95mg,0.78mmol)和苯并[d]异噻唑-3-胺(40mg,0.26mmol),室温搅拌反应12h。反应结束后,反应液加水(5mL)淬灭,使用二氯甲烷(3×10mL)萃取。合并有机相,饱和盐水(10mL)洗涤有机相,无水硫酸钠干燥,减压蒸馏除去溶剂后经柱层析(石油醚:乙酸乙酯=3:1)纯化得到目标化合物为白色固体(40mg,30%)。mp201.8-202.8℃.1H NMR(400MHz,DMSO-d6)δ11.25(s,1H),8.63(d,J=4.7Hz,1H),8.26–8.17(m,4H),8.02(d,J=8.2Hz,1H),7.99–7.92(m,3H),7.90(dt,J=7.9,1.3Hz,1H),7.68–7.59(m,2H),7.51(ddd,J=8.1,7.0,1.0Hz,1H),2.84(d,J=4.5Hz,3H).EI-MS m/z:388[M+H]+.tR=2.218min,HPLC purity:100.0%.
实施例21
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-(2-氟苯基)苯甲酰胺(21)
按照实施例8的方法,用1-溴-2-氟苯替换1-溴-4-(三氟甲基)苯得到目标化合物为白色固体(42mg,56%)。mp>300℃.1H NMR(400MHz,Chloroform-d)δ8.12(dd,J=8.6,1.4Hz,1H),8.08–8.02(m,2H),7.79(dd,J=7.5,1.5Hz,1H),7.72–7.64(m,3H),7.48–7.37(m,2H),7.36–7.28(m,2H),7.20(td,J=7.8,1.4Hz,1H),6.98(s,1H).EI-MS m/z:349[M+H]+.tR=4.208min,HPLC purity:99.6%.
实施例22
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-(3-氯吡啶-2-基)苯甲酰胺(22)
按照实施例8的方法,用2-溴-3-氯吡啶替换1-溴-4-(三氟甲基)苯得到目标化合物为白色固体(38mg,40%)。mp>300℃.1H NMR(500MHz,Chloroform-d)δ8.59(dd,J=4.2,2.2Hz,1H),8.12(dd,J=8.6,1.4Hz,1H),8.08–8.02(m,2H),7.99–7.93(m,2H),7.79(dd,J=7.5,1.5Hz,1H),7.75(dd,J=7.9,2.2Hz,1H),7.44(td,J=7.2,1.3Hz,1H),7.36–7.29(m,2H),6.98(s,1H).EI-MS m/z:366[M+H]+.tR=4.225min,HPLC purity:99.9%.
实施例23
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-(4-氯-2-氟苯基)苯甲酰胺(23)
按照实施例8的方法,用1-溴-2-氟-4-氯苯替换1-溴-4-(三氟甲基)苯得到目标化合物为白色固体(52mg,61%)。mp>300℃.1H NMR(400MHz,Chloroform-d)δ8.12(dd,J=8.6,1.3Hz,1H),8.09–8.03(m,2H),7.79(dd,J=7.5,1.5Hz,1H),7.76–7.66(m,3H),7.48–7.29(m,5H),6.98(s,1H).EI-MS m/z:383[M+H]+.tR=3.825min,HPLC purity:99.9%.
实施例24
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-(4-氯-3-氟苯基)苯甲酰胺(24)
按照实施例8的方法,用1-溴-3-氟-4-氯苯替换1-溴-4-(三氟甲基)苯得到目标化合物为白色固体(32mg,42%)。mp>300℃.1H NMR(500MHz,Chloroform-d)δ8.12(dd,J=8.6,1.4Hz,1H),8.06–8.00(m,2H),7.79(dd,J=7.5,1.5Hz,1H),7.70–7.64(m,2H),7.56–7.38(m,4H),7.33(ddd,J=8.4,7.1,1.3Hz,1H),6.98(s,1H).EI-MS m/z:383[M+H]+.tR=3.825min,HPLC purity:99.9%.
实施例25
4-(4-氨基-2-氟苯基)-N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)苯甲酰胺(25)
按照实施例8的方法,用1-溴-4-氨基苯替换1-溴-4-(三氟甲基)苯得到目标化合物为白色固体(41mg,50%)。mp>300℃.1H NMR(400MHz,Chloroform-d)δ8.12(dd,J=8.6,1.4Hz,1H),8.09–8.03(m,2H),7.79(dd,J=7.5,1.5Hz,1H),7.66(dq,J=8.8,1.7Hz,2H),7.60(dd,J=8.0,5.0Hz,1H),7.44(td,J=7.2,1.3Hz,1H),7.33(ddd,J=8.4,7.1,1.3Hz,1H),6.98(s,1H),6.70(dd,J=8.0,2.3Hz,1H),6.51(dd,J=8.1,2.3Hz,1H),4.80(d,J=5.3Hz,1H),4.69(d,J=5.3Hz,1H).EI-MS m/z:364[M+H]+.tR=2.805min,HPLC purity:99.8%.
实施例26
N-(苯并[d][1,2]硫杂氮杂环戊熳-3-基)-4-(2-氯-4-羟基苯基)苯甲酰胺(26)
按照实施例8的方法,用1-溴-4-羟基苯替换1-溴-4-(三氟甲基)苯得到目标化合物为白色固体(25mg,32%)。mp>300℃.1H NMR(400MHz,Chloroform-d)δ8.12(dd,J=8.6,1.4Hz,1H),8.08–8.02(m,2H),7.79(dd,J=7.5,1.5Hz,1H),7.74–7.68(m,2H),7.66(s,1H),7.60(d,J=9.0Hz,1H),7.44(td,J=7.2,1.3Hz,1H),7.33(ddd,J=8.4,7.1,1.3Hz,1H),7.00–6.95(m,2H),6.76(dd,J=9.1,2.3Hz,1H).EI-MS m/z:381[M+H]+.tR=2.805min,HPLC purity:99.8%.
下面是本发明化合物的部分药效学实验数据:
(1)荧光素酶报告基因实验测试化合物对HIF-2的激动活性
实验方法:将含有缺氧诱导元件和荧光素酶基因序列的商用病毒转染至786-O细胞中,得到稳定转染的786-O-HRE-Luc工具细胞。将786-O-HRE-Luc细胞均匀地接种于96孔白板中。待细胞贴壁,加药组加入用培养基稀释的一定浓度的化合物溶液。在37℃、5%CO2培养条件的培养箱中孵育24小时后,将One-LumiTM萤火虫荧光素酶测定试剂盒(RG055,Beyotime)中荧光素酶底物添加到每个孔中,平衡5min后,使用多功能酶标仪(SpectraMax,Molecular Devices)检测,得到各孔荧光值。加药孔发光值对比空白对照组发光值得到化合物的激动效应E。同时使用Graphpad Prism 8对化合物不同浓度的发光值进行非线性回归分析计算EC50值。
E=加药组发光值/空白对照组发光值×100%
表1、本发明部分化合物在20μM浓度下对HIF-2转录活性的激动效应
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(E20(%):化合物在20μM浓度下的激动效应;a=150%~200%;b=201%~300%)
表1数据为本发明部分化合物在20μM浓度下对HIF-2转录活性的激活效应。测试结果显示本发明中的化合物均表现出一定的上调HIF-2a/ARNT结合的活性且优于阳性化合物M1002(140±8.2%),其中部分化合物的HIF-2激动活性显著优于阳性药化合物M1002,如化合物1、2、15、18和20。
由实验结果可知,本发明化合物具有良好的HIF-2α/ARNT激活活性,其可作为有效的HIF-2α激动剂。
同时,本发明部分化合物在低浓度下即能激活HIF-2转录活性,其在荧光素酶报告基因实验中的EC50数据如表2和图1所示。其中,化合物1、20、22在纳摩尔浓度下即能有效激活HIF-2。而阳性化合物M1002在多浓度荧光素酶报告基因实验中,高浓度荧光数值反常下降,这可能是由于其对786-O-HRE细胞的细胞毒性原因。荧光数值反常导致其EC50数值无法拟合,其活性弱于本发明化合物。
表2、本发明部分化合物在荧光素酶报告基因实验中的EC50
(a=100~500nM;b=501~1000nM)
(2)细胞计数(cell counting kit-8,CCK-8)法测试本发明化合物对肾上皮细胞株HEK293细胞毒性
为了初步评价本发明化合物的安全性,采用CCK-8法测试肾上皮细胞株HEK293的细胞毒性。
实验方法:将HEK293细胞接种在96孔板中,细胞贴壁后,将待测化合物母液用含10%牛胎血清的1640培养基稀释成终浓度为20μM,各取10μL添加到每个给药孔中。同时设置3个复孔。孵育24h后,根据试剂盒说明书将Cell Counting Kit-8(C0037,Beyotime)添加到每个孔中。在37℃培养箱中孵育1-2h后,以620nm波长为参照,在450nm波长下测定吸光度,检测仪器为SpectraMaxGeminiXS酶标仪。计算给药组吸光度值与空白对照组吸光度的比值以确定抑制率I,定义I值高于10%为有细胞毒性。
I=(1-加药组吸光度/空白组吸光度)×100%
CCK-8法测试的实验结果表明,本发明化合物在20μM高浓度条件下均无显著细胞毒性。而阳性化合物M1002在2μM浓度下即展现出细胞毒性。本发明化合物在细胞水平安全性方面优于阳性化合物M1002。
(3)RT-PCR实验测试化合物和PHD抑制剂的协同作用提升EPO
实验所用细胞为Hep-3B细胞系,所用培养基为添加了10%胎牛血清的DMEM培养基,将细胞传代至六孔细胞培养板中。孵育过夜后,去除旧培养基,将相应浓度的化合物溶液并更换至六孔板相应孔中。于细胞培养箱中孵育12h后,使用RNA提取试剂盒(R401-01,Vazyme)按照说明提取各孔RNA。使用Eppendorf Mastercycler nexus GSX1梯度PCR仪进行cDNA合成。RT-PCR在StepOnePlus qPCR仪器(Thermo Fisher Scientific)上进行扩增。使用HPRT基因作为内参基因。
表3、本发明部分化合物与PHD抑制剂联合使用的实验数据
本发明部分化合物和PHD抑制剂在细胞中对HIF-2的激活具有良好的协同作用,其联用提升EPO的效果显著优于单独给药组(如PHI浓度为10μM,本发明化合物浓度为10μM时)。其中,ND表示未测试。实验结果表明,本发明化合物与PHD抑制剂联合使用在提升HIF-2转录活性中可展现协同作用,其联用效果显著优于单独给药组。
本发明的苯并异噻唑苯甲酰胺类化合物具有良好的生物活性,该类化合物能激动缺氧诱导因子2转录活性,增强促红细胞生成素的生成和分泌,从而促进红细胞的生成,其可用于治疗缺氧诱导因子2相关疾病,如缺血性疾病等,在肾性贫血、缺血性脑卒等缺血性疾病中有着一定的应用前景。
Claims (10)
1.苯并异噻唑苯甲酰胺类化合物或其药学上可接受的盐,其特征在于,所述化合物如式I所示:
Ar代表苯环或芳香杂环,所述芳香杂环为五元或六元芳杂环;
R代表单取代、相同或不同的双取代或多取代的R取代基;R取代基任选自氢、C1-C4的烷基、C1-C4的烷氧基、C1-C4卤素取代的烷基、卤素、氨基、羟基、羧基、氰基、氨基甲酰基、C1-C4烷基取代的氨基甲酰基。
2.根据权利要求1所述的苯并异噻唑苯甲酰胺类化合物或其药学上可接受的盐,其特征在于,选自如下化合物:
3.根据权利要求1所述的苯并异噻唑苯甲酰胺类化合物或其药学上可接受的盐,其特征在于,所述药学上可接受的盐包括可药用金属盐或可药用有机伯胺、仲胺和叔胺。
4.权利要求1所述的苯并异噻唑苯甲酰胺类化合物或其药学上可接受的盐的制备方法,其特征在于:
5.一种药物组合物,其包含权利要求1所述的苯并异噻唑苯甲酰胺类化合物或其药学上可接受的盐及其药学上可接受的辅料或它们的组合。
6.权利要求1-3任一项所述的苯并异噻唑苯甲酰胺类化合物或其药学上可接受的盐或权利要求5所述的药物组合物在制备预防和/或治疗缺血性疾病药物中的用途。
7.根据权利要求6所述的用途,其特征在于,所述缺血性疾病包括缺血引起的贫血症、缺血、血管疾病、脑卒、心绞痛和中风。
8.权利要求1-3任一项所述的苯并异噻唑苯甲酰胺类化合物或其药学上可接受的盐或权利要求5所述的药物组合物与脯氨酰羟化酶抑制剂联合使用在制备在预防和/或治疗缺血性疾病药物中的用途。
9.根据权利要求8所述的用途,其特征在于,所述脯氨酰羟化酶抑制剂包括罗沙司他、伐度司他、达度司他、恩那司他与莫立司他。
10.根据权利要求8所述的用途,其特征在于,所述缺血性疾病包括缺血引起的贫血症、缺血、血管疾病、脑卒、心绞痛和中风。
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