CN117903126A - 含炔基噻唑甲酰基的甘氨酰胺类化合物及其制备方法和应用 - Google Patents
含炔基噻唑甲酰基的甘氨酰胺类化合物及其制备方法和应用 Download PDFInfo
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- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- A—HUMAN NECESSITIES
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本申请实施例涉及一种含炔基噻唑甲酰基的甘氨酰胺类化合物及其制备方法和应用，属于药物化学技术领域。本申请实施例的一种含炔基噻唑甲酰基的甘氨酰胺类化合物，所述化合物为式I所示化合物、式I所示化合物的药学上可接受的盐、式I所示化合物的水合物、式I所示化合物的溶剂化物、式I所示化合物的光学异构体或式I所示化合物的衍生物。本申请实施例所提供的含炔基噻唑甲酰基的甘氨酰胺类化合物具有显著的谷胱甘肽过氧化物酶4(GPX4)活性抑制作用。
Description
技术领域
本申请实施例涉及药物化学技术领域，特别是涉及一种含炔基噻唑甲酰基的甘氨酰胺类化合物及其制备方法和应用。
背景技术
恶性肿瘤是世界主要疾病之一，并且严重威胁到人类健康和生命，尽管目前的医疗质量有了显著的改善，但仍缺乏有效的对策能够治疗癌症。2020年全球新发癌症病例1929万例，死亡病例达996万例。其中，中国新发癌症和死亡人数均居世界首位，分别为457万例和300万例。根据2020年全球癌症负担数据和联合国人口数据估算了2040年的癌症新增病例和新增死亡人数，中国癌症新发病例数大幅上涨。
GPX4是谷胱甘肽过氧化物酶家族的成员，是一种含硒半胱氨酸核心的酶，与该家族其他成员不同的是，GPX4是唯一一个可以催化还原脂质过氧化物的过氧化物酶。GPX4活性受到抑制将直接导致细胞内LPO清除受阻，从而诱发铁死亡，因此，抑制GPX4的活性是诱导铁死亡最有效的途径。在谷胱甘肽(Glutathione，GSH)作为辅酶的条件下，GPX4可以将胞内经各种途径产生的LPO(PE-AA-OOH和PE-ADA-OOH等)生物还原为正常脂质。GPX4在纤维肉瘤、淋巴瘤、乳腺癌、肺癌以及肾癌等多种肿瘤中高表达，并与肿瘤MDR相关，研究表明抑制GPX4活性将阻断细胞内脂质过氧化物代谢而诱导铁死亡克服肿瘤MDR。
目前铁死亡诱导剂的研究仍处于早期阶段，尽管多个化合物被发现具有GPX4抑制剂活性和铁死亡诱导活性，如RSL-3、Erastin以及ML-210等，但结构单一，且存在铁死亡诱导活性不足、缺乏选择性以及成药性不佳等问题，尚没有铁死亡诱导剂进入临床。
发明内容
有鉴于此，本申请实施例提供一种含炔基噻唑甲酰基的甘氨酰胺类化合物及其制备方法和应用，该类化合物经过实验证明，具有显著的谷胱甘肽过氧化物酶4(GPX4)活性抑制作用，能够通过抑制GPX4阻断细胞内脂质过氧化物代谢，使LPO(PE-AA-OOH和PE-ADA-OOH等)有毒脂质过氧化物蓄积，诱发细胞发生铁死亡；此外，GPX4在纤维肉瘤、淋巴瘤、乳腺癌、肺癌以及肾癌等多种肿瘤中高表达，该类化合物诱发的铁死亡有效杀伤肿瘤细胞，给患者更多的可选药物；能够有效克服上述现有技术所存在的缺陷。
本申请实施例第一方面提供一种含炔基噻唑甲酰基的甘氨酰胺类化合物，所述化合物为式I所示化合物、式I所示化合物的药学上可接受的盐、式I所示化合物的水合物、式I所示化合物的溶剂化物、式I所示化合物的光学异构体或式I所示化合物的衍生物，所述式I结构如下所示：
式中，R1选自烯丙基、C1-6烷基、环烷基、取代或非取代苄基、苯乙基、含有1-2个取代基的苯乙基、取代或非取代的芳环和卤代烷基；
R2选自含氮芳杂环、饱和含氮杂环或者1-3个相同或不同的R3取代基；
R3选自氢、羟基、烷氧基、卤素、C1-6烷氨基、氰基、C1-6烷基和卤代烷基；
Cyl选自五元芳杂环、六元芳杂环、苯并五元杂环、苯并六元杂环、吡啶并六元杂环、吡啶并五元杂环、脂杂环、萘、蒽、C1-6烷基和环烷基。
在可以包括上述实施例的一些实施例中，R1选自烯丙基、叔丁基、环烷基、苄基、取代或非取代的芳环、苯乙基、含有1-2个取代基的苯乙基、取代或非取代的芳环和卤代烷基；
R2选自含氮五元芳杂环、饱和含氮杂环或者1-3个相同或不同的R3取代基；
R3选自氢、烷氧基、卤素、C1-6烷氨基、氰基、C1-6烷基和卤代烷基；
Cyl选自五元芳杂环、六元芳杂环，苯并五元杂环、苯并六元杂环、萘和环烷基。
在可以包括上述实施例的一些实施例中，所述Cyl选自以下任一结构：
在可以包括上述实施例的一些实施例中，所述化合物选自N-(1-(苯并[b]噻吩-3-基)-2-氧代-2-(苯乙氨基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(1-(苯并[b]噻吩-3-基)-2-((4-氟苯乙基)氨基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(1-(苯并[b]噻吩-3-基)-2-(环己基氨基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(1-(苯并[b]噻吩-3-基)-2-(苄氨基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基-N-(4-(哌嗪-1-基)苯基)噻唑-4-甲酰胺、N-(4-(1H-咪唑-1-基)苯基)-N-(1-(苯并噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基噻唑-4-甲酰胺、N-(4-(1H-吡唑-1-基)苯基)-N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基噻唑-4-甲酰胺、N-(4-(1H-1,2,4-三唑-1-基)苯基)-N-(1-(苯并噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基噻唑-4-甲酰胺、N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基-N-(4-氟苯基)噻唑-4-甲酰胺、N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基-N-(3-氟苯基)噻唑-4-甲酰胺、N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-N-(2,6-二氟苯基)-2-乙炔基噻唑-4-甲酰胺、N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基-N-(4-(三氟甲基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-1-环己基-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-1-(5,6-二氢-2H-吡喃-3-基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-2-氧代-1-(嘧啶-4-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-1-(1H-咪唑-4-基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-2-氧代-1-(噻唑-5-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-2-氧代-1-(1H-吡咯-2-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-2-氧代-1-(噻吩-3-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-2-氧代-1-(噻吩-2-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-2-氧代-1-(吡啶-3-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-2-氧代-1-(1H-吡唑-3-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-1-(萘-2-基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺和N-(2-(叔丁基氨基)-1-(1H-吲哚-3-基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺。
本申请实施例第二方面还提供一种上述的含炔基噻唑甲酰基的甘氨酰胺类化合物的制备方法，包括按照如下反应式获得式I所示化合物的步骤：
即：将化合物1和化合物4溶于0.6mL甲醇中，搅拌15mins后，加入化合物2和化合物3，进行反应，反应时间为8-10h，后处理，得目标化合物。
优选地，所述后处理包括以下步骤：反应结束，减压浓缩，制备薄层板分离，得到目标化合物。
本申请实施例第三方面还提供一种药用组合物，包含上述的含炔基噻唑甲酰基的甘氨酰胺类化合物以及一种或多种药学上可接受的附加剂或赋形剂。
本申请实施例第四方面还提供上述的含炔基噻唑甲酰基的甘氨酰胺类化合物在制备铁死亡诱导剂中的应用。
本申请实施例第五方面还提供上述的含炔基噻唑甲酰基的甘氨酰胺类化合物在制备抗肿瘤的药物中的应用。
在可以包括上述实施例的一些实施例中，所述肿瘤为铁死亡性肿瘤，具体包括纤维肉瘤、淋巴瘤、乳腺癌、肺癌、肾癌。
在可以包括上述实施例的一些实施例中，所述化合物通过抑制GPX4，来引发铁死亡，从而抑制肿瘤细胞的存活，达到抗肿瘤的作用。
本申请实施例与现有技术相比，具有如下有益效果：
本申请实施例的含炔基噻唑甲酰基的甘氨酰胺类化合物具有显著的谷胱甘肽过氧化物酶4(GPX4)活性抑制作用，能够通过抑制GPX4阻断细胞内脂质过氧化物代谢，使LPO(PE-AA-OOH和PE-ADA-OOH等)有毒脂质过氧化物蓄积，诱发细胞发生铁死亡；此外，GPX4在纤维肉瘤、淋巴瘤、乳腺癌、肺癌以及肾癌等多种肿瘤中高表达，该类化合物诱发的铁死亡有效杀伤肿瘤细胞，给患者更多的可选药物。
具体实施方式
为使本申请实施例的目的、技术方案和优点更加清楚，下面将对本申请实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例是本申请一部分实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本申请保护的范围。
在下述实施例和对比例中，如无特殊说明，所有原料均可通过商购或者常规方法制备得到。
本申请实施例中术语“取代的”指基团中的一个或多个氢原子彼此独立地被相应数目的取代基团取代。
本申请实施例中附加剂或赋形剂，是除活性成分以外，在安全性方面已进行了合理的评估，且包含在药物制剂中的物质。可以是阿拉伯胶、糖浆、羊毛脂、淀粉、氯化镁、环糊精、癸二酸、糊精、药用硫酸钙、甘油、甘露醇、山梨醇、肌醇、硫醇、氨丁三醇、苯酚、间甲酚、苯甲醇、对羟基苯甲酸酯、对羟基苯甲酸甲酯、叔丁醇、苯扎氯铵、氯丁醇、硫柳汞等。
本申请实施例中光学异构体(optical isomer)是立体异构体(stereo-isomer)的一种，又称旋光异构体、对掌异构物、光学异构物、镜像异构物、对映异构体或手性异构体，不能与彼此立体异构体镜像完全重叠；
本申请实施例中通式I化合物的衍生物作为前药，指代他们自身可能具有较弱的活性或甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式；
本申请实施例的化学结构均经1H-NMR、13C-NMR确证。快速柱层析在硅胶H(10-40μM)上进行。
实施例1
N-(1-(苯并[b]噻吩-3-基)-2-氧代-2-(苯乙氨基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺的制备过程如下：
目标化合物的制备：将3-苯并噻吩甲醛和4-(恶唑-5-基)苯胺溶于0.6mL甲醇中，搅拌15mins后，加入2-(炔基)噻唑-4-羧酸和化合物苯乙基异腈，进行反应，反应时间为8-10h，后处理，得实施例1化合物，产率95％
1H NMR(400MHz,DMSO-d6)δ8.48(s,1H),8.34(s,1H),7.90(d,J＝7.9Hz,1H),7.84–7.74(m,2H),7.53(s,1H),7.50–7.33(m,3H),7.30–7.13(m,9H),6.75(s,1H),4.84(s,1H),3.68–3.47(m,1H),2.78(t,J＝6.4Hz,2H)。
13C NMR(101MHz,DMSO)δ168.66,163.05,151.80,149.92,149.67,145.68,139.40,139.35,138.95,138.03,130.45,129.47,128.88,128.69,128.26,126.03,125.84,124.61,124.51,123.06,122.90,122.35,121.46,117.35,86.32,75.78,57.65,40.38,34.88。
实施例2
N-(1-(苯并[b]噻吩-3-基)-2-((4-氟苯乙基)氨基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺本申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ8.46(s,1H),8.34(s,1H),7.90(d,J＝8.0Hz,1H),7.85–7.74(m,2H),7.53(s,1H),7.50–7.33(m,3H),7.29–7.22(m,4H),7.18(s,1H),7.05(t,J＝8.8Hz,2H),6.73(s,1H),4.84(s,1H),3.61–3.46(m,1H),2.76(t,J＝7.0Hz,2H)。
13C NMR(101MHz,DMSO)δ168.72,163.05,161.99,159.59,151.82,149.91,149.67,145.68,139.40,138.96,138.02,135.49,135.46,130.51,130.43,129.46,128.88,126.06,125.85,124.63,124.53,123.06,122.93,122.37,121.48,114.98,114.78,86.32,75.78,57.66,54.88,33.95。
实施例3
N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),8.04(s,1H),7.89(d,J＝8.0Hz,1H),7.82(d,J＝7.8Hz,1H),7.75(s,1H),7.54–7.43(m,3H),7.41–7.20(m,5H),6.72(s,1H),4.84(s,1H),1.31(s,9H)。
13C NMR(101MHz,DMSO)δ168.15,163.01,151.77,150.04,149.71,145.67,139.53,138.97,138.15,130.52,130.35,128.18,125.86,125.73,124.58,124.40,122.97,122.85,122.29,121.68,86.29,75.80,59.72,50.55,50.55,28.40,14.06。
实施例4
N-(1-(苯并[b]噻吩-3-基)-2-(环己基氨基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ8.34(s,1H),8.28(d,J＝6.0Hz,1H),7.90(d,J＝8.0Hz,1H),7.83(d,J＝7.9Hz,1H),7.76(s,1H),7.55–7.16(m,8H),6.74(s,1H),4.85(s,1H),3.76–3.63(m,1H),1.83–1.49(m,5H),1.37–1.00(m,5H)。
13C NMR(101MHz,DMSO)δ167.74,163.08,151.79,149.98,149.69,145.69,139.44,138.99,138.11,130.52,129.92,128.57,125.92,125.79,124.61,124.49,122.98,122.90,122.33,121.52,86.33,75.78,57.63,48.05,32.16,32.12,25.15,24.53,24.42。
实施例5
N-(1-(苯并[b]噻吩-3-基)-2-(苄氨基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.34(s,1H),8.00–7.71(m,3H),7.59–7.13(m,13H),6.83(s,1H),4.84(s,1H),4.43(s,2H)。
13C NMR(101MHz,DMSO)δ168.94,163.09,151.81,149.88,149.68,145.69,139.39,138.99,138.06,130.57,129.44,128.93,128.23,127.34,126.81,126.11,125.91,124.65,124.54,123.10,122.92,122.39,121.55,86.33,75.78,57.78,42.55。
实施例6
N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基-N-(4-(哌嗪-1-基)苯基)噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
13C NMR(101MHz,DMSO)δ168.22,150.36,149.70,138.96,138.42,130.82,129.96,127.75,124.46,124.29,122.82,121.67,113.39,86.17,75.93,54.89,50.46,50.38,48.03,47.17,44.87,31.14,29.82,28.42。
实施例7
N-(4-(1H-咪唑-1-基)苯基)-N-(1-(苯并噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),8.06(s,1H),7.92(d,J＝8.0Hz,1H),7.83(d,J＝7.8Hz,1H),7.78(s,1H),7.60(s,1H),7.49(t,J＝7.2Hz,1H),7.38(t,J＝7.3Hz,1H),7.32(s,1H),7.26(s,2H),7.01(s,1H),6.72(s,1H),4.85(s,1H),1.31(s,9H)。
13C NMR(101MHz,DMSO)δ168.21,150.01,139.03,138.20,137.69,135.15,135.07,131.34,130.44,129.90,128.20,126.01,124.64,124.47,122.92,121.69,118.19,117.34,86.31,75.81,54.88,50.56,28.41。
实施例8
N-(4-(1H-吡唑-1-基)苯基)-N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ8.31(d,J＝2.5Hz,1H),8.05(s,1H),7.90(d,J＝8.0Hz,1H),7.84(d,J＝8.0Hz,1H),7.72(s,1H),7.64(s,1H),7.52–7.29(m,5H),6.72(s,1H),6.52–6.39(m,1H),4.84(s,1H),1.32(s,9H)。
13C NMR(101MHz,DMSO)δ168.21,163.06,150.06,145.65,140.96,138.98,138.19,137.91,137.11,131.01,130.92,130.42,128.15,127.47,125.71,124.58,124.41,122.86,121.69,116.66,107.93,86.30,75.83,57.93,54.87,50.54,28.41。
实施例9
N-(4-(1H-1,2,4-三唑-1-基)苯基)-N-(1-(苯并噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ8.65(s,1H),8.07(s,1H),7.96–7.80(m,5H),7.57–7.32(m,6H),6.74(s,1H),4.84(s,1H),1.32(s,9H)。
13C NMR(101MHz,DMSO)δ168.18,162.99,149.93,145.74,139.44,139.02,138.12,134.83,134.42,131.26,130.29,128.31,126.28,124.64,124.47,122.90,122.76,121.69,121.63,118.49,113.80,86.34,75.79,58.01,50.58,28.40。
实施例10
N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基-N-(4-氟苯基)噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.91(d,J＝7.6Hz,1H),7.83–7.70(m,2H),7.47(t,J＝6.7Hz,1H),7.38(d,J＝7.1Hz,1H),7.29(s,1H),6.67(s,4H),4.86(s,1H),1.30(s,9H)。
13C NMR(101MHz,DMSO)δ168.21,163.03,161.73,159.30,150.06,138.99,138.13,135.64,130.40,128.13,125.87,124.59,124.39,122.85,121.68,114.16,113.94,86.24,75.80,57.86,50.53,28.40。
实施例11
N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基-N-(3-氟苯基)噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.96–7.74(m,3H),7.46(t,J＝7.4Hz,1H),7.41–7.29(m,2H),6.93–6.74(m,3H),6.71(s,1H),4.87(s,1H),1.31(s,9H)。
13C NMR(101MHz,DMSO)δ168.64,163.41,160.00,150.42,146.17,141.55,141.45,139.47,138.58,130.69,129.09,129.00,128.70,126.64,125.09,124.87,123.33,122.18,114.53,114.32,86.79,76.28,51.08,28.89。
实施例12
N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-N-(2,6-二氟苯基)-2-乙炔基噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ8.21(s,1H),8.01(s,1H),7.90(s,2H),7.64(s,1H),7.43–7.28(m,3H),7.14(t,2H),6.84(t,J＝8.0Hz,2H),6.65(t,J＝8.2Hz,2H),6.56(s,1H),4.82(s,1H),1.22(s,9H)。
13C NMR(101MHz,DMSO)δ166.34,163.14,149.20,145.76,138.96,138.30,130.33,129.66,127.60,127.51,124.34,123.92,122.67,121.74,111.23,111.01,110.88,110.68,86.29,75.62,57.56,50.34,28.16。
实施例13
N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基-N-(4-(三氟甲基)苯基)噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.96(s,1H),7.90(d,J＝8.0Hz,1H),7.80(d,J＝7.9Hz,1H),7.46(t,J＝7.4Hz,1H),7.41–7.22(m,6H),6.75(s,1H),4.85(s,1H),1.30(s,9H)。
13C NMR(101MHz,DMSO)δ168.05,162.80,149.79,145.72,143.30,139.02,138.00,130.57,130.16,128.36,127.31,126.99,126.93,125.23,124.66,124.46,124.32,122.88,122.53,121.64,86.25,75.64,58.18,50.59,28.37。
实施例14
N-(2-(叔丁基氨基)-1-环己基-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ8.43(s,1H),7.78(d,J＝8.5Hz,2H),7.67(s,1H),7.59(d,J＝8.3Hz,2H),7.26(d,J＝7.3Hz,2H),4.87(d,J＝14.2Hz,2H),1.94(s,1H),1.84(s,1H),1.69(s,2H),1.59(s,2H),1.20(s,9H),1.11(s,5H)。
13C NMR(101MHz,DMSO)δ167.58,163.49,151.94,150.48,149.86,145.60,139.93,130.24,126.12,125.28,123.80,122.44,86.36,75.77,65.47,50.37,36.86,29.40,28.27,25.95,25.37。
实施例15
N-(2-(叔丁基氨基)-1-(5,6-二氢-2H-吡喃-3-基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),7.78(s,1H),7.68(d,J＝8.8Hz,2H),7.58(d,J＝8.1Hz,2H),7.43(s,2H),5.73(s,1H),5.47(s,1H),4.85(s,1H),3.77(q,J＝15.6Hz,2H),3.39(t,1H),3.20(t,1H),1.97(d,J＝10.8Hz,1H),1.80(d,J＝16.9Hz,1H),1.26(s,9H)。
13C NMR(101MHz,DMSO)δ167.71,162.86,151.89,150.20,149.94,145.58,139.74,131.87,131.16,127.11,126.04,125.58,123.34,122.40,86.24,75.83,66.35,62.69,62.43,50.36,28.37,24.84。
实施例16
N-(2-(叔丁基氨基)-2-氧代-1-(嘧啶-4-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),8.73(d,J＝5.2Hz,1H),8.40(s,1H),8.22(s,1H),7.82(s,1H),7.64(s,2H),7.53(d,J＝8.2Hz,4H),7.35(d,J＝8.2Hz,2H),6.28(s,1H),4.86(s,1H),1.10(s,9H).
13C NMR(101MHz,DMSO)δ165.17,164.74,162.77,157.97,157.23,151.96,149.78,149.68,145.84,140.18,130.48,126.33,126.18,123.69,122.49,120.99,86.44,75.81,66.55,50.61,28.04.
实施例17
N-(2-(叔丁基氨基)-1-(1H-咪唑-4-基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ11.95(s,1H),8.38(s,1H),8.04(s,1H),7.73(s,1H),7.60(s,1H),7.56(s,1H),7.43(d,J＝8.2Hz,2H),7.16(s,2H),6.76(s,1H),6.11(s,1H),4.84(s,1H),1.26(s,9H)。
13C NMR(101MHz,DMSO)δ167.85,162.55,151.81,150.42,149.94,145.57,140.64,135.16,135.07,130.64,125.56,123.24,122.21,116.27,86.23,75.86,60.04,54.88,50.28,28.35。
实施例18
N-(2-(叔丁基氨基)-2-氧代-1-(噻唑-5-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ8.91(s,1H),8.40(s,1H),8.01(s,1H),7.80(d,J＝3.6Hz,2H),7.64(s,1H),7.49(d,J＝8.2Hz,2H),7.22(s,2H),6.55(s,1H),4.84(s,1H),1.25(s,9H)。
13C NMR(101MHz,DMSO)δ167.29,162.41,156.22,151.96,149.74,149.72,145.67,144.71,139.30,132.08,131.34,126.40,126.23,123.63,122.59,86.34,75.75,57.50,50.64,28.20。
实施例19
N-(2-(叔丁基氨基)-2-氧代-1-(1H-吡咯-2-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.37(s,1H),7.75(s,1H),7.59(d,J＝10.9Hz,2H),7.38(d,J＝7.9Hz,2H),7.15(s,2H),6.56(s,1H),6.22(s,1H),5.71(d,J＝14.1Hz,2H),4.84(s,1H),1.29(s,9H)。
13C NMR(101MHz,DMSO)δ168.03,162.41,151.74,150.41,150.00,145.52,140.29,130.74,125.54,125.33,124.57,123.04,122.14,118.40,109.47,107.26,86.17,75.88,59.01,50.36,28.43。
实施例20
N-(2-(叔丁基氨基)-2-氧代-1-(噻吩-3-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ8.38(s,1H),7.82(s,1H),7.70(s,1H),7.60(s,1H),7.40(d,J＝7.7Hz,2H),7.25(q,4H),6.78(d,J＝3.8Hz,1H),6.26(s,1H),4.84(s,1H),1.27(s,9H)。
13C NMR(101MHz,DMSO)δ168.54,162.56,151.83,150.22,149.85,145.55,139.96,135.57,131.20,128.79,126.12,125.77,125.67,125.56,123.24,122.32,86.23,75.84,60.10,50.41,28.39。
实施例21
N-(2-(叔丁基氨基)-2-氧代-1-(噻吩-2-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ8.39(s,1H),7.92(s,1H),7.74(s,1H),7.61(s,1H),7.43(d,J＝7.7Hz,2H),7.38(d,J＝4.2Hz,1H),7.21(s,2H),6.93(s,1H),6.85(s,1H),6.45(s,1H),4.84(s,1H),1.27(s,9H)。
13C NMR(101MHz,DMSO)δ167.78,162.47,151.87,150.00,149.82,145.60,139.58,136.87,131.29,129.48,127.77,126.31,126.04,125.79,123.31,122.41,86.27,75.79,59.63,50.51,28.29。
实施例22
N-(2-(叔丁基氨基)-2-氧代-1-(吡啶-3-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ8.38(s,2H),8.34–8.30(m,1H),7.97(s,1H),7.77(s,1H),7.59(s,1H),7.44(dd,J＝22.0,7.3Hz,4H),7.23–7.13(m,2H),6.27(s,1H),4.84(s,1H),1.25(s,9H)。
13C NMR(101MHz,DMSO)δ167.80,162.64,151.90,151.02,149.99,149.68,148.77,145.61,139.59,137.29,131.59,131.11,126.04,125.92,123.52,123.01,122.50,86.27,75.80,62.40,50.52,28.31。
实施例23
N-(2-(叔丁基氨基)-2-氧代-1-(1H-吡唑-3-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ12.78(s,1H),8.38(s,1H),7.85(s,1H),7.72(s,1H),7.60(s,1H),7.42(d,J＝8.1Hz,3H),7.18(s,2H),6.24(s,1H),5.87(s,1H),4.85(s,1H),1.26(s,9H)。
13C NMR(101MHz,DMSO)δ167.76,162.50,151.82,150.22,149.91,145.62,140.39,130.82,128.89,125.76,125.64,123.33,122.28,105.55,86.23,75.86,59.76,50.40,48.59,28.39.
实施例24
N-(2-(叔丁基氨基)-1-(萘-2-基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺
N-(2-(叔丁基氨基)-1-(1H-吲哚-3-基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ8.31(s,1H),7.94(s,1H),7.85–7.65(m,6H),7.50(s,1H),7.48–7.42(m,2H),7.36–7.20(m,4H),6.44(s,1H),4.84(s,1H),1.28(s,9H)。
13C NMR(101MHz,DMSO)δ168.53,162.86,151.77,150.22,149.68,145.60,139.87,132.86,132.39,132.13,131.49,129.38,127.82,127.62,127.37,127.25,126.36,126.21,125.76,125.60,123.23,122.34,86.25,75.85,64.59,50.49,28.42。
实施例25
N-(2-(叔丁基氨基)-1-(1H-吲哚-3-基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺申请实施例的合成路线与实施例1相同。
1H NMR(400MHz,DMSO-d6)δ10.93(s,1H),8.33(s,1H),7.78–7.66(m,2H),7.51(s,2H),7.26(d,J＝7.5Hz,3H),7.02(dq,J＝16.4,6.6Hz,3H),6.94(s,1H),6.56(s,1H),4.84(s,1H),1.29(s,9H)。
13C NMR(101MHz,DMSO)δ169.71,163.32,152.21,151.05,150.34,146.03,140.64,136.16,131.33,127.36,126.65,126.00,125.77,123.33,122.64,121.77,119.45,118.83,112.00,109.38,86.69,76.37,57.70,50.84,28.96。
应用例
表1为本申请部分实施例对肿瘤细胞HT1080的生长抑制活性及诱导铁死亡的选择性数据。表中：“A”指示IC50≤100nM，“B”指示100nM＜IC50≤500nM。
表1
| 化合物 | IC50 | 化合物 | IC50 |
| 实施例1 | A | 实施例14 | B |
| 实施例2 | A | 实施例15 | B |
| 实施例3 | A | 实施例16 | B |
| 实施例4 | A | 实施例17 | B |
| 实施例5 | A | 实施例18 | B |
| 实施例6 | B | 实施例19 | B |
| 实施例7 | B | 实施例20 | B |
| 实施例8 | A | 实施例21 | B |
| 实施例9 | B | 实施例22 | B |
| 实施例10 | A | 实施例23 | B |
| 实施例11 | B | 实施例24 | A |
| 实施例12 | A | 实施例25 | B |
| 实施例13 | A |
化合物对肿瘤细胞HT1080生长的抑制活性研究显示，亲脂性抗氧化剂，如Ferrostatin-1(fer-1)，可以挽救细胞免于GPX4抑制诱导的铁死亡。间充质状态GPX4-基因敲除细胞可以在fer-1存在下存活，但在无fer-1存在时，这些细胞会发生铁死亡。另外，GPX4抑制剂诱发的铁死亡也可以被其他小分子物质阻断，如脂质ROS清除剂Liproxstatin、铁螯合剂DFO等。因此，GPX4抑制剂诱导铁死亡性细胞死亡的能力可以通过添加fer-1逆转进行指示。
表2为部分化合物对肿瘤细胞HT1080生长的抑制活性数据。
表2
由表2所示，本申请的部分化合物在fer-1存在的情况下抑制活性明显减弱，因此是一种有效的GPX4抑制剂。
最后应说明的是：以上各实施例仅用以说明本申请的技术方案，而非对其限制；尽管参照前述各实施例对本申请进行了详细的说明，本领域的普通技术人员应当理解：其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换，并不使相应技术方案的本质脱离本申请各实施例技术方案的范围。
Claims (10)
1.一种含炔基噻唑甲酰基的甘氨酰胺类化合物，其特征在于，所述化合物为式I所示化合物、式I所示化合物的药学上可接受的盐、式I所示化合物的水合物、式I所示化合物的溶剂化物、式I所示化合物的光学异构体或式I所示化合物的衍生物，所述式I结构如下所示：
式中，R1选自烯丙基、C1-6烷基、环烷基、取代或非取代苄基、苯乙基、含有1-2个取代基的苯乙基、取代或非取代的芳环和卤代烷基；
R2选自含氮芳杂环、饱和含氮杂环或者1-3个相同或不同的R3取代基；
R3选自氢、羟基、烷氧基、卤素、C1-6烷氨基、氰基、C1-6烷基和卤代烷基；
Cyl选自五元芳杂环、六元芳杂环、苯并五元杂环、苯并六元杂环、吡啶并六元杂环、吡啶并五元杂环、脂杂环、萘、蒽、C1-6烷基和环烷基。
2.根据权利要求1所述的含炔基噻唑甲酰基的甘氨酰胺类化合物，其特征在于，R1选自烯丙基、叔丁基、环烷基、苄基、取代或非取代的芳环、苯乙基、含有1-2个取代基的苯乙基、取代或非取代的芳环和卤代烷基；
R2选自含氮五元芳杂环、饱和含氮杂环或者1-3个相同或不同的R3取代基；
R3选自氢、烷氧基、卤素、C1-6烷氨基、氰基、C1-6烷基和卤代烷基；
Cyl选自五元芳杂环、六元芳杂环，苯并五元杂环、苯并六元杂环、萘和环烷基。
3.根据权利要求1所述的含炔基噻唑甲酰基的甘氨酰胺类化合物，其特征在于，所述Cyl选自以下任一结构：
4.根据权利要求1所述的含炔基噻唑甲酰基的甘氨酰胺类化合物，其特征在于，所述化合物选自N-(1-(苯并[b]噻吩-3-基)-2-氧代-2-(苯乙氨基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(1-(苯并[b]噻吩-3-基)-2-((4-氟苯乙基)氨基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(1-(苯并[b]噻吩-3-基)-2-(环己基氨基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(1-(苯并[b]噻吩-3-基)-2-(苄氨基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基-N-(4-(哌嗪-1-基)苯基)噻唑-4-甲酰胺、N-(4-(1H-咪唑-1-基)苯基)-N-(1-(苯并噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基噻唑-4-甲酰胺、N-(4-(1H-吡唑-1-基)苯基)-N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基噻唑-4-甲酰胺、N-(4-(1H-1,2,4-三唑-1-基)苯基)-N-(1-(苯并噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基噻唑-4-甲酰胺、N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基-N-(4-氟苯基)噻唑-4-甲酰胺、N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基-N-(3-氟苯基)噻唑-4-甲酰胺、N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-N-(2,6-二氟苯基)-2-乙炔基噻唑-4-甲酰胺、N-(1-(苯并[b]噻吩-3-基)-2-(叔丁基氨基)-2-氧乙基)-2-乙炔基-N-(4-(三氟甲基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-1-环己基-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-1-(5,6-二氢-2H-吡喃-3-基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-2-氧代-1-(嘧啶-4-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-1-(1H-咪唑-4-基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-2-氧代-1-(噻唑-5-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-2-氧代-1-(1H-吡咯-2-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-2-氧代-1-(噻吩-3-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-2-氧代-1-(噻吩-2-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-2-氧代-1-(吡啶-3-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-2-氧代-1-(1H-吡唑-3-基)乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺、N-(2-(叔丁基氨基)-1-(萘-2-基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺和N-(2-(叔丁基氨基)-1-(1H-吲哚-3-基)-2-氧乙基)-2-乙炔基-N-(4-(恶唑-5-基)苯基)噻唑-4-甲酰胺。
5.一种权利要求1-4任一项所述的含炔基噻唑甲酰基的甘氨酰胺类化合物的制备方法，其特征在于，包括按照如下反应式获得式I所示化合物的步骤：
6.一种药用组合物，包含如权利要求1-4任一项所述的含炔基噻唑甲酰基的甘氨酰胺类化合物以及一种或多种药学上可接受的附加剂或赋形剂。
7.权利要求1-4任一项所述的含炔基噻唑甲酰基的甘氨酰胺类化合物在制备铁死亡诱导剂中的应用。
8.权利要求1-4任一项所述的含炔基噻唑甲酰基的甘氨酰胺类化合物在制备抗肿瘤的药物中的应用。
9.根据权利要求8所述的应用，其特征在于，所述肿瘤为铁死亡性肿瘤，具体包括纤维肉瘤、淋巴瘤、乳腺癌、肺癌、肾癌。
10.根据权利要求8所述的应用，其特征在于，所述化合物通过抑制GPX4，来引发铁死亡，从而抑制肿瘤细胞的存活，达到抗肿瘤的作用。
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