CN109810108A - 2,8-二氮杂-螺-[4,5]-癸烷类嘧啶-异羟肟酸化合物及其用途 - Google Patents
2,8-二氮杂-螺-[4,5]-癸烷类嘧啶-异羟肟酸化合物及其用途 Download PDFInfo
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- CN109810108A CN109810108A CN201910214972.3A CN201910214972A CN109810108A CN 109810108 A CN109810108 A CN 109810108A CN 201910214972 A CN201910214972 A CN 201910214972A CN 109810108 A CN109810108 A CN 109810108A
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- pyrimidine
- diaza
- decane
- spiro
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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Abstract
本发明涉及一种2,8‑二氮杂‑螺‑[4,5]‑癸烷类嘧啶‑异羟肟酸类化合物及其用途。所述嘧啶‑异羟肟酸类化合物为式I所示化合物,或其药学上可接受的盐。本发明提供的嘧啶‑异羟肟酸类化合物具有抑制组蛋白去乙酰化酶(HDAC)活性,可用于抗疟疾药物。式I中,R为C4~C16的饱和或不饱和的、取代或非取代的碳环基或碳杂环基;其中,所述取代的取代基为C1~C3烷基,所述碳杂环基的杂原子选自:氧、硫或氮中一种,杂原子个数为1或2。
Description
技术领域
本发明涉及一种嘧啶-异羟肟酸类化合物及其用途;具体地说,涉及一种2,8-二氮杂-螺-[4,5]-癸烷类嘧啶-异羟肟酸类化合物及其用途。
背景技术
疟疾(Malaria)是生物体感染一种名为疟原虫(Plasmodium)的单细胞寄生虫而引起的传染性疾病。疟原虫种类繁多,寄生于人类的疟原虫有6种,即恶性疟原虫(Plasmodiumfalciparum)、间日疟原虫(Plasmodium vivax)、三日疟原虫(Plasmodium malariae)、两种卵形疟原虫(Plasmodium ovale)和诺氏疟原虫(Plasmodium knowlesi)。P.falciparum是临床上引起危害最大的寄生虫,因为它是唯一一种能够引起严重并发症并可导致死亡的疟原虫;P.vivax虽然不像P.falciparum一样引起严重的并发症,但地理分布广泛并可导致病症反复发作;而由P.malariae和P.ovale导致的疟疾并不常见。
耐药问题一直是疟疾防治的重大障碍。耐药性的肆虐已使人们长期依赖的天然(奎宁)或人工合成(氯喹、甲氟喹、伯胺喹等)氨基喹啉类药物或抗生素类药物(磺胺多辛、乙胺嘧啶等)的疗效大打折扣。青蒿素及青蒿素联合疗法(artemisinin combinationtherapy,ACT)改变了抗疟用药的困境,成为当代疟疾治疗的中坚力量。不幸的是,10年前在柬埔寨地区出现了对ACT疗法的抗性。近年来青蒿素耐受的疟疾在东南亚湄公河流域广泛传播,甚至有散布至非洲的风险。目前传统抗疟药物主要集中通过阻止疟色素生成、干扰叶酸合成,破线粒体电子传递链及利用低价铁诱导自由基生成进而导致DNA与蛋白质烷基化等发挥药效。随着时间推移,传统机制的药物面临的抗性威胁越来越大。因此,寻找抗疟药物新靶点,尤其是针对疟原虫生命周期中关键的环节,开发出具有不同于现有化疗药物的新作用机制的抗疟药物,对于解决日益严重的抗药性问题意义重大。
组蛋白去乙酰化酶(histone deacetylase,HDAC)可催化组蛋白中赖氨酸、精氨酸残基的去乙酰化,从而调节细胞染色质的结构、转录过程及基因表达。P.falciparum有五种HDAC,其中3种分别为I类(PfHDAC1)及II类(PfHDAC2/3)HDAC,其余2种则为III类HDAC(PfSir2A/2B)。研究表明PfHDAC1参与组蛋白与非组蛋白的翻译后修饰,从而影响基因的表达结果,对疟原虫的生存意义重大;PfHDAC3对无性期P.falciparum生存与生长至关重要,并在转录调控中发挥作用;PfSir2A与PfSir2B可调节基因表达、维持端粒长度,并影响PfEMP1蛋白的表达,而PfEMP1变异可帮助疟原虫在入侵人体时逃避宿主免疫杀伤。1996年Darkin-Ratray报道环肽类HDAC抑制剂apicidin具有抗疟活性(IC50=200nM),自此以后经过20多年的努力,多个课题组深入研究romidepsin、vorinostat等HDAC抑制剂抗疟疗效,或利用已知HDAC抑制剂进行结构改造以开发新化合物,在提高抗疟疗效,降低集体毒性上取得了显著的成果。
因此,研制性能更为优异、且结构相对简单及制备成本相对较低的新型HDAC抑制剂,成为本发明需要解决的技术问题。
发明内容
本发明公开了一种结构新颖的2,8-二氮杂-螺-[4,5]-癸烷类嘧啶-异羟肟酸类化合物,其在对与疟原虫生存繁殖有密切关系的HDAC酶抑制实验和体内外杀虫药效实验中均显示出较强的抑制活性,且本发明所提供的2,8-二氮杂-螺-[4,5]-癸烷类嘧啶-异羟肟酸类化合物具有结构较为简单、制备工艺简洁和生产成本低等特点。此外,本发明所提供的2,8-二氮杂-螺-[4,5]-癸烷类嘧啶-异羟肟酸类化合物不但有望开发成新型的单一用药方式的抗疟疾药物,而且还可以开发成与现有抗疟疾药物进行组合的抗疟疾药物。
因此,本发明一个目的在于,提供一种结构新颖的2,8-二氮杂-螺-[4,5]-癸烷类嘧啶-异羟肟酸类化合物。
本发明所述的2,8-二氮杂-螺-[4,5]-癸烷类嘧啶-异羟肟酸类化合物为式I所示化合物,或其药学上可接受的盐:
式I中,R为碳原子数为四至十六(简记为“C4~C16”)的饱和或不饱和的、取代(C1~C3烷基)或非取代的碳环基或碳杂环基;
其中,所述取代的碳环基或碳杂环基的取代基为C1~C3烷基,所述碳杂环基的杂原子选自:氧(O)、硫(S)或氮(N)中一种,杂原子个数为1或2。
本发明另一目的在于,提供一种组合物。
所述组合物包含上述2,8-二氮杂-螺-[4,5]-癸烷类嘧啶-异羟肟酸类化合物(式I所示化合物、或其药学上可接受的盐)。
本发明再一个目的在于,揭示上述2,8-二氮杂-螺-[4,5]-癸烷类嘧啶-异羟肟酸类化合物(式I所示化合物,或其药学上可接受的盐)及其组合物的一种用途。
即,式I所示化合物、或其药学上可接受的盐,及其组合物在制备组蛋白去乙酰化酶(HDAC)抑制剂中的应用;或,
式I所示化合物、或其药学上可接受的盐,及其组合物在制备治疗疟疾药物中的应用。
此外,本发明还有一个目的在于,提供一种制备式I所示化合物的方法。
所述方法包括如下步骤:
(1)以2-氯-嘧啶-5-羧酸乙酯(式II所示化合物)和2-叔丁氧羰基-2,8-二氮杂-螺-[4.5]-癸烷(式III所示化合物)为起始原料,由式II所示化合物和式III所示化合物反应,得到式IV所示化合物的步骤;
(2)由式IV所示化合物制备式V所示化合物的步骤;
(3)由式V所示化合物制备式VI所示化合物的步骤;
(4)由式VI所示化合物制备式VII所示化合物的步骤;
(5)由式VII所示化合物制备式VIII所示化合物的步骤;
(6)由式VIII所示化合物制备式IX所示化合物的步骤;
(7)由式IX所示化合物与相应的醛(R1CHO)反应,得到式X所示化合物的步骤;和,
(8)式X所示化合物制得目标物(式I所示化合物)的步骤。
其中,式II和III所示化合物为已知化合物,可按现有文献报道的方法制得,或直接通过市购获得。
附图说明
图1.为本发明部分化合物及阳性对照物磷酸哌喹(PPQ)在小鼠体内药效结果示意图;
图2.式I-31所示化合物及阳性对照物JL01的Western Blot实验结果图。
具体实施方式
在本发明一个优选的技术方案中,R为5~6元的芳环基或芳杂环基,或取代的5~6元的芳环基或芳杂环基;
其中,所述的取代的5~6元的芳环基或芳杂环基的取代基为C1~C3烷基,苯基(曲线标记处为取代位,下同),二价苯基(所述二价苯基为其与被取代母环为“并”的关系,下同)或二价的吡啶基(任意两个相邻的碳原子均可为取代位);
所述的芳杂环基的杂原子选自:氧(O)、硫(S)或氮(N)中一种,杂原子个数为1或2。
在进一步优选的技术方案中,R为下列基团中一种:
其中:X为O或S,R1为氢(H)或C1~C3烷基。
在更进一步优选的技术方案中,R为下列基团中一种:
在本发明另一个优选技术方案中,以所述组合物的总重量为100%计,在所述组合物中可含有0.001wt%~99wt%,较佳地0.1wt%~90wt%,更佳地1wt%~80wt%的式I所示化合物、或其药学上可接受的盐。所述组合物还可含有其它具有抗疟疾活性的药物成分,其包括(但不限于):青蒿素、二氢青蒿素、蒿甲醚、蒿琥酯、本芴醇、磺胺多辛、乙胺嘧啶、咯萘啶、阿托伐醌、奎宁、氯喹、哌喹、甲氟喹、阿莫地喹、伯胺喹或/和他非诺喹等。
本发明提供的制备式I所示化合物的方法,具体包括如下步骤:
(1)将2-氯-嘧啶-5-羧酸乙酯(式II所示化合物)和2-叔丁氧羰基-2,8-二氮杂-螺-[4.5]-癸烷(式III所示化合物)溶于卤代烃(如二氯甲烷等)中,在0-5℃条件下,加入N,N-二异丙基乙胺,加毕,升温至室温(25℃,下同),搅拌5~6小时。向反应液中加入水,振荡分液,减压蒸除溶剂,剩余固体用硅胶柱层析分离纯化,得淡黄色固体2-(2-叔丁氧羰基-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-羧酸乙酯(式IV所示化合物);
(2)将式IV所示化合物溶于溶于卤代烃(如二氯甲烷等)中,加入氯化氢-二氧六环溶液,室温下下搅拌5-6小时。减压蒸除溶剂,得油状2-(2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-羧酸乙酯(式V所示化合物),式V所示化合物可直接用于下一步反应;
(3)将式V所示化合物溶于卤代烃(如二氯甲烷等)中,加入N,N-二异丙基乙胺,在0-5℃条件下,缓慢滴加入氯甲酸苯甲酯,加毕,升温至室温,搅拌5~6小时,加入饱和碳酸氢钠水溶液,振荡分液,减压蒸除溶剂,剩余固体用硅胶柱层析分离纯化,得淡黄色固体2-(2-苯甲氧羰基-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-羧酸乙酯(式VI所示化合物);
(4)将式VI所示化合物用甲醇和水的混合溶液溶解,加入碳酸钾固体,65~70℃加热反应5-6小时。减压蒸除溶剂,残留物用盐酸酸化至pH约为1,抽滤,剩余固体以水洗至pH约为7,干燥,得白色固体2-(2-苯甲氧羰基-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-羧酸(式VII所示化合物);
(5)将式VII所示化合物用N,N-二甲基甲酰胺(DMF)和二氯甲烷的混合溶液溶解,依次加入1-羟基苯并三唑和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,室温下搅拌30分钟后,依次加入O-(四氢-2H-吡喃-2-基)羟胺和三乙胺,室温下搅拌48小时。反应毕,加入饱和碳酸氢钠水溶液,振荡分液,减压蒸除溶剂,剩余固体用硅胶柱层析分离纯化,得米白色固体2-(2-苯甲氧羰基-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-N-(四氢-2H-吡喃-2-基-氧基)嘧啶-5-酰胺(式VIII所示化合物);
(6)将式VIII所示化合物用甲醇和二氯甲烷的混合溶液溶解,依次加入三乙基硅烷和钯碳,35℃下搅拌至原料消失,过滤除去Pd/C,减压蒸除溶剂,得2-(2,8-二氮杂-螺-[4.5]-癸烷-8-基)-N-(四氢-2H-吡喃-2-基-氧基)嘧啶-5-酰胺(式IX所示化合物),式IX所示化合物无需纯化,可直接用于下一步反应;
(7)将式IX所示化合物用甲醇溶解,加入相应的醛(R1CHO),氰基硼氢化钠,室温下搅拌24-60小时,加入饱和碳酸氢钠水溶液,振荡分液,减压蒸除溶剂,剩余固体用硅胶柱层析分离纯化,得取代的2-(2,8-二氮杂-螺-[4.5]-癸烷-8-基)-N-(四氢-2H-吡喃-2-基-氧基)嘧啶-5-酰胺(式X所示化合物);和,
(8)将式X所示化合物用卤代烃(如二氯甲烷等)溶解,加入氯化氢-二氧六环溶液,室温下搅拌至少30分钟,过滤,滤饼用卤代烃(如二氯甲烷等)洗涤后,得到目标物(式I所示化合物)。
以下通过实施例对本发明作进一步阐述,所举之实施例仅用于更好理解发明,但不以任何方式限制本发明的保护范围。实施例中的所用原料和试剂(包括HepG2、293T及其它生化试剂均为市售,疟疾虫株3D7,Dd2等均从ATCC细胞库购得。
实施例1
(1)2-(2-叔丁氧羰基-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-羧酸乙酯(式IV所示化合物)的制备:
将24克2-叔丁氧羰基-2,8-二氮杂-螺-[4.5]-癸烷和22.4克2-氯-嘧啶-5-羧酸乙酯溶于500毫升二氯甲烷中,冰浴冷却至0-5℃,加入25毫升N,N-二异丙基乙胺,加毕,然后撤去冰浴,待反应液温度恢复至室温,搅拌6小时,向反应液中加入水,振荡分液,减压蒸除溶剂,剩余固体用硅胶柱层析分离纯化(石油醚/乙酸乙酯=5/1(v/v)),得淡黄色固体(式IV所示化合物)。
1H NMR(400MHz,DMSO-d6)δ8.77(s,2H),4.26(q,J=7.1Hz,2H),3.93(dd,J=13.4,6.1Hz,2H),3.81(dq,J=13.0,6.8Hz,2H),3.31(d,J=7.7Hz,2H),3.15(d,J=5.4Hz,2H),1.77(t,J=7.1Hz,2H),1.52(q,J=6.4Hz,4H),1.40(s,9H),1.29(t,J=7.1Hz,3H).
(2)2-(2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-羧酸乙酯(式V所示化合物)的制备:
将39克式IV所示化合物溶于500毫升二氯甲烷中,缓慢加入4M的氯化氢-二氧六环溶液100毫升,室温下下搅拌6小时,减压蒸除溶剂,得油状物(式V所示化合物),直接用于下一步反应。
1H NMR(400MHz,DMSO-d6)δ8.77(s,2H),4.26(q,J=7.1Hz,2H),3.90(dd,J=13.4,6.1Hz,2H),3.78(dq,J=13.0,6.8Hz,2H),3.24(d,J=7.7Hz,2H),3.10(d,J=5.4Hz,2H),1.77(t,J=7.1Hz,2H),1.52(q,J=6.4Hz,4H),1.29(t,J=7.1Hz,3H).
(3)2-(2-苯甲氧羰基-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-羧酸乙酯(式VI所示化合物)的制备
将29克式V所示化合物溶于500毫升二氯甲烷中,加入41毫升N,N-二异丙基乙胺,冰浴冷却至0-5℃,缓慢滴加入17毫升氯甲酸苯甲酯,加毕,撤去冰浴,待反应液温度恢复至室温,搅拌6小时,加入饱和碳酸氢钠水溶液,振荡分液,减压蒸除溶剂,剩余固体用硅胶柱层析分离纯化(石油醚/乙酸乙酯=5/1(v/v)),得淡黄色固体(式VI所示化合物)。
1H NMR(400MHz,DMSO-d6)δ8.77(s,2H),7.48–7.27(m,5H),5.07(s,2H),4.26(q,J=7.1Hz,2H),4.01–3.75(m,4H),3.41(dt,J=18.0,7.1Hz,2H),3.26(d,J=8.3Hz,2H),1.80(q,J=7.6Hz,2H),1.54(h,J=7.1Hz,4H),1.29(t,J=7.1Hz,3H).
(4)2-(2-苯甲氧羰基-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-羧酸(式VII所示化合物)的制备:
将40克式VI所示化合物溶于甲醇—水的混合溶液(1:1)500毫升,加入35克碳酸钾固体,65~70℃加热反应6小时,减压蒸除溶剂,残留物用盐酸酸化至pH约为1,抽滤,剩余固体以水洗至pH约为7,干燥后得白色固体(式VII所示化合物)。
1H NMR(400MHz,DMSO-d6)δ8.75(m,2H),7.43–7.25(m,5H),5.07(s,2H),4.03–3.73(m,4H),3.41(dt,J=18.2,7.1Hz,2H),3.26(d,J=8.5Hz,2H),1.80(q,J=7.6Hz,2H),1.54(p,J=7.3,6.8Hz,4H).
(5)2-(2-苯甲氧羰基-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-N-(四氢-2H-吡喃-2-基-氧基)嘧啶-5-酰胺(式VIII所示化合物)的制备:
将19.8克式VII所示化合物溶于N,N-二甲基甲酰胺和二氯甲烷的混合溶液(1:1)250毫升,依次加入13.5克1-羟基苯并三唑和19.2克1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐,室温下搅拌30分钟后,依次加入17.8克O-(四氢-2H-吡喃-2-基)羟胺和21毫升三乙胺,室温下搅拌48小时,加入饱和碳酸氢钠水溶液,振荡分液,减压蒸除溶剂,剩余固体用硅胶柱层析分离纯化(二氯甲烷/甲醇=60/1(v/v)),得米白色固体(式VIII所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),8.67(s,2H),7.46–7.28(m,5H),5.07(s,2H),4.95(d,J=3.4Hz,1H),4.09–3.99(m,1H),3.96–3.72(m,4H),3.53(dd,J=10.6,5.4Hz,1H),3.41(dt,J=18.4,7.1Hz,2H),3.25(d,J=9.0Hz,2H),1.80(q,J=7.6Hz,2H),1.70(t,J=5.6Hz,3H),1.53(p,J=8.0,6.7Hz,7H).
(6)2-(2,8-二氮杂-螺-[4.5]-癸烷-8-基)-N-(四氢-2H-吡喃-2-基-氧基)嘧啶-5-酰胺(式IX所示化合物)的制备:
将5克式VIII所示化合物用50毫升甲醇和二氯甲烷的混合溶液(1:1)溶解,依次加入2.13克10%钯碳和8毫升三乙基硅烷,35℃下搅拌至原料消失,反应毕,过滤除去Pd/C,减压蒸除溶剂,得式IX所示化合物,直接用于下一步反应。
1H NMR(400MHz,DMSO-d6)δ8.69(s,2H),4.95(d,J=3.1Hz,1H),4.02(ddd,J=11.8,8.5,4.0Hz,1H),3.82(tq,J=12.5,7.5,6.8Hz,4H),3.50(dd,J=10.2,5.5Hz,1H),3.20(t,J=7.4Hz,2H),2.98(s,2H),1.80(t,J=7.4Hz,2H),1.69(d,J=3.1Hz,3H),1.54(ddd,J=12.8,9.3,5.1Hz,7H).
(7)2-(2-(N-甲基吲哚-3-甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-N-(四氢-2H-吡喃-2-基-氧基)嘧啶-5-酰胺(式X-1所示化合物)的制备:
将0.36克式IX所示化合物、0.24克N-甲基吲哚-3-甲醛、0.31克氰基硼氢化钠溶于10毫升无水甲醇,室温下搅拌至反应完毕。计入饱和碳酸氢钠水溶液,振荡分液,减压蒸除溶剂,剩余固体用硅胶柱层析分离纯化(二氯甲烷/甲醇=20/1(v/v)),得淡黄色泡沫状固体(式X-1所示化合物)。
1H NMR(400MHz,Chloroform-d)δ8.66(s,2H),7.68(d,J=7.9Hz,1H),7.32(s,1H),7.23(d,J=7.9Hz,1H),7.13(t,J=7.3Hz,2H),5.06–4.97(m,1H),4.00(ddd,J=11.6,9.2,3.1Hz,1H),3.95–3.85(m,4H),3.79–3.70(m,5H),3.65(dd,J=10.6,5.2Hz,1H),2.83(s,2H),2.63(s,2H),1.82(ddt,J=23.7,13.7,7.5Hz,5H),1.61(q,J=5.8Hz,7H).
(8)2-(2-(N-甲基吲哚-3-甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-1所示化合物)的制备:
将0.13克溶于2.5毫升二氯甲烷,缓慢加入4M的氯化氢-二氧六环溶液0.15毫升,加毕,室温下搅拌30分钟。抽滤,滤饼用二氯甲烷洗涤,得到目标物(式I-1所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),8.68(s,2H),7.87(d,J=7.9Hz,1H),7.67(s,1H),7.49(d,J=8.2Hz,1H),7.22(t,J=7.6Hz,1H),7.15(d,J=7.6Hz,1H),4.50(d,J=5.0Hz,2H),3.82(s,2H),3.76–3.65(m,2H),3.47(dt,J=9.8,4.2Hz,1H),3.40–3.33(m,1H),3.27(dq,J=11.1,8.1Hz,1H),3.02(dd,J=11.9,8.0Hz,1H),2.06–1.97(m,1H),1.88(ddd,J=13.2,9.5,7.5Hz,1H),1.76–1.47(m,4H).
HRMS(ESI)[M+H]+,C23H29N6O2,理论值(cal.):421.2347;实验值(found):421.2352。
实施例2
2-(2-(环戊基甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-2所示化合物)的制备:
除以环戊基甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-2所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),10.85(s,1H),8.68(s,2H),3.82(m,4H),3.65–3.58(m,1H),3.52(dd,J=11.7,5.7Hz,1H),3.24–3.05(m,2H),2.90(dd,J=11.8,7.9Hz,1H),2.21(dt,J=15.6,7.8Hz,1H),2.03–1.89(m,2H),1.90–1.79(m,2H),1.76–1.44(m,8H),1.34–1.16(m,2H).HRMS(ESI)[M+H]+,C19H30N5O2,cal.360.2394,found 360.2400.
实施例3
2-(2-(环己基甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-3所示化合物)的制备:
除以环己基甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-3所示化合物)。
1H NMR(400MHz,DMSO-d6)δ10.81(p,J=6.8Hz,1H),8.69(s,2H),3.91–3.72(m,J=7.7,6.7Hz,4H),3.66–3.49(m,2H),3.14(p,J=8.6Hz,1H),2.98(p,J=6.4Hz,2H),2.90(dd,J=11.8,7.5Hz,1H),2.02–1.80(m,4H),1.66(dtd,J=39.9,13.8,12.5,7.3Hz,8H),1.29–1.05(m,3H),0.93(qd,J=12.2,3.3Hz,2H).HRMS(ESI)[M+H]+,C20H32N5O2,cal.374.2551,found374.2557.
实施例4
2-(2-(苯甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-4所示化合物)的制备:
除以苯甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-4所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.50(s,1H),11.14(s,1H),8.68(s,2H),7.67(d,J=4.0Hz,2H),7.44(dd,J=4.9,1.7Hz,3H),4.36(qd,J=12.9,5.8Hz,2H),3.95–3.86(m,2H),3.69(dddd,J=25.0,13.0,8.1,3.7Hz,2H),3.44(dt,J=8.7,3.7Hz,1H),3.25(td,J=11.2,10.7,4.7Hz,2H),2.97(dd,J=11.8,7.8Hz,1H),2.03(ddd,J=12.0,7.6,4.0Hz,1H),1.97–1.87(m,1H),1.66(dddd,J=24.1,16.9,10.1,3.9Hz,4H).HRMS(ESI)[M+H]+,C20H26N5O2,cal.368.2081,found368.2087.
实施例5
2-(2-(2-吡啶甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-5所示化合物):
除以2-吡啶甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-5所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),8.78–8.63(m,3H),8.05(td,J=7.7,1.8Hz,1H),7.83(d,J=7.8Hz,1H),7.58(dd,J=7.6,5.1Hz,1H),4.62(s,2H),3.89(dt,J=13.8,5.4Hz,2H),3.79–3.67(m,2H),3.49(s,2H),3.28(s,2H),2.00(t,J=7.2Hz,2H),1.67(t,J=5.8Hz,4H).HRMS(ESI)[M+H]+,C19H25N6O2,cal.369.2034,found 369.2039.
实施例6
2-(2-(3-吡啶甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-6所示化合物)的制备:
除以3-吡啶甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-6所示化合物)。
1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),9.22(d,J=1.9Hz,1H),8.98(dd,J=5.7,1.4Hz,1H),8.90(dt,J=8.0,1.7Hz,1H),8.69(s,2H),8.11(dd,J=8.1,5.6Hz,1H),4.78–4.52(m,2H),3.79(ddd,J=27.8,12.5,6.7Hz,4H),3.56–3.46(m,1H),3.45–3.24(m,2H),3.09(dd,J=11.7,7.9Hz,1H),2.06(ddd,J=12.0,7.6,3.9Hz,1H),1.92(ddd,J=13.3,9.8,7.7Hz,1H),1.78–1.56(m,4H).HRMS(ESI)[M+H]+,C19H25N6O2,cal.369.2034,found369.2039.
实施例7
2-(2-(4-吡啶甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-7所示化合物)的制备:
除以4-吡啶甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-7所示化合物)。
1H NMR(400MHz,DMSO-d6)δ12.33(s,1H),11.17(s,1H),8.99(m,3H),8.69(m,2H),8.30(m,3H),4.83–4.61(m,2H),4.54(m,1H),3.78(m,4H),3.46–3.21(m,2H),3.01(dd,J=11.8,7.3Hz,1H),2.06(ddd,J=12.0,7.5,3.9Hz,1H),1.96(q,J=12.7,10.6Hz,1H),1.79–1.60(m,4H).HRMS(ESI)[M+H]+,C19H25N6O2,cal.369.2034,found 369.2039.
实施例8
2-(2-(3-呋喃甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-8所示化合物)的制备:
除以3-呋喃甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-8所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.69–11.57(m,1H),8.69(s,2H),7.88(d,J=1.4Hz,1H),7.78–7.69(m,1H),6.85(d,J=1.8Hz,1H),4.21(t,J=5.0Hz,2H),3.95–3.87(m,2H),3.72(tdd,J=13.5,7.7,4.0Hz,2H),3.45(tt,J=13.2,5.6Hz,1H),3.30(dd,J=11.8,5.7Hz,1H),3.25–3.14(m,1H),2.94(dd,J=11.9,7.7Hz,1H),2.05–1.89(m,2H),1.69(d,J=3.9Hz,4H).HRMS(ESI)[M+H]+,C18H24N5O3,cal.358.1874,found 358.1879.
实施例9
2-(2-(3-噻吩甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-9所示化合物)的制备:
除以3-噻吩甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-9所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),8.68(s,2H),7.81(d,J=3.5Hz,1H),7.63(dd,J=5.0,2.9Hz,1H),7.44(dd,J=5.0,1.2Hz,1H),4.43–4.29(m,2H),3.90(ddd,J=12.3,6.5,3.0Hz,2H),3.71(dtt,J=18.1,9.1,3.9Hz,2H),3.43(ddd,J=11.6,6.8,3.6Hz,1H),3.33–3.16(m,2H),2.96(dd,J=11.9,7.7Hz,1H),2.01(ddd,J=12.3,7.7,4.3Hz,1H),1.92(ddd,J=13.2,9.3,7.5Hz,1H),1.66(dtdd,J=20.2,11.6,8.6,3.9Hz,4H).HRMS(ESI)[M+H]+,C18H24N5O2S,cal.374.1645,found 374.1651.
实施例10
2-(2-(3-苯并呋喃甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-10所示化合物)的制备:
除以苯并呋喃-3-甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-10所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.36(s,1H),8.78(s,1H),8.68(d,J=6.6Hz,2H),8.31(s,1H),8.00(d,J=7.5Hz,1H),7.65(d,J=7.9Hz,1H),7.38(p,J=7.2Hz,1H),4.56(d,J=5.3Hz,2H),3.89(dd,J=13.3,5.6Hz,2H),3.72(dtd,J=21.2,8.5,3.7Hz,3H),3.55(dd,J=11.9,7.2Hz,1H),3.37–3.27(m,1H),3.06(dd,J=11.9,8.0Hz,1H),2.04(td,J=8.4,7.8,4.0Hz,1H),1.96–1.86(m,1H),1.74–1.56(m,4H).HRMS(ESI)[M+H]+,C22H26N5O3,cal.408.2030,found408.2036.
实施例11
2-(2-(3-苯并噻吩甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-11所示化合物)的制备:
除以苯并噻吩-3-甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-11所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.58(d,J=9.6Hz,1H),8.69(s,2H),8.30(s,1H),8.19(d,J=7.9Hz,1H),8.07(d,J=7.9Hz,1H),7.47(dt,J=20.0,7.3Hz,2H),4.69(d,J=5.5Hz,2H),4.00–3.81(m,2H),3.72(dddd,J=24.9,12.8,7.7,3.9Hz,2H),3.52(td,J=7.1,3.5Hz,1H),3.47–3.40(m,1H),3.38–3.27(m,1H),3.08(dd,J=11.8,7.9Hz,1H),2.06(ddd,J=11.9,7.5,3.8Hz,1H),1.93(ddd,J=13.1,9.7,7.4Hz,1H),1.68(dddd,J=25.1,19.9,13.5,4.1Hz,4H).HRMS(ESI)[M+H]+,C22H26N5O2S,cal.424.1802,found 424.1807.
实施例12
2-(2-(N-甲基苯并吲唑-3-甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-12所示化合物)的制备:
除以N-甲基苯并吲唑-3-甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-12所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.59–11.40(m,1H),8.70(s,2H),8.10(d,J=8.2Hz,1H),7.71(d,J=8.5Hz,1H),7.58–7.41(m,1H),7.24(t,J=7.5Hz,1H),4.75(d,J=4.9Hz,2H),4.10(s,3H),3.88(ddt,J=18.5,13.7,4.9Hz,2H),3.69(tdd,J=13.1,7.4,4.4Hz,2H),3.63–3.55(m,1H),3.50–3.44(m,1H),3.43–3.32(m,1H),3.14(dd,J=11.9,7.7Hz,1H),2.01(ddd,J=12.2,7.6,4.0Hz,1H),1.90(dt,J=13.2,8.6Hz,1H),1.75–1.52(m,4H).HRMS(ESI)[M+H]+,C22H28N7O2,cal.422.2299,found 422.2304.
实施例13
2-(2-(咪唑并[1,2-a]吡啶-3-甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-13所示化合物)的制备:
除以咪唑并[1,2-a]吡啶-3-甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-13所示化合物)。
1H NMR(400MHz,DMSO-d6)δ12.19(d,J=8.8Hz,1H),9.44(d,J=6.9Hz,1H),8.71(s,2H),8.58(s,1H),8.05(d,J=6.2Hz,2H),7.60(td,J=6.5,2.3Hz,1H),5.13–4.97(m,2H),3.83(dt,J=16.6,5.5Hz,4H),3.67(ddt,J=11.6,8.0,3.9Hz,1H),3.59–3.51(m,1H),3.51–3.41(m,1H),3.22(dd,J=11.7,7.9Hz,1H),2.08(ddd,J=11.8,7.6,3.5Hz,1H),1.92(dt,J=13.2,8.9Hz,1H),1.71(dq,J=11.8,6.2Hz,4H).HRMS(ESI)[M+H]+,C21H26N7O2,cal.408.2142,found 408.2147.
实施例14
2-(2-(7-氮杂吲哚-3-甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-14所示化合物)的制备:
除以7-氮杂吲哚-3-甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-14所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),8.67(s,2H),8.44(d,J=7.8Hz,1H),8.36(d,J=4.8Hz,1H),7.87(s,1H),7.26(dd,J=7.9,4.8Hz,1H),4.59–4.45(m,2H),3.88(m,5H),3.71(dddd,J=21.0,12.8,7.6,3.9Hz,2H),3.49(ddt,J=11.6,8.2,4.5Hz,1H),3.36(dd,J=11.7,5.4Hz,1H),3.33–3.18(m,1H),3.02(dd,J=11.8,8.0Hz,1H),2.01(ddd,J=12.2,7.7,4.0Hz,1H),1.89(dt,J=13.2,8.4Hz,1H),1.72–1.53(m,4H).HRMS(ESI)[M+H]+,C22H28N7O2,cal.422.2299,found 422.2304.
实施例15
2-(2-(6-氮杂吲哚-3-甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-15所示化合物)的制备:
除以6-氮杂吲哚-3-甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-15所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.37(s,1H),8.69(m,2H),8.49(d,J=6.1Hz,1H),8.38(d,J=4.9Hz,1H),7.90(s,1H),7.28(t,J=6.5Hz,1H),4.64–4.47(m,2H),3.91–3.82(m,5H),3.71(dddd,J=21.3,12.8,7.6,4.0Hz,2H),3.49(tt,J=7.2,3.9Hz,1H),3.38(q,J=7.0Hz,1H),3.32–3.21(m,1H),3.02(dd,J=11.8,8.0Hz,1H),2.01(ddd,J=12.2,7.7,4.0Hz,1H),1.89(dt,J=12.9,8.3Hz,1H),1.81–1.51(m,4H).HRMS(ESI)[M+H]+,C22H28N7O2,cal.422.2299,found422.2304.
实施例16
2-(2-(5-氮杂吲哚-3-甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-16所示化合物)的制备:
除以5-氮杂吲哚-3-甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-16所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.73(m,1H),9.74(d,J=3.3Hz,1H),8.68(s,2H),8.56(d,J=6.7Hz,1H),8.29–7.97(m,2H),4.71(qd,J=13.6,5.6Hz,2H),3.93–3.65(m,4H),3.58–3.46(m,1H),3.44–3.28(m,2H),3.08(dd,J=11.8,8.0Hz,1H),2.05(ddd,J=12.1,7.6,3.8Hz,1H),1.91(dt,J=13.0,8.4Hz,1H),1.68(dq,J=12.9,6.1,5.7Hz,4H).HRMS(ESI)[M+H]+,C22H28N7O2,cal.422.2299,found 422.2304.
实施例17
2-(2-(4-氮杂吲哚-3-甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-17所示化合物)的制备:
除以4-氮杂吲哚-3-甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-17所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.69–11.49(m,1H),8.83(d,J=8.4Hz,1H),8.76(d,J=5.7Hz,1H),8.69(s,2H),8.51(s,1H),7.78(dd,J=8.3,5.7Hz,1H),4.90(d,J=4.6Hz,2H),4.06(s,3H),3.91–3.70(m,4H),3.56(q,J=6.2,5.2Hz,1H),3.49–3.37(m,2H),3.24(t,J=9.8Hz,1H),2.14–2.04(m,1H),1.89(dt,J=13.1,8.4Hz,1H),1.69(dt,J=28.4,6.6Hz,4H).HRMS(ESI)[M+H]+,C22H28N7O2,cal.422.2299,found 422.2304.
实施例18
2-(2-(1-萘甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-18所示化合物)的制备:
除以1-萘甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-18所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.11(s,1H),8.68(s,2H),8.41(d,J=8.4Hz,1H),8.13–7.90(m,3H),7.63(dq,J=21.1,7.5Hz,3H),4.99–4.86(m,2H),3.89(dq,J=10.5,5.3Hz,2H),3.75(ddd,J=13.0,7.8,3.8Hz,1H),3.67(ddd,J=12.9,7.6,4.0Hz,1H),3.54–3.34(m,3H),3.15(dd,J=11.8,7.7Hz,1H),2.07(ddd,J=11.4,7.2,3.4Hz,1H),1.98–1.84(m,1H),1.69(pd,J=14.0,13.1,4.1Hz,4H).HRMS(ESI)[M+H]+,C24H28N5O2,cal.418.2238,found 418.2243.
实施例19
2-(2-(异喹啉-4-甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-19所示化合物)的制备:
除以异喹啉-4-甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-19所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.54–11.38(m,1H),9.84(s,1H),9.08(s,1H),8.79–8.64(m,3H),8.51(d,J=8.2Hz,1H),8.21(t,J=7.8Hz,1H),8.01(t,J=7.6Hz,1H),5.04(qt,J=11.8,6.0Hz,2H),3.91–3.76(m,3H),3.70(dt,J=12.8,5.2Hz,1H),3.53(ddd,J=17.2,9.6,4.1Hz,2H),3.42(m,1H),3.23–3.11(m,1H),2.09(dd,J=12.5,7.0Hz,1H),1.96–1.86(m,1H),1.82–1.62(m,4H).HRMS(ESI)[M+H]+,C23H27N6O2,cal.419.2190,found419.2195.
实施例20
2-(2-(喹啉-4-甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-20所示化合物)的制备:
除以喹啉-4-甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-20所示化合物)。
1H NMR(400MHz,DMSO-d6)δ12.18(s,1H),9.35(d,J=5.4Hz,1H),8.69(m,3H),8.57(d,J=5.4Hz,1H),8.46(d,J=8.5Hz,1H),8.14(t,J=7.8Hz,1H),7.99(t,J=7.8Hz,1H),5.35–5.18(m,2H),3.87–3.75(m,4H),3.68(q,J=6.2,5.6Hz,1H),3.63–3.56(m,1H),3.46(q,J=9.0,8.2Hz,1H),3.16(dd,J=11.7,7.3Hz,1H),2.19–2.06(m,1H),2.05–1.93(m,1H),1.72(dt,J=26.5,6.1Hz,4H).HRMS(ESI)[M+H]+,C23H27N6O2,cal.419.2190,found419.2195.
实施例21
2-(2-(喹啉-5-甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-21所示化合物)的制备:
除以喹啉-5-甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-21所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.86(q,J=6.6Hz,1H),9.70(d,J=8.7Hz,1H),9.35(d,J=5.1Hz,1H),8.68(s,2H),8.54(d,J=8.6Hz,1H),8.38(d,J=7.2Hz,1H),8.24–8.17(m,1H),8.13(dd,J=8.7,5.1Hz,1H),5.09(dt,J=12.2,5.9Hz,2H),3.92–3.77(m,3H),3.69(ddd,J=12.8,7.4,4.0Hz,1H),3.58–3.51(m,1H),3.49–3.38(m,2H),3.18(dd,J=11.7,7.8Hz,1H),2.08(ddd,J=13.3,7.3,3.2Hz,1H),1.93(ddd,J=13.1,10.4,7.5Hz,1H),1.80–1.61(m,4H).HRMS(ESI)[M+H]+,C23H27N6O2,cal.419.2190,found 419.2195.
实施例22
2-(2-(异喹啉-8-甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-22所示化合物)的制备:
除以异喹啉-8-甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-22所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.81(s,1H),10.41(s,1H),8.75(d,J=6.4Hz,1H),8.69(m,2H),8.57(d,J=6.4Hz,1H),8.42(d,J=8.3Hz,1H),8.39(d,J=7.1Hz,1H),8.29–8.21(m,1H),5.15(qd,J=13.7,5.7Hz,2H),3.95–3.76(m,3H),3.70(tt,J=8.9,3.8Hz,1H),3.55(d,J=15.5Hz,1H),3.49–3.34(m,2H),3.22(dd,J=11.8,7.8Hz,1H),2.10(ddd,J=13.5,7.4,3.3Hz,1H),1.92(td,J=12.9,11.7,7.7Hz,1H),1.84–1.62(m,4H).HRMS(ESI)[M+H]+,C23H27N6O2,cal.419.2190,found 419.2195.
实施例23
2-(2-(喹啉-8-甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-23所示化合物)的制备:
除以喹啉-8-甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-23所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.46(s,1H),8.70(m,2H),8.53(d,J=8.5Hz,1H),8.09(dd,J=15.1,8.2Hz,2H),7.91–7.81(m,2H),7.70(t,J=7.5Hz,1H),4.81(d,J=4.0Hz,2H),3.90(dt,J=10.6,5.0Hz,2H),3.83–3.71(m,2H),3.57(m,3H),3.38(m,1H),2.04(t,J=7.2Hz,2H),1.71(q,J=5.7,4.6Hz,4H).HRMS(ESI)[M+H]+,C23H27N6O2,cal.419.2190,found 419.2195.
实施例24
2-(2-(2-萘甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-24所示化合物)的制备:
除以2-萘甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-24所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.77–11.50(m,1H),8.68(s,2H),8.16(s,1H),8.06–7.93(m,3H),7.87(d,J=8.4Hz,1H),7.69–7.44(m,2H),4.54(qd,J=12.9,5.8Hz,2H),3.90(dtd,J=16.9,10.1,8.1,4.7Hz,2H),3.70(dddd,J=26.0,12.8,8.1,3.8Hz,2H),3.53–3.43(m,1H),3.30(dd,J=11.8,5.3Hz,2H),3.05(dd,J=11.9,7.8Hz,1H),2.05(td,J=8.2,7.6,3.8Hz,1H),2.00–1.89(m,1H),1.78–1.56(m,4H).HRMS(ESI)[M+H]+,C24H28N5O2,cal.418.2238,found 418.2243.
实施例25
2-(2-(喹啉-3-甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-25所示化合物)的制备:
除以喹啉-3-甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-25所示化合物)。
1H NMR(400MHz,DMSO-d6)δ12.15(s,1H),9.56(d,J=1.9Hz,1H),9.32(d,J=2.0Hz,1H),8.68(s,2H),8.41(d,J=8.6Hz,1H),8.34–8.27(m,1H),8.15(ddd,J=8.5,6.9,1.4Hz,1H),7.95(t,J=7.6Hz,1H),4.88–4.69(m,2H),3.81(dt,J=24.7,5.5Hz,4H),3.68–3.55(m,1H),3.51–3.37(m,2H),3.16(dd,J=11.8,7.9Hz,1H),2.08(ddd,J=11.9,7.6,3.8Hz,1H),1.93(ddd,J=13.2,9.7,7.6Hz,1H),1.70(dq,J=14.0,7.3,6.7Hz,4H).HRMS(ESI)[M+H]+,C23H27N6O2,cal.419.2190,found 419.2195.
实施例26
2-(2-(喹啉-2-甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-26所示化合物)的制备:
除以喹啉-2-甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-26所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.07(s,1H),9.08(d,J=4.1Hz,1H),8.67(s,2H),8.59(d,J=8.0Hz,1H),8.25(d,J=7.1Hz,1H),8.17(d,J=8.2Hz,1H),7.84–7.70(m,2H),5.06(d,J=5.3Hz,2H),3.86(dt,J=13.8,5.3Hz,2H),3.73(s,2H),3.57–3.33(m,3H),3.22(s,1H),2.13–1.84(m,2H),1.67(t,J=5.8Hz,4H).HRMS(ESI)[M+H]+,C23H27N6O2,cal.419.2190,found419.2195.
实施例27
2-(2-(9-蒽甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-27所示化合物)的制备:
除以9-蒽甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-27所示化合物)。
1H NMR(400MHz,DMSO-d6)δ10.33(s,1H),8.84(s,1H),8.66(m,4H),8.21(d,J=8.4Hz,2H),7.73(dd,J=8.7,6.7Hz,2H),7.68–7.51(m,2H),5.56(d,J=5.4Hz,2H),3.93–3.71(m,3H),3.60(dddd,J=26.1,19.4,12.2,6.7Hz,3H),3.38(q,J=7.0Hz,2H),2.08(ddd,J=13.5,7.1,2.7Hz,1H),1.90–1.70(m,3H),1.63(t,J=5.8Hz,2H).HRMS(ESI)[M+H]+,C28H30N5O2,cal.468.2394,found 468.2400.
实施例28
2-(2-(9-菲甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-28所示化合物)的制备:
除以9-菲甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-28所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.14(s,1H),10.84(s,1H),9.00–8.94(m,1H),8.90(d,J=8.2Hz,1H),8.67(s,2H),8.50–8.41(m,1H),8.29(s,1H),8.01(d,J=7.5Hz,1H),7.87–7.67(m,4H),5.00(q,J=6.6,5.2Hz,2H),3.90(ddt,J=14.2,10.8,4.7Hz,2H),3.78(ddd,J=12.9,7.8,3.9Hz,1H),3.73–3.64(m,1H),3.63–3.42(m,3H),3.23(dd,J=11.9,7.6Hz,1H),2.10(ddd,J=11.3,7.2,3.6Hz,1H),1.91(ddd,J=13.1,10.0,7.4Hz,1H),1.81–1.60(m,4H).HRMS(ESI)[M+H]+,C28H30N5O2,cal.468.2394,found 468.2400.
实施例29
2-(2-(1-芘甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-29所示化合物)的制备:
除以1-芘甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-29所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.42(p,J=6.6Hz,1H),8.74(d,J=9.4Hz,1H),8.68(s,2H),8.54(d,J=7.9Hz,1H),8.44–8.34(m,4H),8.27(q,J=9.0Hz,2H),8.14(t,J=7.6Hz,1H),5.29–5.12(m,2H),3.97–3.82(m,2H),3.76(ddd,J=12.9,7.7,3.8Hz,1H),3.66(ddd,J=12.9,7.8,3.9Hz,1H),3.48(ddt,J=22.5,11.8,4.9Hz,3H),3.23(dd,J=11.8,7.9Hz,1H),2.09(ddd,J=13.2,6.8,4.1Hz,1H),2.00–1.87(m,1H),1.71(ddtd,J=20.5,13.0,8.3,7.9,3.8Hz,4H).HRMS(ESI)[M+H]+,C30H30N5O2,cal.492.2394,found 492.2400.
实施例30
2-(2-(4-苯基-1-苯甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-30所示化合物)的制备:
除以4-苯基-1-苯甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-30所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),8.68(s,2H),7.82–7.65(m,6H),7.50(d,J=7.4Hz,2H),7.40(t,J=7.3Hz,1H),4.41(qd,J=12.9,5.8Hz,2H),3.93(ddd,J=14.6,7.3,4.5Hz,2H),3.70(dddd,J=25.4,12.8,8.0,3.8Hz,2H),3.48(td,J=7.1,4.1Hz,1H),3.29(td,J=13.4,12.5,7.9Hz,2H),3.01(dd,J=11.8,7.8Hz,1H),2.05(ddd,J=12.1,7.6,4.0Hz,1H),1.94(dt,J=13.1,8.2Hz,1H),1.69(tdd,J=14.1,8.0,3.4Hz,4H).HRMS(ESI)[M+H]+,C26H30N5O2,cal.444.2394,found 444.2400.
实施例31
2-(2-(3-吲哚甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-31所示化合物)的制备:
除以3-吲哚甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-31所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.52(d,J=2.6Hz,1H),11.14(s,1H),8.68(s,2H),7.84(d,J=7.8Hz,1H),7.70(d,J=2.6Hz,1H),7.44(d,J=7.9Hz,1H),7.18–7.12(m,1H),7.12–7.06(m,1H),4.50(d,J=4.9Hz,2H),3.86(td,J=11.8,10.8,5.1Hz,2H),3.69(tdd,J=13.2,7.7,4.1Hz,2H),3.46(td,J=7.3,3.3Hz,1H),3.39–3.33(m,1H),3.27(dd,J=11.4,8.4Hz,1H),3.03(dd,J=11.8,7.9Hz,1H),1.99(ddd,J=12.2,7.7,4.1Hz,1H),1.88(ddd,J=13.1,9.4,7.4Hz,1H),1.73–1.51(m,4H).HRMS(ESI)[M+H]+,C22H27N6O2,cal.407.2190,found 407.2195.
实施例32
2-(2-(2-苯并呋喃甲基)-2,8-二氮杂-螺-[4.5]-癸烷-8-基)-嘧啶-5-异羟肟酸盐酸盐(式I-32所示化合物)的制备:
除以2-苯并呋喃甲醛替换实施例1中N-甲基吲哚-3-甲醛外,其余步骤及所用原料与实施例1相同,得到标题化合物(式I-32所示化合物)。
1H NMR(400MHz,DMSO-d6)δ11.64–11.49(m,1H),8.67(s,2H),7.72(d,J=7.7Hz,1H),7.63(d,J=8.2Hz,1H),7.40(d,J=7.6Hz,1H),7.31(t,J=7.5Hz,1H),7.23(s,1H),4.66(t,J=4.3Hz,2H),3.89(dt,J=14.8,5.2Hz,2H),3.72(ddd,J=20.6,11.4,6.0Hz,2H),3.65–3.57(m,1H),3.48(dd,J=11.8,5.5Hz,1H),3.37(d,J=6.9Hz,1H),3.10(dd,J=11.9,7.7Hz,1H),2.04(ddd,J=12.5,7.9,4.4Hz,1H),1.92(dt,J=13.0,8.2Hz,1H),1.64(dt,J=23.2,6.1Hz,4H).HRMS(ESI)[M+H]+,C22H26N5O3,cal.408.2030,found 408.2036.
实施例33
化合物I-1~32对两株疟原虫3D7和Dd2的体外生长半数有效抑制浓度(IC50)的测定
a.疟原虫培养:疟原虫培养使用PRMI(含NaHCO3、HEPES、Albumax I、Hypoxanthine、Genaotamicin)完全培养基(complete medium),在37℃培养箱(5%CO2、5%O2)中培养。
b.化合物对疟原虫的体外生长半数有效抑制浓度(IC50)的测定:100μL完全培养基加入到96孔板中,在第一孔加入适量的200μM的化合物并用完全培养基定容至200μL,使化合物终浓度为1000nM,然后按1/2的比例进行梯度稀释(11个浓度梯度),二氢青蒿素(DHA)为阳性对照物,不加任何化合物作为阴性组,不加疟原虫和化合物作为空白组。之后每孔加入100μL的疟原虫培养物(红细胞压积4%,原虫率1%)使最终红细胞压积2%,原虫率1%,化合物终浓度梯度为500nM、250nM、125nM、62.5nM、31.25nM、15.625nM、7.8125nM、3.90625nM、1.953125nM、0.9765625nM、0.48828125nM。加样完成,96孔板置于37℃培养箱(5%CO2、5%O2)中培养72小时。培养完成,每孔除去100μL上清液,加入100μL裂解液(10×SYBR Green I、0.5%v/v Triton X-100,0.5mg/mL saponin、0.75%EDTA/Tris-Cl缓冲液),混合均匀,室温下避光孵育2小时。用孔板荧光读数机读取每孔数值(最大激发光/最大接受光:485nm/535nm),根据荧光值按公式(A)计算每孔抑制率,根据浓度-抑制率,在Graphpad Prism中绘制生长抑制曲线并计算IC50值,结果见表1(化合物I-1~32对3D7和Dd2的IC50值)。
表1
其中3D7为野生型虫株,对药物无明显抗性;Dd2对氯喹、奎宁、磺胺多辛、乙胺嘧啶、阿莫地喹具有抗性。表1显示化合物I-1~32均具有较强的体外杀虫活性,部分化合物对3D7和Dd2的IC50值与DHA相当。
实施例34
化合物I-1~32对两株正常人细胞HepG-2和293-T半数有效抑制浓度(IC50)的测定
准备HepG-2和293-T细胞,10cm dish中于37℃,5%CO2细胞培养箱内培养
第一天
胰酶消化重悬细胞并计数,按100μL/孔的体系,7000细胞的量将细胞转接至96孔板中。37℃,5%CO2细胞培养箱内培养24小时;
第二天
1、准备化合物梯度浓度体系,2倍稀释,体系为100μL/孔。(需根据药物的毒性来确定最高浓度,一般原则是使IC50浓度处于浓度梯度的中间,一般第一次可选取高一些的浓度来进行梯度稀释,并根据结果来调整)。
2、去掉第一天中96孔板细胞培养体系中的上清,并将新配置好的药物浓度体系对应加入到培养细胞的培养板孔内(设置双复孔)。37℃,5%CO2细胞培养箱内培养72h。
第五天
1、细胞培养结束之后,去掉96孔板细胞培养体系中的上清,每孔加入100μL检测溶液(含10%CCK-8的培养基),37℃,5%CO2细胞培养箱内孵育1h,然后取出用酶标仪测定在450nm处的吸光度。
2、进行数据处理,计算不同浓度下化合物对细胞生长的抑制率(抑制率按公式(B)计算),将抑制率输入GraphPad Prism,按照非线性回归方法,计算每个药物的IC50读值。选择性指数SI按公式(C)计算。具体结果见表2(化合物I-1~32对HepG-2和293-T的IC50及SI值)。
公式(B)中,A(加药):具有细胞、CCK-8溶液和药物溶液的孔的吸光度,
A(空白):具有培养基和CCK-8溶液而没有细胞的孔的吸光度,
A(0):具有细胞、CCK-8溶液而没有药物溶液的孔的吸光度
表2
续表2
续表2
由表2可知,显示部分化合物对正常细胞的生长抑制较弱,选择性指数可以达到200。
实施例35
部分化合物对五株临床虫株的半数有效抑制浓度(IC50)的测定
选取杀虫活性及细胞毒性较优的化合物,按照实施例33的方法,测试它们对五株具有不同药物抗性的临床虫株的IC50值,结果见表3(部分化合物对五株临床虫株的IC50值)。
表3
GB4对氯喹具有抗性;C2A对奎宁具有抗性;CP286对磺胺多辛、乙胺嘧啶、甲氟喹具有抗性;6218与6320对青蒿素类药物具有时间依赖的抗性,只在环期同步化后6小时以内显示。综合表1和表3,化合物的72小时IC50值均与DHA相当,显示化合物具有治疗对目前抗疟一线和二线药物耐受的疟疾,应对疟疾耐药性的潜力。
实施例36
部分化合物对小鼠肝微粒体代谢稳定性实验
实验选用小鼠肝微粒体(0.5mg/mL),采购自Corning公司。阳性对照选用酮舍林(ketanserin),待测化合物首先配成10mM的DMSO溶液,用乙腈稀释至0.5mM;取上述0.5mM溶液加入含肝微粒体的缓冲液中,使被测试化合物浓度为1.5μM;取上述1.5μM化合物/肝微粒体混合液30μL,加入15μL的6mM的NADPH溶液,使化合物最终浓度为1.5μM,NADPH最终浓度为2mM。化合物/肝微粒体测试液置于测试板上,在37℃水浴孵育,在每个时间点(0、5、15、30、45分钟)各加入135μL乙腈淬灭。待全部样品淬灭完毕,用振荡器(IKA,MTS 2/4)振荡样品10分钟(600rpm/min),然后以4495g离心15分钟(Thermo Multifuge×3R)。取上层清液,按1:1加入蒸馏水稀释,用LC-MS进行分析。将化合物在5、15、30、45分钟的峰面积响应比率(PARR)与时间0的PARR进行比较,以确定在每个时间点保留的测试化合物的百分比。使用Excel软件拟合单相指数衰减方程计算半衰期,具体结果见表4(部分化合物对小鼠肝微粒体代谢稳定性)。
表4
实施例37
部分化合物小鼠体内药效实验
体内药效实验选用balb-c小鼠感染P.yoelii模型进行。小鼠选用6-8周龄的雌性,每个剂量组设置5只。阳性对照物为磷酸哌喹(PPQ),给药方式为腹腔注射,给药前每组测量平均体重,按15μL/g注射相应体积的药液。化合物注射液的配置方法:先溶于5%v/v的二甲基亚砜,剧烈振荡,使固体部分部分或完全溶解,再加入95%v/v的20%wtβ-羟丙基环糊精水溶液,混匀即可。P.yoelii从-78℃解冻后经转接两只小鼠恢复毒力,取血,加入PBS稀释。每只小鼠接种105只疟原虫,感染后24小时开始给药,一共给药5次,每次间隔24小时。从感染后24h开始定期从小鼠尾静脉取血涂片观察,计算原虫率。感染后观察30天血涂片,计算相应的原虫率(原虫率按公式(D)计算),具体小鼠体内药效测试结果见图1.。
由图1.可知,所选化合物在60mg/kg下具有较好的杀虫活性,且存活的小鼠在第30天时原虫率均为0,显示体内疟原虫已被清除。原虫率曲线和生存曲线综合显示式I-31的化合物在药效和毒性上具有较好的平衡。
实施例38
部分化合物对人源HDAC半数有效抑制浓度(IC50)的测定
(1)hHDAC1-3,6(即hHDAC1,hHDAC2,hHDAC3和hHDAC6)测试方法:通过Echo将250nlDMSO或化合物溶液加入到OptiPlate TM-384F黑色测定板中,依次将15μl酶溶液、10μl GL-8溶液加入测定板中。在25℃下孵育60分钟,使用Ex350-360/Em450-465(敏感60)的设置读取值。计算抑制率(参见实施例34,下同),用GraphPad Prism算出IC50值。
(2)hHDAC8测试方法:通过Echo将250nl DMSO或化合物溶液加入到OptiPlate TM-384 F黑色测定板中,依次加入15μl酶溶液,10μl底物溶液,在25℃反应4小时。添加10μl终止液终止反应,使用Ex350-360/Em450-465的设置读取值。计算抑制率,用GraphPad Prism算出IC50值。
(3)hSirt2测试方法:通过Echo将800nl DMSO或化合物溶液加入到OptiPlate TM-384 F黑色测定板中,依次加入10μl酶溶液、10μl底物溶液,在25℃反应4小时。添加20μl终止液终止反应,使用Ex350-360/Em450-465的设置读取值。计算抑制率,用GraphPad Prism算出IC50值。
上述测试的具体结果见表5.(部分化合物对人源HDAC的IC50值)。
表5
表5中,SAHA与suramin为阳性对照。由表5可知,编号为I-31的化合物对hHDAC1-3有较强抑制,对hSirt2几乎无抑制;对hHDAC1-3活性具有很强的抑制作用,表明其具有作为HDAC抑制剂治疗与HDAC活性相关的疾病的潜力(包括肿瘤等)。
实施例39
优选化合物抑制疟原虫去乙酰化酶活性验证实验
(1)疟原虫培养
疟原虫培养使用RPMI(含NaHCO3,HEPES,Albumax I,HypoxanthineGenaotamicin)完全培养基(Complete Medium),在37℃培养箱中培养;
(2)药物配制
选用式I-31所示化合物进行实验,根据药物前期测出的IC50值,将式I-31所示化合物溶于DMSO中,配制200×20×IC50的初浓度。
(3)药物处理(在生物安全柜中进行)
取44h左右的恶性疟原虫同完全培养基与红细胞在50ml管中配制混合物(红细胞含量为2%,原虫率为8%-10%),在6孔板的每孔中加入6ml混合物,再在每孔中加入30ul药物(工作浓度为20×IC50),加好之后混匀板子,并放入三气培养箱孵育4h。
(4)收取蛋白样
取出6孔板,弃去4mL上清液,余下的2mL虫血混合物转入2mLEP管,离心(4000r/2min,常温),去除上清,再将各孔用1ml PBS重悬残液并转移至原EP管以减少损失,再次离心去上清(注:4000rpm离心后,为防止蛋白降解,之后离心应在4℃进行,并将EP管持续放冰上操作);在各EP管中加入2mL裂解液,涡旋仪振荡混匀,冰上裂解10min,离心(12000r/1min,4℃),弃去上清液;各EP管加入1mlPBS,涡旋仪振荡混匀,离心(12000r/1min,4℃),弃去上清液,再重复此步骤两次;加入90μL 1×PBS重悬并转移至1.5ml超声管,再加入10μL10%SDS,混匀后超声5min(30s on/30s off),离心(12000r/10min,4℃),取上清液,加入loading,振荡,100℃加热10min,样品可保存于-20℃。
(5)Western Blot实验
预制胶各孔上样10ul,电压80V跑30min后将电压调至120V再接着跑至loading接近分离胶下边缘;切取相应覆盖面积的PVDF膜,采用湿转法,快速转膜buffer,400mA恒流转35min,结束后取出PVDF膜;将膜放于封闭液(在TBST中加入5%脱脂奶粉)中,摇床摇晃封闭2h;采用组蛋白histone H3抗体和H3K9乙酰化抗体,与5%脱脂奶粉按照1:2000稀释,于摇床孵育PVDF膜2h后弃去孵育液,加入TBST洗膜三次,每次10min;二抗按照1:5000稀释,于摇床孵育PVDF膜1h后弃去孵育液;临时配制显色液并均匀的铺在PVDF膜上,可根据条带亮度调节曝光时间。其结果见图2。
图2中,JL01为阳性对照化合物,对比化合物处理和DMSO在20×IC50的浓度下处理4h后的疟原虫组蛋白H3乙酰化条带,可以看出化合物上调了乙酰化水平,即抑制了去乙酰化酶的活性,间接证明化合物是pan-pfHDAC抑制剂。
Claims (8)
1.一种2,8-二氮杂-螺-[4,5]-癸烷类嘧啶-异羟肟酸类化合物,其特征在于,所述2,8-二氮杂-螺-[4,5]-癸烷类嘧啶-异羟肟酸类化合物为式I所示化合物,或其药学上可接受的盐:
式I中,R为C4~C16的饱和或不饱和的、取代或非取代的碳环基或碳杂环基;
其中,所述取代的碳环基或碳杂环基的取代基为C1~C3烷基,所述碳杂环基的杂原子选自:氧、硫或氮中一种,杂原子个数为1或2。
2.如权利要求1所述的2,8-二氮杂-螺-[4,5]-癸烷类嘧啶-异羟肟酸类化合物,其特征在于,其中R为5~6元的芳环基或芳杂环基,或取代的5~6元的芳环基或芳杂环基;
其中,所述的取代的5~6元的芳环基或芳杂环基的取代基为C1~C3烷基,苯基,二价苯基或二价吡啶基;
所述的芳杂环基的杂原子选自:氧、硫或氮中一种,杂原子个数为1或2。
3.如权利要求2所述的2,8-二氮杂-螺-[4,5]-癸烷类嘧啶-异羟肟酸类化合物,其特征在于,其中R为下列基团中一种:
其中:X为O或S,R1为氢或C1~C3烷基。
4.如权利要求3所述的2,8-二氮杂-螺-[4,5]-癸烷类嘧啶-异羟肟酸类化合物,其特征在于,其中R为下列基团中一种:
5.一种组合物,其包括权利要求1~4中任意一项所述的2,8-二氮杂-螺-[4,5]-癸烷类嘧啶-异羟肟酸类化合物。
6.如权利要求1~4中任意一项所述的2,8-二氮杂-螺-[4,5]-癸烷类嘧啶-异羟肟酸类化合物在制备组蛋白去乙酰化酶(HDAC)抑制剂中的应用。
7.如权利要求1~4中任意一项所述的2,8-二氮杂-螺-[4,5]-癸烷类嘧啶-异羟肟酸类化合物在制备治疗疟疾药物中的应用。
8.如权利要求5所述组合物在制备治疗疟疾药物中的应用。
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