CN109867662B - 一种咔唑β-氨基醇类衍生物及其制备方法和用途 - Google Patents
一种咔唑β-氨基醇类衍生物及其制备方法和用途 Download PDFInfo
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Abstract
本发明涉及一种咔唑β‑氨基醇类衍生物，其药物组合物、制备方法及用途。本发明化合物能够有效的抑制toll样受体4的活性及水平和对HCN通道亚型有抑制作用，其中具体公开了6种化合物，并公开了所述的化合物及其可药用接受的盐在制备TLR4受体抑制剂及应用为佐剂、抗炎、肿瘤免疫等方面的应用。其结构如下式所示：
其中R1为取代的卤素原子、氨基、硝基、C1‑6烷基、C1‑6烷氧基，和C1‑6烷基中任意一个或多个取代基所取代，R2为取代的H，卤素原子、氨基、硝基、C1‑6烷基、C1‑6烷氧基，和C1‑6烷基中任意一个或多个取代基所取代。n为1，2，3或4。
Description
技术领域
本发明涉及医药领域，具体涉及TLR4抑制活性的一系列化合物，可用于科研，医疗，抗肿瘤等领域。
背景技术
天然免疫系统通过机体自身的模式识别受体识别潜在的微生物和非致病性共生菌群。其中Toll样受体实验就比较清楚的模式识别受体，同时也是识别病原微生物中最具代表性的一类。Toll样受体(以下简称TLR)是一类进化上高度保守且古老的天然免疫受体家族，它识别病原微生物在漫长的进化过程中保留下来的、对生存必不可少的特异性保守成分和机体在应激和损伤时放出的结构成分之后，TLRs构象发生改变，从而招募细胞质中特异的接头蛋白分子以激活信号级联反应。另外，TLRs信号过度活化或活化不足也会导致机体功能的异常和疾病的发生，因此机体采取了一系列正向或负向调控策略来调节TLRs介导的信号转导通路，使之维持适度的活化水平。
TLR4是由Janeway和Medzhitov于1997年发现的与果蝇Toll蛋白同源的哺乳动物第一个TLR，同时存在几个辅助受体，如MD-2等。它们共同识别革兰氏阴性菌的内毒素成分、LPS、病毒囊膜蛋白、真菌的甘露聚糖等，诱导IL-12、IL-6、IL-8、TNF-α等一系列促炎性细胞因子和IFN-β的释放以及募集炎性细胞到感染部位，从而介导机体的天然免疫防御作用，同时也能调节机体的获得性免疫反应。通过一系列具有药理学特性的激活剂、拮抗剂和信号传导抑制剂靶向干涉TLR4极其信号传导通路中的某些环节的关键分子，从而达到预防和治疗疾病的目的。信号转导通路中的关键接头分子Mal/MyD88和TRAM/TRIF，可以作为靶点以选择性调节TLR4的活性，对TLR4活性的调节既是临床治疗肿瘤等疾病的目标，也是十分有意义的科研论题。
发明内容
本发明的目的在于提供咔唑β-氨基醇类衍生物，如式I所示，所述多种化合物能抑制TLR4受体活性，有HCN通道抑制作用，降低一系列疾病的发生与发展，如感染性疾病、AS、哮喘、心脏病、肝病、肾病、肠炎、癌症、肥胖症(I型和II型)、RA、阿尔茨海默病、震颤性麻痹、多重性硬化和非菌性炎症反应。从而为这些的治疗提供一种新的手段和途径，对于治疗肿瘤等相关疾病具有重要的研发价值和开发意义。
本发明提供了式I所示化合物在抑制TLR4发挥抗肿瘤功能等方面应用。
本发明所述的化合物SMU-XY2，能进行结构修饰，获得活性更好的化合物，并用于治疗TLR4相关疾病。
本发明一个方面提供了一种式I所示的化合物或其可药用的盐，
其中，
R1为H、卤素、氨基、硝基、C1-6烷基、C1-6烷氧基、被1个或多个取代基取代的C1-6烷基、苄基、苯乙基、取代的苯乙基、苯丙基、以及取代的苯丙基；
R2为H、卤素、氨基、硝基、C1-6烷基、C1-6烷氧基或被1个或多个取代基取代的C1-6烷基；
n为1，2，3或4。
在本发明的技术方案中，R1与R2中的卤素独立地选自F、Cl、Br、I；R1与R2中C1-6烷基独立地选自甲基、乙基、丙基、丁基、戊基或己基；R1与R2中C1-6烷氧基独立地选自甲氧基、乙氧基、丙氧基、丁氧基、戊氧基或己氧基。
在本发明的技术方案中，R1为2位、3位或4位。
在本发明的技术方案中，化合物选自如下化合物：
本发明另一个方面提供了本发明所述化合物的制备方法，包括下述步骤：
1)化合物a
在碱性条件下与化合物b
取代反应得到化合物
c
2)多聚甲醛、甲胺盐酸盐和化合物c在有机溶剂中回流反应得到化合物d
3)化合物e
在间氯过氧苯甲酸条件下氧化得到化合物
4)化合物f与4-羟基咔唑在碱性条件下反应得到化合物h
5)将化合物d与化合物h在有机溶剂中回流得到式I化合物。
R1、R2、n分别如上所述。
本发明另一个方面提供了一种药物组合物，其包括式I化合物或其药可用的盐，还包括药学上可接受的载体或辅料。
本发明另一个方面提供了本发明式I化合物在制备佐剂，抗炎，TLR4抑制剂，抗肿瘤，心力衰竭的药物中的应用。
本发明另一个方面提供了一种在体外、体内调节TLR4碱性磷酸酶活性的方法，其是将本发明的化合物给予受试者本发明的化合物。
本发明一个具体技术方案提供了化合物SMU-XY系列的制备方法，其包括以下步骤：
1)将4-溴-1-丁烯等烯烃逐滴加入到mCPBA的CH2Cl2溶液中。将反应混合物搅拌24小时，在此期间形成白色沉淀。然后加入NaOH并分离各相。用4M NaOH洗涤有机层一次，随后用水洗涤直至洗涤水溶液达到pH7。有机相用Na2SO4干燥，减压除去溶剂，得到环氧溴丁烷等相对应的环氧烷烃。
2)将2-(溴甲基)环氧乙烷等相对应的环氧烷烃和1M NaOH溶液加入到4-羟基咔唑的DMSO溶液中。反应混合物在60℃下搅拌24小时。然后冷却至20℃，用水稀释并用乙酸乙酯萃取。将收集的有机层用盐水洗涤，Na2SO4干燥并浓缩。通过硅胶色谱法(乙酸乙酯-正己烷)纯化残余物，得到油状的4-(2-(环氧乙烷基)乙氧基)-9H-咔唑等相对应的产物。
3)将3,5-二甲基-1H-吡唑或取代1H-吡唑和KOH溶于DMSO中，并将得到的非均相溶液在80℃下搅拌1.5h，然后冷却至室温。然后在15分钟内加入6M DMSO溶液的邻氯氯苄或其它取代物，并将反应混合物再搅拌2.5小时。TLC观察监测反应是否完全。将反应物溶于水，水相用CHCl3萃取。合并有机层用100ml水洗涤，用无水Na2SO4干燥并减压浓缩。残留物经硅胶快速色谱纯化，用20％乙酸乙酯的石油醚溶液洗脱。得到相对应的产物。
4)将多聚甲醛和甲胺盐酸盐溶于乙醇中搅拌1h，然后加入1-(2-氯苄基)-3,5-二甲基-1H-吡唑等其他取代产物，并将反应混合物回流搅16小时。混合物液体冷却至室温，用NaHCO3中和。有机层用Na2SO4干燥并减压浓缩。通过硅胶快速色谱法用10％甲醇的乙酸乙酯溶液纯化残余物。得到1-1-(2-氯苄基)-3,5-二甲基-1H-4-吡唑-N-甲基甲胺或其他取代物
为黄色油状物。
5)4-(2-(环氧乙烷基)乙氧基)-9H-咔唑和1-1-(2-氯苄基)-3,5-二甲基-1H-4-吡唑-N-甲基甲胺加入到乙醇中，混合溶液回流24小时。将混合物冷却至室温，减压浓缩。同样方法得到式I中多种化合物。
上述所示的部分化合物能剂量依赖性的抑制TLR4受体，抑制HCN等通道亚型。
本发明所述的化合物SMU-XY系列可用于制成TLR4相关佐剂、药物等。结合现代常用药物制剂手段，可将所述化合物制成注射剂、片剂、粉剂、颗粒剂、胶囊，从而采用比较方便的给药形式，其中本发明化合物在所述药物中的质量百分比含量为1～20％。
上述各种剂型的药物均可按照药学领域的常规方法制备。
附图说明
图1为化合物SMU-XY1的1HNMR谱图。
图2为化合物SMU-XY2的1HNMR谱图。
图3为化合物SMU-XY3的1HNMR谱图。
图4为化合物SMU-XY4的1HNMR谱图。
图5为化合物SMU-XY5的1HNMR谱图。
图6为化合物SMU-XY6的1HNMR谱图。
图7为化合物SMU-XY2呈浓度依赖的抑制TLR4活性。
图8为化合物SMU-XY1在PBMC细胞中抑制TNF-α炎症因子。
图9为化合物SMU-XY1在Raw 264.7细胞中抑制NO信号。
图10为化合物SMU-XY1在BV-2细胞中抑制NO信号。
具体实施方式
为了更好地理解本发明的内容，下面结合具体实施方法对本发明内容作进一步说明，但本发明的保护内容不局限以下实施例。
实施例1：制备化合物SMU-XY2
1)
的制备。
将
(1000mg，7.41mmol)滴加到mCPBA(1948mg，11.11mmol)的50ml CH2Cl2溶液中。搅拌反应混合物24小时，在此期间形成白色沉淀。之后加入1M NaOH并将相用乙酸乙酯萃取。用NaOH(4M，50ml)洗涤有机层一次，随后用水洗涤直到洗涤水溶液到pH＝7。有机相用Na2SO4干燥，减压除去溶剂，得到澄清液状的
2)
的制备。
将
(546mg，2.42mmol)和NaOH(97mg，2.42mmol)溶液加入到
(300mg，2.42mmol)的DMSO溶液中。将反应混合物在60℃下搅拌24小时。然后冷却至20℃，用25ml水稀释并用乙酸乙酯萃取。将收集的有机层用盐水洗涤，用Na2SO4干燥并浓缩。残留物经硅胶快速色谱纯化，用20％乙酸乙酯的正己烷溶液纯化残余物。得到
3)
的制备。
将
(1000mg，10.40mmol)和KOH(1675mg，10.40mmol)溶于DMSO中，并将得到的非均相溶液在80℃下搅拌1.5h，然后冷却至室温。然后在15分钟内加入6M DMSO溶液的
(876mg，15.61mmol)，并将反应混合物再搅拌2.5小时。TLC观察监测反应是否完全。将反应物溶于水，水相用CHCl3萃取。合并有机层用100ml水洗涤，用无水Na2SO4干燥并减压浓缩。残留物经硅胶快速色谱纯化，用20％乙酸乙酯的石油醚溶液洗脱。得到
为黄色油状物。
4)
的制备。
将多聚甲醛(820mg，27.2mmol)和甲胺盐酸盐(920mg，13.6mmol)溶于乙醇中搅拌1h，然后加入
(1000mg，4.53mmol)加入并将反应混合物回流搅16小时。混合物液体冷却至室温，用NaHCO3中和。有机层用Na2SO4干燥并减压浓缩。通过硅胶快速色谱法用10％甲醇的乙酸乙酯溶液纯化残余物。得到
为黄色油状物。
5)
的制备。
1H NMR(CDCl3,400MHz)δ8.28(d,J＝7.6Hz,1H),8.22(s,1H),7.42(s,2H),7.35(q,J＝7.6Hz,2H),7.19–7.10(m,2H),7.07(d,J＝8.0Hz,1H),6.68(d,J＝8.0Hz,1H),6.52(d,J＝7.2Hz,1H),5.27(s,2H),4.38–4.29(m,2H),4.25–4.20(m,1H),3.58–3.55(m,1H),3.43–3.39(m,1H),2.83–2.70(m,2H),2.36(s,3H),2.30(s,3H),2.14(s,3H),1.30–1.26(m,1H).13C NMR(CDCl3,101MHz)δ155.34,147.81,140.90,138.69,138.53,135.04,131.72,129.19,128.55,127.39,127.23,126.67,124.79,122.84,122.66,119.41,112.61,109.92,103.42,101.19,64.65,64.34,62.88,51.33,50.03,41.51,34.74,12.08,9.54.ESI-MS:m/zcalc’d for C29H31ClN4O2(M+H+)503.04,found 503.55.
实施例2：化合物1、3-6的制备
实施例2中分别制备了化合物1、3-6。化合物1、3-6制备步骤与实施例1中相同，除了所用原料有所区别。不同之处如下面的表2所示：
表2：化合物1、3-6与实施例1的区别
| 化合物编号 | 与实施例1步骤不同之处 |
| SMU-XY1 | 将4-溴-1-丁烯替换为3-溴丙烯 |
| SMU-XY3 | 将邻氯氯苄替换为苄溴 |
| SMU-XY4 | 将邻氯氯苄替换为4-氯苄氯 |
| XMU-XY5 | 将邻氯氯苄替换为邻氟氯苄 |
| SMU-XY6 | 将3，5-二甲基吡唑替换为3-甲基吡唑 |
实施例3：化合物1-6的结构验证
[SMU-XY1]
1-((9H-carbazol-4-yl)oxy)-3-(((1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amino)propan-2-ol.
1H NMR(CDCl3,400MHz)δ8.28(d,J＝7.6Hz,1H),8.22(s,1H),7.42(s,2H),7.35(q,J＝7.6Hz,2H),7.19–7.10(m,2H),7.07(d,J＝8.0Hz,1H),6.68(d,J＝8.0Hz,1H),6.52(d,J＝7.2Hz,1H),5.27(s,2H),4.38–4.29(m,2H),4.25–4.20(m,1H),3.58–3.55(m,1H),3.43–3.39(m,1H),2.83–2.70(m,2H),2.36(s,3H),2.30(s,3H),2.14(s,3H),1.30–1.26(m,1H).ESI-MS:m/z calc’d for C29H31ClN4O2(M+H+)503.04,found 503.55.
[SMU-XY2]
4-((9H-carbazol-4-yl)oxy)-1-(((1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amino)butan-2-ol.
1H NMR(CDCl3,400MHz)δ8.31(d,J＝8.0Hz,1H),8.21(s,1H),7.43–7.30(m,4H),7.26–7.14(m,3H),7.05(d,J＝8.4Hz,1H),6.71(d,J＝8.0Hz,1H),6.52(d,J＝6.8Hz,1H),5.30(s,2H),4.46–4.40(m,2H),4.18(s,1H),3.55–3.30(m,2H),2.62–2.56(m,1H),2.50-2.46(m,1H),2.27(s,6H),2.11(s,3H),1.29(s,2H).ESI-MS:m/z calc’d for C30H33ClN4O2(M+H+)516.23,found 517.06.
[SMU-XY3]
1-((9H-carbazol-4-yl)oxy)-3-(((1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amino)propan-2-ol.
1H NMR(CDCl3,400MHz)δ8.36–8.27(m,2H),7.42–7.30(m,5H),7.26(d,J＝7.2Hz,1H),7.06(d,J＝7.7Hz,3H),6.67(d,J＝7.2Hz,1H),5.20(s,2H),4.44–4.26(m,2H),4.21–4.14(m,1H),3.56–3.38(m,2H),2.85–2.79(m,1H),2.75–2.70(m,1H),2.34(s,2H),2.29(s,3H),2.15(s,3H),2.10(s,3H),1.37–1.31(m,1H).ESI-MS:m/z calc’d for C29H32N4O2(M+H+)468.25,found 468.59.
[SMU-XY4]
1-((9H-carbazol-4-yl)oxy)-3-(((1-(2-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amino)propan-2-ol.
1H NMR(CDCl3,400MHz)δ8.27(d,J＝7.6Hz,1H),8.18(s,1H),7.46–7.38(m,2H),7.35–7.31(m,1H),7.27–7.20(m,2H),7.06–6.95(m,3H),6.87–6.78(m,1H),6.68(d,J＝8.0Hz,1H),5.24(s,2H),4.40–4.28(m,2H),4.26–4.17(m,1H),3.57-3.42(m,2H),2.91–2.71(m,2H),2.36(s,3H),2.28(s,3H),2.18(s,3H),1.32-1.29(m,1H).ESI-MS:m/z calc’dfor C29H31ClN4O2(M+H+)502.21,found 503.04.
[SMU-XY5]
1-((9H-carbazol-4-yl)oxy)-3-(((1-(4-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amino)propan-2-ol.
1H NMR(CDCl3,400MHz)δ8.38(s,1H),8.28(d,J＝7.6Hz,1H),7.39(d,J＝4.0Hz,2H),7.36–7.21(m,3H),7.04(d,J＝8.0Hz,1H),6.97(d,J＝8.0Hz,2H),6.71–6.64(m,1H),5.13(s,2H),4.32(s,2H),4.25–4.17(m,1H),3.56–3.48(m,1H),3.44–3.38(m,1H),3.23(s,1H),2.89–2.67(m,2H),2.33(s,3H),2.29(s,3H),2.13(s,3H),1.32–1.26(m,1H).ESI-MS:m/z calc’d for C29H31FN4O2(M+H+)486.24,found 486.58.
[SMU-XY6]
1-((9H-carbazol-4-yl)oxy)-3-(((1-(2-chlorobenzyl)-3-methyl-1H-pyrazol-4-yl)me thyl)(methyl)amino)propan-2-ol.
1H NMR(CDCl3,400MHz)δ8.28–8.24(m,1H),8.17(s,1H),7.47–7.30(m,5H),7.28–7.13(m,3H),7.07(d,J＝8.0Hz,1H),6.94–6.90(m,1H),6.69(d,J＝7.6Hz,1H),5.31(s,2H),4.40–4.28(m,2H),4.26–4.20(m,1H),3.66–3.58(m,1H),3.54–3.46(m,1H),2.86–2.79(m,1H),2.77–2.71(m,1H),2.38(s,3H),2.30(s,2H),2.18(s,1H),1.27–1.33(m,1H).ESI-MS:m/z calc’d for C28H29ClN4O2(M+H+)488.20,found 489.01.
实施例4 SMU-XY1的TLR4抑制活性检测
TLR4抑制活性采用TLR4HEK BLUE细胞进行检测。TLR4HEK BLUE细胞培养于含10％胎牛血清，1％青霉素、链霉素的DMEM培养基中，置于含5％CO2的37℃细胞培养箱中培养。
HEK BLUE TLR4细胞以40000个/孔铺于96孔板中，37℃，5％CO2中培养24小时，每孔50μL。待细胞长势良好时，加入100μM浓度的化合物并倍比稀释9个浓度梯度。再于CO2培养箱中放置24小时。新96孔板中加入50μL细胞液上清，后避光加入50μL Quanti-blue溶液，在620nm吸光度下读数，以检测细胞上清中SEAP的信号强度。
如图7所示，SMU-XY1能显著抑制TLR4碱性磷酸酶(SEAP)信号强度，在低浓度的抑制剂SMU-XY1(0.39μM)时，其不能显著抑制TLR4碱性磷酸酶信号强度，而在高浓度的抑制剂SMU-XY1(30μM)时，其能显著抑制TLR4碱性磷酸酶信号强度。
该结果显示该系列化合物具有很好的TLR4抑制活性，具有良好的开发潜力。
实施例5 SMU-XY1可抑制相关炎症因子影响实验
根据制造商的说明使用TNF-α测定试剂盒(Sigma-Aldrich)。将Raw 264.7细胞在6孔板(Thermo Scientific)中以1x106个细胞/孔的密度与3ml的RPMI1640培养基(补充有10％FBS，青霉素(100U/ml)和链霉素(100mg/ml)]，在37℃，5％CO 2加湿培养箱中培养24小时。24小时后，除去未贴壁细胞和培养基，用新的RPMI 1640培养基(每孔3ml，不含FBS和链霉素、青霉素)代替。用指定浓度的SMU-XY1处理细胞，阳性对照为(40ng/ml)LPS(InvivoGen)。温育24小时后，收集细胞培养上清液至-80℃冰箱内，以备测量细胞因子。使用细胞因子特异性抗体，检测抗体和重组人细胞因子来定量TNF-α细胞因子。每个样品中的细胞因子进行测定重复三次。
该结果能有效的抑制细胞内TNF-α炎症因子的释放。结果参见图8。
实施例6 SMU-XY1可抑制Raw 264.7和BV-2细胞系中NO信号实验。
将Raw 264.7细胞(小鼠白血病单核细胞巨噬细胞系)在补充有10％FBS，青霉素(100U/ml)和链霉素(100mg/ml)的RPMI1640的培养基中培养，每孔40,000个细胞接种于96孔板上，并在37℃，5％CO2加湿培养箱中预孵育24小时。除去未粘附的细胞并在培养24小时后用不添加FBS和青霉素、链霉素的RPMI 1640培养基代替。用20μL(20ng/ml)LPS(InvivoGen)和不同浓度的SMU-XY1处理粘附的巨噬细胞。然后将细胞再温育24小时。收集100μL培养基并加入黑色96孔微量荧光平板(Thermo Scientific)中。向每孔中加入10μL2,3-二氨基萘(0.62M HCl水溶液中0.05mg/ml)避光孵育15分钟。通过加入5μL 3M NaOH水溶液终止反应，并在具有450nm的Beckman Coulter DTX 880阅读器上读板。从亚硝酸盐标准曲线的比色测定亚硝酸盐(NO的稳定代谢物)浓度并换算。
Toll样受体4(TLR4)在肿瘤的广泛表达提示其在慢性炎症致瘤机制中发挥重要作用。活化肿瘤细胞TLR4不仅促进肿瘤的生成，而且参与肿瘤的免疫逃逸。同时，TLR4配体LPS能够促进多种肿瘤细胞的侵袭以及转移能力。TLR4配体促进肿瘤转移的机制主要包括MyD88-NF-κB信号通路的活化，细胞因子(TNF-α、IL-6)等的释放以及iNOS的产生。因此本实验通过验证TLR4分泌性碱性磷酸酶的信号，来验证是否抑制其下游通路。对TNF-α细胞因子也有明显的抑制作用。在多种细胞中，也有着明显抑制NO信号的能力。这对抑制肿瘤逃逸，抑制肿瘤细胞增长是有明显作用的。具体实验结果参见图9和10。
Claims (4)
1.式I所示的化合物或其可药用的盐，
其选自如下化合物：
2.权利要求1所述化合物的制备方法，包括下述步骤：
1)化合物a
在碱性条件下与化合物b
取代反应得到化合物c
2)多聚甲醛、甲胺盐酸盐和化合物c在有机溶剂中回流反应得到化合物d
3)化合物e
在间氯过氧苯甲酸条件下氧化得到化合物f
4)化合物f与4-羟基咔唑在碱性条件下反应得到化合物h
5)将化合物d与化合物h在有机溶剂中回流得到式I化合物；
R1、R2、n分别如权利要求1的化合物结构式中所示。
3.一种药物组合物，其包括权利要求1中所述化合物或其药可用的盐，其还包括药学上可接受的载体或辅料。
4.根据权利要求1所述的化合物在制备佐剂、抗炎、TLR4抑制剂、抗肿瘤或心力衰竭的药物中的应用。
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| WO2011150162A1 (en) * | 2010-05-27 | 2011-12-01 | Ptc Therapeutics, Inc. | Methods for treating viral conditions |
| WO2017038909A1 (en) * | 2015-08-28 | 2017-03-09 | Takeda Pharmaceutical Company Limited | Heterocyclic compounds |
| CN106518750A (zh) * | 2015-09-15 | 2017-03-22 | 中国疾病预防控制中心寄生虫病预防控制所 | 咔唑氨基醇类化合物及其制备方法和抗寄生虫病的用途 |
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| WO2011150162A1 (en) * | 2010-05-27 | 2011-12-01 | Ptc Therapeutics, Inc. | Methods for treating viral conditions |
| WO2017038909A1 (en) * | 2015-08-28 | 2017-03-09 | Takeda Pharmaceutical Company Limited | Heterocyclic compounds |
| CN106518750A (zh) * | 2015-09-15 | 2017-03-22 | 中国疾病预防控制中心寄生虫病预防控制所 | 咔唑氨基醇类化合物及其制备方法和抗寄生虫病的用途 |
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