CN115403625A - S-DACOs类非核苷类逆转录酶抑制剂衍生物及其用途 - Google Patents
S-DACOs类非核苷类逆转录酶抑制剂衍生物及其用途 Download PDFInfo
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Abstract
Description
技术领域
本发明属于医药领域,具体涉及S-DACOs类非核苷类逆转录酶抑制剂(NNRTIs)的衍生物及其应用,可作为HIV-1抑制剂并用于制备治疗和/或预防免疫缺陷病毒(HIV)的药物。
背景技术
获得性免疫缺陷综合征(Acquired immunodeficiency syndrome,AIDS)是由人类免疫缺陷病毒(human immunodeficiency virus,HIV)引起人体内的免疫系统逐渐衰竭的疾病,简称艾滋病。自1981年报告第一例艾滋病毒病例开始,HIV在全球范围内蔓延开来,死亡人数已经超过2000万人。鸡尾酒疗法虽能够有效的抑制HIV病毒的复制,降低死亡率,但仍无法彻底清除HIV病毒,故研发出高效低毒、价格低廉的抗HIV药物是治疗艾滋病中急需解决的问题。逆转录酶(RT)催化的逆转录是HIV生命周期的关键阶段,在此期间遗传信息由病毒RNA单链传到宿主细胞DNA双链,一直是药物学家研究抗HIV药物的焦点。逆转录酶抑制剂分为核苷类(NRTls)和非核苷类(NNRTls)两种,而NNRTls因其低毒、高效的特点一直是抗HIV药物研究的热点。
S-DACOs类NNRTIs是本课题组利用计算机辅助药物分子设计的方法,设计合成的一类抗HIV活性化合物,该类化合物可在较低纳摩尔范围内抑制HIV复制,且细胞毒性较低,具有优异的选择性指数。然而,S-DACOs类化合物由于结构中含大量的疏水基团,水溶性较差,导致生物利用度低,影响了其成药性。DB02是S-DACOs类化合物中抗HIV活性最佳的分子,其对多种HIV-1实验株和突变株有很高的抑制活性,但其水溶性较差(S=0.38μM),药代动力学性质不理想,限制了其进一步开发应用。
经分子对接研究发现,以DB02为代表的S-DACO类抑制剂与RT酶间的结合力主要是(1)C-2位β-羰基、3-NH与周围氨基酸残基间的氢键作用;(2)C-6位环己基及C-2侧链末端芳环与周围氨基酸残基的疏水作用和范德华力(图1)。同时我们注意到:DB02的C-2侧链则位于P236与V106等氨基酸残基所组成的柔性疏水口袋中,其末端苯环接近RT酶活性口袋的开口处,周围有较大空间可容纳结构多样的取代基,是调节活性分子的物理化学和药代动力学性质的重要结构修饰位点。
发明内容
本发明提供了一类具有较好水溶性、具有更佳的脂水分配系数、具有很强的抗HIV活性的S-DACOs类非核苷类逆转录酶抑制剂(NNRTIs)衍生物,其结构式如式Ⅰ所示:
本发明基于分子对接分析,对S-DACOs的C-2末端苯环进行结构修饰,引入合适的取代基,在保留高效抗HIV活性的同时,改善药物的脂水分配系数,提高其成药性。
本发明的S-DACOs类非核苷类逆转录酶抑制剂衍生物可作为HIV-1抑制剂并用于制备治疗和/或预防免疫缺陷病毒(HIV)感染的药物。
本发明S-DACOs类非核苷类逆转录酶抑制剂衍生物还包括S-DACOs类非核苷类逆转录酶抑制剂衍生物药学上可接受的盐。
本发明S-DACOs类NNRTIs衍生物选自如下任一化合物:
所述化合物3与磷酰氯类化合物5的摩尔比为1:1~4;碱性试剂为三乙胺、K2CO3、NaHCO3、NaH、NaOCH3、NaOEt和Et3N中的一种或几种;溶剂是四氢呋喃、甲苯、乙腈、二氯甲烷、二甲基甲酰胺、吡啶中的一种或几种。
反应进程中可以采用本领域中的常规测试方法(例如TLC、HPLC或NMR)进行监测,一般以原料消失或不再反应为反应的终点,反应时间为1-4小时;
上述反应中,化合物3是在溶剂、弱碱性试剂存在的条件下,将化合物1与对羟基溴代苯乙酮进行反应制得,反应式如下:
所述化合物1溶解于DMF中,加入弱碱性试剂K2CO3,搅拌后加入对羟基溴代苯乙酮与DMF的混合溶液,继续搅拌反应,反应结束后,将反应液倒入冰水中,剧烈搅拌,产生白色浑浊,过滤,滤饼用冰水洗3次,烘干得化合物3粗产品,可不经纯化直接用于下一步反应。
本发明中,化合物1可采用有机化学领域普通技术人员熟知的方法制备得到,本发明中具体可参考Yan-Ping He,Jin Long,et al.Bioorg.&Med.Chem.2011,21,694~697,其中第695页第三段;以及Zhi-Kun Rao,Jing Long,et al.Monatsh Chem.2008,139,967-974,其具体合成路线如下所示:
本发明中,磷酰氯类化合物5是将二烷基亚磷脂酸脂4用CCl4溶解,缓慢加入TEA,室温搅拌30分钟后,反应结束后,将反应液过滤,滤饼用乙腈洗3次,滤液减压蒸馏得到化合物5;
其中,R1,R2,Rb的定义均同前所述。
根据本发明公开的上述制备方法,本领域技术人员可采用与之相同的原理和方法,制得本发明式Ⅰ所示化合物中涉及的各具体化合物。
本发明中式Ⅰ所示化合物,当Ra为NH2、SO2Me时可采用如下方法制备:
本发明的优点和技术效果:
1、本发明化合物制备方法简单,可实现工业化生产;
2、本发明化合物经过体外细胞水平抗HIV活性实验证明,具有显著抗HIV活性,其对HIVIII的抑制活性优于先导化合物DB02及阳性对照3TC;
3、本发明的S-DACOs类衍生物水溶性明显提高,采用molinspiration软件计算结果表明,其具备更佳脂水分配系数、药代动力学性质优于现有的S-DACOs类NNRTIs。
附图说明
图1为DB02/HIV RT复合物模型。
具体实施方式
下面通过实施例对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例方式,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。原料可以从商业途径获得,或者通过本领域已知的方法制备,或根据本文所述方法制备。化合物的结构通过核磁共振(1H NMR或13C NMR)和质谱(MS)来确定,其中NMR测定使用Bruker DRX 400型核磁共振仪,测定溶剂为氘代吡啶(C5D5N),TMS为内标。
实施例1:目标化合物I-1~I-8的制备
于100mL干燥双口圆底烧瓶内加入10mmol磷酰氯5和6mmol TEA,然后用50mL DCM溶解,冰浴下加入10mmol化合物3,加完撤掉冰浴,室温下反应2小时,TLC跟踪至反应完全,加入1mol/L HCl溶液淬灭反应,去除下层有机相,上层溶液用50mL DCM萃取3-4次,合并有机相,加入50mL饱和碳酸氢钠溶液中和剩余的酸,再用50mL饱和食盐水洗涤3次,无水硫酸钠干燥,减压蒸馏得粗产物,然后经硅胶柱层析(洗脱液乙酸乙酯:石油醚=5:1)分离纯化得到目标化合物I-1的白色粉末固体,产率:38%;
1H NMR(400MHz,Pyridine-d5)δ(ppm):10.41(s,1H,-NH),7.93(d,J=8.5Hz,2H,Ph-H),6.87(d,J=8.5Hz,2H,Ph-H),4.58(s,2H,CH2-S),2.29(q,J=7.3Hz,2H,CH2),2.10(d,J=6.3Hz,2H,CH2-Cyclohexyl),1.47(d,J=8.6Hz,3H,Cyclohexyl),1.30(d,J=13.2Hz,3H,Cyclohexyl),0.99–0.84(m,6H,overlap),0.71(q,J=11.5Hz,2H,Cyclohexyl);HR-MS:m/z calcd.for C21H27N2O6PS[M+H]+:467.1405;found 467.1401.
式I-2到式I-8化合物的制备方法与式I-1化合物的制备不同之处仅在于中间体3或磷酰氯类化合物5不同,其中中间体3分别为 磷酰氯类化合物5分别为 除此之外,其余制备方法与本实施例的式I-1化合物的制备方法相同。
制备得到的式I-2到式I-8化合物的性状、产率以及结构表征结果如下:
操作如上,得白色粉末固体I-2,产率:55%;
1H NMR(400MHz,Pyridine-d5)δ(ppm):8.13(d,J=8.7Hz,2H,Ph-H),7.39(d,J=8.2Hz,2H,Ph-H),4.65(s,2H,CH2-S),3.84(s,3H,CH3-O),3.81(s,3H,CH3-O),2.29(q,J=7.2Hz,2H,CH2),2.07(d,J=6.4Hz,2H,CH2-Cyclohexyl),1.47–1.44(m,3H,Cyclohexyl),1.26–1.23(m,4H,Cyclohexyl),0.92(t,J=7.3Hz,3H,Et),0.87–0.61(m,4H,Cyclohexyl);HR-MS:m/z calcd.for C23H31N2O6PS[M+H]+:495.1713;found 495.1707.
操作如上,得白色粉末固体I-3,产率:55%;
1H NMR(400MHz,Pyridine-d5)δ(ppm):8.13(d,J=8.6Hz,2H,Ph-H),7.38(d,J=8.5Hz,2H,Ph-H),4.65(s,2H,CH2-S),4.19(q,J=8.0,7.6Hz,4H,CH2),2.29(q,J=7.1Hz,2H,CH2),2.07(d,J=6.2Hz,2H,CH2-Cyclohexyl),1.46–1.44(m,3H,Cyclohexyl),1.29–1.23(m,11H,overlap),0.93–0.85(m,4H,Cyclohexyl),0.71–0.67(m,2H,Cyclohexyl);HR-MS:m/z calcd.for C25H35N2O6PS[M+H]+:523.2026;found 523.2031.
操作如上,得白色粉末固体I-4,产率:41%;
1H NMR(400MHz,Pyridine-d5)δ(ppm):8.13(d,J=8.5Hz,2H,Ph-H),7.37(d,J=8.5Hz,2H,Ph-H),4.64(s,2H,CH2-S),4.12(q,J=6.7Hz,4H,CH2-O),2.28(q,J=6.9Hz,2H,CH2),2.06(d,J=6.2Hz,2H,CH2-Cyclohexyl),1.66–1.58(m,4H,CH2),1.46–1.44(m,3H,Cyclohexyl),1.38–1.30(m,4H,CH2),1.30–1.14(m,4H,Cyclohexyl),0.89(m,11H,overlap),0.71–0.62(m,2H,Cyclohexyl);HR-MS:m/z calcd.for C29H43N2O6PS[M+H]+:579.2632;found 579.2635.
操作如上,得白色粉末固体I-5,产率:53%;
1H NMR(400MHz,Pyridine-d5)δ(ppm):8.13(d,J=8.7Hz,2H,Ph-H),7.38(d,J=8.3Hz,2H,Ph-H),4.64(s,2H,CH2-S),2.29(s,3H,CH3),2.08(d,J=6.3Hz,2H,CH2-Cyclohexyl),1.52–1.43(m,3H,Cyclohexyl),1.35–1.21(m,8H,Cyclohexyl);HR-MS:m/zcalcd.for C20H25N2O6PS[M+H]+:453.1235;found 453.1237.
操作如上,得白色粉末固体I-6,产率:58%;
1H NMR(400MHz,Pyridine-d5)δ(ppm):8.13(d,J=8.7Hz,2H,Ph-H),7.38(d,J=8.3Hz,2H,Ph-H),4.64(s,2H,CH2-S),3.59(s,6H,O-CH3),2.28(s,3H,CH3),2.08(d,J=6.3Hz,2H,CH2-Cyclohexyl),1.46–1.44(m,3H,Cyclohexyl),1.30–1.13(m,5H,Cyclohexyl),0.71–0.63(m,3H,Cyclohexyl);HR-MS:m/z calcd.for C22H29N2O6PS[M+H]+:481.1562;found 481.1563.
操作如上,得白色粉末固体I-7,产率:50%
1H NMR(400MHz,Pyridine-d5)δ(ppm):7.92(d,J=8.5Hz,2H,Ph-H),6.87(d,J=8.6Hz,2H,Ph-H),4.59(s,2H,CH2-S),2.33(m,1H,CH),2.11(d,J=6.3Hz,2H,CH2-Cyclohexyl),1.47(d,J=8.6Hz,3H,Cyclohexyl),1.30(d,J=13.2Hz,3H,Cyclohexyl),0.97–0.79(m,9H,overlap),0.71(q,J=11.5Hz,2H,Cyclohexyl);HR-MS:m/z calcd.forC22H29N2O6PS[M+H]+:481.1518;found 481.1515.
操作如上,得白色粉末固体I-8,产率:47%;
1H NMR(400MHz,Pyridine-d5)δ(ppm):8.12(d,J=8.6Hz,2H,Ph-H),7.39(d,J=8.3Hz,2H,Ph-H),4.66(s,2H,CH2-S),3.83(s,3H,CH3-O),3.82(s,3H,CH3-O),2.29(m,1H,CH),2.07(d,J=6.4Hz,2H,CH2-Cyclohexyl),1.47–1.44(m,3H,Cyclohexyl),1.27–1.23(m,4H,Cyclohexyl),0.92(m,6H,CH3),0.87–0.61(m,4H,Cyclohexyl);HR-MS:m/zcalcd.for C24H33N2O6PS[M+H]+:509.1801;found 509.1803.
实施例2:目标化合物I-9的制备
取5-乙基-6环已甲基-2-硫尿嘧啶(0.01mol)置于25mL圆底烧瓶,用10mL干燥的DMF溶解后,加入0.012mol无水碳酸钾,搅拌1h后加入0.01mol对甲磺酰基溴代苯乙酮,TCL跟踪原料点消失后停止反应,将反应液倒入冰水中(50mL)并用乙酸乙酯(每次25mL)提取三次,合并有机相后用饱和食盐水(每次25mL)洗涤三次,无水硫酸钠干燥,减压旋干后通过柱层析可得到白色粉末固体I-9,产率:86%;
1H NMR(500MHz,Pyridine-d5,ppm)δ:8.50(2H,s,aromatic),8.39(2H,s,aromatic),5.00(2H,s,CH2-S),3.42(3H,s,CH3-Ph),2.64(2H,s,CH2-CH3),2.27(2H,s,CH2-CH),2.00-1.96(1H,m,CH),1.61-1.54(5H,m,cyclohexyl),1.19-1.02(6H,m,overlap),0.83-0.78(2H,m,cyclohexyl).HRMS-ESI:m/z calcd for C22H29N2O4S2[M+H]+:449.1563,found 449.1563.
实施例3:目标化合物I-10~I-13的制备
取0.01mol化合物I-A置于2mL圆底烧瓶并用20mL乙醇溶解后,加入0.05mol铁粉,再将0.1mol氯化铵溶解在5mL纯净水后逐滴加入反应液中,85℃回流反应2h后停止反应,将铁粉过滤并用乙醇滤洗三次,滤液倒入冰水中(50mL)并用乙酸乙酯提取三次(每次25mL),合并有机相后用饱和食盐水(每次25mL)洗涤三次,无水硫酸钠干燥,减压旋干后通过硅胶柱层析或重结晶即可得到化合物I-10~I-13;
淡黄色固体,产率68%。1H NMR(400MHz,Pyridine-d5,ppm)δ:8.24-8.22(2H,d,J=8.8Hz,aromatic),7.01-6.99(2H,d,J=8.4Hz,aromatic),6.88(2H,s,NH2),4.96(2H,s,CH2-S),2.69-2.64(2H,q,J=7.2Hz,CH2-CH3),2.42-2.41(2H,d,J=7.2Hz,CH2-CH),1.89-1.85(1H,m,CH),1.67-1.54(5H,m,cyclohexyl),1.24-1.10(6H,m,overlap),0.96-0.88(2H,m,cyclohexyl).HRMS-ESI:m/z calcd for C21H28N3O2S[M+H]+:386.1897,found386.1895.
黄色固体,产率60%.1H NMR(400MHz,Pyridine-d5,ppm)δ:7.85(1H,s,aromatic),7.64-7.62(2H,d,J=8.0Hz,aromatic),7.38-7.34(2H,t,J=7.80Hz,aromatic),6.88(2H,s,NH2),4.95(2H,s,CH2-S),2.67-2.62(2H,t,J=7.3Hz,CH2-CH3),2.38-2.36(2H,q,J=6.8Hz,CH2-CH3),1.84-1.75(1H,m,CH),1.62-1.56(5H,m,cyclohexyl),1.26-1.22(6H,m,overlap),0.93-0.80(2H,m,cyclohexyl).HRMS-ESI:m/zcalcd for C21H28N3O2S[M+H]+386.1897,found 386.1898.
黄色固体,产率56%.1H NMR(400MHz,Pyridine-d5,ppm)δ:8.16-8.14(2H,d,J=8.0Hz,aromatic),8.16-8.14(2H,s,NH2),7.38-7.34(2H,t,J=7.6Hz,aromatic),7.07-7.05(2H,d,J=8.8Hz,aromatic),6.74-6.70(2H,t,J=8.0Hz,aromatic),5.00(2H,s,CH2-S),2.70-2.64(2H,q,J=7.3Hz,CH2-CH3),2.43-2.41(2H,d,J=7.2Hz,CH2cyclohexyl),1.88-1.82(1H,m,CH),1.66-1.55(5H,m,cyclohexyl),1.24-1.08(6H,m,overlap),0.96-0.87(2H,m,cyclohexyl).HRMSESI:m/z calcd for C21H28N3O2S[M+H]+386.1897,found386.1897.
黄色固体,产率60%.1H NMR(400MHz,Pyridine-d5,ppm)δ:7.85(1H,s,aromatic),7.65-7.63(2H,d,J=8.0Hz,aromatic),7.38-7.35(2H,t,J=7.80Hz,aromatic),6.88(2H,s,NH2),4.95(2H,s,CH2-S),3.26-2.91(1H,m,CHMe2),2.43-2.41(2H,d,J=7.2Hz,CH2cyclohexyl),1.84-1.75(1H,m,CH),1.62-1.56(5H,m,cyclohexyl),1.26-1.29(9H,m,overlap),0.91-0.78(2H,m,cyclohexyl).HRMS-ESI:m/z calcd forC22H29N3O2S[M+H]+400.5534,found 400.5528.
实施例4:目标化合物I-14的制备
取50mL圆底烧瓶,加入1mmol化合物I-11,加入5mL CH2Cl2搅拌直至完全溶解后,通入饱和量的HCl气体,常温搅拌有固体析出,TLC检测原料点消失,停止反应,过滤,用乙醇重结晶得I-14纯品。
浅黄色固体,产率95%.1H NMR(400MHz,Pyridine-d5,ppm)δ:7.83(1H,s,aromatic),7.62-7.60(2H,d,J=8.0Hz,aromatic),7.37-7.32(2H,t,J=7.80Hz,aromatic),6.87(2H,s,NH2),6.58(bra,HCl),4.92(2H,s,CH2-S),2.65-2.61(2H,t,J=7.3Hz,CH2-CH3),2.36-2.34(2H,q,J=6.8Hz,CH2-CH3),1.82-1.73(1H,m,CH),1.61-1.56(5H,m,cyclohexyl),1.24-1.20(6H,m,overlap),0.92-0.78(2H,m,cyclohexyl).HRMS-ESI:m/z calcd for C21H29ClN3O2S[M+H]+422.6477,found 422.6474.
实施例5:抗HIV-1活性测试
体外细胞水平抗HIV-1活性测试:采用MTT比色法测定上述制备的化合物对C8166细胞的毒性,计算存活率以及对50%的细胞产生毒性时的浓度(50%cytotoxicconcentration,CC50)。测定化合物对HIV诱导的细胞病变的保护作用,计算抑制率以及抑制50%的合胞体形成时的浓度(50%effective concentration,EC50)。然后,计算治疗指数TI值(CC50/EC50),具体方法如下:
细胞毒性实验:对待测化合物进行5倍稀释,共6个梯度,在96孔板中,每孔加入100μL化合物,且设置复孔3个,然后每孔加入4×104个C8166细胞悬液100μL,3TC为阳性对照药物,同时设置仅含有细胞的阴性对照和仅含培养基的空白对照;在37℃、5%CO2培养箱中培养3天后,每孔加入20μL MTT溶液(5μg/mL)孵育4h,每孔弃100μL上清,再加入12%SDS-50%DMF溶液,培养过夜;采用EL×800酶标仪测定OD值,测定波长为570nm/630nm,计算细胞存活率和CC50值。
合胞体形成抑制实验:将待测化合物5倍梯度稀释后,每孔100μL加入96孔板内,然后每孔加入100μL含4×104个C8166细胞和HIV-1ⅢB的混悬液(MOI=0.03),设置复孔3个,同时设置仅含细胞病毒混悬液的对照孔,3TC为阳性药物对照;然后在37℃、5%CO2培养3天,在倒置显微镜下(100×)计数合胞体,并计算抑制率及EC50值。
本发明用3TC作阳性对照药物,目标化合物对HIV-1IIIB的抑制活性结果见表2:
表2化合物抗HIV-1ⅢB病毒活性
由表2可见,S-DACOs磷酸酯衍生物具有优良的抗HIVIII活性,除化合物I-5、I-6外,其余化合物的EC50值均低于先导化合物DB02(EC50=0.2μM),其中化合物I-2和I-3较阳性对照3TC的活性分别提高了2.2倍和11倍。在DB02嘧啶环C-2侧链末端苯环上引入氨基(-NH2)及甲磺酰基(-SO2Me)同样使其抗HIV活性有了显著提高,化合物I-9~I-14的活性较先导化合物DB02及阳性对照3TC的提高了3.7至50倍。
实施例6:药物溶解度检测及药代动力学性质评估
在纯水中加入磷酸二氢钠、磷酸氢二钠和氢氧化钠配制pH=7.4、100mM的缓冲溶液;在792μL缓冲溶液中加入8μL标准品(Ketoconazole)和10mM测试化合物原液,样品管在室温下在1000rpm的摇床上摇动1h;在甲醇:ACN(体积比4:1)溶液中制备标准曲线;将样品管离心处理,上清液用上述缓冲溶液分别稀释10倍和100倍;将5μL样品和标准曲线样品(不稀释,稀释10倍、稀释100倍)加入95μL乙腈(含IS)中制备HPLC样品,经HPLC检测、计算得到化合物溶解度;由此方法测得本发明部分化合物的溶解度如表3所示。
“五倍率法则”即“Lipinski五倍率法则”是评估一个化合物能否作为药物,或者一个具有药理学活性或生物学活性的化合物能否成为口服药物的经验法则。该法则指出具有成药性的化合物,其脂水分配系数的对数值(ClogP)不大于5;一般如果化合物的ClogP值处于2~4之间,则预示着其具有良好的药代动力学性质;采用molinspiration软件计算化合物I-1~I-14的CLogP,结果如表3所示:
表3化合物溶解度及CLogP值
由表3可见,经磷酸化修饰后,化合物I-1~I-8的水溶性较DB02提高了443~7倍,除I-4外;甲磺酰基衍生物I-9的溶解度较DB02提高了158倍。氨基衍生物I-10~I-13的溶解性虽较DB02仅提高了约16倍,利用氨基的碱性制备而得的盐酸盐I-14,其溶解度为137.21μmol/L,较DB02提高了361倍。采用molinspiration软件计算结果表明,表3所示14个S-DACOs类NNRTIs衍生物的ClogP值较DB02都有所降低,特别是化合物I-1、I-5、I-6、I-7和I-9的ClogP在2.25~3.91区间,预示着这些化合物具有优良的药代动力学性质。
申请人声明,本发明通过上述实施例来说明本发明的一种S-DACOs类NNRTIs的衍生物及用途,但本发明并不局限于上述实施例,即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等,均落在本发明的保护范围和公开范围内。
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