CN108218896B - 一种噻唑并嘧啶类hiv-1逆转录酶抑制剂及其制备方法和应用 - Google Patents
一种噻唑并嘧啶类hiv-1逆转录酶抑制剂及其制备方法和应用 Download PDFInfo
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- CN108218896B CN108218896B CN201810336409.9A CN201810336409A CN108218896B CN 108218896 B CN108218896 B CN 108218896B CN 201810336409 A CN201810336409 A CN 201810336409A CN 108218896 B CN108218896 B CN 108218896B
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- thiazolopyrimidine
- reverse transcriptase
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Abstract
本发明涉及一种噻唑并嘧啶类HIV‑1逆转录酶抑制剂及其制备方法和应用。所述化合物具有式I或II的所示的结构。本发明还涉及含有式I或II结构化合物的药物组合物。本发明还提供上述化合物以及含有一个或多个此类化合物的组合物在制备治疗和预防人免疫缺陷病毒(HIV)药物中的应用。
Description
技术领域
本发明属于有机化合物合成与医药应用技术领域,具体涉及一种噻唑并嘧啶类HIV-1逆转录酶抑制剂及其制备方法和应用。
背景技术
艾滋病(Acquired Immune Deficiency Syndrome,AIDS)主要是由人体免疫缺陷病毒1型(HIV-1)感染引起,属于严重危害人类健康的重大疾病之一。在HIV-1的生命周期中,逆转录酶(reverse transcriptase,RT)负责将携带病毒遗传信息的单链RNA逆转录成双链DNA,是抗艾滋病药物设计的关键靶标。HIV-1逆转录酶抑制剂(NNRTIs)具有高效低毒、特异性强的优点,是高效抗逆转录疗法(Highly Active Antiretroviral Therapy,HAART)疗法的重要组成部分。尽管HAART的实施显著延长患者的生存时间,但长期服用带来的耐药和药物毒副作用等问题,迫使研究者研发高效低毒的新型HIV-1抑制剂。
二芳基嘧啶(diarylpyrimidine,DAPY)类是一类具有高效抗耐药性的HIV-1NNRTIs,最新一代HIV-1上市药物依曲韦林(Etravirine)和利匹韦林(Rilpivirne)均属于此类化合物。但该类化合物由于含有过多的脂溶性芳环结构,导致该类化合物的水溶性和口服生物利用度很低,口服剂量大,在临床使用中也引起了严重的毒副作用和交叉耐药等问题。例如,依曲韦林需要每日多次给药,且伴随着严重的皮肤过敏反应。利匹韦林会引起抑郁、急性呼吸窘迫综合征、头痛及皮疹等毒副作用,大大限制了它们的临床应用。因此,新一代高效抗耐药性NNRTIs的研发是目前抗艾滋病药物研究的重大科研任务。
发明内容
针对现有技术的不足,本发明提供了一种噻唑并嘧啶类HIV-1逆转录酶抑制剂及其制备方法,本发明还提供上述化合物作为HIV-1逆转录酶抑制剂的活性筛选结果及其应用。
本发明的技术方案如下:
1.噻唑并嘧啶类HIV-1逆转录酶抑制剂
一种噻唑并嘧啶类HIV-1逆转录酶抑制剂,或其药学上可接受的盐,具有通式Ⅰ或Ⅱ所示的结构:
其中,
X为:O或者NH;
R为:CH3,CN或者CH=CHCN;
Ar为:苯基或吡啶基;或SO2NH2,SO2NH2CH3,SO2NH(CH2)3,SO2NH(CH2)2O,SO2CH3,CONH2,卤素,NO2,CN,NH2,CF3,NHCH3,OH,COOH,CH2OH,CO2Me,OCH3,NHCOCH3取代的苯基;取代基为邻、间、对位单取代或多取代。
根据本发明优选的,噻唑并嘧啶类HIV-1逆转录酶抑制剂是下列化合物之一:
本发明中所述的“药学上可接受的盐”是指在可靠的医药评价范围内,化合物的盐类适于与人或较低等动物的组织相接触而无不适当的毒性、刺激及过敏反应等,具有相当合理的收益与风险比例,通常是水或油可溶的或可分散的,并可有效地用于其预期的用途。包括药学上可接受的酸加成盐和药学上可接受的碱加成盐,在这里是可做预期的用途并与式I化合物的化学性质相容的。适宜的盐的列表参见S.M.Birge等,J.Pharm.Sci.,1977,66,1-19页。
2.噻唑并嘧啶类HIV-1逆转录酶抑制剂的制备方法
噻唑并嘧啶类HIV-1逆转录酶抑制剂的制备方法,步骤包括:以2,4-二氯取代的噻唑并嘧啶1a或1b为初始原料,首先在N,N-二甲基甲酰胺溶液中与取代苯酚或苯胺经亲核取代生成中间体2a或2b;然后中间体2a或2b分别与N-Boc-4-氨基哌啶发生亲核取代反应生成中间体3a或3b,进而在三氟乙酸中脱去BOC保护得到中间体4a或4b;最后关键中间体4a或4b分别与各种取代氯苄或溴苄的反应生成目标产物5a或5b;合成路线如下:
试剂及条件:(i)取代苯酚或苯胺,N,N-二甲基甲酰胺,碳酸钾,室温;(ii)N-Boc-4-氨基哌啶,N,N-二甲基甲酰胺,碳酸钾,120℃;(iii)二氯甲烷,三氟乙酸,室温;(iv)取代氯苄或溴苄,N,N-二甲基甲酰胺,碳酸钾,室温。
X、R、Ar同上述通式I或II所示。
所述的取代苯酚或苯胺为:均三甲基苯酚,2,6-二甲基-4-氰基苯酚,2,6-二甲基-4-(E)-氰基乙烯基苯酚,均三甲基苯胺,2,6-二甲基-4-氰基苯胺,2,6-二甲基-4-(E)-氰基乙烯基苯胺。
所述的取代氯苄或溴苄为:邻氯氯苄、间氯氯苄、对氯氯苄、邻溴溴苄、间溴溴苄、对溴溴苄、邻氟氯苄、间氟氯苄、对氟氯苄、2,4-二氟溴苄、3,4-二氟溴苄、邻氰基氯苄、间氰基氯苄、对氰基氯苄、邻硝基氯苄、间硝基氯苄、对硝基氯苄、邻甲氧基氯苄、间甲氧基氯苄、对甲氧基氯苄、对甲磺酰基溴苄、间甲磺酰基溴苄、邻甲磺酰基溴苄、对磺酰胺基溴苄、间磺酰胺基溴苄、邻磺酰胺基溴苄、对甲酰胺基溴苄、间甲酰胺基溴苄、邻甲酰胺基溴苄、4-(溴甲基)苯甲酸甲酯、3-(溴甲基)苯甲酸甲酯、2-(溴甲基)苯甲酸甲酯。
本发明所述的室温为20-30℃。
3.噻唑并嘧啶类HIV-1逆转录酶抑制剂的抗HIV-1活性及应用
本发明对按照上述方法合成的部分噻唑并嘧啶类衍生物进行了细胞水平的抗HIV-1(IIIB),单耐药突变株L100I、K103N、Y181C、Y188L、E138K以及双耐药突变株F227L/V106A、RES056(K103N/Y181C)的活性筛选,以奈韦拉平(NVP)和依曲韦林(ETV)为阳性对照。它们的抗HIV-1活性和毒性数据分别列于表1和表2中。
由表1和表2可以看出,本发明的噻唑并嘧啶衍生物是一系列结构新颖的非核苷类HIV-1抑制剂,绝大部分化合物对HIV-1野生株具有优于上市药物ETV的活性,且多数化合物选择性指数大于10000,安全性极高。对HIV-1突变株,所有化合物均具有不同程度的抑制活性,其中化合物SZ1、SZ2、SZ6、SZ7、TZ1-4的活性尤为突出,对大多数突变株的活性均优于ETV。因此该类噻唑并嘧啶类化合物具有进一步研究与开发的价值,可作为抗HIV-1的先导化合物加以利用。
本发明的噻唑并嘧啶类HIV-1逆转录酶抑制剂可作为非核苷类HIV-1抑制剂应用。具体地说,作为HIV-1抑制剂用于制备抗艾滋病药物。
一种抗HIV-1药物组合物,包括本发明的噻唑并嘧啶类HIV-1逆转录酶抑制剂和一种或多种药学上可接受载体或赋形剂。
本发明提供了结构全新的噻唑并嘧啶类HIV-1逆转录酶抑制剂及其制备方法,本发明还提供了化合物抗HIV-1活性筛选结果及其在抗病毒领域中的首次应用。经过试验证明,本发明的噻唑并嘧啶类衍生物可作为HIV-1抑制剂应用并具有很高的应用价值。具体地说,作为HIV-1抑制剂用于制备抗艾滋病药物。
具体实施方式
通过下述实施例有助于理解本发明,但是不能限制本发明的内容。
实施例中所涉及的合成路线如下:
实施例1:4-((5-5-氯噻唑并[4,5-d]嘧啶-7-基)氧基)-3,5-二甲基苄腈(7a)的制备
称取4-羟基-3,5-二甲基苯腈(1.5g,10mmol)和碳酸钾(1.7g,12mmol)于30mL的DMF中,室温搅拌15分钟,然后加入5,7-二氯噻唑并[4,5-d]嘧啶6a(2.1g,10mmol)继续室温搅拌2h(TLC检测反应完毕)。待有大量白色固体生成,慢慢向其中加入100mL冰水,过滤,真空干燥箱干燥,乙醇重结晶得中间体7a。白色固体,收率94%,熔点250-253℃。1H NMR(400MHz,DMSO-d6)δ9.60(s,1H),7.78(s,2H),2.14(s,6H).HRMS:m/z 317.0255[M+1]+.C14H9ClN4OS(316.0186).
实施例2:3,5-二甲基-4-((5-(哌啶-4-基氨基)噻唑并[4,5-d]嘧啶-7-基)氧基)苯甲腈(9a)的制备
依次将7a(1.0g,3.17mmol),N-Boc-3-氟-4-氨基哌啶(0.83g,3.80mmol)与碳酸钾(0.87g,6.33mmol)加入到5mL的DMF中,然后加热回流10h(TLC检测)。待反应冷却至室温,慢慢将反应液滴加到50mL水中,有大量黄色固体生成。静置30min后过滤,真空干燥得粗品。称取该粗品(1.26g,2.53mmol)溶于4mL二氯甲烷中,加入2.22mL三氟乙酸(30mmol),室温条件下搅拌4h(TLC检测)。然后用饱和的碳酸氢钠溶液调节反应液PH为9,二氯甲烷萃取(3×5mL),饱和氯化钠溶液洗涤,分取有机层,无水硫酸钠干燥。然后进行快速柱层析分离得中间体9a。白色固体,收率64%,熔点130-132℃。1H NMR(400MHz,DMSO-d6)δ9.12(s,1H,thiazole-H),8.50(d,J=5.9Hz,1H,NH),7.67(s,2H,C3,C5-Ph-H),3.65–3.62(m,1H),2.78–2.76(m,2H),2.10(s,6H),1.86–1.75(m,2H),1.72–1.55(m,4H).HRMS:m/z 381.1489[M+1]+.C19H20N6OS(380.1419).
实施例3:4-((5-氯噻唑并[5,4-d]嘧啶-7-基)氧基)-3,5-二甲基苄腈(7b)的制备
合成步骤同7a,所不同的是选用5,7-二氯噻唑并[5,4-d]嘧啶(6a)为起始原料。白色固体,收率93%,熔点265-268℃。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),7.67(s,2H,C3,C5-Ph-H),2.14(s,6H).ESI-MS:m/z 317.0260[M+1]+.C14H9ClN4OS(316.0186).
实施例4:3,5-二甲基-4-((5-(哌啶-4-基氨基)噻唑并[5,4-d]嘧啶-7-基)氧基)苄腈(9b)的制备
合成步骤同9a,所不同的是选用4-((5-氯噻唑并[5,4-d]嘧啶-7-基)氧基)-3,5-二甲基苄腈(7a)为起始原料。白色固体,收率90%,熔点135-138℃。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H,thiazole-H),8.42(d,J=7.2Hz,1H,NH),7.67(s,2H,C3,C5-Ph-H),3.65–3.63(m,1H),2.79–2.78(m,2H),2.10(s,6H),1.86–1.82(m,2H),1.70–1.52(m,4H).HRMS:m/z381.1492[M+1]+.C19H20N6OS(380.1419).
实施例5:SZ1-9和TZ1-5的制备
称取化合物9a或9b(0.5mmol)于5mLDMF中,然后依次加入碳酸钾(0.14g,1.0mmol)与取代的氯苄或溴苄(0.6mmol),室温搅拌4-12h(TLC检测)。向反应液中加入饱和氯化钠溶液20mL,乙酸乙酯洗涤(3×10mL),分取有机层,无水硫酸钠干燥。然后经快速柱层析分离得到目标化合物粗品,进而在乙酸乙酯-石油醚体系中重结晶得到目标化合物SZ1-9和TZ1-5。
4-((4-((7-(4-氰基-2,6-二甲基苯氧基)噻唑并[4,5-d]嘧啶-5-基)氨基)哌啶-1-基)甲基)苯磺酰胺(SZ1)
白色固体,收率78%,熔点139-142℃。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H,thiazole-H),8.43(d,J=7.5Hz,1H,NH),7.79(d,J=7.8Hz,2H,C3,C5-Ph’-H),7.67(s,2H,C3,C5-Ph”-H),7.47(d,J=8.0Hz,2H,C2,C6-Ph’-H),7.32(s,2H,SO2NH2),3.67–3.64(m,1H),3.50(s,2H,N-CH2),2.81–2.67(m,2H),2.09(s,6H),1.88–1.75(m,2H),1.65–1.39(s,4H).13C NMR(100MHz,DMSO-d6)δ156.7,154.5,150.0,143.3,143.6,132.9,132.7,129.0,126.1,119.3,108.9,61.9,52.1,48.4,39.4,31.5,16.2.HRMS:m/z 550.1692[M+1]+.C26H27N7O3S2(549.1617).
4-((4-((7-(4-氰基-2,6-二甲基苯氧基)噻唑并[4,5-d]嘧啶-5-基)氨基)哌啶-1-基)甲基)-N-甲基苯磺酰胺(SZ2)
白色固体,收率58%,熔点120-123℃。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H,thiazole-H),8.95(s,1H,SO2NH),8.44(d,J=7.4Hz,1H,NH),7.73(d,J=7.7Hz,2H,C3,C5-Ph’-H),7.67(s,2H,C3,C5-Ph”-H),7.53(d,J=8.3Hz,2H,C2,C6-Ph’-H),3.67–3.64(m,1H),3.52(s,2H,N-CH2),3.34(s,3H),2.80–2.78(m,2H),2.10(s,6H),1.87(t,J=11.6Hz,2H),1.74–1.47(m,4H).13C NMR(100MHz,DMSO-d6)δ161.1,156.6,154.5,150.2,144.0,138.2,133.0,132.7,129.7,129.1,128.2,127.4,127.2,127.1,127.0,108.2,62.6,61.9,52.7,48.8,39.8,31.1,29.1,16.2.HRMS:m/z 564.1845[M+1]+.C27H29N7O3S2(563.1773).
4-((4-((7-(4-氰基-2,6-二甲基苯氧基)噻唑并[4,5-d]嘧啶-5-基)氨基)哌啶-1-基)甲基)-N-环丙级苯磺酰胺(SZ3)
白色固体,收率55%,熔点128-131℃。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H,thiazole-H),8.95(s,1H,SO2NH),8.44(d,J=7.5Hz,1H,NH),7.78(d,J=8.0Hz,2H,C3,C5-Ph’-H),7.67(s,2H,C3,C5-Ph”-H),7.53(d,J=8.6Hz,2H,C2,C6-Ph’-H),3.67–3.64(m,1H),3.53(s,2H,N-CH2),2.80–2.78(m,2H),2.27–2.26(m,1H),2.10(s,6H),1.92–1.52(m,4H),1.42–1.29(m,2H),0.47(dd,J=7.0,3.9Hz,2H),0.38(t,J=3.7Hz,2H).13C NMR(100MHz,DMSO-d6)δ161.1,156.6,154.5,150.2,144.0,139.2,133.0,132.7,130.4,129.6,128.2,127.2,119.2,61.9,52.7,48.8,31.5,31.1,29.1,26.8,24.5,16.2,5.6.HRMS:m/z590.2008[M+1]+.C29H31N7O3S2(589.1930).
3,5-二甲基-4-((5-((1-(4-(吗啉代磺酰基)苄基)哌啶-4-基)氨基)噻唑并[4,5-d]嘧啶-7-基)氧基)苯甲腈(SZ4)
白色固体,收率57%,熔点114-117℃。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H,thiazole-H),8.44(d,J=7.5Hz,1H,NH),7.71(d,J=9.3Hz,2H,C3,C5-Ph’-H),7.67(s,2H,C3,C5-Ph”-H),7.59(d,J=8.3Hz,2H,C2,C6-Ph’-H),3.67–3.64(m,1H),3.63(d,J=4.7Hz,4H),3.56(s,2H,N-CH2),2.86(d,J=4.8Hz,4H),2.80–2.79(m,2H),2.10(s,6H),1.96–1.76(m,2H),1.75–1.52(m,4H).13C NMR(100MHz,DMSO-d6)δ161.1,154.5,150.2,145.1,133.3,133.0,132.7,129.8,128.2,128.2,128.1,108.2,65.7,61.8,52.8,48.8,46.3,39.6,31.1,16.2.HRMS:m/z 620.2111[M+1]+.C30H33N7O4S2(619.2035).
4-((4-((7-(4-氰基-2,6-二甲基苯氧基)噻唑并[4,5-d]嘧啶-5-基)氨基)哌啶-1-基)甲基)苯甲酰胺(SZ5)
白色固体,收率51%,熔点172-174℃。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H,thiazole-H),8.43(d,J=7.5Hz,1H,NH),7.80(d,J=7.8Hz,2H,C3,C5-Ph’-H),7.67(s,2H,C3,C5-Ph”-H),7.45(d,J=8.0Hz,2H,C2,C6-Ph’-H),7.31(s,2H,CONH2),3.68–3.64(m,1H),3.48(s,2H,N-CH2),2.80–2.77(m,2H),2.10(s,6H),1.92–1.78(m,2H),1.70–1.59(m,4H).13C NMR(100MHz,DMSO-d6)δ168.2,161.0,156.5,154.7,150.9,142.2,133.7,133.1,132.7,129.0,127.7,119.2,108.8,62.2,52.4,48.9,39.6,39.3,31.1,16.2.HRMS:m/z514.2020[M+1]+.C27H27N7O2S(513.1947).
3,5-二甲基-4-((5-((1-(4-(甲基磺酰基)苄基)哌啶-4-基)氨基)噻唑并[4,5-d]嘧啶-7-基)氧基)苯甲腈(SZ6)
白色固体,收率76%,熔点118-120℃。1H NMR(400MHz,DMSO-d6)δ9.07(s,1H,thiazole-H),8.44(d,J=7.5Hz,1H,NH),7.88(d,J=8.1Hz,2H,C3,C5-Ph’-H),7.67(s,2H,C3,C5-Ph”-H),7.59(d,J=8.1Hz,2H,C2,C6-Ph’-H),3.65–3.63(m,1H),3.55(s,2H,N-CH2),3.22(s,3H,SO2CH3),2.78(d,J=11.4Hz,2H),2.10(s,6H),1.99–1.83(m,3H),1.77–1.60(m,3H).13C NMR(100MHz,DMSO-d6)δ163.3,160.3,154.4,150.2,145.4,145.3,139.8,139.8,139.5,133.0,132.7,129.8,127.4,119.0,108.9,108.2,62.6,61.8,52.7,48.8,44.1,44.0,39.4,31.5,31.1,16.2.HRMS:m/z 549.1737[M+1]+.C27H28N6O3S2(548.1664).
3,5-二甲基-4-((5-((1-(吡啶-4-基甲基)哌啶-4-基)氨基)噻唑并[4,5-d]嘧啶-7-基)氧基)苄腈(SZ7)
白色固体,收率52%,熔点118-120℃。1H NMR(400MHz,DMSO-d6)δ9.07(s,1H,thiazole-H),8.52(d,J=5.9Hz,1H,NH),8.46(d,J=7.5Hz,2H,C3,C5-Ph’-H),7.67(s,2H,C3,C5-Ph”-H),7.32(d,J=7.2Hz,2H,C2,C6-Ph’-H),3.65(dt,J=8.2,5.6Hz,1H),3.48(s,2H,N-CH2),2.78–2.76(m,2H),2.10(s,6H),1.86(dd,J=11.8,2.7Hz,2H),1.72–1.55(m,4H).13C NMR(100MHz,DMSO-d6)δ163.3,161.1,160.3,156.5,154.4,150.2,150.0,149.9,148.0,133.0,132.7,128.2,124.1,119.0,108.2,61.2,52.7,48.7,39.4,31.1,26.8,16.2.HRMS:m/z 472.1917[M+1]+.C25H25N7OS(471.1841).
3,5-二甲基-4-((5-((1-(4-硝基苄基)哌啶-4-基)氨基)噻唑并[4,5-d]嘧啶-7-基)氧基)苄腈(SZ8)
白色固体,收率66%,熔点145-147℃。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H,thiazole-H),8.45(d,J=7.6Hz,1H,NH),8.21(d,J=8.4Hz,2H,C3,C5-Ph’-H),7.67(s,2H,C3,C5-Ph”-H),7.59(d,J=8.8Hz,2H,C2,C6-Ph’-H),3.65–3.63(m,1H),3.59(s,2H,N-CH2),2.78(d,J=11.5Hz,2H),2.09(s,6H),1.89(dd,J=12.7,10.1Hz,2H),1.78–1.50(m,4H).13CNMR(101MHz,DMSO-d6)δ163.3,161.2,156.6,154.4,150.4,147.0,133.0,132.7,130.1,130.0,123.8,61.6,52.7,48.7,39.8,39.6,39.4,31.1,16.2.ESI-MS:m/z 516.1814[M+1]+.C26H25N7O3S(515.1740).
4-((4-((7-(4-氰基-2,6-二甲基苯氧基)噻唑并[4,5-d]嘧啶-5-基)氨基)哌啶-1-基)甲基)苯甲酰胺(SZ9)
白色固体,收率74%,熔点153-155℃。1H NMR(400MHz,DMSO-d6)δ8.95(s,1H,thiazole-H),7.97(s,1H,NH),7.78(d,J=8.0Hz,2H,C3,C5-Ph’-H),7.73(s,2H,C3,C5-Ph”-H),7.45(d,J=8.4Hz,2H,C2,C6-Ph’-H),7.37(s,2H,CONH2),3.71(s,1H),3.48(s,2H,N-CH2),2.84–2.65(m,2H),2.12(s,6H),2.03–1.75(m,3H),1.63–1.26(m,3H).13C NMR(100MHz,DMSO-d6)δ168.4,163.7,161.1,156.2,154.4,150.4,139.9,134.4,133.0,132.6,132.1,128.7,128.2,126.0,119.2,108.4,62.4,52.3,48.8,31.7,16.2.HRMS:m/z514.2022[M+1]+.C27H27N7O2S(513.1947).
4-((4-((7-(4-氰基-2,6-二甲基苯氧基)噻唑并[5,4-d]嘧啶-5-基)氨基)哌啶-1-基)甲基)苯磺酰胺(TZ1)
白色固体,收率66%,熔点158-161℃。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H,thiazole-H),8.44(d,J=7.5Hz,1H,NH),7.80(d,J=8.0Hz,2H,C3,C5-Ph’-H),7.67(s,2H,C3,C5-Ph”-H),7.49(d,J=8.3Hz,2H,C2,C6-Ph’-H),7.33(s,2H,SO2NH2),3.69–3.55(m,1H),3.50(s,2H,N-CH2),2.82–2.70(m,2H),2.09(s,6H),1.88–1.85(m,3H),1.73–1.54(m,3H).13C NMR(100MHz,DMSO-d6)δ156.5,154.5,150.2,143.2,143.2,133.0,132.7,129.5,126.1,119.2,108.2,61.9,52.7,48.8,39.4,31.1,16.2.HRMS:m/z 550.1691[M+1]+.C26H27N7O3S2(549.1617).
4-((4-((7-(4-氰基-2,6-二甲基苯氧基)噻唑并[5,4-d]嘧啶-5-基)氨基)哌啶-1-基)甲基)苯甲酰胺(TZ2)
白色固体,收率51%,熔点144-146℃。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H,thiazole-H),8.43(d,J=7.5Hz,1H,NH),7.84(d,J=7.9Hz,2H,C3,C5-Ph’-H),7.67(s,2H,C3,C5-Ph”-H),7.37(d,J=8.1Hz,2H,C2,C6-Ph’-H),7.32(s,2H,CONH2),3.70–3.57(m,1H),3.48(s,2H,N-CH2),2.79–2.77(m,2H),2.10(s,6H),1.90–1.80(m,2H),1.75–1.55(m,4H).13C NMR(100MHz,DMSO-d6)δ168.2,161.1,156.5,154.5,150.2,142.4,133.4,133.0,132.7,128.9,127.9,119.2,108.2,62.2,52.7,48.9,39.6,39.4,31.1,16.2.HRMS:m/z514.2019[M+1]+.C27H27N7O2S(513.1947).
3,5-二甲基-4-((5-((1-(4-(甲基磺酰基)苄基)哌啶-4-基)氨基)噻唑并[5,4-d]嘧啶-7-基)氧基)苄腈(TZ3)
白色固体,收率59%,熔点112-114℃。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H,thiazole-H),8.44(d,J=7.5Hz,1H,NH),7.90(d,J=8.0Hz,2H,C3,C5-Ph’-H),7.67(s,2H,C3,C5-Ph”-H),7.58(d,J=8.0Hz,2H,C2,C6-Ph’-H),3.63–3.62(m,1H),3.55(s,2H,N-CH2),3.22(s,3H,SO2CH3),2.78(d,J=11.3Hz,2H),2.10(s,6H),1.98–1.81(m,2H),1.77–1.51(m,4H).13C NMR(100MHz,DMSO-d6)δ163.3,161.1,156.5,154.4,150.2,145.3,139.8,133.0,132.7,129.8,127.4,127.2,119.2,108.2,61.8,52.7,48.8,44.0,39.8,39.4,31.1,16.2.HRMS:m/z549.1714[M+1]+.C27H28N6O3S2(548.1664).
3,5-二甲基-4-((5-((1-(吡啶-4-基甲基)哌啶-4-基)氨基)噻唑并[5,4-d]嘧啶-7-基)氧基)苄腈(TZ4)
白色固体,收率44%,熔点116-118℃。1H NMR(400MHz,DMSO-d6)δ9.07(s,1H,thiazole-H),8.52(d,J=5.5Hz,1H,NH),8.44(d,J=7.5Hz,2H,C3,C5-Ph’-H),7.67(s,2H,C3,C5-Ph”-H),7.34–7.29(m,2H,C2,C6-Ph’-H),3.66–3.63(m,1H),3.48(s,2H,N-CH2),2.78–2.76(m,2H),2.10(s,6H),1.90–1.84(m,3H),1.74–1.36(m,3H).13C NMR(100MHz,DMSO-d6)δ163.3,156.6,154.4,150.2,150.0,149.9,148.0,133.0,132.7,128.2,124.1,119.2,108.2,61.2,52.7,48.7,39.6,31.1,16.2.HRMS:m/z 472.1918[M+1]+.C25H25N7OS(471.1841).
3,5-二甲基-4-((5-((1-(4-硝基苄基)哌啶-4-基)氨基)噻唑并[5,4-d]嘧啶-7-基)氧基)苄腈(TZ5)
白色固体,收率51%,熔点146-148℃。1H NMR(400MHz,DMSO-d6)δ9.07(s,1H,thiazole-H),8.45(d,J=7.5Hz,1H,NH),8.22(d,J=8.4Hz,2H,C3,C5-Ph’-H),7.67(s,2H,C3,C5-Ph”-H),7.59(d,J=8.5Hz,2H,C2,C6-Ph’-H),3.65(dt,J=8.0,5.2Hz,1H),3.59(s,2H,N-CH2),2.78(d,J=11.3Hz,2H),2.10(s,6H),1.89(dt,J=11.6,6.0Hz,2H),1.78–1.55(m,4H).13C NMR(100MHz,DMSO-d6)δ163.3,161.1,156.6,154.4,150.3,147.4,147.0,133.0,132.7,130.1,128.2,123.8,119.2,108.2,61.6,52.7,48.7,31.1,16.2.HRMS:m/z516.1817[M+1]+.C26H25N7O3S(515.1740).
3-((4-((7-(4-氰基-2,6-二甲基苯氧基)噻唑并[5,4-d]嘧啶-5-基)氨基)哌啶-1-基)甲基)苯甲酰胺(TZ6)
白色固体,收率73%,熔点154-156℃。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H,thiazole-H),8.44(d,J=7.6Hz,1H,NH),7.80(d,J=8.4Hz,2H,C3,C5-Ph’-H),7.67(s,2H,C3,C5-Ph”-H),7.47–7.40(m,2H,C2,C6-Ph’-H),7.37(s,2H,CONH2),3.76–3.57(m,1H),3.48(s,2H,N-CH2),2.79–2.77(m,2H),2.10(s,6H),1.90–1.86(m,2H),1.75–1.53(m,4H).13CNMR(100MHz,DMSO-d6)δ168.4,163.3,161.1,156.6,154.4,150.1,139.1,134.7,133.0,132.7,132.1,128.5,128.2,126.5,119.2,108.2,62.4,52.7,48.8,31.1,16.2.HRMS:m/z514.2020[M+1]+.C27H27N7O2S(513.1947).
实施例6:目标化合物的体外抗HIV活性测试实验
测试原理:
化合物体外抗HIV活性筛选采用MTT法。MTT全称为溴化-3-(4,5-二甲基-2-噻唑基)-2,5-二苯基四唑氮(商品名:噻唑蓝),可用于检测细胞的存活和生长。检测原理为:MTT可以与活的细胞内琥珀酸脱氢酶结合还原为水不溶性的蓝紫色结晶甲瓒沉积在细胞中,而死细胞并无此功能。二甲基亚砜可以溶解细胞中的甲瓒,用酶标仪检测其在540nm下的吸光度(A)值可以间接的反映活细胞的数量。在一定的细胞数范围内,MTT结晶形成的量与细胞数成正比。
由于HIV感染的MT-4细胞在一定时间内(5-7天)会发生病变,因此向HIV感染的MT-4细胞悬浊液中加入适当浓度的待检测化合物溶液,经过一段时间(5-7天)的培养后,用MTT分析法测定MT-4细胞活力,得到保护50%细胞免于细胞病变的药物浓度(EC50)即可得出目标化合物的抗HIV的活性。同时得到目标化合物使50%未感染HIV的细胞发生病变的浓度(CC50),计算出选择系数(selectivity index,SI=CC50/EC50)。
测试材料和方法:
(1)HIV-1(IIIB)、HIV-2(ROD)毒株、各种HIV-1耐药株:由比利时鲁汶大学医学院Rega研究所提供。
(2)MT-4细胞:由比利时鲁汶大学医学院Rega研究院提供。
(3)MTT:购自美国Sigma公司。
(4)样品处理:样品临用前溶于DMSO配成适当浓度,并用双蒸水作5倍稀释,各5个稀释度。
(5)阳性对照药:奈韦拉平(NVP)和依曲韦林(ETV)。
(6)测试方法:样品稀释后加入到HIV感染MT-4细胞悬浊液中,经过一段时间后用MTT比色法测定细胞活力,用酶标仪中记录在540nm下的吸光度(A)值,计算出EC50,CC50以及SI。
(7)MTT比色法:加入样品溶液培养一段时间后,向每孔加入MTT溶液(5mg/mL)20μL,继续培养若干小时后,弃染色液,并向每孔加入150μL DMSO,充分混合,用酶标仪中测定540nm下的吸光度(A)值。
实验方法:
在96孔细胞培养板上,加入50μL含1×104MT-4细胞培养液,再分别加入20μL感染HIV-1(IIIB或者RES056)或HIV-2(ROD)的MT-4细胞混悬液(每毫升含100倍CCID50)或者空白(毒性测定),然后加入不同浓度的待测化合物溶液或者阳性对照药物,每个浓度设计3个复孔。接着细胞在5%CO2氛围,37℃下培养5天,向每个孔中加入20μL(5mg/mL)MTT溶液,继续培养2小时,然后加入DMSO,使用酶标仪测定反应溶液在540nm处的吸收度,计算化合物不同浓度下的细胞增值率P%。同时设空白和药物对照组和阳性药物对照组,由此计算化合物保护50%的细胞免于HIV诱导的细胞病变所需浓度(EC50),使50%未感染HIV的细胞发生病变的浓度(CC50)。选择指数的计算:SI=CC50/EC50。
按照上述实验方法对合成的部分噻唑并嘧啶类衍生物进行了细胞水平的抗HIV-1野生株和突变株的活性筛选,活性结果如表1和表2所示。
表1.部分噻唑并嘧啶类类化合物抗HIV-1活性、毒性及选择指数
aEC50:抑制50%的病毒诱导的致细胞突变效应的化合物浓度或保护50%感染病毒的细胞免于细胞病变的化合物浓度。
bCC50:使50%未感染HIV的细胞发生病变的浓度。
cSI:选择系数,CC50/EC50的比值。
表2.部分噻唑并嘧啶类类化合物抗HIV-1突变株活性
Claims (4)
2.如权利要求1所述的噻唑并嘧啶类HIV-1逆转录酶抑制剂TZ1的制备方法,步骤包括:以5,7-二氯噻唑并[5,4-d]嘧啶1为初始原料,首先在N,N-二甲基甲酰胺溶液中与2,6-二甲基-4-氰基苯酚经亲核取代生成中间体2;然后中间体2与N-Boc-4-氨基哌啶发生亲核取代反应生成中间体3,进而在三氟乙酸中脱去BOC保护得到中间体4;最后关键中间体4与对溴甲基苯磺酰胺反应生成目标产物TZ1;合成路线如下:
试剂及条件:(i)2,6-二甲基-4-氰基苯酚,N,N-二甲基甲酰胺,碳酸钾,室温;(ii)N-Boc-4-氨基哌啶,N,N-二甲基甲酰胺,碳酸钾,120℃;(iii)二氯甲烷,三氟乙酸,室温;(iv)对溴甲基苯磺酰胺,N,N-二甲基甲酰胺,碳酸钾,室温。
3.一种如权利要求1所述噻唑并嘧啶类HIV-1逆转录酶抑制剂TZ1在制备治疗和预防人免疫缺陷病毒(HIV)药物中的应用。
4.一种药物组合物,包含权利要求1噻唑并嘧啶类HIV-1逆转录酶抑制剂TZ1和一种或多种药学上可接受载体或赋形剂。
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