CN106831814A - 一种噻吩并[3,2‑d]嘧啶类HIV‑1逆转录酶抑制剂及其制备方法和应用 - Google Patents
一种噻吩并[3,2‑d]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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- CN106831814A CN106831814A CN201710081735.5A CN201710081735A CN106831814A CN 106831814 A CN106831814 A CN 106831814A CN 201710081735 A CN201710081735 A CN 201710081735A CN 106831814 A CN106831814 A CN 106831814A
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- Prior art keywords
- chloride
- substituted
- hiv
- thieno
- pyrimidine
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- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 239000003814 drug Substances 0.000 claims abstract description 16
- 241000725303 Human immunodeficiency virus Species 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
- RBNBDIMXFJYDLQ-UHFFFAOYSA-N thieno[3,2-d]pyrimidine Chemical compound C1=NC=C2SC=CC2=N1 RBNBDIMXFJYDLQ-UHFFFAOYSA-N 0.000 claims description 21
- 239000003419 rna directed dna polymerase inhibitor Substances 0.000 claims description 20
- -1 2, 4-dichloro-substituted thienopyrimidine Chemical class 0.000 claims description 19
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 18
- 101900297506 Human immunodeficiency virus type 1 group M subtype B Reverse transcriptase/ribonuclease H Proteins 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 18
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- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
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- 150000003839 salts Chemical class 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 6
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
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- BFXHJFKKRGVUMU-UHFFFAOYSA-N 4-fluorobenzenesulfonyl chloride Chemical compound FC1=CC=C(S(Cl)(=O)=O)C=C1 BFXHJFKKRGVUMU-UHFFFAOYSA-N 0.000 claims description 3
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- 238000011282 treatment Methods 0.000 claims description 3
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- MOBRMRJUKNQBMY-UHFFFAOYSA-N 1-(chloromethyl)-2-fluorobenzene Chemical compound FC1=CC=CC=C1CCl MOBRMRJUKNQBMY-UHFFFAOYSA-N 0.000 claims description 2
- BXCBUWKTXLWPSB-UHFFFAOYSA-N 1-(chloromethyl)-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1CCl BXCBUWKTXLWPSB-UHFFFAOYSA-N 0.000 claims description 2
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- ZNMPXGQFIKLPTD-UHFFFAOYSA-N 1-(dichloromethyl)-2-methoxybenzene Chemical compound COC1=CC=CC=C1C(Cl)Cl ZNMPXGQFIKLPTD-UHFFFAOYSA-N 0.000 claims description 2
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- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明涉及一种噻吩并[3,2‑d]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的结构。本发明还涉及含有式I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,具体涉及一种噻吩并[3,2-d]嘧啶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)目前已经成为危害人类生命健康的重大传染性疾病,其主要病原体是人免疫缺陷病毒1型(HumanImmunodeficiency Virus Type 1,HIV-1)。尽管高效抗逆转录疗法(Highly ActiveAntiretroviral Therapy,HAART)的实施显著延长患者的生存时间,但是耐药问题和药物毒副作用以及长期服用药物的费用等问题,迫使研究者研发高效低毒的新型HIV-1抑制剂。HIV-1非核苷类逆转录酶抑制剂(NNRTIs)具有高效低毒、特异性强的优点,是HAART疗法的重要组成部分,但该类药物易产生耐药性的缺陷使该类药物迅速丧失临床效价。
二芳基嘧啶(diarylpyrimidine,DAPY)类是一类典型的HIV-1NNRTIs,具有较强的抗HIV活性,对耐药突变毒株也有很好的抑制作用。但较低的水溶性和较差的透膜性导致其生物利用度低、口服剂量加大,引起毒副作用和交叉耐药等问题。例如,依曲韦林(Etravirine)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(Rilpivirne)药代性质有所提高,但仍存在抑郁、失眠、急性呼吸窘迫综合征、头痛及皮疹等毒副作用,限制了其广泛应用。因此,研发高效、广谱抗耐药以及具有良好药代动力学性质的NNRTIs是前抗艾滋病药物研究的重要领域之一。
发明内容
针对现有技术的不足,本发明提供了一种噻吩并[3,2-d]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.噻吩并[3,2-d]嘧啶类HIV-1逆转录酶抑制剂
一种噻吩并[3,2-d]嘧啶类HIV-1逆转录酶抑制剂,或其药学上可接受的盐、酯或前药,具有通式I所示的结构:
其中,
X为:O,NH或者S;
Y为:CH2,CO或者SO2;
R为:CH3,CN或者CH=CHCN;
Ar为:取代苯环、取代萘环、各种取代的六元杂环、各种取代的五元杂环、各种取代的六元并五元杂环、各种取代的六元并六元杂环、各种取代的五元并五元杂环、各种取代的苯并五元杂环或各种取代的苯并六元杂环。
根据本发明优选的,Ar为苯基或4-吡啶基;或卤素,NO2,CN,NH2,CF3,NHCH3,OH,COOH,CH2OH,CO2Me,CONH2,OCH3,NHCOCH3,SO2NH2,SO2CH3取代的苯基;取代基为邻、间、对位单取代或多取代。
进一步优选的,噻吩并[3,2-d]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。
本发明中所述的“前药”是指药学上可接受的衍生物,以便这些衍生物所得的生物转换产物是如式I化合物所定义的活性药物。
2.噻吩并[3,2-d]嘧啶类HIV-1逆转录酶抑制剂的制备方法
噻吩并嘧啶类HIV-1逆转录酶抑制剂的制备方法,步骤如下:以2,4-二氯取代的噻吩并嘧啶1为初始原料,首先在N,N-二甲基甲酰胺溶液中与取代苯酚、苯硫醇或苯胺发生亲核取代生成中间体2;然后中间体2与N-Boc-1,4-环己二胺发生布赫瓦尔德-哈特维希(Buchwald-Hartwig)偶联反应生成中间体3,然后脱BOC保护得到中间体4;最后关键中间体4在N,N-二甲基甲酰胺溶液中和碳酸钾或三乙胺做缚酸剂的条件下,与各种取代氯苄、溴苄、酰氯以及磺酰氯反应生成目标产物5;合成路线如下:
试剂及条件:(i)取代苯酚、苯胺或者苯基硫醇,二甲基甲酰胺,碳酸钾,室温;(ii)N-Boc-4-氨基哌啶,二甲基亚砜,碳酸钾,120℃;(iii)N-Boc-4-氨基哌啶,醋酸钯,4,5-双(二苯基膦)-9,9-二甲基氧杂蒽,碳酸铯,90℃,二氧六环;(iv)二氯甲烷,三氟乙酸,室温;(v)二甲基甲酰胺或二氯甲烷,碳酸钾或者三乙胺,室温。
X、Y、R、Ar同上述通式I所示。
所述的取代苯酚、苯基硫醇或者苯胺为: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,均三甲基苯基硫醇,2,6-二甲基-4-氰基苯基硫醇或2,6-二甲基-4-(E)-氰基乙烯基苯基硫醇;
所述的取代氯苄、溴苄、酰氯及磺酰氯为: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、对磺酰胺基溴苄、对甲酰胺基溴苄、4-(溴甲基)苯甲酸甲酯、邻氯苯甲酰氯、间氯苯甲酰氯、对氯苯甲酰氯、邻溴苯甲酰氯、间溴苯甲酰氯、对溴苯甲酰氯、邻氟苯甲酰氯、间氟苯甲酰氯、对氟苯甲酰氯、2,4-二氟苯甲酰氯、3,4-二氟苯甲酰氯、邻氰基苯甲酰氯、间氰基苯甲酰氯、对氰基苯甲酰氯、邻硝基苯甲酰氯、间硝基苯甲酰氯、对硝基苯甲酰氯、邻甲氧基苯甲酰氯、间甲氧基苯甲酰氯、对甲氧基苯甲酰氯、对甲磺酰基苯甲酰氯、对磺酰胺基苯甲酰氯、对甲酰胺基苯甲酰氯、4-(溴甲基)苯甲酰氯、邻氯苯磺酰氯、间氯苯磺酰氯、对氯苯磺酰氯、邻溴苯磺酰氯、间溴苯磺酰氯、对溴苯磺酰氯、邻氟苯磺酰氯、间氟苯磺酰氯、对氟苯磺酰氯、2,4-二氟苯磺酰氯、3,4-二氟苯磺酰氯、邻氰基苯磺酰氯、间氰基苯磺酰氯、对氰基苯磺酰氯、邻硝基苯磺酰氯、间硝基苯磺酰氯、对硝基苯磺酰氯、邻甲氧基苯磺酰氯、间甲氧基苯磺酰氯、对甲氧基苯磺酰氯、对甲磺酰基苯磺酰氯、对磺酰胺基苯磺酰氯、对甲酰胺基苯磺酰氯或者4-(溴甲基)苯磺酰氯。
本发明所述的室温为20-30℃。
3.噻吩并[3,2-d]嘧啶类HIV-1逆转录酶抑制剂的抗HIV-1野生株及突变株活性及应用
本发明对按照上述方法合成的部分噻吩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K103N、Y181C、Y188L以及双耐药突变株RES056(K103N/Y181C)的活性筛选,以奈韦拉平(NVP)、依法韦伦(EFV)、依曲韦林(ETV)和齐多夫定(AZT)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,本发明的噻吩并[3,2-d]嘧啶衍生物是一系列结构新颖的非核苷类HIV-1抑制剂,绝大部分化合物表现出了比较好的抑制野生株和突变株的活性。其中,化合物DK19的活性尤为突出,其对HIV-1野生株的EC50值达到7.1nM,是第一代抗艾滋病药物奈韦拉平(NVP)的18倍以上。化合物DK19亦表现出了较高的安全性,其对HIV-1野生株的选择性指数为1308。另外,对单突变株K103N和E138K,化合物DK19亦表现出纳摩尔级别的抗病毒活性,分别为70nM与45nM。因此该类噻吩并[3,2-d]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。
本发明的噻吩并[3,2-d]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,包括本发明的噻吩并[3,2-d]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吩并[3,2-d]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,本发明的噻吩并[3,2-d]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:((2-((4-氨基环己基)氨基)噻吩并[3,2-d]嘧啶-4-基)氧基)-3,5-二甲基苄腈(DK1)的制备
称取4-羟基-3,5-二甲基苯腈(0.15g,1mmol)和碳酸钾(0.17g,1.2mmol)于5mL的N,N-二甲基甲酰胺溶液中,室温搅拌15分钟,然后加入2,4-二氯噻吩并[3,2-d]嘧啶(0.21g,1mmol)继续室温搅拌2h(TLC检测反应完毕)。此时有大量的白色固体生成,慢慢地向其中加入25mL冰水,过滤,真空干燥箱干燥,得到白色固体即为化合物4-((2-氯噻吩并[3,2-d]嘧啶-4-基)氧基)-3,5-二甲基苯腈,收率93.8%,熔点258-260℃。
称取化合物4-((2-氯噻吩并[3,2-d]嘧啶-4-基)氧基)-3,5-二甲基苯腈(0.32g,1.0mmol),N-Boc-1,4-环己二胺(0.26g,1.2mmol),醋酸钯(0.02g,0.1mmol),4,5-双(二苯基膦)-9,9-二甲基氧杂蒽(0.06g,0.1mmol)与碳酸铯(0.65g,2mmol)加入于15mL的二氧六环中,在氮气保护的条件下加热回流12小时。待反应冷却到室温以后,加硅藻土过滤,滤液蒸干。然后将该粗品溶于5mL二氯甲烷中,然后慢慢地向其中加入三氟乙酸2mL,室温条件下搅拌4小时(TLC检测反应完毕)。向反应液中加入10mL水,用饱和的碳酸氢钠水溶液调PH为9,二氯甲烷萃取(3×5mL),饱和食盐水水洗,分取有机层,无水硫酸钠干燥。然后进行快速柱层析分离得到白色固体即为化合物((2-((4-氨基环己基)氨基)噻吩并[3,2-d]嘧啶-4-基)氧基)-3,5-二甲基苄腈。收率56.3%,熔点185-190℃。1H NMR(400MHz,CDCl3):δ7.72(d,J=5.4Hz,1H,C6-thienopyrimidine-H),7.36(s,2H,C3,C5-Ph’-H),7.13(d,J=5.4Hz,1H,C7-thienopyrimidine-H),4.78(s,1H,NH),3.06(q,J=7.3Hz,1H),2.80-2.96(m,3H),2.09(s,6H),1.95-1.97(m,4H),1.07-1.35(m,4H).13C NMR(100MHz,CDCl3):δ164.2,161.7,158.9,152.4,132.0,131.3,122.2,117.6,116.8,113.9,108.2,59.3,48.9,44.7,35.5,29.4,28.1,15.3.ESI-MS:m/z 394.4(M+1).C21H23N5OS(393.16).
实施例2:化合物DK2-DK12的制备
称取化合物((2-((4-氨基环己基)氨基)噻吩并[3,2-d]嘧啶-4-基)氧基)-3,5-二甲基苄腈(DK1)(0.5mmol)于10mL DMF中,室温条件下搅拌溶解后加入无水碳酸(0.14g,1.0mmol)与取代的氯苄或溴苄(0.6mmol),室温条件下搅拌6-15h(TLC检测反应完毕)。减压蒸出溶剂,然后向残留底物中加入20mL乙酸乙酯,饱和食盐水溶液洗涤3次,每次10mL,分取有机层,无水硫酸钠干燥,过滤,浓缩。快速柱层析分离得到目标化合物,进而在乙酸乙酯-石油醚体系中重结晶得到目标化合物DK2-DK12。
以不同的取代苄基和((2-((4-氨基环己基)氨基)噻吩并[3,2-d]嘧啶-4-基)氧基)-3,5-二甲基苄腈(DK1)用上述方法分别制得化合物DK2-DK12的目标产物,结果如下:
操作同上,所不同的是使用对溴甲基苯磺酰胺。
产物为白色固体,收率:78.6%,熔点216-218℃。
1H NMR(400MHz,DMSO-d6):δ8.19(d,J=5.4Hz,1H,C6-thienopyrimidine-H),7.76(d,J=8.0Hz,2H,C3,C5-Ph’-H),7.72(s,2H,C3,C5-Ph”-H),7.52(d,J=8.1Hz,2H,C2,C6-Ph’-H),7.27-7.29(m,3H),6.75(s,1H,pyrimidine-NH),4.36(s,1H,cyclohexane-NH),3.79(s,2H,N-CH2),3.24-3.39(m,2H),2.11(s,6H),1.74-1.91(m,4H),1.12-1.20(m,4H).13C NMR(100MHz,DMSO-d6):δ170.8,160.6,142.7,133.2,132.9,128.6,125.9,119.0,109.0,60.2,56.5,55.5,49.9,32.0,31.0,21.2,19.0,16.2,14.5.ESI-MS:m/z 563.2(M+1),585.4(M+Na).C28H30N6O3S2(562.18).
操作同上,所不同的是使用对溴甲基苯甲酰胺。
产物为白色固体,收率:75.2%,熔点224-227℃。
1H NMR(400MHz,CDCl3):δ8.17(d,J=5.4Hz,1H,C6-thienopyrimidine-H),7.76(d,J=8.3Hz,2H,C3,C5-Ph’-H),7.72(s,2H,C3,C5-Ph”-H),7.29-7.35(m,4H),7.27(d,J=5.4Hz,1H,C7-thienopyrimidine-H),6.77(s,1H,pyrimidine-NH),4.36(s,1H,cyclohexane-NH),3.79(s,2H,N-CH2),3.27-3.35(m,2H),2.09(s,6H),1.96-2.08(m,4H),1.19-1.35(m,4H).13C NMR(100MHz,CDCl3):δ165.4,160.1,141.9,133.2,132.4,127.7,125.9,118.6,109.0,60.1,56.7,55.5,48.6,32.2,31.0,21.2,19.0,16.2,14.5.ESI-MS:m/z 527.3(M+1),549.2(M+Na).C29H30N6O2S(526.22).
操作同上,所不同的是使用3-溴甲基苯甲酰胺。
产物为白色固体,收率:51.1%,熔点215-219℃。
1H NMR(400MHz,CDCl3):δ8.17(d,J=5.4Hz,1H,C6-thienopyrimidine-H),7.75-7.78(m,2H),7.72(s,2H,C3,C5-Ph”-H),7.51-7.53(m,2H),7.27(s,2H),7.27(d,J=5.4Hz,1H,C7-thienopyrimidine-H),6.77(s,1H,pyrimidine-NH),4.39(s,1H,cyclohexane-NH),3.79(s,2H,N-CH2),3.21-3.31(m,2H),2.11(s,6H),1.85-2.01(m,4H),1.21-1.35(m,4H).13C NMR(100MHz,CDCl3):δ165.1,160.6,142.3,133.7,131.5,128.1,124.6,119.2,109.7,60.0,57.3,55.5,49.0,32.7,31.0,21.6,18.3,16.7,14.5.ESI-MS:m/z 527.2(M+1),549.1(M+Na).C29H30N6O2S(526.22).
操作同上,所不同的是使用对硝基溴苄。
产物为白色固体,收率:48.2%,熔点185-187℃。
1H NMR(400MHz,CDCl3):δ8.18(d,J=9.2Hz,2H,C3,C5-Ph’-H),7.79(d,J=5.4,1H,C6-thienopyrimidine-H),7.53(d,J=8.6Hz,1H,C2,C6-Ph’-H),7.43(s,1H,C3,C5-Ph”-H),7.21(d,J=5.4Hz,1H,C7-thienopyrimidine-H),6.87(s,1H,pyrimidine-NH),4.73(s,1H,cyclohexane-NH),3.92(s,2H,N-CH2),2.54-2.66(m,2H),2.17(s,6H),1.94-2.05(m,4H),1.12-1.42(m,4H).13C NMR(100MHz,CDCl3):δ165.5,160.3,153.3,147.0,134.9,133.1,132.2,128.6,123.6,123.3,118.7,109.5,60.4,55.8,50.3,31.8,31.4,28.4,27.9,16.4,14.2.ESI-MS:m/z529.5(M+1),551.4(M+Na).C28H28N6O3S(528.19).
操作同上,所不同的是使用4-甲砜基溴苄。
产物为白色固体,收率:61.6%,熔点231-234℃。
1H NMR(400MHz,DMSO-d6):δ8.17(d,J=5.4Hz,1H,C6-thienopyrimidine-H),7.74(d,J=8.1Hz,2H,C3,C5-Ph’-H),7.72(s,2H,C3,C5-Ph”-H),7.52(d,J=8.1Hz,2H,C2,C6-Ph’-H),7.27(d,J=5.4Hz,1H,C7-thienopyrimidine-H),6.71(s,1H,pyrimidine-NH),4.35(s,1H,cyclohexane-NH),3.74(s,2H,N-CH2),3.21-3.27(m,2H),3.06(s,3H,SO2CH3),2.11(s,6H),1.73-1.98(m,4H),1.17-1.26(m,4H).13C NMR(100MHz,DMSO-d6):δ165.2,162.6,159.9,147.7,139.1,133.1,132.2,128.2,127.4,127.2,118.7,63.8,44.5,36.6,31.4,29.6,28.8,19.1,16.4.ESI-MS:m/z 562.5(M+1),584.8(M+Na).C29H31N5O3S2(561.19).
操作同上,所不同的是使用溴苄。
产物为白色固体,收率:65.2%,熔点188-190℃。
1H NMR(400MHz,CDCl3):δ7.79(d,J=5.4Hz,1H,C6-thienopyrimidine-H),7.49-7.53(m,2H),7.45(s,2H,C3,C5-Ph”-H),7.32-7.42(m,3H),7.23(d,J=5.4Hz,1H,C7-thienopyrimidine-H),6.73(s,1H,pyrimidine-NH),4.37(s,1H,cyclohexane-NH),3.74(s,2H,N-CH2),3.23-3.25(m,2H),2.12(s,6H),1.77-1.92(m,5H),1.25-1.27(m,3H).13CNMR(100MHz,CDCl3):δ165.4,162.6,160.0,153.3,134.9,133.1,132.4,130.0,129.2,129.1,123.4,118.7,109.5,60.4,55.5,48.7,30.7,27.9,16.4,14.2.ESI-MS:m/z 484.3(M+1),506.1(M+Na).C28H29N5OS(483.21).
操作同上,所不同的是使用4-溴溴苄。
产物为白色固体,收率:62.3%,熔点203-205℃。
1H NMR(400MHz,CDCl3):δ7.79(d,J=5.4Hz,1H,C6-thienopyrimidine-H),7.44-7.46(m,2H),7.43(s,2H,C3,C5-Ph”-H),7.26(d,J=7.0Hz,2H,C2,C6-Ph’-H),7.21(d,J=5.4Hz,1H,C7-thienopyrimidine-H),6.75(s,1H,pyrimidine-NH),4.37(s,1H,cyclohexane-NH),3.79(s,2H,N-CH2),3.21-3.25(m,2H),2.17(s,6H),1.95-2.05(m,4H),1.21-1.42(m,4H).13C NMR(100MHz,CDCl3):δ165.4,162.7,160.2,153.3,134.9,133.1,132.2,131.6,130.3,123.4,118.7,109.5,106.3,55.5,49.9,31.3,31.1,27.8,16.4.ESI-MS:m/z 562.3(M+1),564.3(M+3),584.1(M+Na).C28H28BrN5OS(561.12).
操作同上,所不同的是使用4-氟溴苄。
产物为白色固体,收率:59.6%,熔点231-233℃。
1H NMR(400MHz,CDCl3):δ7.81(d,J=5.4Hz,1H,C6-thienopyrimidine-H),7.48-7.50(m,2H),7.47(s,2H,C3,C5-Ph”-H),7.26-7.28(m,2H),7.23(d,J=5.4Hz,1H,C7-thienopyrimidine-H),6.77(s,1H,pyrimidine-NH),4.35(s,1H,cyclohexane-NH),3.75(s,2H,N-CH2),3.23-3.26(m,2H),2.17(s,6H),1.93-2.07(m,5H),1.25-1.38(m,3H).13CNMR(100MHz,CDCl3):δ165.5,161.9,160.7,154.1,134.0,133.7,132.1,131.3,130.3(d,J=8.3Hz),123.8,118.4,115.2(d,J=20.7Hz),109.9,106.3,55.8,49.1,31.3,30.8,27.8,16.2.ESI-MS:m/z 502.4(M+1),524.4(M+Na).C28H28FN5OS(501.20).
操作同上,所不同的是使用4-羟基溴苄。
产物为白色固体,收率:53.8%,熔点186-188℃。
1H NMR(400MHz,CDCl3):δ7.81(d,J=5.4Hz,1H,C6-thienopyrimidine-H),7.43(s,2H,C3,C5-Ph”-H),7.31-7.35(m,2H),7.23(d,J=5.4Hz,1H,C7-thienopyrimidine-H),6.94-6.97(m,2H),6.73(s,1H,pyrimidine-NH),4.34(s,1H,cyclohexane-NH),3.77(s,2H,N-CH2),3.21-3.25(m,2H),2.17(s,6H),1.91-2.02(m,3H),1.27-1.45(m,5H).13C NMR(100MHz,CDCl3):δ165.6,161.3,160.7,154.1,134.0,133.8,132.9,132.3,131.3,130.3,123.8,117.8,109.2,107.0,55.8,49.4,31.7,30.8,27.3,16.1.ESI-MS:m/z 500.2(M+1),522.2(M+Na).C28H29N5O2S(499.20).
操作同上,所不同的是使用3-三氟甲基溴苄。
产物为白色固体,收率:58.8%,熔点235-237℃。
1H NMR(400MHz,CDCl3):δ7.79(d,J=5.4Hz,1H,C6-thienopyrimidine-H),7.51-7.61(m,4H),7.45-7.46(m,1H),7.43(s,2H,C3,C5-Ph”-H),7.21(d,J=5.3Hz,1H,C7-thienopyrimidine-H),6.74(s,1H,pyrimidine-NH),4.73(s,1H,cyclohexane-NH),3.88(s,2H,N-CH2),3.21-3.25(m,2H),2.18(s,6H),1.98-2.09(m,4H),1.15-1.43(m,4H).13CNMR(100MHz,CDCl3):δ165.4,162.7,160.3,153.3,141.0,134.9,133.1,132.2,131.5,130.8,130.5,128.9,124.8,123.9,123.4,118.7,109.5,106.3,58.4,55.8,50.5,31.6,27.9,16.4.ESI-MS:m/z 552.4(M+1),574.5(M+Na).C29H28F3N5OS(551.20).
操作同上,所不同的是使用4-氰基溴苄。
产物为白色固体,收率:55.2%,熔点221-224℃。
1H NMR(400MHz,CDCl3):δ8.15(d,J=5.4Hz,1H,C6-thienopyrimidine-H),7.76(d,J=8.2Hz,2H,C3,C5-Ph’-H),7.72(s,2H,C3,C5-Ph”-H),7.53(d,J=8.0Hz,2H,C2,C6-Ph’-H),7.26(d,J=5.4Hz,1H,C7-thienopyrimidine-H),6.68(s,1H,pyrimidine-NH),4.32(s,1H,cyclohexane-NH),3.71(s,2H,N-CH2),3.23-3.26(m,2H),2.11(s,6H),1.87-2.06(m,3H),1.19-1.31(m,5H).13C NMR(100MHz,CDCl3):δ165.1,162.0,159.5,146.3,138.5,133.7,131.8,128.2,127.9,127.1,117.4,63.0,45.2,36.6,31.1,29.3,27.2,19.8,16.2.ESI-MS:m/z 509.4(M+1),531.5(M+Na).C29H28N6OS(508.20).
实施例3:化合物DK13-DK22的制备
称取化合物((2-((4-氨基环己基)氨基)噻吩并[3,2-d]嘧啶-4-基)氧基)-3,5-二甲基苄腈(0.5mmol)于10mL DCM中,室温条件下搅拌溶解后加入三乙胺(0.06g,0.6mmol)与取代的苯甲酰氯或苯磺酰氯(0.6mmol),室温条件下搅拌3-5h(TLC检测反应完毕)。然后反应液加入10mL DCM,饱和食盐水溶液洗涤3次,每次10mL,分取有机层,无水硫酸钠干燥,过滤,浓缩。快速柱层析分离得到目标化合物,进而在乙酸乙酯-石油醚体系中重结晶得到目标化合物DK13-DK22。
以不同的取代苄基和((2-((4-氨基环己基)氨基)噻吩并[3,2-d]嘧啶-4-基)氧基)-3,5-二甲基苄腈(DK1)用上述方法分别制得化合物DK13-DK22的目标产物,结果如下:
操作同上,所不同的是使用苯甲酰氯。
产物为白色固体,收率:67.2%,熔点201-203℃。
1H NMR(400MHz,CDCl3):δ7.80(d,J=5.4Hz,1H,C6-thienopyrimidine-H),7.75-7.78(m,2H),7.48-7.50(m,1H),7.38-7.46(m,4H),7.22(d,J=5.4Hz,1H,C7-thienopyrimidine-H),5.99(s,1H,pyrimidine-NH),3.93(s,1H),3.38-3.55(m,4H),2.18(s,6H),2.02-2.10(m,4H),1.24-1.30(m,4H).13C NMR(100MHz,CDCl3):δ166.9,165.3,162.7,160.1,153.3,134.7,133.1,132.2,131.4,128.5,126.8,123.2,118.8,109.4,60.4,49.8,48.2,31.7,31.5,16.4.ESI-MS:m/z 498.3(M+1).C28H27N5O2S(497.19).
操作同上,所不同的是使用对氟苯甲酰氯。
产物为白色固体,收率:70.3%,熔点220-223℃。
1H NMR(400MHz,DMSO-d6):δ8.21(d,J=5.4Hz,1H,C6-thienopyrimidine-H),7.85-7.96(m,2H),7.73(s,2H,C3,C5-Ph”-H),7.27-7.31(m,2H),5.98(s,1H,pyrimidine-NH),3.71(s,1H),2.14(s,6H),1.83-2.00(m,4H),1.32-1.47(m,5H).13C NMR(100MHz,DMSO):δ165.4,164.9,162.9,162.4,160.5,153.5,133.2,131.7(d,J=2.8Hz),130.3(d,J=8.9Hz),123.7,119.0,115.6(d,J=21.6Hz),109.1,60.2,49.4,48.5,31.3,16.2.ESI-MS:m/z 516.3(M+1),538.1(M+Na).C28H26FN5O2S(515.18).
操作同上,所不同的是使用对溴苯甲酰氯。
产物为白色固体,收率:61.7%,熔点219-221℃。
1H NMR(400MHz,CDCl3):δ7.81(d,J=5.4Hz,1H,C6-thienopyrimidine-H),7.61(d,J=8.1Hz,2H,C2,C6-Ph’-H),7.53(d,J=8.0Hz,2H,C3,C5-Ph’-H),7.43(s,2H,C3,C5-Ph”-H),7.21(d,J=5.4Hz,1H,C7-thienopyrimidine-H),5.97(d,J=8.0Hz,1H,pyrimidine-NH),4.81(s,1H),3.91(s,1H),2.18(s,6H),1.93-2.08(m,5H),1.22-1.31(m,4H).13C NMR(100MHz,CDCl3):δ165.9,165.3,162.7,160.1,153.3,135.1,133.5,133.1,132.2,131.7,128.5,126.0,123.2,118.8,109.4,49.7,48.4,31.4,16.4.ESI-MS:m/z576.4(M+1),598.3(M+Na).C28H26BrN5O2S(575.10).
操作同上,所不同的是使用对氰基苯甲酰氯。
产物为白色固体,收率:66.7%,熔点141-146℃。
1H NMR(400MHz,CDCl3):δ7.81(d,J=5.3Hz,1H,C6-thienopyrimidine-H),7.61(d,J=8.0Hz,2H,C2,C6-Ph’-H),7.54-7.58(m,2H),7.42(s,2H,C3,C5-Ph”-H),7.20(d,J=5.4Hz,1H,C7-thienopyrimidine-H),5.96(s,1H,pyrimidine-NH),4.82(s,1H),3.91-3.92(m,1H),2.18(s,6H),1.90-2.01(m,4H),1.20-1.37(m,5H).13C NMR(100MHz,CDCl3):δ165.7,165.0,162.7,160.4,154.2,135.7,133.5,133.4,132.2,131.6,128.5,126.7,123.2,118.9,109.4,49.2,48.4,31.4,16.2.ESI-MS:m/z 523.7(M+1),545.4(M+Na).C29H26N6O2S(522.18).
操作同上,所不同的是使用间三氟甲基苯甲酰氯。
产物为白色固体,收率:58.2%,熔点113-116℃。
1H NMR(400MHz,CDCl3):δ7.81(d,J=5.3Hz,1H,C6-thienopyrimidine-H),7.61-7.63(m,1H),7.50-7.57(m,3H),7.42(s,2H,C3,C5-Ph”-H),7.21(d,J=5.3Hz,1H,C7-thienopyrimidine-H),5.96(s,1H,pyrimidine-NH),4.80(s,1H),3.88-3.89(m,1H),2.18(s,6H),1.94-2.03(m,4H),1.75-1.83(m,2H),1.22-1.30(m,3H).13C NMR(100MHz,CDCl3):δ165.7,162.6,160.4,154.4,135.3,134.5,133.7,133.0,132.1,131.7,128.5,126.3,123.2,119.2,109.4,49.3,48.4,31.4,16.3.ESI-MS:m/z 566.3(M+1),588.5(M+Na).C29H26F3N5O2S(565.18).
操作同上,所不同的是使用对氟苯磺酰氯。
产物为白色固体,收率:76.2%,熔点187-190℃。
1H NMR(400MHz,CDCl3):δ7.86-7.95(m,2H),7.79(d,J=5.4Hz,1H,C6-thienopyrimidine-H),7.41(s,2H,C3,C5-Ph”-H),7.14-7.24(m,3H),4.72(s,1H),3.07-3.09(m,1H),2.15(s,6H),1.81-1.95(m,5H),1.08-1.14(m,4H).13C NMR(100MHz,CDCl3):δ166.2,165.3,163.7,162.7,160.0,153.2,137.4,135.1,133.0,132.2,129.5(d,J=9.2Hz),123.2,118.7,116.2(d,J=22.6Hz),109.5,60.4,52.2,49.2,32.4,31.3,16.4.ESI-MS:m/z 552.7(M+1).C27H26FN5O3S2(551.15).
操作同上,所不同的是使用对氰基苯磺酰氯。
产物为白色固体,收率:70.9%,熔点258-260℃。
1H NMR(400MHz,CDCl3):δ7.79(d,J=5.3Hz,1H,C6-thienopyrimidine-H),7.76(d,J=8.6Hz,2H,C2,C6-Ph’-H),7.62-7.65(m,2H),7.42(s,2H,C3,C5-Ph”-H),7.18(d,J=5.1Hz,1H,C7-thienopyrimidine-H),4.71(d,J=7.3Hz,1H,pyrimidine-NH),3.07-3.09(m,1H),2.17(s,6H),1.92-2.04(m,5H),1.12-1.24(m,4H).13C NMR(100MHz,CDCl3):δ165.2,162.2,154.1,140.4,135.8,133.4,132.4,132.0,128.4,127.6,123.2,119.1,118.7,109.5,106.1,60.4,58.7,52.3,49.6,32.4,31.8,16.2.ESI-MS:m/z 559.3(M+1),581.2(M+Na).C28H26N6O3S2(558.15).
操作同上,所不同的是使用间三氟甲基苯磺酰氯。
产物为白色固体,收率:65.7%,熔点128-130℃。
1H NMR(400MHz,CDCl3):δ8.16(s,1H,C2-Ph’-H),8.08(d,J=8.1Hz,1H,C4-Ph’-H),7.83(d,J=8.0Hz,1H,C6-Ph’-H),7.79(d,J=5.4Hz,1H,C6-thienopyrimidine-H),7.69(t,J=7.9Hz,1H,C5-Ph’-H),7.42(s,2H,C3,C5-Ph”-H),7.19(d,J=5.4Hz,1H,C7-thienopyrimidine-H),4.76(d,J=7.8Hz,1H,pyrimidine-NH),3.15-3.20(m,1H),2.15(s,6H),1.81-1.95(m,5H),1.08-1.14(m,4H).13C NMR(100MHz,CDCl3):δ165.1,164.2,162.7,159.9,153.2,142.7,133.0,132.2,131.6,130.0(d,J=7.3Hz),129.2(d,J=3.7Hz),124.5,123.9,123.2,121.8,118.7,109.5,106.5,52.5,49.1,32.4,31.2,16.4.ESI-MS:m/z602.7(M+1),624.3(M+Na).C28H26F3N5O3S2(601.14).
操作同上,所不同的是使用对甲酰胺基苯磺酰氯。
产物为白色固体,收率:69.1%,熔点252-254℃。
1H NMR(400MHz,CDCl3):δ8.15(d,J=8.6Hz,2H,C3,C5-Ph’-H),7.79(d,J=5.4Hz,1H,C6-thienopyrimidine-H),7.76(d,J=8.6Hz,2H,C2,C6-Ph’-H),7.43(s,2H,C3,C5-Ph”-H),7.16(d,J=5.4Hz,1H,C7-thienopyrimidine-H),4.78(d,J=7.6Hz,1H,pyrimidine-NH),3.10-3.13(m,1H),2.15(s,6H),2.06(s,3H),1.86-1.99(m,5H),1.10-1.18(m,4H).13CNMR(100MHz,CDCl3):δ168.7,165.3,162.8,160.4,153.1,140.7,135.2,133.4,132.4,132.0,128.4,127.6,123.2,118.9,109.5,106.2,60.4,58.6,52.3,49.2,32.4,31.2,25.6,16.2.ESI-MS:m/z 591.3(M+1),613.6(M+Na).C29H30N6O4S2(590.18).
操作同上,所不同的是使用对溴苯磺酰氯。
产物为白色固体,收率:73.8%,熔点235-237℃。
1H NMR(400MHz,CDCl3):δ7.79(d,J=5.4Hz,1H,C6-thienopyrimidine-H),7.76(d,J=8.6Hz,2H,C2,C6-Ph’-H),7.66(d,J=8.6Hz,2H,C3,C5-Ph’-H),7.42(s,2H,C3,C5-Ph”-H),7.18(d,J=5.4Hz,1H,C7-thienopyrimidine-H),4.76(d,J=7.5Hz,1H,pyrimidine-NH),3.07-3.09(m,1H),2.15(s,6H),1.81-1.95(m,5H),1.08-1.23(m,4H).13CNMR(100MHz,CDCl3):δ165.2,162.6,160.0,153.2,140.4,135.1,133.0,132.4,132.2,128.4,127.4,123.2,118.7,109.5,106.5,60.4,58.4,52.3,49.2,32.4,31.2,16.4.ESI-MS:m/z 612.4(M+1),534.6(M+Na).C27H26BrN5O3S2(611.07).
实施例4: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590nm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)、依法韦仑(EFV)、依曲韦林(ETV)、齐多夫定(AZT)。
(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590nm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590nm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)。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吩并[3,2-d]嘧啶类衍生物进行了细胞水平的抗HIV-1(IIIB),单突变株K103N、Y181C、Y188L以及双突变株RES056(K103N/Y181C)的活性筛选,活性结果如表1和表2所示。
表1.部分噻吩并[3,2-d]嘧啶类类化合物抗HIV活性、毒性及选择指数
a EC50: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。
b CC50:使50%未感染HIV的细胞发生病变的浓度。
c SI:选择系数,CC50/EC50的比值。
表2.部分噻吩并[3,2-d]嘧啶类类化合物抗HIV-1突变株活性
Claims (7)
1.一种噻吩并[3,2-d]嘧啶类HIV-1逆转录酶抑制剂,或其药学上可接受的盐、酯或前药,其特征在于,具有通式I所示的结构:
其中,
X为:O,NH或者S;
Y为:CH2,CO或者SO2;
R为:CH3,CN或者CH=CHCN;
Ar为:取代苯环、取代萘环、各种取代的六元杂环、各种取代的五元杂环、各种取代的六元并五元杂环、各种取代的六元并六元杂环、各种取代的五元并五元杂环、各种取代的苯并五元杂环或各种取代的苯并六元杂环。
2.如权利要求1所述的噻吩并[3,2-d]嘧啶类HIV-1逆转录酶抑制剂,其特征在于Ar为苯基或4-吡啶基;或卤素,NO2,CN,NH2,CF3,NHCH3,OH,COOH,CH2OH,CO2Me,CONH2,OCH3,NHCOCH3,SO2NH2,SO2CH3取代的苯基;取代基为邻、间、对位单取代或多取代。
3.如权利要求2所述的噻吩并[3,2-d]嘧啶类HIV-1逆转录酶抑制剂,其特征在于是下列化合物之一:
4.如权利要求1所述的噻吩并[3,2-d]嘧啶类HIV-1逆转录酶抑制剂的制备方法,以2,4-二氯取代的噻吩并嘧啶1为初始原料,首先在N,N-二甲基甲酰胺溶液中与取代苯酚、苯硫醇或苯胺发生亲核取代生成中间体2;然后中间体2与N-Boc-1,4-环己二胺发生布赫瓦尔德-哈特维希(Buchwald-Hartwig)偶联反应生成中间体3,然后脱BOC保护得到中间体4;最后关键中间体4在N,N-二甲基甲酰胺溶液中和碳酸钾或三乙胺做缚酸剂的条件下,与各种取代氯苄、溴苄、酰氯以及磺酰氯反应生成目标产物5;合成路线如下:
试剂及条件:(i)取代苯酚、苯胺或者苯基硫醇,二甲基甲酰胺,碳酸钾,室温;(ii)N-Boc-4-氨基哌啶,二甲基亚砜,碳酸钾,120℃;(iii)N-Boc-4-氨基哌啶,醋酸钯,4,5-双(二苯基膦)-9,9-二甲基氧杂蒽,碳酸铯,90℃,二氧六环;(iv)二氯甲烷,三氟乙酸,室温;(v)二甲基甲酰胺或二氯甲烷,碳酸钾或者三乙胺,室温;
X、Y、R、Ar同权利要求1中通式I所示。
5.如权利要求4所述的噻吩并[3,2-d]嘧啶类HIV-1逆转录酶抑制剂的制备方法,其特征在于,所述的取代苯酚、苯基硫醇或者苯胺为: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,均三甲基苯基硫醇,2,6-二甲基-4-氰基苯基硫醇或2,6-二甲基-4-(E)-氰基乙烯基苯基硫醇;
所述的取代氯苄、溴苄、酰氯及磺酰氯为: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、对磺酰胺基溴苄、对甲酰胺基溴苄、4-(溴甲基)苯甲酸甲酯、邻氯苯甲酰氯、间氯苯甲酰氯、对氯苯甲酰氯、邻溴苯甲酰氯、间溴苯甲酰氯、对溴苯甲酰氯、邻氟苯甲酰氯、间氟苯甲酰氯、对氟苯甲酰氯、2,4-二氟苯甲酰氯、3,4-二氟苯甲酰氯、邻氰基苯甲酰氯、间氰基苯甲酰氯、对氰基苯甲酰氯、邻硝基苯甲酰氯、间硝基苯甲酰氯、对硝基苯甲酰氯、邻甲氧基苯甲酰氯、间甲氧基苯甲酰氯、对甲氧基苯甲酰氯、对甲磺酰基苯甲酰氯、对磺酰胺基苯甲酰氯、对甲酰胺基苯甲酰氯、4-(溴甲基)苯甲酰氯、邻氯苯磺酰氯、间氯苯磺酰氯、对氯苯磺酰氯、邻溴苯磺酰氯、间溴苯磺酰氯、对溴苯磺酰氯、邻氟苯磺酰氯、间氟苯磺酰氯、对氟苯磺酰氯、2,4-二氟苯磺酰氯、3,4-二氟苯磺酰氯、邻氰基苯磺酰氯、间氰基苯磺酰氯、对氰基苯磺酰氯、邻硝基苯磺酰氯、间硝基苯磺酰氯、对硝基苯磺酰氯、邻甲氧基苯磺酰氯、间甲氧基苯磺酰氯、对甲氧基苯磺酰氯、对甲磺酰基苯磺酰氯、对磺酰胺基苯磺酰氯、对甲酰胺基苯磺酰氯或者4-(溴甲基)苯磺酰氯。
6.一种如权利要求1-3任一项所述化合物在制备治疗和预防人免疫缺陷病毒(HIV)药物中的应用。
7.一种药物组合物,包含权利要求1-3任一项所述化合物和一种或多种药学上可接受载体或赋形剂。
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