CN101367749B - 一组胺基苯酰衍生物及其制备方法和应用 - Google Patents

一组胺基苯酰衍生物及其制备方法和应用 Download PDF

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CN101367749B
CN101367749B CN2008101688244A CN200810168824A CN101367749B CN 101367749 B CN101367749 B CN 101367749B CN 2008101688244 A CN2008101688244 A CN 2008101688244A CN 200810168824 A CN200810168824 A CN 200810168824A CN 101367749 B CN101367749 B CN 101367749B
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compound
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yield
nmr
amino
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CN101367749A (zh
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蒋建东
余利岩
岑山
李卓荣
李艳萍
徐建
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Institute of Medicinal Biotechnology of CAMS
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Priority to PCT/CN2009/001094 priority patent/WO2010037271A1/zh
Priority to BRPI0913730A priority patent/BRPI0913730A2/pt
Priority to CA2738256A priority patent/CA2738256A1/en
Priority to AU2009299062A priority patent/AU2009299062A1/en
Priority to JP2011528163A priority patent/JP2012503607A/ja
Priority to EP09817185.3A priority patent/EP2351731B1/en
Priority to KR1020117007501A priority patent/KR20110053379A/ko
Priority to RU2011115572/04A priority patent/RU2011115572A/ru
Priority to US12/998,210 priority patent/US8710098B2/en
Priority to IL211864A priority patent/IL211864A0/en
Priority to ZA2011/03077A priority patent/ZA201103077B/en
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Abstract

本发明涉及一组胺基苯酰衍生物及其制备方法和应用；通过对hA3G/Vif为靶点的抗病毒药物筛选研究，证明3-胺基苯酰衍生物不仅具有抑制hA3G/Vif结合活性，还具有抑制病毒复制的作用，这对解决HIV耐药性问题可望取得突破性进展，从而为临床提供更有效的新型抗病毒药物。

Description

一组胺基苯酰衍生物及其制备方法和应用
技术领域：
本发明涉及一组胺基苯酰衍生物；本发明又涉及所述化合物的制备方法和在抗病毒中的应用；本发明还涉及所述化合物的药物组合物。
背景技术：
目前，临床上应用的抗病毒药物，其作用靶点均为病毒蛋白，作用机制为抑制病毒的复制或阻断病毒的侵入。病毒是“移动的靶”，依靠不断变异逃避药物攻击。以病毒蛋白为靶点的药物均造成病毒变异和耐药，已成为世界性难题。同样，目前临床常用的抗艾滋病病毒药物，其作用靶点均为HIV病毒蛋白，长期用药后会产生严重耐药问题，导致治疗失败。多药联合应用(鸡尾酒疗法)可大大降低患者病毒载量，减缓耐药发生，但最终还是难免发生耐药；新上市品种在抗耐药毒株上会有一定优势，但随着临床使用时间的延长，耐药性还是无法避免。因此，对付病毒耐药是当前要解决的主要课题。
随着病毒学和细胞生物学研究的不断深入，大量研究成果表明，在生物进化的漫长过程中，宿主细胞普遍形成针对不同病原病毒的防御体系，而病毒也会形成特异性的拮抗机制，来实现对宿主细胞抑制作用的逃避。病毒和宿主细胞之间相互依存和相互拮抗关系，特别是HIV-1相关细胞因子已经成为目前国际医学生物学基础和应用研究中最为前沿的方向和发展最为迅速的领域。
Vif(病毒感染性因子)是HIV-1基因组编码的病毒蛋白，在HIV-1的复制和感染过程中起着关键的作用。近来的研究表明，hA3G与Vif的生物学功能密切相关。hA3G是在人的淋巴细胞中表达的一种RNA/DNA编辑酶，归属于APOBEC蛋白超家族成员。APOBEC3G属于APOBEC家族，最新的研究结果表明，其可以导致HIV-1病毒基因组的GA超突变，高效抑制病毒的复制，是宿主细胞中天然产生的抗艾滋病病毒的细胞因子。
在以hA3G/Vif为靶点的抗病毒药物筛选研究中，本发明证实，3-胺基苯酰衍生物具有抑制hA3G/Vif结合活性，并具有抑制病毒复制的作用。本发明所述化合物及其作用，迄今为止未见有国内外相关文献的报道。发展针对新药物靶点hA3G的新型抗病毒化合物，对于解决HIV耐药性问题可望取得突破性进展，从而为临床提供更有效的新型抗病毒药物。
本发明的主要目的在于，通过对一组胺基苯酰衍生物的构效研究，筛选获得一类新的以hA3G/Vif为靶点的抗病毒化合物及药用盐，该类化合物不仅抑制hA3G/Vif结合，还具有显著的抗病毒活性。
发明内容：
本发明提供了一组胺基取代苯甲酰衍生物。
本发明提供了制备所述衍生物的方法。
本发明提供了含有这种胺基苯酰衍生物作为活性成分的药物组合物。
本发明还提供了该胺基苯酰衍生物及药用盐在抗病毒中的应用，尤其是在治疗HIV感染中的应用，包括与其它抗病毒化疗药物的联合应用。
本发明首先提供了具有以下通式(1)的胺基苯酰衍生物及药用盐：
其中：
R1代表：氢，连接于苯环的一个或多个硝基、卤素、氰基、酯基、酰胺基、羟基、巯基、取代或未取代的低级烷基、低级烷氧基或芳基氧基、低级烷硫基或芳基硫基、氨基、取代的氨基等；
R2，R3可以相同也可以不同，代表：氢，低级烷基，羰基或磺酰基；
X代表：O、S、NH、NR5、CH2或CHR6；
Y代表：C、S或SO；
R4、R5代表：氢、低级烃基、羟基、芳烃或取代的芳烃；
本发明按照上述定义通式(1)的胺基取代苯酰衍生物还包括其与酸发生成盐反应的产物。化合物(I)与酸成盐的例子可以有无机酸，如盐酸盐、氢溴酸盐和硫酸盐等；有机酸盐，如乙酸盐、乳酸盐、琥珀酸盐、富马酸盐、马来酸盐、柠檬酸盐、苯甲酸盐、甲磺酸盐和对苯甲酸盐等。
本发明从大量候选化合物筛选中所定义的胺基苯酰衍生物，其非限定性的结构示例可以有：
Figure G2008101688244D00031
Figure G2008101688244D00041
Figure G2008101688244D00051
Figure G2008101688244D00061
Figure G2008101688244D00071
Figure G2008101688244D00091
本发明进一步提供了该3-胺基苯酰衍生物或其盐作为hA3G/Vif结合抑制剂及其在制备抗病毒药物中的应用。
本发明另一方面还提供了一种抗病毒药物组合物，其包括治疗有效量的上述3-胺基苯酰衍生物或其药用盐及药学上可接受的药用辅料，可将化合物本身或其与可药用赋形剂、稀释剂等的混合物以片剂、胶囊、颗粒剂、散剂或糖浆剂的形式口服给药，或以注射剂的形式非口服给药。
上述制剂可通过常规制药方法制备。可用的药用辅剂的例子包括赋形剂(例如糖类衍生物如乳糖、蔗糖、葡萄糖、甘露糖醇和山梨糖醇；淀粉衍生物如玉米淀粉、土豆淀粉、糊精和羧甲基淀粉；纤维素衍生物如结晶纤维素、羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠；阿拉伯胶；右旋糖酐；硅酸盐衍生物如偏硅酸镁铝；磷酸盐衍生物如磷酸钙；碳酸盐衍生物如碳酸钙；硫酸盐衍生物如硫酸钙等)；粘合剂(例如明胶、聚乙烯吡咯烷酮和聚乙二醇)；崩解剂(例如纤维素衍生物如羧甲基纤维素钠、聚乙烯吡咯烷酮)；润滑剂(例如滑石、硬脂酸钙、硬脂酸镁、鲸蜡、硼酸、苯甲酸钠、亮氨酸)、稳定剂(对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等)；矫味剂(例如常用的甜味剂、酸味剂和香料等)；稀释剂和注射液用溶剂(例如水、乙醇和甘油等)。
本发明的3-胺基苯酰衍生物及可药用盐可以根据目的化合物中的X、Y的结构设计来确定起始物和反应物，例如，当X＝O、S、NH；Y＝羰基、磺酰基时，各类3-胺基苯酰衍生物可利用各类取代的3-胺基苯甲酸(磺酸)与芳基胺或酚进行缩合反应制备，具体过程可以是：
将保护的或酰化后的A与HOBT(1-羟基苯并三唑)，DIC(N，N′-二异丙基碳二亚胺)按适当比例混合溶于DMF(N，N-二甲基亚砜)中，大约半小时后加入B室温下反应24小时，产物用柱层析分离纯化。
其中，
X＝O、S或NH；
Y＝C、S或SO；
R1，R2，R3及R4同前。
上述过程中，起始原料3-胺基苯甲酸(磺酸)、芳基胺(酚)或苄基醇可以购买或由各种已知方法制备。
本发明还提供了所述化合物的药效学实验研究。
根据HIV-1病毒蛋白Vif介导的hA3G的降解作用的研究进展，本发明建立了以Vif介导的降解hA3G为靶点的抗HIV-1药物高通量筛选模型，以筛选能抑制该降解过程的小分子活性物质。这一模型的作用原理是，在细胞内共表达HIV-1的Vif和融合了荧光蛋白(yellow fluorescent protein(YFP))的hA3G，由于Vif对hA3G的降解造成融合在hA3G上的YFP的降解，从而导致胞内荧光强度(530nm)的下降。通过测定荧光强度的变化，可以定量分析筛选样品对Vif降解hA3G的影响。同时为了区分样品对泛素降解途径的非特异性抑制作用，本发明还建立了检测以腺病毒早期基因产物对P53的降解作用为复筛模型，以保证该模型所得到的阳性样品特异性地阻断Vif降解hA3G。结果参见表1。
采用HIV-1P24抗原试剂盒，测定了发明化合物的抑制HIV-1活性，测定结果见表2。
表1  发明化合物对hA3G的上调活性
 
化合物序号 分子式及分子量 hA3G上调活性(％)
1 C19H21ClN2O6408.83 36.3
262 C17H20N2O5332.35 36.2
3 C15H18N4O4318.33 20.2
4 C17H19NO6333.34 1.6
5 C17H19NO5S349.4 14.4
6 C18H21NO5331.36 28.7
261 C20H24N2O6388.41 43.9
351 C20H23NO7389.4 36.7
352 C22H27NO8433.45 37.0
353 C19H18F3NO7429.34 39.0
9 C20H23NO6S405.46 46.5
10 C21H25NO6387.43 28.9
11 C19H22N2O6374.39 22.2
12 C19H21NO7375.37 31.6
13 C20H23NO6373.4 42.1
14 C20H23ClN2O6422.86 11.2
15 C20H22ClNO6S439.91 19.4
16 C21H24ClNO6421.87 17.3
17 C19H21FN2O6392.38 31.1
18 C19H20FNO7393.36 34.5
19 C19H20FNO6S409.43 44.3
 
20 C20H22FNO6391.39 56.0
21 C20H22FNO6S423.46 21.1
22 C19H21NO6S391.44 24.6
23 C20H23FN2O6406.4 29.3
24 C20H22FNO7407.39 18.6
25 C21H24FNO6405.42 19.4
26 C20H23BrN2O6467.31 42.7
2612 C17H17N3O5343.33 22.3
27 C19H20ClNO7409.82 32.1
28 C20H22ClNO6407.84 33.6
29 C19H21BrN2O6453.28 25.3
30 C19H20BrNO7454.27 15.2
31 C21H25BrN2O6481.34 26.4
32 C21H27NO6389.44 17.6
33 C17H20N4O5360.36 21.5
34 C17H20N2O5332.35 38.3
35 C20H22BrNO7468.3 44.9
36 C18H22N2O4330.38 8.6
37 C17H20N2O3300.35 7.7
38 C20H25NO5359.42 17.4
40 C17H20N2O4316.35 12.7
41 C18H22N2O4330.38 21.8
42 C17H20N2O3300.35 34.3
43 C18H22N2O3314.38 26.4
45 C18H24N2O4332.39 27.6
46 C18H20N2O4328.36 29.1
47 C16H18N4O4330.34 18.2
48 C16H18N2O5318.32 16.4
 
49 C16H19N3O4317.34 9.8
50 C17H18N2O4314.34 -3.1
51 C16H17N3O4315.32 0.9
52 C20H23FN2O6406.4 10.1
53 C18H19FN2O4346.35 13.3
54 C16H18N2O3286.33 28.7
55 C15H16N2O3272.3 35.5
56 C15H16N2O2256.3 41.1
57 C19H22N2O4342.39 24.0
58 C19H22N2O6374.39 16.6
59 C20H24N2O6388.41 19.8
60 C17H18N2O3298.34 16.3
61 C15H16N4O3300.31 11.8
62 C20H23NO7389.4 40.1
63 C20H24N2O6388.41 21.3
64 C20H24N2O6388.41 11.7
67 C18H17F3N2O4382.33 11.3
68 C18H18N2O5342.35 9.8
69 C18H17F3N2O3366.33 31.2
70 C17H14F4N2O3370.3 24.7
71 C18H19ClN2O5378.81 30.1
72 C18H18ClNO6379.79 24.3
73 C19H18F3NO6413.34 29.0
74 C19H19F3N2O5412.36 8.5
75 C20H23FN2O6406.4 -1.1
76 C20H21F3N2O5426.39 16.7
77 C20H23FN2O6406.4 14.9
78 C18H19FN2O4 8.8
 
346.35
79 C20H23FN2O6406.4 21.6
80 C17H18FN3O3331.34 37.1
81 C20H25N3O5387.43 14.4
82 C19H24N2O6S408.47 28.5
83 C19H24N2O7S424.47 31.0
84 C19H23NO8S425.45 9.0
85 C16H20N2O6S368.4 6.8
86 C20H23NO7389.4 20.3
87 C17H19NO6333.34 19.7
88 C19H22N2O6374.39 24.8
89 C19H25N3O5375.42 31.3
90 C16H19NO7S369.39 28.2
91 C19H24N2O7S424.47 16.6
92 C16H20N4O6S396.42 23.7
93 C16H20N4O6S396.42 34.2
94 C18H22N2O6S394.44 16.1
95 C18H21FN2O6S412.43 8.7
96 C18H23N3O5S393.46 6.9
97 C18H21N3O6S407.44 6.4
98 C15H16FN3O4S353.37 5.8
99 C18H21N3O6S407.44 23.6
100 C17H18FN3O5S395.41 13.6
101 C18H22N2O7S410.44 22.1
102 C17H20N2O6S380.42 10.3
 
103 C18H21NO8S411.43 26.1
2611 C18H20N2O4328.36 28.9
2613 C17H17ClN2O3332.78 27.8
2621 C15H16N2O3272.3 36.2
263 C19H19F3N2O6428.36 24.4
表2  发明化合物抑制HIV-1活性
 
化合物 IC50(μg/ml)
26 0.0203
261 0.0227
262 0.0244
263 <0.0137
2611 0.0174
2613 0.0138
2621 <0.0137
35 0.0223
351 0.0299
352 0.0554
AZT 5.78×10-5
以上结果初步验证了本发明化合物或其药用盐在抑制hA3G/Vif结合及抗病毒方面的作用，为其作为抗病毒药物的开发应用奠定了基础。
具体实施方式：
以下实施例可以进一步帮助本领域技术人员了解本发明，但不以任何方式限制本发明。
<实施例1>、(3-丙酰胺基-4-甲氧基苯)甲酰(3’，4’，5’-三甲氧基苯)胺(261)的合成
在25ml的烧瓶中，将0.6g3-氨基-4-甲氧基苯甲酸(1.0g，6mmol)溶于干燥的THF(四氢呋喃)后，加入三乙胺(1.2ml，12mmol)得到黄色透明溶液，氮气保护，搅拌，冰水浴条件下向其中滴加丙酰氯(0.78ml，9mmol)，滴加完毕后自然恢复室温反应。过滤反应液，滤液蒸干后上硅胶柱分离得到3-丙酰胺基-4-甲氧基苯甲酸1.3g(收率67％)。
将上述产物100mg在冰水浴条件下与HOBT 53mg(mmol)，DIC 0.03ml(mmol)混合在干燥DMF中，N2保护，搅拌30min后加入3，4，5-三甲氧基苯胺72mg(mmol)，自然恢复室温搅拌过夜。减压蒸干反应液，残余物用乙酸乙酯溶解后过滤，滤液蒸干后用制备薄层硅胶板分离得到化合物261 40mg(收率30％)。
1H NMR(CDCl3，δ)1.3(t，3H，CH3)，2.5(q，2H，CH2)，3.82(s，3H，4’-OCH3)，3.9(s，6H，3’，5’-OCH3)，3.95(s，3H，4-OCH3)，6.98(s，2H，2’，6’-H)，7.0(d，1H，5-H)，7.8(dd，1H，6-H)，7.9(br，2H，NH)，8.9(d，1H，2-H)
<实施例2>、(3-丙酰胺基-4-甲氧基苯)甲酸(3’，4’，5’-三甲氧基苯基)酯(351)的合成
以3-氨基-4-甲氧基苯甲酸、丙酰氯和3，4，5-三甲氧基苯酚为原料，按照实施例1的类似方法，合成得到化合物351，两步收率30％。
1H NMR(CDCl3，δ)1.3(t，3H，CH3)，2.5(q，2H，CH2)，3.8(s，9H，4’，5’，6’-OCH3)，3.95(s，3H，4-OCH3)，6.44(s，2H，2’，6’-H)，6.98(d，1H，5-H)，7.76(br，1H，3-NHCO)，7.9(dd，1H，6-H)，7.9(br，1H，1-CONH)，9.2(d，1H，2-H)
<实施例3>、(3-三氟乙酰胺基-4-甲氧基苯)甲酰(3’，4’，5’-三甲氧基苯基)胺(263)的合成
以3-氨基-4-甲氧基苯甲酸、三氟乙酰氯和3，4，5-三甲氧基苯胺为原料，按照实施例1的类似方法，合成得到化合物263，两步收率50％。
1H NMR(CDCl3，δ)3.84(s，9H，4’，5’，6’-OCH3)，4.0(s，3H，4-OCH3)，6.97(s，2H，2’，6’-H)，7.03(d，1H，5-H)，7.86(d，1H，6-H)，7.9(s，1H，3-NHCOR)，8.6(s，1H，1-CONH)，8.75(s，1H，2-H)
<实施例4>、(3-三氟乙酰胺基-4-甲氧基苯)甲酸(3’，4’，5’-三甲氧基苯基)酯(353)的合成
以3-氨基-4-甲氧基苯甲酸、三氟乙酰氯和3，4，5-三甲氧基苯酚为原料，按照实施例1的类似方法，合成得到化合物353，两步收率40％。
1H NMR(CDCl3，δ)3.85(s，9H，4’，5’，6’-OCH3)，4.0(s，3H，4-OCH3)，6.46(s，2H，2’，6’-H)，7.05(d，1H，5-H)，8.07(dd，1H，6-H)，8.54(s，1H，3-NHCOR)，9.12(s，1H，2-H)
<实施例5>、(3-丙酰胺基-4-甲氧基苯)甲酰(4’-氯苯)胺(2613)的合成
以3-氨基-4-甲氧基苯甲酸、丙酰氯和4-氯苯胺为原料，按照实施例1的类似方法，合成得到化合物2613，两步收率30％。
1H NMR(CDCl3，δ)1.28(t，3H，CH3)，2.48(q，2H，CH2)，3.96(s，3H，4’-OCH3)，6.98(d，1H，5-H)，7.33(d，2H，2’，6’-H)，7.6(d，2H，3’，5’-H)，7.77(dd，1H，6-H)，7.8(s，1H，3-NHCOR)，8.0(br，1H，1-CONH)，8.87(s，1H，2-H)
<实施例6>、(3-丙酰胺基-4-甲氧基苯)甲酰(4’-甲氧基苯)胺(2611)的合成
以3-氨基-4-甲氧基苯甲酸、丙酰氯和4-甲氧基苯胺为原料，按照实施例1的类似方法，合成得到化合物2611，两步收率70％。
1H NMR(DMSO-d6，δ)1.07(t，3H，CH3)，2.4(q，2H，CH2)，3.73(s，3H，4’-OCH3)，3.89(s，3H，4-OCH3)，6.89(d，2H，2’，6’-H)，7.1(d，1H，5-H)，7.6(d，2H，3’，5’-H)，7.7(dd，1H，6-H)，8.48(br，1H，3-NHCOR)，9.15(s，1H，2-H)，10.0(s，1H，1-CONH)
<实施例7>、[3-(2-氯乙酰氨基)-4-甲氧基苯]甲酰(3’，4’，5’-三甲氧基苯)胺(1)的合成
以3-氨基-4-甲氧基苯甲酸、2-氯乙酰氯和3，4，5-三甲氧基苯胺为原料，按照实施例1的类似方法，合成得到化合物1，两步收率56％。
1H NMR(CDCl3，δ)4.5(s，2H，CH2)，3.82(s，3H，4’-OCH3)，3.9(s，6H，3’，5’-OCH3)，3.95(s，3H，4-OCH3)，6.98(s，2H，2’，6’-H)，7.0(d，1H，5-H)，7.8(dd，1H，6-H)，7.9(br，2H，NH)，8.9(d，1H，2-H)
<实施例8>、(3-丙酰胺基-4-甲氧基苯)甲酸(3’，4’5’-三甲氧基苯巯基)酯(9)的合成
以3-氨基-4-甲氧基苯甲酸、丙酰氯和3’，4’，5’-三甲氧基苯硫酚为原料，按照实施例1的类似方法，合成得到化合物9，收率50％。
1H NMR(CDCl3，δ)1.3(t，3H，CH3)，2.5(q，2H，CH2)，3.8(s，9H，4’，5’，6’-OCH3)，3.95(s，3H，4-OCH3)，6.44(s，2H，2’，6’-H)，6.98(d，1H，5-H)，7.76(br，1H，NH)，7.9(dd，1H，6-H)，7.9(br，2H，NH)，9.2(d，1H，2-H)
<实施例9>、[3-(2-氟丙酰胺基)-4-甲氧基苯]甲酸(3’，4’5’-三甲氧基苯巯基)酯(21)的合成
以3-氨基-4-甲氧基苯甲酸、2-氟丙酰氯和3’，4’，5’-三甲氧基苯硫酚为原料，按照实施例1的类似方法，合成得到化合物21，收率54％。
1H NMR(CDCl3，δ)1.3(d，3H，CH3)，4.5(q，1H，CH)，3.8(s，9H，4’，5’，6’-OCH3)，3.95(s，3H，4-OCH3)，6.44(s，2H，2’，6’-H)，6.98(d，1H，5-H)，7.76(br，1H，NH)，7.9(dd，1H，6-H)，7.9(br，2H，NH)，9.2(d，1H，2-H)
<实施例10>、(3-甲氧基-4-丙酰胺基苯)甲酰(3’，4’5’-三甲氧基苯)胺(64)的合成
以3-甲氧基-4-氨基苯甲酸、丙酰氯和3’，4’，5’-三甲氧基苯胺为原料，按照实施例1的类似方法，合成得到化合物64，收率57％。
1H NMR(CDCl3)δ1.3(t，3H，CH3)，2.5(q，2H，CH2)，3.82(s，3H，4’-OCH3)，3.9(s，6H，3’，5’-OCH3)，3.95(s，3H，4-OCH3)，6.98(s，2H，2’，6’-H)，7.0(d，1H，2-H)，7.8(dd，1H，6-H)，7.9(br，2H，NH)，8.0(d，1H，5-H)
<实施例11>、(3-丙酰胺基-4-甲氧基苯)甲酰(4’-甲氧基呋喃-2’-)胺(48)的合成
以3-氨基-4-甲氧基苯甲酸、丙酰氯和4-甲氧基呋喃-2-胺为原料，按照实施例1的类似方法，合成得到化合物48，收率70％。
1H NMR(DMSO-d6，δ)1.07(t，3H，CH3)，2.4(q，2H，CH2)，3.89(s，3H，4-OCH3)，4.73(s，3H，4’OCH3)，6.89(s，1H，5’-H)，7.6(d，1H，5-H)，7.7(dd，1H，6-H)，7.89(s，1H，3’-H)，8.48(br，1H，3-NHCOR)，9.15(s，1H，2-H)，10.0(s，1H，1-CONH)
<实施例12>、(3-丙酰胺基-4-甲氧基苯)甲酰(4’-甲氧基吡咯-2’-)胺(49)的合成
以3-氨基-4-甲氧基苯甲酸、丙酰氯和4-甲氧基吡咯-2-胺为原料，按照实施例1的类似方法，合成得到化合物49，收率68％。
1H NMR(DMSO-d6，δ)1.07(t，3H，CH3)，2.4(q，2H，CH2)，3.89(s，3H，4-OCH3)，4.73(s，3H，4’OCH3)，6.76(s，1H，5’-H)，7.6(d，1H，5-H)，7.7(dd，1H，6-H)，7.72(s，1H，3’-H)，8.48(br，1H，3-NHCOR)，9.15(s，1H，2-H)，10.0(s，1H，1-CONH)
<实施例13>、(3-丙酰胺基-4-甲氧基苯)甲酰-(嘧啶4’-)胺(61)的合成
以3-氨基-4-甲氧基苯甲酸、丙酰氯和4-氨基嘧啶为原料，按照实施例1的类似方法，合成得到化合物61，收率47％。
1H NMR(DMSO-d6，δ)1.07(t，3H，CH3)，2.4(q，2H，CH2)，3.89(s，3H，4-OCH3)，6.76(d，1H，5’-H)，7.2(d，1H，5-H)，7.6(d，1H，5-H)，7.7(dd，1H，6-H)，8.2(s，1H，3’-H)，8.48(br，1H，3-NHCOR)，9.15(s，1H，2-H)，10.0(s，1H，1-CONH)
<实施例14>、(2-丙酰胺基-4-甲氧基苯)甲酰(3’，4’5’-三甲氧基苯)胺(63)的合成
以4-甲氧基-2-氨基苯甲酸、丙酰氯和3’，4’，5’-三甲氧基苯胺为原料，按照实施例1的类似方法，合成得到化合物63，收率64％。
1H NMR(CDCl3，δ)1.3(t，3H，CH3)，2.5(q，2H，CH2)，3.82(s，3H，4’-OCH3)，3.9(s，6H，3’，5’-OCH3)，3.95(s，3H，4-OCH3)，6.98(s，2H，2’，6’-H)，7.0(d，1H，3-H)，7.8(dd，1H，6-H)，7.9(br，2H，NH)，8.0(d，1H，5-H)
<实施例15>、(3--丙酰胺基-4-甲基苯)甲酰(4’-三氟甲氧基苯)胺(69)的合成
以3-氨基-4-甲基苯甲酸、丙酰氯和4-三氟甲氧基苯胺为原料，按照实施例1的类似方法，合成得到化合物69，收率49％。
1H NMR(DMSO-d6，δ)1.07(t，3H，CH3)，2.4(q，2H，CH2)，2.5(s，3H，4-CH3)，3.89(s，3H，4-OCH3)，6.89(d，2H，2’，6’-H)，7.1(d，1H，5-H)，7.6(d，2H，3’，5’-H)，7.7(dd，1H，6-H)，8.48(br，1H，3-NHCOR)，9.15(s，1H，2-H)，10.0(s，1H，1-CONH)
<实施例16>、(3-乙酰胺基-5-三氟甲基苯)甲酸(3’，4’，5’-三甲氧基苯基)酯(73)的合成
3-氨基-5-三氟甲基苯甲酸、乙酰氯和3，4，5-三甲氧基苯酚为原料，按照实施例1的类似方法操作，合成得到化合物73，收率61％。
1H NMR(CDCl3，δ)2.3(s，3H，CH3)，3.8(s，9H，4’，5’，6’-OCH3)，6.44(s，2H，2’，6’-H)，6.98(d，1H，5-H)，7.76(br，1H，NH)，7.9(dd，1H，6-H)，7.9(br，2H，NH)，9.2(d，1H，2-H)
<实施例17>、(3-乙酰胺基-4-氟-5-甲氧基苯)甲酰(3’，4’，5’-三甲氧基苯)胺(75)的合成
以3-氨基-4-氟-5-甲氧基苯甲酸、丙酰氯和3，4，5-三甲氧基苯胺为原料，按照实施例1的类似方法操作，合成得到化合物75，收率76％。
1H NMR(CDCl3，δ)2.3(s，3H，CH3)，3.8(s，9H，4’，5’，6’-OCH3)，3.97(s，3H，5-OCH3)，6.44(s，2H，2’，6’-H)，7.76(br，1H，NH)，7.9(d，1H，6-H)，7.9(br，1H，NH)，9.2(d，1H，2-H)
<实施例18>、(3-丙酰胺基-4-甲氧基-6-氟苯)甲酰(3’，4’，5’-三甲氧基苯)胺(79)的合成
以3-氨基-4-甲氧基-6-氟苯甲酸、丙酰氯和3，4，5-三甲氧基苯胺为原料，按照实施例1的类似方法操作，合成得到化合物79，收率66％。
1H NMR(CDCl3，δ)1.07(t，3H，CH3)，2.3(q，2H，CH2)，3.8(s，9H，4’，5’，6’-OCH3)，3.97(s，3H，4-OCH3)，6.44(s，2H，2’，6’-H)，7.76(br，1H，NH)，7.9(s，1H，5-H)，7.9(br，1H，NH)，9.2(s，1H，2-H)
<实施例19>、(3-丙酰胺基-4-甲氧基苯)甲酰(3’-氟-4’-胺基苯)胺(80)的合成
以3-氨基-4-甲氧基苯甲酸、丙酰氯和3-氟-1，4-苯二胺为原料，按照实施例1的类似方法操作，合成得到化合物80，收率60％。
1H NMR(CDCl3，δ)1.07(t，3H，CH3)，2.4(q，2H，CH2)，3.89(s，3H，4-OCH3)，6.89(d，2H，2’，6’-H)，7.1(d，1H，5-H)，7.6(d，1H，5’-H)，7.7(dd，1H，6-H)，8.3(d，1H，6’-H)，8.48(br，1H，3-NHCOR)，9.15(s，1H，2-H)，9.3(s，1H，2’-H)，10.0(s，1H，1-CONH)
<实施例20>、(3-丙酰胺基-4-甲氧基苯)磺酰(3’，4’5’-三甲氧基苯)胺(83)的合成
以3-氨基-4-甲氧基苯磺酸、丙酰氯和3，4，5-三甲氧基苯胺为原料，按照实施例1的类似方法操作，合成得到化合物83，收率63％。
1H NMR(DMSO-d6，δ)1.03(t，3H，CH3)，2.5(q，2H，CH2)，3.8(s，9H，4’，5’，6’-OCH3)，3.95(s，3H，4-OCH3)，6.7(s，2H，2’，6’-H)，7.3(d，1H，5-H)，7.7(br，1H，CONH)7.9(dd，1H，6-H)，8.8(br，1H，SO2NH)，9.2(d，1H，2-H)。
<实施例21>、(3-丙酰胺基-4-甲氧基苯)磺酸(3’，4’5’-三甲氧基苯基)酯(84)的合成
以3-氨基-4-甲氧基苯磺酸、丙酰氯和3，4，5-三甲氧基苯酚缩合，按照实施例1的类似方法操作，合成得到化合物84，收率53％。
1H NMR(CDCl3，δ)1.03(t，3H，CH3)，2.5(q，2H，CH2)，3.8(s，9H，4’，5’，6’OCH3)，3.95(s，3H，4-OCH3)，6.7(s，2H，2’，6’-H)，7.3(d，1H，5-H)，7.7(br，1H，CONH)7.9(dd，1H，6-H)，9.2(d，1H，2-H)
<实施例22>、(3’，4’，5’-三甲氧基苯)磺酰(3-丙酰胺基-4-甲氧基苯)胺(91)的合成
以3-丙酰胺基-4-甲氧基苯胺和3，4，5-三甲氧基苯磺酸为原料，按照实施例1的类似方法操作，合成得到化合物91，收率40％。
1H NMR(DMSO-d6，δ)1.03(t，3H，CH3)，2.5(q，2H，CH2)，3.8(s，9H，3’，4’，5’-OCH3)，3.95(s，3H，4-OCH3)，6.3(d，1H，6-H)，6.7(br，1H，CONH)6.9(dd，1H，5-H)，7.7(s，2H，2’，6’-H)，8.8(br，1H，SO2NH)，9.2(d，1H，2-H)
<实施例23>、(3-甲磺酰胺基-4-甲氧基苯)甲酸(3’，4’，5’-三甲氧基苯基)酯(103)的合成
以3-氨基-4-甲氧基苯甲酸、甲磺酰氯和3，4，5-三甲氧基苯酚缩合，按照实施例1的类似方法操作，合成得到化合物103，收率52％。
1H NMR(DMSO-d6，δ)2.5(s，3H，CH3)，3.8(s，9H，3’，4’，5’OCH3)，3.95(s，3H，4-OCH3)，6.7(s，2H，2’，6’-H)，7.3(d，1H，5-H)，7.7(br，1H，CONH)7.9(dd，IH，6-H)，9.2(d，1H，2-H)
<实施例24>、(3-三氟乙酰胺基-4-甲氧基苯)甲酸(3’，4’，5’-三甲氧基苯基)酯(353)的合成
以3-氨基-4-甲氧基苯甲酸、三氟乙酰氯和3，4，5-三甲氧基苯酚为原料，按照实施例1的类似方法，合成得到化合物353，两步收率46％。
1H NMR(CDCl3，δ)3.8(s，9H，3’，4’，5’OCH3)，6.44(s，2H，2’，6’-H)，6.98(d，1H，5-H)，7.76(br，1H，NH)，7.9(dd，1H，6-H)，9.2(d，1H，2-H)
<实施例25>、(3-丙酰胺基-4-甲氧基苯)甲酰(4’-硝基苯)胺(2612)的合成
以3-氨基-4-甲氧基苯甲酸、丙酰氯和4-硝基苯胺为原料，按照实施例1的类似方法，合成得到化合物2612，收率53％。
1H NMR(DMSO-d6，δ)1.07(t，3H，CH3)，2.4(q，2H，CH2)，3.73(s，3H，4’OCH3)，3.89(s，3H，4-OCH3)，6.89(d，2H，2’，6’-H)，7.1(d，1H，5-H)，7.7(dd，1H，6-H)，8.3(d，2H，3’，5’-H)，8.48(br，1H，3-NHCOR)，9.15(s，1H，2-H)，10.0(s，1H，1-CONH)
<实施例26>、(3-丙酰胺基-4-甲氧基苯)甲酰(4’-氯苯)胺(2613)的合成
以3-氨基-4-甲氧基苯甲酸、丙酰氯和4-氯苯胺为原料，按照实施例1的类似方法，合成得到化合物2613，收率56％。
1H NMR(DMSO-d6，δ)1.07(t，3H，CH3)，2.4(q，2H，CH2)，3.73(s，3H，4’-OCH3)，3.89(s，3H，4-OCH3)，6.6(d，2H，2’，6’-H)，7.1(d，1H，5-H)，7.7(dd，1H，6-H)，8.2(d，2H，3’，5’-H)，8.48(br，1H，3-NHCOR)，9.15(s，1H，2-H)，10.0(s，1H，1-CONH)
<实施例27>、(3-睛基-4-甲氧基苯)甲酰(3’，4’，5’-三甲氧基苯)胺(68)的合成
以3-睛基-4-甲氧基苯甲酸和3，4，5-三甲氧基苯胺为原料，按照实施例1的类似方法，合成得到化合物68，收率60％。
1H NMR(CDCl3，δ)3.82(s，3H，4’OCH3)，3.9(s，6H，3’，5’-OCH3)，3.95(s，3H，4-OCH3)，6.68(s，2H，2’，6’-H)，6.8(d，1H，5-H)，7.0(dd，1H，6-H)，7.9(br，2H，NH)，8.9(d，1H，2-H)
按照实施例1的类似方法，合成得到的化合物还包括11、12、14、15、17、18、19、21、22、23、24、26、27、29、30、31、33、35、46、47、50、51、52、53、57、58、59、60、62、67、70、71、72、74、76、77、78、81、82、86、88、89、92、93、94、95、96、97、99、100、101、102、104。
<实施例28>、(3-氨基-4-甲氧基苯)甲酰(3’，4’，5’-三甲氧基苯)胺(262)的合成
1)将1.0g(6mmol)3-氨基-4-甲氧基苯甲酸溶于10ml的4N NaOH水溶液中，向其中缓慢滴加2.5ml(11mmol)叔丁酸酐，加热至50℃反应至完全，将碱水液用1N的盐酸快速酸化至Ph＝2，用氯仿提取三次，合并氯仿液，无水硫酸钠干燥后浓缩蒸干得到的类白色固体0.8g，收率50％。
2)将1)的产物200mg(0.8mmol)在冰水浴条件下与120mg(0.9mmol)HOBT，0.06ml(0.6mmol)DIC混合在干燥DMF中，N2保护，搅拌30min后加入160mg(0.9mmol)3，4，5-三甲氧基苯胺，自然恢复室温搅拌过夜。减压蒸干反应液，残余物用乙酸乙酯溶解后过滤，滤液蒸干后用制备薄层硅胶板分离得到产物180mg，收率55.6％。
3)将2)的产物160mg的溶于6ml甲醇，向其中滴加乙酰氯0.12ml，室温反应至完全脱去叔丁酰保护基，蒸干反应液后，残余物用二氯甲烷10ml混匀后过滤得到白色固体(262)60mg，收率49％。
1H NMR(DMSO-d6，δ)3.62(s，3H，4’OCH3)，3.78(s，6H，3’，5’-OCH3)，3.95(s，3H，4-OCH3)，4.5(br，2H，-NH2)，7.1(d，1H，5-H)，7.2(s，2H，2’，6’-H)，7.6(s，1H，6-H)，7.7(s，1H，2-H)，10.0(s，1H，1-CONH)
<实施例29>、(3-氨基-4-甲氧基苯)甲酰苯胺(2621)的合成
以3-氨基-4-甲氧基苯甲酸和苯胺为原料，按照实施例28的类似方法，合成得到化合物2621，收率37％。
1H NMR(DMSO-d6，δ)3.55(s，3H，4-OCH3)，4.5(br，2H，-NH2)，7.0(m，1H，4’-H)，7.1(d，1H，5-H)，7.2(d，2H，2’，6’-H)，7.4(dd，2H，3’，5’-H)，7.6(d，1H，6-H)，7.7(s，1H，2-H)，10.0(s，1H，1-CONH)
<实施例30>、(3-甲胺基-4-甲氧基苯)甲酰(3’-氟-4’-磺胺基苯)胺(98)的合成
以3-甲胺基-4-甲氧基苯甲酸和3-氟-4-磺胺基苯胺为原料，按照实施例28的类似方法操作，合成得到化合物98，收率52％。
1H NMR(DMSO-d6，δ)2.5(br，2H，-NH2)，2.8(d，3H，3-CH3)，3.75(s，3H，4-OCH3)，4.5(br，1H，3-NH)，6.5(m，1H，6’-H)，6.67(s，1H，2’-H)，6.8(d，1H，5-H)，7.2(d，1H，5’-H)，7.4(dd，2H，3’，5’-H)，7.6(d，1H，6-H)，7.7(s，1H，2-H)，10.0(s，1H，1-CONH)
<实施例31>、(3-甲胺基-4-羟基苯)甲酰(2’，6’-二甲氧基嘧啶-4’-)胺(3)的合成
以3-甲胺基-4-羟基苯甲酸和2，6-二甲氧基4-氨基嘧啶为原料，按照实施例28的类似方法，合成得到化合物3，收率67％。
1H NMR(DMSO-d6，δ)2.8(d，3H，3-CH3)，3.73(s，3H，6’-OCH3)，3.77(s，3H，2’OCH3)，4.4(br，1H，3-NH)，5.1(br，1H，4-OH)，6.8(d，1H，5-H)，7.2(d，1H，5’-H)，7.6(d，1H，6-H)，7.7(s，1H，2-H)，9.2(s，1H，1-CONH)
<实施例32>、(3-氨基-4-甲氧基苯)甲酸(3’，4’，5’-三甲氧基苯巯基)酯(5)的合成
以3-氨基-4-甲氧基苯甲酸和3，4，5-三甲氧基苯硫酚为原料，按照实施例28的类似方法，合成得到化合物5，收率47％。
1H NMR(DMSO-d6，δ)3.62(s，3H，4’-OCH3)，3.78(s，6H，3’，5’-OCH3)，3.95(s，3H，4-OCH3)，4.2(br，2H，-NH2)，7.1(d，1H，5-H)，7.3(s，2H，2’，6’-H)，7.6(s，1H，6-H)，7.7(s，1H，2-H)
<实施例33>、(3-甲胺基-4-甲氧基苯)甲酰(3，5-二甲氧基苯)胺(40)的合成
以3-甲胺基-4-甲氧基苯甲酸和3，5-二甲氧基苯胺为原料，按照实施例28的类似方法，合成得到化合物40，收率50％。
1H NMR(DMSO-d6，δ)2.4(d，3H，3-CH3)，3.75(s，3H，4-OCH3)，3.8(s，6H，3’，5’-OCH3)，5.0(br，1H，3-NH)，6.5(s，2H，2’，6’-H)，6.8(d，1H，5-H)，7.6(d，1H，6-H)，7.7(s，1H，2-H)，9.4(s，1H，1-CONH)
<实施例34>、(3-氨基-4-甲氧基苯)磺酰(3，4，5-二甲氧基苯)胺(85)的合成
以3-氨基-4-甲氧基苯磺酸和3，4，5-二甲氧基苯胺为原料，按照实施例28的类似方法，合成得到化合物85，收率52％。
1H NMR(DMSO-d6)δ3.62(s，9H，3’，4’，5’-OCH3)，3.78(s，3H，4-OCH3)，4.2(br，2H，-NH2)，7.1(d，1H，5-H)，7.3(s，2H，2’，6’-H)，7.6(s，1H，6-H)，7.7(s，1H，2-H)，8.5(br，1H，-SO2NH)
<实施例35>、(3-羟基-4-甲氧基苯)甲酰(3’，4’，5’-三甲氧基苯)胺(87)的合成
以3-羟基-4-甲氧基苯甲酸和3，4，5-二甲氧基苯胺为原料，按照实施例28的类似方法，合成得到化合物87，收率34％。
1H NMR(DMSO-d6，δ)3.62(s，9H，3’，4’，5’-OCH3)，3.78(s，3H，4-OCH3)，5.2(br，1H，-OH)，7.1(d，1H，5-H)，7.3(s，2H，2’，6’-H)，7.6(s，1H，6-H)，7.7(s，1H，2-H)，8.9(br，1H，-CONH)
<实施例36>、(3-氨基-4-甲氧基苯)甲酸(3’，4’，5’-三甲氧基苯基)酯(352)的合成
以3-氨基-4-甲氧基苯甲酸和3，4，5-三甲氧基苯酚为原料，按照实施例28的类似方法操作，合成得到化合物352，收率30％。
1H NMR(DMSO-d6，δ)3.65(s，3H，4’-OCH3)，3.75(s，6H，3’，5’OCH3)，3.85(s，3H，4-OCH3)，5.05(br，2H，-NH2)，6.56(s，2H，2’，6’-H)，6.94(d，1H，5-H)，7.35(d，1H，6-H)，7.38(s，1H，2-H)
按照实施例28的类似方法，合成得到的化合物还包括4、6、34、36、37、41、42、43、45、54、55、56、90。
<实施例37>、(3-丙酰胺基-4-甲氧苯基)(3’，4’，5’-三甲氧基苄基)酮(10)的合成
在25ml的烧瓶中将0.6g 3-氨基-4-甲氧基苯甲酸(1.0g，6mmol)溶于干燥的四氢呋喃后，加入三乙胺(1.2ml，12mmol)得到黄色透明溶液，氮气保护，搅拌，冰水浴条件下向其中滴加丙酰氯(0.78ml，9mmol)，滴加完毕后自然恢复室温反应。过滤反应液，滤液蒸干后上硅胶柱分离得到3-丙酰胺基-4-甲氧基苯甲酸1.3g。
3-丙酰胺基-4-甲氧基苯甲酸1.3g与10ml二氯亚砜混合，并于室温下搅拌1小时以上。蒸除过量的二氯亚砜，用甲苯带蒸数次以保证二氯亚砜除干净，残余物溶于无水乙醚中，冰水冷却下加入等当量的3，4，5-三甲氧基苄基镉，维持温度在0～-5℃反应1小时以上。按照格氏反应的常规方法处理反应，得目标化合物物(10)1.2g(收率52％)。
1H NMR(CDCl3，δ)1.03(t，3H，CH3)，2.5(q，2H，CH2)，3.4(s，2H，-COCH2)，3.8(s，9H，4’，5’，6’OCH3)，3.95(s，3H，4-OCH3)，6.7(s，2H，2’，6’-H)，7.3(d，1H，5-H)，7.4(s，1H，3-NHCO)，7.9(dd，1H，6-H)，8.4(s，1H，1-CONH)，9.2(s，1H，2-H)
<实施例38>、[3-(2-氟丙酰胺基)-4-甲氧苯基](3’，4’，5’-三甲氧基苄基)酮(25)的合成
以3-氨基-4-甲氧基苯甲酸、2-氟丙酰氯和3，4，5-三甲氧基苄基镉为原料，按照实施例37类似方法，合成得到化合物25(收率57％)
1H NMR(CDCl3，δ)1.3(d，3H，CH3)，3.2(s，2H，-COCH2)，3.8(s，9H，4’，5’，6’-OCH3)，3.95(s，3H，4-OCH3)，4.5(q，1H，CHF)，6.44(s，2H，2’，6’-H)，6.98(d，1H，5-H)，7.16(br，1H，3-NHCO)，7.4(dd，1H，6-H)，7.9(br，1H，1-CONH)，9.2(d，1H，2-H)
<实施例39>、1-(3’-丙酰胺基-4-甲氧苯基)-2-(3”，4”，5”-三甲氧基苯基)乙醇(32)的合成
将实施例38所得产物25溶于甲醇中，加入适量NaBH4还原，原料消失后终止反应，分离得到目标化合物32(收率86)。
1H NMR(DMSO-d6，δ)1.03(t，3H，CH3)，2.5(q，2H，CH2)，3.8(s，9H，4’，5’，6’-OCH3)，3.95(s，3H，4-OCH3)，4.4(d，2H，2-CH2)，5.0(t，IH，1-CH)，6.7(s，2H，2”，6”-H)，7.3(d，1H，5’-H)，7.4(s，1H，3’-NHCO)，7.9(dd，1H，6’-H)，9.2(s，1H，2’-H)
按照实施例37的类似方法，合成得到的化合物包括13、16、20、28。
<实施例40>、hA3G上调活性筛选实验
取细胞进行培养，待细胞长满培养瓶后，弃旧培养基，用消化液消化。待细胞变圆，弃消化液，立即加入培养基，用吸管轻轻吹打瓶底，使细胞完全脱离瓶底且使之分散为单细胞悬液。血球计数板计数后，取细胞悬液接种于培养皿，用于进行细胞转染。将含有转染质粒和转染试剂的培养基轻轻混匀，室温孵育后，加到细胞培养上清中，培养一段时间。然后吸去旧的培养基，用消化液消化，弃消化液，立即加入培养基，轻轻吹打，使细胞分散为单细胞悬液。血球计数板计数后，接种。
化合物样品：取纯品化合物溶到DMS0中，加水倍比稀释，取
稀释液作用于细胞体系。
在细胞培养上清中加入不同浓度的检测样品。继续培养后，吸去旧的培养基，用磷酸缓冲液(PBS)吹打细胞，直至细胞完全脱离。
将细胞悬液转移到黑板中，检测荧光强度，激发波长为485nm，检测波长为520nm。测量两次取平均值。
测定的荧光强度减去空白对照组的数值作为各组YFP荧光强度数值。
相对荧光强度＝实验组荧光强度/阳性组荧光强度×100％
降解抑制率＝(样品实验组—阴性对照组)/(阳性组—阴性对照组)×100％
筛选结果列入表1。
<实施例41>、抑制HIV-1活性测定实验
在96孔细胞培养中加入8个不同稀释浓度的表2化合物样品的DMSO溶液和阳性对照药AZT(齐多呋啶，0.15ng/ml)DMSO溶液，每个稀释度重复2孔，设细胞对照；再将2×105细胞/ml 100μl接种于含药96孔细胞培养板内。置37℃、5％CO2和饱和湿度培养箱内培养，每天观察细胞病变。按HIV-1 P24抗原试剂盒提供的操作步骤，测定加药后第4天(96小时)细胞培养上清HIV-1 P24抗原含量，计算药物对病毒的抑制活性，结果列入表2。

Claims (7)

1.一组胺基苯酰衍生物，其结构如式（I）所示：
Figure FDA00002682512600011
其中：
R1代表甲氧基；
R2，R3可以相同也可以不同，代表：氢，低级烷基，2-氯乙酰基，2-氟乙酰基，2-溴乙酰基，2-氯丙酰基，2-氟丙酰基，2-溴丙酰基，乙酰基，丙酰基，2-溴丁酰基，甲磺酰基，三氟乙酰基，叔丁氧甲酰基；
X代表NH；
Y代表C；
R4代表
Figure FDA00002682512600012
Figure FDA00002682512600013
Figure FDA00002682512600021
或
Figure FDA00002682512600022
2.制备权利要求1所述式（I）化合物的方法，其具体反应步骤是：将保护的或酰化后的A与1-羟基苯并三唑、N,N’-二异丙基碳二亚胺，按摩尔比1:0.5~3混合溶于N,N’-二甲基亚砜中，约半小时后加入B，室温下反应24小时，产物用柱层析分离纯化；
Figure FDA00002682512600023
其中，
X=NH；
Y=C；
R1，R2，R3及R4同权利要求1。
3.权利要求1所述化合物在药学上可接受的盐。
4.权利要求1所述化合物的药物组合物，以其含有治疗有效量的上述化合物为活性成分，与一种或多种药学上可接受的载体所组成。
5.权利要求1所述化合物在制备抗病毒药物中的应用。
6.权利要求3所述药学上可接受的盐在制备抗病毒药物中的应用。
7.权利要求4所述药物组合物在制备抗病毒药物中的应用。
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