CN101429142A - 一种含氮多羟基芳香类化合物及其制备方法和应用 - Google Patents
一种含氮多羟基芳香类化合物及其制备方法和应用 Download PDFInfo
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Abstract
本发明涉及一种结构如通式1所示的含氮多羟基芳香类化合物,其中,R1为氢、甲基或氟;R2为氢、甲基、乙酰基、氟、氯或溴;R3为氢、甲基、丁基、甲氧基、乙氧基、氟、氯、溴或硝基;R4为氢、甲基、乙酰基、氟、氯或溴;n为0或1。本发明还涉及通式(I)含氮多羟基芳香类化合物的制备方法。该类化合物对HIV整合酶具有明显的抑制活性,用于制备抗艾滋病药物。n=0,1。
Description
技术领域
本发明涉及有机化合物合成及医药应用领域,尤其涉及含氮多羟基芳香类化合物及其制备方法和制药用途。
背景技术
人免疫缺陷病毒(human immunodeficiency virus,HIV)是艾滋病(acquired immunedeficiency syndrome,AIDS)的病原体,分为HIV1和HIV-2型。HIV-1流行于全世界,HIV-2主要局限于非洲西部地区。HIV-1复制需要三个关键酶:逆转录酶(reverse transcriptase)、蛋白酶(protease)和整合酶(integrase)。目前治疗AIDS的药物主要靶向作用于逆转录酶和蛋白酶,阻止单链RNA病毒逆转录或遏制病毒蛋白裂解和成熟病毒释放。由于逆转录酶和蛋白酶极易发生突变,这些药物的效能被快速出现的耐药性限制。采用抗病毒组合疗法(combination therapy)(参见De clercq E.Biochim Biophys Acta,2002,1587(2-3):258-275),即联合使用逆转录酶抑制剂和蛋白酶抑制剂进行治疗,可在短期内使病人血液内病毒迅速降低到检测不出的水平,但药物自身以及药物间相互作用产生的副作用使病人难以长期忍受,限制了这些药物的应用。融合抑制剂是最近上市的抗HIV药物,通过抑制病毒与细胞融合,阻断HIV1进入宿主细胞(参见Fung HB,Guo Y.Clin Ther,2004,26(3):352-378.),但其价格昂贵且不能完全根除体内病毒,因而还需寻找作用于病毒新靶点的药物。
整合酶是HIV-1复制必需的酶,负责把病毒DNA整合到感染的宿主细胞染色体中,由于在人体细胞中不存在该酶的功能类似物(参见De Luca L,Pedretti A,VistoliG,et al.Biochem Biophys Res Commun,2003,310(4):1083-1088.),因此,整合酶是设计抗HIV药物的理想靶点。在报道的HIV-1整合酶抑制剂中,多羟基芳香类化合物的构效关系和作用机制已较明确,进入临床研究的1,5-DCQA(I期)即为该类化合物(参见董俊兴。科技中国,2006,4:63)。多羟基芳香类化合物通过抑制整合酶催化的3’加工和链转移达到抑制病毒复制,具有较高的抗病毒活性(参见Gordon CP,Griffith R,Keller PA.Med Chem,2007,3(2):199-220.)
发明内容
本发明在现有技术基础上,以咖啡酰苯乙酯为先导物,将多羟基芳香基团和磺胺基团通过酰胺键连接起来,设计了一系列新型含氮多羟基芳香类化合物,并通过改变磺胺侧链氮上取代基进一步提高化合物的整合酶抑制活性和选择性。
本发明的目的在于提供一种具有抗病毒活性的含氮多羟基芳香类化合物;本发明的另一目的在于提供该含氮多羟基芳香类化合物的制备方法及其制药用途。
本发明的含氮多羟基芳香类化合物,结构如通式(I)所示:
通式(I)
其中,R1为氢、甲基或氟;R2为氢、甲基、乙酰基、氟、氯或溴;R3为氢、甲基、丁基、甲氧基、乙氧基、氟、氯、溴或硝基;R4为氢、甲基、乙酰基、氟、氯或溴;n为0或1。
上述通式(I)表示的含氮多羟基芳香类化合物的制备方法,化学合成反应式如下:
试剂与反应条件:(i)吡啶,0℃-室温,4h;(ii)NaOH,甲醇,70℃;(iii)醋酸酐,吡啶,室温,24h;(iv)SOCl2,80℃,5h;(v)吡啶,丙酮,0℃-室温,20h;(vi)甲醇,THF,HCl,60℃,1h.
本发明涉及的含氮多羟基芳香类化合物的制备方法,步骤如下:
为了简要说明,以下的代码1-8均与上述反应式一致。
A.将取代芳胺1和干燥吡啶加入装有干燥管的100mL三颈瓶中,冰浴条件下分批加入对乙酰胺基苯磺酰氯,对乙酰胺基苯磺酰氯和取代芳胺1的摩尔比为1:1~2,加毕后搅拌反应10min,撤掉冰浴,室温搅拌反应4h,加入蒸馏水,搅拌20min,析出固体,过滤,水洗滤饼三次,固体用10%氢氧化钠溶液溶解,过滤,滤液用18%盐酸溶液调pH3~4,析出固体,过滤,水洗滤饼三次,干燥得化合物3。将化合物3加入50mL圆底烧瓶中,加入浓度为5摩尔/升的氢氧化钠溶液20mL和甲醇12mL,70℃搅拌反应3h,用浓度为2摩尔/升的盐酸溶液调pH为6,产生沉淀,过滤、干燥,乙醇/水重结晶,过滤、干燥,即得化合物4;
B.将摩尔比为1:3~10的取代芳酸6和乙醋酐与5.0mL吡啶加到50mL圆底烧瓶中,25℃条件下搅拌反应20h,向反应液中加入200mL乙醚或水,静置,析出白色沉淀,过滤,丙酮/环己烷重结晶,过滤、干燥,得中间体;将摩尔比为1:2~10的中间体和氯化亚砜加到装有干燥管、冷凝管的50mL圆底烧瓶中,油浴加热,70-85℃搅拌反应3-10h,于40℃减压蒸除溶剂,即得酰氯5,加入10mL丙酮稀释备用;
C.在装有干燥管、恒压滴液漏斗的100mL三颈瓶中加入4-(N-取代芳基-胺基)-磺胺基-1-苯胺4、10mL的干燥丙酮和吡啶,冰浴下缓慢滴加上述制备酰氯5,酰氯5和化合物4的摩尔比为1:1~2;酰氯5和吡啶的摩尔比为1:1~2的内酮溶液,约1h滴毕,搅拌反应10min,撤去冰浴,室温搅拌反应15-30h,过滤,减压蒸除溶剂得油状物,加入80mL蒸馏水搅拌析出固体,过滤、干燥;粗品用硅胶柱层析纯化,石油醚/乙酸乙酯梯度洗脱,收集合并产物洗脱液,减压蒸除溶剂,向残留物中加入无水乙醚超声,析出固体,过滤、干燥得化合物7;将2.2mmol化合物7加入50mL圆底烧瓶,加入4mL甲醇、4mL四氢呋喃和2mL浓盐酸,50-70℃搅拌反应1h,冷却至室温,减压蒸除溶剂,加入30mL蒸馏水,搅拌析出固体,过滤、干燥,粗品用硅胶柱层析纯化,石油醚/乙酸乙酯梯度洗脱,收集合并产物洗脱液,减压蒸除溶剂,向残留物中加入无水乙醚超声,析出固体,过滤、干燥,丙酮/环己烷重结晶,过滤、干燥,得化合物8。
优选的,步骤A所述的取代芳胺1为苯胺、间溴苯胺、对溴苯胺、对氟苯胺、对氯苯胺、对硝基苯胺、3,5-二甲基苯胺、临甲基苯胺、间乙酰基苯胺、对氯苄胺、对氟苄胺、对甲氧基苯胺、对乙氧基苯胺、对丁基苯胺、3,4-二氟苯胺、3,4二甲基苯胺、3,4-二氯苯胺或2,3,4-三氟苯胺。
优选的,步骤A所述的对乙酰胺基苯磺酰氯和取代芳胺1的摩尔比为1:1.2。
优选的,步骤B所述的取代芳酸为没食子酸。
优选的,步骤B所述的取代芳酸6和乙醋酐摩尔比为1:6~10。
优选的,步骤B所述的反应温度为75℃—80℃。
优选的,步骤C所述的酰氯5和化合物4的摩尔比为1:1.2。
优选的,步骤C所述的酰氯5和吡啶的摩尔比为1:1。
优选的,步骤C所述的反应温度为60℃。
本发明的含氮多羟基芳香类化合物作为人免疫缺陷病毒整合酶抑制剂,用于制备抗艾滋病药物。本发明设计合成了一系列新型含磺胺基团和酰胺键的多羟基芳香类化合物,活性实验表明,该类化合物对HIV整合酶具有抑制作用。
以下实验例仅用于说明本发明的技术效果,但所述的实验例不用于限制本发明。实验例:化合物活性测定
化合物对HIV-1整合酶的抑制活性测定方法,采用文献报道的方法进行,具体参见:Lifan Zeng,Xiaohua Jiang,Tino Sanchez,et al.Novel dimeric aryldiketo containing inhibitors ofHIV-1integrase:Effects of the phenyl substituent and the linker orientation[J].Bioorganic &Medicinal Chemistry,2008,16:7777-7787.
化合物活性实验结果见下表。
上表测试数据表明,本发明的多羟基芳香类化合物具有明显的HIV-1整合酶抑制活性。
具体实施方式
下面结合实施例进一步描述本发明,以利更深入理解本发明及其优点和效果,但所述实施例仪用于说明本发明而不是限制本发明。
实施例1.4-(N-取代苯基或苄基-胺基)-磺胺基-1-苯胺4的制备
将取代苯胺或苄胺120.0mmol和干燥吡啶(10mL,123.9mmol)加入装有干燥管的100mL三颈瓶中,冰浴条件下分批加入对乙酰胺基苯磺酰氯216.0mmol,加毕后搅拌反应10min,撤掉冰浴,室温搅拌反应4h,加入蒸馏水(100mL),搅拌20min,析出固体,过滤,水洗滤饼三次,固体用10%氢氧化钠溶液溶解,过滤,滤液用18%盐酸溶液调pH3~4,析出固体,过滤,水洗滤饼三次,干燥得化合物3,将化合物3加入50mL圆底烧瓶中,加入浓度为5摩尔/升的氢氧化钠溶液(20mL)和甲醇(12mL),70℃搅拌反应3h,用浓度为2摩尔/升的盐酸溶液调pH6,产生沉淀,过滤、干燥,乙醇/水重结晶,过滤、干燥,即得化合物4。
4a:4-(N-苯基-胺基)-磺胺基-1-苯胺,淡黄棕色,收率79.1%,mp:197.2~198.8℃,TLCRf=0.48(石油醚/乙酸乙酯,1:1,V/V),MS:calcd for C12H12N2O6S(M+H)+ 249.30,Found249.3。
4d:4-(N-邻甲基苯基-胺基)-磺胺基-1-苯胺,白色,收率75.0%,mp:153.0~155.0℃,TLC Rf=0.68(石油醚/乙酸乙酯,1:1,V/V)。
4e:4-(N-间乙酰基苯基胺基)-磺胺基-1-苯胺,白色,收率80.5%,mp:197.8~198.7℃,TLC Rf=0.29(石油醚/乙酸乙酯,1:1,V/V)。
实施例2.3,4,5-三乙酰没食子酰氯5的制备
将摩尔比为1:3~10的没食子酸6和乙醋酐与5.0mL吡啶加到50mL圆底烧瓶中,25℃条件下搅拌反应20h,向反应液中加入200mL乙醚或水,静置,析出白色沉淀,过滤,丙酮/环己烷重结晶,过滤、干燥,得中间体;将摩尔比为1:2~10的中间体和氯化亚砜加到装有干燥管、冷凝管的50mL圆底烧瓶中,油浴加热,70-85℃搅拌反应3-10h,于40℃减压蒸除溶剂,即得化合物5,加入10mL丙酮稀释备用。
实施例3.3,4,5-三乙酰氧基-N-(4-(N-取代苯胺或苄胺基磺酰)苯基)苯甲酰胺7的制备
在装有干燥管、恒压滴液漏斗的100mL三颈瓶中加入4-(N-取代芳基-胺基)-磺胺基-1-苯胺4、10mL的干燥丙酮和吡啶,冰浴下缓慢滴加上述实施例2中制备酰氯5,酰氯5和化合物4的摩尔比为1:1~2;酰氯5和吡啶的摩尔比为1:1~2的丙酮溶液,约1h滴毕,搅拌反应10min,撤去冰浴,室温搅拌反应15-30h,过滤,减压蒸除溶剂得油状物,加入80mL蒸馏水搅拌析出固体,过滤、干燥;粗品用硅胶柱层析纯化,石油醚/乙酸乙酯梯度洗脱,收集合并产物洗脱液,减压蒸除溶剂,向残留物中加入无水乙醚超声,析出固体,过滤、干燥得化合物7;
7a:3,4,5-三乙酰氧基-N-(4-(N-苯胺基磺酰)苯基)苯甲酰胺,白色固体,收率79.1%,mp:215.1~217.3℃,TLC Rf=0.56(石油醚/乙酸乙酯,1:1,V/V)。1H-NMR(DMSO-d6)δ:10.65(s,1H,CONH),10.22(s,1H,SO2NH),7.88(d,J=8.4Hz,2H,Ar-H),7.80(s,2H,Ar-H),7.75(d,J=9.0Hz,2H,Ar-H),7.23(t,J=7.8Hz,2H,Ar-H),7.09(d,J=7.8Hz,2H,Ar-H),7.02(t,.J=72Hz,1H,Ar-H),2.34(s,3H,CH 3),2.32(s,6H,CH 3).MS:calcd for C25H22N2O9S(M-1)+ 525.10,Found 525.5.IR(KBr,cm-1):υOH:3341.36;υNH:3294.47,3112.12;υC=O:1778.68,1762.49,1689.88;υC=C:1589.19,1531.64,1495.69;υS=O:1326.81,1157.95;υC-O:1201.45;γ=C-H:844.82,758.59.
7d:3,4,5-三乙酰氧基-N-(4-(N-邻甲基苯胺基磺酰)苯基)苯甲酰胺,白色固体,收率84.0%,mp:201.4~203.0℃,TLC Rf=0.61(石油醚/乙酸乙酯,1:1,V/V)。1H-NMR(DMSO-d6)δ:10.68(s,1H,CONH),9.50(s,1H,SO2NH),7.90(d,J=9.0Hz,2H,Ar-H),7.82(s,2H,Ar-H),7.65(d,J=9.0Hz,2H,Ar-H),7.12(m,3H,Ar-H),6.98(dd,J=9.0Hz,J=3.0Hz,1H,Ar-H),2.35(s,3H,CH 3),2.33(s,6H,CH 3),2.02(s,3H,CH 3).MS:calcd for C26H24N2O9S(M+1)+ 541.12,Found 541.1.IR(KBr,cm-1):υOH:3337.80;:2936.46;υC=O:1776.04,1687.54;υC=C:1588.61,1531.71,1496.08;υS=O:1328.19,1196.03;υC-O:1235.57;γ=C-H:845.53,754.37.
7e:3,4,5-三乙酰氧基-N-(4-(N-间乙酰基苯胺基磺酰)苯基)苯甲酰胺,白色固体,收率73.2%,mp:239.7~241.1℃,TLC Rf=0.56(石油醚/乙酸乙酯,1:1,V/V)。1H-NMR(DMSO-d6)6:11.23(s,1H,CONH),10.70(s,1H,SO2NH),8.14(d,J=9.0Hz,2H,Ar-H),7.94(s,J=9.0Hz,2H,Ar-H),7.88(d,J=9.6Hz,2H,Ar-H),7.79(s,2H,Ar-H),7.31(d,J=9.0Hz.2H,Ar-H),2.50(s,3H,CH 3),2.34(s,9H,CH 3).MS:calcd for C27H24N2O10S(M+1)+ 569.12,Found 569.0.IR(KBr,cm-1):υOH:3372.49;υΦH:3080.01;υC=O:1779.88,1761.23,1681.86;υC=C:1596.75,1533.31,1514.32,1497.92;υS=O:1341.90,1193.62;υC-O:1225.50,1210.89,1155.27;γ=C-H:841.17,749.86.
实施例4.N-(4-(N-取代苯胺或苄胺基磺酰)苯基)苯甲酰胺8的制备
将2.2mmol实施例3中得到的化合物7加入50mL圆底烧瓶,加入4mL甲醇、4mL四氢呋喃和2mL浓盐酸,50-70℃搅拌反应1h,冷却至室温,减压蒸除溶剂,加入30mL蒸馏水,搅拌析出固体,过滤、干燥,粗品用硅胶柱层析纯化,石油醚/乙酸乙酯梯度洗脱,收集合并产物洗脱液,减压蒸除溶剂,向残留物中加入无水乙醚超声,析出固体,过滤、干燥,丙酮/环己烷重结晶,过滤、干燥,得化合物8。
8a:N-(4-(N-苯胺基磺酰基)苯基)没食子酰胺,淡黄色固体,收率68.0%,mp:257.3~259.1℃,TLC Rf=0.43(石油醚/乙酸乙酯,1:1,V/V)。1H-NMR(DMSO-d6)δ:10.22(s,1H,CONH),10.17(s,1H,SO2NH),9.21(s,2H,OH),8.90(s,1H,OH),7.88(d,J=9.0Hz,2H,Ar-H),7.69(d.J=9.0Hz,2H,Ar-H),7.23(t,J=7.20Hz,2H,Ar-H),7.09(d,J=9.0Hz,2H,Ar-H),7.02(t,2H,J=7.20Hz,Ar-H),6.92(s,2H,Ar-H).MS:calcd for C19H16N2O6S(M+1)+401.07,Found 401.4.IR(KBr,cm-1):υOH:3444.79;υNH:3311.73,3222.61;υC=O:1667.96;υC=C:1591.21,1518.26,1442.69;υS=O:1342.43,1159.67;υC-O:1313.09,1260.81,1214.68;γ=C-H:757.59,707.72.
8b:N-(4-(N-对硝基苯胺基磺酰基)苯基)没食子酰胺,白色固体,收率52.3%,mp:256.1~257.5℃,TLC Rf=0.28(石油醚/乙酸乙酯,1:1,V/V)。1H-NMR(DMSO-d6)δ:11.20(s,1H,CONH),10.28(s,1H,SO2NH),9.22(s,2H,OH),8.91(s,1H,OH),8.4(d,.J=9.0Hz,2H,Ar-H),7.94(d,J=9.0Hz,2H,Ar-H),7.83(d,J=8.40Hz,2H,Ar-H),7.31(d,J=9.0Hz,2H,Ar-H),6.93(s,2H,Ar-H).MS:calcd for C19H15N3O8S(M+1)+ 446.06,Found 446.3.IR(KBr,cm-1):υOH:3431.20;υNH:3193.81;υC=O:1656.40;υC=C:1597.41,1586.22,1496.84;,1343.40;υS=O:1149.71;υC-O:1240.82,1195.61,1182.13;γ=C-H:756.31.
8c:N-(4-(N-3,5-二甲基苯胺基磺酰基)苯基)没食子酰胺,棕黄色固体,收率78.3%,mp:266.8~267.7℃,TLC Rf=0.35(石油醚/乙酸乙酯,1:1,V/V)。1H-NMR(DMSO-d6)δ:10.23(s,1H,CONH),10.05(s,1H,SO2NH),9.21(s,2H,OH),8.90(s,1H,OH),7.89(d,J=8.4Hz,2H,Ar-H),7.70(d,J=9.0Hz,2H,Ar-H),6.94(s,2H,Ar-H),6.72(s,2H,Ar-H),6.64(s,1H,Ar-H),2.09(s,6H,CH 3).MS:calcd for C21H20N2O6S(M+1)+429.10,Found 429.5.IR(KBr,cm-1):υOH:3339.34;;υC=O:1661.65;υC=C:1590.17,1519.36,1440.46;υS=O:1314.22,1146.64;υC-O:1253.37,1226.94;γ=C-H:755.38.
8d:N-(4-(N-邻甲基苯胺基磺酰基)苯基)没食子酰胺,白色固体,收率69.7%,mp:263.9~264.8℃,TLC Rf=0.30(石油醚/乙酸乙酯,1:,V/V)。1H-NMR(DMSO-d6)δ:10.25(s,1H,CONH),9.44(s,1H,SO2NH),9.22(s,2H,OH),8.91(s,1H,OH,7.90(d,J=9.0Hz,2H,Ar-H),7.59(d,J=8.4Hz,2H,Ar-H),7.13(dd,1H,J=6.0Hz,J=3.0Hz,Ar-H),7.10(m,2H,Ar-H),7.0(d,1H,J=2.4Hz,Ar-II),6.96(s,2H,Ar-H),2.02(s,3H,CH 3).MS:calcd forC20H18N2O6S(M+1)+ 415.09,Found 415.5.IR(KBr,cm-1):υOH:3449.51;υNH:3329.29,3231.72;υC=O:1665.62;υC=C:1591.26,1522.43,1442.05;υS=O:1309.67,1152.55;υC-O:1257.98,1210.03;γ=C-II:839.62,754.00.
8e:N-(4-(N-间乙酰基苯胺基磺酰基)苯基)没食子酰胺,淡黄色固体,收率68.8%,mp:249.0~250.0℃,TLC Rf=0.55(石油醚/乙酸乙酯,1:1,V/V)。1H-NMR(DMSO-d6)δ:10.44(s,1H,CONH),10.23(s,1H,SO2NH),9.20(s,2H,OH),9.0(s,1H,OH),7.89(d,J=8.4Hz,2H,Ar-H),7.72(d,J=84Hz,2H,Ar-H),7.64(t,2H,J=7.8Hz,Ar-H),740(t,1H,J=7.8Hz,Ar-H),7.36(d,1H,J=7.8Hz,Ar-H),6.93(s,2H,Ar-H),2.49(s,3H,CH 3).MS:calcd forC21H18N2O7S(M+1)+ 443.08,Found 443.3.IR(KBr,cm-1):υOH:3513.50,3365.87;υNH:3269.20,3148.89;,2914.54;υC=O:1655.50,1624.48;υC=C:1592.34,1525.90,1501.73,144443;υS=O:1346.64,1143.02;υC-O:1267.35,1228.77;γ=C-H:793.57,711.82.
8f:N-(4-(N-对氯苄胺基磺酰基)苯基)没食子酰胺,白色固体,收率52.1%,mp:217.2~217.8℃,TLC Rf=0.19(石油醚/乙酸乙酯,1:1,V/V)。1H-NMR(DMSO-d6)δ:10.59(s,1H,CONH),9.64(s,1H,OH),9.31(s,1H,OH),9.15(s,1H,OH),8.03(t,1H,J=6.6Hz,SO2NH),7.87(t,J=8.4Hz,2H,Ar-H),7.77(t,J=8.4Hz,2H,Ar-H),7.26(m,6H,Ar-H),3.95(d,2H,J=6.6Hz,CH 3).MS:calcd for C20H17ClN2O6S(M+1)+ 449.05,Found 449.2.IR(KBr,cm-1):υOH:3553.90,3519.08;υNH:3318.34;υC=O:1671.22;υC=C:1591.76,1533.63,1510.29,1455.98;υS=O:1321.46,1142.46;υC-O:1299.01,1256.86,1207.48;γ=C-H:701.21.
8g:N-(4-(N-对氯苯胺基磺酰基)苯基)没食子酰胺,白色固体,收率58.9%,mp:273.5~275.9℃,TLC Rf=0.31(石油醚/乙酸乙酯,1:1,V/V)。1H-NMR(DMSO-d6)δ:10.28(s,1H,CONH),10.24(s,1H,SO2NH),9.21(s,2H,OH),8.85(s,1H,OH),7.90(d,J=9.0Hz,2H,Ar-H),7.69(d,J=9.0Hz,2H,Ar-H),7.30(d,J=9.0Hz,2H,Ar-H),7.10(d,J=9.0Hz,2H,Ar-H),6.94(s,2H,Ar-H).MS:calcd for C19H15C1N2O6S(M+1)+ 435.03,Found 435.2.IR(KBr,cm-1):υOH:3397.19;υNH:3156.01;υC=O:1678.21;υC=C:1589.50,1537.67,1505.70,1446.78;υS=O:1326.60,1143.40;υC-O:1306.79,1246.77,1209.73;γ=C-H:721.44.
8h:N-(4-(N-对乙氧基苯胺基磺酰基)苯基)没食子酰胺,白色固体,收率55.8%,mp:271.4~272.9℃,TLC Rf=0.17(石油醚/乙酸乙酯,1∶1,V/V)。1H-NMR(DMSO-d6)δ:10.22(s,1H,CONH),9.68(s,1H,SO2NH),9.18(s,3H,OH),7.87(d,J=9.0Hz,2H,Ar-H),7.60(d,J=9.0Hz,2H,Ar-Ⅱ),6.95(m,4H,Ar-H),6.78(d,J=9.0Hz,2H,Ar-H),3.91(q,J=7.2Hz,2H,CH2),1.26(t,J=7.2Hz,3H,CH3).MS:calcd for C21H20N2O7S(M+1)+ 445.10,Found 445.3.IR(KBr,cm-1):υOH:3400.03;υNH:3186.03;;;υC=O:1676.82;υC=C:1589.77,1509.67,1445.41;υS=O:1326.67,1144.63;υC-O:1253.28,1212.47;γ=C-H:756.19.
8i:N-(4-(N-对溴苯胺基磺酰基)苯基)没食子酰胺,白色固体,收率56.7%,mp:271.1~273.3℃,TLC Rf=0.30(石油醚/乙酸乙酯,1:1,V/V)。1H-NMR(DMSO-d6)δ:10.40(s,1H,CONH),10.25(s,1H,SO2NH),9.21(s,3H,OH),7.90(d,J=9.0Hz,2H,Ar-H),7.70(d,J=9.0Hz,2H,Ar-H),7.42(d,J=9.0Hz,2H,Ar-H),7.05(d,J=9.0Hz,2H,Ar-H),6.94(s,2H,Ar-H).MS:calcd for C19H15BrN2O6S(M+1)+ 480.98,found 481.0.IR(KBr,cm-1):υOH:3397.52;υNH:3157.91;υC=O:1676.87;υC=C:1589.25,1504.69,1445.40;υS=O:1327.51,1143.64;υC-O:1306.20,1246.77,1210.30;γ=C-H:708.40.
8j:N-(4-(N-对氟苄胺基磺酰基)苯基)没食子酰胺,黄色固体,收率58.3%,mp:225.4~227.1℃,TLC Rf=0.26(石油醚/乙酸乙酯,1:1,V/V)。1H-NMR(DMSO-d6)δ:10.26(s,1H,CONH),9.21(s,2H,OH),8.90(s,1H,OH),8.04(s,1H,SO2NH),7.95(d,J=9.0Hz,2H,Ar-H),7.74(d,J=8.4Hz,2H,Ar-H),7.29(dd,J=7.8Hz,J=6.0Hz,2H,Ar-H),7.12(t,J=9.0Hz,2H,Ar-H),6.98(s,2H,Ar-H),3.95(s,2H,CH 2).MS:calcd for C20H17FN2O6S(M+1)+ 433.08,Found 433.3.IR(KBr,cm-1):υNH:3269.41;;υC=O:1608.98;υC=C:1591.15,1512.59,1445.86;υS=O:1325.20,1154.31;υC-O:1231.19;γ=C-H:757.05.
8k:N-(4-(N-间溴苯胺基磺酰基)苯基)没食子酰胺,白色固体,收率44.2%,mp:260.6~261.3℃,TLC Rf=0.33(石油醚/乙酸乙酯,1:1,V/V)。1H-NMR(DMSO-d6)δ:10.45(s,1H,CONH),10.26(s,1H,SO2NH),9.12(s,2H,OH),8.91(s,1H,OH),7.91(d,J=9.0Hz,2H,Ar-H),7.72(d,J=9.0Hz,2H,Ar-H),7.25(s,1H,Ar-H),720(d,J=4.8Hz,2H,Ar-H),7.12(m,1H,Ar-H),6.94(s,2H,Ar-H).MS:calcd for C19H15BrN2O6S(M+1)+ 481.0,Found 480.98.IR(KBr,cm-1):υOH:3376.08;υC=O:1653.00;υC=C:1609.83,1590.78,1521.10,1473.20;υS=O:1329.27,1153.64;υC-O:1257.32,1212.64;γ-C-H:838.01,755.03.
81:N-(4-(N-对氟苯胺基磺酰基)苯基)没食子酰胺,黄色固体,收率61.7%,mp:274.7~275.8℃,TLC Rf=0.31(石油醚/乙酸乙酯,1:1,V/V)。1H-NMR(DMSO-d6)δ:10.24(s,1H,CONH),10.13(s,1H,SO2NH),9.22(s,2H,OH),8.92(s,1H,OH),7.89(d,J=9.0Hz,2H,Ar-H),7.72(d,J=84Hz,2H,Ar-H),7.09(d,J=7.2Hz,4H,Ar-H),6.94(s,2H,Ar-H).MS:calcd for C19H15FN2O6S(M+1)+ 419.06,Found 419.2.IR(KBr,cm-1):υOH:3388.90;υC=O:1652.96;υC=C:1610.39,1590.27,1507.16,1444.29;υS=O:1317.34,1153.40;υC-O:1209.12;γ=C-H:757.35.
8m:N-(4-(N-对正丁基苯胺基磺酰基)苯基)没食子酰胺,白色固体,收率73.4%,mp:260.5~261.4℃,TLC Rf=0.57(石油醚/乙酸乙酯,1:1,V/V)。1H-NMR(DMSO-d6)δ:10.22(s,1H,CONH),10.02(s,1H,SO2NH),9.22(s,2H,OH),8.91(s,1H,OH),7.88(d,J=9.0Hz,2H,Ar-H),7.66(d,J=9.0Hz,2H,Ar-H),7.04(d,J=7.8Hz,2H,Ar-II),6.98(d,J=8.4Hz,2H,Ar-II),6.94(s,2H,Ar-H),245(t,J=7.8Hz,2H,CH2),146(quintet,2H,CH 2),1.24(sextet,2H,CH 2),0.85(t,J=7.2Hz,3H,CH 3).MS:calcd for C23H24N2O6S(M+1)+ 457.14,Found 4573.IR(KBr,cm-1):υOH:3433.45;υNH:3333.27,3223.55;;;υC=O:1667.19;υC=C:1592.20,1529.40,1512.43,1442.07;υS=O:1341.85,1159.04;υC-O:1311.75,1263.80,1219.59;γ=C-H:760.55.
8n:N-(4-(N-3,4-二氟苯胺基磺酰基)苯基)没食子酰胺,黄色固体,收率58.6%,mp:265.1~266.7℃,TLC Rf=0.31(石油醚/乙酸乙酯,1:1,V/V)。1H-NMR(DMSO-d6)6:10.41(s,1H,CONH),10.26(s,1H,SO2NH),9.22(s,2H,OH),8.91(s,1II,OH),7.91(d,J=8.4Hz,2H,Ar-H),7.70(d,J=9.0Hz,2H,Ar-H),7.33(m,1H,Ar-H),7.10(m,1H,Ar-H),6.94(s,2H,Ar-H),6.89(d,J=8.4Hz,1H,Ar-H).MS:calcd for C19H14F2N2O6S(M+1)+ 437.05,Found 437.1.IR(KBr,cm-1):υOH:3384.58;υC=O:1652.52;υC=C:1614.13,1590.56,1519.04,1445.08;υS=O:1320.77,1162.37;υC-O:1252.83,1210.51;γ=C-H:757.97.
80:N-(4-(N-3,4-甲氧基苯胺基磺酰基)苯基)没食子酰胺,白色固体,收率73.9%,mp:269.8~271.7℃,TLC Rf=0.23(石油醚/乙酸乙酯,1:1,V/V)。1H-NMR(DMSO-d6)δ:10.22(s,1H,CONH),9.80(s,1H,SO2NH),9.21(s,2H,OH),8.90(s,1H,OH),7.87(d,J=9.0Hz,2H,Ar-H),7.62(d,J=9.0Hz,2H,Ar-H),6.96(m,4H,Ar-H),6.80(d,J=8.4Hz,2H,Ar-H),3.67(s,3H,CH 3).MS:calcd for C20H18N2O7S(M+1)+ 431.08,Found 431.3.IR(KBr,cm-1):υOH:3512.95,3365.67;υNH:3269.09,3149.97;υC=O:1656.12;υC=C:1624.31,1591.57,1524.28,1444.13;υS=O:1317.11,1143.35;υC-O:1267.10,1228.40;γ=C-H:793.31.
8p:N-(4-(N-3,4-二甲基苯胺基磺酰基)苯基)没食子酰胺,黄色固体,收率50.5%,mp:2734~275.1℃,TLC Rf=0.31(石油醚/乙酸乙酯,1:1,V/V)。1H-NMR(DMSO-d6)δ:10.21(s,1H,CONH),9.94(s,1H,SO2NH),9.21(s,2H,OH),8.90(s,1H,OH),7.87(d,J=9.0Hz,2H,Ar-H),7.67(d,J=8.4Hz,2H,Ar-H),6.96(d,J=84Hz,1H,Ar-H),6.94(s,2H,Ar-H),6.87(s,1H,Ar-H),6.81(d,J=7.8Hz,1H,Ar-H),2.10(s,6H,CH 3).MS:calcd for C21H20N2O7S(M+1)+429.10,Found 429.3.IR(KBr,cm-1:υOH:3442.41;υNH:3254.22;υC=O:1659.33;υC=C:1590.35,1522.84,1443.73;υS=O:1309.64,1152.17;υC-O:1254.57,1216.87;γ=C-H:757.37.
8q:N-(4-(N-2,3,4-三氟苯胺基磺酰基)苯基)没食子酰胺,白色固体,收率80.8%,mp:254.1~255.5℃,TLC Rf=0.41(石油醚/乙酸乙酯,1:1,V/V)。1H-NMR(DMSO-d6)δ:10.29(s,1H,CONH),10.27(s,1H,SO2NH),9.23(s,2H,OH),8.92(s,1H,OH),7.93(d,J=9.0Hz,2H,Ar-H),7.65(d,J=9.0Hz,2H,Ar-H),7.28(d,J=8.4Hz,1H,Ar-H),7.01(d,J=7.2Hz,1H,Ar-H),6.97(s,2H,Ar-H).MS:calcd for C19H13F3N2O7S(M+1)+ 455.04,Found 455.2.IR(KBr,cm-1):υOH:3388.04;υC=O:1661.31;υC=C:1617.05,1590.26,1510.49;υS=O:1335.16,1160.41;υC-O:1255.26,1231.65,1208.82;γ=C-H:757.07.
8r:N-(4-(N-3,4-二氯苯胺基磺酰基)苯基)没食子酰胺,黄色固体,收率60.4%,mp:259.4~261.2℃,TLC Rf=0.38(石油醚/乙酸乙酯,1:1,V/V)。1H-NMR(DMSO-d6)δ:10.61(s,1II,CONH),10.27(s,1H,SO2NH),9.22(s,2H,OH),8.91(s,1H,OH),7.93(d,J=9.0Hz,2H,Ar-H),7.73(d,J=9.0Hz,2H,Ar-H),7.51(d,J=9.0Hz,1H,Ar-H),7.28(d,J=3.0Hz,1H,Ar-H),7.28(d,J=9.0Hz,J=2.4Hz,1H,Ar-H),6.94(s,2H,Ar-H).MS:calcd forC21H14C12N2O7S(M+1)+ 468.99,Found 469.0.IR(KBr,cm-1):υOH:3403.21;υC=O:1662.34;υC=C:1590.43,1518.80,1472.34;υS=O:1321.73,1159.18;υC-O:1222.24;γ=C-H:756.69。
Claims (11)
2.如权利要求1所述的含氮多羟基芳香类化合物的制备方法,其特征在于包括如下步骤:
A.将取代芳胺1和干燥吡啶加入装有干燥管的100mL三颈瓶中,冰浴条件下分批加入对乙酰胺基苯磺酰氯,对乙酰胺基苯磺酰氯和取代芳胺1的摩尔比为1:1~2,加毕后搅拌反应10min,撤掉冰浴,室温搅拌反应4h,加入蒸馏水,搅拌20min,析出固体,过滤,水洗滤饼三次,固体用10%氢氧化钠溶液溶解,过滤,滤液用18%盐酸溶液调pH3~4,析出固体,过滤,水洗滤饼三次,干燥得化合物3。将化合物3加入50mL圆底烧瓶中,加入浓度为5摩尔/升的氢氧化钠溶液20mL和甲醇12mL,70℃搅拌反应3h,用浓度为2摩尔/升的盐酸溶液调pH为6,产生沉淀,过滤、干燥,乙醇/水重结晶,过滤、干燥,即得化合物4;
B.将摩尔比为1:3~10的取代芳酸6和乙醋酐与5.0mL吡啶加到50mL圆底烧瓶中,25℃条件下搅拌反应20h,向反应液中加入200mL乙醚或水,静置,析出白色沉淀,过滤,丙酮/环己烷重结晶,过滤、干燥,得中间体;将摩尔比为1:2~10的中间体和氯化亚砜加到装有干燥管、冷凝管的50mL圆底烧瓶中,油浴加热,70-85℃搅拌反应3-10h,于40℃减压蒸除溶剂,即得酰氯5,加入10mL丙酮稀释备用;
C.在装有干燥管、恒压滴液漏斗的100mL三颈瓶中加入4-(N-取代芳基-胺基)-磺胺基-1-苯胺4、10mL的干燥丙酮和吡啶,冰浴下缓慢滴加上述制备酰氯5,酰氯5和化合物4的摩尔比为1:1~2;酰氯5和吡啶的摩尔比为1:1~2的丙酮溶液,约1h滴毕,搅拌反应10min,撤去冰浴,室温搅拌反应15-30h,过滤,减压蒸除溶剂得油状物,加入80mL蒸馏水搅拌析出固体,过滤、干燥;粗品用硅胶柱层析纯化,石油醚/乙酸乙酯梯度洗脱,收集合并产物洗脱液,减压蒸除溶剂,向残留物中加入无水乙醚超声,析出固体,过滤、干燥得化合物7;将2.2mmol化合物7加入50mL圆底烧瓶,加入4mL甲醇、4mL四氢呋喃和2mL浓盐酸,50-70℃搅拌反应1h,优选反应温度为60℃,冷却至室温,减压蒸除溶剂,加入30mL蒸馏水,搅拌析出固体,过滤、干燥,粗品用硅胶柱层析纯化,石油醚/乙酸乙酯梯度洗脱,收集合并产物洗脱液,减压蒸除溶剂,向残留物中加入无水乙醚超声,析出固体,过滤、干燥,丙酮/环己烷重结晶,过滤、干燥,得化合物8。
3.如权利要求书2所述的含氮多羟基芳香类化合物的制备方法,其特征在于,步骤A所述的取代芳胺1为苯胺、间溴苯胺、对溴苯胺、对氟苯胺、对氯苯胺、对硝基苯胺、3,5-二甲基苯胺、临甲基苯胺、间乙酰基苯胺、对氯苄胺、对氟苄胺、对甲氧基苯胺、对乙氧基苯胺、对丁基苯胺、3,4-二氟苯胺、3,4-二甲基苯胺、3,4-二氯苯胺或2,3,4-三氟苯胺。
4.如权利要求书2所述的含氮多羟基芳香类化合物的制备方法,其特征在于,步骤A所述的对乙酰胺基苯磺酰氯和取代芳胺1的摩尔比为1:1.2。
5.如权利要求书2所述的含氮多羟基芳香类化合物的制备方法,其特征在于,步骤B所述的取代芳酸为没食子酸。
6.如权利要求书2所述的含氮多羟基芳香类化合物的制备方法,其特征在于,步骤B所述的取代芳酸6和乙醋酐摩尔比为1:6~10。
7.如权利要求书2所述的含氮多羟基芳香类化合物的制备方法,其特征在于,步骤B所述的反应温度为75℃—80℃。
8.如权利要求书2所述的含氮多羟基芳香类化合物的制备方法,其特征在于,步骤C所述的酰氯5和化合物4的摩尔比为1:1.2。
9.如权利要求书2所述的含氮多羟基芳香类化合物的制备方法,其特征在于,步骤C所述的酰氯5和吡啶的摩尔比为1∶1。
10.权利要求1所述的含氮多羟基芳香类化合物在制备抗艾滋病药物中的应用。
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CN104193690A (zh) * | 2014-08-11 | 2014-12-10 | 广西大学 | 3,4,5-三羟基没食子酰胺苯磺酰胺类衍生物及其制备方法和应用 |
CN104193686A (zh) * | 2014-08-11 | 2014-12-10 | 广西壮族自治区中医药研究院 | N-没食子酰胺-嘧啶基苯磺酰胺类衍生物及其制备方法和应用 |
EP3412651A1 (en) * | 2017-06-06 | 2018-12-12 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Inhibitors of rac1 and uses thereof for inducing bronchodilatation |
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CN104193690A (zh) * | 2014-08-11 | 2014-12-10 | 广西大学 | 3,4,5-三羟基没食子酰胺苯磺酰胺类衍生物及其制备方法和应用 |
CN104193686A (zh) * | 2014-08-11 | 2014-12-10 | 广西壮族自治区中医药研究院 | N-没食子酰胺-嘧啶基苯磺酰胺类衍生物及其制备方法和应用 |
CN104193690B (zh) * | 2014-08-11 | 2017-04-05 | 广西大学 | 一种没食子酰胺苯磺酰胺类化合物的制备方法 |
EP3412651A1 (en) * | 2017-06-06 | 2018-12-12 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Inhibitors of rac1 and uses thereof for inducing bronchodilatation |
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WO2018224560A1 (en) * | 2017-06-06 | 2018-12-13 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Inhibitors of rac1 and uses thereof for inducing bronchodilatation |
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US11795144B2 (en) | 2017-06-06 | 2023-10-24 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Inhibitors of RAC1 and uses thereof for treating cancers |
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