CN103183625A - 抗hiv的化合物及其制备方法和用途 - Google Patents
抗hiv的化合物及其制备方法和用途 Download PDFInfo
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- CN103183625A CN103183625A CN2012104847836A CN201210484783A CN103183625A CN 103183625 A CN103183625 A CN 103183625A CN 2012104847836 A CN2012104847836 A CN 2012104847836A CN 201210484783 A CN201210484783 A CN 201210484783A CN 103183625 A CN103183625 A CN 103183625A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 103
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 39
- 229910052736 halogen Inorganic materials 0.000 claims description 34
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 33
- 150000002367 halogens Chemical class 0.000 claims description 28
- 229910052799 carbon Inorganic materials 0.000 claims description 23
- -1 methoxyl group Chemical group 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
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- 125000003118 aryl group Chemical group 0.000 claims description 10
- 238000001727 in vivo Methods 0.000 claims description 9
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 125000000539 amino acid group Chemical group 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 6
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Abstract
Description
技术领域
本发明属于化学合成药物技术领域,特别涉及抗HIV的化合物及其制备方法和用途。
背景技术
艾滋病是当今世界面临的重大公共卫生问题,艾滋病防治已成为全球关注的重要公共卫生和社会热点问题。
1981年首例艾滋病(AIDS)出现在美国,1985年我国出现首例艾滋病,此后的近二十年间不断有新病例报道,因此对艾滋病的流行。发展及预防已成为一件刻不容缓的事情。由于我国地域广阔,人口众多,近几年国际来往频繁,使得艾滋病的流行。艾滋病又名获得性免疫缺陷综合征(Acquired immunodeficiency syndrome),是一种性传播疾病,是由人类免疫缺陷病毒(human immunodeficiency virus,HIV)引起的,死亡率高,预后差。全世界的艾滋病感染人数突破3900万人,印度已经取代南非,成为艾滋病感染人数最多的国家。
由此可见,全力遏制艾滋病的流行趋势已成为全世界的焦点。在已上市的抗HIV抑制剂中,大部分为逆转录酶抑制剂和蛋白酶抑制剂。此外,人体内存在可以天然抗HIV的APOBEC3G(apolipoprote in B mRNA-editing enzyme catalytic polypeptidelike3G;载脂蛋白BmRNA编辑酶催化多肽样蛋白3G),它可以使HIV逆转录形成的负链HIV cDNA的胞嘧啶脱氨变为尿嘧啶,导致病毒转录产物的突变,从而达到抑制病毒复制的作用,但HIV病毒中的致病因子vif可以抑制APOBEC3G的活性,因此,抑制vif活性也可达到抑制HIV的目的。另外若设计开发同时抑制vif与HIV其它相关酶的多靶点抑制剂,将会进一步提升治疗指数,降低耐药性的出现。
本发明的发明人一直致力于新型抗HIV药物的研究。合成了一系列N-苯基-2-苯硫基苯甲酰胺衍生物和N-苯基-2-巯基苯甲酰胺衍生物。如下:
但是,这一类化合物活性一般,细胞毒性偏大,更关键的是水溶性比较差,口服生物利用度低,不利于后续药物的研发。
在进一步研究中发现,本发明的发明人发现R1位或R2位如果是氨基或带取代基的氨基, 则化合物抗HIV的活性大幅度提高,毒性较低一且水溶性大幅度提高,极大的提升了药物的成药性。
发明内容
本发明所要解决的技术问题是提供一种新的抗HIV药物及其前药,结构如式Ⅰ所示:
式Ⅰ
其中,X=S、SO、SO2、NR7、CH2或O;
其中,R1、R2、R3及R4不同时为H;
R6为H、NO2、C1~C8的烷氧基、C1~C8的烷酰基、C1~C8烷胺基、C1~C8的烷烃基、NH2、羟基、卤素或羧基;
R7为H或C1~C8的烷烃基;
R22为H、C1-C8烷烃基、芳基或带取代基的芳基;
R23、R24、R25独立地为H或C1~C8的烷烃基、C1~C8的烷酰基或带取代基的C1~C8的烷 酰基;
所述取代基为NO2、NH2、OH、或CF3、卤素、羧基、C1~C8的烷氧基、C1~C8的烷胺基、C1~C8的烷酰基或C1~C8的烷烃基;
所述C1~C8的烷酰基为直链或支链或环状的C1~C8的烷酰基;
所述C1~C8的烷烃基为直链或支链或环状的C1~C8的烷烃基;
所述C1~C8的烷胺基为直链或支链的C1~C8烷胺基;
所述C1~C8的烷氧基为直链或支链的C1~C8烷氧基。
作为本发明优选的方案是Y=CONR7,结构式如式Ⅱ:
虽然本发明的实施方式中仅仅是Y=CONR7的例子,但是,本领域技术人员根据生物电子排体及分子的相似性等公知常识,可以显而易见地预见当Y=NR7CO、SO2NR7或NR7SO2时,与Y=CONR7一样具有相似的结构和性能,生物活性会也相似,并且具有相似的合成方法,属于同类化合物。
进一步优选的是R7为H,结构式如下:
作为式Ⅲ优选的方案是:R1为NR15R16;R2~R4都为H;结构式如下:
其中,R5为C1~C8的烷氧基、卤素、羧基、C1~C8的烷烃基或NH2;R6为NO2、NH2、C1~C8的烷烃基或羧基;
其中X=S、SO、SO2或O,优选的是X=S或SO2。
进一步优选的方案是:R20是单个氨基酸残基或由多个氨基酸残基缩合形成的肽链;其中直接与羰基相连的氨基酸残基是缺失α-碳原子上羧基的氨基酸残基;所述的氨基酸是Ala、Arg、Asn、Asp、Cys、Glu、Gln、Gly、His、Ile、Leu、Lys、Met、Phe、Pro、Ser、Thr、Trp、Tyr、Val中的一种;优选的是Phe、Gly、Lys。(化合物66、67、68、83)
本发明所述缺失α-碳原子上羧基的氨基酸残基是本领域技术人员都理解的方式,比如:
艾滋病药物最理想的给药方式是口服,然而口服生物利用度与药物的溶解性息息相关。本研究中R1为氨基的化合物具有最强的抗病毒活性,然而其溶解性一般。为了提高其口服生 物利用度,本发明利用了这些氨基酸类物质作为前药,溶解性获得极大的提升。同时,这些前药在体内可以被水解释成活性更强的化合物,即R1为氨基的。比如67或83号化合物,在体内可以水解成R1为氨基的活性化合物,比如46号化合物,然后发挥抗病毒作用。
进一步优选的方案是,R20是芳基或带取代基的芳基、芳杂环基或带取代基的芳杂环基;所述取代基为NO2、NH2、OH、或CF3、卤素、羧基、C1~C8的烷氧基、C1~C8的烷酰基、C1~C8的烷胺基或C1~C8的烷烃基;所述取代基中,所述C1~C8的烷烃基为直链或支链或环状的C1~C8的烷烃基;所述C1~C8的烷氧基为直链或支链的C1~C8烷氧基;所述C1~C8的烷胺基为直链或支链的C1~C8烷胺基;
优选的是:R20是苯基或带取代基的苯基。
其中,X=S、SO、SO2或O,优选的是X=S或SO2。
作为Ⅲ-11优选的另一个方案是:R16为H;结构式如下:
进一步地,作为Ⅲ-11-1优选的方案是:R6在4位取代,R6为NO2或COOH;结构式如下:
进一步地,作为Ⅲ-11-11优选的方案是:R5在2位取代,结构式如下:
其中,R5为H、C1~C8的烷氧基、羟基、卤素、羧基、C1~C8的烷烃基或NH2;
所述C1~C8的烷烃基为直链或支链或环状的C1~C8的烷烃基;所述C1~C8的烷氧基为直链或支链的C1~C8烷氧基;X=S、SO、SO2或O,优选的是X=S、SO2或O。
进一步地,作为Ⅲ-11-111优选的方案是:R6为NO2,结构式如下:
R5为C1~C8的烷氧基,所述C1~C8的烷氧基为直链或支链的C1~C8烷氧基;优选的是C1~C4的烷氧基,更优选C1~C2的烷氧基,最优秀甲氧基;X=S、SO2或O;(化合物25、46、48)或
R5为卤素;所述卤素为F、Cl、Br、I,卤素优选I;其中X=S或SO2;(化合物71、72)或
R5为C1~C8的烷烃基,优选的为C1~C4的烷烃基;进一步优选的是C1~C2的烷烃基;更优选的是甲基;X优选S或SO2;或
R5为NH2;X优选S或SO2。
进一步地,作为Ⅲ-11-111优选的方案是:R6为COOH;
R5为直链或支链的C1~C8烷氧基;优选的是C1~C4的烷氧基,更优选C1~C2的烷氧基,最优选甲氧基;X=S或SO2。(化合物76、77)
作为Ⅲ-11-11另一个优选的方案是:R6在4位取代的NO2;R5在2位和4位取代,结构式如下:
R5为直链或支链的C1~C8烷氧基;优选的是C1~C4的烷氧基,更优选C1~C2的烷氧基,最优选甲氧基;R5’为NH2或R5’为直链或支链的C1~C8烷氧基;优选的是C1~C4的烷氧基,更优选C1~C2的烷氧基,最优选甲氧基;X优选S或SO2。(化合物50、51)
作为Ⅲ-11-11另一个优选的方案是:R5在3位取代,结构式如下:
优选的是R6为NO2;
R5为C1~C8的烷氧基,所述C1~C8的烷氧基为直链或支链的C1~C8烷氧基;优选的是C1~C4的烷氧基,更优选C1~C2的烷氧基,最优选甲氧基;X=S、SO2或O;或 R5为卤素;所述卤素为F、Cl、Br、I,卤素优选I;其中X=S或SO2;或R5为羧基;X优选S或SO2;或R5为R22为H、直链或支链或环状的C1-C8烷烃基,优选的为C1~C4的烷烃基;进一步优选的是C1~C2的烷烃基;更优选的是甲基;X优选S或SO2或
R5为C1~C8的烷烃基,优选的为C1~C4的烷烃基;进一步优选的是C1~C2的烷烃基;更优选的是甲基;X优选S或SO2;或
R5为NH2;X优选S或SO2。(化合物49)
作为Ⅲ-11-1的另一个优选的方案是:R6在3位和5位取代,3位和5位的R6独立地为C1~C8的烷烃基,优选的为C1~C4的烷烃基;进一步优选的是C1~C2的烷烃基;更优选的是甲基;结构式如下:
其中,R5在2位取代;R5为直链或支链的C1~C8烷氧基;优选的是C1~C4的烷氧基,更优选C1~C2的烷氧基,最优选甲氧基;X优选S或SO2。(化合物75)作为Ⅲ-11的另一个优选的方案是:R16为其中R24、R25独立地为H或C1~C8的烷烃基;优选的是R24、R25独立地为C1~C4的烷烃基,进一步优选的是R24、R25独立地为X=S或SO2。(化合物65)
R22为H、C1~C8的烷烃基、芳基或带取代基的芳基;所述取代基为NO2、NH2、OH、或CF3、卤素、羧基、烷氧基、烷胺基或C1~C8的烷烃基;所述C1~C8的烷烃基为直链或支链或环状的C1~C8的烷烃基;
优选的是R22为苯基或带取代基的苯基,取代基为C1~C8的烷烃基;所述C1~C8的烷烃基为直链或支链或环状的C1~C8的烷烃基;
进一步优选的是取代基为C1~C4的烷烃基;
更进一步优选的是取代基为甲基;最优的是甲基在苯基的4位取代;
其中X=S、SO、SO2或O,优选的是X=S或SO2。(化合物56、57、60、61)
作为Ⅲ-11的另一个优选的方案是:R16为直链或支链或环状的C1~C8的烷烃基;优选的为C1~C4的烷烃基;进一步优选的是C1~C2的烷烃基;更优选的是甲基;其中,X=S、SO、SO2或O,优选的是X=S或SO2。(化合物59)
作为Ⅲ-11的另一个优选的方案是:R16为-A-NH2,其中A为直链或支链或环状的C1~C8的烷烃基;优选的是A为C1~C4的烷烃基,进一步优选的是A为(CH2)2;
其中,X=S、SO、SO2或O,优选的是X=S或SO2。(化合物78、79)
作为Ⅲ-11的另一个优选的方案是:R16为-A-OH;其中A为直链或支链或环状的C1~C8的烷烃基;优选的是A为C1~C4的烷烃基,进一步优选的是A为(CH2)2;
其中,X=S、SO、SO2或O,优选的是X=S或SO2。(化合物80、81)
作为Ⅲ-11的另一个优选的方案是:R16为-A-卤素;其中A为直链或支链或环状的C1~C8的烷烃基;优选的是A为C1~C4的烷烃基,进一步优选的是A为(CH2)2;
所述卤素为F、Cl、Br、I;优选的是Br;
其中,X=S、SO、SO2或O,优选的是X=S或SO2。(化合物64)
作为Ⅲ-1另一个优选的方案是:R15、R16独立地为直链或支链或环状的C1~C8的烷烃基;优选的为C1~C4的烷烃基;进一步优选的是C1~C4的烷烃基;更优选的是R15、R16独立地为甲基;其中,X=S、SO、SO2或O,优选的是X=S或SO2。(化合物58)
作为Ⅲ另一个优选的方案是:X=S,结构式如式下所示:
R1为H、NO2、NR15R16或CF3;R15、R16独立的为H、CH3或乙酰基;R2为H、NO2、 NR15R16或CF3;R15、R16独立的为H、CH3或乙酰基;R1、R2不同时为H;R3~R4为H;R5为H、C1~C8的烷氧基、C1~C8的烷烃、NH2;R6为H、NO2、C1~C8的烷氧基或NH2。
进一步优选的是,R1为H,结构式如下:
其中,R2为H、NO2、NR15R16或CF3;R15、R16独立的为H、CH3或乙酰基;R5为H、C1~C8的烷氧基、C1~C8的烷烃或NH2;R6为H、NO2、C1~C8的烷氧基或NR15R16;R15、R16为H。
作为式Ⅲ-21优选的方案是,R5在邻位取代,R6在对位取代,结构式如下所示:
作为式Ⅲ-21-1优选的方案是,其特征在于:R2为NR15R16,R15、R16独立的为H、CH3或乙酰基,优选R2为NH2,R5为C1~C8的烷氧基、R6为NO2;优选的是R2为NH2,R5为C1~C4的烷氧基、R6为NO2;进一步优选的是R2为NH2,R5为甲氧基、R6为NO2;(24、27、28、29号化合物)
作为式Ⅲ-2另一个优选的方案是,R1为NO2,R2为H,结构式如下:
R5为H、C1~C8的烷氧基或NH2;R6为H、NO2、C1~C8的烷氧基或NH2。
进一步地,作为式Ⅲ-2优选的方案是,R6为4位取代的NO2,R5为2或4位取代的C1~C8的烷氧基或NH2,结构式如下:
进一步地,作为式Ⅲ-2-1优选的方案是,R5为2位取代,结构式如下:
其中,R5为C1~C8的烷氧基,优选的是R5为C1~C4的烷氧基,进一步优选R5为甲氧基;(52号化合物)或R5为NH2。(53号化合物)
作为式Ⅲ-2另一个优选的方案是,R6为4位取代的NO2,R5为3位取代的羧基,结构式如下:
(54号化合物)
作为式Ⅲ-2另一个优选的方案是,R6为4位取代的NO2,R5为4位取代,R5为或NH2,结构式如下:
Ⅲ-24(55号化合物)
作为式Ⅲ另一个优选的方案是,R1为NH2;R2~R4为H;R5为H、C1~C8的烷氧基、C1~C8的烷烃基或NH2;R6为H、NO2、C1~C8的烷氧基或NH2。
作为式Ⅲ另一个优选的方案是,X为S;R1为H、R6为4位取代的NO2;R5为C1~C8的烷氧基,优选R5为C1~C4的烷氧基,进一步优选R5为C1~C2的烷氧基,最优R5为甲氧基;(化合物62、63)或
X为O=S=O;R6为4位取代的NO2;R5为C1~C8的烷氧基,优选R5为C1~C4的烷氧基,进一步优选R5为C1~C2的烷氧基,最优R5为甲氧基。
作为本发明优选的方案,化合物的结构式如下:
本发明还提供了上述化合物的药学上可接受的盐,所述盐为盐酸盐、硫酸盐、磷酸盐、硝酸盐;优选的是盐酸盐。
本发明还提供了上述化合物在制备抗HIV药物中的用途,或是在制备抗肿瘤药物中的用途,或在制备抗肝炎药物中的用途。
进一步地,本发明还提供了上述化合物在制备抗HIV-1型病毒药物中的用途或抗HIV-2型病毒药物中的用途。
式Ⅰ所述的化合物的制备方法,其特征在于:合成方法如下所示:
其中,X=S、SO、SO2或O;
Y=CONR7、NR7CO、SO2NR7或NR7SO2;
V=Cl、Br或I;W=SH或OH。
当X=S时,合成路线如下
其中,Y=CONR7、NR7CO、SO2NR7或NR7SO2;
本发明的有益效果
本发明化合物具有抗HIV-1和抗HIV-2病毒活性,其对C8166的治疗指数最高可达2081.59,对H9的治疗指数最高可达303.03。而且这类化合物水溶液中溶解度很高,可制成口服制剂。
附图说明
图1是化合物67口服灌胃100mg/Kg的剂量下,体内分解为化合物46血药浓度图。
图2化合物67静脉给药500mg/Kg的剂量下,体内分解为化合物46血药浓度图。
图3是化合物67在弱酸性条件下的降解图;从图中可以看出本发明化合物氨基酸前药在在弱酸性条件下较稳定。
图4是化合物67在弱碱性条件下的降解图;从图中可以看出本发明化合物氨基酸前药在在弱碱性条件下降解较快。
图5是46号化合物与VIF可能的作用模式。
具体实施方式
实施例1、25号及其衍生物的制备
1.2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺(化合物25)的制备
2-氨基-6-溴-N-(2-甲氧基苯基)苯甲酰胺(中间体)的制备:
将邻甲氧基苯胺、2-氨基-6-溴苯甲酸和EDCI(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐)溶于THF(四氢呋喃)中,室温搅拌5小时。反应结束后,减压浓缩反应液,用乙酸乙 酯溶解浓缩物,用饱和食盐水洗有机层1次,然后加入无水硫酸钠干燥,水层送废水处理厂处理后弃去(TLC显示已无产品),最后减压浓缩有机层,用柱层析(石油醚:乙酸乙酯)得到黄色固体,用乙酸乙酯/石油醚重结晶得到棕黄色晶体,产率85%。
1H NMR(400MHz,CDCl3):3.875(S,3H),4.493(br,2H),6.670(d,J=8Hz,1H),6.922(d,J=8Hz,1H),6.976(d,J=8Hz,1H),7.030(m,2H),7.112(T,J=8Hz,1H),8.276(br,1H),8.529(dd,J=8Hz,1H).
ESI-MS:[M+Na]+m/z346.
2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺的制备:
将中间体,对硝基苯硫酚,无水K2CO3和铜粉混合后,加入THF,55℃搅拌8小时。反应结束后,过滤掉铜粉,减压浓缩反应液,用乙酸乙酯溶解浓缩物,用饱和食盐水洗有机层1次,然后加入无水硫酸钠干燥,水层送废水处理厂处理后弃去(TLC显示已无产品),最后减压浓缩有机层,用柱层析(石油醚:乙酸乙酯)得到黄色固体,用乙酸乙酯/石油醚重结晶得到黄色晶体,产率70%。
1H NMR(400MHz,CDCl3):3.688(S,3H),4.554(br,2H),6.836(m,2H),6.954(m,2H),7.059(T,J=8Hz,1H),7.209(d,J=9.2Hz,2H),7.262(T,J=4Hz,1H),8.034(d,J=4.4Hz,2H),8.230(br,1H),8.219(dd,J=8Hz,1H).
ESI-MS:[M+Na]+m/z418.
实施例2、化合物22的制备
3-三氟甲基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺
方法参见2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺
1H NMR(400MHz,CDCl3):3.883(S,3H),6.993(d,J=7.2Hz,1H),7.012(T,J=4.8Hz,1H),7.126(T,J=6.8Hz,1H),7.283(m,2H),7.529(d,J=8Hz,1H),7.922(m,2H),8.261(d,J=8.4Hz,2H),8.618(s,1H),8.761(s,1H).
ESI-MS:[M+Na]+m/z471.
实施例3、化合物23的制备
3-硝基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺
1H NMR(400MHz,CDCl3):3.7963(S,3H),6.882(d,J=8Hz,1H),6.918(T,J=8Hz,1H),7.028(T,J=7.2Hz,1H),7.162(m,2H),7.336(d,J=7.2Hz,1H),7.675(d,J=8Hz,1H),7.889(d,J=7.2Hz,1H),8.118(d,J=8Hz,2H),8.425(s,1H),8.567(s,1H).
方法参见2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺
ESI-MS:[M+Na]+m/z448.
实施例4.25号化合物的盐酸盐的制备
2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺盐酸盐
将2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺溶解于适量的乙酸乙酯中制成饱和溶液,室温搅拌,再往反应液中通入HCl气体,直至析出白色固体。反应结束后,过滤,用水洗滤饼,干燥后即得2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺盐酸盐。
1H NMR(400MHz,CDCl3):3.693(S,3H),5.333(br,3H),6.810(d,J=7.6Hz,1H),6.921(m,2H),7.010(d,J=8Hz,1H),7.118(T,J=7.6Hz,1H),7.249(T,J=8Hz,1H),7.306(d,J=8.8Hz,2H),7.758(d,J=8Hz,1H),8.098(d,J=8.4Hz,2H),9.397(br,1H).
实施例5.25号化合物的硫酸盐的制备
2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺硫酸盐
将2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺溶解于适量的乙酸乙酯中制成饱和溶液,室温搅拌,再往反应液中滴入浓H2SO4,直至析出白色固体。反应结束后,过 滤,用水洗滤饼,干燥后即得2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺硫酸盐。
1H NMR(400MHz,CDCl3):3.693(S,3H),4.019(br,3H),6.784(d,J=8.4Hz,1H),6.901(m,2H),7.010(d,J=7.6Hz,1H),7.100(T,J=7.6Hz,1H),7.236(T,J=8Hz,1H),7.305(d,J=8.8Hz,2H),7.753(d,J=7.6Hz,1H),8.097(d,J=8.8Hz,2H),9.379(br,1H).
实施例6.亚砜(g)的制备
将2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺溶解于适量乙酸中,室温搅拌,8小时后,淬灭双氧水,减压浓缩反应液,用乙酸乙酯溶解浓缩物,用饱和食盐水洗有机层1次,然后加入无水硫酸钠干燥,最后减压浓缩有机层,用柱层析(石油醚:乙酸乙酯)得到白色固体,产率35%。
1H NMR(400MHz,CDCl3):3.897(S,3H),4.464(br,2H),6.878(d,J=8Hz,1H),6.956(d,J=8Hz,1H),7.037(T,J=7.6Hz,1H),7.172(T,J=8Hz,1H),7.412(T,J=8Hz,1H),7.471(d,J=7.2Hz,1H),7.914(d,J=8.8Hz,2H),8.209(d,J=8.8Hz,2H),8.283(d,J=7.2Hz,1H),8.753(br,1H)
ESI-MS:[M+Na]+m/z434.
实施例7.46号化合物的制备
将2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺溶解于适量乙酸中,50度搅拌,8小时后,淬灭双氧水,减压浓缩反应液,用乙酸乙酯溶解浓缩物,用饱和食盐水洗有机层1次,然后加入无水硫酸钠干燥,最后减压浓缩有机层,用柱层析(石油醚:乙酸乙酯)得到白色固体2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯磺基)苯甲酰胺,产率68%。
1H NMR(400MHz,CDCl3):3.852(S,3H),4.322(br,2H),6.946(d,J=8Hz,1H),7.001(d,J=8Hz,1H),7.047(T,J=8Hz,1H),7.172(T,J=8Hz,1H),7.397(T,J=8Hz,1H),7.594(d, J=7.6Hz,1H),8.054(d,J=8.4Hz,2H),8.220(br,1H),8.256(d,J=8.4Hz,2H),8.322(d,J=7.6Hz,1H).
ESI-MS:[M+Na]+m/z450.
13C-NMR(400MHz,d6-DMSO):δ55.646,111.475,116.747,120.428,120.975,124.348,124.869,126.218,126.445,129.146,129.963,136.553,146.661,147.200,149.917,151.847.
实施例8、化合物24的制备
1.2-(4-硝基苯硫基)-5-氨基-N-(2-甲氧基苯基)苯甲酰胺
2-溴-5-Boc氨基苯甲酸的制备
将2-溴-5-氨基苯甲酸,BOC酸酐溶于THF中,室温搅拌下再加入DMAP,最后再滴加三乙胺,继续室温搅拌5小时。反应结束后,减压浓缩反应液,用乙酸乙酯溶解浓缩物,用饱和食盐水洗有机层1次,然后加入无水硫酸钠干燥,最后减压浓缩有机层,用柱层析(石油醚:乙酸乙酯)得到黄色固体,产率95%。
ESI-MS:[M+Na]+m/z338.
2-(4-硝基苯硫基)-5-Boc氨基苯甲酸的制备
将2-溴-5-Boc氨基苯甲酸,对硝基苯硫酚,无水K2CO3和铜粉混合后,加入DMF,55℃加热回流搅拌8小时,即得产物。反应结束后,过滤掉铜粉,用5倍体积的水稀释反应液,得到大量固体,过滤,用水洗滤饼,干燥。用乙酸乙酯/石油醚重结晶得到黄色晶体,产率77%。
ESI-MS:[M+Na]+m/z413.
2-(4-硝基苯硫基)-5-Boc氨基-N-(2-甲氧基苯基)苯甲酰胺的制备
将邻甲氧基苯胺、2-(4-硝基苯硫基)-5-Boc氨基苯甲酸和EDCI溶于二氯甲烷中,室温搅拌5小时,即得到中间体。反应结束后,减压浓缩反应液,用乙酸乙酯溶解浓缩物,用饱和食盐水洗有机层1次,然后加入无水硫酸钠干燥,最后减压浓缩有机层,用柱层析(石油醚:乙酸乙酯)得到白色固体,产率79%。
ESI-MS:[M+Na]+m/z518.
2-(4-硝基苯硫基)-5-氨基-N-(2-甲氧基苯基)苯甲酰胺胺的制备
将2-(4-硝基苯硫基)-5-Boc氨基-N-(2-甲氧基苯基)苯甲酰胺溶于适量的二氯甲烷中,室温搅拌下滴加三氟乙酸,再室温搅拌2小时。反应结束后,减压浓缩反应液,用乙酸乙酯溶解浓缩物,用饱和食盐水洗有机层1次,然后加入无水硫酸钠干燥,最后减压浓缩有机层,用柱层析(石油醚:乙酸乙酯)得到黄色固体,产率84%。
1H NMR(400MHz,CDCl3):3.708(S,3H),4.199(br,2H),6.820(m,2H),6.946(T,J=7.6Hz,1H),7.043(T,J=8Hz,1H),7.135(m,3H),7.420(d,J=8Hz,1H),8.028(d,J=9.2Hz,2H),8.395(dd,J=8Hz,1H),8.445(br,1H).
ESI-MS:[M+Na]+m/z418.
实施例9.化合物27的的制备
2-(4-硝基苯硫基)-5-N-甲基氨基-N-(2-甲氧基苯基)苯甲酰胺的制备
将2-(4-硝基苯硫基)-5-氨基-N-(2-甲氧基苯基)苯甲酰胺溶于适量的DMF中,室温搅拌下滴加碘甲烷,再升温到50度,搅拌10小时。反应结束后,加5倍体积的水稀释反应液,析出大量固体,过滤,水洗滤饼,干燥,再用柱层析(石油醚:乙酸乙酯)得到黄色固体,产率43%。
1H NMR(400MHz,CDCl3):2.928(S,3H),3.689(S,3H),4.236(br,1H),7.721(dd,J=8.4Hz,1H),6.817(d,J=8Hz,1H),6.941(T,J=6.4Hz,1H),7.032(m,2H),7.126(d,J=8.8Hz,2H),7.428(d,J=8.4Hz,1H),8.021(d,J=8.8Hz,2H),8.411(dd,J=8Hz,1H),8.453(br,1H).
ESI-MS:[M+Na]+m/z432.
实施例10.化合物28的的制备
2-(4-硝基苯硫基)-5-N,N-二甲基氨基-N-(2-甲氧基苯基)苯甲酰胺的制备
将2-(4-硝基苯硫基)-5-氨基-N-(2-甲氧基苯基)苯甲酰胺溶于适量的DMF中,室温搅拌下滴加碘甲烷,再升温到60度,搅拌10小时。反应结束后,加5倍体积的水稀释反应液,析出大量固体,过滤,水洗滤饼,干燥,再用柱层析(石油醚:乙酸乙酯)得到黄色固体,产率51%。
1H NMR(400MHz,CDCl3):3.089(S,6H),3.691(S,3H),6.831(m,2H),6.949(T,J=7.6Hz,1H),7.039(T,J=8Hz,1H),7.130(m,3H),7.469(d,J=7.6Hz,1H),8.026(d,J=9.6Hz,2H),8.427(dd,J=8Hz,1H),8.475(br,1H).
ESI-MS:[M+Na]+m/z446.
实施例11.化合物29的的制备
2-(4-硝基苯硫基)-5-N-乙酰氨基-N-(2-甲氧基苯基)苯甲酰胺的制备
将2-(4-硝基苯硫基)-5-氨基-N-(2-甲氧基苯基)苯甲酰胺溶于适量的二氯甲烷中,室温搅拌下分别加入乙酸酐与DMAP,再室温搅拌5小时。反应结束后,减压浓缩反应液,用乙酸乙酯溶解浓缩物,用饱和食盐水洗有机层1次,然后加入无水硫酸钠干燥,最后减压浓缩有机层,用柱层析(石油醚:乙酸乙酯)得到黄色固体,产率96%。
1H NMR(400MHz,CDCl3):2.182(S,3H),3.732(S,3H),6.845(d,J=8.4Hz,1H),6.952(T,J=7.6Hz,1H),7.071(T,J=8Hz,1H),7.191(d,J=8.8Hz,2H),7.558(d,J=8.8Hz,1H),7.828(d,J=1.6Hz,1H),7.936(dd,J=8Hz,1H),7.978(br,1H),8.037(d,J=9.2Hz,2H),8.349(d,J=7.6Hz,1H),8.514(br,1H).
ESI-MS:[M+Na]+m/z446.
实施例12.48号化合物的制备
化合物48的制备方法参见2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺的制备。48号化合物结构式如下:
2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯氧基)苯甲酰胺
1H NMR(400MHz,CDCl3):3.774(s,3H),5.875(br,2H),6.279(d,J=8Hz,1H),6.600(d,J=8Hz,1H),6.896(m,2H),7.673(t,J=8Hz,1H),7.002(d,J=8Hz,2H),7.181(t,J=8Hz,1H),8.208(d,J=8.8Hz,2H),8.418(d,J=8Hz,1H),9.486(s,1H).
ESI-MS:[M+H]+m/z:380.12
实施例13.49号化合物的制备
化合物49的制备方法参见2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺。
49号化合物结构式如下:
2-氨基-N-(3-氨基苯基)-6-(4-硝基苯氧基)苯甲酰胺
1H NMR(400MHz,CDCl3):3.621(br,2H),5.779(br,2H),6.310(d,J=8.4Hz,1H),6.621(d,J=7.6Hz,1H),7.012(m,1H),7.451(d,J=8Hz,2H),7.476(m,2H),7.815(d,J=8Hz,1H),7.932(d,J=8.8Hz,2H),8.015(d,J=7.2Hz,1H),8.523(s,1H).
ESI-MS:[M+H]+m/z:381.09
实施例14.50号化合物的制备
化合物50的制备方法参见2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺,化合物50的结构式如下:
2-氨基-N-(2-甲氧基-4-氨基苯基)-6-(4-硝基苯氧基)苯甲酰胺
1H NMR(400MHz,CDCl3):3.818(S,3H),5.663(br,2H),6.422(d,J=8Hz,2H),6.671(t,J=7.2Hz,2H),7.122(t,J=8Hz,1H),7.558(m,4H),8.003(S,1H),8.331(d,J=8Hz,1H),8.922(br,2H).
ESI-MS:[M+H]+m/z:411.10
实施例15.51号化合物的制备
化合物51的制备方法参见2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺,化合物51的结构式如下:
2-氨基-N-(2,4-二甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺
1H NMR(400MHz,CDCl3):3.818(S,3H),3.835(S,3H),6.522(d,J=9.6Hz,2H),6.688(t,J=9.2Hz,2H),7.081(t,J=8Hz,1H),7.649(m,4H),8.151(S,1H),8.288(d,J=8.8Hz,1H),9.053(br,2H).
ESI-MS:[M+Na]+m/z448.09
实施例15.52号化合物的制备
化合物52的制备方法参见2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺, 化合物52的结构式如下:
2-硝基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺
1H NMR(400MHz,CDCl3):3.731(s,3H),6.854(d,J=7.2Hz,1H),7.004(t,J=8Hz,1H),7.100(td,J=8、0.8Hz,1H),7.301(d,J=8.8Hz,2H),7.660(t,J=8Hz,1H),7.854(d,J=8.8Hz,2H),8.093(d,J=9.2Hz,2H),8.281(d,J=7.2Hz,1H),6.854(d,J=7.2Hz,1H).
ESI-MS:[M+H]+m/z:426.07
实施例16.53号化合物的制备
化合物53的制备方法参见2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺,化合物53的结构式如下:
2-硝基-N-(2-氨基苯基)-6-(4-硝基苯硫基)苯甲酰胺
1H NMR(400MHz,CDCl3):3.573(br,2H),6.826(d,J=8Hz,2H),7.140(t,J=7.2Hz,1H),7.218(d,J=8Hz,2H),7.399(d,J=8Hz,2H),7.676(t,J=7.6Hz,1H),7.853(d,J=8Hz,1H),7.090(d,J=8Hz,2H),8.312(d,J=8Hz,1H).
ESI-MS:[M+Na]+m/z:433.06
实施例17.54号化合物的制备
化合物54的制备方法参见2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺,化合物54的结构式如下:
2-硝基-N-(3-羧基苯基)-6-(4-硝基苯硫基)苯甲酰胺
1H NMR(400MHz,d6-DMSO):7.426(d,J=8.8Hz,2H),7.480(d,J=8Hz,1H),7.707(m,2H),7.840(t,J=8Hz,1H),8.032(d,J=8Hz,1H),8.153(d,J=8.8Hz,2H),8.210(S,1H),8.388(d,J=8Hz,1H),10.893(S,1H),13.043(br,1H).
ESI-MS:[M-H]-m/z:438.05
实施例18.58号化合物的制备
化合物58的制备方法参见2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺,化合物58的结构式如下:
2-硝基-N-(4-氨基苯基)-6-(4-硝基苯硫基)苯甲酰胺
1H NMR(400MHz,CDCl3):3.718(br,2H),6.660(d,J=8Hz,1H),6.713(d,J=8.4Hz,2H),7.251(m,1H),7.367(d,J=8.8Hz,2H),7.476(t,J=8Hz,1H),7.613(t,J=8.8Hz,1H),7.799(d,J=8Hz,1H),7.936(d,J=8Hz,1H),7.108(d,J=9.2Hz,1H),8.168(d,J=8Hz,1H).
ESI-MS:[M+H]+m/z:411.07
实施例1956号化合物的制备
化合物56的制备方法:将2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺吡啶中,室温搅拌下滴加苯磺酰氯,搅拌10小时。反应结束后减压浓缩反应液,用乙酸乙酯溶解浓缩物,用饱和食盐水洗有机层1次,然后加入无水硫酸钠干燥,最后减压浓缩有机层,用柱层析(石油醚:乙酸乙酯)得到淡黄色固体,产率67%。
化合物56的结构式如下:
2-苯磺酰胺基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺
1H NMR(400MHz,CDCl3):3.655(s,3H),6.742(d,J=8Hz,1H),6.847(t,J=7.6Hz,1H),6.913(d,J=8Hz,1H),7.016(t,J=7.6Hz,1H),7.284(m,1H),7.372(t,J=8Hz,1H),7.469(t,J=7.6Hz,3H),7.640(m,3H),8.010(m,5H),8.931(s,1H).
ESI-MS:[M-H]-m/z:534.09
实施例2057号化合物的制备
化合物57的制备方法参见2-苯磺酰胺基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺(56)。化合物57的结构式如下:
2-(4-甲基苯磺酰胺基)-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺
1H NMR(400MHz,CDCl3):2.165(s,3H),3.690(s,3H),6.858(d,J=8Hz,1H),6.954(d,J=8.8Hz,3H),7.090(m,3H),7.380(d,J=8Hz,1H),7.472(t,J=8Hz,1H),7.543(d,J=8Hz,2H),7.810(d,J=8Hz,1H),7.946(s,1H),8.013(d,J=8.8Hz,2H),8.162(d,J=8Hz,1H),8.415(s,1H).
ESI-MS:[M-H]-m/z:548.10
实施例2058号化合物的制备
化合物58的制备方法参见2-苯磺酰胺基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺(28)。化合物58的结构式如下:
2-N,N-二甲氨基-N-(2-甲氧基苯基)-6-(4-硝基苯磺基)苯甲酰胺
1H NMR(400MHz,CDCl3):2.762(s,3H),3.282(s,3H),4.079(s,3H),6.606(d,J=8Hz,1H),7.092(t,J=7.6Hz,1H),7.126(d,J=8Hz,1H),7.212(d,J=7.6Hz,2H),7.363(m,2H),7.433(t,J=6.4Hz,1H),7.604(d,J=9.2Hz,2H),7.908(d,J=8Hz,2H).
ESI-MS:[M+H]+m/z:456.12
实施例2159号化合物的制备
化合物59的制备方法参见2-(4-硝基苯硫基)-5-N-甲基氨基-N-(2-甲氧基苯基)苯甲酰胺(27)。化合物59的结构式如下:
2-N-甲氨基-N-(2-甲氧基苯基)-6-(4-硝基苯磺基)苯甲酰胺
1H NMR(400MHz,CDCl3):3.293(s,3H),4.028(s,3H),4.725(br,1H),7.212(dd,J=8、0.8Hz,1H),7.040(td,J=8、1.2Hz,1H),7.147(dd,J=8、1.2Hz,1H),7.235(m,3H),7.406(m,2H),7.567(m,2H),7.954(d,J=12Hz,2H).
ESI-MS:[M+H]+m/z:442.10
实施例2260号化合物的制备
化合物60的制备方法参见2-苯磺酰胺基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺(56)。化合物60的结构式如下:
2-(4-甲基苯磺酰胺基)-N-(2-甲氧基苯基)-6-(4-硝基苯磺基)苯甲酰胺
1H NMR(400MHz,CDCl3):2.173(s,3H),3.636(s,3H),6.774(d,J=8Hz,1H),6.947(m,2H),7.089(t,J=7.2Hz,1H),7.189(d,J=8Hz,1H),7.419(t,J=7.2Hz,2H),7.606(t,J=7.2Hz,1H),7.810(d,J=7.6Hz,1H),7.949(d,J=7.6Hz,2H),8.098(d,J=8Hz,1H),8.255(d,J=8.4Hz,2H),8.332(d,J=8.4Hz,2H),9.181(s,1H).
ESI-MS:[M-H]-m/z:580.09
实施例2361号化合物的制备
化合物61的制备方法参见2-苯磺酰胺基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺(56)。化合物61的结构式如下:
2-苯磺酰胺基-N-(2-甲氧基苯基)-6-(4-硝基苯磺基)苯甲酰胺
1H NMR(400MHz,CDCl3):3.636(s,3H),6.773(d,J=7.2Hz,1H),6.948(m,2H),7.092(t,J=8Hz,1H),7.437(t,J=8Hz,2H),7.489(t,J=7.2Hz,1H),7.613(t,J=7.2Hz,2H),7.946(d,J=7.2Hz,3H),8.100(d,J=9.2Hz,1H),8.353(d,J=7.2Hz,2H),8.322(d,J=7.2Hz,2H),9.175(s,1H).
ESI-MS:[M+H]+m/z:566.08
实施例2462号化合物的制备
将2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺溶于适量的DMF中,室温搅拌下加入2-溴-N-(溴乙基)乙胺与NaOH,搅拌2小时。反应结束后,加5倍体积的水稀释反应液,析出大量固体,过滤,水洗滤饼,干燥,再用柱层析(石油醚:乙酸乙酯)得到白色固体,产率82%。化合物62的结构式如下:
2-哌嗪基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺
1H NMR(400MHz,CDCl3):1.106(s,2H),1.601(s,2H),2.478(t,J=4.8Hz,2H),3.132(t,J=6Hz,2H),3.812(s,3H),5.301(s,1H),6.909(d,J=8Hz,1H),7.024(d,J=8Hz,3H),7.125(t,J=7.6Hz,1H),7.318(m,2H),7.878(s,1H),8.113(d,J=8.8Hz,2H),8.359(d,J=8Hz,1H),9.460(s,1H).
ESI-MS:[M+H]+m/z:465.15
实施例2563号化合物的制备
化合物63的制备方法参见2-哌嗪基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺(62)。化合物63的结构式如下:
2-吗啉基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺
1H NMR(400MHz,CDCl3):1.332(s,2H),1.741(s,2H),2.551(t,J=4.8Hz,2H),3.212(t,J=6Hz,2H),3.822(s,3H),7.021(d,J=7.2Hz,1H),7.121(d,J=8.8Hz,3H),7.226(t,J=7.2Hz,1H),7.323(m,2H),7.912(s,1H),8.216(d,J=8Hz,2H),8.321(d,J=8Hz,1H),9.460(s,1H).
ESI-MS:[M+H]+m/z:466.14
实施例2664号化合物的制备
化合物64的制备方法参见2-(4-硝基苯硫基)-5-N-甲基氨基-N-(2-甲氧基苯基)苯甲酰胺(27)。化合物64的结构式如下:
2-(2-溴基乙氨基)-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺
1H NMR(400MHz,CDCl3):3.271(t,J=7.2Hz,2H),3.452(m,2H),3.867(s,3H),4.138(br,1H),6.492(d,J=9.2Hz,1H),6.675(d,J=4Hz,1H),7.043(m,3H),7.37(m,3H),7.532(t,J=4Hz,1H),7.963(d,J=8Hz,2H),8.204(s,1H).
ESI-MS:[M+H]+m/z:502.04
实施例2765号化合物的制备
化合物65的制备方法参见2-哌嗪基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺(62)。化合物65的结构式如下:
2-N-二异丙基磷酸酯基甲氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺
1H NMR(400MHz,d6-DMSO):1.276(m,12H),3.330(S,3H),3.83(m,2H),5.314(br,1H),6.389(d,J=8Hz,1H),6.706(t,J=7.6Hz,2H),7.041(t,J=7.6Hz,1H),7.417(m,3H),7.548(d,J=8Hz,1H),7.878(d,J=8Hz,2H),8.028(d,J=8Hz,1H),8.563(s,1H).
ESI-MS:[M+H]+m/z:574.17
实施例2766号化合物的制备
将2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺、HOBt(1-羟基苯并***)和EDCI溶于二氯甲烷中,室温搅拌5小时,减压浓缩反应液,用乙酸乙酯溶解浓缩物,用饱和食盐水洗有机层1次,然后加入无水硫酸钠干燥,再减压浓缩有机层。将浓缩物用适量浓盐酸搅拌2小时,过滤,用乙醇洗滤饼1次,再二氯甲烷洗涤至无杂质,得白色粉末状固体,产率为45%。化合物66的结构式如下:
2-氨甲酰氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺盐酸盐
1H NMR(400MHz,d6-DMSO):3.244(S,2H),3.684(S,3H),4.941(br,2H),6.915(t,J=7.6Hz,1H),7.015(d,J=8Hz,1H),7.131(t,J=7.2Hz,1H),7.343(m,3H),7.548(t,J=8Hz,1H),7.875(d,J=8Hz,1H),8.111(d,J=8.8Hz,2H),8.412(d,J=8Hz,1H),9.904(s,1H).
ESI-MS:[M+H]+m/z:453.11
实施例2867号化合物的制备
将2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯磺基)苯甲酰胺、HOBt(1-羟基苯并***)和EDCI溶于二氯甲烷中,室温搅拌8小时,减压浓缩反应液,用乙酸乙酯溶解浓缩物,用饱和食盐水洗有机层1次,然后加入无水硫酸钠干燥,再减压浓缩有机层。将浓缩物用适量 浓盐酸搅拌2小时,过滤,用乙醇洗滤饼1次,再二氯甲烷洗涤至无杂质,得白色粉末状固体,产率为51%。
化合物67的结构式如下:
2-氨甲酰胺基-N-(2-甲氧基苯基)-6-(4-硝基苯磺基)苯甲酰胺盐酸盐
1H NMR(400MHz,d6-DMSO):3.726(S,2H),3.817(S,3H),7.017(t,J=6.8Hz,1H),7.096(d,J=7.6Hz,1H),7.190(t,J=7.2Hz,1H),7.770(t,J=7.2Hz,1H),8.012(t,J=7.6Hz,2H),8.081(d,J=7.2Hz,1H),8.226(d,J=7.6Hz,2H),8.391(d,J=7.6Hz,3H),9.890(s,1H).
13C-NMR(400MHz,d6-DMSO):δ55.806,111.482,120.219,123.511,124.464,125.502,126.684,127.206,129.407,130.138,131.663,131.834,134.979,137.036,146.449,150.147,150.786,162.274,165.962.
ESI-MS:[M+H]+m/z:485.11
实施例2968号化合物的制备
化合物68的制备方法参见2-氨甲酰氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺盐酸盐(66)。化合物68的结构式如下:
2-(N-赖氨酸基氨基)-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺盐酸盐
1H NMR(400MHz,d6-DMSO):1.385(m,8H),1.679(S,1H),3.683(S,3H),6.488(s,1H),6.915(t,J=7.6Hz,1H),7.010(d,J=8Hz,1H),7.124(t,J=7.6Hz,1H),7.341(m,3H),7.539(t,J=7.6Hz,1H),7.882(d,J=7.6Hz,1H),8.111(d,J=8Hz,2H),8.336(d,J=8Hz,1H),9.892(s,1H).
ESI-MS:[M+H]+m/z:524.19
实施例3071号化合物的制备
化合物71的制备方法参见2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺(1)。化合物71的结构式如下:
2-氨基-N-(2-碘苯基)-6-(4-硝基苯硫基)苯甲酰胺
1H NMR(400MHz,CDCl3):4.614(br,2H),6.864(t,J=7.6Hz,2H),6.990(d,J=7.6Hz,1H),7.277(m,4H),7.776(d,J=7.6Hz,1H),8.033(d,J=7.2Hz,3H),8.110(d,J=8Hz,1H).
ESI-MS:[M+H]+m/z:491.98
实施例3172号化合物的制备
化合物72的制备方法参见2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯磺基)苯甲酰胺(46)。化合物72的结构式如下:
2-氨基-N-(2-碘苯基)-6-(4-硝基苯磺基)苯甲酰胺(72)的制备
1H NMR(400MHz,CDCl3):4.363(br,2H),6.994(m,2H),7.398(t,J=8Hz,1H),7.464(t,J=7.2Hz,1H),7.526(d,J=7.6Hz,1H),7.781(s,1H),7.858(d,J=7.6Hz,1H),8.132(d,J=7.6Hz,2H),8.203(d,J=8Hz,1H),8.298(d,J=8Hz,2H).
ESI-MS:[M+H]+m/z:523.97
实施例3273号化合物的制备
化合物73的制备方法参见2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺(1)。化合物73的结构式如下:
2-氨基-N-(2-甲磺酰氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺
1H NMR(400MHz,CDCl3):(S,3H),3.221(S,3H),4.478(br,2H),6.831(d,J=8Hz,1H),6.972(d,J=2.8Hz,1H),7.186(t,J=7.2Hz,1H),7.234(m,4H),7.314(t,J=8Hz,1H),8.054(m,1H),8.354(S,1H).
ESI-MS:[M+Na]+m/z:482.05
实施例3374号化合物的制备
化合物74的制备方法参见2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺(1)。化合物74的结构式如下:
2-氨基-N-(2-甲氧基苯基)-6-(3,5-二甲基苯硫基)苯甲酰胺
1H NMR(400MHz,CDCl3):2.204(S,6H),3.776(S,3H),4.538(br,2H),6.632(d,J=8Hz,1H),7.693(d,J=8Hz,1H),6.865(m,2H),6.885(S,2H),6.971(t,J=8Hz,1H),7.076(m,2H),8.419(d,J=8Hz,1H),8.483(S,1H).
ESI-MS:[M+H]+m/z:379.14
实施例3475号化合物的制备
化合物75的制备方法参见2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯磺基)苯甲酰胺(46)。化合物75的结构式如下:
2-氨基-N-(2-甲氧基苯基)-6-(3,5-二甲基苯磺基)苯甲酰胺
1H NMR(400MHz,CDCl3):2.193(S,6H),3.836(S,3H),4.306(br,2H),6.923(t,J=8Hz,2H),7.003(t,J=8Hz,1H),7.129(m,2H),7.357(m,3H),7.597(d,J=8Hz,1H),8.305(d,J=8Hz,1H),8.373(S,1H).
ESI-MS:[M+H]+m/z:411.13
实施例3576号化合物的制备
化合物76的制备方法参见2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺(1)。化合物76的结构式如下:
2-氨基-N-(2-甲氧基苯基)-6-(4-羧基苯硫基)苯甲酰胺
1H NMR(400MHz,d6-DMSO):3.816(S,3H),5.362(br,2H),6.908(t,J=8Hz,1H),7.013(d,J=8Hz,1H),7.152(m,2H),7.236(d,J=8Hz,2H),7.429(d,J=8Hz,1H),7.600(d,J=8Hz,1H),7.803(d,J=8Hz,2H),8.208(S,2H).
ESI-MS:[M1H]-m/z:393.10
实施例3677号化合物的制备
化合物77的制备方法参见2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯磺基)苯甲酰胺(46)。化合物77的结构式如下:
2-氨基-N-(2-甲氧基苯基)-6-(4-羧基苯磺基)苯甲酰胺
1H NMR(400MHz,d6-DMSO):3.782(S,3H),5.5545(br,2H),7.025(m,2H),7.090(d,J=8Hz,1H),7.230(m,2H),7.336(t,J=7.6Hz,1H),7.774(d,J=7.6Hz,1H),8.040(m,4H),9.598(S,1H),13.479(br,1H).
ESI-MS:[M-H]-m/z:425.09
实施例3778号化合物的制备
化合物78的制备方法参见2-(4-硝基苯硫基)-5-N-甲基氨基-N-(2-甲氧基苯基)苯甲酰胺(27)。化合物78的结构式如下:
2-乙二胺基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺
化合物78的制备方法参见
1H NMR(400MHz,d6-DMSO):0.823(m,2H),1.179(m,2H),2.002(br,2H),3.783(S,3H),6.346(m,3H),6.673(t,J=7.6Hz,2H),6.759(m,2H),7.985(d,J=8Hz,1H),7.162(m,3H),7.442(d,J=8Hz,1H),7.541(s,1H).
ESI-MS:[M+H]+m/z:439.14
实施例3879号化合物的制备
化合物79的制备方法参见2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯磺基)苯甲酰胺(46)。化合物79的结构式如下:
2-乙二胺基-N-(2-甲氧基苯基)-6-(4-硝基苯磺基)苯甲酰胺
1H NMR(400MHz,d6-DMSO):0.854(m,2H),1.255(m,2H),2.085(br,2H),3.720(S,3H),6.884(d,J=8Hz,1H),7.002(m,3H),7.060(S,1H),7.144(t,J=7.6Hz,1H),7.608(t,J=8Hz,1H),7.767(d,J=8Hz,1H),7.827(d,J=8Hz,1H),8.144(d,J=9.2Hz,2H),8.235(d,J=7.2Hz,1H),8.482(S,1H).
ESI-MS:[M+H]+m/z:471.13
实施例3980号化合物的制备
化合物80的制备方法参见2-(4-硝基苯硫基)-5-N-甲基氨基-N-(2-甲氧基苯基)苯甲酰胺(27)。化合物80的结构式如下:
2-(N-2-羟乙基氨基)-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺
1H NMR(400MHz,CDCl3):3.05(t,J=8Hz,2H),3.661(m,2H),3.903(S,3H),6.441(d,J=8Hz,1H),6.775(d,J=8Hz,1H),7.024(m,3H),7.367(m,4H),7.565(m,1H),7.971(d,J=7.2Hz,2H),8.191(S,1H).
ESI-MS:[M+H]+m/z:440.12
实施例4081号化合物的制备
化合物81的制备方法参见2-氨基-N-(2-甲氧基苯基)-6-(4-硝基苯磺基)苯甲酰胺(46)。化合物81的结构式如下:
2-(N-2-羟乙基氨基)-N-(2-甲氧基苯基)-6-(4-硝基苯磺基)苯甲酰胺
1H NMR(400MHz,CDCl3):3.682(m,2H),3.961(t,J=8.4Hz,2H),4.021(s,3H),6.694(d,J=8Hz,1H),7.071(t,J=8Hz,1H),7.142(d,J=8Hz,1H),7.237(m,3H),7.425(m,2H),7.572(d,J=8Hz,3H),7.986(d,J=7.6Hz,2H).
ESI-MS:[M+H]+m/z:472.11
实施例4182号化合物的制备
化合物82的制备方法参见2-(4-硝基苯硫基)-5-N-甲基氨基-N-(2-甲氧基苯基)苯甲酰胺(27)。化合物82的结构式如下:
2-N-氨酰甲氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺
1H NMR(400MHz,d6-DMSO):3.775(S,3H),5.341(br,2H),5.853(S,2H),6.464(m, 2H),6.672(t,J=7.2Hz,2H),6.758(t,J=7.2Hz,2H),6.991(d,J=8Hz,2H),7.162(m,3H),7.428(d,J=7.2Hz,1H),7.551(S,1H).
ESI-MS:[M+H]+m/z:453.12
实施例4283号化合物的制备
化合物83的制备方法参见2-氨甲酰氨基-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺盐酸盐(67)。化合物83的结构式如下:
2-(N-苯丙氨酸基氨基)-N-(2-甲氧基苯基)-6-(4-硝基苯硫基)苯甲酰胺
1H NMR(400MHz,d6-DMSO):2.875(m,1H),3.142(d,J=16Hz,2H),3.442(d,J=8Hz,1H),3.691(S,3H),4.346(br,2H),6.989(m,2H),7.116(t,J=8Hz,1H),7.225(d,J=8Hz,4H),7.773(t,J=8Hz,1H),7.936(d,J=4Hz,1H),8.103(d,J=8Hz,1H),8.31(m,7H),9.875(S,1H).
ESI-MS:[M+H]+m/z:575.15
活性实验:
根据SFDA“抗HIV药物非临床药效学研究技术指导原则(2006)”采用国际通用实验方法对药物的抗HIV活性进行检测。活性结果如表1所示,其中CC50和EC50是分别做了两次测定的平均值。
从表1可以看出,多数化合物都具有体外抑制HIV活性的能力,特别是化合物25、46、67、83体外抑制HIV活性的能力较强,同时其毒性低,具有高的治疗指数,因而能够用于制备新的作用于HIV辅助蛋白Vif的抗HIV病毒小分子抑制剂。
表1
CC50,EC50单位为(μg/mL)
67,83是46号化合物的前药,试验表明,前药化合物在体内经水解释放出46并发挥抗病毒作用。67和83作为前药自身具有抗HIV-1病毒活性,其对C8166的治疗指数分别为388.04和291.4,对H9的治疗指数分别为790.58和756.32。而释放出的46号药物对C8166及H9的治疗指数更强,分别为2081.59及303.03。
表1:67及46化合物的抗病毒活性
对46号药物进行临床株和耐药株抗病毒试验发现对不同的细胞株的毒性都比较小,能有效地抑制实验株HIV-1IIIB诱导C8166细胞病变和在H9细胞中的复制;对HIV-174v、HIV-1A17、HIV-1L10R/M46I/L63P/V82T/I84V都有较好的抑制作用,对临床分离病毒株HIV-1KM018和HIV-1TC-1有较好的抑制作用。具体数据见表2。
表2:46的各种毒株的活性
注:C8166、H9:人T淋巴细胞系;
HIV-1IIIB、HIV-174V:核苷类逆转录酶抑制剂ddI和ddC耐药株;
HIV-1A17:NVP耐药株;
HIV-1L10R/M46I/L63P/V82T/I84V:蛋白酶抑制剂耐药株;
HIVKM018、HIV-1TC-1云南省昆明市HIV/AIDS患者体内分离得到。
同时,此类化合物对HIV-2型病毒株的也有较好的治疗效果,其中25、46和67具有较高的治疗指数且对细胞的毒性较小,具体见表3
表3.25、46和67对HIV-2ROD和HIV-2CBL-20的活性
注:HIV-2ROD:1985年于塞内加尔分离得到;HIV-2CBL-20:于冈比亚分离得到。
溶解性是药物成药性的重要参数。作为前药的化合物66、67及68有很好的溶解性。其中在pH=7的水溶液中67的溶解度达到1730.64μg/ml,在弱酸性情况下(pH=2),66和68化合物溶解度分别达到了1290和2845.5μg/ml。由此可见,前药的溶解性非常好,可制成口服制剂。该类前药在体内水解为脂溶性好、治疗指数高、易分布的药物46。
在药代动力学方面,在67口服灌胃100mg/Kg的剂量下,46的Cmax最大血药浓度达到21.662ug/mL,且67在体内多次释放,其相对生物利用度为161.2%(相对静脉给药的生物利用度而言),详见图1和图2。
体内67代谢成46的药时曲线及生物利用度
Cmax(mg/L) | AUC(0~∞)(mg/L*h) | CL(L/h/kg) | F(%) | |
口服(100mg/kg) | 21.662 | 387.758 | 4.878 | 162.2 |
静脉(50mg/kg) | 326.494 | 120.282 | 0.453 |
在药物毒性方面,分别对67和46进行急性毒性研究。在给药量10g/Kg时,没有出现明显的异常现象。
在药物稳定性方面,经实验验证本类药物比较稳定。以67为例,在pH=4.003、6.864和9.182的PBS缓冲溶液条件下,67在体外降解实验的速率分别为0.2769、0.4956和9.182(图3和图4)。由此可见,氨基酸前药67在弱酸性情况下较稳定,而在弱碱性条件下则相对降解较快。
在作用机理方面,用计算机对接的方法模拟了46与VIF可能的结合模式,其中末端苯环上的硝基与Arg79与Lys178形成氢键,右端酰胺上的氧原子与His141及Arg97形成氢键;中间吡啶氮原子与Gly103形成氢键作用。(与VIF的作用模式见图4)。
Claims (39)
1.结构如式Ⅰ所示的抗HIV的化合物,
其中,X=S、SO、SO2、NR7、CH2或O;
Y=CONR7、NR7CO、SO2NR7或NR7SO2;
其中,R1、R2R3及R4不同时为H;
R5为H、C1~C8的烷氧基、羟基、硝基、卤素、羧基、C1~C8的烷烃基或NH2;
R6为H、NO2、C1~C8的烷氧基、NH2、羟基、卤素、C1~C8的烷烃基或羧基;
R7为H或C1~C8的烷烃基;
R22为H、C1-C8烷烃基、芳基或带取代基的芳基;
R23、R24、R25独立地为H或C1~C8的烷烃基、C1~C8的烷酰基或带取代基的C1~C8的烷酰基;
所述取代基为NO2、NH2、OH、或CF3、卤素、羧基、C1~C8的烷酰基、C1~C8的烷氧基、C1~C8的烷胺基或C1~C8的烷烃基;
所述C1~C8的烷酰基为直链或支链或环状的C1~C8的烷酰基;
所述C1~C8的烷烃基为直链或支链或环状的C1~C8的烷烃基;
所述C1~C8的烷胺基为直链或支链的C1~C8烷胺基;
所述C1~C8的烷氧基为直链或支链的C1~C8烷氧基。
7.根据权利要求6所述的化合物,其特征在于:R20是单个氨基酸残基或由多个氨基酸残基缩合形成的肽链;其中直接与羰基相连的氨基酸残基是缺失α-碳原子上羧基的氨基酸残基;所述的氨基酸是Ala、Arg、Asn、Asp、Cys、Glu、Gln、Gly、His、Ile、Leu、Lys、Met、Phe、Pro、Ser、Thr、Trp、Tyr、Val中的一种。
8.根据权利要求6所述的化合物,其特征在于:R20是芳基或带取代基的芳基、芳杂环基或带取代基的芳杂环基;所述取代基为NO2、NH2、OH、或CF3、卤素、羧基、C1~C8的烷氧基、C1~C8的烷酰基、C1~C8的烷胺基或C1~C8的烷烃基;所述取代基中,
所述C1~C8的烷烃基为直链或支链或环状的C1~C8的烷烃基;
所述C1~C8的烷氧基为直链或支链的C1~C8烷氧基;
所述C1~C8的烷胺基为直链或支链的C1~C8烷胺基;
优选的是:R20是苯基或带取代基的苯基;
其中,X=S、SO、SO2或O,优选的是X=S或SO2。
12.根据权利要求11所述的化合物,其特征在于:R6为NO2,结构式如下:
R5为C1~C8的烷氧基,所述C1~C8的烷氧基为直链或支链的C1~C8烷氧基;优选的是C1~C4的烷氧基,更优选C1~C2的烷氧基,最优秀甲氧基;X=S、SO2或O;
R5为卤素;所述卤素为F、Cl、Br、I,卤素优选I;其中X=S或SO2;或
R5为羧基;X优选S或SO2;或
R5为C1~C8的烷烃基,优选的为C1~C4的烷烃基;进一步优选的是C1~C2的烷烃基;更优选的是甲基;X优选S或SO2;或
R5为NH2;X优选S或SO2。
14.根据权利要求10所述的化合物,其特征在于:R6在4位取代的NO2;R5在2位和4位取代,结构式如下:
R5为直链或支链的C1~C8烷氧基;优选的是C1~C4的烷氧基,更优选C1~C2的烷氧基,最优选甲氧基;
R5’为NH2或R5’为直链或支链的C1~C8烷氧基;优选的是C1~C4的烷氧基,更优选C1~C2的烷氧基,最优选甲氧基;X优选S或SO2。
15.根据权利要求10所述的化合物,其特征在于:R5在3位取代,结构式如下:
优选的是R6为NO2;
R5为C1~C8的烷氧基,所述C1~C8的烷氧基为直链或支链的C1~C8烷氧基;优选的是C1~C4的烷氧基,更优选C1~C2的烷氧基,最优选甲氧基;X=S、SO2或O;或
R5为卤素;所述卤素为F、Cl、Br、I,卤素优选I;其中X=S或SO2;或
R5为羧基;X优选S或SO2;或
R5为C1~C8的烷烃基,优选的为C1~C4的烷烃基;进一步优选的是C1~C2的烷烃基;更优选的是甲基;X优选S或SO2;或
R5为NH2;X优选S或SO2。
19.根据权利要求5所述的化合物,其特征在于:R16为直链或支链或环状的C1~C8的烷烃基;优选的为C1~C4的烷烃基;进一步优选的是C1~C2的烷烃基;更优选的是甲基;其中,X=S、SO、SO2或O,优选的是X=S或SO2。
20.根据权利要求5所述的化合物,其特征在于:R16为-A-NH2,其中A为直链或支链或环状的C1~C8的烷烃基;优选的是A为C1~C4的烷烃基,进一步优选的是A为(CH2)2;
其中,X=S、SO、SO2或O,优选的是X=S或SO2。
21.根据权利要求5所述的化合物,其特征在于:R16为-A-OH;其中A为直链或支链或环状的C1~C8的烷烃基;优选的是A为C1~C4的烷烃基,进一步优选的是A为(CH2)2;
其中,X=S、SO、SO2或O,优选的是X=S或SO2。
22.根据权利要求5所述的化合物,其特征在于:R16为-A-卤素;其中A为直链或支链或环状的C1~C8的烷烃基;优选的是A为C1~C4的烷烃基,进一步优选的是A为(CH2)2;
所述卤素为F、Cl、Br、I;优选的是Br;
其中,X=S、SO、SO2或O,优选的是X=S或SO2。
24.根据权利要求4所述的化合物,其特征在于:R15、R16独立地为直链或支链或环状的C1~C8的烷烃基;优选的为C1~C4的烷烃基;进一步优选的是C1~C4的烷烃基;更优选的是R15、R16独立地为甲基;其中,X=S、SO、SO2或O,优选的是X=S或SO2。
27.根据权利要求26所述的化合物,其特征在于:R5在邻位取代,R6在对位取代,结构式如下所示:
28.根据权利要求27所述的化合物,其特征在于:R2为NR15R16,R15、R16独立的为H、CH3或乙酰基,优选R2为NH2,R5为C1~C8的烷氧基、R6为NO2;优选的是R2为NH2,R5为C1~C4的烷氧基、R6为NO2;进一步优选的是R2为NH2,R5为甲氧基、R6为NO2。
34.根据权利要求3所述的化合物,其特征在于:
R1为NH2;
R2~R4为H;
R5为H、C1~C8的烷氧基、C1~C8的烷烃基或NH2;
R6为H、NO2、C1~C8的烷氧基或NH2。
37.权利要求1-36任一项所述的化合物的药学上可接受的盐,所述盐为盐酸盐、硫酸盐、磷酸盐、硝酸盐;优选的是盐酸盐。
38.权利要求1-36任一项所述的化合物在制备抗HIV药物中的用途,或是在制备抗肿瘤药物中的用途,或在制备抗肝炎药物中的用途。
39.权利要求1-36任一项所述的化合物在制备抗HIV-1型病毒药物中的用途或抗HIV-2型病毒药物中的用途。
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