CN102516244B - 六元芳杂环并咪唑巯乙酰胺类衍生物及其制备方法与应用 - Google Patents
六元芳杂环并咪唑巯乙酰胺类衍生物及其制备方法与应用 Download PDFInfo
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- CN102516244B CN102516244B CN 201110394885 CN201110394885A CN102516244B CN 102516244 B CN102516244 B CN 102516244B CN 201110394885 CN201110394885 CN 201110394885 CN 201110394885 A CN201110394885 A CN 201110394885A CN 102516244 B CN102516244 B CN 102516244B
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- Prior art keywords
- imidazo
- trimethylphenyl
- mercapto
- acetamide
- pyridine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 aromatic heterocyclic imidazole mercapto-acetamide derivative Chemical class 0.000 title claims abstract description 232
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- 238000000034 method Methods 0.000 claims description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 29
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 26
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 13
- 125000003107 substituted aryl group Chemical group 0.000 claims description 13
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 12
- 230000036436 anti-hiv Effects 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
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- 238000006482 condensation reaction Methods 0.000 claims description 4
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Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药技术领域,具体公开了一类如通式I所示的六元芳杂环并咪唑巯乙酰胺类衍生物及其药学上可接受的盐、酯或前药,其制备方法以及含有一个或多个此类化合物的组合物在治疗和预防人免疫缺陷病毒(HIV)感染药物中的应用。
Description
技术领域
本发明属于医药技术领域,具体涉及六元芳杂环并咪唑巯乙酰胺类衍生物及其制备方法与制药用途。
背景技术
人免疫缺陷病毒1型(HIV-1)是艾滋病(AIDS)的主要病原体。自1981年发现以来,艾滋病已成为危害人类生命健康的重大传染性疾病。虽然目前高效抗逆转录疗法(HAART)的实施是抗艾滋病治疗的一项重大突破,但是由于耐药性的出现及长期服药的毒性问题极大地限制了该疗法的应用,新型抗艾滋病药物的研发刻不容缓。逆转录酶(RT)在病毒整个生命周期中起着关键作用,靶向于HIV-1RT非底物结合位点的非核苷类抑制剂(NNRTI)具有高效、低毒的优点,成为HAART疗法的重要组成部分。但是由于NNRTIs结合位点的氨基酸易发生突变,导致耐药毒株的产生及蔓延,使该类药物迅速丧失临床效价。因此研发新型、高效抗耐药的NNRTIs是目前抗艾滋病药物研究的重要方向。(参见①《抗艾滋病药物研究》,刘新泳主编,人民卫生出版社,北京,2006,12.②Zhan P,Chen X,Li D,Fang Z,De Clercq E,Liu X. Med ResRev.2011Apr 26.doi:10.1002/med.20241.)
五元及六元杂环化合物具有广泛的抗HIV活性,它们在HIV非核苷类逆转录酶抑制剂、蛋白酶抑制剂、整合酶抑制剂、CCR5抑制剂、gp41抑制剂、Rev抑制剂等的研究中发挥重要作用。它们可以作为构成药效团的基本结构母核,以适合药物特殊作用靶点的空间要求;还可以作为活性取代基或环系的组成部分而产生相应的生物活性;另外杂环具有较好的体内代谢稳定性及生物相容性。因此,它们被广泛应用于新型抗HIV先导化合物的发现及结构优化。(参见①Zhan P,Liu X,De Clercq E .Curr Med Chem.2008,15(15):1529-1540.②Zhan P,Liu X,De ClercqE.CurrMedChem.2011,18(1),29-46.)。
芳唑巯乙酰胺类化合物是一类新型、高效抗耐药的HIV-1NNRTI,对野生型及多种严重耐药株(K103N、Y181C、Y188L及K103N/Y181C双突变株等)均具有很强的抑制活性。其中1,2,4-三唑衍生物VRX-480773(Zhang Z,et al.Antimicrob Agents Chemother. 2007,51(2):429-37.)和RDEA-806(Moyle G,et al.Antimicrob Agents Chemother. 2010,54(8):3170-8.)正分别处于临床前和临床IIa期研究,RDEA-806对许多耐药性病毒株(包括TMC125产生的耐药病毒株)的抑制活性均优于抗艾滋病上市药物依法韦仑(Efavirenz),具有良好的耐受性,无明显的毒副作用。有望成为新的抗HIV药物。本专利发明人曾对该类抑制剂进行广泛的结构修饰,发现了其它类结构多样的新型芳唑巯乙酰胺衍生物,其中1,2,3-噻二唑系列活性最好,在细胞水平的抗HIV-1活性实验中,有10余个1,2,3-噻二唑衍生物的活性优于上市药物奈韦拉平(NVP)或地拉韦定(DLV),而且细胞毒性较低,代表性化合物为ZP7,具有较大的开发价值。(参见①Wang Z,et al.Bioorg Med Chem Lett.2006,16(16):4174-7.②De La Rosa M,et al.Bioorg MedChem Lett.2006,16(17):4444-9.③Zhang Z,et al.Antimicrob Agents Chemother.2007,51(2):429-37.④RossottiR,et al.HIV Ther.2009,3(1),66-77.⑤Zhan P,et al.Bioorg Med Chem.2009,17(16):5920-7.)。
因此,以芳唑巯乙酰胺类化合物为模板,进行广泛的结构修饰,对发现高效广谱、生物利用度好且具有自主知识产权的新型抗HIV药物具有重要意义。
发明内容
本发明旨在提供一种六元芳杂环并咪唑巯乙酰胺类衍生物及其制备方法,以及其药学上可接受的盐、酯或前药。本发明还提供上述化合物的活性筛选结果及其应用。
1、六元芳杂环并咪唑巯乙酰胺类衍生物
本发明的六元芳杂环并咪唑巯乙酰胺类衍生物或其药学上可接受的盐、酯或前药,结构通式I如下:
其中,
Ar为结构多样的六元嗪类芳杂环;X1,X2,X3,X4各自独立地为N或CH;
杂环Ar任选被(C1-4)烷基、(C3-7)环烷基、(C3-7)环烷基-(C1-3)烷基取代,其中所述烷基、环烷基或环烷基烷基可被-OH单取代。
Ar1为苯基、苯基甲基、5-或6-元芳杂环、稠合的苯基-不饱和的或饱和的5-或6-元碳环、稠合的苯基-(不饱和的或饱和的5-或6-元碳环)甲基、或稠合的苯基-5-或6-元芳杂环;所述的苯基、苯基甲基、芳杂环、稠合的苯基-碳环、稠合的苯基-(碳环)甲基或稠合的苯基-芳杂环各自依次任选被1至3个独立选自下列的取代基所取代:
(C1-6)烷基、(C3-7)环烷基、(C3-7)环烷基-(C1-3)烷基、(C2-6)链烯基、O-(C1-4)烷基、S-(C1-4)烷基、卤素、CF3、OCF3、OH、NO2、CN、任选被C1-6烷基或硝基取代的苯基、任选被C1-6烷基或硝基取代的苯基甲基、SO2NH2、SO2-(C1-4)烷基、C(O)NH2、C(O)OR1、NR2R3、吗啉或1-吡咯基,其中R1是H或(C1-4)烷基,以及其中R2和R3各自独立是H或(C1-4)烷基;其中所述取代基是空间相容的。
Ar2为:
(i)选自下式的苯基或吡啶基:
其中,R4、R5和R6各自独立代表如下:
H、(C1-6)烷基、(C3-7)环烷基、(C3-7)环烷基-(C1-3)烷基、(C2-6)链烯基、O-(C1-6)烷基、S-(C1-6)烷基、卤素、CF3、OCF3、OH、NO2、CN、-NRN1RN2、-C(O)R21、-(C1-3)烷基-C(O)R21、-C(O)OR22、-(C1-3)烷基-C(O)OR22、-SO2-(C1-3)烷基-C(O)OR22,C(O)NH2、-(C1-3)烷基-C(O)NH2,-S(O)-(C1-4)烷基、-SO2-(C1-4)烷基、SO2NH2,苯基、苯基甲基、苯基-SO2-、2-,3-或4-吡啶基、1-吡咯基;
其中,RN1、RN2各自独立选自H或者(C1-6)烷基,其中RN1和RN2可以互相共价结合从而同它们相连的N原子一起形成4至7-元杂环,由此6或7-元杂环4位的-CH2-可以被-O-、-S-或-NRN3-替换,其中RN3代表H、-C(O)OR22、(C1-6)烷基、(C3-7)环烷基或(C3-7)环烷基-(C1-3)烷基;
其中,R21是(C1-4)烷基;R22是H或(C1-4)烷基;所述的苯基、吡啶基和吡咯基可以具有一个或多个选自卤素、NO2、(C1-3)烷基或CF3的取代基;取代基R4、R5和R6空间相容。
(ii)Ar2为任选被1至3个独立选自(C1-4)烷基、O-(C1-4)烷基、S-(C1-4)烷基、NO2或卤素的取代基所取代的稠合的苯基-(饱和或不饱和的5-或6-元碳环);或者
(iii)Ar2为包含1至4个选自N、O或S杂原子的5-或6-元芳杂环或稠合的苯基-5-或6-元杂环,所述芳杂环或稠合的苯基-杂环任选被1至3个独立选自(C1-4)烷基、O-(C1-4)烷基、S-(C1-4)烷基、NO2或卤素的取代基所取代。
优选的,本发明通式I化合物结构通式Ia、Ib如下:
其中,Ar1、Ar2同结构通式I。
更为优选的,上述通式I化合物是下列之一:
2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)-N-苯基乙酰胺(Ia1)、
N-(2-氯苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia2)、
N-(2-氟苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia3)、
N-(2-溴苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia4)、
N-(2-溴-4-甲基苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia5)、
2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)-N-(4-甲基-2-硝基苯基)乙酰胺(Ia6)、
2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)-N-(2-硝基苯基)乙酰胺(Ia7)、
N-(4-乙酰基-2-溴苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia8)、
N-(2-氯吡啶-3-基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia9)、
N-(2,4-二氯苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia10)、
2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)-N-邻甲苯乙酰胺(Ia11)、
甲基3-溴-4-(2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺基)苯甲酸(Ia12)、
乙基3-溴-4-(2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺基)苯甲酸(Ia13)、
1-(2,4-二溴苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酮基(Ia14)、
1-(3,4-二氯苯基)-2-(3-甲苯-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酮基(Ia15)、
1-(3,4-二氢喹啉-1(2H)-基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酮基(Ia16)、
1-(3,4-二氢异喹啉-2(1H)-基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酮基(Ia17)、
N-(2-氯-4-硝基苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia18)、
N-(3-溴-5-甲基吡啶-2-基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia19)、
N-(4-磺酰胺基-2-溴苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia20)、
2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)-N-苯基乙酰胺(Ib1)、
N-(2-氯苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib2)、
N-(2-氟苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib3)、
N-(2-溴苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib4)、
N-(2-溴-4-甲基苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib5)、
2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)-N-(4-甲基-2-硝基苯基)乙酰胺(Ib6)、
2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)-N-(2-硝基苯基)乙酰胺(Ib7)、
N-(4-乙酰基-2-溴苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib8)、
N-(2-氯吡啶-3-基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib9)、
N-(2,4-二氯苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib10)、
2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)-N-邻甲苯乙酰胺(Ib11)、
甲基3-溴-4-(2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺基)苯乙酸(Ib12)、
乙基3-溴-4-(2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺基)苯乙酸(Ib13)、
1-(2,4-二溴苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酮基(Ib14)、
1-(3,4-二氯苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酮基(Ib15)、
1-(3,4-二氢喹啉-1(2H)-基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酮基(Ib16)、
1-(3,4-二氢异喹啉-2(1H)-基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙基(Ib17)、
N-(2-氯-4-硝基苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib18)、
N-(3-溴-5-甲基吡啶-2-yl)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺基(Ib19)或
N-(4-磺酰胺基-2-溴苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib20)。
发明详述
本发明中所采用的术语“(C1-4)烷基”,无论单独出现或与其它基团组合,意指分别包含1至4个碳原子的脂肪族直链或支链烷基。这里的烷基包括甲基(Me)、乙基(Et)、丙基(Pr)、1-甲基乙基(iPr)、丁基(Bu)、2-甲基丙基(iBu)和1,1-二甲基乙基(tBu)。括号中的为通用缩写。
本发明中所采用的术语“O-(C1-4)烷基”,无论单独出现或与其它基团组合,是指包含1至4个碳原子的烷氧基,并包括甲氧基(OMe)、乙氧基(OEt)、丙氧基(OPr)、1-甲基乙氧基(OiPr)、丁氧基(OBu)和1,1-二甲基乙氧基(OtBu)。括号中的为通用缩写。
本发明中所采用的术语“S-(C1-4)烷基”,无论单独出现或与其它基团组合,是指包含1至4个碳原子的烷硫基,并包括甲硫基、乙硫基、丙硫基、(1-甲基乙基)硫基、丁硫基和1,1-二甲基乙硫基。
本发明中所采用的术语“卤素”是指选自氟、氯、溴或碘的卤素基团。
本发明中所采用的术语“(C2-4)链烯基”,无论单独出现或与其它基团组合,是指通过从包含2至4个碳原子的烯烃除去两个氢原子衍生而得的二价链烯烃基,并包含-CH=CH-、-CH2CH=CH-、-CH2CH=CHCH2-和-CH(Me)CH=CH-。该术语可包含(C2-4)链烯基的顺式和反式异构体及其混合物。
本发明中所采用的术语“不饱和的或饱和的5-或6-元碳环”,无论单独出现或与其它基团组合,是指包含5至6个碳原子的不饱和或饱和单环烃,例如苯基、1-环己烯基、1,3-环己二烯基、环己烯基、1-环戊烯基和环戊烷基。
本发明中所采用的术语“稠合的苯基-(不饱和的或饱和的5-或6-元碳环)”或“稠合的苯基-碳环”,无论单独出现或与其它基团组合,是指与不饱和的或饱和的5-或6-元碳环相稠合的苯环。例如萘基、1,2,3,4-四氢萘基、2,3-二氢-1H-茚基和茚基。
本发明中所采用的术语“芳杂环”,无论单独出现或与其它基团组合,是指通过从1至4个选自N、O和原子的5-或6-元杂环除去氢原子衍生而得的单价基团。常见的芳杂环包括三唑、四唑、咪唑、吡唑、哒嗪、三嗪、吡嗪等。
本发明中所采用的术语“稠合的苯基-5-或6-元芳杂环”,无论单独出现或与其它基团组合,是指与含有1至2个N原子的5-或6-元芳杂环稠合的苯基。包括1H-苯并咪唑基、喹啉基和异喹啉基。
本发明中所采用的术语“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/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,在这里是可用途的并与式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。
本发明中所采用的术语“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。这样的衍生物的例子包括但不限于酯和酰胺。
2、六元芳杂环并咪唑巯乙酰胺类衍生物或其可药用盐的制备方法
本发明六元芳杂环并咪唑巯乙酰胺类目标产物的合成以氯和硝基取代的六元杂环Ar为起始原料,与取代芳基(Ar1)胺即取代芳胺Ar1-NH2缩合得到中间体(I-1),依次经过还原、环合反应得到六元杂环并咪唑硫酮母环化合物(I-4),(I-4)与相应的2-氯-N-取代芳基(Ar2)-乙酰胺或其它卤代烷反应得到六元杂环并咪唑巯乙酰胺类衍生物(I);
合成路线如下:
试剂和条件:(i)Ar1-NH2,KF或NaHCO3/EtOH;(ii)H2,Pd/C;(iii)NaHCO3,H2O,EtOH,EtOCS2K,加热回流.(iv)K2CO3,CH3COCH3,2-氯-N-取代芳基(Ar2)-乙酰胺或其它卤代烷.
其中,Ar、Ar1、Ar2及X1、X2、X3、X4的定义同上通式I所述。
优选的,
本发明通式Ia化合物咪唑并[4,5-b]吡啶巯乙酰胺衍生物按照以下合成路线a制备:
以3-硝基-2-氯吡啶(Ia-1)为起始原料,与取代芳基(Ar1)胺在氟化钠的碱性条件下缩合得到中间体(Ia-2),在该步反应中,以过量取代芳胺为溶剂;然后,依次经过还原反应、缩合反应得到母环(Ia-4);最后,(Ia-4)与相应的2-氯-N-取代芳基(Ar2)-乙酰胺或其它卤代烷反应得到咪唑并[4,5-b]吡啶巯乙酰胺类(Ia)目标产物;
合成路线a如下:
试剂和条件:(Ia-i)Ar1-NH2,KF;(Ia-ii)H2,Pd/C;(Ia-iii)NaHCO3,H2O,EtOH,EtOCS2K,加热回流.(Ia-iv)K2CO3,CH3COCH3,2-氯-N-取代芳基(Ar2)-乙酰胺或其它卤代烷.
其中Ar1、Ar2的定义同上通式I所述。
所述取代芳基(Ar1)为2,4,6-三甲苯基、1-萘基、2-萘基、2,4-二氯苯基、2,4-二溴苯基、2-氯-4-烷基苯基、2-溴-4-烷基苯基。
所述取代芳基(Ar2)为苯基、2-氯苯基、2-氟苯基、2-溴苯基、2-溴-4-甲基基苯基、4-甲基-2-硝基苯基、2-硝基苯基、2-氯吡啶-3-基、2,4-二氯苯基、邻甲苯基、2-溴-4-磺酰胺基苯基、2-溴-4-甲酸苯基、2-氯-4-甲酸苯基、2-溴-4-甲氧羰基苯基、2-溴-4-乙氧羰基苯基、2-氯-4-硝基苯基、3-溴-5-甲基吡啶-2-基、4-磺酰胺基-2-溴苯基。
本发明式Ib化合物咪唑并[4,5-c]吡啶巯乙酰胺衍生物按照以下合成路线b制备:
以3-硝基-4-氯吡啶(Ib-1)为起始原料,与取代芳基(Ar1)胺在碳酸氢钠的碱性条件下缩合得到中间体(Ib-2),依次经过还原反应、缩合反应得到母环(Ib-4);最后,(Ib-4)与相应的2-氯-N-取代芳基(Ar2)-乙酰胺或其它卤代烷反应得到咪唑并[4,5-c]吡啶巯乙酰胺类(Ib)目标产物。
合成路线b如下:
试剂和条件:(Ib-i)Ar1-NH2,NaHCO3/EtOH;(Ib-ii)H2,Pd/C;(Ib-iii)NaHCO3,H2O,EtOH,EtOCS2K,加热回流.(Ib-iv)K2CO3,CH3COCH3,2-氯-N-取代芳基(Ar2)-乙酰胺或其它卤代烷.
其中Ar1、Ar2的定义同上通式I所述。
所述取代芳基(Ar1)为2,4,6-三甲苯基、1-萘基、2-萘基、2,4-二氯苯基、2,4-二溴苯基、2-氯-4-烷基苯基、2-溴-4-烷基苯基。
所述取代芳基(Ar2)为苯基、2-氯苯基、2-氟苯基、2-溴苯基、2-溴-4-甲基基苯基、4-甲基-2-硝基苯基、2-硝基苯基、2-氯吡啶-3-基、2,4-二氯苯基、邻甲苯基、2-溴-4-磺酰胺基苯基、2-溴-4-甲酸苯基、2-氯-4-甲酸苯基、2-溴-4-甲氧羰基苯基、2-溴-4-乙氧羰基苯基、2-氯-4-硝基苯基、3-溴-5-甲基吡啶-2-基、4-磺酰胺基-2-溴苯基。
3、本发明通式I的六元芳杂环并咪唑巯乙酰胺类衍生物类化合物的应用
本发明通式I的六元芳杂环并咪唑巯乙酰胺类衍生物类化合物在抑制HIV复制的细胞试验(MT-4细胞)中显示出显著的抗病毒活性和较高的选择性。因此,本发明还提供:
通式I的六元芳杂环并咪唑巯乙酰胺类衍生物类化合物在制备抗HIV的药物中的应用。
一种抗HIV药物组合物,包含本发明所述化合物或其药学上可接受的盐以及一种或多种药学上可接受载体或赋形剂。
本发明化合物既可以其本身也可以其药学上可接受的盐或溶剂化物的形式使用。通式I化合物的药学上可接受的盐包括与药学上可接受的无机酸或有机酸、或者无机碱或有机碱形成的常规盐。合适的酸加成盐的例子包括与盐酸、硫酸、磷酸、硝酸、氢溴酸、高氯酸、富马酸、乙酸、丙酸、琥珀酸、羟基乙酸、甲酸、乳酸、马来酸、酒石酸、柠檬酸、扑酸、丙二酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、富马酸、甲苯磺酸、甲磺酸、萘-2-磺酸、苯磺酸、羟基苯甲酸、氢碘酸、苹果酸、鞣酸等形成的盐。合适的碱加成盐的例子包括与钠、锂、钾、镁、铝、钙、锌、N,N’-二苄基乙二胺、氯代普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖按和普鲁卡因等形成的盐。本文中涉及到本发明化合物时,包括通式I化合物及其药学上可接受的盐或溶剂化物。
根据本发明,本发明式I化合物可与常规药物载体或赋形剂组成药物组合物。该药物组合物可通过口服或非肠道途径给药。本发明的药物组合物可按本领域常规方法制备成各种剂型,包括但不限于片剂、胶囊、溶液、悬浮液、颗粒剂或注射剂等,经口服或非肠道途径给药。
在本发明的化合物上进行新的结构修饰及深入研究也有助于开发出新的抗HIV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1:3-(2,4,6-三甲苯基)-1-H-咪唑并[4,5-b]吡啶-2(3H)-硫酮(Ia-4,Ar1=2,4,6-三甲苯基,下同)的制备
将1.58g(0.01mol)3-硝基-2-氯吡啶(Ia-1),5.4g(0.04mol)2,4,6-三甲基苯胺,0.88g(0.015mol)氟化钾置于250ml圆底烧瓶中,电磁搅拌下油浴120℃加热回流10h,停止加热后冷却至室温,向反应液中加入150ml水和20ml浓氨水充分振荡后,用二氯甲烷萃取(3×30ml),有机相合并用无水硫酸钠干燥。将充分干燥的有机相减压抽滤后浓缩,得褐色油状物。向其中加入乙醇-石油醚后搅动有黄色不溶固体析出。在机械搅拌的条件下加热至沸腾,然后冷却至室温后减压抽虑,得1.5g黄色固体N-(2,4,6-三甲苯基)-3-硝基吡啶-2-氨基(Ia-2)。收率65%,MS(ESI):m/z 258.12(M+1),C14H15N3O2(257.12).
将通过上步反应制得的6g(0.023mol)化合物(Ia-2)与0.2g钯碳置于250ml圆底烧瓶中,然后再向烧瓶中加入乙醇50ml。将该反应体系抽真空3次后通入氢气,并保持整个反应过程中氢气过量,反应15h后将反应液减压抽滤并浓缩。浓缩液用石油醚洗涤,再次减压抽滤,滤饼在空气中干燥,得4.8g化合物N-(2,4,6-三甲苯基)吡啶-2,3-二氨基(Ia-3),收率80.0%.
将1.2g(0.0053mol)化合物N-(2,4,6-三甲苯基)吡啶-2,3-二氨基(Ia-3),1g(0.0062mol)EtOCS2HK,0.1g(0.0012mol)碳酸氢钠置于250ml圆底烧瓶中,再向其中加入25ml乙醇和5ml水。在机械搅拌的条件下加热回流5h。反应停止后冷却至室温,浓缩。在机械搅拌的条件下向该浓缩液中加入50ml水和15ml 2mol/L的氢氧化钠溶液。然后将混合液减压抽滤,过滤掉不溶物,滤液用冰醋酸调至中性,有固体析出。减压抽滤后,滤饼在空气中干燥,得母环化合物3-(2,4,6-三甲苯基)-1-H-咪唑并[4,5-b]吡啶-2(3H)-硫酮(Ia-4)0.8g,收率66.7%。
实施例2:2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)-N-苯基乙酰胺(Ia1)的制备
将0.15g(0.5mmol)3-(2,4,6-三甲苯基)-1-H-咪唑并[4,5-b]吡啶-2(3H)-硫酮(Ia-4)、0.5mmol2-氯-N-取代苯基乙酰胺及0.14g(1.0mmol)碳酸钾置于50ml圆底烧瓶中,室温搅拌10h,TLC监测反应完全,反应液减压浓缩蒸干。快速柱层析分离得到2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)-N-苯基乙酰胺(Ia1)。白色晶体,收率:54.7%.mp:174-181℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.42(s,1H,NH),8.14(d,1H,J=4.2Hz,imidazo[4,5-b]pyridin-5H),8.00(d,1H,J=7.8Hz,imidazo[4,5-b]pyridin-7H),7.56(d,2H,J=7.8Hz,Ph-6H,Ph-2H),7.30(t,2H,J=7.8Hz,Ph-3H,Ph-5H),7.27(dd,1H,J1=4.2Hz,J2=7.8Hz,imidazo[4,5-b]pyridin-6H),7.15(s,2H,PhH),7.05(t,1H,J=7.8Hz,Ph-4H),4.37(s,2H,S-CH2),2.37(s,3H,Me),1.86(s,6H,2×Me).ESI-MS:m/z 403.6(M+1).C23H22N4OS(402.15).
实施例3:N-(2-氯苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia2)的制备
操作方法同实施例2Ia1的制备,所不同的是使用2-氯-N-(2-氯苯基)乙酰胺。所得产物为白色晶体,收率:64.5%.mp:176-180℃.1H NMR(600MHz,DMSO-d6,ppm)δ:9.96(s,1H,NH),8.16(d,1H,J=4.8Hz,imidazo[4,5-b]pyridin-5H),8.06(d,1H,J=7.8Hz,Ph-6H),7.74(d,1H,J=7.8Hz Ph-3H),7.64(d,1H,J=7.8Hz,imidazo[4,5-b]pyridin-7H),7.37(t,1H,J=7.8Hz,Ph-5H),7.30(dd,1H,J1=4.8Hz,J2=7.8Hz,imidazo[4,5-b]pyridin-6H),7.14(s,2H,PhH),7.12(t,1H,J=7.8Hz,Ph-4H),4.37(s,2H,S-CH2),2.36(s,3H,Me),1.85(s,6H,2×Me).ESI-MS:m/z 437.6(M+1),439.5(M+3).C23H21ClN4OS(436.11).
实施例4:N-(2-氟苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia3)的制备
操作方法同实施例2Ia1的制备,所不同的是使用2-氯-N-(2-氟苯基)乙酰胺。所得产物为白色晶体,收率:55.6%.mp:179-181℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.32(s,1H,NH),8.16(d,1H,J=4.8Hz,imidazo[4,5-b]pyridin-5H),8.02(d,1H,J=7.8Hz,Ph-6H),7.90(d,1H,J=9.6Hz imidazo[4,5-b]pyridin-7H),7.29(dd,1H,J1=4.8Hz,J2=9.6Hz,imidazo[4,5-b]pyridin-6H),7.25(m,1H,Ph-5H),7.15(m,4H,PhH),4.39(s,2H,S-CH2),2.50(s,3H,Me),1.85(s,6H,2×Me).ESI-MS:m/z 421.4(M+1),423.4(M+3).C23H23FN4OS(420.14).
实施例5:N-(2-溴苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia4)的制备
操作方法同实施例2Ia1的制备,所不同的是使用2-氯-N-(2-溴苯基)乙酰胺。所得产物为白色晶体,收率:44.6%.mp:188-191℃.1H NMR(600MHz,DMSO-d6,ppm)δ:9.96(s,1H,NH),8.16(d,1H,J=4.8Hz,imidazo[4,5-b]pyridin-5H),8.07(d,1H,J=7.8Hz,Ph-6H),7.74(d,1H,J=7.8Hz Ph-3H),7.65(d,1H,J=7.8Hz,imidazo[4,5-b]pyridin-7H),7.38(t,1H,J=7.8Hz,Ph-5H),7.29(dd,1H,J1=4.8Hz,J2=7.8Hz,imidazo[4,5-b]pyridin-6H),7.14(s,2H,PhH),7.11(t,1H,J=7.8Hz,Ph-4H),4.37(s,2H,S-CH2),2.36(s,3H,Me),1.85(s,6H,2×Me).ESI-MS:m/z 481.4(M+1),483.4(M+3)485.4(M+5).C23H21ClN4OS(480.06).
实施例6:N-(2-溴-4-甲基苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia5)的制备
操作方法同实施例2Ia1的制备,所不同的是使用2-氯-N-(2-溴-4-甲基苯基)乙酰胺。所得产物为白色晶体,收率:67.6%.mp:205-209℃.1H NMR(600MHz,DMSO-d6,ppm)δ:9.87(s,1H,NH),8.16(d,1H,J=5.4Hz,imidazo[4,5-b]pyridin-5H),8.06(d,1H,J=7.8Hz,Ph-6H),7.57(d,1H,J=8.4Hz,imidazo[4,5-b]pyridin-7H),7.47(s,1H,Ph-3H),7.31(dd,1H,J1=4.8Hz,J2=7.8Hz,imidazo[4,5-b]pyridin-6H),7.17(d,1H,J=7.8Hz,PhH),7.14(m,2H,PhH),4.34(s,2H,S-CH2),2.50(s,3H,Me),2.26(s,3H,Me),1.84(s,6H,2×Me).ESI-MS1:m/z 495.4(M+1),497.5(M+3).499.3(M+5).C24H25BrN4OS(494.08).
实施例7:2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)-N-(4-甲基-2-硝基苯基)乙酰胺(Ia6)的制备
操作方法同实施例2Ia1的制备,所不同的是使用2-氯-N-(4-甲基-2-硝基苯基)乙酰胺。所得产物为黄色晶体,收率:65.4%.mp:230-233℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.52(s,1H,NH),8.15(d,1H,J=4.8Hz,imidazo[4,5-b]pyridin-5H),8.02(d,1H,J=7.8Hz,Ph-6H),7.81(d,1H,J=1.8Hz,Ph-3H),7.71(d,1H,J=8.4Hz imidazo[4,5-b]pyridin-7H),7.40(dd,1H,J1=7.8Hz,J2=1.8Hz,Ph-5H),7.28(dd,1H,J1=8.4Hz,J2=4.8Hz,imidazo[4,5-b]pyridin-6H),7.14(s,2H,PhH),4.34(s,2H,S-CH2),2.36(s,6H,2×Me),1.84(s,6H,2×Me).ESI-MS:m/z 462.5(M+1).C24H23N5O3S(461.15).
实施例8:2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)-N-(2-硝基苯基)乙酰胺(Ia7)的制备
操作方法同实施例2Ia1的制备,所不同的是使用2-氯-N-(2-硝基苯基)乙酰胺。所得产物为白色晶体,收率:63.6%.mp:194-197℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.82(s,1H,NH),8.15(d,1H,J=4.8Hz,imidazo[4,5-b]pyridin-5H),8.03(d,1H,J=8.4Hz,Ph-3H),7.98(d,1H,J=8.4Hz,Ph-6H),7.84(d,1H,J=8.4Hz,imidazo[4,5-b]pyridin-7H),7.73(t,1H,J=8.4Hz,Ph-5H),7.38(t,1H,J=8.4Hz,Ph-4H),7.29(dd,1H,J1=4.8Hz,J2=8.4Hz,imidazo[4,5-b]pyridin-6H),7.14(s,2H,PhH),4.36(s,2H,S-CH2),2.36(s,3H,Me),1.84(s,6H,2×Me).ESI-MS:m/z 448.5(M+1),450.4(M+3).C23H21N5O3S(447.14).
实施例9:N-(4-乙酰基-2-溴苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia8)的制备
操作方法同实施例2Ia1的制备,所不同的是使用2-氯-N-(4-乙酰基-2-溴苯基)乙酰胺。所得产物为白色晶体,收率:67.8%.mp:210-213℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.09(s,1H,NH),8.17(d,1H,J=4.8Hz,imidazo[4,5-b]pyridin-5H),8.07(m,1H,Ph-3H),7.95(d,1H,J=8.4Hz Ph-6H),7.63(d,1H,J=7.8Hz imidazo[4,5-b]pyridin-7H),7.30(dd,1H,J1=4.8Hz,J2=7.8Hz,imidazo[4,5-b]pyridin-6H),7.24(t,1H,J=8.4Hz,Ph-5H),7.14(s,2H,PhH),4.37(s,2H,S-CH2),2.50(s,3H,Me),2.36(s,3H,Me),1.85(s,6H,2×Me).ESI-MS:m/z523.4(M+1),525.5(M+3).C25H23BrN4O2S(522.07).
实施例10:N-(2-氯吡啶-3-基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia9)的制备
操作方法同实施例2Ia1的制备,所不同的是使用2-氯-N-(2-氯吡啶-3-基)乙酰胺。所得产物为白色晶体,收率:57.7%.mp:216-220℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.23(s,1H,NH),8.27(d,1H,J=7.8Hz,pyridine-4H),8.19(d,1H,J=4.8Hz,pyridine-6H),8.16(d,1H,J=4.8Hz,imidazo[4,5-b]pyridin-5H),8.04(d,1H,J=8.4Hz imidazo[4,5-b]pyridin-7H),7.44(dd,1H,J1=4.8Hz,J2=8.4Hz,imidazo[4,5-b]-pyridin-6H),7.30(dd,1H,J1=4.8Hz,J2=7.8Hz,pyridine-5H),7.14(s,2H,PhH),4.41(s,2H,S-CH2),2.36(s,3H,Me),1.85(s,6H,2×Me).ESI-MS:m/z 438.5(M+1),440.5(M+3).C22H22ClN5OS(437.11).
实施例11:N-(2,4-二氯苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia10)的制备
操作方法同实施例2Ia1的制备,所不同的是使用2-氯-N-(2,4-二氯苯基)乙酰胺。所得产物为白色晶体,收率:62.6%.mp:185-197℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.14(s,1H,NH),8.16(d,1H,J=4.8Hz,imidazo[4,5-b]pyridin-5H),8.04(d,1H,J=7.8Hz,Ph-6H),7.87(d,1H,J=8.4Hz imidazo[4,5-b]pyridin-7H),7.66(d,1H,J=1.8Hz,Ph-3H),7.42(dd,1H,J1=7.8Hz,J2=1.8Hz,Ph-5H),7.30(dd,1H,J1=4.8Hz,J2=8.4Hz,imidazo[4,5-b]pyridin-6H),7.14(s,2H,PhH),4.38(s,2H,S-CH2),2.36(s,3H,Me),1.84(s,6H,2×Me).ESI-MS:m/z471.4(M+1),474.3(M+3).C23H20C12N4OS(470.07).
实施例12:2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)-N-邻甲苯乙酰胺(Ia11)的制备
操作方法同实施例2Ia1的制备,所不同的是使用2-氯-N-邻甲苯基乙酰胺。所得产物为白色晶体,收率:62.6%.mp:185-197℃.1H NMR(600MHz,DMSO-d6,ppm)δ:9.78(s,1H,NH),8.15(d,1H,J=4.8Hz,imidazo[4,5-b]pyridin-5H),8.02(d,1H,J=8.4Hzimidazo[4,5-b]pyridin-7H),7.43(d,1H,J=7.8Hz,Ph-6H),7.29(t,1H,J=7.8Hz,Ph-5H),7.19(m,2H,imidazo[4,5-b]pyridin-6H,Ph-3H),7.15(s,2H,PhH),7.07(t,1H,J=7.8Hz,Ph-4H),4.35(s,2H,S-CH2),2.36(s,3H,Me),1.85(s,6H,2×Me).ESI-MS:m/z 417.6(M+1).C24H24N4OS(416.17).
实施例13:甲基3-溴-4-(2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺基)苯甲酸(Ia12)的制备
操作方法同实施例2Ia1的制备,所不同的是使用3-溴-4-(2-氯乙酰胺)苯甲酸甲酯。所得产物为白色晶体,收率:59.9%.mp:188-191℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.13(s,1H,NH),8.17(s,1H,J=4.2Hz,imidazo[4,5-b]pyridin-5H),8.13(d,1H,J=2.4Hz Ph-3H),8.07(m,2H,Ph-6H,Ph-5H),7.95(d,1H,J=8.4Hz imidazo-[4,5-b]pyridin-7H),7.30(dd,1H,J1=4.8Hz,J2=7.8Hz,imidazo[4,5-b]pyridin-6H),7.14(s,2H,PhH),4.41(s,2H,S-CH2),3.85(s,3H,COCH3),2.36(s,3H,Me),1.84(s,6H,2×Me).ESI-MS:m/z 539.4(M+1),543.5(M+5).C25H23BrN4O3S(538.07).
实施例14:乙基3-溴-4-(2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺基)苯甲酸(Ia13)的制备
操作方法同实施例2Ia1的制备,所不同的是使用3-溴-4-(2-氯乙酰胺)苯甲酸乙酯。所得产物为白色晶体,收率:63.9%.mp:181-183℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.10(s,1H,NH),8.17(d,1H,J=4.8Hz,imidazo[4,5-b]pyridin-5H),8.16(d,1H,J=1.8Hz,Ph-3H),8.09(m,2H,Ph-6H,Ph-5H),7.95(d,1H,J=8.4Hz imidazo[4,5-b]pyridin-7H),7.30(dd,1H,J1=4.8Hz,J2=8.4Hz,imidazo[4,5-b]pyridin-6H),7.14(s,2H,PhH),4.41(s,2H,S-CH2),4.30(q,2H,J=7.2Hz,OCH2CH3),2.36(s,3H,Me),1.85(s,6H,2×Me).1.31(t,3H,J=7.2Hz,OCH2CH3),ESI-MS:m/z 555.3(M+3).C26H25BrN4O3S(552.38).
实施例15:1-(2,4-二溴苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酮基(Ia14)的制备
操作方法同实施例2Ia1的制备,所不同的是使用2-氯-1-(2,4-二溴苯基)乙酮。所得产物为白色晶体,收率:60.9%.mp:146-152℃.1H NMR(600MHz,DMSO-d6,ppm)δ:8.13(d,1H,J=4.8Hz,imidazo[4,5-b]pyridin-5H),8.00(m,2H,Ph-6H,Ph-3H),7.82(d,1H,J=8.4Hzimidazo[4,5-b]-pyridin-7H),7.75(dd,1H,J1=7.8Hz,J2=1.8Hz,Ph-5H),7.26(dd,1H,J1=4.8Hz,J2=7.8Hz,imidazo[4,5-b]pyridin-6H),7.13(s,2H,PhH),4.81(s,2H,S-CH2),2.35(s,3H,Me),1.76(s,6H,2×Me).ESI-MS:m/z 544.2(M+1),548.2(M+5).C23H19Br2N3OS(542.96).
实施例16:1-(3,4-二氯苯基)-2-(3-甲苯-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酮基(Ia15)的制备
操作方法同实施例2Ia1的制备,所不同的是使用2-溴-1-(3,4-二氯苯基)乙酮。所得产物为白色晶体,收率:59.6%.mp:148-153℃.1H NMR(600MHz,DMSO-d6,ppm)δ:8.31(s,1H,Ph-2H),8.14(d,1H,J=4.8Hz,imidazo[4,5-b]pyridin-5H),8.03(d,1H,J=1.8Hz,Ph-6H),8.02(d,1H,J=1.8Hz,Ph-5H),7.86(d,1H,J=8.4Hz imidazo-[4,5-b]pyridin-7H),7.26(dd,1H,J1=4.8Hz,J2=8.4Hz,imidazo[4,5-b]pyridin-6H),7.15(s,2H,PhH),5.09(s,2H,S-CH2),2.36(s,3H,Me),1.85(s,6H,2×Me).ESI-MS:m/z 456.4(M+1),458.3(M+3).C23H19Cl2N3OS(455.09).
实施例17:1-(3,4-二氢喹啉-1(2H)-基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酮基(Ia16)的制备
操作方法同实施例2Ia1的制备,所不同的是使用2-氯-1-(3,4-二氢喹啉-1(2H)-基)乙酮。所得产物为白色晶体,收率:68.0%.mp:230-236℃.ESI-MS:m/z 443.7(M+1).C26H26N4OS(442.18).
实施例18:1-(3,4-二氢异喹啉-2(1H)-基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酮基(Ia17)的制备
操作方法同实施例2Ia1的制备,所不同的是使用2-氯-1-(3,4-二氢异喹啉-2(1H)-基)乙酮。所得产物为白色晶体,收率:55.1%.mp:175-178℃.ESI-MS:m/z 443.7(M+1).C26H26N4OS(442.18).
实施例19:N-(2-氯-4-硝基苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia18)的制备
操作方法同实施例2Ia1的制备,所不同的是使用2-氯-N-(2-氯-4-硝基苯基)乙酰胺。所得产物为白色晶体,收率:54.9%.mp:268-271℃.ESI-MS:m/z 484.6(M+3).C23H20ClN5O3S(481.1).
实施例20:N-(3-溴-5-甲基吡啶-2-基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia19)的制备
操作方法同实施例2Ia1的制备,所不同的是使用2-氯-N-(3-溴-5-甲基吡啶-2-基)乙酰胺。所得产物为白色晶体,收率:71.7%.mp:171-173℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.43(s,1H,NH),8.37(d,J=3.0Hz,pyridine-5H),8.22(d,J=3.0Hz,pyridine-3H),8.17(d,1H,J=4.8Hz imidazo[4,5-b]pyridin-5H),8.05(dd,1H,J1=8.4Hz,J2=1.2Hz,imidazo[4,5-b]pyridin-7H)7.31(dd,1H,J1=4.8Hz,J2=8.4Hz imidazo[4,5-b]-pyridin-6H),7.15(s,2H,PhH),4.41(s,2H,S-CH2),2.36(s,3H,Me),1.85(s,6H,2×Me)1.27(s,3H,Me).ESI-MS:m/z 496.4(M+1),498.4(M+3).C23H22BrN5OS(495.07).
实施例21:N-(4-磺酰胺基-2-溴苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia20)的制备
操作方法同实施例2Ia1的制备,所不同的是使用2-氯-N-(4-磺酰胺基-2-溴苯基)乙酰胺。所得产物为白色固体收率:75.8%.mp:173-179℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.15(s,1H,NH),8.16(d,1H,J=8.4Hz,Ph-5H),8.08(d,1H,J=4.8Hz,imidazo-[4,5-b]pyridin-5H),8.03(s,1H,Ph-3H),8.01(d,1H,J=8.4Hz,Ph-6H),7.79(d,1H,J=8.4Hz,imidazo[4,5-b]pyridin-7H),7.14(s,2H,PhH),7.30(dd,1H,J1=8.4Hz,J2=4.8Hz,imidazo[4,5-b]pyridin-6H),4.41(s,2H,S-CH2),2.36(s,3H,Me),1.85(s,6H,2×Me).ESI-MS:m/z 562.2(M+3),564.3(M+5).C23H22BrN5O3S2(559.03).
实施例22:1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-硫酮(Ib-4,Ar1=2,4,6-三甲苯基,下同)的制备
将15.8g(0.1mol)3-硝基-4-氯吡啶(Ib-1),14.85g(0.11mol)2,4,6-三甲基苯胺,25.2g(0.3mol)碳酸氢钠置于500ml的圆底烧瓶中,并向其中加入无水乙醇250ml,机械搅拌的条件下加热回流10h,再改为室温搅拌12h停止。将该反应液减压抽滤,滤液浓缩后,柱层析得到黄色固体N-(2,4,6-三甲苯基)-3-硝基吡啶-4-氨基(Ib-2)10.5g,收率66.5%,MS(ESI):m/z 258.12(M+1),C14H15N3O2(257.12)。
将通过上步反应制得的6g(0.023mol)化合物(Ib-2)与0.2g钯碳置于250ml圆底烧瓶中,然后再向烧瓶中加入乙醇50ml。将该反应体系抽真空3次后通入氢气,并保持整个反应过程中氢气过量,反应15h后将反应液减压抽滤并浓缩。浓缩液用石油醚洗涤,再次减压抽滤,滤饼在空气中干燥,得4.5g化合物N-(2,4,6-三甲苯基)吡啶-3,4-二氨基(Ib-3),收率:75.0%。
将1.2g(0.0053mol)化合物N-(2,4,6-三甲苯基)吡啶-3,4-二氨基(Ib-3),1g(0.0062mol)EtOCS2K,0.1g(0.0012mol)碳酸氢钠置于250ml圆底烧瓶中,再向其中加入25ml乙醇和5ml水。在机械搅拌的条件下加热回流5h。反应停止后冷却至室温,浓缩。机械搅拌下向该浓缩液中加入50ml水和15ml 2mol/L的氢氧化钠溶液。然后将混合液减压抽滤,过滤掉不溶物,滤液用冰醋酸调至中性,有固体析出。减压抽滤,滤饼在空气中干燥,得母环化合物1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-硫酮(Ib-4)0.75,收率62.5%。
实施例23:2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)-N-苯基乙酰胺(Ib1)的制备
将0.15g(0.5mmol)Ib-4,0.5mmol 2-氯-N-取代苯基乙酰胺及0.14g(1.0mmol)碳酸钾,置于50ml圆底烧瓶中,室温搅拌10h,TLC监测反应完全,反应液减压浓缩蒸干。快速柱层析分离得到2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)-N-苯基乙酰胺(Ib1)。白色晶体,收率:59.1%.mp:175-178℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.44(s,1H,NH),8.92(s,1H,imidazo[4,5-c]pyridine-4H),8.27(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-6H),7.57(d,2H,J=7.8Hz,Ph-6H,Ph-2H),7.31(t,2H,J=7.8Hz,Ph-5H,Ph-3H),7.19(s,2H,PhH),7.05(m,1H,Ph-4H),6.98(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-7H),4.41(s,2H,S-CH2),2.37(s,3H,Me),1.86(s,6H,2×Me).ESI-MS:m/z 403.5(M+1),C23H22N4OS(402.15).
实施例24:N-(2-氯苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib2)的制备
操作方法同实施例23Ib1的制备,所不同的是使用2-氯-N-(2-氯苯基)乙酰胺。所得产物为白色晶体,收率:63.3%.mp:176-178℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.05(s,1H,NH),8.94(s,1H,imidazo[4,5-c]pyridine-4H),8.28(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-6H),7.81(d,1H,J=7.2Hz,Ph-6H),7.48(d,1H,J=8.4Hz,Ph-3H),7.32(t,1H,J=7.2Hz,Ph-5H),7.18(s,3H,Ph-4H,PhH),7.00(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-7H),4.41(s,2H,S-CH2),2.37(s,3H,Me),1.85(s,6H,2×Me).ESI-MS:m/z 437.5(M+1),439.5(M+3),441.1(M+5),C23H23ClN4OS(436.11).
实施例25:N-(2-氟苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib3)的制备
操作方法同实施例23Ib1的制备,所不同的是使用2-氯-N-(2-氟苯基)乙酰胺。所得产物为灰色晶体,收率:70.3%.mp:178-184℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.30(s,1H,NH),8.92(s,1H,imidazo[4,5-c]pyridine-4H),8.28(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-6H),7.90(m,1H,Ph-6H),7.27(m,1H,Ph-5H),7.15(m,2H,Ph-4H,Ph-3H),7.19(s,2H,PhH),6.99(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-7H),4.43(s,2H,S-CH2),2.37(s,3H,Me),1.85(s,6H,2×Me).ESI-MS:m/z 421.5(M+1),423.5(M+3).C23H21FN4OS(420.14).
实施例26:N-(2-溴苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib4)的制备
操作方法同实施例23Ib1的制备,所不同的是使用2-氯-N-(2-溴苯基)乙酰胺。所得产物为灰色固体,收率:69,0%.mp:179-181℃.1H NMR(600MHz,DMSO-d6,ppm)δ:9.96(s,1H,NH),8.96(s,1H,imidazo[4,5-c]pyridine-4H),8.28(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-6H),7.71(dd,1H,J1=7.2Hz,J2=1.2Hz,Ph-6H),7.65(d,1H,J=7.2Hz,Ph-3H),7.37(t,1H,J=7.2Hz,Ph-5H),7.18(s,2H,PhH),7.12(t,1H,J=7.2Hz,Ph-4H),7.00(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-7H),4.40(s,2H,S-CH2),2.37(s,3H,Me),1.85(s,6H,2×Me).ESI-MS:m/z481.4(M+1),483.3(M+3),485.6(M+5).C23H21BrN4OS(480.06).
实施例27:N-(2-溴-4-甲基苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib5)的制备
操作方法同实施例23Ib1的制备,所不同的是使用2-氯-N-(2-溴-4-甲基苯基)乙酰胺。所得产物为白色晶体,收率:75.5%.mp:191-195℃.1H NMR(600MHz,DMSO-d6,ppm)δ:9.88(s,1H,NH),8.96(s,1H,imidazo[4,5-c]pyridine-4H),8.31(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-6H),7.55(d,1H,J=7.2Hz,Ph-6H),7.45(s,1H,Ph-3H),7.17(s,3H,Ph-5H,PhH),6.98(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-7H),4.37(s,2H,S-CH2),2.37(s,3H,Me),2.27(s,3H,Me),1.85(s,6H,2×Me).ESI-MS:m/z 495.3(M+1),497.5(M+3),599.2(M+5).C24H25BrN4OS(494.08).
实施例28:2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)-N-(4-甲基-2-硝基苯基)乙酰胺(Ib6)的制备
操作方法同实施例23Ib1的制备,所不同的是使用2-氯-N-(4-甲基-2-硝基苯基)乙酰胺。所得产物为黄色晶体,收率:711%.mp:221-223℃.ESI-MS:m/z 462.5(M+1),464.3(M+3).C24H25N5O3S(461.15).
实施例29:2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)-N-(2-硝基苯基)乙酰胺(Ib7)的制备
操作方法同实施例23Ib1的制备,所不同的是使用2-氯-N-(2-硝基苯基)乙酰胺。所得产物为黄色晶体,收率:67.1%.mp:192-195℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.82(s,1H,NH),8.93(s,1H,imidazo[4,5-c]pyridine-4H),8.27(d,1H,J=4.8Hz,imidazo[4,5-c]pyridine-6H),7.98(dd,1H,J1=7.8Hz,J2=1.2Hz,Ph-3H),7.82(dd,1H,J1=7.8Hz,J2=0.6Hz,Ph-6H),7.73(t,1H,J=7.8Hz,Ph-5H),7.38(t,1H,J=7.8Hz,Ph-4H),7.18(s,2H,PhH),6.99(d,1H,J=4.8Hz,imidazo[4,5-c]pyridine-7H),4.44(s,2H,S-CH2),2.50(s,3H,Me),1.85(s,6H,2×Me).ESI-MS:m/z 448.5(M+1).C23H21N5O3S(447.14).
实施例30:N-(4-乙酰基-2-溴苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib8)的制备
操作方法同实施例23Ib1的制备,所不同的是使用2-氯-N-(4-乙酰基-2-溴苯基)乙酰胺。所得产物为白色晶体,收率:70.7%.mp:242-248℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.09(s,1H,NH),8.98(s,1H,imidazo[4,5-c]pyridine-4H),8.28(d,1H,J=4.8Hz,imidazo[4,5-c]pyridine-6H),8.17(s,1H,Ph-3H),7.96(d,1H,J=1.8Hz,Ph-6H),7.95(d,1H,J=1.8Hz,Ph-5H),7.19(s,2H,PhH),7.00(d,1H,J=4.8Hz,imidazo[4,5-c]pyridine-7H),4.44(s,2H,S-CH2),2.50(s,3H,COCH3),2.37(s,3H,Me),1.85(s,6H,2×Me).ESI-MS:m/z 523.5(M+1),525.5(M+3).C25H23BrN4O2S(522.07).
实施例31:N-(2-氯吡啶-3-基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib9)的制备
操作方法同实施例23Ib1的制备,所不同的是使用2-氯-N-(2-氯吡啶-3-基)乙酰胺。所得产物为白色晶体,收率:56.2%.mp:220-223℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.22(s,1H,NH),8.94(s,1H,imidazo[4,5-c]pyridine-4H),8.29(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-6H),8.25(dd,1H,J1=7.8Hz,J2=1.8Hz,pyridine-6H),8.20(dd,1H,J1=4.8Hz,J2=1.8Hz,pyridine-4H),7.44(dd,1H,J1=7.8Hz,J2=4.8Hz,pyridine-5H),7.19(s,2H,PhH),7.00(s,1H,J=5.4Hz,imidazo[4,5-c]pyridine-7H),4.44(s,2H,S-CH2),2.50(s,3H,Me),1.85(s,6H,2×Me).ESI-MS:m/z 438.5(M+1).C22H20ClN5OS(437.11).
实施例32:N-(2,4-二氯苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib10)的制备
操作方法同实施例23Ib1的制备,所不同的是使用2-氯-N-(2,4-二氯苯基)乙酰胺。所得产物为白色晶体,收率:63.7%.mp:250-254℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.11(s,1H,NH),8.32(s,1H,imidazo[4,5-c]pyridine-4H),8.28(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-6H),7.84(d,1H,J=8.4Hz,Ph-6H),7.67(d,1H,J=1.8Hz,Ph-3H),7.42(dd,1H,J1=8.4Hz,J2=1.8Hz,Ph-5H),7.18(s,2H,PhH),6.99(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-7H),4.41(s,2H,S-CH2),2.37(s,3H,Me),1.84(s,6H,2×Me).ESI-MS:m/z 471.8(M+1).C23H20Cl2N4OS(470.07).
实施例33:2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)-N-邻甲苯乙酰胺(Ib11)的制备
操作方法同实施例23Ib1的制备,所不同的是使用2-氯-N-邻甲苯基乙酰胺。所得产物为白色固体,收率:68.5%.mp:153-156℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.70(s,1H,NH),8.93(s,1H,imidazo[4,5-c]pyridine-4H),8.27(d,1H,J=4.8Hz,imidazo[4,5-c]pyridine-6H),7.81(s,1H,Ph-6H),7.68(d,1H,J=8.4Hz,Ph-5H),7.54(m,2H,Ph-3H,Ph-4H),7.18(s,2H,PhH),6.98(d,1H,J=4.8Hz,imidazo[4,5-c]pyridine-7H),4.36(s,2H,S-CH2),2.36(s,6H,2×Me),1.84(s,6H,2×Me).ESI-MS:m/z 417.6(M+1).C24H26N4OS(416.17).
实施例34:甲基3-溴-4-(2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺基)苯乙酸(Ib12)的制备
操作方法同实施例23Ib1的制备,所不同的是使用3-溴-4-(2-氯乙酰胺)苯甲酸甲酯。所得产物为白色晶体,收率:69.7%.mp:202-207℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.10(s,1H,NH),8.97(s,1H,imidazo[4,5-c]pyridine-4H),8.28(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-6H),8.14(d,1H,J=1.8Hz,Ph-3H),8.03(d,1H,J=8.4Hz,Ph-6H),7.94(dd,1H,J1=8.4Hz,J2=1.8Hz,Ph-5H),7.19(s,2H,PhH),6.99(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-7H),4.44(s,2H,S-CH2),3.34(s,3H,OCH3),2.37(s,3H,Me),1.85(s,6H,2×Me).ESI-MS:m/z 539.4(M+1),541.4(M+3),543.5(M+5).C25H23BrN4O3S(538.07).
实施例35:乙基3-溴-4-(2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺基)苯乙酸(Ib13)的制备
操作方法同实施例23Ib1的制备,所不同的是使用3-溴-4-(2-氯乙酰胺)苯甲酸乙酯。所得产物为白色晶体,收率:56.7%.mp:201-203℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.09(s,1H,NH),8.97(s,1H,imidazo[4,5-c]pyridine-4H),8.28(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-6H),8.14(d,1H,J=1.8Hz,Ph-3H),8.02(d,1H,J=8.4Hz,Ph-6H),7.94(dd,1H,J1=8.4Hz,J2=1.8Hz,Ph-5H),7.19(s,2H,PhH),6.99(d,1H,J=4.8Hz,imidazo[4,5-c]pyridine-7H),4.44(s,2H,S-CH2),4.30(q,2H,J=6.6Hz,COCH2),2.37(s,3H,Me),1.85(s,6H,2×Me),1.31(t,3H,J=6.6Hz,Me).ESI-MS:m/z 553.4(M+1),555.4(M+3).C26H25BrN4O3S(552.08).
实施例36:1-(2,4-二溴苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酮基(Ib14)的制备
操作方法同实施例23Ib1的制备,所不同的是使用2-氯-1-(2,4-二溴苯基)乙酮。所得产物为白色固体,收率:54.4%.mp:161-165℃.1H NMR(600MHz,DMSO-d6,ppm)δ:8.90(s,1H,imidazo[4,5-c]pyridine-4H),8.26(d,1H,J=4.8Hz,imidazo[4,5-c]-pyridine-6H),8.00(d,1H,J=1.8Hz,Ph-3H),7.83(d,1H,J=8.4Hz,Ph-6H),7.76(dd,1H,J1=8.4Hz,J2=1.8Hz,Ph-5H),7.18(s,2H,PhH),6.95(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-7H),4.84(s,2H,S-CH2),2.50(s,3H,Me),1.77(s,6H,2×Me).ESI-MS:m/z MS 546.2(M+3).C23H19Br2N3OS(542.96).
实施例37:1-(3,4-二氯苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酮基(Ib15)的制备
操作方法同实施例23Ib1的制备,所不同的是使用2-溴-1-(3,4-二氯苯基)乙酮。所得产物为白色晶体,收率:63.7%.mp:250-254℃.1H NMR(600MHz,DMSO-d6,ppm)δ:8.84(s,1H,imidazo[4,5-c]pyridine-4H),8.31(d,1H,J=1.2Hz,Ph-2H),8.25(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-6H),8.03(dd,1H,J1=8.4Hz,J2=1.2Hz,Ph-6H),7.87(d,1H,J=8.4Hz,Ph-5H),7.19(s,2H,PhH),6.97(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-7H),5.13(s,2H,S-CH2),2.38(s,3H,Me),1.87(s,6H,2×Me).ESI-MS:m/z 456.4(M+1).C23H19Cl2N3OS(455.06).
实施例38:1-(3,4-二氢喹啉-1(2H)-基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酮基(Ib16)的制备
操作方法同实施例23Ib1的制备,所不同的是使用2-氯-1-(3,4-二氢喹啉-1(2H)-基)乙酮。所得产物为黄色晶体,收率:75.6%.mp:192-195℃.ESI-MS:m/z 443.7(M+1),445.4(M+3).C26H26N4OS(442.18).
实施例39:1-(3,4-二氢异喹啉-2(1H)-基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙基(Ib17)的制备
操作方法同实施例23Ib1的制备,所不同的是使用2-氯-1-(3,4-二氢异喹啉-2(1H)-基)乙酮。所得产物为白色固体,收率:61.3%.mp:192-195℃.1H NMR(600MHz,DMSO-d6,ppm)δ:8.84(s,1H,imidazo[4,5-c]pyridine-4H),8.24(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-6H),7.56(s,1H,1,2,3,4-tetrahydroisoquinoline-H),7.26(s,3H,1,2,3,4-tetrahydroisoquinoline-H),7.18(s,2H,PhH),6.94(d,1H,J=5.4Hz,imidazo[4,5-c]-pyridine-7H),4.60(s,2H,S-CH2),3.75(s,2H,1,2,3,4-tetrahydroisoquinoline-H),2.78(m,2H,1,2,3,4-tetrahydroisoquinoline-H),2.37,(s,3H,Me),1.93(s,2H,1,2,3,4-tetrahydroisoquinoline-H),1.83(s,6H,2×Me).ESI-MS:m/z443.7(M+1),445.4(M+3).C26H26N4OS(442.18).
实施例40:N-(2-氯-4-硝基苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib18)的制备
操作方法同实施例23Ib1的制备,所不同的是使用2-氯-N-(2-氯-4-硝基苯基)乙酰胺。
所得产物为灰色晶体,收率:71.2%.mp:245-247℃.ESI-MS:m/z 484.12(M+3).C23H20ClN5O3S(481.1).
实施例41:N-(3-溴-5-甲基吡啶-2-yl)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺基(Ib19)的制备
操作方法同实施例23Ib1的制备,所不同的是使用2-氯-N-(3-溴-5-甲基吡啶-2-基)乙酰胺。所得产物为白色晶体,收率:60.0%.mp:155-160℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.41(s,1H,NH),8.95(s,1H,imidazo[4,5-c]pyridine-4H),8.38(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-6H),8.29(m,2H,pyridine-H),7.19(s,2H,PhH),7.00(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-7H),4.49(s,2H,S-CH2),2.37(s,3H,Me),1.85(s,6H,2×Me).ESI-MS:m/z 498.4(M+3),500.2(M+5).C23H22BrN5OS(495.07).
实施例42:N-(4-磺酰胺基-2-溴苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib20)的制备
操作方法同实施例23Ib1的制备,所不同的是使用2-氯-N-(4-磺酰胺基-2-溴苯基)乙酰胺。所得产物为白色晶体,收率:62.2%.mp:190-195℃.1H NMR(600MHz,DMSO-d6,ppm)δ:10.15(s,1H,NH),8.97(s,1H,imidazo[4,5-c]pyridine-4H),8.28(d,1H,J=5.4Hz,imidazo[4,5-c]pyridine-6H),8.04(s,1H,Ph-3H),7.98(d,1H,J=8.4Hz,Ph-5H),7.79(d,1H,J=8.4Hz,Ph-6H),7.46(s,2H,PhH),7.00(d,1H,J=5.4Hz,imidazo-[4,5-c]pyridine-7H),4.44(s,2H,S-CH2),2.50(s,3H,Me),1.85(s,6H,2×Me).ESI-MS:m/z 562.2(M+3),564.3(M+5).C23H22BrN5O3S2(559.03).
实施例43:抗HIV活性实验(MT-4细胞模型)
参见①Pauwels R,et al.J. Virol.Methods.1988,20,309.②Pannecouque C,et al.NatProtocols 2008,3,427.
术语解释:
MT-4细胞:人急性淋巴母细胞白血病细胞。
MTT分析法:MTT即为3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐,商品名:噻唑蓝。
Nevirapine:抗艾滋病上市药物奈韦拉平。
AZT:抗艾滋病上市药物齐多夫定。
DDC:抗艾滋病上市药物扎西他宾。
Efavirenz:抗艾滋病上市药物依法韦仑。
Delavirdine:抗艾滋病上市药物地拉韦啶。
DMSO:二甲基亚砜。
测试原理
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)。
MTT分析法原理:MTT即溴化-3-(4,5-二甲基-2-噻唑基)-2,5-二苯基四唑氮,可与活的细胞内琥珀酸脱氢酶相结合,而不与死亡细胞发生反应。目前MTT法是一种快速、简洁反映细胞活力的酶分析方法。
测试材料和方法
(1)HIV-1(IIIB)、HIV-2(ROD)毒株、HIV-1双突变(K103N/Y181C)耐药株RES056:由比利时Leuven大学Rega研究院微生物与免疫学研究所提供。
(2)MT-4细胞:由比利时Leuven大学Rega研究院微生物与免疫学研究所提供。
(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:Nevirapine(NVP)、AZT、DDC、Efavirenz(EFV)、Delavirdine(DLV)。
(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,于酶标仪中,在590nm下记录吸光度(A)值,计算出EC50,CC50以及SI。
(7)MTT染色法:加入样品培养一段时间后,再向每孔加入MTT溶液(5mg/ML)20μL,继续培养若干小时,弃染色液,并向每孔加入150μLDMSO,充分混合,于酶标仪中,在590nm下记录吸光度。
具体操作如下:将化合物用DMSO或水溶解后用磷酸盐缓冲液稀释,将3×105MT-4细胞与100μL不同浓度的化合物溶液在37℃共同预孵育1h。然后向该混合物中加入100μL适当浓度的病毒稀释液,将细胞于37℃孵育1h。洗涤三次后,将细胞再次分别悬浮于含有或不含化合物的培养基质中。接着将细胞在5%CO2环境中,于37℃下再孵育7天,并于感染后的第三天用含有或不含化合物的培养基质补充原培养液。每种培养条件都重复操作两次。对病毒的细胞病变作用每天都用反向光学显微镜监控。一般来讲,本实验中所用的病毒稀释液常常会在病毒感染后第五天发生细胞病变。药物抑制浓度以药物对病毒致细胞病变作用产生50%抑制作用而同时对细胞无直接毒性的浓度(EC50)表示。值得强调的是,当化合物水溶性较差,需要用DMSO才能溶解时,DMSO体积比浓度相对于水来讲,一般会低于10%(DMSO在MT-4细胞培养介质中最终浓度小于2%)。因为DMSO能影响测试化合物抗病毒活性,对含有相同浓度DMSO溶液的抗病毒活性对比空白实验也应该平行操作进行。另外,DMSO最终浓度(1/1000)远远低于影响HIV-1在MT-4细胞中复制所需浓度。
目标化合物的体外抗HIV-1(IIIB)、HIV-2(ROD)及HIV-1双突变RES056耐药株活性筛选数据由比利时Leuven大学Rega研究院微生物与免疫学研究所提供,所有的活性数据都经过至少两次独立、平行的实验测得。
部分生物评价结果列于表1、表2、表3中。
表1化合物Ia的抗HIV的活性和毒性(MT-4细胞)
表2化合物Ib的抗HIV的活性和毒性(MT-4细胞)
表3阳性药物的抗HIV活性和毒性(MT-4细胞)
上述实验结果表明:具有本发明通式I的化合物是一类具有新型结构骨架的HIV-1抑制剂,其中有多个化合物对野生型HIV-1的抑制活性处于微摩尔水平,尤其是化合物Ib20的活性与目前临床上广泛应用的抗艾滋病药物奈韦拉平(NVP)相当,活性是上市药物扎西他宾(DDC)的6倍,具有进一步研发的前景。此外,由于该骨架的化合物具有多个修饰位点,可作为先导化合物做广泛的化学修饰。因此,本发明涉及的化合物极有可能对HIV耐药性病毒株产生强的抑制活性,具有发展成为一类全新结构抗HIV新药的潜力。
Claims (5)
1.选自下述的化合物:
2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)-N-苯基乙酰胺(Ia1)、
N-(2-氯苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia2)、
N-(2-氟苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia3)、
N-(2-溴苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia4)、
N-(2-溴-4-甲基苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia5)、
2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)-N-(4-甲基-2-硝基苯基)乙酰胺(Ia6)、
2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)-N-(2-硝基苯基)乙酰胺(Ia7)、
N-(4-乙酰基-2-溴苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia8)、
N-(2-氯吡啶-3-基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia9)、
N-(2,4-二氯苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia10)、
2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)-N-邻甲苯基乙酰胺(Ia11)、
甲基3-溴-4-(2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺基)苯甲酸(Ia12)、
乙基3-溴-4-(2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺基)苯甲酸(Ia13)、
N-(2-氯-4-硝基苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia18)、
N-(3-溴-5-甲基吡啶-2-基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia19)、
N-(4-磺酰胺基-2-溴苯基)-2-(3-(2,4,6-三甲苯基)-3H-咪唑并[4,5-b]吡啶-2-巯基)乙酰胺(Ia20)、
2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)-N-苯基乙酰胺(Ib1)、
N-(2-氯苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib2)、
N-(2-氟苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib3)、
N-(2-溴苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib4)、
N-(2-溴-4-甲基苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib5)、
2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)-N-(4-甲基-2-硝基苯基)乙酰胺(Ib6)、
2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)-N-(2-硝基苯基)乙酰胺(Ib7)、
N-(4-乙酰基-2-溴苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib8)、
N-(2-氯吡啶-3-基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib9)、
N-(2,4-二氯苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib10)、
2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)-N-邻甲苯基乙酰胺(Ib11)、
甲基3-溴-4-(2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺基)苯甲酸(Ib12)、
乙基3-溴-4-(2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺基)苯甲酸(Ib13)、
N-(2-氯-4-硝基苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib18)、
N-(3-溴-5-甲基吡啶-2-基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺基(Ib19)、
N-(4-磺酰胺基-2-溴苯基)-2-(1-(2,4,6-三甲苯基)-1H-咪唑并[4,5-c]吡啶-2-巯基)乙酰胺(Ib20)。
2.权利要求1所述的化合物的制备方法,其特征在于步骤如下:
以3-硝基-2-氯吡啶(Ia-1)为起始原料,与取代芳基Ar1胺在氟化钾的碱性条件下缩合得到中间体(Ia-2),在该步反应中,以过量取代芳胺为溶剂;然后,依次经过还原反应、缩合反应得到母环(Ia-4);最后,(Ia-4)与相应的2-氯-N-取代芳基Ar2-乙酰胺反应得到咪唑并[4,5-b]吡啶巯乙酰胺类(Ia)目标产物;
合成路线a如下:
试剂和条件:(Ia-i)Ar1-NH2,KF;(Ia-ii)H2,Pd/C;(Ia-iii)NaHCO3,H2O,EtOH,EtOCS2K,加热回流,(Ia-iv)K2CO3,CH3COCH3,2-氯-N-取代芳基Ar2-乙酰胺,
所述取代芳基Ar1为2,4,6-三甲苯基;
所述取代芳基Ar2为苯基、2-氯苯基、2-氟苯基、2-溴苯基、2-溴-4-甲基苯基、4-甲基-2-硝基苯基、2-硝基苯基、2-氯吡啶-3-基、2,4-二氯苯基、邻甲苯基、2-氯-4-硝基苯基、3-溴-5-甲基吡啶-2-基、4-磺酰胺基-2-溴苯基。
3.权利要求1所述的化合物的制备方法,其特征在于步骤如下:
以3-硝基-4-氯吡啶(Ib-1)为起始原料,与取代芳基Ar1胺在碳酸氢钠的碱性条件下缩合得到中间体(Ib-2),依次经过还原反应、缩合反应得到母环(Ib-4);最后,(Ib-4)与相应的2-氯-N-取代芳基Ar2-乙酰胺反应得到咪唑并[4,5-c]吡啶巯乙酰胺类(Ib)目标产物;
合成路线b如下:
试剂和条件:(Ib-i)Ar1-NH2,NaHCO3/EtOH;(Ib-ii)H2,Pd/C;(Ib-iii)NaHCO3,H2O,EtOH,EtOCS2K,加热回流,(Ib-iv)K2CO3,CH3COCH3,2-氯-N-取代芳基Ar2-乙酰胺,
所述取代芳基Ar1为2,4,6-三甲苯基;
所述取代芳基Ar2为苯基、2-氯苯基、2-氟苯基、2-溴苯基、2-溴-4-甲基苯基、4-甲基-2-硝基苯基、2-硝基苯基、2-氯吡啶-3-基、2,4-二氯苯基、邻甲苯基、2-氯-4-硝基苯基、3-溴-5-甲基吡啶-2-基、4-磺酰胺基-2-溴苯基。
4.一种抗HIV药物组合物,包含权利要求1所述化合物以及一种或多种药学上可接受载体或赋形剂。
5.权利要求1所述化合物在制备抗HIV的药物中的应用。
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