CN1249061C - 磺酰胺和硫酰胺取代的咪唑并喹啉及其药物组合物和应用 - Google Patents
磺酰胺和硫酰胺取代的咪唑并喹啉及其药物组合物和应用 Download PDFInfo
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- CN1249061C CN1249061C CNB008086834A CN00808683A CN1249061C CN 1249061 C CN1249061 C CN 1249061C CN B008086834 A CNB008086834 A CN B008086834A CN 00808683 A CN00808683 A CN 00808683A CN 1249061 C CN1249061 C CN 1249061C
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- Prior art keywords
- butyl
- quinoline
- imidazo
- amino
- compound
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Abstract
1位含磺酰胺或硫酰胺官能团的咪唑并喹啉和四氢咪唑并喹啉化合物可用作免疫应答反应的调节剂。本发明的化合物和组合物可诱导各种细胞因子的生物合成,可用于治疗包括病毒疾病和肿瘤疾病在内的各种病情。
Description
发明领域
本发明涉及1位有磺酰胺或硫酰胺取代基的咪唑并喹啉化合物,以及含有这些化合物的药物组合物。本发明另一方面涉及这些化合物作为免疫调节剂用于诱导动物细胞因子生物合成、治疗疾病(包括病毒和肿瘤疾病)的用途。
发明背景
Backman等人在J.Org.Chem.15,1278-1284(1950)中关于1H-咪唑并[4,5-c]喹啉环体系的首次可靠报道描述了可用作抗疟药的1-(6-甲氧基-8-喹啉基)-2-甲基-1H-咪唑并[4,5-c]喹啉的合成。随后,报道了各种取代的1H-咪唑并[4,5-c]喹啉的合成。例如,Jain等人在J.Med.Chem.11,87-92页(1968)中合成了可能作为抗惊厥药和心血管药的化合物1-[2-(4-哌啶基)乙基]-1H-咪唑并[4,5-c]喹啉。另外,Baranov等人Chem.Abs.85,94362(1976)也报道了几种2-氧代咪唑并[4,5-c]喹啉,Berenyi等人J.HeterocyclicChem.18,1537-1540(1981)报道了某些2-氧代咪唑并[4,5-c]喹啉。
后来,发现某些1H-咪唑并[4,5-c]喹啉-4-胺及其1-、2-取代的衍生物可用作抗病毒药、支气管扩张药和免疫调节剂。它们在美国专利4,689,338;4,689,348;4,929,624;5,037,986;5,268,376;5,346,905以及5,389,640中有所描述,所有这些专利均纳入本文作为参考。
人们对于咪唑并喹啉环体系仍有兴趣,例如参见WO 98/30562、EP894797和WO 00/09506。EP 894 797描述了可用作免疫应答响应调节化合物的酰胺取代的咪唑并喹啉化合物,而WO 00/09506描述了含磺酰胺取代基的咪唑并喹啉化合物,其中的磺酰胺氮是饱和杂环的一部分。尽管已有这些尝试,但仍然需要能通过诱导细胞因子生物合成或其它机理来调节免疫应答的化合物。
发明概述
我们已经发现一类新的化合物可用于诱导动物体内细胞因子的生物合成。因此,本发明提供了式(I)表示的化合物:
式中R1、R2和R如本文所定义。
式(I)化合物可用作免疫应答调节剂,因为当它们给予动物时,它们能诱导细胞因子生物合成,并能以其它途径调节免疫应答。这使得这些化合物可用来治疗各种病情,例如对免疫应答中的这些变化作出响应的病毒疾病和肿瘤。
本发明还提供了含有治疗有效量的式I化合物的药物组合物,以及通过将式I化合物给予动物来诱导动物体内细胞因子生物合成、治疗动物体内病毒性感染、和/或治疗动物体内肿瘤疾病的方法。
另外,本发明还提供了合成本发明化合物以及用于合成这些化合物的中间产物的方法。
发明详述
如前所述,本发明提供了式I的化合物:
其中
R1是-烷基-NR3-SO2-X-R4或-链烯基-NR3-SO2-X-R4,
X是化学键或-NR5-;
R4是芳基、杂芳基、杂环基、烷基或链烯基,它们每一个可以是未取代的或被选自下列的一个或多个取代基取代:
-烷基;
-链烯基;
-芳基;
-杂芳基;
-杂环基;
-取代的芳基;
-取代的杂芳基;
-取代的杂环基;
-O-烷基;
-O-(烷基)0-1-芳基;
-O-(烷基)0-1-(取代的芳基);
-O-(烷基)0-1-杂芳基;
-O-(烷基)0-1-(取代的杂芳基);
-O-(烷基)0-1-杂环基;
-O-(烷基)0-1-(取代的杂环基);
-COOH;
-CO-O-烷基;
-CO-烷基;
-S(O)0-2-烷基
-S(O)0-2-(烷基)0-1-芳基;
-S(O)0-2-(烷基)0-1-(取代的芳基);
-S(O)0-2-(烷基)0-1-杂芳基;
-S(O)0-2-(烷基)0-1-(取代的杂芳基);
-S(O)0-2-(烷基)0-1-杂环基;
-S(O)0-2-(烷基)0-1-(取代的杂环基);
-(烷基)0-1-NR3R3;
-(烷基)0-1-NR3-CO-O-烷基;
-(烷基)0-1-NR3-CO-烷基;
-(烷基)0-1-NR3-CO-芳基;
-(烷基)0-1-NR3-CO-(取代的芳基);
-(烷基)0-1-NR3-CO-杂芳基;
-(烷基)0-1-NR3-CO-(取代的杂芳基);
-N3;
-卤素;
-卤代烷基;
-卤代烷氧基;
-CO-卤代烷氧基;
-NO2;
-CN;
-OH;
-SH;且在烷基、链烯基、或杂环基的情况下,氧代;
R2选自下列:
-氢;
-烷基;
-链烯基;
-芳基;
-(取代的芳基);
-杂芳基;
-(取代的杂芳基);
-烷基-O-烷基;
-烷基-O-链烯基;和
-被选自下列的一个或多个取代基取代的烷基或链烯基:
-OH;
-卤素;
-N(R3)2;
-CO-N(R3)2;
-CO-C1-10烷基;
-CO-O-C1-10烷基;
-N3;
-芳基;
-(取代的芳基);
-杂芳基;
-(取代的杂芳基);
-杂环基;
-(取代的杂环基);
-CO-芳基;
-CO-(取代的芳基)
-CO-杂芳基;
-CO-(取代的杂芳基)
每个R3独立选自氢和C1-10烷基;
R5选自氢和C1-10烷基;或R4和R5结合形成3-7元杂环或取代的杂环;
n是0-4;每个R独立选自:C1-10烷基、C1-10烷氧基、卤素和三氟甲基,或其药学上可接受的盐。
化合物的制备方法
本发明的咪唑并喹啉可根据反应方案I来制备,其中R、R1、R2和n如上定义。
在反应方案I的步骤(1)中,使式II的4-氯-3-硝基喹啉与式R1NH2(R1如上所述)的胺反应,得到式III的3-硝基喹啉-4-胺。该反应可通过将胺加入式II化合物在合适的溶剂(如氯仿或二氧甲烷)中的溶液并任选地加热来进行。许多式II喹啉是已知的化合物(例如参见美国专利4,689,338及其中引用的文献)。
在反应方案I的步骤(2)中,使式III的3-硝基喹啉-4-胺还原,得到式IV的喹啉-3,4-二胺。较佳的是,还原用常规非均相加氢催化剂(如碳载铂或碳载钯)来进行。该反应可在帕尔装置中在合适的溶剂(如异丙醇或甲苯)中进行。
在反应方案I的步骤(3)中,使式IV的喹啉-3,4-二胺与羧酸或其等价物反应,得到式V的1H-咪唑并[4,5-c]喹啉。合适的羧酸等价物包括酰基卤、原酸酯和链烷酸1,1-二烷氧基烷酯。选择羧酸或其等价物,使得它为式V化合物提供所需的R2取代基。例如,原甲酸三乙酯将提供R2是氢的化合物,原乙酸三乙酯将提供R2是甲基的化合物。反应可在没有溶剂下或诸如甲苯等惰性溶剂中进行。反应进行时用充分加热,以除去形成的反应副产物醇或水。
在反应方案I的步骤(4)中,用能形成氮氧化物的常规氧化剂将式V的1H-咪唑并[4,5-c]喹啉氧化,得到式VI的1H-咪唑并[4,5-c]喹啉-5N-氧化物。较佳的反应条件包括在室温下使氯仿中的式V化合物溶液与3-氯过苯甲酸反应。
在反应方案I的步骤(5)中,使式VI的1H-咪唑并[4,5-c]喹啉-5N-氧化物胺化,得到式VII的1H-咪唑并[4,5-c]喹啉-4-胺,它是式I的亚属。步骤(5)包括(i)使式VI的化合物与酰化剂反应,然后(ii)使产物与胺化剂反应。步骤(5)的部分(i)涉及使式VI的N-氧化物与酰化剂反应。合适的酰化剂包括烷基或芳基磺酰氯(如苯磺酰氯、甲磺酰氯、对甲苯磺酰氯)。芳基磺酰氯是较佳的。对甲苯磺酰氯是最佳的。步骤(5)的部分(ii)涉及使部分(i)的产物与过量胺化剂反应。合适的胺化剂包括氨(例如氢氧化铵形式)和铵盐(例如碳酸铵、碳酸氢铵、磷酸铵)。氢氧化铵是较佳的。反应宜这样进行,将式VI的N-氧化物溶解在惰性溶剂(如二氯甲烷)中,将胺化剂加入溶液中,然后缓慢加入酰化剂。然后用常规方法可分离出产物或其药学上可接受的盐。
或者,步骤(5)可这样进行:(i)使式VI的N-氧化物与异氰酸酯反应,然后(ii)水解所得的产物。部分(i)是使N-氧化物与异氰酸酯反应,其中异氰酸根基团与羰基相连。较佳的异氰酸酯包括异氰酸三氯乙酰酯和异氰酸芳酰酯(如异氰酸苯甲酰酯)。异氰酸酯和N-氧化物的反应在基本上无水的条件下进行,方法是将异氰酸酯加入惰性溶剂(如氯仿或二氯甲烷)中的N-氧化物溶液中。部分(ii)是使部分(i)的产物水解。水解可用常规方法进行,例如在水或低级烷醇存在下,任选地在催化剂(如碱金属氢氧化物或低级醇盐)存在下加热。
反应方案I
R1取代基含有磺酰胺的本发明化合物也可根据反应方案II来制备,其中R、R2、R4和n如上定义,m是1-20。
在反应方案II中,使式VIII的氨基烷基取代的1H-咪唑并[4,5-c]喹啉-4-胺与式IX的磺酰氯反应,得到式X化合物,它是式I的亚属。反应可以在室温、在惰性溶剂(如二氯甲烷)中和在碱(如吡啶或N,N-二异丙基乙胺)的存在下进行。许多式VIII的1H-咪唑并[4,5-c]喹啉-4-胺是已知的化合物,例如参见美国专利6,069,149(Nanba);其它可用已知的合成方法制得。许多式IX的磺酰基氯可市售购得;其它易用已知的合成方法制得。产物或其药学上可接受的盐可用常规方法来分离。
反应方案II
R1取代基含有磺酰胺的本发明化合物也可根据反应方案III来制备,其中R、R2、R4和n如上定义,m是1-20。
在反应方案III中,使式VIII的氨基烷基取代的1H-咪唑并[4,5-c]喹啉-4-胺与式XI的磺酸酐反应,得到式X化合物,它是式I的亚属。反应可以在室温、在惰性溶剂(如二氯甲烷)中和在碱(如吡啶或N,N-二异丙基乙胺)的存在下进行。或者,反应可以在室温和乙腈中进行。许多式XI的磺酸酐可市售购得;其它易用已知的合成方法制得。产物或其药学上可接受的盐可用常规方法来分离。
反应方案III
本发明叔磺酰胺也可根据反应方案IV来制备,其中R、R2、R4和n如上定义,m是1-20。
在反应方案IV中,使式X的1H-咪唑并[4,5-c]喹啉基磺酰胺与式XII的卤化物反应,得到式XIII化合物,它是式I的亚属。反应可在室温下通过将氢化钠加入式X化合物的N,N-二甲基甲酰胺溶液中,然后加入卤化物进行。许多式XII卤化物可市售购得;其它易用已知的合成方法制得。产物或其药学上可接受的盐可用常规方法来分离。
反应方案IV
R1含有硫酰胺基的本发明化合物可根据反应方案V制得,其中R、R2、R4、R5和n如上定义,m是1-20。
在反应方案V的步骤(1)中,使式VIII的氨基烷基取代的1H-咪唑并[4,5-c]喹啉-4-胺与磺酰氯反应,现场得到式XIV的氨磺酰氯。反应可以在1当量4-二甲氨基吡啶的存在下将磺酰氯的二氯甲烷溶液加入到式VIII化合物的二氯甲烷溶液中进行。反应较好在低温(-78°)下进行。任选地,在加完后,可以让反应混合物温热到环境温度。
在反应方案V的步骤(2)中,使式R5R4NH的胺与式XIV的氨磺酰氯反应,得到式XV的1H-咪唑并[4,5-c]喹啉基-硫酰胺,它是式I的亚属。反应可这样进行,将含2当量胺和2当量三乙胺的二氯甲烷溶液加入到步骤(1)的反应混合物中。加料较好在低温(-78°)下进行。任选地在加完后,可以让反应混合物温热到环境温度。产物或其药学上可接受的盐可用常规方法分离。
反应方案V
本发明的四氢咪唑并喹啉可根据反应方案VI制得,其中R2、R3、R4和R5如上定义,m是1-20。
在反应方案VI的步骤(1)中,将式XVI的氨基烷基取代的1H-咪唑并[4,5-c]喹啉-4-胺还原,提供式XVII的氨烷基取代的6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-4-胺。该还原反应较好按下述方法进行,即式XVI的化合物悬浮或溶解在三氟乙酸中,加入催化量的氧化铂(IV),然后对该混合物施加氢压力。该反应可以方便地在帕尔装置中进行。产物或其盐可用常规方法来分离。
在反应方案VI的步骤(2a)中,使式XVII的氨基烷基取代的6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-4-胺反应,得到式XVIII化合物,它是式I的亚属。当R3是氢时,反应可根据上述反应方案II和III描述的方法用式XVII的四氢咪唑并喹啉代替式VIII的咪唑并喹啉来一步进行。当R3不是氢时,反应可以分两步进行,第一步反应按反应方案II和III描述的方法进行,第二步按反应方案IV描述的方法用类似于咪唑并喹啉的四氢咪唑并喹啉进行。可用常规方法分离产物或其药学上可接受的盐。
在反应方案VI的步骤(2b)中,使式XVII的氨基烷基取代的6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-4-胺反应,得到式XIX化合物,它是式I的亚属。反应可根据反应方案V描述的方法用式XVII的四氢咪唑并喹啉代替式VIII的咪唑并喹啉进行。可用常规方法分离产物或其药学上可接受的盐。
反应方案VI
本发明的四氢咪唑并喹啉可根据反应方案VII制得,其中R、R2、R3、R4、R5和n如上定义,m是1-20。
在反应方案VII的步骤(1)中,使式XX的叔丁基氨基甲酸6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉酯水解,得到式XXI的氨基烷基取代的6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-4-胺。反应可这样进行,将式XX化合物溶解在三氟乙酸和乙腈的混合物中,在室温下搅拌。或者,可将式XX化合物与稀盐酸合并,在蒸汽浴上加热。式XX的叔丁基氨基甲酸四氢-1H-咪唑并[4,5-c]喹啉酯可用美国专利5,352,784(Nikolaides)中公开的合成途径来制得。产物或其盐可用常规方法来分离。
步骤(2a)和(2b)可以按与反应方案VI相同的方式进行。
反应方案VII
式I的一些化合物可从式I的其它化合物制得。例如,R4取代基含有氯烷基的化合物可以和胺反应,从而得到R4取代基被仲氨基或叔氨基取代的化合物;R4取代基含有硝基的化合物可以还原得到R4取代基含有伯胺的化合物。
本文所用的术语“烷基”、“链烯基”、“炔基”和前缀“烷”包括直链和支链基团和环状基团,即环烷基和环链烯基。除非另有所述,这些基团含有1-20个碳原子,链烯基和炔基含有2-20个碳原子。较佳的基团总共最多有10个碳原子。环状基团可以是单环或多环,较佳的有3-10个环碳原子。典型的环状基团包括环丙基、环戊基、环己基和金刚烷基。
术语“卤烷基”包括被一个或多个卤原子取代的基团,包括其中所有可利用的氢原子被卤原子代替的基团。对于具有前缀“卤烷(烯、炔)”的基团也是如此。合适的卤烷基例子是氯甲基、三氟甲基等。
本文所用的术语“芳基”包括碳环芳环或环体系。芳基例子包括苯基、萘基、联苯基、芴基和茚基。术语“杂芳基”包括含有至少一个环杂原子(如O、S、N)的芳环或环体系。合适的杂芳基包括呋喃基、噻吩基、吡啶基、喹啉基、四唑基、咪唑基、吡唑基(pyrazolo)、噁唑基(oxazolo)、噻唑基(thiazolo)等。
“杂环基(heterocyclyl)”包括含有至少一个环杂原子(如O、S、N)的非芳环或环体系。典型的杂环基团包括吡咯烷基、四氢呋喃基、吗啉基、硫代吗啉基、哌啶基、哌嗪基、噻唑烷基和咪唑烷基等。
除非另有特指,术语“取代的环烷基”、“取代的芳基”、“取代的杂芳基”和“取代的杂环基”指所述环或环体系被一个或多个取代基进一步取代,这些取代基独立选自烷基、烷氧基、烷硫基、羟基、卤素、卤烷基、卤烷基羰基、卤烷氧基(如三氟甲氧基)、硝基、烷基羰基、链烯基羰基、芳基羰基、杂芳基羰基、芳基、芳烷基、杂芳基、杂芳烷基、杂环基、杂环烷基、腈、烷氧羰基、烷酰氧基、烷酰硫基以及氧代(在环烷基和杂环基情况下)。
在表示本发明化合物的结构式中,某些键用虚线表示。这些线表示虚线表示的键可有可无。因此,本发明的化合物可以是咪唑并喹啉化合物或四氢咪唑并喹啉化合物。
本发明包括文中描述的药学上可接受形式(包括异构体如非对映体和对映体、盐、溶剂合物、多晶型物等)的化合物。
药物组合物和生物活性
本发明的药物组合物含有治疗有效量的上述本发明化合物以及药学上可接受的载体。
术语“治疗有效量”指该化合物的用量足以诱导产生治疗效果,如诱导细胞因子、抗肿瘤活性和/或抗病毒活性。尽管本发明药物组合物中所用活性化合物的确切量将根据本领域技术人员已知的因素(如化合物的物理和化学特性以及载体的性质以及打算采用的剂量方案)而异,但是预计本发明组合物将含有足量的活性组分,为对象提供100毫微克/千克-50毫克/千克、较佳约为10微克/千克-5毫克/千克的化合物剂量。可采用任何常规剂型,如片剂、锭剂、肠胃外制剂、糖浆、软膏、油膏、气溶胶制剂、透皮贴剂、跨粘膜贴剂等。
在根据下述测试进行的试验中,本发明化合物已经显示能诱导产生某些细胞因子。这些结果表明这些化合物可用作免疫应答调节剂,它们能通过许多不同的方式调节免疫应答,从而使得它们能用于治疗各种疾病。
通过给予本发明化合物诱导产生的细胞因子通常包括干扰素-α(IFN-α)和/或肿瘤坏死因子-α(TNF-α),以及某些白细胞介素(IL)。由本发明化合物诱导生物合成的细胞因子包括IFN-α、TNF-α、IL-1、6、10和12,其它各种细胞因子。在其它作用中,细胞因子抑制病毒的产生和肿瘤细胞的生长,使得化合物可用于治疗病毒疾病和肿瘤。
除了能诱导产生细胞因子外,本发明的化合物还能影响先天性免疫应答的其它方面。例如,可以刺激天然杀伤细胞的活性,该作用可能由细胞因子诱导而引起。这些化合物还能激活巨噬细胞,巨噬细胞进而刺激氧化氮的分泌和额外细胞因子的产生。另外,这些化合物还能引起B-淋巴细胞增殖和分化。
本发明化合物对获得性免疫应答也有作用。例如,尽管不认为对T细胞有直接作用或直接诱导T细胞细胞因子,但在给予化合物后,化合物却间接诱导了T辅助细胞1型(Th1)细胞因子IFN-γ的产生,抑制了T辅助细胞2型细胞因子IL-4、IL-5和IL-13的产生。这一活性表明这些化合物可用来治疗需要上调Th1应答和/或下调Th2应答的疾病。鉴于本发明化合物能抑制Th2免疫应答,预计这些化合物可用于治疗特应性疾病,如特应性皮炎、哮喘、变态反应、变应性鼻炎;全身性红斑狼疮;还可作为细胞介导的免疫力的疫苗佐剂;并可用来治疗复发性真菌疾病和衣原体疾病。
这些化合物的免疫应答调节作用使得它们可用来治疗各种情况。由于它们能诱导诸如IFN-α和/或TNF-α等细胞因子的产生,这些化合物特别可用来治疗病毒疾病和肿瘤。该免疫调节活性暗示本发明化合物可用来治疗下列疾病,例如但不局限于,病毒疾病(包括生殖器疣;寻常疣;扁平疣;乙型肝炎;丙型肝炎;I型和II型单纯疱疹病毒;触染性软疣;HIV;CMV;VZV;上皮内肿瘤如子宫颈上皮内肿瘤;人乳头瘤(HPV)和相关的肿瘤;真菌疾病,如念珠菌、曲霉菌和隐球菌脑膜炎;肿瘤疾病,如基底细胞癌瘤、毛细胞白血病、Kaposi肉瘤、肾细胞癌、鳞状上皮细胞癌、粒细胞性白血病、多发性骨髓瘤、黑色素瘤、非Hodgkin淋巴瘤、皮肤T细胞淋巴瘤和其它癌;寄生虫疾病,例如肺炎肺囊虫、似隐胞菌病、组织胞浆菌病、弓形体病、锥体虫感染和立什曼病;和细菌感染,例如结核菌和分支杆菌。可用本发明化合物治疗的其它疾病或情况包括湿疹、嗜曙红细胞增多、原发性血小板减少症、麻风病、多发性硬化、Ommen综合征、盘状狼疮、Bowen疾病、Bowen样丘疹病;以及增强或刺激伤口(包括慢性伤口)愈合。
因此,本发明提供了诱导动物体内细胞因子生物合成的方法,该方法包括将本发明的化合物或组合物给予该动物。化合物诱导细胞因子生物合成的有效量是足以使一种或多种细胞类型(如单核细胞、巨噬细胞、树突细胞和B细胞)产生比这些细胞因子本底水平有所提高的一种或多种细胞因子(例如IFN-α、TNF-α、IL-1、6、10和12)的用量。确切的用量将根据现有技术中已知的因素而异,但是预计剂量约为100毫微克/千克-50毫克/千克,较佳的约为10微克/千克-5毫克/千克。本发明还提供了治疗动物体内病毒性感染的方法和治疗动物体内肿瘤疾病的方法,这些方法包括将有效量的本发明化合物或组合物给予该动物。治疗或抑制病毒性感染的有效量是使病毒感染的一个或多个表现(如病毒病变、病毒装载、病毒产生的速度以及与未处理对照动物相比的死亡率)有所减少的量。确切的用量将根据现有技术中已知的因素而异,但是预计剂量约为100毫微克/千克-50毫克/千克,较佳的约为10微克/千克-5毫克/千克。化合物治疗肿瘤病情的有效量是使肿瘤大小或肿瘤病灶数量减小的量。同样,确切的用量将根据现有技术中已知的因素而异,但是预计剂量约为100毫微克/千克-50毫克/千克,较佳的约为10微克/千克-5毫克/千克。
通过下列实施例来进一步描述,提供这些实施例只是为了描述而没有限制作用。
实施例1
N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-5-(二甲基氨基)-1-萘磺酰胺
将5-二甲氨基-1-萘磺酰氯(1.82克,6.74毫摩尔)加入含N,N-二异丙基乙胺(1.23毫升,7.06毫摩尔)、二氯甲烷(15毫升)和1-(4-氨基丁基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺(2.0克,6.42毫摩尔)的混合物中。让反应混合物在室温下搅拌过夜。向该反应混合物中加入甲醇,直到形成透明溶液为止。向该反应混合物中加入硅胶,然后除去溶剂。将此硅胶放在一个柱上,用氯仿洗脱,洗脱剂逐步变化到9∶1氯仿∶甲醇。所得的产物用N,N-二甲酰胺和去离子水重结晶,得到2.5克N1-[4-(4-氨基-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-5-二甲氨基-1-萘磺酰胺,为黄色结晶固体。C30H36N6O2S的计算值:%C,66.15;%H,6.66:%N,15.43;实测值:%C,66.36;%H,6.34;%N,15.23。
实施例2
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-5-二甲氨基-1-萘磺酰胺
将1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺(0.5克,2.0毫摩尔)在吡啶(250毫升)中的悬浮液温热至60℃,以溶解该胺。让该溶液冷却于30℃左右,然后慢慢加入5-二甲氨基-1-萘磺酰氯(0.5克,1.8毫摩尔)。1小时后加入0.3克5-二甲氨基-1-萘磺酰氯。将反应混合物温热至60℃,然后保持该温度过夜。将反应混合物真空浓缩。残余物用乙酸丙酯重结晶,产生N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-5-二甲氨基-1-萘磺酰胺固体,熔点为200-201℃。
实施例3
N2-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-噻吩磺酰胺
将2-噻吩磺酰氯(0.3克,溶解于10毫升二氯甲烷中,1.6毫摩尔)滴加到搅拌着的1-(4-氨基丁基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺(0.5克,1.6毫摩尔)、二氯甲烷(40毫升)和吡啶(0.8毫升)的溶液中。让该反应在室温下保持几小时,然后加入另一份2-噻吩磺酰氯(0.1克,0.6毫摩尔)。将该反应混合物保持过夜,然后真空浓缩。所得的残余物用快速色谱柱(硅胶,9∶1二氯甲烷/甲醇)提纯,含有产物的馏分用饱和碳酸氢钠水溶液洗涤。将有机层干燥(MgSO4),过滤,并浓缩后得到0.2克N2-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-噻吩磺酰胺灰白色粉末,熔点为137.5-141.5℃。1H NMR(300MHz,DMSO-d6)δ8.00(d,J=8.0Hz,1H),7.89(dd,J=5.0,1.3Hz,1H),7.83(宽s,1H),7.61(dd,J=8.3,1.1Hz,1H),7.54(dd,J=3.7,1.3Hz,1H),7.42(t,J=7.2Hz,1H),7.25(m,1H),7.15(m,1H),6.44(宽s,2H),4.47(t,J=7.4Hz,2H),2.87(m,4H),1.80(m,4H),1.58-1.38(m,4H),0.96(t,J=7.4Hz,3H);IR(KBr)3467,3361,3167,3091,2957,2933,2870,1644,1617,1585,1533,1478,1405,1336,1154,1095,1014,854,761,733cm-1;MS(EI)m/e 457.1606(C22H27N5O2S2的计算值为457.1606);C22H27N5O2S2的计算值:C,57.74;H,5.95;N,15.30.实测值:C,57.50;H,5.98;N,15.15.
实施例4
N-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-苯甲磺酰胺
将α-甲苯磺酰氯(0.5克,溶解于10毫升二氯甲烷中,2.7毫摩尔)滴加到搅拌着的1-(4-氨基丁基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺(0.75克,2.4毫摩尔)、二氯甲烷(115毫升)和吡啶(1毫升)的溶液中。让该反应在室温下保持4小时,然后真空浓缩。所得的残余物用快速色谱柱(硅胶,9∶1二氯甲烷/甲醇,Rf0.16)提纯,合并含有产物的馏分,然后用饱和碳酸氢钠水溶液洗涤。将有机层干燥(MgSO4),过滤,并浓缩。最后用二氯甲烷/乙醚重结晶后得到0.65克N-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-苯甲磺酰胺白色晶体粉末,熔点为197.0-199.5℃。1H NMR(300MHz,DMSO-d6)δ8.02(d,J=7.6Hz,1H),7.62(dd,J=8.3,1.1Hz,1H),7.42(dt,J=7.5,1.1Hz,1H),7.35-7.23(m,7H),7.12(t,J=5.4Hz,1H),6.46(宽s,2H),4.49(t,J=7.5Hz,2H),4.29(s,2H),2.91(m,4H),1.83-1.42(m,8H),0.96(t,J=7.4Hz,3H);IR(KBr)3460,3293,3226,3158,2955,2931,2867,1632,1586,1534,1482,1437,1389,1331,1152,1094,752,700cm-1;MS(EI)m/e 465.2204(C25H31N5O2S的计算值为465.2198);C25H31N5O2S的计算值:C,64.49;H,6.71;N,15.04.实测值:C,64.15;H,6.71;N,15.00.
实施例5
N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-1-苯磺酰胺
将苯磺酰氯(0.45克,溶解于10毫升二氯甲烷中,3.5毫摩尔)滴加到搅拌着的1-(4-氨基丁基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺(1.0克,3.2毫摩尔)、二氯甲烷(140毫升)和吡啶(0.8毫升)的溶液中。让该反应在室温下保持4小时,然后真空浓缩。所得的残余物用快速色谱柱(硅胶,9∶1二氯甲烷/甲醇,Rf0.28)提纯,然后用二氯甲烷/乙醚重结晶后得到1.14克N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-1-苯磺酰胺白色晶体粉末,熔点为75.5-79.0℃。1H NMR(500MHz,DMSO-d6)δ7.99(d,J=7.7Hz,1H),7.76(d,J=7.2,2H),7.63-7.53(m,5H),7.42(m,1H),7.25(m,1H),6.43(宽s,2H),4.45(t,J=7.6Hz,2H),2.87(t,J=7.7Hz,2H),2.78(m,2H),1.79(m,4H),1.55-1.40(m,4H),0.95(t,J=7.4Hz,3H);MS(EI)m/e 451.2036(C24H29N5O2S的计算值为451.2042);C24H29N5O2S的计算值:C,63.83;H,6.47;N,15.51.实测值:C,63.89;H,6.42;N,15.30.
实施例6
N-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-甲磺酰胺
将甲磺酰酐(0.6克,3.4毫摩尔)滴加到搅拌着的1-(4-氨基丁基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺(1.0克,3.2毫摩尔)和乙腈(200毫升)的溶液中。在几分钟内形成沉淀。真空除去溶剂,残余物在二氯甲烷和饱和碳酸氢钠水溶液间进行分配。分相,将有机相干燥(MgSO4),过滤,浓缩后产生白色固体。从乙酸甲酯重结晶,得到N-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-甲磺酰胺白色结晶固体,熔点为195.1-196.0℃。1H NMR(300MHz,DMSO-d6)δ8.04(d,J=7.4Hz,1H),7.61(dd,J=8.3,1.2Hz,1H),7.50(dt,J=7.5,1.1Hz,1H),7.26(dt,J=7.5,1.2Hz,1H),6.99(t,J=5.7Hz,1H),6.44(宽s,2H),4.52(t,J=7.5Hz,2H),3.02-2.86(m,7H),1.82(m,4H),1.62(m,2H),1.46(q,J=7.4Hz,2H),0.96(t,J=7.4Hz,3H);IR(KBr)3348,3299,3152,2952,2931,2869,1642,1584,1530,1480,1323,1155,1142,1094,982,765cm-1;MS(EI)m/e 389.1889(C19H27N5O2S的计算值为389.1885);C19H27N5O2S的计算值:C,58.59;H,6.99;N,17.98.实测值:C,58.26;H,6.64;N.17.69
实施例7
N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-硝基-1-苯磺酰胺盐酸盐
按照实施例5的一般方法,将3-硝基苯磺酰氯和1-(4-氨基丁基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺混合。分离出N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-硝基-1-苯磺酰胺盐酸盐(白色固体),熔点为176.0-178.2℃。1H NMR(300MHz,DMSO-d6)δ8.70(很宽s,2H),8.49-8.42(m,2H),8.21-8.17(m,2H),8.06(t,J=5.7Hz,1H),7.88-7.81(m,2H),7.71(t,J=7.7Hz,1H),7.57(t,J=7.7Hz,1H),4.56(t,J=7.3Hz,2H),2.94(t,J=7.7Hz,2H),2.86(m,2H),1.81(m,4H),1.60-1.42(m,4H),0.96(t,J=7.3Hz,3H);IR(KBr)3096,2954,2869,2771,1671,1607,1528,1351,1335,1163,1128,1083,879,758,735,672,661cm-1;MS(EI)m/e496.1897(C24H28N6O4S的计算值为496.1893).C24H28N6O4S*HCl*H2O的计算值:C,52.31;H,5.67;N,15.25.实测值:C,52.26;H,5.46;N,15.09.
实施例8
N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-氨基-1-苯磺酰胺盐酸盐
在N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-硝基-1-苯磺酰胺盐酸盐(0.4克)的甲醇(250毫升)溶液中加入催化量的10%碳载钯(0.085克)。将该反应混合物放在氢气氛(50psi;3.44×105Pa)下,并放在帕尔装置上摇动2小时。过滤该反应混合物,然后真空除去溶剂。固体产物用2-丙醇重结晶后,得到0.18克N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-氨基-1-苯磺酰胺盐酸盐灰白色固体,熔点为110.2℃(分解)。1H NMR(300MHz,DMSO-d6)δ8.70(很宽s,2H),8.22(d,J=8.2Hz,1H),7.83(d,J=7.8Hz,1H),7.72(t,J=7.6Hz,1H),7.59(t,J=7.7Hz,1H),7.43(t,J=5.9Hz,1H),7.15(t,J=7.9Hz,1H),6.95(t,J=1.9Hz,1H),6.84(d,J=7.7Hz,1H),6.73(dd,J=8.0,1.5Hz,1H),5.63(宽s,2H),4.56(t,J=7.5Hz,2H),2.96(t,J=7.7Hz,2H),2.77(q,J=6.3Hz,2H),1.83(m,4H),1.60-1.40(m,4H),0.97(t,J=7.3Hz,3H);IR(KBr)3313,3135,2957,2870,2782,1671,1599,1485,1454,1313,1155,1084,754,686cm-1;MS(EI)m/e466.2150(C24H30N6O2S的计算值为466.2151).C24H30N6O2S*HCl*0.25H2O的计算值:C,56.79;H,6.26;N,16.56;Cl,6.98.实测值:C,56.87;H,6.22;N,16.19;Cl,7.22.
实施例9
N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-硝基-1-苯磺酰胺盐酸盐
按照实施例5的一般方法,将4-硝基苯磺酰氯和1-(4-氨基丁基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺混合。分离出N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-硝基-1-苯磺酰胺盐酸盐(白色固体),熔点为96.0℃(分解)。1H NMR(300MHz,DMSO-d6)δ8.70(很宽s,2H),8.38-8.34(m,2H),8.19(d,J=8.2Hz,1H),8.09(t,J=5.6Hz,1H),8.03-7.99(m,2H),7.80(d,J=7.4Hz,1H),7.68(t,J=7.4Hz,1H),7.54(t,J=7.2Hz,1H),4.55(t,J=7.4Hz,2H),2.94(t,J=7.7Hz,2H),2.86(q,J=6.2Hz,2H),1.80(m,4H),1.58(m,2H),1.45(q,J=7.5Hz,2H),0.96(t,J=7.3Hz,3H);IR(KBr)3283,3100,2957,2870,2782,1670,1606,1528,1347,1311,1162,1092,854,746,737,686cm-1;MS(EI)m/e 496.1902(C24H28N6O4S的计算值为496.1893).C24H28N6O4S*HCl*0.85H2O的计算值:C,52.57;H,5.64;N,15.33.实测值:C,52.57;H,5.46;N,15.33.
实施例10
N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-氨基-1-苯磺酰胺盐酸盐
在N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-硝基-1-苯磺酰胺盐酸盐(0.38克)的甲醇(250毫升)溶液中加入催化量的10%碳载钯(0.085克)。将该反应混合物放在氢气氛(50psi;3.44×105Pa)下,在帕尔装置上摇动2小时。过滤该反应混合物,然后真空除去溶剂。固体产物用2-丙醇重结晶后,得到0.34克N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-氨基-1-苯磺酰胺盐酸盐白色固体,熔点为203.1-205.0℃灰白色粉末。1H NMR(300MHz,DMSO-d6)δ8.65(很宽s,2H),8.21(d,J=8.0Hz,1H),7.82(m,1H),7.71(t,J=7.7Hz,1H),7.58(t,J=7.7 Hz,1H),7.38(d,J=8.7Hz,2H),7.13(t,J=5.9Hz,1H),6.60(d,J=8.7Hz,2H),5.92(宽s,2H),4.55(t,J=7.6Hz,2H),2.96(t,J=7.6Hz,2H),2.70(q,J=6.4Hz,2H),1.81(m,4H),1.58-1.43(m,4H),0.96(t,J=7.4Hz,3H);IR(KBr)3430,3316,3215,3046,2955,2868,2679,1671,1594,1334,1157,1091,851,776,759cm-1;MS(EI)m/e 466.2145(C24H30N6O2S的计算值为466.2151).C24H30N6O2S*HCl的计算值:C,57.30;H,6.21;N,16.71.实测值:C,57.36;H,6.31;N,16.21.
实施例11
N5-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-5-异喹啉磺酰胺
将异喹啉-5-磺酰氯盐酸盐的悬浮液(0.83克,悬浮于50毫升吡啶,3.1毫摩尔)滴加到搅拌着的1-(4-氨基丁基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺(1.0克,3.2毫摩尔)和二氯甲烷(175毫升)的溶液中。该溶液变成亮黄色,并在室温下保持4小时。再加入0.18克异喹啉-5-磺酰氯盐酸盐,然后再保持60小时。将该黄色溶液真空浓缩,溶解在二氯甲烷中,依次用饱和碳酸氢钠水溶液和水洗涤。将有机部分干燥(MgSO4),过滤,和真空浓缩。残余物用快速色谱柱(硅胶,9∶1二氯甲烷/甲醇提纯,得到0.7克N5-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-5-异喹啉磺酰胺白色结晶固体,熔点为96.0℃(分解)。1H NMR(300MHz,DMSO-d6)δ9.44(d,J=0.7Hz,1H),8.64(d,J=6.1Hz,1H),8.41-8.35(m,2H),8.30(dd,J=7.4,1.2Hz,1H),8.11(t,J=5.6Hz,1H),7.92(d,J=7.6Hz,1H),7.75(t,J=7.7Hz,1H),7.61(dd,J=8.3,1.2Hz,1H),7.41(dt,J=7.7,1.2Hz,1H),7.22(dt,J=7.6,12Hz,1H),6.47(宽s,2H),4.38(t,J=7.5Hz,2H),2.86-2.74(m,4H),1.78-1.63(m,4H),1.50-1.34(m,4H),0.94(t,J=7.4Hz,3H);MS(EI)m/e502.2151(C27H30N6O2S的计算值为502.2151).C27H30N6O2S的计算值:C,64.52;H,6.02;N,16.72.实测值:C,64.03;H,6.03;N,16.55.
实施例12
N-[4-(4-氨基-2-(4-甲氧基苄基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-甲磺酰胺
将甲磺酸酐(0.19克,1.1毫摩尔)加入到搅拌着的1-(4-氨基丁基)-2-(4-甲氧基苄基)-1H-咪唑并[4,5-c]喹啉-4-胺(0.4克,1.07毫摩尔)、二氯甲烷(75毫升)和乙腈(100毫升)的溶液中。室温下将此反应保持60小时。真空除去溶剂,残余物用快速色谱柱(硅胶,9∶1二氯甲烷/甲醇提纯。合并含有产物的馏分,用饱和碳酸氢钠水溶液洗涤,干燥(MgSO4),过滤,并浓缩后得到0.3克N-[4-(4-氨基-2-(4-甲氧基苄基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-甲磺酰胺白色固体,熔点为78.1-79.5℃。1H NMR(300MHz,DMSO-d6)δ7.99(d,J=7.6Hz,1H),7.62(dd,J=8.3,1.2Hz,1H),7.42(m,1H),7.27-7.21(m,3H),6.98(t,J=5.7Hz,1H),6.89(d,J=8.7Hz,2H),6.58(宽s,2H),4.45(宽s,2H),4.33(s,2H),3.72(s,3H),2.87(m,5H),1.55(宽s,2H);MS(CI)m/e 454(M+H).
实施例13
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-1-丁磺酰胺
将装在带螺帽试管中的1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺(9.3毫克,36微摩尔)的二氯甲烷(10毫升)溶液冷却至-5℃。以0.3M的二氯甲烷溶液加入丁磺酰氯(45微摩尔),加料过程中将氩气鼓泡通过该混合物,加完后再通15秒钟。让该混合物在-5℃静置过夜。加入氨甲基聚苯乙烯树脂(约90毫克,0.62meq/g,100-200目,Bachem),然后将该混合物加热至回流,以约600转/分钟的速度摇动3小时。通过Poly-Preg柱(Bio-Rad#731-1500)过滤该混合物,除去树脂。真空除去溶剂,残余物用Gilson系统上的半制备高压液相色谱(Rainin Microsorb C18柱,21.4×250毫米,8微米粒度,60A孔隙,10毫升/分钟,2-95%B梯度洗涤25分钟,在95%B保持5分钟,其中A=0.1%三氟乙酸/水,B=0.1%三氟乙酸/乙腈,在250纳米进行峰值检测,以触发收集馏分)提纯。半制备高压液相色谱馏分用LC-APCI/MS分析,合并合适的馏分,并冻干。将该固体溶解在约3毫升2∶1二氯甲烷-甲醇中,然后与80毫克(300微摩尔)二异丙氨基甲基-聚苯乙烯树脂(Argonaut PS-DIEA,3.86毫摩尔/克)一起摇动,以释放出游离的胺,然后过滤和真空干燥,得到产物固体。MS(APCI)m/e 376.16(M+H)。
实施例14
N1-[4-(4-氨基-2-(2-甲氧基乙基)-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-氟-1-苯磺酰胺
按实施例5的一般方法,混合1-(4-氨基丁基-2-(2-甲氧基乙基)-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-4-胺和4-氟苯磺酰氯。用4∶1乙酸正丙酯/甲醇重结晶,得到N1-[4-(4-氨基-2-(2-甲氧基乙基)-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-氟-1-苯磺酰胺白色结晶固体,熔点191.0-193.0℃。1H NMR(300MHz,DMSO-d6)δ7.86-7.81(m,2H),7.67(宽s,1H),7.45-7.39(m,2H),5.65(宽s,2H),4.15(m,2H),3.76(t,J=6.7Hz,2H),3.27(s,3H),3.00(t,J=6.7Hz,2H),2.90(宽s,2H),2.78(m,2H),2.65(宽s,2H),1.75(宽s,4H),1.61(m,2H),1.43(m,2H);MS(CI)m/e 476(M+H).C23H30FN5O3S的计算值:%C,58.09;%H,6.36;%N,14.73;实测值:%C,58.37;%H,6.35;%N,14.60.
实施例15
N-[4-(4-氨基-2-苯基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-氟-1-苯磺酰胺
A部分
室温下将苯甲酰氯(5.3克,37.7毫摩尔)的二氯甲烷(100毫升)溶液慢慢加入到N-{4-[(3-氨基喹啉-4-基)氨基]丁基}氨基甲酸叔丁酯(12.5克,37.7毫摩尔)的二氯甲烷(250毫升)溶液中。将该反应混合物在室温下保持过夜。过滤分离所得的沉淀物,干燥后得到11.0克N-{4-[(3-苯甲酰氨基喹啉-4-基)氨基]丁基}氨基甲酸叔丁酯盐酸盐白色固体。
B部分
将三乙胺(7.26克,7.17毫摩尔)加入到A部分中制得的物质的乙醇(200毫升)溶液中,并加热回流2天。浓缩该反应混合物,得到橙色糊浆。高压液相色谱质谱分析表明该湖浆含有所需产物和原料。该糊浆放在二氯甲烷(100毫升)中,然后用冰浴冷却。加入三乙胺(5毫升)和苯甲酰氯(1.9毫升)。室温下将反应混合物保持2天。这时,用高压液相色谱分析表示反应没有完全。真空浓缩反应混合物。将残余物放在异丙醇(150毫升)中。加入三乙胺(5毫升),然后将该反应混合物加热回流过夜。真空浓缩反应混合物。残余物用快速色谱柱(硅胶,用10%甲醇在二氯甲烷中的溶液洗脱)提纯。合并含有产物的馏分,并真空浓缩。残余物用乙腈重结晶后得到6.7克N-[4-(2-苯基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]氨基甲酸叔丁酯固体,熔点为158-159℃。
C部分
将3-氯过氧苯甲酸(1.05eq.of 65%)小批量慢慢加入到N-[4-(2-苯基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]氨基甲酸叔丁酯(6.56克,15.75毫摩尔)的二氯甲烷(120毫升)溶液中。3小时后,用1%碳酸氢钠水溶液(200毫升)猝灭反应。分层。水层用二氯甲烷萃取(2×50毫升)。合并有机相,用硫酸镁干燥,然后真空浓缩,得到淡橙色糊浆。该糊浆用乙醚研磨,得到6.8克1-[4-(氨基甲酸叔丁酯)丁基]-2-苯基-1H-咪唑并[4,5-c]喹啉-5N-氧化物,为淡褐色固体,熔点为178-181℃。
D部分
将1-[4-(氨基甲酸叔丁酯)丁基]-2-苯基-1H-咪唑并[4,5-c]喹啉-5N-氧化物的二氯甲烷(100毫升)溶液放在冰浴中冷却。加入浓氢氧化铵(30毫升)。小批量加入甲苯磺酰氯(3.0克,15.75毫摩尔),历时30分钟。让该反应混合物温热至室温过夜。用水(350毫升)猝灭反应。分层,水层用二氯甲烷萃取。合并有机相,用硫酸镁干燥,然后真空浓缩,得到褐色固体。该固体用快速色谱柱(硅胶,用10%甲醇在二氯甲烷中的溶液洗脱)提纯,得到4.8克产物。大部分产物用于下一步。一小部分用甲苯重结晶,得到N-[4-(4-氨基-2-苯基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]氨基甲酸叔丁酯固体,熔点为182-183℃。分析:C25H29N5O2的计算值:%C,69.58;%H,6.77;%N,16.22;实测值:%C,69.86;%H,6.95;%N,15.80。
E部分
将D部分制得的物质溶解在甲醇(15毫升)和1N盐酸(100毫升)中,然后加热回流2小时。将该反应混合物真空浓缩到约50毫升体积。加入浓氢氧化铵至pH 12,没有产生沉淀。用1N浓盐酸将pH调节至7。该混合物用二氯甲烷萃取,然后用乙酸乙酯萃取。将水层浓缩至干。将残余物溶解在水中(50毫升),然后用回流氯仿连接萃取36小时。将氯仿萃取物真空浓缩,得到淡褐色固体。该产物用乙腈重结晶,得到2.5克1-(4-氨基丁基)-2-苯基-1H-咪唑并[4,5-c]喹啉-4-胺灰白色固体,熔点为175-177℃。分析:C20H21N5的计算值:%C,72.48;%H,6.39;%N,21.13;实测值:%C,72.72;%H,6.32;%N,20.71。
F部分
将1-(4-氨基丁基)-2-苯基-1H-咪唑并[4,5-c]喹啉-4-胺(0.331克,1.0毫摩尔)溶解在无水乙腈(35毫升)中,然后将该溶液冷却至4℃。慢慢加入4-氟苯磺酰氯(0.194克,1.0毫摩尔)的无水二氯甲烷(10毫升)溶液。让反应混合物慢慢温热至室温,过周末。加入碳酸氢钠饱和水溶液使反应猝灭。分层,浓缩有机层,得到淡黄色固体。这种物质用异丙醇重结晶,然后用快速色谱(硅胶,用10%甲醇在二氯甲烷中的溶液洗脱)进一步提纯。合并纯的馏分,然后浓缩。残余物用异丙醇重结晶,得到0.2克N-[4-(4-氨基-2-苯基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-氟-1-苯磺酰胺淡黄色固体,熔点为214-216℃。分析:C26H24FN5O2SO的计算值:%C,63.79;%H,4.94;%N,14.30;实测值:%C,63.19;%H,4.85;%N,13.90。质谱M+1=490.2。
实施例16
N-[4-(4-氨基-2-苯基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-甲磺酰胺
用实施例15、F部分中的一般方法,使1-(4-氨基丁基)-2-苯基-1H-咪唑并[4,5-c]喹啉-4-胺(0.331克,1.0毫摩尔)与甲磺酸酐反应,得到0.14克N-[4-(4-氨基-2-苯基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-甲磺酰胺白色固体,熔点为234-235℃。质谱M+1=410.2。
实施例17-33
用上述反应方案II所述的合成方法制备下表所示的化合物。
将1-(2-氨基乙基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺(25毫克)放在2打兰(dram)(7.4毫升)小瓶中。依次加入二异丙基乙胺(11微升,1.2当量)、二氯甲烷(1毫升)和磺酰氯(1.1当量)。把该小瓶在摇动器上放2小时左右,然后在声波振荡器放0.5小时左右。让反应混合物在室温下放置过夜,用LC/MS分析确认形成所需的产物。除去溶剂,残余物用半制备高压液相色谱(CapcellPak C18柱,35毫米×20毫米,5微米粒度,20毫升/分钟,5-95%B梯度洗涤10分钟,在95%B保持2分钟,其中A=0.1%三氟乙酸/水,B=0.1%三氟乙酸/乙腈,在254纳米进行峰值检测,以触发收集馏分)。用LC-APCI/MS分析半制备高压液相色谱馏分,合并合适的馏分,冻干后得到所需磺酰胺的三氟乙酸盐。
实施例34
N-[2-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-甲磺酰胺三氟乙酸盐
本化合物用上述实施例17-33所述的方法制备,所不同的是用1.1当量甲磺酸酐代替磺酰氯。(实测质量-362.2)
实施例35
N-[2-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-三氟甲磺酰胺三氟乙酸盐
本化合物用上述实施例17-33所述的方法制备,所不同的是用1.1当量三氟甲磺酸酐代替磺酰氯。(实测质量-416.1)
实施例36-48
用上述反应方案II所述的合成方法制备下表所示的化合物。
将1-(4-氨基乙基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺(25毫克)放在2打兰(dram)(7.4毫升)小瓶中。依次加入二异丙基乙胺(14微升,1.0当量)、二氯甲烷(1毫升)和磺酰氯(1.0当量)。把该小瓶在摇动器上放30分钟左右,这时几乎所有物质都溶解在溶液中。过一段时间后,形成沉淀。加入少量的甲醇,溶解沉淀。让该反应混合物在振荡器上再放1小时,然后在声波振荡器放0.5小时左右。用LC/MS分析反应混合物,确认形成所需的产物。除去溶剂,残余物用半制备高压液相色谱(Capcell Pak C18柱,35毫米×20毫米,5微米粒度,20毫升/分钟,5-95%B梯度洗涤10分钟,在95%B保持2分钟,其中A=0.1%三氟乙酸/水,B=0.1%三氟乙酸/乙腈,在254纳米进行峰值检测,以触发收集馏分)。用LC-APCI/MS分析半制备高压液相色谱馏分,合并合适的馏分,冻干后得到所需磺酰胺的三氟乙酸盐。
实施例41-52
用上述反应方案II所述的合成方法制备下表所示的化合物。
将1-(4-氨基丁基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺(25毫克)放在2打兰(dram)(7.4毫升)小瓶中。依次加入二异丙基乙胺(14微升,1.0当量)、二氯甲烷(1毫升)和磺酰氯(1.0当量)。把该小瓶在声波振荡器放60分钟左右。用LC/MS分析确认形成所需的产物。除去溶剂,残余物用半制备高压液相色谱(Capcell Pak C18柱,35毫米×20毫米,5微米粒度,20毫升/分钟,5-95%B梯度洗涤10分钟,在95%B保持2分钟,其中A=0.1%三氟乙酸/水,B=0.1%三氟乙酸/乙腈,在254纳米进行峰值检测,以触发收集馏分)。用LC-APCI/MS分析半制备高压液相色谱馏分,合并合适的馏分,冻干后得到所需磺酰胺的三氟乙酸盐。
实施例53
N-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-三氟甲磺酰胺三氟乙酸盐
本化合物用上述实施例41-52所述的方法制备,所不同的是用1.0当量三氟甲磺酸酐代替磺酰氯。(实测质量-444.1)
实施例54-71
用上述反应方案IV所述的合成方法制备下表所示的化合物。
A部分
将催化量的氧化铂(IV)加入到1-(4-氨基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺(2.75克,10.8毫摩尔)的三氟乙酸(150毫升)溶液中。将该反应混合物放在50psi(3.44×105Pa)的氢气氛下。1星期后用质谱分析表明既有原料又有四氢产物。向该反应混合物中加入新鲜的催化剂,在50psi(3.44×105Pa)条件下继续氢化。2星期后,过滤反应混合物,除去催化剂。滤液真空浓缩。将残余物溶解在1N盐酸(120毫升)中,室温下将该溶液搅拌1小时。加入50%氢氧化钠,使溶液变碱性(pH 10),然后用二氯甲烷萃取(5×100毫升)。合并萃取物,真空浓缩,得到2.08克1-(4-氨基丁基)-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-4-胺白色固体。
B部分
将1-(4-氨基丁基)-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-4-胺(25毫克)放在2打兰(7.4毫升)小瓶中。依次加入二异丙基乙胺(11微升,1.2当量)、二氯甲烷(1毫升)和磺酰氯(1.1当量)。把该小瓶在振荡器放6小时左右。让反应混合物在室温下放置过夜,用LC/MS分析确认形成所需的产物。除去溶剂,残余物用半制备高压液相色谱(Capcell Pak C18柱,35毫米×20毫米,5微米粒度,20毫升/分钟,5-95%B梯度洗涤10分钟,在95%B保持2分钟,其中A=0.1%三氟乙酸/水,B=0.1%三氟乙酸/乙腈,在254纳米进行峰值检测,以触发收集馏分)。用LC-APCI/MS分析半制备高压液相色谱馏分,合并合适的馏分,冻干后得到所需磺酰胺的三氟乙酸盐。
实施例72
N-[4-(4-氨基-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-甲磺酰胺三氟乙酸盐
本化合物用上述实施例54-71所述的方法制备,所不同的是用1.1当量甲磺酸酐代替磺酰氯。(实测质量-338.3)
实施例73-201
用上述反应方案II所述的合成方法制备下表所示的化合物。
将1H-咪唑并[4,5-c]喹啉-4-胺(25毫克)放在2打兰(7.4毫升)小瓶中。加入二异丙基乙胺(1.2当量)和二氯甲烷(~1毫升),加入含磺酰氯(1.1当量)的二氯甲烷(~1毫升)溶液。室温下把该小瓶在摇动器上放2-16小时(一般为2小时)左右。用LC/MS分析反应混合物,确认形成所需的产物。除去溶剂,残余物用半制备高压液相色谱(Capcell Pak C18柱,35毫米×20毫米,5微米粒度,20毫升/分钟,5-95%B梯度洗涤10分钟,在95%B保持2分钟,其中A=0.1%三氟乙酸/水,B=0.1%三氟乙酸/乙腈,在254纳米进行峰值检测,以触发收集馏分)。用LC-APCI/MS分析半制备高压液相色谱馏分,合并合适的馏分,冻干后得到所需磺酰胺的三氟乙酸盐。
实施例202-213
用上述反应方案IV所述的合成方法制备下表所示的实施例。
A部分
按如下方法制备四氢喹啉原料。
将催化量的氧化铂(IV)加入到1-(4-氨基丁基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺(2.2克,7.06毫摩尔)的三氟乙酸(200毫升)溶液中。将该反应混合物放在帕尔装置上于50psi(3.44×105Pa)氢化6天。过滤反应混合物,除去催化剂。滤液真空浓缩。将残余物与1N盐酸(100毫升)混合,在水蒸汽浴上加热2小时。冷却该混合物,用氢氧化钠使溶液变碱性,然后用二氯甲烷萃取。真空浓缩萃取物,得到1-(4-氨基丁基)-2-丁基-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-4-胺固体,熔点为63-67℃。
将催化量的氧化铂(IV)加入到1-(4-氨基丁基)-2-甲氧基乙基-1H-咪唑并[4,5-c]喹啉-4-胺(7.7克,24.5毫摩尔)的三氟乙酸(250毫升)溶液中。将该反应混合物放在帕尔装置上于50psi(3.44×105Pa)氢化。用LC/MS监测反应进程。反应开始后7、11和17天时再加入催化剂。25天后,反应完成。通过Celite助滤剂层过滤反应混合物,除去催化剂,真空浓缩滤液。将残余物与1N盐酸(100毫升)混合,搅拌过夜。用氢氧化铵使溶液变碱性(pH=11),然后用二氯甲烷萃取(3×300毫升)。合并萃取物,并真空浓缩萃取物,得到3.5克1-(4-氨基丁基)-6,7,8,9-四氢-2-甲氧基乙基-1H-咪唑并[4,5-c]喹啉-4-胺固体。
B部分
用实施例73-201所述的方法使A部分制得的四氢咪唑并喹啉胺与适当的磺酰氯反应,制备所需的磺酰胺。
实施例214
N-[4-(4-氨基-6,7,8,9-四氢-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-甲磺酰胺三氟乙酸盐
本化合物用上述实施例202-213所述的方法制备,所不同的是用甲磺酸酐代替礴酰氯。
实施例215
N-[4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N-甲基-3,5-二甲基异噁唑4-磺酰胺三氟乙酸盐
A部分
用实施例DC001所述的一般方法,使1-(4-氨基丁基)-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺与3,5-二甲基噁唑-4-磺酰氯反应,得到N-[4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3,5-二甲基异噁唑4-磺酰胺三氟乙酸盐
B部分
将氢化钠(5.8毫克)加入到A部分制得的物质(25.4毫克)的二甲基甲酰胺溶液中。加入碘甲烷(3.2微升),室温下将反应混合物摇动2小时。用LC/MS分析反应混合物,确认形成所需的产物。除去溶剂,残余物用半制备高压液相色谱(Capcell Pak C18柱,35毫米×20毫米,5微米粒度,20毫升/分钟,5-95%B梯度洗涤10分钟,在95%B保持2分钟,其中A=0.1%三氟乙酸/水,B=0.1%三氟乙酸/乙腈,在254纳米进行峰值检测,以触发收集馏分)。用LC-APCI/MS分析半制备高压液相色谱馏分,合并合适的馏分,冻干。冻干后的物质在相同的条件下用半制备高压液相色谱提纯第二次,所不同的是5-95%B梯度洗脱60分钟,而不是10分钟。用LC-APCI/MS分析半制备高压液相色谱馏分,合并合适的馏分,冻干后得到所需磺酰胺的三氟乙酸盐。
实施例216
N-[4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N-甲基三氟甲磺酰胺三氟乙酸盐
本化合物用上述实施例215所述的方法制备,所不同的是用三氟甲磺酸酐代替磺酰氯。
实施例217-221
下表中的实施例用如下通用方法制备。将1H-咪唑并[4,5-c]喹啉-4-胺或6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-4-胺(50毫克)放在2打兰(7.4毫升)小瓶中。加入二氯甲烷(2毫升)和二异丙基乙胺(1.2当量)。加入二甲基氨磺酰氯(1.1当量)。室温下把该小瓶在摇动器上放2-4小时左右。用LC/MS分析反应混合物,确认形成所需的产物。除去溶剂,残余物用半制备高压液相色谱(Capcell Pak C18柱,35毫米×20毫米,5微米粒度,20毫升/分钟,5-95%B梯度洗涤10分钟,在95%B保持2分钟,其中A=0.1%三氟乙酸/水,B=0.1%三氟乙酸/乙腈,在254纳米进行峰值检测,以触发收集馏分)。用LC-APCI/MS分析半制备高压液相色谱馏分,合并合适的馏分,冻干后得到所需磺酰胺的三氟乙酸盐。
实施例222-228
下表中的实施例按上述反应方案V所示的合成方法制备。
将1-(4-氨基丁基)-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺(50毫克)放入2打兰(7.4毫升)小瓶中。加入4-二甲氨基吡啶(19毫克,1.0当量)和二氯甲烷(800微升)。将该小瓶密封,放在干冰/丙酮浴中冷却-78℃。加入硫酰氯(186微升1M二氯甲烷溶液)。将该小瓶在摇动器上放30分钟左右,然后再冷却至-78℃。在另一个小瓶中加入通式为R4R5NH(2.0当量)的胺、三乙胺(2.0当量)和二氯甲烷(1毫升),然后将其冷却至-78℃。将该胺/三乙胺溶液加入到第一个小瓶中。室温下将该小瓶在摇动器上放1小时左右。用LC/MS分析反应混合物,确认形成所需的产物。除去溶剂,残余物用半制备高压液相色谱(Capcell Pak C18柱,35毫米×20毫米,5微米粒度,20毫升/分钟,5-95%B梯度洗涤10分钟,在95%B保持2分钟,其中A=0.1%三氟乙酸/水,B=0.1%三氟乙酸/乙腈,在254纳米进行峰值检测,以触发收集馏分)。用LC-APCI/MS分析半制备高压液相色谱馏分,合并合适的馏分,冻干后得到所需磺酰胺的三氟乙酸盐。
实施例229-231
下表中所示的实施例用上述实施例222-228所述的方法制备,所不同的是使通式为R4R5NH的胺与硫酰氯反应,产生氨磺酰氯中间体,然后再与2.0当量1-(4-氨基丁基)-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-4-胺反应。
人细胞中的细胞因子诱导
用体外人血细胞系统来评价本发明化合物的细胞因子诱导作用。如Testerman等人在“免疫调节剂Imiquimod和S-27609的细胞因子诱导作用”,Journal of Leukocyte Biology,58,365-372(1995年9月)所述,根据分泌到培养基中的干扰素和肿瘤坏死因子(α)来测定活性。
制备血细胞用于培养
通过静脉穿刺到EDTA真空容管(vacutainer tube)收集健康供血者的全血。用Histopaque-1077(Sigma Chemicals,St.Louis,MO)进行密度梯度离心,从全血中分离出外周血单核细胞(PBMC)。将PBMC以3-4×106细胞/毫升的密度悬浮于含有10%胎牛血清、2mM L-谷氨酰胺和1%青霉素/链霉素溶液的RPMI 1640培养基(RPMI完全)中。将PBMC悬浮液加入48孔平底无菌组织培养板(Costar,Cambridge,MA或Becton Dickinson Labware,Lincoln Park,NJ)中,培养板中含有等体积的含测试化合物的RPMI完全培养基。
化合物制剂
将化合物溶解在二甲基亚砜(DMSO)中。加入培养孔中的DMSO浓度不应超过1%的最终浓度。
培育
将以60μM的浓度将测试化合物溶液加入含有RPMI完全培养基的第一个孔内,并作系列稀释(3倍或10倍)。然后将PBMC悬浮液以相同的体积加入孔内,使测试化合物的浓度在所需范围内。PBMC悬浮液的最终浓度为1.5-2×106细胞/毫升。用无菌塑料盖盖住该平板,轻微混合,然后在5%二氧化碳气氛中37℃下培育18-24小时。
分离
培育后,使平板在4℃下1000rpm离心5-10分钟。用无菌聚丙烯移液管取出细胞培养上清,转移到无菌聚丙烯管中。将样品置于-30℃至-70℃,直至分析。用ELISA或生物测定分析样品中的干扰素(α),用ELISA分析肿瘤坏死因子(α)。
用ELISA分析干扰素(α)肿瘤坏死因子(α)
用PBL Biomedical Laboratories,New Brunswick,NJ的HumanMulti-Species试剂盒通过ELISA测定干扰素(α)的浓度。
用Genzyme,Cambridge,MA;R&D Systems,Minneapolis,MN;或Pharmingen,San Diego,CA的ELISA试剂盒测定肿瘤坏死因子(α)(TNF)的浓度。
下表列出了发现诱导出干扰素的最低浓度和发现诱导出肿瘤坏死因子的各化合物最低浓度。“**”表明在任一测试浓度下(0.12,0.37,1.11,3.33,10和30μM)没有诱导作用。“***”表示在任一测试浓度(0.0001,0.001,0.1和10μM)下没有诱导作用。除非另有所述,干扰素的生物合成用ELISA来测定。
人细胞中的细胞因子诱导 | ||
实施例编号 | 最低效应浓度(μM) | |
干扰素 | 肿瘤坏死因子 | |
1 | 0.12 | 3.33 |
2 | ** | ** |
3 | 0.01 | ** |
6 | 0.00017 | 1.11 |
7 | 0.01 | ** |
9 | 0.04 | ** |
11 | 0.01 | 1.11 |
13 | 10 | ** |
17 | 1.11 | 3.33 |
18 | 3.33 | ** |
19 | 0.12 | 3.33 |
20 | 0.12 | 3.33 |
21 | 1.11 | 30 |
22 | 0.37 | ** |
23 | 0.12 | 10 |
24 | 0.12 | 30 |
25 | 3.33 | ** |
26 | 10 | ** |
27 | 1.11 | 30 |
28 | 1.11 | 30 |
29 | 0.37 | 10 |
30 | 1.11 | ** |
31 | 1.11 | ** |
32 | 1.11 | ** |
33 | 1.11 | 10 |
34 | 0.04 | 0.37 |
35 | 1.11 | 10 |
36 | 0.0015 | 3.33 |
37 | 0.01 | 1.11 |
人细胞中的细胞因子诱导 | ||
实施例编号 | 最低效应浓度(μM) | |
干扰素 | 肿瘤坏死因子 | |
38 | 0.0015 | 0.37 |
40 | 0.0015 | 3.33 |
41 | 0.01 | ** |
42 | 0.01 | ** |
43 | 0.04 | ** |
44 | 0.0015 | 1.11 |
45 | 0.37 | ** |
46 | 0.37 | ** |
47 | 0.37 | ** |
48 | 0.37 | 10 |
50 | 0.12 | ** |
51 | 0.0015 | 0.37 |
52 | 0.12 | 10 |
53 | 0.01 | 3.33 |
54 | 10 | ** |
55 | 3.33 | ** |
56 | ** | ** |
57 | 3.33 | ** |
58 | 3.33 | ** |
59 | 3.33 | ** |
60 | ** | ** |
61 | 3.33 | ** |
62 | ** | ** |
63 | ** | ** |
64 | 3.33 | ** |
65 | 3.33 | ** |
66 | ** | 30 |
67 | 10 | ** |
68 | 10 | ** |
69 | 10 | ** |
70 | ** | ** |
人细胞中的细胞因子诱导 | ||
实施例编号 | 最低效应浓度(μM) | |
干扰素 | 肿瘤坏死因子 | |
71 | ** | 30 |
72 | 3.33 | ** |
73 | 0.001 | 0.1 |
74 | 0.001 | 0.01 |
75 | *** | *** |
76 | *** | *** |
77 | 0.001 | 1 |
78 | 0.001 | 0.1 |
79 | 0.01 | 1 |
80 | 1 | 10 |
81 | 0.001 | 1 |
82 | 0.001 | 1 |
83 | 0.001 | 1 |
84 | 1 | 10 |
85 | 1 | *** |
86 | 0.01 | 1 |
87 | 0.001 | 1 |
88 | 0.01 | 1 |
89 | 0.001 | 1 |
90 | 0.01 | 1 |
91 | 0.01 | 1 |
92 | 0.1 | 10 |
93 | 0.001 | 0.1 |
94 | 0.001 | 1 |
95 | 0.001 | 1 |
96 | 1 | *** |
97 | 0.1 | 10 |
98 | 1 | *** |
99 | 0.1 | 10 |
100 | 0.01 | 10 |
101 | 0.01 | 10 |
人细胞中的细胞因子诱导 | ||
实施例编号 | 最低效应浓度(μM) | |
干扰素 | 肿瘤坏死因子 | |
102 | 0.001 | 10 |
103 | 0.1 | 10 |
104 | 0.01 | *** |
105 | 1 | 10 |
106 | 1 | 1 |
107 | 1 | *** |
108 | 0.1 | 10 |
109 | 1 | 10 |
110 | 10 | *** |
111 | 0.001 | 10 |
112 | 0.0001 | *** |
113 | 0.0001 | *** |
114 | 0.01 | *** |
116 | 0.001 | 1 |
117 | 0.0001 | 1 |
120 | 0.0001 | 1 |
121 | 0.0001 | 10 |
122 | 0.0001 | 1 |
123 | 0.0001 | 10 |
127 | 0.0001 | 10 |
128 | 0.0001 | 1 |
131 | 0.0001 | 1 |
138 | 0.0001 | 10 |
148 | 0.0001 | 1 |
152 | 0.0001 | 10 |
154 | 0.001 | 10 |
158 | 0.0001 | 1 |
159 | 0.0001 | 0.1 |
160 | 0.001 | 1 |
161 | 0.01 | 10 |
184 | 0.0001 | 1 |
人细胞中的细胞因子诱导 | ||
实施例编号 | 最低效应浓度(μM) | |
干扰素 | 肿瘤坏死因子 | |
200 | 0.01 | 0.1 |
202 | 0.0001 | 1 |
203 | 0.0001 | 1 |
204 | 0.0001 | 1 |
205 | 0.0001 | 1 |
206 | 1 | *** |
207 | 0.001 | 1 |
208 | 0.0001 | 1 |
209 | 0.0001 | 0.1 |
210 | 0.0001 | 1 |
211 | 0.0001 | 1 |
212 | 0.0001 | 0.01 |
213 | 0.0001 | 1 |
214 | 0.01 | 10 |
215 | 0.01 | 1 |
217 | 1 | *** |
218 | 0.0001 | 1 |
220 | 0.0001 | 1 |
221 | 0.0001 | 1 |
224 | 0.0001 | 10 |
226 | 0.0001 | 0.1 |
227 | 0.001 | *** |
229 | 0.0001 | 0.1 |
230 | 0.0001 | 1 |
231 | 0.0001 | 1 |
本发明已经参照几个实施方案作了描述。前面的详细描述和实施例只是为了清楚地理解,不应理解其有不必要的限制。本领域技术人员显然能在不脱离本发明精神和范围内对所述实施方案作许多改动。因此,本发明范围不应局限于本文所述组成和结构的确切细节,而是由下文权利要求来限定。
Claims (22)
1.一种式(I)表示的化合物:
其中
虚线表示的键可有可无,
R1是-C1-10烷基-NR3-SO2-X-R4,
X是化学键或-NR5-;
R4是C1-10烷基,该C1-10烷基是未取代的或被选自卤素、苯基或二环[2.2.1]庚-1-基的一个或多个取代基取代,二环[2.2.1]庚-1-基被选自甲基或氧代的一个或多个取代基取代;
苯基,所述的苯基是未取代的或被选自-NO2、-NH2、-CN、-COOH、-SO2CH3、卤素、三氟甲基、三氟甲氧基、C1-10烷氧基和C1-10烷基的一个或多个取代基取代;
苯乙烯基;
联苯基;
萘基,所述的萘基是未取代的或被二甲氨基取代;
噻吩基,该噻吩基是未取代的或被选自卤素、甲氧基羰基、和苯基羰基氨基甲基的一个或多个取代基取代;
喹啉基;
被一个或多个甲基取代的噁唑基;
被选自甲基和乙酰氨基的一个或多个取代基取代的噻唑基;或
被选自卤素和甲基的一个或多个取代基取代的吡唑基;
R2选自氢、C1-10烷基、C1-10烷基-O-C1-10烷基和甲氧基苯基C1-10烷基;
R3是氢或C1-10烷基;
R5是氢或C1-10烷基;或R4和R5结合形成哌嗪环、哌啶环、吗啉环、硫代吗啉环或吡咯烷环,其中哌嗪环被乙基取代,哌啶环被乙氧基羰基取代;
n是0。
2.如权利要求1所述的化合物,其特征在于X是化学键。
3.如权利要求2所述的化合物,其特征在于R3都为氢。
4.如权利要求2所述的化合物,其特征在于R1是-(CH2)2-4-NR3-SO2-R4。
5.如权利要求2所述的化合物,其特征在于R4是C1-10烷基。
6.如权利要求2所述的化合物,其特征在于R2选自氢、C1-4烷基和C1-4烷基-O-C1-4烷基。
7.如权利要求2所述的化合物,其特征在于用虚线表示的键存在。
8.如权利要求2所述的化合物,其特征在于用虚线表示的键不存在。
9.如权利要求1所述的化合物,其特征在于X是-NR5-。
10.如权利要求9所述的化合物,其特征在于R1是-(CH2)2-4-NR3-SO2-NR5-R4。
11.如权利要求9所述的化合物,其特征在于R2选自C1-4烷基和C1-4烷基-O-C1-4烷基。
12.如权利要求9所述的化合物,其特征在于R4和R5结合形成吡咯烷环、吗啉环、硫代吗啉环、哌啶环或哌嗪环,其中哌嗪环被乙基取代,哌啶环被乙氧基羰基取代。
13.如权利要求12所述的化合物,其特征在于R3是氢。
14.如权利要求12所述的化合物,其特征在于R2是C1-4烷基-O-C1-4烷基。
15.如权利要求9所述的化合物,其特征在于R4和R5是C1-10烷基。
16.如权利要求15所述的化合物,其特征在于R3是氢。
17.如权利要求15所述的化合物,其特征在于R2是C1-4烷基或C1-4烷基-O-C1-4烷基。
18.如权利要求9所述的化合物,其特征在于R3是氢。
19.如权利要求1所述的化合物,其特征在于所述的化合物选自如下一组的化合物:
N2-[2-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-2-噻吩磺酰胺;
N1-[2-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-2-苯磺酰胺;
N8-[2-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-8-喹啉磺酰胺;
N1-[2-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-5-二甲氨基-1-萘磺酰胺;
N8-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-8-喹啉磺酰胺;
N2-[4-(4-氨基-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-噻吩磺酰胺;
N1-[4-(4-氨基-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-苯磺酰胺;
N8-[4-(4-氨基-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-8-喹啉磺酰胺;
N1-[4-(4-氨基-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-5-二甲氨基-1-萘磺酰胺;
N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-氟-1-苯磺酰胺;
N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-氟-1-苯磺酰胺;
N-[2-(4-氨基-2-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-甲磺酰胺;
N2-[2-(4-氨基-2-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-2-噻吩磺酰胺;
N1-[2-(4-氨基-2-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-5-二甲氨基-1-萘磺酰胺;
N-[4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-甲磺酰胺;
N2-[4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-噻吩磺酰胺;
N1-[4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-5-二甲氨基-1-萘磺酰胺;
N1-[4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-氟-1-苯磺酰胺;
N1-[4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-氟-1-苯磺酰胺;
N1-[4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-1-苯磺酰胺;
N8-[4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-8-喹啉磺酰胺;
N2-[4-(4-氨基-2-(4-甲氧基苄基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-噻吩磺酰胺;
N-[4-(4-氨基-2-丁基-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-甲磺酰胺;
N2-[4-(4-氨基-2-丁基-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-噻吩磺酰胺;
N1-[4-(4-氨基-2-丁基-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-5-二甲氨基-1-萘磺酰胺;
N1-[4-(4-氨基-2-(2-甲氧基乙基)-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-1-苯磺酰胺;
N1-[4-(4-氨基-2-(2-甲氧基乙基)-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-5-二甲氨基-1-萘磺酰胺;
N’-[2-(4-氨基-2-(乙氧基甲基)-1H-咪唑并[4,5-c]喹啉-1-基)乙基]-N,N-二甲基磺酰胺;
N’-[4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N,N-二甲基磺酰胺;
N’-[4-(4-氨基-2-(4-甲氧基苄基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N,N-二甲基磺酰胺;
N’-[4-(4-氨基-2-丁基-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N,N-二甲基磺酰胺;
N’-[4-(4-氨基-2-(2-甲氧基乙基)-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-N,N-二甲基磺酰胺;
N4-[4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-硫代吗啉磺酰胺;
N1-[4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-吡咯烷磺酰胺;
N-[4-(4-氨基-2-(2-甲氧基乙基)-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-甲磺酰胺;
N-[4-(4-氨基-2-(2-甲氧基乙基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-苯基甲磺酰胺。
20.如权利要求1所述的化合物,其特征在于所述的化合物选自如下一组:
N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-5-二甲基氨基-1-萘磺酰胺;
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-5-二甲氨基-1-萘磺酰胺;
N2-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-2-噻吩磺酰胺;
N-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-苯基甲磺酰胺;
N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-1-苯磺酰胺;
N-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-甲磺酰胺;
N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-硝基-1-苯磺酰胺;
N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-3-氨基-1-苯磺酰胺;
N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-硝基-1-苯磺酰胺;
N1-[4-(4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-氨基-1-苯磺酰胺;
N-[4-(4-氨基-2-(4-甲氧基苄基)-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-甲磺酰胺;
N1-[4-(4-氨基-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-1-丁磺酰胺;
N1-[4-(4-氨基-2-(2-甲氧基乙基)-6,7,8,9-四氢-1H-咪唑并[4,5-c]喹啉-1-基)丁基]-4-氟-1-苯磺酰胺。
21.一种药物组合物,它包含治疗有效量的权利要求1所述的化合物以及药学上可接受的载体。
22.权利要求1所述的化合物在制备治疗动物病毒疾病或肿瘤疾病的药中的应用。
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