CN1066447C - 咪唑并[4,5-c]喹啉胺类 - Google Patents
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
Abstract
形式上从式Ⅱ所示的1H-咪唑并[4,5-c]喹啉-4-胺的1位和2位桥连衍生的化合物及其药学上可接受的盐,以及它们在诱导干扰素生物合成上的应用。
Description
发明背景
本发明涉及咪唑并[4,5-c]喹啉胺类化合物。另一方面,本发明涉及免疫调节剂化合物。其它方面,本发明涉及包含这些化合物的药物组合物和使用这些化合物的药理学方法。
相关技术的描述
已知某些1H-咪唑并[4,5-c]喹啉-4-胺是抗病毒剂和/或免疫调节剂。这样的化合物公开在诸如美国专利No.4,689,338、4,929,624、5,037,986、5,266,575、5,268,376、5,346,905,欧洲专利申请No.0,385,630 A2和WO92/15582(全部是授予Gerster等的)。普遍转让的待批申请08/092,002(Lindstrom et al.)公开了下式所示免疫调节剂咪唑并吡啶胺。
其中R1选自氢;CHRxRy,而Rx为氢,Ry选自含1-约10个碳原子的直链、支链或环状烷基,2-约10个碳原子的直链或支链链烯基,含1-约6个碳原子的直链或支链羟基烷基,烷氧基烷基(其中烷氧基含1至约4个碳原子,烷基含1至约6个碳原子)和苯乙基;及-CH=CRzRz,其中每一个Rz独立地为含1至约6个碳原子的直链、支链或环状烷基。
美国专利No.5,352,784(Nickolaides et al.)公开了免疫调节剂6,7-稠合环烷基咪唑并吡啶胺。
发明概述
本发明提供形式上通过1H-咪唑并[4,5c]喹啉-4-胺的1位和2位桥连而衍生的化合物及其药学上可接受的盐。本发明特别提供式Ⅱ所示的化合物及其药学上可接受的盐
其中R、Z和q在下面作详细限定。
本发明还提供包含(ⅰ)诱导动物干扰素生物合成的有效量的式Ⅱ化合物和(ⅱ)药学上可接受的载体的药物制剂。本发明还提供了诱导动物生物合成干扰素的方法,包括对所述的动物给予能诱导干扰素生物合成的有效量的式Ⅱ化合物的步骤。
发明的详述
本发明提供式Ⅱ化合物及其药学上可接受的盐,其中Z选自:
-(CH2)n-,其中n为1-4,
-(CH2)a-C(R1R2)(CH2)b-,其中a和b为整数且a+b为0-3,R1为氢或1-4个碳原子的烷基,R2选自1-4个碳原子的烷基、羟基、-OR3其中R3为1-4个碳原子的烷基,及-NR4R4′,其中R4和R4′独立地为氢或1-4个碳原子的烷基,
-(CH2)a-(Y)-(CH2)b-,其中a和b为整数且a+b为0-3,Y为O、S或-NR5-,其中R5为氢或1-4个碳原子的烷基;
其中q为0或1,R选自1-4个碳原子的烷基、1-4个碳原子的烷氧基,及卤素。
当Z为如上所定义的-(CH2)n-时,较佳为具有1、2或3个碳原子的亚烷基。当Z为如上所定义的-(CH2)a-C(R1R2)(CH2)b-时,R1较佳为氢,R2较佳为1-4个碳原子的烷基,最佳为甲基。当Z为如上所定义的-(CH2)a-(Y)-(CH2)b-时,Y较佳为O,而当Y为O时,a+b较佳为1。
较佳的本发明化合物包括:
8,9,10,11-四氢吡啶并[1′,2′:1,2]咪唑并[4,5-c]喹啉-6-胺,即
8H-9,10,11,12-四氢六亚甲基亚胺并[1′,2′:1,2]咪唑并[4,5-c]喹啉-6-胺,即
反应流程Ⅰ阐明了本发明化合物的制备。未取代的式Ⅺ化合物是已知的市售化合物,其它式Ⅺ化合物可用本领域技术人员已知的方法或Chem.Ber.1927,60,1108(Kohler)和J.Heterocyclic Chem.1988,25,857(Kappe)所公开的方法进行制备。
在步骤(ⅰ)中,将2,4-二羟基-3-硝基喹啉与磺酰卤或较佳与磺酸酐进行反应,先制得3-硝基喹啉-2,4-二磺酸酯。合适的磺酰卤包括烷基磺酰卤,如甲磺酰氯和三氟甲磺酰氯,及芳基磺酰卤,如苯磺酰氯、对溴苯磺酰氯和对甲苯磺酰氯。合适的磺酸酐包括相应于上述磺酰卤的磺酸酐。特别好的磺酸酐是三氟甲磺酸酐。
较佳的反应条件包括先将式Ⅺ所示化合物与碱反应,较佳为与过量叔胺碱(例如三烷基胺碱,如三乙胺)在合适的溶剂如二氯甲烷中进行反应,然后加入磺酰卤或磺酸酐。加料以控制的方式(如滴加)、在降低的温度(如约0℃)下进行为宜。
然后将此二磺酸酯与叔丁胺反应,以在过量叔胺碱存在下、在诸如二氯甲烷的溶剂中进行为宜,得到式Ⅻ所示化合物。反应可以这样进行:将叔胺碱加到步骤(ⅰ)第一部分所得的反应混合物中,冷却至一个降低的温度(如0℃),以控制的方式加入叔丁胺(如滴加)。反应也可这样进行:将叔丁胺加到二磺酸酯和叔胺碱在诸如二氯甲烷的溶剂中的溶液中。为了减少不合需要的2-胺化和2,4-二胺化副产物的量,反应可在较低的温度下如0℃左右进行。为了使反应完全,有时在加料后将反应混合物加热是必需的或合乎需要的。
在步骤(ⅱ)中,将式Ⅻ所示化合物与二苄胺反应。反应可这样进行:将起始物质和二苄胺放在诸如苯、甲苯或二甲苯的惰性溶剂中,加热,加热的温度和时间足以使磺酸基团被二苄胺取代,本领域技术人员可以容易地选择这样的温度和时间。然后在极性溶剂如甲醇中、在酸如盐酸的存在下,通过加热除去叔丁基。
然后将硝基还原成氨基。这种还原的方法是本领域技术人员熟知的。一种较佳的方法涉及在甲醇中从硼氢化钠和NiCl2就地生成Ni2B以提供还原剂溶液。将硝基化合物加到还原剂溶液中使硝基还原。产物为式ⅩⅢ所示的化合物。
在步骤(ⅲ)中,将式ⅩⅢ所示化合物与醋酸或其等价物反应,提供式ⅩⅣ所示的环化化合物。合适的醋酸的等价物包括相应的乙酰卤和原酸酯。当使用醋酸或原酸酯等价物时,反应可在无溶剂时或在惰性溶剂如二甲苯或甲苯中进行,并充分加热(例如,如有溶剂时根据溶剂的不同在约80-150℃)以驱除任何作为反应副产物而形成的醇或水。当使用酰卤时,以在乙酸中加热进行反应为宜。
在步骤(ⅳ)中,为了保护1位氮,先用烷氧基甲基(-CH2OR′,其中R′为烷基,如乙基)对环化的式ⅩⅣ化合物进行1位取代。取代反应的进行可通过用氢化钠和卤甲基烷基醚如氯甲基乙基醚处理式ⅩⅣ所示的化合物。然后将所得的1位受保护的化合物在2-甲基上用式ZCl所示基团取代,得到式ⅩⅤ所示化合物。反应可以这样进行:将1位受保护的化合物的2-甲基金属化,例如,用在四氢呋喃中的正丁基锂处理,然后加人式X′-ZCl所示烷基化剂,其中X′为比氯更易离去的基团(如X′可为溴)。在2-甲基上取代的另一个合适的方法涉及金属化、与环氧化物如环氧乙烷进行反应,并通过在惰性溶剂中与氯化剂如亚硫酰氯反应而将所得的2-(羟基烷基)化合物转化为相应的卤化物。
在步骤(ⅴ)中,将式ⅩⅤ所示化合物的1位去保护,例如,在HCl存在下、在溶剂如甲醇中加热。然后通过用1-氮有效地取代氯而环化所得的1-H化合物。在极性溶剂如丙酮中、在中和用碱(如碳酸钾)存在下用碘化钠处理是引起环化反应的合适方法。生成式ⅩⅥ所示化合物。
在步骤(ⅵ)中,将式ⅩⅥ所示化合物氢解以提供相应的式Ⅱ所示4-氨基化合物。常规公知的催化加氢条件是适当的。较佳的条件包括在Pd(OH)2/C存在下、在甲酸中加热。
反应流程Ⅱ显示不能经反应流程Ⅰ制备的某些本发明化合物的制备途径。反应流程Ⅱ
在步骤(ⅰ)中,用甲酸或其等价物如原甲酸酯(如原甲酸三乙酯)将式ⅩⅢ所示化合物环化以提供式ⅩⅪ所示化合物(见例如反应流程Ⅰ的步骤(ⅲ))。在步骤(ⅱ)中,如上面关于反应流程Ⅰ的步骤(ⅳ)所述的,在1位上将式ⅩⅪ化合物保护起来。然后将受保护的产物在2位上甲酰化,即首先在极性溶剂如四氢呋喃中金属化,例如与正丁基锂反应,然后与甲醛反应。步骤(ⅲ)涉及将式ⅩⅫ所示化合物的2-取代基进行homologating反应,例如与1-溴-2-(三苯基甲氧基)乙烷反应。式ⅩⅩⅢ所示产物可再进行反应直至生成式Ⅱ所示化合物,即通过酸催化的保护基的水解产生式ⅩⅩⅣ所示化合物,将2-取代基上的羟基转化为合适的可离去基团,环化(例如,如上面关于反应流程Ⅰ的步骤(ⅴ)所描述的那样),及如上面关于反应流程Ⅰ的步骤(ⅵ)所描述的那样还原裂解。
不经过反应流程Ⅰ或Ⅱ或本文所描述的其它方面所说明的途径进行制备的式Ⅱ所示化合物可用涉及公知的可供选择的合成方案、步骤顺序的改变等的流程的变化加以制备。
式Ⅱ所示产物化合物可用美国专利No.4,689,338(Gerster)中所公开的常规方法进行分离,例如除去溶剂并从适当的溶剂(如N,N-二甲基甲酰胺)或溶剂混合物中重结晶,或溶解于一种适当的溶剂(如甲醇)并通过加入化合物不溶于其中的第二种溶剂再沉淀。
式Ⅱ所示化合物本身可用作抗病毒剂,或可以药学上可接受的盐的形式,如盐酸、硫酸、磷酸、硝酸、甲磺酸盐或别的药学上可接受的酸的盐使用。式Ⅱ所示化合物的药学上可接受的盐一般通过该化合物与等摩尔较强酸在极性溶剂中的反应容易制备,这种较强酸以无机酸如盐酸、硫酸或磷酸或有机酸如甲磺酸为宜。通过加入该盐不溶于其中的溶剂如乙醚可促进盐的分离。
通过将治疗有效量的式Ⅱ化合物与适合于所选剂型的适当的药学上可接受的载体(包括佐剂和赋形剂)合并,可将本发明化合物配制成用于各种给药途径的制剂(如口服给药的片剂、胶囊剂、口服悬液等,局部给药,经皮给药或注射给药)。合适的制剂包括注射液、局部霜剂、凝胶剂和软膏剂,及口服片剂和胶囊剂。这种药物组合物的制备方法是本领域技术人员熟知的,并公开于Remington′sPharmaceutical Sciences,18th Edition,1990 Mack Publishing Company,A.R.Gennaro,Editor。其结果,适用于所选择的给药途径的特殊制剂可容易地被本领域技术人员所识别和制备。例如,固体剂型包含式Ⅱ所示化合物和一种或几种稀释剂(如磷酸二钙、硫酸钙、乳糖、甘露糖醇、纤维素、高岭土、氯化钠、淀粉、蔗糖、肌醇、山梨醇)、粘合剂(如淀粉、明胶、蔗糖、葡萄糖、右旋糖、糖蜜、乳糖、天然和合成树胶)、润滑剂(如滑石粉、硬脂酸镁、硬脂酸钙、硬脂酸、氢化植物油、聚乙二醇)、崩解剂(如玉米淀粉、马铃薯淀粉、粘土、纤维素、藻酸盐)、着色剂及调味剂。注射液包含式Ⅱ所示化合物和药学上可接受的水性赋形剂,包括足以达到pH2至约6的诸如酸(盐酸、乳酸、乙酸、天冬氨酸或其混合物)或碱(氢氧化钠)的合适的赋形剂,及为使制剂与血清等渗而加入的张力调节剂(如山梨醇或甘油)。局部或经皮制剂包含在霜、软膏或压敏粘合剂组合物中的式Ⅱ化合物。霜可包含润滑药(如十六烷醇、十八烷醇、矿脂、轻矿油、乙酰化羊毛脂)、乳化剂(如聚山梨酸酯60、脱水山梨醇一硬脂酸酯等非离子型表面活性剂)、增稠剂(如蒙脱土或诸如cetearyl alcohol、十六烷醇和十八烷醇等长链醇),及防腐剂(如羟苯甲酸甲酯、羟苯甲酸丙酯、苄醇),它们的量易于被本领域技术人员选择。软膏包含软膏基质(如聚乙二醇、矿脂)和润滑药及增稠剂。
构成治疗有效量的式Ⅱ化合物的量可因所用的具体化合物、所需的治疗效应、所治疗的病情、给药方案和给药途径而异。一般说来,式Ⅱ化合物在注射制剂中的量为按制剂总重量计的0.1%至约10%。类似地,口服片剂或胶囊剂一般含约0.5重量%至约50重量%;局部或经皮制剂可含约0.1重量%至约10重量%。具体的制剂易于被本领域技术人员选择。
本发明者试验了大量式Ⅱ化合物,并发现它们诱导人细胞和小鼠干扰素的生物合成。这些结果提示,至少某些本发明化合物在治疗病毒性疾病(如肝炎、疱疹、疣)和诸如类风湿性关节炎、湿疹、牛皮癣、多发性硬化、特发性血小板增多症等疾病、基底细胞癌等癌症及其它肿瘤疾病上是有用的。
下面的实施例旨在阐明本发明。结构由核磁共振谱加以确认。
实施例1
8,9,10,11-四氢吡啶并[1′,2′:1,2]咪唑并[4,5-c]喹啉-6-胺
A部分
将三乙胺(84ml,0.6mol)加到3-硝基-2,4-喹啉二醇(40g,0.194mol)在二氯甲烷(1200ml)中的悬浮液中。所得溶液于冰浴中冷却并加入三氟甲磺酸酐(67.2ml,0.40mol)。加完后,将反应液在蒸汽浴上加热10分钟,然后再于冰浴中冷却。加入叔丁胺(42ml,0.4mol),然后将反应液在蒸汽浴上加热15分钟。反应混合物用碳酸氢钠水溶液(500ml)洗涤,硫酸镁干燥,然后真空浓缩。浓缩物通过硅胶层,硅胶用二氯甲烷洗脱。二氯甲烷溶液真空蒸发,得到54g[4-(1,1-二甲基乙基)氨基-3-硝基喹啉-2-基]三氟甲磺酸酯。
B部分
将三乙胺(19.2ml,0.137mol)加到[4-(1,1-二甲基乙基)氨基-3-硝基喹啉-2-基]三氟甲磺酸酯(54g,0.137mol)的甲苯(约1L)溶液中。加入二苄胺(27ml,0.137mol),将反应混合物加热回流约2小时。将反应混合物真空浓缩,残渣用甲醇(900ml)稀释。加入盐酸(6N,100ml),反应混合物加热回流1小时。将反应混合物室温搅拌过夜。用过滤法分离所得的沉淀,用甲醇洗涤,然后干燥,得到42.1gN2,N2-二(苯基甲基)-3-硝基喹啉-2,4-二胺盐酸盐,为黄色固体。
C部分
将硼氢化钠(5.5g,0.147mol)小心地加到甲醇(1200ml)中含氯化镍(Ⅱ)水合物(11.9g,0.05mol)的溶液中。将N2,N2-二(苯基甲基)-3-硝基喹啉-2,4-二胺盐酸盐(42.1g,0.1mol)溶解在二氯甲烷(400ml)和甲醇(200ml)的混合物中,并加到硼酸镍试剂中。再小心地加入硼氢化钠直至生成的泡沫无色,将反应混合物经一层CeliteTM助滤剂过滤。滤液真空浓缩。将残渣在二氯甲烷和水之间分配。二氯甲烷层用硫酸镁干燥,然后真空浓缩。残渣吸收在乙醚(约1200ml)中。将氢氯酸气泡通入醚液5分钟。收集所得的沉淀,干燥,得到32克N2,N2-二(苯基甲基)喹啉-2,3,4-三胺盐酸盐。
D部分
将三乙胺(3.6ml,25.6mmol)加到N2,N2-二(苯基甲基)喹啉-2,3,4-三胺盐酸盐(5g,12.8mmol)的乙酸(120ml)悬浮液中。加入乙酰氯(0.91ml.12.8mmol),并将反应混合物加热回流5-6小时,然后真空浓缩。将残渣在乙醚和饱和碳酸氢钠溶液之间分配。将醚层干燥然后真空浓缩,残渣用柱层析提纯(硅胶,以含1-5%v/v乙酸乙酯的二氯甲烷洗脱),得到约2.4g N,N-二(苯基甲基)-2-甲基-1H-咪唑并[4,5-c]喹啉-4-胺。
E部分
将氢化钠(0.064g,2mmol)在四氢呋喃(15ml)中的悬浮液予冰浴中冷却。加入N,N-二(苯基甲基)-2-甲基-1H-咪唑并[4,5-c]喹啉-4-胺(0.5g,1.32mmol),使反应混合物温热至室温20分钟。加入氯甲基乙基醚,将反应混合物搅拌30分钟。将反应混合物用乙醚稀释,用水洗涤两次,经硫酸镁干燥,然后真空浓缩。残渣用柱层析提纯(硅胶,以二氯甲烷洗脱),得到0.43gN,N-二(苯基甲基)-1-乙氧基甲基-2-甲基-1H-咪唑并[4,5-c]喹啉-4-胺。
F部分
在氮气氛围下,将N,N-二(苯基甲基)-1-乙氧基甲基-2-甲基-1H-咪唑并[4,5-c]喹啉-4-胺(1.12g,2.56mmol)在四氢呋喃(20ml)中的溶液冷却至-78℃。加入丁基锂(2.5M己烷溶液1.03ml,2.56mmol),将反应混合物搅拌5分钟。加入1-溴-3-氯丙烷(2.7ml,25mmol),使反应混合物温热至环境温度。当薄层层析(硅胶,30%乙酸乙酯/己烷v/v)显示反应完成时,用乙醚和水稀释反应混合物。分离乙醚层,硫酸镁干燥,然后真空浓缩。所得残渣用柱层析提纯(硅胶,以10-20%乙酸乙酯/己烷v/v洗脱),得到0.76gN,N-二(苯基甲基)-2-(4-氯丁基)-1-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-4-胺。
G部分
将甲醇(若于ml)加到N,N-二(苯基甲基)-2-(4-氯丁基)-1-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-4-胺(0.76g,1.5mmol)在3N盐酸(20ml)中的悬浮液中。将反应混合物在蒸汽浴上加热4小时,然后在二氯甲烷和饱和碳酸氢钠水溶液之间分配。分离二氯甲烷层,硫酸镁干燥,然后真空浓缩。得到0.64g N,N-二(苯基甲基)-2-(4-氯丁基)-1H-咪唑并[4,5-c]喹啉-4-胺。
H部分
将碘化钠(1g,6mmol)和碳酸钾(0.8g,6mmol)加到N,N-二(苯基甲基)-2-(4-氯丁基)-1H-咪唑并[4,5-c]喹啉-4-胺(0.55g,1.2mmol)的丙酮溶液中。反应混合物加热回流4小时,过滤,然后真空浓缩。残渣用快速层析法提纯(硅胶,以10-15%乙酸乙酯/己烷v/v洗脱)。核磁共振谱表明可能存在碘代中间体,因此将残渣溶解在丙酮中,与碘化钠和碳酸钾合并,加热回流过夜。反应进行到得到0.38gN,N-二(苯基甲基)-8,9,10,11-四氢吡啶并[1′,2′:1,2]咪唑并[4,5-c]喹啉-4-胺。
I部分
将氢氧化钯炭(0.35g)加到N,N-二(苯基甲基)-8,9,10,11-四氢吡啶并[1′,2′:1,2]咪唑并[4,5-c]喹啉-4-胺(0.38g,0.9mmol)的甲酸(约15ml)溶液中。反应混合物加热回流3天,然后用二氯甲烷稀释,并用10%氢氧化钠调节成碱性(约pH9),分离二氯甲烷层,用硫酸镁干燥,然后真空浓缩,得到白色固体。将此物质用柱层析法提纯(硅胶,以4-10%甲醇/二氯甲烷v/v洗脱),得一固体。将此固体悬浮在二氯甲烷(20ml)中,然后过滤分离并干燥,得到70mg 8,9,10,11-四氢吡啶并[1′,2′:1,2]咪唑并[4,5-c]喹啉-4-胺,为一固体,m.p.275-278℃。C14H14N4+0.2CH2Cl2计算值:%C,66.81;%H,5.69;%N,21.95;实测值:%C,67.06;%H,5.60;%N,21.18。
实施例2
10-甲基-8,9,10,11-四氢吡啶并[1′,2′:1,2]咪唑并[4,5-c]喹啉-6-胺
A部分
将N,N-二(苯基甲基)-1-乙氧基甲基-2-甲基-1H-咪唑并[4,5-c]喹啉-4-胺(1.8g,4.12mmol,实施例1的E部分)在四氢呋喃(40ml)中的溶液冷却至-78℃。加入丁基锂(2.5M己烷溶液1.7ml,4.2mmol),将反应混合物搅拌20分钟。加入1-溴-3-氯-2-甲基丙烷(4.8ml,41mmol),使反应混合物温热至环境温度,历时1小时。将反应混合物用乙醚和水稀释。分离乙醚层,硫酸镁干燥,然后真空浓缩。所得残渣用快速层析提纯(硅胶,以5-20%乙酸乙酯/己烷v/v洗脱),得到0.65gN,N-二(苯基甲基)-2-(4-氯-3-甲基丁基)-1-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-4-胺。
B部分
将盐酸(6N,80ml)加到N,N-二(苯基甲基)-2-(4-氯-3-甲基丁基)-1-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-4-胺(0.64g,1.2mmol)在甲醇(40ml)中的悬浮液中。反应混合物加热回流2小时(此段时间中驱除全部甲醇),用二氯甲烷稀释,然后用10%氢氧化钠调节成碱性。分离二氯甲烷层,用硫酸镁干燥,然后浓缩,得到约0.5gN,N-二(苯基甲基)-2-(4-氯-3-甲基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺。
C部分
将大量过量(约10倍)的碘化钠和碳酸钾加到N,N-二(苯基甲基)-2-(4-氯-3-甲基丁基)-1H-咪唑并[4,5-c]喹啉-4-胺(约0.5g)的丙酮(约75ml)溶液中。反应混合物加热回流过夜,再加丙酮稀释,过滤,然后真空浓缩。残渣用二氯甲烷洗涤,从盐中回收产物,然后用柱层析提纯(硅胶,以3%乙酸乙酯/二氯甲烷v/v洗脱),得到0.35g N,N-二(苯基甲基)-8,9,10,11-四氢-10-甲基吡啶并[1′,2′:1,2]咪唑并[4,5-c]喹啉-4-胺。
D部分
将氢氧化钯炭(0.35g)加到N,N-二(苯基甲基)-8,9,10,11-四氢-10-甲基吡啶并[1′,2′:1,2]咪唑并[4,5-c]喹啉-4-胺(0.35g,0.809mmol)的甲酸(约15ml)溶液中。反应混合物加热回流3天,用甲醇和水的混合物稀释,然后通过CeliteTM助滤剂过滤。滤液真空浓缩并用10%氢氧化钠调节成碱性。过滤分离所得的沉淀,然后用柱层析法提纯(硅胶,以2-5%甲醇/二氯甲烷v/v洗脱),得到0.1g 10-甲基-8,9,10,11-四氢吡啶并[1′,2′:1,2]咪唑并[4,5-c]喹啉-6-胺,为一固体,m.p.279-281℃。C15H16N4计算值:%C,71.40;%H,6.39;%N,22.20;实测值:%C,71.10;%H,6.46;%N,22.25。
实施例3
8H-9,10,11,12-四氢六亚甲基亚胺并[1′,2′:1,2]咪唑并[4,5-c]喹啉-6-胺水合物
A部分
将N,N-二(苯基甲基)-1-乙氧基甲基-2-甲基-1H-咪唑并[4,5-c]喹啉-4-胺(1.5g,3.43mmol,实施例1的E部分)在四氢呋喃(30ml)中的溶液冷却至-78℃。滴加丁基锂(2.5M己烷溶液1.4ml,3.5mmol),然后加入1-溴-4-氯丁烷(4ml,34mmol)。使反应混合物温热至环境温度,然后用乙醚和水使反应停止。分离乙醚层,硫酸镁干燥,然后真空浓缩。所得残渣用柱层析提纯(硅胶,以10%乙酸乙酯/己烷v/v洗脱),得到1.5g N,N-二(苯基甲基)-2-(5-氯戊基)-1-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-4-胺。
B部分
将N,N-二(苯基甲基)-2-(5-氯戊基)-1-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-4-胺(1.5g,3mmol)在6N盐酸(100ml)中的悬浮液加热回流1小时。将反应混合物冷却,用二氯甲烷稀释,以10%氢氧化钠调节成碱性,然后用二氯甲烷(总量400ml)萃取。合并二氯甲烷萃取液,用硫酸镁干燥,然后真空浓缩,得到约1.3g N,N-二(苯基甲基)-2-(5-氯戊基)-1H-咪唑并[4,5-c]喹啉-4-胺。
C部分
用实施例2C部分的方法,将N,N-二(苯基甲基)-2-(5-氯戊基)-1H-咪唑并[4,5-c]喹啉-4-胺(1.3g,3mmol)环化,得到1.1g N,N-二(苯基甲基)-8H-9,10,11,12-四氢六亚甲基亚胺并[1′,2′:1,2]咪唑并[4,5-c]喹啉-6-胺,为白色固体。
D部分
将氢氧化钯炭(1g)加到N,N-二(苯基甲基)-8H-9,10,11,12-四氢六亚甲基亚胺并[1′,2′:1,2]咪唑并[4,5-c]喹啉-6-胺(1g,2.3mmol)的甲酸(约30ml)溶液中。反应混合物加热回流4天,过滤,用甲醇/二氯甲烷洗涤,然后真空浓缩。残渣在二氯甲烷和10%氢氧化钠之间进行分配。分离二氯甲烷层,用硫酸镁干燥,然后真空浓缩。残渣用柱层析法提纯(硅胶,以3-10%甲醇/二氯甲烷v/v洗脱),得到0.4g 8H-9,10,11,12-四氢六亚甲基亚胺并[1′,2′:1,2]咪唑并[4,5-c]喹啉-6-胺水合物,为一白色固体,m.p.237-240℃。C15H16N4+1/3H2O计算值:%C,69.74;%H,6.50;%N,21.69;实测值:%C,69.74;%H,6.27;%N,21.37。
实施例4
9,10-二氢-8H-吡咯并[1′,2′:1,2]咪唑并[4,5-c]喹啉-4-胺水合物
A部分
将N,N-二(苯基甲基)-1-乙氧基甲基-2-甲基-1H-咪唑并[4,5-c]喹啉-4-胺(1.7g,3.9mmol,实施例1E部分)在四氢呋喃(50ml)中的溶液冷却至-78℃。滴加丁基锂(2.5M己烷溶液1.6ml,4.1mmol);将反应混合物搅拌5分钟。让环氧乙烷溢出反应混合物的表面。10分钟后,使反应混合物温热至环境温度。当反应混合物温度达到0℃时停止加入环氧乙烷。用乙醚和水使反应停止。分离乙醚层,硫酸镁干燥,然后真空浓缩。所得残渣用柱层析提纯(硅胶,以5-10%乙酸乙酯/二氯甲烷v/v洗脱),得到1.4g N,N-二(苯基甲基)-2-(3-羟基丙基)-1-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-4-胺。
B部分
将亚硫酰氯(5ml,68mmol)加到N,N-二(苯基甲基)-2-(3-羟基丙基)-1-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-4-胺(1g,2.1mmol)中,将反应混合物快速搅拌直至薄层层析(硅胶,以10%乙酸乙酯/二氯甲烷v/v洗脱)表明反应完全。将反应混合物用二氯甲烷稀释,然后用10%氢氧化钠和碳酸氢钠中和。分离二氯甲烷层,硫酸镁干燥,然后真空浓缩。所得残渣用柱层析提纯(硅胶,以10-30%乙酸乙酯/己烷v/v洗脱),得到1g N,N-二(苯基甲基)-2-(3-氯丙基)-1-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-4-胺。
C部分
将N,N-二(苯基甲基)-2-(3-氯丙基)-1-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-4-胺(1g,2.0mmol)在6N盐酸(80ml)中的悬浮液加热回流2小时。然后在室温下搅拌过夜。将反应混合物以10%氢氧化钠调节成中性,然后用二氯甲烷萃取。萃取液用硫酸镁干燥,然后真空浓缩,得到约0.8gN,N-二(苯基甲基)-2-(3-氯丙基)-1H-咪唑并[4,5-c]喹啉-4-胺。
D部分
将碳酸钾(10倍过量)和碘化钠(5倍过量)加到N,N-二(苯基甲基)-2-(3-氯丙基)-1H-咪唑并[4,5-c]喹啉-4-胺(0.8g,1.8mmol)的丙酮溶液中。将反应液加热回流2小时,过滤,然后真空浓缩。残渣在二氯甲烷和水之间进行分配。分离二氯甲烷层,用硫酸镁干燥,然后真空浓缩。残渣用柱层析法提纯(硅胶,以10-30%乙酸乙酯/己烷v/v洗脱),得到0.25g N,N-二(苯基甲基)-9,10-二氢-8H-吡咯并[1′,2′:1,2]咪唑并[4,5-c]喹啉-4-胺。
E部分
将氢氧化钯炭(0.5g)加到N,N-二(苯基甲基)-9,10-二氢-8H-吡咯并[1′,2′:1,2]咪唑并[4,5-c]喹啉-4-胺(0.25g,0.62mmol)的甲酸(75ml)溶液中。将反应混合物加热回流4天,然后用甲醇稀释并过滤。滤液真空浓缩,然后与水和碳酸氢钠混合。过滤分离出灰色沉淀。将滤液浓缩。所得残渣用甲醇和二氯甲烷拌成淤浆,然后过滤。滤液与前面分离所得的灰色沉淀合并,然后用柱层析法提纯(硅胶,以3-5%甲醇/二氯甲烷v/v洗脱),得到80mg N,N-二(苯基甲基)-9,10-二氢-8H-吡咯并[1′,2′:1,2]咪唑并[4,5-c]喹啉-4-胺,为一白色固体,m.p.275-277℃。C13H12N4+1/3H2O计算值:%C,67.8l;%H,5.54;%N,24.33;实测值:%C,67.80;%H,5.26;%N,24.28。
实施例5
10,11-二氢-8H-[1,4]噁嗪并[4′,3′:l,2]咪唑并[4,5-c]喹啉-6-胺
A部分
将N2,N2-二(苯基甲基)喹啉-2,3,4-三胺盐酸盐(10g,25.6mmol,实施例1C部分)在原甲酸三乙酯(40ml)中的悬浮液于约120℃加热30分钟,冷却至室温后用乙醚稀释。过滤分离所得的沉淀,然后在氢氧化铵和二氯甲烷之间进行分配。分离二氯甲烷层,水洗两次,硫酸镁干燥,然后真空浓缩,得到8.6g N,N-二(苯基甲基)-1H-咪唑并[4,5-c]喹啉-4-胺,为一深棕色固体。
B部分
将N,N-二(苯基甲基)-1H-咪唑并[4,5-c]喹啉-4-胺(2g,5.49mmol)的四氢呋喃(10ml)溶液加到氢化钠(0.21g,6.58mmol)在四氢呋喃(25ml)中的悬浮液中。30分钟后,加入氯甲基乙基醚(0.61ml,6.58mmol),将反应混合物搅拌2小时。将反应混合物用乙醚稀释,水洗,硫酸镁干燥,然后真空浓缩,得到粗产物,为棕色油状物。将此油状物用柱层析法提纯(硅胶,以20-30%乙酸乙酯/己烷v/v洗脱),得到1.77g N,N-二(苯基甲基)-1-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-4-胺,为白色/褐色固体。
C部分
将丁基锂(2.5M己烷溶液1.6ml,4mmol)加到N,N-二(苯基甲基)-1-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-4-胺(1.7g,4mmol)在四氢呋喃中的冷(干冰/丙酮浴)溶液中。未观察到颜色变化。将反应混合物温热至-20℃(干冰/四氯化碳),溶液颜色变红。将以氮气流所载的甲醛气体加到反应混合物中。几分钟后,反应物转变为固体,撤去冰浴。使反应混合物温热至环境温度,反应混合物的颜色由红变黄。将反应物用乙醚和水稀释。分离乙醚层,硫酸镁干燥,然后真空浓缩。残渣用柱层析法提纯(硅胶,以10-20%乙酸乙酯/己烷v/v洗脱),得到1g 4-二(苯基甲基)氮基-1-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-2-甲醇。
D部分
将氢化钠(0.11g,3.3mmol)加到4-二(苯基甲基)氨基-1-乙氧基甲基-1H-咪唑并[4,5-c]喹啉-2-甲醇(1g,2.21mmol)的N,N-二甲基甲酰胺(15ml)溶液中,将所得的混合物搅拌10分钟。加入1-溴-2-(三苯甲氧基)乙烷,室温下连续搅拌3-4小时。用乙醚和水使反应停止。分离乙醚层,水洗几次,硫酸镁干燥,然后真空浓缩。残渣用柱层析法提纯(硅胶,以10-30%乙酸乙酯/己烷v/v洗脱),得到1.1g N,N-二(苯基甲基)-1-乙氧基甲基-2-[(2-三苯基甲氧基)乙氧基]甲基-1H-咪唑并[4,5-c]喹啉-4-胺。
E部分
将N,N-二(苯基甲基)-1-乙氧基甲基-2-[(2-三苯基甲氧基)乙氧基]甲基-1H-咪唑并[4,5-c]喹啉-4-胺(1.1g,1.5mmol)在6N盐酸(25ml)中的悬浮液在蒸汽浴上加热1.5小时。将反应混合物中和至pH7,然后用二氯甲烷萃取。然后将萃取液干燥,真空浓缩。残渣用柱层析法提纯(硅胶,以10-50%乙酸乙酯/己烷v/v洗脱),得到0.5g N,N-二(苯基甲基)-2-(2-羟基乙氧基)甲基-1H-咪唑并[4,5-c]喹啉-4-胺。
F部分
将三乙胺(0.17ml,1.25mmol)加到N,N-二(苯基甲基)-2-(2-羟基乙氧基)甲基-1H-咪唑并[4,5-c]喹啉-4-胺(0.5g,1.14mmol)的二氯甲烷(20ml)溶液中。加入甲磺酰氯(0.09ml,1.14mmol),将反应混合物室温搅拌1小时。将反应混合物用二氯甲烷稀释,水洗,硫酸镁干燥,然后真空浓缩,得到0.6g N,N-二(苯基甲基)-2-(2-甲磺酰氧基乙氧基)甲基-1H-咪唑并[4,5-c]喹啉-4-胺。
G部分
将过量碳酸钾和过量碘化钠加到N,N-二(苯基甲基)-2-(2-甲磺酰氧基乙氧基)甲基-1H-咪唑并[4,5-c]喹啉-4-胺(0.6g,1.14mmol)的丙酮(200ml)溶液中。反应混合物加热回流过夜,然后真空浓缩。残渣在二氯甲烷(150ml)和水(50ml)之间进行分配。分离二氯甲烷层,硫酸镁干燥,然后真空浓缩。残渣用柱层析提纯(硅胶,以10∶10∶80v/v/v二氯甲烷∶乙酸乙酯∶己烷洗脱),得到0.42g N,N-二(苯基甲基)-10,11-二氢-8H-[1,4]噁嗪并[4′,3′:1,2]咪唑并[4,5-c]喹啉-6-胺,为一白色固体。
H部分
将氢氧化钯炭(0.5g)加到N,N-二(苯基甲基)-10,11-二氢-8H-[1,4]噁嗪并[4′,3′:1,2]咪唑并[4,5-c]喹啉-6-胺(0.4g,0.95mmol)的甲酸(约40ml)溶液中,反应混合物加热回流6天,然后用甲醇稀释,并通过CeliteTM助滤剂层过滤,滤液用氢氧化铵调节成碱性后真空浓缩。将残渣用甲醇和二氯甲烷的混合液溶解。加入硅胶,所得混合物真空浓缩。将固体放在柱上,以2-5%甲醇的二氯甲烷溶液洗脱,得到白色固体。核磁共振谱与所需产物的甲酸盐一致。将此盐溶解在5%盐酸中,在蒸汽浴上加热30分钟。混合物以10%氢氧化钠调节成碱性。过滤分离所得的沉淀,水洗,真空干燥,得到75mg 10,11-二氢-8H-[1,4]噁嗪并[4′,3′:1,2]咪唑并[4,5-c]喹啉-6-胺,为一固体,m.p.258-259℃。分析:C13H12N4O计算值:%C,64.99;%H,5.03;%N,23.32;实测值:%C,64.61;%H,4.88;%N,23.18。
人体细胞中干扰素(a)的诱导
用一个体外人体血细胞系统评价本发明化合物对干扰素的诱导作用。测定分泌入培养基的干扰素,确定其活性。干扰素以生物检定法测定。
用于培养的血细胞的制备
静脉穿刺采全血于含EDTA的试管中。用LeucoPREPTM牌的细胞分离管(购自Becton Dickinson)或Ficoll-PaqueR溶液(购自Pharmacia LKB Biotechnology Inc,Piscataway,NJ)从全血分离得到外周血单核细胞(PBM)。将PBM以1×106个细胞/ml悬浮于含有25mM HEPES(N-2-羟乙基哌嗪-N′-2-乙磺酸)和L-谷氨酰胺(加入1%青霉素-链霉素溶液)的RPMI 1640培养基(购自GIBCO,Grand Island,NY)中,并加入10%热灭活(56℃30分钟)的自体血清。向96孔(平底)Micro TestⅢ灭菌组织培养板每孔加入200μl PBM悬液。
化合物的配制
将化合物溶于乙醇、二甲亚砜或组织培养水中,然后用组织培养水、0.01N氢氧化钠或0.01N盐酸稀释(溶剂的选择根据受试化合物的化学特性而定)。乙醇和DMSO的浓度不应超过加到培养孔中的终浓度的1%。将化合物在约0.1μg/ml至约5μg/ml的浓度范围内进行初步试验。然后将在0.5μg/ml浓度时显示诱导作用的化合物在更宽的浓度范围内进行试验。
培养
将受试化合物的溶液以一定体积(小于或等于50μl)加到含有全血或PBM的培养基的稀释液200μl的孔中。将溶剂和/或培养基加到对照孔(无受试化合物的孔)中,需要时调节终体积为每孔250μl。用塑料盖盖住板,轻轻打旋,然后于37℃和5%二氧化碳氛围下培养48小时。
分离
培养后,将板以石蜡膜覆盖,然后在Damon IEC型CRU-5000离心机中于4℃以1000rpm离心10-15分钟。从4-8个孔中移出培养基(约200μl),集中在2ml灭菌冷冻小瓶中。将样品保持于-70℃直至分析。
干扰素分析/计算
用脑心肌炎攻击A549人肺癌细胞以生物检定法测定干扰素。生物检定方法的细节已描述于G.L.Brennan和L.H.Kronenberg的″Automated Bioassay ofInterferons in Micro-test Plates",Biotechniques,June/July,78,1983,在此引作参考。该方法简述如下:将干扰素稀释液和A549细胞于37℃培养12-24小时。培养的细胞以脑心肌炎病毒接种物感染。将受感染的细胞再于37℃培养一段时间,然后对病毒的致细胞病变效应作定量分析。通过染色然后作分光光度吸光度测定来进行病毒致细胞病变效应的定量分析。以NIH HU IF-L标准品所得的值作为基准,将结果表示为α参比单位/ml。采用以脑心肌炎病毒攻击的A549细胞单层,在棋盘中和检定中以家兔抗人干扰素(β)和山羊抗人干扰素(α)进行测试,鉴定此干扰素基本上全部是α-干扰素。结果见下表,其中无记载的表示化合物未在该特定的浓度进行测定。
人体细胞干扰素(a)的诱导 | ||||||
实施例的化合物 | 参比单位/ml | |||||
剂量浓度(mg/ml) | ||||||
0.01 | 0.05 | 0.10 | 0.50 | 1.0 | 5.0 | |
1 | 2 | 5 | 320 | 1000 | 370 | 46 |
2 | - | - | 4 | 50 | 66 | 7 |
3 | - | - | 4 | 100 | 130 | 32 |
4 | 5 | 510 | 1200 | 160 | 190 | 380 |
5 | 1 | 1 | 510 | 310 | 170 | 210 |
小鼠干扰素的诱导
用本试验方法评估本发明化合物诱导小鼠干扰素生物合成的能力。
每个受试剂量水平有三组(每组3只)雄性小鼠(未禁食)经口给予化合物。1小时后,从眼球后血管丛取血,放在一起。将血液离心,收集血清,分成若干份,将血清样品冻结后储存于-70℃,直至分析。第二组小鼠在给药后2小时、第三组小鼠在给药后4小时重复此过程。
如上面关于人细胞干扰素诱导的分析所述,对样品进行测定。以小鼠MU-1-IF标准品所得值为基准,将结果以α/β参比单位/ml表示于下表。结果见下表,其中表示为“<”某一数值的结果表明在试验的该较低敏感度水平以上未能检出的干扰素量。
小鼠干扰素诱导 | ||||
实施例的化合物 | 剂量浓度(mg/kg) | 参比单位/ml | ||
1h | 2h | 4h | ||
1 | 0.3 | <250 | <250 | <250 |
1 | 1.0 | 480 | 480 | <250 |
1 | 3.0 | 480 | 1300 | 330 |
1 | 10.0 | 1600 | 4300 | 480 |
3 | 0.3 | <380 | <380 | <380 |
3 | 1.0 | <380 | <380 | <380 |
3 | 3.0 | 1100 | 820 | <380 |
3 | 10.0 | 1500 | 2900 | 660 |
4 | 0.3 | <520 | 520 | <520 |
4 | 1.0 | 1100 | 1100 | <520 |
4 | 3.0 | 2700 | 3500 | <520 |
4 | 10.0 | 4700 | 11000 | <520 |
5 | 0.3 | <310 | <310 | <310 |
5 | 1.0 | 310 | <310 | <310 |
5 | 3.0 | 1100 | 1200 | 310 |
5 | 10.0 | 1700 | 2100 | 630 |
体外间接抗病毒活性
如下所述的试验方法证明了本发明化合物抑制病毒感染进展的能力。
静脉穿刺取全血至含EDTA的试管中。用Ficoll-PaqueR溶液(购自PharmaciaLKB Biotechnology Inc,Piscataway,NJ)分离得到外周血单核细胞(PBM)。将PBM用磷酸盐缓冲盐水洗涤,然后以RPMI 1640培养基(购自GIBCO,Grand Island,New York)和10%胎牛血清稀释,得到终浓度为2.5×106个细胞/ml。将PBM培养基稀释液按每份1ml放在15ml的聚丙烯试管内。将受试化合物溶于二甲亚砜然后用RPMI 1640培养基稀释。将受试化合物的溶液加到含有PBM的试管中,得到终浓度为0.05μg/ml-1.0μg/ml。对照试管不加任何受试化合物。然后将试管于37℃和5%二氧化碳氛围下培养24小时。培养后,将试管于400×g离心5分钟。除去上清液。将PBM收集在100μl RPMI 1640培养基中,然后用含组织培养物50%感染剂量的疱疹性口炎病毒(VSV)105个100μl使其感染。将试管于37℃培养30分钟,使病毒吸附。每个试管中加1ml RPMI 1640培养基,将试管于37℃培养48小时。将试管冷冻再融化以溶解细胞。将试管以400×g离心5分钟,除去细胞碎片,然后将上清液作系列10倍稀释,依次加在96孔微量滴定板上的Vero细胞上进行检测。感染细胞于37℃培养24小时,然后定量分析病毒的致细胞病变效应。用0.05%结晶紫染色对病毒的致细胞病变效应进行定量。结果表示为VSV抑制作用,定义为log10(VSV对照组的量/VSV实验组的量)。结果见下表,其中无记载的表示化合物未在该特定的浓度进行测定。对照试管的数值为0。
体外抗病毒活性 | ||||
实施例的化合物 | 对VSV的量的抑制 | |||
剂量浓度(μg/ml) | ||||
0.05 | 0.1 | 0.5 | 1.0 | |
1 | 8.0 | 8.0 | 8.0 | -- |
2 | -- | 2.0 | 4.0 | 5.0 |
Claims (9)
1.式Ⅱ所示化合物及其药学上可接受的盐
其中Z选自:
-(CH2)n-,其中n为1-4,
-(CH2)a-C(R1R2)(CH2)b-,其中a和b为整数且a+b为0-3,R1为氢或1-4个碳原子的烷基,R2选自1-4个碳原子的烷基、羟基、-OR3。其中R3为1-4个碳原子的烷基,及-NR4R4′,其中R4和R4′独立地为氢或1-4个碳原子的烷基,
-(CH2)a-(Y)-(CH2)b-,其中a和b为整数且a+b为0-3,Y为O、S或-NR5-,其中R5为氢或1-4个碳原子的烷基;
且其中q为0或1,R选自1-4个碳原子的烷基、1-4个碳原子的烷氧基,及卤素。
2.如权利要求1所述的化合物及其药学上可接受的盐,其中Z为-(CH2)n-,n为1-3。
3.如权利要求1所述的化合物及其药学上可接受的盐,其中Z为-(CH2)a-C(R1R2)(CH2)b-,其中a和b为整数且a+b为0-3,R1为氢或1-4个碳原子的烷基,R2选自1-4个碳原子的烷基、羟基、-OR3其中R3为1-4个碳原子的烷基,及-NR4R4′,其中R4和R4′独立地为氢或1-4个碳原子的烷基。
4.如权利要求3所述的化合物及其药学上可接受的盐,其中R1为氢,R2为1-4个碳原子的烷基。
5.如权利要求1所述的化合物及其药学上可接受的盐,其中Z为(CH2)a-(Y)-(CH2)b-,其中a和b为整数且a+b为0-3,Y为O、S或-NR5-,其中R5为氢或1-4个碳原子的烷基。
6.如权利要求5所述的化合物及其药学上可接受的盐,其中Y为O。
7.如权利要求6所述的化合物及其药学上可接受的盐,其中a+b为1。
8.如权利要求1所述的化合物及其药学上可接受的盐,其中化合物选自:
8,9,10,11-四氢吡啶并[1’,2’:1,2]咪唑并[4,5-c]喹啉-6-胺,
10-甲基-8,9,10,11-四氢吡啶并[1’,2’:1,2]咪唑并[4,5-c]喹啉-4-胺,
8H-9,10,11,12-四氢六亚甲基亚胺并[1’,2’:1,2]咪唑并[4,5-c]喹啉-6-胺,
9,10-二氢-8H-吡咯并[1’,2’:1,2]咪唑并[4,5-c]喹啉-6-胺,
及10,11-二氢-8H-[1,4]噁嗪并[4’,3’:1,2]咪唑并[4,5-c]喹啉-6-胺。
9.药物制剂,包括:(ⅰ)诱导动物干扰素生物合成的有效量的权利要求1所述化合物和(ⅱ)药学上可接受的载体。
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