CN103097386A - 脂质化免疫反应调节剂化合物的组合物、制剂及方法 - Google Patents
脂质化免疫反应调节剂化合物的组合物、制剂及方法 Download PDFInfo
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Abstract
本发明涉及化合物N-(4-{[4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}丁基)硬脂酰胺,所述化合物N-(4-{[4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}丁基)硬脂酰胺为用于增强免疫反应的有效的药物化合物且可被用作,例如,疫苗辅剂及癌症治疗。
Description
背景技术
近几年来,已具有显著成功的努力是,发现通过促进免疫***的某些关键方面以及通过抑制其它某些方面(参见,例如,美国专利No.6,039,969(Tomai等人)和6,200,592(Tomai等人)而起作用的新药物化合物。这些化合物,在本文中被称为免疫反应调节剂(IRM),看起来通过称为Toll样受体(TLR)的基本免疫***机理引起选定的细胞因子生物合成、共刺激分子的诱导及增加抗原呈递的能力而起作用。
许多IRM可用于治疗多种疾病和病症。例如,某些IRM可用于治疗病毒性疾病(如,人***状瘤病毒、肝炎、疱疹)、瘤形成(如,基底细胞癌、鳞状上皮细胞癌、光化的角化症、黑素瘤)、TH2-介导的疾病(如,哮喘、过敏性鼻炎、特应性皮炎)以及自身免疫性疾病。某些IRM也可用作,例如,疫苗辅剂。
许多已知的IRM为咪唑并喹啉胺衍生物(参见,如,美国专利No.4,689,338(Gerster)),但是其它化合物类也是已知的(参见,如,美国专利No.5,446,153(Lindstrom等人);6,194,425(Gerster等人);和6,110,929(Gerster等人);以及国际专利公开号WO2005/079195(Hays等人)。
根据IRM在处理多种疾病和病症的巨大治疗潜能,和尽管已经做出了重要的工作,但是仍然需要通过细胞因子生物合成的诱导或其它机理可有效地调节免疫反应的新化合物。
发明内容
在一个方面,本发明提供了可用于诱导细胞因子生物合成的新化合物。该化合物(即,N-(4-{[4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}丁基)硬脂酰胺)具有下式(I):
也可使用化合物的配药学上可接受的盐。
式I化合物在生物学活性方面具有出乎意料地有益的性质。特别可取的是掺入到基于脂质体的制剂中。看来这类制剂对促进局部的免疫反应和减少***TNF诱导具有惊人的效用。
诱导动物体内细胞因子生物合成的能力使得式I化合物可用于治疗多种病症诸如在免疫反应中响应这类变化的病毒性疾病和肿瘤。因此,本发明还提供了通过对动物施用有效量的式I化合物而诱导动物体内细胞因子生物合成、治疗动物体内的病毒感染和/或治疗动物体内赘生性疾病的方法。本发明还提供了包含对动物施用有效量的式I化合物作为疫苗辅剂的接种动物的方法。
本发明还提供包含式I化合物配药学上合格的载体以及治疗学上有效量的药物组合物。在一些实施例中,药物组合物还包含抗原(如,疫苗)。在药物组合物的一些实施例中,式I化合物被掺入到均匀分散的制剂中。在药物组合物的一些实施例中,式I化合物被掺入到乳化的制剂中。在药物组合物的一些实施例中,式I化合物被掺入到水包油制剂中(例如,包含大豆油、TWEEN 80、SPAN 85以及PBS的制剂)。在药物组合物的一些实施例中,式I化合物被掺入到基于脂质体的制剂中。
用作对抗原疫苗的疫苗辅剂,式I化合物增加了对疫苗的抗体反应。它可降低需要实现所需的/治疗学上有效的抗体反应的抗原疫苗的量。例如,它可2倍、10倍、15倍、25倍、50倍或多达100倍或更多倍地降低所需疫苗抗原的量。
如通过本文所示出的非限制性实例的部分所示,式I化合物可用于各种广泛的用途,包括但不限于类似用于流行性感冒疫苗的疫苗辅剂之类的情况。例如,当用作疫苗辅剂时,与流行性感冒疫苗抗原相结合的式I化合物提供了针对H1N1流行性感冒感染(以及流行性感冒A、B和猪流感)的保护。具体地讲,当用作疫苗辅剂时,与凝集素抗原相结合的式I化合物提供了针对H1N1流行性感冒感染的保护。
式I化合物主要在给药位点(或在施加的局部位点)诱导细胞因子的生成,并且能够在基本上无***细胞因子诱导的情况下这样做,这对减少副作用可为重要的。例如,式I化合物可主要在给药位点(或在施加的局部位点)诱导TNF生成而未诱导***TNF水平高于背景水平(即,在施用式I化合物之前测得的***水平)。在一些应用中,式I化合物皮下注射可在局部引流***(而非外周***)用于诱导细胞因子的生成(诸如TNF的生成)。例如,式I化合物皮下注射可在局部引流***以至少为外周***细胞因子的2倍、3倍、5倍、10倍或高达100倍多或更多的水平诱导细胞因子的生成(诸如TNF的生成)。
除了式I化合物,据信化合物N-(4-{[4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}丁基)十六碳酰胺可使用类似的合成路线合成且也可用作与本文示出化学式的化合物相同的用途、药物组合物以及制剂。
当术语“包含”及其变型形式出现在具体实施方式和权利要求中时不具有限制的意思。
本文所用的“一种”、“该”、“至少一种”和“一种或多种”可互换使用。
另外,本文通过端点表述的数值范围包括所述范围内包含的所有数值(如,1到5包括1、1.5、2、2.75、3、3.80、4、5等)。
“改善”是指在程度、烈度、频率和/或症状可能性或特定状况临床征象特征的减少。
“抗原”是指可通过抗体以一种方式界定的任何物质,该方式在一定程度上为免疫特异性的。
“诱导”及其变型形式是指在细胞活性上任何可测量的增加。例如,免疫反应的诱导可包含,例如,细胞因子产量的增加,一组免疫细胞的活化、增殖或成熟和/或增加免疫功能的其它指标。
在此所用的“脂质体”或“基于脂质体的”通常是指由两亲的分子诸如,(但不限于)脂质、类脂或聚合物质构成的自组装粒子。它们也可包括脂肽和糖脂。
“症状”是指疾病或患者状况的任何主观证据。
“治疗剂”及其变型形式是指改善一种或多种与状况相关的现有病症或临床症状的治疗。
“治疗”及其变型形式是指任何程度上减少、限制累进、改善、预防或消除与状况相关的病症或症状。
本文所述的化合物N-(4-{[4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}丁基)硬脂酰胺可为其配药学上可接受的任何形式包括固体、半固体、溶剂化物(如,水合物)、全部或部分溶解(如,在药物组合物中)或分散在配药学上可接受的载体中。这也将会了解,也可使用式I化合物(N-(4-{[4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}丁基)硬脂酰胺)任何配药学上可接受的盐形式。
本发明的上述发明内容并不打算描述本发明的每个公开的实施例或每种实施方式。以下描述更具体地举例说明了示例性实施例。在整个说明的若干部分中,通过实例列表提供指导,这些实例可以各种组合加以使用。在各种情形下,所列举的清单仅仅作为代表性群组,而不应被理解为排他性清单。
具体实施方式
实例1
N-(4-{[4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}丁基)硬脂酰胺
A部分
戊酸酐(6.03g)和含吡啶盐酸盐(0.198g)的吡啶(8.28g)溶液添加至含3-氨基-4-氯喹啉(2.94g)的吡啶(5.0g)溶液中,且将反应物在室温下搅拌16小时,然后在60℃加热3小时。将反应物在减压下浓缩且添加碳酸钠溶液(15mL的10%的水溶液)。将反应物搅拌30分钟,然后过滤。将所得的固体用水(60mL)洗涤且在真空下干燥4小时从而得到4.59g粗品N-(4-氯喹-3-基)戊酰胺,为棕色薄片。将粗产物从庚烷(10mL)中重结晶且将回收产物利用庚烷回流通过16小时的索氏提取进一步纯化。将来自索氏提取装置的收集烧瓶在冰箱中冷却2小时。通过过滤收集所得的固体且将所得的固体在真空下干燥,得到2.00g的N-(4-氯喹-3-基)戊酰胺,为白色固体。
B部分
4-氨基-1-丁醇(7.68g)和含吡啶(7.00g)的二氯甲烷(100mL)溶液冰浴冷却且在30分钟期间内在搅拌下缓慢加入含氯甲酸苄酯(14.37g)的二氯甲烷(100mL)溶液。移除冰浴且将反应物搅拌额外的16小时。加入盐酸(1.2M,200mL)且分离相。在减压下将有机相进行干燥(MgSO4)、过滤以及浓缩。将所得的残余物从甲苯中重结晶且在真空下干燥以提供5.15g的苄基(4-羟基丁基)氨基甲酸酯。.
将含N-羟基邻苯二甲酰亚胺(3.36g)、苄基(4-羟基丁基)氨基甲酸酯(4.18g)以及三苯膦(7.41g)的二氯甲烷(100mL)溶液在冰浴中冷却且在搅拌下缓慢加入约三分之二的含偶氮二异丙基二羧酸(DIAD,5.68g)的二氯甲烷(50mL)溶液。监控反应物的内部温度且当不再能检测到放热时停止添加DIAD溶液。移除冰浴且让反应物升温至室温。在减压下浓缩反应物且将所得的残余物溶解在乙醇中(200proof,100mL)。添加肼(1.98g,水中含35%)且将反应物搅拌6小时。将反应物在冰箱中冷却且通过过滤移除所得的固体。将该固体用乙醇(50mL)洗涤。将合并滤液在减压下浓缩且添加二乙基醚(100mL)。通过过滤移除不溶解的杂质且向溶液中添加含2.0M HCl的醚(10mL)。立即形成沉淀。将该粗产物添加至甲苯(100mL)且在回流温度加热一小时。在冷却至室温后,通过过滤回收该固体产物,用甲苯洗涤且在真空下干燥得到3.76g苄基(4-氨氧丁基)氨基甲酸酯。
C部分
将N-(4-氯喹-3-基)戊酰胺(1.97g)、苄基(4-氨氧丁基)氨基甲酸酯(2.99g)、三乙胺(0.89g)和2-丙醇(40.69g)合并且在80℃加热3.5小时。将反应物冷却至室温、过滤且将滤液在减压下浓缩。将二氯甲烷(20mL)添加至所得的固体且将混合物搅拌二十分钟。通过过滤移除未溶解的固体且将滤液用两份10mL的水洗涤,该水为通过添加20滴的盐酸(1.2M)制得的微酸性的水。干燥有机镏分且在减压下浓缩。将粗品固体从四氢呋喃中重结晶以提供2.56g的苄基4-{[2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}氨基甲酸丁酯。
D部分
将苄基4-{[2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}氨基甲酸丁酯盐酸盐(10.05g)溶解在二氯甲烷(80mL)中且用30ml含碳酸钠(2.02g)的H2O溶液提取。将有机层在冰浴中冷却且缓慢添加溶解在二氯甲烷(30mL)中的间氯过苯甲酸(5.93g,1.24当量)溶液。6小时后,向反应物中添加氢氧化铵(10mL的28-30%水溶液)。将溶解在10ml二氯甲烷的苯磺酰基氯(6.96g)溶液在有力的搅动下缓慢添加。移除冷水浴且将反应物搅拌额外的12小时。将反应物用水(100mL)稀释且分离有机部分和水性部分。将水性部分用二氯甲烷(30mL)提取。将合并的有机部分用两份90ml的5%的碳酸钠洗涤。
将该二氯甲烷溶液转移至蒸馏装置且添加1-戊醇(50mL)。将此加热至40℃且在减压下移除二氯甲烷。然后添加浓缩的盐酸(50ml)且将反应物搅拌且加热至80°。在11小时后,将溶液冷却至室温且用水(100mL)稀释。将水性部分从1-戊醇中分离且用水(25mL)提取该1-戊醇。将水性部分合并。将1-戊醇(50mL)添加至合并的水性部分且将此在冰浴中冷却。在有力的搅动下,添加固体碳酸钠使pH至9-10。将混合物转移至分液漏斗中且进行级分分离。将水性部分用两份25ml的1-戊醇提取。将合并的1-戊醇部分在硫酸钠上干燥且过滤以提供溶解在1-戊醇中的1-(4-氨基丁氧基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺。
1-(4-氨基丁氧基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺的马来酸盐的制备通过在1-戊醇(50mL)中溶解马来酸(4.83g)且在搅拌下将它添加至含1-(4-氨基丁氧基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺的1-戊醇溶液中。通过过滤收集所得的沉淀且干燥得到7.69g的1-(4-氨基丁氧基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺双马来酸盐。1H-核磁共振(DMSO-d6):δ0.96(t,3H)、1.44(m,2H)、1.7-1.95(m,4H)、2.02(m,2H)、2.8-3.1(m,4H)、δ4.43(t,2H)、6.07(s,4H)、7.57(t,1H)、7.73(t,1H)、7.80(d,1H)、8.16(d,1H)。铵质子的宽峰在大约δ7.8和δ8.7处可见。
1-(4-氨基丁氧基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺的可替代延胡索酸盐通过以下工序制备。将1-(4-氨基丁氧基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺(6.53g)溶解在2-丙醇(75mL)中且添加脱色碳。将反应物加热至回流、趁热过滤且冷却至室温。添加含延胡索酸(2.5g)的2-丙醇溶液且将反应物在回流温度加热5分钟。冷却至室温时形成沉淀。过滤,然后在真空下干燥产物得到6.6g的1-(4-氨基丁氧基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺延胡索酸盐。
1H-核磁共振(DMSO-d6):δ0.95(t,3H)、1.42(m,2H)、1.70-1.92(m,4H)、1.92-2.10(m,2H)、2.85-3.05(m,4H)、4.34(t,3H)、δ6.46(s,2H)、7.30(t,1H)、7.47(t,1H)、7.60(d,1H)、8.02(d,1H)。宽铵峰在δ6.77处出现。
E部分
将1-(4-氨基丁氧基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺延胡索酸盐(1.30g)溶解在二氯甲烷(25mL)中且将该溶液用3×15ml份的饱和碳酸钠洗涤。然后将有机部分用15ml饱和氯化钠洗涤且在MgSO4上干燥。过滤溶液,在减压下移除溶剂且在真空下干燥产物以得到0.79g的作为游离碱的1-(4-氨基丁氧基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺。
将1-(4-氨基丁氧基)-2-丁基-1H-咪唑并[4,5-c]喹啉-4-胺溶解在二氯甲烷(20mL)和甲醇(5mL)中。添加硬脂酸(0.71g)且搅拌该反应物以溶解硬脂酸。添加1-乙基-3-(3-二甲基氨丙基)碳二亚胺HCl(EDC,0.45g)且将反应物在环境温度下搅拌16小时。添加额外份的EDC(0.23g)且将该反应物搅拌额外24小时。添加最终份的硬脂酸(0.22g)和EDC(0.37g)以驱动反应的完成且将该反应物在环境温度下搅拌另外24小时。在减压下浓缩该反应物且所得的残余物通过使用Biotage色谱法体系(Si40+M2358-1SiGel柱,85∶15二氯甲烷/甲醇等度洗脱)的快速柱层析纯化。半纯产物再次通过快速柱层析使用90∶10二氯甲烷/甲醇等度洗脱,然后95∶5二氯甲烷/甲醇等度洗脱两次。对包含产物的部分进行浓缩以得到1.12g的N-(4-{[4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}丁基)硬脂酸酰胺,为米白蜡质固体。
1H-核磁共振(CDCl3):δ0.89(t,3H)、1.01(t,3H)、1.14-1.42(m,28H)、1.50(m,2H)、1.65(m,2H)、1.74-1.94(m,4H)、2.02(m,2H)、2.20(t,2H)、2.95(t,2H)、3.40(q,2H)、4.33(t,2H)、5.59(t,1H)、6.10(broad s,2H)、7.39(m,1H)、δ7.57(m,1H)、7.83(d,1H)、8.07(m,1H)。
实例2
N-(4-{[4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}丁基)硬脂酸酰胺(实例1中的化合物)的疫苗辅剂的活性使用重组凝集素1(HA)免疫的小鼠进行评估。IgG2a抗原特异性抗体反应使用五种不同的制剂测量(1.单纯HA(对照);2.HA+瑞喹莫德(比较制剂);3.HA+在二油酰基卵磷脂(DOPC)中制得的实例1中的化合物(脂质体的制剂);3.HA+实例1中的化合物;5.HA+DOPC(对照)。
实例1中的化合物以及瑞喹莫德各自在磷酸盐缓冲液(PBS)中制备为水性悬浮液。在DOPC脂质体的制剂中制得的实例1中的化合物如下制备。实例1中化合物的储备溶液以10mg/ml的浓度在氯仿中制备。二油酰基卵磷脂(DOPC)的储备溶液也以10mg/ml的浓度在氯仿中制备。分别合并每份储备溶液以提供包含DOPC和实例1化合物质量比10∶1的溶液。将溶液吹干且通过探头超声波降解在无菌PBS中重新悬浮。
用PBS中的10μg的HA抗原,单独地或结合表1中引用的lmg/Kg的化合物对包括5只小鼠的组各自进行皮下免疫。DOPC对照动物接受如实例1化合物制备的相同量的DOPC。在初始免疫后的2周和4周使用相同的组合对小鼠进行追加。在7周的免疫后,将小鼠放血且确定HA-特异性IgG2a的滴度。由标准血清ELISA在HA-涂覆的微量滴定板上通过血清样品的系列稀释进行测定。IgG2a数据示于实现端点(2X基线)的血清稀释度且为每组5只小鼠的几何平均值。
表1
实例3
在由相同动物构建的脾细胞培养物中确定抗原依赖性干扰素-γ(IFNγ)的反应,其中IgG2a抗体对相同动物的反应在实例2中确定。移除该动物的脾脏,合并以形成每组5只动物的两组,切碎以产生单细胞悬浮液且置于96孔微量滴定板的培养物中。每组产生三个孔用于对照PBS测试且三个孔用于10mg的HA测试。然后将培养物在37℃温育72小时。然后移除培养基且通过ELISA分析测量产生的干扰素-γ(pg/m1)(表2)。IFNγ数据报告为每组使用三个重复测量值的几何平均值。
表2
实例4
对小鼠体内N-(4-{[4-氨基-2-丁基-1H咪唑并[4,5-c]喹啉-1-基]氧基}丁基)硬脂酰胺(实例1中的化合物)诱导***肿瘤坏死因子(TNF)的形成进行评估。使用四种不同的制剂测量***TNF的诱导。(1.PBS(对照);2.瑞喹莫德(比较制剂);3.在二油酰基卵磷脂(DOPC)中制得的瑞喹莫德(比较制剂);4.在二油酰基卵磷脂(DOPC)中制得的实例1中的化合物(脂质体)。
在二油酰基卵磷脂(DOPC)脂质体中制得的实例1中的化合物如实例2所述的那样制备。在DOPC中制得的瑞喹莫德以与DOPC中实例1化合物相类似的方式制备。瑞喹莫德制剂在PBS中制得为水性悬浮液。
用包含1mg/Kg每组测试化合物(即,瑞喹莫德或实例1中的化合物)的制剂皮下注射小鼠。在给药后一小时和三小时,将小鼠放血且通过ELISA分析在血清中测量***TNF(pg/mL)。结果以五只动物每组所获得的几何平均值示出。表3的数据示出多种形式瑞喹莫德的皮下注射诱导***TNF反应,然而N-(4-{[4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}丁基)硬脂酰胺(实例1中的化合物)不会诱导***TNF反应。这对提供无***TNF副作用的局部免疫***的增强是重要的。
表3
实例5
用10μg的HA抗原,单独或者与表4中所引用的增加量的N-(4-{[4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}丁基)硬脂酰胺(实例1中的化合物)/DOPC各自皮下免疫5只小鼠的群组。在初始免疫后的2周和4周用相同的组合对小鼠进行追加。在7周的免疫后,将小鼠放血且确定HA-特异性IgG2a的滴度。由标准血清ELISA在HA-涂覆的微量滴定板上通过血清样品的系列稀释进行测定。IgG2a数据为实现端点(2X基线)的血清稀释液且为每组5只小鼠的几何平均值。
表4
实例6
在由相同动物构建的脾细胞培养物中确定抗原依赖性干扰素-γ(IFNγ)的反应,其中IgG2a抗体对相同动物的反应在实例5中确定。移除该动物的脾脏,合并以形成每组5只动物的两组,切碎以产生单细胞悬浮液且置于96孔微量滴定板的培养物中。每组产生三个孔用于对照PBS测试且三个孔用于10mg的HA测试。然后将培养物在37℃温育72小时。然后移除培养基且通过ELISA分析测量产生的干扰素-γ(pg/ml)(表5)。IFNγ数据报告为每组使用三个重复测量值的几何平均值。
表5
实例7
确定N-(4-{[4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}丁基)硬脂酰胺(实例1中的化合物)诱导人外周单核细胞(PBMC)产生肿瘤坏死因子(TNF)的能力。从人类志愿者中制备人外周血单核细胞且放置在96孔微量滴定板的培养物中。将实例1中化合物以下列浓度添加至孔中:30、10、3.3、1.1、0.37、0.13、0.043和0.014μM。然后将细胞在37℃温育过夜。移除培养基且通过ELISA分析测量TNF的浓度(ng/mL)(表6)。
表6
实例8
N-(4-{[4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}丁基)硬脂酰胺(实例1中的化合物)的病毒保护活性在Balb/c雄性小鼠中(马萨诸塞州威尔明顿的查尔斯河(Charles River,Wilmington,MA))进行评估,用小鼠适应的H1N1 A/Puerto Rico/8/34(可购自弗吉尼亚州马纳萨斯的美国典型培养物保藏中心(American Type Culture Collection,Manassas,VA))对该雄性小鼠进行鼻内感染。感染前四周,10只小鼠的群组分别各自用以下物质进行免疫1.PBS;2.10μg HA;或3.10μg HA+0.1mg/Kg的DOPC脂质体的实例1中的化合物。在感染前两周,相同的群组用它们对应的免疫药追加。在鼻内给药感染后11天检测小鼠的存活且数据以每天存活的百分比示于表7中。组1中的一只小鼠和组2中的两只小鼠未能实现感染,由于小鼠感染的前3天无重量损失确定。因此,到第5天时,组1由9只小鼠构成,组2由8只小鼠构成且组3和组4各由10只小鼠构成。
表7
实例9
N-(4-{[4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}丁基)硬脂酰胺(实例1中的化合物)的免疫活化活性在小鼠预防性的抗肿瘤免疫模型中评估。对C57/B1的雄性小鼠群组(马萨诸塞州威尔明顿的查尔斯河)进行免疫且在两周间隔内用下述物质追加两次1)PBS;2)20μg卵清蛋白;或3)20μg卵清蛋白+1.0mg/Kg实例1中的化合物。在最终追加后一周,用4E5B16Ova黑素瘤肿瘤细胞皮内注射每只小鼠。在肿瘤注射后11天处死小鼠,以肿瘤的最大直径和最小直径测量肿瘤且确定两次测量的结果。以mm2+/-标准偏差(s.d.)确定每组的平均肿瘤尺寸。结果示于表8中。
表8
免疫材料 | 小鼠的数目 | 平均肿瘤尺寸(s.d.) |
PBS | 7 | 10.21(4.34) |
卵清蛋白 | 8 | 10.18(8.95) |
卵清蛋白+实例1中的化合物 | 8 | 0.99(0.81) |
实例10
-(4-{[4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}丁基)硬脂酰胺(实例1中的化合物)的剂量节省活性在用不同量的具有或者不具有实例1中化合物的HA的量免疫的小鼠进行评估。五只Balb/c雄性小鼠(马萨诸塞州威尔明顿的查尔斯河)的群组用1μg、5μg或15μg的带有或不带有0.1mg/kg实例1中的化合物的HA免疫。然后将小鼠在免疫后2周和4周用相同的制剂追加。在最终追加后的三周,将小鼠放血且HA-特异性IgG1和IgG2a的滴度使用标准血清ELISA分析在HA-涂覆的微量滴定板上通过血清样品的系列稀释来确定。IgG1和IgG2a数据以实现端点(2X基线)的血清稀释液示于表9且为每组5只小鼠的几何平均值。将0.1mg/Kg实施例1中化合物添加至HA很大的增强了对这个抗原的抗体反应。
表9
免疫群组 | IgG1端点 | IgG2a端点 |
HA1μg | 2.5E4 | 3.3E2 |
HA5μg | 6.7E4 | 1.0E3 |
HA15μg | 6.7E4 | 2.5E3 |
HA1μg+实例1中的化合物 | 1.7E7 | 3.3E6 |
HA5μg+实例1中的化合物 | 1.4E7 | 2.5E7 |
HA15μg+实例1中的化合物 | 1.1E7 | 1.0E8 |
实例11
局部体内的N-(4-{[4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}丁基)硬脂酰胺(实例1中的化合物)的活性在四只Balb/c雄性小鼠(查尔斯河)的群组中评估且与瑞喹莫德(比较化合物)的活性进行比较。在给药后1小时、3小时、6小时和18小时的时间点评估实例1化合物或瑞喹莫德溶液皮下注射小鼠的四个独立的群组。任一化合物的最终剂量为1.0mg/kg。在每个时间点,将小鼠放血、杀死并移除引流轴和肱***且放置在RNA保存流体中(RNAlater试剂可购自德克萨斯州奥斯汀的Ambion公司(AmbionCorporation,Austin,TX))。对于TNF蛋白浓度(pg/ml),经由ELISA分析血清样品作为本细胞因子***存在的量度。处理引流***用于通过定量的PCR(7900HT热循环仪,可购自加利福尼亚州卡尔斯巴德的美国应用生物***公司(Applied Biosystems,Carlsbad,CA))测定TNF mRNA的基因表达。报告的数据(表10)为每个群组的平均+/-标准偏差(s.d.)。血清TNF浓度“未检测到”水平为小于10pg/ml。在注射实例1化合物之后,在引流***中TNF mRNA基因表达而在血清中未检测到TNF蛋白的诱导表明实例1化合物中细胞因子的诱导效应主要为局部的。
表10
因此,本发明提供了式I化合物以及药物组合物及其化学式。在一些实施例中,式I化合物被掺入到基于脂质体的制剂。也可结合抗原,该抗原与这类制剂混合或结合但独立地施用。例如,抗原可在自组装脂质体粒子的腔内制得。这类脂质体将包括在大小上最适于得到所需尺寸和直径的稳定粒子这类物质的复合物。对模拟的病毒病原体,尺寸可为亚微米范围以及对模拟的细菌抗原可为微米尺寸。这些尺寸可通过粒子组成及形成方法控制。
在本文所公开方法的一些实施例中,将式I化合物(如,在本文所公开的药物组合物中)施用给局部组织区域,诸如施用给肿瘤团块。在这些实施例中的一些实施例,式I化合物在脂质体的制剂中施用给局部组织,诸如肿瘤团块。也可包括癌症疫苗。
“局部组织区域”通常为主体相对小的部分,如,按体积计小于10%以及按体积计通常小于1%。例如,根据,如,实体瘤或癌性器官的大小,局部组织区域通常将为大约不大于约500立方厘米(cm3),通常小于约100cm3且在许多情况下为10cm3或更小。对于一些应用,局部组织区域将为1cm3或更小(如,对于小的肿瘤、病毒病变或接种点)。然而,在某些情况下,局部组织区域可为特别大的区域,高达若干升,例如,以治疗整个腹膜腔内扩散的癌症。局部组织区域可为,例如,癌症、病毒感染病变或器官或接种点。它可为,例如,实体瘤、淋巴组织、网状内皮***、骨髓、粘膜组织等。局部组织区域可为,如,乳癌瘤、胃癌瘤、肺癌瘤、头部或颈杆癌瘤、结肠直肠癌瘤、肾细胞恶性肿瘤、胰癌瘤、基底细胞癌瘤、子***瘤、黑素瘤癌瘤、***癌瘤、卵巢癌瘤或膀胱癌瘤。式I化合物至局部组织区域的递送可结合图像引导技术使用,例如,超声、MRI以及实时X-射线(荧光检查法)。
在本文所公开的药物组合物和方法的一些实施例中,药物组合物还包括有效量的抗原以生成针对抗原的免疫反应。在一些实施例中,该抗原为疫苗。疫苗包括施用于提高或者体液的和/或细胞介导的免疫反应的任何物质,诸如活的或减毒的病毒和细菌免疫原和进行灭活的病毒、肿瘤来源的、原生动物的、生物体来源的、真菌的和细菌的免疫原、类毒素、毒素、多糖、蛋白质、糖蛋白、肽、细胞疫苗(如,使用树枝状的细胞)、DNA疫苗、重组蛋白、糖蛋白和肽。示例性的疫苗包括用于癌症、BCG、霍乱、瘟疫、伤寒、肝炎A,B和C、流行性感冒A和B、变异流行性感冒病毒、脑灰质炎、狂犬病、麻疹、腮腺炎、风疹、黄热病、破伤风、白喉、流感嗜血杆菌b、肺结核、流行性脊髓膜炎和肺炎球菌的疫苗、腺病毒、HIV、水痘、细胞巨化病毒、登革热、猫白血、禽类瘟疫、HSV-1和HSV-2、猪瘟、日本脑炎、呼吸性合胞病毒、轮状病毒、***状瘤病毒、严重急性呼吸***综合症(SARS)、炭疽热和黄热病的疫苗。还可参见,如,公开于国际专利公开No.WO02/24225(Thomsen等人)的疫苗。
抗原可与式I化合物共递送,例如,根据本发明在药物组合物中混合。这类药物组合物可包括在脂质体中的式I化合物。这可使得式I的化合物与抗原几乎同时到达,例如,抗原呈递细胞。在其它实施例中,式I化合物和抗原可大约同时或独立地施用。向免疫细胞共递送疫苗辅剂(如,诸如式I化合物的IRM化合物)和抗原可增加对抗原的免疫反应和改善抗原特异性免疫记忆。例如,当该辅剂和抗原同时在一个抗原呈递细胞中处理时,可进行最佳递送。
除了上文具体所述的递送方法,式I化合物(如,在本文所公开的药物组合物中)可以任何其它合适的方式(如,肠道或非肠道)施用。如本文所用,肠道是指通过消化道(包括通过口服法)给药。非肠道是指给除去通过消化道之外的给药,包括鼻腔的(如,通过吸入转化粘液质)、局部的、眼科的和口腔的给药,但是在实施过程中通常是指使用,例如,常规的针头注射、使用微针阵列注射或任何其它已知的注射方法的注射(如,静脉注射、肌内注射、皮下注射、瘤内或透皮)。
式I化合物可以任何适用于给药的药物组合物提供给受试者和可以任何合适的形式(如,溶液、悬浮液、乳状液或混合物的任何形式)存在于药物组合物中。药物组合物可由任何配药学上可接受的赋形剂、载体或媒介物制得。在一些实施例中,配药学上可接受的载体包括水(如,磷酸盐缓冲液或柠檬酸盐缓冲盐水)。在一些实施例中,配药学上可接受的载体包括油(如,玉米、芝麻、角鲨烯、棉籽、大豆或红花油)。该药物组合物还可包含一种或者多种添加剂包括透皮促进剂、着色剂、芳香剂、调味剂、增湿剂、增稠剂、悬浮剂、表面活性剂和分散剂。
除了上述具体描述的的抗原,本发明的药物组合物及方法可包括其它添加活性剂,如,混合或单独施用。这种添加剂可包括化学治疗剂、细胞类毒素剂、抗体、抗病毒素剂、细胞因子、肿瘤坏死因子受体(TNFR)激动剂或额外的免疫反应调节剂。可结合式I化合物被传送的TNFR激动剂包括CD40受体激动剂,诸如公开在同时待审的申请美国专利公布2004/0141950(Noelle等人)。用于与本发明的IRM制剂结合的其它活性成分包括在,如,美国专利公布No.2003/0139364(Krieg等人)公开的那些。
在一些实施例中,根据本发明的药物组合物可为常规的局部剂型制剂(如,霜剂、膏剂、气溶胶制剂、非气溶胶喷剂、凝胶或洗剂)。合适类型的制剂在,例如,美国专利No.5,238,944(Wick等人);美国专利No.5,939,090(Beaurline等人);美国专利No.6,245,776(Skwierczynski等人);欧洲专利No.EP 0394026(Schultz);和美国专利公布No.2003/0199538(Skwierczynski等人)中有所描述。
式I化合物在上述中已经示出诱导TNF-α的产生。诱导TNF产生的能力表明式I化合物可用于免疫反应调节剂,该免疫反应调节剂能以多个不同的方式调节免疫反应,使得免疫反应调节剂可用于多种疾病的治疗。可由施用式I化合物诱导产生的其它细胞因子通常包括I型干扰素(如,INF-α)、IL-1、IL-6、IL-8、IL-10、IL-12、MIP-1、MCP-1和多种其它的细胞因子。除了其他效应,这些和其它细胞因子抑制病毒的产生和肿瘤细胞的生长,使得式I化合物可用于病毒性疾病和赘生性疾病的治疗。因此,本发明提供了在动物中诱导细胞因子生物合成的方法,该方法包括向动物施用有效量的式I化合物(如,在药物组合物中)。施用式I化合物用于诱导细胞因子生物合成的动物可具有疾病(如,病毒性疾病或赘生性疾病),且化合物的施用可提供治疗处理。另外,式I化合物可在动物获得疾病之前施用给动物使得式I化合物的施用可提供预防性的治疗。
除了诱导细胞因子产生的能力,式I化合物可影响固有免疫反应的其它方面。例如,可以刺激自然杀伤细胞的活性,可能是由于细胞因子的诱导而产生的效应。式I化合物的IRM活性还可包括激发巨噬细胞,这继而刺激了硝酸氧化物的分泌和另外的细胞因子的生成。式I化合物的IRM活性还可包括通过T细胞诱导细胞因子的生成、激发对抗原特异性的T细胞和/或激发树枝状的细胞。另外,式I化合物的IRM活性可包括B-淋巴细胞的增殖和分化。式I化合物的IRM活性还可影响获得性免疫反应。例如,IRM的活性可包括诱导1型T辅助细胞(TH1)细胞因子IFN-γ的产生和/或抑制2型T辅助细胞(TH2)细胞因子IL-4、IL-5和/或IL-13的产生。
可通过施用式I化合物治疗的示例性病症包括:
(a)病毒性疾病诸如由腺病毒、疱疹病毒(如,HSV-I、HSV-II、CMV或VZV)、痘病毒(如,正痘病毒诸如天花或牛痘或***)、小核糖核酸病毒(如,鼻病毒或肠病毒)、正粘液病毒(如,流感病毒)、副粘病毒(如,副流感病毒、腮腺炎病毒、麻疹病毒和呼吸性合胞病毒(RSV))、冠状病毒(如,SARS)、乳多泡病毒(如,***瘤病毒,诸如引起生殖器疣、寻常疣或脚底疣的那些)、肝性DNA病毒(如,B型肝炎病毒)、黄病毒(如,C型肝炎病毒或登革热病毒)或逆转录病毒(如,慢病毒属诸如HIV)感染而引起的疾病;
(b)细菌疾病诸如由细菌,例如,埃希杆菌属、肠杆菌属、沙门氏菌属、葡萄球菌属、志贺氏杆菌属、李斯特氏菌属、产气杆菌属、螺杆菌属、克雷白氏杆菌属、变形杆菌属、假单胞菌属、链球菌属、衣原体、支原体、肺炎球菌属、奈瑟氏球菌属、梭状芽孢杆菌属、芽孢杆菌属、棒状杆菌属、分枝杆菌属、弯曲菌属、弧菌属、沙雷氏菌、普罗威登斯菌属、色素杆菌属、布氏杆菌属、耶尔森氏菌属、嗜血杆菌属或博德特氏杆菌属的感染引起的疾病;
(c)其它感染性疾病诸如衣原体、真菌疾病(诸如,念珠菌病、曲霉病、组织胞浆菌病或隐球菌脑膜炎)或寄生虫病(如,疟疾、间质性浆细胞肺炎、利什曼病、隐孢子虫病、弓形体病和锥体虫感染);
(d)赘生性疾病诸如上皮内瘤变、宫颈异常、光化学的角化症、基底细胞癌、鳞状上皮细胞癌、肾细胞恶性肿瘤、卡波西恶性毒瘤、黑素瘤、白血病(如,骨髓性白血病、慢性淋巴细胞白血病、多发性骨髓瘤、非霍奇金氏淋巴瘤、皮肤T-细胞淋巴瘤、B-细胞淋巴瘤以及毛发细胞白血病)、乳腺癌、肺癌、***癌、结肠癌以及其它癌症;
(e)TH2-介导的、特应性疾病诸如特应性皮炎或湿疹、嗜曙红细胞过多、哮喘、过敏症、过敏性鼻炎和奥门(Ommen’s)综合征;
(f)某些自体免疫疾病诸如***性红斑狼疮、原发性的血小板减少症、多发性的硬化症、盘状狼疮和斑秃症;和
(g)与伤口修复相关的疾病诸如抑制瘢痕疙瘩形成和其它类型的瘢痕化(如,增强伤口的愈合,包括长期伤口)。
式I化合物的抗病毒素和抗肿瘤活活性机理可能大部分因为通过多种重要的细胞因子(如,至少肿瘤坏死因子、干扰素或白细胞介素中的一种)的诱导而产生的免疫反应的增强。这类化合物已经示出能刺激某些单核细胞/巨噬细胞衍生的细胞因子的迅速释放且也能够刺激B细胞分泌抗体,该抗体在这些IRM化合物的抗病毒素和抗肿瘤活性方面可能起着重要作用。
应当理解,上文所述的疾病的治疗,例如,式I化合物可与其它疗法诸如上文所述的活性剂和其它操作(如,化学消融术、激光烧蚀、冷冻疗法和外科手术切除)联合使用。
能够有效的诱导细胞因子生物合成的化合物的量为足以引起一种或多种细胞类型,诸如单核细胞、巨噬细胞、树枝状细胞和B细胞产生相当数量的一种或多种细胞因子诸如,例如,IFN-α、TNF-α、IL-1、IL-6、IL-lO和IL-12的量,该量增加超过这些细胞因子的背景水平。根据在本领域中已知的因子,精确的量将会有差别,但是预计剂量为约100纳克/千克(ng/kg)至约50毫克/千克(mg/kg),在一些实施例中为约10微克/千克(μg/kg)至约5mg/kg。本发明还提供了治疗动物病毒性感染的方法和治疗动物赘生性疾病的方法,该方法包括向动物施用有效量的本发明的化合物或药物组合物。与未治疗的对照动物相比,能有效地治疗或抑制病毒性感染的量为将引起一种或多种病毒感染的临床表现,诸如病毒病变、病毒载量、病毒复制的速率以及死亡率减少的量。根据在本领域中已知的因子,对于这种处理有效的精确的量将会有差别,但是预计剂量为约100ng/kg至约50mg/kg,在一些实施例中为约10μg/kg至约5mg/kg。能够有效地治疗赘生性病症的化合物或药物组合物的量为将引起肿瘤尺寸或肿瘤灶数目减低的量。此外,根据在本领域中已知的因子,精确的量将会有差别,但是预计剂量为约100ng/kg至约50mg/kg,在一些实施例中为约10μg/kg至约5mg/kg。本发明的方法可在任何合适的受试者上执行。合适的受试者包括动物诸如人类、非人灵长类、啮齿类、狗、猫、马、猪、绵羊、山羊或牛。
例如:用于实施本发明制剂的组合物、有效用于根据本发明方法的式I化合物的精确的量和剂量服法,根据在本领域中已知的因子包括载体的性质、受试者免疫***的状态(如,抑制的、失能的、刺激的)、施用式I化合物的方法以及施用制剂的物类,将会有差别。因此,总体上示出包括式I化合物的制剂化合物、组成有效量的式I化合物的量或对所有可能应用有效的剂量服法是不切实际的。然而,本领域的普通技术人员在充分考虑这些因子后,可易于确定合适的制剂、式I化合物的量以及剂量服法。
在一些实施例中,本发明的方法包括以制剂向受试者施用式I化合物,例如,化合物的浓度为约0.0001%至约20%(除非另外指明,否则本文所提供的所有百分百比相对于总制剂均为重量/重量),尽管在一些实施例中,式I化合物可用作制剂施用,该制剂以此范围之外的浓度提供给化合物。在一些实施例中,该方法包括将包含施用给受试者包括约0.01%至约1%的式I化合物的制剂,例如,包含约0.1%至约0.5%的式I化合物的制剂。
在一些实施例中,本发明的方法包括施用给受试者足够的化合物以提供,例如,约100ng/kg至约50mg/kg的剂量,尽管在一些实施例中可通过施用在该范围之外剂量的化合物执行该方法。在这些实施例的一些中,该方法包括施用足够的化合物给受试者以提供约10μg/kg至约5mg/kg的剂量,例如,约100μg/kg至约1mg/kg的剂量。在一些实施例中,本发明的方法可包括施用足够的化合物以提供,例如,约0.01mg/m2至约10mg/m2的剂量。或者,可使用刚好在处理过程开始之前获得的实际的身体重量计算剂量。针对用这种方式计算的剂量,在处理过程开始之前使用杜波伊斯方法(Duboismethod)计算身体的表面积(m2):m2=(wt kg0.425×height cm0.725)×0.007184。
在本文所公开方法的一些实施例中,可施用式I化合物,例如,从每周单剂量至多剂量,尽管在本发明方法的一些实施例中,可通过在这范围外的频率施用式I化合物来进行。在一些实施例中,式I的化合物的可施用从约每月一次至约每周五次。在一些实施例中,式I中的化合物每周施用一次。
因为可制得式I化合物从而得到化合物的降低的***水平同时诱导高水平的细胞因子,据信这对提供增强的局部免疫反应同时最小化不期望的***副效应非常有用。这对多种使用可为有利的,诸如直接施用至肿瘤和/或疫苗辅剂。
上述实例说明了本发明的目的和优点,但列举的具体材料及其量以及其它病症和细节不应被理解为是对本发明的不当限制。
将本文所引用的专利、专利文献以及出版物中的完全公开内容以引用方式全文并入本文,就如同将它们各自单独并入本文一样。不脱离本发明的范围和精神的前提下,对本发明的各种修改和更改对于本领域技术人员将是显而易见的。应当理解,本发明不旨在不恰当地限于本文提供的示例性实施例和实例,这些实例和实施例仅以举例的方式提出,而且本发明的范围旨在仅受所附权利要求书的限制。
Claims (14)
2.一种药物组合物,所述药物组合物包含配药学上可接受的载体以及根据权利要求1所述的化合物。
3.一种药物组合物,所述药物组合物包含在含有脂质体的制剂中的根据权利要求1所述的化合物。
4.根据权利要求2或3所述的药物组合物,还包括抗原。
5.根据权利要求4所述的药物组合物,其中所述化合物及抗原被混合成单一组合物。
6.根据权利要求4所述的药物组合物,其中所述化合物及抗原存在于待组合施用的所述组合物的单独组分中。
7.根据权利要求4至6中任一项所述的药物组合物,其中所述抗原为癌症疫苗。
8.根据权利要求4至6中任一项所述的药物组合物,其中所述抗原为病毒疫苗。
9.一种增强疫苗抗原所述效用的方法,所述方法为将化合物N-(4-{[4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}丁基)硬脂酰胺或其配药学上可接受的盐施用为疫苗辅剂。
10.根据权利要求9所述的方法,其中所述化合物被掺入到脂质体的制剂中。
11.一种治疗赘生性疾病的方法,所述方法包括将所述化合物N-(4-{[4-氨基-2-丁基-1H-咪唑并[4,5-c]喹啉-1-基]氧基}丁基)硬脂酰胺或其配药学上可接受的盐施用至具有所述赘生性疾病的人或动物。
12.根据权利要求11所述的方法,其中所述化合物在脂质体的制剂中。
13.根据权利要求12所述的方法,其中所述制剂直接地施用在局部肿瘤团块上。
14.根据权利要求11至13中任一项所述的方法,还包括癌症疫苗抗原的施用。
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