CN102264394B - 脂化咪唑并喹啉衍生物 - Google Patents
脂化咪唑并喹啉衍生物 Download PDFInfo
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Abstract
本发明化合物是佐剂分子，其包括共价连接磷脂基或膦脂基的咪唑并喹啉分子。本发明化合物已表明是干扰素-a、IL-12和其它免疫刺激细胞因子的诱导剂，且当用作疫苗抗原的佐剂时，与已知细胞因子诱导剂相比，具有提高的活性特征。
Description
背景
本发明涉及新的佐剂化合物、它们的制备方法、包含它们的组合物以及它们作为疫苗佐剂的用途。
微生物疫苗的精制和简化以及合成和重组亚基抗原用于提高疫苗的可制造性和安全导致疫苗效能的下降。这引起了对佐剂与抗原共同给药以提高疫苗活性以及合成和重组表位的弱免疫原性的研究。佐剂是增强针对疫苗抗原的体液和/或细胞介导免疫应答的添加物。但是，由于免疫***功能所涉及分子机制的复杂性质，疫苗佐剂的设计历史上是困难的。虽然长久以来已知添加微生物组分以增强适应性免疫应答，但是最近才表明，免疫监视所涉及细胞(例如上皮细胞和树突细胞)上的Toll样受体(TLR)通过所谓“病原相关模式”或“PAMP”结合许多的这些微生物产品。许多疫苗佐剂和独立的免疫调节剂似乎与TLR家族成员相互作用。
已鉴定的10种已知人TLR中，5种与细菌组分识别有关(TLR1、2、4、5、6)，4种其它的(TLR3、7、8、9)似乎被限制在胞质小室中并与病毒RNA(TLR3、7、8)和去甲基化DNA(TLR9)的检测有关(Iwasaki，A.，Nat Immunol 2004，5，987)。TLR的活化调节胞内信号转导途径，并通过与胞内衔接物分子如MyD88、TRIF、TIRAP和TRAM的相互作用引起基因表达(Akira，S.Nat Rev Immunol 2004，4，499；Takeda，K.Semin Immunol 2004，16，3)。这些衔接物分子可有差别地调节炎症细胞因子/趋化因子和I型干扰素(IFNa/b)(可引起优先增强抗原特异性体液和细胞介导免疫应答)的表达(Zughaier，S.InfectImmun 2005，73，2940)。体液免疫是防御细菌病原体的主线，但是在病毒疾病和癌症情况下，细胞毒性T淋巴细胞(CTL)的诱导似乎对保护性免疫是决定性的。
目前，一组称为明矾的铝盐是人疫苗所用的主要佐剂。但是明矾通常只增强体液(Th2)免疫，并由于通过其它途径(例如皮下或皮内接种引起肉芽肿)的局部毒性而一般肌内使用(Aguilar，J.Vaccine 2007，25，3752)。明矾的其它潜在副作用包括增加IgE产生、变应原性和神经毒性。因此，需要新的安全有效的疫苗佐剂，其能够刺激抗体和Tb1型免疫应答，并与不同给药途径和抗原制剂兼容。
在TLR7和TLR8活化的情况下，必须识别天然(富含U和/或G)病毒ssRNA配体的几个不同类小分子模拟物。它们包括主要与TLR7相互作用的一些与氧化鸟苷代谢物(氧代鸟苷)相关的抗病毒化合物(Heil，F.Eur J Immunol 2003，33，2987；Hemmi，2002)，以及结合TLR7和/或TLR8的腺嘌呤衍生物。这些化合物的免疫刺激能力归因于TLR/MyD88依赖性信号转导途径和细胞因子(包括IL-6以及I型(尤其干扰素-a)和II型干扰素)的产生。TLR7或TLR8活化引起上调树突细胞(DC)上的共刺激分子(例如CD-40、CD-80、CD-86)以及I类和II类MHC分子。DC是涉及T淋巴细胞吸收和提呈抗原的免疫***的主要细胞。浆细胞样树突细胞(plasmacytoid dendritic cell，pDC)优先表达TLR7，是专职的干扰素-a生产细胞；而mDC仅表达TLR8。mDC上的TLR8活化引起优先产生促炎细胞因子如IL-12、TNF-a和IFN-g以及细胞介导免疫(CMI)。
已受到相当关注的一类腺嘌呤衍生物是1H-咪唑并[4，5-c]喹啉(IQ)。当以乳膏形式局部施用时，发现该类咪喹莫德(imiquimod)(R847，S-26398)的原型成员有效对抗生殖***瘤病毒感染、光化性角化病和基底细胞癌。但是，咪喹莫德具有相当低的干扰素诱导活性，且口服和局部制剂均不无副作用。事实上，在利用咪喹莫德的HCV临床试验中报道了严重的副作用。TLR7激动剂的大部分免疫“足迹”通常已引起对毒性的关注：由于毒性问题最近暂停了利用另一TLR7激动剂ANA-975(氧代鸟苷衍生物)的临床试验。
瑞喹莫德(resiquimod)是IQ类TLR7/8配体的另一成员和咪喹莫德代谢物的衍生物。瑞喹莫德(R-848，S-28609)还以MyD88依赖性方式直接或间接地通过辅助分子活化巨噬细胞和DC中的TLR7，并上调DC中的共刺激分子和MHC I/II。与咪喹莫德相比，更具效能和毒性的瑞喹莫德还是TLR8信号转导的配体，其引起CD4+调节(Treg)细胞功能的逆转。最近利用转染HEK293细胞显示，TLR7激动剂在产生IFN-a和IFN调节细胞因子方面更有效，而TLR8激动剂在诱导促炎细胞因子如TNF-a和IL-12方面更有效，表明TLR7活化可能对抗体应答(Th2型应答)更为重要，而TLR8活化应促进CMI或Th1型免疫应答。然而如上所述，许多TLR7/8激动剂经常表现毒性、不稳定和/或具有非实质性免疫刺激作用。因此，发现和开发有效且安全的活化TLR7和/或TLR8的佐剂对通过帮助控制针对抗原的免疫应答大小、方向和持续时间来提高现有疫苗和新疫苗的功效和安全性是必要的。
与识别细胞表面上的PAMP的TLR2和LTR4不同，TLR7/8PAMP在内体/溶酶体小室中被感知，并需要内体成熟。在天然和异生素(zenobiotic)TLR7/8配体如咪喹莫德和瑞喹莫德情况下，细胞吸收是细胞活化的先决条件。因此，提高TLR7/8配体穿透DC和其它免疫细胞的策略可增强TLR活化和疫苗功效以及改善毒性作用。
核苷药物的脂缀合物是本领域已知一般用以增强口服生物利用度，以及允许将获得的“核苷脂(nucleolipid)”结合到脂质体的脂膜中。将不稳定和/或毒性药物结合到脂质体中建立了缓释载体***或分子贮库制剂，其保护药物免受降解并降低毒副作用。已报道这种“脂前药”的效能可比得上非衍生药物(US 5,827,831-NeXstar)。本领域已报道咪唑并喹啉和脂酰化IQ的贮库制剂用于在局部组织区域中维持IQ延长的时间以降低代谢和毒性之目的(WO 2005/001022-3M)。但是，当单独给药或与抗原一起以贮库制剂给药时，以特异方式将咪唑并喹啉与磷脂或膦脂缀合以促进到免疫细胞内的吸收，并增强内体TLR7/8活化和抗原呈递是本领域未知的。利用本发明化合物的增强免疫应答可能是因为式(I)化合物与内体TLR7和/或TLR8直接相互作用和/或在酶作用后活性代谢物的相互作用。
发明简述
本发明化合物已表明是干扰素-a、IL-12和其它免疫刺激细胞因子的诱导剂，且当用作治疗性或预防性治疗感染性疾病和癌症中的疫苗抗原的佐剂时，与已知细胞因子诱导剂相比，其可具有提高的活性-毒性特征。这些化合物本身也是新颖的。
附图说明
图1显示研究设计的示意图。
图2显示p27特异性CD8应答。
图3显示体内检测的p27特异性细胞毒活性。
图4阐述抗原特异性CD4T细胞应答。
图5显示用不含(-)或含不同量TLR7/8配体以及QS21和MPL的脂质体基制剂免疫的组中的血清细胞因子应答。
图6显示用不含(-)或含不同量TLR7/8配体以及QS21和MPL的乳剂基制剂免疫的组中的血清细胞因子应答。
发明概述
本发明化合物是佐剂分子，其包括可共价连接磷脂基或膦脂基的咪唑并喹啉分子。本发明化合物由式I或其药学上可接受的盐概括描述：
其中
R1＝H、支链或直链且任选地末端用羟基、氨基、巯基、肼基、酰肼基、叠氮基、乙炔基、羧基或马来酰亚胺基(maleimido)取代的C1-6烷基、C1-6烷基氨基、C1-6烷氧基、C3-6环烷基C1-6烷基、C3-6环烷基C1-6烷基氨基、C3-6环烷基C1-6烷氧基、C1-6烷氧基C1-6烷基氨基、C1-6烷氧基C1-6烷氧基，
Z＝未取代或末端由-(O-C2-C6烷基)1-6-取代的C2-C6烷基或烯基，
Y＝O、NH
X＝O、CH2、CF2
W＝O或S
m＝1-2，
其中
R2＝H或直链/支链/不饱和C4-C24烷基或酰基
R3＝直链/支链/不饱和C4-C24烷基或酰基
R4、R5＝独立地为H、C1-C6烷基、C1-C6烷氧基、卤素或三氟甲基；或者一起结合形成未取代或由一个或多个C1-C6烷基、C1-C6烷氧基、卤素或三氟甲基取代的六员芳基、含一个氮原子的杂芳基、环烷基或含一个氮原子的杂环烷基。
在一个实施方案中，本发明化合物更具体地由式II描述：
其中
R1＝H、支链或直链且任选地末端用羟基、氨基、巯基、肼基、酰肼基、叠氮基、乙炔基、羧基或马来酰亚胺基取代的C1-6烷基、C1-6烷基氨基、C1-6烷氧基、C3-6环烷基C1-6烷基、C3-6环烷基C1-6烷基氨基、C3-6环烷基C1-6烷氧基、C1-6烷氧基C1-6烷基、C1-6烷氧基C1-6烷基氨基、C1-6烷氧基C1-6烷氧基，
n＝1-6
Y＝O、NH
X＝O、CH2、CF2
W＝O或S
m＝1-2
R2＝H或直链/支链/不饱和C4-C24烷基或酰基
R3＝直链/支链/不饱和C4-C24烷基或酰基(例如当W＝O、X＝O、m＝1时，为磷脂酰基醚或酯、溶血磷脂酰基醚或酯)
表1
| 实施例 | 引用号 | R1 | n | m |
| 1 | - | - | - | - |
| 2 | - | - | - | - |
| 3 | L1 | H | 2 | 1 |
| 4 | L2 | n-Bu | 2 | 1 |
| 5 | L3 | CH2OEt | 2 | 1 |
| 6 | L4 | CH2OEt | 4 | 1 |
| 7 | - | - | - | - |
| 8 | L5 | CH2OEt | 2 | 2 |
| 9 | - | - | - | - |
对于所有示出实施例：Y＝W＝X＝O；R2＝R3＝十六酰
实施例1
制备4-氨基-1-[2-(1，2-二软脂酰-sn-甘油基-3-磷酰)烷基]-1H-咪唑并[4，5-c]喹啉(化合物(I)，Y＝W＝X＝O，m＝1)的一般步骤：
依据下述本领域已知方法(Crossman，等.J ChemSoc，Perkin Trans1，1997，2769；Westerduin，等.Tet Lett，1986，15，6271；Nikolaev，等，Carbohydr Res，1990，204，65)通过偶联4-氨基-1-羟烷基-咪唑并喹啉III(Gerster等.J Med Chem 2005，48，3481；Izumi等.Bioorg Med Chem2003，11，2541)和1-H膦酸酯IV来制备咪唑并喹啉单磷酸甘油二酯V：将咪唑并喹啉III(1当量)和H-膦酸酯IV(2当量)悬浮到正庚烷中，并在蒸发溶剂之后在高真空下干燥过夜。将所得残余物溶于吡啶(0.01M化合物III)，用新戊酰氯(12.4当量)处理，然后室温搅拌6小时。加入碘(4当量)的19∶1吡啶-水溶液(0.04M)，室温搅拌所得混合物1小时，然后在CHCl3和1M Na2S2O5水溶液之间分配。将层分离，并用CHCl3萃取水层两次。用1M硼酸三乙铵缓冲液(pH 8)洗涤合并的有机萃取物，干燥(Na2SO4)并浓缩。通过硅胶快速色谱(梯度洗脱，0→25％MeOH-CHCl3)纯化所得残余物，再通过反相色谱(含1％TEA的CH3CN中的Bakerbond C8，用0→60％含1％Et3N的MeOH-CH3CN洗脱)得到无色固体化合物V。
实施例2
制备盐酸4-氨基-1-(4-羟丁基)-2-乙氧基甲基-1H-咪唑并[4，5-c]喹啉(化合物(III)，R1＝CH2OCH2CH3，n＝4)
(1)在50℃用POCl3(1.2当量)逐滴处理并搅拌4-羟基-3-硝基喹啉(Gerster等.J Med Chem 2005，48，3481)的DMF悬浮液(0.7M)30分钟。将反应混合物倒入冰水，并用CH2Cl2萃取两次。用水洗涤合并的有机层，干燥(Na2SO4)并浓缩。将所得粗制品加到4-氨基-丁醇(1.3当量)和三乙胺(1.9当量)的EtOH溶液，并加热回流15分钟。浓缩后，硅胶快速色谱产出收率97％的黄色固体4-(4-羟丁基)氨基-3-硝基喹啉。
(2)将上面(1)所制化合物的EtOAc溶液(0.1M)在5％Pt/C(5％w/w)和MgSO4(1.5当量)存在下于50psig氢化6小时。将反应混合物过滤通过硅澡土并浓缩。将所得橙色油体与乙氧基乙酸(11当量)一起于150℃加热1小时。冷却反应混合物至0℃，用浓缩NH4OH碱化至pH 10，并用CH2Cl2萃取两次。干燥(Na2SO4)合并的有机层并浓缩。硅胶快速色谱(1∶60MeOH-CHCl3)产出乙氧基乙酸酯衍生物，用2.6M NaOH(5.0当量)的EtOH溶液(0.20M)室温处理1小时。减压除去乙醇，用AcOEt和CH2Cl2萃取水层数次。干燥(Na2SO4)合并的有机层并浓缩。硅胶快速色谱(梯度洗脱，1∶50→1∶15MeOH-CHCl3)产出收率74％的固体1-(4-羟丁基)-1H-咪唑并[4，5-c]喹啉。1H NMR(CDCl3，400MHz)δ9.29(s，1H)，8.25(dd，2H)，7.67(m，2H)，4.89(s，2H)，4.71(t，2H)，3.79(m，2H)，3.62(dd，2H)，2.12(m，2H)，1.82(m，2H)，1.25(t，3H)。
(3)将上面(2)所制化合物和过乙酸(1.2当量)的乙醇溶液(0.4M)在60℃加热2.5小时。浓缩后，通过硅胶色谱(梯度洗脱，1∶30→1∶6MeOH-CHCl3)纯化得到的粗制品，以产出收率94％的黄色固体1-(4-羟丁基)-1H-咪唑并[4，5-c]喹啉5-N-氧化物。
(4)用NH4OH(30％水溶液，2,7mL)处理上面(3)所制化合物的CH2Cl2悬浮液(0.43M)，之后滴加对甲苯磺酰氯(1.0当量)。室温搅拌所得混合物1.5小时并浓缩。硅胶快速色谱(梯度洗脱，1∶30→1∶9MeOH-CHCl3)产出定量产率的橙色固体4-氨基-1-(4-羟丁基)-1H-咪唑并[4，5-c]喹啉。
(5)在50℃滴加4N HCl的二
烷溶液处理上面(4)所制化合物的二烷溶液(0.12M)，之后使其冷却至室温。收集固体沉淀，用二
烷洗涤，干燥产出收率89％的盐酸4-氨基-1-(4-羟丁基)-1H-咪唑并[4，5-c]喹啉：1H NMR(CDCl3-CD3OD，400MHz)δ8.13(d，1H)，7.97(d，1H)，7.65(t，1H)，7.55(t，1H)，4.89(bs，2H)，4.68(m，2H)，3.75(m，2H)，3.68(dd，2H)，2.10(m，2H)，1.80(m，2H)，1.29(t，3H)。13C NMR(CDCl3-CD3OD，100MHz)δ151.9，148.1，135.8，133.7，130.2，128.7，125.8，125.4，122.5，121.2，118.8，112.1，66.8，64.0，60.8，46.8，28.6，26.6，14.5。HRMS[M+H]+计算值315.1821，实测值315.1839。
实施例3(L1)
制备4-氨基-1-[2-(1，2-二软脂酰-sn-甘油基-3-磷酰)乙基]-1H-咪唑并[4，5-c]喹啉(化合物(I)，R1＝H，Y＝W＝X＝O，n＝2，m＝1，R2＝R3＝n-C15H31CO)
按照上面实施例1所述一般步骤以收率80％制备化合物L1：1HNMR(CDCl3-CD3OD，400MHz)δ8.22(s，1H)，8.16(d，1H)，7.41(t，1H)，7.21(t，1H)，6.92(d，1H)，5.26(m，1H)，4.82(bs，2H)，4.67(bs，2H)，4.42(dd，1H)，4.20(dd，1H)，4.05(t，2H)，3.14(q，1H)，2.31(m，4H)，1.59(m，4H)，1.25(m，48H)，0.88(m，6H)；13C NMR(CDCl3-CD3OD，100MHz)：δ173.6，173.2，148.1，145.8，134.5，133.9，129.3，125.5，124.5，118.4，112.3，100.3，77.2，70.1，70.0，63.5，62.3，45.9，34.1，33.9，31.7，29.5，29.5，29.3，29.2，29.1，29.1，28.9，28.9，24.7，24.7，22.5，13.9，8.3。HRMS[M+H]+计算值859.5714，实测值859.5688。
实施例4(L2)
制备4-氨基-1-[2-(1，2-二软脂酰-sn-甘油基-3-磷酰)乙基]-2-丁基-1H-咪唑并[4，5-c]喹啉(化合物(I)，R1＝n-C4H9，Y＝W＝X＝O，n＝2，m＝1，R2＝R3＝n-C15H31CO)
按照上面实施例1所述一般步骤以收率78％制备化合物L2：1HNMR(CDCl3-CD3OD，400MHz)：δ8.23(bs，1H)，7.39(t，1H)，7.22(bs，1H)，6.93(bs，1H)，5.25(m，1H)，4.7(bs，2H)，4.6(bs，2H)，4.42(dd，1H)，4.19(dd，1H)，4.04(t，2H)，3.06(bs，2H)2.32(m，4H)，1.96(p，2H)1.59(m，6H)1.26(m，48H)，1.07(t，3H)，0.88(m，6H)；13C NMR(CDCl3-CD3OD，100MHz)：δ173.6，173.2，157.2，147.4，135.2，133.6，128.8，124.2，123.6，120.9，118.2，112.2，77.2，70.0，69.9，63.2，62.2，46.3，33.9，33.7，31.6，29.3，29.3，29.3，29.1，29.0，28.95，28.9，28.8，28.7，28.6，27.0，24.5，24.5，22.3，22.1，13.6，13.4。HRMS：[M+H]+计算值915.6340，实测值915.6309。
实施例5(L3)
制备4-氨基-1-[2-(1，2-二软脂酰-sn-甘油基-3-磷酰)乙基]-2-乙氧基甲基-1H-咪唑并[4，5-c]喹啉(化合物(I)，R1＝CH2OCH2CH3，Y＝W＝X＝O，n＝2，m＝1，R2＝R3＝n-C15H31CO)
按照上面实施例1所述一般步骤以收率86％制备化合物L3：1HNMR(CDCl3-CD3OD，400MHz)：δ8.05(bs，1H)，7.29(t，1H)，7.09(bs，1H)，6.78(bs，1H)，5.11(m，1H)，4.80(bs，4H)，4.60(bs，2H)，4.28(dd，1H)，4.07(dd，1H)，3.90(t，2H)，3.54(q，2H)2.18(m，4H)，1.59(m，4H)1.16(m，51H)，0.76(m，6H)；13C NMR(CDCl3-CD3OD，100MHz)：δ173.4，173.0，153.3，148.2，135.7，134.7，129.1，124.4，124.2，121.1，119.1，112.8，77.2，70.2，66.6，65.4，63.5，62.5，57.7，47.1，45.7，34.3，34.1，31.9，29.7，29.7，29.6，29.5，29.3，29.3，29.1，29.1，24.9，22.7，15.0，14.1，8.6。HRMS：[M+H]+计算值915.6340，实测值915.6309。
实施例6(L4)
制备4-氨基-1-[2-(1，2-二软脂酰-sn-甘油基-3-磷酰)丁基]-2-乙氧基甲基-1H-咪唑并[4，5-c]喹啉(化合物(I)，R1＝H，Y＝W＝X＝O，n＝4，m＝1，R2＝R3＝n-C15H31CO)
按照上面实施例1所述一般步骤以收率26％制备化合物L4：1HNMR(CDCl3，400MHz)：δ11.2(bs，1H)，7.78(d，1H)，7.30(t，1H)，7.20(d，1H)，6.78(t，1H)，6.39(bs，1H)，5.28(m，1H)，4.79(s，2H)，4.43-4.50(m，3H)，4.11-4.27(m，5H)，3.67(dd，2H)，2.41(bs，2H)，2.30(dd，4H)，1.96(bs，1H)，1.60(m，4H)，1.25(m，54H)，0.88(1，6H)；13C NMR(CDCl3，100MHz)：δ173.4，173.0，150.9，148.9，134.7，134.2，128.0，124.3(2)，120.5，118.4，111.8，70.3，70.2，66.8，64.7，64.4，64.3，63.4(2)，62.4，46.6，34.2，34.1，31.9，29.6(3)，29.4，29.3(2)，29.2，29.1，28.2，27.4，24.8(2)，22.6，15.1，14.1。HRMS[M-H]-计算值943.6289，实测值943.6251。
实施例7
制备4-氨基-1-[2-(1，2-二软脂酰-sn-甘油基-3-二磷酰)烷基]-1H-咪唑并[4，5-c]喹啉(化合物(I)，Y＝W＝X＝O，m＝2)的一般步骤
依据下述本领域已知方法(Biochim.Biophys.Acta 1980，619，604，J.Biol.Chem.，1990，265(11)，(6112-6117)J. Org.Chem.1997，62，2144-2147)通过偶联咪唑并喹啉单磷酸吗啉酯VI(由咪唑并喹啉III制备的粗制形式)和1，2-二酰基-sn-甘油-3-磷酸酯钠盐VII来制备咪唑并喹啉二磷酸甘油二酯VIII：在0℃将POCl3(2.0当量)和咪唑并喹啉III(1.0当量)加入磷酸三甲基酯(0.38M)。在0℃搅拌15小时后，在H2O和Et2O之间分配反应混合物并分离各层。用H2O萃取有机层3次，并用NH4OH水溶液调节合并水层的pH至pH 9。浓缩水溶液，高真空下干燥，并通过利用CHCl3-MeOH-H2O-Et3N(梯度洗脱，90∶10∶0.5∶0.5→60∶40∶5∶1)的硅胶色谱纯化所得残余物。将所得产物在50℃溶于二
烷(0.12M)，并用4N HCl(1.5当量)处理。收集沉淀的HCl盐，用二
烷冲洗，并高真空下干燥。将吗啉(5.0当量)加入该盐的1∶1t-BuOH-H2O(0.5M)悬浮液中，加热反应混合物至90℃，并用1，3-二环己基碳二亚胺的t-BuOH溶液(0.33M)处理。在90℃维持1小时后，在H2O和Et2O之间分配冷却的反应混合物，并分离各层。用H2O萃取有机层两次，浓缩合并的水层并高真空下干燥。真空浓缩所得粗磷酸吗啉酯VI(1.5当量)和VII(1.0当量)的小体积吡啶悬浮液，然后用甲苯共蒸发两次，并高真空下干燥；再重复该步骤两次。然后将4，5-二氰基咪唑(DCI，3.0当量)加入干燥固体的吡啶悬浮液(0.10M)中，室温搅拌反应混合物10天。浓缩得到的混合物，在H2O-CH2Cl2之间分配所得残余物，并分离各层。用CH2Cl2萃取水层两次，干燥(Na2SO4)并浓缩合并的有机层。利用CHCl3-MeOH-H2O(梯度洗脱，90∶10∶0.5→70∶30∶2)的硅胶色谱产出无色固体化合物VIII。
实施例8(L5)
制备4-氨基-1-[2-(1，2-二软脂酰-sn-甘油-3-二磷酰)乙基]-2-乙氧基甲基-1H-咪唑并[4，5-c]喹啉(化合物(I)，R1＝CH2OCH2CH3，Y＝W＝X＝O，n＝2，m＝2，R2＝R3＝n-C15H31CO)
按照上面实施例6所述一般步骤以收率22％制备化合物L5：1HNMR(CDCl3，400MHz)：δ8.17(bs，1H)，7.10-7.40(2-3m，2-3H)，5.25(bs，1H)，4.60-5.00(bm，3H)，4.38(m，1H)，4.05-4.22(m，3H)，3.60-3.82(m，4H)，3.41(bs，1H)，3.10(dd，Et3N的2H)，2.28(m，4H)，1.84(dd，1H)，1.56(m，5H)，1.25(m，54H)，0.88(t，7H)；13C NMR(CDCl3，100MHz)：δ173.5，173.1，152.4，147.7，135.8，134.2，128.8，124.5，123.6，122.0，118.8，112.2，77.2，70.0，68.1，66.5，63.8，62.4，54.6，46.5，45.5，38.5，33.9，33.0，29.5，29.4，29.1，28.9，28.7，25.0，24.6，23.5，22.7，22.5，14.6，13.8，13.7，13.2，10.7，8.1。HRMS[M+H]+计算值997.5796，实测值997.5776。
实施例9
脂化TLR7/8的体内试验
TLR7/8配体可促进小鼠多个方面的免疫应答，引人注意的是CD8应答。利用例如下述技术研究TLR7/8配体(“核心”化合物)和其对应脂化衍生物之间的应答差异。
用于比较研究的化合物制剂需要考虑核心和脂化分子间的不同分子量(例如45和4.5μg脂化化合物L3对应约15和1.5μg对应核心化合物“L3核心”)，以便能够在研究中并列比较对应基团。还测试了较高剂量的L3(200μg)和L3核心(150μg)。在一个这样的研究中，下面概括和描述的制剂用于接种6-8周龄C57BL/6(H2Kb)雌小鼠(10只/组)。小鼠接受间隔14天的两次注射，并在第1、3和4周抽血(精确抽血日见图1)。肌内接种小鼠。利用编码SIV-p27蛋白的重组腺病毒和加佐剂的p27的相异的初次免疫/加强免疫用作对照组，腺病毒注射剂量为5x 108VP。研究设计示于图1。
| 说明 | p27 | QS21 | MPL | SB62cb | L3 | L3核心 |
| QS/MPL(脂质体基制剂) | 5 | 5 | 5 | - | - | - |
| QS/MPL+200μg L3 | 5 | 5 | 5 | - | 200 | - |
| QS/MPL+45μg L3 | 5 | 5 | 5 | - | 45 | - |
| QS/MPL+4.5μg L3 | 5 | 5 | 5 | - | 4.5 | - |
| QS/MPL+150μg L3核心 | 5 | 5 | 5 | - | - | 150 |
| QS/MPL+15μg L3核心 | 5 | 5 | 5 | - | - | 15 |
| QS/MPL+1.5μg L3核心 | 5 | 5 | 5 | - | - | 1.5 |
| QS/MPL/SB62C(乳剂基制剂) | 5 | 5 | - | 5μl | - | - |
| QS/MPL/SB62C+200μg L3 | 5 | 5 | 5 | 5μl | 200 | - |
| QS/MPL/SB62C+45μg L3 | 5 | 5 | 5 | 5μl | 45 | - |
| QS/MPL/SB62C+4.5μg L3 | 5 | 5 | 5 | 5μl | 4.5 | - |
| QS/MPL/SB62C+150μg L3核心 | 5 | 5 | 5 | 5μl | - | 150 |
| QS/MPL/SB62C+15μg L3核心 | 5 | 5 | 5 | 5μl | - | 15 |
| QS/MPL/SB62C+1.5μg L3核心 | 5 | 5 | 5 | 5μl | - | 1.5 |
| p27 | 5 | - | - | - | - | - |
| 未用药的 | - | - | - | - | - | - |
表1：制剂概述
除非另外指明，所有化合物以μg计。
bSB62c包含水包油SB62和胆固醇
在研究设计中，将分子配制成含QS21和MPL免疫刺激剂的脂质体基或水包油基佐剂组合物。为评估TLR7/8L的加入值，将由包含TLR7/8L、QS21和MPL的制剂诱导的先天和适应性免疫应答与由对应的包含QS21和MPL的制剂诱导的比较。
通过在第二次注射后7天测量胞内细胞因子来评估抗原特异性CD8和CD4应答的诱导。在包括整个p27抗原(15-聚体肽，重叠11)的多种肽的合并物存在下刺激外周血淋巴细胞(PBL)。通过布雷菲尔德菌素A阻断细胞因子的分泌，并在用合适抗体胞内染色之后，通过流式细胞术评估3种细胞因子(IFNγ、TNFα和IL2)的存在情况。
利用CRX-642及其脂化物L3进行与上述类似的研究。图2和3显示第二次免疫后7天观察的p27特异性T细胞频度。与无TLR7/8L的对照制剂相比，当含L3的脂质体与MPL和QS-21制剂共同给药时，明显以剂量依赖方式增加了p27特异性CD8频度(图2)。引人注意的是，与对应的无TLR7/8L的对照制剂相比，在脂化TLR7/8L存在下，脂质体基制剂和水包油基制剂均得以提高CD8应答。而且，生成产细胞因子CD8T细胞的能力取决于TLR7/8配体的脂化性质，因为核心分子L3核心相比L3未提高应答。
作为对评估诱导的CD8应答的补充，还可体内评估抗原特异性胞毒活性。简言之，将跨整个蛋白的p27肽的脉冲靶标和对照未脉冲靶标注射到免疫小鼠中，并在注射后24小时，通过脉冲靶标的消失评估p27特异性胞毒性。
与上面说明的L3核心和L3的诱导CD8应答的评估一起进行补体胞毒活性(complementary cytotoxic activity)研究。与接受核心TLR7/8配体基制剂的小鼠相比，在用脂化TLR7/8配体基制剂免疫的小鼠中检测到更高的胞毒活性(图3)。该活性比由仅基于QS21和MPL的对照制剂诱导的活性高，特别是在使用高剂量脂化TLR7/8L时。
如对于CD8应答所示，当含L3的脂质体与含MPL和QS-21的脂质体基制剂一起给药时，与对照制剂相比，p27特异性CD4频度增加(图4)。对于CD8应答，核心分子L3核心不能够诱导超过由对照制剂诱导的CD4应答。
当以乳剂基制剂给药时，脂化TLR7/8L也能够提高CD4T细胞应答超过由对照制剂达到的水平。
当被脂化时，不同制剂中TLR7/8配体的增加值通过产细胞因子T细胞频度5倍的增加来表示(CD8和CD4T细胞二者)。令人关注的是，T细胞应答的细胞因子特征由高频度双阳性T细胞(IFNγ+TNFα+)表征。
另外的研究阐述了脂化TLR7/8化合物诱导内源趋化因子和促炎细胞因子的能力，其中已知I型IFN为稚CD8T细胞的程序(存活、分化和记忆发育)所需要。在第一次注射3和24小时后，在小鼠血清中测量这些细胞因子(图5和6)。
L3核心和L3的细胞因子特征结果显示在脂质体基和乳剂基制剂之间观察到类似的细胞因子特征。已知TLR7/8配体因它们刺激浆细胞样树突细胞的能力诱导IFNα，且确实在用L3免疫小鼠中以剂量依赖方式检测到IFNα，与其核心物L3核心相比处于较高水平。也检测到接近本底水平的低IL-12p70产生。在低剂量L3时INFγ水平增加，而当L3核心和L3均加入QS21和MPL中时，其它炎症细胞因子如TNFα或IL-6提高。对于两种化合物，趋化因子MCP-1和MIG均增加至10倍。总之，这些数据表明，与对应的核心分子相比，受试脂化分子在体内诱导细胞因子产生方面即使不更具效能也是等效的。
Claims (1)
1.选自下列的化合物或其药学上可接受的盐：
。
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