CN107108684B - 尤其用于治疗癌症的环状二核苷酸 - Google Patents
尤其用于治疗癌症的环状二核苷酸 Download PDFInfo
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- CN107108684B CN107108684B CN201680006178.4A CN201680006178A CN107108684B CN 107108684 B CN107108684 B CN 107108684B CN 201680006178 A CN201680006178 A CN 201680006178A CN 107108684 B CN107108684 B CN 107108684B
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Abstract
一种式(I)的化合物或其药学上可接受的盐和互变异构体,含有所述化合物的组合物、组合产品和药物,以及它们的制备方法。本发明还涉及所述化合物、组合产品、组合物和药物在治疗STING(干扰素基因刺激蛋白)的调节是有益的的疾病和病症中的用途,例如炎症,过敏性和自身免疫性疾病,感染性疾病,癌症,癌前综合征,以及作为疫苗佐剂。
Description
发明领域
本发明涉及化合物,含有所述化合物的组合物、组合产品和药物,以及制备它们的方法。本发明还涉及所述化合物、组合产品、组合物和药物在治疗其中STING(干扰素基因刺激蛋白(Stimulator of Interferon Genes))的调节有益的疾病和病症中的用途,例如炎症、过敏性和自身免疫性疾病、感染性疾病、癌症、癌前综合征、以及作为疫苗佐剂。
发明背景
脊椎动物不断受到微生物侵袭的威胁,并进化出免疫防御机制,以消除感染的病原体。在哺乳动物中,这种免疫系统包括两个分支:天然免疫和适应性免疫。天然免疫系统是由模式识别受体(PRRs)启动的第一道防线,所述模式识别受体检测来自病原体的配体以及损伤相关的分子模式(Takeuchi O. et al, Cell, 2010: 140, 805-820)。已经识别出越来越多的这些受体,包括Toll样受体(TLR)、C型凝集素受体、视黄酸诱导型基因I(RIG-1)样受体和NOD样受体(NLR)以及双链DNA传感器。PRRs的激活导致参与炎症应答的基因的上调,包括抑制病原体复制并促进适应性免疫的1型干扰素、促炎细胞因子和趋化因子。
衔接蛋白STING(干扰素基因刺激蛋白)也已知为TMEM 173、MPYS、MITA和ERIS,其已经被识别为对胞质核酸的天然免疫应答中的中心信号分子(Ishikawa H and Barber G N, Nature, 2008: 455, 674-678; WO2013/1666000)。STING的激活引起导致干扰素-β和其他细胞因子诱导的IRF3和NFκB通路的上调。STING对于病原体或宿主来源的胞质DNA的应答是至关重要的,并且对称为环状二核苷酸(CDN)的不寻常核酸也是至关重要的。
CDN首先被识别为负责控制原核细胞中的众多应答的细菌二级信使。细菌CDN(如c-di-GMP)是以两个3',5'磷酸二酯连接键为特征的对称分子。
近来已经通过X射线晶体学证实了由细菌CDN直接激活STING(Burdette D L and Vance R E, Nature Immunology, 2013: 14, 19-26)。因此,细菌CDN及其类似物作为潜在的疫苗佐剂已经引起了人们的兴趣(Libanova R. et al, Microbial Biotechnology 2012: 5, 168-176; WO2007/054279, WO2005/087238)。
最近,已经阐明了对胞质DNA的应答,并且显示出涉及通过称为环状GMP-AMP合酶(cGAS,先前称为C6orfl50或MB21D1)的酶产生一种新型哺乳动物CDN信号分子(称为cGAMP),其随后激活STING。与细菌CDN不同,cGAMP是一种不对称分子,特征在于它是混合的2',5'和3',5'磷酸二酯键(Gao P et al, Cell, 2013: 153, 1-14)。cGAMP(II)与STING的相互作用也已经通过X射线晶体学证明(Cai X et al, Molecular Cell, 2014: 54, 289- 296)。
干扰素首先被描述为可以保护细胞免受病毒感染的物质 (Isaacs & Lindemann, J. Virus Interference. Proc. R. Soc. Lon. Ser. B. Biol. Sci. 1957: 147, 258- 267)。在人类中,I型干扰素是由染色体9上的基因编码并且编码干扰素α(IFNα)的至少13种同种型和干扰素β(IFNβ)的一种同种型的相关蛋白家族。重组IFNα是第一个批准的生物治疗剂,并且已成为病毒感染和癌症中的重要疗法。除了对细胞的直接抗病毒活性外,已知干扰素是作用于免疫系统细胞的免疫应答的高效调节剂。
施用可以刺激天然免疫应答(包括I型干扰素和其他细胞因子的活化)的小分子化合物可以成为治疗或预防包括病毒感染在内的人类疾病的重要策略。这种类型的免疫调节策略有可能识别出这样的化合物:其不仅可以用于感染性疾病而且用于癌症 (Krieg. Curr. Oncol. Rep., 2004: 6(2), 88-95), 过敏性疾病(Moisan J. et al, Am. J. Physiol. Lung Cell Mol. Physiol., 2006: 290, L987-995), 其他炎性病症如肠易激综合征(Rakoff-Nahoum S., Cell., 2004, 23, 118(2): 229-41), 以及作为疫苗佐剂(Persing et al. Trends Microbiol. 2002: 10(10 Suppl), S32-7)。
过敏性疾病与对过敏原的Th2优势免疫应答有关。Th2应答与升高的IgE水平相关,IgE通过其对肥大细胞的作用促进对过敏原的超敏反应,导致例如在过敏性鼻炎和哮喘中出现的症状。在健康人群中,对过敏原的免疫应答用混合的Th2/Th1和调节性T细胞应答更为平衡。1型干扰素的诱导已经显示会引起局部环境中Th2型细胞因子的减少并促进Th1/Treg应答。在这种情况下,通过例如STING的激活来诱导1型干扰素,可以在治疗过敏性疾病(如哮喘和过敏性鼻炎)方面提供益处(Huber J.P. et al J Immunol 2010: 185, 813- 817)。
本发明的某些化合物在与人PBMC一起孵育时已经显示出与STING结合并诱导1型干扰素和其它细胞因子。诱导人类干扰素的化合物可用于治疗各种疾病,例如治疗过敏性疾病和其它炎性病症,例如过敏性鼻炎和哮喘,治疗感染性疾病、癌前综合征和癌症,并且还可以用作疫苗佐剂。本发明的某些化合物可以结合STING,但作为拮抗剂,并且它们可用于治疗,例如自身免疫性疾病。
据预测,用激活或抑制剂靶向STING可能是治疗其中1型IFN途径的调节有益的疾病和病症的有希望的方法,包括炎症、过敏性和自身免疫疾病、感染性疾病、癌症、癌前综合征和作为疫苗佐剂。
本发明的一个目的是进一步提供适合用于癌症治疗的环状二核苷酸。
本发明的某些化合物可以是高效的免疫调节剂,因此在其处理中应该小心。
发明概述
在一个方面,提供了式(I)的化合物或其药学上可接受的盐:
其中,
R1为OH且R2为NH2或者R1为NH2且R2为H;
R3为OH且R4为NH2或者R3为NH2且R4为H;
R5和R6之一为F,另一个为F或OH。
在本发明的另一方面,提供了一种药物组合物,其包含式(I)的化合物或其药学上可接受的盐和一种或多种药学上可接受的赋形剂。
在本发明的另一方面,提供了用于治疗的式(I)的化合物或其药学上可接受的盐。
在本发明的另一方面,提供了用于治疗调节STING有益的疾病或病症的式(I)的化合物或其药学上可接受的盐。
在本发明的另一方面,提供了用于治疗炎症、过敏性和自身免疫性疾病、感染性疾病、癌症、癌前综合征以及作为疫苗佐剂的式(I)的化合物或其药学上可接受的盐。
在本发明的另一方面,提供了一种在个体中治疗其中调节STING有益的疾病或病症的方法,包括施用治疗有效量的式(I)化合物或其药学上可接受的盐。
在本发明的另一方面,提供了一种在个体中治疗炎症、过敏性和自身免疫性疾病、感染性疾病和癌症的方法,包括施用治疗有效量的式(I)化合物或其药学上可接受的盐。
在本发明的另一方面,提供了式(I)的化合物或其药学上可接受的盐在制备用于治疗调节STING有益的疾病或病症的药物中的用途。
在本发明的另一方面,提供了式(I)的化合物或其药学上可接受的盐在制备用于治疗炎症、过敏性和自身免疫性疾病、感染性疾病、癌前综合征和癌症的药物中的用途。
在本发明的另一方面,提供了一种组合产品,其包含式(I)的化合物或其药学上可接受的盐和至少一种另外的治疗剂。
在本发明的另一方面,提供了一种药物组合物,其包含式(I)的化合物或其药学上可接受的盐和至少一种另外的治疗剂,以及一种或多种药学上可接受的赋形剂。
在本发明的另一方面,提供了一种用于治疗的组合产品,其包含式(I)的化合物或其药学上可接受的盐和至少一种另外的治疗剂。
在本发明的另一方面,提供了用于治疗调节STING有益的疾病或病症的组合产品,其包含式(I)的化合物或其药学上可接受的盐和至少一种另外的治疗剂。
在本发明的另一方面,提供了用于治疗炎症、过敏性和自身免疫性疾病、感染性疾病、癌前综合征和癌症的组合产品,其包含式(I)的化合物或其药学上可接受的盐和至少一种另外的治疗剂。
在本发明的另一方面,提供了一种在个体中治疗其中调节STING有益的疾病或病症的方法,包括施用治疗有效量的包含式(I)的化合物或其药学上可接受的盐和至少一种另外的治疗剂的组合产品。
在本发明的另一方面,提供了一种在个体中治疗炎症、过敏性和自身免疫性疾病、感染性疾病和癌症的方法,包括施用治疗有效量的包含式(I)的化合物或其药学上可接受的盐和至少一种另外的治疗剂的组合产品。
在本发明的另一方面,还提供了一种疫苗佐剂,其包含式(I)的化合物或其药学上可接受的盐。
在本发明的另一方面,还提供了一种免疫原性组合物,其包含:抗原或抗原组合物,以及式(I)的化合物或其药学上可接受的盐。
在本发明的另一方面,还提供了一种用于治疗或预防疾病的免疫原性组合物,其包含:抗原或抗原组合物,以及式(I)的化合物或其药学上可接受的盐。
在本发明的另一方面,还提供了式(I)的化合物或其药学上可接受的盐在制备用于治疗或预防疾病的包含抗原或抗原组合物的免疫原性组合物的用途。
在本发明的另一方面,还提供了一种治疗或预防疾病的方法,其包括向患有或易患疾病的人类个体施用包含抗原或抗原组合物以及式(I)的化合物或其药学上可接受的盐的免疫原性组合物。
在本发明的另一方面,还提供了一种用于治疗或预防疾病的疫苗组合物,其包含:抗原或抗原组合物,以及式(I)的化合物或其药学上可接受的盐。
在本发明的另一方面,还提供了一种用于治疗或预防疾病的疫苗组合物,其包含:抗原或抗原组合物,以及式(I)的化合物或其药学上可接受的盐。
在本发明的另一方面,还提供了式(I)的化合物或其药学上可接受的盐在制备用于治疗或预防疾病的包含抗原或抗原组合物的疫苗组合物的用途。
在本发明的另一方面,还提供了一种治疗或预防疾病的方法,其包括向患有或易患疾病的人类个体施用包含抗原或抗原组合物以及式(I)的化合物或其药学上可接受的盐的疫苗组合物。
发明详述
本文所用的“本发明化合物”包括式(I)化合物及其盐的所有溶剂化物、络合物、多晶型物、放射性标记的衍生物、互变异构体、立体异构体和光学异构体。
本文所用的术语“有效量”是指将引起例如由研究人员或临床医生寻求的组织、系统、动物或人的生物或医学响应的药物或药剂的量。此外,术语“治疗有效量”是指与未接受该量的相应个体相比,导致对疾病、紊乱或副作用的改善的治疗、治愈、预防、或缓解,或降低疾病或紊乱的进展速度的任何量。该术语还包括在其范围内有效地增强正常生理功能的量。
术语“预防”包括防止,并且是指防止而不是治愈或治疗疾病的措施或程序。预防是指降低得病或发病的风险,使得在疾病发生之前在可能暴露于致病物的个体或者易患该病的个体中该病的至少一种临床症状的不发展。
本文所用的术语“药学上可接受的”是指在合理的医学判断范围内适合用于与人类和动物的组织接触而没有过度的毒性、刺激或其他问题或并发症,与合理的收益/风险比相称的那些化合物、材料、组合物和剂型。
本文所用的“药学上可接受的赋形剂”包括与本发明化合物一起施用的所有稀释剂、载体粘合剂、助流剂和药物制剂的其它组分。
本发明的化合物可以以固体或液体形式存在。在固体形式下,本发明的化合物可以以固态的连续体存在,从完全无定形到完全结晶。术语“无定形”是指材料在分子水平上缺少长程有序的状态,并且根据温度可以显示固体或液体的物理性质。通常,这些材料不能给出独特的X射线衍射图案,并且在显示固体的性质的同时,更正式地描述为液体。在加热时,发生从固体到液体性质的变化,其特征在于状态的改变,通常是二级(“玻璃化转变”)。术语“结晶”是指其中材料在分子水平上具有规则有序的内部结构,并给出具有确定峰的独特的X射线衍射图的固相。当充分加热时,这种材料也将表现出液体的性质,但是从固体到液体的变化的特征在于相变,通常是一级(“熔点”)。
本发明的化合物可以具有以多于一种形式结晶(被称为多晶型现象(“多晶型物”)的特性)的能力。多晶型现象通常可以作为对温度或压力变化或两者的变化的响应而发生,并且还可以由结晶过程的变化引起。多晶型物可以通过本领域已知的各种物理特性来区分,例如x射线衍射图、溶解度和熔点。
式(I)化合物可以以溶剂化和非溶剂化形式存在。本文所用的术语“溶剂合物”是指由溶质(在本发明中,式(I)化合物或其盐)和溶剂形成的可变化学计量的复合物。用于本发明目的的这些溶剂不会干扰溶质的生物活性。本领域技术人员将理解,药学上可接受的溶剂合物可以形成为结晶化合物,其中溶剂分子在结晶期间结合到晶格中。结合的溶剂分子可以是水分子或非水性的,例如乙醇、异丙醇、DMSO、乙酸、乙醇胺和乙酸乙酯分子。与水分子结合的结晶晶格通常称为“水合物”。水合物包括化学计量的水合物以及含有可变量的水的组合物。本发明包括所有这些溶剂合物。
还应注意,式(I)的化合物可以形成互变异构体。“互变异构体”是指为特定化合物结构的可互换形式,并且氢原子和电子的置换发生变化的化合物。因此,两个结构可以通过π电子和原子(通常为H)的运动而处于平衡状态。例如,烯醇和酮是互变异构体,因为它们通过用酸或碱处理而快速相互转化。应当理解,本发明化合物的所有互变异构体和互变异构体的混合物都包括在本发明化合物的范围内。例如和为了绝对清晰,在式(I)的化合物中,当R1或R3表示OH时,该化合物将形成酮互变异构体(=O)。
在一个方面,R5和R6均为F。
在一个方面,R5为F且R6为OH。
在一个方面,R5为OH且R6为F。
在一个方面,R1为OH,R2为NH2,R3为OH且R4为NH2(R1和R3处于酮互变异构体形式,=O)。
在一个方面,R1为OH,R2为NH2,R3为NH2且R4为H(R1处于酮互变异构体形式,=O)。
在一个方面,R1为NH2,R2为H,R3为OH且R4为NH2(R3处于酮互变异构体形式,=O)。
在一个方面,R1为NH2,R2为H,R3为NH2且R4为H。
虽然每个变量的各方面对于每个变量已经大体在上面单独列出,但是本发明包括其中式(I)中的几个或每个方面都选自上面列出的各个方面中的每一个的那些化合物。本发明意图包括每个变量的多个方面的所有组合,如下所示:
本发明化合物的实例包括以下化合物:
(1R,6R,8R,9R,10R,15R,17R,18R)-17-(2-氨基-6-氧代-6,9-二氢-1H-嘌呤-9-基)-8-(6-氨基-9H-嘌呤-9-基)-9-氟-3,12,18-三羟基-2,4,7,11,13,16-六氧杂-3λ5,12λ5-二磷杂三环[13.2.1.06,10]十八烷-3,12-二酮,特别是其盐,更特别是双铵盐;
(1R,6R,8R,9R,10R,15R,17R,18R)-8,17-双(6-氨基-9H-嘌呤-9-基)-9-氟-3,12,18-三羟基-2,4,7,11,13,16-六氧杂-3λ5,12λ5-二磷杂三环[13.2.1.06,10]十八烷-3,12-二酮,特别是其盐,更特别是双铵盐。
式(I)的化合物可以是盐的形式。
通常,本发明的盐是药学上可接受的盐。术语“药学上可接受的盐”包括的盐是指本发明化合物的无毒盐。关于合适的盐的综述,参见Berge et al, J. Pharm. Sci. 1977, 66, 1-19。
合适的药学上可接受的盐可包括酸加成盐。
药学上可接受的酸加成盐可以通过式(I)化合物与合适的无机或有机酸(如氢溴酸,盐酸,硫酸,硝酸,磷酸,对甲苯磺酸,苯磺酸,甲磺酸,乙磺酸,萘磺酸(例如2-萘磺酸)),任选地在合适的溶剂(如有机溶剂)中反应,得到所述盐,其通常通过例如结晶和过滤分离。式(I)化合物的药学上可接受的酸加成盐可包括或为,例如,氢溴酸盐,盐酸盐,硫酸盐,硝酸盐,磷酸盐,对甲苯磺酸盐,苯磺酸盐,甲磺酸盐,乙磺酸盐,萘磺酸盐(例如2-萘磺酸盐)。
其它非药学上可接受的盐(例如三氟乙酸盐)可用于,例如,分离本发明化合物,并且包括在本发明的范围内。
本发明在其范围内包括式(I)化合物的所有可能的化学计量和非化学计量的形式。
虽然为了用于治疗,可能可以将本发明的化合物以原料化学品的方式施用,但是可以将本发明化合物作为活性成分呈现为药物组合物的形式。这样的组合物可以以制药领域众所周知的方式制备并且包含至少一种活性化合物。因此,本发明还提供包含本发明化合物和一种或多种药学上可接受的赋形剂的药物组合物。所述赋形剂必须在与组合物的其它成分相容的意义上是可接受的,并且对其接受者无害。根据本发明的另一方面,还提供了一种制备药物组合物的方法,所述药物组合物包含所述药剂或其药学上可接受的盐,和一种或多种药学上可接受的赋形剂。所述药物组合物可用于治疗和/或预防本文所述的任何病症。
通常,本发明的化合物以药学有效量施用。实际施用的化合物的量通常由医师根据相关情况确定,包括待治疗的病症,所选择的施用途径,所施用的实际的化合物,个体患者的年龄、体重和响应,患者症状的严重程度等。
药物组合物可以以每单位剂量含有预定量的活性成分的单位剂量形式呈现。术语“单位剂量形式”是指适合作为人类个体和其他哺乳动物的单位剂量的物理上不连续的单位,每个单位都含有计算产生所需治疗效果的预定量的活性物质,以及合适的药物赋形剂,媒介物或载体。典型的单位剂型包括:液体组合物的预先填充的、预先测量的安瓿或注射器,或在固体组合物的情况下,药丸,片剂,胶囊等。
优选的单位剂量组合物是含有日剂量或亚剂量或其适当部分的活性成分的那些。因此,这样的单位剂量可以每天施用一次或多于一次。这样的药物组合物可以通过药学领域众所周知的任何方法制备。
药物组合物可适于通过任何适当途径施用,例如经口(包括口腔或舌下),直肠,吸入,鼻内,局部(包括口腔,舌下或透皮),阴道或肠胃外(包括皮下,肌内,静脉内或皮内)途径。这样的组合物可以通过药学领域已知的任何方法制备,例如通过使活性成分与载体或赋形剂结合。
除了上述施用途径之外,对于癌症的治疗,药物组合物可以适于通过肿瘤内或肿瘤周围注射施用。以这种方式激活免疫系统以杀死远端部位的肿瘤通常被称为远位作用,并且已经用多种治疗方式在动物中得到证实(van der Jeught, et al., Oncotarget, 2015, 6(3), 1359-1381)。局部或肿瘤内或肿瘤周围施用的另一个优点是能够以低得多的剂量实现相同的疗效,从而最小化或消除在高得多的全身剂量下可观察到的不良事件(Marabelle, A., et al., Clinical Cancer Research, 2014, 20(7), p1747-1756)。
适于口服施用的药物组合物可以作为离散单位呈现,例如胶囊或片剂;粉末或颗粒;在水性或非水性液体中的溶液或悬浮液;可食用泡沫(foams或 whips);或水包油液体乳剂或油包水液体乳剂。
例如,对于片剂或胶囊形式的口服施用,可以将活性药物组分与口服无毒的药学上可接受的惰性赋形剂如乙醇、甘油、水等组合。通过将化合物减小至合适的细小尺寸并与类似制备的药物赋形剂(如可食用的碳水化合物,例如淀粉或甘露糖醇)混合制备粉末。还可以存在调味剂,防腐剂,分散剂和着色剂。
通过如上所述制备粉末混合物并填充形成的明胶鞘制备胶囊。在填充操作之前,可以向粉末混合物中加入包括助流剂和润滑剂在内的赋形剂,例如胶体二氧化硅,滑石,硬脂酸镁,硬脂酸钙或固体聚乙二醇。还可以加入崩解剂或增溶剂如琼脂,碳酸钙或碳酸钠,以改善胶囊消化时药物的可利用性。
此外,当需要或必需时,也可以将包括合适的粘合剂、助流剂、润滑剂、甜味剂、调味剂、崩解剂和着色剂的赋形剂加入混合物中。合适的粘合剂包括淀粉,明胶,天然糖如葡萄糖或β-乳糖,玉米甜味剂,天然和合成树胶如阿拉伯胶、黄蓍胶或海藻酸钠,羧甲基纤维素,聚乙二醇,蜡等。用于这些剂型的润滑剂包括油酸钠,硬脂酸钠,硬脂酸镁,苯甲酸钠,乙酸钠,氯化钠等。崩解剂包括但不限于淀粉,甲基纤维素,琼脂,膨润土,黄原胶等。制备片剂,例如通过制备粉末混合物,造粒或压块,加入润滑剂和崩解剂并压制成片剂。制备粉末化合物,通过将适当粉碎的化合物与如上所述的稀释剂或碱,并任选地与粘合剂(如羧甲基纤维素、海藻酸盐、明胶或聚乙烯吡咯烷酮),溶剂阻滞剂(如石蜡),吸收加速剂(如季盐)和/或吸收剂(如膨润土、高岭土或磷酸二钙)混合。所述粉末混合物可以通过用粘合剂(如糖浆、淀粉糊、阿卡迪亚粘液(acadia mucilage)或纤维素或聚合物材料的溶液)润湿并强制通过筛网来造粒。作为造粒的替代方案,粉末混合物可以运行通过压片机,并将所得物不完美形成的碎块破碎成颗粒。可以通过加入硬脂酸、硬脂酸盐、滑石或矿物油来润滑颗粒以防止粘附到片剂成型模具上。然后将润滑的混合物压成片剂。本发明的化合物还可以与自由流动的惰性载体组合并直接压制成片剂,而不经过造粒或压块步骤。可以提供透明或不透明的保护包衣,其由虫胶的密封包衣、糖或聚合物材料的包衣和蜡的抛光包衣组成。可以将染料加入到这些包衣中以区分不同的单位剂量。
口服流体如溶液、悬浮液、糖浆和酏剂可以以剂量单位形式制备,以使给定的量含有预定量的化合物。可以通过将化合物溶解在适当调味的水溶液中制备糖浆,而通过使用无毒的醇类媒介物制备酏剂。可以通过将化合物分散在无毒的媒介物中来配制悬浮液。还可以加入增溶剂和乳化剂(如乙氧基化异硬脂醇类和聚氧乙烯山梨醇醚类),防腐剂,风味添加剂(如薄荷油或天然甜味剂或糖精或其它人造甜味剂)等。
在合适的情况下,口服施用的剂量单位组合物可以微胶囊化。还可以制备组合物以延长或维持释放,例如通过将颗粒材料涂覆或包埋在聚合物、蜡或类似物中。
本发明的化合物还可以以脂质体递送系统的形式施用,例如小单层囊泡,大单层囊泡和多层囊泡。脂质体可以由多种磷脂形成,例如胆固醇、硬脂胺或磷脂酰胆碱。
适于透皮施用的药物组合物可以作为离散贴片来呈现,其意图是与接受者的表皮保持长时间的密切接触。
适于局部施用的药物组合物可以配制成软膏、乳膏、悬浮液、洗剂、粉末、溶液、糊剂、凝胶剂、喷雾剂、气雾剂或油剂。
对于眼睛或其他外部组织(例如口腔和皮肤)的治疗,组合物优选以局部软膏或乳膏的形式施用。当配制成软膏时,活性成分可以与石蜡或水混溶性软膏基质一起使用。或者,活性成分可以用水包油乳膏基质或油包水基质配制成乳膏。
适于局部施用于眼睛的药物组合物包括滴眼剂,其中活性成分溶解或悬浮在合适的载体,特别是水性溶剂中。
适用于口腔局部施用的药物组合物包括锭剂、含片和漱口剂。
适于直肠施用的药物组合物可呈现为栓剂或灌肠剂。
用于鼻或吸入施用的剂型可以方便地配制成气雾剂、溶液、悬浮液滴、凝胶或干粉。
用于鼻内施用的组合物包括通过滴剂或通过加压泵施用到鼻子的水性组合物。为此目的,合适的组合物含有水作为稀释剂或载体。用于施用到肺或鼻的组合物可以含有一种或多种赋形剂,例如一种或多种悬浮剂,一种或多种防腐剂,一种或多种表面活性剂,一种或多种张力调节剂,一种或多种共溶剂,并且可以包括控制组合物的pH的组分,例如缓冲体系。此外,组合物可以含有其它赋形剂,例如抗氧化剂(例如偏亚硫酸氢钠)和掩味剂。组合物也可以通过雾化施用于呼吸道的鼻子或其它区域。
鼻内组合物可以允许式(I)的化合物或(a)其药学上可接受的盐被递送到鼻腔(靶组织)的所有区域,并且还可以允许式(I)的化合物或(a)其药学上可接受的盐与靶组织保持更长时间的接触。用于鼻内组合物的合适的给药方案是使患者在清洗鼻腔之后通过鼻子缓慢吸入。在吸入期间,组合物将被施用于一个鼻孔,而另一个被用手压住。然后对另一鼻孔重复该程序。通常,每鼻孔一次或两次喷雾将通过上述步骤每天施用一次、两次或三次,理想地每天一次。特别令人感兴趣的是适合每日一次施用的鼻内组合物。
如果包括的话,基于组合物的总重量,悬浮剂通常以0.1至5%(w/w),例如1.5%至2.4%(w/w)的量存在。药学上可接受的悬浮剂的实例包括但不限于Avicel®(微晶纤维素和羧甲基纤维素钠),羧甲基纤维素钠,维格姆(veegum),黄蓍胶,膨润土,甲基纤维素,黄原胶,卡波姆和聚乙二醇。
用于施用至肺或鼻子的组合物可含有一种或多种赋形剂,可以通过包含一种或多种防腐剂来保护其免受微生物或真菌的污染和生长。药学上可接受的抗微生物剂或防腐剂的实例包括,但不限于,季铵化合物(例如苯扎氯铵、苄索氯铵、西曲溴铵、氯化十六烷基吡啶鎓,劳拉氯铵和米吡氯铵),汞剂(例如硝酸苯汞,乙酸苯汞和硫柳汞),醇类试剂(例如氯丁醇,苯乙醇和苄醇),抗菌酯(例如对羟基苯甲酸的酯),螯合剂(如乙二胺四乙酸二钠(EDTA))和其他抗微生物剂(如氯己定、氯甲酚、山梨酸及其盐(如山梨酸钾)和多粘菌素)。药学上可接受的抗真菌剂或防腐剂的实例包括,但不限于,苯甲酸钠,山梨酸,丙酸钠,对羟基苯甲酸甲酯,对羟基苯甲酸乙酯,对羟基苯甲酸丙酯和对羟基苯甲酸丁酯。如果包括的话,基于组合物的总重量,防腐剂可以以0.001至1%(w/w),例如0.015%至0.5%(w/w)的量存在。
组合物(例如其中至少一种化合物处于悬浮液中)可以包括一种或多种表面活性剂,用于促进药物颗粒在组合物的水相中的溶解。例如,表面活性剂的使用量是在混合期间不会引起发泡的量。药学上可接受的表面活性剂的实例包括脂肪醇、酯和醚,例如聚氧乙烯(20)脱水山梨糖醇单油酸酯(聚山梨酯80),聚乙二醇醚和泊洛沙姆。表面活性剂可以以约0.01至10%(w/w),例如0.01至0.75%(w/w),例如约0.5%(w/w)的量存在,基于组合物的总重量。
可以包括一种或多种张力调节剂以实现与体液(例如鼻腔的流体)的渗透压,导致刺激性水平降低。药学上可接受的张力调节剂的实例包括,但不限于,氯化钠,葡萄糖,木糖醇,氯化钙,葡萄糖,甘油和山梨糖醇。如果存在的话,张力调节剂的含量可以为0.1至10%(w/w),例如4.5至5.5%(w/w),例如约5.0%(w/w),基于组合物的总重量。
本发明的组合物可以通过加入合适的缓冲剂来缓冲,所述缓冲剂例如柠檬酸钠、柠檬酸、氨丁三醇、磷酸盐(如磷酸二钠(例如十二水合物、七水合物、二水合物和无水形式)或磷酸钠)及它们的混合物。
如果存在的话,基于组合物的总重量,缓冲剂的含量可以为0.1至5%(w/w),例如1至3%(w/w)的量。
掩味剂的实例包括三氯蔗糖,蔗糖,糖精或其盐,果糖,葡萄糖,甘油,玉米糖浆,阿斯巴甜,安赛蜜,木糖醇,山梨糖醇,赤藓糖醇,甘草酸铵,索马甜(thaumatin),纽甜(neotame),甘露醇,薄荷醇,桉树油,樟脑,天然调味剂,人造调味剂及其组合。
可以包括一种或多种共溶剂以帮助药物化合物和/或其它赋形剂的溶解性。药学上可接受的共溶剂的实例包括,但不限于,丙二醇,二丙二醇,乙二醇,甘油,乙醇,聚乙二醇(例如PEG300或PEG400)和甲醇。在一个实施方案中,共溶剂是丙二醇。
如果存在的话,共溶剂的含量可以为0.05至30%(w/w),例如1至25%(w/w),例如1至10%(w/w),基于组合物的总重量。
用于吸入施用的组合物包括通过加压泵或吸入器施用于呼吸道的水的、有机或水的/有机混合物、干粉或结晶组合物,所述吸入器例如贮库干粉吸入器,单位剂量干粉吸入器,预计量多剂量干粉吸入器,鼻吸入器或加压气雾剂吸入器,雾化器或吹入器。合适的组合物含有水作为用于此目的的稀释剂或载体,并且可以提供常规赋形剂如缓冲剂,张力调节剂等。水性组合物也可以通过雾化施用于鼻子和呼吸道的其它区域。这样的组合物可以是使用合适的液化推进剂从加压包装(例如计量吸入器)输送的水溶液或悬浮液或气雾剂。
用于局部地施用于鼻部(例如用于治疗鼻炎)或肺部的组合物包括通过加压泵输送到鼻腔的加压气雾剂组合物和水性组合物。非加压的并适合局部施用于鼻腔的组合物是特别令人感兴趣的。为此目的,合适的组合物含有水作为稀释剂或载体。用于施用于肺或鼻的水性组合物可以提供有常规赋形剂,例如缓冲剂、张力调节剂等。也可以通过雾化将水性组合物施用于鼻子。
通常可以使用流体分配器将流体组合物递送到鼻腔。流体组合物可以是水性或非水性的,但通常是水性的。这种流体分配器可以具有分配喷嘴或分配孔口,在将用户施加的力施加到流体分配器的泵装置上时,通过该分配喷嘴或分配孔口分配计量剂量的流体组合物。这种流体分配器通常设置有多个计量剂量的流体组合物的贮库,所述剂量在序贯的泵驱动时是可分配的。分配喷嘴或孔口可以被构造为用于插入到使用者的鼻孔中以将流体组合物喷雾分散到鼻腔中。上述类型的流体分配器在国际专利申请公开号WO 2005/044354(Glaxo Group Limited)中描述和示出。分配器具有壳体,所述壳体容纳流体排出装置,该流体排出装置具有安装在用于容纳流体组合物的容器上的压缩泵。壳体具有至少一个可手指操作的侧杆,其可相对于壳体向内移动,以通过凸轮在壳体中向上移动容器,以使泵压缩并将计量剂量的组合物通过壳体的鼻喷嘴从泵杆泵出。在一个实施方案中,流体分配器是WO 2005/044354的图30-40中所示的一般类型。
含有式(I)化合物或其药学上可接受的盐的含水组合物也可以通过如国际专利申请公开号WO2007/138084(Glaxo Group Limited)中公开的,例如参考其图22-46公开的泵进行递送,或如英国专利申请号GB0723418.0(Glaxo Group Limited)中公开的,例如参考其图7-32公开的泵进行递送。泵可以由如GB0723418.0的图1-6中公开的驱动器驱动。
用于通过吸入局部递送至肺的干粉组合物可以例如存在于例如明胶的胶囊和药筒中,或例如层压铝箔的泡罩中,以用于吸入器或吹入器。粉末共混组合物通常含有用于吸入式(I)化合物或其药学上可接受的盐的粉末混合物和合适的粉末基质(载体/稀释剂/赋形剂物质),例如单糖、二糖或多糖(例如乳糖或淀粉)。除了药物和载体外,干粉组合物还可以包括其它赋形剂(例如三元合剂,例如糖酯,例如纤维二糖八乙酸酯,硬脂酸钙或硬脂酸镁)。
在一个实施方案中,可以将适合于吸入施用的组合物加入到在安装在合适的吸入装置内的药物包装上设置的多个密封剂量容器中。如本领域已知的,所述容器可以是一次一个地可破裂的、可剥离的或以其他方式可打开的,并且干粉组合物的剂量在吸入装置的口上通过吸入施用。药物包装可以采取许多不同的形式,例如盘形或细长条。代表性的吸入装置是由GlaxoSmithKline销售的DISKHALER™和DISKUST™装置。
干粉可吸入组合物也可以作为吸入装置中的大容量贮库(bulk reservoir)提供,然后该装置设置有计量装置,用于计量从贮库到吸入通道的组合物的剂量,其中计量的剂量能够通过患者在装置口的吸气而被吸入。这种类型的示例性市售装置是TURBUHALER™(AstraZeneca)、TWISTHALER™(Schering)和CLICKHALER™ (Innovata)。
用于干粉可吸入组合物的另一种递送方法是用于使计量剂量的组合物以胶囊(每个胶囊一个剂量)提供,然后将其装载到吸入装置中,通常由患者按需要装载。该装置具有破裂、刺穿或以其它方式打开胶囊的装置,使得当患者在装置口处吸气时剂量能够被带入患者的肺中。作为这种装置的市售实例,可以提及ROTAHALER™ (GlaxoSmithKline)和HANDIHALER™(Boehringer Ingelheim)。
适于吸入的加压气雾剂组合物可以是悬浮液或溶液,并且可以含有式(I)化合物或其药学上可接受的盐和合适的推进剂,例如碳氟化合物或含氢氯氟烃或其混合物,特别是氢氟烷烃,特别是1,1,1,2-四氟乙烷、1,1,1,2,3,3,3-七氟-正丙烷或其混合物。气雾剂组合物可任选含有本领域熟知的其它组合物赋形剂,如表面活性剂例如油酸,卵磷脂或寡聚乳酸或其衍生物,例如如WO 94/21229和WO 98/34596(Minnesota mining andManufacturing Company)中所述,和共溶剂例如乙醇。加压组合物通常保留在用阀(例如计量阀)封闭的罐(例如铝罐)中并装配到设置有口的驱动器中。
适于阴道施用的药物组合物可以作为阴道栓剂、棉塞、乳膏、凝胶、糊剂、泡沫或喷雾制剂呈现。
适于肠胃外给予的药物组合物包括含水和非含水无菌注射液,其可含有抗氧化剂、缓冲剂、抑菌剂和溶质,其使组合物与预期接受者的血液等渗;以及含水和非含水无菌悬浮液,其可以包括悬浮剂和增稠剂。组合物可以存在于单位剂量或多剂量容器中,例如密封的安瓿瓶和小瓶中,并且可以储存在冷冻干燥(冻干)条件下,仅需要在临使用前加入无菌液体载体,例如注射用水。临时注射液和悬浮液可以由无菌粉末、颗粒和片剂制备。
应当理解,除了上述特别提及的成分之外,考虑到所讨论的制剂类型,组合物可以包括本领域常规的其它试剂,例如适合于口服施用的那些可以包括调味剂。
可将反义或RNA干扰分子施用于有需要的哺乳动物。或者,可以施用包含其的构建体。这样的分子和构建体可用于干扰有兴趣的蛋白质的表达,例如组蛋白去甲基化酶的表达,并且因此改变组蛋白去甲基化。通常,通过本领域已知的方式递送。
反义或RNA干扰分子可以在体外递送至细胞或在体内递送至,例如哺乳动物的肿瘤。可以无限制地使用递送节点,包括:静脉内,肌内,腹膜内,动脉内,手术期间的局部递送,腔内,皮下和口服。可以选择载体用于任何特定应用的所需性质。载体可以是病毒或质粒。腺病毒载体在这方面是有用的。组织特异性、细胞类型特异性或其它可调节启动子可用于控制抑制性多核苷酸分子的转录。也可以使用非病毒载体如脂质体或纳米球。
式(I)化合物及其药学上可接受的盐也可以作为佐剂与疫苗一起配制以调节其活性。这样的组合物可以包含抗体或抗体片段或抗原成分,包括,但不限于,蛋白质、DNA、活或死的细菌和/或病毒或病毒样颗粒,以及一种或多种具有佐剂活性的组分,包括,但不限于,铝盐、油和水乳液、热休克蛋白、脂质A制剂和衍生物、糖脂、其他TLR激动剂如CpG DNA或类似药剂、细胞因子如GM-CSF或IL-12或类似药剂。
药物的治疗有效量将取决于许多因素,包括例如个体的年龄和体重,要求治疗的精确病症及其严重程度,制剂的性质和施用途径,并且将会最终由主治医师或兽医自主决定。特别地,待治疗的个体是哺乳动物,特别是人。
该药剂可以以日剂量施用。该量可以以每天单次剂量或更通常以每天多次(例如两次、三次、四次、五次或六次)亚剂量施用,使得总日剂量相同。
适当地,根据本发明施用的本发明化合物的量将为选自每天0.01mg至1g(以游离或未成盐化合物计算)的量。
式(I)的化合物及其药学上可接受的盐可以单独使用或与其它治疗剂组合使用。式(I)化合物及其药学上可接受的盐和其它药物活性剂可以一起或分开施用,并且当分别施用时,可以在单独或组合的药物组合物中通过任何方便的途径同时或以任何顺序序贯进行施用。
选择式(I)化合物或其药学上可接受的盐和其它药学活性剂的量和相对施用时间以实现期望的组合治疗效果。本发明的化合物和其它治疗剂可以通过以包含两种化合物的单一药物组合物的形式同时施用来组合使用。或者,所述组合产品可以以序贯方式以单独的药物组合物分开施用,每种药物组合物包含一种化合物,其中例如首先施用本发明的化合物,其次施用另一种化合物,反之亦然。这种序贯施用可以在时间上接近(例如同时)或在时间上遥远。此外,化合物是否以相同的剂型施用并不重要,例如,一种化合物可以局部施用,另一种化合物可以口服施用。合适地,两种化合物都口服施用。
组合产品可以作为组合试剂盒提供。本文使用的术语“组合试剂盒”或“试剂盒”是指用于施用根据本发明的组合产品的一种或多种药物组合物。当两种化合物同时施用时,组合试剂盒可以在单一药物组合物中(例如片剂)或分开的药物组合物中含有两种化合物。当化合物不同时施用时,组合试剂盒将在分开的药物组合物中以单独的包装或单独的包装中的分开的药物组合物中含有每种化合物。
组合试剂盒也可以通过说明,如剂量和施用说明提供。这样的剂量和施用说明可以是例如通过药物产品标签提供给医生的那种类型,或者它们可以是由医生提供的那种类型,例如给患者的说明。
当以序贯方式分别施用组合产品时,其中首先施用一种,其次施用另一种,反之亦然,这种序贯施用可以在时间上接近或时间上遥远。例如,包括在施用第一药剂之后数分钟至几十分钟施用另一种药剂,和在施用第一药剂后数小时至数天施用另一种药剂,其中时间的间隔没有限制,例如,一种药剂可以每天施用一次,而另一种药剂可以每天施用2或3次,或者一种药剂可以每周施用一次,而另一种药剂可以每天施用一次等。
本领域技术人员将清楚,在适当的情况下,其它治疗成分可以以下列形式使用:盐,例如作为碱金属或胺盐或作为酸加成盐,或前药,或作为酯,例如低级烷基酯,或作为溶剂合物,例如水合物,以最优化治疗成分的活性和/或稳定性和/或物理特性,例如溶解度。还将清楚的是,在适当的情况下,治疗成分可以以光学纯的形式使用。
当组合产品在相同的组合物中时,应当理解,两种化合物必须是稳定的,并且彼此之间和与组合物的其它组分之间相容,并且可以配制用于给药。当单独配制时,它们可以以任何方便的组合物提供,方便地,以本领域中对这种化合物已知的方式。
当式(I)化合物与对相同疾病、病症或紊乱有活性的第二治疗剂组合使用时,每种化合物的剂量可以不同于单独使用该化合物时的剂量。本领域技术人员将容易理解适当的剂量。
在一个实施方案中,本发明的方法和用途中的哺乳动物是人。
本发明的化合物可用于治疗其中STING的调节有益的疾病和病症。这包括炎症、过敏性和自身免疫性疾病、感染性疾病、癌症和癌前综合征。
作为免疫应答的调节剂,式(I)化合物及其药学上可接受的盐也可独立或作为佐剂组合用于其中STING的调节有益的疾病和病症的治疗中。
在一个方面,所述疾病或病症是炎症、过敏和自身免疫紊乱。
相关的自身免疫性疾病包括但不限于系统性红斑狼疮、牛皮癣、胰岛素依赖性糖尿病(IDDM)、皮肌炎和干燥综合征(SS)。
炎症代表一组对创伤的血管、细胞和神经响应。炎症可以表征为炎症细胞如单核细胞、嗜中性粒细胞和粒细胞移动进入组织。这通常与减少的内皮屏障功能和水肿进入组织有关。炎症可分为急性或慢性。急性炎症是身体对有害刺激的初始应答,并且是通过血浆和白细胞从血液向损伤组织的移动增加而实现的。一系列生化事件传播并使炎症应答成熟,涉及损伤组织内的局部血管系统、免疫系统和各种细胞。称为慢性炎症的长期炎症导致存在于炎症部位的细胞类型的进行性变化,并且其特征在于来自炎性过程的组织的同时破坏和愈合。
当作为对感染的免疫应答的一部分或作为对创伤的急性响应发生时,炎症可能是有益的并且通常是自限制性的。然而,炎症在多种条件下可能是有害的。这包括响应感染剂而产生过度炎症,这可导致显著的器官损伤和死亡(例如,在败血症的环境中)。此外,慢性炎症通常是有害的,并且是许多慢性疾病的根源,其对组织造成严重和不可逆的损伤。在这种情况下,免疫应答通常针对自身组织(自身免疫),尽管对外来实体的慢性应答也可能导致对自身组织的旁观者损伤(bystander damage)。
因此,抗炎治疗的目的是减少这种炎症,以当存在时抑制自身免疫,并允许生理过程或愈合和组织修复进展。
所述药剂可用于治疗身体的任何组织和器官的炎症,包括肌肉骨骼炎症、血管炎症、神经炎症、消化系统炎症、眼部炎症、生殖系统炎症和其它炎症,如下所例示。
肌肉骨骼炎症是指肌肉骨骼系统的任何炎性病症,特别是影响骨骼关节,包括手、腕、肘、肩、颚、脊柱、颈、髋部、膝盖、踝和脚的关节的那些病症,以及影响连接肌肉到骨骼的组织例如腱的病症。可以用本发明化合物治疗的肌肉骨骼炎症的实例包括关节炎(包括,例如,骨关节炎、类风湿性关节炎、牛皮癣性关节炎、强直性脊柱炎、急性和慢性感染性关节炎、与痛风和假性痛风有关的关节炎和幼年特发性关节炎)、腱炎、滑膜炎、腱鞘炎、滑囊炎、纤维组织炎(纤维肌痛)、上髁炎、肌炎和骨炎(包括,例如,佩吉特氏病、耻骨炎和囊性纤维性骨炎)。
眼部炎症是指眼睛任何结构(包括眼睑)的炎症。可以用本发明化合物治疗的眼部炎症的实例包括睑炎、睑皮松垂症、结膜炎、泪腺炎、角膜炎、干性角结膜炎(干眼病)、巩膜炎、倒睫症和葡萄膜炎。
可以用本发明化合物治疗的神经系统的炎症的实例包括脑炎、吉兰巴雷综合征、脑膜炎、神经性肌强直、发作性睡眠、多发性硬化、脊髓炎和精神分裂症。
可以用本发明化合物治疗的脉管系统或淋巴系统的炎症的实例包括关节硬化、关节炎、静脉炎、血管炎和淋巴管炎。
可以用本发明化合物治疗的消化系统的炎性病症的实例包括胆管炎、胆囊炎、肠炎、小肠结肠炎、胃炎、胃肠炎、炎性肠病(例如克罗恩病和溃疡性结肠炎)、回肠炎和直肠炎。
可用本发明化合物治疗的生殖系统的炎性病症的实例包括子宫颈炎、绒毛膜羊膜炎、子宫内膜炎、附睾炎、脐炎、卵巢炎、睾丸炎、输卵管炎、输卵管卵巢脓肿、尿道炎、阴道炎、外阴炎和外阴痛。
所述药剂可用于治疗具有炎性成分的自身免疫病症。这种病症包括普遍性急性播散性脱发、Behcet氏病(Behcet’s disease)、查加斯病(Chagas’ disease)、慢性疲劳综合征、家族性自主神经异常、脑脊髓炎、强直性脊柱炎、再生障碍性贫血、化脓性汗腺炎、自身免疫性肝炎、自身免疫性卵巢炎、乳糜泻、克罗恩病、1型糖尿病、巨细胞动脉炎、古德帕斯彻综合征、格雷夫斯病、吉兰巴雷综合征、桥本氏病、过敏性紫癜、川崎病、红斑狼疮、显微镜下结肠炎、显微镜下多动脉炎、混合性结缔组织病、多发性硬化、重症肌无力、肌阵挛综合征、视神经炎、ord’s甲状腺炎、天疱疮、结节性多动脉炎、多肌痛、类风湿性关节炎、莱特尔氏综合征、干燥综合征、颞动脉炎、韦格纳肉芽肿病、温抗体型自身免疫性溶血性贫血、间质性膀胱炎、莱姆病、硬斑病、牛皮癣、结节病、硬皮病、溃疡性结肠炎和白癜风。
所述药剂可用于治疗具有炎性组分的T细胞介导的超敏性疾病。这些病症包括接触性超敏反应、接触性皮炎(包括由毒葛所致的)、荨麻疹、皮肤过敏、呼吸道过敏(枯草热、过敏性鼻炎)和谷蛋白敏感性肠病(乳糜泻)。
可用所述药剂治疗的其它炎性病症包括例如阑尾炎、皮炎、皮肌炎、心内膜炎、纤维组织炎、牙龈炎、舌炎、肝炎、化脓性汗腺炎、虹膜炎、喉炎、乳腺炎、心肌炎、肾炎、耳炎、胰腺炎、腮腺炎、心外膜炎、腹膜炎、咽炎、胸膜炎、肺炎、前列腺炎、肾盂肾炎和口腔炎、移植排斥(涉及器官如肾、肝、心、肺、胰腺(例如,胰岛细胞)、骨髓、角膜、小肠、皮肤同种异体移植物、皮肤同种移植物和心脏瓣膜异种移植物、血清病和移植物抗宿主病)、急性胰腺炎、慢性胰腺炎、急性呼吸窘迫综合征、Sexary's综合征、先天性肾上腺增生、非化脓性甲状腺炎、与癌症相关的高钙血症、天疱疮、大疱疱疹性皮炎、重症多形性红斑、剥脱性皮炎、脂溢性皮炎、季节性或常年性过敏性鼻炎、支气管哮喘、接触性皮炎、异位性皮炎、药物超敏反应、过敏性结膜炎、角膜炎、眼带状疱疹、虹膜炎和虹膜睫状体炎(oiridocyclitis)、脉络膜视网膜炎、视神经炎、症状性结节病、爆发性或播撒性肺结核化疗、成人的特发性血小板减少性紫癜、成人的继发性血小板减少症、成人的获得性(自身免疫性)溶血性贫血、成人白血病和淋巴瘤、儿童急性白血病、局限性肠炎、自身免疫性血管炎、多发性硬化、慢性阻塞性肺病、实体器官移植排斥、败血症。优选的治疗包括移植排斥、类风湿性关节炎、牛皮癣性关节炎、多发性硬化、1型糖尿病、哮喘、炎性肠病、系统性红斑狼疮、牛皮癣、慢性肺部疾病和炎症伴感染病症(例如败血症)的治疗。
在本发明的另一方面,提供了式(I)化合物或其药学上可接受的盐,其用于治疗炎症、过敏性和自身免疫性疾病。
在另一方面,提供了治疗炎症、过敏性和自身免疫性疾病的方法,包括向需要该治疗的人施用治疗有效量的式(I)化合物或其药学上可接受的盐。
在另一方面,提供了式(I)化合物或其药学上可接受的盐在制备用于治疗炎症、过敏性和自身免疫性疾病的药物中的用途。
在一个方面,待治疗的疾病是哮喘。
式(I)化合物及其药学上可接受的盐可以与一种或多种可用于预防或治疗过敏性疾病、炎性疾病、自身免疫性疾病的其它药剂组合使用,例如:抗原免疫疗法、抗组胺剂、类固醇、NSAID、支气管扩张剂(例如β2激动剂、肾上腺素激动剂、抗胆碱能剂、茶碱)、甲氨蝶呤、白细胞三烯调节剂和类似药剂;单克隆抗体疗法例如抗IgE、抗TNF、抗IL-5、抗IL-6、抗IL-12、抗IL-1和类似药剂;受体疗法例如依那西普和类似药剂;抗原非特异性免疫疗法(例如干扰素或其它细胞因子/趋化因子、细胞因子/趋化因子受体调节剂、细胞因子激动剂或拮抗剂、TLR激动剂和类似药剂)。
在另一方面,提供了包含式(I)化合物或其药学上可接受的盐和至少一种可用于治疗过敏性疾病、炎症或自身免疫性疾病的其它治疗剂的组合产品。
在另一方面,提供了包含式(I)化合物或其药学上可接受的盐和至少一种可用于治疗过敏性疾病、炎症或自身免疫性疾病的其它治疗剂的组合产品,其用于治疗。
在另一方面,提供了包含式(I)化合物或其药学上可接受的盐和至少一种可用于治疗过敏性疾病、炎症或自身免疫性疾病的其它治疗剂的组合产品,其用于治疗过敏性疾病、炎症或自身免疫性疾病。
在另一方面,提供了包含式(I)化合物或其药学上可接受的盐和至少一种可用于治疗过敏性疾病、炎症或自身免疫性疾病的其它治疗剂的组合产品在制备用于治疗过敏性疾病、炎症或自身免疫性疾病的药物中的用途。
在另一方面,提供了治疗过敏性疾病、炎症或自身免疫性疾病的方法,包括向需要该治疗的人施用治疗有效量的包含式(I)化合物或其药学上可接受的盐和至少一种可用于治疗过敏性疾病、炎症或自身免疫性疾病的其它治疗剂的组合产品。
在另一方面,提供了药物组合物,其包括包含式(I)化合物或其药学上可接受的盐和至少一种可用于治疗过敏性疾病、炎症或自身免疫性疾病的其它治疗剂的组合产品和一种或多种的药学上可接受的赋形剂。
在一个方面,待用这种组合治疗的疾病是哮喘。
在一个方面,待治疗的疾病或病症是癌症。
其中式(I)化合物或其药学上可接受的盐或溶剂合物可具有潜在有益的抗肿瘤作用的癌症疾病和病症的实例包括但不限于肺、骨、胰腺、皮肤、头、颈、子宫、卵巢、胃、结肠、乳腺、食道、小肠、肠、内分泌系统、甲状腺、甲状旁腺、肾上腺、尿道、前列腺、阴茎、睾丸、输尿管、膀胱、肾或肝的癌症;直肠癌;肛门区癌;输卵管、子宫内膜、宫颈、阴道、外阴、肾盂、肾细胞的癌;软组织肉瘤;粘液瘤;横纹肌瘤;纤维瘤;脂肪瘤;畸胎瘤;胆管癌;肝母细胞瘤;血管肉瘤;血管瘤;肝癌;纤维肉瘤;软骨肉瘤;骨髓瘤;慢性或急性白血病;淋巴细胞性淋巴瘤;原发性CNS淋巴瘤;CNS的肿瘤;脊椎(spinal axis)肿瘤;鳞状细胞癌;滑膜肉瘤;恶性胸膜间皮瘤;脑干胶质瘤;垂体腺瘤;支气管腺瘤;软骨瘤样错构瘤;间皮瘤;霍奇金病或一种或多种前述癌症的组合。
适合地,本发明涉及治疗或减轻选自下列癌症的严重程度的方法:脑癌(胶质瘤),成胶质细胞瘤,星形细胞瘤,多形性成胶质细胞瘤,Bannayan-Zonana综合征,Cowden病,Lhermitte-Duclos病,Wilm's 肿瘤,尤因氏肉瘤,横纹肌肉瘤,室管膜瘤,成神经管细胞瘤,头颈癌,肾癌,肝癌,黑素瘤,卵巢癌,胰腺癌,腺癌,导管腺癌,腺鳞癌,腺泡细胞癌,胰高血糖素瘤,胰岛素瘤,前列腺癌,肉瘤,骨肉瘤,骨巨细胞瘤,甲状腺癌,淋巴细胞性T细胞白血病,慢性粒细胞性白血病,慢性淋巴细胞性白血病,毛细胞白血病,急性淋巴细胞性白血病,急性骨髓性白血病,慢性嗜中性白血病,急性淋巴细胞性T细胞白血病,浆细胞瘤,免疫母细胞性大细胞白血病,外套细胞白血病,多发性骨髓瘤,巨核细胞白血病,多发性骨髓瘤,急性巨核细胞白血病,早幼粒细胞白血病,红白血病,恶性淋巴瘤,霍奇金淋巴瘤,非霍奇金淋巴瘤,淋巴细胞性T细胞淋巴瘤,伯基特淋巴瘤,滤泡淋巴瘤,神经母细胞瘤,膀胱癌,尿路上皮癌,外阴癌,子宫颈癌,子宫内膜癌,肾癌,间皮瘤,食管癌癌症,唾液腺癌,肝细胞癌,胃癌,鼻咽癌,颊癌,口腔癌,GIST(胃肠道间质瘤)和睾丸癌。
适合地,本发明涉及治疗或减轻包括人在内的哺乳动物的癌前综合征的严重程度的方法,其中所述癌前综合征选自:宫颈上皮内瘤变,未知意义的单克隆丙种球蛋白病(MGUS),骨髓增生异常综合征,再生障碍性贫血,宫颈病变,皮肤痣(前黑素瘤),前列腺上皮内(导管内)瘤形成。
本发明化合物还可用于治疗一种或多种困扰哺乳动物的疾病,所述疾病的特征在于与新血管形成和/或血管通透性相关的病状领域中的细胞增殖,包括:血管增殖性紊乱,包括关节炎(类风湿性关节炎)和再狭窄;纤维化紊乱,包括肝硬化和动脉粥样硬化;系膜细胞增殖性紊乱,包括肾小球肾炎、糖尿病性肾病、恶性肾硬化、血栓性微血管病综合征、增殖性视网膜病、器官移植排斥和肾小球病;和代谢紊乱,包括牛皮癣、糖尿病、慢性伤口愈合、炎症和神经变性疾病。
在本发明的另一方面,提供了式(I)化合物或其药学上可接受的盐,其用于治疗和/或癌前综合征。
在另一方面,提供了治疗癌症的方法,包括向需要该治疗的人施用治疗有效量的式(I)化合物或其药学上可接受的盐。
在另一方面,提供了式(I)化合物或其药学上可接受的盐在制备用于治疗和/或癌前综合征的药物中的用途。
在一个实施方案中,本发明化合物可以与癌症治疗的其它治疗方法一起使用。特别地,在抗肿瘤治疗中,设想与其它化疗剂、激素、抗体剂以及除了上述那些之外的外科手术和/或放射治疗的组合疗法。
在一个实施方案中,所述其它抗癌疗法是外科手术和/或放射疗法。
在一个实施方案中,所述其它抗癌疗法是至少一种另外的抗肿瘤剂。
在本发明的另一方面,提供了一种组合产品,其包含式(I)的化合物或其药学上可接受的盐和至少一种抗肿瘤剂。
在本发明的另一方面,提供了一种组合产品,其包含式(I)的化合物或其药学上可接受的盐和至少一种抗肿瘤剂,用于治疗。
在本发明的另一方面,提供了一种组合产品,其包含式(I)的化合物或其药学上可接受的盐和至少一种抗肿瘤剂,用于治疗和/或癌前综合征。
在另一方面,提供了一种组合产品在制备用于治疗和/或癌前综合征的药物中的用途,所述组合产品包含式(I)的化合物或其药学上可接受的盐和至少一种抗肿瘤剂。
在另一方面,提供了治疗癌症的方法,包括向需要该治疗的人施用治疗有效量的一种组合产品,所述组合产品包含式(I)的化合物或其药学上可接受的盐和至少一种抗肿瘤剂。
在另一方面,提供了药物组合物,其包括:包含式(I)化合物或其药学上可接受的盐和至少一种其它治疗剂,特别是至少一种抗肿瘤剂的组合产品;和一种或多种药学上可接受的载体、稀释剂和赋形剂。
任何对于要治疗的易感肿瘤具有活性的抗肿瘤剂都可以用于组合产品中。可用的典型抗肿瘤剂包括,但不限于,抗微管剂,例如二萜类化合物和长春花生物碱;铂配位络合物;烷化剂,例如氮芥、氧氮磷杂环己烯(oxazaphosphorines)、烷基磺酸酯、亚硝基脲和三氮烯类;抗生素,例如蒽环类、放线菌素和博来霉素;拓扑异构酶II抑制剂,例如表鬼臼毒素;抗代谢物,例如嘌呤和嘧啶类似物和抗叶酸化合物;拓扑异构酶I抑制剂,例如喜树碱;激素和激素类似物;信号转导通路抑制剂;非受体酪氨酸血管生成抑制剂;免疫治疗剂;促凋亡剂;和细胞周期信号转导抑制剂,免疫肿瘤学试剂和免疫刺激剂。
抗微管或抗有丝分裂剂:
抗微管或抗有丝分裂剂是在细胞周期的M期或有丝分裂期对肿瘤细胞的微管具有活性的时相特异性药物。抗微管剂的实例包括,但不限于,二萜类化合物和长春花生物碱。
源自天然来源的二萜类化合物是在细胞周期的G2/M期起作用的时相特异性抗癌剂。据信二萜类化合物通过与该蛋白质结合来稳定微管的β-微管蛋白亚单位。然后蛋白质的分解似乎受到抑制,同时阻止有丝分裂,随后细胞死亡。二萜类化合物的实例包括,但不限于,紫杉醇及其类似物多西他赛。
紫杉醇,5β,20-环氧-1,2α,4,7β,10β,13α-六羟基紫杉烷-11-烯-9-酮 4,10-二乙酸酯2-苯甲酸酯13-[(2R,3S)-N-苯甲酰基-3-苯基异丝氨酸酯],是从太平洋紫衫树短叶红豆杉(Taxus brevifolia)中分离的天然二萜产物,并且可作为注射液TAXOL®商购得到。它是萜烯的紫杉烷家族的成员。紫杉醇已被批准临床用于治疗难治性卵巢癌(在美国)(Markman et al., Yale Journal of Biology and Medicine, 64:583, 1991; McGuireet al., Ann. lntem, Med., 111:273,1989)和用于治疗乳腺癌(Holmes et al., J.Nat. Cancer Inst., 83:1797,1991)。其是治疗皮肤肿瘤(Einzig et. al., Proc. Am.Soc. Clin. Oncol., 20:46)和头颈癌(Forastire et. al., Sem. Oncol., 20:56,1990)的潜在候选物。该化合物还显示了治疗多囊性肾病(Woo et. al., Nature, 368:750. 1994)、肺癌和疟疾的潜力。用紫杉醇治疗患者导致骨髓抑制(multiple celllineages, Ignoff, R.J. et. al, Cancer Chemotherapy Pocket Guide, 1998),涉及高于阈浓度(50nM)的药量持续时间(Kearns, C.M. et. al., Seminars in Oncology, 3(6)p.16-23, 1995)。
多西他赛,(2R,3S)-N-羧基-3-苯基异丝氨酸,N-叔丁基酯,13-[5β-20-环氧-1,2α,4,7β,10β,13α-六羟基紫杉烷-11-烯-9-酮4-乙酸酯2-苯甲酸酯],三水合物;可作为注射液以TAXOTERE®商购得到。多西他赛被指示用于治疗乳腺癌。多西他赛是使用从欧洲紫杉树的针叶提取的天然前体10-去乙酰基-浆果赤霉素III制备的紫杉醇q.v.的半合成衍生物。
长春花生物碱是源自长春花植物的时相特异性抗肿瘤剂。长春花生物碱通过与微管蛋白特异性结合而作用于细胞周期的M期(有丝分裂)。因此,结合的微管蛋白分子不能聚合成微管。有丝分裂被认为在中期停止,随后细胞死亡。长春花生物碱的实例包括但不限于长春碱、长春新碱和长春瑞滨。
长春碱,长春花碱硫酸盐,可作为注射液以VELBAN®商购得到。尽管其可能指示作为各种实体瘤的二线治疗,但其主要指示用于治疗睾丸癌和各种淋巴瘤,包括霍奇金病;以及淋巴细胞性和组织细胞性淋巴瘤。骨髓抑制是长春碱的剂量限制性副作用。
长春新碱,22-氧代-长春花碱硫酸盐,可以作为注射液以ONCOVIN®商购得到。长春新碱被指示用于治疗急性白血病,并且还发现可用于霍奇金和非霍奇金恶性淋巴瘤的治疗方案。脱发和神经学效应是长春新碱的最常见的副作用,并且在较小程度上发生骨髓抑制和胃肠道粘膜炎效应。
长春瑞滨,3’,4’-二去氢-4’-去氧-C’-去甲长春碱[R-(R*,R*)-2,3-二羟基丁二酸(1:2)(盐)],可作为酒石酸长春瑞滨注射液(NAVELBINE®)商购得到,其是一种半合成长春花生物碱。长春瑞滨被指示作为单一药剂或与其它化疗剂如顺铂组合用于治疗各种实体瘤,特别是非小细胞肺癌、晚期乳腺癌和激素难治性前列腺癌。骨髓抑制是长春瑞滨的最常见的剂量限制性副作用。
铂配位络合物:
铂配位络合物是非时相特异性抗癌剂,其与DNA相互作用。铂络合物进入肿瘤细胞,经历水合作用并与DNA形成链内和链间交联,导致对肿瘤不利的生物效应。铂配位络合物的实例包括但不限于奥沙利铂、顺铂和卡铂。
顺铂,顺式-二氨二氯铂,可作为注射液以PLATINOL®商购得到。顺铂被主要指示用于治疗转移性睾丸癌和卵巢癌以及晚期膀胱癌。
卡铂,二氨[1,1-环丁烷-二羧酸根(2-)-O,O’]合铂,可以作为注射液以PARAPLATIN®商购得到。卡铂被主要指示用于晚期卵巢癌的一线和二线治疗。
烷化剂:
烷化剂是非时相特异性抗癌剂和强亲电子药剂。通常,烷化剂通过烷基化经DNA分子的亲核部分如磷酸基(phosphate)、氨基、巯基、羟基、羧基和咪唑基与DNA形成共价键。这种烷基化破坏了核酸功能,导致细胞死亡。烷化剂的实例包括但不限于氮芥,例如环磷酰胺,美法仑和苯丁酸氮芥;烷基磺酸酯,例如白消安;亚硝基脲,例如卡莫司汀;和三氮烯类,例如达卡巴嗪。
环磷酰胺,2-[双(2-氯乙基)氨基]四氢-2H-1,3,2-氧氮磷杂环己烯2-氧化物一水合物,可作为注射液或片剂以CYTOXAN®商购得到。环磷酰胺被指示为单一药剂或与其它化疗剂组合用于治疗恶性淋巴瘤、多发性骨髓瘤和白血病。
美法仑,4-[双(2-氯乙基)氨基]-L-苯丙氨酸,可作为注射液或片剂以ALKERAN®商购得到。美法仑被指示用于姑息性治疗多发性骨髓瘤和不可切除的卵巢上皮癌。骨髓抑制是美法仑的最常见的剂量限制性副作用。
苯丁酸氮芥,4-[双(2-氯乙基)氨基]苯丁酸,可作为LEUKERAN®片剂商购得到。苯丁酸氮芥被指示用于姑息性治疗慢性淋巴性白血病和恶性淋巴瘤如淋巴肉瘤、巨滤泡型淋巴瘤和霍奇金病。
白消安,二甲磺酸-1,4-丁二醇酯,可作为MYLERAN®片剂商购得到。白消安被指示用于姑息性治疗慢性骨髓性白血病。
卡莫司汀,1,3-[双(2-氯乙基)-1-亚硝基脲,可作为单瓶的冻干材料以BiCNU®商购获得。卡莫司汀被指示作为单一药剂或与其它药剂组合用于姑息性治疗脑肿瘤、多发性骨髓瘤、霍奇金病和非霍奇金淋巴瘤。
达卡巴嗪,5-(3,3-二甲基-1-三氮烯基)-咪唑-4-甲酰胺,可作为单瓶的物质以DTIC-Dome®商购获得。达卡巴嗪被指示用于治疗转移性恶性黑素瘤并且与其它药剂组合用于霍奇金病的二线治疗。
抗生素抗肿瘤剂:
抗生素抗肿瘤剂是非时相特异性药剂,其结合或插入DNA。通常,这种作用导致稳定的DNA络合物或链断裂,这破坏核酸的正常功能,导致细胞死亡。抗生素抗肿瘤剂的实例包括但不限于放线菌素如更生霉素、蒽环类如柔红霉素和多柔比星;和博来霉素。
更生霉素,也称为放线菌素D,可以注射形式以COSMEGEN®商购得到。更生霉素被指示用于治疗Wilm's 肿瘤和横纹肌肉瘤。
柔红霉素,(8S-顺式)-8-乙酰基-10-[(3-氨基-2,3,6-三去氧-α-L-来苏-己吡喃糖基)氧基]-7,8,9,10-四氢-6,8,11-三羟基-1-甲氧基-5,12并四苯二酮盐酸盐,可以脂质体注射形式以DAUNOXOME®或作为注射剂以CERUBIDINE®商购得到。柔红霉素被指示用于在急性非淋巴细胞性白血病和晚期HIV相关的卡波西肉瘤的治疗中诱导缓解。
多柔比星,(8S,10S)-10-[(3-氨基-2,3,6-三去氧-α-L-来苏-己吡喃糖基)氧基]-8-乙醇酰基,7,8,9,10-四氢-6,8,11-三羟基-1-甲氧基-5,12并四苯二酮盐酸盐,可作为注射形式以RUBEX®或ADRIAMYCIN RDF®商购得到。多柔比星被主要指示用于治疗急性成淋巴细胞性白血病和急性髓系白血病,但也是治疗一些实体瘤和淋巴瘤的有用成分。
博来霉素是从轮枝链霉菌(Streptomyces verticillus)菌株中分离的细胞毒性糖肽类抗生素的混合物,可以BLENOXANE®商购得到。博来霉素被指示作为单一药剂或与其它药剂组合用于姑息性治疗鳞状细胞癌、淋巴瘤和睾丸癌。
拓扑异构酶II抑制剂:
拓扑异构酶II抑制剂包括但不限于表鬼臼毒素。
表鬼臼毒素是源自曼德拉草(mandrake)植物的时相特异性抗肿瘤剂。表鬼臼毒素通常通过与拓扑异构酶II和DNA形成三元复合物导致DNA链断裂而影响细胞周期的S和G2期中的细胞。链断裂积累,接着细胞死亡。表鬼臼毒素的实例包括但不限于依托泊苷和替尼泊苷。
依托泊苷,4’-去甲基-表鬼臼毒素9[4,6-0-(R)-亚乙基-β-D-吡喃葡萄糖苷],可作为注射液或胶囊以VePESID®商购获得,并且通常称为VP-16。依托泊苷被指示作为单一药剂或与其它化疗剂组合用于治疗睾丸癌和非小细胞肺癌。
替尼泊苷,4’-去甲基-表鬼臼毒素9[4,6-0-(R)-噻吩亚甲基-β-D-吡喃葡萄糖苷],可作为注射液以VUMON®商购获得,并且通常称为VM-26。替尼泊苷被指示作为单一药剂或与其它化疗剂组合用于治疗儿童的急性白血病。
抗代谢物肿瘤剂:
抗代谢物肿瘤剂是时相特异性抗肿瘤剂,其作用于细胞周期的S期(DNA合成),通过抑制DNA合成或通过抑制嘌呤或嘧啶碱基合成从而限制DNA合成。因此,S期不继续进行,接着细胞死亡。抗代谢物抗肿瘤剂的实例包括但不限于氟尿嘧啶、甲氨蝶呤、阿糖胞苷、巯基嘌呤、硫鸟嘌呤和吉西他滨。
5-氟尿嘧啶,5-氟-2,4-(1H,3H)嘧啶二酮,可作为氟尿嘧啶商购获得。施用5-氟尿嘧啶导致抑制胸苷酸合成,并且也掺入到RNA和DNA二者中。结果通常是细胞死亡。5-氟尿嘧啶被指示作为单一药剂或与其它化疗剂组合用于治疗乳腺癌、结肠癌、直肠癌、胃癌和胰腺癌。其它氟嘧啶类似物包括5-氟脱氧尿苷(氟尿苷)和5-氟脱氧尿苷一磷酸。
阿糖胞苷,4-氨基-1-β-D-阿拉伯呋喃糖基-2(1H)-嘧啶酮,可作为CYTOSAR-U®商购获得,并且通常称为Ara-C。据信阿糖胞苷通过将阿糖胞苷末端掺入到生长的DNA链中来抑制DNA链延长,而在S期显示细胞时相特异性。阿糖胞苷被指示作为单一药剂或与其它化疗剂组合用于治疗急性白血病。其它胞苷类似物包括5-氮杂胞苷和2’,2’-二氟脱氧胞苷(吉西他滨)。
巯基嘌呤,1,7-二氢-6H-嘌呤-6-硫酮一水合物,可作为PURINETHOL®商购得到。巯基嘌呤通过至今尚未确定的机制抑制DNA合成,而在S期显示细胞时相特异性。巯基嘌呤被指示作为单一药剂或与其它化疗剂组合用于治疗急性白血病。有用的巯基嘌呤类似物是硫唑嘌呤。
硫鸟嘌呤,2-氨基-1,7-二氢-6H-嘌呤-6-硫酮,可作为TABLOID®商购得到。硫鸟嘌呤通过至今尚未确定的机制抑制DNA合成,而在S期显示细胞时相特异性。硫鸟嘌呤被指示作为单一药剂或与其它化疗剂组合指示用于治疗急性白血病。其它嘌呤类似物包括喷司他丁、赤羟基壬基腺嘌呤、磷酸氟达拉滨和克拉屈滨。
吉西他滨,2’-脱氧-2’,2’-二氟胞苷一盐酸盐(β-异构体),可作为GEMZAR®商购得到。吉西他滨通过阻断细胞通过G1/S边界的进展而在S期显示细胞时相特异性。吉西他滨被指示与顺铂组合用于治疗局部晚期非小细胞肺癌和单独用于治疗局部晚期胰腺癌。
甲氨蝶呤,N-[4[[(2,4-二氨基-6-蝶啶基)甲基]甲基氨基]苯甲酰基]-L-谷氨酸,可作为甲氨蝶呤钠商购得到。甲氨蝶呤通过抑制合成嘌呤核苷酸和胸苷酸所需的二氢叶酸还原酶抑制DNA合成、修复和/或复制,而在S期显示细胞时相特异性效应。甲氨蝶呤被指示作为单一药剂或与其它化疗剂组合用于治疗绒毛膜癌、脑膜白血病、非霍奇金淋巴瘤,以及乳腺癌、头癌、颈癌、卵巢癌和膀胱癌。
拓扑异构酶I抑制剂:
喜树碱,包括喜树碱和喜树碱衍生物,可作为拓扑异构酶I抑制剂得到或在开发中。喜树碱的细胞毒活性被认为与其拓扑异构酶I抑制活性有关。喜树碱的实例包括但不限于伊立替康、托泊替康和下文所述的7-(4-甲基哌嗪子基-亚甲基)-10,11-亚乙基二氧基-20-喜树碱的各种光学形式。
盐酸伊立替康,(4S)-4,11-二乙基-4-羟基-9-[(4-哌啶子基哌啶子基)羰基氧基]-1H-吡喃并[3’,4’,6,7]氮茚并[1,2-b]喹啉-3,14(4H,12H)-二酮盐酸盐,可作为注射液CAMPTOSAR®商购得到。伊立替康是喜树碱的衍生物,其与其活性代谢物SN-38一起结合到拓扑异构酶I-DNA复合物。据信通过拓扑异构酶I:DNA:伊立替康或SN-38三元复合物与复制酶的相互作用导致了不可修复的双链断裂,作为结果发生了细胞毒性。伊立替康被指示用于治疗结肠或直肠的转移性癌症。
盐酸托泊替康,(S)-10-[(二甲基氨基)甲基]-4-乙基-4,9-二羟基-1H-吡喃并[3’,4’,6,7]氮茚并[1,2-b]喹啉-3,14-(4H,12H)-二酮单盐酸盐,可作为注射液HYCAMTIN®商购获得。托泊替康是喜树碱的衍生物,其结合拓扑异构酶I-DNA复合物并防止由拓扑异构酶I响应于DNA分子的扭转张力而引起的单链断裂的再连接。托泊替康被指示用于转移性卵巢癌和小细胞肺癌的二线治疗。
激素和激素类似物:
激素和激素类似物是用于治疗癌症的有用化合物,其中在激素和癌症的生长和/或生长缺乏之间存在关系。可用于癌症治疗的激素和激素类似物的实例包括但不限于肾上腺皮质类固醇,例如泼尼松和泼尼松龙,其可用于治疗儿童的恶性淋巴瘤和急性白血病;氨鲁米特和其它芳香酶抑制剂,例如阿那曲唑、来曲唑、伏氯唑和依西美坦,其可用于治疗肾上腺皮质癌和激素依赖性乳腺癌,其含有雌激素受体;孕激素,例如醋酸甲地孕酮,其可用于治疗激素依赖性乳腺癌和子宫内膜癌;雌激素、雌激素和抗雌激素,例如氟维司群、氟他胺、尼鲁米特、比卡鲁胺、乙酸环丙孕酮和5α-还原酶例如非那雄胺和度他雄胺,其用于治疗前列腺癌和良性前列腺增生;抗雌激素,例如他莫昔芬、托瑞米芬、雷洛昔芬、屈洛昔芬、吲哚昔芬(iodoxyfene),以及选择性雌激素受体调节剂(SERMS),如美国专利号5,681,835、5,877,219和6,207,716中描述的那些,其可用于治疗激素依赖性乳腺癌和其它易受影响的癌症;和促性腺激素释放激素(GnRH)及其类似物,其刺激促黄体生成素(LH)和/或促卵泡激素(FSH)的释放,可用于治疗前列腺癌,例如LHRH激动剂和拮抗剂如醋酸戈舍瑞林和亮丙瑞林。
信号转导通路抑制剂:
信号转导通路抑制剂是阻断或抑制引起细胞内变化的化学过程的那些抑制剂。如本文所用,这种变化是细胞增殖或分化。可用于本发明的信号转导抑制剂包括下列的抑制剂:受体酪氨酸激酶、非受体酪氨酸激酶、SH2/SH3结构域阻断剂、丝氨酸/苏氨酸激酶、磷脂酰肌醇-3激酶、肌醇信号转导和Ras致癌基因。
几种蛋白酪氨酸激酶催化参与调节细胞生长的各种蛋白质中特定酪氨酰残基的磷酸化。这种蛋白酪氨酸激酶可以广义地分类为受体或非受体激酶。
受体酪氨酸激酶是具有胞外配体结合结构域、跨膜结构域和酪氨酸激酶结构域的跨膜蛋白。受体酪氨酸激酶参与细胞生长的调节,并通常称为生长因子受体。许多这些激酶的不适当或不受控制的活化,即异常激酶生长因子受体活性,例如通过过表达或突变导致,已显示导致不受控制的细胞生长。因此,这种激酶的异常活性已经与恶性组织生长相联系。因此,这种激酶的抑制剂可以提供癌症治疗方法。生长因子受体包括例如表皮生长因子受体(EGFr)、血小板衍生生长因子受体(PDGFr)、erbB2、erbB4、ret、血管内皮生长因子受体(VEGFr)、具有免疫球蛋白样和表皮生长因子同源结构域的酪氨酸激酶(TIE-2)、胰岛素样生长因子-I(IGFI)受体、巨噬细胞集落刺激因子(cfms)、BTK、ckit、cmet、成纤维细胞生长因子(FGF)受体、Trk受体(TrkA、TrkB和TrkC)、肝配蛋白(eph)受体和RET原癌基因。几种生长受体抑制剂正在开发中,包括配体拮抗剂、抗体、酪氨酸激酶抑制剂和反义寡核苷酸。生长因子受体和抑制生长因子受体功能的药剂描述于例如Kath, John C., Exp. Opin.Ther. Patents (2000) 10(6):803-818;Shawver et al DDT Vol 2, No. 2 February1997;和 Lofts, F. J. et al, “Growth factor receptors as targets”, NewMolecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr, David,CRC press 1994, London中。
酪氨酸激酶,其不是生长因子受体激酶,被称为非受体酪氨酸激酶。可用于本发明的作为抗癌药物靶标或潜在靶标的非受体酪氨酸激酶包括cSrc、Lck、Fyn、Yes、Jak、cAb1、FAK(粘着斑激酶)、Brutons酪氨酸激酶和Bcr-Abl。这种非受体激酶和抑制非受体酪氨酸激酶功能的药剂描述于 Sinh, S. and Corey, S.J., (1999) Journal of Hematotherapyand Stem Cell Research 8 (5): 465 – 80;和Bolen, J.B., Brugge, J.S., (1997)Annual review of Immunology. 15: 371-404中。
SH2/SH3结构域阻断剂是破坏各种酶或衔接蛋白中的SH2或SH3结构域结合的药剂,所述酶或衔接蛋白包括PI3-K p85亚单元、Src家族激酶、衔接分子(Shc、Crk、Nck、Grb2)和Ras-GAP。作为抗癌药物靶标的SH2/SH3结构域论述于Smithgall, T.E. (1995),Journal of Pharmacological and Toxicological Methods. 34(3) 125-32中。
丝氨酸/苏氨酸激酶抑制剂,包括MAP激酶级联阻断剂,其包括Raf激酶(rafk)、丝裂原或细胞外调节激酶(MEK)和细胞外调节激酶(ERK)的阻断剂;和蛋白激酶C家族成员阻断剂,包括PKC(α、β、γ、ε、μ、λ、ι、ζ)、IkB激酶家族(IKKa、IKKb)、PKB家族激酶、akt激酶家族成员和TGFβ受体激酶的阻断剂。这种丝氨酸/苏氨酸激酶及其抑制剂描述于Yamamoto, T.,Taya, S., Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803;Brodt, P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60.1101-1107;Massague, J., Weis-Garcia, F. (1996) Cancer Surveys. 27:41-64;Philip, P.A., and Harris, A.L. (1995), Cancer Treatment and Research. 78: 3-27;Lackey, K. et al Bioorganic and Medicinal Chemistry Letters, (10), 2000,223-226;美国专利No. 6,268,391;和Martinez-Iacaci, L., et al, Int. J. Cancer(2000), 88(1), 44-52中。
磷脂酰肌醇-3激酶家族成员的抑制剂,包括PI3激酶、ATM、DNA-PK和Ku的阻断剂也可用于本发明。这种激酶论述于Abraham, R.T. (1996), Current Opinion inImmunology. 8 (3) 412-8;Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25)3301-3308;Jackson, S.P. (1997), International Journal of Biochemistry andCell Biology. 29 (7):935-8;和Zhong, H. et al, Cancer res, (2000) 60(6), 1541-1545中。
还可用于本发明的是肌醇信号转导抑制剂,例如磷脂酶C阻断剂和肌醇类似物。这种信号抑制剂描述于Powis, G., and Kozikowski A., (1994) New Molecular Targetsfor Cancer Chemotherapy ed., Paul Workman and David Kerr, CRC press 1994,London中。
另一组信号转导通路抑制剂是Ras致癌基因的抑制剂。这种抑制剂包括法尼基转移酶、香叶烯基转移酶和CAAX蛋白酶的抑制剂以及反义寡核苷酸、核酶和免疫疗法。这种抑制剂已经显示阻断含有野生型突变ras的细胞中的ras活化,从而起到抗增殖剂的作用。Ras致癌基因抑制论述于Scharovsky, O.G., Rozados, V.R., Gervasoni, S.I. Matar, P.(2000), Journal of Biomedical Science. 7(4) 292-8;Ashby, M.N. (1998), CurrentOpinion in Lipidology. 9 (2) 99 – 102;和BioChim. Biophys. Acta, (19899) 1423(3):19-30中。
如上所述,受体激酶配体结合的抗体拮抗剂也可以用作信号转导抑制剂。这组信号转导通路抑制剂包括将人源化抗体用于受体酪氨酸激酶的细胞外配体结合结构域。例如Imclone C225 EGFR特异性抗体(参见Green, M.C. et al, Monoclonal AntibodyTherapy for Solid Tumors, Cancer Treat. Rev., (2000), 26(4), 269-286);Herceptin® erbB2抗体(参见Tyrosine Kinase Signalling in Breast cancer:erbBFamily Receptor Tyrosine Kinases, Breast cancer Res., 2000, 2(3), 176-183);和2CB VEGFR2特异性抗体(参见Brekken, R.A. et al, Selective Inhibition of VEGFR2Activity by a monoclonal Anti-VEGF antibody blocks tumor growth in mice,Cancer Res. (2000) 60, 5117-5124)。
抗血管生成剂:
包括非受体MEK血管生成抑制剂的抗血管生成剂也可能是有用的。抗血管生成剂例如抑制血管内皮生长因子的作用的那些(例如抗血管内皮细胞生长因子抗体贝伐单抗[Avastin™],以及通过其它机制起作用的化合物(例如利诺胺、整联蛋白αvβ3功能抑制剂、内皮他丁(endostatin)和血管他丁(angiostatin))。
免疫治疗剂:
用于免疫治疗方案的药剂也可以与式(I)化合物组合使用。免疫治疗方法,包括例如增加患者肿瘤细胞的免疫原性的离体和体内方法,例如用细胞因子如白细胞介素2、白细胞介素4或粒细胞-巨噬细胞集落刺激因子转染,降低T细胞无能的方法,使用转染的免疫细胞例如细胞因子转染的树突细胞的方法,使用细胞因子转染的肿瘤细胞系的方法和使用抗独特型抗体的方法。
促凋亡剂:
用于促凋亡方案的药剂(例如,bcl-2反义寡核苷酸)也可用于本发明的组合产品中。
细胞周期信号传导抑制剂
细胞周期信号传导抑制剂抑制参与细胞周期控制的分子。称为细胞周期蛋白依赖性激酶(CDK)的蛋白激酶家族及其与称为细胞周期蛋白的蛋白质家族的相互作用控制通过真核细胞周期的进展。不同细胞周期蛋白/CDK复合物的配位活化和失活对于通过细胞周期的正常进展是必需的。几种细胞周期信号转导的抑制剂正在开发中。例如,细胞周期蛋白依赖性激酶包括CDK2、CDK4和CDK6及其抑制剂的实例描述于例如Rosania et al, Exp.Opin. Ther. Patents (2000) 10(2):215-230中。
在一个实施方案中,本发明的组合产品包含式I的化合物或其盐或溶剂合物和至少一种抗肿瘤剂,所述抗肿瘤剂选自抗微管剂、铂配位络合物、烷化剂、抗生素、拓扑异构酶II抑制剂、抗代谢物、拓扑异构酶I抑制剂、激素和激素类似物、信号转导通路抑制剂、非受体酪氨酸MEK血管生成抑制剂、免疫治疗剂、促凋亡剂和细胞周期信号传导抑制剂。
在一个实施方案中,本发明的组合产品包含式I的化合物或其盐或溶剂合物和至少一种抗肿瘤剂,所述抗肿瘤剂是选自二萜类化合物和长春花生物碱的抗微管剂。
在另一实施方案中,至少一种抗肿瘤剂是二萜类化合物。
在另一实施方案中,至少一种抗肿瘤剂是长春花生物碱。
在一个实施方案中,本发明的组合产品包含式I的化合物或其盐或溶剂合物和至少一种抗肿瘤剂,所述抗肿瘤剂是铂配位络合物。
在另一实施方案中,至少一种抗肿瘤剂是紫杉醇、卡铂或长春瑞滨。
在另一实施方案中,至少一种抗肿瘤剂是卡铂。
在另一实施方案中,至少一种抗肿瘤剂是长春瑞滨。
在另一实施方案中,至少一种抗肿瘤剂是紫杉醇。
在一个实施方案中,本发明的组合产品包含式I的化合物及其盐或溶剂合物和至少一种抗肿瘤剂,所述抗肿瘤剂是信号转导通路抑制剂。
在另一实施方案中,信号转导通路抑制剂是生长因子受体激酶VEGFR2、TIE2、PDGFR、BTK、erbB2、EGFr、IGFR-1、TrkA、TrkB、TrkC或c-fms的抑制剂。
在另一实施方案中,所述信号转导通路抑制剂是丝氨酸/苏氨酸激酶rafk、akt或PKC-ζ的抑制剂。
在另一实施方案中,所述信号转导通路抑制剂是选自src家族激酶的非受体酪氨酸激酶的抑制剂。
在另一实施方案中,所述信号转导通路抑制剂是c-src的抑制剂。
在另一实施方案中,所述信号转导通路抑制剂是Ras致癌基因的抑制剂,其选自法尼基转移酶和香叶烯基转移酶的抑制剂。
在另一实施方案中,所述信号转导通路抑制剂是选自PI3K的丝氨酸/苏氨酸激酶的抑制剂。
在另一实施方案中,所述信号转导通路抑制剂是双重EGFr/erbB2抑制剂,例如N-{3-氯-4-[(3-氟苄基)氧基]苯基}-6-[5-({[2-甲磺酰基)乙基]氨基}甲基)-2-呋喃基]-4-喹唑啉胺(以下结构):
在一个实施方案中,本发明的组合产品包含式I的化合物或其盐或溶剂合物和至少一种抗肿瘤剂,所述抗肿瘤剂是细胞周期信号传导抑制剂。
在其它实施方案中,细胞周期信号传导抑制剂是CDK2、CDK4或CDK6的抑制剂。
用于与本发明的式(I)化合物组合或共同施用的另外的一种或多种活性成分(抗肿瘤剂)的另外的实例是抗-PD-L1药剂。
抗PD-L1抗体及其制备方法是本领域已知的。
PD-L1的这种抗体可以是多克隆或单克隆的,和/或重组的,和/或人源化的。
示例性的PD-L1抗体公开在:
美国专利No.8,217,149; 12/633339;
美国专利No.8,383,796; 13/091936;
美国专利No.8,552,154; 13/120406;
美国专利公开No.20110280877; 13/068337;
美国专利公开No.20130309250; 13/892671;
WO2013019906;
WO2013079174;
美国申请No.13/511,538(2012年8月7日提交),其是国际申请PCT/US10/58007(2010年提交)的美国国家阶段;和
美国申请No.13/478,511(2012年5月23日提交)。
另外的示例性的PD-L1(也称为CD274或B7-H1)抗体和使用方法公开在美国专利No.7,943,743;US20130034559,WO2014055897,美国专利No.8,168,179;和美国专利No.7,595,048中。正在开发PD-L1抗体作为治疗癌症的免疫调节剂。
在一个实施方案中,PD-L1抗体是美国专利No.8,217,149中公开的抗体。在另一个实施方案中,抗PD-L1抗体包含美国专利No.8,217,149中公开的抗体的CDR。
在另一个实施方案中,PD-L1抗体是美国申请No.13/511,538中公开的抗体。在另一个实施方案中,抗PD-L1抗体包含美国申请No.13/511,538中公开的抗体的CDR。
在另一个实施方案中,PD-L1抗体是美国申请No.13/478,511中公开的抗体。在另一个实施方案中,抗PD-L1抗体包含美国申请No.13/478,511中公开的抗体的CDR。
在一个实施方案中,抗-PD-L1抗体是BMS-936559(MDX-1105)。在另一个实施方案中,抗-PD-L1抗体是MPDL3280A(RG7446)。在另一个实施方案中,抗-PD-L1抗体是MEDI4736。
用于与本发明的式(I)化合物组合或共同施用的另外的一种或多种活性成分(抗肿瘤剂)的另外的实例是PD-1拮抗剂。
“PD-1拮抗剂”是指阻断在癌细胞上表达的PD-L1与在免疫细胞(T细胞,B细胞或NKT细胞)上表达的PD-1结合,并且优选还阻断在癌细胞上表达的PD-L2与免疫细胞表达的PD-1结合的任何化学化合物或生物分子。PD-1及其配体的替代名称或同义词包括:用于PD-1的PDCD1、PD1、CD279和SLEB2;用于PD-L1的PDCD1L1、PDL1、B7H1、B7-4、CD274和B7-H;和用于PD-L2的PDCD1L2、PDL2、B7-DC、Btdc和CD273。在其中要治疗人类个体的本发明方面或实施方案的任何实施方案中,PD-1拮抗剂阻断人PD-L1与人PD-1的结合,并且优选同时阻断人PD-L1和PD-L2与人PD-1的结合。人PD-1氨基酸序列可以在NCBI Locus No.: NP_005009中找到。人PD-L1和PD-L2氨基酸序列分别可以在NCBI Locus No.: NP_054862和NP_079515中找到。
可用于本发明任何方面的PD-1拮抗剂包括特异性结合PD-1或PD-L1,并且优选特异性结合人PD-1或人PD-L1的单克隆抗体(mAb)或其抗原结合片段。所述mAb可以是人抗体,人源化抗体或嵌合抗体,并且可以包括人恒定区。在一些实施方案中,人恒定区选自IgG1,IgG2,IgG3和IgG4恒定区,并且在优选的实施方案中,人恒定区是IgG1或IgG4恒定区。在一些实施方案中,抗原结合片段选自Fab,Fab'-SH,F(ab')2,scFv和Fv片段。
结合人PD-1并且可用于本发明各个方面和实施方案的mAb的实例描述在US7488802,US7521051,US8008449,US8354509,US8168757,WO2004/004771,WO2004/072286,WO2004/056875和US2011/0271358中。
在本发明的任何方面和实施方案中用作PD-1拮抗剂的具体抗人PD-1 mAb包括:MK-3475,一种人源化IgG4 mAb,具有WHO Drug Information,Vol. 27,No. 2, pages 161-162 (2013) 中描述的结构,并且其包含图6所示的重链和轻链氨基酸序列;纳武单抗(nivolumab),一种人IgG4单克隆抗体,具有WHO Drug Information,Vol. 27,No. 1,pages 68-69 (2013)中描述的结构,并且其包含图7所示的重链和轻链氨基酸序列;人源化抗体h409A11、h409A16和h409A17(它们描述在WO2008/156712中)以及AMP-514(其正在由Medimmune开发)。
可用于本发明的任何方面和实施方案的其它PD-1拮抗剂包括特异性结合PD-1并优选特异性结合人PD-1的免疫粘附素,例如含有融合到免疫球蛋白分子的恒定区(如Fc区)的PD-L1或PD-L2的胞外或PD-1结合部分的融合蛋白。特异性结合PD-1的免疫粘附分子的实例描述于WO2010/027827和WO2011/066342中。在本发明的治疗方法、药物和用途中可用作PD-1拮抗剂的具体融合蛋白包括AMP-224(也称为B7-DCIg),其为PD-L2-FC融合蛋白并结合人PD-1。
结合人PD-L1并可用于本发明的治疗方法、药物和用途中的mAb的其它实例描述于WO2013/019906,W02010/077634A1和US8383796。在本发明的治疗方法、药物和用途中可用作PD-1拮抗剂的具体的抗人PD-L1 mAb包括MPDL3280A,BMS-936559,MEDI4736,MSB0010718C。
KEYTRUDA/派姆单抗(pembrolizumab)是由Merck销售用于治疗肺癌的抗PD-1抗体。派姆单抗的氨基酸序列和使用方法公开在美国专利No.8,168,757中。
Opdivo/纳武单抗是一种完全人单克隆抗体,由Bristol Myers Squibb销售,针对负免疫调节性人类细胞表面受体PD-1(程序性死亡-1或程序性细胞死亡-1/PCD-1),具有免疫增强活性。纳武单抗通过其配体PD-L1和PD-L2结合并阻断PD-1(Ig超家族跨膜蛋白)的活化,导致T细胞的活化和针对肿瘤细胞或病原体的细胞介导的免疫应答。活化的PD-1通过抑制P13k/Akt通路激活负调节T细胞活化和效应子功能。纳武单抗的其他名称包括:BMS-936558,MDX-1106和ONO-4538。纳武单抗的氨基酸序列以及使用和制备方法公开在美国专利No.US 8,008,449中。
用于与本发明的式(I)化合物组合或共同施用的另外的一种或多种活性成分(抗肿瘤剂)的另外的实例是免疫调节剂。
本文所用的“免疫调节剂”是指影响免疫系统的包括单克隆抗体在内的任何物质。本发明的ICOS结合蛋白可以被认为是免疫调节剂。免疫调节剂可用作抗肿瘤剂用于治疗癌症。例如,免疫调节剂包括但不限于抗CTLA-4抗体,例如伊匹单抗(ipilimumab)(YERVOY)和抗PD-1抗体(Opdivo/纳武单抗和Keytruda/派姆单抗)。其他免疫调节剂包括,但不限于,OX-40抗体,PD-L1抗体,LAG3抗体,TIM-3抗体,41BB抗体和GITR抗体。
Yervoy(伊匹单抗)是由Bristol Myers Squibb销售的全人CTLA-4抗体。伊匹单抗的蛋白质结构和使用的方法描述于美国专利No.6,984,720和7,605,238中。
CD134,也称为OX40,与CD28不同,是不在静息(resting)幼稚(naïve)T细胞上组成性表达的受体的TNFR-超家族的成员。OX40是辅助共刺激分子(secondary costimulatorymolecule),活化后24至72小时后表达;其配体OX40L也不在静息抗原呈递细胞上表达,而是在其活化之后表达。OX40的表达依赖于T细胞的完全活化;没有CD28,OX40的表达被延迟并且降低了四倍。OX-40抗体,OX-40融合蛋白及其使用方法公开于美国专利No. US7,504,101;US 7,758,852;US 7,858,765;US 7,550,140;US 7,960,515;WO2012027328;WO2013028231。
免疫刺激剂:
本文所用的“免疫刺激剂”是指可以刺激免疫系统的任何药剂。本文所用的免疫刺激剂包括,但不限于,疫苗佐剂。
本文所用的术语“Toll样受体”(或“TLR”)是指感测微生物产物和/或启动适应性免疫应答的蛋白或其片段的Toll样受体家族的成员。在一个实施方案中,TLR激活树突状细胞(DC)。Toll样受体(TLR)是模式识别受体家族,最初被确认为识别微生物病原体的天然免疫系统的传感器。TLR识别微生物中的不同结构,通常称为“PAMP”(病原体相关分子模式)。与TLR结合的配体引起细胞内信号传导通路的级联,其诱导涉及炎症和免疫的因子的产生。在人类中,已经鉴定了十种TLR。在细胞表面表达的TLR包括TLR-1、-2、-4、-5和-6,而TLR-3、-7/8和-9用ER区表达。人类DC亚型可以根据不同的TLR表达模式进行鉴定。举例来说,DC的粒细胞或“常规”亚型(mDC)在被刺激时表达TLR 1-8,和活化标记(例如,CD80,CD86,I类和II类MHC,CCR7)的级联,产生了促炎细胞因子和趋化因子。这种刺激和产生的表达的结果是抗原特异性CD4+和CD8+ T细胞的引发(priming)。这些DC获得增强的获取抗原的能力,并将其以适当的形式呈递给T细胞。相比之下,DC的浆细胞样亚型(pDC)在激活时仅表达TLR7和TLR9,导致激活NK细胞以及T细胞。因为死亡肿瘤细胞可能不利地影响DC功能,已经提出用TLR激动剂激活DC可能有益于在用于治疗癌症的免疫治疗方法中引发抗肿瘤免疫。还有人建议,使用放射和化学疗法成功治疗乳腺癌需要TLR4激活。
本领域已知且在本发明中有用的TLR激动剂包括,但不限于,以下:Pam3Cys,一种TLRI/2激动剂;CFA,一种TLR2激动剂;MALP2,一种TLR2激动剂;Pam2Cys,一种TLR2激动剂;FSL-1,一种TLR-2激动剂;Hib-OMPC,一种TLR-2激动剂;多核糖苷酸:多核糖胞苷酸(PolyI:C),一种TLR3激动剂;聚腺苷多聚尿酸(poly AU),一种TLR3激动剂;用聚-L-赖氨酸和羧甲基纤维素稳定的聚肌苷酸-聚胞苷酸(Hiltonol),一种TLR3激动剂;细菌鞭毛蛋白,一种TLR5激动剂;咪喹莫特,一种TLR7激动剂;雷曲霉,一种TLR7/8激动剂;洛匹康碱,一种TLR7/8激动剂;和未甲基化的CpG二核苷酸(CpG-ODN),一种TLR9激动剂。
本领域已知的并且在本发明中有用的另外的TLR激动剂还包括,但不限于,氨基烷基氨基葡糖苷磷酸酯(AGP),其结合TLR4受体,已知可用作疫苗佐剂和免疫刺激剂用于在免疫动物中刺激细胞因子产生,激活巨噬细胞,促进天然免疫应答,以及增强抗体产生。天然存在的TLR4激动剂的实例是细菌LPS。半合成TLR4激动剂的实例是单磷酰脂质A(MPL)。AGP及其通过TLR4的免疫调节作用公开在专利公开文献中,例如WO 2006/016997,WO 2001/090129和/或美国专利No.6,113,918,并已在文献中报道。另外的AGP衍生物公开在美国专利No.7,129,219,美国专利No.6,525,028和美国专利No.6,911,434中。某些AGP作为TLR4的激动剂起作用,而其他AGP被认为是TLR4拮抗剂。
除了上文所述的免疫刺激剂之外,本发明的组合物还可以包含一种或多种另外的物质,由于它们的佐剂性质,其可以起作用来刺激免疫系统对存在于灭活肿瘤细胞上的癌抗原作出响应。这些佐剂包括,但不限于,脂质,脂质体,诱导天然免疫的灭活的细菌(例如,灭活或减毒的I/ster/一种产单核细胞),通过(NOD)样受体(NLDs)、基于视黄酸诱导基因(RIG)-I样受体(RLR)和/或C型凝集素受体(CLR)介导天然免疫激活的组合物。PAMP的实例包括脂蛋白,脂多肽,肽聚糖,酵母聚糖,脂多糖,奈瑟氏孔蛋白,鞭毛蛋白,抑制蛋白,半乳聚酰胺,胞壁酰二肽。肽聚糖,脂蛋白和脂磷壁酸是革兰氏阳性的细胞壁组分。脂多糖由大多数细菌表达,MPL是一个例子。鞭毛蛋白是指由致病菌和共生细菌分泌的细菌鞭毛的结构成分。rt.-半乳糖苷神经酰胺(rt.-GalCer)是自然杀伤T(NKT)细胞的激活剂。胞壁酰二肽是所有细菌共有的生物活性肽聚糖基序。
由于它们的佐剂特质,优选TLR激动剂与其它疫苗、佐剂和/或免疫调节剂组合使用,并且可以以各种组合产品进行组合。因此,在某些实施方案中,本文所述的结合STING并诱导STING依赖性TBKI活化的式(I)化合物和表达并分泌刺激DC诱导、募集和/或成熟的一种或多种细胞因子的灭活肿瘤细胞,如本文所述,可以与一种或多种TLR激动剂一起施用以用于治疗目的。
用于与本发明的式(I)化合物组合或共同施用的另外的一种或多种活性成分(抗肿瘤剂)的其它实例是ICOS抗体。
PCT/EP2012/055735(WO 2012/131004)显示了具有激动剂活性的人ICOS的鼠抗体的CDR。ICOS的抗体也公开在WO 2008/137915,WO 2010/056804,EP 1374902,EP 1374901和EP 1125585中。
在一个方面,待治疗的疾病是感染性疾病,例如由细菌或病毒引起的疾病。
在本发明的另一方面,提供了用于治疗感染性疾病的式(I)化合物或其药学上可接受的盐。
在另一方面,提供了治疗感染性疾病的方法,包括向需要其的人施用治疗有效量的式(I)化合物或其药学上可接受的盐。
在另一方面,提供式(I)化合物或其药学上可接受的盐在制备用于治疗感染性疾病的药物中的用途。
在一个实施方案中,本发明化合物可以与治疗感染性疾病的其它治疗方法一起使用。特别地,设想抗病毒剂和抗菌剂。
式(I)化合物及其药学上可接受的盐可以与一种或多种可用于预防或治疗细菌和病毒感染的药剂组合使用。这种药剂的实例包括但不限于:聚合酶抑制剂,例如WO 2004/037818-A1中公开的那些,以及WO 2004/037818和WO 2006/045613中公开的那些;JTK-003、JTK-019、NM-283、HCV-796、R-803、R1728、R1626以及WO 2006/018725、WO 2004/074270、WO2003/095441、US2005/0176701、WO 2006/020082、WO 2005/080388、WO 2004/064925、WO2004/065367、WO 2003/007945、WO 02/04425、WO 2005/014543、WO 2003/000254、EP1065213、WO 01/47883、WO 2002/057287、WO 2002/057245中公开的那些和类似药剂;复制抑制剂,例如阿昔洛韦、泛昔洛韦、更昔洛韦、西多福韦、拉米夫定和类似药剂;蛋白酶抑制剂,例如HIV蛋白酶抑制剂沙奎那韦、利托那韦、茚地那韦、奈非那韦、安普那韦、福沙那韦、贝卡那韦、阿扎那韦、替拉那韦、帕利那韦、拉西那韦和HCV蛋白酶抑制剂BILN2061、VX-950、SCH503034;和类似药剂;核苷和核苷酸逆转录酶抑制剂,例如齐多夫定、地达诺新、拉米夫定、扎西他滨、阿巴卡韦、司他夫定、阿德福韦、阿德福韦酯、福齐夫定、todoxil、恩曲他滨、阿洛夫定、amdoxovir、艾夫他滨和类似药剂;非核苷逆转录酶抑制剂(包括具有抗氧化活性的药剂,例如怡妙康、奥替普拉等),例如奈韦拉平、地拉韦啶、依法韦仑、洛韦胺、怡妙康、奥替普拉、卡普韦林、TMC-278、TMC-125、依曲韦林和类似药剂;进入抑制剂,例如恩夫韦地(T-20)、T-1249、PRO-542、PRO-140、TNX-355、BMS-806、5-Helix和类似药剂;整合酶抑制剂,例如L-870,180和类似药剂;芽殖抑制剂,例如PA-344和PA-457,以及类似的药剂;趋化因子受体抑制剂,例如vicriviroc(Sch-C)、Sch-D、TAK779、maraviroc(UK-427,857)、TAK449,以及WO 02/74769、WO 2004/054974、WO 2004/055012、WO 2004/055010、WO 2004/055016、WO2004/055011和WO 2004/054581中公开的那些,以及类似药剂;神经氨酸酶抑制剂,例如CS-8958、扎那米韦、奥司他韦、帕拉米韦和类似药剂;离子通道阻断剂,例如金刚烷胺或金刚乙胺和类似药剂;和干扰RNA和反义寡核苷酸和例如ISIS-14803和类似药剂;未确定作用机制的抗病毒剂,例如WO 2005/105761、WO 2003/085375、WO 2006/122011中公开的那些、利巴韦林和类似药剂。式(I)化合物及其药学上可接受的盐还可以与一种或多种其它药剂组合使用,所述药剂可用于预防或治疗病毒感染,例如免疫治疗(例如干扰素或其它细胞因子/趋化因子、细胞因子/趋化因子受体调节剂、细胞因子激动剂或拮抗剂和类似药剂);和治疗疫苗、抗纤维化剂、抗炎剂例如皮质类固醇或NSAID(非甾体抗炎剂)和类似药剂。
在另一方面,提供了包含式(I)化合物或其药学上可接受的盐和至少一种可用于治疗感染性疾病的其它治疗剂的组合产品。
在另一方面,提供了包含式(I)化合物或其药学上可接受的盐和至少一种可用于治疗感染性疾病的其它治疗剂的组合产品,其用于治疗。
在另一方面,提供了包含式(I)化合物或其药学上可接受的盐和至少一种可用于治疗感染性疾病的其它治疗剂的组合产品,其用于治疗感染性疾病。
在另一方面,提供了包含式(I)化合物或其药学上可接受的盐和至少一种可用于治疗感染性疾病的其它治疗剂的组合产品在制备用于治疗感染性疾病的药物中的用途。
在另一方面,提供了治疗感染性疾病的方法,包括向需要该治疗的人施用治疗有效量的包含式(I)化合物或其药学上可接受的盐和至少一种可用于治疗感染性疾病的其它治疗剂的组合产品。
在另一方面,提供了药物组合物,其包括包含式(I)化合物或其药学上可接受的盐和至少一种可用于治疗感染性疾病的其它治疗剂的组合产品和一种或多种药学上可接受的赋形剂。
因此,还提供了包含式(I)化合物或其药学上可接受的盐的疫苗佐剂。
还提供了包含抗原或抗原组合物和式(I)化合物或其药学上可接受的盐的免疫原性组合物。
还提供了包含抗原或抗原组合物和式(I)化合物或其药学上可接受的盐的疫苗组合物。
还提供了治疗或预防疾病的方法,包括向患有或易患疾病的人个体施用包含抗原或抗原组合物和式(I)化合物或其药学上可接受的盐的免疫原性组合物。
还提供了治疗或预防疾病的方法,包括向患有或易患疾病的人个体施用包含抗原或抗原组合物和式(I)化合物或其药学上可接受的盐的疫苗组合物。
还提供了式(I)化合物或其药学上可接受的盐在制备用于治疗或预防疾病的包含抗原或抗原组合物的免疫原性组合物中的用途。
还提供了式(I)化合物或其药学上可接受的盐在制备用于治疗或预防疾病的包含抗原或抗原组合物的疫苗组合物中的用途。
式(I)化合物可以通过如下面方案和/或下述具体实施例中所述的有机合成领域已知的方法制备。在所有方法中,应充分理解的是,按照化学的一般原理,在必要时可以使用敏感或反应性基团的保护基。根据有机合成的标准方法处理保护基(T. W. Green andP. G. M. Wuts (1999) Protective Groups in Organic Synthesis, 3rd edition,John Wiley & Sons)。这些基团在化合物合成的方便阶段使用本领域技术人员容易明白的方法除去。选择方法以及反应条件和它们的执行顺序应与式(I)化合物的制备一致。
化合物制备
式(I)化合物及其盐可通过下文所述的方法制备,其构成本发明的其它方面。
因此,提供了制备式(I)化合物的方法,其中R5是F且R6是OH,该方法包括式(II)化合物的脱保护:
其中R1、R2、R3和R4如上文对式(I)化合物所定义,以及P是合适的保护基,例如叔丁基二甲基甲硅烷氧基(OTBDMS),然后如果需要,制备如此形成的化合物的盐。
例如,将式(II)化合物溶于合适的溶剂,例如吡啶中,并在合适的温度,例如50℃下加热,然后用三乙胺三氢氟酸盐和三乙胺的混合物处理合适的时间段,例如2-3小时。通过加入溶剂例如丙酮沉淀来分离产物(I),并且如果需要,进行纯化。
式(II)化合物可以通过式(III)化合物的脱保护来制备:
其中,P是如对式(II)化合物所定义的保护基团,且R5、R6、R7和R8定义为:
R5为OH且R6为NHCOiPr或者R5为NHBz且R6为H;
R7为OH且R8为NHCOiPr或者R7为NHBz且R8为H。
例如,将式(III)化合物溶于合适的混合物,例如甲胺的甲醇溶液或氨水的甲醇溶液中,并在合适的温度,例如50-55℃下加热合适的时间段,例如2-72小时。通过除去溶剂来分离产物(II),并且如果需要,进行纯化。
式(III)化合物可通过式(IV)化合物的反应制备:
其中,P、R5、R6、R7和R8如之前对式(III)化合物的定义。
例如,将式(IV)化合物溶于合适的溶剂,例如吡啶中,并用合适的偶联剂,例如2-氯-5,5-二甲基-1,3,2-二氧杂磷杂环己烷2-氧化物处理,并在合适的温度,例如20℃下加热合适的时间段,例如1-3小时。通过加入合适的溶剂,例如水淬灭反应,然后在加入氧化剂,例如碘后,在合适的温度,例如20℃下搅拌合适的时间段,例如5分钟。通过除去溶剂来分离产物(IV),并且如果需要,进行纯化。
式(IV)化合物可以通过式(V)化合物与式(VI)化合物的反应制备:
其中,P、R5、R6、R7和R8如之前对式(III)化合物的定义,并且DMTr是4,4'-二甲氧基三苯甲基保护基。
例如,在分子筛存在下,将式(VI)化合物溶于合适的溶剂,例如乙腈中,并用溶于合适溶剂,例如乙腈中的式(V)化合物的溶液处理,并在合适的温度,例如20℃下搅拌合适的时间段,例如1-2小时。加入合适的氧化剂溶液,例如叔丁基过氧化氢的癸烷溶液,并将混合物在合适的温度,例如20℃下搅拌合适的时间段,例如0.5-1小时。在淬灭过量氧化剂,例如通过加入亚硫酸氢钠水溶液,并蒸发溶剂后,将残余物溶于合适的溶剂,例如二氯甲烷和水的混合物中,并用合适的试剂,例如二氯乙酸处理,并在合适的温度,例如20℃下搅拌合适的时间段,例如15分钟。通过加入合适的溶剂,例如吡啶,并通过蒸发浓缩,得到含有产物(IV)的溶液。
式(V)化合物可以通过式(VII)化合物的反应制备:
其中,R7和R8如之前对式(III)化合物的定义,并且DMTr是4,4'-二甲氧基三苯甲基保护基。
例如,将式(VII)化合物溶于合适的混合物,例如含有水的乙腈中,用三氟乙酸吡啶鎓处理,并在合适的温度,例如20℃下搅拌合适的时间段,例如1分钟,然后加入叔丁胺并将混合物在合适的温度,例如20℃下搅拌合适的时间段,例如10分钟。通过蒸发溶剂,然后溶于合适的溶剂,例如含有水的二氯甲烷中分离产物,用二氯乙酸处理并在合适的温度,例如20℃下搅拌合适的时间段,例如15分钟。通过加入吡啶,然后与无水乙腈共沸该混合物,得到产物(VII)的乙腈浓溶液。
式(VI)和(VII)的亚磷酰胺是文献中已知的,或可从供应商(例如Sigma、Chemgenes和CarboSynth)购买到,或者可以用文献中描述的方法制备。
本发明的方面通过参考以下实施例来说明但不以任何方式受限于以下实施例。
分析方法
1H NMR
1H NMR光谱在CDCl3、DMSO-d6、CD3CN或D2O中在Bruker DPX 400或Bruker AvanceDRX,Varian Unity 400光谱仪或JEOL Delta上记录,均在400MHz下工作。所用内标为四甲基甲硅烷或残留的质子化溶剂,对于CDCl3为7.25ppm,或对于DMSO-d6为2.50ppm。
LCMS
系统A
色谱柱:50mm x 2.1mm ID, 1.7μm Acquity UPLC CSH C18
流速:1mL/min.
温度:40℃
注射体积 0.3μL
UV检测范围:210至350nm
质谱:使用交替扫描正和负模式电喷雾离子化在质谱仪上记录
溶剂: A:10mM 碳酸氢铵水溶液,用氨溶液调节至pH10
B:乙腈
梯度: 时间 (min.) A% B%
0 97 3
0.05 97 3
1.5 5 95
1.9 5 95
2.0 97 3
系统B
色谱柱:50mm x 2.1mm ID, 1.7μm Acquity UPLC BEH C18
流速:1mL/min.
温度:40℃
UV检测范围:210至350nm
质谱:使用交替扫描正和负模式电喷雾离子化在质谱仪上记录
溶剂: A:10mM 碳酸氢铵水溶液,用氨溶液调节至pH10
B:乙腈
梯度: 时间 (min.) A% B%
0 99 1
1.5 3 97
1.9 3 97
2.0 99 1
系统C
LC: Waters Acquity二元溶剂管理器,色谱柱管理器 55 ℃
自动进样器: CTC Leap PAL自动进样器
UV: Waters Acquity PDA (210-350nm)
ELS: Waters Acquity ELSD (50℃)
MS; Waters Acquity SQD
极性(正或负);模式(连续介质);扫描时间(0.15s)
毛细管V(3500);锥体V(25-35);
色谱柱: Thermo Hypersil Gold (C18, 20x2.1 mm, 1.9 μm粒径)
溶剂A:H2O, 0.02% TFA
溶剂B: MeCN, 0.02% TFA
梯度:时间(min) 流速(mL/min) 溶剂B
0.02 1.6 2.0
1.90 1.6 95.0
1.91 停止 4.0
缩写
以下列表提供了本文所用的某些缩写的定义。应当理解,该列表不是穷尽的,但本文下面未定义的那些缩写的含义对于本领域技术人员将是非常明显的。
DCM 二氯甲烷
DMF N,N-二甲基甲酰胺
DMSO 二甲亚砜
DMTr 二甲氧基三苯甲基
THF 四氢呋喃
EtOAc 乙酸乙酯
MeOH 甲醇
EtOH 乙醇
MeCN 乙腈
HCl 盐酸
HPLC 高效液相色谱
MDAP 质量定向自动化制备HPLC
SPE 固相萃取
MeOH 甲醇
TBDMS 叔丁基二甲基甲硅烷基
TBME 叔丁基甲基醚
TFA 三氟乙酸
DIPEA N,N-二异丙基乙胺。
命名
使用Chem Draw(CambridgeSoft)或Marvin Sketch(ChemAxon)中的命名工具由结构命名化合物。
反应中间体
中间体1:(2R,3R,4R,5R)-5-(6-苯甲酰胺基-9H-嘌呤-9-基)-4-氟-2-(羟甲基)四
氢呋喃-3-基氢磷酸酯
在室温下向(2R,3R,4R,5R)-5-(6-苯甲酰胺基-9H-嘌呤-9-基)-2-((双(4-甲氧基苯基)(苯基)甲氧基)甲基)-4-氟四氢呋喃-3-基(2-氰基乙基)二异丙基亚磷酰胺(695 mg,0.793 mmol)的乙腈(4.1mL)和水(14.3 μl, 0.793 mmol)的溶液中加入三氟乙酸吡啶鎓(184 mg, 0.952 mmol)。将反应混合物在室温下搅拌1分钟。立即加入叔丁胺(3.96 ml,37.7 mmol),并将反应混合物在室温下搅拌10分钟。将反应混合物真空蒸发(35℃水浴),得到白色泡沫,将其溶于乙腈(10 mL)中,并真空蒸发,得到白色泡沫。将泡沫再次溶于乙腈(10mL)中,并真空蒸发,得到白色泡沫。将泡沫溶于二氯甲烷(19mL)和水(0.145mL,8.079mmol)中,加入二氯乙酸(0.576 mL, 6.98 mmol),并将红色溶液在室温下搅拌15分钟。反应混合物用吡啶(1.129 mL, 13.96 mmol)淬灭并真空浓缩至约3mL体积(35-40℃水浴)。将所得白色悬浮液与无水乙腈(5 x 6 mL)共沸5次(35-40℃水浴),在第一、第二、第三和第四共沸物上浓缩至约3mL体积,并在最终共沸物上浓缩至约2mL体积,得到不纯的题述 化合物的悬浮液。
LCMS (系统B):tRET = 0.50 min;MH- 436
用suba封条塞住烧瓶,用氮气抽空/冲洗,并将悬浮液立即用于下一反应。
中间体2:(2R,3R,4R,5R)-5-(6-苯甲酰胺基-9H-嘌呤-9-基)-2-((((((2R,3R,4R,
5R)-4-((叔丁基二甲基甲硅烷基)氧基)-5-(羟甲基)-2-(2-异丁酰胺基-6-氧代-1H-嘌呤-
9(6H)-基)四氢呋喃-3-基)氧基)(2-氰基乙氧基)磷酰基)氧基)甲基)-4-氟四氢呋喃-3-基
氢磷酸酯
将(2R,3R,4R,5R)-5-((双(4-甲氧基苯基)(苯基)甲氧基)甲基)-4-((叔丁基二甲基甲硅烷基)氧基)-2-(2-异丁酰胺基-6-氧代-1H-嘌呤-9(6H)-基)四氢呋喃-3-基(2-氰基乙基)二异丙基亚磷酰胺(1.00 g,1.031 mmol)溶于无水乙腈(3mL)中,加入四个3A分子筛,并将溶液在氮气氛下储存约45分钟。将该溶液经30秒滴加到粗(2R,3R,4R,5R)-5-(6-苯甲酰胺基-9H-嘌呤-9-基)-4-氟-2-(羟甲基)四氢呋喃-3-基氢磷酸酯(通过将0.793 mmol的4,4'-二甲氧基三苯甲基衍生物脱保护而制备)在无水乙腈(2 mL)的悬浮液中,并将该混合物在氮气氛下在室温下搅拌20分钟。加入无水叔丁基过氧化氢溶液(约5.5M,在癸烷中)(0.433 mL,2.379 mmol),并将反应混合物在室温下搅拌30分钟。加入更多的无水叔丁基过氧化氢溶液(约5.5M,在癸烷中)(0.072 mL,0.397 mmol),并将反应混合物在室温下搅拌20分钟,然后在冰/水浴中冷却,并用33%亚硫酸氢钠水溶液(0.464 mL)淬灭。将混合物真空蒸发,并将残余油状物在带塞的烧瓶中储存在冰箱中17小时。然后溶于二氯甲烷(25 mL)和水(0.145 mL,8.079 mmol)中。加入二氯乙酸(0.759 mL,9.20 mmol),并将橙色溶液在室温下搅拌15分钟。反应混合物用无水吡啶(8 mL)淬灭,并真空浓缩(35-40℃水浴)至约8 mL体积。加入另外的无水吡啶(20 mL),并将反应混合物再次真空浓缩(35-40℃水浴)至约8 mL体积。将与吡啶(20 mL)的共沸再重复一次得到不纯的题述化合物在吡啶中的溶液(8 mL)。
LCMS (系统A):tRET = 0.88 min;MH+ 1020
该溶液立即用在下一反应中。
中间体3:N-{9-[(1R,6R,8R,9R,10R,15R,17R,18R)-18-[(叔丁基二甲基甲硅烷
基)氧基]-3-(2-氰基乙氧基)-9-氟-12-羟基-17-[2-(2-甲基丙酰胺基)-6-氧代-6,9-二
氢-1H-嘌呤-9-基]-3,12-二氧代-2,4,7,11,13,16-六氧杂-3λ5,12λ5-二磷杂三环
[13.2.1.06,10]十八烷-8-基]-9H-嘌呤-6-基}苯甲酰胺
向不纯的(2R,3R,4R,5R)-5-(6-苯甲酰胺基-9H-嘌呤-9-基)-2-((((((2R,3R,4R,5R)-4-((叔丁基二甲基甲硅烷基)氧基)-5-(羟甲基)-2-(2-异丁酰胺基-6-氧代-1H-嘌呤-9(6H)-基)四氢呋喃-3-基)氧基)(2-氰基乙氧基)磷酰基)氧基)甲基)-4-氟四氢呋喃-3-基氢磷酸酯(由从0.793 mmol的(2R,3R,4R,5R)-5-(6-苯甲酰胺基-9H-嘌呤-9-基)-2-(双(4-甲氧基苯基(苯基)甲氧基)甲基)-4-氟四氢呋喃-3-基(2-氰基乙基)二异丙基亚磷酰胺开始的序列反应制备)在无水吡啶(8 mL)中的溶液加入更多的无水吡啶(16 mL)。加入2-氯-5,5-二甲基-1,3,2-二氧杂磷杂环己烷2-氧化物(512 mg,2.78 mmol),并在氮气氛下将反应混合物在室温下搅拌1小时。然后加入更多的2-氯-5,5-二甲基-1,3,2-二氧杂磷杂环己烷2-氧化物(512 mg,2.78 mmol),并在氮气氛下将反应混合物在室温下再搅拌50分钟。加入另一份2-氯-5,5-二甲基-1,3,2-二氧杂磷杂环己烷2-氧化物(146 mg,0.793 mmol),并将反应混合物搅拌25分钟。当加入更多的2-氯-5,5-二甲基-1,3,2-二氧杂磷杂环己烷2-氧化物(512 mg,2.78 mmol时,将反应混合物再搅拌25分钟。用水(1.644 ml,91.33 mmol)淬灭反应,并立即加入碘(262 mg,1.031 mmol)。将反应混合物在室温下搅拌5分钟,然后倾倒入0.14%的亚硫酸氢钠水溶液(115 mL)中。5分钟后,分批加入固体碳酸氢钠(3.210 g),混合物用乙酸乙酯(125 mL)萃取。分离有机层,并用乙酸乙酯 (125 mL)反萃取水溶液层。有机层合并,通过疏水玻璃料,并真空蒸发,得到橙色油状物(2.88 g)。将该粗产物的一部分(1 g)溶于最小体积的二氯甲烷中,施加到10%甲醇的二氯甲烷溶液预处理的100g硅胶短柱上,并使用10-40%甲醇/二氯甲烷梯度洗脱20个柱体积(检测波长280nm)。合并适当的级分,并真空蒸发,得到浅黄色固体(120 mg),通过LCMS证实包含所期望的产物。将该粗产物的剩余部分(1.88 g)溶于最小体积的二氯甲烷中,施加到10%甲醇的二氯甲烷溶液预处理的340g硅胶短柱上,并使用10-40%甲醇/二氯甲烷梯度洗脱19个柱体积(检测波长280nm),
合并适当的级分,并真空蒸发,得到另两批不纯产物(110 mg和27 mg)。这三批产物合并得到不纯的标题化合物,为浅黄色固体(257 mg)。
LCMS (系统A):tRET = 0.89-0.93 min;MH+ 1018
该材料直接用在下一反应中。
中间体4:(1R,6R,8R,9R,10R,15R,17R,18R)-17-(2-氨基-6-氧代-6,9-二氢-1H-
嘌呤-9-基)-8-(6-氨基-9H-嘌呤-9-基)-18-[(叔丁基二甲基甲硅烷基)氧基]-9-氟-3,12-
二羟基-2,4,7,11,13,16-六氧杂-3λ5,12λ5-二磷杂三环[13.2.1.06,10]十八烷-3,12-二酮
向粗N-{9-[(1R,6R,8R,9R,10R,15R,17R,18R)-18-[(叔丁基二甲基甲硅烷基)氧基]-3-(2-氰基乙氧基)-9-氟-12-羟基-17-[2-(2-甲基丙酰胺基)-6-氧代-6,9-二氢-1H-嘌呤-9-基]-3,12-二氧代-2,4,7,11,13,16-六氧杂-3λ5,12λ5-二磷杂三环[13.2.1.06,10]十八烷-8-基]-9H-嘌呤-6-基}苯甲酰胺(257 mg,0.252 mmol)在甲醇(7 mL)的溶液中加入0.88 氨溶液(7 mL)。将悬浮液在密封的微波小瓶中在50℃下搅拌并加热47小时,然后冷却并真空蒸发(在蒸发期间将甲醇加入到反应混合物中以减少起泡),得到浅黄色固体(268mg)。将该材料溶解在甲醇(10 mL)中,并加入0.88 氨溶液(8 mL),然后将悬浮液在密封的微波小瓶中在50℃下再搅拌23小时。反应混合物冷却并真空蒸发(在蒸发期间将甲醇加入到反应混合物中以减少起泡),得到浅黄色固体(280 mg),将其溶于最小体积的DMSO中,施加到预处理的反相Biotage 120g KP-C18-HS短柱上,并使用10 mM碳酸氢铵水溶液中的0-35%乙腈(+0.1% 0.88氨溶液)(用氨溶液调节至pH 10)梯度洗脱16个柱体积(检测波长254nm)。合并适当的级分,并真空蒸发,得到标题化合物,为浅黄色固体(45 mg)。
LCMS (系统A):tRET = 0.54 min;MH- 789
中间体5:(2R,3R,4R,5R)-5-(6-苯甲酰胺基-9H-嘌呤-9-基)-2-((((((2R,3R,4R,
5R)-2-(6-苯甲酰胺基-9H-嘌呤-9-基)-4-((叔丁基二甲基甲硅烷基)氧基)-5-(羟甲基)四
氢呋喃-3-基)氧基)(2-氰基乙氧基)磷酰基)氧基)甲基)-4-氟四氢呋喃-3-基氢磷酸酯
在室温下在N2气氛下向(2R,3R,4R,5R)-5-(6-苯甲酰胺基-9H-嘌呤-9-基)-4-氟-2-(羟甲基)四氢呋喃-3-基氢磷酸酯 (如上所示制备的中间体1)(1.093 g,2.5 mmol)在乙腈(6 mL)的悬浮液中加入(2R,3R,4R,5R)-2-(6-苯甲酰胺基-9H-嘌呤-9-基)-5-((双(4-甲氧基苯基)(苯基)甲氧基)甲基)-4-((叔丁基二甲基甲硅烷基)氧基)四氢呋喃-3-基 (2-氰基乙基)二异丙基亚磷酰胺(3.21 g,3.25 mmol)在乙腈(10.00 mL)的溶液中(注意:两个溶液都用活化3A分子筛预干燥约1小时)。在室温下在N2气氛下将该混合物搅拌15分钟。加入无水叔丁基过氧化氢溶液(约5.5M,在癸烷中)(1.364 mL,7.50 mmol),并将反应混合物在室温下搅拌30分钟。将反应在冰/水浴中冷却,并用亚硫酸氢钠(NaHSO3,33%水溶液)(1.250mL,6.00 mmol)淬灭。移除冰/水浴,并将混合物搅拌5分钟。将混合物浓缩至小体积,然后溶解在二氯甲烷(80.00 mL)中,随后加入水 (0.450 mL,25.00 mmol),然后是2,2-二氯乙酸(2.475 mL,30.0 mmol)。将混合物在室温下搅拌10分钟,然后用吡啶(25.00 mL)淬灭。浓缩混合物,然后加入另一份吡啶(75.00 mL)并将其浓缩至~50 mL,得到在吡啶中的不纯标题 化合物的溶液(~50 mL)。
LCMS (系统C):tRET = 1.04-1.08 min;MH+ 1038
该材料直接用在下一反应中。
中间体6:N-{9-[(1R,6R,8R,9R,10R,15R,17R,18R)-17-(6-苯甲酰胺基-9H-嘌呤-
9-基)-18-[(叔丁基二甲基甲硅烷基)氧基]-3-(2-氰基乙氧基)-9-氟-12-羟基-3,12-二氧
代-2,4,7,11,13,16-六氧杂-3λ5,12λ5-二磷杂三环[13.2.1.06,10]十八烷-8-基]-9H-嘌呤-
6-基}苯甲酰胺
向上述得到的(2R,3R,4R,5R)-5-(6-苯甲酰胺基-9H-嘌呤-9-基)-2-((((((2R,3R,4R,5R)-4-((叔丁基二甲基甲硅烷基)氧基)-5-(羟甲基)-2-(2-异丁酰胺基-6-氧代-1H-嘌呤-9(6H)-基)四氢呋喃-3-基)氧基)(2-氰基乙氧基)磷酰基)氧基)甲基)-4-氟四氢呋喃-3-基氢磷酸酯(2.55 g,2.5 mmol)在吡啶(50.00 mL)中的不纯溶液中加入2-氯-5,5-二甲基-1,3,2-二氧杂磷杂环己烷2-氧化物(DMOCP) (1.615 g,8.75 mmol)。将该混合物在室温下在N2下搅拌30分钟。通过加入水(1.576 mL,88 mmol) (相对于DMOCP为10当量)淬灭反应,随后加入I2(0.825 g,3.25 mmol)。将混合物搅拌5分钟,然后倾倒人含有亚硫酸氢钠(NaHSO3) (0.520 g,5.00 mmol)的水(350 mL)中。搅拌5分钟后,缓慢加入碳酸氢钠(NaHCO3) (10.50 g,125 mmol) (注意:气体放出),并将混合物搅拌5分钟。将产物用EtOAc(400 mL x 2) 萃取,萃取液合并并浓缩。通过用甲苯 (5 mL x 2)浓缩除去过量的吡啶。将残余物分成三份,并将每份都用硅胶快速层析 (Biotage, 50 g 快速层析色谱柱, 0-30%MeOH/DCM)进行纯化。将所期望的级分合并并浓缩得到不纯的标题化合物,为白色固体(0.84 g)。
LCMS (系统C):tRET = 0.95-0.99 min;MH+ 1036
该材料直接用在下一反应中。
中间体7:(1R,6R,8R,9R,10R,15R,17R,18R)-8,17-双(6-氨基-9H-嘌呤-9-基)-
18-[(叔丁基二甲基甲硅烷基)氧基]-9-氟-3,12-二羟基-2,4,7,11,13,16-六氧杂-3λ5,12
λ5-二磷杂三环[13.2.1.06,10]十八烷-3,12-二酮双铵盐
将不纯的N-{9-[(1R,6R,8R,9R,10R,15R,17R,18R)-17-(6-苯甲酰胺基-9H-嘌呤-9-基)-18-[(叔丁基二甲基甲硅烷基)氧基]-3-(2-氰基乙氧基)-9-氟-12-羟基-3,12-二氧代-2,4,7,11,13,16-六氧杂-3λ5,12λ5-二磷杂三环[13.2.1.06,10]十八烷-8-基]-9H-嘌呤-6-基}苯甲酰胺(0.84 g)和甲胺(33wt%,在EtOH中)(40.4 ml,324 mmol)的混合物在室温下搅拌20小时。将混合物浓缩,残余物在Gilson 反相HPLC (phenomenex Gemini-NX 5u C18(2) 100A, AXIA. 30x100 mm 5 微米, 40mL/min, 0-40% CH3CN/H2O (含有0.1% NH4OH),在214nm进行UV检测)上进行纯化。将适当的级分合并并浓缩得到为双铵盐的不纯的标题化 合物,为白色固体(0.32 g)。
LCMS (系统C):tRET = 0.66 min;MH+ 775。
实施例
实施例1:(1R,6R,8R,9R,10R,15R,17R,18R)-17-(2-氨基-6-氧代-6,9-二氢-1H-
嘌呤-9-基)-8-(6-氨基-9H-嘌呤-9-基)-9-氟-3,12,18-三羟基-2,4,7,11,13,16-六氧杂-
3λ5,12λ5-二磷杂三环[13.2.1.06,10]十八烷-3,12-二酮双铵盐
将(1R,6R,8R,9R,10R,15R,17R,18R)-17-(2-氨基-6-氧代-6,9-二氢-1H-嘌呤-9-基)-8-(6-氨基-9H-嘌呤-9-基)-18-[(叔丁基二甲基甲硅烷基)氧基]-9-氟-3,12-二羟基-2,4,7,11,13,16-六氧杂-3λ5,12λ5-二磷杂三环[13.2.1.06,10]十八烷-3,12-二酮 (45 mg,0.057 mmol)悬浮在吡啶(0.8 ml)中,并将混合物在50℃的油浴中在氮气下加热。经1分钟同时滴加三乙胺(1.0 mL)和三乙胺三氢氟酸盐(0.46 ml,2.84 mmol) ,随后在50℃搅拌2.5小时。使所得溶液冷却至室温,此时经2分钟滴加HPLC级丙酮(6 mL)。使所得非常细的悬浮液沉降。滗掉大部分的液体部分,并连续用丙酮(2 x 3 mL)洗涤淤浆。将所得湿固体真空干燥而得到无色油状物,将其溶于最小体积的水中,施加到预处理的反相Biotage 60g KP-C18-HS短柱上,并使用用氨溶液调节至pH 10的10 mM碳酸氢铵水溶液(3个柱体积)洗脱,随后用10 mM碳酸氢铵水溶液中的0-15%乙腈(+0.1% 0.88氨溶液)(用氨溶液调节至pH 10)梯度洗脱17个柱体积(检测波长254nm)。合并适当的级分,并真空蒸发,得到标题化合物,为白色固体(21 mg)。
LCMS (系统A):tRET = 0.18 min;MH+ 677
精确质量 MH+ 677.1039;C20H24O12N10FP2要求 MH+ 677.1029
该化合物用类似于Li等人 (Nature Chemical Biology, 10, 1043-1048,(2014))描述的STING结合试验进行测试并具有>7的pIC50。
实施例2:(1R,6R,8R,9R,10R,15R,17R,18R)-8,17-双(6-氨基-9H-嘌呤-9-基)-9-
氟-3,12,18-三羟基-2,4,7,11,13,16-六氧杂-3λ5,12λ5-二磷杂三环[13.2.1.06,10]十八
烷-3,12-二酮双铵盐
在带有排气针的小瓶中将上述得到的不纯(1R,6R,8R,9R,10R,15R,17R,18R)-8,17-双(6-氨基-9H-嘌呤-9-基)-18-((叔丁基二甲基甲硅烷基)氧基)-9-氟-3,12-二羟基-2,4,7,11,13,16-六氧杂-3λ5,12λ5-二磷杂三环[13.2.1.06,10]十八烷-3,12-二酮 (中间体7) (200 mg,0.247 mmol)在吡啶(4 mL)和三乙胺(4.00 mL)中的悬浮液加热至50℃。然后加入三乙胺三氢氟酸盐(1.007 mL,6.18 mmol),并将混合物在50℃搅拌2小时。向混合物中加入HPLC级丙酮(10 mL)并搅拌10分钟。通过过滤收集所得沉淀并用丙酮(5 x 1 mL)彻底淋洗。将产物在Gilson 反相HPLC (phenomenex Gemini-NX 5u C18(2) 100A, AXIA.30x100 mm 5 微米, 40mL/min, 0-10% CH3CN/H2O (含有0.1% NH4OH), 在214nm进行UV检测)上进行纯化。将适合的级分合并并浓缩。残余物进一步在制备HILIC色谱柱(Luna HILIC5u 21 x 250 mm, 20%NH4HCO2H水溶液 (30 mM;pH 4)和80% CH3CN, 20 ml/min,在254 nm进行UV检测)上纯化。将适合的级分合并并蒸发以除去CH3CN,然后冻干。然后加入水(10mL),接着冻干。再加入10 mL水,同时加入5滴浓NH4OH,并再次冻干得到为双铵盐的标题化 合物,为白色固体(45 mg)。
LCMS (系统C):tRET = 0.18 min;MH+ 661
1H NMR (400 MHz, D2O) δ 8.30 (s, 1H), 8.06 (br. s., 1H), 7.95 (br. s.,2H), 6.27 (d, J=15.97 Hz, 1H), 6.14 (d, J=8.11 Hz, 1H), 5.47 (d, J=51.71 Hz,1H), 5.05-5.18 (m, 1H), 4.82-4.97 (m, 1H), 4.48-4.56 (m, 1H), 4.39-4.47 (m,1H), 4.33 (br. s., 1H), 4.15-4.31 (m, 2H), 3.95-4.09 (m, 2H).
实施例3:实施例1化合物的佐剂活性的评估
缩写列表
• IM – 肌内注射
• HBsAg – 乙型肝炎病毒抗原
• 14dp1 – 初次接种疫苗后14天
• 14dp2 – 二次接种疫苗后14天
• ELISA – 酶联免疫吸附测定
• LLOQ – 定量下限
• CDN – 环状二核苷酸
• STING – 干扰素基因刺激蛋白
• IFN – 干扰素
• TNF – 肿瘤坏死因子
• 1401A - GSK3371401A – GSK药物公司修饰的CDN
• IP – 知识产权
• HBsAg – 乙型肝炎病毒表面抗原
• ICS – 细胞内细胞因子染色
• Ab - 抗体。
本研究的目的是在小鼠中使用HBsAg模型评估本发明的STING激动剂作为佐剂的潜力。本研究比较了含有实施例1的化合物的佐剂化制剂与经典的哺乳动物产生的STING激动剂cGAMP的制剂的免疫原性。本研究旨在评估:1)通过IM施用的1401A的总全身佐剂剂量反应;2)与cGAMP、明矾或非佐剂疫苗相比,对用实施例1的化合物作为佐剂的疫苗的IgG1和IgG2a亚型特异性免疫应答;3)对用实施例1的化合物、cGAMP或明矾作为佐剂的疫苗产生的T细胞细胞因子谱。
雌性Balb/C小鼠IM接种。
使用实施例1的这种化合物的四种不同剂量来评估剂量反应。以21天间隔肌内递送疫苗两次,并评估血清的全身抗体反应。收集脾(3只小鼠/组)用于进行Luminex/ICS分析。
初次接种后14天和二次疫苗接种后14天收获血清。血清通过ELISA评价抗HBsAgIgG,IgG1和IgG2a效价。
二次疫苗接种后5天收获脾脏,并进行处理用于流式细胞术ICS分析。除了进行活体/死亡染色外,分析脾细胞的细胞标志物CD3、CD4、CD8。细胞进一步染色用于胞内细胞因子IL-2、IL-4、IFNγ、TNFα和IL-17。
总结
乙型肝炎表面抗原(HBsAg)在肌内注射(IM)施用并用干扰素基因刺激蛋白(STING)激动剂cGAMP或实施例1的化合物作为佐剂时,是强免疫原性的,具有高水平的HBsAg特异性血清IgG。
当IM施用时,实施例1的化合物和cGAMP都显著辅助对HBsAg的免疫应答。IM接种的小鼠中的抗HBsAg效价显著高于未佐剂化的基准。加入实施例1的化合物导致剂量反应性HBsAg特异性IgG水平。相对于剂量,在经典的哺乳动物产生的STING激动剂cGAMP和实施例1的化合物之间没有观察到抗体效价的显著差异。
施用CDN的小鼠组的HBsAg特异性IgG2a水平显著高于接受明矾的小鼠中观察到的HBsAg特异性IgG2a水平,表明强烈的Th1型反应。HBsAg特异性的IgG1抗体水平与用明矾和CDN作为佐剂的组相似。
流式细胞术和ICS数据支持在用CDN作为佐剂的小鼠组中观察到的强烈的Th1型反应。对IFN-γ染色阳性的CD4+细胞的数量在用CDN处理的小鼠的再刺激脾细胞中比在明矾或非佐剂组中看到的水平高。
Claims (5)
2.一种药物组合物,其包含根据权利要求1所述的式(I)的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的赋形剂。
3.根据权利要求1所述的式(I)的化合物或其药学上可接受的盐在制备用于治疗其中STING的调节有益的疾病和病症的药物中的用途。
4.一种组合产品,其包含根据权利要求1所述的式(I)的化合物或其药学上可接受的盐和至少一种另外的治疗剂。
5.包含根据权利要求1所述的式(I)的化合物或其药学上可接受的盐和至少一种另外的治疗剂的组合产品在制备用于治疗其中STING的调节有益的疾病和病症的药物中的用途。
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IL252935A0 (en) | 2017-08-31 |
MX2017009837A (es) | 2018-02-09 |
JP6722682B2 (ja) | 2020-07-15 |
PH12017501233A1 (en) | 2017-10-30 |
CR20170350A (es) | 2017-12-05 |
PE20171322A1 (es) | 2017-09-11 |
WO2016120305A1 (en) | 2016-08-04 |
EP3250573A1 (en) | 2017-12-06 |
BR112017016006A2 (pt) | 2018-03-20 |
JP2018507192A (ja) | 2018-03-15 |
US10047115B2 (en) | 2018-08-14 |
US20180002369A1 (en) | 2018-01-04 |
AU2016212085B2 (en) | 2018-06-14 |
CN107108684A (zh) | 2017-08-29 |
GB201501462D0 (en) | 2015-03-18 |
SG11201705077VA (en) | 2017-07-28 |
KR20170102362A (ko) | 2017-09-08 |
DOP2017000175A (es) | 2017-09-15 |
CL2017001932A1 (es) | 2018-02-16 |
EA201791607A1 (ru) | 2018-01-31 |
CO2017007293A2 (es) | 2017-10-31 |
CA2973806A1 (en) | 2016-08-04 |
EA031728B1 (ru) | 2019-02-28 |
MA41415A (fr) | 2017-12-05 |
ZA201704732B (en) | 2019-02-27 |
AU2016212085A1 (en) | 2017-07-20 |
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