CN101304748A - Tlr激动剂 - Google Patents
Tlr激动剂 Download PDFInfo
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- CN101304748A CN101304748A CNA200680038761XA CN200680038761A CN101304748A CN 101304748 A CN101304748 A CN 101304748A CN A200680038761X A CNA200680038761X A CN A200680038761XA CN 200680038761 A CN200680038761 A CN 200680038761A CN 101304748 A CN101304748 A CN 101304748A
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Abstract
本发明提供了TLR激动剂轭合物(化合物)和组合物,以及使用它们的方法。本发明化合物是广谱性的、耐用的且无毒的合成免疫激活剂的结合,其对于活化哺乳动物、优选人的免疫系统是有益的,并且有助于将药效基团引至靶细胞核内体中的受体上,增强该药效基团诱导的信号转导。
Description
相关申请
本申请要求以2005年8月22日提交的序列号为60/710,337的美国临时申请作为优先权基础,该申请的内容以引用的方式纳入本说明书。
政府资助
本文所述发明是在美国国立卫生研究院给予的编号为3 UO1 AI056453-01的政府甚金的资助下完成的。美国政府对于本发明享有一定权利。
背景技术
最近十年来已获悉很多关于微生物病原体的先天识别的分子机理。普遍接受的是,许多体细胞能够表达多种能检测与适应性免疫系统无关的潜在病原体的模式识别受体。(见Janeway et al.,Annu Rev Immunol,20:197-216(2002)。)认为所述受体与被称为病原体相关分子模式(PAMP)的微生物组分相互作用。PAMP的实例包括肽聚糖、革兰氏阳性细胞壁中的脂磷壁酸、甘露糖(其通常存在于微生物的碳水化合物中,但在人体内罕有)、细菌的DNA、病毒的双链RNA,以及真菌细胞壁中的葡聚糖。PAMP通常满足某些标准,所述标准包括:(a)它们由微生物表达而不是由微生物的哺乳动物宿主表达,(b)在多种不同的病原体中都具有保守的结构,和(c)能够激活先天免疫。已发现toll样受体(TLR)在PAMP检测中和对微生物感染的早期应答中发挥关键性作用。(见Underhill et al.,Curr Opin Immunol,14:103-110(2002)。)已经识别了十种哺乳动物的TLR和许多这些TLR的激动剂。例如,TLR7和TLR9分别对咪喹莫特(imiquimod)和免疫激活剂CpG寡核苷酸(ISS-ODN)进行识别和应答。合成免疫调节剂R-848(雷西莫特(res iquimod))能够激活TLR7和TLR8。尽管TLR的激活能够引发共有的信号级联反应(包括衔接蛋白MyD88、转录因子NF-kB、以及促炎细胞因子和效应细胞因子),但某种细胞类型仍倾向于产生特定的TLR。例如,TLR7和TLR9主要存在于树突状细胞(DC)与B淋巴细胞中的内体的内表面上(在人体内;小鼠的巨噬细胞表达TLR7和TLR9)。另一方面,TLR8存在于人的血液单核细胞中。(见Hornung et al.,J.Immunol,168:4531-4537(2002))。
干扰素(INF)类也涉及免疫响应的有效诱导,尤其在病毒感染之后(Brassard et al.,J.Leukoc Biol,71:568-581(2002).)。但是,许多病毒能产生多种在各种水平阻碍干扰素的产生或作用的蛋白质。干扰素的拮抗被认为是一种规避先天性免疫以及适应性免疫的一般策略。(见Levy et al.,Cytokine Growth Factor Rev,12:143-156(2001)。)尽管TLR激动剂(TLR-L)对一些治疗方法来说可以具有足够的活性,但是在一些情况下微生物干扰素拮抗剂能够减小合成性TLR-L的辅助效果。
因此,需要能增强TLR诱导的信号转导的化合物,即需要能够抑制病毒或细菌对于干扰素产生的阻碍的化合物,或能够调节与TLR激动剂相关的先天性免疫系统的化合物。
发明内容
本发明提供了TLR激动剂轭合物(化合物)和组合物,以及它们的使用方法。本发明化合物是广谱性的、长效的且无毒的合成免疫刺激剂的结合,其可用于激活哺乳动物、优选人的免疫系统,并有助于将药效基团引至靶细胞内体中的受体上,并增强该药效基团诱导的信号转导。本发明的化合物含有共价连接至辅助基团上的药效基团。因此本发明提供一种式(I)化合物或其可药用的盐:
其中X1为-O-、-S-或-NRc-;
其中Rc为氢、C1-10烷基或被C3-6-环烷基取代的C1-10烷基,或者Rc和R1与氮原子一起形成一个杂环或一个被取代的杂环,其中取代基为羟基、C1-6烷基、羟基C1-6亚烷基、C1-6烷氧基、C1-6烷氧基C1-6亚烷基,或氰基;
R1为(C1-C10)烷基、被取代的(C1-C10)烷基、C6-10芳基、被取代的C6-10芳基、C5-9杂环基、或被取代的C5-9杂环基;
每一个R2独立地为氢、-OH、(C1-C6)烷基、被取代的(C1-C6)烷基、(C1-C6)烷氧基、被取代的(C1-C6)烷氧基、-C(O)-(C1-C6)烷基(烷酰基)、被取代的-C(O)-(C1-C6)烷基、-C(O)-(C6-C10)芳基(芳酰基)、被取代的-C(O)-(C6-C10)芳基、-C(O)OH(羧其)、-C(O)O(C1-C6)烷基(烷氧基羰基)、被取代的-C(O)O(C1-C6)烷基、-NRaRb、-C(O)NRaRb(氨甲酰基)、被取代的-C(O)NRaRb、卤代、硝基或氰基;
每一个Ra和Rb独立地为氢、(C1-C6)烷基、(C3-C8)环烷基、(C1-C6)烷氧基、卤代(C1-C6)烷基、(C3-C8)环烷基(C1-C6)烷基、(C1-C6)烷酰基、羟基(C1-C6)烷基、芳基、芳基(C1-C6)烷基、Het、Het(C1-C6)烷基或(C1-C6)烷氧基羰基;
X2为一个键或一个连接基团;R3为一个辅助基团;
n为1、2、3或4;m为1或2;q为1或2。
辅助基团可以包括由碳、氧、氢、氮、硫、磷原子组成的有机分子。这些基团对身体组织无害(例如,它们是无毒的和/或不会引起炎症)。
此外,本发明还提供了一种药物组合物,所述药物组合物含有至少一种式(I)的化合物或其可药用的盐,并与可药用的稀释剂或载体相结合。
在一个实施方案中,本发明提供了一种预防或治疗哺乳动物,例如人的病理病症或症状的治疗方法,其中涉及TLR激动剂的活性并且需要激发所述TLR激动剂的,所述方法包括将有效量的一种式(I)化合物或其可药用的盐给药至需要所述治疗的哺乳动物。适于治疗的病理病症或症状的非限制性实例包括癌症、细菌性或病毒性疾病的治疗、自身免疫性疾病的治疗,以及克罗恩病的治疗。
本发明的化合物也可用作或用于制备抵抗细菌、病毒、癌细胞、癌特异性肽的疫苗,抗癌的单克隆抗体的增强剂,CNS兴奋剂或用于生物防御。
本发明提供了用于医学疗法的式(I)化合物(例如,用作抗癌剂、细菌性疾病的治疗、病毒性疾病例如丙型肝炎和乙型肝炎的治疗、克罗恩病的治疗,和用作治疗免疫性疾病的治疗剂)。此外,认为式(I)化合物能预防丙型肝炎和乙型肝炎的致癌作用,并提供了式(I)化合物用于制备治疗哺乳动物例如人的癌症、病毒性疾病、克罗恩病和免疫疾病的药物的用途。
在一个具体实施方案中,本发明提供了一种通过给予式(I)的TLR激动剂化合物治疗哺乳动物病毒感染的方法。该病毒感染可由RNA病毒、起TLR激动剂作用的RNA病毒的产物和/或DNA病毒引起。可治疗的一种具体的DNA病毒为乙型肝炎病毒。
在另一具实方案中,本发明提供了一种通过给予有效量的式(I)的TLR激动剂化合物治疗癌症的方法。所述癌症可以是一种干扰素敏感性癌症,例如,白血病、淋巴瘤、骨髓瘤、黑素瘤或肾癌。
在另一具体实施方案中,本发明提供了一种通过给予治疗有效量的式(I)的TLR激动剂化合物或该化合物的可药用盐来治疗自身免疫性疾病的方法。具体的自身免疫性疾病为多发性硬化、狼疮、风湿性关节炎等。
在另一具体实施方案中本发明提供了一种通过给药式(I)的TLR激动剂化合物治疗克罗恩病的方法。
TLR激动剂可以是功能相同的TLR激动剂的聚合物,并且可由一种TLR-7激动剂或一种TLR-8激动剂构成。TLR7激动剂可为7-硫代-8-氧鸟苷基(OG)部分、7-去氮鸟苷基(7DG)部分、雷西莫特部分或咪喹莫特部分。TLR8激动剂可为雷西莫特部分。另一方面,TLR激动剂为功能不同的TLR激动剂的聚合物。功能不同的TLR激动剂的聚合物可以包括TLR-7激动剂和TLR-8激动剂或TLR-9激动剂或所有这三种激动剂。功能不同的TLR激动剂的聚合物可以包括TLR-8激动剂和TLR-9激动剂。
本发明还提供了本文所公开的用于制备式(I)的化合物或其盐的方法和中间体。
附图说明
图1为一种式(I)化合物(OVA/IV150轭合物)的吸收发色团(~350nm处)的图解说明。
图2为骨髓来源树突状细胞(BMDC)激活作用的图解明。
图3说明了一种TLR7激动剂UC-1V150对小鼠血清白蛋白(MSA)的轭合作用。所述轭合作用的成功通过UV光谱显示。UC-1V150与MSA的比例约为5∶1。
图4A和B说明了UC-1V150和MSA的轭合物能够激活鼠类动物的骨髓来源巨噬细胞(4A)和人外周血液单核细胞(4B)。将细胞与0.5nM-10μM的多种浓度的化合物在BMDM中培养,或与0.1-10μM的多种浓度的化合物在PBMC中培养。24h后收集培养上清液并用Luminex分析细胞因子水平。
图5A、5B、5C和5D说明了UC-1V150/MSA的药效的增加和作用时间的延长。每只C57BL/6小鼠用以下物质注射(静脉内):(A)0.1微摩尔SM-360320--一种TLR7配体,或(B)等量的TLR7激动剂UC-1V150(醛基修饰的SM-360320)或UC-1V150/MSA或500μg MSA。在指定时间点时收集血清试样并用Luminex分析细胞因子。MSA=小鼠血清白蛋白。原始TLR7配体——SM-360320的作用仅持续2小时,而UC-1V150/MSA能持续作用至少6小时。
图6说明了与失活的SIV轭合的UC-IV150(6A)和与OVA和/或ODN轭合的UC-1V150(6B)的作用情况。如图所示用0.1μg/ml的浓度将骨髓性BMDC在多种条件下培养24h。用ELISA测量细胞上清液中IL-12的水平。
图7A和7B说明了UC-1V150/MSA药效的增加。用380纳摩尔SM-360320或UC-1V150、或500μg UC-1V150/MSA(相当于3.8纳摩尔UC-1V150)对每只C57BL/6小鼠进行静脉内注射。2h后采集血清样本并用Luminex分析细胞因子水平。为达到类似效果,UC-1V150或SM-360320的浓度需要比UC-1V150/MSA的浓度高出至少100倍。
图8为一种双轭合物(OVA/IV150/1043)的uv光谱的示意图。
图9为用OVA/ODN/IV150轭合物在BMDC中诱导IL-12的示意图。
图10说明SIV颗粒对IA化合物IV150的直接轭合作用。
图11说明用连至式IA化合物的病毒颗粒来制备本发明化合物的能力以及本发明化合物的TLR激动剂活性。
图12说明针对于含有连接物和TLR配体的轭合物的抗体所特异性针对的分子区域。
图13A和13B说明了Western印迹分析中加入到凝胶各泳道的四种物质之间的区别。在图13A中,凝胶膜用抗卵清蛋白(抗OVA)抗体进行检测,所有泳道均得到阳性条带,表明同所预期的一样在所有泳道均检测到OVA。在图13B中,凝胶膜用针对轭合物的TLR配体部分选择性抗体进行检测,而只有泳道4呈阳性,证实了抗体对于TLR配体的特异性。
具体实施方式
辅助基团的非限制性实例包括能增加溶解性的侧链,例如含有吗啉环、哌啶环、吡咯烷环或哌嗪环等的基团;氨基酸类、氨基酸聚合物类(蛋白质或肽),例如二肽或三肽等;碳水化合物(多糖)、核苷酸,例如PNA、RNA和DNA等;有机物质聚合物,例如聚乙二醇、聚交酯等;单体脂质和聚合脂质;不溶性有机纳米颗粒;无毒的机体物质,例如细胞类、脂质类、维生素类、辅助因子类、抗原类,例如微生物,所述微生物例如病毒、细菌、真菌等。抗原类可以包括失活的整个生物体或其亚组分等。
本发明的化合物可使用式(IA)的化合物进行制备:
其中X为一个能够反应而形成与连接基团连接的键或能够反应而形成与辅助基团连接的键的基团。具有式(IA)的化合物的具体基团在美国专利6,329,381中被公开。
除非另有所述,否则使用以下定义:卤代指氟代、氯代、溴代或碘代。烷基、烷氧基、烯基、炔基等表示直链和支链基团;但是当具体提及了支链异构体例如“异丙基”时,再提及的个体基团例如“丙基”就仅包含直链基团。芳基表示苯基基团或具有约9至10个环原子并且环中至少一个环是芳香族环的单边稠合双环碳环基团。杂芳基包括经由含5或6个环原子的单环芳环的环碳原子连接的基团,所述环原子由碳原子和1-4个杂原子组成,所述杂原子各自选自非过氧化物的氧、硫和N(X),其中X不存在或为H、O、(C1-C4)烷基、苯基或苯甲基,以及由上述基团衍生出的约8至10个环原子的单边稠合双环杂环,特别是苯衍生物,或者通过将1,2-亚丙基、1,3-亚丙基或1,4-亚丁基双基稠合于其上而得到的衍生物。
本领域技术人员应当理解的是,具有一个手性中心的本发明化合物可以以旋光活性体和外消旋体形式存在,并且可以以旋光活性体和外消旋体的形式被分离。一些化合物可能具有多晶型性。应该理解的是,本发明包括本发明化合物的任意外消旋体、旋光活性体、同质多晶体或立体异构体,或它们的混合物,本发明化合物具有本文所述的有用特性,本领域公知如何制备旋光活性体(例如通过重结晶技术拆分外消旋体,通过由旋光活性的起始原料来合成,通过手性合成,或通过使用手性固定相的色谱分离)和如何使用本文所述标准试验或使用本领域公知的其他类似试验来测定烟碱激动剂的活性。
本发明的其他实施方案提供了制备式I化合物的方法或制备用于制备式I化合物的中间体的方法。本发明的其他实施方案还提供了用于制备式I化合物的中间体。
在化合物具有足够的碱性或酸性以至于足以形成酸式盐或碱式盐的情况下,使用盐形式的化合物可能是合适的。可接受的盐的实例有,与能形成生理上可接受的阴离子的酸一起形成的有机酸加成盐,例如,甲苯磺酸盐、甲基磺酸盐、乙酸盐、柠檬酸盐、丙二酸盐、酒石酸盐、丁二酸盐、苯甲酸盐、抗坏血酸盐、α-酮戊二酸盐及α-甘油磷酸盐。也可形成合适的无机盐,包括盐酸盐、硫酸盐、硝酸盐、碳酸氢盐及碳酸盐。
可接受的盐可使用本领域公知的标准方法获得,例如通过使一种足够碱性的化合物例如胺与一种能够提供生理上可接受的阴离子的合适的酸反应。也可制备羧酸的碱金属(例如,钠、钾或锂)盐或碱土金属(例如钙)盐。
烷基包括直链的或支链的C1-10烷基,例如甲基、乙基、丙基、丁基、戊基、异丙基、异丁基、1-甲基丙基、3-甲基丁基、己基等。
低级烷基包括直链的或支链的C1-6烷基,例如,甲基、乙基、丙基、1-甲基乙基、丁基、1-甲基丙基、2-甲基丙基、1,1-二甲基乙基、戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基等。
术语“亚烷基”指的是二价的直链的或支链的烃链(例如亚乙基-CH2-CH2-)。
C3-7环烷基包括例如环丙基、环戊基、环己基、环庚基等的基团和烷基取代的C3-7环烷基,所述烷基取代基优选为直链的或支链的C1-6烷基,例如甲基、乙基、丙基、丁基或戊基,以及C5-7环烷基例如环戊基或环己基等。
低级烷氧基包括C1-6烷氧基,例如甲氧基、乙氧基或丙氧基等。
低级烷酰基包括C1-6烷酰基,例如甲酰基、乙酰基、丙酰基、丁酰基、戊酰基或己酰基等。
C7-11芳酰基包括例如苯甲酰基或萘甲酰基的基团;
低级烷氧基羰基包括C2-7烷氧基羰基,例如甲氧基羰基、乙氧基羰基或丙氧基羰基等。
低级烷基氨基意指被C1-6烷基取代的氨基,例如甲基氨基、乙基氨基、丙基氨基、丁基氨基等。
二(低级烷基)氨基意指被相同或不同的C1-6烷基取代的氨基(例如二甲基氨基、二乙基氨基、乙基甲基氨基)。
低级烷基氨甲酰基意指被C1-6烷基取代的氨甲酰基(例如甲基氨甲酰基、乙基氨甲酰基、丙基氨甲酰基、丁基氨甲酰基)。
二(低级烷基)氨甲酰基意指被相同或不同的C1-6烷基取代的氨甲酰基(例如二甲基氨甲酰基、二乙基氨甲酰基、乙基甲基氨甲酰基)。
卤原子意指例如氟原子、氯原子、溴原子或碘原子的卤原子。
芳基指C6-10单环或稠环芳基,例如苯基、茚基或萘基等。
杂环基指含有至少一个杂原子的饱和的单环杂环基或不饱和的单环或稠环杂环基,所述杂原子例如0-3个氮原子(-NRd-)、0-1个氧原子(-O-)和0-1个硫原子(-S-)。饱和单环杂环基的非限制性实例包括5元或6元的饱和杂环基,例如四氢呋喃基、吡咯烷基、吗啉基、哌啶基、哌嗪基或吡唑烷基。不饱和单环杂环基的非限制性实例包括5元或6元的不饱和杂环基,例如呋喃基、吡略基、吡唑基、咪唑基、噻唑基、噻吩基、吡啶基或嘧啶基。不饱和稠杂环基的非限制性实例包括不饱和的双环杂环基,例如吲哚基、异吲哚基、喹啉基、苯并噻唑基、苯并二氢呋喃基、苯并呋喃基等。
Rc和R1与其所连接的氮原子一起形成一个杂环。杂环的非限制性的实例包括5元或6元的饱和杂环,例如1-吡咯烷基、4-吗啉基、1-哌啶基、1-哌嗪基或1-吡唑烷基,5元或6元的不饱和杂环例如1-咪唑基等。
烷基、芳基、杂环基R1可任选被一个或多个取代基取代,其中所述取代基可相同或不同,并且包括低级烷基;环烷基、羟基;羟基C1-6亚烷基,例如羟基甲基、2-羟基乙基或3-羟基丙基;低级烷氧基;C1-6烷氧基C1-6烷基,例如2-甲氧基乙基、2-乙氧基乙基或3-甲氧基丙基;氨基;烷基氮基;二烷基氮基;氰基;硝基;酰基;羧基;低级烷氧基羰基;卤素;巯基;C1-6烷硫基,例如甲硫基、乙硫基、丙硫基或丁硫基;被取代的C1-6烷硫基,例如甲氧基乙硫基、甲硫基乙硫基、羟基乙硫基或氯代乙硫基;芳基;被取代的C6-10单环或稠环芳基,例如4-羟基苯基、4-甲氧基苯基、4-氟代苯基、4-氯代苯基或3,4-二氯代苯基;5-6元的不饱和杂环,例如呋喃基、吡咯基、吡唑基、咪唑基、噻唑基、噻吩基、吡啶基或嘧啶基;以及不饱和的双环杂环基,例如吲哚基、异吲哚基、喹啉基、苯并噻唑基、苯并二氢呋喃基、苯并呋喃基或邻苯二甲酰亚氨基。
烷基、芳基、杂环基R2可任选被一个或多个取代基取代,其中所述取代基可相同或不同,并且包括羟基;C1-6烷氧基,例如甲氧基、乙氧基或丙氧基;羧基;C2-7烷氧基羰基,例如甲氧基羰基、乙氧基羰基或丙氧基羰基及卤素。
烷基、芳基、杂环基Rc可任选被一个或多个取代基取代,其中所述取代基可相同或不同,并且包括C3-6环烷基;羟基;C1-6烷氧基;氨基;氰基;芳基;被取代的芳基,例如4-羟基苯基、4-甲氧基苯基、4-氯苯基或3,4-二氯苯基;硝基和卤素。
Rc和R1以及它们所连接的氮原子一起形成的杂环可任选被一个或多个取代基取代,其中所述取代基可相同或不同,并且包括C1-6烷基;羟基C1-6亚烷基;C1-6烷氧基C1-6亚烷基;羟基;C1-6烷氧基;以及氰基。
本文所用术语“氨基酸”,包括D型或L型的天然氨基酸残基(例如Ala、Arg、Asn、Asp、Cys、Glu、Gln、Gly、His、Hyl、Hyp、Ile、Leu,Lys、Met、Phe、Pro、Ser、Thr、Trp、Tyr及Val),以及非天然氨基酸(例如,磷酸丝氨酸、磷酸苏氨酸、磷酸酪氨酸、羟脯氨酸、γ-羧基谷氨酸;马尿酸、八氢吲哚-2-羧酸、施德丁(statine)、1,2,3,4-四氢异喹啉-3-羧酸、青霉胺、鸟氨酸、瓜氨酸、-甲基丙氨酸、对-苯甲酰基苯丙氨酸、苯甘氨酸、炔丙基甘氨酸、肌氨酸,以及叔丁基甘氨酸)残基。该术语也包括带有一个常规氨基保护基(例如,乙酰基或苯甲氧基羰基)的天然及非天然氨基酸类,以及羧基末端被保护(例如,以(C1-C6)烷基、苯基或苯甲基酯或酰胺;或以-甲基苯甲基酰胺)的天然及非天然氨基酸类。其他合适的氨基和羧基保护基为本领域技术人员已知(参见,例如,T.W.Greene,Protecting Groups In Organic Synthesis;Wiley:New York,1981,及其中引用的参考文。氨基酸可以通过羧基末端、氨基末端,或通过任意其他常规连接点,例如通过半胱氨酸的硫,连接到式I化合物的其余部位。
术语“toll样受体”(TLR)指的是可以与病原体相关分子模式(PAMP)结合并且促进哺乳动物免疫响应的受体家族的成员。已经知道十种哺乳动物的TLR,例如TLR1-10。
术语“toll样受体激动剂”(TLR激动剂)指的是可以与TLR结合并且激活该受体的分子。合成的TLR激动剂是被设计成可以与TLR结合并且激活该受体的化合物。本文提供的示例性新型TLR激动剂包括“TLR-7激动剂”“TLR-8激动剂”和“TLR-9激动剂”。
本文所用术语“核酸”指的是DNA、RNA、单链的、双链的或更高度聚集度的杂合基序(hybridization motif),及其任何化学修饰物。修饰包括但不限于,提供对核酸配体碱基或对整个核酸配体引入附加电荷、极性、氢键、静电相互作用及流变性的化学基团的修饰。这类修饰包括但不限于肽核酸(PNA)、磷酸二酯基修饰(例如,硫代磷酸酯、甲基膦酸酯)、2’-位糖修饰、5-位嘧啶修饰、7-位嘌呤修饰、8-位嘌呤修饰、9-位嘌呤修饰、环外胺的修饰、4-硫代尿苷的取代、5-溴-尿嘧啶或5-碘-尿嘧啶的取代;主链修饰、甲基化、异常碱基配对的结合,例如异碱基(isobase)、异胞苷(isocytidine)和异胍等。核酸还可包括非天然碱基,例如硝基吲哚。修饰还可包括3’位和5’位的修饰,例如用BHQ、荧光基团或其他部分加帽。
X1的一个具体含义为硫原子、氧原子或-NRc-。
另一个具体的X1为硫原子。
另一个具体的X1为氧原子。
另一个具体的X1为-NRc-。
另一个具体的X1为-NH-。
Rc的一个具体含义为氢、C1-4烷基或被取代的C1-4烷基。
连接在一起的R1和Rc的一个具体含义为它们形成一个杂环或一个被取代的杂环。
连接在一起的R1和Rc的另一具体含义为被取代的或未被取代的吗啉基、哌啶基、吡咯烷基或哌嗪基环。
R1的一个具体含义为氢、C1-4烷基或被取代的C1-4烷基。
R1的另一具体含义为2-羟基乙基、3-羟基丙基、4-羟基丁基、2-氨基乙基、3-氨基丙基、4-氨基丁基、甲氧基甲基、2-甲氧基乙基、3-甲氧基丙基、乙氧基甲基、2-乙氧基乙基、甲硫基甲基、2-甲硫基乙基、3-甲硫基丙基、2-氟乙基、3-氟丙基、2,2,2-三氟乙基、氰基甲基、2-氰基乙基、3-氰基丙基、甲氧基甲基、2-甲氧基羰基乙基、3-甲氧基羰基丙基、苯甲基、苯乙基、4-吡啶基甲基、环己基甲基、2-噻吩基甲基、4-甲氧基苯基甲基、4-羟基苯基甲基、4-氟苯基甲基或4-氯苯基甲基。
R1的另一具体含义为氢、CH3-、CH3-CH2-、CH3CH2CH2-、羟基C1-4亚烷基或C1-4烷氧基C1-4亚烷基。
R1的另一具体含义为氢、CH3-、CH3-C2-、CH3-O-CH2CH2-或CH3-CH2-O-CH2CH2-。
R2的一个具体含义为氢、卤素或C1-4烷基。
R2的另一具体含义为氢、氯、溴、CH3-或CH3-CH2-。
可用于烷基、芳基或杂环基上取代的具体取代基为羟基、C1-6烷基、羟基C1-6亚烷基、C1-6烷氧基、C1-6烷氧基C1-6亚烷基、C3-6环烷基、氨基、氰基、卤素或芳基。
X2的一个具体含义为键或具有最多约24个原子的链;其中所述原子选自碳、氮、硫、非过氧化物的氧及磷。
X2的另一具体含义为键或具有约4至约12个原子的链。
X2的另一具体含义为键或具有约6至约9个原子的链。
X2的另一具体含义为
X2的另一具体含义为
一个具体的辅助基团为氨基酸、碳水化合物、肽、抗原、核酸、机体物质或微生物。
一种具体的肽具有2至约20个氨基酸残基。
另一种具体的肽具有10至约20个氨基酸残基。
一个具体的辅助基团为碳水化合物。
一种具体的核酸为DNA、RNA或PNA。
一种具体的机体物质为细胞、脂质、维生素或辅助因子。
另一种具体的机体物质为细胞或脂质。
一种具体的抗原为微生物。
一种具体的微生物为病毒、细菌或真菌。
另一种具体的微生物为病毒或细菌。
具体的细菌为炭疽杆菌(Bacillus anthracis)(炭疽(anthrax))、单核细胞增生性李斯特菌(Listeria monocytogenes)、土拉热弗朗西丝氏菌(Francisellatularensis)或沙门氏菌(Salmonella)。
具体的沙门氏菌为鼠伤寒(typhimurium)沙门氏菌或肠炎(enteritidis)沙门氏菌。
具体的病毒为RNA病毒、RNA病毒的产物或DNA病毒。
具的DNA病毒为乙型肝炎病毒。
本发明的具体化合物具有以下通式:
IA-L-A1;
IA-L-(A1)2;
IA-L-A1-A1;
IA-L-A1-L-A1;
(IA)2-L-A1-A1;
(IA)2-L-A1-L-A1;
(IA)2-L-A1;或
(IA)2-L-(A1)2;
其中IA为本文所公开的含义;L不存在或为一个连接基团;并且每一个A1基团独立地代表一个辅助基团。
在一个实施方案中,病毒感染由引起严重急性呼吸综合症(SARS)的冠状病毒、乙型肝炎病毒或丙型肝炎病毒引起。
可治疗的具体癌症包括黑素瘤、浅表性膀胱癌(superficial bladdercancer)、光化性角化症、上皮内瘤样病变(intraepithelial neoplasia),以及基底细胞皮肤癌、鳞状癌(squamous)等。此外,本发明的方法包括治疗癌症前期症状,例如,光化性角化症或上皮内瘤样病变、家族性息肉病(息肉)、子宫颈发育异常(cervical dysplasia)、子宫颈癌、浅表性磅胱癌,以及与感染有关的任何其他癌症(例如淋巴瘤卡波西氏肉瘤或白血病)等。
可治疗的病理性病症或症状的非限制性实例包括病毒性疾病,癌症,胃肠道、脑、皮肤、关节及其他组织的炎性疾病。
认为辅助基团能通过以下步骤提高药效团(式(I)化合物)的药物活性:(a)帮助药效团定位至靶细胞内体中的受体上;(b)通过使受体交联从而增强由药效团引发的信号转导;和/或(c)所述药效团可以提高对辅助基团的应答(例如,免疫应答)。所述辅助基团应该与所述药效团形成常规稳定的键,并且不用作药物前体。
本发明包括式(I)化合物任选地与肌苷酸脱氢酶(inosine monophosphatedehydrogenase)(IMPDH)的抑制剂、所述化合物的对映体、所述化合物的药物前体或所述化合物的可药用盐相结合形成的组合物。本文所用“IMPDH抑制剂”指的是肌苷酸脱氢酶的抑制剂。目前,临床上使用三种IMPDH抑制剂:利巴韦林(ribavirin)、咪唑立宾和吗替麦考酚酯(mycophenolate mofetil)。利巴韦林和咪唑立宾为在细胞内磷酸化产生IMP类似物的药物前体(Goldstein et al.,Cuff Med Chem,6:519-536(1999))。viramidine为利巴韦林的药物前体。吗替麦考酚酯具有免疫抑制性,并且可能由于其肠肝再循环而具有胃肠刺激性(Papageorgiou C,Mini Rev Med Chem.,1:71-77(2001))。咪唑立宾苷元,一种药物前体,被用作IMPDH抑制剂。IMPDH抑制剂的其他非限制性实例,包括咪唑立宾和咪唑立宾苷元的药物前体在内,是已知的并且在美国专利申请公布No.20050004144中被公开。
在化合物具有足够的碱性或酸性能形成稳定的无毒的酸式盐或碱式盐的情况下,将所述化合物以盐的形式给药可能是合适的。可药用盐的实例为与能形成生理上可接受的阴离子的酸形成的有机酸加成盐,例如,甲苯磺酸盐、甲磺酸盐、乙酸盐、柠檬酸盐、丙二酸盐、酒石酸盐、丁二酸盐、苯甲酸盐、抗坏血酸盐、α-酮戊二酸盐和α-甘油磷酸盐。也可形成合适的无机盐,包括盐酸盐、硫酸盐、硝酸盐、碳酸氢盐和碳酸盐。
可药用的盐可用本领域公知的标准方法制备,例如通过使一种具有足够碱性的化合物例如一种胺与一种适宜的可提供可药用的阴离子的酸反应来制备。还可制备羧酸的碱金属(例如,钠、钾或锂)盐或碱土金属(例如钙)盐。
本发明的化合物(轭合物)可用本领域公知的标准合成方法制备。以下对常规酯的合成进行说明:
常规合成
醛的合成
本文还包括制备特定化合物的其他实例。
式I的化合物可制备成药物组合物并以与选择的给药途径相适应的各种形式给药至哺乳动物宿主,例如人类患者,所述给药途径即,口腔给药或通过静脉内、肌肉内、局部或皮下途径进行肠胃外给药。
因此,本发明化合物可全身给药,例如与一种可药用的载体例如惰性稀释剂或可吸收的可食用载体相结合的口腔给药。可将化合物包入硬壳或软壳明胶胶囊中,可压缩成片剂,或可直接与患者饮食的食物相混合。对于治疗性口腔给药,活性化合物可与一种或多种赋形剂混合并以可吸收的片剂、口含片、锭剂、胶囊剂、酏剂、悬浮剂、糖浆剂、圆片剂等形式使用。所述组合物和制剂应该含有至少0.1%的活性化合物。组合物和制剂的百分数当然是可以变化的,通常可为给定单位剂型重量的约2%至约60%之间。在这类治疗有用的组合物中活性化合物的量应为能够获得治疗效果的剂量水平。
片剂、锭剂、丸剂、胶囊剂等还可含有以下物质:粘合剂,例如西黄蓍胶、阿拉伯胶、玉米淀粉或明胶;赋形剂,例如磷酸氢钙;崩解剂,例如玉米淀粉、马铃薯淀粉、海藻酸等;润滑剂,例如硬脂酸镁;以及甜味剂,例如蔗糖、果糖、乳糖或阿司帕坦,或增香剂,例如薄荷、冬绿油,或可以添加樱桃调味剂。单位剂型为胶囊时,除上述类型的物质外,其还可含有一种液体载体,例如植物油或聚乙二醇。各种其他物质可以包衣形式存在,或用以改变固体单位剂型的物理形态。例如,片剂、丸剂或胶囊剂可用明胶、蜡、紫胶或糖等进行包衣。糖浆或酏剂可含有活性化合物、作为甜味剂的蔗糖或果糖、作为防腐剂的对羟基苯甲酸甲酯或对羟基苯甲酸丙酯、染料及调味剂例如樱桃或橙子调味剂。当然,制备任何单位剂型所用的任何物质应该是可药用的并且在所使用的量下是基本上无毒的。此外,可将活性化合物掺入持续释放的制剂和装置中。
活性化合物也可通过输注或注射进行静脉内或腹膜内给药。活性化合物溶液或其盐溶液可在水中,任选地与一种无毒的表面活性剂混合而制备。分散剂也可在甘油、液态聚乙二醇、三乙酸甘油酯、及其混合物中,以及油中制备。在常规贮存及使用条件下,所述制剂含有防腐剂以防止微生物的生长。
适于注射或输注的药物剂型可包括无菌水溶液或分散系,或者含有适于临时配制为无菌可注射或可输注的溶液或分散系的无菌粉末,所述无菌粉末任选地被包封在脂质体中。在所有情况下,最终剂型在生产和贮存条件下应该是无菌的、流动的并且稳定的。液体载体或运载体可以是溶剂或液体分散介质,包括例如,水、乙醇、多元醇(例如,甘油、丙二醇、液态聚乙二醇等)、植物油、无毒的甘油酯、以及它们的合适的混合物。可例如通过形成脂质体、在分散剂情形下通过维持所需的粒度或通过使用表面活性剂从而保持适当的流动性。可通过各种抗细菌剂和抗真菌剂,例如对羟基苯甲酸酯、氯代丁醇、苯酚、山梨酸、乙基汞硫代水杨酸钠等预防微生物的活动。在许多情况下,还优选地含有等渗剂,例如糖类、缓冲剂或氯化钠。可通过在组合物中使用延迟吸收剂,例如单硬脂酸铝和明胶,从而延长可注射组合物的吸收。
无菌可注射溶液通过将所需量的活性化合物,根据需要与多种以上所列举的其他成分一起加入适当溶剂中,接着进行过滤灭菌来制备。在用无菌粉末制备无菌可注射溶液的情况下,优选的制备方法为真空干燥和冷冻干燥技术,该方法产生活性成分与任何其他所需的在前述过滤灭菌溶液中存在的成分的粉末。
对于局部给药,本发明化合物可以纯的形式施用,即,当其为液体时以纯化合物形式施用。但是,通常希望将本发明化合物与一种皮肤学上可接受的载体相结合,以组合物或制剂形式给药至皮肤上,所述皮肤学上可接受的载体可为固体或液体。
可用的固体载体包括精细分散的固体,例如滑石、粘土、微晶纤维素、二氧化硅、氧化铝等。可用的液体载体包括水、醇或二醇或水-醇/二醇掺合物,本发明化合物可任选借助无毒的表面活性剂以有效水平溶解或分散于液体载体中。可添加辅助剂例如芳香剂及其他抗微生物剂来优化给定用途的性能。得到的液体组合物可通过吸收衬垫施用,用于浸渍绷带及其他敷料,或用泵型喷雾器或气溶胶喷雾器喷洒在受侵染区域。
增稠剂例如合成聚合物、脂肪酸、脂肪酸盐及酯、脂肪醇、改性纤维素或改性矿物材料,也可与液体载体一起使用来形成展膜膏剂、凝胶剂、软膏、皂剂等,直接应用至使用者的皮肤。
可用于将式I的化合物送递至皮肤的皮肤学上可用的组合物的实例为本领域已知;例如,见Jacquet等人(美国专利4,608,392)、Geria(美国专利4,992,478)、Smith等人(美国专利4,559,157)和Wortzman(美国专利4,820,508)。
式I化合物的可用剂量可通过比较它们在动物模型中的体外活性和体内活性而确定。将小鼠及其他动物体内的有效剂量外推至人类的方法是本领域已知的;例如,见美国专利4,938,949。
通常,液体组合物例如洗剂中的一种或多种式I化合物的浓度可为约0.1-25重量%、优选约0.5-10重量%。在半固体或固体组合物例如凝胶或粉末中的浓度可为约0.1-5重量%,优选约0.5-2.5重量%。
用于治疗所需的化合物,或其活性盐或其衍生物的量,不仅随所选的具体的盐而变化,而且随给药途径、所治疗病症的性质及患者年龄及状况而变化,并最终应由治疗的内科医生或临床医生决定。
但是,通常的适宜剂量在每天约0.5至约100mg/kg体重,例如约10至约75mg/kg体重的范围内,例如每天3至约50mg/kg受治疗者体重,优选在6至约90mg/kg/天的范围内,最优选在15至60mg/kg/天的范围内。
化合物通常以单位剂型进行给药;例如,每单位剂型含有5-1000mg、通常10-750mg、最常用的为50-500mg的活性组分。
理想地,应给药活性成分以获得约0.5至约75μM,优选约1至50μM,最优选约2至约30μM的活性化合物峰值血浆浓度。这可以通过例如静脉内注射0.05-5%活性成分的溶液,任选其盐水溶液而实现,或者通过口服含有约1-100mg活性成分的药丸进行给药。可通过连续输注提供约0.01-5.0mg/kg/hr,或通过间歇性输注含有约0.4-15mg/kg的一种或多种活性成分,从而保持需要的血浆水平。
所需剂量通常可以单次剂量或以合适的时间间隔给药的分隔剂量存在,例如每天两次、三次、四次或更多次的亚剂量。所述亚剂量本身还可再分成例如多个不连续的疏散间隔的给药;例如通过吹药器多次吸入或通过多次滴入眼中来施用。
本发明化合物用作TLR激动剂的效能可使用本领域公知的药学模型,包括Lee等人;PNAS,100p6646-6651,2003中公开的方法进行确定。
制备式(I)化合物的方法作为本发明的其他实施方案给出并且通过以下步骤进行说明,在以下步骤中除非另有限定,否则一般的基团含义如上所述。
实施例
普通化学。试剂和溶剂购于Aldrich,Milwaukee,WI.。未校正的熔点用Laboratory Device Mel-Temp II毛细管熔点装置测定。用Varian Unity 500NMR分光光度计记录499.8MHz处的质子核磁共振光谱或用Varian MercuryNMR分光光度计记录400.06MHz处的质子核磁共振光谱。化学位移以ppm记录距离所示参考基准的数值。阳离子和阴离子回路质谱由Department ofChemistry UCSD,San Diego,CA进行。元素分析由NuMega Resonance Labs,San Diego,CA进行。柱色谱分析用所示的溶剂体系在E Merck硅胶(230-400筛目)上进行。在硅胶60F-254板(EM Reagents)上进行分析性薄层色谱法(TLC)。
实施例1 4-(2,6-二氯嘌呤-9-基甲基)苯基氰的制备
将2,6-二氯-9H-嘌呤(16mmol)溶解在DMF(50mL)中并添加碳酸钾(50mmol)。然后添加α-溴-对甲苯基氰(22mmol),并将该混合物在室温下搅拌16h。过滤除去不溶性无机盐后,将滤液倒入水(1500mL)中并用乙酸乙酯萃取(2×400mL),用硫酸镁干燥,蒸发得到剩余物,该剩余物通过使用1∶2∶10的乙酸乙酯/丙酮/己烷的快速硅胶色谱纯化。产率3.33g(69%)。UV、NMR和MS与指定的结构相一致。
实施例2 4-(6-氨基-2-氯嘌呤-9-基甲基)苯基氰的制备
将实施例1的产物(1.9g)放入钢反应容器中并添加甲醇氨(80mL,7N)。将密封的容器在60℃下加热12h,在冰中冷却并滤掉固体产物。产率1.09g。UV、NMR和MS与指定的结构一致。
实施例3 4-[6-氨基-2-(2-甲氧基乙氧基)嘌呤-9-基甲基]苯基氰的制备
通过将金属钠(81mg)在加热条件下溶解于2-甲氧基乙醇(30mL)中生成2-甲氧基乙醇的钠盐。向该溶液中添加溶解在甲氧基乙醇中(300mL,加热)的实施例2的产物(1.0g)。将反应混合物在115℃浴温下加热8h,真空浓缩至近干燥状态,将剩余物分配与乙酸乙酯和水。将有机层通过使用含5%甲醇的二氯甲烷溶液的快速硅胶色谱纯化,得到763mg产物。NMR与指定的结构相一致。
实施例4 4-[6-氨基-8-溴-2-(2-甲氧基乙氧基)嘌呤-9-基甲基]苯基氰的制备
将实施例3的产物(700mg)溶解在二氯甲烷(400mL)中并逐滴添加溴(7mL)。混合物在室温下搅拌过夜并用硫代硫酸钠水溶液(0.1M,2L)萃取,然后用碳酸氢钠水溶液(500mL,饱和的)萃取。有机层剩余物通过使用含3%甲醇的二氯甲烷溶液的硅胶色谱法纯化,得到460mg溴代产物。NMR、UV和MS与指定的结构一致。
实施例5 4-[6-氨基-8-甲氧基-2-(2-甲氧基乙氧基)嘌呤-9-基甲基]苯基氰的制备
甲醇钠由钠金属(81mg)在无水甲醇(30ml)中反应生成。将实施例4的产物(700mg)溶解在无水二甲氧基乙烷中并将温度升至100℃。反应过夜后,将混合物真空浓缩,剩余物通过使用含5%甲醇的二氯甲烷溶液硅胶色谱法纯化,产量120mg。NMR与指定的结构一致。
实施例6 氢化N,N′-(二甲基亚乙基二氨基)铝锂的制备
用于将腈转化成醛官能团的还原剂主要按Bull.Korean Chem.Soc.(2002),23(12),1697-1698中所述进行制备。制成含0.5M该还原剂的无水THF溶液。
实施例7 4-[6-氨基-8-甲氧基-2-(2-甲氧基乙氧基)嘌呤-9-基甲基]苯甲醛的制备
将实施例5的产物(100mg)溶解在无水THF(3mL)中并在氩气氛下冷却至0℃。将实施例6中生成的试剂(0.72mL)添加至反应烧瓶中并将混合物在0-5℃下搅拌1h,然后通过添加3M HCl终止反应。然后将混合物用乙酸乙酯萃取,再用二氯甲烷进行萃取并真空浓缩,得到85mg。NMR与指定的结构一致。
实施例8 4-[6-氨基-8-羟基-2-(2-甲氧基乙氧基)嘌呤-9-基甲基]苯甲醛(1V150)的制备
将实施例7的产物(800mg)与碘化钠(504mg)和乙腈(40mL)混合,然后缓慢添加三甲基氯硅烷(0.5mL)。将混合物在70℃下加热3.5h,冷却并过滤。固体产物用水洗涤,然后用醚洗涤,得到406mg。NMR、UV、MS与指定的结构相一致。该物质适于连接体和辅助基之间的轭合反应。
实施例9 4-[6-氨基-8-甲氧基-2-(2-甲氧基乙氧基)嘌呤-9-基甲基]苯甲酸甲酯的制备(方法如Jayachitra,et al.,Synth.Comm.,(2003)33(19),3461-3466所述)
将实施例5的产物(1mmol)溶解在无水甲醇(5mL)中并将新蒸馏的BF3醚合物(4mmol)添加至该溶液中。将得到的混合物在氩气气氛下回流20h。在真空下除去溶剂并用二氯甲烷(10mL)溶解剩余物,用稀释的碳酸氢钠水溶液(2×10mL)萃取并用硫酸镁干燥有机层。蒸发之后产物通过使用含5%甲醇的二氯甲烷溶液的硅胶柱色谱法进行纯化,得到0.8mmol。
实施例10 4-[6-氨基-8-羟基-2-(2-甲氧基乙氧基)嘌呤-9-基甲基]苯甲酸的制备
将实施例9的产物(100mg)与碘化钠(63mg)和乙腈(10mL)混合,然后缓慢添加三甲基氯硅烷(120mL)。将混合物在70℃下加热6h,冷却并过滤。固体产物用水洗涤,然后用醚洗涤,得到51mg。
实施例11 4-[6-氨基-8-羟基-2-(2-甲氧基乙氧基)嘌呤-9-基甲基)苯甲酸2,5-二氧代吡咯烷-1-酯的制备
将实施例10的产物(2mmol)溶解在二氯甲烷或二氧杂环己烷(10mL)中并添加EDC(2mmol)。向该溶液中添加N-羟基丁二酰亚胺(2mmol)并将得到的混合物在室温下搅拌1h。将混合物在真空下干燥,并将粗产物用硅胶色谱纯化,得到2mmol适用于伯胺的轭合反应的产物。
实施例12 IV150与小鼠血清白蛋白(MSA)的轭合
用SANH对MSA进行修饰:将200μl MSA(25mg/ml)与100μl轭合缓冲液(1M NaPi,pH=7.2)和690μl PBS进行混合。将含844μg SANH的10μl DFM的溶液(摩尔数超过MSA的40倍)添加至蛋白溶液中(反应混合物中MSA的最终浓度为5mg/ml)。小心混合后使反应在室温下进行2h。将反应混合物装载至用PBS平衡的NAP-10柱上,用1.5ml的PBS洗脱经修饰的MSA,以除去过量的SANH。
将IV150连接至经SANH修饰的MSA上:将460μg IV150溶解在10μl的DMF中,并添加至经SANH修饰的MSA中,该反应混合物在室温下培养过夜。首先将反应混合物用微旋柱(微孔:BIOMAX 5K)浓缩至1ml,然后装载至如上所述的NAP-10柱上进行纯化,以除去过量的IV150。
本文所用缩写具有其在化学和生物学领域中的常规含义。本说明书中引用的所有出版物、专利及专利文献以引用的方式纳入本文,如同逐一地通过引用而纳入的一样。在任何不一致的情况下,以本发明公开的内容为准,包括其中的任何定义。已参照多种具体的和优选的实施方案和技术对本发明进行了描述。但应该理解的是,在本发明的主旨和范围内可以进行多种改变和改进。
Claims (43)
1.一种具有式(IA)的化合物或其可药用的盐:
其中,X1为-O-、-S-或-NRc-;
其中Rc为氢、C1-10烷基或被取代的C1-10烷基,或者Rc和R1与氮原子一起形成一个杂环或一个被取代的杂环,其中烷基、芳基或杂环基上的取代基为羟基、C1-6烷基、羟基C1-6亚烷基、C1-6烷氧基、C3-6环烷基、C1-6烷氧基C1-6亚烷基、氨基、氰基、卤素或芳基;
R1为氢、(C1-C10)烷基、被取代的(C1-C10)烷基、C6-10芳基、或被取代的C6-10芳基、C5-9杂环基、被取代的C5-9杂环基;其中烷基、芳基或杂环基上的取代基为羟基、C1-6烷基、羟基C1-6亚烷基、C1-6烷氧基、C3-6环烷基、C1-6烷氧基C1-6亚烷基、氨基、氰基、卤素或芳基;
每一个R2独立地为氢、-OH、(C1-C6)烷基、被取代的(C1-C6)烷基、(C1-C6)烷氧基、被取代的(C1-C6)烷氧基、-C(O)-(C1-C6)烷基(烷酰基)、被取代的-C(O)-(C1-C6)烷基、-C(O)-(C6-C10)芳基(芳酰基)、被取代的-C(O)-(C6-C10)芳基、-C(O)OH(羧基)、-C(O)O(C1-C6)烷基(烷氧基羰基)、被取代的-C(O)O(C1-C6)烷基、-NRaRb、-C(O)NRaRb(氨甲酰基)、被取代的-C(O)NRaRb、卤代、硝基或氰基;其中烷基、芳基或杂环基上的取代基为羟基、C1-6烷基、羟基C1-6亚烷基、C1-6烷氧基、C3-6环烷基、C1-6烷氧基C1-6亚烷基、氨基、氰基、卤素或芳基;
每一个Ra和Rb独立地为氢、(C1-C6)烷基、(C3-C8)环烷基、(C1-C6)烷氧基、卤代(C1-C6)烷基、(C3-C8)环烷基(C1-C6)烷基、(C1-C6)烷酰基、羟基(C1-C6)烷基、芳基、芳基(C1-C6)烷基、Het、Het(C1-C6)烷基或(C1-C6)烷氧基羰基;
X2为一个键或一个连接基团;并且R3为一个辅助基团。
2.权利要求1的化合物,其中X1为硫原子。
3.权利要求1的化合物,其中X1为氧原子。
4.权利要求1的化合物,其中X1为-NRc-,其中Rc为氢、C1-6烷基或被取代的C1-6烷基;
其中所述烷基取代基为C3-6环烷基、羟基、C1-6烷氧基、氨基、氰基或芳基。
5.权利要求4的化合物,其中X1为-NH-。
6.权利要求1-5的任一项的化合物,其中R1和Rc一起形成一个杂环或一个被取代的杂环。
7.权利要求6的化合物,其中R1和Rc一起形成一个被取代的或未被取代的吗啉基、哌啶基、吡咯烷基或哌嗪基环。
8.权利要求1-7的任一项的化合物,其中R1为氢、C1-4烷基或被取代的C1-4烷基。
9.权利要求8的化合物,其中R1为氢、CH3-、CH3-CH2-、CH3CH2CH2-、羟基C1-4亚烷基、或C1-4烷氧基C1-4亚烷基。
10.权利要求9的化合物,其中R1为氢、CH3-、CH3-CH2-、CH3-O-CH2CH2-或CH3-CH2-O-CH2CH2-。
11.权利要求1-10的任一项的化合物,其中R2为氢、卤素或C1-4烷基。
12.权利要求11的化合物,其中R2为氢、氯、溴、CH3-或CH3-CH2-。
13.权利要求1-12的任一项的化合物,其中烷基、芳基或杂环基上的取代基为羟基、C1-6烷基、羟基C1-6亚烷基、C1-6烷氧基、C1-6烷氧基C1-6亚烷基、C3-6环烷基、氨基、氰基、卤素或芳基。
14.权利要求1-13的任一项的化合物,其中X2为一个键或一个具有最多约24个原子的链;其中所述原子选自碳,氮,硫,非过氧化物的氧,和磷。
15.权利要求14的化合物,其中X2为一个键或一个具有约4至约12个原子的链。
16.权利要求14的化合物,其中X2为一个键或一个具有约6至约9个原子的链。
18.权利要求1-17的任一项的化合物,其中辅助基团为氨基酸、碳水化合物、肽、抗原、核酸、机体物质或微生物。
19.权利要求18的化合物 ,其中所述肽具有2至约200个氨基酸残基。
20.权利要求19的化合物,其中所述肽具有10至约200个氨基酸残基。
21.权利要求1-18的任一项的化合物,其中所述辅助基团为碳水化合物。
22.权利要求18的化合物,其中所述核酸为DNA、RNA或PNA。
23.权利要求18的化合物,其中所述机体物质为细胞、脂质、维生素或辅助因子。
24.权利要求23的化合物,其中所述机体物质为细胞或脂质。
25.权利要求18的化合物,其中所述抗原为微生物。
26.权利要求25的化合物,其中所述微生物为病毒、细菌、寄生虫或真菌。
27.权利要求26的化合物,其中所述微生物为病毒或细菌。
28.权利要求27的化合物,其中所述细菌为炭疽杆菌、单核细胞增生性李斯特菌、土拉热弗朗西丝氏菌或沙门氏菌。
29.权利要求28的化合物,其中所述沙门氏菌为鼠伤寒沙门氏菌或肠炎沙门氏菌。
30.权利要求26的化合物,其中所述病毒为RNA病毒、RNA病毒的产物或DNA病毒。
31.权利要求30的化合物,其中所述DNA病毒为乙型肝炎病毒。
32.一种药物组合物,含有权利要求1-31的任一项的一种化合物和可药用的载体。
33.一种预防或治疗哺乳动物的病理病症或症状的治疗方法,其中涉及TLR受体的活性并且需要激发所述活性,该方法包括将有效量的权利要求1-31的任一项的化合物给药至需要这类治疗的哺乳动物。
34.权利要求33的方法,其中所述病症或症状为癌症、细菌性疾病、病毒性疾病、自身免疫性疾病或克罗恩病。
35.权利要求34的方法,其中所述细菌为炭疽杆菌、单核细胞增生性李斯特菌、土拉热弗朗西丝氏菌或沙门氏菌。
36.权利要求35的方法,其中所述沙门氏菌为鼠伤寒沙门氏菌或肠炎沙门氏菌。
37.权利要求34的方法,其中所述病毒为RNA病毒、RNA病毒的产物或DNA病毒。
38.权利要求37的方法,其中所述DNA病毒为乙型肝炎病毒。
39.权利要求34的方法,其中癌症可以为干扰素敏感性癌症,例如,白血病、淋巴瘤、骨髓瘤、黑素瘤或肾癌。
40.权利要求1-31的任一项的化合物用于药物治疗的用途。
41.权利要求40的用途,其中所述药物治疗为治疗癌症、细菌性疾病、病毒性疾病、自身免疫性疾病或克罗恩病。
42.权利要求1-31的任一项的化合物用于制备治疗癌症、细菌性疾病、病毒性疾病、自身免疫性疾病或克罗恩病的药物的用途。
43.权利要求42的用途,其中所述药物包括生理上可接受的载体。
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- 2006-08-21 JP JP2008528017A patent/JP2009504803A/ja active Pending
- 2006-08-21 WO PCT/US2006/032371 patent/WO2007024707A2/en active Application Filing
- 2006-08-21 CA CA002620182A patent/CA2620182A1/en not_active Abandoned
- 2006-08-21 CN CNA200680038761XA patent/CN101304748A/zh active Pending
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2012
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Cited By (11)
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US9050376B2 (en) | 2007-02-07 | 2015-06-09 | The Regents Of The University Of California | Conjugates of synthetic TLR agonists and uses therefor |
CN102300990A (zh) * | 2009-01-30 | 2011-12-28 | 艾德拉药物股份有限公司 | Tlr9的合成激动剂 |
CN102439011A (zh) * | 2009-02-11 | 2012-05-02 | 加利福尼亚大学校务委员会 | Toll样受体调节剂和疾病的治疗 |
US8729088B2 (en) | 2009-02-11 | 2014-05-20 | The Regents Of The University Of California | Toll-like receptor modulators and treatment of diseases |
CN102439011B (zh) * | 2009-02-11 | 2016-05-04 | 加利福尼亚大学校务委员会 | Toll样受体调节剂和疾病的治疗 |
US11697851B2 (en) | 2016-05-24 | 2023-07-11 | The Regents Of The University Of California | Early ovarian cancer detection diagnostic test based on mRNA isoforms |
WO2019196918A1 (zh) * | 2018-04-13 | 2019-10-17 | 罗欣药业(上海)有限公司 | 五元杂环并嘧啶类化合物、药物组合物及用途 |
CN109608462A (zh) * | 2018-12-15 | 2019-04-12 | 华南理工大学 | 一种7-烃基-9-烷氧/硫基嘌呤-8-酮类化合物及其合成方法与在药物中的应用 |
CN109608462B (zh) * | 2018-12-15 | 2021-11-23 | 华南理工大学 | 一种7-烃基-9-烷氧/硫基嘌呤-8-酮类化合物及其合成方法与在药物中的应用 |
CN114787165A (zh) * | 2020-09-27 | 2022-07-22 | 上海维申医药有限公司 | 大环tlr7激动剂、其制备方法、药物组合物及其用途 |
CN114787165B (zh) * | 2020-09-27 | 2023-02-28 | 上海维申医药有限公司 | 大环tlr7激动剂、其制备方法、药物组合物及其用途 |
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US20090324551A1 (en) | 2009-12-31 |
ES2577514T3 (es) | 2016-07-15 |
AU2006283524A2 (en) | 2008-06-05 |
WO2007024707A3 (en) | 2007-09-20 |
AU2006283524A1 (en) | 2007-03-01 |
WO2007024707A2 (en) | 2007-03-01 |
CA2620182A1 (en) | 2007-03-01 |
EP1931352A2 (en) | 2008-06-18 |
US9359360B2 (en) | 2016-06-07 |
JP2009504803A (ja) | 2009-02-05 |
EP1931352B1 (en) | 2016-04-13 |
JP2013040209A (ja) | 2013-02-28 |
EP1931352A4 (en) | 2011-11-23 |
US20130165455A1 (en) | 2013-06-27 |
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