CN101287716A - 氨基二氮杂䓬作为类toll受体调节剂 - Google Patents
氨基二氮杂䓬作为类toll受体调节剂 Download PDFInfo
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- CN101287716A CN101287716A CNA2006800381346A CN200680038134A CN101287716A CN 101287716 A CN101287716 A CN 101287716A CN A2006800381346 A CNA2006800381346 A CN A2006800381346A CN 200680038134 A CN200680038134 A CN 200680038134A CN 101287716 A CN101287716 A CN 101287716A
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- alkyl
- compound
- thiazolinyl
- alkynyl
- amino
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Abstract
本发明提供用于通过类Toll受体TLR8调节信号传导的组合物和方法。所述组合物和方法用于治疗自身免疫、炎症、过敏、哮喘、移植排斥、移植物抗宿主疾病、感染、脓毒、癌症和免疫缺陷。
Description
本申请根据35 U.S.C.§119要求2005年8月19日提交的美国临时专利申请60/709,667的权益,其全文通过引用结合到本文中。
发明背景
发明领域
本发明涉及用于调节免疫功能的方法和组合物。更具体地讲,本发明涉及用于调节TLR8-介导的信号传导的组合物和方法。
现有技术描述
免疫系统刺激,包括先天免疫和适应性免疫之一或二者的刺激,是一种能够导致宿主保护性或不利生理后果的复杂现象。近年来,人们逐渐对先天免疫下的机理产生兴趣,相信其引发和支持适应性免疫。这种兴趣部分由目前发现一系列高保守图式识别受体蛋白质引起,这种蛋白质被称为类Toll受体(TLRs),相信这种受体与病原体相关性分子图式(PAMPs)的受体的先天免疫相关。因此,用于调节先天免疫的组合物和方法最令人感兴趣,因为它们可影响包括自身免疫、炎症、过敏、哮喘、移植排斥、移植物抗宿主疾病(GvHD)、感染、癌症和免疫缺陷的病症的治疗方法。
类Toll受体(TLRs)为I型跨膜蛋白质,这种蛋白质允许生物体(包括哺乳动物)检测微生物,并引发先天免疫反应(Beutler,B.,Nature2004,430:257-263)。它们包含同源胞质域和富亮氨酸胞外域,并且一般生成同源二聚体,同源二聚体感觉胞外(或内化)信号,随后通过衔接分子如MyD88(髓样分化因子88)引发信号转导级联系统。在TLR的胞质域中有这种高同源性,以至于最初有人提出,对于所有的TLR均存在相似的信号传导途径(Re,F.,Strominger,J.L.,Immunobiology2004,209:191-198)。实际上,所有的TLR均可激活NF-kB和MAP激酶;然而,由TLR激活衍生的细胞因子/趋化因子释放分布似乎对各TLR是唯一的。此外,TLR刺激的信号传导途径非常类似于细胞因子受体IL-1R诱导的途径。这可能是由于这些受体共有的同源物,即TIR(Toll/IL-1R同源结构)域。一旦在TLR中激活TIR域并且征集MyD88,就会激活丝氨酸/苏氨酸激酶的IRAK族,最终促进Ik-B降解并激活NF-kB(Means T.K.,等人,Life Sci.2000,68:241-258)。尽管似乎设想此级联允许胞外刺激以增加胞内事件,但有证据表明一些TLR迁移到细胞内体,在内体也可引发信号传导。此过程允许与被吞没微生物紧密接触,并且适应这些受体在先天免疫反应中担当的角色(Underhill,D.M.,et al.,Nature 1999,401:811-815)。此过程也可能允许受损组织(例如,在炎性疾病中)或凋亡细胞释放的宿主核酸通过内体呈递触发反应。在哺乳动物中,有与此快速反应协同的11种TLR。数年前曾提出一种假设(Janeway,C.A.,Jr.,Cold Spring Harb.Symp.Quant.Biol.1989,54:1-13),先天免疫反应通过微生物导致的TLR激活模型引发适应性免疫反应,现在这已得到证实。因此,由不同族感染生物体呈递的病原体相关性分子图式(PAMP)产生先天免疫反应,包括某些细胞因子、趋化因子和生长因子,随后引发精确适应性免疫反应,以通过抗原呈递适应感染性病原体,从而制造抗体并产生细胞毒素T细胞。
格兰氏阴性菌脂多糖(LPS)一直被看作是诱导哺乳动物类似于败血性休克的炎症反应的辅助物质和免疫刺激物质,也是一种药理学工具。利用基因方法,识别出TLR4为LPS的受体。LPS是TLR4的激动剂的这一发现说明TLR调节可用于疫苗和人类疾病的治疗(Aderem,A.;Ulevitch,R.J.,Nature 2000,406:782-787)。现在已认识到,各种TLR激动剂可激活B细胞、嗜中性粒细胞、肥大细胞、嗜酸性粒细胞、内皮细胞和数种上皮细胞,并且调节某些类型细胞的增殖和凋亡。
至今,有些类似的TLR7和TLR8被表征为在内体分室中发现的单条RNA的受体,因为被认为对病毒攻击的免疫反应重要。咪喹莫特,一种被批准的局部抗病毒/抗癌症药物,最近被描述成TLR7激动剂,已证明这种激动剂对某些皮肤疾病有临床效果(Miller R.L.,et al.,Int.J.Immunopharm.1999,21:1-14)。这种小分子药物被描述成ssRNA的结构模拟。TLR8最初描述于2000(Du,X.,et al.,European CytokineNetwork 2000(Sept.),11(3):362-371),并且很快被归属与病毒感染先天免疫反应有关(Miettinen,M.,et al.,Genes and Immunity 2001(Oct.),2(6):349-355)。
最近报告具有抗病毒活性的某些咪唑并喹啉化合物是TLR7和TLR8的配体(Hemmi H.,et al.(2002)Nat.Immunol.3:196-200;Jurk M.,et al.(2002)Nat.Immunol.3:499)。咪唑并喹啉是具有抗病毒性质和抗肿瘤性质的免疫细胞的有效合成活化剂。最近,Hemmi等人用野生型巨噬细胞和MyD88-缺陷的鼠报告,两种咪唑并喹啉,咪喹莫特和瑞喹莫德(R848),诱导肿瘤坏死因子(TNF)和白介素-12(IL-12),并且只在野生型细胞中激活NF-κB,与通过TLR激活一致(Hemmi H.,etal.(2002)Nat.Immunol.3:196-200)。自TLR7缺乏而其他TLR不缺乏鼠的巨噬细胞没有响应这些咪唑并喹啉产生可测的细胞因子。此外,咪唑并喹啉诱导脾B细胞剂量依赖性增生,并且在野生但不是TLR7-/-鼠的细胞中激活细胞内信号传导级联。荧光素酶分析确定,人胚胎肾细胞中的人TLR7但不是TLR2或TLR4的表达导致响应瑞喹莫德NF-κB激活。Hemmi等人的发现提示,这些咪唑并喹啉化合物为能够通过TLR7诱导信号传导的TLR7的非天然配体。最近报告R848也是人TLR8的配体(Jurk M.,et al.(2002)Nat.Immunol.3:499)。
发明概述
本文所述组合物用于调节体外和体内免疫反应。已发现此类组合物用于多种临床应用,如用于治疗包括不需要的免疫活性的病症的方法,包括炎性和自身免疫疾病。
更具体地讲,本发明的一个方面提供一种式I的化合物
及其代谢物、溶剂化物、互变异构体以及药学上可接受的盐和前药,其中Z、R1、R2、R3、R4、R5和n如下限定。
本发明的另一个方面提供一种式II的化合物
及其代谢物、溶剂化物、互变异构体以及药学上可接受的盐,其中Z、R1、R2、R3、R4和R5如下限定。
本发明还涉及药物组合物,该组合物包含式I或式II的化合物或其代谢物、互变异构体、溶剂化物或药学上可接受的前药或盐。
本发明的化合物可有利与其他已知的治疗剂组合使用。因此,本发明还涉及药物组合物,该组合物包含治疗有效量的式I或式II的化合物或其代谢物、互变异构体、溶剂化物或药学上可接受的前药或盐以及第二治疗剂。
本发明还提供调节TLR8-介导的信号传导的方法,所述方法包括使表达TLR8的细胞与有效量的式I或式II的化合物或其代谢物、互变异构体、溶剂化物或药学上可接受的前药或盐接触。在一个方面,所述方法抑制TLR8-介导的免疫刺激信号传导。
本发明还提供调节患者TLR8-介导的免疫刺激的方法,所述方法包括给予有TLR8-介导的免疫刺激发展或有这种风险的患者有效量的式I或式II的化合物或其代谢物、互变异构体、溶剂化物或药学上可接受的前药或盐,以抑制或促进患者TLR8-介导的免疫刺激。
本发明还提供治疗可由调节TLR8-介导的细胞活性治疗的病症或疾病的方法,所述方法包括给予有所述病症或疾病发展或有这种风险的哺乳动物(例如人)有效量的式I或式II的化合物或其代谢物、互变异构体、溶剂化物或药学上可接受的前药或盐,以治疗所述病症或疾病。
本发明还提供调节哺乳动物免疫系统的方法,所述方法包括给予哺乳动物有效量的式I或式II的化合物或其代谢物、互变异构体、溶剂化物、药学上可接受的前药或盐,以调节所述免疫系统。
本发明还提供在为有此类疾病或病症的哺乳动物(例如人)治疗所述疾病或病症中用作药物的式I或式II的化合物或其代谢物、互变异构体、溶剂化物或药学上可接受的前药或盐。本发明还提供式I或式II的化合物或其代谢物、互变异构体、溶剂化物或药学上可接受的前药或盐在制备药物中的用途,所述药物用于治疗有此类疾病的人的所述疾病和病症。
本发明还提供试剂盒,所述试剂盒包含一种或多种式I或式II的化合物或其代谢物、互变异构体、溶剂化物或药学上可接受的前药或盐。试剂盒还可包含第二化合物或包含第二药剂的制剂。
本发明的其他优点和新颖特征将部分在以下说明中阐明,部分在详查以下说明时对本领域的技术人员显而易见,或者通过实施本发明认识。本发明的优点可通过在附加权利要求书中特别指出的手段、组合、组合物和方法实现和获得。
发明详述
在某些方面,本发明提供用于调节TLR8-介导的信号传导的组合物和方法。更具体地讲,本发明的一个方面提供一种式I的化合物
及其代谢物、溶剂化物、互变异构体和药学上可接受的前药及盐,其中:
Z为H、烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基、杂芳基、OR6或NR6R7,其中所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代;
R1、R2、R3和R4独立选自H、烷基、烯基、炔基、杂烷基、环烷基、环烯基、杂环烷基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、环烷基、环烯基、杂环烷基、芳基和杂芳基任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代,
或者R1和R2与它们结合的原子一起形成饱和或部分不饱和的碳环,其中所述碳环任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代;
或者R3和R4共同为氧代;
各个R5独立选自H、F、Cl、Br、I、OMe、CH3、CH2F、CHF2、CF3和CF2CF3;
R6和R7独立选自H、烷基、烯基、炔基、杂烷基、环烷基、环烯基、杂环烷基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、环烷基、环烯基、杂环烷基、芳基和杂芳基任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代,
或者R6和R7与它们结合的原子一起形成饱和或部分不饱和的杂环,其中所述杂环任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代;
n为0、1、2、3或4。
本发明还提供式II的化合物
及其代谢物、溶剂化物、互变异构体和药学上可接受的盐及前药,其中:
Z为H、烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基、杂芳基、OR6或NR6R7,其中所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代;
R1、R2、R3和R4独立选自H、烷基、烯基、炔基、杂烷基、环烷基、环烯基、杂环烷基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、环烷基、环烯基、杂环烷基、芳基和杂芳基任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代,
或者R1和R2与它们结合的原子一起形成饱和或部分不饱和的碳环,其中所述碳环任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代;
或者R3和R4共同为氧代;
R5为H、F、Cl、Br、I、OMe、CH3、CH2F、CHF2、CF3或CF2CF3;
R6和R7独立选自H、烷基、烯基、炔基、杂烷基、环烷基、环烯基、杂环烷基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、环烷基、环烯基、杂环烷基、芳基和杂芳基任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代;
或者R6和R7与它们结合的原子一起形成饱和或部分不饱和的杂环,其中所述杂环任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代;并且
n为0、1、2、3或4。
在某些实施方案中,Z为OR6。在某些实施方案中,R6为烷基,如(1-4C)烷基。在特定实施方案中,R6为乙基、丙基、异丙基或异丁基。
在某些实施方案中,Z为NR6R7。在某些实施方案中,R6和R7独立为H或烷基,如(1-6C)烷基。在特定实施方案中,R6和R7为乙基。
在某些实施方案中,n为0或1。在特定实施方案中,R5为CF2CF3。
在某些实施方案中,R3为H或烷基,如(1-4C)烷基,并且R4为H。在某些实施方案中,R3为烷基,如(1-4C)烷基。在特定实施方案中,R3为甲基。在其他特定实施方案中,R3为H。
在某些实施方案中,R1为H或烷基,如(1-4C)烷基,并且R2为H。在某些实施方案中,R1为烷基。在特定实施方案中,R1为甲基。在其他特定实施方案中,R1为H。
本文所用术语“烷基”是指具有1至12个碳原子(包括1至10个碳原子、1至6个碳原子和1至4个碳原子)的饱和线形或支链单价烃基,其中烷基可任选独立用一个或多个下述取代基取代。烷基的实例包括C1-C12烃部分,如但不限于:甲基(Me,-CH3)、乙基(Et,-CH2CH3)、1-丙基(n-Pr,正丙基,-CH2CH2CH3)、2-丙基(i-Pr,异丙基,-CH(CH3)2)、1-丁基(n-Bu,正丁基,-CH2CH2CH2CH3)、2-甲基-1-丙基(i-Bu,异丁基,-CH2CH(CH3)2)、2-丁基(s-Bu,仲丁基,-CH(CH3)CH2CH3)、2-甲基-2-丙基(t-Bu,叔丁基,-C(CH3)3)、1-戊基(正戊基,-CH2CH2CH2CH2CH3)、2-戊基(-CH(CH3)CH2CH2CH3)、3-戊基(-CH(CH2CH3)2)、2-甲基-2-丁基(-C(CH3)2CH2CH3)、3-甲基-2-丁基(-CH(CH3)CH(CH3)2)、3-甲基-1-丁基(-CH2CH2CH(CH3)2)、2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)、1-己基(-CH2CH2CH2CH2CH2CH3)、2-己基(-CH(CH3)CH2CH2CH2CH3)、3-己基(-CH(CH2CH3)(CH2CH2CH3))、2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)、3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)、4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)、3-甲基-3-戊基(-C(CH3)(CH2CH3)2)、2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)、2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)、3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3、1-庚基和1-辛基。
本文所用术语“烯基”是指具有2至10个碳原子(包括2至6个碳原子和2至4个碳原子)且具有至少一个双键的线形或支链单价烃基,包括但不限于乙烯基、丙烯基、1-丁-3-烯基、1-戊-3-烯基、1-己-5-烯基等,其中烯基可任选独立用一个或多个本文所述取代基取代,并且包括具有“顺式”和“反式”取向或者“E”和“Z”取向的基团。术语“烯基”包括烯丙基。
本文所用术语“炔基”是指2至12个碳原子(包括2至6个碳原子和2至4个碳原子)的包含至少一个叁键的线形或支化单价烃基。实例包括但不限于乙炔基、丙炔基、丁炔基、戊炔-2-基等,其中炔基可任选独立用一个或多个本文所述取代基取代。
本文所用术语“碳环”、“碳环基”或“环烷基”可互换使用,是指具有3至12个碳原子(包括3至10个碳原子和3至6个碳原子)的饱和或部分不饱和环状烃基。术语“环烷基”包括单环和多环(例如二环和三环)环烷基结构,其中多环结构任选包括稠合到饱和或部分不饱和环烷基或杂环烷基环或芳基或杂芳基环的饱和或部分不饱和环烷基。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基等。二环碳环具有例如排成二环[4,5]、[5,5]、[5,6]或[6,6]系统的7-12个环原子,具有排成二环[5,6]或[6,6]系统的9或10个环原子,或排成桥连系统,如二环[2.2.1]庚烷、二环[2.2.2]辛烷和二环[3.2.2]壬烷。环烷基可任选独立在一个或多个可取代位置用一个或多个本文所述取代基取代。此环烷基可任选用例如一个或多个独立选自C1-C6烷基、C1-C6烷氧基、卤素、羟基、氰基、硝基、氨基、单(C1-C6)烷基氨基、二(C1-C6)烷基氨基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6卤代烷氧基、氨基(C1-C6)烷基、单(C1-C6)烷基氨基(C1-C6)烷基和二(C1-C6)烷基氨基(C1-C6)烷基的基团取代。
术语“环烯基”是指具有3至10个碳原子(包括3至6个碳原子)且在碳环内具有至少一个双键的部分不饱和环状烃基。
术语“杂烷基”是指1至12个碳原子(包括1至6个碳原子和1至4个碳原子)的饱和线形或支链单价烃基,其中至少一个碳原子用选自N、O或S的杂原子代替,并且其中所述基团可以为碳基团或杂原子基团(即,杂原子可出现于基团的中间或末端)。杂烷基可任选独立用一个或多个本文所述取代基取代。术语“杂烷基”包括烷氧基和杂烷氧基。
本文所用术语“杂环烷基”、“杂环”和“杂环基”可互换使用,是指3至8个环原子的饱和或部分不饱和碳环基团,其中至少一个环原子为选自氮、氧和硫的杂原子,其余环原子为C,其中一个或多个环原子可任选独立用一个或多个下述取代基取代。该基团可以为碳基团或杂原子基团。术语“杂环”包括杂环烷氧基。该术语还包括包含稠合到芳族基团的杂环的稠合环系统。“杂环烷基”也包括其中杂环基团与芳族或杂芳族环稠合的基团。杂环烷基环的实例包括但不限于吡咯烷基、四氢呋喃基、二氢呋喃基、四氢噻吩基、四氢吡喃基、二氢吡喃基、四氢噻喃基、哌啶子基、吗啉代、硫吗啉代(thiomorpholino)、噻噁烷基、哌嗪基、高哌嗪基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基(thietanyl)、高哌啶基、氧杂环庚烷基、硫杂环庚烷基、氧氮杂基、二氮杂基、硫氮杂基、1,2,3,6-四氢吡啶基、2-吡咯啉基、3-吡咯啉基、吲哚啉基、2H-吡喃基、4H-吡喃基、二氧杂环己烷基、1,3-二氧戊环基、吡唑啉基、二噻烷基、二硫杂环戊烷基、二氢吡喃基、二氢噻吩基、二氢呋喃基、吡唑烷基咪唑啉基、咪唑烷基、3-氮杂二环[3.1.0]己烷基、3-氮杂二环[4.1.0]庚烷基、氮杂二环[2.2.2]己烷基、3H-吲哚基喹嗪基和N-吡啶基脲。在此定义范围内也可包括螺部分。如果可能,由上列基团衍生的前述基团可C-连接或N-连接。例如,由吡咯衍生的基团可以为吡咯-1-基(N-连接)或吡咯-3-基(C-连接)。此外,由咪唑衍生的基团可以为咪唑-1-基(N-连接)或咪唑-3-基(C-连接)。其中2个环碳原子用氧代(=O)部分取代的杂环基团的实例为1,1-二氧代-硫吗啉基。本文杂环基可不取代,或如规定用不同基团在一个或多个可取代位置取代。例如,此杂环基可任选用例如一个或多个独立选自C1-C6烷基、C1-C6烷氧基、卤素、羟基、氰基、硝基、氨基、单(C1-C6)烷基氨基、二(C1-C6)烷基氨基、C2-C6烯基、C2-C6炔基、C1-C6卤代烷基、C1-C6卤代烷氧基、氨基(C1-C6)烷基、单(C1-C6)烷基氨基(C1-C6)烷基或二(C1-C6)烷基氨基(C1-C6)烷基的基团取代。
术语“芳基”是指具有单环(例如苯基)、多环(例如联苯)或其中至少一个为芳族的多个稠合环(例如,1,2,3,4-四氢萘基、萘基等)的单价芳族碳环基团,该基团任选用一个或多个独立选自例如卤素、低级烷基、低级烷氧基、三氟甲基、芳基、杂芳基和羟基的取代基取代。
本文所用术语“杂芳基”是指5-、6-或7-元环且包括5-10个原子的稠合环系统(至少一个为芳族)的单价芳族基团,该基团包含至少一个且最多4个选自氮、氧和硫的杂原子。杂芳基的实例为吡啶基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、噌啉基、吲唑基、吲嗪基、2,3-二氮杂萘基、哒嗪基、三嗪基、异吲哚基、蝶啶基、嘌呤基、噁二唑基、三唑基、噻二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并噻吩基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喔啉基、萘啶基和呋喃并吡啶基(furopyridinyl)。在此定义范围内也可包括螺部分。杂芳基任选用一个或多个独立选自例如卤素、低级烷基、低级烷氧基、卤代烷基、芳基、杂芳基和羟基的取代基取代。
术语“卤素”表示氟、溴、氯和碘。
术语“氧代”表示=O。
通常,式I或式II的化合物的各个部分或官能团可任选由一个或多个取代基取代。适用于本发明的取代基的实例包括但不限于氧代、卤素、氰基、硝基、三氟甲基、二氟甲氧基、三氟甲氧基、叠氮基、-NR″SO2R′、-SO2NR′R″、-C(O)R′、-C(O)OR′、-OC(O)R′、-NR″C(O)OR′、-NR″C(O)R′、-C(O)NR′R″、-NR′R″、-NR″′C(O)N′R″、-NR″′C(NCN)NR′R″、-OR′、芳基、杂芳基、芳基烷基、杂芳基烷基、杂环基和杂环基烷基,其中R′、R″和R″′独立为H、烷基、杂烷基、环烷基、杂环烷基、烯基、炔基、芳基或杂芳基。
应了解,在连续使用两个或多个基团以限定连接到一个结构的取代基的情况下,将第一命名的基团认为是末端,而将最后命名的基团认为是连接到所述结构。因此,例如,芳基烷基通过烷基连接到所述结构。
本发明的化合物可具有一个或多个不对称中心;因此,此化合物作为单独(R)-或(S)-立体异构体或其混合物制备。除非另外指明,说明书和权利要求书中特定化合物的描述或命名旨在包括其两种单独的对映异构体、非对映异构体混合物、外消旋或其他化合物。因此,本发明也包括所有此类异构体,包括式I和式II化合物的非对映异构体混合物、纯非对映异构体和纯对映异构体。可通过本领域的技术人员已知的方法,例如色谱法或分级结晶,根据物理化学差异将非对映异构体混合物分离成单独的非对映异构体。可将对映异构体分离,可通过与适合光学活性化合物(例如,醇)反应将对映异构体混合物转化成非对映异构体混合物,分离非对映异构体并将单独非对映异构体转化(例如水解)成相应的纯对映异构体。对映异构体也可用手性HPLC柱分离。测定立体化学和分离立体异构体的方法在本领域已知(讨论于″Advanced Organic Chemistry″,4th edition,Chapter 4,J.March,JohnWiley and Sons,New York,1992)。
在本文所示结构中,在未规定任何特定手性原子的立体化学时,则指所有立体异构体,并且所有立体异构体均作为本发明的化合物被包含。在由表示特定构型的实楔线或虚线指定立体化学结构时,也就如此规定和确定了这种立体异构体。
单一立体异构体,例如实质不含其立体异构体的对映异构体,可通过用光学活性拆分剂用一种方法(如形成非对映异构体)拆分外消旋混合物获得(Eliel,E.and Wilen,S.Stereochemistry of OrganicCompounds,John Wiley&Sons,Inc.,New York,1994;Lochmuller,C.H.,(1975)J.Chromatogr.,113(3):283-302)。本发明的手性化合物的外消旋混合物可由任何适合方法分离,包括:(1)用手性化合物形成离子、非对映异构盐,并由分级结晶或其他方法分离;(2)用手性衍生化剂形成非对映异构化合物,分离非对映异构体,并转化成纯立体异构体;和(3)直接在手性条件下分离实质纯或浓化的立体异构体。参阅:Drug Stereochemistry,Analytical Methods and Pharmacology,Irving W.Warner,Ed.,Marcel Dekker,Inc.,New York(1993)。
在方法(1)下,形成非对映异构盐可使对映异构纯手性碱(如二甲氧基马钱子碱、奎宁、麻黄碱、马钱子碱、α-甲基-β-苯基乙基胺(苯异丙胺)等)与携带酸官能团(如羧酸和磺酸)的不对称化合物反应。可通过分级结晶或离子色谱诱导非对映异构盐分离。为了分离氨基化合物的光学异构体,加入手性羧酸或磺酸(如樟脑磺酸、酒石酸、扁桃酸或乳酸)可使非对映异构盐形成。
或者,通过方法(2),使待拆分基质与手性化合物的一种对映异构体反应生成非对映异构对(E.and Wilen,S.″Stereochemistry of OrganicCompounds″,John Wiley&Sons,Inc.,1994,p.322)。形成非对映异构化合物可使不对称化合物与对映异构纯手性衍生化剂(如薄荷基衍生物)反应,随后分离非对映异构体,并水解得到纯或浓化对映异构体。测定光学纯度的一种方法包括在碱存在下制备外消旋混合物的手性酯,例如薄荷酯(如(-)氯甲酸薄荷酯)或Mosher酯,乙酸α-甲氧基-α-(三氟甲基)苯基酯(Jacob III,(1982)J.Org.Chem.47:4165),并分析存在两种阻转异构对映异构体或非对映异构体的NMR谱。阻转异构体化合物的稳定非对映异构体可按照分离阻转异构萘基异喹啉的方法通过正相和反相色谱法(WO 96/15111)分离。利用方法(3),可用手性固定相由色谱分离两种对映异构体的外消旋混合物(Chiral LiquidChromatography(1989)W.J.Lough,Ed.,Chapman and Hall,New York;Okamoto,(1990)J.of Chromatogr.513:375-378)。利用区分具有不对称碳原子的其他手性分子的方法,如旋光和圆二色谱,可区分浓化或纯化的对映异构体。
除了式I和式II的化合物外,本发明还包括此类化合物的溶剂化物、药学上可接受的前药、药物活性的代谢物、溶剂化物和药学上可接受的盐。
术语“溶剂化物”是指一种分子与一种或多种溶剂分子的聚集物。
“药学上可接受的前药”是可在生理条件下或通过溶剂分解转化成特定化合物或转化成此类化合物的药学上可接受的盐的化合物。前药包括其中氨基酸残基或两种或多种(例如二、三或四种)氨基酸残基的多肽链通过酰胺键或酯键共价结合到本发明化合物的游离氨基、羟基或羧酸基团的化合物。氨基酸残基包括但不限于一般由三字母符号指定的20种天然氨基酸,也包括磷酸丝氨酸、磷酸苏氨酸、磷酸酪氨酸、4-羟基脯氨酸、羟基赖氨酸、demosine、isodemosine、γ-羧基谷氨酸盐、马尿酸、八氢吲哚-2-甲酸、抑胃酶氨酸、1,2,3,4-四氢异喹啉-3-甲酸、青霉胺、鸟氨酸、3-甲基组氨酸、正缬氨酸、β-丙氨酸、γ-氨基丁酸、瓜氨酸、高胱氨酸、高丝氨酸、甲基丙氨酸、对苯甲酰基苯基丙氨酸、苯基甘氨酸、炔丙基甘氨酸、肌氨酸、蛋氨酸砜和叔丁基甘氨酸。本发明的前药的具体实例包括共价结合到磷酸盐残基或缬氨酸残基的式I或式II的化合物。
前药的其他类型也包含在内。例如,可将游离羧基衍生化为酰胺或烷基酯。作为另一实例,可将含游离羟基的本发明的化合物衍生化为前药,可通过使羟基转化成如但不限于磷酸酯、半琥珀酸酯、二甲基氨基乙酸酯或磷酰基氧基甲氧基羰基的基团来衍生,如AdvancedDrug Delivery Reviews,(1996)19:115所概述。也可包括羟基和氨基的氨基甲酸酯前药,羟基的碳酸酯前药、磺酸酯和硫酸酯。也包括羟基衍生化为(酰基氧基)甲基醚和(酰基氧基)乙基醚,其中酰基可以为任选用包括但不限于醚、胺和羧酸官能团的基团取代的烷基酯,或者酰基为上述氨基酸酯。此类型前药描述于J.Med.Chem.,(1996)39:10。更具体的实例包括用以下基团代替醇基团的氢原子,如(C1-C6)烷酰基氧基甲基、1-((C1-C6)烷酰基氧基)乙基、1-甲基-1-((C1-C6)烷酰基氧基)乙基、(C1-C6)烷氧基羰基氧基甲基、N-(C1-C6)烷氧基羰基氨基甲基、琥珀酰基、(C1-C6)烷酰基、α-氨基(C1-C4)烷酰基、芳基酰基和α-氨基酰基或α-氨基酰基-α-氨基酰基,其中各α-氨基酰基独立选自天然L-氨基酸、P(O)(OH)2、-P(O)(O(C1-C6)烷基)2或糖基(基团由半缩醛型糖类去掉羟基产生)。
可使游离胺衍生为酰胺、磺酰胺或膦酰胺。所有这些前药部分可结合包括但不限于醚、胺和羧酸官能团的基团。例如,前药可通过用以下基团代替胺基团中的氢原子生成,如R-羰基、RO-羰基、NRR′-羰基(其中R和R′分别独立为(C1-C10)烷基、(C3-C7)环烷基、苄基,或者R-羰基为天然α-氨基酰基或天然α-氨基酰基-天然α-氨基酰基)、-C(OH)C(O)OY(其中Y为H、(C1-C6)烷基或苄基)、-C(OY0)Y1(其中Y0为(C1-C4)烷基,Y1为(C1-C6)烷基、羧基(C1-C6)烷基、氨基(C1-C4)烷基或单-N-或二-N,N-(C1-C6)烷基氨基烷基)、-C(Y2)Y3(其中Y2为H或甲基,Y3为单-N-或二-N,N-(C1-C6)烷基氨基)、吗啉代、哌啶-1-基或吡咯烷-1-基。
对于前药衍生物的其他实例,参阅,例如,a)Design of Prodrugs,edited by H.Bundgaard,(Elsevier,1985)和Methods in Enzymology,Vol.42,p.309-396,edited by K.Widder,et al.(Academic Press,1985);b)A Textbook of Drug Design and Development,edited byKrogsgaard-Larsen and H.Bundgaard,Chapter 5″Design and Applicationof Prodrugs″by H.Bundgaard p.113-191(1991);c)H.Bundgaard,Advanced Drug Delivery Reviews,(1992);8:1-38d)H.Bundgaard,etal.,Journal of Pharmaceutical Sciences,(1988)77:285;和e)N.Kakeya,et al.,Chem.Pharm.Bull,(1984)32:692,各文献明确通过引用结合到本文中。
“药物活性代谢物”为通过指定化合物或其盐在体内代谢产生的药理学活性产物。化合物的代谢物可用本领域已知的常规技术鉴定,其活性用如本文所述的检验方法测定。
化合物的前药和活性代谢物可用本领域已知的常规技术鉴定。
除非另外指明,“药学上可接受的盐”包括保持指定化合物的游离酸和碱的生物学效力且不在生物学上或在其他方面不合乎需要的盐。本发明的化合物可具有足够酸性、足够碱性或两种官能团,因此可与多种无机或有机碱和无机和有机酸的任何一种反应生成药学上可接受的盐。药学上可接受的盐的实例包括由本发明的化合物与无机或有机酸或无机碱反应制备的盐,这些盐包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯基乙酸盐、苯基丙酸盐、苯基丁酸盐、柠檬酸盐、乳酸盐、γ-羟基丁酸盐、乙醇酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐和扁桃酸盐。由于本发明的单一化合物可包括多于一个酸性或碱性部分,因此本发明的化合物可包括单一化合物中的单、二或三盐。
如果本发明的化合物为碱,则可由本领域可利用的任何适合方法制备所需的药学上可接受的盐,例如用酸性化合物处理游离碱,尤其用无机酸处理,如盐酸、氢溴酸、硫酸、硝酸、磷酸等,或者用有机酸处理,如乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、乙醇酸、水杨酸,吡喃糖苷酸(pyranosidyl acid)如葡糖醛酸或半乳糖醛酸、α-羟基酸如柠檬酸或酒石酸、氨基酸如天冬氨酸或谷氨酸、芳族酸如苯甲酸或肉桂酸、磺酸如对甲苯磺酸或乙磺酸等。
如果本发明的化合物为酸,则可由任何适合方法制备所需的药学上可接受的盐,例如用无机或有机碱处理游离酸。适合的无机盐的实例包括用碱金属和碱土金属(如锂、钠、钾、钡和钙)生成的盐。适合的有机碱盐的实例包括例如铵、二苄基铵、苄基铵、2-羟基乙基铵、双(2-羟基乙基)铵、苯基乙基苄基胺、二苄基乙二胺等盐。酸性部分的其他盐包括例如用普鲁卡因、奎宁和N-甲基葡糖胺生成的盐与用碱性氨基酸如甘氨酸、鸟氨酸、组氨酸、苯基甘氨酸、赖氨酸和精氨酸生成的盐。
利用本领域可用技术且使用易得原料,可用如以下所述的反应路线和合成方案制备本发明的化合物,或者可用本领域已知的方法合成本发明的化合物。
方案I
在方案I中,通过在还原剂(如NaCNBH3)存在下用适当取代的氨基乙腈处理,可由式III的芳基醛制备式IV的化合物。反应可在约0℃至100℃的温度在适合溶剂(如MeOH或EtOH)中进行约0.1至100小时(例如约1小时)。可在适合碱(如吡啶)存在下,用酰化或磺酰化剂由式IV的化合物制备式V的化合物。可使反应在约0℃至200℃进行约0.1至100小时(例如约5小时)。将式V的化合物还原,随后环化,提供式I的化合物。环化反应可在约0℃至100℃的温度在金属(例如Fe)和酸(例如,乙酸)存在下进行约0.5至72小时(例如5小时)。
应注意到,制备本文所述式I和式II的化合物可能需要保护远处的官能团。这种保护需要根据官能性质和制备方法所用条件而变化,并且可很容易由本领域的技术人员确定。这种保护/脱保护方法为本领域的技术人员所熟悉。
本发明的化合物可用于多种应用。例如,在某些方面,本发明提供用于调节TLR8-介导的信号传导的方法。例如,在需要响应适合TLR8配体或TLR8信号传导激动剂改变TLR8-介导的信号传导时,本发明的方法有用。本文所用术语“TLR8配体”和相当术语“用于TLR8的配体”和“TLR8信号传导激动剂”是指通过TIR8域以外的TLR8域直接或间接与TLR8作用且诱导TLR8-介导的信号传导的式I或式II的化合物以外的分子。在某些实施方案中,TLR8配体为天然配体,即天然发现的TLR8配体。在某些实施方案中,TLR8配体是指TLR8天然配体以外的分子,例如由人类活动制备的分子。
本文所用与TLR8受体相关的术语“调节”是指介导患者药效反应,可通过(i)抑制或激活受体,或(ii)直接或间接影响受体活性的正常调节。调节受体活性的化合物包括激动剂、拮抗剂、混合激动剂/拮抗剂以及直接或间接影响受体活性调节的化合物。
本文所用术语“激动剂”是指与受体(例如TLR)组合能够产生细胞反应的化合物。激动剂可以为直接结合到受体的配体。或者,通过例如(a)与直接结合到受体的另一种分子形成复合体或(b)另外改变另一种化合物以便另一种化合物直接结合到所述受体,激动剂可与受体间接结合。可将激动剂称为特定TLR的激动剂(例如TLR8激动剂)。
本文所用术语“拮抗剂”是指与激动剂或逆激动剂竞争结合到受体,从而阻止激动剂或逆激动剂作用于受体的化合物。然而,拮抗剂(也被称为“中性”拮抗剂)对组成性受体活性没有作用。更具体地讲,拮抗剂是在TLR8受体处抑制TLR8活性的化合物。
本文所用术语“抑制”是指生物活性可测降低。因此,在本文中“抑制”或“抑制作用”可以为正常活性水平的百分率。
在本发明的一个方面,治疗可由调节患者TLR8-介导的细胞活性治疗的病症或疾病的方法包括给予有所述病症或疾病的患者有效治疗所述病症或疾病的量的式I或式II的化合物。术语“TLR8-介导的”是指由TLR8功能产生的生物或生物化学活性。
可由本发明方法治疗的病症和疾病包括但不限于癌症、免疫复合物相关性疾病、炎性疾病、免疫缺陷、移植排斥、移植物抗宿主疾病、过敏、哮喘、感染及脓毒。更具体地讲,用于治疗包括自身免疫、炎症、过敏、哮喘、移植排斥和GvHD的病症的方法一般利用响应适合TLR8配体或适合TLR8信号传导激动剂抑制TLR8-介导的信号传导的式I或式II的化合物。或者,用于治疗包括感染、癌症和免疫缺陷的疾病的方法一般利用响应适合TLR8配体增强TLR8-介导的信号传导的式I或式II的化合物。在某些情况下,可用组合物响应TLR8配体或TLR8信号传导激动剂抑制或促进TLR8-介导的信号传导。在其他情况下,可用组合物在患者中抑制或促进TLR8-介导的免疫刺激。
除非另外指明,本文所用术语“治疗”是指哺乳动物(如人)的疾病病症的至少缓解,包括但不限于调节和/或抑制这些疾病病症,和/或减轻这些术语适用的疾病病症或者此疾病或病症的一种或多种症状。除非另外指明,本文所用术语“治疗”是指以上定义的“治疗”的治疗行为。
本文所用术语“自身免疫疾病”、“自身免疫病症”和“自身免疫”是指免疫介导的对宿主组织或器官的急性或慢性伤害。该术语包括细胞和抗体介导的自身免疫现象以及器官特异和器官非特异自身免疫。自身免疫疾病包括胰岛素依赖性糖尿病、类风湿性关节炎、系统性红斑狼疮、多发性硬化、动脉硬化和炎性肠疾病。自身免疫疾病还包括但不限于关节强硬性脊椎炎、自身免疫溶血性贫血、贝赫切特综合征、古德帕斯彻综合征、格雷夫斯病、急性热病性多神经炎、桥本甲状腺炎、自发性血小板减少、重症肌无力、恶性贫血、结节性多动脉炎、多肌炎/皮肤肌炎、原发性胆道硬化、银屑病、结节病、硬化性胆管炎、斯耶格伦综合征、全身性硬化症(硬皮病和肢端硬皮综合征(CRESTsyndrome))、高安氏动脉炎(Takayssu’s arteritis)、颞动脉炎和韦格纳肉芽肿。自身免疫疾病也包括某些免疫复合物相关性疾病。
本文所用术语“癌”和“肿瘤”是指其中在患者中存在可测量量的宿主起源的异常复制细胞的病症。癌可以是恶性癌或良性癌。癌或肿瘤包括但不限于胆道癌、脑癌、乳腺癌、子宫颈癌、绒毛膜癌、结肠癌、子宫内膜癌、食道癌、胃癌、上皮内瘤、白血病、淋巴瘤、肝癌、肺癌(例如,小细胞和非小细胞)、黑素瘤、成神经细胞瘤、口腔癌、卵巢癌、胰腺癌、前列腺癌、直肠癌、肾癌、肉瘤、皮肤癌、睾丸癌、甲状腺癌以及其他癌和肉瘤。癌可以为原发性或转移性。
本文所用术语“免疫复合物相关性疾病”是指任何具有免疫复合物(包含抗体和由抗体特异结合的抗原的任何缀合物)产生和/或组织沉积特征的疾病,包括但不限于系统性红斑狼疮(SLE)和相关结缔组织疾病、类风湿性关节炎、丙肝和乙肝相关性免疫复合物疾病(例如,冷球蛋白血病)、贝赫切特综合征、自身免疫肾小球肾炎和与存在LDL/抗-LDL免疫复合物相关的血管病变。
本文所用术语“免疫缺陷”是指一种疾病或病症,其中患者的免疫系统不以正常能力起作用,或者有用提高患者的免疫反应例如以消除患者的肿瘤或癌(例如,脑、肺(例如小细胞和非小细胞)、卵巢、乳腺、前列腺、结肠的肿瘤以及其他癌和肉瘤)或感染。免疫缺陷可以是获得的,或者可以是先天的。
本文所用术语“移植排斥”是指由宿主以外的源产生的对组织或器官的免疫介导的超急性、急性或慢性伤害。因此,该术语包括细胞和抗体介导的排斥以及同种异体移植和异种移植两者的排斥。
“移植物抗宿主疾病”(GvHD)是移植的骨髓对抗患者自身组织的反应。GVHD最常见于血髓给体与患者不相关或者给体与患者相关但不完全匹配的情况。GVHD有两种形式:一种早期形式被称为急性GVHD,在移植后不久出现白细胞增多时发生,一种为晚期形式,被称为慢性GVHD。
TH2介导的特应性疾病包括但不限于遗传过敏性皮炎或特应性湿疹、嗜曙红细胞增多、哮喘、过敏、过敏性鼻炎和奥曼综合征(Ommen’ssyndrome)。
本文所用术语“过敏”是指对物质(过敏原)的获得的过敏性。过敏病症包括湿疹、过敏性鼻炎或鼻炎、花粉症、哮喘、荨麻疹和食物过敏及其他特应性病症。
本文所用术语“哮喘”是指一种呼吸系统疾病,其特点是炎症、呼吸道变窄并且呼吸道对吸入剂的反应性增加。哮喘是经常性的,虽然不排除与特应性或过敏症状有联系。例如,哮喘可能由暴露于过敏原、暴露于冷空气、呼吸感染和活动突发。
本文所用术语“感染”和相当术语“感染性疾病”是指其中在患者血液或正常无菌组织或正常无菌腔室中存在可测量量的感染性生物体或感染物的病症。感染性生物体和感染物包括病毒、细菌、真菌和寄生虫。此术语包括急性和慢性感染及脓毒。
本文所用术语“脓毒”是指在血液(败血症)或其他身体组织中存在细菌(菌血症)或其他感染性生物体或其毒素。
本发明还提供在为有此类疾病或病症的温血动物(如哺乳动物,例如人)治疗上述疾病或病症中用作药物的式I或式II的化合物或其代谢物、互变异构体、溶剂化物或药学上可接受的前药或盐。本发明还提供式I或式II的化合物或其代谢物、互变异构体、溶剂化物或药学上可接受的前药或盐在制备药物中的用途,所述药物用于为有此类疾病的温血动物(如哺乳动物,例如人)治疗上述疾病和病症。
本发明还包括含式I或式II的化合物或其代谢物、互变异构体、溶剂化物或药学上可接受的前药或盐的药物组合物,和治疗可通过调节TLR8-介导的细胞活性治疗的病症和疾病的方法,所述方法通过给予需要的患者一种包含式I或式II的化合物或其代谢物、互变异构体、溶剂化物或药学上可接受的前药或盐的药物组合物进行。
为了用式I或式II的化合物或其药学上可接受的盐、溶剂化物、代谢物或前药治病性治疗(包括预防性治疗)包括人的哺乳动物,一般根据标准药物规范配制成药物组合物。本发明的这一方面提供一种药物组合物,该组合物包含如前所述的式I或式II的化合物或其药学上可接受的盐、溶剂化物、代谢物或前药以及药学上可接受的稀释剂或载体。
为了制备本发明的药物组合物,将治疗或预防有效量的式I或式II的化合物或其代谢物、互变异构体、溶剂化物或药学上可接受的前药或盐(单独或与本文所述其他治疗剂一起)与例如药学上可接受的载体根据常规药物混合技术紧密混合,以产生一定剂量。载体可根据给药(例如口服或肠胃外)所需的制剂形式采取多种形式。适合载体的实例包括任何及所有溶剂、分散介质、佐剂、包衣料、抗菌和抗真菌剂、等渗和吸收延迟剂、甜味剂、稳定剂(用于促进长期储存)、乳化剂、粘合剂、增稠剂、盐、防腐剂、溶剂、分散介质、包衣料、抗菌和抗真菌剂、等渗和吸收延迟剂、增香剂及为了制备特定治疗组合物所需的混杂物质,如缓冲剂和吸收剂。此类介质和剂与药物活性物质的使用在本领域是熟知的。除了常规介质或剂与式I或式II的化合物不相容外,其在治疗组合物和制剂中的使用均为本发明所包含。也可将辅助活性成分加入本文所述的组合物和制剂中。
本发明的组合物可以为适用于口服使用(例如,作为片剂、锭剂、硬或软胶囊、水性或油性混悬剂、乳剂、可分散粉剂或颗粒剂、糖浆剂或酏剂)、局部使用(例如,作为乳膏剂、软膏剂、凝胶或水性或油性溶液或混悬剂)、吸入给药(例如,作为精细粉剂或液体气雾剂)、吹入给药(例如,作为精细粉剂)或肠胃外给药(例如,作为无菌水或油溶液用于静脉、皮下或肌内给药或作为栓剂用于直肠给药)的形式。例如,口服使用的组合物可包含例如一种或多种着色剂、甜味剂、增香剂和/或防腐剂。
适用于片剂制剂的药学上可接受的赋形剂包括例如惰性稀释剂,如乳糖、碳酸钠、磷酸钙或碳酸钙;粒化剂和崩解剂,如玉米淀粉或藻酸(algenic acid);粘合剂,如淀粉;润滑剂,如硬脂酸镁、硬脂酸或滑石粉;防腐剂,如对羟基苯甲酸乙酯或丙酯;和抗氧化剂,如抗坏血酸。片剂可不包衣,或者用本领域熟知的常规包衣剂和方法包衣,以改进其崩解和随之活性成分在胃肠道内的吸收,或者改善其稳定性和/或外观。
适合口服使用的组合物可以为其中活性成分与惰性固体稀释剂(例如碳酸钙、磷酸钙或高岭土)混合的硬明胶胶囊的形式,或者作为其中活性成分与水或油(如花生油、液体石蜡或橄榄油)混合的软明胶胶囊。
含水混悬剂一般包含细粉状活性成分与一种或多种悬浮剂,如羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮、黄芪胶和阿拉伯胶;分散剂或湿润剂,如卵磷脂或环氧烷与脂肪酸的缩合产物(例如聚氧乙烯硬脂酸酯)、或环氧乙烷与长链脂肪醇的缩合产物(例如十七(亚乙氧基)鲸蜡醇(heptadecaethyleneoxycetanol))、或环氧乙烷与衍生自脂肪酸和己糖醇的偏酯的缩合产物(例如聚氧乙烯山梨糖醇单油酸酯)、或环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物(例如聚乙烯脱水山梨糖醇单油酸酯)。含水混悬剂也可包含一种或多种防腐剂(如对羟基苯甲酸乙酯或丙酯)、抗氧化剂(如抗坏血酸)、着色剂、增香剂和/或甜味剂(如蔗糖、糖精或阿斯巴甜)。
油性混悬剂可通过在植物油(如花生油、橄榄油、芝麻油或椰子油)或在矿物油(如液体石蜡)中悬浮活性成分配制。油性混悬剂也可包含增稠剂,如蜂蜡、硬石蜡或鲸蜡醇。也可加入如上所述的甜味剂和增香剂以提供可口的口服制剂。这些组合物可通过加入抗氧化剂如抗坏血酸防腐。
适合通过加水制备含水混悬剂的可分散粉末和颗粒一般包含活性成分与分散剂或湿润剂、悬浮剂和一种或多种防腐剂。适合的分散剂或湿润剂和悬浮剂由以上已提到的那些作为示例。也可存在其他赋形剂,如甜味剂、增香剂和着色剂。
本发明的药物组合物也可以为水包油型乳剂形式。油相可以为植物油(如橄榄油或花生油)或矿物油(例如液体石蜡)或任何这些油的混合物。适合的乳化剂可以为例如天然胶(如阿拉伯胶或黄芪胶)、天然磷脂(如大豆、卵磷脂)、衍生自脂肪酸和己糖醇酐的酯或偏酯(例如脱水山梨糖醇单油酸酯)和所述偏酯与环氧乙烷的缩合产物(如聚氧乙烯脱水山梨糖醇单油酸酯)。乳剂也可包含甜味剂、增香剂和防腐剂。
糖浆剂和酏剂可用甜味剂如甘油、丙二醇、山梨糖醇、阿斯巴甜或蔗糖配制,并且也可包含缓和剂、防腐剂、增香剂和/或着色剂。
药物组合物也可以为无菌可注射的水性或油性混悬剂的形式,可根据已知方法用一种或多种以上已提到的适合分散剂或湿润剂和悬浮剂配制。对于胃肠外制剂,载体通常包含无菌水、含水氯化钠溶液、1,3-丁二醇或任何其他适合的无毒胃肠外可接受的稀释剂或溶剂。可包含帮助分散的其他成分。当然,在无菌水待用并且保持为无菌时,也必须使组合物和载体无菌。也可以制备可注射混悬剂,在此情况下可利用适合的液体载体、悬浮剂等。
可通过混合活性成分与适合的非刺激性赋形剂制备栓剂,所述赋形剂在常温为固体,但在直肠温度为液体,因此在直肠中将融化释放药物。适合的赋形剂包括例如可可豆脂和聚乙二醇。
局部用药制剂,如乳膏剂、软膏剂、凝胶和水性或油性溶液或混悬剂,一般用本领域熟知的常规方法配制活性成分与常规局部用药可接受的媒剂或稀释剂获得。
由吹入给药的组合物可以为包含例如30μm或更小平均直径的颗粒的精细粉末剂型,粉末可自身包含单独活性成分或用一种或多种生理可接受的载体(如乳糖)稀释。然后,可方便地将用于吹入的粉末保持在包含例如1-50mg活性成分的囊中供涡轮吸入器使用,如用于已知剂色甘酸钠的吹入。
用于吸入给药的组合物可以为常规加压气雾剂的形式,这种形式布置成将活性成分分散为含微细固体或液体微滴的气雾剂。可使用常规气雾剂抛射剂,如挥发性氟化烃或烃,并且可很方便地将气雾剂装置布置成能够分散计量活性成分。
用于透皮给药的组合物可以为本领域的技术人员熟知的透皮皮肤贴剂形式。
其他递药系统可包括定时释药、延迟释药或缓释递药系统。此类系统可避免化合物重复给药,为患者和医生增加便利。这些递药系统的很多类型可以利用,并且为本领域的技术人员所熟悉。它们包括聚合物基系统,如聚(丙交酯-乙交酯)、共聚草酸酯、聚己内酯、聚酯酰胺、聚原酸酯、聚羟基丁酸和聚酐。含药物的前述聚合物的微囊描述于例如美国专利5,075,109中。递药系统也可包括非聚合物系统,这些系统为:脂类,包括甾醇(如胆甾醇)、胆甾醇酯和脂肪酸或中性脂肪如甘油单酯、二酯和三酯;水凝胶释药系统;硅橡胶系统;肽基系统;蜡包衣料;利用常规粘合剂和赋形剂的压制片剂;部分融合的植入物等。具体实例包括但不限于:(a)其中本发明的剂以基质内形式包含的腐蚀系统,如美国专利4,452,775、4,675,189和5,736,152所述,和(b)其中活性组分以控制速率从聚合物渗透的扩散系统,如美国专利3,854,480、5,133,974和5,407,686所述。此外可使用基于泵的硬件递药系统,其中一些适用于植入。
关于制剂的其他资料,参见Comprehensive MedicinalChemistry(Corwin Hansch;Chairman of Editorial Board),Volume 5,Chapter 25.2,Pergamon Press 1990,此文献明确通过引用结合到本文中。
与一种或多种赋形剂组合制备单一剂型的本发明化合物的量当然要根据要治疗的患者、疾病或病症的严重性、给药速率、化合物的处置和开方医生的判断变化。然而,在单剂量或分开剂量中,有效剂量为约0.001至约100mg/kg体重/天,例如约0.5至约35mg/kg体重/天。对于70kg的人,这将是约0.0035至2.5g/天,例如约0.05至约2.5g/天。在某些情况下,低于前述范围下限的剂量可能足够,而在其他情况下,可使用更大量剂量而不产生任何有害副作用,其条件为首先将此较大剂量分成供一天给药的数个小剂量。关于给药途径和剂量方案的其他资料,参见Comprehensive Medicinal Chemistry(CorwinHansch;Chairman of Editorial Board),Volume 5,Chapter 25.3,Pergamon Press 1990,此文献明确通过引用结合到本文中。
根据熟知的医学原理,用于治疗或预防的式I或式II化合物的剂量大小当然要根据病症的性质和严重性、动物或患者的年龄和性别以及给药途径而变化。应了解,对于任何特定患者的具体剂量和给药频率可以变化,并且取决于多种因素,包括具体式I或式II化合物的活性、物种、患者的年龄、体重,一般健康状况、性别和饮食、给药方式和时间、排泄率、药物组合以及特定病症的严重性,然而可由本领域的技术人员按常规确定。
在一些实施方案中,式I或式II的化合物可与另一种治疗剂组合(“组合治疗”)给予个体患者(例如,在同一制剂或在单独制剂中)。式I或式II的化合物可与另一种治疗剂混合给药,或者可在单独的制剂中给药。当在单独的制剂中给药时,式I或式II的化合物与另一种治疗剂可基本同时或顺序给药。
除了本发明的化合物外,这种组合治疗可包括常规手术或放射治疗或化学治疗。此类化学治疗可包括一种或多种以下抗肿瘤剂种类:(i)抗增殖活性/抗肿瘤药物及其组合;(ii)细胞生长抑制剂;(iii)癌细胞侵入抑制剂;(iv)生长因子功能抑制剂;(v)抗血管形成剂;(vi)血管损伤剂;(vii)反义治疗药;(viii)基因治疗剂;(ix)干扰素;和(x)免疫治疗剂。
可与题述方法中式I或式II化合物组合给药的用于治疗呼吸疾病的治疗剂包括但不限于β-肾上腺素能药物,包括支气管扩张药,包括沙丁胺醇、硫酸异丙肾上腺素、硫酸奥西那林、硫酸特布他林、乙酸吡布特罗和沙美特罗、福莫特罗;类固醇,包括丙酸倍氯米松、氟尼缩松、氟替卡松、布地奈德和曲安奈德。与治疗呼吸疾病结合使用的抗炎药物包括类固醇,如丙酸倍氯米松、曲安奈德、氟尼缩松和氟替卡松。其他抗炎药物包括色甘酸盐,如色甘酸二钠。获准成为支气管扩张药的其他呼吸药物包括抗胆碱能药,包括异丙托溴铵。抗组胺药包括但不限于苯海拉明、卡比沙明、氯马斯汀、茶苯海明、美吡拉敏、曲吡那敏、氯苯那敏、溴苯那敏、羟嗪、赛克力嗪、美克洛嗪、氯环力嗪、异丙嗪、多西拉敏、氯雷他定和特非那定。具体的抗组胺药包括氮卓斯汀(rhinolast)claratyneclaratyneDtelfast 和伯克纳。
在一些实施方案中,式I或式II的化合物与γ-干扰素(IFN-γ)、皮质甾类如泼尼松、泼尼松龙、甲泼尼龙、氢化可的松、可的松、地塞米松、倍他米松等或其组合作为组合治疗给药用于治疗间质性肺病,例如特发性肺纤维变性。
在一些实施方案中,式I或式II的化合物与一种已知治疗剂在组合疗法中给药用于治疗CF。治疗CF使用的治疗剂包括但不限于抗生素;抗炎剂;DNAse(例如,重组人DNAse;阿法链道酶、氯化钙和氯化钠溶液;阿法链道酶);溶粘蛋白剂(例如,N-乙酰基半胱氨酸;MucomystTM;MucosilTM);减充血剂;支气管扩张剂(例如,茶碱、异丙托溴铵)等。
在本发明的另一个实施方案中提供包含用于治疗上述疾病的物质的制品或“试剂盒”。在一个实施方案中,试剂盒包括容器,容器包含式I或式II的组合物或其代谢物、互变异构体、溶剂化物或药学上可接受的前药或盐。在一个实施方案中,本发明提供用于治疗TLR8-介导的疾病的试剂盒。在另一个实施方案中,本发明提供适用于可由调节患者免疫系统治疗的病症或疾病的试剂盒。试剂盒可进一步包含在容器上或与容器相关的标签或包装说明书。适合的容器包括例如瓶、小瓶、注射器、泡罩包装等。容器可用多种材料制成,如玻璃或塑料。容器容纳治疗病症有效量的式I或式II的化合物或其药物制剂,并且可具有无菌入口(例如,容器可以为具有塞子的静脉注射液袋或瓶,塞子可被皮下注射针头穿透)。标签或包装说明书标明用组合物治疗所选择的病症。在一个实施方案中,标签或包装说明书标明可用包含式I或式II的化合物的组合物例如治疗可由调节TLR8-介导的细胞活性治疗的疾病。标签或包装说明书也可标明可用组合物治疗其他疾病。作为选择或另外,试剂盒可进一步包含第二容器,第二容器包含药学上可接受的缓冲剂,如注射用抑菌水(BWFI)、磷酸盐缓冲盐水、林格氏液和葡萄糖溶液。从商业和用户的观点,可进一步包含其他所需物质,包括其他缓冲剂、稀释剂、滤器、针头和注射器。
试剂盒还可包含式I或式II化合物和(如果存在)第二药物制剂的给药说明。例如,如果试剂盒包括含有式I或式II化合物的第一组合物和第二药物制剂,则试剂盒还可以包含第一和第二药物组合物同时、顺序或单独给予需要的患者的说明。
在另一个实施方案中,试剂盒适用于式I或式II的化合物的固体口服剂型的递药,例如片剂或胶囊。这种试剂盒包括例如一些单位剂量。这种试剂盒可包括具有以预期使用顺序导向的剂量的卡。这种试剂盒的实例为“泡罩包装”。泡罩包装在包装工业上熟知,并且广泛用于包装药物单位剂型。如果需要,可提供记忆帮助,例如,以数字、字母或其他标志形式,或者使用日程说明,指定其中能够给予剂量的治疗日程中的天数。
根据一个实施方案中,试剂盒包含(a)其中含有式I或式II的化合物的第一容器;和任选的(b)其中含有第二药物制剂的第二容器,其中第二药物制剂包含第二化合物,第二化合物可有效治疗可由选择性调节TLR8-介导的细胞活性治疗的病症或疾病。作为选择或另外,试剂盒可进一步包含第三容器,第三容器包含药学上可接受的缓冲剂,如注射用抑菌水(BWFI)、磷酸盐缓冲盐水、林格氏液和葡萄糖溶液。从商业和用户的观点,可进一步包含其他所需物质,包括其他缓冲剂、稀释剂、滤器、针头和注射器。
在试剂盒包含式I或式II化合物的药物制剂和包含第二治疗剂的第二制剂的某些其他实施方案中,试剂盒可包含容纳单独制剂的容器,如分开的瓶或分开的箔小包装;然而,也可在单一不分开的容器中容纳单独的组合物。通常,试剂盒包含单独组分给药的说明。在单独组分以不同剂型给药(例如,口服和胃肠外),以不同用药间隔给药时,或者在处方医生需要滴入组合的单独组分时,试剂盒形式特别有利。
实施例
为说明本发明包含以下实施例。然而,应了解,这些实施例并不限制本发明,只意味建议实施本发明的方法。本领域的技术人员应认识到,可很容易地改变所述化学反应制备本发明的一些其他化合物,制备本发明化合物的供选方法也应被认为在本发明的范围内。例如,通过对本领域技术人员显而易见的修改,例如,适当保护干扰基团,利用本领域已知的所述那些以外的其他适合试剂,和/或常规改变反应条件,可成功地合成本发明的非示例性化合物。作为选择,应认为本文公开或本领域已知的其他反应也可用于制备本发明的其他化合物。
在下述实施例中,除非另外指明,所有温度均为摄氏度。试剂购自供应商,如Aldrich Chemical Company,Lancaster,TCI或Maybridge,使用无需纯化,除非另外指明。
下述反应一般在氮或氩正压下或利用干燥管(除非另外说明)在无水溶剂中进行,反应烧瓶通常配有橡胶塞,用于通过注射器引入底物和试剂。玻璃器皿经烘箱干燥和/或加热干燥。
柱层析在具有硅胶柱的Biotage系统(制造商:Dyax Corporation)或在氧化硅SepPak柱体(Waters)上进行。在以400MHz操作的Varian仪器上记录1H NMR谱图。1H NMR谱作为CDCl3或DMSO-d6溶液获得(以ppm报告),用氯仿作为参比标准(7.25ppm)。如需要,使用其他NMR溶剂。在报告峰多重性时,使用以下略语:s(单峰)、d(二重峰)、t(三重峰)、m(多重峰)、br(增宽)、dd(双二重峰)、dt(双三重峰)。给出时,偶合常数以赫兹(Hz)报告。
实施例1
步骤A:制备2-(2-硝基苄基氨基)乙腈(1)
将2-氨基乙腈盐酸盐(3.67g,39.7mmol)加入到溶于无水MeOH(30mL)的2-硝基苯甲醛(5.00g,33.1mmol)的溶液中。将反应在室温搅拌5分钟,以得到溶液。加入NaCNBH3(2.08g,33.1),并将反应混合物在室温搅拌过夜。在减压下将反应混合物浓缩,然后用EtOAc(50mL)稀释。将有机相用饱和NaHCO3(30mL)和盐水(30mL)洗涤,经Na2SO4干燥,浓缩得到4.20g(22.0mmol,66%收率)2-(2-硝基苄基氨基)乙腈(1),为一种棕褐色油4.20g(22.0mmol,66%收率)。所得物质无需进一步纯化即可用于下一步骤。
步骤B:制备2-硝基苄基(氰基甲基)氨基甲酸乙酯(2)
将吡啶(151mg,1.91mmol)加入到包含2-(2-硝基苄基氨基)乙腈(1)(122mg,0.638mmol)的CH2Cl2溶液(20mL)中。在氮气气氛下使反应混合物冷却到0℃,并滴加氯甲酸乙酯(0.182mL,1.914)。在室温搅拌反应混合物1小时,然后用1N HCl(50mL)和盐水(50mL)洗涤。有机层经Na2SO4干燥,并在减压下浓缩。所得油通过柱层析(Biotage40m,100%CH2Cl2)纯化,得到97mg(0.37mmol,58%收率)2-硝基苄基(氰基甲基)氨基甲酸乙酯(2),为一种黄色油。
步骤C:制备(E)-2-氨基-3H-苯并[e][1,4]二氮杂-4(5H)-甲酸乙酯(3)
在氮气气氛下将Fe(289mg,5.17mmol)加入到溶于乙酸(5mL)的2-硝基苄基-(氰基甲基)氨基甲酸乙酯(2)(227mg,0.862mmol)的溶液中。将反应混合物加热到90℃经历4小时,然后冷却至室温,并在减压下浓缩。用EtOAc(20ml)稀释得到的棕色油,通过GF/F纸过滤(用10mL EtOAc清洗)。将有机相用饱和Na2CO3(20mL)和盐水(20mL)洗涤,经Na2SO4干燥并浓缩。所得棕色油通过柱层析(5%MeOH/CH2Cl2,然后20%MeOH/CH2Cl2)纯化,得到52mg(0.223mmol,26%收率)(E)-2-氨基-3H-苯并[e][1,4]二氮杂-4(5H)-甲酸乙酯(3),为一种棕褐色固体。
1HNMR(400MHz,DMSO-d6)δ1.17-1.25(m,3H),3.81(s,2H),4.02-4.12(m,2H),4.23(s,2H),6.79(br s,1H),6.85-6.92(m,2H),7.18-7.24(m,2H).
实施例2
步骤A:制备2-(2-硝基-4-(全氟乙基)苄基氨基)乙腈(4):
用2-硝基-4-(全氟乙基)苯甲醛代替2-硝基苯甲醛,以类似于实施例1步骤A所述的方式制备化合物(4),得到83mg(0.27mmol,42%收率)所需产物。
步骤B:制备2-硝基-4-(全氟乙基)苄基(氰基甲基)氨基甲酸乙酯(5):
用2-(2-硝基-4-(全氟乙基)苄基氨基)乙腈(4)代替2-(2-硝基苄基氨基)乙腈(1),以类似于实施例1步骤B所述的方式制备化合物(5),得到69mg(0.18mmol,68%收率)所需产物。
用2-硝基-4-(全氟乙基)苄基(氰基甲基)氨基甲酸乙酯(5)代替2-硝基苄基-(氰基甲基)氨基甲酸乙酯(2),以类似于实施例1步骤C所述的方式制备化合物(6),得到2.5mg(4%收率)所需产物。
1HNMR(400MHz,CDCl3)δ1.26-1.37(m,3H),3.94-3.99(m,2H),4.21-4.22(m,2H),4.39-4.45(m,2H),5.00(br s,1H),7.24-7.36(m,3H).
实施例3
合成(E)-2-氨基-5-甲基-3H-苯并[e][1,4]二氮杂-4(5H)-甲酸乙酯(9)
步骤A:制备2-(1-(2-硝基苯基)乙基氨基)乙腈(7):
用1-(2-硝基苯基)乙酮代替2-硝基苯甲醛,以类似于实施例1步骤A所述的方式制备此化合物,得到2.40g(11.7mmol,56%收率)所需产物。
步骤B:制备氰基甲基(1-(2-硝基苯基)乙基)氨基甲酸乙酯(8):
用2-(1-(2-硝基苯基)乙基氨基)乙腈(7)代替2-(2-硝基苄基氨基)乙腈(1),以类似于实施例1步骤B所述的方式制备此化合物,得到75mg(27mmol,32%收率)所需产物。
用氰基甲基(1-(2-硝基苯基)乙基)氨基甲酸乙酯(8)代替2-硝基苄基-(氰基甲基)氨基甲酸乙酯(2),以类似于(E)-2-氨基-3H-苯并[e][1,4]二氮杂-4(5H)-甲酸乙酯(3)的方式制备此化合物,得到2.6mg(0.011mmol,13%收率)所需产物。
1H NMR(400MHz,CDCl3)δ1.26(br s,3H),1.40(d,3H),3.45-3.58(br s,1H),4.15-4.29(m,2H),4.44(br s,1H),4.97(br s,1H),7.03-7.06(m,2H),7.18-7.31(m,2H).
实施例4
步骤A:制备2-(2-硝基苄基氨基)乙腈(1)
如实施例1步骤A制备化合物(1)。
步骤B:2-硝基苄基(氰基甲基)氨基甲酸异丙酯(10)
用氯甲酸异丙酯代替氯甲酸乙酯,以类似于实施例1步骤B所述的方式制备化合物(1),得到270mg(0.974mmol,41%收率)所需产物。
步骤C:(E)-2-氨基-3H-苯并[e][1,4]二氮杂-4(5H)-甲酸异丙酯(11)
用2-硝基苄基(氰基甲基)氨基甲酸异丙酯(10)代替2-硝基苄基(氰基甲基)氨基甲酸乙酯(2),以类似于实施例1步骤C所述的方式制备此化合物,得到3.2mg(0.013mmol,1%收率)所需产物。
1H NMR(400MHz,CDCl3)δ1.35(br s,6H),3.86-3.97(m,2H),4.36-4.45(m,2H),4.98-5.02(m,1H),7.02-7.08(m,2H),7.20-7.38(m,2H).
实施例5
步骤A:制备2-(2-硝基苄基氨基)乙腈(1)
如实施例1步骤A制备化合物(1)。
步骤B:制备2-硝基苄基(氰基甲基)氨基甲酸正丙酯(12)
用氯甲酸正丙酯代替氯甲酸乙酯,以类似于实施例1步骤B所述的方式自化合物(1)制备化合物(12),得到64mg(0.23mmol,36%收率)所需产物。
用2-硝基苄基(氰基甲基)氨基甲酸正丙酯(12)代替2-硝基苄基(氰基甲基)氨基甲酸乙酯(2),以类似于实施例1步骤C所述的方式制备化合物(13),得到6.8mg(0.028mmol,13%收率)所需产物。
1H NMR(400MHz,CDCl3)δ0.87-0.94(m,3H),1.59-1.66(m,2H),4.03-4.05(m,2H),4.35(s,1H),4.50(br s,2H)4.59(s,1H),6.89(d,1H),7.09-7.15(m,1H),7.22-7.33(m,2H),7.62(br d,1H).
实施例6
步骤A:制备2-(2-硝基苄基氨基)乙腈(1)
如实施例1步骤A制备化合物(1)。
步骤B:制备2-硝基苄基(氰基甲基)氨基甲酸异丁酯(14)
用氯甲酸异丁酯代替氯甲酸乙酯,以类似于实施例1步骤B所述的方式制备化合物(14),得到43.2mg(0.148mmol,14%收率)所需产物。
用2-硝基苄基(氰基甲基)氨基甲酸异丁酯(14)代替2-硝基苄基-(氰基甲基)氨基甲酸乙酯(2),以类似于实施例1步骤C所述的方式制备化合物(15),得到2.8mg(0.011mmol,7%收率)所需产物。
1H NMR(400MHz,CDCl3)δ0.95-1.10(m,6H),2.00(m,1H),3.90-3.97(m,4H),4.37-4.41(m,2H),7.03-7.06(m,2H),7.20-7.39(m,2H).
实施例7
步骤A:制备2-(2-硝基苄基氨基)乙腈(1)
如实施例1步骤A制备化合物(1)。
步骤B:制备1-(2-硝基苄基)-1-(氰基甲基)-3,3-二乙基脲(16)
用二乙基氨基甲酰氯代替氯甲酸乙酯,以类似于实施例1步骤B所述的方式制备化合物(16),得到24.9mg(0.0858mmol,19%收率)所需产物。
步骤C:制备(E)-2-氨基-N,N-二乙基-3H-苯并[e][1,4]二氮杂-4(5H)-甲酰胺(17):
用1-(2-硝基苄基)-1-(氰基甲基)-3,3-二乙基脲(16)代替2-硝基苄基(氰基甲基)氨基甲酸乙酯(2),以类似于实施例1步骤C所述的方式制备化合物(17),得到2.6mg(0.01mmol,11%收率)所需产物。
1H NMR(400MHz,CDCl3)δ1.19(t,6H),3.33(q,4H),3.66(s,2H),4.11(s,2H),7.01-7.05(m,2H),7.18(d,1H),7.31(t,1H).
实施例8
步骤A:制备2-(1-(2-硝基苯基)乙基氨基)乙腈(18)
在氮气气氛下,将2-硝基苄基胺(513mg,3.37mmol)加入到包含K2CO3(932mg,6.74mmol)和2-溴丙腈(677mg,5.06mmol)的乙腈(40mL)中。将反应混合物加热到65℃经历14小时。所得产物(18)无需纯化或浓缩即可用于下一步骤。
步骤B:制备氰基甲基(1-(2-硝基苯基)乙基)氨基甲酸乙酯(19):
将饱和NaHCO3(5mL)和氯甲酸乙酯(1.83g,16.86mmol)加入到从前面步骤得到的包含2-(1-(2-硝基苯基)乙基氨基)乙腈(18)的乙腈溶液。在室温剧烈搅拌反应混合物14小时。用EtOAc(50ml)稀释反应,随后用盐水(40ml)洗涤。分离的有机相经Na2SO4干燥,过滤并浓缩。纯化(Biotage 40s,3∶1 CH2Cl2∶己烷,然后100%CH2Cl2)得到37.1mg(0.134mmol,4%收率)氰基甲基(1-(2-硝基苯基)乙基)氨基甲酸乙酯(19),为一种浅黄色油。
用氰基甲基(1-(2-硝基苯基)乙基)氨基甲酸乙酯(19)代替2-硝基苄基-(氰基甲基)氨基甲酸乙酯(2),以类似于实施例1步骤C所述的方式制备此化合物,得到3.1mg(0.013mmol,9%收率)所需产物。
1H NMR(400MHz,CDCl3)δ1.01(d,3H),1.25-1.34(m,3H),4.13-4.23(m,3H),4.70(br d,2H),6.95-7.03(m,2H),7.20(d,1H),7.30(t,1H).
用以下试验测定本发明化合物的活性。
实施例9
HEK/TLR试验
用不同浓度的化合物过夜培育人胚胎肾(HEK)细胞,这种细胞稳定表达不同的人TLR基因,包括TLR8以及NFkB-荧光素酶报道基因。通过在650nm读取吸光度确定诱导的荧光素酶的量。本发明的化合物具有100μM或更小的MC50,其中MC50被定义为见到50%最大诱导的浓度。
实施例10
TLR8的PBMC试验
用具有柠檬酸钠的BD Vacutainer Cell Preparation Tube(细胞制备管)从人血分离外周血单核细胞(PBMC)。细胞用化合物培育过夜。TLR8活性通过由ELISA检测上清液中TNFα的量测定。本发明的化合物具有100μM或更小的MC50,其中MC50为见到50%最大诱导的浓度。
前述说明仅为本发明原理的示例。此外,由于许多改进和变化对本领域的技术人员显而易见,因此本发明不限于上述确切结构和所示方法。因此,所有适合改进及同等物应在以下权利要求限定的本发明的范围内。
在说明书和以下权利要求中使用时,“包括”和“包含”旨在说明所述特征、整数、组分或步骤的存在,但它们不排除一个或多个其他特征、整数、组分、步骤或组的存在或加入。
Claims (35)
1.一种下式的化合物及其代谢物、溶剂化物、互变异构体和药学上可接受的盐
其中:
Z为H、烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基、杂芳基、OR6或NR6R7,其中所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代;
R1、R2、R3和R4独立选自H、烷基、烯基、炔基、杂烷基、环烷基、环烯基、杂环烷基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、环烷基、环烯基、杂环烷基、芳基和杂芳基任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代,
或者R1和R2与它们结合的原子一起形成饱和或部分不饱和碳环,其中所述碳环任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代;
或者R3和R4共同为氧代;
各个R5独立选自H、F、Cl、Br、I、OMe、CH3、CH2F、CHF2、CF3和CF2CF3;
R6和R7独立选自H、烷基、烯基、炔基、杂烷基、环烷基、环烯基、杂环烷基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、环烷基、环烯基、杂环烷基、芳基和杂芳基任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代;
或者R6和R7与它们结合的原子一起形成饱和或部分不饱和杂环,其中所述杂环任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代;并且
n为0、1、2、3或4。
2.权利要求1的化合物,其中Z为OR6。
3.权利要求2的化合物,其中R6为烷基。
4.权利要求3的化合物,其中R6为乙基、丙基、异丙基或异丁基。
5.权利要求1的化合物,其中Z为NR6R7。
6.权利要求5的化合物,其中R6和R7独立为H或烷基。
7.权利要求6的化合物,其中R6和R7为乙基。
8.权利要求1至7中任一项的化合物,其中n为0或1。
9.权利要求8的化合物,其中R5为CF2CF3。
10.权利要求1至9中任一项的化合物,其中R3为H或烷基,并且R4为H。
11.权利要求10的化合物,其中R3为甲基。
12.权利要求1至11中任一项的化合物,其中R1为H或烷基,并且R2为H。
13.权利要求12的化合物,其中R1为甲基。
14.权利要求1的化合物,所述化合物选自:
(E)-2-氨基-3H-苯并[e][1,4]二氮杂-4(5H)-甲酸丙酯;
(E)-2-氨基-N,N-二乙基-3H-苯并[e][1,4]二氮杂-4(5H)-甲酰胺;和
其药学上可接受的盐。
15.一种下式的化合物及其代谢物、溶剂化物、互变异构体和药学上可接受的盐
其中:
Z为H、烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基、杂芳基、OR6或NR6R7,其中所述烷基、烯基、炔基、杂烷基、环烷基、杂环烷基、芳基和杂芳基任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代;
R1、R2、R3和R4独立选自H、烷基、烯基、炔基、杂烷基、环烷基、环烯基、杂环烷基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、环烷基、环烯基、杂环烷基、芳基和杂芳基任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代,
或者R1和R2与它们结合的原子一起形成饱和或部分不饱和的碳环,其中所述碳环任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代,
或者R3和R4共同为氧代;
R5为H、F、Cl、Br、I、OMe、CH3、CH2F、CHF2、CF3或CF2CF3;
R6和R7独立选自H、烷基、烯基、炔基、杂烷基、环烷基、环烯基、杂环烷基、芳基和杂芳基,其中所述烷基、烯基、炔基、杂烷基、环烷基、环烯基、杂环烷基、芳基和杂芳基任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代;
或者R6和R7与它们结合的原子一起形成饱和或部分不饱和的杂环,其中所述杂环任选用一个或多个独立选自烷基、烯基、炔基、F、Cl、Br、I、CN、OR6、NR6R7、C(=O)R6、C(=O)OR6、OC(=O)R6、C(=O)NR6R7、(C1-C6烷基)氨基、CH3OCH2O-、R6OC(=O)CH=CH2-、NR6SO2R7、SR6和SO2R6的基团取代;并且
n为0、1、2、3或4。
16.权利要求15的化合物,其中Z为OR6。
17.权利要求16的化合物,其中R6为烷基。
18.权利要求17的化合物,其中R6为乙基、丙基、异丙基或异丁基。
19.权利要求15的化合物,其中Z为NR6R7。
20.权利要求19的化合物,其中R6和R7独立为H或烷基。
21.权利要求20的化合物,其中R6和R7为乙基。
22.权利要求15至21中任一项的化合物,其中R5为H或CF2CF3。
23.权利要求22的化合物,其中R5为CF2CF3。
24.权利要求15至23中任一项的化合物,其中R1为H或烷基,并且R2为H。
25.权利要求24的化合物,其中R1为甲基。
26.权利要求15至25中任一项的化合物,其中R3为H或烷基,并且R4为H。
27.权利要求26的化合物,其中R3为甲基。
28.一种用于治疗TLR8-介导的病症的试剂盒,所述试剂盒包含:
a)包含权利要求1至27中任一项的化合物的第一药物组合物;和
b)任选的使用说明书。
29.权利要求28的试剂盒,所述试剂盒进一步包含(c)第二药物组合物,其中所述第二药物组合物包含具有抗过度增殖活性的第二化合物。
30.权利要求29的试剂盒,所述试剂盒进一步包含用于对需要的患者同时、顺序或单独给予所述第一药物组合物和第二药物组合物的说明书。
31.一种药物组合物,所述组合物包含权利要求1至27中任一项的化合物以及药学上可接受的稀释剂或载体。
32.权利要求1至27中任一项的化合物,所述化合物用作治疗人或动物的TLR8-介导的病症的药物。
33.权利要求1至27中任一项的化合物用于制备药物的用途,所述药物用于治疗人或动物的TLR8-介导的病症。
34.一种治疗TLR8-介导的病症的方法,所述方法包括给予需要的患者有效量的权利要求1的化合物。
35.一种调节患者的免疫系统的方法,所述方法包括给予需要的患者有效量的权利要求1的化合物。
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CN102753542A (zh) * | 2009-08-18 | 2012-10-24 | 文蒂雷克斯药品公司 | 作为toll样受体调节剂的取代的苯并氮杂* |
CN102753542B (zh) * | 2009-08-18 | 2016-01-20 | 文蒂雷克斯药品公司 | 作为t0ll样受体调节剂的取代的苯并氮杂* |
CN105669553A (zh) * | 2009-08-18 | 2016-06-15 | 文蒂雷克斯药品公司 | 作为toll样受体调节剂的取代的苯并氮杂* |
CN103562186A (zh) * | 2011-01-12 | 2014-02-05 | 帆德制药股份有限公司 | 作为toll样受体调节剂的取代的苯并氮杂卓 |
CN103562186B (zh) * | 2011-01-12 | 2017-02-15 | 帆德制药股份有限公司 | 作为toll样受体调节剂的取代的苯并氮杂卓 |
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HK1122018A1 (en) | 2009-05-08 |
WO2007040840A3 (en) | 2007-06-14 |
TW200740774A (en) | 2007-11-01 |
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EP1928845B1 (en) | 2013-07-10 |
TWI382019B (zh) | 2013-01-11 |
US20120208801A1 (en) | 2012-08-16 |
EP1928845A2 (en) | 2008-06-11 |
WO2007040840A2 (en) | 2007-04-12 |
HRP20130942T1 (hr) | 2013-11-08 |
US8673898B2 (en) | 2014-03-18 |
US8163738B2 (en) | 2012-04-24 |
SI1928845T1 (sl) | 2013-10-30 |
JP2009504764A (ja) | 2009-02-05 |
JP5246865B2 (ja) | 2013-07-24 |
DK1928845T3 (da) | 2013-08-05 |
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