CN106279110B - 杂环化合物、含有所述化合物的药物及其用途和其制备方法 - Google Patents
杂环化合物、含有所述化合物的药物及其用途和其制备方法 Download PDFInfo
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- CN106279110B CN106279110B CN201610685839.2A CN201610685839A CN106279110B CN 106279110 B CN106279110 B CN 106279110B CN 201610685839 A CN201610685839 A CN 201610685839A CN 106279110 B CN106279110 B CN 106279110B
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Abstract
本发明涉及通式(I)的化合物及其互变异构体和盐,特别是其与无机或有机酸和无机或有机碱的药用盐,其具有有价值的药理学特性,尤其是对上皮钠通道具有抑制作用,并具有治疗疾病的用途,尤其是肺和气道疾病。
Description
本申请是中国发明专利申请号201280065806.8(发明名称:杂环化合物、含有所述化合物的药物及其用途和其制备方法,其治疗方法及用途,申请日:2012年10月29日)的分案申请。
技术领域
本发明涉及通式(I)的化合物
及其互变异构体和盐,尤其是其与无机或有机酸和无机或有机碱形成的药用盐,其具有有价值的药理学特性,尤其是对上皮钠通道具有抑制作用,并具有治疗疾病的用途,尤其是肺和气道疾病。
背景技术
阿米洛利型化合物是现有技术中已知的活性物质,如用于治疗肺和气道疾病(J.Med.Chem.49(2006)4098-4115)。WO 08135557公开了类似结构的化合物,其显示出ENaC(上皮钠通道)抑制活性。
本发明的问题是制备具有治疗用途的新化合物,其通过阻断上皮钠通道进行病理生理方法的治疗,尤其是肺和气道的治疗。
发明内容
已经惊奇地发现本发明式(I)和(IC)化合物解决上述问题。
因此,本发明涉及式(I)的化合物
其中
A表示化学键或选自O、-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2-O-、-CH2-NRA1-和-NRA1-,优选化学键、-CH2-和-CH2CH2-,
其中
RA1表示氢或C1-6-烷基,优选氢或C1-2-烷基,
B表示-CH2-或-CH2CH2-,优选-CH2-,或
前提是A不为O或-NRA1时,B表示化学键,
D、E相互独立地表示化学键或-CH2-,优选-CH2-,
F表示任选取代的芳基,优选苯基,优选被R2、R3、R4、R6、R7、R2a、R3a、R4a、R6a或R7a取代,
或任选取代的杂芳基,优选噻吩基、吡啶基、嘧啶基或吡啶酮基,优选被R2、R3、R4、R6、R7、R2a、R3a、R4a、R6a或R7a取代。
F最优选表示苯基、4-卤代-苯基,尤其优选苯基,
G表示式(g.1)、(g.2)或(g.3)基团
R1选自氢、C1-6-烷基、任选取代的5-到7-元杂环基-CO-、任选取代的5-到7-元杂环基-NH-CO-、R1.1-SO2-、R1.2-C2-4-烷基-NH-CO-、H3C-NH-CO-、R1.2.4-O-CO-CH2-NH-CO-、R1.2-C2-4-烷基-N(C1-4-烷基)-CO-、H3C-N(C1-4-烷基)-CO-、R1.2.4-O-CO-CH2-N(C1-4-烷基)-CO-、R1.3-C1-6-烷基-CO-、R1.4-C2-6-烷基-、任选取代的苯基-CH2-、R1.4.3-O-CO-CH2-、HO-CO-CH2-和HOSO2-CH2-、R1.5-C1-6-烷基-CO-和R1.6-C(NH)-,
其中
R1.1选自C1-4-烷基-、H2NC(NH)NH-C1-6-烷基-、R1.2.1R1.2.2N-C1-4-烷基-、R1.2.1R1.2.2R1.2.3N+-C1-4-烷基、HOCO-C1-4-烷基-和C1-3-烷基-OCO-C1-4-烷基-,
R1.2选自氢、H2NC(NH)NH-、R1.2.1R1.2.2N-、R1.2.1R1.2.2R1.2.3N+-、R1.2.3-HN-C(NR1.2.3)-NH-、R1.2.4-O-CO-、R1.2.5-O-CO-NH-和HO-CO-、HOSO2-,优选R1.2.1R1.2.2N-、R1.2.1R1.2.2R1.2.3N+-和R1.2.3-HN-C(NR1.2.3)-NH-
其中
R1.2.1表示氢或C1-6-烷基,优选氢或C1-4-烷基,最优选C1-4-烷基,
R1.2.2表示氢或C1-6-烷基,优选氢或C1-4-烷基,最优选C1-4-烷基,
或
R1.2.1和R1.2.2一起形成含有一个N原子的4到7元杂环,优选6-或5-元杂环,
R1.2.3表示氢或C1-6-烷基,优选C1-4-烷基,
R1.2.4表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.2.5表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.3选自氢、C1-6-烷基、C1-6-烷基-O-、任选取代的苯基、R1.3.1R1.3.2N-、R1.2.1R1.2.2R1.2.3N+-、R1.2.3-HN-C(NR1.2.3)-NH-、H2NC(NH)NH-、R1.2.4-O-CO、HO-CO-和HOSO2-,
其中R1.3.1表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.3.2表示氢或C1-6-烷基,
或
R1.3.1和R1.3.2一起形成含有一个N原子的4到7元杂环,优选含一个N原子的6元杂环,
优选氢或C1-4-烷基,
R1.4选自氢、R1.4.1R1.4.2N-、R1.4.1R1.4.2R1.4.3N+-、H2N-C(NH)-NH-、R1.4.3-HN-C(NR1.4.4)-NH、任选取代的苯基、R1.4.3-O-CO-、R1.4.4-O-CO-NH-、HO-CO-和HOSO2-,
其中R1.4.1表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.4.2表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.4.3表示氢或C1-6-烷基,优选氢或C1-4-烷基,最优选C1-4-烷基,
R1.4.4表示氢或C1-6-烷基,优选氢或C1-4-烷基,最优选C1-4-烷基,
R1.5选自氢、C1-6-烷基-O-、R1.5.1R1.5.2N-、R1.5.1R1.5.2R1.5.3N+-、H2N-C(NH)-NH-、任选取代的苯基、R1.5.3-O-CO-、R1.5.4-O-CO-NH-、HO-CO-、HOSO2-,
其中
R1.5.1表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.5.2表示氢或C1-6-烷基,优选氢或C1-4-烷基,最优选C1-4-烷基,
R1.5.3表示氢或C1-6-烷基优选氢或C1-4-烷基,最优选C1-4-烷基,
R1.5.4表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.6表示R1.6.1R1.6.2N-,
其中
R1.6.1表示氢或C1-6-烷基;优选氢或甲基,
R1.6.2表示氢或C1-6-烷基;优选氢或甲基,
R1b选自C1-4-烷基、R1.4-C2-6-烷基-、任选取代的苯基-CH2-、R1.4.3-O-CO-CH2-和HO-CO-CH2-,优选C1-4-烷基,特别优选甲基,
其中R1.4选自氢、R1.4.1R1.4.2N-、R1.4.1R1.4.2R1.4.3N+-、H2N-C(NH)-NH-、R1.4.3-HN-C(NR1.4.4)-NH、任选取代的苯基、R1.4.3-O-CO-、R1.4.4-O-CO-NH-、HO-CO-和HOSO2-,
其中
R1.4.1表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.4.2表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.4.3表示氢或C1-6-烷基,优选氢或C1-4-烷基,最优选C1-4-烷基,
R1.4.4表示氢或C1-6-烷基,优选氢或C1-4-烷基,最优选C1-4-烷基,
R1s表示C1-6-烷基,优选甲基,
X-表示形成药用盐的任意阴离子,优选选自CF3-COO-、Cl-、I-、Br-、HCOO-和CH3-COO-,最优选Cl-和CF3-COO-,
L表示形成式(IC)化合物的桥连基团-CO-NH-C2-6-烷基-NH-CO-、-COC1-6-烷基-CO-或-C2-6-烷基-,
由此通过L连接的式(IC)的分子实体可以相同或不同,
R5表示Cl或Br,优选Cl,
所述式(I)的化合物任选以互变异构体、外消旋化合物、对映异构体、非对映异构体及其混合物的形式,任选以其水合物、溶剂合物或前药形式且任选其药用酸加成盐。
式(IA)、(IB)或(IC.1)的优选化合物如下所示
A表示化学键、-CH2-、-CH2CH2-或CH2-O-,优选-CH2CH2-,
R1选自氢、C1-6-烷基、任选取代的哌嗪基-CO-、任选取代的哌啶基-NH-CO-、R1.1-SO2-、R1.2-C2-4-烷基-NH-CO-、H3C-NH-CO-、R1.2.4-O-CO-CH2-NH-CO-、R1.2-C2-4-烷基-N(C1-4-烷基)-CO-、H3C-N(C1-4-烷基)-CO-、R1.2.4-O-CO-CH2-N(C1-4-烷基)-CO-、R1.3-C1-6-烷基-CO-、R1.4-C2-6-烷基-、任选取代的苯基-CH2-、R1.4.3-O-CO-CH2-、HO-CO-CH2-和HOSO2-CH2-、R1.5-C1-6-烷基-CO-和R1.6-C(NH)-,
其中
R1.1表示C1-4-烷基-;
R1.2选自氢、R1.2.1R1.2.2N-、R1.2.1R1.2.2R1.2.3N+-、R1.2.4-O-CO-、HO-CO-和R1.2.5-O-CO-NH-,
其中
R1.2.1表示氢或C1-6-烷基;优选氢或C1-4-烷基,
R1.2.2表示氢或C1-6-烷基;优选氢或C1-4-烷基,
R1.2.3表示氢或C1-6-烷基;优选氢或C1-4-烷基,
R1.2.4表示C1-6-烷基;优选C1-4-烷基,
R1.2.5表示C1-6-烷基;优选C1-4-烷基,
R1.3选自氢、C1-6-烷基、C1-6-烷基-O-和任选取代的苯基
R1.4选自氢、R1.4.1R1.4.2N-、R1.4.1R1.4.2R1.4.3N+-、H2N-C(NH)-NH-、R1.4.3-HN-C(NR1.4.4)-NH-、任选取代的苯基、R1.4.3-O-CO-、R1.4.4-O-CO-NH-、HO-CO-和HOSO2-,
其中
R1.4.1表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.4.2表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.4.3表示氢或C1-6-烷基,优选氢或C1-4-烷基,最优选C1-4-烷基,
R1.4.4表示氢或C1-6-烷基,优选氢或C1-4-烷基,最优选C1-4-烷基,
R1.5选自氢、C1-6-烷基-O-、R1.5.1R1.5.2N-、R1.2.1R1.2.2R1.2.3N+-、H2N-C(NH)-NH-、R1.5.3-O-CO-、R1.5.4-O-CO-NH-、任选取代的苯基,
其中
R1.5.1表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.5.2表示氢或C1-6-烷基,优选氢或C1-4-烷基,最优选C1-4-烷基,
R1.5.3表示氢或C1-6-烷基,优选氢或C1-4-烷基,最优选C1-4-烷基,
R1.5.4表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.6表示R1.6.1R1.6.2N-,
其中
R1.6.1表示氢或C1-6-烷基;优选氢或甲基,
R1.6.2表示氢或C1-6-烷基;优选氢或甲基,
R1b表示C1-4-烷基,优选甲基,
R1s表示C1-6-烷基,优选甲基,
X-表示形成药用盐的任意阴离子,优选选自CF3-COO-、Cl-、I-、Br-、HCOO-和CH3-COO-,最优选Cl-和CF3-COO-,
L表示形成式(IC.1)化合物的桥连基团-CO-NH-C2-6-烷基-NH-CO-、-COC1-6-烷基-CO-或-C2-6-烷基-,
由此通过L连接的式(IC.1)的分子实体可以是相同或不同的
R2、R3、R4、R6、R7、R2a、R3a、R4a、R6a、R7a互相独立地选自氢、卤素、CN、C1-4-烷基、C1-3-烷基-O-、C1-3-烷基-OCO-、-COOR4.1、-CONR4.2R4.3和-OR4.1,优选氢,
其中
R4.1表示氢或C1-4-烷基,优选氢或C1-2-烷基,尤其优选氢或甲基
R4.2表示氢或C1-4-烷基,优选氢或C1-2-烷基,尤其优选氢或甲基
R4.3表示氢或C1-4-烷基,优选氢或C1-2-烷基,尤其优选氢或甲基
或
R3和R4,或R3a和R4a一起表示-O-C1-3-烷基-O-;
优选-O-C1-2-烷基-O-,
任选以互变异构体、外消旋化合物、对映异构体、非对映异构体及其混合物的形式,任选以其水合物、溶剂合物或前药形式且任选其药用酸加成盐。
尤其优选是式(IA)化合物,其中
A表示化学键、-CH2-或-CH2CH2-,
R1选自氢、任选取代的哌嗪基-CO-、任选取代的哌啶基-NH-CO-、C1-6-烷基、C1-4-烷基-SO2-、C1-4-烷基-NH-CO-、H2N-CO-、H2N-C1-4-烷基-、H2N-C1-4-烷基-CO-、H2N-C1-4-烷基-NH-CO-、苯基-CO-、苯基-CH2-CO-、苯基-CH2-、C1-6-烷基-CO-、C1-6-烷基-O-C1-4-烷基-CO-、(CH3)2N-C1-4-烷基-、(CH3)2N-C1-4-烷基-NH-CO-、(CH3)3N+-C1-4-烷基-NH-CO-、(CH3)3N+-C1-4-烷基-CO-、(CH3)3N+-C2-4-烷基-、(CH3)3N+-C1-4-烷基-N(C1-4-烷基)-CO-、H2N-C(NH)-NH-C1-6-NH-CO-、C1-6-烷基-O-CO-、C1-6-烷基-O-CO-C1-4-烷基-、C1-6-烷基-O-CO-C1-4-烷基-CO-、C1-6-烷基-O-CO-C1-4-烷基-NH-CO-、C1-6-烷基-O-CO-NH-C1-4-烷基-、C1-6-烷基-O-CO-NH-C1-4-烷基-CO-、C1-6-烷基-O-CO-NH-C1-4-烷基-NH-CO-、HOCO-C1-4-烷基-、HOCO-C1-4-烷基-CO-、HOCO-C1-4-烷基-NH-CO-、H2N-CNH-和H2NC(NH)NH-C1-6-烷基-CO-,
R2互相独立地选自氢、卤素、CN、C1-4-烷基和C1-烷基-O-,
R6互相独立地选自氢、卤素、CN、C1-4-烷基和C1-烷基-O-,
R3选自氢、卤素、CN和C1-4-烷基,
R4互相独立地选自氢、卤素、CN、C1-4-烷基,C1-4-烷基-OCO-、-COOR4.1和-CONR4.2R4.3,
其中
R4.1表示氢或C1-4-烷基,优选氢或甲基;
R4.2表示氢或C1-4-烷基,优选氢或甲基;
R4.3表示氢或C1-4-烷基,优选氢或甲基;
或
R3和R4一起表示-O-C1-3-烷基-O-;优选-O-C1-2-烷基-O-;
任选以互变异构体、外消旋化合物、对映异构体、非对映异构体及其混合物的形式,且任选其药用酸加成盐。
也尤其优选式(IC.1)化合物,其中
A表示化学键、-CH2-或-CH2CH2-,
L表示形成式IC或IC.1化合物的桥连基团-CO-NH-C2-6-烷基-NH-CO-,
R2、R2a互相独立地选自氢、卤素、CN、C1-4-烷基和C1-烷基-O-,
R6、R6a互相独立地选自氢、卤素、CN、C1-4-烷基和C1-烷基-O-
R3、R3a选自氢、卤素、CN和C1-4-烷基,
R4、R4a互相独立地选自氢、卤素、CN、C1-4-烷基,C1-4-烷基-OCO-、-COOR4.1和-CONR4.2R4.3,
其中
R4.1表示氢或C1-4-烷基,优选氢或甲基;
R4.2表示氢或C1-4-烷基,优选氢或甲基;
R4.3表示氢或C1-4-烷基,优选氢或甲基;
或
R3和R4,或R3a和R4a一起表示-O-C1-3-烷基-O-;优选O-C1-2-烷基-O-;
任选以互变异构体、外消旋化合物、对映异构体、非对映异构体及其混合物的形式,且任选其药用酸加成盐。
也尤其优选式(IB)化合物,其中
R1b表示C1-4-烷基,优选甲基,
和
R1s表示C1-6-烷基,优选甲基,
任选以互变异构体、外消旋化合物、对映异构体、非对映异构体及其混合物的形式,任选以其水合物、溶剂合物或前药形式且任选其药用酸加成盐。
也尤其优选式(IC)化合物,其中
L表示形成式(IC)或(IC.1)化合物的桥连基团-CO-NH-C2-6-烷基-NH-CO-,
任选以互变异构体、外消旋化合物、对映异构体、非对映异构体及其混合物的形式,任选以其水合物、溶剂合物或前药形式且任选其药用酸加成盐。
特别优选的是式(IA)、(IB)或(IC.1)化合物,其中
R2、R3、R4、R6和R7表示氢。
也特别优选的是式(IA)、(IB)或(IC.1)化合物,其中
R2、R3、R4、R6、R7、R2a、R3a、R4a、R6a和R7a表示氢。
也特别优选的是式(IA)、(IB)或(IC)化合物,其中
A表示-CH2CH2-,和
E、D表示-CH2-。
本发明的另一实施方案是作为药物的式(I)、(IA)、(IB)或(IC)化合物或其药用盐,优选式(IA)、(IB)或(IC)化合物。
本发明的另一实施方案是式(I)、(IA)、(IB)或(IC)化合物,优选式(IA)、(IB)或(IC)化合物,或其药用盐,其用于治疗呼吸系统疾病或病症和气道过敏性疾病。
优选为式(I)或(IC)化合物,优选式(IA)、(IB)或(IC)化合物,或其药用盐,其用于治疗选自下述的疾病:慢性支气管炎、急性支气管炎、由细菌或病毒感染或真菌或寄生虫引起的支气管炎、过敏性支气管炎、中毒性支气管炎、慢性阻塞性支气管炎(COPD)、哮喘(内因性或过敏性)、小儿哮喘、支气管扩张、过敏性肺泡炎、过敏性或非-过敏性鼻炎、慢性窦炎、囊性纤维化或粘液粘稠病、α-1-抗胰蛋白酶缺乏、咳嗽、肺气肿、间质性肺疾病、肺泡炎、高反应性气道、鼻息肉、肺水肿、不同原因的肺炎如辐射诱发或呼吸引起或感染性肺炎、优选慢性支气管炎、急性支气管炎、支气管炎、慢性阻塞性支气管炎(COPD)、哮喘(内因性或过敏性)、囊性纤维化和小儿哮喘,优选慢性支气管炎、COPD和囊性纤维化。
药物组合物包含至少一种本发明化合物或其药用盐,以及药用载体。
本发明的另一实施方案是药物组合,除了一种或多种本发明化合物之外,其还含有作为其它活性物质的一种或多种化合物,其选自以下类别:其它ENaC抑制剂、β模拟药、抗胆碱药、皮质类固醇、PDE4-抑制剂、LTD4-拮抗剂、EGFR-抑制剂、多巴胺激动剂、H1-抗组胺药、PAF-拮抗剂、MAP-激酶抑制剂、MPR4-抑制剂、iNOS-抑制剂、SYK-抑制剂和囊性纤维化跨膜调节剂(CFTR)和CFTR增强剂,优选VX-770和VX-809,或它们的两种或三种的组合。
使用的术语或定义
本申请未明确定义的术语应为本领域的技术人员根据公开内容及上下文即可给出的含义。如本说明书中所用,除非有相反指示,否则以下术语具有所指示的含义,下面给出习惯用法。
在下述定义的基团、基或部分中,碳原子的数目通常表示于基团的前面,如C1-6-烷基指的是具有1到6个碳原子的烷基。
通常在单一基团如HO、H2N、OS、O2S、NC(氰基)、HOOC、F3C等中,本领域技术人员可由基团自身的自由价了解到与分子的基团连接点。对于包括两个或多个子基团的组合基团,在末端带有连字符号的最后或第一个命名的子基团是基团连接点,例如取代基“芳基-C1-3-烷基-”指的是连接到C1-3-烷基上的芳基,所述C1-3-烷基连接到中心或取代基所连接的基团。
当本发明化合物以化学命名形式和作为分子式描述时,一旦有任何不一致的情况,以分子式为准。星号可用于亚分子式中以表明连接到所定义的中心分子的键。
例如,术语“3-羧基丙基-”表示下述取代基:
其中羧基连接到丙基的第三个碳原子。术语“1-甲基丙基-”、“2,2-二甲基丙基-”或“环丙基甲基-”表示下述基团:
星号可用于亚分子式中以表明连接到所定义中心分子的键。
许多下述术语可以分子式或基团的定义重复使用,且在每种情况下具有彼此独立的上述给出的含义中的一种。
除非特别指出,否则本发明给出的化学分子式或命名应包括互变异构体和所有立体异构体、旋光异构体和几何异构体(如对映异构体、非对映异构体、E/Z异构体等)及其外消旋物,以及分开的对映异构体的不同比例的混合物、非对映异构体混合物或任意前述形式(其中存在所述异构体和对映异构体)的混合物,以及它们包括药用盐在内的盐,及其溶剂合物如水合物,该溶剂合物包括游离化合物的溶剂合物或所述化合物的盐的溶剂合物。
本申请使用的术语“取代的”指的是指定原子上的任意一个或多个氢被选择的指定基团取代,条件是不能超出指定原子的一般价态,且取代后化合物是稳定的。
本发明范围内的术语“任选取代的”指的是上述基团任选被低级分子基团取代。化学意义上的低级分子基团的实例是由1-200个原子组成的基团。优选这些基团对于化合物的药理学效能没有副作用。例如所述基团可包括:
●直链或支化碳链,任选被杂原子间隔,任选被环、杂原子或其它一般官能团取代。
●由碳原子和任选杂原子组成的芳香或非芳香环系,其可继而被官能团取代。
●由碳原子和任选杂原子组成的众多芳香或非芳香环系,其可被一个或多个碳链连接,任选被杂原子间隔,任选被杂原子或其它一般官能团取代。
表述“治疗”或“疗法”指的是已经发展成一种或多种征候、急性或慢性形式的上述病症的患者的治疗性处置,包括为了减轻特殊适应症的症状的症状疗法,或为了逆转或部分逆转病症或尽可能延缓适应症进程的病因疗法,这取决于病症和其严重程度。因此本申请使用的表述“疾病治疗”指的是对已经发展疾病、病症或障碍的患者的处置和照顾。治疗的目的是与疾病、病症或障碍斗争。治疗包括给予活性化合物以消除或控制疾病、病症或障碍以及减轻与疾病、病症或障碍相关的症状或并发症。
本申请使用的术语“药用的”指的是那些化合物、材料、组合物和/或剂型,其在合理的医药判断范围内,适用于与人和动物的组织接触而没有过度毒性、刺激、过敏性反应或其它问题或并发症,且具有合理的益处/风险比例。
本申请使用的“药用盐”指的是公开化合物的衍生物,其中母体化合物通过形成其酸或碱式盐进行修饰。药用盐的实例包括但不限于碱性残基如胺的无机或有机酸盐;酸性残基如羧酸的碱盐或有机盐;等。例如,这些盐包括来自于下述物质的盐:氨、L-精氨酸、甜菜碱、苯乙苄胺、苄星青霉素、氢氧化钙、胆碱、丹醇、二乙醇胺(2,2’-亚氨基二(乙醇))、二乙胺、2-(二乙基氨基)-乙醇、2-氨基乙醇、乙二胺、N-乙基-葡萄糖胺、哈胺、1H-咪唑、赖氨酸、氢氧化镁、4-(2-羟基乙基)-吗啉、哌嗪、氢氧化钾、1-(2-羟基乙基)-吡咯烷、氢氧化钠、三乙醇胺(2,2’,2”-次氮基三(乙醇))、氨基丁三醇、氢氧化锌、乙酸、2.2-二氯-乙酸、己二酸、海藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、2,5-二羟基苯甲酸、4-乙酰氨基-苯甲酸、(+)-樟脑酸、(+)-樟脑-10-磺酸、碳酸、肉桂酸、柠檬酸、环拉酸、癸酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基-乙磺酸、乙二胺四乙酸、甲酸、富马酸、粘酸、龙胆酸、D-葡庚糖酸、D-葡萄糖酸、D-葡糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、甘氨酸、羟乙酸、己酸、马尿酸、氢溴酸、盐酸、异丁酸、DL-乳酸、乳糖酸、月桂酸、赖氨酸、马来酸、(-)-L-苹果酸、丙二酸、DL-扁桃酸、甲磺酸、粘酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘酸、烟酸、硝酸、辛酸、油酸、乳清酸、草酸、棕榈酸、扑酸(双羟萘酸)、磷酸、丙酸、(-)-L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、鞣酸、(+)-L-酒石酸、硫氰酸、对甲苯磺酸和十一烯酸。其它药用盐可与金属阳离子如铝、钙、锂、镁、钾、钠、锌等形成(可参见Pharmaceutical salts,Berge,S.M.et al.,J.Pharm.Sci.,(1977),66,1-19)。当不存在碱性残基如胺而存在季铵化合物时,相应于例如上述所列酸的阴离子可提供药用抗衡离子。其它实例是碳酸氢盐、碳酸盐和碳酸盐x0.5。本领域技术人员可理解的是包括潜在多价离子的盐可以不同化学计量比存在,这取决于多价离子是以单电荷形式存在还是以多电荷形式存在。例如多价酸的电荷状态取决于其去质子化程度。
本发明的药用盐可由含有碱性或酸性部分的母体化合物通过常规化学方法合成。通常,这些盐可通过使得这些化合物的游离酸或碱形式与充足量的合适碱或酸在水或有机稀释液如乙醚、乙酸乙酯、乙醇、异丙醇、乙腈或其混合物中反应而制备得到。
如可用于纯化或分离本发明化合物的除了上述提及的酸之外的其它酸的盐(例如三氟乙酸盐)也是本发明的一部分。
本申请使用的术语“前药”指的是(i)药物的惰性形式,其在体内经代谢过程而转化为有用或活性形式后发挥其作用,或(ii)虽然自身没有活性(即惰性前体),但可产生药理活性代谢物的物质。
术语“前药”或“前药衍生物”指的是母体化合物或活性药物物质的共价键合衍生物、载体或前体,其在展现其药理学作用之前进行至少某些生物转化。这些前药具有可以代谢断裂或可转化的基团,且可快速在体内转化产生母体化合物,例如通过血液中的水解作用或在存在硫醚基团的情况下通过氧化作用进行活化。最常见的前药包括母体化合物的酯和酰胺类似物。针对以下目标配制这些前药:改善化学稳定性、改善患者接受性和顺应性、改善生物可利用度、延长作用时间、改善器官选择性、改善配方(如增加水溶性)和/或减少副作用(如毒性)。通常,前药自身具有弱或没有生物活性,且在通常条件下是稳定的。前药很容易利用现有技术中已知方法由母体化合物进行制备,如详细公开于A Textbook ofDrug Design and Development,Krogsgaard-Larsen and H.Bundgaard(eds.),Gordon&Breach,1991,particularly Chapter 5:“Design and Applications of Prodrugs”;Design of Prodrugs,H.Bundgaard(ed.),Elsevier,1985;Prodrugs:Topical and OcularDrug Delivery,K.B.Sloan(ed.),Marcel Dekker,1998;Methods in Enzymology,K.Widder et al.(eds.),Vol.42,Academic Press,1985,particularly pp.309-396;Burger’s Medicinal Chemistry and Drug Discovery,5th Ed.,M.Wolff(ed.),JohnWiley&Sons,1995,particularly Vol.1and pp.172-178and pp.949-982;Pro-Drugs asNovel Delivery Systems,T.Higuchi and V.Stella(eds.),Am.Chem.Soc.,1975;Bioreversible Carriers in Drug Design,E.B.Roche(ed.),Elsevier,1987,将每篇文献的全部内容引入本申请作为参考。
本申请使用的术语“药用前药”指的是本发明化合物的前药,在合理的医药判断范围内,适用于与人和低级动物的组织接触而没有过度毒性、刺激、过敏性反应等,其具有合理的益处/风险比例,并且有效用于其意在用途并可能具有两性离子形式。
本申请使用的术语“芳基”在单独使用或与其它基团组合使用时表示含6个碳原子的碳环芳香单环基团,并可进一步稠合第二个可为芳香、饱和或不饱和的5或6元碳环基。芳基包括但不限于苯基、茚满基、茚基、萘基、蒽基、菲基、四氢萘基和二氢萘基。
术语“杂环基”或“杂环”指的是由3到14个环原子组成的饱和或不饱和单或多环环系,其含有一个或多个选自N、O或S(O)r中的杂原子,其中r=0、1或2。术语“杂环”意在包括所有可能的异构形式。
因此,术语“杂环基”或“杂环”包括下述示例性结构,其未被描述为基团,这是因为每种形式可通过共价键连接到任何原子,只要保持合适的价态:
术语“杂芳基”指的是由5到14个环原子组成的单或多环环系,其含有一个或多个选自N、O或S(O)r中的杂原子,其中r=0、1或2。术语“杂芳基”意在包括所有可能的异构形式。
因此,术语“杂芳基”包括下述示例性结构,其未被描述为基团,这是因为每种形式可通过共价键连接到任何原子,只要保持合适的价态:
术语“单环C5-7杂环基”指的是由5到7个环原子组成的饱和或不饱和非芳香单环环系,其含有一个或多个选自N、O或S(O)r中的杂原子,其中r=0、1或2。术语“单环C5-7杂环基”意在包括所有可能的异构形式。
因此,术语“单环C5-7杂环”包括下述示例性结构,其未被描述为基团,这是因为每种形式可通过共价键连接到任何原子,只要保持合适的价态:
术语“单环C5-6杂芳基”指的是由5或6个环原子组成的单环环系,其含有一个或多个选自N、O或S(O)r中的杂原子,其中r=0、1或2。术语“单环C5-6-杂芳基”意在包括所有可能的异构形式。
因此术语“单环C5-6-杂芳基”包括下述示例性结构,其未被描述为基团,这是因为每种形式可通过共价键连接到任何原子,只要保持合适的价态:
术语“二环C8-10杂环基”指的是由8到10个环原子组成的包括芳香环系的饱和或不饱和二环环系,其含有一个或多个选自N、O或S(O)r中的杂原子,其中r=0、1或2,其中杂原子任选为芳香环的一部分。术语“二环C8-10杂环基”意在包括所有可能的异构形式。
因此术语“双环C8-10杂环”包括下述示例性结构,其未被描述为基团,这是因为每种形式可通过共价键连接到任何原子,只要保持合适的价态:
本申请使用的术语“芳基或杂环基的增环种类”在单独使用或与其它取代基组合使用时(其中增环种类表示为芳基-杂(a)、杂-芳基(b)或杂-杂(c)增环),指的是通过从含有碳原子的芳香单环环系或芳香多环环系除去一个氢原子而衍生得到的单价取代基,其增环至5、6或7元饱和或不饱和(包括芳香)的含有碳原子和1、2、3或4个选自氮、氧和硫环杂原子的杂环,或
含有碳原子和1、2、3或4个选自氮、氧和硫的环杂原子的5、6或7元饱和或不饱和(包括芳香)杂环,其增环至含有碳原子的芳香单环体系或芳香多环体系或
含有碳原子和1、2、3或4个选自氮、氧和硫的环杂原子的5、6或7元饱和或不饱和(包括芳香)杂环,其增环至含有碳原子和1、2、3或4个选自氮、氧和硫的环杂原子的5、6或7元饱和或不饱和(包括芳香)杂环。
芳基或杂环基的增环种类的适合实例包括:喹啉基、1-吲哚基、3-吲哚基、5-吲哚基、6-吲哚基、吲嗪基、苯并咪唑基或嘌呤基。
本申请使用的术语“卤素”指的是选自氟、氯、溴或碘中的卤素取代基。
术语“C1-n烷基”,其中n为2到n的整数,其在单独使用或与其它基团组合使用时表示具有1到n个C原子的非环状的、饱和、支化或直链烃基。例如术语C1-5烷基包括基团H3C-、H3C-CH2-、H3C-CH2-CH2-、H3C-CH(CH3)-、H3C-CH2-CH2-CH2-、H3C-CH2-CH(CH3)-、H3C-CH(CH3)-CH2-、H3C-C(CH3)2-、H3C-CH2-CH2-CH2-CH2-、H3C-CH2-CH2-CH(CH3)-、H3C-CH2-CH(CH3)-CH2-、H3C-CH(CH3)-CH2-CH2-、H3C-CH2-C(CH3)2-、H3C-C(CH3)2-CH2-、H3C-CH(CH3)-CH(CH3)-和H3C-CH2-CH(CH2CH3)-。
术语“C3-n环烷基”,其中n为4到n的整数,其在单独使用或与其它基团组合使用时表示具有3到n个碳原子的环状、饱和、非支化烃基。例如术语C3-7环烷基包括环丙基、环丁基、环戊基、环己基和环庚基。
在结构和其命名相矛盾的所有情况下,以结构为准。
优选实施方案
标记A表示化学键或选自O、-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH2-O-、-CH2-NRA1-和-NRA1-,优选化学键、-CH2-和-CH2CH2-,
其中RA1表示氢或C1-6-烷基,优选氢或C1-2-烷基。
标记B表示-CH2-或-CH2CH2-,优选-CH2-,或
前提是A不为O或-NRA1时,则标记B表示化学键。
标记D表示化学键或-CH2-,优选-CH2-。
标记E表示化学键或-CH2-,优选-CH2-。
标记F表示任选取代的芳基,优选苯基,优选被R2、R3、R4、R6、R7、R2a、R3a、R4a、R6a或R7a取代,
或任选取代的杂芳基,优选噻吩基、吡啶、嘧啶基或吡啶酮基,
最优选苯基、4-卤代-苯基或吡啶基,尤其优选苯基。
标记G表示式(g.1)、(g.2)或(g.3)的基团
取代基R1选自氢、C1-6-烷基、任选取代的5-到7-元杂环基-CO-,其中优选含1或2个N原子的杂环、任选取代的5-到7-元杂环基-NH-CO-,其中优选含1或2个N原子的杂环,R1.1-SO2-、R1.2-C2-4-烷基-NH-CO-、H3C-NH-CO-、R1.2.4-O-CO-CH2-NH-CO-、R1.2-C2-4-烷基-N(C1-4-烷基)-CO-、H3C-N(C1-4-烷基)-CO-、R1.2.4-O-CO-CH2-N(C1-4-烷基)-CO-、R1.3-C1-6-烷基-CO-、R1.4-C2-6-烷基-、任选取代的苯基-CH2-、R1.4.3-O-CO-CH2-、HO-CO-CH2-和HOSO2-CH2-、R1.5-C1-6-烷基-CO-和R1.6-C(NH)-,其中
R1.1选自C1-4-烷基-、H2NC(NH)NH-C1-6-烷基-、R1.2.1R1.2.2N-C1-4-烷基-、R1.2.1R1.2.2R1.2.3N+-C1-4-烷基、HOCO-C1-4-烷基-和C1-3-烷基-OCO-C1-4-烷基-,
R1.2选自氢、H2NC(NH)NH-、R1.2.1R1.2.2N-、R1.2.1R1.2.2R1.2.3N+-、R1.2.3-HN-C(NR1.2.3)-NH-、R1.2.4-O-CO-、R1.2.5-O-CO-NH-和HO-CO-、HOSO2-,优选R1.2.1R1.2.2N-、R1.2.1R1.2.2R1.2.3N+-、R1.2.3-HN-C(NR1.2.3)-NH-,
其中
R1.2.1表示氢或C1-6-烷基,优选氢或C1-4-烷基,更优选C1-4-烷基,最优选甲基,
R1.2.2表示氢或C1-6-烷基,优选氢或C1-4-烷基,更优选C1-4-烷基,最优选甲基,
或
R1.2.1和R1.2.2一起形成含1个N原子的4到7元杂环,优选5-或6-元杂环,
R1.2.3表示C1-6-烷基,优选C1-4-烷基,最优选甲基,
R1.2.4表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.2.5表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.3选自氢、C1-6-烷基、C1-6-烷基-O-、任选取代的苯基、R1.3.1R1.3.2N-、R1.2.1R1.2.2R1.2.3N+-、R1.2.3-HN-C(NR1.2.3)-NH、H2NC(NH)NH-、R1.2.4-O-CO、HO-CO-和HOSO2-,其中
R1.3.1表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.3.2表示氢或C1-6-烷基,
或
R1.3.1和R1.3.2一起形成含1个N原子的4到7元杂环,优选含1个N原子的5-或6-元杂环,优选氢或C1-4-烷基,
R1.4选自氢、R1.4.1R1.4.2N-、R1.4.1R1.4.2R1.4.3N+-、H2N-C(NH)-NH-、R1.4.3-HN-C(NR1.4.4)-NH-、任选取代的苯基,R1.4.3-O-CO-、R1.4.4-O-CO-NH-、HO-CO-和HOSO2-,
其中
R1.4.1表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.4.2表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.4.3表示氢或C1-6-烷基,优选氢或C1-4-烷基,最优选C1-4-烷基,
R1.4.4表示氢或C1-6-烷基,优选氢或C1-4-烷基,最优选C1-4-烷基,
R1.5选自氢、C1-6-烷基-O-、R1.5.1R1.5.2N-、R1.5.1R1.5.2R1.5.3N+-、H2N-C(NH)-NH-、任选取代的苯基、R1.5.3-O-CO-、R1.5.4-O-CO-NH-、HO-CO-、HOSO2-,
其中
R1.5.1表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.5.2表示氢或C1-6-烷基,优选氢或C1-4-烷基,最优选C1-4-烷基,
R1.5.3表示氢或C1-6-烷基,优选氢或C1-4-烷基,最优选C1-4-烷基,
R1.5.4表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.6表示R1.6.1R1.6.2N-,
其中
R1.6.1表示氢或C1-6-烷基,优选氢或甲基,
R1.6.2表示氢或C1-6-烷基,优选氢或甲基。
优选R1选自氢、C1-6-烷基、C1-4-烷基-SO2-、C1-4-烷基-NH-CO-、H2N-CO-、H2N-C1-4-烷基-、H2N-C1-4-烷基-CO-、H2N-C1-4-烷基-NH-CO-、苯基-CO-、苯基-CH2-CO-、苯基-CH2-、C1-6-烷基-CO-、C1-6-烷基-O-C1-4-烷基-CO-、(CH3)2N-C1-4-烷基-、(CH3)2N-C1-4-烷基-NH-CO-、(CH3)3N+-C1-4-烷基-NH-CO-、(CH3)3N+-C1-4-烷基-N(C1-4-烷基)-CO-、(CH3)3N+-C2-4-烷基-、(CH3)3N+-C1-4-烷基-CO-,H2N-C(NH)-NH-C1-6-NH-CO-、C1-6-烷基-O-CO-、C1-6-烷基-O-CO-C1-4-烷基-、C1-6-烷基-O-CO-C1-4-烷基-CO-、C1-6-烷基-O-CO-C1-4-烷基-NH-CO-、C1-6-烷基-O-CO-NH-C1-4-烷基-、C1-6-烷基-O-CO-NH-C1-4-烷基-CO-、C1-6-烷基-O-CO-NH-C1-4-烷基-NH-CO-、HOCO-C1-4-烷基-、HOCO-C1-4-烷基-CO-、HOCO-C1-4-烷基-NH-CO-、H2N-CNH-和H2NC(NH)NH-C1-6-烷基-CO-。
或
R1也优选选自下述式(c1)到(c5)的基团:
尤其优选R1表示氢或选自C1-6-烷基、C1-4-烷基-SO2-、C1-4-烷基-NH-CO-、H2N-CO-、H2N-C1-4-烷基-、H2N-C1-4-烷基-CO-、H2N-C1-4-烷基-NH-CO-、苯基-CO-、苯基-CH2-CO-、苯基-CH2-、C1-6-烷基-CO-、C1-6-烷基-O-C1-4-烷基-CO-、(CH3)2N-C1-4-烷基-、(CH3)2N-C1-4-烷基-NH-CO-、(CH3)3N+-C1-4-烷基-NH-CO-、(CH3)3N+-C2-4-烷基-、(CH3)3N+-C1-4-烷基-CO-,H2N-C(NH)-NH-C1-6-NH-CO-、C1-6-烷基-O-CO-、C1-6-烷基-O-CO-C1-4-烷基-、C1-6-烷基-O-CO-C1-4-烷基-CO-、C1-6-烷基-O-CO-C1-4-烷基-NH-CO-、C1-6-烷基-O-CO-NH-C1-4-烷基-、C1-6-烷基-O-CO-NH-C1-4-烷基-CO-、C1-6-烷基-O-CO-NH-C1-4-烷基-NH-CO-、HOCO-C1-4-烷基-、HOCO-C1-4-烷基-CO-、HOCO-C1-4-烷基-NH-CO-和H2N-CNH-。
取代基R1s表示C1-6-烷基,优选甲基。
X-表示形成药用盐的任意阴离子,优选选自CF3-COO-、Cl-、I-、Br-、HCOO-和CH3-COO-,最优选Cl-和CF3-COO-。
取代基R1b选自C1-4-烷基、R1.4-C2-6-烷基-、任选取代的苯基-CH2-、R1.4.3-O-CO-CH2-和HO-CO-CH2-,优选C1-4-烷基,尤其优选甲基,
其中
R1.4选自氢、R1.4.1R1.4.2N-、R1.4.1R1.4.2R1.4.3N+-、H2N-C(NH)-NH-、R1.4.3-HN-C(NR1.4.4)-NH、任选取代的苯基,R1.4.3-O-CO-、R1.4.4-O-CO-NH-、HO-CO-和HOSO2-,
其中R1.4.1表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.4.2表示氢或C1-6-烷基,优选氢或C1-4-烷基,
R1.4.3表示氢或C1-6-烷基,优选氢或C1-4-烷基,最优选C1-4-烷基,
R1.4.4表示氢或C1-6-烷基,优选氢或C1-4-烷基,最优选C1-4-烷基。
标记L表示形成式(IC)化合物的桥连基团-CO-NH-C2-6-烷基-NH-CO-、-COC1-6-烷基-CO-或-C2-6-烷基-,
由此通过L连接的式(IC)分子实体可以相同或不同的,
优选形成式(IC.1)化合物,
由此通过L连接的式(IC.1)分子实体可以相同或不同的,
取代基R2和R2a互相独立地选自氢、卤素、CN、C1-6-烷基、C1-3-烷基-O-、C1-3-烷基-OCO-、-COOR4.1、-CONR4.2R4.3和-OR4.1,优选氢,
其中
R4.1表示氢或C1-4-烷基,优选氢或C1-2-烷基,尤其优选氢或甲基,
R4.2表示氢或C1-4-烷基,优选氢或C1-2-烷基,尤其优选氢或甲基,
R4.3表示氢或C1-4-烷基,优选氢或C1-2-烷基,尤其优选氢或甲基。
取代基R3和R3a互相独立地选自氢、卤素、CN、C1-4-烷基、C1-3-烷基-O-、C1-3-烷基-OCO-、-COOR4.1、-CONR4.2R4.3和-OR4.1,优选氢,
其中
R4.1表示氢或C1-4-烷基,优选氢或C1-2-烷基,尤其优选氢或甲基,
R4.2表示氢或C1-4-烷基,优选氢或C1-2-烷基,尤其优选氢或甲基,
R4.3表示氢或C1-4-烷基,优选氢或C1-2-烷基,尤其优选氢或甲基。
取代基R4和R4a互相独立地选自氢、卤素、CN、C1-3-烷基-O-C1-3-烷基-OCO-、-COOR4.1、-CONR4.2R4.3和-OR4.1,优选氢,
其中
R4.1表示氢或C1-4-烷基,优选氢或C1-2-烷基,尤其优选氢或甲基,
R4.2表示氢或C1-4-烷基,优选氢或C1-2-烷基,尤其优选氢或甲基,
R4.3表示氢或C1-4-烷基,优选氢或C1-2-烷基,尤其优选氢或甲基,
或
R3和R4,或R3a和R4a一起表示-O-C1-3-烷基-O-;优选-O-C1-2-烷基-O-。
取代基R5表示Cl或Br,优选Cl。
取代基R6和R6a互相独立地选自氢、卤素、CN、C1-4-烷基、C1-3-烷基-O-、C1-3-烷基-OCO-、-COOR4.1、-CONR4.2R4.3和-OR4.1,优选氢,
其中
R4.1表示氢或C1-4-烷基,优选氢或C1-2-烷基,尤其优选氢或甲基,
R4.2表示氢或C1-4-烷基,优选氢或C1-2-烷基,尤其优选氢或甲基,
R4.3表示氢或C1-4-烷基,优选氢或C1-2-烷基,尤其优选氢或甲基。
取代基R7和R7a互相独立地选自氢、卤素、C1-4-烷基、CN、C1-3-烷基-O-、C1-3-烷基-OCO-、-COOR4.1、-CONR4.2R4.3和-OR4.1,优选氢,
其中
R4.1表示氢或C1-4-烷基,优选氢或C1-2-烷基,尤其优选氢或甲基,
R4.2表示氢或C1-4-烷基,优选氢或C1-2-烷基,尤其优选氢或甲基,
R4.3表示氢或C1-4-烷基,优选氢或C1-2-烷基,尤其优选氢或甲基。上述R1到R7的任何定义可相互组合形成本发明的实施方案。
制备
下述方法适于制备通式(IA)、(IB)或(IC)的化合物。
本发明的化合物可利用本领域技术人员已知的和公开于有机合成文献中的合成方法得到。官能团保护和脱保护步骤的一般方法公开于如Greene,T.W.和Wuts,P.G.M.(eds.):Protective Groups in Organic Synthesis,third edition 1999;John Wiley和Sons,inc。优选所述化合物以类似于以下更详细的制备方法得到,尤其公开于实验部分。
通式(I)的化合物可通过使式(II)的S-甲基异硫脲与式(III)伯胺在溶剂如THF、乙腈、DMF或溶剂混合物中反应进行制备,优选在碱的存在下进行,特别是当采用伯胺(III)作为酸加成盐时,优选在18℃到90℃之间进行。
在碱,优选三乙胺存在下,在溶剂如THF中,通过与BOC2O反应,可将通式(I)的化合物转化为通式(Ia)化合物。
通式(I)和(Ia)的化合物可利用本领域技术人员已知且公开于有机合成文献中的方法进行修饰,优选通过官能团保护或脱保护步骤,或氢化作用。此外,通式(Ia)化合物中的基团R1可在不与存在于通式I化合物中的酰基胍基相容的条件下进行修饰,优选通过叔氨基的烷基化反应生成季铵化合物。
在标准酸性脱保护条件下,通过除去BOC部分,可将通式(Ia)化合物转化为通式(I)化合物。
方案1:
方案1的优选实现方式是方案1.1。
方案1.1:
在溶剂如DCM、THF或这些溶剂的混合物中,通式(II)化合物可通过使S-甲基异硫脲(其可通过加入碱由其盐原位形成)与通式(IV)的羧酸1-(叔丁基氨基甲酰基)丙-1-烯-2-基酯反应进行制备,优选在-10℃到25℃之间。
通式(IV)化合物可由通式(V)各自的羧酸与通式(VI)的2-叔丁基-5-甲基-异唑鎓盐进行制备,所述盐可用作为单独的盐(如六氟磷酸盐;X=PF6)或由叔丁醇、5-甲基异唑和三氟甲磺酸原位产生。后面的反应优选在溶剂如DMF或加入三乙胺或其它碱后的溶剂混合物中进行,优选在冷却至0-10℃的情况下进行。
方案2:
由通式(XV)化合物通过氰基还原得到通式(III)化合物,优选利用兰尼镍作为催化剂,在氢气压力下,在过量氨水存在下,在溶剂如甲醇中进行氢化反应。通式(XV)化合物中的基团Rc可利用本领域技术人员已知并公开于有机合成文献中的方法进行修饰,优选通过官能团保护或脱保护步骤、酯化、酰胺化或氢化反应。取决于Rc的性质,利用本领域技术人员已知并公开于有机合成文献中的方法除去该部分,特别是除去保护基团得到通式(XVI)化合物。通式(XVI)化合物可利用本领域技术人员已知并公开于有机合成文献中的方法转化为通式(XV)化合物,特别是通过酰化作用、烷基化作用或还原胺化作用。
通式(XV)化合物,其中D表示-CH2-或-CH2-CH2-,可通过使通式(VI)的烷化剂与通式(VII)的4-氰基哌啶在溶剂如THF中反应进行制备,其中通式(VII)的化合物通过碱优选LDA、n-BuLi或NaH进行脱质子化,优选温度在-80℃和0℃之间,其中LG表示离去基团,优选Cl、Br、I、甲磺酸酯或甲苯磺酸酯,其中G表示酰基部分,优选BOC基团。
通式(XV)化合物,其中A表示化学键,可通过加入碱优选NaH,在溶剂优选DMF中,通过通式(IX)的苯乙腈与通式(VIII)的二氯乙胺进行双烷基化反应来制备,其中Rc表示酰基部分,优选BOC基团。
方案3:
通式(X)的化合物,其中L表示具有至少2个碳原子的链,可通过使(XI)与酸,优选TFA或HCl,在溶剂如THF、二烷、二氯甲烷、DMF或水中反应进行反应制备,优选10℃和50℃之间的温度。
通式(XII)的化合物,其中L表示具有至少2个碳原子的链,可通过先将(XIII)以BOC酐保护,以烷基卤化物优选烷基碘,在溶剂如丙酮、THF、二烷或二氯乙烷中,优选在10℃至50℃的温度进行季铵化,然后用酸进行脱保护的系列反应进行制备。
通式(XIV)的化合物,其中L表示具有至少2个碳原子的链,可通过使通式(X)化合物与1H-1.2.4-三唑-1-甲脒或S-甲基异硫脲在DMF中,优选在50℃和90℃之间的温度反应来制备。
实施例
中间体的合成
中间体A.61
3,5-二氨基-6-氯吡嗪-2-羧酸
将3,5-二氨基-6-氯吡嗪-2-羧酸甲酯(100g;494mmol)、甲醇(1l)和NaOH(6mol/l,水中;240mL;1.44mol)的混合物回流3h。混合物冷却至室温,接着加入盐酸(6mol/l,水中;约240mL)中和。加入水(200mL)。将形成的析出物经抽滤滤出,以水洗涤,并在60℃干燥。
产率:99.6g(理论的107%)
C5H5ClN4O2ESI质谱:m/z=189[M+H]+;m/z=187[M-H]-
中间体A.62
以类似于前述中间体A.61公开的合成方法,由3,5-二氨基-6-溴吡嗪-2-羧酸甲酯(由3,5-二氨基-6-氯吡嗪-2-羧酸甲酯进行制备,公开于J.Med.Chem.10(1967)66-75中)制备3,5-二氨基-6-溴吡嗪-2-羧酸。
中间体B.61
3,5-二氨基-6-氯吡嗪-2-羧酸1-(叔丁基氨基甲酰基)丙-1-烯-2-酯
阶段1:
将叔丁醇(21.0mL;226mmol)和5-甲基异唑(18.0mL;221mmol)的混合物以冰浴冷却。滴加连续冷却的三氟甲磺酸(20.0mL;221mmol)。所得混合物搅拌1h,不再进一步冷却。
阶段2:
向3,5-二氨基-6-氯吡嗪-2-羧酸(中间体A.61;14.0g;74.2mmol)和三乙胺(31.0mL;222mmol)在DMF(100mL)中的溶液或悬浮液中加入阶段1中制备的混合物。所得混合物室温搅拌4小时。边搅拌边加入冰水。抽滤滤出形成的析出物,以水洗涤,65℃干燥得到标题化合物。
产率:18.2g(理论的75%)
C13H18ClN5O3ESI质谱:m/z=328[M+H]+;m/z=326[M-H]-
TLC(硅胶;DCM/MeOH 9:1):Rf=0.4
中间体B.62
3,5-二氨基-6-溴吡嗪-2-羧酸1-(2-甲基-2-丁基-氨基甲酰基)丙-1-烯-2-酯
阶段1:
将2-甲基-2-丁醇(5.75mL;51mmol)和5-甲基异唑(4.42mL;51mmol)的混合物以冰浴冷却。滴加连续冷却的三氟甲磺酸(4.84mL;54mmol)。所得混合物搅拌过夜,不再进一步冷却。
阶段2:
向冰浴冷却的3,5-二氨基-6-溴吡嗪-2-羧酸(中间体A.62;5.00g;21.5mmol)和三乙胺(7.48mL;54mmol)在DMF(50mL)中的溶液或悬浮液中滴加阶段1中制备的混合物。所得混合物室温搅拌4h,接着倾倒在冰水上。抽滤滤出形成的析出物,以水洗涤,并在50℃干燥,生成标题化合物。
产率:7.53g(理论的91%)
C14H20BrN5O3ESI质谱:m/z=386[M+H]+;m/z=384[M-H]-
中间体C.61
3,5-二氨基-6-氯-N-[(甲基硫基)亚氨甲酰基]吡嗪-2-甲酰胺
向NaOH(1mol/l,水中;9.2mL;9.2mmol)中加入S-甲基异硫脲硫酸盐(1.78g;6.1mmol)。搅拌混合物直到得到完全的溶液。加入TBME/THF(1:1;30mL),接着加入3,5-二氨基-6-氯吡嗪-2-羧酸1-(叔丁基氨基甲酰基)丙-1-烯-2-酯(中间体B.61;2.00g;6.10mmol),混合物在室温搅拌过夜,接着加入水(6mL)。抽滤滤出形成的析出物,依次用水、甲醇和乙醚洗涤,接着在50℃干燥生成标题化合物。
产率:1.33g(理论的84%)
C7H9ClN6OS ESI质谱:m/z=261[M+H]+;m/z=259[M-H]-
中间体C.62
3,5-二氨基-6-溴-N-[(甲基硫基)亚氨甲酰基]吡嗪-2-甲酰胺
向NaOH(1mol/l,水中;30mL;30mmol)中加入S-甲基异硫脲硫酸盐(5.42g;19.5mmol)。搅拌混合物直到得到完全的溶液。加入TBME/THF(1:1;100mL),接着加入3,5-二氨基-6-溴吡嗪-2-羧酸1-(2-甲基-2-丁基-氨基甲酰基)丙-1-烯-2-酯(中间体B.62;7.52g;19.5mmol),室温搅拌混合物过夜,接着加入水(100mL)。抽滤滤出形成的析出物,用THF/水(1:2)洗涤,接着在50℃干燥生成标题化合物。
产率:5.44g(理论上的92%)
C7H9BrN6OS ESI质谱:m/z=305[M+H]+
D.2
在-78℃,向21.10g二异丙胺在300mL无水THF中的溶液中滴加83.7mL 2.5M正丁基锂在THF中的溶液。在该温度所得溶液搅拌30min。接着滴加40.00g 1-N-BOC-4-氰基哌啶在300mL THF中的溶液。搅拌1h之后,滴加51.99ml(2-溴-乙基)-苯。加入之后,反应混合物温热至室温并搅拌过夜。加入100mL水淬灭反应。除去THF留下浆液,将其在乙酸乙酯和水之间分配。分离之后,有机层用饱和NH4Cl水溶液和盐水洗涤,Na2SO4干燥,减压浓缩。柱色谱纯化得到57.23g中间体D.2。TLC(EA/PE 1/8)Rf:0.4。
D.8
利用苄基溴作为烷化剂,以类似于中间体D.2公开的操作得到中间体D.8。TLC(乙酸乙酯(EA)/石油醚(PE))1/9)Rf:0.3。
C.17
利用4-(2-溴乙基)苯甲酸作为烷化剂,以类似于中间体D.2公开的操作得到中间体C.17。TLC(MeOH/二氯甲烷(DCM)5/95)Rf:0.4。
C.18
将C.17用氨水和TBTU在二氯甲烷中处理得到中间体C.18。
B.17
向4.00g中间体C.17在40ml无水DMF的溶液中加入5.40g K2CO3,然后滴加2.40ml碘甲烷。反应混合物室温搅拌12h。接着加入水,并用乙醚萃取混合物。合并有机相,Na2SO4干燥,蒸发。通过FC纯化所得粗产物,得到3.40g of中间体B.17。TLC(EA/PE 2/3)Rf:0.6。
D.45
向2.00g N-BOC-N,N-二(2-氯乙基)胺和1.10g(2-甲氧基苯基)-乙腈在15ml THF和5ml DMF的溶液中室温分批加入0.78g NaH,混合物在55℃搅拌16h。通过加入冷水淬灭反应,以乙酸乙酯萃取。用盐水和水洗涤有机相,Na2SO4干燥,过滤并减压蒸发。粗固体用CHCl3和乙醚的混合物研磨,过滤并干燥得到1.0g中间体D.45。TLC(EA:PE 3/7)Rf:0.6。
D.43和D.44
利用相应的氰基甲苯,使用中间体D.45公开的类似方法得到D.43和D.44。
C.2
将2.50g哌啶D.2和40ml 25%TFA在二氯甲烷中的混合物室温搅拌1.5h。蒸发溶剂,加入甲醇化盐酸,再次蒸发溶剂得到2.53g中间体C.2。
ESI-MS m/z:215。利用TFA作为改性剂,通过制备型反相HPLC纯化粗产物得到C.2相应的TFA盐。
C.8,C.43,C.44和C.45
利用修饰后处理,利用中间体C.2公开的类似方法得到下述中间体:利用饱和NaHCO3溶液中和反应混合物,然后经水后处理。
B.2
将2.30g哌啶盐酸盐C.2、1.08ml 2-异氰酰-丙烷、1.99ml三乙胺和50ml THF的混合物在50℃搅拌2h。减压浓缩反应混合物并加入水,最后用二氯甲烷萃取。合并的有机相通过MgSO4干燥并蒸发生成1.65g中间体B.2。
ESI-MS m/z:300,344
B.4、B.8、B.12、B.18、B.19、B.43、B.44、B.45、B.48和B.49
利用相应的异氰酸酯,使用中间体B.2公开的类似方法得到下述中间体。使用DCM作为可选择的溶剂。
B.10
将0.22ml三乙胺慢慢加入到0.34g哌啶三氟乙酸盐C.2、0.32g三光气和5ml二氯甲烷的混合物中。室温搅拌混合物4h,加入0.17ml N,N-二甲基-乙二胺,室温搅拌反应混合物过夜。减压浓缩反应混合物,加入DMF、甲醇和TFA的混合物,过滤所得混合物,通过制备型反相HPLC纯化。收集含产物的馏分并蒸发。用二氯甲烷吸收所得残余物,加入4N NaOH溶液。通过相分离柱分离有机相。蒸发产生0.22g中间体B.10。ESI-MS m/z:329。
B.33、B.34、B.39、B.35、B.36、B.38、B.40、B.51、B.52、B.53、B.54、B.55和B.56
利用相应的胺,使用中间体B.10类似的方法得到下述中间体。
B.53
向0.75g 1,1’-羰基二(1,2,4-三唑)在5ml THF的悬浮液中滴加0.5ml 1-甲基哌嗪溶于5ml THF中的溶液。反应混合物在室温搅拌40分钟,接着滴加0.5g中间体C.2(作为游离碱)在5ml THF中的溶液,反应混合物在60℃搅拌过夜。蒸发溶剂,得到的粗产物在二氯甲烷和水之间分配,分离有机相,硫酸钠干燥,真空浓缩。通过快速色谱纯化粗产物(洗脱液:AcOEt/MeOH=80/20),通过制备型LC-MS再纯化(反相;NH4COOH)得到150mg中间体B.53。
B.54和B.55
利用相应的胺,使用中间体B.53公开的相似方法得到下述中间体。
B.56
起始于商购的4-氰基-4-苯基哌啶和N,N-二甲基乙二胺,按照类似于制备B.53的操作制备B.56。
B.3
利用甲醛和NaCNBH3在THF中的溶液,通过中间体C.2的还原性氨化反应制备中间体B.3。
B.7和B.21
利用相应的羰基化合物,使用中间体B.3公开的类似方法得到下述中间体。
B.5
利用苯甲酰氯和在二氯甲烷中的三乙胺,通过中间体C.2的酰化反应制备中间体B.5。
B.1、B.11、B.13、B.14、B.9、B.20和B.47
利用相应的酰氯,使用中间体B.5公开的类似方法得到下述中间体。
B.22
向1.07g中间体C.2、1.42g N-BOC-β丙氨酸、2.5g EDCI在50ml无水THF中的混合物中加入4.90ml三乙胺和0.1g DMAP。反应混合物室温搅拌过夜。加入水,浓缩混合物,以乙酸乙酯萃取。利用饱和NH4Cl水溶液和盐水洗涤合并有机相,Na2SO4干燥,浓缩。残余的粗产物通过FC纯化得到中间体B.22。
B.23、B.25、B.24、B.26、B.27、B.46和B.42
利用相应的酸,使用中间体B.22公开的类似方法得到下述中间体。
B.46(原材料:3-羧基-丙基-三甲基-氯化铵)
B.6
利用苄基溴和在乙腈中的Cs2CO3,通过中间体C.2的烷基化作用制备中间体B.6。
B.15
利用下述方法得到中间体B.15。
将0.1g C.2溶于5ml丙酮中,先加入0.1g K2CO3,然后室温滴加碘甲烷。将所得反应混合物搅拌16小时。接着反应混合物用乙酸乙酯稀释,以水洗涤,然后以盐水洗涤。有机层用Na2SO4干燥,并减压浓缩。通过色谱在硅胶柱上纯化粗产物(用18%乙酸乙酯/石油醚洗脱)。
B.50
利用碘甲烷,使用中间体B.15公开的类似方法得到下述中间体。
B.16、B.28、B.29、B.30、B.31、B.32和B.37
利用作为烷化剂的相应的胺和相应的烷基卤,以及K2CO3和丙酮,使用中间体B.6公开的类似方法得到下述中间体。
A.2
将1.83g腈B.2、0.40g兰尼镍和40ml氨水的甲醇化溶液的悬浮液在室温利用3巴氢气氢化23h。在不完全转化的情况下,再加入催化剂和溶剂,在50℃持续氢化5h。过滤除去催化剂,蒸发滤液得到1.95g中间体A.2。ESI-MS m/z:304
A.1、A.3、A.4、A.5、A.6、A.7、A.10、A.11、A.12、A.13、A.14、A.15、A.16、A.17、A.18、
A.19、A.22、A.23、A.25、A.28、A.29、A.32、A.33、A.34、A.39、A.48、A.51、A.52、A.53、A.54、
A.55、A.56和A.57
利用中间体A.2公开的类似方法,由相应的腈得到下述中间体。
A.59
向50mg中间体B.55在3ml的THF溶液中滴加0.1ml甲硼烷-四氢呋喃络合物。反应混合物在室温搅拌30min,接着在40℃搅拌3h。再加入0.1ml甲硼烷-四氢呋喃络合物,反应混合物在50℃搅拌过夜。反应混合物在二氯甲烷和水之间分配,有机相用饱和NaHCO3水溶液洗涤,相分离器干燥,真空浓缩得到42mg中间体A.59。
A.60
向在-78℃搅拌的1g中间体B.56在20ml THF的溶液中滴加1.2ml 2M氢化锂铝的THF溶液。混合物达到室温并搅拌过夜。浓缩溶剂,反应混合物在二氯甲烷和水之间分配,有机相用相分离器干燥,真空浓缩得到500mg粗产物。制备型LC-MS(反相;NH4COOH)纯化200mg粗产物。得到60mg纯中间体A.60。
合成实施例
实施例1
4-[N'-(3,5-二氨基-6-氯-吡嗪-2-羰基)-胍基甲基]-4-苯乙基-哌啶-1-羧酸叔丁基酯
将80mg(0.3mmol)4-氨基甲基-4-苯乙基-哌啶-1-羧酸叔丁基酯(A.55)和104mg(0.3mmol)1-(3,5-二氨基-6-氯-吡嗪-2-羰基)-2-甲基-异硫脲(中间体C.61)在2ml乙腈中的混合物在70℃搅拌48小时。接着将反应混合物减压浓缩,通过制备型反相HPLC(梯度:乙腈和水+0.2%三氟乙酸,25℃)纯化残余物。将含有标题化合物的馏分减压浓缩。
产率:116mg.
ESI质谱:[M+H]+=531
保留时间HPLC:2,51min(方法M1)。
由指出的原材料相应地制备下述化合物:
表1
实施例1.53
向140mg(0.36mmol)中间体A.57在2.5ml的DMF溶液中加入0.13ml N,N-二异丙基乙胺。室温搅拌反应混合物10分钟,接着加入85mg(0.33mmol)1-(3,5-二氨基-6-氯-吡嗪-2-羰基)-2-甲基-异硫脲。在70℃加热反应混合物3小时。
除去溶剂,通过快速色谱(第一洗脱液:AcOEt/MeOH=90/10以除去杂质;第二洗脱液:二氯甲烷/MeOH/NH3,由90/10/0.1到50/50/0.1,得到所需产物)纯化得到的粗产物。
产率:55mg.
IC50[μM]=0.014
ESI质谱:[M+H]+=557
保留时间HPLC:5.60min(方法M9).
根据指明的原材料相应地制备下述化合物:
表1.1
实施例2
N-(3,5-二氨基-6-氯-吡嗪-2-羰基)-N’-(4-苯乙基-哌啶-4-基甲基)-胍
将50mg(0,3mmol)4-[N'-(3,5-二氨基-6-氯-吡嗪-2-羰基)-胍基甲基]-4-苯乙基-哌啶-1-羧酸叔丁基酯(实施例1)在1ml二氯甲烷中的混合物与250μl三氟乙酸在室温搅拌2h。
然后将反应混合物减压浓缩。
产率:40mg.
ESI质谱:[M+H]+=431
保留时间HPLC:1,78min(方法M1).
根据指明的原材料相应地制备下述化合物:
表2:
实施例3
(4-(N’-(3,5-二氨基-6-氯-吡嗪-2-羰基)-胍基甲基]4-苯乙基-哌啶-1-基)乙酸
将145mg(0,23mmol){4-[N'-(3,5-二氨基-6-氯-吡嗪-2-羰基)-胍基甲基]-4-苯乙基-哌啶-1-基}-乙酸甲酯(实施例1.16)的5ml甲醇溶液和235μl 4N NaOH的混合物在50℃搅拌1小时。接着溶液用470μl 4N HCl酸化并减压浓缩。残余物通过制备型反相HPLC(梯度:乙腈和水+0.2%三氟乙酸,25℃)纯化。含有标题化合物的馏分减压浓缩。
产率:35mg.
ESI质谱:[M+H]+=489
保留时间HPLC:1.33min(方法M2)
根据指明的原材料相应地制备下述化合物:
表3:
实施例4
4-[N'-(3,5-二氨基-6-氯-吡嗪-2-羰基)-胍基甲基]-4-苯乙基-哌啶-1-甲脒
将70mg(0,15mmol)N-(3,5-二氨基-6-氯-吡嗪-2-羰基)-N’-(4-苯乙基-哌啶-4-基甲基-胍(实施例2)、124μl三乙胺和28mg(0,19mmol)1H-1,2,4-三唑-1-甲脒单盐酸盐在5ml DMF中的混合物在70℃搅拌2小时。接着加入1ml甲醇,通过制备型反相HPLC(梯度:乙腈和水+0.2%三氟乙酸,25℃)纯化混合物。含有标题化合物的馏分减压浓缩。
产率:15mg.
ESI质谱:[M+H]+=473
保留时间HPLC:0.93min(方法M7)
根据指明的原材料相应地制备下述化合物:
表4:
实施例5
(2-((4-[N'-(3,5-二氨基-6-氯-吡嗪-2-羰基)-胍基甲基]-4-苯乙基-哌啶-1-羰基)-氨基)-乙基]-三甲基-氯化铵
将1.55g 4-[N'-(3,5-二氨基-6-氯-吡嗪-2-羰基)-胍基甲基]-4-苯乙基-哌啶-1-羧酸(2-二甲基氨基-乙基)-酰胺(实施例1.40)、0.9ml三乙胺和1.1g BOC酐溶于50mlTHF中,并搅拌过夜。分离有机相并减压浓缩。
产率:1.3g
将1.3g Ex.5.A和200μl碘甲烷在10ml丙酮中的混合物室温搅拌过夜。接着减压浓缩反应混合物,加入5ml 50%三氟乙酸在二氯甲烷中的溶液,并在室温搅拌2h。接着反应混合物与甲醇化盐酸共蒸发。通过制备型反相HPLC(梯度:乙腈和水+0.2%三氟乙酸,25℃)纯化残余物。含有化合物的馏分减压浓缩,最后与甲醇化盐酸共蒸发。
产率:820mg.
ESI质谱:[M]+=559
保留时间HPLC:0.97min(方法M7)
根据指明的原材料相应地制备下述化合物:
表5:
实施例6
将115mg A.48和104mg(0.3mmol)1-(3,5-二氨基-6-氯-吡嗪-2-羰基)-2-甲基-异硫脲在25ml THF中的混合物在70℃搅拌80小时。接着将反应混合物减压浓缩,残余物通过色谱(硅胶,二氯甲烷/甲醇加上10%氨9:1到6/4)纯化。含有标题化合物的馏分减压浓缩。
产率:27mg.
ESI质谱:[M+H]+=1001
保留时间HPLC:1.41min(方法M2).
根据指明的原材料相应地制备下述化合物:
表6
实施例7
N-(3,5-二氨基-6-氯-吡嗪-2-羰基)-N'-(4-苯乙基-1-苯基乙酰基-哌啶-4-基甲基)-胍
向70mg(0.14mmol)N-(3,5-二氨基-6-氯-吡嗪-2-羰基)-N'-(4-苯乙基-哌啶-4-基甲基)-胍(实施例2)和118μl许尼希碱在5ml二氯甲烷中的混合物中滴加27μM(0,21mmol)苯乙酰氯,并在室温搅拌过夜。接着减压浓缩混合物。残余物通过制备型反相HPLC(梯度:乙腈和水+0.2%三氟乙酸,25℃)纯化残余物。含有标题化合物的馏分减压浓缩。
产率:9mg.
ESI质谱:[M+H]+=549
保留时间HPLC:1.42min(方法M2)
实施例8
4-[N'-(3,5-二氨基-6-氯-吡嗪-2-羰基)-胍基甲基]-4-苯乙基-哌啶-1-羧酸丙酰胺
向100mg(0.198mmol)N-(3,5-二氨基-6-氯-吡嗪-2-羰基)-N'-(4-苯乙基-哌啶-4-基甲基)-胍(实施例2)和29μl DBU在5ml THF中的混合物中滴加12μM(0.2mmol)N-丙基异氰酸酯,并在室温搅拌2h。然后减压浓缩反应混合物。残余物通过制备型反相HPLC(梯度:乙腈和水+0.2%三氟乙酸,25℃)纯化。将含有标题化合物的馏分减压浓缩。
产率:10mg.
ESI质谱:[M+H]+=516
保留时间HPLC:2.2min(方法M1)
实施例9
N-[1-(2-氨基-乙酰基)-4-苯乙基-哌啶-4-基甲基-N'-(3,5-二氨基-6-氯-吡嗪-2-羰基)-胍
将130mg(0,35mmol)[2-(4-氨基甲基-4-苯乙基-哌啶-1-基)-2-氧代-乙基]-氨基甲酸叔丁基酯(A.50)和80mg(0,3mmol)1-(3,5-二氨基-6-氯-吡嗪-2-羰基)-2-甲基-异硫脲在5ml四氢呋喃中的混合物在70℃搅拌过夜。接着减压浓缩反应混合物,残余物通过制备型反相HPLC(梯度:乙腈和水+0.2%三氟乙酸,25℃)纯化。将含有标题化合物的馏分减压浓缩。接着残余物与甲醇化盐酸共蒸发以除去保护基团。
产率:37mg.
ESI质谱:[M+H]+=488
保留时间HPLC:1.08min(方法M7).
实施例10
4-{4-[N'-(3,5-二氨基-6-溴-吡嗪-2-羰基)-胍基甲基]-4-苯乙基-哌啶-1-基}-4-氧代-丁酸甲酯
采用3,5-二氨基-6-溴-N-[(甲基硫基)亚氨甲酰基]吡嗪-2-甲酰胺(中间体C.62)代替中间体C.61,按照实施例1.14的方法制备所述化合物。
ESI质谱:[M+H]+=589
保留时间HPLC:0.72min(方法M12)
IC50[μM]=0.032
实施例11
4-{4-[N'-(3,5-二氨基-6-溴-吡嗪-2-羰基)-胍基甲基]-4-苯乙基-哌啶-1-基}-4-氧代-丁酸
采用实施例10作为原材料,以类似于实施例3的方法制备所述化合物。
ESI质谱:[M+H]+=575
保留时间HPLC:0.49min(方法M13)
IC50[μM]=0.502
分析方法
HPLC/MS方法
方法:M1
Waters ZQ2000;Waters 1515泵,Waters PDA 996检测器,Waters 2747注射器
流动相:A:水+0.1%甲酸
B:乙腈+0.1%甲酸
梯度:
时间(min) | %A | %B | 流速(ml/min) |
0.00 | 95.0 | 5.0 | 1.00 |
0.10 | 95.0 | 5.0 | 1.00 |
3.10 | 2.00 | 98.00 | 1.00 |
4.50 | 2.00 | 98.00 | 1.00 |
5.00 | 95.0 | 5.0 | 1.00 |
固定相:X-terraTM MS C18 2,5μm 4.6mm x 30mm
柱温约25℃
二极管阵列检测波长范围210–420nm
质量范围m/z 80至800
离子化:ESI阳性
方法:M2
Waters ZQ2000;Waters 1515泵,Waters PDA 996检测器,Waters 2747注射器
流动相:A:水+0.1%甲酸
B:乙腈+0.1%甲酸
梯度:
时间(min) | %A | %B | 流速(ml/min) |
0.00 | 95.0 | 5.0 | 1.5 |
2.00 | 0.0 | 100 | 1.5 |
2.50 | 0.0 | 100 | 1.5 |
2.60 | 95.0 | 5.0 | 1.5 |
固定相:X-terraTM MS C18 2,5μm 4,6mm x 30mm
柱温约25℃
二极管阵列检测范围210-420nm
质量范围m/z 80至800
离子化:ESI阳性/阴性
方法:M3分析柱:XBridge C18(Waters technologies)
XBridge C18,4.6x30mm,2.5μm柱温60℃
流动相A:H2O:三氟乙酸99.9:0.1
流动相B:甲醇:三氟乙酸99.9:0.1
梯度:
方法:M4
分析柱:XBridge C18(Waters technologies)
XBridge C18,4.6x30mm,2.5μm柱温60℃
流动相A:H2O:三氟乙酸99.9:0.1
流动相B:甲醇:100
梯度:
时间(min) | %A | %B | 流速(ml/min) |
0.0 | 95 | 5 | 4 |
0.05 | 95 | 5 | 3 |
2.05 | 0 | 100 | 3 |
2.10 | 0 | 100 | 4.5 |
2.40 | 0 | 100 | 4.5 |
方法:M5
分析柱:Sunfire C18(Waters technologies)
Sunfire C18,4.6x30mm,2.5μm柱温60℃
流动相A:H2O:三氟乙酸99.9:0.1
流动相B:甲醇:100
梯度:
时间(min) | %A | %B | 流速(ml/min) |
0.0 | 95 | 5 | 4 |
0.05 | 95 | 5 | 3 |
2.05 | 0 | 100 | 3 |
2.10 | 0 | 100 | 4.5 |
2.40 | 0 | 100 | 4.5 |
方法:M6
分析柱:XBridge C18(Waters technologies)
XBridge C18,3.0x30mm,2.5μm柱温60℃
流动相A:H2O:三氟乙酸99.9:0.1
流动相B:甲醇:100
梯度:
时间(min) | %A | %B | 流速(ml/min) |
0.0 | 95 | 5 | 2.2 |
0.30 | 95 | 5 | 2.2 |
1.50 | 0 | 100 | 2.2 |
1.55 | 0 | 100 | 2.9 |
1.65 | 0 | 100 | 2.9 |
方法:M7
分析柱:Sunfire C18(Waters technologies)
Sunfire C18,3.0x30mm,2.5μm柱温60℃
流动相A:H2O:三氟乙酸99.9:0.1
流动相B:甲醇:100
梯度:
时间(min) | %A | %B | 流速(ml/min) |
0.0 | 95 | 5 | 1.8 |
0.25 | 95 | 5 | 1.8 |
1.70 | 0 | 100 | 1.8 |
1.75 | 0 | 100 | 2.5 |
1.90 | 0 | 100 | 2.5 |
方法:M8
分析柱:XBridge C18(Waters technologies)
XBridge C18,3.0x30mm,2.5μm柱温60℃
流动相A:H2O:氨99.9:0.1
流动相B:甲醇:100
梯度:
时间(min) | %A | %B | 流速(ml/min) |
0.0 | 95 | 5 | 2.2 |
0.30 | 95 | 5 | 2.2 |
1.50 | 0 | 100 | 2.2 |
1.55 | 0 | 100 | 2.9 |
1.70 | 0 | 100 | 2.9 |
方法:M9
设备:LC/MS ThermoFinnigan HPLC Surveyor DAD,MSQ单相四极柱:SynergiHydro RP100A,2,5μm,3x50mm
流动相:A=H2O 90%+10%CH3CN+NH4COOH 5mM
B=CH3CN 90%+H2O 10%
梯度:
时间(min) | %A | %B | 流速(ml/min) |
0.0 | 100 | 0 | 1.2 |
4.00 | 0 | 100 | 1.2 |
5.30 | 0 | 100 | 1.2 |
5.50 | 100 | 0 | 1.2 |
6.00 | 100 | 0 | 1.2 |
检测:UV 254nm
检测:Finnigan MSQ,单相四极
离子源:APCI+/APCI-
扫描范围:100-900amu
方法:M10
设备:LC/MS ThermoFinnigan HPLC Surveyor DAD,MSQ单相四极
柱:Synergi Hydro RP100A,2,5μm,3x50mm
流动相:A=H2O 90%+10%CH3CN+NH4COOH 5mM
B=CH3CN 90%+H2O 10%
梯度:
时间(min) | %A | %B | 流速(ml/min) |
0.0 | 100 | 0 | 1.2 |
1.5 | 100 | 0 | 1.2 |
9.00 | 0 | 100 | 1.2 |
10.50 | 0 | 100 | 1.2 |
11.00 | 100 | 0 | 1.2 |
12.00 | 100 | 0 | 1.2 |
检测:UV 254nm
检测:Finnigan MSQ,单相四极
离子源:APCI+/APCI-
扫描范围:100-900amu
方法:M11
设备:LC/MS Waters Alliance 2695HPLC System DAD,Quattro Micro三相四极
柱:Atlantis dC18 5μm 4,6x50mm,温度35℃
流动相:A=H2O 90%+10%CH3CN+CF3COOH 0,05%
B=CH3CN 90%+10%H2O
梯度:
时间(min) | %A | %B | 流速(ml/min) |
0.0 | 100 | 0 | 1.3 |
0.70 | 100 | 0 | 1.3 |
4.5 | 0 | 100 | 1.3 |
5.8 | 0 | 100 | 1.3 |
6.00 | 100 | 0 | 1.3 |
检测:UV 254nm
检测:Quattro Micro,三相四极
离子源:ES+
扫描范围:90-1000amu
方法:M12
方法:M13
药理学测试方法
尤斯室:小鼠肾脏M-1细胞在含有5%FCS和5μM地塞米松的DMEM中在聚酯Transwell过滤器上培养10到12天。过滤器插入至内部配置有尤斯室体系的特氟隆涂敷的孔板中。测量前,M-1细胞培养基以Caco-2传输缓冲液(Invitrogen,Germany)替换。测量过程中,尤斯室温度保持在37℃。在电压钳模式中测量短路电流(I_sc),利用内部建立放大器(Boehringer Ingelheim,Biberach)与数据获得和分析的软件包Lab View。采用每5秒±5mV的电压阶跃,确定经上皮电阻(TEER)。以最终3μM或逐渐增加的浓度(1-3-10μM)施予化合物至顶端溶液。每个实验结束时,通过加入3μM阿米洛利至顶端室测量阿米洛利敏感I_SC。将结果表示为阿米洛利效果的抑制百分数或IC50。结果示于表1到5中,其它实施例如上所述。
适应症
已经发现,式(I)化合物的特征在于可广泛的应用于治疗领域。特别应提及的这些应用为本发明式(I)化合物基于其药学活性优选作为ENaC抑制剂。实例包括呼吸系统疾病或症状,或气道的过敏性疾病。
特别应提及预防及治疗伴有气道的黏液产生增加、炎症和/或阻塞性疾病的气道和肺部疾病。这些疾病的实例包括急性、过敏性或慢性支气管炎;慢性阻塞性支气管炎(COPD);咳嗽;肺气肿;过敏性或非过敏性鼻炎或鼻窦炎;慢性鼻炎或鼻窦炎;哮喘;肺泡炎;农民肺病(farmers'disease);高反应性气道;传染性支气管炎或肺炎;小儿哮喘;支气管扩张症;肺纤维化;ARDS(急性成人呼吸窘迫综合征);支气管水肿;肺气肿;支气管炎;各种原因如呼吸、吸入有毒气体引起的肺炎或间质性肺炎;心力衰竭、扩散、化疗、囊性纤维化或粘液粘稠病导致的支气管炎、肺炎或间质性肺炎;或α1-抗胰蛋白酶缺乏。
本发明特别优选地涉及式(I)化合物在制备用于治疗包括肺的上和下呼吸道的炎性或阻塞性疾病的药物组合物中的用途,所述疾病如过敏性鼻炎、慢性鼻炎、支气管扩张、囊性纤维化、COPD、慢性支气管炎、慢性鼻窦炎、哮喘,特别是COPD、慢性支气管炎、囊性纤维化和哮喘。
最优选地使用式(I)化合物治疗炎性和阻塞性疾病如COPD、慢性支气管炎、慢性鼻窦炎、哮喘、囊性纤维化,特别是COPD、慢性支气管炎和囊性纤维化。
实际药效量或治疗剂量当然取决于本领域技术人员已知的因素,如患者的年龄和体重、施药途径和疾病严重程度。在任何情况下,组合以基于患者特有情况递送药物有效量的剂量和方式施予。
组合
式(I)化合物可单独使用或与本发明式(I)的其它活性物质组合使用。如果需要,式(I)化合物也可与其它药理活性物质组合使用。
因此本发明进一步涉及药物组合,除了一种或多种式(I)化合物之外,其还优选含有作为其它活性物质的选自下述类别的一种或多种化合物:其它ENaC抑制剂、β模拟药、抗胆碱药、皮质类固醇、PDE4-抑制剂、LTD4-拮抗剂、EGFR-抑制剂、多巴胺激动剂、H1-抗组胺药、PAF-拮抗剂、MAP-激酶抑制剂、MPR4-抑制剂、iNOS-抑制剂、SYK-抑制剂、囊性纤维化跨膜调节剂(CFTR)和CFTR增强剂或其两种或三种的组合。
可提及的优选β模拟药的实例包括阿布特罗(Albuterole)、阿福特罗(Arformoterol)、班布特罗(Bambuterol)、比托特罗(Bitolterol)、溴沙特罗(Broxaterol)、卡布特罗(Carbuterol)、克仑特罗(Clenbuterol)、非诺特罗(Fenoterol)、福莫特罗(Formoterol)、海索那林(Hexoprenalin)、异丁特罗(Ibuterol)、异他林(Isoetharin)、异丙肾上腺素(Isoprenalin)、左沙丁胺醇(Levosalbutamol)、马布特罗(Mabuterol)、美卢君(Meluadrine)、间羟异丙肾上腺素(Metaproterenol)、米维特罗(Milveterol)、奥西那林(Orciprenalin)、吡布特罗(Pirbuterol)、丙卡特罗(Procaterol)、瑞普特罗(Reproterol)、利米特罗(Rimiterol)、利托君(Ritodrin)、沙甲胺醇(Salmefamol)、沙美特罗(Salmeterol)、甲磺喘宁(Soterenol)、Sulphonterole、特布他林(Terbutalin)、噻拉米特(Tiaramide)、妥布特洛(Tolubuterol)、净特罗(Zinterol)、诺罗米罗(Noromirole)和
●1-(2-氯-4-羟基苯基)-叔丁基氨基乙醇,
●(-)-2-[7(S)-[2(R)-羟基-2-(4-羟基苯基)-乙基氨基]-5,6,7,8-四氢-2-萘基氧基]-N,N-二甲基乙酰胺盐酸盐一水合物,
●3-(4-{6-[2-羟基-2-(4-羟基-3-羟基甲基-苯基)-乙基氨基]-己基氧基}-丁基)-苄基-磺酰胺
●5-[2-(5,6-二乙基-茚满-2-基氨基)-1-羟基-乙基]-8-羟基-1H-喹啉-2-酮
●4-羟基-7-[2-{[2-{[3-(2-苯基乙氧基)丙基]磺酰基}乙基]-氨基}乙基]-2(3H)-苯并噻唑酮
●1-(2-氟-4-羟基苯基)-2-[4-(1-苯并咪唑基)-2-甲基-2-丁基氨基]乙醇
●1-[3-(4-甲氧基苄基-氨基)-4-羟基苯基]-2-[4-(1-苯并咪唑基)-2-甲基-2-丁基氨基]乙醇
●1-[2H-5-羟基-3-氧代-4H-1,4-苯并嗪-8-基]-2-[3-(4-N,N-二甲基氨基苯基)-2-甲基-2-丙基氨基]乙醇
●1-[2H-5-羟基-3-氧代-4H-1,4-苯并嗪-8-基]-2-[3-(4-甲氧基苯基)-2-甲基-2-丙基氨基]乙醇
●1-[2H-5-羟基-3-氧代-4H-1,4-苯并嗪-8-基]-2-[3-(4-正丁基氧基苯基)-2-甲基-2-丙基氨基]乙醇
●1-[2H-5-羟基-3-氧代-4H-1,4-苯并嗪-8-基]-2-{4-[3-(4-甲氧基苯基)-1,2,4-三唑-3-基]-2-甲基-2-丁基氨基}乙醇
●5-羟基-8-(1-羟基-2-异丙基氨基丁基)-2H-1,4-苯并嗪-3-(4H)-酮
●1-(4-氨基-3-氯-5-三氟甲基苯基)-2-叔丁基氨基)乙醇
●6-羟基-8-{1-羟基-2-[2-(4-甲氧基-苯基)-1,1-二甲基-乙基氨基]-乙基}-4H-苯并[1,4]嗪-3-酮
●6-羟基-8-{1-羟基-2-[2-(4-苯氧基-乙酸乙酯)-1,1-二甲基-乙基氨基]-乙基}-4H-苯并[1,4]嗪-3-酮
●6-羟基-8-{1-羟基-2-[2-(4-苯氧基-乙酸)-1,1-二甲基-乙基氨基]-乙基}-4H-苯并[1,4]嗪-3-酮
●8-{2-[1,1-二甲基-2-(2,4,6-三甲基苯基)-乙基氨基]-1-羟基-乙基}-6-羟基-4H-苯并[1,4]嗪-3-酮
●6-羟基-8-{1-羟基-2-[2-(4-羟基-苯基)-1,1-二甲基-乙基氨基]-乙基}-4H-苯并[1,4]嗪-3-酮
●6-羟基-8-{1-羟基-2-[2-(4-异丙基-苯基)-1,1-二甲基-乙基氨基]-乙基}-4H-苯并[1,4]嗪-3-酮
●8-{2-[2-(4-乙基-苯基)-1,1-二甲基-乙基氨基]-1-羟基-乙基}-6-羟基-4H-苯并[1,4]嗪-3-酮
●8-{2-[2-(4-乙氧基-苯基)-1,1-二甲基-乙基氨基]-1-羟基-乙基}-6-羟基-4H-苯并[1,4]嗪-3-酮
●4-(4-{2-[2-羟基-2-(6-羟基-3-氧代-3,4-二氢-2H-苯并[1,4]嗪-8-基)-乙基氨基]-2-甲基-丙基}-苯氧基)-丁酸
●8-{2-[2-(3,4-二氟-苯基)-1,1-二甲基-乙基氨基]-1-羟基-乙基}-6-羟基-4H-苯并[1,4]嗪-3-酮
●1-(4-乙氧基-羰基氨基-3-氰基-5-氟苯基)-2-(叔丁基氨基)乙醇
●N-[2-羟基-5-(1-羟基-2-{2-[4-(2-羟基-2-苯基-乙基氨基)-苯基]-乙基氨基}-乙基)-苯基]-甲酰胺
●8-羟基-5-(1-羟基-2-{2-[4-(6-甲氧基-联苯-3-基氨基)-苯基]-乙基氨基}-乙基)-1H-喹啉-2-酮
●8-羟基-5-[1-羟基-2-(6-苯乙基氨基-己基氨基)-乙基]-1H-喹啉-2-酮
●5-[2-(2-{4-[4-(2-氨基-2-甲基-丙氧基)-苯基氨基]-苯基}-乙基氨基)-1-羟基-乙基]-8-羟基-1H-喹啉-2-酮
●[3-(4-{6-[2-羟基-2-(4-羟基-3-羟基甲基-苯基)-乙基氨基]-己基氧基}-丁基)-5-甲基-苯基]-脲
●4-(2-{6-[2-(2,6-二氯-苄基氧基)-乙氧基]-己基氨基}-1-羟基-乙基)-2-羟基甲基-苯酚
●3-(4-{6-[2-羟基-2-(4-羟基-3-羟基甲基-苯基)-乙基氨基]-己基氧基}-丁基)-苯磺酰胺
●3-(3-{7-[2-羟基-2-(4-羟基-3-羟基甲基-苯基)-乙基氨基]-庚基氧基}-丙基)-苯磺酰胺
●4-(2-{6-[4-(3-环戊磺酰基-苯基)-丁氧基]-己基氨基}-1-羟基-乙基)-2-羟基甲基-苯酚
●N-金刚烷-2-基-2-(3-{2-[2-羟基-2-(4-羟基-3-羟基甲基-苯基)-乙基氨基]-丙基}-苯基)-乙酰胺
●(R,S)-4-(2-{[6-(2,2-二氟-4-苯基丁氧基)己基]氨基}-1-羟基-乙基)-2-(羟基甲基)苯酚
●(R,S)-4-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1-羟基-乙基)-2-(羟基甲基)苯酚
●(R,S)-4-(2-{[4,4-二氟-6-(4-苯基丁氧基)己基]氨基}-1-羟基-乙基)-2-(羟基甲基)苯酚
●(R,S)-4-(2-{[6-(4,4-二氟-4-苯基丁氧基)己基]氨基}-1-羟基-乙基)-2-(羟基甲基)苯酚
●(R,S)-5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1-羟基-乙基)-8-羟基喹啉-2(1H)-酮
●(R,S)-[2-({6-[2,2-二氟-2-(3-甲基苯基)乙氧基]己基}氨基)-1-羟基乙基]-2-(羟基甲基)苯酚
●4-(1R)-2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1-羟基乙基)-2-(羟基甲基)苯酚
●(R,S)-2-(羟基甲基)-4-(1-羟基-2-{[4,4,5I5-四氟-6-(3-苯基丙氧基)己基]氨基}乙基)苯酚
●(R,S)-[5-(2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1-羟基-乙基)-2-羟基苯基]甲酰胺
●(R,S)-4-[2-({6-[2-(3-溴苯基)-2,2-二氟乙氧基]己基}氨基)-1-羟基乙基]-2-(羟基甲基)苯酚
●(R,S)-N-[3-(1,1-二氟-2-{[6-({2-羟基-2-[4-羟基-3-(羟基甲基)苯基]乙基}氨基)己基]氧基}乙基)苯基]脲
●3-[3-(1,1-二氟-2-{[6-({2-羟基-2-[4-羟基-3-(羟基甲基)苯基]乙基}氨基)己基]氧基}乙基)苯基]咪唑烷-2,4-二酮
●(R,S)-4-[2-({6-[2,2-二氟-2-(3-甲氧基苯基)乙氧基]己基}氨基)-1-羟基乙基]-2-(羟基甲基)苯酚
●5-((1R)-2-{[6-(2,2-二氟-2-苯基乙氧基)己基]氨基}-1-羟基乙基)-8-羟基喹啉-2(1H)-酮
●4-((1R)-2-{[4,4-二氟-6-(4-苯基丁氧基)己基]氨基}-1-羟基-乙基)-2-(羟基甲基)苯酚
●(R,S)-4-(2-{[6-(3,3-二氟-3-苯基丙氧基)己基]氨基}-1-羟基-乙基)-2-(羟基甲基)苯酚
●(R,S)-(2-{[6-(2,2-二氟-2-苯基乙氧基)-4,4-二氟己基]氨基}-1-羟基乙基)-2-(羟基甲基)苯酚
●(R,S)-4-(2-{[6-(2,2-二氟-3-苯基丙氧基)己基]氨基}-1-羟基乙基)-2-(羟基甲基)苯酚
●3-[2-(3-氯-苯基)-乙氧基]-N-(2-二乙基氨基-乙基)-N-{2-[2-(4-羟基-2-氧代-2,3-二氢-苯并噻唑-7-基)-乙基氨基]-乙基}-丙酰胺
●N-(2-二乙基氨基-乙基)-N-{2-[2-(4-羟基-2-氧代-2,3-二氢-苯并噻唑-7-基)-乙基氨基]-乙基}-3-(2-萘-1-基-乙氧基)-丙酰胺
●7-[2-(2-{3-[2-(2-氯-苯基)-乙基氨基]-丙基硫基}-乙基氨基)-1-羟基-乙基]-4-羟基-3H-苯并噻唑-2-酮和7-[(1R)-2-(2-{3-[2-(2-氯-苯基)-乙基氨基]-丙基硫基}-乙基氨基)-1-羟基-乙基]-4-羟基-3H-苯并噻唑-2-酮,
任选以外消旋形式、对映异构体、非对映异构体或药用盐、溶剂合物或水合物。优选为盐,其选自盐酸胺、氢溴酸盐、氢碘酸盐、硫酸氢盐、磷酸氢盐、甲磺酸氢盐、硝酸氢盐、马来酸氢盐、乙酸氢盐、柠檬酸氢盐、富马酸氢盐、酒石酸氢盐、草酸氢盐、琥珀酸氢盐、苯甲酸氢盐和对甲苯磺酸氢盐。
可提及的抗胆碱药的优选实例包括噻托铵(Tiotropium)盐,优选溴化物盐;氧托铵(Oxitropium)盐,优选溴化物盐;氟托铵(Flutropium)盐,优选溴化物盐;异丙托铵(Ipratropium)盐,优选溴化物盐;阿地铵(Aclidinium)盐,优选溴化物盐;格隆铵(Glycopyrronium)盐,优选溴化物盐;曲司铵(Trospium)盐,优选氯化物盐;托特罗定(Tolterodin)。在上述盐中,药理活性成份为阳离子,可能的阴离子为氯离子、溴离子、碘离子、硫酸根、磷酸根、甲磺酸酯、硝酸根、马来酸根、乙酸根、柠檬酸根、富马酸根、酒石酸根、草酸根、琥珀酸根、苯甲酸根或对甲苯磺酸酯。其它抗胆碱药的优选实例选自:
●2,2-二苯基丙酸甲氧莨菪醇(tropenole)酯-甲溴化物
●2,2-二苯基丙酸东莨菪醇(scopine)酯-甲溴化物
●2-氟-2,2-二苯基乙酸东莨菪醇酯-甲溴化物
●2-氟-2,2-二苯基乙酸甲氧莨菪醇酯-甲溴化物
●3,3',4,4'-四氟二苯乙醇酸甲氧莨菪醇酯-甲溴化物
●3,3',4,4'-四氟二苯乙醇酸东莨菪醇酯-甲溴化物
●4,4'-二氟二苯乙醇酸甲氧莨菪醇酯-甲溴化物
●4,4'-二氟二苯乙醇酸东莨菪醇酯-甲溴化物
●3,3'-二氟二苯乙醇酸甲氧莨菪醇酯-甲溴化物
●3,3'-二氟二苯乙醇酸东莨菪醇酯-甲溴化物
●9-羟基-芴-9-碳酸甲氧莨菪醇酯-甲溴化物
●9-氟-芴-9-碳酸甲氧莨菪醇酯-甲溴化物
●9-羟基-芴-9-碳酸东莨菪醇酯-甲溴化物
●9-氟-芴-9-碳酸东莨菪醇酯甲溴化物
●9-甲基-芴-9-碳酸甲氧莨菪醇酯甲溴化物
●9-甲基-芴-9-碳酸东莨菪醇酯甲溴化物
●二苯乙醇酸环丙基莨菪醇(tropine)酯-甲溴化物
●2,2-二苯基丙酸环丙基莨菪醇酯-甲溴化物
●9-羟基-呫吨-9-碳酸环丙基莨菪醇酯-甲溴化物
●9-甲基-芴-9-碳酸环丙基莨菪醇酯-甲溴化物
●9-甲基-呫吨-9-碳酸环丙基莨菪醇酯-甲溴化物
●9-羟基-芴-9-碳酸环丙基莨菪醇酯-甲溴化物
●4,4'-二氟二苯乙醇酸甲酯环丙基莨菪醇酯-甲溴化物
●9-羟基-呫吨-9-碳酸甲氧莨菪醇酯-甲溴化物
●9-羟基-呫吨-9-碳酸东莨菪醇酯甲溴化物
●9-甲基-呫吨-9-碳酸甲氧莨菪醇酯-甲溴化物
●9-甲基-呫吨-9-碳酸东莨菪醇酯甲溴化物
●9-乙基-呫吨-9-碳酸甲氧莨菪醇酯甲溴化物
●9-二氟甲基-呫吨-9-碳酸甲氧莨菪醇酯-甲溴化物
●9-羟基甲基-呫吨-9-碳酸东莨菪醇酯-甲溴化物。
可提及的皮质类固醇的实例优选包括倍氯米松、倍他米松、布地奈德、布替可特、环索奈德、地夫可特、地塞米松、埃普瑞诺、氟尼缩松、氟替卡松、氯替泼诺、莫米松、泼尼松龙、泼尼松、罗氟奈德、曲安西龙、替泼尼旦和
●{20R-16α,17α-[亚丁基二(氧基)]-6α,9α-二氟-11β-羟基-17β-(甲基硫基)雄甾-4-烯-3-酮},
●9-氟-11β,17,21-三羟基-16α-甲基孕甾-1,4-二烯-3,20-二酮21-环己羧酸酯17-环丙羧酸酯,
●16,17-亚丁基二氧基-6,9-二氟-11-羟基-17-(甲基硫基)雄甾-4-烯-3-酮
●氟尼缩松-21-[4′-(硝基氧基甲基)苯甲酸酯]
●6,9-二氟-17-[(2-呋喃基羰基)氧基]-11-羟基-16-甲基-3-氧代-雄甾-1,4-二烯-17-硫代碳酸(S)-氟甲酯,
●6,9-二氟-11-羟基-16-甲基-3-氧代-17-丙酰基氧基-雄甾-1,4-二烯-17-硫代碳酸(S)-(2-氧代-四氢-呋喃-3S-基)酯,和
●6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-(2,2,3,3-四甲基环丙基羰基)氧基-雄甾-1,4-二烯-17β-羧酸氰基甲酯,
任选以外消旋体形式、对映异构体、非对映异构体或药用盐、溶剂合物或水合物。优选盐和衍生物的实例是碱盐即钠或钾盐、磺基苯甲酸盐、磷酸盐、异烟酸盐、乙酸盐、二氯乙酸盐、丙酸盐、磷酸二氢盐、棕榈酸盐、新戊酸盐或糠酸盐。
优选的可提及的PDE4-抑制剂的实例包括恩丙茶碱(Enprofyllin)、茶碱(Theophyllin)、罗氟司特(Roflumilast)、Ariflo(西洛司特(Cilomilast))、妥非司特(Tofimilast)、普马芬群(Pumafentrin)、利米司特(Lirimilast)、Apremilast、阿罗茶碱(Arofyllin)、阿替唑兰(Atizoram)、Oglemilast、替托司特(Tetomilast)和
●5-[(N-(2,5-二氯-3-吡啶基)-甲酰胺]-8-甲氧基-喹啉
●5-[N-(3,5-二氯-1-氧化-4-吡啶基)-甲酰胺]-8-甲氧基-2-(三氟甲基)-喹啉
●N-(3,5-二氯吡啶-4-基)-[1-(4-氟苄基)-5-羟基-吲哚-3-基]乙醛酸酰胺),9-[(2-氟苯基)甲基]-N-甲基-2-(三氟甲基)-9H-嘌呤-6-胺4-[(2R)-2-[3-(环戊基氧基)-4-甲氧基苯基]-2-苯基乙基]-吡啶,
●N-[(3R)-3,4,6,7-四氢-9-甲基-4-氧代-1-苯基吡咯并[3,2,1-jk][1,4]苯并二氮杂-3-基]-4-吡啶甲酰胺,
●4-[6,7-二乙氧基-2,3-二(羟基甲基)-1-萘基]-1-(2-甲氧基乙基)-2(1H)-吡啶酮,
●2-[4-[6,7-二乙氧基-2,3-二(羟基甲基)-1-萘基]-2-吡啶基]-4-(3-吡啶基)-1(2H)-酞嗪酮,
●(3-(3-环戊基氧基-4-甲氧基苄基)-6-乙基氨基-8-异丙基-3H-嘌呤,
●β-[3-(环戊基氧基)-4-甲氧基苯基]-1,3-二氢-1,3-二氧代-2H-异吲哚-2-丙酰胺,
●9-乙基-2-甲氧基-7-甲基-5-丙基-咪唑并[1,5-a]吡啶并[3,2-e]吡嗪-6(5H)-酮
●5-[3-(环戊基氧基)-4-甲氧基苯基]-3-[(3-甲基苯基)甲基](3S,5S)-2-哌啶酮,
●4-[1-[3,4-二(二氟甲氧基)苯基]-2-(3-甲基-1-氧化-4-吡啶基)乙基]-α,α-二(三氟甲基)-苯甲醇
●N-(3,5-二氯-1-氧代-吡啶-4-基)-4-二氟甲氧基-3-环丙基甲氧基苯甲酰胺
●(-)p-[(4aR*,10bS*)-9-乙氧基-1,2,3,4,4a,10b-六氢-8-甲氧基-2-甲基苯并[s][1,6]萘啶-6-基]-N,N-二异丙基苯甲酰胺
●(R)-(+)-1-(4-溴苄基)-4-[(3-环戊基氧基)-4-甲氧基苯基]-2-吡咯烷酮
●3-(环戊基氧基-4-甲氧基苯基)-1-(4-N'-[N-2-氰基-S-甲基-异硫脲基]苄基)-2-吡咯烷酮
●顺[4-氰基-4-(3-环戊基氧基-4-甲氧基苯基)环己-1-碳酸]
●2-甲酯基-4-氰基-4-(3-环丙基甲氧基-4-二氟甲氧基苯基)环己-1-酮
●顺[4-氰基-4-(3-环丙基甲氧基-4-二氟甲氧基苯基)环己-1-醇]
●(R)-(+)-[4-(3-环戊基氧基-4-甲氧基苯基)吡咯烷-2-亚基]乙酸乙酯
●(S)-(-)-[4-(3-环戊基氧基-4-甲氧基苯基)吡咯烷-2-亚基]乙酸乙酯
●9-环戊基-5,6-二氢-7-乙基-3-(2-噻吩基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-a]吡啶
●9-环戊基-5,6-二氢-7-乙基-3-(叔丁基)-9H-吡唑并[3,4-c]-1,2,4-三唑并[4,3-a]吡啶,
任选以外消旋体形式、对映异构体、非对映异构体或药用盐、溶剂合物或水合物。优选为盐,其选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸氢盐、磷酸氢盐、甲烷磺酸氢盐、硝酸氢盐、马来酸氢盐、乙酸氢盐、柠檬酸氢盐、富马酸氢盐、酒石酸氢盐、草酸氢盐、琥珀酸氢盐、苯甲酸氢盐及对甲苯磺酸氢盐。
●可提及的LTD4-拮抗剂的优选实例包括孟鲁司特(Montelukast)、普仑司特(Pranlukast)、扎鲁司特(Zafirlukast)、Masikulast、L-733321(参见D.Guay et al,Bioorg.Med.Chem.Lett.8(1998)453-458的化合物2ab)和(E)-8-[2-[4-[4-(4-氟苯基)丁氧基]苯基]乙烯基]-2-(1H-四唑-5-基)-4H-1-苯并吡喃-4-酮(MEN-91507)
●4-[6-乙酰基-3-[3-(4-乙酰基-3-羟基-2-丙基苯基硫基)丙氧基]-2-丙基苯氧基]-丁酸(MN-001)
●1-(((R)-(3-(2-(6,7-二氟-2-喹啉基)乙烯基)苯基)-3-(2-(2-羟基-2-丙基)苯基)硫基)甲基环丙-乙酸,
●1-(((1(R)-3(3-(2-(2,3-二氯噻吩并[3,2-b]吡啶-5-基)-(E)-乙烯基)苯基)-3-(2-(1-羟基-1-甲基乙基)苯基)丙基)硫基)甲基)环丙乙酸
●[2-[[2-(4-叔丁基-2-噻唑基)-5-苯并呋喃基]氧基甲基]苯基]乙酸,
任选以外消旋体形式、对映异构体、非对映异构体或药用盐、溶剂合物或水合物。优选为盐,其选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸氢盐、磷酸氢盐、甲烷磺酸氢盐、硝酸氢盐、马来酸氢盐、乙酸氢盐、柠檬酸氢盐、富马酸氢盐、酒石酸氢盐、草酸氢盐、琥珀酸氢盐、苯甲酸氢盐及对甲苯磺酸氢盐。优选盐和衍生物的另外实例是碱盐,即钠或钾盐,磺基苯甲酸盐、磷酸盐、异烟酸盐、乙酸盐、丙酸盐、磷酸二氢盐、棕榈酸盐、新戊酸盐或糠酸盐。
可提及的EGFR-抑制剂的优选实例包括西妥昔单抗、曲妥珠单抗、盘尼图单抗、吉非替尼、卡纽替尼、埃罗替尼、Mab ICR-62和
●4-[(3-氯-4-氟苯基)氨基]-6-{[4-(吗啉-4-基)-1-氧代-2-丁烯-1-基]氨基}-7-环丙基甲氧基-喹唑啉
●4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二乙基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-环丙基甲氧基-喹唑啉
●4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-环丙基甲氧基-喹唑啉
●4-[(R)-(1-苯基-乙基)氨基]-6-{[4-(吗啉-4-基)-1-氧代-2-丁烯-1-基]氨基}-7-环戊基氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{[4-((R)-6-甲基-2-氧代-吗啉-4-基)-1-氧代-2-丁烯-1-基]氨基}-7-环丙基甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{[4-((R)-6-甲基-2-氧代-吗啉-4-基)-1-氧代-2-丁烯-1-基]氨基}-7-[(S)-(四氢呋喃-3-基)氧基]-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{[4-((R)-2-甲氧基甲基-6-氧代-吗啉-4-基)-1-氧代-2-丁烯-1-基]氨基}-7-环丙基甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-[2-((S)-6-甲基-2-氧代-吗啉-4-基)-乙氧基]-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟苯基)氨基]-6-({4-[N-(2-甲氧基-乙基)-N-甲基-氨基]-1-氧代-2-丁烯-1-基}氨基)-7-环丙基甲氧基-喹唑啉
●4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-环戊基氧基-喹唑啉
●4-[(R)-(1-苯基-乙基)氨基]-6-{[4-(N,N-二-(2-甲氧基-乙基)-氨基)-1-氧代-2-丁烯-1-基]氨基}-7-环丙基甲氧基-喹唑啉
●4-[(R)-(1-苯基-乙基)氨基]-6-({4-[N-(2-甲氧基-乙基)-N-乙基-氨基]-1-氧代-2-丁烯-1-基}氨基)-7-环丙基甲氧基-喹唑啉
●4-[(R)-(1-苯基-乙基)氨基]-6-({4-[N-(2-甲氧基-乙基)-N-甲基-氨基]-1-氧代-2-丁烯-1-基}氨基)-7-环丙基甲氧基-喹唑啉
●4-[(R)-(1-苯基-乙基)氨基]-6-({4-[N-(四氢吡喃-4-基)-N-甲基-氨基]-1-氧代-2-丁烯-1-基}氨基)-7-环丙基甲氧基-喹唑啉
●4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-((R)-四氢呋喃-3-基氧基)-喹唑啉
●4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-((S)-四氢呋喃-3-基氧基)-喹唑啉
●4-[(3-氯-4-氟苯基)氨基]-6-({4-[N-(2-甲氧基-乙基)-N-甲基-氨基]-1-氧代-2-丁烯-1-基}氨基)-7-环戊基氧基-喹唑啉
●4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N-环丙基-N-甲基-氨基)-1-氧代-2-丁烯-1-基]氨基}-7-环戊基氧基-喹唑啉
●4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-[(R)-(四氢呋喃-2-基)甲氧基]-喹唑啉
●4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-[(S)-(四氢呋喃-2-基)甲氧基]-喹唑啉
●4-[(3-乙炔基-苯基)氨基]-6,7-二-(2-甲氧基-乙氧基)-喹唑啉
●4-[(3-氯-4-氟苯基)氨基]-7-[3-(吗啉-4-基)-丙基氧基]-6-[(乙烯基羰基)氨基]-喹唑啉
●4-[(R)-(1-苯基-乙基)氨基]-6-(4-羟基-苯基)-7H-吡咯并[2,3-d]嘧啶
●3-氰基-4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-乙氧基-喹啉
●4-{[3-氯-4-(3-氟-苄基氧基)-苯基]氨基}-6-(5-{[(2-甲磺酰基-乙基)氨基]甲基}-呋喃-2-基)喹唑啉
●4-[(R)-(1-苯基-乙基)氨基]-6-{[4-((R)-6-甲基-2-氧代-吗啉-4-基)-1-氧代-2-丁烯-1-基]氨基}-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟苯基)氨基]-6-{[4-(吗啉-4-基)-1-氧代-2-丁烯-1-基]氨基}-7-[(四氢呋喃-2-基)甲氧基]-喹唑啉
●4-[(3-氯-4-氟苯基)氨基]-6-({4-[N,N-二-(2-甲氧基-乙基)-氨基]-1-氧代-2-丁烯-1-基}氨基)-7-[(四氢呋喃-2-基)甲氧基]-喹唑啉
●4-[(3-乙炔基-苯基)氨基]-6-{[4-(5,5-二甲基-2-氧代-吗啉-4-基)-1-氧代-2-丁烯-1-基]氨基}-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-[2-(2,2-二甲基-6-氧代-吗啉-4-基)-乙氧基]-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-[2-(2,2-二甲基-6-氧代-吗啉-4-基)-乙氧基]-7-[(R)-(四氢呋喃-2-基)甲氧基]-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-7-[2-(2,2-二甲基-6-氧代-吗啉-4-基)-乙氧基]-6-[(S)-(四氢呋喃-2-基)甲氧基]-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{2-[4-(2-氧代-吗啉-4-基)-哌啶-1-基]-乙氧基}-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-[1-(叔丁基氧基羰基)-哌啶-4-基氧基]-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(反-4-氨基-环己-1-基氧基)-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(反-4-甲磺酰基氨基-环己-1-基氧基)-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(四氢吡喃-3-基氧基)-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(1-甲基-哌啶-4-基氧基)-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(吗啉-4-基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(甲氧基甲基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(哌啶-3-基氧基)-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-[1-(2-乙酰基氨基-乙基)-哌啶-4-基氧基]-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(四氢吡喃-4-基氧基)-7-乙氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-((S)-四氢呋喃-3-基氧基)-7-羟基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(四氢吡喃-4-基氧基)-7-(2-甲氧基-乙氧基)-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{反-4-[(二甲基氨基)磺酰基胺]-环己-1-基氧}-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{反-4-[(吗啉-4-基)羰基氨基]-环己-1-基氧基}-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{反-4-[(吗啉-4-基)磺酰基氨基]-环己-1-基氧基}-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(四氢吡喃-4-基氧基)-7-(2-乙酰基氨基-乙氧基)-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(四氢吡喃-4-基氧基)-7-(2-甲磺酰基氨基-乙氧基)-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(哌啶-1-基)羰基]-哌啶-4-基氧}-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(1-氨基羰基甲基-哌啶-4-基氧基)-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(顺-4-{N-[(四氢吡喃-4-基)羰基]-N-甲基-氨基}-环己-1-基氧基)-7-甲氧基喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(顺-4-{N-[(吗啉-4-基)羰基]-N-甲基-氨基}-环己-1-基氧基)-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(顺-4-{N-[(吗啉-4-基)磺酰基]-N-甲基-氨基}-环己-1-基氧基)-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(反-4-乙磺酰基氨基-环己-1-基氧基)-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(1-甲磺酰基-哌啶-4-基氧基)-7-乙氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(1-甲磺酰基-哌啶-4-基氧基)-7-(2-甲氧基-乙氧基)-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-[1-(2-甲氧基-乙酰基)-哌啶-4-基氧基]-7-(2-甲氧基-乙氧基)-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(顺-4-乙酰基氨基-环己-1-基氧基)-7-甲氧基-喹唑啉
●4-[(3-乙炔基-苯基)氨基]-6-[1-(叔丁基氧基羰基)-哌啶-4-基氧基]-7-甲氧基-喹唑啉
●4-[(3-乙炔基-苯基)氨基]-6-(四氢吡喃-4-基氧基]-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(顺-4-{N-[(哌啶-1-基)羰基]-N-甲基-氨基}-环己-1-基氧基)-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(顺-4-{N-[(4-甲基-哌嗪-1-基)羰基]-N-甲基-氨基}-环己-1-基氧基)-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{顺-4-[(吗啉-4-基)羰基氨基]-环己-1-基氧}-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{1-[2-(2-氧代吡咯烷-1-基)乙基]-哌啶-4-基氧}-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(吗啉-4-基)羰基]-哌啶-4-基氧}-7-(2-甲氧基-乙氧基)-喹唑啉
●4-[(3-乙炔基-苯基)氨基]-6-(1-乙酰基-哌啶-4-基氧基)-7-甲氧基-喹唑啉
●4-[(3-乙炔基-苯基)氨基]-6-(1-甲基-哌啶-4-基氧基)-7-甲氧基-喹唑啉
●4-[(3-乙炔基-苯基)氨基]-6-(1-甲磺酰基-哌啶-4-基氧基)-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(1-甲基-哌啶-4-基氧基)-7(2-甲氧基-乙氧基)-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(1-异丙基氧基羰基-哌啶-4-基氧基)-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(顺-4-甲基氨基-环己-1-基氧基)-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{顺-4-[N-(2-甲氧基-乙酰基)-N-甲基-氨基]-环己-1-基氧基}-7-甲氧基-喹唑啉
●4-[(3-乙炔基-苯基)氨基]-6-(哌啶-4-基氧基)-7-甲氧基-喹唑啉
●4-[(3-乙炔基-苯基)氨基]-6-[1-(2-甲氧基-乙酰基)-哌啶-4-基氧基]-7-甲氧基-喹唑啉
●4-[(3-乙炔基-苯基)氨基]-6-{1-[(吗啉-4-基)羰基]-哌啶-4-基氧}-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(顺-2,6-二甲基-吗啉-4-基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(2-甲基-吗啉-4-基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(S,S)-(2-氧杂-5-氮杂-二环[2.2.1]庚-5-基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(N-甲基-N-2-甲氧基乙基-氨基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(1-乙基-哌啶-4-基氧基)-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(2-甲氧基乙基)羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-{1-[(3-甲氧基丙基-氨基)-羰基]-哌啶-4-基氧基}-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-[顺-4-(N-甲磺酰基-N-甲基-氨基)-环己-1-基氧基]-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-[顺-4-(N-乙酰基-N-甲基-氨基)-环己-1-基氧基]-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(反-4-甲基氨-环己-1-基氧基)-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-[反-4-(N-甲磺酰基-N-甲基-氨基)-环己-1-基氧基]-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(反-4-二甲基氨基-环己-1-基氧基)-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(反-4-{N-[(吗啉-4-基)羰基]-N-甲基-氨基}-环己-1-基氧基)-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-[2-(2,2-二甲基-6-氧代-吗啉-4-基)-乙氧基]-7-[(S)-(四氢呋喃-2-基)甲氧基]-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(1-甲磺酰基-哌啶-4-基氧基)-7-甲氧基-喹唑啉
●4-[(3-氯-4-氟-苯基)氨基]-6-(1-氰基-哌啶-4-基氧基)-7-甲氧基-喹唑啉,
任选以外消旋体形式、对映异构体、非对映异构体或药用盐、溶剂合物或水合物。优选为盐,其选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸氢盐、磷酸氢盐、甲烷磺酸氢盐、硝酸氢盐、马来酸氢盐、乙酸氢盐、柠檬酸氢盐、富马酸氢盐、酒石酸氢盐、草酸氢盐、琥珀酸氢盐、苯甲酸氢盐及对甲苯磺酸氢盐。
可提及的多巴胺拮抗剂的优选实例包括溴麦角环肽(Bromocriptine)、卡麦角林(Cabergoline)、α-二氢麦角隐亭(Alpha-Dihydroergocryptine)、麦角乙脲(Lisuride)、培高利特(Pergolide)、普拉克索(Pramipexol)、洛克星多(Roxindol)、罗匹尼罗(Ropinirol)、他利克索(Talipexol)、特麦角脲(Terguride)和维尔松(Viozan),任选以外消旋体形式、对映异构体、非对映异构体或药用盐、溶剂合物或水合物。
优选为盐,其选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸氢盐、磷酸氢盐、甲烷磺酸氢盐、硝酸氢盐、马来酸氢盐、乙酸氢盐、柠檬酸氢盐、富马酸氢盐、酒石酸氢盐、草酸氢盐、琥珀酸氢盐、苯甲酸氢盐及对甲苯磺酸氢盐。
可提及的抗过敏性试剂的优选实例包括依匹斯汀(Epinastine)、西替利嗪(Cetirizine)、氮斯汀(Azelastine)、非索非那定(Fexofenadine)、左卡巴斯汀(Levocabastine)、氯雷他定(Loratadine)、咪唑斯汀(Mizolastine)、酮替芬(Ketotifen)、依美斯汀(Emedastine)、扑尔敏(Dimetinden)、氯马斯汀(Clemastine)、巴米品(Bamipin)、右氯苯那敏(Cexchlorpheniramine)、非尼拉敏(Pheniramine)、多西拉敏(Doxylamine)、氯苯沙明(Chlorophenoxamine)、茶苯海明(Dimenhydrinate)、苯海拉明(Diphenhydramine)、普敏太定(Promethazine)、依巴斯汀(Ebastine)、奥洛他定(Olopatadine)、地氯雷他定(Desloratidine)和美克洛嗪(Meclozine),任选以外消旋体形式、对映异构体、非对映异构体或药用盐、溶剂合物或水合物。
优选为盐,其选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸氢盐、磷酸氢盐、甲烷磺酸氢盐、硝酸氢盐、马来酸氢盐、乙酸氢盐、柠檬酸氢盐、富马酸氢盐、酒石酸氢盐、草酸氢盐、琥珀酸氢盐、苯甲酸氢盐及对甲苯磺酸氢盐。
可提及的PAF拮抗剂的优选实例包括来昔帕泛(Lexipafant)和
●4-(2-氯苯基)-9-甲基-2-[3(4-吗啉基)-3-丙酮-1-基]-6H-噻吩并-[3,2-f]-[1,2,4]三唑并[4,3-a][1,4]二氮杂
●6-(2-氯苯基)-8,9-二氢-1-甲基-8-[(4-吗啉基)羰基]-4H,7H-环-戊二烯并-[4,5]噻吩并-[3,2-f][1,2,4]三唑并[4,3-a][1,4]二氮杂
任选以外消旋体形式、对映异构体、非对映异构体或药用盐、溶剂合物或水合物。优选为盐,其选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸氢盐、磷酸氢盐、甲烷磺酸氢盐、硝酸氢盐、马来酸氢盐、乙酸氢盐、柠檬酸氢盐、富马酸氢盐、酒石酸氢盐、草酸氢盐、琥珀酸氢盐、苯甲酸氢盐及对甲苯磺酸氢盐。
可提及的MAP激酶抑制剂的优选实例包括
●苯塔马比莫(Bentamapimod,AS-602801)
●达马莫德(Doramapimod,BIRB-796),
●5-氨基甲酰基吲哚(SD-169),
●6-[(氨基羰基)(2,6-二氟苯基)氨基]-2-(2,4-二氟苯基)-3-吡啶甲酰胺(VX-702),
●α-[2-[[2-(3-吡啶基)乙基]氨基]-4-嘧啶基]-2-苯并噻唑乙腈(AS-601245),
●9,12-环氧-1H-二吲哚并[1,2,3-fg:3',2',1'-kl]吡咯并[3,4-i][1,6]苯并二氮杂环辛四烯-10-羧酸(CEP-1347),
●4-[3-(4-氯苯基)-5-(1-甲基-4-哌啶基)-1H-吡唑-4-基]-嘧啶(SC-409),
任选以外消旋体形式、对映异构体、非对映异构体或药用盐、溶剂合物或水合物。优选为盐,其选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸氢盐、磷酸氢盐、甲烷磺酸氢盐、硝酸氢盐、马来酸氢盐、乙酸氢盐、柠檬酸氢盐、富马酸氢盐、酒石酸氢盐、草酸氢盐、琥珀酸氢盐、苯甲酸氢盐及对甲苯磺酸氢盐。
可提及的MRP4抑制剂的优选实例包括N-乙酰基-二硝基苯基-半胱胺酸、cGMP、胆酸盐、双氯芬酸、3-葡糖苷酸脱氢表雄固酮、3-硫酸脱氢表雄固酮、地拉齐普(Dilazep)、二硝苯基-s-谷胱甘肽、17-β-葡糖苷酸雌二醇、3,17-硫酸氢雌二醇、3-葡糖苷酸雌二醇、3-硫酸雌二醇、3-硫酸雌酮、氟吡洛芬、叶酸、N5-甲酰基-四氢叶酸、甘胆酸盐、葡糖石胆酸硫酸盐、布洛芬、吲哚美辛、吲哚洛芬、酮洛芬、石胆酸硫酸盐、甲胺喋呤、((E)-3-[[[3-[2-(7-氯-2-喹啉基)乙烯基]苯基]-[[(3-二甲基胺基)-3-氧代丙基]硫基]甲基]硫基]-丙酸)、α-萘基-β-D-葡糖苷酸、硝基苄基巯基嘌呤核糖苷、丙磺舒(Probenecid)、伐司朴达(Valspodar)、西地那非(Sildenafil)、磺吡酮(Sulfinpyrazone)、牛磺鹅脱氧胆酸酯、牛胆酸酯(Taurocholate)、牛磺脱氧胆酸酯、牛磺石胆酸酯、牛磺石胆酸硫酸盐、拓扑替康(Topotecan)、曲喹辛(Trequinsin)和扎普司特(Zaprinast)、待匹力达(Dipyridamole),任选以外消旋体形式、对映异构体、非对映异构体或药用盐、溶剂合物或水合物。
优选为盐,其选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸氢盐、磷酸氢盐、甲烷磺酸氢盐、硝酸氢盐、马来酸氢盐、乙酸氢盐、柠檬酸氢盐、富马酸氢盐、酒石酸氢盐、草酸氢盐、琥珀酸氢盐、苯甲酸氢盐及对甲苯磺酸氢盐。
可提及的iNOS-抑制剂的优选实例包括S-(2-氨基乙基)异硫脲、氨基胍、2-氨基甲基吡啶、5,6-二氢-6-甲基-4H-1,3-噻嗪-2-胺(AMT)、L-刀豆胺酸、2-亚氨基哌啶、S-异丙基异硫脲、S-甲基异硫脲、S-乙基异硫脲、S-甲硫基瓜氨酸、S-乙硫基瓜氨酸、L-NA(Nω-硝基-L-精氨酸)、L-NAME(Nω-硝基-L-精氨酸甲酯)、L-NMMA(Nω-单甲基-L-精氨酸)、L-NIO(Nω-亚氨基乙基-L-鸟氨酸)、L-NIL(Nω-亚氨基乙基-赖氨酸)、(S)-6-乙酰亚氨酰基氨基-2-氨基-己酸(1H-四唑-5-基)-酰胺、N-[[3-(氨基甲基)苯基]甲基]-乙醚、(S)-4-(2-乙酰亚氨酰基氨基-乙基硫基)-2-氨基-丁酸、2-[2-(4-甲氧基-吡啶-2-基)-乙基]-3H-咪唑并[4,5-b]吡啶、2-((R)-3-氨基-1-苯基-丙氧基)-4-氯-5-氟苯甲腈、2-((1R,3S)-3-氨基-4-羟基-1-噻唑-5-基-丁基硫基)-6-三氟甲基-烟碱腈、2-((1R,3S)-3-氨基-4-羟基-1-噻唑-5-基-丁基硫基)-4-氯-苯甲腈、2-((1R,3S)-3-氨基-4-羟基-1-噻唑-5-基-丁基硫基)-5-氯-苯甲腈、(2S,4R)-2-氨基-4-(2-氯-5-三氟甲基-苯基硫基)-4-噻唑-5-基-丁-1-醇、2-((1R,3S)-3-氨基-4-羟基-1-噻唑-5-基-丁基硫基)-5-氯-烟碱腈、4-((S)-3-氨基-4-羟基-1-苯基-丁基硫基)-6-甲氧基-烟碱腈和取代的3-苯基-3,4-二氢-1-异喹啉胺如(1S,5S,6R)-7-氯-5-甲基-2-氮杂-二环[4.1.0]庚-2-烯-3-基胺、(4R,5R)-5-乙基-4-甲基-噻唑烷-2-亚基胺、(1S,5S,6R)-7-氯-5-甲基-2-氮杂-二环[4.1.0]庚-2-烯-3-基胺、(4R,5R)-5-乙基-4-甲基-噻唑烷-2-亚基胺、(4R,5R)-5-乙基-4-甲基-硒唑啶-2-亚基胺、4-氨基四氢生物蝶呤、(E)-3-(4-氯-苯基)-N-(1-{2-氧代-2-[4-(6-三氟甲基-嘧啶-4-基氧基)-哌啶-1-基]-乙基氨基甲酰基}-2-吡啶-2-基-乙基)-丙烯酰胺、3-(2,4-二氟-苯基)-6-[2-(4-咪唑-1-基甲基-苯氧基)-乙氧基]-2-苯基-吡啶、3-{[(苯并[1,3]间二氧杂环戊烯-5-基甲基)-氨基甲酰基]-甲基}-4-(2-咪唑-1-基-嘧啶-4-基)-哌嗪-1-碳酸甲酯、(R)-1-(2-咪唑-1-基-6-甲基-嘧啶-4-基)-吡咯烷-2-碳酸(2-苯并[1,3]二氧代-5-基-乙基)-酰胺,任选以外消旋体形式、对映异构体、非对映异构体或药用盐、溶剂合物或水合物。优选为盐,其选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸氢盐、磷酸氢盐、甲烷磺酸氢盐、硝酸氢盐、马来酸氢盐、乙酸氢盐、柠檬酸氢盐、富马酸氢盐、酒石酸氢盐、草酸氢盐、琥珀酸氢盐、苯甲酸氢盐及对甲苯磺酸氢盐。
可提及的iNOS-抑制剂的优选实例包括反义寡核苷酸,具体是结合iNOS编码核酸的这些反义寡核苷酸,实例公开于WO 01/52902中。
可提及的SYK-抑制剂的优选实例包括
●2-[(2-氨基乙基)氨基]-4-[(3-溴苯基)氨基]-5-嘧啶甲酰胺;
●2-[[7-(3,4-二甲氧基苯基)咪唑并[1,2-c]嘧啶-5-基]氨基]-3-吡啶甲酰胺;
●6-[[5-氟-2-[3,4,5-三甲氧基苯基)氨基]-4-嘧啶基]氨基]-2,2-二甲基-2H-吡啶并[3,2-b]-1,4-嗪-3(4H)-酮;
●N-[3-溴-7-(4-甲氧基苯基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●7-(4-甲氧基苯基)-N-甲基-1,6-二氮杂萘-5-胺;
●N-[7-(4-甲氧基苯基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-(2-噻吩基)-1,6-二氮杂萘-5-基-1,3-丙二胺;
●N-[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]-1,2-乙二胺;
●N-[7-(4-甲氧基苯基)-2-(三氟甲基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-(4-甲氧基苯基)-3-苯基-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-(7-苯基-1,6-二氮杂萘-5-基)-1,3-丙二胺;
●N-[7-(3-氟苯基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-(3-氯苯基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-[3-(三氟甲氧基)苯基]-1,6-二氮杂萘-5基]-1,3-丙二胺;
●N-[7-(4-氟苯基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-(4-氟苯基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-(4-氯苯基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-(4'-甲基[1,1'-联苯]-4-基)-1,6-二氮杂萘-1,3-丙二胺;
●N-[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-[4-(二乙基氨基)苯基]-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-[4-(4-吗啉基)苯基]-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-[4-[[2-(二甲基氨基)乙基]甲基氨基]苯基]-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-(4-溴苯基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-(4-甲基苯基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-[4-(甲基硫基)苯基]-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-[4-(1-甲基乙基)苯基]-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●7-[4-(二甲基氨基)苯基]-N-甲基-1,6-二氮杂萘-5-胺;
●7-[4-(二甲基氨基)苯基]-N,N-二甲基-1,6-二氮杂萘-5-胺;
●N-[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]-1,4-丁二胺;
●N-[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]-1,5-戊二胺;
●3-[[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]氧基]-1-丙醇;
●4-[5-(4-氨基丁氧基)-1,6-二氮杂萘-7-基]-N,N-二甲基-苯胺;
●4-[[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]氨基]-1-丁醇;
●N-[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]-N-甲基-1,3-丙二胺;
●N-[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]-N'-甲基-1,3-丙二胺;
●N-[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]-N,N'-二甲基-1,3-丙二胺;
●1-氨基-3-[[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]氨基]-2-丙醇;
●N-[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]-2,2-二甲基-1,3-丙二胺;
●7-[4-(二甲基氨基)苯基]-N-(3-吡啶基甲基)-1,6-二氮杂萘-5-胺;
●N-[(2-氨基苯基)甲基]-7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-胺;
●N-[7-[6-(二甲基氨基)[1,1'-联苯]-3-基]-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-[3-氯-4-(二乙基氨基)苯基]-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-[4-(二甲基氨基)-3-甲氧基苯基]-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-[4-(二乙基氨基)苯基]-3-甲基-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-(3'-氟[1,1'-联苯]-3-基)-1,6-二氮杂萘-5-基]-1,2-乙二胺,
●N-[7-(4-甲氧基苯基)-1,6-二氮杂萘-5-基]-1,6-二氮杂萘-1,3-丙二胺;
●N,N'-二(3-氨基丙基)-7-(4-甲氧基苯基)-2,5-二胺;
●N-[7-(4-甲氧基苯基)-2-(苯基甲氧基)-1,6-二氮杂萘-5-基]-1,6-二氮杂萘-1,3-丙二胺;
●N5-(3-氨基丙基)-7-(4-甲氧基苯基)-N2-(苯基甲基)-2,5-二胺;
●N-[7-(2-萘基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-(2'-氟[1,1'-联苯]-4-基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-(3,4,5-三甲氧基苯基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-(3,4-二甲基苯基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●1-氨基-3-[[7-(2-萘基)-1,6-二氮杂萘-5-基]氨基]-2-丙醇;
●1-氨基-3-[[7-(2'-氟[1,1'-联苯]-4-基)-1,6-二氮杂萘-5-基]氨基]-2-丙醇;
●1-氨基-3-[[7-(4'-甲氧基[1,1'-联苯]-4-基)-1,6-二氮杂萘-5-基]氨基]-2-丙醇;
●1-氨基-3-[[7-(3,4,5-三甲氧基苯基)-1,6-二氮杂萘-5-基]氨基]-2-丙醇;
●1-氨基-3-[[7-(4-溴苯基)-1,6-二氮杂萘-5-基]氨基]-2-丙醇;
●N-[7-(4'-甲氧[1,1'-联苯]-4-基)-1,6-二氮杂萘-5-基]-2,2-二甲基-1,3-丙二胺;
●1-[[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]氨基]-2-丙醇;
●2-[[2-[[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]氨基]乙基]硫基]-乙醇;
●7-[4-(二甲基氨基)苯基]-N-(3-甲基-5-异唑基)-1,6-二氮杂萘-5-胺;
●7-[4-(二甲基氨基)苯基]-N-4-嘧啶基-1,6-二氮杂萘-5-胺;
●N-[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]-1,3-环己二胺;
●N,N-二甲基-4-[5-(1-哌嗪基)-1,6-二氮杂萘-7-基]-苯胺;
●4-[5-(2-甲氧基乙氧基)-1,6-二氮杂萘-7-基]-N,N-二甲基-苯胺;
●1-[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]-4-哌啶醇;
●1-[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]-3-吡咯烷酮;
●7-[4-(二甲基氨基)苯基]-N-(2-呋喃基甲基)-1,6-二氮杂萘-5-胺;
●7-[4-(二甲基氨基)苯基]-N-[3-(1H-咪唑-1-基)丙基]-1,6-二氮杂萘-5-胺;
●1-[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]-4-哌啶甲酰胺;
●1-[3-[[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]氨基]丙基]-2-吡咯烷酮;
●N-[3'-[5-[(3-氨基丙基)氨基]-1,6-二氮杂萘-7-基][1,1'-联苯]-3-基]-乙酰胺;
●N-[7-(4'-氟[1,1'-联苯]-4-基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[4'-[5-[(3-氨基丙基)氨基]-1,6-二氮杂萘-7-基][1,1'-联苯]-3-基]-乙酰胺;
●N-[7-[4-(1,3-苯并间二氧杂环戊烯-5-基)苯基]-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-[4-(2-噻吩基)苯基]-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-[4-氟-3-(三氟甲基)苯基]-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-[4-(3-吡啶基)苯基]-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-(1,3-苯并间二氧杂环戊烯-5-基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-(6-甲氧基-2-萘基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●7-[4-(二甲基氨基)苯基]-N-(4-吡啶基甲基)-1,6-二氮杂萘-5-胺;
●3-[[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]甲基氨基]-丙腈;
●7-[4-(二甲基氨基)苯基]-N-[1-(苯基甲基)-4-哌啶基]-1,6-二氮杂萘-5-胺;
●N-[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]-1,2-环己二胺,
●N-[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]-1,2-环己二胺,(1R,2S)-rel-.
●N-[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]-1,2-苯二甲胺;
●N-[7-[4-(二乙基氨基)苯基]-1,6-二氮杂萘-5-基]-1,4-丁二胺;
●N-[7-[3',5'-二(三氟甲基)[1,1'-联苯]-4-基]-1,6-二氮杂萘-5-基]-,3-丙二胺;
●N-[7-(3'-甲氧基[1,1'-联苯]-4-基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-(3'-氟[1,1'-联苯]-4-基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●4-[[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]氧基]-1-丁醇;
●N-[7-[4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]-1,4-环己二胺;
●7-[4-(二甲基氨基)苯基]-N-(2,2,6,6-四甲基-4-哌啶基)-1,6-二氮杂萘-5-胺;
●N-[7-[3-溴-4-(二甲基氨基)苯基]-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-(1-甲基-1H-吲哚-5-基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-[3-(三氟甲基)苯基]-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-[4-(三氟甲基)苯基]-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-(3-溴-4-甲氧基苯基)-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N-[7-[4-[[3-(二甲基氨基)丙基]甲基氨基]苯基]-1,6-二氮杂萘-5-基]-1,4-环己二胺;
●N-[7-[4-[[2-(二甲基氨基)乙基]甲基氨基]苯基]-1,6-二氮杂萘-5-基]-1,4-环己二胺;
●N-[7-[4-(二甲基氨基)-3-甲氧基苯基]-1,6-二氮杂萘-5-基]-1,4-环己二胺;
●N-[7-[4-(4-吗啉基)苯基]-1,6-二氮杂萘-5-基]-1,4-环己二胺;
●N-[7-[3-溴-4-(4-吗啉基)苯基]-1,6-二氮杂萘-5-基]-1,4-环己二胺;
●4-[[7-[4-[[2-(二甲基氨基)乙基]甲基氨基]苯基]-1,6-二氮杂萘-5-基]氧基]-环己醇;
●N-[7-[3-溴-4-(4-吗啉基)苯基]-1,6-二氮杂萘-5-基]-1,3-丙二胺;
●N,N-二甲基-4-[5-(4-甲基-1-哌嗪基)-1,6-二氮杂萘-7-基]-苯胺;
●4-[[7-[4-[[3-(二甲基氨基)丙基]甲基氨基]苯基]-1,6-二氮杂萘-5-基]氧基]-环己醇;
●N-[7-[4-[[2-(二甲基氨基)乙基]甲基氨基]苯基]-1,6-二氮杂萘-5-基]-1,4-丁二胺;
●[3-[[5-[(3-氨基丙基)氨基]-7-(4-甲氧基苯基)-1,6-二氮杂萘-2-基]氨基]丙基]-氨基甲酸-1,1-二甲基乙酯,
任选以外消旋体形式、对映异构体、非对映异构体或药用盐、溶剂合物或水合物。优选为盐,其选自盐酸盐、氢溴酸盐、氢碘酸盐、硫酸氢盐、磷酸氢盐、甲烷磺酸氢盐、硝酸氢盐、马来酸氢盐、乙酸氢盐、柠檬酸氢盐、富马酸氢盐、酒石酸氢盐、草酸氢盐、琥珀酸氢盐、苯甲酸氢盐及对甲苯磺酸氢盐。
可提及的囊性纤维化跨膜调节剂(CFTR)和CFTR增强剂的优选实例包括优选VX-770和VX-809。
制剂
适用于给药的形式例如是可吸入粉末或气雾剂。药学上有效的化合物的含量在各情况下应处于总组合物的0.2到50wt%的范围,优选5到25wt.%,即足以达成下文所指定的剂量范围的量。
当吸入给药时,活性物质组合可以粉末、水溶液或乙醇水液形式或使用推进剂气体制剂来给予。
因此,优选地,药物制剂的特征在于上文优选实施方案的一或多种式(I)化合物的含量。
也优选通过吸入方式给药的式(I)化合物,特别优选为一天给药一或两次。出于此目的,式(I)化合物须制成可适用于吸入的形式使用。可吸入制剂包括可吸入粉末、含推进剂的定剂量气雾剂或不含推进剂的可吸入溶液,其任选与生理学上可接受的常规赋形剂混合存在。
在本发明的范围内,术语“不含推进剂的可吸入溶液”也包括浓缩物或无菌即用型可吸入溶液。在本说明书的下一部分中更详细描述可根据本发明使用的制剂。
可吸入粉末
若式(I)的活性物质与生理学上可接受的赋形剂混合存在,则可使用生理学上可接受的以下赋形剂来制备本发明的可吸入粉末:单糖(例如葡萄糖或阿拉伯糖)、二糖(例如乳糖、蔗糖、麦芽糖)、寡糖及多糖(例如葡聚糖)、多元醇(例如山梨糖醇、甘露醇、木糖醇)、盐(例如氯化钠、碳酸钙)或这些赋形剂彼此的混合物。优选使用单糖或二糖,而特别优选使用乳糖或葡萄糖,但非仅为其水合物形式。出于本发明的目的,乳糖为特别优选的赋形剂,而最优选乳糖单水合物。用已知的现有技术通过研磨及微粉化且最终将各组份混合在一起来制备可吸入粉末的方法。
含有推进剂的可吸入气雾剂
本发明可使用的含有推进剂的可吸入气雾剂可含有溶解在推进剂气体中或呈分散形式的式(I)化合物。已知的现有技术可用于制备本发明的吸入气雾剂的推进剂气体。合适推进剂气体选自烃(例如正丙烷、正丁烷或异丁烷)和卤代烃(例如优选为甲烷、乙烷、丙烷、丁烷、环丙烷或环丁烷的氟化衍生物)。上述推进剂气体可独立或以其混合物的形式使用。特别优选的推进剂气体为选自TG134a(1,1,1,2-四氟乙烷)、TG227(1,1,1,2,3,3,3-七氟丙烷)及其混合物的氟化烷烃衍生物。在本发明的用途范围内所使用的推进剂驱动吸入气雾剂也可含有其它成份,例如共溶剂、稳定剂、表面活性剂、抗氧化剂、润滑剂和pH值调节剂。所有这些成份在此项技术中均为已知的。
不含推进剂的可吸入溶液
本发明的式(I)化合物优选用于制备不含推进剂的可吸入溶液及可吸入混悬液。用于该目的的溶剂包括水溶液或醇溶液,优选为乙醇溶液。溶剂可仅为水或水与乙醇的混合物。可使用合适酸将溶液或混悬液调节至pH值为2至7,优选为2至5。pH值可使用选自无机酸或有机酸来调节。特别适合的无机酸的实例包括盐酸、氢溴酸、硝酸、硫酸和/或磷酸。特别适合的有机酸的实例包括抗坏血酸、柠檬酸、苹果酸、酒石酸、马来酸、琥珀酸、富马酸、乙酸、甲酸及/或丙酸等。优选无机酸为盐酸和硫酸。也有可能使用已与一种活性物质形成酸加成盐的酸。在有机酸中,优选抗坏血酸、富马酸及柠檬酸。必要时,也可使用以上酸的混合物,特别在酸(例如柠檬酸或抗坏血酸)具有除其酸化性质之外的其它性质(例如作为调味剂、抗氧化剂或络合剂)的情况下。根据本发明,特别优选使用盐酸调节pH值。
可将共溶剂和/或其它赋形剂加入于用于本发明目的的不含推进剂的可吸入溶液中。优选共溶剂为含有羟基或其它极性基团的共溶剂,例如醇,特别是异丙醇;乙二醇,特别是丙二醇、聚乙二醇、聚丙二醇、乙二醇醚、甘油、聚氧乙烯醇及聚氧乙烯脂肪酸酯。上下文中的术语赋形剂及添加剂表示并非活性物质的任何药理学上可接受的物质,但其可在药理学上适合的溶剂中与活性物质调配以改良活性物质制剂的定性性质。优选地,这些物质不具有药理学效应,或者,就所需疗效而言,无可察觉的药理学作用或至少无不需要的药理学作用。赋形剂和添加剂包括例如表面活性剂(例如大豆卵磷脂)、油酸、脱水山梨糖醇酯(例如聚山梨醇酯)、聚乙烯吡咯烷酮、其它稳定剂、络合剂、抗氧化剂和/或防腐剂(其确保或延长成品药物制剂的存放期)、调味剂、维生素和/或本领域已知的其它添加剂。添加剂也包括药理学上可接受的盐,例如作为等渗剂的氯化钠。例如,优选赋形剂包括例如抗坏血酸的抗氧化剂(限制条件为其尚未用于调节pH值)、维生素A、维生素E、生育酚及在人体内产生的原维生素或类似维生素。防腐剂可用于保护所述制剂免受病原体污染。适合的防腐剂为本领域已知的防腐剂,特别是氯化十六烷基吡啶、氯苄烷铵或苯甲酸或苯甲酸盐(例如现有技术已知浓度的苯甲酸钠)。
对于上述治疗形式,提供了用于治疗呼吸病症的即用型药包,含有包括例如呼吸道疾病、COPD或哮喘等字的所附说明书,以及本发明化合物和选自上述化合物的一或多种组合搭配物。
下述实施例示例说明本发明而没有限制其范围:
粉末吸入胶囊
1个胶囊含有:
活性物质 0.5mg
可吸入乳糖 5.0mg
5.5mg
制备:
活性物质与乳糖混合以用于吸入。以胶囊制备机器将混合物装入胶囊(空胶囊重量约50mg)。
胶囊重量:55.5mg
胶囊尺寸:=3。
Claims (18)
1.式(IA)化合物和其药用酸加成盐,
其中:
A表示化学键、-CH2-、-CH2CH2-或-CH2CH2CH2-,
R1选自氢、C1-6-烷基、C1-4-烷基-SO2-、C1-4-烷基-NH-CO-、H2N-CO-、H2N-C1-4-烷基-、H2N-C1-4-烷基-CO-、H2N-C1-4-烷基-NH-CO-、苯基-CO-、苯基-CH2-CO-、苯基-CH2-、C1-6-烷基-CO-、C1-6-烷基-O-C1-4-烷基-CO-、(CH3)2N-C1-4-烷基-、(CH3)2N-C1-4-烷基-NH-CO-、(CH3)3N+-C1-4-烷基-NH-CO-、(CH3)3N+-C1-4-烷基-N(C1-4-烷基)-CO-、(CH3)3N+-C2-4-烷基-、(CH3)3N+-C1-4-烷基-CO-、H2N-C(NH)-NH-C1-6-烷基-NH-CO-、C1-6-烷基-O-CO-、C1-6-烷基-O-CO-C1-4-烷基-、C1-6-烷基-O-CO-C1-4-烷基-CO-、C1-6-烷基-O-CO-C1-4-烷基-NH-CO-、C1-6-烷基-O-CO-NH-C1-4-烷基-、C1-6-烷基-O-CO-NH-C1-4-烷基-CO-、C1-6-烷基-O-CO-NH-C1-4-烷基-NH-CO-、HOCO-C1-4-烷基-、HOCO-C1-4-烷基-CO-、HOCO-C1-4-烷基-NH-CO-、H2N-CNH-和H2NC(NH)NH-C1-6-烷基-CO-,或选自下述式(c1)到(c5)的基团:
R2、R3、R4、R6、R7彼此独立地表示氢、卤素、C1-4-烷基、C1-3-烷基-O-或C1-3-烷基-OCO-。
2.根据权利要求1所述的化合物和其药用酸加成盐,其中:
A表示-CH2CH2-。
3.根据权利要求1或2的化合物或其药用酸加成盐,其中:
R1表示氢或选自C1-6-烷基、C1-4-烷基-SO2-、C1-4-烷基-NH-CO-、H2N-CO-、H2N-C1-4-烷基-、H2N-C1-4-烷基-CO-、H2N-C1-4-烷基-NH-CO-、苯基-CO-、苯基-CH2-CO-、苯基-CH2-、C1-6-烷基-CO-、C1-6-烷基-O-C1-4-烷基-CO-、(CH3)2N-C1-4-烷基-、(CH3)2N-C1-4-烷基-NH-CO-、(CH3)3N+-C1-4-烷基-NH-CO-、(CH3)3N+-C2-4-烷基-、(CH3)3N+-C1-4-烷基-CO-、H2N-C(NH)-NH-C1-6-烷基-NH-CO-、C1-6-烷基-O-CO-、C1-6-烷基-O-CO-C1-4-烷基-、C1-6-烷基-O-CO-C1-4-烷基-CO-、C1-6-烷基-O-CO-C1-4-烷基-NH-CO-、C1-6-烷基-O-CO-NH-C1-4-烷基-、C1-6-烷基-O-CO-NH-C1-4-烷基-CO-、C1-6-烷基-O-CO-NH-C1-4-烷基-NH-CO-、HOCO-C1-4-烷基-、HOCO-C1-4-烷基-CO-、HOCO-C1-4-烷基-NH-CO-和H2N-CNH-。
4.根据权利要求1或2的化合物或其药用酸加成盐,其中:
R1表示氢或选自H2N-C1-4-烷基-CO-、苯基-CH2-CO-、(CH3)3N+-C1-4-烷基-NH-CO-、(CH3)3N+-C1-4-烷基-CO-、C1-6-烷基-O-CO-、HOCO-C1-4-烷基-。
5.根据权利要求1或2的化合物或其药用酸加成盐,其中R1选自下述式(c1)到(c5)的基团:
6.根据权利要求1或2的化合物或其药用酸加成盐,其中R1选自下述式(c1)和(c4)的基团:
7.根据权利要求1或2的化合物或其药用酸加成盐,其中R1为:
8.根据权利要求1或2的化合物或其药用酸加成盐,其中
R3表示H或CH3OCO-,
R6和R7彼此独立地表示H或CH3O-,
R2和R4表示H。
9.根据权利要求1的化合物或其药用酸加成盐,其中
R2、R3、R4、R6、R7表示氢。
10.权利要求1-9中任一项所述的化合物或其药用盐在制备药物中的用途,所述药物用于治疗选自呼吸道疾病或症状和气道变应性疾病的疾病。
11.权利要求1-9中任一项所述的化合物或其药用盐在制备药物中的用途,所述药物用于治疗选自以下的疾病:慢性支气管炎、急性支气管炎、过敏性支气管炎、中毒性支气管炎、哮喘、支气管扩张、过敏或非过敏性鼻炎、慢性窦炎、囊性纤维化或粘液粘稠病、α-1-抗胰蛋白酶缺乏、肺气肿、间质性肺疾病、肺泡炎、高反应性气道、鼻息肉、肺水肿、肺炎。
12.权利要求1-9中任一项所述的化合物或其药用盐在制备药物中的用途,所述药物用于治疗选自以下的疾病:过敏性肺泡炎,以及细菌或病毒感染或真菌或蠕虫引起的支气管炎。
13.权利要求1-9中任一项所述的化合物或其药用盐在制备药物中的用途,所述药物用于治疗咳嗽。
14.权利要求11的用途,其中所述哮喘为内因性或过敏性哮喘。
15.权利要求11的用途,其中所述哮喘为小儿哮喘。
16.权利要求11的用途,其中所述慢性支气管炎为慢性阻塞性支气管炎(COPD)。
17.药物组合物,其包含至少一种权利要求1-9中任一项所述的化合物或其药用盐,和药用载体。
18.药物组合,除含有一种或多种权利要求1-9中任一项所述的化合物之外,还含有作为另外的活性物质的一种或多种选自以下类别的化合物:其它ENaC抑制剂类、β模拟药、抗胆碱药、皮质类固醇、PDE4-抑制剂、LTD4-拮抗剂、EGFR-抑制剂、多巴胺激动剂、H1-抗组胺药、PAF-拮抗剂、MAP-激酶抑制剂、MPR4-抑制剂、iNOS-抑制剂、SYK-抑制剂、囊性纤维化跨膜调节蛋白(CFTR)的调节剂和CFTR增强剂或它们的两种或三种的组合。
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GB201808093D0 (en) | 2018-05-18 | 2018-07-04 | Enterprise Therapeutics Ltd | Compounds |
MX2023002850A (es) | 2020-09-10 | 2023-07-07 | Precirix N V | Fragmento de anticuerpo contra proteina activadora de fibroblastos (fap). |
CN112107580A (zh) * | 2020-09-29 | 2020-12-22 | 北京鑫开元医药科技有限公司 | 一种脾酪氨酸激酶抑制剂的制剂组合物及其制备方法 |
WO2023203135A1 (en) | 2022-04-22 | 2023-10-26 | Precirix N.V. | Improved radiolabelled antibody |
WO2023213801A1 (en) | 2022-05-02 | 2023-11-09 | Precirix N.V. | Pre-targeting |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008135557A1 (en) * | 2007-05-07 | 2008-11-13 | Novartis Ag | Organic compounds |
WO2009138378A1 (en) * | 2008-05-13 | 2009-11-19 | Novartis Ag | 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid derivatives and their use as epithelial sodium channel blockers for the treatment of arway diseases |
CN104024244B (zh) * | 2011-11-02 | 2016-09-14 | 勃林格殷格翰国际有限公司 | 杂环化合物、含有所述化合物的药物及其用途和其制备方法 |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL6812003A (zh) | 1967-09-07 | 1969-03-11 | ||
US3953476A (en) | 1971-12-27 | 1976-04-27 | Merck & Co., Inc. | 3-Amino-5-sulfonylbenzoic acids |
US6475509B1 (en) | 1999-07-19 | 2002-11-05 | The University Of North Carolina At Chapel Hill | Covalent conjugates of sodium channel blockers and active compounds |
JP2003520042A (ja) | 2000-01-24 | 2003-07-02 | アイシス・ファーマシューティカルス・インコーポレーテッド | 誘導性一酸化窒素シンターゼ発現のアンチセンスモジュレーション |
JP2008510702A (ja) | 2004-08-18 | 2008-04-10 | マイケル・アール・ジョンソン | 脂肪族アミド及びエステルピラジノイルグアニジンナトリウムチャネル遮断薬 |
GB0526244D0 (en) | 2005-12-22 | 2006-02-01 | Novartis Ag | Organic compounds |
JP2009544313A (ja) * | 2006-07-24 | 2009-12-17 | インターナショナル ステム セル コーポレイション | 網膜幹細胞由来の合成角膜 |
TWI439462B (zh) | 2007-12-10 | 2014-06-01 | Novartis Ag | 作為enac阻抑劑之螺環胍化合物 |
CN102112130A (zh) | 2008-06-10 | 2011-06-29 | 诺瓦提斯公司 | 作为上皮钠通道阻滞剂的吡嗪衍生物 |
US8372845B2 (en) | 2010-09-17 | 2013-02-12 | Novartis Ag | Pyrazine derivatives as enac blockers |
US9050339B2 (en) | 2010-09-17 | 2015-06-09 | Novartis Ag | Pyrazine derivatives as ENaC blockers |
PL2723176T3 (pl) | 2011-06-27 | 2018-01-31 | Parion Sciences Inc | Chemicznie i metabolicznie stabilny dipeptyd o silnej aktywności blokera kanału sodowego |
AR086745A1 (es) | 2011-06-27 | 2014-01-22 | Parion Sciences Inc | 3,5-diamino-6-cloro-n-(n-(4-(4-(2-(hexil(2,3,4,5,6-pentahidroxihexil)amino)etoxi)fenil)butil)carbamimidoil)pirazina-2-carboxamida |
BR112014010462A2 (pt) | 2011-11-02 | 2017-04-18 | Boehringer Ingelheim Int | processo para a preparação de acilguanidinas e acetioureias |
-
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008135557A1 (en) * | 2007-05-07 | 2008-11-13 | Novartis Ag | Organic compounds |
WO2009138378A1 (en) * | 2008-05-13 | 2009-11-19 | Novartis Ag | 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid derivatives and their use as epithelial sodium channel blockers for the treatment of arway diseases |
CN104024244B (zh) * | 2011-11-02 | 2016-09-14 | 勃林格殷格翰国际有限公司 | 杂环化合物、含有所述化合物的药物及其用途和其制备方法 |
Non-Patent Citations (1)
Title |
---|
Design, Synthesis, and Structure-Activity Relationships of Novel 2-Substituted Pyrazinoylguanidine Epithelial Sodium Channel Blockers: Drugs for Cystic Fibrosis and Chronic Bronchitis;Andrew J. Hirsh,et al.;《J. Med. Chem.》;20060613;4098-4115 * |
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