CN1400969A - 稠合的咪唑鎓衍生物 - Google Patents

稠合的咪唑鎓衍生物 Download PDF

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Publication number
CN1400969A
CN1400969A CN01804905A CN01804905A CN1400969A CN 1400969 A CN1400969 A CN 1400969A CN 01804905 A CN01804905 A CN 01804905A CN 01804905 A CN01804905 A CN 01804905A CN 1400969 A CN1400969 A CN 1400969A
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low
substituent
grade alkylidene
groups
methyl
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CN01804905A
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CN100436425C (zh
Inventor
松久彰
木野山功
丰岛启
中原崇人
竹内雅博
冈田稔
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Yamanouchi Pharmaceutical Co Ltd
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Yamanouchi Pharmaceutical Co Ltd
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
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    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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Abstract

本发明涉及用作药物、尤其是治疗癌症的新的稠合的咪唑鎓衍生物和用于制备该衍生物的新的中间体。新的咪唑鎓衍生物与芳族碳环或杂环稠合并以在1和/或3位被携带－ORa、－SRa或其它取代基的烷基取代为特征，该衍生物表现出优良的抗肿瘤活性和低的毒性，因此可用作安全域广的抗癌药。

Description

稠合的咪唑鎓衍生物
技术领域
本发明涉及药物，具体涉及对于治疗癌症有用的新的稠合的咪唑鎓衍生物及其新的合成的中间体化合物。
发明背景
作为具有抗肿瘤活性的与芳环或杂芳环稠合的咪唑鎓衍生物，以前只在Khim.Pharm.Zh.，32(6)，10-11(1998)中公开了具有下式的4，9-二氧代萘并[2，3-d]咪唑鎓化合物(KP-1，KP-3等)。
Figure A0180490500081
(式中，Et和Me分别表示乙基和甲基，下同)。
在J.Med.Chem.，(7)3，362-364(1964)中公开了具有抗菌作用的化合物，在该化合物中，R1和R2均为低级烷基，或一个是低级亚烷基-(可有一个或多个取代基的芳基)而另一个是-CH3，-(CH2)3CH3或苯基，或一个是低级亚烷基-CO-(可有一个或多个取代基的芳基)而另一个是-(CH2)2CH(CH3)2或-(CH2)3CH3，但是没有公开其有抗肿瘤活性。
另外，J.Org.Chem.USSR，1，1479-85(1965)、日本专利公开公报平3-258765和平6-59371等中公开了在下述本发明通式(I)中R1和R2均为低级烷基的4，9-二氧代萘并[2，3-d]咪唑鎓衍生物。然而，却没有公开这些化合物的药物用途。
英国专利1314881中公开了用作除草剂的1，4-二氢-1，4-二氧代萘衍生物，日本特许特公昭54-25085中公开了用作除草剂的异喹啉-5，8-二酮衍生物。另外，在Zh.Org.Khim.，22(8)，1736-42(1986)、J.Gen.Chem.USSR，36，649-652(1966)和试剂目录[SigmaAldrich Library of Rare Chemicals Structure Index(Aldrich Chemical Company，Inc.)等中，几个1，4-二氢-1，4-二氧代萘衍生物是公知的。然而，所有这些文献均没有公开这些化合物的药物用途。
WO 97/30022，J.Med.Chem.，39，1447-1451(1996)和J.Med.Chem.，7(3)，362-364(1964)中公开了与芳环稠合的咪唑衍生物。
发明概述
目前仍然希望创制具有良好抗癌作用而且毒性低的抗癌药。
本发明者对具有副作用少的抗癌药作了深入的研究，结果发现，以1位和/或3位被有取代基的烷基等取代为特征的、与芳环或杂芳环稠合的新的咪唑鎓衍生物表现出优良的抗肿瘤活性和低的毒性，因此它们可用作安全域广的抗癌药。另外，通过发现2-酰基氨基-3-氨基-1，4-醌衍生物和稠合的咪唑衍生物可用作它们的合成中间体，且进一步发现该合成的中间体2-酰基氨基-3-氨基-1，4-醌衍生物本身也显示出毒性低且抗肿瘤活性高，从而完成了本发明。
即，本发明涉及一种由下述通式(I)表示的稠合的咪唑鎓衍生物和一种包含该稠合咪唑鎓衍生物和制药学上容许的载体的药物组合物(具体是抗癌药)。
Figure A0180490500091
(式中的记号具有以下意思。
R1和R2：相同或不同，各自表示-(具有一个或多个选自B组的取代基的低级烷基)，-(具有一个或多个选自B组的取代基的低级链烯基)、-(具有一个或多个选自B组的取代基的低级炔基)、-RinD、-低级烷基、-低级链烯基或-低级炔基，条件是R1和R2中的至少一个是-(具有一个或多个选自B组的取代基的低级烷基)、-(具有一个或多个选自B组的取代基的低级链烯基)、-(具有一个或多个选自B组的取代基的低级炔基)、-(有一个或多个取代基的环烷基)或-(可有一个或多个取代基的5至7元饱和杂环)，
B组：-ORa、-SRa、-前药化的OH、-O-低级亚烷基-ORa、-O-低级亚烷基-O-低级亚烷基-ORa、-O-低级亚烷基-NRaRb、-O-低级亚烷基-O-低级亚烷基-NRaRb、-O-低级亚烷基-NRc-低级亚烷基-NRaRb、-OCO-NRaRb、-SORa、-SO2Ra、-SO2NRaRb、-NRa-SO2Rb、-CO2H、-NRaRb、-NRc-低级亚烷基-NRaRb、-N(-低级亚烷基-NRaRb)2、-RinD、-NO2、-CN、-卤素、-CO2Ra、-COO-、-CONRaRb、-CONRa-O-Rb、-NRa-CORb、-NRa-CO-NRbRc、-OCORa和-CO-Ra，
Ra、Rb和Rc：相同或不同，各自表示-H、-低级烷基、-低级亚烷基-RinD或-RinD，
RinD：-(可有一个或多个取代基的5至7元饱和杂环)，-(可有一个或多个取代基的环烷基)、-(可有一个或多个取代基的环烯基)、-(可有一个或多个取代基的芳基)或-(可有一个或多个取代基的杂芳基)，
R3：-H或-(可有一个或多个取代基的低级烷基)，或R2和R3可一起形成具有2-5个碳原子的可被O、S或NR4(R4是-H或-低级烷基)中断的低级亚烷基，
A环：可有一个或多个取代基的芳环或可有一个或多个取代基的杂芳环，和
X-：抗衡阴离子，条件是当B组的取代基-COO-与咪唑鎓阳离子形成分子内盐时，X-不存在，
条件是具有下列R1和R2组合的化合物被排除在外：
(1)一个是-低级亚烷基-(可有一个或多个取代基的芳基)，另一个是-CH3、-(CH2)3CH3或-苯基，
(2)一个是-低级亚烷基-CO-(可有一个或多个取代基的芳基)，另一个是-(CH2)2CH(CH3)2或-(CH2)3CH3，或
(3)R1和R2均为-苄基、-(CH2)2OC2H5或-(CH2)2O-COCH3；下同。)
另外，本发明还涉及下述通式(II)表示的2-酰基氨基-3-氨基-1，4-醌衍生物或其盐，它是上述通式(I)的合成中间体，且其本身具有优良的抗肿瘤活性；本发明还涉及一种药物组合物，具体是抗癌药，它含有该化合物或其盐以及制药学上容许的载体。
Figure A0180490500101
(式中的记号具有以下意思。
R1和R2：相同或不同，各自表示-(具有一个或多个选自B组的取代基的低级烷基)，-(具有一个或多个选自B组的取代基的低级链烯基)、-(具有一个或多个选自B组的取代基的低级炔基)、-RinD、-低级烷基、-低级链烯基或-低级炔基，条件是R1和R2中的至少一个是-(具有一个或多个选自B组的取代基的低级烷基)、-(具有一个或多个选自B组的取代基的低级链烯基)、-(具有一个或多个选自B组的取代基的低级炔基)、-(有一个或多个取代基的环烷基)或-(可有一个或多个取代基的5至7元饱和杂环)，
B组：-ORa、-SRa、-前药化的OH、-O-低级亚烷基-ORa、-O-低级亚烷基-O-低级亚烷基-ORa、-O-低级亚烷基-NRaRb、-O-低级亚烷基-O-低级亚烷基-NRaRb、-O-低级亚烷基-NRc-低级亚烷基-NRaRb、-OCO-NRaRb、-SORa、-SO2Ra、-SO2NRaRb、-NRa-SO2Rb、-CO2H、-NRaRb、-NRc-低级亚烷基-NRaRb、-N(-低级亚烷基-NRaRb)2、-RinD、-NO2、-CN、-卤素、-CO2Ra、-CONRaRb、-CONRa-O-Rb、-NRa-CORb、-NRa-CO-NRbRc、-OCORa和-CO-Ra，
Ra、Rb和Rc：相同或不同，各自表示-H、-低级烷基、-低级亚烷基-RinD或-RinD，
RinD：-(可有一个或多个取代基的5至7元饱和杂环)，-(可有一个或多个取代基的环烷基)、-(可有一个或多个取代基的环烯基)、-(可有一个或多个取代基的芳基)或-(可有一个或多个取代基的杂芳基)，
R3：-H或-(可有一个或多个取代基的低级烷基)，或R2和R3可一起形成具有2-5个碳原子的可被O、S或NR4(R4是-H或-低级烷基)中断的低级亚烷基，和
A环：可有一个或多个取代基的芳环或可有一个或多个取代基的杂芳环，
条件是排除下表中的化合物；
                         表2
Figure A0180490500121
(在该表中，Comp指化合物的编号，Me指甲基、Et指乙基、Ph指苯基，另外，在取代的苯基场合，取代基和取代位置显示在Ph之前，例如，3，4-Cl-Ph表示3，4-二氯苯基；下同)。
上表2所示化合物是与除草剂有关的英国专利1314881和日本特许特公昭54-25085中、与合成法有关的文献Zh.Org.Khim.，22(8)，1736-42(1986)和J.Gen.Chem.USSR，36，649-652(1966)、以及试剂目录[Sigma Aldrich Library of Rare ChemicalsStructure Index(Aldrich Chemical Company，Inc.)等]中公知的。
另外，本发明涉及一种下述通式(III)表示的稠合的咪唑衍生物或其盐，它是上述通式(I)的一种新的合成的中间体。(式中的记号具有以下意思。
R1：-(具有一个或多个选自B组的取代基的低级烷基)，-(具有一个或多个选自B组的取代基的低级链烯基)、-(具有一个或多个选自B组的取代基的低级炔基)或-(具有一个或多个取代基的环烷基)，条件是排除具有一个或多个选自-NH2、-NMe2、-NEt2、-OH、-卤素和-(可被-Cl、-F、-Me或-OMe取代的苯基)的取代基的低级烷基，
B组：-ORa、-SRa、-前药化的OH、-O-低级亚烷基-ORa、-O-低级亚烷基-O-低级亚烷基-ORa、-O-低级亚烷基-NRaRb、-O-低级亚烷基-O-低级亚烷基-NRaRb、-O-低级亚烷基-NRc-低级亚烷基-NRaRb、-OCO-NRaRb、-SORa、-SO2Ra、-SO2NRaRb、-NRa-SO2Rb、-CO2H、-NRaRb、-NRc-低级亚烷基-NRaRb、-N(-低级亚烷基-NRaRb)2、-RinD、-NO2、-CN、-卤素、-CO2Ra、-CONRaRb、-CONRa-O-Rb、-NRa-CORb、-NRa-CO-NRbRc、-OCORa和-CO-Ra，
Ra、Rb和Rc：相同或不同，各自表示-H、-低级烷基、-低级亚烷基-RinD或-RinD，
RinD：-(可有一个或多个取代基的5至7元饱和杂环)，-(可有一个或多个取代基的环烷基)、-(可有一个或多个取代基的环烯基)、-(可有一个或多个取代基的芳基)或-(可有一个或多个取代基的杂芳基)，
R3：-H或-(可有一个或多个取代基的低级烷基)，和
A环：可有一个或多个取代基的芳环或可有一个或多个取代基的杂芳环，下同。)
下面将进一步描述通式(I)、(II)和(III)的化合物。
在本说明书中，术语“低级”指有1-6个碳原子的直链或支链烃链。“低级烷基”宜为有1-4个碳原子的烷基，特别佳的是甲基、乙基、正丙基、异丙基、正丁基和异丁基。“低级链烯基”宜为乙烯基、烯丙基、1-丙烯基、异丙烯基、1-丁烯基、2-丁烯基和3-丁烯基。“低级炔基”宜为乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基和1-甲基-2-丙炔基。另外，“低级亚烷基”宜为亚甲基、亚乙基、三亚甲基和2，2-二甲基三亚甲基。
“芳基”指芳族烃环基团，较佳的是有6-14个碳原子的芳基，更佳的是苯基、萘基和芴基。另外，A环中的“芳环”是形成上述芳基的环，较佳地是苯环和萘环。
“杂芳基”是具有1至4个选自N，S，O的杂原子的5-6元单环杂芳基，以及它们与苯环或5-6元单环杂芳基稠合而成的双环杂芳基(它可以是部分饱和的)。另外，在含有N原子的场合，可形成N-氧化物。在这种情况下，5-6元单环杂芳基宜为呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、噁二唑基、噻二唑基、三唑基、四唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基和三嗪基，双环杂芳基宜为苯并呋喃基、苯并噻吩基、苯并噻二唑基、苯并噻唑基、苯并噁唑基、苯并噁二唑基、苯并咪唑基、吲哚基、异吲哚基、吲唑基、喹啉基、异喹啉基、噌啉基、喹唑啉基、喹喔啉基、苯并间二氧杂环戊烯基、中氮茚基和咪唑并吡啶基。部分饱和的杂芳基例如有1，2，3，4-四氢喹啉基。更佳的是呋喃基、噻吩基、咪唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吲哚基、苯并咪唑基、苯并间二氧杂环戊烯基(benzodioxonyl)和喹啉基，特别佳的是吡啶基、吡嗪基和嘧啶基。
A环中的杂芳环是形成上述杂芳基的环，较佳的是5-6元单环杂芳环，更佳的是噻吩、呋喃、吡咯、咪唑、噁唑、噻唑、吡啶、吡嗪和嘧啶环。
“环烷基”宜为3-10个碳原子的环烷基，特别佳的是环丙基、环戊基、环己基和金刚烷基。“环烯基”宜是3-8个碳原子的环烯基，特别佳的是环戊烯基和环己烯基。
至于“抗衡阴离子”，没有特别的限制，只要它作为咪唑鎓阳离子的抗衡阴离子是制药学上容许的阴离子即可，其较佳是单价或二价阴离子如卤素离子，有机磺酸根离子(甲磺酸根离子、乙磺酸根离子、苯磺酸根离子、甲苯磺酸根离子等)、乙酸根离子、三氟乙酸根离子、碳酸根离子、硫酸根离子等，其中卤素离子是特别佳的。
作为“卤素”可列举F、Cl、Br和I原子，“卤素离子”指它们的离子。“卤代低级烷基”是被一个或多个上述卤素取代的上述低级烷基，较佳地是-CF3。
“5-7元饱和杂环”是具有1-4个选自N，S，O的杂原子的5-7元单环饱和杂环或其桥环。较佳地是四氢吡喃基、四氢呋喃基、吡咯烷基、哌嗪基、氮杂环庚烷基(azepanyl)、二氮杂环庚烷基(diazepanyl)、奎宁环基、哌啶基和吗啉基。
“前药化的OH”是形成可逆的前药衍生物的基团，该前药衍生物能在活体内恢复成其母体化合物(最初的羟基化合物)，例如在Prog.Med.5：2157-2161(1985)中记载的基团。较佳的例子包括：-OCO-可有取代基的低级亚烷基-COOR(R表示H或低级烷基，下同)、-OCO-可有取代基的低级亚烯基-COOR、-OCO-可有取代基的芳基、-OCO-低级亚烷基-O-低级亚烷基-COOR、-OCO-CO-R、-OCO-可有取代基的低级烷基、-OSO2O-可有取代基的低级亚烷基-COOR、-O-苯并[c]呋喃酮基、5-甲基-1，3-二氧杂环戊烯-2-酮-4-基-甲氧基等。
-(可有一个或多个取代基的5至7元饱和杂环)、-(可有一个或多个取代基的环烷基)、-(有一个或多个取代基的环烷基)、-(可有一个或多个取代基的环烯基)、-(可有一个或多个取代基的芳基)或-(可有一个或多个取代基的杂芳基)中的取代基没有特别限制，较佳的是选自以下C组的1-4个取代基。
C组：-低级烷基、-卤素、-卤代低级烷基、-ORa、-O-低级亚烷基-ORa、-SRa、-NRaRb、-NO2、-CN、-CO2Ra、-CO-NRaRb、-CORa、-NRa-CORb、-SO2NRaRb、-低级亚烷基-NRaRb、-芳基、-低级亚烷基-芳基和-OCO-Ra(式中Ra和Rb如上定义)。
在C组中，更佳的是基团是-低级烷基、-卤素、-卤代低级烷基、-OH、-O-低级烷基、-O-低级亚烷基-OH、-O-低级亚烷基-O-低级烷基、-低级亚烷基-NH2、-NH2、-NH-低级烷基、-N(低级烷基)2、-CO2H、-CO2-低级烷基、-CO-NH2、-SO2-NH2、-NO2和-CN。下同。
作为A环中的“可有一个或多个取代基的芳环”或“可有一个或多个取代基的杂芳环”中的取代基，较佳的是上述C组中列举的基团，更佳的基团也如上所述。特别佳的是-NO2。
R3的“可有一个或多个取代基的低级烷基”中的取代基没有特别限制，但是，较佳的是上述B组的取代基，更佳的是-卤素、-ORa、SRa、NRaRb、-NO2或-CN。
另外，在上述B组和C组中，对于采用Ra、Rb和Rc来表示的基团，Ra、Rb和Rc是-H或-低级烷基是更佳的。
术语“R2和R3一起形成具有2-5个碳原子的可被O、S或NR4(R4是-H或-低级烷基)中断的低级亚烷基”意思指，R2和R3形成的可被O、S或NR4中断的低级亚烷基链(较佳的是-(CH2)4-、-(CH2)2OCH2-和-(CH2)2N(Me)CH2-)，然后其两端的N和C原子形成一体，与咪唑环稠合形成5-8元杂环。
在本发明化合物(I)或(II)中，较佳的化合物是
(1)这样的化合物，其中：R1和R2的至少一个是-(具有一个或多个选自B组的取代基的低级烷基)、-(具有一个或多个选自B组的取代基的低级链烯基)、-(具有一个或多个选自B组的取代基的低级炔基)、-(具有一个或多个选自C组的取代基的环烷基)或-(可有一个或多个选自C组的取代基的5-7元饱和杂环)；RinD是-(可有一个或多个选自C组的取代基的5-7元饱和杂环)，-(可有一个或多个选自C组的取代基的环烷基)、-(可有一个或多个选自C组的取代基的环烯基)、-(可有一个或多个选自C组的取代基的芳基)或-(可有一个或多个选自C组的取代基的杂芳基)；R3是-H或-(可有一个或多个选自B组的取代基的低级烷基)，或R2和R3能一起形成具有2-5个碳原子、可被O、S或NR4(R4：-H或-低级烷基)中断的低级亚烷基；A环是可有一个或多个选自C组的取代基的芳环，或是可有一个或多个选自C组的取代基的杂芳环，
(2)R1和R2中的至少一个是具有一个或多个选自B组的取代基的低级烷基的化合物，
(3)R1和R2是相同或不同的具有一个或多个选自B组的取代基的低级烷基的化合物，
(4)R1和R2的至少一个是具有一个或多个取代基的低级烷基的化合物，其中该取代基选自-ORa、-NRaRb、-NRa-CORb、-O-低级亚烷基-ORa、-O-低级亚烷基-O-低级亚烷基-ORa、-SRa、-CONRaRb、-CN、-(可有一个或多个选自C组的取代基的环烷基)、-(可有一个或多个选自C组的取代基的5-7元饱和杂环)、-(可有一个或多个选自C组的取代基的芳基)和-(可有一个或多个选自C组的取代基的杂芳基)，
(5)R1和R2的至少一个是低级烷基的化合物，该低级烷基具有一个或多个选自下列的取代基：-ORa、-O-低级亚烷基-ORa、-O-低级亚烷基-O-低级亚烷基-ORa、-(可有一个或多个选自C组的取代基的5-7元饱和杂环)、-(可有一个或多个选自C组的取代基的芳基)和-(可有一个或多个选自C组的取代基的杂芳基)，
(6)R1和R2的至少一个是被杂芳基取代的低级烷基的化合物，该杂芳基选自呋喃基、噻吩基、咪唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、吲哚基、苯并咪唑基、苯并间二氧杂环戊烯基(benzodioxonyl)和喹啉基，该杂芳基可有一个或多个选自C组的取代基，
(7)这样的化合物，其中R1和R2之一是被-O-低级烷基取代的低级烷基，另一个是具有一个选自-O-低级亚烷基-O-低级烷基、-O-低级亚烷基-O-低级亚烷基-O-低级烷基、-(可有一个或多个选自C组的取代基的芳基)、-(可有一个或多个选自C组的取代基的杂芳基)和-O-低级烷基的取代基的低级烷基，
(8)这样的化合物，其中R1和R2的至少一个是具有一个选自下列的取代基的低级烷基，该取代基选自-(可有一个或多个选自C组的取代基的选自吡啶基、吡嗪基和嘧啶基的杂芳基)、-O-低级亚烷基-O-低级烷基和-O-低级烷基，
(9)R3是甲基的化合物，
(10)这样的化合物，其中A环是可有一个或多个选自C组的取代基的苯环、或是可有一个或多个选自C组的取代基的选自噻吩、呋喃、吡咯、咪唑、噁唑、噻唑、吡啶、吡嗪、哒嗪和嘧啶环的杂芳环，
(11)A环是可被-NO2取代的苯环的化合物，
(12)X-是是卤素离子的化合物。
另外，本发明化合物(I)的特别佳的化合物是稠合的咪唑鎓衍生物，其中R1和R2相同或不同，各表示-(具有一个或多个选自B′组的取代基的低级烷基)、-(具有一个或多个选自B′组的取代基的低级链烯基)、-(具有一个或多个选自B′组的取代基的低级炔基)、-(可有一个或多个选自C′组的取代基的环烷基)、-(可有一个或多个选自C′组的取代基的5-6元单环杂芳基)、-(可有一个或多个选自C′组的取代基的芳基)、-(可有一个或多个选自C′组的取代基的5-7元饱和杂环)、-低级亚烷基-(可有一个或多个选自C′组的取代基的芳基)、-低级亚烷基-CO-(可有一个或多个选自C′组的取代基的芳基)、-低级烷基、-低级链烯基或-低级炔基，条件是R1和R2的至少一个是-(具有一个或多个选自B′组的取代基的低级烷基)、-(具有一个或多个选自B′组的取代基的低级链烯基)或-(具有一个或多个选自B′组的取代基的低级炔基)；B′组是-ORa、-SRa、-前药化的OH、-O-低级亚烷基-RinD、-SORa、-SO2Ra、-SO2NRaRb、-NRa-SO2Rb、-CO2H、-NRaRb、-NRc-低级亚烷基-RinD、-N(-低级亚烷基-RinD)2、-NRc-低级亚烷基-NRaRb、-N(低级亚烷基-NRaRb)2、-(可有一个或多个选自C′组的取代基的5-7元饱和杂环)、-(可有一个或多个选自C′组的取代基的5-6元单环杂芳基)、-环烷基、-S-低级亚烷基-RinD、-NO2、-CN、-CO2Ra、-CONRaRb、-NRa-CORb、-OCORa和-CO-低级烷基和-CO-(可有一个或多个选自C′组的取代基的5-6元单环杂芳基)；Ra、Rb和Rc相同或不同，是-H、-低级烷基或-RinD；RinD是-(可有一个或多个选自C′组的取代基的5-7元饱和杂环)，-(可有一个或多个选自C′组的取代基的芳基)或-(可有一个或多个选自C′组的取代基的5-6元单环杂芳基)；C′组是-低级烷基、-卤素、-ORa、-SRa、-NRaRb、-NO2、-CN、-CO2Ra、-CO-NRaRb、-CORa、-NRa-CORb和-OCO-Ra；R3是-H或-低级烷基；A环是可有选自-低级烷基、-ORa、-NRaRb、-CN、-卤素原子和-NO2的取代基的苯环；X-是抗衡阴离子。
在本发明化合物(I)中，特别佳的化合物是1-[(6-氯-3-吡啶基)甲基]-3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1，2-二甲基-4，9-二氧代-3-[(2-四氢呋喃基)甲基]-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1，3-二(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-1-(2-吡嗪基甲基)-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1-[3-(1H-4-咪唑基)丙基]-3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、3-(2-甲氧基乙基)-2-甲基-1-[(5-甲基-2-吡嗪基)甲基]-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、2-甲基-4，9-二氧代-1，3-二(2-吡嗪基甲基)-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1-[2-(2-甲氧基乙氧基)乙基]-3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1-{2-[2-(2-甲氧基乙氧基)乙氧基]乙基}-3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1-(2-甲氧基乙基)-2-甲基-4，9-二氧代-3-(3-吡啶基甲基)-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-1-(2-吡啶基甲基)-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-1-(4-吡啶基甲基)-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1-[(2-氯-3-吡啶基)甲基]-3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1-[(2-羟基-4-吡啶基)甲基]-3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、3-(2-甲氧基乙基)-1-[(6-甲氧基-3-吡啶基)甲基]-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1-[(2-氯-4-吡啶基)甲基]-3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1-(4-氯苄基)-3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1-(4-氟苄基)-3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓和1，3-二(2-甲氧基乙基)-2-甲基-5-硝基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓或其互变异构体和其与卤素离子的盐。
本发明的化合物由于阳离子的非定域作用而存在下式所示的互变异构体，本发明也包括分离的互变异构体或其混合物。因此，在本说明书中，用1H-咪唑-3-鎓衍生物表示的化合物包括3H-咪唑-1-鎓衍生物这一互变异构体和两个异构体的混合物。另外，当化合物(I)有取代基-COO-且和咪唑鎓阳离子形成分子内盐时，X-不存在。
除了上述与抗衡阴离子的盐外，根据取代基种类的不同，本发明化合物(I)有时形成了其它盐，这些盐也包括在本发明内。另外，本发明化合物(II)或(III)有时也根据取代基种类形成了盐，这些盐也包括在本发明内。这些盐没有特别的限制，只要其是制药学上容许的盐即可。作为酸加成盐，可具体列举盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸等无机酸，甲酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸、天冬氨酸、谷氨酸等有机酸的酸加成盐；作为与碱的盐，可列举含有钠、钾、镁、钙、铝等金属的无机碱的盐、甲胺、乙胺、乙醇胺、赖氨酸、鸟氨酸等有机碱的盐和铵盐。
在一些情况下，根据取代基的种类，本发明化合物(I)、(II)或(III)存在几何异构体和互变异构体。这些异构体的分离形式或其混合物均包括在本发明内。而且，由于本发明化合物有时有不对称碳原子的情况，因此存在基于该不对称碳原子的异构体。本发明包括这些光学异构体的混合和分离形式。另外，在一些情况下，根据取代基的种类，本发明化合物形成了N-氧化物，这些N-氧化物化合物也包括在本发明中。另外，本发明还包含本发明化合物(I)、(II)或(III)的各种水合物、溶剂化物和多晶型物质。
(合成方法)
本发明化合物(I)、(II)和(III)容易根据文献记载的方法，例如J.Org.Chem.USSR，1，1479-85(1965)、J.Med.Chem.，7(3)，362-364(1964)以及日本专利公开公报平3-258765中记载的相似方法，或用本领域技术人员公知的方法来制得。
还有，根据官能团的种类，有时在原料阶段或合成中间体阶段用合适的保护基团(即容易转变成该官能团的基团)代替该官能团在制造技术上是有效的。随后，根据需要除去保护基团，就能得到所需的化合物。这些官能团的例子包括氨基、羟基、羧基等，这些保护基团可列举例如Greene和Wuts编著的“有机合成中的保护基团”第2版中记载的保护基团，它们可根据反应条件来任选地使用。
下面描述典型的合成方法。(式中，R′表示氢、甲氧基或卤素基团，H-X表示形成阴离子的酸(较佳的是氟化氢、氯化氢、溴化氢、碘化氢、甲磺酸、乙磺酸等)。下同。)
制法1
本发明化合物(II)可根据常规方法使化合物(IV)与胺类(V)反应来制得。例如用Chem.Pharm.Bull.，44(6)，1181-1187(1996)、Syn.Comm.，27(12)，2143-2157(1997)、Tetrahedron.Lett.，39(42)，7677-7678(1998)中记载的方法进行反应，有利的是，在常温乃至加热下、在合适的惰性溶剂(例如苯等)中，使用反应当量的化合物(IV)和(V)或其中之一过量，如果需要，使用合适的无机碱(碳酸钾等)或有机碱(三乙胺等)作为酸捕获剂。
制法2
本发明化合物(I)可根据常规方法使本发明化合物(II)环化并季铵盐化来制得。例如采用J.Org.Chem.USSR，1，1479-85(1965)中记载的方法进行反应，在合适的惰性溶剂(例如醇溶剂)中，在常温至加热下用反应当量或过量酸进行反应是有利的。
制法3(式中Rd和Re表示R1和R2中定义的任何基团。下同。)
本发明化合物(I)用常规方法水解后可得到2种本发明化合物(IIa)和(IIb)。对所得化合物进一步进行众所周知的基团修饰反应，就能得到所需的本发明化合物(I)的制造中间体。
水解反应可用J.Med.Chem.，7(3)，362-364(1964)等中记载的方法来进行。在水和合适的惰性溶剂(例如乙醇等)中，在常温至加热下，采用反应当量或过量的碱进行反应是有利的。在这里，作为碱可列举氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸钾等。
制法4
本发明化合物(III)可根据J.Med.Chem.，39(7)，1447-1451(1996)等中记载的方法，使化合物(VI)在氢氧化钠等碱存在下环化制得。
制法5
本发明化合物(I)可通过使本发明化合物(III)与卤化物(VII)反应形成季铵盐来制得。反应例如可采用J.Med.Chem.，7(3)，362-364(1964)中记载的方法来进行。较佳的是，在合适的惰性溶剂(例如醇溶剂)中，采用反应当量的化合物(III)和(VII)或其中任一过量，在常温至加温下(较佳的在溶剂回流温度下)进行反应。
其它制法
除了上述制法外，本发明化合物还可用各种公知的取代基修饰反应来制得。例如，具有含磺酰基的取代基的化合物可以用常规的氧化反应从具有硫化物键或亚磺酰键的化合物制得。另外，具有吡啶基等含N原子的杂芳基作为取代基的化合物的N-氧化物衍生物可用常规的氧化反应方法来制得。具有含羧酸取代基的化合物可用常规的水解反应从具有酯或酰胺键的化合物制得。具有含氨基烷基的取代基的化合物可用常规的胺化反应从具有卤素取代的烷基键的化合物制得。当本发明化合物(II)和(III)是游离形式时，它们可用常规的成盐反应根据所希望的那样制成盐。
原料化合物的合成
本发明化合物的一些原料化合物是新的化合物，这些化合物容易用与公知原料化合物相同的方法或本领域技术人员公知的方法合成。下面显示了代表性合成方案。
合成方案1
Figure A0180490500211
化合物(IV)可根据例如J.Org.Chem.USSR，1，1479-85(1965)等中记载的方法，通过常规的酰化反应使化合物(VIII)与酰基卤、酸酐等反应性羧酸反应来制得。
合成方案2
(式中，B1表示可有一个或多个取代基的吡啶环。下同。)
氨基甲基吡啶衍生物(X)可根据德国专利3726993(1989)中记载的方法通过化合物(IX)还原来制得。
合成方案3
化合物(VI)可根据J.Med.Chem.，39(7)，1447-1451(1996)等中记载的方法通过化合物(XI)胺化来制得。
合成方案4
化合物(VIII)可根据J.Het.Chem.，33(1)，113-117(1996)、Syn.Comm.，27(12)，2143-2157(1997)、Tetrahedron.Lett.，39(42)，7677-7678(1998)等中记载的方法通过化合物(XII)胺化制得。
合成方案5
Figure A0180490500222
化合物(IV)可通过化合物(XII)酰胺化制得。较佳的是，在合适的惰性溶剂(例如N，N-二甲基甲酰胺(DMF)等)中，在用合适的无机碱(NaH等)或有机碱(NaOMe等)使反应当量的化合物(XIII)活化后，与反应当量或过量的化合物(XII)在常温至加热下进行反应。
如此制得的本发明化合物的分离和纯化可用萃取、浓缩、蒸馏、结晶、过滤、重结晶、各种色谱等常用化学操作来进行。
各种异构体可利用异构体之间的物理化学性质的差异用常规方法来分离。例如，外消旋化合物可用常规的光学拆分方法[例如，与通常光学活性酸(酒石酸等)制成非对映体盐、然后进行光学拆分的方法]变成光学纯异构体。另外，非对映体混合物可用分级结晶、色谱等方法来分离。另外，光学活性化合物还可用合适的光学活性原料来制得。
产业上的利用可能性
本发明的化合物(I)和(II)可用作具有良好的癌细胞增殖抑制作用、毒性低、安全域广的抗癌药。因此，本发明化合物对于癌、较佳的是所有的实体肿瘤和淋巴瘤、尤其是皮肤癌、膀胱癌、乳癌、子宫癌、卵巢癌、前列腺癌、肺癌、大肠癌、胰癌、肾癌、胃癌等肿瘤的增殖有抑制作用，因此它可用于治疗这些疾病。具体地说，在癌细胞增殖抑制试验和采用小鼠肿瘤模型的体内癌增殖抑制试验中，它们对许多肿瘤有比现有抗癌药更好的抗肿瘤活性。因此，预计它们可作为对现有抗癌药有耐药性的肿瘤的治疗药。
本发明化合物的效果在下面的试验中得到确认。
试验例1癌细胞增殖抑制试验
(试验方法)细胞培养：HeLaS3细胞或A375细胞在加入10％FCS的Dalbeco改进的Eagle培养基(DMEM)(GIBCO)中进行培养。
化合物评价：将子宫颈癌HeLaS3细胞或黑色素瘤A375细胞接种在明胶包被的96孔板(IWAKI社制造)中，在DMEM中培养过夜。第二天，在其中添加各种浓度的测试化合物的DMSO溶液，使DMSO的最终浓度均为0.1％。添加48小时后，通过Alarmar Blue(Biosource)的显色反应来评价细胞增殖。
(结果)本发明化合物(I)和(II)良好地抑制了癌细胞的增殖，其IC50值在1μM以下。
另外，本发明化合物(I)和(II)对于其它癌细胞(非小细胞肺癌(EKVX、HOP-92、NCI-H358、A-549、NCI-H460)、乳癌(MDA-MB-231、MCF7)、前列腺癌(PC-3)、胰癌(MIA PaCa-2)、大肠癌(WiDr)、肾癌(A-498)、胃癌(MKN28)、膀胱癌(UC-14)和纤维肉瘤(HT-1080)同样有抑制细胞增殖的良好活性。
试验例2体内癌增殖抑制试验
(试验方法)将2×106个黑色素瘤A375细胞株移植入雄性Balb/c裸鼠的背侧部皮下。从肿瘤体积达到50-100立方毫米时起在2周内每日1次静脉给予评价化合物。另外，对照组静脉给予生理盐水。用测径器定期测定肿瘤直径，直至最终给药的次日。用下面的计算式计算出肿瘤体积。
肿瘤体积(mm3)＝1/2×[短径(mm)]2×长径(mm)
(结果)在本试验中，本发明化合物(I)和(II)良好地抑制了癌增殖，例如实施例4、37、118、121、148、154、180和182的化合物在0.3或1毫克/千克的给药剂量下显示出与对照组相比有50％以上的增殖抑制活性。
本发明化合物在移植了其它癌细胞(前列腺癌(PC-3)或非小细胞肺癌(NCI-H358、A-549、NCI-H460)的动物模型中同样显示有良好的抑制癌增殖的作用。
试验例3小鼠单次给药毒性试验
(试验方法)将本发明化合物静脉内单次给予Balb/c小鼠，在2周的观察期内检查有无死亡例。
(结果)本发明实施例4、9、35、37、52、72、121、133、148、154、158、180、182、184、185、186、192和197的化合物每一个以3毫克/千克单次给药均无死亡例。另一方面，以前的文献Khim.Pharm.Zh.，32(6)，10-11(1998)中揭示KP-1和KP-3的3毫克/千克单次给药的各2例全部死亡。因此，本发明化合物显示出比以前文献报道的化合物毒性低。
因此，由于本发明化合物(I)和(II)对多种肿瘤有良好的抗肿瘤活性，而且毒性低，因此显示它们可用作具有良好性质的抗癌药。
本发明的药物组合物可用通式(I)或(II)中所示的一种或两种以上化合物以及本领域中常用的制药学上容许的载体(药物载体、赋形剂等)通过常用方法制得。给药通过片剂、丸剂、胶囊剂、颗粒剂、散剂、液剂、吸入剂等经口给予，或通过静脉注射、肌内注射等注射剂、栓剂、滴眼剂、眼膏、经皮用液剂、软膏、经皮用贴剂、经粘膜液剂、经粘膜贴剂等非经口给药的任何一种形态给予均可。
作为用于本发明经口给药的固体组合物，可用片剂、散剂、颗粒剂等。在这些固体组合物中，将一种或多种活性物质与至少一种惰性赋形剂(如乳糖、甘露糖醇、葡萄糖、羟丙基纤维素、微晶纤维素、淀粉、聚乙烯吡咯烷酮、偏硅酸铝镁等)混合。根据通常的步骤，该组合物可含有惰性添加剂如润滑剂(硬脂酸镁等)和崩解剂(羧甲基淀粉钠等)和助溶剂。根据需要，片剂或丸剂可用糖衣或胃溶性或肠溶性包衣剂来包衣。
用于口服给药的液体组合物包括药剂上容许的乳剂、液剂、悬浮剂、糖浆剂、酏剂等，并含有常用的惰性溶剂如纯化水或乙醇。除惰性溶剂外，该组合物还可含有增溶剂、润湿剂、悬浮剂等助剂、增甜剂、调味剂、芳香剂和防腐剂。
用于非经口给药的注射剂含有无菌水性或非水性液剂、悬浮剂和乳剂。水性溶剂的例子包括注射用蒸馏水和生理盐水。非水性溶剂例如是丙二醇、聚乙二醇、橄榄油等植物油、乙醇等醇类、聚山梨酯80(商品名)等。这些组合物还可含有等渗剂、防腐剂、湿润剂、乳化剂、分散剂、稳定剂和助溶剂。这些组合物例如通过除菌滤膜过滤、与杀菌剂混合或辐照等方式来灭菌。另外，可以制成无菌固体组合物，在使用前用无菌水或无菌注射用溶剂溶解或悬浮使用。
通常，在经口给药的场合，1日的给药量约为0.001-50毫克/千克，较佳的为0.01-30毫克/千克。在静脉内给药的场合，1日的给药量约为0.0001-10毫克/千克，较佳的约0.001-3毫克/千克，该日剂量可1日1次至1日数次分次给药。每一场合的给药量应根据症状、年龄和性别等来适当地确定。
实施发明的最佳方式
下面将根据实施例更详细地说明本发明。本发明化合物绝非局限于下面实施例中记载的化合物。另外，在参考例中显示了本发明化合物的原料化合物的制备例。
参考例1：在3-氰基-2-(二甲基氨基)吡啶(2.45克)的乙醇(50毫升)溶液中，加入饱和氨水(17毫升)和瑞尼镍(3.0克)，在1个大气压的氢气氛下室温下搅拌8小时。在760毫升氢吸收后，过滤除去催化剂。浓缩母液，得到黄色油状的3-(氨基甲基)-2-(二甲基氨基)吡啶(2.61克)。
参考例2：在2-氯-3-[(2-甲氧基乙基)氨基]-1，4-萘醌(33克)的乙酸酐(100毫升)溶液中，加入数滴浓硫酸，45℃下搅拌1小时。在反应液中加入乙醇(100毫升)，使过量的乙酸酐酯化。冷却后，加入乙酸乙酯，用水和饱和盐水洗净后，用无水硫酸钠干燥。蒸发除去溶剂，残余物用乙醚结晶，得到黄色粉末的N-(3-氯-1，4-二氢-1，4-二氧代-2-萘基)-N-(2-甲氧基乙基)乙酰胺(29克)。
参考例3：在N-(3-氯-1，4-二氢-1，4-二氧代-2-萘基)乙酰胺(1.0克)的苯(20毫升)溶液中加入2-甲氧基乙胺(0.8毫升)，在室温下搅拌1小时。在反应液中加入水，用氯仿萃取。用水、饱和盐水洗净有机层后，用无水硫酸钠干燥。蒸发除去溶剂，残余物用乙酸乙酯重结晶，得到红色粉末N-[3-(2-甲氧基乙基)氨基-1，4-二氢-1，4-二氧代-2-萘基]乙酰胺(0.87克)。
参考例4：在2，3-二氯-1，4-二氢-1，4-二氧代萘(3.0克)的苯(90毫升)溶液中加入2-(氨基甲基)吡嗪(3.2克)和二异丙基乙胺(5.8毫升)，在室温下搅拌8小时。在反应液中加入水，滤去析出的固体，用乙酸乙酯萃取滤液。用水、饱和盐水洗净有机层后，用无水硫酸钠干燥。蒸发除去溶剂，残余物用硅胶柱色谱(用氯仿洗脱)纯化，得到浅棕色粉末的2-氯-1，4-二氢-1，4-二氧代-3-[(2-吡嗪基甲基)氨基]萘(0.23克)。
参考例5：在2-氯-1，4-二氢-3-甲基氨基-1，4-二氧代萘(2.2克)的1，4-二噁烷(30毫升)溶液中加入2-氯乙酰氯(3.3毫升)，回流下搅拌该混合物14小时。冷却反应液后，蒸发除去溶剂。在残余物中加入乙醇，滤取析出的固体。所得固体从乙醇中重结晶，得到黄色粉末2-氯-N-(3-氯-1，4-二氢-1，4-二氧代-2-萘基)-N-甲基乙酰胺(2.6克)。
参考例6：在2-氧代哌啶(1.0克)的DMF(20毫升)溶液中加入NaH(440毫克)，在室温下搅拌30分钟。将该溶液一次性加入2，3-二氯-1，4-二氢-1，4-二氧代萘(6.9克)的DMF(150毫升)溶液中，在室温下搅拌17小时。将反应液倒入饱和氨水，滤去析出的固体，滤液用乙酸乙酯萃取。有机层在用水、饱和盐水洗净后用无水硫酸钠干燥。蒸发除去溶剂，残余物用硅胶柱色谱(用乙酸乙酯∶己烷为1∶10的溶液洗脱)纯化，得到浅棕色粉末2-氯-1，4-二氢-1，4-二氧代-3-(2-氧代哌啶-1-基)萘(0.49克)。
参考例7：在4，7-二氢-4，7-二氧代苯并[b]噻吩-2-羧酸甲酯(2.4克)的四氢呋喃(100毫升)溶液中加入2-甲氧基乙胺(1.6毫升)，在室温下搅拌27小时。蒸发除去溶剂后，残余物用硅胶柱色谱(用氯仿洗脱)纯化，得到黄色粉末4，7-二氢-5-(2-甲氧基乙基)氨基-4，7-二氧代苯并[b]噻吩-2-羧酸甲酯(1.5克)。
参考例8：在4，7-二氢-5-(2-甲氧基乙基)氨基-4，7-二氧代苯并[b]噻吩-2-羧酸甲酯(1.2克)的乙酸酐(20毫升)溶液中加入5滴浓硫酸，在室温下搅拌1小时。在反应液中缓缓加入甲醇(20毫升)，蒸发除去溶剂。在残余物中加入水，用乙酸乙酯萃取。有机层在用水、饱和盐水洗净后，用无水硫酸钠干燥。蒸发除去溶剂后，残余物用硅胶柱色谱(用乙酸乙酯∶己烷1∶1的溶液洗脱)纯化，得到红棕色油状5-[N-乙酰-N-(2-甲氧基乙基)氨基]-4，7-二氢-4，7-二氧代苯并[b]噻吩-2-羧酸甲酯(0.39克)。
与参考例1一样得到表3所示的参考例9-11的化合物，如参考例2一样得到表4所示的参考例12的化合物，与参考例3一样得到表4所示的参考例13-15的化合物，与参考例5一样得到表4所示的参考例16的化合物。
实施例1：在N-[3-(2-甲氧基乙基)氨基-1，4-二氢-1，4-二氧代-2-萘基]乙酰胺(0.5克)的乙醇(10毫升)溶液中加入2M氢氧化钠水溶液(0.9毫升)，在室温下搅拌15分钟。在反应液中加入水，用乙酸乙酯萃取。有机层在用水、饱和盐水洗净后用无水硫酸钠干燥。蒸发除去溶剂，滤取残余物，用乙醇洗净，得到浅橙色粉末1-(2-甲氧基乙基)-2-甲基-4，9-二氢-4，9-二氧代-1H-萘并[2，3-d]咪唑(0.58克)。
实施例2：在N-(3-氯-1，4-二氢-1，4-二氧代-2-萘基)-N-(2-甲氧基乙基)乙酰胺(0.5克)的苯(15毫升)溶液中加入苄胺(0.5毫升)，在室温下搅拌4小时。在反应液中加入乙酸乙酯，用水和饱和盐水洗净后，用无水硫酸镁干燥。蒸发除去溶剂，残余物用乙酸乙酯∶己烷结晶，得到红色粉末N-(3-苄基氨基-1，4-二氢-1，4-二氧代-2-萘基)-N-(2-甲氧基乙基)乙酰胺(0.51克)。
实施例3：在N-(2-甲氧基乙基)-N-[3-(3-吡啶基甲基)氨基-1，4-二氢-1，4-二氧代-2-萘基]乙酰胺(0.95克)的二氯甲烷(20毫升)溶液中，加入80％的3-氯过苯甲酸(0.6克)，在室温下搅拌18小时。在反应液中加入饱和碳酸氢钠水溶液，用二氯甲烷萃取。有机层用水、饱和盐水洗净后用无水硫酸钠干燥。蒸发除去溶剂，残余物用硅胶柱色谱(用氯仿∶甲醇∶饱和氨水10∶1∶0.1的溶液洗脱)纯化，得到褐色无定形固体3-[({3-[N-乙酰-N-(2-甲氧基乙基)]氨基-1，4-二氢-1，4-二氧代-2-萘基}氨基)甲基]吡啶1-氧化物(0.84克)。
实施例4：在氯化1-(2-甲氧基乙基)-2-甲基-3-(4-吡啶基甲基)-4，9-二氢-4，9-二氧代-1H-萘并[2，3-d]咪唑-3-鎓一盐酸盐(1.1克)的乙醇(30毫升)溶液中加入1M氢氧化钠水溶液(5.0毫升)，在室温下搅拌30分钟。在反应液中加入水，用乙酸乙酯萃取。有机层用水和饱和盐水洗净后用无水硫酸镁干燥。蒸发除去溶剂后，残余物用硅胶柱色谱(级分A：用乙酸乙酯∶己烷1∶1的溶液洗脱；级分B：用乙酸乙酯洗脱)纯化。级分A用二乙醚结晶，得到红色粉末N-[3-(2-甲氧基乙基)氨基-1，4-二氢-1，4-二氧代-2-萘基]-N-(4-吡啶基甲基)乙酰胺(0.2克)。另外，级分B用乙酸乙酯结晶，得到黄色粉末(0.31克)。它与下文实施例37记载的N-(2-甲氧基乙基)-N-[3-(4-吡啶基甲基)氨基-1，4-二氢-1，4-二氧代-2-萘基]乙酰胺是同一化合物。
实施例5：在N-甲基-N-{3-[2-(甲基亚磺酰)乙基]氨基-1，4-二氢-1，4-二氧代-2-萘基}乙酰胺(0.52克)的二氯甲烷(10毫升)溶液中加入80％的3-氯过苯甲酸(0.78克)，在室温下搅拌3小时。在反应液中加入饱和碳酸氢钠水溶液，用二氯甲烷萃取。有机层用水和饱和盐水洗净后用无水硫酸钠干燥。蒸发除去溶剂，残余物用硅胶柱色谱(用氯仿∶甲醇50∶1的溶液洗脱)纯化，得到橙色无定形固体N-甲基-N-{3-[2-(甲基磺酰)乙基]氨基-1，4-二氢-1，4-二氧代-2-萘基}乙酰胺(0.39克)。
实施例6：将N-[3-(2-羟基乙基)氨基-1，4-二氢-1，4-二氧代-2-萘基]-N-甲基乙酰胺(0.4克)悬浮在乙醇(3毫升)中，然后加入4M氯化氢/乙酸乙酯溶液(3毫升)，45℃下搅拌1小时。冷却后，滤取产生的沉淀，用乙酸乙酯洗净。所得固体从乙醇-乙酸乙酯中重结晶，得到无色粉末氯化1-(2-羟基乙基)-2，3-二甲基-4，9-二氢-4，9-二氧代-1H-萘并[2，3-d]咪唑-3-鎓(0.28克)。
实施例7：在1-异丙基-2-甲基-4，9-二氢-4，9-二氧代-1H-萘并[2，3-d]咪唑(0.8克)的乙腈(20毫升)溶液中加入苄基溴(1.9毫升)，回流下搅拌6小时。冷却后滤取产生的沉淀，用乙酸乙酯洗净。所得固体从甲醇中重结晶，得到黄色粉末溴化1-苄基-3-异丙基-2-甲基-4，9-二氢-4，9-二氧代-1H-萘并[2，3-d]咪唑-3-鎓(0.47克)。
实施例8：用与实施例6相同的方法，从N-(2-甲氧基乙基)-N-{3-[(2-甲氧基-3-吡啶基)甲基]氨基-1，4-二氢-1，4-二氧代-2-萘基}乙酰胺(0.49克)得到茶色粉末氯化1-(2-羟基-3-吡啶基)甲基-3-(2-甲氧基乙基)-2-甲基-4，9-二氢-4，9-二氧代-1H-萘并[2，3-d]咪唑-3-鎓(0.39克)。
实施例9：在N-{3-[(6-氯-3-吡啶基)甲基]氨基-1，4-二氢-1，4-二氧代-2-萘基}-N-(2-甲氧基乙基)乙酰胺(0.8克)的乙醇(10毫升)溶液中加入4M氯化氢/乙酸乙酯溶液(10毫升)，在室温下搅拌1日。蒸发除去溶剂后，滤取残余物，用乙酸乙酯洗净，得到浅黄色粉末氯化1-[(6-氯-3-吡啶基)甲基]-3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓(0.82克)。
实施例10：在2-氯-N-[1，4-二氢-3-(2-甲氧基乙基)氨基-1，4-二氧代-2-萘基]-N-甲基乙酰胺(0.5克)的四氢呋喃(30毫升)溶液中加入2M二甲基胺/四氢呋喃溶液(3.0毫升)，室温下搅拌18小时。在反应液中加入水，用乙酸乙酯萃取。有机层用水和饱和盐水洗净后用无水硫酸镁干燥。蒸发除去溶剂后，残余物用甲醇结晶，得到褐色粉末N-[1，4-二氢-3-(2-甲氧基乙基)氨基-1，4-二氧代-2-萘基]-N-甲基-2-(二甲基氨基)乙酰胺(0.19克)。
实施例11：在5-[N-乙酰-N-(2-甲氧基乙基)氨基]-4，7-二氢-4，7-二氧代苯并[b]噻吩-2-羧酸甲酯(0.39克)的四氢呋喃(30毫升)溶液中加入2-甲氧基乙胺(0.15毫升)，在室温下搅拌6.5小时。蒸发除去溶剂后，残余物用硅胶柱色谱(用己烷∶乙酸乙酯50∶1的溶液洗脱)纯化，得到紫红色油状5-[N-乙酰-N-(2-甲氧基乙基)氨基]-4，7-二氢-6-(2-甲氧基乙基)氨基-4，7-二氧代苯并[b]噻吩-2-羧酸甲酯(0.39克)。
实施例12：在3-{[3-(N-乙酰-N-甲基)氨基-1，4-二氢-1，4-二氧代-2-萘基]氨基}丙酰胺(0.32克)的甲醇(30毫升)悬浮液中加入4M氯化氢/乙酸乙酯溶液(2.5毫升)，在室温下搅拌16小时。冷却后，蒸发除去溶剂，在乙醇中加热搅拌残余物。冷却后，滤取产生的沉淀，用乙醇洗净，得到无色粉末氯化1-(2-羧基乙基)-4，9-二氢-2，3-二甲基-4，9-二氧代-1H-萘并[2，3-d]咪唑-3-鎓(0.15克)。
用与上述实施例1-9相同的方法得到下表6-20中记载的实施例化合物。
下表3-5中显示了参考例化合物的结构式和理化性质，下表6-20中显示了实施例化合物的结构式和理化性质。另外，具有表21-27中揭示化学结构式的化合物易用与上述实施例或制备方法中记载的方法几乎相同的方法，或用本领域技术人员显然知道的一些变化方法来制得。
表中的缩写如下：Ref表示参考例；Ex表示实施例；Co表示化合物编号；Sal表示盐；Sy表示制备方法(数字表示上述实施例的编号，表明该化合物用与该实施例相同的方法制得)；-表示不存在；Dat表示理化性质(F：FAB-MS(M)+；F′：FAB-MS(M)-；F+：FAB-MS(M+H)+；F-：FAB-MS(M-H)-；E：EI-MS(M)+；N1：1H-NMR(DMSO-d6，TMS作内标)的特征峰δppm)；i-Pr表示异丙基；c-Pr表示环丙基；Ad表示1-金刚烷基；Ac表示乙酰基；Bn表示苄基；Pipe表示哌啶-1-基；Morp表示吗啉-4-基；Py2表示2-吡啶基；Py3表示3-吡啶基；Py4表示4-吡啶基；Th表示2-噻吩基；Fu表示2-呋喃基；Thf表示2-四氢呋喃基；Pyr表示2-吡嗪基；5-MePyr表示5-甲基吡嗪-2-基；Pym表示4-嘧啶基；Qu表示3-喹啉基；Dio表示4-苯并间二氧杂环戊烯基；Im表示4-咪唑基；Bim表示2-苯并咪唑基和In表示2-吲哚基。另外，取代基前的数字表示取代位置，例如，3，4-Cl表示3位和4位分别被-Cl取代。
                              表3
 Ref  B1 -Rf   Dat  Ref  B1 -R1   Dat
 1  Py3  2-NMe2  F+：152  10  Py4  2-NMe2 F+：152
 9  Py3  6-NMe2  F+：152  11  Py3  2-OMe E：138
表4
Figure A0180490500292
(IVa)或(VIa)或(VIIIa)
Ref      -Rg     -Rh     R2            Dat
2 -Cl -Ac -(CH2)2OMe   N1：1.88(3H，s)，2.99(3H，s)，3.3-3.9(4H，m)，7.9-8.2(4H，m)
  3 -NH-(CH2)2OMe -Ac -H   F+：289
  4 -Cl -H -CH2Pyr   F’：299
  5 -Cl -COCH2Cl -Me   F：298
  6 -Cl           -CO(CH2)4-   F+：290
  12 -Cl -Ac -CH2Pyr   F’：341
  13 -NH-CH2(Py3) -Ac -H   F+：322
  14 -NH-CH2(Py4) -Ac -H   F+：322
  15 -NH-CH2(Pyr) -Ac -H   F+：323
  16 -Cl -COCH2OMe -Me   F+：294
表5(IVb)或(VIIIb)
    Ref   Rh     R2     Dat
    7 -H -(CH2)2OMe  F+：296
    8 -Ac -(CH2)2OMe  F+：338
表6
 EX.   -R1   Dat  Ex.   -R1     Dat
  1   -(CH2)2OMe   F+：271   14   -CH2(Py4)   F+：304
  13   -CH2(Py3)   F+：304   15   -CH2(Pyr)   F+：305
表7
 Ex      -Rj Sy                                    Dat
2 -H -  F+：379N1：1.34(3H，br)，3.06(3H，s)，3.1-3.8(4H，m)，4.5-4.8(2H，m)，7.2-7.4(5H，m)，7.77(1H，dt)，7.85(1H，dt)，7.93(1H，br)，7.98(1H，d)，8.03(1H，d)
  16  2-Cl  2  F+：413
  17  3-Cl  2  F+：413
18 4-Cl 2  F+：413N1：1.39(3H，br)，3.06(3H，s)，3.1-3.4(2H，m)，3.4-3.5(1H，m)，3.6-3.9(1H，m)，4.5-4.8(2H，m)，7.27(2H，d)，7.38(2H，d)，7.7-8.1(4H，m)
  19  3，4-Cl  2  F：447
  20  2-OMe  2  F+：409
  21  3-OMe  2  F+：409
  22  4-OMe  2  F+：409
  23  4-Ph  2  F+：455
  24  2-CN  2  F+：404
  25  3-CN  2  F+：404
  26  4-CN  2  F+：404
  27  4-SO2NH2  2  F+：458
  28  4-CF3  2  F+：447
29 4-F 2  F+：397N1：1.40(3H，br)，3.06(3H，s)，3.1-3.6(3H，m)，3.79(1H，br)，4.5-4.8(2H，m)，7.1-7.2(2H，m)，7.2-7.5(2H，m)，7.7-8.2(4H，m)
  30  4-Br  2  F+：457，459
  31  3-CH2NH2  2  F+：408
  32  4-CH2NH2  2  F：407
  33  3-NO2  2  F+：424
34 4-NO2 2  F+：424N1：1.39(3H，br)，3.07(3H，s)，3.1-3.6(3H，m)，3.6-3.9(1H，m)，4.6-5.0(2H，m)，7.54(2H，d)，7.7-8.2(5H，m)，8.19(2H，d)
表8
  Ex   B1   -Rf  Sy                                      Dat
  3   Py3   1-oxide   -   F+：396
35 Py3 -H   2   F+：380N1：1.40(3H，s)，3.06(3H，s)，3.1-3.8(4H，m)，4.6-4.8(2H，m)，7.34(1H，dd)，7.6-8.1(6H，m)，8.4-8.5(2H，m)
36 Py2 -H   2   F+：380N1：1.62(3H，s)，3.06(3H，s)，3.2-3.9(4H，m)，4.5-5.0(4H，m)，7.2-7.5(2H，m)，7.7-8.2(6H，m)，8.54(1H，d)
37 Py4 -H   2   F+：380N1：1.38(1H，br)，3.07(3H，s)，3.1-3.8(4H，m)，4.6-4.8(2H，m)，7.26(2H，d)，7.77(1H，dt)，7.85(1H，dt)，7.95(1H，d)，8.01(1H，d)，8.48(2H，d)
38 Py3 2-Cl   2   F+：414N1：1.49(3H，s)，3.07(3H，s)，3.1-3.4(2H，m)，3.4-3.6(1H，m)，3.6-3.8(1H，m)，4.6-4.9(2H，m)，7.3-7.5(1H，m)，7.7-8.2(6H，m)
39 Py3 6-Cl   2   F+：414N1：1.47(3H，br)，3.07(3H，s)，3.1-3.6(3H，m)，3.6-4.0(1H，m)，4.6-4.9(2H，m)，7.48(1H，d)，7.6-8.1(6H，m)，8.34(1H，d)
  40   Py3   2-OMe   2   F+：410
41 Py3 6-OMe   2   F+：410N1：1.49(3H，s)，3.07(3H，s)，3.1-3.5(3H，m)，3.6-3.9(4H，m)，4.5-4.8(2H，m)，6.79(1H，d)，7.5-7.7(1H，m)，7.7-8.2(5H，m)
  42   Py3   2-NMe2   2   F+：423
  43   Py3   6-NMe2   2   F+：423
  44   Py3   5-Me   2   F+：394
  45   Py3   6-Me   2   F：393
  46   Py3   6-CF3   2   F+：448
47 Py4 2-Cl   2   F+：414N1：1.48(3H，br)，3.09(3H，s)，3.1-3.6(3H，m)，3.6-3.9(1H，m)，4.5-5.0(2H，m)，7.33(1H，d)，7.45(1H，s)，7.6-8.2(5H，m)，8.34(1H，d)
  48   Py4   2-NMe2   2   F+：423
  49   Py4   2-OMe   2   F+：410
表9
 Ex -R1 -R2 Sy                           Dat
4 -(CH2)2OMe -CH2(Py4) - F+：380N1：1.19(3H，s)，3.26(3H，s)，3.47(4H，br)，4.27(1H，d)，4.81(1H，d)，7.10(1H，br)，7.35(2H，d)，7.74(1H，dt)，7.82(1H，dt)，7.92(1H，d)，7.98(1H，d)，8.41(2H，d)
50 -(CH2)2OMe -(CH2)2OMe 2 N1：1.83(3H，s)，3.0-3.8(14H，m)，6.9-7.1(1H，m)，7.7-7.9(2H，m)，7.9-8.1(2H，m)
51 -(CH2)2OMe -Bn 2 N1：1.88(3H，s)，3.23(3H，s)，3.3-3.5(4H，m)，4.4-4.7(2H，m)，6.91(1H，br)，7.1-7.4(5H，m)，7.6-8.1(4H，m)
52 -(CH2)2OMe -CH2(Py3) 4 F+：380N1：1.87(3H，s)，3.25(3H，s)，3.4-3.6(4H，m)，4.31(1H，d)，4.81(1H，d)，7.08(1H，br)，7.23(1H，dd)，7.6-7.8(2H，m)，7.81(1H，t)，7.88(1H，d)，7.98(1H，d)，8.37(1H，d)，8.45(1H，s)
53 -Bn -Bn 2  F+：411
54 -CH2(Py4) -Bn 2  F+：412
55 -CH2(Py3) -Bn 2  F+：412
56 -(CH2)2Ph -(CH2)2OMe 2  F+：393
57 -CH2Th -(CH2)2OMe 2  F+：387
58 -CH2Fu -(CH2)2OMe 2  F+：369
59 -CH2Pyr -(CH2)2OMe 2  F+：381N1：1.60(3H，s)，3.07(3H，s)，3.2-3.8(4H，m)，4.5.5.3(2H，m)，7.5-8.2(5H，m)，8.5-8.8(3H，m)
60 -CH2Qu -(CH2)2OMe 2  F+：430
61 -(CH2)2(Py2) -(CH2)2OMe 2  F+：394
62 -(CH2)2(Py3) -(CH2)2OMe 2  E：393
63 -(CH2)2(Py4) -(CH2)2OMe 2  F+：394
64 -(CH2)2In -(CH2)2OMe 2  F+：432
65 -CH2Dio -(CH2)2OMe 2  F+：423
66 -(CH2)3Im -(CH2)2OMe 2  F+：397
67 -(CH2)2Im -(CH2)2OMe 2  F+：383
68 -CH2Bim -(CH2)2OMe 2  F+：419
69 -(CH2)2O(CH2)2NH2 -(CH2)2OMe 2  F+：376
70 -(CH2)5NH2 -(CH2)2OMe 2  F+：374
71 -(CH2)2O(CH2)2-O(CH2)2NH2 -(CH2)2OMe 2  F+：420
表10
Figure A0180490500331
Ex -B Sy                                Dat
5 -SO2Me  F+：351
72 -OMe 2  F+：303N1：1.83(3H，s)，2.92(3H，s)，3.29(3H，s)，3.4-3.7(4H，m)，7.11(1H，br)，7.7-7.9(2H，m)，7.9-8.1(2H，m)
73 -OPh  2  N1：1.83(3H，s)，2.93(3H，s)，3.6-3.9(2H，m)，4.21(2H，t)，6.8-7.1(3H，m)，7.2-7.5(3H，m)，7.7-7.9(2H，m)，7.9-8.1(2H，m)
74 -OBn  2  N1：2.89(3H，s)，3.90(2H，t)，4.19(3H，s)，4.45(2H，s)，4.89(2H，t)，7.1-7.5(5H，m)，7.9-8.1(2H，m)，8.1-8.3(2H，m)
75 -NMe2 2  F+：316N1：1.83(3H，s)，2.18(6H，s)，2.4-2.6(2H，m)，2.94(3H，s)，3.2-3.5(2H，m)，7.14(1H，t)，7.7-7.9(2H，m)，7.9-8.1(2H，m)
76 -OEt 2  F+：317N1：1.10(3H，t)，1.82(3H，s)，2.92(3H，s)，3.3-3.7(6H，m)，7.09(1H，br)，7.7-7.9(2H，m)，7.9-8.1(2H，m)
77 -OPr 2  F+：331N1：0.85(3H，t)，1.4-1.6(2H，m)，1.83(3H，s)，2.92(3H，s)，3.37(2H，t)，3.4-3.7(4H，m)，7.08(1H，br)，7.7-7.9(2H，m)，7.9-8.1(2H，m)
78 -O(i-Pr) 2  F+：331N1：1.07(6H，d)，1.82(3H，s)，2.92(3H，s)，3.4-3.7(5H，m)，7.08(1H，br)，7.7-7.9(2H，m)，7.9-8.1(2H，m)
79 -O(CH2)2NH2  2  F+：332
80 -OCH2(Py3) 2  F+：413N1：1.79(3H，s)，2.90(3H，s)，3.5-3.8(4H，m)，4.55(2H，s)，7.1-7.3(1H，m)，7.2-7.5(1H，m)，7.7-7.9(3H，m)，7.9-8.1(2H，m)，8.4-8.6(2H，m)
81 -SMe  2  F+：319
82 -NEt2  2  F+：344
83 -N(i-Pr)2  2  F+：372
84 -Pipe  2  F+：356
85 -Morp  2  F+：358
86 -NHAc 2  F+：330N1：1.81(6H，s)，2.90(3H，s)，3.2-3.7(4H，m)，7.36(1H，br)，7.7-8.2(5H，m)
87 -OCONHPh  2  F+：408
88 -CONH2  2  F+：316
89 -CN  2  F+：298
90 -O(CH2)2OMe  2  F+：347
表11
Figure A0180490500341
表12
Ex -R1 -R2 Sy                      Dat
107 -CH2Pyr -CH2Pyr 2  F+：415N1：1.72(3H，s)，4.3-5.3(4H，m)，7.6-8.1(4H，m)，8.2-8.7(5H，m)，8.69(1H，s)，8.79(1H，s)
108 -CH2(Py4) -CH2Pyr 2  F+：414N1：1.58(3H，br)，4.2-5.1(4H，m)，7.29(2H，d)，7.6-8.1(4H，m)，8.28(1H，s)，8.3-8.7(4H，m)，8.78(1H，d)
109 -(CH2)17Me -(CH2)2OMe  2  F+：541
110 -CH2Ad -(CH2)2OMe  2  F：437
111 -CH2CHPh2 -(CH2)2OMe  2  F：469
112 -(CH2)2O(CH2)2OMe -(CH2)2OMe 2  F：391N1：1.84(3H，s)，3.0-3.9(18H，m)，6.9-7.2(1H，m)，7.7-7.9(2H，m)，7.9-8.1(2H，m)
113 -(CH2)2O(CH2)2O(CH2)2OMe -(CH2)2OMe  2  F：435
114 -(CH2)2O(4-BnO-Ph) -(CH2)2OMe  2  F：515
表13表14
 Ex     -B  Sal Sy                               Dat
6 -OH - -  F-：270N1：2.90(3H，s)，3.8(2H，br)，4.17(3H，s)，4.74(2H，t)，7.9-8.2(4H，m)
118 -OMe - 6  F：285N1：2.89(3H，s)，3.25(3H，s)，3.77(2H，t)，4.20(3H，s)，4.8-5.0(2H，m)，7.9-8.3(4H，m)
119 -OPh - 6  F-：346N1：3.01(3H，s)，4.21(3H，s)，4.43(2H，t)，5.13(2H，t)，6.8-7.0(3H，m)，7.2-7.4(2H，m)，7.9-8.1(2H，m)，8.1-8.3(2H，m)
120 -OBn - 6  F-：360N1：2.89(3H，s)，3.90(2H，t)，4.19(3H，s)，4.45(2H，s)，4.89(2H，t)，7.1-7.5(5H，m)，7.9-8.1(2H，m)，8.1-8.3(2H，m)
121 -NMe2 HCl 6  F：298N1：2.8-3.0(6H，m)，3.02(3H，s)，3.5-3.8(2H，m)，4.16(3H，s)，5.0-5.2(2H，m)，7.9-8.1(2H，m)，8.1-8.3(2H，m)，11.2-11.5(1H，br)
122 -OEt - 6  F：299N1：1.06(3H，t)，2.89(3H，s)，3.44(2H，q)，3.80(2H，t)，4.20(3H，s)，4.86(2H，t)，7.9-8.1(2H，m)，8.1-8.3(2H，m)
123 -OPr - 6  F：313N1：0.80(3H，t)，1.3-1.6(2H，m)，2.90(3H，s)，3.35(2H，t)，3.80(2H，t)，4.20(3H，s)，4.87(2H，t)，7.9-8.1(2H，m)，8.1-8.3(2H，m)
124 -O(i-Pr) - 6  F：313N1：1.02(6H，d)，2.89(3H，s)，3.4-3.7(1H，m)，3.79(2H，t)，4.21(3H，s)，4.83(2H，t)，7.9-8.1(2H，m)，8.1-8.3(2H，m)
125 -O(CH2)2NH2  HCl  6  F：314
126 -OCH2(Py3) HCl 6  F：362N1：2.90(3H，s)，3.98(2H，t)，4.21(3H，s)，4.68(2H，s)，4.95(2H，t)，7.8-8.1(3H，m)，8.1-8.4(3H，m)，8.6-8.9(2H，m)
127 -SMe  -  6  F：301
128 -SO2Me  -  6  F：333
129 -NEt2  HCl  6  E：326
130 -N(i-Pr)2  HCl  6  E：354
131 -Pipe  HCl  6  E：338
132 -Morp  HCl  6  E：340
表15
Figure A0180490500371
 Ex       -R1 Sat Sy                   Dat
133 -(CH2)2NHAc - 6  F：312N1：1.76(3H，s)，2.86(3H，s)，3.4-3.7(2H，m)，4.18(3H，s)，4.69(2H，t)，7.9-8.1(2H，m)，8.1-8.3(2H，m)，8.34(1H，t)
 134 -(CH2)2OCONHPh   -  6  F：390
135 -(CH2)3OMe - 6  F：299N1：2.0-2.2(2H，m)，2.88(3H，s)，3.24(3H，s)，3.42(2H，t)，4.18(3H，s)，4.69(2H，t)，7.9-8.1(2H，m)，8.1-8.3(2H，m)
 136 -(CH2)3NMe2 HCl  6  F：312
137 -CH2(Py2) HCl 6  F：318N1：2.96(3H，s)，4.25(3H，s)，6.14(2H，s)，7.3-7.6(1H，m)，7.72(1H，d)，7.8-8.3(5H，m)，8.53(1H，d)
 138 -CH2(Py3) HCl  6  F：318
 139 -CH2(Py4) HCl  6  F：318
 140 -CH2CF3 -  6  F：309
 141 -(CH2)2CONH2 -  6  F：298
 142 -(CH2)2CN -  6  F：280
 143 -(CH2)2O(CH2)2OMe -  6  F：329
 144 -CH2Thf -  6  F：311
 145 -CH2CONH2 -  6  F：284
 146 -CH2CN -  6  F：266
表16
Figure A0180490500381
 Ex -R1 -R2  X  Sal Sy                          Dat
7 -Bn -i-Pr Br - -  F：345N1：1.67(6H，d)，2.95(3H，s)，5.44(1H，br)，6.01(2H，s)，7.3-7.5(5H，m)，7.9-8.3(4H，m)
147 -Bn -(CH2)2OH Cl - 6  F-：346N1：2.88(3H，s)，3.86(2H，t)，4.75(2H，t)，6.02(2H，s)，7.3-7.5(5H，m)，7.9-8.3(4H，m)
148 -(CH2)2OMe -(CH2)2OMe Cl - 6  F-：328N1：2.89(3H，s)，3.24(6H，s)，3.78(4H，t)，4.87(4H，t)，7.9-8.1(2H，m)，8.1-8.3(2H，m)
149 -CH2(Py4) -Bn Cl  HCl  6  F：394
150 -CH2(Py3) -Bn Cl  HCl  6  F：394
151 -(CH2)2Ph -(CH2)2OMe Cl   -  6  F：375
152 -CH2Th -(CH2)2OMe Cl   -  6  F：367
153 -CH2Fu -(CH2)2OMe Cl   -  6  F：351
154 -CH2Pyr -(CH2)2OMe Cl - 6  F：363N1：2.8-3.2(6H，m)，3.84(2H，t)，4.92(2H，t)，6.19(2h，s)，7.8-8.0(2H，m)，8.0-8.2(2H，m)，8.52(1H，dd)，8.62(1H，d)，8.92(1H，d)
155 -CH2Qu -(CH2)2OMe Cl  HCl  6  F：412
156 -(CH2)2(Py2) -(CH2)2OMe Cl  HCl  6  F：376
157 -(CH2)2(Py3) -(CH2)2OMe Cl  HCl  6  F：376
158 -(CH2)2(Py4) -(CH2)2OMe Cl  HCl  6  F：376
159 -(CH2)2In -(CH2)2OMe Cl   -  6  F：414
160 -CH2Dio -(CH2)2OMe Cl   -  6  F：405
161 -(CH2)3Im -(CH2)2OMe Cl HCl 6  F：379N1：2.3-2.6(2H，m)，2.98(3H，s)，3.27(3H，s)，3.79(2H，t)，4.45(2H，t)，4.76(2H，t)，4.86(2Ht)，7.73(1H，d)，7.95(1H，d)，7.9-8.1(2H，m)，8.1-8.3(2H，m)，9.40(1H，s)，15.14(1H，br)
162 -(CH2)2Im -(CH2)2OMe Cl HCl 6  F：365N1：2.71(3H，s)，3.26(3H，s)，3.34(2H，t)，3.79(2H，t)，4.81(2H，t)，5.00(2H，t)，7.50(1H，s)，7.9-8.1(2H，m)，8.1-8.3(2H，m)，9.04(1H，s)，14.76(1H，br)，15.49(1H，br)
163 -CH2Bim -(CH2)2OMe Cl  HCl  6  F：401
表17
Figure A0180490500391
表18
 Ex B1 -Rf  Sal Sy                           Dat
 8  Py3  2-OH  -  -  F：378
9 Py3 6-Cl - -  F：396N1：2.91(3H，s)，3.25(3H，s)，3.79(2H，t)，4.86(2H，t)，6.05(2H，s)，7.59(1H，d)，7.87(1H，dd)，7.9-8.1(2H，m)，8.1-8.3(2H，m)，8.45(1H，d)
180 Py3 H HCl 6  F：362N1：2.93(3H，s)，3.26(3H，s)，3.80(2H，t)，4.88(2H，t)，6.16(2H，s)，7.8-8.3(6H，m)，8.7-8.9(2H，m)
181 Py2 H HCl 6  F：362N1：2.98(3H，s)，3.28(3H，s)，3.84(2H，t)，4.93(2H，t)，6.17(2H，s)，7.3-7.6(1H，m)，7.71(1H，d)，7.8-8.4(5H，m)，8.52(1H，d)
182 Py4 H HCl 6  F：362N1：2.92(3H，s)，3.28(3H，s)，3.83(2H，t)，4.92(2H，t)，6.35(2H，s)，7.9-8.3(6H，m)，8.98(2H，d)
 183  Py3  1-oxide  HCl  6  F：378
184 Py3 2-Cl HCl 6  F：396N1：2.92(3H，s)，3.28(3H，s)，3.84(2H，t)，4.93(2H，t)，6.03(2H，s)，7.3-7.6(2H，m)，7.9-8.0(2H，m)，8.0-8.3(2H，m)，8.42(1H，dd)
185 Py4 2-OH - 8  F：378N1：2.84(3H，s)，3.26(3H，s)，3.81(2H，t)，4.88(2H，t)，5.84(2H，s)，5.96(1H，s)，6.22(1H，dd)，7.44(1H，d)，7.9-8.1(2H，m)，8.1-8.3(2H，m)
186 Py3 6-OMe HCl 6  F：392N1：2.92(3H，s)，3.24(3H，s)，3.7-4.0(5H，m)，4.6-5.5(2H，m)，5.97(2H，s)，6.87(1H，d)，7.75(1H，d)，7.9-8.1(2H，m)，8.1-8.4(3H，m)
 187  Py3  2-NMe2  HCl  6  F：405
 188  Py3  6-NMe2  HCl  6  F：405
 189  Py3  5-Me  HCl  6  F：376
 190  Py3  6-Me  HCl  6  F：376
 191  Py3  6-CF3  HCl  6  F：430
192 Py4 2-Cl HCl 6  F：396N1：2.87(3H，s)，3.27(3H，s)，3.81(2H，t)，4.90(2H，t)，6.09(2H，s)，7.3-7.5(3H，m)，7.8-8.4(4H，m)，8.45(1H，d)
 193  Py4  2-NMe2  HCl  6  F：405
表19
Ex -Rj  Sal Sy                               Dat
194 H - 6  F：361N1：2.85(3H，s)，3.24(3H，s)，3.80(2H，t)，4.88(2H，t)，6.05(3H，s)，7.2-7.5(5H，m)，7.9-8.3(4H，m)
195  2-Cl -  6  F：395
196  3-Cl -  6  F：395
197 4-Cl - 6  F：395N1：2.85(3H，s)，3.24(3H，s)，3.79(2H，t)，4.86(2H，t)，6.02(2H，s)，7.34(2H，d)，7.48(2H，d)，7.9-8.1(2H，m)，8.1-8.3(2H，m)
198  3，4-Cl -  6  F+：431
199  2-OMe -  6  F：391
200  3-OMe -  6  F：391
201  4-OMe -  6  F：391
202  4-Ph -  6  F：437
203  3-CN -  6  F：386
204  4-CN -  6  F：386
205  4-SO2NH2 -  6  F：440
206  4-CF3 -  6  F：429
207 4-F - 6  F：379N1：2.87(3H，s)，3.24(3H，s)，3.79(2H，t)，4.87(2H，t)，6.03(2H，s)，7.1-7.6(4H，m)，7.9-8.1(2H，m)， 8.1-8.3(2H，m)
208  4-Br -  6  F：439，441
209  3-CH2NH2 HCl  6  F：390
210  4-CH2NH2 HCl  6  F：390
211  3-NO2 -  6  F：406
212 4-NO2 - 6  F：406N1：2.87(3H，s)，3.26(3H，s)，3.81(2H，t)，4.89(2H，t)，6.18(2H，s)，7.61(2H，d)，7.9-8.4(6H，m)
表20表21
 Co      R1        R2  R3  Co      R1         R2     R3
1 -CH2CH＝CHCH2OMe -(CH2)2N(Bn)2 Me 18 -(CH2)2OMe     -(CH2)2N(Me)COPh    Me
  2 -(CH2)2OMe    -CH(Ph)CO2Et  Me  19     Me     -(CH2)2NO2    Me
  3 -(CH2)2OMe    -(CH2)2SO2NH2  Me  20  -(CH2)2OMe     -(CH2)2CN    Me
  4     Me    -(CH2)2SCH2Ph  Me  21  -(CH2)2OMe     -CH2COPh    Me
  5 -(CH2)2OMe    -(CH2)2CO2H  Me  22  -(CH2)2OMe     -CH2CONH2    Me
  6 -(CH2)2OMe    -(CH2)2CO(Pyr)  Me  23  -(CH2)2OMe     -(CH2)2OAc    Me
  7 -(CH2)2OMe    -(CH2)2CONH2  Me  24     Me     -(CH2)2Ac    Me
8 -(CH2)2OMe       -(CH2)2N[(CH2)2NMe2]2  Me  25  -(CH2)2NH(CH2)2NH2     -(CH2)2N(Me)Bn    Me
9 -(CH2)2OMe   -(CH2)2O(CH2)2NH(CH2)2NMe2  Me  26  -(CH2)2OMe     -(CH2)2NHSO2Me    Me
10 -(CH2)2OMe -(CH2)2O(Py4) Me 27 -(CH2)2OMe     -(CH2)2CONHOMe    Me
11 -CH2C≡CCH2OMe        -(CH2)2NHCONH2  Me  28  -(CH2)2OMe     CH2CO2Et-(CH2)2OCO Me
  12 -(CH2)2OMe     -(CH2)2CO2Me  Me  29     Me    -(CH2)2SOMe    Me
  13 -(CH2)2OMe         Me  CF3  30  -(CH2)2OMe        Me   c-Pr
  14 -CH2(Pyr)     -(CH2)2OMe  H  31     Me    -(CH2)2OMe -(CH2)2OMe
  15 -(CH2)2OMe     -(CH2)2O(CH2)2NMe2  Me  32  -(CH2)2OMe    -(CH2)3O(CH2)2NMe2    Me
16 -(CH2)2O(c-Pr) -(CH2)2OMe Me 33  -(CH2)2O-(CH2)2(Morp) -(CH2)2OMe Me
  17 -(CH2)2OMe     -(CH2)2OCH2-  34  -(CH2)2OMe     -(CH2)2N(Me)CH2-
表22
Figure A0180490500432
  Co     R1   R3     R4  Co     R1   R3     R4
  35   -CH2(Py4)   Me     7-CF3  37  -CH2(Pyr)   H     6-NMe2
  36   -CH2(Py3)   Me   5-CH2NH2  38  -(CH2)2OMe   Me     5-NO2
表23
  Co     R2 R3    R4  Co     R2  R3       R4
  39   -CH2(Pyr) Me   5-F  57 -CH2(Py4) i-Pr      5-OMe
  40   -CH2(Py4) Me   6-F  58 -CH2(Py3) Me      6-OMe
  41   -(CH2)2OMe Me   7-F  59 -CH2(Pyr) Me      7-OMe
  42   -CH2(Py3) H   8-F  60 -(CH2)2OMe Me      8-OMe
  43   -CH2(Pyr) Me   8-CN  61 -CH2(Py4) Me      5-CN
  44   -CH2(Py3) Me   5-CF3  62 -CH2(Py3) Et      6-CN
  45   -(CH2)2OMe Et   6-CF3  63 -(CH2)2OMe Me      7-CN
  46   -(CH2)2OMe Me   5，8-OH  64 -CH2(Pyr) Me      8-CF3
  47   -CH2(Py4) Me   8-CH2NH2  65 -(CH2)2OMe Me    5-CH2N(Me)Bn
  48   -CH2(Py4) Me   7-Me  66 -(CH2)2OMe H     6-CH2NH2
  49   -CH2(Py3) Me   8-Me  67 -CH2(Pyr) Me     7-CH2NH2
  50   -(CH2)2OMe Me   7-NMe2  68 -CH2(Py4) Me     6-Me，7-F
  51   -CH2(Py4) Me   8-NMe2  69 -CH2(Py3) Me     5-NMe2
  52   -CH2(Pyr) Me   6，7-diMe  70 -(CH2)2OMe Me     5，8-OMe
  53   -CH2(Py4) H   6-NO2  71 -(CH2)2OMe Me 5-CH2N(Me)COPh
  54   -(CH2)2OMe Me   5-Me  72 -CH2(Py3) Me     7-NO2
  55   -CH2(Pyr) i-Pr   6-Me  73 -CH2(Pyr) Me     8-NO2
  56   -(CH2)2OMe Me   5-CH2NMe2  74 -(CH2)2OMe Me   5-CH2(Morp)
表24
  Co     R1       R2    X   Co      R1       R2  X
  75   -CH2(Pyr)   -(CH2)2OMe   Br   81   -CH2(Pyr)   -(CH2)2CO2 -  -
  76   -CH2(Py3)   -(CH2)2OMe   Br   82   -CH2(Py4)   -(CH2)2CO2 -  -
  77   -CH2(Py4)   -(CH2)2OMe   AcO   83   -CH2(Py3)   -CH2CO2 -  -
  78   -CH2(Pyr)   -(CH2)2OMe   AcO   84   -(CH2)2OMe   -CH2CO2 -  -
  79   -CH2(Py3)   -(CH2)2OMe  PhSO3   85   -CH2(Py4)   -(CH2)2OMe  I
  80   -(CH2)2OMe   -(CH2)2OMe  PhSO3   86   -(CH2)2OMe   -(CH2)2OMe  I
表25
Figure A0180490500451
表26表27

Claims (12)

1.一种下述通式(I)表示的稠合的咪唑鎓衍生物
Figure A0180490500021
式中的记号具有以下意思：
R1和R2：相同或不同，各自表示-(具有一个或多个选自B组的取代基的低级烷基)、-(具有一个或多个选自B组的取代基的低级链烯基)、-(具有一个或多个选自B组的取代基的低级炔基)、-RinD、-低级烷基、-低级链烯基或-低级炔基，条件是R1和R2中的至少一个是-(具有一个或多个选自B组的取代基的低级烷基)、-(具有一个或多个选自B组的取代基的低级链烯基)、-(具有一个或多个选自B组的取代基的低级炔基)、-(有一个或多个取代基的环烷基)或-(可有一个或多个取代基的5至7元饱和杂环)，
B组：-ORa、-SRa、-前药化的OH、-O-低级亚烷基-ORa、-O-低级亚烷基-O-低级亚烷基-ORa、-O-低级亚烷基-NRaRb、-O-低级亚烷基-O-低级亚烷基-NRaRb、-O-低级亚烷基-NRc-低级亚烷基-NRaRb、-OCO-NRaRb、-SORa、-SO2Ra、-SO2NRaRb、-NRa-SO2Rb、-CO2H、-NRaRb、-NRc-低级亚烷基-NRaRb、-N(-低级亚烷基-NRaRb)2、-RinD、-NO2、-CN、-卤素、-CO2Ra、-COO-、-CONRaRb、-CONRa-O-Rb、-NRa-CORb、-NRa-CO-NRbRc、-OCORa和-CO-Ra，
Ra、Rb和Rc：相同或不同，各自表示-H、-低级烷基、-低级亚烷基-RinD或-RinD，
RinD：-(可有一个或多个取代基的5至7元饱和杂环)，-(可有一个或多个取代基的环烷基)、-(可有一个或多个取代基的环烯基)、-(可有一个或多个取代基的芳基)或-(可有一个或多个取代基的杂芳基)，
R3：-H或-(可有一个或多个取代基的低级烷基)，或R2和R3可一起形成具有2-5个碳原子的可被O、S或NR4中断的低级亚烷基，其中R4是-H或-低级烷基，
A环：可有一个或多个取代基的芳环或可有一个或多个取代基的杂芳环，和
X-：抗衡阴离子，条件是当B组的取代基-COO-与咪唑鎓阳离子形成分子内盐时，X-不存在，
条件是具有下列R1和R2组合的化合物被排除在外：
(1)一个是-低级亚烷基-(可有一个或多个取代基的芳基)，另一个是-CH3、-(CH2)3CH3或-苯基，
(2)一个是-低级亚烷基-CO-(可有一个或多个取代基的芳基)，另一个是-(CH2)2CH(CH3)2或-(CH2)3CH3，或
(3)R1和R2均为-苄基、-(CH2)2OC2H5或-(CH2)2O-COCH3。
2.根据权利要求1所述的稠合的咪唑鎓衍生物，其中R1和R2的至少一个是-(具有一个或多个选自B组的取代基的低级烷基)、-(具有一个或多个选自B组的取代基的低级链烯基)、-(具有一个或多个选自B组的取代基的低级炔基)、-(具有一个或多个选自C组的取代基的环烷基)或-(可有一个或多个选自C组的取代基的5-7元饱和杂环)；C组是-低级烷基、-卤素、-卤代低级烷基、-ORa、-O-低级亚烷基-ORa、-SRa、-NRaRb、-NO2、-CN、-CO2Ra、-CO-NRaRb、-CORa、-NRa-CORb、-SO2NRaRb、-低级亚烷基-NRaRb、-芳基、-低级亚烷基-芳基和-OCO-Ra；RinD是-(可有一个或多个选自C组的取代基的5-7元饱和杂环)，-(可有一个或多个选自C组的取代基的环烷基)、-(可有一个或多个选自C组的取代基的环烯基)、-(可有一个或多个选自C组的取代基的芳基)或-(可有一个或多个选自C组的取代基的杂芳基)；R3是-H或-(可有一个或多个选自B组的取代基的低级烷基)，或R2和R3可一起形成具有2-5个碳原子、可被O、S或NR4中断的低级亚烷基；A环是可有一个或多个选自C组的取代基的芳环，或是可有一个或多个选自C组的取代基的杂芳环。
3.根据权利要求2所述的稠合的咪唑鎓衍生物，其中R1和R2的至少一个是具有一个或多个选自B组的取代基的低级烷基；R3是甲基；A环是可有一个或多个选自C组的取代基的苯环、或是可有一个或多个选自C组的取代基的选自噻吩、呋喃、吡咯、咪唑、噁唑、噻唑、吡啶、吡嗪、哒嗪和嘧啶环的杂芳环。
4.根据权利要求2或3所述的稠合的咪唑鎓衍生物，其中R1和R2的至少一个是具有一个或多个取代基的低级烷基，该取代基选自-ORa、-NRaRb、-NRa-CORb、-O-低级亚烷基-ORa、-O-低级亚烷基-O-低级亚烷基-ORa、-SRa、-CONRaRb、-CN、-(可有一个或多个选自C组的取代基的环烷基)、-(可有一个或多个选自C组的取代基的5-7元饱和杂环)、-(可有一个或多个选自C组的取代基的芳基)和-(可有一个或多个选自C组的取代基的杂芳基)。
5.根据权利要求2或3所述的稠合的咪唑鎓衍生物，其中R1和R2的至少一个是具有一个选自下列的取代基的低级烷基，该取代基选自-(可有一个或多个选自C组的取代基的选自吡啶基、吡嗪基和嘧啶基的杂芳基)、-O-低级亚烷基-O-低级烷基和-O-低级烷基；A环是可被-NO2取代的苯环。
6.根据权利要求1所述的稠合的咪唑鎓衍生物，其中它选自1-[(6-氯-3-吡啶基)甲基]-3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1，2-二甲基-4，9-二氧代-3-[(2-四氢呋喃基)甲基]-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1，3-二(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-1-(2-吡嗪基甲基)-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1-[3-(1H-4-咪唑基)丙基]-3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、3-(2-甲氧基乙基)-2-甲基-1-[(5-甲基-2-吡嗪基)甲基]-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、2-甲基-4，9-二氧代-1，3-二(2-吡嗪基甲基)-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1-[2-(2-甲氧基乙氧基)乙基]-3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1-{2-[2-(2-甲氧基乙氧基)乙氧基]乙基}-3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1-(2-甲氧基乙基)-2-甲基-4，9-二氧代-3-(3-吡啶基甲基)-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-1-(2-吡啶基甲基)-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-1-(4-吡啶基甲基)-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1-[(2-氯-3-吡啶基)甲基]-3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1-[(2-羟基-4-吡啶基)甲基]-3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、3-(2-甲氧基乙基)-1-[(6-甲氧基-3-吡啶基)甲基]-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1-[(2-氯-4-吡啶基)甲基]-3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1-(4-氯苄基)-3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓、1-(4-氟苄基)-3-(2-甲氧基乙基)-2-甲基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓和1，3-二(2-甲氧基乙基)-2-甲基-5-硝基-4，9-二氧代-4，9-二氢-1H-萘并[2，3-d]咪唑-3-鎓或其互变异构体和其与卤素离子的盐。
7.一种药物组合物，它包含权利要求1所述的稠合的咪唑鎓衍生物和制药学上容许的载体。
8.根据权利要求7所述的药物组合物，其中该药物组合物是抗癌药。
9.一种由下述通式(II)表示的2-酰基氨基-3-氨基-1，4-醌衍生物或其盐式中的记号具有以下意思：
R1和R2：相同或不同，各自表示-(具有一个或多个选自B组的取代基的低级烷基)，-(具有一个或多个选自B组的取代基的低级链烯基)、-(具有一个或多个选自B组的取代基的低级炔基)、-RinD、-低级烷基、-低级链烯基或-低级炔基，条件是R1和R2中的至少一个是-(具有一个或多个选自B组的取代基的低级烷基)、-(具有一个或多个选自B组的取代基的低级链烯基)、-(具有一个或多个选自B组的取代基的低级炔基)、-(有一个或多个取代基的环烷基)或-(可有一个或多个取代基的5至7元饱和杂环)，
B组：-ORa、-SRa、-前药化的OH、-O-低级亚烷基-ORa、-O-低级亚烷基-O-低级亚烷基-ORa、-O-低级亚烷基-NRaRb、-O-低级亚烷基-O-低级亚烷基-NRaRb、-O-低级亚烷基-NRc-低级亚烷基-NRaRb、-OCO-NRaRb、-SORa、-SO2Ra、-SO2NRaRb、-NRa-SO2Rb、-CO2H、-NRaRb、-NRc-低级亚烷基-NRaRb、-N(-低级亚烷基-NRaRb)2、-RinD、-NO2、-CN、-卤素、-CO2Ra、-CONRaRb、-CONRa-O-Rb、-NRa-CORb、-NRa-CO-NRbRc、-OCORa和-CO-Ra，
Ra、Rb和Rc：相同或不同，各自表示-H、-低级烷基、-低级亚烷基-RinD或-RinD，
RinD：-(可有一个或多个取代基的5至7元饱和杂环)，-(可有一个或多个取代基的环烷基)、-(可有一个或多个取代基的环烯基)、-(可有一个或多个取代基的芳基)或-(可有一个或多个取代基的杂芳基)，
R3：-H或-(可有一个或多个取代基的低级烷基)，或R2和R3可一起形成具有2-5个碳原子的可被O、S或NR4中断的低级亚烷基，其中R4是-H或-低级烷基，和
A环：可有一个或多个取代基的芳环或可有一个或多个取代基的杂芳环，
条件是排除下表中的化合物；
                 表1
Figure A0180490500061
上表中，Comp指化合物编号，Me指甲基，Et指乙基，Ph指苯基，另外，在取代的苯基场合，取代基和取代位置显示在Ph之前，例如，3，4-Cl-Ph表示3，4-二氯苯基。
10.一种药物组合物，它包含权利要求9所述的2-酰基氨基-3-氨基-1，4-醌衍生物或其盐，以及制药学上容许的载体。
11.根据权利要求10所述的药物组合物，其中该药物组合物是抗癌药。
12.一种以下通式(III)表示的稠合的咪唑衍生物或其盐，
式中的记号具有以下意思：
R1：-(具有一个或多个选自B组的取代基的低级烷基)，-(具有一个或多个选自B组的取代基的低级链烯基)、-(具有一个或多个选自B组的取代基的低级炔基)或-(具有一个或多个取代基的环烷基)，条件是排除具有一个或多个选自-NH2、-NMe2、-NEt2、-OH、-卤素和-(可被-Cl、-F、-Me或-OMe取代的苯基)的取代基的低级烷基，
B组：-ORa、-SRa、-前药化的OH、-O-低级亚烷基-ORa、-O-低级亚烷基-O-低级亚烷基-ORa、-O-低级亚烷基-NRaRb、-O-低级亚烷基-O-低级亚烷基-NRaRb、-O-低级亚烷基-NRc-低级亚烷基-NRaRb、-OCO-NRaRb、-SORa、-SO2Ra、-SO2NRaRb、-NRa-SO2Rb、-CO2H、-NRaRb、-NRc-低级亚烷基-NRaRb、-N(-低级亚烷基-NRaRb)2、-RinD、-NO2、-CN、-卤素、-CO2Ra、-CONRaRb、-CONRa-O-Rb、-NRa-CORb、-NRa-CO-NRbRc、-OCORa和-CO-Ra，
Ra、Rb和Rc：相同或不同，各自表示-H、-低级烷基、-低级亚烷基-RinD或-RinD，
RinD：-(可有一个或多个取代基的5至7元饱和杂环)，-(可有一个或多个取代基的环烷基)、-(可有一个或多个取代基的环烯基)、-(可有一个或多个取代基的芳基)或-(可有一个或多个取代基的杂芳基)，
R3：-H或-(可有一个或多个取代基的低级烷基)，和
A环：可有一个或多个取代基的芳环或可有一个或多个取代基的杂芳环。
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