CN1993329A - 作为神经激肽受体拮抗剂的喹啉衍生物 - Google Patents
作为神经激肽受体拮抗剂的喹啉衍生物 Download PDFInfo
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- CN1993329A CN1993329A CNA2005800263487A CN200580026348A CN1993329A CN 1993329 A CN1993329 A CN 1993329A CN A2005800263487 A CNA2005800263487 A CN A2005800263487A CN 200580026348 A CN200580026348 A CN 200580026348A CN 1993329 A CN1993329 A CN 1993329A
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- Prior art keywords
- alkyl
- group
- phenyl
- randomly
- compound
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- 229940044551 receptor antagonist Drugs 0.000 title description 4
- 102000009493 Neurokinin receptors Human genes 0.000 title description 2
- 108050000302 Neurokinin receptors Proteins 0.000 title description 2
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 title description 2
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- CPWKEFDYIVVJHG-UHFFFAOYSA-N quinoline-4-carbohydrazide Chemical class C1=CC=C2C(C(=O)NN)=CC=NC2=C1 CPWKEFDYIVVJHG-UHFFFAOYSA-N 0.000 claims abstract description 3
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- KONLJZOUIRNGGA-UHFFFAOYSA-N 3-(morpholin-4-ylmethyl)-2-phenylquinoline-4-carboxylic acid Chemical compound C=1C=CC=CC=1C1=NC2=CC=CC=C2C(C(=O)O)=C1CN1CCOCC1 KONLJZOUIRNGGA-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
本发明涉及本文定义的取代的喹啉-4-羧酸酰肼,含有它们的药物组合物以及它们在治疗由神经激肽-2和/或神经激肽-3(NK-3)受体所介导的疾病中的用途。
Description
本发明涉及在此定义的取代的喹啉-4-羧酸酰肼,含有它们的药物组合物以及它们在治疗由神经激肽-2和/或神经激肽-3(NK-3)受体所介导的疾病中的用途。因此这些化合物能够被用于抑制和治疗这些紊乱的治疗方法中。
在文献综述例如Giardina和Raveglia,Exp.Opin.Ther.Patents(1997)7(4):307-323和Giardina等,Exp.Opin.Ther.Patents(2000)10(6):939-960中可以发现关于NK-3受体拮抗剂的背景资料。这些参考文献还包含了关于用NK-3拮抗剂治疗疗法的临床前验证的相关信息。
在WO-A-9719926(SmithKline Beecham S.p.a.)和US-A-5741910(Sanofi)中能够得到现有技术中作为NK-3拮抗剂制备的化合物的典型例子。在国际专利申请no.PCT/GB2004/000415中公开了作为NK-3和/或NK-2受体拮抗剂的结构上相关的化合物。
本发明因此提供了一种式(I)化合物:
其中:
R1是芳基或杂芳基环,其中芳基是苯基或萘基并且杂芳基是包含1、2、3或4个氮原子和/或氧或硫原子且条件是至多存在两个氮原子的5-元不饱和环,或者是包含1、2或3个氮原子的6-元不饱和环,所述环任选地被一个、两个或三个独立地选自羟基、卤素、硝基、氰基、氨基、CF3、C1-4烷基、C2-4烯基和C2-4炔基的基团所取代;
或者R1是ORa、C(O)Ra、COORa、S(O)2Ra、NRaRb、CONRaRb、SO2NRaRb或具有3到8个环原子的非芳香环,所述环任选地包含双键,并且所述环任选地包含1、2或3个选自N、O或S的杂原子或者包含C(O)、S(O)、S(O)2、NH或NC1-4烷基基团,并且所述环还任选地与芳基稠合,并且所述环进一步任选地通过(CH2)1-4桥联,以及所述环还任选地被1、2或3个独立地选自羟基、卤素、NO2、CN、NH2、CF3、C1-4烷基、C2-4烯基、C2-4炔基、ORa和CO2Ra的基团所取代,
其中Ra和Rb独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基和(CH2)0-3芳基,任选地被羟基或卤素取代,
或者,当R1是CONRaRb或SO2NRaRb时,Ra、Rb和与它们相连的氮原子一起组成哌啶、哌嗪、吡咯烷、吗啉、氮丙啶、氮杂环丁烷或氮杂环,其任选地被羟基、C1-4烷基或C1-4烷氧基所取代;
R2是氢、羟基、卤素或CN;
或者R2是C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、C1-6烷氧基、(CH2)0-6NRcRd、被NRcRd取代的C1-6烷氧基、OC3-8环烷基、OHet、Het、O杂芳基、杂芳基、O芳基、芳基、(CH2)0-4NReC(O)Rf、(CH2)0-4NReC(O)ORf、(CH2)0-4NReS(O)2Rf、SO2Rc、SO2NRcRd、COORc、C(O)Rc、C(O)NRcRd,
任选地被1到8个卤素原子取代,
其中Rc、Rd、Re和Rf独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基和芳基,
或者Rc和Rd,与和它们相连的氮原子一起,形成饱和的含氮3-7元杂环,该杂环任选地包含进一步的氮或氧原子并且任选地被NR’R”所取代,
其中R’和R”独立地选自氢和C1-6烷基,
或者Re和Rf连接成为C2-6亚烷基、C2-6亚烯基或C3-6亚炔基基团,
任选地被羟基或卤素取代,
其中Het如下文所定义;
R3是氢或C1-6烷基;
R4是氢、C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、芳基或芳基C1-6烷基,任选地被羟基、C1-6烷氧基、CN、NH2、或1到8个卤素原子所取代;
或者R4是包含至少一个芳环并且具有5、6、9或10个环原子的片段,所述环原子中1、2、3或4个原子是独立地选自N、O和S的杂原子,所述环系统在任意可取代位置上任选地被1、2或3个选自羟基、卤素、NO2、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基或C(O)OC1-6烷基的基团所取代,所述基团任选地被1到8个卤素原子取代;
R5是氢、C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、芳基、芳基C1-6烷基、(CH2)0-4杂芳基、(CH2)0-4Het、C(O)NRgRh、S(O)2NRgRh、S(O)2Rg、C(O)ORg或C(O)Rg,
其中Rg和Rh分别独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、(CH2)0-4C3-8环烷基、(CH2)0-4芳基、(CH2)0-4杂芳基和(CH2)0-4Het,任选地被羟基和1到8个卤素原子所取代;
或者R4和R5,与和它们相连的氮原子一起,形成具有3到10个环原子的单-或二环片段,所述环原子中任选地1、2、3或4个原子为独立地选自N、O和S的杂原子,所述环系统在任意可取代位置上任选地被1、2或3个选自卤素、NO2、CN、NH2、氧代基、C1-4烷基、C2-4烯基、C2-4炔基和C1-6烷氧基的基团所取代,所述基团任选地被1到8个卤素原子取代;
X和Y独立地选自氢、羟基、硝基、氰基、CF3、卤素、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、C1-6烷氧基、C(O)NRiRj、CO2Ri、(CH2)0-4NRkRm、SO2Ri和SO2NRiRj,任选地被卤素所取代;
Ri和Rj独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基和(CH2)0-4芳基;
Rk和Rm独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、芳基、C(O)Rp、COORp和S(O)2)Rp;
Rp是氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基或(CH2)0-4芳基;
或其药学上可接受的盐;
前提条件是式(I)化合物不是:
其中:
R1是芳基或杂芳基环,其中芳基是苯基或萘基并且杂芳基是包含1、2、3或4个氮原子和/或氧或硫原子且条件是至多存在两个氮原子的5-元不饱和环,或者是包含1、2或3个氮原子的6-元不饱和环,所述环任选地被一个、两个或三个独立地选自羟基、卤素、硝基、氰基、氨基、CF3、C1-4烷基、C2-4烯基和C2-4炔基的基团所取代;
R2是羟基、C1-6烷氧基、C1-6烷基、氨基、NR’R”或C1-6烷基-NR’R”其中R’和R”独立地选自氢和C1-4烷基并且其中R’和R”与和它们相连的氮原子一起形成含氮的饱和3-7元杂环,所述杂环任选地包含进一步的氮原子并且任选地被上述定义的NR’R”所取代,或者R2是被上述定义的NR’R”所取代的C1-6烷氧基;
R3是氢或C1-6烷基;
R4是氢、C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、芳基或芳基C1-6烷基;
R5是氢、C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、芳基、芳基C1-6烷基或C1-6烷氧基羰基;
或者R4和R5,与和它们相连的氮原子一起,形成C3-C10单-或二环的饱和环;
X和Y独立地选自氢、羟基、硝基、氨基、氰基、CF3、卤素和C1-4烷基;
或其药学上可接受的盐;
适合的R1基团的实例包括氮杂双环[3.2.2]壬基、二氢喹啉基、四氢喹啉基、二氢异喹啉基和四氢异喹啉基。
R1优选是未取代的或被羟基、卤素、硝基、氰基、氨基、CF3或CH3单取代。优选地,R1是芳基例如苯基,或Het。更优选地,R1是
其中
被定义为4-到7-元杂脂肪环,所述杂脂肪环中包含1、2或3个选自N、O或S的杂原子,或者包含S(O)、S(O)2、NH或NC1-4烷基基团,所述环通过氮原子连接。最优选地,R1是氮丙啶、氮杂环丁基、吡咯烷基、哌啶基、氮杂基或哌嗪基,尤其是吡咯烷基或哌啶基,其中所述环任选地被1、2或3个独立地选自羟基、卤素、NO2、CN、NH2、CF3、C1-4烷基、C2-4烯基和C2-4炔基的基团所取代,优选被羟基、卤素、CF3或C1-4烷基所取代,更优选被CF3或C1-4烷基所取代。
优选地,R2是C1-6烷基、C1-6烷氧基或NRcRd,其被1到8个卤素原子取代,优选地被1到5个氟、氯或溴原子所取代。合适的R2基团的实例包括CH2F、CHF2、CF3、CH2CF3、OCF3、OCH2CF3、N(H)CF3、N(H)CH2CF3、N(CH3)CF3、N(CH3)CH2CF3、N(CF3)2、N(CF3)CH2CF3、N(CH2CF3)2、N(CH2CH3)CH2CF3。优选R2基团是N(H)CH2CF3和OCH2CF3。
合适的具有9个环原子的R4片段实例包括吡唑并嘧啶基、咪唑并吡啶基、嘌呤基、吲哚基、二氢吲哚基、异二氢吲哚基、苯并呋喃基、二氢苯并呋喃基、N-邻苯二酰苯胺基、苯并噻吩基、吲唑基、苯并咪唑基、苯并唑基、苯并异唑基、苯并噻唑基、苯并三唑基。
合适的具有10个环原子的R4片段实例包括2,3-二氮杂萘基、喹唑啉基、喹喔啉基、嘧啶并嘧啶基、萘啶基、蝶啶基、苯并吡喃基、苯并二氢吡喃基、苯并噻嗪基、喹啉基、异喹啉基、吡啶并吡啶基、蝶啶基。
优选地,R4是苯基或包含1、2或3个选自N、O和S的杂原子的五-或六-元芳环,其中R4在任意取代位置任选地被1、2或3个选自卤素、CF3、C1-4烷基和CN的基团所取代。
包含1、2或3个选自N、O和S的杂原子的五-元芳环例子包括吡咯基、吡唑基、咪唑基、三唑基、呋喃基、噻吩基、唑基、异唑基、噻唑基、异噻唑基、二唑基和噻二唑基。优选的五-元环是噻吩基和噻唑基。
包含选自N、O和S的1、2或3个杂原子的六元芳环例子包括吡啶基、吡嗪基、嘧啶基、哒嗪基、三嗪基和对噻嗪基。优选的六-元环是吡啶基和嘧啶基。
优选地,R4是未取代的或被1或2个选自卤素、CF3、甲基、乙基和CN的基团所取代。
R5优选是氢、C1-6烷基、芳基、S(O)2Rg、C(O)ORg或C(O)Rg,其中Rg如先前所定义。更优选地,R5是氢、C1-4烷基、苯基、S(O)2Rg或C(O)Rg,其中Rg是C1-6烷基或杂芳基。最优选地,R5是氢、甲氧基羰基、乙基、甲基、苯基、S(O)2CH3、C(O)CH3、
当R4和R5,与和它们相连的氮原子一起,形成单-或二环时,其优选包含5到8个碳原子,例如氮杂环庚烷基或六氢环戊二烯并[c]吡咯-2(1H)-基。
X和Y优选独立地为氢或甲基,最优选氢。
在本发明的一个实施方案中,提供了式(Ia)化合物:
或其药学上可接受的盐,
其中R4如式(I)中所定义,R5为C(O)NRgRh、S(O)2NRgRh、S(O)2Rg、C(O)OPh、C(O)OCH2Ph或C(O)Rg,其中Rg如式(I)中所定义。
优选地,R4是苯基、吡啶基、嘧啶基或苯并噻唑基,任选地被1或2个选自卤素、CF3、甲基、乙基和CN的基团所取代。
优选地,R5是S(O)2Rg、C(O)OCH2Ph或C(O)Rg,其中Rg选自甲基、乙基、异-丙基、苯甲基、(CH2)0-1杂芳基、苯基、(CH2)0-1C3-8环烷基和(CH2)0-1Het,任选地被1到5个氟原子所取代。
在本发明的另一个实施方案中,提供了式(Ib)化合物:
或其药学上可接受的盐,
其中R4是C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、芳基或芳基C1-6烷基,并且被羟基和1到8个卤素原子所取代,
或者R4是包含至少一个芳环并且具有5、6、9或10个环原子的片段,所述环原子中1、2、3或4个原子是独立地选自N、O和S的杂原子,所述环系统在任意可取代位置上任选地被1、2或3个选自羟基、卤素、NO2、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基和C(O)OC1-6烷基的基团所取代,所述基团任选地被1到8个卤素原子取代;和
R5如式(I)中所定义。
优选地,R4是被1或2个选自卤素、CF3、OCF3、甲基、乙基和CN的基团所取代的苯基,
或者R4是被1或2个选自卤素、C1-4烷基、C1-4烷氧基、CF3、OCF3和NH2的基团所取代的吡啶基、嘧啶基或苯并噻唑基。
优选地,R5是氢、C1-6烷基、芳基、S(O)2Rg、C(O)ORg或C(O)Rg,其中Rg如式(I)中所定义。更优选地,R5是S(O)2Rg、C(O)OCH2Ph或C(O)Rg,其中Rg选自甲基、乙基、异-丙基、(CH2)0-1苯基、(CH2)0-1C3-8环烷基、(CH2)0-1杂芳基和(CH2)0-1Het,任选地被1到5个氟原子所取代。
在本发明的另一个实施方案中,提供了式(Ic)化合物:
或其药学上可接受的盐,
其中R1是具有3到8个环原子的非芳香环,所述环任选地包含双键,并且所述环任选地包含1、2或3个选自N、O或S的杂原子或者包含C(O)、S(O)、S(O)2、NH或NC1-4烷基基团,并且所述环还任选地与芳基稠合,并且所述环进一步任选地通过(CH2)1-4桥联,以及所述环还任选地被1、2或3个独立地选自羟基、卤素、NO2、CN、NH2、CF3、C1-4烷基、C2-4烯基、C2-4炔基、ORa和CO2Ra的基团所取代,
其中Ra如式(I)中所定义,和
R4和R5如式(I)中所定义。
优选地,R4是苯基、吡啶基、嘧啶基或苯并噻唑基,任选地被1或2个选自卤素、CF3、甲基、乙基和CN的基团所取代。
优选地,R5是氢、C1-6烷基、芳基、S(O)2Rg、C(O)ORg或C(O)Rg,其中Rg如式(I)中所定义。更优选地,R5是S(O)2Rg、C(O)OCH2Ph或C(O)Rg,其中Rg选自甲基、乙基、异-丙基、(CH2)0-1苯基、(CH2)0-1C3-8环烷基、(CH2)0-1杂芳基和(CH2)0-1Het,任选地被1到5个氟原子所取代。
在本发明的另一个实施方案中,提供了式(Id)化合物:
或其药学上可接受的盐,其中R2如式(I)中所定义。
优选地,R2是(CH2)0-6NRcRd或被NRcRd取代的C1-6烷氧基,其中Rc和Rd如式(I)中所定义。更优选地,R2是CH2NRcRd或OCH2CH2NRcRd其中Rc和Rd如式(I)中所定义。合适的NRcRd基团的例子是N(CH3)2、N(CH3)(环己基)和吗啉基。
任何光学异构体的单独合成或其色谱分离可以通过本领域公知的方法实现。其绝对立体化学可以通过结晶产品或结晶中间体的x-射线晶体衍射法而确定,如果必要,它们可以使用包含已知绝对构型的不对称中心的试剂衍生化。
如这里使用的,术语“C1-8烷基”意指具有1到8个碳原子的直链或支链烷基并且包括所有的辛基、庚基、己基和戊基的烷基异构体以及正-、异-、仲-和叔-丁基、正-和异丙基、乙基和甲基。“C1-6烷基”、“C1-4烷基”和“C1-2烷基”应当以类似的方式理解,“C1-6烷氧基”和“C1-4烷氧基”也是如此。
术语“C2-8烯基”意指具有2到8个碳原子的直链或支链烯基并且包括所有的己烯基和戊烯基异构体以及1-丁烯基、2-丁烯基、3-丁烯基、异丁烯基、1-丙烯基、2-丙烯基和乙烯基(或乙烯基)。
术语“C2-8炔基”意指具有2到8个碳原子的直或支链的炔基并且包括所有的辛炔基、庚炔基、己炔基和戊炔基异构体以及1-丁炔基、2-丁炔基、3-丁炔基、1-丙炔基、2-丙炔基和乙炔基(或乙炔基)。
术语“C3-8环烷基”意指具有三到八个总碳原子的环状烷烃环(即环丙基、环丁基、环戊基、环己基、环庚基和环辛基)。术语“C4-7环烷基”是指选自环丁基、环戊基、环己基和环庚基的环状的环。
术语“卤素”是指氟、氯、溴和碘。
这里使用的术语“杂芳基”意图包括下列基团:呋喃基、咪唑基、异噻唑基、异唑基、二唑基、唑基、吡嗪基、吡唑基、哒嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、四唑基、噻二唑基、噻唑基、噻吩基、三唑基和吡咯烷基。
术语“Het”意指3到7个环原子的杂脂肪环,所述环包括1、2或3个选自N、O或S的杂原子或S(O)、S(O)2、NH或NC1-4烷基基团。Het的例子包括氮丙啶基、氮杂环丁烷基、吡咯烷基、哌啶基、氮杂环庚烷基、哌嗪基、咪唑烷基、吡唑烷基、四氢呋喃基、二氧戊环基、吡喃、二烷基、吗啉、氧硫环戊基(oxathiolanyl)、二噻烷基、噻烷基、硫代吗啉基、三烷基、三噻烷基。
术语“噻吩基(thiophenyl)”和“噻吩基(thienyl)”在这里具有相同的含义并且可以互换使用。同样地,以下术语对具有相同的含义“吡啶基(pyridinyl)”和“吡啶基(pyridyl)”。
本发明的示例性化合物包括:
1-(2-氟苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(3-氟苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(4-氟苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(2-氯苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(3-氯苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(4-氯苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]-1-(2-甲基苯基)肼羧酸甲基酯、
2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]-1-(3-甲基苯基)肼羧酸甲基酯、
2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]-1-(4-甲基苯基)肼羧酸甲基酯、
1-(2-乙基苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]-1-[3-(三氟甲基)苯基]肼羧酸甲基酯、
1-(4-溴苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(4-碘苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(4-氰基苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]-1-[4-(三氟甲氧基)苯基]肼羧酸甲基酯、
1-(2,5-二氟苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(3-氯-4-氟苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(2,6-二氯苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(3,5-二氯苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(2,5-二氯苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(3-氯-4-甲基苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-[2-氯-5-(三氟甲基)苯基]-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]-1-吡啶-2-基肼羧酸甲基酯、
2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]-1-[4-(三氟甲基)嘧啶-2-基]肼羧酸甲基酯、
1-(1,3-苯并噻唑-2-基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯,
和其药学上可接受的盐。
本发明进一步的示例性化合物包括:
2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]-1-苯基肼羧酸苯甲基酯、
N’-乙酰基-3-甲氧基-N’,2-二苯基喹啉-4-碳酰肼、
N’-异丁酰基-3-甲氧基-N’,2-二苯基喹啉-4-碳酰肼、
N’-(环戊基乙酰基)-3-甲氧基-N’,2-二苯基喹啉-4-碳酰肼、
N’-(4-氟苯甲酰基)-3-甲氧基-N’,2-二苯基喹啉-4-碳酰肼、
N’-2-呋喃甲酰基-3-甲氧基-N’,2-二苯基喹啉-4-碳酰肼、
3-甲氧基-N’,2-二苯基-N’-(苯基乙酰基)喹啉-4-碳酰肼、
3-甲氧基-N’,2-二苯基-N’-(2-噻吩基乙酰基)喹啉-4-碳酰肼、
3-甲氧基-N’-(甲磺酰基)-N’,2-二苯基喹啉-4-碳酰肼、
3-甲氧基-N’,2-二苯基-N’-(2-噻吩基磺酰基)喹啉-4-碳酰肼、
3-甲氧基-N’-(吗啉-4-基羰基)-N’,2-二苯基喹啉-4-碳酰肼、
2-[(3-甲基-2-吡咯烷-1-基喹啉-4-基)羰基]-1-苯基肼羧酸甲基酯,和其药学上可接受的盐。
本发明另外的示例性化合物包括
3-[2-(二甲基氨基)乙氧基]-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼、
3-[2-(4-吗啉基)乙氧基]-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼、
3-(4-吗啉基甲基)-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼、
3-[(环己基甲基氨基)甲基]-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼,
和其药学上可接受的盐。
这些化合物以及通过刚刚在前面定义的那些化合物在治疗方面是有效的,尤其是作为NK-2和/或NK-3拮抗剂,特别是作为NK-3拮抗剂。
术语“给药”和或“用药”化合物应当被理解为向需要治疗的个体提供本发明化合物的含义。
在这里使用的术语“受试者,”(在这里替代地相当于“患者”)是指已经成为治疗、观察或试验的对象的动物,优选哺乳动物,最优选人。
本发明的化合物可以以药学上可接受的盐的形式给药。术语“药学上可接受的盐”意图包括所有的可接受的盐例如醋酸盐、乳糖酸盐、苯磺酸盐、月桂酸盐、苯甲酸盐、苹果酸盐、碳酸氢盐、顺丁烯二酸盐、硫酸氢盐、苦杏仁酸盐、酒石酸氢盐、甲磺酸盐、硼酸盐、甲基溴化物、溴化物、甲硝酸盐、钙乙二胺四乙酸盐、甲硫酸盐(methylsulfate)、右旋樟脑磺酸盐、粘酸盐(mucate)、碳酸盐、萘磺酸盐、氯化物、硝酸盐、克拉维酸盐、N-甲基葡糖胺、柠檬酸盐、铵盐、二盐酸化物、油酸盐、乙二胺四乙酸盐、乙二酸盐、乙二磺酸盐、双羟萘酸盐,依托酸盐、棕榈酸盐、乙磺酸盐、泛酸盐、延胡索酸盐、磷酸盐/二磷酸盐、葡庚糖酸盐、多聚半乳糖醛酸盐、葡糖酸盐、水杨酸盐、谷氨酸盐、硬脂酸盐、乙醇酰阿散酸盐、硫酸盐、己基间苯二酚盐、碱式醋酸盐、哈胺(hydrabamine)、琥珀酸盐、氢溴化物、单宁酸盐、盐酸盐、酒石酸盐、羟基萘甲酸盐、茶氯酸盐、碘化物、甲苯磺酸盐、异硫代硫酸盐、三乙基碘化物(triethiodide)、乳酸盐、panoate、戊酸盐、等等,其可以用作用于改变溶解或水解特性的剂型,或者以缓释或前-药制剂的形式使用。取决于本发明化合物的特别的官能团,本发明的化合物的药学上可接受的盐包括由阳离子例如钠、钾、铝、钙、锂、镁、锌所形成的盐,和由碱例如氨、乙二胺、N-甲基-谷氨酰胺、赖氨酸、精氨酸、鸟氨酸、胆碱、N,N’-二苯甲基乙烯-二胺、氯普鲁卡因、二乙醇胺、普鲁卡因、N-苯甲基苯乙基-胺、二乙胺、哌嗪、三(羟基甲基)氨基甲烷和氢氧化四甲铵所形成的盐。这些盐可以通过标准方法制备,例如通过游离酸和适当的有机或无机碱反应。在碱性基团例如氨基的存在下,可以将酸式盐,即盐酸盐、氢溴化物、醋酸盐、双羟基萘酸盐等等以剂型的形式使用。
同时,在醇基存在的情况下,药学上可接受的酯也可以使用,例如醋酸酯、顺丁烯二酸酯、pivaloyloxymethyl、等等,以及那些本领域公知的用于改变溶解或水解特性从而用作缓释或前药配制物的酯。
本发明的化合物可以通过口服、肠胃外(例如肌肉内的、腹膜内的、静脉内的、ICV、脑池内的注射或灌注、皮下注射、或植入物)给药,也可以通过喷雾吸入、鼻的、阴道的、直肠的、舌下的、或局部的给药途径给药,并且可以单独或一起以适当的剂量单元配制物配制,所述配制物包含惯用的无毒的药学上可接受的载体、助剂和适于每种给药途径的介质。除了治疗恒温动物例如小鼠、大鼠、马、牛、羊、狗、猫、猴、等等,本发明的化合物用于人也是有效的。
用于本发明化合物给药的药物组合物可以方便地以剂量单位的形式存在,也可以通过药学领域熟知的任何方法制备。所有的方法都包括将活性成分与载体混合的步骤,所述载体组成一种或多种附属成分。通常,药物组合物通过将活性成分与液体载体或精细分割的固体载体或者二者进行均匀且紧密地结合而制备,然后,如果必要,将产品成形为期望的配制物。将活性对象化合物以足以对疾病的过程或条件产生预期效果的量加入到药物组合物中。在这里使用的术语“组合物”意图包括包含指定量的指定成分的产品,以及直接地或间接地由指定量的指定成分混合而产生的任何产品。
包含活性成分的药物组合物可以以适于口服使用的方式存在,例如,作为片剂、锭剂(troches)、糖锭(lozenges)、水性或油性悬浮液、可分散性粉剂或颗粒剂、乳化液、硬或软胶囊、或糖浆或酏剂。为口服使用而设计的组合物可以根据本领域已知的用于药物组合物制备的任何方法制备,并且该组合物可以包含一种或多种选自由甜味剂、调味剂、着色剂和防腐剂所组成组的成分从而提供药学上精致的和可口的制品。所述片剂包含活性成分和无-毒的药学上可接受的赋形剂的混合物,所述赋形剂适于片剂的制备。这些赋形剂可以是例如,惰性稀释剂,例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠;造粒和崩解剂,例如玉米淀粉或藻酸;粘合剂,例如淀粉、明胶或阿拉伯树胶,和润滑剂,例如硬脂酸镁、硬脂酸或滑石粉。所述片剂可以是未包覆的或者它们可以是通过已知工艺包覆的以延迟在胃肠道中的崩解和吸收,并且因此提供了一个较长周期的持续作用。例如,可以使用时间延迟材料例如单硬脂酸甘油酯或二硬脂酸甘油酯。它们还可以通过美国专利4,256,108;4,166,452;和4,265,874中描述的工艺进行包覆从而形成用于控释的渗透性治疗片剂。
用于口服使用的配制物还可以作为硬胶囊而存在,其中活性成分与惰性固体稀释剂,例如碳酸钙、磷酸钙或高岭土混合,或者作为软胶囊,其中活性成分与水或油介质,例如花生油、液体石蜡或橄榄油混合。
水悬浮液包含活性材料与适于水悬浮液制备的赋形剂的混合物。这样的赋形剂是悬浮剂,例如羧甲基纤维素钠、甲基纤维素、羟基-丙基甲基纤维素,藻酸钠、聚乙烯-吡咯烷酮、黄蓍胶和阿拉伯胶;分散剂或润湿剂可以是天然-存在的磷脂,例如卵磷脂,或环氧烷与脂肪酸的缩合产物,例如聚氧乙烯硬脂酸酯,或环氧乙烷与长链脂肪醇的缩合产物,例如十七乙烯氧基十六烷醇,或环氧乙烷与由脂肪酸和己糖醇得到的偏酯的缩合产物,例如聚氧乙烯山梨糖醇单油酸酯,或环氧乙烷与由脂肪酸和己糖醇酐得到的偏酯的缩合产物,例如聚乙烯山梨聚糖单油酸酯。所述水悬浮液还可以包含一种或多种防腐剂,例如对-羟基苯甲酸乙基酯或正-丙基酯,一种或多种着色剂,一种或多种调味剂,和一种或多种甜味剂,例如蔗糖或糖精。
油悬浮液可以通过在植物油例如花生油、橄榄油、芝麻油或椰子油,或矿物油例如液体石蜡中悬浮活性成分而配制。所述油悬浮液可以包含增稠剂,例如蜂蜡、硬石蜡或十六烷醇。可以加入例如以上所述的甜味剂,和调味剂从而提供可口的口服制品。这些组合物可以通过加入抗氧化剂例如抗坏血酸进行保存。
适于通过加入水而制备水悬浮液的可分散性粉剂和颗粒剂提供了活性成分和分散剂或润湿剂、悬浮剂和一种或多种防腐剂的混合物。适当的分散剂或润湿剂和悬浮剂由上述已经提到的那些物质例证。另外的赋形剂,例如甜味剂、调味剂和着色剂,也可以存在。
本发明的药物组合物也可以以水包油乳化液的形式存在。所述油相可以是植物油,例如橄榄油或花生油,或者是矿物油,例如液体石蜡或这些的混合物。适当的乳化剂可以是天然-存在的树胶,例如阿拉伯树胶或黄蓍树胶,天然-存在的磷脂,例如大豆、卵磷脂,和由脂肪酸和己糖醇酐得到的酯或偏酯,例如山梨聚糖单油酸酯,和所述偏酯与环氧乙烷的缩合产物,例如聚氧乙烯山梨聚糖单油酸酯。所述乳化液也可以包含甜味剂和调味剂。
糖浆和酏剂可以用甜味剂例如甘油、丙二醇、山梨糖醇或蔗糖来配制。这样的配制物也可以包含缓和剂、防腐剂和调味剂和着色剂。
药物组合物可以以无菌注射用水或油悬浮液的形式存在。该悬浮液可以根据公知技术用上述已经提到的适当的分散或润湿剂和悬浮剂配制。无菌注射制品也可以是在无毒的非肠道-可接受的稀释剂或溶剂中的无菌注射溶液或悬浮液,例如为1,3-丁二醇中的溶液。在可接受的介质和溶剂中其可以使用的是水、生理盐水和等渗氯化钠溶液。此外,无菌的固定油类也是常用的溶剂或悬浮介质。为了这个目的,任何温和的固定油都可以使用包括合成的单-或二甘油酯。此外,脂肪酸例如油酸在注射制品的制备中也可以使用。
本发明的化合物也可以以栓剂的形式通过直肠给药。这些组合物能够通过将药物与适当的无-刺激性的赋形剂混合而制备,所述赋形剂在常温下是固体但在直肠温度下是液体,并且将因此在直肠中熔化从而释放药物。这样的材料是可可脂和聚乙二醇。
为了局部应用,可以使用包含本发明化合物的乳膏剂、软膏剂、胶状物、溶液或悬浮液、等等。(为了此应用目的,局部应用将包括漱口水和含漱剂。)
本发明的药物组合物和方法可以进一步包括如在此指出的其它治疗活性化合物,这些化合物同样应用于上述提到的病理学情况的治疗中。
在治疗和预防需要NK-3受体调节的情况中,适当的剂量水平将通常为约0.01到500mg每kg患者体重每天,此剂量水平可以以单一或多次的剂量给药。优选地,剂量水平为约0.1到约250mg/kg每天;更优选为约0.5到约100mg/kg每天。适当的剂量水平可以是约0.01到250mg/kg每天,约0.05到100mg/kg每天,或约0.1到50mg/kg每天。在这些范围中剂量可以是0.05到0.5,0.5到5或5到50mg/kg每天。对于口服给药,所述组合物优选以包含1.0到100毫克活性分的片剂的形式提供,特别是1.0、5.0、10.0、15.0、20.0、25.0、50.0、75.0、100.0、150.0、200.0、250.0、300.0、400.0、500.0、600.0、750.0、800.0、900.0和1000.0毫克活性成分,根据症状调整所要治疗患者的剂量。所述化合物可以按照每天1到4次服用,优选每天一次或两次的给药方案给药。
然而,应当理解,对任何特殊患者的剂量水平和剂量频率是可以改变的,并且取决于包括使用的特定化合物的活性、那些化合物的代谢稳定性和作用长度、年龄、体重、一般健康状况、性别、饮食、给药的方式和时间、排泄率、联合用药、特定情况的严重性和接受治疗的主体在内的多种因素。
本发明还提供一种包含式(I)化合物或其药学上可接受的盐以及药学上可接受的赋形剂的药物组合物。
因此,提供了一种通过治疗用于人或动物体处理方法的式(I)化合物或其药学上可接受的盐。
同样地,提供了一种式(I)化合物在制备用于治疗神经激肽-2和/或神经激肽-3所介导的疾病的药物中的用途。
本发明还公开了一种对患有神经激肽-2和/或神经激肽-3所介导的疾病的受试者的治疗方法,其包括将治疗有效量的式(I)化合物或其药学上可接受的盐给予那些患者。
神经激肽-2和/或神经激肽3所介导的疾病的实例包括CNS紊乱例如抑郁症(此术语包括双相(狂躁的)抑郁(包括I型和II型),单相抑郁,具有或不具有精神病特征、紧张症特征、忧郁症特征、非典型特征(例如嗜睡、过渡-饮食/肥胖、睡眠过度)或产后发作的单一的或循环的重性抑郁发作,季节性情感障碍和情绪不良,抑郁相关的焦虑、精神病性抑郁症和由包括,但不限于,心肌梗死、糖尿病、流产或堕胎的一般医学情况所导致的抑郁障碍);焦虑障碍(包括广泛性焦虑障碍(GAD),社交焦虑障碍(SAD),激动、紧张、精神病患者中的社交或情绪冷淡,恐慌障碍和强迫症);恐惧症(包括旷野恐惧症和社交恐惧症);精神病和精神病障碍(包括精神分裂症,分裂-情感障碍,精神分裂症样-疾病,-急性精神病,酒精精神病,孤独症,精神错乱,狂躁(包括急性狂躁),狂躁抑郁精神病,幻觉,内因性精神病,有机精神综合症,偏执狂样和妄想障碍,产后精神病和与神经病变疾病例如阿尔茨海默氏病相关的精神病);创伤后的应激障碍;注意缺陷多动障碍(ADHD);认识损伤(例如认知功能损伤的治疗包括注意力、方向感、记忆力(记忆障碍,健忘症,遗忘障碍和年龄-相关记忆损伤)和语言功能,以及包括由中风,阿尔茨海默氏病,艾滋病-相关的痴呆或其它痴呆状态,以及其它可以导致认知下降的急性或亚-急性情况例如精神错乱或抑郁(假性痴呆状态))导致的认知损伤;痉挛性障碍例如癫痫(其包括单纯部分性发作,复杂部分性发作,继发性全面发作,全面发作包括失神性发作,肌阵挛发作,阵挛发作,强直性发作,强直阵挛发作和失张力性发作);性心理的机能障碍(包括抑制性性需求(低性欲),抑制的性觉醒或兴奋,高潮技能障碍,抑制性雌性高潮和抑制性雄性高潮,活动减退性欲障碍(HSDD),雌性性欲障碍(FSDD),和通过用SSRI-类抗抑郁药物治疗而诱发的性机能副-作用);睡眠障碍(包括昼夜节奏扰乱,睡眠障碍,失眠,睡眠呼吸暂停和嗜眠病);饮食行为障碍(包括神经性厌食症和食欲过盛性厌食症);神经病变性疾病(例如阿尔茨海默氏病,ALS,运动神经元病和其它运动障碍例如帕金森氏症(包括运动缺乏和/或运动无力引起的运动缓减,包括在有目的的运动中缓增的无力,颤动,运动徐缓,运动过度(中等的和严重的),运动不能,僵化,平衡和协调扰乱,和姿态扰乱),帕金森氏症中的痴呆、亨廷顿氏症中的痴呆、安定药-诱发的帕金森神经机能障碍和迟发性运动障碍、中风、心动停止、肺迂回、脑创伤、脊髓损伤等等后的神经退行性病变,和脱髓鞘疾病例如多发性硬化和肌萎缩性硬化);滥用药物的戒除包括吸烟中断或这些活动的水平或频率的降低(例如古柯碱、乙醇、烟碱、苯二氮、酒精、咖啡因、苯西克定和苯西克定-样化合物、麻醉剂例如大麻、海洛因、吗啡、镇静剂、催眠剂、安非他明或安非他明-相关毒品例如右旋苯异丙胺、甲基苯丙胺或其组合物);疼痛(其包括神经性疼痛(包括糖尿病性神经病变;坐骨神经痛;非-特异性的下背部疼痛;多发性硬化疼痛;与肌纤维痛或癌症相关的疼痛;AIDS-相关和HIV-相关的神经病;化疗-诱发的神经病;神经痛,例如带状疱疹后的神经痛和三叉神经痛;交感神经持续疼痛和物理外伤、截肢、癌症、毒物或慢性炎症情况例如类风湿性关节炎和骨关节炎所导致的疼痛;反射交感性营养不良例如肩/手综合症),剧痛(例如肌与骨痛、外科术后痛和外科痛),炎症性疼痛和慢性疼痛,与正常无-痛感觉例如“发麻”(感觉倒错和感觉迟钝)有关的疼痛,增强性触觉敏感(感觉过敏),无害刺激后的疼痛感觉(动态的、静态或热的感觉超敏),对有害刺激增强性的敏感(热的、冷的、机械的痛觉过敏),刺激解除后的延续痛觉(痛觉过敏)或选择感觉传导通路的缺失或缺乏(痛觉减退),与偏头痛有关的疼痛,和非-心脏的胸痛);某些CNS-介导障碍例如呕吐,过敏性肠综合症和非-溃疡性消化不良;COPD,哮喘,咳嗽、胃-食管反流引发的咳嗽,和恶化的哮喘;尿失禁;高血压;和与血小板过度聚集有关的情况例如组织溃疡,肾病综合症,糖尿病,偏头痛,冠状动脉病,预-惊厥和中风。优选地,本发明的化合物用于治疗抑郁症;焦虑障碍;恐怖症;精神病和精神病障碍;创伤后应激障碍;注意缺陷多动障碍(ADHD);滥用药用的戒除包括吸烟中断或这种活动的水平或频率的降低;和过敏性肠综合症。更优选地,本发明的化合物用于治疗抑郁症;焦虑障碍;恐怖症;和精神病和精神病障碍(尤其是精神分裂症,分裂-情感障碍,精神分裂症样-疾病)。最优选地,本发明的化合物用于治疗精神分裂症。
用于本发明的化合物通常在以下测试中具有活性。它们一般具有小于1μM并且优选小于100nM的IC50。
NK-2受体及其变种表达的详细描述可以在Gerard等,J.Biol.Chem.,265:20455-20462,1990和Huang等,Biochem.,33:3007-3013,1994中找到。后一论文还包括了突变体扫描的细节。
NK-3受体及其变种表达的详细描述可以在Hung等,BBRC,1992,184:966-972和Sadowski等,Neuropeptides,1993,24:317-319中找到。
通过如下过程制备膜制品。将10-层细胞工厂用稳定地表达NK-3受体的CHO细胞接种。该CHO细胞是在三个一组的T175烧瓶在1l生长培养基中制备的,所述生长培养基包含Iscore修饰的Dulbecco培养基,其包含10ml/l 200mM L-谷氨酰胺,10ml/l青霉素-链霉素,一小瓶次黄嘌呤-胸苷500x/l,1mg/ml遗传霉素和10%胎牛血清(灭活的)。细胞在孵化器中生长3天。将培养基洗掉并且将所述工厂用400mlPBS(不含钙、镁)漂洗两次。加400ml不含酶的溶解溶液(EFDS)并且将所述工厂在室温下维持10分钟。将细胞驱逐并且将悬浮液灌500ml离心瓶。用200ml EFDS重复所述方法并且总共收集到6瓶所述混合物,其在2200rpm下在离心机中旋转10分钟。
吸出上层清夜并且将剩余的细胞球在-80℃下冷冻30分钟以改善细胞溶解作用,然后每细胞工厂用40ml加入抑制剂的Tris再悬浮。所述细胞用设置为40的8冲程玻璃聚四氟乙烯磨床以40ml等分试样的量进行匀浆。将所述匀浆转移倒50ml的离心管中并且在室温下置于摇床上15分钟。将所述匀浆进行再匀化并且如果需要的话,在再一次进行如上所述的离心之前将其置于冰上保存。
将所述上层清液转移到SS-34离心机使用的Sorvall管中并且置于冰上保存。
用40ml冷的具有抑制剂的Tris用于再悬浮和结合再一次进行了上述旋转的小球。将上层清液再次移Sorvall管中,与上述的那些一起在1800rpm下旋转20分钟。
弃去上层清液并且将小球再悬浮在存储缓冲剂中,所述存储缓冲剂的组成为2.50ml 1M pH为7.4的Tris,50μl 1000x蛋白酶抑制剂(4mg/ml亮肽素(Sigmo),400mg/ml杆菌肽(Sigma)和10mMphosphoranidon(Peninsula)上述物质全部溶解于水中)加上0.5ml0.5M的MnCl2,其用H2Odd配成50ml。用20-、23-和25-规格的针头顺序地使用一个10ml注射器。
在500-1000μl等分试样用保存在-80℃下的液氮速-冻之前,以BSA作为标准在2-10μl等分试样上进行Bradford蛋白试验。
膜结合试验按照如下进行。预先确定特定结合≤10%的125I-神经肽B所需的膜的量。然后将冷冻的料液稀释到允许以50μl的量加入。
将测试化合物溶于DMSO。自动装置(Tecan)被设定为将5μl化合物或DMSO,在20μl缓冲液中的大约100,000cpm的同位素(所述缓冲液是由50μM Tris,pH7.5,150μMNaCl,0.02%牛血清蛋白,和与所述存储缓冲剂中相同的蛋白酶抑制剂,补足为0.5M料液组成的),以及175μl试验缓冲液(如同存储缓冲剂但是包含5μM MnCl2且不含NaCl)加入到96-孔型深孔Marsh盒(Marsh Biomedical出品)。手工加入过量未标记的竞争肽用于如下所示的非特异性结合。所述结合反应通过加入50μl细胞膜而引发。所述管在室温下摇动1h进行培养并且在Tomtec 96孔细胞收集器上用Mach III滤膜(Tomtec),或者使用unifilter GF/C(Packard)Packard 96-孔收集器或Tomtec 9600中的一种进行过滤,在0.25%聚乙烯亚胺中预浸渍和用1X洗涤缓冲液(0.1M.Tris,pH7.4和1M NaCl,1X=100ml的10X料液每升冷却蒸馏水)洗涤五次。如果使用unifilter板,将60μl Microscint 20(Packard)加入到每个孔中并且所述板然后在Packard Topcunt中计数之前热-封。或者替代地,将得自过滤垫的过滤物置于75×100mm的塑料管中并且在Cobraγ计数器上计数。
对于本试验,一般在25,000cpm下使用10μg膜,其通过预浸渍在0.5%BSA中的unifilterGF/C进行过滤。
对于结合神经激肽-2受体的试验可以通过类似的方式进行。
本说明书,尤其是流程图、描述和实施例中所使用的缩写包括下述内容:Ac=乙酰基;9-BBN=9-硼杂双环[3.3.1]壬烷;Bn=苯甲基;BOC或Boc=t-丁氧基羰基;Bu=丁基;t-Bu=叔-丁基;CBZ=苄氧基羰基(或者替代地,苯甲氧基羰基);CDI=羰基二咪唑;DAST=(二乙氨基)三氟化硫;DCC=双环己基碳二酰亚胺;DCM=二氯甲烷;DIBAL=二异丁基铝氢化物;DIEA或DIPEA=二异丙基乙胺;DIAD=二异丙基偶氮二羧酸酯;DMA=N,N-二甲基乙酰胺;DMF=N,N-二甲基甲酰胺;DMSO=二甲基亚砜;EDAC=1-(3-二甲基氨基)丙基-3-乙基碳二酰亚胺;Et=乙基;醚=二乙醚;EtOAc=乙酸乙酯;h=小时;HMDS=六甲基二硅胺烷;HOBT或HOBt=1-羟基苯并三唑水合物;KHMDS=六甲基二硅胺钾盐;LDA=二异丙基氨基锂;Me=甲基;m=分钟;Ph=苯基;Pr=丙基;i-Pr=异丙基;PMB=邻-甲氧基苯甲基;PS=聚合物-载体;sat’d=饱和的水溶液;rt=室温;TBSO=叔-丁基二甲基甲硅烷氧基;TEA=三乙胺;Tf=三氟甲磺酸或三氟甲磺酸酯;TFA=三氟乙酸;THF=四氢呋喃;TPAP=四丙基铵过钌酸盐。
式(I)化合物可以通过式(II)化合物与式(III)化合物反应而制备:
其中R1、R2、R3、R4、R5、X和Y如前面所定义。所述反应通常在溶剂例如CH2Cl2和/或THF中在碱例如Et3N和缩合剂例如HBTU或HOBT和EDC.HCl的存在下进行。取决于试剂的准确特征,反应条件可以从1小时延续到18小时以及从0℃到回流温度。
如果必要,式(II)化合物可以在与式(III)化合物反应之前转化为它的酰基氯;这可以通过与草酰氯在室温下反应约18小时而完成。
如果需要,式(I)化合物可以通过本领域已知的方法转化为其它式(I)化合物,尤其是当其希望将一个基团R5转换成另一个基团的时候。例如R5是H的化合物可以通过与氯甲酸甲酯任选地在碱例如Et3N和溶剂例如CH2Cl2的存在下在室温下反应约4小时而转化为R5是甲氧基羰基的化合物。
式(II)和式(III)化合物通常是在本领域已知的或能够由已知化合物通过本领域已知的方法制备的。例如,式(II)化合物能够通过式(IV)化合物和式(V)化合物反应而制得:
其中R1、R2、X和Y如前面所定义。所述反应通常在强碱例如氢氧化钾,溶剂例如乙醇和在回流的存在下进行。
式(IV)和式(V)化合物是本领域已知的或能够通过已知方法由已知化合物制备的。
R2是C1-6烷基NR’R”的式(II)化合物能够通过R2是C1-6烷基的式(II)化合物先后与N-溴化琥珀酰亚胺(通常在溶剂例如CH3CN中,在回流条件下进行并且使用引发剂例如二苯甲酰过氧化物)和然后的HNR’R”(通常在碱例如二异丙基乙胺的存在下,在溶剂例如THF中在约50℃下进行)反应而制备得到。在此过程中,式(II)化合物的羧基能够以甲酯的形式进行保护。
式HNR’R”组分是本领域已知的或可以通过已知的方法由已知化合物制备的。
本发明的化合物能够根据以下反应流程图和实施例,或其改进而很容易地制备。起始原料可以由本领域已知的或如图所示的方法制备。在这些反应中,还可以使用本领域普通技术人员所公知的,但是没有更具体地提到的变体。而且,在参考以下反应流程图和实施例以后制备本发明化合物的其它方法对于本领域普通技术人员来说将是显而易见的。除非另有指明,所述变量如前面所定义。
R2是O-连接基团的式(I)化合物可以通过图解1中所示的一般方法制备:
图解1
试剂:i)PhCH2OCOCl,NaHCO3;ii)R5Cl;iii)H2,Pd-C;iv)HCl;v)PhCH2Br,K2CO3,NaI;vi)NaOH;vii)(COCl)2,DMF;viii)R4R5N-NHR3.HCl,Et3N;ix)H2,Pd-C;x)RCl,K2CO3,NaI
R2是CH2NRcRd的式(I)化合物可以通过图解2中所示的一般方法制备:
图解2
试剂:i)R1COCH2CH3,AcOH;ii)(COCl)2,DMF;iii)R4NHNHR3.HCl,Et3N;iv)R5Cl;v)NBS,uv;vi)RcRdNH;vii)(COCl)2,DMF;viii)R4R5N-NHR3.HCl,Et3N
1H核磁共振谱是在(报告的)300到600MHz之间的频率下操作的Bruker AM系列光谱仪上记录得到的。与非-可交换质子(和明显的可交换质子)相关的信号的化学位移(δ)是以相对于四甲基硅烷百万分之一(ppm)为单位记录的,并且使用剩余溶剂峰作为基准测量的。信号报告顺序:质子数;多重性(s,单重峰;d,双重峰;t,三重峰;q,四重峰;m,多重峰;br,宽峰;和其组合形式);以赫兹计的耦合常数。质谱(MS)数据是在阴性(ES-)或阳性(ES+)电离模式下操作的Waters Micromass ZQ或Waters Micromass ZMD上获得的并且结果是仅以母离子质量对电荷的比(m/z)的形式报告的。制备级的HPLC分离是通过使用制备Agligent100分离模块上的质量触发器HPLC而进行的。化合物用线性梯度的乙腈/0.1%TFA和水/0.1%TFA或者用乙腈和水(含有碳酸铵以使pH值达到10)进行洗脱。在所有情况下使用15到25mL/分钟的流速。
以下描述和实施例进一步阐明了本发明:
描述1:2-苯基肼羧酸苯甲基酯
向搅拌冷却(5℃)的苯肼(20g,0.185摩尔)EtOAc溶液和饱和的NaHCO3(200mL)水溶液中加入K2CO3(10g,0.72摩尔)接着缓慢加入(超过0.5小时)氯甲酸苄基酯(34.8g,0.204摩尔)的EtOAc(100mL)溶液。混合物在0℃到5℃下搅拌0.5小时,分层,将有机相干燥(MgSO4)并且减压蒸发溶剂。将剩余物用异己烷(2×100mL)洗涤并且真空干燥从而得到43.9g标题化合物。
1H NMR(CDCl3,500Mz)δ7.42-7.05(11H,m),5.23(2H,m),3.79(3H,m)作为旋转异构体混合物。
描述2:1-苯基-1,2-肼二羧酸的1-甲基酯2-苯甲基酯
向描述1的产品的甲苯(500mL)悬浮液中加入氯甲酸甲酯(17.5mL,0.226摩尔)并且混合物在100℃下搅拌1.5小时。将产生的透明溶液冷却至室温并且减压蒸发溶剂从而得到泡沫形式的标题化合物(58g)。
描述3:1-苯基肼羧酸甲基酯盐酸盐
将描述2的产品(58g)和10%钯碳(4g)的在甲醇(400mL)中的混合物在30-40psi的氢气下氢化1小时。过滤所述混合物并且加入氯化氢甲醇溶液(1M,200mL)。减压蒸发溶剂并且用醚洗涤固体剩余物从而得到31.9g标题化合物。
1H NMR(CDCl3,500Mz)δ9.2(3H,宽s),7.55(2H,d,J 7.5),7.45(2H,t,J 6.7),7.35(1H,t,J 7.5),3.73(3H,s)作为旋转异构体混合物。
描述4:2-苯基-3-(苯甲氧基)喹啉-4-羧酸
向3-羟基-2-苯基喹啉-4-羧酸(2.65g,0.01摩尔,如Giardina等,J.Med.Chem.1999,42,1053-1065中所描述)和K2CO3(5.53g,0.04摩尔)的THF(50mL)悬浮液中加入溴化苄(2.99mL,0.025摩尔)和碘化钠(0.01g)并且将混合物在回流条件下加热14小时。将所述混合物冷却,溶剂在减压下部分蒸发到大约20mL,加入另外一份溴化苄(1mL,0.008摩尔)并且混合物在回流条件下加热24小时。将所述混合物冷却,过滤并且减压蒸发溶剂。剩余物溶于甲醇(100mL),加入NaOH水溶液(2N,25mL)并且混合物在回流条件下加热4小时。将所述混合物冷却,减压蒸发溶剂并且将剩余物在水(100mL)和醚(2×100mL)中分配。将水层用浓盐酸酸化并且通过过滤收集产生的固体,用水和醚洗涤并且在80℃下真空干燥从而得到2.45g为无色固体标的题化合物。
1H NMR(500MHz,DMSO-d6):δ14.30(br,s,1H),8.12(d,1H),8.00(dd,2H),7.85-7.79(m,2H),7.71(t,1H),7.55(t,3H),7.36-7.34(m,3H),7.18-7.16(m,2H),4.68(s,2H).m/z(ES+)356[M+H+]
描述5:2-苯基-3-(苯甲氧基)-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼
向2-苯基-3-(苯甲氧基)喹啉-4-羧酸(描述4,2.12g,6毫摩尔)的DCM(60mL)溶液中加入草酰氯(0.782mL,9毫摩尔)和1滴DMF。所述溶液在室温下搅拌1小时,然后减压蒸发溶剂。加入另外两份DCM(50mL)并在减压条件下蒸发。将剩余物在DCM(50mL)中再溶解并且加入到含有1-苯基肼羧酸甲基酯盐酸盐(描述3,1.8g,9毫摩尔)和TEA(3.3mL,24毫摩尔)的DCM(90mL)溶液中。将透明溶液在室温下搅拌14小时然后在DCM和饱和的NaHCO3水溶液中分配。将有机相干燥(Na2SO4)并且蒸发溶剂至小体积。将所述溶液加到包含硅胶的柱上并且用增加浓度的(0%到30%)EtOAc的异己烷溶液洗脱产品从而得到为泡沫体的标题化合物(2.45g)。
1H NMR(500MHz,CDCl3):δ8.26(2H,s),8.17(1H,d,J 8.3),7.99(2H,s),7.72(1H,t,J 7.1),7.63(1H,t,J 7.2),7.49(5H,s),7.19(2H,t,J 7.3),6.92(2H,d,J 7.2),4.66(2H,s),3.88(3H,s).m/z(ES+)504[M+H+].
描述6:3-羟基-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼
在氮气氛下向2-苯基-3-(苯甲氧基)-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼(描述5,2.4g,0.048毫摩尔)的甲醇(80mL)溶液中加入10%钯碳(0.2g)。在50psi的氢气下在Parr设备上摇动所述混合物18小时。将混合物过滤并且减压蒸发溶剂。剩余物在异丙醇中重结晶从而得到0.73g为无色固体的标题化合物。
1H NMR(500MHz,CDCl3):9.95(1H,br s),8.46(1H,br s),8.13-8.04(4H,m),7.60-7.42(9H,m),7.33(1H,t),3.90(3H,s).m/z(ES+)414[M+H+].
描述7:3-甲基-2-苯基喹啉-4-羧酸
向靛红(20g,0.136摩尔)的乙酸(370mL)浆液中加入苯基·乙基甲酮(18mL,0.136摩尔)。在75℃下加热所述混合物5分钟,加入浓盐酸(124mL)并且在100℃下加热所述混合物16小时。将混合物冷却并且加入水(800mL)。通过过滤收集形成的固体,用醚洗涤并且在60℃下真空干燥从而得到15.6g(43%)为褐色固体的标题化合物。
1H NMR(400MHz,DMSO-d6)δ8.08(1H,d,J 8.3),7.83(2H,t,J 8.0),7.71(1H,t,J7.6),7.63(2H,dd,J 2.0,7.8),7.57-7.51(3H,m),2.39(3H,s).m/z(ES+)264[M+H+]
描述8:3-甲基-2-苯基-4喹啉羧酸,2-苯基酰肼
向3-甲基-2-苯基喹啉-4-羧酸(描述7,5.0g,0.019摩尔)的DCM(60mL)悬浮液中加入草酰氯(3.32mL,0.038摩尔)然后加入DMF(2滴)。将混合物在室温下搅拌1小时并且减压蒸发溶剂。向剩余物的DCM(30mL)溶液中加入TEA(5.30mL,0.038摩尔)然后加入苯肼(2.80mL,0.028摩尔)的DCM(30mL)溶液。所述混合物在室温下搅拌5小时,用水/盐水稀释并且用DCM(5次)萃取。将合并的有机层干燥(MgSO4),减压蒸发溶剂并且剩余物通过在硅胶上用30%EtOAc/异己烷洗脱的快速色谱纯化从而得到4.0g标题化合物(59%)。
1H NMR(400MHz,CDCl3)δ8.16(1H,d,J 8.3),7.84(1H,d,J8.4),7.76-7.70(2H,m),7.61-7.43(6H,m),7.32(2H,dd,J 7.2,8.5),7.02(3H,d,J 7.9),6.56(1H,d,J 4.6),2.46(3H,s).m/z(ES+)354[M+H+]
描述9:3-甲基-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼
向3-甲基-2-苯基-4-喹啉羧酸,2-苯基酰肼(描述8,4.0g,0.011摩尔)的甲苯(120mL)悬浮液中加入氯甲酸甲酯(1.75mL,0.022摩尔)并且在回流条件下加热所述混合物16小时。将该混合物冷却,用水稀释并且用EtOAc(3次)萃取。将合并的有机相干燥(MgSO4)并且减压蒸发溶剂从而得到4.26g标题化合物(95%)。
1H NMR(400MHz,CDCl3)δ8.13(2H,d,J 8.15),8.01(1H,br s),7.71-7.65(1H,m),7.58-7.42(8H,m),7.34(1H,t,J 7.4),7.26(1H,m),7.17(1H,m),3.89(3H,s),2.42(3H,s).m/z(ES+)412[M+H+]
描述10:3-(溴甲基)-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼
将3-甲基-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼(描述9,0.15g,0.365毫摩尔)和N-溴化琥珀酰亚胺(0.129g,0.725毫摩尔)的CCl4(20mL)悬浮液用石英灯光照射1.5小时,其允许温度增加到大约75℃。减压蒸发溶剂并且通过在硅胶上用10%到20%异己烷中的EtOAc洗脱而纯化溶于DCM中的剩余物溶液。剩余物在醚/异己烷(1∶1)中结晶从而得到标题化合物。m/z(ES+)490/492(M+H)。
描述11:3-(溴甲基)-2-苯基喹啉-4-羧酸
将3-甲基-2-苯基喹啉-4-羧酸(描述7,0.200g,0.76毫摩尔)和N-溴化琥珀酰亚胺(0.270g,1.52毫摩尔)的1,2-二氯乙烷(20mL)悬浮液暴露于石英灯光下5小时。将混合物冷却并且减压蒸发溶剂。将剩余物溶于EtOAc和水中并且用EtOAc(2次)萃取产品。合并有机层,干燥(MgSO4)并且减压蒸发溶剂。剩余物通过在硅胶上用EtOAc/异己烷/AcOH(70∶30∶1)洗脱的快速色谱纯化从而得到混有剩余琥珀酰亚胺和3-(氯甲基)-2-苯基喹啉-4-羧酸的标题化合物。
m/z(ES+)342/344[M+H+]
描述12:3-(氯甲基)-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼
向3-(溴甲基)-2-苯基喹啉-4-羧酸(描述11,0.100g,0.29毫摩尔)的DCM(2mL)悬浮液中加入草酰氯(0.051mL,0.58毫摩尔)接着加入DMF(1滴)并且在室温下搅拌混合物1小时。减压蒸发溶剂,将剩余物溶于DCM(2mL)和TEA(0.081mL,0.58毫摩尔)中接着加入1-苯基肼羧酸甲基酯盐酸盐(描述3,0.060g,0.29毫摩尔)。所述混合物在室温下搅拌过夜,在水和DCM中分配,用DCM(2次)萃取并且将有机层干燥(MgSO4)并且减压蒸发溶剂。剩余物通过在硅胶上用异己烷/EtOAc(70∶30)洗脱的快速色谱纯化从而得到0.043g标题化合物(33%)。
1H NMR(400MHz,DMSO-d6)δ8.39(1H,s),8.17(1H,d,J 8.4),7.80(1H,t,J 7.1),7.66-7.60(5H,m),7.55-7.43(6H,m),7.36-7.32(1H,m),4.79(2H,br s),3.92(3H,s).m/z(ES+)446/448[M+H+]
实施例1-25
列于表1中的实施例1-25的化合物通过如下一般方法制备:
向3-甲氧基-2-苯基喹啉-4-羧酸(Giardina等.J.Med.Chem.1999,42,1053-1065)(0.050g,0.18毫摩尔)的N,N-二甲基乙酰胺(1.5mL)溶液中加入PS-碳二亚胺(0.275g,0.36毫摩尔)、HOBT(0.036g,0.27毫摩尔)和适当的肼(0.18毫摩尔)。当使用所述肼的盐酸盐的时候加入TEA(0.025mL,0.18毫摩尔)。将混合物在室温和氮气条件下搅拌过夜。然后将溶液通过硅-碳酸盐清除剂筒(6mL,1g)过滤并且在Gene Vac设备中蒸干溶剂。
将剩余物溶于甲苯(1.5mL)并且加入氯甲酸甲酯(0.014mL,0.89毫摩尔)。将溶液加热回流(110℃)过夜然后在Gene Vac中除去溶剂。剩余物通过HPLC纯化,所述HPLC使用Waters X-TerraC18(30×100mm)5μL柱,用H2O/MeCN/0.1%TFA以15-100%的MeCN梯度洗脱,流速为50mL/分钟。表1中的HPLC保留时间是在Phenomenex Luna CN 5μM 4.6×50mm柱,用2mL/分钟的5-95%MeCN/H2O+0.1TFA洗脱的条件下获得的。
表1
实施例26-36
列于表2中的实施例26-36的化合物通过如下一般方法制备:
向3-甲氧基-N’,2-二苯基喹啉-4-碳酰肼(0.040g,0.11毫摩尔)的甲苯(1.5mL)溶液中加入适当的氯碳酸酯/酰基氯/磺酰氯(0.22毫摩尔)。当使用磺酰氯的时候加入TEA(0.030mL,0.22毫摩尔)。将溶液加热回流(110℃)过夜然后在Gene Vac中除去溶剂。剩余物通过HPLC纯化,所述HPLC使用Waters X-Terra C18(30×100mm)5μL柱,用15-100%的MeCN/H2O+0.1%TFA梯度洗脱,流速为50mL/分钟。
表2中的HPLC保留时间是在Phenomenex Luna CN 5μM 4.6×50mm柱,用2mL/分钟的5-95%MeCN/H2O+0.1TFA洗脱的条件下获得的。
表2
实施例37:2-[(3-甲基-2-吡咯烷-1-基喹啉-4-基)羰基]-1-苯基肼羧酸甲基酯
a)3-甲基-2-氧代-N’-苯基-1,2-二氢喹啉-4-碳酰肼
在氮气下向搅拌的3-甲基-2-氧代-1,2-二氢喹啉-4-羧酸(R.E.LyIe等.J.Org.Chem.1972,37,3967-3968)(0.404g,1.99毫摩尔)的无水DMF(20mL)溶液中加入苯肼(0.235mL,2.39毫摩尔)、HOBT(0.4031g,2.98毫摩尔)、1-[3-(二甲氨基)丙基]-3-乙基碳二酰亚胺盐酸盐(0.5719g,2.98毫摩尔)和TEA(0.416mL,2.98毫摩尔)。然后将混合物在氮气下在室温搅拌23小时。蒸发溶剂并且向剩余物中加入水(~20mL)。通过过滤收集产生的固体,用水(2次)、然后用醚(2次)、然后用EtOAc(2次)洗涤。将固体在真空枪中在50℃下干燥过夜从而产生0.1889g(32%)为黄色固体的标题混合物。将滤液用更多的EtOAc(50mL)和水(20mL)稀释。用柠檬酸水溶液(30mL)、水(30mL)、NaHCO3溶液(30mL)和盐水(30mL)溶液洗涤有机层。将剩余有机层蒸发并且剩余物在硅胶柱上纯化,用5-10%MeOH/CH2Cl2洗脱从而得到另一份114.5mg(20%)为黄色固体的标题化合物:
1H NMR(500MHz,DMSO-d6)δ12.00(1H,s),10.44(1H,d,J 2.9Hz),8.19(1H,d,J 2.8Hz),7.53-7.47(2H,m),7.36(1H,d,J 8.0Hz),7.27-7.21(3H,m),6.86(2H,d,J 7.7Hz),6.78(1H,t,J 7.2Hz),2.14(3H,s).
b)2-[(3-甲基-2-氧代-1,2-二氢喹啉-4-基)羰基]-1-苯基肼羧酸甲基酯
在氮气下向搅拌的3-甲基-2-氧代-N’-苯基-1,2二氢喹啉-4-碳酰肼(来自步骤a),448.8mg,1.53毫摩尔)的无水甲苯(10mL)混合物中加入氯甲酸甲酯(0.355mL,4.59毫摩尔)并且在回流条件下(110℃)将混合物加热22.5小时。混合物冷却至室温,然后过滤。固体用甲苯洗涤两次并且在真空枪中在50℃下干燥过夜从而产生0.4605g(86%)为白色固体的标题化合物:
1HNMR(500MHz,DMSO-d6)δ12.01(1H,s),11.51(1H,s),7.50-7.43(6H,m),7.34(1H,d,J 8.2Hz),7.31(1H,t,J 6.8Hz),7.19(1H,s),3.79(3H,s),2.01(3H,s).
c)2-[(2-溴-3-甲基喹啉-4-基)羰基]-1-苯基肼羧酸甲基酯
在氮气下向搅拌的2-[(3-甲基-2-氧代-1,2-二氢喹啉-4-基)羰基]-1-苯基肼羧酸甲基酯(来自步骤b),453.7mg,1.29毫摩尔)的无水甲苯(15mL)混合物中加入在无水甲苯(3+2mL)中的氧溴化磷(766.3mg,2.67毫摩尔)并且在回流条件下(125℃)将混合物加热30分钟。冷却至室温后,混合物在EtOAc(80mL)和水(80mL)之间分配。水层进一步用EtOAc(80mL)萃取。合并所有的有机萃取物,干燥(Na2SO4)并且蒸发。剩余物在硅胶柱上用快速色谱纯化,其是用40%EtOAc/异己烷洗脱从而产生512.6mg(96%)为无色泡沫固体的标题化合物:
1H NMR(400MHz,CDCl3)δ8.27(1H,s),7.99(1H,d,J 8.4Hz),7.94(1H,br s),7.70-7.64(1H,m),7.59-7.55(3H,m),7.47-7.43(2H,m),7.37(1H,t,J7.3Hz),3.90(3H,s),2.50(3H,s).
d)2-[(3-甲基-2-吡咯烷-1-基喹啉-4-基)羰基]-1-苯基肼羧酸甲基酯
将2-[(2-溴-3-甲基喹啉-4-基)羰基]-1-苯基肼羧酸甲基酯(来自步骤c),29.9mg,0.072毫摩尔)和吡咯烷(0.018mL,0.216毫摩尔)的无水DMA(1mL)溶液在120℃下在高吸收水平的Smith微波装置中加热4分钟。(反应在110-120℃花费~2分钟。)蒸发溶剂并且剩余物用制备TLC纯化(硅胶,25%EtOAc/异己烷)从而提供17.0mg(58%)为无色固体的标题化合物:
1H NMR(500MHz,CDCl3)δ8.50(1H,s),7.67(1H,s),7.62-7.58(3H,m),7.47-7.43(3H,m),7.35(1H,t,J 7.4Hz),7.17(1H,t,J7.5Hz),3.89(3H,s),3.59(4H,s),2.33(3H,s),1.90(4H,s);MS(ES+)m/z 405[M+H]+.
实施例38:3-[2-(二甲基氨基)乙氧基]-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼
向3-羟基-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼(描述6,0.2g,0.48毫摩尔)的THF(10mL)溶液中加入K2CO3(0.2g,1.44毫摩尔)、2-氯-N,N-二甲基乙胺盐酸盐(0.076g,0.53毫摩尔)和碘化钠(5mg)。混合物在60℃下加热16小时,冷却,过滤并且减压蒸发溶剂。剩余物用硅胶上的色谱纯化,其使用DCM中0-4%的甲醇作为洗脱液从而得到为泡沫体的标题化合物(34mg)。
1H NMR(500MHz,CDCl3):12.80(1H,br s),s),8.10(2H,t),7.94(2H,d),7.67-7.40(9H,m),7.24(1H,t),3.92(3H,s),3.76(2H,br s),2.26(2H,br,s),1.91(6H,br,s).m/z(ES+)485[M+H+].
实施例39:3-[2-(4-吗啉基)乙氧基]-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼
向3-羟基-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼(描述6,0.2g,0.48毫摩尔)的THF(10mL)溶液中加入K2CO3(0.2g,1.44毫摩尔)、N-(2-氯乙基)吗啉盐酸盐(0.098g,0.53毫摩尔)和碘化钠(5mg)。混合物在60℃下加热48小时,冷却,过滤并且减压蒸发溶剂。剩余物用硅胶上的色谱纯化,其使用DCM中0-100%的EtOAc作为洗脱液从而得到为泡沫体的标题化合物(56mg)。
1H NMR(500MHz,CDCl3):11.71(1H,br s),s),8.12(2H,t),7.93(2H,d),7.70-7.40(9H,m),7.24(1H,t),3.94(3H,s),3.79(2H,br s),3.43(4H,s),2.30(2H,br,s),2.07(4H,s).m/z(ES+)527[M+H+].
实施例40:3-(4-吗啉基甲基)-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼
向3-(溴甲基)-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼(0.146g,描述10)的THF(3mL)溶液中加入吗啉(0.047mL)的THF(3mL)溶液并且将混合物在室温下搅拌60分钟。减压蒸发溶剂并且剩余物用硅胶上的色谱纯化(用异己烷中0%-40%的EtOAc洗脱)。将剩余物溶于醚并且加入氯化氢的醚溶液(1M,0.3mL)。减压蒸发溶剂并且用异己烷洗涤剩余物以及真空干燥从而得到标题化合物。
1H NMR(360MHz,DMSO d6,)δ11.8(1H,宽s),8.10(1H,dJ 8.4Hz),8.01(1H,宽s),7.88(1H,t J 7.7Hz),7.71(1H,t J 7.6Hz),7.56-7.43(7H,m),7.35(1H,t J 7.1Hz),4.1-3.1(13H,宽m).m/z(ES+)497[M+H+].
实施例41:3-[(环己基甲基氨基)甲基]-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼
向3-(氯甲基)-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼(描述12)(30mg,0.0672毫摩尔)的THF(2mL)溶液中加入N-甲基环己基胺(17.6μL,0.135毫摩尔)并且将混合物在回流条件下加热过夜。冷却混合物,减压蒸发溶剂并且剩余物用LC-MS纯化从而得到标题化合物(24.5mg,70%)。
1H NMR(400MHz,DMSO-d6)δ8.04(1H,d,J 8.3Hz),7.82(1H,t,J 7.7Hz),7.69(1H,宽t),7.53-7.38(10H,m),7.31(1H,t,J 7.3Hz),3.81(3H,s),1.73(1H,m),1.61(3H,s),1.47(2H,m),1.41(1H,m),1.02(2H,m),0.91-0.69(5H,m).
Claims (37)
1.一种式(I)化合物:
其中:
R1是芳基或杂芳基环,其中芳基是苯基或萘基并且杂芳基是包含1、2、3或4个氮原子和/或氧或硫原子且条件是至多存在两个氮原子的5-元不饱和环,或者是包含1、2或3个氮原子的6-元不饱和环,所述环任选地被一个、两个或三个独立地选自羟基、卤素、硝基、氰基、氨基、CF3、C1-4烷基、C2-4烯基和C2-4炔基的基团所取代;
或者R1是ORa、C(O)Ra、COORa、S(O)2Ra、NRaRb、CONRaRb、SO2NRaRb或具有3到8个环原子的非芳香环,所述环任选地包含双键,并且所述环任选地包含1、2或3个选自N、O或S的杂原子或者包含C(O)、S(O)、S(O)2、NH或NC1-4烷基基团,并且所述环还任选地与芳基稠合,并且所述环进一步任选地通过(CH2)1-4桥联,以及所述环还任选地被1、2或3个独立地选自羟基、卤素、NO2、CN、NH2、CF3、C1-4烷基、C2-4烯基、C2-4炔基、ORa和CO2Ra的基团所取代,
其中Ra和Rb独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基和(CH2)0-3芳基,任选地被羟基或卤素取代,
或者,当R1是CONRaRb或SO2NRaRb时,Ra、Rb和与它们相连的氮原子组成哌啶、哌嗪、吡咯烷、吗啉、氮丙啶、氮杂环丁烷或氮杂环,任选地被羟基、C1-4烷基或C1-4烷氧基所取代;
R2是氢、羟基、卤素或CN;
或者R2是C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、C1-6烷氧基、(CH2)0-6NRcRd、被NRcRd取代的C1-6烷氧基、OC3-8环烷基、OHet、Het、O杂芳基、杂芳基、O芳基、芳基、(CH2)0-4NReC(O)Rf、(CH2)0-4NReC(O)ORf、(CH2)0-4NReS(O)2Rf、SO2Rc、SO2NRcRd、COORc、C(O)Rc、C(O)NRcRd,
任选地被1到8个卤素原子取代,
其中Rc、Rd、Re和Rf独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基和芳基,
或者Rc和Rd,与和它们相连的氮原子一起,形成饱和的含氮3-7元杂环,该杂环任选地包含进一步的氮或氧原子并且任选地被NR’R”所取代,
其中R’和R”独立地选自氢和C1-6烷基,
或者Re和Rf连接成为C2-6亚烷基、C2-6亚烯基或C3-6亚炔基基团,
任选地被羟基或卤素取代,
其中Het如下文所定义;
R3是氢或C1-6烷基;
R4是氢、C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、芳基或芳基C1-6烷基,其任选地被羟基、C1-6烷氧基、CN、NH2、或1到8个卤素原子所取代;
或者R4是包含至少一个芳环并且具有5、6、9或10个环原子的片段,所述环原子中1、2、3或4个原子是独立地选自N、O和S的杂原子,所述环系统在任意可取代位置上任选地被1、2或3个选自羟基、卤素、NO2、CN、NH2、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基或C(O)OC1-6烷基的基团所取代,所述基团任选地被1到8个卤素原子取代;
R5是氢、C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、芳基、芳基C1-6烷基、(CH2)0-4杂芳基、(CH2)0-4Het、C(O)NRgRh、S(O)2NRgRh、S(O)2Rg、C(O)ORg或C(O)Rg,
其中Rg和Rh分别独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、(CH2)0-4C3-8环烷基、(CH2)0-4芳基、(CH2)0-4杂芳基和(CH2)0-4Het,任选地被羟基和1到8个卤素原子所取代;
或者R4和R5,与和它们相连的氮原子一起,形成具有3到10个环原子的单-或二环片段,所述环原子中任选地1、2、3或4个原子为独立地选自N、O和S的杂原子,所述环系统在任意可取代位置上任选地被1、2或3个选自卤素、NO2、CN、NH2、氧代基、C1-4烷基、C2-4烯基、C2-4炔基和C1-6烷氧基的基团所取代,所述基团任选地被1到8个卤素原子取代;
X和Y独立地选自氢、羟基、硝基、氰基、CF3、卤素、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、C1-6烷氧基、C(O)NRiRj、CO2Ri、(CH2)0-4NRkRm、SO2Ri和SO2NRiRj,任选地被卤素所取代;
Ri和Rj独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基和(CH2)0-4芳基;
Rk和Rm独立地选自氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基、芳基、C(O)Rp、COORp和S(O)2Rp;
Rp是氢、C1-6烷基、C2-6烯基、C2-6炔基、C3-8环烷基或(CH2)0-4芳基;
或其药学上可接受的盐;
前提条件是式(I)化合物不是:
其中:
R1是芳基或杂芳基环,其中芳基是苯基或萘基并且杂芳基是包含1、2、3或4个氮原子和/或氧或硫原子且条件是至多存在两个氮原子的5-元不饱和环,或者是包含1、2或3个氮原子的6-元不饱和环,所述环任选地被一个、两个或三个独立地选自羟基、卤素、硝基、氰基、氨基、CF3、C1-4烷基、C2-4烯基和C2-4炔基的基团所取代;
R2是羟基、C1-6烷氧基、C1-6烷基、氨基、NR’R”或C1-6烷基-NR’R”,其中R’和R”独立地选自氢和C1-4烷基并且其中R’和R”与和它们相连的氮原子一起形成含氮的饱和3-7元杂环,所述杂环任选地包含进一步的氮原子和任选地被上述定义的NR’R”所取代,或者R2是被上述定义的NR’R”所取代的C1-6烷氧基;
R3是氢或C1-6烷基;
R4是氢、C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、芳基或芳基C1-6烷基;
R5是氢、C1-8烷基、C2-8烯基、C2-8炔基、C3-8环烷基、芳基、芳基C1-6烷基或C1-6烷氧基羰基;
或者R4和R5,与和它们相连的氮原子一起,形成C3-C10单-或二环的饱和环;
X和Y独立地选自氢、羟基、硝基、氨基、氰基、CF3、卤素和C1-4烷基;
或其药学上可接受的盐。
2.如权利要求1所述的化合物,其中R1是芳基或Het,其任选地被1、2或3个独立地选自羟基、卤素、NO2、CN、NH2、CF3、C1-4烷基、C2-4烯基和C2-4炔基的基团所取代。
4.如权利要求3所述的化合物,其中R1是氮丙啶、氮杂环丁基、吡咯烷基、哌啶基、氮杂基或哌嗪基,任选地被1、2或3个独立地选自羟基、卤素、NO2、CN、NH2、CF3、C1-4烷基、C2-4烯基和C2-4炔基的基团所取代。
5.如权利要求1到4任一项所述的化合物,其中R2是C1-6烷基、C1-6烷氧基或NRcRd,并且被1到8个卤素原子所取代,其中Rc和Rd如权利要求1中所定义。
6.如权利要求5所述的化合物,其中R2是CH2F、CHF2、CF3、CH2CF3、OCF3、OCH2CF3、N(H)CF3、N(H)CH2CF3、N(CH3)CF3、N(CH3)CH2CF3、N(CF3)2、N(CF3)CH2CF3、N(CH2CF3)2或N(CH2CH3)CH2CF3。
7.如权利要求6所述的化合物,其中R2是N(H)CH2CF3或OCH2CF3。
8.如权利要求1到7任一项所述的化合物,其中R4是苯基或包含1、2或3个选自N、O和S的杂原子的五-或六-元芳环,任选地被1、2或3个选自卤素、CF3、C1-4烷基和CN的基团所取代。
9.如权利要求1到8任一项所述的化合物,其中R5是氢、C1-6烷基、芳基、S(O)2Rg、C(O)ORg或C(O)Rg,其中Rg如权利要求1中所定义。
10.如权利要求9所述的化合物,其中R5是氢、C1-4烷基、苯基、S(O)2Rg或C(O)Rg,其中Rg是C1-6烷基或杂芳基。
12.如权利要求1到11任一项所述的化合物,其中X和Y独立地是氢或甲基。
13.如权利要求12所述的化合物,其中X和Y都是氢。
15.如权利要求14所述的化合物,其中R4是苯基、吡啶基、嘧啶基或苯并噻唑基,任选地被1或2个选自卤素、CF3、甲基、乙基和CN的基团所取代。
16.如权利要求14或15所述的化合物,其中R5是S(O)2Rg、C(O)OCH2Ph或C(O)Rg,其中Rg选自甲基、乙基、异-丙基、苯甲基、(CH2)0-1杂芳基、苯基、(CH2)0-1C3-8环烷基和(CH2)0-1Het,任选地被1到5个氟原子所取代。
18.如权利要求17所述的化合物,其中R4是被1或2个选自卤素、CF3、OCF3、甲基、乙基和CN的基团所取代的苯基,
或者R4是吡啶基、嘧啶基或苯并噻唑基,任选地被1或2个选自卤素、C1-4烷基、C1-4烷氧基、CF3、OCF3和NH2的基团所取代。
19.如权利要求17或18所述的化合物,其中R5是氢、C1-6烷基、芳基、S(O)2Rg、C(O)ORg或C(O)Rg,其中Rg如权利要求1中所定义。
20.如权利要求19所述的化合物,其中R5是S(O)2Rg、C(O)OCH2Ph或C(O)Rg,其中Rg选自甲基、乙基、异-丙基、(CH2)0-1苯基、(CH2)0-1C3-8环烷基、(CH2)0-1杂芳基和(CH2)0-1Het,任选地被1到5个氟原子所取代。
22.如权利要求21所述的化合物,其中R1是Het。
24.如权利要求23所述的化合物,其中R1是吡咯烷基、哌啶基或哌嗪基。
25.如权利要求21到24任一项所述的化合物,其中R4是苯基、吡啶基、嘧啶基或苯并噻唑基,任选地被1或2个选自卤素、CF3、甲基、乙基和CN的基团所取代。
26.如权利要求21到25任一项所述的化合物,其中R5是氢、C1-6烷基、芳基、S(O)2Rg、C(O)ORg或C(O)Rg,其中Rg如权利要求1中所定义。
27.如权利要求26所述的化合物,其中R5是S(O)2Rg、C(O)OCH2Ph或C(O)Rg,其中Rg选自甲基、乙基、异-丙基、(CH2)0-1苯基、(CH2)0-1C3-8环烷基、(CH2)0-1杂芳基和(CH2)0-1Het,任选地被1到5个氟原子所取代。
28.如式(Id)所示的权利要求1所述的化合物:
或其药学上可接受的盐,其中R2如权利要求1中所定义。
29.如权利要求28所述的化合物,其中R2是(CH2)0-6NRcRd或被NRcRd取代的C1-6烷氧基,其中Rc和Rd如权利要求1中所定义。
30.如权利要求29所述的化合物,其中R2是CH2NRcRd或OCH2CH2NRcRd其中Rc和Rd如权利要求1中所定义。
31.如权利要求1所述的化合物,其选自:
1-(2-氟苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(3-氟苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(4-氟苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(2-氯苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(3-氯苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(4-氯苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]-1-(2-甲基苯基)肼羧酸甲基酯、
2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]-1-(3-甲基苯基)肼羧酸甲基酯、
2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]-1-(4-甲基苯基)肼羧酸甲基酯、
1-(2-乙基苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]-1-[3-(三氟甲基)苯基]肼羧酸甲基酯、
1-(4-溴苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(4-碘苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(4-氰基苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]-1-[4-(三氟甲氧基)苯基]肼羧酸甲基酯、
1-(2,5-二氟苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(3-氯-4-氟苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(2,6-二氯苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(3,5-二氯苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(2,5-二氯苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-(3-氯-4-甲基苯基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
1-[2-氯-5-(三氟甲基)苯基]-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯、
2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]-1-吡啶-2-基肼羧酸甲基酯、
2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]-1-[4-(三氟甲基)嘧啶-2-基]肼羧酸甲基酯、
1-(1,3-苯并噻唑-2-基)-2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]肼羧酸甲基酯,
2-[(3-甲氧基-2-苯基喹啉-4-基)羰基]-1-苯基肼羧酸苯甲基酯、
N’-乙酰基-3-甲氧基-N’,2-二苯基喹啉-4-碳酰肼、
N’-异丁酰基-3-甲氧基-N’,2-二苯基喹啉-4-碳酰肼、
N’-(环戊基乙酰基)-3-甲氧基-N’,2-二苯基喹啉-4-碳酰肼、
N’-(4-氟苯甲酰基)-3-甲氧基-N’,2-二苯基喹啉-4-碳酰肼、
N’-2-呋喃甲酰基-3-甲氧基-N’,2-二苯基喹啉-4-碳酰肼、
3-甲氧基-N’,2-二苯基-N’-(苯基乙酰基)喹啉-4-碳酰肼、
3-甲氧基-N’,2-二苯基-N’-(2-噻吩基乙酰基)喹啉-4-碳酰肼、
3-甲氧基-N’-(甲磺酰基)-N’,2-二苯基喹啉-4-碳酰肼、
3-甲氧基-N’,2-二苯基-N’-(2-噻吩基磺酰基)喹啉-4-碳酰肼、
3-甲氧基-N’-(吗啉-4-基羰基)-N’,2-二苯基喹啉-4-碳酰肼、
2-[(3-甲基-2-吡咯烷-1-基喹啉-4-基)羰基]-1-苯基肼羧酸甲基酯、
3-[2-(二甲基氨基)乙氧基]-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼、
3-[2-(4-吗啉基)乙氧基]-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼、
3-(4-吗啉基甲基)-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼、
3-[(环己基甲基氨基)甲基]-2-苯基-4-喹啉羧酸,2-(甲氧基羰基)-2-苯基酰肼,
和其药学上可接受的盐。
32.用于治疗的如权利要求1到31任一项所述的化合物。
33.一种药物组合物,其包含如权利要求1到31任一项所述的化合物或其药学上可接受的盐以及药学上可接受的赋形剂。
34.如权利要求1到31任一项所述的化合物在制备治疗神经激肽-2和/或神经激肽-3所介导的疾病的药物中的用途。
35.一种对患有神经激肽-2和/或神经激肽-3所介导的疾病的受试者治疗的方法,其包括将治疗有效量的如权利要求1到31任一项所述的化合物或其药学上可接受的盐给予那些患者。
36.如权利要求34所述的用途或如权利要求35所述的方法,其中神经激肽-2和/或神经激肽-3所介导的疾病是精神分裂症。
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