CN1585763A - 哌啶衍生物及其作为趋化因子受体(尤其是ccr5)活性调节剂的用途 - Google Patents
哌啶衍生物及其作为趋化因子受体(尤其是ccr5)活性调节剂的用途 Download PDFInfo
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- CN1585763A CN1585763A CNA028225406A CN02822540A CN1585763A CN 1585763 A CN1585763 A CN 1585763A CN A028225406 A CNA028225406 A CN A028225406A CN 02822540 A CN02822540 A CN 02822540A CN 1585763 A CN1585763 A CN 1585763A
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- Prior art keywords
- alkyl
- phenyl
- optionally substituted
- radical
- halogen
- Prior art date
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Abstract
式(I)的化合物,其中L是CH或N;M是CH或N;条件是L和M不都为CH;包含它们的组合物;制备它们的方法和它们在药物治疗上的用途(例如调节温血动物CCR5受体活性)。
Description
本发明涉及具有药物活性的杂环衍生物、制备这些衍生物的方法、含有这些衍生物的药物组合物以及这些衍生物作为活性治疗剂的用途。
具有药物活性的哌啶衍生物公开在PCT/SE01/01053、EP-A1-1013276、WO00/08013、WO9938514和WO99/04794中。
趋化因子是由各种细胞释放的将巨嘘细胞、T细胞、嗜酸性粒细胞、嗜碱性粒细胞和嗜中性粒细胞吸引至炎症部位的趋化细胞因子,还在免疫系统细胞的成熟中发挥作用。在各类疾病和病症(包括哮喘和应变性疾病以及自身免疫病理(如类风湿性关节炎)和动脉粥样硬化症)的免疫和炎症反应中,趋化因子起着重要的作用。这些小的分泌性分子是一个日益增长的8-14kDa蛋白质超家族的成员,其特征为保守的四个半胱氨酸基序。可将这个趋化因子超家族主要分为呈现特性结构基序的两组,即Cys-X-Cys(C-X-X,或α)和Cys-Cys(C-C,或β)家族。根据在NH-附近的半胱氨酸残基对之间插入的单个氨基酸和序列类似性来区分这两个家族。
C-X-C趋化因子包括嗜中性粒细胞如白细胞介素-8(IL-8)和嗜中性粒细胞活化肽2(NAP-2)的几种有效化学引诱物和活化剂。
C-C趋化因子包括单核细胞核淋巴细胞(但不包括嗜中性粒细胞)的有效化学引诱物,如人单核细胞趋化蛋白1-3(MCP-1、MCP-2和MCP-3)、RANTES(调节活化、正常T细胞表达和分泌的)、嗜伊红粒细胞趋化蛋白和巨嗜细胞炎性蛋白1α和1β(MIP-1α和MIP-1β)。
研究表明趋化因子的作用由G-蛋白偶联受体的亚族介导,其中将这些受体称为CCR1、CCR2、CCR3、CCR4、CCR5、CCR6、CCR7、CCR8、CCR9、CCR10、CXCR1、CXCR2、CXCR3和CXCR4。由于调节这些受体的药物可用于治疗如前提到的那些病症和疾病,所有这些受体代表药物研制的好的靶标。
CCR5受体在T-淋巴细胞、单核细胞、巨嗜细胞、树突细胞、小胶质细胞和其它类型的细胞中表达。这些细胞对几种趋化因子,主要为“调节活化正常T细胞表达和分泌的”(RANTES)、巨嗜细胞炎性蛋白(MIP)MIP-1α和MIP-1β以及单核细胞趋化蛋白2(MCP-2)进行检测并产生响应。
这将导致免疫系统的细胞募集至疾病部位。在许多疾病中,正是这些表达CCR5的细胞直接或间接地对组织造成损伤。因此,抑制这些细胞的募集对于多种疾病是有益的。
CCR5还是HIV-1和其它病毒的共同受体(co-receptor),使得这些病毒得以进入细胞中。采用CCR5拮抗剂阻断这些受体或用CCR5激动剂诱导这些受体内化,可保护这些细胞不受病毒感染。
本发明提供式(I)的化合物或其药学上可接受的盐或溶剂合物:
其中
L是CH或N;M是CH或N;条件是L和M不同时为CH;
R1是氢、C1-6烷基[任选被苯基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、OCF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}或杂芳基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}取代]、苯基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、OCF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}、杂芳基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}、S(O)2R6、S(O)2R10R11、C(O)R7、C(O)2(C1-6烷基)(例如叔丁氧羰基)、C(O)2(C1-2烷基)(例如苄氧基羰基)或C(O)NHR7;以及当M是CH,R1还可以是NHS(O)2R6、NHS(O)2NHR7、NHC(O)R7或NHC(O)NHR7;
R2是任选被卤素、C1-4烷基、C1-4烷氧基、S(O)n(C1-4烷基)、硝基、氰基或CF3取代的苯基或杂芳基;
R3是氢或C1-4烷基;
R4是氢、甲基、乙基、烯丙基或环丙基;
R5是苯基、杂芳基、苯基NH、杂芳基NH、苯基(C1-2)烷基、杂芳基(C1-2)烷基、苯基(C1-2烷基)NH或杂芳基(C1-2烷基)NH;其中R5的苯环和杂芳环任选被卤素、氰基、硝基、羟基、C1-4烷基、C1-4烷氧基、S(O)k(C1-4烷基)、S(O)2NR8R9、NHS(O)2(C1-4烷基)、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NHC(O)NH2、C(O)NH2、C(O)NH(C1-4烷基)、NHC(O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、C(O)(C1-4烷基)、CF3、CHF2、CH2F、CH2CF3或OCF3取代;
k、m和n独立地是0、1或2;
R6是C1-6烷基[任选被卤素(例如氟)、C1-4烷氧基、苯基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、OCF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}或杂芳基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}取代]、C3-7环烷基、吡喃基、苯基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、OCF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}或杂芳基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、(C1-4烷基)C(O)NH、S(O)2NH2,C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代};
R7是氢、C1-6烷基[任选被卤素(例如氟)、C1-4烷氧基、苯基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、OCF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}或杂芳基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}取代]、C3-7环烷基、吡喃基、苯基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、OCF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}或杂芳基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代};
R8和R9独立地是氢或C1-4烷基、或可以与氮或氧原子一起形成任选被C1-4烷基、C(O)H或C(O)(C1-4烷基)取代的5-或6-元环;
R10和R11独立地是氢或C1-4烷基、或连在一起形成5-或6-元环,其中该环任选被C1-4烷基或苯基取代(其中苯环任选被卤素、氰基、硝基、羟基、C1-4烷基、C1-4烷氧基、S(O)mC1-4烷基、S(O)2NH2、S(O)2NH(C1-4烷基)、S(O)2N(C1-4烷基)2、NHS(O)2(C1-4烷基)、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NHC(O)NH2、C(O)NH2、C(O)NH(C1-4烷基)、NHC(O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、C(O)(C1-4烷基)、CF3、CHF2、CH2F、CH2CF3或OCF3取代);
条件是当R1是氢或未取代的烷基,R4是氢、甲基或乙基,L是CH以及M是N时,则R5的苯基或杂芳基部分被下面一个基团取代:S(O)kC1-4烷基、NHC(O)NH2、C(O)(C1-4烷基)、CHF2、CH2F、CH2CF3或OCF3,并且任选进一步被一个或多个卤素、氰基、硝基、羟基、C1-4烷基、C1-4烷氧基、S(O)kC1-4烷基、S(O)2NR8R9、NHS(O)2(C1-4烷基)、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NHC(O)NH2、C(O)NH2、C(O)NH(C1-4烷基)、NHC(O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、C(O)(C1-4烷基)、CF3、CHF2、CH2F、CH2CF3或OCF3取代。
本发明的某些化合物可以以各种异构体的形式(例如对映异构体、非对映异构体、几何异构体或互变异构体)存在。本发明包括所有的这些异构体及其所有比例的混合物。
合适的盐包括酸加成盐、如盐酸盐、氢溴酸盐、磷酸盐、乙酸盐、富马酸盐、马来酸盐、酒石酸盐、柠檬酸盐、草酸盐、甲磺酸盐和对甲苯磺酸盐。
本发明的化合物可以作为溶剂合物(例如水合物)存在,本发明包括所有这些溶剂合物。
烷基基团和部分是直链或支链的,例如是甲基、乙基、正丙基、异丙基、正丁基、仲丁基或叔丁基。在下文中甲基有时也简写为Me。
氟代烷基例如包括1-6个例如1-3个氟原子,并包括CF3基团。氟代烷基例如是CF3或CH2CF3。
环烷基例如是环丙基、环戊基或环己基。
苯基(C1-2烷基)烷基例如是苄基、1-(苯基)乙-1-基或1-(苯基)乙-2-基。
杂芳基(C1-2烷基)烷基例如是吡啶基甲基、嘧啶基甲基或1-(吡啶基)乙-2-基。
苯基(C1-2烷基)NH例如是苄氨基。杂芳基(C1-2烷基)NH例如是吡啶基CH2NH、嘧啶基CH2NH或吡啶基CH(CH3)NH。
杂芳基是含有至少一个选自氮、氧和硫的杂原子的芳族5或6元环,任选与一个或多个其它环稠合;或者其N-氧化物或S-氧化物或S-二氧化物。杂芳基例如是呋喃基、噻吩基(也称为thiophenyl)、吡咯基、噻唑基、异噻唑基、吡唑基、噁唑基、异噁唑基、咪唑基、[1,2,4]-三唑基、吡啶基、嘧啶基、吲哚基、苯并[b]呋喃基(亦称为苯并呋喃基)、苯并[b]噻吩基(亦称为苯并噻吩基或benzthiophenyl)、吲唑基、苯并咪唑基、苯并三唑基、苯并噁唑基、苯并噻唑基、1,2,3-苯并噻二唑基、咪唑并吡啶基(例如咪唑并[1,2a]吡啶基)、噻吩并[3,2-b]吡啶-6-基、1,2,3-苯并噁二唑基(亦称为[1,2,3]噻二唑基)、2,1,3-苯并噻二唑基、苯并呋咱(亦称为2,1,3-苯并噁二唑基)、喹喔啉基、吡唑并吡啶(例如1H-吡唑并[3,4-b]吡啶基)、喹啉基、异喹啉基、二氮杂萘基(例如[1,6]二氮杂萘基或[1,8]二氮杂萘基)、苯并噻嗪基、硫芴基(亦称为二苯并噻吩基);或其N-氧化物,或其S-氧化物或S-二氧化物。杂芳基还可以是吡嗪基。杂芳基例如是吡啶基、嘧啶基、吲哚基或苯并咪唑基。
在本发明的一个具体方面,本发明提供式(I)的化合物,L是CH或N;M是CH或N;条件是L和M不全都是CH;R1是氢、C1-6烷基[任选被苯基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}或杂芳基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}取代]、苯基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}、杂芳基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}、S(O)2R6、S(C)2NHR7、C(O)R7、C(O)2(C1-6烷基)或C(O)NHR7;并且当M是CH时,R1还可以是NHS(O)2R6、NHS(O)2NHR7、NHC(O)R7或NHC(O)NHR7;R2是苯基或杂芳基,苯基或杂芳基中的任何一个都可以任选在邻位或间位被卤素、C1-4烷基、C1-4烷氧基、S(O)n(C1-4烷基)、硝基、氰基或CF3取代;R3是氢或C1-4烷基;R4是氢、甲基、乙基、烯丙基或环丙基;R5是苯基、杂芳基、苯基NH、杂芳基NH、苯基(C1-2)烷基、杂芳基(C1-2)烷基、苯基(C1-2烷基)NH或杂芳基(C1-2烷基)NH;其中R5的苯环和杂芳环任选被卤素、氰基、硝基、羟基、C1-4烷基、C1-4烷氧基、S(O)kC1-4烷基、S(O)2NR8R9、NHS(O)2(C1-4烷基)、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NHC(O)NH2、C(O)NH2、C(O)NH(C1-4烷基)、NHC(O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、C(O)(C1-4烷基)、CF3、CHF2、CH2F、CH2CF3或OCF3取代;R8和R9独立地是氢或C1-4烷基,或可以与氮或氧原子一起形成任选被C1-4烷基、C(O)H或C(O)(C1-4烷基)取代的5-或6-元环;k和n独立地是0、1或2;R6是C1-6烷基[任选被苯基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}或杂芳基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3,C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}取代]、C3-7环烷基、苯基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}或杂芳基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代};R7是氢、C1-6烷基[任选被苯基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}或杂芳基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}取代]、C3-7环烷基、苯基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}或杂芳基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代},或者其可药用盐或溶剂合物;条件是当R1是氢或未取代的烷基,R4是氢、甲基或乙基,L是CH以及M是N时,R5的苯基或杂芳基部分被下面一个基团取代:S(O)kC1-4烷基、NHC(O)NH2、C(O)(C1-4烷基)、CHF2、CH2F、CH2CF3或OCF3,并且任选进一步被一个或多个卤素、氰基、硝基、羟基、C1-4烷基、C1-4烷氧基、S(O)kC1-4烷基、S(O)2NR8R9、NHS(O)2(C1-4烷基)、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NHC(O)NH2、C(O)NH2、C(O)NH(C1-4烷基)、NHC(O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、C(O)(C1-4烷基)、CF3、CHF2、CH2F、CH2CF3或OCF3取代。
在本发明的另一个方面,本发明提供一种化合物,其中当L和M都是N,并且R1是氢、C1-4烷基或苯基(苯基可以被0、1或2个选自:氟、氯、C1-4烷基、C1-4烷氧基、氰基、CF3、OCF3、(C1-4烷基)C(O)NH和S(O)2NH2的取代基取代)时;则R5的苯基或杂芳基部分可以带有一个S(O)2(C1-4烷基)取代基,并且任选带有一个或多个其它的取代基。
在本发明的另一方面,杂芳基是吡咯基、噻吩基、咪唑基、噻唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基或喹啉基。
在另一方面,M是N以及L是CH或N。
在还有另一方面,L和M两个都是N。
在其它方面,L是CH以及M是N。
在还有其它方面,L是N以及M是CH。
在本发明的另一方面,R1是氢、C1-6烷基[任选被苯基{其本身任选被卤素取代}取代]、S(O)2R6、S(O)2NHR7、C(O)R7、C(O)2(C1-6烷基)或C(O)NHR7取代;并且当M是CH时,R1也可以是NHS(O)2R6、NHS(O)2NHR7、NHC(O)R7或NHC(O)NHR7;R6是C1-6烷基[任选被苯基{其本身任选被卤素取代}取代]、C3-7环烷基、苯基{任选被卤素取代};以及R7是氢、C1-6烷基[任选被苯基{其本身任选被卤素取代}取代]、C3-7环烷基、苯基{任选被卤素取代}。
在本发明的另一方面,R1是C1-6烷基[被苯基{其本身任选被卤素取代}取代]、S(O)2R6、S(O)2NHR7、C(O)R7、C(O)2(C1-6烷基)或C(O)NHR7;并且当M是CH时,R1可以是NHS(O)2R6、NHS(O)2NHR7、NHC(O)R7或NHC(O)NHR7;R6是C1-6烷基[任选被苯基{其本身任选被卤素取代}取代]、C3-7环烷基、苯基{任选被卤素取代};以及R7是氢、C1-6烷基[任选被苯基{其本身任选被卤素取代}取代]、C3-7环烷基、苯基{任选被卤素取代}。
在本发明的再一方面,R1是S(O)2R6、C(O)R7、C(O)2(C1-6烷基)或C(O)NHR7;并且当M是CH时,R1还可以是NHS(O)2R6或NHC(O)R7;且R6和R7如上所定义。
在本发明的另一方面,R1是氢、C1-6烷基[任选被苯基{其本身任选被卤素取代}取代]、S(O)2R6、C(O)R7、C(O)2(C1-6烷基)或C(O)NHR7;并且当M是CH时,R1还可以是NHS(O)2R6或NHC(O)R7;R6是C1-6烷基[任选被苯基{其本身任选被卤素取代}取代]、C3-7环烷基、苯基{任选被卤素取代};以及R7是氢、C1-6烷基[任选被苯基{其本身任选被卤素取代}取代]、C3-7环烷基、苯基{任选被卤素取代}。
在另一方面R1是苯基(任选被卤素(例如氟)、C1-4烷基(例如甲基)、C1-4烷氧基(例如甲氧基)、CF3或OCF3取代)、S(O)2(C1-4烷基)(例如S(O)2CH3、S(O)2CH2CH3或S(O)2CH(CH3)2)、S(O)2(C1-4氟代烷基)(例如S(O)2CF3或S(O)2CH2CF3)、S(O)2苯基(任选被卤素(例如氯)、氰基、C1-4烷基、C1-4烷氧基、CF3、OCF3、S(O)2(C1-4烷基)(例如S(O)2CH3或S(O)2CH2CH2CH3)取代(例如单取代)或S(O)2(C1-4氟代烷基)(例如S(O)2CH2CF3)、苄基(任选被卤素(例如氯或氟)、C1-4烷基、C1-4烷氧基(例如甲氧基)、CF3或OCF3取代)、苯甲酰基(任选被卤素(例如氯或氟)、C1-4烷基(例如甲基)、C1-4烷氧基、CF3或OCF3取代)、C(O)NH苯基(任选被卤素(例如氟)、C1-4烷基、C1-4烷氧基、CF3或OCF3取代)、S(O)2噻吩基、CH2吡啶基、CH2喹啉基或CH2噻唑基。
再一个方面,R1是苯基(任选被卤素(例如氟)、C1-4烷基(例如甲基)或C1-4烷氧基(例如甲氧基)取代(例如单取代))、S(O)2(C1-4烷基)(例如S(O)2CH3、S(O)2CH2CH3或S(O)2CH(CH3)2)、S(O)2(C1-4氟代烷基)(例如S(O)2CF3或S(O)2CH2CF3)、S(O)2苯基(任选被卤素(例如氯)、氰基、CF3、OCF3、S(O)2(C1-4烷基)(例如S(O)2CH3或S(O)2CH2CH2CH3)或S(O)2(C1-4氟代烷基)(例如S(O)2CH2CF3)取代(例如单取代))、苄基(任选被卤素(例如氯或氟)或C1-4烷氧基(例如甲氧基)取代)、苯甲酰基(任选被卤素(例如氯或氟)或C1-4烷基(例如甲基)取代)、C(O)NH苯基(任选被卤素(例如氟)取代)、S(O)2噻吩基、CH2吡啶基、CH2喹啉基或CH2噻唑基。
另一方面,R1是苯基(任选被卤素(例如氟)或C1-4烷基(例如甲基)取代(例如单取代))、S(O)2(C1-4烷基)(例如S(O)2CH3、S(O)2CH2CH3或S(O)2CH(CH3)2)、S(O)2(C1-4氟代烷基)(例如S(O)2CF3或S(O)2CH2CF3)、S(O)2苯基(任选被CF3、OCF3或S(O)2(C1-4烷基)(例如S(O)2CH3)取代(例如单取代))、苄基(任选被卤素(例如氯或氟)或C1-4烷氧基(例如甲氧基)取代)、苯甲酰基(任选被卤素(例如氯或氟)取代)、C(O)NH苯基(任选被卤素(例如氟)取代)、CH2吡啶基、CH2喹啉基或CH2噻唑基。
还有一方面,R1是氢、C1-6烷基[任选被苯基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、OCF3、(C1-4烷基)C(O)NH、S(O)2NH2或S(O)2(C1-4烷基)取代}或杂芳基{其本身任选被卤素、C1-4烷基或(C1-4烷基)C(O)NH取代}取代]、苯基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、OCF3、(C1-4烷基)C(O)NH、S(O)2NH2或S(O)2(C1-4烷基)取代}、杂芳基{任选被卤素、C1-4烷基或(C1-4烷基)C(O)NH取代}、S(O)2R6、S(O)2NR10R11、C(O)R7或C(O)NHR7;并且当M是CH时,R1还可以是NHC(O)R7;R6是C1-6烷基[任选被卤素(例如氟)、苯基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、OCF3、(C1-4烷基)C(O)NH、S(O)2NH2或S(O)2(C1-4烷基)取代}或杂芳基{其本身任选被卤素、C1-4烷基或(C1-4烷基)C(O)NH取代}取代]、苯基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、OCF3、(C1-4烷基)C(O)NH、S(O)2NH2或S(O)2(C1-4烷基)取代}或杂芳基{任选被卤素、C1-4烷基或(C1-4烷基)C(O)NH取代};R7是氢、C1-6烷基[任选被卤素(例如氟)、C1-4烷氧基、苯基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、OCF3、(C1-4烷基)C(O)NH、S(O)2NH2或S(O)2(C1-4烷基)取代}或杂芳基{其本身任选被卤素、C1-4烷基或(C1-4烷基)C(O)NH取代}取代]、C3-7环烷基、吡喃基、苯基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、OCF3、(C1-4烷基)C(O)NH、S(O)2NH2或S(O)2(C1-4烷基)取代}或杂芳基{任选被卤素、C1-4烷基或(C1-4烷基)C(O)NH取代};以及R10和R11独立地是氢或C1-4烷基。
另一方面,R1是苯基(任选被卤素(例如氟)或C1-4烷基(例如甲基)取代(例如单取代))、S(O)2(C1-4烷基)(例如S(O)2CH3或S(O)2CH2CH3)、S(O)2(C1-4氟代烷基)(例如S(O)2CF3)、S(O)2苯基(任选被CF3或OCF3取代(例如单取代))、苄基、苯甲酰基(任选被卤素(例如氯或氟)取代)或C(O)NH苯基(任选被卤素(例如氟)取代)。
本发明的再一个方面,R2是苯基或杂芳基,苯基或杂芳基的任意一个任选在邻位或间位被卤素、C1-4烷基、C1-4烷氧基、S(O)n(C1-4烷基)、硝基、氰基或CF3取代;其中n是0、1或2,例如0或2。(邻位和间位是相对于式(I)的结构与环的相连位置而言)
还有一方面,R2是任选取代的苯基(例如任选被卤素(例如氯或氟)、氰基、甲基、乙基、甲氧基、乙氧基或CF3取代)。在一个方面,取代在苯环的邻位或间位。
在另一个方面,R2是任选取代的苯基(例如任选被卤素或CF3取代)。R2例如是3-氟苯基、3-氯苯基、4-氟苯基或4-CF3-苯基。在另一方面,R2是苯基、3-氟苯基、4-氟苯基、3-氯苯基、3,4-二氟苯基或3,5-二氟苯基。在另一个方面。R2是苯基、3-氟苯基、4-氟苯基、3,4-二氟苯基或3,5-二氟苯基。在本发明的还有一方面,R2是苯基或3-氟苯基。
在本发明的另一方面,R3是氢或甲基。在本发明的另一方面,当R3是C1-4烷基(例如甲基)时,与R3相连的碳具有R绝对构型。本发明的再有一个方面,R3是氢。
在本发明的另一方面,R4是乙基。
在本发明的另一方面,本发明提供一种化合物,其中R5是苯基(C1-2)烷基、苯基(C1-2烷基)NH、苯基、杂芳基或杂芳基(C1-2)烷基;其中苯环和杂芳环任选被卤素、氰基、硝基、羟基、C1-4烷基、C1-4烷氧基、S(O)kC1-4烷基、S(O)2NR8R9、NHS(O)2(C1-4烷基)、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NHC(O)NH2、C(O)NH2、C(O)NH(C1-4烷基)、NHC(O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、C(O)(C1-4烷基)、CF3、CHF2、CH2F、CH2CF3或OCF3取代;以及R8和R9独立地是氢或C1-4烷基,或者可以与氮或氧原子一起形成任选被C1-4烷基、C(O)H或C(O)(C1-4烷基)取代的5-或6-元环;以及k是0、1或2(例如2)。
在本发明的另一个方面,本发明提供一种化合物,其中R5是苯基(C1-2)烷基或苯基(C1-2烷基)NH;其中R5的苯环任选被卤素、氰基、硝基、羟基、C1-4烷基、C1-4烷氧基、S(O)kC1-4烷基、S(O)2NR8R9、NHS(O)2(C1-4烷基)、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NHC(O)NH2、C(O)NH2、C(O)NH(C1-4烷基)、NHC(O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、C(O)(C1-4烷基)、CF3、CHF2、CH2F、CH2CF3或OCF3取代;R8和R9独立地是氢或C1-4烷基或者可以与氮或氧原子一起形成任选被C1-4烷基、C(O)H或C(O)(C1-4烷基)取代的5-或6-元环;以及k是0、1或2。
在本发明的还有一方面,R5是苯基、杂芳基、苯基(C1-2)烷基或杂芳基(C1-2)烷基;其中苯环和杂芳环任选被卤素、氰基、硝基、羟基、C1-4烷基、C1-4烷氧基、S(O)kC1-4烷基、S(O)2NR8R9、NHS(O)2(C1-4烷基)、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NHC(O)NH2、C(O)NH2、C(O)NH(C1-4烷基)、NHC(O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、C(O)(C1-4烷基)、CF3、CHF2、CH2F、CH2CF3或OCF3取代;k是0、1或2;以及R8和R9独立地是氢或C1-4烷基或者可以与氮或氧原子一起形成任选被C1-4烷基、C(O)H或C(O)(C1-4烷基)取代的5-或6-元环。
在另一个方面,R5是苯基或苄基;其中芳环任选被卤素、氰基、硝基、羟基、C1-4烷基、C1-4烷氧基、S(O)kC1-4烷基、S(O)2NR8R9、NHS(O)2(C1-4烷基)、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NHC(O)NH2、C(O)NH2、C(O)NH(C1-4烷基)、NHC(O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、C(O)(C1-4烷基)、CF3、CHF2、CH2F、CH2CF3或OCF3取代;k是0、1或2;以及R8和R9独立地是氢或C1-4烷基或者可以与氮或氧原子一起形成任选被C1-4烷基、C(O)H或C(O)(C1-4烷基)取代的5-或6-元环。
在另一方面,R5是苯基或苄基;其中芳环任选被卤素、氰基、硝基、羟基、C1-4烷基、C1-4烷氧基、S(O)2C1-4烷基、S(O)2NR8R9、NHS(O)2(C1-4烷基)、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NHC(O)NH2、C(O)NH2、C(O)NH(C1-4烷基)、NHC(O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、C(O)(C1-4烷基)、CF3取代;以及R8和R9独立地是氢或C1-4烷基。
在另一个方面,R5是NHCH2苯基,其中苯环任选被卤素、氰基、硝基、羟基、C1-4烷基、C1-4烷氧基、S(O)2C1-4烷基、S(O)2NR8R9、NHS(O)2(C1-4烷基)、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NHC(O)NH2、C(O)NH2、C(O)NH(C1-4烷基)、NHC(O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、C(O)(C1-4烷基)、CF3取代;以及R8和R9独立地是氢或C1-4烷基。
再有一个方面,R5是苄基,其中苯环任选被卤素、氰基、硝基、羟基、C1-4烷基、C1-4烷氧基、S(O)2C1-4烷基、S(O)2NR8R9、NHS(O)2(C1-4烷基)、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NHC(O)NH2、C(O)NH2、C(O)NH(C1-4烷基)、NHC(O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、C(O)(C1-4烷基)、CF3取代;以及R8和R9独立地是氢或C1-4烷基。
在另一个方面,R5是NHCH2苯基,其中芳环任选被卤素(例如氟、氯或溴)、氰基、C1-4烷基(例如甲基)、C1-4烷氧基(例如甲氧基)或S(O)2C1-4烷基(例如S(O)2CH3)取代。
再有一个方面,R5是苄基,其中芳环任选被卤素(例如氟、氯或溴)、氰基、C1-4烷基(例如甲基)、C1-4烷氧基(例如甲氧基)或S(O)2C1-4烷基(例如S(O)2CH3)取代。
在还有一方面,R5是苯基或苄基,其中芳环被S(O)2C1-4烷基取代(例如在对位)以及该芳环任选进一步被卤素、氰基、硝基、羟基、C1-4烷基或C1-4烷氧基取代。
在另一个方面,R5是NHCH2苯基或苄基,其中芳环被S(O)2C1-4烷基(例如S(O)2CH3)取代(例如在对位)以及该芳环任选进一步被卤素、氰基、硝基、羟基、C1-4烷基或C1-4烷氧基取代。
在另一个方面,R5是NHCH2苯基,其中芳环被S(O)2C1-4烷基(例如S(O)2CH3)取代(例如在对位),R5例如是NHCH2(4-S(O)2CH3-C6H4)。
在另一个方面,R5是苄基,其中芳环被S(O)2C1-4烷基(例如S(O)2CH3)取代(例如在对位),R5例如是NHCH2(4-S(O)2CH3-C6H4)。
在下式(I)中表示的标记^的碳始终是手性的。
当L是N时,标记为^的碳例如具有S绝对构型。当L是CH时,标记为^的碳例如具有R绝对构型。
在本发明的另一个方面,本发明提供一种式(Ia)的化合物:
其中L、M和R1如上所定义。
在另一方面,本发明提供一种式(Ib)的化合物:
其中L、M和R1如上所定义;以及R是氢、一个或两个氟原子、S(O)n(C1-4烷基)或C1-4烷氧基;以及n是0、1或2(例如2)。
在本发明的另一个方面,本发明提供一种式(Ic)的化合物:
其中L、M和R1如上所定义;以及R是氢、一个或两个氟原子、S(O)n(C1-4烷基)或C1-4烷氧基;以及n是0、1或2(例如2)。
在本发明的另一方面,本发明提供一种式(Id)的化合物:
其中L、M和R1如上所定义;R是氢、一个或两个氟原子、S(O)n(C1-4烷基)或C1-4烷氧基;X是NHCH2、NH或CH2;n是0、1或2(例如2);以及R*是卤素(例如氟、氯或溴)、氰基、C1-4烷基(例如甲基)、C1-4烷氧基(例如甲氧基)或S(O)2C1-4烷基(例如S(O)2CH3)。
在本发明的另一个方面,本发明提供一种式(Ie)的化合物:
其中L、M和R1如上所定义。
再有一个方面,本发明提供一种式(If)的化合物:
其中L、M、X和R1如上所定义。
在本发明的另一方面,本发明提供一种式(Ig)的化合物:
其中R5上所定义。
列于表I-VI中的化合物用来说明本发明。
表I
表I包括式(Ib)的化合物。
化合物号 | L | M | R | R1 | LCMS(MH+) |
1 | N | N | H | 甲酰基 | 555 |
2 | N | N | H | 异丁酰基 | 597 |
3 | N | N | H | 乙酰基 | 569 |
4 | N | N | H | 苯甲酰基 | 631 |
5 | N | N | H | 乙基 | 555 |
6 | N | N | H | 甲基 | 541 |
7 | N | N | H | 苯磺酰基 | 667 |
8 | N | CH | H | 苄基 | 616 |
9 | N | CH | H | 乙酰基 | 568 |
10 | N | CH | H | 苄基氨基羰基 | 659 |
11 | N | CH | H | 乙氧基羰基 | 598 |
12 | N | CH | H | 甲基 | 540 |
13 | N | CH | H | 苯基乙酰基氨基 | 659 |
14 | N | CH | H | 乙酰氨基 | 583 |
15 | N | CH | H | 甲磺酰氨基 | 618 |
16 | N | CH | H | 苯磺酰氨基 | 681 |
17 | CH | N | H | H | 526 |
18 | CH | N | H | 苄基 | 616 |
19 | CH | N | H | 苯基乙酰基 | 644 |
20 | CH | N | H | 异丁酰基 | 596 |
21 | CH | N | H | 乙酰基 | 568 |
22 | CH | N | H | 环己基氨基羰基 | 651 |
23 | CH | N | H | 叔丁氧羰基 | 626 |
24 | CH | N | H | 4-氯苯甲酰基 | 664 |
25 | CH | N | H | 乙基 | 554 |
26 | CH | N | H | 甲基 | 540 |
27 | CH | N | H | 乙磺酰基 | 618 |
28 | CH | N | H | 甲磺酰基 | 604 |
29 | N | CH | H | 苯基脲基 | 660 |
30 | N | CH | H | 异丙基氨基羰基 | 611 |
31 | N | CH | H | 4-氯苯基氨基羰基 | 679 |
32 | N | CH | H | 4-氟苯基氨基羰基 | 663 |
33 | N | CH | H | 4-氯苯甲酰基氨基 | 679 |
34 | N | N | H | 苯基氨基羰基 | 546 |
35 | N | N | H | 丙基氨基羰基 | 612 |
36 | N | N | H | 甲磺酰基 | 605 |
37 | N | N | H | 乙磺酰基 | 619 |
38 | N | N | H | 1-甲基乙磺酰基 | 633 |
39 | N | N | H | 苯基甲磺酰基 | |
40 | N | N | H | 苯磺酰基(S-异构体) | |
41 | CH | N | H | 苯甲酰基 | |
42 | CH | N | H | 苯磺酰基 | |
43 | CH | N | H | 异丙基磺酰基 | |
44 | CH | N | H | 苯基氨基羰基 | |
45 | N | N | H | 苯基 | 603 |
46 | N | N | H | 4-氟苯基 | 621 |
47 | N | N | H | 4-甲氧基苯基 | 633 |
48 | N | N | H | 2-氯苯基 | 637 |
49 | N | N | H | 4-氯苯基 | 637 |
50 | N | N | H | 3-氯苯基 | 637 |
51 | N | N | H | 2-氟苯基 | 637 |
52 | N | N | H | 4-甲磺酰基苯甲酰基 | 709 |
53 | N | N | H | 2-甲磺酰基苯磺酰基 | 745 |
54 | N | N | H | 3-甲磺酰基苯甲酰基 | 709 |
55 | N | N | H | 3-氟苯基 | 621 |
56 | N | N | 3-氟 | 苯基 | 621 |
57 | N | N | 3-氟 | 4-甲磺酰基苯基 | 699 |
58 | N | N | 3-氟 | 苯磺酰基 | 685 |
59 | N | N | 3-氟 | 4-甲磺酰基苯磺酰基 | 763 |
60 | N | N | 3-氟 | 乙磺酰基 | 637 |
61 | N | N | 3-氟 | 甲磺酰基 | 623 |
62 | N | N | 3-氟 | 4-氯苯基 | 655 |
63 | N | N | 3-氟 | 3-氯苯基 | 655 |
64 | N | N | 3-氟 | 2-氟苯基 | 639 |
65 | N | N | 3-氟 | 4-氟苯基 | 639 |
66 | N | N | H | 5-溴嘧啶-2-基 | 683 |
67 | N | N | 3-氟 | 3-氟苯基 | 639 |
68 | CH | N | 3-氟 | 吡啶-3-基甲基 | 635 |
69 | CH | N | 3-氟 | 吡啶-4-基甲基 | 635 |
70 | CH | N | 3-氟 | 喹啉-2-基甲基 | 685 |
71 | CH | N | H | 吡啶-2-基甲基 | 617 |
72 | CH | N | H | 吡啶-3-基甲基 | 617 |
73 | CH | N | H | 吡啶-4-基甲基 | 617 |
74 | CH | N | H | 喹啉-2-基甲基 | 667 |
75 | CH | N | H | 喹啉-4-基甲基 | 667 |
76 | CH | N | H | 2-咪唑基甲基 | 605 |
77 | CH | N | H | (1-甲基-2-咪唑基)甲基 | 620 |
78 | CH | N | H | 2-吡咯基甲基 | 605 |
79 | CH | N | H | (1-甲基-2-吡咯基)甲基 | 619 |
80 | CH | N | H | 2-噻唑基甲基 | 623 |
81 | CH | N | H | 4-氯苯甲基 | 650 |
82 | CH | N | H | 3-氯苯甲基 | 650 |
83 | CH | N | H | 2-氯苯甲基 | 650 |
84 | CH | N | H | 4-氟苯甲基 | 634 |
85 | CH | N | H | 4-甲氧基苯甲基 | 646 |
86 | CH | N | H | 氢 | 526 |
87 | CH | N | H | 氢 | 543 |
88 | CH | N | H | 甲基 | 540 |
89 | CH | N | H | 乙酰基 | 568 |
90 | CH | N | H | 环己基氨基羰基 | 651 |
91 | CH | N | 3-氟 | 甲磺酰基 | 622 |
92 | CH | N | 3-氟 | 乙磺酰基 | 635 |
93 | CH | N | 3-氟 | 异丙基磺酰基 | 650 |
94 | CH | N | 3-氟 | 苯磺酰基 | 684 |
95 | CH | N | 3-氟 | 4-甲磺酰基苯磺酰基 | 762 |
96 | CH | N | 3-氟 | 4-氯苯甲酰基 | 682 |
97 | CH | N | 3-氟 | 4-甲氧基苯基甲基氨基羰基 | 707 |
98 | CH | N | 3-氟 | 环己基氨基羰基 | 668 |
99 | CH | N | 3-氟 | 苯基氨基羰基 | 663 |
100 | CH | N | 3-氟 | 苯基甲基氨基羰基 | 677 |
101 | CH | N | 3-氟 | (4-磺酰胺基苯基)甲基羰基 | 741 |
102 | CH | N | 3-氟 | 吡喃-4-基羰基 | 656 |
103 | CH | N | H | 4-氟苯甲酰基 | 648 |
104 | CH | N | H | 3-氟苯甲酰基 | 648 |
105 | CH | N | H | 2-氟苯甲酰基 | 648 |
106 | CH | N | H | 2-氯苯甲酰基 | 664 |
107 | CH | N | H | 3-氯苯甲酰基 | 664 |
108 | CH | N | H | 2-甲基苯甲酰基 | 644 |
109 | CH | N | H | 3-甲基苯甲酰基 | 644 |
110 | CH | N | H | 4-甲基苯甲酰基 | 644 |
111 | CH | N | H | 环戊基羰基 | 622 |
112 | CH | N | H | 丙酰基 | 582 |
113 | CH | N | H | 环丙基羰基 | 594 |
114 | CH | N | H | 吡嗪-2-基羰基 | 632 |
115 | CH | N | H | 3-甲磺酰基苯甲酰基 | 708 |
116 | CH | N | H | (2-甲基噻唑-4-基)羰基 | 651 |
117 | CH | N | H | 甲氧基甲基羰基 | 598 |
118 | CH | N | H | 2,2,2-三氟乙基羰基 | 636 |
119 | CH | N | H | 3-氰基苯基氨基羰基 | 670 |
120 | CH | N | H | 3-氟苯基氨基羰基 | 663 |
121 | CH | N | H | 3-氯苯基氨基羰基 | 679 |
122 | CH | N | H | 3-甲氧基苯基氨基羰基 | 675 |
123 | CH | N | H | 2-甲基苯基氨基羰基 | 659 |
124 | CH | N | H | 吡喃-4-基羰基 | 638 |
125 | CH | N | H | 三氟乙酰基 | 622 |
126 | CH | N | H | 4-氯苯基氨基羰基 | 679 |
127 | CH | N | H | 4-氟苯基氨基羰基 | 663 |
128 | CH | N | H | 4-甲氧基苯基氨基羰基 | 675 |
129 | CH | N | H | 2,5-二氟苯基氨基羰基 | 681 |
130 | CH | N | H | 3,4-二氯苯基氨基羰基 | 713 |
131 | CH | N | H | 2-甲氧基苯基氨基羰基 | 675 |
132 | CH | N | H | 2-氯代苯基氨基羰基 | 279 |
133 | CH | N | H | 三氟甲基磺酰基 | 658 |
134 | N | N | H | 4-甲磺酰基苯磺酰基 | 745 |
135 | N | N | H | 4-氰基苯磺酰基 | 692 |
136 | N | N | H | 2-三氟甲氧基苯磺酰基 | |
137 | N | N | H | 3-氯苯磺酰基 | 701 |
138 | N | N | H | 4-三氟甲基苯磺酰基 | 735 |
139 | N | N | H | 4-三氟甲氧基苯磺酰基 |
140 | N | N | H | 4-氯苯磺酰基 | 701 |
141 | N | N | H | (3,5-二甲基异噁唑)磺酰基 | 686 |
142 | N | N | H | 2-噻吩基磺酰基 | 673 |
143 | N | N | H | (2-乙酰氨基-3-甲基)噻唑-5-基磺酰基 | 745 |
144 | N | N | H | 4-乙酰氨基苯磺酰基 | 724 |
145 | CH | N | 3-氟 | 苯基 | 620 |
146 | CH | N | 3-氟 | 4-甲氧基苯基 | 650 |
147 | CH | N | 3-氟 | 4-氟苯基 | 638 |
148 | CH | N | H | 3-氯苯基 | 654 |
149 | CH | N | H | 4-氯苯基 | 654 |
150 | N | N | H | 2-氯苯磺酰基 | 701 |
151 | N | N | H | 4-氯苯甲酰基 | 665 |
152 | CH | N | H | 叔丁氧羰基 | 626 |
153 | CH | N | 3-氟 | 叔丁氧羰基 | 612 |
154 | CH | N | H | 2,2,2-三氟乙磺酰基 | 672 |
155 | N | N | 4-氟 | 甲磺酰基 | 623 |
156 | N | N | 4-氟 | 4-甲磺酰基苯磺酰基 | 763.3 |
157 | N | N | 3,4-二氟 | 甲磺酰基 | 641.4 |
158 | N | N | 3-氯 | 甲磺酰基 | 639 |
表II
表II包含式(Ic)的化合物。
化合物号 | L | M | R | 立体化学 | R1 | LCMS(MH+) |
1 | N | N | H | R或S | 苯磺酰基 | 667 |
2 | N | N | H | S或R | 4-甲磺酰基苯磺酰基 | 745 |
3 | N | N | H | S或R | 3-甲基苯基 | 617 |
4 | N | N | H | S或R | 4-甲基苯基 | 617 |
5 | N | N | H | S或R | 2-甲基苯基 | 617 |
6 | N | N | H | S或R | 2-甲氧基苯基 | 633 |
7 | N | N | H | S或R | 3-甲氧基苯基 | 633 |
8 | N | N | H | S或R | 2,6-二甲基苯基 | 631 |
9 | N | N | H | S或R | 2-氰基苯基 | 628 |
10 | N | N | H | S或R | 2-硝基苯基 | 648 |
11 | N | N | H | S或R | 2-甲硫基苯基 | 649 |
12 | N | N | H | S或R | 4-氟代苯基 | 621 |
13 | N | N | H | S或R | 2,6-二氯苯基 | 672 |
14 | N | N | H | S或R | 正丙基磺酰基 | 633 |
15 | N | N | H | S或R | 2,2,2-三氟乙基酰基 | 673 |
16 | N | N | 3-氟 | S或R | 4-甲磺酰基苯磺酰基 | |
17 | N | N | 3-氟 | R或S | 4-甲磺酰基苯磺酰基 | |
18 | CH | N | H | R | 乙磺酰基 | 654 |
19 | CH | N | H | S | 乙磺酰基 | 654 |
20 | CH | N | H | R | 甲磺酰基 | 604 |
21 | CH | N | H | S | 甲磺酰基 | 604 |
22 | CH | N | 3-氟 | R | 乙磺酰基 | 636 |
23 | CH | N | 3-氟 | S | 乙磺酰基 | 636 |
24 | CH | N | H | R | 苄氧基羰基 | 659 |
25 | CH | N | H | R | 苯基氨基羰基 | |
26 | CH | N | H | R | 4-氯苯甲酰基 | |
27 | CH | N | H | R | 4-甲磺酰基苯磺酰基 | |
28 | CH | N | 3-氟 | R | 4-氯苯甲酰基 | |
29 | CH | N | 3-氟 | S | 4-氯苯甲酰基 | |
30 | CH | N | 3-氟 | R | 4-甲磺酰基苯磺酰基 | |
31 | CH | N | 3-氟 | S | 4-甲磺酰基苯磺酰基 | |
32 | CH | N | 3,5-二氟 | R | 三氟甲基磺酰基 | 694 |
33 | CH | N | H | R | 4-氟苯甲酰基 | 648 |
34 | CH | N | H | S | 4-氟苯甲酰基 | 648 |
35 | CH | N | H | R | 氢 | 526 |
36 | CH | N | H | R | 三氟甲基磺酰基 | 658 |
37 | CH | N | H | S | 三氟甲基磺酰基 | 658 |
38 | CH | N | 2-甲硫基 | R | 甲磺酰基 | 650 |
39 | CH | N | H | R | N,N-二甲基氨基磺酰基 | 633 |
表III
表III包含式(Id)的化合物。
化合物号 | L | M | X | R | R* | R1 | LCMS(MH+) |
1 | N | N | NHCH2 | H | 4-甲磺酰基 | 苯磺酰基 | 682 |
2 | N | N | NHCH2 | H | 4-甲磺酰基 | 苯甲酰基 | 646 |
3 | N | N | NHCH2 | H | 4-甲磺酰基 | 乙磺酰基 | 634 |
4 | N | N | NHCH2 | H | 4-甲磺酰基 | 甲磺酰基 | 620 |
5 | N | N | NHCH2 | H | 4-甲磺酰基 | 4-氯苯甲酰基 | 680 |
6 | CH | N | NHCH2 | H | 4-甲磺酰基 | 苯磺酰基 | 681 |
7 | CH | N | NHCH2 | H | 4-甲磺酰基 | 乙磺酰基 | 633 |
8 | CH | N | NHCH2 | H | 4-甲磺酰基 | 氢 | 541 |
9 | CH | N | NHCH2 | H | 4-甲磺酰基 | 甲磺酰基 | 619 |
10 | CH | N | NHCH2 | H | 4-甲磺酰基 | 4-甲磺酰基苯磺酰基 | |
11 | CH | N | NHCH2 | H | 4-甲磺酰基 | 苯基甲基羰基 | 659 |
12 | CH | N | NHCH2 | H | 4-甲磺酰基 | 4-氯苯甲酰基 | 679 |
13 | CH | N | NHCH2 | H | 4-甲磺酰基 | 环己基氨基羰基 | 666 |
14 | CH | N | NHCH2 | H | 4-甲磺酰基 | 4-氟代苯基甲基氨基羰基 | 692 |
15 | CH | N | NHCH2 | H | 4-甲磺酰基 | 4-甲磺酰基苯甲酰基 | 723 |
16 | CH | N | NHCH2 | H | 4-甲磺酰基 | 吡啶-2-基甲基羰基 | 660 |
17 | CH | N | NHCH2 | H | 4-甲磺酰基 | 吡啶-3-基甲基羰基 | 660 |
18 | CH | N | NHCH2 | H | 氢 | 乙磺酰基 | 555 |
19 | CH | N | NHCH2 | H | 4-甲氧基 | 乙磺酰基 | 585 |
20 | CH | N | NHCH2 | H | 4-氟 | 乙磺酰基 | 573 |
21 | CH | N | NHCH2 | H | 3-甲基 | 乙磺酰基 | 569 |
22 | CH | N | NHCH2 | H | 3-甲氧基 | 乙磺酰基 | 571 |
23 | CH | N | NH | H | 3-氯 | 乙磺酰基 | 574 |
24 | CH | N | NH | H | 2-甲基 | 乙磺酰基 | 554 |
25 | CH | N | NH | H | 4-溴 | 乙磺酰基 | 621 |
26 | CH | N | NH | H | 3-氰基 | 乙磺酰基 | 566 |
27 | CH | N | NHCH2 | H | 氢 | 苯磺酰基 | 603 |
28 | CH | N | NHCH2 | H | 4-甲氧基 | 苯磺酰基 | 633 |
29 | CH | N | NHCH2 | H | 4-氟 | 苯磺酰基 | 621 |
30 | CH | N | NHCH2 | H | 3-甲基 | 苯磺酰基 | 616 |
31 | CH | N | NH | H | 3-氟 | 苯磺酰基 | 607 |
32 | CH | N | NH | H | 3-甲氧基 | 苯磺酰基 | 619 |
33 | CH | N | NH | H | 3-氯 | 苯磺酰基 | 623 |
34 | CH | N | NH | H | 2-甲基 | 苯磺酰基 | 603 |
35 | CH | N | NH | H | 4-溴 | 苯磺酰基 | 669 |
36 | CH | N | NH | H | 3-氰基 | 苯磺酰基 | 614 |
37 | CH | N | CH2 | 3-氟 | 4-磺酰胺基 | 叔丁氧基羰基 | 645 |
38 | CH | N | CH2 | 3-氟 | 4-磺酰胺基 | 氢 | 545 |
39 | CH | N | CH2 | 3-氟 | 4-磺酰胺基 | 4-甲磺酰基苯磺酰基 | 763 |
40 | CH | N | CH2 | 3-氟 | 4-磺酰胺基 | 环己基氨基羰基 | 670 |
41 | CH | N | CH2 | 3-氟 | 4-磺酰胺基 | 甲磺酰基 | 623 |
42 | CH | N | CH2 | 3-氟 | 4-磺酰胺基 | 乙磺酰基 | 637 |
43 | CH | N | NHCH2 | H | 4-甲磺酰基 | 1-甲基乙磺酰基 | 647 |
表IV
表IV包含式(Ie)的化合物。
化合物号 | L | M | 立体化学 | R1 | LCMS(MH+) |
1 | N | N | S或R | 苯磺酰基 | 682 |
2 | N | N | S或R | 乙磺酰基 | 634 |
3 | N | N | S或R | 甲磺酰基 | 620 |
4 | CH | N | R | 甲磺酰基 | 650 |
表V
表V包含式(If)的化合物。
化合物号 | L | M | X | R1 | LCMS(MH+) |
1 | N | N | CH2 | 苯磺酰基 | 681 |
2 | N | N | NHCH2 | 苯磺酰基 | 696 |
3 | N | N | NHCH2 | 甲磺酰基 | 634 |
表VI
表VI包含的化合物式(Ig)。
化合物号 | R5 | LCMS(MH+) |
1 | 吡啶-2-基CH2 | 589 |
2 | 吡啶-3-基CH2 | 589 |
3 | 吡啶-4-基CH2 | 589 |
在本发明的又一个方面,本发明提供列在上表中的各个化合物。
式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(If)和(Ig)的化合物可以按照如下所示的方法(例如在方案2和3中,方案1表示中间体的制备)进行制备。在方案1-3中:PG是一个保护基;Ac是乙酰基;Boc是叔丁氧羰基;Bn是苄基;Bz是苯甲酰基;DIBAL是二异丁基氢化铝;Et是乙基;Ms是甲磺酰基;以及TFA是三氟乙酸。
其中L是N的本发明化合物可以通过将式(II)的化合物:
其中R2、R3、R4和R5如上所定义,与式(III)的化合物:
其中R1如上所定义,在碘化钠和合适的碱(例如三(C1-6烷基)胺例如三乙胺或Hunig碱)存在下,在合适的溶剂(例如氯化溶剂,例如二氯甲烷)中以及例如在室温下(例如10-30℃)进行反应制备。
其中L是CH的本发明化合物可以通过将式(IV)的化合物:
其中R2、R3、R4和R5如上所定义,取决于本发明需要制备的化合物,与下面的一种化合物:
a)式R1CO2H的酸,在合适的偶联剂(例如PyBrOP[六氟磷酸溴-三-吡咯烷酮基-鏻盐]或HATU)存在下、在合适的碱(三(C1-6烷基)胺,例如二异丙基乙胺)、在合适的溶剂(例如N-甲基吡咯烷酮或氯代溶剂,例如,二氯甲烷)中、在室温下(例如10-30℃)进行反应;
b)式R1C(O)Cl的酰基氯或式R1S(O)2Cl的磺酰氯,在合适的碱(例如三(C1-6烷基)胺,例如三乙胺或二异丙基乙胺)、在合适的溶剂(例如氯代溶剂,例如二氯甲烷)中、在室温下(例如10-30℃)进行反应;或者,
c)式R1CHO的醛,在NaBH(OAc)3(其中Ac是C(O)CH3)和乙酸存在下、在合适的溶剂(例如C1-6脂肪醇,例如乙醇)、在室温下(例如10-30℃)下,进行反应制备。
做为选择,本发明的化合物可以通过将式(V)的化合物:
其中L、M、R1、R2、R3和R4如上所定义,与:
a)式R5CO2H的酸在合适的偶联剂(例如PyBrOP或HATU)存在下、在合适的碱(三(C1-6烷基)胺,例如二异丙基乙胺)、在合适的溶剂(例如N-甲基吡咯烷酮或氯代溶剂,例如二氯甲烷)中、在室温下(例如10-30℃)进行反应;或者,
b)式R5C(O)Cl的酰基氯,在合适的碱(例如三(C1-6烷基)胺,例如三乙胺或二异丙基乙胺)存在下、在合适的溶剂(例如氯代溶剂,例如二氯甲烷)中、在室温下(例如10-30℃)进行反应。
这些方法中的起始原料或者是市场上可买到的或者可以通过现有文献中的方法、改进的现有文献中的方法或者通过下面描述的方法或其改进方法制备。
本发明的另一方面是提供式(V)的中间体。
本发明的再有另外一个方面是提供式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(If)和(Ig)的制备方法。在方法中的许多中间体是新的并且这些中间体构成本发明的另一特征。
本发明的化合物具有药物活性,特别是可以作为趋化因子受体(尤其是CCR5)活性的调节剂(例如激动剂、部分激动剂、反向激动剂或拮抗剂),以及可以用于治疗自身免疫、炎症、增生或过度增生疾病、或者免疫调节疾病(包括移植器官或组织的排斥反应以及艾滋病(AIDS))。
本发明的化合物在抑制病毒(例如艾滋病毒(HIV))进入靶细胞上也具有价值,因此,在预防病毒(例如HIV)感染上、治疗病毒(例如HIV)感染和预防和/或治疗艾滋病(AIDS)上也有价值。
根据本发明的再一特点,本发明提供一种式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(If)和(Ig)的化合物(例如(I)或(Ia))、或其药学上可接受的盐或溶剂合物,在治疗(包括预防)温血动物(例如人)的方法中的用途。
根据本发明的再一特点,本发明提供一种用于调节需要这样治疗的温血动物,例如人的趋化因子受体活性(尤其是CCR5受体活性)的方法,其中包括给所述动物服用有效量的本发明的化合物,或其药学上可接受的盐或溶剂合物。
本发明还提供一种式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(If)和(Ig)的化合物(例如(I)或(Ia))、或其药学上可接受的盐或溶剂合物作为药物的用途,尤其是作为治疗移植排斥反应、呼吸道疾病、牛皮癣或类风湿性关节炎(尤其是类风湿性关节炎)的药物的用途。呼吸系统疾病为例如COPD,哮喘{如支气管、过敏性、内源性、外源性或粉尘性哮喘,特别是慢性或绵延难治的哮喘(例如晚期哮喘或气道高反应性)}或鼻炎{急性、过敏性、萎缩性鼻炎或慢性鼻炎包括干酪性鼻炎、肥厚性鼻炎、脓性鼻炎、干燥性鼻炎或药物性鼻炎;膜性鼻炎包括格鲁布性、纤维蛋白性或假膜性鼻炎或结核性鼻炎;季节性鼻炎包括神经性鼻炎(花粉症)或血管运动性鼻炎};并且特别是哮喘或鼻炎]。
本发明另一方面是提供一种式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(If)和(Ig)的化合物(例如(I)或(Ia))、或其药学上可接受的盐或溶剂合物在制备用于治疗(例如温血动物,例如人的调节趋化因子受体活性(尤其是CCR5受体活性(尤其是类风湿性关节炎))的药物上的用途。
本发明还提供一种式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(If)和(Ig)的化合物(例如(I)或(Ia))、或其药学上可接受的盐或溶剂合物用作药物的用途,尤其是用作治疗类风湿性关节炎的药物的用途。
本发明另一方面是提供一种式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(If)和(Ig)的化合物(例如(I)或(Ia))、或其药学上可接受的盐或溶剂合物在制备用于治疗(例如温血动物,例如人的调节趋化因子受体活性(尤其是CCR5受体活性(尤其是类风湿性关节炎))的药物上的用途。
本发明还提供一种式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(If)和(Ig)的化合物(例如(I)或(Ia))、或其药学上可接受的盐或溶剂合物在制备用于治疗温血动物例如人中的下列疾病的药物中的用途:
(1)(呼吸道)气道的阻塞性疾病包括:慢性阻塞性肺疾病(COPD)(如不可逆COPD);哮喘{如支气管、过敏性、内源性、外源性或粉尘性哮喘,特别是久喘或绵延难治的哮喘(例如晚期哮喘或气道高反应性)};支气管炎{如嗜酸性的支气管炎};急性、过敏性、萎缩性鼻炎或慢性鼻炎包括干酪性鼻炎、肥厚性鼻炎、脓性鼻炎、干燥性鼻炎或药物性鼻炎;膜性鼻炎包括格鲁布性、纤维蛋白性或假膜性鼻炎或结核性鼻炎;季节性鼻炎包括神经性鼻炎(花粉症)或血管运动性鼻炎;结节病;农夫肺和相关的疾病;鼻息肉病;纤维化肺或特发性间质性肺炎;
(2)(骨头和关节)关节炎包括风湿性关节炎、感染性关节炎、自身免疫性关节炎、血清阴性脊柱关节病(如强直性脊柱炎、银屑病关节炎或莱特病)、贝赫切特病、Sjogren氏综合征或全身性硬化症;
(3)(皮肤和眼睛)牛皮癣、特应性皮炎、接触性皮炎或其它湿疹性皮炎、脂溢性皮炎、扁平苔藓、Phemphigus、泡状Phemphigus、大疱性片剂皮松解症、荨麻疹、血管胚层症(angiodermas)、红斑血管炎、皮肤的嗜酸粒细胞增多、葡萄膜炎、斑秃或春季结膜炎;
(4)(胃肠道)腹部疾病、直肠炎、嗜酸细胞性胃肠炎、肥大细胞增生病、节段性回肠炎、溃疡性结肠炎、过敏性肠病或食物相关的变态反应,其在远离消化道起作用(例如偏头痛、鼻炎或湿疹);
(5)(同种异体移植物排斥)下列的急性和慢性疾病:例如肾、心脏、肝脏、肺、骨髓、皮肤或角膜的移植;或慢性移植物抗宿主病;和/或
(6)(其它组织或疾病)阿耳茨海默病、多发性硬化症、动脉粥样硬化、获得性免疫缺陷综合征(AIDS)、狼疮病(如红斑狼疮或全身性红斑狼疮)、全身性红斑狼疮、桥本甲状腺炎、重症肌无力、I型糖尿病、肾病综合征、嗜曙红细胞增多筋膜炎、高IgE综合征、麻疯病(如瘤型麻风)、牙周病、恶性皮肤网状细胞增多综合征、特发性血小板减少性紫癫或月经周期紊乱。
本发明还提供一种治疗温血动物(例如人)中由趋化因子介导的疾病(尤其是CCR5介导的疾病)的方法,所述方法包括给予需要这种治疗的动物有效量的式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(If)或(Ig)(例如(I)或(Ia))的化合物或其药学上可接受的盐或其溶剂合物。
为了将本发明化合物或其药学上可接受的盐或其溶剂合物用于治疗温血动物(例如人),特别是调节趋化因子受体(例如CCR5受体)活性,一般可根据标准制药技术,将所述组分配制成药物组合物。
因此,本发明另一方面是提供一种药物组合物,所述组合物包含式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(If)或(Ig)(例如(I)或(Ia))的化合物或其药学上可接受的盐或其溶剂合物(活性成分),以及药学上可接受的辅剂、稀释剂或载体。本发明的另一方面是提供制备所述组合物的方法,所述方法包括将活性成分与药学上可接受的辅剂、稀释剂或载体相混合。根据给药方式不同,所述药物组合物优选地包含0.05-99%w(重量百分比),更优选包含0.05-80%w,尤其更优选包含0.10-70%w,甚至更优选0.10-50%w的活性成分,所有重量百分比都以组合物总重量计。
本发明的药物组合物可以以治疗疾病希望的标准方式给予,例如通过局部(例如经肺和/或气道或皮肤)、口服、直肠或肠胃外给药。为了达到上述目的,本发明的化合物可以通过本领域已知的方法配制成,例如气雾剂、干粉制剂、片剂、胶囊、糖浆、粉剂、粒剂、水溶液或油溶液或悬浮液、(脂质)乳剂、分散性粉剂、栓剂、软膏剂、乳膏剂、滴剂以及无菌注射水溶液或油溶液或悬浮液。
本发明的适宜的药物组合物是一种适于口服的单位剂型,例如包含0.1mg-1g活性成分的片剂或胶囊。
另一方面,本发明的组合物药物是一种适于静脉内、皮下或肌肉注射的组合物。
例如,每个患者可以通过静脉内、皮下或肌内接受0.01mgkg-1~100mgkg-1,优选在0.1mgkg-1~20mgkg-1范围内的本发明的化合物,该组合物每天给药1-4次。静脉内、皮下和肌内剂量可以通过快速注射方式给予。或者,静脉内剂量可以一段时间内的连续输液给予。或者,每个患者可接受约相当于每日胃肠外剂量的日口服剂量,该组合物每日分1-4次给予。
以下说明用于人的治疗或预防用途的含式(I)、(Ia)、(Ib)、(Ic)、(Id)、(Ie)、(If)或(Ig)(例如(I)或(Ia))的化合物或其药学上可接受的盐或其溶剂合物(以下称为化合物X)的示范性药物制剂:
(a)
片剂I | mg/片 |
化合物X | 100 |
乳糖Ph.Eur. | 179 |
交联羧甲基纤维素钠 | 12.0 |
聚乙烯吡咯烷酮 | 6 |
硬脂酸镁 | 3.0 |
(b)
片剂II | mg/片 |
化合物X | 50 |
乳糖Ph.Eur. | 229 |
交联羧甲基纤维素钠 | 12.0 |
聚乙烯吡咯烷酮 | 6 |
硬脂酸镁 | 3.0 |
(c)
片剂III | mg/片 |
化合物X | 1.0 |
乳糖Ph.Eur. | 92 |
交联羧甲基纤维素钠 | 4.0 |
聚乙烯吡咯烷酮 | 2.0 |
硬脂酸镁 | 1.0 |
(d)
胶囊 | mg/胶囊 |
化合物X | 10 |
乳糖Ph.Eur. | 389 |
交联羧甲基纤维素钠 | 100 |
硬脂酸镁 | 1.0 |
(e)
注射剂I | (50mg/ml) |
化合物X | 5.0%w/v |
等张水溶液 | 至100% |
可使用缓冲液、药学上可接受的助溶剂(例如聚乙二醇、聚丙二醇、甘油或乙醇)或络合剂(例如羟丙基β-环糊精)来帮助配制。
上述制剂可以通过药物领域公知的常规方法得到。可以通过常规方法对片剂(a)-(c)进行肠溶包衣,例如获得一种乙酸邻苯二甲酸纤维素包衣。
本发明现在通过以下非限制性实施例进行说明,其中除非另有说明:
(i)温度单位为摄氏度(℃);在室温或环境温度操作是指在18-25℃下进行操作;
(ii)用无水硫酸镁干燥有机溶液;溶剂的蒸发使用旋转蒸发仪在减压下(600-4000帕斯卡;4.3-30mmHg)、浴温高达60℃下进行;
(iii)除非另有说明,层析法是指在硅胶上的快速层析;薄层层析法(TLC)在硅胶板上进行;其中“Bond Elut”柱是指从Varian,Harbor City,California,USA获得,名称为“Bond Elut SI”的含10g或20g粒径为40微米的硅胶柱,其中所述硅胶包装在60ml的一次性注射器中并由多孔板支撑。其中“IsoluteTM SCX柱”是指从International Sorbent Technology Ltd.,lst House,DuffrynIndustial Estate,Ystrad Mynach,Hengoed,Mid Glamorgan,UK处获得的含苯磺酸的柱(末端没有封闭的)。其中“Argonaut TM PS-三-胺清除剂树脂”是指从Argonaut Technologies Inc.,887 Industrial Road,Suite G,San Carlos,Califomia,USA处获得的三-(2-氨乙基)胺聚苯乙烯树脂;
(iv)通常,反应过程由TLC进行监测,给出的反应时间仅作为举例之用;
(v)给出的收率仅仅用来说明,不一定是那些通过努力工艺发展得到的量;如果要求更多的物质,可重复进行制备;
(vi)除非另有说明,以δ值的形式给出主要特征质子的1H NMR数据,相对于作为内标的四甲基硅烷(TMS)的百万分之一(ppm)形式给出,在300MHz下,使用氘代二甲亚砜(CD3SOCD3)作为溶剂测定;耦合常数(J)的单位是Hz;
(vii)所用化学符号具有它们常见的含义;使用国际单位制单位和符合;
(viii)溶剂比率为体积百分率;
(ix)质谱(MS)采用70电子伏特的电子能、以化学电离(APCI)方式、使用直接暴露探头进行测定;其中所述的电离通过电喷射(ES)进行;其中m/z值通常仅仅是以离子形式得到,并且以分子质量报道,除非另有说明,所述的分子离子以正分子离子的形式(M+H)+给出;
(x)LCMS表征使用带Gilson 233 XL取样机和Waters ZMD4000质谱仪以及一对Gilson 306泵进行。LC包括water symmetry 4.6×50 C18柱,具有5微米粒径。洗脱液是:A:水和0.05%甲酸;以及B:乙腈和0.05%甲酸。洗脱液梯度在6分钟内从95%A变为95%B。其中所述电离通过电喷射(ES)进行;其中m/z值仅仅以离子的形式给出并且以分子离子报道,除非另有说明,所述的分子离子以正分子离子(M+H)+给出;以及
(xi)使用下列缩写:
DMSO 二甲亚砜;
DMF N-二甲基甲酰胺;
DCM 二氯甲烷;
THF 四氢呋喃;
DIPEA N,N-二异丙基乙胺;
NMP N-甲基吡咯啉酮;
HATU O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐;
HBTU O-(7-苯并三唑-1-基)-N,N,N′,N′-四甲基脲鎓六氟磷酸盐;
Boc 叔丁氧基羰基;
MeOH 甲醇;
EtOH 乙醇;和
EtOAc 乙酸乙酯。
实施例1
本实施例说明N-[1-(3-苯基-3-[4-甲基哌嗪-1-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(表I的6号化合物)的制备。
向1-甲基哌嗪(42μL,0.38mmol)在DCM(10ml)中的溶液中加入三乙胺(0.1mL,0.72mmol),然后加入N-[1-(3-苯基-3-氯丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(方法A;180mg,0.38mmol)和碘化钠(50mg)。将所得混合物在室温下搅拌48小时,然后用水和盐水洗涤,干燥(MgSO4),蒸发。将残余物通过20g Bond Elut,用10%的甲醇在乙酸乙酯中的溶液、接着甲醇、然后1%三乙胺的甲醇溶液进行洗脱,得到标题化合物(58mg);NMR:1.2(t,1H),1.3(t,2H),1.4(m,1H),1.6(m,2H),1.8(m,4H),1.9(m,2H),2.1(m,2H),2.2(s,3H),2.4(m,8H),2.9(m,2H),3.0(s,3H),3.3(m,2H),3.8(s,2H),7.2(m,2H),7.4(m,2H),7.9(d,2H);MS:541。
用不同的仲胺(例如4-甲酰基哌嗪、4-异丁酰基哌嗪或4-苄基哌啶)代替1-甲基哌嗪,可以重复实施例1中描述的方法。
实施例2
本实施例说明N-[1-(3-苯基-3-[哌啶-4-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(表I的17号化合物)的制备。
将N-[1-(3-苯基-3-[1-叔丁基羰基氧基哌啶-4-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(实施例3,4g)溶于三氟乙酸(25ml)中,然后所得混合物在室温下搅拌2小时。蒸发混合物,将残余物与甲苯进行共沸。将所得物质与2M的氢氧化钠水溶液(25mL)搅拌,然后所得混合物用DCM(8×25mL)进行萃取。干燥合并的萃取物然后蒸发得到标题化合物(2.5g);MS:526。
实施例3
本实施例说明N-[1-(3-苯基-3-[1-叔丁基羰基氧基-哌啶-4-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(表I的23号化合物)的制备。
向3-苯基-3-(1-叔丁基羰基氧基哌啶-4-基)丙醛(方法C;14.4mmol)在DCM(100mL)中的溶液中,加入N-(4-哌啶基)-N-乙基-4-甲磺酰基苯乙酰胺(方法B;4.6g,14.4mmol),然后所得混合物在室温下搅拌30分钟。加入三乙酰氧基硼氢化钠(3.05g,14.4mmol),所得混合物在室温下搅拌2小时。反应混合物用2M的氢氧化钠水溶液(3×25mL)洗涤,干燥,通过50g SCX柱体用DCM(3×25mL)、乙酸乙酯(4×25mL)、甲醇(4×25mL)进行洗脱,最后用1M氨的甲醇溶液(4×50mL)进行洗脱,得到粗产品,该粗产品用硅胶色谱法(洗脱液:乙酸乙酯然后10%甲醇的乙酸乙酯溶液)进行提纯,得到标题化合物(4.2g);MS:626。
实施例4
本实施例说明N-[1-(3-苯基-3-[1-甲基哌啶-4-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(表I的26号化合物)的制备。
向N-[1-(3-苯基-3-[哌啶-4-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯基乙酰胺(实施例2,250mg,4.76mmol)以及甲醛(0.2mL,37%的水溶液)在DCM(10mL)中的混合物中,加入三乙酰氧基硼氢化钠(9.52mmol),并将得到的混合物在室温搅拌18小时。混合物用2M的氢氧化钠水溶液(10mL)洗涤,通过10g SCX柱体用DCM(2×10mL)、甲醇(2×10mL)并且最后用1M的氨水在甲醇中的溶液(4×10mL)进行洗脱,得到标题化合物(172mg);MS:540。
用各种醛(例如乙醛和苯甲醛)代替甲醛,可以重复实施例4中描述的方法。
实施例5
本实施例说明N-[1-(3-苯基-3-[1-乙酰基哌啶-4-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(表I的21号化合物)的制备。
向N-[1-(3-苯基-3-[哌啶-4-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(实施例2,250mg,4.76mmol)和三乙胺(48mg,4.76mmol)在DCM中的混合物中加入乙酰氯(37mg,4.76mmol)。所得混合物在室温下搅拌18小时,用饱和碳酸氢钠水溶液(10mL)洗涤,干燥并通过10g SCX柱体用DCM(2×10mL)、甲醇(4×10mL)并且最后用1M氨水的甲醇溶液(4×10mL)进行洗脱,得到标题化合物(180mg);MS:568。
用各种酰氯(例如苯乙酰氯和4-氯苯甲酰氯)或磺酰氯(例如甲磺酰氯)代替乙酰氯,可以重复实施例5中描述的方法。
实施例6
本实施例说明N-[1-(3-苯基-3-[1-环己基氨基羰基哌啶-4-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(表I的22号化合物)的制备。
向N-[1-(3-苯基-3-[哌啶-4-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(实施例2,250mg,4.76mmol)和DCM(10mL)的混合物中加入异氰酸环己酯(59mg,4.6mmol),然后所得混合物在室温下搅拌18小时。将混合物通过10g SCX柱体用DCM(4×10mL)、甲醇(2×10mL)并且最后用1M的氨水在甲醇中的溶液(4×10mL)进行洗脱,得到标题化合物(300mg);MS:651。
实施例7
本实施例说明N-[1-(3-苯基-3-[4-(2-氯苯基磺酰基)哌嗪-1-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(表I的150号化合物)的制备。
将2-氯苯基磺酰氯(40.1mg)加入到N-[1-(3-苯基-3-[哌嗪-1-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(100毫克)和三乙胺(53μl)在二氯甲烷(5ml)的溶液中,将混合物搅拌1小时。反应混合物用水、盐水洗涤并干燥,除去溶剂,残余物通过10g硅胶Bond-Elut柱进行色谱提纯,用溶剂梯度(乙酸乙酯-20%甲醇/乙酸乙酯)洗脱,得到标题化合物,收率90mg。MH+701。
用适当的(1-叔丁氧羰基)-哌嗪类似物,按照实施例2中描述的方法,制备作为原料的N-[1-(3-苯基-3-[哌嗪-1-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(表1的化合物86)。
用适当的(1-叔丁氧羰基)-哌嗪类似物作为胺成分,按照实施例1中描述的方法,制备作为原料的N-[1-(3-苯基-3-[1-叔丁氧羰基哌嗪-1-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(表1的化合物152)。
实施例8
(R或S)N-[1-(3-苯基-3-[(4-{2,2,2-三氟乙基磺酰基-哌嗪基}丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺。(表2的化合物15)
将三乙胺(50μl)加入到(R或S)N-[1-(3-苯基-3-哌嗪}丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(175mg)在二氯甲烷(5ml)中的溶液中,接着加入2,2,2-三氟乙磺酰氯(37μl),然后将混合物在室温下搅拌14小时。反应混合物用水洗涤,然后干燥。除去溶剂,得到的残余物在20g硅胶Bond-Elut柱上进行色谱提纯,用溶剂梯度(乙酸乙酯-40%甲醇/乙酸乙酯)洗脱,得到白色泡沫形式的标题化合物,收率79mg,MH+673。NMR(CDCl3):1.2(t,1H),1.3(t,2H),1.4(m,1H),1.6-1.8(m,8H),2.1(m,2H),2.25(m,1H),2.5(m,4H),2.9(m,2H),3.0(s,3H),3.3(m,5H),3.4(m,1H),3.6(q,2H),3.8(m,2H),7.2(m,2H),7.3(m,3H),7.4(m,2H),7.9(d,2H)。
实施例9
(R或S)N-[1-(3-苯基-3-[(叔丁氧羰基-哌嗪基}丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺
在室温下,向三乙胺(0.35ml)和Boc-哌嗪(233mg)在二氯甲烷(10ml)的溶液中加入(R或S)N-[1-(3-苯基-3-氯丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(594mg),然后将混合物搅拌14小时。反应混合物在20g硅胶Bond-Elut柱上进行色谱提纯,用溶剂梯度(乙酸乙酯-40%甲醇/乙酸乙酯)洗脱,得到泡沫形式的标题化合物,收率440mg,MH+627。
(R或S)N-[1-(3-苯基-3-氯丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺
在0℃下,将甲磺酰氯(0.5ml)加入到SN-[1-(3-苯基-3-羟丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(2.7g)和三乙胺(1.64ml)在二氯甲烷(50ml)的搅拌混合物中,然后将混合物在环境温度下搅拌15小时。反应混合物用水洗涤,然后干燥。除去溶剂,得到橙色泡沫形式的标题化合物,收率2.4g,MH+477。
(S)N-[1-(3-苯基-3-羟丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺
向N-(哌啶-4-基)-N-乙基-4-甲磺酰基苯乙酰胺(5.3g)和碳酸钾(2.71g)在DMF(100ml)的混合物中加入(S)1-苯基-3-(4-甲苯磺酰氧基)丙烷-1-醇(5g),然后将混合物在80-90℃下搅拌加热6小时。将冷却反应混合物并蒸干。将得到的残余物溶于二氯甲烷(50ml)中,用水洗涤并干燥。除去溶剂,反应混合物在90g硅胶Bond-Elut柱上进行色谱提纯,用溶剂梯度(乙酸乙酯-20%甲醇/乙酸乙酯)洗脱,得到标题化合物,收率2.7g,MH+ 459。NMR(CDCl3):1.2(t,1H),1.3(t,2H),1.6(m,2H),1.75(m,3H),1.85(m,3H),2.2(m,1H),2.55-2.7(m,2H),3.0(s,3H),3.1-3.2(m,2H),3.3(q,2H),3.8(m,2H),4.9(m,1H),7.3(m,5H),7.45(d,2H),7.9(d,2H)。
(S)1-苯基-3-(4-甲苯磺酰氧基)丙烷-1-醇是一种已知的化合物(CAS号156453-52-0)
实施例10
(R或S)N-[1-(3-苯基-3-哌嗪}丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺
将三氟乙酸(5ml)加入到(R或S)N-[1-(3-苯基-3(Boc-哌嗪}丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(440mg)在二氯甲烷(10ml)中的溶液中,将混合物搅拌1小时。浓缩反应混合物,残余物溶于2M氢氧化钠水溶液中,用二氯甲烷萃取两次(每次10ml)。干燥合并的萃取液并蒸发至干,得到泡沫形式的标题化合物,收率370mg,MH+527。
实施例11
(R)N-[1-(3-苯基-3-{1(4-氯苯甲酰基哌啶-4-基)丙基}哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺。(表2的化合物26)
向(R)N-[1-3-苯基-3-[哌啶-4-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(330mg)和MP碳酸酯树脂(670mg的2.8mM/g材料)在二氯甲烷(10ml)的混合物中,加入4-氯苯甲酰氯(111mg),混合物在室温下搅拌15小时。过滤反应混合物,将MP4-甲苯磺酸树脂(1g)加入到滤液中,然后搅拌30分钟。过滤反应混合物,树脂先后用二氯甲烷(4×10ml)、1M甲醇/NH3(3×10ml)进行洗涤。将合并的洗液蒸发至干,残余物通过硅胶Bond-Elut柱进行色谱提纯,用溶剂梯度(乙酸乙酯-20%甲醇在乙酸乙酯中)洗脱,得到标题化合物,收率121mg。NMR(DMSOd6):0.8-2.2(m,6H),1.2-1.5(m,4H),1.5-2.1(m,13H),2.4(m,1H),2.7(m,3H),3.3(m,4H),3.8(d,2H),7-7.5(m,11H),7.8(d,2H)。在Chiral cel OJ柱(250mm×4.6mm)上用甲醇洗脱,进行HPLC分析,表明手性纯度>99%。
(R)N-[1-3-苯基-3-[哌啶-4-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(表2的化合物35)
将(R)N-[1-(3-苯基-3-{1-(苄氧基羰基哌啶-4-基)丙基}哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(1.5g)在含20%钯/碳催化剂(200mg)的乙醇(100ml)的溶液在氢气氛中进行氢化。过滤除去催化剂,将滤液蒸发至干,得到标题化合物,收率1.1g。MS(MH+)526。
(R)N-[1-(3-苯基-3-{1-(苄氧基羰基哌啶-4-基)丙基}哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺。(表2的化合物24)
将乙酰氧基硼氢化钠(890mg)加入到(R)3-苯基-3-(苄氧基羰基哌啶-4-基)丙醛(1.49g)和N-(4-哌啶基)-N-乙基-4-甲磺酰基苯乙酰胺(1.4g)在二氯甲烷(25ml)中的溶液中,将混合物搅拌1小时。反应混合物用2MNaOH(2×50ml)洗涤,干燥。除去溶剂,残余物通过硅胶Bond-Elut柱进行色谱提纯,用溶剂梯度(乙酸乙酯-20%甲醇/乙酸乙酯)洗脱,得到标题化合物,收率1.5g。MS(MH+)660。
(R)3-苯基-3-(苄氧基羰基哌啶-4-基)丙醛
将Dess-Martin periodinane(1,1,1-三乙酰氧基-1,1-二氢-1,2-benziodoxol-3(1H)-酮)(1.8g)加入到(R)3-苯基-3-(苄氧基羰基哌啶-4-基)丙醇在二氯甲烷(25ml)的溶液中,所得混合物搅拌1小时,然后用2M NaOH洗涤(2×20ml)并干燥。含标题化合物的二氯甲烷溶液直接用于下一步反应中。
(R)3-苯基-3-(苄氧基羰基哌啶-4-基)丙醇
以温度不超过0℃的速度,将氢化铝锂(9.46ml的1M LAH的四氢呋喃溶液)滴加到(R)3-[3-苯基-3-(苄氧基羰基哌啶-4-基)丙酰基]-(4R,5S)-1,5-二甲基-4-苯基-2-咪唑烷酮(5.1g)在THF(100ml)的溶液中。反应混合物在-5℃下搅拌10分钟,然后加入2MNaOH(10ml)。用硅藻土过滤反应混合物,然后将滤液蒸发至干。将残余物溶于二氯甲烷(20ml)中并干燥。除去溶剂,残余物通过Bond-Elut柱进行色谱提纯,用溶剂梯度(异己烷-60%乙酸乙酯/异己烷)洗脱,得到标题化合物,收率1.6g。MS(MH+)354。
3-[(R)3-苯基-3-(苄氧基羰基哌啶-4-基)丙酰基]-(4R,5S)-1,5-二甲基-4-苯基-2-咪唑烷酮
将TMEDA(2.4g)加入到碘化亚铜(4.02g)在THF(100ml)的悬浮液中,在室温下将混合物搅拌30分钟。反应混合物冷却至-78℃,加入溴化苯基镁(11.69ml的1M在THF中的溶液),将混合物在-78℃下搅拌30分钟。将二丁基硼三氟甲磺酸酯(11.69ml,1M在乙醚中的溶液)加入到3-[3-(苄氧基羰基哌啶-4-基)丙烯酰]-(4R,5S)-1,5-二甲基-4-苯基-2-咪唑烷酮(4.9g)在THF(50ml)的溶液中,然后将此混合物在10分钟内滴加到铜酸盐试剂的溶液中。反应混合物在-78℃下搅拌1小时,然后让其温热至环境温度。蒸发除去溶剂,将残余物溶于乙酸乙酯中,通过二氧化硅(100g)进行过滤。乙酸乙酯溶液用2M HCl(1×100ml)洗涤,干燥并蒸发至干。残余物通过Bond-Elut柱,用乙酸乙酯和异己烷(1∶1)的混合物洗脱,得到单一非对映异构体形式的标题化合物,通过NMR确认。收率5.1g。NMR(DMSOd6):0.5(d,3H),0.8-1.1(m,2H),1.3(d,1H),1.7(m,2H),2.6(m,5H),2.85-3.1(m,4H),5.05(s,2H),5.2(d,1H),6.8(m,2H),7.1-7.5(m,13H)。
3-[3-(苄氧基羰基哌啶-4-基)丙烯酰]-(4R,5S)-1,5-二甲基-4-苯基-2-咪唑烷酮
在10分钟内,将1-氯-N,N,2-三甲基-1-丙烯基胺(1.37g)滴加至3-(苄氧基羰基哌啶-4-基)丙烯酸(2.5g)在THF(20ml)的溶液中,混合物搅拌1.5小时。在-10℃下,将二(三甲基甲硅烷基)酰胺锂(8.65ml)加入到(4R,5S)-1,5-二甲基-4-苯基-2-咪唑烷酮(1.64g)在THF(20ml)的溶液中,混合物在-10℃下搅拌10分钟,让其温热至0℃,然后再次冷却至-10℃。滴加酰氯溶液(上述制备),混合物温热至室温。将反应混合物倒入水(100mL)中并用乙酸乙酯(3×50mL)萃取。将合并的萃取液干燥,蒸发至干,残余物用Bond-Elut柱进行色谱提纯,用乙酸乙酯/异己烷混合物(1∶1)洗脱,得到标题化合物,收率3.6g。NMR(DMSOd6):0.6(d,3H),0.95(d,1H),1.2(m,2H),1.55(m,2H),2.4(m,1H),2.3(s,3H),2.8(m,2H),3.95(m,3H),5(s,2H),5.3(d,1H),6.9(m,1H),7.1(m,2H),7.2-7.4(m,8H)。
3-(苄氧基羰基哌啶-4-基)丙烯酸
将N-苄氧基羰基-4-甲酰基哌啶(10g)、丙二酸(4.2)、吡啶(4ml)和哌啶(0.4ml)的混合物在100℃加热2小时。将反应混合物冷却,用乙酸乙酯(100ml)稀释。溶液用2M HCl(2×100ml)洗涤,干燥并蒸发至干。将残余物用异己烷研磨,得到标题化合物,收率13.5g。NMR(DMSOd6):1.2(m,2H),1.7(m,2H),2.35(m,1H),2.85(m,2H),4(d,2H),5.05(s,2H),5.75(d,1H),6.75(m,1H),7.35(m,5H),12.25(宽峰,1H)。
实施例12
N-[1-3-苯基[(3-氟苯基)-3-[1-苯基哌啶-4-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(表1的化合物145)。
将2M NaOH加入到N-[1-[3-(3-氟苯基-3-[哌啶-4-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺二盐酸盐(0.85g)在二氯甲烷(25ml)的悬浮液中,搅拌混合物直到获得一种透明溶液为止。将二氯甲烷溶液进行干燥并过滤。向此二氯甲烷溶液中加入苯硼酸(330mg)、三乙胺(280mg)和乙酸铜(276mg)。将反应混合物搅拌15小时,用水洗涤,通过Chem Elute柱体进行过滤。将该二氯甲烷滤液用2M NaOH(3×20ml)洗涤,干燥,然后倒在20g SCX柱体上,用甲醇(6×20ml)和1M氨水的甲醇溶液(6×20ml)分别进行洗脱。将合并的洗液蒸发至干,获得的残余物通过Bond-Elut柱进行色谱提纯,用溶剂梯度(乙酸乙酯-20%甲醇在乙酸乙酯中)洗脱,得到标题化合物,收率179mg。
用作起始原料的N-[1-3(3-氟苯基-3-[哌啶-4-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺二盐酸盐(表1的化合物87),按照实施例3和方法C的步骤制备。
实施例13
通过色谱法在Gilson制备性HPLC上使用50mm 20μm Chiracel OD柱,用乙醇∶异己烷(9∶1)的混合物洗脱,将外消旋的N-[1-(3-(3-氟苯基)-3-[4-(4-甲磺酰基)苯磺酰基)哌嗪-1-基]丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(78mg)(表1的化合物59)拆分成单一对映体。
较少的极性异构体,收率20mg(表2的化合物16)
较多的极性异构体,收率22mg(表2的化合物17)
实施例14
N-1-[1-(3-苯基)-3-{1-(乙磺酰基哌啶-4-基)丙基}哌啶-4-基]-N1-乙基-N3-4-甲磺酰基苯基甲基脲。(表3的化合物7)
将4-甲磺酰基苯基甲基异氰酸酯(99mg)在THF(10ml)中的溶液加入到4-N-乙基-[1-(3-苯基)-3-{1-(乙磺酰基哌啶-4-基)丙基}哌啶(200mg)中,混合物在室温下静置16小时。将反应混合物倒在5g SCX柱体上,分别用二氯甲烷(3×10ml)、甲醇(3×10ml)和氨水的甲醇溶液(1M,3×10ml)进行洗涤。蒸发掉甲醇氨水洗液,残余物溶于二氯甲烷(20ml)中,然后加入异氰酸酯树脂(200mg)。混合物搅拌16小时,过滤,然后将滤液蒸发至干。残余物通过Bond-Elut柱进行色谱提纯,用溶剂梯度(乙酸乙酯-25%甲醇/乙酸乙酯)洗脱,得到标题化合物,收率37mg。MS(MH+)633。
4-N-乙基-[1-(3-苯基)-3-{1-(乙磺酰基哌啶-4-基)丙基}哌啶
将N-乙基-N-[1-(3-苯基)-3-{1-(乙磺酰基哌啶-4-基)丙基}哌啶-4-基]-氨基甲酸苄基酯(5g)和10%钯碳(2g)在乙醇(200ml)的混合物在氢气氛中氢化。过滤除去催化剂,将滤液蒸发至干,得到标题化合物,收率2.78g。
N-乙基-N-[1-(3-苯基)-3-{1-(乙磺酰基哌啶-4-基)丙基}哌啶-4-基]-氨基甲酸苄酯
保持在0℃下,将乙磺酰氯(2.3g)加入到N-乙基-N-[1-(3-苯基)-3-{哌啶-4-基)丙基}哌啶-4-基]-氨基甲酸苄酯二盐酸盐(8.5g)和三乙胺(4.8g)在二氯甲烷(200ml)的溶液中。反应混合物温热至室温并搅拌4小时。反应混合物用2MNaOH(2×100ml)洗涤,干燥并蒸发至干。残余物通过Bond-Elut柱进行色谱提纯,用溶剂梯度(乙酸乙酯-20%甲醇/乙酸乙酯)洗脱,得到标题化合物,收率5g。NMR(DMSOd6):1(t,3H),1.1(t,3H),1.3-3(m,14H),2.2(m,1H),2.55-2.9(m,5H),2.95(q,2H),3.1(q,2H),3.4-3.7(m,3H),5.05(s,2H),7.1-7.4(m,10H)。MS(MH+)556。
N-乙基-N-[1-(3-苯基)-3-{哌啶-4-基)丙基}哌啶-4-基]-氨基甲酸苄酯二盐酸盐
在0℃下,将HCl的二噁烷溶液(50ml,4M)加入到N-乙基-N-[1-(3-苯基)-3-{1-叔丁氧基羰基哌啶-4-基)丙基}哌啶-4-基]-氨基甲酸苄酯(26g)。反应混合物温热至室温并搅拌2小时。反应混合物用乙醚(200ml)稀释,过滤析出的固体二盐酸盐并干燥(吸湿的)。收率17g。MS(MH+)464。
N-乙基-N-[1-(3-苯基)-3-{1-叔丁氧羰基哌啶-4-基)丙基}哌啶-4-基]-氨基甲酸苄基酯
将3-苯基-3-(1-叔丁氧基羰基哌啶-4-基)丙醛(7.8g)[按照实施例11中描述的方法制备]在二氯甲烷(200ml)中的溶液加入到N-乙基-N-哌啶-4-基氨基甲酸苄基酯盐酸盐(7.4g)(CAS号220395-87-9)和乙酸钠(2.17g)在乙醇(50ml)中的混合物中,并搅拌30分钟。在15分钟内,将乙酰氧基硼氢化钠(5.2g)分几批加入,继续搅拌2小时。滴加入NaOH水溶液(2M,200ml),收集二氯甲烷层并用2MNaOH(2×100ml)洗涤,干燥,蒸发至干得到标题化合物,收率26g。NMR(DMSOd6):1(t,3H),1.35(s,9H),1.4-2(m,14H),2.3(m,2H),2.6-2.7(m,4H),3.15(q,2H),3.4-4(m,3H),5.05(s,2H),7.1-7.2(m,10H)。MS(MH+)563。
4-甲磺酰基苯基甲基异氰酸酯
将二苯基磷酰基叠氮化物(260mg)加入到4-甲磺酰基苯乙酸(200mg)和三乙胺(191mg)在THF(20ml)中的混合物中,反应混合物加热回流4小时。冷却反应混合物,并直接用于下一步反应。
方法A
N-[1-(3-苯基-3-氯丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺
步骤1:N-[1-(3-苯基-3-氧代丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺的制备
向N-(4-哌啶基)-N-乙基-4-甲磺酰基苯乙酰胺(方法B;3.24g,10mmol)在DMF(50mL)中的溶液加入碳酸钾(2.76g,20mmol),接着加入3-氯苯基乙基酮(1.85g,11mmol)。所得混合物在室温下搅拌18小时,然后蒸发。残余物溶于DCM中,所得溶液用水(4×10mL)和盐水(10mL)洗涤,干燥(MgSO4)并蒸发,得到粗品,通过50g Bond Elut进行纯化,用10%甲醇的乙酸乙酯溶液洗脱,得到副标题化合物(2.4g,53%);
NMR(CDCl3):1.1(t,1H),1.2(m,2H),1.6(m,6H),2.2(m,1H),2.8(m,2H),3.0(m,5H),3.2(m,2H),3.3(m,2H),3.8(m,2H),7.4(m,5H),7.9(m,4H)。MS:457。
步骤2:N-[1-(3-苯基-3-羟丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺的制备
在0℃下,向N-[1-(3-苯基-3-氧代丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(912mg,2mmol)在乙醇(20ml)中的溶液中加入硼氢化钠(76mg,2mmol)。所得混合物在室温下搅拌30分钟。然后蒸发。残余物溶于DCM中,所得溶液用水(2×5mL)和盐水(5mL)洗涤,干燥(MgSO4)并蒸发,得到副标题化合物(812mg,87%);
NMR(CDCl3):1.1(t,1H),1.2(m,2H),1.6(m,8H),2.0(m,1H),2.2(m,1H),2.6(m,2H),3.0(s,3H),3.2(m,2H),3.3(m,2H),3.8(m,2H),4.9(d,1H),7.3(m,5H),7.4(d,2H),7.9(d,2H);MS:459。
步骤3:标题化合物的制备
在0℃下,向N-[1-(3-苯基-3-羟丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(400mg,0.87mmol)和三乙胺(0.24ml,1.04mmol)在DCM(10mL)中的混合物中加入甲磺酰氯(67μl0.87mmol)。所得混合物在室温下搅拌30分钟。然后蒸发。残余物通过20g Bond Elut洗脱进行纯化,得到标题化合物(180mg,44%);NMR(CDCl3):1.1(t,1H),1.2(m,2H),1.6(m,7H),2.2(m,2H),2.4(m,2H),2.8(m,2H),3.0(s,3H),3.3(m,2H),3.8(m,2H),5.0(m,1H),7.3(m,5H),7.4(d,2H),7.9(d,2H);MS:477。
方法B
N-(4-哌啶基)-N-乙基-4-甲磺酰基苯乙酰胺
步骤1:1-苯基甲基-4-乙基氨基哌啶二盐酸化物的制备
向1-苯基甲基-4-哌啶酮(25.0g,132mmol)在THF(250mL)中的溶液中加入盐酸乙胺(12.0g,147mol)和甲醇(50mL),所得混合物在室温下搅拌10分钟。分批加入乙酰氧基硼氢化钠(40g,189mmol),所得混合物在室温下搅拌1小时。加入2M氢氧化钠溶液(250mL),所得混合物用乙醚萃取。有机萃取液进行干燥(K2CO3),蒸发,得到油形式的1-苯基甲基-4-乙基氨基哌啶。将此油溶于乙醇(500mL)中,加入浓盐酸(20mL)。收集所得晶体,用乙醚洗涤,干燥,得到固体形式的副标题化合物(38g);NMR:(CDCl3):1.10(t,3H),1.40(m,2H),1.83(m,2H),2.02(m,2H),2.65(q,2H),2.85(m,2H),3.50(s,2H),3.75(m,1H),7.2-7.4(m,5H);MS:219(MH+)。
步骤2:N-(1-苯基甲基-4-哌啶基)-N-乙基-4-甲磺酰基苯乙酰胺的制备
搅拌下,向1-苯基甲基-4-乙基氨基哌啶二盐酸化物(32.0g,110mmol)在DCM(500mL)中的溶液中加入N,N-二异丙基乙胺(60mL),以确保完全溶解。加入4-甲磺酰基苯乙酸(25.0g,117mmol)、4-二甲基氨基吡啶(2.0g)和二环己基碳二亚胺(25.0g,121mmol),所得混合物在室温下搅拌20小时。过滤除去沉淀,所得溶液先后用2N HCl水溶液、水和1N NaOH水溶液洗涤,干燥(MgSO4)并蒸发。残余物用硅胶层析法进行提纯(洗脱液:10%甲醇/乙酸乙酯),得到副标题化合物(35g,76%);NMR:1.00 and 1.14(t,3H),1.45和1.70(m,2H),1.95(br m,2H),2.80(br m,2H),3.18(s,3H),3.20和3.33(q,2H),3.45(s,2H),3.80和3.87(s,2H),3.70和4.10(m,1H),7.2-7.3(m,5H),7.48(m,2H),7.82(m,2H);MS:415(MH+)。
步骤3:标题化合物的制备
向N-(1-苯基甲基-4-哌啶基)-N-乙基-4-甲磺酰基苯乙酰胺(34g,82mmol)在乙醇(600mL)中的溶液中加入甲酸铵(40g)。混合物用氩气净化,加入30%钯碳(4.2g)。所得混合物在回流搅拌4小时,然后让其冷却,通过硅藻土过滤。蒸发滤液,得到浓稠油形式的标题化合物(24.9g,94%),其在放置时固化;NMR:1.02和1.15(t,3H),1.4-1.6(br m,4H),2.45(m,2H),2.93(br m,2H),3.18(s,3H),3.20 and 3.32(q,2H),3.72和4.18(m,1H),3.80和3.87(s,2H),7.50(m,2H),7.85(m,2H);MS:325(MH+)。
方法C
3-苯基-3-(1-叔丁基羰基氧基哌啶-4-基)丙醛
步骤1:1-叔丁基羰基氧基-4-苯甲酰基哌啶的制备
向4-苯甲酰基哌啶(6g,26.5mmol)在2M氢氧化钠水溶液(26.5mL)的溶液中加入二叔丁基焦碳酸酯(5.79g,26.5mmol),所得混合物在室温下搅拌18小时。过滤分离固体产物,在40℃下在真空下干燥,得到副标题化合物(7g);NMR:1.3-1.4(m,11H),1.7(m,2H),2.9(m,2H),3.6(m,1H),3.95(m,2H),7.5-7.6(m,3H),7.95(d,2H)。
步骤2:3-苯基-3-(1-叔丁基羰基氧哌啶-4-基)丙烯酸乙酯的制备
在0℃下,向三乙基膦酰乙酸酯(6.2g,27mmol)在THF(100mL)中的溶液中加入二(三甲基甲硅烷基)酰胺锂(32.5ml,1M,32.5mmol)。所得混合物在0℃下搅拌20分钟。加入1-叔丁基羰基氧-4-苯甲酰基哌啶(7g,25mmol),所得混合物在室温下搅拌48小时。混合物进行蒸发,将残余物溶于乙酸乙酯(200mL)中。溶液用2M HCl(2×100mL)洗涤,干燥并蒸发至干,得到副标题化合物。
步骤3:3-苯基-3-(1-叔丁基羰基氧哌啶-4-基)丙酸乙酯的制备
将3-苯基-3-(1-叔丁基羰基氧基哌啶-4-基)丙烯酸乙酯(~25mmol)溶于乙醇(200mL)中,所得溶液用氩气净化。加入20%氢氧化钯(2g),所得混合物在氢气氛下在室温下搅拌72小时。用氩气净化混合物,过滤,然后将滤液蒸发至干。粗品用硅胶层析法提纯(洗脱液:异己烷,然后35%乙酸乙酯的异己烷溶液),得到副标题化合物(5.3g)。
步骤4:3-苯基-3-(1-叔丁基羰基氧基哌啶-4-基)丙烷-1-醇的制备
在20分钟内,向3-苯基-3-(1-叔丁基羰基氧基哌啶-4-基)丙酸乙酯(5.3g,14.6mmol)在THF(100mL)中的溶液中滴加氢化铝锂(14.6ml,1M,14.6mmol)。所得混合物在0℃下搅拌1小时。滴加2M氢氧化钠水溶液(20mL)。通过Celite过滤混合物,用乙酸乙酯洗涤(3×25mL)。合并滤液和洗液并蒸发。残余物溶于乙酸乙酯(100mL)中,所得溶液用水(3×50mL)洗涤,干燥并蒸发,得到副标题化合物(4.6g);NMR:0.9-1(m,2H),1.25(m,1H),1.35(s,9H),1.5-2(m,5H),2.6(m,2H),3.1(m,2H),3.8-4(m,2H),4.2(t,1H)。
步骤5:标题化合物的制备
向3-苯基-3-(4-1-叔丁基羰基氧基哌啶-4-基)丙烷-1-醇(4.6g,14.6mmol)在DCM(100mL)中的溶液中加入Dess-Martin periodinane(6.1g,14.6mmol),所得混合物在室温下搅拌2小时。混合物用2M氢氧化钠水溶液(3×50mL)洗涤,干燥并蒸发至干,得到副标题化合物。
方法D
N-(叔丁氧基羰基哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺
在氩气下,向4-甲磺酰基苯乙酸(16.1g)在甲苯(200ml)中的溶液中加入二苯基磷酰基叠氮化物(16.2ml)和三乙胺(10.4ml)。混合物在90℃加热3小时,然后冷却。加入叔丁基-1-氧代-4-氨乙基-哌啶[CAS 264905-39-7](17.10g)在甲苯(100ml)中的溶液,混合物搅拌18小时,然后用EtOAc/H2O(500ml/400ml)将其分配,过滤,分离有机层并用饱和NaHCO3溶液(2×300ml)、盐水(300ml)洗涤,在MgSO4上干燥,过滤并蒸发。所得棕色油在硅胶上进行提纯,使用0-3%甲醇的EtOAc溶液梯度洗脱,得到黄色固体形式的标题化合物(7.10g);NMR:(DMSO):1.4(t,3H),1.40(s,9H),1.52(m,4H),2.73(m,2H),3.15(m,5H),4.02(m,3H),4.32(d,2H),6.89(t,1H),7.43(d,2H),7.87(d,2H)。MS340(MH+-Boc)
N-(哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺
将哌啶(6.84g)溶于DCM(39ml)中,然后慢慢地加入TFA(39ml)。混合物放置40分钟,然后蒸发。残余物溶于2M NaOH中,用DCM(3×150ml)进行萃取,萃取液在MgSO4上干燥,过滤并蒸发,得到黄色固体形式的标题化合物(5.00g);NMR:(DMSO):1.05(t,3H),1.41(m,4H),2.42(m,2H),2.96(d,2H),3.20(m,5H),3.90(quint,1H),4.29(d,2H),6.84(t,1H),7.43(d,2H),7.85(d,2H),
MS 340(MH+)。
方法E
N-[1-(3-[3,4-二氟苯基]-3-羟丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺
在氩气氛在0℃下,将硼氢化钠(7.7mg)在乙醇(1ml)中的溶液加入到N-[1-(3-[3,4-二氟苯基]-3-氧代丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(0.25g)的乙醇(3.2ml)溶液中,用20小时使反应温热至室温。反应用盐水终止,用醚萃取三次,将合并的萃取进行干燥。将滤液浓缩至澄清的油状物,收率0.21g。MS(MH+)495。
N-[1-(3-[3,4-二氟苯基]-3-氧代丙基)-哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺:
在氩气氛下,将DBU加入到哌啶-4-基]-N-乙基-4-甲磺酰基苯乙酰胺(CAS号374725-04-9)(320mg)和3,4-二氟苯基乙烯基酮(654mg)在二氯甲烷(9ml)中的溶液中,反应混合物搅拌36小时。反应混合物在真空中进行浓缩,用硅胶快速层析法进行提纯,用溶剂梯度(甲醇10-15%,甲醇的二氯甲烷溶液)进行洗脱,收率250mg,MH+493。
3,4-二氟苯基烯基酮
在氩气氛下,在0℃,将Dess martin periodinane(3.18g)加入到3,4-二氟乙烯基醇(CAS号149946-84-9)(1.18g)在二氯甲烷(22ml)中的溶液中,反应混合物搅拌1小时。混合物直接放到快速层析柱上进行纯化,用(乙酸乙酯-10%,乙酸乙酯和异己烷)进行梯度洗脱,收率654mg。NMR(CDCl3):6.0(d,1H),6.50(d,1H),7.10(dd,1H),7.30(m,1H),7.80(m,2H)。
实施例15
通过体外放射性配体结合测试法评估化合物抑制RANTES结合的能力。由表达重组人CCR5受体的中国仓鼠卵巢细胞制备膜。在96孔板中,将这些膜与0.1nM碘化RANTES、闪烁亲近珠和各种浓度的本发明的化合物一起培养。通过闪烁计数测定结合到所述受体上的碘化RANTES量。得到各种化合物的竞争曲线,并计算出置换50%结合的碘化RANTES的化合物浓度(IC50)。优选的式(I)化合物具有小于50μm的IC50。
实施例16
通过体外放射性配体结合测试法评估化合物抑制MIP-1α结合的能力。由表达重组人CCR5受体的中国仓鼠卵巢细胞制备膜。在96孔板中,将这些膜与0.1nM碘化MIP-1α、闪烁亲近珠和各种浓度的本发明的化合物一起培养。通过闪烁计数测定结合到所述受体上的碘化MIP-1α量。得到各种化合物的竞争曲线,并计算出置换了50%结合的碘化MIP-1α的化合物浓度(IC50)。优选的式(I)化合物具有小于50μm的IC50。
本发明的某些化合物的测试结果列于表II中。在表II中,结果以Pic50值表示。Pic50值是IC50的负对数(以10为底),因此1μm(即1×10-6M)的IC50的Pic50值是6。如果化合物测试的次数超过1,则下述结果为测定结果的平均值。
表VII
号化合物 | 表号 | Pic50 |
4 | I | 7.84 |
6 | I | 6.44 |
7 | I | 8.0 |
9 | I | 6.51 |
12 | I | 6.47 |
18 | I | 8.05 |
24 | I | 8.78 |
27 | I | 8.9 |
34 | I | 7.23 |
37 | I | 7.84 |
号化合物 | 表号 | Pic50 |
42 | I | 9.2 |
45 | I | 8.3 |
65 | I | 8.37 |
69 | I | 8.85 |
99 | I | 8.2 |
142 | I | 8.63 |
15 | II | 8.25 |
18 | II | 8.46 |
3 | III | 8.25 |
47 | III | 8.23 |
方案1
方案2
条件
a)烷基卤化物,碱
b)R2C(=O)CH2,R3CHO,AcOH
c)R2C(=O)CH=CHR3
d)还原然后MsCl,碱
e)环状胺,碱,NaI
方案3
条件
a)(i)(EtO)2P(=O)CH2CO2Et,碱;(ii)氢化(例如Pd(OH)2,H2)
b)还原(例如LiAlH4)(R3是H)
c)(i)还原成醛(例如DIBAL-H);(ii)R3MgBr
d)氧化(例如Dess-Martin periodinane)
e)(i)MeONHMe,AlMe3;(ii)还原(R3是H)或R3MgBr
f)还原性氨化反应(NaBH(OAc)3,AcOH)
g)HCl或TFA
h)形成酰胺(酸&偶合剂或酰基卤,碱)
i)形成磺酰胺(亚硫酰氯,碱)
j)还原性氨化反应(醛,NaBH(OAc)3)
Claims (14)
1.式(I)的化合物或其药学上可接受的盐或溶剂合物:
其中
L是CH或N;M是CH或N;条件是L和M不同时为CH;
R1是氢、C1-6烷基[任选被苯基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、OCF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}或杂芳基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}取代]、苯基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、OCF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}、杂芳基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}、S(O)2R6、S(O)2R10R11、C(O)R7、C(O)2(C1-6烷基)、C(O)2(C1-2烷基)或C(O)NHR7;以及当M是CH,R1还可以是NHS(O)2R6、NHS(O)2NHR7、NHC(O)R7或NHC(O)NHR7;
R2是任选被卤素、C1-4烷基、C1-4烷氧基、S(O)n(C1-4烷基)、硝基、氰基或CF3取代的苯基或杂芳基;
R3是氢或C1-4烷基;
R4是氢、甲基、乙基、烯丙基或环丙基;
R5是苯基、杂芳基、苯基NH、杂芳基NH、苯基(C1-2)烷基、杂芳基(C1-2)烷基、苯基(C1-2烷基)NH或杂芳基(C1-2烷基)NH;其中R5的苯环和杂芳环任选被卤素、氰基、硝基、羟基、C1-4烷基、C1-4烷氧基、S(O)k(C1-4烷基)、S(O)2NR8R9、NHS(O)2(C1-4烷基)、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NHC(O)NH2、C(O)NH2、C(O)NH(C1-4烷基)、NHC(O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、C(O)(C1-4烷基)、CF3、CHF2、CH2F、CH2CF3或OCF3取代;
k、m和n独立地是0、1或2;
R6是C1-6烷基[任选被卤素、C1-4烷氧基、苯基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、OCF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}或杂芳基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}取代]、C3-7环烷基、吡喃基、苯基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、OCF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}或杂芳基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代};
R7是氢、C1-6烷基[任选被卤素(例如氟)、C1-4烷氧基、苯基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、OCF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}或杂芳基{其本身任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、(C1-4烷基)C(O)NH、S(O)2NH2,C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}取代]、C3-7环烷基、吡喃基、苯基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、OCF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代}或杂芳基{任选被卤素、C1-4烷基、C1-4烷氧基、氰基、硝基、CF3、(C1-4烷基)C(O)NH、S(O)2NH2、C1-4烷硫基、S(O)(C1-4烷基)或S(O)2(C1-4烷基)取代};
R8和R9独立地是氢或C1-4烷基、或可以与氮或氧原子一起形成任选被C1-4烷基、C(O)H或C(O)(C1-4烷基)取代的5-或6-元环;
R10和R11独立地是氢或C1-4烷基、或连在一起形成5-或6-元环,其中该环任选被C1-4烷基或苯基取代(其中苯环任选被卤素、氰基、硝基、羟基、C1-4烷基、C1-4烷氧基、S(O)mC1-4烷基、S(O)2NH2、S(O)2NH(C1-4烷基)、S(O)2N(C1-4烷基)2、NHS(O)2(C1-4烷基)、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NHC(O)NH2、C(O)NH2、C(O)NH(C1-4烷基)、NHC(O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、C(O)(C1-4烷基)、CF3、CHF2、CH2F、CH2CF3或OCF3取代);
条件是当R1是氢或未取代的烷基,R4是氢、甲基或乙基,L是CH以及M是N时,则R5的苯基或杂芳基部分被下面一个基团取代:S(O)kC1-4烷基、NHC(O)NH2、C(O)(C1-4烷基)、CHF2、CH2F、CH2CF3或OCF3,并且任选进一步被一个或多个卤素、氰基、硝基、羟基、C1-4烷基、C1-4烷氧基、S(O)kC1-4烷基、S(O)2NR8R9、NHS(O)2(C1-4烷基)、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NHC(O)NH2、C(O)NH2、C(O)NH(C1-4烷基)、NHC(O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、C(O)(C1-4烷基)、CF3、CHF2、CH2F、CH2CF3或OCF3取代。
2.权利要求1的化合物,其中L是CH。
3.权利要求1、2或3的化合物,其中M是N。
4.权利要求1或2的化合物,其中R1是苯基(任选被卤素、C1-4烷基、C1-4烷氧基、CF3、OCF3取代)、S(O)2(C1-4烷基)、S(O)2(C1-4氟代烷基)、S(O)2苯基(任选被卤素、氰基、C1-4烷基、C1-4烷氧基、CF3、OCF3、S(O)2(C1-4烷基)或S(O)2(C1-4氟代烷基)取代)、苄基(任选被卤素、C1-4烷基、C1-4烷氧基、CF3或OCF3取代)、苯甲酰基(任选被卤素、C1-4烷基、C1-4烷氧基、CF3或OCF3取代)、C(O)NH苯基(任选被卤素、C1-4烷基、C1-4烷氧基、CF3或OCF3取代)、S(O)2噻吩基、CH2吡啶基、CH2喹啉基或CH2噻唑基。
5.权利要求1、2、3或4的化合物,其中R2是任选被卤素取代的苯基。
6.权利要求1、2、3、4或5的化合物,其中R3是氢或甲基。
7.权利要求1、2、3、4、5或6的化合物,其中R4是乙基。
8.权利要求1、2、3、4、5、6或7的化合物,其中R5是苯基(C1-2)烷基、苯基(C1-2烷基)NH、苯基、杂芳基或杂芳基(C1-2)烷基;其中苯环和杂芳环任选被卤素、氰基、硝基、羟基、C1-4烷基、C1-4烷氧基、S(O)kC1-4烷基、S(O)2NR8R9、NHS(O)2(C1-4烷基)、NH2、NH(C1-4烷基)、N(C1-4烷基)2、NHC(O)NH2、C(O)NH2、C(O)NH(C1-4烷基)、NHC(O)(C1-4烷基)、CO2H、CO2(C1-4烷基)、C(O)(C1-4烷基)、CF3、CHF2、CH2F、CH2CF3或OCF3取代;以及R8和R9独立地是氢或C1-4烷基,或者可以与氮或氧原子一起形成任选被C1-4烷基、C(O)H或C(O)(C1-4烷基)取代的5-或6-元环;以及k是0、1或2。
9.一种制备权利要求1的化合物的方法,包括
i.其中L是N,式(II)的化合物:
与式(III)的化合物:
在碘化钠和合适的碱存在下,在合适的溶剂进行反应;
ii.其中L是CH,将式(IV)的化合物:
与:
a)式R1CO2H的酸,在合适的偶联剂存在下、在合适的碱存在下、在合适的溶剂中进行反应;
b)式R1C(O)Cl的酰基氯或式R1S(O)2Cl的磺酰氯,在一种合适的碱存在下、在一种合适的溶剂进行反应;或,
c)式R1CHO的醛,在NaBH(OAc)3(其中Ac是C(O)CH3)和乙酸存在下、在合适的溶剂中进行反应;
iii.将式(V)的化合物:
与:
a)式R5CO2H的酸在合适的偶联剂存在下、在合适的碱存在下、在合适的溶剂中进行反应;或,
b)式R5C(O)Cl的酰基氯,在合适的碱存在下、在合适的溶剂中进行反应。
10.一种药物组合物,包括权利要求1的化合物或其药学上可接受的盐或溶剂合物,以及药学上可接受的辅助剂、稀释剂或载体。
11.权利要求1的化合物或其药学上可接受的盐或溶剂合物作为药物的用途。
12.权利要求1的化合物或其药学上可接受的盐或溶剂合物在制备用于治疗的药物中的用途。
13.一种治疗CCR5介导的疾病的方法,包括给予需要这种治疗的患者有效量的权利要求1的化合物或其药学上可接受的盐或溶剂合物。
14.一种式(V)的中间体:
其中L、M、R1、R2、R3和R4如权利要求1所定义。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN113527259A (zh) * | 2014-03-07 | 2021-10-22 | 赫尔森保健股份公司 | 对位取代的不对称脲及其医疗用途 |
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JP2005510522A (ja) | 2005-04-21 |
SE0103818D0 (sv) | 2001-11-15 |
MXPA04004503A (es) | 2004-08-11 |
IL196059A (en) | 2010-04-29 |
PL369758A1 (en) | 2005-05-02 |
US7192973B2 (en) | 2007-03-20 |
CN100398535C (zh) | 2008-07-02 |
HUP0402261A3 (en) | 2009-07-28 |
JP4459622B2 (ja) | 2010-04-28 |
BR0214140A (pt) | 2004-10-19 |
NO327221B1 (no) | 2009-05-18 |
TW200407139A (en) | 2004-05-16 |
NZ532411A (en) | 2005-11-25 |
US20070161646A1 (en) | 2007-07-12 |
ZA200403688B (en) | 2005-08-10 |
IS7256A (is) | 2004-05-10 |
IL161699A0 (en) | 2004-09-27 |
WO2003042205A1 (en) | 2003-05-22 |
RU2345990C2 (ru) | 2009-02-10 |
KR20050044470A (ko) | 2005-05-12 |
AR037351A1 (es) | 2004-11-03 |
EP1448548A1 (en) | 2004-08-25 |
RU2004111601A (ru) | 2005-10-20 |
IL161699A (en) | 2012-12-31 |
UA77969C2 (en) | 2007-02-15 |
AU2002353691B2 (en) | 2008-04-03 |
MY137144A (en) | 2008-12-31 |
US20040267016A1 (en) | 2004-12-30 |
CA2464347A1 (en) | 2003-05-22 |
NO20042157L (no) | 2004-08-11 |
HUP0402261A2 (hu) | 2005-02-28 |
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