CN1395566A - 促肾上腺皮质激素释放因子拮抗剂 - Google Patents
促肾上腺皮质激素释放因子拮抗剂 Download PDFInfo
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- CN1395566A CN1395566A CN01803846A CN01803846A CN1395566A CN 1395566 A CN1395566 A CN 1395566A CN 01803846 A CN01803846 A CN 01803846A CN 01803846 A CN01803846 A CN 01803846A CN 1395566 A CN1395566 A CN 1395566A
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- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 1
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- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
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- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
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- C07D213/643—2-Phenoxypyridines; Derivatives thereof
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Abstract
本发明涉及具有通式(I),(II)或(III)的促肾上腺皮质激素释放因子(CRF)拮抗剂,其中虚线、A、B、Y、Z、G、R3、R4、R5、R6、R16和R17如申请中所定义,以及它们的制备方法。这些化合物和它们的药用盐可用于治疗包括CNS和与应激有关的障碍。
Description
发明背景
本发明涉及吡啶、嘧啶、6-羟基嘌呤、吡咯并嘧啶酮和吡咯并吡啶酮,它们的制备方法,含有它们的药物组合物,和使用它们治疗某些中枢神经系统(CNS)和其它障碍的方法。
CRF拮抗剂在1986年8月12日公开的U.S.专利4,605,642和1991年11月5日公开的5,063,245中提及,分别称为肽和吡唑啉酮。CRF拮抗剂也描述在1999年10月5日公开的U.S.专利5,96,479中。CRF拮抗剂的重要性在文献中发表,如,描述在U.S.专利5,063,245中,该文献在此引入作为参考。CRF拮抗剂具有不同活性的最新概要发现在M.J.Owens等人,Pharm.Rev.43卷,425-473页(1991),该文献也在此引入作为参考。基于在这两个和其它参考文献中的研究,CRF拮抗剂对于宽范围的与应激有关疾病的治疗是有效的,如抑郁、焦虑、头痛、肠易激综合征、炎症性疾病、免疫抑制、阿尔茨海默病、胃肠道病、神经性厌食、出血性应激反应、药物和酒精戒断症状、药物成瘾、不孕症、头外伤、中风以及人体和动物体内应激诱导的感染。CRF拮抗剂用于治疗综合征X的用途也描述在2000年10月26日提交的U.S.专利申请No.09/696,822以及2000年10月26日提交的欧洲专利申请No.00309441.4中,这些文献在此全文引入作为参考。使用CRF拮抗剂治疗充血性心力衰竭的方法描述在1999年2月10日提交的U.S.系列No.09/248,073中,现在为U.S.专利6,043,260(2000年3月28日公开)中,这些文献也在此全文引入作为参考。
发明概述
本发明提供具有如下通式的化合物和其药用盐,或其中虚线表示任选的双键,条件是当C
---G中的虚线表示双键时,则N(R)
---C中的虚线不表示双键;和条件是当N(R)
---C中的虚线表示双键时,R在通式III中不存在并且C
---G中的虚线不表示双键;
A是-CR或N;
B是-NR R、-CR R R、-C(=CR R)R、-NHCHR R、-OCHR1R2、-CHR1R2、-CHR2OR1、-CHR1OR2、-CHR2R1、-C( )R2、-C(O)R2、-CHR2NR1R2、-CHR1NHR2、-CHR1N(CH3)R2、或-NR12NR1R2;
当C
---G中的虚线表示双键时,则G是氢、氧、硫、NH、或N(C1-C4烷基);
当C
---G中的虚线不表示双键时,则C---G是C(H)(NH2)、CH2、C(H)(甲氧基)、C(H)(乙氧基)、C(H)(O(C3-C4烷基))、C(H)(卤素)、C(H)(三氟甲氧基)、C(H)(甲基)、C(H)(乙基)、C(H)(C3-C4烷基)、C(H)(S(C1-C4烷基))、C(C1-C4烷基)(C1-C4烷基)、环丙基、C(H)(环丙基)、硫代甲氧基、C(H)(H2)、C(H)(HCH3)、C(H)((CH3)2)、或C(H)(三氟甲基);
其中C
---的环丙基、甲氧基、乙氧基、C3-C4烷基、和C1-C4烷基可以任选地被一个H、甲氧基、或三氟甲氧基取代,或可以任选地-个氟原子取代;
是CH或;
是H、、S、-(C1-C2烷基)、-C( )C3、或-C(13 14),其中13和14各自任选地,是氢、三氟甲基或甲基,或13和14的一个是氰基和另一个是氢或甲基,或-C(13 14)是环丙基,或 是氮或CH和形成与5稠合的五元或六元杂环,该环任选地包括两个或三个独立地选自氧、氮、12、和S( )m的另外杂成员,并任选地包含-个双键,和任选地被卤素、C1-C4烷基、-(C1-C4烷基)、H2、HCH3、(CH3)2、C3、或C3取代,条件是该环不包含任何-S-S-、-S--、--S-、或---键,和不包括多于两个氧或S( )m异种成员;
1是C( )H、C( )(C1-C6烷基)、C( )(C1-C6亚烷基)(C3-C8环烷基)、C( )(C3-C8亚环烷基)(C3-C8环烷基)、C( )(C1-C6亚烷基)(C4-C8杂环烷基)、-C( )(C3-C8亚环烷基)(C4-C8杂环烷基)、C1-C6烷基、C3-C8环烷基、C4-C8杂环烷基、(C1-C6亚烷基)(C3-C8环烷基)、-(C3-C8亚环烷基)(C3-C8环烷基)、-(C1-C6亚烷基)(C4-C8杂环烷基)、-(C3-C8亚环烷基)(C4-C8杂环烷基)、或--芳基、或--(C1-C6亚烷基)-芳基;其中芳基、C4-C8杂环烷基、C1-C6烷基、C3-C8环烷基、C3-C8亚环烷基、和C1-C6亚烷基可以每个独立地任选地被-个氟取代并且可以每个独立地任选地被一个或两个取代基8取代,8独立地选自C1-C4烷基、C3-C8环烷基、羟基、氟、氯、溴、碘、C3、--(C1-C6烷基)、--(C3-C5环烷基)、--C-(C1-C4烷基)、--C-H(C1-C4烷基)、--C-(24)(25)、-(24)(25)、-S(C1-C4烷基)、-S(C3-C5环烷基)、-(C1-C4烷基)C(C1-C4烷基)、-HC(C1-C4烷基)、-C(C1-C4烷基)、-CH(C1-C4烷基)、-C(C1-C4烷基)(C1-C2烷基)、CN、NO2、-OSO2C1-C4烷基)、S+C1-C6烷基)C1-C2烷基)-、-SO C1-C4烷基)和-SO2C1-C4烷基);并且其中1的C1-C6烷基、C1-C6亚烷基、C5-C8环烷基、C5-C8亚环烷基、和C5-C8杂环烷基部分可任选地包含-个双键或三键;和其中8的C1-C4烷基部分和C1-C6烷基部分可以任选独立地被羟基、C1-C4烷基、氨基、芳基、-C2-芳基、C3-C5环烷基、或-O-C1-C4烷基)取代,和可以任选地被-个氟取代,和可以任选地包含-个双键或三键;和其中1的每个杂环基包含-个选自氧、SO)m、氮、和N12的杂部分;
2是氢、C1-C12烷基、C3-C8环烷基、C4-C6杂环烷基、-C1-C6亚烷基)C3-C8环烷基)、-C3-C8亚环烷基)C3-C8环烷基)、-C1-C6亚烷基)C4-C8杂环烷基)、-C3-C8亚环烷基)C4-C8杂环烷基)、芳基、-C1-C6亚烷基)芳基、或-C3-C8亚环烷基)芳基);其中每个上述2基团可以任选地被-个选自氯、氟、和C1-C6烷基的取代基取代,其中-个取代基之一可进一步选自溴、碘、C1-C6烷氧基、-O、-O-CO-C1-C6烷基)、-O-CO-NC1-C4烷基)C1-C2烷基)、-SC1-C6烷基)、-S O)C1-C6烷基)、-SO)2C1-C6烷基)、S+C1-C6烷基)C1-C2烷基)-、CN、和NO2、和其中2的C1-C12烷基、-C1-C6亚烷基)、-C5-C8环烷基)、-C5-C8亚环烷基)、和-C5-C8杂环烷基)部分可任选地包含-个双键或三键;并且其中2的每个杂环烷基包含-个选自氧、SO)m、氮、和N12的杂部分;
或当1和2如在-NC12、-OC12、-SC12、-C12、或N12中时,的1和2可形成元-元环,该环可任选地包含一个或两个双键和其中一个或两个环碳可任选地被氧、SO)m、和N12代替;并且该碳环可任选地被-个选自如下的取代基取代:羟基、C1-C4烷基、氟、氯、溴、碘、C3、-O-C1-C4烷基)、-O-CO-C1-C4烷基)、-O-CO-NC1-C4烷基)、-O-CO-NC1-C4烷基)C1-C2烷基)、-NC1-C4烷基)、-NC1-C2烷基)C1-C4烷基)、-SC1-C4烷基)、-NC1-C4烷基)COC1-C4烷基)、-NCOC1-C4烷基)、-COOC1-C4烷基)、-CONC1-C4烷基)、-CONC1-C4烷基)C1-C2烷基)、CN、NO2、-OSO2C1-C4烷基)、-SOC1-C4烷基)和-SO2(C1-C4烷基),其中该1-3个取代基之一可进一步选自苯基;
R3是甲基、乙基、氟、氯、溴、碘、氰基、甲氧基、OCF3、NH2、-NH(C1-C2烷基)、-NHCOCF3、-N(CH3)2、-NHCH2CF3、S(O)m(C1-C4烷基)、CONH2、-CONHCH3、-CON(CH3)2、-CF3、或CH2OCH3;
R4是氢、C1-C4烷基、C3-C5环烷基、-(C1-C4亚烷基)(C3-C5环烷基)、-(C3-C5亚环烷基)(C3-C5环烷基)、氰基、氟、氯、溴、碘、-OR24、C1-C6烷氧基、-O-(C3-C5环烷基)、-O-(C1-C4亚烷基)(C3-C5环烷基)、-O-(C3-C5亚环烷基)(C3-C5环烷基)、CH2SC(S)O(C1-C4烷基)、CH2OCF3、-CF3、氨基、硝基、-NR24R25、-(C1-C4亚烷基)OR24、-(C1-C4亚烷基)Cl、-(C1-C4亚烷基)NR24R25、-NHCOR24、-NHCONR24R25、-C=NOR24、NHNR24R25、S(O)mR24、-C(O)R24、-OC(O)R24、-C(O)CN、-C(O)NR24R25、-C(O)NHNR24R25、和-COOR24,其中R4的烷基和亚烷基可任选地独立地包含一个或两个双键或三键并可任选地独立地被1-2个取代基R10取代,R10独立地选自羟基、氨基、-NHCOCH3、-NHCOCH2Cl、-NH(C1-C2烷基)、-N(C1-C2烷基)(C1-C2烷基)、-COO(C1-C4烷基)、-COOH、-CO(C1-C4烷基)、C1-C6烷氧基、C1-C3硫代烷基、氰基和硝基,和含有1-4个独立地选自氟和氯的取代基;
R5是芳基或杂芳基并被1-4个取代基R27取代,R27独立地选自卤素、C1-C10烷基、-(C1-C4亚烷基)(C3-C8环烷基)、-(C1-C4亚烷基)(C4-C8杂环烷基)、-(C3-C8环烷基)、-(C4-C8杂环烷基)、-(C3-C8亚环烷基)(C3-C8环烷基)、-(C3-C8亚环烷基)(C4-C8杂环烷基)、C1-C4卤代烷基、C1-C4卤代烷氧基、硝基、氰基、-NR24R25、-NR24COR25、-NR24CO2R26、-COR24、-OR25、-CONR24R25、-CO(NOR22)R23、-CO2R26、-C=N(OR22)R23、和S(O)mR23;其中该C1-C10烷基、C3-C8环烷基、(C1-C4亚烷基)、(C3-C8环烷基)、(C3-C8亚环烷基)、和(C4-C8杂环烷基)基团可任选地被1-3个独立地选自如下的取代基取代:C1-C4烷基、C3-C8环烷基、-(C1-C4亚烷基)(C3-C8环烷基)、-(C3-C8亚环烷基)(C3-C8环烷基)、C1-C4卤代烷基、羟基、C1-C6烷氧基、硝基、卤素、氰基、-NR24R25、-NR24COR25、-NR24CO2R26、-COR24、-OR25、-CONR24R25、-CO2R26、-CO(NOR22)R25、和S(O)mR23;并且其中R5基团的两个相邻取代基可形成饱和或未饱和的、稠合到R5上的5-7元环,该环任选地包含-个,两个,或三个独立地选自O、S(O)m和N的异种成员,但没有任何-S-S-、-O-O-、-S-O-、或-N-S-键,和该环可任选地被C1-C4烷基、C3-C8环烷基、-(C1-C4亚烷基)(C3-C8环烷基)、-(C3-C8亚环烷基)(C3-C8环烷基)、C1-C4卤代烷基、硝基、卤素、氰基、-NR24R25、-NR24COR25、-NR24CO2R26、-COR24、-OR25、-CONR24R25、-CO2R26、-CO(NOR26)R25、和S(O)mR23取代;其中该1-4个任选的取代基R27之一可进一步选自-SO2NH(C1-C4烷基)、-SO2NH(C1-C4亚烷基)(C3-C8环烷基)、-SO2NH(C3-C8环烷基)、-SO2NH(C3-C8亚环烷基)(C3-C8环烷基)、-SO2N(C1-C4烷基)(C1-C2烷基)、-SO2NH2、-NHSO2(C1-C4烷基)、-NHSO2(C3-C8环烷基)、-NHSO2(C1-C4亚烷基)(C3-C8环烷基)、和-NHSO2(C3-C8亚环烷基)(C3-C8环烷基);并且其中R5的烷基和亚烷基可独立地任选地包含一个双键或三键;
R6是氢、C1-C4烷基、C3-C8环烷基、-(C1-C6亚烷基)(C3-C8环烷基)、或-(C3-C8亚环烷基)(C3-C8环烷基),其中该烷基或环烷基可任选地被一个羟基、甲氧基、乙氧基或氟基团取代;
或,其中化合物是通式II的化合物,R6和R4可以一起形成氧代(=O)基团,或可以连接以形成3-8元碳环,任选地包含1-3个双键,和任选地包含一个、两个、或三个选自氧、SOm、N、和NR12的异种环成员,但不包含任何-O-O-、-S-O-、-S-S-、或-N-S-键,并进一步任选地被C1-C4烷基或C3-C8环烷基取代,其中该C1-C4烷基取代基可任选地包含一个双键或三键;
R7是氢、甲基、氟、氯、溴、碘、氰基、羟基、-O(C1-C2烷基)、-O(环丙基)、-COO(C1-C2烷基)、-COO(C3-C8环烷基)、-OCF3、CF3、-CH2OH、或CH2OCH3;
R11是氢、羟基、氟、乙氧基、或甲氧基;
R12是氢或C1-C4烷基;
R16和R17每个独立地是氢、羟基、甲基、乙基、甲氧基、或乙氧基,除了R16和R17两者不同时为甲氧基或乙氧基;
或R16和R17一起形成氧代(=O)基团;
或R16和R17连接以形成3-8元碳环,任选地包含1-3个双键,和任选地包含选自O、SOm、N、和NR12的异种环成员,但不包含任何-O-O-、-S-O-、-S-S-、或-N-S-键,和进一步任选地被C1-C4烷基或C3-C6环烷基取代,其中该C1-C4烷基取代基可任选地包含一个双键或三键;
R22在每种情况下独立地选自氢、C1-C4烷基、C1-C4卤代烷基、C3-C6链烯基、C3-C6链炔基、C3-C8环烷基、-(C3-C8亚环烷基)(C3-C8环烷基)和-(C1-C4亚烷基)(C3-C8环烷基);
R23在每种情况下独立地选自C1-C4烷基、C1-C4卤代烷基、C2-C8烷氧基烷基、C3-C8环烷基、-(C1-C4亚烷基)(C3-C8环烷基)、-(C3-C8亚环烷基)(C3-C8环烷基)、芳基、-(C1-C4亚烷基)芳基、哌啶、吡咯烷、哌嗪、N-甲基哌嗪、吗啉、和硫代吗啉;
R24和R25在每种情况下独立地选自氢、C1-C4烷基、C1-C4卤代烷基,特别是CF3、CHF2、CF2CF3、或CH2CF3,-(C1-C4亚烷基)OH、-(C1-C4亚烷基)-O-(C1-C4烷基)、-(C1-C4亚烷基)-O-(C3-C5环烷基)、C3-C8环烷基、-(C1-C4亚烷基)(C3-C8环烷基)、-(C3-C8亚环烷基)(C3-C8环烷基)、-C4-C8杂环烷基、-(C1-C4亚烷基)(C4-C8杂环烷基)、-(C3-C8亚环烷基)(C4-C8杂环烷基)、芳基、和-(C1-C4亚烷基)芳基,其中-C4-C8杂环烷基可以每个独立地任选地被芳基、CH2-芳基、或C1-C4烷基取代,并可以任选地包含一个或两个双键或三键;或当R24和R25是如NR24R25、-C(O)NR24R25、-(C1-C4亚烷基)NR24R25、或-NHCONR24R25、则NR24R25可进一步任选地形成4-8元杂环,任选地包含一个或两个独立地选自S(O)m、氧、氮、和NR12的另外杂成员,和任选地包含1-3个双键;
R26在每种情况下独立地选自C1-C4烷基、C1-C4卤代烷基、C3-C8环烷基、-(C1-C4亚烷基)(C3-C8环烷基)、-(C3-C8亚环烷基)(C3-C8环烷基)、芳基、和-(C1-C4亚烷基)(芳基);和
其中每个m独立地是0、1、或2,
条件是通式I、II、III化合物的杂环烷基不包括任何-S-S-、-S-O-、-N-S-、或-O-O-键,和不包括多于两个氧或S(O)m异种成员。
在一个实施方案中,本发明提供通式I或II的化合物,其中R4是-NHCH2CF3、-CONHNH2、-CONHNHCH3。在另一个实施方案中,R4是-OCF3或氟。在另一个实施方案中,R4是-OCHF2。
在另一个实施方案中,本发明提供通式I或II,优选通式I的化合物,其中R4是-C(O)NR24R25或-C(O)NHNR24R25。在优选的实施方案中,R4是-C(O)NR24R25。如果R4是-C(O)NR24R25或-C(O)NHNR24R25,则R24和R25在更特别的实施方案中独立地选自氢和C1-C4烷基。在另一个实施方案中,R4是-C(O)NH2或-C(O)NHCH3。在另一个实施方案中,R4是-C(O)N(CH3)2。
在另一个更特别的实施方案中,本发明提供上述通式I或II,优选I的化合物,其中R4是-C(O)NHCH2(C3-C5环烷基)、-C(O)NH(C3-C5环烷基)、-C(O)N(C3-C5环烷基)2、-C(O)NR24R25,其中R24和R25形成4,5,或6元杂环、-C(O)NH(C4-C8杂环烷基)或-C(O)NH(CH2(C4-C8杂环烷基))。
在另一个实施方案中,本发明提供通式I或II,优选I的化合物,其中R4是-(C1-C4亚烷基)NR24R25。如果R4是-(C1-C4亚烷基)NR24R25,则R24和R25在更特别的实施方案中独立地选自氢、C1-C4烷基、-(C1-C4亚烷基)(C3-C8环烷基)、和C3-C8环烷基。
在另一个实施方案中,本发明提供上述通式I或II的化合物,其中R4是-OCH2(C3-C5环烷基)、-O(C3-C5环烷基)、-SCH2(C3-C5环烷基)、或-S(C3-C5环烷基)。
在本发明的另一个实施方案中,提供上述通式I或II,优选I的化合物,其中R4是-COOCH3。在本发明的另一个实施方案中,提供上述通式I或II,优选I的化合物,其中R4是-COOCH2CH3。
本发明的另一个实施方案提供上述通式I或II,优选I的化合物,其中R4是-OCH3。在本发明的另一个实施方案中,提供通式I或II的化合物,其中R4是-CH3。在另一个实施方案中,R4是-CH2CH3。在另一个实施方案中,R4是氯。在另一个实施方案中,R4是溴。
在另一个实施方案中,提供上述通式I或II,优选I的化合物,其中R4是-CF3。
在另一个实施方案中,提供上述通式I或II,优选I的化合物,其中R4是-CH2OH。
在另一个实施方案中,提供上述通式I或II,优选I的化合物,其中R4是-CH2OCH3。
在另一个实施方案中,提供上述通式I或II,优选I的化合物,其中R4是-CH2OCF3。
在另一个实施方案中,通式I或II,优选I的化合物如上所定义,和R4是-SCH3。
在另一个实施方案中,提供上述通式I或II,优选I的化合物,其中R4是-S(O)CH3。
在另一个实施方案中,提供上述通式I或II,优选I的化合物,其中R4是-S(O)2CH3。
在另一个实施方案中,提供上述通式I或II,优选I的化合物,其中R4是-C(O)CH3。
在另一个实施方案中,提供上述通式I或II,优选I的化合物,其中R4是-NR24R25。优选,R24和R25是C1-C4烷基或氢。在更特别的实施方案中,R4是-NH2、-NHCH3、或-N(CH3)2。
在另一个实施方案中,提供上述通式I或II,优选I的化合物,其中R4是-NO2。
在另一个实施方案中,提供上述通式I或II,优选I的化合物,其中R4是-CH(OH)CH3。
在另一个实施方案中,提供上述通式I或II,优选I的化合物,其中R4是-CN。
在另一个实施方案中,本发明提供上述通式I,II,或III的化合物,其中B是-NR1R2或-NHCHR1R2。如果B是-NR1R2,R1优选是C1-C6烷基、C3-C8环烷基、或(C1-C6亚烷基)(C3-C8环烷基),更优选(C1-C6亚烷基)(C3-C8环烷基),和R2优选是-C1-C12烷基,任选地包含1-3个双键或三键和任选地被1-3个氟原子取代。优选,B是-N(CH2-环丙基)(CH2CH3)或-N(CH2-环丙基)(CH2CF3)。
如果B是-NHCHR1R2,则R1优选是-C(O)H、-C(O)(C1-C6烷基)、或-C1-C6烷基,其中该C1-C6烷基任选地被1-6个氟原子或一个或两个独立地选自-C1-C4烷基、羟基和-O(C1-C6烷基)的R8取代,并且R2优选是-C1-C12烷基,任选地包含1-3个双键或三键和任选地被1-3个选自氟和C1-C6烷基的取代基取代。优选,如果B是-NHCHR1R2,则R1独立地选自-CH2CH3和-CF2CH3,和R1独立地选自-CH2CH3、-CF2CH3、-CH(OH)CH3、-CH(OCH3)CH3、-CH(OH)(CH3)2、和-C(O)CH3。优选B是-NHCH(CH2CH3)2、-NHCH(CH2CH3)(CF2CH3)、-NHCH(CF2CH3)2、-NHCH(CH(OH)CH3)(CF2CH3)、-NHCH(CH(OH)CH3)(CH2CH3)、-NHCH(CH(OCH3)CH3)(CH2CH3)、-NHCH(C(O)CH3)(CH2CH3)、-NHCH(C(O)CH3)(CF2CH3)、-NHCH(C(OH)(CH3)2)(CH2CH3)、或NHCH(C(OH)(CH3)2)(CF2CH3)。
或优选,B是-N(CH2-环丙基)(CH2CH3)、-NHCH(CH2CH3)2、-NHCH(CH(OH)CH3)(CF2CH3)、-NHCH(CH(OH)CH3)(CH2CH3)、-NHCH(CH(OCH3)CH3)(CH2CH3)、-NHCH(C(O)CH3)(CH2CH3)、或-NHCH(C(OH)(CH3)2)(CH2CH3)。
在本发明的另一个实施方案中,B选自-OCHR1R2、SCHR1R2、-CHR1NHR2、-CHR1N(CH3)R2、-CHR2OR1、或-CHR1OR2。
在本发明的另一个实施方案中,提供上述通式定义的I,II,或III的化合物,其中R3是甲基、乙基、O-CH3、-OCF3、Cl、S-CH3、或CF3。优选R3是甲基。
在本发明的另一个实施方案中,提供上述通式III的化合物,其中C
---N(R6)中的虚线表示双键,并且C
---G中的虚线不表示双键,和C
---G是CH2、C(H)(CH3)、或C(H)(CH2CH3)。
在本发明的另一个实施方案中,提供上述通式III的化合物,其中C
---G中的虚线表示双键,和C
---G是C=O、C=S、或C=NH,和C
---N(R6)是C-NH或C-N(C1-C4烷基)。
在本发明的另一个实施方案中,提供上述通式II的化合物,其中CR16R17和CR4R6每个独立地选自-C=O、-CH2、-CH(C1-C4烷基)、-C(C1-C2烷基)2、环丙基、-CHOH、-CHOCH3、-C(OCH2CH3)、和-C(CH2OCH2)。
在另一个实施方案中,提供通式II的化合物,其中CR16R17选自-CH2、-CH(C1-C4烷基)、-C(C1-C2烷基)2、环丙基、-CHOH、并且-CHOCH3,和CR4R6是C=O、CH2、CH(C1-C2烷基)、或CHOCH3。
在本发明的另一个实施方案中,提供上述通式I,II,或III的化合物,其中R5任选地被选自如下的芳基或杂芳基取代:任选取代的苯基、噻唑基、萘基、噻吩基、苯并噻吩基、吡啶基、喹啉基、喹唑啉基、喹喔啉基、吡嗪基、嘧啶基、吲唑基、咪唑基、呋喃基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并异噁唑基、异噻唑基、吡唑基、吡咯基、吲哚基、吡咯并吡啶基、噁唑基、苯并噁唑基、苯并噻二唑基、吡啶基、苯并[1,3]间二氧杂环戊烯基、和2,3-二氢-苯并[1,4]二噁烯基(dioxinyl)。
在另一个实施方案中,R5被独立地选自如下的1-4个R27取代:C1-C4烷基、-O-(C1-C4烷基)、氯、溴、-CH(CH3)(OH)、-C(CH3)2(OH)、-CH(CH3)(OCH3)、-C(CH3)2(OCH3)、OCF3、OCHF2、-O-环丙基、-(-CH2-环丙基、-CH(CF3)(OH)、-CH(CF3)(OCH3)、-CH(=O)(CF3)、-2-环丙基-1-OH、-1-环丙基-2-OH、-1-环丙基-1-NH2、-O-氧杂环丁烷基(oxetanyl)、-O-四氢呋喃基、环丙基和-SCH3。
在本发明的另一个实施方案中,提供上述通式I,II,或III的化合物,其中R5是苯基、吡啶基或嘧啶基,被两个或三个R27基团取代。在更特别的实施方案中,R5是苯基,被两个或三个R27基团取代。
在另一个实施方案中,提供上述通式I,II,或III的化合物,其中R5是苯基、吡啶基或嘧啶基,被选自如下的两个或三个R27基团取代:卤素、-(C1-C4卤代烷基)、-C(O)R24、-OR25、-C(O)NR24R25、和C1-C10烷基,它任选地被选自如下的1-3个取代基,优选被1个取代基取代:羟基、C1-C6烷氧基、和NR24R25。优选,每个R27独立地选自甲基、乙基、-CF3、-OCH3、-OCF3、-C(O)NH2、-C(O)NHCH3、-C(O)CF3、-C(O)CH3、-CH(OH)CH3、氯、溴、氟、-OCH2CH3、-O-环丙基、-CH2NH2、-CH2NHCH3、-CH2N(CH3)2、-CH2OCH3、和-CH(OCH3)CH3。更优选,每个R27独立地选自甲基、乙基、-CF3、-OCH3、-OCF3、-C(O)NH2、-C(O)NHCH3、氯、溴、氟。
在另一个实施方案中,提供通式I,II,或III,优选I的化合物,其中-是苯基和被独立地选自如下的两个或三个取代基R27取代:甲基、氯、-OCH3、-OCF3、溴、和-C(O)NH2。
在本发明的另一个实施方案中,提供上述通式I的化合物,其中Z是O、NH、或NC(=O)CF3。优选Z是O。
在本发明的优选实施方案中,提供上述通式I的化合物,其中Z是O;B是-NHCHR1R2,其中优选是-C(O)H、-C(O)(C1-C6烷基)、或-C1-C6烷基,其中该C1-C6烷基任选地被1-6个氟原子或独立地选自如下的一个或两个R8取代:-C1-C4烷基、羟基和-O-(C1-C6烷基),和其中R2优选是-C1-C12烷基,任选地包含1-3个双键或三键和任选地被1-3个选自氟和C1-C6烷基的取代基取代;R5是苯基、吡啶基或嘧啶基,被两个或三个选自如下的R27基团取代:卤素、(C1-C4卤代烷基)、-C(O)R24、-OR25、-C(O)NR24R25、和C1-C10烷基,它任选地被选自羟基、C1-C6烷氧基、和-NR24R25的1-3个取代基,优选一个取代基取代,和R4是-C(O)NR24R25。-C(O)NR24R25的R24和R25在更特别的实施方案中独立地选自氢和-C1-C4烷基。
在本发明的另一个优选实施方案中,提供通式I的化合物,其中Z是O;B是-NHCHR1R2,其中-NHCHR1R2的R1优选是-C(O)H、-C(O)(C1-C6烷基)、或-C1-C6烷基,其中该C1-C6烷基任选地被1-6个氟原子或一个或两个独立地选自-C1-C4烷基、羟基和-O-(C1-C6烷基)的R8取代,并且其中-NHCHR1R2的R2优选是-C1-C12烷基,任选地包含1-3个双键或三键和任选地被1-3个选自氟和C1-C6烷基的取代基取代;R5是苯基、吡啶基或嘧啶基,被两个或三个选自如下的R27基团取代:卤素、(C1-C4卤代烷基)、-C(O)R24、-OR25、-C(O)NR24R25、和C1-C10烷基,它任选地被选自羟基、C1-C6烷氧基、和-NR24R25的1-3个取代基,优选一个取代基取代,并且R4是-NR1R2,其中-NR1R2的R1优选是C1-C6烷基、C3-C8环烷基、或-(C1-C6亚烷基)(C3-C8环烷基),更优选是-(C1-C6亚烷基)(C3-C8环烷基),和-NR1R2的R2优选是-C1-C12烷基,任选地包含1-3个双键或三键和任选地被1-3个氟原子取代。优选,B是-N(CH2-环丙基)(CH2CH3)或-N(CH2-环丙基)(CH2CF3)。
本发明优选化合物的例子是:
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-羟甲基-丙基氨基)-6,N-二甲基-烟酰胺;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-甲氧基甲基-丙基氨基)-6,N-二甲基-烟酰胺;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-甲氧基甲基-丙基氨基)-6-甲基-烟酰胺;
2-(4-溴-2-甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酰胺;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基-2-甲氧基-丙基氨基)-6-甲基-烟酰胺;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基-2-甲氧基-丙基氨基)-6,N-二甲基-烟酰胺;
2-(4-氯-2-三氟甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酰胺;
2-(4-氯-2-三氟甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6,N-二甲基-烟酰胺;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1S,2R-1-乙基-2-甲氧基-丙基氨基)-6,N-二甲基-烟酰胺;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1S,2S-1-乙基-2-甲氧基-丙基氨基)-6,N-二甲基-烟酰胺;
及其药用盐。
本发明优选化合物的其它例子是:
2-(4-溴-2-甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟腈(nicotinonitrile);
4-[4-(1-乙基-丙氧基)-3,6-二甲基-吡啶-2-基氧]-3,5-二甲基-苯甲酰胺;
2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-(1-甲基硫基(sulfanyl)甲基-丙基氨基)-烟酸甲酯;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-羟甲基-丙基氨基)-6-甲基-烟酸甲酯;
2-(4-溴-2-甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟腈;
2-(4-氯-2-三氟甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酸甲酯;和
2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-(四氢-呋喃-3-基氨基)-烟酸甲酯;
及其药用盐。
本发明化合物的其它例子是:
2-(4-溴-2-甲氧基-苯基氨基)-4-(1-乙基-丙氧基)-6-甲基-烟酸;
[2-(4-溴-2-甲氧基-苯基氨基)-4-(1-乙基-丙氧基)-6-甲基-吡啶-3-基]-甲醇;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-羟甲基-丙基氨基)-6-甲基-烟酸;
2-(4-氯-2,6-二甲基-苯氧基-4-(1-羟甲基-丙基氨基)-6-甲基烟酰胺;
2-(4-氯-2,6-二甲基-苯氧基)-N-乙基-4-(1-羟甲基-丙基氨基)-6-甲基-烟酰胺;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-羟甲基-丙基氨基)-6,N-二甲基-烟酰胺;
环丙基甲基-[2,5,6-三甲基-7-(2,4,6-三甲基-苯基)-7H-吡咯并[2,3-d]嘧啶-4-基]-胺;
环丙基甲基-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-乙胺;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-甲氧基羰基-丙基氨基)-6-甲基-烟酸甲酯;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-甲氧基羰基-丙基氨基)-6-甲基-烟酸甲酯;
3,3’,6’-三甲基-2’-(2,4,6-三甲基-苯氧基)-3,4,5,6-四氢-2H-[1,4’]双吡啶基;
2-(4-氯-2,6-二甲基-苯氧基)-6,N-二甲基-4-(S)-(四氢-呋喃-3-基氨基)-烟酰胺;
[7-(4-溴-2,6-二甲基-苯氧基)-2,5-二甲基-7H-吡咯并[2,3-d]嘧啶-4-基]-(四氢-呋喃-3-基)-胺;
2,5,6-三甲基-4-吡啶烷-1-基-7-(2,4,6-三甲基-苯基)-7H-吡咯并[2,3-d]嘧啶;
(2-吡啶烷-1-基乙基)-[2,5,6-三甲基-7-(2,4,6-三甲基-苯基)-7H-吡咯并[2,3-d]嘧啶-4-基]-胺;
(四氢-呋喃-3-基)-[2,5,6-三甲基-7-(2,4,6-三甲基-苯基)-7H-吡咯并[2,3-d]嘧啶-4-基]-胺;
2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-(四氢-呋喃-3-基)-吡啶-3-羰基醛(carbal dehyde)肟;
[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-(2-吡咯烷-1-基-乙基)-胺;
N-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-2,2,2-三氟-N-(2-吡咯烷-1-基-乙基)-乙酰胺;
N2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-N1,N1-二甲基-丁烷-1,2-二胺;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基-2-甲基氨基-丙基氨基)-6-甲基-烟酸甲酯;
[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-(3-甲基-丁基)-(2-吡咯烷-1-基-乙基)-胺;
(3,3-二甲基-丁基)-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-(2-吡咯烷-1-基-乙基)-胺;
[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-吗啉-4-基-胺;
4-(1-乙基-丙氧基)-2-(4-甲氧基-2-甲基-苯基氨基)-6-甲基-烟酸;
2-(4-氯-2-甲基-苯基氨基)-4-(1-乙基-丙氧基)-6-甲基-烟酸;
4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-吡啶-3-基氧)-烟酸;
N2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-N1-吡啶-3-基甲基-丁烷-1,2-二胺;
N2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-N1-噻唑-2-基甲基-丁烷-1,2-二胺;
2-(2,4-二甲基-苯基氨基)-4-(1-乙基-丙氧基)-6-甲基-烟酸;
[2-(4-氯-2-甲基-苯基氨基)-4-(1-乙基-丙氧基)-6-甲基-吡啶-3-基]-甲醇;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-羟甲基-丙基氨基)-6-甲基-烟腈;
1-(4-氯-2-甲基-苯基)-5-(1-乙基-丙氧基)-7-甲基-1,4-二氢-2H-3-噁-1,8-二氮杂-萘;
4-(1-乙基-丙基氨基)-2-甲基-7-(2,4,6-三甲基-苯基)-7H-吡咯并[2,3-d]嘧啶-5,6-二酮;
4-(1-乙基-丙基氨基)-2-甲基-7-(2,4,6-三甲基-苯基)-5,7-二氢-吡咯并[2,3-d]嘧啶-6-酮;
4-[3-氰基-4-(1-乙基-丙基氨基)-6-甲基-吡啶-2-基氧]-3-甲氧基-苯甲酸;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-甲氧基甲基-丙基氨基)-6-甲基-烟酰胺;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-甲氧基甲基-丙基氨基)-6,N-二甲基-烟酰胺;
2-(4-氯-2,6-二甲基-苯氧基)-N-(1-羟甲基-丙基)-4-(1-羟甲基-丙基氨基)-6-甲基-烟酰胺;
及上述化合物的药用盐。
本发明也涉及一种用于如下治疗的药物组合物:(a)其治疗可由拮抗CRF影响或促进的障碍或病情,包括但不限于由CRF诱导或促进的障碍,(b)选自如下的障碍或病情:炎症性障碍如风湿性关节炎和骨关节炎、疼痛、哮喘、牛皮癣和变应性;普通性焦虑障碍、恐惧、恐怖症,包括社交恐怖症、广场恐怖症和特异性恐怖症、强迫观念与行为症、外伤后应激性障碍、由应激反应诱导的睡眠障碍、痛觉如纤维肌痛、情感障碍如忧郁症,包括重性抑郁、单发作抑郁、复发性抑郁、儿童虐待诱导的抑郁、与月经前综合征有关的情感障碍、和产后精神抑郁、精神抑郁症、双极情感障碍、循环性气质、慢性疲乏综合征、应激诱导的头痛、癌症、肠易激综合征、局限性肠炎、痉挛性结肠、术后肠梗阻、溃疡、腹泻、应激诱导的发烧、人免疫缺陷病毒感染、神经退化疾病如阿尔茨海默病、帕金森病和享廷顿病、胃肠道病、进食障碍如食欲减退和神经性贪食、出血性应激反应、化学品依赖或成瘾、包括对于酒精、可卡因、海洛因、苯并二氮,或其它药物的依赖或成瘾、药物或酒精戒断症状、应激诱导的精神病发作、甲状腺功能正常病综合征、不适当抑制尿分泌激素的综合征、肥胖症、不孕症、头创伤、脊髓创伤、局部缺血性神经元损害,包括大脑缺血、例如大脑海马缺血、神经毒素神经元损害、癫痫、中风、免疫功能障碍包括应激诱导的免疫功能障碍、包括猪紧张综合征、牛船热(bovineshipping fever)、马阵发性纤维颤动、鸡囚禁功能障碍、羊sheering紧张和狗的人动物相互作用紧张、肌肉痉挛、尿失禁、阿尔茨海默类型老年痴呆、多梗塞性痴呆、肌萎缩性侧索硬化、高血压、心动过速、充血性心力衰竭、骨质疏松症、早产、低血糖,和包括人在内的哺乳动物或鸟中的综合征X,包括数量为有效用于治疗这样障碍或病情的根据权利要求I、II或III化合物或其药学上可接受的盐以及药用载体。
本发明进一步包括一种用于如下治疗的方法:(a)其治疗可由拮抗CRF影响或促进的障碍或病情,包括但不限于由CRF诱导或促进的障碍,(b)选自如下的障碍或病情:炎症性障碍如风湿性关节炎和骨关节炎、疼痛、哮喘、牛皮癣和变应性;普通性焦虑障碍、恐惧、恐怖症,包括社交恐怖症、广场恐怖症和特异性恐怖症、强迫行为与观念症、外伤后应激性障碍、由应激反应诱导的睡眠障碍、痛觉如纤维肌痛、情感障碍如忧郁症,包括重性抑郁、单发作抑郁、复发性抑郁、儿童虐待诱导的抑郁、与月经前综合征有关的情感障碍、和产后精神抑郁、精神抑郁症、双极情感障碍、循环性气质、慢性疲乏综合征、应激诱导的头痛、癌症、肠易激综合征、局限性肠炎、痉挛性结肠、术后肠梗阻、溃疡、腹泻、应激诱导的发烧、人免疫缺陷病毒感染、神经退化疾病如阿尔茨海默病、帕金森病和享廷顿病、胃肠道病、进食障碍如食欲减退和神经性贪食、出血性应激反应、化学品依赖或成瘾、包括对于酒精、可卡因、海洛因、苯并二氮,或其它药物的依赖或成瘾、药物或酒精戒断症状、应激诱导的精神病发作、甲状腺功能正常病综合征、不适当抑制尿分泌激素的综合征、肥胖症、不孕症、头创伤、脊髓创伤、局部缺血性神经元损害,包括大脑缺血、例如大脑海马缺血、神经毒素神经元损害、癫痫、中风、免疫功能障碍包括应激诱导的免疫功能障碍、包括猪紧张综合征、牛船热、马阵发性纤维颤动、鸡囚禁功能障碍、羊sheering紧张和狗的人动物相互作用紧张、肌肉痉挛、尿失禁、阿尔茨海默类型老年痴呆、多梗塞性痴呆、肌萎缩性侧索硬化、高血压、心动过速、充血性心力衰竭、骨质疏松症、早产、低血糖,和包括人在内的哺乳动物或鸟中的综合征X,包括给予需要所述治疗的对象治疗这样的障碍或病情有效量的通式I,II或III化合物或其药用盐。
本发明也提供用于治疗病情的药物组合物和方法,包括以有效治疗该病情的量给予I,II,或III的化合物,其中该病情选自:a)异常昼夜节律;b)抑郁,进一步地其中给予用于治疗抑郁的第二种化合物,该用于治疗抑郁的第二种化合物就所述CRF拮抗剂的作用而言,它延迟发挥作用;和c)呕吐。上述方法可根据在1999年8月27日提交的U.S.临时专利申请No.60/151,183中提供的信息实施,该文献概括描述了使用CRF拮抗剂对上述病情的治疗并且它在此全文引入作为参考。
在此描述的通式I,II,和III的化合物也可用于治疗在上述U.S.系列No.09/248,073中描述的心力衰竭的形式病,并且因此可以制备成药物组合物。
可根据本发明治疗的异常昼夜节律的具体形式或现象的例子包括,但不限于,发生的时区变化综合征、季节性情感障碍、换班工作睡眠障碍、不规则睡眠-觉醒型式、由于该异常昼夜节律的延迟睡眠期综合征、提前的睡眠期综合征、或由于该异常昼夜节律的非24小时睡眠觉醒障碍。此外,在用于治疗异常昼夜节律的方法或药物组合物中,通式I,II或III的化合物可以与如下用于治疗睡眠障碍的第二种化合物结合:例如速激肽拮抗剂、用于GABA脑受体的激动剂、metalonergic化合物、GABA脑受体激动剂、5HT2受体拮抗剂、和D4受体结合化合物。然而,用于治疗睡眠障碍的其它化合物或物质可以与通式I,II或III的化合物结合。这样的方法和组合物更详细地描述在前述的U.S.临时专利申请No.60/151,183中。
在另一个实施方案中,该病情是抑郁,并且其中具有治疗抑郁延迟作用的该第二种化合物选自选择性5-羟色胺再摄取抑制剂、三环类抗抑郁剂、去甲肾上腺素摄取抑制剂、锂、安非他酮、舍曲林、氟西汀、曲唑酮、和选自丙咪嗪、阿米替林、曲米帕明、多塞平、地昔帕明、去甲替林、普罗替林、阿莫沙平、氯米帕明、马普替林和卡马西平的三环类抗抑郁剂,以及上述化合物的药用盐及酯。
在另一个实施方案中,要治疗的病情是呕吐,并且该方法进一步包括给予用于治疗呕吐的第二种化合物。用于治疗呕吐的第二种化合物选自但不限于速激肽拮抗剂、5HT3拮抗剂、GABA激动剂、和物质P抑制剂。包括在本发明中的呕吐的更具体类别的呕吐包括由选自如下的病情或药剂诱导的呕吐:妊娠、前庭病症、术后病、胃肠道梗阻、降低的胃肠道动力、内脏性痛、偏头痛、颅间压力变化、化学疗法、辐射、毒素和阿片样止痛剂。
发明详述
以下描述本发明化合物和组合物的制备方法。在以下的讨论和反应方案中,除非另外说明,R1-R9,R11,R12,R16,R17,R19,A,B,G,虚线和通式I,II,III,X,XI,XII和IV如下所定义。
在此每当提到烷基时,包括直链和支链烷基两者。例如,“C1-C6烷基”包括直链和支链1-6个碳原子的烷基,包括(但不限于)甲基、乙基、异丙基、叔丁基和己基。
每当R2或R5是杂环基团时,基团的连接是通过碳原子。
在此每当提到在上述定义中的“可包含一个双键或三键”的C1-C4烷基或C1-C6烷基时,应理解为在烷基中对于一个双键或三键存在至少两个碳。
在此每当提及卤或卤素时,除非另外说明表示氟、氯、溴、或碘。
术语“治疗(treatment)”,“治疗(treating)”等表示包括障碍进展的减缓或反转,以及治愈障碍。这些术语也包括障碍或病情症状的减轻或减低,即使没有真实地消除障碍或病情和即使障碍或病情的进展自身没有减缓或反转。术语“治疗”等术语也包括障碍和病情的预防性治疗。
术语“卤代烷基”表示被一个或多个卤素原子,即一个或多个氟、溴、碘、或氯原子取代的烷基。另外,理解根据此说明书和权利要求,当烷基可以被如1-9个,如9个原子取代时,当在烷基中存在足够数目的碳原子时,任选的1-9个氟原子仅是一种选择。
除非另外说明,在上述定义中的术语“芳基”表示通过除去一个氢原子衍生自芳族烃的有机基团。芳基的例子是苯基和萘基。
除非另外说明,术语“杂环烷基”表示4-8元单碳环或双环,其中至少一个碳原子被选自氧、氮、N-(烷基)、或S(O)m的杂成员代替,其中m是0,1,2或3。一般情况下,杂环烷基包括至多四个杂成员,优选1,2或3个杂成员。本发明化合物的杂环烷基可任选地包含1-3个双键。术语“杂环烷基”也包括杂芳基基团。杂芳基的例子包括噻吩基、苯并噻吩基、吡啶基、噻唑基、喹啉基、吡嗪基、嘧啶基、咪唑基、呋喃基、苯并呋喃基、苯并噻唑基、异噻唑基、苯并异噻唑基、苯并异噁唑基、苯并咪唑基、吲哚基、和苯并噁唑基。芳基的其它例子是吡唑基、三唑基、四唑基、异噁唑基、噁唑基、吡咯基、异喹啉基、噌啉基、吲唑基、中氮茚基、2,3-二氮杂萘基、哒嗪基、三嗪基、异吲哚基、嘌呤基、噁二唑基、噻二唑基、呋咱基、苯并呋咱基、苯并硫苯基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喔啉基、萘啶基、和furopyridinyl。优选的杂芳基是噻唑基、噻吩基、苯并噻吩基、吡啶基、喹啉基、喹唑啉基、喹喔啉基、吡嗪基、嘧啶基、吲唑基、咪唑基、呋喃基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并异噁唑基、异噁唑基、吡唑基、吡咯基、吲哚基、吡咯并吡啶基、噁唑基、苯并噁唑基、和苯并噻二唑基。其它优选的杂环烷基是四氢呋喃并、四氢吡喃并、吗啉代、吡咯烷并、哌啶子基、哌嗪并、[2,2,1]-氮杂双环、[2,2,2]-氮杂双环、[3,3,1]-氮杂双环、奎宁环并、氮杂环丁烷并、2-吖丁啶酮并(azetidinono)、羟吲哚并、二氢咪唑并和pyrrolidinono。本发明化合物中的杂环烷基可以是其中这样是可能的C-连接或N-连接的。
通式I的化合物,其中B是-NR1R2、-NHCHR1R2、-OCHR1R2、或-SCHR1R2,并且R3是甲基、乙基或氯(下文中的R19),可以由通式IV的化合物,其中D是Cl,并且A,R4,R5,和Z参见如上通式I所定义,与通式BH的化合物制备,其中B如以上刚刚所定义。反应在溶剂中、在碱存在下,在约0°-约230℃的温度下进行。合适的溶剂是有机溶剂,如四氢呋喃(THF)、乙腈、二甲基亚砜(DMSO)、丙酮、C2-C15烷醇、氯仿(CHCl3)、苯、二甲苯、甲苯、环丁砜、吡啶、喹啉、2,4,6-三甲基吡啶、乙酰胺、二-(C1-C2)烷基乙酰胺或1-甲基-2-吡咯烷酮。
通式I化合物,其中A是-CR7和B是-NR1R2或-NHCHR1R2的制备方法是下述的两步骤工艺。首先,将通式IV的化合物与过量R1NH2或NH3或等当量NH3前体(如NaN3、nBu4N+N3 -或NH2OH)在约75℃-约250℃的温度下、在约O-约300psi的压力下、在上述合适的溶剂中反应,以形成通式I的化合物,其中B是-NHR1、-NH2、-NH2OH、-N3。可以通过本领域公知的方法,如氢化或还原,将通式I的化合物,其中B是-N3或-NH2OH,转化成通式I的相应化合物,其中B是-NH2。在合适碱、如双三甲基甲硅烷基酰胺锂或钠、二异丙酰胺锂或钠、正丁基锂或叔丁醇钠存在下,在合适的溶剂如THF、二噁烷或二氯甲烷中,采用合适的烷基卤化物对通式I化合物进行烷基化,其中B是-NHR1或-NH2,得到通式I的相应化合物,其中B是-NR1R2。或者,进行通式I的化合物的还原胺化,其中B是-NHR1或-NH2,例如酰化,随后与氢硼化物(如氢硼化钠)的反应,形成通式I的相应化合物,其中B是-NR1R2或-NHCHR1R2。
当B是-NR1R2或-NHCHR1R2时,可以使用过量BH作为试剂并作为碱。也可以使用不是BH的碱如碳酸钾、三-(C1-C6)烷基胺或氢化钠。反应在约75℃-约230℃的温度下进行。当反应在碱、如氢化钠、C1-C4醇钾、或有机锂化合物如正丁基锂存在下进行时,使用摩尔当量胺。
当B是-OCHR1R2或-SCHR1R2时,可以使用能够将BH脱质子化的碱,如碱金属氢化物如氢化钠或氢化钾、或有机金属碱如二异丙酰胺钠、双(三甲基甲硅烷基)酰胺钠、二异丙酰胺锂、双(三甲基甲硅烷基)酰胺锂、或C1-C4醇钾、或正丁基锂。使用的溶剂可以是,例如,四氢呋喃、乙腈、二甲亚砜、丙酮、二氯甲烷、甲苯、C2-C5醇、氯仿、苯、二甲苯、或1-甲基-2-吡咯烷酮,并且反应温度可为约0℃-约180℃,并且优选约50℃-约80℃。
通式I,II和III的化合物,其中B如通式I,II和III定义,并且R3定义相同,区别在于R3不是甲基或乙基(下文中的R20,它定义为R3,区别在于它不能是甲基或乙基)可以通过如下方式制备:使通式I,II或III的化合物,其中R3是氯,与通式R20H的亲核试剂反应,有或没有有机或无机碱。合适的碱包括,当R20H是链烷醇或烷烃硫醇时,为钠和氢化钠;和当R20H是胺时,弱碱为如碳酸钾或三乙胺。可以与氟化四丁基铵反应,从相应的化合物,其中R20是氯,制备通式I的化合物,其中R20是氟。合适的溶剂是二甲亚砜、四氢呋喃、或二氯甲烷,优选四氢呋喃。
如上定义的通式I化合物,其中B是-CR1R2R11、-C(C=CR2R12)R1、-CHR2OR12、-CHR2SR12、或-C(O)R2,并且R3是R19,可以如方案1所示制备。
方案1
将通式IV的化合物,其中D是氰基和A,R4,R5,和R19如以上通式IVA(未示出)所定义,它是通过相应的化合物,其中D是氯与氰化钾或氰化铜在二甲亚砜、1-甲基-2-吡咯烷酮、N,N-二甲基甲酰胺(DMF)或乙酰胺中制备的,与上述包含基团R2的格氏试剂反应,以形成通式IA的化合物。通式IA化合物与包含上述基团R1的格氏试剂反应,提供通式IB的化合物。通式IC的相应化合物,其中B”是-CR1R2R11、或-C(C=CR2R12)R1可以由通常的方法制备。因此,IB与酸,如在乙酸中的浓硫酸,或Burgess内盐,如氢氧化(羧基氨磺酰基)三乙基铵甲基酯的反应,得到通式IC的化合物,其中B’是-C(=CR2R12)R1。使用钯/碳(Pd/C)或二氧化铂催化剂进行化合物的氢化,其中B’是-C(=CR2R12)R1,得到通式IC的化合物,其中B’是-CR1R2。化合物IB与三氟化二乙基氨基硫或三苯基膦/四氯化碳的反应提供了化合物IC,其中B’分别是-CR1R2F或-CR1R2Cl。通式IA化合物与氢硼化钠的反应得到通式I的化合物,其中B是-CHR2OH。采用烷基卤化物如烷基碘化物,在碱如氢化钠存在下,在室温下-CHR2OH基团的烷基化,得到通式I的化合物,其中B是-CHR2OR12。
通式II的化合物,其中R3是上述R19,可以从通式IV的化合物制备,其中R19,R4,R5和A如上定义,D是氯,并且YR21是NH或-CHR21,其中R21是氰基或-COO(C1-C4烷基),以下通式IVB,如方案2所示。
可以在合适的溶剂,如甲苯、苯、叔丁醇、乙腈和丙酮,优选甲苯中,通过加热通式IVB的化合物和酸催化剂,制备通式VII的化合物,其中R4和R6各自为氢并且Y是N。酸催化剂可以是硫酸、盐酸、对甲苯磺酸、或甲磺酸,优选对甲苯磺酸。
当通式IVB中的Y是CH或N时,可以使用碱以将通式IVB的化合物质子脱质子化。合适的溶剂是四氢呋喃、甲苯、和二氯甲烷,合适的反应温度是约-78℃到约100℃,优选-78℃到约50℃,和合适的碱是氢化钠、氢化钾、叔丁醇钾、双(三甲基甲硅烷基)酰胺锂、和二异丙酰胺锂或钠。
通式VII的化合物,其中R4和R6各自为氢,可以采用碱如氢化钠、或有机金属化合物如双(三甲基甲硅烷基)酰胺锂脱质子化,随后采用包含基团R4,如R4L其中L是离去基团,如碘、溴、甲磺酸酯、甲苯磺酸酯的亲电子试剂化合物,或采用对甲苯基-N-氟-N-C1-C6烷基磺酰胺、碘、对硝基苯、二甲基甲酰胺、二(C1-C4烷基)酮、甲醛、(C1-C4烷基)醛或溴骤冷,以提供通式VII的化合物,其中R4是氟、氯、溴、碘、羟基、C1-C4烷基、S(C1-C4烷基)、CHO、CH(OH)(C1-C4烷基)、CH(OH)(二C1-C4烷基)或CH2OH。羟基的另外烷基化或硫代烷基的氧化分别导致通式VII的化合物,其中R4是C1-C4烷氧基或SOn(C1-C4烷基),其中n是1是2。通式VII化合物的氧化,其中R4是羟基和R6是氢,提供相应的化合物,其中CR4R6是C=O,它用合适胺进行还原胺化转化成相应的化合物,其中R4是氨基。通式VII的化合物,其中R4是硝基或氨基可以通过如下方式形成:将通式VII的化合物,其中R4和R6两者都是氢与亚硝酸烷基酯反应,以形成化合物,其中CR4R6是C=NOH,并且进行氧化或还原分别得到通式VII的化合物,其中R4是硝基或胺。
当R4和R6之一是氢时,通过采用还原剂如氢化铝锂在四氢呋喃中的还原,通式VII的化合物可以转化成相应的化合物,其中R16和R17两者都是氢。当R4和R6两者不是氢时,相同的还原导致这样的化合物,其中R16是氢并且R17是羟基。当R17是羟基时,在氢化钠存在下采用C1-C4烷基碘化物的烷基化,得到相应的化合物,其中R17是O(C1-C4烷基)。通式VII的化合物与有机金属化合物如二(C1-C6烷基)锌、C1-C6烷基锂、或C1-C6烷基溴化镁的反应,得到通式VIII的化合物,其中R16或R17之一是C1-C6烷基和另一个是羟基。
通式VIII化合物向通式IIA相应化合物的转化是通过上述用于通式I化合物的制备方法。
可以通过通式I化合物,其中R4是氨基并且Z是NH,与光气、双光气、三光气或硫光气的反应,制备通式III的化合物,其中G是氧或硫并且R6是氢。反应在碱如三(C1-C4烷基)胺存在下、在合适的溶剂优选四氢呋喃中、在-78℃到约50℃,优选在0℃到室温下进行。在合适的溶剂如干燥四氢呋喃中,采用合适碱如氢化钠的这些化合物的标准烷基化,其中R6是氢,提供了通式III的化合物,其中R6是C1-C4烷基。
可以在酸如对甲苯磺酸(p-TsOH)、甲磺酸(MsOH)、氯化氢气体(HClg)或浓硫酸(H2SO4)存在下,在合适的溶剂如甲苯、二甲苯、苯、二噁烷或THF中,在从约室温到约140℃的温度下,优选约50℃到约回流温度,通过通式I的化合物,其中R4是氨基并且Z是NH,与通式GC(OC1-C2烷基)3的化合物反应,制备通式III的化合物,其中G是烷基。或者,在碱如吡啶、吡啶衍生物或三-(C1-C4)烷基胺存在下,在合适溶剂如CH2Cl2、CHCl3、THF、二噁烷、甲苯或苯中,在约0℃到约反应混合物的回流温度,优选约0℃到约室温下,通式I的化合物,其中R4是氨基并且Z是NH,可以与[G(C=O)]2O、G(C=O)Cl或G(C=O)F反应,随后在酸性条件下进行环的环化(如,采用pTSOH、MSOH、HClg、溴化氢气体(HBrg)或浓硫酸)。环的环化可以在合适溶剂如C1-C5烷基醇、甲苯、二甲苯、苯、二噁烷或THF中进行。用于此反应的合适温度可以为约室温到约140℃。优选,反应温度为约50℃-约回流温度。
通式III的化合物,其中G是-O-(C1-C2烷基)或-OCF3,可以通过如下方式制备:将通式III的化合物,其中G是氧和R6是氢,在碱如三(C1-C4烷基)胺存在下,与通式GOSO2CF3化合物反应,或与双三甲基甲硅烷基酰胺锂在HMPA或DMF中反应,随后用通式GOSO2OG或G-X的化合物骤冷反应,其中X是溴、氯或SO3CF3。
其中A和R4如通式I定义,并且R19如上所定义。反应在四氢呋喃或二甲亚砜中,在约0℃-约150℃,优选50℃-130℃下进行。可以通过将通式V的化合物与R5OH、R5SH、R5NH2或R5CHR21反应,制备通式IV的化合物,其中D是氯和Z是O、S、CHR21,其中R21是缺电子基团如氰基、C(=O)R、COOR,其中R是C1-C4烷基、苯甲酰基或烯丙基、或SOn -苯基,其中n是0、1或2。反应在如下能够将R5ZH脱质子化的碱存在下进行:如氢化钠、氢化钾、碳酸钾、双(三甲基甲硅烷基)酰胺锂或钠、二烷基酰胺锂或钠、(C1-C4烷基醇)钠或钾或正丁基锂,有或没有有机金属卤化物如溴化铜(I)、碘化铜(I)或氯化铜(I)、氧化铜(II)、氧化铜(I)、铜金属和氯化三烷基锡。可以使用的溶剂的例子是四氢呋喃、二甲亚砜、乙腈、二氯甲烷、1-甲基-2-吡咯烷酮、吡啶、喹啉、N,N-二烷基乙酰胺、2,4,6-三甲基吡啶、N,N-二烷基甲酰胺、如,N,N-二甲基甲酰胺(DMF)、六甲基磷酰胺和甲苯。反应温度可以为约0℃-约180℃,和优选约0℃-约150℃。
通式IV的化合物,其中A是CR7,D是氯和Z是O、S、CHR21,可以通过如下方式制备:在合适溶剂如二氯甲烷或氯仿中、在约0℃-约100℃、和优选约室温-约溶剂的回流温度下,将如下所示的通式X化合物,其中R7和Z如刚刚所定义,用还原剂如三氯化磷还原。
可以从通式XI的化合物,如上所示,其中R4如在通式I中定义和R19如上所定义(即,甲基或乙基),通过与通式R5OH、R5SH、或R5CHR21的化合物反应,制备通式X的化合物。此反应在如下能够将R5ZH脱质子化的碱存在下进行:如氢化钠、氢化钾、双(三甲基甲硅烷基)酰胺锂、钠或钾、二烷基酰胺锂、钠或钾、C1-C4烷基醇钠或钾或正丁基锂。合适的溶剂包括四氢呋喃、二噁烷、二甲亚砜、1-甲基-2-吡咯烷酮、吡啶、N,N-二-(C1-C4烷基)乙酰胺、乙酰胺、N,N-二-(C1-C4烷基)甲酰胺、乙腈、二氯甲烷、甲苯和二甲苯。合适的反应温度可为约-78℃到约150℃,和优选约-40℃到约150℃。
可以通过如下方式制备通式XI的化合物:在溶剂如二氯甲烷、氯仿、乙酸、DMF、甲醇或一种或多种上述溶剂的混合物中,在从约0℃到约100℃,和优选约室温到约60℃的温度下,将通式V的相应化合物,其中A是-CR7并且R4和R19如上所定义,与氧化剂如间氯过苯甲酸、过乙酸或过三氟乙酸反应。
当R4是电子抽出(withdrawing)基团如NO2、-COO(C1-C4烷基)、-COOH、CN或-COO(C1-C4)烷基时,偶联反应的反应顺序可以颠倒,该反应在通式I化合物的合成中,将B和ZR5基团引入。可以使用相似于上述那些的方法在ZR5偶联步骤之前引入B基团。例如,可以通过将通式XII的化合物与通式HZR5的化合物反应,制备通式I的化合物,其中R4是缺电子基团。可以在碱存在下,通过将通式V的化合物,其中A是CR7并且R19和R4如上所定义,与通式B”H的化合物反应,制备通式XII的化合物。
通式IV的化合物,其中D是氯并且Z是-N(C1-C4烷基),可以通过如下方式制备:在约-78℃到约100℃,和优选约0℃到约室温的温度下,将相应的化合物,其中Z是NH,与碱反应,随后采用C1-C4烷基碘化物或溴化物骤冷。合适的碱包括,例如,氢化钠、双(三甲基甲硅烷基)酰胺锂或钠、二烷基酰胺锂或钠和正丁基锂。合适的溶剂包括,例如,四氢呋喃、二甲亚砜、甲苯、苯或二氯甲烷。
通式IV的化合物,其中D是氯、羟基或OP,其中P是羟基的标准保护基团并且Z是-CR13R14,可以通过如下方式制备:在上述能够将Z基团中质子脱质子化的碱存在下,使用包含R13的烷基化剂如R13I,进行通式IV化合物的烷基化,其中Z是-CHR21,随后采用包含R14的烷基化剂如R14I骤冷。在约85%磷酸中,在约回流温度下,加热通式IV的化合物,其中D是氯或氢并且Z是-CH(CN),产生通式IV的相应化合物,其中D是羟基并且Z是CH2。采用碱,如用于R5ZH脱质子化的上述那些,进行通式IV化合物的脱质子化,其中Z是CH2,随后采用如下的合适亲电子试剂骤冷:如(C1-C6烷基)碘化物、碘、溴、乙酰氯、甲醛、丙酮、对甲苯基-N-氟-N-(C1-C6烷基)磺酰胺、硝基苯、亚硝酸C1-C6烷基酯、环氧乙烷或二卤化乙烷,产生通式IV的相应化合物,其中Z是-CHR13、-CH(OH)、环丙基或-C(NOH)。采用通式R14I烷基化剂,如,以上刚刚所述的其中Z是-CHR13的化合物的进一步烷基化,产生相应的化合物,其中Z是C(R13R14)。
-C(R5)NOH或-CH(OH)R5向C(O)R5的转化可以通过已知方法完成。其中Z是-C=NOH的化合物的氢化或还原提供其中Z是-CHNH2的化合物。使用标准有机化学,一些中间体可要求保护或解保护步骤以控制反应的选择性。
通式V的化合物,其中A是N(下文称为通式VB的化合物)或A是CR7(即通式VA的化合物)并且R4和R19如通式I所定义,可以通过如下方式制备:在约室温到约180℃的温度下,优选在回流温度下,将通式VIB和VIA的化合物在有或没有溶剂的情况下分别与1当量或过量POCl3反应。通式VIA的化合物可以通过相似于文献中描述的在对于本领域技术人员公知的那些方法制备。(参见Helv.ChimicaActa.,25,1306-1313页(1942))。
通式VIB的化合物可以通过如下方式制备:在醇(如甲醇)和丙酮的混合物中,在约50℃-约200℃的温度下,优选在回流温度下,将1当量R19C(=NH)(NH2)的HCl盐、1当量R4CH(COO-(C1-C2烷基))2和2当量碱如醇钠如甲醇钠进行反应。VIA,A=CR7VIB,A=N
当本发明的化合物包含一个或多个手性中心时,应理解本发明包括这样化合物的外消旋混合物以及所有单个对映体和非对映体及其混合物。
本发明也包括同位素标记的化合物,它们与在通式I,II,或III中引用的那些相同,但事实是一个或多个原子被原子质量或质量数与通常在自然中发现的原子质量或质量数不同的原子代替。可以引入到本发明化合物中的同位素的例子包括氢、碳、氮、氧、磷、氟、碘、和氯的同位素,如3H、11C、14C、18F、123I、和125I。包含上述同位素和/或其它原子同位素的本发明的化合物和该化合物的药用盐在本发明的范围之内。本发明的同位素标记化合物,例如其中引入辐射同位素如3H和14C的那些可以用于药物和/或底物组织分布测定。由于它们制备容易和可检测性,含氚的,即3H和碳-14,即14C同位素是特别优选的。11C和18F同位素特别用于PET(正电子发射断层X射线照相法)并且125I同位素特别用于SPECT(单光子放射计算机断层X射线照相法),均可用于用于脑成象。此外,采用重同位素如氘,即2H的取代,可以提供由于更大代谢稳定性带来的某些治疗优势,例如增加的体内半衰期或降低的剂量要求,并因此可以在一些情况下是优选的。一般可以通过进行在方案中和/或在以下实施例中公开的步骤,通过将容易获得的同位素标记试剂代替非同位素标记的试剂,制备本发明通式I,II,或III的同位素标记化合物。
可以采用常规的方式,通过采用化学当量药用酸处理相应游离碱的溶液或悬浮液,制备通式I,II,或III化合物的酸加成盐(本发明的活性化合物)。可以采用通常的浓缩或结晶技术以分离盐。合适酸的示例是乙酸、乳酸、琥珀酸、马来酸、酒石酸、柠檬酸、葡萄糖酸、抗坏血酸、苯甲酸、肉桂酸、富马酸、硫酸、磷酸、盐酸、氢溴酸、氢碘酸、氨基磺酸、磺酸如甲磺酸、苯磺酸、对甲苯磺酸和相关的酸。
本发明的活性化合物可以单独给予,或与药用载体结合,以单个或多个剂量给予。合适的药物载体包括惰性固体稀释剂或填料、无菌水溶液和各种有机溶剂。通过将通式I,II,或III的新颖化合物与它们的药用载体结合形成的药物组合物可以各种剂量形式,如片剂、粉末、锭剂、糖浆、注射液等容易地给予。如需要,这些药物组合物可包含另外的成分,如调味剂、粘合剂、赋形剂等。因此,对于口服给药的目的,可以采用包含各种赋形剂如柠檬酸钠、碳酸钙和磷酸钙的片剂,并可与各种崩解剂如淀粉、甲基纤维素、海藻酸和某些复合硅酸盐一起、并可与粘合剂聚乙烯基吡咯烷酮、蔗糖、明胶和阿拉伯胶一起应用。另外,润滑剂如硬脂酸镁、十二烷基硫酸钠和滑石通常用于成片剂目的。也可以在软和硬填充的明胶胶囊中,采用相似类型的固体组合物作为填充剂。用于此的优选材料包括乳糖或牛奶糖以及高分子量聚乙二醇。当需要含水悬浮液或酏剂用于口服给药时,其中必须的活性成分可以与各种甜味剂或调味剂、着色物质或染料和,如需要,乳化剂或悬浮剂结合,并可与稀释剂如水、乙醇、丙二醇、甘油和其结合物一起使用。
对于胃肠外给药,可以采用在芝麻油或花生油、含水丙二醇中、或在无菌水溶液中的含有本发明活性化合物或其药用盐的溶液。如需要这样的水溶液应当合适地缓冲和采用足量的盐水或葡萄糖首先将液体稀释成等渗的。这些特定水溶液特别适于静脉内、肌内、皮下和腹膜内给药。采用的无菌含水介质所有都是通过本领域技术人员已知的标准技术容易可获得的。
通式I,II,或III化合物和它们的盐的有效剂量依赖于所需的给药途径和如患者的年龄和体重等因素,如医师一般已知的那样。剂量也依赖于要治疗的特定疾病。例如,对于应激反应诱导的疾病、炎症性障碍、阿尔茨海默病、胃肠病、神经性厌食、出血性应激反应和药物和酒精戒断症状而言,每日剂量一般为约0.1-约50mg/kg待治疗的患者体重。本领域技术人员可以通过参考涉及待治疗的特定障碍或病情附属的文本确定有效剂量。
可用于确定本发明活性化合物及其药用盐的CRF拮抗剂活性的方法描述在Endocrinology,116,1653-1659(1985)和Peptides,10,179-188(1985)中。表达为IC50值的通式I,II和III化合物的结合活性一般为约0.5毫微摩尔-约10微摩尔。
通过如下实施例说明本发明。然而,应当理解,本发明并不限于这些实施例的具体详细情况。熔点是未校正的。质子核磁共振光谱(1HNMR)和C13核磁共振光谱(C13 NMR)测量是对在氘代氯仿(CDCl3)中的溶液进行的,峰位置表达为距离四甲基硅烷(TMS)的低磁场的百万分之份数(ppm)。峰形状表示如下:s,单峰;d,双峰;t,三重峰;q,四重峰;m,多重峰;b,宽峰。
在实施例中使用如下缩写:Ph=苯基;iPr=异丙基;HRMS=高分辨率质谱。
实施例1
通过相似于以下的方法,通过(2-氯-6-甲基-3-硝基-吡啶-4-基)-(烷基-或二烷基)-胺与取代苯酚的反应,制备如下化合物:向在干燥THF中的(2-氯-6-甲基-3-硝基-吡啶-4-基)-(烷基-或二烷基)-胺(1mmol)和2,4,6-三甲基苯酚(1mmol)的混合物中,加入叔丁醇钾(1mmol)和将获得的混合物在室温下搅拌直到所有的起始原料消耗完。将混合物采用水骤冷并采用乙酸乙酯萃取。将有机层干燥和浓缩以在通过硅胶柱色谱的纯化之后得到标题化合物:
2-[2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-3-硝基-吡啶-4-(S)-基氨基]-丁-1-醇
1H NMR(CDCl3)d 7.69(,1H),6.289s,1H),3.65-3.80(m,2H),3.60m,1H),2.12(s,3H),2.08(s,6H),1.8(brs,1H),1.5-1.8(m,2H),1.01(t,3H)ppm.
(1-甲氧基甲基-丙基)-[6-甲基-3-硝基-2-(4-三氟甲氧基-苯氧基)-吡啶-4-基]-胺
黄色固体75-76℃,元素分析,C18H20N3O5F3,计算值C52.05;H,4.85;N,10.12;实测值,C,52.14;H,5.04;N,10.13
2-(2-氨基-4,6-二氯-苯氧基)-6-甲基-3-硝基-吡啶-4-基]-(1-甲氧基甲基-丙基)-胺
1H NMR(CDCl3)d 9.55(d,1H),7.23(d,1H),7.00(d,1H),6.05(s,1H),3.69(m,1H),3.49(m,2H),3.38(s,3H),2.35(s,3H),1.78(m,1H),1.65(m,1H),0.99(t,3H)ppm.
3-甲氧基-2-[4-(1-甲氧基甲基-丙基氨基)-6-甲基-3-硝基-2-基氧]-苯甲醛
黄色固体126.5-130.5℃,元素分析,C19H23N3O6,计算值C58.60;H,5.95;N,10.79;实测值,C,58.45;H,6.11;N,10.32
[2-(2,6-二溴-4-三氟甲氧基-苯氧基)-6-甲基-3-硝基-吡啶-4-基]-(1-甲氧基甲基-丙基)-胺
黄色固体1H NMR(CDCl3)d 8.00(d,1H),7.49(,2H),6.35(s,1H),3.64(m,1H),3.53(m,2H),3.43(s,3H),2.20(s,3H),1.6-1.9(m,4H),1.04(t,3H)ppm.
[2-(2-溴-4-氯-6-甲氧基-苯氧基)-6-甲基-3-硝基-吡啶-4-基]-(1-甲氧基甲基-丙基)-胺
黄色固体111.8-113.6℃,元素分析,C15H21N3O5BrCl,计算值C,45.54;H,4.46;N,8.85;实测值,C,45.94;H,4.32;N,8.68
[2-(2,4-二氯-苯氧基)-6-甲基-3-硝基-吡啶-4-基]-(1-甲氧基甲基-丙基)-胺
1H NMR(CDCl3)d 7.83(d,1H),7.46(d,1H),7.30(dd,1H),7.15(dd,1H),6.33(s,1H),3.65(m,1H),3.51(m,2H), 3.42(s,3H),2.21(s,3H),1.82(m,1H),1.66(m,1H),1.03(t,3H)ppm.
[2-(2-溴-6-氯-4-甲氧基-苯氧基)-6-甲基-3-硝基-吡啶-4-基]-(1-甲氧基甲基-丙基)-胺
1H NMR(CDCl3)d 7.88(d,1H),7.04(d,1H),6.93(d,1H),6.27(s,1H),3.79(s,3H),3.60(m,1H),3.4-3.5(m,2H),3.38(s,3H),2.15(s,3H),1.78(m,1H),1.64(m,1H),0.99(t,3H)
(1-甲氧基甲基-丙基)-[6-甲基-3-硝基-2-(2,4,6-三甲氧基-苯氧基)-吡啶-4-基]-胺
mp.126.8-129.5℃,元素分析,C20H27N3O7计算值C,57.00;H,6.46;N,9.97;实测值,C,56.94;H,6.85;N,9.66.
实施例2
2-氯-N-[4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-基]-乙酰胺
在0℃下,向N-4-(1-乙基-丙基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3,4-二胺(250mg,0.763mmol)在干燥THF中的溶液中,加入氯化乙酰氯(80mg,0.763mmol)和三乙胺(77mg,0.763mmol)。将获得的混合物升温到室温的搅拌1hr。将混合物采用水骤冷和采用乙酸乙酯萃取。将有机层通过无水硫酸钠干燥,过滤,浓缩到干燥,得到为固体的标题化合物。将固体通过硅胶柱色谱纯化得到280mg(91%)黄褐色晶体,mp.152-154℃。
1H NMR(CDCl3)d 8.07(brs,1H),6.88(s,2H),6.16(s,1H),4.75(m,1H),4.25(s,2H),3.33(m,1H),2.30(s,3H),2.18(s,3H),2.08(s,6H),1.4-1.75(m,4H),0.97(t,6H)ppm.
通过相似于在前述段落中的方法制备如下化合物:
3-氯-N-[4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-基]-丙酰胺
褐色固体183-185℃,元素分析,C23H32ClN3O2计算值C,66.09;H,7.72;N,10.05;实测值,C,66.27;H,7.87;N,9.99.
2-氯-N-[4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-基]-丙酰胺
mp.170-172℃,元素分析,C23H32ClN3O2计算值C,66.09;H,7.72;N,10.05;实测值,C,66.20;H,7.52;N,10.09.
实施例3
N3-烯丙基-N4-(1-乙基-丙基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3,4-二胺
在-78℃下,向在干燥THF中的N-4-(1-乙基-丙基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3,4-二胺(500mg,1.52mmol)溶液中加入1M在THF中的双(三甲基甲硅烷基)酰胺锂(1.6ml,1.6mmol)。在-78℃下搅拌10min之后,加入烯丙基溴(0.13ml,1.52mmol)并将获得的混合物在该温度下搅拌20min,然后加热到室温过夜。将混合物采用水骤冷和采用乙酸乙酯萃取。将有机层通过无水硫酸钠干燥,过滤,浓缩到干燥,得到为绿-蓝色油状的标题化合物。使用在己烷中的5%乙酸乙酯作为洗脱剂,将油通过硅胶柱色谱纯化得到黄色晶体,mp.86-88℃。
1H NMR(CDCl3)d 6.87(s,2H),6.0(m,2H),5.2-5.35(m,2H),4.8(d,1H),3.54(d,2H),3.3(m,1H),3.05(s,1H),2.30(s,3H),2.14(s,3H),2.09(s,6H),1.4-1.6(m,4H),0.96(t,6H)ppm.
通过相似的方法制备如下化合物:
N3-(3-氯-丙基)-N4-(1-乙基-丙基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3,4-二胺
1H NMR(CDCl3)d 6.85(s,2H),6.05(s,1H),4.9(d,1H),3.8(m,2H), 3.3(m,1H),3.1(m,2H),2.3(s,3H),2.159s,3H),2.04(s,6H),1.79m,2H),1.5(m,2H),1.0(m,6H)ppm.
N4-(1-乙基-丙基)-6-甲基-N3-丙-1,2-二烯基-2-(2,4,6-三甲基-苯氧基)-吡啶-3,4-二胺
1H NMR(CDCl3)d 8.93(d,1H),6.86(s,2H),6.66(m,1H),6.09(s,1H),5.4-5.6(m,2H),5.54(d,1H),3.27(m,1H),2.27(s,3H),2.12(s,3H),2.05(s,6H),1.6(m,4H),0.94(t,6H)ppm.
实施例4
2-[3-氨基-2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-吡啶-4-(S)-基氨基]-丁-1-醇
在回流下,将2-[2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-3-硝基-吡啶-4-(S)-基氨基]-丁-1-醇(120mg)和Fe(73mg)在12ml的1∶1AcOH∶H2O中的混合物加热2hr。将反应混合物浓缩到干燥。将残余物采用水骤冷,碱化到pH12并通过C盐过滤。将滤液采用氯仿萃取。将有机层采用盐水洗涤,干燥和浓缩得到为黄色固体的标题化合物。使用1∶1EtOAc∶己烷作为洗脱剂,将固体通过硅胶柱色谱纯化得到白色固体,mp.161-162℃。
1H NMR(CDCl3)d 7.03(s,2H),6.15(s,1H),3.75(m,2H),3.47(m,1H),2.25(brs,3H),2.08(s,6H),1.5-1.8(m,2H),0.98t,3H)ppm
实施例5
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酸甲酯
在120℃下,将4-氯-6-甲基-2-(4-氯-2,6-二甲基-苯氧基)-烟酸甲酯(77mg,0.226mmol)和1-乙基-丙基-胺在DMSO中的混合物加热4hr。将混合物采用饱和氯化铵、水、盐水骤冷并采用乙酸乙酯萃取。将有机层干燥和浓缩得到140mg黄色固体。
1HNMR(CDCl3)d 8.10(d,1H),7.03(s,2H),6.09(s,1H),3.88(s,3H),3.35(m,1H),2.10(s,3H),2.08(s,6H),1.5-1.7(m,4H),0.96(t,6H)ppm.
实施例6
2-(4-溴-2,6-二甲基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酸甲酯
在120℃下,将4-氯-6-甲基-2-(4-溴-2,6-二甲基-苯氧基)-烟酸甲酯和1-乙基-丙基-胺在DMSO中的混合物加热16hr。将混合物采用水、盐水骤冷和采用乙酸乙酯萃取。将有机层干燥浓缩到干燥。使用己烷到在己烷中的3%乙酸乙酯作为洗脱剂,将残余物通过硅胶柱色谱纯化得到白色固体的标题化合物。
1H NMR(CDCl3)d 8.1(d,1H),7.18(s,2H),6.08(s,1H),3.87(s,3H).3.35(m,1H),2.10(s,3H),2.08(s,6H),1.4-1.7(m,4H),0.96(t,6H)ppm.
实施例7
4-(1-乙基-丙-2-炔基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸甲酯
在130℃下,将4-氯-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸甲酯和1-乙基-丙基-胺在DMSO中的混合物加热过夜。将混合物采用水、盐水骤冷和采用乙酸乙酯萃取。将有机层干燥浓缩到干燥。将残余物通过硅胶柱色谱纯化得到标题化合物。
1H NMR(CDCl3)d 8.26(d,1H),6.87(s,2H),6.26(s,1H),4.11(m,1H),3.87(s,3H),2.324(m,1H),2.30(s,3H),2.17s,3H),2.08(s,6H),1.92(q,2H),1.16(t,3H)ppm.
实施例8
4-(s)-(1-羟甲基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸甲酯
在130℃油浴中,将4-氯-2-(2,4,6-三甲基-苯氧基)-6-甲基-烟酸甲酯(500mg,1.56mmol)和(S)-2-氨基-1-丁醇(696mg,7.82mmol)在DMSO中的混合物加热24hr。将混合物冷却到室温和采用水骤冷和采用乙酸乙酯萃取。将有机层分离,采用水洗涤,通过无水硫酸钠干燥,过滤,并浓缩到干燥得到610mg为油的粗产物。使用在己烷中的30%乙酸乙酯作为洗脱剂,将油通过硅胶柱色谱纯化得到标题化合物。元素分析计算值C21H28N2O4.1/2H2O:C,66.11;H,7.66;N,7.34;实测值:C,66.27;H,7.60;N,7.21.
实施例9
4-(1-乙基-2-羟基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸甲酯
在130℃油浴中,将4-氯-2-(2,4,6-三甲基-苯氧基)-6-甲基-烟酸甲酯(250mg,0.78mmol)和3-氨基-戊-2-醇(320mg,3.13mmol)在DMSO中的混合物加热24hr。将混合物冷却到室温和采用水骤冷和采用乙酸乙酯萃取。将有机层分离,采用水洗涤,通过无水硫酸钠干燥,过滤,浓缩到干燥得到280mg为油的粗产物。使用在己烷中的20%乙酸乙酯作为洗脱剂,将油通过硅胶柱色谱纯化得到为黄色固体的标题化合物,mp116-120℃。
1H NMR(CDCl3)d 8.17(m,1H),6.87(s,2H),6.21&6.14(two s,1H),3.88(s,3H),3.8-4.0(m,2H),3.5(m,1H),3.3(m,1H),2.30(s,3H),2.12(s,3H),2.09(s,6H),1.8(d,1H),1.5-1.8(m,2H),1.26(d,3H),0.99(t,3H)ppm.
实施例10
2-(4-溴-2,6-二甲基-苯氧基)-4-(S)-(1-羟甲基-丙基氨基)-6-甲基-烟酸甲酯
在130℃油浴中,将4-氯-2-(4-溴-2,6-三甲基-苯氧基)-6-甲基-烟酸甲酯(850mg)和(S)-2-氨基-1-丁醇在DMSO中的混合物加热24hr。将混合物冷却到室温和采用水骤冷和采用乙酸乙酯萃取。将有机层分离,采用水洗涤,通过无水硫酸钠干燥,过滤,浓缩到干燥得到764mg为油的粗产物。将油通过硅胶柱色谱纯化得到标题化合物。1H NMR(CDCl3)d 8.15(d,1H),7.16(s,2H),6.18(s,1H),3.86(s,3H),3.72(m,1H),3.70(m,1H),3.54(m,1H),2.10(s,3H),2.06(s,6H),1.5-1.8(m,2H),1.00(t,3H)ppm.
实施例11
2-(4-溴-2,6-二甲基-苯氧基)-4-(S)-(1-甲氧基甲基-丙基氨基)-6-甲基-烟酸甲酯
在130℃油浴中,将4-氯-2-(4-溴-2,6-三甲基-苯氧基)-6-甲基-烟酸甲酯和1-甲氧基甲基-丙胺在DMSO中的混合物加热24hr。将混合物冷却到室温和采用水骤冷和采用乙酸乙酯萃取。将有机层分离,采用水洗涤,通过无水硫酸钠干燥,过滤,浓缩到干燥得到粗产物。将粗产物通过硅胶柱色谱纯化得到标题化合物。
实施例12
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-羟甲基-丙基氨基)-6-甲基-烟酸甲酯
在130℃下,将4-氯-2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-烟酸甲酯(9.000g,26.45mmol)和(S)-2-氨基-1-丁醇(12.7ml)在1-甲基-2-吡咯烷酮中的混合物加热2hr,然后在100℃下过夜。将混合物冷却到室温并倾入冰水中和采用乙酸乙酯稀释。将有机层分离,采用水洗涤,通过无水硫酸钠干燥,过滤,浓缩到干燥得到13.6g为淡黄色油的粗产物。使用氯仿到在氯仿中2%MeOH作为洗脱剂,将油通过硅胶柱色谱纯化得到6.6839g(64%)为白色玻璃泡沫状的标题化合物。将玻璃泡沫采用己烷研制得到白色固体。将固体从二异丙醚重结晶得到白色晶体。mp 122.5-124℃元素分析计算值C20H25ClN2O4:C,61.14;H,6.41;N,7.13;实测值:C,60.98;H,6.43;N,6.95.
实施例13
2-(4-氯-2,6-二甲氧基-苯氧基)-4-(S)-(1-羟甲基-丙基氨基)-6-甲基-烟酸甲酯
在130℃下,将4-氯-2-(4-氯-2-甲氧基-苯氧基)-6-甲基-烟酸甲酯和(S)-2-氨基-1-丁醇在1-甲基-2-吡咯烷酮中的混合物加热过夜。将混合物冷却到室温和倾入冰水中和采用乙酸乙酯稀释。将有机层分离,采用水洗涤,通过无水硫酸钠干燥,过滤,浓缩到干燥。将残余物通过硅胶柱色谱纯化得到为固体的标题化合物。mp.92.8-93.8℃,元素分析C19H23N2O5Cl:计算值,C,57.80;H,5.87;7.09;实测值,C,57.70;H,5.89;7.02.
实施例14
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基-2-羟基-丙基氨基)-6-甲基-烟酸甲酯
在130℃油浴中,将4-氯-2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-烟酸甲酯(500mg,1.47mmol)和3-氨基-戊-2-醇(758mg,7.35mmol)在1-甲基-2-吡咯烷酮中的混合物加热24hr。将混合物冷却到室温和采用水骤冷和采用乙酸乙酯萃取。将有机层分离,采用水洗涤,通过无水硫酸钠干燥,过滤,浓缩到干燥得到油。使用在己烷中的20%乙酸乙酯作为洗脱剂,将油通过硅胶柱色谱纯化得到为白色晶体的标题化合物,mp133-135℃。
1H NMR(CDCl3)d 8.19(m,1H),7.00(s,2H),6.20&6.14(两套s,1H),3.8-3.9(m,1H),3.86(s,3H),3.3&3.5(两套m,1H),2.07(s,3H),2.06(s,6H),1.75(m,1H),1.55(m,1H),1.24(d,3H),0.96(t,3H)ppm.
实施例15
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基-2-甲氧基-丙基氨基)-6-甲基-烟酸甲酯
向在干燥THF中的2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基-2-羟基-丙基氨基)-6-甲基-烟酸甲酯(50mg,0.123mmol)溶液中加入NaH并搅拌20min。加入过量MeI并将获得的混合物在室温下搅拌过夜。将混合物冷却到室温和采用水骤冷和采用乙酸乙酯萃取。将有机层分离,采用水洗涤,通过无水硫酸钠干燥,过滤,浓缩到干燥得到油。使用在己烷中的20%乙酸乙酯作为洗脱剂,将油通过硅胶柱色谱纯化得到为澄清油状的标题化合物。
1H NMR(CDCl3)d 8.20(d,1H),7.00(s,2H),6.14&6.10(两套s,1H),3.859s,3H),3.47(m,1H),3.39&3.37(两套s,3H),2.08(s,3H),2.06(s,6H),1.75(m,1H),1.58(m,1H),1.14(t,3H),0.95(t,3H)ppm.
实施例16
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基-2-氧代-丙基氨基)-6-甲基-烟酸甲酯
通过2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基-2-羟基-丙基氨基)-6-甲基-烟酸甲酯的Dess-Martin氧化制备标题化合物。在硅胶柱色谱之后获得白色固体。1H NMR(CDCl3)d8.6(d,1H),7.01(s,2H),5.899s,1H),3.9-4.0(m,1H),3.90(s,3H),2.17(s,3H),2.07(s,3H),2.05(s,3H),1.859m,1H),1.93(m,1H),1.00(t,3H)ppm.
实施例17
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-甲酰基-丙基氨基)-6-甲基-烟酸甲酯
通过2-(4-氯-2,6-二甲基-苯氧基)-4-(1-羟甲基-丙基氨基)-6-甲基-烟酸甲酯的Dess-Martin氧化制备标题化合物。在柱色谱之后获得标题化合物。1H NMR(CDCl3)9.54(d,1H),8.56(d,1H),7.01(s,2H),5.93(s,1H),3.92(m,1H),3.89(s,3H),2.08(s,3H),2.05(s,6H),1.05(t,3H)ppm.
实施例18
2-(4-氯-2,6-二甲基-苯氧基)-4-(S)-(4-乙基-2-氧代-噁唑烷-3-基)-6-甲基-烟酸甲酯
将2-(4-氯-2,6-二甲基-苯氧基)-4-(1-羟甲基-丙基氨基)-6-甲基-烟酸甲酯(106mg,0.27mmol),三光气(27mg,0.090mmol),三乙胺(27mg,0.27mmol)在干燥THF中的混合物在室温下搅拌2hr。将混合物采用水骤冷和采用乙酸乙酯萃取。将有机层分离,采用水洗涤,通过无水硫酸钠干燥,过滤,浓缩到干燥得到13.6g为白色玻璃泡沫状的粗产物。将泡沫采用己烷/乙醚研制得到白色固体。mp.144-145.5℃,元素分析C21H23ClN2O5计算值:C,60.22;H,5.53;N,6.69;实测值:C,60.10,H,5.79;N,6.66.
实施例19
2-(4-氯-2,6-二甲基-苯氧基)-4-(S)-(1-[(2-羟基-乙基氨基)-甲基]-丙基氨基}-6-甲基-烟酸甲酯
向2-(4-氯-2,6-二甲基-苯氧基)-4-(1-甲酰基-丙基氨基)-6-甲基-烟酸甲酯在二氯乙烷中的溶液中加入2-氨基-乙醇、氰基硼氢化钠、乙酸、无水硫酸钠。将获得的混合物在回流下加热和冷却到室温。将混合物采用水骤冷和采用氯仿萃取。将有机层分离,采用水洗涤,通过无水硫酸钠干燥,过滤,浓缩到干燥。在色谱之后,获得为白色玻璃泡沫状的标题化合物。1H NMR(CDCl3)d 8.3(d,1H),7.0(s,2H),6.1(s,1H),3.9(s,3H),3.64(m,2H),3.57(m,1H),2.90(m,2H),2.83(m,2H),2.5(brs,2H),2.09(s,3H),2.06(s,6H),1.65(m,2H),0.97(t,3H)ppm.
实施例20
4-[乙基-(2-羟基-乙基)-氨基]-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸甲酯
在130℃下,将4-氯-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸甲酯和1-乙基-丙基-胺在1-甲基-2-吡咯烷酮中的混合物加热直到起始原料消耗完。将混合物采用水、盐水骤冷和采用乙酸乙酯萃取。将有机层干燥浓缩到干燥。将残余物通过硅胶柱色谱纯化得到标题化合物。1H NMR(CDCl3)d 6.85(s,2H),6.40(s,1H),3.88(s,3H),3.73(t,2H),3.43(t,2H),3.31(q,2H),2.27(s,3H),2.22(s,3H),2.06(s,6H),1.15(t,3H)ppm.
实施例21
4-[乙基-(2-甲磺酰氧基-乙基)-氨基]-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸甲酯
将4-[乙基-(2-羟基-乙基)-氨基]-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸甲酯、甲磺酰氯和三乙胺在二氯甲烷的混合物在室温下搅拌直到所有的起始原料消耗完。将混合物采用水、盐水骤冷和采用乙酸乙酯萃取。将有机层干燥浓缩到干燥。将残余物通过硅胶柱色谱纯化得到标题化合物。1H NMR(CDCl3)d 6.83(s,2H),6.25(s,1H),4.34(t,2H),3.86(s,3H),3.6(t,2H),3.38(t,2H),3.09s,3H),2.25(s,3H),2.20(s,3H),2.04(s,6H),1.18(t,3H)ppm.
实施例22
4-[(2-羟基-乙基)-噻吩-2-基甲基-氨基]-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸甲酯
在130℃下,将4-氯-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸甲酯和2-[(噻吩-2-基甲基)-氨基]-乙醇在1-甲基-2-吡咯烷酮中的混合物加热过夜。将混合物采用水、盐水骤冷和采用乙酸乙酯萃取。将有机层干燥浓缩到干燥。将残余物通过硅胶柱色谱纯化得到标题化合物。1H NMR(CDCl3)d 7.22(m,1H),6.94m,2H),6.84(s,2H),6.44(s,1H),4.52(s,2H),3.91(s,3H),3.679t,2H),3.369t,2H),2.279s,3H),2.20(s,3H),2.07(s,6H)ppm.
实施例23
通过相似于在实施例5中的方法,采用合适的4-氯-6-甲基-2-(取代的-苯氧基)-烟酸烷基酯和合适的烷基-或二烷基-胺开始,制备如下化合物。
4-(2,2-二甲基-4-苯基-[1,3]二噁烷-5-基-氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸甲酯
1H NMR(CDCl3)d 8.71(d,2H),7,1-7.4(m,5H),6.82(s,2H),5.55(s,1H),5.229s,1H),4.29(d,1H),3.97(d,1H),3.869s,3H),3.61(d,1H),2.25(s,3H),2.01(s,6H),1.91(s,3H),1.65(s,3H),1.61(s,3H)ppm.
2-(4-氯-2,6-二甲基-苯氧基)-4-(S)-(1-羟甲基-丙基氨基)-6-甲基-烟酸乙酯
1H NMR(CDCl3)d 8.01(d,1H),7.02(s,2H),6.17(s,1H),4.33(q,2H),3.71(m,1H),3.66(m,1H),3.54m,1H),2.10(s,3H),2.07(s,6H),1.5-1.8(m,2H),1.33(t,3H),1.00(t,3H)ppm.
4-[乙基-(2-甲氧基-乙基)-氨基]-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸甲酯
1H NMR(CDCl3)d 6.83(s,2H),6.19(s,1H),3.869s,3H),3.35-3.6(m,4H),3.35(s,3H),2.26(s,3H),2.15(s,3H),2.06(s,6H),1.179t,3H)ppm.
2-(4-氯-2,6-二甲基-苯氧基)-4-(S,R)-&(S,S)-(1-乙基-2-羟甲基-丙基氨基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.2(d,1H),7.01(s2H),6.20(s,0.2H),6.15(s,0.8H),3.92(m,1H),3.87(s,3H),3.48(m,0.2H),3.31(m,0.8H),2.08(s,3H),2.06(s,6H),1.5-1.8(m,2H),1.25(d,3H),0.96(t,3H)ppm.
2-(4-氯-2,6-二甲基-苯氧基)-4-(R)-(1-羟甲基-丙基氨基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)8.12(d,1H),7.00(s,2H),6.16(s,1H),3.85(s,3H),3.6-3.8(m,2H),3.53(m,1H),2.08(s,3H),2.05(s,6H),1.5-1.8(m,2H),0.98(t,3H)ppm.
4-(2-羟基-1-羟甲基-乙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸甲酯
1H NMR(CDCl3)d 8.44(d,1H),6.84(s,2H),6.17(s,1H),3.8-4.0(m,4H),3.85(s,3H),3.70(m,1H),2.60(s,3H),2.27(s,3H),2.11(s,2H),2.05(s,6H)ppm.
4-(2-甲氧基-1-甲氧基甲基-乙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸甲酯
1H NMR(CDCl3)d 8.38(d,1H),6.88(s,2H),6.18(s,1H),3.88(s,3H),3.78(m,1H),3.56(m,2H),3.44(s,6H),2.31(s,3H),2.15(s,3H),2.09(s,6H)ppm.
4-(1-羟甲基-2-甲氧基-乙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸甲酯
1H NMR(CDCl3)d 8.44(d,1H),6.88(s,2H),6.21(s,1H),3.89(s,3H),3.80(m,1H),3.5-3.7(m,2H),3.45(s,3H),2.31(s,3H),2.16(s,3H),2.09(s,6H)ppm.
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基-2-羟基-丁基氨基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.34(d,1H),7.069s,2H),6.16(s,1H),3.91(s,3H),3.70(m,1H),3.5(m,1H),2.13(s,3H),2.11(s,6H),1.5-1.9(m,4H),1.01(m,6H)ppm.
实施例24
[2-(4-氯-2,6-二甲基-苯基氨基)-4-(1-乙基-丙基氨基)-6-甲基-吡啶-3-基]-甲醇
在-78℃下,将4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸甲酯(130mg,0.332mmol)和过量1M氢化二异丁基铝在干燥THF中的混合物搅拌10min,然后升温到室温。将混合物采用甲醇骤冷和在室温下搅拌20min,通过C盐过滤和采用甲醇和氯仿洗涤。将滤液浓缩到干燥。将残余物通过硅胶柱色谱纯化得到标题化合物。
1HNMR(CDCl3)d 7.03(s,2H),6.11(s,1H),5.03(d,1H),4.96(s,2H),3.32(m,1H),2.14(s,3H),2.07(s,6H),1.4-1.7(m,4H),0.96(t,6H)ppm.
[2-(4-溴-2,6-二甲基-苯基氨基)-4-(1-乙基-丙基氨基)-6-甲基-吡啶-3-基]-甲醇
通过相似于前述段落的方法制备标题化合物。
1H NMR(CDCl3)d 7.18(s,2H),6.11(s,1H),5.05(d,1H),4.91(d,2H),3.31(m,1H),2.14(s,3H),2.07(s,6H),1.4-1.7(m,4H),0.96(t,6H)ppm.
实施例25
2-[3-羟甲基-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-(S)-基氨基]-丁-1-醇
在回流下,将4-(S)-(1-羟甲基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸甲酯和1M氢化铝锂和氯化铝在THF中的混合物加热。将混合物冷却和采用水、2N NaOH、然后水骤冷并在室温下搅拌10min。形成白色固体并将白色固体通过C盐过滤,采用THF洗涤。在柱色谱之后,将滤液浓缩到干燥得到为白色固体的标题化合物。
mp.135-137℃;元素分析C20H28N2O3计算值C,69.74;H,8.19;N,8.13;实测值C,69.42;H,8.34;N,7.95
通过相似于在前述段落中的方法,采用相应的酯开始并使之与氢化铝锂和氯化铝的反应,制备如下化合物。
3-[2-(4-氯-2,6-二甲基-苯氧基)-3-羟甲基-6-甲基-吡啶-4-基氨基]-戊-2-醇
mp.180-182℃.1H NMR(CDCl3)7.0(s,2H),6.18&6.15(两套s,1H),5.1和5.22(m,1H),4.92(m,2H),3.80-4.0(m,1H),3.20-3.5(m,1H),2.11(s,3H),2.04(s,6H),1.4-1.8(m,2H),1.23(m,3H),0.98(m,3H)ppm.
2-[2-(2,6-二甲基-苯氧基)-3-羟甲基-6-甲基-吡啶-4-基氨基]-丁-1-醇
1H(CDCl3)d 7.05(m,3H),6.20(s,1H),4.8-5.0(m,2H),3.74(m,1H),3.66(m,1H),3.50(m,1H),2.0-2.29m,9H),1.55-1.75(m,2H),0.99(t,3H)ppm.
3-[3-羟甲基-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基氨基]-戊-2-醇
1H NMR(CDCl3)d 6.86(s,2H),6.17(s,1H),4.0(d,1H),3.9(m,1H),3.3(m,1H),2.29(s,3H),2.14(s,3H),2.13(s,3H),2.07(s,6H),1.8(d,1H),1.4-1.8(m,2H),1.25(d,3H),0.99(t,3H)ppm.
2-[2-(4-氯-2-甲氧基-苯氧基)-3-羟甲基-6-甲基-吡啶-4-基氨基]-丁-1-醇
1H NMR(CDCl3)6.8-7.0(m,3H),6.2(s,1H),5.02(d,1H),4.7(ABq,2H),3.74(m,5H),3.350-3.5(m,2H),2.9(brs,2H),2.18(s,3H),1.4-1.7(m,2H),1.23(m,3H),0.95(t,3H)ppm.
实施例26
2-[2-(4-氯-2,6-二甲基-苯氧基)-3-羟甲基-6-甲基-吡啶-4-基氨基]-丁-1-醇
在室温下,将4-(S)-(1-羟甲基-丙基氨基)-6-甲基-2-(4-氯-2,6-二甲基-苯氧基)-烟酸甲酯和1M氢化铝锂和氯化铝在THF中的混合物搅拌2hr。将混合物冷却和采用水、2N NaOH、然后水骤冷和在室温下搅拌10min。形式白色固体并将白色固体通过C盐过滤,采用THF洗涤。在柱色谱之后,将滤液浓缩到干燥得到为白色固体的标题化合物。
mp 133-135℃,1H NMR(CDCl3)7.00(s,2H),6.17(s,1H),5.12(d,1H),4.90(m,2H),3.4-3.8(m,3H),2.12(s,3H),2.04(s,6H),1.4-1.6(m,2H),0.99(t,3H)ppm.
通过相似于在前述段落中的方法,采用相应的甲酯和氢化铝锂开始,制备如下化合物。
2-{乙基-[3-羟甲基-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-氨基}-乙醇
1H NMR(CDCl3)d 1H NMR(CDCl3)6.86(s,2H),6.53(s,1H),4.94(s,2H),3.67(m,2H),3.1-3.3(m,4H),2.28(s,3H),2.20(s,3H),2.04(s,6H),1.09(t,3H)ppm.
4-[2-(4-氯-2,6-二甲基-苯氧基)-3-羟甲基-6-甲基-吡啶-4-基氨基]-己-3-醇
mp.145-148℃.1H NMR(CDCl3)d 1H NMR(CDCl3)7.05(s,2H),6.16(s,1H),5.3(d,1H),4.94(s,2H),3.67(m,1H),3.40(m,1H),2.151(s,3H),2.09(s,6H), 1.4-1.8(m,4H),1.23(m,3H),1.02(m,6H)ppm.
2-[2-(4-氯-2-甲氧基-苯氧基)-3-羟甲基-6-甲基-吡啶-4-(S)-基氨基]-丁-1-醇
1H NMR(CDCl3)d 7.8-7.95(m,2H),5.02(d,1H),4.74(ABq,2H),3.74(s,3H),3.72(m,2H),3.45m,1H),2.98(brs,1H),2.18(s,3H),1.4-1.7(m,2H),0.95(t,3H)ppm.
4-[2-(4-氯-2,6-二甲基-苯氧基)-3-羟甲基-6-甲基-吡啶-4-基氨基]-己-3-醇
1H NMR(CDCl3)d 7.05(s,2H),6.16(s,1H),5.30(d,1H),4.94(s,2H),3.67(m,1H),3.4(m,1H),2.15(s,3H),2.09(s,6H),1.5-1.9(m,4H),1.01(m,6H)ppm.
[2-(2,4-二甲氧基-苯基氨基)-4-(1-甲氧基甲基-丙氧基)-6-甲基-吡啶-3-基]-甲醇
1H NMR(CDCl3)d 6.90(d,1H),6.42(s,1H),6.40(d,1H),5.91(s,1H),4.42(m,1H),4.28(s,2H),3.79(s,3H),3.76(s,3H),3.56(m,2H),3.40(s,3H),2.33(s,3H),1.5-1.85(m,2H),1.02(t.3H)ppm.
实施例27
2-(4-氯-2,6-二甲基-苯氧基)-4-(S)-(1-羟甲基-丙基氨基)-6-甲基-烟酸
在室温下,将2-(4-氯-2,6-二甲基-苯氧基)-4-(S)-(1-羟甲基-丙基氨基)-6-甲基-烟酸甲酯(113mg)和氢氧化锂在二噁烷/THF/水的混合物搅拌过夜。将混合物采用氯化铵骤冷并采用氯仿萃取。将有机层干燥和浓缩得到78mg为白色固体的标题化合物。
1H NMR(CDCl3)d 10.55(brs,1H),9.2(d,1H),7.06(s,2H),6.3(s,1H),3.5-3.8(m,3H),2.11(s,3H),2.09(s,3H),2.08(s,3H),1.78(m,1H),1.62(m,1H),1.00(t,3H)ppm.
4-(1-乙基-丙-2-炔基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸
mp.131-133℃,1H NMR(CDCl3)d 11.29(brs,1H),9.35(d,1H),6.91(s,2H),6.38(s,1H),4.12(m,1H),2.88(m,1H),2.32(s,3H),2.19(s,3H),2.09(s,6H),1.96(m,2H),1.17(t,6H)ppm.
2-(4-溴-2,6-二甲基-苯氧基)-4-(S)-(1-甲氧基甲基-丙基氨基)-6-甲基-烟酸
1H NMR(CDCl3)d 10.5(brs,1H),8.6(d,1H),7.15(d,2H),6.25(s,1H),3.3-3.6(m,3H),3.38(s,3H),2.11(s,3H),2.09(s,3H),2.08(s,3H),1.5-1.85(m,2H),0.91(t,3H)ppm.
4-(2-甲氧基-1-甲氧基甲基-乙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸
1H NMR(CDCl3)d 9.44(d,1H),6.92(s,2H),6.30(s,1H),3.80(m,1H),3.58(m,2H),3.44(s,6H),2.33(s,3H),2.16(s,3H),2.10(s,6H)ppm.
实施例28
通过将相应的[2-(取代的-苯氧基)-3-氯甲基-6-甲基-吡啶-4-基]-(烷基)-胺与合适的胺反应,制备如下化合物。
[2-(4-氯-2,6-二甲基-苯氧基)-3-异丁氧基甲基-6-甲基-吡啶-4-基]-(1-乙基-丙基)-胺
1H NMR(CDCl3)d 6.94(s,2H),6.0(s,1H),5.13(d,1H),4.7(s,2H),3.2(m,1H),3.16(d,2H),2.02(s,3H),1.96(s,6H),1.8(m,1H),1.3-1.6(m,4H),0.82(t,6H),0.8(d,6H)ppm.
[3-乙氧基甲基-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-(1-乙基-丙基)-胺
1H NMR(CDCl3)d 6.86(s,2H),6.03(s,1H),5.30(d,1H),4.83(s,2H),3.58(q,2H),3.35(m,1H),2.29(s,3H),2.15(s,3H),2.06(s,6H),1.5-1.78(m,4H),1.23(t,3H),0.967(t,6H)ppm.
2-[3-丁氧基甲基-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基氨基]-丁-1-醇
1H NMR(CDCl3)d 6.85(s,2H),6.179s,1H),5.3(d,1H),4.82(Abq,2H),3.5-3.8(m,2H),3.5(t,2H),2.3(s,3H),2.15(s,3H,2.02(s,6H),1.75(brs,1H),1.5-1.8(m,4H),1.3-1.5(m,2H),1.02(t,3H),0.9(t,3H)ppm.
实施例29
1-[4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-基]-乙醇
在THF中,在-78℃下,将4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-羰基醛(carbaldehyde)与甲基锂反应,制备标题化合物。在硅胶柱色谱之后,将所需产物分离得到60.1%的无色油。1H NMR(CDCl3)d 6.87(s,2H),6.06(s,1H),5.7(q,1H),3.3(m,1H),2.29(s,3H),2.12(s,6H),2.069s,3H),1.4-1.7(m,4H),1.59(d,3H),0.8-1.0(m,6H)ppm.
实施例30
乙酸4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-基甲酯
通过[2-(2,4,6-三甲基-苯氧基)-3-羟甲基-6-甲基-吡啶-4-基]-(1-乙基-丙基)-胺的酰基化,获得标题化合物。
1H NMR(CCl3)d 6.84(s,2H),6.04(s,1H),5.35(s,2H),5.23(d,1H),3.32(m,1H),2.28(s,3H),2.12(s,3H),2.08(s,3H),2.07(s,6H),1.4-1.7(m,4H),0.93(t,6H)ppm.
实施例31
2-[2-(4-氯-2,6-二甲基-苯氧基)-3-(1-羟基-1-甲基-乙基)-6-甲基-吡啶-4-(S)-基氨基]-丁-1-醇
在室温下,在THF中,通过将2-(4-氯-2,6-二甲基-苯氧基)-4-(1-羟甲基-丙基氨基)-6-甲基-烟酸甲酯与过量1M溴化甲基镁反应过夜,制备标题化合物。在硅胶色谱之后,标准处理步骤得到标题化合物。
1H NMR(CDCl3)d 7.4(brs,1H),7.01(s,2H),6.13(s,1H),3.7(m,1H),3.6(m,1H),3.45(m,1H),2.04(s,3H),2.03(s,3H),2.02(s,3H),1.5-1.7(m,2H),0.98(t,3H)ppm.
实施例32
[2-(4-氯-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-(1-乙基-丙基)-胺
向在干燥THF中的[2-(4-氯-2,6-二甲基-苯氧基)-3-氯甲基-6-甲基-吡啶-4-基]-(1-乙基-丙基)-胺(75mg,0.196mmol)中,加入在TFH中的1.0M BH3(0.59ml,0.59mmol)并搅拌2hr。将混合物采用稀HCl骤冷和搅拌5min。将反应混合物采用2N NaOH、水中和并采用乙酸乙酯萃取。将有机层分离,干燥浓缩到干燥。将残余物通过硅胶柱色谱纯化,得到为无色油的标题化合物。
1H NMR(CDCl3)d 7.03(s,2H),6.08(s,1H),3.73(d,1H),3.3(m,1H),2.15(s,3H),2.12(s,3H),2.08(s,6H),1.4-1.6(m,4H),0.96(t,6H)ppm.
实施例33
[2-(2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-(1-乙基-丙基)-胺
向在干燥THF中的[2-(4-溴-2-甲氧基-苯基氨基)-4-(1-乙基-丙基氨基)-6-甲基-吡啶-3-基]-甲醇(43mg,0.106mmol)溶液加入在乙醚(0.25ml)中的1.0M氢化铝锂和氯化铝(28mg)。将获得的混合物在室温下搅拌过夜。将混合物采用水、2NaOH、然后水骤冷。形成固体和将固体通过C盐过滤,采用THF、然后氯仿洗涤。将滤液浓缩到干燥。将残余物采用水和乙酸乙酯稀释。将有机层分离,干燥和浓缩得到粗材料。在硅胶色谱之后分离标题化合物。1H NMR(CDCl3)d 6.9-7.1(m,3H),6.07(s,1H),3.35(d,1H),3.33(m,1H),2.14(s,3H),2.13(s,3H),2.12(s,6H),1.5-1.8(m,4H),0.97(t,6H)ppm.
实施例34
[2-(4-溴-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-(1-乙基-丙基)-胺
通过相似于在实施例145中的方法制备标题化合物,为白色固体。
1H NMR(CDCl3)d 7.19(s,2H),6.09(s,1H),3.36(d,1H),3.33(m,1H),2,15(s,3H),2.12(s,3H),2.09(s,6H),1.4-1.8(m,4H),0.97(t,6H)ppm.
实施例35
4-[4-(1-乙基-丙基氨基)-3,6-二甲基-吡啶-2-基氧]-3,5-二甲基-苯甲醛
在-78℃下,向在干燥THF中的[2-(4-溴-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-(1-乙基-丙基)-胺的溶液中,加入正丁基锂。在-78℃下搅拌10min之后,加入N,N-二甲基甲酰胺并将获得的混合物在-78℃下搅拌20min,除去干冰浴。在搅拌5min之后,将混合物采用稀HCl、水骤冷和调节到pH7.5并采用乙酸乙酯萃取。将有机层分离,干燥,浓缩到干燥。将残余物通过硅胶色谱纯化得到标题化合物。1H NMR(CDCl3)d 9.93(s,1H),7.60(s,2H),6.10(s,1H),3.75(d,1H),3.35(m1H),2.17(s,6H),2.13(s,3H),2.12(s,3H),1.4-1.8(m,4H),0.97(t,6H)ppm.
实施例36
{4-[4-(1-乙基-丙基氨基)-3,6-二甲基-吡啶-2-基氧]-3,5-二甲基-苯基}-甲醇
在室温下,搅拌4-[4-(1-乙基-丙基氨基)-3,6-二甲基-吡啶-2-基氧]-3,5-二甲基-苯甲醛和硼氢化钠在甲醇中的混合物。在标准处理步骤和纯化之后,获得为固体的标题化合物。1HNMR(CDCl3)d 7.06(s,2H),6.08(s,1H),4.64(s,2H),3.74(d,1H),3.33(m,1H),2.14(s,3H),2.13(s,3H),2.11(s,6H)ppm.
实施例37
(1-乙基-丙基)-[2-(4-甲氧基甲基-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-胺
向在干燥THF中的{4-[4-(1-乙基-丙基氨基)-3,6-二甲基-吡啶-2-基氧]-3,5-二甲基-苯基}-甲醇的溶液中,加入在油中的60%NaOH和搅拌5min。加入过量MeI和在室温下搅拌2hr。在标准处理步骤和纯化之后,获得澄清金色油的标题化合物。1HNMR(CDCl3)d.7.02(s,2H),6.06(s,1H),4.40(s,3H),3.72(d,1H),3.39(s,3H),3.36(m,1H),2.12(s,3H),2.11(s,3H),2.10(s,6H),1.4-1.7(m,4H),0.95(t,6H)ppm.
实施例38
[2-(4-乙基-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-(1-乙基-丙基)-胺
在-78℃下,向在干燥THF中的[2-(4-溴-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-(1-乙基-丙基)-胺溶液中,加入正丁基锂。在-78℃下搅拌10min之后,加入碘乙烷和将获得的混合物在-78℃下搅拌30min,除去干冰浴。在搅拌5min之后,将混合物采用盐水骤冷和采用乙酸乙酯萃取。将有机层分离,干燥,浓缩到干燥。将残余物通过硅胶色谱纯化得到标题化合物。
1H NMR(CDCl3)d 6.89(s,2H),6.07(s,1H),3.72(d,1H),3.34(m,1H),2.58(q,2H),2.16(s,3H),2.12(s,3H),2.09(s,6H),1.4-1.7(m,4H),1.25(t,3H),0.96(t,6H)ppm.
实施例39
2-{4-[4-(1-乙基-丙基氨基)-3,6-二甲基-吡啶-2-基氧]-3,5-二甲基-苯基}-丙-2-醇
在-78℃下,向在干燥THF中的[2-(4-溴-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-(1-乙基-丙基)-胺溶液中,加入正丁基锂。在-78℃下搅拌10min之后,加入丙酮和将获得的混合物在-78℃下搅拌30min,除去干冰浴。在搅拌5min之后,将混合物采用盐水骤冷和采用乙酸乙酯萃取。将有机层分离,干燥,浓缩到干燥。将残余物通过硅胶色谱纯化得到标题化合物。
1H NMR(CDCl3)d 7.17(s,2H),6.08(s,1H),3.73(d,1H),3.33(m,1H),2.19(s,3H),2.15(s,3H),2.12(s,6H),1.4-1.7(m,4H),1.26(s,6H),0.96(t,6H)ppm.
实施例40
1-{4-[4-(1-乙基-丙基氨基)-3,6-二甲基-吡啶-2-基氧]-3,5-二甲基-苯基}-乙醇
在-78℃下,向在干燥THF中的[2-(4-溴-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-(1-乙基-丙基)-胺溶液中,加入正丁基锂。在-78℃下搅拌10min之后,加入乙醛并将获得的混合物在-78℃下搅拌30min,除去干冰浴。在搅拌5min之后,将混合物采用盐水骤冷并采用乙酸乙酯萃取。将有机层分离,干燥,浓缩到干燥。将残余物通过硅胶色谱纯化得到标题化合物。
1H NMR(CDCl3)d 7.06(s,2H),4.84(m,1H),6.08(s,1H),3.73(d,1H),3.35(m,1H),2.14(s,3H),2.12(s,3H),2.11(s,6H),1.4-1.7(m,4H),1.51(d,3H),0.96(t,6H)ppm.
实施例41
(1-乙基-丙基)-[2-(4-异丙烯基-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-胺
在苯中,在回流下,通过{2-4-[4-(1-乙基-丙基氨基)-3,6-二甲基-吡啶-2-基氧]-3,5-二甲基-苯基}-丙-2-醇与Burgess内盐(Et3NS(O)2NCOOMe)的反应30分钟,制备标题化合物。
1H NMR(CDCl3)d 7.17(s,2H).6.08(s,1H),5.34(s,1H),5.02(s,1H),3.72(d,1H),3.32(m,1H),2.12和2.15(两套s,12H),1.4-1.6(m,4H),0.97(t,6H)ppm.
实施例42
(1-乙基-丙基)-[2-(4-异丙基-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-胺
使用10%Pd/C作为催化剂,在乙酸乙酯中,在55psi下,通过(1-乙基-丙基)-[2-(4-异丙烯基-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-胺的氢化,制备标题化合物,直到所有的起始原料消耗完。在纯化之后,获得油状标题化合物。1H NMR(CDCl3)d 6.93(s,2H),6.10(s,1H),3.73(brs,1H),3.36(m,1H),2.18(s,3H),2.14(s,3H),2.12(s,6H),1.4-1.8(m,4H),1.27(d,6H),0 98(t,6H)ppm.
实施例43
[3,6-二甲基-[2-(2,4,6-三甲基-苯氧基)吡啶-4-基]-(1-乙基-烯丙基)-胺
采用氢化铝锂和氯化铝,通过4-(1-乙基-丙-2-炔基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸的还原,制备标题化合物,其为澄清油状物。1H NMR(CDCl3)d 6.87(s,2H),6.08(s,1H),5.7-5.9(m,1H),5.1-5.3(m,2H),3.75-4.0(m,2H),2.30(s,3H),2.16(s,3H),2.15(s,3H),2.08(s,6H),1.70(m,2H),1.03(t,3H)ppm.
实施例44
(1-乙基-丙基)-[2-(4-氟-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-胺
在-78℃下,向在干燥THF中的[2-(4-溴-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-(1-乙基-丙基)-胺溶液中,加入正丁基锂。在-78℃下搅拌10min之后,加入(PhSO2)2NF并将获得的混合物在-78℃下搅拌30min,除去干冰浴。在搅拌5min之后,将混合物采用盐水骤冷和采用乙酸乙酯萃取。将有机层分离,干燥,浓缩到干燥。将残余物通过硅胶色谱纯化得到标题化合物。
1H NMR(CDCl3)d 6.77(s,1H),6.73(s,1H),6.08(s,1H),3.3(m,1H),2.12(s,3H),2.09(s,6H),2.08(s,3H),1.4-1.8(m,4H),0.97(t,6H)ppm.
实施例45
2-[2-(2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基氨基]-丁-1-醇
通过相似于实施例33的方法制备标题化合物。
1H NMR(CDCl3)d 7.05(m,3H),6.24(s,1H),3.4-3.8(m,3H),2.24(s,3H),2.16(s,3H),2.10(s,6H),1.5-1.8(m,2H),0.99(t3H)ppm.
实施例46
2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-(S)-基氨基]-丁-1-醇
向在干燥THF中的2-(2,4,6-三甲基-苯氧基)-4-(1-羟甲基-丙基氨基)-6-甲基-烟酸甲酯的溶液中加入在乙醚(0.25ml)中的1.0M氢化铝锂和氯化铝。将获得的混合物在回流下加热2hr。将混合物采用水、2NaOH、然后水骤冷和搅拌。形成固体和将固体通过C盐过滤,然后采用水和乙酸乙酯洗涤。将有机层分离,干燥,浓缩,纯化得到为白色固体的标题化合物。元素分析C20H28N2O2. 1/2H2O计算值C,70.90;H,8.52;N,8.01;实测值C,71.18;H,8.66;N,8.30
通过相似于在前述段落中的方法,使用相应的2-(取代的苯氧基)-4-(烷基-氨基)-6-甲基-烟酸甲酯与氢化铝锂和氯化铝,制备如下的化合物。
3-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基氨基]-戊-2-醇
1H NMR(CDCl3)d 6.86(s,2H),6.17&6.13(两套s,1H),5.0-5.2(m,1H),4.9(s,2H),3.9-4.1(m,1H),3.5(m,1H),3.3(m,1H),2.29(s,3H),2.14(s,3H),2.08(s,6H),1.4-1.8(m,2H),1.27(m,3H),0.98(m,3H)ppm.
3-[2-(4-氯-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基氨基]-戊-2-醇
1H NMR(CDCl3)d 7.01(s,2H),6.14&6.11(two sets of s,1H),4.04&3.82(两套d,1H),3.92(m,1H),3.4&3.2(m,1H),2.13(s,3H),2.11(s,3H),2.05(s,6H),1.4-1.8(m,2H),1.25(两套d,3H),0.98&0.96(两套t,3H)ppm.
实施例47
苄基-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-乙基-胺
在回流下,将4-溴-3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶(250mg,0.78mmol),苄基乙胺(127mg,0.937mmol),Pd(OAc)2(3.6mg,0.0156mmol),(S)-2,2’-双(二苯基膦基)-1,1’-双萘(BINAP)(9.7mg,0.0156mmol),叔丁醇钾(105mg,0.781mmol)在25ml甲苯中的混合物加热2hr。将混合物冷到室温,采用水骤冷和采用乙酸乙酯萃取。将有机层分离,干燥(Na2SO4),过滤,浓缩得到棕色油。将粗产物通过硅胶柱色谱纯化得到标题化合物。1HNMR(CDCl3)d 7.2-7.4(m,5H),6.86(s,2H),6.41(s,1H),4.23(s,2H),3.07(q,2H),2.31(s,3H),2.29(s,3H),2.16(s,3H),2.06(s,6H),1.05(t,3H)ppm.
通过相似于前述段落中的方法,使用合适的4-溴-2-(取代的苯氧基)-3-甲基-6-烷基或烷氧基-吡啶与合适的胺,制备如下化合物。
[2-(4-氯-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-(1-甲氧基甲基-丙基)-胺
1H NMR(CDCl3)d 7.06(s,2H),6.13(s,1H),4.14(d,1H),3.3-3.6(m,3H),3.42(s,3H),2.16(s,3H),2.14(s,3H),2.09(s,6H),1.5-1.8(m,2H0,1.03(t,3H)ppm.
2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基氨基]-3-苯基-丙-1-醇
1H NMR(CDCl3)d 8.6(d,1H),7.2-7.4(m5H),6.84(s,2H),6.169s,1H),4.099d,1H),3.82(m,1H),3.5-3.7(m,2H),2.95(d,2H),2.96(s,3H),2.27(s,3H),2.14(s,3H),2.05(s,6H)ppm.
[2-(4-氯-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-(1-甲氧基甲基-丙基)-胺
1H NMR(CDCl3)d 7.06(s,2H),6.13(s,1H),4.2(m,1H),3.53(m,2H),3.42(s,3H),2.19(s,3H),2.14(s,3H),2.10(s,6H),1.5-1.8(m,2H),1.03(t,3H)ppm.
[2-(4-氯-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-(1-乙氧基甲基-丙基)-胺
1H NMR(CDCl3)d 7.06(s,2H),6.14(s,1H),4.24(d,1H),4.4-4.65(m,5H),2.19(s,3H),2.14(s,3H),2.10(s,6H),1.8(m,1H),1.65(m,1H),1.25(t,3H),1.03(t,3H)ppm.
[3,6-二甲基-2-(2,4,6-三甲氧基-苯氧基)-吡啶-4-基]-(1-甲氧基甲基-丙基)-胺
1H NMR(CDCl3)d 6.20(s,2H),6.08(s,1H),3.80(s,3H),3.73(s,6H),3.8(m,2H),3.39(m,1H),3.36(s,3H),2.23(brs,3H),2.10(s,3H),1.74(m,1H),1.59(m,1H),0.969t,3H)ppm.
[2-(4-溴-2,6-二甲基-苯氧基)-3-甲氧基-6-甲基-吡啶-4-基]-(1-乙基-丙基)-胺
1H NMR(CDCl3)d 7.18(s,2H),6.09(s,1H),4.43(d,1H),3.89(s,3H),3,25(m,1H),2.10(s,9H),1.4-1.8(m,4H),0.95(t,6H)ppm.
(1-乙基-丙基)-[3-甲氧基-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-胺
1H NMR(CDCl3)d6.85(s,2H),6.07(s,1H),4.44(m,1H),3.89(s,3H),3.23(m,1H),2.27(s,3H),2.09(s,6H),2.08(s,3H),1.65(m,2H),1.45(m,2H),0.93(m,6H)ppm.
[2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-3-丙基-吡啶-4-基]-(1-乙基-丙基)-胺
[2-(4-溴-2,6-二甲基-苯氧基)-6-甲基-3-丙基-吡啶-4-基]-(1-乙基-丙基)-胺
1H NMR(CDCl3)d 7.03(s,2H),6.13(s,1H),3.8(m,1H),3.74(s,2H),3.38(m,1H),2.15(s,3H),2.05(s,6H),1.50-1.7(m,4H),0.97(t,6H)ppm.
(1-乙基-丙基)-[6-甲基-3-丙基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-胺
[2-(2,4-二氯-6-甲基-苯氧基)-3-甲氧基-6-甲基-吡啶-4-基]-(1-乙基-丙基)-胺
1H NMR(CDCl3)7.24(d,1H),7.1(d,1H),6.1(s,1H),4.47(d,1H),3.9(s,3H),3.22(m,1H),2.12(s,3H),2.08(s,3H),1.4-1.7(m,4H),0.9(t,6H)ppm.
[2-(4-氯-2,6-二甲基-苯氧基)-3-甲氧基-6-甲基-吡啶-4-基]-(1-乙基-丙基)-胺
1H NMR(CDCl3)7.02(s,2H),6.07(s,1H),4.44(brs,1H),3.8-3.95(m,3H),3.23(m,1H),2.09(s,6H),2.08(s,3H),1.4-1.7(m,4H),0.93(t,6H)ppm.
[2-(4-氯-2,6-二甲基-苯氧基)-3-甲氧基-6-甲基-吡啶-4-基]-(1-甲氧基甲基-丙基)-胺
1H NMR(CDCl3)d 7.02(s,2H),6.11(s,1H),4.71(d,1H),3.88(s,3H),3.45(m,2H),3.37(s,3H),2.10(s,3H),2.09(s,6H),1.73(m,1H),1.59(m,1H),0.98(m,3H)ppm.
[2-(2,4-二氯-6-甲基-苯氧基)-3-甲氧基-6-甲基-吡啶-4-基]-(1-甲氧基甲基-丙基)-胺
1H NMR(CDCl3)d 7.1-7.25(m,2H),6.13(s,1H),4.74(d,1H),3.91(s,3H),3.47(m,1H),3.39(m,2H),3.37(s,3H),2.14(s,3H),2.10(s,3H),1.78(m,1H),1.59(m,1H),0.98(t,3H)ppm.
[2-(4-氯-2-甲氧基-苯氧基)-3-甲氧基-6-甲基-吡啶-4-基]-(1-甲氧基甲基-丙基)-胺
1H NMR(CDCl3)d 6.8-7.0(m,3H),6.17(s,1H),4.76(d,1H),3.82(s,3H),3.75(s,3H),3.3-3.5(m,3H),3.35(s,3H),2.19(s,3H),1.73(m,1H),1.56(m,1H),0.96(t,3H)ppm.
[2-(3-氯-2,6-二甲氧基-苯氧基)-3-甲氧基-6-甲基-吡啶-4-基]-(1-甲氧基甲基-丙基)-胺
1H NMR(CDCl3)d 7.12(d,1H),6.64(d,1H),6.12(s,1H)<4.73(d,1H),3.88(s,3H),3.78(s,3H),3.70(s,3H),3.3-3.5(m,3H),3.35(s,3H),2.11(s,3H),1.5-1.8(m,2H),0.96(t,3H)ppm.
(1-甲氧基甲基-丙基)-[3-甲氧基-6-甲基-2-(2,4,6-三甲氧基-苯氧基)-吡啶-4-基]-胺
1H NMR(CDCl3)d 6.19(s,2H),6.10s,1H),4.75(m,1H),3.87(s,3H),3.80(s,3H),3.73(s,6H),3.3-3.5(m,2H),3.35(s,3H),2.17(s,3H),1.78(m,1H),1.5(m,1H),0.96(t,3H)ppm.
[3-甲氧基-2-(4-甲氧基-2,6-二甲氧基-苯氧基)-6-甲基-吡啶-4-基]-(1-乙氧基甲基-丙基)-胺
1H NMR(CDCl3)d 6.59(s,2H),6.10(s,1H),4.70(d,1H),3.89s,3H),3.77(s,3H),3.48(m,1H),3.39(m,2H),3.37(s,3H),2.11(s,3H),2.10(s,6H),1.74(m,1H),1.57(m,1H),0.98(t,3H)ppm.
[2-(4-氯-2,6-二甲氧基-苯氧基)-3-乙氧基-6-甲基-吡啶-4-基]-(1-甲氧基甲基-丙基)-胺
1H NMR(CDCl3)d 7.07(s,2H),6.16(s,1H),4.82(d,1H),4.20(q,2H),3.54(m,1H),3.43(m,2H),3.42(s,3H),2.15(s,3H),2.13(s,6H),1.5-1.9(m,2H),1.439t,3H),1.02(t,3H)ppm.
实施例48
2-[2-(4-氯-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-(S)-基氨基]-丁-1-醇
在室温下,向在干燥THF中的[1-(叔丁基-二甲基-硅烷氧基甲基)-丙基]-[2-(4-氯-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-胺的溶液中加入在THF中的1M氟化四丁基铵。将混合物在室温下搅拌2hr,采用水骤冷,采用乙酸乙酯萃取。将有机层分离,干燥浓缩到干燥。使用在己烷中的15%乙酸乙酯作为洗脱剂,将残余物通过Biotage纯化,得到为白色固体的标题化合物。1HNMR(CDCl3)d 7.06(s,2H),6.18(s,1H),4.04(d,1H),3.74(m,1H),3.69(m,1H),3.53(m,1H),2.18(s,3H),2.16(s,3H),2.10(s,6H),1.6-1.8(m,2H),1.04(t,3H)ppm.
通过相似于前述段落的方法,采用相应的叔丁基-二烷基-硅烷氧基甲基衍生物和氟化四丁基铵,制备如下化合物。
2-[3-甲氧基-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-(S)-基氨基]-丁-1-醇
1H NMR(CDCl3)d 6.85(s,2H),6.15(s,1H),4.57(d,1H),3.91(s,3H),3.72(m,1H),3.61(m,1H),3.41(m,1H),2.27(s,3H),2.10(s,3H),2.07(s,6H),1.5-1.8(m,3H),0.98(t,3H)ppm.
2-[2-(4-氯-2,6-二甲氧基-苯氧基)-3-甲氧基-6-甲基-吡啶-4-基氨基]-丁-1-醇
1H NMR(CDCl3)d 7.02(s,2H),6.16(s,1H),4.60(d,1H),3.91(s,3H),3.71(m,1H),3.61(m,1H),3.40(m,1H),2.10(s,3H),2.08(s,6H),1.8(brs,1H),1.71(m,1H),1.68(m,1H),0.99(t,3H)ppm.
4-[4-(1-羟甲基-丙基氨基)-3-甲氧基-6-甲基-吡啶-2-基氧]-3,5-二甲基-苄腈
1H NMR(CDCl3)d 7.35(s,2H),6.19(s,1H),4.7(brs,1H),3.88(s,3H),3.731(m,1H),3.64(m,1H),3.43(m,1H),2.14(m,9H),1.8(brs,1H),1.71(m,1H),1.58(m,1H),0.99(t,3H)ppm.
实施例49
通过如下方式制备标题化合物:在室温下,通过2-[2-(4-氯-2,6-二甲氧基-苯氧基)-3,6-二甲基-吡啶-4-(S)-基氨基]-丁-1-醇二氯甲烷的Dess Martin氧化,随后通过在THF中使用溴化甲基镁进行格氏反应。1HNMR(CDCl3)d 7.07(s,2H),6.18(s,1H),4.3(brs,1H),3.32(m,1H),2.22(s,3H),2.17(s,3H),2.11(s,6H),1.6-1.8(m,2H),1.30(d,3H),1.01(t,3H)ppm.
实施例50
2-[2-甲基-6-(2,4,6-三甲基-苯氧基)-吡啶-4-基氨基]-丁-1-醇
在160℃下,通过加热2-(2,4,6-三甲基-苯氧基)-4-(S)-(1-羟甲基-丙基氨基)-6-甲基-烟酸直到所有的起始原料消耗完,制备标题化合物。元素分析C19OH26N2O2H2O计算值C,68.65;H,8.49;N,8.42;实测值C,69.04;H,8.14;N,8.91
实施例51
(1-乙基-丙-2-炔基)-[2-甲基-6-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-胺]
通过相似于实施例163的方法制备标题化合物。
1H NMR(CDCl3)d 6.89(s,2H),6.12(d,1H),5.41(d,1H),3.9-4.2(m,2H),2.37s,3H),2.30(s,3H),2.27(m,1H),1.76(m,2H),1.05(t,3H)ppm.
实施例52
2-(4-溴-2,6-二甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-吡啶-3-醇
在0℃下,向[2-(4-溴-2,6-二甲氧基-苯氧基)-3-甲氧基-6-甲基-吡啶-4-基]-(1-乙基-丙基)-胺在二氯甲烷中的溶液中加入BBr3并搅拌hr。将混合物采用水骤冷和采用氯仿萃取。将有机层分离,干燥,和浓缩得到标题化合物。1H NMR(CDCl3)d 7.20(s,2H),6.12(s,1H),4.77(d,1H),3.27(m,1H),2.13(s,3H),2.10(s,6H),1.4-1.8(m
通过相似于在前述段落中的方法,采用合适的[2-(取代苯氧基)-3-甲氧基-6-甲基-吡啶-4-基]-(烷基)-胺与BBr3或BCl3开始,制备如下化合物。
4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-醇
1H NMR(CDCl3)d6.85(s,2H),6.10(s,1H),5.12(brs,1H),4.21(m,1H),3.27(m,1H),2.28(s,3H),2.09(s,9H),1.5-1.8(m,4H),0.96(m,6H)ppm.
4-(S)-(1-羟甲基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-醇
1H NMR(CDCl3)d 6.85(s,2H),6.17(s,1H),5.13(brs,1H),4.28(d,1H),3.73(m,1H),3.60(m,1H),3.50(m,1H),2.27(s,3H),2.12(s,3H),2.07(s,6H),1.75(brs,1H),1.5-1.7(m,2H),0.99(t,3H)ppm.
2-(4-氯-2,6-二甲氧基-苯氧基)-4-(1-羟甲基-丙基氨基)-6-甲基-吡啶-3-醇
1H NMR(CDCl3)d 7.032(s,2H),6.10(s,1H),5.2(brs,1H),4.35(brs,1H),3.71(m,1H),3.61(m,1H),3.40(m,1H),2.07(s,9H),1.8(brs,1H),1.71(m,1H),1.60(m,1H),0.99(m,3H)ppm.
2-(4-氯-2,6-二甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-吡啶-3-醇
1H NMR(CDCl3)d 7.02(s,2H),6.10(s,1H),5.02(brs,1H),4.22(brs,1H),3.25(brs,1H),2.08(brs,9H),1.62(m,2H),1.52(m,2H),0.95(brs,6H)ppm.
实施例53
氯乙酸4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-基酯
在0℃到室温下,在THF中,通过使4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-醇和氯乙酰氯/三乙胺反应,制备标题化合物。
to rt.1H NMR(CDCl3)d 6.84(s,2H),6.15(s,1H),4.3(s,2H),4.0(d,1H),3.3(m,1H),2.28(s,3H),2.17(s,3H),2.08(s,6H),1/6-1.7(m,4H),0.9(t,6H)ppm.
实施例54
2-(4-氯-2,6-二甲氧基-苯氧基)-4-[(1-乙基-丙基氨基)-甲基-氨基]-6-甲基-吡啶-3-醇
1H NMR(CDCl3)d 7.03(s,2H),6.25(s,1H),5.4(brs,1H),3.93(m,1H),2.70(s,3H),2.12(s,3H),2.08(s,6H),1.55(m,4H),0.89(t,6H)ppm.
实施例55
[4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-基]-乙腈
1H NMR(CDCl3)d 6.87(s,2H),6.13(s,1H),3.83(d,1H),3.79(s,2H),3.38(m,1H),2.30(s,3H),2.27(s,3H),2.21(s,6H),1.4-1.8(m,4H),1.00(t,6H)ppm.
实施例56
4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-羰基醛
1H NMR(CDCl3)d 10.52(s,1H),9.26(d,1H),6.89(s,2H),6.11(s,1H),3.42(m,1H),2.31(s,3H0,2.15(s,3H),2.11(s,6H),1.45-1.75(m,4H),0.97(t,6H)ppm.
实施例57
(1-乙基-丙基)-[3-[(1-乙基-丙基亚氨基)-甲基]-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-胺
1H NMR(CDCl3)d 10.33(d,1H),8.94(s,1H),6.89(s,2H),6.10(s,1H),3.41(m,1H),2.86(m,1H),2.99(s,3H),2.14(s,3H),2.10(s,6H),1.4-1.89m,8H),0.94(t,6H),0.87(t,6H)ppm.
实施例58
2-[4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-基甲基]-丙二酸二甲酯
在室温下,在1hr之内,向丙二酸二甲酯(60mg,0.44mmol)和在油中60%NaH(20mg,0.44mmol)在干燥THF中的溶液中,加入[3-氯甲基-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-(1-乙基-丙基)-胺盐酸盐(50mg,0.146mmol)。将混合物采用水骤冷和采用乙酸乙酯萃取。将有机层分离,干燥浓缩到干燥。将残余物通过硅胶柱色谱纯化得到为澄清油的标题化合物。1HNMR(CDCl3)d 6.88(s,2H),6.03(s,1H),4.85(m,1H),4.03(t,1H),3.73(s,6H),3.26(m,1H),3.18(d,2H),2.30(s,3H),2.13s,3H),2.07(s,6H),1.5-1.8(m,4H),0.97(t,6H)ppm.
实施例59
2-[4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-基甲基]-丙二酸二并丙酯
通过相似于实施例581的方法制备标题化合物。1H NMR(CDCl3)d 6.87(s,2H),6.03(s,1H),5.10(m,2H),4.90(d,1H),3.94(t,1H),3.31(m,1H),3.16(d,2H),2.30(s,3H),2.13s,3H0,2.08(s,6H),1.5-1.8(m,4H),1.1-1.3(两套d,6H),0.97(t,6H)ppm.
实施例60
4-(1-乙基-丙氧基)-6-甲基-3-硝基-2-(2,4,6-三甲基-苯氧基)-吡啶
向2-氯-4-(1-乙基-丙氧基)-6-甲基-3-硝基-吡啶(500mg,1.93mmol)和2,4,6-三甲基苯酚(289mg,2.13mmol)在干燥THF中的混合物中加入叔丁醇钾。将获得的混合物在室温下搅拌过夜。将混合物采用水,盐水骤冷和采用乙酸乙酯萃取3次。将有机层分离,干燥(MgSO4)浓缩到干燥。在硅胶柱色谱纯化之后,以淡黄色晶体获得标题化合物。mp 106-109℃.元素分析C20H26N2O4计算值C,67.02;H,7.31;N,7.82;实测值,C,67.34;H,7.40;N,7.42.
实施例61
4-(1-乙基-丙氧基)-6-甲基-3-硝基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-基胺
在50psi下,将4-(1-乙基-丙氧基)-6-甲基-3-硝基-2-(2,4,6-三甲基-苯氧基)-吡啶(150mg,0.418mmol)和10%Pd/C(23mg)在乙醇中的混合物氢化15小时。加入另外的10Pd/C并将获得的混合物氢化另外24hr。将混合物通过C盐过滤和将滤液浓缩到干燥,得到200mg粗材料。在柱色谱之后,得到标题化合物相应的HCl盐,为白色固体,mp 96-98℃。
实施例62
[4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-基]-二甲胺
在-78℃下,向在干燥THF中的4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-基胺的溶液中,加入双(三甲基甲硅烷基)酰胺锂。在-78℃下搅拌10分钟之后,加入过量碘甲烷。在采用水骤冷和采用乙酸乙酯萃取之后,分离标题化合物。通过硅胶柱色谱纯化粗材料,得到为褐色泡沫状的标题化合物。
实施例63
N-[4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-基]-琥珀酰胺酸
在室温下,将4-(1-乙基-丙氧基)-6-甲基-3-硝基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-基胺(100mg,0.304mmol),琥珀酸酐(31mg,0.304mmol)和三乙胺在二氯甲烷中的混合物搅拌过夜。将混合物采用水骤冷,并采用二氯甲烷萃取。将有机层分离,干燥和浓缩得到固体。在硅胶柱色谱之后,分离标题化合物,其为白色晶体。
1H NMR(CDCl3)d 6.90(brs,1H),6.84(s,2H),6.37(s,1H),4.2(m,1H),2.6-2.8(m,4H),2.28(s,3H),2.22(s,3H),2.03(s,6H),1.69(m,4H),0.94(t,6H)ppm.
实施例64
4-(1-乙基-丙氧基)-3,6-二甲基-2-[3-(2,4,6-三甲基-吡啶氧基)]-吡啶
向3-戊醇(0.11ml)在干燥THF中的溶液中,加入氢化钠(在油中60%,20mg)。在搅拌5min之后,加入在THF中的4-氯-2,5-二甲基-6-[3-(2,4,6-三甲基-吡啶氧基)]-吡啶(92mg,0.332mmol)的溶液。加入DMSO并将获得的混合物在130℃油浴下加热过夜。将混合物采用水、盐水骤冷和采用乙酸乙酯萃取3次。将有机层分离,干燥(MgSO4)浓缩到干燥。在硅胶柱色谱纯化之后,以澄清油获得标题化合物。
1H NMR(CDCl3)d 6.88(s,1H),6.37(s,1H),4.21(m,1H),2.5(s,3H),2.29(s,3H),2.19(s,3H),2.18(s,3H),2.07(s,3H),1.70(m,4H),0.98(t,6H)ppm.
将油制备为相应的HCl盐得到白色固体(63mg)。
通过相似于在实施例64的方法,采用合适的6-烷基-4-氯-或溴-3-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶与3-戊醇/NaH开始,制备如下实施例65和66的标题化合物:
实施例65
6-乙基-4-(1-乙基-丙氧基)-3-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶
1H NMR(CDCl3)d 6.87(s,2H),6.28(s,1H),4.20(m,1H),2.46(q,2H),2.30(s,3H),2.20(s,3H),2.07(s,6H),1.72(m,4H),1.05(t,3H),0.99(t,6H)ppm.
实施例66
4-(1-乙基-丙氧基)-2-(4-氟-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶
无色油。元素分析C20H26FNO2计算值C,72.48;H,7.91;N,4.23;实测值C,72.39;H,7.77;N,4.10.
实施例67
[4-(1-乙基-丙氧基)-3,6-二甲基-吡啶-2-基]-(2,4,6-三甲基-苯基)-胺
向在干燥THF的4-(1-乙基-丙氧基)-6-甲基-(2,4,6-三甲基-苯基氨基)-烟酸(240mg,0.673mmol)的溶液中,加入氢化铝锂和氯化铝。将获得的混合物在回流下加热3小时。将混合物采用0.1ml水和0.1ml2N NaOH骤冷,然后采用水和乙酸乙酯骤冷,分离有机层、干燥、浓缩,得到250mg棕色油。在硅胶柱色谱之后,获得170mg(78%)标题化合物,将它制备为HCl盐得到标题化合物,为白色固体。mp.132-133℃.1H NMR(CDCl3)d 6.87(s,2H),6.09(s,1H),5.399brs,1H),4.13(m,1H),2.27(s,3H),2.22(s,3H),2.15(s,6H),1.98(s,3H),1.67(m,4H),0.94(t,6H)ppm.
实施例68
[4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-吡啶-3-基]-甲醇
向在干燥THF的4-(1-乙基-丙氧基)-6-甲基-(2,4,6-三甲基-苯基氨基)-烟酸(100mg,0.281mmol)的溶液中,加入BH3.DMS。将获得的混合物在回流下加热过夜。将混合物采用稀HCl骤冷和搅拌30分钟,调节pH到7.5-8.5,然后采用乙酸乙酯萃取。将有机层分离,干燥和浓缩得到100mg棕色油。在硅胶柱色谱之后,获得91mg(95%)标题化合物,为白色泡沫状。元素分析C21H30N2O2.1/2H2O计算值C,71.76;H,8.89;N,7.97;实测值C,71.97;H,8.90;N,7.69.
实施例69
[4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-吡啶-3-基]-氧代-乙腈
通过如下方式制备标题化合物:在苯中使[4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-吡啶-3-基]-甲醇和亚硫酰氯反应,浓缩到干燥,随后与氰化二乙基铝反应。在标准处理步骤和硅胶柱色谱之后,获得为黄色晶体的标题化合物,mp.108-110℃。
1H NMR(CDCl3)d 8.57(s,1H),6.97(s,2H),6.37(s,1H),4.46(m,1H),2.35(s,3H),2.34(s,3H),2.09(s,6H),1.6-1.8(m,4H),0.99(t,6H)ppm.
实施例70
[4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-吡啶-3-基]-咪唑-1-基-甲酮(methanone)
向在2ml DMF中的4-(1-乙基-丙氧基)-6-甲基-(2,4,6-三甲基-苯基氨基)-烟酸(250mg,0.701mmol)的溶液中,加入羰基二咪唑(190mg,1.19mmol)并将获得的混合物在室温下搅拌过夜。在标准处理步骤和硅胶柱色谱之后,获得为金色晶体的260mg(91.2%)标题化合物mp.120-122℃,元素分析C24H30N4O2.1/4H2O计算值:C,70.13;H,7.48;N,13.63;实测值:C,70.06;H,7.69;N,13.37.
实施例71
2-[4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-吡啶-3-基]-丙-2-醇
通过在THF中,在室温下使[4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-吡啶-3-基]-咪唑-1-基-甲酮和过量MeMgBr反应,获得标题化合物。在标准处理步骤和硅胶柱色谱之后,获得为褐色固体的标题化合物。mp.81-83℃,元素分析C22H30N2O2.1.5H2O计算值:C,69.49;H,9.38;N,7.04;实测值:C,69.49;H,9.27;N,6.86
实施例72
2-[4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-吡啶-3-基甲基]-丙二酸二甲酯
通过如下方式制备标题化合物:在苯中使[4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-吡啶-3-基]-甲醇和亚硫酰氯反应,浓缩到干燥,随后在DMSO中与丙二酸甲酯/NaH反应。在标准处理步骤和硅胶柱色谱之后,获得为固体的标题化合物mp.96-98℃;元素分析C26H36N2O5.1/3H2O计算值:C,67.51;H,7.99;N,6.04;实测值:C,67.48;H,7.99;N,6.02.
实施例73
3-[4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-吡啶-3-基]-丙酸
在回流下,进行磷酸/水的2-[4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-吡啶-3-基甲基]-丙二酸二甲酯的水解,得到为白色泡沫的标题化合物。元素分析C23H32N2O3.3/4H2O计算值:C,69.40;H,8.48;N,7.04;实测值:C,69.17;H,8.62;N,6.90.
实施例74
[3-氨基甲基-4-(1-乙基-丙氧基)-6-甲基-吡啶-2-基]-(2,4,6-三甲基-苯基)-胺
通过如下方式制备标题化合物:在苯中将[4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-吡啶-3-基]-甲醇与亚硫酰氯反应,浓缩到干燥,随后在室温下与NH3(g)反应。在标准处理步骤和硅胶柱色谱之后,获得为金色油(80%)的标题化合物,元素分析C21H31N3O.计算值:C,73.86;H,9.15;N,12.3;实测值:C,73.50;H,9.25;N,11.39.
实施例75
2-氯-N-[4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-吡啶-3-基甲基]-乙酰胺
通过采用氯乙酰氯进行3-氨基甲基-4-(1-乙基-丙氧基)-6-甲基-吡啶-2-基]-(2,4,6-三甲基-苯基)-胺的酰基化,制备标题化合物。在标准处理步骤和硅胶柱色谱之后,获得为灰白结晶的标题化合物,mp.142-144℃,元素分析C23H32ClN3O2.计算值:C,66.09;H,7.72;N,10.05;实测值:C,65.81;H,7.64;N,9.86.
实施例76
[3-二甲基氨基甲基-4-(1-乙基-丙氧基)-6-甲基-吡啶-2-基]-(2,4,6-三甲基-苯基)-胺盐酸盐
通过如下方式制备标题化合物:在苯中将[4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-吡啶-3-基]-甲醇与亚硫酰氯反应,浓缩到干燥,随后在室温下与二甲胺反应。在标准处理步骤和硅胶柱色谱之后,获得为油的标题化合物。制备相应的HCl盐为白色固体,mp.85-88℃,元素分析C23H35N3O.2HCl.1.5H2O计算值:C,58.83;H,8.588;N,8.94;实测值:C,58.32;H,8.5327;N,8.64.
实施例77
二硫代碳酸O-乙酯S-[4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-吡啶-3-基甲基]-酯
通过如下方式制备标题化合物:在苯中将[4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-吡啶-3-基]-甲醇与亚硫酰氯反应,浓缩到干燥,随后在室温下与NaSCSOEt反应。在标准处理步骤和硅胶柱色谱之后,获得为白色固体的标题化合物。mp.55-57℃,元素分析C24H34N2O2S2.计算值:C,64.54;H,7.67;N,6.27;实测值:C,64.67;H,7.78;N,6.26.
实施例78
4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-烟酰胺
通过如下方式制备标题化合物:在苯中将4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-烟酸与亚硫酰氯反应,浓缩到干燥,随后在室温下与NH3(g)反应。在标准处理步骤和硅胶柱色谱之后,获得为油的标题化合物。制备相应的HCl盐为灰白色固体,mp.185-187℃;元素分析C21H29N3O2.计算值:C,70.96;H,8.22;N,11.82;实测值:C,71.30;H,8.33;N,11.78.
实施例79
4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-烟腈
在THF中,通过使4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-烟酰胺和三光气/三乙胺反应,制备标题化合物,mp105-107℃。1HNMR(CDCl3)d6.90(s,2H),6.26(brs,1H),6.05(s,1H),4.24(m,1H),2.28(s,3H),2.25(s,3H),2.17(s,6H),1.72(m,H),0.97(t,6H)ppm.
实施例80
4-(1-乙基-丙氧基)-6,N,N-三甲基-2-(2,4,6-三甲基-苯基氨基)-烟酰胺
通过如下方式制备标题化合物:在苯中将4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)烟酸与亚硫酰氯反应,浓缩到干燥,随后在室温下与二甲胺反应。在标准处理步骤和硅胶柱色谱之后,获得为油的标题化合物。制备相应的HCl盐为白色固体。mp.197-200℃,元素分析C23H33N3O2.H2O.计算值:C,63.07;H,8.28;N,9.59;实测值:C,63.24;H,8.07;N,9.61.
实施例81
[4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-吡啶-3-基]-乙腈
通过如下方式制备标题化合物:在苯中将[4-(1-乙基-丙氧基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-吡啶-3-基]-甲醇与亚硫酰氯反应,浓缩到干燥,随后在DMSO中在室温下与氰化钾反应。在标准处理步骤和硅胶柱色谱之后,获得为淡橙色固体的标题化合物。mp.112-115℃。1H NMR(CDCl3)d 6.9(s,2H),6.14(s,1H),5.6(brs,1H),4.22(m,1H),3.49(s,2H),2.28(s,3H),2.22(s,3H),2.16(s,6H),1.71(m,4H),0.95(t,6H)ppm.
实施例82
[2-(4-溴-2,6-二甲基-苯基氨基)-4-(1-乙基-丙氧基)-6-甲基--吡啶-3-基]-甲醇
向在干燥THF中的4-(1-乙基-丙氧基)-6-甲基-2-(4-溴-2,6-二甲基-苯基氨基)-烟酸(130mg,0.309mmol)的溶液中,加入BH3.DMS。将获得的混合物在回流下加热过夜。将混合物采用稀HCl骤冷和搅拌30分钟,调节pH到7.5-8.5,然后采用乙酸乙酯萃取。将有机层分离,干燥和浓缩得到100mg棕色油。在硅胶柱色谱之后,获得110mg(87.3%)标题化合物,为白色半固体。
1H NMR(CDCl3)d 7.25(s,2H),6.85(brs,1H),4.8(brs,2H),4.18(m,1H),2.2(s,3H),2.07(s,6H),1.7(m,4H),0.95(t,6H)ppm.
实施例83
[2-(4-氯-2,6-二甲基-苯基氨基)-4-(1-乙基-丙氧基)-6-甲基--吡啶-3-基]-甲醇
向在干燥THF中的4-(1-乙基-丙氧基)-6-甲基-2-(4-氯-2,6-二甲基-苯基氨基)-烟酸的溶液中,加入BH3.DMS。将获得的混合物在回流下加热过夜。将混合物采用稀HCl骤冷和搅拌30分钟,调节pH到7.5-8.5,然后采用乙酸乙酯萃取。将有机层分离,干燥和浓缩得到棕色油。在硅胶柱色谱之后,获得标题化合物,为绿色油。
1H NMR(CDCl3)d 7.02(s,2H),6.83(brs,1H),4.78(s,2H),4.14(m,1H),2.2(s,3H),2.13(s,6H),1.66(m,4H),0.93(9t,6H)ppm.
实施例84
[2-(2,4-二氯-苯基氨基)-4-(1-乙基-丙氧基)-6-甲基-吡啶-3-基]-甲醇
向在干燥THF中的4-(1-乙基-丙氧基)-6-甲基-2-(2,4-二氯-苯基氨基)-烟酸的溶液中,加入BH3.DMS。将获得的混合物在回流下加热过夜。将混合物采用稀HCl骤冷和搅拌30分钟,调节pH到7.5-8.5,然后采用乙酸乙酯萃取。将有机层分离,干燥和浓缩得到金色油。在硅胶柱色谱之后,获得标题化合物,为金色油。
1H NMR(CDCl3)d 8.44(d,1H),8.18(s,1H),7.32(d,1H),7.179d,1H),6.28(s,1H),4.82(s,2H),4.21(m,1H),2.42(s,3H),1.6-1.8(m,4H),0.94(t,6H)ppm.
实施例85
[2-(2,4-二甲氧基-苯基氨基)-4-(1-甲氧基甲基-丙氧基)-6-甲基-吡啶-3-基]-甲醇
通过相似于实施例84中的方法,采用相应的烟酸和BH3.DMS开始,制备标题化合物。1H NMR(CDCl3)d6.91(d,1H),6.50(m,2H),5.91(s,1H),4.42(m,1H),4.281(s,2H),3.79(s,3H),3.76(s,3H),3.56(m,2H),3.40(s,3H),2.33(s,3H),1.6-1.8(m,2H),1.02(t,3H)ppm.
实施例86
[4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-吡啶-3-基]-咪唑-1-基-甲酮
通过相似于实施例70中的方法,采用相应的烟酸和羰基二咪唑开始,制备标题化合物。
1HNMR(CDCl3)d 8.1(s,1H),7.52(s,1H),7.05(s,1H),6.78(s,2H),6.17(s,1H),5.97(d,1H),3.3(m,1H),2.23(s,3H),2.18(s,3H),2.00(s,6H),1.4-1.7(m,4H),0.93(t,6H)ppm.
实施例87
1-[4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-基]-乙酮
在二氯甲烷中,通过使[4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-基]-咪唑-1-基-甲酮和溴化甲基镁/乙醚反应,制备标题化合物。1H NMR(CDCl3)d 9.7(d,1H),6.88(s,2H),6.10(s,1H),3.32(m,1H),2.73(s,3H),2.31(s,3H),2.10(s,3H),2.09(s,6H),1.5-1.7(m,4H),0.95(t,6H)ppm.
实施例88
(1-乙基-丙基)-[6-甲基-3-丙基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-胺
1H NMR(CDCl3)d 6.84(s,2H),6.04(s,1H),3.81(d,1H),3.31(m,1H),2.56(t,2H),2.27(s,3H),2.12(s,3H),2.04(s,6H),1.4-1.7(6H),1.02(t,3H),0.93(t,6H)ppm.
实施例89
2-[4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-吡啶-3-基甲基]-丙二酸二甲酯
通过相似于实施例72中的方法,制备标题化合物。
1H NMR(CDCl3)6.87(s,2H),6.01(s,1H),5.05(m,1H),3.70(s,6H),3.4(s,2H),3.3(m,1H),2.27(s,3H),2.12(s,3H),2.07(s,6H),1.4-1.7(m,4H),1.48(s,3H),0.949t,6H)ppm.
实施例90
[4-(1-乙基-丙氧基)-6-甲基-吡啶-2-基]-(2,4,6-三甲基-苯基)-胺
在160℃油浴中,通过相应烟酸的脱羧化,制备标题化合物。mp.98-100℃;元素分析C20H28N2O计算值C,76.88;H,9.03;N,8.97;实测值:C,76.97;H,9.21;N,8.99.
通过3-甲氧基-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-羰基醛和溴化烷基镁在THF中的反应,制备实施例204和205的如下化合物:
实施例91
2-乙基-1-[3-甲氧基-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-丁-1-醇
1H NMR(CDCl3)6.87(s,2H),6.72(s,1H),4.90(t,1H),4.00(s,3H),2.29(s,3H),2.19(s,3H),2.06(s,6H),1.2-1.6(m,5H),0.92(t,3H),0.88(t,3H)ppm.
实施例92
1-[3-甲氧基-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-2-甲基-丁-1-醇
1H NMR(CDCl3)6.88(s,2H),6.74(s,1H),5.00(m,1H),4.00(s,3H),2.29(s,3H),2.19(s,3H),2.06(s,6H),1.4-1.9(m,3H),0.992(t,3H),0.989(d,3H)ppm.
实施例93
1-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-丙-1-醇
向-78℃在干燥THF中的4-溴-3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶的溶液中,加入nBuLi并在该温度下搅拌20分钟。加入过量丙醛和在-78℃下搅拌2小时。将混合物采用水骤冷,采用乙酸乙酯萃取。将有机层采用盐水洗涤,干燥和浓缩。在柱色谱之后,获得灰白色固体。mp.119-120℃。
1H NMR(CDCl3)d 6.86(s,3H),4.90(m,1H),2.281(s,3H),2.28(s,3H),2.21(s,3H),2.02(s,6H),1.65-1.8(m,2H),1.00(t,3H)ppm.
实施例94
4-(1-甲氧基-丙基)-3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶
通过如下方式制备标题化合物:1-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-丙-1-醇和氢化钠的反应,随后采用碘甲烷骤冷。
1H NMR(CDCl3)d 6.87(s,2H),6.74(s,1H),4.33(m,1H),3.25(s,3H),2.28(s,3H),2.27(s,3H),2.21(s,3H),2.03(s,6H),1.6-1.8(m,2H),0.94(t,3H)ppm.
实施例95
4-(1-乙氧基-丙基)-3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶
通过如下方式制备标题化合物:使1-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-丙-1-醇和氢化钠反应,随后采用碘乙烷骤冷。
1H NMR(CDCl3)d 6.86(s,2H),6.77(s,1H),4.41(m,1H),3.22-3 45(m,2H),2.28(s,3H),2.27(s,3H),2.21(s,3H),2.03(s,6H),1.6-1.8(m,2H),1.20(t,3H),0.95(t,3H)ppm.
实施例96
4-(1-烯丙氧基-丙基)-3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶
通过如下方式制备标题化合物:使1-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-丙-1-醇和氢化钠反应,随后采用烯丙基溴骤冷。
1H NMR(CDCl3)d 6.87(s,2H),6.78(s,1H),5.93(m,1H),5.1-5.3(m,2H),4.48(m,1H),3.95(m,1H),3.76(m,1H),2.29(s,3H),2.26(s,3H),2.21(s,3H),2.03(s,6H),1.6-1.8(m,2H),0.96(t,3H)ppm.
实施例97
4-(1-丁氧基-丙基)-3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶
通过如下方式制备标题化合物:使1-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-丙-1-醇和氢化钠反应,随后采用碘丁烷骤冷。
1H NMR(CDCl3)d 6.86(s,2H),6.76(s,1H),4.37(m,1H),3.35(m,1H),3.25(m,1H),2.28(s,3H),2.26(s,3H),2.20(s,3H),2.03(s,6H),1.6-1.8(m,2H),1.5-1.65(m,2H),1.3-1.5(m,2H),0.96(t,3H),0.89(t,3H)ppm.
通过相似于实施例93中的方法,采用合适的4-溴-2-(取代苯氧基)-吡啶衍生物与nBuLi反应,随后采用合适的醛骤冷,制备如下实施例98-102的标题化合物。
实施例98
1-[2-(2,4-二氯-6-甲基-苯氧基)-3-甲氧基-6-甲基-吡啶-4-基]-2-乙基-丁-1-醇
一个消旋体1H NMR(CDCl3)d 7.28(d,1H),7.14(d4.00(s,3H),2.21(s,3H),2.13(s,3H),1.3-1.65(m,5H),0.93(t,3H),0.87(t,3H)ppm.
另一个消旋体1H NMR(CDCl3)d 7.18(s,1H),7.08(d,1H),6.74(d,1H),5.17(m,1H),3.93(s,3H),2.75(m,1H),2.1-2.25(m,1H),2.16(s,3H),2.13(s,3H),1.6-1.8(m,2H),1.0-1.3(m,2H),0.93(t,3H),0.72(t,3H)ppm.
实施例99
1-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-2,2,2-三氟-乙醇
mp.134-139℃,元素分析C18H20F3NO2计算值:C,63.71;H,5.94;N,4.13;实测值:C,63.59;H,6.00;N,4.02.
实施例100
1-[2-(4-氯-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-2,2,2-三氟-乙醇
1H NMR(CDCl3)d 6.979s,2H),6.19(s,1H),2.14(s,6H),2.06(s,6H)ppm.
实施例101
[2-(4-氯-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-吡啶-2-基-甲醇
1H NMR(CDCl3)d 8.61(d,1H),7.71(m,1H),7.30(m,1H),7.10(m,1H),7.03(s,2H),6.70(s,1H),6.03(s,1H),2.37(s,3H),2.16(s,3H),2.03(s,6H),ppm.
实施例102
1-[2-(4-氯-2,6-二甲基-苯氧基)-3-甲氧基-6-甲基-吡啶-4-基]-2-乙基-丁-1-醇
1H NMR(CDCl3)d 7.05(s,2H),6.759s,1H),4.90(t,1H),3.98(s,3H),2.19(s,3H),2.06(s,6H),2.13(d,1H),1.25-1.65(m,5H),0.92(t,3H),0.87(t,3H)ppm.
通过在DMSO/二氯甲烷中采用Dess Martin试剂或在二氯甲烷中采用氯铬酸吡啶鎓氧化相应醇,制备如下实施例103-106的标题化合物。
实施例103
1-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-丙-1-酮
mp.82-85.5℃,元素分析C19H25NO2计算值:C,76.74;H,7.80;N,4.71;实测值:C,76.61;H,7.94;N,4.66.
实施例104
1-[2-(4-氯-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-2,2,2-三氟-乙酮
1H NMR(CDCl3)d 7.06(s,2H),6.99(s,1H),2.42(s,3H),2.30(s,3H),2.03(s,6H)ppm.
实施例105
[2-(4-氯-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-吡啶-2-基-甲酮
1H NMR(CDCl3)d 8.72(d,1H),8.17(d,1H),7.95(m,1H),7.52(m,1H),7.05(s,2H),6.75(s,1H),2.25(s,3H),2.22(s,3H),2.07(s,6H)ppm.
实施例106
1-[2-(4-氯-2,6-二甲基-苯氧基)-3-甲氧基-6-甲基-吡啶-4-基]-2-乙基-丁-1-酮
1H NMR(CDCl3)d 7.05(s,2H),6.67(s,1H),3.98(s,3H),3.09(m,1H),2.61(s,3H),2.06(s,6H),1.76(m,2H),1.51(m,2H),0.92(t,6H)ppm.
实施例107
4-(1-乙氧基-2,2,2-三氟-乙基)-3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶
通过如下方式制备标题化合物:使相应的醇和NaH反应,随后采用碘乙烷骤冷。
1H NMR(CDCl3)d 6.92(s,1H),6.87(s,2H),4.92(m,1H),3.60(m2H),2.349s,3H),2.29(s,3H),2.26(s,3H),2.03(s,6H),1.26(t,3H)ppm.
通过相应的酮与烷基锂或烷基镁反应,制备如下实施例108-109的标题化合物。
实施例108
2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-丁-2-醇
1H NMR(CDCl3)d 6.86(m,3H),2.48(s,3H),2.28(s,3H),2.21(s,3H),2.02(s,6H),1.8-2.1(m,2H),1.61(s,3H),0.84(t,3H)ppm.
实施例109
3-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-戊-3-醇
1H NMR(CDCl3)d 6.87(s,1H),6.86(s,2H),2.43(s,3H),2.28(s,3H0,2.21(s,3H),2.0-2.2(m,2H),2.02(s,6H),1.7-1.9(m,2H),1.69(brs,1H),0.8(t,6H)ppm.
实施例110
1-[2-(4-氯-2,6-二甲基-苯氧基)-3-羟基-6-甲基-吡啶-4-基]-2-乙基-丁-1-酮
在THF或二氯甲烷中,使1-[2-(4-氯-2,6-二甲基-苯氧基)-3-甲氧基-6-甲基-吡啶-4-基]-2-乙基-丁-1-酮BBr3和BCl3反应,制备标题化合物。
1H NMR(CDCl3)d 7.04(s,2H),7.01(s,1H),3.26(m,1H),2.24(s,3H),2.08(s,6H),1.80(m,2H),1.63(m,2H),0.91(t,6H)ppm.
实施例111
4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酰胺
向在无水二氯甲烷中的4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟酸溶液中,加入亚硫酰氯。在搅拌1hr之后,将反应混合物浓缩到干燥。将残余物溶于干燥THF并将NH3(g)鼓泡加入。将反应混合物采用水骤冷和采用乙酸乙酯萃取。将有机层分离,干燥和浓缩得到淡黄色固体。使用在氯仿中的1%甲醇作为洗脱剂,将固体通过硅胶柱色谱纯化,得到为白色固体的标题化合物。mp.85-88℃.1H
NMR(CDCl3)d 9.69(brs,1H),8.01(brs,1H),6.87(s,2H),6.11(s,1H),5.48(brs,1H),3.31(m,1H),
2.29(s,3H),2.10(s,3H),2.07(s,6H),1.60(m,4H),0.95(t,6H)ppm.
通过相似于在前述段落中描述的方法,采用相应烟酸或吡啶-5羧酸衍生物开始并采用合适亲核试剂骤冷,制备如下实施例112-118的标题化合物。
实施例112
4-(1-乙基-丙基氨基)-6,N-二甲基-2-(2,4,6-三甲基-苯氧基)-烟酰胺
1H NMR(CDCl3)d 9.8(brs,1H),8.21(brs,1H),6.88(s,2H),6.11(s,1H),3.31(m,1H),2.92(d,3H),2.30(s,3H),2.10(s,3H).2.07(s,6H),1.60(m,4H),0.95(t,6H)ppm.
实施例113
2-(4-氯-2,6-二甲基-苯氧基)-4-(S)-(1-羟甲基-丙基氨基)-6-甲基-烟酰胺
1H NMR(CDCl3)d 9.7(d,1H),7.9(brs,1H),7.0(s,2H),6.2(s,1H),5.6(brs,1H),3.7(m,1H),3.66(m,1H),3.54(m,1H),2.07(s,3H),2.068(s,3H),2.06(s,3H),1.7(m,1H),1.6(m,1H),0.99(t,3H)ppm
实施例114
2-(4-氯-2,6-二甲基-苯氧基)-4-(S)-(1-羟甲基-丙基氨基)-6-甲基-烟酰肼
1H NMR(CDCl3)d 9.15(s,1H),7.04(s,2H),6.23(s,1H),3.6-3.8(m,2H),3.53(m,1H),2.08(s,6H),2.05(s,3H),2.04(s,3H),1.5-1.8(m,2H),1.01(t,3H)ppm.
实施例115
2-(4-氯-2,6-二甲基-苯氧基)-N-乙基-4-(S)-(1-羟甲基-丙基氨基)-6-甲基-烟酰胺
1H NMR(CDCl3)d 9.74(d,1H),8.12(s,1H),7.05(s,2H),6.23(s,1H),3.5-3.8(m,3H),3.43(m,2H),2.06(s,9H),1.8(brs,1H),1.5-1.7(m,2H),1.19(t,3H),1.00(t,3H)ppm.
实施例116
2-(4-氯-2,6-二甲基-苯氧基)-4-(S)-(1-羟甲基-丙基氨基)-6,N-二甲基-烟酰胺
1H NMR(CDCl3)d 9.80(d,1H),8.12(s,1H),7.04(s,2H),6.22(s,1H),3.5-3.8(m,3H),2.93(d,3H),2.06(s,9H),1.8(brs,1H),1.5-1.7(m,2H),0.99(t,3H)ppm.
实施例117
2-(4-氯-2,6-二甲基-苯氧基)-N-环戊基-4-(S)-(1-羟甲基-丙基氨基)-6-甲基-烟酰胺
1H NMR(CDCl3)d 9.69(d,1H),8.13(d,1H),7.04(s,2H),6.22(s,1H),4.35(m,1H),3.4-3.8(m,3H),2.056(s,9H),1.4-2.0(m,10H),0.99(t,3H)ppm.
实施例118
2-(4-氯-2,6-二甲基-苯氧基)-N-环丙基甲基-4-(S)-(1-羟甲基-丙基氨基)-6-甲基-烟酰胺
1H NMR(CDCl3)d 9.71(d,1H),8.24(s,1H),7.05(s,2H),6.23(s,1H),3.5-3.8(m,3H),3.27(t,2H),2.08(s,6H),2.07(s,3H),1.8(brs,1H),1.5-1.75(m,2H),0.99(t,3H),0.46(m,2H),0.21(m,2H)ppm.
通过相似于实施例224中的方法,制备如下实施例232-236的标题化合物。
实施例119
4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-烟酰胺
棕色固体,mp.204-206℃。
实施例120
4-(1-乙基-丙氧基)-2-甲基-6-(2,4,6-三甲基-苯基氨基)-嘧啶-5-羧酸酰胺
Mp.174-176℃;元素分析C20H28N4O2计算值:C,67.39;H,7.92;N,15.72;实测值:C,67.90;H,8.19;N,14.66.1H NMR(CDCl3)d 7.95(s,1H),6.89(s,2H),5.58(s,1H),5.4(m,1H),2.28(s,3H),2.25(s,3H),2.15(s,6H),1.75(m,4H),0.96(t,6H)ppm.
实施例121
4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯氧基)-烟腈
1H NMR(CDCl3)d 6.85(s,2H),6.06(s,1H),4.72(d,1H),3.36(m,1H),2.28(s,3H),2.17(s,3H),2.09(s,6H),1.5-1.8(m,4H),0.96(t,6H)ppm.
实施例122
[4-(1-乙基-丙氧基)-6-甲基-3-硝基-吡啶-2-基]-(2,4,6-三甲基-苯基)-胺
在DMSO中,在130℃下,通过使2-溴(或氯)-4-(1-乙基-丙氧基)-6-甲基-3-硝基-吡啶和2,4,6-三甲基苯胺反应,制备标题化合物。将反应混合物采用水骤冷和采用乙酸乙酯萃取。将有机层分离,干燥和浓缩得到粗材料。将该材料通过硅胶柱色谱纯化,得到为黄色固体的标题化合物。1H NMR(CDCl3)d8.52(s,1H),6.92(s,2H),6.12(s,1H),4.31(m,1H),2.32(s,3H),2.24(s,3H),2.18(s,6H),1.77(m,4H0,1.01(t,6H)ppm.
实施例123
4-(1-乙基-丙氧基)-6-甲基-N2-(2,4,6-三甲基-苯基)-吡啶-2,3-二胺
在乙醇中,在50psi下,采用10%Pd/C,通过对相应3-硝基衍生物氢化,制备标题化合物。以97%收率获得淡灰色固体。mp.73-75℃.1H NMR(CDCl3)d 6.89(s,2H),6.18(s,1H),4.22(m,1H),3.2(brs,2H),2.29(s,3H),2.19(s,6H),1.7(m,4H),0.97(t,6H)ppm.
实施例124
2-氯-N-[4-(1-乙基-丙氧基)-6-甲基-(2,4,6-三甲基-苯基氨基)-吡啶-3-基]-乙酰胺
在THF中,在室温下,采用氯乙酰氯,Net3对4-(1-乙基-丙氧基)-6-甲基-N2-(2,4,6-三甲基-苯基)-吡啶-2,3-二胺进行酰基化,制备标题化合物。分离褐色固体。mp.79-82℃,元素分析C22H30ClN3O2计算值C,65.41;H,7.49;N,10.40;实测值:C,65.56;H,7.62;N,10.98.
实施例125
N-丁基-N-乙基-6-甲基-3-硝基-N-(2,4,6-三甲基-苯基)-吡啶-2,4-二胺
在140℃油浴中,将丁基-(2-氯-6-甲基-3-硝基-吡啶-4-基)-乙基-胺(700mg,2.58mmol)和2,4,6-三甲基苯胺在DMSO中的混合物加热过夜。加入另外0.75ml的2,4,6-三甲基苯胺并将获得的混合物加热另外的48小时。将混合物采用水、盐水骤冷和采用乙酸乙酯萃取3次。将有机层分离,干燥(MgSO4)浓缩到干燥。在硅胶柱色谱纯化之后,获得标题化合物,其为油状物。
实施例126
4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-烟酸
在碳酸钾和铜存在下,在DMF中,通过加热2-氯-4-(1-乙基-丙基氨基)-6-甲基-烟酸和三甲基苯胺,制备标题化合物。使用在氯仿中的5%甲醇作为溶剂,通过硅胶柱色谱分离所需产物,得到褐色固体,mp.130-135℃。
实施例127
4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-烟酸甲酯
在回流下,将2-氯-4-(1-乙基-丙基氨基)-6-甲基-烟酸甲酯、三甲基苯胺、碳酸钾、铜在DMF中的混合物加热。将混合物采用氯化铵骤冷并搅拌20min,通过C盐过滤和采用乙酸乙酯洗涤。将滤液采用乙酸乙酯萃取。将有机层分离,干燥浓缩到干燥。使用在氯仿中的2%甲醇作为洗脱剂,将残余物通过硅胶柱色谱纯化,得到为固体的标题化合物。
1H NMR(CDCl3)d 8.9(s,1H),8.0(d,1H),6.91(s,2H),5.79s,1H),3.92(s,3H),3.37(m,1H),2.30(s,3H),2.17(s,3H),2.10(s,6H),1.5-1.7(m,4H),0.96(t,6H)ppm.
实施例128
N4-(1-乙基-丙基)-3,6-二甲基-N2-(2,4,6-三甲基-苯基)-吡啶-2,4-二胺
在回流下,采用在乙醚中的1M氢化铝锂和三氯化铝还原4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-苯基氨基)-烟酸,制备标题化合物。
1H NMR(CDCl3)6.9(s,2H),6.0(s,1H),5.4(brs,1H),3.6(d,1H),3.3(m,1H),2.32(s,3H),2.2(s,3H),2.15(s,6H),1.4-1.7(m,4H),1.0(t,6H)ppm.
实施例129
2-[4-(1-乙基-丙基)-6-甲基-N2-(2,4,6-三甲基-苯基)-吡啶-3-基甲基]-丙二酸二甲酯
Mp.136-138℃;元素分析C26H37N3O4.3/4 H2O计算值:C,66.57;H,8.27;N,8.96;实测值:C,66.67;H,7.95;N,8.88.
实施例130
[2-(4-溴-2,6-二甲基-苯基氨基)-4-(1-乙基-丙基氨基)-6-甲基-吡啶-3-基]-甲醇
在回流下,在THF中,通过用BH3.DMS还原相应烟酸衍生物,制备标题化合物。标准处理步骤得到为白色泡沫状的标题化合物。
1H NMR(CDCl3)7.15(s,2H),6.2(brs,1H),5.92(s,1H),4.479m,1H),4.43(s,2H),3.25(m,1H),2.17(s,3H),2.10(s,6H),1.58(m,2H),1.47(m,2H),0.90(t,6H)ppm.
实施例131
N2-(2,4-二氯-苯基)-N4-(1-乙基-丙基)-3,6-二甲基-吡啶-2,4-二胺
通过相似于实施例33中描述的方法,制备标题化合物。
1H NMR(CDCl3)d 7.79(dd,1H),7.30(d,1H),7.10(dd,1H),6.53(brs,1H),6.13(s,1H),3.79(d,1H),3.2-3.4(m,1H),2.36(s,3H),1.92(s,3H),1.4-1.6(m,4H),0.93(t,6H)ppm.
实施例132
[2-(2,4-二氯-苯基氨基)-4-(1-乙基-丙基氨基)-6-甲基-吡啶-3-基]-甲醇
在回流下,在THF中,通过用BH3.DMS还原相应烟酸衍生物,制备标题化合物。1H NMR(CDCl3)d 7.22(d,1H),7.07(d,1H),7.00(d,1H),6.10(s,1H),5.7(brs,1H),4.4(s,2H),3.3(m,1H),2.35(s,3H),2.02(s,3H),1.4-1.6(m,4H),0.92&0.91(两套t,6H)ppm.
实施例133
2-[6-甲基-3-硝基-2-(2,4,6-三甲基-苯氨基氧基)-吡啶-4-基氨基]-丁-1-醇
在DMSO中,在130℃下,通过加热2-[6-甲基-3-硝基-2-氯-吡啶-4-基氨基]-丁-1-醇和三甲基苯胺,制备标题化合物。
1H NMR(CDCl3)d 9.38(brs,1H),6.93(s,3H).3.7-3.8(m,3H),2.30(s,3H),2.12(s,6H),1.8(m,1H),1.65(m,1H),1.02(t,3H)ppm
实施例134
2-[4-(1-乙基-丙基氨基)-2-甲基-6-(2,4,6-三甲基-苯氧基)-嘧啶-5-基]-丙酸乙酯
1H NMR(CDCl3)d 6.85(s,2H),5.16(d,1H),4.49(q,1H),4.0-4.2(m,3H),2.289s,3HO.2.20(s,3H),2.06(s,6H),1.4-1.7(m,4H),1.44(d,3H),1.21(t,3H),0.93(t,3H),0.87(t,3H)ppm.
实施例135
[3-氨基甲基-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-(1-乙基-丙基)-胺
通过相似于实施例75的方法制备标题化合物。mp.117-119℃;元素分析C21H31N3O.1/3 H2O计算值:C,72.58;H,9.18;N,12.09;实测值:C,72.93;H,9.28;N,12.02.
通过如下方式制备实施例136-138的如下标题化合物:在苯中将4-(1-乙基-丙基氨基)-6-甲基-2-(4-卤素-26-二甲基-苯氧基)-吡啶-3-基]-甲醇和亚硫酰氯反应,浓缩到干燥,随后在室温下在DMSO中与氰化钾反应。
实施例136
[2-(4-溴-2,6-二甲基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-吡啶-3-基]-乙腈
1H NMR(CDCl3)d 7.2(s,2H),6.1(s,1H),3.82(d,1H),3.7(s,2H),3.34(m,1H),2.1(s,3H),2.03(s,6H),1.45-1.7(m,4H),0.99(t,6H)ppm.
实施例137
[2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-吡啶-3-基]-乙腈盐酸盐
1H NMR(CDCl3)d 7.08(s,2H),6.2(s,1H),4.92(d,1H),3.45(m,1H),2.71(s,3H),2.549m,2H),2.14(s,6H),1.7(m,2H),1.40-1.6(m,4H),0.95(t,6H)ppm.
实施例138
[6-(1-乙基-丙氧基)-2-甲基-嘧啶-4-基]-(2,4,6-三甲基-苯基)-胺
MP.149-151℃,元素分析C20H26N4O计算值:C,72.81;H,8.68;N,13.41;实测值:C,72.70;H,8.86;N,13.14
实施例139
2-[2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-吡啶-4-(S)-基氨基]-丁-1-醇
在160-170℃油浴中,通过加热相应的烟酸衍生物,制备标题化合物。1H NMR(CDCl3)d 7.05(s,2H),6.09(s,1H),5.35(s,1H),4.43(s,1H),3.68(m,1H),3.64(m,1H),3.29(m,1H),2.30(s,3H),2.09(s,6H),1.60(m,1H),1.47(m,1H),0.89(t,3H)ppm.
实施例140
[3-氨基甲基-2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-吡啶-4-(S)-基]-(1-氯甲基-丙基)-胺
通过如下方式制备标题化合物:在苯中将2-[2-(4-氯-2,6-二甲基-苯氧基)-3-吡啶-4-(S)-基氨基]-丁-1-醇和亚硫酰氯反应,浓缩到干燥,随后在室温下与NH3(g)反应。在标准处理步骤和硅胶柱色谱之后,获得标题化合物。1H NMR(CDCl3)d7.00(s,2H),6.3(brs,1H),6.07(s,1H),4.0-4.2(m,2H),3.9(brs,2H),3.5-3.8(m,3H),2.12(s,3H),2.03(s,6H),1.6-1.9(m,2H),1.00(t,3H)ppm
通过如下方式制备实施例254和255的如下标题化合物:在苯中将2-[2-(4-氯-2,6-二甲基-苯氧基)-3-吡啶-4-(S)-基氨基]-丁-1-醇和亚硫酰氯反应,浓缩到干燥,随后在室温下在THF中与合适的胺反应。在标准处理步骤和硅胶柱色谱之后,获得标题化合物。
实施例141
2-[2-(4-氯-2,6-二甲基-苯氧基)-6-3-甲基氨基甲基-吡啶-4-(S)-基氨基]-丁-1-醇
1H NMR(CDCl3)d 7.01(s,2H),6.14(s,1H),4.55(brs,1H),3.6-3.8(m,2H),3.4(m,1H),2.6(s,3H),2.11(s,3H),2.02(brs,6H),1.65(m,2H),0.97(t,3H)ppm.
实施例142
2-[3-甲基氨基-2-(4-氯-2,6-二甲基-苯氧基)-6-吡啶-4-(S)-基氨基]-丁-1-醇
1H NMR(CDCl3)d 6.999s,2H),6.10(s,1H),4.4.00(Abq,2H),3.5-3.75(m,2H),3.4(m,1H),2.73(brs,4H),2.08(s,3H),2.00(s,6H),1.58(m,4H),0.94(t,3H)ppm.
在二氯甲烷或氯仿中,在室温下,通过采用NBS或NCS进行2-[2-(取代苯氧基)-6-甲基-吡啶-4-烷基胺的溴化或氯化,制备如下实施例143-149的标题化合物。
实施例143
[3-溴-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-(1-乙基-丙基)-胺
1H NMR(CDCl3)d 6.85(s,2H),6.04(s,1H),4.62(d,1H),3.33(m,1H),2.27(s,3H),2.13(s,3H),2.08(s,6H),1.5-1.7(m,2H),0.95(t,3H)ppm.
实施例144
2-[3,5-二溴-2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-吡啶-4-基氨基]-丁-1-醇
1H NMR(CDCl3)d 7.02(s,2H),4.34(m,1H),3.6-3.8(m,2H),2.30(s,3H),2.05(s,6H),1.5-1.8(m,2H),0.98(t,3H)ppm.
实施例145
2-[3-溴-6-(4-氯-2,6-二甲基-苯氧基)-2-甲基-吡啶-4-(S)-基氨基]-丁-1-醇
1H NMR(CDCl3)d 7.05(s,2H),5.62(s,1H),4.86(d,1H),3.55-3.7(m,2H),3.3(m,1H),2.428(s,3H),2.09(s,6H),1.4-1.7(m,3H),0.91(t,3H)ppm.
实施例146
2-[3-溴-2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-吡啶-4-(S)-基氨基]-丁-1-醇
1H NMR(CDCl3)d 7.02(s,2H),6.14(s,1H),4.81(d,1H),3.6-3.8(m,2H),3.45(m,1H),2.12(s,3H),2.08(s,6H),1.5-1.8(m,2H),1.00(t,3H)ppm.
实施例147
2-[3-氯-2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-吡啶-4-(S)-基氨基]-丁-1-醇
1H NMR(CDCl3)d 7.02(s,2H),6.18(s,1H),4.76(d,1H),3.6-3.8(m,2H),3.45(m,1H),2.13(s,3H),2.07(s,6H),1.5-1.8(m,2H),0.99(t,3H)ppm.
实施例148
2-[3,5-二氯-2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-吡啶-4-基氨基]-丁-1-醇
1H NMR(CDCl3)d 7.03(s,2H),4.34(m,1H),3.6-3.8(m,2H),2.40(s,3H),2.05(s,6H),1.5-1.8(m,2H),0.99(t,3H)ppm.
实施例149
2-[3-氯-6-(4-氯-2,6-二甲基-苯氧基)-2-甲基-吡啶-4-(S)-基氨基]-丁-1-醇
1H NMR(CDCl3)d 7.05(s,2H),5.66(s,1H),4.86(brs,1H),3.5-3.8(m,2H),3.3(m,1H),2.38(s,3H),2.09(s,6H),1.4-1.7(m,3H),0.91(t,3H)ppm.
实施例150
2-(4-氯-2,6-二甲基-苯氧基)-4-(S)-(4-乙基-2-氧代-噁唑烷-3-基)-6-甲基-烟腈
在THF中,通过使2-(4-氯-2,6-二甲基-苯氧基)-4-(1-羟甲基-丙基氨基)-6-甲基-烟酸与三光气/NEt3反应反应,制备标题化合物。1HNMR(CDCl3)d 7.18(s,1H),7.06(s,2H),5.00(m,1H),4.64(t,1H),4.23(dd,1H),2.339s,3H),2.08(s,6H),1.5-1.8(m,2H),0.949t,3H)ppm.
实施例151
2-(2,4-二甲氧基-苯基氨基)-4-(1-甲氧基甲基-丙氧基)-6-甲基-烟酸
1H NMR(CDCl3)d 8.3(brs,1H),6.5(m,3H),6.26(s,1H),4.66(m,1H),3.92(s,3H),3.85(s,3H),3.66(m,2H),3.43(s,3H),2.52(s,3H),1.91(m,2H),1.07(t,3H)ppm.
实施例152
4-(1-乙基-丙氧基)-2-甲基-6-(2,4,6-三甲基-苯基氨基)-嘧啶-5-腈
1H NMR(CDCl3)d 6.92(s,2H),6.45(s,1H),5.22(m,1H),2.29(s,6H),2.16(s,6H),1.70(m,4H),0.93(t,6H)ppm.
实施例153
N-(1-乙基-丙基)-2,5-二甲基-N’-(2,4,6-三甲基-苯基)-嘧啶-4,6-二胺
1H NMR(CDCl3)d 8.9(s,1H),6.85(s,2H),4.95(d,1H),4.21(m,1H),2.5(s,3H),2.25(s,3H),2.13(s,6H),1.4-1.7(m,4H),1.3(s,3H),0.85(t,6H)ppm
实施例154
5-氯-N4-(1-乙基-丙基)-2-甲基-N6-(2,4,6-三甲基-苯基)-嘧啶-4,6-二胺
1H NMR(CDCl3)d 6.85(s,2H),6.0(s,1H),4.D(m,1H),4.2(m,1H),2.3(s,3H),2.22(,3H),2.17(s,6H),1.4-1.70(m,4H),0.97(t,6H)ppm.
实施例155
5-溴-N-(1-乙基-丙基)-2-甲基-N’-(2,4,6-三甲基-苯基)-嘧啶-4,6-二胺
MP.117-119℃,元素分析C19H21BrN4计算值:C,58.31;H,6.95;N,14.32;实测值:C,58.43;H,7.08;N,14.23.
实施例156
4-(1-乙基-丙基氨基)-2-甲基-6-(2,4,6-三甲基-苯基氨基)-嘧啶-5-甲酸
1H NMR(CDCl3)d 12.2(brs,1H),11.1(brs,1H), 6.84(s,2H),4.18(m,1H),2.38(s,3H),2.18(s,3H),2.15(s,6H),1.56(m,4H),0.90(t,6H)ppm.
实施例157
[4-(环丙基甲基-丙基-氨基)-2-甲基-6-(2,4,6-三甲基-苯基氨基)-嘧啶-5-基]-甲醇
1H NMR(CDCl3)d 7.49s,2H),4.95(s,2H),4.92(s,1H),3.28(brs,4H),2.359s,3H),1.54(m,2H),0.95(m,1H),0.81(t,3H),0.44(m,2H),0.19(m,2H)ppm.
实施例158
6-(1-乙基-丙氧基)-2,N5,N5-三甲基-N4-(2,4,6-三甲基-苯基)-嘧啶-4,5-二胺
通过如下方式制备标题化合物:在THF中采用双(三甲基甲硅烷基)酰胺锂对6-(1-乙基-丙氧基)-2-甲基-N4-(2,4,6-三甲基-苯基)-嘧啶-4,5-二胺进行甲基化,随后采用碘甲烷骤冷。
1H NMR(CDCl3)d 7.35(s,1H),6.90(s,2H),5.16(m,1H),2.73(s,6H),2.29(s,3H),2.27(s,3H),2.18(s,6H),1.6-1.8(m,4H),0.96(t,6H) ppm.
实施例159
[5-溴-6-(1-乙基-丙氧基)-2-甲基-嘧啶-4-基]-(2,4,6-三甲基-苯基)-胺
在回流下,在THF中,通过将[5-溴-6-(1-乙基-丙氧基)-2-甲基-嘧啶-4-基]-(2,4,6-三甲基-苯基)-胺与3-戊醇/NaH反应过夜,制备标题化合物。在标准处理和纯化之后,以白色固体获得标题化合物。mp.94-96℃.1H NMR(CDCl3)d 6.91(s,2H),6.41(s,1H),5.13(m,1H),2.29(s,3H),2.26(,3H),2.17(s,6H),1.70(m,4H),0.95(t,6H)ppm.
实施例160
4-(1-乙基-丙氧基)-2-甲基-6-(2,4,6-三甲基-苯基氨基)-嘧啶-5-甲酸
在-78℃下,向在THF中的n-BuLi溶液中,加入在THF中的[5-溴-6-(1-乙基-丙氧基)-2-甲基-嘧啶-4-基]-(2,4,6-三甲基-苯基)-胺的溶液。在搅拌10分钟之后,在-78℃下加入CO2(g)并在该温度下搅拌1小时,然后逐渐升温到室温。将获得的混合物采用水骤冷并调节到pH2-3和采用氯仿萃取。将有机层分离,干燥浓缩到干燥。将残余物通过硅胶柱色谱纯化得到为固体的标题化合物。mp.118-120℃,元素分析C20H27N3O3计算值:C,67.20;H,7.61;N,11.76;实测值:C,67.25;H,7.87;N,11.48.
实施例161
[4-(1-乙基-丙氧基)-2-甲基-6-(2,4,6-三甲基-苯基氨基)-嘧啶-5-基]-甲醇
向在干燥THF中的4-(1-乙基-丙氧基)-2-甲基-6-(2,4,6-三甲基-苯基氨基)-嘧啶-5-甲酸溶液中加入BH3.DMS。将获得的混合物在回流下加热。将混合物采用稀HCl骤冷和搅拌30分钟,将pH调节到7.5-8.5,然后采用乙酸乙酯萃取。将有机层分离,干燥和浓缩得到粗材料。将粗材料通过硅胶柱色谱纯化得到为固体的标题化合物。mp.121-123℃,元素分析C20H29N3O2计算值C,69.94;H,8.51;N,12.23;实测值:C,69.73;H,8.47;N,11.99.
实施例162
[6-(1-乙基-丙氧基)-5-甲氧基甲基-2-甲基-嘧啶-4-基]-(2,4,6-三甲基-苯基)-胺
通过如下方式制备标题化合物:将[4-(1-乙基-丙氧基)-2-甲基-6-(2,4,6-三甲基-苯基氨基)-嘧啶-5-基]-甲醇和NaH反应,随后采用MeI骤冷。
1H NMR(CDCl3)d 7.0(s,1H),6.89(s,2H),5.12(m,1H),4.62(s,2H),3.33(s,3H),2.28(s,3HO,2.27(s,3H),2.14(s,6H),1.66(m,4H),0.91(t,6H)ppm.
实施例163
[5-氨基甲基-6-(1-乙基-丙氧基)-2-甲基-嘧啶-4-基]-(2,4,6-三甲基-苯基)-胺
向在无水二氯甲烷中的[4-(1-乙基-丙氧基)-2-甲基-6-(2,4,6-三甲基-苯基氨基)-嘧啶-5-基]-甲醇溶液中加入亚硫酰氯。在搅拌1小时之后,将反应混合物浓缩到干燥。将残余物溶于干燥THF并将NH3(g)鼓泡加入。将反应混合物采用水骤冷和采用乙酸乙酯萃取。将反应通过标准步骤处理和纯化得到标题化合物。
1H NMR(CDCl3)d 8.50(s,1H),6.88(s,2H),5.08(m,1H),3.97(s,2H),2.279s,3H),2.25(s,3H),2.159s,6H),1.74(brs,2H),1.65(m,4H),0.91(t,6H)ppm.
实施例164
7-(1-乙基-丙氧基)-5-甲基-3-(2,4,6-三甲基-苯基)-3H-咪唑并[4,5-b]吡啶-2-基胺
在乙腈中,在室温下,通过将4-(1-乙基-丙基)-6-甲基-N2-(2,4,6-三甲基-苯基)-吡啶-2,3-二胺和BrCN反应过夜,制备标题化合物。将混合物采用水骤冷和采用饱碳酸氢钠调节到pH8.0和采用乙酸乙酯萃取。将有机层分离,干燥和浓缩得到粗材料。将材料通过硅胶柱色谱纯化得到为白色固体的标题化合物。mp.159-161℃.1H NMR(CDCl3)d 7.05(s,2H),6.5(s,1H),4.6(m,1H),4.3(m,2H),2.45(s,3H),2.35(s,3H),2.0(s,6H),1.7(m,4H),1.0(t,6H)ppm.
实施例165
7-(1-乙基-丙氧基)-5-甲基-3-(2,4,6-三甲基-苯基氨基)-3H-咪唑并[4,5-b]吡啶
在回流下,使用Dean-Stark设备,将4-(1-乙基-丙氨基)-6-甲基-N2-(2,4,6-三甲基-苯基)-吡啶-2,3-二胺、原甲酸三甲酯、对甲苯磺酸-水合物在甲苯中的混合物加热24小时。在回流下,将混合物加热过夜。将混合物采用水、饱和NaHCO3骤冷,采用乙酸乙酯萃取。将有机层分离,干燥(MgSO4)浓缩到干燥。在纯化之后,分离标题化合物。元素分析C21H29N3O.1/4H2O计算值C,73.76;H,8.10;N,12.29;实测值:C,73.22;H,7.96;N,12.42.
实施例166
7-(1-乙基-丙氧基)-5-甲基-3-(2,4,6-三甲基-苯基氨基)-1,3-二氢-咪唑并[4,5-b]吡啶-2-酮
在THF中,在室温下,通过使4-(1-乙基-丙氧基)-6-甲基-N2-(2,4,6-三甲基-苯基)-吡啶-2,3-二胺和三光气、NEt3反应制备标题化合物。分离白色固体。mp.184-186℃。元素分析C21H27N3O2计算值C,71.36;H,7.70;N,11.89;实测值:C,71.09;H,7.75;N,11.63.
实施例167
7-(1-乙基-丙氧基)-1,5-二甲基-3-(2,4,6-三甲基-苯基)-1,3-二氢-咪唑并[4,5-b]吡啶-2-酮
通过如下方式制备标题化合物:将7-(1-乙基-丙氧基)-5-甲基-3-(2,4,6-三甲基-苯基)-1,3-二氢-咪唑并[4,5-b]吡啶-2-酮和双(三甲基甲硅烷基)酰胺锂反应,随后采用碘甲烷骤冷。Mp.151-153℃.元素分析C22H29N3O2.1/4H2O计算值C,71.03;H,7.99;N,11.30;实测值:C,71.29;H,8.01;N,11.03.
实施例168
(1-乙基-丙基)-[5-甲基-3-(2,4,6-三甲基-苯基)-3H-咪唑并[4,5-b]吡啶-7-基]-胺
在回流下,使用Dean-Stark设备,将N-4-(1-乙基-丙基)-6-甲基-N-2-(2,4,6-三甲基-苯基)-吡啶-2,3,4-三胺(250mg,0.77mmol)、原甲酸三甲酯(0.081g,0.766mmol)、对甲苯磺酸一水合物(0.01g)在苯中的混合物加热24小时。除去苯和加入甲苯和向反应混合物中加入过量原甲酸三甲酯(0.084ml)。将混合物在回流下加热过夜。将混合物采用水、饱和NaHCO3骤冷,采用乙酸乙酯萃取。将有机层分离,干燥(MgSO4)浓缩到干燥。在纯化之后,分离为白色晶体的标题化合物,mp 78-80℃。
实施例169
[2,5-二甲基-3-(2,4,6-三甲基-苯基)-3H-咪唑并[4,5-b]吡啶-7-基]-(1-乙基-丙基)-胺
在回流下,使用Dean-Stark设备,将N-4-(1-乙基-丙基)-6-甲基-N-2-(2,4,6-三甲基-苯基)-吡啶-2,3,4-三胺(250mg,0.77mmol)、原甲酸三甲酯(0.184g,1.532mmol)、对甲苯磺酸一水合物(0.01g)在甲苯中的混合物加热3小时。将混合物采用水、盐水骤冷,采用乙酸乙酯萃取。将有机层分离,干燥(MgSO4)浓缩到干燥。在纯化之后,分离为白色晶体的标题化合物。mp.101-103℃.元素分析C22H30N4计算值C,75.39;H,8.63;N,15.98;实测值,C,75.44;H,8.95;N,15.95.
实施例170
N7-(1-乙基-丙基)-5-甲基-3-(2,4,6-三甲基-苯基)-3H-咪唑并[4,5-b]吡啶-2,7-二胺
在乙腈中,在室温下,通过使N4-(1-乙基-丙基)-6-甲基-N-2-(2,4,6-三甲基-苯基)-吡啶-2,3,4-三胺和BrCN反应,制备标题化合物。将混合物采用水骤冷和采用饱和碳酸氢钠调节到pH8.0并采用乙酸乙酯萃取。将有机层分离,干燥和浓缩得到粗材料。将材料通过硅胶柱色谱纯化得到为棕色固体的标题化合物。mp.158-160℃;元素分析C21H29N51/4H2O计算值C,70.85;H,8.35;N,19.67;实测值:C,71.07;H,8.30;N,19.63.
实施例171
6-(1-乙基-丙基氨基)-2,7-二甲基-9-(2,4,6-三甲基-苯基)-7,9-二氢-嘌呤-8-酮
在THF中,通过采用双(三甲基甲硅烷基)酰胺锂对6-(1-乙基-丙基氨基)-2-甲基-9-(2,4,6-三甲基-苯基)-7,9-二氢-嘌呤-8-酮进行甲基化,随后采用碘甲烷骤冷,制备标题化合物。
1H NMR(CDCl3)d 6.98(s,2H),4.45(d,1H),4.3(m,1H),3.7(s,3H),2.4(s,3H),2.3(s,3H),2.1(s,6H),1.5-1.8(m,4H),1.0(t,6H)ppm.
实施例172
6-(1-乙基-丙氧基)-2,7-二甲基-9-(2,4,6-三甲基-苯基)-7,9-二氢-嘌呤-8-酮
在THF中,通过采用双(三甲基甲硅烷基)酰胺锂对6-(1-乙基-丙氧基)-2-甲基-9-(2,4,6-三甲基-苯基)-7,9-二氢-嘌呤-8-酮进行甲基化,随后采用碘甲烷骤冷,制备标题化合物。
1H NMR(CDCl3)d7.00(s,2H),5.31(m,1H),3.66(s,3H).2.479s,3H),2.33(s,3H),2.06(s,6H),1.79(m,4H),1.01(t,6H)ppm.
实施例173
[2-(4-甲氧基-2,6-二甲基-苯氧基)-6-甲基-3-硝基-吡啶-4-基]-(1-甲氧基甲基-丙基)-胺
1H NMR(CDCl3)d 7.71(d,1H),6.57(s,2H), 6.21(s,1H),3.76(s,3H), 3.59(m,1H),3.48(m,1H),3.45(m,1H),3.37(s,3H),2.13(s,3H),2.08(s,6H),1.6-1.8(m,4H),0.86(t,3H)ppm.
实施例174
(1-乙基-丙基)-[2-(4-甲氧基-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-胺
1H NMR(CDCl3)d 6.64(s,2H),6.12(s,1H),3.82(s,3H),3.36(m,1H),2.26(s,3H),2.13(s,6H),2.10(s,3H),1.5-1.8m,4H),0.99(t,6H).
实施例175
2-[2-(4-甲氧基-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基氨基]-丁-1-醇
1H NMR(CDCl3)d 6.64(s,2H),6.13(s,1H),4.10(m,1H),3.76(s,3H),3.7-3.8(m,21H),3.57(m,1H),2.21(s,3H),2.19(s,6H),2.12(s,3H),1.6-1.8(m,2H),1.04(t,3H)ppm.
实施例176
仲丁基-[3-甲氧基-2-(4-甲氧基-2,6-二甲基-苯氧基)-6-甲基-吡啶-4-基]-胺
1H NMR(CDCl3)d 6.64(s,2H),6.13(s,1H),4.51(d,1H),3.92(s,3H),3.82(s,3H),3.469m,1H),2.18(s,3H),2.15(s,6H),1.60(m,2H),1.26(d,3H),1.00(t,3H)ppm.
实施例177
2-(4-氯-2,6-二甲基-苯氧基)-4-(4-乙基-噁唑烷-3-基)-3,6-二甲基-吡啶
1H NMR(CDCl3)d 7.07(s,2H),6.36(s,1H),4.98(m,1H),4.78(m,1H),4.23(m,1H),3.83(m,1H),3.71(m,1H),2.28(s,3H),2.20(s,3H),2.09(s,6H),1.81(m,1H),1.58(m,1H),0.98(t,3H)ppm.
实施例178
4-(4-乙基-噁唑烷-3-基)-2-(4-甲氧基-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶
1H NMR(CDCl3)d 6.65(s,2H),6.36(s,1H),4.98(m,1H),4.77(m,1H),4.23(m,1H),3.83(s,3H),3.71(m,1H),),2.29(s,3H),2.22(s,3H),2.119(s,6H),1.82(m,1H),1.56(m,1H),0.99(t,3H)ppm
实施例179
2-(4-甲氧基-2,6-二甲基-苯氧基)-N%4&-(1-甲氧基甲基-丙基)-6-甲基-吡啶-3,4-二胺
1H NMR(CDCl3)d 6.64(s,2H),6.16(s,1H),4.3(m,1H),3.82(s,3H),3.6-3.8(m,2H).3.42(s,3H),3.2(brs,2H),2.18(s,3H),2.13(s,6H),1.6-1.8(m,2H),1.03(t,3H)ppm.
实施例180
3-[2-(4-氯-2,6-二甲基-苯氧基)-3-羟甲基-6-甲基-吡啶-4-基氨基]-戊-2-醇
1H NMR(CDCl3)d 7.01(s,2H),6.16(s,1H),5.19(d,1H),4.94(m,2H),3.88(m,1H),3.27(m,1H),2.11(s,3H),2.05(s,6H),1.73(m,1H),1.57(m,1H),1.24(d,3H),0.97(t,3H)ppm.
实施例181
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基-2-氧代-丙基氨基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.63(d,1H),7.01(s,2H),5.90(s,1H),3.95(m,1H),3.90(s,3H),2.08(s,3H),2.05(s,3H),2.03(s,6H),1.8-2.0(m,2H),1.00(t,3H)ppm.
实施例182
3-[2-(4-氯-2,6-二甲基-苯氧基)-3-甲氧基甲基-6-甲基-吡啶-4-基氨基]-戊-2-醇
1H NMR(CDCl3)d 7.08(s,2H),6.21(s,1H),5.40(brs,1H),4.83(q,2H),3.91(m,1H),3.40(s,3H),3.33(m,1H),2.20(s,3H),2.10(s,6H),1.78(m,1H),1.58(m,1H),1.29(d,3H),1.01(t,3H)ppm.
实施例183
3-[2-(4-甲氧基-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基氨基]-戊-2-醇
1H NMR(CDCl3)d 6.66(s,2H),6.27(s,1H),4.05(m,1H),3.82(s,3H),3.38(m,1H),2.35(s,3H),2.21(s,3H),2.14(s,6H),1.6-1.9(m,2H),1.30(m,3H),1.01(t,3H)ppm.
实施例184
4-仲丁基氨基-2-(4-甲氧基-2,6-二甲基-苯氧基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.01(d,1H),6.58(s,2H),6.06(s,1H),3.85(s,3H),3.77(s,3H),2.10(s,3H),2.07(s,6H),1.21(d,3H0,0.97(t,3H)ppm.
实施例185
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基-2-羟基-2-甲基-丙基氨基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.28(d,1H),7.06(s,2H),6.32(s,1H),3.92(s,3H),3.41(m,1H),2.14(s,3H),2.12(s,6H),1.91(m,1H),1.44(m,1H),1.33(s,3H),1.30(s,3H0,0.99(s,3H)ppm.
实施例186
4-(1-羟甲基-丙基氨基)-2-(4-甲氧基-2,6-二甲基-苯氧基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.13(d,1H),6.63(s,2H),6.21(s,1H),3.91(s,3H0,3.82(s,3HO,3.81(m,2H),3.59(m,1H),2.16(s,3H),2.12(s,6H),1.6-1.859m,2H),1.05(t,3H)ppm.
实施例187
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-羟甲基-3-甲基硫基-丙基氨基)-6-甲基-烟酸甲酯
在134℃油浴中,将2-(4-氯-2,6-二甲基-苯氧基)-4-氯-6-甲基-烟酸甲酯和L-methioninol在N-甲基-2-吡咯烷酮(NMP)中的混合物加热3hr。标准处理步骤和纯化提供标题化合物。1H
NMR(CDCl3)d 8.25(d,1H),7.02(s,2H),6.30(s,1H),3.85(s,3H),3.6-3.9(m,3H),2.5-2.7(m,2H),
2.14(s,3H),2.10(s,3H),2.06(s,6H),1.8-2.1(m,2H)ppm.
实施例188
2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-(S)-(四氢-呋喃-3-基氨基)-烟酸甲酯
在-10℃下,向在干燥THF中的{3-[2-(4-氯-2,6-二甲基-苯氧基)-3-甲氧基羰基-6-甲基-吡啶-4-基氨基]-4-羟基-丁基)-二甲基-锍碘化物溶液中加入t-BuOK。将混合物在-10℃下搅拌,直到所有的起始原料消耗完。标准处理步骤和硅胶纯化得到标题化合物。
1H NMR(CDCl3)d 8.25(d,1H),7.01(s,2H),6.05(s,1H),4.11(m,1H),3.9-4.1(m,2H).3.8-3.9(m,1H),3.86(s,3H),3.73(m,1H),2.2-2.4(m,1H),2.11(s,3H),2.05(s,6H),1.95(m,1H)ppm.
实施例189
{3-[2-(4-氯-2,6-二甲基-苯氧基)-3-甲氧基羰基-6-甲基-吡啶-4-基氨基]-4-羟基-丁基}-二甲基-锍碘化物
在回流下,在密封管中,将2-(4-氯-2,6-二甲基-苯氧基)-4-(1-羟甲基-3-甲基硫基-丙基氨基)-6-甲基-烟酸甲酯和MeI在EtOAc中的混合物加热。将混合物浓缩到干燥并采用乙醚研制,得到标题化合物。
1H NMR(CD3OD)d 7.11(s,2H),6.61(s,1H),4.00(m,1H),3.86(s,3H),3.6-3.9(m,3H),2.95(d,6H),2.5-2.7(m,2H),2.22(s,3H),2.07(s,6H),1.8-2.1(m,2H)ppm.
实施例190
4-(1-羟甲基-3-甲基硫基-丙基氨基)-2-(4-甲氧基-2,6-二甲基-苯氧基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.15(d,1H),6.58(s,2H),6.28(s,1H),3.85(s,3H),3.76(s,3H),3.6-3.9(m,3H),2.5-2.7(m,2H),2.12(s,3H),2.09(s,3H),2.07(s,6H),1.8-2.1(m,2H)ppm.
实施例191
4-(1-羟甲基-丙基氨基)-2-(4-甲氧基-2,6-二甲基-苯氧基)-6,N-二甲基-烟酰胺
1H NMR(CDCl3)d 9.84(d,1H),8.31(m,1H),6.66(s,2H),6.29(s,1H),3.81(s,3H),3.5-3.9(m,3H),2.98(d,3H),2.15(s,3H),2.12(s,6H),1.6-1.8(m,2H),1.05(t,3H)ppm.
实施例192
4-仲丁基氨基-2-(4-甲氧基-2,6-二甲基-苯氧基)-6,N-二甲基-烟酰胺
1H NMR(CDCl3)d 9.77(brs,1H),8.22(brs,1H),6.61(s,2H),6.11(s,1H),3.78(s,3H),3.45(m,1H),2.93(d,3H),2.10(s,3H),2.07(s,6H),1.5-1.7(m,2H),1.23(m,3H),0.98(t,3H)ppm.
实施例193
2-(4-甲氧基-2,6-二甲基-苯氧基)-6-甲基-4-(四氢-呋喃-3-基氨基)-烟酸甲酯
1H NMR(CDCl3)d 8.28(d,1H),6.63(s,2H),6.09(s,1H),4.15(m,1H),3.98-4.1(m,2H),3.8-3.98(m,1H),3.90(s,3H),3.81(s,3H),3.76(m,1H),2.32-2.36(m,1H),2.19(s,3H),2.11(s,6H),1.95(m,1H)ppm.
实施例194
4-仲丁基氨基-2-(4-甲氧基-2,6-二甲基-苯氧基)-6-甲基-烟酰胺
1H NMR(CDCl3)d 9.74(ds,1H),8.05(brs,1H),6.65(s,2H),6.16(s,1H),5.55(brs,1H),3.83(s,3H),3.51(m,1H),2.16(s,3H),2.12(s,6H),1.5-1.7(m,2H),1.26(d,3H),1.02(t,3H)ppm.
如下实施例195-256涉及本发明通式I的其它化合物,其中R4是-COOCH3:
通过相似于实施例13中描述的方法,采用4-氯-2-(取代的苯氧基)-6-甲基-烟酸甲酯和合适的胺开始,制备实施例195-209的如下标题化合物:
实施例195
2-(4-乙氧基-2,6-二甲基-苯氧基)-4-(1-羟甲基-3-甲基硫基-丙基氨基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.35(d,1H),6.60(s,2H),6.41(s,1H),4.03(q,2H),3.90(m,1H),3.86(s,3H),3.75(m,2H),2.60(,2H),2.21(s,3H),2.11(s,3H),2.09(s,6H),2.03(m,1H),1.88(m,1H),1.40(t,1.39)ppm
实施例196
4-(1-羟甲基-3-甲基硫基-丙基氨基)-2-[4-(2-甲氧基-乙氧基)-2,6-二甲基-苯氧基]-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.38(d,1H),6.64(s,2H),6.42(s,1H),4.10(m,2H),3.92(m,1H),3.86(s,3H),3.73(m,5H),3.45(s,3H),2.60(m,2H),2.22(s,3H),2.13(s,3H),2.09(s,6H),1.87(m,2H)ppm
实施例197
2-(2,6-二甲基-4-三氟甲氧基-苯氧基)-4-(1-羟甲基-3-甲基硫基-丙基氨基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.21(br d,1H,J=8Hz),6.91(s,2H),6.28(s,1H),3.87(s,3H),3.84(m,1H),3.70-3.76(m,2H),2.53-2.68(m,2H),2.11(m,12H),1.88-2.06(m,2H).
实施例198
2-(4-氯-2,6-二甲基-苯氧基)-4-(R)-(1-羟甲基-3-甲基硫基-丙基氨基)-6-甲基-烟酸甲酯
C21H27ClN2O4s:MS:M+1[439.2]
实施例199
2-(4-氯-2,6-二甲氧基-苯氧基)-4-(1-羟甲基-丙基氨基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.29(d,1H,J+8Hz),6.63(s,2H),6.23(s,1H),3.86(s,3H),3.74(s,6H),3.69-3.72(m,1H),3.62-3.66(m,1H),3.52-3.58(m,1H),2.83(s,1H),2.13(s,3H),1.70-1.77(m,1H),1.54-1.61(m,1H),0.99(t,3H,J=7Hz)
13C NMR(CDCl3)d.169.75,158.50,153.43,130.15,106.96,101.49,64.67,56.95,56.12,56.05,52.18,46.05,24.92,10.67
实施例200
2-(4-氯-2,6-二甲氧基-苯氧基)-4-(1-羟甲基-3-甲基硫基-丙基氨基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.39(br d,1H,J=7Hz),6.64(s,2H),6.30(s,1H),3.87(s,3H),3.75(s,6H),3.36-3.39(m,1H),2.84(s,1H),2.53-2.70(m,2H),2.35-2.39(m,1H),2.14(d,3H,J=9Hz),1.94-2.07(m,2H),1.79-1.92(m,2H)ppm.APCI+m/z=471.2(M+1),473.2(M+3)
实施例201
2-(4-氯-2,6-二甲基-苯氧基)-4-[(1-羟甲基-丙基)-甲基-氨基)]-6-甲基-烟酸甲酯
实施例202
4-(1-乙基-丙基氨基)-2-(4-甲氧基-2,6-二甲氧基-苯氧基)-6-甲基-烟酸甲酯
APCI M=![387.3].1H NMR(CDCl3)
实施例203
2-(2,6-二甲基-4-[1,3,4]噁二唑-2-基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.43(s,1H),8.22(br d,1/2H),7.80(s,2H),6.12(s,1H),3.88(s,3H),3.3-3.4(m,1H),2.15-2.2(m,9H),1.5-1.7(m,4H),0.967(t,6H,J=7Hz)
13C NMR(CDCl3)d.
APCI+m/z=425.3(M+1)
实施例204
2-(4-氯-2-甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.14(d,1H,J=8Hz),6.90-7.26(m,3H),6.14(s,1H),3.82(s,3H),3.77(s,3H),3.32-3.73(m,1H),2.17(s,3H),1.49-1.67(m,4H),0.94(t,6H,J=7Hz)ppm.
实施例205
4-(1-羟甲基-丙基氨基)-2-(4-甲氧基-2,6-二甲基-苯氧基)-6-甲基-烟酸甲酯
1HNMR(CDCl3)8.21(d,1H),6.60(s,2H),6.30(s,1H),3.87(s,3H),3.78(s,3H),3.65(m,3H),2.17(s,3H0,2.09(s,6H),1.75(m,1H),1.61(m,1H),1.01(t,3H)ppm
实施例206
2-(4-氯-2-氟-6-甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酸甲酯
APCI+m/z=411(M+1),413(M+3)
实施例207
2-(4-氯-2-甲氧基-6-甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.16-8.20(m,1H),6.82(d,1H, J=1.5Hz),6.78(d,1H,J=1.5Hz),6.09(s,1H),3.85(s,3H),3.72(s,3H),3.3-3.8(m,1H),2.12(s,3H),1.51-1.67(m,4H),0.95(t,6H,J=7Hz)ppm.
APCI+m/z=407.2(M+1),409.2(M+3)
实施例208
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-甲氧基甲基-丙基氨基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.2(d,1H),7.02(s,2H),6.14(s,1H),3.87(s,3H),3.6(m,1H),3.56(m,1H),3.4(m,1H),3.39(s,3H),2.10(s,3H),2.07(s,6H),1.78(m,1H),1.61(m,1H),1.00(t,3H)ppm.
实施例209
2-(4-溴-2-甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.14(br d,1H),7.03-7.07(m,2H),6.88(d,1H,J=8Hz),6.14(s,1H),3.82(s,3H),3.77(s,3H),3.32-3.37(m,1H),2.18(s,3H),1.49-1.68(m,4H),0.94(t,6H,J=7Hz)APCI+m/z=437.1(M+1),439.1(M+3)
实施例210
2-(4-氯-2-羟基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酸甲酯
在二氯甲烷中,在室温下,通过将2-(4-氯-2-甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酸甲酯与BBr3反应,直到所有的起始原料消耗,制备标题化合物。标准处理步骤得到标题化合物。APCI+m/z=379.2(M+1),381.2(M+3)
实施例211
2-(4-氯-2-乙氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.10(br d,1H),6.98(d,1H,J=8Hz),6.86-6.91(m,2H),6.14(s,1H),3.97(q,2H,J=7Hz),3.83(s,3H),3.32-3.37(m,1H),2.16(s,3H),1.50-1.68(m,4H),1.19(t,3H,J=7Hz),0.94(t,6H,J=7Hz)ppm.APCI+m/z=407.1(M+1),409.1(M+3)
实施例212
4-(2-羟基-1-羟甲基-乙基氨基)-2-(4-甲氧基-2,6-二甲基-苯氧基)-6-甲基-烟酸甲酯
1HNMR(CDCl3)8.42(d,1H),7.02(s,2H),6.17(s,1H),3.89(m,2H),3.86(s,3H),3.85(m,2H),3.67(m,1H),2.10(s,3H),2.05(s,6H)ppm
实施例213
4-(1-羧基-丙基氨基)-2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-烟酸甲酯
在室温下,将2-(4-氯-2,6-二甲基-苯氧基)-4-(1-甲酰基-丙基氨基)-6-甲基-烟酸甲酯、2-甲基-2-丁烯、过量NaClO2和NaH2PO4的混合物搅拌15min。将混合物采用饱和碳酸氢钠骤冷和采用己烷萃取。将水层酸化到pH4和采用乙醚萃取两次。将有机层分离,干燥和浓缩得到标题化合物。将粗材料通过硅胶柱色谱纯化,在重结晶之后得到为白色晶体的所需产物。元素分析C20H23N2O5Cl计算值,C,59.04;H,5.70;N,6.89;实测值C,59.29;H,5.73;N,6.83.
实施例214
4-(1-羧基-丙基氨基)-2-(4-氯-2,6-二甲基-苯氧基)-5-氯-6-甲基-烟酸甲酯
通过相似于实施例213中的方法制备标题化合物,区别在于用在不存在2-甲基-2-丁烯的情况下搅拌过夜代替15分钟反应时间。
实施例215
4-(1-氨基甲酰基-丙基氨基)-5-氯-2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-烟酸甲酯
将4-(1-羧基-丙基氨基)-2-(4-氯-2,6-二甲基-苯氧基)-5-氯-6-甲基-烟酸甲酯和过量亚硫酰氯在二氯甲烷中的混合物搅拌15min。将混合物浓缩到干燥。将残余物采用二氯甲烷稀释并将氨气(ammonium)鼓泡加入到反应混合物中。在搅拌30min之后,将混合物采用水骤冷,采用二氯甲烷萃取。将有机层浓缩到干燥。将残余物通过硅胶Biotage纯化得到标题化合物。
1HNMR(CDCl3)7.02(s,2H),6.34(s,1H),5.92(d,1H),5.81(s,1H),4.05(m,1H),3.92(s,3H),2.27(s,3H),2.05(s,6H),1.80(m,2H),1.00(t,3H)ppm
通过相似于上述方法,在二氯甲烷中,采用羧酸和过量亚硫酰氯开始,浓缩,采用铵、烷基胺、二烷基胺或链烷醇(如甲醇,乙醇等)骤冷,制备如下化合物(实施例216-223):
实施例216
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-甲氧基羰基-丙基氨基)-6-甲基-烟酸甲酯
1HNMR(CDCl3)8.52(d,1H),7.02(s,2H),5.97(s,1H),4.09(m,1H),3.89(s,3H),3.78(s,3H),2.09(s,3H),2.06(s,6H),1.98(m,2H),1.04(t,3H)ppm
实施例217
4-(1-氨基甲酰基-丙基氨基)-2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.56(d,1H),7.04(s,2H),6.38(s,1H),6.12(s,1H),5.44(s,1H),3.91(s,3H),3.88(m,1H),2.15(s,1H),2.07(s,1H),1.95(m,2H),1.24(t,3H)ppm
实施例218
2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-(1-甲氧基氨基甲酰基-丙基氨基)-烟酸甲酯
1HNMR(CDCl3)8.49(d,1H),7.05(s,2H),6.48(s,1H),6.08(s,1H),3.91(s,3H),3.90(m,1H),2.83(m,3H),2.15(s,3H),2.08(m,6H),1.08(t,3H)ppm
实施例219
5-氯-2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-(1-甲氧基氨基甲酰基-丙基氨基)-烟酸甲酯
1HNMR(CDCl3)7.02(s,2H),6.42(m,1H),5.80(m,1H),3.96(m,1H),3.89(s,3H),2.86(d,3H),2.28(s,3H),2.04(m,6H),1.78(m,2H),0.98(t,3H)ppm
实施例220
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-二甲基氨基甲酰基-丙基氨基)-6-甲基-烟酸甲酯
1HNMR(CDCl3)8.67(d,1H),7.02(s,2H),5.97(s,1H),4.39(m,1H),3.89(s,3H),3.13(s,3H),3.02(s,3H),2.13(s,3H),2.06(m,6H),1.92(m,2H),1.00(t,3H)ppm
实施例221
5-氯-2-(4-氯-2,6-二甲基-苯氧基)-4-(1-二甲基氨基甲酰基-丙基氨基)-6-甲基-烟酸甲酯
1HNMR(CDCl3)7.02(s,2H),6.42(d,1H),4.66(m,1H),3.93(s,3H),3.06(s,3H),3.01(s,3H),2.27(s,3H),1.82(m,2H),0.90(t,3H)ppm
实施例222
2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-[(1-(吡咯烷-1-羰基)-丙基氨基]-烟酸甲酯
1HNMR(CDCl3)8.61(d,1H),7.02(s,2H),5.97(s,1H),4.20(m,1H),3.89(s,3H),3.59(m,4H),2.13(s,3H),2.01(m,12H),1.02(t,3H)ppm
实施例223
5-氯-2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-[(1-(吡咯烷-1-羰基)-丙基氨基]-烟酸甲酯
1HNMR(CDCl3)7.02(s,2H),6.41(d,1H),4.44(m,1H),3.93(s,3H),3.56(m,2H),3.47(m,2H),2.26(s,3H),2.06(s,6H),2.00(m,6H),0.91(t,3H)ppm
实施例224
2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-(1-甲基氨基甲基-丙基氨基)-烟酸甲酯
将2-(4-氯-2,6-二甲基-苯氧基)-4-(1-甲酰基-丙基氨基)-6-甲基-烟酸甲酯(67mg,0.17mmol)在二氯乙烷(2ml)中的混合物用甲胺、1滴乙酸、无水Na2SO4和无水氰基硼氢化钠处理,并在室温下搅拌过夜。混合物用水骤冷,二氯甲烷提取,将有机层分离,干燥,浓缩,并使用二氯甲烷至在二氯甲烷中的5%甲醇作为洗脱剂,通过硅胶Biotage纯化,得到为灰白色固体的标题化合物。1HNMR(CDCl3)8.07(d,1H),7.02(s,2H),6.29(s,1H),3.87(s,3H),3.80(m,1H),2.88(m,2H),2.56(s,3H),2.11(s,3H),2.06(s,6H),1.63(m,2H),0.99(t,3H)ppm
用与在实施例224中描述的相似的还原胺化方法,制备如下化合物(实施例225-227)。
实施例225
2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-(1-吡咯烷-1-基甲基-丙基氨基)-烟酸甲酯
1HNMR(CDCl3)8.11(d,1H),6.99(s,2H),6.12(s,1H),3.84(s,3H),3.54(m,1H),3.43(m,2H),2.56(m,4H),2.07(s,3H),2.06(s,6H),1.84(m,6H),.96(t,3H)ppm
实施例226
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-环丙基氨基甲基-丙基氨基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.07(d,1H),7.02(s,2H),6.31(s,1H),3.87(s,3H),3.79(m,1H),2.96(m,1H),2.36(m,1H),2.11(s,3H),2.07(s,6H),1.83(m,1H),1.61(m,1H),0.99(t,3H),0.98(m,4H)ppm
实施例227
2-(4-氯-2,6-二甲基-苯氧基)-4-{1-[(环丙基甲基-氨基)-甲基]-丙基氨基}-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.07(d,1H),7.02(s,2H),6.55(s,1H),4.12(m,1H),3.88(s,3H),3.06(d,2H),2.87(m,2H),2.16(s,3H),2.05(s,6H),2.03(m,1H),1.69(m,1H)1.25(m,1H)1.03(t,3H),0.66(m,2H),0.38(m,2H)ppm
实施例228
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基氨基甲基-丙基氨基)-6-甲基-烟酸甲酯
将2-(4-氯-2,6-二甲基-苯氧基)-4-(1-甲磺酰氧基甲基-丙基氨基)-6-甲基-烟酸甲酯在乙腈中的溶液采用碘化钠、乙胺和三乙胺处理。将获得的混合物加热到70℃过夜,然后在85℃下6hrs,然后于100℃过夜,直到薄层色谱显示无起始原料。将获得的混合物采用水骤冷并采用乙酸乙酯萃取。将有机层分离,干燥,浓缩,纯化得到为油的标题化合物。1HNMR(CDCl3)d 8.06(d,1H),7.02(s,2H),6.31(s,1H),3.88(s,3H),3.86(m,1H),2.85(m,4H),2.12(s,3H),2.07(s,6H),1.64(m,1H),1.60(m,1H),1.27(m,3H),.99(t,3H)
实施例229
2-(4-氯-2,6-二甲基-苯氧基)-4-{1-[(乙基-甲基-氨基)-甲基]-丙基氨基}-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.18(d,1H),7.02(s,2H),6.19(m,1H),3.86(s,3H),3.56(m,3H),3.37(m,2H),2.11(s,3H),2.07(s,6H),1.80(m,1H),1.60(m,2H),1.25(m,4H),0.97(t,3H)ppm
实施例230
4-(1-丁基氨基甲基-丙基氨基)-2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.07(d,1H)7.02(s,1H),6.25(s,1H),3.87(s,3H),3.79(m,1H),2.79(m,2H),2.69(m,2H),2.10(s,3H),2.07(s,6H),1.75(m,2H),1.57(m,4H),1.00(t,3H),0.92(t,6H)ppm
实施例231
2-(4-氯-2,6-二甲基-苯氧基)-4-{1-[(环丙基甲基-丙基-氨基)-甲基]-丙基氨基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.01(d,1H),7.02(s,2H),6.13(s,1H),3.85(s,3H),3.48(m,1H),2.58(m,2H),2.37(m,1H),2.09(s,3H),2.07(s,6H),1.82(m,1H)1.42(m,2H),1.25(m 4H),0.97(t,t,3H),0.86(m,6H)ppm
实施例232
2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-(1-丙基氨基甲基-丙基氨基)-烟酸甲酯
1H NMR(CDCl3)d 8.09(d,1H),7.02(s,2H),6.19(s,1H),3.86(s,3H),3.60(m,1H),2.76(m,2H),2.61(t,2H),2.10(s,3H),2.07(s,6H),1.61(m,6H),0.97(t,3H),0.91(t,3H)ppm
实施例233
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-{[(呋喃-2-基甲基)-氨基]-甲基}-丙基氨基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.09(d,1H),7.37(s,1H),7.02(s,2H),6.31(dd,2H),6.17(s,1H),3.87(s,3H),3.84(s,2H),3.58(m,1H),2.75(m,2H),2.09(s,3H),2.07(s,6H),1.70(m,1H),1.58(m,1H),0.95(t,3H)ppm
实施例234
2-(4-氯-2,6-二甲基-苯氧基)-4-{1-[(2-甲氧基-乙基氨基)-甲基]-丙基氨基}}-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.10(d,1H),7.02(s,2H),6.19(s,1H),3.87(s,3H),3.61(m,1H),3.51(m.2H),3.34(s,3H),2.84(m,2H),2.79(m,2H),2.10(s,3H),2.07(s,6H),1.71(m,1H),1.57(m,1H),0.98(t,3H)ppm
实施例235
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-二甲基氨基甲基-丙基氨基)-6-甲基-烟酸甲酯
1HNMR(CDCl3)8.14(d,1H),7.02(s,2H),6.10(s,1H),3.86(s,3H),3.53(m,1H),2.44(m,2H),2.29(s,6H),2.10(s,3H),2.07(s,6H),1.78(m,1H),1.56(m,1H),0.97(t,3H)ppm
实施例236
4-[(2-丁基氨基-乙基)-乙基-氨基]-2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-烟酸甲酯
1HNMR(CDCl3)7.00(s,2H),6.31(s,1H),3.88(s,3H),3.41(t,2H),3.26(m,2H),2.82(t,2H),2.65(t,2H),2.15(s,3H),2.05(s,6H),1.51(m,2H),1.34(m,2H),1.12(t,3H),0.89(t,3H)ppm
实施例237
2-(4-氯-2,6-二甲基-苯氧基)-4-(S,S)-(1-乙基-2-甲基氨基-丙基氨基)-6-甲基-烟酸甲酯
通过如上所示的还原胺化,采用2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基-2-氧代-丙基氨基)-6-甲基-烟酸甲酯和甲胺开始,制备标题化合物。
APCI M+1[420.2].1H NMR(CDCl3)
实施例238
2-(4-氯-2,6-二甲基-苯氧基)-4-(S,R)-(1-乙基-2-甲基氨基-丙基氨基)-6-甲基-烟酸甲酯
通过如上所示的还原胺化,采用2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基-2-氧代-丙基氨基)-6-甲基-烟酸甲酯和甲胺开始,制备标题化合物。
APCI M+1[420.2],1H NMR(CDCl3)
实施例239
2-(4-甲氧基-2,6-二甲基-苯氧基)-6-甲基-4-(1-甲基硫基甲基-丙基氨基)-烟酸甲酯
在室温下,将2-(4-甲氧基-2,6-二甲基-苯氧基)-4-(1-甲磺酰氧基甲基-丙基氨基)-6-甲基-烟酸甲酯和碘化钠在乙腈中的混合物搅拌2hr,然后加入NaSMe。将混合物在60℃下加热过夜。加入DMSO和另外的NaSMe并加热另外的数小时直到所有的起始原料消耗完。将混合物采用水骤冷,采用乙酸乙酯萃取。将有机层分离,干燥,浓缩,纯化得到标题化合物。
1HNMR(CDCl3)8.23(d,1H),6.59(s,2H),6.10(s,1H),3.87(s,3H),3.78(s,3H),3.60(m,1H),2.75(m,1H),2.65(m,1H),2.14(s,3H),2.08(m,9H),1.85(m,1H),1.66(m,1H),1.00(t,3H)ppm
通过相似于实施例239中描述的方法,采用合适的2-(取代苯氧基)-4-(1-甲磺酰氧基甲基-丙基氨基)-3,6-取代吡啶和合适的亲核试剂,制备如下化合物(实施例240-243):
实施例240
2-(4-甲氧基-2,6-二甲基-苯氧基)-6-甲基-4-(1-[1,2,4]三唑-1-基甲基-丙基氨基)-烟酸甲酯
1H(CDCl3)8.23(d,1H),8.02(s,1H),7.95(s,2H),5.92(s,1H),6.59(s,2H),5.93(s,1H),4.31(m,1H),4.22(m,1H),3.93(m,1H),3.87(s,3H),3.77(s,3H),2.10(s,3H),2.07(s,6H),1.70(m,1H),1.59(m,1H),1.04(t,3H)ppm
实施例241
2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-(1-甲基硫基甲基-丙基氨基)-烟酸甲酯
1HNMR(CDCl3)8.27(d,1H),7.02(s,2H),6.12(s,1H),3.87(s,3H),3.61(m,1H),2.70(m,2H),2.17(s,3H),2.14(s,3H),2.08(s,6H),1.85(m,2H),1.00(t,3H)ppm
实施例242
2-(4-氯-2,6-二甲基-苯氧基)-4-(2-乙基-氮丙啶-1-基)-6-甲基-烟酸甲酯
7.02(s,2H),6.38(s,1H),3.95(s,3H),2.27(m,1H),2.18(s,3H),2.15(m,2H),2.06(s,6H),1.75(m,1H),1.63(m,1H),1.06(t,3H)ppm.
实施例243
2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-[1-(3H-[1,2,3]三唑-4-基硫基甲基)-丙基氨基]-烟酸甲酯
1HNMR(CDCl3)8.32(d,1H),7.54(s,1H),6.95(s,2H),6.13(s,1H),3.87(s,3H),3.67(m,1H),3.20(m,1H),3.05(m,1H),2.05(m,9H),1.99(m,1H),1.67(m,1H),1.01(t,3H)ppm
实施例244
2-(4-氯-2,6-二.甲基-苯氧基)-4-(1-羟甲基-3-甲磺酰基-丙基氨基)-6-甲基-烟酸甲酯
在二氯甲烷中,在室温下,采用间氯过苯甲酸对2-(4-氯-2,6-二甲基-苯氧基)-4-(1-羟甲基-3-甲基硫基-丙基氨基)-6-甲基-烟酸甲酯进行氧化2hrs,制备标题化合物。1H NMR(CDCl3)d 8.32(d,1H),7.04(s,2H),6.23(s,1H),3.88(s,3H),3.7-3.9(m,3H),3.1-3.3(m,2H),2.95(s,3H),2.0-2.4(m,2H),2.13(s,3H),2.07(s,6H)ppm.
通过相似于实施例188中描述的方法,制备如下化合物(实施例245-248)。
实施例245
2-(4-乙氧基-2,6-二甲基-苯氧基)-6-甲基-4-(四氢-呋喃-3-基氨基)-烟酸甲酯
1H NMR(CDCl3)d 8.35(d,1H),6.59(s,2H),6.08(s,1H),4.03(m,1H),4.01(m,4H),3.99(m,1H),3.92(s,3H),3.89(m,1H),2.34(m,1H),2.25(m,3H),2.08(s,6H),1.39(t,3H)ppm
实施例246
2-[4-(2-甲氧基-乙氧基)-2,6-二甲基-苯氧基]-6-甲基-4-(四氢-呋喃-3-基氨基)-烟酸甲酯
1H NMR(CDCl3)d 8.30(d,1H),6.62(s,2H),6.07(s,1H),4.10(m,3H),4.02(m,2H),3.98(m,1H),3.85(s,2H),3.75(m,3H),3.45(s,3H),2.32(m,1H),2.19(s,3H),2.07(s,6H)ppm
实施例247
2-(2,6-二甲基-4-三氟甲氧基-苯氧基)-6-甲基-4-(四氢-呋喃-3-基氨基)-烟酸甲酯
1H NMR(CDCl3)d 8.29(d,1H,J=6Hz),6.91(s,2H),6.06(s,1H),4.11-4.33(m,1H),3.97-4.05(m,2H),3.89-3.93(m,1H),3.87(s,3H),3.72-3.76(m,1H),2.31-2.35(m,1H),2.14(s,3H),2.10(s.6H),1.94-1.96(m,1H)ppm.APCI+m/z=441.2(M+1)
实施例248
2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-(R)-(四氢-呋喃-3-基氨基)-烟酸甲酯
APCI+m/z=391.3(M+1)
实施例249
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-羟甲基-3-碘-丙基氨基)-6-甲基-烟酸甲酯
APCI[M+1]518.9,520.9
实施例250
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-羟甲基-3-甲烷亚硫酰基-丙基氨基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 8.31(d,1H),7.03(s,2H),6.24(s,0.5H),6.28(s,0.5H),3.87(s,3H),3.65-3.9(m,3H),2.7-3.0(m,2H),2.60(s,3H),2.0-2.4(m,2H),2.14(s,3H),2.07(s,6H)ppm.
实施例251
2-(4-环丙氧基-2,6-二甲基-苯氧基)-6-甲基-4-(四氢-呋喃-3-基氨基)-烟酸甲酯
1H NMR(CDCl3)d 8.32(d,1H),6.73(s,2H),6.07(s,1H),4.13(m,1H),4.01(m,4H),3.98(m,1H),3.85(s,3H),3.72(m,2H),2.22(s,3H),2.09(s,6H0,.87(m,2H),.75(m,4H)ppm
实施例252
2-(4-氯-2,6-二甲氧基-苯氧基)-6-甲基-4-(四氢-呋喃-3-基氨基)-烟酸甲酯
实施例253
4-仲丁基氨基-6-甲基-2-(2,4,6-三甲基-吡啶-3-基氧)-烟酸甲酯;
1H NMR(CDCl3)8.08(d,1H),686(s,1H),6.09(s,1H),3.86(s,3H),3.48(m,1H),2.49(s,3H),2.31(s,3H),2.08(s,6H),1.63(m,2H),1.21(d,3H),0.98(t,3H)ppm
实施例254
2-(4-氯-2,6-二甲基-苯氧基)-4-{乙基-[2-(乙基-甲基-氨基)-乙基]-氨基}-6-甲基-烟酸甲酯
实施例255
2-(4-氯-2,6-二甲基-苯氧基)-4-[乙基-(2-丙基氨基-乙基)-氨基]-6-甲基-烟酸甲酯
实施例256
4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-吡啶-3-基氧)-烟酸甲酯;
1H NMR(CDCl3)8.09(d,1H),6.86(s,1H),6.08(s,1H),3.86(s,3H),3.33(m,1H),2.49(s,3H),2.31(s,3H),2.07(s,6H),1.63(m,4H),0.94(t,6H)ppm
1H NMR(CDCl3)d 8.39 d,1H,J=6Hz),6.63(s,2H),6.06(s,1H),4.08-4.15(m,1H),3.95-4.05(m,2H),3.88-3.92(m,1H),3.86(s,3H),3.73(s,6H),3.67-3.73(m,1H),2.26-2.35(m,1H),2.14(s,3H),1.89-1.96(m,1H)ppm.
如下实施例257-287涉及本发明通式I的其它化合物,其中R4是-C(O)NR24R25:
通过相似于实施例113中的方法,从相应的烟酸或嘧啶-5-羧酸衍生物开始并采用合适的亲核试剂骤冷,制备如下化合物(实施例257-280);也可以在NMP中,在130-160℃下,通过2-(取代苯氧基)-6-甲基-4-氯-烟酰胺和/或-N-取代烟酰胺的偶联,制备这些化合物:
实施例257
2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-(四氢-呋喃-3-基氨基)-烟酰胺
1H NMR(CDCl3)d 9.99(d,1H),7.85(brs,1H),7.07(s,2H),6.13(s,1H),5.62(brs,1H),3.7-4.2(m,5H),2.95(d,3H),2.31(m,1H),2.20(s,3H),2.09(s,6H),2.01(m,1H)ppm.
实施例258
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-羟甲基-3-甲基硫基-丙基氨基)-6-甲基-烟酰胺
1H NMR(CDCl3)d 9.78(d,1H),7.97(brs,1H),7.06(s,2H),6.32(s,1H),5.77(brs,1H),3.6-3.9(m,3H),2.5-2.7(m,2H),2.0-2.2(m,12H),1.8-2.0(m,2H)ppm.
实施例259
2-(4-氯-2,6-二甲基-苯氧基)-6,N-二甲基-4-(S)-(四氢-呋喃-3-基氨基)-烟酰胺
1H NMR(CDCl3)d 10.00(d,1H),8.05(brs,1H),7.06(s,2H),6.10(s,1H),4.09(m,1H),3.96-4.05(m,3H),3.73(m,1H),2.95(d,3H),2.31(m,1H),2.12(s,3H),2.06(s,6H),1.96(m,1H)ppm.
实施例260
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基-丙基氨基)-6,N-二甲基-烟酰胺
1H NMR(CDCl3)d 9.78(d,1H),8.10(brs,1H),7.06(s,2H),6.13(s,1H),3.32(m,1H),2.96(d,3H),2.09(s,3H),2.08(s,6H),1.65(m,4H),0.96(t,6H)ppm.
实施例261
4-仲丁基氨基-2-(4-氯-2,6-二甲基-苯氧基)-6,N-二甲基-烟酰胺
1H NMR(CDCl3)d 9.78(d,1H),8.04(brs,1H),7.07(s,2H),6.14(s,1H),3.46(m,1H),2.95(d,3H),2.15(s,3H),2.09(s,6H),1.1.58(m,2H),1.23(d,3H),0.99(t,6H)ppm.
实施例262
4-(1-乙基-丙基氨基)-2-(4-甲氧基-2,6-二甲基-苯氧基)-6-甲基-烟酰胺
Mp=184℃实测值:C,67.68,H,8.12,N,10.81;计算值:C,67.90,H,7.87,N,11.31.
1H(CDCl3)9.67(d,1H),8.06(m,1H)6.61(s,2H),6.11(s,1H),5.48(s,1H),3.79(s,3H),3.32(m,
1H),2.09(s,9H),1.61(s,4H),0.95(t,6H)ppm
实施例263
4-(1-乙基-丙基氨基)-2-(4-甲氧基-2,6-二甲基-苯氧基)-6,N-二甲基-烟酰胺
1H(CDCl3)9.78(d,1H),8.22(m,1H),6.60(s,2H),6.10(s,1H),3.78(s,3H),3.25(m,1H),2.93(d,3H),2.07(s,9H),1.61(m,4H),0.95(t.6H)ppm
实施例264
2-(4-甲氧基-2,6-二甲基-苯氧基)-4-(1-甲氧基甲基-丙基氨基)-6-甲基-烟酰胺
1HNMR(CDCl3)9.80(d,1H),8.04(s,1H),6.61(s,2H),6.18(s,1H),5.62(s,1H),3.78(s,3H),3.51(m,2H),3.39(s,3H),2.09(s,3H),2.08(s,6H),1.79(m,1H),1.59(m,1H),0.99(t,3H)ppm
实施例265
2-(4-甲氧基-2,6-二甲基-苯氧基)-4-(1-甲氧基甲基-丙基氨基)-6,N-二甲基-烟酰胺
1HNMR(CDCl3)9.92(d,1H),8.22(s,1H),6.62(s,2H),6.19(s,1H),3.79(s,3H),3.5(m,2H),3.38(s,3H),2.94(d,3H),2.12(s,3H),2.08(s,6H),1.80(m,1H),1.61(m,1H),1.00(t,3H)ppm
实施例266
4-(1-羟甲基-丙基氨基)-2-(4-甲氧基-2,6-二甲基-苯氧基)-6,N-二甲基-烟酰胺
1HNMR(CDCl3)9.79(d,1H),8.28(d,1H),6.62(s,2H),6.24(s,1H),3.79(s,3H),3.70(m,2H),3.54(m,1H),2.94(d,3H),2.08(s,6H),1.62(m,2H),1.01(t,3H)ppm
实施例267
4-仲丁基氨基-2-(4-甲氧基-2,6-二甲基-苯氧基)-6,N-二甲基-烟酰胺
1HNMR(CDCl3)9.76(d,1H),8.26(d,1H),6.61(s,2H),6.12(s,1H),3.79(s,3H),3.46(m,1H),2.94(d,3H),2.09(s,3H),2.07(s,6H),1.64(m,2H),1.24(m,3H),0.98(t,3H)ppm
实施例268
2-(4-氯-2,6-二甲基-苯氧基)-4-(S)-(1-甲氧基甲基-丙基氨基)-6,N-二甲基-烟酰胺
元素分析C21H28ClN3O3计算值C,62.14%H,6.95%,N,10.35%;实测值C,62.12%,H,6.95%,N,10.42%.
实施例269
2-(4-氯-2,6-二甲基-苯氧基)-4-(S)-(1-甲氧基甲基-丙基氨基)-6-甲基-烟酰胺
元素分析C20H26ClN3O3计算值C,61.30%H,6.69%,N,10.725%;实测值C,60.97%,H,6.53%,N,10.47%.
实施例270
2-(4-氯-2,6-二甲基-苯氧基)-6,N-二甲基-4-(1-甲基硫基甲基-丙基氨基)-烟酰胺
1HNMR(CDCl3)9.97(d,1H),8.1(brs,1H),7.06(s,2H),6.16(s,1H),3.56(m,1H),2.96(s,3H),2.6-2.8(m,2H),2.17(s,3H),2.11(s,3H),2.08(s,6H),1.6-1.9(m,2H),1.24(m,3H),1.00(t,3H)ppm
实施例271
2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-(1-甲基硫基甲基-丙基氨基)-烟酰胺
1HNMR(CDCl3)9.89(d,1H),7.9(brs,1H),7.06(s,2H),6.16(s,1H),3.56(m,1H),2.6-2.8(m,2H),2.17(s,3H),2.11(s,3H),2.07(s,6H),1.6-1.9(m,2H),1.24(m,3H),0.99(t,3H)ppm
实施例272
2-(4-氯-2-甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6,N-二甲基-烟酰胺
1H NMR(CDCl3)d 9.40(d,1H,J+8Hz),8.10(br s,1H),7.17(d,1H,J=9Hz),6.94-6.96(m,2H),6.14(s,1H),3.79(s,3H),3.27-3.31(m,1H),2.93(d,J=5Hz)2.14(s,3H),1.51-1.66(m,4H),0.95(t,6H,J=7Hz)ppm..CI+m/z=392.2(M+1),394.2(M+3)
实施例273
2-(4-氯-2-甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酰胺
1H NMR(CDCl3)d 9.40(d,1H),7.92(brs,1H),7.17(d,1H,J=9Hz),6.94-6.96(m,2H),6.15(s,1H),5.48(br s,1H),3.77(s,3H),3.28-3.36(m,1H),2.16(s,3H),1.52-1.66(m,4H),0.94(t,6H,J=7Hz)ppm.APCI+m/z=378.1(M+1),380.1(M+3)
实施例274
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-环丙基甲氧基甲基-丙基氨基)-6-甲基-烟酰胺
1H NMR(CDCl3)d 9.70(d,1H),7.90(brs,1H),7.05(s,1H),6.22(s,1H),5.6(br s,1H),3.57(m,2H),3.43(m,1H),3.33(d,3H),2.09(s,6H),2.07(s,3H),1.5-1.9(m,2H),0.9-1.0(m,4H),0.53(m,2H),0.50(m,2H)ppm.
实施例275
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙氧基甲基-丙基氨基)-6-甲基-烟酰胺
1H NMR(CDCl3)d 9.75(d,1H),7.90(brs,1H),7.05(s,1H),6.21(s,1H),5.6(br s,1H),3.3-3.6(m,4H),2.08(s,6H),2.07(s,3H),1.5-1.9(m,2H),1.20(t,3H),1.00(t,3H)ppm.
实施例276
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙氧基甲基-丙基氨基)-N-乙基-6-甲基-烟酰胺
1H NMR(CDCl3)d 9.78(d,1H),8.09(t,1H),7.06(s,1H),6.22(s,1H),5.6(br s,1H),3.3-3.6(m,6H),2.09(s,3H),2.08(s,6H),1.5-1.9(m,2H),1.20-1.4(m,6H),1.00(t,3H)ppm.
实施例277
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙氧基甲基-丙基氨基)-6,N-.二甲基-烟酰胺
1H NMR(CDCl3)d 9.8(d,1H),8.1(brs,1H),7.06(s,1H),6.22(s,1H),3.54(m,3H),3.38(m,1H),2.94(d,3H),2.08(s,6H),2.07(s,3H),1.83(m,1H),1.60(m,1H),1.20(t,3H),1.00(t,3H)ppm.
实施例278
2-(4-溴-2-甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6,N-二甲基-烟酰胺
1H NMR(CDCl3)d 9.41(br d,1H),8.08(br s,1H),7.09-7.12(m,3H),6.15(s,1H),3.79(s,1H),3.28-3.33(m,1H),2.93(d,3H,J=5Hz),2.15(s,3H),1.501-1.65(m,4H),0.95(t,6H,J=8Hz)APCI+m/z=436.1(M+1),438.1(M+3)
实施例279
2-(4-溴-2-甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酰胺
1H NMR(CDCl3)d 9.39(br d,1H),7.91(br s,1H),7.09-7.11(m,3H),6.15(s,1H),5.49(br s,1H),3.77(s,3H),3.29-3.34(m,1H),2.15(s,3H),1.51-1.67(m,4H),0.94(t,6H,J=7Hz)ppm.APCI+m/z=422.1(M+1),424.1(M+3)
实施例280
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-氯甲基-丙基氨基)-6-甲基-烟酰胺
1H NMR(CDCl3)d 9.93(d,1H),7.9(brs,1H),7.06(s,2H),6.16(s,1H),5.6(brs,1H),3.4-3.7(m,3H),2.1(s,3H),2.08(s,6H),1.9(m,1H),1.65(m,1H),1.03(t,3H)ppm.
实施例281
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-甲酰基-丙基氨基)-6-甲基-烟酰胺
在室温下,将2-(4-氯-2,6-二甲基-苯氧基)-4-(1-羟甲基-丙基氨基)-6-甲基-烟酰胺和Dess-Martin试剂在二氯甲烷/DMSO中的混合物搅拌4hr。在标准处理和硅胶Biotage纯化之后,分离标题化合物。
1H NMR(CDCl3)d 9.52(s,1H),8.00(brs,1H),7.06(s,22H),5.99(s,1H),5.8(brs,1H),3.85(m,1H),2.09(s,3H),2.08(s,6H),1.8-2.2(m,2H),1.08(t,3H)ppm.
实施例282
4-(1-甲酰基-丙基氨基)-2-(4-甲氧基-2,6-二甲基-苯氧基)-6,N-二甲基-烟酰胺
通过相似于在实施例281中描述的方法,制备标题化合物。
1HNMR(CDCl3)9.51(s,1H),8.32(m,1H),6.62(s,2H),5.97(s,1H),3.81(m,1H),3.79(s,3H),2.96(m,3H),2.08(m,9H),1.89(m,2H),1.09(t,3H)ppm
实施例283
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基-2-羟基-丙基氨基)-6-甲基-烟酰胺
在-78℃下,向在干燥THF中的MeMgBr溶液中,加入在干燥THF中的2-(4-氯-2,6-二甲基-苯氧基)-4-(1-甲酰基-丙基氨基)-6-甲基-烟酰胺溶液。将混合物在-78℃下搅拌2hr,然后采用稀酸骤冷。在标准萃取和纯化之后,获得标题化合物。1H NMR(CDCl3)d 9.8(d,1H),7.9(nbrs,1H),7.05(s,2H),6.27(s,0.5H),6.24(s,0.5H),5.6(brs,1H),3.91(m,0.5H),3.89(m,0.5H),3.51(m,0.5H),3.3(m,0.5H),2.09(s,9H),1.5-1.8(m,2H),1.26(d,3H),0.98(t,3H)ppm.
实施例284
4-(1-乙基-2-甲氧基-丙基氨基)-2-(4-甲氧基-2,6-二甲基-苯氧基)-6,N-二甲基-烟酰胺
1HNMR(CDCl3)9.87(d,1H),8.26(d,1H),6.61(s,2H),6.16(s,1H),3.79(s,3H),3.46(m,1H),3.40(s,3H),2.94(d,3H),2.08(s,9H),1.76(m,1H),1.65(m,1H),1.25(m,1H),1.17(d,3H),0.98(t,3H)ppm mp=122.6℃
实施例285
2-(4-溴-2,6-二甲基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酰胺
向2-氯-4-(1-乙基-丙基氨基)-6-甲基-烟酰胺和2,6-二甲基-4-溴-苯酚在NMP的混合物中加入t-BuOK。将获得的混合物在160℃油浴中加热过夜。将混合物采用水骤冷和采用乙酸乙酯萃取。将有机层分离,干燥和浓缩,然后通过硅胶Biotage纯化,得到标题化合物。
1H NMR(CDCl3)d 9.69(d,1H),7.89(brs,1H),7.20(s,2H),6.13(s,1H),5.5(brs,1H),3.3(m,1H),2.10(s,3H),2.09(s,6H),1.6(m,4H),0.95(t,6H)ppm.
实施例286
4-(1-乙基-2-甲氧基-丙基氨基)-6,N-二甲基-2-(2,4,6-三甲基-吡啶-3-基氧)-烟酰胺
1H(CDCl3)9.74(d,1H),8.08(s,1H),6.90(s,1H),6.12(s,1H),3.31(m,1H),2.96(d,3H),2.51(s,3H),2.30(s,3H),2.08(s,3H),2.05(s,3H),1.60(m,4H),0.95(t,3H)ppm
实施例287
4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-吡啶-3-基氧)-烟酰胺
MP=164.3℃ 1H NMR(CDCl3)9.65(d,1H),7.8(s,1H),6.91(s,1H),6.14(s,1H),5.50(s,1H),3.32(m,1H),2.53(s,3H),2.34(s,3H),2.17(s,3H),2.10(s,3H),1.60(m,4H),0.95(t,6H)ppm
如下实施例288-294涉及本发明通式I的其它化合物,其中R4是-C(O)R24,例如-C(O)CH3:
实施例288
1-[4-(1-乙基-丙基氨基)-2-(4-甲氧基-2,6-二甲基-苯氧基)-6-甲基-吡啶-3-基]-乙酮
1HNMR(CDCl3)9.74(d,1H),6.61(s,2H),6.10(s,1H),3.79(s,3H),3.39(m,1H),2.73(s,3H),2.10(s,9H),1.62(m,4H),0.94(t,6H)ppm
实施例289
N-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-N-(2-吡咯烷-1-基-乙基)-乙酰胺
1H NMR(CDCl3)d 6.89(s,2H),6.60(s,1H),4.00-4.07(m,1H),3.53-3.59(m,1H),2.59-2.72(m,2H),2.52(br s,4H),2.30(s,3H),2.24(s,3H),2.22(s,3H),2.04(s,6H),1.84(s,3H),1.74(br s,4H)ppm.
实施例290
N-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-N-(2-吡咯烷-1-基-乙基)-异丁酰胺
1H NMR(CDCl3)d 6.89(s,2H),6.56(s,1H),4.09-4.17(m,1H),3.38-3.48(m,1H),2.65-2.77(m,2H),2.61(br s,4H),2.33-2.40(m,1H),2.30(s,3H),2.24(s,3H),2.20(s,3H),2.05(s,6H),1.77(br s,4H),1.04(t,6H,J=7Hz)ppm.
实施例291
N-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-N-(2-吡咯烷-1-基-乙基)-丙酰胺酸乙酯
1H NMR(CDCl3)d 6.89(s,2H),6.63(s,1H),4.11-4.17(m,3H),3.44-3.56(m,1H),3.15(s,2H),2.72(br s,2H),2.57(br s,4H),2.30(s,3H),2.24(s,3H),2.23(s,3H),2.04(s,6H),1.77(br s,4H),1.24(t,3H,J=7Hz)
实施例292
2-(4-氯-2,6-二甲基-苯氧基)-4-环戊基氨基-6-甲基-6-吡啶-3-羰基醛
1H NMR(CDCl3)d 9.42(d,1H),7.05(s,2H),6.09(s,1H),4.18(brs,1H),4.06(m,2H),3.95(m,1H),3.77(m,1H),2.35(m,1H),2.17(s,3H),2.09(s,6H),1.98(m,1H)ppm.
实施例293
4-(1-乙基-丙基氨基)-2-(4-甲氧基-2,6-二甲基-苯氧基)-6-甲基-6-吡啶-3-羰基醛
1HNMR(CDCl3)9.26(d,1H),6.60(s,2H),6.10(s,1H),3.78(s,3H),3.40(m,1H),2.14(s,3H),2.11(s,6H),1.66(m,4H),0.96(t,6H)ppm
实施例294
1-[2-(4-氯-2-甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-吡啶-3-基]-乙酮
1H NMR(CDCl3)d 9.59(br d,1H),6.93-7.02(m,3H),6.14(s,1H),3.78(s,3H),3.33-3.38(m,1H),2.69(s,3H),2.14(s,3H),1.49-1.67(m,4H),0.94(t,6H,J=7Hz)ppm.
如下实施例295-329涉及本发明通式I的其它化合物,其中R4是甲基:
实施例295
仲丁基-[2-(2,6-二甲基-4-三氟甲氧基-苯氧基)-3,6-二甲基-吡啶-4-基]-胺
1H NMR(CDCl3)d 6.90(s,2H),6.09(s,1H),3.78(d,1H,J=8Hz),3.45-3.52(m,1H),2.15(s,3H),2.10(s,9H),1.51-1.67(m,2H),1.23(d,3H,J=8Hz),0.98(t,3H,J=7Hz)ppm.
实施例296
[2-(2,6-二甲基-4-三氟甲氧基-苯氧基)-3,6-二甲基-吡啶-4-基]-(1-乙基-丙基)-胺
1H NMR(CDCl3)d 6.91(s,2H),6.08(s,1H),3.74(d,1H,J=8Hz),3.31-3.34(m,1H),2.15(s,3H),2.11(s,6H),2.08(s,3H),1.49-1.68(m,4H),.96(t,6H,J=8Hz)ppm.
实施例297
[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-(2-吡咯烷-1-基-乙基)-(2,2,2-三氟-乙基)-胺
1H NMR(CDCl3)d 6.87(s,2H),6.55(s,1H),3.78(q,2H,J=9Hz),3.60-3.72(m,2H),2.82-2.98(m,6H),2.29(s,3H),2.26(s,3H),2.20(s,3H),2.03(s,6H),1.96(br s,4H)ppm.
采用合适的2-(取代苯氧基)-4-(1-甲磺酰氧基甲基-丙基氨基)-3,6-取代吡啶及合适的胺开始,制备如下化合物(实施例298和299):
实施例298
N2-[2-(4-氯-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-N1-环丙基甲基-丁烷-1,2-二胺
1H NMR(CDCl3)d 7.01(s,2H),6.17(s,1H),4.40(d,1H),3.82(m,1H),3.05(m,2H),2.69(m,2H),2.20(s,3H),2.12(s,3H),2.04(s,6H),1.70(m,2H),.98(t,3H),.96(m,4H)ppm
实施例299
N-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-N-乙基-N’,N’-二甲基-乙烷-1,2-二胺
1H NMR(CDCl3)d 6.86(s,2H),6.43(s,1H),3.26(AB quartet,2H),3.12(q,2H,J=7Hz),2.51(AB quartet,2H),2.34(s,6H),2.29(s,3H),2.23(s,3H),2.18(s,3H),2.05(s,6H),1.09(t,3H,J=7Hz)ppm.
实施例300
N-2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-N-1-甲基-丁烷-1,2-二胺
1HNMR(CDCl3)6.85(s,2H),6.12(s,1H),4012(d,1H),3.56(m,1H),2.79(m,2H),2.47(s,3H),2.28(s,3H),2.14(d,6H),2.06(s,6H),1.62(m,2H),0.97(t,3H)ppm
实施例301
N-2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-N-1-乙基-丁烷-1,2-二胺
1H NMR(CDCl3)d 7.80(s,1H),6.85(s,2H),6.12(s,1H),4.22(d,1H),3.57(m,1H),2.82(m,2H),2.72(q,2H),2.28(s,3H),2.13(s,6H),2.06(s,6H),1.63(m,2H),1.16(t,3H),0.97(t,3H)ppm
实施例302
N2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-N1-乙基-N1-甲基-丁烷-1,2-二胺
1H NMR(CDCl3)d 6.85(s,2H),6.06(s,1H),4.58(m,1H),3.39(m,1H),2.49(m,4H),2.28(s,6H),2.14(s,6H),2.06(s,6H),1.66(m,2H),1.08(m,3H),0.96(t,3H)ppm
实施例303
N-1-丁基-N-2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-丁烷-1,2-二胺
1H NMR(CDCl3)d 6.85(s,2H),6.11(s,1H),4.21(d,1H),3.51(q,1H),2.79(m,2H),2.65(t,2H),2.28(s,3H),2.14(s,6H),2.06(s,6H),1.62(m,2H),1.49(m,2H),1.35(m,2H),0.97(t,3H),0.91(t,3H)ppm
实施例304
N-1-环丙基甲基-N-2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-N-1-丙基-丁烷-1,2-二胺
1H NMR(CDCl3)d 6.85(s,2H),6.06(s,1H),4.65(m,1H),3.32(m 1H),2.61(m,4H),2.28(s,3H),2.14(s,3H),2.12(s,2H),2.06(s,6H),1.71(m,2H),1.46(m,2H),0.96(t,3H),0.87(t,3H)ppm
实施例305
N-2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-N-1-丙基-丁烷-1,2-二胺
1H NMR(CDCl3)d 6.85(s,2H),6.11(s,1H),4.21(d,1H),3051(q,1H),2.79(m,2H),2.62(m,2H),2.28(s,3H),2.13(s,6H),2.06(s,6H),1.62(m,2H),1.54(m,2H),0.97(t,3H),0.91(t,3H)ppm
实施例306
N-2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-N-1-(2-甲氧基-乙基)-丁烷-1,2-二胺
1H NMR(CDCl3)d 6.85(s,2H),6.11(s,1H),4.18(d,1H),3.51(m,3H),3.35(s,2H),2.82(m,4H),2.28(s,3H),2.14(s,6H),2.06(s,6H),1.62(m,2H),0.97(t,3H)ppm
实施例307
N-2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-N-1-呋喃-2-基甲基-丁烷-1,2-二胺
1HNMR(CDCl3)7.36(s,1H),6.85(s,2H),6.32(d,1H),6.24(d,1H),6.09(s,1H),4.15(d,1H),3.84(d,2H),3.58(m 1H),2.79(m,2H),2.28(s,3H),2.13(d,6H),2.05(s,6H),1.62(m,2H),0.95(t,3H)ppm
实施例308
N-1-环丙基甲基-N-2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-丁烷-1,2-二胺
1HNMR(CDCl3)6.85(s,2H),6.14(s,1H),4.39(m,1H),3.70(m,1H),3.01(m,2H),2.67(d,2H),2.28(s,3H),2.20(s,3H),2.14(s,3H),2.05(s,6H),1.71(m,2H),0.98(t.3H),0.55(d,2H),0.21(d,2H)ppm.
实施例309
[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-(1-噻唑烷-3-基甲基-丙基)-胺
1HNMR(CDCl3)6.85(s,2H),6.07(s,1H),4.21(d,1H),4.06(d,2H),3.41(m,1H),3.07(m,2H),2.89(m,2H),2.52(m,2H),2.28(s,3H),2.15(d,6H),2.06(s,6H),1.75(m,1H),1.66(m,1H0,0.98(t,3H)ppm
实施例310
N-2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-丁烷-1,2-二胺
在0℃下,向(1-羟甲基-丙基)-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-胺在甲苯的溶液中,加入二苯基磷酰基叠氮化物和1,8-二氮杂双环[3,4,0]十-碳-7-烯。将获得的混合物在室温下搅拌30min,然后加热75℃过夜。将反应混合物采用水骤冷和采用二氯甲烷萃取。将有机层分离,干燥,浓缩和使用1∶1二氯甲烷/己烷到二氯甲烷作为洗脱剂,通过硅胶Biotage纯化,得到为淡黄色油的(1-叠氮甲基-丙基)-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-胺。将油采用三苯基膦还原得到标题化合物。1H NMR
(CDCl3)d 6.86(s,2H),6.11(s,1H),4.02(d,1H),3.40(q,1H),2.84(m,2H),2.28(s,3H),2.13(s,
6H),2.06(s,6H),1.61(m,2H),0.98(t,3H)ppm
实施例311
1-{2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基氨基]-丁基}-3-乙基-脲
将N-2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-丁烷-1,2-二胺和异氰酸乙酯在二氯乙烷中的混合物在室温下搅拌过夜。标准处理和纯化得到标题化合物。APCI[M+1]=399.3,1H NMR(CDCl3)
实施例312
N-{2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基氨基]-丁基}-甲磺酰胺
将N-2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-丁烷-1,2-二胺和甲磺酰氯在二氯乙烷中的混合物在室温下搅拌过夜。标准处理和纯化得到标题化合物。APCI[M+1]=406.2,1H NMR(CDCl3)
实施例313
N-{2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基氨基]-丁基}-乙酰胺
将N-2-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-丁烷-1,2-二胺和乙酰氯在二氯乙烷中的混合物在室温下搅拌过夜。标准处理和纯化得到标题化合物。APCI[M+1]=370.3,1H NMR(CDCl3)
实施例314
环丙基甲基-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-丙基-胺
1H NMR(CDCl3)d 6.85(s,2H),6.44(s,1H),3.13(AB q,2H),2.90(d,2H,J=8Hz),2.28(s,3H),2.24(s,3H),2.16(s,3H),2.05(s,6H),1.47-1.65(m,2H),0.86-0.92(m,4H),0.42-0.46(m,2H),0.04-0.08(m,2H)APCI+m/z=353.3(M+1)
实施例315
环丙基甲基-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-丙基-胺
1H NMR(CDCl3)d 6.85(s,2H),6.44(s,1H),3.13(AB q,2H),2.90(d,2H,J=8Hz),2.28(s,3H),2.24(s,3H),2.16(s,3H),2.05(s,6H),1.47-1.65(m,2H),0.86-0.92(m,4H),0.42-0.46(m,2H),0.04-0.08(m,2H)
APCI+m/z=353.3(M+1)
实施例316
3,6-二甲基-4-(2-甲基-氮丙啶-1-基)-2-(2,4,6-三甲基-苯氧基)-吡啶
1H NMR(CDCl3)d 6.86(s,2H),6.29(s,1H),2.31(sa,3H),2.29(s,3H),2.19(m,1H),2.15(s,3H),2.10(m,2H),2.04(s,6H),1.44(d, 3H,J=5Hz)
实施例317
4-(2-甲氧基甲基-吡咯烷-1-基)-3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶
1H NMR(CDCl3)d 6.86(s,2H),6.34(s,1H),3.99(q,1H,J=4Hz),3.67(m,1H),3.49(dd,1H,J=9Hz,4Hz),3.32(s,3H),3.15(m,2H)2.29(s,3H),2.24(s,3H),2.16(s,3H),2.06(s,6H),1.78-1.97(m,4H)ppm.
实施例318
[2-(4-氯-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-(四氢-呋喃-3-基)-胺
1H NMR(CDCl3)d 7.04(s,2H),6.11(s,1H),4.27(brs,1H),3.7-4.1(m,4H),2.2-2.4(m,1H0,2.08(s,6H),2.07(s,6H),1.94(m,1H)ppm.
实施例319
[1-(叔丁基-二甲基-硅烷氧基甲基-丙基]-[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-胺
1H NMR(CDCl3)d 6.85(s,2H),6.07(s,1H),3.71(m,2H),3.39(m,1H),2.28(s,3H),2.16(s,3H),2.09(s,3H),2.06(s,6H),1.70(m,2H),0.91(s 9H)ppm
实施例320
[3,6-二甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-4-基]-乙基-(2-吡咯烷-1-基-乙基)-胺
1H NMR(CDCl3)d 6.86(s,2H),6.44(s,1H),3.25-3.30(m,2H),3.12(q,2H,J=7Hz),2.56-2.66(m,6H),2.29(s,3H),2.23(s,3H),2.17(s,3H),2.05(s,6H),1.80(br s,4H),1.09(t,3H,J=7Hz)
13C NMR(CDCl3)d.
APCI+m/z=382(M+1)
实施例321
4-[4-(1-乙基-丙氧基)-3,6-二甲基-吡啶-2-基氧]-3,5-二甲基-苯甲酸
向在干燥THF的中间体的-78℃溶液中加入n-BuLi。在该温度下搅拌10min之后,将CO2(g)鼓泡加入到反应混合物中。将获得的混合物在-78℃下搅拌2hr,逐渐升温到室温。将混合物采用稀HCl骤冷和采用二氯甲烷萃取。将有机层分离,干燥,浓缩,和纯化得到为白色固体的标题化合物,mp.168.4℃。1HNMR(CDCl3)7.58(s,2H),6.36(s,1H),4.24(m,1H),2.35(s,3H),2.22(s,3H),2.14(s,6H),1.75(m,4H),0.99(t,6H)ppm.
根据如下一般步骤制备如下实施例322-326:向在无水二氯甲烷的4-[4-(1-乙基-丙氧基)-3,6-二甲基-吡啶-2-基氧]-3,5-二甲基-苯甲酸的溶液中加入SOCl2和在室温下搅拌1hr。将混合物浓缩到干燥以提供相应的酰氯。将酰氯采用合适的亲核试剂(如,NH3、MeNH2、Me2NH、EtNH2、或甲醇)骤冷并在室温下搅拌以提供标题化合物:
实施例322
4-[4-(1-乙基-丙氧基)-3,6-二甲基-吡啶-2-基氧]-3,5-二甲基-苯甲酰胺
1H NMR(CDCl3)d 7.51(s,2H),6.32(s,1H),6.2(brs,1H),5.7(brs,1H),4.20(m,1H),2.22(s,3H),2.19(s,3H),2.12(s,6H),1.72(m,4H),0.97(t,6H)ppm.
实施例323
4-[4-(1-乙基-丙氧基)-3,6-二甲基-吡啶-2-基氧]-3,5,N-三甲基-苯甲酰胺
1H NMR(CDCl3)d 7.43(s,2H),6.30(s,1H),6.19(brs,1H),4.19(m,1H),2.95(d,3H),2.19(s,3H),2.18(s,3H),2.10(s,6H),1.71(m,4H),0.97(t,6H)ppm.
实施例324
4-[4-(1-乙基-丙氧基)-3,6-二甲基-吡啶-2-基氧]-3,5,N,N-四甲基-苯甲酰胺
1H NMR(CDCl3)d 7.12(s,2H),6.30(s,1H),4.18(m,1H),3.09(s,3H),3.05(s,3H),2.18(s,6H),2.10(s,6H),1.71(m,4H),0.97(t,6H)ppm.
实施例325
N-乙基-4-[4-(1-乙基-丙氧基)-3,6-二甲基-吡啶-2-基氧]-3,5-二甲基-苯甲酰胺
1H NMR(CDCl3)d 7.46(s,2H),6.30(s,1H),6.1(brs,1H),4.19(m,1H),3.48(m,2H),2.18(s,6H),2.12(s,6H),1.72(m,4H),1.25(t,3H),0.97(t,6H)ppm.
实施例326
4-[4-(1-乙基-丙氧基)-3,6-二甲基-吡啶-2-基氧]-3,5-二甲基-苯甲酸甲酯
1H NMR(CDCl3)d 7.76(s,2H),6.30(s,1H),4.17(m,1H),3.89(s,3H),2.19(s,3H),2.169(s,3H),2.12(s,6H),1.712(m,4H),0.97(t,6H)ppm.
根据如下一般步骤制备如下实施例327-329:向在无水二氯甲烷的4-[4-(1-乙基-丙基氨基)-3,6-二甲基-吡啶-2-基氧]-3,5-二甲基-苯甲酸的溶液中加入SOCl2和在室温下搅拌1hr。将混合物浓缩到干燥以提供相应的酰氯。将酰氯采用合适的亲核试剂(如,NH3、MeNH2、或甲醇)骤冷并在室温下搅拌以提供标题化合物:
实施例327
4-[4-(1-乙基-丙基氨基)-3,6-二甲基-吡啶-2-基氧]-3,5-二甲基-苯甲酰胺
1H NMR(CDCl3)d 7.51(s,2H),6.2(brs,1H),6.1(s,1H),5.5(brs,1H),3.9(d,1H),3.3(m,1H),2.19(s,3H),2.14(s,6H),2.12(s,3H),1,7(m,2H),1.5(m,2H),0.96(t,6H)ppm.
实施例328
4-[4-(1-乙基-丙基氨基)-3,6-二甲基-吡啶-2-基氧]-3,5,N-三甲基-苯甲酰胺
1H NMR(CDCl3)d 7.431(s,2H),6.3(ds,1H),6.091(s,1H),3.8(d,1H),3.35(m,1H),2.96(d,3H),2.16(s,3H),2.12(s,9H),1.65(m,2H),1.53(m,2H),0.95(t,6H)ppm.
实施例329
4-[4-(1-乙基-丙基氨基)-3,6-二甲基-吡啶-2-基氧]-3,5-二甲基-苯甲酸甲酯
1H NMR(CDCl3)d 7.751(s,2H),6.08(s,1H),3.89(s,3H),3.80(d,1H),3.34(m,1H),2.13(s,6H),2.11(s,6H),1.66(m,2H),1.54(m,2H),0.95(t,6H)ppm.
如下实施例330-340涉及本发明通式I的其它化合物,其中R4是-CN:
实施例330
2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-(四氢-呋喃-3-基氨基)-烟腈
APCI[M+1]358.3
实施例331
4-(1-乙基-丙基氨基)-2-(4-甲氧基-2,6-二甲基-苯氧基)-6-甲基-烟腈
计算值C:71.36;H:7.70;N:11.89;实测值C:71.16,H:8.09,N:11.47;HNMR(CDCl3)6.59(s,2H),6.08(s,1H),4.74(d,1H),3.78(s,3H),3.38(m,1H),2.18(s,3H),2.10(s,6H),1.64(m,2H),1.55(m,2H),0.96(t,6H)ppm.
实施例332
4-(1-乙基-丙基氨基)-6-甲基-2-(2,4,6-三甲基-吡啶-3-基氧)-烟腈
通过在NMP中加热2-氯-4-(1-乙基-丙基氨基)-6-甲基-烟腈和2,4,6-三羟基-3-吡啶,制备标题化合物。
1HNMR(CDCl3)7.02(m,1H),6.13(s,1H),4.81(d,1H),3.40(m,1H0,2.67(s,3H0,2.48(s,3H0,2.25(s,3H),2.16(s,3H),1.68(m,4H),0.97(t,6H)ppm
实施例333
2-(4-甲氧基-2,6-二甲基-苯氧基)-4-(1-甲氧基甲基-丙基氨基)-6-甲基-烟腈
1HNMR(CDCl3)6.59(s,2H),6.11(s,1H),5.08(d,1H),3.78(s,3H),3.56(m,1H),3.47(m,1H),3.38(s,3H),2.19(s,3H),2.10(s,6H),1.61(m,2H),0.99(t,3H)ppm
实施例334
2-(4-溴-2,6-二甲基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟腈
1H NMR(CDCl3)d 7.19(s,2H),6.09(s,1H),4.77(d,1H),3.39(m,1H),2.18(s,3H),2.10(s,6H),1.65(m,2H),1.55(m,2H),0.96(t,3H)ppm.
实施例335
4-[3-氰基-4-(1-乙基-丙基氨基)-6-甲基-吡啶-2-基氧]-3-甲氧基-苯甲酸甲酯
APCI[M+1]=384.2,1H NMR(CDCl3)
实施例336
4-[3-氰基-4-(1-乙基-丙基氨基)-6-甲基-吡啶-2-基氧]-3-甲氧基-苯甲酰胺
1H NMR(CDCl3)d 7.52(s,1H),7.32(d,1H),7.16(d,1H),6.25(brs,1H),6.12(s,1H),5.8(brs,1H),4.78(d,1H),3.80(s,3H),3.39(m,1H),2.20(s,3H),1.67(m,2H), 1.55(m,2H),0.95(t,3H)ppm.
实施例337
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-甲氧基甲基-丙基氨基)-6-甲基-烟腈
1H NMR(CDCl3)d 7.03(s,2H),6.12(s,1H),5.08(d,1H),3.47(m,1H),3.43(m,2H),3.38(s,3H),2.18(s,3H),2.09(s,6H),1.76(m,2H),1.61(m,2H),0.99(t,6H)ppm.
实施例338
2-(4-氯-2,6-二甲基-苯氧基)-4-[(1-甲氧基甲基-丙基)-甲基-氨基)-6-甲基-烟腈
1H NMR(CDCl3)d 7.03(s,2H),6.27(s,1H),4.33(m,1H),3.59(m,1H),3.52(m,1H),3.35(s,3H),3.06(s,3H),2.16(s,3H),2.11(s,6H),1.69(m,4H),0.97(t,6H)ppm..
实施例339
2-(4-氯-2-甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟腈
1H NMR(CDCl3)d 7.04(d,1H,J=9Hz),6.91-6.94(m,2H),6.10(s,1H),4.73(d,1H,J=9Hz),3.75(s,3H),3.35-3.38(m,1H),2.19(s,3H),1.47-1.70(m,4H),0.95(t,6H,J=8Hz)APCI+m/z=360.1(M+1),362.1(M+3)
实施例340
2-(4-溴-2-甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟腈
1H NMR(CDCl3)d 7.06-7.09(m,2H),6.98-7.00(m,1H),6.10(s,1H),4.73(br d,1H),3.75(s,3H),3.35-3.42(m,1H),2.21(s,3H),1.43-1.72(m,4H),0.95(t,6H,J=7Hz)ppm.
本发明的其它实施例如下:
实施例341
[2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-吡啶-4-基]-(1-甲氧基甲基-丙基)-胺
1H NMR(CDCl3)d 7.05(s,2H),6.04(s,1H),5.33(s,1H),4.26(br d,1H),3.34-3.39(m,1H),3.31(s,6H),2.31(s,3H),2.12(s,6H),1.47-1.61(m,4H),0.89(t,6H,J=8Hz)ppm.
实施例342
[2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-3-甲基氨基甲基-吡啶-4-基]-(四氢-呋喃-3-基)-胺
1H NMR(CDCl3)d 7.03(s,2H),6.08(s,1H),4.18(s,2H),3.8-4.2(m,5H),2.57(s,3H),2.2-2.4(m,2H),2.15(s,3H),2.04(s,6H)ppm.
实施例343
[2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-(四氢-呋喃-3-基)-吡啶-3-基]-胺
1H NMR(CDCl3)d 7.02(s,2H),6.10(s,1H),5.49(brs,1H),4.89(t,2H),4.12(brs,1H),4.01(m,2H),3.99(m,1H),3.75(m,1H),2.30(m,1H),2.16(s,3H),2.05(s,6H),1.95(m,1H)ppm.
实施例344
2-[2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-基氨基]-4-甲基硫基-丁-1-醇
1H NMR(CDCl3)d 7.06(s,2H),6.29(s,1H),5.47(s,1H),3.6-3.8(m,2H),3.5(m,1H),2.38(s,3H),2.11(s,6H),2.03(s,3H),1.87(m,1H),1.69(m,1H)ppm.
制备A
(6-氯-2-甲基-5-硝基-嘧啶-4-基)-(2,4,6-三甲基-吡啶-3-基)-胺
将2-甲基-5-硝基-4,6-二氯-嘧啶(208mg,1.00mmol)在2.5ml乙腈中的溶液采用2,4,6-三甲基-3-氨基-吡啶(273mg,2mmol)处理,在室温下搅拌2小时。将混合物采用水骤冷和采用乙酸乙酯萃取。将有机层采用盐水洗涤,干燥和浓缩得到残余物。使用氯仿到在氯仿中6%甲醇作为洗脱剂,将残余物通过硅胶柱色谱纯化,得到为橙色油的标题化合物(110mg,36%)。1HNMR(CDCl3)δ8.78(brs,1H),6.97(s,1H),2.54(s,3H),2.43(s,3H),2.40(s,3H),2.17(s,3H)ppm.
制备B
2-氯-4-(1-乙基-丙基氨基)-6-甲基-烟酸
在水和二噁烷混合物中,在室温下,通过2-氯-4-(1-乙基-丙基氨基)-6-甲基-烟酸甲酯与LiOH.H2O的反应,制备标题化合物。将所需产物酸化到pH3和采用乙酸乙酯萃取。将有机层干燥浓缩到干燥。在采用乙酸乙酯滴定之后,以白色晶体获得标题化合物。mp.164-165℃;元素分析C12H17Cl2O2计算值C,56.14;H,6.67;N,10.91;实测值:C,56.40;H,6.53;H,10.93.
制备C
4-氯-6-乙基-3-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-1-氧化物
向在干燥THF中的2,4,6-三甲基苯酚溶液中,加入NaH并在室温下搅拌20分钟。加入2,4-二氯-6-乙基-3-甲基-吡啶-1-氧化物的溶液并将获得的混合物在回流下加热1.5小时。将混合物冷却到室温,采用水骤冷,采用乙酸乙酯萃取。将有机层分离,干燥和浓缩得到标题化合物,它可直接用于下一步骤的反应。
制备D
4-氯-6-乙基-3-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶
向4-氯-6-乙基-3-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-1-氧化物在二氯甲烷的溶液中,加入PCl3并将获得的混合物在回流下加热20min,冷却到室温。将混合物浓缩到干燥。使用标准步骤处理残余物得到标题化合物。在硅胶纯化之后,分离白色固体得到标题化合物。mp.42-44℃.元素分析C17H20CINO计算值C,70.46;H,6.96;N,4.83;实测值,C,70.35;H,7.13;N,4.58.
制备E
2-[4-氯-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶-3-基甲基]-丙二酸二甲酯
在甲醇中,通过使4-氯-3-氯甲基-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶和丙二酸二甲酯/NaH反应,制备标题化合物。标题化合物分离为无色油。
制备F
4-氯-3,6-二甲基-2-(2,4,6-三甲基-3-吡啶基)-吡啶
制备G
2-氯-4-(1-甲氧基甲基-丙氧基)-6-甲基-烟酸乙酯
1H NMR(CDCl3)d 6.72(s,1H),4.5(m,1H),4.4(q,2H),3.49(d,2H),3.31(s,3H),2.46(s,3H),1.68(m,2H),1.34(t,3H),0.93(t,3H)ppm.
制备H
2-氯-4-(1-甲氧基甲基-丙氧基)-6-甲基-烟酸
1H NMR(CDCl3)d 6.81(s,2H),4.51(m,1H),3.60(m,2H),3.40(s,3H),2.55(s,3H),1.77(m,2H),1.02(t,3H)ppm.
制备I
(2-氯-6-甲基-3-硝基-吡啶-4-基)-(1-甲氧基甲基-丙氧基)-胺
mp.63-65℃,元素分析C11H16N3O3Cl计算值C,48.27;H,5.89,N,15.35;实测值C,48.65;H,6.03,N,15.11.
制备J
(5-溴-6-氯-2-甲基-嘧啶-4-基)-(2,4-二氯-苯基)-胺
Mp.165-167℃;元素分析C11H7BrCl3计算值:C,35.95;H,1.92;N,11.43;实测值:C,36.41;H,1.91;N,11.05.
制备K
(6-氯-2-甲基-嘧啶-4-基)-(2,4-二氯-苯基)-胺
Mp.134-136℃;元素分析C11H8Cl3N3计算值:C,45.79;H,2.79;N,14.56;实测值:C,45.91;H,2.69;N,14.50.
制备L
[4-氯-6-(1-乙基-丙基氨基)-2-甲基-嘧啶-5-基]-乙酸乙酯
Mp.78-80℃,元素分析C14H22ClN3O2计算值:C,56.09;H,7.40;N,14.02;实测值:C,56.31;H,7.60;N,13.94.
制备M
2-[4-溴-2-甲基-6-(2,4,6-三甲基-苯氧基)-嘧啶-5-基]-丙酸乙酯
1H NMR(CDCl3)d 6.86(s,2H),4.2-4.359m,2H),4.C-4.15(m,1H),2.4(s,3H),2.28(s,3H),1.99(s,3H),1.97(s,3H),1.58(d,3H),1.22(t,3H)ppm.
制备N
2-(4,6-二溴-2-甲基-嘧啶-5-基]-丙酸乙酯
1H NMR(CDCl3)4.36(m,1H),4.19(m,2H),2.68(s,3H),1.549d,3H),1.22(t,3H)ppm.
制备O
4-溴-3-甲氧基-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶
1H NMR(CDCl3)d 6.92(s,1H),6.87(s,2H),4.00(s,3H),2.299s,3H),2.18(s,3H),2.059s,6H)ppm.
制备P
4-溴-2-(4-氯-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶
1H NMR(CDCl3)d 7.04(s,2H),6.97(s,1H),2.42(s,3H),2.17(s,3H),2.03(s,6H)ppm.
制备Q
4-溴-2-(2,4-二氯-6-甲基-苯氧基)-3-甲氧基-6-甲基-吡啶
1H NMR(CDCl3)d 7.3(d,1H),7.18(d,1H),4.0(s,3H),2.2(s,3H),2.15(s,3H)ppm.
制备R
4-溴-2-(4-氯-2,6-二甲基-苯氧基)-3-甲氧基-6-甲基-吡啶
元素分析C15H15BrCINO2计算值:C,50.52;H,4.24;N,3.93;实测值:C,50.52;H,4.37;N,3.91.
制备S
4-溴-2-(4-氯-2-甲氧基-苯氧基)-3-甲氧基-6-甲基-吡啶
1H NMR(CDCl3)d 6.9-7.1(m,4H),3.94(s,3H),3.71(s,3H),2.21s,3H)ppm.
制备T
4-溴-2-(3-氯-2,6-二甲氧基-苯氧基)-3-甲氧基-6-甲基-吡啶
1H NMR(CDCl3)d 7.17(d,1H),6.96(s,1H),6.66(d,1H),3.97(s,3H),3.79(s,3H),3.70(s,3H),2.18(s,3H)ppm.
制备U
4-溴-3-甲氧基-6-甲基-2-(2,4,6-三甲基-苯氧基)-吡啶
1H NMR(CDCl3)d 6.90(s,1H),6.19(s,2H),3.968(s,3H),3.80(s,3H),3.71(s,6H),2.18(s,3H)ppm.
制备V
4-溴-3-甲氧基-2-(4-甲氧基-2,6-二甲基-苯氧基)-6-甲基-吡啶
1H NMR(CDCl3)d 6.92(s,1H),6.60(s,2H),3.98(s,3H),3.78(s,3H),2.18(s,3H),2.07(s,6H)ppm.
制备W
4-溴-2-(4-氯-2,6-二甲基-苯氧基)-3-乙氧基-6-甲基-吡啶
1H NMR(CDCl3)d 7.099s,2H),7.00(s,1H),4.28(q,2H),2.22(s,3H),2.10(s,6H),1.51(t,3H)ppm.
制备X
4-溴-3,6-二甲基-2-(2,4,6-三甲氧基-苯氧基)-吡啶
1H NMR(CDCl3)d 6.99(s,1H),6.25(s,2H),3.86(s,3H),3.77(s,6H),2.47(s,3H).2.25(s,3H)ppm.
制备Y
4-氯-2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-1-氧-烟酸甲酯
制备RR
4-氯-2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-烟酸甲酯
1H NMR(CDCl3)d 7.03(s,2H),6.869s,1H),3.969s,3H),2.259s,3H),2.05(s,6H)ppm.
制备Z
4-氯-6-甲基-2-(2,4,6-三甲氧基-苯氧基)-吡啶-3-羰基醛
在二氯甲烷中,在室温下,通过采用氯铬酸吡啶鎓氧化4-氯-6-甲基-2-(2,4,6-三甲氧基-苯氧基)-吡啶-3-基-甲醇,制备标题化合物。在柱色谱之后,将所需产物分离得到绿色固体(80%收率)。
1H NMR(CDCl3)d 10.66(s,1H),6.91(s,3H),2.31(s,3H),2.07(s,3H)ppm.
制备AA
2-(4-溴-2,6-二甲基-苯氧基)-4-氯-6-甲基-烟酸甲酯
mp.108-110℃;元素分析C16H15BrCINO3计算值,49.96;H,3.93;N,3.64;实测值:C,50.07;H,4.10;N,3.57.
制备BB
4-氯-2-(4-氯-2-甲氧基-苯氧基)-6-甲基-1-氧-烟酸甲酯
mp.117-120℃,元素分析C15H13NO5Cl2计算值:C,50.30;H,3.66;N,3.91;实测值:C,50.41;H,3.55;N,4.00.
制备CC
4-氯-2-(4-氯-2-甲氧基-苯氧基)-6-甲基-烟酸甲酯
mp.92-93℃,元素分析C15H13NO4Cl2计算值:C,52.65;H,3.83;N,4.09;实测值:C,52.34;H,3.85;N,4.13.
制备DD
[1-(叔丁基-二甲基-硅烷氧基甲基)-丙基]-[2-(4-氯-2,6-二甲基-苯氧基)-3,6-二甲基-吡啶-4-基]-胺
1H NMR(CDCl3)d 7.06(s,2H),6.12(s,1H),4.3(d,1H),3.6-3.8(m,2H),3.4(m,1H),2.16(s,3H),2.14(s,3H),2.10(s,6H),1.5-1.8(m,2H),1.03(t,3H),0.95(s,9H),0.09(m,6H)ppm.
通过相似于在实施例160中描述的方法,使用合适的4-溴-2-(取代苯氧基)-6-烷基或烷氧基-吡啶和1-(叔丁基-二甲基-硅烷氧基甲基)-丙胺,制备如下化合物。
制备EE
[1-(叔丁基-二甲基-硅烷氧基甲基)-丙基]-[3-甲氧基-6-甲基-2-(2,4,6-三甲氧基-苯氧基)-吡啶-4-(S)-基]-胺
1H NMR(CDCl3)d 6.84(s,2H),6.08(s,1H),4.8(d,1H),3.88(s,3H),3.5-3.7(m,2H),3.3(m,1H),2.27(s,3H),2.099s,3H),2.07(s,6H),1.75(m,1H),1.55(m,1H),0.97(t,3h),0.89(s,9H),0.04(s,6H)ppm.
制备FF
[1-(叔丁基-二甲基-硅烷氧基甲基)-丙基]-[2-(4-氯-2,6-二甲基-苯氧基)-3-甲氧基-6-甲基-吡啶-4-基]-胺
1H NMR(CDCl3)d 7.02(s,2H),6.10(s,1H),4.80(d,1H),3.87(s,3H),3.6-3.7(m,2H),3.30(m,1H),2.09(s,3H),2.08(s,6H),1.75(m,1H),1.55(m,1H),0.97(t,3H),0.89(s,9H),0.03(s,6H)ppm.
制备GG
4-[1-(叔丁基-二甲基-硅烷氧基甲基)-丙基氨基]-2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-吡啶-3-醇
1H NMR(CDCl3)d 7.01(s,2H),6.15(s,1H),4.46(d,1H),3.7(m,1H),3.6(m,1H),3.4(m,1H),2.09(s,3H),2.08(s,6H),1.5-1.8(m,2H),1.06(s,9H),0.98(t,3H),0.24(s,6H)ppm.
制备HH
[1-(叔丁基-二甲基-硅烷氧基甲基)-丙基]-[3-甲氧基-6-甲基-2-(2,4,6-三甲氧基-苯氧基)-吡啶-4-基]-胺
1H NMR(CDCl3)d 6.19(s,2H),6.09(s,1H),3.86(s,3H),3.80(s,3H),3.73(s,6H),3.3(m,1H),2.16(s,3H),1.75(m,1H),1.5(m,1H),0.95(t,3H),0.89(s,9H),0.04(s,6H)ppm.
制备II
4-{4-[1-(叔丁基-二甲基-硅烷氧基甲基)-丙基氨基]-3-甲氧基-6-甲基-吡啶-2-基氧}-3,5-二甲基-基]-苄腈
1H NMR(CDCl3)d 7.40(s,2H),6.19(s,1H),4.90(brs,1H),3.87(s,3H),3.70(m,2H),3.3(m,1H),2.19(m,9H),1.5-1.8(m,2H),1.02(t,3H),093(s,9H),0.09(s,6H)ppm.
Claims (24)
或其药用盐,其中虚线表示任选的双键,条件是当C
---G中的虚线表示双键时,则N(R6)
---C中的虚线不表示双键;并且条件是当N(R6)
---C中的虚线表示双键时,R6在通式III中不存在并且C
---G中的虚线不表示双键;
A是-CR7或N;
B是-NR1R2、-CR1R2R11、-C(=CR2R12)R1、-NHCHR1R2、-OCHR1R2、-SCHR1R2、-CHR2OR1、-CHR1OR2、-CHR2SR1、-C(S)R2、-C(O)R2、-CHR2NR1R2、-CHR1NHR2、-CHR1N(CH3)R2、或-NR12NR1R2;
当C
---G中的虚线表示双键时,则G是氢、氧、硫、NH、或N(C1-C4烷基);
当C
---G中的虚线不表示双键时,则C
---G是C(H)(NH2)、CH2、C(H)(甲氧基)、C(H)(乙氧基)、C(H)(O(C3-C4烷基))、C(H)(卤素)、C(H)(三氟甲氧基)、C(H)(甲基)、C(H)(乙基)、C(H)(C3-C4烷基)、C(H)(S(C1-C4烷基))、C(C1-C4烷基)(C1-C4烷基)、环丙基、C(H)(环丙基)、硫代甲氧基、C(H)(NH2)、C(H)(NHCH3)、C(H)(N(CH3)2)、或C(H)(三氟甲基);
其中C
---G的环丙基、甲氧基、乙氧基、C3-C4烷基、和C1-C4烷基可以任选地被一个OH、甲氧基、或三氟甲氧基取代,或可以任选地1-6个氟原子取代;
Y是CH或N;
Z是NH、O、S、-N(C1-C2烷基)、-NC(O)CF3、或-C(R13R14),其中R13和R14各自,任选地,是氢、三氟甲基或甲基,或R13和R14的一个是氰基和另一个是氢或甲基,或-C(R13R14)是环丙基,或Z是氮或CH和形成与R5稠合的五元或六元杂环,该环任选地包括两个或三个独立地选自氧、氮、NR12、和S(O)m的另外杂成员,并任选地包含1-3个双键,和任选地被卤素、C1-C4烷基、-O(C1-C4烷基)、NH2、NHCH3、N(CH3)2、CF3、或OCF3取代,条件是该环不包含任何-S-S-、-S-O-、-N-S-、或-O-O-键,和不包括多于两个氧或S(O)m异种成员;
R1是C(O)H、C(O)(C1-C6烷基)、C(O)(C1-C6亚烷基)(C3-C8环烷基)、C(O)(C3-C8亚环烷基)(C3-C8环烷基)、C(O)(C1-C6亚烷基)(C4-C8杂环烷基)、-C(O)(C3-C8亚环烷基)(C4-C8杂环烷基)、C1-C6烷基、C3-C8环烷基、C4-C8杂环烷基、(C1-C6亚烷基)(C3-C8环烷基)、-(C3-C8亚环烷基)(C3-C8环烷基)、-(C1-C6亚烷基)(C4-C8杂环烷基)、-(C3-C8亚环烷基)(C4-C8杂环烷基)、或-O-芳基、或-O-(C1-C6亚烷基)-芳基;其中芳基、C4-C8杂环烷基、C1-C6烷基、C3-C8环烷基、C3-C8亚环烷基、和C1-C6亚烷基可以每个独立地任选地被1-6个氟取代并且可以每个独立地任选地被一个或两个取代基R8取代,R8独立地选自C1-C4烷基、C3-C8环烷基、羟基、氯、溴、碘、CF3、-O-(C1-C6烷基)、-O-(C3-C5环烷基)、-O-CO-(C1-C4烷基)、-O-CO-NH(C1-C4烷基)、-O-CO-N(R24)(R25)、-N(R24)(R25)、-S(C1-C4烷基)、-S(C3-C5环烷基)、-N(C1-C4烷基)CO(C1-C4烷基)、-NHCO(C1-C4烷基)、-COO(C1-C4烷基)、-CONH(C1-C4烷基)、-CON(C1-C4烷基)(C1-C2烷基)、CN、NO2、-OSO2(C1-C4烷基)、S+(C1-C6烷基)(C1-C2烷基)I-、-SO(C1-C4烷基)和-SO2(C1-C4烷基);并且其中R1的C1-C6烷基、C1-C6亚烷基、C5-C8环烷基、C5-C8亚环烷基、和C5-C8杂环烷基部分可任选地包含1-3个双键或三键;和其中R8的C1-C4烷基部分和C1-C6烷基部分可以任选独立地被羟基、氨基、C1-C4烷基、芳基、-CH2-芳基、C3-C5环烷基、或-O-(C1-C4烷基)取代,和可以任选地被1-6个氟取代,和可以任选地包含1-2个双键或三键;和其中R1的每个杂环基包含1-3个选自氧、S(O)m、氮、和NR12的杂部分;
R2是氢、C1-C12烷基、C3-C8环烷基、C4-C6杂环烷基、-(C1-C6亚烷基)(C3-C8环烷基)、-(C3-C8亚环烷基)(C3-C8环烷基)、-(C1-C6亚烷基)(C4-C8杂环烷基)、-(C3-C8亚环烷基)(C4-C8杂环烷基)、芳基、-(C1-C6亚烷基)芳基、或-(C3-C8亚环烷基)(芳基);其中每个上述R2基团可以任选地被1-3个选自氯、氟、和C1-C6烷基的取代基取代,其中1-3个取代基之一可进一步选自溴、碘、C1-C6烷氧基、-OH、-O-CO-(C1-C6烷基)、-O-CO-N(C1-C4烷基)(C1-C2烷基)、-S(C1-C6烷基)、-S(O)(C1-C6烷基)、-S(O)2(C1-C6烷基)、S+(C1-C6烷基)(C1-C2烷基)I-、CN、和NO2、和其中R2的C1-C12烷基、-(C1-C6亚烷基)、-(C5-C8环烷基)、-(C5-C8亚环烷基)、和-(C5-C8杂环烷基)部分可任选地包含1-3个双键或三键;并且其中R2的每个杂环烷基包含1-3个选自氧、S(O)m、氮、和NR12的杂部分;
或当R1和R2如在-NHCHR1R2、-OCHR1R2、-SCHR1R2、-CHR1R2、或NR1R2中时,B的R1和R2可形成5元-8元环,该环可任选地包含一个或两个双键和其中一个或两个环碳可任选地被氧、S(O)m、和NR12代替;并且该碳环可任选地被1-3个选自如下的取代基取代:羟基、C1-C4烷基、氟、氯、溴、碘、CF3、-O-(C1-C4烷基)、-O-CO-(C1-C4烷基)、-O-CO-NH(C1-C4烷基)、-O-CO-NH(C1-C4烷基)(C1-C2烷基)、-NH(C1-C4烷基)、-N(C1-C2烷基)(C1-C4烷基)、-S(C1-C4烷基)、-N(C1-C4烷基)CO(C1-C4烷基)、-NHCO(C1-C4烷基)、-COO(C1-C4烷基)、-CONH(C1-C4烷基)、-CON(C1-C4烷基)(C1-C2烷基)、CN、NO2、-OSO2(C1-C4烷基)、-SO(C1-C4烷基)和-SO2(C1-C4烷基),其中该1-3个取代基之一可进一步选自苯基;
R3是甲基、乙基、氟、氯、溴、碘、氰基、甲氧基、OCF3、NH2、-NH(C1-C2烷基)、-N(CH3)2、-NHCOCF3、-NHCH2CF3、S(O)m(C1-C4烷基)、CONH2、-CONHCH3、-CON(CH3)2、-CF3、或CH2OCH3;
R4是氢、C1-C4烷基、C3-C5环烷基、-(C1-C4亚烷基)(C3-C5环烷基)、-(C3-C5亚环烷基)(C3-C5环烷基)、氰基、氟、氯、溴、碘、-OR24、C1-C6烷氧基、-O-(C3-C5环烷基)、-O-(C1-C4亚烷基)(C3-C5环烷基)、-O-(C3-C5-亚环烷基(C3-C5环烷基)、CH2SC(S)O(C1-C4烷基)、CH2OCF3、-CF3、氨基、硝基、-NR24R25、-(C1-C4亚烷基)OR24、-(C1-C4亚烷基)Cl、-(C1-C4亚烷基)NR24R25、-NHCOR24、-NHCONR24R25、-C=NOR24、NHNR24R25、S(O)mR24、-C(O)R24、-OC(O)R24、-C(O)CN、-C(O)NR24R25、-C(O)NHNR24R25、和-COO R24,其中R4的烷基和亚烷基可任选地独立地包含一个或两个双键或三键并可任选地独立地被1-2个取代基R10取代,R10独立地选自羟基、氨基、-NHCOCH3、-NHCOCH2Cl、-NH(C1-C2烷基)、-N(C1-C2烷基)(C1-C2烷基)、-COO(C1-C4烷基)、-COOH、-CO(C1-C4烷基)、C1-C6烷氧基、C1-C3硫代烷基、氰基和硝基,和含有1-4个独立地选自氟和氯的取代基;
R5是芳基或杂芳基并被1-4个取代基R27取代,R27独立地选自卤素、C1-C10烷基、-(C1-C4亚烷基)(C3-C8环烷基)、-(C1-C4亚烷基)(C4-C8杂环烷基)、-(C3-C8环烷基)、-(C4-C8杂环烷基)、-(C3-C8亚环烷基)(C3-C8环烷基)、-(C3-C8亚环烷基)(C4-C8杂环烷基)、C1-C4卤代烷基、C1-C4卤代烷氧基、硝基、氰基、-NR24R25、-NR24COR25、-NR24CO2R26、-COR24、-OR25、-CONR24R25、-CO(NOR22)R23、-CO2R26、-C=N(OR22)R23、和S(O)mR23;其中该C1-C10烷基、C3-C8环烷基、(C1-C4亚烷基)、(C3-C8环烷基)、(C3-C8亚环烷基)、和(C4-C8杂环烷基)基团可任选地被1-3个独立地选自如下的取代基取代:C1-C4烷基、C3-C8环烷基、-(C1-C4亚烷基)(C3-C8环烷基)、-(C3-C8亚环烷基)(C3-C8环烷基)、C1-C4卤代烷基、羟基、C1-C6烷氧基、硝基、卤素、氰基、-NR24R25、-NR24COR25、-NR24CO2R26、-COR24、-OR25、-CONR24R25、-CO2R26、-CO(NOR22)R25、和S(O)mR23;和其中R5基团的两个相邻取代基可形成的饱和或未饱和的、稠合到R5上的5-7元环,该环任选地包含一个,两个,或三个独立地选自O、S(O)m和N的异种成员,但没有任何-S-S-、-O-O-、-S-O-、或-N-S-键,和该环可任选地被C1-C4烷基、C3-C8环烷基、-(C1-C4亚烷基)(C3-C8环烷基)、-(C3-C8亚环烷基)(C3-C8环烷基)、C1-C4卤代烷基、硝基、卤素、氰基、-NR24R25、-NR24COR25、-NR24CO2R26、-COR24、-OR25、-CONR24R25、-CO2R26、-CO(NOR26)R25、和S(O)mR23取代;其中该1-4个任选的取代基R27之一可进一步选自-SO2NH(C1-C4烷基)、-SO2NH(C1-C4亚烷基)(C3-C8环烷基)、-SO2NH(C3-C8环烷基)、-SO2NH(C3-C8亚环烷基)(C3-C8环烷基)、-SO2N(C1-C4烷基)(C1-C2烷基)、-SO2NH2、-NHSO2(C1-C4烷基)、-NHSO2(C3-C8环烷基)、-NHSO2(C1-C4亚烷基)(C3-C8环烷基)、和-NHSO2(C3-C8亚环烷基)(C3-C8环烷基);并且其中R5的烷基和亚烷基可独立地任选地包含一个双键或三键;
R6是氢、C1-C4烷基、C3-C8环烷基、-(C1-C6亚烷基)(C3-C8环烷基)、或-(C3-C8亚环烷基)(C3-C8环烷基),其中该烷基或环烷基可任选地被一个羟基、甲氧基、乙氧基或氟基团取代;
或,其中化合物是通式II的化合物,R6和R4可以一起形成氧代(=O)基团,或可以连接以形成3-8元碳环,任选地包含1-3个双键,和任选地包含一个、两个、或三个选自氧、SOm、N、和NR12的异种环成员,但不包含任何-O-O-、-S-O-、-S-S-、或-N-S-键,并进一步任选地被C1-C4烷基或C3-C8环烷基取代,其中该C1-C4烷基取代基可任选地包含一个双键或三键;
R7是氢、甲基、氟、氯、溴、碘、氰基、羟基、-O(C1-C2烷基)、-O(环丙基)、-COO(C1-C2烷基)、-COO(C3-C8环烷基)、-OCF3、CF3、-CH2OH、或CH2OCH3;
R11是氢、羟基、氟、乙氧基、或甲氧基;
R12是氢或C1-C4烷基;
R16和R17每个独立地是氢、羟基、甲基、乙基、甲氧基、或乙氧基,除了R16和R17两者不同时为甲氧基或乙氧基;
或R16和R17一起形成氧代(=O)基团;
或R16和R17连接以形成3-8元碳环,任选地包含1-3个双键,和任选地包含选自O、SOm、N、和NR12的异种环成员,但不包含任何-O-O-、-S-O-、-S-S-、或-N-S-键,和进一步任选地被C1-C4烷基或C3-C6环烷基取代,其中该C1-C4烷基取代基可任选地包含一个双键或三键;
R22在每种情况下独立地选自氢、C1-C4烷基、C1-C4卤代烷基、C3-C6链烯基、C3-C6链炔基、C3-C8环烷基、-(C3-C8亚环烷基)(C3-C8环烷基)和-(C1-C4亚烷基)(C3-C8环烷基);
R23在每种情况下独立地选自C1-C4烷基、C1-C4卤代烷基、C2-C8烷氧基烷基、C3-C8环烷基、-(C1-C4亚烷基)(C3-C8环烷基)、-(C3-C8亚环烷基)(C3-C8环烷基)、芳基、-(C1-C4亚烷基)芳基、哌啶、吡咯烷、哌嗪、N-甲基哌嗪、吗啉、和硫代吗啉;
R24和R25在每种情况下独立地选自氢、C1-C4烷基、C1-C4卤代烷基,特别是CF3、CHF2、CF2CF3、或CH2CF3,-(C1-C4亚烷基)OH、-(C1-C4亚烷基)-O-(C1-C4烷基)、-(C1-C4亚烷基)-O-(C3-C5环烷基)、C3-C8环烷基、-(C1-C4亚烷基)(C3-C8环烷基)、-(C3-C8亚环烷基)(C3-C8环烷基)、-C4-C8杂环烷基、-(C1-C4亚烷基)(C4-C8杂环烷基)、-(C3-C8亚环烷基)(C4-C8杂环烷基)、芳基、和-(C1-C4亚烷基)芳基,其中-C4-C8杂环烷基可以每个独立地任选地被芳基、CH2-芳基、或C1-C4烷基取代,并可以任选地包含一个或两个双键或三键;或当R24和R25是如NR24R25、-C(O)NR24R25、-(C1-C4亚烷基)NR24R25、或-NHCONR24R25、则NR24R25可进一步任选地形成4-8元杂环,任选地包含一个或两个独立地选自S(O)m、氧、氮、和NR12的另外杂成员,和任选地包含1-3个双键;
R26在每种情况下独立地选自C1-C4烷基、C1-C4卤代烷基、C3-C8环烷基、-(C1-C4亚烷基)(C3-C8环烷基)、-(C3-C8亚环烷基)(C3-C8环烷基)、芳基、和-(C1-C4亚烷基)(芳基);和
其中每个m独立地是0、1、或2,
条件是通式I、II、III化合物的杂环烷基不包括任何-S-S-、-S-O-、-N-S-、或-O-O-键,和不包括多于两个氧或S(O)m异种成员。
2.根据权利要求1的化合物,其中R4是-NHCH2CF3、-CONHNH2、-CONHNHCH3、-OCF3、氟、-OCHF2、-OCH2(C3-C5环烷基)、-O-(C3-C5环烷基)、-SCH2(C3-C5环烷基)、-S(C3-C5环烷基)、-OCH3、-CH3、-CH2CH3、氯、溴、-CF3、-CH2OH、-CH2OCH3、-CH2OCF3、-SCH3、-S(O)CH3、-S(O)2CH3、-C(O)CH3、-NR24R25、-NO2、-CH(OH)CH3、或-CN。
3.根据权利要求1的化合物,其中R4是-C(O)NR24R25或-C(O)NHNR24R25。
4.根据权利要求3的化合物,其中R24和R25独立地选自氢和C1-C4烷基。
5.根据权利要求1的化合物,其中R4是-(C1-C4亚烷基)NR24R25。
6.根据权利要求1的化合物,其中R4是-COOCH3或-COOCH2CH3。
7.根据权利要求6的化合物,其中R4是-COOCH3。
8.根据权利要求1通式I的化合物,其中Z是O;B是-NHCHR1R2,其中R1是C(O)H、C(O)(C1-C6烷基)、或-C1-C6烷基,其中所述C1-C6烷基任选地被1-6个氟原子或一个或两个独立地选自-C1-C4烷基、羟基和-O-(C1-C6烷基)的R8取代,并且其中R2是-C1-C12烷基,任选地包含1-3个双键或三键和任选地被1-3个选自氟和C1-C6烷基的取代基取代;R5是苯基、吡啶基或嘧啶基,被两个或三个选自如下的R27基团取代:卤素、(C1-C4卤代烷基)、-C(O)R24、-OR25、-C(O)NR24R25、和C1-C10烷基,它任选地被选自羟基、C1-C6烷氧基、和-NR24R25的1-3个取代基,优选一个取代基取代,并且R4是-C(O)NR24R25。
9.根据权利要求1通式I的化合物,其中Z是O;B是-NHCHR1R2,其中-NHCHR1R2的R1是C(O)H、C(O)(C1-C6烷基)、或-C1-C6烷基,其中该C1-C6烷基任选地被1-6个氟原子或一个或两个独立地选自-C1-C4烷基、羟基和-O-(C1-C6烷基)的R8取代,和其中-NHCHR1R2的R2是-C1-C12烷基,任选地包含1-3个双键或三键和任选地被1-3个选自氟和C1-C6烷基的取代基取代;R5是苯基、吡啶基或嘧啶基,被两个或三个选自如下的R27基团取代:卤素、(C1-C4卤代烷基)、-C(O)R24、-OR25、-C(O)NR24R25、和C1-C10烷基,它任选地被选自羟基、C1-C6烷氧基、和-NR24R25的1-3个取代基,优选一个取代基取代,和R4是-NR1R2,其中-NR1R2的R1是C1-C6烷基、C3-C8环烷基、或-(C1-C6亚烷基)(C3-C8环烷基),并且-NR1R2的R2是-C1-C12烷基,任选地包含1-3个双键或三键和任选地被1-3个氟原子取代。
10.根据权利要求1的化合物,选自:
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-羟甲基-丙基氨基)-6,N-二甲基-烟酰胺;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-甲氧基甲基-丙基氨基)-6,N-二甲基-烟酰胺;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-甲氧基甲基-丙基氨基)-6-甲基-烟酰胺;
2-(4-溴-2-甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酰胺;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基-2-甲氧基-丙基氨基)-6-甲基-烟酰胺;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-乙基-2-甲氧基-丙基氨基)-6,N-二甲基-烟酰胺;
2-(4-氯-2-三氟甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酰胺;
2-(4-氯-2-三氟甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6,N-二甲基-烟酰胺;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1S,2R-1-乙基-2-甲氧基-丙基氨基)-6,N-二甲基-烟酰胺;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1S,2S-1-乙基-2-甲氧基-丙基氨基)-6,N-二甲基-烟酰胺;
2-(4-溴-2-甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酰胺;
4-[4-(1-乙基-丙氧基)-3,6-二甲基-吡啶-2-基氧]-3,5-二甲基-苯甲酰胺;
2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-(1-甲基硫基甲基-丙基氨基)-烟酸甲酯;
2-(4-氯-2,6-二甲基-苯氧基)-4-(1-羟甲基-丙基氨基)-6-甲基-烟酸甲酯;
2-(4-溴-2,6-二甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟腈;
2-(4-氯-2-三氟甲氧基-苯氧基)-4-(1-乙基-丙基氨基)-6-甲基-烟酸甲酯;和
2-(4-氯-2,6-二甲基-苯氧基)-6-甲基-4-(四氢-呋喃-3-基氨基)-烟酸甲酯;
及其药用盐。
11.一种用于如下治疗的药物组合物:(a)其治疗可由拮抗CRF影响或促进的障碍或病情,包括但不限于由CRF诱导或促进的障碍,(b)选自如下的障碍或病情:炎症性障碍如风湿性关节炎和骨关节炎、疼痛、哮喘、牛皮癣和变应性;普通性焦虑障碍、恐惧、恐怖症,包括社交恐怖症、广场恐怖症和特异性恐怖症、强迫观念与行为症、外伤后应激性障碍、由应激反应诱导的睡眠障碍、痛觉如纤维肌痛、情感障碍如忧郁症,包括重性抑郁、单发作抑郁、复发性抑郁、儿童虐待诱导的抑郁、与月经前综合征有关的情感障碍、和产后精神抑郁、精神抑郁症、双极情感障碍、循环性气质、慢性疲乏综合征、应激诱导的头痛、癌症、肠易激综合征、局限性肠炎、痉挛性结肠、术后肠梗阻、溃疡、腹泻、应激诱导的发烧、人免疫缺陷病毒感染、神经退化疾病如阿尔茨海默病、帕金森病和享廷顿病、胃肠道病、进食障碍如食欲减退和神经性贪食、出血性应激反应、化学品依赖或成瘾、包括对于酒精、可卡因、海洛因、苯并二氮,或其它药物的依赖或成瘾、药物或酒精戒断症状、应激诱导的精神病发作、甲状腺功能正常病综合征、不适当抑制尿分泌激素的综合征、肥胖症、不孕症、头创伤、脊髓创伤、局部缺血性神经元损害,包括大脑缺血、例如大脑海马缺血、神经毒素神经元损害、癫痫、中风、免疫功能障碍包括应激诱导的免疫功能障碍、包括猪紧张综合征、牛船热、马阵发性纤维颤动、鸡囚禁功能障碍、羊sheering紧张和狗的人动物相互作用紧张、肌肉痉挛、尿失禁、阿尔茨海默类型老年痴呆、多梗塞性痴呆、肌萎缩性侧索硬化、高血压、心动过速、充血性心力衰竭、骨质疏松症、早产、低血糖,和哺乳动物或鸟中的综合征X,其包含数量为有效用于治疗这样障碍或病情的根据权利要求1化合物和药用载体。
12.一种用于如下治疗的方法:(a)障碍或病情,它的治疗可由拮抗CRF影响或促进,包括但不限于由CRF诱导或促进的障碍,(b)选自如下的障碍或病情:炎症性障碍如风湿性关节炎和骨关节炎、疼痛、哮喘、牛皮癣和变应性;普通性焦虑障碍、恐惧、恐怖症,包括社交恐怖症、广场恐怖症和特异性恐怖症、强迫观念与行为症、外伤后应激性障碍、由应激反应诱导的睡眠障碍、痛觉如纤维肌痛、情感障碍如忧郁症,包括重性抑郁、单发作抑郁、复发性抑郁、儿童虐待诱导的抑郁、与月经前综合征有关的情感障碍、和产后精神抑郁、精神抑郁症、双极情感障碍、循环性气质、慢性疲乏综合征、应激诱导的头痛、癌症、肠易激综合征、局限性肠炎、痉挛性结肠、术后肠梗阻、溃疡、腹泻、应激诱导的发烧、人免疫缺陷病毒感染、神经退化疾病如阿尔茨海默病、帕金森病和享廷顿病、胃肠道病、进食障碍如食欲减退和神经性贪食、出血性应激反应、化学品依赖或成瘾、包括对于酒精、可卡因、海洛因、苯并二氮,或其它药物的依赖或成瘾、药物或酒精戒断症状、应激诱导的精神病发作、甲状腺功能正常病综合征、不适当抑制尿分泌激素的综合征、肥胖症、不孕症、头创伤、脊髓创伤、局部缺血性神经元损害,包括大脑缺血、例如大脑海马缺血、神经毒素神经元损害、癫痫、中风、免疫功能障碍包括应激诱导的免疫功能障碍、包括猪紧张综合征、牛船热、马阵发性纤维颤动、鸡囚禁功能障碍、羊sheering紧张和狗的人动物相互作用紧张、肌肉痉挛、尿失禁、阿尔茨海默类型老年痴呆、多梗塞性痴呆、肌萎缩性侧索硬化、高血压、心动过速、充血性心力衰竭、骨质疏松症、早产、低血糖,和哺乳动物或鸟中的综合征X,包括给予需要该治疗的对象治疗这样的障碍或病情的有效量的根据权利要求1化合物。
13.一种治疗病情的方法,包括以治疗该病情有效的数量给予权利要求1的化合物,其中该病情选自:
a)异常昼夜节律;
b)抑郁,另外其中给予用于治疗抑郁的第二种化合物,所述用于治疗抑郁的第二种化合物相对于所述CRF拮抗剂而言,它的作用是延迟的;和
c)呕吐。
14.权利要求13的方法,其中病情是异常昼夜节律,并将化合物与用于治疗睡眠障碍的第二种化合物结合。
15.权利要求14的方法,其中该第二种化合物选自速激肽拮抗剂、用于GABA脑受体的激动剂、metalonergic化合物、GABA脑受体激动剂、5HT2受体拮抗剂和D4受体结合物。
16.权利要求13的方法,其中该病情是抑郁,并且其中具有治疗抑郁延迟作用的该第二种化合物选自选择性的5-羟色胺再摄取抑制剂、三环类抗抑郁剂、去甲肾上腺素摄取抑制剂、锂、安非他酮、舍曲林、氟西汀、曲唑酮、和选自丙咪嗪、阿米替林、曲米帕明、多塞平、地昔帕明、去甲替林、普罗替林、阿莫沙平、氯米帕明、马普替林、和卡马西平的三环类抗抑郁剂,和上述化合物的药用盐及酯。
17.权利要求13的方法,其中该病情是呕吐,进一步包括给予用于治疗呕吐的第二种化合物。
18.权利要求17的方法,其中用于治疗呕吐的该第二种化合物选自速激肽拮抗剂、5HT3拮抗剂、GABA激动剂和物质P抑制剂。
19.一种治疗病情的药物组合物,包括治疗该病情有效的数量的权利要求1的化合物和药用载体,其中该病情选自:
a)异常昼夜节律;
b)抑郁,另外其中给予用于治疗抑郁的第二种化合物,所述用于治疗抑郁的第二种化合物相对于所述CRF拮抗剂而言,它的作用是延迟的;和
c)呕吐。
20.根据权利要求19的药物组合物,其中病情是异常昼夜节律,并将化合物与用于治疗睡眠障碍的第二种化合物结合。
21.根据权利要求20的药物组合物,其中该第二种化合物选自速激肽拮抗剂、用于GABA脑受体的激动剂、metalonergic化合物、GABA脑受体激动剂、5HT2受体拮抗剂和D4受体结合物。
22.根据权利要求19的药物组合物,其中该病情是抑郁,并且其中具有治疗抑郁延迟作用的该第二种化合物选自选择性的5-羟色胺再摄取抑制剂、三环类抗抑郁剂、去甲肾上腺素摄取抑制剂、锂、安非他酮、舍曲林、氟西汀、曲唑酮、和选自丙咪嗪、阿米替林、曲米帕明、多塞平、地昔帕明、去甲替林、普罗替林、阿莫沙平、氯米帕明、马普替林、和卡马西平的三环类抗抑郁剂,和上述化合物的药用盐及酯。
23.根据权利要求19的药物组合物,其中该病情是呕吐,进一步包括给予用于治疗呕吐的第二种化合物。
24.根据权利要求23的药物组合物,其中用于治疗呕吐的该第二种化合物选自速激肽拮抗剂、5HT3拮抗剂、GABA激动剂和物质P抑制剂。
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Families Citing this family (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6956047B1 (en) * | 1995-06-06 | 2005-10-18 | Pfizer Inc. | Corticotropin releasing factor antagonists |
EP1449532A1 (en) * | 1999-08-27 | 2004-08-25 | Pfizer Products Inc. | Compound [2-(4-chloro-2,6-dimethyl-phenoxy)- 3,6-dimethyl-pyridin-4-yl]- (1-ethyl-propyl)- amine and use as CRF antagonist |
GB0117396D0 (en) | 2001-07-17 | 2001-09-05 | Glaxo Group Ltd | Chemical compounds |
US7323469B2 (en) | 2001-08-07 | 2008-01-29 | Novartis Ag | 7H-pyrrolo[2,3-d]pyrimidine derivatives |
GB0119249D0 (en) | 2001-08-07 | 2001-10-03 | Novartis Ag | Organic compounds |
AR040456A1 (es) | 2002-06-27 | 2005-04-06 | Bristol Myers Squibb Co | Piridina n-oxidos 2,4 -disubstituidos utiles como inhibidores de transcriptasa inversa del virus de inmunodeficiencia humana |
EP1688408A3 (en) * | 2002-08-08 | 2007-08-22 | Amgen, Inc | Vanilloid receptor ligands and their use in treatments |
KR20050055694A (ko) | 2002-08-08 | 2005-06-13 | 암젠 인코포레이티드 | 바닐로이드 수용체 리간드 및 치료시 이들의 용도 |
EP1599468B1 (en) | 2003-01-14 | 2007-10-03 | Arena Pharmaceuticals, Inc. | 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia |
WO2004062665A1 (en) * | 2003-01-16 | 2004-07-29 | Sb Pharmco Puerto Rico Inc | Heteroaryl- substituted pyrrolo` 2, 3- b! pyridine derivatives as crf receptor antagonists |
GB0308208D0 (en) | 2003-04-09 | 2003-05-14 | Glaxo Group Ltd | Chemical compounds |
US7112585B2 (en) | 2003-04-18 | 2006-09-26 | Bristol-Myers Squibb Company | Pyrimidine derivatives as corticotropin releasing factor inhibitors |
US7030145B2 (en) | 2003-04-18 | 2006-04-18 | Bristol-Myers Squibb Company | Pyridinyl derivatives for the treatment of depression |
AR045047A1 (es) * | 2003-07-11 | 2005-10-12 | Arena Pharm Inc | Derivados arilo y heteroarilo trisustituidos como moduladores del metabolismo y de la profilaxis y tratamiento de desordenes relacionados con los mismos |
NZ544200A (en) | 2003-07-14 | 2009-07-31 | Arena Pharm Inc | Fused-aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto |
US20050171095A1 (en) * | 2004-01-06 | 2005-08-04 | Pfizer Inc | Combination of CRF antagonists and 5-HT1B receptor antagonists |
RU2006128580A (ru) * | 2004-01-06 | 2008-02-20 | Тайсо Фармасьютикал Ко., Лтд. (Jp) | Производные тиенопиримидина и тиенопиридина, замещенные циклической аминогруппой |
MY139645A (en) | 2004-02-11 | 2009-10-30 | Amgen Inc | Vanilloid receptor ligands and their use in treatments |
WO2005077938A1 (en) | 2004-02-11 | 2005-08-25 | Amgen Inc. | Vanilloid receptor ligands and their use in treatments |
JP4185154B2 (ja) | 2004-04-30 | 2008-11-26 | ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー | 中枢神経系障害治療用の置換モルホリン化合物 |
AU2005245389A1 (en) * | 2004-05-12 | 2005-12-01 | Bristol-Myers Squibb Company | Urea antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions |
EP2316457A1 (en) | 2004-09-20 | 2011-05-04 | Xenon Pharmaceuticals Inc. | Pyridine derivatives for inhibiting human stearoyl-coa-desaturase |
US7301022B2 (en) | 2005-02-15 | 2007-11-27 | Amgen Inc. | Vanilloid receptor ligands and their use in treatments |
US8153791B2 (en) | 2005-12-21 | 2012-04-10 | Janssen Pharmaceutica N.V. | Substituted pyrimidinyl oxime kinase inhibitors |
US8013153B2 (en) * | 2006-03-23 | 2011-09-06 | Janssen Pharmaceutica, N.V. | Substituted pyrimidine kinase inhibitors |
ES2357340T3 (es) | 2006-10-18 | 2011-04-25 | Pfizer Products Inc. | Compuestos de biaril éter urea. |
WO2009144632A1 (en) * | 2008-05-30 | 2009-12-03 | Pfizer Limited | Novel compounds |
GB0913636D0 (en) * | 2009-08-05 | 2009-09-16 | Univ Leuven Kath | Novel viral replication inhibitors |
AU2011305525B2 (en) | 2010-09-22 | 2016-08-18 | Arena Pharmaceuticals, Inc. | Modulators of the GPR119 receptor and the treatment of disorders related thereto |
MA38661A1 (fr) | 2013-06-27 | 2017-03-31 | Pfizer | Composés hétéro-aromatiques et leur utilisation en tant que ligands d1 de la dopamine |
MX2021011472A (es) | 2015-01-06 | 2022-08-17 | Arena Pharm Inc | Metodos de condiciones de tratamiento relacionadas con el receptor s1p1. |
US10766860B2 (en) | 2015-03-06 | 2020-09-08 | Pharmakea, Inc. | Lysyl oxidase-like 2 inhibitors and uses thereof |
EP3265456B1 (en) | 2015-03-06 | 2020-11-18 | Pharmakea, Inc. | Fluorinated lysyl oxidase-like 2 inhibitors and uses thereof |
PL3310760T3 (pl) | 2015-06-22 | 2023-03-06 | Arena Pharmaceuticals, Inc. | Krystaliczna sól L-argininy kwasu (R)-2-(7-(4-cyklopentylo-3-(trifluorometylo)benzyloksy)- 1,2,3,4-tetrahydrocyklo-penta[b]indol-3-ilo)octowego do zastosowania w zaburzeniach związanych z receptorem S1P1 |
WO2018007331A1 (en) * | 2016-07-08 | 2018-01-11 | F. Hoffmann-La Roche Ag | Fused pyrimidine derivatives |
SG11201901999XA (en) | 2016-09-07 | 2019-04-29 | Pharmakea Inc | Crystalline forms of a lysyl oxidase-like 2 inhibitor and methods of making |
US11077108B2 (en) * | 2016-09-07 | 2021-08-03 | The Regents Of The University Of California | Allosteric corticotropin-releasing factor receptor 1 (CRFR1) antagonists that decrease p-tau and improve cognition |
US11793797B2 (en) | 2016-09-07 | 2023-10-24 | Pharmakea, Inc. | Uses of a lysyl oxidase-like 2 inhibitor |
CN110520124A (zh) | 2017-02-16 | 2019-11-29 | 艾尼纳制药公司 | 用于治疗原发性胆汁性胆管炎的化合物和方法 |
ES2963044T3 (es) | 2017-03-13 | 2024-03-25 | Raqualia Pharma Inc | Derivados de tetrahidroquinolina como antagonistas del receptor P2X7 |
US20220125762A1 (en) * | 2019-02-13 | 2022-04-28 | The University Of Vermont And State Agricultural College | Small molecule antagonist to pacap receptor and uses thereof |
JP2022554350A (ja) * | 2019-11-06 | 2022-12-28 | アルベルト・アインシュタイン・カレッジ・オブ・メディシン | 小分子プロスタグラジン輸送阻害剤 |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3145287A1 (de) | 1981-11-14 | 1983-05-19 | Troponwerke GmbH & Co KG, 5000 Köln | Pyrrolo (2.3-d)pyrimidine, verfahren zu ihrer herstellung und ihre verwendung als arzneimittel |
US4605642A (en) | 1984-02-23 | 1986-08-12 | The Salk Institute For Biological Studies | CRF antagonists |
EP0264883A3 (en) | 1986-10-21 | 1990-04-04 | Banyu Pharmaceutical Co., Ltd. | Substituted pyridine derivatives |
US5063245A (en) | 1990-03-28 | 1991-11-05 | Nova Pharmaceutical Corporation | Corticotropin-releasing factor antagonism compounds |
CA2051012C (en) | 1990-09-14 | 2002-04-02 | David R. Borcherding | Carbocyclic adenosine analogs useful as immunosupressants |
DE59303950D1 (de) | 1992-08-10 | 1996-10-31 | Volkswagen Ag | Schalteinrichtung für ein Getriebe |
KR19990067704A (ko) * | 1992-12-17 | 1999-08-25 | 디. 제이. 우드, 스피겔 알렌 제이 | 부신피질자극호르몬 유리인자 길항제로서의 피롤로피리미딘을함유하는 약학 조성물 |
CN1142817A (zh) * | 1993-10-12 | 1997-02-12 | 杜邦麦克制药有限公司 | 1n-烷基-n-芳基嘧啶胺及其衍生物 |
TW530047B (en) * | 1994-06-08 | 2003-05-01 | Pfizer | Corticotropin releasing factor antagonists |
US5691364A (en) | 1995-03-10 | 1997-11-25 | Berlex Laboratories, Inc. | Benzamidine derivatives and their use as anti-coagulants |
US6403599B1 (en) * | 1995-11-08 | 2002-06-11 | Pfizer Inc | Corticotropin releasing factor antagonists |
PA8467401A1 (es) * | 1998-02-17 | 2000-09-29 | Pfizer Prod Inc | Procedimiento para tratar la insuficiencia cardiaca |
US6130188A (en) * | 1998-05-05 | 2000-10-10 | American Cyanamid Company | Herbicidal pyridine compounds |
EP1040831A3 (en) * | 1999-04-02 | 2003-05-02 | Pfizer Products Inc. | Use of corticotropin releasing factor (CRF) antagonists to prevent sudden death |
US6387894B1 (en) * | 1999-06-11 | 2002-05-14 | Pfizer Inc. | Use of CRF antagonists and renin-angiotensin system inhibitors |
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