CN101646654A - 可用作糖皮质激素调节剂的吲唑基磺酰胺衍生物 - Google Patents
可用作糖皮质激素调节剂的吲唑基磺酰胺衍生物 Download PDFInfo
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- CN101646654A CN101646654A CN200780043684A CN200780043684A CN101646654A CN 101646654 A CN101646654 A CN 101646654A CN 200780043684 A CN200780043684 A CN 200780043684A CN 200780043684 A CN200780043684 A CN 200780043684A CN 101646654 A CN101646654 A CN 101646654A
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- Prior art keywords
- alkyl
- indazole
- phenyl
- fluorophenyl
- oxy
- Prior art date
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
本发明披露了式(I)化合物或其可药用盐;含有它们的药物组合物;制备它们的方法;以及它们在药物治疗(例如在温血动物中调节糖皮质激素受体)中的用途。
Description
技术领域
本发明涉及新颖的吲唑基磺酰胺衍生物,涉及包含这些衍生物的药物组合物,涉及制备这些新颖衍生物的方法,以及涉及这些衍生物作为药物(例如在治疗炎性病症(inflammatory disease state)中)的用途。
背景技术
WO 2004/019935和WO 2004/050631披露了磺酰胺衍生物作为抗炎药物。Arch.Pharm.(1980)313 166-173、J.Med.Chem.(2003)46 64-73、J.Med.Chem(1997)40 996-1004、EP 0031954、EP 1190710(WO 200124786)、US5861401、US 4948809、US 3992441和WO 99/33786也披露了具有药物活性的磺酰胺。
已知某些非甾体化合物与糖皮质激素受体(glucocorticoid receptor,GR)相互作用,作为这种相互作用的结果,产生对炎症的抑制(例如参见US6323199)。这样的化合物可显示出在抗炎作用和代谢作用之间的完全不相关性,这使它们优于较早报道的甾类糖皮质激素和非甾类糖皮质激素。本发明提供了另外的非甾体化合物作为糖皮质激素受体的调节剂(例如作为激动剂、拮抗剂、部分激动剂或部分拮抗剂)。
发明内容
本发明提供式(I)化合物或其可药用盐:
其中
A为C1-10烷基、C5-10芳基、C5-10芳基C1-6烷基-、C5-10杂芳基、C5-10杂芳基C1-6烷基-、C5-10芳基C1-6烷氧基-、C1-10卤代烷基、C3-7环烷基、C3-7环烷基C1-4烷基-、C1-6烷基OC(O)C1-6烷基-、C1-6烷基C(O)OC1-6烷基-、C5-10芳基氧基C1-10烷基-或NR5R6C0-6烷基-,其中所述芳基任选地经一个或多个选自B的取代基取代;
R1和R1a独立地选自氢、C1-4烷基、C1-4卤代烷基、C1-4羟基烷基和C1-4烷基OC1-4烷基-;
R2为氢或C1-4烷基;
R3为C3-7环烷基(任选地经卤素或C1-6烷基取代)、C5-10芳基C0-3烷基-、C5-10芳基OC0-3烷基-、C5-10杂芳基C0-3烷基-、C1-6烷基、C1-6烯基或C1-6炔基,这些基团任选地经一个或多个B取代;
B为C0-3羟基烷基、C1-4烷基、C1-4烷氧基、C0-4烷基硫基C0-4烷基-、C3-6环烷基C0-4烷基硫基-、C0-4烷基S(O)nC0-4烷基-、C1-6卤代烷基、C1-4卤代烷氧基、卤素、硝基、氰基、C1-4烷基OC1-6烷基-、C0-6烷基OC1-4烷基OC0-4烷基-、C0-6烷基C(O)C0-6烷基-、C0-4烷基C(O)OC0-4烷基-、C0-4烷基OC(O)C0-4烷基-、NR5R6C0-4烷基-、NR5R6C(O)C0-4烷基-、NR5R6OC(O)C0-4烷基-、NR5R6C(O)OC0-4烷基-、R6C(O)R5NC0-4烷基-、C0-4烷基OC(O)C0-4烷基NH-、C0-4烷基C(O)OC0-4烷基NH-、C0-4烷基C(O)C0-4烷基NH-或NR5R6S(O)nC0-4烷基-;
R4为氢、羟基、卤素、C1-4烷基或C1-4卤代烷基;
W为氢、C3-7环烷基、C1-4烷基、苯基、噻吩基、异噁唑基、吡唑基、吡啶基或嘧啶基,所有这些基团任选地经一个或多个选自下列的取代基取代:卤素、C0-3羟基烷基、C1-4烷基、C1-4烷氧基、C0-4烷基硫基C0-4烷基-、C3-6环烷基C0-4烷基硫基-、C0-4烷基S(O)nC0-4烷基-、C1-6卤代烷基、C1-4卤代烷氧基、卤素、硝基、氰基、C1-4烷基OC1-6烷基-、C1-6烷基OC1-6烷基OC1-6烷基-、C0-6烷基C(O)C0-6烷基-、C0-4烷基C(O)OC0-4烷基-、C0-4烷基OC(O)C0-4烷基-、NR5R6C0-4烷基-、NR5R6C(O)C0-4烷基-、NR5R6C(O)OC0-4烷基-、NR5R6OC(O)C0-4烷基-、R6C(O)R5NC0-4烷基-、C0-4烷基OC(O)C0-4烷基NH-、C0-4烷基C(O)OC0-4烷基NH-、C0-4烷基C(O)C0-4烷基NH-和NR5R6S(O)nC0-4烷基-;
X为CH2、O、S、S(O)、S(O)2或NH;
Y为氢、卤素、C1-6烷基、C1-4烷氧基、C1-4烷基硫基、C1-4卤代烷基、C1-4卤代烷氧基、硝基、氰基、羟基、R5C(O)-、R5OC(O)-、R5C(O)O-、C1-4烷基S(O)n-、R5R6NS(O)n-、苄基氧基、咪唑基、C1-4烷基NHC(O)-、NR5R6C(O)-、C1-4烷基C(O)NH-或-NR5R6;
R5和R6独立地选自氢、C1-4烷基和C3-7环烷基,或R5和R6一起形成基团-(O)C5-10芳基C(O)-;以及
n为1或2。
一个实施方案涉及式(I)化合物或其可药用盐,其中
A为C1-10烷基、C5-10芳基、C5-10芳基C1-6烷基-、C5-10杂芳基、C5-10杂芳基C1-6烷基-、C5-10芳基C1-6烷氧基-、C1-10卤代烷基、C3-7环烷基、C3-7环烷基C1-4烷基-、C1-6烷基OC(O)C1-6烷基-、C1-6烷基C(O)OC1-6烷基-、C5-10芳基氧基C1-10烷基-或NR5R6C0-6烷基-,其中所述芳基任选地经一个或多个选自B的取代基取代;
R1和R1a独立地选自氢和C1-4烷基;
R2为氢;
R3为C5-10芳基C0-3烷基-、C5-10芳基OC0-3烷基-或C5-10杂芳基C0-3烷基-,这些基团任选地经一个或多个B取代;
B为C0-3羟基烷基、C1-4烷基、C1-4烷氧基、C1-6卤代烷基、C1-4卤代烷氧基、卤素或NR5R6C0-4烷基-;
R4为氢;
W为C3-7环烷基、C1-4烷基、苯基或吡啶基,所有这些基团任选地经一个或多个选自卤素的取代基取代;
X为O、S或S(O)2;
Y为氢或卤素;以及
R5和R6独立地选自氢和C1-4烷基,或R5和R6一起形成基团-(O)C5-10芳基C(O)-。
一个实施方案涉及式化合物(I)或其可药用盐,其中
A为C1-10烷基、C1-10卤代烷基、C3-7环烷基、C3-7环烷基C1-4烷基-、C1-6烷基OC(O)C1-6烷基-、C1-6烷基C(O)OC1-6烷基-或NR5R6C0-6烷基-,这些基团任选地经一个或多个选自B的取代基取代。
R1和R1a独立地选自氢和C1-4烷基;
R2为氢;
R3为C5-10芳基C0-3烷基-、C5-10芳基OC0-3烷基-或C5-10杂芳基C0-3烷基-,这些基团任选地经一个或多个B取代;
B为C0-3羟基烷基、C1-4烷基、C1-4烷氧基、C1-6卤代烷基、C1-4卤代烷氧基、卤素或NR5R6C0-4烷基-;
R4为氢;
W为C3-7环烷基、C1-4烷基、苯基或吡啶基,所有这些基团任选地经一个或多个选自卤素的取代基取代;
X为O、S或S(O)2;
Y为氢或卤素;以及
R5和R6独立地选自氢和C1-4烷基,或R5和R6一起形成基团-(O)C5-10芳基C(O)-。
另一个实施方案涉及式(I)化合物或其可药用盐,其中
A为C5-10芳基、C5-10芳基C1-6烷基-、C5-10芳基C1-6烷氧基-或C5-10芳基氧基C1-10烷基-,其中所述芳基任选地经一个或多个选自B的取代基取代;
R1和R1a独立地选自氢和C1-4烷基;
R2为氢;
R3为C5-10芳基C0-3烷基-、C5-10芳基OC0-3烷基-或C5-10杂芳基C0-3烷基-,这些基团任选地经一个或多个B取代;
B为C0-3羟基烷基、C1-4烷基、C1-4烷氧基、C1-6卤代烷基、C1-4卤代烷氧基、卤素或NR5R6C0-4烷基-;
R4为氢;
W为C3-7环烷基、C1-4烷基、苯基或吡啶基,所有这些基团任选地经一个或多个选自卤素的取代基取代;
X为O、S或S(O)2;
Y为氢或卤素;以及
R5和R6独立地选自氢和C1-4烷基,或R5和R6一起形成基团-(O)C5-10芳基C(O)-。
另一个实施方案涉及式(I)化合物或其可药用盐,其中
A为C5-10杂芳基或C5-10杂芳基C1-6烷基-,这些基团任选地经一个或多个选自B的取代基取代;
R1和R1a独立地选自氢和C1-4烷基;
R2为氢;
R3为C5-10芳基C0-3烷基-、C5-10芳基OC0-3烷基-或C5-10杂芳基C0-3烷基-,这些基团任选地经一个或多个B取代;
B为C0-3羟基烷基、C1-4烷基、C1-4烷氧基、C1-6卤代烷基、C1-4卤代烷氧基、卤素或NR5R6C0-4烷基-;
R4为氢;
W为C3-7环烷基、C1-4烷基、苯基或吡啶基,所有这些基团任选地经一个或多个选自卤素的取代基取代;
X为O、S或S(O)2;
Y为氢或卤素;以及
R5和R6独立地选自氢和C1-4烷基,或R5和R6一起形成基团-(O)C5-10芳基C(O)-。
一个实施方案涉及式(I)化合物或其可药用盐,其中
A为C1-10烷基、C5-10芳基、C5-10芳基C1-6烷基-、C5-10杂芳基、C5-10杂芳基C1-6烷基-、C5-10芳基C1-6烷氧基-、C1-10卤代烷基、C3-7环烷基、C3-7环烷基C1-4烷基-、C1-6烷基OC(O)C1-6烷基-、C1-6烷基C(O)OC1-6烷基-、C5-10芳基氧基C1-10烷基-或NR5R6C0-6烷基-,其中所述芳基任选地经一个或多个选自B的取代基取代;
R1和R1a独立地选自氢、C1-4烷基、C1-4卤代烷基、C1-4羟基烷基和C1-4烷基OC1-4烷基-;
R2为氢或C1-4烷基;
R3为C3-7环烷基(任选地经卤素或C1-6烷基取代)、C5-10芳基C0-3烷基-、C5-10芳基OC0-3烷基-、C5-10杂芳基C0-3烷基-、C1-6烷基、C1-6烯基或C1-6炔基,这些基团任选地经一个或多个B取代;
B为C0-3羟基烷基、C1-4烷基、C1-4烷氧基、C0-4烷基硫基C0-4烷基-、C3-6环烷基C0-4烷基硫基-、C0-3烷基S(O)nC0-4烷基-、C1-6卤代烷基、C1-4卤代烷氧基、卤素、硝基、氰基、C1-4烷基OC1-6烷基-、C0-6烷基OC1-4烷基OC0-4烷基-、C0-6烷基C(O)C0-6烷基-、C0-4烷基C(O)OC0-4烷基-、C0-4烷基OC(O)C0-4烷基-、NR5R6C0-4烷基-、NR5R6C(O)C0-4烷基-、NR5R6OC(O)C0-4烷基-、NR5R6C(O)OC0-4烷基-、R6C(O)R5NC0-4烷基-、C0-4烷基OC(O)C0-4烷基NH-、C0-4烷基C(O)OC0-4烷基NH-、C0-4烷基C(O)C0-4烷基NH-或NR5R6S(O)nC0-4烷基-;
R4为氢、羟基、卤素、C1-4烷基或C1-4卤代烷基;
W为C3-7环烷基、C1-4烷基、苯基、噻吩基、异噁唑基、吡唑基、吡啶基或嘧啶基,所有这些基团任选地经一个或多个选自下列的取代基取代:卤素、C0-3羟基烷基、C1-4烷基、C1-4烷氧基、C0-4烷基硫基C0-4烷基-、C3-6环烷基C0-4烷基硫基-、C0-4烷基S(O)nC0-4烷基-、C1-6卤代烷基、C1-4卤代烷氧基、卤素、硝基、氰基、C1-4烷基OC1-6烷基-、C1-6烷基OC1-6烷基OC1-6烷基-、C0-6烷基C(O)C0-6烷基-、C0-4烷基C(O)OC0-4烷基-、C0-4烷基OC(O)C0-4烷基-、NR5R6C0-4烷基-、NR5R6C(O)C0-4烷基-、NR5R6C(O)OC0-4烷基-、NR5R6OC(O)C0-4烷基-、R6C(O)R5NC0-4烷基-、C0-4烷基OC(O)C0-4烷基NH-、C0-4烷基C(O)OC0-4烷基NH-、C0-4烷基C(O)C0-4烷基NH-和NR5R6S(O)nC0-4烷基-;
X为CH2、O、S、S(O)、S(O)2或NH;
Y为氢、卤素、C1-6烷基、C1-4烷氧基、C1-4烷基硫基、C1-4卤代烷基、C1-4卤代烷氧基、硝基、氰基、羟基、R5C(O)-、R5OC(O)-、R5C(O)O-、C1-4烷基S(O)n-、R5R6NS(O)n-、苄基氧基、咪唑基、C1-4烷基NHC(O)-、NR5R6C(O)-、C1-4烷基C(O)NH-或-NR5R6;
R5和R6独立地选自氢、C1-4烷基和C3-7环烷基,或R5和R6一起形成基团-(O)C5-10芳基C(O)-;以及
n为1或2。
一个实施方案涉及式(I)化合物,其中
A为C1-10烷基、C5-10芳基、C5-10芳基C1-6烷基-、C5-10杂芳基、C5-10杂芳基C1-6烷基-、C5-10芳基C1-6烷氧基-、C1-10卤代烷基、C3-7环烷基、C3-7环烷基C1-4烷基-、C1-6烷基OC(O)C1-6烷基-、C1-6烷基C(O)OC1-6烷基-、C5-10芳基氧基C1-10烷基-或NR5R6C0-6烷基-,其中所述芳基任选地经一个或多个选自B的取代基取代。
在另一个实施方案中,A为C3-6环烷基。在另一个实施方案中,A为环丙基或环戊基。
在另一个实施方案中,A为C3-6环烷基C1-2烷基-。在另一个实施方案中,A为环戊基-甲基-。
在另一个实施方案中,A为C1-10烷基。在一个实施方案中,A为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基或异己基。
在另一个实施方案中,A为甲基。在另一个实施方案中,A为正丙基。在另一个实施方案中,A为正戊基或仲戊基(s-pentyl)。在另一个实施方案中,A为仲丁基或正丁基。在另一个实施方案中,A为正己基。
在一个实施方案中,A为C1-6卤代烷基。在另一个实施方案中,A为氟甲基、二氟甲基、三氟甲基、氟乙基、二氟乙基、三氟乙基或三氟丙基。在另一个实施方案中,A为三氟甲基。在另一个实施方案中,A为三氟甲基、三氟乙基或三氟丙基。
在另一个实施方案中,A为C5-10杂芳基C1-6烷基-。在一个实施方案中,A为二氧代异吲哚基-乙基-。
在另一个实施方案中,A为任选地经B取代的C5-6杂芳基。在另一个实施方案中,A为咪唑基或异噁唑基,这些基团任选地经B取代。在另一个实施方案中,A为咪唑基或异噁唑基,这些基团经一个或两个甲基取代。
在一个实施方案中,A为任选地经C1-4烷氧基取代的C5-6芳基C1-6烷氧基-。在另一个实施方案中,A为经甲氧基取代的苯基-乙氧基-。
在另一个实施方案中,A为C1-4烷基OC(O)C1-4烷基-。在一个实施方案中,A为C1-2烷基OC(O)C1-2烷基,在另一个实施方案中,A为丙酸酯基团(propanoate)。
在一个实施方案中,A为C5-10杂芳基。在另一个实施方案中,A为吡啶基。
一个实施方案涉及式(I)化合物,其中R1和R1a独立地选自氢和C1-4烷基。在另一个实施方案中,R1为氢。在另一个实施方案中,R1为甲基。
在另一个实施方案中,R1a为氢。
在另一个实施方案中,R2为氢。
一个实施方案涉及式(I)化合物,其中R3为C5-10芳基C0-3烷基-、C5-10芳基OC0-3烷基-或C5-10杂芳基C0-3烷基-,这些基团任选地经一个或多个B取代。在另一个实施方案中,R3为C5-6芳基。在另一个实施方案中,R3为苯基。在另一个实施方案中,R3为经B取代的苯基。在另一个实施方案中,R3为经卤素或R5S(O)2-取代的苯基,其中R5为C1-4烷基。在一个实施方案中,B为氟。在另一个实施方案中,B为甲基-S(O)2-。
在另一个实施方案中,R3为C5-6杂芳基。在一个实施方案中,R3为经B取代的吡啶基。在另一个实施方案中,R3为经C1-4烷氧基取代的吡啶基。在一个实施方案中,R3为经甲氧基取代的吡啶基。
在另一个实施方案中,R3与B一起形成如实施43中的二氢苯并二氧杂环己二烯基团。
一个实施方案涉及式(I)化合物,其中R1为C1-4烷基,R1a为氢,R2为氢,以及R3为C5-10芳基,其中所述芳基任选地经一个或多个B取代。在另一个实施方案中,B为卤素或R5S(O)2-。
一个实施方案涉及式(I)化合物,其中W为C3-7环烷基、C1-4烷基、苯基或吡啶基,所有这些基团任选地经一个或多个选自卤素的取代基取代。在另一个实施方案中,W为C3-6环烷基、C1-4烷基、苯基或吡啶基,这些基团任选地经一个选自卤素的取代基取代。在另一个实施方案中,W为苯基。在另一个实施方案中,W为经卤素取代的苯基。在另一个实施方案中,W为经氟取代的苯基。
在一个实施方案中,W为环戊基。在另一个实施方案中,W为异丙基。
在另一个实施方案中,W为吡啶基。
一个实施方案涉及式(I)化合物,其中X为O。
在另一个实施方案中,X为S。在另一个实施方案中,X为S(O)2。
一个实施方案涉及式(I)化合物,其中R1为C1-4烷基,R1a为氢,R2为氢,X为O,以及R3为C5-10芳基,其中所述芳基任选地经一个或多个B取代。在另一个实施方案中,B为卤素或R5S(O)2-。
一个实施方案涉及式(I)化合物,其中Y为氢。
在另一个实施方案中,Y为卤素。在另一个实施方案中,Y为氯。
一个实施方案涉及式(I)化合物,其中R5和R6独立地选自氢和C1-4烷基。在另一个实施方案中,R5和R6一起形成基团-(O)C5-10芳基C(O)-。
另一个实施方案涉及如下的式(IA)化合物或其可药用盐:
其中A、R3和W如上所定义。
一个实施方案涉及式(I)化合物,其中如下基团与吲唑基环系的5位相连:
为了避免引起疑问,应当理解的是,当在本说明书中用“如上所定义”来限定基团时,所述基团涵盖针对该基团第一次出现以及范围最宽的定义,并且涵盖针对该基团的其它每个定义和所有定义。
为了避免引起疑问,应当理解的是,在本说明书中“C0-6”是指具有0、1、2、3、4、5或6个碳原子的碳基团。
在本说明书中,除非另有说明,术语″烷基″包括直链和支链烷基,并且可以是但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基或异己基。术语“C1-4烷基”具有1至4个碳原子,并且可以是但不限于甲基、乙基、正丙基、异丙基或叔丁基。术语“C0”是指不存在任何碳原子的情况。
除非另有说明,术语“烷氧基”是指通式R-O-的基团,其中R选自烃基。术语“烷氧基”可包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、异丁氧基、环丙基甲氧基、烯丙基氧基或炔丙基氧基。
在本说明书中,除非另有说明,术语“环烷基”是指任选经取代的部分或完全饱和的单环烃环系、二环烃环系或桥连烃环系。术语“C1-6环烷基”可以是但不限于环丙基、环丁基、环戊基或环己基。
在本说明书中,除非另有说明,术语“卤代”和“卤素”可以是氟、碘、氯或溴。
在本说明书中,除非另有说明,术语“卤代烷基”是指如上所定义的烷基,所述烷基经如上所定义的卤素取代。术语“C1-6卤代烷基”可以包括但不限于氟甲基、二氟甲基、三氟甲基、氟乙基、二氟乙基或溴丙基。术语“C1-3卤代烷基O-”可包括但不限于氟甲氧基、二氟甲氧基、三氟甲氧基、氟乙氧基或二氟乙氧基。
在本说明书中,除非另有说明,术语“C5-10芳基”是指芳香族基团例如苯基或萘基。
在本说明书中,除非另有说明,术语“C5-10杂芳基”是指含有一个或多个独立地选自氮、氧和硫的杂原子的,单环或二环的,芳香族或部分芳香族的环基团。杂芳基的例子为噁唑基、呋喃基、噻吩基、吡咯基、吡唑基、咪唑基、吡啶基、嘧啶基、吲哚基、吲唑基、苯并呋喃基或苯并噻吩基。杂芳基也可以是二氢苯并二氧杂环己二烯基(dihydrobenzodioxinyl)、喹啉基或异喹啉基。
当苯基经-OCH2O-、-OCH2CH2O-或-OCH2CH2-取代时,这些基团连接在苯环的相邻碳上。
C5-10芳基C1-4烷基-为例如苄基。C5-10芳基C1-4烷氧基-为例如经苯基取代的甲氧基。C1-4烷氧基C5-10芳基-为例如经甲氧基取代的苯基。
应当理解的是,在整个说明书中,可对在本发明化合物的环上的取代基的数目和性质进行选择,从而避免立体不期望的组合。
已经借助计算机软件(ACDLabs 8.0/Name(IUPAC))对本发明化合物进行了命名。
在另一个实施方案中,本发明化合物选自下列化合物或其可药用盐:
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]丙-1-磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-4-基]氧基-1-苯基-丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-[1-(6-氟吡啶-3-基)吲唑-5-基]氧基-1-苯基-丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]甲磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]-1-苯基-甲磺酰胺,
1,1,1-三氟-N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]甲磺酰胺,
5-[(1R,2S)-2-(二甲基氨磺酰基氨基)-1-苯基-丙氧基]-1-(4-氟苯基)吲唑,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]丙-2-磺酰胺,
2-(1,3-二氧代异吲哚-2-基)-N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]乙磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]-3-(4-甲氧基苯氧基)丙-1-磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]乙磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]戊-2-磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]丁-2-磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]丁-1-磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]-2-甲基-丙-1-磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]戊-1-磺酰胺,
3,3,3-三氟-N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]丙-1-磺酰胺,
3-[[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]氨磺酰基]丙酸甲酯,
1-环戊基-N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]甲磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]环戊基磺酰胺,
2,2,2-三氟-N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]乙磺酰胺,
1-环己基-N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]甲磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]己-1-磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]吡啶-3-磺酰胺,
N-[1-[1-(4-氟苯基)吲唑-5-基]氧基-2-甲基-1-苯基-丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-(4-(甲基硫基)苯基)丙-2-基]环丙基磺酰胺,
N-[(1S,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-(4-(甲基硫基)苯基)丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-(4-(甲基硫基)苯基)丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-苯基-1-(1-(丙-2-基)吲唑-5-基)氧基-丙-2-基]甲磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-(4-(甲基亚磺酰基)苯基)丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-(1-环戊基吲唑-5-基)氧基-1-苯基-丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-苯基-1-(1-(丙-2-基)吲唑-5-基)氧基-丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-(4-(甲基磺酰基)苯基)丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-[6-氯-1-(4-氟苯基)吲唑-5-基]氧基-1-(4-氟苯基)丙-2-基]环丙基磺酰胺,
N-[(1R,2R)-1-[6-氯-1-(4-氟苯基)吲唑-5-基]氧基-1-(4-氟苯基)丙-2-基]环丙基磺酰胺,
N-[2-[1-(4-氟苯基)吲唑-5-基]硫基-2-苯基-乙基]环丙基磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]硫基-1-苯基-丙-2-基]甲磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]磺酰基-1-苯基-丙-2-基]甲磺酰胺,
N-[(2R)-2-[1-(4-氟苯基)吲唑-5-基]氧基-2-苯基-乙基]环丙基磺酰胺,
N-[(2S)-2-[1-(4-氟苯基)吲唑-5-基]氧基-2-苯基-乙基]环丙基磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-(喹啉-3-基)-丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-(2,5-二氧杂二环[4.4.0]癸-7,9,11-三烯-8-基)-1-[1-(4-氟苯基)吲唑-5-基]氧基-丙-2-基]环丙基磺酰胺,
N-{1-[6-甲氧基吡啶-3-基]-1-[(1-(吡啶-2-基)-1H-吲唑-5-基)氧基]丙-2-基}环丙基磺酰胺,
N-{1-[6-甲氧基吡啶-3-基]-1-[(1-(吡啶-3-基)-1H-吲唑-5-基)氧基]丙-2-基}环丙基磺酰胺,
N-{1-[2-甲氧基吡啶-4-基]-1-[(1-(吡啶-2-基)-1H-吲唑-5-基)氧基]丙-2-基}环丙基磺酰胺,
N-{1-[2-甲氧基吡啶-4-基]-1-[(1-(吡啶-2-基)-1H-吲唑-5-基)氧基]丁-2-基}环丙基磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]1-甲基-1H-咪唑-4-磺酰胺,以及
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]3,5-二甲基异噁唑-4-磺酰胺。
在另一个方面,本发明提供了如下的单个化合物或其可药用盐:
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]环丙基磺酰胺。
式(I)化合物及其可药用盐可按溶剂化形式(例如水合形式)或非溶剂化形式存在,以及可按共结晶形式(cocrystalline form)存在,本发明涵盖所有这些形式。
可将上述式(I)化合物转化为其可药用盐,优选转化为酸加成盐,例如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、醋酸盐、抗坏血酸盐、苯甲酸盐、富马酸盐、半富马酸盐(hemifumarate)、糠酸盐、琥珀酸盐、马来酸盐、酒石酸盐、柠檬酸盐、草酸盐、昔萘酸盐(xinafoate)、甲磺酸盐、对甲苯磺酸盐、苯磺酸盐、乙磺酸盐、萘-2-磺酸盐、mesytilenesulfonate、硝酸盐、萘-1,5-二磺酸盐、对二甲苯磺酸盐、天冬氨酸盐或谷氨酸盐。
可药用盐也可包括碱加成盐,所述碱加成盐例如:碱金属盐例如钠盐或钾盐,碱土金属盐例如钙盐或镁盐,过渡金属盐例如锌盐,有机胺盐例如三乙胺盐、二乙胺盐、吗啉盐、N-甲基哌啶盐、N-乙基哌啶盐、哌嗪盐、普鲁卡因盐、二苄胺盐、N,N-二苄基乙胺盐、胆碱盐或2-氨基乙醇盐,或氨基酸盐例如赖氨酸盐或精氨酸盐。
式(I)化合物可具有非对称中心,并且本质上可以是手性的。当化合物为手性时,其可以是单一立体异构体形式,例如是对映异构体形式,或者其可以是这些立体异构体的任何比例混合物形式,包括外消旋混合物。因此,所有对映异构体、非对映异构体、外消旋体和它们的混合都包括在本发明的范围内。可使用常规技术来分离化合物的外消旋混合物,由此对各种光学异构体进行分离,所述常规技术例如分级结晶或HPLC。可选择地,可通过非对称合成来得到光学异构体,或通过从光学活性起始物质进行合成来得到光学异构体。
方法
可使用或调整本领域公开的方法来制备式(I)化合物,或者使用或调整以下实施例公开的方法来制备式(I)化合物。用于制备方法的起始物质可商购或可使用或调整文献方法来制备。
本发明一个实施方案涉及制备式(I)化合物的方法,所述方法如下进行:在合适的溶剂(例如吡啶、THF(四氢呋喃)或DMF(二甲基甲酰胺))中,在合适的碱(例如三(C1-6烷基)胺[例如二异丙基乙胺]或吡啶)存在下,和在合适的温度(例如-10至50℃),使式(II)化合物与式(III)化合物偶联,
式(II)化合物为:
式(III)化合物为:
其中L1是离去基团(例如卤素(例如氯)或甲磺酸酯基团(mesylate)或甲苯磺酸酯基团(tosylate))。
本发明一个实施方案涉及制备式(II)化合物的方法,其中X为O、S或NH,所述方法如下进行:
(a)使式(IV)化合物与式(V)化合物偶联,
式(IV)化合物为:
其中R4、W和Y如在式(I)化合物中所定义,以及L2为离去基团(例如卤素或三氟甲磺酸酯基团(triflate)),
式(V)化合物为:
其中R1、R1a和R2如在式(I)化合物中所定义,以及G对应于R3或对应于R3的经保护前体,其中所述反应可在以下条件下进行:在合适的溶剂(例如芳香族溶剂(例如甲苯)或极性非质子性溶剂(例如DMF或丁腈))中,在合适的碱(例如碱金属烷氧化物(例如叔丁醇钠)或碳酸铯)存在下,优选地通过合适的金属催化剂(例如碘化亚铜(I))介导,和在合适的温度(例如在80℃至120℃),
或者
(b)使式(VII)化合物与式(VIII)化合物反应,
式(VII)化合物为:
式(VIII)化合物为:
其中R1、R2、R4、X、W和Y如在式(I)化合物中所定义,G对应于R3或对应于R3的经保护前体,以及L3为离去基团(例如卤素、甲磺酸酯基团或甲苯磺酸酯基团),以及其中所述反应可在合适的溶剂(例如DCM、DMF或乙腈)中在合适的碱(例如碱金属碳酸盐(例如碳酸铯或碳酸钾))存在下和在合适的温度(例如-10至50℃)进行,然后使用或调整文献方法来进行还原性氨化步骤,
或者
(c)使式(VIII)化合物与式(IX)化合物反应,
式(VIII)化合物为:
其中R1、R1a、R2和R3如在式(I)化合物中所定义,以及PG为合适的保护基例如BOC(叔丁氧羰基)、Ms(甲磺酸酯基团)、Ns(硝苯磺酸酯基团)、Ts(甲苯磺酸酯基团)、相关的羰基残基或相关的磺酰基残基,以及其中所述反应可在合适的溶剂(例如DCM或甲苯)中在合适的碱(例如NaH或KOtBu(叔丁醇钾))存在下进行,然后使用或调整文献方法来进行脱保护步骤。
作为式(V)化合物的具体情况,可使用式(X)化合物来制备式(II)化合物,
式(X)化合物为:
其中R1、R2和G如在式(V)化合物中所定义。
式(X)化合物可如下制备:使亲核试剂G-M与式(XI)羰基化合物反应,然后对式(XII)中间体进行还原和随后的脱保护,
其中R1、R1a如在式(I)化合物中所定义,以及G对应于R3或对应于R3的经保护前体,以及L为离去基团(例如烷氧基、甲氧基(甲基)氨基)。M为金属例如Li或M为Mg-卤化物(Mg-halide)。
亲核试剂的加入可在合适的非质子性溶剂(例如THF)中在-10至50℃的适当温度进行。可使用或调整文献方法来进行随后的还原和脱保护步骤。
可选择地,式(X)化合物可如下制备:使亲核试剂G-M与式(XIII)醛反应,随后进行脱保护,
其中R1、R1a如在式(I)化合物中所定义,G对应于R3或对应于R3的经保护前体,以及PG为保护基或氢。M为金属例如碱金属(例如Li)或M为Mg-卤化物。所述反应可按照用于将碳负离子(carbanion)加至醛中的公开方案来进行。
制备式(X)化合物的另一种方法是使式(XIV)硝基烃基化合物(nitroalkyle)与式(XV)醛反应,然后对硝基官能团进行还原,
其中R1和R1a如在式(I)化合物中所定义,G对应于R3或对应于R3的经保护前体,以及PG为保护基或氢。这两个步骤可按照或调整文献方法来进行。
本发明涉及制备式(I)化合物及中间体的方法。
医药用途
因为式(I)化合物具有与糖皮质激素受体结合的能力,所以它们可用作抗炎剂,并且还可显示出抗变应性(antiallergic)作用、免疫抑制性(immunosuppressive)作用和抗增殖性(anti-proliferative)作用。因此,式(I)化合物或其可药用盐可用作在哺乳动物(例如人)中治疗或预防一种或多种以下病理状态(病症)的药物:
(i)与炎性过程、变应性过程和/或增殖性过程相关的肺病:
·任意起源的慢性阻塞性肺病(chronically obstructive lung disease),主要是支气管哮喘;
·不同起源的支气管炎;
·各种形式的再构造性肺病(restructive lung disease),主要是变应性肺泡炎(allergic alveolitis);
·各种形式的肺水肿(pulmonary edema),主要是中毒性肺水肿(toxicpulmonary edema);
·结节病(sarcoidosis)和肉芽肿病(granulomatosis),如伯克病(Boeck’sdisease);
(ii)与炎性过程、变应性过程和/或增殖性过程相关的风湿性疾病/自身免疫性疾病/变性关节病:
·各种形式的风湿性疾病,尤其是类风湿性关节炎、急性风湿热、风湿性多肌痛、胶原性疾病(collagenosis);
·反应性关节炎;
·其它起源的炎性软组织疾病(inflammatory soft-tissue disease);
·变性关节病(关节病(arthrosis))中的关节炎病状;
·创伤性关节炎(traumatic arthritide);
·其它起源的胶原性疾病,例如系统性红斑狼疮、硬皮病、多肌炎、皮肌炎、结节性多动脉炎、颞动脉炎;
(iii)与炎性过程、变应性过程和/或增殖性过程相关的变态反应:
·各种形式的变态反应,例如血管神经性水肿(Quincke’s edema)、枯草热、昆虫叮咬、对药物、血液衍生制品(blood derivative)、造影剂等的变态反应、过敏性休克、荨麻疹、接触性皮炎;
(iv)与炎性过程、变应性过程和/或增殖性过程相关的皮肤病:
·特应性皮炎(主要在儿童中);
·牛皮癣;
·由不同致病因素例如辐射、化学品、烧伤等触发的红斑病(erythematousdisease);
·酸性灼伤(acid burn);
·大疱性皮肤病;
·苔癣样疾病(disease of the lichenoid group);
·瘙痒(例如过敏性起源的瘙痒);
·各种形式的湿疹(例如特应性湿疹或脂溢性湿疹);
·酒渣鼻(rosacea);
·寻常型天疱疮(pemphigus vulgaris);
·渗出性多形性红斑(erythema exudativum multiforme);
·结节性红斑(erythema nodosum);
·龟头炎;
·外阴炎;
·炎性脱发(inflammatory hair loss),如斑秃;
·皮肤T细胞淋巴瘤(cutaneous T-cell lymphoma);
(v)与炎性过程、变应性过程和/或增殖性过程相关的肾病:
·肾病综合征;
·各种肾炎;
(vi)与炎性过程、变应性过程和/或增殖性过程相关的肝病:
·急性肝细胞分解(acute liver cell decomposition);
·不同起源的急性肝炎,例如病毒性、中毒性或药物引起的急性肝炎;
·慢性攻击性肝炎和/或慢性间歇性肝炎;
(vii)与炎性过程、变应性过程和/或增殖性过程相关的胃肠疾病:
·节段性回肠炎(克罗恩病(Crohn’s disease));
·溃疡性结肠炎;
·其它起源的肠胃炎,例如先天性啖性腹泄(native sprue);
(viii)与炎性过程、变应性过程和/或增殖性过程相关的直肠病:
·肛门湿疹(anal eczema);
·龟裂(fissure);
·痔疾;
·特发性直肠炎(idiopathic proctitis);
(ix)与炎性过程、变应性过程和/或增殖性过程相关的眼病:
·变应性角膜炎(allergic keratitis)、色素层炎(uvenitis)、虹膜炎(iritis);
·结膜炎;
·睑炎;
·视神经炎;
·脉络膜炎;
·交感性眼炎;
(x)与炎性过程、变应性过程和/或增殖性过程相关的耳-鼻-喉区疾病:
·变应性鼻炎、枯草热;
·外耳炎,例如由接触性皮炎、感染等引起的外耳炎;
·中耳炎;
(xi)与炎性过程、变应性过程和/或增殖性过程相关的神经疾病:
·脑水肿,主要是肿瘤引起的脑水肿;
·多发性硬化;
·急性脑脊髓炎;
·不同形式的惊厥,例如婴儿点头状痉挛(infantile nodding spasm);
(xii)与炎性过程、变应性过程和/或增殖性过程相关的血液病:
·获得性溶血性贫血(acquired haemolytic anemia);
·特发性血小板减少(idiopathic thrombocytopenia);
(xiii)与炎性过程、变应性过程和/或增殖性过程相关的肿瘤疾病:
·急性淋巴性白血病(acute lymphatic leukaemia);
·恶性淋巴瘤;
·淋巴肉芽肿病(lymphogranulomatosis);
·淋巴肉瘤;
·广泛性转移(extensive metastasis),主要在乳腺癌和前列腺癌中;
(xiv)与炎性过程、变应性过程和/或增殖性过程相关的内分泌疾病:
·内分泌眼眶病(endocrine orbitopathy);
·甲状腺危象(thyrotoxic crisis);
·德奎尔万甲状腺炎(de Quervain’s thyroiditis);
·桥本甲状腺炎(Hashimoto’s thyroiditis);
·甲状腺功能亢进(hyperthyroidism);
(xv)与炎性过程、变应性过程和/或增殖性过程相关的移植;
(xvi)与炎性过程、变应性过程和/或增殖性过程相关的重度休克病症(severe shock condition),例如过敏性休克;
(xvii)与炎性过程、变应性过程和/或增殖性过程相关的替代疗法:
·先天原发性肾上腺机能不全(innate primary suprarenal insufficiency),例如先天性肾上腺性性腺综合征(congenital adrenogenital syndrome);
·后天原发性肾上腺机能不全(acquired primary suprarenal insufficiency),例如艾迪生病(Adidison’s disease)、自身免疫性肾上腺炎(autoimmuneadrenalitis)、感染后(meta-infective)、肿瘤、转移等;
·先天继发性肾上腺机能不全(innate secondary suprarenal insufficiency),例如先天性垂体机能减退(congenital hypopituitarism);
·后天继发性肾上腺机能不全(acquired secondary suprarenalinsufficiency),例如感染后(meta-infective)、肿瘤等;
(xviii)与炎性过程、变应性过程和/或增殖性过程相关的呕吐:
·例如在细胞生长抑制剂诱导的呕吐中与5-HT3拮抗剂联用。
在不对上述病症有所偏见的情况下,式(I)化合物还可用于治疗以下疾病,例如康恩综合征(Conies syndrome)、原发性和继发性醛甾酮过多症(primary and secondary hyperaldosteronism)、钠滞留增加、镁和钾排泄增加(多尿症(diuresis))、水滞留增加、高血压(单纯收缩期(isolated systolic)高血压和混合型收缩期/舒张期(combined systolic/diastolic)高血压)、心律失常、心肌纤维化、心肌梗塞、巴特综合征(Bartter’s Syndrome)、与儿茶酚胺水平过度有关的疾病、舒张期和收缩期充血性心力衰竭(diastolic and systoliccongestive heart failure(CHF))、外周血管疾病、糖尿病性肾病、伴有水肿和腹水的肝硬化(cirrhosis with edema and ascites)、食管脉管曲张(oesophagealvaricies)、艾迪生病、肌无力、皮肤黑色素沉着增加、体重减轻(weight loss)、低血压、低血糖、库欣综合征(Cushing’s Syndrome)、肥胖、高血压、葡萄糖耐受不良、高血糖症、糖尿病、骨质疏松症、多尿症、多饮、炎症、自身免疫性疾病、与器官移植有关的组织排斥、恶性肿瘤如白血病和淋巴瘤、急性肾上腺机能不全、先天性肾上腺增生、风湿热、结节性多动脉炎、肉芽肿性多动脉炎、对骨髓细胞系的抑制、免疫增殖/细胞凋亡、对下丘脑-垂体-肾上腺轴(HPA axis)的抑制和调节、高皮质醇血症(hypercortisolemia)、对Th1/Th2细胞因子平衡的调节、慢性肾病、中风和脊髓损伤、高钙血症、高血糖、急性肾上腺机能不全、慢性原发性肾上腺机能不全、继发性肾上腺机能不全、先天性肾上腺增生、脑水肿、血小板减少和Little综合征(Little’ssyndrome)、系统性炎症(systemic inflammation)、炎性肠病、系统性红斑狼疮、盘状红斑狼疮(discoid lupus erythematosus)、结节性多关节炎(polyartitisnodosa)、韦格纳肉芽肿病(Wegener’s granulomatosis)、巨细胞关节炎(giant cellarthritis)、类风湿性关节炎、骨性关节炎、枯草热、变应性鼻炎、接触性皮炎、特应性皮炎、剥脱性皮炎(exfoliative dermatitis)、荨麻疹、血管神经性水肿、慢性阻塞性肺病、哮喘、腱炎、滑囊炎、克罗恩病、溃疡性结肠炎、自身免疫性慢性活动性肝炎、肝炎、cinhosis、炎性脱发(inflammatory scalpalopecia)、脂膜炎、牛皮癣、炎性囊肿(inflamed cyst)、坏疽性脓皮症、寻常型天疱疮、大疱性类天疱疮、皮肌炎、嗜酸细胞性筋膜炎、复发性多软骨炎、炎性血管炎、结节病、Sweet病(Sweet’s disease)、1型反应性麻风、毛细血管瘤、扁平苔藓、结节性红斑痤疮(erythema nodosum acne)、多毛症、中毒性表皮坏死松解症(toxic epidermal necrolysis)、多形红斑(erythemamultiform)、皮肤T细胞淋巴瘤、精神病、认知障碍(如记忆紊乱)、心境障碍(如抑郁和双相性精神障碍)、焦虑障碍和人格障碍。
本文使用的术语“充血性心力衰竭”(CHF)或“充血性心脏病”是指以下的心血管系统病症,其中心脏不能有效泵出足够体积的血液来满足身体组织和器官系统的需要。通常,CHF的特征在于左心室衰竭(收缩期功能障碍)和肺内积液,根本原因在于一种或多种心脏病症或心血管病症,包括冠状动脉疾病、心肌梗塞、高血压、糖尿病、瓣膜性心脏病和心肌病。术语“舒张期充血性心力衰竭(diastolic congestive heart failure)”是指以心脏适当松弛和充血的能力受损为特征的CHF病症。相反地,术语“收缩期充血性心力衰竭(systolic congestive heart failure)”是指以心脏适当收缩和射血的能力受损为特征的CHF病症。
本领域技术人员应该认识到的是,生理疾病可按“慢性”病症或“急性”发作的形式存在。本文使用的术语“慢性”是指缓慢进展并长期持续的病症。因此,当确诊慢性疾病时,对其进行治疗,并且治疗持续整个疾病过程。相反地,术语“急性”是指短过程的恶化事件或发作然后是缓解期。因此,对生理疾病的治疗既涉及急性事件又涉及慢性病症。在急性事件中,在症状发作时给药化合物,当症状消失时停药。
在另一个方面,本发明提供式(I)化合物或其可药用盐,其用在治疗(例如上述疗法)中。
在另一个方面,本发明提供式(I)化合物或其可药用盐在制备用于治疗糖皮质激素受体所介导的病症(例如上述病症)的药物中的用途。
在另一个方面,本发明提供式(I)化合物或其可药用盐在制备用于治疗炎性(例如关节炎性)病症的药物中的用途。
在另一个方面,本发明提供式(I)化合物或其可药用盐在制备用于治疗哮喘病症的药物中的用途。
在另一个方面,本发明提供式(I)化合物或其可药用盐在制备用于治疗COPD(慢性阻塞性肺病)的药物中的用途。
本发明还提供在哺乳动物(例如人)中治疗糖皮质激素受体所介导的病症、炎性病症、哮喘病症和/或COPD的方法,所述方法包括向需要所述治疗的哺乳动物给药有效量的式(I)化合物或其可药用盐。
在本说明书的上下文中,除非给出相反的具体说明,术语″治疗″也包括″预防″。术语″治疗的″和″治疗地″应该相应地解释。
在本说明书中,除非另有说明,术语“抑制剂”和“拮抗剂”是指这样的化合物,所述化合物通过任何方式部分或完全地阻断导致激动剂所致应答产生的转导途径。术语“激动剂”是指这样的化合物,所述化合物通过任何方式部分或完全地激发导致应答产生的转导途径。
除非另有说明,术语“障碍(disorder)”是指与糖皮质激素受体活性有关的任何病症和疾病。
药物组合物
为了将式(I)化合物或其可药用盐用于对哺乳动物进行治疗性处置,通常按照标准药物实践将所述活性成分配制成药物组合物。
因此,在另一个方面,本发明提供包括式(I)化合物或其可药用盐(活性成分)以及可药用辅料、稀释剂或载体的药物组合物。在另一个方面,本发明提供制备所述组合物的方法,所述方法包括将活性成分与可药用辅料、稀释剂或载体混合。基于给药模式,所述药物组合物可包含0.05-99%w(重量百分数)、例如0.05-80%w、例如0.10-70%w(例如0.10-50%w)的活性成分,所有重量百分数都基于全部组合物。
对于需要治疗的病症,本发明的药物组合物可按标准方式给药,例如通过局部给药(如给药至肺和/或气道或给药至皮肤)、口服给药、直肠给药或肠胃外给药。因此,可将式(I)化合物或其可药用盐配制成以下形式:例如气雾剂、粉剂(例如干粉剂或可分散粉剂)、片剂、胶囊剂、糖浆剂、颗粒剂、水性或油性溶液剂或混悬剂、(脂质)乳剂、栓剂、软膏剂、乳膏剂、滴剂或无菌可注射水性或油性溶液剂或混悬剂。
本发明的合适药物组合物为适于以单位剂量形式口服给药的药物组合物,例如含有0.1mg-1g活性成分的片剂或胶囊剂。
在另一个方面,本发明的药物组合物为适于静脉内、皮下、关节内或肌内注射的药物组合物。
可使用缓冲剂,可药用共溶剂如聚乙二醇、聚丙二醇、甘油或乙醇,或络合剂如羟丙基β-环糊精来辅助配制。
可通过药学领域熟知的常规过程得到上述制剂。可通过常规手段对片剂进行肠溶性包衣,例如进行邻苯二甲酸醋酸纤维素包衣。
本发明还涉及联合治疗或组合物,其中式(I)GR激动剂或其可药用盐,或包含式(I)GR激动剂或其可药用盐的药物组合物,与一种或多种用于治疗任何上述病症的药物同时(可能在同一组合物中)或依次给药。
例如,为了治疗类风湿性关节炎、骨关节炎、COPD、哮喘或变应性鼻炎,本发明的GR激动剂可以与治疗所述病症的一种或多种药物联用。当通过吸入给药这样的组合时,所述一种或多种药物选自:
·PDE4抑制剂,包括同工型PDE4D的抑制剂;
·选择性β2肾上腺素受体激动剂,例如间羟异丙肾上腺素(metaproterenol)、异丙肾上腺素(isoproterenol)、去甲肾上腺素(isoprenaline)、沙丁胺醇(albuterol)、柳丁氨醇(salbutamol)、福莫特罗(formoterol)、沙美特罗(sameterol)、特布他林(terbutaline)、奥西那林(orciprenaline)、甲磺酸比托特罗(bitolterol mesylate)、吡布特罗(pirbuterol)或茚达特罗(indacaterol);
·蕈毒碱性受体(muscarinic receptor)拮抗剂(例如M1、M2和M3拮抗剂,如选择性M3拮抗剂),如异丙托溴铵(ipratropium bromide)、噻托溴铵(titropium bromide)、氧托溴铵(oxitropium bromide)、哌仑西平(pirenzepine)或替仑西平(telenzepine);
·甾体(例如布地奈德(budesonide));
·趋化因子受体功能的调节剂(例如CCR1受体拮抗剂);或
·p38激酶功能的抑制剂。
在本发明的另一个实施方案中,当这样的组合用于治疗COPD、哮喘或变应性鼻炎时,式(I)GR激动剂或其可药用盐可以通过吸入途径或口服途径给药,并与能够通过吸入途径或口服途径给药的黄嘌呤(如氨茶碱(aminophylline)或茶碱(theophylline))联用。式(I)GR激动剂和黄嘌呤可一起给药。它们可依次给药。或它们可分开给药。
具体实施方式
实施例
以下实施例说明了本发明。在实施例中使用以下缩写:
TFA 三氟乙酸;
THF 四氢呋喃
DCM 二氯甲烷
HPLC 高效液相色谱
LC/MS 液相柱色谱/质谱
GC 气相色谱
DMSO 二甲基亚砜
APCI-MS 大气压化学电离质谱
r.t. 室温(范围为16℃至25℃的温度)
一般方法
在Varian Mercury-VX 300MHz仪器或Varian Inova 400MHz仪器上记录NMR光谱。氯仿-d的中间峰(H7.27ppm)、丙酮的中间峰(H2.05ppm)、二氯甲烷-d2的中间峰(H5.32ppm)或DMSO-d6的中间峰(H2.50ppm)用作内标。
以下方法用于LC/MS分析:
仪器:Agilent 1100;柱:Waters Symmetry 2.1×30毫米;质谱:APCI;流速:0.7mL/分钟;波长:254纳米;溶剂A:水+0.1%TFA;溶剂B:乙腈+0.1%TFA;梯度:历时2.7分钟从15%/B变为95%/B,以及在95%B保持0.3分钟。
以下方法用于GC-MS分析:
在配备有EI电离室(70eV)的Hewlett-Packard GC.MS系统上记录低分辨率质谱和精确质量数据。
以下方法用于LC分析:
方法A:仪器为Agilent 1100;柱为Kromasil C18 100×3毫米,5μ粒度;溶剂A为0.1%TFA/水;溶剂B为0.08%TFA/乙腈;流速为1mL/分钟;梯度为历时20分钟从10%B变为100%B,以及在100%B保持1分钟;在220、254和280纳米测量吸收度。
Kromasil KR-100-5-C18柱(250×20毫米,Akzo Nobel)和流速为10mL/分钟的乙腈/水(0.1%TFA)混合物用于制备性HPLC。
除非另有说明,起始原料是商购的。所有溶剂和商购试剂是实验室级的并且按原样使用。
实施例1
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]环丙基磺酰胺
将(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-胺(1a,16mg,0.044毫摩尔)溶解在无水吡啶(2mL)中,并冷却到0℃。加入环丙基磺酰氯(16μl,0.056毫摩尔),将混合物在室温搅拌45分钟。通过HPLC(反相C-18,CH3CN/水(0.1%TFA)的梯度为20-90%)跟踪反应的进展。45分钟后和75分钟后加入额外部分的环丙基磺酰氯(分别为5μl和6μl)。由于反应进行得非常慢,在搅拌总共2.5小时后,加入三乙胺(27μl,0.2mmol)。在环境温度再继续搅拌18.5小时,然后将反应混合物在乙酸乙酯和盐酸水溶液(1.7M)之间分配。将有机相用盐酸水溶液(1.7M)洗涤两次,然后用水洗涤,最后用盐水洗涤。蒸发并进行快速色谱(硅胶,EtOAc/庚烷的梯度为0-50%),最后从二噁烷中冷冻干燥,得到标题化合物(7mg,33%),其含有15mol%(摩尔百分比)的二噁烷。
1H-NMR(300MHz,DMSO-d6)δ8.16(1H,s),7.76-7.73(2H,m),7.70(1H,d),7.44-7.34(7H,m),7.28(1H,t,进一步偶合的),7.11(1H,d),7.24(1H,dd),5.33(1H,d),3.73(1H,m),2.39-2.33(1H,m),1.24(3H,d),0.89-0.79(4H,m)。
19F-NMR(DMSO-d6):-115.8(tt,未分辨的)。
APCI-MS m/z:466.0[MH+]。
(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-胺(1a)
基本通过Job & Buchwald:Org.Lett.2002,4(21),3703-3706中描述的方法来制备小标题化合物。
将1-(4-氟苯基)-5-碘吲唑(43mg,0.12毫摩尔)、(1R,2S)-降麻黄碱[(1R,2S)-norephedrine](16mg,0.1mmol)、碘化亚铜(I)(2.2mg,5mol%)和碳酸铯(84mg,0.26毫摩尔)悬浮在丁腈(1ml)中。将反应容器盖好,并将混合物在125℃搅拌。通过HPLC(反相C-18,CH3CN/水(0.1%TFA)的梯度为20-90%)跟踪反应的进展。7.5小时后,加入额外的(1R,2S)-降麻黄碱(70mg)、碘化亚铜(I)(16mg)和碳酸铯(136mg),在125℃继续搅拌。2小时后,所有1-(4-氟苯基)-5-碘吲唑已经耗尽,将混合物冷却,过滤并蒸发。进行快速色谱(硅胶,MeOH(甲醇)/EtOAc(乙酸乙酯)的梯度为0-30%),得到小标题化合物(19mg,41%)。
1H-NMR(300MHz,DMSO-d6+D2O,添加有TFA)δ8.16(1H,d),7.76-7.68(3H,m),7.43-7.28(8H,m),7.12(1H,d),5.64(1H,d),3.70(1H,qd),1.16(3H,d)。
19F-NMR(DMSO-d6):δ-115.97(tt,未分辨的)。
APCI-MS m/z:362.2[MH+]。
实施例2
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]丙-1-磺酰胺
向搅拌的(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-胺(1a,18mg,50μmol)于乙腈(1ml)中的溶液中加入三乙胺(100μl),然后加入丙-1-磺酰氯(21mg,150μmol)。继续搅拌过夜。然后将混合物用水(300μl)稀释,通过制备性HPLC对标题化合物进行分离,得到23mg(83%),其为白色固体。
1H NMR(400MHz,d6-丙酮)δ8.04(d,J=0.7Hz,1H),7.77(m,2H),7.71(d,J=9.2Hz,1H),7.49(d,J=7.3Hz,2H),7.41-7.29(m,5H),7.27(dd,J=9.1,2.4Hz,1H),7.16(d,J=2.3Hz,1H),6.25(d,J=9.0Hz,1H),5.47(d,J=4.2Hz,1H),3.89(m,1H),2.86(m,2H),1.67(m,2H),1.33(d,J=6.7Hz,3H),0.92(t,J=7)。
APCI-MS m/z:468[MH+]。
实施例3
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-4-基]氧基-1-苯基-丙-2-基]环丙基磺酰胺
按照就实施例1描述的方案使用(1R,2S)-1-[1-(4-氟苯基)吲唑-4-基]氧基-1-苯基-丙-2-胺(3a,30mg,0.08mmol)和环丙基磺酰氯(22μl,0.21mmol)进行制备。收率:20mg(53%)。
1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),7.77(td,J=8.7,3.8Hz,2H),7.49(d,J=8.5Hz,1H),7.44-7.35(m,6H),7.31-7.20(m,3H),6.40(d,J=6.9Hz,1H),5.50(d,J=4.4Hz,1H),3.85-3.77(m,1H),2.43-2.35(m,1H),1.31(d,J=6.7Hz,3H),0.90-0.79(m,4H)。
APCI-MS:466 m/z[MH+]。
(1R,2S)-1-[1-(4-氟苯基)吲唑-4-基]氧基-1-苯基-丙-2-胺(3a)
按照就1a描述的方案从4-碘-1-(4-氟苯基)吲唑(3b,332mg,0.98mmol)和(1R,2S)-降麻黄碱(742mg,4.9mmol)开始进行制备。收率:150mg(42%)。
APCI-MS:362 m/z[MH+]。
4-碘-1-(4-氟苯基)吲唑(3b)
将4-溴-1-(4-氟苯基)吲唑(291mg,1mmol)、碘化亚铜(I)(9.5mg,0.05mmol)、碘化钠(300mg,2mmol)和(1R,2R)-N,N’-二甲基环己烷-1,2-二胺(14.2mg,0.1mmol)在二噁烷(1ml)中混合,并在氩气中在110℃搅拌。所有起始物质在24小时后耗尽。将混合物冷却,加入氨(5ml,28%水溶液)和水(20ml),然后用DCM(2×15ml)萃取。浓缩有机相,粗产物通过快速色谱(EtOAc/庚烷)纯化,得到标题化合物(322mg,98%)。
APCI-MS m/z:339[MH+]。
实施例4
N-[(1R,2S)-1-[1-(6-氟吡啶-3-基)吲唑-5-基]氧基-1-苯基-丙-2-基]环丙基磺酰胺
按照就实施例1描述的方案使用1-[1-(6-氟-吡啶-3-基)吲唑-5-基]氧基-1-苯基-丙-2-胺(20mg,0.06mmol)和环丙基磺酰氯(18μl,0.17mmol)进行制备。收率:5mg(71%)。
1H NMR(400MHz,DMSO-d6)δ8.63(s,1H),8.36(ddd,J=9.1,6.8,2.6Hz,1H),8.24(s,1H),7.78(d,J=9.2Hz,1H),7.45-7.34(m,6H),7.30-7.25(m,2H),7.14(d,J=2.3Hz,1H),5.34(d,J=4.4Hz,1H),3.76-3.70(m,1H),2.40-2.31(m,1H),1.24(d,J=6.9Hz,3H),0.88-0.80(m,4H)。
APCI-MS:466 m/z[MH+]。
1-[1-(6-氟-吡啶-3-基)吲唑-5-基]氧基-1-苯基-丙-2-胺(4b)
将4-碘-1-(6-氟-吡啶-3-基)吲唑(4c,191mg,0.56mmol)、(1R,2S)-降麻黄碱(426mg,2.8mmol)、碘化亚铜(I)(139mg,0.73mmol)和碳酸铯(1.8g,5.6mmol)在丁腈(3ml)中混合,在氩气气氛中在125℃搅拌2小时。LC-MS显示起始物质耗尽。粗混合物先后通过快速色谱(EtOAc/庚烷/甲醇)和制备性HPLC(MeCN(乙腈)/水/1%TFA)进行纯化,得到标题化合物(20mg,10%)。
APCI-MS m/z:363[MH+]。
4-碘-1-(6-氟-吡啶-3-基)吲唑(4c)
将4-溴-1-(6-氟-吡啶-3-基)吲唑(184mg,0.63mmol)、碘化钠(189mg,1.26mmol)、碘化亚铜(I)(6mg,0.03mmol)和(1R,2R)-N,N’-二甲基环己烷-1,2-二胺(8.5mg,0.06mmol)在二噁烷(1ml)中混合,在氩气中在110℃搅拌。加入氨(5ml,28%水溶液)和水(20ml),将混合物用2×15ml DCM萃取。浓缩有机相,通过快速色谱(EtOAc/庚烷)对粗产物进行纯化,得到标题化合物(191mg,89%)。
APCI-MS m/z:340[MH+]。
实施例5
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]甲磺酰胺
使用实施例2中描述的步骤进行制备和纯化。收率:11mg。
APCI-MS m/z:440[MH+]。
实施例6
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]-1-苯基-甲磺酰胺
使用实施例2中描述的步骤进行制备和纯化。收率:5.7mg。
APCI-MS m/z:516[MH+]。
实施例7
1,1,1-三氟-N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]甲磺酰胺
使用实施例2中描述的步骤进行制备和纯化。收率:9.5mg。
APCI-MS m/z:494[MH+]。
实施例8
5-[(1R,2S)-2-(二甲基氨磺酰基氨基)-1-苯基-丙氧基]-1-(4-氟苯基)吲唑
使用实施例2中描述的步骤进行制备和纯化。收率:12.3mg。
APCI-MS m/z:469[MH+]。
实施例9
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]丙-2-磺酰胺
使用实施例2中描述的步骤进行制备和纯化。收率:1.2mg。
APCI-MS m/z:468[MH+]。
实施例10
2-(1,3-二氧代异吲哚-2-基)-N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]乙磺酰胺
使用实施例2中描述的步骤进行制备和纯化。收率:2.8mg。
APCI-MS m/z:599[MH+]。
实施例11
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]-3-(4-甲氧基苯氧基)丙-1-磺酰胺
使用实施例2中描述的步骤进行制备和纯化。收率:11.3mg。
APCI-MS m/z:590[MH+]。
实施例12
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]乙磺酰胺
使用实施例2中描述的步骤进行制备和纯化。收率:10.6mg。
APCI-MS m/z:454[MH+]。
实施例13
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]戊-2-磺酰胺
使用实施例2中描述的步骤进行制备和纯化。收率:0.4mg。
APCI-MS m/z:496[MH+]。
实施例14
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]丁-2-磺酰胺
使用实施例2中描述的步骤进行制备和纯化。收率:0.9mg。
APCI-MS m/z:482[MH+]。
实施例15
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]丁-1-磺酰胺
使用实施例2中描述的步骤进行制备和纯化。收率:1.2mg。
APCI-MS m/z:482[MH+]。
实施例16
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]-2-甲基-丙-1-磺酰胺
使用实施例2中描述的步骤进行制备和纯化。收率:7.2mg。
APCI-MS m/z:482[MH+]。
实施例17
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]戊-1-磺酰胺
使用实施例2中描述的步骤进行制备和纯化。收率:8.8mg。
APCI-MS m/z:496[MH+]。
实施例18
3,3,3-三氟-N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]丙-1-磺酰胺
使用实施例2中描述的步骤进行制备和纯化。收率:16.4mg。
APCI-MS m/z:522[MH+]。
实施例19
3-[[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]氨磺酰基]丙酸甲酯
使用实施例2中描述的步骤进行制备和纯化。收率:8mg。
APCI-MS m/z:512[MH+]。
实施例20
1-环戊基-N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]甲磺酰胺
使用实施例2中描述的步骤进行制备和纯化。收率:9.1mg。
APCI-MS m/z:508[MH+]。
实施例21
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]环戊基磺酰胺
使用实施例2中描述的步骤进行制备和纯化。收率:0.7mg。
APCI-MS m/z:494[MH+]。
实施例22
2,2,2-三氟-N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]乙磺酰胺
使用实施例2中描述的步骤进行制备和纯化。收率:6.7mg。
APCI-MS m/z:508[MH+]。
实施例23
1-环己基-N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]甲磺酰胺
使用实施例2中描述的步骤进行制备和纯化。收率:5.6mg。
APCI-MS m/z:522[MH+]。
实施例24
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]己-1-磺酰胺
使用实施例2中描述的步骤进行制备和纯化。收率:5.3mg。
APCI-MS m/z:510[MH+]。
实施例25
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]吡啶-3-磺酰胺
使用实施例2中描述的步骤进行制备和纯化。收率:18.6mg。
APCI-MS m/z:503[MH+]。
实施例26
(R)-N-(2-甲基-1-苯基-1-(1-对甲苯基-1H-吲唑-5-基氧基)丙-2-基)环丙基磺酰胺
在Thales SFC,Chiralpak IA柱(70%CO2,20%MeOH)上对N-(1-(1-(4-甲基苯基)-1H-吲唑-5-基氧基)-2-甲基-1-苯基-丙-2-基)环丙基磺酰胺(26-外消旋体,10mg)的外消旋混合物进行分离,收集第一洗脱峰。收率:4mg(40%)。
APCI-MS:m/z 468[MH+]。
(RS)-N-(2-甲基-1-苯基-1-(1-对甲苯基-1H-吲唑-5-基氧基)丙-2-基)环丙基磺酰胺(26-外消旋体)
在室温将环丙基磺酰氯(155μl,1.52mmol)加到1-(1-(4-甲基苯基)-1H-吲唑-5-基氧基)-2-甲基-1-苯基-丙-2-胺(26a,0.070g,0.19mmol)和三乙胺(80μl,0.57mmol)于MeCN(3ml)中的溶液中。将反应混合物搅拌过夜,浓缩,用10%NaHSO4(水溶液)稀释,并用EtOAc萃取。有机相用10%NaHSO4(水溶液)洗涤。通过HPLC对粗产物进一步纯化。收率:25mg(30%)。
1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),7.73(dd,J=9.0,4.8Hz,2H),7.67(d,J=9.2Hz,1H),7.48(d,J=7.3Hz,2H),7.37(m,4H),7.25(m,2H),7.05(d,J=2.3Hz,1H),7.00(s,1H),5.46(s,1H),2.56(m,1H),1.46(s,3H),1.27(s,3H),0.89(m,4H)。
APCI-MS:m/z 480.2[MH+]。
1-(1-(4-甲基苯基)-1H-吲唑-5-基氧基)-2-甲基-1-苯基-丙-2-胺(26a)
基本通过Job & Buchwald:Org.Lett.2002,4(21),3703-3706中描述的方法来制备小标题化合物。
在密封的用氩气冲洗的瓶中将2-氨基-2-甲基-1-苯基-丙-1-醇(26b,231mg,1.39mmol)、1-(4-甲基苯基)-5-碘-1H-吲唑(47mg,1.39mmol)、碘化亚铜(I)(38.1mg,0.20mmol)和Cs2CO3(1.3g,4.20mmol)于丁腈(20mL)中的混合物在100℃加热5小时。将反应混合物冷却下来,在EtOAc(20mL)和水(5mL)之间分配,将有机相用盐水洗涤。在HPLC上对粗产物进行纯化。收率:70mg(14%)。
APCI-MS:m/z 376.2[MH+]。
2-氨基-2-甲基-1-苯基-丙-1-醇(26b)
将37%盐酸(1mL)加到搅拌的2-甲基-2-硝基-1-苯基-丙-1-醇(26c,0.12g,0.6mmol)于EtOH(10mL)和水(5mL)的溶液中。分小份缓慢加入锌粉(0.241g,3.6mmol),将混合物在+70℃搅拌4小时。将混合物过滤以除去固体锌残余物,并通过蒸发浓缩至1/3体积,用水(50mL)稀释并用乙醚(125mL)洗涤。使用KOH(水溶液)溶液使酸性水相成为碱性,形成的浆液用乙醚(3×150mL)萃取。对有机相进行干燥(MgSO4)、过滤和蒸发。通过HPLC对粗产物进一步纯化。收率:60mg(60%)。
1H NMR(400MHz,DMSO-d6)δ7.27(m,5H),6.14(s,1H),5.47(d,J=4.8Hz,1H),4.90(s,1H),1.26(s,3H),1.00(s,3H)。
APCI-MS:m/z 164[MH+]。
2-甲基-2-硝基-1-苯基-丙-1-醇(26c)
向圆底烧瓶中加入无水硫酸镁(3.5g,29mmol)和2-硝基丙烷(16ml)。将烧瓶抽真空并用氩气填充。将反应混合物剧烈搅拌以得到均匀悬浮液,然后加入苯甲醛(1.3ml,13.1mmol)。搅拌5分钟后,加入2,8,9-三(1-甲基乙基)-2,5,8,9-四氮杂-1-磷杂二环[3.3.3]十一烷(395mg,1.3mmol)。将反应混合物在室温搅拌过夜,然后通过快速色谱(硅胶,庚烷-乙酸乙酯)进行纯化。收率:0.8g(30%)。
1H NMR(300MHz,DMSO-d6)δ7.35(m,5H),6.07(d,J=4.5Hz,1H),5.08(d,J=4.4Hz,1H),1.39(s,3H),1.33(s,3H)。
APCI-MS:m/z 376.2[MH+]。
实施例27
N-[(1RS,2SR)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-(4-(甲基硫基)苯基)丙-2-基]环丙基磺酰胺
a=相对混合物(relative mixture)
将(1RS,2SR)-1-{[1-(4-氟苯基)-1H-吲唑-5-基]氧基}-1-[4-(甲基硫基)苯基]丙-2-胺(27a,11mg,0.02mmol)的外消旋混合物溶解在THF(1.5mL)中。历时3小时逐份加入过量的N-乙基二异丙胺(0.185mL,1.1mmol)和环丙基磺酰氯(0.063mL,0.62mmol)。将反应混合物在室温搅拌过夜,通过加入水来淬灭,并通过HPLC纯化。将含有产物的馏分冷冻干燥,得到标题化合物,其为无色固体。使用Chiralpak IBTM,150×0.46mm柱、15%EtOH的异己烷溶液、0.5mL/min、UV=254nm进行手性HPLC,观察到比例为1∶1的两个峰。收率:6mg(58%)。
手性HPLC:两个峰,1∶1比例,保留时间=30.64、32.92分钟。
1H-NMR(300MHz,DMSO-d6):δ8.16(d,1H),7.78-7.66(m,3H),7.44-7.30(m,5H),7.28-7.19(m,3H),7.11(d,1H),5.28(d,J=4.38Hz,1H),3.71(m,1H),2.44(s,3H),2.42(m,1H),1.24(d,J=6.76Hz,3H),0.90-0.80(m,4H)。
APCI-MS m/z:512.1[MH+]。
(1RS,2SR)-1-{[1-(4-氟苯基)-1H-吲唑-5-基]氧基}-1-[4-(甲基硫基)苯基]丙-2-胺(27a)
a=相对混合物
如实施例1a中所述,从外消旋的(1RS,2SR)-2-氨基-1-[4-(甲基硫基)苯基]丙-1-醇(49mg,0.25mmol)、1-(4-氟苯基)-5-碘吲唑(27b-赤型,100mg,0.3mmol)、CuI(5mg,0.03mmol)、Cs2CO3(163mg,0.5mmol)于丁腈(0.5mL)中的溶液开始,在+125℃过夜,制备外消旋的小标题化合物。后处理并通过HPLC纯化后,分离出小标题化合物,为其三氟乙酸盐形式,没有对该物质进行NMR,使用LC/MS来鉴定,并且将得到的所有物质直接用在下一步骤中。收率:11mg(8%)。
APCI-MS m/z:408.1[MH+-TFA]。
(1RS,2SR)-2-氨基-1-[4-(甲基硫基)苯基]丙-1-醇和(1R*,2R*)-2-氨基-1-[4-(甲基硫基)苯基]丙-1-醇(27b-赤型)
a=相对混合物
向搅拌的1-[4-(甲基硫基)苯基]-2-硝基丙-1-醇(2.14g,9.41mmol)于EtOH(乙醇)(60mL)和水(30mL)中的溶液中加入37%盐酸(13mL,166mmol)。分小份缓慢加入锌粉(3.7g,56.6mmol),将混合物在+70℃搅拌4小时。将混合物过滤以除去固体锌残余物,并通过蒸发浓缩至1/3体积,用水(50mL)稀释,并用乙醚(125mL)洗涤。使用KOH(水溶液)溶液使酸性水相成为碱性,形成的浆液用乙醚(3×150mL)萃取。对有机相进行干燥(MgSO4)、过滤和蒸发。通过HPLC对粗产物进一步纯化并分离出两对外消旋的非对映异构体。
将每对的少量样品溶解在DCM/THF中,并用1摩尔当量的1,1’-羰基二咪唑处理,环化成相应的噁唑烷酮,对所述噁唑烷酮进行分离并通过NMR分析。与从具有已知立体化学的降麻黄碱制备的噁唑烷酮(Tetrahedron assym,1993,vol 4.no 12,pp 2513-2516和Org.lett,2005,7,13,2755-2758)的文献值比较位移和偶合常数,由此确定所得外消旋体的相对立体化学。
所得到的外消旋小标题化合物27b-赤型:
收率:243mg(13%)。
HPLC:保留时间=3.9分钟,99.3%d.e.(非对映异构体过量百分比)。
APCI-MS m/z:198.2[MH+]。
1H-NMR(300MHz,DMSO-d6):δ7.22(m,4H),5.14(vbrs,1H,-OH),4.28(d,J=4.78Hz,1H),3.26(vbrs,3.3H,-NH2+水),2.86(brm,1H),2.45(s,3H),0.84(d,J=6.37Hz,1H)。
将上述物质环化成相应的外消旋噁唑烷酮:
(4R*,5S*)-4-甲基-5-[4-(甲基硫基)苯基]-1,3-噁唑烷-2-酮
HPLC:保留时间=6.27分钟,100%d.e.。
APCI-MS m/z:223.9[MH+]。
1H-NMR(300MHz,CDCl3):δ7.25(m,4H),5.68(d,J=7.83Hz,1H),5.45(brs,1H),4.19(m,1H),2.51(s,3H),0.83(d,J=6.63Hz,3H)。
(1RS,2RS)-2-氨基-1-[4-(甲基硫基)苯基]丙-1-醇(27b-苏型)
a=相对混合物
如就27b-赤型所描述的那样,通过对2-氨基-1-[4-(甲基硫基)苯基]丙-1-醇的非对映异构体进行分离,得到27b-苏型,其为第二个洗脱出来的异构体。收率:418mg(22%)。
HPLC:保留时间=4.5分钟,96.4%d.e.。
APCI-MS m/z:198.2[MH+]。
1H-NMR(300MHz,DMSO-d6):δ7.21(m,4H),5.22(vbrs,1H,-OH),4.07(brd,1H),2.75(brm,1H),2.45(s,3H),1.51(vbrs,2H,-NH2),0.76(brd,3H)。
将上述物质环化成相应的外消旋噁唑烷酮:
(4R*,5R*)-4-甲基-5-[4-(甲基硫基)苯基]-1,3-噁唑烷-2-酮
HPLC:保留时间=6.41分钟,100%d.e.。
APCI-MS m/z:224.0[MH+]。
1H-NMR(300MHz,CDCl3):δ7.29(m,4H),5.59(brs,1H),5.01(d,J=7.43Hz,1H),3.82(m,1H),2.50(s,3H),1.38(d,J=6.11Hz,3H)。
1-[4-(甲基硫基)苯基]-2-硝基丙-1-醇(27c)
在室温将2,8,9-三异丙基-2,5,8,9-四氮杂-1-磷杂二环[3.3.3]十一烷(395mg,1.3mmol)于硝基乙烷(8mL)中的溶液加到搅拌的无水MgSO4(3.5g)和4-(甲基硫基)苯甲醛(2g,13.1mmol)于硝基乙烷(8mL)中的悬浮液中。将黄色浆液搅拌过夜,用乙醚稀释,过滤通过短硅胶塞,用乙醚洗涤所述硅胶塞。蒸发除去溶剂,粗产物通过快速色谱(使用0%-30%EtOAc/庚烷的梯度)纯化。得到产物,其为油状物,所述油状物在静止时结晶。LC/MS和GC/MS没能给出任何对应于所期望质量的m/z。NMR确认了结构,并表明是10∶19的非对映异构体混合物。收率:2.4g(81%)。
1H-NMR(300MHz,CDCl3):δ7.29(m,4H),5.36(d,J=3.74Hz,0.35H),5.00(d,J=9Hz,0.65H),4.81-4.63(m,1H),2.51+2.50(s+s,总共3H),2.39(vbrs,1H),1.52(d,J=6.84Hz,1.02H),1.33(d,J=6.84Hz,1.98H)。
实施例28
N-[(1RS,2RS)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-(4-(甲基硫基)苯基)丙-2-基]环丙基磺酰胺
a=相对混合物
将(1RS,2RS)-1-{[1-(4-氟苯基)-1H-吲唑-5-基]氧基}-1-[4-(甲基硫基)苯基]丙-2-胺(28a,32mg,0.06mmol)的外消旋混合物溶解在THF(2mL)中。历时3小时逐份加入过量的N-乙基二异丙胺(0.285mL,1.7mmol)和环丙基磺酰氯(0.069mL,0.68mmol)。将反应混合物在室温搅拌过夜,通过加入水来淬灭,并通过HPLC进行纯化。将含有产物的馏分冷冻干燥,得到标题化合物,其为无色固体。使用Chiralpak IBTM,150×0.46mm柱、15%EtOH的异己烷溶液、0.5mL/min、UV=254nm进行手性HPLC。观察到比例为1∶1的两个峰。收率:9mg(29%)。
手性HPLC:两个峰,1∶1比例,保留时间=30.07、35.59分钟。
1H-NMR(300MHz,DMSO-d6):δ8.16(d,1H),7.78-7.64(m,3H),7.44-7.34(m,4H),7.30-7.13(m,5H),5.25(d,J=5.57Hz,1H),3.80(m,1H),2.48(m,1H),2.43(s,3H),1.14(d,J=6.77Hz,3H),0.90-0.81(m,4H)。
APCI-MS m/z:512.1[MH+]。
(1RS,2RS)-1-{[1-(4-氟苯基)-1H-吲唑-5-基]氧基}-1-[4-(甲基硫基)苯基]丙-2-胺(28a)
a=相对混合物
如实施例1中描述的那样制备外消旋的小标题化合物。
从外消旋的(1RS,2RS)-2-氨基-1-[4-(甲基硫基)苯基]丙-1-醇(27b-苏型,46mg,0.23mmol)、1-(4-氟苯基)-5-碘吲唑(95mg,0.28mmol)、CuI(5mg,0.03mmol)、Cs2CO3(163mg,0.5mmol)于丁腈(0.5mL)中的溶液开始,在+125℃过夜。后处理并通过HPLC纯化后,分离出小标题化合物,为其三氟乙酸盐形式,没有对该物质进行NMR,使用LC/MS来鉴定,得到的所有物质直接用在下一步骤中。收率:32mg(26%)。
APCI-MS m/z:408.2[MH+-TFA]。
实施例29
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-(4-(甲基硫基)苯基)丙-2-基]环丙基磺酰胺
将(1R,2S)-1-{[1-(4-氟苯基)-1H-吲唑-5-基]氧基}-1-[4-(甲基硫基)苯基]丙-2-胺(29a,100mg,0.24mmol)溶解在MeCN(3mL)中,加入三乙胺(0.104mL,0.75mmol),然后加入环丙基磺酰氯(0.025mL,0.25mmol)。通过LC/MS跟踪反应。1小时后,检测转化为约50%,加入更多试剂即环丙基磺酰氯(0.025mL,0.25mmol)和三乙胺(0.07mL,0.50mmol),试图增加转化但没有任何成效。通过加入饱和NH4Cl(水溶液)将反应淬灭,然后浓缩。通过HPLC对残余物进行纯化,将所收集的馏分冷冻干燥,得到标题化合物,其为无色固体。使用Chiralpak IBTM,150×0.46mm柱、15%EtOH的异己烷溶液、0.5mL/min、UV=254nm进行手性HPLC,一个主要峰在32.39分钟(99.7%)和一个次要峰在30.69分钟(0.3%)。收率:48mg(39%)。
手性HPLC:保留时间=32.39分钟,99.4%e.e.(对映异构体过量)。
1H-NMR(300MHz,DMSO-d6):δ8.16(d,1H),7.79-7.66(m,3H),7.45-7.30(m,5H),7.28-7.18(m,3H),7.11(d,1H),5.28(d,J=4.34Hz,1H),3.71(m,1H),2.44(s,3H),2.41(m,1H),1.24(d,3H),0.89-0.81(m,4H)
APCI-MS m/z:512.2[MH+]。
(1R,2S)-1-{[1-(4-氟苯基)-1H-吲唑-5-基]氧基}-1-[4-(甲基硫基)苯基]丙-2-胺盐酸盐(29a)
如实施例1中所述制备小标题化合物。
将(1R,2S)-2-氨基-1-[4-(甲基硫基)苯基]丙-1-醇(595mg,3mmol)、1-(4-氟苯基)-5-碘吲唑(913mg,2.7mmol)、CuI(28mg,0.15mmol)、Cs2CO3(1.95g,6mmol)于丁腈(5mL)和甲苯(2mL)中的溶液在+125℃保持6小时。后处理并通过HPLC纯化后,如下分离出呈盐酸盐形式的小标题化合物:加入6-7NHCl/2-丙醇溶液,并用MeCN反复蒸发,得到小标题化合物,其为米色固体。收率:300mg(25%)。
1H-NMR(300MHz,DMSO-d6):δ8.40(brs,3H),8.20(d,1H),7.79-7.71(m,3H),7.45-7.24(m,7H),7.14(d,1H),5.69(d,J=2.92Hz,1H),3.65(m,1H),2.45(s,3H),1.19(d,3H)。
APCI-MS m/z:408.0[MH+-HCl]。
(1R,2S)-2-氨基-1-[4-(甲基硫基)苯基]丙-1-醇盐酸盐(29b)
按照Jingjun Yin等人在J.Org.Chem.2006,71,840-843中描述的方法来制备小标题化合物。
将(S)-1-(4-(甲基硫基)苯基)-1-氧代丙-2-基氨基甲酸叔丁酯(29c,2.7g,9.14mmol)、异丙醇铝(0.373g,1.83mmol)和2-丙醇(7.75mL,100.54mmol)于甲苯(11.5mL)中的溶液在氩气下在+50℃加热16小时。使反应混合物冷却,加入EtOAc(100mL)和0.5N HCl(60mL),有机层用水和盐水洗涤,经Na2SO4干燥,过滤并蒸发,得到2.65g粗产物,其为无色固体。
粗产物通过硅胶快速色谱进一步纯化,使用10%-30%EtOAc/庚烷的梯度,然后保持在最终浓度直到所有产物被洗脱。得到2.18g中间体即经BOC(叔丁氧羰基)保护的小标题化合物,其为无色固体。APCI-MS m/z:180.1,198.1,224.1[MH+-BOC-水,MH+-BOC,MH+-叔丁基-水]。将所得到的物质溶解在EtOAc(50mL)中,用1.5M HCl的EtOAc溶液(40ml,60.00mmol)在+70℃处理90分钟。蒸发除去溶剂,将固体残余物悬浮在EtOAc(30mL)和Et2O(乙醚)(100mL)中,盐通过过滤来收集,用乙醚(50mL)洗涤。收率:1.68g(78%收率)。
APCI-MS m/z:198.1[MH+]。
1H-NMR(400MHz,DMSO-d6):δ8.05(brs,3H),7.30(d,2H),7.26(d,2H),6.02(d,J=4.24Hz,1H),4.89(t,1H),3.35(m,1H),2.47(s,3H),0.94(d,3H)。
用1摩尔当量的1,1’-羰基二咪唑和三乙胺于DCM中的溶液将上述物质的样品环化成相应的噁唑烷酮。
通过NMR分析并与从具有已知立体化学的降麻黄碱制备的噁唑烷酮的文献值(Tetrahedron assym,1993,vol 4.no 12,pp 2513-2516和Org.lett,2005,7,13,2755-2758)比较位移和偶合常数来确定小标题化合物的相对立体化学,随后确定小标题化合物的绝对立体化学。
(4S,5R)-4-甲基-5-[4-(甲基硫基)苯基]-1,3-噁唑烷-2-酮
APCI-MS m/z:224.0[MH+]。
1H-NMR(500MHz,CDCl3):δ7.27(d,2H,Ar-H),7.22(d,2H),5.77(brs,1H,-NH),5.68(d,J=7.96Hz,1H,PhCH-),4.19(m,1H,-CH(Me)-),2.50(s,3H,Ar-SCH 3),0.83(d,J=6.5Hz,3H,-CH 3)ppm。
(S)-1-(4-(甲基硫基)苯基)-1-氧代丙-2-基氨基甲酸叔丁酯(29c)
将(S)-1-(甲氧基(甲基)氨基)-1-氧代丙-2-基氨基甲酸叔丁酯(2.32g,9.99mmol)悬浮在无水THF(20mL)中,用氩气钝化。使用冰/丙酮浴将浆液冷却到-15至-10℃,缓慢加入异丙基氯化镁的THF溶液(2.0M,4.74mL,9.49mmol)。加完后,得到透明溶液,向该溶液中缓慢加入4-(甲基硫基)苯基溴化镁(4-thioanisolemagnesium bromide)的THF溶液(0.5M,24mL,12.00mmol),加完后,将反应混合物在室温搅拌4小时。通过将反应混合物倒入1N HCl(100mL)中将反应混合物淬灭,向混合物中加入EtOAc(250mL)。分离各相,有机相用盐水洗涤,以及水相用EtOAc反萃取一次。对合并的EtOAc相进行干燥(Na2SO4)、过滤和蒸发。粗产物通过硅胶快速色谱进行纯化。使用100%庚烷-50%庚烷/DCM+5%MeOH的溶剂梯度,然后保持在最终溶剂比例直到产物被洗脱。将含有产物的馏分合并,蒸发溶剂,得到小标题化合物,其为无色固体。收率:2.7g(92%)。
LC/MS(APCI):(M+1)=295.9。
1H-NMR(300MHz,DMSO-d6):δ7.89(d,2H),7.36(d,2H),7.28(d,1H),5.00(m,1H),2.54(s,3H),1.35(s,9H),1.21(d,3H)。
APCI-MS m/z:295.9,195.9[MH+,MH+-BOC]。
实施例30
N-[(1R,2S)-1-苯基-1-(1-(丙-2-基)吲唑-5-基)氧基-丙-2-基]甲磺酰胺
如实施例2b中所描述的那样,从(1R,2S)-1-[(1-异丙基-1H-吲唑-5-基)氧基]-1-苯基-丙-2-胺(30b,31mg,100μmol)和甲磺酰氯(34mg,300μmol)制备标题化合物。收率:28mg(72%)。
APCI-MS:m/z 388[MH+]
1H NMR(400MHz,d6-丙酮)δ7.75(s,1H),7.50(m,3H),7.38(t,J=7.5Hz,2H),7.29(m,1H),7.15(dd,J=9.0,2.3Hz,1H),7.03(d,J=2.3Hz,1H),6.26(d,J=8.8Hz,1H),5.41(d,J=4.4Hz,1H),4.88(七重峰,J=6.7Hz,1H),3.90(m,1H),2.77(s,3H),1.47(dd,J=6.7,3.5Hz,6H),1.32(d,J=6.7Hz,3H)。
(1R,2S)-1-[(1-异丙基-1H-吲唑-5-基)氧基]-1-苯基-丙-2-胺(30b)
将5-碘-1-异丙基-1H-吲唑(30c,461mg,1.26mmol)、(1R,2S)-2-氨基-1-苯基-丙-1-醇(286mg,1.89mmol)、碘化亚铜(I)(25mg,130μmol)和碳酸铯(1.45g,3.8mmol)于丁腈(5ml)中的溶液在125℃搅拌2h。然后将混合物冷却到室温。过滤除去无机物质,并用乙酸乙酯洗涤。将合并的有机溶液在真空中浓缩,通过硅胶快速色谱(乙酸乙酯/甲醇)对产物进行纯化。收率:200mg(51%),其为棕色油状物。
APCI-MS:m/z 310[MH+]。
1H NMR(400MHz,DMSO-d6/D2O/TFA)δ7.80(s,1H),7.53(d,J=9.0Hz,1H),7.40(d,J=7.1Hz,2H),7.33(t,J=7.5Hz,2H),sH),7.08(dd,J=9.0,2.3Hz,1H),6.98(d,J=2.1Hz,1H),5.75(s,1H),5.03(d,J=5.3Hz,1H),4.86(七重峰,J=6.7Hz,1H),3.15(五重峰,J=6.0Hz,1H),1.41(dd,J=6.4,5.5Hz,6H),1.06(d,J=6.5Hz,3H)。
5-碘-1-异丙基-1H-吲唑(30c)
将5-碘-1H-吲唑(488mg,2mmol)、异丙基溴(244mg,2mmol)和KOtBu(叔丁醇钾)(336mg,3mmol)于无水DMF(4ml)中的混合物在室温搅拌过夜。然后用乙酸乙酯(50ml)对其进行稀释,用水(2×50ml)洗涤,以及用Na2SO4干燥。蒸发溶剂并通过硅胶快速色谱(正庚烷/乙酸乙酯)纯化,得到小标题化合物(298mg,52%)以及5-碘-2-异丙基-2H-吲唑(227mg,40%)。
1H NMR(400MHz,CDCl3)δ8.11(d,J=0.9Hz,1H),7.94(s,1H),7.60(dd,J=8.8,1.5Hz,1H),7.26(d,J=8.8Hz,1H),4.83(七重峰,J=6.8Hz,1H),1.61(d,J=6.7Hz,6H)。
APCI-MS:m/z 287[MH+]。
实施例31
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-(4-(甲基亚磺酰基)苯基)丙-2-基]环丙基磺酰胺
将N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-(4-(甲基硫基)苯基)丙-2-基]环丙基磺酰胺(29,20.5mg,0.04mmol)溶解在DCM(2mL)中,并在冰浴中冷却。加入3-氯过氧苯甲酸(70-75%)(10mg,0.04mmol)于DCM(0.1mL)中的溶液。将反应混合物搅拌30分钟,通过加入10%Na2SO3溶液(0.5mL)将其淬灭。通过HPLC纯化并对含有产物的馏分进行冷冻干燥,得到标题化合物,其为无色固体。收率:17mg(80%)。
1H-NMR(300MHz,DMSO-d6):δ8.17(d,1H),7.78-7.58(m,7H),7.48-7.35(m,3H),7.25(dd,1H),7.16(d,1H),5.40(d,J=4.51Hz,1H),3.77(m,1H),2.72(s,3H),2.42(m,1H),1.25(d,3H),0.90-0.80(m,4H)。
APCI-MS m/z:528.1[MH+]。
实施例32
N-[(1R,2S)-1-(1-环戊基吲唑-5-基)氧基-1-苯基-丙-2-基]环丙基磺酰胺
如实施例2b中描述的那样,从(1R,2S)-1-[(1-环戊基-1H-吲唑-5-基)氧基]-1-苯基-丙-2-胺(32b,17mg,51μmol)和环丙基磺酰氯(34mg,153μmol)制备标题化合物。收率:10mg(45%)。
1H NMR(400MHz,d6-丙酮)δ7.73(s,1H),7.49(m,3H),7.37(t,J=7.5Hz,2H),7.28(m,1H),7.16(dd,J=9.0,2.3Hz,1H),7.02(d,J=2.3Hz,1H),6.30(d,J=9.0Hz,1H),5.47(d,J=3.9Hz,1H),5.06(五重峰,J=7.1Hz,1H),3.90(m,1H),2.42(m 1H),1.88(m,2H),1.70(m,2H),1.33(d,J=6.7Hz,3H),1.01-0.83(m,4H)。
APCI-MS:m/z 440[MH+]。
(1R,2S)-1-[(1-环戊基-1H-吲唑-5-基)氧基]-1-苯基-丙-2-胺(32b)
如就30b描述的那样,从1-环戊基-5-碘-1H-吲唑(32c,158mg,500μmol)进行制备。收率:34mg(20%)。
APCI-MS:m/z 336[MH+]。
1-环戊基-5-碘-1H-吲唑(32c)
将2-氟-5-碘苯甲醛(500mg,2mmol)、环戊基肼(273mg,2mmol)和碳酸铯(1.91g,5mmol)于NMP(N-甲基-2-吡咯烷酮)(5ml)中的混合物在100℃搅拌过夜。然后加入KOtBu(560mg,5mmol)和DMF(10ml),并将混合物在150℃搅拌5h。冷却到室温后,用乙酸乙酯(100ml)对混合物进行稀释,并用水(3×50ml)洗涤,然后干燥。蒸发溶剂,得到批次残余物(balch residue),将所述残余物溶解在乙腈(50ml)中,过滤除去不溶物。进行硅胶快速色谱(正庚烷/乙酸乙酯),得到黄色油状物,158mg(25%)。
1H NMR(400MHz,CDCl3)δ8.08(d,J=0.9Hz,1H),7.91(s,1H),7.59(dd,J=8.8,1.5Hz,1H),7.26(d,J=9.4Hz,1H,被溶剂信号部分覆盖),4.95(五重峰,J=7.4Hz,1H),2.17(m,4H),1.98(m,2H),1.75(m,2H)。
APCI-MS:m/z 313[MH+]。
实施例33
N-[(1R,2S)-1-苯基-1-(1-(丙-2-基)吲唑-5-基)氧基-丙-2-基]环丙基磺酰胺
如实施例2b中所述,从(1R,2S)-1-[(1-异丙基-1H-吲唑-5-基)氧基]-1-苯基-丙-2-胺(30b,31mg,100μmol)和环丙基磺酰氯(42mg,300μmol)制备标题化合物。收率:33mg(80%)。
1H NMR(400MHz,d6-丙酮)δ7.74(s,1H),7.49(m,3H),7.38(t,J=7.5Hz,2H),7.28(m,1H),7.16(dd,J=9.2,2.3Hz,1H),7.03(d,J=2.3Hz,1H),6.30(d,J=8.8Hz,1H),5.47(d,J=4.1Hz,1H),4.88(七重峰,J=6.7Hz,1H),3.90(m,1H),2.42(m,1H),1.48(dd,J=6.6,3.8Hz,6H),1.33(d,J=6.9Hz,3H),1.01-0.83(m,4H)。
APCI-MS:m/z 414[MH+]。
实施例34
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-(4-(甲基磺酰基)苯基)丙-2-基]环丙基磺酰胺
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-(4-(甲基硫基)苯基)丙-2-基]环丙基磺酰胺(29,19mg,0.037mmol)溶解在乙酸(1.5mL)中,加入35%H2O2(1mL),将混合物在+60℃搅拌45分钟。冷却到室温后,用水稀释反应混合物,并通过HPLC纯化。收集含有所期望产物的馏分并冷冻干燥。得到标题化合物,其为无色固体。收率:16mg(57%)。
1H-NMR(300MHz,DMSO-d6):δ8.17(d,1H),7.94(d,2H),7.78-7.65(m,5H),7.49-7.35(m,3H),7.26(dd,1H),7.16(d,1H),5.45(d,J=4.51Hz,1H),3.80(m,1H),3.20(s,3H),2.45(m,1H),1.25(d,3H),0.90-0.80(m,4H)。
APCI-MS m/z:544.1[MH+]。
实施例35
N-[(1RS,2SR)-1-[6-氯-1-(4-氟苯基)吲唑-5-基]氧基-1-(4-氟苯基)丙-2-基]环丙基磺酰胺
a=相对混合物
按照就实施例1描述的方法,从(1RS,2SR)-1-[6-氯-1-(4-氟苯基)吲唑-5-基]氧基-1-(4-氟苯基)丙-2-胺(35a-外消旋体-2,55mg,0.13mmol)和环丙基磺酰氯(42μl,0.4mmol)开始进行制备。收率:2mg(3%)。
1H NMR(400MHz,CD3OD)δ8.02(d,J=0.7Hz,1H),7.78(s,1H),7.67(td,J=8.7,3.8Hz,2H),7.48(dd,J=8.7,5.3Hz,2H),7.31(ddd,J=12.4,8.5,3.7Hz,2H),7.19(s,1H),7.11(t,J=8.8Hz,2H),5.48(d,J=4.6Hz,1H),3.90(dt,J=11.5,6.8Hz,1H),2.39(tt,J=8.0,4.8Hz,1H),1.41(d,J=6.9Hz,3H),1.03-0.99(m,2H),0.92-0.87(m,2H)。
APCI-MS:518 m/z[MH+]。
1-[6-氯-1-(4-氟苯基)吲唑-5-基]氧基-1-(4-氟苯基)丙-2-胺(35a)
a=相对混合物
将1-{[6-氯-1-(4-氟苯基)-1H-吲唑-5-基]氧基}-1-(4-氟苯基)丙酮(500mg,1.21mmol)、乙酸铵(35b,934mg,12.11)和在聚合物载体上的氰基硼氢化物(cyanoborohydride)(1.82g,3.63mmol)在甲醇(3ml)中混合,并在微波中在140℃加热10分钟。将混合物浓缩并用NaHCO3和DCM处理。浓缩有机相,通过快速色谱(用EtOAc/庚烷洗脱然后用EtOAc/甲醇洗脱)对粗产物进行纯化。非对映异构体在制备性HPLC(Kromasil柱,水(用2g NH4OAc缓冲并用HOAc将pH调节为5.5)和MeCN,25%-75%)上进行分离,得到顺式异构体(1RS,2RS)-1-[6-氯-1-(4-氟苯基)吲唑-5-基]氧基-1-(4-氟苯基)丙-2-胺(35a-外消旋体-1),其为第一个洗脱出来的异构体(通过1H-NMR指定(assignment))。
1H NMR(400MHz,CD3OD)δ8.05(d,J=0.9Hz,1H),7.75(s,1H),7.65(tt,J=4.6,2.3Hz,2H),7.53(dd,J=12.0,1.9Hz,2H),7.34-7.26(m,3H),7.13(t,J=8.8Hz,2H),5.28(d,J=8.3Hz,1H),3.69(dd,J=8.2,6.8Hz,1H),1.17(d,J=6.7Hz,3H)。
APCI-MS:414 m/z[MH+]。
反式异构体(1RS,2SR)-1-[6-氯-1-(4-氟苯基)吲唑-5-基]氧基-1-(4-氟苯基)丙-2-胺(35a-外消旋体-2)被第二个洗脱出来。
1H NMR(400MHz,CD3OD)δ8.02(s,1H),7.79(s,1H),7.69-7.64(m,2H),7.48-7.43(m,2H),7.31(dd,J=20.8,3.4Hz,2H),7.18-7.10(m,3H),5.41(d,J=4.6Hz,1H),3.46(dt,J=11.1,6.6Hz,1H),1.27(d,J=6.5Hz,3H)。
APCI-MS:414 m/z[MH+]。
1-{[6-氯-1-(4-氟苯基)-1H-吲唑-5-基]氧基}-1-(4-氟苯基)丙酮(35b)
将4-氟苯基丙酮(388μl,2.9mmol)于DCM(12ml)中的溶液冷却到0℃,缓慢加入溴(672mg,2.9mmol)。将混合物搅拌30分钟,然后真空浓缩。将粗中间体加到6-氯-1-(4-氟苯基)-1H-吲唑-5-醇(如在案号102561的实施例4中所描述的那样进行制备)(762mg,2.9mmol)和碳酸钾(804mg,5.8mmol)于THF(12ml)中的混合物中。将混合物搅拌4小时,过滤并浓缩。通过快速色谱(EtOAc/庚烷,产物在40%EtOAc时被洗脱)对粗产物进行纯化,得到标题化合物(1.06g,88%)。
APCI-MS:413 m/z[MH+]。
实施例36
N-[(1RS,2RS)-1-[6-氯-1-(4-氟苯基)吲唑-5-基]氧基-1-(4-氟苯基)丙-2-基]环丙基磺酰胺
a=相对混合物
按照就实施例1描述的方法,从(1RS,2SR)-1-[6-氯-1-(4-氟苯基)吲唑-5-基]氧基-1-(4-氟苯基)丙-2-胺(35a-外消旋体-1,35mg,0.08mmol)和环丙基磺酰氯(27μl,0.25mmol)开始进行制备。收率:2mg(5%)。
1H NMR(400MHz,CD3OD)δ8.04(d,J=0.7Hz,1H),7.77(s,1H),7.67(td,J=8.7,4.1Hz,2H),7.53(dd,J=8.8,5.4Hz,2H),7.31(ddd,J=15.6,5.3,3.3Hz,2H),7.26(s,1H),7.10(t,J=8.8Hz,2H),5.49(d,J=5.1Hz,1H),4.04(dt,J=12.0,6.8Hz,1H),2.52(tt,J=8.0,4.9Hz,1H),1.29(d,J=6.9Hz,3H),1.05-0.90(m,4H)。
APCI-MS:518 m/z[MH+]。
实施例37
(R)-N-[2-[1-(4-氟苯基)吲唑-5-基]硫基-2-苯基-乙基]环丙基磺酰胺
在Thales SFC,Chiralpak IA柱(74%CO2,26%MeOH)上对N-(1-(1-(4-氟苯基)-1H-吲唑-5-基硫基)-2-甲基-1-苯基-丙-2-基)环丙基磺酰胺的外消旋混合物(37-外消旋体,10mg)进行分离,收集第一个洗脱峰。收率:4mg(40%)。
APCI-MS:m/z 376.2[MH+]。
N-(2-(1-(4-氟苯基)-1H-吲唑-5-基硫基)-2-苯基乙基)环丙基磺酰胺(37a)
在室温将环丙基磺酰氯(7μl,0.068mmol)加到2-苯基-2-(4-对甲苯基-1H-吲唑-5-基氧基)-乙胺(37b,0.01g,0.027mmol)和三乙胺(15μl,0.11mmol)于MeCN(1ml)中的溶液中。将反应混合物搅拌2小时,浓缩,用10%NaHSO4(水溶液)稀释,用EtOAc萃取。将有机相用10%NaHSO4(水溶液)洗涤。通过HPLC对粗产物进一步纯化。收率:12mg(95%)。
1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),7.92(s,1H),7.78(dd,J=8.9,4.8Hz,1H),7.73(d,J=9.2Hz,2H),7.43(s,3H),7.31(d,J=4.2Hz,6H),4.43(t,J=22.1Hz,1H),3.49(s,2H),2.41(m,1H),0.78(s,4H)。
APCI-MS:m/z 468[MH+]。
2-(1-(4-氟苯基)-1H-吲唑-5-基硫基)-2-苯基-乙胺(37b)
将1-(4-氟苯基)-1H-吲唑-5-硫醇(37c,0.068g,0.28mmol)、(E)-(2-硝基乙烯基)苯(0.055g,0.37mmol)和DMAP(4-二甲氨基吡啶)(催化量)于THF(5ml)中的溶液在70℃搅拌2小时。蒸发溶剂,并将混合物在水和EtOAc之间分配。干燥有机相,减压蒸发。向该混合物中加入EtOH(5ml)、水(3ml)、浓HCl(1ml)和Zn(0.26g),将混合物在70℃搅拌2小时。冷却到室温后,加入水(15ml),蒸发EtOH。用NaOH(5N,水溶液)将混合物的pH调节到10,用EtOAc(3×25ml)萃取。合并有机相,干燥,减压蒸发溶剂。通过HPLC进行纯化。收率:0.010g(10%)。
APCI-MS:m/z 364[MH+]。
1-(4-氟苯基)-1H-吲唑-5-硫醇(37c)
向苯甲硫羟酸1-(4-氟苯基)-1H-吲唑-5-基酯(S-1-(4-Fluorophenyl)-1H-indazol-5-yl benzothioate)(37d,0.046g,0.13mmol)于甲醇(3mL)中的溶液中加入碳酸钾(0.011mL,0.20mmol),将混合物在室温搅拌2小时,然后加入水和1N HCl(2ml),并用EtOAc(2×20ml)萃取,干燥,蒸发,然后在HPLC上纯化。收集相关馏分,冷冻干燥,并通过LC/MS进行分析。
APCI-MS:m/z 245[MH+]。
苯甲硫羟酸1-(4-氟苯基)-1H-吲唑-5-基酯(37d)
向1-(4-氟苯基)-5-碘-1H-吲唑(0.224g,0.66mmol)、苯甲硫羟酸(0.093ml,0.79mmol)、3,4,7,8-四甲基-1,10-菲咯啉(3,4,7,8-tetramethyl-1,10-phenantroline)(0.031g,0.13mmol)和N,N-二异丙基胺(0.220ml,1.32mmol)于甲苯(2.5ml)中的溶液中加入碘化亚铜(I)(2.245μl,0.07mmol)。将所得混合物在110℃搅拌。将反应混合物冷却到室温,用EtOAc稀释,并用水洗涤。干燥有机相,蒸发溶剂,然后在HPLC上纯化。收集相关馏分,冷冻干燥,得到45mg(20%)产物,通过LC/MS对所述产物进行分析。
APCI-MS:m/z 349[MH+]。
实施例38
N-((1R,2S)-1-(1-(4-氟苯基)-1H-吲唑-5-基硫基)-1-苯基-丙-2-基)甲磺酰胺
在冰浴上在搅拌情况下向(2R,3R)-2-甲基-1-(甲基磺酰基)-3-苯基氮丙啶(38a,0.03g,0.14mmol)于THF(4ml)中的溶液中加入1-(4-氟苯基)-1H-吲唑-5-硫醇(37c,0.038g,0.16mmol)和氢化钠(5.11mg,0.21mmol)。移去冰浴,将混合物在室温搅拌过夜。除去溶剂,将混合物在HPLC上纯化。收率:0.007g(11%)。
1H NMR(500MHz,DMSO-d6)δ8.27(d,J=0.7Hz,1H),7.79(d,J=1.0Hz,1H),7.74(m,2H),7.66(d,J=8.9Hz,2H),7.40(m,5H),7.29(t,J=7.6Hz,2H),7.19(m,2H),4.42(d,J=6.3Hz,1H),4.14(t,J=5.2Hz,1H),2.62(s,3H),1.35(s,3H)。
APCI-MS:m/z 456[MH+]。
(2R,3R)-2-甲基-1-(甲基磺酰基)-3-苯基氮丙啶(38a)
向(2R,3R)-2-甲基-3-苯基氮丙啶(38b,0.08g,0.60mmol)于CH2Cl2(3ml)中的溶液中加入N,N-二异丙基甲胺(0.219ml,1.32mmol),将反应混合物冷却到-10℃,然后加入甲磺酰氯(0.051ml,0.66mmol)。将混合物在-10℃搅拌30分钟,然后在室温搅拌1小时。将粗样品加载到Chromasil C18柱上,用MeCN/H2O 35-70%(历时20分钟)洗脱。收率:0.055g(43%)。
1H NMR(300MHz,DMSO-d6)δ7.36(m,5H),3.72(d,J=4.4Hz,1H),3.13(s,3H),3.03(m,1H),1.64(d,J=6.0Hz,3H)。
APCI-MS:m/z 253.1[MH+]。
(2R,3R)-2-甲基-3-苯基氮丙啶(38b)
向(1R,2S)-(-)-降麻黄碱(1g,6.61mmol)于THF(20mL)中的溶液中加入三苯基膦(1.98ml,7.94mmol)、偶氮二羧酸二异丙酯(1.401ml,7.27mmol)和三乙胺(2.6ml,18.8mmol),并将反应混合物在室温搅拌过夜。蒸发溶剂,在硅胶上对粗物质进行纯化(用庚烷/EtOAc 1∶4至100%EtOAc以及EtOAc/MeOH95%∶5%洗脱),收集含有产物的馏分,得到2.5g固体,根据LC/MS确定其含有很多P(Ph)3O。将该固体在己烷(50ml)中搅拌,然后过滤通过Celite 545垫,得到0.6g油状物。
1H NMR(400MHz,CDCl3)δ7.32(m,5H),2.75(d,J=2.7Hz,1H),2.22(m,1H),1.45(d,J=5.5Hz,3H)。
APCI-MS m/z 134.1[MH+]。
实施例39
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]磺酰基-1-苯基-丙-2-基]甲磺酰胺
将N-((1R,2S)-1-(1-(4-氟苯基)-1H-吲唑-5-基硫基)-1-苯基-丙-2-基)甲磺酰胺(实施例38,3.00mg,6.59μmol)溶解在H2O2(0.5ml,16.32mmol)和乙酸(0.5ml)中,并在50℃搅拌120分钟。除去溶剂后,将混合物在HPLC上纯化。收率:0.0015g(46%)。
1H NMR(500MHz,DMSO-d6)δ8.51(s,1H),8.19(d,J=1.1Hz,1H),7.75(q,J=4.6Hz,3H),7.56(m 1H),7.46(d,J=8.8Hz,2H),7.26(m,2H),7.20(m,3H),7.08(m,1H),4.58(m,1H),4.40(m,1H),2.61(s,3H),1.46(d,J=6.6Hz,3H)。
APCI-MS:m/z 505[MH++18]。
实施例40
N-[(2R)-2-[1-(4-氟苯基)吲唑-5-基]氧基-2-苯基-乙基]环丙基磺酰胺
按照就实施例1描述的方法,从(1R)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-乙-2-胺(40a,31mg,0.09mmol)和环丙基磺酰氯(28μl,0.27mmol)进行制备。收率:10mg(25%)。
1H NMR(400MHz,CD3OD)δ8.01(s,1H),7.68-7.63(m,2H),7.58(d,J=9.2Hz,1H),7.47(d,J=7.3Hz,2H),7.37(t,J=7.4Hz,2H),7.32-7.24(m,4H),7.14(d,J=2.3Hz,1H),5.41(dd,J=8.1,4.1Hz,1H),3.61-3.47(m,2H),2.51(tt,J=8.0,4.8Hz,1H),1.06-0.90(m,4H)。
APCI-MS:452 m/z[MH+]。
(1R)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-乙-2-胺(40a)
按照用于1a的方案,从(1R)-1-苯基-1-羟基-乙-2-胺(294mg,2.15mmol)和1-(4-氟苯基)-5-碘吲唑(484mg,1.43mmol)进行制备。收率:125mg(17%)。
APCI-MS:348 m/z[MH+]。
实施例41
N-[(2S)-2-[1-(4-氟苯基)吲唑-5-基]氧基-2-苯基-乙基]环丙基磺酰胺
按照就实施例1描述的方法,从(1S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-乙-2-胺(41a,31mg,0.09mmol)和环丙基磺酰氯(28μl,0.27mmol)进行制备。收率:22mg(54%)。
(1S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-乙-2-胺(41a)
按照用于1a的方案,从(1S)-1-苯基-1-羟基-乙-2-胺(294mg,2.15mmol)和1-(4-氟苯基)-5-碘吲唑(484mg,1.43mmol)进行制备。收率:175mg(23%)。
APCI-MS:348 m/z[MH+]。
实施例42
N-((1R,2S)-1-(1-(4-氟苯基)-1H-吲唑-5-基氧基)-1-(喹啉-3-基)丙-2-基)环丙基磺酰胺
(1R,2S)-1-(1-(4-氟苯基)-1H-吲唑-5-基氧基)-1-(喹啉-3-基)丙-2-胺二(2,2,2-三氟乙酸盐)(42a,65mg,0.10mmol)溶解在THF(1.5mL),加入三乙胺(75μl,0.54mmol),然后加入环丙基磺酰氯(15μl,0.15mmol)。将反应混合物在室温搅拌,1.5小时后,加入另一份三乙胺(75μl,0.54mmol)和过量的环丙基磺酰氯(50μl,0.49mmol)。将反应混合物在室温放置过夜。蒸发除去溶剂,通过HPLC对残余物进行纯化。收率:18mg(34%)。
1H-NMR(300MHz,DMSO-d6):δ8.99(d,1H),8.37(d,1H),8.14(d,1H),8.00(m,2H),7.80-7.66(m,4H),7.60(m,1H),7.48-7.22(m,5H),5.53(d,J=5.3Hz,1H),3.94(m,1H),2.45(m,1H),1.35(d,3H),0.89-0.74(m,4H)。
APCI-MS m/z:517[MH+]。
(1R,2S)-1-(1-(4-氟苯基)-1H-吲唑-5-基氧基)-1-(喹啉-3-基)丙-2-胺二(2,2,2-三氟乙酸盐)(42a)
按照实施例1中描述的方法,从(1R,2S)-2-氨基-1-(喹啉-3-基)丙-1-醇二盐酸盐(42b,250mg,0.80mmol)、1-(4-氟苯基)-5-碘-1H-吲唑(340mg,1.01mmol)、Cs2CO3(1070mg,3.28mmol)和CuI(36mg,0.19mmol)于丁腈(4mL)中的溶液开始,将反应容器密封并用氩气冲洗,将所得浆液在+125℃搅拌5小时,然后将温度降低至100℃,并将混合物搅拌过夜16小时。进行后处理并通过HPLC纯化,得到小标题化合物,其为吸湿性黄色粉末。收率:200mg(39%)。
1H-NMR(300MHz,DMSO-d6):δ9.01(d,1H),8.41(d,1H),8.26(brs,3H),8.17(d,1H),8.02(t,2H),7.84-7.68(m,4H),7.64(m,1H),7.44-7.34(m,3H),7.28(d,1H),5.89(d,J=3.32Hz,1H),3.95(m,1H),1.26(d,3H)。
APCI-MS m/z:413.1[MH+-2TFA]。
(1R,2S)-2-氨基-1-(喹啉-3-基)丙-1-醇二盐酸(42b)
按照就制备29b而描述的方法,从(S)-1-氧代-1-(喹啉-3-基)丙-2-基氨基甲酸叔丁酯(42c,1.6g,5.33mmol)、异丙醇铝(0.68g,3.33mmol)和2-丙醇(4.5mL,59.16mmol)于甲苯(7mL)中的溶液开始,在密封的用氩气冲洗的反应管(reaction tube)中在+50℃搅拌16小时。进行后处理并对中间体即经BOC保护的胺进行脱保护,得到小标题化合物,其为无色固体。收率:1.29g(88%)。
1H-NMR(400MHz,DMSO-d6):δ9.23(d,1H),8.97(s,1H),8.42-8.24(m,5H),8.06(t,1H),7.89(t,1H),6.68(vbrs,1H),5.28(d,J=3.72Hz,1H),3.68(m,1H),1.10(d,3H)。
APCI-MS m/z:203[MH+-2HCl]。
(S)-1-氧代-1-(喹啉-3-基)丙-2-基氨基甲酸叔丁酯(42c)
将(S)-1-(甲氧基(甲基)氨基)-1-氧代丙-2-基氨基甲酸叔丁酯(2.5g,10.76mmol)悬浮在THF(5mL)中,并在-10℃搅拌,加入异丙基氯化镁的THF溶液(2.0M,5.4ml,10.80mmol),形成溶液。向该溶液中加入三(喹啉-3-基)镁化锂(lithium tri(3-quinolinyl)magnesiate)于THF/己烷中的溶液(1.471ml,10.81mmol),所述三(喹啉-3-基)镁化锂根据Sylvain Dumouchel等人在Tetrahedron 59(2003)8629-8640中描述的方法从3-溴喹啉制备。将混合物在-10℃搅拌30分钟,然后使其达到室温并搅拌过夜15小时。将反应混合物即透明红色溶液缓慢倒入冰冷却的1M HCl(水溶液)(100mL)中。加入EtOAc(150mL),将混合物搅拌几分钟,水相用EtOAc萃取一次,合并的EtOAc溶液用饱和NaHCO3(水溶液)和盐水进一步洗涤。通过硅胶快速色谱(使用0%-40%EtOAc/庚烷的梯度)对粗物质进行纯化。所得到的物质通过HPLC进一步纯化,得到小标题化合物,其为黄色粘性油状物。收率:1.6g(49%)。
1H-NMR(400MHz,CDCl3):δ9.44(d,1H),8.81(s,1H),8.20(d,1H),7.98(d,1H),7.89(t,1H),7.67(t,1H),5.53(brd,1H),5.42(m,1H),1.48(d,3H),1,47(s,9H)。
APCI-MS m/z:301.1[MH+]。
实施例43
N-((1R,2S)-1-(2,3-二氢苯并[b][1,4]二氧杂环己二烯-6-基)-1-(1-(4-氟苯基)-1H-吲唑-5-基氧基)丙-2-基)环丙基磺酰胺
将(1R,2S)-1-(2,3-二氢苯并[b][1,4]二氧杂环己二烯-6-基)-1-(1-(4-氟苯基)-1H-吲唑-5-基氧基)丙-2-胺(43a,102mg,0.24mmol)和DIPEA(二异丙基乙胺)(170μL,0.97mmol)溶解在NMP(2mL)中。加入环丙基磺酰氯(40μL,0.39mmol),将反应混合物在室温搅拌1小时。将反应混合物用水(10mL)稀释并用EtOAc(2×10mL)萃取,有机相用盐水洗涤,干燥(Na2SO4),过滤并蒸发,得到油状残余物(NMP残余物)。通过HPLC对粗物质进一步纯化。收率:80mg(62%)。
1H-NMR(300MHz,DMSO-d6):δ8.18(d,1H),7.79-7.67(m,3H),7.46-7.32(m,3H),7.21(dd,1H),7.12(d,1H),6.89-6.81(m,3H),5.21(d,1H),4.20(s,4H),3.67(m,1H),2.39(m,1H),1.22(d,3H),0.90-0.81(m,4H)。
APCI-MS m/z:524.1[MH+]。
(1R,2S)-1-(2,3-二氢苯并[b][1,4]二氧杂环己二烯-6-基)-1-(1-(4-氟苯基)-1H-吲唑-5-基氧基)丙-2-胺三氟乙酸盐(43a)
按照实施例1中描述的方法来制备小标题化合物。从(1R,2S)-2-氨基-1-(2,3-二氢苯并[b][1,4]二氧杂环己二烯-6-基)丙-1-醇盐酸盐(43b,1.46g,5.94mmol)、1-(4-氟苯基)-5-碘-1H-吲唑(2.4g,7.10mmol)、碳酸铯(5.8g,17.80mmol)和CuI(0.23g,1.21mmol)于丁腈(18mL)中的溶液开始进行制备。将反应管盖好并用氩气冲洗,将反应混合物在+100℃搅拌16小时。最后的纯化是通过HPLC进行的。收率:1.16g(36%)。
1H-NMR(300MHz,DMSO-d6):δ8.22(d,1H),8.13(brs,3H),7.79-7.69(m,3H),7.41(m,2H),7.27(dd,1H),7.15(d,1H),6.94-6.82(m,3H),5.51(d,J=3.32Hz,1H),4.21(s,4H),3.68(m,1H),1.17(d,3H)。
APCI-MS m/z:420.1[MH+-TFA]。
(1R,2S)-2-氨基-1-(2,3-二氢苯并[b][1,4]二氧杂环己二烯-6-基)丙-1-醇盐酸盐(43b)
按照就制备29b而描述的方法,从(S)-1-(2,3-二氢苯并[b][1,4]二氧杂环己二烯-6-基)-1-氧代丙-2-基氨基甲酸叔丁酯(43c,3.76g,12.23mmol)、2-丙醇(12mL,157.75mmol)和异丙醇铝(0.5g,2.45mmol)于甲苯(22mL)中的溶液开始,在氩气下在+50℃搅拌16小时。进行后处理并通过快速色谱(EtOAc∶己烷=1∶2作为洗脱剂)纯化,得到3.19g(84%)中间体即经BOC保护的小标题化合物。APCI-MS m/z:236,210,192。化合物在LC/MS系统中是不稳定的。
对BOC基团进行脱保护,得到小标题化合物,其为吸湿性盐。
收率:2.10g(70%)。
1H-NMR(300MHz,DMSO-d6):δ8.01(brs,3H),6.87-6.75(m,3H),5.93(brd,1H),4.79(brt,1H),4.22(s,4H),3.32(m,1H),0.95(d,3H)。
APCI-MS m/z:210[MH+-HCl]。
(S)-1-(2,3-二氢苯并[b][1,4]二氧杂环己二烯-6-基)-1-氧代丙-2-基氨基甲酸叔丁酯(43c)
将异丙基氯化镁的THF溶液(2M,6.5mL,13.00mmol)加到(S)-1-(甲氧基(甲基)氨基)-1-氧代丙-2-基氨基甲酸叔丁酯(3g,12.92mmol)于THF(30mL)中的悬浮液中,保持温度低于-10℃。加入(2,3-二氢苯并[b][1,4]二氧杂环己二烯-6-基)溴化镁的THF溶液(0.7M,20mL,14.00mmol)。将反应混合物在室温搅拌17小时。将1N HCl(300mL)在冰浴上冷却到+10℃,将上述反应混合物倒入上述酸性水溶液中,用TBME(叔丁基甲基醚)萃取。醚相用水、盐水洗涤,干燥(Na2SO4)。过滤并蒸发溶剂,得到粗产物,其为浅黄色油状物,通过快速色谱(使用TBME∶庚烷=1∶2作为洗脱剂)对所述油状物进行纯化。
收率:3.76g(95%),其为浅黄色粘性油状物/胶状物。
1H-NMR(300MHz,DMSO-d6):δ7.50(dd,1H),7.46(d,1H),7.23(d,1H),6.97(d,1H),4.97(m,1H),4.30(m,4H),1.36(s,9H),1.19(d,3H)。
APCI-MS m/z:208[MH+-BOC]。
实施例44
N-{1-[6-甲氧基吡啶-3-基]-1-[(1-(吡啶-2-基)-1H-吲唑-5-基)氧基]丙-2-基}环丙基磺酰胺
向搅拌的1-[6-甲氧基吡啶-3-基]-1-[1-(吡啶-2-基)吲唑-5-基]氧基丙-2-胺(50mg,130μmol)于二氯甲烷(5mL)中的溶液中加入三乙胺(44μl),然后加入环丙基磺酰氯(28mg,200μmol)和DMAP(1.6mg,13μmol)。在室温继续搅拌20分钟。将反应混合物倒入饱和NH4Cl溶液中,用二氯甲烷萃取,然后真空除去溶剂,通过硅胶色谱对产物进行纯化。收率:24mg,其为两种非对映异构体的外消旋混合物(37%)。
ESI+MS:m/z 480[MH+]。
1H-NMR(CDCl3);δ=8.74(d,1H),8.49(d,1H),8.24(d,0.5H),8.20(d,0.5H),8.01(s,1H),8.00(d,1H),7.80(ddd,1H),7.66(dd,0.5H),7.59(dd,0.5H),7.21(dd,0.5H),7.18(dd,0.5H),7.13(m,1H),7.0(d,0.5H),6.98(d,0.5H),6.75(d,1H),5.42(d,0.5H),5.22(d,0.5H),4.66(d,0.5H),4.58(d,0.5H),3.94(m,1H),3.92(s,3H),2.43(dddd,0.5H),2.18(dddd,0.5H),1.45(d,1.5H),1.33(d,1.5H),1.20-0.78(m,4H)。
1-[6-甲氧基吡啶-3-基]-1-[1-(吡啶-2-基)吲唑-5-基]氧基丙-2-胺
基本通过Job & Buchwald:Org.Lett.2002,4(21),3703-3706中描述的方法来制备标题化合物。
将5-碘-1-(吡啶-2-基)吲唑(2.82g,8.8毫摩尔)、2-氨基-1-[6-甲氧基吡啶-3-基]丙-1-醇(1.6g,8.8mmol,非对映异构体的混合物)、碘化亚铜(I)(167mg,0.88mmol)和碳酸铯(5.72g,17.6毫摩尔)悬浮在丁腈(6mL)和甲苯(12mL)中。将反应容器盖好,并将混合物在130℃搅拌3天。用二氯甲烷稀释反应混合物,并过滤通过一段硅藻土。然后真空除去溶剂,以及通过硅胶色谱对产物进行纯化。收率:1.2g(36%),其为两种非对映异构体的外消旋混合物。
ESI+MS:m/z 376[MH+]。
1H-NMR(CDCl3);δ=8.70(d,0.5H),8.68(d,0.5H),8.47(d,1H),8.20(d,0.5H),8.17(d,0.5H),7.99(s,1H),7.98(d,1H),7.79(ddd,1H),7.62(dd,0.5H),7.59(dd,0.5H),7.20(dd,1H),7.12(m,1H),7.03(d,0.5H),6.98(d,0.5H),6.75(d,1H),5.08(br.,0.5H),4.91(br.,0.5H),3.91(s,3H),3.50(br.,3H),1.24(br.,1.5H),1.11(br.,1.5H)。
2-氨基-1-[6-甲氧基吡啶-3-基]丙-1-醇
将1-(6-甲氧基吡啶-3-基)-2-硝基-丙-1-醇(2.20g,10.37mmol)溶解在甲醇(410mL)中,使用配备有10%Pd/C盒(cartridge)的H-CubeTM氢化反应器(THALES纳米技术(nanotechnology))进行氢化。将流速设为0.8mL/min,温度为80℃,并以完全模式(full mode)充分产生氢气。蒸发溶液后,在制备性HPLC(XTerrra C18,19×50mm)上使用5-30%乙腈/水(+1%NH3)的梯度来分离非对映异构体,得到纯的小标题化合物(448mg,24%)。
1H-NMR(400MHz,DMSO-d6):δ=8.05(1H,d);7.63(1H,dd);6.76(1H,d);4.29(1H,d);3.82(3H,s);2.90(1H,五重峰);0.87(3H,d)。
APCI-MS:m/z 183.0[MH+]。
1-(6-甲氧基吡啶-3-基)-2-硝基-丙-1-醇
向圆底烧瓶中加入无水硫酸镁(4.77g,40mmol)和硝基乙烷(15ml)。将烧瓶抽真空并充入氩气。将反应混合物剧烈搅拌,使之成为均匀悬浮液,然后加入6-甲氧基-吡啶-3-甲醛(2.37g,18mmol于5mL硝基乙烷中)。搅拌5分钟后,加入2,8,9-三(1-甲基乙基)-2,5,8,9-四氮杂-1-磷杂二环[3.3.3]十一烷(1082mg,3.6mmol)。将反应混合物在室温搅拌过夜,然后通过快速色谱(硅胶,庚烷-乙酸乙酯)对其进行纯化。收率:2.22g,58%。
APCI-MS:m/z 213.1[MH+]。
5-碘-1-(吡啶-2-基)吲唑
将碳酸铯(29.86g,91.6mmol)加到2-氟-5-碘苯甲醛(11.45g,45.8mmol)和吡啶-2-基肼(5g,45.8mmol)于230mL N-甲基吡咯烷酮中的悬浮液中。将反应混合物在室温搅拌2小时。检查(通过1H-NMR)已经形成腙后,将反应混合物在150℃加热3小时。使反应混合物冷却下来,并将深棕色悬浮液倒入冰水中。在室温剧烈搅拌15分钟后,用乙酸乙酯萃取混合物。用盐水洗涤有机相,经Na2SO4干燥,真空除去溶剂,并通过硅胶色谱对产物进行纯化。收率:4.8g(33%)。
ES+MS:322(MH+)。
1H-NMR(CDCl3);δ=7.18(ddd,1H),7.75(dd,1H),7.84(ddd,1H),8.05(d,1H),8.11(s,1H),8.14(d,1H),8.53(m,1H),8.66(1H)。
实施例45
N-{1-[6-甲氧基吡啶-3-基]-1-[(1-(吡啶-3-基)-1H-吲唑-5-基)氧基]丙-2-基}环丙基磺酰胺
向搅拌的1-[6-甲氧基吡啶-3-基]-1-[1-(吡啶-3-基)吲唑-5-基]氧基丙-2-胺(45mg,120μmol)于二氯甲烷(4.5mL)中的溶液中加入三乙胺(40μl),然后加入环丙基磺酰氯(25mg,180μmol)和DMAP(1.5mg,12μmol)。在室温继续搅拌20小时。将反应混合物倒入饱和NH4Cl溶液中,用二氯甲烷萃取,然后真空除去溶剂,并通过硅胶色谱对产物进行纯化。收率:4mg(7%),其为两种非对映异构体的外消旋混合物。
ES+MS:m/z 480[MH+]。
1H-NMR(CDCl3);δ=9.03(br.,1H),8.60(br.,1H),8.24(d,0.5H),8.20(d,0.5H),8.07(s,0.5H),8.06(s,0.5H),8.03(d,1H),7.66(dd,0.5H),7.64(d,1H),7.59(dd,0.5H),7.48(ddd,1H),7.19(dd,0.5H),7.16(dd,0.5H),7.05(d,0.5H),7.02(d,0.5H),6.76(d,1H),5.42(d,0.5H),5.22(d,0.5H),4.71(d,0.5H),4.60(d,0.5H),3.93(s,3H),3.92(m,1H),2.44(dddd,0.5H),2.19(dddd,0.5H),1.43(d,1.5H),1.33(d,1.5H),1.24-0.78(m,4H)。
1-[6-甲氧基吡啶-3-基]-1-[1-(吡啶-3-基)吲唑-5-基]氧基丙-2-胺
将5-碘-1-(吡啶-3-基)吲唑(750mg,2.3毫摩尔)、2-氨基-1-[6-甲氧基吡啶-3-基]丙-1-醇(410mg,2.2mmol)、碘化亚铜(I)(42mg,0.22mmol)和碳酸铯(1.45g,4.5毫摩尔)悬浮在丁腈(2.4mL)和甲苯(4.8mL)中。将反应容器盖好并将混合物在130℃搅拌20小时。然后真空除去溶剂,通过硅胶色谱对产物进行纯化。收率:254mg(30%),其为两种非对映异构体的外消旋混合物。
ESI+MS:m/z 376[MH+]。
1H-NMR(CDCl3);δ=9.01(br.,1H),8.57(d,1H),8.19(d,0.5H),8.17(d,0.5H),8.04(s,1H),8.01(m,1H),7.59(m,2H),7.46(ddd,1H),7.18(d,0.5H),7.14(d,0.5H),7.05(d,0.5H),7.02(d,0.5H),6.75(d,1H),5.16(d,0.5H),5.15(d,0.5H),3.93(s,3H),3.13(dq,0.5H),3.11(dq,0.5H),1.20(d.,1.5H),1.10(d,1.5H)。
5-碘-1-(吡啶-3-基)-1H-吲唑
将碳酸铯(26.84g,82.38mmol)加到2-氟-5-碘苯甲醛(6.87g,27.46mmol)和吡啶-3-基肼二盐酸盐(5g,27.46mmol)于136mL N-甲基吡咯烷酮中的悬浮液中。将反应混合物在室温搅拌过夜。检查(通过1H-NMR)已经形成腙后,将反应混合物在160℃加热4小时。使反应混合物冷却下来,将深棕色悬浮液倒在1000mL冰水上。在室温剧烈搅拌45分钟后,经由玻璃微纤维过滤器对沉淀的产物进行抽吸,用水洗涤,并用旋转蒸发仪在45℃进行干燥。得到8.28g(93.9%)标题化合物。
MS(CI+):m/z 322(M+)。
1H-NMR(400MHz,DMSO[d6]):δ=7.62(1H),7.72(2H),8.20(1H),8.32(1H),8.49(1H),8.61(1H),9.01(1H)。
实施例46
N-{1-[2-甲氧基吡啶-4-基]-1-[(1-(吡啶-2-基)-1H-吲唑-5-基)氧基]丙-2-基}环丙基磺酰胺
向搅拌的1-[2-甲氧基吡啶-4-基]-1-[1-(吡啶-2-基)吲唑-5-基]氧基丙-2-胺(41mg,110μmol)于二氯甲烷(4ml)中的溶液中加入三乙胺(36μl),然后加入环丙基磺酰氯(23mg,160μmol)和DMAP(1.3mg,11μmol)。在室温继续搅拌20小时。将反应混合物倒入饱和NH4Cl溶液中,并用二氯甲烷萃取,然后真空除去溶剂,通过硅胶色谱对产物进行纯化。收率:4mg(7.6%),其为一种非对映异构体的外消旋混合物。
ES+MS:m/z 480[MH+]。
1H-NMR(CDCl3);δ=9.04(d,1H),8.61(d,1H),8.18(d,1H),8.06(s,1H),7.66(d,1H),7.49(dd,1H),7.19(dd,1H),6.97(d,1H),6.90(dd,1H),6.76(s,1H),5.42(d,1H),4.74(d,1H),3.95(m,1H),3.92(s,3H),2.44(dddd,1H),1.29(d.,3H),1.21(m,1H),1.01(m,3H)。
1-[2-甲氧基吡啶-4-基]-1-[1-(吡啶-2-基)吲唑-5-基]氧基丙-2-胺
基本通过Job & Buchwald:Org.Lett.2002,4(21),3703-3706中描述的方法来制备标题化合物。
将5-碘-1-(吡啶-3-基)吲唑(750mg,2.3毫摩尔)、2-氨基-1-[6-甲氧基吡啶-3-基]丙-2-醇(410mg,2.2mmol)、碘化亚铜(I)(42mg,0.22mmol)和碳酸铯(1.45g,4.5毫摩尔)悬浮在丁腈(2.4mL)和甲苯(4.8mL)中。将反应容器盖好,并将混合物在130℃搅拌20小时。然后真空除去溶剂,并通过硅胶色谱对产物进行纯化。收率:243mg(30%),其为一种非对映异构体的外消旋混合物。
1H-NMR(CDCl3);δ=9.01(d,1H),8.58(dd,1H),8.12(d,1H),8.04(s,1H),8.02(m,1H),7.63(d,2H),7.46(dd,1H),7.18(dd,1H),6.96(d,1H),6.85(dd,1H),6.72(s,1H),4.14(d,1H),3.93(s,3H),3.12(dq,1H),1.27(d,3H)。
2-氨基-1-[2-甲氧基吡啶-4-基]丙-1-醇
将甲酸铵(1.13g,18mmol)和钯/炭(10%,175mg)加到1-(2-甲氧基吡啶-4-基)-2-硝基-丙-1-醇(760mg,3.6mmol)于17.5ml THF和17.5ml甲醇中的溶液中。将反应混合物在室温搅拌过夜,过滤通过一段硅藻土,然后浓缩。收率:620mg(95%),其为两种非对映异构体的外消旋混合物。
1H-NMR(CDCl3);δ=8.11(d,1H),6.85(d,0.5H),6.83(d,0.5H),6.74(s,0.5H),6.73(s,0.5H),4.53(d,0.5H),4.22(d,0.5H),3.93(s,3H),3.24(dq,0.5H),3.03(d,0.5H),1.63(br.2H),1.11(d,1.5H),0.90(d,1.5H)。
1-(2-甲氧基吡啶-4-基)-2-硝基丙-1-醇
向圆底烧瓶中加入无水硫酸镁(0.97g,8mmol)和硝基乙烷(1.34ml,18.7mmol)。将烧瓶抽真空并充入氩气。将反应混合物剧烈搅拌以得到均匀悬浮液,然后加入2-甲氧基-吡啶-4-甲醛(500mg,3.65mmol)。搅拌5分钟后,加入2,8,9-三(1-甲基乙基)-2,5,8,9-四氮杂-1-磷杂二环[3.3.3]十一烷(109mg,0.36mmol)。将反应混合物在室温搅拌过夜,然后通过快速色谱(硅胶,乙醚)对其进行纯化。收率:770mg(99%),其为两种非对映异构体的外消旋混合物。
1H-NMR(CDCl3);δ=8.17(d,0.5H),8.15(d,0.5H),6.87(d,0.5H),6.85(d,0.5H),6.80(s,0.5H),6.75(s,0.5H),5.42(d,0.5H),4.98(d,0.5H),4.73(dq,0.5H),4.67(d,0.5H),3.94(s,3H),1.47(d,1.5H),1.40(d,1.5H)。
实施例47
N-{1-[2-甲氧基吡啶-4-基]-1-[(1-(吡啶-2-基)-1H-吲唑-5-基)氧基]丁-2-基}环丙基磺酰胺
向搅拌的1-[2-甲氧基吡啶-4-基]-1-[(1-(吡啶-2-基)-1H-吲唑-5-基)氧基]丁-2-胺(122mg,310μmol)于二氯甲烷(11ml)中的溶液中加入三乙胺(100μl),然后加入环丙基磺酰氯(66mg,470μmol)和DMAP(3,8mg,31μmol)。在室温继续搅拌48小时。将反应混合物倒入饱和NH4Cl溶液中,并用二氯甲烷萃取,然后真空除去溶剂,并通过硅胶色谱对产物进行纯化。收率:10mg(6,5%),其为两种非对映异构体的外消旋混合物。
ESI+MS:m/z 494[MH+]。
1H-NMR(CDCl3);δ=8.76(d,1H),8.49(d,1H),8.21(d,0.5H),8.16(d,0.5H),8.02(s,1H),8.00(d,1H),7.81(ddd,1H),7.19(dd,1H),7.13(m,1H),6.94(m,2H),6.83(br,0.5H),6.77(br.0.5H),5.47(d,0.5H),5.29(d,0.5H),4.62(d,0.5H),4.56(d,0.5H),3.94(m,1H),3.91(s,3H),2.47(dddd,0.5H),2.28(dddd,0.5H),1.94(m,1H),1.64(m,1H),1.22(t,1.5H),1.09(t,1.5H),0.98(m,2.5H),0.78(m,0.5H)。
1-[2-甲氧基吡啶-4-基]-1-[1-(吡啶-2-基)吲唑-5-基]氧基丁-2-胺
基本通过Job & Buchwald:Org.Lett.2002,4(21),3703-3706中描述的方法来制备标题化合物。
将5-碘-1-(吡啶-2-基)吲唑(830mg,2.6mmol)、2-氨基-1-[2-甲氧基吡啶-4-基]丁-1-醇(510mg,2.6mmol)、碘化亚铜(I)(49mg,0.26mmol)和碳酸铯(1.68g,5.2mmol)悬浮在丁腈(1.7mL)和甲苯(3.5mL)中。将反应容器盖好,并将混合物在130℃搅拌60小时。然后真空除去溶剂,并通过硅胶色谱对产物进行纯化。收率:680mg(67%),其为两种非对映异构体的外消旋混合物。
1H-NMR(CDCl3);δ=8.71(d,1H),8.48(d,1H),8.15(d,0.5H),8.11(d,0.5H),8.00(s,1H),7.99(d,1H),7.80(dd,1H),7.22(dd,1H),7.13(dd,1H),6.94(m,2H),6.77(s,0.5H),6.72(s,0.5H),5.22(d,0.5H),5.05(d,0.5H),3.93(s,3H),3.12(m,0.5H),2.98(m,0.5H),2.36(br.,2H),1.60(m,2H),1.02(t,1.5H),0.98(t,1.5H)。
2-氨基-1-[2-甲氧基吡啶-4-基]丁-1-醇
将甲酸铵(2.5g,40mmol)和钯/炭(10%,390mg)加到1-(2-甲氧基吡啶-4-基)-2-硝基丁-1-醇(1.7g,7.5mmol)于38ml THF和38ml甲醇中的溶液中。将反应混合物在室温搅拌过夜,过滤通过一段硅藻土,然后浓缩。收率:620mg(42%),其为两种非对映异构体的外消旋混合物。
1H-NMR(CDCl3);δ=8.11(d,0.5H),8.10(d,0.5H),6.84(d,0.5H),6.83(d,0.5H),6.74(s,0.5H),6.72(s,0.5H),4.61(d,0.5H),4.31(d,0.5H),3.92(s,3H),2.95(ddd,0.5H),2.77(ddd,0.5H),2.33(br.2H),1.55(m,0.5H),1.38(m,0.5H),1.30(m,0.5H),1.12(m,0.5H),0.96(t,1.5H),0.90(t,1.5H)。
1-(2-甲氧基吡啶-4-基)-2-硝基丁-1-醇
向圆底烧瓶中加入无水硫酸镁(3.09g,25.7mmol)和硝基丙烷(5.35ml,60mmol)。将烧瓶抽真空并充入氩气。将反应混合物剧烈搅拌以得到均匀悬浮液,然后加入2-甲氧基-吡啶-4-甲醛(500mg,3.65mmol)于5ml中的溶液。搅拌5分钟后,加入2,8,9-三(1-甲基乙基)-2,5,8,9-四氮杂-1-磷杂二环[3.3.3]十一烷(350mg,1.2mmol)于5ml硝基丙烷中的溶液。将反应混合物在室温搅拌过夜,然后通过快速色谱(硅胶,乙醚)对其进行纯化。收率:1.7g(64%),其为两种非对映异构体的外消旋混合物。
1H-NMR(CDCl3);δ=8.17(d,0.5H),8.15(d,0.5H),6.87(d,1H),6.79(s,0.5H),6.74(s,0.5H),5.19(d,0.5H),4.98(d,0.5H),4.58(ddd,0.5H),4.55(ddd,0.5H),3.94(s,3H),2.16(m,0.5H),1.90(m,0.5H),1.78(m,0.5H),1.55(m,0.5H),0.93(t,1.5H),0.92(t,1.5H)。
实施例48
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]1-甲基咪唑-4-磺酰胺
向(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-胺(1a,60mg,0.14mmol)130μmol)于二氯甲烷(6mL)中的溶液中加入三乙胺(55μl),然后加入1-甲基咪唑-4-磺酰氯(36mg,200μmol)和DMAP(2mg,17μmol)。在室温继续搅拌18小时,将反应混合物倒入水中,用二氯甲烷萃取。合并的有机相用盐水洗涤,经硫酸钠干燥,真空除去溶剂,以及通过硅胶色谱对产物进行纯化。收率:39mg(46%)。
MS(CI+):m/z 506(MH+)。
1H-NMR(300MHz,CDCl3)δ=7.93(s,1H),7.62(dd,2H),7.53(d,1H),7.40(d,2H),7.33(m,4H),7.28(t,1H),7.20(t,2H),7.14(dd,1H),6.85(d,1H),5.46(d,1H),5.24(d,1H),3.93(dq,1H),3.63(s,3H),1.12(d,3H)。
实施例49
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]3,5-二甲基异噁唑-4-磺酰胺
向(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-胺(1a,60mg,0.14mmol)130μmol)于二氯甲烷(6mL)中的溶液中加入三乙胺(55μl),然后加入3,5-二甲基异噁唑-4-磺酰氯(39mg,200μmol)和DMAP(2mg,17μmol)。在室温继续搅拌18小时,将反应混合物倒入水中,用二氯甲烷萃取。合并的有机相用盐水洗涤,经硫酸钠干燥,真空除去溶剂,以及通过硅胶色谱对产物进行纯化。收率:31mg(36%)。
MS(CI+):m/z 521(MH+)。
1H-NMR(300MHz,CDCl3)δ=7.96(s,1H),7.62(dd,2H),7.54(d,1H),7.35(m,3H),7.28(m,1H),7.21(t,2H),7.04(dd,1H),6.87(d,1H),5.26(d,1H),4.97(d,1H),3.77(dq,1H),2.64(s,3H),2.38(s,3H),1.22(d,3H)。
测定
人糖皮质激素受体(GR)测定
所述测定基于来自Panvera/Invitrogen(物品号P2893)的商购试剂盒。测定技术是荧光偏振(fluorescence polarization)。所述试剂盒使用重组人GR(Panvera,物品号P2812)、FluoromoneTM标记的示踪剂(GS Red,Panvera,物品号P2894)和稳定肽10×(Stabilizing Peptide 10×)(Panvera,物品号P2815)。将GR和稳定肽试剂在-70℃储藏,而将GS Red在-20℃储藏。所述试剂盒还包括1MDTT(Panvera,物品号P2325,在-20℃储藏)和GR筛选缓冲液10×(GR Screeningbuffer 10×)(Panvera,物品号P2814,开始在-70℃储藏但一旦解冻就在室温储藏)。对于所有试剂,避免重复冷冻/解冻。所述GR筛选缓冲液10×包含100mM磷酸钾、200mM钼酸钠、1mM EDTA和20%DMSO。
将测试化合物于100%DMSO中的溶液(1μL)和对照品于100%DMSO中的溶液(1μL)加到黑色聚苯乙烯384孔板(Greiner低容积黑色平底,物品号784076)中。0%对照品为100%DMSO,以及100%对照品为10μM地塞米松。将本底溶液(background solution)(8μL;测定缓冲液10×、稳定肽、DTT和冰冷的MQ水)加到本底孔(the background well)中。将GS Red溶液(7μL;测定缓冲液10×、稳定肽、DTT、GS Red和冰冷的水)加到除本底孔外的所有孔中。将GR溶液(7μL;测定缓冲液10×、稳定肽、DTT、GR和冰冷的水)加到所有孔中。将板密封,并在室温避光孵育2小时。在Analyst板读数仪(LJL Biosystems/MolecularDevices Corporation)或其它能够记录荧光偏振的类似板读数仪中对板进行读数(激发波长为530nm,发射波长为590nm,以及分色镜(dichroic mirror)在561nm)。使用XLfit模型205来计算IC50值。
Claims (19)
1.式(I)化合物或其可药用盐:
其中
A为C1-10烷基、C5-10芳基、C5-10芳基C1-6烷基-、C5-10杂芳基、C5-10杂芳基C1-6烷基-、C5-10芳基C1-6烷氧基-、C1-10卤代烷基、C3-7环烷基、C3-7环烷基C1-4烷基-、C1-6烷基OC(O)C1-6烷基-、C1-6烷基C(O)OC1-6烷基-、C5-10芳基氧基C1-10烷基-或NR5R6C0-6烷基-,其中所述芳基任选地经一个或多个选自B的取代基取代;
R1和R1a独立地选自氢、C1-4烷基、C1-4卤代烷基、C1-4羟基烷基和C1-4烷基OC1-4烷基-;
R2为氢或C1-4烷基;
R3为C3-7环烷基,所述C3-7环烷基任选地经卤素或C1-6烷基取代;C5-10芳基C0-3烷基-;C5-10芳基OC0-3烷基-;C5-10杂芳基C0-3烷基-;C1-6烷基;C1-6烯基;或C1-6炔基;这些基团任选地经一个或多个B取代;
B为C0-3羟基烷基、C1-4烷基、C1-4烷氧基、C0-4烷基硫基C0-4烷基-、C3-6环烷基C0-4烷基硫基-、C0-3烷基S(O)nC0-4烷基-、C1-6卤代烷基、C1-4卤代烷氧基、卤素、硝基、氰基、C1-4烷基OC1-6烷基-、C0-6烷基OC1-4烷基OC0-4烷基-、C0-6烷基C(O)C0-6烷基-、C0-4烷基C(O)OC0-4烷基-、C0-4烷基OC(O)C0-4烷基-、NR5R6C0-4烷基-、NR5R6C(O)C0-4烷基-、NR5R6OC(O)C0-4烷基-、NR5R6C(O)OC0-4烷基-、R6C(O)R5NC0-4烷基-、C0-4烷基OC(O)C0-4烷基NH-、C0-4烷基C(O)OC0-4烷基NH-、C0-4烷基C(O)C0-4烷基NH-或NR5R6S(O)nC0-4烷基-;
R4为氢、羟基、卤素、C1-4烷基或C1-4卤代烷基;
W为氢、C3-7环烷基、C1-4烷基、苯基、噻吩基、异噁唑基、吡唑基、吡啶基或嘧啶基,所有这些基团任选地经一个或多个选自下列的取代基取代:卤素、C0-3羟基烷基、C1-4烷基、C1-4烷氧基、C0-4烷基硫基C0-4烷基-、C3-6环烷基C0-4烷基硫基-、C0-4烷基S(O)nC0-4烷基-、C1-6卤代烷基、C1-4卤代烷氧基、卤素、硝基、氰基、C1-4烷基OC1-6烷基-、C1-6烷基OC1-6烷基OC1-6烷基-、C0-6烷基C(O)C0-6烷基-、C0-4烷基C(O)OC0-4烷基-、C0-4烷基OC(O)C0-4烷基-、NR5R6C0-4烷基-、NR5R6C(O)C0-4烷基-、NR5R6C(O)OC0-4烷基-、NR5R6OC(O)C0-4烷基-、R6C(O)R5NC0-4烷基-、C0-4烷基OC(O)C0-4烷基NH-、C0-4烷基C(O)OC0-4烷基NH-、C0-4烷基C(O)C0-4烷基NH-和NR5R6S(O)nC0-4烷基-;
X为CH2、O、S、S(O)、S(O)2或NH;
Y为氢、卤素、C1-6烷基、C1-4烷氧基、C1-4烷基硫基、C1-4卤代烷基、C1-4卤代烷氧基、硝基、氰基、羟基、R5C(O)-、R5OC(O)-、R5C(O)O-、C1-4烷基S(O)n-、R5R6NS(O)n-、苄基氧基、咪唑基、C1-4烷基NHC(O)-、NR5R6C(O)-、C1-4烷基C(O)NH-或-NR5R6;
R5和R6独立地选自氢、C1-4烷基和C3-7环烷基,或R5和R6一起形成基团-(O)C5-10)芳基C(O)-;以及
n为1或2。
2.权利要求1所述的化合物,其中A为C1-10烷基、C5-10芳基、C5-10芳基C1-6烷基-、C5-10杂芳基、C5-10杂芳基C1-6烷基-、C5-10芳基C1-6烷氧基-、C1-10卤代烷基、C3-7环烷基、C3-7环烷基C1-4烷基-、C1-6烷基OC(O)C1-6烷基-、C1-6烷基C(O)OC1-6烷基-、C5-10芳基氧基C1-10烷基-或NR5R6C0-6烷基-,其中所述芳基任选地经一个或多个选自B的取代基取代。
3.权利要求1所述的化合物,其中A为C3-6环烷基。
4.权利要求1至3任一项所述的化合物,其中R3为C5-10芳基C0-3烷基-、C5-10芳基OC0-3烷基-或C5-10杂芳基C0-3烷基-,这些基团任选地经一个或多个B取代。
5.权利要求1至3任一项所述的化合物,其中R3为苯基,或R3与B一起形成二氢苯并二氧杂环己二烯基团。
6.权利要求1至5任一项所述的化合物,其中W为C3-7环烷基、C1-4烷基、苯基或吡啶基,所有这些基团任选地经一个或多个选自卤素的取代基取代。
7.权利要求1至5任一项所述的化合物,其中W为经氟取代的苯基。
8.权利要求1至7任一项所述的化合物,其中R1为C1-4烷基,R1a为氢,R2为氢,X为O,以及R3为C5-10芳基,其中所述芳基任选地经一个或多个B取代。
9.一种化合物或其可药用盐,所述化合物选自:
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]丙-1-磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-4-基]氧基-1-苯基-丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-[1-(6-氟吡啶-3-基)吲唑-5-基]氧基-1-苯基-丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]甲磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]-1-苯基-甲磺酰胺,
1,1,1-三氟-N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]甲磺酰胺,
5-[(1R,2S)-2-(二甲基氨磺酰基氨基)-1-苯基-丙氧基]-1-(4-氟苯基)吲唑,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]丙-2-磺酰胺,
2-(1,3-二氧代异吲哚-2-基)-N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]乙磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]-3-(4-甲氧基苯氧基)丙-1-磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]乙磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]戊-2-磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]丁-2-磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]丁-1-磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]-2-甲基-丙-1-磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]戊-1-磺酰胺,
3,3,3-三氟-N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]丙-1-磺酰胺,
3-[[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]氨磺酰基]丙酸甲酯,
1-环戊基-N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]甲磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]环戊基磺酰胺,
2,2,2-三氟-N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]乙磺酰胺,
1-环己基-N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]甲磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]己-1-磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]吡啶-3-磺酰胺,
N-[1-[1-(4-氟苯基)吲唑-5-基]氧基-2-甲基-1-苯基-丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-(4-(甲基硫基)苯基)丙-2-基]环丙基磺酰胺,
N-[(1S,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-(4-(甲基硫基)苯基)丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-(4-(甲基硫基)苯基)丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-苯基-1-(1-(丙-2-基)吲唑-5-基)氧基-丙-2-基]甲磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-(4-(甲基亚磺酰基)苯基)丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-(1-环戊基吲唑-5-基)氧基-1-苯基-丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-苯基-1-(1-(丙-2-基)吲唑-5-基)氧基-丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-(4-(甲基磺酰基)苯基)丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-[6-氯-1-(4-氟苯基)吲唑-5-基]氧基-1-(4-氟苯基)丙-2-基]环丙基磺酰胺,
N-[(1R,2R)-1-[6-氯-1-(4-氟苯基)吲唑-5-基]氧基-1-(4-氟苯基)丙-2-基]环丙基磺酰胺,
N-[2-[1-(4-氟苯基)吲唑-5-基]硫基-2-苯基-乙基]环丙基磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]硫基-1-苯基-丙-2-基]甲磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]磺酰基-1-苯基-丙-2-基]甲磺酰胺,
N-[(2R)-2-[1-(4-氟苯基)吲唑-5-基]氧基-2-苯基-乙基]环丙基磺酰胺,
N-[(2S)-2-[1-(4-氟苯基)吲唑-5-基]氧基-2-苯基-乙基]环丙基磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-(喹啉-3-基)-丙-2-基]环丙基磺酰胺,
N-[(1R,2S)-1-(2,5-二氧杂二环[4.4.0]癸-7,9,11-三烯-8-基)-1-[1-(4-氟苯基)吲唑-5-基]氧基-丙-2-基]环丙基磺酰胺,
N-{1-[6-甲氧基吡啶-3-基]-1-[(1-(吡啶-2-基)-1H-吲唑-5-基)氧基]丙-2-基}环丙基磺酰胺,
N-{1-[6-甲氧基吡啶-3-基]-1-[(1-(吡啶-3-基)-1H-吲唑-5-基)氧基]丙-2-基}环丙基磺酰胺,
N-{1-[2-甲氧基吡啶-4-基]-1-[(1-(吡啶-2-基)-1H-吲唑-5-基)氧基]丙-2-基}环丙基磺酰胺,
N-{1-[2-甲氧基吡啶-4-基]-1-[(1-(吡啶-2-基)-1H-吲唑-5-基)氧基]丁-2-基}环丙基磺酰胺,
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]1-甲基-1H-咪唑-4-磺酰胺,以及
N-[(1R,2S)-1-[1-(4-氟苯基)吲唑-5-基]氧基-1-苯基-丙-2-基]3,5-二甲基异噁唑-4-磺酰胺。
10.一种药物组合物,其包含权利要求1至9任一项所述的式(I)化合物或其可药用盐,以及可药用辅料、稀释剂或载体。
11.权利要求1至9任一项所述的式(I)化合物或其可药用盐,其用在治疗中。
12.权利要求1至9任一项所述的式(I)化合物或其可药用盐在制备用于治疗糖皮质激素受体所介导的病症的药物中的用途。
13.权利要求1至9任一项所述的式(I)化合物或其可药用盐在制备用于治疗炎性病症的药物中的用途。
14.权利要求1至9任一项所述的式(I)化合物或其可药用盐在制备用于治疗哮喘病症的药物中的用途。
15.权利要求1至9任一项所述的式(I)化合物或其可药用盐在制备用于治疗慢性阻塞性肺病的药物中的用途。
16.在哺乳动物中治疗糖皮质激素受体所介导的病症、炎性病症、哮喘病症和/或慢性阻塞性肺病的方法,所述方法包括向需要所述治疗的哺乳动物给药有效量的权利要求1至9任一项所述的式(I)化合物或其可药用盐。
17.权利要求1所述的式(I)化合物或其可药用盐与一种或多种药物的组合,所述药物选自:
·PDE4抑制剂;
·选择性β2肾上腺素受体激动剂;
·蕈毒碱性受体拮抗剂;
·甾体;
·趋化因子受体功能的调节剂;或
·p38激酶功能的抑制剂。
19.制备式(II)化合物的方法,所述方法为:
a)当X为O、S或NH时,在合适的溶剂中在合适的碱存在下使式(IV)化合物与式(V)化合物偶联,
式(IV)化合物为:
其中R4、W和Y如权利要求1中所定义,以及L2为离去基团,
式(V)化合物为:
其中R1、R1a和R2如权利要求1中所定义,以及G对应于R3或对应于R3的经保护前体,或
b)在合适的溶剂中在合适的碱存在下使式(VII)化合物与式(VIII)化合物反应,然后进行还原性氨化步骤,
式(VII)化合物为:
式(VIII)化合物为:
其中R1、R2、R4、X、W和Y如权利要求1中所定义,G对应于R3或对应于R3的经保护前体,以及L3为离去基团,或
c)在合适的溶剂中在合适的碱存在下使(VIII)化合物与式(IX)化合物反应,然后进行脱保护步骤,
式(IX)化合物为:
其中R1、R1a、R2和R3如权利要求1中所定义,以及PG为合适的保护基例如BOC、Ms、Ns、Ts、相关的羰基残基或相关的磺酰基残基。
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PCT/SE2007/001031 WO2008063116A1 (en) | 2006-11-23 | 2007-11-22 | Indozalyl sulphonamide derivatives useful as glucocorticoid modulators |
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CN103080108A (zh) * | 2010-08-27 | 2013-05-01 | 科赛普特治疗公司 | 吡啶基-胺稠合的氮杂萘烷调节剂 |
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CN103080108A (zh) * | 2010-08-27 | 2013-05-01 | 科赛普特治疗公司 | 吡啶基-胺稠合的氮杂萘烷调节剂 |
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