6-substituted-1,2,3,4-tetrahydro-9H-carbazoles and 7-substituted-10H-cyclohepta(7,6-B)indoles
申请人:ELI LILLY AND COMPANY
公开号:EP0749962A1
公开(公告)日:1996-12-27
The present invention provides novel agonists of the serotonin 5-HT1F receptor of formula I which are useful in a method of inhibiting neuronal protein extravasation without causing vasoconstriction.
wherein:
R1 and R2are independently hydrogen, C1-C4 alkyl, or -CH2CH2-Aryl where Aryl is phenyl, phenyl monosubstituted with halo, or 1-(C1-C6 alkyl) pyrazol-4-yl;
Xis -OH, -NHC(O)R3, -NHC(Y)NHR4, -NHC(O)OR5, -C(O)R6 or -NHSO2R7;
R3is C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloakyl, phenyl, substituted phenyl, naphthyl, (C1- C4 alkylene)phenyl, thienylmethyl, or a heterocycle;
R4is C1-C6 alkyl, phenyl, or phenyl disubstituted with halo;
R5is C1-C6 alkyl, C2-C6 alkenyl, benzyl or phenyl monosubstituted with halo;
R6is C1-C6 alkyl, phenyl, or phenyl monosubstituted with halo or C1-C4 alkoxy;
R7is dimethylamino, phenyl or phenyl monosubstituted with halo or C1-C4 alkyl;
mis 0 or 1;
nis 1 or 2; and
Yis S or O; and parmaceutically acceptable salts and hydrates thereof, providing:
Xis not -OH when m is 0, n is 1, and R1 and R2 are independently hydrogen or C1-C6 alkyl; and
R3is not C1-C6 alkyl when m is 0, n is 1, and R1 and R2 are independently hydrogen or C1-C6 alkyl.
本发明提供了式 I 的新型血清素 5-HT1F 受体激动剂,可用于抑制神经元蛋白外渗而不引起血管收缩的方法。
其中
R1 和 R2 独立地为氢、C1-C4 烷基或-CH2CH2-芳基,其中芳基为苯基、卤代单取代苯基或 1-(C1-C6烷基)吡唑-4-基;
X为-OH、-NHC(O)R3、-NHC(Y)NHR4、-NHC(O)OR5、-C(O)R6 或-NHSO2R7;
R3 是 C1-C6 烷基、C2-C6 烯基、C3-C8 环烷基、苯基、取代苯基、萘基、(C1-C4 亚烷基)苯基、噻吩甲基或杂环;
R4 是 C1-C6 烷基、苯基或与卤代物二取代的苯基;
R5 是被卤素单取代的 C1-C6 烷基、C2-C6 烯基、苄基或苯基;
R6 是卤代或 C1-C4 烷氧基单取代的 C1-C6 烷基、苯基或苯基;
R7 是二甲基氨基、苯基或与卤素或 C1-C4 烷基单取代的苯基;
mis为 0 或 1;
n 是 1 或 2;以及
Y 是 S 或 O;以及它们的法玛西亚可接受盐和水合物,条件是
当 m 为 0,n 为 1,且 R1 和 R2 独立为氢或 C1-C6 烷基时,X 不是-OH;以及
当 m 为 0,n 为 1,且 R1 和 R2 独立为氢或 C1-C6 烷基时,R3 不是 C1-C6 烷基。