CN103328492A - 作为受体调节剂具有疗效的新型化合物 - Google Patents
作为受体调节剂具有疗效的新型化合物 Download PDFInfo
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- CN103328492A CN103328492A CN2011800612036A CN201180061203A CN103328492A CN 103328492 A CN103328492 A CN 103328492A CN 2011800612036 A CN2011800612036 A CN 2011800612036A CN 201180061203 A CN201180061203 A CN 201180061203A CN 103328492 A CN103328492 A CN 103328492A
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- amino
- phenyl
- oxygen base
- phenylpentyl
- furyl
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Abstract
本发明涉及新型衍生物、制备新型衍生物的工艺、含有新型衍生物的药物组合物及其作为如1-磷酸鞘氨醇受体调节剂的药物的用途。
Description
相关申请的交叉引用
本申请要求2010年11月22日提交的美国临时申请序列号61/416,081的利益,其据此通过引用整体并入。
技术领域
本发明涉及新型衍生物、制备新型衍生物的工艺、含有新型衍生物的药物组合物及其作为如1-磷酸鞘氨醇受体调节剂的药物的用途。本发明特别涉及这些化合物及其药物组合物治疗与1-磷酸鞘氨醇(S1P)受体调节相关的病症的用途。
发明背景
在缺乏负责分解代谢的酶的人血小板中储存了相对高浓度的1-磷酸鞘氨醇,并且一激活生理刺激物,例如生长因子、细胞因子和受体激动剂和抗原,1-磷酸鞘氨醇就释放至血液中。在血小板聚集和血栓形成中1-磷酸鞘氨醇也可能有关键作用并且可使心血管疾病恶化。另一方面,高密度脂蛋白(HDL)中相对高浓度的代谢产物可能对动脉粥样化形成有有益启示。例如,最近表明,1-磷酸鞘氨醇连同其它溶血磷脂,例如鞘氨醇磷脂酰胆碱和溶血硫脑苷脂,通过刺激血管内皮生成有效抗动脉粥样硬化信号分子一氧化氮负责HDL的有益临床效果。另外,和溶血磷脂酸一样,它是某些类型癌症的标志,并且有证据表明它在细胞分裂和增殖中的作用可能对癌症发展有影响。这些是当前在医学研究人员中引起极大兴趣的话题,并且在1-磷酸鞘氨醇代谢中治疗性干预的潜力正在积极研究中。
发明概述
我们现在已经发现了一类为有效的选择性1-磷酸鞘氨醇调节剂的新型化合物。同样地,本文所述的化合物在治疗多种与1-磷酸鞘氨醇受体调节相关的病症中有用。如本文所使用的术语“调节剂”包括但不限于:受体激动剂、拮抗剂、反向激动剂、反向拮抗剂、部分激动剂、部分拮抗剂。
本发明描述了式I的化合物,其具有1-磷酸鞘氨醇受体生物活性。因此根据本发明所述的化合物在医学上有用,例如在具有通过S1P调节减轻的疾病和病状的人类的治疗中。一方面,本发明提供了具有式I的化合物或其药学上可接受的盐或其立体异构形式或几何异构体、对映异构体、非对映异构体、互变异构体、两性离子及其药学上可接受的盐。
在本发明的一个实施方案中,提供了具有以下式I的化合物及其药学上可接受的盐、其对映异构体、非对映异构体、水合物、溶剂、晶体形式及其单独异构体、互变异构体或药学上可接受的盐,
其中:
R1为N或C-R9;
R2为经取代或未经取代的芳香族杂环、C5-8环烯基或C6-10芳基;
R3为O、N-R10、CH-R11、S、-CR12=CR13-、-C≡C-或-C(O)-;
R4为H、C5-8环烯基、C3-8环烷基或经取代或未经取代的C6-10芳基;
R5为H、卤素、-OC1-3烷基、C1-3烷基或羟基;
R6为H、卤素、-OC1-3烷基、C1-3烷基或羟基;
a为0、1、2、3或4;
b为0、1、2、3或4;
L为CHR7、O、S、NR8或-C(O)-;
R7为H、C1-3烷基、-OC1-3烷基、卤素、羟基或NR9R10;
R8为H或C1-3烷基;
R9为H、卤素或C1-3烷基;
R10为H或C1-3烷基;
R11为H或C1-3烷基;
R12为H或C1-3烷基;
R13为H或C1-3烷基;
Q1为-CR14R15-;
R14为H、卤素或C1-3烷基;
R15为H、卤素或C1-3烷基;
m为0、1、2或3;
“*”表示与分子其余部分的连接点;
R18为NR9、O或S;
条件是R3为O、N-R10、S、-CR12=CR13-、-C≡C-或-C(O)-并且b为0或1时,则L不为O、S、NR8或-C(O)-。
另一方面,本发明提供了具有式I的化合物,其中;
R1为N或C-R9;
R2为经取代或未经取代的5元芳香族杂环或C5-8环烯基;
R3为O、N-R10、CH-R11、S;
R4为经取代或未经取代的C6-10芳基;
R5为H或卤素;
R6为H或卤素;
R8为H或C1-3烷基;
R9为H或C1-3烷基;
R10为H或C1-3烷基;
R11为H或C1-3烷基;
a为0、1、2、3或4;
b为0、1、2、3或4;
L为CH2;
m为0;
T为-NH-Q2;
“*”表示与分子其余部分的连接点。
另一方面,本发明提供了具有式I的化合物,其中:
R1为N或C-R9;
R2为呋喃、2-呋喃基和3-呋喃基衍生物;噻吩、2-噻吩基和3-噻吩基衍生物;吡咯、噁唑、噻唑、吡咯烷、吡咯啉、咪唑、吡唑、吡唑啉,异噁唑、异噻唑、吡唑烷、咪唑啉、噻唑啉、噁唑啉、二氢噻吩、二氢呋喃、四唑、三唑、噁二唑、1,2,5-噁二唑、噻二唑、1,2,3-三唑、1,2,4-三唑、吡咯烷酮、吡咯-2(3H)-酮、咪唑烷-2-酮或1,2,4-三唑-5(4H)和类似的5元杂环;
R3为O、N-R10、CH-R11、S;
R4是经例如以下的基团邻位、间位和对位取代的苯基:卤素氟、氯和溴;短链烷基甲基、乙基、丙基、异丙基等;甲氧基、三氟甲氧基、三氟甲基和全氟化短链烷基;
R5为H或卤素;
R6为H或卤素;
R8为H或C1-3烷基;
R9为H或C1-3烷基;
R10为H或C1-3烷基;
R11为H或C1-3烷基;
a为0、1、2、3或4;
b为0、1、2、3或4;
L为CH2;
m为0;
T为-NH-Q2;
“*”表示与分子其余部分的连接点。
另一方面,本发明提供了具有式I的化合物,其中:
R1为C-R9;
R2为经取代或未经取代的5元芳香族杂环或C5-8环烯基;
R3为O、N-R10、CH-R11、S;
R4为经取代或未经取代的C6-10芳基;
R5为H或卤素;
R6为H或卤素;
R8为H或C1-3烷基;
R9为H或C1-3烷基;
R10为H或C1-3烷基;
R11为H或C1-3烷基;
a为0、1、2、3或4;
b为0、1、2、3或4;
L为CH2;
m为0;
T为-NH-Q2;
“*”表示与分子其余部分的连接点。
另一方面,本发明提供了具有式I的化合物,其中:
R1为C-R9;
R2为经取代或未经取代的5元芳香族杂环;
R3为O;
R4为经取代或未经取代的苯基;
R5为H、Cl、Br或F;
R6为H、Cl、Br或F;
a为1、2或3;
b为1、2或3;
L为CHR7;
R7为H或C1-3烷基;
m为0;
T为-NH-Q2;
“*”表示与分子其余部分的连接点。
另一方面,本发明提供了具有式I的化合物,其中:
R1为C-R9;
R2为经取代或未经取代的5元芳香族杂环;
R3为O;
R4为经取代或未经取代的苯基;
R5为H、Cl、Br或F;
R6为H、Cl、Br或F;
a为1、2或3;
b为1、2或3;
L为CHR7;
R7为H或C1-3烷基;
m为0;
T为-NH-Q2;
“*”表示与分子其余部分的连接点。
另一方面,本发明提供了具有式I的化合物,其中:
R1为C-R9;
R2为经取代或未经取代的5元芳香族杂环;
R3为O;
R4为经取代或未经取代的苯基;
R5为H或F;
R6为H或F;
R8为H或C1-3烷基;
R9为H或C1-3烷基;
a为1、2或3;
b为1、2或3;
L为CH2;
m为0;
T为-NH-Q2;
“*”表示与分子其余部分的连接点。
另一方面,本发明提供了具有式I的化合物,其中:
R1为C-R9;
R2为经取代或未经取代的5元芳香族杂环;
R3为O;
R4为经取代或未经取代的苯基;
R5为H或F;
R6为H或F;
R9为H;
a为2;
b为2;
L为CH2;
m为0;
T为-NH-Q2;
“*”表示与分子其余部分的连接点。
另一方面,本发明提供了具有式I的化合物,其中:
R1为C-R9或N;
R2为经取代或未经取代的5元芳香族杂环;
R3为O;
R4为经取代或未经取代的C6-10芳基;
a为0、1、2、3或4;
b为0、1、2、3或4;
R5为H或F;
R6为H或F;
R9为H或C1-3烷基;
L为CH2;
Q1为-CR14R15-;
R14为H;
R15为H;
m为2;
“*”表示与分子其余部分的连接点;
R18为NR9;
Q2为-OPO3H2、-OH、羧酸、-PO3H2、H、-C1-6烷基、-P(O)MeOH或-P(O)(H)OH。
另一方面,本发明提供了具有式I的化合物,其中:
R1为C-R9或N;
R2为经取代或未经取代的5元杂环;
R3为O;
R4为经取代或未经取代的苯基;
R5为H或F;
R6为H或F;
a为1、2或3;
b为1、2或3;
R9为H或C1-3烷基;
L为CH2;
Q1为-CR14R15-;
R14为H;
R15为H;
m为2;
“*”表示与分子其余部分的连接点;
Q2为-OPO3H2、-OH、羧酸、-PO3H2、H、-C1-6烷基、-P(O)MeOH或-P(O)(H)OH。
另一方面,本发明提供了具有式I的化合物,其中:
R1为C-R9;
R2为经取代或未经取代的5元芳香族杂环;
R3为O;
R4为经取代或未经取代的苯基;
R5为H或F;
R6为H或F;
R9为H;
a为2;
b为2;
L为CH2;
Q1为-CR14R15-;
R14为H;
R15为H;
m为2;
T为
“*”表示与分子其余部分的连接点;
Q2为-OPO3H2、-OH、羧酸、-PO3H2、H、-C1-6烷基、-P(O)MeOH或-P(O)(H)OH。
另一方面,本发明提供了具有式I的化合物,其中:
R1为N或C-R9;
R2为经取代或未经取代的5元芳香族杂环;
R3为O;
R4为经取代或未经取代的苯基;
R5为H或F;
R6为H或F;
a为1、2或3;
b为1、2或3;
L为CH2;
R9为H或C1-3烷基;
m为0;
“*”表示与分子其余部分的连接点;
R18为NR9;
Q2为-OPO3H2、-OH、羧酸、-PO3H2、H、-C1-6烷基、-P(O)MeOH或-P(O)(H)OH。
另一方面,本发明提供了具有式I的化合物,其中:
R1为C-R9;
R2为经取代或未经取代的5元芳香族杂环;
R3为O;
R4为经取代或未经取代的苯基;
R5为H或F;
R6为H或F;
R9为H;
a为2;
b为2;
L为CH2;
m为0;
“*”表示与分子其余部分的连接点;
R18为NR9;
Q2为-OPO3H2、-OH、羧酸、-PO3H2、H、-C1-6烷基、-P(O)MeOH或-P(O)(H)OH。
另一方面,本发明提供了具有式I的化合物,其中:
R1为N或C-R9;
R2为经取代或未经取代的杂环、C5-8环烯基或C6-10芳基;
R3为O、N-R10、CH-R11、S、-CR12=CR13-、-C≡C-或-C(O)-;
R4为H、C5-8环烯基、C3-8环烷基或经取代或未经取代的C6-10芳基;
R5为H、卤素、-OC1-3烷基、C1-3烷基或羟基;
R6为H、卤素、-OC1-3烷基、C1-3烷基或羟基;
a为0、1、2、3或4;
b为0、1、2、3或4;
L为CHR7、O、S、NR8或-C(O)-;
R7为H、C1-3烷基、-OC1-3烷基、卤素、羟基或NR9R10;
R8为H或C1-3烷基;
R9为H、卤素或C1-3烷基;
R10为H或C1-3烷基;
R11为H或C1-3烷基;
R12为H或C1-3烷基;
R13为H或C1-3烷基;
Q1为-CR14R15-;
R14为H、卤素或C1-3烷基;
R15为H、卤素或C1-3烷基;
m为0、1、2或3;
“*”表示与分子其余部分的连接点;
R18为NR9、O或S;
条件是R3为O、N-R10、S、-CR12=CR13-、-C≡C-或-C(O)-并且b为0或1时,则L不为O、S、NR8或-C(O)-。
另一方面,本发明提供了具有式I的化合物,其中:
R1为C-R9;
R2为经取代或未经取代的5元杂环;
R3为O;
R4为经取代或未经取代的C6-10芳基;
R5为H或卤素;
R6为H或卤素;
a为1或2;
b为1或2;
L为CHR7;
R7为H;
R9为H或C1-3烷基;
Q1为-CR14R15-;
R14为H;
R15为H;
m为2;
“*”表示与分子其余部分的连接点;
R18为NR9;
Q2相同或独立地为-OPO3H2、羧酸、-PO3H2、-C1-6烷基、H、-P(O)MeOH、-P(O)(H)OH、-OH。
另一方面,本发明提供了具有式I的化合物,其中:
R1为C-R9;
R2为经取代或未经取代的5元杂环;
R3为O;
R4为经取代或未经取代的C6-10芳基;
R5为H或卤素;
R6为H或卤素;
a为1或2;
b为1或2;
L为CHR7;
R7为H;
R9为H或C1-3烷基;
Q1为-CR14R15-;
R14为H;
R15为H;
m为2;
T为-NH-Q2、
“*”表示与分子其余部分的连接点;
R18为NR9;
Q2相同或独立地为-OPO3H2、羧酸、-PO3H2、-C1-6烷基、H、-P(O)MeOH、-P(O)(H)OH、-OH。
另一方面,本发明提供了具有式I的化合物,其中:
R1为C-R9;
R2为经取代或未经取代的5元杂环;
R3为O;
R4为经取代或未经取代的C6-10芳基;
R5为H或卤素;
R6为H或卤素;
a为1或2;
b为1或2;
L为CHR7;
R7为H;
R9为H或C1-3烷基;
Q1为-CR14R15-;
R14为H;
R15为H;
m为2;
“*”表示与分子其余部分的连接点;
Q2相同或独立地为-OPO3H2、羧酸、-PO3H2、-C1-6烷基、H、-P(O)MeOH、-P(O)(H)OH、-OH。
另一方面,本发明提供了具有式I的化合物,其中:
R1为C-R9;
R2为经取代或未经取代的杂环;
R3为O;
R4为经取代或未经取代的苯基;
R5为H或卤素;
R6为H或卤素;
a为2;
b为2;
L为CHR7;
R7为H;
R9为H;
m为0;
T为-NH-Q2;
“*”表示与分子其余部分的连接点;
另一方面,本发明提供了具有式I的化合物,其中:
R1为C-R9;
R2为经取代或未经取代的杂环;
R3为O;
R4为经取代或未经取代的苯基;
R5为H或卤素;
R6为H或卤素;
a为2;
b为2;
L为CHR7;
R7为H;
R9为H;
m为0;
T为-NH-Q2;
“*”表示与分子其余部分的连接点;
另一方面,本发明提供了具有式I的化合物,其中:
R1为C-R9;
R2为经取代或未经取代的杂环;
R3为O;
R4为经取代或未经取代的苯基;
R5为H或卤素;
R6为H或卤素;
a为2;
b为2;
L为CHR7;
R7为H;
R9为H;
m为0;
T为-NH-Q2;
“*”表示与分子其余部分的连接点;
另一方面,本发明提供了具有式I的化合物,其中:
R1为C-R9;
R2为经取代或未经取代的杂环;
R3为O;
R4为经取代或未经取代的苯基;
R5为H或卤素;
R6为H或卤素;
a为2;
b为2;
L为CHR7;
R7为H;
R9为H;
m为0;
T为-NH-Q2;
“*”表示与分子其余部分的连接点;
另一方面,本发明提供了具有式I的化合物,其中:
R1为C-R9;
R2为经取代或未经取代的杂环;
R3为O;
R4为经取代或未经取代的苯基;
R5为H或卤素;
R6为H或卤素;
a为2;
b为2;
L为CHR7;
R7为H;
R9为H;
m为0;
T为-NH-Q2;
“*”表示与分子其余部分的连接点;
如本文所使用,术语“烷基”指具有直链或支链部分或其组合并且含有1-6个碳原子的饱和、单价烃部分。烷基的一个亚甲基(-CH2-)可被氧、硫、亚砜、氮、羰基、羧基、磺酰基或二价C3-6环烷基置换。烷基可被卤素、氨基、羟基、环烷基、氨基、非芳香族杂环、羧酸、膦酸基团、磺酸基团、磷酸取代。
如本文所使用,术语“短链烷基”指含有1-3个碳原子的饱和单价直链或支链部分。
如本文所使用,术语全氟化短链烷基指CF3-CF2-、CF3、(CF3)2-CH-、CF3-(CF3)2-。
如本文所使用,术语“亚烃基”指具有直链或支链部分或其组合并且含有1-6个碳原子的饱和、二价烃部分。亚烃基的一个亚甲基(-CH2-)可被氧、硫、亚砜、氮、羰基、羧基、磺酰基置换。
如本文所使用,术语“环烷基”指具有3-8个碳原子,源自饱和环烃的单价或二价基团。环烷基可为单环或多环。环烷基可被1-3个C1-3烷基或1或2个卤素取代。
如本文所使用,术语“环烯基”指具有5-8个碳原子,源自具有一个双键的饱和环烷基的单价或二价基团。环烯基可为单环或多环。环烯基可被C1-3烷基或卤素取代。
如本文所使用,术语“卤素”指氯、溴、氟、碘原子。
如本文所使用,术语“烯基”指具有2-6个碳原子,源自具有至少一个双键的饱和烷基的单价或二价烃基。C2-6烯基可呈E或Z构型。烯基可被C1-3烷基取代。
如本文所使用,术语“炔基”指具有2-6个碳原子,源自具有至少一个三键的饱和烷基的单价或二价烃基。
如本文所使用,术语“杂环”指3-1O元环,其为芳香族或非芳香族、饱和或不饱和并且含有中断碳环结构,选自O或N或S的至少一个杂原子或其中至少两个的组合。杂环可被C=O中断;可氧化S杂原子。杂环可为单环或多环。杂环部分可被羟基、C1-3烷基或卤素取代。芳香族杂环的实例为(但不限于):呋喃、2-呋喃基和3-呋喃基衍生物;噻吩、2-噻吩基、3-噻吩基衍生物;吡咯、噁唑、噻唑、咪唑、吡唑、异噁唑、异噻唑、四唑、三唑、噁二唑、1,2,5-噁二唑、噻二唑、1,2,3-三唑、1,2,4-三唑。
非芳香族杂环的实例包括但不限于:吡咯烷、吡咯啉、吡唑啉、吡唑烷、咪唑啉、噻唑啉、噁唑啉、二氢噻吩、二氢呋喃、吡咯烷酮、吡咯-2(3H)-酮、咪唑烷-2-酮或1,2,4-三唑-5(4H)-酮。
通常,在目前情况下,杂环基团为5或6元环,包括但不限于:1-取代-1H-1,2,4-三唑、1-取代-氮杂环丁烷-3-CO2H、4-连接-吲哚、6-甲基-5-连接-吲唑或6-氢-5-连接-吲唑。R2位置处的一些优选杂环包括以下:呋喃、2-呋喃基和3-呋喃基衍生物;噻吩、2-噻吩基和3-噻吩基衍生物;吡咯、噁唑、噻唑、吡咯烷、吡咯啉、咪唑、吡唑、吡唑啉、异噁唑、异噻唑、吡唑烷、咪唑啉、噻唑啉、噁唑啉、二氢噻吩、二氢呋喃、四唑、三唑、噁二唑、1,2,5-噁二唑、噻二唑、1,2,3-三唑、1,2,4-三唑、吡咯烷酮、吡咯-2(3H)-酮、咪唑烷-2-酮或1,2,4-三唑-5(4H)-酮和类似的5元杂环。
如本文所使用,术语“芳基”指源自由含6-10个碳原子的环,去除一个氢组成的芳香烃的有机部分。芳基经卤素原子或C1-3烷基任选取代。R4位置处的优选芳基包括:经例如以下基团邻位、间位和对位取代的苯基:卤素氟、氯和溴;短链烷基甲基、乙基、丙基、异丙基等;甲氧基、三氟甲氧基、三氟甲基和全氟化短链烷基。
如本文所使用,式“-CR12=CR13-”的基团表示烯基。
如本文所使用,式“-C≡C-”的基团表示炔基。
如本文所使用,术语“羟基”表示式“-OH”的基团。
如本文所使用,术语“羰基”表示式“-C(O)”的基团。
如本文所使用,术语“羧基”表示式“-C(O)O-”的基团。
如本文所使用,术语“磺酰基”表示式“-SO2”的基团。
如本文所使用,术语“硫酸酯”表示式“-O-S(O)2-O-”的基团。
如本文所使用,术语“羧酸”表示式“-C(O)OH”的基团。
如本文所使用,术语“亚砜”表示式“-S=O”的基团。
如本文所使用,术语“膦酸”表示式“-P(O)(OH)2”的基团。
如本文所使用,术语“磷酸”表示式“-(O)P(O)(OH)2”的基团。
如本文所使用,术语“硼酸”表示式“-B(OH)2”的基团。
如本文所使用,术语“磺酸”表示式“-S(O)2OH”的基团。
如本文所使用,式“H”表示氢原子。
如本文所使用,式“O”表示氧原子。
如本文所使用,式“N”表示氮原子。
如本文所使用,式“S”表示硫原子。
本发明的一些化合物为:
(2R)-2-氨基-2-甲基-3-氧代-3-({4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}氨基)丙基二氢磷酸酯;
(2S)-2-氨基-2-甲基-3-氧代-3-({4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}氨基)丙基二氢磷酸酯;
2-氨基-3-羟基-2-甲基-N-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}丙酰胺;
2-氨基-3-羟基-2-甲基-N-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}丙酰胺;
(2S)-2-氨基-3-({3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}氨基)-3-氧代丙基二氢磷酸酯;
(2S)-2-氨基-3-氧代-3-({4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}氨基)丙基二氢磷酸酯;
2-氨基-N-{3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-3-羟基丙酰胺;
2-氨基-3-羟基-N-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}丙酰胺;
2-氨基-3-({3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}氨基)-3-氧代丙基二氢磷酸酯;
2-氨基-3-{[4-{[5-(4-氟苯基)戊基]氧基}-3-(2-呋喃基)苯基]氨基}-3-氧代丙基二氢磷酸酯;
2-氨基-3-({3-(3-呋喃基)-4-[(5-苯基戊基)氧基]苯基}氨基)-3-氧代丙基二氢磷酸酯;
2-氨基-3-氧代-3-({4-[(5-苯基戊基)氧基]-3-(3-噻吩基)苯基}氨基)丙基二氢磷酸酯;
2-氨基-3-({6-(2-呋喃基)-5-[(5-苯基戊基)氧基]吡啶-2-基}氨基)-3-氧代丙基二氢磷酸酯;
2-氨基-N-{3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-3-羟基丙酰胺;
2-氨基-N-{3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-3-羟基丙酰胺;
2-氨基-N-{3-(3-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-3-羟基丙酰胺;
2-氨基-3-羟基-N-{4-[(5-苯基戊基)氧基]-3-(3-噻吩基)苯基}丙酰胺;
2-氨基-N-{6-(2-呋喃基)-5-[(5-苯基戊基)氧基]吡啶-2-基}-3-羟基丙酰胺;
2-氨基-4-{3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-2-(羟基甲基)丁基二氢磷酸酯;
2-氨基-2-(羟基甲基)-4-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}丁基二氢磷酸酯;
2-氨基-4-{3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-2-(羟基甲基)丁基二氢磷酸酯;
2-氨基-4-[4-{[5-(4-氟苯基)戊基]氧基}-3-(2-呋喃基)苯基]-2-(羟基甲基)丁基二氢磷酸酯;
2-氨基-4-{3-(3-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-2-(羟基甲基)丁基二氢磷酸酯;
2-氨基-2-(羟基甲基)-4-{4-[(5-苯基戊基)氧基]-3-(3-噻吩基)苯基}丁基二氢磷酸酯;
2-氨基-4-{6-(2-呋喃基)-5-[(5-苯基戊基)氧基]吡啶-2-基}-2-(羟基甲基)丁基二氢磷酸酯;
2-氨基-2-(2-{3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}乙基)丙-1,3-二醇;
2-氨基-2-(2-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}乙基)丙-1,3-二醇;
2-氨基-2-(2-{3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}乙基)丙-1,3-二醇;
2-氨基-2-{2-[4-{[5-(4-氟苯基)戊基]氧基}-3-(2-呋喃基)苯基]乙基}丙-1,3-二醇;
2-氨基-2-(2-{3-(3-呋喃基)-4-[(5-苯基戊基)氧基]苯基}乙基)丙-1,3-二醇;
2-氨基-2-(2-{4-[(5-苯基戊基)氧基]-3-(3-噻吩基)苯基}乙基)丙-1,3-二醇;
2-氨基-2-(2-{6-(2-呋喃基)-5-[(5-苯基戊基)氧基]吡啶-2-基}乙基)丙-1,3-二醇;
2-氨基-2-(4-{3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-1H-咪唑-2-基)乙基二氢磷酸酯;
2-氨基-2-(4-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}-1H-咪唑-2-基)乙基二氢磷酸酯;
2-氨基-2-(4-{3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-1H-咪唑-2-基)乙基二氢磷酸酯;
2-氨基-2-{4-[4-{[5-(4-氟苯基)戊基]氧基}-3-(2-呋喃基)苯基]-1H-咪唑-2-基}乙基二氢磷酸酯;
2-氨基-2-(4-{3-(3-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-1H-咪唑-2-基)乙基二氢磷酸酯;
2-氨基-2-(4-{4-[(5-苯基戊基)氧基]-3-(3-噻吩基)苯基}-1H-咪唑-2-基)乙基二氢磷酸酯;
2-氨基-2-(4-{6-(2-呋喃基)-5-[(5-苯基戊基)氧基]吡啶-2-基}-1H-咪唑-2-基)乙基二氢磷酸酯;
2-氨基-2-(4-{3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-1H-咪唑-2-基)乙醇;
2-氨基-2-(4-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}-1H-咪唑-2-基)乙醇;
2-氨基-2-(4-{3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-1H-咪唑-2-基)乙醇;
2-氨基-2-{4-[4-{[5-(4-氟苯基)戊基]氧基}-3-(2-呋喃基)苯基]-1H-咪唑-2-基}乙醇;
2-氨基-2-(4-{3-(3-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-1H-咪唑-2-基)乙醇;
2-氨基-2-(4-{4-[(5-苯基戊基)氧基]-3-(3-噻吩基)苯基}-1H-咪唑-2-基)乙醇;
2-氨基-2-(4-{6-(2-呋喃基)-5-[(5-苯基戊基)氧基]吡啶-2-基}-1H-咪唑-2-基)乙醇。
式I的一些化合物及其一些中间体在其结构中具有至少一个立体中心。该立体中心可呈R或S构型存在,根据Pure Appli.Chem.(1976),45,11-13中描述的规则使用所述R和S符号。
术语“药学上可接受的盐”指维持以上鉴定的化合物的所需生物活性并表现出最低限度或无有害毒理效应的盐或复合物。根据本发明所述的“药学上可接受的盐”包括式I化合物能够形成的治疗活性、无毒碱或酸式盐形式。
可通过用适当酸,例如无机酸(例如,氢卤酸(例如盐酸、氢溴酸、硫酸、磷酸、硝酸等));或有机酸,例如乙酸、羟基乙酸、丙酸、乳酸、丙酮酸、丙二酸、延胡索酸、马来酸、草酸、酒石酸、琥珀酸、苹果酸、抗坏血酸、苯甲酸、鞣酸、扑酸、柠檬酸、甲基磺酸、乙磺酸、苯磺酸、甲酸等处理游离碱获得呈其游离形式,以碱的形式出现的式I化合物的酸加成盐形式(Handbook of Pharmaceutical Salts,P.Heinrich Stahal& Camille G.Wermuth(Eds),Verlag Helvetica ChemicaActa-Zürich,2002,329-345)。
式I化合物及其盐可呈溶剂化物形式,其包括在本发明的范围内。此类溶剂化物包括(例如)水合物、醇化物等。
关于本发明,除非特别提到特殊异构形式,提到化合物旨在涵盖呈其每一种可能异构形式的化合物及其混合物。根据本发明所述的化合物可呈不同多晶形式存在。虽然在上式中未明确指出,旨在将此类形式包括在本发明的范围内。
指示本发明的化合物用于治疗或预防其中很可能存在牵涉1-磷酸鞘氨醇受体的组分的病状。
在另一实施方案中,提供了在药学上可接受的载体中包括至少一种本发明化合物的药物组合物。
在本发明的又一实施方案中,提供了治疗与1-磷酸鞘氨醇受体调节相关的病症的方法。例如,可通过向有需要的受试者施用含有治疗有效量的至少一种本发明化合物的药物组合物进行此类方法。
这些化合物对具有通过S1P调节减轻的一系列病状和疾病的哺乳动物(包括人)的治疗有用:不限于糖尿病性视网膜病、其它视网膜退行性病状、干眼病、血管发生和创伤的治疗。
S1P调节剂的疗效为眼病,例如但不限于:湿性和干性老年黄斑变性、糖尿病性视网膜病、早产儿视网膜病变、视网膜水肿、地图样萎缩、青光眼视神经损害、脉络膜视网膜病变、高血压性视网膜病、眼部缺血综合征,预防眼睛后部炎症诱导的纤维化、各种眼部炎症疾病,包括葡萄膜炎、巩膜炎、角膜炎和视网膜血管炎;或全身血管屏障相关疾病,例如但不限于:各种炎症性疾病,包括急性肺损伤、其预防,脓毒症、肿瘤转移、动脉粥样硬化、肺水肿和呼吸所致肺损伤;或自身免疫性疾病和免疫抑制,例如但不限于:类风湿性关节炎、克罗恩病(Crohn’s disease)、格雷夫斯病(Graves’disease)、炎症性肠病、多发性硬化、重症肌无力、牛皮癣、溃疡性结肠炎、自身免疫性葡萄膜炎、肾缺血/灌注损伤、接触性超敏反应、过敏性皮炎和器官移植;或变态反应和其它炎症性疾病,例如但不限于:荨麻疹、支气管哮喘和其它气道炎症,包括肺气肿和慢性阻塞性肺病;或心脏保护,例如但不限于:缺血再灌注损伤和动脉粥样硬化;或创伤,例如但不限于:来自整容皮肤手术、眼科手术、胃肠手术、普通手术、口腔损伤、各种机械、热和烧伤的创伤的无疤痕愈合,预防和治疗光老化和皮肤老化,和预防辐射造成的损伤;或骨形成,例如但不限于:治疗骨质疏松症和各种骨折,包括臀部和脚踝;或抗伤害性活动,例如但不限于:内脏痛、与糖尿病性神经病、风湿性关节炎相关的疼痛、慢性膝盖和关节痛、肌腱炎、骨关节炎、神经性疼痛;或阿尔茨海默病(Alzheimer’sdisease)、老年性神经损伤中的中枢神经系统神经元活动;或在气管移植,例如肾脏、角膜、心脏或脂肪组织移植中的中枢神经系统神经元活动;炎症性皮肤病、硬皮病、皮肌炎、特应性皮炎、红斑狼疮、大疱性表皮松解和大疱性类天疱疮。局部使用S1P(鞘氨醇)化合物在各种痤疮性疾病、寻常痤疮和酒渣鼻的治疗中有用。
在本发明的再一实施方案中,提供了治疗与1-磷酸鞘氨醇受体调节相关的病症的方法。例如,可通过向有需要的受试者施用治疗有效量的至少一种本发明化合物或其组合或其药学上可接受的盐、水合物、溶剂化物、晶体形式和单独异构体、对映异构体和非对映异构体进行此类方法。
本发明涉及使用式I化合物或其药学上可接受的盐生产药剂以治疗眼病、湿性和干性老年黄斑变性、糖尿病性视网膜病、早产儿视网膜病变、视网膜水肿、地图样萎缩、青光眼视神经损害、脉络膜视网膜病变、高血压性视网膜病、眼部缺血综合征,预防眼睛后部炎症所致纤维化、各种眼部炎症疾病,包括葡萄膜炎、巩膜炎、角膜炎和视网膜血管炎;或全身血管屏障相关疾病,各种炎症性疾病,包括急性肺损伤、其预防,脓毒症、肿瘤转移、动脉粥样硬化、肺水肿和呼吸所致肺损伤;或自身免疫性疾病和免疫抑制、类风湿性关节炎、克罗恩病、格雷夫斯病、炎症性肠病、多发性硬化、重症肌无力、牛皮癣、溃疡性结肠炎、自身免疫性葡萄膜炎、肾缺血/灌注损伤、接触性超敏反应、过敏性皮炎和器官移植;或变态反应和其它炎症性疾病,荨麻疹、支气管哮喘和其它气道炎症,包括肺气肿和慢性阻塞性肺病;或心脏保护,缺血再灌注损伤和动脉粥样硬化;或创伤愈合,来自整容皮肤手术、眼科手术、胃肠手术、普通手术、口腔损伤、各种机械、热和烧伤的创伤的无疤痕愈合,预防和治疗光老化和皮肤老化,和预防辐射造成的损伤;或骨形成,治疗骨质疏松症和各种骨折,包括臀部和脚踝;或抗伤害性活动,内脏痛、与糖尿病性神经病、风湿性关节炎相关的疼痛、慢性膝盖和关节痛、肌腱炎、骨关节炎、神经性疼痛;或阿尔茨海默病、老年性神经损伤中的中枢神经系统神经元活动;或在气管移植,例如肾脏、角膜、心脏或脂肪组织移植中的中枢神经系统神经元活动;炎症性皮肤病、硬皮病、皮肌炎、特应性皮炎、红斑狼疮、大疱性表皮松解和大疱性类天疱疮。
在任何指定情况下,待施用的化合物的实际量将由医师考虑到相关情况确定,例如病状的严重程度、患者的年龄和体重、患者的总体身体状况、病状的原因和施用途径。
患者将口服呈任何可接受的形式的化合物,例如片剂、液体、胶囊、粉剂等,或尤其如果患者感到恶心时,其它途径可取或必需。此类其它途径可包括(没有例外)经皮、肠胃外、皮下、鼻内、经由植入支架、鞘内、玻璃体内、向眼部、眼后部局部递送、肌肉、静脉和直肠递送模式。另外,可将制剂设计成在指定时间段延迟释放活性化合物,或谨慎控制在治疗过程中的指定时间释放的药物的量。
在本发明的另一实施方案中,提供了在其药学上可接受的载体中包括至少一种本发明化合物的药物组合物。短语“药学上可接受”指载体、稀释剂或赋形剂必须与制剂的其它成分相容并且对其受体无毒。
可使用呈固体、溶液、乳液、分散物、贴片、微胶粒、脂质体等形式的本发明药物组合物,其中所得组合物在与适合肠内或肠胃外应用的有机或无机载体或赋形剂的混合物中含有一种或多种作为活性成分的本发明化合物。对于片剂、颗粒剂、胶囊剂、栓剂、溶液剂、乳剂、混悬剂和适合使用的任何其它形式,发明化合物可与(例如)通常无毒的药学上可接受的载体合并。可用的载体包括葡萄糖、乳糖、阿拉伯树胶、明胶、甘露糖醇、淀粉糊、三硅酸镁、滑石、玉米淀粉、角蛋白、硅胶、马铃薯淀粉、尿素、中等链长甘油三酯、葡聚糖和其它适合用于生产呈固体、半固体或液体形式的制剂的载体。另外,可使用助剂、稳定剂、增稠剂和着色剂及香料。在药物组合物中包括足以对过程或病情产生所需作用的量的发明化合物。
含发明化合物的药物组合物可呈适合口服使用的形式,例如片剂、锭剂、糖锭、水或油混悬剂、可分散性粉剂或颗粒剂、乳剂、硬或软胶囊剂或糖浆剂或酏剂。可根据本领域中已知的生产药物组合物的方法制备旨在口服使用的组合物并且此类组合物可含有一种或多种选自甜味剂(例如蔗糖、乳糖或糖精)、调味剂(例如薄荷、冬青油或樱桃)、着色剂和防腐剂的试剂以便提供药学上一流的美味制剂。也可通过已知方法生产含有与药学上可接受的无毒赋形剂混合的发明化合物的片剂。所用赋形剂可为(例如)(1)惰性稀释剂,例如碳酸钙、乳糖、磷酸钙或磷酸钠;(2)成粒剂和崩解剂,例如玉米淀粉、马铃薯淀粉或褐藻酸;(3)粘合剂,例如黄蓍胶、玉米淀粉、明胶或阿拉伯树胶,和(4)润滑剂,例如硬脂酸镁、硬脂酸或滑石。片剂可无包衣或可通过已知技术涂包衣以延迟在胃肠道内的分解和吸收,从而在更长时间内提供持续作用。例如,可采用延时物质,例如单硬脂酸甘油酯或二硬脂酸甘油酯。
在一些情况下,供口服使用的制剂可呈硬明胶胶囊形式,其中发明化合物与惰性固体稀释剂(例如碳酸钙、磷酸钙或高岭土)混合。供口服使用的制剂也可呈软明胶胶囊形式,其中发明化合物与水或油介质(例如花生油、液体石蜡或橄榄油)混合。
药物组合物可呈无菌注射悬浮液形式。可根据已知方法,使用适合分散剂或湿润剂和助悬剂配制该悬浮液。无菌注射制剂也可为于肠胃外可接受的无毒稀释剂或溶剂中的无菌注射溶液或悬浮液,例如于1,3-丁二醇中的溶液。按照惯例采用无菌不挥发性油作为溶剂或悬浮介质。为了这个目的,可采用任何无味的不挥发性油,包括合成的甘油单酯或甘油二酯、脂肪酸(包括油酸)、天然植物油(如芝麻油、椰子油、花生油、棉籽油等)或合成脂肪媒介物(如油酸乙酯等)。可根据需要并入缓冲液、防腐剂、抗氧化剂等。
发明化合物也可呈栓剂形式施用,以直肠施用药物。可通过使发明化合物与适合的非刺激性赋形剂(例如在常温下为固体的可可油、合成的聚乙二醇甘油酯)混合制备这些组合物,但是在直肠腔内液化和/或溶解以释放药物。
因为个别受试者的症状严重程度可能存在很大变化并且每种药物具有其独特的治疗特征,所以对每位受试者采用的精确施用模式和剂量交给医师决定。
本文描述的化合物和药物组合物作为药剂,在哺乳动物(包括人)中,用于治疗对用1-磷酸鞘氨醇激动剂或功能拮抗剂治疗做出反应的疾病和/或减轻病状。因此,在本发明的又一实施方案中,提供了治疗与1-磷酸鞘氨醇受体调节相关的病症的方法。例如,可通过向有需要的受试者施用含有治疗有效量的至少一种本发明化合物的药物组合物进行此类方法。如本文所使用,术语“治疗有效量”指研究人员、兽医、医学博士或其它临床医师正在寻找的会引起有需要的受试者的生物或医学反应的药物组合物的量。在一些实施方案中,有需要的受试者为哺乳动物。在一些实施方案中,哺乳动物为人。
本发明还涉及制备式I化合物的工艺。可如有机合成化学领域中技术人员所理解的那样,类似于常规方法制备根据本发明所述的式I化合物。以下提出的合成方案说明了可如何制备根据本发明所述的化合物。本领域的技术人员将能够常规性地修改和/或使下列方案适合于合成式I所涉的本发明任何化合物。
在方案I中,芳胺或芳胺衍生物或前体与功能化合物(例如卤化或羟基化化合物)在如合成化学家所知促进烷基化的试剂存在下反应,以产生相应的醚中间体。这种来自最后一个步骤的中间体与通常牵涉金属催化剂的硼酸或锡酸盐在适当条件下经R2基团偶联以产生相应的中间体。根据下一步骤的需要,可通过去保护或还原法将来自偶联过程的先前中间体转化为芳胺。来自前一步骤的中间体在可采用羧酸等产生式I中间体的条件下反应形成酰胺。这种来自最后一个步骤的中间体与适当试剂反应以促进磷酸化并且在去除需要的所有保护基后产生作为本发明化合物的式I衍生物。
方案I
在方案II中,可能含有卤素(例如溴原子)的芳胺/胺前体与功能化合物(例如卤化或羟基化化合物),在如合成化学家众所周知促进烷基化的试剂存在下反应,以产生相应的醚中间体。这种来自最后一个步骤的中间体与通常牵涉金属催化剂的硼酸或锡酸盐在适当条件下经R2基团(如以下2-呋喃基衍生物所示)偶联以产生相应的中间体。根据下一步骤的需要,可通过去保护或还原法将来自前一步骤的中间体转化为芳胺。这种来自最后一个步骤的芳胺在可采用羧酸等产生式I中间体的条件下反应形成酰胺。这种中间体与适当试剂反应以促进磷酸化并且在去除需要的所有保护基后产生作为本发明化合物的式I衍生物。
方案II
在方案III中,根据适当合成制剂的应用获得详细阐述的芳基溴,可在促进烷基化的试剂存在下与化合物反应。这种来自最后一个步骤的中间体含R3基团(表示-O-、-S-、-NH-、-CH2-)或其它基团与硼酸或锡酸盐在适当条件下经R2基团偶联以产生相应的中间体。这种来自前一步骤的中间体与适当试剂反应以促进磷酸化并且在去除需要的所有保护基后产生作为本发明化合物的式I衍生物。
方案III
附图简述
图1描绘了用化合物4处理24h后淋巴细胞计数减少(<1淋巴细胞数量103个/μL血液)。
发明详述
应理解,前述总体描述和下列详述仅为示例性和说明性并不限制要求的本发明。如本文所使用,除非另有特别说明,单数的使用包括复数。
对于本领域技术人员而言显而易见的是,本发明的一些化合物可能含有一个或多个不对称中心,以致化合物可能以对映异构体以及非对映异构体形式存在。除非另外特别注明,本发明的范围包括所有对映异构体、非对映异构体和外消旋混合物。本发明的一些化合物可与药学上可接受的酸或碱形成盐,并且本文所述化合物的药学上可接受的盐也在本发明的范围之内。
本发明包括所有药学上可接受的同位素富集化合物。本发明的任何化合物可能含有一种或多种富集或不同于自然比例的同位素原子,例如氘2H(或D)代替氕1H(或H)或使用13C富集物质代替12C等。对于N、O和S可采用类似取代。使用同位素可协助本发明的分析以及治疗方面。例如,使用氘可通过改变本发明化合物的代谢(率)增加体内半衰期。可与描述的制剂一致,使用同位素富集试剂制备这些化合物。
下列实施例仅仅是为了说明的目的并非旨在,也不得将其视为以任何方式限制本发明。本领域的技术人员将认识到,在不超出本发明精神和范围的前提下可对下列实施例进行改变和修改。
正如本领域技术人员所显而易见,可通过以常规方式分离其混合物获得单独的异构体形式。例如,在非对映异构体的情况下,可采用色谱分离。
用第8版ACD生成化合物名称,并且用例如来自MDL ISIS Draw2.5SP1或来自商业供应商目录(例如Sigma-Aldrich)的Chem Bio DrawUltra 12.0版或Auto Nom2000等软件生成实施例中使用的一些中间体和试剂的名称。
一般而言,使用在300和/或600MHz Varian上记录并且在室温下获得的NMR波谱进行化合物的表征。参考内部TMS或溶剂信号按ppm给出化学位移。按Hz,赫兹报道偶联常数J。
未描述合成的所有试剂、溶剂、催化剂均从化学品卖方购买,例如Sigma Aldrich、Fluka、Bio-Blocks、Combi-blocks、TCI、VWR、Lancaster、Oakwood、Trans World Chemical、Alfa、Fisher、Maybridge、Frontier、Matrix、Ukrorgsynth、Toronto、Ryan Scientific、SiliCycle、Anaspec、Syn Chem、Chem-Impex、MIC-scientific,Ltd;然而一些已知中间体根据公开程序制备。
通常除非另外注明,通过柱色谱法(自动柱(Auto-column)),在Teledyne-ISCO CombiFlash上用硅胶柱纯化本发明的化合物。
在实施例中使用了下列缩写:
s、m、h、d 秒、分钟、小时、天
CH3CN 乙腈
PSI 磅/平方英寸
DCM 二氯甲烷
DMF N,N-二甲基甲酰胺
NaOH 氢氧化钠
MeOH 甲醇
CD3OD 氘化甲醇
NH3 氨
HCl 盐酸
Na2SO4 硫酸钠
RT或rt 室温
MgSO4 硫酸镁
EtOAc 乙酸乙酯
CDCl3 氘代氯仿
DMSO-d6 氘代二甲亚砜
Auto-column 自动闪烁液相色谱法
TFA 三氟乙酸
THF 四氢呋喃
M 摩尔
PdCl2(PPh3)2 双(三苯基膦)氯化钯(II)
AcOH 乙酸
K2CO3 碳酸钾
NaCl 氯化钠
CHCl3 氯仿
HATU (O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸盐)
本领域的技术人员将能够常规性地修改和/或使下列程序适合于合成式I所涉的本发明任何化合物。
实施例1
中间体1
2-溴代-4-硝基-1-((5-苯基戊基)氧基)苯
将2-溴代-4-硝基苯酚(CAS 5847-59-6)(2.05g,9.4mmol)、(5-溴戊基)苯(CAS 14469-83-1)(2.41g,10.6mmol)和K2CO3(3.5g,19.1mmol)的混合物溶于DMF(20mL)中。在100℃下加热反应混合物~18h。用己烷∶EtOAc(1∶1)(~200mL)稀释混合物并且用H2O(3×)洗涤。在MgSO4上干燥有机溶液,过滤并且在真空下浓缩至硅胶上。自动柱(Auto-column)(9.5己烷∶0.5EtOAc)产生呈白色固体的1.91g(56%)中间体1。
实施例2
中间体2
2-[5-硝基-2-(5-苯基-戊氧基)-苯基]-噻吩
使中间体1(1.91g,5.25mmol)、三丁基-噻吩-2-基-锡烷(CAS54663-78-4)(3.4mL,10.7mmol)和PdCl2(PPh3)2(0.55g,15mol%)于DMF(12mL)中的混合物在MWI下,在160℃下反应15m。使混合物冷却至室温并且用己烷∶EtOAc(1∶1,200mL)稀释。用水(3×)洗涤混合物,在MgSO4上干燥,过滤并且在真空下浓缩至硅胶上。自动柱(9.5己烷∶0.5EtOAc)产生呈橙色固体的1.10g(57%)中间体2。
实施例3
中间体3
4-(5-苯基-戊氧基)-3-噻吩-2-基-苯胺
加热铁屑(0.62g,11.1mmol)、NH4Cl(0.88g,16.4mmol)、水(3.3mL)和乙醇(10mL)的混合物至回流达15m。将该混合物转移至中间体2(1.0g,2.72mmol)于EtOH(8mL)中的溶液中。加热所得混合物至回流达5h。过滤混合物,用EtOAc洗涤并且在EtOAc和水之间分配。在MgSO4上干燥有机层,过滤并且浓缩至硅胶上。自动柱(7己烷∶3EtOAc)产生呈棕褐色固体的0.55g(60%)中间体3。
实施例4
中间体4
(R)-(3-羟基-2-甲基-1-氧代-1-((4-((5-苯基戊基)氧基)-3-(噻吩-2-基)苯基)氨基)丙-2-基)氨基甲酸叔丁酯
使于DMF(20mL)中的中间体3(0.30g,0.89mmol)、Boc-D-丝氨酸(CAS84311-18-2)(0.25g,1.11mmol)、HATU(CAS148893-10-1)(0.51g,1.34mmol)、二异丙基乙胺(CAS7087-68-5)(0.46mL)在室温下反应~18h。水后处理和用(己烷∶EtOAc)萃取后,合并有机层并浓缩至硅胶上。自动柱(3%MeOH于CH2Cl2中)产生0.28g(58%)中间体4。
实施例5
中间体5
2-氨基-2-甲基-3-氧代-3-({4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}氨基)丙基二氢磷酸酯
在室温下搅拌于DMF(5mL)中的中间体4(0.28g,5.20mmol)、四唑(7.0mL,3.15mmol;0.45M于CH3CN中)和二叔丁基二异丙基-亚磷酰胺(0.65mL,2.06mmol)达~18h。在0℃下添加过量过氧化氢35%(0.19mL,2.2mmol)并且使混合物升温至室温并搅拌1h。在真空下去除溶剂并且用饱和Na2S2O3(10%水溶液)淬灭并且用EtOAc萃取。在MgSO4上干燥有机层,过滤,在真空下浓缩至硅胶上。自动柱(6己烷∶4EtOAc)产生呈白色固体的0.27g(71%)中间体5。
实施例6
化合物1
(2R)-2-氨基-2-甲基-3-氧代-3-({4-[(5-苯基戊基)氧基]-3-(2-噻吩基)
苯基}氨基)丙基二氢磷酸酯
使中间体5溶于CH2Cl2中并且使其于二噁烷中与HCl反应。使混合物在室温下反应~18h。在真空下去除溶剂并且用乙醚研磨几次以产生呈固体的~160mg化合物1。
(300MHz,CD3OD):δ7.89(d,J=2.4,1H),7.50-7.44(m,2H),7.37(d,J=5.4,1H),7.26-7.21(m,2H),7.17-7.13(m,3H),7.06-7.00(m,2H),4.42(dd,J=5.1,11.4,1H),4.20(dd,J=4.8,11.7,1H),4.08(t,J=6.3,2H),2.63(t,J=7.2,2H),1.91-1.84(m,2H),1.74-1.65(m,2H),1.68(s,3H),1.62-1.53(m,2H)。
以类似于对化合物1描述的程序的方式由相应原材料制备化合物2。以下在表1中把结果制成了表格。
表1
实施例7
中间体7
2-(2-(苄氧基)-5-硝基苯基呋喃
以类似于实施例2中对中间体2描述的程序的方式由中间体1和三丁基-2-呋喃基-锡烷制备中间体7。
实施例8
中间体8
3-呋喃-2-基-4-(5-苯基-戊氧基)-苯胺
以类似于实施例3中对中间体3描述的程序的方式由中间体7制备中间体8。
实施例9
中间体9
{(S)-1-[3-呋喃-2-基-4-(5-苯基-戊氧基)-苯基氨甲酰基]-2-羟基-乙基}-氨基甲酸苄酯
使于DMF(30mL)中的中间体8(0.98g,3.05mmol)、N-苄氧羰基-L-丝氨酸(0.82g,3.36mmol)、HATU(2.0g,5.1mmol)和二异丙基乙胺(1.8mL,10.3mmol)在室温下反应~18h。自动柱(6己烷∶4EtOAc)产生呈黄色固体的1.32g(80%)粗中间体9。
实施例10
中间体10
[2-({3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}氨基)-1-{[(3-氧化-1,5-二氢-2,4,3-苯并二噁磷环庚烷-3-基)氧基]甲基}-2-氧代乙基]氨基甲酸苄酯
在室温下将于THF(25mL)中的中间体9(1.32g,2.43mmol)、四唑(16.2mL,7.29mmol;0.45M于CH3CN中)和3-(二乙基氨基)-1,5-二氢-2,4,3-二噁磷环庚烷(CAS82372-35-8)(0.88mL,3.67mmol)搅拌达~24h。添加过量过氧化氢35%(4.7mL,54.6mmol)并且搅拌混合物达1h。在真空下去除溶剂并且用饱和Na2S2O3淬灭并且用EtOAc萃取。在MgSO4上干燥有机层。自动柱(5己烷∶5EtOAc)产生呈黄色油状物的~0.86g中间体10。
实施例11
化合物3
(2S)-2-氨基-3-({3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}氨基)-3-氧代丙基二氢磷酸酯
用10%钯碳(0.30g)和50psi的氢处理中间体10(0.86g,1.19mmol)达3h。通过硅藻土过滤混合物。将滤液浓缩至硅胶上并且用自动柱(梯度0→100%MeOH于CH2Cl2中)纯化以产生呈固体的~50mg化合物3。
(300MHz,DMSO-d6)δ:8.10(d,J=2.7,1H),7.70(s,1H),7.47(dd,J=2.1,8.7,1H),7.27-7.14(m,6H),6.99(d,J=8.7,1H),6.85(d,J=3.0,1H),6.54(dd,J=1.8,3.6,1H),4.02(t,J=6.3,2H),3.98-3.90(m,3H),2.58(t,J=7.5,2H),1.84-1.78(m,2H),1.67-1.62(m,2H),1.52-1.44(m,2H)。
由中间体3和如同对中间体10的制备和实施例11中对化合物3描述的相应程序制备化合物4。以下在表2中把结果制成了表格。
表2
生物学实施例
体外测定
使用GTPγ35S结合测定测试化合物的S1P1活性。可估计这些化合物活化或阻滞活化稳定表达S1P1受体的细胞中的人S1P1受体的能力。
在150μl体积中含有(mM)HEPES25(pH7.4)、MgCl210、NaCl100、二硫苏糖醇0.5、毛地黄皂苷0.003%、0.2nM GTPγ35S和5μg膜蛋白的培养基中测量GTpγ35S结合。除非另外指出,包括浓度范围从0.08至5,000nM的试验化合物。用100μM5’-腺苷亚氨基二磷酸温育膜30min,随后于冰上用10μM GDP温育10min。混合药溶液和膜,然后通过添加GTPγ35S开始反应并且在25℃持续30min。在真空下在WhatmanGF/B过滤器上过滤反应混合物,并且用3mL冰冷缓冲液(HEPES25(pH7.4)、MgCl210和NaCl100)洗涤3次。干燥过滤器并且混合闪烁材料,并且使用β-计数器计数35S活性。通过减去无激动剂时的GTPγ35S结合得到激动剂诱导的GTPγ35S结合。使用非线性回归方法分析结合数据。在拮抗剂测定的情况下,在浓度范围从0.08至5,000nM的测试拮抗剂存在下,反应混合物含有10nM S1P。
活性效能:来自GTPγ35S的S1P1受体:nM,(EC50),
表3
对小鼠的淋巴细胞减少测定
于含有3%(w/v)2-羟丙基β-环式糊精(HPBCD)和1%DMSO的溶液中制备最终浓度为1mg/ml的试验药物,随后按10mg/Kg的剂量注射至20-25g重的雌性C57BL6小鼠(CHARLES RIVERS)。通过在用药后24、48、72和96h用Goldenrod动物柳叶刀刺穿下颌下皮肤获得血样。将血液收集至装有EDTA三钾盐的微量试管(SARSTEDT)中。使用HEMAVET多物种血液系统,HEMAVET HV950FS(DrewScientific Inc.)为血样中的淋巴细胞计数。(Hale,J.等人,Bioorg.& Med.Chem.Lett.14(2004)3351)。
如前所述,采用对小鼠的淋巴细胞减少测定测量服用(2S)-2-氨基-3-氧代-3-({4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}氨基)丙基二氢磷酸酯后体内血液淋巴细胞削减。这种S1P1激动剂对S1P相关疾病有用并且由体内淋巴细胞减少反应所例证。于含有3%(w/v)2-羟丙基β-环式糊精(HPBCD)和1%DMSO的溶液中制备最终浓度为1mg/ml的试验药物(2S)-2-氨基-3-氧代-3-({4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}氨基)丙基二氢磷酸酯,随后按10mg/Kg的剂量注射至20-25g重的雌性C57BL6小鼠(CHARLES RIVERS)。通过在不同时间间隔(例如:用药后24、48、72和96h)用Goldenrod动物柳叶刀刺穿下颌下皮肤获得血样。将血液收集至装有EDTA三钾盐的微量试管(SARSTEDT)中。使用HEMAVET多物种血液系统,HEMAVETHV950FS(Drew Scientific Inc.)为血样中的淋巴细胞计数。在绘有24h后淋巴细胞计数减少(1淋巴细胞数量<103个/μL血液)的图1中示出了结果。
Claims (17)
1.一种具有式I的化合物、其对映异构体、非对映异构体、水合物、溶剂、晶体形式及其单独异构体、互变异构体或药学上可接受的盐
式I
其中:
R1为N或C-R9;
R2为经取代或未经取代的杂环、C5-8环烯基或C6-10芳基;
R3为O、N-R10、CH-R11、S、-CR12=CR13-、-C≡C-或-C(O)-;
R4为H、C5-8环烯基、C3-8环烷基或经取代或未经取代的C6-10芳基;
R5为H、卤素、-OC1-3烷基、C1-3烷基或羟基;
R6为H、卤素、-OC1-3烷基、C1-3烷基或羟基;
a为0、1、2、3或4;
b为0、1、2、3或4;
L为CHR7、O、S、NR8或-C(O)-;
R7为H、C1-3烷基、-OC1-3烷基、卤素、羟基或NR9R10;
R8为H或C1-3烷基;
R9为H、卤素或C1-3烷基;
R10为H或C1-3烷基;
R11为H或C1-3烷基;
R12为H或C1-3烷基;
R13为H或C1-3烷基;
Q1为-CR14R15-;
R14为H、卤素或C1-3烷基;
R15为H、卤素或C1-3烷基;
m为0、1、2或3;
“*”表示与分子其余部分的连接点;
R18为NR9、O或S;
条件是R3为O、N-R10、S、-CR12=CR13-、-C≡C-或-C(O)-并且b为0或1时,则L不为O、S、NR8或-C(O)-。
2.根据权利要求1所述的化合物,其中:
R2选自:呋喃、2-呋喃基和3-呋喃基衍生物;噻吩、2-噻吩基和3-噻吩基衍生物;吡咯、噁唑、噻唑、吡咯烷、吡咯啉、咪唑、吡唑、吡唑啉,异噁唑、异噻唑、吡唑烷、咪唑啉、噻唑啉、噁唑啉、二氢噻吩、二氢呋喃、四唑、三唑、噁二唑、1,2,5-噁二唑、噻二唑、1,2,3-三唑、1,2,4-三唑、吡咯烷酮、吡咯-2(3H)-酮、咪唑烷-2-酮和1,2,4-三唑-5(4H)。
3.根据权利要求1所述的化合物,其中:
R4是经选自以下的基团邻位、间位和对位取代的苯基:
氟代、氯代和溴代;
短链烷基:甲基、乙基、丙基、异丙基等;
甲氧基、三氟甲氧基、三氟甲基和全氟化短链烷基。
4.根据权利要求1所述的化合物,其中:
R3为O。
5.根据权利要求1所述的化合物,其中:
R1为N。
6.根据权利要求1所述的化合物,其中:
R1为C-R9;
R2为经取代或未经取代的杂环、C5-8环烯基或C6-10芳基;
R3为O、N-R10、CH-R11、S、-CR12=CR13-、-C≡C-或-C(O)-;
R4为H、C5-8环烯基、C3-8环烷基或经取代或未经取代的C6-10芳基;
R5为H、卤素、-OC1-3烷基、C1-3烷基或羟基;
R6为H、卤素、-OC1-3烷基、C1-3烷基或羟基;
a为0、1、2、3或4;
b为0、1、2、3或4;
L为CHR7、O、S、NR8或-C(O)-;
R7为H、C1-3烷基、-OC1-3烷基、卤素、羟基或NR9R10;
R8为H或C1-3烷基;
R9为H、卤素或C1-3烷基;
R10为H或C1-3烷基;
R11为H或C1-3烷基;
R12为H或C1-3烷基;
R13为H或C1-3烷基;
Q1为-CR14R15-;
R14为H、卤素或C1-3烷基;
R15为H、卤素或C1-3烷基;
m为0、1、2或3;
T为-NH-Q2、
“*”表示与分子其余部分的连接点;
R18为NR9、O或S;
条件是R3为O、N-R10、S、-CR12=CR13-、-C≡C-或-C(O)-并且b为0或1时,则L不为O、S、NR8或-C(O)-。
11.根据权利要求6所述的化合物,其中:
R1为C-R9;
R2为经取代或未经取代的杂环;
R3为O;
R4为经取代或未经取代的苯基;
R5为H或F;
R6为H或F;
a为2;
b为2;
L为CHR7;
R7为H;
R9为H;
m为0;
T为-NH-Q2,
“*”表示与分子其余部分的连接点;
Q2相同或独立地为-OPO3H2、羧酸、-PO3H2、-C1-6烷基、H、-S(O)2OH、-P(O)MeOH、-P(O)(H)OH、-OH
13.根据权利要求6所述的化合物,其中:
R1为C-R9;
R2为经取代或未经取代的杂环;
R3为O;
R4为经取代或未经取代的苯基;
R5为H或F;
R6为H或F;
a为2;
b为2;
L为CHR7;
R7为H;
R9为H;
m为0;
T为-NH-Q2,
“*”表示与分子其余部分的连接点;
Q2相同或独立地为-OPO3H2、羧酸、-PO3H2、-C1-6烷基、H、-S(O)2OH、-P(O)MeOH、-P(O)(H)OH、-OH
15.根据权利要求1所述的化合物,选自以下:
(2R)-2-氨基-2-甲基-3-氧代-3-({4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}氨基)丙基二氢磷酸酯;
(2S)-2-氨基-2-甲基-3-氧代-3-({4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}氨基)丙基二氢磷酸酯;
2-氨基-3-羟基-2-甲基-N-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}丙酰胺;
2-氨基-3-羟基-2-甲基-N-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}丙酰胺;
(2S)-2-氨基-3-({3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}氨基)-3-氧代丙基二氢磷酸酯;
(2S)-2-氨基-3-氧代-3-({4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}氨基)丙基二氢磷酸酯;
2-氨基-N-{3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-3-羟基丙酰胺;
2-氨基-3-羟基-N-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}丙酰胺;
2-氨基-3-({3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}氨基)-3-氧代丙基二氢磷酸酯;
2-氨基-3-{[4-{[5-(4-氟苯基)戊基]氧基}-3-(2-呋喃基)苯基]氨基}-3-氧代丙基二氢磷酸酯;
2-氨基-3-({3-(3-呋喃基)-4-[(5-苯基戊基)氧基]苯基}氨基)-3-氧代丙基二氢磷酸酯;
2-氨基-3-氧代-3-({4-[(5-苯基戊基)氧基]-3-(3-噻吩基)苯基}氨基)丙基二氢磷酸酯;
2-氨基-3-({6-(2-呋喃基)-5-[(5-苯基戊基)氧基]吡啶-2-基}氨基)-3-氧代丙基二氢磷酸酯;
2-氨基-N-{3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-3-羟基丙酰胺;
2-氨基-N-{3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-3-羟基丙酰胺;
2-氨基-N-{3-(3-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-3-羟基丙酰胺;
2-氨基-3-羟基-N-{4-[(5-苯基戊基)氧基]-3-(3-噻吩基)苯基}丙酰胺;
2-氨基-N-{6-(2-呋喃基)-5-[(5-苯基戊基)氧基]吡啶-2-基}-3-羟基丙酰胺;
2-氨基-4-{3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-2-(羟基甲基)丁基二氢磷酸酯;
2-氨基-2-(羟基甲基)-4-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}丁基二氢磷酸酯;
2-氨基-4-{3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-2-(羟基甲基)丁基二氢磷酸酯;
2-氨基-4-[4-{[5-(4-氟苯基)戊基]氧基}-3-(2-呋喃基)苯基]-2-(羟基甲基)丁基二氢磷酸酯;
2-氨基-4-{3-(3-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-2-(羟基甲基)丁基二氢磷酸酯;
2-氨基-2-(羟基甲基)-4-{4-[(5-苯基戊基)氧基]-3-(3-噻吩基)苯基}丁基二氢磷酸酯;
2-氨基-4-{6-(2-呋喃基)-5-[(5-苯基戊基)氧基]吡啶-2-基}-2-(羟基甲基)丁基二氢磷酸酯;
2-氨基-2-(2-{3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}乙基)丙-1,3-二醇;
2-氨基-2-(2-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}乙基)丙-1,3-二醇;
2-氨基-2-(2-{3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}乙基)丙-1,3-二醇;
2-氨基-2-{2-[4-{[5-(4-氟苯基)戊基]氧基}-3-(2-呋喃基)苯基]乙基}丙-1,3-二醇;
2-氨基-2-(2-{3-(3-呋喃基)-4-[(5-苯基戊基)氧基]苯基}乙基)丙-1,3-二醇;
2-氨基-2-(2-{4-[(5-苯基戊基)氧基]-3-(3-噻吩基)苯基}乙基)丙-1,3-二醇;
2-氨基-2-(2-{6-(2-呋喃基)-5-[(5-苯基戊基)氧基]吡啶-2-基}乙基)丙-1,3-二醇;
2-氨基-2-(4-{3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-1H-咪唑-2-基)乙基二氢磷酸酯;
2-氨基-2-(4-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}-1H-咪唑-2-基)乙基二氢磷酸酯;
2-氨基-2-(4-{3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-1H-咪唑-2-基)乙基二氢磷酸酯;
2-氨基-2-{4-[4-{[5-(4-氟苯基)戊基]氧基}-3-(2-呋喃基)苯基]-1H-咪唑-2-基}乙基二氢磷酸酯;
2-氨基-2-(4-{3-(3-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-1H-咪唑-2-基)乙基二氢磷酸酯;
2-氨基-2-(4-{4-[(5-苯基戊基)氧基]-3-(3-噻吩基)苯基}-1H-咪唑-2-基)乙基二氢磷酸酯;
2-氨基-2-(4-{6-(2-呋喃基)-5-[(5-苯基戊基)氧基]吡啶-2-基}-1H-咪唑-2-基)乙基二氢磷酸酯;
2-氨基-2-(4-{3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-1H-咪唑-2-基)乙醇;
2-氨基-2-(4-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}-1H-咪唑-2-基)乙醇;
2-氨基-2-(4-{3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-1H-咪唑-2-基)乙醇;
2-氨基-2-{4-[4-{[5-(4-氟苯基)戊基]氧基}-3-(2-呋喃基)苯基]-1H-咪唑-2-基}乙醇;
2-氨基-2-(4-{3-(3-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-1H-咪唑-2-基)乙醇;
2-氨基-2-(4-{4-[(5-苯基戊基)氧基]-3-(3-噻吩基)苯基}-1H-咪唑-2-基)乙醇;和
2-氨基-2-(4-{6-(2-呋喃基)-5-[(5-苯基戊基)氧基]吡啶-2-基}-1H-咪唑-2-基)乙醇。
16.一种药物组合物,其包含作为活性成分的治疗有效量的根据权利要求1所述的化合物和药学上可接受的佐剂、稀释剂或载体。
17.根据权利要求16所述的药物组合物,其中所述化合物选自:
(2R)-2-氨基-2-甲基-3-氧代-3-({4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}氨基)丙基二氢磷酸酯;
(2S)-2-氨基-2-甲基-3-氧代-3-({4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}氨基)丙基二氢磷酸酯;
2-氨基-3-羟基-2-甲基-N-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}丙酰胺;
2-氨基-3-羟基-2-甲基-N-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}丙酰胺;
(2S)-2-氨基-3-({3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}氨基)-3-氧代丙基二氢磷酸酯;
(2S)-2-氨基-3-氧代-3-({4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}氨基)丙基二氢磷酸酯;
2-氨基-N-{3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-3-羟基丙酰胺;
2-氨基-3-羟基-N-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}丙酰胺;
2-氨基-3-({3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}氨基)-3-氧代丙基二氢磷酸酯;
2-氨基-3-{[4-{[5-(4-氟苯基)戊基]氧基}-3-(2-呋喃基)苯基]氨基}-3-氧代丙基二氢磷酸酯;
2-氨基-3-({3-(3-呋喃基)-4-[(5-苯基戊基)氧基]苯基}氨基)-3-氧代丙基二氢磷酸酯;
2-氨基-3-氧代-3-({4-[(5-苯基戊基)氧基]-3-(3-噻吩基)苯基}氨基)丙基二氢磷酸酯;
2-氨基-3-({6-(2-呋喃基)-5-[(5-苯基戊基)氧基]吡啶-2-基}氨基)-3-氧代丙基二氢磷酸酯;
2-氨基-N-{3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-3-羟基丙酰胺;
2-氨基-N-{3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-3-羟基丙酰胺;
2-氨基-N-{3-(3-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-3-羟基丙酰胺;
2-氨基-3-羟基-N-{4-[(5-苯基戊基)氧基]-3-(3-噻吩基)苯基}丙酰胺;
2-氨基-N-{6-(2-呋喃基)-5-[(5-苯基戊基)氧基]吡啶-2-基}-3-羟基丙酰胺;
2-氨基-4-{3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-2-(羟基甲基)丁基二氢磷酸酯;
2-氨基-2-(羟基甲基)-4-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}丁基二氢磷酸酯;
2-氨基-4-{3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-2-(羟基甲基)丁基二氢磷酸酯;
2-氨基-4-[4-{[5-(4-氟苯基)戊基]氧基}-3-(2-呋喃基)苯基]-2-(羟基甲基)丁基二氢磷酸酯;
2-氨基-4-{3-(3-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-2-(羟基甲基)丁基二氢磷酸酯;
2-氨基-2-(羟基甲基)-4-{4-[(5-苯基戊基)氧基]-3-(3-噻吩基)苯基}丁基二氢磷酸酯;
2-氨基-4-{6-(2-呋喃基)-5-[(5-苯基戊基)氧基]吡啶-2-基}-2-(羟基甲基)丁基二氢磷酸酯;
2-氨基-2-(2-{3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}乙基)丙-1,3-二醇;
2-氨基-2-(2-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}乙基)丙-1,3-二醇;
2-氨基-2-(2-{3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}乙基)丙-1,3-二醇;
2-氨基-2-{2-[4-{[5-(4-氟苯基)戊基]氧基}-3-(2-呋喃基)苯基]乙基}丙-1,3-二醇;
2-氨基-2-(2-{3-(3-呋喃基)-4-[(5-苯基戊基)氧基]苯基}乙基)丙-1,3-二醇;
2-氨基-2-(2-{4-[(5-苯基戊基)氧基]-3-(3-噻吩基)苯基}乙基)丙-1,3-二醇;
2-氨基-2-(2-{6-(2-呋喃基)-5-[(5-苯基戊基)氧基]吡啶-2-基}乙基)丙-1,3-二醇;
2-氨基-2-(4-{3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-1H-咪唑-2-基)乙基二氢磷酸酯;
2-氨基-2-(4-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}-1H-咪唑-2-基)乙基二氢磷酸酯;
2-氨基-2-(4-{3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-1H-咪唑-2-基)乙基二氢磷酸酯;
2-氨基-2-{4-[4-{[5-(4-氟苯基)戊基]氧基}-3-(2-呋喃基)苯基]-1H-咪唑-2-基}乙基二氢磷酸酯;
2-氨基-2-(4-{3-(3-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-1H-咪唑-2-基)乙基二氢磷酸酯;
2-氨基-2-(4-{4-[(5-苯基戊基)氧基]-3-(3-噻吩基)苯基}-1H-咪唑-2-基)乙基二氢磷酸酯;
2-氨基-2-(4-{6-(2-呋喃基)-5-[(5-苯基戊基)氧基]吡啶-2-基}-1H-咪唑-2-基)乙基二氢磷酸酯;
2-氨基-2-(4-{3-(2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-1H-咪唑-2-基)乙醇;
2-氨基-2-(4-{4-[(5-苯基戊基)氧基]-3-(2-噻吩基)苯基}-1H-咪唑-2-基)乙醇;
2-氨基-2-(4-{3-(5-氟代-2-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-1H-咪唑-2-基)乙醇;
2-氨基-2-{4-[4-{[5-(4-氟苯基)戊基]氧基}-3-(2-呋喃基)苯基]-1H-咪唑-2-基}乙醇;
2-氨基-2-(4-{3-(3-呋喃基)-4-[(5-苯基戊基)氧基]苯基}-1H-咪唑-2-基)乙醇;
2-氨基-2-(4-{4-[(5-苯基戊基)氧基]-3-(3-噻吩基)苯基}-1H-咪唑-2-基)乙醇;和
2-氨基-2-(4-{6-(2-呋喃基)-5-[(5-苯基戊基)氧基]吡啶-2-基}-1H-咪唑-2-基)乙醇。
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KR101830244B1 (ko) | 2016-01-20 | 2018-02-21 | 서울대학교 산학협력단 | 신규한 헤테로방향족 고리 화합물, 이의 제조방법 및 이를 유효성분으로 함유하는 s1p 수용체 관련 질환의 예방 또는 치료용 약학적 조성물 |
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