CN102712618B - 作为具有治疗效用的受体调节剂的新型化合物 - Google Patents
作为具有治疗效用的受体调节剂的新型化合物 Download PDFInfo
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- CN102712618B CN102712618B CN201080062128.0A CN201080062128A CN102712618B CN 102712618 B CN102712618 B CN 102712618B CN 201080062128 A CN201080062128 A CN 201080062128A CN 102712618 B CN102712618 B CN 102712618B
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- carboxylic acid
- benzyl
- azetidine
- phenylpentyl
- oxygen
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Abstract
本发明涉及新型的环胺和环烷基衍生物、它们的制备方法、含有它们的药物组合物和它们作为鞘氨醇-1-磷酸酯受体的调节剂的药物的用途。
Description
相关申请的交叉参考
本申请要求2009年11月24日提交的系列号为61/264,038的美国临时申请的权益,该申请的内容在此以全文引用的方式并入。
技术领域
本发明涉及新型的环胺和环烷基衍生物、它们的制备方法、含有它们的药物组合物和它们作为鞘氨醇-1-磷酸酯受体的调节剂的药物的用途。本发明具体涉及这些化合物及其药物组合物治疗与鞘氨醇-1-磷酸酯(S1P)受体调节相关的病症的用途。
背景技术
鞘氨醇-1磷酸酯以相对较高的浓度储存在人血小板中,后者缺少负责其分解代谢的酶,并且它在经生理刺激(如生长因子、细胞因子和受体激动剂及抗原)激活时被释放到血流当中。它还可能在血小板凝聚及血栓形成中起到关键作用,并可恶化心血管疾病。另一方面,高密度脂蛋白(HDL)中相对高浓度的代谢物对于动脉粥样化形成来说可能具有有益的影响。例如,最近有建议认为鞘氨醇-1-磷酸酯连同诸如神经鞘氨醇磷酸胆碱和溶血硫脑苷脂的其它溶血脂质是HDL的有益临床效果的原因,方式是通过血管内皮细胞刺激有效抗动脉粥样硬化信号分子一氧化氮的产生。此外,像溶血磷脂酸一样,它是某些类型癌症的标记,并且有证据表明它在细胞分裂或增殖中的作用可能对癌症的发展有影响。这些是目前极大地吸引医学研究者兴趣的课题,并且鞘氨醇-1-磷酸酯代谢中的治疗干预可能性的研究正处于活跃状态。
发明内容
我们现在已经发现了一组新型化合物,它们是有效和选择性的鞘氨醇-1-磷酸酯调节剂。因此,本文中所述的化合物适用于治疗与鞘氨醇-1-磷酸酯受体的调节相关的许许多多种病症。用在本文中的术语“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。
本发明描述了具有鞘氨醇-1-磷酸酯受体生物活性的式I化合物。因此根据本发明的化合物可用于医学,例如用于治疗患有可通过S1P调节而缓解的疾病和病状的人。
一方面,本发明提供式I化合物或其药学上可接受的盐或其立体异构体形式或几何异构体、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:
式I
其中:
R1是N或C-R11;
R2是芳族杂环、非芳族杂环、环烷基、环烯基或芳基;
R3是O、N-R12、CH-R13、S、-CR14=CR15-、-C≡C-或-C(O)-;
R4是H、芳族杂环、非芳族杂环、环烯基、环烷基或芳基;
R5是H、卤素、-OC1-3烷基、C1-3烷基或羟基;
R6是H、C1-3烷基、卤素、羟基或-OC1-3烷基;
R7是H或C1-6烷基;
R8是H或C1-6烷基;
R9是CH或N;
R10是OPO3H2、羧酸、PO3H2、C1-6烷基、-S(O)2OH、-P(O)MeOH、-P(O)(H)OH或OR16;
R11是H、C1-6烷基、卤素、羟基或-OC1-3烷基;
R12是H或C1-3烷基;
R13是H、C1-3烷基、卤素、羟基、-OC1-3烷基或氨基;
R14是H或C1-3烷基;
R15是H或C1-3烷基;
R16是H或C1-6烷基;
a是0、1、2、3或4;
b是0、1、2、3或4;
c是0或1;
d是0或1;
e是0、1、2或3;
f是0、1、2或3;
g是0、1、2或3;
L是CHR17、O、S、NR18或-C(O)-;
R17是H、C1-3烷基、–OC1-3烷基、卤素、羟基或氨基;且
R18是H或C1-3烷基;
附带条件是当R3是O、N-R12或S且b是0或1时,L不是O、S、NR18。
用在本文中的术语“烷基”是指具有直链或支链部分或其组合且含有1至6个碳原子的饱和单价或二价烃部分。烷基的一个亚甲(-CH2-)基可被氧、硫、亚砜、氮、羰基、羧基、磺酰基或被二价C3-6环烷基取代。烷基可经卤素、羟基、环烷基、氨基、非芳族杂环、羧酸、膦酸基、磺酸基、磷酸取代。
用在本文中的术语“环烷基”是指衍生自饱和环烃的3至8个碳原子、优选3至5个碳原子的单价或二价基团。环烷基可以是单环或多环的。环烷基可以经1至3个C1-3烷基或者1或2个卤素取代。通常在本发明的情况中,环烷基是环戊烷。
用在本文中的术语“环烯基”是指衍生自具有一个双键的饱和环烷基的3至8个碳原子、优选3至6个碳原子的单价或二价基团。环烯基可以是单环或多环的。环烯基可以经1至3个C1-3烷基或者1或2个卤素取代。通常在本发明的情况中,环烯基是环戊烯。
用在本文中的术语“卤素”是指氯、溴、氟、碘原子。
用在本文中的术语“烯基”是指衍生自具有至少一个双键的饱和烷基的具有2至6个碳原子的单价或二价烃基。C2-6烯基可以是E或Z构型的。烯基可以经1至2个C1-3烷基取代。
用在本文中的术语“炔基”是指衍生自具有至少一个三键的饱和烷基的具有2至6个碳原子的单价或二价烃基。
用在本文中的术语“杂环”是指3至10员环,其可以是芳族或非芳族、饱和或不饱和的,含有至少一个选自O或N或S的杂原子或它们中的至少两个的组合,所述杂原子中断碳环结构。杂环可以是饱和或不饱和的。杂环可以被C=O中断;S杂原子可以被氧化。杂环可以是单环或多环的。杂环部分可以经羟基、1至2个C1-3烷基或1至2个卤素取代。通常在本发明的情况中,杂环基团是5或6员环。通常在本发明的情况中,杂环基团是吡啶、氮杂环丁烷、吡唑烷、吡咯啉、吡咯烷、咪唑啉、吡唑啉、噻唑啉、噁唑啉、噻吩、二氢噻吩、呋喃、二氢呋喃、吡咯、吡咯啉、吡咯烷、噁唑、噁唑啉、噻唑、咪唑、吡唑、吡唑啉、异噁唑、异噻唑、四唑、噁二唑、1,2,5-噁二唑、噻二唑、1,2,3-三唑、1,2,4-三唑、咪唑、咪唑啉、吡咯烷酮、吡咯-2(3H)-酮、咪唑烷-2-酮或1,2,4-三唑-5(4H)-酮。
用在本文中的术语“芳基”是指衍生自由含6至10个碳原子的环组成的芳族烃去除一个氢的有机部分,其可以经1至3个卤原子或经1至2个C1-3烷基取代。通常芳基是苯基。
用在本文中的式“-CR14=CR15-”基团代表烯基。
用在本文中的式“-C≡C-”基团代表炔基。
用在本文中的术语“羟基”代表式“–OH”基团。
用在本文中的术语“羰基”代表式“-C(O)”基团。
用在本文中的术语“羧基”代表式“-C(O)O-”基团。
用在本文中的术语“磺酰基”代表式“-SO2”基团。
用在本文中的术语“硫酸酯”代表式“-O-S(O)2-O-”基团。
用在本文中的术语“羧酸”代表式“-C(O)OH”基团。
用在本文中的术语“亚砜”代表式“-S=O”基团。
用在本文中的术语“膦酸”代表式“-P(O)(OH)2”基团。
用在本文中的术语“磷酸”代表式“-(O)P(O)(OH)2”基团。
用在本文中的术语“硼酸”代表式“-B(OH)2”基团。
用在本文中的术语“磺酸”代表式“-S(O)2OH”基团。
用在本文中的式“H”代表氢原子。
用在本文中的式“O”代表氧原子。
用在本文中的式“N”代表氮原子。
用在本文中的式“S”代表硫原子。
通常R1是N或C-R11。通常在本发明的情况中,R1是C-R11。
通常R2是芳族杂环、非芳族杂环、环烷基、环烯基或芳基。通常在本发明情况中,R2是芳族杂环、环烷基、环烯基或芳基。优选的R2基团是环戊烷、环戊烯、吡唑烷、吡咯啉、吡咯烷、咪唑啉、吡唑啉、噻唑啉、噁唑啉、噻吩、二氢噻吩、呋喃、二氢呋喃、吡咯、吡咯啉、吡咯烷、噁唑、噁唑啉、噻唑、咪唑、吡唑、吡唑啉、异噁唑、异噻唑、四唑、噁二唑、1,2,5-噁二唑、噻二唑、1,2,3-三唑、1,2,4-三唑、咪唑、咪唑啉、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R3是O、N-R12、CH-R13或S;-CR14=CR15-;-C≡C-。通常在本发明情况中,R3是O或S。
通常R4是芳族杂环、非芳族杂环、环烯基、环烷基或芳基。通常在本发明情况中,R4是芳基。
通常R5是H、卤素、-OC1-3烷基或C1-6烷基。通常在本发明的情况中,R5是H、卤素或-OC1-3烷基。
通常R6是H、C1-3烷基、卤素、羟基或-OC1-3烷基。通常在本发明的情况中,R6是H。
通常R7是H或C1-6烷基。
通常R8是H或C1-6烷基。通常在本发明的情况中,R8是H。
通常R9是CH或N。
通常R10是OPO3H2、COOH、PO3H2、C1-6烷基、-S(O)2OH、-P(O)MeOH、-P(O)(H)OH或OR16。通常在本发明的情况中,R10是COOH。
通常R11是H、C1-3烷基、卤素、羟基或-OC1-3烷基。通常在本发明的情况中,R11是H。
通常R12是H或C1-3烷基。
通常R13是H、C1-3烷基、卤素、羟基、-OC1-3烷基或氨基。
通常R14是H或C1-3烷基。
通常R15是H或C1-3烷基。
通常R16是H或C1-6烷基。
通常a是0、1、2、3或4。通常在本发明的情况中,a是0、1、2或3。
通常b是0、1、2、3或4。通常在本发明的情况中,b是1、2或3。
通常c是0或1。
通常d是0或1。通常在本发明的情况中,d是0或1。
通常e是0至3。通常在本发明的情况中,e是0或1。
通常f是0至3。通常在本发明的情况中,f是1。
通常g是0至3。通常g是0。
通常L是CHR17、O、S、-C(O)或NR18。通常在本发明的情况中,L是CHR17或O。
通常R17是H、C1-3烷基、–OC1-3烷基、卤素、羟基或氨基。通常在本发明情况中,R17是H或C1-3烷基。
通常R18是H或C1-3烷基。
在本发明的一个实施方案中
R1是N或C-R11;
R2是5员芳族杂环或5员环烯基;
R3是O、N-R12、CH-R13、S、-CR14=CR15-、-C≡C-或-C(O)-;
R4是H、芳族杂环、非芳族杂环、环烷基、环烯基或芳基;
R5是H、卤素、-OC1-3烷基、C1-3烷基或羟基;
R6是H、C1-3烷基、卤素、羟基或-OC1-3烷基;
R7是H或C1-6烷基;
R8是H或C1-6烷基;
R9是CH或N;
R10是OPO3H2、羧酸、-PO3H2、C1-6烷基、-S(O)2OH、-P(O)MeOH、-P(O)(H)OH或-OR16;
R11是H、C1-6烷基、卤素、羟基或-OC1-3烷基;
R12是H或C1-3烷基;
R13是H、C1-3烷基、卤素、羟基、-OC1-3烷基或氨基;
R14是H或C1-3烷基;
R15是H或C1-3烷基;
R16是H或C1-6烷基;
a是0、1、2、3或4;
b是0、1、2、3或4;
c是0或1;
d是0或1;
e是0、1、2或3;
f是0、1、2或3;
g是0、1、2或3;
L是CHR17、O、S、NR18或-C(O)-;
R17是H、C1-3烷基、-OC1-3烷基、卤素、羟基或氨基,且
R18是H或C1-3烷基;
附带条件是当R3是O、N-R12、S且b是0或1时,L不是O、S或NR18。
在本发明的另一实施方案中
R1是N或C-R11;
R2是环戊烷、环戊烯、吡唑烷、吡咯啉、吡咯烷、咪唑啉、吡唑啉、噻唑啉、噁唑啉、噻吩、二氢噻吩、呋喃、二氢呋喃、吡咯、吡咯啉、吡咯烷、噁唑、噁唑啉、噻唑、咪唑、吡唑、吡唑啉、异噁唑、异噻唑、四唑、噁二唑、1,2,5-噁二唑、噻二唑、1,2,3-三唑、1,2,4-三唑、咪唑、咪唑啉、吡咯烷酮、吡咯-2(3H)-酮、咪唑烷-2-酮或1,2,4-三唑-5(4H)-酮;
R3是O、N-R12、CH-R13、S、-CR14=CR15-、-C≡C-或-C(O)-;
R4是H、芳族杂环、非芳族杂环、环烷基、环烯基或芳基;
R5是H、卤素、-OC1-3烷基、C1-3烷基或羟基;
R6是H、C1-3烷基、卤素、羟基或-OC1-3烷基;
R7是H或C1-6烷基;
R8是H或C1-6烷基;
R9是CH或N;
R10是OPO3H2、羧酸、-PO3H2、C1-6烷基、-S(O)2OH、-P(O)MeOH、-P(O)(H)OH或-OR16;
R11是H、C1-6烷基、卤素、羟基或-OC1-3烷基;
R12是H或C1-3烷基;
R13是H、C1-3烷基、卤素、羟基、-OC1-3烷基或氨基;
R14是H或C1-3烷基;
R15是H或C1-3烷基;
R16是H或C1-6烷基;
a是0、1、2、3或4;
b是0、1、2、3或4;
c是0或1;
d是0或1;
e是0、1、2或3;
f是0、1、2或3;
g是0、1、2或3;
L是CHR17、O、S、NR18或-C(O)-;
R17是H、C1-3烷基、-OC1-3烷基、卤素、羟基或氨基,且
R18是H或C1-3烷基;
附带条件是当R3是O、N-R12、S且b是0或1时,L不是O、S或NR18。
在本发明的另一实施方案中
R1是N;
R2是芳族杂环、非芳族杂环、环烷基、环烯基或芳基;
R3是O、N-R12、CH-R13、S、-CR14=CR15-、-C≡C-或-C(O)-;
R4是H、芳族杂环、非芳族杂环、环烷基、环烯基或芳基;
R5是H、卤素、-OC1-3烷基、C1-3烷基或羟基;
R6是H、C1-3烷基、卤素、羟基或-OC1-3烷基;
R7是H或C1-6烷基;
R8是H或C1-6烷基;
R9是CH或N;
R10是OPO3H2、羧酸、-PO3H2、C1-6烷基、-S(O)2OH、-P(O)MeOH、-P(O)(H)OH或-OR16;
R12是H或C1-3烷基;
R13是H、C1-3烷基、卤素、羟基、-OC1-3烷基或氨基;
R14是H或C1-3烷基;
R15是H或C1-3烷基;
R16是H或C1-6烷基;
a是0、1、2、3或4;
b是0、1、2、3或4;
c是0或1;
d是0或1;
e是0、1、2或3;
f是0、1、2或3;
g是0、1、2或3;
L是CHR17、O、S、NR18或-C(O)-;
R17是H、C1-3烷基、-OC1-3烷基、卤素、羟基或氨基,且
R18是H或C1-3烷基;
附带条件是当R3是O、N-R12、S且b是0或1时,L不是O、S或NR18。
在本发明的另一实施方案中
R1是C-R11;且
R2是芳族杂环、非芳族杂环或环烯基;且
R3是O或S;且
R4是芳基;且
R5是H、-OC1-3烷基或卤素;且
R6是H;且
R7是H或C1-6烷基;且
R8是H;且
R9是CH或N;且
R10是COOH;且
R11是H;且
a是0、1、2或3;且
b是1、2或3;且
c是0或1;且
d是0或1;且
e是0或1;且
f是1;且
g是0;且
L是CHR17或O;且
R17是H或C1-3烷基;
附带条件是当R3是O或S且b是1时,L不是O。
在本发明的另一实施方案中
R1是C-R11;且
R2是芳族杂环、非芳族杂环或环烯基;且
R3是O;且
R4是芳基;且
R5是H、-OC1-3烷基或卤素;且
R6是H;且
R7是H或C1-6烷基;且
R8是H;且
R9是CH;且
R10是COOH;且
R11是H;且
a是0、1、2或3;且
b是1、2或3;且
c是1;且
d是1;且
e是0或1;且
f是1;且
g是0;且
L是CHR17;且
R17是H。
在本发明的另一实施方案中
R1是C-R11;且
R2是芳族杂环、非芳族杂环或环烯基;且
R3是S;且
R4是芳基;且
R5是H、-OC1-3烷基或卤素;且
R6是H;且
R7是H或C1-6烷基;且
R8是H;且
R9是CH或N;且
R10是COOH;且
R11是H;且
a是0、1、2或3;且
b是1、2或3;且
c是0或1;且
d是0或1;且
e是0或1;且
f是1;且
g是0;且
L是CHR17或O;且
R17是H或C1-3烷基;
附带条件是当R3是S且b是1时,L不是O。
在本发明的另一实施方案中
R1是C-R11;且
R2是芳族杂环、非芳族杂环或环烯基;且
R3是O;且
R4是芳基;且
R5是H、-OC1-3烷基或卤素;且
R6是H;且
R7是H或C1-6烷基;且
R8是H;且
R9是CH或N;且
R10是COOH;且
R11是H;且
a是0、1、2或3;且
b是1、2或3;且
c是0或1;且
d是0或1;且
e是0或1;且
f是1;且
g是0;且
L是CHR17或O;且
R17是H或C1-3烷基;
附带条件是当R3是O且b是1时,L不是O。
在本发明的另一实施方案中
R1是C-R11;且
R2是芳族杂环、芳基或环烯基;且
R3是O;且
R4是芳基;且
R5是H或卤素;且
R6是H;且
R7是H或C1-6烷基;且
R8是H;且
R9是CH或N;且
R10是COOH;且
R11是H;且
a是0、1、2或3;且
b是1、2或3;且
c是0或1;且
d是0或1;且
e是0或1;且
f是1;且
g是0;且
L是CHR17;且
R17是H。
在本发明的另一实施方案中
R1是C-R11;且
R2是芳族杂环或环烯基;且
R3是O或S;且
R4是芳基;且
R5是H、-OC1-3烷基或卤素;且
R6是H;且
R9是N;且
R10是COOH;且
R11是H;且
a是0、1、2或3;且
b是1、2或3;且
c是0;且
d是0;且
e是1;且
f是1;且
g是0;且
L是CHR17或O;且
R17是H或C1-3烷基;
附带条件是当R3是O或S且b是1时,L不是O。
本发明的化合物是:
1-{3-(3-呋喃基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{3-甲氧基-4-[(5-苯基戊基)氧]-5-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(6-苯基己基)氧]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[3-(苄氧基)丙氧基]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[3-(4-异丁基苯基)丙氧基]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-[4-(2-联苯-4-基乙氧基)-3-(2-噻吩基)苄基]氮杂环丁烷-3-羧酸;
1-{3-氯-4-[(5-苯基戊基)氧]-5-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{3-氯-4-[(5-苯基戊基)氧]-5-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(3-甲基-5-苯基戊基)氧]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{3-(5-甲基-2-噻吩基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{3-(4-甲基-2-噻吩基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{3-(3-甲基-2-噻吩基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1,3-噻唑-5-基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1,3-噻唑-4-基)苄基}氮杂环丁烷-3-羧酸;
1-{3-环戊-1-烯-1-基-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1H-吡唑-5-基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1H-吡唑-4-基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-吡啶-4-基苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(3-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-({6-[(5-苯基戊基)氧]联苯-3-基}甲基)氮杂环丁烷-3-羧酸;
1-{3-(2-呋喃基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1,3-噻唑-2-基)苄基}氮杂环丁烷-3-羧酸;
1-{3-(1,3-噁唑-2-基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1H-吡唑-1-基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)硫代]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{3-环戊-1-烯-1-基-4-[(5-苯基戊基)硫代]苄基}氮杂环丁烷-3-羧酸;
3-({4-[(5-苯基戊基)氧]-3-(2-噻吩基)苄基}氨基)环丁烷羧酸;
3-[(1-{4-[(5-苯基戊基)氧]-3-(2-噻吩基)苯基}乙基)氨基]环丁烷羧酸。
本发明的优选化合物是:
1-{3-(3-呋喃基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{3-氯-4-[(5-苯基戊基)氧]-5-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1,3-噻唑-5-基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1,3-噻唑-4-基)苄基}氮杂环丁烷-3-羧酸;
1-{3-环戊-1-烯-1-基-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1H-吡唑-5-基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1H-吡唑-4-基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(3-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{3-(2-呋喃基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1,3-噻唑-2-基)苄基}氮杂环丁烷-3-羧酸;
1-{3-(1,3-噁唑-2-基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1H-吡唑-1-基)苄基}氮杂环丁烷-3-羧酸;
3-({4-[(5-苯基戊基)氧]-3-(2-噻吩基)苄基}氨基)环丁烷羧酸;
3-[(1-{4-[(5-苯基戊基)氧]-3-(2-噻吩基)苯基}乙基)氨基]环丁烷羧酸。
一些式I化合物及一些它们的中间体在它们的结构中具有至少一个手性中心。此手性中心可以R或S构型存在,所述R和S标记的使用与Pure Appli.Chem.(1976),45,11-13中所述的规则一致。
术语“药学上可接受的盐”是指保持上述认定化合物的所需生物活性并表现出最少或没有不期望的毒理效应的盐或复合物。根据本发明的“药学上可接受的盐”包括式I化合物能够形成的有治疗活性的无毒碱或酸盐的形式。
以作为碱的游离形式存在的式I化合物的酸加成盐形式可以通过以下方式获得,即用适当的酸处理游离碱,所述适当的酸如:无机酸,例如氢卤酸(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、富马酸、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(Handbook ofPharmaceutical Salts,P.Heinrich Stahal& Camille G.Wermuth(Eds),Verlag Helvetica Chemica Acta-Zürich,2002,329-345)。
式I化合物及其盐可以是溶剂化物形式的,这也包括在本发明的范围内。这种溶剂化物包括例如水合物、醇化物等。
关于本发明,提到化合物或多种化合物旨在包括每种可能的异构体形式的该化合物及其混合物,除非具体所指的是特定的异构体形式。根据本发明的化合物可以不同的多态形式存在。虽然在上述式中并没有明确地指出,但这种形式也旨在包括于本发明的范围内。
本发明的化合物适用于治疗或预防有可能有涉及鞘氨醇-1-磷酸酯受体的成分的病状。
在另一实施方案中提供了在药学上可接受的载体中包含至少一种本发明化合物的药物组合物。
在本发明进一步的实施方案中提供了治疗与鞘氨醇-1-磷酸酯受体的调节相关的病症的方法。这种方法的实施方式可以是例如对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。
这些化合物适用于治疗包括人在内的哺乳动物的一系列可通过S1P调节而缓解的病状和疾病:不限于治疗糖尿病性视网膜病变、其它视网膜变性病状、干眼症、血管生成和创伤。
有与S1P受体有关的治疗效用的是眼部疾病,例如但不限于:湿性及干性年龄相关性黄斑变性、糖尿病性视网膜病变、早产儿视网膜病变、视网膜水肿、地图样萎缩、青光眼性视神经病变、脉络膜视网膜病变、高血压性视网膜病变、眼部缺血综合症、预防眼背部中炎症引起的纤维化、各种眼部炎症性疾病,包括葡萄膜炎、巩膜炎、角膜炎和视网膜血管炎;或与全身血管障碍有关的疾病,例如但不限于:各种炎症性疾病,包括急性肺损伤、其预防、败血症、肿瘤转移、动脉粥样硬化、肺水肿和通气引起的肺损伤;或自身免疫性疾病和免疫抑制,例如但不限于:类风湿关节炎、克罗恩病、格雷夫斯病、炎症性肠病、多发性硬化症、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、接触性过敏反应、特应性皮炎和器官移植;或过敏及其它炎症性疾病,例如但不限于:荨麻疹、支气管哮喘及其它呼吸道炎症,包括肺气肿和慢性阻塞性肺病;或心肌保护,例如但不限于:缺血再灌注损伤和动脉粥样硬化;或伤口愈合,例如但不限于:整容皮肤手术、眼科手术、GI手术、普通外科、口腔受伤、各种机械、热及烧伤的伤口的无疤痕愈合、预防和治疗光老化及皮肤老化和预防辐射引起的损伤;或骨形成,例如但不限于:治疗骨质疏松症及包括髋关节和踝关节在内的各种骨折;或抗伤害性活动,例如但不限于:内脏痛、与糖尿病性神经病变相关的疼痛、类风湿关节炎、慢性膝盖及关节疼痛、肌腱炎、骨关节炎、神经性疼痛;或阿尔茨海默氏症中的中枢神经系统神经元活动、与年龄有关的神经元损伤;或在器官移植中,如肾、角膜、心脏或脂肪组织移植。
在本发明的又一实施方案中提供了治疗与鞘氨醇-1-磷酸酯受体的调节相关的病症的方法。这种方法的实施方式可以是例如对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任意组合或其药学上可接受的盐、水合物、溶剂化物、晶型和单独的同分异构体、对映异构体和非对映异构体。
本发明涉及式I化合物或其药学上可接受的盐用于制造治疗以下疾病的药剂的用途:眼部疾病、湿性及干性年龄相关性黄斑变性、糖尿病性视网膜病变、早产儿视网膜病变、视网膜水肿、地图样萎缩、青光眼性视神经病变、脉络膜视网膜病变、高血压性视网膜病变、眼部缺血综合症、预防眼背部中炎症引起的纤维化、各种眼部炎症性疾病,包括葡萄膜炎、巩膜炎、角膜炎和视网膜血管炎;或与全身血管障碍有关的疾病、各种炎症性疾病,包括急性肺损伤、其预防、败血症、肿瘤转移、动脉粥样硬化、肺水肿和通气引起的肺损伤;或自身免疫性疾病和免疫抑制、类风湿关节炎、克罗恩病、格雷夫斯病、炎症性肠病、多发性硬化症、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、接触性过敏反应、特应性皮炎和器官移植;或过敏及其它炎症性疾病、荨麻疹、支气管哮喘及其它呼吸道炎症,包括肺气肿和慢性阻塞性肺病;或心肌保护、缺血再灌注损伤和动脉粥样硬化;或整容皮肤手术、眼科手术、GI手术、普通外科、口腔受伤、各种机械、热及烧伤的伤口愈合、伤口的无疤痕愈合、预防和治疗光老化及皮肤老化和预防辐射引起的损伤;或骨形成、治疗骨质疏松症及包括髋关节和踝关节在内的各种骨折;或抗伤害性活动、内脏痛、与糖尿病性神经病变相关的疼痛、类风湿关节炎、慢性膝盖及关节疼痛、肌腱炎、骨关节炎、神经性疼痛;或阿尔茨海默氏症中的中枢神经系统神经元活动、与年龄有关的神经元损伤;或在器官移植中,如肾、角膜、心脏或脂肪组织移植。
在任何给定病例中要施用的化合物的实际量将由医生考虑相关的情况予以确定,如考虑病状的严重程度、患者的年龄及体重、患者的一般身体状况、病因和施用途径。
将以任何可接受的形式给患者口服施用所述化合物,如片剂、液体、胶囊、粉末等,或者其它途径可能是可取的或必要的,特别是如果患者出现恶心的情况。这种其它途径可以毫无例外地包括透皮、肠胃外、皮下、鼻内、通过植入支架、鞘内、玻璃体内、眼局部、眼背部、肌内、静脉内和直肠内递送模式。另外,可设计配方以在治疗过程期间的给定时间段上延迟活性化合物的释放,或者在给定的时间仔细地控制释放的药量。
在本发明的另一实施方案中提供了包含至少一种本发明化合物的药物组合物,所述化合物在其药学上可接受的载体中。短语“药学上可接受的”表示载体、稀释剂或赋形剂必须与其它配方成分相容,并且不对其接受者有害。
本发明的药物组合物的使用形式可以是固体、溶液、乳液、分散体、膏药、胶束、脂质体等,其中所得到的组合物含有作为活性成分的一种或多种本发明化合物与适合肠内或肠胃外应用的有机或无机载体或赋形剂混合。本发明化合物可与通常无毒的药学上可接受的载体结合,用于片剂、丸剂、胶囊、栓剂、溶液、乳液、混悬液和任何其它适用的形式。可用的载体包括葡萄糖、乳糖、阿拉伯树胶、明胶、甘露醇、淀粉糊、三硅酸镁、滑石粉、玉米淀粉、角蛋白、硅胶、马铃薯淀粉、尿素、中等链长甘油三酯、右旋糖酐及适合用于生产制备的固体、半固体或液体形式的其它载体。此外可以使用辅剂、稳定剂、增稠剂和着色剂及香料。本发明化合物在药物组合物中的含量足以对进程或病情产生所需的效果。
含有本发明化合物的药物组合物可以是适合口服使用形式的,例如作为片剂、糖剂、锭剂、水性或油性混悬液、分散性粉末或颗粒、乳液、硬或软胶囊或糖浆或酏剂。可以根据药物组合物生产领域中已知的任何方法制备拟用于口服使用的组合物,并且这种组合物可含有一种或多种选自以下的试剂:甜味剂,如蔗糖、乳糖或糖精;调味剂,如薄荷、冬青或樱桃油;着色剂和防腐剂,以便提供药学上雅致且可口的制剂。也可以按已知的方法生产含有本发明化合物与无毒药学上可接受的赋形剂混合的片剂。所用的赋形剂可以为,例如(1)惰性稀释剂,如碳酸钙、乳糖、磷酸钙或磷酸钠;(2)成粒剂和崩解剂,如玉米淀粉、马铃薯淀粉或海藻酸;(3)粘结剂,如黄蓍胶、玉米淀粉、明胶或阿拉伯树胶,和(4)润滑剂,如硬脂酸镁、硬脂酸或滑石粉。片剂可以是未包衣的,或者可以通过已知的技术对它们进行包衣以延迟在胃肠道中的崩解和吸收,并从而提供较长时期的持续作用。例如,可以使用延时材料,如单硬脂酸甘油酯或二硬脂酸甘油酯。
在一些情况下,口服使用的制剂形式可以是硬明胶胶囊,其中本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。它们的形式也可以是软明胶胶囊,其中本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。
药物组合物的形式可以是无菌注射用混悬液。可以根据已知的方法使用合适的分散或润湿剂和助悬剂配制这种混悬液。无菌注射用制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中的无菌注射溶液或混悬液,例如作为在1,3-丁二醇中的溶液。常规上使用无菌不挥发性油作为溶剂或混悬介质。为此目的可以使用任何无刺激性的不挥发性油,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)或合成的脂肪媒介物(如油酸乙酯)等。根据需要可以掺入缓冲剂、防腐剂、抗氧化剂等。
本发明化合物的施用形式也可以为用于药物直肠施用的栓剂。可以通过将本发明化合物与合适的非刺激性赋形剂混合来制备这些组合物,所述赋形剂如可可油、合成的聚乙二醇甘油酯,它们在常温下为固体,但在直肠腔中液化和/或溶解以释出药物。
因为个别受试者可能呈现症状严重程度的广泛变化,且每种药物有其独特的治疗特点,所以对每一受试者的精确施用模式和用量有待医师酌处。
本文所述的化合物和药物组合物适合作为包括人在内的哺乳动物的药剂,用于治疗疾病和/或缓解对通过激动剂或鞘氨醇-1-磷酸酯受体的功能性拮抗剂治疗有反应的病状。因此,在本发明的进一步实施方案中提供了治疗与鞘氨醇-1-磷酸酯受体的调节相关的病症的方法。这种方法的实施方式例如可以是对有需要的受试者施用含治疗有效量的至少一种本发明化合物的药物组合物。用在本文中的术语“治疗有效量”表示会引起有需要的受试者的生物或医学反应的药物组合物量,所述反应是研究者、兽医、医师或其他临床医生所寻求的。在一些实施方案中,有需要的受试者是哺乳动物。在一些实施方案中,所述哺乳动物是人。
本发明还涉及式I化合物的制备方法。可以按类似于合成有机化学领域的技术人员理解的常规方法制备根据本发明的式I化合物。下面给出的合成方案例示可如何制备根据本发明的化合物。本领域技术人员将能够按常规方式修改和/或改动以下方案以合成由式I所涵盖的任何本发明的化合物。
在方案1中,羟基苯甲醛与羟基化的化合物在三苯基膦和偶氮二甲酸二乙酯的存在下反应,得到相应的醚中间体。此中间体与硼酸或相应R2基团的锡酸酯偶联,得到相应的中间体。此中间体在还原胺化条件下与氮杂环丁烷-3-羧酸反应,得到式I的衍生物。
方案1
在方案2中,巯基苯甲醛与溴化的化合物在三乙胺的存在下反应,得到相应的硫代中间体。此中间体与硼酸或相应R2基团的锡酸酯偶联,得到相应的中间体。此中间体在还原胺化条件下与氮杂环丁烷-3-羧酸反应,得到式I的衍生物。
方案2
在方案3中,如方案1或2中所述得到的醚或硫代中间体与3-氨基环丁烷羧酸乙酯-HCl盐在三乙酰氧基硼氢化钠的存在下反应,得到式I的衍生物。
方案3
在方案4中,如方案1或2中所述得到的醚或硫代中间体与烷基溴化镁衍生物和3-氨基环丁烷羧酸乙酯-HCl盐在氧化镁的存在下反应,得到式I的衍生物。
方案4
发明详述
要理解的是,前面的一般描述和下面的详细描述都只是示例和说明性的,并不限制请求保护的本发明。除另有明确指示外,用在本文中的单数包括复数。
本领域技术人员显而易见的是,一些本发明的化合物可含有一个或多个不对称中心,使得所述化合物可以对映异构体形式以及以非对映异构体形式存在。除另有特别注明外,本发明的范围包括所有的对映异构体、非对映异构体和外消旋混合物。一些本发明的化合物可与药学上可接受的酸或碱形成盐,并且本文所述的化合物的这种药学上可接受的盐也在本发明的范围内。
本发明包括所有药学上可接受的富同位素化合物。本发明的任何化合物可富含一种或多种同位素原子或含有不同于天然比例的一种或多种同位素原子,如氘2H(或D)代替氕1H(或H),或者使用富13C的材料代替12C等。类似的取代可用于N、O和S。同位素的使用可有助于本发明的分析以及治疗方面。例如,氘的使用可通过改变本发明化合物的代谢(率)而增加体内半衰期。这些化合物的制备可与使用富同位素试剂描述的制备一致。
以下实施例仅用于示例的目的,并不旨在也不应将其解释为以任何方式限制本发明。本领域技术人员将会意识到,可以在不超出本发明的实质或范围的情况下对以下实施例进行变动和修改。
对本领域技术人员显而易见的是,可以按常规方式通过对其混合物进行分离得到单独的异构体形式。例如,在非对映异构体的情况下可以采用色谱分离。
用ACD第8版生成化合物名称;用软件生成实施例中使用的中间体及试剂的名称,所述软件如Chem Bio Draw Ultra 12.0版或MDLISIS Draw 2.5SP1中的Auto Nom 2000。
一般情况下,根据以下方法进行化合物表征:
在300和/或600MHz Varian上记录并在室温下获得NMR谱。参考内部TMS或参考溶剂信号以ppm给出化学位移。
没有描述合成的所有试剂、溶剂、催化剂均购自化学品供应商,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,一些已知的中间体是通过公开的程序制备的。
除另指出外,一般通过柱色谱法(Auto-column)在带有二氧化硅柱的Teledyne-ISCO CombiFlash上纯化本发明的化合物。
在实施例中使用以下缩写:
以下合成方案例示可如何制备根据本发明的化合物。本领域技术人员将能够按常规方式修改和/或改动以下方案以合成由式I所涵盖的任何本发明的化合物。
实施例1
化合物1
1-{3-(3-呋喃基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸
步骤-1:使5-苯基-戊-1-醇[CAS 10521-91-2](4.50mL,26.6mmol)、3-溴-4-羟基苯甲醛[CAS 2973-78-6](5.36g,26.7mmol)、三苯基膦(9.1g,34.6mmol)和DEAD(14.5mL,在甲苯中40%,~1.2当量)在THF(100mL)中的溶液在室温下反应1h,接着加热到60℃达2天。加硅胶并在真空下除去溶剂。在带有二氧化硅柱(自动柱)的Teledyne-ISCO CombiFlash上进行色谱法,9.5己烷/0.5EtOAC至9己烷/1EtOAc,得到中间体1:3-溴-4-(5-苯基-戊氧基)-苯甲醛,为澄清的油状物,其经搁置凝固,5.38g(58%)。
1H NMR(300MHz,CDCl3):δ9.83(s,1H),8.07(d,J=2.1Hz,1H),7.78(dd,J=8.7,2.1Hz,1H),7.28-7.18(m,5H),6.96(d,J=8.4Hz,1H),4.11(t,J=6.3Hz,2H),2.67(t,J=7.2Hz,2H),1.92-1.55(m,6H)。
步骤-2:用MWI(微波辐射:Biotage Initiator 2.5)使DMF(12mL)中的中间体1(290mg,0.87mmol)与呋喃-3-基硼酸[CAS5552-70-0](195mg,1.74mmol)、Na2CO3(2.8mL,2M)和PdCl2(PPh3)2(69mg,~11mol%)在120℃反应20m。用水稀释反应混合物并用1:1EtOAc:己烷(200mL)萃取(两次)。用水洗涤有机层(三次),经MgSO4干燥,过滤并浓缩到硅胶上面。自动柱色谱法(9己烷/1 EtOAc)得到中间体2:3-(呋喃-3-基)-4-((5-苯基戊基)氧)苯甲醛230mg(29%)。
1H NMR(300MHz,CDCl3):δ9.92(s,1H),8.03(d,J=2.4Hz,1H),7.75-7.72(m,1H),7.48(s,15H),7.30-7.16(m,3H),7.19-7.16(m,3H),7.02(d,J=8.7Hz,1H),6.85(d,J=1.2Hz,1H),4.14(t,J=6.3Hz,2H),2.70-2.60(m,2H),2.01-1.50(m系列,6H)。
步骤3:用Si-CBH,即结合二氧化硅的氰基硼氢化物(0.71g,在硅胶载体上0.93mmol/g)处理中间体2(230mg,0.66mmol)和氮杂环丁烷-3-羧酸[CAS 36476-78-5](66mg,0.65mmol)在AcOH(0.2mL)、THF(2mL)和MeOH(10mL)中的溶液,并使混合物在rt下反应~16-18h。将混合物浓缩到硅胶上面并在真空下除去溶剂。自动柱色谱法(25→40% MeOH:CH2Cl2)得到白色固体的标题化合物:1-{3-(3-呋喃基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸189mg(69%)。
1H NMR(300MHz,CD3OD):δ8.02(s,1H),7.64(d,J=2.4Hz,1H),7.53(t,J=1.8Hz,1H),7.30-7.20(m,3H),7.16-7.0(m,3H),7.06(d,J=8.7Hz,1H),6.90(d,J=1.2Hz,1H),4.26(s,2H),4.14-4.07(m,6H),3.40-3.33(m,1H),2.63(t,J=7.8Hz,2H),1.94-1.84(m,2H),1.75-1.65(m,2H),1.58-1.48(m,2H)。
由相应的苯甲醛和氮杂环丁烷-3-羧酸按类似于在实施例1中针对化合物1所述的程序制备化合物2-21。所用的试剂和结果描述在下表1中。
表1
实施例2
化合物22
1-{3-(2-呋喃基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸
步骤-1:用MWI(微波辐射:Initiator 2.5)使DMF(14mL)中的中间体1(0.65g,1.87mmol)与三丁基(呋喃-2-基)锡烷[CAS118486-94-5](1.2mL,3.70mmol)和PdCl2(PPh3)2(0.197g,~15mol%)在160℃反应15m。用2:1 EtOAc/己烷(~150mL)稀释反应混合物,用水洗涤(三次)并经MgSO4干燥,过滤并浓缩到硅胶上面。自动柱色谱法(9.5己烷/0.5 EtOAc)得到中间体3:3-呋喃-2-基-4-(5-苯基-戊氧基)-苯甲醛,为白色固体,0.44g(70%)。
1H NMR(300MHz,CD3OD):δ9.94(s,1H),8.37(d,J=2.1Hz,1H),7.77-7.74(m,1H),7.49(d,J=1.2Hz,1H),7.30-7.10(m,5H),7.04-6.90(m,2H),6.50(brs,1H),4.21-4.05(m,2H),2.70-2.60(m,2H),2.10-1.50(系列m,6H)。
步骤-2:如实施例1程序中所述使中间体3与氮杂环丁烷-3-羧酸反应,生成标题化合物:1-{3-(2-呋喃基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸。
1H NMR(300MHz,CD3OD):δ7.90(s,1H),7.53(s,1H),7.28(t,J=8.1Hz,1H),7.21(d,J=6.9Hz,2H),7.16-7.12(m,3H),7.06(d,J=8.7Hz,1H),6.92(d,J=3.3Hz,1H),6.48(s,1H),4.28(s,2H),4.15-4.07(s,2H),3.40-3.33(m,1H),2.62(t,J=7.2Hz,2H),1.93-1.84(m,2H),1.75-1.65(m,2H),1.58-1.48(m,2H)。
由相应的锡酸酯和氮杂环丁烷-3-羧酸按类似于实施例2中针对化合物22所述的程序制备化合物23和24。所用的试剂和结果描述在下表2中。
表2
实施例3
化合物25
1-{4-[(5-苯基戊基)氧]-3-(1H-吡唑-1-基)苄基}氮杂环丁烷-3-羧酸
步骤-1:将中间体1(0.41g,1.18mmol)、K2CO3(0.49g,3.54mmol)、CuI(0.23g,2.39mmol)、吡唑[CAS 288-13-1](0.18g,2.64mmol)和N,N-二甲基乙烷-1,2-二胺(0.1mL,0.93mmol)在二噁烷中的溶液加热到105℃达16-18h。向混合物中加Cs2CO3(1.0g,3.07mmol)Cu-Sn合金(500mg,200目)和DMF(~15mL),继续在160℃下加热达16-18h。将混合物冷却到rt并进行标准的水性处理。自动柱色谱法(8:2己烷/EtOAc)纯化粗物质,得到中间体4,为白色固体,4-(5-苯基戊基oxy)-3-(1H-吡唑-1-基)苯甲醛120mg(51%)。
1H NMR(300MHz,CD3OD):δ9.94(s,1H),8.31(d,J=1.8Hz,1H),8.05(d,J=1.8Hz,1H),7.84-7.80(m,1H),7.79(s,1H),7.29-7.24(m,2H),7.78-7.11(m,4H),6.42(s,1H),4.14(t,J=6.3Hz,2H),2.63(t,J=7.8Hz,2H),1.83-1.39(m系列,6H)。
步骤-2:如实施例1程序中所述使中间体4与氮杂环丁烷-3-羧酸反应,生成标题化合物:1-{4-[(5-苯基戊基)氧]-3-(1H-吡唑-1-基)苄基}氮杂环丁烷-3-羧酸。
1H NMR(300MHz,CD3OD):δ8.01(d,J=2.1Hz,1H),7.68(dd,J=2.1,7.8Hz,2H),7.43(dd,J=2.1,8.4Hz,1H),7.25-7.20(m,3H),6.44(t,J=2.4Hz,1H),4.26(s,2H),4.16-4.04(m,6H),3.40-3.32(m,1H),2.58(t,J=7.5Hz,2H),1.83-1.74(m,2H),1.68-1.58(m,2H),1.47-1.39(m,2H)。
实施例4
化合物26
1-{4-[(5-苯基戊基)硫代]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸
步骤-1:用硫化钠Na2S9H2O(6.80g,27.7mmol)处理3-溴-4-氟苯甲醛[CAS 77771-02-9](5.1g,24.6mmol)在DMF(25mL)中的混合物,并将混合物在rt下搅拌9d。在进行酸性处理并用己烷/EtOAc(1:1)萃取后,用水洗涤合并的有机层(三次)并经MgSO4干燥,过滤并浓缩到硅胶上面。自动柱色谱法(9:1己烷/EtOAc)得到中间体5,为固体3.07g(58%)3-溴-4-巯基苯甲醛。
1H NMR(300MHz,CD3OD):δ9.86(s,1H),7.98(d,J=1.5Hz,1H),7.64(d,J=1.8Hz,1H),7.47(d,J=7.8Hz,1H),4.31(s,1H)。
步骤-2:在rt下将中间体5(2.80g,11.3mmol)和(5-溴戊基)苯[CAS14469-83-1](2.61g,11.5mol)的溶液与三乙胺(3.1mL)在THF(30mL)中搅拌18小时。在真空下除去溶剂,并将残余物溶解在EtOAc/己烷(200mL,1:1)中,用水洗涤,经MgSO4干燥,过滤并浓缩到硅胶上面。自动柱色谱法(9.5己烷/0.5 EtOAc)得到中间体6,为油状物1.74g(42%)3-溴-4-((5-苯基戊基)硫代)苯甲醛。
1H NMR(300MHz,CDCl3):δ9.86(s,1H),7.98(d,J=1.8Hz,1H),7.72(dd,J=8.4,1.2Hz,1H),7.28-7.15(m,6H),2.97(t,J=7.5Hz,2H),2.63(t,J=7.5Hz,2H),1.79-1.54(m系列,6H)。
步骤-3:如实施例1程序中所述使中间体6和噻吩-2-基硼酸与氮杂环丁烷-3-羧酸反应,生成标题化合物:1-{4-[(5-苯基戊基)硫代]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸。
1H NMR(600MHz,CD3OD):δ7.48-7.47(m,1H),7.46-7.45(m,2H),7.36(dd,J=2.4,8.4Hz,1H),7.26-7.25(m,1H),7.23-7.21(m,2H),7.13-7.11(m,3H),7.10(dd,J=4.2,5.4Hz,1H),4.26(s,2H),4.14-4.08(m,4H),3.39-3.34(m,1H),2.86 9t,J=7.8Hz,2H),2.56(t,J=7.8Hz,2H),1.64-1.56(m,4H),1.44-1.39(m,2H)。
实施例5
化合物27
1-{3-环戊-1-烯-1-基-4-[(5-苯基戊基)硫代]苄基}氮杂环丁烷-3-羧酸
根据实施例4中所述的程序合成标题化合物;其中中间体6在步骤3中与环戊-1-烯-1-基硼酸反应。
1H NMR(600MHz,CD3OD):δ7.34(d,J=8.4,1H),7.26-7.21(m,4H),7.14-7.11(m,3H),5.91(五重峰,J=2.4Hz,1H),4.23(s,2H),4.13-4.08(m,4H),3.39-3.33(m,1H),2.90(t,J=7.8Hz,2H),2.73-2.70(m,2H),2.58(t,J=7.2Hz,2H),2.54-2.509m,2H),2.03-1.98(m,2H),1.66-1.59(m,4H),1.48-1.43(m,2H)。
实施例6
化合物28
3-({4-[(5-苯基戊基)氧]-3-(2-噻吩基)苄基}氨基)环丁烷羧酸
步骤-1:中间体7的溶液:在rt下将4-((5-苯基戊基)氧)-3-(噻吩-2-基)苯甲醛[在由中间体1和噻吩-2-基硼酸合成化合物16期间制备](230mg,0.66mmol)和3-氨基环丁烷羧酸乙酯-HCl盐[CAS957793-35-0](150mg,0.84mmol)在THF(11mL)、乙酸(1.2mL)和EtOH(6mL)中搅拌1h。
中间体7:1H NMR(300MHz,CDCl3):δ9.92(s,1H),8.17(d,J=2.1Hz,1H),7.75(dd,J=9.9,2.1Hz,1H),7.56(dd,J=3.6,1.2Hz,1H),7.37-7.02(m系列,8H),4.16(t,J=6.6Hz,2H),2.66(t,J=7.2Hz,2H),2.01-1.54(m系列,6H)。
加NaBH(OAc)3(320mg,1.43mmol)并将混合物在rt下搅拌18h。在真空下除去溶剂,并用NaOH(1M)处理混合物以调节pH>7。用EtOAc萃取混合物并合并有机层,经MgSO4干燥,过滤并浓缩到硅胶上面。自动柱色谱法(EtOAc)得到中间体8,为澄清油状物3-((4-((5-苯基戊基)氧)-3-(噻吩-2-基)苄基)氨基)环丁烷羧酸乙酯。
1H NMR(300MHz,CDCl3):δ7.57(d,J=1.8Hz,1H),7.50(dd,J=0.9,2.7Hz,1H),7.31-7.14(m,7H),7.06(dd,J=3.9,1.5Hz,1H),6.90(d,J=8.4Hz,1H),4.15-4.03(m,4H),3.69(s,2H),3.29-3.18(m,1H),2.78-2.46(m,5H),2.01-1.49(m系列,8H),1.24(t,J=6.9Hz,3H)。
步骤2:在rt下将二噁烷(10mL)中的中间体8(200mg,0.42mmol)用NaOH(3.5mL,1M)处理1h。在真空下除去溶剂,并用HCl(1M)将pH值调到3-4。用CHCl3:异丙醇(3:1)萃取溶液。在真空下除去有机溶剂以得到标题化合物:3-({4-[(5-苯基戊基)氧]-3-(2-噻吩基)苄基}氨基)环丁烷羧酸。
1H NMR(300MHz,CD3OD):δ7.83(d,J=2.1Hz,1H),7.58(dd,J=0.9,3.9Hz,1H),7.41(d,J=5.4Hz,1H),7.35(dd,J=2.1,8.4Hz,1H),7.25-7.20(m,2H),7.16-7.13(m,3H),7.10-7.06(m,2H),4.15-4.09(m,4H),3.77(五重峰,J=8.4Hz,1H),3.02(五重峰,J=9.0Hz,1H),2.65-2.56(m,4H),2.45-2.35(m,2H),1.95-1.86(m,2H),1.75-1.65(m,2H),1.62-1.52(m,2H)。
实施例7
化合物29
3-[(1-{4-[(5-苯基戊基)氧]-3-噻吩基)苯基}乙基)氨基]
环丁烷羧酸
步骤-1:使中间体7(600mg,1.71mmol)在THF(15mL)中的-78℃混合物与MeMgBr(2.0mL,在二乙醚中3.0M)反应并升温至0℃达3h。用水急冷混合物并在真空下除去THF。用EtOAc萃取水层。合并的有机萃取物经MgSO4干燥,过滤并浓缩到硅胶上面。自动柱色谱法(8.5己烷/1.5EtOAc)得到中间体9,为油状物450mg(72%):1-(4-((5-苯基戊基)氧)-3-(噻吩-2-基)苯基)乙醇。
1H NMR(600MHz,CDCl3):δ7.63(d,J=4.2Hz,1H),7.49(dd,J=1.2,4.2Hz,1H),7.29-7.16(m系列,7H),7.05(dd,J=3.6,4.8Hz,1H),6.87(d,J=9.0Hz,1H),4.83(q,J=6.0Hz,1H),4.02(d,J=6.0Hz,2H),2.63(t,J=7.8Hz,2H),1.91-1.54(m系列,6H),1.48(d,J=6.6Hz,3H)。
步骤2:将中间体9(450mg,1.23mmol)和MnO2(1.1g,10.7mmol(85%))在二噁烷(20mL)中的混合物在100℃下加热18h。过滤混合物并在真空下除去溶剂。将残余物溶于氯仿并在减压下浓缩到硅胶上面。自动柱色谱法(9己烷:1EtOAc)得到中间体10,为白色固体350mg(78%)1-(4-((5-苯基戊基)氧)-3-(噻吩-2-基)苯基)乙酮。MS[M+23]+387.19
步骤-3:在rt下将THF(8mL)中的3-氨基环丁烷羧酸酯–HCl盐(260mg,1.45mmol)用三乙胺(0.185mL,1.33mmol)处理1h。在rt下加Ti(OEt)4(0.32mL),接着加THF(6mL)中的中间体10(350mg,0.96mmol)达2.5h。加硼氢化钠(190mg),并将混合物在rt下搅拌~18h。加氢氧化铵水溶液(2.5mL)并将混合物在rt下搅拌1h。除去溶剂并用EtOAc、水稀释混合物,并通过硅藻土进行过滤。分离有机层并用EtOAc萃取水层。合并有机物质,经MgSO4干燥,过滤并浓缩到硅胶上面。自动柱色谱法(8 EtOAc:2己烷)得到中间体11,为澄清油状物100mg,(21%),3-((1-(4-((5-苯基戊基)氧)-3-(噻吩-2-基)苯基)乙基)氨基)环丁烷羧酸乙酯。
1H NMR(600MHz,CDCl3):δ7.56(d,J=2.4Hz,1H),7.51-7.50(m,1H),7.31-7.25(m,3H),7.19-7.15(m,4H),7.06(dd,J=3.6,5.4Hz,1H),6.89(d,J=8.4Hz,1H),4.11-4.05(m,4H),3.08(m,1H),2.66-2.62(m,3H),2.60-2.30(m系列,2H),1.94-1.22(m系列,12H)
步骤-4:根据实施例6步骤2中所述的程序水解中间体11的混合物,并得到81mg标题化合物3-[(1-{4-[(5-苯基戊基)氧]-3-(2-噻吩基)苯基}乙基)氨基]环丁烷羧酸
1H NMR(600MHz,CD3OD):δ7.76(d,J=2.4Hz,1H),7.56(dd,J=1.2,4.2Hz,1H),7.41(dd,J=1.2,5.4Hz,1H),7.31(dd,J=2.4,9.0Hz,1H),7.23(t,J=7.8Hz,2H),7.16(d,J=7.8Hz,2H),7.14-7.12(m,2H),7.08(dd,J=3.6,5.4Hz,1H),4.32(q,J=7.2Hz,1H),4.14(t,J=6.0Hz,2H),3.50(t,J=7.8Hz,1H),2.81-2.75(m,1H),2.64(t,J=7.8Hz,2H),2.56-2.53(m,1H),2.35-2.27(m,2H),2.14-2.11(m,1H),1.93-1.89(m,2H),1.74-1.66(m,2H),1.65(d,J=6.6Hz,3H),1.61-1.57(m,2H)。
实施例8
生物学数据
合成化合物并采用GTPγ35S结合测定来测试S1P1活性。可以评估这些化合物激发或阻断稳定地表达S1P1受体的细胞中的人S1P1受体的活化的能力。
在介质中测量GTPγ35S结合,所述介质在150μl体积中含有(mM)HEPES 25,pH 7.4、MgCl210、NaCl 100、二硫苏糖醇0.5、洋地黄皂苷0.003%、0.2nM GTPγ35S和5μg膜蛋白。除另指出外,包括的测试化合物浓度范围在0.08至5,000nM。膜用100μM 5’-腺苷酰亚胺二磷酸培养30分钟,随后在冰上用10μM GDP培养10分钟。将药物溶液与膜混合,然后通过加入GTPγ35S引发反应,并在25℃下持续30分钟。在Whatman GF/B过滤器上真空过滤反应混合物,并用3mL冰冷缓冲液(HEPES 25,pH7.4、MgCl2 10和NaCl 100)洗涤三次。干燥过滤器并与闪烁体混合,使用β-计数器对35S活性进行计数。通过减去不存在激动剂的情况获得激动剂诱导的GTPγ35S结合。采用非线性回归方法分析结合数据。在拮抗剂检测的情况下,反应混合物在浓度范围0.08至5000nM的测试拮抗剂的存在下含有10nMS1P。
表3显示活性潜能:自GTPγ35S的S1P1受体,nM,(EC50),%刺激。
活性潜能:自GTPγ35S的S1P1受体:nM,(EC50),
表3
实施例9
小鼠中的淋巴细胞减少测定
在含有3%(w/v)2-羟丙基β-环糊精(HPBCD)和1%DMSO的溶液中制备测试药物到终浓度为1mg/ml,并以10mg/Kg剂量对体重20-25g的雌性C57BL6小鼠(CHARLES RIVERS)进行皮下注射。通过在施药后的5、24、48、72和96小时用Goldenrod动物刺血针穿刺颌下皮肤获得血样。将血液收集到含有EDTA三钾盐的microvette(SARSTEDT)里。使用HEMAVET Multispecies HematologySystem,HEMAVET HV950FS(Drew Scientific Inc.)对血样中的淋巴细胞进行计数。
(Hale,J.et al Bioorg.& Med.Chem.Lett.14(2004)3351)。小鼠中S1P1激动剂诱导的淋巴细胞减少:时间进程(10mg/Kg ip)
1-{4-[(5-苯基戊基)氧]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸
Claims (20)
1.一种式I化合物,其对映异构体、非对映异构体、及单独的互变异构体或其药学上可接受的盐
其中:
R1是C-R11;
R2是5员或6员芳族杂环、5员环烯基或C6-10芳基;
R3是O或S;
R4是C6-10芳基;
R5是H、卤素或-OC1-3烷基;
R6是H;
R7是H或C1-6烷基;
R8是H;
R9是CH或N;
R10是COOH;
R11是H;
a是0、1、2、3或4;
b是0、1、2、3或4;
c是0或1;
d是0或1;
e是0或1;
f是1;
g是0;
L是CHR17或O;且
R17是H或C1-3烷基;
附带条件是当R3是O、S且b是0或1时,L不是O。
2.根据权利要求1所述的化合物,其中:
R1是C-R11;
R2是5员芳族杂环或5员环烯基;
R3是O或S;
R4是C6-10芳基;
R5是H、卤素或-OC1-3烷基;
R6是H;
R7是H或C1-6烷基;
R8是H;
R9是CH或N;
R10是COOH;
R11是H;
a是0、1、2、3或4;
b是0、1、2、3或4;
c是0或1;
d是0或1;
e是0或1;
f是1;
g是0;
L是CHR17或O;且
R17是H或C1-3烷基;
附带条件是当R3是O、S且b是0或1时,L不是O。
3.根据权利要求1所述的化合物,其中:
R1是C-R11;
R2是环戊烯、噻吩、呋喃、吡咯、噁唑、噻唑、咪唑、吡唑、异噁唑、异噻唑、四唑、噁二唑、1,2,5-噁二唑、噻二唑、1,2,3-三唑、1,2,4-三唑、或咪唑;
R3是O或S;
R4是C6-10芳基;
R5是H、卤素或-OC1-3烷基;
R6是H;
R7是H或C1-6烷基;
R8是H;
R9是CH或N;
R10是COOH;
R11是H;
a是0、1、2、3或4;
b是0、1、2、3或4;
c是0或1;
d是0或1;
e是0或1;
f是1;
g是0;
L是CHR17或O;且
R17是H或C1-3烷基;
附带条件是当R3是O、S且b是0或1时,L不是O。
4.根据权利要求1所述的化合物,其中:
R1是C-R11;且
R2是5员或6员芳族杂环或5员环烯基;且
R3是O或S;且
R4是C6-10芳基;且
R5是H、-OC1-3烷基或卤素;且
R6是H;且
R7是H或C1-6烷基;且
R8是H;且
R9是CH或N;且
R10是COOH;且
R11是H;且
a是0、1、2或3;且
b是1、2或3;且
c是0或1;且
d是0或1;且
e是0或1;且
f是1;且
g是0;且
L是CHR17或O;且
R17是H或C1-3烷基;
附带条件是当R3是O或S且b是1时,L不是O。
5.根据权利要求1所述的化合物,其中:
R1是C-R11;且
R2是5员或6员芳族杂环或5员环烯基;且
R3是O;且
R4是C6-10芳基;且
R5是H、-OC1-3烷基或卤素;且
R6是H;且
R7是H或C1-6烷基;且
R8是H;且
R9是CH;且
R10是COOH;且
R11是H;且
a是0、1、2或3;且
b是1、2或3;且
c是1;且
d是1;且
e是0或1;且
f是1;且
g是0;且
L是CHR17;且
R17是H。
6.根据权利要求1所述的化合物,其中:
R1是C-R11;且
R2是5员或6员芳族杂环或5员环烯基;且
R3是S;且
R4是C6-10芳基;且
R5是H、-OC1-3烷基或卤素;且
R6是H;且
R7是H或C1-6烷基;且
R8是H;且
R9是CH或N;且
R10是COOH;且
R11是H;且
a是0、1、2或3;且
b是1、2或3;且
c是0或1;且
d是0或1;且
e是0或1;且
f是1;且
g是0;且
L是CHR17或O;且
R17是H或C1-3烷基;
附带条件是当R3是S且b是1时,L不是O。
7.根据权利要求1所述的化合物,其中:
R1是C-R11;且
R2是5员或6员芳族杂环或5员环烯基;且
R3是O;且
R4是C6-10芳基;且
R5是H、-OC1-3烷基或卤素;且
R6是H;且
R7是H或C1-6烷基;且
R8是H;且
R9是CH或N;且
R10是COOH;且
R11是H;且
a是0、1、2或3;且
b是1、2或3;且
c是0或1;且
d是0或1;且
e是0或1;且
f是1;且
g是0;且
L是CHR17或O;且
R17是H或C1-3烷基;
附带条件是当R3是O且b是1时,L不是O。
8.根据权利要求1所述的化合物,其中:
R1是C-R11;且
R2是5员或6员芳族杂环、C6-10芳基或5员环烯基;且
R3是O;且
R4是C6-10芳基;且
R5是H或卤素;且
R6是H;且
R7是H或C1-6烷基;且
R8是H;且
R9是CH或N;且
R10是COOH;且
R11是H;且
a是0、1、2或3;且
b是1、2或3;且
c是0或1;且
d是0或1;且
e是0或1;且
f是1;且
g是0;且
L是CHR17;且
R17是H。
9.根据权利要求1所述的化合物,其中:
R1是C-R11;且
R2是5员或6员芳族杂环或5员环烯基;且
R3是O或S;且
R4是C6-10芳基;且
R5是H、-OC1-3烷基或卤素;且
R6是H;且
R9是N;且
R10是COOH;且
a是0、1、2或3;且
b是1、2或3;且
c是0;且
d是0;且
e是1;且
f是1;且
g是0;且
L是CHR17或O;且
R17是H或C1-3烷基;
附带条件是当R3是O或S且b是1时,L不是O。
10.根据权利要求1所述的化合物,选自:
1-{3-(3-呋喃基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{3-甲氧基-4-[(5-苯基戊基)氧]-5-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(6-苯基己基)氧]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[3-(苄氧基)丙氧基]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[3-(4-异丁基苯基)丙氧基]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-[4-(2-联苯-4-基乙氧基)-3-(2-噻吩基)苄基]氮杂环丁烷-3-羧酸;
1-{3-氯-4-[(5-苯基戊基)氧]-5-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{3-氯-4-[(5-苯基戊基)氧]-5-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(3-甲基-5-苯基戊基)氧]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{3-(5-甲基-2-噻吩基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{3-(4-甲基-2-噻吩基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{3-(3-甲基-2-噻吩基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1,3-噻唑-5-基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1,3-噻唑-4-基)苄基}氮杂环丁烷-3-羧酸;
1-{3-环戊-1-烯-1-基-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1H-吡唑-5-基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1H-吡唑-4-基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-吡啶-4-基苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(3-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-({6-[(5-苯基戊基)氧]联苯-3-基}甲基)氮杂环丁烷-3-羧酸;
1-{3-(2-呋喃基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1,3-噻唑-2-基)苄基}氮杂环丁烷-3-羧酸;
1-{3-(1,3-噁唑-2-基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1H-吡唑-1-基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)硫代]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{3-环戊-1-烯-1-基-4-[(5-苯基戊基)硫代]苄基}氮杂环丁烷-3-羧酸;
3-({4-[(5-苯基戊基)氧]-3-(2-噻吩基)苄基}氨基)环丁烷羧酸;
3-[(1-{4-[(5-苯基戊基)氧]-3-(2-噻吩基)苯基}乙基)氨基]环丁烷羧酸。
11.根据权利要求1所述的化合物,选自:
1-{3-(3-呋喃基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{3-氯-4-[(5-苯基戊基)氧]-5-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1,3-噻唑-5-基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1,3-噻唑-4-基)苄基}氮杂环丁烷-3-羧酸;
1-{3-环戊-1-烯-1-基-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1H-吡唑-5-基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1H-吡唑-4-基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(3-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{3-(2-呋喃基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1,3-噻唑-2-基)苄基}氮杂环丁烷-3-羧酸;
1-{3-(1,3-噁唑-2-基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1H-吡唑-1-基)苄基}氮杂环丁烷-3-羧酸;
3-({4-[(5-苯基戊基)氧]-3-(2-噻吩基)苄基}氨基)环丁烷羧酸;
3-[(1-{4-[(5-苯基戊基)氧]-3-(2-噻吩基)苯基}乙基)氨基]环丁烷羧酸。
12.一种药物组合物,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。
13.根据权利要求12所述的药物组合物,其中所述化合物选自:
1-{3-(3-呋喃基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{3-甲氧基-4-[(5-苯基戊基)氧]-5-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(6-苯基己基)氧]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[3-(苄氧基)丙氧基]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[3-(4-异丁基苯基)丙氧基]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-[4-(2-联苯-4-基乙氧基)-3-(2-噻吩基)苄基]氮杂环丁烷-3-羧酸;
1-{3-氯-4-[(5-苯基戊基)氧]-5-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{3-氯-4-[(5-苯基戊基)氧]-5-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(3-甲基-5-苯基戊基)氧]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{3-(5-甲基-2-噻吩基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{3-(4-甲基-2-噻吩基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{3-(3-甲基-2-噻吩基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1,3-噻唑-5-基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1,3-噻唑-4-基)苄基}氮杂环丁烷-3-羧酸;
1-{3-环戊-1-烯-1-基-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1H-吡唑-5-基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1H-吡唑-4-基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-吡啶-4-基苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(3-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-({6-[(5-苯基戊基)氧]联苯-3-基}甲基)氮杂环丁烷-3-羧酸;
1-{3-(2-呋喃基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1,3-噻唑-2-基)苄基}氮杂环丁烷-3-羧酸;
1-{3-(1,3-噁唑-2-基)-4-[(5-苯基戊基)氧]苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)氧]-3-(1H-吡唑-1-基)苄基}氮杂环丁烷-3-羧酸;
1-{4-[(5-苯基戊基)硫代]-3-(2-噻吩基)苄基}氮杂环丁烷-3-羧酸;
1-{3-环戊-1-烯-1-基-4-[(5-苯基戊基)硫代]苄基}氮杂环丁烷-3-羧酸;
3-({4-[(5-苯基戊基)氧]-3-(2-噻吩基)苄基}氨基)环丁烷羧酸;
3-[(1-{4-[(5-苯基戊基)氧]-3-(2-噻吩基)苯基}乙基)氨基]环丁烷羧酸。
14.一种包含治疗有效量的至少一种式I化合物的药物组合物用于制备治疗与鞘氨醇-1-磷酸酯(S1P)受体调节相关的病症的药剂的用途
其中:
R1是C-R11;
R2是5员或6员芳族杂环、5员环烯基或C6-10芳基;
R3是O或S;
R4是C6-10芳基;
R5是H、卤素或-OC1-3烷基;
R6是H;
R7是H或C1-6烷基;
R8是H;
R9是CH或N;
R10是COOH;
R11是H;
a是0、1、2、3或4;
b是0、1、2、3或4;
c是0或1;
d是0或1;
e是0或1;
f是1;
g是0;
L是CHR17或O;且
R17是H或C1-3烷基;
附带条件是当R3是O或S且b是0或1时,L不是O。
15.根据权利要求14所述的用途,其中对所述哺乳动物施用所述药物组合物以治疗:眼部疾病;或与全身血管障碍有关的疾病、各种炎症性疾病;或自身免疫性疾病和免疫抑制;或过敏及其它炎症性疾病;或心肌保护、缺血再灌注损伤和动脉粥样硬化;或整容皮肤手术、眼科手术、GI手术、普通外科、口腔受伤、各种机械、热及烧伤的伤口愈合、伤口的无疤痕愈合、预防和治疗光老化及皮肤老化和预防辐射引起的损伤;或骨形成、治疗骨质疏松症及包括髋关节和踝关节在内的各种骨折;或抗伤害性活动、内脏痛、与糖尿病性神经病变相关的疼痛、类风湿关节炎、慢性膝盖及关节疼痛、肌腱炎、骨关节炎、神经性疼痛。
16.根据权利要求14所述的用途,其中对所述哺乳动物施用所述药物组合物以治疗:湿性及干性年龄相关性黄斑变性、糖尿病性视网膜病变、早产儿视网膜病变、视网膜水肿、地图样萎缩、青光眼性视神经病变、脉络膜视网膜病变、高血压性视网膜病变、眼部缺血综合症、预防眼背部中炎症引起的纤维化、各种眼部炎症性疾病;或类风湿关节炎、克罗恩病、格雷夫斯病、炎症性肠病、多发性硬化症、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、接触性过敏反应、特应性皮炎和器官移植;或荨麻疹、支气管哮喘及其它呼吸道炎症。
17.根据权利要求16所述的用途,其中所述各种眼部炎症性疾病包括葡萄膜炎、巩膜炎、角膜炎和视网膜血管炎。
18.根据权利要求15所述的用途,其中所述各种炎症性疾病包括急性肺损伤、其预防、败血症、肿瘤转移、动脉粥样硬化、肺水肿和通气引起的肺损伤。
19.根据权利要求16所述的用途,其中所述其它呼吸道炎症包括肺气肿和慢性阻塞性肺病。
20.根据权利要求15-19中任一项所述的用途,其中所述哺乳动物是人。
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RU2013150173A (ru) * | 2011-04-14 | 2015-05-20 | Аллерган, Инк. | Метиламинные производные бициклического фенила как модуляторы рецепторов сфингозин-1-фосфата |
EP2817290A1 (en) | 2012-02-21 | 2014-12-31 | Allergan, Inc. | Phenoxy-azetidine derivatives as sphingosine 1-phosphate (s1p) receptor modulators |
US20140171393A1 (en) * | 2012-12-13 | 2014-06-19 | Allergan, Inc. | Novel aromatic thio compounds as receptor modulators |
MX370032B (es) | 2013-02-20 | 2019-11-28 | Lg Chemical Ltd | Agonistas del receptor de esfingosina-1-fosfato, metodos para prepararlos y composiciones farmaceuticas que contienen los mismos como un agente activo. |
WO2014138075A1 (en) * | 2013-03-07 | 2014-09-12 | Allergan, Inc. | Phosphonic acid compounds as sphingosine-1-phosphate receptor modulators |
WO2015021112A1 (en) * | 2013-08-08 | 2015-02-12 | Allergan, Inc. | Disubstituted aryl oxy derivatives as sphingosine-1- phosphate receptors modulators |
US20150045341A1 (en) * | 2013-08-08 | 2015-02-12 | Allergan, Inc. | Disubstituted aryl azetidine derivatives as sphingosine-1 phosphate receptors modulators |
WO2015073547A1 (en) * | 2013-11-13 | 2015-05-21 | Allergan, Inc. | Disubstituted phenoxy azetidine derivatives as sphingosine-1-phosphate (s1p) receptor modulators |
US20210113529A1 (en) | 2018-02-02 | 2021-04-22 | Kyoto University | Medicine for preventing or treating ophthalmic disease associated with enhanced intraocular neovascularization and/or intraocular vascular permeability |
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003061567A2 (en) * | 2002-01-18 | 2003-07-31 | Merck & Co., Inc. | Selective s1p1/edg1 receptor agonists |
WO2008030843A1 (en) * | 2006-09-07 | 2008-03-13 | Allergan, Inc. | Heteroaromatic compounds having sphingosine-1-phosphate (s1p) receptor agonist and/or antagonist biological activity |
Family Cites Families (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0146810A3 (de) * | 1983-12-05 | 1987-05-13 | Solco Basel AG | Verfahren zur Herstellung von Sphingosinderivaten |
US5110987A (en) * | 1988-06-17 | 1992-05-05 | Emory University | Method of preparing sphingosine derivatives |
NZ233285A (en) | 1989-04-18 | 1992-06-25 | Duphar Int Res | Imidazole-substituted carbamoyl-indoles and condensed analogues thereof and pharmaceutical compositions |
US5294722A (en) * | 1992-04-16 | 1994-03-15 | E. R. Squibb & Sons, Inc. | Process for the preparation of imidazoles useful in angiotensin II antagonism |
US5403851A (en) | 1994-04-05 | 1995-04-04 | Interneuron Pharmaceuticals, Inc. | Substituted tryptamines, phenalkylamines and related compounds |
US6235912B1 (en) * | 1997-03-12 | 2001-05-22 | Takara Shuzo Co., Ltd. | Sphingosine analogues |
DE69835223T2 (de) | 1997-09-11 | 2007-05-31 | Takara Bio Inc., Otsu | Sphingosinderivate und medizinische zubereitung |
DE10010067A1 (de) * | 2000-03-02 | 2001-09-06 | Bayer Ag | Neue Imidazotriazinone und ihre Verwendung |
DK1397130T3 (da) * | 2001-06-20 | 2007-11-12 | Wyeth Corp | Substituerede indolsyrederivater som inhibitorer af plasminogenaktivatorinhibitor-1 (PAI-1) |
EP1470137B1 (en) * | 2002-01-18 | 2009-09-02 | Merck & Co., Inc. | Edg receptor agonists |
JP4709488B2 (ja) * | 2002-01-18 | 2011-06-22 | メルク・シャープ・エンド・ドーム・コーポレイション | Edg受容体作動薬としてのN−(ベンジル)アミノアルキルカルボン酸化合物、ホスフィン酸化合物、ホスホン酸化合物およびテトラゾール類 |
CN1787817B (zh) * | 2003-05-19 | 2011-09-07 | Irm责任有限公司 | 免疫抑制剂化合物及组合物 |
CN1874991A (zh) * | 2003-08-29 | 2006-12-06 | 小野药品工业株式会社 | 能够结合s1p受体的化合物及其药物用途 |
KR20110140139A (ko) * | 2003-08-29 | 2011-12-30 | 오노 야꾸힝 고교 가부시키가이샤 | S1p 수용체 결합능을 갖는 화합물 및 그 의약 용도 |
KR20070042553A (ko) * | 2004-08-17 | 2007-04-23 | 갈데르마 리써어치 앤드 디벨로프먼트 | Ppar 유형의 수용체를 활성화시키는 신규 이방향족화합물 및 화장용 또는 약학 조성물에서의 그의 용도 |
GB0612721D0 (en) * | 2006-06-27 | 2006-08-09 | Novartis Ag | Organic compounds |
BRPI0716601A2 (pt) * | 2006-09-07 | 2013-09-17 | Allergan Inc | compostos de heteroaromÁticos tendo atividade biolàgica agonista de receptor de esfingosina-1-fosfato(s1p) |
US8614103B2 (en) * | 2006-10-27 | 2013-12-24 | Lpath, Inc. | Compositions and methods for treating sphingosine-1-phosphate (S1P) related ocular diseases and conditions |
TW200827346A (en) * | 2006-11-03 | 2008-07-01 | Astrazeneca Ab | Chemical compounds |
US8633245B2 (en) | 2008-04-11 | 2014-01-21 | Institute Of Medicinal Molecular Design, Inc. | PAI-1 inhibitor |
-
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003061567A2 (en) * | 2002-01-18 | 2003-07-31 | Merck & Co., Inc. | Selective s1p1/edg1 receptor agonists |
WO2008030843A1 (en) * | 2006-09-07 | 2008-03-13 | Allergan, Inc. | Heteroaromatic compounds having sphingosine-1-phosphate (s1p) receptor agonist and/or antagonist biological activity |
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