CN103338765A - 作为鞘氨醇1-磷酸(s1p)受体调节剂的新型苯基噁二唑衍生物 - Google Patents
作为鞘氨醇1-磷酸(s1p)受体调节剂的新型苯基噁二唑衍生物 Download PDFInfo
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- CN103338765A CN103338765A CN2011800666322A CN201180066632A CN103338765A CN 103338765 A CN103338765 A CN 103338765A CN 2011800666322 A CN2011800666322 A CN 2011800666322A CN 201180066632 A CN201180066632 A CN 201180066632A CN 103338765 A CN103338765 A CN 103338765A
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Classifications
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Abstract
本发明涉及新型苯基噁二唑衍生物、制备它们的工艺、包含它们的药物组合物以及它们作为药物、作为鞘氨醇-1-磷酸受体调节剂的用途。
Description
相关申请的交叉引用
本申请要求于2010年12月3日提交的美国临时申请序列号61/419,306的权益,该申请据此以引用方式全文并入本文。
技术领域
本发明涉及新型苯基噁二唑衍生物、制备它们的工艺、包含它们的药物组合物以及它们作为药物、作为鞘氨醇-1-磷酸受体调节剂的用途。本发明具体涉及这些化合物以及它们的药物组合物在治疗与鞘氨醇-1-磷酸(S1P)受体调节相关的障碍中的用途。
发明背景
鞘氨醇-1-磷酸以相对高的浓度储存在缺乏负责其分解代谢的酶的人血小板中,并且其在生理刺激(诸如生长因子、细胞因子以及受体激动剂和抗原)的激活下释放到血流中。其还可在血小板聚集和血栓形成中起关键作用,并可加重心血管疾病。在另一方面,在高密度脂蛋白(HDL)中相对高浓度的代谢物对动脉粥样化形成可具有有益的影响。例如,最近有研究表明鞘氨醇-1-磷酸与诸如鞘氨醇磷酸胆碱和血硫脑苷脂(lysosulfatide)的其他血溶性脂类一起通过刺激血管内皮产生强效抗动脉粥样硬化信号分子一氧化氮而负责HDL的有益临床效果。此外,与溶血磷脂酸一样,其为某些类型的癌症的标志物,并且有证据表明其在细胞分裂或增殖中的作用可对癌症发展具有影响。这些是目前在医药研究人员中产生了极大兴趣的热点,并且鞘氨醇-1-磷酸代谢中治疗性干预的潜能正受到积极的研究。
发明概要
现已发现了一组为强效的选择性鞘氨醇-1-磷酸调节剂的新型苯基噁二唑衍生物。因此,本文所述的化合物可用于治疗多种与鞘氨醇-1-磷酸受体调节相关的障碍。如本文所用的术语“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。
本发明描述式I的化合物,其具有鞘氨醇-1-磷酸受体生物活性。根据本发明的化合物因此具有在医学中的用途,例如在治疗患有由S1P调节所减轻的疾病和病症的人中的用途。
在一方面中,本发明提供具有式I的化合物或其药学上可接受的盐或其立体异构形式、或者几何异构体、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:
A是C6-10芳基、杂环、C3-8环烷基或C3-8环烯基;
B是C6-10芳基、杂环、C3-8环烷基或C3-8环烯基;
R1是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R2是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R3是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R4是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R5是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R6是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R7是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R8独立地为卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
L1是O、C(O)、S或NH;
R9是O、S、C(O)或CH2;
R10是H或C1-8烷基;
L2是CHR16、O、S、NR17、直接键或-C(O)-;
R11是H、OPO3H2、羧酸、PO3H2、C1-8烷基、-S(O)2H、-P(O)MeOH、-P(O)(H)OH或OR12;
R12是H或C1-8烷基;
a是0、1或2;
b是0或1;
c是0、1、2或3;
R13是H、C1-8烷基;
R14是H或C1-8烷基;以及
R15是H或C1-8烷基;
R16是H、OH或C1-8烷基;以及
R17是H或C1-8烷基。
在另一方面中,本发明提供具有式I的化合物,其中L1是O、C(O)、S或NH。
在另一方面中,本发明提供具有式I的化合物,其中L1是O、S或NH。
在另一方面中,本发明提供具有式I的化合物,
其中:
在另一方面中,本发明提供具有式I的化合物,
其中:
在另一方面中,本发明提供具有式I的化合物,
其中:
在另一方面中,本发明提供具有式I的化合物,
其中:
R1是H、卤素或C1-6烷基;
R2是H、卤素或C1-6烷基;
R3是H、卤素或C1-6烷基;
R4是H、卤素、-OC1-6烷基或C1-6烷基;
R5是H、卤素、-OC1-6烷基或C1-6烷基;
R6是H、卤素、-OC1-6烷基或C1-6烷基;
R7是H或C1-6烷基;
R8是C1-6烷基;
R9是O或CH2;
R10是H;
L1是O、S或NH;
L2是CHR16或直接键;
R11是羧酸或OR12;
R12是H;
a是0或2;
b是0或1;
c是0或1;以及
R16是H或OH。
在另一方面中,本发明提供具有式I的化合物,
其中:
R1是H、卤素、-OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R2是H、卤素、-OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R3是H、卤素、-OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R4是H、卤素、-OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R5是H、卤素、-OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R6是H、卤素、-OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R7是H、卤素、-OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R8独立地为卤素、-OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
L1是O、S或NH;
R9是O、S、C(O)或CH2;
R10是H或C1-6烷基;
L2是CHR16、O、S、NR17、直接键或-C(O)-;
R11是H、OPO3H2、羧酸、PO3H2、C1-6烷基、-S(O)2H、-P(O)MeOH、-P(O)(H)OH或OR12;
R12是H或C1-6烷基;
a是0、1或2;
b是0或1;
c是0、1、2或3;
R13是H、C1-6烷基;
R14是H或C1-6烷基;以及
R15是H或C1-6烷基;
R16是H、OH或C1-6烷基;以及
R17是H或C1-6烷基。
在另一方面中,本发明提供具有式I的化合物,其中
A是C6芳基;
B是C6芳基;
R1是H、卤素或C1-6烷基;
R2是H、卤素或C1-6烷基;
R3是H、卤素或C1-6烷基;
R4是H、卤素、-OC1-6烷基或C1-6烷基;
R5是H、卤素、-OC1-6烷基或C1-6烷基;
R6是H、卤素、-OC1-6烷基或C1-6烷基;
R7是H或C1-6烷基;
R8是C1-6烷基;
R9是O或CH2;
R10是H;
L1是O、S或NH;
L2是CHR16或直接键;
R11是羧酸或OR12;
R12是H;
a是0或2;
b是0或1;
c是0或1;以及
R16是H或OH。
在另一方面中,本发明提供具有式I的化合物,其中
A是C6芳基;
B是C6芳基;
R1是H、卤素、-OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R2是H、卤素、-OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R3是H、卤素、-OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R4是H、卤素、-OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R5是H、卤素、-OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R6是H、卤素、-OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R7是H、卤素、-OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R8独立地为卤素、-OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
L1是O、S或NH;
R9是O、S、C(O)或CH2;
R10是H或C1-6烷基;
L2是CHR16、O、S、NR17、直接键或-C(O)-;
R11是H、OPO3H2、羧酸、PO3H2、C1-6烷基、-S(O)2H、-P(O)MeOH、-P(O)(H)OH或OR12;
R12是H或C1-6烷基;
a是0、1或2;
b是0或1;
c是0、1、2或3;
R13是H、C1-6烷基;
R14是H或C1-6烷基;以及
R15是H或C1-6烷基;
R16是H、OH或C1-6烷基;以及
R17是H或C1-6烷基。
在另一方面中,本发明提供具有式I的化合物,
其中:
R1是H或氯代;
R2是H或氯代;
R3是H或氯代;
R4是H、甲基或氯代;
R5是H、甲基、乙基、丙基或甲氧基;
R6是H;
R7是H;
R8是甲基;
R9是O或CH2;
R10是H;
L1是O、S或NH;
L2是CHR16或直接键;
R11是羧酸或OR12;
R12是H;
a是0或2;
b是0或1;
c是0或1;以及
R16是H或OH。
在另一实施方案中,本发明提供具有式I的化合物,其中:
R1是H或氯代;
R2是H或氯代;
R3是H;
R4是H、甲基或氯代;
R5是H、甲基、乙基、丙基或甲氧基;
R6是H;
R7是H;
R9是CH2;
R10是H;
L1是O;
L2是直接键;
R11是羧酸;
R12是H;
a是0;
b是1;以及
c是0。
在另一实施方案中,本发明提供具有式I的化合物,其中:
R1是H或氯代;
R2是H或氯代;
R3是H或氯代;
R4是H;
R5是甲基;
R6是甲基;
R7是H;
R8是甲基;
R9是O或CH2;
R10是H;
L1是S;
L2是CHR16或直接键;
R11是羧酸或OR12;
R12是H;
a是0或2;
b是0或1;
c是0或1;以及
R16是H或OH。
在另一实施方案中,本发明提供具有式I的化合物,其中:
R1是H;
R2是氯;
R3是H;
R4是甲基;
R5是甲基;
R6是H;
R7是H;
R9是CH2;
R10是H;
L1是NH;
L2是直接键;
R11是羧酸;
a是0;
b是1;以及
c是0。
在另一实施方案中,本发明提供具有式I的化合物,其中:
R1是H、卤素或C1-6烷基;
R2是H、卤素或C1-6烷基;
R3是H、卤素或C1-6烷基;
R4是H、卤素、-OC1-6烷基或C1-6烷基;
R5是H、卤素、-OC1-6烷基或C1-6烷基;
R6是H、卤素、-OC1-6烷基或C1-6烷基;
R7是H或C1-6烷基;
R8是C1-6烷基;
R9是O或CH2;
R10是H;
L1是O、S或NH;
L2是CHR16或直接键;
R11是羧酸或OR12;
R12是H;
a是0或2;
b是0或1;
c是0或1;以及
R16是H或OH。
在另一实施方案中,本发明提供具有式I的化合物,其中:
R1是H、卤素或C1-6烷基;
R2是H、卤素或C1-6烷基;
R3是H、卤素或C1-6烷基;
R4是H、卤素、-OC1-6烷基或C1-6烷基;
R5是H、卤素、-OC1-6烷基或C1-6烷基;
R6是H、卤素、-OC1-6烷基或C1-6烷基;
R7是H或C1-6烷基;
R8是C1-6烷基;
R9是O或CH2;
R10是H;
L1是O;
L2是CHR16或直接键;
R11是羧酸或OR12;
R12是H;
a是0或2;
b是0或1;
c是0或1;以及
R16是H或OH。
在另一实施方案中,本发明提供具有式I的化合物,其中:
R1是H、卤素或C1-6烷基;
R2是H、卤素或C1-6烷基;
R3是H、卤素或C1-6烷基;
R4是H、卤素、-OC1-6烷基或C1-6烷基;
R5是H、卤素、-OC1-6烷基或C1-6烷基;
R6是H、卤素、-OC1-6烷基或C1-6烷基;
R7是H或C1-6烷基;
R8是C1-6烷基;
R9是O或CH2;
R10是H;
L1是S;
L2是CHR16或直接键;
R11是羧酸或OR12;
R12是H;
a是0或2;
b是0或1;
c是0或1;以及
R16是H或OH。
在另一实施方案中,本发明提供具有式I的化合物,其中:
R1是H、卤素或C1-6烷基;
R2是H、卤素或C1-6烷基;
R3是H、卤素或C1-6烷基;
R4是H、卤素、-OC1-6烷基或C1-6烷基;
R5是H、卤素、-OC1-6烷基或C1-6烷基;
R6是H、卤素、-OC1-6烷基或C1-6烷基;
R7是H或C1-6烷基;
R8是C1-6烷基;
R9是O或CH2;
R10是H;
L1是NH;
L2是CHR16或直接键;
R11是羧酸或OR12;
R12是H;
a是0或2;
b是0或1;
c是0或1;以及
R16是H或OH。
如本文所用的术语“烷基”是指具有直链或支链部分或它们的组合并包含1至8个碳原子的饱和的、单价烃部分。烷基的一个亚甲基(-CH2-)基团可被氧、硫、亚砜、氮、羰基、羧基、磺酰基或被二价C3-8环烷基代替。烷基基团可被卤素、羟基、环烷基、氨基、非芳族杂环、羧酸、膦酸基团、磺酸基团、磷酸取代。
如本文所用的术语“环烷基”是指衍生自饱和环状烃的3至8个碳原子的单价或二价基团。环烷基基团可以为单环或多环的。环烷基可被烷基基团或卤素原子取代。
如本文所用的术语“环烯基”是指衍生自具有一个双键的饱和环烷基的3至8个碳原子的单价或二价基团。环烯基基团可以为单环或多环的。环烯基基团可被烷基基团或卤素原子取代。
如本文所用的术语“卤素”是指氯、溴、氟、碘原子。
如本文所用的术语“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自由基。C2-6烯基可以为E或Z构型。烯基基团可被烷基基团取代。
如本文所用的术语“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自由基。炔基可被烷基基团取代。
如本文所用的术语“杂环”是指3至10元环,其可以为芳族的或非芳族的、饱和的或非饱和的,包含至少一个选自O或N或S或它们中至少两个的组合的杂原子,这些杂原子中断碳环结构。杂环可以被C=O中断;S杂原子可以被氧化。杂环可以为单环的或多环的。杂环部分可被羟基、烷基或卤素原子取代。
如本文所用的术语“芳基”是指去除一个氢的衍生自由6至10个碳原子组成的芳香烃的有机部分。芳基可以为单环或多环的。芳基可以被卤素原子、-OC1-6烷基、烷基、CN、C(O)(C1-6烷基)、N(C1-6烷基)(C1-6烷基)或NH2、或NH(C1-6烷基)、或羟基基团取代。通常芳基是苯基。在芳基上优选的取代位置是间位和对位。
如本文所用的术语“羟基”代表式“-OH”的基团。
如本文所用的术语“羰基”代表式“-C(O)”的基团。
如本文所用的术语“羧基”代表式“-C(O)O-”的基团。
如本文所用的术语“磺酰基”代表式“-SO2”的基团。
如本文所用的术语“硫酸酯”代表式“-O-S(O)2-O-”的基团。
如本文所用的术语“羧酸”代表式“-C(O)OH”的基团。
如本文所用的术语“亚砜”代表式“-S=O”的基团。
如本文所用的术语“膦酸”代表式“-P(O)(OH)2”的基团。
如本文所用的术语“磷酸”代表式“-(O)P(O)(OH)2”的基团。
如本文所用的术语“硼酸”代表式“-B(OH)2”的基团。
如本文所用的术语“磺酸”代表式“-S(O)2OH”的基团。
如本文所用的式“H”代表氢原子。
如本文所用的式“O”代表氧原子。
如本文所用的式“N”代表氮原子。
如本文所用的式“S”代表硫原子。
本发明的一些化合物为:
3-[(4-{5-[(3-氯苯氧基)(2-氯苯基)甲基]-1,2,4-噁二唑-3-基}苄基)氨基]丙酸;
3-{[4-(5-{(4-氯苯基)[(3,4-二甲基苯基)硫代]甲基}-1,2,4-噁二唑-3-基)苄基]氨基}丙酸;
3-{[4-(5-{(3-氯苯基)[(3,4-二甲基苯基)硫代]甲基}-1,2,4-噁二唑-3-基)苄基]氨基}丙酸;
3-{[4-(5-{(2-氯苯基)[(3,4-二甲基苯基)硫代]甲基}-1,2,4-噁二唑-3-基)苄基]氨基}丙酸;
3-[(4-{5-[(3-氯苯基)(4-丙基苯氧基)甲基]-1,2,4-噁二唑-3-基}苄基)氨基]丙酸;
3-[(4-{5-[(3-氯苯基)(4-乙基苯氧基)甲基]-1,2,4-噁二唑-3-基}苄基)氨基]丙酸;
3-[(4-{5-[(3-氯苯基)(4-甲基苯氧基)甲基]-1,2,4-噁二唑-3-基}苄基)氨基]丙酸;
3-{[4-(5-{(3-氯苯基)[(3,4-二甲基苯基)氨基]甲基}-1,2,4-噁二唑-3-基)苄基]氨基}丙酸;
3-[(4-{5-[(2-氯苯基)(4-甲氧基-3-甲基苯氧基)甲基]-1,2,4-噁二唑-3-基}苄基)氨基]丙酸;
3-[4-(5-{(3-氯苯基)[(3,4-二甲基苯基)硫代]甲基}-1,2,4-噁二唑-3-基)-2,6-二甲基苯氧基]丙-1,2-二醇。
式I的一些化合物及其中间体中的一些在其结构中具有至少一个立体中心。该立体中心可以R或S构型存在,所述R和S符号根据Pure Appli.Chem.(1976),45,11-13中所述的规则使用。
术语“药学上可接受的盐”是指保持上文确定的化合物的所需生物活性并表现出最小的或不表现出非期望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化合物能够形成的具有治疗活性的无毒碱式或酸式盐形式。
作为碱以其游离形式存在的式I化合物的酸加成盐形式可通过用合适的酸处理游离碱而获得,诸如无机酸,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、甲磺酸、乙磺酸、苯磺酸、甲酸等(Handbook of Pharmaceutical Salts,P.Heinrich Stahal&Camille G.Wermuth(Eds),Verlag Helvetica Chemica Acta-Zürich,2002,329-345)。
式I化合物及其盐可以为溶剂化物的形式,溶剂化物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。
至于本发明提及一种化合物或多种化合物,旨在涵盖该化合物的每一种可能的同分异构形式及其混合物,除非具体提及了特定的同分异构形式。
根据本发明的化合物可以不同的多晶型形式存在。虽然未在上式中明确指明,但是此类形式旨在包括在本发明的范围内。
本发明的化合物适用于治疗或预防其中可能存在涉及鞘氨醇-1-磷酸受体的组分的病症。
在另一个实施方案中,提供在药学上可接受的载体中包含本发明的至少一种化合物的药物组合物。
在又一个实施方案中,提供用于治疗与鞘氨醇-1-磷酸受体的调节相关的障碍的方法。此类方法可例如通过向对其有需要的受试者施用包含治疗有效量的本发明的至少一种化合物的药物组合物而执行。
这些化合物可用于治疗哺乳动物,包括人,范围为通过S1P调节而缓解的病症和疾病。
S1P调节剂的治疗效用为眼病:
湿性和干性年龄相关性黄斑变性、糖尿病性视网膜病、早产儿视网膜病变、视网膜水肿、地图状萎缩、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、眼部缺血综合征、眼睛后部炎症所致的纤维化的预防、包括葡萄膜炎、巩膜炎、角膜炎和视网膜脉管炎的各种眼部炎症疾病;
系统性血管屏障相关疾病:包括急性肺损伤、其预防的各种炎性疾病、败血病、肿瘤转移、动脉粥样硬化、肺水肿和机械通气所致的肺损伤;
自身免疫疾病和免疫抑制:类风湿性关节炎、克罗恩病、格雷夫斯病、炎性肠病、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、特应性皮炎和器官移植;
过敏和其他炎性疾病:荨麻疹、支气管哮喘以及包括肺气肿和慢性阻塞性肺病的其他气道炎症;
心脏功能:心动过缓、充血性心力衰竭、心律失常、预防和治疗动脉粥样硬化、以及缺血/再灌注损伤;
伤口愈合:皮肤美容手术、眼科手术、GI手术、普外科手术、口腔损伤、各种机械性损伤、灼伤和烧伤后伤口的无疤痕愈合、预防和治疗光老化和皮肤老化、以及预防辐射所致的损伤;
骨形成:治疗骨质疏松以及包括髋和踝的各种骨折;
抗伤害性活动:内脏痛、与糖尿病性神经病变相关的疼痛、类风湿性关节炎、慢性膝盖和关节疼痛、肌腱炎、骨关节炎、神经性疼痛;
抗纤维化:眼、心脏、肝和肺纤维化、增殖性玻璃体视网膜病变、瘢痕性类天疱疮、手术所致的角膜、结膜和筋膜纤维化;
疼痛和抗炎:急性疼痛、慢性疼痛发作、肌肉骨骼疼痛、内脏疼痛、与糖尿病性神经病变相关的疼痛、类风湿性关节炎、慢性膝盖和关节疼痛、肌腱炎、骨关节炎、滑囊炎、神经性疼痛;
CNS神经元损伤:阿尔茨海默病、年龄相关神经元损伤;
器官移植:肾、角膜、心脏和脂肪组织移植。
在再一个实施方案中,提供用于治疗与鞘氨醇-1-磷酸受体的调节相关的障碍的方法。此类方法可例如通过向对其有需要的受试者施用治疗有效量的本发明的至少一种化合物、或其任何组合、或药学上可接受的盐、水合物、溶剂化物、晶体形式、其各个异构体、对映异构体和非对应异构体而执行。
本发明涉及式I的化合物或其药学上可接受的盐在制造用于治疗以下方面的药剂中的用途:
眼病:湿性和干性年龄相关性黄斑变性、糖尿病性视网膜病、早产儿视网膜病变、视网膜水肿、地图状萎缩、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、眼部缺血综合征、眼睛后部炎症所致的纤维化的预防、包括葡萄膜炎、巩膜炎、角膜炎和视网膜脉管炎的各种眼部炎症疾病;
系统性血管屏障相关疾病:包括急性肺损伤、其预防的各种炎性疾病、败血病、肿瘤转移、动脉粥样硬化、肺水肿和机械通气所致的肺损伤;
自身免疫疾病和免疫抑制:类风湿性关节炎、克罗恩病、格雷夫斯病、炎性肠病、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、特应性皮炎和器官移植;
过敏和其他炎性疾病:荨麻疹、支气管哮喘以及包括肺气肿和慢性阻塞性肺病的其他气道炎症;
心脏功能:心动过缓、充血性心力衰竭、心律失常、预防和治疗动脉粥样硬化、以及缺血/再灌注损伤;
伤口愈合:皮肤美容手术、眼科手术、GI手术、普外科手术、口腔损伤、各种机械性损伤、灼伤和烧伤后伤口的无疤痕愈合、预防和治疗光老化和皮肤老化、以及预防辐射所致的损伤;
骨形成:治疗骨质疏松以及包括髋和踝的各种骨折;
抗伤害性活动:内脏痛、与糖尿病性神经病变相关的疼痛、类风湿性关节炎、慢性膝盖和关节疼痛、肌腱炎、骨关节炎、神经性疼痛;
抗纤维化:眼、心脏、肝和肺纤维化、增殖性玻璃体视网膜病变、瘢痕性类天疱疮、手术所致的角膜、结膜和筋膜纤维化;
疼痛和抗炎:急性疼痛、慢性疼痛发作、肌肉骨骼疼痛、内脏疼痛、与糖尿病性神经病变相关的疼痛、类风湿性关节炎、慢性膝盖和关节疼痛、肌腱炎、骨关节炎、滑囊炎、神经性疼痛;
CNS神经元损伤:阿尔茨海默病、年龄相关神经元损伤;
器官移植:肾、角膜、心脏和脂肪组织移植。
在任何给定情况下将施用的化合物的实际量将由医生考虑到相关情况而确定,诸如病症的严重性、患者的年龄和体重、患者的一般身体状况、病症的原因和施用途径。
将以任何可接受的剂型向患者经口施用化合物,诸如片剂、液体剂、胶囊剂、散剂等,或者其他途径可能是所需的或必要的,尤其是在患者出现恶心时。此类其他途径可包括但不限于透皮、肠胃外、皮下、鼻内、通过植入支架、鞘内、玻璃体内、眼睛局部、眼睛后部、肌内、静脉内和直肠内递送模式。另外,可对制剂进行设计以经历一段给定的时间延迟活性化合物的释放,或仔细控制疗程中给定时间释放的药物量。
在本发明的另一个实施方案中,提供在其药学上可接受的载体中包含本发明的至少一种化合物的药物组合物。短语“药学上可接受的”意指载体、稀释剂或赋形剂必须与制剂中的其他成分相容并且对其受体无害。
本发明的药物组合物可以固体、溶液、乳液、混悬液、贴片、胶束、脂质体等剂型使用,其中所得组合物包含作为活性成分与适用于肠内或肠胃外应用的有机或无机载体或赋形剂配混的本发明的一种或多种化合物。本发明的化合物可例如与常用的无毒、药学上可接受的片剂、丸剂、胶囊剂、栓剂、溶液剂、乳剂、混悬剂和任何其他适用剂型的载体结合。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、胶态二氧化硅、马铃薯淀粉、脲、中长链三甘油酯、葡聚糖和适用于制造固体、半固体或液体形式的制剂的其他载体。此外,可以使用助剂、稳定剂、增稠剂、着色剂和芳香剂。本发明的化合物以足以对病程或病况产生所需效果的量包含在药物组合物中。
包含本发明的化合物的药物组合物可以为适于经口使用的剂型,例如作为片剂、糖锭剂、锭剂、水性或油性混悬剂、可分散粉末或颗粒剂、乳剂、硬胶囊剂或软胶囊剂、或糖浆剂或酏剂。适于经口使用的组合物可根据本领域已知的用于制造药物组合物的任何方法制备,并且此类组合物可包含选自以下的一种或多种物质:甜味剂,诸如蔗糖、乳糖或糖精;矫味剂,诸如薄荷油、冬青油或桂樱油;着色剂和防腐剂,以便提供药学上美观和可口的制剂。包含与无毒药学上可接受的赋形剂配混的本发明化合物的片剂也通过已知的方法制造。所用的赋形剂可以例如为:(1)惰性稀释剂,诸如碳酸钙、乳糖、磷酸钙或磷酸钠;(2)制粒剂和崩解剂,诸如玉米淀粉、马铃薯淀粉或藻酸;(3)粘合剂,诸如黄蓍胶、玉米淀粉、明胶或阿拉伯树胶;以及(4)润滑剂,诸如硬脂酸镁、硬脂酸或滑石。片剂可以无包衣或者它们可通已知的技术包衣以延迟在胃肠道中的崩解和吸收并因此经历较长的时间提供持续作用。例如,可以采用诸如单硬脂酸甘油酯或二硬脂酸甘油酯的延时材料。
在一些情况下,经口使用的制剂可以为硬明胶胶囊剂形式,其中将本发明的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。它们也可以为软明胶胶囊剂形式,其中将本发明的化合物与水或油介质例如花生油、液体石蜡或橄榄油混合。
药物组合物可以为无菌注射用混悬剂。该混悬剂可根据已知的方法使用合适的分散剂或润湿剂和助悬剂配制。无菌注射用制剂也可以为无毒、肠胃外可接受的稀释剂或溶剂中的无菌注射用溶液剂或混悬剂,例如作为1,3-丁二醇中的溶液。通常将无菌、固定油用作溶剂或助悬介质。为此,可以采用任何温和的固定油,包括合成的单或二甘油酯、脂肪酸(包括油酸)、天然存在的植物油(如芝麻油、椰子油、花生油、棉籽油等)或合成的脂肪载剂(如油酸乙酯)等等。可根据需要掺入缓冲剂、防腐剂、抗氧化剂等。
本发明的化合物可以用于经直肠给药的栓剂施用。这些组合物可通过将本发明的化合物与合适的非刺激性赋形剂混合而制备,诸如可可油、合成的聚乙二醇甘油酯,这些赋形剂在常温下为固体,但在直肠腔内则液化和/或溶解以释放药物。
由于个体受试者在症状严重性方面可表现出较大的变化并且每种药物具有其独特的治疗特性,因此每名受试者所采用的精确施用模式和剂量将由从业者决定。
本文所述的化合物和药物组合物可在哺乳动物(包括人)中用作药剂以用于对鞘氨醇-1-磷酸受体的激动剂或功能性拮抗剂治疗有反应的疾病治疗和/或病症缓解。因此,在本发明另外的实施方案中,提供用于治疗与鞘氨醇-1-磷酸受体的调节相关的障碍的方法。此类方法可例如通过向对其有需要的受试者施用包含治疗有效量的至少一种本发明化合物的药物组合物而执行。如本文所用,术语“治疗有效量”意指研究人员、兽医、医生或其他临床医生所寻求的将引起对其有需要的受试者出现生物学或医学反应的药物组合物的量。在一些实施方案中,对其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。
本发明还涉及用于制备式I化合物的工艺。根据本发明的式I化合物可采用与合成有机化学领域技术人员所理解的常规方法相似的方式制备。下文所示的合成方案示出了可以如何制备根据本发明的化合物。
以下缩写将用在一般方案和具体实施例中:
CDI 1,1′-羰基二咪唑
THF 四氢呋喃
RT 室温
MPLC 中压液相色谱
NMO 4-甲基吗啉N-氧化物
AcCN 乙腈
DCM 二氯甲烷
TPAP 四甲基过钌酸铵
MeOH 甲醇
NaCNBH3 氰基硼氢化钠
H2O 水
CD3OD 氘化甲醇
MgCl2 氯化镁
NaCl 氯化钠
DMSO-d6 氘化二甲亚砜
Im 咪唑
获得式I的化合物的一般流程A,其中R11是羧酸
L1是O,NH或S
式I
将取代羧酸(1当量)(根据Vaccaro等人,Journal of MedicinalChemistry,1996,39(8),1704-1719)制备)和CDI(1-1.5当量)在THF中的溶液在rt下搅拌30min。将N-羟基-4-(羟基甲基)苄脒(1当量)(根据Li,Zhen等人,J.Med.Chem.,2005,48(20),pp6169-6173制备)加入,将所得溶液在rt下搅拌过夜。然后将反应混合物转移至微波反应容器以及在150℃、微波条件下加热20min。在冷却至rt之后,将溶剂在减压下去除。将所得醇通过MPLC使用在己烷中的5至10%乙酸乙酯来分离。将醇(1当量)与NMO(2.5当量)、分子筛(600mg)在AcCN(5.00mL)和DCM(25.00mL)中混合。将催化量的TPAP(28.00mg)加入。将所得反应混合物在RT下搅拌1小时以及蒸发至干。然后将所得醛通过MPLC使用在己烷中的0-10%乙酸乙酯来纯化。将醛(1当量)、氨基试剂(1.3当量)和TEA(1.5当量)与MeOH(8ml)一起混合。在60℃下搅拌90min之后,将反应溶液冷却至RT。将NaBH4(3当量)加入,将反应溶液在rt下搅拌2小时。将式I的化合物通过MPLC使用在EtOAc中的10至90%MeOH来分离。
用于获得式I的化合物的一般流程B,其中R11是羧酸
将4-氰基苯甲醛衍生物(10.83g)和氨基丙酸叔丁酯盐酸盐(15.00g)在MeOH(100mL)中混合,将20mL的Hunig碱加入,将所得反应混合物在50℃下加热,并搅拌60分钟。然后将反应混合物在0℃下冷却,将NaBH4(9.35g)缓慢加入,在14小时内将所得混合物缓慢加温至室温。将NaOH(2N,20mL)加入,使用乙醚来萃取反应混合物,使用盐水来洗涤合并的有机层,然后经硫酸钠干燥,并浓缩。将粗品溶解在DCM(150mL)中,冷却至0℃,将BOC酸酐(21.43g)加入,随后加入20mL的Hunig碱。将所得反应混合物在室温下搅拌14小时,然后浓缩。使用乙醚来稀释混合物,使用盐水来洗涤乙醚层,然后经硫酸镁干燥,并浓缩。然后将受BOC保护的化合物粗品与NH2OH(10mL)在异丙醇(20mL)中混合,在60分钟内加热至55℃。在浓缩和在真空下干燥之后获得所需(Z)-3-((叔丁氧基羰基)(4-(N′-羟基氨基甲酰基亚氨基)苯基)氨基)丙酸叔丁酯。
L1是O,NH或S
式I
以在一般工序A中描述的方式使(Z)-3-((叔丁氧基羰基)(4-(N′-羟基氨基甲酰基亚氨基)苯基)氨基)丙酸叔丁酯与合适取代的二芳基乙酸反应以得到环化的噁二唑化合物,将其溶解在DCM中,用TFA在室温下处理2小时,然后使用氨-MeOH碱化。浓缩,随后通过MPLC纯化,得到式I的所需化合物。
获得式I的化合物的一般流程,其中R11是P03H2
为了获得膦酸衍生物,将醛(1当量)(根据以上所述工序获得)、3-氨基丙基膦酸(1当量)和四丁基氢氧化铵(1.00Min MeOH,1当量)在MeOH(10.00mL)中搅拌。在50℃下搅拌30min之后,将NaBH3CN(1当量)加入,将所得反应混合物在50℃下搅拌3小时。使用0.5mL的水猝灭反应,浓缩至最小量。将标题化合物通过MPLC使用在EtOAc中的10至90%MeOH来分离。
本领域技术人员能够常规地修改和/或变更以下流程以合成通过式I涵盖的本发明的任何化合物。
发明详述
应当理解,前文一般性描述和下文详细描述均仅仅为示例性和阐释性的,而不限制受权利要求书保护的本发明。如本文所用,除非另外具体指明,否则单数的使用包括复数。
对本领域技术人员将显而易见的是,本发明的一些化合物可包含一个或多个不对称中心,使得化合物可以对映体以及以非对映体形式存在。除非另外具体指明,否则本发明的范围包括所有对映异构体、非对映体和外消旋混合物。本发明的一些化合物可与药学上可接受的酸或碱形成盐,并且本文所述的化合物的此类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含同位素的化合物。本发明的任何化合物可包含丰度高于或不同于天然比率的一个或多个同位素原子,诸如氘2H(或D)替代氕1H(或H),或使用富含13C的材料替代12C,等等。相似的取代可用于N、O和S。使用同位素可有助于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)而延长体内半衰期。这些化合物可根据通过使用富含同位素的试剂所述的制备方法而制备。
以下实施例仅为了进行示意性的说明,而非意在也不应视为以任何方式限制本发明。本领域的技术人员将会知道,可在不超出本发明的精神或范围的情况下对以下实施例作出变化和修改。
对本领域技术人员显而易见的是,各个同分异构形式可通过以常规方式分离其混合物而获得。例如,就非对映异构体而言,可以采用色谱分离。
化合物名称由ACD版本8生成;以及在实施例中所使用的中间体和试剂名称由诸如Chem Bio Draw Ultra版本12.0或来自MDL ISISDraw2.5SP1的Auto Nom2000的软件生成。
通常,根据以下方法来进行化合物的表征:将质子核磁共振(1HNMR)光谱记录在氘代溶剂中Varian300或600MHz光谱仪上。化学位移记录为相对作为内标(0.00ppm)的四甲基硅烷(TMS)的百万分之一表示的δ(delta)值,并且峰裂数记录为s,单峰;d,双重峰;t,三重峰;q,四重峰;m,多重峰;br,宽峰。以以下格式记录数据:化学位移(峰裂数,以赫兹(Hz)表示的耦合常数(s)J,累积强度)。
所有未描述其合成的试剂、溶剂、催化剂均购自化学品供应商,诸如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则根据已公布的程序制备。
除非另外指明,否则通常将本发明的化合物在具有硅胶柱的Teledyne-ISCO CombiFlash上通过柱色谱法(自动柱色谱仪)纯化。
实施例1
中间体1
(3-氯苯基)(3,4-二甲基苯氧基)乙酸
将3-氯苯基乙酸(20.90g,122.51mmol)和NBS(23.50g,132.03mmol)溶解在四氯化碳(300mL)中,然后将BPO(300mg)加入,在太阳灯下将所得反应加热回流5小时,然后冷却至室温,过滤和浓缩以得到所需α-溴-3-氯苯基乙酸。根据一般工序C使1.40g的α-溴-3-氯苯基乙酸与3,4-二甲基苯酚(686mg)反应以得到1.47g的所需标题化合物。光谱数据:1H NMR(300MHz,CDCl3)ppm2.17(s,3H)2.21(s,3H)5.58(s,1H)6.65(dd,J=8.20,2.64Hz,1H)6.78(d,J=2.64Hz,1H)7.01(d,J=8.20Hz,1H)7.29-7.40(m,2H)7.42-7.52(m,1H)7.59(s,1H)。
实施例2
中间体2
3-[(叔丁氧基羰基)(4-{5-[(3-氯苯基)(3,4-二甲基苯氧基)甲基]-1,2,4-噁二唑-3-基}苄基)氨基]丙酸叔丁酯
根据在以上一般工序C中所述合成方案在纯化之后通过MPLC由650mg的(3-氯苯基)(3,4-二甲基苯氧基)乙酸、羰基二咪唑(380mg,1.05当量)和3-[{4-[氨基(肟基)甲基]苄基}(叔丁氧基羰基)氨基]丙酸叔丁酯(880mg,1.0当量)获得475mg的中间体2。
1H NMR(300MHz,CDCl3)ppm1.36-1.57(m,18H)2.17(s,3H)2.21(s,3H)2.35-2.59(m,2H)3.30-3.61(m,2H)4.40-4.56(m,2H)6.44(s,1H)6.68-6.78(m,1H)6.82-6.90(m,1H)6.95-7.07(m,1H)7.35(d,J=5.27Hz,4H)7.46-7.57(m,1H)7.63-7.73(m,1H)8.02(d,J=8.20Hz,2H)。
实施例3
中间体3
2-(3-氯苯基)-2-((3,4-二甲基苯基)硫代)乙酸
将3-氯苯基乙酸(20.90g,122.52mmol)和NBS(23.50g,133.14mmol)溶解在四氯化碳(300mL)中,然后将BPO(300mg)加入,在太阳灯下将所得反应加热回流5小时,然后冷却至室温,过滤和浓缩以得到所需α-溴-3-氯苯基乙酸。然后使5.00g的该酸和3,4-二甲基苯硫酚(2.85g,20.62mmol)以及氢化钠(60%油状悬浮液,4.50g,87.50mmol))反应以得到中间体3,在未进一步纯化下将其用于下一合成步骤中。
实施例4
中间体4
4-(5-((3-氯苯基)((3,4-二甲基苯基)硫代)甲基)-1,2,4-噁二唑-3-基)-2,6-二甲基苯酚
将2-(3-氯苯基)-2-((3,4-二甲基苯基)硫代)乙酸(3.00g,9.78mmol)溶解在二氯乙烷中,然后将羰基二咪唑(2.00g,12.35mmol)加入,将所得反应混合物搅拌10分钟,将N′,4-二羟基-3,5-二甲基苯甲脒粗品(根据Diana,Guy D等人,Journal of MedicinalChemistry,1994,vol.37(15)p.2421-2436)(1.80g,9.99mmol)制备)加入。将反应混合物搅拌30分钟,然后浓缩。经快速色谱法(40%EtOAc/己烷),得到所需混合物,将其溶解在二甲苯(10mL)中,在30分钟内加热至125℃,然后冷却。经快速色谱法(20%EtAc/己烷)得到中间体4。
1H NMR(300MHz,DMSO-d6)δppm2.11(s,3H),2.14(s,3H),2.20(s,6H),6.21(s,1H),6.93-7.14(m,2H),7.18(s,1H),7.33-7.66(m,6H),8.95(s,1H)。
实施例5
化合物1
3-((4-(5-((3-氯苯基)(3,4-二甲基苯氧基)甲基)-1,2,4-噁二唑-3-基)苄基)氨基)丙酸
通过使用TFA处理,随后通过反相MPLC纯化由中间体2获得化合物1。
1H NMR(300MHz,CD3OD)δppm2.13(s,6H)2.79(t,J=6.74Hz,2H)3.31(s,3H)3.53(dd,J=13.48,8.50Hz,1H)4.32(s,2H)4.67(t,J=7.90Hz,1H)6.84(m,1H)6.88-6.95(m,2H)7.23-7.34(m,3H)7.40(m,1H)7.65(d,J=8.20Hz,2H)8.13(d,J=8.20Hz,2H)。
以在一般工序中描述的方法的类似方式来制备化合物2至11。各情况下起始材料和结果列表示出在下表1中。
表1
实施例6
化合物11
3-[4-(5-{(3-氯苯基)[(3,4-二甲基苯基)硫代]甲基}-1,2,4-噁二唑-3-基)-2,6-二甲基苯氧基]丙-1,2-二醇
向中间体4(0.40g,0.89mmol)在甲基乙基酮(10mL)中的溶液加入3-溴丙-1,2-二醇(0.80g,5.16mmol)和K2CO3(0.80g,5.79mmol),将所得反应混合物在90℃下搅拌16小时。将反应混合物冷却至室温,使用乙酸乙酯(40mL)来稀释。使用水来洗涤有机层,然后经干燥(Na2SO4)和浓缩。经快速色谱法(50%EtOAc/己烷)得到所需标题化合物。
1H NMR(300MHz,DMSO-d6)δppm2.11(s,3H),2.14(s,3H),2.20(s,6H),3.38-3.54(m,1H),3.74-3.89(m,1H),4.51-4.75(m,2H),4.84-5.00(m,1H),6.21(s,1H),6.93-7.14(m,2H),7.18(s,1H),7.33-7.66(m,6H)。
生物学数据
合成了化合物并使用GTPγ35S结合测定法测试了它们的S1P1活性。对这些化合物活化或阻断稳定表达S1P1受体的细胞中人S1P1受体活化的能力进行了评估。
GTPγ35S结合在150μl体积的含有(mM)以下物质的培养基中进行测量:HEPES25,pH7.4、MgCl210、NaCl100、二硫苏糖醇0.5、洋地黄皂苷0.003%、0.2nM GTPγ35S和5μg膜蛋白。除非另外指明,否则所含的测试化合物的浓度范围为0.08至5,000nM。将膜用100μM5’-腺苷酰亚胺基二磷酸孵育30min,然后用10μM GDP在冰上孵育10min。将药物溶液和膜混合,然后通过添加GTPγ35S引发反应,并在25℃下继续30min。将反应混合物经Whatman GF/B滤器真空过滤,用3mL冰冷的缓冲液(HEPES25,pH7.4、MgCl210和NaCl100)洗涤三次。干燥滤器,与闪烁体混合,使用β计数器对35S活性计数。通过减去在不存在激动剂时的值,得到激动剂诱导的GTPγ35S结合。使用非线性回归方法对结合数据进行分析。就拮抗剂测定而言,反应混合物在存在浓度范围为0.08至5000nM的测试拮抗剂的情况下包含10nM S1P。
表2显示活性效能:来自GTPγ35S的S1P1受体:nM,(EC50)
活性效能:来自GTPγ35S的S1P1受体:nM,(EC50)
表2
Claims (12)
1.一种具有式1的化合物、它的对映异构体、非对映异构体、水合物、溶剂化物、晶体形式和各个异构体、互变异构体或其药学上可接受的盐,
其中:
A是C6-10芳基、杂环、C3-8环烷基或C3-8环烯基;
B是C6-10芳基、杂环、C3-8环烷基或C3-8环烯基;
R1是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R2是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R3是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R4是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R5是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R6是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R7是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R8独立地为卤素、-OC1-8烷基、C1-8烷基、CN、C(O)Rl3、NR14R15或羟基;
L1是O、C(O)、S或NH;
R9是O、S、C(O)或CH2;
R10是H或C1-8烷基;
L2是CHR16、O、S、NR17、直接键或-C(O)-;
R11是H、OPO3H2、羧酸、PO3H2、C1-8烷基、-S(O)2H、-P(O)MeOH、-P(O)(H)OH或OR12;
R12是H或C1-8烷基;
a是0、1或2;
b是0或1;
c是0、1、2或3;
Rl3是H、C1-8烷基;
R14是H或c1-8烷基;以及
R15是H或c1-8烷基;
R16是H、OH或c1-8烷基;以及
R17是H或c1-8烷基。
2.根据权利要求1所述的化合物,其中
R1是H、卤素、-OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R2是H、卤素、-OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R3是H、卤素、-OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R4是H、卤素、-OCl-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R5是卤素、一OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R6是卤素、一OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R7是卤素、一OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R8独立地为卤素、一OC1-6烷基、C1-6烷基、CN、C(O)R13、NR14R15或羟基;
R9是O、S、C(O)或CH2;
R10是H或C1-6烷基;
L1,邑0、S或NH;
L2是CHR16、0、S、NR17、直接键或-C(O)-;
R11是H、OPO3H2、羧酸、PO3H2,C1-6I'-S(O)2H,-P(O)MeOH,-P(O)(H)OH或OR12;
R12是H或C1-6烷基;
a是0、1或2;
b是0或1;
c是0、1、2或3;
R13是H、C1-6烷基;
R14是H或C1-6烷基以及
R15是H或C1-6烷基;
R16是H、OH或C1-6烷基;以及
R17是H或C1-6烷基。
4.根据权利要求3所述的化合物,其中
L1是O。
5.根据权利要求3所述的化合物,其中
L1是S。
6.根据权利要求3所述的化合物,其中
L1是NH。
7.根据权利要求1所述的化合物,其选自:
3-([4-(5-{(3-氯苯基)[(3,4-二甲基苯基)氨基]甲基}-1,2,4-噁二唑-3-基)苄基]氨基}丙酸;
3-{[4-(5-{(4-氯苯基)[(3,4-二甲基苯基)硫代]甲基}-1,2,4-噁二唑-3-基)苄基]氨基}丙酸;
3-{[4-(5-{(3-氯苯基)[(3,4-二甲基苯基)硫代]甲基}-1,2,4-噁二唑-3-基)苄基]氨基}丙酸;
3-[4-(5-{(3-氯苯基)[(3,4-二甲基苯基)硫代]甲基)-1,2,4-噁二唑-3-基)-2,6-二甲基苯氧基]丙-1,2-二醇
3-{[4-(5-{(2-氯苯基)[(3,4-二甲基苯基)硫代]甲基}-1,2,4-噁二唑-3-基)苄基]氨基}丙酸;
3-[(4-{5-[(3-氯苯基)(3,4-二甲基苯氧基)甲基]-1,2,4-噁二唑-3-基}苄基)氨基]丙酸;
3-[(4-{5-W-氯苯基)(4-甲氧基-3-甲基苯氧基)甲基]-1,2,4-噁二唑-3-基}苄基)氨基]丙酸;
3-[(4-{5-[(3-氯苯氧基)(2-氯苯基)甲基]-1,2,4-噁二唑-3-基}苄基)氨基]丙酸;
3-[(4-{5-[(3-氯苯基)(3-丙基苯氧基)甲基]-1,2,4-噁二唑-3-基}苄基)氨基]丙酸;
3-[(4-{5-[(3-氯苯基)(4-甲基苯氧基)甲基]-1,2,4-噁二唑-3-基}苄基)氨基]丙酸;
3-[(4-{5-[(3-氯苯基)(4-丙基苯氧基)甲基]-1,2,4-噁二唑-3-基}苄基)氨基]丙酸;
3-[(4-{5-[(3-氯苯基)(4-乙基苯氧基)甲基]-1,2,4-噁二唑-3-基}苄基)氨基]丙酸。
8.一种药物组合物,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。
9.根据权利要求8所述的药物组合物,其中所述化合物选自:
3-{[4-(5-{(3-氯苯基)[(3,4-二甲基苯基)氨基]甲基}-1,2,4-噁二唑-3-基)苄基]氨基}丙酸;
3-{[4-(5-{(4-氯苯基)[(3,4--二甲基苯基)硫代]甲基}-1,2,4-噁二唑-3-基)苄基]氨基}丙酸;
3-{[4-(5-{(3-氯苯基)[(3,4-二甲基苯基)硫代]甲基}-1,2,4-噁二唑-3-基)苄基]氨基}丙酸;
3-[4-(5-{(3-氯苯基)[(3,4-二甲基苯基)硫代]甲基}-1,2,4-噁二唑-3-基)-2,6-二甲基苯氧基]丙-1,2-二醇
3-{[4-(5-{(2-氯苯基)[(3,4-二甲基苯基)硫代]甲基}-1,2,4-)二唑-3-基)苄基]氨基}丙酸;
3-[(4-{5-[(3-氯苯基)(3,4-二甲基苯氧基)甲基]-1,2,4-噁二唑-3-基}苄基)氨基]丙酸;
3-[(4-{5-[(2-氯苯基)(4-甲氧基-3-甲基苯氧基)甲基]-1,2,4-噁二唑-3-基}苄基)氨基]丙酸;
3-[(4-{5-[(3-氯苯氧基)(2-氯苯基)甲基]-1,2,4-噁二唑-3-基}苄基)氨基]丙酸;
3-[(4-{5-[(3-氯苯基)(3-丙基苯氧基)甲基]-1,2,4-噁二唑-3-基}苄基)氨基]丙酸;
3-[(4-{5-[(3-氯苯基)(4-甲基苯氧基)甲基]-1,2,4-噁二哇-3-基}苄基)氨基]丙酸;
3-[(4-{5-[(3-氯苯基)(4-丙基苯氧基)甲基]-1,2,4-噁二唑-3-基}苄基)氨基]丙酸;
3-[(4-{5-[(3-氯苯基)(4-乙基苯氧基)甲基]-1,2,4-噁二唑-3-基}苄基)氨基]丙酸。
10.一种治疗与鞘氨醇-1-磷酸受体调节相关的障碍的方法,其包括向需要其的哺乳动物施用包含治疗有效量的至少一种式1的化合物的药物组合物:
其中:
A是C6-10芳基、杂环、C3-8环烷基或C3-8环烯基;
B是C6-10芳基、杂环、C3-8环烷基或C3-8环烯基;
R1是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R2是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R3是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R4是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R5是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R6是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R7是H、卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
R8独立地为卤素、-OC1-8烷基、C1-8烷基、CN、C(O)R13、NR14R15或羟基;
L1是O、S或NH;
R9是0、S、C(O)或CH2;
R10是H或C1-8烷基;
L2是CHR16、0、S、NR17、直接键或-C(O)-;
R11是H、OP03H2、羧酸、PO3H2、C1-8烷基、-S(O)2H、-P(O)MeOH、-P(O)(H)OH或OR12;
R12是H或C1-8烷基;
a是0、1或2;
b是0或1;
c是0、1、2或3;
R13是H、C1-8烷基;
R14是H或C1-8烷基;以及
R15是H或C1-8烷基;
R16是H、OH或C1-8烷基;以及
R17是H或C1-8烷基。
11.根据权利要求10所述的方法,其中将所述药物组合物施用给所述哺乳动物以治疗眼病、湿性和干性年龄相关性黄斑变性、糖尿病性视网膜病、早产儿视网膜病变、视网膜水肿、地图状萎缩、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、眼部缺血综合征、眼睛后部炎症所致的纤维化的预防、包括葡萄膜炎、巩膜炎、角膜炎和视网膜脉管炎的各种眼部炎症疾病;或系统性血管屏障相关疾病、包括急性肺损伤、其预防的各种炎性疾病、败血病、肿瘤转移、动脉粥样硬化、肺水肿和机械通气所致的肺损伤;或自身免疫疾病和免疫抑制、类风湿性关节炎、克罗恩病、格雷夫斯病、炎性肠病、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、特应性皮炎和器官移植;或过敏和其他炎性疾病、荨麻疹、支气管哮喘以及包括肺气肿和慢性阻塞性肺病的其他气道炎症;或心脏保护、缺血再灌注损伤和动脉粥样硬化;或伤口愈合、皮肤美容手术、眼科手术、GI手术、普外科手术、口腔损伤、各种机械性损伤、灼伤和烧伤后伤口的无疤痕愈合、预防和治疗光老化和皮肤老化、以及预防辐射所致的损伤;或骨形成、治疗骨质疏松以及包括髋和踝的各种骨折;或抗伤害性活动、内脏痛、与糖尿病性神经病变相关的疼痛、类风湿性关节炎、慢性膝盖和关节疼痛、肌腱炎、骨关节炎、神经性疼痛。
12.根据权利要求11所述的方法,其中所述哺乳动物为人。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104478822A (zh) * | 2014-11-26 | 2015-04-01 | 张�焕 | 一种治疗骨质疏松的药物组合物 |
CN107001806A (zh) * | 2014-09-29 | 2017-08-01 | 斯克利普斯研究院 | 用于治疗心肺疾病的鞘氨醇‑1‑磷酸盐受体调节剂 |
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WO2011154953A1 (en) | 2010-06-10 | 2011-12-15 | Technion R&D Foundation Ltd. | Process for the preparation of iodides |
US20140135293A1 (en) * | 2012-11-14 | 2014-05-15 | Allergan, Inc. | Allene derivatives as sphingosine 1-phosphate (s1p) receptor modulators |
US8729110B1 (en) | 2012-11-14 | 2014-05-20 | Allergan, Inc. | 2-thio-1,3,4-oxadiazoles derivatives as sphingosine-1 phosphate receptors modulators |
US8735433B1 (en) | 2012-11-14 | 2014-05-27 | Allergan, Inc. | Aryl oxadiazole derivatives as sphingosine 1-phosphate (S1P) receptor modulators |
WO2014130947A1 (en) * | 2013-02-25 | 2014-08-28 | Allergan, Inc. | Pyrazole derivatives as sphingosine 1-phosphate (s1p) receptor modulators |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008076356A1 (en) * | 2006-12-15 | 2008-06-26 | Abbott Laboratories | Novel oxadiazole compounds |
WO2008091967A1 (en) * | 2007-01-26 | 2008-07-31 | Smithkline Beecham Corporation | Chemical compounds |
Family Cites Families (2)
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-
2011
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008076356A1 (en) * | 2006-12-15 | 2008-06-26 | Abbott Laboratories | Novel oxadiazole compounds |
WO2008091967A1 (en) * | 2007-01-26 | 2008-07-31 | Smithkline Beecham Corporation | Chemical compounds |
Non-Patent Citations (1)
Title |
---|
KANDE K. D. AMARASINGHE ET AL: "One-pot synthesis of 1,2,4-oxadiazoles from carboxylic acid esters and amidoximes using potassium carbonate. Kande K. D. Amarasinghe et al.Tetrahedron Letters.47 (2006) 3629–3631", 《TETRAHEDRON LETTERS》 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107001806A (zh) * | 2014-09-29 | 2017-08-01 | 斯克利普斯研究院 | 用于治疗心肺疾病的鞘氨醇‑1‑磷酸盐受体调节剂 |
US11034691B2 (en) | 2014-09-29 | 2021-06-15 | The Scripps Research Institute | Sphinogosine-1 -phosphate receptor modulators for treatment of cardiopulmonary disorders |
CN104478822A (zh) * | 2014-11-26 | 2015-04-01 | 张�焕 | 一种治疗骨质疏松的药物组合物 |
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