CN1454204A - Il-8受体拮抗剂 - Google Patents
Il-8受体拮抗剂 Download PDFInfo
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- CN1454204A CN1454204A CN01810362A CN01810362A CN1454204A CN 1454204 A CN1454204 A CN 1454204A CN 01810362 A CN01810362 A CN 01810362A CN 01810362 A CN01810362 A CN 01810362A CN 1454204 A CN1454204 A CN 1454204A
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Abstract
本发明涉及二苯胺基方形烷(squarane)在治疗趋化因子白介素-8(IL-8)介导的疾病中的应用。
Description
发明领域
本发明涉及一组新的二苯胺基方形烷(squarane)化合物、其制备方法、用于治疗IL-8、GROα、GROβ、GROγ、NAP-2、和ENA-78介导的疾病的应用以及用于这些治疗中的药物组合物。
发明背景
白细胞介素-8(IL-8)有许多不同的名称,例如嗜中性引诱剂/活化蛋白-1(NAP-1)、单核细胞衍生的嗜中性趋化因子(MDNCF)、嗜中性活化因子(NAF)、和T-淋巴细胞趋化因子。白细胞介素-8是嗜中性细胞、嗜碱性细胞和T-细胞亚群的化学引诱剂。它是通过许多有核细胞产生,包括暴露于TNF、IL-1α、IL-1β或LPS的巨噬细胞、纤维原细胞、内皮细胞和上皮细胞,或通过暴露于LPS或趋化因子例如FMLP的嗜中性粒细胞本身而产生。M.Baggiolin等,《临床研究杂志》(
J.Clin.Invest.)84,1045(1989);J.Schroder等,《免疫学杂志》(
J.Immunol.)139,3474(1987)和《免疫学杂志》(
J.Immunol.)144,2223(1990);Strieter,等,《科学》(
Science)243,1467(1989)和《生物化学杂志》(
J.Biol.Chem.)264,10621(1989);Cassatella等,《免疫学杂志》(
L Immunol.)148,3216(1992)。
GROα、GROβ、GROγ和NAP-2也属于α趋化因子家族。和IL-8一样,这些趋化因子也有不同的名称。例如GROα、GROβ、GROγ被分别称作MGSAα、β、和γ(刺激黑素瘤生长的活性),参见Richmond等,《细胞生理学杂志》(
J.Cell Physiology)129,375(1986)和Chang等,《免疫学杂志》(
J.Immunol)148,451(1992)。所有具有直接领先于CXC基元的ELR基元的α家族趋化因子都与IL-8B受体结合。
IL-8、GROα、GROβ、GROγ、NAP-2和ENA-78刺激体外的许多功能。已证实它们都具有对嗜中性粒细胞的化学趋化特性,同时还证实IL-8和GROOM具有T-淋巴细胞和嗜碱性细胞活性。另外,IL-8可从正常的和遗传性过敏症个体的嗜碱性细胞中诱导组胺释放。此外,GRO-α和IL-8可从嗜中性粒细胞诱导溶酶体酶释放和呼吸爆发。还证实在没有全程蛋白质合成的情况下、IL-8可增加嗜中性粒细胞上的Mac-1(CDl lb/CD18)的表面表达。这可能是由于嗜中性粒细胞与血管内皮细胞的附着增强了的缘故。许多已知的疾病是根据块状嗜中性粒细胞的渗透来进行分类的。由于IL-8、GROα、GROβ、GROγ和NAP-2促进嗜中性粒细胞的聚集和活化,在包括牛皮癣和风湿性关节炎的许多急慢性炎性疾病中都涉及这些趋化因子,Baggiolini等,FEBS Lett.307,97(1992);Miller等,Crit.Rev.
Immunol.12,17(1992);Oppenheim等,Annu.Rev.
Immunol.9,617(1991);Seitz等,
J.Clin.Invest.-87,463(1991);Miller等,
Am.Rev.Respir.Dis.146,427(1992);Donnely等,
Lancet341,643(1993)。另外,在血管停滞中也涉及ELR趋化因子(那些在CXC基元之前含氨基酸ELR基元的趋化因子),Strieter等,《科学》(
Science)258,1798(1992)。
在体外,IL-8、GROα、GROβ、GROγ和NAP-2通过结合并激活七跨膜的受体、G蛋白偶联族,尤其是与IL-8受体(最典型的是B受体)结合,引起嗜中性粒细胞形状改变、趋化现象、颗粒释放、和突发性呼吸,Thomas等,J.Biol.Chem.266,14839(1991);和Holmes et al.,Science 253,1278(1991)。用于这种受体家族成员的非肽类小分子拮抗剂的发展具有先例性。有一评述,参见R.Freidinger在“药物研究的进展”(Progress in Drug Research),Vol.40,pp.33-98,Birkhauser Verlag,Basel 1993。因此,IL-8受体代表有希望的新抗炎剂的发展目标。
高亲和性人IL-8受体(77%同源性)分为两种:IL-8Rα、它仅结合具有高亲和性的IL-8,和IL-8RB、它对IL-8以及GROα、GROβ、GROγ和NAP-2都有亲和性。参见,Holmes等,前面所述;Murphy等,《科学》(Science)253,1280(1991);Lee等,《生物化学杂志》(J.Biol.Chem.)267,16283(1992);LaRosa等,《生物化学杂志》(J.Biol.Chem.)267,25402(1992);以及Gayle等,《免疫学杂志》(J.Biol.Chem.)268,7283(1993)。
在此领域中,需要能与IL-8α或β受体结合的、用于治疗的化合物。因此,对于与IL-8产物(它是造成嗜中性粒细胞和T细胞亚群在炎性部位趋化的许多原因)增加相关的疾病,使用IL-8受体结合抑制剂化合物将是有效的。
发明概要
本发明提供一种治疗趋化因子介导的疾病的方法,其中趋化因子是一种与IL-8α或β受体结合的因子,该方法包括施用有效量的式(I)化合物或其药学上可接受的盐。尤其是,趋化因子为IL-8。
本发明还涉及一种在需要的哺乳动物中抑制IL-8与其受体结合的方法,该方法包括给所述哺乳动物施用有效量的式(I)化合物。
R1独自选自氢、卤素、硝基、氰基、卤素取代的C1-10烷基、C1-10烷基、C2-10链烯基、C1-10烷氧基、卤素取代的C1-10烷氧基、叠氮基、(CR8R8)qS(O)tR4、羟基、羟基C1-4烷基、芳基、芳基C1-4烷基、芳氧基、芳基C1-4烷氧基、杂芳基、杂芳基烷基、杂环、杂环C1-4烷基、杂芳基C1-4烷氧基、芳基C2-10链烯基、杂芳基C2-10链烯基、杂环C2-10链烯基、(CR8R8)qNR4R5、C2-10链烯基C(O)NR4R5、(CR8R8)qC(O)NR4R5、(CR8R8)qC(O)NR4R10、S(O)3H、S(O)3R8、(CR8R8)qC(O)R11、C2-10链烯基C(O)R11、C2-10链烯基C(O)OR11、(CR8R8)qC(O)OR12、(CR8R8)qOC(O)R11、(CR8R8)qNR4C(O)R11、(CR8R8)qNHS(O)2R17、(CR8R8)qS(O)2NR4R5;或者两个R1部分一起形成O-(CH2)sO-或未取代的5-6元环;
q为0,或1-10的整数;
t为0,或1-2的整数;
s为1-3的整数;
R4和R5各自选自氢、可被取代或不被取代的C1-4烷基、可被取代或不被取代的芳基、可被取代或不被取代的芳基C1-4烷基、可被取代或不被取代的杂芳基、可被取代或不被取代的杂芳基C1-4烷基、杂环、和杂环C1-4烷基,或R4和R5与它们相连的氮一起形成5-7元环,所述的环可以包括或不包括选自氧、氮或硫的另外的杂原子;
Y独自选自氢、卤素、硝基、氰基、卤素取代的C1-10烷基、C1-10烷基、C2-10链烯基、C1-10烷氧基、卤素取代的C1-10烷氧基、叠氮基、(CR8R8)qS(O)tR4、羟基、羟基C1-4烷基、芳基、芳基C1-4烷基、芳氧基、芳基C1-4烷氧基、杂芳基、杂芳基烷基、杂芳基C1-4烷氧基、杂环、杂环C1-4烷基、芳基C2-10链烯基、杂芳基C2-10链烯基、杂环C2-10链烯基、(CR8R8)qNR4R5、C2-10链烯基C(O)NR4R5、(CR8R8)qC(O)NR4R5、(CR8R8)qC(O)NR4R10、S(O)3H、S(O)3R8、(CR8R8)qC(O)R11、C2-10链烯基C(O)R11、C2-10链烯基C(O)OR11、C(O)R11、(CR8R8)qC(O)OR12、(CR8R8)qOC(O)R11、(CR8R8)qNR4C(O)R11、CR8R8)qNHS(O)2Rd、和(CR8R8)qS(O)2NR4R5;或者两个Y一起形成O-(CH2)sO-或未饱和的5-6元环;
n为1-5的整数;
m为1-4的整数;
R8为氢或C1-4烷基;
R10为C1-10烷基C(O)2R8;
R11选自氢、C1-4烷基、可被取代或不被取代的芳基、可被取代或不被取代的芳基C1-4烷基、可被取代或不被取代的杂芳基、可被取代或不被取代的杂芳基C1-4烷基、可被取代或不被取代的杂环基、和可被取代或不被取代的杂环C1-4烷基;
R12选自氢、C1-10烷基、可被取代或不被取代的芳基、可被取代或不被取代的芳基烷基;
R17选自C1-4烷基、芳基、芳基烷基、杂芳基、杂芳基C1-4烷基、杂环、和杂环C1-4烷基,其中芳基、杂芳基和杂环都可被取代或不被取代。
发明的详细说明
式(I)化合物也可用于除人外的哺乳动物的兽医治疗,该哺乳动物需要抑制与IL-8RA和RB受体结合的IL-8或其它趋化因子。治疗学或预防学上治疗动物中趋化因子介导的疾病包括本文在治疗方法部分所述的那些。
用于本文的下列术语意指:
·“卤代”---所有卤素,即氯、氟、溴和碘。
·“C2-5烷基”或“烷基”---指含2-5个碳原子的直链和支链部分,除非另外限定了该链长,包括,但不限于,甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基等。
·本文所用的术语“链烯基”在所有情况下都指含2-5个碳原子的直链和支链部分,除非另外限定了该链长,包括,但不限于,乙烯基、1-丙烯基、2-丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基等。
·“芳基”---苯基和萘基;
·“杂芳基”(其本身或其任何组合,例如“杂芳氧”、或“杂芳烷基”)---5-10元芳环系统,其中一个或多个环含一个或多个选自N、O或S的杂原子,例如,但不限于吡咯、吡唑、呋喃、噻吩、喹啉、异喹啉、喹唑啉基、吡啶、嘧啶、噁唑、噻唑、噻二唑、三唑、咪唑、或苯并咪唑。
·“杂环”(其本身或其任何组合,例如“杂环烷基”)---饱和的或部分不饱和的4-10元环系统,其中一个或多个环含一个或多个选自N、O或S的杂原子,例如,但不限于吡咯烷、哌啶、哌嗪、吗啉、四氢吡喃、或咪唑啉。
·本文的术语“芳基烷基”或“杂芳基烷基”、或“杂环烷基”是指C1-10烷基,如上所定义,它与芳基、杂芳基或杂环部分连接,也如上所述,除非另有说明。
式(I)的例证性化合物包括:
3-(2-羟基-苯基氨基)-4-(2-溴苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2,3-二氯苯基氨基)-环丁-3-烯-1,2-二酮,
3-(4-硝基-2-羟基-苯基氨基)-4-苯基氨基-环丁-3-烯-1,2-二酮,
3-(4-氰基-2-羟基-苯基氨基)-4-苯基氨基-环丁-3-烯-1,2-二酮,
3-(2-甲氧基-苄基氨基)-4-苯基氨基-环丁-3-烯-1,2-二酮,
3-(4-氰基-2-羟基-苯基氨基)-4-(2-溴苯基氨基)-环丁-3-烯-1,2-二酮,
3-(4-氰基-2-羟基-苯基氨基)-4-(2-氯苯基氨基)-环丁-3-烯-1,2-二酮,
3-(4-氰基-2-羟基-苯基氨基)-4-(2,3-二氯苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2-苯基苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2-甲氧基苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2-乙基苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2-苯氧基苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2-氯苯基氨基)-环丁-3-烯-1,2-二酮,
6-氯-3-(3,4-二氧-2-苯基氨基-环丁-1-烯基氨基)-2-羟基-苯磺酰胺、
3,4-二-(4-氰基-2-羟基苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2,3-二甲基苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2-甲基-4-溴苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2-丙基苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2-甲基-3-氯苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2,3-二甲氧基苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2-氯-3-甲基苯基氨基)-环丁-3-烯-1,2-二酮,
3-(4-硝基-2-羟基-苯基氨基)-4-(2-溴苯基氨基)-环丁-3-烯-1,2-二酮,
3-(4-硝基-2-羟基-苯基氨基)-4-(2-氯苯基氨基)-环丁-3-烯-1,2-二酮,
3,4-二-(4-硝基-2-羟基苯基氨基)-环丁-3-烯-1,2-二酮,
3-[(2-羟基-苯基)-甲基-氨基]-4-苯基氨基-环丁-3-烯-1,2-二酮,
3-(3-羟基-吡啶-2-基氨基)-4-苯基氨基-环丁-3-烯-1,2-二酮,
或其药学上可接受的盐。
制备方法
可通过合成的方法得到式(I)化合物,其中一些方法在下图中进行了举例说明。在这些图中所提供的合成过程可适用于制造具有各种不同反应基团R、R1和芳基的式(I)化合物,使用被适当保护的任选的取代基、以达到与此处所述反应的相容性。在那些情况下,随后的去保护产生性能通常被公开的化合物。一旦建立了胍核,通过采用本领域众所周知的标准的功能基团互变方法可制备更多此通式的化合物。这些图仅列出了具有式(I)的化合物、这仅仅是为了举例说明。
a)Br2,NaOAc,HOAc;b)CuCN,DMF,回流;c)(BOC)2O,DMAP,TEA;d)K2CO3,MeOH;e)TFA
由市售的苯并唑啉酮
1-反应方案-1可制备所需的苯胺
6-反应方案- 1。采用标准的溴化作用条件例如醋酸中的溴和醋酸钠可从苯并唑啉酮
1- 反应方案-1制备溴化物
2-反应方案-1。用标准方法例如回流DMF中的氰化铜(I)可将溴化物
2-反应方案-1转化为氰化物。通过标准的条件例如BOC酸酐和三乙胺与亚甲基氯化物或另一种适合的有机溶剂中的催化量的二甲氨基吡啶,可将酰胺
3-反应方案-1转化为BOC保护的化合物
4-反应方案-1。用下列方法可将唑啉酮
4-反应方案-1转化为所需的苯胺
6-反应方案-1,即采用标准的条件例如甲醇中的碳酸钾首先为苯酚
5-反应方案-1、然后采用标准的条件例如亚甲基氯化物或另一种适合的有机溶剂中的三氟醋酸除去BOC保护基团、得到苯胺
6-反应方案-1。
由图1所示由市售的二甲醚方形酯(squarate)1可得到结构5化合物。将二乙醚squarate 1与所需的苯胺2在回流乙醇或其它适合的有机溶剂中反应可得到中间体3。将方形烷(squarane)3与第二种苯胺4在回流乙醇或其它适合的有机溶剂中反应可得到所需的方形烷化合物5。
合成实施例
现通过下列实施例对本发明进行描述,这些实施例仅仅是举例说明、而不应理解为限定本发明的范围。所有的温度为摄氏度,所有溶剂为可得到的最高纯度,所有反应是在无水条件下在氩大气压下进行,除非另有指明。
在实施例中,所有温度为摄氏度(℃)。在VG Zab质谱仪上用快速原子轰击完成质谱,除非另有说明。用Bruker AM 250或Am 400光谱仅在250MHz记录1H-NMR(以下为“NMR”)。所显示的多重态为s=单峰,d=双峰,t=三重峰,q=四重峰,m=多重峰,br表示宽信号。Sat.表示饱和溶液,eq表示试剂的摩尔当量相对于主要反应物的比例。
3-(2,3-二氯苯氨基)-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮。
在3-乙氧基-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮(100mg,0.43mmol)的甲苯(2mL)和DMSO(1滴)溶液中加入2,3-二氯苯胺(0.07mL,0.43mmol)、并在110℃搅拌该反应过夜。通过过滤收集所得到的固体。用醋酸乙酯洗涤以除去甲苯,在真空下干燥。LC-MS(m/z)349(M+).
3-(2-溴苯氨基)-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮。
在3-乙氧基-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮(50mg,0.21mmol)的DMSO(1.5mL)溶液中加入2-溴苯胺(36.9mg,0.21mmol)、并在110℃搅拌该反应过夜。在HPLC(乙腈∶水)上纯化该反应、并浓缩出产物。将固体在真空下干燥。
LC-MS(m/z)359(M-)。
3-(2-苯基苯氨基)-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮。
在3-乙氧基-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮(50mg,0.21mmol)的DMSO(1.5mL)溶液中加入2-氨基联苯(36.3mg,0.21mmol)、并在110℃搅拌该反应过夜。在HPLC(乙腈∶水)上纯化该反应、并浓缩出产物。将固体在真空下干燥。LC-MS(m/z)357.2(M+)。
3-(2-甲氧苯氨基)-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮。
在3-乙氧基-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮(50mg,0.21mmol)的DMSO(1.5mL)溶液中加入2-甲氧苯胺(0.024mL,0.21mmol)、并在110℃搅拌该反应过夜。在HPLC(乙腈∶水)上纯化该反应、并浓缩出产物。将固体在真空下干燥。LC-MS(m/z)311.4(M+)。
3-(2-乙基苯氨基)-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮。
在3-乙氧基-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮(50mg,0.21mmol)的DMSO(1.5mL)溶液中加入2-乙基苯胺(0.024mL,0.21mmol)、并在110℃搅拌该反应过夜。在HPLC(乙腈∶水)上纯化该反应、并浓缩出产物。将固体在真空下干燥。LC-MS(m/z)309(M+)。
3-(2-苯氧基苯氨基)-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮。
在3-乙氧基-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮(50mg,0.21mmol)的DMSO(1.5mL)溶液中加入2-苯氧苯胺(49mg,0.21mmol)、并在110℃搅拌该反应过夜。在HPLC(乙腈∶水)上纯化该反应、并浓缩出产物。将固体在真空下干燥。
LC-MS(m/z)373(M+)。
3-(2-氯苯氨基)-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮,
在3-乙氧基-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮(50mg,0.21mmol)的DMSO(1.5mL)溶液中加入2-氯苯胺(0.023mL,0.21mmol)、并在110℃搅拌该反应过夜。在HPLC(乙腈∶水)上纯化该反应、并浓缩出产物。将固体在真空下干燥。LC-MS(m/z)315(M+)。
3-(2-甲基苯氨基)-4-(2-羟基苯氨基)-环丁-3-烯-12-二酮。
在3-乙氧基-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮(50mg,0.21mmol)的DMSO(1.5mL)溶液中加入2-甲基苯胺(0.023mL,0.21mmol)、并在110℃搅拌该反应过夜。在HPLC(乙腈∶水)上纯化该反应、并浓缩出产物。将固体在真空下干燥。LC-MS(nez)295(M+)。
3-(2,3-二甲基苯氨基)-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮。
在3-乙氧基-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮(50mg,0.21mmol)的DMSO(1.5mL)溶液中加入2,3-二甲基苯胺(0.026mL,0.21mmol)、并在110℃搅拌该反应过夜。在HPLC(乙腈∶水)上纯化该反应、并浓缩出产物。将固体在真空下干燥。LC-MS(m/z)309(M+)。
3-(4-溴-2-甲基苯氨基)-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮。
在3-乙氧基-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮(50mg,0.21mmol)的DMSO(1.5mL)溶液中加入4-溴-2-甲基苯胺(40mg,0.21mmol)、并在110℃搅拌该反应过夜。在HPLC(乙腈∶水)上纯化该反应、并浓缩出产物。将固体在真空下干燥。LC-MS(m/z)373(M+)。
3-(2-丙基苯氨基)-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮。
在3-乙氧基-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮(50mg,0.21mmol)的DMSO(1.5mL)溶液中加入2-丙基苯胺(0.030mL,0.21mmol)、并在110℃搅拌该反应过夜。在HPLC(乙腈∶水)上纯化该反应、并浓缩出产物。将固体在真空下干燥。
LC-MS(m/z)323(M+)。
3-(3-氯-2-甲基苯氨基)-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮。
在3-乙氧基-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮(50mg,0.21mmol)的DMSO(1.5mL)溶液中加入3-氯-2-甲基苯胺(0.026mL,0.21mmol)、并在110℃搅拌该反应过夜。在HPLC(乙腈∶水)上纯化该反应、并浓缩出产物。将固体在真空下干燥。LC-MS(m/z)329(M+)。
3-(2,3-甲氧苯氨基)-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮。
在3-乙氧基-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮(50mg,0.21mmol)的DMSO(1.5mL)溶液中加入2,3-甲氧苯胺(0.031mL,0.21mmol)、并在110℃搅拌该反应过夜。在HPLC(乙腈∶水)上纯化该反应、并浓缩出产物。将固体在真空下干燥。LC-MS(m/z)341(M+)。
3-(2-氯-3-甲基苯氨基)-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮。
在3-乙氧基-4-(2-羟基苯氨基)-环丁-3-烯-1,2-二酮(50mg,0.21mmol)的DMSO(1.5mL)溶液中加入2-氯-3-甲基苯胺(0.026mL,0.21mmol)、并在110℃搅拌该反应过夜。在HPLC(乙腈∶水)上纯化该反应、并浓缩出产物。将固体在真空下干燥。LC-MS(m/z)329(M+)。
3-(2-羟基苯氨基)-4-(2-溴苯氨基)-3-环丁烯-1,2-二酮
于室温下在溴苯胺(74mg,0.43mmol)中加入甲苯中的214μL 2M三甲基铝。搅拌该混合物直到气体排放停止,然后加入1M1亚甲基氯化物中的3-乙氧基-4-(2-羟基苯氨基)-3-环丁烯-1,2-二酮(50mg,0.21mmol)。在室温下令该混合物反应过夜。用水使反应混合物冷却、然后水法后处理。将有机层经硫酸钠干燥并浓缩。Gilson HPLC后,得到14mg(12%)纯产物。LCMS(H+)359
3-(2-溴苯氨基)-4-(2-羟基-4-氰基苯氨基)-3-环丁烯-1,2-二酮
将乙醇中的3,4-二乙氧基-3-环丁烯-1,2-二酮(1.2mL,8.12mmol)和3-羟基-4-氨基苄腈(1.25g,8.12mmol)溶液在185℃加热过夜。形成黄褐色沉淀物。过滤固体并收集。得到1.12g(53%)3-乙氧基-4-(2-羟基-4-氰基苯氨基)-3-环丁烯-1,2-二酮。LC/MS(H+)259
在6ml DMSO中将3-乙氧基-4-(2-羟基-4-氰基苯氨基)-3-环丁烯-1,2-二酮(0.7g,2.71mmol)和2-溴苯胺(0.47g,2.73mmol)的混合物加热过夜。冷却该反应混合物至室温,加入醋酸乙酯、形成沉淀物。将滤液分配在醋酸乙酯和水之间。将有机层经硫酸钠干燥并浓缩。Gilson HPLC后,得到34mg(3%)纯产物。LC/MS(H+)386
3-(2-溴苯氨基)-4-(2-羟基-4-硝基苯氨基)-3-环丁烯-1,2-二酮
将2ml DMSO中的3-乙氧基-4-(2-羟基-4-硝基苯氨基)-3-环丁烯-1,2-二酮(0.39g,1.4mmol)和2-溴苯胺(0.36g,2.09mmol)溶液在110℃加热过夜。冷却该反应混合物至室温,加入醋酸乙酯、形成沉淀物。将滤液分配在醋酸乙酯和水之间。将有机层经硫酸钠干燥并浓缩。用丙酮和己烷滴定得到106mg(19%)3-(2-溴苯氨基)-4-(2-羟基-4-硝基苯氨基)-3-环丁烯-1,2-二酮。LCMS(H+)404
3-(2-氯苯氨基)-4-(2-羟基-4-硝基苯氨基)-3-环丁烯-1,2-二酮
将2ml DMSO中的3-乙氧基-4-(2-羟基-4-硝基苯氨基)-3-环丁烯-1,2-二酮(0.38g,1.37mmol)和2-氯苯胺(0.23mL,2.2mmol)溶液在110℃加热过夜。冷却该反应混合物至室温,加入醋酸乙酯、形成沉淀物。将滤液分配在醋酸乙酯和水之间。将有机层经硫酸钠干燥并浓缩。用醋酸乙酯和己烷再结晶,得到3-(2-氯苯氨基)-4-(2-羟基-4-硝基苯氨基)-3-环丁烯-1,2-二酮。LCMS(H+)360.
3-(2,3-二氯苯氨基)-4-(2-羟基-4-硝基苯氨基)-3-环丁烯-1,2-二酮
将2mL DMSO中的3-乙氧基-4-(2-羟基-4-硝基苯氨基)-3-环丁烯-1,2-二酮(0.40g,1.44mmol)和2,3-二氯苯胺(0.34g,2.10mmol)溶液在110℃加热过夜。冷却该反应混合物至室温,加入醋酸乙酯、形成沉淀物。收集滤饼。用丙酮和己烷滴定得到68mg(11%)3-(2-氯苯氨基)-4-(2-羟基-4-硝基苯氨基)-3-环丁烯-1,2-二酮。LCMS(H+)394。
治疗方法
式(I)化合物、或其药学上可接受的盐可用于制备一种药物,该药物用于预防或治疗人或其它哺乳动物中由它们的细胞过量或失控的IL-8细胞因子产生而导致或加剧的任何疾病,所述的细胞包括,但不限于:单核细胞和/或巨噬细胞、或其它与IL-8α或β受体(也叫I型或II型受体)结合的趋化因子。
因此,本发明提供一种治疗趋化因子介导的疾病的方法,其中趋化因子是一种与IL-8α或β受体结合的因子,该方法包括施用有效量的式(I)化合物或其药学上可接受的盐。尤其是,这些趋化因子为IL-8、GROα、GROβ、GROγ、NAP-2或ENA-78。
按足以抑制细胞因子功能(尤其是IL-8、GROα、GROβ、GROγ、NAP-2或ENA-78)的用量施用式(I)化合物,以便对它们进行生物调节而达到正常的生理功能水平、或在某些情况下达到亚正常水平,从而缓解病情。本发明中所述的IL-8、GROα、GROβ、GROγ、NAP-2或ENA-78的异常水平例如包括:(i)游离IL-8水平大于或等于1微微克/mL;(ii)任何细胞相关的IL-8、GROα、GROβ、GROγ、NAP-2或ENA-78大于正常生理水平;或(iii)在分别产生IL-8、GROα、GROβ、GROγ、NAP-2或ENA-78的细胞或组织中,IL-8、GROα、GROβ、GROγ、NAP-2或ENA-78超过基本水平。
通常,已知式(I)化合物较本发明引用的参考文献WO 96/25157和WO97/29743中公开的化合物具有较长的t1/2和改进的口服生物可利用度。
有许多疾病,其中过量的或失控的IL-8产生与这些疾病的加剧和/或引起有关。趋化因子介导的疾病包括牛皮癣、特异反应性皮炎、骨关节炎、类风湿性关节炎、哮喘、慢性阻碍性肺疾病、成人呼吸窘迫综合征、炎性肠疾病、节段性回肠炎、溃疡性结肠炎、中风、脓毒性休克、多发性硬化、内毒素性休克、革兰氏阴性脓毒症、中毒性休克综合征、心脏的和肾的再灌注损伤、肾小球性肾炎、血栓形成、移植物抗宿主反应、阿耳茨海默氏病、同种移植排斥、疟疾、再狭窄、血管生成、动脉粥样硬化、骨质疏松症、齿龈炎和不需要的造血干细胞释放以及由呼吸病毒、疱疹病毒、和肝炎病毒引起的疾病、脑膜炎、疱疹性脑炎、CNS结节性脉管炎、外伤性脑损伤、CNS肿瘤、蛛网膜下出血、手术后创伤、间质性肺炎、过敏症、晶体诱导的关节炎、急性和慢性胰腺炎、急性酒精中毒性肝炎、引起坏死的小肠结肠炎、慢性窦炎、眼色素层炎、多肌炎、结节性脉管炎、痤疮、胃和十二指肠溃疡、腹腔疾病、食管炎、舌炎、气流梗阻、导气管反应过强、细支气管炎闭塞性组织肺炎、支气管扩张、细支气管炎、闭塞性支气管炎、慢性支气管炎、肺源性心脏病、呼吸困难、肺气肿、高钙酸血、过度膨胀、低氧血、低氧症、手术性肺容量减少、肺纤维变性、肺性高血压、右心室肥大、肉样瘤病、小导气管病、换气-灌注失配、喘鸣和狼疮。
这些疾病的主要特征是:大块嗜中性粒细胞渗透、T-细胞渗透、或新血管生长,并与增加的IL-8、GROα、GROβ、GROγ、NAP-2或ENA-78的产生相关,这些产物是形成嗜中性粒细胞向炎性部位趋化或内皮细胞的方向生长的原因。与其它炎性细胞因子(IL-1、TNF、和IL-6)相比,IL-8、GROα、GROβ、GROγ、NAP-2或ENA-78具有以下独特的特性:促进嗜中性粒细胞趋化、酶释放包括不限于弹性蛋白酶释放、以及过氧化物产生和激活。α-趋化因子而尤其是IL-8、GROα、GROβ、GROγ、NAP-2或ENA-78,通过IL-8I型或II型受体的作用,由于促进内皮细胞的方向性生长而能促进肿瘤的新血管形成。因此,抑制IL-8诱导的趋化或激活将导致方向性的嗜中性粒细胞渗透减少。
最近的证据还表明趋化因子在治疗HIV感染中的作用,Littleman等,《自然》381,pp.661(1996)和Koup等,《自然》381,pp.667(1996)。
本发明的证据还指出了IL-8抑制剂在治疗动脉硬化症中的应用。第一篇参考文献,Boisvert等,《临床研究杂志》
J.Clin.Invest,1998,101:353363表明,通过骨髓移植,干细胞上的IL-8受体缺失(和由此而在单核细胞/巨嗜细胞上的)可导致LDL受体缺陷小鼠的动脉粥样硬化血小板减少。另外的支持参考文献有:Apostolopoulos,等,
Arterioscler.Thromb.Vase.Biol.1996,16:1007-1012;Liu,等,
Arterioscler.Thromb.Vase.Biol,1997,17:17323;Rus,等,《动脉粥样硬化》1996,127:263-271;Wang等,《生物化学杂志》1996,271:8837-8842;Yue,等,《欧洲药理学杂志》(
Eur.J.Pharmacol.)1993,240:81-84;Koch,等,《美国病理学杂志》(
Am.J.Pathol.),1993,142:1423-1431;Lee,等,《免疫学通报》(
Immunol.Lett.),1996,53,109-113;和Terkeltaub等,Arterioscler,Thromb.,1994,14:47-53。
本发明还提供了使用趋化因子受体拮抗剂式(I)化合物来治疗急性发作CNS损伤的方法以及对于那些被认为易受CNS损伤的个体提供预防CNS损伤的方法。
本文定义的CNS损伤包括开放式或穿透性头外伤,例如由于外科手术引起;或闭合性头外伤,例如由于头部区域受损伤。局部缺血性中风也包括在此定义中,尤其是脑区域。
局部缺血性中风可定义为由大脑特定区域的供血不足所引起的病灶神经失调,通常结果是栓塞、血栓症、或血管的局部动脉粥样化性闭合。炎性细胞因子在此区域的作用已经表现出来,因此本发明提供一种可能治疗这些损伤的方法。现有的治疗方法中对急性损伤的治疗比较少。
TNF-α是一种具有炎性前作用的细胞因子,包括内皮白细胞粘附分子表达。白细胞浸润到局部缺血的脑损伤,因此抑制或降低TNF水平的化合物将用于治疗局部缺血性脑损伤。参见本发明引作参考的Liu等,《中风》,Vol.25.,No.7,pp.1481-88(1994)。
闭合性头损伤的模型和使用混合的5-LO/CO剂的治疗公开在本发明引作参考的Shohami等,
J,of Vaisc & Clinical Physiology and Pharmacology,Vol.3,No.2,pp.99-107(1992)中。在这些治疗的动物中发现减少水肿形成的治疗可改善功能性结果。
按足以抑制与IL-8α或β受体结合的IL-8与这些受体结合的用量施用式(I)化合物,例如这种抑制已被降低嗜中性白细胞的趋化性和激活所证实。式(I)化合物为IL-8结合的抑制剂这一发现是基于本文所述的在体外受体结合试验中的式(I)化合物的作用。式(I)化合物已表明其是II型IL-8受体的抑制剂。
本文所用的术语“IL-8介导的疾病或疾病症状”是指以下任何疾病和所有疾病症状:其中IL-8、GROα、GROβ、GROγ、NAP-2或ENA-78起作用、或者本身产生IL-8、GROα、GROβ、GROγ、NAP-2或ENA-78,或因IL-8、GROα、GROβ、GROγ、NAP-2或ENA-78引起另一种单核因子释放所致的疾病,该单核因子例如但不限于IL-1、IL-6或TNF。因此,例如其中IL-1为主要成分并且其产生或作用是根据IL-8而加重或减轻的疾病,被认为是IL-8介导的疾病。
本文所用的术语“趋化因子介导的疾病或疾病症状”是指其中与IL-8α或β受体结合的趋化因子起作用的任何和所有疾病症状,该趋化因子为例如但不限于IL-8、GROα、GROβ、GROγ、NAP-2或ENA-78。这包括以下疾病症状:其中IL-8起作用、或者IL-8本身产生、或者IL-8引起另一种单核因子释放所致的疾病,该单核因子例如、但不限于IL-1、IL-6或TNF。因此,例如其中IL-1为主要成分并且其产生或作用是根据IL-8而加重或减轻的疾病,被认为是IL-8介导的疾病。
本文所用的术语“细胞因子”是指影响细胞功能的任何分泌多肽、并且是一种在免疫、炎性或造血反应中调节细胞间的相互作用的分子。细胞因子包括,但不限于,单核因子和淋巴因子,不论是哪种细胞产生的。例如,单核因子通常是指由单核的细胞产生和分泌的,例如巨噬细胞和/或单核细胞。但是许多其它细胞也产生单核因子,例如天然杀伤细胞、成纤维细胞、嗜碱细胞、嗜中性白细胞、内皮细胞、脑星形胶质细胞、骨髓基质细胞、表皮角化细胞和B-淋巴细胞。淋巴因子通常是指由淋巴细胞产生的。细胞因子的例子包括但不限于白介素-1(IL-1)、白介素-6(IL-6)、白介素8(IL-8)、α肿瘤坏死因子(TNF-α)和β肿瘤坏死因子(TNF-β)。
本文所用的术语“趋化因子”是指影响细胞功能的任何分泌多肽、并且是一种在免疫、炎性或造血反应中调节细胞间的相互作用的分子,与上述术语“细胞因子”相似。趋化因子是主要通过细胞跨膜分泌的,并引起特殊血白细胞或白细胞、嗜中性白细胞、单核细胞、巨噬细胞、T-细胞、B-细胞、内皮细胞和平滑肌细胞的趋化性和激活。趋化因子的例子包括但不限于IL-8、GROα、GROβ、GROγ、NAP-2、ENA-78、IP-10、MIP-1α、MIP-β、PF4和MCP1、2、和3。
治疗中为了使用式(I)化合物或其药学上可接受的盐,通常根据标准的制药实践将其配制成药物组合物。因此,本发明还涉及含有效、无毒量的式(I)化合物和其药学上可接受的载体或稀释剂的药物组合物。
式(I)化合物、其药学上可接受的盐和含这些的药物组合物可按任何常规的给药途径很方便地给药,例如,口服、局部、非肠道或吸入给药。式(I)化合物的给药剂型可按常规方法将式(I)化合物与标准的药用载体结合制备成常规的剂型。式(I)化合物也可按与已知的第二种治疗活性化合物联合给药的常规剂量给药。这些方法包括将组分混合、制粒、和压缩或溶解成为所需的制剂。大家都清楚,药学上可接受的载体或稀释剂的形式和特性是根据所要联合的活性成分的量、给药途径和其它众所周知的变量来确定的。载体必须在与制剂的其它组分相容这一点上是“可接受的”、并不对其容器有害。
所使用的药用载体可以是,例如固体或液体。固体载体例如有乳糖、白土、蔗糖、滑石、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸等。液体载体例如有糖浆、花生油、橄榄油、水等。同样,载体或稀释剂可包括本领域众所周知的延时物质,例如硬脂酸甘油酯或甘油二硬脂酸酯本身、或还含有蜡。
可以采用各种药物剂型。因此,如果使用固体载体,可将该制剂压片、以粉末或小球形式置于硬明胶胶囊中、或者为片剂或锭剂。固体载体的用量可在较大范围变化,但优选约25mg-约1g。当使用液体载体时,该制剂为糖浆剂、乳剂、软明胶胶囊、无菌注射液例如安瓿或非水性液体悬浮液的形式。
式(I)化合物可以局部给药,即非全身给药。这包括将式(I)化合物外用于表皮或口腔,以及将这种化合物滴于耳、眼和鼻中,以便该化合物不明显进入血流。相反,全身给药是指口服的、静脉内的、腹膜内的和肌内的给药方式。
适用于局部给药的制剂包括液体或半液体制剂,该制剂适于经皮肤渗透到炎症部位,例如搽剂、洗剂、乳膏、软膏或糊剂、和适用于眼、耳或鼻给药的滴剂。对于局部给药,活性成分可包括该制剂的0.001%-10%w/w,例如,1%-2%w/w。然而也可包括该制剂的近10%w/w,但优选包括小于5%w/w,更优选0.1%-1%w/w。
本发明的洗剂包括那些适用于皮肤或眼使用的剂型。眼洗剂可包括任意含杀菌剂的无菌水溶液,并可通过类似滴剂的制备方法进行制备。用于皮肤的洗剂或搽剂也可包括促干剂或使皮肤凉爽剂,例如醇或丙酮,和/或加湿剂例如甘油或诸如蓖麻油或花生油之类的油。本发明的乳膏、软膏或糊剂为外用活性成分的半固体制剂。它们可以以下方法制备,即在合适的机器帮助下、将微粒或粉末形式的活性成分单独或者在含水流体或非水流体的溶液或悬浮液中与油脂性基质或非油脂性基质混合。该基质可包括,烃,例如硬、软或液体石蜡、甘油、蜂蜡、金属皂;胶浆;天然油例如杏仁、玉米、花生、蓖麻、或橄榄油;羊毛脂或其衍生物或脂肪酸例如硬脂酸或油酸以及醇例如丙二醇或大粒凝胶。该制剂可加入任何适合的表面活性剂,例如阴离子、阳离子或非离子型表面活性剂,如脱水山梨糖醇酯或其聚氧乙烯衍生物。也可包括,悬浮剂,例如天然树胶、纤维素衍生物或无机物例如硅石(silicaceous silicas),以及其它成分例如羊毛脂。
本发明的滴剂可包括无菌水溶液或油性溶液或悬浮液,并可通过以下方法制备,即将活性成分溶液在适合的杀菌剂和/或杀真菌剂和/或任何其它适合的防腐剂(优选包括表面活性剂)中。然后可通过过滤使所得到的溶液澄清、转移至适合的容器中,该容器之后被密封并通过高压灭菌法或在98-100℃保持1.5小时而进行灭菌。或者,可通过过滤对该溶液进行灭菌并转移至采用了防腐技术的容器中。适于用于滴剂中的杀菌剂和杀真菌剂例如有硝酸苯汞或乙酸苯汞(0.002%)、苄烷铵氯化物(0.01%)和醋酸洗必太(0.01%)。用于制备油性溶液的适合溶剂包括甘油、稀释的醇和丙二醇。
式(I)化合物可经非肠道给药,即通过静脉内的、肌内的、皮下的、鼻内的、直肠内的、阴道内的或腹膜内的给药。一般优选非肠道的皮下和肌内给药形式。通过常规工艺可制备用于这种给药的适合剂型。式(I)化合物也可通过吸入给药,即通过鼻内和口吸入给药。通过常规工艺可制备用于此给药形式的适合剂型,例如气雾剂或计量吸入剂。
对于本发明公开的用于式(I)化合物的所有方法,每天口服剂量方案优选约占总体重的0.01-80mg/kg。每天非肠道剂量方案优选约占总体重的0.001-80mg/kg。每天局部剂量方案优选0.1mg-150mg,每天给药1-4次,优选每天2-3次。每天吸入剂量方案优选每天约0.01mg/kg-1mg/kg。本领域技术人员还清楚,式(I)化合物或其药学上可接受的盐的最佳用量和个体剂量的差异可根据所治疗的疾病的性质和程度、给药的形式、途径和部位、以及所治疗的特定患者来确定,并且可通过常规技术来确定这些最佳量。本领域技术人员还知道,本领域技术人员可采用常规的疗程判定试验来确定最佳的疗程,即每天给药的式(I)化合物或其药学上可接受的盐用一定天数的每天剂量数。
现参考下列生物学实施例对本发明进行描述,这些实施例仅仅是对本发明进行举例说明、而不应解释为限定本发明的范围。
生物学实施例
通过下列体外试验来确定本发明化合物的IL-8、和Gro-α趋化因子抑制作用:
受体结合试验:
从Amersham Corp.,Arlington Heights,IL得到[125I]IL-8(人重组体),它具有2000 Ci/mmol特异活性。从NEN-New England Nuclear得到Gro-oc。所有其它化学制品均为分析级。如前所述(Holmes,等,《科学》,1991,253,1278),在中国仓鼠卵巢细胞中各自表达了高水平的重组人IL-8α型和β型受体。根据前面所述的方案(Haour,等,《生物化学杂志》,249 pp 2195-2205(1974))使中国仓鼠卵巢膜均化。但均化缓冲液改为pH7.5的10mMTris-HCL、1mM MgSO4、0.5mM EDTA(环丙基甲酸-双胺四乙酸)、1mMPMSF(α-甲苯磺酰氟化物)、0.5mg/L亮抑酶肽。用Pierce公司的微量测定试剂盒以牛血清白蛋白为标准确定膜蛋白质浓度。所有试验是在96-孔微量培养板上进行。每一反应混合物包含存在于pH8.0的20mM Bis-Tris丙烷和0.4mM TrisHCl缓冲液中的125I IL-8(0.25nM)或125I Gro-α和0.5μg/mLIL-8Rα或1.0μg/mL IL-8Rβ膜,该缓冲液含1.2mM MgSO4、0.1mM EDTA、25mM NaCl和0.03%CHAPS。另外,加入有关的预先溶解在DMSO中的药物或化合物以便最终浓度达0.01nM-100μM。加入125I-IL-8开始该试验。于室温下1小时后,用玻璃纤维滤垫上的96孔收获器收获该培养板,其中的滤垫用1%聚乙烯亚胺/0.5%BSA阻挡,再用pH7.4的25mM NaCl、10mMTrisHCl、1mM MgSO4、0.5mM EDTA、0.03%CHAPS洗涤该板三次。然后将滤器干燥并在Betaplate液体闪烁计数器上计数。重组IL-8Rα或I型受体在此也指非许可受体,而重组IL-8Rβ或II型受体指许可受体。
在合成化学部分实施例1-15中所述的所有举例的式(I)化合物,在IL-8受体抑制的许可模型中IC50为大约45-约<1μg/mL。在那些试验的化合物中,还发现在大约同样水平时实施例1-12的化合物是Gro-α结合的抑制剂。
趋化性试验:
按《免疫学》vol I,Suppl 1,6.12.3单元的最新方案中所述的嗜中性粒细胞趋化性试验确定这些化合物的体外抑制特性,该文献公开文本在此全文引作参考。从人血液中分离的嗜中性粒细胞如本发明引用的《免疫学》volI,Suppl 1,7.23.1单元的最新方案中所述。将化学引诱剂IL-8、GRO-α、GRO-β、GRO-γ和NAP-2置于48多孔室(Neuro Probe,Cabin John,MD)底室、浓度为0.1-100nM。用5μm聚碳酸酯过滤器将两室分开。当试验本发明化合物时,在将细胞加入上面的室中之前将它们与细胞(0.001-1000nM)混合。于大约37℃下,在含5%CO2的湿润培养箱中继续进行培养约45-90分钟。在培养期末,除去聚碳酸酯膜、洗涤顶侧,然后用Diff Quick染色方案(Baxter产品,McGaw Park,IL,USA)使该膜进行染色。用显微镜对趋向趋化因子的细胞进行肉眼计数。通常,每个样本计数四个视野,平均这些数得到平均迁移细胞数。每个样本重复试验三次、每个化合物重复至少4次。某些细胞(阳性对照细胞)中未加入化合物,这些细胞代表细胞的最大趋化反应。在需要阴性对照(未刺激的)的情况下,在底室中不加入趋化因子。阳性对照与阴性对照之间的差异代表细胞的趋化活性。
弹性蛋白酶释放试验:
对本发明化合物测试了它们阻止弹性蛋白酶从人嗜中性粒细胞释放的能力。嗜中性粒细胞按《免疫学》vol I,Suppl 1,7.23.1单元的最新方案中所述的方法分离嗜中性粒细胞。将悬浮在Ringer氏溶液(NaCl 118,KCl 4.56,NaHCO3 25,KH2PO4 1.03,葡萄糖11.1,HEPES 5mM,pH7.4)中的PMNs 0.88×106细胞置于体积为50μl的96孔培养板的每一孔中。在此培养板中加入体积为50μl的试验化合物(0.001-1000nM)、体积为50μl的细胞松弛素B(20μg/ml)和体积为50μl的Ringers缓冲液。在加入0.01-1000nM最终浓度的IL-8、GRO-α、GRO-β、GRO-γ和NAP-2之前,将这些细胞加温(37℃,5%CO2,95%RH)。使反应继续进行45分钟、然后离心(800×g5分钟)该96孔培养板、除去100μl上清夜。将该上清夜加入第二个96孔培养板中、之后加入溶解在磷酸盐缓冲盐水中的人造弹性蛋白酶底物(MeOSuc-Ala-Ala-Pro-Val-AMC,Nova Biochem,La Jolla,CA)直至最终浓度为6μg/ml。立即将培养板置于荧光96孔培养板读数器(Cytofluor 2350,Millipore,Bedford,MA)中,根据Nakajima等《生物化学杂志》254 4027(1979)所述的方法每隔3分钟收集数据。通过测定MeOSuc-Ala-Ala-Pro-Val-AMC的降解率计算从PMNs释放的弹性蛋白酶的量。
外伤性脑损伤中的TNF-α测定:
本试验用于检测肿瘤坏死因子mRNA在大鼠实验诱导的液体叩击的外伤性侧脑损伤(TBI)后的特定脑区域中的表达。用戊巴比妥钠(60mg/kg,i.p.)麻醉成年Sprague-Dawley大鼠(n=42)、并使其产生中心位于左颞顶皮层的中度(2.4atm.)液体叩击的侧脑损伤(n=18),或“假性”治疗(麻醉并手术,但未损伤,n=18)。在损伤后1、6和24小时时用断头术杀死动物、去脑、准备好以下组织样本:左侧(受损伤的)顶骨皮层(LC)、位于对侧右皮层(RC)的相应区域、与受损伤的顶骨皮层(LA)相邻的皮层、右皮层(RA)中的相应的邻近区域、左海马(LH)和右海马(RH)。分离出总RNA、并进行Northern印迹杂交、相对于TNF-α阳性对照RNA(巨噬细胞=100%)进行定量。在损伤后1小时的受损伤大脑半球中,观察到LH(阳性对照的104±17%,与假治疗动物相比p<0.05)、LC(105±21%,p<0.05)和LA(69±8%,p<0.01)中的TNF-αmRNA表达显著增加。在损伤后6小时时在LH(46±8%,p<0.05)、LC(30±3%,p<0.01)和LA(32±3%,p<0.01)中同样观察到增加的TNF-αmRNA表达,它在损伤后24小时消失。在对侧半球中,在损伤后1小时时RH(46±2%,p<0.01),RC(4±3%)和RA(22±8%)中的TNF-αmRNA表达增加、在6小时时(而不是24小时)RH(28±11%),RC(75%)和RA(266%,p<0.05)中的TNF-αmRNA表达增加。在假治疗(手术但无损伤)或幼小动物中,任何时候在任一大脑半球的任一6个脑区域中均未观察到TNF-αmRNA表达的不一致变化。这些结果表明液体叩击的旁矢状面脑损伤后,TNF-αmRNA的暂时表达在特定脑区域发生改变,包括那些非损伤性大脑半球。由于TNF-α能诱导神经生长因子(NGF)和刺激其它细胞因子从激活的星形胶质细胞释放,TNF-α的基因表达中的这种损伤后变化在对CNS损伤的急性和再生性反应两着中起重要作用。
IL-mRNA的CNS损伤模型
本试验描述了大鼠液体叩击的外伤性侧脑损伤(TBI)后的特定脑区域中的白介素-1β(IL-1β)mRNA的区域性表达。用戊巴比妥钠(60mg/kg,i.p.)麻醉成年Sprague-Dawley大鼠(n=42)、并使其产生中心位于左颞顶皮层的中度(2.4atm.)液体叩击的侧脑损伤(n=18),或“假性”治疗(麻醉并手术,但未损伤,n=18)。在损伤后1、6和24小时时杀死动物、去脑、准备好以下组织样本:左侧(受损伤的)顶骨皮层(LC)、位于对侧右皮层(RC)的相应区域、与受损伤的顶骨皮层(LA)相邻的皮层、右皮层(RA)中的相应的邻近区域、左海马(LH)和右海马(RH)。分离出总RNA、并进行Northern印迹杂交、脑组织IL-1βmRNA的数量表示为负载在同一凝胶上的IL-1β阳性巨噬细胞RNA的相对放射性百分数。在脑损伤后1小时,在受损伤的大脑半球中,观察到LC(阳性对照的20.7±0.7%,n=6,与假治疗动物相比p<0.05)、LH(24.5±0.9%,p<0.05)和LA(21.5±3.1%,p<0.05)中的IL-1βmRNA的表达显著增加,在LC(4.0±0.4%,n=6,p<0.05)和LH(5.0±1.3%,p<0.05)中保持时间升高到损伤后约6小时。在假治疗或幼小动物中,任一大脑区域中均未观察到IL-1βmRNA表达。这些结果表明TBI后,IL-1βmRNA的暂时表达在特定脑区域受到区域性刺激。细胞因子中的这些区域性变化,例如IL-1β在损伤后期起一定作用。
本申请说明书中引用的所有出版物,包括但不限于在本说明书中所引证的专利和专利申请,全部引作本发明的参考文献,就如同专门或单独指定每一篇全文引作参考一样。
上面的说明充分公开了本发明,包括其优选的实施方式。本文特别公开的实施方式的变化和改进都在权利要求的范围之内。一般认为,本领域技术人员不需更多的发挥,根据前面的说明就可以最大程度地利用本发明。因此,在此的实施例仅仅是举例说明、而不是以任何方式限定本发明的范围。其中要求保护排他权或特权的本发明实施方案在权利要求书中进行了定义。
Claims (6)
R1独自选自氢、卤素、硝基、氰基、卤素取代的C1-10烷基、C1-10烷基、C2-10链烯基、C1-10烷氧基、卤素取代的C1-10烷氧基、叠氮基、(CR8R8)qS(O)tR4、羟基、羟基C1-4烷基、芳基、芳基C1-4烷基、芳氧基、芳基C1-4烷氧基、杂芳基、杂芳基烷基、杂环、杂环C1-4烷基、杂芳基C1-4烷氧基、芳基C2-10链烯基、杂芳基C2-10链烯基、杂环C2-10链烯基、(CR8R8)qNR4R5、C2-10链烯基C(O)NR4R5、(CR8R8)qC(O)NR4R5、(CR8R8)qC(O)NR4R10、S(O)3H、S(O)3R8、(CR8R8)qC(O)R11、C2-10链烯基C(O)R11、C2-10链烯基C(O)OR11(CR8R8)qC(O)OR12、(CR8R8)qOC(O)R11、(CR8R8)qNR4C(O)R11、(CR8R8)qNHS(O)2R17、(CR8R8)qS(O)2NR4R5;或者两个R1部分一起形成O-(CH2)sO-或未取代的5-6元环;
q为0,或1-10的整数;
t为0,或1-2的整数;
s为1-3的整数;
R4和R5各自选自氢、可被取代或不被取代的C1-4烷基、可被取代或不被取代的芳基、可被取代或不被取代的芳基C1-4烷基、可被取代或不被取代的杂芳基、可被取代或不被取代的杂芳基C1-4烷基、杂环、和杂环C1-4烷基,或R4和R5与它们相连的氮一起形成5-7元环,所述的环可以包括或不包括选自氧、氮或硫的另外的杂原子;
Y独自选自氢、卤素、硝基、氰基、卤素取代的C1-10烷基、C1-10烷基、C2-10链烯基、C1-10烷氧基、卤素取代的C1-10烷氧基、叠氮基、(CR8R8)qS(O)tR4、羟基、羟基C1-4烷基、芳基、芳基C1-4烷基、芳氧基、芳基C1-4烷氧基、杂芳基、杂芳基烷基、杂芳基C1-4烷氧基、杂环、杂环C1-4烷基、芳基C2-10链烯基、杂芳基C2-10链烯基、杂环C2-10链烯基、(CR8R8)qNR4R5、C2-10链烯基C(O)NR4R5、(CR8R8)qC(O)NR4R5、(CR8R8)qC(O)NR4R10、S(O)3H、S(O)3R8、(CR8R8)qC(O)R11、C2-10链烯基C(O)R11、C2-10链烯基C(O)OR11、C(O)R11、(CR8R8)qC(O)OR12、(CR8R8)qOC(O)R11、(CR8R8)qNR4C(O)R11、(CR8R8)qNHS(O)2Rd、和(CR8R8)qS(O)2NR4R5;或者两个Y一起形成O-(CH2)SO-或未饱和的5-6元环;
n为1-5的整数;
m为1-4的整数;
R8为氢或C1-4烷基;
R10为C1-10烷基C(O)2R8;
R11选自氢、C1-4烷基、可被取代或不被取代的芳基、可被取代或不被取代的芳基C1-4烷基、可被取代或不被取代的杂芳基、可被取代或不被取代的杂芳基C1-4烷基、可被取代或不被取代的杂环基、和可被取代或不被取代的杂环C1-4烷基;
R12选自氢、C1-10烷基、可被取代或不被取代的芳基、可被取代或不被取代的芳基烷基;
R17选自C1-4烷基、芳基、芳基烷基、杂芳基、杂芳基C1-4烷基、杂环、和杂环C1-4烷基,其中芳基、杂芳基和杂环都可被取代或不被取代。
2.根据权利要求1的化合物,为:
3-(2-羟基-苯基氨基)-4-(2-溴苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2,3-二氯苯基氨基)-环丁-3-烯-1,2-二酮,
3-(4-硝基-2-羟基-苯基氨基)-4-苯基氨基-环丁-3-烯-1,2-二酮,
3-(4-氰基-2-羟基-苯基氨基)-4-苯基氨基-环丁-3-烯-1,2-二酮,
3-(2-甲氧基-苄基氨基)-4-苯基氨基-环丁-3-烯-1,2-二酮,
3-(4-氰基-2-羟基-苯基氨基)-4-(2-溴苯基氨基)-环丁-3-烯-1,2-二酮,
3-(4-氰基-2-羟基-苯基氨基)-4-(2-氯苯基氨基)-环丁-3-烯-1,2-二酮,
3-(4-氰基-2-羟基-苯基氨基)-4-(2,3-二氯苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2-苯基苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2-甲氧基苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2-乙基苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2-苯氧基苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2-氯苯基氨基)-环丁-3-烯-1,2-二酮,
6-氯-3-(3,4-二氧-2-苯基氨基-环丁-1-烯基氨基)-2-羟基-苯磺酰胺、
3,4-二-(4-氰基-2-羟基苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2,3-二甲基苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2-甲基-4-溴苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2-丙基苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2-甲基-3-氯苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2,3-二甲氧基苯基氨基)-环丁-3-烯-1,2-二酮,
3-(2-羟基-苯基氨基)-4-(2-氯-3-甲基苯基氨基)-环丁-3-烯-1,2-二酮,
3-(4-硝基-2-羟基-苯基氨基)-4-(2-溴苯基氨基)-环丁-3-烯-1,2-二酮,
3-(4-硝基-2-羟基-苯基氨基)-4-(2-氯苯基氨基)-环丁-3-烯-1,2-二酮,
3,4-二-(4-硝基-2-羟基苯基氨基)-环丁-3-烯-1,2-二酮,
3-[(2-羟基-苯基)-甲基-氨基]-4-苯基氨基-环丁-3-烯-1,2-二酮,
3-(3-羟基-吡啶-2-基氨基)-4-苯基氨基-环丁-3-烯-1,2-二酮,
或其药学上可接受的盐。
3.一种药物组合物,它包括有效量的权利要求1的化合物、和药学上可接受的载体或稀释剂。
4.一种治疗趋化因子介导的疾病的方法,其中趋化因子与哺乳动物的IL-8α或β受体结合,该方法包括给予所述哺乳动物施用有效量的权利要求1的通式化合物。
5.根据权利要求4的方法,其中哺乳动物患有选自17的趋化因子介导的疾病。
6.根据权利要求16的方法,其中哺乳动物患有选自以下的趋化因子介导的疾病:特异反应性皮炎、骨关节炎、类风湿性关节炎、哮喘、慢性阻碍性肺疾病、成人呼吸窘迫综合征、炎性肠疾病、节段性回肠炎、溃疡性结肠炎、中风、脓毒性休克、多发性硬化、内毒素性休克、牛皮癣、革兰氏阴性脓毒症、中毒性休克综合征、心脏的和肾的再灌注损伤、肾小球性肾炎、血栓形成、移植物抗宿主反应、阿耳茨海默氏病、同种移植排斥、疟疾、再狭窄、血管生成、动脉粥样硬化、骨质疏松症、齿龈炎和不需要的造血干细胞释放、由呼吸病毒、疱疹病毒、和肝炎病毒引起的疾病、脑膜炎、疱疹性脑炎、CNS结节性脉管炎、外伤性脑损伤、CNS肿瘤、蛛网膜下出血、手术后创伤、囊肿性纤维化、早产、咳嗽、瘙痒症、间质性肺炎、过敏症、晶体诱导的关节炎、莱姆关节炎、进行性骨化性纤维发育不良、急性和慢性胰腺炎、急性酒精中毒性肝炎、引起坏死的小肠结肠炎、慢性窦炎、眼色素层炎、多肌炎、结节性脉管炎、痤疮、胃和十二指肠溃疡、腹腔疾病、食管炎、舌炎、气流梗阻、导气管反应过强、细支气管炎闭塞性组织肺炎、支气管扩张、细支气管炎、闭塞性支气管炎、慢性支气管炎、肺源性心脏病、呼吸困难、肺气肿、高钙酸血、过度膨胀、低氧血、低氧症、手术性肺容量减少、肺纤维变性、肺性高血压、右心室肥大、肉样瘤病、小导气管病、换气-灌注失配、喘鸣和狼疮。
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JP2004521106A (ja) * | 2001-01-16 | 2004-07-15 | スミスクライン・ビーチャム・コーポレイション | Il−8受容体アンタゴニスト |
ATE419845T1 (de) * | 2001-01-16 | 2009-01-15 | Smithkline Beecham Corp | Il-8-rezeptor-antagonisten |
KR20030090629A (ko) * | 2001-02-02 | 2003-11-28 | 쉐링 코포레이션 | Cxc 케모카인 수용체 길항제로서의 3,4-디-치환된사이클로부텐-1,2-디온 |
US7132445B2 (en) | 2001-04-16 | 2006-11-07 | Schering Corporation | 3,4-Di-substituted cyclobutene-1,2-diones as CXC-chemokine receptor ligands |
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US6878709B2 (en) | 2002-01-04 | 2005-04-12 | Schering Corporation | 3,4-di-substituted pyridazinediones as CXC chemokine receptor antagonists |
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