CN1244867A - 作为p38蛋白激酶抑制剂的取代的含氮杂环 - Google Patents
作为p38蛋白激酶抑制剂的取代的含氮杂环 Download PDFInfo
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- CN1244867A CN1244867A CN97181382A CN97181382A CN1244867A CN 1244867 A CN1244867 A CN 1244867A CN 97181382 A CN97181382 A CN 97181382A CN 97181382 A CN97181382 A CN 97181382A CN 1244867 A CN1244867 A CN 1244867A
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Abstract
本发明涉及与细胞增殖、细胞死亡和对外界刺激产生应答有关的哺乳动物蛋白激酶p38的抑制剂。本发明还涉及制备这些抑制剂的方法。本发明还提供了包含本发明抑制剂的药物组合物以及这些组合物在治疗或预防各种疾病中的使用方法。
Description
发明技术领域
本发明涉及参与细胞增殖、细胞死亡和对胞外刺激产生应答的哺乳动物蛋白激酶p38的抑制剂。本发明还涉及制备这些抑制剂的方法。本发明还提供包含本发明抑制剂的药物组合物以及那些组合物在治疗和预防各种疾病中的使用方法。
发明背景
蛋白激酶参与对胞外信号的各种细胞应答。最近,发现了一类促有丝分裂剂活化的蛋白激酶(MAPK)。该类酶是通过磷酸化活化其底物的Ser/Thr激酶[B.Stein等药物化学年鉴,31,pp.289-98(1996)]。MAPKs本身通过各种信号而活化,包括生长因子、细胞因子、UV照射和应激诱导剂。
一种另人尤其感兴趣的MAPK为p38。p38还被称作细胞因子抑制性抗炎药物结合蛋白(CSBP)和RK,它是从被脂多糖(LPS)受体CD14转染并被LPS诱导的小鼠前B细胞中分离的。后来分离和测定了人和小鼠中的p38以及编码它的cDNA的序列。在通过应激,如脂多糖(LPS)处理、UV、茴香霉素或渗压震扰和通过细胞因子,如IL-1和TNF刺激的细胞中观察到p38的活化。
p38激酶的抑制导致IL-1和TNF的产生的阻断。IL-1和TNF刺激其它促炎细胞因子,如IL-6和IL-8的产生,并且涉及急性和慢性炎症疾病以及绝经后骨质疏松症[R.B.Kimble等内分泌腺学,136,pp.3054-61(1995)]。
根据这一发现认为p38与其它MAPKs一起在介导对炎症刺激的细胞应答中起作用,如白细胞聚集、巨嗜细胞/单核细胞的活化、组织吸收作用、发烧、急性期反应和嗜中性白细胞增多症。此外,MAPKs,如p38参与癌症、凝血酶诱导的血小板聚集、免疫缺陷病、自身免疫疾病、细胞死亡、变态反应、骨质疏松和神经变性疾病。p38的抑制剂还通过抑制前列腺素内过氧化物合成酶-2的诱导涉及到疼痛治疗领域。WO96/21654提出了与IL-1、IL-6、IL-8或TNF过度产生有关的其它疾病。
其它人已开始努力开发特异性抑制MAPKs的药物。例如,PCT公开WO95/31451描述了抑制MAPKs,尤其是p38的吡唑化合物。然而,这些抑制剂在体内的功效仍在研究中。
因此,仍非常需要开发其它有效的可用于治疗各种与p38的活化相关的疾病的p38特异性抑制剂。
发明概述
本发明通过提供对p38显示强的特异性抑制的化合物而解决了这个问题。
构成Q1的环被1-4个取代基取代,其中各取代基独立地选自卤素;任选被NR’2、OR’、CO2R’或CONR’2取代的C1-C3烷基;任选被NR’2、OR’、CO2R’或CONR’2取代的O-(C1-C3)-烷基;NR'2;OCF3;OCF3;NO2;OO2R’;CONR’;SR’;S(O2)N(R’)2;SCF3;CN;N(R’)C(O)R4;N(R’)C(O)OR4;N(R’)C(O)C(O)R4;N(R’)S(O2)R4;N(R’)R4;N(R4)2;OR4;OC(O)R4;OP(O)3H2;或N=C-N(R’)2。
构成Q2的环任选被至多4个的取代基取代,其中各取代基独立地选自卤素;任选被NR’2、OR’、CO2R’、S(O2)N(R’)2、N=C-N(R’)2、R3或CONR’2取代的C1-C3直链或支链烷基;O-(C1-C3)-烷基;任选被NR’2、OR’、CO2R’、S(O2)N(R’)2、N=C-N(R’)2、R3或CONR’2取代的O-(C1-C3)-烷基;NR’2;OCF3;CF3;NO2;CO2R’;CONR’;R3;OR3;NR3;SR3;C(O)R3;C(O)N(R’)R3;C(O)OR3;SR’;S(O2)N(R’)2;SCF3;N=C-N(R’)2或CN。
R’选自氢、(C1-C3)-烷基;(C2-C3)-链烯基或炔基;苯基或被1-3个独立地选自卤素、甲氧基、氰基、硝基、氨基、羟基、甲基或乙基的取代基取代的苯基。
R3选自5-6元芳香碳环或杂环系。
R4为任选被N(R’)2、OR’、CO2R’、CON(R’)2或S(O2)N(R2)2取代的(C1-C4)-烷基;或任选被N(R’)2、OR’、CO2R’、CON(R’)2或S(O2)N(R2)2取代的5-6元碳环或杂环系。
X选自-S-、-O-、-S(O2)-、-S(O)-、-S(O2)-N(R2)-、-N(R2)-S(O2)-、-N(R2)-C(O)O-、-O-C(O)-N(R2)、-C(O)-、-C(O)O-、-O-C(O)-、-C(O)-N(R2)-、-N(R2)-C(O)-、-N(R2)-、-C(R2)2-或-C(OR2)2-。
每个R独立地选自氢、-R2、-N(R2)2、-OR2、SR2、-C(O)-N(R2)2、-S(O2)-N(R’)2或-C(O)-OR2,其中两个相邻的R任选相互连接并与分别与它们相连的各个Y一起形成4-8元碳环或杂环;
R2选自氢、(C1-C3)-烷基或(C1-C3)-链烯基;其中各个任选被-N(R’)2、-OR’、SR’、-C(O)-N(R’)2、-S(O2)-N(R’)2、-C(O)-OR’或R3取代。
Y为N或C;
A如果存在,为N或CR’;
n为0或1;
R1选自氢、(C1-C3)-烷基、OH或O-(C1-C3)-烷基。
在另一个具体实施方案中,本发明提供包含本发明的p38抑制剂的药物组合物。这些组合物可用于治疗或预防各种疾病中,如癌症、炎症疾病、自身免疫疾病、破坏性骨病、增生性疾病、感染性疾病、病毒性疾病和神经变性疾病。这些组合物还可用于预防细胞死亡和增生的方法中,因此可被用来治疗或预防中风中的再灌注/局部缺血、心脏病、器官低氧。组合物还可用于预防凝血酶诱导的血小板凝集的方法中。上述各方法也为本发明的一部分。发明详述
构成Q1的环被1-4个取代基取代,其中各取代基独立地选自卤素;任选被NR’2、OR’、CO2R’或CONR’2取代的C1-C3烷基;任选被NR’2、OR’、CO2R’或CONR’2取代的O-(C1-C3)-烷基;NR’2;OCF3;CF3;NO2;CO2R’;CONR’;SR’;S(O2)N(R’)2;SCF3;CN;N(R’)C(O)R4;N(R’)C(O)OR4;N(R’)C(O)C(O)R4;N(R’)S(O2)R4;N(R’)R4;N(R4)2;OR4;OC(O)R4;OP(O)3H2;或N=C-N(R’)2。
构成Q2的环任选被至多4个的取代基取代,其中各取代基独立地选自卤素;任选被NR’2、OR’、CO2R’、S(O2)N(R’)2、N=C-N(R’)2、R3或CONR’2取代的C1-C3直链或支链烷基;O-(C1-C3)-烷基;任选被NR’2、OR’、CO2R’、S(O2)N(R’)2、N=C-N(R’)2、R3或CONR’2取代的O-(C1-C3)-烷基;NR’2;OCF3;CF3;NO2;CO2R’;CONR’;R3;OR3;NR3;SR3;C(O)R3;C(O)N(R’)R3;C(O)OR3;SR’;S(O2)N(R’)2;SCF3;N=C-N(R’)2或CN。
R’选自氢、(C1-C3)-烷基;(C2-C3)-链烯基或炔基;苯基或被1-3个独立地选自卤素、甲氧基、氰基、硝基、氨基、羟基、甲基或乙基的取代基取代的苯基。
R3选自5-6元芳香碳环或杂环系。
R4为任选被N(R’)2、OR’、CO2R’、CON(R’)2或S(O2)N(R2)2取代的(C1-C4)-烷基;或任选被N(R’)2、OR’、CO2R’、CON(R’)2或S(O2)N(R2)2取代的5-6元碳环或杂环系。
X选自-S-、-O-、-S(O2)-、-S(O)-、-S(O2)-N(R2)-、-N(R2)-S(O2)-、-N(R2)-C(O)O-、-O-C(O)-N(R2)、-C(O)-、-C(O)O-、-O-C(O)-、-C(O)-N(R2)-、-N(R2)-C(O)-、-N(R2)-、-C(R2)2-或-C(OR2)2-。
每个R独立地选自氢、-R2、-N(R2)2、-OR2、SR2、-C(O)-N(R2)2、-S(O2)-N(R2)2或-C(O)-OR2,其中两个相邻的R任选相互连接并与分别与它们相连的各个Y一起形成4-8元碳环或杂环;
当两个R部分与分别与它们连接的Y部分一起形成环时,对于本领域技术人员而言从各个未稠合的R部分失去末端氢是显而易见的。例如,如果通过将两个R部分连接在一起形成环结构,其中一个为-NH-CH3,另一个为-CH2-CH3,将失去各个R部分(黑体字所示)中的末端氢。因此,产生的环结构部分将具有式-NH-CH2-CH2-CH2-结构。
R2选自氢、(C1-C3)-烷基或(C1-C3)-链烯基;其中各个任选被-N(R’)2、-OR’、SR2、-C(O)-N(R’)2、-S(O2)-N(R’)2、-C(O)-OR’或R3取代。
Y为N或C;
A如果存在,为N或CR’;
n为1或1;
根据另一个优选的具体实施方案,Q1选自包含1-3个取代基的苯基或吡啶基,其中至少一个所述取代基是在邻位,所述取代基独立地选自氯、氟、溴、-CH3-、-OCH3、-OH、-CF3、-OCF3、-O(CH2)CH3、、NH2、3,4-亚甲二氧基、-N(CH3)2、-NH-S(O)2-苯基、-NH-C(O)O-CH2-4-吡啶、-NH-C(O)CH2-吗啉、-NH-C(O)CH2-N(CH3)2、-NH-C(O)CH2-哌嗪、-NH-C(O)CH2-吡咯烷酮、-NH-C(O)C(O)-吗啉、-NH-C(O)C(O)哌嗪、-NH-C(O)C(O)-吡咯烷酮、-O-C(O)CH2-N(CH3)2或-O-(CH2)2-N(CH3)2。
更优选的为包含至少2个在邻位的上述取代基的苯基或吡啶基。
最优选的,Q1选自2-氟-6-三氟甲基苯基、2,6-二氟苯基、2,6-二氯苯基、2-氯-4-羟基苯基、2-氯-4-氨基苯基、2,6-二氯-4-氨基苯基、2,6-二氯-3-氨基苯基、2,6-二甲基-4-羟基苯基、2-甲氧基-3,5-二氯-4-吡啶基、2-氯-4,5-亚甲二氧基苯基或2-氯-4-(N-2-吗啉代-乙酰氨基)苯基。
根据一个优选的具体实施方案,Q2为含有0-3个取代基的苯基或吡啶基,其中各取代基独立地选自氯、氟、溴、甲基、乙基、异丙基、-OCH3、-OH、-NH2、-CF3、-OCF3、-SCH3、-OCH3、-C(O)OH、-C(O)OCH3、-CH2NH2、-N(CH3)2、-CH2-吡咯烷酮和-CH2OH。
最优选的为其中Q2选自苯基、2-异丙基苯基、3,4-二甲基苯基、2-乙基苯基、3-氟苯基。2-甲基苯基、3-氯-4-氟苯基、3-氯苯基、2-羧甲基苯基、2-羧基苯基、2-甲基-4-氯苯基、2-溴苯基、2-吡啶基、2-亚甲基羟基苯基、4-氟苯基、2-甲基-4-氟苯基、2-氯-4-氟苯基、2,4-二氟苯基、2-羟基-4-氟苯基或2-亚甲基羟基-4-氟苯基的化合物。
根据另一个优选的具体实施方案,X为-S-、-O-、-S(O2)-、-S(O)-、-NR-、-C(R2)-或-C(O)-。X最优选为S。
根据另一个优选的具体实施方案,n为1而A为N。
根据另一个优选的具体实施方案,每个Y为C。
根据一个更优选的具体实施方案,每个Y为C,与那些Y部分相连的R选自氢或甲基。
下表提供了本发明一些具体的抑制剂。
表中cpd#表示化合物号。
根据另一个具体实施方案,本发明提供制备上述式(Ia)的p38抑制剂的方法。这些方法包括将式II化合物:其中上式中的各个可变量与上面对本发明抑制剂所定义的相同,与式IIa的离去基团试剂:其中R’如上定义,或式IIb的离去基团试剂反应:其中L1、L2和L3各自独立地代表离去基团。
以过量或净量或与共溶剂,如甲苯一起加入反应所用的离去基团试剂。反应在25-150℃温度下进行。
可用于制备本发明p38抑制剂的式IIa的离去基团试剂包括二甲基甲酰胺二甲基乙缩醛、二甲基乙酰胺二甲基乙缩醛、原甲酸酯三甲酯、二甲基甲酰胺二乙基乙缩醛和其它相关的试剂。优选地,用于制备本发明抑制剂的式IIa离去基团试剂是二甲基甲酰胺二甲基乙缩醛。
可用于制备本发明p38抑制剂的式IIb的离去基团试剂包括光气、羰基二咪唑、碳酸二乙酯和三光气。
制备本发明化合物的较优选的方法采用式II化合物,其中各个可变基团根据如上提供的用于本发明的化合物的较优选和最优选的选择来定义。
由于R1的来源为离去基团试剂(C-R’或C=O),因此,其性质当然取决于该试剂的结构。因此,在R1为OH的化合物中,使用的试剂必须为IIb。类似地,当R1为H或(C1-C3)-烷基时,使用的试剂必须为IIa。为了产生其中R1为O-(C1-C3)-烷基的抑制剂,首先产生其中R1为OH的化合物,接着用标准方法将羟基烷基化,如在DMF、甲基碘和乙基碘中用氢化钠处理。
本发明式Ia的抑制剂的瞬间前体(即式II化合物)可通过下述一种合成线路合成:
线路1
在线路1中,可互换步骤1)和2)的顺序。而且,起始的腈可被相应的酸或酯代替。另外,其它熟知可能的羧基或羧酰胺部分可被用来代替腈(参见线路2)。通过使用本领域熟知的随后的去保护和官能化的方法,可将可变基团如羧酸、羧酸酯、噁唑啉或噁唑烷酮掺入到该线路中。
线路1(和下面的线路2)的第一个步骤中采用的碱选自氢化钠、氨基钠、LDA、六甲基二硅氮化(silazide)锂、六甲基二硅氮化锂或在位置α对腈去质子化的任何其它的非亲核碱。
而且,在上述一个步骤中加入HX-Q2可被两个步骤代替--加入保护或未保护的X衍生物,接着在随后的步骤中加入Q2衍生物。
线路2
在线路2中,Z选自COOH、COOR’、CON(R’)2、噁唑啉、噁唑烷酮或CN。R’如上定义。
根据另一个具体实施方案,本发明提供制备上述式(Ib)的p38抑制剂的方法。这些方法包括将式III化合物:其中上式中的各个可变基团与上面对本发明抑制剂所定义的相同,与如下所示的式IIa或IIb离去基团试剂反应:本发明式(Ib)的p38抑制剂的两个完整的合成线路描述如下。线路3
在线路3中,可将Q1取代的衍生物用碱如氢化钠、氨基钠、LDA、六甲基二硅氮化锂、六甲基二硅氮化钠或任何其它的非亲核碱在对Z基团α的位置进行去质子化处理,其代表掩蔽的酰胺部分。或者,Z为羧酸、羧酸酯、噁唑啉或噁唑烷酮。接着在存在钯催化剂下,将去质子化产生的阴离子与包含两个离去基团或潜在的离去基团的含氮杂环化合物接触。该化合物的一个实例可为2,6-二氯吡啶。
在步骤2中,引入Q2环部分。这可通过使用许多本领域熟知的导致产生联芳基化合物的反应来进行。一个实例可为将芳基锂化合物与步骤1产生的吡啶中间体反应。或者,可在Pd°催化剂存在下,将芳基金属化合物,如芳基锡或芳基硼酸与吡啶中间体的芳基卤部分反应。
在步骤3中,Z基团被去保护和/或官能化形成酰胺化合物。当Z为羧酸、羧酸酯、噁唑啉或噁唑烷酮时,可采用本领域熟知的各种去保护和官能化方法产生酰胺。最后在步骤4中,使用纯的或在有机溶剂中的试剂,如DMF乙缩醛或类似的试剂,将酰胺化合物环化成终产物。
线路4
线路4是类似的,除了在与Q1起始物反应之前首先产生联芳基中间体。
根据另一个具体实施方案,本发明提供类似于上面式Ia和Ib那些的p38抑制剂,但其中含有Q1取代基的环中的C=N被还原。这些抑制剂结构式如下:其中A、Q1、Q2、R、R’、X、Y和n以如式Ia和Ib化合物提供的相同方式定义。这些定义适用于各个可变基团的所有具体实施方案(即基本的,优选的,较优选的和最优选的)。R5选自氢、-CR’2OH、-C(O)R4、-C(O)OR4、-CR’2OPO3H2、-PO3H2和-PO3H2的盐。
当R5不为氢时,期望产生的化合物为在体内将被裂解产生其中R5为氢的化合物的前药形式。
根据其它优选的具体实施方案,在式Ic化合物中,A优选为氮,n优选为1,X优选为硫。在式Ic或Id化合物中,Q1和Q2优选为与上面对式Ia和Ib化合物中的那些可变基团所述的相同部分。
可直接从式Ia或Ib化合物制备式Ic和Id化合物,其中式Ia或Ib化合物在R1的位置含有氢、C1-C3烷基或C2-C3链烯基或炔基(例如其中R1=R’)。下面线路5和6描述了这些化合物的合成线路。
在这些线路中,通过与过量氢化二异丁基铝或等量的试剂反应还原式Ia或Ib化合物以分别产生式Ic和Id环还原化合物。
通过将上述式Ic或Id化合物与一种或多种适宜试剂反应来完成将不为氢的R5部分加入到环氮上的反应。在下面的实施例部分提供了这些修饰的实施例。
下表提供了式Ic的本发明的一些具体抑制剂。
表中cpd#表示化合物号。
表2式Ic化合物 根据另一个具体实施方案,本发明提供下式的p38抑制剂:其中A、Q1、Q2、R、X、Y和n以如式Ia和Ib化合物提供的相同方式定义。这些定义适用于各个可变基团的所有具体实施方案(即基本的,优选的,较优选的和最优选的)。较优选在式Ie化合物中,Q2为未取代的苯基。
Q3为5-6元芳香碳环或杂环系,或包含芳香碳环、芳香杂环或芳香碳环和芳香杂环相结合的8-10元双环系。Q3的环被1-4个取代基取代,其中各取代基独立地选自卤素;任选被NR’2、OR’、CO2R’或CONR’2取代的C1-C3烷基;任选被NR’2、OR'、CO2R’或CONR’2取代的O-(C1-C3)-烷基;NR’2;OCF3;CF3;NO2;CO2R’;CONR’;SR’;S(O2)N(R’)2;SCF3;CN;N(R’)C(O)R4;N(R’)C(O)OR4;N(R’)C(O)C(O)R4;N(R’)S(O2)R4;N(R’)R4;N(R4)2;OR4;OC(O)R4;OP(O)3H2;或N=C-N(R’)2。
根据本发明的一个优选的具体实施方案,Q3被2-4个取代基取代,其中至少一个所述取代基存在于相对于Q3与抑制剂其余部分相连点为邻位的位置上。当Q3为双环时,邻位上的两个取代基存在于最接近(即直接相连)抑制剂分子其余部分的环中。其它两个任选的取代基可存在于任一环中。较优选这两个邻位位置均被一个所述取代基占据。
根据另一个优选的具体实施方案,Q3为单环碳环,其中各邻位取代基独立地选自卤素或甲基。根据另一个优选的具体实施方案,Q3包含1或2个另外的独立选自NR’2、OR’、CO2R’、CN、N(R’)C(O)R4;N(R’)C(O)OR4;N(R’)C(O)C(O)R4;N(R’)S(O2)R4;N(R’)R4;N(R4)2;OR4;OC(CO)R4;OP(O)3H2;或N=C-N(R’)2的取代基。
优选地,Q3选自任何存在于下面表3提供的Ie化合物中的Q3部分,或任何存在于下面表4提供的Ig化合物中的Q3部分。
技术人员将认识到式Ie化合物为某些本发明式Ia和式Ic p38抑制剂的直接前体(即其中Q1=Q3的那些)。技术人员还将认识到式Ig化合物为某些本发明式Ib和式Id p38抑制剂的前体(即其中Q1=Q3的那些)。因此,式Ie抑制剂的合成被描述在上面线路1和2中,其中Q1被Q3取代。类似地,式Ig抑制剂的合成被描述在上面线路3和4中,其中Q1被Q3取代。
式If和式Ih抑制剂的合成被描述在下面线路7和8中。
线路8描述了类型Ih化合物的合成。例如,在碱,如氢化钠存在下,将起始的二溴衍生物,如2,6-二溴吡啶用胺处理产生2-氨基-6-溴衍生物。在存在钯催化剂下,将该中间体用苯基硼酸类似物(Q2-硼酸),如苯基硼酸处理产生可接着被酰化为终产物的二取代的衍生物。该合成的前两个步骤的顺序可互换。
不被理论所约束,申请人认为式Ie和Ig抑制剂的Q3环中的二邻位取代以及与式If和Ih抑制剂的Q1环直接相连的氮的存在导致该化合物“平化”,从而使其有效抑制p38。
本发明优选的式Ie抑制剂是其中A为碳,n为1,X为硫,每个Y为碳,每个R为氢,Q3为2,6-二氯苯基而Q2为苯基的化合物,所述化合物被称为化合物201。本发明优选的式Ig抑制剂是其中Q3为2,6-二氯苯基,Q2为苯基,每个Y为碳,每个R为氢的化合物。该化合物在本文被称为化合物202。本发明另一个优选的式Ig化合物为下表4列出的那些。
本发明优选的Ih化合物为下表5描述的那些。其它优选的Ih化合物是其中Q1为在2和6位被氯或氟独立地取代的苯基;每个Y为碳;每个R为氢;而Q2为2-甲基苯基、4-氟苯基、2,4-二氟苯基、2-亚甲基羟基-4-氟苯基或2-甲基-4-氟苯基的化合物。
式Ie、Ig和Ih的一些具体的抑制剂描述在下表中。
表3式Ie抑制剂
可在体外,体内或细胞系中测定本发明p38抑制剂的活性。体外测定包括确定活化的p38的激酶活性或ATP酶活性的抑制。另一种体外测定定量抑制剂与p38结合的能力,并可通过结合前放射性标记抑制剂,分离抑制剂/p38复合物,测定结合的放射性标记的量或通过进行其中将新的抑制剂与和已知的放射配体结合的p38一起保温的竞争实验来测定。
本发明化合物的抑制效果的细胞培养物测定可确定与用阴性对照处理的细胞比较,在用抑制剂处理的全血或细胞的细胞级分中产生的TNF、IL-1、IL-6或IL-8的量。可通过使用市场上可获得的ELISAs确定这些细胞因子的水平。
可用于确定本发明p38抑制剂的抑制活性的体内测定是在患丁酸分枝杆菌诱导的佐剂性关节炎的大鼠中的后足水肿的抑制。这描述在J.C.Boehm等医学化学杂志,39,pp.3929-37(1996),其公开被本文引作参考。还可在关节炎、骨吸收、内毒素性休克和免疫功能的动物模型中分析本发明的p38抑制剂,如其公开被本文引作参考的A.M.Badger等,药物实验治疗杂志,279,pp.1453-61(1996)所描述的。
可将p38抑制剂或其药用盐配制成用于对动物或人给药的药物组合物。包含有效量的治疗和预防p38介导的疾病的38抑制剂和药物可接受载体的这些药物组合物为本发明的另一个具体实施方案。
如本文所使用的术语“p38介导的疾病”指已知其中p38起作用的任何疾病或其它有害病症。这包括已知由IL-1、TNF、IL-6或IL-8过度产生导致的疾病。这些疾病包括,不限制于炎症疾病、自身免疫疾病、破坏性骨疾病、增生性疾病、感染性疾病、神经变性疾病、变态反应、中风中的再灌注/局部缺血、心脏病、血管原性疾病、器官缺氧、血管增生、心脏肥大、凝血酶诱导的血小板凝集和与前列腺素内过氧化物酶合成酶-2相关的疾病。
可被治疗或预防的炎症疾病包括,但不局限于急性胰腺炎、慢性胰腺炎、哮喘、变态反应和成人呼吸窘迫症。可被治疗或预防的自身免疫疾病包括,但不局限于肾小球肾炎、类风湿性关节炎、系统性红斑狼疮、硬皮病、慢性甲状腺炎、格雷夫斯病、自身免疫胃炎、糖尿病、自身免疫溶血性贫血、自身免疫中性白细胞减少症、血小板减少症、特应性皮炎、慢性活动性肝炎、重症肌无力、多发性硬化、炎性肠疾病、结肠溃疡、节段性回肠炎、牛皮癣或宿主移植疾病。
可被治疗或预防的破坏性骨疾病包括,但不局限于骨质疏松症、骨关节炎和与多发性骨髓瘤相关的骨疾病。
可被治疗或预防的增生性疾病包括,但不局限于急性骨髓性白血病、慢性骨髓性白血病、转移性黑素瘤、卡波西肉瘤和多发性骨髓瘤。
可被治疗或预防的血管原性疾病包括实体瘤、眼新血管形成、婴儿期血管瘤。
可被治疗或预防的感染性疾病包括,但不局限于脓毒症、败血性休克和志贺氏菌病。
可被治疗或预防的病毒性疾病包括,但不局限于急性肝炎感染(包括甲型肝炎、乙型肝炎和丙型肝炎)、HIV感染和CMV视网膜炎。
可被本发明化合物治疗或预防的神经变性疾病包括,但不局限于阿尔茨海默氏病、帕金森氏病、脑局部缺血、或由创伤导致的神经变性疾病。
“p38介导的疾病”还包括中风中的局部缺血和再灌注、心脏病、心肌缺血、器官缺氧、血管增生、心肌肥大和凝血酶诱导的血小板聚集。
此外,本发明的p38抑制剂还能抑制可诱导的促炎蛋白的表达,如前列腺素内过氧化物合成酶-2(PGHS-2),其还被称为环加氧酶-2(COX-2)。因此,其它“p38介导的疾病”为水肿、痛觉缺失、发烧和疼痛,如神经肌肉痛、头疼、癌症疼痛、牙疼和关节疼。
可通过本发明p38抑制剂治疗或预防的疾病还通常通过被认为导致疾病的细胞因子(IL-1、TNF、IL-6、IL-8)来分类。
因此,IL-1介导的疾病或病症包括类风湿性关节炎、骨关节炎、中风、内毒素血症和/或毒性休克综合症、由内毒素诱导的炎性反应、炎性肠病、结核病、动脉粥样硬化、肌肉退化、恶病质、牛皮癣性关节炎、赖特病综合症、痛风、创伤性关节炎、风疹性关节炎、急性滑膜炎、糖尿病、胰β细胞疾病和阿尔茨海默氏病。
TNF介导的疾病或病症包括类风湿性关节炎、类风湿性脊椎炎、骨质疏松症、痛风性关节炎和其它关节炎疾病、脓毒症、败血性休克、内毒素休克、革兰氏阴性细菌脓毒症、中毒性休克综合症、成人呼吸窘迫症、脑型疟、慢性肺炎症疾病、硅肺、肺肉样瘤病、骨吸收疾病、再灌注损伤、移植物与宿主的反应、同种移植物排斥反应、由于感染导致的发烧和肌痛、感染继发性恶质病、AIDS、ARC或恶性肿瘤、疤痕疙瘩形成、瘢痕组织的形成、节段性回肠炎、结肠溃疡或热病(pyresis)。TNF介导的疾病还包括病毒感染,如HIV、CMV、流感和疱疹;以及动物病毒感染,如慢病毒感染,包括但不局限于马感染性贫血症病毒、羊关节炎病毒、羊髓鞘脱落病毒或羊肺腺瘤病毒;或逆转录病毒感染,包括猫免疫缺陷病毒、牛免疫缺陷病毒或狗免疫缺陷病毒。
IL-8介导的疾病或病症包括特征在于大量嗜中性白细胞浸入的疾病,如牛皮癣、炎性肠疾病、哮喘、心和肾再灌注损伤、成人呼吸窘迫综合症、血栓形成和肾小球肾炎。
此外,本发明的化合物可被局部用于治疗或预防由IL-1或TNF导致或加重的疾病。这些疾病包括发炎的关节、湿疹、牛皮癣。炎症性皮肤疾病如晒伤、炎症性眼病如结膜炎、热病、疼痛和与发炎相关的其它疾病。
除本发明的化合物外,本发明化合物的药物可接受的盐也可用于组合物中以治疗或预防上述疾病。
本发明化合物药物可接受的盐包括从药物可接受的无机和有机酸和碱产生的那些。适宜酸的盐的实例包括乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙基磺酸盐、甲酸盐、富马酸盐、葡庚酸盐、甘油磷酸盐、甘醇酸盐、半硫酸盐、庚酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙基磺酸盐、乳酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、棕榈酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐和十一酸盐。其它的酸,如草酸,虽然其本身不是药物可接受的,但可被用于可作为在获得本发明化合物和其药物可接受的酸加成盐中的中间体的盐的制备中。来自适宜碱的盐包括碱金属(例如钠和钾)、碱土金属(例如镁)、铵和N-(C1-4烷基)4+盐。本发明还设想将本文公开的化合物的所有碱性含氮基团进行季铵化作用。通过该季铵化作用可获得水或油可溶的或可分散的产物。
可用于这些药物组合物中的药物可接受的载体包括,但不局限于离子交换剂、矾土、硬脂酸铝、卵磷脂、血清蛋白如人血清白蛋白、缓冲物质,如磷酸盐、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质,如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶态硅酸、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸、蜡、聚乙烯-聚氧丙烯嵌段聚合物、聚乙二醇和羊毛脂。
可通过口服、胃肠外、经吸入喷雾、局部、直肠、鼻、口腔含化、阴道或通过植入贮器来给药本发明的组合物。本文所采用的术语“胃肠外”包括皮下、静脉内、肌肉内、关节内、滑膜内、胸骨内、胸内、肝内、损伤内部和颅内注射或输注方法。优选经口服、腹膜内或静脉内给药组合物。
本发明组合物的无菌可注射形式可为含水或含油悬液。可根据本领域已知的方法,使用适宜的分散剂或湿润剂和悬浮剂配制这些悬液。无菌的可注射制剂还可为在无毒胃肠外可接受的稀释剂或溶剂中的无菌可注射溶液或悬液,例如在1,3-丁二醇中的溶液。其中可采用的可接受的赋形剂和溶剂为水、林格氏溶液和等渗氯化钠溶液。此外,通常采用无菌固定油作为溶剂或悬浮介质。为此目的,可采用包括合成单或二甘油酯的任何刺激性小的固定油。脂肪酸,如油酸和其甘油酯衍生物以及天然药物可接受的油,如橄榄油或蓖麻油,尤其是其聚氧乙基化的形式可用于注射用的制剂中。这些油溶液或悬液还可包含长链醇稀释剂或分散剂,如羧甲基纤维素或通常用于配制药物可接受的剂型(包括乳剂和悬浮剂)的类似的分散剂。其它常用的表面活性剂,如吐温、司盘和其它乳化剂或通常用于制备药物可接受固体、液体或其它剂型的生物利用率增强剂也可用于配制的目的。
本发明的药物组合物可以任何口服可接受的剂型经口服给药,包括但不局限于胶囊剂、片剂、含水悬浮剂或溶液剂。在用于口服用途的片剂的情况下,常用的载体包括乳糖和玉米淀粉。通常还加入润滑剂,如硬脂酸镁。对于胶囊剂形式的口服给药,可使用的稀释剂包括乳糖和干燥的玉米淀粉。当需要含水悬液用于口服使用时,将活性成分与乳化剂和悬浮剂混合。如果需要,还可加入某些甜味剂、调味剂或着色剂。
另一方面,可采用用于经直肠给药的栓剂的形式给药本发明的药物组合物。这可通过将活性成分与适宜的无刺激的赋形剂混合来制备,其中该赋形剂在室温下为固体,但在直肠温度下为液体,从而在直肠中将熔化释放药物。这些物质包括可可脂、蜂蜡和聚乙二醇。
还可局部施用的本发明的药物组合物,尤其是当治疗靶包括局部施用容易到达的区域或器官,包括眼、皮肤或下部肠道的疾病。很容易制备用于这些区域或器官的适宜的局部制剂。
可以直肠栓剂制剂(见上文)或在适宜的灌肠制剂来完成用于下部肠道的局部施用。还可使用局部透皮药贴。
为了局部施用,可将药物组合物配制成包含悬浮或溶解在一种或多种载体中的活性成分的适宜的软膏。用于局部施用本发明化合物的载体包括,但不局限于矿物油、液体凡士林、白凡士林、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡和水。另一方面,可将药物组合物配制成包含悬浮或溶解在一种或多种药用载体中的活性成分的适宜洗剂或乳膏。适宜的载体包括,但不局限于矿物油、脱水山梨糖醇一硬脂酸酯、缩聚山梨醇油酸酯60、十六烷基酯蜡、十六芳基醇、2-辛基十二烷醇、苄醇和水。
为了对于眼的使用,可将药物组合物配制成等渗、pH调节的无菌盐溶液中的微粉化的悬液,或优选为在等渗、pH调节的无菌盐溶液中的溶液,其中含有或不含防腐剂,如氯化苄基鎓(alkonium)。另一方面,为了眼的施用,可将药物组合物配制成软膏,如凡士林软膏。
还可通过鼻烟雾剂或吸入给药本发明的药物组合物。这些组合物可根据药物制剂领域熟知的方法来制备并被配制成盐溶液的形式,其中采用苄醇或其它适宜的防腐剂、提高生物利用率的吸收促进剂、碳氟化合物和/或其它常规的增溶剂和分散剂。
可与载体物质混合以产生单剂形式的p38抑制剂的量将取决于治疗的宿主、具体的给药方式而变化。优选地,配制组合物以致可对服用这些组合物的病人给药0.01-100mg/kg体重/天的抑制剂的剂量。
还应理解任何特定的病人的具体剂量和治疗方案将取决于各种因素,包括采用的具体化合物的活性、年龄、体重、通常的健康状况、性别、饮食、给药时间、排泄的速率、联合用药、以及治疗医生的判断以及被治疗的具体疾病的严重性。抑制剂的量还将取决于组合物中的具体化合物。
根据另一个具体实施方案,本发明提供了治疗或预防p38介导的疾病的方法,包括对病人给药一种上述药物组合物的步骤。如本文所采用的,术语“病人”指动物,优选为人。
优选地,该方法被用来治疗或预防选自炎症疾病、自身免疫疾病、破坏性骨疾病、增生性疾病、感染性疾病、变性疾病、变态反应、中风中的再灌注/缺血、心脏病、生血管疾病、器官缺氧、血管增生、心脏肥大和凝血酶诱导的血小板凝集等疾病。
根据另一个具体实施方案,本发明的抑制剂被用来治疗或预防IL-1、IL-6、IL-8或TNF介导的疾病或病症。上文描述了这些疾病。
取决于治疗或预防的具体的p38介导的疾病,可将通常被给药以治疗或预防疾病的其它药物与本发明的抑制剂一起给药。例如,化疗剂或其它抗增生剂可与本发明的p38抑制剂混合以治疗增生性疾病。
那些另外的试剂可作为多份剂量方案的一部分与含p38抑制剂的组合物分开给药。另外,这些试剂可为单剂形式的一部分,并在单一组合物中与p38抑制剂混合在一起。
为了能够更全面地理解本文公开的本发明,提供了下面的实施例。应理解这些实施例是仅用于说明的目的而决不被认为是限制本发明。实施例1p38抑制剂化合物1的合成
室温下,向90%(1.17g,30mmol)氨基钠的无水四氢呋喃淤浆(20ml)中加入苄基氰(2.92g,25.0ml)的无水四氢呋喃溶液(10ml)。室温下,将混合物搅拌30分钟。向反应混合物中加入3,6-二氯哒嗪(3.70g,25.0mmol)无水四氢呋喃(10ml)溶液。搅拌30分钟后,将反应混合物用饱和碳酸氢钠水溶液稀释。接着将反应混合物用乙酸乙酯萃取。分离各层,并将有机层用水、盐水洗涤,硫酸镁干燥,过滤并真空浓缩。
室温下,向95%(0.14g,6.0mmol)氢化钠的无水四氢呋喃淤浆(10mml)中加入苯硫酚(0.66g,6.0ml)。搅拌反应混合物10分钟。向反应混合物中加入上面步骤A的产物(1.31g,5.72mmol)的无水乙醇溶液(20ml)。接着将反应混合物回流并搅拌1小时。将冷却的反应化合物真空浓缩。将残留物用1N氢氧化钠溶液(10ml)稀释,接着用二氯甲烷萃取。将有机层用水、盐水洗涤,硫酸镁干燥,并真空浓缩。
将来自步骤B的产物(0.17g,0.69mmol)与浓硫酸(5ml)的混合物加热到100℃达1小时。将溶液冷却并用饱和碳酸氢钠溶液调节至pH8。将反应混合物用二氯甲烷萃取。将有机层用水、盐水洗涤,硫酸镁干燥,真空浓缩以产生0.22g(0.69mmol~100%)化合物前体-1的橙色油。1H NMR(500MHz,CD30D)d7.7(d),7.5(d),7.4(m),7.3-7.2(m).
将来自步骤C的前体-1(0.22g,0.69mmol)和N,N-二甲基甲酰胺二甲基乙缩醛(0.18g,1.5mmol)的甲苯溶液(5ml)在100℃加热1小时。冷却下,过滤产生的固体并溶解在温乙酸乙酯中。用滴加二乙醚沉淀产物。接着过滤产物并用二乙基醚洗涤以产生0.038g化合物1(描述在表1中)的黄色固体1H NMR(500MHz,CDCl3)d8.63(s),7.63-7.21(m),6.44(d).实施例2p38抑制剂化合物2的合成以与实施例1A类似的方式,使用4-氟苯基乙腈制备上述第一个中间体以产生1.4g(5.7mmol,~15%)产物。
以与实施例1C类似的方式,制备上面的中间体。这产生0.10g(0.29mmol,45%)化合物前体-2。1H NMR(500MHz,CDCl3)d7.65-7.48(m),7.47-7.30(m),7.29-7.11(m),7.06-6.91(m),5.85(s,br).
以与实施例1D类似的方式由前体2制备化合物2(描述在表1)。这产生0.066g产物。1H NMR(500MHz,CDCl3)d8.60(s),7.62-7.03,6.44(d).实施例3p38抑制剂化合物6的合成
以与实施例1C类似的方式制备最后中间体,前体-6。这产生0.89g(2.3mmol,85%)产物。1H NMR(500MHz,CD30D)d7.5-7.4(dd),7.4(m),7.3(d),7.2(m),7.05(d)。
以如实施例1D所描述的进行化合物6(描述在表1)合成的最后一步。这产生0.06g产物。1H NMR(500MHz,CDCl3)d8.69(s),7.65-7.59(d),7.58-7.36(m),7.32-7.22(m),6.79(d),6.53(d)。实施例4p38抑制剂化合物5的制备
以与实施例1A类似的方式,使用2,4-二氯苯基乙腈制备用于制备化合物5的第一个中间体以产生3.67g(12.36,49%)产物。
以与实施例1C类似的方式制备最后中间体,前体-5。这产生0.10g(0.24mmol,92%)产物。1H NMR(500MHz,CD30D)d7.9(d),7.7(d),7.6-7.5(dd),7.4-7.3(m),2.4(s)。
以与实施例1D类似的方式进行化合物5(描述在表1)合成的最后一步。这产生0.06g产物。1H NMR(500MHz,CDCl3)d8.64(s),7.51-7.42(m),7.32-7.21(m),6.85(d),6.51(d),2.42(s)。
可以类似的方式,使用适宜的起始物合成本发明的式Ia的其它化合物。实施例5式Ib的p38抑制剂化合物的制备
室温下,向90%(1.1当量(eq))氨基钠的无水四氢呋喃淤浆中加入2,6-二氯苄基氰(1.0eq)的无水四氢呋喃溶液。室温下,将混合物搅拌30分钟。向反应混合物中加入2,6-二氯吡啶(1eq)的无水四氢呋喃溶液。用TLC监测反应,当完成后,将反应混合物用饱和碳酸氢钠水溶液稀释。接着将反应混合物用乙酸乙酯萃取。分离各层,并将有机层用水、盐水洗涤,硫酸镁干燥,过滤并真空浓缩。将残留物通过硅胶层析以产生纯的产物。
-78℃下,向4-氟-溴苯(1eq)的无水四氢呋喃溶液中加入叔丁基锂(2eq,在己烷中的溶液)。接着将反应混合物搅拌30分钟。向反应混合物中加入来自步骤A的产物(1eq)的无水THF溶液。接着监测反应混合物并缓慢降至室温。将反应混合物用水骤冷,随后用二氯甲烷萃取。将有机相用水、盐水洗涤,硫酸镁干燥,并真空浓缩。将残留物通过硅胶层析纯化以产生产物。
将步骤B的产物与浓硫酸的混合物加热到100℃达1小时。将溶液冷却并用饱和碳酸氢钠溶液调节至pH8。将反应混合物用二氯甲烷萃取。将有机层用水、盐水洗涤,硫酸镁干燥,真空浓缩以产生产物。终产物通过硅胶快速层析纯化。
将步骤C的产物(1eq)和N,N-二甲基甲酰胺二甲基乙缩醛(2eq)的甲苯溶液(5ml)在100℃加热1小时。冷却下,过滤产生的固体并溶解在温乙酸乙酯中。用滴加乙醚沉淀产物。接着过滤产物并用乙醚洗涤以产生式Ib的p38抑制剂。终产物通过硅胶层析进一步纯化。
可以类似的方式,使用适宜的起始物合成本发明的式Ib的其它化合物。实施例6p38抑制剂化合物103的合成
本实施例提供了式Ic化合物的常规合成。A.本质上如实施例4所提供的制备p38抑制剂化合物12,除了在步骤B中使用4-氟苯硫基。B.室温下,将化合物12溶解在无水THF(5ml)中。向该溶液中加入氢化二异丁基铝(1M在甲苯中的溶液,5ml,5mmol),室温下,将反应液搅拌1小时。接着将反应混合物用乙酸乙酯稀释,通过加入罗谢尔(Rochelle)盐骤冷。将各层分开,分离有机层,用水、盐水洗涤、硫酸镁干燥,过滤以产生粗化合物103。将粗产物进行硅胶层析,用2%甲醇的二氯甲烷溶液洗脱。由此获得纯的化合物103(210mg,50%产率):1HNMR(500MHz,CDC13)7.51(m,1H),7.38(d,2H),7.20(t,2H),7.08(t,2H),6.70(宽s,1H),6.30(dd,2H),5.20(s,2H)。实施例7p38抑制剂化合物201的合成
室温下,将上面所示的起始腈(5.9g,31.8mmol)溶解在DMF(20ml)中。接着加入氢化钠(763mg,31.8mmol),产生亮黄色溶液。15分钟后,加入2,5二溴吡啶(5.0gr,21.1mmol)的DMF溶液(10ml),接着加入四(三苯基膦)钯(3mmol)。接着将溶液回流3小时。将反应冷却至室温,用乙酸乙酯稀释。接着分离有机层,用水洗涤,接着用盐水洗涤,硫酸镁干燥,过滤,真空蒸发为粗油。用10%乙酸乙酯的己烷溶液洗脱的快速柱层析提供灰白色固体产物(5.8g,84%)。
将步骤A中产生的溴化物(194.8mg,0.57mmol)溶解在二甲苯(15ml)中。向该溶液中加入苯硫基锡烷(200μl,587mmol)和四(三苯基膦)钯(25mg)。将溶液回流过夜,冷却,过滤并真空蒸发。将粗产物在硅胶上层析,用二氯甲烷洗脱,以产生黄色油状的纯的产物(152mg,72%)。
将步骤B产生的腈(1.2g,3.37mmol)溶解在冰乙酸(30ml)中。向该溶液中加入水(120μl,6.67mmol),接着加入四氯化钛(760μl,6.91mmol),这导致放热。将溶液回流2小时,冷却,倒入1NHCl中。将水层用二氯甲烷萃取。将有机层用1N NaOH回洗,硫酸镁干燥,硅胶柱过滤。将柱首先用二氯甲烷洗脱以除去未反应的起始物,接着用乙酸乙酯洗脱以产生化合物201。将乙酸乙酯蒸发以产生纯的化合物201(1.0g,77%)。实施例8p38抑制剂化合物110的合成
首先将起始的腈(3.76g,11.1mmol)溶解在冰乙酸(20ml)中。向该溶液中加入四氯化钛(22.2mmol)和水(22.2mmol),并将溶液加热回流1小时。冷却反应混合物,用水/乙酸乙酯稀释。分离有机层,用盐水洗涤,硫酸镁干燥。过滤有机层,真空蒸发。将产生的粗产物在硅胶上进行层析,用5%甲醇的二氯甲烷溶液洗脱,以产生黄色泡沫状纯的产物(2.77g,70%)。
将步骤A产生的酰胺(1.54g,4.3mmol)溶解在甲苯(20ml)中。接着加入N,N-二甲基甲酰胺二甲基乙缩醛(1.53g,12.9mmol),将产生的溶液加热10分钟,然后让其冷却至室温。将反应物在真空中蒸发,将残留物在硅胶上进行层析,用2-5%甲醇的二氯甲烷溶液洗脱。将回收物溶解在热的乙酸乙酯中。让溶液冷却,产生为黄色固体的纯的产物晶体(600mg,40%)。从母液中可获得另外的物质(~800mg)。
将来自步骤B的溴化物(369mg,1mmol)溶解在THF(10ml)中。接着加入氢化二异丁基铝(1.0M溶液,4mmol),室温下,将反应物搅拌10分钟,用甲醇(1ml)骤冷反应物。接着加入Rochelle盐的饱和水溶液,将混合物用乙酸乙酯萃取。分离有机层,硫酸镁干燥,蒸发,残留物在硅胶上进行层析,用1-3%甲醇的二氯甲烷溶液洗脱以产生亮橙色固体(85mg,23%产率)。
将步骤C中产生的溴化物(35.2mg,0.1mmol)溶解在二甲苯(12ml)中。向该溶液中加入苯硫酚(0.19mmol),接着加入三丁基甲醇锡(0.19mmol)。将产生的溶液加热回流10分钟,接着加入四(三苯基膦)钯(0.020mmol)。加热反应物,监测溴化物起始物的消失。将反应物冷却到室温,通过硅胶柱。最初将柱用二氯甲烷洗脱,以除去过量的锡试剂,接着用5%甲醇的乙酸乙酯溶液洗脱以洗脱p38抑制剂。浓缩滤液,在硅胶上再进行再层析,其中使用5%甲醇的乙酸乙酯溶液作为洗脱液,产生纯的化合物110(20mg,52%)。实施例9p38抑制剂化合物202的合成
室温下,将起始腈(2.32g,12mmol)溶解在DMF(10ml)中。接着加入氢化钠(12mmol),产生亮黄色溶液。15分钟后,加入2,6二溴吡啶(2.36gr,10mmol)的DMF溶液(5ml),接着加入四(三苯基膦)钯(1.0mmol)。接着将溶液回流3小时。将反应冷却至室温,用乙酸乙酯稀释。接着分离有机层,用水和盐水洗涤,硫酸镁干燥,过滤,真空干燥为粗油。用10%乙酸乙酯的己烷溶液洗脱的快速柱层析提供白色固体产物(1.45g,42%)。
将步骤A产生的溴化物(1.77g,5.2mmol)溶解在甲苯(20ml)中,将产生的溶液脱气。氮气氛下,加入苯基硼酸(950mg,7.8mmol)的乙醇(4ml)溶液和碳酸钠(1.73g,14mmol)的水(4ml)溶液。将反应混合物加热回流1小时,接着冷却到室温,将反应物用乙酸乙酯稀释,用水和盐水洗涤。将有机层用硫酸镁干燥,过滤,真空浓缩。残留物在硅胶上进行层析,用30%乙酸乙酯的己烷溶液洗脱以产生为白色固体的产物(1.56g,88%)。
将来自步骤B的产物(700mg,2.07mmol)溶解在浓硫酸(10ml)中,加热到80℃达1小时。将溶液冷却至室温,并用6N氢氧化钠调节至pH8。将混合物用乙酸乙酯萃取。分离有机层,硫酸镁干燥,真空浓缩以产生为黄色泡沫的化合物202(618mg,84%)。实施例10化合物410的合成
在火焰干燥的100ml圆底烧瓶中,向50ml无水四氢呋喃中加入2.28g(93.8mmol)镁碎片。加入一粒碘晶体,形成浅棕色。向溶液中加入1.5ml的10.0ml(79.1mmol)2-溴-5-氟甲苯的样品。将溶液回流加热。棕色褪色,当撤去外界热源时保持回流,表明格利雅反应形成。当回流平静时,加入另外1.0-1.5ml溴化物,导致剧烈回流。重复该过程直至加入所有的溴化物。将橄榄绿溶液外部加热至回流达1小时以确保完全反应。将溶液在冰浴中冷却,-78℃下,借助于注射器加入到9.3ml(81.9mmol)的硼酸三甲酯的100ml四氢呋喃溶液中。加入格利雅试剂后,将烧瓶从冰浴中取出,室温下,将溶液搅拌过夜。将灰白色淤浆倒至300ml水中,真空蒸发挥发性物质。加入HCl(400ml 2N溶液),室温下,将奶白色混合物搅拌1小时。白色固体沉淀。将混合物用乙酸乙酯萃取,干燥有机萃取物(MgSO4),真空蒸发以产生11.44g(94%)为白色固体的硼酸。
在100ml圆底烧瓶中,将7.92(33.4mmol)2,6-二溴吡啶溶解在50ml无水甲苯中,形成清亮无色溶液。加入步骤A中产生的4-氟-2-甲基苯硼酸(5.09g,33.1mmol),形成白色悬液。加入碳酸铊(17.45g,37.2mmol),接着加入催化量(150mg)的Pd(PPH3)4。将混合物加热回流过夜,冷却,硅胶柱过滤。将硅胶用CH2Cl2洗涤,蒸发滤液以产生白色固体。将固体溶解在最少量的50%CH2Cl2/己烷中,使用30%CH2Cl2/已烷,在硅胶短柱上进行层析以产生6.55g(74%)的2-溴-6-(4-氟-2-甲基苯基)吡啶白色固体。在50ml圆底烧瓶中,将步骤B产生的550mg(2.07mmol)2-溴-6-(4-氟-2-甲基苯基)吡啶溶解在30ml无水四氢呋喃中,形成清亮无色溶液。加入2,6-二氟苯胺(2.14g,2.14mmol),接着加入112mg(2.79mmol)60%NaH的矿物油悬液。观察到气体放出和温和的放热。将反应溶液加热回流过夜,冷却。将反应混合物倒入10%NH4Cl中,用CH2Cl2萃取。干燥有机萃取物(MgSO4),真空蒸发以产生为产物和起始物混合物的棕色油。使用50%CH2Cl2/己烷,在硅胶短柱上进行层析以产生262mg(40%)为无色油状物的2-(2,6-二氟苯基-6-(4-氟-2-甲基苯基)吡啶。
在100ml圆底烧瓶中,将步骤C中产生的262mg(834mmol)2-(2,6-二氟苯基-6-(4-氟-2-甲基苯基)吡啶溶解在30ml无水CHCl3中形成清亮无色溶液。加入异氰酸氯磺酰酯(1.0ml,11.5mmol),室温下,将浅黄色溶液搅拌过夜。加入水(~30ml),导致中等的放热和剧烈的气体释放。搅拌过夜后,分离有机层,干燥(MgSO4),真空蒸发以产生为产物与起始物混合物的棕色油。将物质在使用10%EtOAc/CH2Cl2的硅胶短柱上进行层析。将回收的起始物重新放置于反应条件下,并以相同方式纯化以产生总共205mg(69%)为白色固体的脲。实施例11化合物138的合成
将化合物103(106mg,0.25mmol)溶解在THF(0.5ml)中,向该溶液中加入三乙胺(35μl,0.25mmol),接着加入过量的甲醛(37%水溶液,45mg)。室温下,将反应搅拌过夜。减压下,将反应混合物旋转蒸发,将残留物溶解在二氯甲烷中,加样至快速硅胶柱中。将柱用2%甲醇的二氯甲烷洗脱以产生纯的产物(78mg,70%产率)。实施例12化合物103的前药的合成
将化合物138(1当量)溶解在二氯甲烷中,向该溶液中加入三乙胺(1当量),接着加入二苄基膦酰氯(1当量)。室温下搅拌溶液,用TLC监测起始物的消耗。接着将二氯甲烷层用乙酸乙酯稀释,并用1N HCl、饱和碳酸氢钠和饱和NaCl洗涤。接着干燥有机层,旋转蒸发,硅胶纯化粗产物。然后将纯的产物溶解在甲醇中,氢气氛下,将二苄基酯用10%位于活性碳上的钯去保护。当反应被监测为完全时,硅藻土过滤催化剂,将滤液旋转蒸发以产生磷酸盐产物。
将化合物105(210mg,1.05mmol)溶解在THF(2ml)中,氮气氛下,冷却至-50℃。向该溶液中加入六甲基二硅氮化锂(1.1mmol),接着加入氯乙酰氯(1.13mmol)。将反应从冷浴中撤出,让其升温至室温,此后,将反应物用乙酸乙酯稀释并用水骤冷。将有机层用盐水洗涤,干燥并旋转蒸发至干燥。使用25%乙酸乙酯的己烷溶液作为洗脱液,使粗产物在硅胶上进行快速层析以产生172mg(70%)纯的所需产物,它被用于下一反应中。
将来自实施例5步骤A的腈(300mg,1.0mmol)溶解在乙醇(10ml)中,向该溶液中加入硫脲(80.3mg,1.05mmol)。将反应回流4小时,此时TLC表明所有起始物已被消耗。冷却反应物,减压下除去所有挥发性物质,将残留物溶解在丙酮(10ml)中。
向该溶液中加入2,5-二氟硝基苯(110μl,1.01mmol),接着加入碳酸钾(200mg,1.45mmol)和水(400μl)。室温下,将反应物搅拌过夜。将反应物用二氯甲烷(25ml)稀释,经棉塞过滤。减压下除去所有挥发性物质,将残留物在硅胶中进行快速层析,用10%-25%梯度的乙酸乙酯的己烷溶液洗脱以产生所需产物(142mg,33%)。
将来自步骤A的腈化合物(142mg,0.33mmol)与浓硫酸(2ml)混合,加热回流1小时,接着让其冷却至室温。将混合物用乙酸乙酯稀释,并小心地用饱和碳酸钾溶液(含水)中和。分离各层,用水、盐水洗涤有机层,硫酸镁干燥。过滤混合物并蒸发至干燥。残留物不经进一步纯化而用于下一步骤(127mg,85%产率)。将步骤B产生的酰胺(127mg,0.28mmol)溶解在THF(3ml)中,向该溶液中加入二甲基甲酰胺二甲基乙缩醛(110μl,0.83mmol)。将反应物加热回流5分钟,接着冷却至室温。真空除去所有挥发性物质,将残留物在硅胶上进行闪蒸层析,用2.5%甲醇的二氯甲烷溶液洗脱以产生纯的所需化合物34(118mg,92%)。
将二氯化镍六水合物(103mg,0.44mol)在苯/甲醇混合物(0.84mL/0.84ml)的溶液加入到化合物34(100.8mg,0.22mmol)的苯溶液(3.4ml)中,将该溶液冷却到0℃。接着向该溶液中加入硼氢化钠(49mg,1.3mmol)。搅拌反应物并升至室温。真空蒸发反应物,将残留物进行闪蒸层析,用2%甲醇的二氯甲烷溶液洗脱以产生纯的所需产物,化合物117(21mg,25%产物)。实施例14化合物53和142的合成采用实施例1步骤B的方法,使用氯哒嗪(359mg,1.21mmol)和2,4-二氟苯硫酚(176mmg,1.21mmol)合成上面反应所述的产物。快速硅胶层析后获得产物(451mg,92%)。
如实施例1步骤C所述,使用451mg起始物和5ml浓硫酸进行上面的反应以产生所述产物(425mg,90%)。
如实施例1,步骤D所述,使用起始酰胺(410mg,0.96mmol)和二甲基甲酰胺二甲基乙缩醛(3mmol)进行上面的反应。将反应在50℃加热30分钟,并如前所述进行处理。获得化合物53(313mg,75%)。
将化合物34(213,0.49mmol)溶解在THF(10ml)中,冷却至0℃,向该溶液中加入甲硼烷的THF溶液(1M,0.6mmol)。将反应物搅拌30分钟,用水骤冷,乙酸乙酯稀释。将有机层用水和盐水洗涤,干燥和旋转蒸发。将残留物在硅胶上进行纯化,用1%-5%梯度的甲醇的二氯甲烷溶液洗脱以产生化合物142(125mg,57%)。实施例15在昆虫细胞中克隆p38激酶
鉴别了人p38激酶的两个剪接变体CSBP1和CSBP2。采用HeLa细胞文库(Stratagene)作为模板,用特定的寡核苷酸引物扩增CSBP2 cDNA的编码区域。将聚合酶链反应产物克隆至pET-15b载体(Novagen)中。通过将pET15b-(His)6-p38的XbaI-BamHI片段亚克隆至质粒pVL1392(Pharmingen)的互补位点中构建杆状病毒转移载体pVL-(His)6-p38。
质粒pVL-(His)6-p38控制由在框内与p38的N末端融合的23个残基肽(MGSSHHHHHHSSGLVPRGSHMLE,其中LVPRGS代表凝血酶裂解位点)组成的重组蛋白的合成,这通过DNA序列测定和表达蛋白的N末端序列测定而得以证实。27℃下,在T型烧瓶中将草地贪夜蛾(Sf9)昆虫细胞(ATCC)的单层培养物保存在补充有10%胎牛血清的TNM-FH培养基(Gibco BRL)中。使用脂转染试剂(Invitrogen),将对数期的Sf9细胞用苜蓿银纹夜蛾核型多角体病毒(Pharmingen)的线性病毒DNA和转移载体pVL-(His)6-p38共转染。使用1%低熔化的琼脂糖,通过噬菌斑分析纯化各个重组杆状病毒克隆。实施例16重组p38激酶的表达和纯化
27℃下,在摇瓶中,将粉纹夜蛾(Tn-368)High-FiveTM细胞(Invitrogen)培养在不含Excel-405蛋白的培养基(JRH Bioscience)的悬液中。以5的感染复数将密度为1.5×106细胞/ml的细胞用上述重组杆状病毒感染。使用兔抗p38抗体(Santa Cruz Biotechnology),通过免疫印迹监测重组p38的表达水平。感染后72小时,当p38的表达水平达到其最大时,收集细胞块。
将来自表达(His)6-标记的p38的细胞的冷冻细胞膏融化在5体积的缓冲液A(50mM NaH2PO4 pH 8.0,200mM NaCl,2mMβ-疏基乙醇,10%甘油和0.2mM PMSF)。在显微流化仪中将细胞机械破碎后,将裂解液以30,000×g离心30分钟。4℃下,以1ml树脂/2-4mg预期的p38的比例,将上清与TalonTM(Clontech)金属亲和性树脂分批保温3-5小时。以500×g离心5分钟沉淀收集树脂,并用缓冲液A轻轻地分批洗涤。将树脂浆化,倒入柱中(约2.6×5.0cm),用缓冲液A+5mM咪唑洗涤。
将(His)6-p38用缓冲液A+100mM咪唑洗脱,随后4℃下,对2升缓冲液B(50mM HEPES,pH7.5,25mM β甘油磷酸,5%甘油,2mM DTT)透析过夜。通过加入1.5单位的凝血酶(Calbiochem)/mg p38并在20℃保温2-3小时来除去His6标记。通过加入0.2mM PMSF骤冷凝血酶,接着将全部样品加至2ml苯甲脒琼脂糖(American International Chemical)柱中。
将经分离的液体直接上样至预先用缓冲液B+0.2mM PMSF平衡的2.6×5.0cm Q-琼脂糖(Pharmacia)柱上。将p38用在缓冲液B中线性梯度至0.6M NaCl的20倍柱体积洗脱。收集洗脱的蛋白峰,4℃下对缓冲液C(50mMHEPES pH7.5,5%甘油,50mM NaCl,2mM DTT,0.2mM PMSF)透析过夜。
在Centriprep(Amicom)中将透析的蛋白浓缩至3-4ml,并上样至2.6×100cm Sephacryl S-100HR(Pharmacia)柱。以35ml/小时的流速洗脱蛋白。收集主峰,调节至20mM DTT,浓缩至10-80mgs/ml,-70℃下以等分试样冷冻或立即使用。实施例17p38的活化
通过在20℃下,将0.5mg/ml p38与0.005mg/ml DD-双突变的MKK6的缓冲液B+10mM MgCl2,2mM ATP,0.2mM Na2VO4混合30分钟活化p38。接着将活化的混合物上样至1.0×10cm MonoQ柱(Pharmacia)上,用梯度至1.0M NaCl的缓冲液B的线性20柱体积洗脱。活化的p38在ADP和ATP之后被洗脱。收集活化的p38峰,对缓冲液B+0.2mM Na2VO4透析以除去NaCl。通过加入4.0M储液将透析的蛋白调节至1.1M磷酸钠溶液,并上样至预先用缓冲液D(10%甘油,20mM β甘油磷酸,2.0mM DTT)+1.1M K2HPO4的1.0×10cm HIC(Rainin Hydropore)柱上。将蛋白用线性梯度至缓冲液D+50mM K2HPO4的20柱体积洗脱。二磷酸化的p38被洗脱作为主峰,收集,用于对缓冲液B+0.2mM Na2VO4透析。将活化的p38存贮在-70℃下。实施例18p38抑制测定A.EGF受体肽的磷酸化的抑制
在pH7.6,在存在10mM MgCl2,25mM β甘油磷酸,10%甘油和100mMHEPES缓冲液时进行本次测定。为了典型的IC50测定,制备包含所有上述成分以及活化的p38(5nM)的储液。将储液等分至小瓶中。将固定体积的DMSO或抑制剂的DMSO溶液(反应中DMSO的最终浓度为5%)加入到各小瓶中,混合并在室温下保温15分钟。将EGF受体肽,KRELVEPLTPSGEAPNQALLR,p38催化的激酶反应(1)中的磷酰基受体加入到各小瓶中直至最终浓度为200μM。用ATP(100μM)启动激酶反应,将小瓶保温于30℃。30分钟后,将反应用等体积的10%三氟乙酸(TFA)猝灭。
通过HPLC分析定量磷酸化的肽。用各自含0.1%TFA的水和乙腈双梯度洗脱液在反相柱(Deltapak,5μm,C18 100D)上进行磷酸化肽与未磷酸化肽的分离。通过将剩余活性的百分数对抑制剂浓度作图确定IC50(产生50%抑制的抑制剂的浓度)。B.ATP酶活性的抑制
在pH7.6,在存在10mM MgCl2,25mM β甘油磷酸,10%甘油和100mMHEPES缓冲液时进行本次测定。为了典型的Ki测定,在不存在抑制剂和存在两种浓度的抑制剂时测定ATP在活化的p38反应中的ATP酶活性中的km。制备包含所有上述成分以及活化的p38(60nM)的储液。将储液等分至小瓶中。将固定体积的DMSO或抑制剂的DMSO溶液(反应中DMSO的最终浓度为2.5%)加入到各小瓶中,混合并在室温下保温15分钟。通过加入各种浓度的ATP启动反应,接着保温于30℃。30分钟后,将反应用50μl的EDTA(0.1M的最终浓度),pH8.0猝灭。用HPLC分析定量产生的p38 ATP酶活性ADP。
使用双溶剂梯度的下列成分在反相柱(Supelcosil,LC-18,3μm,批号5-8985)中从ATP中分离ADP:溶剂A-包含8mM硫酸氢四丁基铵的0.1M磷酸缓冲液(Sigma Chemical Co.,目录号T-7158),溶剂B-含有30%甲醇的溶剂A。
从作为抑制剂和ATP浓度函数的速率数据确定Ki。一些本发明抑制剂的结果描述在下表6中:表6化合物 Ki(μM)1 >202 153 5.05 2.96 0.4
本发明其它p38抑制剂也抑制p38的ATP酶活性。C.在LPS-刺激的PBMCs中产生的IL-1、TNF、IL-6和IL-8的抑制
用DMSO从20mM储液系列稀释抑制剂。制备至少6个系列稀释液。接着通过将4μl抑制剂稀释液加入到1ml RPMI1640培养基/10%胎牛血清中制备4×抑制剂储液。4×抑制剂储液包含80μm、32μm、12.8μm、5.12μm、2.048μm、0.819μm、0.328μm、0.131μm、0.052μm、0.021μm等浓度的抑制剂。37℃下,将4×抑制剂储液预加温直至使用。
通过以1500×g离心15分钟,在来自Bectou & Dickinson的Vacutainer CPT(包含4ml血和足够的不含Mg2+/Ca2+的DPBS以填充血管)中将新鲜人血buffy细胞与其它细胞分离。除去位于Vacutainer中的梯度顶部的外周血单核细胞(PBMCs),用RPMI1640培养基/10%胎牛血清洗涤两次。通过以500×g离心10分钟收集PBMCs。使用Neubauer细胞室(Neubauer Cell Chamber)测定总细胞数目,将细胞调节为在细胞培养基中为4.8×106细胞/ml的浓度(补充有10%胎牛血清的RPMI1640)。
另一方面,含有抗促凝剂的全血被直接用于测定。
将100μl细胞悬液或全血放置在96孔细胞培养平板中的各孔中。接着向细胞中加入50μl 4×抑制剂储液。最后,加入50μl脂多糖(LPS)工作储液(在细胞培养基中为16ng/ml)从而在测定中产生4ng/ml LPS的最终浓度。还通过加入50μl细胞培养基将载体对照的总的测定体积调节至200μl。37℃/5%CO2湿润空气中,将PBMC细胞或全血保温过夜(达12-15小时)。
第二天,在以500×g离心5分钟之前,将细胞在振荡器上混合3-5分钟。收集细胞培养物上清液,根据制造商的说明用ELISA分析IL-1b(R&D系统,Quantikine试剂盒,#DBL50)、TNF-α(Biosource,#KHC3012)、IL-6(Endogen,#EH2-IL-6)和IL-8(Endogen,#EH2-IL8)的水平。ELISA数据被用来制备从中产生IC50值的剂量应答曲线。
本发明各种p38抑制剂对激酶测定(“激酶”;上文小节A)、在LPS刺激的PBMC(细胞)中的IL-1和TNT,全血(“WB”)中的TNF和IL-6的结果示于下表7中:表中cmpd#表示化合物序号,kinase表示激酶,cell表示细胞。cmpd# kinase cell IL-1 cell TNF WB IL-1 WB TNF WB IL-6
IC50 IC50 IC50 IC50 C50 IC502 + N.D. N.D. N.D. N.D. N.D.3 + N.D. N.D. N.D. N.D. N.D.5 + N.D. N.D. N.D. N.D. N.D.6 ++ ++ + N.D N.D. N.D.7 + + + N.D. N.D. N.D.8 + + + N.D. N.D. N.D.9 + + + N.D. N.D. N.D.10 + N.D. N.D. N.D. N.D. N.D.11 + + + N.D. N.D. N.D.12 ++ ++ ++ + + +cmpd# kinase cell IL-1 cell TNF WB IL-1 WB TNF WB IL-6
IC50 IC50 IC50 IC50 IC50 IC5013 + + + N.D. N.D. N.D.14 + ++ + N.D. N.D. N.D.15 + ++ ++ N.D. N.D. N.D.16 ++ + ++ N.D. N.D. N.D.17 + + + N.D. N.D. N.D.18 + + + N.D. N.D. N.D.19 + + + N.D. N.D. N.D.20 ++ + + N.D. N.D. N.D.21 ++ ++ + N.D. N.D. N.D.22 + + + N.D. N.D. N.D.23 ++ ++ + + + +24 ++ ++ ++ + + N.D.25 +++ ++ + N.D. N.D. N.D.26 + +++ ++ + + +27 ++ + + + + +28 ++ ++ ++ N.D. N.D. N.D.29 ++ ++ ++ N.D. N.D. N.D.30 + + + + N.D. N.D.31 + + + N.D. N.D. N.D.32 ++ + ++ + + +33 ++ ++ ++ + + +34 + + + N.D. N.D. N.D.35 ++ ++ + + + +36 + + + + + +37 ++ ++ + + + +38 +++ +++ ++ ++ ++ ++39 ++ + + N.D. N.D. N.D.40 ++ ++ + N.D. N.D. N.D.41 +++ +++ +++ N.D. N.D. N.D.cmpd# kinase cell IL-1 cell TNF WB IL-1 WB TNF WB IL-6
IC50 IC50 IC50 IC50 IC50 IC5042 + N.D. N.D. N.D. N.D. N.D.43 ++ + + N.D. N.D. N.D.44 ++ + + N.D. N.D. N.D.45 ++ N.D. N.D. N.D. N.D. N.D.46 ++ + + N.D. N.D. N.D.47 ++ ++ + N.D. N.D. N.D.48 ++ ++ + N.D. N.D. N.D.49 ++ +++ + + + +50 + N.D. N.D. N.D. N.D. N.D.51 ++ N.D. N.D. N.D. N.D. N.D.52 ++ N.D. N.D. N.D. N.D. N.D.53 +++ +++ +++ +++ +++ +++101 ++ +++ +++ + + ++102 +++ +++ +++ + ++ ++103 +++ +++ +++ + ++ ++104 ++ ++ ++ + + +105 ++ + + N.D. N.D. N.D.106 +++ +++ +++ + ++ ++107 ++ + + N.D. N.D. N.D.109 +++ +++ +++ + + ++108 +++ ++ +++ ++ +++ +++110 ++ + + N.D. N.D. N.D.111 ++ + + N.D. N.D. N.D.112 ++ ++ + + + +113 +++ +++ ++ + + +114 +++ +++ +++ ++ ++ +++115 +++ +++ +++ + + +116 +++ +++ ++ + + +117 +++ +++ +++ ++ ++ +++cmpd# kinase cell IL-1 cell TNF WB IL-1 WB TNF WB IL-6
IC50 IC50 IC50 IC50 IC50 IC50118 ++ ++ ++ + + +119 ++ N.D. N.D. N.D. N.D. N.D.120 N.D. ++ + + + +121 +++ +++ ++ + + +122 ++ ++ + + + +123 ++ ++ ++ + + +124 + + + N.D. N.D. N.D.125 +++ +++ +++ + + +126 + ++ + N.D. N.D. N.D.127 +++ +++ +++ ++ ++ +++128 + + + N.D. N.D. N.D.129 +++ +++ +++ ++ + ++130 +++ ++ + N.D. N.D. N.D.131 +++ +++ +++ N.D. N.D. N.D.132 +++ +++ ++ N.D. N.D. N.D.133 +++ +++ +++ N.D. N.D. N.D.134 +++ ++ + N.D. N.D. N.D.135 +++ ++ + + + +136 +++ +++ +++ + + ++137 +++ +++ ++ + + ++138 ++ +++ ++ + + +++139 +++ +++ + + + +140 +++ +++ +++ ++ + ++141 +++ +++ +++ + + +142 +++ +++ +++ +++ +++ +++143 +++ +++ ++ + + +144 +++ +++ ++ + + ++145 +++ +++ +++ +++ +++ +++201 ++ + + + +++ +cmpd# kinase cell IL-1 cell TNF WB IL-1 WB TNF WB IL-6
IC50 IC50 IC50 IC50 IC50 IC50203 + N.D. N.D. N.D. N.D. N.D.204 + N.D. N.D. N.D. N.D. N.D.205 + N.D. N.D. N.D. N.D. N.D.206 ++ + + N.D. N.D. N.D.207 + N.D. N.D. N.D. N.D. N.D.208 N.D. ++ N.D. N.D. N.D. N.D.209 N.D. + N.D. N.D. N.D. N.D.202/ +++ ++ ++ + + +301302 +++ +++ ++ + + +303 + + + + + +304 + + + + + +305 +++ +++ + + + +306 ++ ++ + + + +307 +++ ++ + + + +308 + N.D. N.D. N.D. N.D. N.D.309 ++ ++ ++ + + +310 ++ + + N.D. N.D. N.D.311 ++ + + N.D. N.D. N.D.312 +++ ++ + + + +313 ++ + + N.D. N.D. N.D.314 + N.D. N.D. N.D. N.D. N.D.315 + N.D. N.D. N.D. N.D. N.D.316 + N.D. N.D. N.D. N.D. N.D.317 + + + N.D. N.D. N.D.318 ++ N.D. N.D. N.D. N.D. N.D.319 + N.D. N.D. N.D. N.D. N.D.320 +++ ++ ++ N.D. N.D. N.D.321 + N.D. N.D. N.D. N.D. N.D.cmpd# kinase cell IL-1 cell TNF WB IL-1 WB TNF WB IL-6
IC50 IC50 IC50 IC50 IC50 IC50322 ++ + + N.D. N.D. N.D.323 ++ ++ ++ N.D. N.D. N.D.324 ++ ++ + N.D. N.D. N.D.325 +++ +++ ++ + + +326 + N.D. N.D. N.D. N.D. N.D.327 ++ N.D. N.D. N.D. N.D. N.D.328 + N.D. N.D. N.D. N.D. N.D.329 ++ ++ + + + +330 + N.D. N.D. N.D. N.D. N.D.331 + N.D. N.D. N.D. N.D. N.D.332 ++ ++ + + + +333 ++ + + N.D. N.D. N.D.334 + N.D. N.D. N.D. N.D. N.D.335 ++ + + + + +336 + N.D. N.D. N.D. N.D. N.D.337 + N.D. N.D. N.D. N.D. N.D.338 + N.D. N.D. N.D. N.D. N.D.339 + N.D. N.D. N.D. N.D. N.D.340 + N.D. N.D. N.D. N.D. N.D.341 ++ ++ ++ N.D. N.D. N.D.342 + N.D. N.D. N.D. N.D. N.D.343 + N.D. N.D. N.D. N.D. N.D.344 + N.D. N.D. N.D. N.D. N.D.345 + N.D. N.D. N.D. N.D. N.D.346 ++ + + + + +347 + N.D. N.D. N.D N.D. N.D.348 + N.D. N.D. N.D. N.D. N.D.349 + ++ + + + +350 + ++ + N.D N.D. N.D.cmpd# kinase cell IL-1 cell TNF WB IL-1 WB TNF WB IL-6
IC50 IC50 IC50 IC50 IC50 IC50357 + + + N.D. N.D. N.D.352 + + N.D. N.D. N.D. N.D.353 ++ + + N.D. N.D. N.D.354 + N.D. N.D. N.D. N.D. N.D.355 + N.D. N.D. N.D. N.D. N.D.356 + N.D. N.D. N.D. N.D. N.D.357 + N.D. N.D. N.D. N.D. N.D.358 ++ ++ + N.D. N.D. N.D.359 + N.D. N.D. N.D. N.D. N.D.360 + N.D. N.D. N.D. N.D. N.D.361 ++ ++ + N.D. N.D. N.D.362 +++ ++ ++ + + +363 +++ +++ ++ + + +364 +++ +++ ++ + + +365 N.D. N.D. N.D. N.D. N.D. N.D.366 + N.D. N.D. N.D. N.D. N.D.367 N.D. N.D. N.D. N.D. N.D. N.D.368 N.D. N.D. N.D. N.D. N.D. N.D.369 N.D. N.D. N.D. N.D. N.D. N.D.370 N.D. N.D. N.D. N.D. N.D. N.D.371 N.D. N.D. N.D. N.D. N.D. N.D.372 N.D. N.D. N.D. N.D. N.D. N.D.373 N.D. N.D. N.D. N.D. N.D. N.D.374 ++ N.D. N.D. N.D. N.D. N.D.375 +++ N.D. N.D. N.D. N.D. N.D.376 +++ N.D. N.D. N.D. N.D. N.D.377 +++ N.D. N.D. N.D. N.D. N.D.378 +++ N.D. N.D. N.D. N.D. N.D.379 +++ N.D. N.D. N.D. N.D. N.D.cmpd# kinase cell IL-1 cell TNF WB IL-1 WB TNF WB IL-6
IC50 IC50 IC50 IC50 IC50 IC50380 ++ N.D. N.D. N.D. N.D. N.D.381 ++ N.D. N.D. N.D. N.D. N.D.382 +++ N.D. N.D. N.D. N.D. N.D.383 +++ N.D. N.D. N.D. N.D. N.D.384 ++ N.D. N.D. N.D. N.D. N.D.385 ++ N.D. N.D. N.D. N.D. N.D.386 + N.D. N.D. N.D. N.D. N.D.387 + N.D. N.D. N.D. N.D. N.D.388 +++ N.D. N.D. N.D. N.D. N.D.389 ++ N.D. N.D. N.D. N.D. N.D.390 + N.D. N.D. N.D. N.D. N.D.391 ++ N.D. N.D. N.D. N.D. N.D.392 ++ N.D. N.D. N.D. N.D. N.D.393 ++ N.D. N.D. N.D. N.D. N.D.394 +++ N.D. N.D. N.D. N.D. N.D.395 +++ N.D. N.D. N.D. N.D. N.D.396 +++ N.D. N.D. N.D. N.D. N.D.397 + N.D. N.D. N.D. N.D. N.D.398 N.D. N.D. N.D. N.D. N.D. N.D.399 +++ N.D. N.D. N.D. N.D. N.D.1301 +++ N.D. N.D. N.D. N.D. N.D.401 +++ ++ ++ + + +402 +++ +++ +++ + + +403 +++ +++ +++ + + ++404 +++ +++ +++ + + +405 +++ +++ ++ N.D. N.D. N.D.406 ++ ++ + N.D. N.D. N.D.407 ++ ++ + N.D. N.D. N.D.408 +++ +++ ++ N.D. N.D. N.D.cmpd# kinase cell IL-1 cell TNF WB IL-1 WB TNF WB IL-6
IC50 IC50 IC50 IC50 IC50 IC50409 +++ +++ +++ + + ++410 +++ +++ +++ ++ ++ ++411 +++ +++ +++ + + +412 N.D. N.D. N.D. N.D. N.D. N.D.
对于激酶,IC50值“+++”代表>0.1μM,“++”代表在0.1-1.0μM之间,“+”代表<1.0μM。对于细胞IL-1和TNF值,“+++”代表>0.1μM,“++”代表在0.1-0.5μM之间,“+”代表<0.5μM。对于全血(WB)测定值,“+++”代表>0.25μM,“++”代表在0.25-0.5μM之间,“+”代表<0.5μM。在上表所示的所有测定中,“N.D.”代表未测定的值。
本发明其它的p38抑制剂也将抑制EGF受体肽的磷酸化以及在LPS-刺激的PBMCs或全血中的IL-1、TNF、IL-6以及IL-8的产生。D.IL-1刺激的PBMCs中产生的IL-6和IL-8的抑制
用几乎与上面相同的方法对PBMCs进行本测定,除了将50μl IL-1b工作储液(在细胞培养基中为2ng/ml)加入测定中以代替(LPS)工作储液。
如上所述收集细胞培养上清并根据制造商的说明用ELISA分析IL-6(Endogen,#EH2-IL6)和IL-8(Endogen,#EH2-IL8)的水平。ELISA数据被用来制备从中产生IC50值的剂量应答曲线。
p38抑制剂化合物6的结果示于下表8中:表8分析白细胞因子 IC50(μM)IL-6 0.60IL-8 0.85E.在PBMCs中LPS诱导的前列腺素内过氧化物酶-2(PGHS-2,或COX-2)诱导的抑制
通过在Vacutainer CPT(Becton&Dickinson)中离心从新鲜人血buffy表层中分离人外周血单核细胞(PBMCs)。将15×106细胞放入包含补充有10%胎牛血清,500U/ml青霉素,50μg/ml链霉素和2mM L-谷氨酰铵的RPMI1640的6孔组织培养皿中。以在DMSO中为0.2、2.0和20μM的最终浓度加入化合物6(上面)。接着以4ng/ml的最终浓度加入LPS以诱导酶的表达。最终培养体积为10ml/孔。
37℃,5%CO2培养过夜后,通过刮取和随后的离心收集细胞,除去上清,将细胞用冰冷的DPBS(Dulbecco氏磷酸缓冲盐溶液,BioWhittaker)洗涤两次。在冰上将细胞在50μl含有1μl Benzonase(来自Merck的DNA酶)的冷的溶胞缓冲液(20mM Tris-HCl,pH7.2,150mM NaCl,1%Triton-X-100,1%脱氧胆酸,0.1%SDS,1mM EDTA,2%抑酶肽(Sigma),10μg/ml胃蛋白酶抑制剂,10μg/ml亮抑蛋白酶肽,2mM PMSF,1mM苄脒,1mM DTT)中溶胞10分钟。使用BCA测定(Pierce)并以牛血清白蛋白作为标准确定各样品的蛋白浓度。用冷的溶胞缓冲液将各样品的蛋白浓度调节至1mg/ml。向100μl溶胞液中加入等体积的2xSDS PAGE加样缓冲液,将样品煮沸5分钟。在4-20%SDS PAGE梯度凝胶(Novex)中分级分离蛋白(30μg/道),接着通过在包含20%甲醇的Towbin转移缓冲液(25mM Tris,192mM甘氨酸)中,以100mA进行2小时电穿孔方法转移至硝酸纤维素膜中。室温下,将膜用封闭缓冲液(本充有0.1%Tween-20的5%脱脂奶粉的DPBS溶液)预处理1小时,用DPBS/0.1%Tween-20洗涤3次。4℃下,将膜与在封闭缓冲液中为1∶250稀释度的单克隆抗COX-2抗体(Transduction实验室)一起保温过夜。用DPBS/0.1%Tween-20洗涤3次后,室温下,将膜在封闭缓冲液中与1∶1000稀释度的联接辣根过氧化物酶的抗小鼠Ig(Amersham)的羊抗血清一起保温1小时。接着将膜再用DPBS/0.1%Tween-20洗涤3次,ECL检测系统(SuperSignalTMCL-HRP底物系统,Pierce)被用来测定COX-2的表达水平。
上述测定结果表明在PBMC中化合物6抑制LPS诱导的PGHS-2的表达。
虽然我们在此提供了许多本发明的具体实施方案,很显然可改变基本组成以提供利用本发明方法的其它具体的实施方案。
Claims (36)
1.下式化合物:其中Q1和Q2各自独立地选自5-6元芳香碳环或杂环系,或包含芳香碳环、芳香杂环或芳香碳环与芳香杂环相结合的8-10元双环系;其中:
Q1被1-4个取代基取代,其中各取代基独立地选自卤素;任选被NR’2、OR’、CO2R’或CONR’2取代的C1-C3烷基;任选被NR’2、OR’、CO2R’或CONR’2取代的O-(C1-C3)-烷基;NR’2;OCF3;CF3;NO2;CO2R’;CONR’;SR’;S(O2)N(R’)2;SCF3;CN;N(R’)C(O)R4;N(R’)C(O)OR4;N(R’)C(O)C(O)R4;N(R’)S(O2)R4;N(R’)R4;N(R4)2;OR4;OC(O)R4;OP(O)3H2;或N=C-N(R’)2;
Q2任选被至多4个的取代基取代,其各取代基独立地选自卤素;任选被NR’2、OR’、CO2R’、S(O2)N(R’)2、N=C-N(R’)2、R3或CDNR’2取代的C1-C3直链或支链烷基;任选被NR’2、OR’、CO2R’、S(O2)N(R’)2、N=C-N(R’)2、R3或CONR’2取代的O-(C1-C3)-烷基;NR’2;OCF3;CF3;NO2;CO2R’;CDNR’;R3;OR3;NR3;SR3;C(O)R3;C(O)N(R’)R3;C(O)OR3;SR’;S(O2)N(R’)2;SCF3;N=C-N(R’)2或CN;
其中R’选自氢、(C1-C3)-烷基;(C2-C3)-链烯基或炔基;苯基或被1-3个独立地选自卤素、甲氧基、氰基、硝基、氨基、羟基、甲基或乙基的取代基取代的苯基;
R3选自5-6元芳香碳环或杂环系;和
R4为任选被N(R’)2、OR’、CO2R’、CON(R’)2或S(O2)N(R2)2取代的(C1-C4)-烷基;或任选被N(R’)2、OR’、CO2R’、CON(R’)2或S(O2)N(R2)2取代的5-6元碳环或杂环系;
X选自-S-、-O-、-S(O2)-、-S(O)-、-S(O2)-N(R2)-、-N(R2)-S(O2)-、-N(R2)-C(O)O-、-O-C(O)-N(R2)、-C(O)-、-C(O)O-、-O-C(O)-、-C(O)-N(R2)-、-N(R2)-C(O)-、-N(R2)-、-C(R2)2-或-C(OR2)2-;
每个R独立地选自氢、-R2、-N(R2)2、-OR2、SR2、-C(O)-N(R2)2、-S(O2)-N(R’)2或-C(O)-OR2,其中两个相邻的R任选相互连接并与分别与它们相连的各个Y一起形成4-8元碳环或杂环;
R2选自氢、(C1-C3)-烷基或(C1-C3)-链烯基;其中各个任选被-N(R’)2、-OR’、SR’、-C(O)-N(R’)2、-S(O2)-N(R’)2、-C(O)-OR’或R3取代。
Y为N或C;
A如果存在,为N或CR’;
n为0或1;
R1选自氢、(C1-C3)-烷基、OH或O-(C1-C3)-烷基。
3.下式化合物: 其中:Q3为5-6元芳香碳环或杂环系,或包含芳香碳环的8-10元双环系、芳香杂环或芳香碳环和芳香杂环的结合物。Q3的环被1-4个取代基取代,其中各取代基独立地选自卤素;任选被NR’2、OR’、CO2R’或(CONR’2取代的C1-C3烷基;任选被NR’2、OR’、CO2R’或CONR’2取代的O-(C1-C3)-烷基;NR’2;OCF3;CF3;NO2;CO2R’;CONR’;SR’;S(O2)N(R’)2;SCF3;CN;N(R’)C(O)R4;N(R’)C(O)OR4;N(R’)C(O)C(O)R4;N(R’)S(O2)R4;N(R’)R4;N(R4)2;OR4;OC(O)R4;OP(O)3H2;或N=C-N(R’)2;而A、Q1、Q2、R、R’、X、Y和n如权利要求1所定义。
4.根据权利要求1-3任一项的化合物,其中:Q1选自包含1-3个取代基的苯基或吡啶基,其中至少一个所述取代基是在邻位,所述取代基独立地选自氯、氟、溴、-CH3-、-OCH3、-OH、-CF3、-OCF3、-O(CH2)CH3、NH2、3,4-亚甲二氧基、-N(CH3)2、-NH-S(O)2-苯基、-NH-C(O)O-CH2-4-吡啶、-NH-C(O)CH2-吗啉、-NH-C(O)CH2-N(CH3)2、-NH-C(O)CH2-哌嗪、-NH-C(O)CH2-吡咯烷酮、-NH-C(O)C(O)-吗啉、-NH-C(O)C(O)哌嗪、-NH-C(O)C(O)-吡咯烷酮、-O-C(O)CH2-N(CH3)2或-O-(CH2)2-N(CH3)2。
5.根据权利要求4的化合物,其中Q1包含至少两个在邻位的取代基。
7.根据权利要求6的化合物,其中Q1选自2-氟-6-三氟甲基苯基、2,6-二氟苯基、2,6-二氯苯基、2-氯-4-羟基苯基、2-氯-4-氨基苯基、2,6-二氯-4-氨基苯基、2,6-二氯-3-氨基苯基、2,6-二甲基-4-羟基苯基、2-甲氧基-3,5-二氯-4-吡啶基、2-氯-4,5-亚甲二氧基苯基或2-氯-4-(N-2-吗啉代-乙酰氨基)苯基。
8.根据权利要求1-3任一项的化合物,其中Q2选自苯基或吡啶基,其中Q2任选包含至多3个的取代基,各取代基独立地选自氯、氟、溴、甲基、乙基、异丙基、-OCH3、-OH、-NH2、-CF3、-OCF3、-SOH3、-OCH-3、-C(O)OH、-C(O)OCH3、-CH2NH2、-N(CH3)2、-CH2-吡咯烷酮和-CH2OH。
10.根据权利要求9的化合物,其中Q2选自苯基、2-异丙基苯基、3,4-二甲基苯基、2-乙基苯基、3-氟苯基。2-甲基苯基、3-氯-4-氟苯基、3-氯苯基、2-羧甲氧基苯基、2-羧基苯基、2-甲基-4-氯苯基、2-溴苯基、2-吡啶基、2-亚甲基羟基苯基、4-氟苯基、2-甲基-4-氟苯基、2-氯-4-氟苯基、2,4-二氟苯基、2-羟基-4-氟苯基或2-亚甲基羟基-4-氟苯基。
11.根据权利要求1-3任一项的化合物,其中X选自-S-、-O-、-S(O2)-、-S(O)-、-NR-、-C(R2)-或-C(O)-。
12.根据权利要求10的化合物,其中X为S。
13.根据权利要求1-3任一项的化合物,其中n为1和A为N。
14.根据权利要求1-3任一项的化合物,其中每个Y为C。
15.根据权利要求14的化合物,其中与Y相连的各个R独立地选自氢或甲基。
16.根据权利要求1的化合物,其中所述化合物选自表1描述的化合物2-3或5-53中的任一化合物。
17.根据权利要求2的化合物,其中所述化合物选自表2提供的化合物101-145中的任一化合物。
18.根据权利要求3的化合物,其中Q3被2-4个取代基取代,其中至少一个所述取代基以相对于Q3与抑制剂其余部分相连的点为邻位而存在。
19.根据权利要求18的化合物,其中两个邻位均被所述独立选择的取代基中的一个所占据。
20.根据权利要求19的化合物,其中Q3为单环碳环;而Q3中所述邻位取代基的每一个独立地选自卤素或甲基。
21.根据权利要求19的化合物,其中除了所述邻位取代基外Q3还包含1至2个取代基,其中所述另外的取代基独立选自NR’2、OR’、CO2R’、CN、N(R’)C(O)R4;N(R’)C(O)OR4;N(R’)C(O)C(O)R4;N(R’)S(O2)R4;N(R’)R4;N(R4)2;OR4;OC(O)R4;OP(O)3H2;或N=C-N(R’)2。
22.根据权利要求3的化合物,其中所述化合物为式Ie化合物,并且其选自表3提供的化合物201或203-209中的任一个。
23.根据权利要求3的化合物,其中所述化合物为式Ig化合物,并且选自表5提供的化合物202/301、302-399或1301中的任一个。
24.根据权利要求3的化合物,其中所述化合物为式Ih化合物,并且选自表5提供的化合物401-412中的任一个。
25.包含有效抑制p38量的根据权利要求1-3任一项的化合物和药物可接受的载体的药物组合物。
26.一种治疗或预防炎症疾病、自身免疫疾病、破坏性骨疾病、增生性疾病、感染性疾病、神经变性疾病、变态反应、中风中的再灌注/局部缺血、心脏病、血管原性疾病、器官缺氧、血管增生、心脏肥大、凝血酶诱导的血小板凝集或与前列腺素内过氧化物酶合成酶-2相关的疾病的方法,所述方法包括对所述病人给药根据权利要求25的组合物。
27.根据权利要求26的方法,其中所述方法被用来治疗或预防选自急性胰腺炎、慢性胰腺炎、哮喘、变态反应或成人呼吸窘迫症的炎症性疾病。
28..根据权利要求26的方法,其中所述方法被用来治疗或预防选自肾小球肾炎、类风湿性关节炎、系统性红斑狼疮、硬皮病、慢性甲状腺炎、格雷夫斯病、自身免疫胃炎、糖尿病、自身免疫溶血性贫血、自身免疫中性白细胞减少症、血小板减少症、特应性皮炎、慢性活动性肝炎、重症肌无力、多发性硬化、炎性肠疾病、结肠溃疡、节段性回肠炎、牛皮癣或宿主移植疾病的自身免疫疾病。
29.根据权利要求26的方法,其中所述方法被用来治疗或预防选自骨质疏松症、骨关节炎或多发性骨髓瘤相关的骨疾病的破坏性骨疾病。30.根据权利要求26的方法,其中所述方法被用来治疗或预防选自急性骨髓性白血病、慢性骨髓性白血病、转移性黑素瘤、卡波西肉瘤或多发性骨髓瘤的增生性疾病。
31.根据权利要求26的方法,其中所述方法被用来治疗或预防选自脓毒症、败血性休克或志贺氏菌病的感染性疾病。
32.根据权利要求26的方法,其中所述方法被用来治疗或预防选自急性肝炎感染、HIV感染或CMV视网膜炎的病毒性疾病。
33.根据权利要求26的方法,其中所述方法被用来治疗或预防选自阿尔茨海默氏病、帕金森氏病、脑局部缺血或由创伤导致的神经变性疾病。
34.根据权利要求26的方法,其中所述方法被用来治疗或预防中风中的局部缺血/再灌注、或心肌缺血、肾缺血、心脏病、器官缺氧、或凝血酶诱导的血小板凝集。
35.根据权利要求26的方法,其中所述方法被用来治疗或预防选自水肿、发烧痛觉缺失、或疼痛的与前列腺素内过氧化物合成酶-2相关的疾病。
36.根据权利要求35的方法,其中所述疼痛选自神经肌肉痛、头疼、癌症疼痛、牙疼或关节疼。
37.根据权利要求26的方法,其中所述方法被用来治疗或预防选自实体瘤、眼新血管形成或婴儿期血管瘤的血管生成性疾病。
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US08/822,373 US5945418A (en) | 1996-12-18 | 1997-03-20 | Inhibitors of p38 |
US08/862,925 US6147080A (en) | 1996-12-18 | 1997-06-10 | Inhibitors of p38 |
US08/862,925 | 1997-06-10 |
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CN102026972B (zh) * | 2008-04-11 | 2014-05-07 | 奥米罗有限公司 | 螺[环烷基-1,3′-吲哚]-2′(1′H)-酮的取代衍生物及其作为p38促分裂原活化蛋白激酶抑制剂的应用 |
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