CN1471523A - 咪唑类棉子糖激酶抑制剂 - Google Patents
咪唑类棉子糖激酶抑制剂 Download PDFInfo
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- CN1471523A CN1471523A CNA018182135A CN01818213A CN1471523A CN 1471523 A CN1471523 A CN 1471523A CN A018182135 A CNA018182135 A CN A018182135A CN 01818213 A CN01818213 A CN 01818213A CN 1471523 A CN1471523 A CN 1471523A
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Abstract
新化合物(I)及它们作为药物的用途,特别是作为Raf激酶抑制剂,用于治疗神经外伤性疾病、癌症、慢性神经退化、疼痛、偏头痛、心脏肥大,其中Ar为式a)或b)基团。
Description
本发明涉及新型化合物及其药用,特别是作为Raf(棉子糖)激酶抑制剂,用于治疗神经外伤性疾病,癌症,慢性神经退化,疼痛,偏头痛,心脏肥大。
Raf蛋白激酶是信号转导通路中的关键要素,哺乳动物细胞中特定的细胞外刺激引起精确的细胞内应答。激活的细胞表面受体激活浆-膜内部的ras/rap蛋白,其进而募集和激活Raf蛋白。激活的Raf蛋白磷酸化和激活细胞内蛋白激酶MEK1,MEK2。激活的MEKs再催化p42/p44***素-活化蛋白激酶(MAPK)的磷酸化和激活。已知有多种细胞质和细胞核内激活的MAPK底物直接或间接地参与细胞对环境变化的应答。已经确定三种不同的编码哺乳动物Raf蛋白的基因;已经知道A-Raf,B-Raf和C-Raf(也称为Raf-1)以及由mRNA剪接差异导致的同种型变体。
已有人建议将Raf激酶抑制剂用于破坏肿瘤细胞生长,进而用于癌症治疗,如,组织细胞淋巴瘤,肺腺癌,肺小细胞癌和胰腺和乳癌;也用于治疗和/或预防由局部出血导致的与神经细胞退化关联的疾病,包括患心脏、中风、多发梗塞性痴呆后的脑出血以及脑局部出血事故如头部受伤、外科手术和/或分娩后的脑出血;也用于治疗和/或预防慢性神经退化如Alzheimer氏疾病,Parkinson氏疾病;也用于治疗疼痛,偏头痛,心脏肥大。
我们已经发现一类新型I化合物,它们是Raf激酶抑制剂,特别是B-Raf激酶抑制剂。
Y1和Y2独立地为N或CH;
R1为氢,C1-6烷基,C3-7环烷基,芳基,芳基C1-6烷基,杂环基,杂环基C1-6烷基,杂芳基或杂芳基C1-6烷基,其任何一种可被任选取代;并且当X为CH2时,R1可为羟基或可被任选取代的C1-6烷氧基;
R2为氢,C1-6烷基,C2-6链烯基,C3-7环烷基,C5-7环烯基,杂环基,芳基或杂芳基,其任何一种可被任选取代;
Ar为基团式a)或b)的基团:
其中A代表稠合的5~7-元环,任选包含最多2个杂原子,选自O,S,NR5,其中R5为氢或C1-6烷基,该环被最多2个取代基任选取代,取代基选自卤素,C1-6烷基,羟基,C1-6烷氧基或酮基(keto);
R3和R4独立地选自氢,卤素,C1-6烷基,芳基,芳基C1-6烷基,C1-6烷氧基,C1-6烷氧基C1-6烷基,卤代C1-6烷基,芳基C1-6烷氧基,羟基,硝基,氰基,叠氮基,氨基,单-和二-N-C1-6烷基氨基,酰基氨基,芳基羰基氨基,酰基氧,羧基,羧基盐,羧基酯,氨基甲酰基,单-和二-N-C1-6烷基氨基甲酰基,C1-6烷氧基羰基,芳氧基羰基,脲基,胍基,C1-6烷基胍基,脒基,C1-6烷基脒基,磺酰基氨基,氨基磺酰基,C1-6烷硫基,C1-6烷基亚磺酰基或C1-6烷基磺酰基;
R15为O或N-OH;
X1和X2中的一个为N,另一个为NR6,其中R6为氢或C1-6烷基。
这里,式(I)中虚线表示的双键,代表了化合物的可能互变异构环形式,包括在本发明的范围内。可以理解双键指向未取代氮。
肟部分可以位于基团a)和b)中非芳香环上任何一个碳原子。
烷基和烯基基团,单独或作为大基团如烷氧基的部分,这里指最多包含6个碳原子的支链或直链基团。
环烷基和环烯基这里分别指包括3~7和5~7个环碳原子的基团。
烷基、链烯基、环烷基和环烯基的任选取代基包括芳基,杂芳基,杂环基,C1-6烷氧基,C1-6烷硫基,芳基C1-6烷氧基,芳基C1-6烷硫基,氨基,单-或二-C1-6烷基氨基,氨基磺酰基,环烷基,环烯基,羧基及其酯,酰胺,脲基,胍基,C1-6烷基胍基,脒基,C1-6烷基脒基,C1-6酰氧基,羟基及卤素或它们的任何合并取代基。另外取代基也可为氰基。
优选任选取代基包含水溶性基团;本领域的普通技术人员熟悉合适水溶性部分,包括羟基,氨基基团。更优选的任选取代基包括氨基,单或双C1-6烷基,氨基,含氨基杂环基或羟基或它们的任何合并的取代基。
这里的术语″芳基″为单和稠合环,每个环合适地包含4~7,优选5或6个环原子。每个环可不被取代或被,例如,最多3个取代基取代。稠合环可包括脂肪环并只须包括一个芳香环。合适的芳基包括苯基和萘基如1-萘基或2-萘基。
这里术语″杂环基″合适地包括(除非另有定义)非芳族的、饱和或不饱和的单环和稠合环。每个或两个环合适地包含最多4个杂原子,每个杂原子选自O,N,S。这些环可不被取代或被例如最多3个取代基取代。每个杂环合适地包含4~7,优选5或6个环原子。稠合杂环体系可包括碳环并只需包括一个杂环。杂环基的具体实例包括吡咯烷,哌啶,哌嗪,吗啉,硫代吗啉,咪唑烷,吡唑烷。优选杂环基具体实例包括吡咯烷,哌啶,哌嗪,吗啉,咪唑烷,吡唑烷。
这里术语″杂芳基″合适地包括(除非另有定义)单-和二环杂芳香环体系,最多包含4个,优选1个或2个杂原子,每个选自O,N,S。每个环可有4~7,优选5或6个环原子。二环杂芳香环体系可包括一个碳环。杂芳基具体实例包括吡咯,喹啉,异喹啉,吡啶,嘧啶,噁唑,噻唑,噻二唑,***,咪唑,苯并咪唑。
合适的芳基、杂环基和杂芳基优选可被最多3个取代基任选取代。合适的取代基包括卤素,羟基,C1-6烷基,芳基,芳基C1-6烷基,C1-6烷氧基,C1-6烷氧基C1-6烷基,卤代C1-6烷基,芳基C1-6烷氧基,硝基,氰基,叠氮基,氨基,单-和二-N-C1-6烷基氨基,酰基氨基,芳基羰基氨基,酰氧基,羧基,羧基盐,羧基酯,氨基甲酰基,单和二-N-C1-6烷基氨基甲酰基,C1-6烷氧基羰基,芳基氧羰基,脲基,胍基,C1-6烷基胍基,脒基,C1-6烷基脒基,脲,氨基甲酸酯,酰基,磺酰基氨基,氨基磺酰基,C1-6烷硫基,C1-6烷基亚磺酰基,C1-6烷基磺酰基,杂环基,杂芳基,杂环基C1-6烷基和杂芳基C1-6烷基,及其任何合并的取代基。并且2个环碳原子可连接在一起形成二环体系。
这里卤素为氟,氯,溴或碘。
在式(I)化合物中:
X优选为O,CH2,S或NH,或X-R1部分为氢。
更优选X为CH2或NH或X-R1为氢,最优选X为NH或X-R1为氢。
优选地Y1为CH,Y2为N或CH。
优选R15为N-OH。
或者,R1为氢,C1-6烷基,芳基,芳基C1-6烷基,杂环基,杂环基C1-6烷基,杂芳基,或杂芳基C1-6烷基,其任何一种可被任选取代;并且当X为CH2时,R1可为羟基或可被任选取代的C1-6烷氧基。
R2可为C1-6烷基,C2-6链烯基,C3-7环烷基,C5-7环烯基或杂环基,其任何一种可被任选取代。或者R2为芳基或杂芳基,其任何一种可被任选取代。
其中,R4与式(I)化合物中定义一致,n为1,2或3。
n优选为1。
Ar优选为二氢茚酮基。
R2合适的任选取代基,包括一个或多个基团,选自芳基,杂芳基,杂环基,C1-6烷氧基,C1-6烷硫基,芳基C1-6烷氧基,芳基C1-6烷硫基,氨基,单-或二-C1-6烷基氨基,氨基磺酰基,环烷基,环烯基,羧基,羧基酯,酰胺,脲基,胍基,C1-6烷基胍基,脒基,C1-6烷基脒基,C1-6酰基氧,羟基,和卤素或其任何合并取代基。或者取代基可为C1-6烷基芳基。
R2优选为含水溶性部分的取代基,本领域普通技术人员熟悉合适的水溶性部分,包括碱性(basic)基团。特别需要提到的水溶性基团包括胺和羟基基团。例如,氨基,单-或二-C1-6烷基氨基,含氨基的杂环基或羟基及其任何合并取代基。
需要提及的特定R2基团包括-CR7R8-CH2-Z,-CH2-Z和杂环基,其中R7,R8独立地代表任选取代的C1-6烷基,或R7和R8由碳原子连接形成任选取代的C3-7环烷基或C5-7环烯基环;Z为NR9R10,NR9C(Q)NR9R10,NR9COOR10,NR9SO2R10,NR9C(Q)R10或杂环基,其中R9和R10独立地选自氢,C1-6烷基,C3-7环烷基,杂环基,杂环基C1-6烷基,芳基,芳基C1-6烷基,杂芳基,杂芳基C1-6烷基,其任何一种可被任选取代或当为R9R10时连接形成杂环基团;Q为O或S,优选O;以及当R2或Z为杂环基,如哌啶基,哌嗪或吗啉时,该杂环基可被任选取代。
需要提及的特定R2基团包括任选取代的苯基,吡啶基,嘧啶基,呋喃基。
其他需要提及的特定的R2基团包括取代苯基,其取代基为-O-(CH2)m-NR18R19或-(CH2)m-NR18R19,其中m为1~6的整数,如2或3,R18,R19独立地代表氢,C1-6烷基,或R18和R19由氮原子连接形成任选取代的5~7-元环,任选包含另一个选自NR20和O杂原子,其中R20为氢或C1-6烷基,如吗啉基。
或者,R7或R8为氢。
R3优选为氢。
R4优选为氢。
R6优选为氢。
式(I)化合物优选分子量小于800。
可以理解本发明包括式(I)化合物药用衍生物,这些化合物都包括在本发明的范围内。
本发明的特定化合物包括实施例中提及的化合物及其可药用盐。这里″药用衍生物″包括任何式(I)化合物药用盐,酯或该酯的盐,对受体(recipient)给药能提供(直接或间接)的式(I)化合物或活性代谢物或其残留物。
优选的衍生物为盐。
本发明的特定化合物包括实施例中提及的化合物及其可药用盐。
应该意识到,用于医学的式(I)化合物盐应该是可以药用的。合适的药用盐对本领域普通技术人员而言是显而易见的,包括J.Pharm.Sci.,1977,66,1-19中描述的那些盐,如,酸加成盐,与无机酸形成的,如盐酸,氢溴酸,硫酸,硝酸或磷酸;和有机酸,如琥珀酸,顺丁烯二酸,乙酸,反丁烯二酸,柠檬酸,酒石酸,苯甲酸,对甲苯磺酸,甲磺酸或萘磺酸。其他盐,如草酸盐,例如可用于分离式(I)化合物,也包括在本发明的范围内。
本发明化合物为晶形或非晶形,如果是晶形,可任选为水合晶形或溶剂化晶形。本发明范围包括化学计量水合物,以及包含不定量水的化合物。
本发明延伸包括式(I)化合物的所有异构体形式,包括式(I)化合物的立体异构体和几何异构体,包括对映异构体及其混合物,如外消旋物。不同的异构体形式用常规方法可分离或拆分出来,或任何指定异构体形式可用常规合成方法或用立体特异或不对称合成方法得到。
由于式(I)化合物是要用于药物组合物的,很易理解它们每种优选以足够的纯度提供,如至少60%纯度,更合适的至少75%纯度,优选至少85%,尤其至少98%纯度(重量比)。化合物的不纯制品可被用来制备纯度更高的形式,用于药物组合物。
式(I)化合物为咪唑衍生物,用本领域普通技术人员熟悉的方法可很方便地制备,例如描述在Comprehensive Heterocyclic Chemistry,编者Katritzkv,Rees,Pergamon Press,1984,5,457-497,可用商品原料或已知方法的类似方法制备的原料开始。
本发明化合物制备方法实例概述在方案1和2中。这些方案举例说明了化合物(其中-X-R1,R3、R4为氢,X1为NH,Y1和Y2为CH,Ar为式a)基团,其中n为1)的制备方法,但是该方法对所有的式(I)化合物制备都适用。在第一个方法(方案1)中,α-二酮的制备是用4-吡啶-甲醇的O-保护衍生物的阴离子,与适当保护的稠合二环芳基-醛反应,其中PG为肟保护基团如=N-OR11,其中R11为任选取代的C1~6烷基如甲基,任选取代的芳基或甲硅烷基,或PG为酮保护基。O-脱保护,接着氧化二醇中间体,得到前述的α-二酮。该二酮与合适的醛和乙酸铵在溶剂如乙酸、甲氧t丁基醚、或甲醇中反应,形成咪唑核。进而,R2基团利用常规官能基团相互转换工艺,可被转化为其他R2基团,而PG基团转化为肟基(=NOH)。
第二个方法(方案2)与Liverton等(J.Med.Chem.,1999,42,2180)描述的方法类似。在该方法中,2-溴-1-吡啶-4-基-乙酮与合适的脒反应形成中心咪唑核。然后保护不稳定的(labile)咪唑氢(典型保护基团,PG’为2-三甲基甲硅烷基乙氧甲基-,SEM;和甲氧甲基-,MOM),使咪唑环金属化。其余取代基的导入用过渡金属催化交叉偶合(cross-coupling)可以实现,即金属化的咪唑与合适地保护的、被卤素或磺酸酯取代的稠合二环芳香体系反应,其中PG为=O或如上述方案1定义的保护基团。本领域普通技术人员熟悉这种过渡金属偶合方法,例如描述在D.W.Knight in ComprehensiveOrganic Synthesis,volume 4,page 481,编辑者B.M.Trost,和I.Fleming,Pergamon Press,1991。其后,基团R2用常规官能基团转换工艺,可转化为其他基团R2,脱掉保护基团PG′,基团PG转化为肟基(=N-OH)。应意识到交叉偶合工艺是可逆的,即用卤代咪唑与合适的保护的金属化稠合二环芳香体系偶合。
方案2
式(I)化合物(其中R6为C1-6烷基),可由式(II)化合物烷基化,然后脱去保护基团PG′制备得到,类似Liverton等描述的方法(J.Med.Chem.,1999,42,2180)。得到的异构体用层析技术分离出来。
式(I)化合物合成过程中,中间体化合物中的不稳定官能基团,即羟基,羧酸和氨基基团,可先保护。多种不稳定官能基团的保护和保护后衍生物的脱保护方法,综合讨论在例如Protective Groups in Organic Chemistry,T.W.Greene,P.G.M.Wuts,(Wiley-Interscience,New York,2nd edition,1991)中。
式(I)化合物可制备成单个化合物或化合物库,包括至少2个,例如5~1,000化合物,更优选10~100式(I)化合物。式(I)化合物库可用组合的“分离和混合”(combinatorial′split and mix′)方法制备或用溶液相或固相多重平行合成(multiple parallel synthesis)方法制备,都是本领域普通技术人员熟悉的方法。
因此,本发明另外也提供了包含至少2个式(I)化合物、或其药用盐的化合物库。
药用盐可与合适的酸或酸衍生物反应,用常规方法制备。
用于式(I)化合物制备的多种中间体都是新化合物,因此,本发明另外也提供了式(II),(III)或(IV)化合物,其中PG代表=O或保护基团,PG′代表保护基团。合适的保护基团包括上述基团。
如上所述,式(I)化合物及其药用衍生物,有用于治疗和/或预防Raf激酶,特别是B-Raf激酶参与的疾病。
本发明另外也提供了式(I)化合物或其可药用衍生物作为B-Raf激酶抑制剂的用途。
如上所述,式(I)化合物及其药用衍生物可用于治疗和/或预防由局部出血引起的神经元退化相关的疾病,以及慢性神经退化,疼痛,偏头痛,心脏肥大。
本发明另外也提供了一种治疗或预防哺乳动物神经外伤疾病的方法,包括对所说的哺乳动物施用有效量的式(I)化合物或其可药用衍生物。
本发明另外也提供了式(I)化合物或其可药用衍生物在制备药物中的用途,该药物用来治疗或预防人或其他哺乳动物中神经外伤加剧或引起的任何疾病症状。
这里定义的神经外伤疾病/事故(event)包括开放式(open)或透入式(penetrating)头部外伤,如外科手术引起,或封闭的(closed)头部外伤损伤,如头部损伤引起。该定义也包括为局部出血中风,特别是脑部、冠状搭桥(by-pass)后发生短暂局部出血和其他短暂局部出血后认知下降。
局部出血中风可定义为由脑部特定区域供血不足导致的病灶(focal)神经疾病,通常产生栓塞、血栓症、或局部动脉粥样血管闭锁的后果。在该区域出现了紧张刺激(如缺氧症)、氧化还原(redox)损伤、过度神经元兴奋刺激和炎性细胞因子的这些作用时,本发明为这些损伤提供了有效的治疗手段。对这样的一些急性损伤,现有的治疗措施很少。
本发明化合物也可用于治疗或预防癌症。
本发明另外也提供了一种治疗或预防哺乳动物癌症的方法,包括对所述哺乳动物施用有效量的式(I)化合物或其可药用衍生物。
本发明另外也提供了式(I)化合物或其可药用衍生物在制备药物中的用途,该药用来治疗或预防癌症。
本发明另外也提供了一种方法,用于治疗或预防哺乳动物的慢性神经退化、疼痛、偏头痛、心脏肥大,包括对所述哺乳动物施用有效量式(I)化合物或药用衍生物。
本发明另外也提供了式(I)化合物或药用衍生物用于制备药物,用来治疗或预防慢性神经退化、疼痛、偏头痛、心脏肥大。
为了将式(I)化合物用于治疗,通常按照标准药学操作,将它们配制成药物组合物。
本发明另外也提供了一种药物组合物,包含式(I)化合物或药用衍生物及药用载体。
式(I)化合物可用任何~种常规给药途径,方便地给药。例如,肠胃外,口服,局部或吸入给药。式(I)化合物可按照常规方法,将其与标准药物载体混合,制备成常规剂型给药。式(I)化合物也可用常规剂量与已知的第二种治疗活性化合物联合用药。这些工艺包括将所需制剂的组分进行混合、成粒、压制或溶解。应该意识到药用载体形态和特征取决于与该载体组合的式(I)化合物剂量、给药途径及其他已知变量。就与其他配方组分兼容性而言,载体必须是″可接受的″,并对受体无害。
例如,应用的药物载体可为固体或液体。典型的固体载体为乳糖、石膏粉、蔗糖、滑石粉、白明胶、琼脂、胶质、***树胶、硬脂酸镁、硬脂酸及其类似物。典型的液体载体为糖浆、花生油、橄榄油、水及其类似物。类似地,载体或稀释剂可包括本领域普通技术人员熟悉的时间延迟材料,如单独的甘油单硬酯酸酯或甘油双硬酯酸酯或与蜡混合。
可以使用多种药物形式。因此,如果使用固体载体,制剂可为片剂,以粉末或小丸形式装在硬明胶胶囊中或为锭剂或糖锭形式。固体载体的用量变化范围很大,但优选约25mg~1g。使用液体载体时,该制剂可制备成糖浆、乳剂、软明胶胶囊、无菌注射液体如安瓿或非水液体混悬液。
式(I)化合物优选肠胃外给药,即静脉注射、肌肉内、皮下、舌下、鼻内、直肠内、鞘膜内或腹膜内给药。
通常优选肠胃外静脉注射给药。化合物可药团(bolus)给药或连续输液如6小时,最多可达3天。用常规技术可制备这种给药方式的合适剂型。
式(I)化合物也可口服给药。用常规技术制备这种给药方式的合适的剂型。
式(I)化合物也可吸入给药,即鼻内和口腔吸入给药。用常规技术可制备这种给药方式的合适剂型,如气雾制剂。
式(I)化合物也可局部给药,即非全身给药。这包括将抑制剂外用于上皮或颊腔以及滴注至耳、眼、鼻中,这样,化合物不会明显进入到血流中。
这里公开的所有使用方法中,每日口服剂量按体重优选约0.1~约200mg/kg,优选约0.2~约300mg/kg,更优选约0.5~约5mg/kg。每日肠胃外剂量按体重约0.1~200mg/kg,优选0.2~30mg/kg,更优选0.5~15mg/kg。每日局部剂量优选0.1mg~150mg,给药1~4次,优选每日2~3次。每日吸入剂量优选约0.01mg/kg~1mg/kg。本领域普通专业技术人员应意识到,抑制剂的最佳量和单剂量间隔应该取决于治疗疾病的性质、严重程度、药物剂型、给药途径和部位、治疗的特定病人,用常规技术可以判断这些最适宜条件。本领域普通专业技术人员也应意识到最佳治疗疗程,即抑制剂在一定期限内每天服用次数,本领域普通技术人员用常规治疗判断试验方法可以确定。使用药用盐时,上述数据根据母体式(I)化合物计算出来。
按上述剂量范围施用式(I)化合物时。没有毒性作用显现/预见。
所有的出版物,包括但不限于本说明书引用作为文献的专利及专利申请,每个特定地单独出版物与在这里作为文献整体引入一样说明充分。
下列实施例举例说明了本发明药理活性化合物的制备。
所用的缩写是:
THF为四氢呋喃
DMF为N,N-二甲基甲酰胺
TBAF为氟化四丁铵
DMSO为二甲基亚砜
LDA为二异丙基氨化锂
实施例1
5-[2-(2-氨基-1,1-二甲基-乙基)-5-吡啶-4-基-1H-咪唑-4-基]-茚-1-酮肟
5-溴-茚酮(100g,0.474mol)的乙醇(650ml)溶液中,在氩气保护条件下,加入甲氧胺盐酸盐(198g,2.38mol)和吡啶(125ml)。混合物回流2.5小时,冷却至室温,倾入饱和碳酸氢钠水溶液中,乙酸乙酯萃取,有机相干燥(Na2SO4),真空浓缩,粗品从异丙醇重结晶,得到标题化合物(110g,97%),为棕色固体;
1HNMR(CDCl3)7.52(1H,d,J8.3Hz),7.43(1H,d,J1Hz),7.35(1H,dd,J8.3,1Hz),3.97(3H,s),2.99(2H,m),2.99(2H,m),2.85(2H,m).
步骤2:1-甲氧亚氨基-茚-5-甲醛(1-methoxyimino-indan-5-carbaldehyde)
步骤1产物(112g,0.46mol)的THF(1500ml)溶液中,在-60℃,氩气保护下,用1小时加入n-BuLi(325ml,0.52mol)。60℃搅拌1小时,用1小时滴加DMF(39.7ml)的THF(50ml)溶液。反应60℃搅拌1小时,恢复至室温。1小时后,反应用饱和碳酸氢钠水溶液中止,用乙酸乙酯萃取,有机相干燥(Na2SO4),真空浓缩,残留物硅胶色谱纯化,得到标题化合物(57g,65%),为黄色固体;
1HNMR(CDCl3)10.0(1H,s),7.83-7.73(3H,m),4.02(3H,s),3.10(2H,m),2.92(2H,m).
步骤3:5-(1,2-二羟基-2-吡啶-4-基-乙基)-茚-1酮-O-甲基-肟
4-(叔丁-甲基-硅基氧甲基)-吡啶[Gallagher,等Bioorg.Med.Chem.,1997,5,49](71.5g,0.32mol)的THF(800ml)溶液中,在-50℃氩气保护下,用1小时加入LDA(162ml,2M的庚烷/THF/乙苯溶液,0.324mol)。混合物在-40℃继续搅拌1小时后,用1小时加入步骤2产物(55g,0.29mol)的THF(600ml)溶液。反应然后恢复至室温过夜,用饱和碳酸氢钠水溶液中止反应,用乙酸乙酯萃取,有机相干燥(Na2SO4),真空浓缩得到棕色油状物(125g)。
油状物然后溶解在THF(1500ml)中,用TBAF(356ml,0.356mol)处理,搅拌1小时,蒸发反应混合物,残留物分配在水和乙酸乙酯中,有机相干燥(Na2SO4),浓缩得到标题化合物(57g,64%),为淡黄色固体,未经进一步纯化直接应用。
1HNMR(CDCl3)8.38(2H,m),7.57(1H,m),7.12-6.99(4H,m),4.88(1H,m),4.66(1H,m),3.96(3H,s),2.93(2H,m),2.85(2H,m).
步骤4:1-(1-甲氧亚氨基-茚-5-基)-2-吡啶-4-基-乙烷-1,2-二酮
DMSO(43ml,0.56mol)与二氯甲烷(800ml)的混合液中,在-70℃氩气保护下,加入乙二酰氯(71.4g),随后在-60℃下,用2小时加入步骤3产物(55g,0.185mol)的二氯甲烷/DMSO(1000ml/60ml)溶液。-60℃搅拌2小时,滴加三乙基胺(154ml),混合物然后恢复至室温过夜。反应混合物用水中止,分离出有机相,水洗,(Na2SO4)干燥,浓缩得到标题化合物(51g,94%),为黄色固体。
1HNMR(CDCl3)8.87(2H,d),7.89-7.77(SH,m),4.03(3H,s),3.09(2H,m),2.93(2H,m).
步骤5:{2-[4-(1-甲氧亚氨基-茚-5-基)-5-吡啶-4-基-1H-咪唑-2-基]-2-甲基-丙基}-氨基甲酸叔丁酯
步骤4产物(1.02g,3.47mmol),(2,2-甲基-3-氧-丙基)氨基甲酸叔丁酯(0.84g,4.16mmol)[Guindon等,J.Am.Chem.Soc.,1997,119,9289]和乙酸铵(1.34g,17.4mmol)在甲醇(15ml)和叔丁甲基醚(30ml)中的混合物,室温搅拌2小时。反应液倾入水中,用乙酸乙酯萃取,有机萃取相干燥(MgSO4),真空浓缩,粗品硅胶色谱纯化,用乙酸乙酯洗脱,得到标题化合物(0.450g,27%),为无色固体;MS(AP+)m/e477[M+H]+
步骤6:5-[2-(2-氨基-1,1-二甲基-乙基)-5-吡啶-4-基-1H-咪唑-4-基]-茚-1-酮
步骤5产物(0.400g,0.839mmol)和5M HCl(2ml)与二氧六环(4ml)的混合物,100℃加热1小时,加入丙酮(10滴),继续加热1小时后,混合物冷却至室温,真空浓缩,残留物硅胶色谱纯化,用0.88氨水溶液-甲醇-乙酸乙酯(2∶18∶80)混合物洗脱,得到标题化合物(0.18g,62%),为黄色固体;MS(AP+)m/e348[M+H]+.
步骤7:5-[2-(2-氨基-1,1-二甲基-乙基)-5-吡啶-4-基-1H-咪唑-4-基]-茚-1-酮肟
步骤6产物(0.12g,0.350mmol)溶解在乙醇(5ml)中,80C时加入羟基胺(0.07g,1.04mmol,50%的水溶液)。30分钟后,混合物冷却至室温,真空浓缩,得到标题化合物(0.124g,100%),为黄色固体;MS(AP+)m/e362[M+H]+.
实施例2 N{2-[5-(1-羟基亚氨基-茚-5-基)-4-吡啶-4-基-1H-咪唑-2-基]-2-甲基丙基}-甲磺酰胺
步骤1:N-{2-甲基-2-[5-(1-氧-茚-5-基)-4-吡啶-4-基-1H-咪唑-2-基]-丙基}-甲磺酰胺
实施例1,步骤6产物(0.1g,0.29mmol)和甲磺酰氯(0.023ml,0.3mmol)在二氯甲烷(3ml)中的混合物,室温搅拌2小时。反应液倾入乙酸乙酯中,水洗,碳酸氢钠溶液洗,干燥(MgSO4),真空浓缩。粗品硅胶色谱纯化,用0.88氨水溶液-甲醇-二氯甲烷(1∶9∶90)混合物洗脱,得到标题化合物(0.075g,61%),为黄色固体;MS(AP+)m/e425[M+H]+.
步骤2:
N-{2-[5-(1-羟基亚氨基-茚-5-基)-4-吡啶-4-基-1H-咪唑-2-基]-2-甲基-丙基}-甲磺酰胺
用步骤1产物如实施例1步骤7所述制备得到标题化合物(0.06g,90%);MS(AP+)m/e440[M+H]+.
实施例3
步骤1:1-(2-甲氧-乙基)-哌啶-4-羧酸{2-甲基-2-[5-(1-氧-茚-5-基)-4-吡啶-4-基-1H-咪唑-2-基]-丙基}-酰胺
实施例1步骤6产物(0.1g,0.29mmol),1-羟基苯并***(0.06g,0.44mmol)和结合了1,3-二环己基碳二亚氨的聚合物(0.4g,0.6mmol,1.52mmol/g)混合在1∶1二氯甲烷-DMF(4ml)混合液中,室温搅拌30分钟。加入1-(2-甲氧-乙基)-哌啶-4-羧酸盐酸盐[WO97/25309](0.098g,0.44mmol)的DMF溶液(2ml),混合物室温搅拌过夜。反应混合物过滤,真空除溶剂,粗品硅胶色谱纯化,用0.88氨水溶液-甲醇-二氯甲烷(1∶9∶90)混合物洗脱,得到标题化合物(0.12g,80%),为黄色油状物;MS(AP+)m/e516[M+H]+.
步骤2:1-(2-甲氧-乙基)-哌啶-4-羧酸{2-[5-(1-羟基亚氨基-茚-5-基])-4-吡
啶-4-基-1H-咪唑-2-基]-2-甲基-丙基}-酰胺
用步骤1产物如实施例1步骤7所述制备得到标题化合物(0.07g,70%);MS(AP+)m/e531[M+H]+.
实施例4
5-(2-哌啶-4-基-5-吡啶-4-基-1H-咪唑-4-基)-茚-1酮肟
步骤1.4-[4-(1-甲氧亚氨基-茚-5-基)-5-吡啶-4-基-1H-咪唑-2-基]哌啶-1-羧酸叔丁酯
用实施例1步骤4产物和4-甲酰基-哌啶-1-羧酸叔丁酯(Klein等;J.Med.Chem.,1998,41,2492),如实施例1步骤5所述制备标题化合物(0.765g,79%);MS(AP+)m/e488[M+H]+.
步骤2.
5-(2-哌啶-4-基-5-吡啶-4-基-1H-咪唑-4-基)-茚-1酮
如实施例1步骤6所述方法,用步骤1产物制备得到标题化合物(0.55g,90%);MS(AP+)m/e359[M+H]+.
步骤3.5-(2-哌啶-4-基-5-吡啶-4-基-1 H-咪唑-4-基)-茚-1酮肟
用步骤2产物,如实施例1步骤7所述,然后硅胶色谱纯化,用0.88氨水溶液-甲醇-二氯甲烷混合物洗脱,得到标题化合物(0.35g,90%)MS(AP+)m/e374[M+H]+.
实施例5
用实施例4产物和1-(2-甲氧-乙基)-哌啶-4-羧酸盐酸盐[WO97/25309],如实施例3步骤1所述方法,制备标题化合物(0.028g,28%)MS(AP+)m/e543[M+H]+.
实施例6
实施例4产物(0.093g,0.25mmol),3-呋喃醛(0.024g,0.25mmol),结合在聚合物上的氰基硼氢化三甲基铵(0.125g,0.5mmol,4mmol/g),与包含乙酸(0.1ml)的甲醇(3ml)混合,室温搅拌24小时,反应混合物倾注到SCX柱上,0.880氨水溶液-甲醇(0-10%)洗脱,产物进一步用硅胶色谱纯化,0.880氨水溶液-乙醇-二氯甲烷(1∶9∶90)洗脱,得到标题化合物(0.070g,62%),为固体;MS(AP+)m/e454[M+H]+.
实施例7
步骤1.1-(2-甲氧-乙基)-哌啶-4-甲醛
1-(2-甲氧-乙基)-哌啶-4-羧酸乙酯[WO97/25309](2.0g,9.3mmol)的甲苯(40ml)溶液中,在-78℃下,用1小时加入氢化二异丁基铝(10.2ml,1M的四氢呋喃溶液,10.2mmol)。1小时后,反应混合物用甲醇(5ml)和饱和乙酸铵溶液(5ml)中止。混合物室温搅拌1小时,过滤,滤液浓缩,得到标题化合物,为黄色油状物(1.1g,69%);MS(AP+)m/e172[M+H]+.
步骤2.5-{2-[1-(2-甲氧-乙基)-哌啶-4-基]-5-吡啶-4-基-1H-咪唑-4-基}茚-1酮-O-甲基-肟
用步骤1产物与实施例1步骤4的产物,如实施例1步骤5所述的方法,制备标题化合物(0.27g,32%)MS(AP+)m/e446[M+H]+.
步骤3.5-{2-[1-(2-甲氧-乙基)-哌啶-4-基]-5-吡啶-4-基-1H-咪唑-4-基}-茚-1酮
用步骤2产物,如实施例1步骤6所述,制备标题化合物(0.193g,93%);MS(AP+)m/e417[M+H]+.
步骤4.5-{2-[1-(2-甲氧-乙基)-哌啶-4-基]-5-吡啶-4-基-1H-咪唑-4-基}茚-1
酮肟
用步骤3产物,如实施例4步骤3,制备标题化合物(0.105g,68%);
MS(AP+)m/e432[M+H]+.
实施例8
5-(2-氨基甲基-5-吡啶-4-基-1H-咪唑-4-基)-茚-1酮肟
步骤1.[4-(1-甲氧亚氨基-茚-5-基)-5-吡啶-4-基-1H-咪唑-2-基甲基]-氨基甲酸叔丁酯
用实施例1步骤4产物和(2-氧-乙基)-氨基甲酸叔丁酯,如实施例1步骤5所述,制备得到标题化合物(1.04g,70%);MS(AP+)m/e434[M+H]+.
步骤2.5-(2-氨基甲基-5-吡啶-4-基-1H-咪唑-4-基)-茚-1酮
用步骤1产物,如实施例1步骤6所述,制备标题化合物(0.21g,30%);MS(AP+)m/e305[M+H]+.
步骤3.5-(2-氨基甲基-5-吡啶-4-基-1H-咪唑-4-基)-茚-1酮肟
用步骤2产物,如实施例4步骤3所述,制备标题化合物(0.064g,80%),MS(AP+)m/e320[M+H]+.
实施例9
1-(2-甲氧-乙基)-哌啶-4-羧酸[4-(1-羟基亚氨基-茚-5-基)-5-吡啶-4-基)-1H-咪唑-2-基甲基]-酰胺
步骤1.1-(2-甲氧-乙基)-哌啶-4-羧酸[4-(I-氧-茚-5-基)-5吡啶-4-基)-1H-咪唑-2-基甲基]-酰胺
用实施例8步骤2产物与1-(2-甲氧-乙基)-哌啶-4-羧酸盐酸盐[WO97/25309],如实施例3步骤1所述,制备标题化合物(0.095g,67%);MS(AP+)m/e474[M+H]+.
步骤2.1-(2-甲氧-乙基)-哌啶-4-羧酸[4-(I-羟基亚氨基-茚-5-基)-5-吡啶-4-基)-1H-咪唑-2-基甲基]-酰胺
用步骤1产物,如实施例4步骤3所述,制备标题化合物(0.041g,42%);MS(AP+)m/e531[M+H]+.
实施例10
步骤1.5-[2-(1,1-二甲氧-甲基)-5-吡啶-4-基-1H-咪唑-4-基]-茚-1酮O-甲基肟。
用实施例1步骤4产物,二甲氧-乙醛(45%的叔丁基甲基醚溶液),如实施例1步骤5所述,制备标题化合物(1.05g,79%);MS(AP+)m/e379[M+H]+.
步骤2.4-(I-氧-茚-5-基)-5-吡啶-4-基-1H-咪唑-2-甲醛
用步骤1产物,如实施例1步骤6所述,制备标题化合物(0.92g,90%);MS(AP+)m/e303[M+H]+.
步骤3.5-(2-哌啶-1-基甲基-5-吡啶-4-基-1H-咪唑-4-基)-茚-1酮.
用步骤2产物与哌啶,如实施例6所述,制备标题化合物(0.1g,44%);MS(AP+)m/e373[M+H]+.
步骤4.5-(2-哌啶-1-基甲基-5-吡啶-4-基-1H-咪唑-4-基)-茚-1酮肟.
用步骤3产物,如实施例4步骤3所述,制备标题化合物(0.55g,53%);MS(AP+)m/e387[M+H]+.
实施例11
用实施例10步骤2产物与吗啉,按照实施例10步骤3和4所述过程,制备标题化合物(0.034g,13%);MS(AP+)m/e390[M+H]+.
实施例12
用实施例10步骤2产物和3,4,5,6-四氢-2H-[1,2′]二吡嗪基,按照实施例10步骤3,4所述过程,制备标题化合物(0.038g,17%);MS(AP+)m/e467[M+H]+.
实施例13
步骤1.4-[4-(1-氧-茚-5-基)-5-吡啶-4-基-1H-咪唑-2-甲基]哌嗪-1羧酸叔丁酯。
用实施例10步骤2产物和哌嗪-1-羧酸叔丁酯,如实施例6所述,制备标题化合物(0.35g,74%);MS(AP+)m/e474[M+H]+.
步骤2.5-(2-哌嗪-1-基甲基-5-吡啶-4-基-1H-咪唑-4-基)-茚-1酮
步骤1产物(0.350g,0.74mmol)的二氯甲烷与三氟乙酸(5ml)溶液(10ml),室温搅拌3小时。浓缩溶液,残留物与二氯甲烷共蒸。残留物溶解在水中(10ml),用碳酸钠溶液调至中性。减压蒸发溶剂,得到的固体在五氧化二磷上干燥,得到用于下步的标题化合物;MS(AP+)m/e374[M+H]+.
步骤3.5-(2-哌嗪-1-基甲基-5-吡啶-4-基-1H-咪唑-4-基]-茚-1酮肟.
用步骤2产物,如实施例4步骤3所述,制备标题化合物(0.105g,37%);MS(AP+)m/e389[M+H]+.
实施例14
步骤1:5-溴-茚-1酮O-甲基-肟
5-溴-茚酮(100g,0.474mol)的乙醇溶液(650ml),在氩气保护下,加入甲氧胺盐酸盐(198g,2.38mol)和吡啶(125ml),混合物回流2.5小时,冷却至室温,倾入饱和碳酸氢钠水溶液,混合物用乙酸乙酯萃取,有机相干燥(硫酸钠),真空浓缩,粗品异丙醇重结晶,得到标题化合物(110g,97%),为棕色固体;
1HNMR(CDCl3)7.52(1H,d,J8.3Hz),7.43(1H,d,J1Hz),7.35(1H,dd,J8.3,1Hz),3.97(3H,s),2.99(2H,m),2.99(2H,m),2.85(2H,m).
步骤2:1-甲氧亚氨基-茚-5-甲醛
步骤1产物(112g,0.46mol)的THF溶液(1500ml),在-60℃氩气保护下,用1小时加入n-BuLi(325ml,0.52mol)。-60C搅拌1小时,用1小时滴加DMF(39.7ml)的THF(50ml)溶液。反应-60℃搅拌1小时,然后恢复至室温。1小时后,反应用饱和碳酸氢钠水溶液中止,用乙酸乙酯萃取,有机相干燥(硫酸钠),真空浓缩,残留物硅胶色谱纯化,得到标题化合物(57g,65%),为黄色固体;
1HNMR(CDCl3)10.0(1H,s),7.83-7.73(3H,m),4.02(3H,s),3.10(2H,m),2.92(2H,m).
步骤3:5-(1,2-二羟基-2-吡啶-4-基-乙基)-茚-I酮-O-甲基-肟
4-(叔丁-二甲基-硅氧甲基)-吡啶[T.F.Gallagher等;Bioorg.Med.Chem.,1997,5,49](71.5g,0.32mol)的THF溶液(800ml),在-50℃氩气保护下,用1小时加入LDA(162ml,2M的庚烷/THF/乙基苯溶液,0.324mol)。混合物-40℃继续搅拌1小时后,用1小时加入步骤2产物(55g,0.29mol)的THF(600ml)溶液。反应然后温热至室温过夜,加入饱和碳酸氢钠水溶液终止反应,用乙酸乙酯萃取,有机相干燥(硫酸钠),真空浓缩,得到棕色油状物(125g)。
油状物然后溶解在THF(1500ml)中,加入TBAF(356ml,0.356mol),搅拌1小时。反应混合物然后蒸发出溶剂,残留物分配到水与乙酸乙酯中,有机相干燥(硫酸钠),浓缩得到标题化合物(57g,64%),为淡黄色固体,未经进一步纯化直接使用。
1HNMR(CDCl3)8.38(2H,m),7.57(1H,m),7.12-6.99(4H,m),4.88(1H,m),4.66(1H,m),4.88(1H,m),4.66(1H,m),3.96(3H,s),2.93(2H,m),2.85(2H,m).
步骤4:1-(1-甲氧亚氨基-茚-5-基)-2-吡啶-4-基-乙烷-1,2-二酮
DMSO(43ml,0.56mol)与二氯甲烷(800ml)的混合液中,在-70℃氩气保护下,加入乙二酰氯(43.2g);然后在-60C,用2小时加入步骤3产物(55g,0.185mol)的氯甲烷/DMSO(1000ml/60ml)溶液。-60℃搅拌2小时,滴加三乙基胺(154ml),混合物然后温热至室温过夜。用水中止反应,分离出有机相,水洗,干燥(硫酸钠),浓缩得到标题化合物(51g,94%),为黄色固体。
1HNMR(CDCl3)8.87(2H,d),7.89-7.77(5H,m),4.03(3H,s),3.09(2H,m),2.93(2H,m).
步骤5:5-{2-[4-(3-甲基氨基-丙基氧)-苯基]-5-苯基-1H-咪唑-4-基}-茚-1酮-O-甲基-肟
步骤4产物(0.3g,1.02mmol),4-(3-甲基氨基-丙基氧)-苯甲醛(0.27ml,1.33mmol)和乙酸铵(0.785g,10.2mmol)加到乙酸(10ml)中,100C加热1小时。反应冷却至室温,倾入冰/0.880氨水溶液中,用乙酸乙酯萃取,有机萃取相干燥(硫酸镁),真空浓缩,粗品硅胶色谱纯化,用0.88氨水溶液-甲醇-乙酸乙酯(1∶9∶90)洗脱,得到标题化合物(0.08g,16%),为黄色固体;MS(AP+)m/e483[M+H]+.
步骤6:5-{2-[4-(3-甲基氨基-丙基氧)-苯基]-5-吡啶-4-基-1H-咪唑-4-基}-茚-1酮
步骤5产物(0.07g,0.146mmol)和5M HCl(4ml)在二氧六环(3ml)中的混合物在100℃下加热1小时。加入丙酮(3ml),继续加热1.5小时,混合物冷却至室温,用1M氢氧化钠溶液调至中性,用乙酸乙酯萃取,有机萃取相水洗,干燥(硫酸镁),真空浓缩,粗品硅胶色谱纯化,用0.88氨水溶液-甲醇-乙酸乙酯(2∶18∶80)洗脱,得到标题化合物(0.035g,53%),为黄色固体;MS(AP+)m/e453[M+H]+.
实施例15
步骤1:5-{2-[4-(3-甲基氨基-丙基氧)-苯基]-5-吡啶-4-基-1H-咪唑-4-基}-茚-1-酮肟
实施例14,步骤6产物(0.07g,0.155mmol)的乙醇(3ml)溶液中,在80℃下,加入羟胺(1.5ml,50%的水溶液)。30分钟后,混合物冷却至室温,真空浓缩,得到标题化合物,(0.072g,100%),为黄色固体;MS(AP+)m/e468[M+H]+.
实施例16
5-{2-[4-(2-甲基氨基-乙氧)-苯基]-5-吡啶-4-基-1H-咪唑-4-基}-1-茚酮
步骤1:5-{2-[4-(2-甲基氨基-乙氧)-苯基]-5-吡啶-4-基-1H-咪唑-4-基}-茚-1酮-O-甲基-肟
用实施例14步骤4产物与4-(2-甲基氨基-乙氧)-苯甲醛[WO99/19293]如实施例14步骤5所述,制备标题化合物(0.19g,30%);MS(AP+)m/e468[M+H]+.
步骤2:5-{2-[4-(2-甲基氨基-乙氧)-苯基]-5-吡啶-4-基-1H-咪唑-4-基}-1-茚酮
用步骤1产物,如实施例14步骤6所述,制备标题化合物(0.313g,56%);MS(AP+)m/e439[M+H]+.
实施例17
5-{2-[4-(2-甲基氨基-乙氧)-苯基]-5-吡啶-4-基-1H-咪唑-4-基}-茚-1酮肟
步骤15-{2-[2-甲基氨基-乙氧)-苯基]-5-吡啶-4-基-1H-咪唑-4-基}茚-1酮肟
用实施例16步骤2产物,如实施例15步骤1所述,制备标题化合物(0.321g,100%);MS(AP+)m/e454[M+H]+.
实施例18
5-{2-[4-(2-吗啉-4-基-乙氧)-苯基]-5-吡啶-4-基-1H-咪唑-4-基}-茚1酮
步骤1:5-{2-[2-吗啉-4-基-乙氧)-苯基]-5-吡啶-4-基-1H-咪唑-4-基}茚-1酮-O-甲基-肟
用实施例14步骤4产物,4-(2-吗啉-4-基-乙氧)-苯甲醛[WO96/28448],如实施例14步骤5所述,制备标题化合物(0.1 g,20%);MS(AP+)m/e510[M+H]+
步骤2:5-{2-[4-(2-吗啉-4-基-乙氧)-苯基]-5-吡啶-4-基-1H-咪唑-4-基}-茚-1酮
用步骤1产物,如实施例14步骤6所述,制备标题化合物(0.048g,36%);MS(AP+)m/e481[M+H]+.
步骤1:5-{2-[4-(2-吗啉-4-基-乙氧)-苯基]-5-吡啶-4-基-1H-咪唑-4-基}-茚-1酮肟
用实施例18步骤2产物,如实施例15步骤1所述,制备标题化合物(0.048g,97%);MS(AP+)m/e496[M+H]+.
实施例20
5-(5-吡啶-4-基-2-吡啶-3-基-1H-咪唑-4-基)-茚-1酮
步骤1:5-(5-吡啶-4-基-2-吡啶-3-基-1H-咪唑-4-基)-茚-I酮-O-甲基-肟
用实施例14步骤4产物与吡啶-3-甲醛,如实施例14步骤5所述,制备标题化合物(0.1lg,28%);MS(AP+)m/e382[M+H]+.
步骤2:5-(5-吡啶-4-基-2-吡啶-3-基-1H-咪唑-4-基)-茚-1酮
用步骤1产物,如实施例14步骤6所述,制备标题化合物(0.025g,25%);MS(AP+)m/e353[M+H]+.
实施例21
5-(5-吡啶-4-基-2-吡啶-3-基-1H-咪唑-4-基}-茚-1酮肟
步骤1:5-(5-吡啶-4-基-2-吡啶-3-基-1H-咪唑-4-基}-茚-1酮肟
用实施例20步骤2产物,如实施例15步骤1所述,制备标题化合物(0.075g,76%);MS(AP+)m/e368[M+H]+.
实施例22
5-(2-苯基-5-吡啶-4-基-1H-咪唑-4-基)-茚-1-酮
步骤1:4-[2-苯基-1-(2-三甲基硅基-乙氧甲基)-1H-咪唑-4-基]-吡啶
4-(2-苯基-1H-咪唑-4-基)-吡啶[Liverton等,J.Med.Chem.,1999,42,2180](17.8g,80.5mmol)溶解在DMF(150ml)中,冷却至0℃,用氢化钠(3.54g,60%分散液,88.6mmol)处理,保持0℃搅拌25分钟。
用5分钟滴加2-(三甲基甲硅烷基)乙氧甲基氯化物(14.77g,88.6mmol),混合物温热至室温过夜。反应液倾入饱和碳酸氢钠溶液,***萃取数次,合并的醚萃取相,干燥(硫酸钠),真空浓缩,残留物硅胶色谱纯化,乙酸乙酯洗脱,得到标题化合物,为淡黄色固体(16.8g,59%);MS(AP+)m/e 353[M+H]+.
步骤2:4-[5-溴-2-苯基-1-(2-三甲基硅烷基-乙氧甲基)-1H-咪唑-4-基]-吡啶
步骤1产物(15g,42.6mmol)的二氯甲烷(300ml)溶液中,在室温下加入溴(6.81g,2.38ml,46.5mmol),然后加入饱和碳酸钠溶液(150ml),混合物搅拌40分钟后,分离出有机层,依次用水、盐水洗,有机层干燥(硫酸镁),真空浓缩,得到标题化合物(18.1g,99%),为棕色粘性油状物,未经进一步纯化直接使用;MS(AP+)m/e431/433[M+H]+.
步骤3:4-[2-苯基-5-三丁基锡-1-(2-三甲基硅烷基-乙氧甲基)-1H-咪唑-
4-基]-吡啶.
步骤2产物(13.4g,31.2mmol)的THF溶液(200ml),在-78C滴加tBuLi(22ml,1.7M,38mmol)。25分钟后,滴加氯化三丁锡(12.37g,10.3ml,38mmol),混合物恢复至室温过夜。反应液倾入饱和碳酸氢钠溶液,***洗数次,合并有机层。干燥(硫酸镁),真空浓缩,残留物硅胶色谱纯化,0.88氨水溶液-甲醇-己烷∶***(0.5∶4.5∶45∶50)洗脱,得到标题化合物(18.5g,93%),为棕色粘性油状物;MS(AP+)m/e641/643/644[M+H]+.
步骤4:5-[2-苯基-5-吡啶-4-基-3-(2-三甲基硅烷基-乙氧甲基)-1H咪唑-
4-基]-茚-1酮
乙酸钯(0.025g,0.1lmmol)与三苯基膦(0.06g,0.22mmol)悬浮在甲苯(1ml)中,加入5-溴茚酮(240mg,1.1mmol),混合物100℃加热5分钟,然后用步骤3产物(0.6g,0.94mmol)的甲苯(1ml)溶液处理,100℃搅拌18小时。冷却后,减压蒸除溶剂,残留物硅胶色谱纯化,乙酸乙酯洗脱,得到标题化合物(0.25g,55%),为黄色固体;MS(AP+)m/e482[M+H]+.
步骤5:5-(2-苯基-5-吡啶-4-基-1H-咪唑-4-基)-茚-1酮
步骤4产物(0.32g,0.66mmol)溶解在乙醇(4ml)中,加入5M盐酸溶液(3ml),混合物加热回流30分钟。冷却后,减压蒸除溶剂,得到标题化合物,为黄色固体(0.27g,96%);MS(AP+)m/e352[M+H]+.
实施例23
5-(2-苯基-5-吡啶-4-基-IN-咪唑-4-基)-茚-1酮肟
步骤1:5-(2-苯基-5-吡啶-4-基-1H-咪唑-4-基)-茚-1酮肟
实施例22步骤5产物(0.06g,0.17mmol)与羟胺盐酸盐(0.035g,0.5mmol)的40%氢氧化钠水溶液(2ml)和乙醇(3ml),加热回流30分钟。冷却后,混合物用2M盐酸调至中性,用乙酸乙酯萃取,有机相用盐水洗,干燥(硫酸镁),真空浓缩,残留物硅胶色谱纯化,用0.88氨水溶液-甲醇-二氯甲烷(1∶9∶90)洗脱,得到标题化合物(0.05g,80%),为黄色固体;MS(AP+)m/e367[M+H]+.
生物学实施例
式(I)化合物作为B-Raf抑制剂的活性用下列体外分析来测定:
荧光各向异性激酶结合分析
激酶、荧光配体和多种浓度的受试化合物一起孵育达到热力学平衡。孵育条件为:无受试化合物时,荧光配体与酶结合显著(>50%);强活性抑制剂有足够浓度(>10×Ki)条件下,未结合与结合荧光配体的各向异性,在数值上有可检测的差异。
激酶浓度应当优选21×Kf。荧光配体需要的浓度取决于使用仪器,荧光及物理化学性质。使用浓度必须低于激酶浓度,优选小于1/2激酶浓度。典型的方案为:
所有的成分溶解在缓冲液中,缓冲液组成为50mM HEPES,pH7.5,1mMCHAPS,10mM MgCl2;
B-Raf酶浓度:1nM
荧光配体浓度:0.5nM
受试化合物浓度:0.1nM-100uM
组分在LJL HE 384 B型黑色微量滴定板孵育,终体积为10ul,直至平衡(多于3小时,最多30小时)
荧光各向异性用LJL Acquest读取。
定义:Ki=抑制剂结合解离常数
Kf=荧光配体结合解离常数
由5-[2-(4-氨基甲基苯基)-5-吡啶-4-基-1H-咪唑-4-基]-2-氯苯酚和罗丹明绿(rhodamine green)衍生得到。
Raf激酶分析
重组人B-Raf蛋白活性的体外评价是通过分析重组MAP激酶(MEK,一种已知的B-Raf生理底物)中放射标记磷酸盐的掺入来进行。催化活性的重组B-Raf蛋白从sf9昆虫细胞中纯化得到,后者用人B-Raf重组杆状病毒表达载体转染。为保证B-Raf活性诱导的所有底物都能磷酰化,使用无催化活性的MEK。该蛋白以无活性MEK突变体与谷胱甘肽-S-转移酶(GST-kdMEK)形成的融合蛋白形式,从细菌细胞表达中纯化出来。
方法:B-Raf催化活性标准的分析条件为3ug的GST-kdMEK,10uMATP和2uCi 33P-ATP,50mM MOPS,0.1mM EDTA,0.1M蔗糖,10mM MgCl2加0.1%二甲基亚砜(需要的时候包含化合物),总反应体积为30ul。反应在25℃孵育90分钟,加入EDTA至终浓度50uM,终止反应。将10ul的反应物点到P30磷酸纤维素纸上,空气干燥。接着用冰冷的10%三氯乙酸,0.5%磷酸洗四次,将纸空气干燥后,加入液体闪烁体,用闪烁计数仪测量放射性。
结果:_实施例化合物能有效抑制B-Raf介导的GST-kdMEK底物的磷酰化,IC50<3uM。
化合物的Raf抑制剂活性也可以用下述文献的方法评价:WO99/10325;McDonald等(A scintillation proximity assay for theRaf/MEK/ERK kinase cascade:high throughput screening andidentification of selective enzyme inhibitor,Anal.Biochem.1999,268:318-329),AACR meeting New Orleans 1998 Poster 3793.
B-Raf抑制剂的神经保护特性可用下述体外分析来判断:
B-Raf抑制剂在大鼠海马(hippocampal)切片培养中的神经保护特性
器官型培养物提供了离解神经元细胞培养物和体内氧和葡萄糖缺失(oxygen and glucose deprivation,OGD)模型之间的中间状态。主要的胶质神经元相互作用和神经元回路(circuitry)在培养的海马切片中都保留着。因此有利于研究类似体内情形模型中不同类型细胞的死亡模式。这些培养条件为损伤后24小时甚至更长时间后延迟细胞损伤及死亡的研究及长期的培养条件变化的后果评价提供了可能。许多实验室已经报告了海马器官型培养物中由于OGD而延迟的神经元损伤。(Vornov等,Stroke,1994,25,57-465;Newell等,Brain Res.,1995,676,38-44)。几种类型的化合物在这种模型中显示出保护作用,包括EAA拮抗剂(Strasser等,Brain Res.,1995,687,167-174),Na通道阻滞剂(Tasker等,J.Neurosci.,1992,12,98-4308)和Ca通道阻滞剂(Pringle等,Stroke,1996,7,2124-2130)。截至目前,细胞内激酶介导的信号通路在该模型神经元细胞死亡中的作用,知道的相对甚少。
方法:器官型海马切片培养物用Stoppini等的方法(J.Neurosci.Methods,1995,37,173-182)制备。简言之,从出生7-8天的Sprague Dawley大鼠的海马制备400μm断片,在半孔(semiporous)膜上培养9-12天。厌氧箱中无葡萄糖血清培养液中培养45分钟诱导OGD,然后在空气/CO2培养箱中培养23小时,随后进行分析。Propidium iodide(PI)作为细胞死亡指示剂。PI对神经元无毒,在很多研究中用来判断细胞生存能力。在损伤的神经元中,PI进入与核酸结合,用540nm激发时,结合PI在635nm的发射增强。获取一张PI荧光图象和一张白光图象,就可以分析出细胞的死亡比率。在白光图象界定出CA1区域,与PI图象叠加。设定PI信号阈值,PI损伤区域表示为CA1区域的百分率。PI荧光和组织学证实细胞死亡的相关性先前已用羟苯甲基快速紫(cresyl fast violet)进行Nissl染色的方法确定了(Newell等,J.Neurosci.,1995,15,7702-7711)。
整个说明书及随后的权利要求中,除非上下文另有要求,“包括”应理解为意味着包含数个整体中的所指明的整体或步骤或基团,但不排除数个整体或数个步骤中任何其他整体或步骤或基团。
本说明书和权利要求部分的申请可作为任何随后申请的优先权的基础。随后申请的权利要求可指向任何一项这里所述的特征或特征的组合。它们可以组合物、方法、或用途权利要求的形式,可包括实施例而不限于下列权利要求。
Claims (12)
其中,
X为O,CH2,CO,S或NH,或X-R1部分为氢;
Y1和Y2独立地为N或CH;
R1为氢,C1-6烷基,C3-7环烷基,芳基,芳基C1-6烷基,杂环基,杂环基C1-6烷基,杂芳基或杂芳基C1-6烷基,其任何一种基团可被任选取代;并且当X为CH2时,R1为羟基或可被任选取代的C1-6烷氧基;
R2为H,C1-6烷基,C2-6链烯基,C3-7环烷基,C5-7环烯基,杂环基,芳基或杂芳基,其任何一种可被任选取代;
Ar为式a)或b)基团:
其中A代表稠和的5~7-元环,任选包含最多2个杂原子,选自O,S,NR5,其中R5为氢或C1-6烷基,该环被最多2取代基任选取代,取代基选自卤素,C1-6烷基,羟基,C1-6烷氧基或酮基;
R3和R4独立地选自氢,卤素,C1-6烷基,芳基,芳基C1-6烷基,C1-6烷氧基,C1-6烷氧基C1-6烷基,卤代C1-6烷基,芳基C1-6烷氧基,羟基,硝基,氰基,叠氮基,氨基,单-和二-N-C1-6烷基氨基,酰基氨基,芳基羰基氨基,酰基氧,羧酸,羧酸盐,羧酸酯,氨基甲酰基,单-和二-N-烷基C1-6氨基甲酰基,C1-6烷氧基羰基,芳氧基羰基,脲基,胍基,C1-6烷基胍基,脒基,C1-6烷基脒基,磺酰基氨基,氨基磺酰基,C1-6烷硫基,C1-6烷基亚磺酰基或C1-6烷基磺酰基;
R15为O或N-OH;
X1和X2之一为N,另一个为NR6,其中R6为氢或C1-6烷基。
2.权利要求1的式(I)化合物,其中X为NH或X-R1为氢。
3.权利要求1或2的式(I)化合物,其中R15为N-OH。
4.前述任何一项权利要求的式(I)化合物,其中R2为i)-CR7R8-CH2-Z,-CH2-Z和杂环基,其中R7,R8独立地代表氢或任选取代的C1-6烷基,或R7和R8通过碳原子连接在一起形成任选取代的C3-7环烷基或C5-7环烯基环;Z为NR9R10,NR9C(Q)NR9R10,NR9COOR10,NR9SO2R10,NR9C(Q)R10或杂环基,其中R9,R10独立地选自氢,C1-6烷基,C3-7环烷基,杂环基,杂环基C1-6烷基,芳基,芳基C1-6烷基,杂芳基,杂芳基C1-6烷基,其中任何一种可被任选取代或当为NR9R10时连接一起形成一个杂环基团;Q为O或S,优选O;以及R2或Z为杂环基时,如哌啶基、哌嗪或吗啉时,杂环基可被任选取代;或ii)任选取代的苯基,吡啶基,嘧啶基,呋喃基。
5.任何一项前述权利要求所述式(I)化合物,其中R3为氢。
6.任何一项前述权利要求所述式(I)化合物,其中R4为氢。
7.任何一项前述权利要求所述式(I)化合物,其中R6为氢。
8.如实施例1~23任何一项定义的式(I)化合物,或药用盐。
9.一种药物组合物,包含权利要求1~8任何一项所述化合物或其可药用盐及可药用载体。
10.权利要求1~8任何一项所述化合物或其可药用盐在制备药物中的用途,该药物用于预防或治疗人或其他哺乳动物中由神经外伤引起或加剧的任何疾病。
11.权利要求1~8任何一项所述化合物或其可药用盐在制备药物中的用途,该药物用于癌症的预防或治疗。
12.权利要求1~8任何一项所述化合物或其可药用衍生物在制备预防或治疗慢性神经退化、疼痛、偏头痛、心脏肥大的药物中的用途。
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103159736A (zh) * | 2011-12-10 | 2013-06-19 | 通化四环医药有限公司 | 取代的吡唑激酶抑制剂 |
CN103159735A (zh) * | 2011-12-10 | 2013-06-19 | 通化四环医药有限公司 | 取代的咪唑激酶抑制剂 |
CN108484587A (zh) * | 2018-06-03 | 2018-09-04 | 刘思良 | 一种Raf激酶抑制剂及其在癌症治疗中的应用 |
Families Citing this family (52)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2003514906A (ja) * | 1999-11-22 | 2003-04-22 | スミスクライン ビーチャム パブリック リミテッド カンパニー | イミダゾール誘導体およびrafキナーゼ阻害剤としてのその使用 |
JP2003525936A (ja) * | 2000-03-06 | 2003-09-02 | スミスクライン ビーチャム パブリック リミテッド カンパニー | Rafキナーゼ阻害物質としてのイミダゾール誘導体 |
ES2289004T3 (es) * | 2000-11-20 | 2008-02-01 | Smithkline Beecham Corporation | Nuevos compuestos. |
GB0112348D0 (en) * | 2001-05-19 | 2001-07-11 | Smithkline Beecham Plc | Compounds |
US7446106B2 (en) | 2001-09-05 | 2008-11-04 | Smithkline Beecham Plc | Pyridylfurans and pyrroles as Raf kinase inhibitors |
US20040192689A1 (en) * | 2001-09-05 | 2004-09-30 | Dean David Kenneth | Heterocycle-carboxamide derivatives as raf kinase inhibitors |
GB0121490D0 (en) | 2001-09-05 | 2001-10-24 | Smithkline Beecham Plc | Ciompounds |
GB0121488D0 (en) | 2001-09-05 | 2001-10-24 | Smithkline Beecham Plc | Compounds |
AR039241A1 (es) * | 2002-04-04 | 2005-02-16 | Biogen Inc | Heteroarilos trisustituidos y metodos para su produccion y uso de los mismos |
AU2003221684A1 (en) * | 2002-04-08 | 2003-10-27 | Smithkline Beecham Corporation | Cancer treatment method comprising administering an erb-family inhibitor and a raf and/or ras inhibitor |
CN1894241A (zh) | 2002-08-09 | 2007-01-10 | 阿斯利康(瑞典)有限公司 | 作为代谢型谷氨酸受体-5调节剂的“1,2,4” 噁二唑 |
NZ538339A (en) * | 2002-08-09 | 2007-01-26 | Astrazeneca Ab | Oxadiazoles as modulators of metabotropic glutamate receptor-5 |
MXPA05001590A (es) * | 2002-08-09 | 2005-05-23 | Astrazeneca Ab | Compuestos que tienen actividad en los receptores metabotropicos de glutamato. |
US7884120B2 (en) | 2002-08-19 | 2011-02-08 | Lorus Therapeutics Inc. | 2,4,5-trisubstituted imidazoles and their use as anti-microbial agents |
UA80295C2 (en) * | 2002-09-06 | 2007-09-10 | Biogen Inc | Pyrazolopyridines and using the same |
US20050250837A1 (en) * | 2002-10-18 | 2005-11-10 | D Mello Santosh R | Use of C-Raf inhibitors for the treatment of neurodegenerative diseases |
US20090264494A1 (en) * | 2002-10-18 | 2009-10-22 | Board Of Regents, The University Of Texas System | Use of neuroprotective 3-substituted indolone compositions |
WO2004090545A2 (en) * | 2003-04-14 | 2004-10-21 | Novartis Ag | Methods for treating proliferative diseases and for monitoring the effectiveness of treatment of proliferative diseases |
US7569593B2 (en) * | 2003-10-02 | 2009-08-04 | Irm Llc | Compounds and compositions as protein kinase inhibitors |
JP5095216B2 (ja) | 2003-11-14 | 2012-12-12 | ローラス セラピューティクス インコーポレーテッド | アリールイミダゾールおよびその抗癌剤としての使用 |
TW200639163A (en) * | 2005-02-04 | 2006-11-16 | Genentech Inc | RAF inhibitor compounds and methods |
ES2473597T3 (es) | 2005-05-25 | 2014-07-07 | Lorus Therapeutics Inc. | Derivados de 2-indolil imidazo[4,5-d]fenantrolina y su uso en el tratamiento del cáncer |
US9957569B2 (en) * | 2005-09-12 | 2018-05-01 | The Regents Of The University Of Michigan | Recurrent gene fusions in prostate cancer |
WO2007033187A2 (en) | 2005-09-12 | 2007-03-22 | The Regents Of The University Of Michigan | Recurrent gene fusions in prostate cancer |
US20090018142A9 (en) * | 2006-05-02 | 2009-01-15 | Zhengping Zhuang | Use of phosphatases to treat tumors overexpressing N-CoR |
CN103233063A (zh) * | 2006-11-08 | 2013-08-07 | 密歇根大学董事会 | ***癌标志物spink1及其应用 |
EA023804B1 (ru) | 2007-02-06 | 2016-07-29 | Ликсте Байотекнолоджи, Инк. | Оксабициклогептаны, их получение и применение |
EP2162445B1 (en) | 2007-06-05 | 2013-11-27 | Takeda Pharmaceutical Company Limited | Heterobicyclic compounds as kinase inhibitors |
EP2171094B1 (en) * | 2007-07-06 | 2011-11-16 | The Regents of the University of Michigan | Mipol1-etv1 gene rearrangements |
CA2695004C (en) | 2007-07-17 | 2016-01-19 | Plexxikon, Inc. | Compounds and methods for kinase modulation, and indications therefor |
WO2009025358A1 (ja) | 2007-08-23 | 2009-02-26 | Takeda Pharmaceutical Company Limited | 複素環化合物およびその用途 |
WO2009028629A1 (ja) | 2007-08-29 | 2009-03-05 | Takeda Pharmaceutical Company Limited | 複素環化合物およびその用途 |
WO2009045440A1 (en) | 2007-10-01 | 2009-04-09 | Lixte Biotechnology Holdings, Inc. | Hdac inhibitors |
AU2009277086B2 (en) | 2008-08-01 | 2015-12-10 | Lixte Biotechnology, Inc. | Neuroprotective agents for the prevention and treatment of neurodegenerative diseases |
US8227473B2 (en) | 2008-08-01 | 2012-07-24 | Lixte Biotechnology, Inc. | Oxabicycloheptanes and oxabicycloheptenes, their preparation and use |
WO2010147612A1 (en) | 2009-06-18 | 2010-12-23 | Lixte Biotechnology, Inc. | Methods of modulating cell regulation by inhibiting p53 |
JP5579619B2 (ja) | 2008-12-01 | 2014-08-27 | 武田薬品工業株式会社 | 複素環化合物およびその用途 |
JO3101B1 (ar) | 2008-12-02 | 2017-09-20 | Takeda Pharmaceuticals Co | مشتقات بنزوثيازول كعوامل مضادة للسرطان |
CA2774349C (en) | 2009-09-17 | 2019-03-19 | The Regents Of The University Of Michigan | Recurrent gene fusions in prostate cancer |
CA2786424A1 (en) * | 2010-01-08 | 2011-07-14 | Ruga Corporation | Raf kinase inhibitors |
US8945556B2 (en) | 2010-11-19 | 2015-02-03 | The Regents Of The University Of Michigan | RAF gene fusions |
US8962650B2 (en) | 2011-04-18 | 2015-02-24 | Eisai R&D Management Co., Ltd. | Therapeutic agent for tumor |
WO2012145503A1 (en) | 2011-04-21 | 2012-10-26 | Novartis Ag | Pharmaceutical combinations |
WO2013109142A1 (en) | 2012-01-16 | 2013-07-25 | Stichting Het Nederlands Kanker Instituut | Combined pdk and mapk/erk pathway inhibition in neoplasia |
WO2014047330A1 (en) * | 2012-09-19 | 2014-03-27 | Jean-Michel Vernier | Novel raf kinase inhibitors |
US9309247B2 (en) | 2013-03-20 | 2016-04-12 | Lorus Therapeutics Inc. | 2-substituted imidazo[4,5-D]phenanthroline derivatives and their use in the treatment of cancer |
CA2909160C (en) | 2013-04-09 | 2021-05-25 | Lixte Biotechnology, Inc. | Formulations of oxabicycloheptanes and oxabicycloheptenes |
WO2015041534A1 (en) | 2013-09-20 | 2015-03-26 | Stichting Het Nederlands Kanker Instituut | P90rsk in combination with raf/erk/mek |
WO2015041533A1 (en) | 2013-09-20 | 2015-03-26 | Stichting Het Nederlands Kanker Instituut | Rock in combination with mapk-pathway |
JP6946000B2 (ja) | 2013-10-04 | 2021-10-06 | アプトース バイオサイエンシーズ, インコーポレイテッド | がんの治療用組成物及び方法 |
CN111417395A (zh) | 2017-10-30 | 2020-07-14 | 艾普托斯生物科学公司 | 用于治疗癌症的芳基咪唑 |
WO2022249192A1 (en) * | 2021-05-27 | 2022-12-01 | Ramot At Tel-Aviv University Ltd. | Broad-spectrum metastasis suppressing compounds and therapeutic uses thereof in human tumors |
Family Cites Families (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5236917A (en) | 1989-05-04 | 1993-08-17 | Sterling Winthrop Inc. | Saccharin derivatives useful as proteolytic enzyme inhibitors and compositions and method of use thereof |
ZA945363B (en) | 1993-07-21 | 1995-03-14 | Smithkline Beecham Corp | Novel compounds |
US5620999A (en) | 1994-07-28 | 1997-04-15 | Weier; Richard M. | Benzenesulfonamide subtituted imidazolyl compounds for the treatment of inflammation |
US5514505A (en) | 1995-05-15 | 1996-05-07 | Xerox Corporation | Method for obtaining improved image contrast in migration imaging members |
AU6269496A (en) | 1995-06-12 | 1997-01-09 | G.D. Searle & Co. | Combination of a cyclooxygenase-2 inhibitor and a leukotrien e b4 receptor antagonist for the treatment of infla mmations |
US5717100A (en) | 1995-10-06 | 1998-02-10 | Merck & Co., Inc. | Substituted imidazoles having anti-cancer and cytokine inhibitory activity |
GB2306108A (en) | 1995-10-13 | 1997-04-30 | Merck & Co Inc | Treatment of Raf-mediated cancers with imidazole derivatives |
JP2000504023A (ja) | 1996-04-03 | 2000-04-04 | メルク エンド カンパニー インコーポレーテッド | 癌治療方法 |
JP3418624B2 (ja) | 1996-06-10 | 2003-06-23 | メルク エンド カンパニー インコーポレーテッド | サイトカイン阻害活性を有する置換イミダゾール類 |
EP0915825B1 (en) | 1996-06-21 | 2004-05-06 | Allergan, Inc. | Substituted tetrahydronaphthalene and dihydronaphthalene derivatives having retinoid and/or retinoid antagonist-like biological activity |
TWI235060B (en) | 1996-10-15 | 2005-07-01 | Searle & Co | Pharmaceutical compositions comprising substituted pyrazolyl benzenesulfonamide derivatives for use in treating or preventing an epithelial cell-derived neoplasia |
ATE325118T1 (de) | 1996-10-30 | 2006-06-15 | Schering Corp | Piperazinoderivate als neurokinin-antagonisten |
EP1027050B1 (en) | 1997-10-27 | 2004-01-14 | Takeda Chemical Industries, Ltd. | 1,3-thiazoles as adenosine a3 receptor antagonists for the treatment of allergy, asthma and diabetes |
KR20010032102A (ko) | 1997-11-14 | 2001-04-16 | 가와무라 요시부미 | 피리딜피롤 유도체 |
US6482518B1 (en) | 1998-07-30 | 2002-11-19 | Point Biomedical Corporation | Excipient for the lyophilization of aqueous suspensions of microparticles |
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Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103159736A (zh) * | 2011-12-10 | 2013-06-19 | 通化四环医药有限公司 | 取代的吡唑激酶抑制剂 |
CN103159735A (zh) * | 2011-12-10 | 2013-06-19 | 通化四环医药有限公司 | 取代的咪唑激酶抑制剂 |
CN103159736B (zh) * | 2011-12-10 | 2015-05-13 | 通化济达医药有限公司 | 取代的吡唑激酶抑制剂 |
CN103159735B (zh) * | 2011-12-10 | 2015-12-09 | 通化济达医药有限公司 | 取代的咪唑激酶抑制剂 |
CN108484587A (zh) * | 2018-06-03 | 2018-09-04 | 刘思良 | 一种Raf激酶抑制剂及其在癌症治疗中的应用 |
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BR0114023A (pt) | 2004-02-03 |
WO2002024680A1 (en) | 2002-03-28 |
ATE300529T1 (de) | 2005-08-15 |
KR20030030027A (ko) | 2003-04-16 |
JP2004509882A (ja) | 2004-04-02 |
AU2001287901A1 (en) | 2002-04-02 |
IL154949A0 (en) | 2003-10-31 |
NO20031270D0 (no) | 2003-03-19 |
US20040038964A1 (en) | 2004-02-26 |
DE60112312D1 (de) | 2005-09-01 |
HUP0301181A2 (en) | 2007-02-28 |
ES2242767T3 (es) | 2005-11-16 |
NO20031270L (no) | 2003-05-19 |
CZ2003793A3 (cs) | 2004-04-14 |
DE60112312T2 (de) | 2005-12-29 |
EP1318992B1 (en) | 2005-07-27 |
EP1318992A1 (en) | 2003-06-18 |
CY1105251T1 (el) | 2010-03-03 |
PT1318992E (pt) | 2005-11-30 |
US7199137B2 (en) | 2007-04-03 |
CA2423154A1 (en) | 2002-03-28 |
PL361397A1 (en) | 2004-10-04 |
MXPA03002449A (es) | 2003-06-19 |
DK1318992T3 (da) | 2005-11-21 |
US20070135433A1 (en) | 2007-06-14 |
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