CN102480966B - 融合的杂环化合物及其用途 - Google Patents
融合的杂环化合物及其用途 Download PDFInfo
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- CN102480966B CN102480966B CN201080031345.3A CN201080031345A CN102480966B CN 102480966 B CN102480966 B CN 102480966B CN 201080031345 A CN201080031345 A CN 201080031345A CN 102480966 B CN102480966 B CN 102480966B
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- alkyl
- aryl
- heteroaryl
- heterocycle
- compound
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- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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Abstract
本申请涉及治疗性有机化合物;包含有效量的治疗性有机化合物的组合物;以及用于治疗和预防疾病的方法,所述方法包括向有需要的受试者施用有效量的治疗性有机化合物。
Description
相关申请
本申请要求2009年6月12日递交的美国临时申请号61/186,584的优先权。此专利申请的全部内容在此通过引用而并入。
背景技术
根据美国癌症协会所收集的数据,2008年美国有超过1百43万人被诊断患有癌症。虽然更早的诊断和改善的治疗允许了五年存活率的适度增加,自1950年以来,由于同一时期中数种癌症增加的发病率,总体死亡率/100,000人仅下降了5%(SEER Cancer Statistics Review1975-2004,NCI“55-Year Trends in U.S.Cancer Death Rates”)。
面对这种持续的医疗需求,针对癌细胞增殖和存活的机制进行的研究暗示了蛋白激酶的失调。因此,调节或抑制激酶活性的方法(包括使用小分子试剂)代表肿瘤学药物开发中有前景的方向。
因此,仍需要抑制一种或多种蛋白激酶活性的化合物,因为可期望它们在癌症的治疗中是有用的。
发明概述
本发明提供了化合物、包含所述化合物的药物组合物以及使用所述化合物来治疗或预防与异常或失调的激酶活性相关的疾病或病症的方法,所述疾病或病症特别是涉及Abl,BCR-Abl,c-kit,PDGFR和Src激酶的异常活化的疾病或病症。此类疾病包括,例如癌症,如胰腺癌、非小细胞肺癌、胃肠道基质瘤或慢性骨髓性白血病。
因此,一方面,本申请提供了式I的化合物。在一个实施方式中,式I是被表示为式II。
另一方面,本申请提供了式III的化合物。
另一方面,本申请提供了治疗癌症的方法,所述方法包括向有需要的受试者施用式I的化合物。所述癌症可选自:多发性骨髓瘤、慢性骨髓性白血病、胰腺癌、非小细胞肺癌、肺癌、乳腺癌、结肠癌、卵巢癌、前列腺癌、恶性黑色素瘤、非黑色素瘤皮肤癌、胃肠道基质瘤、血液肿瘤、血液恶性疾病、儿童白血病、儿童淋巴瘤、多发性骨髓瘤、霍奇金病、淋巴细胞起源的淋巴瘤、皮肤起源的淋巴瘤、急性白血病、慢性白血病、急性淋巴细胞白血病,急性髓细胞白血病、慢性髓细胞白血病、浆细胞肿瘤、淋巴肿瘤以及与AIDS相关的癌症。在另一个实施方式中,所述癌症为胰腺癌或非小细胞肺癌。在又一个实施方式中,所述癌症为胃肠道基质瘤或慢性骨髓性白血病。在另一个实施方式中,所述癌症为急性髓细胞白血病。所述癌症可以是对用格列卫或伊马替尼进行的治疗有抵抗性的,其中治疗抗性可以是由于Abl激酶、BCR-Abl激酶结构域、c-kit激酶、Src激酶或PDGFR激酶中的一个或多个点突变。
另一方面,本申请提供了式I的化合物用于制备药物的用途,所述药物用于治疗受试者中的癌症。
另一方面,本申请提供了式III的化合物用于制备药物的用途,所述药物用于治疗受试者中的癌症。
又一方面,本申请提供了抑制激酶的活性的方法,所述方法包括利用式I的化合物。在一个实施方式中,所述激酶选自:Abl,Abl(T315I),BCR-Abl,BRAF,CDK11,CDK5,CDK2,CDK3,CDK7,DDR1,FLT1,FLT3,FLT4,HIPK1,kit,LOK,p38-gamma,PDGFRA,PDGFRB或Src,包括利用式I的化合物。
又一方面,本申请提供了抑制激酶的活性的方法,所述方法包括利用式III的化合物。在一个实施方式中,所述激酶选自:Abl,Abl(T315I),BCR-Abl,BRAF,CDK11,CDK5,CDK2,CDK3,CDK7,DDR1,FLT1,FLT3,FLT4,HIPK1,kit,LOK,p38-gamma,PDGFRA,PDGFRB或Src,包括利用式III的化合物。
另一方面,本申请提供了抑制Abl激酶,BCR-Abl激酶,c-kit激酶,PDGFRA或PDGFRB激酶,或者Src激酶的活性的方法,所述方法包括利用式I的化合物。在又一个实施方式中,本申请提供了治疗受试者中的疾病的方法,其中疾病病因或进展至少部分地是由Abl激酶,BCR-Abl激酶,c-kit激酶,Src激酶或PDGFR激酶的活性所介导的,所述方法包括向受试者施用式I的化合物。在另一个实施方式中,本申请提供了治疗癌症的方法,所述方法包括向有需要的受试者施用式I的化合物,与药学上有效量的其它抗癌试剂相组合。所述其它抗癌试剂可以是伊马替尼或尼罗替尼。
另一方面,本申请提供了抑制Abl激酶,BCR-Abl激酶,c-kit激酶,PDGFRA或PDGFRB激酶,或者Src激酶的活性的方法,所述方法包括利用式III的化合物。在另一个实施方式中,本申请提供了治疗受试者中的疾病的方法,其中疾病病因或进展至少部分地是由Abl激酶,BCR-Abl激酶,c-kit激酶,Src激酶,或PDGFR激酶的活性介导的,所述方法包括向受试者施用式III的化合物。在另一个实施方式中,本申请提供了治疗癌症的方法,所述方法包括向有需要的受试者施用式III的化合物,与药学上有效量的其它抗癌试剂相组合。所述其它抗癌试剂可以是伊马替尼或尼罗替尼。
另一方面,本申请提供了抑制FLT3激酶的活性的方法,所述方法包括利用式III的化合物。在另一个实施方式中,本申请提供了治疗受试者中的疾病的方法,其中疾病病因或进展至少部分地是由FLT3激酶的活性介导的,所述方法包括向受试者施用式III的化合物。在另一个实施方式中,本申请提供了治疗癌症的方法,所述方法包括向有需要的受试者施用式III的化合物,与药学上有效量的其它抗癌试剂相组合。
附图说明
图1A显示了化合物2(表A)的化学结构。图1B显示了化合物2的激酶选择性。图1C显示了化合物2与Src激酶结构域的晶体结构,其显示出ATP-结合位点。
发明详述
本发明的化合物
本发明涉及化合物、其中间体及其衍生物,以及含有所述化合物的药物组合物,用于治疗蛋白激酶相关的病症。本发明的化合物或其组合物可用作激酶c-Abl,c-kit,BCR-Abl,PDGFR及其组合的抑制剂。此外,本发明的化合物或其组合物可被用于治疗癌症,例如胰腺癌,非小细胞肺癌,胃肠道基质瘤或慢性骨髓性白血病。本发明还涉及使用本发明的化合物或药物组合物与其它的抗癌试剂相组合而抑制细胞中蛋白激酶活性的方法,或用于治疗、预防或减轻癌症的一种或多种症状的方法。
一方面,本发明提供式I的化合物及其药学上可接受的盐、对映异构体、立体异构体、旋转异构体、互变异购体、非对映异构体或外消旋体;
其中,Q为CH或N;
R1为H,C(O)-C3-6-环烷基,芳基,杂芳基,C(O)N(H)-杂芳基,C(O)-杂芳基,C(O)-杂环,C(O)-芳基,C(O)-C1-6-烷基,CO2-C1-6-烷基,C3-6-环烷基或C(O)-C1-6-烷基-杂环,其中所述芳基或杂芳基可以是经取代的或未取代的;
R2为H,C1-6-烷基,C1-6-烷氧基或卤素;
R3为H,C(O)-N(H)-芳基,C(O)-N(H)-C1-6-烷基-杂环,C(O)-N(H)-C1-6-烷基-杂芳基,其中所述芳基,杂芳基或杂环可以是经取代的或未取代的;以及
R4为H,C(O)N(H)-芳基,N(H)C(O)N(H)-芳基,C(O)N(H)-C1-6-烷氧基,C(O)-N(H)-C3-6-环烷基,C(O)N(H)-C1-6-烷基-杂环,CO2-C1-6-烷基,CO2H,C(O)N(H)-C1-6-烷基-杂芳基,N(H)CO2-C1-6-烷基,NH2,N(H)C(O)芳基或N(H)C(O)N(H)-C1-6-烷基-杂环,其中所述芳基,杂芳基或杂环可以是经取代的或未取代的,并且其中R3和R4之一不是H。
在式I的一个实施方式中,R1、R3和R4的芳基、杂芳基和杂环基团可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-杂环,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;
其中取代基芳基,杂芳基和杂环基团可进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次。
在另一个实施方式中,R1、R3和R4的芳基、杂芳基和杂环基团可任选地独立地用C1-6-烷基,C1-6-烷氧基,SO2-杂环,C1-6-烷基-杂环,杂环,CF3或杂芳基取代一次或多次;
其中取代基杂环和杂芳基可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
在又一个式I的实施方式中,R1为H,C(O)-C3-6-环烷基,嘧啶基,C(O)N(H)-哌啶基,C(O)-哌啶基,C(O)-C1-6-烷基,C3-6-环烷基,吡啶基,苯基,C(O)-苯基,C(O)-C1-6-烷基-哌嗪基或C(O)-噁唑烷酮,其中R1的嘧啶基,哌啶基,吡啶基和苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;并且其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
在式I的另一个实施方式中,R3为H,C(O)-N(H)-苯基,C(O)-N(H)-(CH2)2-吗啉基,C(O)-N(H)-C1-6-烷基-吗啉基或C(O)-N(H)-C1-6-烷基-咪唑,其中R3的吗啉基,咪唑和苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次,并且其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
在式I的另一个实施方式中,R4为H,C(O)N(H)Ph,N(H)C(O)N(H)Ph,C(O)N(H)-C1-6-烷氧基,C(O)-N(H)-C3-6-环烷基,C(O)N(H)-C1-6-烷基-吗啉基,C(O)N(H)(CH2)3-吗啉基,CO2-C1-6-烷基,CO2H,C(O)-N(H)-C1-6-烷基-咪唑,N(H)CO2C1-6-烷基,NH2,N(H)C(O)Ph,N(H)C(O)N(H)Ph,N(H)C(O)N(H)-C1-6-烷基-吗啉基或N(H)C(O)Ph,其中R4的吗啉基,咪唑和苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次,其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
在另一个实施方式中,R3和R4中的至少一个不是H。在另一个实施方式中,R1为C(O)-C3-6-环烷基,嘧啶基,C(O)N(H)-哌啶基,C(O)-哌啶基,C(O)C1-6-烷基,H,C3-6-环烷基,吡啶基,Ph-SO2-哌嗪基,C(O)-PhCH2-哌嗪基-C1-6-烷基,C(O)-C1-6-烷基-哌嗪基,Ph-哌嗪基-C1-6-烷基,C(O)-噁唑烷酮-C1-6-烷基-吗啉基,其中嘧啶基任选地独立地用C1-6-烷基或哌嗪基取代一次或多次,其中哌嗪基任选地用C1-6-烷基-OH取代;并且其中C(O)-C1-6-烷基-哌嗪基任选地用C(O)C1-6-烷基取代。
在式I的另一个实施方式中,R3为H,C(O)-N(H)-Ph,C(O)-N(H)-C1-6-烷基-吗啉基,C(O)-N(H)-C1-6-烷基-吗啉基或C(O)-N(H)-C1-6-烷基-咪唑,其中Ph任选地用CF3,C1-6-烷基-哌嗪基-C1-6-烷基或咪唑-C1-6-烷基取代一次或多次。在另一个实施方式中,R4为H,C(O)N(H)Ph,N(H)C(O)N(H)Ph,C(O)N(H)C1-6-烷氧基,C(O)-N(H)-C3-6-环烷基,C(O)N(H)-C1-6-烷基-吗啉基,CO2-C1-6-烷基,CO2H,N(H)CO2-C1-6-烷基,NH2或N(H)C(O)N(H)-C1-6-烷基-吗啉基,其中Ph基团任选地独立地用CF3,C1-6-烷基-哌嗪基-C1-6-烷基,咪唑-C1-6-烷基,咪唑,四唑,吡唑,哌嗪基,C1-6-烷基-哌嗪基-C1-6-烷基,吗啉基,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-咪唑,C1-6-烷基-吗啉基,C1-6-烷基-哌啶基-OH,C1-6-烷基-哌嗪基-C1-6-烷基),咪唑-C1-6-烷基,哌嗪基-C1-6-烷基-OH或O-哌啶基-C1-6-烷基取代一次或多次。
在另一个实施方式中,R1为C(O)-环丙基,嘧啶基,C(O)N(H)-哌啶基,C(O)-哌啶基,C(O)CH3,H,环丙基,吡啶基,Ph-SO2-哌嗪基,C(O)-PhCH2-哌嗪基-CH2CH3,C(O)-(CH2)2-哌嗪基,Ph-哌嗪基-CH3或C(O)-噁唑烷酮-(CH2)3-吗啉基,其中嘧啶基用CH3和哌嗪基取代且该哌嗪基任选地用(CH2)2OH取代,并且其中C(O)-(CH2)2-哌嗪基的哌嗪基任选地用C(O)CH3取代;R2为H,CH3,F或Cl;R3为H,C(O)-N(H)-Ph,C(O)-N(H)-(CH2)2-吗啉基,C(O)-N(H)-(CH2)3-吗啉基或C(O)-N(H)-(CH2)3-咪唑,其中Ph用CF3和CH2-哌嗪基-CH2CH3取代、或者用CF3和咪唑-CH3取代;且R4为H,C(O)N(H)Ph-CF3,N(H)C(O)N(H)Ph(CF3)(CH2-哌嗪基-CH2CH3),C(O)N(H)Ph(CF3)(CH2-哌嗪基-CH2CH3),C(O)N(H)OCH3,C(O)N(H)Ph(CF3)(咪唑-CH3),C(O)-N(H)-环丙基,C(O)N(H)(CH2)2-吗啉基,C(O)N(H)(CH2)3-吗啉基,CO2CH2CH3,C(O)N(H)Ph-咪唑,C(O)N(H)Ph-四唑,C(O)N(H)Ph-吡唑,C(O)N(H)Ph(CF3)(哌嗪基),CO2H,C(O)N(H)Ph-CH2-哌嗪基-CH2CH3,C(O)-N(H)Ph-吗啉基,C(O)-N(H)Ph-t-丁基,-C(O)N(H)Ph(OCH2CH3)(吗啉基),C(O)N(H)Ph(OCH3)(吗啉基),C(O)N(H)Ph(OCH3)2,C(O)-N(H)-(CH2)3-咪唑,C(O)N(H)(CH2)2-吗啉基,N(H)CO2-t-丁基,NH2,N(H)C(O)Ph(CF3)(CH2-哌啶基-OH),N(H)C(O)Ph(CF3)(CH2-哌嗪基-CH2CH3),N(H)C(O)N(H)Ph(CF3)(咪唑-CH3),N(H)C(O)N(H)-(CH2)2-吗啉基,N(H)C(O)N(H)-(CH2)3-吗啉基,N(H)C(O)Ph(CF3)(哌嗪基-(CH2)2OH)或N(H)C(O)Ph(CF3)(O-哌啶基-CH3)。
在本发明的另一个实施方式中,式I由式II表示:
其中Q为CH;R1为C(O)-C3-6-环烷基,C(O)N(H)-杂芳基,C(O)-杂芳基,C(O)-芳基,C(O)-C1-6-烷基,CO2-C1-6-烷基,C3-6-环烷基或C(O)-C1-6-烷基-杂芳基;R2和R3为H;以及R4为C(O)N(H)-芳基,N(H)C(O)N(H)-芳基,C(O)N(H)-C1-6-烷氧基,C(O)-N(H)-C3-6-环烷基,C(O)N(H)-C1-6-烷基-杂环,CO2-C1-6-烷基,CO2H,C(O)N(H)-C1-6-烷基-杂芳基,N(H)CO2-C1-6-烷基,NH2,N(H)C(O)芳基或N(H)C(O)N(H)-C1-6-烷基-杂环,其中芳基,杂芳基或杂环基团可以是经取代的或未取代的。
在式II的一个实施方式中,R1为C(O)-C3-6-环烷基;Q为C(H);R2和R3为H;以及R4为C(O)N(H)Ph,其中Ph基团任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次,其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
在式II的另一个实施方式中,Ph任选地独立地用CF3,哌嗪基,C1-6-烷基-哌嗪基,C1-6-烷基-哌嗪基-C1-6-烷基,CH2CH3,咪唑或咪唑-C1-6-烷基取代一次或多次。
在式II的又一个实施方式中,R1为C(O)-C3-6-环烷基;Q为C(H);R2和R3为H;以及R4为C(O)N(H)Ph,其中Ph基团任选地独立地用CF3,C1-6-烷基-哌嗪基或咪唑取代一次或多次,并且其中取代基哌嗪基或咪唑任选地独立地用C1-6-烷基取代一次或多次。
在式II的又一个实施方式中,Ph任选地独立地用CF3,哌嗪基,C1-6-烷基-哌嗪基,C1-6-烷基-哌嗪基-C1-6-烷基,CH2CH3,咪唑或咪唑-C1-6-烷基取代一次或多次。
在另外的实施方式中,本发明包括式(III)的化合物:
其中G为CR10或N;
R1为H,C(O)-C3-6-环烷基,芳基,杂芳基,C(O)N(H)-杂芳基,C(O)-杂芳基,C(O)-杂环,C(O)-NH-杂环,C(O)-芳基,C(O)-C1-6-烷基,CO2-C1-6-烷基,C3-6-环烷基或C(O)-C1-6-烷基-杂环;
其中所述芳基,杂芳基和杂环基团可任选地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;并且
其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
R10为H或C1-3-烷基;
R12为H,C1-6-烷基,C1-6-烷氧基或卤素;
R13为H,C(O)-N(R28)-芳基,C(O)-N(R29)-C1-6-烷基-杂环,C(O)-N(R30)-C1-6-烷基-杂芳基,其中所述芳基,杂芳基或杂环基团任选地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-杂环,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素中的一个或多个取代;
其中取代基芳基,杂芳基和杂环基团可进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;以及
R14为H,C(O)NR15-芳基,NR16C(O)NR17-芳基,C(O)NR18-C1-6-烷氧基,C(O)-NR19-C3-6-环烷基,C(O)NR20-C1-6-烷基-杂环,CO2-C1-6-烷基,CO2H,C(O)NR21-C1-6-烷基-杂芳基,NR22CO2-C1-6-烷基,NR23R24,NR25C(O)芳基或NR26C(O)NR27-C1-6-烷基-杂环,其中所述芳基,杂芳基或杂环基团任选地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-杂环,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素中的一个或多个取代;
其中取代基芳基,杂芳基和杂环基团可进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次,以及
其中R13和R14之一不是H;
R15,R16,R17,R18,R19,R20,R21,R22,R23,R24,R25,R26,R27,R28,R29,和R30独立地为C1-6烷基,卤素或H。
在式III的一个实施方式中,R1为H,C(O)-C3-6-环烷基,嘧啶基,C(O)N(H)-哌啶基,C(O)-哌啶基,C(O)-C1-6-烷基,C3-6-环烷基,吡啶基,苯基,C(O)-苯基,C(O)-C1-6-烷基-哌嗪基或C(O)-噁唑烷酮,其中R1的嘧啶基,哌啶基,吡啶基和苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;并且其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
在式III的另一个实施方式中,R13为H,C(O)-N(R28)-苯基,C(O)-N(R29)-(CH2)2-吗啉基,C(O)-N(R30)-C1-6-烷基-吗啉基或C(O)-N(R30)-C1-6-烷基-咪唑,其中R13的吗啉基,咪唑和苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次并且其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
在式III的另一个实施方式中,R14为H,C(O)N(R15)Ph,N(R16)C(O)N(R17)Ph,C(O)N(R18)-C1-6-烷氧基,C(O)-N(R19)-C3-6-环烷基,C(O)N(R20)-C1-6-烷基-吗啉基,C(O)N(R20)(CH2)3-吗啉基,CO2-C1-6-烷基,CO2H,C(O)-N(R21)-C1-6-烷基-咪唑,N(R22)CO2C1-6-烷基,N R23R24,N(R25)C(O)Ph,NR26C(O)NR27-C1-6-烷基-吗啉基,其中R14的吗啉基,咪唑,和苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次,其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
在式III的另一个实施方式中,R13和R14中的至少一个不是H。
在另一个实施方式中,R1为C(O)-C3-6-环烷基,嘧啶基,C(O)N(H)-哌啶基,C(O)-哌啶基,C(O)C1-6-烷基,H,C3-6-环烷基,吡啶基,Ph-SO2-哌嗪基,C(O)-PhCH2-哌嗪基-C1-6-烷基,C(O)-C1-6-烷基-哌嗪基,Ph-哌嗪基-C1-6-烷基,C(O)-噁唑烷酮-C1-6-烷基-吗啉基,其中所述嘧啶基任选地独立地用C1-6-烷基或哌嗪基取代一次或多次,其中哌嗪基任选地用C1-6-烷基-OH取代;并且其中C(O)-C1-6-烷基-哌嗪基任选地用C(O)C1-6-烷基取代。
在式III的另一个实施方式中,R13为H,C(O)-N(H)-Ph,C(O)-N(H)-C1-6-烷基-吗啉基,C(O)-N(H)-C1-6-烷基-吗啉基或C(O)-N(H)-C1-6-烷基-咪唑,其中Ph任选地用CF3,C1-6-烷基-哌嗪基-C1-6-烷基或咪唑-C1-6-烷基取代一次或多次。在另一个实施方式中,R14为H,C(O)N(R15)Ph,N(R16)C(O)N(R17)Ph,C(O)N(R18)-C1-6-烷氧基,C(O)-N(R19)-C3-6-环烷基,C(O)N(R20)-C1-6-烷基-吗啉基,CO2-C1-6-烷基,CO2H,N(R22)CO2C1-6-烷基,N R23R24,N(R25)C(O)Ph,NR26C(O)NR27-C1-6-烷基-吗啉基,其中Ph基团任选地独立地用CF3,C1-6-烷基-哌嗪基-C1-6-烷基,咪唑-C1-6-烷基,咪唑,四唑,吡唑,哌嗪基,C1-6-烷基-哌嗪基-C1-6-烷基,吗啉基,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-咪唑,C1-6-烷基-吗啉基,C1-6-烷基-哌啶基-OH,C1-6-烷基-哌嗪基-C1-6-烷基),咪唑-C1-6-烷基,哌嗪基-C1-6-烷基-OH或O-哌啶基-C1-6-烷基取代一次或多次。
在式III的又一个实施方式中,R1为C(O)-环丙基,嘧啶基,C(O)N(H)-哌啶基,C(O)-哌啶基,C(O)CH3,H,环丙基,吡啶基,Ph-SO2-哌嗪基,C(O)-PhCH2-哌嗪基-CH2CH3,C(O)-(CH2)2-哌嗪基,Ph-哌嗪基-CH3或C(O)-噁唑烷酮-(CH2)3-吗啉基,其中所述嘧啶基用CH3和哌嗪基取代且该哌嗪基任选地用(CH2)2OH取代,且其中C(O)-(CH2)2-哌嗪基的哌嗪基任选地用C(O)CH3取代;R12为H,CH3,F或Cl;R13为H,C(O)-N(H)-Ph,C(O)-N(H)-(CH2)2-吗啉基,C(O)-N(H)-(CH2)3-吗啉基或C(O)-N(H)-(CH2)3-咪唑,其中Ph用CF3和CH2-哌嗪基-CH2CH3取代、或者用CF3和咪唑-CH3取代;以及R14为H,C(O)N(H)Ph-CF3,N(H)C(O)N(H)Ph(CF3)(CH2-哌嗪基-CH2CH3),C(O)N(H)Ph(CF3)(CH2-哌嗪基-CH2CH3),C(O)N(H)OCH3,C(O)N(H)Ph(CF3)(咪唑-CH3),C(O)-N(H)-环丙基,C(O)N(H)(CH2)2-吗啉基,C(O)N(H)(CH2)3-吗啉基,CO2CH2CH3,C(O)N(H)Ph-咪唑,C(O)N(H)Ph-四唑,C(O)N(H)Ph-吡唑,C(O)N(H)Ph(CF3)(哌嗪基),CO2H,C(O)N(H)Ph-CH2-哌嗪基-CH2CH3,C(O)-N(H)Ph-吗啉基,C(O)-N(H)Ph-t-丁基,-C(O)N(H)Ph(OCH2CH3)(吗啉基),C(O)N(H)Ph(OCH3)(吗啉基),C(O)N(H)Ph(OCH3)2,C(O)-N(H)-(CH2)3-咪唑,C(O)N(H)(CH2)2-吗啉基,N(H)CO2-t-丁基,NH2,N(H)C(O)Ph(CF3)(CH2-哌啶基-OH),N(H)C(O)Ph(CF3)(CH2-哌嗪基-CH2CH3),N(H)C(O)N(H)Ph(CF3)(咪唑-CH3),N(H)C(O)N(H)-(CH2)2-吗啉基,N(H)C(O)N(H)-(CH2)3-吗啉基,N(H)C(O)Ph(CF3)(哌嗪基-(CH2)2OH)或N(H)C(O)Ph(CF3)(O-哌啶基-CH3)。
式I的优选实施方式等同于式III的优选实施方式(包括其药学上可接受的盐,以及其对映异构体,立体异构体,旋转异构体,互变异构体,非对映异构体,阻转异构体或外消旋体)并且在下文显示在表A中,而且也被认为是“本发明的化合物”。在本文中,本发明的化合物也称为“蛋白激酶抑制剂”。
表A
治疗方法
本发明的化合物可用于治疗蛋白激酶相关病症。
如本申请中所使用的,术语“蛋白激酶相关病症”包括与蛋白激酶的活性相关的病症和状态(例如疾病状态)。蛋白激酶相关病症的非限制性实例包括异常细胞增殖,包括蛋白激酶相关癌症、病毒感染、真菌感染、自体免疫疾病和神经退行性病症。
蛋白激酶相关病症的非限制性实例包括增殖性疾病,例如病毒感染、自体免疫疾病、真菌疾病、癌症、银屑病、与动脉粥样硬化相关的血管平滑细胞增殖、肺纤维化、关节炎肾小球性肾炎、慢性炎症、神经退行性病症例如阿尔茨海默病,以及手术后狭窄和再狭窄。蛋白激酶相关病症还包括与异常细胞增殖相关的疾病,包括但不限于:头颈、乳腺、卵巢、宫颈、前列腺、睾丸、食道、胃、皮肤、肺、骨、结肠、胰腺、甲状腺、胆汁通道、口腔和咽(口的)、喉、唇、舌、嘴、小肠、结肠-直肠、大肠、直肠、前列腺、脑和中枢神经系统的癌症、成胶质细胞瘤、成神经细胞瘤、角化棘皮瘤、鳞状细胞癌、大细胞癌、腺癌、腺瘤、滤泡癌、未分化的癌、乳头状癌、精原细胞癌、黑色素瘤、肉瘤、膀胱癌、肝癌、肾癌、骨髓病症、淋巴病症、霍奇金氏、毛细胞和白血病。
蛋白激酶相关病症还包括与凋亡相关的疾病,包括但不限于癌症、病毒感染、自体免疫疾病和神经退行性病症。
蛋白激酶相关癌症的实例包括癌、淋巴系的造血肿瘤、髓系的造血肿瘤、间叶细胞来源的肿瘤、中枢和外周神经系统的肿瘤、黑色素瘤、精原细胞瘤、畸胎癌、骨肉瘤、着色性干皮病(xenoderoma pigmentosum)、角化棘皮瘤、甲状腺滤泡癌和卡波西肉瘤。
此外,蛋白激酶相关病症的非限制性实例包括肿瘤血管生成和转移。蛋白激酶相关病症的非限制性实例还包括与动脉粥样硬化相关的血管平滑细胞增殖、手术后血管狭窄和再狭窄以及子宫内膜异位。
蛋白激酶相关病症的非限制性实例包括有需要的患者中的病毒感染,其中所述病毒感染包括但不限于HIV、人乳头状瘤病毒、疱疹病毒、痘病毒、EB病毒、辛德比斯病毒和腺病毒。
蛋白激酶相关病症的其它非限制性实例包括与感染性物质相关的那些,所述感染性物质包括酵母、真菌、原生动物寄生虫(例如恶性疟原虫)以及DNA和RNA病毒。
本发明的化合物可用于治疗癌症,其中所述癌症选自多发性骨髓瘤,慢性骨髓性白血病,胰腺癌,非小细胞肺癌,肺癌,乳腺癌,结肠癌,卵巢癌,前列腺癌,恶性黑色素瘤,非黑色素瘤皮肤癌,胃肠道基质瘤,血液肿瘤,血液恶性疾病,儿童白血病,儿童淋巴瘤,多发性骨髓瘤,霍奇金氏病,淋巴细胞起源的淋巴瘤,皮肤起源的淋巴瘤,急性白血病,慢性白血病,急性淋巴细胞白血病,急性髓细胞白血病,慢性髓细胞白血病,浆细胞肿瘤,淋巴肿瘤和与AIDS相关的癌症。
在另一个实施方式中,本发明的化合物用于调节蛋白激酶的活性,包括但不限于选自下组的蛋白激酶:Abl,ATK,BCR-Abl,Blk,Brk,Btk,BRAF,c-fms,e-kit,c-met,c-src,CDK,cRafl,CSFIR,CSK,EGFR,ErbB2,ErbB3,ErbB4,ERK,DDR-1,Fak,fes,FGFRI,FGFR2,FGFR3,FGFR4,FGFR5,Fgr,FLK-4,flt-1,flt-3,flt-4,Fps,Frk,Fyn,GSK,Gst-Flk1,Hck,Her-2,Her-4,HIPK-1,IGF-lR,INS-R,Jak,JNK,KDR,Lck,LOK,Lyn,MEK,p38,panHER,PDGFR,PLK,PKC,PYK2,Raf,Rho,ros,SRC,TRK,TYK2,UL97,VEGFR,Yes,Zap70,Aurora-A,GSK3-alpha,HIPK1,HIPK2,HIP3,IRAK1,JNK1,JNK2,JNK3,TRKB,CAMKII,CK1,CK2,RAF,GSK3Beta,MAPK1,MKK4,MKK7,MST2,NEK2,AAK1,PKCalpha,PKD,RET,RIPK2,ROCK-II和TIE2。
如本申请中所使用的,术语“调节(modulating)”或“调节(modulation)”是指改变蛋白激酶的催化活性。特别地,调节是指激活或抑制蛋白激酶的催化活性,这取决于蛋白激酶所暴露于的化合物或盐的浓度;或者更优选地,抑制蛋白激酶的催化活性。如本申请中所使用的,术语“催化活性”是指在蛋白激酶的影响下(直接的或间接的),酪氨酸、丝氨酸或苏氨酸的磷酸化速度。
激酶活性的药理学抑制剂被分为的三个主要类别是:(1)I型或“DFG-内”ATP竞争性抑制剂,其在ATP结合位点中直接与ATP竞争(即双重SRrc ABL抑制剂达沙替尼),(2)II型或“DFG-外”ATP竞争性抑制剂,其除了结合ATP结合位点外,还占据邻近的疏水性结合位点,所述疏水性结合位点只有当激酶为灭活的构型(即活化环被定向为将阻碍底物结合的构象)时才可接触到(即伊马替尼,尼罗替尼),和(3)非ATP竞争性抑制剂,其结合ATP结合位点外面的、影响激酶活性的位点(即GNF-2)。
第二代Abl抑制剂(例如达沙替尼和尼罗替尼)针对伊马替尼抗性白血病是高度有活性的。两种试剂针对Bcr-Abl都是比伊马替尼显著更有效的,并且针对许多伊马替尼抗性的Bcr-Abl突变体都是有活性的。然而,由于残基315处苏氨酸至异亮氨酸的突变(T315I,“守门者”位置),两种试剂都不能克服伊马替尼抗性。这一高度普遍并且伊马替尼高度抗性的突变位于Abl的核苷酸结合槽中央。达沙替尼和尼罗替尼都与T 315的侧链羟基形成氢键相互作用,所述T315的侧链羟基对这些化合物有抗性,这是由于异丁基侧链的直接空间侵入以及在ATP-槽的中央丧失氢键相互作用。
除了BCR-Abl T315I之外,在伊马替尼抗性疾病中起重要作用的其它守门者残基包括:c-kit-T670I,其与伊马替尼-抗性胃肠道基质瘤(特征在于早期转移和更短的无进展存活期)相关;此突变实质上修饰c-Kit的结合袋,并且只在伊马替尼疗法的选择压力下发生,PDGFRA-T674M/I其在FIP1LI-PDGFRA激酶结构域中被发现并在原发性嗜伊红性白血球增多症候群(HES)中产生伊马替尼抗性;和PDGFRB-T681M/I。
本发明的化合物为II型激酶抑制剂,其以适应各种大小的氨基酸侧链的方式穿过守门者位置。化合物2(表A)和Src的共结晶结构表明化合物2的确作为II型抑制剂结合(图1)。
上文列出的蛋白激酶可显示一个或多个点突变,包括但不限于铰链区域的突变,P-环的突变和A-环的突变。
在优选的实施方式中,所述蛋白激酶选自突变的或非突变的Abl,突变的或非突变的c-kit,突变的或非突变的BCR-Abl,突变的或非突变的PDGFR,突变的或非突变的Src及其任意组合。在特别优选的实施方式中,所述蛋白激酶选自突变的或非突变的c-kit,突变的或非突变的BCR-Abl,突变的或非突变的PDGFR和突变的或非突变的Src。
在一个实施方式中,本发明的化合物被表征为蛋白激酶的组合的抑制剂,例如BCR-Abl和/或c-kit和/或PDGFR。
在某些实施方式中,本发明的化合物用于蛋白激酶相关疾病,和/或作为任何一种或多种蛋白激酶的抑制剂。所想到的是用途可涉及抑制蛋白激酶的一种或多种同种型。
在一个实施方式中,本发明的化合物选择性地抑制FLT3激酶活性和带有突变体FLT3的白血病细胞的增殖、存活和细胞周期进程。
在另一个实施方式中,本发明的化合物选择性地抑制FLT3激酶活性和带有突变体FLT3的白血病细胞的增殖、存活和细胞周期进程,而对于带有野生型FLT3的细胞没有明显的影响。
治疗性激酶抑制剂(例如伊马替尼,达沙替尼和尼罗替尼)的效力通常与其对于一种或多种与特定疾病状态相关的激酶靶标的亲和力有关。点突变(其可自然地产生或在化学疗法的选择压力下产生)可降低化学治疗剂对于其激酶靶标的亲和力,从而赋予对这些治疗剂的抗性。
本发明的化合物可用于克服由于分子靶标中所获得的点突变而产生的药物抗性。
本发明的化合物也是突变或非突变形式的激酶Abl,BCR-Abl,c-kitPDGFR和Src的抑制剂,所述激酶牵涉与癌症(例如胰腺癌,非小细胞肺癌,胃肠道基质瘤或慢性骨髓性白血病)相关的某些疾病状态。BCR-Abl激活许多细胞周期控制蛋白和酶,加速细胞分裂并抑制DNA修复,因此造成基因组不稳定性和潜在地造成CML中的急性转化期。在大多数胃肠道基质瘤中观察到了c-kit的异常活化,而PDGFR的影响包括细胞增殖和血管生成。
不受理论的束缚,相信激酶Abl,BCR-Abl,c-kit,PDGFR和Src的抑制将促进凋亡、抑制癌细胞增殖以及抑制肿瘤生长。
本发明还包括治疗一种或多种癌症症状,所述癌症为例如胰腺癌,非小细胞肺癌,胃肠道基质瘤或慢性骨髓性白血病,以及治疗上文所述的蛋白激酶相关病症,但是本发明不欲被所述化合物实行其所欲的治疗疾病的功能的方式所限。本发明包括以允许治疗发生的任何方式治疗本文所述的疾病。
在某些实施方式中,本发明的化合物被单独使用或与其它治疗剂(例如伊马替尼,尼罗替尼或达沙替尼)组合使用。
在另一个实施方式中,本发明提供任何本发明的化合物的药物组合物。在相关的实施方式中,本发明提供任何本发明的化合物与药学上可接受的载体或赋形剂的药物组合物。在某些实施方式中,本发明包括所述化合物作为新颖的化学实体。
在其它的实施方式中,本发明提供抑制蛋白激酶活性的方法。所述方法包括使细胞与任何本发明的化合物接触。在相关的实施方式中,所述方法还提供所述化合物以有效选择性抑制蛋白激酶活性的量存在。
此外,本发明的方法包括向受试者施用有效量的本发明的蛋白激酶-调节化合物,例如式I,式II或式III、以及表A的蛋白激酶-调节化合物(包括其药学上可接受的盐,以及其对映异构体、立体异构体、旋转异构体、互变异构体、非对映异构体、阻转异构体或外消旋体)。
在某些实施方式中,本发明的化合物用于治疗癌症。在一个实施方式中,化合物2用于治疗癌症。在另一个实施方式中,化合物3用于治疗癌症。
在其它的实施方式中,本发明提供任何本发明的化合物用于制备药物的用途,所述药物用于治疗癌症。
在其它的实施方式中,本发明提供制备药物的方法,包括配制任何本发明的化合物用于治疗受试者。
本申请的一个实施方式提供了治疗胰腺癌的方法,包括向有需要的受试者施用化合物2,从而治疗胰腺癌。
本申请的另一个实施方式提供了治疗非小细胞肺癌的方法,包括向有需要的受试者施用化合物2,从而治疗非小细胞肺癌。
在另一个实施方式中,本申请提供了治疗胃肠道基质瘤的方法,包括向有需要的受试者施用化合物2,从而治疗胃肠道基质瘤。
在又一个实施方式中,本申请的实施方式提供了治疗慢性骨髓性白血病的方法,包括向有需要的受试者施用化合物2,从而治疗慢性骨髓性白血病。
在另一个实施方式中,本申请的实施方式提供了治疗急性髓性白血病的方法,包括向有需要的受试者施用化合物2,从而治疗急性髓性白血病。
本申请的另一个实施方式提供了治疗胰腺癌的方法,包括向有需要的受试者施用化合物3,从而治疗胰腺癌。
本申请的另一个实施方式提供了治疗非小细胞肺癌的方法,包括向有需要的受试者施用化合物3,从而治疗非小细胞肺癌。
在另一个实施方式中,本申请提供了治疗胃肠道基质瘤的方法,包括向有需要的受试者施用化合物3,从而治疗胃肠道基质瘤。
在另一个实施方式中,本申请的实施方式提供了治疗慢性骨髓性白血病的方法,包括向有需要的受试者施用化合物3,从而治疗慢性骨髓性白血病。
在另一个实施方式中,本申请的实施方式提供了治疗急性髓性白血病的方法,包括向有需要的受试者施用化合物3,从而治疗急性髓性白血病。
在某些实施方式中,本发明的化合物用作药物。在一个实施方式中,化合物2用作药物。在另一个实施方式中,化合物3用作药物。
一个实施方式,本申请提供了化合物2用于制备药物的用途,所述药物用于治疗有需要的受试者中的胰腺癌。
在另一个实施方式中,本申请提供了化合物2用于制备药物的用途,所述药物用于治疗有需要的受试者中的非小细胞肺癌。
在另一个实施方式中,本申请提供了化合物2用于制备药物的用途,所述药物用于治疗有需要的受试者中的胃肠道基质瘤。
在另一个实施方式中,本申请提供了化合物2用于制备药物的用途,所述药物用于治疗有需要的受试者中的慢性骨髓性白血病。
在一个实施方式中,本申请提供了化合物2用于制备药物的用途,所述药物用于治疗有需要的受试者中的急性髓性白血病。
另一个实施方式,本申请提供了化合物3用于制备药物的用途,所述药物用于治疗有需要的受试者中的胰腺癌。
在另一个实施方式中,本申请提供了化合物3用于制备药物的用途,所述药物用于治疗有需要的受试者中的非小细胞肺癌。
在另一个实施方式中,本申请提供了化合物3用于制备药物的用途,所述药物用于治疗有需要的受试者中的胃肠道基质瘤。
在另一个实施方式中,本申请提供了化合物3用于制备药物的用途,所述药物用于治疗有需要的受试者中的慢性骨髓性白血病。
在另一个实施方式中,本申请提供了化合物3用于制备药物的用途,所述药物用于治疗有需要的受试者中的急性髓性白血病。
定义
术语“治疗”,“治疗的(treated)”,“治疗(treating)”或“治疗(treatment)”包括与减少或缓和与被治疗的状态、病症或疾病相关的、或由其引起的至少一种症状。在某些实施方式中,治疗包括诱导蛋白激酶相关病症,随后激活本发明的化合物,其将转而减少或缓和与被治疗的蛋白激酶相关病症相关的、或由其引起的至少一种症状。例如,治疗可以是减少病症的一种或数种症状或完全根除病症。
术语“用途”如不另外述及,在适当和得当的时候,分别包括下列本发明的实施方式中的任意一种或多种:治疗蛋白激酶相关病症的用途;制备用于治疗这些疾病的药物组合物的用途,例如制备药物的用途;利用本发明的化合物来治疗这些疾病的方法;具有本发明的化合物的药物制备物用于治疗这些疾病;以及本发明的化合物,用于治疗这些疾病。特别地,优选利用本发明的化合物治疗的疾病选自癌症,例如胰腺癌,非小细胞肺癌,胃肠道基质瘤或慢性骨髓性白血病,或炎症,心脏肥大和HIV感染,以及依赖于蛋白激酶活性的那些疾病。术语“用途”还包括本文的组合物的实施方式,其充分地结合蛋白激酶以作为示踪物或标记物,从而当与荧光剂或标签偶联、或使得为放射性时,其可被用作研究试剂或者作为诊断剂或显像剂。
术语“受试者”意在包括生物体(例如原核生物和真核生物),其能够患有或患上与蛋白激酶的活性相关的疾病、病症或病况。受试者的实例包括哺乳动物(例如人、狗、母牛、马、猪、绵羊、山羊、猫、小鼠、兔子、大鼠和转基因的非人动物)。在某些实施方式中,受试者为人,例如患有癌症或处于患癌症的风险中或潜在能够患有癌症的人,所述癌症为例如胰腺癌,非小细胞肺癌,胃肠道基质瘤或慢性骨髓性白血病,或者炎症、心脏肥大、和HIV感染,以及本文所述的其它疾病或病况(例如,蛋白激酶相关病症)。在另一个实施方式中,所述受试者为细胞。
用语“蛋白激酶-调节化合物”,“蛋白激酶的调节剂”或“蛋白激酶抑制剂”是指调节(例如抑制或者改变)蛋白激酶活性的化合物。蛋白激酶-调节化合物的实例包括本发明的化合物,即式I以及表A的化合物(包括其药学上可接受的盐,以及其对映异构体、立体异构体、旋转异构体、互变异构体、非对映异构体、阻转异构体或外消旋体)。
如本申请中所使用的,术语“烷基”是指完全饱和的分支的或未分支的烃部分。优选地,烷基包含1至20个碳原子,更优选地1至16个碳原子,1至10个碳原子,1至7个碳原子,1至6个碳,1至4个碳,或1至3个碳原子。烷基的代表性实例包括但不限于甲基,乙基,正丙基,异丙基,正丁基,仲丁基,异丁基,叔丁基,正戊基,异戊基,新戊基,正己基,3-甲基己基,2,2-二甲基戊基,2,3-二甲基戊基,正庚基,正辛基,正壬基,正癸基等。此外,表述“Cx-Cy-烷基”,其中x为1-5且y为2-10表示特定范围的碳的特定烷基(直链或支链)。例如,表述C1-C4-烷基包括但不限于甲基,乙基,丙基,丁基,异丙基,叔丁基和异丁基。
术语“烯基”(单独的或在组合中)是指直链、环状或分支的烃残基,其包含至少一个烯键和所示数目的碳原子。优选的烯基具有至多8个,优选至多6个,特别优选至多4个碳原子。烯基的实例为乙烯基,1-丙烯基,2-丙烯基,异丙烯基,1-丁烯基,2-丁烯基,3-丁烯基,异丁烯基,1-环己烯基,1-环戊烯基。
术语“炔基”包括不饱和的脂肪族基团,其在长度上类似于上文所述的烷基,但是含有至少一个三键。例如,术语“炔基”包括直链炔基(例如乙炔基,丙炔基,丁炔基,戊炔基,己炔基,庚烯基,辛炔基,壬炔基,癸炔基等),支链炔基,和经环烷基或环烯基取代的炔基。术语炔基还包括这样的炔基:其包括替代烃主链的一个或多个碳的氧、氮、硫或磷原子。在某些实施方式中,直链或支链炔基在其主链中具有6个或更少的碳原子(例如,对于直链为C2-C6,对于支链为C3-C6)。术语C2-C6包括含有2-6个碳原子的炔基。
如本申请中所使用的,术语“环烷基”指饱和的或不饱和的3-12个碳原子(优选3-9或3-7个碳原子)的单环、二环或三环烃基。示例性的单环烃基包括但不限于环丙基,环丁基,环戊基,环戊烯基,环己基和环己烯基等。示例性的二环烃基包括龙脑基,吲哚基,六氢化吲哚基,四氢化萘基,十氢化萘基,二环[2.1.1]己基,二环[2.2.1]庚基,二环[2.2.1]庚烯基,6,6-二甲基二环[3.1.1]庚基,2,6,6-三甲基二环[3.1.1]庚基,二环[2.2.2]辛基等。示例性的三环烃基包括金刚烷基等。
术语“环烯基”是指含有1至3个环且每环含有4至8个碳的、部分不饱和的环烃基。示例性的基团包括环丁烯基,环戊烯基和环己烯基。术语“环烯基”还包括二环和三环的基团,其中至少所述环之一是部分不饱和的含碳的环,且第二或第三个环可以是碳环的或杂环的,条件是连接点是至环烯基。
“烷氧基”是指这样的烷基:其具有1至10个碳原子,所述碳原子通过氧原子连接至分子的其余部分。优选的是具有1-8个碳原子的烷氧基。烷氧基的烷基部分可以是线性的,环状的或分支的,或其组合。烷氧基的实例包括甲氧基、乙氧基,异丙氧基,丁氧基,环戊氧基等。烷氧基还可由下式表示:-ORi,其中Ri为烷氧基的“烷基部分”。
术语“杂烷基”(其本身或与另一个术语相组合),除非另有所述,是指稳定的直链或支链,或其组合,其由所述数目的碳原子和1-5个杂原子(更优选1-3个杂原子)组成,所述杂原子选自O,N,Si和S,并且其中氮和硫原子可任选地被氧化,且氮杂原子可任选地被季铵化。杂烷基通过碳原子或杂原子连接于分子的其余部分。
术语“烷基羰基”是指具有式-C(O)-Rii的基团,其中Rii为如上文所定义的烷基并且其中碳原子的总数目是指组合的烷基和羰基部分。“烷基羰基”可以通过烷基连接至分子的其余部分(即-烷基-C(O)-Rii)。
术语“烷氧基羰基”是指具有式-C(O)O-Riii的基团,其中Riii为如上文中所定义的烷基并且其中碳原子的总数目是指组合的烷基和羰基部分。“烷氧基羰基”可以通过烷基连接至分子的其余部分(即-烷基-C(O)O-Riii)。
术语“杂烷基羰基”是指具有式-C(O)Riv的基团,其中Riv为如上文所定义的杂烷基并且其中碳原子的总数目是指组合的烷基和羰基部分。“杂烷基羰基”可以通过烷基或杂烷基连接至分子的其余部分(即-烷基-C(O)O-Riv或-杂烷基-C(O)O-Riv)。
术语“芳基”包括芳香单环的或多环的(例如三环的、二环的)烃环系统,其仅由氢和碳组成并且含有6-19个碳原子,或6-10个碳原子,其中所述环系统可以是部分饱和的。芳基包括但不限于例如下列基团:苯基,甲苯基,二甲苯基,蒽基,萘基和菲基。芳基也可以与非芳香的脂环或杂环融合或桥接以形成多环(例如萘满)。
如本申请中所使用的,术语“杂芳基”代表稳定的单环或双环,每个环中有至多7个原子,其中至少一个环是芳香的并且含有1至4个选自O,N和S的杂原子。此定义范围内的杂芳基包括但不限于:吖啶基,咔唑基,噌啉基,喹喔啉基,吡唑基,吲哚基,苯并三唑,呋喃基,噻吩基,苯并噻吩基,苯并呋喃基,喹啉基,异喹啉基,噁唑基,异噁唑基,吲哚基,吡嗪基,哒嗪基,吡啶基,嘧啶基,吡咯基,四氢喹啉。如下文的杂环所定义的,“杂芳基”也理解为包括任何含氮杂芳基的氮氧化物衍生物。在杂芳基取代基为二环且一个环是非芳香的或不含有杂原子的情形中,所理解的是连接是分别通过芳香环或通过含有杂原子的环。
术语“杂环”或“杂环基”是指含有至少一个杂原子(例如O,S或N)的五元至十元、完全饱和的或部分不饱和的非芳香杂环基团。最常见的实例是哌啶基,吗啉基,哌嗪基,吡咯烷基或吡嗪基。杂环取代基的连接可通过碳原子或通过杂原子发生。
此外,上文所述的烷基,烯基,环烷基,环烯基,烷氧基,芳基,杂芳基和杂环基团可以是“未取代的”或“经取代的”。术语“经取代的”意在描述具有替代一个或多个原子上的氢的取代基的部分,例如分子的C,O或N。此类取代基可独立地包括例如下列的一种或多种:直链或分支的烷基(优选C1-C5),环烷基(优选C3-C8),烷氧基(优选C1-C6),硫代烷基(优选C1-C6),烯基(优选C2-C6),炔基(优选C2-C6),杂环的,碳环的,芳基(例如苯基),芳氧基(例如苯氧基),芳烷基(例如苄基),芳氧基烷基(例如,苯氧基烷基),芳基乙酰氨基,烷基芳基,杂芳烷基,烷基羰基和芳基羰基或其它此类芳基、杂芳基羰基或杂芳基,(CR’R”)0-3NR’R”(例如,-NH2),(CR’R”)0-3CN(例如,-CN),-NO2,卤素(例如,-F,-Cl,-Br,或-I),(CR’R”)0-3C(卤素)3(例如,-CF3),(CR’R”)0-3CH(卤素)2,(CR’R”)0-3CH2(卤素),(CR’R”)0-3CONR’R”,(CR’R”)0-3(CNH)NR’R”,(CR’R”)0-3S(O)1-2NR’R”,(CR’R”)0-3CHO,(CR’R”)0-3O(CR’R”)0-3H,(CR’R”)0-3S(O)0-3R’(例如,-SO3H,-OSO3H),(CR’R”)0-3O(CR’R”)0-3H(例如,-CH2OCH3和-OCH3),(CR’R”)0-3S(CR’R”)0-3H(例如,-SH和-SCH3),(CR’R”)0-3OH(例如,-OH),(CR’R”)0-3COR’,(CR’R”)0-3(经取代的或未取代的苯基),(CR’R”)0-3(C3-C8环烷基),(CR’R”)0-3CO2R’(例如,-CO2H),或(CR’R”)0-3OR’基团,或任何天然产生的氨基酸的侧链;其中R’和R”各自独立地是氢,C1-C5烷基,C2-C5烯基,C2-C5炔基或芳基。
术语“胺”或“氨基”应被理解为广泛适用于分子、部分或官能团,如本领域中所普遍理解的,并且可以是伯胺、仲胺或叔胺。术语“胺”或“氨基”包括这样的化合物,其中氮原子共价结合于至少一个碳、氢或杂原子。此术语包括例如但不限于,“烷基氨基”,“芳基氨基”,“二芳基氨基”,“烷基芳基氨基”,“烷基氨基芳基”,“芳基氨基烷基”,“alkaminoalkyl”,“酰胺”,“氨基”和“氨基羰基”。术语“烷基氨基”包括这样的基团和化合物,其中氮与至少一个另外的烷基相结合。术语“二烷基氨基”包括这样的基团,其中氮原子与至少两个另外的烷基相结合。术语“芳基氨基”和“二芳基氨基”包括这样的基团,其中氮分别与至少一个或两个芳基相结合。术语“烷基芳基氨基”,“烷基氨基芳基”或“芳基氨基烷基”是指这样的氨基,其与至少一个烷基及至少一个芳基相结合。术语“alkaminoalkyl”是指与还与烷基相结合的氮原子连接的烷基,烯基或炔基。
术语“酰胺”,“氨基”或“氨基羰基”包括这样的化合物或部分,其含有与羰基或硫羰基的碳相结合的氮原子。此术语包括“alkaminocarbonyl”或“烷基氨基羰基”,其包括与结合于羰基的氨基相结合的烷基,烯基,芳基或炔基。其包括芳基氨基羰基和芳基羰基氨基(包括与结合于羰基或硫羰基的碳的氨基结合的芳基或杂芳基部分)。术语“烷基氨基羰基”,“烯基氨基羰基”,“炔基氨基羰基”,“芳基氨基羰基”,“烷基羰基氨基”,“烯基羰基氨基”,“炔基羰基氨基”和“芳基羰基氨基”包括在术语“酰胺”中。酰胺还包括尿素基团(氨基羰基氨基)和氨基甲酸盐(氧化羰基氨基)。
在本发明的特定实施方式中,术语“胺”或“氨基”是指式N(R8)R9,CH2N(R8)R9和CH(CH3)N(R8)R9的取代基,其中R8和R9各自独立地选自H和(C1-C4-烷基)0-1G,其中G选自COOH,H,PO3H,SO3H,Br,Cl,F,O-C1-4-烷基,S-C1-4-烷基,芳基,C(O)OC1-C6-烷基,C(O)C1-C4-烷基-COOH,C(O)C1-C4-烷基和C(O)-芳基。
本文的公开的描述应该与化学键结的定律和原则相一致而进行解释。例如,可能需要移除氢原子从而在任何给定的位置安置取代基。另外,要理解变量(即“R基团”)的定义、以及本发明的通式(例如,式I,II或III)的键的位置将与本领域已知的化学键结定律一致。还要理解所有上文所描述的本发明的化合物将进一步包括邻近原子和/或氢之间的键,如为了满足每个原子的效价所要求的。即添加了键和/或氢原子以为下列每一类原子提供下列数目的总的键:碳:四个键;氮:三个键;氧:两个键;以及硫:2-6个键。
本发明的化合物可包括不对称的碳原子。要相应地理解,在本发明的范围内包括了由此种不对称性引起的同分异构物(例如,所有的对映异构体,立体异构体,旋转异构体,互变异构体,非对映异构体,或外消旋体)。可通过经典的分离技术以及通过立体化学控制的合成而以基本上纯的形式获得此类同分异构物。此外,本申请中所讨论的结构和其它化合物及部分也包括其所有的互变异构体。本文所描述的化合物可通过本领域所认可的合成策略而获得。
还将注意到,一些本发明的化合物的取代基包括同分异构的环状结构。因此要理解,除非另外说明,特定取代基的结构异构体包括在本发明的范围内。例如,术语“四唑”包括四唑,2H-四唑,3H-四唑,4H-四唑和5H-四唑。
同位素
本发明包括所有药学上可接受的同位素标记的本发明的化合物,即式(I),(II)和(III)的化合物,其中一个或多个原子被具有相同原子数但具有与自然中通常发现的原子量或质量数不同的原子量或质量数的原子所替代。
适于包括在本发明的化合物中的同位素的实例包括:氢的同位素,例如2H和3H;碳的同位素,例如11C,13C和14C;氯的同位素,例如36Cl;氟的同位素,例如18F;碘的同位素,例如123I和125I;氮的同位素,例如13N和15N;氧的同位素,例如15O,17O和18O;磷的同位素,例如32P;和硫的同位素,例如35S。
某些经同位素标记的式(I),(II)和(III)的化合物(例如,掺入了放射性同位素的那些)可用于药物和/或底物组织分布研究。鉴于其易于掺入和预备好的检测手段,放射性同位素氚(即3H)和碳-14(即14C)对于此目的是特别有用的。
具有更重的同位素(例如氘,即2H)的取代基可提供某些产生自更大的代谢稳定性的治疗优势,例如增加的体内半衰期或降低的剂量要求,并因此在一些情况下可能是优选的。
具有正电子发射同位素的取代基,例如11C,18F,15O和13N,可被用于正电子发射计算机断层扫描(PET)研究而用于检测底物受体占据。
经同位素标记的式(I),(II)和(III)的化合物通常可通过使用合适的经同位素标记的试剂来代替之前采用的未标记的试剂而由本领域技术人员已知的常规技术制备或由类似于所附实施例和制备物中所描述的那些的方法制备。
组合
本发明的化合物也可用于与已知的抗癌试剂相组合。此类已知的抗癌试剂包括下列:雌激素受体调节剂,雄性激素受体调节剂,类视黄醇受体调节剂,细胞毒性试剂,抗增殖试剂,异戊二烯基-蛋白转移酶抑制剂,HMG-CoA还原酶抑制剂,HIV蛋白酶抑制剂,反转录酶抑制剂及其它血管生成抑制剂。
“雌激素受体调节剂”是指干扰或抑制雌激素与受体结合的化合物,无论机制如何。雌激素受体调节剂的实例包括但不限于,它莫西芬,雷洛昔芬,吲哚昔酚,LY353381,LY117081,托瑞米芬,氟维司群,4-[7-(2,2二甲基-1-氧丙氧基-4-甲基-2-[4-[2-(1-哌啶基)乙氧基]苯基]-2H-1-苯并吡喃-3-基]-苯基-2,2-二甲基丙酸甲酯,4,4′-二羟基二苯甲酮-2,4-二硝基苯基-腙和SH646。
“雄性激素受体调节剂”是指干扰或抑制雄性激素与受体结合的化合物,无论机制如何。雄性激素受体调节剂的实例包括非那雄胺和其它5α-还原酶抑制剂,尼鲁米特,flutamide,比卡鲁胺,利阿唑和醋酸阿比特龙。
“类视黄醇受体调节剂”指干扰或抑制类视黄醇与受体结合的化合物,无论机制如何。此类类视黄醇受体调节剂的实例包括蓓萨罗丁,维甲酸,13-顺-视黄酸,9-顺-视黄酸,α-二氟甲基鸟氨酸,ILX23-7553,反-N-(4′-羟苯基)维甲酰胺,和N-4-羧基苯基维甲酰胺。
“细胞毒性试剂”指主要通过直接干扰细胞的功能或者抑制或干扰细胞减数分裂而引起细胞死亡的化合物,包括烷化剂,肿瘤坏死因子,嵌合剂,微管蛋白抑制剂和拓扑异构酶抑制剂。
细胞毒性试剂的实例包括但不限于tirapazimine,sertenef,恶病质素,异环磷酰胺,他索纳明,氯尼达明,卡铂,多柔比星,六甲蜜胺,泼尼莫司汀,二溴去羟卫矛醇,雷莫司汀,福莫司汀,奈达铂,奥沙利铂,temozolomnide,heptaplatin,雌莫司汀,英丙舒凡甲苯磺酸盐,trofosfainide,尼莫司汀,二溴螺氯铵,嘌嘧替派,洛铂,沙铂,甲基丝裂霉素,顺铂,伊罗夫文,dexifosfamide,顺-胺二氯(2-甲基-吡啶基)铂,苄基鸟嘌呤,葡磷酰胺,GPX100,(反,反,反)-二-μ-(己烷-1,6-二胺)-μ-[二胺-铂(II)]二[二胺(-氯)铂(II)]四氯化物,二氮丙定基精胺,三氧化砷,1-(11-十二烷基氨基-10-羟基十一烷基)-3,7-二甲基黄嘌呤,佐柔比星,伊达比星,柔红霉素,比生群,米托蒽醌,吡柔比星,吡萘非特,戊柔比星,氨柔比星,抗瘤物(antineoplaston),3′-脱氨基-3′-吗啉基-13-脱氧-10-羟基洋红霉素,安那霉素,加柔比星,依利奈法德,MEN10755和4-脱甲氧基-3-脱氨基-3-氮丙定基-4-甲磺酰基-柔红霉素(见WO 00/50032)。
微管蛋白抑制剂的实例包括紫杉醇,长春地辛硫酸盐,3′,4′-二脱氢-4′-脱氧-8′-去甲长春碱,多西紫杉醇,根霉素,多拉司他汀,米伏布林羟乙磺酸盐,auristatin,西马多丁,RPR109881,BMS184476,长春氟宁,cryptophycin,2,3,4,5,6-五氟-N-(3-氟4-甲氧基苯基)苯磺酰胺,脱水长春碱,N,N-二甲基-L-缬氨酰-L-缬氨酰-N-甲基-L-缬氨酰-L-腈氨酰-L-脯氨酸-t-丁酰胺,TDX258和BMS188797。
拓扑异构酶抑制剂的一些实例为托泊替康,hycaptamine,伊立替康,卢比替康,6-乙氧基丙酰-3′,4′-O-外-亚苄基-教酒菌素,9-甲氧基-N,N-二甲基-5-硝基吡唑[3,4,5-k1]吖啶-2-(6H)丙胺,1-氨基-9-乙基-5-氟-2,3-二氢-9-羟基4-甲基-1H,12H-苯并[de]吡喃[3′,4′:b,7]吲嗪[1,2b]喹啉-10,13(9H,15H)二酮,勒托替康,7-[2-(N-异丙胺基)乙基]-(20S)喜树碱,BNP1350,BNPI1100,BN80915,BN80942,依托泊苷磷酸盐,替尼泊苷,索布佐生,2′-二甲基氨基-2′-脱氧-依托泊苷,GL331,N-[2-(二甲基氨基)乙基]-9-羟基-5,6-二甲基-6H-吡啶[4,3-b]咔唑-1-甲酰胺,asulacrine,(5a,5aB,8aa,9b)-9-[2-[N-[2-(二甲基氨基)乙基]-N-甲基氨基]乙基]-5-[4-羟基-3,5-二甲氧基苯基]-5,5a,6,8,8a,9-六氢呋喃(3′,4′:6,7)萘并(2,3-d-)-1,3-二氧杂环戊烯-6-酮,2,3-(甲二氧基)-5-甲基-7-羟基-8-甲氧基苯并[c]-菲啶鎓,6,9-二[(2-氨乙基)氨基]苯并[g]异喹啉-5,10-二酮,5-(3-氨基丙胺基)-7,10-二羟基-2-(2-羟乙基氨基甲基)-6H-吡唑[4,5,1-de]吖啶-6-酮,N-[1-[2(二乙基氨基)乙基氨基]-7-甲氧基-9-氧代-9H-噻吨4-基甲基-]甲酰胺,N-(2-(二甲基氨基)乙基)吖啶4-氨甲酰,6-[[2-(二甲基氨基)乙基]氨基]-3-羟基-7H-茚并[2,1-c]喹啉-7-酮和地美司钠。
“抗增殖剂”包括反义RNA和DNA寡核苷酸,例如G3139,ODN698,RVASKRAS,GEM231和INX3001,以及抗代谢物例如依诺他滨,卡莫氟,替加氟,喷司他丁,去氧氟尿苷,三甲曲沙,氟达拉滨,卡培他滨,加洛他滨,阿糖胞苷烷磷酯,fosteabine钠水合物,雷替曲塞,paltitrexid,乙嘧替氟,噻唑羧胺核苷,地西他滨,诺拉曲塞,培美曲塞,奈拉滨,2′-脱氧-2′-甲基胞嘧啶核苷,2′-氟代亚甲基-2′-脱氧胞苷,N-[5-(2,3-二氢-苯并呋喃基)磺酰基]-N′-(3,4-二氯苯基)脲,N6-[4-脱氧-4-[N2-[2(E),4(E)-四癸二烯]甘氨酰氨基]-L-甘油基-B-L--甘露糖型-吡喃庚糖基]腺嘌呤,aplidine,海鞘素,曲沙他滨,4-[2-氨基4-氧代4,6,7,8-四氢-3H-嘧啶[5,4-b][1,4]噻嗪-6-基-(-S)-乙基]-2,5-噻吩-L-谷氨酸,氨基蝶呤,5-氟尿嘧啶,阿拉诺新,11-乙酰基-8-(氨基甲酰氧甲基)4-甲酰基-6-甲氧基-14-氧杂-1,11-二氮杂四-环(7.4.1.0.0)-十四碳-2,4,6-三亚乙基四胺-9-基乙酸酯,苦马豆素,洛美曲索,右雷佐生,甲硫氨酸酶,2′-氰基-2′-脱氧-N4-棕榈酰-1-B-D-阿糖胞苷和3-氨基吡啶基-2-甲醛氨硫脲。
“抗增殖剂”还包括除了在“血管生成抑制剂”之下所列的之外的、生长因子的单克隆抗体(例如曲妥珠单抗),以及肿瘤抑制剂基因(例如p53),其可通过重组病毒介导的基因转移而递送(例如,见美国专利号6,069,134)。
″HMG-CoA还原酶抑制剂″指3-羟基-3-甲戊二酰-CoA还原酶抑制剂。通过使用本领域熟知的测定可容易地鉴别对于HMG-CoA还原酶有抑制活性的化合物。例如,见美国专利号4,231,938第6栏和WO 84/02131第30-33页中所描述或引用的测定。当在本申请中使用时,术语″HMG-CoA还原酶抑制剂″与″HMG-CoA还原酶的抑制剂″具有相同的含义。
可使用的HMG-CoA还原酶抑制剂的实例包括但不限于洛伐他汀,辛伐他汀,普伐他汀,氟伐他汀,阿托伐他汀和西立伐他汀。这些以及其它可在本方法中使用的HMG-CoA还原酶抑制剂的结构式描述于M.Yalpani,″Cholesterol Lowering Drugs″,Chemistry & Industry,pp.85-89(5Feb.1996)的第87页,和美国专利号4,782,084及4,885,314中。如本申请中所使用的,术语HMG-CoA还原酶抑制剂包括具有HMG-CoA还原酶抑制活性的化合物的所有药学上可接受的内酯和开放-酸形式(即其中的内酯环是开放的以形成游离酸)以及盐和酯形式,因此所述盐、酯、开放-酸和内酯形式的应用包括在本发明的范围内。
“异戊二烯基-蛋白转移酶抑制剂”指抑制任意一种或任何组合的异戊二烯基-蛋白转移酶的化合物,包括法尼基-蛋白转移酶(FPTase),I型香叶基香叶基-蛋白转移酶(GGPTase-I)和II型香叶基香叶基-蛋白转移酶(GGPTase-II,也称作Rab GGPTase)。异戊二烯基-蛋白转移酶抑制化合物的实例包括(+/-)-6-[氨基(4-氯苯基)(1-甲基-1H-咪唑-5-基)甲基]-4-(3-氯苯基)-1-甲基-2(1H)-喹喏酮,(-)-6-[氨基(4-氯苯基)(1-甲基-1H-咪唑-5-基)甲基]4-(3-氯-苯基)-1-甲基-2(1H)-喹喏酮,(+)-6-[氨基(4-氯苯基)(1-甲基-1H-咪唑-5-基)甲基]4-(3-氯苯基)-1-甲基-2(1H)-喹喏酮,5(S)-n-丁基-1-(2,3-二甲基苯基)4-[1-(4-氰苯基)-5-咪唑甲基]-2-哌嗪酮,(S)-1-(3-氯苯基)4-[1-(4-氰苯基)-5-咪唑甲基]-5-[2-(乙磺酰基)甲基)-2-哌嗪酮,5(S)-n-丁基-1-(2-甲基苯基)4-[1-(4-氰苯基)-5-咪唑甲基]-2-哌嗪酮,1-(3-氯苯基)-4-[1-(4-氰苯基)-2-甲基-5-咪唑甲基]-2-哌嗪酮,1-(2,2-二苯基乙基)-3-[N-(1-(4-氰苯基)-1H-咪唑-5-基乙基)氨基甲酰]哌啶,4-{5-[4-羟甲基4-(4-氯吡啶-2-基甲基)-哌啶基-1-基甲基-]-2-甲基咪唑-1-基甲基}苄腈,4-{5-[4-羟甲基-4-(3-氯苯基)-哌啶基-1-基甲基]-2-甲基咪唑-1-基甲基}苄腈,4-{3-[4-(2-氧代-2H-吡啶-1-基)苄基]-3H-咪唑4-基甲基}苄腈-,4-{3-[4-(5-氯-2-氧代-2H-[1,2′]二吡啶-5′-基甲基]-3H-咪唑4-基甲基}苄腈,4-{3-[4-(2-氧代-2H-[1,2′]二吡啶-5′-基甲基]-3H-咪唑4-基甲基}苄腈,4-[3-(2-氧代-1-苯基-1,2-二氢嘧啶4-基甲基)-3H-咪唑4--基甲基}苄腈,18,19-二氢-19-氧代-5H,17H-6,10:12,16-二甲烯基-1H--咪唑[4,3-c][1,11,4]二氧杂氮杂环-十九碳九烯-9-腈,(+/-)-19,20-二氢-19-氧代-5H-18,21-亚乙基-12,14-亚乙烯基-6,10-甲烯基-22H--苯并[d]咪唑[4,3-k][1,6,9,12]氧杂三氮杂-环十八碳九烯-9-腈,19,20-二氢-19-氧代-5H,17H-18,21-亚乙基-6,10:12,16-二甲烯基-22H-咪唑并-[3,4-h][1,8,11,14]氧杂三氮杂环十二烷-9-腈,和(+/-)-19,20-二氢-3-甲基-19-氧代-5H-18,21-亚乙基-12,14-亚乙烯基-6,10-甲烯基-22H-苯并[d]咪唑[4,3-k][1,6,9,12]氧杂-三氮杂环十八碳九烯-9-腈。
异戊二烯基-蛋白转移酶抑制剂的其它实例可在下列出版物和专利中找到:WO 96/30343,WO 97/18813,WO 97/21701,WO 97/23478,WO97/38665,WO 98/28980,WO 98/29119,WO 95/32987,美国专利号5,420,245,5,523,430,5,532,359,5,510,510,5,589,485,5,602,098,欧洲专利公开0618221,欧洲专利公开0675112,欧洲专利公开0604181,欧洲专利公开0 696 593,WO 94/19357,WO 95/08542,WO 95/11917,WO 95/12612,WO 95/12572,WO 95/10514,美国专利号5,661,152,WO95/10515,WO 95/10516,WO 95/24612,WO 95/34535,WO 95/25086,WO 96/05529,WO 96/06138,WO 96/06193,WO 96/16443,WO 96/21701,WO 96/21456,WO 96/22278,WO 96/24611,WO 96/24612,WO 96/05168,WO 96/05169,WO 96/00736,美国专利号5,571,792,WO 96/17861,WO96/33159,WO 96/34850,WO 96/34851,WO 96/30017,WO 96/30018,WO 96/30362,WO 96/30363,WO 96/31111,WO 96/31477,WO 96/31478,WO 96/31501,WO 97/00252,WO 97/03047,WO 97/03050,WO 97/04785,WO 97/02920,WO 97/17070,WO 97/23478,WO 97/26246,WO 97/30053,WO 97/44350,WO 98/02436和美国专利号5,532,359。关于异戊二烯基-蛋白转移酶抑制剂对于血管生成的作用的实例,见European J.ofCancer,Vol.35,No.9,pp.1394-1401(1999)。
HIV蛋白酶抑制剂的实例包括氨普那韦,阿巴卡韦,CGP-73547,CGP-61755,DMP-450,英地纲韦,奈非那韦,替拉那韦,利托那韦,沙奎那韦,ABT-378,AG 1776和BMS-232,632。反转录酶抑制剂的实例包括delaviridine,依法韦仑,GS-840,HB Y097,拉米夫定,奈韦拉平,AZT,3TC,ddC和ddI。
“血管生成抑制剂”指抑制新血管形成的化合物,无论机制如何。血管生成抑制剂的实例包括但不限于,酪氨酸激酶抑制剂,例如酪氨酸激酶受体Flt-1(VEGFR1)和Flk-1/KDR(VEGFR20)的抑制剂,源自表皮的、源自成纤维细胞的或源自血小板的生长因子的抑制剂,MMP(基质金属蛋白酶)抑制剂,整联蛋白阻断剂,干扰素-α,白细胞介素-12,戊聚糖多硫酸酯,环氧合酶抑制剂,包括非类固醇类抗炎剂(NSAIDs)如阿司匹林和布洛芬,以及选择性环氧合酶-2抑制剂如塞来考昔和罗非昔布(PNAS,Vol.89,p.7384(1992);JNCI,Vol.69,p.475(1982);Arch.Opthalmol.,Vol.108,p.573(1990);Anat.Rec.,Vol.238,p.68(1994);FEBS Letters,Vol.372,p.83(1995);Clin,Orthop.Vol.313,p.76(1995);J.Mol.Endocrinol.,Vol.16,p.107(1996);Jpn.J.Pharmacol.,Vol.75,p.105(1997);Cancer Res.,Vol.57,p.1625(1997);Cell,Vol.93,p.705(1998);Intl.J.Mol.Med.,Vol.2,p.715(1998);J.Biol.Chem.,Vol.274,p.9116(1999)),羧基氨基三唑,考布他汀A-4,squalamnine,6-O-氯乙酰基-羰基)-夫马洁林,沙立度胺,血管抑制素,肌钙蛋白-1,血管紧张素II拮抗剂(见Fernandez et al.,J.Lab.Clin.Med.105:141-145(1985))和VEGF的抗体(见Nature Biotechnology,Vol.17,pp.963-968(October1999);Kim et al.,Nature,362,841-844(1993);WO 00/44777和WO 00/61186)。
测定
可使用本领域中可获得的许多测定来测量本发明的化合物对蛋白激酶活性的抑制。在下面的示例部分描述此类测定的实例。
药物组合物
本发明的化合物适于作为药物组合物中的活性剂,其特别对于治疗蛋白激酶相关病症和癌症(例如胰腺癌,非小细胞肺癌,胃肠道基质瘤或慢性骨髓性白血病)是有效的。各种实施方式中的药物组合物具有药学上有效量的本发明的活性剂以及其它药学上可接受的赋形剂、载体、填充剂、稀释剂等。
用语所述化合物的“药学上有效量”或“药学上可接受的量”是治疗或预防蛋白激酶相关病症所需要或足够的量,例如预防蛋白激酶相关病症的各种形态和躯体症状,和/或本文所描述的疾病或病况。在实例中,本发明的化合物的有效量是足以治疗受试者中的蛋白激酶相关病症的量。所述有效量可根据例如下列因素而变化:受试者的尺寸和重量,疾病的类型或本发明的具体化合物。例如,对于本发明的化合物的选择可影响什么构成“有效量”。本领域普通技术人员将无需过度实验而能够研究本文所包含的因素并关于本发明的化合物的有效量作出决定。
施用方案可影响什么构成药学上的有效量。可在蛋白激酶相关病症开始之前或之后向受试者施用本发明的化合物。此外,可每天或顺次施用数个分开的剂量,以及交错的剂量,或者剂量可持续输注,或者可以是推注。此外,本发明的化合物的剂量可如治疗性或预防性情形的紧急性所示而成比例地增加或减少。
在一个非限制性实施方式中,用语“药学上有效量”是指这样的本发明的化合物的量,当施用给受试者时其对于下列是有效的:(1)至少部分地缓解、抑制、预防和/或改善病况或病症或疾病,所述病况或病症或疾病是(i)由激酶c-Abl,BCR-Abl,c-kit和/或PDGFR介导的,或(ii)与激酶c-Abl,BCR-Abl,c-kit和/或PDGFR活性相关,或(iii)特征在于激酶c-Abl,BCR-Abl,c-kit和/或PDGFR的异常活性;或(2)降低或抑制激酶c-Abl,BCR-Abl,c-kit和/或PDGFR的活性;或(3)降低或抑制激酶c-Abl,BCR-Abl,c-kit和/或PDGFR的表达。在另一个非限制性实施方式中,用语“药学上有效量”是指这样的本发明的化合物的量,当施用给受试者时,其对于至少部分地缓解、抑制、防止和/或改善癌症(例如胰腺癌,非小细胞肺癌,胃肠道基质瘤或慢性骨髓性白血病)是有效的。在另一个非限制性实施方式中,术语“药学上有效量”是指这样的本发明的化合物的量,当向细胞或组织或非细胞生物材料或介质施用时,其对于至少部分地降低或抑制激酶c-Abl,BCR-Abl,c-kit和/或PDGFR的活性,或者至少部分地降低或抑制激酶c-Abl,BCR-Abl,c-kit和/或PDGFR的表达是有效的。
所述有效量可根据例如下列因素而变化:受试者的尺寸和重量,疾病的类型或具体的有机化合物。例如,对于本发明的有机化合物的选择可影响什么构成“有效量”。本领域普通技术人员将无需过度实验而能够研究前述因素并关于所述有机化合物的可接受的量作出决定。
本发明的化合物可被用于治疗本文中所描述的状态、病症或疾病,或用于制备用来治疗这些疾病的药物组合物。使用本发明的化合物来治疗这些疾病的方法,或具有本发明的化合物的、用于治疗这些疾病的药物制备物。
用语“药物组合物”包括适于向哺乳动物(例如人类)施用的制备物。当本发明的化合物作为药物向哺乳动物(例如人类)施用时,可给予其本身或作为药物组合物而给予,所述药物组合物含有例如0.1至99.5%(更优选地0.5至90%)的活性成分,与药学上可接受的载体相组合。
用语“药学上可接受的载体”是本领域所认可的并包括适于向哺乳动物施用本发明的化合物的药学上可接受的物质、组合物或媒介。所述载体包括液体或固体填充剂、稀释剂、赋形剂、溶剂或成胶囊化物质,它们参与将主题试剂从一个器官或身体的部分携带或转运到另一个器官或身体的部分。在与制剂的其它成分相容并且对患者没有伤害的意义上,每种载体都必须是“可接受的”。可作为药学上可接受的载体的物质的一些实例包括:糖(例如乳糖、葡萄糖和蔗糖);淀粉(例如玉米淀粉和土豆淀粉);纤维素及其衍生物(例如羧甲基纤维素钠,乙基纤维素和醋酸纤维素);粉末的黄芪胶;麦芽;明胶;滑石;赋形剂,例如可可脂和栓剂蜡;油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇类,例如丙二醇;多元醇,例如甘油,山梨糖醇,甘露糖醇和聚乙二醇;酯类,例如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,例如氢氧化镁和氢氧化铝;藻酸;无热原的水;等渗的盐水;林格氏溶液;乙醇;磷酸盐缓冲液;和药物制剂中采用的其它非毒性相容物质。
所述组合物中还可存在润湿剂,乳化剂和润滑剂(例如月桂基硫酸钠和硬脂酸镁)以及着色剂,释放剂,包被剂,甜味剂,调味剂和香化剂,防腐剂和抗氧化剂。
药学上可接受的抗氧化剂的实例包括:水溶性抗氧化剂,例如抗坏血酸,半胱氨酸盐酸化物,硫酸氢钠,偏亚硫酸氢钠,亚硫酸钠等;油溶性的抗氧化剂,例如抗坏血酸基棕榈酸盐,丁羟茴醚(BHA),丁羟甲苯(BHT),卵磷脂,丙基没食子酸盐,α-生育酚等;以及金属螯合剂,例如柠檬酸,乙二胺四乙酸(EDTA),山梨糖醇,酒石酸,磷酸等。
本发明的制剂包括适于口、鼻、表面、颊、舌下、直肠、阴道和/或肠胃外施用的那些。所述制剂可方便地以单位剂量形式被呈递并且可通过药学领域中任何熟知的方法制备。可与载体材料相结合以产生单一剂量形式的活性成分的量将通常为产生治疗效果的化合物的量。通常,在一百个百分比中,此量的范围为约1%至约99%的活性成分,优选约5%至约70%,最优选约10%至约30%。
制备这些制剂或组合物的方法包括下列步骤:使本发明的化合物与载体和任选地,一种或多种辅助成分相联合。通常,如下制备所述制剂:使本发明的化合物与液体载体,或经细分的固体载体或二者均一且密切地相联合,然后(如果需要的话)使产品成型。
适于经口施用的本发明的制剂可以是胶囊、扁囊剂、丸剂、片剂、锭剂(使用经调味的基底,通常是蔗糖和阿拉伯胶或黄芪胶)、粉末、颗粒的形式,或者作为水性或非水性液体中的溶液或悬浮液,或作为水包油或油包水的液体乳剂,或作为酏剂或糖浆,或者作为软锭剂(使用惰性基底,例如明胶和甘油,或蔗糖和阿拉伯胶)和/或作为漱口水等,每种都含有预定量的本发明的化合物作为活性成分。本发明的化合物也可作为大丸药、煎膏剂或糊剂施用。
在用于经口施用的本发明的固体剂型(胶囊,片剂,丸剂,锭剂,粉末,颗粒等)中,活性成分与一种或多种药学上可接受的载体(例如柠檬酸钠或磷酸二钙)和/或下列的任何相混合:填充剂或扩充剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和/或硅酸;粘合剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶;保湿剂,例如甘油;崩解剂,例如琼脂、碳酸钙、土豆或木薯淀粉、藻酸、某些硅酸盐和碳酸钠;溶液阻滞剂,例如石蜡;吸收加速剂,例如季铵化合物;润湿剂,例如鲸蜡基醇和单硬脂酸甘油酯;吸附剂,例如高岭土和膨润土;润滑剂,例如滑石,硬脂酸钙,硬脂酸镁,固体聚乙二醇,月桂基硫酸钠及其混合物;和着色剂。在胶囊、片剂和丸剂的情形中,药物组合物还可包含缓冲剂。在软填充和硬填充的凝胶胶囊中也可采用相似类型的固体组合物作为填充剂,其中使用的赋形剂为例如乳糖(lactose)或乳糖(milk sugars),以及高分子量聚乙二醇等。
可通过压缩或模制来制造片剂,任选地具有一种或多种辅料。可通过使用粘合剂(例如明胶或羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如,羟基乙酸淀粉钠或交联的羧甲基纤维素钠),表面活性剂或分散剂来制备压缩的片剂。可通过在合适的机器中模制用惰性液体稀释剂润湿的粉末化合物的混合物来制造模制的片剂。
本发明的药物组合物的片剂和其它固体剂型(例如锭剂,胶囊,丸剂和颗粒)可任选地用包衣和外壳进行刻痕(scored)或制备,所述包衣和外壳为例如肠衣和药物制剂领域中熟知的其它包衣。也可使用例如不同比例的羟丙基甲基纤维素以提供所需的释放谱、其它聚合物基质,脂质体和/或微滴来配制它们从而提供其中活性成分的缓释或受控释放。可通过例如滤过保留细菌的过滤器,或通过在临使用之前掺入可溶于无菌水或一些其它的无菌可注射介质中的、无菌固体组合物形式的灭菌剂来对它们进行灭菌。这些组合物还可任选地含有乳浊剂并且可以是这样的组合物,其仅在或优先在胃肠道的某个部分释放活性成分,任选地,以延迟的方式。可使用的包埋组合物的实例包括聚合物和蜡。活性成分也可以是微胶囊化的形式,如果适当的话,含有一种或多种上文所述的赋形剂。
用于经口施用本发明的化合物的液体剂型包括药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆和酏剂。除了活性成分之外,液体剂型可含有本领域中通常使用的惰性稀释剂,例如水或其它溶剂,溶解剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苄基苯甲酸酯、丙二醇、1,3-丁烯二醇、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃醇、聚乙二醇和山梨聚糖的脂肪酸酯,及其混合物。
除了惰性稀释剂外,口服组合物还可包括佐剂,例如润湿剂、乳化剂和悬浮剂、甜味剂、调味剂、着色剂、香化剂和防腐剂。
除了活性化合物之外,悬浮液可含有悬浮剂例如乙氧基化异硬脂醇,聚氧乙烯山梨糖醇和聚山梨糖醇酯,微晶纤维素,偏氢氧化铝,膨润土,琼脂和黄芪胶,及其混合物。
用于直肠或阴道施用的本发明的药物组合物的制剂可作为栓剂呈递,其可通过将一种或多种本发明的化合物与一种或多种合适的无刺激性赋形剂或载体相混合而制备,所述赋形剂或载体包括例如可可脂、聚乙二醇、栓剂蜡或水杨酸盐,并且其在室温下为固体的但在体温下为液体的,因此其将在直肠或阴道腔中融化并释放活性化合物。
适于阴道施用的本发明的制剂还包括含有本领域中已知为适当的此类载体的阴道栓、棉塞、霜剂、凝胶、糊剂、泡沫或喷雾制剂。
用于表面或经皮施用本发明的化合物的剂型包括粉末、喷雾、软膏、糊剂、霜剂、乳液、凝胶、溶液、贴剂和吸入剂。可在无菌条件下将活性化合物与药学上可接受的载体、以及与可能需要的任何防腐剂、缓冲剂或推进剂相混合。
除了本发明的活性化合物外,所述软膏、糊剂、霜剂和凝胶可含有赋形剂,例如动物和植物脂肪、油、蜡、石蜡、淀粉、黄芪胶、纤维素衍生物、聚乙二醇、有机硅、膨润土、硅酸、滑石和氧化锌,或其混合物。
除了本发明的化合物之外,粉末和喷雾可含有赋形剂,例如乳糖、滑石、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末,或这些物质的混合物。喷雾还可含有惯常的推进剂,例如氯氟烃和挥发性未取代的烃,例如丁烷和丙烷。
经皮贴剂具有下列附加的优势:向身体提供本发明的化合物的受控递送。可通过使所述化合物溶解或分散在适当的介质中而制造此类剂型。吸收增强剂也可用于增加化合物穿过皮肤的流通。可通过提供速度控制膜或将活性化合物分散在聚合物基质或凝胶中而控制此类流通的速度。
眼科制剂、眼膏剂、粉末、溶液等也包括在本发明的范围内。
适于肠胃外施用的本发明的药物组合物包括:一种或多种本发明的化合物,其与一种或多种药学上可接受的无菌等张水性或非水性溶液、分散液、悬浮液或乳剂相组合;或与无菌粉末相组合,其可在临使用之前被重构为无菌的可注射的溶液或分散液,其可含有抗氧化剂、缓冲剂、抑菌剂、使得所述制剂与预期接受者的血液等张的溶质、或悬浮剂或增稠剂。
本发明的药物组合物中可采用的水性和非水性载体的实例包括水、乙醇、多元醇(例如甘油、丙二醇、聚乙二醇等),及其适当的混合物,植物油(例如橄榄油),和可注射的有机酯(例如油酸乙酯)。可例如通过使用包被物质(例如卵磷脂),通过保持所需的粒度(在分散体的情形中)和通过使用表面活性剂,来保持适当的流动性。
这些组合物还可含有佐剂,例如防腐剂、湿润剂、乳化剂和分散剂。可通过包括各种抗细菌和抗真菌的试剂(例如对羟基苯甲酸酯,三氯叔丁醇,苯酚山梨酸等)来确保防止微生物的作用。还可能希望在组合物中包括等张剂,例如糖、氯化钠等。此外,可通过包括延迟吸收的试剂(例如单硬脂酸铝和明胶)而带来对可注射药物形式的延长的吸收。
在一些情形中,为了延长药物的效果,希望减缓来自皮下或肌内注射的药物的吸收。这可通过使用具有不良水溶性的晶体或无定形物质的悬浮液而实现。药物的吸收速度取决于其溶解速度,而这又可以取决于晶体大小和晶形。备选地,肠胃外施用的药物形式的延迟吸收是通过将药物溶解或悬浮于油媒介中实现的。
通过在生物可降解的聚合物(例如聚交酯-聚乙醇酸交酯)中形成主题化合物的微胶囊基质而制成可注射的储存形式。取决于药物与聚合物的比率,以及所采用的特定聚合物的性质,可以控制药物释放的速度。其它生物可降解聚合物的实例包括聚(原醋酯)和聚(酸酐)。还通过将药物捕获在与身体组织相容的脂质体或微乳液中而制备储存可注射制剂。
本发明的制备物可经口、肠胃外地、表面地、或直肠地给予。它们当然是通过适于每种施用途径的形式给予的。例如,它们是以片剂或胶囊形式,通过注射、吸入、眼洗液、软膏、栓剂等施用的,通过注射、输注或吸入施用;通过洗液或软膏表面施用;以及通过栓剂直肠施用。优选的是经口和/或IV施用。
如本申请中所使用的,用语“肠胃外施用”和“肠胃外地施用”是指除了肠和表面施用之外的施用模式,通常是通过注射,并且包括但不限于静脉内、肌内、动脉内、鞘内、囊内、眶内、心内、真皮内、腹膜内、经气管的、皮下、表皮下、关节内、囊下、蛛网膜下、脊柱内和胸骨内注射和输注。
如本申请中所使用的,用语“全身性施用”、“全身地施用”,“外周施用”和“外周地施用”是指除了直接向中枢神经系统中施用之外而施用化合物、药物或其他物质,从而其进入患者的系统并因此经受新陈代谢和其它类似的过程,例如皮下施用。
这些化合物可通过任何合适的施用途径被施用于人类和其它动物而用于治疗,包括经口地、经鼻地(例如通过作为喷雾)、经直肠地、阴道内地、肠胃外地、脑池内地和表面地(如通过粉末、软膏或滴剂),包括面颊地和舌下地。
无论所选择的施用途径为何,通过本领域技术人员已知的常规方法将本发明的化合物(其可以合适的水合形式使用)和/或本发明的药物组合物配制为药学上可接受的剂型。
本发明的药物组合物中活性成分的实际剂量水平可以是变化的,从而获得这样的活性成分的量:其对于实现对特定患者、组合物和施用模式的所需治疗性应答是有效的而对于患者没有毒性。
所选择的剂量水平将取决于各种因素,包括所采用的本发明的具体化合物、或其酯、盐或酰胺的活性,施用途径,施用时间,排泄所采用的特定化合物的速度,治疗的持续时间,与所采用的具体化合物组合使用的其它的药物、化合物和/或物质,被治疗的患者的年龄、性别、重量、状况、一般性健康和以前的医疗史,以及医疗领域中熟知的类似因素。
具有本领域普通技术的医师或兽医可容易地确定并开处方有效量的所需药物组合物。例如,医师或兽医可在低于所需的水平开始给予药物组合物中所采用的本发明的化合物,以实现所需的治疗效果并逐渐增加剂量直至达到所需的效果。
一般而言,本发明的化合物的合适的每日剂量将是有效产生治疗效果的最低剂量的化合物的量。此类有效剂量将通常取决于上文所述的因素。通常,当用于所标明的镇痛效果时,对患者静脉内和皮下应用的本发明的化合物的剂量将在下列范围内:约0.0001至约100mg/千克体重/天,更优选约0.01至约50mg/kg/天,更优选约1.0至约100mg/kg/天。有效的量是治疗蛋白激酶相关病症的量。
如果需要,活性化合物的有效日剂量可作为2、3、4、5、6或更多的亚剂量在一天中以合适的间隔分别施用,任选地,以单位剂量形式施用。
虽然有可能单独施用本发明的化合物,优选将所述化合物作为药物组合物施用。
合成程序
使用本领域技术人员已知的程序由通常可获得的化合物制备本发明的化合物,没有限制地包括下列条件的一种或多种:
本发明的化合物的酸加成盐最合适地是由药学上可接受的酸形成的,并且包括例如以无机酸(例如盐酸,氢溴酸,硫酸或磷酸)和有机酸(例如琥珀酸、马来酸、乙酸或富马酸)形成的那些。其它非药学上可接受的盐(例如草酸盐)可用于例如本发明的化合物的分离、用于实验室应用、或用于随后转化为药学上可接受的酸加成盐。还包括在本发明范围内的是本发明的溶剂合物和水合物。
将给定的化合物盐转化为所需的化合物盐是通过应用标准技术实现的,其中用碱溶液(例如碳酸钠或氢氧化钾)处理给定盐的水性溶液以释放游离碱,所述游离碱然后被提取到适当的溶剂(例如乙醚)中。然后将游离碱从水性部分分离、干燥并用必要的酸处理,以给出所需的盐。
药学上可接受的加成盐的实例包括但不限于,非毒性无机酸加成盐和有机酸加成盐,例如源自盐酸的盐酸盐、源自氢溴酸的氢溴酸盐、源自硝酸的硝酸盐、源自高氯酸的高氯酸盐、源自磷酸的磷酸盐、源自硫酸的硫酸盐、源自甲酸的甲酸盐、源自乙酸的乙酸盐、源自乌头酸的乌头酸盐、源自抗坏血酸的抗坏血酸盐、源自苯磺酸的苯磺酸盐、源自苯甲酸的苯甲酸盐、源自肉桂酸的肉桂酸盐、源自柠檬酸的柠檬酸盐,源自扑酸的扑酸盐、源自庚酸的庚酸盐、源自富马酸的富马酸盐、源自谷氨酸的谷氨酸盐、源自乙醇酸的乙醇酸盐、源自乳酸的乳酸盐、源自马来酸的马来酸盐、源自丙二酸的丙二酸盐、源自扁桃酸的扁桃酸盐、源自甲磺酸的甲磺酸盐、源自萘-2-磺酸的萘-2-磺酸盐、源自邻苯二甲酸的邻苯二甲酸酯、源自水杨酸的水杨酸盐、源自山梨酸的山梨酸盐、源自硬脂酸的硬脂酸盐、源自琥珀酸的琥珀酸盐、源自酒石酸的酒石酸盐、源自对甲苯磺酸的对甲苯磺酸盐等。特别优选的盐是本发明的化合物的钠盐,赖氨酸盐和精氨酸盐。可通过本领域中熟知的和所描述的程序形成此类盐。
其它不能被认为是药学上可接受的酸(例如草酸)可用于制备在获得本发明的化合物及其药学上可接受的酸加成盐中用于作为中间产物的盐。
本发明的化合物的金属盐包括碱金属盐,例如含有羧基的本发明的化合物的钠盐。
某些本发明的化合物的体内可水解的酯或酰胺可通过在惰性溶剂(例如二氯甲烷或氯仿)中、在碱的存在下用所需酯的酸性氯化物处理具有游离羟基或氨基官能团的那些化合物而形成。合适的碱包括三乙胺或吡啶。相反,可使用标准条件来酯化具有游离羧基的本发明的化合物,所述标准条件可包括在合适的碱的存在下活化,继而用所需的醇处理。
根据本发明可获得的同分异构物的混合物可以已知的方式本身被分离为单独的同分异构物;非对映异构体可例如通过在多相溶剂混合物之间分配、重结晶和/或色谱分离(例如在硅胶上)或通过例如在反相柱上进行中压液相层析而分离;以及外消旋体可例如通过与光学纯的成盐试剂形成盐以及分离如此可获得的非对映异构体的混合物(例如介由分步结晶或通过在光学活性柱材料上的层析)而分离。
可根据标准方法来制作(work up)和/或纯化中间产物和终产物,例如使用层析法、分配法、(重)结晶等。
在反应的所有阶段,所形成的同分异构物的混合物可被分离为单独的同分异构物,例如非对映异构体或对映异构体,或者分离为任何所需的同分异构物的混合物,例如外消旋体或非对映异构体的混合物,例如与Science of Synthesis:Houben-Weyl Methods of MolecularTransformation.Georg Thieme Verlag,Stuttgart,Germany,2005中所描述的方法类似地分离。
适于任何特定反应的那些溶剂可选自的溶剂包括具体提及的那些,或者例如水,酯(例如低级烷基-低级链烷酸酯,如乙酸乙酯),醚(例如脂肪族醚(例如二乙醚)或环状醚(例如四氢呋喃或二噁烷)),液体芳香烃(例如苯或甲苯)),醇(例如甲醇、乙醇或者1-或2-丙醇),腈(例如乙腈),卤化烃(例如二氯甲烷或氯仿),酰胺(例如二甲基甲酰胺或二甲基乙酰胺),碱(例如杂环氮碱,例如吡啶或N-甲基吡咯烷-2-酮),羧酸酐(例如低级烷酸酐,例如乙酸酐),环状、线性或分支的烃(例如环己烷、己烷或异戊烷),或者那些溶剂的混合物,例如水性溶液,除非在方法的描述中另外指明。此类溶剂混合物也可被用于制作,例如通过层析或分配。
化合物(包括它们的盐)也可以水合物的形式获得,或者它们的晶体可例如包括用于结晶的溶剂。可存在不同的晶形。
本发明还涉及所述方法的那些形式,其中可作为中间产物而在所述方法的任何阶段获得的化合物被用作起始材料并进行余下的方法步骤,或者其中在反应条件下形成起始材料或者以衍生物的形式(例如以受保护的形式或以盐的形式)使用,或者通过根据本发明的方法可获得的化合物是在方法条件下产生的并且在原位被进一步加工。
前药
本发明还包括含有本发明的化合物的药学上可接受的前药的药物组合物,以及通过施用本发明的化合物的药学上可接受的前药而治疗蛋白激酶相关病症的方法。例如,具有游离氨基,胺基,羟基或羧基的本发明的化合物可被转化为前药。前药包括这样的化合物,其中氨基酸残基、或两个或更多个(例如,二、三或四)氨基酸残基的多肽链通过酰胺键或酯键与本发明的化合物的游离氨基、羟基或羧酸基团共价结合。氨基酸残基包括但不限于通常由三个字母的符号表示的20种天然存在的氨基酸并且还包括4-羟脯氨酸、羟赖氨酸、锁链赖氨酸、异锁链赖氨酸、3-甲基组氨酸、norvalin、β-丙氨酸、γ-氨基丁酸、瓜氨酸高半胱氨酸、高丝氨酸、鸟氨酸和甲硫氨酸砜。还包括其它类型的前药。例如,游离羧基可衍生为酰胺或烷基酯类。可使用包括但不限于下列的基团衍生游离羟基:半琥珀酸盐、磷酸酯、二甲基氨基乙酸盐和磷酰氧基甲基氧基羰基,如Advanced Drug Delivery Reviews,1996,19,115中所概述的。还包括羟基和氨基的氨基甲酸酯前药,如羟基的碳酸酯前药、磺酸酯和硫酸酯。还包括的是羟基衍生为(酸氧基)甲基和(酸氧基)醚,其中酰基可以是烷基酯,任选地经包括但不限于下列的基团取代:醚,胺和羧酸官能团,或者其中酰基为上文所述的氨基酸酯。此类前药描述于J.Med.Chem.1996,39,10中。游离的胺也可衍生为酰胺,磺酰胺或磷酰胺。所有的这些前药部分可并入包括但不限于下列的基团:醚,胺和羧酸官能团。
因此,如适当和得当的,关于本发明的化合物的任何所指要被理解为也是指本发明的化合物的相应前药。
试剂盒
有利地,本发明还提供供消费者使用而用于治疗疾病的试剂盒。所述试剂盒包括:a)包含抗生素和药学上可接受的载体、媒介或稀释剂的药物组合物以及,任选地b)描述使用所述药物组合物来治疗具体疾病的方法的说明书。所述说明书还可表明所述试剂盒用于治疗疾病且大幅减少与抗生素施用相关的副作用的伴随责任。
如本申请中所使用的,“试剂盒”包括用于含有单独的单位剂型(例如分开的瓶或分开的箔包)的容器。所述容器可以是本领域已知的任何常规形状或形式,其由药学上可接受的材料制成,例如纸或卡纸板盒、玻璃或塑料瓶或罐、可再密封的袋(例如,为了承载用于置于不同的容器中的“再填装”的片剂),或具有用于根据治疗方案压出包装的单独剂量的泡罩包装。所采用的容器可取决于所涉及的确切剂型,例如常规的卡纸板盒通常将不用于承载悬浮液。可以在单一包装中共同使用多于一种容器以在市场销售单一剂型。例如,片剂可包含在瓶中,而所述瓶转而包含在盒中。
此类试剂盒的实例是所谓的泡罩包装。泡罩包装在包装工业中是熟知的并且被广泛用于包装药物单位剂型(片剂、胶囊等)。泡罩包装通常由覆盖了优选透明塑料材料的箔的相对刚性的材料的板组成。在包装过程中,在塑料箔中形成凹陷。所述凹陷具有待包装的单个片剂或胶囊的大小和形状或可能具有安置多个待包装的片剂和/或胶囊的大小和形状。然后,将片剂或胶囊相应地置于所述凹陷中并且在与凹陷所形成的方向相反的箔面将所述相对刚性的材料的板对着所述塑料箔密封。因此,片剂或胶囊单独地或共同地(如所需的)被密封在塑料箔与板之间的凹陷中。优选地,所述板的强度使得所述片剂或胶囊可通过手动在凹陷上施压而从所述泡罩包装中被移除,其中在板中、在所述凹陷的位置形成开口。然后,可通过所述开口将片剂或胶囊移除。
可能希望提供书面的记忆辅助物,其中所述书面记忆辅助物是含有针对医师、药剂师或受试者的信息和/或指导的类型,例如,以紧靠着片剂或胶囊的数字的形式,其中所述数字相应于被如此规定的片剂或胶囊应当被摄取的方案的天数;或者以卡片的形式,所述卡片含有相同类型的信息。此类记忆辅助物的另一个实例是印在卡片上的日历,例如如下的“第一周,星期一,星期二,...”等....“第二周,星期一,星期二,...”等。记忆辅助物的其它变化将是很显然的。“每日剂量”可以是指定的天将摄取的单一片剂或胶囊或者数个片剂或胶囊。
试剂盒的另一个具体实施方式是被设计为一次分配一个每日剂量的分配器。优选地,所述分配器装配有记忆辅助物,从而进一步促进与方案相符合。此类记忆辅助物的实例是机械计数器,其指示已经分配的每日剂量的数目。此类记忆辅助物的另一个实例是电池驱动的微芯片记忆,其与液晶读出或可听提醒信号相结合,所述信号例如读出摄取上次日剂量的日期和/或提醒何时应摄取下一剂。
本发明的范例
通过下面的实施例进一步阐释本发明,所述实施例不应被解释为进一步的限制。本发明的实施将采用(除非另外指明)本领域技术内的、细胞生物学、细胞培养、分子生物学、转基因生物学、微生物学和免疫学的常规技术。
一般合成过程
图示1
图示2
图示3
一般合成方法
在图示1-3中描绘了非限制性的一般合成程序。各种备选的条件是本领域技术人员已知的。
如图示1中所显示的,A至B的转化涉及利用本领域中熟知的条件(例如使用金属催化剂如二氯二(三苯基膦)钯(II)、配体如2-二-叔丁膦基-2′,4′,6′-三异丙基联苯、碱如Na2CO3,和溶剂如二噁烷)将芳基化合物A与有机金属偶联伴侣(例如硼酸)偶联。B至C的转化涉及使用本领域熟知的条件形成2-氨基噻唑部分。例如,当Y为NH2且Z为卤素时,可在例如50℃的温度下,用例如下列试剂处理所述化合物:溶剂(例如丙酮和二噁烷)中的环丙烷羰基氯,铵硫氰酸盐和碳酸钾。B至C的转化还涉及利用本领域中熟知的条件(例如使用溶剂,如水、甲醇和四氢呋喃,以及试剂例如一水氢氧化锂和盐酸)而用取代基R’(例如H)替代取代基R(例如C1-C6烷基)。
如图示2中所显示的,C至D的转化涉及利用本领域中熟知的条件(例如使用溶剂如DMF和试剂如N,N-二异丙基乙胺和2-(1H-7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基脲甲烷亚胺鎓六氟磷酸盐,在例如室温的温度下),羧酸或羧酸衍生物C与化合物RR-NH2的反应。
如图示3中所显示的,C至E的转化涉及本领域中熟知的条件(例如,使用溶剂如甲苯和试剂如三乙胺和二苯基磷酰基叠氮化物),继而用本领域中熟知的条件(例如使用溶剂如DMF和试剂例如N,N-二异丙基乙胺和2-(1H-7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基脲甲烷亚胺鎓六氟磷酸盐,在例如室温的温度下)与化合物如RR-NH2、或化合物如RR-CO2H反应。
所有用于合成本发明的化合物的起始材料、构件材料、试剂、酸、碱、脱水剂、溶剂和催化剂是商业上可得的或是可通过本领域普通技术人员已知的有机合成方法生产的(Houben-Weyl 4th Ed.1952,Methodsof Organic Synthesis,Thieme,Volume 21)。此外,本发明的化合物可通过如下面的实施例中所示的本领域普通技术人员已知的有机合成方法生产。
关于下面的实施例,优选实施方式的化合物是使用本文中描述的方法或本领域中已知的其它方法合成的。
合成实施例
实施例1:3-(2-(环丙烷羧酰胺)噻唑[5,4-b]吡啶-5-基)-N-(3-(三氟甲基)苯基)苯甲酰胺
部分A向2-氯-5-硝基吡啶(5.23g,32.99mmol)在二噁烷(170mL)的溶液中加入3-(乙氧基羰基)苯基硼酸硼酸(6.28g,32.99mmol)和1N Na2CO3水性溶液(82.5mL,82.5mmol)。使用氩气将反应混合物脱气20min,继而加入二氯二(三苯基膦)钯(II)(1.38g,1.99mmol)和2-二-叔丁膦基-2′,4′,6′-三异丙基联苯(1.26g,2.97mmol)。将反应摇瓶放入经预热的90℃油浴中。在90℃将反应混合物再搅拌10h,然后将其过滤并在乙酸乙酯和水之间进行分配。分离有机层并用乙酸乙酯提取水性层。用卤水清洗组合的有机提取物,在MgSO4上干燥,过滤并浓缩。使用95∶5v/v己烷∶乙酸乙酯作为溶剂、通过快速柱层析法纯化粗制产物,以提供作为明黄色固体的乙基3-(5-硝基吡啶-2-基)苯甲酸盐(8.0g,89%产率)。
1H NMR 600MHz(CDCl3)δ9.50(s,1H),8.71(s,1H),8.55(d,J=7.8Hz,1H),8.32(d,J=7.2Hz,1H),8.18(d,J=7.2Hz,1H),7.98(d,J=8.4Hz,1H),7.61(t,J=7.2Hz,1H),4.43(q,2H),1.43(t,3H),MS m/z:273.22(M+1)。
部分B向乙基3-(5-硝基吡啶-2-基)苯甲酸盐(8.0g,29.40mmol)在乙醇(150mL)的溶液中加入5%Pd/C(800mg)。在H2充气(balloon)压力下搅拌反应混合物16h。将反应混合物过滤和浓缩,以给出6.9g(97%,产率)作为棕褐色固体的乙基3-(5-氨基吡啶-2-基)苯甲酸盐。
1H NMR 600MHz(CDCl3)δ8.52(s,1H),8.18(d,J=2.4Hz,1H),8.13(d,J=7.8Hz,1H),8.00(d,J=7.8Hz,1H),7.59(d,J=8.4Hz,1H),7.49(t,J=7.8Hz,1H),7.06(dd,J=2.4Hz,J=8.4Hz,1H),4.40(q,2H),3.82(s,2H),1.48(t,3H),MS m/z:243.35(M+1)。
部分C向乙基3-(5-氨基吡啶-2-基)苯甲酸盐(7.52g,31.06mmol)在DMF(150mL)的溶液中加入N-溴代琥珀酰亚胺(5.58g,31.37mmol),于0℃进行5min。用饱和的NaHCO3溶液(150mL)在0℃将反应混合物淬火。使混合物在乙酸乙酯和水之间进行分配。分离有机层并用乙酸乙酯提取水性层。用卤水清洗组合的有机提取物,在MgSO4上干燥,过滤并浓缩。使用85∶15v/v己烷∶乙酸乙酯作为溶剂、通过快速柱层析法纯化粗制产物,以提供作为红棕色固体的乙基3-(5-氨基-6-溴吡啶-2-基)苯甲酸盐(8.6g,86%产率)。
1H NMR 600MHz(CDCl3)δ8.49(s,1H),8.16(d,J=7.8Hz,1H),8.05(d,J=7.8Hz,1H),7.59(d,J=7.8Hz,1H),7.49(t,J=7.8Hz,1H),7.09(d,J=8.4Hz,1H),4.43(q,2H),4.21(s,2H),1.42(t,3H),MS m/z:321.22(M+1)。
部分D向乙基3-(5-氨基-6-溴吡啶-2-基)苯甲酸盐(10.44g,32.60mmol)在NMP(150mL)的溶液中加入乙基黄原酸钾(26.14g,163.11mmol)和乙酸(9.4mL,163.11mmol)。将反应混合物在150℃加热16小时。将混合物冷却到50℃并加入碘代甲烷(20.3mL,326mmol)。将反应混合物再搅拌30分钟并在乙酸乙酯和水之间进行分配。分离有机层并用乙酸乙酯提取水性层。用卤水清洗组合的有机提取物,在MgSO4上干燥,过滤并浓缩。使用85∶15v/v己烷∶乙酸乙酯作为溶剂、通过快速柱层析法纯化粗制产物,以提供作为明棕色固体的乙基3-(2-(甲硫基)噻唑[5,4-b]吡啶-5-基)苯甲酸盐(7.6g,70%产率)。
1H NMR 600MHz(CDCl3)δ8.67(t,J=1.8Hz,1H),8.27(dt,J=7.8Hz,1H),8.13(d,J=8.4Hz,1H),8.10(dt,J=7.8Hz,1H),7.81(d,J=8.4Hz,1H),7.57(t,1H),4.43(q,2H),2.82(s,3H),1.43(t,3H),MS m/z:331.11(M+1)。
部分E向乙基3-(2-(甲硫基)噻唑[5,4-b]吡啶-5-基)苯甲酸盐(5.6g,16.9mmol)在THF(25mL)和甲醇(25mL)的溶液中加入水(25mL)中的硫酸氢钾(41.55g,67.67mmol)。在室温下搅拌反应混合物16个小时。过滤和浓缩反应混合物以给出5.8g(94%,产率)作为明棕色固体的乙基3-(2-(甲磺酰基)噻唑[5,4-b]吡啶-5-基)苯甲酸盐。
1H NMR 600MHz(DMSO-d6)δ8.77(m,2H),8.47(d,J=7.8Hz,1H),8.44(d,J=8.4Hz,1H),8.09(d,J=7.8Hz,1H),7.71(t,J=7.8Hz,1H),4.38(q,2H),3.62(s,3H),1.35(t,3H),MS m/z:363.09(M+1)。
部分F将乙基3-(2-(甲磺酰基)噻唑[5,4-b]吡啶-5-基)苯甲酸盐(3.6g,9.91mmol)加入IPA(24.8mL,49.57mmol)中的2N氨溶液中。将反应混合物在90℃加热并搅拌30h。在真空中除去溶剂以给出2.7g(91%,粗产率)作为黄色固体的乙基3-(2-氨基噻唑[5,4-b]吡啶-5-基)苯甲酸盐。
1H NMR 600MHz(DMSO-d6)δ8.58(t,J=1.8Hz,1H),8.26(dt,J=1.2Hz,J=7.8Hz,1H),7.93(dt,J=1.2Hz,J=7.8Hz,1H),7.89(s,2H),7.87(d,J=8.4Hz,1H),7.68(d,J=8.4Hz,1H),7.58(t,J=7.8Hz,1H),4.34(q,2H),1.33(t,3H),MS m/z:300.19(M+1)。
部分G向乙基3-(2-氨基噻唑[5,4-b]吡啶-5-基)苯甲酸盐(800mg,2.67mmol)在二氯甲烷(13mL)的溶液中加入吡啶(0.74mL,4.05mmol)和环丙烷甲酰氯(0.27mL,2.94mmol)。将反应混合物搅拌4小时。用二氯甲烷(20mL)稀释反应混合物并用1N水性HCl溶液和卤水清洗,在MgSO4上干燥,过滤并浓缩。不进一步纯化而将粗制产物用于下个步骤。
1H NMR 600MHz(CDCl3)δ10.50(s,1H),8.61(s,1H),8.24(d,J=7.8Hz,1H),8.03(d,J=7.8Hz,1H),7.97(d,J=8.4Hz,1H),7.81(d,J=8.4Hz,1H),7.50(t,1H),4.37(q,2H),2.38(m,1H),1.36(t,3H),0.99(m,4H),MS m/z:368.14(M+1)。
部分H将乙基3-(2-(环丙烷甲酰胺)噻唑[5,4-b]吡啶-5-基)苯甲酸盐(870mg,2.37mmol)溶解在水(3.0mL),THF(3.0mL)和甲醇(3.0mL)的混合物中,继而加入一水氢氧化锂(497mg,11.85mmol)。将反应混合物在室温下搅拌16h并用1N含水HCl中和直至pH=6(用pH试纸监测)。在真空中去除有机溶剂后,收集所产生的棕色固体并干燥,以给出620mg(87%产率)的3-(2-(环丙烷甲酰胺)噻唑[5,4-b]吡啶-5-基)苯甲酸。
MS m/z:340.19(M+1)。
部分I向3-(2-(环丙烷甲酰胺)噻唑[5,4-b]吡啶-5-基)苯甲酸(35mg,0.10mmol)在DMF(1.0mL)的溶液中加入N,N-二异丙基乙胺(50μL,0.31mmol),2-(1H-7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基脲甲烷亚胺鎓六氟磷酸盐(59mg,0.15mmol)和3-(三氟甲基)苯胺(26μL,0.21mmol)。将反应混合物在室温下搅拌16h。用DMSO(1mL)稀释粗制产物并通过制备反相HPLC(乙腈/水梯度)进行纯化,以给出作为TFA盐形式的标题化合物。
1H NMR 600MHz(DMSO-d6)δ12.81(s,1H),10.67(s,1H),8.66(s,1H),8.34(d,J=6.6Hz,1H),8.24(s,1H),8.19(d,J=8.4Hz,1H),8.16(d,J=8.4Hz,1H),8.07(d,J=7.8Hz,1H),8.00(d,J=7.2Hz,1H),7.76(t,J=7.2Hz,1H),7.59(t,J=7.2Hz,1H),7.45(d,J=7.2Hz,1H),2.01(m,1H),0.96(m,4H),MS m/z:483.22(M+1)。
实施例2:3-(2-(2-甲基-6-(哌嗪-1-基)嘧啶-4-基氨基)噻唑[5,4-b]吡啶-5-基)-N-(3-(三氟甲基)苯基)苯酰胺
部分A向乙基3-(2-氨基噻唑[5,4-b]吡啶-5-基)苯甲酸盐(400mg,1.34mmol)在水(2.0mL),THF(2.0mL)和甲醇(2.0mL)的混合物的溶液中加入一水氢氧化锂(281mg,11.85mmol)。将反应混合物在室温下搅拌16h并用并用1N的含水HCl中和直至pH=6(用pH试纸进行监测)。在真空中去除有机溶剂,收集所产生的棕色固体并干燥,以给出310mg(85%产率)的3-(2-氨基噻唑[5,4-b]吡啶-5-基)苯甲酸。
MS m/z:272.18(M+1)。
部分B向3-(2-氨基噻唑[5,4-b]吡啶-5-基)苯甲酸(310mg,1.14mmol)在DMF(5.0mL)的溶液中加入N,N-二异丙基乙胺(0.56mL,3.42mmol),2-(1H-7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基脲甲烷亚胺鎓六氟磷酸盐(649mg,1.71mmol)和3-(三氟甲基)苯胺(0.28mL,2.28mmol)。将反应混合物在室温下搅拌16h。用饱和的NH4Cl溶液(10mL)稀释粗制产物。收集所产生的棕色固体并用水清洗并干燥,以给出320mg(67%产率)的3-(2-氨基噻唑[5,4-b]吡啶-5-基)-N-(3-(三氟甲基)苯基)苯酰胺。
1H NMR 600MHz(DMSO-d6)δ10.64(s,1H),8.57(s,1H),8.24(m,2H),8.06(d,J=7.8Hz,1H),7.91(m,2H),7.87(m,2H),7.71(d,J=7.8Hz,1H),7.60(m,2H),7.44(d,J=7.2Hz,1H),MS m/z:415.20(M+1)。
部分C向3-(2-氨基噻唑[5,4-b]吡啶-5-基)-N-(3-(三氟甲基)苯基)苯酰胺(33mg,0.079mmol)在2-丁醇(1mL)的溶液中加入叔丁基4-(6-氯-2-甲基嘧啶-4-基)哌嗪基-1-羧酸盐(24mg,0.079mmol)和K2CO3(82.5mL)。使用氩气将反应混合物脱气20min,其中加入三(二亚苄基茚丙酮)二钯(0)(4mg,7.1μmol)和9,9-二甲基-4,5-二(二苯基膦)氧杂蒽(4mg,4.7μmol)。将反应摇瓶放入经预热的90℃油浴中。在90℃将反应混合物再搅拌4h,然后将其过滤和浓缩。将粗制反应混合物溶解于二氯甲烷(1mL)中,向其中加入三氟乙酸(30μL,0.40mmol)。将反应混合物搅拌4h。在真空中移除大部分有机溶剂并用DMSO(1mL)稀释粗制产物且通过制备HPLC进行纯化,以给出作为TFA盐的标题化合物。
1H NMR 600MHz(DMSO-d6)δ11.75(s,1H),10.67(s,1H),8.82(bs,1H),8.66(s,1H),8.33(d,J=7.2Hz,1H),8.25(s,1H),8.10(d,J=9.0Hz,1H),8.08(m,2H),7.99(d,J=7.8Hz,1H),7.65(t,1H),7.60(t,1H),7.46(d,J=7.2Hz,1H),6.22(s,1H),3.74(m,4H),3.18(m,4H),2.45(s,3H),MS m/z:591.34(M+1)。
实施例3:3-(2-(3-哌啶-4-基脲)噻唑[5,4-b]吡啶-5-基)-N-(3-(三氟甲基)苯基)苯酰胺
于0℃,向3-(2-氨基噻唑[5,4-b]吡啶-5-基)-N-(3-(三氟甲基)苯基)苯酰胺(50mg,0.12mmol)和三乙基胺(25μL,0.18mmol)在二氯甲烷(1.0mL)的溶液中加入4-硝基氯甲酸苯酯(26mg,0.13mmol)。将反应混合物在室温下搅拌1h。将叔丁基4-氨基哌啶基-1-羧酸盐(36mg,0.18mmole)和三乙基胺(25μL,0.18mmol)加入反应混合物中。将反应混合物搅拌4h,然后在真空中移除溶剂。用二氯甲烷(5mL)稀释反应混合物并用1N的含水HCl和卤水洗涤。在MgSO4上干燥有机层并在真空中浓缩。向二氯甲烷(1mL)中的粗制混合物溶液中加入三氟乙酸(40μL,0.60mmol)。将反应混合物搅拌4h。在真空中移除大部分有机溶剂并用DMSO(1mL)稀释粗制产物且通过制备HPLC纯化,以给出TFA盐形式的标题化合物。
1H NMR 600MHz(DMSO-d6)δ10.68(s,1H),8.65(s,1H),8.32(d,J=8.4Hz,1H),8.26(s,1H),8.13(m,3H),8.00(d,J=7.2Hz,1H),7.66(t,1H),7.62(t,1H),7.47(d,J=8.4Hz,1H),7.31(d,J=6.0Hz,1H),6.09(d,J=7.2Hz,1H),3.62(m,1H),3.28(m,2H),2.93(m,2H),1.88(m,2H),1.45(m,2H),MS m/z:541.20(M+1)。
实施例4:N-(5-(3-(3-(三氟甲基)苯氨基甲酰)苯基)噻唑[5,4-b]吡啶-2-基)哌啶基-4-甲酰胺
向1-(叔丁氧基羰基)哌啶基-4-羧酸(15mg,0.07mmol),1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸(26mg,0.14mmol),4-二甲基氨基吡啶(8mg,0.07mmol)在DMF的溶液中加入3-(2-氨基噻唑[5,4-b]吡啶-5-基)-N-(3-(三氟甲基)苯基)苯酰胺(28mg,0.07mmol)。将反应混合物在室温下搅拌16h。用乙酸乙酯(5mL)稀释反应混合物并用1N的含水HCl和卤水清洗。在MgSO4上干燥有机层并在真空中移除溶剂。向二氯甲烷(1mL)中的粗制混合物溶液中加入三氟乙酸(30μL,0.34mmol)。将反应混合物搅拌4h。在真空中移除大部分有机溶剂并用DMSO(1mL)稀释粗制产物且通过制备HPLC纯化,以给出作为TFA盐形式的标题化合物。
1H NMR 600MHz(DMSO-d6)δ12.71(s,1H),10.71(s,1H),8.69(s,1H),8.46(m,1H),8.36(d,J=8.4Hz,1H),8.27(s,1H),8.24(d,J=8.4Hz,1H),8.20(d,J=9.0Hz,1H),8.09(d,J=7.8Hz,1H),8.03(d,J=7.2Hz,1H),7.68(t,1H),7.62(t,1H),7.47(d,J=7.8Hz,1H),3.66(m,2H),2.96(m,2H),2.88(m,1H),2.06(m,2H),1.83(m,2H),MS m/z:526.32(M+1)。
实施例5:N-(5-(3-(3-(4-((4-乙基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)脲)苯基)噻唑[5,4-b]吡啶-2-基)环丙烷甲酰胺
向3-(2-(环丙烷甲酰胺)噻唑[5,4-b]吡啶-5-基)苯甲酸(150mg,0.44mmol)和三乙基胺(90μL,0.66mmol)在甲苯(2mL)的溶液中加入二苯基磷酰基叠氮化物(0.11mL,0.49mmol)。将所产生的混合物在室温下搅拌30分钟并在80℃加热1h。向反应混合物中加入4-((4-乙基哌嗪-1-基)甲基)-3-(三氟甲基)苯胺(121mg,0.42mmol)和三乙基胺(90μL,0.66mmol)。将反应混合物在80℃下搅拌2h并在真空中去除大多数有机溶剂。用DMSO(3mL)稀释粗制产物并通过制备HPLC进行纯化,以给出作为TFA盐的标题化合物。
1H NMR 600MHz(CDCl3)δ8.51(s,1H),7.83(d,J=1.8Hz,1H),7.48(m,2H),7.19(m,3H),7.12(m,2H),6.85(d,J=3.0Hz,1H),6.49(m,1H),6.19(m,2H),3.84(m,1H),3.78(s,3H),3.46(m,2H),3.19(m,1H),2.90(m,2H),1.99(m,2H),1.69(m,2H),1.19(d,J=6.6Hz,6H),MSm/z:624.36(M+1)。
实施例6:3-(2-(环丙烷甲酰胺)噻唑[5,4-b]吡啶-6-基)-N-(4-((4-乙基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯酰胺
部分A向5-溴-3-硝基吡啶-2-胺(5.00g,23.97mmol)在二噁烷的溶液(115mL)中加入3-(乙氧基羰基)苯基硼酸(4.65g,23.97mmol)和1N Na2CO3水性溶液(92.2mL,92.2mmol)。使用氩气将反应混合物脱气20min,随后加入二氯二(三苯基膦)钯(II)(971mg,1.38mmol)和2-二-叔丁膦基-2′,4′,6′-三异丙基联苯(881mg,2.07mmol)。将反应摇瓶放入经预热的90℃油浴中。在90℃将反应混合物再搅拌10h,然后将其过滤并在乙酸乙酯和水之间进行分配。分离有机层且用乙酸乙酯提取水性层。用卤水清洗组合的有机提取物,在MgSO4上干燥,过滤并浓缩。使用90∶10v/v己烷∶乙酸乙酯作为溶剂、通过快速柱层析法纯化粗制产物,以提供作为棕褐色固体的乙基3-(6-氨基-5-硝基吡啶-3-基)苯甲酸盐(5.2g,78%产率)。
MS m/z:288.23(M+1)。
部分B将叔丁基亚硝酸酯(3.23mL,27.17mmol)、无水氯化铜(II)(2.9g,21.74mmol)和无水乙腈(90mL)温热至70℃。然后按比例地将乙基3-(6-氨基-5-硝基吡啶-3-基)苯甲酸盐(5.2g,18.11mmol)在10分钟的时间段中加入反应溶液中。将反应混合物保持在70℃2小时,然后允许其冷却至室温。然后将反应混合物倒入110mL的20%含水HCl溶液中,继而用乙酸乙酯进行提取。用卤水清洗有机提取物,在MgSO4上干燥、过滤并在真空中浓缩。使用95∶5v/v己烷∶乙酸乙酯作为溶剂,通过快速柱层析法纯化粗制产物,以提供作为棕褐色固体的乙基3-(6-氯-5-硝基吡啶-3-基)苯甲酸盐(3.4g,61%产率)。
MS m/z:307.16(M+1)。
部分C向乙基3-(6-氯-5-硝基吡啶-3-基)苯甲酸盐(3.0g,9.08mmol)在乙酸乙酯的溶液(50mL)中加入二水氯化锡(II)(11.06g,49.01mmol)。将反应混合物在室温下搅拌10小时。使反应混合物冷却至0℃,然后将NH4OH溶液加入反应混合物中并允许其达到约pH=5(用pH试纸进行监测)。用Na2CO3中和反应混合物,过滤所产生的白色固体并用乙醚(100mL)清洗三次。浓缩有机层以给出2.3g(84%,产率)作为棕褐色固体的乙基3-(5-氨基-6-氯吡啶-3-基)苯甲酸盐。
MS m/z:277.20(M+1)。
部分D将硫氰酸铵(303mg,3.98mmol)溶解在丙酮(10mL)中并加热至50℃,这时获得澄清的溶液。逐滴加入环丙烷甲酰氯(0.37mL,3.98mmol)并将所产生的白色悬浮物回流20分钟。将乙基3-(5-氨基-6-氯吡啶-3-基)苯甲酸盐(1.0g,3.62mmol)溶解于二噁烷(18mL)中并将K2CO3(2.0g,14.48mmol)加入反应混合物中。使反应混合物在120℃回流8小时。冷却至室温后,将反应溶液倒入冰水中并通过过滤收集所产生的棕褐色固体、将其用水和乙醚清洗并干燥。不进一步纯化而将粗制产物用于下个步骤。
1H NMR 600MHz(DMSO-d6)δ8.68(d,J=1.8Hz,1H),8.49(s,1H),8.26(d,J=1.8Hz,1H),8.23(s,1H),8.03(d,J=7.2Hz,1H),7.97(d,J=7.8Hz,1H),7.64(t,1H),4.32(q,2H),1.99(m,1H),1.33(t,3H),0.93(m,4H),MS m/z:368.22(M+1)。
部分E将乙基3-(2-(环丙烷甲酰胺)噻唑[5,4-b]吡啶-6-基)苯甲酸盐(900mg,2.45mmol)溶解于水(4.0mL),THF(4.0mL)和甲醇(4.0mL)的混合物中,并加入一水氢氧化锂(513mg,12.23mmol)。将反应混合物在室温下搅拌16h并用1N的含水HCl中和直至pH 6(用pH试纸进行监测)。在真空中去除有机溶剂并通过过滤收集所产生的棕色固体且干燥以给出720mg(86%产率)的3-(2-(环丙烷甲酰胺)噻唑[5,4-b]吡啶-5-基)苯甲酸。
MS m/z:340.20(M+1)。
部分F向3-(2-(环丙烷甲酰胺)噻唑[5,4-b]吡啶-5-基)苯甲酸(40mg,0.12mmol)在DMF(1.0mL)的溶液中加入N,N-二异丙基乙胺(60μL,0.35mmol),2-(1H-7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基脲甲烷亚胺鎓六氟磷酸盐(90mg,0.24mmol)和4-((4-乙基哌嗪-1-基)甲基)-3-(三氟甲基)苯胺(41mg,0.14mmol)。将反应混合物在室温下搅拌16h。用DMSO(1mL)稀释粗制产物并通过制备反相HPLC(乙腈/水梯度)进行纯化,以给出作为TFA盐形式的标题化合物。
1H NMR 600MHz(DMSO-d6)δ12.87(s,1H),10.65(s,1H),9.74(bs,1H),8.47(d,J=1.8Hz,1H),8.37(s,1H),8.23(s,1H),8.11(d,J=8.4Hz,1H),8.06(d,J=7.8Hz,1H),8.01(d,J=7.8Hz,1H),7.73(d,J=8.4Hz,1H),7.68(t,1H),3.69(s,2H),3.48(m,2H),3.14(q,2H),2.98(m,4H),2.45(m,2H),2.05(m,1H),1.20(m,3H),0.99(m,4H),MS m/z:609.37(M+1)。
实施例7:4-(2-(环丙烷甲酰胺)噻唑[4,5-b]吡嗪-6-基)-N-(4-((4-乙基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯酰胺
部分A在50℃将硫氰酸铵(668mg,8.77mmol)与丙酮(10mL)的混合物加热直至获得澄清的溶液。逐滴加入环丙烷甲酰氯(0.80mL,8.77mmol)并将所产生的白色悬浮物回流20分钟。将3,5-二溴吡嗪-2-胺(2.0g,7.97mmol)溶解于丙酮中(18mL)并将K2CO3(4.4g,31.88mmol)加入反应混合物中。使反应混合物回流4小时。冷却至室温后,将反应溶液倒入冰水中,通过过滤收集所产生的棕褐色固体、将其用水和乙醚清洗并干燥。不进一步纯化而将粗制产物(1.6g,67%产率)用于下个步骤。
1H NMR 600MHz(DMSO-d6)δ13.28(s,1H),8.71(s,1H),2.02(m,1H),1.02(m,4H),MS m/z:298.98(M+1)。
部分B向N-(6-溴噻唑[4,5-b]吡嗪-2-基)环丙烷甲酰胺(1.00g,3.36mmol)在二噁烷的溶液(16mL)中加入4-硼酸苯甲酸(557mg,3.36mmol)和1N的Na2CO3水性溶液(13.2mL,13.2mmol)。使用氩气将反应混合物脱气20min,随后加入二氯二(三苯基膦)钯(II)(141mg,0.20mmol)和2-二-叔丁膦基-2′,4′,6′-三异丙基联苯(128mg,0.30mmol)。将反应摇瓶放入经预热的120℃油浴中。在120℃将反应混合物再搅拌10h,然后将其过滤。向过滤物中加入2.0N NaOH溶液直至pH 10(用pH试纸进行监测),然后在乙酸乙酯与水之间进行分配。向水层中加入6.0N的含水HCl溶液直至pH 6(用pH试纸进行监测)。通过过滤收集所产生的棕色固体并干燥,以给出740mg(64%产率)的4-(2-(环丙烷甲酰胺)噻唑[4,5-b]吡嗪-6-基)苯甲酸。
MS m/z:341.18(M+1)。
部分C向4-(2-(环丙烷甲酰胺)噻唑[4,5-b]吡嗪-6-基)苯甲酸(50mg,0.15mmol)在DMF(1.0mL)的溶液中加入N,N-二异丙基乙胺(70μL,0.44mmol),2-(1H-7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基脲甲烷亚胺鎓六氟磷酸盐(112mg,0.29mmol)和4-((4-乙基哌嗪-1-基)甲基)-3-(三氟甲基)苯胺(51mg,0.17mmol)。将反应混合物在室温下搅拌16h。用DMSO(1mL)稀释粗制产物并通过制备反相HPLC(乙腈/水梯度)进行纯化,以给出作为TFA盐的标题化合物。
1H NMR 600MHz(DMSO-d6)δ13.21(s,1H),10.65(s,1H),9.56(bs,1H),9.29(s,1H),8.36(d,J=7.2,1H),8.24(s,1H),8.13(m,3H),7.72(d,J=7.8Hz,1H),3.69(s,2H),3.46(m,2H),3.13(m,2H),2.98(m,4H),2.40(m,2H),2.06(m,1H),1.19(m,3H),1.02(m,4H),MS m/z:610.25(M+1)。
实施例8:3-(2-(环丙烷甲酰胺)噻唑[4,5-b]吡嗪-6-基)-N-(4-((4-乙基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)苯酰胺
向3-(2-(环丙烷甲酰胺)噻唑[5,4-b]吡啶-5-基)苯甲酸(40mg,0.12mmol)在DMF的溶液(1.0mL)中加入N,N-二异丙基乙胺(60μL,0.35mmol),2-(1H-7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基脲甲烷亚胺鎓六氟磷酸盐(90mg,0.24mmol)和4-((4-乙基哌嗪-1-基)甲基)-3-(三氟甲基)苯胺(41mg,0.14mmol)。将反应混合物在室温下搅拌16h。用DMSO(1mL)稀释粗制产物并通过制备反相HPLC(乙腈/水梯度)进行纯化,以给出作为TFA盐形式的标题化合物。
1H NMR 600MHz(DMSO-d6)δ12.87(s,1H),10.65(s,1H),9.74(bs,1H),8.47(d,J=1.8Hz,1H),8.37(s,1H),8.23(s,1H),8.11(d,J=8.4Hz,1H),8.06(d,J=7.8Hz,1H),8.01(d,J=7.8Hz,1H),7.73(d,J=8.4Hz,1H),7.68(t,1H),3.69(s,2H),3.48(m,2H),3.14(q,2H),2.98(m,4H),2.45(m,2H),2.05(m,1H),1.20(m,3H),0.99(m,4H),MS m/z:609.37(M+1)。
实施例9:3-(2-(环丙烷甲酰胺)噻唑[5,4-b]吡啶-5-基)-N-(3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯基)苯酰胺
向3-(2-(环丙烷甲酰胺)噻唑[5,4-b]吡啶-5-基)苯甲酸(40mg,0.12mmol)在DMF(1.0mL)的溶液中加入N,N-二异丙基乙胺(60μL,0.35mmol),2-(1H-7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基脲甲烷亚胺鎓六氟磷酸盐(90mg,0.24mmol)和3-(4-甲基-1H-咪唑-1-基)-5-(三氟甲基)苯胺(34mg,0.14mmol)。将反应混合物在室温下搅拌16h。用DMSO(1mL)稀释粗制产物并通过制备反相HPLC(乙腈/水梯度)进行纯化,以给出作为TFA盐形式的标题化合物。
1H NMR 600MHz(DMSO-d6)δ12.83(s,1H),10.84(s,1H),8.71(s,1H),8.37(d,J=7.2Hz,1H),8.31(s,1H),8.22(m,2H),8.18(d,J=8.4Hz,1H),8.04(d,J=7.8Hz,1H),7.74(s,1H),7.69(t,1H),7.49(s,1H),3.29(s,3H),2.17(s,3H),2.03(m,1H),0.99(m,4H),MS m/z:563.18(M+1)。
化合物和生物学试剂
所有的化合物起初都溶解在DMSO中以制备10mM的储液,然后系列稀释以获得用于体外实验的终浓度。
细胞系和细胞培养物
通过用含有p210BCR-ABL(B2A2)cDNA的pGD载体(Daley andBaltimore,1988;Sattler et al.,1996;Okuda et al.,1996)转染IL-3-依赖性海洋造血Ba/F3细胞系而获得Ba/F3.p210细胞。用逆转录病毒转导海洋造血32D细胞以表达p210Bcr-ABL(32D.p210细胞)(Matulonis et al.,1993);通过用伊马替尼抗性BCR-ABL构建体(pCI-neo哺乳动物表达载体;Promega(#E1841)带有点突变T315I(Weisberg et al.,2005))进行电穿孔而转染32D-T315I细胞系。通过用伊马替尼抗性BCR-ABL构建体(pCI-neo哺乳动物表达载体;Promega(#E1841)带有点突变T315I,F317L,F486S和M351T)进行电穿孔而稳定转染Ba/F3细胞;就新霉素抗性和IL-3-不依赖性生长选择转染物(Weisberg et al.,2005)。通过用BCR-ABL点突变体进行电穿孔而稳定转染Ba/F3细胞,所述点突变体是在就赋予对尼罗替尼的抗性的BCR-ABL点突变体的随机诱变筛选中鉴别的:Q252H,E292K,Y253C,Y253H,E255K和V289L(Ray et al.,2007)。如Golub等人(1994)和Carroll等人(1996)所描述的,使Ba/F3细胞表达Te l-PDGFRβ。将克隆到pcDNA3.1中的D842V-PDGFRα和V561D-PDGFRαcDNA的构建体通过电穿孔稳定转染到Ba/F3细胞中,并且就新霉素抗性和IL-3不依赖性生长对细胞进行选择,如Weisberg等人(2006)所描述的。
以5%CO2、在37℃下、在含有10%胎牛血清(FCS)并补充了1%L-谷氨酸的RPMI(Mediatech,Inc.,Herndon,VA)中培养所有的细胞系。用经15%WEHI条件化的培养基作为IL-3的来源类似地培养亲本Ba/F3细胞。在补充了1mg/ml G418的培养基中培养经转染的细胞系。
抗体和免疫印迹以及免疫沉淀
抗-p-Tyr(克隆4G10,Upstate Biotechnology,NY)以1∶1000用于免疫印迹。ABL抗体(克隆24-21,Calbiochem,San Diego,CA)以1∶1000用于免疫印迹。KIT抗体(C-19,Santa Cruz Biotechnology,CA)以1∶1000用于免疫印迹。磷酸化-KIT抗体(Tyr719,Cell Signaling,Danvers,MA)以1∶1000用于免疫印迹。PDGFRA抗体(C-20,Santa CruzBiotechnology,CA)以1∶200用于免疫印迹。单克隆抗β肌动蛋白抗体(克隆AC-15)(Sigma-Aldrich,St.Louis,MO)以1∶2000的稀释使用。在裂解缓冲液(0.02M Tris[pH 8.0],0.15M NaCl,10%甘油,1%NP-40(wt/vol),0.1M NaF,1mM苯甲基磺酰化氟,1mM原钒酸钠,40μg/ml亮肽酶素和20μg/ml抗蛋白酶肽)中裂解细胞。将蛋白裂解物在冰上孵育25min,以5min的间隔振荡,然后以12,000xg离心15min。保留上清液,并使用Bio-Rad蛋白测定来确定蛋白产率(Bio-RadLaboratories,Hercules,CA)。随后将同等量的蛋白直接加载在凝胶上用于免疫印迹实验。对于免疫沉淀,在4℃下伴随摇动,用FLT3/Flk-2(C-20)抗体和蛋白A琼脂糖过夜孵育细胞裂解物。作为对照,也用单独的蛋白A琼脂糖珠孵育细胞裂解物。孵育之后,用裂解缓冲液清洗免疫复合物两次,并用1xPBS清洗2次,通过煮沸5分钟将其溶解在Laemmeli’s样品缓冲液中。对于免疫印迹和免疫沉淀,分别在十二烷基硫酸钠(SDS)-7.5%聚丙烯酰胺凝胶上辨析全细胞裂解物和免疫复合物。此后,将蛋白质电转移到Protran硝酸纤维素转移和固定膜(Schleicher and Schuell,Dassel,Germany)上。然后在4℃、用1x TBS(10mM Tris-HCl[pH 8.0],150mM NaCl)中的5%脱脂奶粉将所述膜过夜封闭,然后用pTYR、抗体在25℃探测2hr或用1x TBST缓冲液(10mMTris-HCl[pH 8.0],150mM NaCl,0.05%Tween20)中的FLT3/Flk-2(C-20)抗体在4℃过夜探测。用1x TBST清洗3次后,用抗小鼠免疫球蛋白(辣根过氧化酶连接的来自绵羊的全抗体)或抗兔免疫球蛋白(辣根过氧化酶连接的来自驴的全抗体)(Amersham Life Science,Inc.,ArlingtonHeights,IL)在25℃将所述膜孵育1hr。在1x TBST缓冲液中,将膜清洗5次,在缓冲液更换之间有5min的间隔,并且如生产商(NEN LifeScience Products,Boston,MA)所说明的、以增强的鲁米诺(luminol)和氧化试剂检测所结合的抗体。在50℃下,用膜再生液(strippingbuffer)(2%SDS,0.0625mol/L Tris[pH 6.8]和0.7%2-巯基乙醇)移除所结合的抗体30min。然后用其它的抗体探测过滤器。
细胞周期分析
使用约500,000个细胞进行细胞周期分析,其中以1500rpm将所述细胞离心5min,在PBS中清洗,并将粒状沉淀重悬于500μl的碘化丙啶溶液中(50μg/ml碘化丙啶,0.1%NP-40,0.1%柠檬酸钠)。将混合物储存在黑暗中,于4℃至少15min,然后通过流式细胞术进行分析。使用Annexin-V-Fluos染色试剂盒(Boehringer Mannheim,Indianapolis)测量经药物处理的细胞的凋亡。
凋亡测定
用磷酸盐缓冲盐水(PBS)清洗在存在或不存在药物时培养的细胞一次,并以1500rpm离心5min。将经清洗的细胞粒状沉淀重悬于100μl的20%Annexin-V-荧光素标记试剂和HEPES缓冲液中的20%碘化丙啶(PI)中。在室温下孵育细胞15min,随后用0.8ml的HEPES缓冲液进行稀释。然后通过流式细胞术对样品进行分析。作为对照,用单独的PI、单独的Annexin-V-荧光素标记试剂,或HEPES缓冲液孵育细胞15min,然后用HEPES缓冲液进行稀释并通过流式细胞术进行分析。
药物组合研究
对于药物组合研究,以固定的比例将化合物同时加入细胞中,并通过锥蓝排除法测定细胞存活,且表示为经药物处理的细胞相对于对照细胞的受影响的生长的函数(FA)。使用Chou-Talalay方法(Chou andTalalay,1984),通过Calcusyn软件(Biosoft,Ferguson,MO andCambridge,UK)评估协同作用。组合指数=[D]1[Dx]1+[D]2/[Dx]2,其中[D]1和[D]2是达到与单独的每种药物的浓度[Dx]1和[Dx]2相同的效果的、组合中每种药物所需的浓度。小于1的值表示协同作用,而大于1的值表示拮抗作用。
生物发光成像
用编码萤火虫荧光素酶的逆转录病毒(MSCV-Luc)转导细胞,并以2μg/ml的嘌呤霉素进行选择以产生32D.p210-luc+细胞,如Weisberg等人(2005)所述。按照如Weisberg等人(2005)所述的相同的方案,用MSCV-luc-neo载体转导Ba/F3-KIT-T670I细胞。
激酶筛选
对于化合物2使用KINOMEscanTM(Ambit Biosciences,San Diego,CA)(用于针对一大组人类激酶而筛选小分子试剂的高通量方法)。此技术是竞争结合测定,其描绘了化合物2针对350种激酶的选择性,每种激酶都与专有的标签相融合。在化合物2存在和不存在时,测量结合于固定的、针对活性位点的配体的每种激酶的量。
图1描绘了:A)化合物2(表A)的化学结构,其中标示了亚结构的名称;B)基于筛选400种激酶的化合物2的激酶选择性。其中对以10μM检测到了显著的结合亲和力的激酶以剂量应答形式再测试以确定解离常数。红圈的大小与Kd成比例。表IV中列出了数值的Kd;和C)化合物2与Src激酶结构域的晶体结构,其显示出ATP结合位点。化合物2(蓝色棒)和Src(绿色带)被显示为与铰链残基(Y340,M341)、αC-螺旋(E310)、DFG-基序(D404)及V383是氢键相互作用(橙色阴影线)。通过F405的位置使得以“DFG-外”构象结合的化合物是显然的。邻近守门者残基T338处有充足的空间,这为在此位置容忍更大的氨基酸提供了理论基础。
表I.
表I.化合物2在表达BCR-Abl,kit和PDGFR的细胞系中的相对IC50范围。所有的测定都是在2.5-3天期间进行的,除了D842V-PDGFRα、V561D-PDGFRα、Ba/F3-Y572C、Ba/F3-N841I和Ba/F3-D835Y是2天的实验。
表II.
表II.在处理24小时后,化合物2对于表达BCR-Abl,BCR-Abl-T315I,kit-T670I,PDGFRα-T674M和PDGFRα-T674I的细胞的细胞周期进程的影响。
表III.
表III.化合物2在表达BCR-Abl,BCR-Abl-T315I,kit-T670I,PDGFRα-T674M和PDGFRα-T674I的细胞中、在处理大约3天后由化合物2对凋亡的诱导。
表IV.
激酶 | Kd(nM) |
ABL1 | 3.3 |
ABL1(T315I) | 1.2 |
BRAF | 36 |
CDK11 | 32 |
CDK2 | 840 |
CDK3 | 250 |
CDK5 | 150 |
CDK7 | 13 |
DDR1 | 3.4 |
FLT1 | 74 |
FLT3 | 2.3 |
FLT4 | 31 |
HIPK1 | 34 |
KIT | 2.9 |
LOK | 9.5 |
p38-gamma | 100 |
PDGFRA | 7.7 |
PDGFRB | 1.8 |
RET | 5.6 |
TIE2 | 57 |
VEGFR2 | 58 |
表IV.化合物2(表A)的激酶选择性。
等同者
通过利用不超过常规的实验,本领域技术人员将认识到,或者能够确定本文中所描述的具体实施方式和方法的许多等同者。此类等同者意欲被包括在下列权利要求的范围内。
通过引用而并入
本文中所引用的所有专利、公开的专利申请和其它参考文献的全部内容都在本申请中明确地以其全部通过引用而并入。
Claims (67)
1.式I的化合物:
及其药学上可接受的盐;
其中
Q为CH;
R1为C(O)-C3-6-环烷基,芳基,杂芳基,C(O)-芳基,C(O)-C1-6-烷基,或C3-6-环烷基,其中所述芳基或杂芳基可以是经取代的或未取代的;
R2为H,C1-6-烷基或卤素;
R3为H,C(O)-N(H)-芳基或C(O)-N(H)-C1-6-烷基-杂环,其中所述芳基或杂环基团可以是经取代的或未取代的;以及
R4为H,C(O)N(H)-芳基,N(H)C(O)N(H)-芳基或N(H)C(O)芳基,其中所述芳基基团可以是经取代的或未取代的,并且其中R3和R4之一不是H。
2.权利要求1的化合物,其中R1,R3和R4的芳基,杂芳基和杂环基团可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-杂环,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;
其中取代基芳基,杂芳基和杂环基团可进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次。
3.权利要求1或2的化合物,其中R1,R3和R4的芳基,杂芳基和杂环基团可任选地独立地用C1-6-烷基,C1-6-烷氧基,SO2-杂环,C1-6-烷基-杂环,杂环,CF3或杂芳基取代一次或多次;
其中取代基杂环和杂芳基可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
4.权利要求1或2的化合物,其中
R1为C(O)-C3-6-环烷基,嘧啶基,C(O)-C1-6-烷基,C3-6-环烷基,吡啶基,苯基,或C(O)-苯基;
其中R1的嘧啶基,吡啶基和苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;以及
其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
5.权利要求3的化合物,其中
R1为C(O)-C3-6-环烷基,嘧啶基,C(O)-C1-6-烷基,C3-6-环烷基,吡啶基,苯基或C(O)-苯基;
其中R1的嘧啶基,吡啶基和苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;以及
其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
6.权利要求1或2的化合物,其中
R3为H,C(O)-N(H)-苯基,C(O)-N(H)-(CH2)2-吗啉基或C(O)-N(H)-C1-6-烷基-吗啉基;
其中R3的吗啉基和苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;以及
其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
7.权利要求3的化合物,其中
R3为H,C(O)-N(H)-苯基,C(O)-N(H)-(CH2)2-吗啉基或C(O)-N(H)-C1-6-烷基-吗啉基;
其中R3的吗啉基和苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;以及
其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
8.权利要求4的化合物,其中
R3为H,C(O)-N(H)-苯基,C(O)-N(H)-(CH2)2-吗啉基或C(O)-N(H)-C1-6-烷基-吗啉基;
其中R3的吗啉基和苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;以及
其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
9.权利要求5的化合物,其中
R3为H,C(O)-N(H)-苯基,C(O)-N(H)-(CH2)2-吗啉基或C(O)-N(H)-C1-6-烷基-吗啉基;
其中R3的吗啉基和苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;以及
其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
10.权利要求1或2的化合物,其中
R4为H,C(O)N(H)Ph,N(H)C(O)N(H)Ph或N(H)C(O)Ph;
其中R4的苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;
其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
11.权利要求3的化合物,其中
R4为H,C(O)N(H)Ph,N(H)C(O)N(H)Ph,或N(H)C(O)Ph;
其中R4的苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;
其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
12.权利要求4的化合物,其中
R4为H,C(O)N(H)Ph,N(H)C(O)N(H)Ph或N(H)C(O)Ph;
其中R4的苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;
其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
13.权利要求5的化合物,其中
R4为H,C(O)N(H)Ph,N(H)C(O)N(H)Ph或N(H)C(O)Ph;
其中R4的苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;
其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
14.权利要求6的化合物,其中
R4为H,C(O)N(H)Ph,N(H)C(O)N(H)Ph或N(H)C(O)Ph;
其中R4的苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;
其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
15.权利要求7的化合物,其中
R4为H,C(O)N(H)Ph,N(H)C(O)N(H)Ph或N(H)C(O)Ph;
其中R4的苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;
其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
16.权利要求8的化合物,其中
R4为H,C(O)N(H)Ph,N(H)C(O)N(H)Ph或N(H)C(O)Ph;
其中R4的苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;
其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
17.权利要求9的化合物,其中
R4为H,C(O)N(H)Ph,N(H)C(O)N(H)Ph或N(H)C(O)Ph;
其中R4的苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;
其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
18.权利要求1或2的化合物,其中R3和R4中的至少一个不是H。
19.权利要求3的化合物,其中R3和R4中的至少一个不是H。
20.权利要求4的化合物,其中R3和R4中的至少一个不是H。
21.权利要求5的化合物,其中R3和R4中的至少一个不是H。
22.权利要求6的化合物,其中R3和R4中的至少一个不是H。
23.权利要求7的化合物,其中R3和R4中的至少一个不是H。
24.权利要求8的化合物,其中R3和R4中的至少一个不是H。
25.权利要求9的化合物,其中R3和R4中的至少一个不是H。
26.权利要求10的化合物,其中R3和R4中的至少一个不是H。
27.权利要求11的化合物,其中R3和R4中的至少一个不是H。
28.权利要求12的化合物,其中R3和R4中的至少一个不是H。
29.权利要求13的化合物,其中R3和R4中的至少一个不是H。
30.权利要求14的化合物,其中R3和R4中的至少一个不是H。
31.权利要求15的化合物,其中R3和R4中的至少一个不是H。
32.权利要求16的化合物,其中R3和R4中的至少一个不是H。
33.权利要求17的化合物,其中R3和R4中的至少一个不是H。
34.权利要求1或2的化合物,其中
R1为C(O)-C3-6-环烷基,嘧啶基,C(O)C1-6-烷基,C3-6-环烷基,吡啶基,Ph-SO2-哌嗪基,C(O)-PhCH2-哌嗪基-C1-6-烷基,或Ph-哌嗪基-C1-6-烷基,其中嘧啶基任选地独立地用C1-6-烷基或哌嗪基取代一次或多次,并且其中哌嗪基任选地用C1-6-烷基-OH取代。
35.权利要求1或2的化合物,其中R3为H,C(O)-N(H)-Ph,C(O)-N(H)-C1-6-烷基-吗啉基或C(O)-N(H)-C1-6-烷基-吗啉基,其中Ph任选地用CF3,C1-6-烷基-哌嗪基-C1-6-烷基或咪唑-C1-6-烷基取代一次或多次。
36.权利要求1或2的化合物,其中R4为H,C(O)N(H)Ph或N(H)C(O)N(H)Ph,其中Ph基团任选地独立地用CF3,C1-6-烷基-哌嗪基-C1-6-烷基,咪唑-C1-6-烷基,咪唑,四唑,吡唑,哌嗪基,C1-6-烷基-哌嗪基-C1-6-烷基,吗啉基,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-咪唑,C1-6-烷基-吗啉基,C1-6-烷基-哌啶基-OH,C1-6-烷基-哌嗪基-C1-6-烷基),咪唑-C1-6-烷基,哌嗪基-C1-6-烷基-OH或O-哌啶基-C1-6-烷基取代一次或多次。
37.权利要求1或2的化合物,其中
R1为C(O)-环丙基,嘧啶基,C(O)CH3,环丙基,吡啶基,Ph-SO2-哌嗪基,C(O)-PhCH2-哌嗪基-CH2CH3,或Ph-哌嗪基-CH3,其中嘧啶基用CH3和哌嗪基取代且该哌嗪基任选地用(CH2)2OH取代;
R2为H,CH3,F或Cl;
R3为H,C(O)-N(H)-Ph,C(O)-N(H)-(CH2)2-吗啉基或C(O)-N(H)-(CH2)3-吗啉基,其中Ph用CF3和CH2-哌嗪基-CH2CH3取代或者用CF3和咪唑-CH3取代;以及
R4为H,C(O)N(H)Ph-CF3,N(H)C(O)N(H)Ph(CF3)(CH2-哌嗪基-CH2CH3),C(O)N(H)Ph(CF3)(CH2-哌嗪基-CH2CH3),C(O)N(H)Ph(CF3)(咪唑-CH3),C(O)N(H)Ph-咪唑,C(O)N(H)Ph-四唑,C(O)N(H)Ph-吡唑,C(O)N(H)Ph(CF3)(哌嗪基),C(O)N(H)Ph-CH2-哌嗪基-CH2CH3,C(O)-N(H)Ph-吗啉基,C(O)-N(H)Ph-叔-丁基,C(O)N(H)Ph(OCH2CH3)(吗啉基),C(O)N(H)Ph(OCH3)(吗啉基),C(O)N(H)Ph(OCH3)2,N(H)C(O)Ph(CF3)(CH2-哌啶基-OH),N(H)C(O)Ph(CF3)(CH2-哌嗪基-CH2CH3),N(H)C(O)N(H)Ph(CF3)(咪唑-CH3),N(H)C(O)Ph(CF3)(哌嗪基-(CH2)2OH)或N(H)C(O)Ph(CF3)(O-哌啶基-CH3)。
38.由式II表示的化合物:
或其药学上可接受的盐,
其中
Q为CH;
R1为C(O)-C3-6-环烷基,C(O)-芳基,C(O)-C1-6-烷基,或C3-6-环烷基;
R2和R3为H;以及
R4为C(O)N(H)-芳基,N(H)C(O)N(H)-芳基,或N(H)C(O)芳基,其中芳基基团可以是经取代的或未取代的。
39.权利要求38的化合物,其中
R1为C(O)-C3-6-环烷基;
R4为C(O)N(H)Ph,其中Ph基团任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次,其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
40.权利要求38-39中任一项的化合物,其中
R1为C(O)-C3-6-环烷基;
R4为C(O)N(H)Ph,其中Ph基团任选地独立地用CF3,C1-6-烷基-哌嗪基或咪唑取代一次或多次;
其中取代基哌嗪基或咪唑任选地独立地用C1-6-烷基取代一次或多次。
41.权利要求38-39中任一项的化合物,其中Ph任选地独立地用CF3,哌嗪基,C1-6-烷基-哌嗪基,C1-6-烷基-哌嗪基-C1-6-烷基,CH2CH3,咪唑或咪唑-C1-6-烷基取代一次或多次。
42.式III的化合物:
及其药学上可接受的盐;
其中
G为CR10;
R1为C(O)-C3-6-环烷基,嘧啶基,C(O)N(H)-哌啶基,C(O)-C1-6-烷基,C3-6-环烷基,吡啶基,苯基或C(O)-苯基;
其中R1的嘧啶基,哌啶基,吡啶基和苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;并且其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次;
R10为H或C1-3烷基;
R12为H,C1-6-烷基或卤素;
R13为H,C(O)-N(R28)-芳基或C(O)-N(R29)-C1-6-烷基-杂环,其中芳基或杂环基团任选地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-杂环,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素中的一个或多个取代;
其中取代基芳基,杂芳基和杂环基团可进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;以及
R14为H,C(O)NR15-芳基,NR16C(O)NR17-芳基,或NR25C(O)芳基,其中芳基基团任选地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-杂环,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素中的一个或多个取代;
其中取代基芳基,杂芳基和杂环基团可进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;
其中R13和R14之一不是H;并且
R15,R16,R17,R25,R28和R29为C1-6烷基,卤素或H。
43.权利要求42的化合物,其中
R12为H,CH3,F或Cl;
R13为H,C(O)-N(H)-Ph,C(O)-N(H)-(CH2)2-吗啉基或C(O)-N(H)-(CH2)3-吗啉基,其中Ph用CF3和CH2-哌嗪基-CH2CH3取代或者用CF3和咪唑-CH3取代;以及
R14为C(O)N(H)Ph-CF3,N(H)C(O)N(H)Ph(CF3)(CH2-哌嗪基-CH2CH3),C(O)N(H)Ph(CF3)(CH2-哌嗪基-CH2CH3),C(O)N(H)Ph(CF3)(咪唑-CH3),C(O)N(H)Ph-咪唑,C(O)N(H)Ph-四唑,C(O)N(H)Ph-吡唑,C(O)N(H)Ph(CF3)(哌嗪基),C(O)N(H)Ph-CH2-哌嗪基-CH2CH3,C(O)-N(H)Ph-吗啉基,C(O)-N(H)Ph-叔-丁基,C(O)N(H)Ph(OCH2CH3)(吗啉基),C(O)N(H)Ph(OCH3)(吗啉基),C(O)N(H)Ph(OCH3)2,N(H)C(O)Ph(CF3)(CH2-哌啶基-OH),N(H)C(O)Ph(CF3)(CH2-哌嗪基-CH2CH3),N(H)C(O)N(H)Ph(CF3)(咪唑-CH3),N(H)C(O)Ph(CF3)(哌嗪基-(CH2)2OH)或N(H)C(O)Ph(CF3)(O-哌啶基-CH3)。
44.式I的化合物:
或其药学上可接受的盐;
其中
Q为CH;
R1为C(O)-C3-6-环烷基,芳基,杂芳基,C(O)-芳基,或C3-6-环烷基,其中所述芳基或杂芳基可以是经取代的或未取代的;
R2为H,C1-6-烷基或卤素;
R3为H,C(O)-N(H)-芳基或C(O)-N(H)-C1-6-烷基-杂环,其中所述芳基或杂环基团可以是经取代的或未取代的;以及
R4为H,C(O)N(H)-芳基,N(H)C(O)N(H)-芳基,或N(H)C(O)芳基,其中所述芳基基团可以是经取代的或未取代的,并且其中R3和R4中的至少一个不是H。
45.权利要求44的化合物或其药学上可接受的盐,其中
R1,R3和R4的芳基,杂芳基和杂环基团可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-杂环,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;其中取代基芳基,杂芳基和杂环基团可进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次。
46.权利要求44的化合物或其药学上可接受的盐,其中
R1为C(O)-C3-6-环烷基,嘧啶基,C3-6-环烷基,吡啶基,苯基或C(O)-苯基;其中R1的嘧啶基,吡啶基和苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;以及其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次;
R3为H,C(O)-N(H)-苯基或C(O)-N(H)-C1-6-烷基-吗啉基;其中R3的吗啉基和苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;以及其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次;以及
R4为H,C(O)N(H)Ph,N(H)C(O)N(H)Ph,或N(H)C(O)Ph;其中R4的苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
47.权利要求44的化合物或其药学上可接受的盐,其中
R1为C(O)-C3-6-环烷基,嘧啶基,C3-6-环烷基,吡啶基,Ph-SO2-哌嗪基,C(O)-PhCH2-哌嗪基-C1-6-烷基,或Ph-哌嗪基-C1-6-烷基,其中嘧啶基任选地独立地用C1-6-烷基或哌嗪基取代一次或多次,并且其中哌嗪基任选地用C1-6-烷基-OH取代;
R3为H,C(O)-N(H)-Ph,C(O)-N(H)-C1-6-烷基-吗啉基或C(O)-N(H)-C1-6-烷基-吗啉基,其中Ph任选地用CF3,C1-6-烷基-哌嗪基-C1-6-烷基或咪唑-C1-6-烷基取代一次或多次;以及
R4为H,C(O)N(H)Ph或N(H)C(O)N(H)Ph,其中Ph基团任选地独立地用CF3,C1-6-烷基-哌嗪基-C1-6-烷基,咪唑-C1-6-烷基,咪唑,四唑,吡唑,哌嗪基,C1-6-烷基-哌嗪基-C1-6-烷基,吗啉基,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-咪唑,C1-6-烷基-吗啉基,C1-6-烷基-哌啶基-OH,C1-6-烷基-哌嗪基-C1-6-烷基,咪唑-C1-6-烷基,哌嗪基-C1-6-烷基-OH或O-哌啶基-C1-6-烷基取代一次或多次。
48.权利要求44的化合物或其药学上可接受的盐,其中
R1为C(O)-环丙基,嘧啶基,环丙基,吡啶基,Ph-SO2-哌嗪基,C(O)-PhCH2-哌嗪基-CH2CH3,或Ph-哌嗪基-CH3,其中嘧啶基用CH3和哌嗪基取代且该哌嗪基任选地用(CH2)2OH取代;
R2为H,CH3,F或Cl;
R3为H,C(O)-N(H)-Ph,C(O)-N(H)-(CH2)2-吗啉基或C(O)-N(H)-(CH2)3-吗啉基,其中Ph用CF3和CH2-哌嗪基-CH2CH3取代或者用CF3和咪唑-CH3取代;以及
R4为H,C(O)N(H)Ph-CF3,N(H)C(O)N(H)Ph(CF3)(CH2-哌嗪基-CH2CH3),C(O)N(H)Ph(CF3)(CH2-哌嗪基-CH2CH3),C(O)N(H)Ph(CF3)(咪唑-CH3),C(O)N(H)Ph-咪唑,C(O)N(H)Ph-四唑,C(O)N(H)Ph-吡唑,C(O)N(H)Ph(CF3)(哌嗪基),C(O)N(H)Ph-CH2-哌嗪基-CH2CH3,C(O)-N(H)Ph-吗啉基,C(O)-N(H)Ph-叔-丁基,C(O)N(H)Ph(OCH2CH3)(吗啉基),C(O)N(H)Ph(OCH3)(吗啉基),C(O)N(H)Ph(OCH3)2,N(H)C(O)Ph(CF3)(CH2-哌啶基-OH),N(H)C(O)Ph(CF3)(CH2-哌嗪基-CH2CH3),N(H)C(O)N(H)Ph(CF3)(咪唑-CH3),N(H)C(O)Ph(CF3)(哌嗪基-(CH2)2OH)或N(H)C(O)Ph(CF3)(O-哌啶基-CH3)。
49.一种化合物或其药学上可接受的盐,其中所述化合物由式II表示:
或其药学上可接受的盐
其中
Q为CH;
R1为C(O)-C3-6-环烷基,C(O)-芳基或C3-6-环烷基;
R2和R3为H;以及
R4为C(O)N(H)-芳基,N(H)C(O)N(H)-芳基,或N(H)C(O)芳基,其中芳基基团可以是经取代的或未取代的。
50.权利要求49的化合物或其药学上可接受的盐,其中
R1为C(O)-C3-6-环烷基;
R4为C(O)N(H)Ph,其中Ph基团任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次,其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次。
51.权利要求50的化合物或其药学上可接受的盐,其中Ph任选地独立地用CF3,哌嗪基,C1-6-烷基-哌嗪基,C1-6-烷基-哌嗪基-C1-6-烷基,CH2CH3,咪唑或咪唑-C1-6-烷基取代一次或多次。
52.式III的化合物:
或其药学上可接受的盐;
其中
G为CR10;
R1为C(O)-C3-6-环烷基,嘧啶基,C(O)N(H)-哌啶基,C3-6-环烷基,吡啶基,苯基或C(O)-苯基;
其中R1的嘧啶基,哌啶基,吡啶基和苯基可任选地独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;并且其中取代基芳基,杂芳基和杂环基团可任选地进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-OH或C(O)-C1-6-烷基取代一次或多次,
R10为H或C1-3烷基;
R12为H,C1-6-烷基或卤素;
R13为H,C(O)-N(R28)-芳基或C(O)-N(R29)-C1-6-烷基-杂环,其中芳基或杂环基团任选地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-杂环,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素中的一个或多个取代;
其中取代基芳基,杂芳基和杂环基团可进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;以及
R14为H,C(O)NR15-芳基,NR16C(O)NR17-芳基,或NR25C(O)芳基,其中芳基基团任选地用OH,C1-6-烷基,C1-6-烷氧基,C1-6-烷基-杂环,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素中的一个或多个取代;
其中取代基芳基,杂芳基和杂环基团可进一步独立地用OH,C1-6-烷基,C1-6-烷氧基,C(O)-C1-6-烷基,CO2-C1-6-烷基,芳基,杂芳基,杂环,SO2-杂环,SO2-芳基,SO2-杂芳基,C1-6-烷基-杂环,C1-6-烷基-芳基,C1-6-烷基-杂芳基,CF3或卤素取代一次或多次;
其中R13和R14之一不是H;并且
R15,R16,R17,R25,R28和R29为C1-6烷基,卤素或H。
53.权利要求52的化合物或其药学上可接受的盐,其中
R12为H,CH3,F或Cl;
R13为H,C(O)-N(H)-Ph,C(O)-N(H)-(CH2)2-吗啉基或C(O)-N(H)-(CH2)3-吗啉基,其中Ph用CF3和CH2-哌嗪基-CH2CH3取代或者用CF3和咪唑-CH3取代;以及
R14为H,C(O)N(H)Ph-CF3,N(H)C(O)N(H)Ph(CF3)(CH2-哌嗪基-CH2CH3),C(O)N(H)Ph(CF3)(CH2-哌嗪基-CH2CH3),C(O)N(H)Ph(CF3)(咪唑-CH3),C(O)N(H)Ph-咪唑,C(O)N(H)Ph-四唑,C(O)N(H)Ph-吡唑,C(O)N(H)Ph(CF3)(哌嗪基),C(O)N(H)Ph-CH2-哌嗪基-CH2CH3,C(O)-N(H)Ph-吗啉基,C(O)-N(H)Ph-叔-丁基,C(O)N(H)Ph(OCH2CH3)(吗啉基),C(O)N(H)Ph(OCH3)(吗啉基),C(O)N(H)Ph(OCH3)2,N(H)C(O)Ph(CF3)(CH2-哌啶基-OH),N(H)C(O)Ph(CF3)(CH2-哌嗪基-CH2CH3),N(H)C(O)N(H)Ph(CF3)(咪唑-CH3),N(H)C(O)Ph(CF3)(哌嗪基-(CH2)2OH)或N(H)C(O)Ph(CF3)(O-哌啶基-CH3)。
54.选自下式的化合物及其药学上可接受的盐:
55.权利要求1、2、38、42、44、49、52和54中任一项的化合物在制备用于治疗受试者中癌症的药物的用途。
56.权利要求55的用途,其中所述癌症选自多发性骨髓瘤,慢性骨髓性白血病,胰腺癌,非小细胞肺癌,肺癌,乳腺癌,结肠癌,卵巢癌,前列腺癌,恶性黑色素瘤,非黑色素瘤皮肤癌,胃肠道基质瘤,血液肿瘤,血液恶性疾病,儿童白血病,儿童淋巴瘤,霍奇金病,淋巴细胞起源的淋巴瘤,皮肤起源的淋巴瘤,急性白血病,慢性白血病,急性淋巴细胞白血病,急性髓细胞白血病,慢性髓细胞白血病,浆细胞肿瘤,淋巴肿瘤和与AIDS相关的癌症。
57.权利要求55的用途,其中所述癌症为胰腺癌或非小细胞肺癌。
58.权利要求55的用途,其中所述癌症为胃肠道基质瘤或慢性骨髓性白血病。
59.权利要求55的用途,其中所述癌症为对于用伊马替尼治疗有抗性的。
60.权利要求59的用途,其中治疗抗性是由于Abl激酶,BCR-Abl激酶结构域,c-kit激酶,Src激酶或PDGFR激酶中的一个或多个点突变。
61.权利要求1、2、38、42、44、49、52和54中任一项的化合物在制备用于抑制激酶活性的药物中的用途,其中所述激酶选自Abl,Abl(T315I),BCR-Abl,BRAF,CDK11,CDK5,CDK2,CDK3,CDK7,DDR1,FLT1,FLT3,FLT4,HIPK1,kit,LOK,p38-gamma,PDGFRA,PDGFRB,Src,RET,TIE2和VEGFR2。
62.权利要求61的用途,其中所述激酶选自Abl,BCR-Abl,c-kit,PDGFRA或PDGFRB以及Src。
63.权利要求61的用途,其中所述激酶选自Abl,BCR-Abl,c-kit,Src以及PDGFR。
64.权利要求1、2、38、42、44、49、52和54中任一项的化合物在制备用于治疗癌症的药物中的用途,所述药物与药学上有效量的其它抗癌试剂相组合。
65.权利要求64的用途,其中其它抗癌试剂为伊马替尼或尼罗替尼。
66.权利要求64的用途,其中其它抗癌试剂为伊马替尼。
67.权利要求64的用途,其中其它抗癌试剂为尼罗替尼。
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WO2010144909A1 (en) | 2010-12-16 |
JP6073677B2 (ja) | 2017-02-01 |
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EP2440058A4 (en) | 2012-11-21 |
CN102480966A (zh) | 2012-05-30 |
US20120088766A1 (en) | 2012-04-12 |
US9505784B2 (en) | 2016-11-29 |
EP2440058A1 (en) | 2012-04-18 |
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