CN108473476B - 用于抑制蛋白激酶活性的炔基杂环类化合物 - Google Patents
用于抑制蛋白激酶活性的炔基杂环类化合物 Download PDFInfo
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- CN108473476B CN108473476B CN201780004843.0A CN201780004843A CN108473476B CN 108473476 B CN108473476 B CN 108473476B CN 201780004843 A CN201780004843 A CN 201780004843A CN 108473476 B CN108473476 B CN 108473476B
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- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
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Landscapes
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Abstract
本发明涉及对蛋白激酶活性具有抑制作用的炔基杂环类化合物,以及涉及它们的制备和用途。具体地,该发明公开了式(I)所示的炔基杂环类化合物以及含有该化合物、其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素变体的药物组合物。本发明化合物可作为蛋白激酶抑制剂,用于制备抗肿瘤药物。
Description
技术领域
本发明属于医药领域。具体地,本发明涉及对蛋白激酶活性具有抑制作用的炔基杂环类化合物,包含它们的药物组合物,以及它们的制备方法和用途。
背景技术
蛋白酪氨酸激酶(PTKs)是一类能够催化ATP上γ-磷酸转移到蛋白酪氨酸残基上的激酶,通过催化多种蛋白酪氨酸残基上的酚羟基发生磷酸化,进而激活功能蛋白作用的蛋白质酶系。蛋白酪氨酸激酶在细胞内的信号传导通路中占据十分重要的地位,可调节细胞生长、分化、死亡等一系列生理生化过程。蛋白酪氨酸激酶的异常表达可以导致细胞增殖调节发生紊乱,进而导致肿瘤的发生。此外,蛋白酪氨酸激酶的异常表达还与肿瘤的侵袭和转移,肿瘤新生血管的生成,肿瘤的化疗抗药性密切相关。
Bcr-Abl融合基因表达出的酪氨酸激酶能引起细胞增殖、黏附和生存性质的改变,导致多种肿瘤的产生。例如,人体9号染色体上的癌基因c-Abl链接到22号染色体上的断点簇集区(Bcr),形成p210 Bcr-Abl融合基因和p185 Bcr-Abl融合基因,这两种融合基因使相应的Bcr-Abl酪氨酸激酶持续激活,引起细胞增殖、黏附和生存性质的改变,分别导致产生慢性粒细胞白血病(CML)和急性粒细胞白血病(ALL)。抑制Bcr-Abl酪氨酸激酶可有效抑制肿瘤生长。
在过去20多年中,研究人员发现Bcr-Abl激酶在细胞信号转导和转化中发挥重要作用,它通过磷酸化和活化一系列下游底物,促使CML成熟粒细胞无限增生。Bcr-Abl在正常细胞中不表达,所以它是治疗CML理想的药物靶标。20世纪90年代初,研究人员期望通过RNA途径抑制Bcr-Abl融合基因发挥作用,但没能有效治疗CML。随着融合基因结构和表达产物的阐明,研究者把注意力转移到能直接作用于Bcr-Abl蛋白的小分子药物的设计和开发上。
目前临床上最常用的针对Bcr-Abl酪氨酸激酶的小分子抑制剂(TKI)包括:第一代药物伊马替尼(Imatinib);第二代药物达沙替尼(Dasatinib)、尼洛替尼(Nilotinib)和伯舒替尼(Bosutinib);第三代药物普纳替尼(Ponatinib)。伊马替尼是瑞士诺华公司研发的口服抗慢性粒细胞白血病小分子酪氨酸激酶抑制剂。它开创了以激酶为靶标治疗疾病的新时代,伊马替尼能够与Bcr-Abl激酶区域的ATP位点结合,阻止氨基酸残基磷酸化,从而阻断信号传导途径,抑制细胞增殖,可以有效缓解CML。治疗后患者5年存活率可达90%,并且它能特异性的作用于CML癌细胞,而对正常细胞几乎没有伤害,毒副作用大大降低。随着伊马替尼的使用,Bcr-Abl基因的突变导致了耐药性的出现,很大程度上降低了伊马替尼的疗效。达沙替尼是一种针对Bcr-Abl酪氨酸激酶、Src激酶家族(Src,Lck,Fyn)、c-Kit和PDGFR-B等多种激酶都作用的多靶点口服激酶抑制剂,于2006年6月28日由百时美施贵宝研发获得FDA批准上市。和伊马替尼一样,竞争性地和Bcr-Abl激酶区域的ATP位点结合,但是抑制Bcr-Abl激酶的活性是伊马替尼的300倍。尽管能克服多种伊马替尼出现的耐药性,但对T315I突变无效。尼洛替尼一种新型苯胺嘧啶类的衍生物,于2007年10月29日获得美国FDA批准上市。它对Bcr-Abl激酶的亲和力比伊马替尼强20倍,并且对出现伊马替尼耐药性的患者(T315I突变除外)有广泛的活性。使用尼洛替尼治疗CML的大多数患者会存在肠胃反应、骨髓抑制、高胆红素血症等常见的不良反应。针对伊马替尼、达沙替尼和尼洛替尼所产生的耐药性,美国惠氏制药公司研发了4-取代苯胺-3-喹啉加甲腈类药物伯舒替尼,用于治疗CML,于2012年9月4日被FDA批准上市。博舒替尼既能抑制多种人肿瘤细胞中Src蛋白的自主磷酸化,也能抑制Bcr-Abl蛋白的自主磷酸化,并且在针对KU812和K562细胞(含Bcr-Abl的CML细胞)的抗增殖试验中,博舒替尼活性要明显高于伊马替尼,另外其口服生物利用度较高,但是接受博舒替尼治疗的患者经常会出现腹痛、腹泻、血小板减少、发热和疲劳等不良发应。普纳替尼是一种能够作用于Abl,PDGFRα,VEGFR2,FGFR1和Src激酶的口服多靶点抑制剂。由于它独特的作用机制,服用可抑制对T315I突变在内的Bcr-Abl激酶活性。但是据FDA最新报道服用Ponatinib的患者,会出现严重的心血管问题。
因此,有必要进一步研发新的Bcr-Abl抑制剂,并在降低其副作用的同时,能够有效抑制对T315I突变在内的Bcr-Abl激酶活性。
发明内容
本发明提供了一种新的炔基杂环类化合物及包含该化合物的组合物及其用途,其具有更好的Bcr-Abl激酶抑制活性和/或具有更好药效学/药代动力学性能,且具有较小的毒性,可用于制备由Bcr-Abl激酶介导的疾病的药物。
对此,本发明采用的技术方案如下:
本发明的第一方面中,提供了一种式(I)所示的炔基杂环类化合物,
其中,环A为5-6元杂芳环或者5-6元杂环;其中,所述杂芳环或杂环包含1-3个选自N、O和S的杂原子,且所述环可被选自氢、卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、羧基、氧代基团、C3-C7环烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、C3-C7杂环烷基、C3-C7杂环烯基、C1-C6烷硫基、C1-C6烷氨基或C1-C6烷酰基中的取代基所取代;
K选自CH、NH或者S;
M选自CH、C或者N;
X1、X2、X3、X4和X5独立地为N或CR1,R1独立地为H、羟基、卤素、硅烷基、腈基、硝基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-7杂环烷基或C3-7杂环烯基;
L选自O、S、NR2、CR2R2、C(=O)、C(=O)NR2、NR2C(=O)、NR2C(=O)NR2、OC(=O)NR2、NR2C(=O)O、S(=O)、S(=O)2、S(=O)NR2、S(=O)2NR2、NR2S(=O)、NR2S(=O)2、NR2S(=O)NR2、NR2S(=O)2NR2、OP(=O)R2、P(=O)OR2,其中R2独立选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基基、C1-6卤代烷氧基、C3-7环烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-7杂环烷基或C3-7杂环烯基;
环C为含有1-5个取代基的5-6元芳环或含有1-5个取代基的5-6元杂芳环,所述取代基可选自卤素、-R、-CN、-COOH、-OH、-SH、-OR、-C(=O)R、-C(=O)OR、-OC(=O)R、-S(=O)R、-S(=O)2R、-NR2、-NHC(=O)R、-NHC(=O)OR、-C(=O)NHR、-C(=O)ONHR,其中R独立地为H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-7杂环烷基或C3-7杂环烯基;两个相邻的R与其所连接的环C上的碳原子可一起形成任选取代的C5-8碳环基、任选取代的5至8元杂环基、任选取代的C6-14芳基或任选取代的5至10元杂芳基;
或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素变体。
在另一方面,本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物。在具体实施方案中,本发明化合物以有效量提供在所述药物组合物中。在具体实施方案中,本发明化合物以治疗有效量提供。在具体实施方案中,本发明化合物以预防有效量提供。
在另一方面,本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物,其还含有其它治疗剂。
在另一方面,本发明提供了包含本发明化合物、其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素变体,和其它治疗剂以及药学上可接受的载剂、佐剂或媒剂的试剂盒。
在另一个方面,本发明提供了一种将本发明化合物用于制备抗肿瘤或其他疾病的药物的用途,在具体实施方案中,所述疾病是由Bcr-Abl导致的增殖性疾病。
在具体实施方案中,所述疾病可选自:实体瘤、肉瘤、慢性髓性白血病、慢性粒细胞白血病、胃肠道间质瘤、急性粒细胞白血病、甲状腺癌、胃癌、直肠癌、多发性骨髓瘤、瘤形成以及其他增生性或增殖性疾病。
在具体实施方案中,所述Bcr-Abl导致的病症是慢性粒细胞白血病、胃肠道间质瘤、急性粒细胞白血病、甲状腺癌或其组合。
在具体实施方案中,口服、皮下、静脉内或肌肉内给药所述化合物。在具体实施方案中,长期给药所述化合物。
由随后的具体实施方式、实施例和权利要求,本发明的其它目的和优点将对于本领域技术人员显而易见。
定义
化学定义
下面更详细地描述具体官能团和化学术语的定义。
当列出数值范围时,既定包括每个值和在所述范围内的子范围。例如“C1-C6烷基”包括C1、C2、C3、C4、C5、C6、C1-C6、C1-C5、C1-C4、C1-C3、C1-C2、C2-C6、C2-C5、C2-C4、C2-C3、C3-C6、C3-C5、C3-C4、C4-C6、C4-C5和C5-C6烷基。
应该理解,当本文描述时,任何下面所定义的部分可以被许多取代基取代,而且相应的定义在下面列出的它们的范围内,包括这种取代部分。除非另作说明,否则,术语“取代”如下面所定义。
“C1-C6烷基”是指具有1至6个碳原子的直链或支链饱和烃基团,本文也称为“低级烷基”。在一些实施方案中,C1-4烷基是特别优选的。所述烷基的实例包括但不限于:甲基(C1)、乙基(C2)、正丙基(C3)、异丙基(C3)、正丁基(C4)、叔丁基(C4)、仲丁基(C4)、异丁基(C4)、正戊基(C5)、3-戊基(C5)、戊基(C5)、新戊基(C5)、3-甲基-2-丁基(C5)、叔戊基(C5)和正己基(C6)。除非另作说明,否则,烷基的每个独立地任选被取代,即,未取代的(“未取代的烷基”)或被一个或多个取代基取代(“取代的烷基”);例如,1至5个取代基、1至3个取代基或1个取代基。在一些实施方案中,烷基是未取代的C1-C6烷基(例如,-CH3)。在一些实施方案中,烷基是取代的C1-C6烷基。
“C1-C6烷氧基”是指基团-OR,其中,R为取代或未取代的C1-C6烷基。在一些实施方案中,C1-4烷氧基是特别优选的。具体的所述烷氧基包括但不限于:甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、叔丁氧基、仲丁氧基、正戊氧基、正己氧基和1,2-二甲基丁氧基。
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。在一些实施方案中,卤素基团是F、Cl或Br。在一些实施方案中,卤素基团是F或Cl。在一些实施方案中,卤素基团是F。
因此,“C1-C6卤代烷基”和“C1-C6卤代烷氧基”是指上述“C1-C6烷基”和“C1-C6烷氧基”,其被一个或多个卤素基团取代。在一些实施方案中,C1-C4卤代烷基是特别优选的,更优选C1-C2卤代烷基。在一些实施方案中,C1-4卤代烷氧基是特别优选的,更优选C1-C2卤代烷氧基。示例性的所述卤代烷基包括但不限于:-CF3、-CH2F、-CHF2、-CHFCH2F、-CH2CHF2、-CF2CF3、-CCl3、-CH2Cl、-CHCl2、2,2,2-三氟-1,1-二甲基-乙基,等等。示例性的所述卤代烷氧基包括但不限于:-OCH2F、-OCHF2、-OCF3,等等。
“C3-C10碳环基”是指具有3至10个环碳原子和零个杂原子的非芳香环烃基团。在一些实施方案中,C3-C6碳环基是特别优选的,更优选C5-C6碳环基。碳环基还包括其中上述碳环基环与一个或多个芳基或杂芳基稠合的环体系,其中连接点在碳环基环上,且在这样的情况中,碳的数目继续表示碳环基体系中的碳的数目。示例性的所述碳环基包括但不限于:环丙基(C3)、环丙烯基(C3)、环丁基(C4)、环丁烯基(C4)、环戊基(C5)、环戊烯基(C5)、环己基(C6)、环己烯基(C6)、环已二烯基(C6)、环庚基(C7)、环庚烯基(C7)、环庚二烯基(C7)、环庚三烯基(C7)、环辛基(C8)、环辛烯基(C8)、二环[2.2.1]庚基(C7)、二环[2.2.2]辛基(C8)、环壬基(C9)、环壬烯基(C9)、环癸基(C10)、环癸烯基(C10)、八氢-1H-茚基(C9)、十氢萘基(C10)、螺[4.5]癸基(C10),等等。除非另作说明,否则碳环基的每个独立地为任选取代的,即,未取代的(“未取代的碳环基”)或被一个或多个取代基取代(“取代的碳环基”)。在一些实施方案中,碳环基是未取代的C3-C10碳环基。在一些实施方案中,碳环基是取代的C3-C10碳环基。
“3至10元杂环基”或是指具有环碳原子和1至4个环杂原子的3至10元非芳香环系的基团,其中,每个杂原子独立地选自氮、氧、硫、硼、磷和硅。在包含一个或多个氮原子的杂环基中,只要化合价允许,连接点可为碳或氮原子。在一些实施方案中,3至6元杂环基是特别优选的,其为具有环碳原子和1至3个环杂原子的3至6元非芳香环系;更优选5至6元杂环基,其为具有环碳原子和1至3个环杂原子的5至6元非芳香环系。除非另作说明,否则,杂环基的每个独立地为任选取代的,即,未取代的(“未取代的杂环基”)或被一个或多个取代基取代(“取代的杂环基”)。在一些实施方案中,杂环基是未取代的3-10元杂环基。在一些实施方案中,杂环基是取代的3-10元杂环基。杂环基还包括其中上述杂环基环与一个或多个碳环基稠合的环体系,其中连接点在碳环基环上,或其中上述杂环基环与一个或多个芳基或杂芳基稠合的环体系,其中连接点在杂环基环上;且在这样的情况下,环成员的数目继续表示在杂环基环体系中环成员的数目。示例性的包含一个杂原子的3元杂环基包括但不限于:氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基(thiorenyl)。示例性的含有一个杂原子的4元杂环基包括但不限于:氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。示例性的含有一个杂原子的5元杂环基包括但不限于:四氢呋喃基、二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基和吡咯基-2,5-二酮。示例性的包含两个杂原子的5元杂环基包括但不限于:二氧杂环戊烷基、氧硫杂环戊烷基(oxasulfuranyl)、二硫杂环戊烷基(disulfuranyl)和噁唑烷-2-酮。示例性的包含三个杂原子的5元杂环基包括但不限于:三唑啉基、噁二唑啉基和噻二唑啉基。示例性的包含一个杂原子的6元杂环基包括但不限于:哌啶基、四氢吡喃基、二氢吡啶基和硫杂环己烷基(thianyl)。示例性的包含两个杂原子的6元杂环基包括但不限于:哌嗪基、吗啉基、二硫杂环己烷基、二噁烷基。示例性的包含三个杂原子的6元杂环基包括但不限于:六氢三嗪基(triazinanyl)。示例性的含有一个杂原子的7元杂环基包括但不限于:氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。示例性的包含一个杂原子的8元杂环基包括但不限于:氮杂环辛烷基、氧杂环辛烷基和硫杂环辛烷基。示例性的与C6芳基环稠合的5元杂环基(在本文中也称作5,6-双环杂环基)包括但不限于:二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基,等等。示例性的与C6芳基环稠合的6元杂环基(本文还指的是6,6-双环杂环基)包括但不限于:四氢喹啉基、四氢异喹啉基,等等。
“C6-C14芳基”是指具有6-14个环碳原子和零个杂原子的单环或多环的(例如,双环或三环)4n+2芳族环体系(例如,具有以环状排列共享的6、10或14个π电子)的基团。在一些实施方案中,芳基具有六个环碳原子(“C6芳基”;例如,苯基)。在一些实施方案中,芳基具有十个环碳原子(“C10芳基”;例如,萘基,例如,1-萘基和2-萘基)。在一些实施方案中,芳基具有十四个环碳原子(“C14芳基”;例如,蒽基)。在一些实施方案中,C6-10芳基是特别优选的,更优选C6芳基。芳基还包括其中上述芳基环与一个或多个碳环基或杂环基稠合的环系统,而且连接点在所述芳基环上,在这种情况下,碳原子的数目继续表示所述芳基环系统中的碳原子数目。除非另作说明,否则,芳基的每个独立地任选被取代,即,未取代(“未取代的芳基”)或被一个或多个取代基取代(“取代的芳基”)。在一些实施方案中,芳基是未取代的C6-14芳基。在一些实施方案中,芳基是取代的C6-14芳基。
“C5-C10杂芳基”是指具有环碳原子和1-4个环杂原子的5-10元单环或双环的4n+2芳族环体系(例如,具有以环状排列共享的6或10个π电子)的基团,其中每个杂原子独立地选自氮、氧和硫。在含有一个或多个氮原子的杂芳基中,只要化合价允许,连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。杂芳基还包括其中上述杂芳基环与一个或多个碳环基或杂环基稠合的环系统,而且连接点在所述杂芳基环上,在这种情况下,碳原子的数目继续表示所述杂芳基环系统中的碳原子数目。在一些实施方案中,C5-6杂芳基是特别优选的,其为具有环碳原子和1-4个环杂原子的5-6元单环或双环的4n+2芳族环体系。除非另作说明,否则,杂芳基的每个独立地任选被取代的,即,未取代(“未取代的杂芳基”)或被一个或多个取代基取代(“取代的杂芳基”)。在一些实施方案中,杂芳基是未取代的5-10元杂芳基。在一些实施方案中,杂芳基是取代的5-10元杂芳基。示例性的含有一个杂原子的5元杂芳基包括但不限于:吡咯基、呋喃基和噻吩基。示例性的含有两个杂原子的5元杂芳基包括但不限于:咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。示例性的含有三个杂原子的5元杂芳基包括但不限于:三唑基、噁二唑基和噻二唑基。示例性的含有四个杂原子的5元杂芳基包括但不限于:四唑基。示例性的含有一个杂原子的6元杂芳基包括但不限于:吡啶基。示例性的含有两个杂原子的6元杂芳基包括但不限于:哒嗪基、嘧啶基和吡嗪基。示例性的含有三个或四个杂原子的6元杂芳基分别包括但不限于:三嗪基和四嗪基。示例性的含有一个杂原子的7元杂芳基包括但不限于:氮杂环庚三烯基、氧杂环庚三烯基和硫杂环庚三烯基。示例性的5,6-双环杂芳基包括但不限于:吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基和嘌呤基。示例性的6,6-双环杂芳基包括但不限于:萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。
其它定义
术语“药学上可接受的盐”是指,在可靠的医学判断范围内,适合与人和低等动物的组织接触而没有过度毒性、刺激性、变态反应等等,并且与合理的益处/危险比例相称的那些盐。药学上可接受的盐在本领域是众所周知的。例如,Berge等人在J.PharmaceuticalSciences(1977)66:1-19中详细描述的药学上可接受的盐。本发明化合物的药学上可接受的盐包括衍生自合适无机和有机酸和碱的盐。药学上可接受的无毒酸加成盐的实例是氨基与无机酸形成的盐,例如盐酸、氢溴酸、磷酸、硫酸和高氯酸,或与有机酸形成的盐,例如乙酸、草酸、马来酸、酒石酸、枸橼酸、琥珀酸或丙二酸,或使用本领域使用的方法形成的盐,例如,离子交换方法。其它药学上可接受的盐包括:已二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡萄糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酯酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐,等等。衍生自合适的碱的药学上可接受的盐包括碱金属、碱土金属、铵和N+(C1-4烷基)4盐。代表性的碱金属或碱土金属盐包括钠、锂、钾、钙、镁盐,等等。如果合适的话,进一步的药学上可接受的盐包括使用反离子形成的无毒的铵盐、季铵盐和胺阳离子,反离子例如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根和芳基磺酸根。
给药的“受试者”包括但不限于:人(即,任何年龄组的男性或女性,例如,儿科受试者(例如,婴儿、儿童、青少年)或成人受试者(例如,年轻的成人、中年的成人或年长的成人))和/或非人的动物,例如,哺乳动物,例如,灵长类(例如,食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中,受试者是人。在一些实施方案中,受试者是非人动物。本文可互换使用术语“人”、“患者”和“受试者”。
“疾病”、“障碍”和“病症”在本文中可互换地使用。
除非另作说明,否则,本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用,它降低疾病、障碍或病症的严重程度,或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”),还包括受试者开始患有具体疾病、障碍或病症之前发生的作用(“预防性治疗”)。
通常,化合物的“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样,本发明化合物的有效量可以根据下列因素而改变:例如,生物学目标、化合物的药物动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗和预防性治疗有效量。
除非另作说明,否则,本文使用的化合物的“治疗有效量”是在治疗疾病、障碍或病症的过程中足以提供治疗益处的数量,或使与疾病、障碍或病症有关的一或多种症状延迟或最小化。化合物的治疗有效量是指单独使用或与其它疗法联用的治疗剂的数量,它在治疗疾病、障碍或病症的过程中提供治疗益处。术语“治疗有效量”可以包括改善总体治疗、降低或避免疾病或病症的症状或病因、或增强其它治疗剂的治疗效能的数量。
除非另作说明,否则,本文使用的化合物的“预防有效量”是足以预防疾病、障碍或病症的数量,或足以预防与疾病、障碍或病症有关的一或多种症状的数量,或防止疾病、障碍或病症复发的数量。化合物的预防有效量是指单独使用或与其它药剂联用的治疗剂的数量,它在预防疾病、障碍或病症的过程中提供预防益处。术语“预防有效量”可以包括改善总体预防的数量,或增强其它预防药剂的预防效能的数量。
“组合”以及相关术语是指同时或依次给药本发明的治疗剂。例如,本发明化合物可以与另一治疗剂以分开的单位剂型同时或依次给药,或与另一治疗剂一起呈单一单位剂型同时给药。
本发明的物质还用于治疗由Bcr-Abl激酶介导的下述疾病、障碍或病症:呼吸系统疾病、变态反应、类风湿性关节炎、骨关节炎、风湿性病症、银屑病、溃疡性结肠炎、局限性回肠炎、败血症性休克、增殖性病症、动脉粥样硬化、移植后的同种异体移植物排斥反应、糖尿病、中风、肥胖症或再狭窄、白血病、间质瘤、甲状腺癌、系统性肥大细胞病、嗜酸性粒细胞增多综合征、纤维变性、类风湿性关节炎、多关节炎、硬皮病、红斑狼疮、移植物抗宿主病、神经纤维瘤、肺高压、阿尔茨海默病、精原细胞瘤、无性细胞瘤、肥大细胞肿瘤、肺癌、支气管癌、无性细胞瘤、睾丸上皮内瘤形成、黑色素瘤、乳癌、神经母细胞瘤、乳头状/滤泡型甲状旁腺增生/腺瘤、结肠癌、结肠直肠腺瘤、卵巢癌、前列腺癌、成胶质细胞瘤、脑肿瘤、恶性神经胶质瘤、胰腺癌、恶性胸膜间皮瘤、成血管细胞瘤、血管瘤、肾癌、肝癌、肾上腺癌、膀胱癌、胃癌、直肠癌、阴道癌、宫颈癌、子宫内膜癌、多发性骨髓瘤、颈和头部肿瘤、瘤形成以及其他增生性或增殖性疾病、或其组合。
具体实施方式
化合物
本文中,“本发明化合物”指的是以下的式(I)合物、其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素变体。
在一个实施方案中,本发明涉及式(I)化合物:
其中,环A为5-6元杂芳环或者5-6元杂环;其中,所述杂芳环或杂环包含1-3个选自N、O和S的杂原子,且所述环可被选自氢、卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、羧基、氧代基团、C3-C7环烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、C3-C7杂环烷基、C3-C7杂环烯基、C1-C6烷硫基、C1-C6烷氨基或C1-C6烷酰基中的取代基所取代;
K选自CH、NH或者S;
M选自CH、C或者N;
X1、X2、X3、X4和X5独立地为N或CR1,R1独立地为H、羟基、卤素、硅烷基、腈基、硝基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-7杂环烷基或C3-7杂环烯基;
L选自O、S、NR2、CR2R2、C(=O)、C(=O)NR2、NR2C(=O)、NR2C(=O)NR2、OC(=O)NR2、NR2C(=O)O、S(=O)、S(=O)2、S(=O)NR2、S(=O)2NR2、NR2S(=O)、NR2S(=O)2、NR2S(=O)NR2、NR2S(=O)2NR2、OP(=O)R2、P(=O)OR2,其中R2独立选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基基、C1-6卤代烷氧基、C3-7环烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-7杂环烷基或C3-7杂环烯基;
环C为含有1-5个取代基的5-6元芳环或含有1-5个取代基的5-6元杂芳环,所述取代基可选自卤素、-R、-CN、-COOH、-OH、-SH、-OR、-C(=O)R、-C(=O)OR、-OC(=O)R、-S(=O)R、-S(=O)2R、-NR2、-NHC(=O)R、-NHC(=O)OR、-C(=O)NHR、-C(=O)ONHR,其中R独立地为H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-7杂环烷基或C3-7杂环烯基;两个相邻的R与其所连接的环C上的碳原子可一起形成任选取代的C5-8碳环基、任选取代的5至8元杂环基、任选取代的C6-14芳基或任选取代的5至10元杂芳基;
或其药学上可接受的盐、立体异构体、溶剂合物、水合物、晶型、前药或同位素变体。
在一些实施实例中,环A与环B组成的并环具有下述结构:
其中,M为C或N,环A为5-6元杂芳环或者5-6元杂环;Ra选自氢、卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、羧基、氧代基团、C3-C7环烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、C3-C7杂环烷基、C3-C7杂环烯基、C1-C6烷硫基、C1-C6烷氨基或C1-C6烷酰基,且m为0、1、2、3或4。
更优选地,环A与环B组成的并环具有下述结构:
其中,X6、X7和X8独立地为C(Ra)2、CRa、NRa、N、O或S,Ra选自氢、卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、羧基、氧代基团、C3-C7环烷基、C2-C6烯基、C2-C6炔基、C6-C10芳基、C3-C7杂环烷基、C3-C7杂环烯基、C1-C6烷硫基、C1-C6烷氨基或C1-C6烷酰基;在化学允许的情况下,X6、X7和X8之间的键可任选自单键或双键。
优选地,环A与环B组成的并环选自:
其中,X5、X6、X7和X8如前文所定义;
优选地,环A与环B组成的并环选自:
其中,X5和Ra如前文所定义。
在一些实施实例中,X1、X2、X3、X4和X5独立地为N或CR1,R1独立地为H、羟基、卤素、硅烷基、腈基、硝基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-7杂环烷基或C3-7杂环烯基。
优选地,X1、X2、X3、X4为CR1,且X5为N或CR1,R1独立地为H、羟基、卤素、硅烷基、腈基、硝基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-7杂环烷基或C3-7杂环烯基。
在一些实施例中,L选自O、S、NR2、CR2R2、C(=O)、C(=O)NR2、NR2C(=O)、NR2C(=O)NR2、OC(=O)NR2、NR2C(=O)O、S(=O)、S(=O)2、S(=O)NR2、S(=O)2NR2、NR2S(=O)、NR2S(=O)2、NR2S(=O)NR2、NR2S(=O)2NR2、OP(=O)R2、P(=O)OR2,其中R2独立选自H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基基、C1-6卤代烷氧基、C3-7环烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-7杂环烷基或C3-7杂环烯基。
优选地,L选自C(=O)NR2、NR2C(=O)、NR2C(=O)NR2、OC(=O)NR2、NR2C(=O)O、S(=O)、S(=O)2、S(=O)NR2、S(=O)2NR2、NR2S(=O)、NR2S(=O)2、NR2S(=O)NR2、NR2S(=O)2NR2、OP(=O)R2、P(=O)OR2,其中R2独立选自H或C1-6烷基。
在一些实施例中,环C为含有1-5个取代基的5-6元芳环或含有1-5个取代基的5-6元杂芳环,所述取代基可选自卤素、-R、-CN、-COOH、-OH、-SH、-OR、-C(=O)R、-C(=O)OR、-OC(=O)R、-S(=O)R、-S(=O)2R、-NR2、-NHC(=O)R、-C(=O)NHR、-NHC(=O)OR、-C(=O)ONHR,其中R独立地为H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-7杂环烷基或C3-7杂环烯基,两个相邻的R与其所连接的环C上的碳原子可一起形成任选取代的C5-8碳环基、任选取代的5至8元杂环基、任选取代的C6-14芳基或任选取代的5至10元杂芳基。
优选地,环C为含1-5个取代基的5-6元芳环,所述取代基可选自卤素、-R、-CN、-COOH、-OH、-SH、-OR、-C(=O)R、-C(=O)OR、-OC(=O)R、-S(=O)R、-S(=O)2R、-NR2、-NHC(=O)R、-NHC(=O)OR、-C(=O)NHR、-C(=O)ONHR,其中R独立地为H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-7杂环烷基或C3-7杂环烯基,两个相邻的R与其所连接的环C上的碳原子可一起形成任选取代的C5-8碳环基、任选取代的5至8元杂环基、任选取代的C6-14芳基或任选取代的5至10元杂芳基。
更优选地,环C为1-5个取代基的苯环,所述取代基可选自卤素、-R、-CN、-COOH、-OH、-SH、-OR、-C(=O)R、-C(=O)OR、-OC(=O)R、-S(=O)R、-S(=O)2R、-NR2、-NHC(=O)R、-NHC(=O)OR、-C(=O)NHR、-C(=O)ONHR,其中R独立地为H、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、C2-6烯基、C2-6炔基、C6-10芳基、C3-7杂环烷基或C3-7杂环烯基,两个相邻的R与其所连接的环C上的碳原子可一起形成任选取代的C5-8碳环基、任选取代的5至8元杂环基、任选取代的C6-14芳基或任选取代的5至10元杂芳基。
优选地,环C为:
其中,R如权利要求8或9所定义,L1为任何方向连接的取代或者未取代的(CH2)x,O(CH2)x,NR(CH2)x,S(CH2)x,或(CH2)xNRC(O)(CH2)x,x为1,2,3或4。
优选地,环C选自:
在一些实施例中,本发明化合物可选自下述化合物:
本发明也包括本发明化合物的所有合适的同位素变体。本发明化合物的同位素变体的定义为其中至少一个原子被具有相同原子数但原子质量与自然界中通常发现的原子质量不同的原子代替。可以掺入本发明化合物中的同位素的实例包括氢、碳、氮、氧、氟和氯的同位素,例如分别为2H、3H、13C、14C、15N、17O、18O、18F、31P、32P、35S和36Cl。本发明化合物的一些同位素变体,例如其中掺入放射性同位素如3H或14C的那些,可用于药物和/或底物组织分布研究。氚化(即3H)和碳-14(即14C)同位素因其易于制备和可检测性而为特别优选的。此外,用同位素(例如氘,即2H)取代可以提供由于更大的代谢稳定性而得到的一些治疗优点,例如增加的体内半衰期或减少的剂量需要,并且因此在一些情况下可以是优选的。本发明化合物的同位素变体通常可以通过如下制备:常规程序例如通过说明性方法或通过下文实施例中描述的制备,其使用合适试剂的适当同位素变体。
本发明化合物或其药学上可接受的盐可以是无定形或结晶形式。此外,本发明化合物可以以一种或多种结晶形式存在。因此,本发明在其范围内包括本发明化合物的所有无定形或结晶形式。
本领域技术人员将理解,许多有机化合物可以与溶剂形成复合物,其在该溶剂中发生反应或从该溶剂中沉淀或结晶出来。这些复合物称为“溶剂合物”。当溶剂是水时,复合物称为“水合物”。本发明涵盖了本发明化合物的所有溶剂合物。
此外,前药也包括在本发明的上下文内。本文所用的术语“前药”是指在体内通过例如在血液中水解转变成其具有医学效应的活性形式的化合物。药学上可接受的的前药描述于T.Higuchi和V.Stella,Prodrugs as Novel Delivery Systems,A.C.S.SymposiumSeries的Vol.14,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,以及D.Fleisher、S.Ramon和H.Barbra“Improved oral drug delivery:solubility limitations overcomeby the use of prodrugs”,Advanced Drug Delivery Reviews(1996)19(2)115-130,每篇引入本文作为参考。
前药为任何共价键合的载体,当将这种前药给予患者时,其在体内释放式(I)化合物。通常通过修饰官能团来制备前药,修饰是以使得该修饰可以通过常规操作或在体内裂解产生母体化合物的方式进行的。前药包括,例如,其中羟基、胺或巯基与任意基团键合的本发明化合物,当将其给予患者时,可以裂解形成羟基、胺或巯基。因此,前药的代表性实例包括(但不限于)式(I)化合物的醇、巯基和胺官能团的乙酸酯、甲酸酯和苯甲酸酯衍生物。另外,在羧酸(-COOH)的情况下,可以使用酯,例如甲酯、乙酯等。酯本身可以是有活性的和/或可以在人体体内条件下水解。合适的药学上可接受的体内可水解的酯基包括容易在人体中分解而释放母体酸或其盐的那些基团。
药物组合物、制剂和试剂盒
在另一方面,本发明提供了药物组合物,其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中,所述药物组合物包含有效量的活性组分。在一些实施方案中,所述药物组合物包含治疗有效量的活性组分。在一些实施方案中,所述药物组合物包含预防有效量的活性组分。
用于本发明的药学上可接受的赋形剂是指不会破坏一起调配的化合物的药理学活性的无毒载剂、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载剂、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。
本发明还包括试剂盒(例如,药物包装)。所提供的试剂盒可以包括本发明化合物、其它治疗剂,以及含有本发明化合物、其它治疗剂的第一和第二容器(例如,小瓶、安瓿瓶、瓶、注射器和/或可分散包装或其它合适的容器)。在一些实施方案中,提供的试剂盒还可以任选包括第三容器,其含有用于稀释或悬浮本发明化合物和/或其它治疗剂的药用赋形剂。在一些实施方案中,提供在第一容器和第二容器中的本发明化合物和其它治疗剂组合形成一个单位剂型。
下列制剂实施例说明可根据本发明制备的代表性的药物组合物。然而,本发明不限于下列药物组合物。
示例性的制剂1-片剂:可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为0.3-30mg片剂(每个片剂含有0.1-10mg活性化合物)。
示例性的制剂2-片剂:可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为30-90mg片剂(每个片剂含有10-30mg活性化合物)。
示例性的制剂3-片剂:可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为90-150mg片剂(每个片剂含有30-50mg活性化合物)。
示例性的制剂4-片剂:可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为150-240mg片剂(每个片剂含有50-80mg活性化合物)。
示例性的制剂5-片剂:可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为240-270mg片剂(每个片剂含有80-90mg活性化合物)。
示例性的制剂6-片剂:可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为270-450mg片剂(每个片剂含有90-150mg活性化合物)。
示例性的制剂7-片剂:可以将干粉形式的本发明化合物与干燥的凝胶粘合剂以约1:2的重量比混合。加入较少量的硬脂酸镁作为润滑剂。使该混合物在压片机中成型为450-900mg片剂(每个片剂含有150-300mg活性化合物)。
示例性的制剂8-胶囊剂:可以将干粉形式的本发明化合物与淀粉稀释剂以约1:1的重量比混合。将该混合物填充到250mg胶囊中(每个胶囊含有125mg活性化合物)。
示例性的制剂9-液体:可以将本发明化合物(125mg)与蔗糖(1.75g)和黄原胶(4mg)混合,且可将得到的混合物共混,通过No.10筛目美国筛,然后与预先制备的微晶纤维素和羧甲基纤维素钠(11:89,50mg)的水溶液混合。将苯甲酸钠(10mg)、调味剂和着色剂用水稀释,并在搅拌下加入。然后,可以加入充足的水,得到5mL的总体积。
示例性的制剂10-注射剂:可以将本发明化合物溶解或悬浮在缓冲无菌盐水可注射的水性介质中,达到约5mg/mL的浓度。
给药
本发明提供的药物组合物可以通过许多途径给药,包括但不限于:口服给药、肠胃外给药、吸入给药、局部给药、直肠给药、鼻腔给药、口腔给药、阴道给药、通过植入剂给药或其它给药方式。例如,本文使用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给药、动脉内给药、滑膜腔内给药、胸骨内给药、脑脊髓膜内给药、病灶内给药、和颅内的注射或输液技术。
通常,给予有效量的本文所提供的化合物。按照有关情况,包括所治疗的病症、选择的给药途径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度,等等,可以由医生确定实际上给予的化合物的量。
当用于预防本发明所述病症时,给予处于形成所述病症危险之中的受试者本文所提供的化合物,典型地基于医生的建议并在医生监督下给药,剂量水平如上所述。处于形成具体病症的危险之中的受试者,通常包括具有所述病症的家族史的受试者,或通过遗传试验或筛选确定尤其对形成所述病症敏感的那些受试者。
还可以长期给予本文所提供的药物组合物(“长期给药”)。长期给药是指在长时间内给予化合物或其药物组合物,例如,3个月、6个月、1年、2年、3年、5年等等,或者可无限期地持续给药,例如,受试者的余生。在一些实施方案中,长期给药意欲在长时间内在血液中提供所述化合物的恒定水平,例如,在治疗窗内。
可以使用各种给药方法,进一步递送本发明的药物组合物。例如,在一些实施方案中,可以推注给药药物组合物,例如,为了使化合物在血液中的浓度提高至有效水平。推注剂量取决于通过身体的活性组分的目标全身性水平,例如,肌内或皮下的推注剂量使活性组分缓慢释放,而直接递送至静脉的推注(例如,通过IV静脉滴注)能够更加快速地递送,使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中,可以以持续输液形式给予药物组合物,例如,通过IV静脉滴注,从而在受试者身体中提供稳态浓度的活性组分。此外,在其它实施方案中,可以首先给予推注剂量的药物组合物,而后持续输液。
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而,更通常,为了便于精确地剂量给药,以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位,每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器,或者在固体组合物情况下的丸剂、片剂、胶囊剂等。在这种组合物中,所述化合物通常为较少的组分(约0.1至约50重量%,或优选约1至约40重量%),剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。
对于口服剂量,代表性的方案是,每天一个至五个口服剂量,尤其是两个至四个口服剂量,典型地是三个口服剂量。使用这些剂量给药模式,每个剂量提供大约0.01至大约20mg/kg的本发明化合物,优选的剂量各自提供大约0.1至大约10mg/kg,尤其是大约1至大约5mg/kg。
为了提供与使用注射剂量类似的血液水平,或比使用注射剂量更低的血液水平,通常选择透皮剂量,数量为大约0.01至大约20%重量,优选大约0.1至大约20%重量,优选大约0.1至大约10%重量,且更优选大约0.5至大约15%重量。
从大约1至大约120小时,尤其是24至96小时,注射剂量水平在大约0.1mg/kg/小时至至少10mg/kg/小时的范围。为了获得足够的稳定状态水平,还可以给予大约0.1mg/kg至大约10mg/kg或更多的预载推注。对于40至80kg的人类患者来说,最大总剂量不能超过大约2g/天。
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂,等等。固体形式可包括,例如,任何下列组份,或具有类似性质的化合物:粘合剂,例如,微晶纤维素、黄蓍胶或明胶;赋形剂,例如,淀粉或乳糖,崩解剂,例如,褐藻酸、Primogel或玉米淀粉;润滑剂,例如,硬脂酸镁;助流剂,例如,胶体二氧化硅;甜味剂,例如,蔗糖或糖精;或调味剂,例如,薄荷、水杨酸甲酯或橙味调味剂。
可注射的组合物典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水,或本领域中已知的其它可注射的赋形剂。如前所述,在这种组合物中,活性化合物典型地为较少的组分,经常为约0.05至10%重量,剩余部分为可注射的赋形剂等。
典型地将透皮组合物配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时,活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者,活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的,且通常包括用于提升活性组分或制剂的稳定的皮肤渗透的其它组份。所有这种已知的透皮制剂和组份包括在本发明提供的范围内。
本发明化合物还可通过经皮装置给予。因此,经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。
用于口服给予、注射或局部给予的组合物的上述组份仅仅是代表性的。其它材料以及加工技术等阐述于Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania的第8部分中,本文以引用的方式引入该文献。
本发明化合物还可以以持续释放形式给予,或从持续释放给药系统中给予。代表性的持续释放材料的描述可在Remington's Pharmaceutical Sciences中找到。
本发明还涉及本发明化合物的药学上可接受的制剂。在一个实施方案中,所述制剂包含水。在另一个实施方案中,所述制剂包含环糊精衍生物。最常见的环糊精为分别由6、7和8个α-1,4-连接的葡萄糖单元组成的α-、β-和γ-环糊精,其在连接的糖部分上任选包括一个或多个取代基,其包括但不限于:甲基化的、羟基烷基化的、酰化的和磺烷基醚取代。在一些实施方案中,所述环糊精为磺烷基醚β-环糊精,例如,磺丁基醚β-环糊精,也称作Captisol。参见,例如,U.S.5,376,645。在一些实施方案中,所述制剂包括六丙基-β-环糊精(例如,在水中,10-50%)。
治疗
本发明的物质还用于治疗由Bcr-Abl激酶介导的下述疾病、障碍或病症:呼吸系统疾病、变态反应、类风湿性关节炎、骨关节炎、风湿性病症、银屑病、溃疡性结肠炎、局限性回肠炎、败血症性休克、增殖性病症、动脉粥样硬化、移植后的同种异体移植物排斥反应、糖尿病、中风、肥胖症或再狭窄、白血病、间质瘤、甲状腺癌、系统性肥大细胞病、嗜酸性粒细胞增多综合征、纤维变性、类风湿性关节炎、多关节炎、硬皮病、红斑狼疮、移植物抗宿主病、神经纤维瘤、肺高压、阿尔茨海默病、精原细胞瘤、无性细胞瘤、肥大细胞肿瘤、肺癌、支气管癌、无性细胞瘤、睾丸上皮内瘤形成、黑色素瘤、乳癌、神经母细胞瘤、乳头状/滤泡型甲状旁腺增生/腺瘤、结肠癌、结肠直肠腺瘤、卵巢癌、前列腺癌、成胶质细胞瘤、脑肿瘤、恶性神经胶质瘤、胰腺癌、恶性胸膜间皮瘤、成血管细胞瘤、血管瘤、肾癌、肝癌、肾上腺癌、膀胱癌、胃癌、直肠癌、阴道癌、宫颈癌、子宫内膜癌、多发性骨髓瘤、颈和头部肿瘤、瘤形成以及其他增生性或增殖性疾病、或其组合。
本发明因此提供了在治疗中、特别是在治疗由不适当的Bcr-Abl活性介导的疾病和病况中使用的(I)的化合物及其盐、溶剂合物、生理学上的功能性化合物。
在本文中提及的不适当的Bcr-Abl活性是在特定哺乳动物对象中偏离预期的正常Bcr-Abl活性的任何Bcr-Abl活性。不适当的Bcr-Abl活性可以呈例如以下形式:活性异常增加,或者Bcr-Abl活性的时机和或控制的畸变。这种不适当的活性则可以由例如导致不适当或失控的活化的蛋白激酶的过表达或突变所导致。
在另一个实施方案中,本发明涉及为了预防和/或治疗与失调的或不适当的Bcr-Abl活性有关的病症而调节、调控或抑制Bcr-Abl的方法。
在另一个实施方案中,所述由Bcr-Abl活性介导的病症是呼吸系统疾病。在另一个实施方案中,所述病症是增殖性病症。在又一个实施方案中,所述病症是癌症。在另一个实施方案中,所述病症是白血病。
另一个实施方案中,本发明提供了式(I)的化合物或其药学上可接受的盐或溶剂合物、或其生理学上的功能性衍生物在制备用于治疗由Bcr-Abl活性介导的病症的药物中的用途。
本发明的其他方面在于式(I)化合物或其药学上可接受的盐用于制备用于治疗Bcr-Abl介导的疾病或Bcr-Abl介导的病况的药物的用途。
在另一个实施方案中,本发明提供了一种治疗患有由Bcr-Abl活性介导的病症的哺乳动物的方法,所述方法包括:向所述哺乳动物给予有效量的式(I)的化合物或其药学上可接受的盐、溶剂合物或生理学上的功能性衍生物。
本发明化合物的有效量通常在平均日剂量为0.01mg至50mg化合物/千克患者体重,优选0.1mg至25mg化合物/千克患者体重,以单次或多次给药。通常,本发明化合物可向该有此治疗需要的患者以每位患者约1mg至约3500mg的日剂量范围给药,优选10mg至1000mg。例如,每位患者的日剂量可为10、20、30、40、50、60、70、80、90、100、150、200、250、300、350、400、500、600、700、800、900或1000mg。可每天、每周(或间隔数天)或以间歇时间表,给药一次或多次。例如,可在每周的基础上(例如每周一),每天给予所述化合物一次或多次,不定地或持续几周,例如4-10周。或者,可每天给药持续几天(例如2-10天),然后几天(例如1-30天)不给药所述化合物,不定地重复该循环或重复给定的次数,例如4-10个循环。例如,本发明化合物可每天给药持续5天,然后间断9天,然后再每天给药持续5天,然后间断9天,以此类推,不定地重复该循环或共重复4-10次。
组合治疗
本发明的化合物、其盐和溶剂合物和其生理学上的功能性衍生物可以单独使用或与用于治疗与不适当的Bcr-Abl活性相关的Bcr-Abl介导的疾病和病况的其他治疗剂组合使用。根据本发明的组合治疗因此包括给予至少一种式(I)化合物或其药学上可接受的盐或溶剂合物或其生理学上的功能性衍生物和使用至少一种其他的药学活性剂。一种或多种式(I)化合物和一种或多种其他药学活性剂可以一起给药或分开给药,当分开给药时,可以同时进行或以任何顺序相继进行。将选择一种或多种式(I)化合物和一种或多种其他药学活性剂的量和相对给药时机以实现期望的组合治疗效果。
对于癌症治疗,式(I)化合物可以与一种或多种抗癌剂组合。这样的药剂的实例可以在Cancer Principles and Practice of Oncology by V.T.Devita and S.Hellman(编),第6版(2001年2月15日),Lippincott Williams&Wilkins Publishers中找到。领域普通技术人员将能够识别哪种药剂组合可以基于药物和所涉及的癌症的特定特征而使用。这样的抗癌剂包括但不限于:(1)雌激素受体调节剂如diethyltibestral,三苯氧胺,雷洛昔芬,艾多昔芬,LY353381,LY117081,托瑞米芬,氟甲睾酮,和SH646;(2)其他激素药剂包括芳香化酶抑制剂(例如氨鲁米特,四唑阿那曲唑,来曲唑和依西美坦),促黄体激素释放激素(LHRH)类似物,酮康唑,醋酸戈舍瑞林,亮丙瑞林,醋酸甲地孕酮和米非司酮;(3)雄激素受体调节素如非那雄胺和其他5α-还原酶抑制剂,尼鲁米特,氟他米特,比卡鲁胺,利阿唑,和乙酸阿比特龙;(4)类维生素A受体调节剂如贝沙罗汀,维甲酸,13-顺式-视黄酸,9-顺式-视黄酸,α-二氟甲基鸟氨酸,ILX23-7553,反式-N-(4’-羟基苯基)维甲酚酰胺,和N-4-羧基苯基维甲酚酰胺;(5)抗增殖剂如反义RNA和DNA寡核苷酸如G3139,ODN698,RVASKRAS,GEM231,和INX3001,和抗代谢物如依诺他滨,卡莫氟,喃氟啶,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(tiazofurin),地西他滨,洛拉曲塞,培美曲塞,奈拉滨,2’-去氧-2’-甲叉基胞啶,2’-氟亚甲基-2’-去氧胞啶,N6-[4-去氧-4-[N2-[2(E),4(E)-十四碳二烯酰基]甘氨酰基氨基]-L-丙三氧基-B-L-甘露糖-吡喃庚糖基]腺嘌呤,aplidine,海鞘素,曲沙他滨,氨蝶呤,5-氟尿嘧啶,氟脲苷,甲氨蝶呤,亚叶酸,羟基脲,硫鸟嘌呤(6-TG),巯嘌呤(6-MP),阿糖胞苷,喷司他丁,磷酸氟达拉滨,克拉屈滨(2-CDA),天冬酰胺酶,吉西他滨,阿拉诺新,苦马豆素,洛美曲索,右丙亚胺,methioninase,和3-氨基吡啶-2-甲醛氨苯硫脲;(6)异戊二烯基-蛋白转移酶抑制剂包括法呢基-蛋白转移酶(FPTase),香叶酰香叶酰-蛋白转移酶I型(GGPTase-I),和香叶酰香叶酰-蛋白转移酶-II型(GGPTase-II,也称为Rab GGPTase);(7)HMG-CoA还原酶抑制剂如洛伐他汀,辛伐他汀,普伐他汀,阿托伐他汀,氟伐他汀和罗苏伐他汀;(8)血管生成抑制剂如酪氨酸激酶受体Flt-1(VEGFR1)和Flk-1/KDR(VEGFR2)抑制剂,表皮-衍生的、纤维原细胞-衍生的或血小板衍生的生长因子的抑制剂,MMP(基质金属蛋白酶)抑制剂,整合蛋白阻滞剂,干扰素-α,白介素-12,红细胞生成素(红细胞生成素-α),粒细胞-CSF(非尔司亭),粒细胞,巨噬细胞-CSF(沙格司亭),戊聚糖多硫酸酯,环氧酶抑制剂,甾族抗炎剂,羧基酰胺基三唑,康普立停A-4,角鲨胺,6-O-氯乙酰基-羰基)-烟霉醇,萨力多胺,血管抑素,肌钙蛋白-1,血管紧缩素II拮抗剂,肝素,羧肽酶U抑制剂,和对如下物质的抗体:VEGF,内皮抑素,ukrain,豹蛙酶,IM862,乙酰地那林(acetyldinanaline),5-氨基-1-[[3,5-二氯-4-(4-氯苯甲酰基)苯基]甲基]-1H-1,2,3-三唑-4-甲酰胺,CM101,角鲨胺,康普立停,RPI4610,NX31838,硫酸化磷酸甘露五糖,和3-[(2,4-二甲基吡咯-5-基)亚甲基]-2-吲哚啉酮(SU5416);(9)PPAR-γ激动剂,PPAR-δ激动剂,噻唑烷二酮(如DRF2725,CS-011,曲格列酮,罗格列酮,和吡格列酮),非诺贝特,二甲苯氧庚酸,安妥明,GW2570,SB219994,AR-H039242,JTT-501,MCC-555,GW2331,GW409544,NN2344,KRP297,NP0110,DRF4158,NN622,GI262570,PNU182716,DRF552926,2-[(5,7-二丙基-3-三氟甲基-1,2-苯并异噁唑-6-基)氧基]-2-甲基丙酸(在USSN 09/782,856中公开),和(2R)-7-(3-(2-氯-4-(4-氟苯氧基)苯氧基)丙氧基)-2-乙基色满-2-甲酸(在USSN60/235,708和60/244,697中公开);(9)固有多药耐药抑制剂包括p-糖蛋白(P-gp)抑制剂,如LY335979,XR9576,OC144-093,R101922,VX853和PSC833(valspodar);(10)细胞增殖和存活信号传导抑制剂如EGFR抑制剂(例如吉非替尼、埃罗替尼、埃克替尼和奥西替尼(AZD9291)),ERB-2抑制剂(例如曲妥单抗),IGF1R抑制剂如MK-0646(dalotuzumab),CD20抑制剂(利妥昔单抗),细胞因子受体抑制剂,MET抑制剂,PI3K家族激酶抑制剂(例如LY294002),丝氨酸/苏氨酸激酶(包括但不限于Akt抑制剂如在(WO 03/086404,WO 03/086403,WO03/086394,WO 03/086279,WO 02/083675,WO 02/083139,WO 02/083140和WO 02/083138)中描述,Raf激酶的抑制剂(例如BAY-43-9006),MEK抑制剂(例如CI-1040和PD-098059)和mTOR抑制剂(例如Wyeth CCI-779和Ariad AP23573);(11)双膦酸盐如依替膦酸盐,帕米膦酸盐,阿仑膦酸盐,利塞膦酸盐,唑来膦酸盐,伊班膦酸盐,因卡膦酸盐或英卡膦酸盐(cimadronate),氯膦酸盐,EB-1053,米诺膦酸盐,奈力膦酸盐,吡利膦酸盐(piridronate)和替鲁膦酸盐;(12)γ-分泌酶抑制剂,(13)干扰受体酪氨酸激酶(RTK)的药剂,包括c-Kit,Eph,PDGF,Flt3和c-Met的抑制剂;(14)干扰细胞周期检验点的药剂包括ATR,ATM,Chk1和Chk2激酶和CDK的抑制剂和CDC激酶抑制剂和尤其例如7-羟基星形孢菌素(7-hydroxystaurosporin),夫拉平度,CYC202(Cyclacel)和BMS-387032;(15)BCR-ABL抑制剂如PCI32765,AVL-292和AVL-101;(16)PARP抑制剂包括iniparib,奥拉帕尼,AGO14699,ABT888和MK4827;(16)ERK抑制剂;(17)mTOR抑制剂如雷帕霉素,42-(二甲基亚膦酰)雷帕霉素,替西罗莫司,依维莫司;(18)细胞毒性/细胞抑制剂。
“细胞毒性/细胞抑制剂”是指主要通过直接干扰细胞功能化导致细胞死亡或抑制细胞增殖或抑制或干扰细胞有丝分裂的化合物,包括烷基化剂,肿瘤坏死因子、嵌入剂、低氧可活化化合物、微管抑制剂/微管稳定化剂、有丝分裂驱动蛋白的抑制剂、组蛋白脱乙酰酶的抑制剂、参与有丝分裂进程的激酶的抑制剂、抗代谢物、生物反应调节剂、激素/抗激素治疗剂、造血生长因子、单克隆抗体靶向的治疗剂、拓扑异构酶抑制剂、蛋白酶体抑制剂。
细胞毒性剂的实例包括但不限于sertenef,恶病质素,瘤可宁,环磷酰胺,异环磷酰胺,氮芥,美法仑,尿嘧啶芥,噻替哌,白消安,卡莫司汀,环己亚硝脲,链脲菌素,他索纳明,氯尼达明,卡铂,六甲蜜胺,达卡巴嗪,甲基苄肼,泼尼氮芥,二溴卫矛醇,雷莫司汀,福莫司汀,奈达铂,奥沙利铂,替莫唑胺,庚铂(heptaplatin),雌氮芥,甲磺丙胺,曲洛磷胺,尼莫司汀,二溴螺氯胺,嘌嘧替派,洛铂,赛特铂,紫菜霉素,顺铂,伊洛福芬,右异环磷酰胺(dexifosfamide),顺式-胺二氯(2-甲基-吡啶)铂,苄基鸟嘌呤,葡磷酰胺,GPX100,(反式,反式,反式)-双-mu-(己烷-1,6-二胺)-mu-[二胺-铂(II)]双[二胺(氯)铂(II)]四氯化物,二吖丙啶基精胺(diarizidinylspermine),三氧化二砷,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,阿霉素,道诺霉素,伊达比星,蒽醌,争光霉素,丝裂霉素C,更生霉素,plicatomycin,比生群,米托蒽醌,吡柔比星,吡萘菲特,戊柔比星,氨柔比星,抗瘤酮,3’-去氨基-3’-吗啉代-13-去氧-10-羟基洋红霉素,卡那霉素,加柔比星(galarubicin),依利奈法德,MEN10755,和4-去甲氧基-3-去氨基-3-氮杂环丙烷基-4-甲基磺酰基-道诺霉素。
蛋白酶体抑制剂的实例包括但不限于乳胞素和硼替佐米。
微管抑制剂/微管稳定化剂的实例包括长春新碱、长春花碱、长春地辛、长春利定、长春瑞滨、硫酸长春地辛、3’,4’-二去氢-4’-去氧-8’-去甲长春碱二酒石酸盐,足叶草毒素(例如依托泊苷(VP-16)和替尼泊苷(VM-26)),紫杉醇,多西紫杉醇,根霉素,尾海兔素,mivobulin isethionate,auristatin,西马多丁,RPR109881,BMS184476,长春氟宁,cryptophycin,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-脯氨酰-L-脯氨酸-叔丁基酰胺,TDX258,埃博霉素(参见例如美国专利No.6,284,781和6,288,237)和BMS188797。
拓扑异构酶抑制剂的一些实例为拓扑替康,hycaptamine,伊立替康,鲁比替康,6-乙氧基丙酰基-3’,4’-O-外-苄叉基-教酒菌素,勒托替康,7-[2-(N-异丙基氨基)乙基]-(20S)喜树碱,BNP1350,BNPI1100,BN80915,BN80942,磷酸依托泊苷,替尼泊苷,索布佐生,2’-二甲基氨基-2’-去氧-依托泊苷,GL331,N-[2-(二甲基氨基)乙基]-9-羟基-5,6-二甲基-6H-吡啶并[4,3-b]咔唑-1-甲酰胺,asulacrine,2,3-(亚甲基二氧基)-5-甲基-7-羟基-8-甲氧基苯并[c]-菲啶鎓,5-(3-氨基丙基氨基)-7,10-二羟基-2-(2-羟基乙基氨基甲基)-6H-吡唑并[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-硫代黄嘌呤-4-基甲基]甲酰胺,N-(2-(二甲基氨基)乙基)吖啶-4-甲酰胺,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。
组蛋白脱乙酰酶抑制剂”的实例包括但不限于伏立诺他,曲古抑菌素A,oxamflatin,PXD101,MG98,丙戊酸和scriptaid。
“参与有丝分裂进程的激酶的抑制剂”包括但不限于极光激酶抑制剂、Polo样激酶抑制剂(PLK;特别是PLK-1的抑制剂),bub-1抑制剂和bub-R1抑制剂。“极光激酶抑制剂”的实例为VX-680。
“抗增殖剂包括反义RNA和DNA寡核苷酸如G3139,ODN698,RVASKRAS,GEM231和INX3001,和抗代谢物如依诺他滨,卡莫氟,喃氟啶,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,地西他宾,洛拉曲塞,培美曲塞,奈拉滨,2’-去氧-2’-甲叉基胞啶,2’-氟亚甲基-2’-去氧胞啶,N6-[4-去氧-4-[N2-[2,4-十四碳二烯酰基]甘氨酰基氨基]-L-丙三氧基-B-L-甘露糖-吡喃庚糖基]腺嘌呤,aplidine,海鞘素,曲沙他滨,氨蝶呤,5-氟尿嘧啶,氟脲苷,甲氨蝶呤,亚叶酸,羟基脲,硫鸟嘌呤(6-TG),巯嘌呤(6-MP),阿糖胞苷,喷司他丁,磷酸氟达拉滨,克拉屈滨(2-CDA),天冬酰胺酶,吉西他滨,阿拉诺新,苦马豆素,洛美曲索,右丙亚胺,methioninase,和3-氨基吡啶-2-甲醛氨苯硫脲。
在癌症治疗中使用的与式(I)化合物组合的合适的药剂的非限定性实例包括但不限于:阿巴瑞克;阿地白介素;阿仑单抗;阿利维A酸;别嘌呤醇;六甲蜜胺;氨磷汀;阿那曲唑;三氧化二砷;天冬酰胺酶;阿扎胞苷;苯达莫司汀;贝伐单抗;贝沙罗汀;争光霉素;硼替佐米;白消安;卡普睾酮;卡培他滨;卡铂;卡莫司汀;西妥昔单抗;瘤可宁;顺铂;克拉屈滨;氯法拉滨;环磷酰胺;阿糖腺苷;达卡巴嗪;更生霉素,放线菌素D;达肝素钠;促红细胞生成素;达沙替尼;道诺霉素;地加瑞克;地尼白介素;右丙亚胺;多西他赛;阿霉素;曲他雄酮丙酸酯;依库丽单抗;Elliott's B溶液;伊曲泼帕;表柔比星;重组人促红细胞生成素;埃罗替尼;雌氮芥;磷酸依托泊苷;依托泊苷;依维莫司;依西美坦;菲格司亭;氟脲苷;氟达拉滨;氟尿嘧啶;氟维司群;易瑞沙;特罗凯;奥西罗;吉西他滨;吉妥单抗;醋酸戈舍瑞林;醋酸组胺瑞林;羟基脲;替依莫单抗;伊达比星;异环磷酰胺;甲磺酸伊马替尼;干扰素α-2a;干扰素α-2b;伊立替康;伊莎匹隆;拉帕替尼;雷利度胺;来曲唑;亚叶酸;醋酸亮丙瑞林;左旋咪唑;洛莫司汀;meclorethamine,氮芥;醋酸甲地孕酮;美法仑,L-PAM;巯嘌呤;美司钠;甲氨蝶呤;甲氧沙林;丝裂霉素C;米托坦;米托蒽醌;苯丙酸诺龙;奈拉滨;尼罗替尼;诺莫单抗(Nofetumomab);奥法木单抗(ofatumumab);奥普瑞白介素;奥沙利铂;紫杉醇;帕利夫明;帕米膦酸二钠;帕尼单抗(panitumumab);帕唑帕尼;培加酶;培门冬酶;培非格司亭Pegfilgrastim);培美曲塞二钠;喷司他丁;哌泊溴烷;普乐沙福;普卡霉素,光神霉素);卟菲尔钠;普拉曲沙;甲基苄肼;奎纳克林;拉布立酶;盐酸雷洛昔芬;利妥昔单抗;罗咪酯肽;罗米司亭;沙格司亭;沙格司亭;赛特铂;索拉非尼;链脲菌素;马来酸舒尼替尼;三苯氧胺;替莫唑胺;替西罗莫司;替尼泊苷;睾内酯;硫鸟嘌呤;噻替哌;拓扑替康;托瑞米芬;托西莫单抗;曲妥珠单抗;维甲酸;尿嘧啶芥;戊柔比星;长春花碱;长春新碱;长春瑞滨;伏立诺他;和唑来膦酸。
对于本领域技术人员清楚的是,在适当时,所述其他一种或多种治疗成分可以以盐,例如碱金属盐或胺盐或酸加成、或前药、或酯例如低级烷基酯、或溶剂合物例如水合物的形式使用,以优化治疗成分的活性和/或稳定性和/或物理特性如溶解性。还清楚的是,在适当时,所述治疗成分可以以光学纯形式使用。
上述组合可以合宜地以药物组合物形式使用,因此包含上述组合以及药学上可接受的稀释剂或载体的药物组合物代表本发明的另一方面。这些组合特别可用于呼吸系统疾病,并合宜地适用于吸入或鼻内递送。
这种组合的各化合物可以以分开的或者组合的药物组合物的形式相继或同时给药。优选地,各化合物以组合的药物组合物的形式同时给药。本领域技术人员容易了解已知治疗剂的合适剂量。
实施例
提供以下实施例以便为本领域技术人员提供如何进行、制备和评估本文请求保护的方法和化合物的完整公开和说明,旨在仅仅示例本发明而非限制发明人认为的发明范围。
合成方法
本发明化合物可按照本领域常规方法,并使用合适的试剂、原料和本领域技术人员已知的纯化方法制备。
下面更具体地描述本发明式(I)结构化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。
通常,在制备中,各反应通常在惰性溶剂中,在室温至回流温度(如0℃~100℃,优选0℃~80℃)进行。反应时间通常为0.1小时-60小时,优选0.5-24小时。
中间体N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-碘-4-甲基苯甲酰胺(化合物3)的合成
将化合物2(1.05g,3.74mmol)溶于10mL四氢呋喃中,依次加入化合物1(1.03g,3.74mmol),4-二甲氨基吡啶(4-DMAP,0.046g,0.374mmol)和二异丙基乙胺(1.3mL,7.49mmol),室温下搅拌1小时后加入50mL水,用乙酸乙酯萃取三次,合并有机相,通过柱层析纯化得白色固体产物1.7g,收率为88%。LC-MS(APCI):m/z=517(M+1)+。
实施例1制备N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((2-氧代-
2,3-二氢-1H-咪唑并[4,5-b]吡嗪-5-基)乙炔基)-4-甲基苯甲酰胺(化合物8)
具体合成步骤如下:
步骤1.5-溴-1,3-二氢-2H咪唑并[4,5-b]吡嗪-2-酮(化合物5)的合成。
氮气保护下将5-溴吡嗪-2,3-二胺(0.75g,4mmol)加入到10mL四氢呋喃(THF)中,冰浴下缓慢加入羰基二咪唑(CDI,1.95g,12mmol),搅拌10分钟,升温至回流反应过夜。反应完全后冷却到室温,移至冰浴,缓慢滴加15mL水淬灭反应,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,柱层析得到淡黄色固体0.7g,收率82%。LC-MS(APCI):m/z=216(M+1)+。
步骤2.5-((三甲基硅基)乙炔基)-1,3-二氢-2H-咪唑并[4,5-b]吡嗪-2-酮(化合物6)的合成。
将5-溴-1,3-二氢-2H咪唑并[4,5-b]吡嗪-2-酮(0.7g,3.27mmol)和三甲基硅基乙炔(0.42g,4.25mmol),Pd(PPh3)4(173mg,0.15mmol),CuI(49mg,0.26mmol)和1.2mL N,N-二异丙基乙胺(DIEA)加入到5mL DMF中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入20mL水,用乙酸乙酯萃取,有机相用20mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色油状物0.53g,收率70%。LC-MS(APCI):m/z=233(M+1)+。
步骤3.5-乙炔基-1,3-二氢-2H-咪唑并[4,5-b]吡嗪-2-酮(化合物7)的合成。
将5-((三甲基硅基)乙炔基)-1,3-二氢-2H-咪唑并[4,5-b]吡嗪-2-酮(0.53g,2.3mmol)溶于5mL四氢呋喃,加入四丁基氟化铵(TBAF,1.2g,4.6mmol),于室温下搅拌1小时。旋蒸蒸除溶剂,加入10mL水,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体0.32g,收率88%。LC-MS(APCI):m/z=161(M+1)+。
步骤4.N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡嗪-5-基)乙炔基)-4-甲基苯甲酰胺(化合物8)的合成。
将5-乙炔基-1,3-二氢-2H-咪唑并[4,5-b]吡嗪-2-酮(60mg,0.37mmol)和化合物3(160mg,0.31mmol),Pd(PPh3)4(16mg,0.01mmol),CuI(5mg,0.02mmol)和0.12mL N,N-二异丙基乙胺加入到3mL DMF中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入10mL水,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体119mg,收率70%。LC-MS(APCI):m/z=550(M+1)+;1H NMR(300MHz,DMSO-d6)δ10.53(s,1H),8.28–8.11(m,3H),8.06(d,J=8.6Hz,1H),7.93(d,J=8.0Hz,1H),7.70(d,J=8.5Hz,1H),7.52(d,J=8.1Hz,1H),3.56(s,2H),2.55(s,3H),2.37(s,8H),2.16(s,3H)。
实施例2制备N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((3-甲基-
2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡嗪-5-基)乙炔基)-4-甲基苯甲酰胺(化合物14)。
具体合成步骤如下:
步骤1.6-溴-N2-甲基吡嗪-2,3-二胺(化合物10)的合成。
将3,5-二溴吡嗪-2-胺(化合物9,0.44g,1.75mmol)装入封管中,加入10mL乙醇和5mL 1M的甲胺水溶液,氮气置换1次,密封置于油浴中,加热至100℃反应过夜。反应完全后降至室温,减压浓缩至干,加入20mL水和20mL乙酸乙酯,搅拌分层,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,柱层析得到淡黄色油状物0.3g,收率85%。LC-MS(APCI):m/z=204(M+1)+。
步骤2.6-溴-1-甲基-1,3-二氢-2H-咪唑并[4,5-b]吡嗪-2-酮(化合物11)的合成。
氮气保护下将6-溴-N2-甲基吡嗪-2,3-二胺(0.29g,1.44mmol)加入到5mL四氢呋喃中,冰浴下缓慢加入羰基二咪唑(CDI,0.7g,4.32mmol),搅拌10分钟,升温至回流反应过夜。反应完全后冷却到室温,移至冰浴,缓慢滴加10mL水淬灭反应,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,柱层析得到淡黄色固体0.26g,收率80%。LC-MS(APCI):m/z=230(M+1)+。
步骤3.1-甲基-6-((三甲基硅基)乙炔基)-1,3-二氢-2H-咪唑并[4,5-b]吡嗪-2-酮(化合物12)的合成。
将6-溴-1-甲基-1,3-二氢-2H-咪唑并[4,5-b]吡嗪-2-酮(0.26g,1.14mmol)和三甲基硅基乙炔(0.15g,1.48mmol),Pd(PPh3)4(66mg,0.06mmol),CuI(16mg,0.08mmol)和0.42mL N,N-二异丙基乙胺加入到20mL DMF中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入20mL水,用乙酸乙酯萃取,有机相用20mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色油状物0.21g,收率75%。LC-MS(APCI):m/z=247(M+1)+。
步骤4.6-乙炔基-1-甲基-1,3-二氢-2H-咪唑并[4,5-b]吡嗪-2-酮(化合物13)的合成。
将1-甲基-6-((三甲基硅基)乙炔基)-1,3-二氢-2H-咪唑并[4,5-b]吡嗪-2-酮(210mg,0.85mmol)溶于5mL四氢呋喃,加入四丁基氟化铵(TBAF,0.44g,1.7mmol),于室温下搅拌1小时。旋蒸蒸除溶剂,加入10mL水,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体130mg,收率88%。LC-MS(APCI):m/z=175(M+1)+。
步骤5.N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((3-甲基-2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡嗪-5-基)乙炔基)-4-甲基苯甲酰胺(化合物14)的合成。
将6-乙炔基-1-甲基-1,3-二氢-2H-咪唑并[4,5-b]吡嗪-2-酮(65mg,0.37mmol)和化合物3(160mg,0.31mmol),Pd(PPh3)4(16mg,0.01mmol),CuI(5mg,0.02mmol)和0.12mL N,N-二异丙基乙胺加入到3mL DMF中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入10mL水,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体118mg,收率68%。LC-MS(APCI):m/z=564(M+1)+;1H NMR(300MHz,DMSO-d6)δ10.56(s,1H),8.22(s,3H),8.13–8.03(m,1H),7.95(dd,J=8.0,2.0Hz,1H),7.71(d,J=8.6Hz,1H),7.53(d,J=8.1Hz,1H),3.59(s,2H),3.31(s,3H),2.67–2.58(m,4H),2.57(s,3H),2.48–2.37(m,4H),2.33(s,3H)。
实施例3制备N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((1-甲基-
2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-6-基)乙炔基)-4-甲基苯甲酰胺(化合物14)
具体合成步骤如下:
步骤1.苄基(2-氨基-5-溴吡啶-3-基)氨基甲酸酯(化合物16)的合成。
将5-溴吡啶-2,3-二胺(0.8g,4.25mmol)和吡啶(0.67g,8.5mmol)溶于10mL四氢呋喃中,冰浴下缓慢滴加氯甲酸苄酯(0.87g,5.1mmol),滴加完毕撤去冰浴,于室温下反应3小时,TLC检测反应至完全。向反应液中加入20mL水,用乙酸乙酯萃取,有机相用20mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体1.1g,收率80%。LC-MS(APCI):m/z=323(M+1)+。
步骤2.5-溴-N3-甲基吡啶-2,3-二胺(化合物17)的合成。
将氢化铝锂(0.24g,6.2mmol)加入到10mL四氢呋喃中,冰浴降至-5℃,逐滴滴加苄基(2-氨基-5-溴吡啶-3-基)氨基甲酸酯(1.1g,3.1mmol)的5mL四氢呋喃溶液。滴加完毕后继续搅拌30分钟,撤去冰浴,室温下反应2小时。待TLC检测反应完全,冰浴下缓慢滴入0.3mL水淬灭反应,再依次加入0.6mL 15%的氢氧化钠溶液和2mL水,移至室温,搅拌15分钟后滤去白色沉淀,滤液旋干,柱层析得到淡黄色固体0.3g,收率43%。LC-MS(APCI):m/z=203(M+1)+。
步骤3.6-溴-1-甲基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(化合物18)的合成。
氮气保护下将5-溴-N3-甲基吡啶-2,3-二胺(0.29g,1.44mmol)加入到5mL四氢呋喃中,冰浴下缓慢加入羰基二咪唑(0.7g,4.32mmol),搅拌10分钟,升温至回流反应过夜。反应完全后冷却到室温,移至冰浴,缓慢滴加10mL水淬灭反应,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,柱层析得到淡黄色固体0.26g,收率80%。LC-MS(APCI):m/z=229(M+1)+。
步骤4.1-甲基-6-((三甲基硅基)乙炔基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(化合物19)的合成。
将6-溴-1-甲基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(0.26g,1.14mmol)和三甲基硅基乙炔(0.15g,1.48mmol),Pd(PPh3)4(66mg,0.06mmol),CuI(16mg,0.08mmol)和0.42mL N,N-二异丙基乙胺加入到20mL DMF中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入20mL水,用乙酸乙酯萃取,有机相用20mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色油状物0.21g,收率75%。LC-MS(APCI):m/z=246(M+1)+。
步骤5.6-乙炔基-1-甲基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(化合物20)的合成。
将1-甲基-6-((三甲基硅基)乙炔基)-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(210mg,0.85mmol)溶于5mL四氢呋喃,加入四丁基氟化铵(0.44g,1.7mmol),于室温下搅拌1小时。旋蒸蒸除溶剂,加入10mL水,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体130mg,收率88%。LC-MS(APCI):m/z=174(M+1)+。
步骤6.N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((1-甲基-2-氧代-2,3-二氢-1H-咪唑并[4,5-b]吡啶-6-基)乙炔基)-4-甲基苯甲酰胺(化合物21)的合成。
将6-乙炔基-1-甲基-1,3-二氢-2H-咪唑并[4,5-b]吡啶-2-酮(64mg,0.37mmol)和化合物3(160mg,0.31mmol),Pd(PPh3)4(16mg,0.01mmol),CuI(5mg,0.02mmol)和0.12mL N,N-二异丙基乙胺加入到3mL DMF中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入10mL水,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体115mg,收率66%。LC-MS(APCI):m/z=563(M+1)+。1H NMR(400MHz,DMSO-d6)δ11.85(s,1H),10.61(s,1H),8.24(d,J=2.2Hz,1H),8.17(dd,J=4.7,1.9Hz,2H),8.13–8.08(m,1H),7.94(dd,J=8.0,2.0Hz,1H),7.74–7.65(m,2H),7.51(d,J=8.1Hz,1H),3.62(s,2H),3.33(s,6H),2.87(d,J=12.5Hz,5H),2.56(s,6H)。
实施例4制备N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((2-氧代-
2,3-二氢噁唑并[4,5-b]吡啶-6-基)乙炔基)-4-甲基苯甲酰胺(化合物26)
具体合成步骤如下:
步骤1.6-溴恶唑并[4,5-b]吡啶-2(3H)-酮(化合物23)的合成。
将噁唑并[4,5-b]吡啶-2(3H)-酮(0.39g,2.87mmol)溶于5mL DMF中,冰浴下缓慢滴加液溴(0.91g,5.7mmol),滴加完毕撤去冰浴,室温反应2小时,TLC检测反应至完全。加入20mL10%的亚硫酸钠溶液淬灭反应,用乙酸乙酯萃取,有机相用无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体0.52g,收率84%。LC-MS(APCI):m/z=216(M+1)+。
步骤2.6-((三甲基硅基)乙炔基)恶唑并[4,5-b]吡啶-2(3H)-酮(化合物24)的合成。
将6-溴恶唑并[4,5-b]吡啶-2(3H)-酮(0.25g,1.14mmol)和三甲基硅基乙炔(0.15g,1.48mmol),Pd(PPh3)4(66mg,0.06mmol),CuI(16mg,0.08mmol)和0.42mL N,N-二异丙基乙胺加入到20mL DMF中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入20mL水,用乙酸乙酯萃取,有机相用20mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色油状物0.2g,收率74%。LC-MS(APCI):m/z=233(M+1)+。
步骤3.化合物6-乙炔基恶唑并[4,5-b]吡啶-2(3H)-酮(化合物25)的合成。
将6-((三甲基硅基)乙炔基)恶唑并[4,5-b]吡啶-2(3H)-酮(197mg,0.85mmol)溶于5mL四氢呋喃,加入四丁基氟化铵(0.44g,1.7mmol),于室温下搅拌1小时。旋蒸蒸除溶剂,加入10mL水,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体120mg,收率88%。LC-MS(APCI):m/z=161(M+1)+。
步骤4.N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((2-氧代-2,3-二氢噁唑并[4,5-b]吡啶-6-基)乙炔基)-4-甲基苯甲酰胺(化合物26)的合成。
将6-乙炔基恶唑并[4,5-b]吡啶-2(3H)-酮(60mg,0.37mmol)和化合物3(160mg,0.31mmol),Pd(PPh3)4(16mg,0.01mmol),CuI(5mg,0.02mmol)和0.12mL N,N-二异丙基乙胺加入到3mL DMF中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入10mL水,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体115mg,收率68%。LC-MS(APCI):m/z=550(M+1)+;1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),8.22(dd,J=4.1,2.0Hz,2H),8.15(d,J=2.0Hz,1H),8.09(dd,J=8.8,2.2Hz,1H),7.91(dd,J=7.9,1.9Hz,1H),7.73–7.66(m,2H),7.50(d,J=8.1Hz,1H),3.62(s,2H),2.78(s,6H),2.55(s,5H),2.47(s,3H)。
实施例5制备N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((2-氧代-
2,3-二氢噻唑并[4,5-b]吡嗪-5-基)乙炔基)-4-甲基苯甲酰胺(化合物31)
具体合成步骤如下:
步骤1.3-氨基-6-溴吡嗪-2-硫醇(化合物27)的合成。
将3,5-二溴吡嗪-2-胺(0.6g,2.37mmol)溶于10mL甲醇,加入70%纯度的硫氢化钠(0.38g,4.75mmol),氮气保护下回流反应过夜。反应降至室温,过滤,滤液用1N盐酸调节PH=7,有大量固体析出。过滤,滤饼用5mL冷的甲醇洗涤,干燥,得到淡黄色固体产物0.3g。收率62%。LC-MS(APCI):m/z=207(M+1)+。
步骤2.6-溴噻唑并[4,5-b]吡嗪-2(3H)-酮(化合物28)的合成。
氮气保护下将3-氨基-6-溴吡嗪-2-硫醇(0.29g,1.44mmol)加入到5mL四氢呋喃中,冰浴下缓慢加入羰基二咪唑(0.7g,4.32mmol),搅拌10分钟,升温至回流反应过夜。反应完全后冷却到室温,移至冰浴,缓慢滴加10mL水淬灭反应,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,柱层析得到淡黄色固体0.26g,收率80%。LC-MS(APCI):m/z=233(M+1)+。
步骤3.6-((三甲基硅基)乙炔基)噻唑并[4,5-b]吡嗪-2(3H)-酮(化合物29)的合成。
将6-溴噻唑并[4,5-b]吡嗪-2(3H)-酮(0.26g,1.14mmol)和三甲基硅基乙炔(0.15g,1.48mmol),Pd(PPh3)4(66mg,0.06mmol),CuI(16mg,0.08mmol)和0.42mL N,N-二异丙基乙胺加入到20mL DMF中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入20mL水,用乙酸乙酯萃取,有机相用20mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色油状物0.21g,收率75%。LC-MS(APCI):m/z=250(M+1)+。
步骤4.6-乙炔基噻唑并[4,5-b]吡嗪-2(3H)-酮(化合物30)的合成。
将6-((三甲基硅基)乙炔基)噻唑并[4,5-b]吡嗪-2(3H)-酮(210mg,0.85mmol)溶于5mL四氢呋喃,加入四丁基氟化铵(0.44g,1.7mmol),于室温下搅拌1小时。旋蒸蒸除溶剂,加入10mL水,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体130mg,收率88%。LC-MS(APCI):m/z=178(M+1)+。
步骤5.N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((2-氧代-2,3-二氢噻唑并[4,5-b]吡嗪-5-基)乙炔基)-4-甲基苯甲酰胺(化合物31)的合成。
将6-乙炔基噻唑并[4,5-b]吡嗪-2(3H)-酮(65mg,0.37mmol)和化合物3(160mg,0.31mmol),Pd(PPh3)4(16mg,0.01mmol),CuI(5mg,0.02mmol)和0.12mL N,N-二异丙基乙胺加入到3mL DMF中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入10mL水,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体115mg,收率66%。LC-MS(APCI):m/z=567(M+1)+;1H NMR(500MHz,DMSO-d6)δ10.58(s,1H),8.31(s,1H),8.24(d,J=2.2Hz,1H),8.19(d,J=1.9Hz,1H),8.11(dd,J=8.6,2.2Hz,1H),7.93(dd,J=8.0,2.0Hz,1H),7.71(d,J=8.6Hz,1H),7.52(d,J=8.2Hz,1H),3.66(s,2H),2.72(s,3H),2.55(s,3H),2.48–2.51(s,8H)。
实施例6制备N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((2,3-二
氢-1H-吡咯并[2,3-b]吡啶-5-基)乙炔基)-4-甲基苯甲酰胺(化合物34)
具体合成步骤如下:
步骤1.5-溴-2,3-二氢-1H-吡咯并[2,3-b]吡啶(化合物33)的合成。
将7-氮杂吲哚啉(0.37g,3.1mmol)溶于5mL DMF中,冰浴下缓慢滴加液溴(1.0g,6.2mmol),滴加完毕撤去冰浴,室温反应2小时。反应液加入20mL10%的亚硫酸钠溶液淬灭,用乙酸乙酯萃取,有机相用无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体0.5g,收率82%。LC-MS(APCI):m/z=200(M+1)+。
下面的步骤与实施例5步骤3-5相同,不同点在于用5-溴-2,3-二氢-1H-吡咯并[2,3-b]吡啶替代6-溴噻唑并[4,5-b]吡嗪-2(3H)-酮,最终得到产物化合物34为淡黄色固体,共107mg,收率为65%。LC-MS(APCI):m/z=534(M+1)+;1H NMR(500MHz,DMSO-d6)δ10.54(s,1H),8.22(d,J=2.2Hz,1H),8.13–8.03(m,2H),7.95(d,J=1.9Hz,1H),7.86(dd,J=8.0,2.0Hz,1H),7.70(d,J=8.6Hz,1H),7.46(d,J=8.0Hz,1H),7.37(s,1H),6.98(s,1H),3.62(s,2H),3.54(t,J=8.5Hz,2H),3.33(s,8H),3.01(t,J=8.5Hz,2H),2.84(s,3H),2.58(s,3H)。
实施例7制备N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((噻吩并
[2,3-b]吡啶-5-基)乙炔基)-4-甲基苯甲酰胺(化合物40)
具体合成步骤如下:
步骤1.5-溴-3-碘吡啶-2-醇(化合物36)的合成。
将5-溴吡啶-2-醇(1.2g,6.9mmol)和NIS(1.55g,6.9mmol)溶于20mL甲苯,于90℃油浴中反应30分钟,降至室温,过滤,滤饼用甲醇洗涤,干燥得到淡粉色固体1.8g,收率86%。LC-MS(APCI):m/z=301(M+1)+。
步骤2.5-溴-3-((三甲基硅基)乙炔基)吡啶-2醇(化合物37)的合成。
将5-溴-3-碘吡啶-2-醇(1.8g,6mmol),三甲基硅基乙炔(1.1g,9mmol),醋酸钯(14mg,0.06mmol),碘化亚铜(23mg,0.12mmol),三苯基膦(32mg,0.12mmol)和2mL N,N-二异丙基乙胺加入到10mL的干燥甲苯中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入20mL水,用乙酸乙酯萃取,有机相用20mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色油状物1.3g,收率80%。LC-MS(APCI):m/z=271(M+1)+。
步骤3.5-溴-2-(三甲基硅基)噻吩并[2,3-b]吡啶(化合物38)的合成。
将5-溴-3-((三甲基硅基)乙炔基)吡啶-2醇(1.3g,4.8mmol)溶于20mL甲苯,加入劳森试剂(LR,0.97g,2.4mmol),升温至120℃反应1小时。反应降至室温,旋蒸蒸除溶剂,加入20mL水,用乙酸乙酯萃取,有机相用20mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体1.1g,收率80%。LC-MS(APCI):m/z=287(M+1)+。
步骤4.5-溴噻吩并[2,3-b]吡啶(化合物39)的合成。
将5-溴-2-(三甲基硅基)噻吩并[2,3-b]吡啶(1.06g,3.7mmol)溶于10mL甲醇,加入碳酸钾(1.02g,7.4mmol),于室温下搅拌1小时。旋蒸蒸除溶剂,加入10mL水,用乙酸乙酯萃取,有机相用20mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体0.7g,收率88%。LC-MS(APCI):m/z=215(M+1)+。
下面的步骤与实施例5步骤3-5相同,不同点在于用5-溴噻吩并[2,3-b]吡啶替代6-溴噻唑并[4,5-b]吡嗪-2(3H)-酮,最终得到产物化合物40为淡黄色固体,共119mg,收率为65%。LC-MS(APCI):m/z=549(M+1)+;1H NMR(400MHz,DMSO-d6)δ10.60(s,1H),8.78(d,J=2.0Hz,1H),8.55(d,J=2.1Hz,1H),8.23(d,J=3.1Hz,2H),8.10(d,J=8.6Hz,1H),7.98(dd,J=19.1,7.1Hz,2H),7.71(d,J=8.5Hz,1H),7.52(dd,J=14.1,7.0Hz,2H),3.62(s,2H),2.76(s,5H),2.60(s,3H),2.54(s,3H),2.46(s,3H)。
实施例8制备N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(吡咯并
[1,2-a]嘧啶-3-基乙炔基)-4-甲基苯甲酰胺(化合物46)
具体合成步骤如下:
步骤1.5-溴-2-(丙-1-炔-1-基)嘧啶(化合物42)的合成。
将2,5-二溴嘧啶(2.07g,8.7mmol),双三苯基膦氯化钯(1.22g,17.4mmol)和三丁基丙炔锡烷(3.73g,11.3mmol)加入到20mL的无水二氧六环中,氮气置换三次,升温至90℃反应过夜。反应完全后冷却至室温,加入40mL水,用乙酸乙酯萃取,有机相用20mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体1.2g,收率70%。LC-MS(APCI):m/z=198(M+1)+。
步骤2.3-溴吡咯并[1,2-a]嘧啶(化合物43)的合成。
将5-溴-2-(丙-1-炔-1-基)嘧啶(1.2g,6.1mmol),氯化亚铜(120mg,1.21mmol)和三乙胺(1.85g,18.3mmol)加入到20mLN,N-二甲基乙酰胺中,氮气置换三次,升温至140℃反应4小时。反应完全后冷却至室温,加入40mL水,用乙酸乙酯萃取,有机相用20mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体0.23g,收率19%。LC-MS(APCI):m/z=198(M+1)+。
步骤3.3-((三甲基硅基)乙炔基)吡咯并[1,2-a]嘧啶(化合物44)的合成。
将3-溴吡咯并[1,2-a]嘧啶(0.23g,1.16mmol)和三甲基硅基乙炔(0.15g,1.48mmol),Pd(PPh3)4(66mg,0.06mmol),CuI(16mg,0.08mmol)和0.42mL N,N-二异丙基乙胺加入到20mL DMF中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入20mL水,用乙酸乙酯萃取,有机相用20mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色油状物0.19g,收率76%。LC-MS(APCI):m/z=251(M+1)+。
步骤4.3-乙炔基吡咯并[1,2-a]嘧啶(化合物45)的合成。
将3-((三甲基硅基)乙炔基)吡咯并[1,2-a]嘧啶(182mg,0.85mmol)溶于5mL四氢呋喃,加入四丁基氟化铵(0.44g,1.7mmol),于室温下搅拌1小时。旋蒸蒸除溶剂,加入10mL水,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体106mg,收率88%。LC-MS(APCI):m/z=143(M+1)+。
步骤5.N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(吡咯并[1,2-a]嘧啶-3-基乙炔基)-4-甲基苯甲酰胺(化合物46)的合成。
将3-乙炔基吡咯并[1,2-a]嘧啶(53mg,0.37mmol)和化合物3(160mg,0.31mmol),Pd(PPh3)4(16mg,0.01mmo),CuI(5mg,0.02mmol)和0.12mL N,N-二异丙基乙胺加入到3mLDMF中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入10mL水,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体107mg,收率65%。LC-MS(APCI):m/z=532(M+1)+。1H NMR(400MHz,DMSO-d6)δ10.57(s,1H),9.12(d,J=2.1Hz,1H),8.22(t,J=2.7Hz,2H),8.17(s,1H),8.08(d,J=8.4Hz,1H),7.94(d,J=8.0Hz,1H),7.71(d,J=8.5Hz,1H),7.53(d,J=8.1Hz,2H),7.05(t,J=3.5Hz,1H),6.60(d,J=4.0Hz,1H),3.59(s,2H),2.57(s,3H),2.48–2.51(s,8H),2.33(s,3H)。
实施例9制备N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(异噻唑并
[4,3-b]吡啶-6-基乙炔基)-4-甲基苯甲酰胺(化合物52)
具体合成步骤如下:
步骤1.3-氨基-5-溴吡啶-2-甲腈(化合物48)的合成。
将5-溴-2-氰基-3-硝基吡啶(4.6g,20.2mmol)溶于50mL冰乙酸中,冰浴降温至15℃,分批加入还原铁粉(5.65g,101mmol),控制反应液温度不超过35℃,加料完毕后于室温下搅拌2小时,TLC监测反应完全,过滤,滤饼经10mL甲苯洗涤后转移至二氯甲烷-甲醇(100mL-10mL)溶液中,室温搅拌2小时,过滤,滤液用30mL饱和碳酸氢钠溶液洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体2.4g,收率60%。LC-MS(APCI):m/z=199(M+1)+。
步骤2.3-氨基-5-溴吡啶-2-硫代甲酰胺(化合物49)的合成。
将3-氨基-5-溴吡啶-2-甲腈(2.4g,12.1mmol)溶于30mL乙醇中,加入劳森试剂(2.5g,6.1mmol),升温至回流反应过夜。TLC(薄层色谱)监测反应完全,旋蒸蒸除溶剂,加入30mL水,用乙酸乙酯萃取,有机相用20mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体2.4g,收率85%。LC-MS(APCI):m/z=233(M+1)+。
步骤3.6-溴异噻唑并[4,3-b]吡啶-3-胺(化合物50)的合成。
将3-氨基-5-溴吡啶-2-硫代甲酰胺(2.37g,10.2mmol)溶于10mL甲醇中,冰浴下缓慢滴加3mL 30%的过氧化氢,滴加完毕后移至室温反应过夜。TLC监测反应完全,过滤,滤饼用冷的甲醇洗涤,干燥得到淡黄色色固体1.88g,收率80%。LC-MS(APCI):m/z=231(M+1)+。
步骤4.6-溴异噻唑并[4,3-b]吡啶(化合物51)的合成。
将6-溴异噻唑并[4,3-b]吡啶-3-胺(1.88g,8.2mmol)溶于50mL 85%磷酸和15mL浓硝酸中,冰浴降温至-5℃,缓慢滴加6mL亚硝酸钠水溶液(0.6g,8.7mmol),滴加完毕后于-5℃下继续搅拌30分钟。将上述所得反应液分批加入到25mL 30%的次磷酸中,加料完毕后于室温下反应1小时,反应液用20%氢氧化钠水溶液调节PH=13,甲基叔丁基醚萃取,饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体0.7g,收率40%。LC-MS(APCI):m/z=216(M+1)+。
下面的步骤与实施例8步骤3-5相同,不同点在于用6-溴异噻唑并[4,3-b]吡啶替代3-溴吡咯并[1,2-a]嘧啶,最终得到产物化合物52为淡黄色固体,共105mg,收率62%。LC-MS(APCI):m/z=550(M+1)+;1HNMR(400MHz,DMSO-d6)δ10.57(s,1H),10.05(s,1H),8.96(d,J=2.0Hz,1H),8.58–8.51(m,1H),8.23(dd,J=13.8,2.2Hz,2H),8.07(dd,J=8.5,2.1Hz,1H),7.97(dd,J=8.0,2.0Hz,1H),7.71(d,J=8.5Hz,1H),7.56(d,J=8.1Hz,1H),3.57(s,2H),2.62(s,3H),2.38(s,8H),2.18(s,3H)。
实施例10制备N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((异噻唑
并[5,4-b]吡啶-5-基)乙炔基)-4-甲基苯甲酰胺(化合物58)
具体合成步骤如下:
步骤1.2,5-二溴-3-(二溴甲基)吡啶(化合物54)的合成。
将2,5-二溴-3-甲基吡啶(3.0g,12mmol),过氧化苯甲酰(BPO,0.31g,1.3mmol)和N-溴代丁二酰亚胺(NBS,4.7g,26.4mmol)溶于30mL四氯化碳,升温至回流反应过夜。TLC监测反应完全,冷却至室温,过滤,滤液用20mL水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得白色固体4.2g,收率86%。LC-MS(APCI):m/z=409(M+1)+。
步骤2.2,5-二溴吡啶-3-甲醛(化合物55)的合成。
将2,5-二溴-3-(二溴甲基)吡啶(4.2g,10.3mmol)溶于40mL乙醇和10mL水中,加入硝酸银(8.8g,51.5mmol),升温至回流反应过夜。TLC监测反应完全,冷却至室温,减压蒸除溶剂,加入50mL水稀释,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色油状物2.5g,收率92%。LC-MS(APCI):m/z=266(M+1)+。
步骤3.5-溴-2-硫氰基-3-甲醛(化合物56)的合成。
将2,5-二溴吡啶-3-甲醛(2.05g,7.7mmol)溶于15mL甲酸中,冰浴下分批加入硫氰酸钾(0.78g,8.0mmol),自然升至室温反应过夜。TLC监测反应完全,加入30mL水稀释,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体0.98g,收率52%。LC-MS(APCI):m/z=244(M+1)+。
步骤4.5-溴异噻唑并[5,4-b]吡啶(化合物57)的合成。
将5-溴-2-硫氰基-3-甲醛(0.93g,3.8mmol)溶于10mL 30%的氨甲醇溶液中,室温下搅拌过夜。TLC监测反应完全,加入20mL水稀释,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体0.7g,收率85%。LC-MS(APCI):m/z=216(M+1)+。
下面的步骤与实施例8步骤3-5相同,不同点在于用5-溴异噻唑并[5,4-b]吡啶替代3-溴吡咯并[1,2-a]嘧啶,最终得到产物化合物58为淡黄色固体,共110mg,收率65%。LC-MS(APCI):m/z=550(M+1)+;1HNMR(500MHz,DMSO-d6)δ10.57(s,1H),9.26(s,1H),9.06(d,J=1.9Hz,1H),8.91(d,J=2.0Hz,1H),8.22(dd,J=9.8,2.1Hz,2H),8.10–8.04(m,1H),7.97(dd,J=8.1,1.9Hz,1H),7.71(d,J=8.5Hz,1H),7.56(d,J=8.0Hz,1H),3.57(s,2H),2.61(s,3H),2.38(s,8H),2.17(s,3H)。
实施例11制备N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((2-氧
代-1,2-二氢噻唑并[5,4-b]吡啶-6-基)乙炔基)-4-甲基苯甲酰胺(化合物62)
具体合成步骤如下:
步骤1.3-氨基-5-溴吡啶-2-硫醇(化合物60)的合成。
将2,5-二溴吡啶-3-胺(0.61g,2.4mmol)溶于10mL乙二醇,加入70%纯度的硫氢化钠(0.38g,4.75mmol),氮气保护下回流反应过夜。反应降至室温,过滤,滤液用1N盐酸调节PH=7,有大量固体析出。过滤,滤饼用5mL冷的甲醇洗涤,干燥,得到淡黄色固体产物0.3g。收率60%。LC-MS(APCI):m/z=206(M+1)+。
步骤2.6-溴噻唑并[5,4-b]吡啶-2(1H)-酮(化合物61)的合成。
氮气保护下将3-氨基-5-溴吡啶-2-硫醇(0.3g,1.46mmol)加入到5mL四氢呋喃中,冰浴下缓慢加入羰基二咪唑(0.71g,4.38mmol),搅拌10分钟,升温至回流反应过夜。反应完全后冷却到室温,移至冰浴,缓慢滴加10mL水淬灭反应,用乙酸乙酯萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,柱层析得到淡黄色固体0.26g,收率77%。LC-MS(APCI):m/z=232(M+1)+。
下面的步骤与实施例8步骤3-5相同,不同点在于用6-溴噻唑并[5,4-b]吡啶-2(1H)-酮替代3-溴吡咯并[1,2-a]嘧啶,最终得到产物化合物62为淡黄色固体,共105mg,收率60%。LC-MS(APCI):m/z=566(M+1)+;1HNMR(500MHz,DMSO-d6)δ10.53(s,1H),8.38(d,J=1.8Hz,1H),8.20(dd,J=10.2,2.1Hz,2H),8.13–8.00(m,1H),7.93(dd,J=8.0,2.0Hz,1H),7.70(d,J=8.5Hz,1H),7.57–7.45(m,2H),3.58(s,2H),2.56(s,3H),2.45(m,8H),2.30(s,3H)。
实施例12制备N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((噻吩并
[2,3-b]吡嗪-5-基)乙炔基)-4-甲基苯甲酰胺(化合物68)。
具体合成步骤如下:
步骤1.5-溴-3-碘吡嗪-2-醇(化合物64)的合成。
将5-溴吡嗪-2-醇(1.36g,7.8mmol)和NIS(1.8g,8.0mmol)溶于20mL甲苯,于90℃油浴中反应30分钟,降至室温,过滤,滤饼用甲醇洗涤,干燥得到淡粉色固体1.87g,收率80%。LC-MS(APCI):m/z=302(M+1)+。
步骤2.5-溴-3-((三甲基硅基)乙炔基)吡嗪-2醇(化合物65)的合成。
将5-溴-3-碘吡嗪-2-醇(1.87g,6.2mmol),三甲基硅基乙炔(1.1g,9mmol),醋酸钯(14mg,0.06mmol),碘化亚铜(23mg,0.12mmol),三苯基膦(32mg,0.12mmol)和2mLN,N-二异丙基乙胺加入到10mL的干燥甲苯中,氮气置换三次,升温到90℃,反应3小时。反应完全后冷却至室温,加入20mL水,用乙酸乙酯萃取,有机相用20mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色油状物1.32g,收率78%。LC-MS(APCI):m/z=272(M+1)+。
步骤3.5-溴-2-(三甲基硅基)噻吩并[2,3-b]吡嗪(化合物66)的合成。
将5-溴-3-((三甲基硅基)乙炔基)吡嗪-2醇(1.32g,4.8mmol)溶于20mL甲苯,加入劳森试剂(LR,0.97g,2.4mmol),升温至120℃反应1小时。反应降至室温,旋蒸蒸除溶剂,加入20mL水,用乙酸乙酯萃取,有机相用20mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体1.14g,收率81%。LC-MS(APCI):m/z=288(M+1)+。
步骤4.5-溴噻吩并[2,3-b]吡嗪(化合物67)的合成。
将5-溴-2-(三甲基硅基)噻吩并[2,3-b]吡嗪(1.14g,4mmol)溶于10mL甲醇,加入碳酸钾(1.1g,8mmol),于室温下搅拌1小时。旋蒸蒸除溶剂,加入10mL水,用乙酸乙酯萃取,有机相用20mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体0.77g,收率90%。LC-MS(APCI):m/z=216(M+1)+。
下面的步骤与实施例5步骤3-5相同,不同点在于用5-溴噻吩并[2,3-b]吡嗪替代6-溴噻唑并[4,5-b]吡嗪-2(3H)-酮,最终得到产物化合物40为淡黄色固体,共120mg,收率为71%。LC-MS(APCI):m/z=549(M+1)+;1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.90(s,1H),8.45(d,J=6.1Hz,1H),8.31(s,1H),8.23(s,1H),8.10(d,J=8.7Hz,1H),8.01(d,J=8.1Hz,1H),7.69(dd,J=18.5,7.4Hz,2H),7.57(d,J=8.1Hz,1H),3.63(s,2H),2.84(s,3H),2.62(s,3H),2.58–2.50(s,8H).
实施例13制备N-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-((噻唑并
[4,5-b]吡啶-6-基)乙炔基)-4-甲基苯甲酰胺(化合物72)。
具体合成步骤如下:
步骤1.3-氨基-5-溴吡啶-2-硫醇(化合物70)的合成。
将2,5-二溴吡啶-3-胺(2.2g,8.7mmol)和硫氢化钠(70%,2.08g,26mmol)加入到20mL2-戊醇中,升温到90℃反应过夜。反应完全后冷却至室温,加入30mL水,用乙酸乙酯(20mL*3)萃取,有机相用10mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体1.3g,收率72%。LC-MS(APCI):m/z=206(M+1)+。
步骤2.6-溴噻唑并[5,4-b]吡啶(化合物71)的合成。
将3-氨基-5-溴吡啶-2-硫醇(1.27g,6.2mmol)加入到10mL原甲酸三乙酯中,升温到120℃反应3小时。反应完全后冷却至室温,加入30mL水,用乙酸乙酯(20mL*3)萃取,有机相用20mL饱和食盐水洗涤,无水硫酸钠干燥,浓缩,经硅胶柱分离得淡黄色固体0.8g,收率60%。LC-MS(APCI):m/z=216(M+1)+。
下面的步骤与实施例5步骤3-5相同,不同点在于用6-溴噻唑并[5,4-b]吡啶替代6-溴噻唑并[4,5-b]吡嗪-2(3H)-酮,最终得到产物化合物72为淡黄色固体,共130mg,收率为76%。LC-MS(APCI):m/z=550(M+1)+;1H NMR(400MHz,DMSO-d6)δ10.56(s,1H),9.65(s,1H),8.90(d,J=1.9Hz,1H),8.74(d,J=1.9Hz,1H),8.22(dd,J=5.9,2.0Hz,2H),8.07(dd,J=8.6,2.2Hz,1H),7.96(dd,J=8.1,1.9Hz,1H),7.70(d,J=8.6Hz,1H),7.54(d,J=8.1Hz,1H),3.57(s,2H),2.60(s,3H),2.40(s,8H),2.20(s,3H).
生物活性测试
(1)激酶抑制作用
试剂和耗材:ABL(ThermoFisher,Cat.No PV3585),ABLT315I(Thermo Fisher,Cat.No.PR7429B),ATP(Sigma,Cat.No.A7699-1G),DMSO(Sigma,Cat.No.D2650),96孔板(Corning,Cat.No.3365),384孔板(Greiner,Cat.No.784076),缓冲液(Thermo Fisher,Cat.No.PR4876B)。
具体实验方法:
化合物配制:将受试化合物溶于DMSO配成20mM母液。使用前将化合物在DMSO中稀释成0.1mM,并做3倍梯度稀释11个浓度。加药时再用缓冲液稀释成4倍终浓度的稀释液。
激酶检测方法:配制缓冲液后,将酶与预先稀释配制的不同浓度化合物混合,室温放置30分钟,每个浓度双复孔。加入对应底物及ATP,室温反应60分钟(其中设置阴阳性对照)。反应完毕加入抗体检测,室温孵育60分钟后Evnvision检测,采集数据。根据XLfit5软件进行数据分析及拟图。实施例中的对细胞的体外增殖的抑制作用的结果归纳于下表1中,其中A表示IC50<50nM,B表示50nM≤IC50≤100nM,C表示100nM≤IC50≤1000nM,D表示IC50>1000nM。
表1实施例1-10的激酶抑制作用对比表
实施例编号 | ABL IC<sub>50</sub> | ABL<sup>T315I</sup> IC<sub>50</sub> |
实施例1 | A | A |
实施例2 | A | A |
实施例3 | A | A |
实施例4 | A | A |
实施例5 | A | A |
实施例6 | A | A |
实施例7 | A | A |
实施例8 | A | B |
实施例9 | A | A |
实施例10 | A | A |
实施例11 | A | A |
实施例12 | A | A |
实施例13 | A | A |
(2)细胞毒性实验
检测实施例化合物对Ba/F3,Ba/F3 Bcr-Abl T315I细胞活性的抑制效应。
耗材及试剂:RPMI-1640培养基(GIBCO,目录号A10491-01)、胎牛血清(GIBCO,目录号10099141)、抗生素(Penicillin-Streptomycin),IL-3(PeproTech),嘌呤霉素;细胞系:Ba/F3,Ba/F3 Bcr-Abl T315I(购自美国标准生物品收藏中心,ATCC),活细胞检测试剂盒CellTiter-Glo4(Promega,目录号G7572),96孔黑壁透明平底细胞培养板(Corning,目录号3340)。
实验方法:1.制备细胞板将Ba/F3,Ba/F3 Bcr-Abl T315I细胞分别种于96孔板中,并在Ba/F3细胞中加入8ng/ml IL-3,细胞板置于二氧化碳培养箱中过夜培养。2.用DMSO溶解被测化合物并进行3.16倍梯度稀释,9个化合物浓度,设置三复孔实验。3.化合物处理细胞将化合物转移到细胞板中,化合物起始浓度为10μM。细胞板置于二氧化碳培养箱中培养3天。4.检测向细胞板中加入CellTiter-Glo试剂,室温孵育30分钟使发光信号稳定。采用PerkinElmer Envision多标记分析仪读数。实施例中的对细胞的体外增殖的抑制作用的结果归纳于下表2中,其中A表示IC50<100nM,B表示100nM≤IC50≤500nM,C表示500nM≤IC50≤1000nM,D表示IC50>1000nM。
表2实施例1-10的细胞毒性作用对比表
实施例编号 | Ba/F3 IC<sub>50</sub> | Ba/F3 Bcr-Abl <sup>T315I</sup> IC<sub>50</sub> |
实施例1 | D | B |
实施例2 | D | A |
实施例3 | D | A |
实施例4 | D | C |
实施例5 | D | - |
实施例6 | D | A |
实施例7 | D | B |
实施例8 | D | B |
实施例9 | D | B |
实施例10 | D | B |
实施例11 | D | C |
实施例12 | D | B |
实施例13 | D | B |
实验结果表明,本发明化合物对与药物副作用相关的Ba/F3表现出相对低的抑制活性(IC50大于1000nM),而对Ba/F3 Bcr-Abl T315I突变体的细胞表现出优良的抑制活性(IC50<100nM或100nM≤IC50≤500nM),因此本发明化合物可作为Bcr-Abl抑制剂,用于对酪氨酸激酶抑制剂(TKI)治疗耐药或抵抗的肿瘤病患者,例如慢性粒细胞白血病(CML)慢性期、急变期、加速期患者以及费城染色体阳性(Ph+)的慢性粒细胞白血病和急性淋巴细胞白血病患者具有好的前景。
(3)代谢稳定性评价
微粒体实验:人肝微粒体:0.5mg/mL,Xenotech;大鼠肝微粒体:0.5mg/mL,Xenotech;辅酶(NADPH/NADH):1mM,Sigma Life Science;氯化镁:5mM,100mM磷酸盐缓冲剂(pH为7.4)。
储备液的配制:精密称取一定量的实施例化合物和阳性对照物的粉末,并用DMSO分别溶解至5mM。
磷酸盐缓冲液(100mM,pH7.4)的配制:取预先配好的0.5M磷酸二氢钾150mL和700mL的0.5M磷酸氢二钾溶液混合,再用0.5M磷酸氢二钾溶液调节混合液pH值至7.4,使用前用超纯水稀释5倍,加入氯化镁,得到磷酸盐缓冲液(100mM),其中含100mM磷酸钾,3.3mM氯化镁,pH为7.4。
配制NADPH再生系统溶液(含有6.5mM NADP,16.5mM G-6-P,3U/mL G-6-P D,3.3mM氯化镁),使用前置于湿冰上。
配制终止液:含有50ng/mL盐酸普萘洛尔和200ng/mL甲苯磺丁脲(内标)的乙腈溶液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中,分别加入812.5μL人肝微粒体,混匀,得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。取25057.5μL磷酸盐缓冲液(pH7.4)至50mL离心管中,分别加入812.5μL SD大鼠肝微粒体,混匀,得到蛋白浓度为0.625mg/mL的肝微粒体稀释液。
样品的孵育:用含70%乙腈的水溶液将相应化合物的储备液分别稀释至0.25mM,作为工作液,备用。分别取398μL的人肝微粒体或者大鼠肝微粒体稀释液加入96孔孵育板中(N=2),分别加入2μL 0.25mM的的工作液中,混匀。
代谢稳定性的测定:在96孔深孔板的每孔中加入300μL预冷的终止液,并置于冰上,作为终止板。将96孔孵育板和NADPH再生系统置于37℃水浴箱中,100转/分钟震荡,预孵5min。从孵育板每孔取出80μL孵育液加入终止板,混匀,补充20μL NADPH再生系统溶液,作为0min样品。再向孵育板每孔加入80μL的NADPH再生系统溶液,启动反应,开始计时。相应化合物的反应浓度为1μM,蛋白浓度为0.5mg/mL。分别于反应10、30、90min时,各取100μL反应液,加入终止板中,涡旋3min终止反应。将终止板于5000×g,4℃条件下离心10min。取100in上清液至预先加入100μL蒸馏水的96孔板中,混匀,采用LC-MS/MS进行样品分析。
数据分析:通过LC-MS/MS系统检测相应化合物及内标的峰面积,计算化合物与内标峰面积比值。通过化合物剩余量的百分率的自然对数与时间作图测得斜率,并根据以下公式计算t1/2和CLint,其中V/M即等于1/蛋白浓度。
实验结果:
实验结果如下表3所示,本发明化合物具有优越的代谢稳定性。
表3实施例化合物的肝微粒代谢评价
(4)大鼠的药代动力学实验
8只雄性Sprague-Dawley大鼠,7-8周龄,体重约210g,分成2组,每组4只,分别静脉注射给予0.5mg/kg剂量和单次口服给予10mg/kg剂量的(a)对照组:参照化合物;(b)试验组:实施例化合物,比较其药代动力学差异。
大鼠采用标准饲料饲养,给予水。试验前16小时开始禁食。药物用PEG400和二甲亚砜溶解。眼眶采血,采血的时间点为给药后0.083小时,0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、12小时和24小时。
大鼠吸入乙醚后短暂麻醉,眼眶采集300μL血样于试管。试管内有30μL1%肝素盐溶液。使用前,试管于60℃烘干过夜。在随后一个时间点血样采集完成之后,大鼠乙醚麻醉后处死。
血样采集后,立即温和地颠倒试管至少5次,保证混合充分后放置于冰上。血样在4保证5000rpm离心5分钟,将血浆与红细胞分离。用移液器吸出100μL血浆到干净的塑料离心管中,标明化合物的名称和时间点。血浆在进行分析前保存在-80℃。用LC-MS/MS测定血浆中本发明化合物的浓度。药代动力学参数基于每只动物在不同时间点的血药浓度进计算。
在上述大鼠的药代动力学实验中测试了本发明化合物,发现本发明化合物具有优异的药代动力学性质。
应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围,实施例中未注明具体条件的实验方法,通常按照常规条件,或按照制造厂商所建议的条件。除非另外说明,否则份数和百分比为重量份和重量百分比。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明,不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干简单推演或替换,都应当视为属于本发明的保护范围。
Claims (11)
4.根据权利要求1所述的化合物,R1为H或C1-6烷基。
6.药物组合物,其含有权利要求1-5中任一项所述的化合物或其药学上可接受的盐和药学上可接受的赋形剂。
7.权利要求6的药物组合物,其还含有其它治疗剂。
8.试剂盒,其包括:
第一容器,其中含有权利要求1-5中任一项所述的化合物或其药学上可接受的盐;和
任选地,第二容器,其中含有其它治疗剂;和
任选地,第三容器,其中含有用于稀释或悬浮所述化合物和/或其它治疗剂的药用赋形剂。
9.权利要求1-5中任一项所述的化合物或其药学上可接受的盐在制备用于治疗抗肿瘤或其他疾病的药物中的用途。
10.权利要求9的用途,其中所述的疾病是由Bcr-Abl导致的增殖性疾病。
11.权利要求10的用途,其中所述的增殖性疾病选自:慢性髓性白血病、慢性粒细胞白血病、胃肠道间质瘤、急性粒细胞白血病、甲状腺癌、胃癌、直肠癌或多发性骨髓瘤。
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