CN104619327A - 作为激酶抑制剂的氨基喹唑啉的前药 - Google Patents
作为激酶抑制剂的氨基喹唑啉的前药 Download PDFInfo
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- CN104619327A CN104619327A CN201380047261.2A CN201380047261A CN104619327A CN 104619327 A CN104619327 A CN 104619327A CN 201380047261 A CN201380047261 A CN 201380047261A CN 104619327 A CN104619327 A CN 104619327A
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- Prior art keywords
- base
- compound
- salt
- amino
- pharmaceutically acceptable
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Classifications
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Landscapes
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Abstract
本申请公开了具有式(I)的化合物以及制备和使用该化合物的方法,化合物中X如本申请所定义。
Description
发明背景
发明领域
本发明涉及抑制RIP2激酶的喹唑啉胺的新的前药及其制备和使用方法。具体地,本发明涉及2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙醇的新的前药。
背景技术
受体相互作用蛋白-2(RIP2)激酶,其也被称为CARD3、RICK、CARDIAK或RIPK2,是参与先天性免疫信号传导的TKL家族丝氨酸/苏氨酸蛋白激酶。RIP2激酶由通过过渡(IM)区域连接的N-末端激酶域和C-末端半胱天冬酶-募集域(CARD)组成((1998)J.Biol.Chem.273,12296-12300;(1998)Current Biology 8,885-889;和(1998)J.Biol.Chem.273,16968-16975)。RIP2激酶的CARD域介导与其它含CARD的蛋白(例如NOD1和NOD2)间的相互作用((2000)J.Biol.Chem.275,27823-27831和(2001)EMBO reports 2,736-742)。NOD1和NOD2为细胞质受体,其在先天性免疫监视中起到重要作用。它们识别出革兰氏阳性菌和革兰氏阴性菌病原体并分别通过特定的肽聚糖基序、二氨基庚二酸(即DAP)和胞壁酰基二肽(MDP)激活((2007)J Immunol 178,2380-2386)。
激活后,RIP2激酶结合NOD1或NOD2,并且似乎主要地起到分子支架的功能,来将参与NF-κB和分裂素激活蛋白激酶的活化的其它激酶(TAK1,IKKα/β/γ)连接在一起((2006)Nature Reviews Immunology 6,9-20)。RIP2激酶经历了赖氨酸-209上的K63-连接的多泛素化,其促进了TAK1的募集((2008)EMBO Journal 27,373-383)。这个翻译后修饰是信号传导所必需的,因为该残基突变阻止NOD1/2介导的NF-kB的激活。RIP2激酶还在丝氨酸-176和其它可能的残基上发生自磷酸化作用((2006)CellularSignalling 18,2223-2229)。使用激酶失活突变体(K47A)和非选择性小分子抑制剂的研究已经证明了RIP2激酶的活性对调节RIP2激酶表达和信号传导的稳定性是重要的((2007)Biochem J 404,179-190和(2009)J.Biol.Chem.284,19183-19188)。
RIP2-依赖性信号传导的失调与自身炎症性疾病相关联。在NOD2的NACHT-域中的功能增强突变引起Blau综合征、早发性结节病、特征在于葡萄膜炎的儿科肉芽肿病、皮炎和关节炎((2001)Nature Genetics 29,19-20;(2005)Journal of Rheumatology 32,373-375;(2005)Current RheumatologyReports 7,427-433;(2005)Blood 105,1195-1197;(2005)European Journal ofHuman Genetics 13,742-747;(2006)American Journal of Ophthalmology 142,1089-1092;(2006)Arthritis&Rheumatism 54,3337-3344;(2009)Arthritis&Rheumatism 60,1797-1803;和(2010)Rheumatology 49,194-196)。在NOD2的LRR-域中的突变与节段性回肠炎(Crohn’s disease)的易感性密切相关((2002)Am.J.Hum.Genet.70,845-857;(2004)European Journal of HumanGenetics 12,206-212;(2008)Mucosal Immunology(2008)1(Suppl 1),S5–S9.1,S5-S9;(2008)Inflammatory Bowel Diseases 14,295-302;(2008)ExperimentalDermatology 17,1057-1058;(2008)British Medical Bulletin 87,17-30;(2009)Inflammatory Bowel Diseases 15,1145-1154和(2009)Microbes and Infection11,912-918)。NOD1中的突变已与哮喘((2005)Hum.Mol.Genet.14,935-941)、早发性和肠外炎性肠病((2005)Hum.Mol.Genet.14,1245-1250)相关。遗传和功能研究也已经指出RIP2-依赖性信号传导在多种其它肉芽肿病,例如结节病((2009)Journal of Clinical Immunology 29,78-89和(2006)SarcoidosisVasculitis and Diffuse Lung Diseases 23,23-29)和韦格纳肉芽肿((2009)Diagnostic Pathology 4,23)中的作用。
RIP2激酶活性的强效性、选择性小分子抑制剂将阻断RIP2-依赖的促炎性信号传导,从而在特征在于RIP2激酶活性增加和/或失调的自身炎症性疾病中提供治疗益处。国际专利申请PCT/US2012/051247(WO2013/025958)描述了一系列的喹唑啉胺化合物,其作为RIP2激酶抑制剂。特别地,在该申请中公开了化合物2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙醇。
正如本领域所已知的,一种结构类型的化合物的生物利用度难于预测。相对较小的结构修饰通常会对化合物的吸收、其血中浓度和/或其半衰期产生巨大的影响。因此,具有非常好的体外效力的结构相关化合物可能在治疗效果上不同。推定药物的能力(viability)可能会被较差的口服生物利用度削弱。
前药是药物分子生物可逆的衍生物,其在体内经历酶和/或化学转化以释放活性的母体药物,然后其可发挥所需的药理学作用。在药物发现和研发中,前药成为改善药理学活性药物的物理化学、生物药剂学或药物代谢动力学特性的既定工具。在某些情况下,为了获得有效的口服给药治疗,对于合适前药的确认可能是必需的。
发明概述
本发明涉及式(I)的喹唑啉胺化合物或其盐:
其中:
X选自:
R1a和R1b各自独立地为H、(C1-C4)烷基或-CH2OCO2(C1-C4)烷基;
或R1a和R1b一起表示-(CH2)2-或-(CH2)3-;
R2a、R2b、R3a和R3b各自独立地为H或(C1-C4)烷基,其中所述(C1-C4)烷基任选被-CO2(C1-C4)烷基所取代;
或R2a和R2b一起表示-(CH2)4-、-(CH2)5-、-(CH2)2O(CH2)2-、-(CH2)2NH(CH2)2-或-(CH2)2N(CH3)(CH2)2-;
或R3a和R3b一起表示-(CH2)4-、-(CH2)5-、-(CH2)2O(CH2)2-、-(CH2)2NH(CH2)2-或-(CH2)2N(CH3)(CH2)2-;
或R2b和R3b一起表示-(CH2)2-或-(CH2)3-;
R4为-OH或-NH2;
R5为(C1-C6)烷基、-O(C1-C4)烷基、-NR6R7或5-或6-元杂环烷基,其中所述(C1-C6)烷基被-OH、-OP(=O)(OH)2、-NH2或-NHCO(C1-C4)烷基所取代,其中所述-NHCO(C1-C4)烷基中的所述(C1-C4)烷基任选被-NH2所取代,并且其中所述5-或6-元杂环烷基任选独立地被下列基团取代一次或两次:(C1-C4)烷基、氧代、或另外的5-或6-元杂环烷基;和
R6和R7各自独立地为H或(C1-C4)烷基。
式(I)化合物或其盐,尤其是药学上可接受的盐在给予接受者(host)后,转化为RIP2激酶的抑制剂。本发明具体涉及根据式(I)的喹唑啉胺化合物或其盐,尤其是药学上可接受的盐,或其水合物,其在给予接受者后转化为RIP2激酶的抑制剂。
因此,本发明还涉及抑制RIP2激酶的方法,所述方法包括给予接受者式(I)化合物或其盐,尤其是药学上可接受的盐。
本发明还涉及一种治疗RIP2激酶介导的疾病或病症的方法,其包括对有需要的患者(人或其它哺乳动物,尤其是人)给药治疗有效量的式(I)的化合物或其盐,尤其是药学上可接受的盐。RIP2激酶介导的疾病或病症的实例包括葡萄膜炎、节段性回肠炎、溃疡性结肠炎、早发性和肠外炎性肠病和肉芽肿病,例如结节病、Blau综合征、早发性结节病和韦格纳肉芽肿。
本发明还涉及药物组合物,其包含式(I)化合物或其盐,尤其是药学上可接受的盐,以及药学上可接受的赋形剂。具体地,本发明涉及治疗RIP2激酶介导的疾病或病症的药物组合物,其中所述组合物包含式(I)的化合物或其盐,尤其是药学上可接受的盐,以及药学上可接受的赋形剂。
附图简述
图1是磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯半钙盐(calcium(I)2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl hydrogen phosphate)三水合物晶型的粉末X-射线衍射(PXRD)图。
图2是磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯(2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl dihydrogen phosphate)盐酸盐一水合物晶型的PXRD图。
图3显示对大鼠预先给药化合物2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙醇或泼尼松龙,随后给药L18-MDP之后获得的大鼠全血样品中组合的细胞因子响应。
图4显示向大鼠、狗和小型猪(minipig)口服给药磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯之后2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙醇的血中分布(blood profile)。
发明详述
在整个说明书中所提供的式(I)的各种基团和取代基的可选定义旨在个别地具体描述在本文中公开的各化合物物质,以及一个或多个化合物物质的组。本发明的范围包括这些基团和取代基定义的任一组合。本发明的化合物仅为那些本领域技术人员认为“化学稳定”的化合物。
此外,根据进一步的取代,本领域技术人员将理解本发明化合物可存在其它互变异构体形式。本文所描述化合物的所有互变异构体形式均包含在本发明的范围内。应当理解,提及本发明中命名的化合物时,也包括所述命名化合物的所有互变异构体以及所述命名化合物互变异构体的任一混合物。
本文所用术语“烷基”表示饱和的、直链或支链烃部分。烷基的实例包括但不限于甲基(Me)、乙基(Et)、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基和戊基。术语"C1-C4烷基"表示具有1到4个碳原子的烷基基团或部分。
"5-或6-元杂环烷基"表示包含非芳香的单环基团的基团或部分,其是饱和的或部分不饱和的(包含5到6个环原子),其包含1到4个选自氮、氧和硫的杂原子。杂环烷基的说明性实例包括但不限于,吡咯烷基(pyrrolidyl或pyrrolidinyl)、哌啶基、哌嗪基、吗啉基、四氢-2H-1,4-噻嗪基、四氢呋喃基(tetrahydrofuryl或tetrahydrofuranyl)、二氢呋喃基、唑啉基、噻唑啉基、吡唑啉基、四氢吡喃基、二氢吡喃基、1,3-二氧杂环戊烷基、1,3-二氧杂环己烷基、1,4-二氧杂环己烷基、1,3-氧杂硫杂环戊烷基、1,3-氧杂硫杂环己烷基和1,3-二噻烷基。
杂环烷基基团包括5-元杂环烷基基团,其含有一个选自氮、氧和硫的杂原子,且任选含有一或二个另外的氮原子,或任选含有一个另外的氧或硫原子,所述基团例如吡咯烷基、四氢呋喃基、四氢噻吩基、二氢呋喃基、唑啉基、噻唑啉基、咪唑啉基、吡唑啉基、1,3-二氧杂环戊烷基和1,3-氧杂硫杂环戊烷-2-酮-基。
杂环烷基基团为6-元杂环烷基基团,其包含一个选自氮、氧和硫的杂原子且任选地包含一个或两个另外的氮原子或一个另外的氧或硫原子,例如哌啶基(piperidyl或piperidinyl)、哌嗪基、吗啉基、硫吗啉基、1,1-二氧代-硫吗啉-4-基、四氢吡喃基、二氢吡喃基、四氢-2H-1,4-噻嗪基、1,4-二氧杂环己烷基、1,3-氧硫杂环己烷基和1,3-二噻烷基。
应理解术语杂环烷基包括稳定的杂环状基团,其中一个环氮杂原子任选地被氧化(例如含N-氧化物的杂环基团)或其中一个环硫杂原子任选地被氧化(例如包含砜或亚砜部分的杂环基团,例如四氢噻吩-1-氧化物(四氢噻吩亚砜)或四氢噻吩-1,1-二氧化物(四氢噻吩砜))。
“氧代”表示双键的氧部分;例如,如果直接连接到碳原子上形成羰基部分(C=O)。
本文所用术语“本发明化合物”或“该发明化合物"表示如上文所定义的式(I)化合物,其为任何形式,即,任何盐或非盐形式(例如以游离酸或碱的形式,或以盐的形式,尤其是其药学上可接受的盐)以及其任一生理形式(例如包括非固体形式(例如液体或半固体形式),以及固体形式(例如无定形或晶体形式,尤其是多晶形式),溶剂合物形式,包括水合物形式(例如单水合物、二水合物、三水合物和半水合物)),以及不同形式(不同盐形式的水合物)的混合物。
本文所用术语“任选取代的”表示基团(例如烷基或杂环烷基)或环或部分可不被取代,或所述基团、环或部分可被一个或多个所定义的取代基取代。在其中基团可选自许多可选基团的情况下,该所选的基团可以相同或不同。
术语“独立地”是指当一个以上的取代基选自许多可能的取代基时,那些取代基可以相同或不同。
此外,本领域技术人员应了解,本发明化合物,根据进一步的取代,可以以其它的互变异构体形式存在。本文描述的所述化合物的所有互变异构体形式包含在本发明的范围内。应理解,任何提及本发明的命名化合物旨在包含所述命名化合物的所有互变异构体和所述命名化合物的互变异构体的任何混合物。
在本发明的式(I)化合物的一个实施方案中,
X为且R1a和R1b各自独立地为H、(C1-C4)烷基或-CH2OCO2(C1-C4)烷基。
在另一实施方案中,X为且R1a和R1b各自独立地为H或甲基。
在另一实施方案中,X为且R5为被-OH、-OP(=O)(OH)2、-NH2或-NHCO(C1-C4)烷基所取代的(C1-C6)烷基,其中所述-NHCO(C1-C4)烷基中的所述(C1-C4)烷基任选被-NH2所取代。
在另一实施方案中,X为且R5为被-OH或-NH2所取代的(C1-C6)烷基。
在另一实施方案中,X为且R5为被-NH2所取代的(C1-C6)烷基。
在另一实施方案中,X为且R5为-CH(NH2)(C1-C4)烷基。
在优选的实施方案中,X为且R1a和R1b各自独立地为H,或其药学上可接受的盐。
在另一优选的实施方案中,X为且R1a和R1b各自独立地为H,或其药学上可接受的盐,或其水合物。
在另一优选的实施方案中,X为且R5为被-NH2所取代的(C1-C4)烷基。
本发明代表性的化合物包括:
磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯,
(S)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯,
(R)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯,和
(2S,3S)-2-氨基-3-甲基戊酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯,
或其盐。
在另一实施方案中,本发明代表性的化合物包括实施例1-7的化合物,具体为:
磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯,
磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯二钠盐,
磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯半钙盐三水合物,
磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯盐酸盐一水合物,
(S)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯·二盐酸盐,
(R)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯·二盐酸盐,和
(2S,3S)-2-氨基-3-甲基戊酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯。
在另一实施方案中,本发明代表性的化合物包括:
磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯,
磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯二钠盐,和
(S)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯·二盐酸盐。
应当理解本发明包括游离碱或游离酸形式的式(I)化合物及其盐,例如其药学上可接受的盐。在一个实施方案中,本发明涉及游离碱或游离酸形式的式(I)化合物。在另一个实施方案中,本发明涉及式(I)化合物或其药学上可接受的盐。更进一步应当理解式(I)化合物及其盐可以水合物形式存在,例如一水合物或三水合物。
在一个实施方案中,本发明化合物为游离酸形式的磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯。在另一实施方案中,本发明化合物为磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或其盐。在另一实施方案中,本发明化合物为磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或其药学上可接受的盐。在另一实施方案中,本发明化合物为磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或其水合物。在另一实施方案中,本发明化合物为磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯的药学上可接受的盐或其水合物。在另一实施方案中,本发明化合物为磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯的钠盐、钙盐或盐酸盐或其水合物。
在具体的实施方案中,本发明化合物为磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯二钠盐。
在另一具体的实施方案中,本发明化合物为磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯半钙盐三水合物。在另一具体的实施方案中,本发明化合物为磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯半钙盐三水合物,其具有图1的PXRD。
在另一具体的实施方案中,本发明化合物为磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯盐酸盐一水合物。在另一具体的实施方案中,本发明化合物为磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯盐酸盐一水合物,其具有图2的PXRD。
在另一具体的实施方案中,本发明化合物为游离碱形式的(S)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯。在另一实施方案中,本发明化合物为(S)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或其盐。在另一实施方案中,本发明化合物为(S)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或其药学上可接受的盐。
在另一实施方案中,本发明化合物为游离碱形式的(R)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯。在另一实施方案中,本发明化合物为(R)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或其盐。在另一实施方案中,本发明化合物为(R)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或其药学上可接受的盐。
在另一实施方案中,本发明化合物为游离碱形式的(2S,3S)-2-氨基-3-甲基戊酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯。在另一实施方案中,本发明化合物为(2S,3S)-2-氨基-3-甲基戊酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或其盐。在另一实施方案中,本发明化合物为(2S,3S)-2-氨基-3-甲基戊酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或其药学上可接受的盐。
因此,本发明化合物包括式(I)化合物,尤其是文中所述的具体化合物或其盐,尤其是药学上可接受的盐。具体地,本发明化合物包括式(I)化合物或其药学上可接受的盐、或其水合物、或式(I)化合物的药学上可接受的盐的水合物,以及特别是文中所述的具体化合物。在一个实施方案中,本发明涉及一种抑制RIP2激酶的方法,该方法包括将本发明化合物给予接受者。在另一实施方案中,本发明涉及治疗RIP2激酶介导的疾病或病症的方法,该方法包括向有需要的人给药治疗有效量的本发明化合物。
本发明涉及治疗通过抑制RIP2激酶介导的疾病或病症的方法,其包括向有需要的人给药治疗有效量的本发明化合物。本发明特别涉及治疗通过抑制RIP2激酶介导的疾病或病症的方法,其包括向有需要的人给药治疗有效量的式(I)化合物或其药学上可接受的盐。
本发明还涉及本发明化合物或包含本发明化合物的药物组合物在抑制RIP2激酶和/或治疗RIP2激酶介导的疾病或病症中的用途。
式(I)化合物可包含一个或多个不对称中心(也称为手性中心),因此可以各自的对映异构体、非对映异构体或其它立体异构体的形式或以其混合物的形式存在。当存在于本发明化合物(例如,化合物名称)或本文所说明的任何化学结构中的手性中心的立体化学未指明时,该化合物、化合物名称或结构包含所有单独的立体异构体及其所有的混合物。因此,包含一个或多个手性中心的式(I)化合物可以以外消旋混合物、对映异构体富集混合物或对映异构体纯的个别立体异构体存在。
含有一个或多个不对称中心的根据式(I)的化合物的各种立体异构体可以通过本领域技术人员已知的方法拆分。例如,可如下进行所述拆分:(1)通过形成非对映异构体盐、复合物或其它衍生物;(2)通过与立体异构体特异性试剂的选择性反应,例如通过酶促氧化或还原;或(3)通过在手性环境中的气-液色谱或液相色谱,所述手性环境例如在手性载体(例如连接有手性配体的硅胶)或在手性溶剂存在下。本领域技术人员将会理解,当将所需立体异构体通过上述分离方法之一转化成另一化学实体时,需要其它步骤来释放所需形式。或者,特异性立体异构体可通过使用光学活性试剂、基质、催化剂或溶剂的不对称合成法来合成,或通过不对称转化将一种对映异构体转化成另一种异构体。
应理解本发明化合物的固体形式可以晶型、非晶型或其混合物存在。所述晶型也可显示多晶型(即出现不同晶型的能力)。这些不同晶型,通常称为“多晶型物”。多晶型物有相同的化学组成,但是不同的堆积(packing)、几何排列和其它可描述的晶体固态的性质。因此,多晶型物可具有不同的物理性质,例如形状、密度、硬度、可变形性、稳定性和溶解性质。多晶型物通常具有不同的熔点、IR光谱和X-射线粉末衍射图,其可用于鉴定。本领域一般技术人员将会理解,可制备不同多晶型物,例如,通过改变或调整在结晶/重结晶所述化合物中所用的条件。
当本发明化合物为碱(含有碱性部分)时,所需盐形式可通过本领域已知的任一适当方法制备,包括用无机酸(例如盐酸、氢溴酸、硫酸、硝酸、磷酸等)处理游离碱,或用有机酸(例如乙酸、三氟乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、羟乙酸、水杨酸等)处理游离碱,或用吡喃糖苷酸(例如葡糖醛酸或半乳糖醛酸)处理游离碱,或用α-羟基酸(例如柠檬酸或酒石酸)处理游离碱,或用氨基酸(例如天冬氨酸或谷氨酸)处理游离碱,或用芳香酸(例如苯甲酸或桂皮酸)处理游离碱,或用磺酸(例如对甲苯磺酸、甲磺酸、乙磺酸等)处理游离碱。
合适的加成盐包括乙酸盐、对氨基苯甲酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、碳酸氢盐、二亚甲基水杨酸盐、硫酸氢盐、酒石酸氢盐、硼酸盐、依地酸钙盐、樟脑磺酸盐、碳酸盐、克拉维酸盐、柠檬酸盐、环己基氨基磺酸盐、依地酸盐、乙二磺酸盐、丙酸酯月桂硫酸盐(estolate)、乙磺酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、乙醇酸盐、乙醇酰对氨基苯基胂酸盐、己基间苯二酸盐(hexylresorcinate)、海巴明、氢溴酸盐、盐酸盐、二盐酸盐、富马酸氢盐(hydrofumarate)、磷酸氢盐、氢碘酸盐、马来酸氢盐(hydromaleate)、琥珀酸氢盐(hydrosuccinate)、羟萘甲酸盐、羟乙基磺酸盐、衣康酸盐、乳酸盐、乳糖醛酸盐、月桂酸盐、苹果酸盐、马来酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、马来酸单钾盐、粘酸盐、萘磺酸盐、硝酸盐、N-甲基葡糖胺盐、草酸盐、草酰乙酸盐、扑酸盐(双羟萘酸盐)、棕榈油酸盐、棕榈酸盐、泛酸盐、磷酸盐/二磷酸盐、丙酮酸盐、聚半乳糖醛酸盐、丙酸盐、糖二酸盐、水杨酸盐、硬脂酸盐、碱式乙酸盐、琥珀酸盐、硫酸盐、鞣酸盐、酒石酸盐、氯茶酸盐、甲苯磺酸盐、三乙基碘(triethiodide)、三氟乙酸盐和戊酸盐。
酸加成盐的其它实例包括焦硫酸盐、亚硫酸盐、亚硫酸氢盐、癸酸盐、辛酸盐、丙烯酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、辛二酸盐、癸二酸盐、丁炔-1,4-二酸盐、乙炔-1,6-二酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、酞酸盐、苯基乙酸盐、苯基丙酸盐、苯基丁酸盐、乳酸盐、γ-羟基丁酸盐、扁桃酸盐和磺酸盐类,例如二甲苯磺酸盐、丙磺酸盐、萘-1-磺酸盐和萘-2-磺酸盐。
如果发明的碱性化合物以盐的形式被分离,那么所述化合物对应的游离碱可以用本领域已知的任一合适的方法制备,包括用无机碱或有机碱处理所述盐,使用比所述化合物游离碱的pKa更高的无机碱或有机碱合适。
当本发明化合物为酸(含有酸性部分)时,所需盐可通过本领域已知的任一适当方法制备,包括用无机或有机碱处理游离酸,所述无机或有机碱例如胺(伯胺、仲胺或叔胺)、碱金属或碱土金属氢氧化物等。合适的盐的说明性实例包括有机盐,其衍生自例如甘氨酸和精氨酸的氨基酸、氨、伯胺、仲胺和叔胺以及环胺,例如N-甲基-D-葡萄糖胺、二乙胺、异丙胺、三甲胺、乙二胺、二环己胺、乙醇胺、哌啶、吗啉和哌嗪,以及衍生自钠、钙、钾、镁、锰、铁、铜、锌、铝和锂的无机盐。
由于其在药物中潜在的用途,式(I)化合物的盐优选为药学上可接受的盐。合适的药学上可接受的盐包括例如在Berge,Bighley and MonkhouseJ.Pharm.Sci(1977)66,pp 1-19和"Pharmaceutical Salts:Properties,Selection,and Use,2nd Revised Edition,"P.H.Stahl and C.G.Wermuth(eds.),Wiley,Hoboken,NJ,US(2011)中所描述的那些。术语“药学上可接受的”是指那些化合物、物质、组合物和剂型,其在合理医学判断的范围内,适合与人和动物组织接触使用,而没有过度的毒性、刺激性或其它问题或并发症,具有相称的合理受益/风险比。
“药学上可接受的盐”是指适合于药学上使用的化合物。适合于在医学中使用的式(I)化合物的盐和溶剂化物(例如水合物和盐的水合物)是那些,其中该抗衡离子或有关溶剂是药学上可接受的。然而,具有非药学上可接受的抗衡离子或有关溶剂的盐和溶剂化物也在本发明的范围之内,例如,在制备本发明其它化合物和它们的盐和溶剂化物的过程中用作中间体。
药学上可接受的酸加成盐的实例包括乙酸盐、己二酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、樟脑酸盐、樟脑-磺酸盐(camsylate)、癸酸盐(decanoate)、己酸盐(hexanoate)、辛酸盐(octanoate)、碳酸盐、碳酸氢盐、肉桂酸盐、柠檬酸盐、环己烷氨基磺酸盐、十二烷基硫酸盐(estolate)、乙烷-1,2-二磺酸盐(乙二磺酸盐)、乙磺酸盐(esylate)、甲酸盐、富马酸盐、半乳糖酸盐(粘酸盐)、龙胆酸盐(2,5-二羟基苯甲酸盐)、葡庚糖酸盐(gluceptate)、葡萄糖酸盐、葡萄糖醛酸、谷氨酸盐、戊二酸盐、甘油磷酸盐、乙醇酸盐、马尿酸盐、氢溴酸盐、盐酸盐、氢碘酸盐、异丁酸盐、乳酸盐、乳糖醛酸盐、月桂酸盐、马来酸盐、苹果酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐(mesylate)、萘-1,5-二磺酸盐(萘二磺酸盐)、萘-磺酸盐(萘磺酸盐)、羟丙茶碱、硝酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、磷酸盐、二磷酸盐、丙酸盐、焦谷氨酸盐、水杨酸盐、癸二酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐、十一烯酸盐、1-羟基-2-萘甲酸盐、2,2-二氯乙酸盐、2-羟基乙磺酸盐(isethionate)、2-氧代戊二酸盐、4-乙酰氨基苯甲酸盐和4-氨基水杨酸盐。在一个实施方案中,药学上可接受的酸加成盐为盐酸盐(例如单盐酸盐或二盐酸盐)。在分离式(I)化合物中可使用非药学上可接受的盐例如三氟乙酸盐,并且其包括在本发明的范围内。
药学上可接受的碱加成盐的实例包括铵盐、锂盐、钠盐、钾盐、钙盐、镁盐、铝盐、锌盐、三甲基胺、三乙基胺、吗啉、吡啶、哌啶、甲基吡啶、二环己基胺、N,N’-二苄基乙二胺、2-羟基乙胺、双-(2-羟基乙基)胺、三-(2-羟基乙基)胺、普鲁卡因、二苄基哌啶、去氢枞胺、葡萄糖胺、N-甲基葡萄糖胺、三甲基吡啶、奎宁、喹啉、赖氨酸和精氨酸。在一个实施方案中,药学上可接受的碱加成盐为钠盐或钙盐。在另一实施方案中,药学上可接受的碱加成盐为钠盐。在另一实施方案中,药学上可接受的碱加成盐为钙盐。
本发明的某些化合物可与一个或多个当量的酸(如果化合物包含碱性部分)或碱(如果化合物包含酸性部分)形成盐。本发明在其范围内包含所有可能的化学计量和非化学计量盐形式。
同时具有碱性和酸性两部分的本发明化合物可以以两性离子的形式存在,碱性部分形成酸加成盐或酸性部分形成碱盐。
本发明还提供本发明化合物的一种药学上可接受的盐向本发明化合物的另一种药学上可接受的盐的转化。
如果本发明的碱性化合物以盐的形式分离,则该化合物的相应游离酸或游离碱形式可以通过本领域已知的任何合适的方法制备。
对于式(I)化合物的溶剂合物,包括以晶体形式存在的式(I)化合物的盐的溶剂合物,本领域技术人员将理解可形成药学上可接受的溶剂合物,其中在结晶时溶剂分子被掺入晶格中。溶剂合物可包含非水溶剂例如乙醇、异丙醇、DMSO、乙酸、乙醇胺和EtOAc,或者它们可包含水作为溶剂(该溶剂被掺入到晶格中)。其中水为溶剂(该溶剂被并入晶格中)的溶剂合物通常称为“水合物”。水合物包括化学计量量的水合物以及含有可变量水的组合物(compositions)。本发明包括所有该类溶剂合物,特别是水合物例如一水合物或三水合物。因此,本发明化合物包括式(I)化合物或其盐,特别是其药学上可接受的盐,或其水合物,式(I)化合物的药学上可接受的盐的水合物,并且具体包括实施例中所述的每个化合物。因此,本发明提供了式(I)化合物或其盐,尤其是其药学上可接受的盐,溶剂合物,特别是水合物例如一水合物或三水合物。
由于式(I)化合物用于药物组合物,将容易理解其各自优选以基本上纯的形式提供,例如至少60%的纯度,更合适为至少75%的纯度,以及优选为至少85%,尤其至少98%的纯度(%指重量百分比)。所述化合物的不纯的制备品可用于制备药物组合物中使用的更纯的形式。
本发明化合物尤其可用于治疗RIP2激酶介导的疾病或病症,特别是由抑制RIP2激酶介导的疾病或病症,例如葡萄膜炎、白介素-1转换酶(ICE,也被称为半胱天冬酶-1)相关的发热综合征(ICE发热)、皮炎、急性肺损伤、2型糖尿病、关节炎(特别是类风湿性关节炎)、炎性肠病(例如溃疡性结肠炎和节段性回肠炎)、早发性炎性肠病、肠外炎性肠病、预防响应于由心脏手术、器官移植、肠外炎性肠病导致的缺血在实体器官(特别是肾)移植中的缺血再灌注损伤、肝脏疾病(非酒精性脂肪肝、酒精性脂肪肝和自身免疫性肝炎)、过敏性疾病(例如哮喘)、移植反应(例如移植物抗宿主病)、自身免疫性疾病(例如系统性红斑狼疮和多发性硬化)和肉芽肿病(例如结节病、Blau综合征、早发性结节病、韦格纳肉芽肿以及间质性肺病)。
本发明化合物尤其可用于治疗葡萄膜炎、ICE发热、Blau综合征、早发性结节病、溃疡性结肠炎、节段性回肠炎、韦格纳肉芽肿和结节病。
在一个实施方案中,本发明涉及治疗葡萄膜炎的方法,所述方法包括向有需要的人给药治疗有效量的式(I)化合物或其药学上可接受的盐。在另一实施方案中,本发明涉及治疗白介素-1转换酶相关的发热综合征的方法,所述方法包括向有需要的人给药治疗有效量的式(I)化合物或其药学上可接受的盐。在另一实施方案中,本发明涉及治疗Blau综合征的方法,所述方法包括向有需要的人给药治疗有效量的式(I)化合物或其药学上可接受的盐。在另一实施方案中,本发明涉及治疗早发性结节病的方法,所述方法包括向有需要的人给药治疗有效量的式(I)化合物或其药学上可接受的盐。在另一实施方案中,本发明涉及治疗溃疡性结肠炎的方法,所述方法包括向有需要的人给药治疗有效量的式(I)化合物或其药学上可接受的盐。在另一实施方案中,本发明涉及治疗节段性回肠炎的方法,所述方法包括向有需要的人给药治疗有效量的式(I)化合物或其药学上可接受的盐。在另一实施方案中,本发明涉及治疗韦格纳肉芽肿的方法,所述方法包括向有需要的人给药治疗有效量的式(I)化合物或其药学上可接受的盐。在另一实施方案中,本发明涉及治疗结节病的方法,所述方法包括向有需要的人给药治疗有效量的式(I)化合物或其药学上可接受的盐。
治疗RIP2激酶介导的疾病或病症,或更广泛地,治疗免疫介导的疾病包括但不限于,过敏性疾病、自身免疫性疾病、预防移植排异反应等,可使用本发明化合物以单一治疗或双重或多重组合治疗来实现,尤其是用于治疗顽固性病例,例如与其它抗炎药物和/或抗TNF药物的组合,其可根据本领域已知的治疗有效量进行给药。
式(I)化合物及其药学上可接受的盐可单独使用或与其它的治疗剂组合。因此,本发明的组合治疗包括给药至少一种式(I)化合物或其药学上可接受的盐,以及使用至少一种其它的治疗活性剂。优选地,本发明的组合治疗包括给药至少一种式(I)化合物或其药学上可接受的盐,以及至少一种其它的治疗活性剂。式(I)化合物及其药学上可接受的盐,以及其它的治疗活性剂可在单一的药物组合物中一起给药或者分开给药,并且当分开给药时可以同时或按照任何顺序依次给药。式(I)化合物及其药学上可接受的盐和其它治疗活性剂的量,以及给药的相关周期将为了获得所需的组合治疗效果而选择。因此,在另一方面提供了一种组合,其包括式(I)化合物或其药学上可接受的盐,以及一种或多种其它治疗活性剂。
因此一方面,式(I)化合物或其药学上可接受的盐以及包含本发明的式(I)化合物或其药学上可接受的盐的药物组合物可与一种或多种其它治疗活性剂(例如抗炎药剂和/或抗-TNF药剂)组合使用或包括一种或多种其它治疗活性剂。
本发明化合物可以与皮质激素和/或抗TNF药物组合给药治疗Blau综合征、早发性结节病;或与抗TNF生物制剂或其它抗炎性生物制剂组合给药治疗节段性回肠炎;或与5-ASA(美沙拉嗪)或柳氮磺吡啶组合给药治疗溃疡性结肠炎;或与低剂量皮质激素和/或甲氨喋呤组合给药治疗韦格纳肉芽肿或结节病或间质性肺病;或与生物制剂(例如抗TNF药物、抗IL-6药物等)组合给药治疗类风湿性关节炎;或与抗IL6剂和/或甲氨喋呤组合给药治疗ICE发热。
合适的抗炎药物的实例包括5-氨基水杨酸和美沙拉嗪制剂,柳氮磺吡啶、羟基氯喹、硫代嘌呤(硫唑嘌呤、巯基嘌呤)、甲氨喋呤、环磷酰胺、环孢菌素A、JAK抑制剂(tofacitinib)、皮质激素,尤其是低剂量皮质激素(例如泼尼松()和布地奈德)和抗炎性生物制剂例如抗-IL6R mAbs((tocilizumab))、抗-IL6生物制剂、抗-IL1或IL12或IL23生物制剂(ustekinumab())、抗整联蛋白药剂(那他珠单抗())、抗-CD20mAbs(利妥昔单抗和奥法木单抗())和其它药剂,例如阿巴西普()、阿那白滞素()和贝利单抗()、CD4生物制剂和其它细胞因子抑制剂或对T-细胞或B-细胞受体或白细胞介素的生物制剂。合适的抗TNF药物的实例包括抗TNF生物制剂,例如(依那西普)、(阿达木单抗)、(英夫利昔单抗)、(certolizumab)和(戈利木单抗)。
本发明提供本发明化合物,其用于治疗。本发明还提供式(I)化合物或其药学上可接受的盐,其用于治疗。特别地,本发明提供文中所述的化合物,其用于治疗。
在另一实施方案中,本发明提供本发明化合物,其用于治疗通过抑制RIP2激酶介导的疾病或病症。在另一实施方案中,本发明提供式(I)化合物或其药学上可接受的盐,其用于治疗通过抑制RIP2激酶介导的疾病或病症。特别地,本发明提供了文中所述的化合物,其用于治疗通过抑制RIP2激酶介导的疾病或病症。在另一实施方案中,本发明提供式(I)化合物或其药学上可接受的盐,其用于治疗葡萄膜炎、白介素-1转换酶相关的发热综合征、皮炎、急性肺损伤、2型糖尿病、关节炎、炎性肠病、溃疡性结肠炎、节段性回肠炎、早发性炎性肠病、肠外炎性肠病、预防在实体器官移植中的缺血再灌注损伤、非酒精性脂肪肝、酒精性脂肪肝、自身免疫性肝炎、哮喘、移植物抗宿主病、系统性红斑狼疮、多发性硬化、结节病、Blau综合征/早发性结节病、韦格纳肉芽肿或间质性肺病。在另一实施方案中,本发明提供式(I)化合物或其药学上可接受的盐,其用于治疗葡萄膜炎。在另一实施方案中,本发明提供式(I)化合物或其药学上可接受的盐,其用于治疗白介素-1转换酶相关的发热综合征。在另一实施方案中,本发明提供式(I)化合物或其药学上可接受的盐,其用于治疗Blau综合征。在另一实施方案中,本发明提供式(I)化合物或其药学上可接受的盐,其用于治疗早发性结节病。在另一实施方案中,本发明提供式(I)化合物或其药学上可接受的盐,其用于治疗溃疡性结肠炎。在另一实施方案中,本发明提供式(I)化合物或其药学上可接受的盐,其用于治疗节段性回肠炎。在另一实施方案中,本发明提供式(I)化合物或其药学上可接受的盐,其用于治疗早发性炎性肠病。在另一实施方案中,本发明提供式(I)化合物或其药学上可接受的盐,其用于治疗肠外炎性肠病。在另一实施方案中,本发明提供式(I)化合物或其药学上可接受的盐,其用于治疗韦格纳肉芽肿。在另一实施方案中,本发明提供式(I)化合物或其药学上可接受的盐,其用于治疗结节病。
本发明具体地提供式(I)化合物或其药学上可接受的盐作为活性治疗物质在治疗RIP2激酶介导的疾病或病症(例如本文中所述的疾病和病症)中的用途。更具体地,本发明提供式(I)化合物或其药学上可接受的盐在治疗通过抑制RIP2激酶介导的疾病和病症中的用途。本发明具体地提供了文中所述的化合物在治疗通过抑制RIP2激酶介导的疾病和病症中的用途。因此,本发明提供式(I)化合物或其药学上可接受的盐作为活性治疗物质在有此需要的人中治疗通过抑制RIP2激酶介导的疾病中的用途。
本发明还提供式(I)化合物或其药学上可接受的盐在制备用于治疗RIP2激酶介导的疾病或病症(例如文中所述的疾病和病症)的药物中的用途。更具体地,本发明提供了式(I)化合物或其药学上可接受的盐在制备用于治疗通过抑制RIP2激酶介导的疾病或病症的药物中的用途。因此,本发明提供了式(I)化合物或其药学上可接受的盐在制备用于在有需要的人中治疗通过抑制RIP2激酶介导的疾病或病症的药物中的用途。在一个实施方案中,本发明提供了式(I)化合物或其药学上可接受的盐在制备用于治疗葡萄膜炎、白介素-1转换酶相关的发热综合征、皮炎、急性肺损伤、2型糖尿病、关节炎、炎性肠病、溃疡性结肠炎、节段性回肠炎、早发性炎性肠病、肠外炎性肠病、预防在实体器官移植中的缺血再灌注损伤、非酒精性脂肪肝、酒精性脂肪肝、自身免疫性肝炎、哮喘、移植物抗宿主病、系统性红斑狼疮、多发性硬化、结节病、Blau综合征/早发性结节病、韦格纳肉芽肿或间质性肺病的药物中的用途。在另一实施方案中,本发明提供了式(I)化合物或其药学上可接受的盐在制备用于治疗葡萄膜炎的药物中的用途。在另一实施方案中,本发明提供了式(I)化合物或其药学上可接受的盐在制备用于治疗白介素-1转换酶相关的发热综合征的药物中的用途。在另一实施方案中,本发明提供了式(I)化合物或其药学上可接受的盐在制备用于治疗早发性结节病的药物中的用途。在另一实施方案中,本发明提供了式(I)化合物或其药学上可接受的盐在制备用于治疗溃疡性结肠炎的药物中的用途。在另一实施方案中,本发明提供了式(I)化合物或其药学上可接受的盐在制备用于治疗节段性回肠炎的药物中的用途。在另一实施方案中,本发明提供了式(I)化合物或其药学上可接受的盐在制备用于治疗韦格纳肉芽肿的药物中的用途。在另一实施方案中,本发明提供了式(I)化合物或其药学上可接受的盐在制备用于治疗结节病的药物中的用途。在另一实施方案中,本发明提供了式(I)化合物或其药学上可接受的盐在制备用于治疗早发性炎性肠病的药物中的用途。在另一实施方案中,本发明提供了式(I)化合物或其药学上可接受的盐在制备用于治疗肠外炎性肠病的药物中的用途。在另一实施方案中,本发明提供了式(I)化合物或其药学上可接受的盐在制备用于治疗Blau综合征的药物中的用途。
在治疗上的“有效量”是指如本文所定义,当给予需要该类治疗的患者时,足够达到治疗效果的化合物的量。因此式(I)化合物或其药学上可接受的盐或其水合物的治疗有效量是:当给予有此需要的人时,足以调节或抑制RIP2激酶活性,使该活性介导的疾病症状降低、减缓或受阻的活性成分的量。给定化合物的量依据多种因素而改变,例如具体化合物(例如,效力(pIC50)、有效性(EC50)和具体化合物的生物半衰期)、疾病症状及其严重程度、所需治疗患者的特性(例如,年龄、体型和体重),但是本领域技术人员仍可以按常规决定。同样地,所述化合物治疗的持续时间和给药的时间期限(给药间的时间期限和给药时机,例如,饭前/随餐/饭后)根据需治疗的哺乳动物的特性(例如,体重)、具体化合物及其性质(例如,药学特性)、疾病或病症及其严重程度和具体的药物组合物及其使用方法而变化,但是本领域技术人员仍可以决定。
“治疗”或“疗法”是指患者的疾病或病症至少有所减轻。减轻疾病或病症的治疗方法包括本发明化合物在任一常规可接受方法中的使用,例如用于阻止、阻滞、预防、治疗或治愈介导的疾病或病症。使用本发明化合物可容易治疗的具体的疾病和病症在本文中描述。
本发明化合物可以以任一合适的给药途径给药,包括全身给药和局部给药。全身给药包括口服给药、肠胃外给药、透皮给药、直肠给药和吸入给药。肠胃外给药表示除肠内、透皮或吸入以外的给药途径,通常为注射或输注。肠胃外给药包括静脉、肌内和皮下注射或输注。吸入表示给药至患者肺部,无论是通过嘴或是鼻道吸入。局部给药包括施用至皮肤。
在给定时间内,本发明化合物可给药一次或根据给药方案以不同的时间间隔给药一定次数。例如,剂量可以每天给药一、二、三或四次。剂量可以给药直到实现所需治疗效果,或无限期给药以维持所需治疗效果。本发明化合物的合适给药方案取决于化合物的药代动力学性质,例如吸收、分布和半衰期,其可由本领域技术人员确定。此外,本发明化合物的合适的给药方案(包括该给药方案的持续时间)取决于待治疗的疾病或病症、待治疗的疾病或病症的严重程度、待治疗的患者的年龄和身体状况、待治疗的患者的病史、并行治疗的性质、所期望的治疗效果和本领域技术人员知识和专业内的类似因素。该技术人员还将理解,合适的给药方案可根据个别患者对于给药方案的反应或由于个别患者需要随时间变化来进行调整。
对于治疗用途而言,本发明化合物通常(但不必须)在给药患者前配制成药物组合物。因此,本发明也涉及药物组合物,其包含本发明化合物以及一种或多种药学上可接受的赋形剂。
在一个实施方案中,本发明提供了药物组合物,其包含游离酸形式的磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯以及一种或多种药学上可接受的赋形剂。在另一实施方案中,本发明提供了药物组合物,其包含磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或其药学上可接受的盐以及一种或多种药学上可接受的赋形剂。在另一实施方案中,本发明提供了药物组合物,其包含磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或其水合物以及一种或多种药学上可接受的赋形剂。在另一实施方案中,本发明提供了药物组合物,其包含磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯的药学上可接受的盐或其水合物以及一种或多种药学上可接受的赋形剂。在另一实施方案中,本发明提供了药物组合物,其包含磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯的钠盐、钙盐或盐酸盐,或其水合物以及一种或多种药学上可接受的赋形剂。
在具体的实施方案中,本发明提供了药物组合物,其包含磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯二钠盐以及一种或多种药学上可接受的赋形剂。
在另一具体的实施方案中,本发明提供了药物组合物,其包含磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯半钙盐三水合物以及一种或多种药学上可接受的赋形剂。在另一具体的实施方案中,本发明提供了药物组合物,其包含磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯半钙盐三水合物(其具有图1的PXRD)以及一种或多种药学上可接受的赋形剂。
在另一具体的实施方案中,本发明提供了药物组合物,其包含磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯盐酸盐一水合物以及一种或多种药学上可接受的赋形剂。在另一具体的实施方案中,本发明提供了药物组合物,其包含磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯盐酸盐一水合物(其具有图2的PXRD)以及一种或多种药学上可接受的赋形剂。
在另一实施方案中,本发明提供了药物组合物,其包含游离碱形式的(S)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯以及一种或多种药学上可接受的赋形剂。在另一实施方案中,本发明提供了药物组合物,其包含(S)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或其药学上可接受的盐以及一种或多种药学上可接受的赋形剂。
在另一实施方案中,本发明提供了药物组合物,其包含游离碱形式的(R)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯以及一种或多种药学上可接受的赋形剂。在另一实施方案中,本发明提供了药物组合物,其包含(R)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或其药学上可接受的盐以及一种或多种药学上可接受的赋形剂。
在另一实施方案中,本发明提供了药物组合物,其包含游离碱形式的(2S,3S)-2-氨基-3-甲基戊酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯以及一种或多种药学上可接受的赋形剂。在另一实施方案中,本发明提供了药物组合物,其包含(2S,3S)-2-氨基-3-甲基戊酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或其药学上可接受的盐以及一种或多种药学上可接受的赋形剂。
本发明的药物组合物可被制备和包装成散装形式,其中可以提取有效量的本发明化合物然后给予患者,例如用粉末、糖浆和注射用溶液。或者,本发明的药物组合物可被制备和包装成单位剂型。对于口服给药,例如,可给药一个或多个片剂或胶囊。所述药物组合物的量至少包含治疗有效量的本发明化合物(即式(I)化合物或其盐,尤其是药学上可接受的盐)。当制备单位剂型时,本发明的药物组合物可包含1mg到1000mg的本发明化合物。
如文中所提供的,含有1mg至1000mg的本发明化合物的单位剂型(药物组合物)可每天给药一、二、三或四次,优选每天给药一、二或三次,并且更优选每天给药一或二次以有效地治疗RIP2介导的疾病或病症。本发明的药物组合物通常包含一种本发明化合物。但是,在一些实施方案中,本发明的药物组合物包含多于一种本发明化合物。此外,本发明的药物组合物还可任选地包含一种或多种其它的药学活性化合物。
本文所用“药学上可接受的赋形剂”表示在给药形式中涉及的或与组合物相容的物质、组合物或载体。当混合时,各赋形剂必须与药物组合物的其它成分相容,使得对患者给药时将基本上降低本发明化合物的疗效的相互作用和将导致药物组合物成为药学上不可接受的相互作用得以避免。此外,各赋形剂的纯度当然必须足够高,使其为药学上可接受。
本发明化合物和药学上可接受的赋形剂通常被配制成通过所需给药途径适于给药患者的剂型。常规的剂型包括那些(1)适于口服给药的剂型,例如片剂、胶囊剂、小胶囊剂、丸剂、锭剂、粉末、糖浆、酏剂、悬浮液、溶液、乳剂、囊剂和扁囊剂;(2)适于肠胃外给药的剂型,例如无菌溶液、悬浮液和用于重构(reconstitution)的粉末;(3)适于透皮给药的剂型,例如透皮贴剂;(4)适于直肠给药的剂型,例如栓剂;(5)适于吸入的剂型,例如气雾剂和溶液;和(6)适于局部给药的剂型,例如乳膏、软膏、洗剂、溶液、糊剂、喷雾剂、泡沫剂和凝胶剂。
合适的药学上可接受的赋形剂将根据所选具体的剂型而变化。此外,可根据在组合物中的具体功能来选择合适的药学上可接受的赋形剂。例如,可根据促进制备均一剂型的能力来选择某些药学上可接受的赋形剂。可根据促进制备稳定的剂型的能力来选择某些药学上可接受的赋形剂。可根据在给药患者后促进本发明化合物从一个器官或身体部分携带或运输至另一器官或身体部分的能力来选择某些药学上可接受的赋形剂。某些药学上可接受的赋形剂可根据其提高患者顺应性的能力进行选择。
合适的药学上可接受的赋形剂包括下列赋形剂类型:稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、粒化剂、包衣剂、润湿剂、溶剂、共溶剂、助悬剂、乳化剂、增甜剂、调味剂、掩味剂、着色剂、防结块剂、保湿剂、螯合剂、增塑剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂。本领域技术人员将理解,某些药学上可接受的赋形剂可以以多于一种功能和以替代性功能来使用,取决于所述赋形剂在制剂中存在多少和在制剂中存在何种其它成分。
具有本领域的知识和技术的技术人员能够选择出以适当量用于本发明的合适的药学上可接受的赋形剂。此外,有许多本领域技术人员可用的资源,这些资源描述了药学上可接受的赋形剂且其可用于选择合适的药学上可接受的赋形剂。实例包括Remington's Pharmaceutical Sciences(Mack PublishingCompany),The Handbook of Pharmaceutical Additives(Gower PublishingLimited),和The Handbook of Pharmaceutical Excipients(the AmericanPharmaceutical Association and the Pharmaceutical Press)。
本发明的药物组合物使用本领域技术熟练人员已知的技术和方法制备。通常用于本领域的一些方法描述在Remington's Pharmaceutical Sciences(Mack Publishing Company)中。
一方面,本发明涉及固体口服剂型,例如片剂或胶囊剂,其包含有效量的本发明化合物以及稀释剂或填充剂。合适的稀释剂和填充剂包括乳糖、蔗糖、葡萄糖、甘露醇、山梨醇、淀粉(例如玉米淀粉、马铃薯淀粉和预胶化淀粉)、纤维素及其衍生物(例如微晶纤维素)、硫酸钙和磷酸氢钙。口服固体给药剂型还可包含粘合剂。合适的粘合剂包括淀粉(例如玉米淀粉、马铃薯淀粉和预胶化淀粉)、明胶、阿拉伯胶、海藻酸钠、海藻酸、西黄蓍胶、瓜尔胶、聚维酮和纤维素及其衍生物(例如微晶纤维素)。口服固体给药剂型还可包含崩解剂。合适的崩解剂包括交聚维酮、淀粉羟乙酸钠、交联羧甲基纤维素、海藻酸和羧甲基纤维素钠。口服固体给药剂型还可包含润滑剂。合适的润滑剂包括硬脂酸、硬脂酸镁、硬脂酸钙和滑石。
实施例
用下列实施例说明本发明。这些实施例不是用于限制本发明的范围,而是为本领域技术人员提供关于制备和使用本发明化合物、组合物和方法的指导。虽然本发明描述了具体的实施方案,本领域技术人员将理解,在不脱离本发明精神和范围的情况下,可作出各种变化和修改。
使用软件命名程序ACD/Name Pro V6.02(可获自Advanced ChemistryDevelopment,Inc.,110Yonge Street,14th Floor,Toronto,Ontario,Canada,M5C 1T4(http://www.acdlabs.com/))或ChemDraw中的命名程序(Struct=NamePro 12.0,作为ChemBioDraw Ultra的部分,可获自CambridgeSoft.100CambridgePark Drive,Cambridge,MA 02140 USA(www.cambridgesoft.com))得到本文所述的中间体和最终化合物的名称。本领域技术人员应了解,在某些情况下,该程序将结构描述的化合物命名为该化合物的互变异构体。应理解,任何提及命名化合物或结构描述的化合物旨在包含此类化合物的所有互变异构体及其互变异构体的任何混合物。
在下列实验说明中,可使用下列缩写:
制备1
N-(6-(叔丁基硫基)-7-甲氧基喹唑啉-4-基)苯并[d]噻唑-5-胺
步骤1.2-氨基-4-甲氧基苯甲酸甲酯:向2-氨基-4-(甲氧基)苯甲酸(5g,30mmol)在MeOH(30mL)和甲苯(60mL)中的溶液中加入三甲基硅烷基重氮甲烷(30mL,60mmol)。将反应混合物于0℃搅拌1小时。将反应混合物温热至室温,并将溶剂真空除去。将粗物质通过柱色谱法(0至15%EtOAc/己烷)纯化,得到4.2g的标题化合物(74%)。MS:m/z:182[M+H]+。
步骤2.2-氨基-5-碘-4-甲氧基苯甲酸甲酯:将2-氨基-4-(甲氧基)苯甲酸甲酯(3.78g,20.86mmol)溶于25mL的水、15mL乙醇和2.2mL浓HCl中。在5℃下将ICl(1.1mL,21.9mmol)在3.8mL浓HCl和14mL水中的溶液加入到苯胺溶液中。将该反应混合物搅拌过夜,并然后过滤得到6.9g的淡褐色固体。MS:m/z:308[M+H]+。
步骤3.6-碘-7-甲氧基喹唑啉-4(1H)-酮:将2-氨基-5-碘-4-(甲氧基)苯甲酸甲酯(2g,6.5mmol)和甲脒(2.0g,19.5mmol)在2-甲氧基乙醇(15mL)中的溶液于125℃搅拌6小时。真空除去溶剂,并将残余物悬浮在水中,并将该固体过滤收集,用水洗涤并真空干燥(50℃),得到2.1g的标题化合物(96%纯)。MS:m/z:303[M+H]+。
步骤4.4-氯-6-碘-7-(甲氧基)喹唑啉:将6-碘-7-(甲氧基)-4(1H)-喹唑啉酮(2.0g,6.6mmol)、POCl3(3.1mL,33.1mmol)和DIPEA(6.9mL,40mmol)在圆底烧瓶中在DCE(50mL)中混合。将反应混合物于80℃加热5小时,随后于70℃加热过夜。将反应混合物冷却至室温。沉淀出黄色固体。将该固体过滤。浓缩该溶液,并用饱和的NaHCO3溶液中和,用CH2Cl2萃取,经Na2SO4干燥。过滤混合物,并真空除去溶剂。合并固体部分,得到2.0g的标题化合物(88%,93%纯))。MS:m/z:321[M+H]+。
步骤5.N-1,3-苯并噻唑-5-基-6-碘-7-(甲氧基)-4-喹唑啉胺:向4-氯-6-碘-7-(甲氧基)喹唑啉(2.0g,5.4mmol)的1-丙醇(30mL)溶液中加入1,3-苯并噻唑-5-胺(1.2g,8.1mmol)。将悬浮液在油浴中于90℃(预加热)加热。将反应混合物在此温度下搅拌30分钟。使反应混合物冷却至室温时黄色固体沉淀出来。将该固体过滤,用甲苯洗涤,并干燥,得到1.3g的标题化合物(55.2%,99%纯)。MS:m/z:435[M+H]+。
步骤6.N-(6-(叔丁基硫基)-7-甲氧基喹唑啉-4-基)苯并[d]噻唑-5-胺:向N-1,3-苯并噻唑-5-基-6-碘-7-(甲氧基)-4-喹唑啉胺(2.1g,4.5mmol)、2-甲基-2-丙三醇(483mg,5.35mmol)、Et3N(1.9mL,13.4mmol)在DMF(5mL)中的溶液中加入Pd(Ph3P)4(516mg,0.45mmol)。将反应混合物于90-100℃搅拌1小时。将大部分DMF真空除去。将粗物质用MeOH研磨。将红色固体过滤,并用Et2O洗涤,得到1.7g的标题化合物,为灰白色固体(92%,96%纯)。MS:m/z:397[M+H]+。
制备2
N-(6-(叔丁基磺酰基)-7-甲氧基喹唑啉-4-基)苯并[d]噻唑-5-胺
向N-(6-(叔丁基硫基)-7-甲氧基喹唑啉-4-基)苯并[d]噻唑-5-胺(1.0g,2.5mmol)在THF(20mL)和水(2mL)中的溶液中加入过硫酸氢钾制剂(Oxone)(3.1g,5.0mmol)。将反应混合物在室温下搅拌8小时。将饱和的NaHCO3水溶液加入到反应混合物中以调节pH~7。将混合物用EtOAc(100mL x 2)和CH2Cl2(100mL x 2)萃取,经Na2SO4干燥,并过滤。真空除去溶剂,并将粗物质通过柱色谱法(0至8%MeOH/CH2Cl2)纯化,得到530mg的标题化合物(43.6%,89%纯)。MS:m/z:429[M+H]+。
N-(6-(叔丁基磺酰基)-7-甲氧基喹唑啉-4-基)苯并[d]噻唑-5-胺的1HNMR:δ(400MHz,DMSO-d6)δ1.34(s,9H),4.01(s,3H),7.40(s,1H),7.89(dd,J=8.80,1.78Hz,1H),8.17(d,J=8.80Hz,1H),8.59(d,J=1.78Hz,1H),8.64(s,1H),9.14(s,1H),9.42(s,1H),10.55(s,1H)。
制备3
4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-醇
向N-(6-(叔丁基磺酰基)-7-甲氧基喹唑啉-4-基)苯并[d]噻唑-5-胺(2.0g,4.7mmol)在DMF(30mL)中的溶液中加入异丙基硫醇钠(2.7g,28.0mmol),并将该溶液于150℃搅拌1小时。将溶剂真空除去。将1N HCl水溶液加入到反应混合物中以中和至pH=6。沉淀出黄色固体,将其过滤,并通过柱色谱法(0至5%MeOH/CH2Cl2)纯化,得到1.5g的标题化合物(65.9%,85%纯)。MS:m/z:415[M+H]+。
4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-醇的1H NMR:(400MHz,DMSO-d6)δ1.15-1.46(s,9H),7.21(s,1H),7.89(dd,J=8.72,1.78Hz,1H),8.16(d,J=8.72Hz,1H),8.55(s,1H),8.58(d,J=1.78Hz,1H),9.07(s,1H),9.42(s,1H),10.47(s,1H),11.45(宽单峰,1H)。
制备4
2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙醇
将4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-醇(8.0g,19.3mmol)和K2CO3(5.9g,42.5mmol)溶于98ml DMF中,并搅拌2分钟,随后加入2-溴乙醇(5.1mL,72.4mmol)。将该混合物于70℃加热3小时,然后冷却至室温并搅拌18小时。加入水(300mL),并将得到的固体过滤,用水洗涤。将该湿的滤饼在水中再次浆化,并过滤得到黄褐色固体。将该固体溶于热的EtOAc/MeOH(150mL/50mL)中,并冷却至室温,得到白色的固体沉淀,将其过滤并真空干燥,得到产物,为白色固体(2.4g)。将得到的滤液蒸发至干,用EtOAc研磨,过滤,并干燥得到淡褐色固体(3.1g)。将该固体合并(5.5g,62%产率)。合并几个批次的该物质,得到15g原料(input material)。向该固体中加入水(150mL)。将混合物进行超声处理,并在室温下搅拌15分钟。将该固体过滤,并于70℃真空干燥3天,得到作为固体的标题化合物(14.8g,98%回收率)。MS:m/z:459[M+H]+;1H NMR(400MHz,DMSO-d6)δ1.36(s,9H),3.81(q,J=4.80Hz,2H),4.28(t,J=4.80Hz,2H),4.81(t,J=4.80Hz,1H),7.41(s,1H),7.89(d,J=8.40Hz,1H),8.17(d,J=8.40Hz,1H),8.58(s,1H),8.63(s,1H),9.14(s,1H),9.42(s,1H),10.55(s,1H)。
实施例1
磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯
将2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙醇(4g,8.72mmol)和Et3N(1.824mL,13.08mmol)悬浮在(使用空气加热枪加热以溶解尽可能多,但在该浓度下无法完全溶解)磷酸三乙酯(40mL)中,并冷却至0℃。在0℃下,在剧烈搅拌下缓慢地滴加POCl3(1.220mL,13.08mmol)。将该反应混合物在0℃下搅拌1小时直至反应完全。将该反应混合物在0℃下历时10分钟用水(4mL)淬灭,悬浮于DMSO-CH3CN-50mM磷酸氢氨钠(pH=7)(比例为1:1:8)中,然后用NH4OH调节至pH为7,得到完全的溶液,并通过制备型C18HPLC(Luna C18,10μ,101x 250mm柱,500mL/min)纯化,使用15-21%的CH3CN于50mM磷酸氢氨钠(pH=7)中的缓冲液梯度洗脱。将含所需产物(得自多次操作)的级分合并,使用甲酸调节pH至3.6,并浓缩至300mL,得到黄色的悬浮液。将悬浮液再次调节至pH为3.6,在冰浴中冷却2小时;滤出产物,用50mL冷水洗涤,并于40℃在高真空下干燥18小时,得到黄色固体,磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯(76%总产率)。1H NMR(400MHz,DMSO-d6)δppm 1.36(s,9H)4.16-4.28(m,3H)4.45(t,J=4.55Hz,2H)7.43(s,1H)7.89(dd,J=8.72,1.64Hz,1H)8.17(d,J=8.59Hz,1H)8.58(d,J=1.52Hz,1H)8.64(s,1H)9.15(s,1H)9.42(s,1H)10.58(宽单峰,1H);MS(m/z)539(M+H+)。
实施例2
磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯二钠盐
将磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯(95mg,0.176mmol)悬浮于CH3CN(2mL)和水(2mL)中,加入碳酸氢钠(29.6mg,0.353mmol)的水(1mL)溶液,得到澄清的溶液,将其在旋转式蒸发器上浓缩至干。将得到的残余物用CH3CN研磨,并在旋转式蒸发器上蒸发至干,得到白色固体,磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯二钠盐(103mg,100%)。1H NMR(400MHz,D2O)δppm 1.15(s,9H)3.94(d,J=18.95Hz,4H)6.31(s,1H)6.82-7.02(m,2H)7.37(宽单峰,1H)7.76(s,1H)7.90(s,1H)8.70(s,1H);MS(m/z)539(M-2Na++3H+)。
实施例3
磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯半钙盐三水合物
将乙腈(11.0mL)加入到磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯(407.1mg)中。将悬浮液加热至40℃,并以3批相等的量(相隔10分钟)加入Ca(OAc)2(0.5M的水溶液,0.5当量),随后种晶。然后将悬浮液的温度在40℃至5℃之间循环~20小时。在氮气保护(nitrogen tent)下通过真空-过滤分离结晶固体。过滤的固体的产率为90.1%(411.5mg)。图1的PXRD图是将固体在40℃下真空干燥4小时后获得的。通过ICP-AES确定半-钙盐的化学计量为1:0.5(API:CI)(3.8%,半-Ca盐的理论值为:3.3%)。
通过进行小规模的类似方法(不同的是没有进行种晶),获得半-钙盐的水合物形式的晶种。
实施例4
磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯盐酸盐一水合物
将THF(11.0mL)加入到磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯(401.0mg)中。将悬浮液加热至40℃,并以3批相等的量(相隔10分钟)加入HCl酸(5M的水溶液,1.0当量),随后种晶。然后将悬浮液的温度在40℃至5℃之间循环~20小时。在氮气保护下通过真空过滤分离结晶固体。过滤的固体的产率为85.9%(379.4mg)。图2的PXRD图是将固体在40℃下真空干燥4小时后获得的。通过测定氯化物含量的离子色谱法确定该HCl盐的化学计量为1:1(API:CI)(5.99±0.42%,HCl盐的理论值为:6.15%)。
通过进行小规模的类似方法(不同的是没有进行种晶),获得HCl盐的水合物形式的晶种。
实施例5
(S)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯二盐酸盐
a)(S)-2-((叔丁氧基羰基)氨基)-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯
在室温下,将(S)-2-((叔丁氧基羰基)氨基)-3-甲基丁酸(171mg,0.785mmol)和HATU(498mg,1.308mmol)溶于DMF(4mL)中,加入i-Pr2NEt(0.229mL,1.308mmol),继续搅拌15分钟,随后加入2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙醇(300mg,0.654mmol)和DMAP(15.99mg,0.13mmol)。将反应混合物在室温下搅拌16小时,用EtOAc(100ml)稀释,用水、盐水洗涤,经MgSO4干燥,并浓缩。将残余物在硅胶(40g,5%MeOH/DCM)上纯化,得到(S)-2-((叔丁氧基羰基)氨基)-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯(387mg,90%)。1H NMR(400MHz,DMSO-d6)δppm 0.87(t,6H)1.36(s,9H)1.38(s,9H)2.03-2.14(m,1H)3.92(dd,J=8.08,6.06Hz,1H)4.47(d,J=10.86Hz,4H)7.14(d,J=8.34Hz,1H)7.44(s,1H)7.89(dd,J=8.59,2.02Hz,1H)8.17(d,J=8.59Hz,1H)8.58(d,J=2.02Hz,1H)8.64(s,1H)9.16(s,1H)9.43(s,1H)10.57(s,1H);MS(m/z)658(M+H+)。
b)(S)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯二盐酸盐
将HCl的1,4-二烷(4.33mL,17.33mmol)溶液加入到含有(S)-2-((叔丁氧基羰基)氨基)-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯(380mg,0.578mmol)的小瓶中,将悬浮液于室温搅拌1小时,浓缩,将该固体过滤收集,用EtOAc洗涤,并在高真空下干燥16小时,得到灰白色固体(S)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯二盐酸盐(326mg,89%)。1HNMR(400MHz,DMSO-d6)δppm 0.99(d,J=7.07Hz,6H)1.37(s,9H)2.26(dd,1H)3.91(d,J=5.31Hz,1H)4.60(d,J=11.87Hz,4H)7.71(s,1H)7.78(dd,J=8.72,1.64Hz,1H)8.30(d,J=8.59Hz,1H)8.44(d,J=1.77Hz,1H)8.56(宽单峰,3H)8.95(s,1H)9.34(s,1H)9.50(s,1H)12.09(宽单峰,1H);MS(m/z)558(M+H+)。
按照相同的方法,使用(R)-2-((叔丁氧基羰基)氨基)-3-甲基丁酸制备下列化合物。
实施例6:(R)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯·二盐酸盐
1H NMR(400MHz,DMSO-d6)δppm 0.99(d,6H)1.37(s,9H)2.21-2.32(m,1H)3.90(d,J=4.80Hz,1H)4.48-4.69(m,4H)7.69(s,1H)7.80(dd,J=8.72,1.89Hz,1H)8.28(d,J=8.59Hz,1H)8.46(d,J=2.02Hz,1H)8.58(d,J=3.79Hz,3H)8.91(s,1H)9.32(s,1H)9.49(s,1H)11.88(宽单峰,2H);MS(m/z)558(M+H+)。
实施例7
(2S,3S)-2-氨基-3-甲基戊酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯
将(2S,3S)-2-((叔丁氧基羰基)氨基)-3-甲基戊酸(60.5mg,0.262mmol)和HATU(166mg,0.436mmol)溶于DMF(2mL)中,于23℃冷却,加入DIEA(0.076mL,0.436mmol)和DMAP(5.33mg,0.044mmol),继续搅拌30分钟,随后加入2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙醇(100mg,0.218mmol)。将反应混合物在室温下搅拌3天,然后于50℃加热20小时,反应没有完成。
制备(2S,3S)-2-((叔丁氧基羰基)氨基)-3-甲基戊酸(121mg,0.52mmol)和HATU(332mg,0.87mmol)和DIEA(0.15mL,0.87mmol)在DMF(1ml)中的溶液,并搅拌15分钟,随后加入到上述反应混合物中。将得到的反应混合物于50℃加热4小时,使用20-70%ACN/水/TFA(0.05%)在Gilson HPLC(100x150mm RP Sunfire柱)上纯化。合并含有所需产物的级分,在旋转式蒸发器上浓缩。将残余物溶于二烷(1ml)中,然后在室温下加入HCl(1ml,4M的二烷溶液),并将得到的混合物搅拌1小时,直至所有的起始物转化为所需的产物。将反应混合物浓缩,在EtOAc和碳酸氢钠水溶液之间分配,分离有机层,用盐水洗涤,干燥(MgSO4),并浓缩,得到白色固体(2S,3S)-2-氨基-3-甲基戊酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯(74mg,0.126mmol,57.6%产率)。1H NMR(400MHz,DMSO-d6)δppm 0.78-0.83(m,3H)0.85(d,J=6.82Hz,3H)1.05-1.21(m,1H)1.35(s,9H)1.43(ddd,J=13.45,7.52,4.29Hz,1H)1.57-1.70(m,1H)3.15-3.23(m,1H)4.34-4.57(m,4H)7.44(s,1H)7.89(dd,J=8.72,1.89Hz,1H)8.17(d,J=8.59Hz,1H)8.58(d,J=1.77Hz,1H)8.64(s,1H)9.15(s,1H)9.42(s,1H)10.56(s,1H);MS(m/z)572(M+H+)。
实施例8
生物试验
体内试验(I)
RIP2抑制剂的有效性可在啮齿类动物体内进行评估。已证实小鼠腹膜内(i.p.)或静脉内(i.v.)给药L18-MDP可通过激活NOD2信号传导通路诱导炎性响应(Rosenweig,H.L.等,2008.Journal of Leukocyte Biology 84:529-536)。利用常规技术监测经L18-MDP治疗的小鼠/大鼠的炎性响应水平,这通过测量细胞因子(IL8、TNFα、IL6和IL-1β)在血清和/或腹膜灌洗液中含量的增加,以及测量流入腹膜空间的中性粒细胞(当腹膜内给药L18-MDP时)实现。可通过以下证明在经治疗的啮齿类动物中抑制L18-MDP诱导的炎性响应:口服预先给药测试化合物,然后利用常规技术测量并比较在血清和/或腹膜灌洗液中的细胞因子水平(IL8、TNFα、IL6和IL-1β)以及流入腹膜空间的中性粒细胞(当腹膜内给药L18-MDP时)。
对大鼠口服预先给药化合物2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙醇,剂量为2mg/kg(8只大鼠)和泼尼松龙(8只大鼠,用作阳性对照),预先给药之后给药L18-MDP(50μg/只大鼠)0.25h/min。从本研究所用大鼠体内获取的全血样品中,利用基于抗体的检测(Meso-ScaleDiscovery平台)对组合的细胞因子水平(IL8、TNFα、IL6和IL-1β)进行测量。组合的细胞因子响应计算为相对于载体处理的小鼠观察到的响应而言对四种细胞因子测得的平均响应,并且如图3中所示,作为平均值±平均值的标准差(n=8只大鼠/组)。
体内试验(II)
向一组测试动物口服给药磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯,剂量当量为2mg/kg的2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙醇。向大鼠(n=2)和狗(n=3)给药磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯,而向小型猪(雄性小型猪(n=3))给药磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯二钠盐。从每个测试动物中以给药后0至24小时(在狗中为25小时)的时间间隔获取血样品。通过LC/MS确定每个样品中2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙醇的浓度。口服给药磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或磷酸酯二钠盐后,每个测试物种中2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙醇的平均血液浓度示于图4中。
确定磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯在大鼠中的半衰期(T1/2)为15分钟,在狗中的半衰期(T1/2)为5分钟。确定磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯二钠盐在小型猪中的半衰期(T1/2)为26分钟。
药物组合物
实施例A
使用常规方法制备片剂并按以下配方配制:
实施例B
使用常规方法制备胶囊并按以下配方配制:
Claims (18)
1.式(I)的化合物或其盐:
其中:
X选自:
R1a和R1b各自独立地为H、(C1-C4)烷基或-CH2OCO2(C1-C4)烷基;
或R1a和R1b一起表示-(CH2)2-或-(CH2)3-;
R2a、R2b、R3a和R3b各自独立地为H或(C1-C4)烷基,其中所述(C1-C4)烷基任选被-CO2(C1-C4)烷基所取代;
或R2a和R2b一起表示-(CH2)4-、-(CH2)5-、-(CH2)2O(CH2)2-、-(CH2)2NH(CH2)2-或-(CH2)2N(CH3)(CH2)2-;
或R3a和R3b一起表示-(CH2)4-、-(CH2)5-、-(CH2)2O(CH2)2-、-(CH2)2NH(CH2)2-或-(CH2)2N(CH3)(CH2)2-;
或R2b和R3b一起表示-(CH2)2-或-(CH2)3-;
R4为-OH或-NH2;
R5为(C1-C6)烷基、-O(C1-C4)烷基、-NR6R7或5-或6-元杂环烷基,其中所述(C1-C6)烷基被-OH、-OP(=O)(OH)2、-NH2或-NHCO(C1-C4)烷基所取代,其中所述-NHCO(C1-C4)烷基中的所述(C1-C4)烷基任选被-NH2所取代,并且其中所述5-或6-元杂环烷基任选独立地被下列基团取代一次或两次:(C1-C4)烷基、氧代、或另外的5-或6-元杂环烷基;和
R6和R7各自独立地为H或(C1-C4)烷基。
2.根据权利要求1的化合物或其盐,其中X为且R1a和R1b各自独立地为H或甲基。
3.根据权利要求1的化合物或其盐,其中X为且R5为被-NH2取代的(C1-C6)烷基。
4.化合物,其为磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或其盐。
5.化合物,其为磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或其盐或其水合物。
6.根据权利要求4的化合物或其盐,其为磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯二钠盐。
7.根据权利要求5的化合物或其盐,其为磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯半钙盐三水合物。
8.根据权利要求5的化合物或其盐,其为磷酸单2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯盐酸盐一水合物。
9.化合物,其为(S)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或其盐。
10.化合物,其为(R)-2-氨基-3-甲基丁酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或其盐。
11.化合物,其为(2S,3S)-2-氨基-3-甲基戊酸2-((4-(苯并[d]噻唑-5-基氨基)-6-(叔丁基磺酰基)喹唑啉-7-基)氧基)乙基酯或其盐。
12.根据权利要求1-11中任一项的化合物或其盐,其中所述盐是药学上可接受的盐。
13.药物组合物,其包含权利要求12的化合物或其药学上可接受的盐,以及药学上可接受的赋形剂。
14.治疗通过抑制RIP2激酶介导的疾病或病症的方法,所述方法包括向需要该治疗的人给药治疗有效量的权利要求12的化合物或其药学上可接受的盐。
15.根据权利要求12的化合物或其药学上可接受的盐,其用于治疗。
16.根据权利要求12的化合物或其药学上可接受的盐,其用于治疗通过抑制RIP2激酶介导的疾病。
17.根据权利要求12的化合物或其药学上可接受的盐在制备用于治疗通过抑制RIP2激酶介导的疾病的药物中的用途。
18.根据权利要求14的方法,其中所述疾病或病症选自葡萄膜炎、白介素-1转换酶相关的发热综合征、皮炎、急性肺损伤、2型糖尿病、关节炎、类风湿性关节炎、溃疡性结肠炎、节段性回肠炎、早发性炎性肠病、肠外炎性肠病、预防在实体器官移植中的缺血再灌注损伤、非酒精性脂肪肝、酒精性脂肪肝、自身免疫性肝炎、哮喘、移植物抗宿主病、系统性红斑狼疮、多发性硬化、结节病、Blau综合征/早发性结节病、韦格纳肉芽肿或间质性肺病。
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