CN113260616A - 用于治疗呼吸系统疾病的新型化合物 - Google Patents
用于治疗呼吸系统疾病的新型化合物 Download PDFInfo
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- CN113260616A CN113260616A CN201980087269.9A CN201980087269A CN113260616A CN 113260616 A CN113260616 A CN 113260616A CN 201980087269 A CN201980087269 A CN 201980087269A CN 113260616 A CN113260616 A CN 113260616A
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Abstract
本发明涉及用于预防或治疗呼吸系统疾病的新型化合物,所述呼吸系统疾病例如为哮喘、急性和慢性炎性病症以及纤维化疾病或其中纤维化导致该病症病理的病症。本发明还涉及这些化合物的制备,并涉及包括所述化合物的组合物。本发明还涉及所述化合物以及包括所述化合物的组合物在治疗或预防呼吸系统疾病、急性和慢性炎性病症以及纤维化疾病或其中纤维化导致所述病症病理的病症中的用途。
Description
相关申请
本申请要求AU2018904241和AU2018904242(各自于2018年11月7日提交)的优先权。AU2018904241和AU2018904242各自的全部内容通过引用并入本文。
技术领域
本发明提供了基于咪唑的化合物,其在治疗呼吸系统疾病(如哮喘和相关病症、急性和慢性炎症病症、纤维化疾病或其中纤维化导致该病症病理的病症)方面具有潜力。
背景技术
哮喘是一种综合征,包含各种不同类型的疾病,其严重程度、原因和触发因素各不相同。哮喘综合征的共同特征是可逆性气道阻塞、气道高反应性和气道炎症,最显著的特征是除肥大细胞激活外的气道壁被嗜酸性粒细胞和T淋巴细胞浸润。
目前的哮喘药物包括短效和长效β2-肾上腺受体选择性激动剂(SABA和LABA)和吸入皮质类固醇(ICS)。现在也可以用Ultra-LABA。短效和长效毒蕈碱受体拮抗剂(SAMA和LAMA)通常与其他支气管扩张剂和抗炎药(尤其是ICS)联合用于一些患者。白三烯受体拮抗剂(LTRA)也可以添加到不同的治疗方案中。最近,中和嗜酸性粒细胞的化学引诱剂(白细胞介素-5)的单克隆抗体美泊利珠单抗(mepolizumab)已被证明在特定患者中具有ICS和LABA组合之外的益处。然而,特别是对于严重的哮喘,患者仍然有症状并且有周期性疾病恶化(称为恶化)。在严重哮喘的药物治疗方面存在相当大的未得到满足的需求。在大多数情况下,这些哮喘恶化被认为是由下呼吸道的呼吸系统病毒感染引起的。导致这些恶化的病毒包括感染呼吸系统上皮细胞的呼吸系统合胞病毒、流感病毒和鼻病毒。哮喘个体的上皮细胞被认为特别容易受到这种感染,并且与炎症反应的恶化有关。
研究表明,TGF-β能够损害ICS的有效性。此外,发明人已经证明气道上皮细胞的病毒感染通过诱导TGF-β活性而损害ICS活性。TGF-β的药物靶向具有自身免疫和二尖瓣缺损的风险。发明人使用化合物PF670462(WO2016/149756)出人意料地将酪蛋白激酶1δ/ε确定为TGF-β诱导ICS不敏感的介质,并证明了该制剂在逆转类固醇不敏感中的用途。
这将有益于开发可用于预防或治疗一种或多种呼吸系统疾病、急性和慢性炎性病症以及纤维化疾病或其中纤维化导致该病症病理的病症的替代化合物。
发明内容
本文描述的是式(II)化合物或其盐、溶剂化物、N-氧化物、互变异构体、立体异构体、多晶型物和/或前药:
其中:
R1和R2各自独立地选自于由H、C1-3烷基C6-12芳基、C1-3烷基C5-11杂芳基、C1-3烷基C3-6环烷基和C1-3烷基C3-6杂环基组成的组;
R3选自于由H、F、Cl和CH3组成的组;
R4选自于由C0-3烷基C3-12环烷基和C1-12烷基组成的组;
其中R1、R2、R3和R4中的每一个都任选地被取代。
在一些实施方案中,式(II)化合物是式(I)化合物
其中:
R1选自于由C2-3烷基C6-12芳基、C1烷基C10-12芳基、C1-3烷基C5-11杂芳基、C1-3烷基C3-6环烷基和C1-3烷基C3-6杂环基组成的组;
R2是H;
R3选自于由H、F、Cl和CH3组成的组;
R4选自于由C0-3烷基C3-12环烷基和C1-12烷基组成的组;
其中R1、R2、R3和R4中的每一个都任选地被取代,
附带条件是该化合物不选自:
在另一方面,提供了一种治疗或预防有需要的受试者的呼吸系统疾病的方法,该方法包括向受试者施用治疗有效量的式(I)或(II)化合物或其盐、溶剂化物、N-氧化物、互变异构体、立体异构体、多晶型物和/或前药,从而治疗或预防受试者的呼吸系统疾病。
进一步提供了用于治疗或预防受试者的呼吸系统疾病的式(I)或(II)化合物或其盐、溶剂化物、N-氧化物、互变异构体、立体异构体、多晶型物和/或前药。
呼吸系统疾病可以选自哮喘、慢性阻塞性肺疾病、间质性肺病(例如特发性肺纤维化)和与组织重塑相关的其它病症、原发性或继发性肺肿瘤、枯草热、慢性和急性鼻窦炎、以及慢性和急性呼吸道病毒、真菌和细菌感染。
在另一方面,提供了一种改善有需要的受试者的呼吸功能的方法,该方法包括向受试者施用治疗有效量的式(I)或(II)化合物或其盐、溶剂化物、N-氧化物、互变异构体、立体异构体、多晶型物和/或前药,从而改善受试者的呼吸功能。
进一步提供了用于改善受试者的呼吸功能的式(I)或(II)化合物或其盐、溶剂化物、N-氧化物、互变异构体、立体异构体、多晶型物和/或前药。
呼吸功能的改善可以选自肺部收缩水平的降低、呼吸系统弹性刚度的降低和/或呼吸系统可以伸展的容易程度的增加。优选地,所述改善选自肺部收缩水平的降低和呼吸系统弹性刚度的降低。在另一方面,提供了一种组合物,其包含式(I)或(II)的化合物或其盐、溶剂化物、N-氧化物、互变异构体、立体异构体、多晶型物和/或前药,以及药学上可接受的赋形剂。
该组合物可以配制成用于口服给药或通过吸入或注射给药。
还描述了本发明的化合物或组合物在制备用于治疗或预防受试者的呼吸系统疾病的药物中的用途。
如本文所用,除非上下文另有要求,否则术语“包括”和该术语的变体,例如“包含”和“所包括的”,并不旨在排除进一步的添加剂、组分、整体或步骤。
在说明书中对任何现有技术的引用不是承认或暗示该现有技术在任何管辖范围内构成公知常识的一部分,或者可以合理地预期该现有技术被本领域技术人员理解、视为相关和/或与现有技术其他片段结合。
从以实施例的方式并参考附图给出的以下描述,本发明的进一步的方面以及在前述段落中描述的方面的进一步实施方案将变得清楚。
附图说明
图1定义了许多已知化合物。
图2TGF-β诱导的IL-11的抑制(从对数浓度小分子与IL-11水平的线性回归进行插值)的PIC50值(将IL-11水平抑制50%的浓度的负对数)。
具体实施方式
将理解的是,在本说明书中公开和定义的本发明扩展到在文本或附图中所提到的或从文本或附图中变得明显的两个或更多个单独特征的所有可替代组合。所有这些不同的组合构成了本发明的各种替代方面。
现在将详细参考本发明的某些实施方式。虽然本发明将结合实施方式进行描述,但应理解其意图不在于将本发明局限于这些实施方式。相反,本发明旨在覆盖所有替代、修改和等同形式,其可以包括在如由权利要求所限定的本发明的范围内。
本领域技术人员将意识到许多与本文描述的方法和材料相似或等同的方法和材料,其可用于实施本发明。本发明绝不限于所述的方法和材料。将理解的是,在本说明书中公开和定义的本发明扩展到在文本或附图中所提到的或从文本或附图中变得明显的两个或更多个单独特征的所有替代组合。所有这些不同的组合构成了本发明的各种替代方面。
本文引用的所有专利和出版物均通过引用而整体并入本文。
为了解释本说明书,以单数形式使用的术语也将包括复数形式,反之亦然。
本文描述的是式(II)化合物或其盐、溶剂化物、N-氧化物、互变异构体、立体异构体、多晶型物和/或前药:
其中:
R1和R2各自独立地选自于由H、C1-3烷基C6-12芳基、C1-3烷基C5-11杂芳基、C1-3烷基C3-6环烷基和C1-3烷基C3-6杂环基组成的组;
R3选自于由H、F、Cl和CH3组成的组;
R4选自于由C0-3烷基C3-12环烷基和C1-12烷基组成的组;
其中R1、R2、R3和R4中的每一个都任选地被取代。
在一些实施方案中,式(II)化合物由式(I)化合物提供
其中:
R1选自于由C2-3烷基C6-12芳基、C1烷基C10-12芳基、C1-3烷基C5-11杂芳基、C1-3烷基C3-6环烷基和C1-3烷基C3-6杂环基组成的组;
R2是H;
R3选自于由H、F、Cl和CH3组成的组;
R4选自于由C0-3烷基C3-12环烷基和C1-12烷基组成的组;
其中R1、R2、R3和R4中的每一个都任选地被取代,
附带条件是该化合物不选自:
在任意一个实施方案中,本发明提供式(I)或(II)的化合物,条件是该化合物不选自图1中的化合物列表。Keenan等人,Frontiers in Pharmacology,2018,第9卷,第738条;WO2016/149756A1;WO1996/021654A1;WO1999/032121A1;WO1997/035856A1;Kim,D-K.等人,Bioorganic&Medicinal Chemistry Letters,2008,18,4006-4010;WO1999/001136A1;US6369068B1;和WO2018/201192A1中也描述了各种化合物。在一些实施方案中,在这些文件中的一个或多个中所描述的任何特定化合物可以通过附带条件排除。
在任意一个实施方案中,本发明提供式(I)化合物,其中R2为H。
在任意一个实施方案中,R1为C1-3烷基C6-12芳基。R1可以是C2-3烷基C6-12芳基或C1-3烷基C10-12芳基。在一些实施方案中,R1为任选取代的C2-3烷基C6-12芳基或C1-3烷基C10-12芳基(例如未取代的C1-3烷基C10-12芳基)。在一些实施方案中,C2-3烷基C6-12芳基是任选取代的C2-3烷基C6芳基。一个或多个C6-12芳基可以由两个环体系构成。与C1-3烷基连接的环可以在任何位置(即邻位、间位或对位)具有第二个环。当R1是C1-3烷基C6-12芳基时,R2可以是H。
在任意一个实施方案中,R1为C1-3烷基C5-11杂芳基。R1可以是C1-2烷基C5-11杂芳基。C5-11杂芳基可以由两个环体系构成。与C1-3烷基连接的环可以在任何位置(即邻位、间位或对位)具有第二个环。杂芳基可以选自含氧杂芳基、含氮杂芳基或含硫杂芳基,或含两个或多个氧、氮和硫原子的组合的杂芳基。示例包括呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、三唑基、四唑基、噻唑基、恶唑基、异恶唑基、恶二唑基、氧代吡啶基、噻二唑基、异噻唑基、吡啶基、哒嗪基(pyridazyl)、吡嗪基和嘧啶基。杂原子可以在相对于C1-3烷基的邻位和/或对位。当R1是C1-3烷基C5-11杂芳基时,R2可以是H。
在任意一个实施方案中,R1为C1-3烷基C3-6环烷基。R1可以是C1-2烷基C3-6环烷基。C3-6环烷基可选自环丙基、环丁基、环戊基和环己基。当R1是C1-3烷基C3-6环烷基时,R2可以是H。当R1是C1-3烷基C3-6环烷基时,R1可以被取代。取代基可以选自C1-3烷基。
在任意一个实施方案中,R1为C1-3烷基C3-6杂环基。R1可以是C1-2烷基C3-6杂环基。R1可以选自含氧杂环基、含氮杂环基、或含硫杂环基,或含有两个或多个氧、氮和硫原子的组合的杂环基。示例包括氧杂环丁烷基(oxetanyl)、硫杂环丁烷基(thietanyl)、吡咯烷基、吡啶基、吡唑烷基、咪唑烷基、四氢呋喃基、1,3-二氧戊环基(1,3-dioxolanyl)、四氢吡喃基、四氢噻吩基(tetrahydrothipheneyl)和1,2-和1,3-氧硫杂环戊基(1,2-和1,3-oxathiolanyl)。当R1是C1-3烷基C3-6杂环基时,R2可以是H。
在任意一个实施方案中,R1可以选自下组G1-G7中的任意一个:
其中,
每个R5选自本文所述的任何任选的取代基。在一些实施方案中,R5选自于由C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6羟烷基、C3-7杂环基、C3-7环烷基、C2-6烷氧基、C1-6烷基硫烷基(alkylsulfanyl)、C1-6烷基亚氧硫基(alkylsulfenyl)、C1-6烷基磺酰基(alkylsulfonyl)、C1-6烷基磺酰基氨基、芳基磺酰基氨基、烷基羧基(alkylcarboxy)、烷基羧酰胺(alkylcarboxyamide)、氧代、羟基、巯基、氨基、酰基、羧基、氨基甲酰基、芳基、芳氧基、杂芳基、氨基磺酰基、芳酰基、芳酰基氨基、杂芳酰基、酰氧基、芳酰氧基(aroyloxy)、杂芳酰氧基(heteroaroyloxy)、烷氧羰基、硝基、氰基、氟代、碘代、溴代、脲基或C1-6全氟烷基组成的组,其中每一个都可以任选地被取代;
R6是任选取代的C1-2烷基;
L为(CR7R8)m;
L1是(CR7R8)p任选取代的C1-2烷基;
R7和R8独立地选自H和任选取代的C1-6烷基;
n选自0、1、2和3;
m选自1、2和3;以及
p选自1和2。
在组G1-G7的任意一个实施方案中,n可以为0、1或2。
在任意一个实施方案中,R5是氟代。
在任意一个实施方案中,n为0、1或2。
在任意一个实施方案中,R1可以选自G1至G5。
在任意一个实施方案中,R1可以是G6。在G6的一些实施方案,R6是任选取代的甲基。
在任意一个实施方案中,R1是选自G1-G7的基团,并且R4选自C3-12环烷基、C1-12烷基和卤代C1-12烷基。在一些实施方案中,R4可以未被取代。在一些实施方案中,R4任选地被一个或多个选自C1-6烷基和卤代的取代基取代。
在任意一个实施方案中,本发明提供式(I)化合物,其中R3为CH3。R3可以是F或Cl。优选地,R3是F。
在任意一个实施方案中,本发明提供式(I)化合物,其中R4为C0-3烷基C3-12环烷基。R4可以是C0-3烷基C3-12环烷基,其中C3-12环烷基选自环丙基、环丁基、环戊基、环己基和环庚基。在优选形式中,R4是C3-12环烷基。更优选地,R4选自环丙基、环丁基、环戊基、环己基和环庚基。R4可以是C1-2烷基C3-12环烷基。R4可以是C1烷基C3-12环烷基。在一些实施方案中,R4选自C0-3烷基C4-12环烷基、C3环烷基和C2-3烷基C3环烷基。C3-12环烷基可以选自环丙基、环丁基、环戊基、环己基和环庚基。当R4是C0-3烷基C3-12环烷基时,R4可以被取代。C3-12环烷基可以被取代。取代基可以选自一个或多个C1-6烷基、一个或多个卤代基团和一个或多个OH基团。在一些实施方案中,取代基选自一个或多个C1-6烷基和一个或多个卤代基团(例如-F)。
在任意一个实施方案中,本发明提供式(I)化合物,其中R4为C1-12烷基。R4可以是甲基、乙基、丙基或丁基。R4可以是支链C1-12烷基,例如支链C3、C4或C5烷基。R4可以被一个或多个选自卤代和OH的基团取代。例如,R4可以被一个、两个或更多个卤代基团取代。
在任意一个实施方案中,R4选自C5-6环烷基和卤代C2-5烷基。在一些实施方案中,R4选自环己基和三氟乙基(例如-CH2CF3)。
在任意一个实施方案中,R1、R2、R3和R4任选地被一个或多个选自OH、C1-6烷氧基、卤代(例如氟代)、氨基、巯基和C1-6烷基的基团取代。
如本文所用,术语“C1-12烷基”是指具有1至12个碳原子或介于两者之间的任何范围内的碳原子的直链或支链烃基,即其包含1、2、3、4、5、6、7、8、9、10、11或12个碳原子。烷基任选地被取代基取代,允许多个取代度。如本文所用的“C1-12烷基”的示例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基等。
优选“C1-3烷基”、“C1-4烷基”和“C1-6烷基”。这些基团是指分别含有1-3、1-4或1-6个碳原子或介于两者之间的任何范围内的碳原子的烷基(例如含有2-5个碳原子(即2、3、4或5个碳原子)的烷基也在C1-6的范围内)。在使用术语“C0-2烷基”等的情况下,可以是没有烷基,或含有1或2个碳原子的烷基。
术语“C2-6烯基”是指具有至少一个E或Z立体化学的双键(如果使用)和2至6个碳原子的任选取代的直链或支链烃基。示例包括乙烯基、1-丙烯基、1-和2-丁烯基和2-甲基-2-丙烯基。除非上下文另有要求,否则术语“C2-6烯基”还包括少含一个氢原子的烯基,使得该基团通过两个位置连接,即二价。优选“C2-4烯基”和“C2-3烯基”包括乙烯基、丙烯基和丁烯基,特别优选乙烯基。
术语“C2-6炔基”是指具有至少一个三键和2至6个碳原子的任选取代的直链或支链烃基。示例包括乙炔基、1-丙炔基、1-和2-丁炔基、2-甲基-2-丙炔基、2-戊炔基、3-戊炔基、4-戊炔基、2-己炔基、3-己炔基、4-己炔基和5-己炔基等。除非上下文另有说明,否则术语“C2-6炔基”还包括少含一个氢原子的炔基,使得该基团通过两个位置连接,即二价。优选C2-3炔基。
如本文所用,术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I),并且术语“卤代(halo)”是指卤素自由基氟代(-F)、氯代(-Cl)、溴代(-Br)和碘代(-I)。优选地,“卤代”是氟代。
如本文所用,术语“环烷基”是指非芳族环状烃环。术语“C3-7环烷基”是指具有三至七个碳原子或介于两者之间的任何整数范围的碳原子的非芳族环状烃环。例如,C3-7环烷基还包括含有4至6个(即4、5或6个)碳原子的环烷基。烷基如上所定义,并且可以被取代。可用于本发明的示例性“C3-7环烷基”包括但不限于环丙基、环丁基、环戊基、环己基和环庚基。
环烷基可以任选地稠合至一个或多个杂环环或环烷基环。环烷基环可以在环上的任何碳原子处被另一个环烷基或杂环部分取代以形成螺环烷基或螺杂烷基化合物。
环烷基上的两个非相邻原子可以被烷基或杂烷基桥连以形成桥连系统。优选地,桥连基团的长度为1-3个原子。
如本文所用,术语“杂环”或“杂环基”是指饱和的或具有一个或多个不饱和度的非芳族杂环环,其含有一个或多个选自S、S(O)、S(O)2、O或N的杂原子取代。术语“C3-7杂环基”是指具有三至七个碳原子(即3、4、5、6或7个碳原子)的非芳族环状烃环,其含有一个或多个如本文所指的杂原子取代。杂环部分可以被取代,允许有多个取代度。术语“C3-7杂环基”还包括含有C4-5、C5-7、C6-7、C4-7、C4-6和C5-6碳原子的杂环基。优选地,杂环环含有四到六个碳原子和一个或两个杂原子。更优选地,杂环环含有五个碳原子和一个杂原子,或四个碳原子和两个杂原子取代,或五个碳原子和一个杂原子。杂环基可以是3元至10元环体系,其表示环体系内包含的原子(碳原子和杂原子)的总数。在这种情况下,前缀3-、4-、5-、6-、7-、8-、9-和10-元表示环原子的数目或环原子的范围,无论是碳原子还是杂原子。例如,如本文所用的术语“3-10元杂环基”涉及具有3、4、5、6、7、8、9或10个环原子的杂环基。杂环基的示例包括5-6元单环杂环基和9-10元稠合双环杂环基。因此,本文所述的杂环环可以任选地稠合至一个或多个其他“杂环”环、环烷基环、芳环或杂芳环。“杂环”部分的示例包括但不限于四氢呋喃、吡喃、氧杂环丁烷、1,4-二恶烷、1,3-二恶烷、哌啶、哌嗪、N-甲基哌嗪基、2,4-哌嗪二酮、吡咯烷、咪唑烷、吡唑烷、吗啉、硫代吗啉、四氢噻喃、四氢噻吩等。
杂环基可以在环上的任何碳原子处被另一个杂环或环烷基部分取代以形成螺环烷基或螺杂烷基化合物。
杂环基上的两个非相邻原子可以进一步被烷基或杂烷基桥连以形成桥连系统。优选地,桥连基团的长度为1-3个原子。
作为取代的杂环基的示例,术语“C0-2烷基C3-7杂环基”包括不含烷基作为化合物与杂环之间的连接基的杂环基,或含有含1或2个碳原子的烷基作为化合物与杂环之间的连接基的杂环基(即杂环、-CH2-杂环或-CH2CH2-杂环)。这些杂环可以被进一步取代。
取代的环烷基和杂环基可以被如下所述的任何合适的取代基取代。
如本文所用,术语“芳基”是指任选取代的苯环,或是指与一个或多个任选取代的苯环稠合以形成例如蒽、菲或萘环体系的任选取代的苯环体系。“芳基”基团的示例包括但不限于苯基、2-萘基、1-萘基、联苯基及其取代的衍生物。优选的取代的芳基包括芳氨基、芳烷基、芳烷基卤代(arylalkylhalo)、芳卤代(arylhalo)和芳烷氧基(aralkoxy)。
如本文所用,术语“杂芳基”是指单环的五、六或七元芳环,或指包含至少一个单环的五、六或七元芳环的稠合双环或三环芳环体系。这些杂芳环含有一个或多个氮、硫和/或氧杂原子,并且可以任选地被多达三个成员取代。含N杂芳基可以是N-氧化物的形式,含S杂芳基可以是硫氧化物和硫二氧化物的形式。本文所用的“杂芳基”基团的示例包括呋喃基、噻吩基、吡咯基、咪唑基、吡唑基、三唑基、四唑基、噻唑基、恶唑基、异恶唑基、恶二唑基、氧代吡啶基、噻二唑基、异噻唑基、吡啶基、哒嗪基、吡嗪基、嘧啶基、喹啉基、异喹啉基、苯并呋喃基、苯并噻吩基、吲哚基、吲唑基、苯并咪唑基及其取代的形式。
术语“氢氧根的(hydroxy)”和“羟基(hydroxyl)”是指基团-OH。
术语“氧代(oxo)”是指基团=O。
术语“C1-6烷氧基”是指通过O键共价结合的含有1至6个碳原子的如上定义的烷基,例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基和戊氧基。优选“C1-4烷氧基”和“C1-3烷氧基”包括甲氧基、乙氧基、丙氧基和丁氧基,特别优选甲氧基。
术语“卤代C1-6烷基”和“C1-6烷基卤代”是指被一个或多个卤素取代的C1-6烷基。优选卤代C1-3烷基,例如-CH2CF3和-CF3。
术语“卤代C1-6烷氧基”和“C1-6烷氧基卤代”是指被一个或多个卤素取代的C1-6烷氧基。优选C1-3烷氧基卤代基,例如-OCF3。
术语“羧化物”或“羧基”是指-COO-或-COOH基团。
术语“酯”是指氢被例如C1-6烷基替换的羧基(“羧基C1-6烷基”或“烷基酯”)、氢被芳基或芳烷基替换的羧基(“芳基酯”或“芳烷基酯”)等。优选CO2C1-3烷基,例如甲酯(CO2Me)、乙酯(CO2Et)和丙酯(CO2Pr)并且包括其反向酯(reverse ester)(例如-OC(O)Me、-OC(O)Et和–OC(O)Pr)。
术语“氰基”和“腈”是指-CN基团。
术语“硝基”是指基团-NO2。
术语“氨基”是指基团-NH2。
术语“取代的氨基”或“仲氨基”是指氢被例如C1-6烷基替换的氨基(“C1-6烷基氨基”)、氢被芳基或芳烷基替换的氨基(“芳氨基”、“芳烷基氨基”)等。优选C1-3烷基氨基,例如甲氨基(NHMe)、乙氨基(NHEt)和丙氨基(NHPr)。
术语“二取代的氨基”或“叔氨基”是指两个氢被例如C1-6烷基(其可以相同或不同)替换的氨基(“二烷基氨基”)、两个氢被芳基和烷基替换的氨基(“芳基(烷基)氨基”)等。优选二(C1-3烷基)氨基,例如二甲氨基(NMe2)、二乙氨基(NEt2)、二丙氨基(NPr2)及其变体(例如N(Me)(Et)等)。
术语“醛”是指-C(=O)H基团。
术语“酰基”是指-C(O)CH3基团。
术语“酮”是指可以由-C(O)-表示的羰基。
术语“取代的酮”是指与至少一个进一步的基团共价连接的酮基团,所述进一步的基团例如为C1-6烷基(“C1-6烷基酰基”或“烷基酮”或“酮烷基”)、芳基(“芳基酮”)、芳烷基(“芳烷基酮”)等。优选C1-3烷基酰基。
术语“酰胺基”或“酰胺”是指基团-C(O)NH2。
术语“取代的酰胺基”或“取代的酰胺”是指氢被例如C1-6烷基替换的酰胺基(“C1-6烷基酰胺基”或“C1-6烷基酰胺”)、氢被芳基替换的酰胺基(“芳基酰胺基”)、氢被芳烷基替换的酰胺基(“芳烷基酰胺基”)等。优选C1-3烷基酰胺基,例如甲酰胺(-C(O)NHMe)、乙酰胺(-C(O)NHEt)和丙酰胺(-C(O)NHPr),并且包括其反向酰胺(例如-NHMeC(O)-、-NHEtC(O)-和–NHPrC(O)-)。
术语“二取代的酰胺基”或“二取代的酰胺”是指两个氢被例如C1-6烷基替换的酰胺基(“二(C1-6烷基)酰胺基”或“二(C1-6烷基)酰胺”)、两个氢被芳烷基和烷基替换的酰胺基(“烷基(芳烷基)酰胺基”)等。优选二(C1-3烷基)酰胺基,例如二甲酰胺(-C(O)NMe2)、二乙酰胺(-C(O)NEt2)和二丙酰胺((-C(O)NPr2)及其变体(例如-C(O)N(Me)Et等),并且包括其反向酰胺。
术语“硫醇”是指基团-SH。
术语“C1-6烷硫基(alkylthio)”是指氢被C1-6烷基替换的硫醇基。优选C1-3烷硫基,例如硫醇甲基(thiolmethyl)、硫醇乙基(thiolethyl)和硫醇丙基(thiolpropyl)。
术语“硫代”是指基团=S。
术语“亚磺酰基(sulfinyl)”是指基团-S(=O)H。
术语“取代的亚磺酰基”或“亚砜”是指氢被例如C1-6烷基替换的亚磺酰基(“C1-6烷基亚磺酰基”或“C1-6烷基亚砜”)、氢被芳基替换的亚磺酰基(“芳基亚磺酰基”)、氢被芳烷基替换的亚磺酰基(“芳烷基亚磺酰基”)等。优选C1-3烷基亚磺酰基,例如-SO甲基、-SO乙基和-SO丙基。
术语“磺酰基”是指基团-SO2H。
术语“取代的磺酰基”是指氢被例如C1-6烷基替换的磺酰基(“磺酰基C1-6烷基”)、氢被芳基替换的磺酰基(“芳基磺酰基”)、氢被芳烷基替换的磺酰基(“芳烷基磺酰基”)等。优选磺酰基C1-3烷基,例如-SO2Me、-SO2Et和-SO2Pr。
术语“磺酰氨基”或“磺酰胺”是指基团-SO2NH2。
术语“取代的磺酰氨基”或“取代的磺酰胺”是指氢被例如C1-6烷基替换的磺酰氨基(“磺酰氨基C1-6烷基”)、氢被芳基替换的磺酰氨基(“芳基磺酰胺”)、氢被芳烷基替换的磺酰氨基(“芳烷基磺酰胺”)等。优选磺酰氨基C1-3烷基,例如-SO2NHMe、-SO2NHEt和-SO2NHPr,并且包括其反向磺酰胺(例如-NHSO2Me、-NHSO2Et和-NHSO2Pr)。
术语“二取代的磺酰氨基”或“二取代的磺酰胺”是指两个氢被例如C1-6烷基(其可以相同或不同)替换的磺酰氨基(“磺酰氨基二(C1-6烷基)”)、两个氢被芳烷基和烷基替换的磺酰氨基(“磺酰氨基(芳烷基)烷基”)等。优选磺酰氨基二(C1-3烷基)基团,例如-SO2NMe2、-SO2NEt2和-SO2NPr2及其变体(例如-SO2N(Me)Et等),并且包括其反向磺酰胺(例如-N(Me)SO2Me等)。
术语“硫酸酯”是指基团OS(O)2OH,包括氢被例如C1-6烷基替换的基团(“烷基硫酸酯”)、氢被芳基替换的基团(“芳基硫酸酯”)、氢被芳烷基替换的基团(“芳烷基硫酸酯”)等。优选C1-3硫酸酯,例如OS(O)2OMe、OS(O)2OEt和OS(O)2OPr。
术语“磺酸酯”是指基团SO3H,包括氢被例如C1-6烷基替换的基团(“烷基磺酸酯”)、氢被芳基替换的基团(“芳基磺酸酯”)、氢被芳烷基替换的基团(“芳烷基磺酸酯”)等。优选C1-3磺酸酯,例如SO3Me、SO3Et和SO3Pr。
本文中所使用的“取代基”是指与感兴趣的分子内的原子共价结合的分子部分。例如,“环取代基”可以是与作为环成员的原子、优选地碳或氮原子共价结合的部分(例如卤素、烷基或本文所述的其他取代基)。本文中所使用的术语“取代的”是指指定原子上的任何一个或多个氢被选自指定取代基的取代基所取代,条件是不超过指定原子的正常化合价,并且取代产生稳定的化合物,即,可以被分离、表征和测试生物活性的化合物。
如在整个说明书中所使用的,术语“任选取代的”或“可以被取代”等表示该基团可以被或可以不被一个或多个非氢取代基进一步取代,或者可以与或可以不与一个或多个非氢取代基稠合(以形成多环体系)。对于特定官能团的合适的化学上可行的取代基对于本领域技术人员是明显的。在一些实施方案中,任选取代的部分可以被或可以不被1、2、3、4或多个基团,优选1、2或3个,更优选1或2个基团进一步取代。
取代基的示例包括但不限于:
C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6羟基烷基、C3-7杂环基、C3-7环烷基、C1-6烷氧基、C1-6烷基硫烷基(alkylsulfanyl)、C1-6烷基亚氧硫基(alkylsulfenyl)、C1-6烷基磺酰基、C1-6烷基磺酰基氨基、芳基磺酰基氨基、烷基羧基、烷基羧基酰胺、氧代、羟基、巯基、氨基、酰基、羧基、氨基甲酰基、芳基、芳氧基、杂芳基、氨基磺酰基、芳酰基、芳酰基氨基、杂芳酰基、酰氧基、芳酰氧基、杂芳酰氧基、烷氧基羰基、硝基、氰基、卤代、脲基、C1-6全氟烷基、C2-6烯基、C2-6炔基、C1-6烷氧基芳基、酯、取代的氨基、二取代的氨基、酰基、酮、取代的酮、酰胺、氨酰基、取代的酰胺、二取代的酰胺、硫醇、烷硫基(alkylthio)、硫代、硫酸酯、磺酸酯、亚磺酰基、取代的亚磺酰基、磺酰基、取代的磺酰基、磺酰胺、取代的磺酰胺、二取代的磺酰胺、芳基C1-6烷基、杂环基C1-6烷基和C3-7环烷基C1-6烷基,其中每个烷基、烯基、炔基、环烷基、芳基和杂环基以及含有它们的基团可以进一步任选地被取代。在一些实施方案中,部分可以被选自上述那些的任选取代基的任何子集任选地取代。
在含N的杂环(杂环基和杂芳基)情况下的任选取代基还可以包括但不限于C1-6烷基,即N-C1-3烷基,更优选甲基,特别是N-甲基。
在一个实施方案中,环状或杂环取代基可以与环状或杂环基团被取代的部分中的碳形成螺环烷基或螺杂烷基取代基。在另一个实施方案中,环状或杂环取代基可以是桥连的。
对于任选取代的“C1-6烷基”、“C2-6烯基”和“C2-6炔基”,任选的一个或多个取代基优选选自卤代、芳基、杂环基、C3-8环烷基、C1-6烷氧基、羟基、氧代、芳氧基、卤代C1-6烷基、卤代C1-6烷氧基和羧基。在一些实施方案中,任选取代的“C1-6烷基”、“C2-6烯基”和“C2-6炔基”可以被选自上述那些的任选取代基的任何子集任选地取代。
在适当的情况下,这些基团中的任何基团可以进一步被上述基团中的任何基团取代。例如,烷基氨基、或二烷基氨基、C1-6烷氧基等。
本发明化合物的示例在下表1中给出。
表1本发明化合物的示例。
式(I)化合物的盐优选地是药学上可接受的,但将理解的是,非药学上可接受的盐也落入本公开的范围内,因为这些非药学上可接受的盐可以用作制备药学上可接受的盐的中间体。
术语“药学上可接受的”可以用于描述任何药学上可接受的盐、溶剂化物、互变异构体、N-氧化物、立体异构体、多晶型物和/或前药、或任何在施用于受试者后能够(直接或间接地)提供式(I)化合物的其他化合物、或其活性代谢物或残基,并且通常对受试者无害。
合适的药学上可接受的盐包括但不限于药学上可接受的无机酸的盐或药学上可接受的有机酸的盐,其中,所述无机酸例如为盐酸、硫酸、磷酸、硝酸、碳酸、硼酸、氨基磺酸和氢溴酸,所述有机酸例如为乙酸、丙酸、丁酸、酒石酸、马来酸、羟基马来酸、富马酸、苹果酸、柠檬酸、乳酸、粘酸、葡糖酸、苯甲酸、琥珀酸、草酸、苯乙酸、甲磺酸、甲苯磺酸、苯磺酸、水杨酸、对氨基苯磺酸(sulphanilic acid)、天冬氨酸、谷氨酸、依地酸、硬脂酸、棕榈酸、油酸、月桂酸、泛酸、鞣酸、抗坏血酸、戊酸和1-羟基-2-萘甲酸(xinafoic acid)。
碱盐包括但不限于与药学上可接受的阳离子例如钠、钾、锂、钙、镁、锌、铵形成的那些盐、烷基铵(例如由三乙胺形成的盐)、烷氧基铵(例如与乙醇胺形成的那些盐)、以及由乙二胺、胆碱或氨基酸(比如精氨酸、赖氨酸或组氨酸)形成的盐。关于药学上可接受的盐的类型及其形成的一般信息是本领域技术人员已知的,并且如一般文本比如“Handbook ofPharmaceutical Salts”(药用盐手册),P.H.Stahl,C.G.Wermuth,第1版,2002年,Wiley-VCH中所述。
碱性含氮基团可以用下述制剂进行季化(quarternised):例如,低级烷基卤化物,如甲基、乙基、丙基和丁基氯化物、溴化物和碘化物;二烷基硫酸酯,如二甲基和二乙基硫酸酯;以及其他。
“前药”是可能不完全满足本文所提供的化合物的结构要求,但在向受试者或患者施用后在体内修饰以产生本文所提供的式(I)化合物的化合物。例如,前药可以是本文所提供的化合物的酰化衍生物。前药包括化合物,其中羟基、羧基、胺或巯氢基基团与任何基团结合,当施用于哺乳动物受试者时,裂解分别形成游离的羟基、羧基、氨基或巯氢基。前药的示例包括但不限于本文所提供的化合物内的醇和胺官能团的乙酸酯、甲酸酯、磷酸酯和苯甲酸酯衍生物。本文所提供的化合物的前药可以通过修饰化合物中存在的官能团来制备,通过这种方式使得修饰在体内裂解以产生母体化合物。
前药包括其中氨基酸残基或两个或多个(例如两个、三个或四个)氨基酸残基的多肽链共价连接到式(I)化合物的游离氨基和/或酰胺基的化合物。氨基酸残基包括通常用三字母符号表示的20种天然存在的氨基酸,并且还包括4-羟脯氨酸、羟赖氨酸、锁链素(demosine)、异锁链素(isodemosine)、3-甲基组氨酸、正缬氨酸(norvlin)、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。前药还包括其中碳酸酯、氨基甲酸酯、酰胺和烷基酯通过前药侧链的羰基碳共价结合到上述式(I)的取代基上的化合物。前药可以包括共价不可逆抑制剂和可逆抑制剂。
在化合物为固体的情况下,本领域技术人员将理解的是,本发明的化合物、制剂和盐可以以不同的结晶或多晶型形式存在,所有这些形式都旨在在本发明和特定形式的范围内。
本发明包括式(I)化合物的所有结晶形式,包括无水结晶形式、水合物、溶剂化物和混合溶剂化物。如果这些晶型中的任何一种表现出多晶型,则所有多晶型物都在本发明的范围内。
在适用的情况下,式(I)旨在涵盖化合物的溶剂化和非溶剂化形式。因此,式(I)包括具有所示结构的化合物,包括水合或溶剂化形式,以及非水合和非溶剂化形式。
式(I)化合物或其盐、互变异构体、N-氧化物、多晶型物或前药可以溶剂化物的形式提供。溶剂化物包含化学计量或非化学计量的溶剂,并且可以在结晶过程中与药学上可接受的溶剂例如水、醇(例如甲醇、乙醇或异丙醇)、DMSO、乙腈、二甲基甲酰胺(DMF)、乙酸等形成,其中通过非共价结合或通过占据晶格中的空穴从而溶剂化物形成晶格的一部分。当溶剂为水时形成水合物,当溶剂为醇时形成醇化物。本发明化合物的溶剂化物可以在本文所述的方法中方便地制备或形成。通常,出于本发明的目的,溶剂化形式被认为等同于非溶剂化形式。
形成结晶固体的式(I)化合物或其盐、互变异构体、N-氧化物、溶剂化物和/或前药可能会表现出多晶型。所述化合物、盐、互变异构体、N-氧化物、溶剂化物和/或前药的所有多晶型形式都在本发明的范围内。
式(I)化合物可能表现出互变异构。互变异构体是分子的两种可互换形式,通常存在于平衡中。式(I)化合物的任何互变异构体均应理解为在本发明的范围内。
式(I)化合物可以包含一个或多个立体中心。式(I)化合物的所有立体异构体均在本发明的范围内。立体异构体包括对映异构体、非对映异构体、几何异构体(E和Z烯属(olephinic)形式、以及顺式和反式取代模式)和阻转异构体。在一些实施方案中,该化合物是式(I)化合物在任何立体中心的立体异构富集形式。该化合物在一种立体异构体中可以比另一种立体异构体中富集至少约60%、70%、80%、90%、95%、98%或99%。
式(I)化合物或其盐、互变异构体、溶剂化物、N-氧化物和/或立体异构体可以以存在于化合物中的原子的一种或多种同位素来同位素富集。例如,该化合物可以富集一种或多种以下较小同位素:2H、3H、13C、14C、15N和/或17O。当同位素的丰度大于其天然丰度时,可以认为同位素是富集的。
在一些实施方案中,式(I)化合物或其盐、溶剂化物、N-氧化物、互变异构体、立体异构体、多晶型物和/或前药的pIC50至少为7。抑制活性可以使用激酶测定来确定。此类测定是本领域技术人员熟知的,并且合适的测定的示例在实施例中描述。
在另一方面,提供了一种组合物,其包含式(I)化合物或其盐、溶剂化物、N-氧化物、互变异构体、立体异构体、多晶型物和/或前药,以及药学上可接受的赋形剂。
合适的剂量水平通常为每天每千克患者体重约0.01mg至500mg,可以单剂量或多剂量给药。优选地,剂量水平为每天约0.1mg/kg至约250mg/kg;更优选每天约0.5mg/kg至约100mg/kg。合适的剂量水平可以是每天约0.01mg/kg至250mg/kg、每天约0.05mg/kg至100mg/kg或每天约0.1mg/kg至50mg/kg。在该范围内,剂量可以是每天0.05mg/kg至0.5mg/kg、0.5mg/kg至5mg/kg、或5mg/kg至50mg/kg。对于口服给药,组合物优选以包含1.0毫克至1000毫克活性成分,特别是1.0毫克、5.0毫克、10.0毫克、15.0毫克、20.0毫克、25.0毫克、50.0毫克、75.0毫克、100.0毫克、150.0毫克、200.0毫克、250.0毫克、300.0毫克、400.0毫克、500.0毫克、600.0毫克、750.0毫克、800.0毫克、900.0毫克和1000.0毫克活性成分的片剂形式提供以用于对待治疗的患者进行剂量的对症调整。化合物可以按每天1次至4次、优选地每天一次或两次的方案给药。然而,应当理解的是,对于任何特定患者的具体剂量水平和剂量频率可以变化,并且将取决于多种因素,包括所用具体化合物的活性、该化合物的代谢稳定性和作用时间长度、年龄、体重、一般健康状况、性别、饮食、给药模式和时间、排泄速率、药物组合、特定病症的严重性和接受治疗的宿主。本发明的化合物在组合物中的量还取决于组合物中的特定化合物。
在吸入产品的情况下,典型的吸入剂量比其他形式的剂量小,对于单次抽吸而言从1微克开始上升到1000微克。在优选形式中,剂量为每次抽吸25微克至250微克。在另一优选形式中,剂量为每次抽吸500微克至1000微克。在另一形式中,剂量选自由每次抽吸1微克、2.5微克、10.0微克、25.0微克、50.0微克、75.0微克、100.0微克、150.0微克、200.0微克、250.0微克、300.0微克、400.0微克、500.0微克、600.0微克、750.0微克、800.0微克、900.0微克和1000.0微克或者在这些值中的两个值之间并包括这两个值的任何范围。药物可以是每天抽吸一次或者增加到一天四次且每次抽吸两次。
药物组合物可以进一步包含通常用于治疗所公开的疾病或病症的其他治疗活性化合物。本领域普通技术人员可以根据常规的药物学原理选择用于联合治疗的合适的制剂。治疗剂的组合可以协同作用,以影响本文公开的各种疾病或病症的治疗或预防。使用这种方法,人们能够用较低剂量的各种制剂来实现治疗功效,从而降低潜在的不良副作用。
本发明的化合物和组合物可以配制成用于任何合适的给药途径,所述任何合适的给药途径包括例如局部(例如,经皮或眼部)给药、肺给药、口服给药、口腔给药、鼻部给药、阴道给药、直肠给药或肠胃外给药。本文所用的术语肠胃外的包括皮下注射、皮内注射、血管内注射(如静脉注射)、肌肉注射、脊髓注射、颅内注射、鞘内注射、眼内注射、眼周注射、眶内注射、滑膜内和腹膜内注射,以及任何类似的注射或输注技术。在某些实施方案中,优选适于口服使用或肠胃外使用的形式的组合物。合适的口服形式包括,例如,片剂、糖锭、锭剂、水性或油性悬浮液、可分散性粉末或颗粒、乳剂、硬胶囊或软胶囊、或糖浆或酏剂。在其他实施方案中,可以将本文提供的组合物配制成冷冻干产物。
在优选的形式中,该组合物适合给药至呼吸道。在另一种形式中,该组合物适合于口服给药。
各种剂量单元各自优选地作为分开剂量的片剂、胶囊、锭剂、糖衣丸、胶质或其他类型的固体制剂而提供。胶囊可以封装粉末、液体或凝胶。固体制剂可以被吞咽,或者可以是可吸入类型或可咀嚼类型(易碎的或胶状的)。本发明考虑了除泡罩包装外的剂量单元保持装置,例如,诸如瓶、管、罐、小包的包装。剂量单元可以进一步包括在药物制剂实践中公知的常规赋形剂,例如粘合剂、胶凝剂、填充剂、压片润滑剂、崩解剂、表面活性剂和着色剂;以及用于可吸入或可咀嚼的制剂。
旨在口服使用的组合物可以进一步包含一种或多种组分,例如甜味剂、调味剂、着色剂和/或防腐剂,以提供诱人且可口的制剂。片剂包含与适于片剂制造的生理学上可接受的赋形剂混合的活性成分。这类赋形剂包括例如诸如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠之类的惰性稀释剂、诸如玉米淀粉或藻酸之类的成粒剂和崩解剂、诸如淀粉、明胶或阿拉伯胶之类的粘合剂、以及诸如硬脂酸镁、硬脂酸或滑石之类的润滑剂。片剂可以是未包衣的,或者其可以通过已知技术进行包衣,以延迟在胃肠道中的崩解和吸收,从而提供更长时间的持续作用。例如,可以使用延时材料,例如单硬脂酸甘油酯或二硬脂酸甘油酯。
口服使用的制剂也可以以硬明胶胶囊剂的形式存在,其中活性成分与惰性固体稀释剂(如碳酸钙、磷酸钙或高岭土)混合,或以软明胶胶囊剂的形式存在,其中活性成分与水或油介质(例如花生油、液体石蜡或橄榄油)混合。
水性悬浮液包含与适于制备水性悬浮液的赋形剂混合的一种或多种活性成分。这类赋形剂包括悬浮剂、以及分散剂或润湿剂,其中,悬浮剂例如为羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮、黄蓍胶和阿拉伯胶,分散剂或润湿剂例如为天然存在的磷脂(例如卵磷脂)、环氧烷烃与脂肪酸的缩合产物酸(例如聚氧乙烯硬脂酸酯)、环氧乙烷与长链脂族醇的缩合产物(例如十七烷乙烯氧基鲸蜡醇(heptadecaethyleneoxycetanol))、环氧乙烷与衍生自脂肪酸和己糖醇的偏酯(partialesters)的缩合产物(例如聚氧乙烯山梨醇单油酸酯)、或环氧乙烷与衍生自脂肪酸和己糖醇酐的偏酯的缩合产物(例如聚乙烯山梨醇酐单油酸酯)。水性悬浮液还可以包含一种或多种防腐剂(例如对羟基苯甲酸乙酯或对羟基苯甲酸正丙酯)、一种或多种着色剂、一种或多种调味剂以及一种或多种甜味剂(例如蔗糖或糖精)。
油性悬浮液可以通过将活性成分悬浮在植物油(例如花生油、橄榄油、芝麻油或椰子油)或矿物油(例如液体石蜡)中来配制。油性悬浮液可以含增稠剂,例如蜂蜡、硬石蜡或鲸蜡醇。可以添加诸如上述的甜味剂和/或调味剂以提供可口的口服制剂。这种悬浮液可以通过添加诸如抗坏血酸的抗氧化剂来保存。
适用于通过添加水来制备水性悬浮液的可分散粉末和颗粒提供了与分散剂或润湿剂、悬浮剂以及一种或多种防腐剂混合的活性成分。合适的分散剂或润湿剂和悬浮剂的示例是上面已经提到的那些分散剂或润湿剂和悬浮剂。也可以存在额外的赋形剂,如甜味剂、调味剂和着色剂。
药物组合物也可以是水包油乳剂的形式。油相可以是植物油(如橄榄油或花生油)、矿物油(如液体石蜡)、或其混合物。合适的乳化剂包含天然存在的胶质(如阿拉伯胶或黄蓍胶)、天然存在的磷脂(如大豆卵磷脂)、和衍生自脂肪酸和己糖醇、酸酐的酯或偏酯(如山梨糖醇酐单油酸酯)、以及衍生自脂肪酸和己糖醇的偏酯与环氧乙烷的缩合产物(如聚氧乙烯山梨糖醇酐单油酸酯)。乳剂还可以包含一种或多种甜味剂和/或调味剂。
糖浆剂和酏剂可以与甜味剂如甘油、丙二醇、山梨糖醇或蔗糖一起配制。此类制剂还可以包含一种或多种缓和剂、防腐剂、调味剂和/或着色剂。
本发明的组合物可以配置成用于区域或局部给药,如局部给药至皮肤。用于局部给药的制剂通常包含与一种或多种活性剂组合的局部载体,其具有或不具有额外的任选组分。
合适的局部载体和额外组分在本领域中是公知知的,并且清楚的是,载体的选择将取决于特定的物理形式和递送方式。局部载体包括有机溶剂,所述有机溶剂例如为醇(例如乙醇、异丙醇或甘油)、诸如丁二醇、异戊二醇或丙二醇之类的二醇、诸如羊毛脂的脂族醇,并且包括水和有机溶剂的混合物、以及有机溶剂(如醇和甘油)的混合物、诸如脂肪酸的脂质基材料、含有油(如矿物油)的酰基甘油、以及天然或合成来源的脂肪、磷酸甘油酯、鞘脂和蜡、诸如胶原和明胶的蛋白质基材料、硅氧烷基材料(非挥发性和挥发性)、以及诸如微海绵和聚合物基质的烃基材料。
组合物可以进一步包括一种或多种适于改善所应用的制剂的稳定性或有效性的组分,例如稳定剂、悬浮剂、乳化剂、粘度调节剂、胶凝剂、防腐剂、抗氧化剂、透皮促进剂、保湿剂和持续释放材料。在Martindale–The Extra Pharmacopoeia(英国医药出版社(Pharmaceutical Press),伦敦,1993)和Martin(编辑),Remington's PharmaceuticalSciences中描述了这种组分的例子。制剂可以包含微胶囊,例如羟甲基纤维素或明胶微胶囊、脂质体、白蛋白微球、微乳剂、纳米颗粒或纳米胶囊。
可以以多种物理形式制备局部制剂,所述物理形式包括例如固体、糊剂、乳膏、泡沫、洗剂、凝胶、粉末、水性液体、乳剂、喷雾剂和皮肤贴剂。此类形式的物理外观和粘度可以由制剂中存在的一种或多种乳化剂和一种或多种粘度调节剂的存在和量来控制。固体通常是坚硬的和不可倾倒的,并且通常被配制成条状或棒状,或为颗粒形式。固体可以是不透明的或透明的,并且可以任选地包含溶剂、乳化剂、保湿剂、润肤剂、香料、染料/着色剂、防腐剂和其他增加或增强最终产品功效的活性成分。乳膏和洗剂通常彼此相似,主要在于其粘度不同。乳膏和洗剂均可以是不透明的、半透明的或透明的,并且通常包含乳化剂、溶剂和粘度调节剂、以及保湿剂、润肤剂、香料、染料/着色剂、防腐剂和其他增加或增强最终产品功效的活性成分。可以制备具有一系列粘度的凝胶,从浓稠或高粘度至稀或低粘度。这些制剂,如洗剂和乳膏的制剂一样,也可以包含溶剂、乳化剂、保湿剂、润肤剂、香料、染料/着色剂、防腐剂和其他增加或增强最终产品功效的活性成分。液体比乳膏、洗剂或凝胶稀,并且通常不包含乳化剂。液体局部用产品通常包含溶剂、乳化剂、保湿剂、润肤剂、香料、染料/着色剂、防腐剂和其他增加或增强最终产品功效的活性成分。
用于局部制剂的乳化剂包括但不限于离子型乳化剂、鲸蜡硬脂醇、如聚氧乙烯油基醚的非离子型乳化剂、PEG-40硬脂酸酯、鲸蜡硬脂醇聚醚-12、鲸蜡硬脂醇聚醚-20、鲸蜡硬脂醇聚醚-30、鲸蜡硬脂醇聚醚醇(ceteareth alcohol)、PEG-100硬脂酸酯和甘油硬脂酸酯。合适的粘度调节剂包括但不限于保护胶体或非离子胶,例如羟乙基纤维素、黄原胶、硅酸镁铝、二氧化硅、微晶蜡、蜂蜡、石蜡和鲸蜡醇十六酸酯。可以通过添加胶凝剂例如壳聚糖、甲基纤维素、乙基纤维素、聚乙烯醇、聚季铵盐、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、卡波姆或氨化甘草酸来形成凝胶组合物。合适的表面活性剂包括但不限于非离子型、两性、离子型和阴离子型表面活性剂。例如,在局部制剂中可以使用聚二甲基硅氧烷共聚醇(dimethicone copolyol)、聚山梨醇酯20、聚山梨醇酯40、聚山梨醇酯60、聚山梨醇酯80、月桂酰胺DEA、椰油酰胺DEA和椰油酰胺MEA、油基甜菜碱、椰油酰胺丙基磷脂酰PG-二甲基氯化铵(cocamidopropyl phosphatidyl PG-dimonium chloride)和月桂基聚氧乙烯醚硫酸铵(ammonium laureth sulfate)中的一种或多种可以。
防腐剂包括但不限于抗菌剂、以及物理稳定剂和抗氧化剂,所述抗菌剂例如为对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、山梨酸、苯甲酸和甲醛,所述物理稳定剂和抗氧化剂为例如维生素E、抗坏血酸钠/抗坏血酸和没食子酸丙酯。合适的保湿剂包括但不限于乳酸和其他羟基酸及其盐、甘油、丙二醇和丁二醇。合适的润滑药包括羊毛脂醇、羊毛脂、羊毛脂衍生物、胆固醇、凡士林油、异硬脂醇新戊酸酯和矿物油。合适的香料和颜料包括但不限于FD&C红色40号和FD&C黄色5号。可以包含在局部制剂中的其他合适的额外成分包括但不限于研磨剂、吸收剂、抗结块剂、消泡剂、抗静电剂、收敛剂(例如金缕梅)、醇和草药提取物(例如洋甘菊提取物)、粘合剂/赋形剂、缓冲剂、螯合剂、成膜剂、调理剂、推进剂、乳浊剂、pH调节剂和保护剂。
局部组合物的典型递送方式包括使用手指施用、使用物理涂抹器(例如布、纸巾、棉签、棍棒或刷子)施用、喷雾(包括雾气、气溶胶或泡沫喷雾)、滴管施用、喷洒、浸泡和冲洗。也可以使用控释载体,并且组合物可以配制成用于透皮给药(例如,作为透皮贴剂)。
药物组合物可以被配制成持续释放制剂,例如在给药后产生调节剂的缓慢释放的胶囊。这种制剂通常可以使用公知的技术来制备,并且可以通过例如口服、直肠或皮下植入或通过在期望的靶点处植入来进行给药。在此类制剂中使用的载体是生物相容的,并且也可以是生物可降解的。优选地,所述制剂提供了相对恒定水平的调节剂释放。持续释放制剂中所含调节剂的量取决于例如植入部位、释放的速率和预期持续时间、以及待治疗或待预防的疾病的性质。
药物组合物可以配制成吸入制剂,包括喷雾、雾气或气溶胶。例如以用于呼吸道给药。这对于呼吸系统疾病的治疗、涉及如本文所述的纤维化的气道或肺的病症的治疗可能是特别优选的。吸入制剂可以用于上呼吸道(包括鼻腔、咽和喉)和下呼吸道(包括气管、支气管和肺)。对于吸入制剂,可以通过本领域技术人员已知的任何吸入方法来递送本文所提供的组合物或组合。这种吸入方法和装置包括但不限于具有诸如HFA的推进剂或者生理和环境可接受的推进剂的计量剂量吸入器。其他合适的装置是呼吸操作吸入器、多剂量干粉吸入器和气溶胶雾化器。用于本主题方法的气溶胶制剂通常包括推进剂、表面活性剂和助溶剂,并且可以填充到由合适的计量阀封闭的常规气雾剂容器中。根据应用于上呼吸道(包括鼻腔、咽和喉)或下呼吸道(包括气管、支气管和肺),可以使用不同的装置和赋形剂,并且可以由本领域技术人员确定。此外,本领域技术人员还已知用于制备本文中所描述的、在诸如干粉吸入器的吸入器中使用的化合物的微粉化和纳米颗粒形成的方法。
吸入组合物可以包含液体或粉末状组合物,所述液体或粉末状组合物包含适合于雾化和支气管内使用的活性成分,或者通过气雾剂单元分配计量剂量的施用的气雾剂组合物。合适的液体组合物包含在水性、药学上可接受的吸入溶剂(如等渗盐水或抑菌水)中的活性成分。溶液借助于泵或挤压致动的雾化喷雾分配器或通过任何其他常规方式施用,以引起或使得必需剂量的液体组合物被吸入患者的肺中。用于给药的合适制剂(其中,载体是液体)例如鼻喷雾剂或滴鼻剂包括活性成分的水溶液或油性溶液。在Ibraim等人,MedicalDevices:Evidence and Research 2015:8 131–139中描述了吸入药物递送装置的示例,并被预期用于本发明。
在另一方面,提供了一种治疗或预防有需要的受试者的呼吸系统疾病的方法,该方法包括向受试者施用治疗有效量的式(I)化合物或其盐、溶剂化物、N-氧化物、互变异构体、立体异构体、多晶型物和/或前药,从而治疗或预防受试者的呼吸系统疾病。
进一步提供了式(I)化合物或其盐、溶剂化物、N-氧化物、互变异构体、立体异构体、多晶型物和/或前药,以用于治疗或预防有需要的受试者的呼吸系统疾病。
还描述了式(I)化合物或其盐、溶剂化物、N-氧化物、互变异构体、立体异构体、多晶型物和/或前药在制备用于治疗或预防有需要的受试者的呼吸系统疾病的药物中的用途。
如本文所用,“预防”或“防治”旨在指至少降低获得疾病或病况的风险(或易感性)的可能性(即,在可能暴露于或易患该疾病但尚未经历或未表现出该疾病症状的患者中,使该疾病的至少一种临床症状不发展)。本文提供了用于鉴定此类患者的生物和生理参数,并且这些参数也为医生所熟知。
术语“治疗(treatment)”或“治疗(treating)”受试者包括向受试者应用或施用本发明的化合物(或向来自受试者的细胞或组织应用或施用本发明的化合物),其目的在于延迟、减缓、稳定、治愈、愈合、减轻、缓解、改变、补救、减轻、恶化、改善、改进或影响疾病或病症、疾病或病症的症状、或疾病或病症的风险(或易感性)。术语“治疗”是指在损伤、病理或病症的治疗或改善中成功的任何指示,包括任何客观或主观参数,例如减轻;缓解;降低恶化率;减轻疾病的严重性;稳定、减轻症状或使损伤、病理或病症对受试者更耐受;减缓退化或衰退的速率;使退化的终点较少衰弱;或改善受试者的身体或精神健康。
本文中所使用的术语“拮抗”是指“降低”或“减少”。足够的时间段可以是一周、或1周至1个月、或1个月至2个月、或2个月或更长。对于慢性病症,本发明的化合物可以在生存期有利地施用。
术语“呼吸”是指通过包括鼻、咽喉、喉、气管、支气管和肺在内的身体系统将氧气摄入身体并将二氧化碳排出的过程。
术语“呼吸系统疾病”或“呼吸系统病症”是指可能涉及影响呼吸系统的组成部分的炎症和/或组织重塑的若干种病痛中的任一种,所述呼吸系统的组成部分包括上呼吸道(包括鼻腔、咽和喉)和下呼吸道(包括气管、支气管和肺)。这些病痛包括肺纤维化(间质性肺病)、鼻窦炎、流感、结节病、支气管癌(包括但不限于的非小细胞肺癌和小细胞肺癌,以及来自其他器官的肿瘤的肺转移)、矽肺、尘肺病、急性肺损伤、通气诱导的肺损伤、先天性肺气肿、支气管肺发育不良、支气管扩张、肺不张、鼻息肉、石棉肺、间皮瘤、肺嗜酸粒细胞增多、弥漫性肺出血综合征、闭塞性细支气管炎、肺泡蛋白沉积症、影响肺的胶原和血管疾病、以及咳嗽。优选地,呼吸系统疾病是阻塞性气道疾病,此类病痛包括:哮喘病症,其包括枯草热、过敏原诱导的哮喘、运动诱导的哮喘、污染诱导的哮喘、低温诱导的哮喘、应激诱导的哮喘、病毒诱导的哮喘、肥胖相关的哮喘、职业性哮喘、暴风雨诱导的哮喘、哮喘COPD重叠综合征(ACOS);慢性阻塞性肺病,其包括伴有正常气流的慢性支气管炎、伴有气道阻塞的慢性支气管炎(慢性阻塞性支气管炎)、肺气肿、哮喘性支气管炎;以及大疱性疾病;以及其他涉及炎症的肺疾病,其包括囊性纤维化、好鸽者病(pigeon fancier's disease)、农民肺、急性呼吸窘迫综合症、真菌性肺炎、病毒性肺炎、细菌性肺炎、混合型或未知病因、吸气或吸入损伤、肺中脂肪栓塞、肺的酸中毒性炎症、急性肺水肿、急性高山病、心脏手术后、急性肺高血压、新生儿的持续性肺高血压、围产期吸入综合征、透明膜病、急性肺血栓栓塞、肝素-鱼精蛋白反应、脓毒症、哮喘持续状态和缺氧。上呼吸道和下呼吸道中的炎症可以与病毒感染或过敏原有关或由病毒感染或过敏原引起。预期的是,单独或与糖皮质激素共同给药时化合物的抗炎活性将使它们特别适合于治疗这些疾病或病症。
呼吸系统疾病或病症可以与过敏原(比如尘螨)相关或由过敏原引起。呼吸系统疾病或病症可以是过敏原诱导的炎症的结果。本发明特别适用于气道或肺的过敏性疾病和该疾病的恶化,比如由病毒感染(例如RSV感染)引起的恶化。
呼吸系统疾病的症状可以包括咳嗽、产生过量痰液、呼吸困难或胸闷并伴有听得见的喘息。锻炼能力可能相当有限。在哮喘中,FEV1.0(一秒内用力呼气体积)占基于体重、身高和年龄的列线图预测的百分比,可能会随着用力呼气中的峰值呼气流速降低。在COPD中,FEV1.0是用力肺活量(FVC)的比率通常降低至小于0.7。在IPF中,FVC逐渐下降。这些病症中的每一种病症的影响还可以通过缺席工作/学业的天数、睡眠障碍、对支气管扩张药的需求、对糖皮质激素(包括口服糖皮质激素)的需求来测量。这些病症的影响的进一步测量包括经验证的与健康相关的生活质量测量。包括但不限于X射线、高分辨率计算机断层摄影、磁共振成像、正电子发射断层摄影、超声、光学相干断层摄影和荧光透视的医学成像程序也可以用于评估疾病和治疗反应。
呼吸系统疾病的存在、改善、治疗或预防可以通过受试者或其活组织检查的任何临床或生化相关方法进行。例如,测量的参数可以是肺功能的存在或程度、阻塞的体征和症状;运动耐受性;夜间觉醒;缺席学业或工作的天数;支气管扩张药的使用;ICS剂量;口服GC的使用;对其他药物的需求;对医学治疗的需求;住院。
如本文中所使用的,术语“哮喘”是指特征在于由以下三个主要因素中的任一个因素或组合引起的阵发性呼吸困难的呼吸病症:1)支气管痉挛(即,由于气道肌肉收缩引起的可变和可逆的气道阻塞),2)气道内层的炎症,和3)导致气道中粘液过多的支气管高反应性,其可以通过暴露于过敏原或过敏原组合(即,尘螨和霉菌)、病毒或细菌感染(即,普通感冒病毒)、环境污染物(即,化学烟气或烟雾)、体力消耗(即,在锻炼期间)、压力或吸入冷空气触发。如本文中所使用的,术语“哮喘病况”是指个体在暴露于任一种或多种对于该个体而言的哮喘引发物时经受哮喘发作的特征。个体的特征可以是经受例如过敏原诱导的哮喘、运动诱导的哮喘、污染诱导的哮喘、病毒诱导的哮喘或冷诱导的哮喘。
哮喘治疗的功效可以通过本领域公知的方法来测量,例如肺功能的增加(肺活量测定)、哮喘恶化的减少、晨峰呼气流速的增加、救援药物使用的减少、白天和夜间哮喘症状的减少、无哮喘天数的增加、达到哮喘恶化时间的增加和一秒钟用力呼气体积的增加(FEV1.0)。
本文可互换使用的术语“慢性阻塞性肺病”和“COPD”是指特征在于最大呼气流量减小和肺的强制排空缓慢的慢性病症或病症的组合,其在数月内没有显著变化并且使用传统的支气管扩张剂不可逆转或仅可最低限度逆转。最常见地,COPD是慢性支气管炎的组合,即,存在咳嗽和痰超过三个月持续约连续两年,以及存在肺气肿,即肺泡损伤。然而,COPD可以涉及伴随正常气流的慢性支气管炎、伴随气道阻塞的慢性支气管炎(慢性阻塞性支气管炎)、肺气肿、哮喘性支气管炎和大疱性疾病、以及其组合。慢性阻塞性肺病是一种通常但不排他地由暴露于烟草烟雾诱导的慢性肺损伤而引起的病症。其他有害的气载污染物比如室内烹饪废气和汽车废气在长期内可能会导致COPD或增加COPD的风险,老化也是如此。
短语“涉及纤维化的气道或肺的病症”或“具有纤维化组分的气道或肺的病症”包括其中在气道或肺中形成或发展过量纤维结缔组织(纤维化)从而导致瘢痕(纤维化)组织发展的任何疾病或病症。这包括间质性肺病,例如肺纤维化(pulmonary fibrosis)、肺部纤维化(lung fibrosis)或特发性肺纤维化(IPF)。更准确地说,肺纤维化是引起肺泡和肺间质组织的肿胀和瘢痕形成的慢性疾病。疤痕组织取代健康组织并引起炎症。这种对肺组织的损伤导致肺的硬化,这随后使得呼吸越来越困难。肺部纤维化可能是由辐射损伤或暴露于治疗剂如博来霉素引起的。
“特发性肺纤维化(IPF)”是特发性间质性肺炎(IIP)的具体表现,其是一类间质性肺病。间质性肺病,也称为弥漫性实质肺病(DPLD),是指影响间质的一类肺病。在显微镜下,来自IPF患者的肺组织显示出了被称为普通型间质性肺炎(UIP)的组织学特征的一组特性。因此UIP是IPF的病理表现。
涉及纤维化、特别是肺纤维化/肺部纤维化或特发性肺纤维化的气道或肺病症的存在、改善、治疗或预防可以通过受试者或其活组织检查的任何临床或生化相关方法进行。例如,FVC的下降率或肺的高分辨率计算机断层摄影图像的出现可用于诊断IPF。此外,测量的参数可以是纤维化的存在或程度,胶原蛋白、纤连蛋白或另一细胞外基质蛋白的含量,细胞或细胞中任何细胞外基质组分的增殖速率,或细胞转分化成肌成纤维细胞。
在一个实施方案中,呼吸系统疾病选自哮喘、慢性阻塞性肺病、间质性肺病(例如特发性肺纤维化)和与组织重塑相关的其他病症、原发性或继发性肺肿瘤、枯草热、慢性和急性鼻窦炎、和慢性和急性呼吸道病毒、真菌和细菌感染。
在一个实施方式中,呼吸功能的改善可以选自肺收缩水平的降低、呼吸系统弹性刚度的降低、和/或呼吸系统可以被伸展的容易度的增加。优选地,所述改善选自肺收缩水平的降低和呼吸系统弹性刚度的降低。在另一方面,提供了一种组合物,其包含根据式(I)的化合物或其盐、溶剂化物、N-氧化物、互变异构体、立体异构体、多晶型物和/或前药,以及药学上可接受的赋形剂。
制剂的治疗有效量取决于特定呼吸系统疾病指征(例如严重慢性哮喘)的严重性、患者的临床病史和反应、以及主治医师的判断。制剂可以一次或经过一系列治疗施用于患者。可以将初始候选剂量施用于患者,并且通过使用本领域普通技术人员公知的常规技术对该患者的进展进行监测来建立适当的剂量和治疗方案。优选地,活性化合物的治疗有效浓度将在0.1nM至100μM的范围内。更优选地,范围是0.1μM至10μM。然而,应当理解的是,通过吸入进行递送可能导致气道内的细胞短时间暴露于超过上述浓度的浓度一段时间,同时药物在气道表面流体中被稀释并且还被从气道和肺表面吸收。
在一个方面,本发明的治疗方法进一步包括施用用于目标疾病指征的伴随药物。例如,可以与本发明的方法一起使用的伴随哮喘药物(用于慢性和急性两者)包括但不限于:吸入和口服类固醇(例如,倍氯米松、布地奈德、氟尼缩松、氟替卡松、曲安西龙、莫米松);全身性皮质类固醇(例如,甲基强的松龙、泼尼松龙、泼尼松、地塞米松和地夫可特);吸入或口服β2-肾上腺素受体激动剂(例如,沙美特罗、福莫特罗、比托特罗、吡布特罗、维兰特罗、特布他林、班布特罗和沙丁胺醇);色甘酸和奈多罗米;抗过敏眼科药物(例如,地塞米松);调节转化生长因子-β的产生和作用的制剂,包括吡非尼酮和尼达尼布;甲基黄嘌呤和其他磷酸二酯酶抑制剂(例如,茶碱和美吡拉敏-乙酸茶碱(mepyramine-theophyllineacetate)、罗氟司特);白三烯调节剂(例如,扎鲁司特、齐留通、孟加拉司特(montekulast)和普鲁司特);抗胆碱能类(例如,异丙托溴铵(ipatropium bromide));任何形式的其他治疗性抗体(例如,针对白介素5的抗体如美泊利单抗,或针对IgE的抗体如奥马珠单抗(Omalizumab)、那些单克隆形式的抗体、Fab、scFV、多价组合物、异种抗体等),天然或工程化抗体模拟物(例如,化学污染物模拟抗体(anticalin))或天然、工程化或合成肽;血栓烷A2合成酶抑制剂;血栓烷前列腺素类受体拮抗剂;其他类花生酸调节剂(例如,前列地尔相对于PGE1、地诺前列酮相对于PGE2、依前列醇相对于前列环素和PGI2类似物(例如,PG12贝前列素)、塞曲司特、磷酸二酯酶4同工酶抑制剂、血栓烷A2合成酶抑制剂(例如,ozmagrel、达美格雷或奥扎格雷);ditec(低剂量色甘酸二钠和非诺特罗);血小板活化因子受体拮抗剂;抗组胺剂或组胺拮抗剂:异丙嗪、氯苯那敏、氯雷他定、西替拉嗪(cetirazine)、氮卓斯汀;血栓烷A2受体拮抗剂;缓激肽受体拮抗剂(例如,艾替班特);抑制活化的嗜酸性粒细胞和T细胞募集的药剂(例如,酮替芬)、IL-13阻断剂(例如,可溶性IL-13受体片段)、IL-4阻断剂(例如,可溶性IL-4受体片段);和结合并阻断IL-13或IL-4的活性的配体,以及黄嘌呤衍生物(例如,己酮可可碱);和趋化因子受体拮抗剂和CRTH2受体拮抗剂。
在某些实施方案中,本发明的治疗方法包括向受试者伴随性提供抑制性RNA分子(RNA干扰分子),以减少、抑制或阻止编码靶蛋白的基因的表达。例如,抑制性RNA分子可以用于减少或抑制下述中的一种或多种的表达:与病原体(病毒、细菌、真菌)或哺乳动物细胞相关联的蛋白质,其包括但不限于酪蛋白激酶1同种型和CLOCK调节网络的其他组分(例如ARNT1,周期1-3)、以及其他有助于呼吸系统中炎性反应的蛋白质,如白介素-5和NALP炎性体。
技术人员熟悉利用抑制性RNA分子以干扰受试者中基因表达的各种方法。例如,抑制性RNA分子可以是下述中的任何一种:短干扰RNA(siRNA)、微小RNA模拟物(miRNA)、短发夹RNA(shRNA)或长双链RNA(长dsRNA)分子。抑制性RNA分子可以直接施用于需要治疗的受试者(例如,通过吸入、气管内、口服或经鼻给药或通过胃肠外给药),或者替代性地,在施用编码双链RNA(dsRNA)分子(其能够形成抑制性RNA分子)的多核苷酸(载体)构建体后,在接受治疗的受试者中形成抑制性RNA分子。本领域技术人员还熟悉本领域已知的配制用于给药的抑制性RNA分子的各种方法(例如,在脂质体、纳米颗粒等中)。本发明还包括施用酪蛋白激酶1抑制剂和用于上述目标疾病指征的药物,其中,任一种或两种都通过吸入给药或配制成用于口服给药。
尽管本发明适用于人类,但本发明也可用于兽医治疗目的。本发明用于家畜或农场动物,例如牛、绵羊、马和家禽,用于猫和狗等伴侣动物,以及用于动物园里的动物。
如本文中所使用的,“受试者”是指动物,比如哺乳动物或禽类,哺乳动物或禽类包括人、猿、马、牛、绵羊、山羊、狗、猫、豚鼠、大鼠、小鼠、鸡等。
CK1δ同源物在自然界中无处不在,包括在原生动物(如疟疾)、真菌和细菌中。因此,预期本发明的化合物可用于需要抑制CK1δ同源物的任何应用中。此类用途可以包括将本发明的化合物施用于经受与感染和/或原生动物、真菌和/或细菌感染相关的疾病、病症和/或病况的受试者。
另一方面,本发明提供了抑制酪蛋白激酶1δ(CK1δ)的方法,包括使细胞与有效量的如本文定义的式(I)化合物或其盐、溶剂化物、N-氧化物、互变异构体、立体异构体、多晶型物和/或前药接触。
令人惊奇的是,本发明的化合物或其盐、溶剂化物、N-氧化物、互变异构体、立体异构体、多晶型物和/或前药可用作CK1δ的选择性抑制剂。与一种或多种其他激酶,例如ALK5/TGFBR1、ARK5/NUAK1、酪蛋白激酶1ε(CK1ε)、p38a/MAPK14等相比,任何公开形式的本发明化合物可以选择性地抑制CK1δ。在一些实施方案中,本发明的化合物对CK1δ的选择性可以超过至少一种激酶至少约1、5、10或100倍。
在另一方面,本发明提供了一种试剂盒或制品,其包括本文所述的式(I)化合物或包括本文所述的式(I)化合物的药物组合物。
在其他实施方案中,提供了用于本文所提及的治疗或预防应用的试剂盒,该试剂盒包括:容纳式(I)化合物或包括式(I)化合物的药物组合物的容器;以及带有使用说明的标签或包装说明书。
试剂盒或“制品”可以包括容器和在容器上或与容器相关联的标签或包装说明书。合适的容器包括例如瓶子、小瓶、注射器、一个或多个泡罩包装等。容器可以由多种材料形成,例如玻璃或塑料。该容器容纳有式(I)化合物或可有效治疗病症的组合物,并且可以具有无菌进入端口(例如,所述容器可以是静脉注射溶液袋或具有可通过皮下注射针刺入的塞子的小瓶)。标签或包装说明书表明该组合物用于治疗疾病。在一个实施方案中,标签或包装说明书包括使用说明,并表明所述治疗或预防组合物能够用于治疗本文所述的疾病。
试剂盒可以包括(a)治疗性或预防性组合物;(b)第二容器,其中装有第二活性要素或成分。本发明的该实施方案中的试剂盒可进一步包含包装说明书,所述包装说明书表明所述组合物和其他活性要素可用于治疗疾病或预防由本文所述的疾病引起的并发症。替代地或另外地,所述试剂盒可以进一步包括第二(或第三)容器,其包含药学上可接受的缓冲液,例如注射用抑菌水(BWFI)、磷酸盐缓冲盐水,林格氏溶液和葡萄糖溶液。它还可以包括从商业和用户的角度来看所需的其他材料,包括其他缓冲液、稀释剂、过滤器、针头和注射器。
在某些实施方案中,治疗性组合物可以一次性或可重复使用的装置的形式提供,包括用于容纳式(I)化合物或包括式(I)化合物的治疗或预防性药物组合物的容器。在一个实施方案中,所述装置是注射器。可以在装置中以准备使用的状态或需要混合或添加其他组分的状态提供治疗性或预防性组合物。
实施例
体外测试
激酶抑制测试
所使用的测试是HotSpot测试(Reaction Biology公司)。
化合物以10剂量IC50模式进行测试,从10μM开始进行3倍连续稀释。对照化合物十字孢碱(Staurosporine)以10剂量IC50模式进行测试,从20μM开始进行4倍连续稀释。反应在10μM ATP下进行。
试剂
碱性反应缓冲液;20mM Hepes(pH 7.5)、10mM MgCl2、1mM EGTA、0.02%Brij35、0.02mg/mL BSA、0.1mM Na3VO4、2mM DTT、1%DMSO。
*需要的辅因子单独添加到各激酶反应中
反应程序
1.肽底物是在碱性反应缓冲液中新鲜制备的
2.任何所需的辅助因子都被递送到上述底物溶液中
3.将人重组酪蛋白激酶1δ递送到底物溶液中并轻轻混合
4.通过声学技术(Echo550;纳升范围)将DMSO中的化合物递送到激酶反应混合物中,并在室温下孵育20分钟
5.33P-ATP(比活10mCi/mL)与ATP(10μM)一起被递送到反应混合物中
6.激酶反应在室温下孵育2小时
7.将反应混合物点在P81离子交换纸上
8.通过使用过滤结合法测量33P-ATP标记的产物肽来检测激酶活性。
测试结果(对酪蛋白激酶1δ进行)在下表2(pIC50)和表3(IC50)中给出。
表2.一些本发明化合物的抑制活性
化合物 | pIC<sub>50</sub> |
ZH2-102 | 8.77 |
ZH2-130 | 8.71 |
ZH2-62 | 7.42 |
ZH2-66 | 5.86 |
ZH2-86 | 8.15 |
ZH2-98 | 7.91 |
ZH3-74 | 8.53 |
ZH3-90 | 6.57 |
ZH3-94 | 7.46 |
ZH3-98 | 8.59 |
D4476 | 6.67 |
表3.一些本发明化合物的酪蛋白激酶1δ抑制活性
人实质成纤维细胞测试
原代人实质成纤维细胞(pFb)是从肺切除标本的实质(parenchyma)和没有慢性呼吸系统疾病的供体的非移植肺中培养的。pFb在含有10%(v/v)热灭活胎牛血清(FCS)、15mMHEPES、0.2%(v/v)碳酸氢钠、2mM L-谷氨酰胺、1%(v/v)非必需氨基酸、1%(v/v)丙酮酸钠、2.5μg/mL两性霉素、5IU/mL青霉素和50μg/mL链霉素的Dulbecco’sModified Eagle’s培养基(DMEM)中传代。
在实验之前,将pFb在含有0.25%牛血清白蛋白(BSA)和含胰岛素-转铁蛋白-硒的补充剂(Monomed A;CSL,Parkville,墨尔本,澳大利亚)的无血清DMEM中培养。将细胞与小分子CK1δelta抑制剂(0.1μM至10μM)孵育30分钟,然后与100pM TGF-β1(R&DSystems,明尼阿波里斯市,明尼苏达州)孵育,继续孵育16小时至24小时,然后收集上清液以检测免疫反应性IL-11。在100%DMSO中制成10mM的储备溶液,并在含有0.1%DMSO的培养基中稀释至所需浓度(最终浓度)。
收集上清液,按照制造商的说明通过ELISA测量IL-11(R&D DuoSet,DY218)。通常,捕获抗体最初使用PBS缓冲液稀释至推荐浓度,然后通过加入50μL/孔用于包被96孔微孔板(Greiner,#655061)的孔,并在室温下孵育过夜。第二天,丢弃溶液并用洗涤缓冲液(含有0.1%(v/v)吐温-20的PBS)洗涤孔3次,然后加入200μL封闭溶液(含有1%(v/v)BSA的PBS)1小时以封闭非特异性位点。然后将板用洗涤缓冲液洗涤3次,然后将50μL样品或标准品加入孔中并在室温下孵育2小时。孵育后,将板用洗涤缓冲液洗涤3次,向孔中加入50μL检测抗体并在室温下孵育2小时。然后将板洗涤3次,然后加入链霉亲和素偶联的辣根过氧化物酶(streptavidin-conjugated horseradish peroxidase)(以推荐浓度)45分钟。然后将板用洗涤缓冲液洗涤5次,并将100μL TMB底物溶液(A和B等份,BD Biosciences)添加到每个孔中,直到出现足够的信号。通过加入100μL硫酸(2M H2SO4)使反应失活。使用Multiskan读板器在450nm处测量吸光度。细胞因子标准品的吸光度符合逻辑方程,从而允许确定样品中细胞因子的浓度。
抑制TGF-β诱导的IL-11的PIC50值(抑制IL-11水平50%的浓度的负对数)是从对数浓度小分子对IL-11水平的线性回归进行插值的(表4和图2)。
表4.一些本发明化合物的IL-11抑制活性
*在100mM时没有产生50%或更多抑制作用的化合物的pIC50值指定为4.00。
合成
通用
在氘化溶剂中获得质子核磁共振光谱(1H NMR,400,600MHz)和质子去耦碳-13核磁共振光谱(13C NMR,100,150MHz),其中残留的氕化(protiated)溶剂作为内标。化学位移之后是多重性、耦合常数(J,Hz)、积分和可能的分配。根据Still等人1的方法使用自动化系统进行快速色谱。分析薄层色谱(t.l.c.)在铝背衬的2mm厚硅胶60GF254上进行,并且色谱图在紫外灯下可视化。通过使用电喷雾电离(ESI)和飞行时间质量分析仪电离样品获得高分辨率质谱(HRMS)。通过Pangborn等人2的方法获得干燥THF和CH2Cl2。石油醑剂(pet.spirit)是指石油醚,沸程为40℃-60℃。所有其他市售试剂均按原样使用。
1 W.C.Still,M.Kahn和A.M.Mitra,J.Org.Chem.,1978,43,2923。
2 A.B.Pangborn,M.A.Giardello,R.H.Grubbs,R.K.Rosen和F.J.Timmers,Organometallics,1996,15,1518。
2-(甲硫基)嘧啶-4-甲醛(1)
将4M HCl水溶液(13mL)加入4-二甲氧基甲基-2-甲基硫烷基-嘧啶(2.42g,12.1mmol)的溶液中。将所得混合物在50℃下加热18小时。1H NMR分析表明转化为甲醛,因此将混合物冷却至室温。反应混合物用EtOAc稀释并用45%KOH溶液中和。水相用EtOAc萃取,用MgSO4干燥并浓缩。粗物质不经纯化即用于下一步(2.74g,87%)。1H NMR(CDCl3,400MHz)δ2.64(3H,s),7.44(1H,d,J=4.8Hz),8.77(1H,d,J=4.8Hz),9.96(1H,s)。
4-((环己基亚氨基)-甲基)-N-甲基硫烷基嘧啶-2-胺(12)
将K2CO3 20%w/v(0.55g,0.39mmol)水溶液和环己胺(2.45mL,21.4mmol)加入粗醛(2.74g,17.8mmol)在CH2Cl2(15mL)中的溶液中。反应混合物在室温下搅拌过夜。1H NMR分析表明醛完全消耗。含有亚胺的反应混合物不经分离直接用于下一步。
4-(1-环己基-4-(4-氟苯基)-1H-咪唑-5-基)-2-(甲基硫烷基)嘧啶(13)
α-(对甲苯磺酰基)-4-氟苯甲基异腈(5.67g,19.6mmol)、12(2.74g,17.8mmol)和K2CO3(2.71g,19.6mmol)在CH2Cl2(15mL)中的混合物在室温下搅拌过夜。反应混合物用CH2Cl2稀释,水洗,干燥(MgSO4),过滤并浓缩。残余物进行快速色谱(EtOAc/石油醑剂1:1(EtOAc/pet.spirits 1:1))得到固体,将其从EtOAc/石油醑剂重结晶得到硫化物,为淡黄色晶体,(2.32g,35%),熔点为192-195℃。1H-NMR(400MHz;CDCl3):δ1.41-1.19(3H,m),1.75-1.59(3H,m),1.88(2H,d,J=13.3Hz),2.16(2H,d,J=11.3Hz),2.58(3H,s),4.62(1H,tt,J=11.9,3.4Hz),6.76(1H,d,J=5.2Hz),6.99(2H,t,J=8.6Hz),7.40(2H,dd,J=8.5,5.5Hz),7.76(1H,s),8.31(1H,d,J=5.2Hz);13C-NMR(101MHz;CDCl3):δ14.2,25.4,26.0,34.7,55.9,115.5,115.71(s,1C),117.2,124.2,130.3(d,JC-F=8.0Hz),130.6(d,JC-F=3.2Hz),136.6,143.1,157.1,158.2,162.6(d,JC-F=247Hz),173.0;对C20H22FN4S(M+H)计算的HRMS(ESI+)为369.1549。实测值为369.1545。
4-(1-环己基-4-(4-氟苯基)-1H-咪唑-5-基)-2-甲基磺酰基嘧啶-2-胺(14)
将mCPBA(55-86%)(0.569g,3.30mmol)分批加入13(0.404g,1.10mmol)在CH2Cl2(20mL)中的混合物中,并将混合物在室温下搅拌过夜。混合物用Na2CO3水溶液、水、盐水淬灭,用Na2SO4干燥,真空浓缩得到为无色固体的砜(0.440g,87%),熔点为196-202℃。1H-NMR(400MHz;CDCl3):δ1.93-1.21(8H,m),2.23(2H,d,J=11.3Hz),3.39(3H,s),4.85(1H,tt,J=11.8,3.4Hz),7.08(2H,t,J=8.6Hz),7.27(1H,m),7.43(2H,dd,J=8.5,5.5Hz),7.86(1H,s),8.59(1H,d,J=5.4Hz);13C-NMR(101MHz;CDCl3):δ25.5,25.8,34.9,39.2,56.9,116.0,116.3,123.1,130.3(d,JC-F=3.6Hz,1C),130.7(d,JC-F=8.2Hz),138.2,146.0,157.5,159.8,163.1(d,JC-F=249Hz),166.3;对C20H22FN4O2S(M+H)计算的HRMS(ESI+)为401.1447。实测值为401.1444。
4-(1-环己基-4-(4-氟苯基)-1H-咪唑-5-基)-N-((四氢-2H-吡喃-4-基)甲基)嘧啶-2-胺(15;ZH2-102)
将4-氨基甲基四氢吡喃(95.0μL,0.776mmol)加入到14(31.1mg,0.078mmol)在THF(5mL)中的溶液中,并将混合物在40℃下搅拌2天。混合物在真空下浓缩并且通过快速色谱(EtOAc/石油醑剂35%至100%)纯化残余物以得到浅黄色固体(24.4mg,72%)。1H-NMR(400MHz;CDCl3):δ1.23-1.42(6H,m),1.60-1.75(5H,m),1.89(2H,m),2.17(2H,m),3.38(4H,m),3.99(2H,dd,J=3.7,11.3Hz),4.54(1H,s),5.41(1H,s),6.40(1H,d,J=5.1Hz),6.98(2H,t,J=8.7Hz),7.44(2H,dd,J=5.6,8.5Hz),7.74(1H,s),8.13(1H,d,J=3.9Hz);13C-NMR(101MHz;CDCl3):δ25.4,26.1,31.0,34.6,35.3,47.5,55.6,67.8,112.0,115.2,115.4,125.2,130.0(d,JC-F=8.0Hz),130.72(d,JC-F=3.1Hz),135.8,141.5,158.2,159.0,162.4(d,JC-F=248Hz),162.7。
4-(1-环己基-4-(4-氟苯基)-1H-咪唑-5-基)-N-(吡啶-2-基甲基)嘧啶-2-胺(2-甲基吡啶)(19;ZH2-130)
将2-氨甲基吡啶(74.0μL,0.724mmol)加入到14(29.0mg,0.072mmol)在THF(5mL)中的溶液中,并将混合物在40℃下搅拌2天。混合物在真空下浓缩并且通过快速色谱(EtOAc/石油醑剂70%至100%)纯化残余物以得到浅黄色固体(30.9mg,99%)。1H-NMR(500MHz;CDCl3):δ1.20-1.27(3H,m),1.58-1.68(3H,m),1.83-1.85(2H,m),2.14-2.16(2H,m),4.56(1H,tt,J=12.0,3.6Hz),4.80(2H,d,J=5.5Hz),6.35(1H,m),6.44(1H,d,J=5.1Hz),6.95-7.00(2H,m),7.19-7.21(1H,m),7.32(1H,d,J=7.8Hz),7.43-7.47(2H,m),7.66(1H,td,J=1.8,7.7Hz),7.73(1H,s),8.18(1H,d,J=5.1Hz),8.58(1H,dt,J=0.7,4.9Hz).13C-NMR(126MHz;CDCl3):δ25.4,25.9,34.7,46.7,55.7,112.3,115.3,115.4,121.6,122.4,125.2,130.1(d,JC-F=8.0Hz),130.7(d,JC-F=3.2Hz),135.8,136.8,141.5,149.4,157.7,158.4,159.0,162.4(d,JC-F=247Hz),162.5。
N-([1,1'-联苯]-4-基甲基)-4-(1-环己基-4-(4-氟苯基)-1H-咪唑-5-基)嘧啶-2-胺(25;ZH2-66)
将4-苯基苯甲基胺(30.0mg,0.162mmol)加入到14(32.6mg,0.081mmol)在THF(5mL)中的溶液中,并将混合物在室温下搅拌6天。混合物在真空下浓缩并且通过快速色谱(EtOAc/石油醑剂50%至100%)纯化残余物,然后从PhMe/EtOAc重结晶以得到浅黄色晶体(20.9mg,51%)。1H-NMR(400MHz;CDCl3):1H-NMR(400MHz;CDCl3):δ1.12-1.26(2H,m),1.56-1.62(2H,m),1.81(2H,m),1.89-1.96(2H,m),2.13(2H,d,J=12.0Hz),4.52-4.59(1H,m),4.77(2H,d,J=6.0Hz),5.66(1H,t,J=0.8Hz),6.46(1H,d,J=5.1Hz),7.00(2H,t,J=8.6Hz),7.35(1H,t,J=7.2Hz),7.42-7.48(6H,m),7.59(4H,m),7.75(1H,s),8.18(1H,d,J=4.7Hz);13C-NMR(101MHz;CDCl3):δ25.4,25.8,34.7,45.2,55.6,112.5,115.3,115.5,127.2,127.5,127.6,127.7,129.0,130.2(d,JC-F=7.8Hz),130.6(d,JC-F=3.3Hz),135.9,138.2,140.6,158.4,159.1,162.5,162.5(d,JC-F=247Hz)。
4-(1-环己基-4-(4-氟苯基)-1H-咪唑-5-基)-N-(环戊基甲基)嘧啶-2-胺(27;ZH2-86)
将环戊甲基胺(96.0μL,0.973mmol)加入到14(39.0mg,0.097mmol)在THF(5mL)中的溶液中,并将混合物在40℃下搅拌18小时。混合物在真空下浓缩并且通过快速色谱(EtOAc/石油醑剂50%至100%)纯化残余物以得到浅黄色固体(17.2mg,42%)。1H-NMR(400MHz;CDCl3):δ1.19-1.41(5H,m),1.53-1.90(11H,m),2.16-2.25(3H,m),3.38(2H,t,J=6.5Hz),4.57-4.59(1H,m),5.28-5.33(1H,bs),6.38(1H,d,J=5.1Hz),6.98(2H,t,J=8.7Hz),7.45(2H,dd,J=5.6,8.5Hz),7.74(1H,s),8.12(1H,bs,J=0.6Hz);13C-NMR(101MHz;CDCl3):δ25.5,26.0,30.6,34.7,39.7,46.9,55.6,111.8,115.2,115.5,125.3,130.1(d,JC-F=8.0Hz),130.7(d,JC-F=3.0Hz),135.8(d,JC-F=8.0Hz),141.5,158.1,159.0,162.3,162.4(d,JC-F=248Hz)。
4-(1-环己基-4-(4-氟苯基)-1H-咪唑-5-基)-N-(环己基甲基)嘧啶-2-胺(28;ZH2-98)
将环己基甲基胺(92.0μL,0.706mmol)加入到14(28.3mg,0.071mmol)在THF(5mL)中的溶液中,并将混合物在室温下搅拌2天。混合物在真空下浓缩并且通过快速色谱(EtOAc/石油醑剂40%至70%)纯化残余物以得到浅黄色固体(28.4mg,92%)。1H-NMR(400MHz;CDCl3):δ0.93-1.03(2H,m),1.11-1.37(7H,m),1.54-1.89(10H,m),2.16(2H,d,J=11.2Hz),3.29(2H,t,J=6.4Hz),4.57(1H,bs),5.37(1H,bs),6.36(1H,d,J=5.1Hz),6.97(2H,t,J=8.7Hz),7.44(2H,dd,J=5.6,8.6Hz),7.72(1H,s),8.10(1H,s);13C-NMR(101MHz;CDCl3):δ25.5,26.0,26.6,31.2,34.7,38.0,48.0,55.6,111.7,115.2,115.4,125.3,130.1(d,JC-F=8.0Hz),130.8(d,JC-F=3.1Hz),135.8,141.5,158.2,159.0,162.4(d,JC-F=247Hz),162.8。
4-(1-环己基-4-(4-氟苯基)-1H-咪唑-5-基)-N-((4,4-二氟环己基)甲基)嘧啶-2-胺(32;ZH3-74)
将4,4-二氟环己基甲胺盐酸盐(96.0mg,0.519mmol)和K2CO3(72.0mg,0.519mmol)加入到14(52.0mg,0.130mmol)在THF/H2O(5:1,6mL)中的溶液中,并将混合物在40℃下搅拌5天。混合物在真空下浓缩并且通过快速色谱(EtOAc/石油醑剂20%至70%)纯化残余物以得到浅黄色固体(56.8mg,93%)。1H-NMR(400MHz;CDCl3):δ1.61-1.9(10H,m),2.12(4H,dt,J=12.1,20.9Hz),3.38(2H,t,J=6.5Hz),4.51-4.56(1H,m),5.59(1H,s),6.41(1H,d,J=5.1Hz),6.98(2H,t,J=8.6Hz),7.44(2H,dd,J=5.6,8.3Hz),7.76(1H,s),8.12-8.13(1H,m);13C-NMR(101MHz;CDCl3):δ25.4,26.1,26.9,27.0,33.0,33.3(2C),33.5,34.7,36.2,46.5,55.7,112.0,115.3,115.5,121.2,123.6,125.2,126.0,130.1(d,JC-F=7.9Hz),130.6(d,JC-F=3.1Hz),135.9,141.6,158.0,159.1,161.4(d,JC-F=247Hz),162.6;对C26H26F2N5[M+H]+计算的HRMS(ESI+)为470.2532。实测值为470.2524。
(S)-4-(1-环己基-4-(4-氟苯基)-1H-咪唑-5-基)-N-(1-环己基乙基)嘧啶-2-胺(34;ZH3-90)
将(S)-环己基乙胺(61.0μL,0.479mmol)加入到14(24.0mg,0.060mmol)在THF(4mL)中的溶液中,并将混合物在40℃下搅拌6天。混合物在真空下浓缩并且通过快速色谱(EtOAc/石油醑剂50%至100%)纯化残余物以得到浅黄色的油(24.6mg,91%),[α]D 24-9.3°(c 0.24,CH2Cl2)。1H-NMR(400MHz;CDCl3):δ0.85-2.36(24H,m),3.98-4.05(1H,m),4.62-4.65(1H,m),5.99-6.00(1H,m),6.36(1H,d,J=5.0Hz),7.02(2H,t,J=8.5Hz),7.47(2H,dd,J=5.7,8.1Hz),7.84(1H,d,J=14.5Hz),8.02-8.12(1H,m);13C-NMR(101MHz;CDCl3):δ18.2,25.4-26.6(m),29.1-29.8(m),34.5,34.7,43.4,51.2,55.6,111.3,115.3,115.6,125.3,130.2(d,JC-F=7.9Hz),130.3,135.9,159.3,161.9,162.5(d,JC-F=248Hz);对C27H35FN5[M+H]+计算的HRMS(ESI+)为448.2876。实测值为448.2856。
(R)-4-(1-环己基-4-(4-氟苯基)-1H-咪唑-5-基)-N-(1-环己基乙基)嘧啶-2-胺(35;ZH3-94)
将(R)-环己基乙胺(56.0μL,0.437mmol)加入到14(21.9mg,0.055mmol)在THF(4mL)中的溶液中,并将混合物在40℃下搅拌6天。混合物在真空下浓缩并且通过快速色谱(EtOAc/石油醑剂50%至100%)纯化残余物以得到浅黄色的油(24.1mg,99%),[α]D 24+8.7(c 0.22,CH2Cl2)。1H-NMR(400MHz;CDCl3):δ1.01-2.17(24H,m),3.98(1H,td,J=6.6,7.7Hz),4.59(1H,bs),6.31(1H,d,J=5.0Hz),6.98(2H,t,J=8.6Hz),7.43(2H,s,J=5.6,8.1Hz),7.78(1H,s),8.04(1H,s);13C-NMR(101MHz;CDCl3):δ18.2,21.5,25.5-26.6(m),29.1,29.6,34.5,34.7,43.4,51.2,55.6,111.3,115.3,115.5,125.3,130.1(d,JC-F=8.0Hz),130.4(d,JC-F=2.8Hz),135.9,159.3,162.0,162.4(d,JC-F=248Hz);对C27H35FN5[M+H]+计算的HRMS(ESI+)为448.2876。实测值为448.2864。
4-(1-环己基-4-(4-氟苯基)-1H-咪唑-5-基)-N-(3-苯丙基)嘧啶-2-胺(36;ZH3-98)
将3-苯丙胺(60.0μL,0.439mmol)加入到14(22.0mg,0.055mmol)在THF(5mL)中的溶液中,并将混合物在40℃下搅拌3天。将混合物在真空下浓缩并且通过快速色谱(EtOAc/石油醑剂50%至70%)纯化残余物以得到浅黄色的油(22.1mg,88%)。1H-NMR(500MHz;CDCl3):δ1.22-1.34(3H,m),1.60-1.73(3H,m),1.86-1.89(2H,m),2.01(2H,dt,J=7.4,15Hz),2.16(2H,d,J=11Hz),2.76(2H,t,J=7.7Hz),3.50(2H,q,J=6.6Hz),4.57(1H,s),5.49(1H,s),6.41(1H,d,J=5.0Hz),7.00(2H,t,J=8.6Hz),7.21(3H,t,J=7.9Hz),7.27-7.31(2H,m),7.47(2H,dd,J=5.6,8.2Hz),7.77(1H,s),8.14(1H,s);13C-NMR(126MHz;CDCl3):δ25.7,26.2,31.6,33.6,34.9,41.5,55.9,112.1,115.6,115.7,125.5,126.4,126.4,128.7,128.8,130.4(d,JC-F=8.0Hz),130.9(d,JC-F=2.5Hz),136.1,141.8,158.2,159.4,162.7,162.7(d,JC-F=247Hz)。
与上述R4=环己基化合物类似,可以如以下示例性合成中所述制备其中R4=2,2,2-三氟乙基的化合物。
1-(2-(甲硫基)嘧啶-4-基)-N-(2,2,2-三氟乙基)甲亚胺(1-(2-Methylthio)pyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)methanimine)
将2,2,2-三氟乙胺盐酸盐(1.96g,14.5mmol)和K2CO3(3.68g,26.6mmol)加入粗醛(1.87g,12.1mmol)在CH2Cl2(20mL)中的溶液中。反应混合物在室温下搅拌过夜。1H NMR分析表明醛完全消耗。含有亚胺的反应混合物不经分离直接用于下一步。
4-(4-(4-氟苯基)-1-(2,2,2-三氟乙基)-1H-咪唑-5-基)-2-(甲硫基)嘧啶
将α-(对甲苯磺酰基)-4-氟苯甲基异腈(3.33g,11.5mmol)、1-(2-(甲硫基)嘧啶-4-基)-N-(2,2,2-三氟乙基)甲亚胺(2.26g,9.60mmol)和20%的K2CO3水溶液(8.00mL,11.5mmol)在CH2Cl2(20mL)中的混合物在室温下搅拌5天。反应混合物用CH2Cl2稀释,水洗,干燥(MgSO4),过滤并浓缩。对残余物进行快速色谱(EtOAc/石油醑剂10%至50%)提供不可分离产物的混合物(3.04g粗品)。
4-(4-(4-氟苯基)-1-(2,2,2-三氟乙基)-1H-咪唑-5-基)-2-(甲磺酰基)嘧啶
将mCPBA(57-86%)(4.27g,24.7mmol)分批加入粗硫化物(3.04g,8.24mmol)在CH2Cl2(20mL)中的混合物中,并将混合物在室温下搅拌过夜。混合物用Na2CO3水溶液、水、盐水淬灭,用MgSO4干燥,真空浓缩。通过快速色谱(EtOAc/石油醑剂50%)纯化残余物并浓缩以提供黄色固体状的砜(0.438g,经过4个步骤9%)。1H-NMR(400MHz;CDCl3):δ3.37(3H,s),5.41(2H,q,J=8.4Hz),7.13(2H,t,J=8.5Hz),7.32(1H,d,J=5.4Hz),7.49(2H,dd,J=8.4,5.4Hz),7.87(1H,s),8.65(1H,d,J=5.4Hz)。
4-(4-(4-氟苯基)-1-(2,2,2-三氟乙基)-1H-咪唑-5-基)-N-(3-苯丙基)嘧啶-2-胺(123;ZH4-166)
将3-苯丙胺(30.0μL,0.211mmol)加入到4-(4-(4-氟苯基)-1-(2,2,2-三氟乙基)-1H-咪唑-5-基)-2-(甲基磺酰基)嘧啶(21.1mg,0.053mmol)在THF(5mL)中的混合物中,并将混合物在40℃下搅拌72小时。混合物在真空下浓缩并且通过快速色谱(EtOAc/石油醑剂20%)纯化化合物以得到浅黄色的油(11.0mg,46%)。1H-NMR(400MHz;CDCl3):δ2.00(2H,m),2.75(2H,t,J=7.5Hz),3.48(2H,q,J=6.7Hz),5.12(2H,q,J=8.6Hz),5.24(1H,bs),6.41(1H,d,J=5.1Hz),7.04(2H,t,J=8.6Hz),7.22(3H,d,J=6.0Hz),7.29(2H,dd,J=7.4,14.4Hz),7.50(2H,dd,J=5.5,8.5Hz),7.68(1H,s),8.13(1H,d,J=4.6Hz);13C-NMR(101MHz;CDCl3):δ31.3,33.4,41.2,46.7(q,JC-F=35.6Hz),111.1,115.5,115.8,124.5,125.1,126.2,128.6,130.1(d,JC-F=2.7Hz),130.5(d,JC-F=8.3Hz),140.1,141.5,143.3,157.6,158.7,162.3,162.8(d,JC-F=248Hz)。对C24H22F4N5(M+H)计算的HRMS(ESI+)为456.1811。实测值为456.1808。
本文所述的其他化合物可以通过与上述那些方法类似的方法制备。
这里还描述了以下实施方案:
1.式(II)化合物或其盐、溶剂化物、N-氧化物、互变异构体、立体异构体、多晶型物和/或前药:
其中:
R1和R2各自独立地选自于由H、C1-3烷基C6-12芳基、C1-3烷基C5-11杂芳基、C1-3烷基C3-6环烷基和C1-3烷基C3-6杂环基组成的组;
R3选自于由H、F、Cl和CH3组成的组;
R4选自于由C0-3烷基C3-12环烷基和C1-12烷基组成的组;
其中R1、R2、R3和R4中的每一个都任选地被取代。
2.根据实施方案1所述的化合物,其中所述化合物不选自图8中的化合物列表。
3.根据实施方案1所述的化合物,其中R1为C1-3烷基C6-12芳基。
4.根据实施方案3所述的化合物,其中R1为C1-2烷基C6-12芳基。
5.根据实施方案3或实施方案4所述的化合物,其中C6-12芳基由两个环体系构成。
6.根据实施方案1所述的化合物,其中R1为C1-3烷基C5-11杂芳基。
7.根据实施方案6所述的化合物,其中R1为C1-2烷基C5-11杂芳基。
8.根据实施方案6或实施方案7所述的化合物,其中C5-11杂芳基由两个环体系构成。
9.根据实施方案6或实施方案7所述的化合物,其中C5-11杂芳基的杂原子位于相对于C1-3烷基的邻位或对位。
10.根据实施方案6至9中任一项所述的化合物,其中C5-11杂芳基为含氮杂芳基。
11.根据实施方案1所述的化合物,其中R1为C1-3烷基C3-6环烷基。
12.根据实施方案11所述的化合物,其中R1为C2-3烷基C3-6环烷基。
13.根据实施方案11或实施方案12所述的化合物,其中R1被取代。
14.根据实施方案13所述的化合物,其中R1的C1-3烷基被取代。
15.根据实施方案13或实施方案14所述的化合物,其中所述取代基是C1-3烷基。
16.根据实施方案1所述的化合物,其中R1为C1-3烷基C3-6杂环基。
17.根据实施方案16所述的化合物,其中R1为C1-2烷基C3-6杂环基。
18.根据实施方案16或实施方案17所述的化合物,其中C3-6杂环基为含氧杂环基。
19.根据前述实施方案中任一项所述的化合物,其中R2是H。
20.根据前述实施方案中任一项所述的化合物,其中R3是CH3。
21.根据实施方案1至19中任一项所述的化合物,其中R3是F或Cl。
22.根据前述实施方案中任一项所述的化合物,其中R4是C0-3烷基C3-12环烷基。
23.根据实施方案22所述的化合物,其中R4为C1烷基C3-12环烷基。
24.根据实施方案22所述的化合物,其中R4为C3-12环烷基。
25.根据实施方案22至24中任一项所述的化合物,其中所述C3-12环烷基选自环丙基、环丁基、环戊基、环己基和环庚基。
26.根据实施方案22至25中任一项所述的化合物,其中R4被取代。
27.根据实施方案26所述的化合物,其中所述C3-12环烷基被取代。
28.根据实施方案26或实施方案27所述的化合物,其中所述取代基选自一个或多个C1-6烷基、一个或多个卤代基团和一个或多个OH基团。
29.根据实施方案1至21中任一项所述的化合物,其中R4为C1-12烷基。
30.根据实施方案29所述的化合物,其中R4为甲基、乙基、丙基或丁基。
31.根据实施方案29或实施方案30所述的化合物,其中R4是支链烷基。
32.根据实施方案29至31中任一项所述的化合物,其中R4被取代。
33.根据实施方案32所述的化合物,其中所述取代基选自一个或多个OH基团和/或一个或多个卤代基团。
34.一种治疗或预防有需要的受试者的呼吸系统疾病的方法,该方法包括向所述受试者施用治疗有效量的根据实施方案1至33中任一项所述的式(II)化合物,从而治疗或预防受试者的呼吸系统疾病。
35.根据实施方案1至33中任一项所述的式(II)化合物,其用于治疗或预防受试者的呼吸系统疾病。
36.一种组合物,其包含根据实施方案1至33中任一项所述的式(II)化合物和药学上可接受的赋形剂。
37.根据实施方案1至33中任一项所述的化合物或根据实施方案36所述的组合物在制备用于治疗或预防受试者的呼吸系统疾病的药物中的用途。
Claims (36)
2.根据权利要求1所述的化合物,其中R1选自以下基团:
其中,
每个R5选自于由C1-6烷基、C1-6卤代烷基、C1-6卤代烷氧基、C1-6羟烷基、C3-7杂环基、C3-7环烷基、C2-6烷氧基、C1-6烷基硫烷基、C1-6烷基亚氧硫基、C1-6烷基磺酰基、C1-6烷基磺酰基氨基、芳基磺酰基氨基、烷基羧基、烷基羧酰胺、氧代、羟基、巯基、氨基、酰基、羧基、氨基甲酰基、芳基、芳氧基、杂芳基、氨基磺酰基、芳酰基、芳酰基氨基、杂芳酰基、酰氧基、芳酰氧基、杂芳酰氧基、烷氧羰基、硝基、氰基、氟代、碘代、溴代、脲基或C1-6全氟烷基组成的组,其中每一个都可以任选地被取代;
R6是任选取代的C1-2烷基;
L为(CR7R8)m;
L1是(CR7R8)p任选取代的C1-2烷基;
R7和R8独立地选自H和任选取代的C1-6烷基;
n选自0、1、2和3;
m选自1、2和3;以及
p选自1和2。
3.根据权利要求2所述的化合物,其中n为0、1或2。
4.根据权利要求3所述的化合物,其中R5为氟代。
5.根据权利要求2至4中任一项所述的化合物,其中R1选自G1至G5。
6.根据权利要求2至4中任一项所述的化合物,其中R1是G6。
7.根据权利要求2至6中任一项所述的化合物,其中R4选自C3-12环烷基、C1-12烷基和卤代C1-12烷基。
8.根据权利要求1至7中任一项所述的化合物,其中R1是任选取代的C2-3烷基C6-12芳基或C1-3烷基C10-12芳基。
9.根据权利要求8所述的化合物,其中R1是任选取代的C2-3烷基C6芳基。
10.根据权利要求1至7中任一项所述的化合物,其中R1是任选取代的C1-3烷基C5-11杂芳基。
11.根据权利要求10所述的化合物,其中R1是任选取代的C1-2烷基C5-11杂芳基。
12.根据权利要求10或11所述的化合物,其中C5-11杂芳基的杂原子位于相对于C1-3烷基的邻位或对位。
13.根据权利要求10至12中任一项所述的化合物,其中C5-11杂芳基是含氮杂芳基。
14.根据权利要求1至7中任一项所述的化合物,其中R1是任选取代的C1-3烷基C3-6环烷基。
15.根据权利要求13所述的化合物,其中R1是任选取代的C2-3烷基C3-6环烷基。
16.根据权利要求13或权利要求14所述的化合物,其中R1被取代。
17.根据权利要求1至6中任一项所述的化合物,其中R1是任选取代的C1-3烷基C3-6杂环基。
18.根据权利要求17所述的化合物,其中R1是任选取代的C1-2烷基C3-6杂环基。
19.根据权利要求17或权利要求18所述的化合物,其中C3-6杂环基是含氧杂环基。
20.根据权利要求1至19中任一项所述的化合物,其中R3是F。
21.根据前述权利要求中任一项所述的化合物,其中R4是C0-3烷基C3-12环烷基。
22.根据权利要求21所述的化合物,其中R4为C1烷基C3-12环烷基。
23.根据权利要求22所述的化合物,其中R4为C3-12环烷基。
24.根据权利要求21至23中任一项所述的化合物,其中所述C3-12环烷基选自环丙基、环丁基、环戊基、环己基和环庚基。
25.根据权利要求20至22中任一项所述的化合物,其中R4是环己基。
26.根据权利要求1至20中任一项所述的化合物,其中R4为C1-12烷基。
27.根据权利要求26所述的化合物,其中R4为甲基、乙基、丙基或丁基。
28.根据权利要求27所述的化合物,其中R4是乙基。
29.根据权利要求26或27所述的化合物,其中R4是支链烷基。
30.根据权利要求26至29中任一项所述的化合物,其中R4被取代。
31.根据权利要求30所述的化合物,其中所述取代基选自一个或多个OH基团和/或一个或多个卤代基团。
32.根据权利要求30或31所述的化合物,其中所述取代基选自一个或多个氟代基团。
33.选自表1的化合物,或其药学上可接受的盐、溶剂化物、N-氧化物、互变异构体、立体异构体、前药和/或多晶型物。
34.一种药物组合物,其包含根据权利要求1至33中任一项所述的式(I)化合物或其药学上可接受的盐、溶剂化物、N-氧化物、互变异构体、立体异构体、前药和/或多晶型物,以及药学上可接受的赋形剂。
36.根据权利要求33所述的方法,其中式(II)化合物是如权利要求1至33中任一项所定义的式(I)化合物。
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AU2018904242 | 2018-11-07 | ||
AU2018904242A AU2018904242A0 (en) | 2018-11-07 | Compounds and compositions for the treatment of respiratory diseases | |
AU2018904241A AU2018904241A0 (en) | 2018-11-07 | Novel compounds for the treatment of respiratory diseases | |
AU2018904241 | 2018-11-07 | ||
PCT/AU2019/051225 WO2020093098A1 (en) | 2018-11-07 | 2019-11-07 | Novel compounds for the treatment of respiratory diseases |
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- 2019-11-07 AU AU2019374731A patent/AU2019374731A1/en active Pending
- 2019-11-07 EP EP19881903.9A patent/EP3877382A4/en active Pending
- 2019-11-07 EP EP19882432.8A patent/EP3877383A4/en active Pending
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- 2019-11-07 JP JP2021525326A patent/JP2022507118A/ja active Pending
- 2019-11-07 CN CN201980087269.9A patent/CN113260616A/zh active Pending
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WO2020093098A1 (en) | 2020-05-14 |
US20220002269A1 (en) | 2022-01-06 |
CN113272298A (zh) | 2021-08-17 |
EP3877383A4 (en) | 2022-09-21 |
US20220281846A1 (en) | 2022-09-08 |
EP3877382A4 (en) | 2022-07-27 |
EP3877382A1 (en) | 2021-09-15 |
EP3877383A1 (en) | 2021-09-15 |
AU2019376684A1 (en) | 2021-05-27 |
JP2022507118A (ja) | 2022-01-18 |
WO2020093097A1 (en) | 2020-05-14 |
AU2019374731A1 (en) | 2021-05-27 |
JP2022507117A (ja) | 2022-01-18 |
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