CN113149983A - 酪氨酸激酶抑制剂 - Google Patents
酪氨酸激酶抑制剂 Download PDFInfo
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- CN113149983A CN113149983A CN202011284728.3A CN202011284728A CN113149983A CN 113149983 A CN113149983 A CN 113149983A CN 202011284728 A CN202011284728 A CN 202011284728A CN 113149983 A CN113149983 A CN 113149983A
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Abstract
本发明提供化合物,所述化合物为酪氨酸激酶抑制剂,确切地说为布鲁顿(Bruton)酪氨酸激酶(“BTK”)抑制剂,且因此适用于治疗可通过抑制BTK治疗的疾病,例如癌症、自身免疫性疾病、炎性疾病和血栓栓塞性疾病。还提供含有此些化合物的药物组合物和用于制备此些化合物的方法。
Description
本发明申请是基于申请日为2016年6月2日,申请号为201680000891.8,发明名称为“酪氨酸激酶抑制剂”的专利申请的分案申请。
本申请案主张于2015年6月3日申请的美国临时申请案第62/170,547号和于2015年12月28日申请的美国临时申请案第62/271,689号的权益,所述申请案中的每一者以其全文引用的方式并入本文中。
技术领域
本发明提供为酪氨酸激酶抑制剂(确切地说布鲁顿(Bruton)酪氨酸激酶(“BTK”)抑制剂)且因此适用于治疗例如癌症、自身免疫疾病、炎性疾病和血栓栓塞性疾病的疾病的化合物。还提供含有此些化合物的药物组合物和用于制备此些化合物的方法。
背景技术
BTK(Tec家族非受体酪氨酸激酶中的一个成员)是B细胞从B细胞受体向下游传导信号所必需的。其表达于B细胞和例如单核细胞、巨噬细胞和肥大细胞的其它造血细胞中。其在维持B细胞所有组成成分的B细胞功能的多个方面中起作用(参见Gauld S.B.等人,Bcell antigen receptor signaling:roles in cell development anddisease.Science,296:1641-2.2002.)B细胞参与类风湿性关节炎(参见Perosa F.等人,CD20-depleting therapy in autoimmune diseases:from basic research to theclinic.J Intern Med.267:260-77.2010和T等人Targeting B cells in immune-mediated inflammatory disease:a comprehensive review of mechanisms of actionand identification of biomarkers.Pharmacol Ther.125:464-75.2010和Honigberg,L.等人,The selective BTK inhibitor PCI-32765blocks B cell and mast cellactivation and prevents mouse collagen indiced arthritis.Clin.Immunol.127S1:S111.2008)及例如系统性红斑狼疮和癌症的其它自身免疫疾病(参见Shlomchik M.J.等人,The role of B cells in lpr/lpr-induced autoimmunity.J.Exp Med.180:1295–1306.1994;Honigberg L.A.,The Bruton tyrosine kinase inhibitor PCI-32765blocksB-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy.Proc.Natl.Acad.Sci.107:13075-80.2010;和Mina-Osorio P等人,Suppression of glomerulonephritis in lupus-prone NZB x NZW mice by RN486,aselective inhibitor of Bruton's tyrosine kinase.Arthritis Rheum.65:2380-91.2013)。
BTK抑制剂还有可能治疗过敏性疾病(参见Honigberg,L.等人,The selectiveBTK inhibitor PCI-32765blocks B cell and mast cell activation and preventsmouse collagen indiced arthritis.Clin.Immunol.127S1:S111.2008)。注意到,不可逆抑制剂抑制小鼠中的IgE抗原复合体诱导的被动皮肤过敏反应(PCA)。这些发现与关于BTK突变肥大细胞和基因敲除小鼠所注意到的那些发现一致,且表明BTK抑制剂可适用于治疗哮喘、呼吸道的IgE依赖性过敏性疾病。
因此,抑制BTK的化合物将适用于治疗例如自身免疫疾病、炎性疾病和癌症的疾病。
发明内容
在第一方面中,本发明是针对一种式(I)化合物:
其中:
R1和R2独立地为氢、烷基、烷氧基、卤代烷基或卤代基;
X为-O-、-CONR-、-NRCO-或-NR-CO-NR’,其中R和R’独立地为氢或烷基;
Ar为杂芳基或苯基,其中杂芳基和苯基任选地由独立地选自烷基、卤代基、卤代烷基、烷氧基和羟基的一个、两个或三个取代基取代;
A为-N-或-CR3-,其中R3为氢、烷基、环丙基、卤代基、卤代烷基、卤代烷氧基、烷氧基或氰基;
Y为化学键或亚烷基;
环Z为任选地由独立地选自烷基、羟基、烷氧基和氟代基的一个或两个取代基取代的杂环氨基;
R5为式(i)、(ii)、(iii)或(iv)的基团:
其中:
Ra为氢、氟代基或氰基;其限制条件是当Ra为氰基时,那么Rb为氢且Rc不为氢;
Rb为氢或烷基;且
Rc为氢、羟烷基、烷氧烷基、烷基(其任选地由独立地选自羟基、羟烷基、杂芳基(其任选地由独立地选自烷基和杂环基的一个或两个取代基取代,其中杂环基任选地由独立地选自卤代基和烷基的一个或两个取代基取代)和-CONR9R10(其中R9及R10独立地为氢或烷基,或R9和R10与其附接到的氮原子一起形成任选地由选自烷基和杂环基的一个或两个取代基取代的杂环基)的一个或两个取代基取代)、环烷基(其任选地由独立地选自卤代基、烷基、烷氧烷基和芳基的一个或两个取代基取代;或其中所述环烷基的两个相邻取代基与其附接到的碳原子一起形成杂环基)、杂环基烷基、杂环基(其中杂环基和杂环基烷基中的杂环基视情况经由一个、两个或三个取代基取代,其中所述任选取代基中的两个独立地选自烷基、烷氧基、羟基、卤代基、氨基和氧代基,且所述任选取代基中的一个为烷基、羟烷基、烷氧基、烷氧烷基、酰基、卤代烷基、烷基磺酰基、烷氧羰基或杂环基,其中所述杂环基经由独立地选自氢、烷基、卤代基、羟基和烷氧基的一个或两个取代基取代)或-(亚烷基)-NR6R7(其中R6和R7独立地为氢、烷基、卤代烷基、羟烷基、烷氧烷基、环烷基或杂环基,其中所述杂环基视情况经由独立地选自烷基、卤代基、羟基、羟烷基、烷氧烷基、酰基和烷氧羰基的一个或两个取代基取代;或R6和R7与其附接到的氮原子一起形成其中X1、X2和X3中的一个或两个为氮,且其余为碳,并且环视情况经由独立地选自烷基、卤代烷基和卤代基的一个或两个取代基取代);及/或
其医药学上可接受的盐,其限制条件是:
当A为-N-时,那么Ra为氰基且Rc为杂环氨基烷基,其中杂环氨基烷基中的杂环氨基任选地由独立地选自烷基、烷氧基、羟基、卤代基、氨基和氧代基的一个或两个取代基取代,且杂环氨基的氮原子任选地由杂环基取代,其中所述杂环基经由独立地选自氢、烷基、卤代基、羟基和烷氧基的一个或两个取代基取代。
在一个实施例中,当式(I)化合物及/或其医药学上可接受的盐(及本文中所公开的其任何实施例)中的R5为式(i)、(ii)或(iii)的基团(其中Ra为氰基)时,本发明的化合物为BTK的可逆共价抑制剂,即,其可与半胱氨酸残基的硫醇基,确切地说与BTK的Cys481形成可逆共价键。
在另一实施例中,当式(I)化合物及/或其医药学上可接受的盐(及本文中所公开的其任何实施例)中的R5为式(i)、(ii)或(iii)的基团(其中Ra为氢或氟代基),或R5为式(iv)的基团时,本发明的化合物为BTK的不可逆共价抑制剂,即,其可与半胱氨酸残基的硫醇基,确切地说与BTK的Cys481形成不可逆共价键。
在第二方面中,本发明是针对一种包括式(I)化合物(或本文中所描述的其实施例中的任一者)及/或其医药学上可接受的盐的药物组合物;以及一种医药学上可接受的赋形剂。
(a)在第二方面的实施例(a)中,制剂为固体口服制剂,其包括:
(i)式(I)化合物及/或其医药学上可接受的盐(或本文中所公开的其任何实施例);及
(ii)用于将所述化合物及/或其医药学上可接受的盐释放于肠道中的装置。
(b)在第二方面的实施例(b)中,制剂为固体口服制剂,其包括用于将在治疗上有效量的式(I)化合物及/或其医药学上可接受的盐(或本文中所公开的其任何实施例)从所述口服制剂释放于肠道中的装置。
在实施例(a)或(b)内,在一个实施例中,式(I)化合物及/或其医药学上可接受的盐(或本文中所公开的其任何实施例)释放于小肠中。
在实施例(a)或(b)及其中含有的实施例中的又一实施例中,其中(i)式(I)化合物及/或其医药学上可接受的盐(或本文中所公开的其实施例);及/或(ii)包括式(I)化合物(或本文中所公开的其实施例)的剂型;及/或其医药学上可接受的盐;涂布有至少一层包衣,其中所述包衣独立地(当存在大于一层包衣时)选自肠溶包衣和非肠溶缓释包衣,优选的是,所述包衣为一层或多层肠溶包衣。
在一个实施例中,当式(I)化合物及/或其医药学上可接受的盐(或本文中所公开的其实施例)及/或包括式(I)化合物及/或其医药学上可接受的盐(或本文中所公开的其实施例)的剂型涂布有肠溶包衣时,所述肠溶包衣为聚合物。在另一实施例中,当式(I)化合物及/或其医药学上可接受的盐及/或包括式(I)化合物及/或其医药学上可接受的盐的剂型涂布有肠溶包衣时,所述肠溶包衣为选自以下各者的阴离子聚合物:聚甲基丙烯酸酯(例如,甲基丙烯酸甲基丙烯酸酯聚酯、甲基丙烯酸甲基丙烯酸甲酯聚酯);纤维素类聚合物(例如,邻苯二甲酸乙酸纤维素CAP、偏苯三酸乙酸纤维素CAT、琥珀酸乙酸纤维素CAS、邻苯二甲酸羟丙基甲基纤维素HPMCP、琥珀酸乙酸羟丙基甲基纤维素HPMCAS)和聚乙烯衍生物(例如聚醋酸乙烯邻苯二甲酸酯PVAP)。在又一实施例中,肠溶包衣在pH为约4.5到约7或者约5(或5.5)到约7的胃肠道中腐蚀以释放式(I)化合物及/或其医药学上可接受的盐(或本文中所公开的其实施例)。
当采用非肠溶包衣时,可在禁食状态下投与非肠溶缓释剂型,且缓释包衣可经设计以在投药后的约0.3小时至约3小时或约0.5小时至约2小时内腐蚀、破裂或变得高度可渗透以释放式(I)化合物(或本文中所公开的其实施例)及/或其医药学上可接受的盐。
在第三方面中,本发明是针对一种治疗有需要的哺乳动物中可通过BTK的抑制剂治疗的疾病的方法,所述方法包括将一种药物组合物投与给有需要的哺乳动物,所述药物组合物包括在治疗上有效量的式(I)化合物(或本文中所公开的其实施例中的任一者)及/或其医药学上可接受的盐以及医药学上可接受的赋形剂。在一个实施例中,所述疾病为癌症、自身免疫性疾病、炎性疾病或血栓栓塞性疾病。在一个实施例中,所述疾病为急性出血性坏死性脑白质炎、急性播散性脑脊髓炎、阿狄森氏病(Addison’s disease)、无丙种球蛋白血症、斑秃、普秃、淀粉样变性病、强直性脊椎炎、抗GBM/抗TBM肾炎、抗磷脂综合征(APS)、抗磷脂抗体综合征、再生障碍性贫血、关节炎、自身免疫性血管性水肿、自身免疫性家族性自主神经机能异常、自身免疫性肝炎、自身免疫性高血脂、自身免疫性免疫缺陷、自身免疫性内耳疾病(AIED)、自身免疫性心肌炎、自身免疫性卵巢炎、自身免疫性胰腺炎、自身免疫性视网膜病、自身免疫性血小板减少性紫癜(ATP)、自身免疫性甲状腺疾病、自身免疫性荨麻疹、自身免疫性溶血性贫血、轴突及神经元神经病变、巴洛病(Balo disease)、白塞氏病(Behcet’s disease)、大疱性类天疱疮、心肌症、卡斯特雷曼氏症(Castleman disease)、乳糜泻、查加斯病(Chagas disease)、慢性疲劳综合征、慢性炎性脱髓鞘性多发性神经病(CIDP)、慢性复发性多灶性骨髓炎(CRMO)、过敏性肉芽肿血管炎(Churg-Strausssyndrome)、瘢痕性类天疱疮/良性黏膜类天疱疮、腹腔病、耳蜗前庭综合征(Coganssyndrome)、冷凝集素病、先天性心脏传导阻滞、柯萨奇病毒性心肌炎(coxsackiemyocarditis)、CREST病、克罗恩病(Crohn’s disease)、脱髓鞘性神经病变、疱疹样皮炎、皮肌炎、德维克氏病(Devic’s disease)(视神经脊髓炎)、糖尿病、盘状狼疮、杜丝勒综合征(Dressler’s syndrome)、干眼病、家族性自主神经异常、子宫内膜异位、嗜酸细胞性食管炎、嗜酸性筋膜炎、结节性红斑、自发混合性冷球蛋白血症、伊文氏综合征(Evanssyndrome)、实验性过敏性脑脊髓炎、纤维肌痛症、纤维化性肺泡炎、巨细胞性动脉炎(颞动脉炎)、巨细胞性心肌炎、肾小球性肾炎、古德帕斯特综合征(Goodpasture’s syndrome)、肉芽肿性多血管炎(GPA)(以前被称为韦格纳肉芽肿(Wegener’s Granulomatosis))、格雷夫斯病(Graves’disease)、格林-巴利综合征(Guillain-Barre syndrome)、桥本氏甲状腺炎(Hashimoto's thyroiditis)、溶血性贫血、亨-舍二氏紫癜(Henoch-Schonlein purpura)、妊娠疱疹、低丙球蛋白血症、特发性肺纤维化、特发性血小板减少性紫癜(ITP)、IgA肾病、IgG4相关的硬化性疾病、免疫调节脂蛋白、包涵体肌炎、炎性肠病、间质性膀胱炎、幼年型关节炎、幼年型糖尿病(1类糖尿病)、幼年型肌炎、川崎综合征(Kawasaki syndrome)、兰伯特-伊顿综合征(Lambert-Eaton syndrome)、白细胞破碎性血管炎、扁平苔癣、硬化性苔藓、木样结膜炎、线性IgA疾病(LAD)、狼疮(SLE)、包含狼疮性肾炎的狼疮、莱姆病(lymedisease)、慢性病、梅尼埃病(Meniere’s disease)、显微镜下多血管炎、混合性结蒂组织病(MCTD)、蚕蚀性角膜溃疡、Mucha-Habermann氏病、黏膜类天疱疮、多发性硬化、重症肌无力、肌炎、发作性嗜睡病、神经性肌强直、嗜中性白血球减少症、眼部瘢痕性类天疱疮、眼阵挛-肌阵挛综合征、视神经炎、Ord氏甲状腺炎、骨关节炎、复发性风湿病、PANDAS(链球菌相关的儿童自身免疫性神经精神障碍)、副肿瘤性小脑变性、阵发性睡眠性血红蛋白尿症(PNH)、Parry Romberg综合征、睫状体扁平部炎(周边葡萄膜炎)、Parsonnage-Turner综合征、周围神经病变、静脉周性脑脊髓炎、恶性贫血、天疱疮(例如寻常天疱疮、落叶型天疱疮)、POEMS综合征、结节性多动脉炎、风湿性多肌痛症、多肌炎、心肌梗死后综合征、心包切开术后综合征、原发性胆汁性肝硬化、原发性硬化性胆管炎、原发性胆汁性肝硬化、孕酮性皮炎、银屑病、银屑病性关节炎、银屑病性关节炎、纯红细胞再生障碍、坏疽性脓皮病、雷诺氏现象(raynauds phenomenon)、反应性关节炎、反射交感性营养不良、赖特综合征(Reiter’ssyndrome)、复发性多软骨炎、不宁腿综合征、腹膜后纤维化、风湿热、类风湿性关节炎、类肉状瘤病、施密特综合征(Schmidt syndrome)、巩膜炎、硬皮病、休格兰氏综合征(Sjogren’ssyndrome)、精子及睾丸自身免疫、僵人综合征、斯提耳氏病(Still's disease)、亚急性细菌性心内膜炎(SBE)、Susac氏综合征、交感性眼炎、高安氏大动脉炎(Takayasu’sarteritis)、颞动脉炎/巨细胞性动脉炎、血小板减少性紫癜(TTP)、托-享二氏综合征(Tolosa-Hunt syndrome)、横贯性脊髓炎、I、II和III类自身免疫多腺性综合征、溃疡性结肠炎、未分化结缔组织病(UCTD)、葡萄膜炎、血管炎、水疱大疱性皮肤病、白癜风、外阴痛或狼疮。
在第三方面的一个实施例中,所述哺乳动物患有自身免疫性疾病,例如炎性肠病、关节炎、包含狼疮性肾炎的狼疮、类风湿性关节炎、银屑病性关节炎、骨关节炎、斯提耳氏病、幼年型关节炎、糖尿病、重症肌无力、肉芽肿性多血管炎、桥本氏甲状腺炎、Ord氏甲状腺炎、格雷夫斯病、休格兰氏综合征、干眼病(包含休格兰氏干眼病和非休格兰氏干眼病)、多发性硬化、格林-巴利综合征、急性播散性脑脊髓炎、阿狄森氏病、眼阵挛-肌阵挛综合征、强直性脊椎炎、抗磷脂抗体综合征、再生障碍性贫血、自身免疫性肝炎、腹腔病、古德帕斯特综合征、特发性血小板减少性紫癜、视神经炎、硬皮病、原发性胆汁性肝硬化、赖特综合征、高安氏大动脉炎、颞动脉炎、自身免疫性溶血性贫血、韦格纳肉芽肿、银屑病、普秃、白塞氏病、慢性疲劳、家族性自主神经异常、子宫内膜异位、间质性膀胱炎、神经性肌强直、硬皮病、天疱疮(例如寻常天疱疮及/或落叶型天疱疮)、大疱性类天疱疮、老年性黄斑变形(湿性和非出血性)、糖尿病黄斑水肿、角膜移植、腹主动脉瘤、黏膜类天疱疮或外阴痛。
在另一实施例中,所述自身免疫性疾病为狼疮、寻常天疱疮、重症肌无力、休格兰氏综合征、干眼病、多发性硬化、韦格纳肉芽肿、自身免疫性溶血性贫血、特发性血小板减少性紫癜、肉芽肿性多血管炎、或类风湿性关节炎。
在第三方面的另一实施例中,所述哺乳动物患有异种免疫病况或疾病,例如移植物抗宿主疾病、移植、输血、过敏反应、变态反应、I类过敏症、过敏性结膜炎、过敏性鼻炎或特应性皮炎。在另一实施例中,所述疾病为特应性皮炎。
在第三方面的又一实施例中,所述哺乳动物患有炎性疾病,例如哮喘、阑尾炎、睑炎、细支气管炎、支气管炎、黏液囊炎、子宫颈炎、胆管炎、胆囊炎、结肠炎、结膜炎、膀胱炎、泪腺炎、皮炎、皮肌炎、脑炎、心内膜炎、子宫内膜炎、肠炎、小肠结肠炎、上髁炎、附睾炎、筋膜炎、纤维组织炎、胃炎、肠胃炎、肝炎、化脓性汗腺炎、喉炎、乳腺炎、脑膜炎、脊髓炎性心肌炎、肌炎、肾炎、卵巢炎、睾丸炎、骨炎、耳炎、胰腺炎、腮腺炎、心包炎、腹膜炎、咽炎、胸膜炎、静脉炎、局限性肺炎、肺炎、直肠炎、前列腺炎、肾盂肾炎、鼻炎、输卵管炎、窦炎、口腔炎、滑膜炎、肌腱炎、扁桃体炎、葡萄膜炎、阴道炎、血管炎或外阴炎。在此方面的另一实施例中,所述哺乳动物患有炎性皮肤病,所述炎性皮肤病包含(例如)皮肤、关节或其它组织或器官中的皮炎、接触性皮炎、湿疹、荨麻疹、红斑痤疮和疤痕银屑病皮损。在另一实施例中,所述炎性疾病为哮喘或皮炎。
在第三方面的又一实施例中,所述哺乳动物患有炎性及/或自身免疫性疾病,包含急性炎性及/或自身免疫性疾病,其中使用皮质类固醇疗法作为一线或二线疗法,或者一线或二线维持疗法。在一个实施例中,式(I)化合物(或本文中所公开的其任何实施例)用于以下各者的治疗:
内分泌失调:原发性或继发性肾上腺皮质功能不全(皮质醇或肾上腺皮质酮为首选:适用时,合成类似物可结合盐皮质激素使用;在婴儿期补充盐皮质激素尤其重要);先天性肾上腺皮质增生症;非化脓性甲状腺炎;与癌症相关的血钙过多。
风湿病:在以下各者中作为短期投药的辅助疗法(以帮助患者度过急性发作或恶化):银屑病性关节炎、类风湿性关节炎(包含幼年型类风湿性关节炎(所选案例可能需要小剂量的维持疗法))、强直性脊椎炎、急性和亚急性黏液囊炎、急性非特异性腱鞘炎、痛风、急性痛风性关节炎、创伤后骨关节炎、滑膜炎性关节骨性关节炎、上髁炎。
胶原病:在以下各者的恶化期间或在以下各者的所选案例中作为维持疗法:系统性红斑狼疮、系统性皮肌炎(多肌炎)、急性风湿性心脏炎。
皮肤疾病:天疱疮;大疱性疱疹样皮炎;重症多形红斑(史蒂文斯-约翰逊综合征(Stevens-Johnson syndrome));剥脱性皮炎;蕈样真菌病;重症银屑病;重症皮脂溢性皮炎。
过敏性状态:控制对于传统治疗的充分试验来说棘手的重症或失能过敏性病况:季节性或常年性过敏性鼻炎;支气管哮喘;接触性皮炎;特应性皮炎;血清病;药物超敏反应。
眼部疾病:涉及眼睛和其附器的重症急性及慢性过敏性以及炎性过程,例如:过敏性角膜边缘性溃疡、眼部带状疱疹、前段发炎、分散后葡萄膜炎和脉络膜炎、交感性眼炎、过敏性结膜炎、角膜炎、脉络膜视网膜炎、视神经炎、虹膜炎及虹膜睫状体炎。
呼吸道疾病:症状性类肉状瘤病;以其它方式不易控制的吕弗勒氏综合征(Loeffler’s syndrome);铍中毒;(在与适当的抗结核化学疗法一起使用时)吸入性肺炎、爆发性或播散性肺结核
血液系统异常:成人特发性血小板减少性紫癜;成人继发性血小板减少症;获得性(自身免疫性)溶血性贫血;红芽球减少症(RBC贫血);先天性(红细胞)发育不良性贫血。
肿瘤疾病:用于以下各者的姑息性治疗:成人白血病和淋巴瘤、儿童急性白血病。
水肿状态:在没有特发性类型尿毒症或由红包狼疮引起的尿毒症的情况下,诱导肾病综合征中蛋白尿的利尿或缓解。
胃肠疾病:帮助病人度过以下疾病的关键期:溃疡性结肠炎、局限性肠炎。
其它疾病:(在与适当的抗结核化学疗法一起使用时)蛛网膜下腔阻滞或即将阻滞的结核性脑膜炎;神经或心肌受累的旋毛虫病。
式(I)化合物及/或其医药学上可接受的盐可视情况与皮质类固醇、非皮质激素、免疫抑制剂及/或抗炎药组合以用于治疗上文所列疾病。在一个实施例中,免疫抑制剂选自干扰素α、干扰素γ、环磷酰胺、他克莫司(tacrolimus)、霉酚酸酯、甲氨蝶呤、氨苯砜、柳氮磺胺吡啶、咪唑硫嘌呤、抗CD20剂(例如,利妥昔单抗(rituximab)、奥法木单抗(ofatumumab)、奥必珠单抗(obinutuzumab)或维妥珠单抗(obinutuzumab),或其生物仿制药)、抗TNFα剂(例如,依那西普(entanercept)、英利昔单抗(infliximab)、高利单抗(golilumab)、阿达木单抗(adalimumab)或赛妥珠单抗(certolizumab pegol)或其生物仿制药)、针对配体或其受体的抗IL6剂(例如,托珠单抗(tocilizumab)、萨鲁单抗(sarilumab)、奥克珠单抗(olokizumab)、埃西露单抗(elsililumab)或西托昔单抗(siltuximab))、针对配体或其受体的抗IL17剂(例如,苏金单抗(secukinumab)、优特克单抗(ustekinumab)、博路达单抗(brodalumab)或衣克珠单抗(ixekizumab))、针对配体或其受体的抗IL1剂(例如,利纳西普(rilonacept)、康纳单抗(canakinumab)或阿那白滞素(anakinra))、针对配体或其受体的抗IL2剂(例如,巴利昔单抗(basiliximab)或达利珠单抗(daclizumab))、例如阿法西普(alefacept)的抗CD2剂、例如莫罗单抗(muromonab)-cd3的抗CD3剂、例如阿巴西普(abatacept)或贝拉西普(belatacept)的抗CD80/86剂、例如芬戈莫德(fingolimod)的抗1-磷酸鞘氨醇受体剂、例如依库丽单抗(eculizumab)的抗C5剂、例如那他珠单抗(natalizumab)的抗整合素α4剂、例如维多珠单抗(vedolizumab)的抗整合素α4β7剂、例如西罗莫司(sirolimus)或依维莫司(everolimus)的抗mTOR剂、例如他克莫司(tacrolimus)的抗钙调磷酸酶剂和抗BAFF/BlyS剂(例如贝利木单抗(belimumab)、VAY736或利西莫德(blisibimod))、来氟米特(leflunomide)和特立氟胺(teriflunomide)。优选的是,免疫抑制剂为利妥昔单抗、奥法木单抗、奥必珠单抗或维妥珠单抗或其生物仿制药。
在第三方面的又一实施例中,所述哺乳动物患有癌症。在一个实施例中,癌症为B细胞增生性疾病,例如弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞性淋巴瘤(CLL)、慢性淋巴细胞性白血病、慢性骨髓性白血病、B细胞急性淋巴细胞性白血病(B-ALL)、费城染色体阳性B-ALL、B细胞幼淋巴细胞性白血病、小淋巴细胞性淋巴瘤(SLL)、多发性骨髓瘤、B细胞非霍奇金淋巴瘤(B-cell non-Hodgkin lymphoma)、淋巴浆细胞性淋巴瘤/瓦尔登斯特伦巨球蛋白血症(Waldenstrom macroglobulinemia)、脾边缘区淋巴瘤、浆细胞骨髓瘤、浆细胞瘤、淋巴结外边缘区B细胞淋巴瘤、节点边缘区B细胞淋巴瘤、套细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特(burkitt)淋巴瘤/白血病或淋巴瘤样肉芽肿。
在第三方面的又一实施例中,所述哺乳动物患有血栓栓塞性疾病,例如,心肌梗死、心绞痛、血管成形术后再闭塞、血管成形术后再狭窄、主动脉冠状动脉分流术后再闭塞、主动脉冠状动脉分流术后再狭窄、中风、暂时性局部贫血、周围动脉闭塞性疾病、肺血管阻塞症或深静脉血栓形成。
在第四方面中,本发明是针对一种用作药剂的式(I)化合物(和本文中所公开的其任何实施例)及/或其医药学上可接受的盐。在一个实施例中,式(I)化合物及/或其医药学上可接受的盐的用途是用于治疗由BTK介导的疾病,例如,所述疾病为在第三方面和其中实施例中所描述的炎性疾病、自身免疫性疾病、癌症或血栓栓塞性疾病。
在第五方面中,式(I)化合物(或本文中所公开的其实施例中的任一者)及/或其医药学上可接受的盐的用途是用于制造用于治疗哺乳动物的疾病的药剂,其中BTK引起所述疾病的病理及/或症状。在此方面的一个实施例中,所述疾病为在第三方面和其中实施例中所描述的癌症、自身免疫性疾病、炎性疾病或血栓栓塞性疾病。
在涉及癌症治疗的前述方面中的任一者中,存在其它实施例,其包括与抗癌剂结合地投与式(I)化合物(或本文中所公开的其实施例中的任一者)及/或其医药学上可接受的盐。当使用联合疗法时,可同时(例如,固定组合药品产品)或依序地投与所述药剂。在第六方面中,本发明是针对一种式(II)中间体:
其中:
R1、R2、R3、X、Ar、Y和环Z如上文第一方面中所定义;
或其盐。
在第七方面中,提供一种制备以下各者的方法:
(1).式(I)化合物,其中Ra为氰基,A为-CR3-,且其它基团如上文所定义;或
其医药学上可接受的盐;
其包括:
(a)使式(II)化合物:
其中:
R1、R2、R3、X、Ar、Y和环Z如上文第一方面中所定义;
与式RcCHO的醛反应,其中Rc如上文第一方面中所定义;或
(b)使式(III)化合物:
其中:
R1、R2、R3、X、Ar、Y和Z如上文第一方面中所定义;
与式RcCH=C(CN)COL化合物反应,其中L在酰化反应条件下为离去基团,其中Rc如上文第一方面中所定义;或
(2).式(I)化合物,其中Ra为氢,A为-CR3-,且其它基团如上文第一方面中所定义:或其药用盐;其包括使式(III)化合物:
其中:
R1、R2、R3、X、Ar、Y和环Z如上文第一方面中所定义;
与式RcRbC=CHCOL化合物反应,其中L在酰化反应条件下为离去基团,其中Rb和Rc如上文第一方面中所定义;
(c)视情况制成由上文步骤(1)或(2)获得的化合物的酸加成盐;
(d)视情况制成由上文步骤(1)或(2)获得的化合物的游离碱。
定义:
除非另有说明,否则说明书和权利要求书中所使用的下列术语是出于此发明的目的而加以定义且具有下列含义:
“烷基”意味着具有一至六个碳原子的直链饱和单价烃基或具有三至六个碳原子的分支链饱和单价烃基,例如甲基、乙基、丙基、2-丙基、丁基(包含所有同分异构形式)、戊基(包含所有同分异构形式)和类似物。
除非另有说明,否则“亚烷基”意味着具有一至六个碳原子的直链饱和二价烃基或具有三至六个碳源子的分支链饱和二价烃基,例如亚甲基、亚乙基、亚丙基、1-甲基亚丙基、2-甲基亚丙基、亚丁基、亚戊基和类似物。
“烷基磺酰基”意味着-SO2R基团,其中R为如上文所定义的烷基,所述烷基磺酰基例如甲基磺酰基、乙基磺酰基和类似物。
“氨基”意味着-NH2。
“烷氧基”意味着-OR基团,其中R为如上文所定义的烷基,所述烷氧基例如甲氧基、乙氧基、丙氧基或2-丙氧基、正丁氧基、异丁氧基或叔丁氧基和类似物。
“烷氧烷基”意味着经由如上文所定义的烷氧基(在一个实施例中经由一个或两个烷氧基)取代的具有一至六个碳原子的直链单价烃基或具有三至六个碳原子的分支链单价烃基,例如:2-甲氧乙基;1-、2-或3-甲氧丙基;2-乙氧乙基;和类似物类似物。
“烷氧羰基”意味着-C(O)OR基团,其中R为如上文所定义的烷基,所述烷氧羰基例如甲氧羰基、乙氧羰基和类似物。
“酰基”意味着-COR基团,其中R为烷基、卤代烷基或环烷基,所述酰基例如乙酰基、丙酰基、环丙基羰基和类似物。当R为烷基时,所述基团在本文中也被称作烷基羰基。
“环烷基”意味着具有三至十个碳原子的环状饱和单价烃基,其中一个或两个碳原子可由氧代基代替,所述环烷基例如环丙基、环丁基、环戊基或环己基和类似物。
“羧基”意味着-COOH。
“卤代基”意味着氟代基、氯代基、溴代基或碘代基;在一个实施例中为氟代基或氯代基。
“卤代烷基”意味着经由一个或一至五个卤素原子(在一个实施例中,氟或氯)取代的如上文所定义的烷基,包含经由不同卤素取代的那些烷基,所述卤代烷基例如-CH2Cl、-CF3、-CHF2、-CH2CF3、
-CF2CF3、-CF(CH3)2和类似物。当所述烷基仅经由氟代基取代时,其在本发明中可被称为氟代烷基。
“卤代烷氧基”意味着-OR基团,其中R为如上文所定义的卤代烷基,所述卤代烷氧基例如-OCF3、-OCHF2和类似物。当R为烷基仅经由氟代基取代的卤代烷基时,其在本发明中可被称作氟代烷氧基。
“羟烷基”意味着经由一个或两个羟基取代的具有一至六个碳原子的直链单价烃基或具有三至六个碳原子的分支链单价烃基,其限制条件是如果存在两个羟基,那么其不都在同一个碳原子上。代表性实例包含(但不限于)羟甲基、2-羟乙基、2-羟丙基、3-羟丙基、1-(羟甲基)-2-甲基丙基、2-羟丁基、3-羟丁基、4-羟丁基、2,3-二羟丙基、1-(羟甲基)-2-羟乙基、2,3-二羟丁基、3,4-二羟丁基和2-(羟甲基)-3-羟丙基。其它实例包含(但不限于)2-羟乙基、2,3-二羟丙基和1-(羟甲基)-2-羟乙基。
“杂环基”意味着具有4至10个环原子的饱和或不饱和单价单环或双环基团(稠合双环或桥联双环),其中一个或两个环原子为选自N、O和S(O)n的杂原子,其中n为0至2的整数,其余环原子为C。另外,杂环基环中的一个或两个环碳原子可视情况由-CO-基团代替。更具体地说,术语杂环基包含(但不限于)氧杂环丁烷基、吡咯烷子基、哌啶基、高哌啶子基、2-氧代吡咯烷基、2-氧代哌啶基、吗啉子基、哌嗪子基、四氢哌喃基、硫代吗啉子基、六氢吡咯[1,2-a]吡嗪-6(2H)-酮-基、四氢-1H-唑并[3,4-a]吡嗪-3(5H)-酮-基、5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪-基、3-氧杂-8-氮杂双环[3.2.1]辛烷-基和类似物。当所述杂环基环不饱和时,那么其可含有一个或两个环双键,其限制条件是所述环并非芳香族
“杂环烷基”意味着-(亚烷基)-R基团,其中R为如上文所定义的杂环基环,所述杂环烷基例如四氢呋喃基甲基、哌嗪基甲基、吗啉基乙基和类似物。
“杂环氨基”意味着具有4至8个环原子的饱和或不饱和单价单环基团,其中一个或两个环原子为选自N、O或S(O)n的杂原子,其中n为0至2的整数,其余环原子为C,其限制条件是环原子中的至少一个为N。另外,杂环氨基环中的一个或两个环碳原子可视情况由-CO-基团代替。当所述杂环氨基环不饱和时,其可含有一个或两个环双键,其限制条件是所述环并非芳香族。
“杂环氨基烷基”意味着-(亚烷基)-R基团,其中R为如上文所描述的杂环氨基。
“杂芳基”意味着具有5至10个环原子的单价单环或双环芳香基,其中一个或多个(在一个实施例中,一个、两个或三个)环原子为选自N、O和S的杂原子,其余环原子为碳。代表性实例包含(但不限于)吡咯基、噻吩基、噻唑基、咪唑基、呋喃基、吲哚基、异吲哚基、恶唑基、异恶唑基、苯并噻唑基、苯并恶唑基、喹啉基、异喹啉基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三唑基、四唑基和类似物。
如本文中所使用的“哺乳动物”意味着驯养动物(例如,狗、猫和马)和人类。在一个实施例中,所述哺乳动物为人类。
本发明还包含式(I)化合物(或本文中所描述的其实施例中的任一者)及/或其医药学上可接受的盐的前药。术语前药意图表示在将所述前药投与给哺乳类个体时能够释放式(I)活性成分(或本文中所描述的其实施例中的任一者)的共价结合载体。所述活性成分的释放发生在活体内。可通过本领域技术人员已知的技术来制备前药。这些技术通常对给定化合物中的合适官能团进行改性。然而,这些经改性官能团在活体内或通过常规操作再生原始官能团。式(I)化合物(或本文中所描述的其实施例中的任一者)的前药包含其中羟基、氨基、羧基或类似基团被改性的化合物。前药的实例包含(但不限于)酯(例如,乙酸酯、甲酸酯和苯甲酸酯衍生物)、氨基甲酸酯(例如,式(I)化合物中的羟基或氨基官能团的N,N-二甲基氨基酰基)、酰胺(例如,三氟乙酰氨基、乙酰氨基和类似物)和类似物。式(I)化合物(或本文中所描述的其实施例中的任一者)及/或其医药学上可接受的盐的前药也在本发明的范围内。
本发明还包含式(I)化合物(或本文中所描述的其实施例中的任一者)及/或其医药学上可接受的盐的多晶形式(非晶质以及晶质)和氘化形式。
化合物的“医药学上可接受的盐”意味着在医药学上可接受且具有母体化合物的所要药理活性的盐。此类盐包含:
与无机酸形成的酸加成盐,所述无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸和类似物;或与有机酸形成的酸加成盐,所述有机酸例如甲酸、乙酸、丙酸、己酸、环戊烷丙酸、乙醇酸、丙酮酸、乳酸、丙二酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、3-(4-羟基苯基酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、1,2-乙二磺酸、2-羟乙磺酸、苯磺酸、4-氯苯磺酸、2-萘磺酸、4-甲苯磺酸、樟脑磺酸、葡萄庚酸、4,4'-亚甲基双-(3-羟基-2-烯-1-羧酸)、3-苯基丙酸、三甲基乙酸、叔丁基乙酸、月桂基硫酸、葡萄糖酸、谷氨酸、羟萘甲酸、水杨酸、硬脂酸、粘康酸和类似物;或
当母体化合物中存在的酸性质子被例如碱金属离子、碱土金属离子或铝离子的金属离子取代,或与例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺和类似物的有机碱配位时形成的盐。应理解,医药学上可接受的盐为无毒的。关于合适的医药学上可接受的盐的额外信息可见于Remington's Pharmaceutical Sciences(第17版,MackPublishing Company,Easton,PA,1985),其以引用的方式并入本文中。
本发明的化合物可具有不对称中心。含有经不对称取代的原子的本发明化合物可以旋光形式或消旋形式分离。制备旋光形式的方法是本领域中熟知的,例如通过材料的解析。作为单独形式和其混合物的所有手性形式、非对映形式、消旋形式在本发明的范围内,除非明确指出具体立体化学形式或同分异构形式。
某些式(I)化合物(或本文中所描述的其实施例中的任一者)及/或其医药学上可接受的盐可以互变异构体及/或几何异构体存在。作为单独形式和其混合物的所有可能的互变异构体以及顺式和反式异构体在本发明的范围内。另外,如本文所使用,尽管仅阐述了少数实例,术语烷基包含所述烷基基团的所有可能异构形式。此外,尽管仅阐述了少数实例,但当例如杂芳基、杂环基的环基团被取代时,其包含所有的位置异构体。此外,式(I)化合物(或本文中所描述的其实施例中的任一者)及/或其医药学上可接受的盐的所有水合式在本发明的范围内。
“氧代基”或“羰基”意味着=(O)基团。
“任选的”或“任选地”意味着随后描述的事件或情况可发生但不必发生,且所述描述包含所述事件或情况发生的例子和所述事件或情况不发生的例子。举例来说,“任选地由烷基取代的杂环基”意味着烷基可存在但不必存在,且所述描述包含杂环基被烷基取代的情况和杂环基未被烷基取代的情况。
“医药学上可接受的载体或赋形剂”意味着适用于制备通常安全无毒且在生物学上或其它方面都合乎需要的药物组合物的载体或赋形剂,且包含兽用以及人类药用可接受的载体或赋形剂。如说明书和权利要求书中所使用的“医药学上可接受的载体/赋形剂”包含一种及大于一种此类赋形剂两者。
在式(I)中Rc的杂环基的定义中,片语“其中所述任选取代基中的两个独立地选自烷基、烷氧基、羟基、卤代基和氧代基,且所述任选取代基中的一个为烷基、环烷基、羟烷基、烷氧烷基、酰基、卤代烷基、烷基磺酰基、烷氧羰基或杂环基”(及权利要求书及/或说明书中其它地方的类似片语)意味着当杂环基由一个取代基取代时,所述取代基可为所列任选取代基中的任一个。当杂环基环由两个取代基取代时,那么两个取代基可选自烷基、烷氧基、羟基、卤代基和氧代基,或两个取代基中的一个选自烷基、烷氧基、羟基、卤代基和氧代基且另一个取代基选自烷基、环烷基、羟烷基、烷氧烷基、酰基、卤代烷基、烷基磺酰基、烷基羰基和杂环基。并且,当杂环基环由三个取代基取代时,那么两个取代基选自烷基、烷氧基、羟基、卤代基和氧代基且第三个取代基选自烷基、环烷基、羟烷基、烷氧烷基、酰基、卤代烷基、烷基磺酰基、烷基羰基和杂环基。
疾病的“治疗(treating/treatment)”包含:
(1)预防疾病,即,使得疾病的临床症状不在可能暴露于疾病或易患疾病但尚未经历或显示疾病症状的哺乳动物体内发展;
(2)抑制疾病,即,控制或减缓疾病或其临床症状的发展;或
(3)缓解疾病,即,使得疾病或其临床症状消退。
“在治疗上有效的量”意味着当将其投与给哺乳动物以用于治疗一种疾病时,足以影响所述疾病的此治疗的式(I)化合物(或本文中所描述的其实施例中的任一者)的量。“在治疗上有效的量”将根据化合物、疾病和其严重性以及待治疗的哺乳动物的年龄、体重等改变。
具体实施方式
实施例
在下方实施例1至24和其中所含实施例或子实施例中,本发明包含:
1.一种如上文第一方面的第一实施例中所定义的式(I)化合物,其包含其E或Z异构体及/或其医药学上可接受的盐。
2.实施例1的化合物及/或其医药学上可接受的盐,其中:R1和R2独立地为氢、烷基、烷氧基、卤代烷基或卤代基;
X为-O-、-CONR-、-NRCO-或-NR-CO-NR’,其中R和R’独立地为氢或烷基;
Ar为杂芳基或苯基,其中杂芳基和苯基任选地由独立地选自烷基、卤代基、卤代烷基、烷氧基和羟基的一个、两个或三个取代基取代;
A为-N-或-CR3-,其中R3为氢、烷基、环丙基、卤代基、卤代烷基、卤代烷氧基、烷氧基或氰基;
Y为化学键或亚烷基;
环Z为任选地由独立地选自烷基、羟基、烷氧基和氟代基的一个或两个取代基取代的杂环氨基;
R5为式(i)、(ii)、(iii)或(iv)的基团:
其中:
Ra为氢、氟代基或氰基;其限制条件是当Ra为氰基时,那么Rb为氢且Rc不为氢;
Rb为氢或烷基;且
Rc为氢、任选地由独立地选自OH、杂芳基(其任选地由独立地选自烷基和杂环基的一个或两个取代基取代,其中所述杂环基任选地由独立地选自卤代基和烷基的一个或两个取代基取代)的一个或两个取代基取代的烷基,及-CONR9R10(其中R9和R10独立地为氢或烷基,或R9和R10与其附接到的氮原子一起形成杂环基,所述杂环基任选地由选自烷基和杂环基的一个或两个取代基取代),
任选地由独立地选自卤代基、烷基和芳基的一个或两个取代基取代的环烷基,
羟烷基,
烷氧烷基,
杂环烷基、杂环基(其中杂环基和杂环烷基中的杂环基任选地由一个、两个或三个取代基取代,其中所述任选取代基中的两个独立地选自烷基、烷氧基、羟基、卤代基、氨基和氧代基,且所述任选取代基中的一个为烷基、羟烷基、烷氧基、烷氧烷基、酰基、卤代烷基、烷基磺酰基、烷氧羰基或杂环基,其中所述杂环基由独立地选自氢、烷基、卤代基、羟基和烷氧基的一个或两个取代基取代),或
-(亚烷基)-NR6R7(其中R6和R7独立地为氢、烷基、卤代烷基、羟烷基、烷氧烷基、环烷基或杂环基,其中所述杂环基任选地由独立地选自烷基、卤代基、羟基、羟烷基、烷氧烷基、酰基和烷氧羰基的一个或两个取代基取代;或R6和R7与其附接到的氮原子一起形成其中X1、X2和X3中的一个或两个为氮且其余为碳,并且所述环任选地由独立地选自烷基、卤代烷基和卤代基的一个或两个取代基取代);
及/或其医药学上可接受的盐,其限制条件是:
当A为-N-时,那么Ra为氰基且Rc为杂环氨基烷基,其中杂环氨基烷基中的杂环氨基任选地由独立地选自烷基、烷氧基、羟基、卤代基、氨基和氧代基的一个或两个取代基取代,且杂环氨基的氮原子任选地由杂环基取代,其中所述杂环基经由独立地选自氢、烷基、卤代基、羟基和烷氧基的一个或两个取代基取代。
3.实施例1至2的化合物及/或其医药学上可接受的盐,其中A为-N-。
4.实施例1至2的化合物及/或其医药学上可接受的盐,其中A为-CR3-。在实施例4的一个实施例中,R3为氢、甲基、乙基、异丙基、氟代基或氯代基。在实施例3的第二实施例中,R3为氢。
5.实施例1至4和其中所含实施例中的任一者的化合物及/或其医药学上可接受的盐,其中-X-Ar在苯环的位置4处附接至碳,苯环中附接至环状脲环的N的碳为位置1。
6.实施例1至5和其中所含实施例中的任一者的化合物及/或其医药学上可接受的盐,其中X为-O-。在实施例6内,在第四实施例中,Ar为杂芳基或苯基,其中杂芳基和苯基任选地由独立地选自烷基、卤代基、卤代烷基、烷氧基和羟基的一个、两个或三个取代基取代。在实施例6内,在第五实施例中,Ar为任选地由独立地选自烷基、卤代基、卤代烷基、烷氧基和羟基的一个、两个或三个取代基取代的吡啶基、嘧啶基、噻吩基或吡嗪基。在实施例6内,在第六实施例中,Ar为苯基,其中苯基任选地由独立地选自烷基、卤代基、卤代烷基、烷氧基和羟基的一个、两个或三个取代基取代,优选地由一个或两个氟代基取代。
7.实施例1至6和其中所含实施例中的任一者的化合物及/或其医药学上可接受的盐,其中X为-CONR-或-NRCO-。在实施例6内,在第四实施例中,Ar为杂芳基或苯基,其中杂芳基和苯基任选地由独立地选自烷基、卤代基、卤代烷基、烷氧基和羟基的一个、两个或三个取代基取代。在实施例7内,在第五实施例中,Ar为任选地由独立地选自烷基、卤代基、卤代烷基、烷氧基和羟基的一个、两个或三个取代基取代的吡啶基、嘧啶基、噻吩基或吡嗪基。在实施例7内,在第六实施例中,Ar为苯基,其中苯基任选地由独立地选自烷基、卤代基、卤代烷基、烷氧基和羟基的一个、两个或三个取代基取代,优选地由一个或两个氟代基取代。
8.实施例1至7和其中所含实施例中的任一者的化合物及/或其医药学可接受的盐,其中R1和R2独立地为氢或卤代基,优选地为氢或氟代基,更优选的是,R1和R2为氢或R1为氢且R2为氟代基。
9.实施例1至8和其中所含实施例中的任一者的化合物及/或其医药学上可接受的盐,其中Y为亚烷基且环Z为吡咯烷基,且在一个实施例中为吡咯烷-2-基或氮杂环丁-3-基。在实施例9内,在一个实施例中,Y为亚甲基。在实施例9内,在第二实施例中,附接于C2处的吡咯烷基环和附接至Y的吡咯烷基环的碳处的立体化学为(R)或(S)。在实施例9内,在另一实施例中,其中R5为式(i)或(iv)的基团。
10.实施例1至9和其中所含实施例中的任一者的化合物及/或其医药学上可接受的盐,其中Y为化学键,且环Z为吡咯烷基或哌啶基且在C-3碳处附接至环状脲氮,吡咯烷基或哌啶基的氮原子为位置C-1。在一个实施例中,附接至环状脲氮的吡咯烷基或哌啶基的碳处的立体化学为(R)。
11.实施例1至10和其中所含实施例中的任一者的化合物及/或其医药学上可接受的盐,其中Ra为氢。在实施例11内,在一个实施例中,R5为式(i)的基团。在实施例11内,在第二实施例中,R5为式(ii)或(iii)的基团。在实施例11内,在第三实施例中,R5为式(iv)的基团。在实施例11的实施例一至三内,在一个子实施例中,Rb和Rc为氢。在实施例11的实施例一至三内,在另一子实施例中,Rb为氢且Rc为烷基或-(亚烷基)-NR6R7(其中R6和R7独立地为氢、烷基、卤代烷基、羟烷基、烷氧烷基、环烷基或杂环基,其中杂环基环任选地由独立地选自烷基、卤代基、羟基、羟烷基、烷氧烷基、酰基和烷氧羰基的一个或两个取代基取代),优选的是,R6和R7独立地为氢或烷基。
12.实施例1至11和其中所含实施例中的任一者的化合物及/或其医药学上可接受的盐,其中Ra为氰基。在实施例12内,在一个实施例中,R5为式(i)的基团。在实施例12内,在第二实施例中,R5为式(ii)或(iii)的基团。
(a)在实施例12中的实施例一和二内,在一个子实施例中,Rc为环烷基,所述环烷基任选地由独立地选自卤代基、烷基、烷氧烷基和酰基的一个或两个取代基取代;或其中所述环烷基的两个相邻取代基与其附接到的碳原子一起形成杂环基。在一个实施例中,Rc为环丙基、1-甲基环丁基、1-苯基环丙基、1-甲基环丙基、2,2-二氟环丙基、
(b).在实施例12中的实施例一和二内,在第二子实施例中,Rc为未经取代的烷基。在一个实施例中,Rc为异丙基或叔丁基。
(c).在实施例11中的实施例一和二内,在一个子实施例中,Rc为-(亚烷基)-NR6R7(其中R6和R7独立地为氢、烷基、卤代烷基、羟烷基、烷氧烷基、环烷基或杂环基。在另一子实施例中,Rc为-C(CH3)2NH2、-C(CH3)2NHCH3、-C(CH3)2N(CH3)2、-C(CH3)2NHCH2CH3、-C(CH3)2NHCH(CH3)2、-C(CH3)2NH环丙基、-C(CH3)2NH(CH2)2OCH3、-C(CH3)2OCH2CH3、-C(CH3)2N(CH2CH3)(氧杂环丁-3-基)、-C(CH3)2N(CH3)(氧杂环丁-3-基)或-C(CH3)2NH(氧杂环丁-3-基)。
(d)在实施例12中的实施例一和二内,在另一子实施例中,Rc为杂环烷基,其中杂环烷基中的杂环基任选地由一个、两个或三个取代基取代,其中所述任选取代基中的两个独立地选自烷基、烷氧基、羟基、卤代基、氨基和氧代基,且所述任选取代基中的一个为烷基、羟烷基、烷氧烷基、酰基、卤代烷基、烷基磺酰基、烷氧羰基或杂环基,其中所述杂环基任选地由独立地选自烷基、卤代基、羟基和烷氧基的一个或两个取代基取代。
在子实施例(d)的一个子实施例中,Rc为-C(CH3)2吗啉-4-基、-C(CH3)2-4-(2,2,2-三氟乙基)哌嗪-1-基、-C(CH3)2-4-(1-甲基)哌啶-1-基、-C(CH3)2-4-乙基-3-氧代哌嗪-1-基、C(CH3)2四氢吡喃-4-基、-C(CH3)2-4-甲氧羰基哌嗪-1-基、-C(CH3)2-4-(氧杂环丁-4-基)哌嗪-1-基、-C(CH3)2-4-(3-甲基氧杂环丁-4-基)哌嗪-1-基、-C(CH3)2-4-叔丁氧羰基哌嗪-1-基、-C(CH3)2-4-乙酰基哌嗪-1-基、-C(CH3)2-4-甲氧羰基哌嗪-1-基、-C(CH3)2-哌嗪-1-基、-C(CH3)2-3,3-二氟吡咯烷-1-基、-C(CH3)2-(S)-3-甲氧吡咯烷-1-基、-C(CH3)2-(R)-3-甲氧吡咯烷-1-基、
-C(CH3)2-(S)-2-(甲氧甲基)吡咯烷-1-基、-C(CH3)2-(R)-2-(甲氧甲基)吡咯烷-1-基、-C(CH3)2-4-甲基哌嗪-1-基、-C(CH3)2-4-乙基哌嗪-1-基、-C(CH3)2-4-异丙基哌嗪-1-基、-C(CH3)2-4-(2-甲氧乙基)哌嗪-1-基、-C(CH3)2-4-乙酰基哌嗪-1-基、-C(CH3)2-4-(3R,5S)-3,4,5-三甲基哌嗪-1-基、-C(CH3)2-4-(3R,5S)-3,5-二甲基哌嗪-1-基、-C(CH3)2-4-(3R,5S)-二甲基吗啉-4-基、-C(CH3)2-哌啶-1-基、-C(CH3)2-吡咯烷-1-基、-C(CH3)2-3-氧代-哌嗪-1-基或-C(CH3)2-(3-氧代-4-甲基哌嗪-1-基)。在子实施例(d)的第二子实施例中,Rc为杂环烷基,其中杂环烷基中的杂环基由另一杂环基取代,其中所述另一杂环基由所述另一杂环基的碳上的烷基取代。
(e).在实施例12中的实施例一和二内,在又一子实施例中,Rc为任选地由一个、两个或三个取代基取代的杂环基,其中所述任选取代基中的两个独立地选自烷基、烷氧基、羟基、卤代基、氨基和氧代基,且所述任选取代基中的一个为烷基、羟烷基、烷氧烷基、酰基或杂环基。在子实施例(e)的一个子实施例中,Rc为3-甲基氧杂环丁-3-基、3-乙基氧杂环丁-3-基、3-氟氧杂环丁-3-基、3-氨基氧杂环丁-3-基、4-甲基哌啶-4-基、3-甲基氮杂环丁-3-基、1-甲基氮杂环丁-3-基、4-甲基-4-四氢吡喃基或1,3-二甲基氮杂环丁-3-基。在另一子实施例(f)中,Rc为
(g)在实施例12的另一子实施例中,Rc为任选地由独立地选自羟基、羟烷基和杂芳基的一个或两个取代基取代的烷基,所述杂芳基由独立地选自烷基和杂环基的一个或两个取代基取代,其中杂环基任选地由独立地选自卤代基和烷基的一个或两个取代基取代。在另一实施例中,Rc为由一个或两个羟基取代基取代的烷基。在另一实施例中,Rc为
在一子实施例中,Rc为由杂芳基取代的烷基,所述杂芳基任选地由独立地选自烷基和杂环基的一个或两个取代基取代,其中杂环基任选地由独立地选自卤代基和烷基的一个或两个取代基取代。在此子实施例内,在另一实施例中,Rc为
在另一子实施例中,Rc为由-CONR9R10取代的烷基,其中R9和R10独立地为氢或烷基,或R9和R10与其附接到的氮原子一起形成任选地由选自烷基和杂环基的一个或两个取代基取代的杂环基。其中R9和R10两者都为氢或烷基的实施例在此子实施例内。在另一实施例中,Rc为-C(CH3)2-CONH2或-C(CH3)2-CON(CH3)2。
在另一子实施例中,Rc为由-CONR9R10取代的烷基,其中R9和R10与其附接到的氮原子一起形成任选地由选自烷基和杂环基的一个或两个取代基取代的杂环基。其中由R9和R10与其附接到的氮原子一起形成的杂环基为4-甲基哌嗪基或4-(氧杂环丁-3-基)哌嗪-1-基的实施例在此子实施例内。
13.实施例3、5、6和8至10中任一者的化合物(即,A为-N-;-X-Ar在苯环的4位置处附接至碳,苯环中附接至环状脲环的N的碳为位置1;X为O;Y为化学键;环Z为吡咯烷基或哌啶基且在C-3碳处附接至环状脲氮,吡咯烷基或哌啶基环的氮原子为C-1;附接至环氮的吡咯烷基或哌啶基的碳处的立体化学为(R)),其中R5为式(i)的基团,Ra为氰基,Rb为氢且Rc为杂环烷基,其中杂环烷基中的杂环基任选地由一个、两个或三个取代基取代,其中所述任选取代基中的两个独立地选自烷基、烷氧基、羟基、卤代基、氨基和氧代基,且所述任选取代基中的一个为烷基、羟烷基、烷氧基、烷氧烷基、酰基、卤代烷基、烷基磺酰基、烷氧羰基或杂环基,其中所述杂环基由独立地选自氢、烷基、卤代基、羟基和烷氧基的一个或两个取代基取代。
在此实施例的一子实施例中,Rc为
代表性化合物列于下表I中:
表I
表1的化合物中任一者的E或Z异构体及/或这些化合物中任一者的医药学上可接受的盐也包含在本发明的范围内。
本发明还针对下列化合物:
4-氨基-1-((3S)-1-(环氧乙烷-2-羰基)哌啶-3-基)-3-(4-苯氧苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮;
4-氨基-1-((3S)-1-(2,3-二羟丙酰基)哌啶-3-基)-3-(4-苯氧苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮;
4-氨基-1-((3S)-1-(2-羟丙酰基)哌啶-3-基)-3-(4-苯氧苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮;
(S)-4-氨基-1-(1-(3-羟丙酰基)哌啶-3-基)-3-(4-苯氧苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮;
4-氨基-1-(((2R)-1-(环氧乙烷-2-羰基)吡咯烷-2-基)甲基)-3-(4-苯氧苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮;
4-氨基-1-(((2R)-1-(2,3-二羟丙酰基)吡咯烷-2-基)甲基)-3-(4-苯氧苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮;
4-氨基-1-(((2R)-1-(2-羟丙酰基)吡咯烷-2-基)甲基)-3-(4-苯氧苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮;和
(R)-4-氨基-1-((1-(3-羟丙酰基)吡咯烷-2-基)甲基)-3-(4-苯氧苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮;
及/或其医药学上可接受的盐。
这些化合物可根据下文所阐述的流程4来制备且具有与式(I)化合物相同的用途。
通用合成流程
本发明的化合物可通过下文所展示的反应流程中描绘的方法来制得。
用于制备这些化合物的起始材料和试剂可向例如Aldrich化工有限公司(威斯康星州,密尔沃基)、Bachem(加利福尼亚州,托伦斯)或Sigma(密苏里州,圣路易斯)的商业供应商购买,或遵循参考文献中所阐述的步骤通过本领域技术人员已知的方法制备,所述参考文献例如:Fieser and Fieser's Reagents for Organic Synthesis,卷1至17(JohnWiley和Sons,1991);Rodd's Chemistry of Carbon Compounds,卷1至5和附录(ElsevierScience Publishers,1989);Organic Reactions,卷1至40(John Wiley和Sons,1991);March's Advanced Organic Chemistry,(John Wiley和Sons,第4版);以及Larock'sComprehensive Organic Transformations(VCH Publishers有限公司,1989)。这些流程仅说明可合成本发明化合物的一些方法,并且可对这些流程作出各种修改,并将向已经参考本发明的本领域技术人员提出所述修改。在需要时,可使用习知技术分离和纯化起始材料和中间体以及反应的最终产物,所述习知技术包含(但不限于)过滤、蒸馏、结晶、层析和类似技术。可使用常规方式(包含物理常数和光谱数据)来表征这些材料。
除非相反地说明,否则本文中描述的反应在大气压力下、在约–78℃至约150℃(或约0℃至约125℃)的温度范围内或在约室内(或环境)温度(例如,约20℃)下发生。
其中R5为式(i)的基团且其它基团如发明内容中所定义的的式(I)化合物可按照下方流程1中所说明及描述进行制备。
流程1
二卤杂芳基化合物(例如,4,6-二氯-5-硝基嘧啶)与式NH(PG)2的胺反应得到式1化合物,其中PG为合适的氨基保护基(例如,苯甲基)。所述反应在合适的有机溶剂中进行,所述有机溶剂例如二恶烷、二氯甲烷和类似物。第二卤代基由式2的氨基化合物取代得到式3化合物,其中Y和环Z如发明内容中所定义,且PG1为合适的氨基保护基(例如,叔丁氧羰基)。所述反应在具有额外碱(例如,三乙胺)的二氯甲烷、二恶烷、四氢呋喃和类似物中进行。式2化合物可从市场上购买或可通过本领域中熟知的方法制备,所述化合物例如(R)-叔丁基3-氨基哌啶-1-羧酸盐、(S)-叔丁基3-氨基哌啶-1-羧酸盐、(R)-叔丁基3-(氨甲基)吡咯烷-1-羧酸盐、(S)-叔丁基3-(氨甲基)吡咯烷-1-羧酸盐、(R)-叔丁基2-(氨甲基)氮杂环丁烷-1-羧酸盐和(S)-叔丁基2-(氨甲基)氮杂环丁烷-1-羧酸盐。可使用例如Zn和氯化铵于EtOAc中的试剂或例如乙酸于EtOH中的溶剂中的Fe或SnCl还原式3化合物的硝基以得到式4化合物。
可通过用羰基二咪唑、光气或光气等效物在碱(例如,三乙胺、二异丙乙胺和类似物)的存在下、在有机溶剂(例如,二氯乙烷和类似物)中加热4,使式4化合物环化以形成式5的苯并咪唑。移除氨基保护基PG得到式6化合物。所利用的反应条件是根据氨基保护基的性质。举例来说,当PG为苯基时,可使用具有添加剂(例如,乙酸)的Pd/C催化剂和类似物经由氢化作用移除PG以得到式6化合物。使用(例如)Cu(OAc)2作为催化剂、在具有添加剂(例如,TEMP或氧)和碱(例如,吡啶或三乙胺)的溶剂(例如,DCM)中经由铜介导的偶联反应(Chan-Lam偶联反应)使6与式7的芳基硼酸(其中R1、R2、Ar和X如发明内容中所定义)反应,得到式8化合物。式7化合物可从市场上购买或可由苯基卤化物通过锂卤素交换并用硼酸三异丙酯淬灭来制备,所述化合物例如(4-苯氧苯基)硼酸、2-[4-(3-氟苯氧基)-苯基]-4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷、4-(4-氟苯氧基)苯基硼酸、4-(3-氟苯氧基)苯基硼酸、4-(3,5-二氟苯氧基)-苯基硼酸、4-(4-氯-2-氟苯氧基)苯基-硼酸和4-(3-(三氟甲基)苯氧基)苯基硼酸。
替代地,可通过首先使化合物5与硼酸7反应,接着在上文所描述的条件下移除氨基保护基来制备化合物8。移除化合物8中的氨基保护基PG1得到式9化合物。所利用的反应条件是根据氨基保护基的性质。举例来说,当PG1为叔丁氧羰基时,其可在酸解反应条件(例如,用例如TFA、HCl和类似物的酸处理)下被移除。
随后可通过本领域中已知的方法将化合物9转化成式(I)化合物。举例来说,可通过使化合物9与式10的酸或式10的酸衍生物(例如,酸性氯化物)偶联来制备式(I)化合物,其中Ra、Rb和Rc如发明内容中所描述以得到式(I)化合物。当使用化合物10时,所述反应在标准酰胺偶联条件下进行,例如在HATU、DCC、碳二咪唑(CDI)和类似物的存在下进行。式10化合物或其酸性氯化衍生物可从市场购买(例如,丙烯酰氯)或其可通过本领域中熟知的方法制备,例如氰基乙酸与醛(例如,异丁醛或特戊醛)的缩合产物。
其中Ra为氰基的式(I)化合物还可通过首先使化合物9与2-氰基乙酸在标准酰胺偶联条件(例如,碳二咪唑(CDI)和类似物)下缩合以得到式11化合物来制备。随后,式11化合物与式RcCHO(其中Rc如发明内容中所定义)的醛在标准缩合反应条件下(例如,使用例如哌啶和类似物的碱)、在存在或不存在乙酸和类似物的情况下、在例如乙醇和类似物的溶剂中、在室内温度至回流范围内的温度下缩合得到式(I)化合物。式RcCHO化合物可从市场上购买或其可通过本领域中已知的方法制备,例如,乙醛、环丙醛、异丁醛、3-甲基氧杂环丁烷-3-甲醛、2-(二甲基氨基)-2-甲基丙醛、2-甲基-2-(1-哌啶基)丙醛、叔丁基(2S)-2-甲酰基吡咯烷-1-羧酸盐和2-甲基-2-(吗啉-4-基)丙醛为从市场上购买的。乙氧-2-甲基丙醛由异丁醛制备,如PCT国际申请案2007142576中所描述。化合物RCCHO(其中Rc为-(亚烷基)-NR6R7)可通过用溴处理异丁醛以形成溴异丁醛,接着添加HNR6R7取代溴化物而制备。
替代地,化合物11还可与RcCHO的前体基团缩合并且然后转化成式(I)化合物。举例来说,化合物11可与叔丁基2-甲基-1-氧代丙-2-基氨基甲酸盐缩合,接着移除氨基保护基以得到式(I)化合物,其中Rc为2-氨基丙-2-基。还可通过在具有例如吡咯烷或哌啶的碱、具有或不具有三甲基氯硅烷的情况下,将RcCHO的所要醛添加于二氯甲烷或其它合适溶剂(例如,二恶烷和乙醇)中来进行缩合反应。其中R5为式(ii)至(iv)的基团的式(I)化合物可如流程2中所描述地制备。通过遵循上文所描述的步骤并且用合适的起始材料来取代化合物9可获得式(I)化合物,所述起始材料例如2-丁炔酸、乙烯基磺酰氯、(E)-丙-1-烯-1-磺酰氯、1-丙炔-1-磺酰氯。
替代地,为了制备其中R5为式(ii)基团的式(I)化合物,可使式11化合物与氰基甲磺酰氯(可从市场上购买)反应得到氰基甲磺酰胺,所述氰基甲磺酰胺可与具有TMSCl和吡咯烷的式12的醛缩合得到式(I)结构。
流程2
其中A=CH的式(I)化合物可如流程3中所描述地制备。可首先使2,4-二氯-3-硝基吡啶与式2的氨基化合物反应,其中Y和环Z如发明内容中所定义且PG1为合适的氨基保护基,例如叔丁氧羰基。随后与式NH(PG)2(其中PG为合适的氨基保护基,例如4-甲氧苯甲基)的胺在例如DMF的溶剂中反应得到式14化合物。用Pd/C通过氢化反应还原硝基或在标准条件下用Zn、Fe或SnCl还原硝基得到式15化合物。与羰基二咪唑或光气等效物缩合得到环脲16。可在此阶段进行Chan-Lam偶联反应,且如流程1中所描述地完成化合物(I)的合成。
替代地,化合物17可通过首先用例如TFA的酸处理以移除两种保护基并随后安装PG1(例如,叔丁氧羰基)基团而制备。随后用二甲基甲酰胺二甲缩醛处理得到式18化合物。接着在如上文所描述的Chan-Lam条件下反应得到化合物19。随后通过用例如HCl或TFA的酸在例如二氯甲烷、二恶烷、MeOH或EtOH的溶剂中处理19而去保护,得到式20化合物。式(I)化合物的制备接着以与流程1和2中所描述的方法类似的方式进行制备。
流程3
下方流程4展示式21、式22、式24和式25化合物的制备。使用例如HATU的试剂使可从市场上购买的酸(例如,3-羟基丙酸或2-羟基丙酸(作为外消旋体或者作为(S)或(R)异构体))与流程2的化合物20在例如DMF的溶液中偶联,分别得到式21和式22化合物。可将丙烯酰氯与例如三甲胺或二异丙基乙胺的碱添加到例如DMF的溶剂中的化合物20以得到式23化合物。用例如四氧化锇和正甲基氧化吗啉(NMO)于丙酮和水的混合物中的试剂进行氧化而得到式24的二醇。可通过在例如甲苯或二氯甲烷的溶液中使用例如mCPBA的氧化剂来氧化或通过叔丁基过氧化氢(TBHP)和金鸡纳生物碱催化剂(夏普莱斯不对称环氧化反应)而由式23化合物制备化合物25。
流程4
通用方法A
可使用下方所展示的通用方法来制备一些其它化合物。
步骤1
向用O2吹扫并维持O2氛围的100mL圆底烧瓶中置入于二氯甲烷(0.1mM)中的芳基硼酸(1.0当量)、TEA(4.0当量)、Cu(OAc)2(0.50当量)、TEMPO(1.10当量)和分子筛(4A)(500mg)。搅拌所得溶液30分钟,且接着添加芳基硼酸(2.00当量)。将所得溶液在室温下搅拌过夜。在真空下浓缩所得混合物。将残余物涂覆至用二氯甲烷/甲醇洗脱的硅胶柱上以得到所要产物A。
步骤2
向A(1.0当量)于二恶烷中的溶液添加氯化氢(12M)。将所得溶液在油浴中在85℃下搅拌3小时。接着通过添加(饱和)碳酸氢钠淬灭所述反应。用DCM/MeOH(10:1)萃取所得溶液,且有机层合并。用饱和氯化钠洗涤所得混合物。通过无水硫酸钠干燥混合物并在真空下浓缩。得到360mg(100%)的B。
步骤3
向50mL圆底烧瓶中置入B(1.0当量)、2-氰基乙酸(1.0当量)、HATU(1.5当量)、TEA(3.0当量)和N,N-二甲基甲酰胺(0.1mMol)。将所得溶液在室温下搅拌2小时。用二氯甲烷萃取所得溶液,并且合并有机层。用6×100mL的水来洗涤所得混合物。通过无水硫酸钠干燥混合物并在真空下浓缩。将残余物涂覆至具有二氯甲烷/甲醇的硅胶柱上以得到化合物C。
步骤4
向圆底烧瓶中置入在DCM中溶解到0.2M浓度的C(1.0当量)。使所述溶液冷却至0℃,并且添加醛(3.0当量),接着添加吡咯烷(6.0当量)和TMSCl(4.0当量)。将所述反应温热至室温并搅拌3小时或直到sm耗尽。添加水且层分离。有机层通过硫酸钠干燥,过滤并在真空中移除溶剂。通过硅胶层析法或制备性HPLC进行纯化得到所要化合物D。醛可从市场上购买、通过下方所展示方法制备或通过本领域中已知的方法(即,经由斯文(Swern)条件或者用例如PCC或戴斯马丁高价碘(Dess-Martin periodinane)的氧化剂氧化乙醇)制备。
通用方法B
由异丁醛制备醛
向用冰浴冷却的2-甲基丙醛(1.0当量)于DCM(0.2M)中的溶液逐滴添加溴(1.0当量)。1小时之后,在真空下从所得2-溴-2-甲基丙醛溶液移除大部分溶剂。在室温下用DCM(8ml)稀释此材料并添加胺(2.0当量)。在搅拌过夜之后,用盐水(30mL)稀释混合物且层分离。将有机层干燥(MgSO4),过滤并浓缩以分离所要醛,所述醛直接用于下一步骤或在使用前通过硅胶层析法纯化。
试验
BTK抑制活性、抑制剂BTK结合复合物的滞留时间,和本发明化合物与BTK的Cys481(UniprotKB序列IDQ06187)形成不可逆共价键或可逆共价键的能力可使用下文生物学实例中所描述的活体外及/或活体内检定来测试。
本发明的式(I)化合物及/或其医药学上可接受的盐的BTK抑制活性可使用下文生物学实例1、3、4和5中所描述的活体外及/或活体内检定来测试。通过那些检定中的任一者对激酶抑制活性的测定被视为本发明范围内的激酶抑制活性,即使其它检定中的任一者或全部并未得到对激酶抑制活性的测定。
不受任何特定机制理论的束缚,在本发明化合物为可逆共价抑制剂的那些实施例中,据信半胱氨酸巯基与形成式(I)化合物中R5基团中的碳-碳双键的一部分的碳原子(其中R5为式(i)、(ii)和(iii)的基团,其中Ra为氰基(参见式(I)))可形成可逆的(即,不稳定)共价键,例如其中BTK的Cys 481攻击本发明化合物中的上方所列R5基团中的碳-碳双键的缺电子碳原子从而形成硫醇加合物。
在一些实施例中,烯烃的缺电子碳原子在附接到Ra基团(其中Ra为氰基)的碳原子远侧,即附接到Rb和Rc基团的碳原子远侧(参见本发明化合物中的式(I))。因此,本发明的化合物中的Ra基团(其中Ra为氰基)和“-N-CO-、-NSO2或-N-SO-”部分以及其结合到的烯族部分的组合可提高烯烃与BTK中的活性部位半胱氨酸残基形成硫醇加合物的反应性。
为可逆共价抑制剂的本发明化合物可以两种不同方式与BTK结合。除了上文所论述的不稳定共价结合,据信其还与BTK形成非共价结合(例如,经由范德瓦尔斯(van derWaals)结合、氢键结合、疏水性结合、亲水性结合及/或静电荷结合),所述非共价结合足以至少部分抑制BTK的激酶活性。
如本文中所公开,不稳定共价结合发生于抑制剂中的烯烃与半胱氨酸481残基硫醇侧链之间,所述侧链在抑制剂与BTK发生前述非共价结合的部位处或附近。
明显的是,为可逆共价抑制剂的本发明化合物与BTK发生半胱氨酸介导的共价结合和非共价结合两者。这与非共价可逆抑制剂相反,所述非共价可逆抑制剂仅经由非共价结合抑制BTK且没有半胱氨酸介导的共价结合。
在一些情况下与没有形成永久不可逆蛋白质加合物的不可逆共价抑制剂相比,上文所提及的本发明化合物以两种不同方式与BTK的结合提供作用解离率缓慢且持续时间延长的可逆共价抑制剂。不可逆共价抑制剂与可逆共价抑制剂(确切地说本文中公开的化合物)之间的差异可利用本文中公开的检定来确定。
通常,涉及与BTK形成可逆共价键的抑制剂的结合在BTK呈某些配置时稳定,且在BTK呈不同配置时容易断裂(两种情况都在生理条件下),而形成不可逆共价键的抑制剂与BTK之间的相互作用在生理条件下为稳定的,即使在BTK呈不同配置时。
可逆共价键常常赋予与化合物在含有半胱氨酸的结合部位内的滞留时间相关的独特性质。在此上下文中,滞留时间是指化合物靶向复合物在不同条件下的暂时持续时间(参见Copeland RA、Pompliano DL、Meek TD.Drug–target residence time and itsimplications for lead optimization.Nat.Rev.Discov.5(9),730–739(2006)。
在同不与BTK形成共价键的化合物相比时,本文中所公开的可逆共价抑制剂中的可逆共价键的存在可使得滞留时间延长。在本文中所公开的一个实施例中,为可逆共价抑制剂的本发明化合物具有至少约1小时的滞留时间。可使用占据检定在生物化学或细胞环境中测量滞留时间(参见下方生物学实例2和9)。另外,可在所定义洗脱期之后使用功能性检定来测量滞留时间。
不可逆共价抑制剂中形成不可逆共价键的化合物共同具有这些经延长滞留时间性质,但仍然可使用可逆性检定与可逆共价抑制剂区分开。本发明化合物与BTK的Cys481形成可逆或不可逆共价键的能力可通过下方生物学实例2、6至8中所描述的检定来确定。通过下方生物学实例2、6至8中的任一者对半胱氨酸残基与本发明化合物的烯键之间的共价键的结合可逆性的确定被视为本发明范围内的可逆结合,即使其它方法中的一者或两者并未得到对结合可逆性的确定。
投与和药物组合物
通常,将通过用作类似用途的药剂的可接受投与方式中的任一者以在治疗上有效的量来投与本发明化合物。式(I)化合物的在治疗上有效的量可介于约0.01毫克/千克患者体重/天至约500毫克/千克患者体重/天的范围内,所述量可以单次剂量或多次剂量投与。在一个实施例中,剂量水平将为约0.1毫克/千克/天至约250毫克/千克/天。在另一实施例中,剂量水平将为约0.5毫克/千克/天至约100毫克/千克/天。合适的剂量水平可为约0.01毫克/千克/天至约250毫克/千克/天,约0.05毫克/千克/天至约100毫克/千克/天,或约0.1毫克/千克/天至约50毫克/千克/天。在此范围内,剂量可在约0.05毫克/千克/天至约0.5毫克/千克/天,约0.5毫克/千克/天至约5毫克/千克/天,或约5毫克/千克/天至约50毫克/千克/天。对于口服投药,组分可以含有约1.0毫克至约1000毫克活性成分,确切地说含有约1.0毫克、5.0毫克、10毫克、15毫克、20毫克、25毫克、50毫克、75毫克、100毫克、150毫克、200毫克、250毫克、300毫克、400毫克、500毫克、600毫克、750毫克、800毫克、900毫克和1000毫克活性成分的药片形式提供。本发明化合物(即活性成分)的实际量将取决于许多因素,例如待治疗疾病的严重性、个体的年龄和相对健康、所利用化合物的效能、投药路径和形式以及其它因素。
通常,本发明化合物将作为药物组合物通过以下路径中的任一者给药:口服给药、全身给药(例如,经皮给药、鼻腔给药或通过栓剂)或肠胃外给药(例如,肌肉内给药、静脉给药或皮下给药)。优选的给药方式为使用方便的每日剂量方案的口服,其可根据病痛程度加以调整。组分可采用药片、药丸、胶囊、半固体、粉末、缓释制剂、溶液、悬浮液、酏剂、气溶胶或任何其它合适组分的形式。
制剂的选择取决于各种因素,例如给药模式(例如,对于内服给药,呈药片、药丸或胶囊形式的制剂为优选的)和药品的生物利用度。近来,基于可通过增大表面积(即,减小粒径)而提高生物利用度的原则,已经尤其针对展示不佳生物利用度的药物研发药物制剂。举例来说,美国专利第4,107,288号描述具有10nm至1,000nm大小范围的粒子的药物制剂,其中活性材料负载于大分子的交联基质上。美国专利第5,145,684号描述一种药物制剂的产品,其中药品在表面改性剂的存在下粉碎成纳米粒子(平均粒径为400nm)并且随后分散于液体介质中以得到呈现极高生物利用度的药物制剂。在胃pH下分解的药物的生物利用度可通过以在十二指肠内释放药物的药剂来投与此类药物而提高。
组分通常由式(I)化合物及/或其医药学上可接受的盐与医药学上可接受的赋形剂组合构成,所述赋形剂例如粘合剂、表面活性剂、稀释剂、缓冲剂、抗粘附剂、助流剂、亲水性或疏水性聚合物、抑止剂、安定剂或稳定剂、崩解剂或超级崩解剂、抗氧化剂、消泡剂、填充剂、香料、颜料、润滑剂、吸附剂、防腐剂、增塑剂或甜味剂或其混合物,所述赋形剂促进将式(I)化合物(或本文中所公开的其实施例)及/或其医药学上可接受的盐加工成在医药学上可使用的剂型。熟知技术和赋形剂中的任一者可用作合适的和本领域中理解的,参见(例如):Remington:The Science and Practice of Pharmacy,第二十一版(PharmaceuticalPress,2005);Liberman,H.A.、Lachman,L.和Schwartz,J.B.Eds.,Pharmaceutical DosageForms,卷1至2,Taylor&Francis 1990;以及R.I.Mahato、Ansel的Pharmaceutical DosageForms and Drug Delivery Systems,第二版(Taylor&Francis,2012)。
在某些实施例中,制剂可包含一或多种pH调整剂或缓冲剂,举例来说:酸,例如乙酸、硼酸、柠檬酸、富马酸、马来酸、酒石酸、苹果酸、乳酸、磷酸和盐酸;碱,例如氢氧化钠、磷酸钠、硼酸钠、柠檬酸钠、乙酸钠、乳酸钠和三羟甲基氨基甲烷;以及缓冲剂,例如柠檬酸盐/葡萄糖、碳酸氢钠、氯化铵和类似物。用作碱的此类缓冲剂可具有除钠以外的平衡离子,例如钾、镁、钙、铵和其它平衡离子。以将组分的pH维持在可接受范围内所需的量包含此类酸、碱和缓冲剂。
在某些实施例中,制剂还可以使组分的渗透压达到可接受范围所需要的量包含一或多种盐。此类盐包含具有钠、钾或铵阳离子和氯离子、柠檬酸根、抗坏血酸根、硼酸根、磷酸根、碳酸氢根、硫酸根、硫代硫酸根或亚硫酸氢根阴离子的那些盐;合适的盐包含氯化钠、氯化钾、硫代硫酸钠、亚硫酸氢钠和硫酸铵。
在某些实施例中,制剂还可包含一或多种消泡剂以减少可导致水性分散液凝结、成品薄膜起泡的加工或一般削弱加工期间的发泡。示范性消泡剂包含硅乳液或倍半油酸山梨坦。
在某些实施例中,制剂还可包含一或多种抗氧化剂,例如非硫醇抗氧化剂,例如丁羟甲苯(BHT)、抗坏血酸钠、抗坏血酸或其衍生物,和生育酚或其衍生物。在某些实施例中,抗氧化剂在需要时增强化学稳定性。还可添加例如柠檬酸或柠檬酸盐或EDTA的其它药剂以延缓氧化。
在某些实施例中,制剂还可包含一或多种防腐剂以抑制微生物活性。合适的防腐剂包含:含汞物质,例如苯汞和硫柳汞;稳定的二氧化氯;和四级铵化合物,例如氯化苯甲烃铵、溴化十六烷基三甲铵和氯化十六烷基吡啶。
在某些实施例中,制剂还可包含一种或多种粘合剂。粘合剂给予粘聚性并且包含(例如):藻酸和其盐;纤维素衍生物,例如羧甲基纤维素、甲基纤维素(例如,)、羟丙基甲基纤维素、羟乙基纤维素、羟丙基纤维素(例如,)、乙基纤维素(例如,)和微晶纤维素(例如,);微晶葡萄糖;淀粉糖;镁铝硅酸盐;多聚糖酸;皂土;明胶;聚乙烯吡咯烷酮/醋酸乙烯酯共聚物;交联聚维酮;聚维酮;淀粉;预胶凝淀粉;黄芪胶、糊精、糖(例如,蔗糖)、葡萄糖、右旋糖、糖浆、甘露醇、山梨醇、木糖醇(例如,)和乳糖;天然树胶或合成树胶,例如阿拉伯树胶、黄芪胶、伊丝布尔树皮的印度树胶粘液、聚乙烯吡咯烷酮(例如,CL、CL、XL-10)、落叶松阿拉伯半乳聚糖、聚乙二醇、聚氧化乙烯、蜡、藻酸钠和类似物。
在某些实施例中,制剂还可包含分散剂及/或黏度调节剂。分散剂及/或黏度调节剂包含通过液体介质或粒化法或混合法控制药物的弥散和均匀性的材料。在一些实施例中,这些药剂还促进包衣基质或溶蚀性基质的效力。示范性弥散促进剂/分散剂包含(例如)亲水性聚合物、电解质、60或80、PEG、聚乙烯吡咯烷酮(PVP;市场上称为)和碳水化合物类分散剂,例如羟丙基纤维素(例如,HPC、H--PC-SL和HPC-L)、羟丙基甲基纤维素(例如,HPMC K100、RPMC K4M、HPMC K15M和HPMC K100M)、羧甲基纤维素钠、甲基纤维素、羟乙基-纤维素、羟丙基-纤维素、羟丙基甲基纤维素邻苯二甲酸酯、羟丙基-甲基纤维素硬脂酸酯(HPMCAS)、非晶质纤维素、聚氧化乙烯、硅酸镁铝、三乙醇胺、聚乙烯醇(PVA)、乙烯基吡咯烷酮/醋酸乙烯酯共聚物(S630)、具有氧化乙烯和甲醛的4-(1,1,3,3-四甲基丁基)-苯酚聚合物(也被称作四丁酚醛)、泊洛沙姆(poloxamer)(例如,Pluronics 和8,其为氧化乙烯与氧化丙烯的嵌段共聚物);和泊洛沙胺(poloxamine)(例如,Tetronic也被称作Poloxamine其为通过将氧化丙烯和氧化乙烯依序添加到乙二胺而得到的四功能嵌段共聚物(新泽西州,帕西帕尼,BASF公司))、聚乙烯吡咯烷酮K12、聚乙烯吡咯烷酮K17、聚乙烯吡咯烷酮K25或聚乙烯吡咯烷酮K30、聚乙烯吡咯烷酮/醋酸乙烯酯共聚物(S-630)、聚乙二醇(例如,所述聚乙二醇可具有约300至约6000,或约3350至约4000,或约7000至5400的分子量)、羧甲基纤维素钠、甲基纤维素、聚山梨醇酯-80、藻酸钠、树胶(例如,黄芪树胶和阿拉伯树胶)、瓜尔胶、黄原胶(包含黄原树胶)、糖、纤维素(例如,羧甲基纤维素钠、甲基纤维素)、羧甲基纤维素钠、聚山梨醇酯-80、藻酸钠、聚氧乙烯醚类去水山梨糖醇月桂酸酯、聚氧乙烯醚类去水山梨糖醇月桂酸酯、聚维酮、卡波姆(carbomer)、聚乙烯醇(PVA)、藻酸盐、壳聚糖和其组合物。例如纤维素和三乙基纤维素的增塑剂还可用作分散剂。尤其适用于脂质体分散液和自乳化分散液的分散剂为豆蔻酰磷脂酰胆碱、来自鸡蛋的天然磷脂酰胆碱、来自鸡蛋的天然磷脂酰甘油、胆固醇和肉豆蔻酸异丙酯。通常,约10%至约70%的粘合剂水平用于粉末填充的明胶胶囊制剂中。无论直接压片、湿制颗粒、碾压还是使用其它赋形剂(例如其自身可充当温和粘合剂的填充剂),药片制剂中的粘合剂使用水平都会变化。本领域中熟练的制剂调配者可确定用于制剂的粘合剂水平,但是在药片制剂中粘合剂使用水平达90%且更典型地达70%是常见的。
在某些实施例中,剂型还可包含一种或多种稀释剂,所述稀释剂是指用于在递送前稀释所关注化合物的化学化合物。稀释剂还可用于使化合物稳定,因为其可提供更稳定的环境。溶解于缓冲溶液中的盐(其还可提供pH控制或维持)在本领域中用作稀释剂,包含但不限于磷酸盐缓冲盐水溶液。在某些实施例中,稀释剂增加组分的体积以促进压缩或产生足够的体积以用于胶囊填充的均匀混合。这类化合物包含(例如)乳糖、淀粉、甘露醇、山梨醇、右旋糖、微晶质纤维素(例如,);磷酸氢钙、二水磷酸二钙;磷酸三钙、磷酸钙;无水乳糖、喷雾干燥乳糖;预胶凝淀粉、可压缩糖(例如,(Amstar));羟基-甲基纤维素、羟丙基甲基纤维素硬脂酸酯、蔗糖类稀释剂、糖粉;单碱硫酸钙一水合物、硫酸钙二水合物;乳酸钙三水合物、葡萄糖结合剂;谷物水解固形物、多糖;粉状纤维素、碳酸钙;甘氨酸、瓷土;甘露醇、氯化钠;肌糖、皂土和类似物。
在某些实施例中,制剂还可包含一种或多种崩解剂,所述崩解剂在与胃肠液接触时包含所述剂型的溶解和分散两者。崩解药剂或崩解剂促进物质的分裂或崩解。崩解药剂的实例包含:淀粉,例如天然淀粉(例如玉米淀粉或马铃薯淀粉)、预胶凝淀粉(例如National 1551)或羧基乙酸淀粉钠(例如或);纤维素,例如木产品、甲基晶质纤维(例如,PH101、PH 102、PH105、P100、和)、甲基纤维素、交联甲羧纤维素或交联状纤维素(例如,交联状羧甲基纤维素钠交联状羧甲基纤维素或交联状交联甲羧纤维素);交联淀粉,例如羧基乙酸淀粉钠;交联聚合物,例如交联聚维酮、交联聚乙烯吡咯烷酮;藻酸盐,例如藻酸或藻酸的盐(例如藻酸钠);粘土,例如HV(硅酸镁铝);树胶,例如琼脂、瓜胶、刺槐豆胶、梧桐胶、果胶或黄芪胶;羧基乙酸淀粉钠;皂土;天然海绵;表面活性剂;树脂,例如阳离子交换树脂;柑橘渣;月桂醇硫酸钠、结合淀粉的月桂醇硫酸钠和类似者。
在某些实施例中,制剂还可包含腐蚀促进剂。腐蚀促进剂包括控制特定材料在胃肠液中的腐蚀的材料。腐蚀促进剂通常是本领域中一般技术人员已知的。示范性腐蚀促进剂包含(例如)亲水性聚合物、电解液、蛋白质、肽和氨基酸。
在某些事实例中,剂型还可包含一或多种填充剂,所述填充剂包含化合物,例如,乳糖、碳酸钙、磷酸钙、磷酸氢钙、硫酸钙、微晶纤维素、纤维素粉、右旋糖、葡糖糖结合剂、右旋糖酐、淀粉、预胶凝淀粉、蔗糖、木糖醇、乳糖醇、甘露醇、山梨醇、氯化钠、聚乙二醇和类似者。
在某些实施例中,剂型还可包含一或多种香料及/或甜味剂,例如,糖浆、安赛蜜K、阿力甜、大茴香、苹果、阿斯巴甜、香蕉、巴伐利亚奶油草莓、黑加仑子、奶油糖果、柠檬酸钙、樟脑、焦糖、樱桃、樱桃奶油巧克力、肉桂、泡泡糖、柑橘、柑橘饮料、柑橘奶油、棉花糖、可可饮料、可乐、冷樱桃、冷柑橘、甜蜜素、甜精、右旋糖、桉树、丁子香氛、果糖、水果饮料、姜、甘草酸、甘草(甘草汁)糖、葡萄、葡萄柚、蜂蜜、异麦芽、柠檬、青柠、柠檬奶油、甘草酸铵甘草酸、麦芽酚、甘露醇、枫树、药蜀葵、薄荷醇、薄荷乳、浆果、新橙皮苷DC、纽甜、橙子、梨、桃子、薄荷、薄荷奶油、粉、覆盆子、沙土、朗姆酒、糖精、黄樟油精、山梨醇、绿薄荷、绿薄荷奶油、草莓、草莓奶油、甜叶菊、三氯蔗糖、蔗糖、糖精钠、糖精、阿斯巴甜、乙酰氨基磺酸钾、甘露醇、蛋白、木糖醇、三氯蔗糖、山梨醇、瑞士奶油、塔格糖、橘子、索马甜、白果糖、香草、胡桃、西瓜、野樱桃、冬青、木糖醇或这些调味料的任何组合,例如大茴香-薄荷、蜂蜜-柠檬、柠檬-青柠、柠檬-薄荷、薄荷醇-桉、橙子-奶油、香草-薄荷和其混合物。
在某些事实例中,剂型还可包含一或多种润滑油和助流剂,所述润滑油和助流剂是防止,减小或抑制材料的粘结或摩擦。示范性润滑油包含(例如)硬脂酸、氢氧化钙、滑石、硬脂乳酸钠、例如矿物油的碳氢化合物或例如氢化大豆油的氢化植物油、高级脂肪酸和其碱金属和碱土金属盐,例如,铝、钙、镁、锌、硬脂酸、硬脂酸钠、甘油、滑石、蜡、硼酸、苯甲酸钠、乙酸钠、氯化钠、亮氨酸、聚乙二醇(例如,PEG4000)或聚乙二醇单甲醚,例如,油酸钠、苯酸钠、山嵛酸甘油酯、聚乙二醇、月桂酸硫酸镁或钠、硅胶,例如 例如玉米淀粉的淀粉、硅油、表面活性剂和类似物。
在某些实施例中,剂型还可包含一或多种增塑剂,所述增塑剂为用于软化肠道或缓释肠衣以使他们变得不那么易碎的化合物。合适增塑剂包含(例如)聚乙二醇,例如PEG300、PEG 400、PEG 600、PEG 1450、PEG 3350和PEG 800、硬脂酸、丙二醇、油酸、柠檬酸三乙酯、癸二酸二丁酯、三乙基纤维素和三乙酸甘油酯。在一些实施例中,增塑剂还可充当分散剂或润湿剂。
在某些实施例中,剂型还可包含一或多种增溶剂,所述增溶剂包含化合物,例如,三乙酸甘油酯、柠檬酸三乙酯、油酸乙酯、辛酸乙酯、月桂酸硫酸钠、多库酯钠、维生素ETPGS、二甲基乙酰胺、N-甲基吡咯烷酮、N-羟乙基吡咯烷酮、聚乙烯吡咯烷酮、羟丙基甲基纤维素、羟丙基环糊精,例如,乙醇、正丁醇、异丙醇、胆固醇、胆盐、聚乙二醇200-600、四氢呋喃聚乙二醇醚、还氧二元醇、丙二醇和二甲基异山梨醇和类似物。在一个实施例中,增溶剂为维生素E TPGS及/或或β-羟丙基环糊精。
在某些实施例中,剂型还可包含一种或多种悬浮剂,所述悬浮液包含化合物,例如聚乙烯吡咯烷酮(例如,聚乙烯吡咯烷酮K112、聚乙烯吡咯烷酮K17、聚乙烯吡咯烷酮K25或聚乙烯吡咯烷酮K30)、乙烯基吡咯烷酮/醋酸乙烯酯共聚物(S630)、聚乙二醇(例如,聚乙二醇可具有约300至约6000或约3350至约4000或约7000至约5400的分子量)、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素硬脂酸酯、聚山梨酯-80、羧乙基纤维素、藻酸钠、树胶(例如,黄芪胶和阿拉伯树胶、瓜尔胶)、黄原胶(包含黄胞胶)、糖、纤维素(例如,羧甲基纤维素钠、甲基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、羟乙基纤维素)、聚山梨酯-80、藻酸钠、聚乙氧去水山梨糖醇单月桂酸酯、聚乙氧去水山梨醇酐单油酸酯、聚维酮和类似物。
在某些实施例中,剂型还可包含一或多种表面活性剂,所述表面活性剂包含化合物,例如,月桂酸硫酸钠、多库酯钠、吐温20、60或80、三乙酸甘油酯、维生素E TPGS、去水山梨糖醇单油酸酯、聚氧乙烯山梨醇酐单油酸酯、聚氧乙烯去水山梨糖醇单月桂酸酯、聚山梨醇酯、泊咯沙姆、胆盐、单硬脂酸甘油酯、环氧乙烷和环氧丙烯的共聚物,例如(BASF)和类似物。一些其它表面活性剂包含聚氧化乙烯脂肪酸甘油酯和植物油,例如,聚氧化乙烯(60)氢化蓖麻油;和聚氧化乙烯烷基醚和烷基苯基醚,例如,辛苯昔醇10、辛苯昔醇40。在一实施例中,还可包含表面活性剂以增强物理稳定性或用于其它目的。
在一些实施例中,剂型还可包含一或多种黏性增强剂,所述黏性增强剂包含(例如)甲基纤维素、黄原胶、羧甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羟丙基甲基醋酸纤维素硬脂酸酯、羟丙基甲基纤维素邻苯二甲酸酯、高分子胶、聚乙烯醇藻酸、阿拉伯树胶、壳聚糖和其组合物。
在一些实施例中,剂型还可包含一或多种润湿剂,所述润湿剂包含化合物,例如,油酸、单硬脂酸甘油酯、去水山梨醇酐单油酸、去水山梨糖醇单月桂酸酯、油酸三乙醇胺、聚氧乙烯山梨醇酐单油酸酯、聚氧乙烯去水山梨糖醇单月桂酸酯、多库酯钠、油酸钠、月桂酸硫酸钠、多库酯钠、三乙酸甘油酯、吐温80、维生素E TPGS、铵盐和类似物。
本文所公开的药物制剂可通过混合一或多种固体赋形剂而获得,所述固体赋形剂例如,载体、粘合剂、填充剂、悬浮剂、调料、甜味剂、崩解剂、分散剂、表面活性剂、润滑剂、着色稀释剂、润湿剂、增塑剂、稳定剂、渗透促进剂、润湿剂、消泡剂、抗氧化剂、防腐剂或其与本文中所描述的化合物中的一或多种的一或多种组合,可选地研磨所得混合物并在添加合适赋形剂(如果需要的话)之后加工颗粒混合物,从而获得药片。
本文中所公开的药物制剂还包含由明胶制成的胶囊,以及由明胶和增塑剂(例如,甘油或山梨醇)制成的软的密封胶囊。胶囊还可由例如羟甲基纤维素的聚合物制成。所述胶囊可获得与例如乳糖的填充剂,例如淀粉的粘合剂及/或例如滑石或硬脂酸镁和可选地稳定剂的润滑油混合的活性成分。在软胶囊中,活性化合物可在合适液体中溶解或悬浮,所述液体例如,脂肪油、液状石蜡、脂肪、增溶剂或液体聚乙二醇。另外,还可添加稳定剂。用于内服的所有剂型应为适合此类投与的剂型。
这些剂型可由传统药理学技术来制造。传统药理学技术包含(例如)以下方法中的一个或组合:(1)干混法,(2)直接压缩,(3)研磨,(4)干制或无水颗粒化,(5)湿式颗粒化,(6)融化或(7)挤压。见例如Lachman等人的工业药剂的理论和实践,第3版(1986)。其它方法包含(例如)喷雾干燥、锅包衣法、熔融颗粒化、颗粒化、流化床喷雾干燥或包衣法(例如,沃斯特(wurster)包衣法)、切线包衣法、顶喷、制锭、挤压/滚圆和类似者。
应理解,用于本文中所描述的固体剂型的赋形剂之间存在相当大的间隙。因此,上文所列出的添加剂应仅作为示范性,但不限于可包含于本文中所描述的固体剂型中的赋形剂类型。此类赋形剂的类型和量可已经由此领域中的一个熟练人员根据所要的特定属性而确定。
在一些实施例中,本文中所描述的固体剂型为肠溶内服剂型,及,如本文中所描述的药物组合物的内服剂型,所述内服剂型利用肠溶包衣来影响化合物在胃肠道的肠中释放。“肠道包衣的”药物及/或药片指代涂布有在胃中保持完整但一旦到达肠部(在一个实施例中为小肠)时就溶解并释放药物的物质。如本文中所使用,“肠溶包衣”为材料,例如,聚合材料或将医药学活性剂核心包装为剂型或颗粒的材料。通常,大量或所有肠溶包衣材料在医药学活性剂从剂型释放之前溶解,以便实现小肠及/或大肠中的医药学活性剂核心或颗粒的延迟溶解。肠溶包衣经论述,例如,Loyd、V.Allen、Remington:The Science andPractice of Pharmacy,第二十一版(Pharmaceutical Press,2005;及P.J.Tarcha,Polymers for Controlled Drug Delivery,第3章,CRC Press,1991。用于将肠溶包衣涂布于药物组合物的方法在本领域中为已知的,并且包含(例如)美国专利申请案第2006/0045822。
所述肠溶包衣剂型可为经压缩或模塑或挤压药片(经包覆或未包覆)所述药片含有式(I)化合物(或其任何实施例)及/或其医药学上可接受的盐及/或其它赋形剂的颗粒、粉末、微丸、珠或颗粒,如果至少药片或式(I)化合物经包覆,赋形剂自身经包覆或未包覆。肠溶包衣内服剂型还可为含有含有式(I)化合物(或其任何实施例)及/或其医药学上可接受的盐及/或其它赋形剂的微丸、珠或颗粒的胶囊(经包覆或未包覆),如果他们中的至少一者经包覆,赋形剂自身经包覆或未包覆。最初用作肠溶包衣的包衣的一些实例为蜂蜡和单硬脂酸甘油酯;蜂蜡、虫胶和纤维素;及鲸蜡醇、乳香和虫胶以及虫胶和硬脂酸(美国专利第2,809,918号);聚蜡酸乙烯和乙基纤维素(美国专利第3,835,221号)。近来,所使用的肠衣为聚甲基丙烯酸醚的中性共聚物(Eudragit L30D)(F.W.Goodhart等人,药学技术,64-71页,1984年4月);甲基丙烯酸和甲基丙烯酸甲醚的共聚物(Eudragit S)或含有金属硬脂酸盐的聚甲基丙烯酸醚的共聚物(Mehta等人,美国专利第4,728,512号和第4,794,001号)、醋酸琥珀酸纤维素和羟丙甲纤维素酞酸酯。
展现pH依赖性溶解表面的任何阴离子聚合物可在本文中所描述的方法和组合物中用作肠溶包衣从而给药到肠。在一个实施例中,给药到小肠。在另一实施例中,给药到十二指肠。在一些实施例中,本文中所描述的聚合物为阴离子羧基聚合物。在其它实施例中,聚合物和其兼容混合物,及他们的属性中的一些包含但不限于:虫胶:
也称作纯化虫胶,其为从昆虫的树脂分泌物中获得的精炼产物。此包衣在pH>7的介质中溶解;
丙烯酸聚合物:
丙烯酸聚合物的性能(主要为他们在生物液体中的溶解度)可根据取代的程度和类型而变化。合适丙烯酸聚合物的实例包含甲基丙烯酸聚合物和甲基丙烯酸胺共聚物。Eudragit系列L、S和RS(制造Rohm Pharma并且已知为)可用于在有机溶剂、水分散剂或干粉中溶解。Eudragit系列RL、NE和RS在胃肠道中不可溶解但能渗透并且主要用作结肠靶向。Eudragit系列L、L-30D和S在胃中不可溶解且在肠中可溶解,并且可经选择并调配以在大于5.5或与大于5一样低或与大于7一样高的pH值不可溶。
纤维素衍生物:
合适纤维素衍生物的实例为:乙基纤维素;纤维素的部分醋酸酯与邻苯二甲酸酐的反应混合物。性能可根据取代的程度和类型来变化。邻苯二甲酸乙酸纤维素(CAP)在pH>6中溶解。Aquateric(FMC)是基于水的系统并且是喷雾干燥的CAP准乳胶,粒度<1μm。Aquateric中的其它组分可包含嵌段共聚物、吐温和乙酰化单甘酯。其它合适纤维素衍生物包含;纤维素醋酸苯三酸盐(Eastman);甲基纤维素(Pharmacoat,Methocel);羟丙基甲基纤维素邻苯二甲酸酯(HPMCP);羟丙基甲基琥珀酸纤维素(HPMCS);及羟丙基甲基醋酸琥珀酸纤维素(HPMCAS,例如AQOAT(Shin Etsu))。性能可根据取代的程度和类型来变化。例如,HPMCP,例如HP-50、HP-55、HP-55S、HP-55F等级为合适的。性能可根据取代的程度和类型来变化。例如,羟丙基甲基醋酸琥珀酸纤维素的合适等级包含但不限于在pH 5下溶解AS-LG(LF)、在pH 5.5下溶解的AS-MG(MF)和在更高pH下溶解的AS-HG(HF)。这些聚合物经提供为颗粒,或用于水分散的细粉;磷酸聚醋酸乙烯邻苯二甲酸酯(PVAP):
PVAP在pH>5下溶解,并且其在水蒸气和胃液中不那么可渗透。上述聚合物的详细描述和他们的pH依赖溶解度可在http://pop.www.capsugel.com/media/library/enteric-coated-hard-gelatin-capsules.pdf.见于由教授Karl Thoma和KarolineBechtold的标题为“肠溶包衣硬胶囊”的文章中。在一些实施例中,包衣可并且通常含有增塑剂和可能在本领域中著名的其它包衣赋形剂,例如,着色剂、滑石及/或硬脂酸镁。合适增塑剂包含柠檬酸三乙酯(柠檬酸三乙酯2)、三乙酸甘油酯(三乙酸甘油酯)、乙酰柠檬酸三乙酯(柠檬酸三乙酯A2)、聚乙二醇400(聚乙二醇400)、邻苯二甲酸二乙酯、柠檬酸三丁酯、乙酰化单甘酯、甘油、脂肪酸酯、丙二醇和邻苯二甲酸二丁酯。特别是,阴离子羧基丙烯酸聚合物通常将含有10-25重量%的增塑剂,尤其是邻苯二甲酸二丁酯、聚乙二醇、柠檬酸三乙酯和三乙酸甘油酯。采用习知涂布技术(例如,流化床或沃斯特(Wurster)涂布机)或喷雾涂布或锅包衣法来涂覆包衣。包衣厚度必须足够以确保口服剂型保持完好无损直到到达肠道中局部给药的所要部位。
除增塑剂外,可将着色剂、表面活性剂、抗粘附剂、消泡剂、润滑油(例如,加洛巴蜡或PEG)和其它添加剂添加到包衣以使包衣材料溶解或分散,并且提高包衣性能和带包衣产品。
为了使肠溶包衣的溶解加快,可应用半厚度双包衣的肠溶聚合物(例如,EudragitL30 D-55),且内肠溶包衣可具有在10%柠檬酸的存在下达pH 6.0的缓冲剂,接着为标准Eudragit L 30D-55的最终层。相比于应用无缓冲的类似包衣系统作为单一层,应用两层肠溶包衣(每一层为典型肠溶包衣的一半厚度)Liu和Basit能够使肠溶包衣溶解加速(Liu,F和Basit,A.Journal of Controlled Release,147(2010)242-245)。
举例来说,可通过微药丸内的药物的降解来测量肠溶包衣的完整度。可以溶出试验来测试带肠溶包衣的剂型或药丸,首先在胃液中且单独地在肠液中(如USP中所描述)以确定其功能。
含有所公开化合物的带肠溶包衣的药片和胶囊制剂可通过本领域中熟知的方法制备。举例来说,可使用侧通风包衣锅(Freund Hi-Coater)使含有本文中所公开化合物的药片肠溶地涂布有含有对苯二甲酯乙酯、异丙醇、滑石粉和水的包衣溶液。
替代地,可如下制备包括可并入到药片或胶囊中的带肠溶包衣的药丸的多单元剂型。
核心材料:
用于个别肠溶包衣层化微丸的核心材料可根据不同原则构成。层化有活性剂的晶种(即,式(I)化合物(包含本文中所公开的实施例)及/或其医药学上可接受的盐),可选地与碱性物质或缓冲剂混合的晶种可用作用于进一步处理的核心材料。待层化有活性剂的晶种可为水溶晶种,所述水溶晶种包括不同氧化物、纤维素、有机聚合物和其它材料,独自地或以混合形式或水溶晶种包括不同无机盐、糖、那普瑞尔和其它材料,独自地或以混合形式。再有,晶种可包括结晶、团聚体、压块等形式的活性剂。晶种的大小对于本发明不是必不可少的但是可在大约0.1到2mm之间变化。经层化有活性剂的晶种使用(例如)颗粒化或喷雾包衣层设备通过粉或溶解/悬浮层化而产生。
层化晶种之前,活性剂可与其它化合物混合。此类化合物可为粘合剂、表面活性剂、填充剂、崩裂剂、碱性添加剂或其它及/或医药学上可接受成分独自地或以混合形式。粘合剂为(例如)实例聚合物,例如羟丙甲纤维素(HPMC)、羟基纤维素(HPC)、羧甲基纤维素钠、聚乙烯吡咯烷酮(PVP)或糖、淀粉或具有粘着属性的其它医药学上可接受物质。合适表面活性剂发现于医药学上可接受非离子或离子表面活性剂(例如,月桂酸硫酸钠)的基团中。
或者,可选地与合适成分混合的活性剂可调配成核心材料。所述核心材料可利用传统工艺设备挤压/滚圆、成球或压缩而产生。所调配的核心材料的大小为约0.1到4mm之间且例如0.1和2mm之间。所制造的核心材料可进一步经层化有包括活性剂的额外成分及/或用于进一步处理。
活性剂与医药学成分混合以获得优选的处置和处理属性及在最终制备中活性剂的合适浓缩。可使用医药学成分,例如填充剂、粘合剂、润滑油、崩解剂、表面活性剂和其它医药学上可接受添加剂。
或者,前文所提到的核心材料可通过使用喷雾干燥或喷雾冻结技术来制备。
肠溶包衣层:
在将肠溶包衣层涂覆至呈单独药丸形式的核心材料上之前,药丸可任选地覆盖有包括药用赋形剂的一个或多个分离层,所述药用赋形剂任选地包含碱性化合物,例如pH缓冲化合物。这/这些分离层将核心材料与为肠溶包衣层的外层分离。保护活性剂的核心材料的这/这些分离层应为水溶性的或在水中迅速分解。
分离层可通过包衣或层化程序在合适设备中而可选涂布于核心材料,所述合适设备例如包衣锅、包衣颗粒机,或使用水及/或有机溶剂在流化床装置中以用于包衣过程。作为替代,可通过使用粉末涂布技术将分离层涂覆至核心材料。用于分离层的材料为医药学上可接受化合物,例如,糖、聚乙二醇、聚乙烯吡咯烷酮、聚乙烯醇、聚醋酸乙烯酯、羟丙基纤维素、甲基纤维素、乙基纤维素、羟丙基甲基纤维素、羧丙基纤维素钠、肠溶包衣聚合物和其它的水溶性盐,独自或以混合形式使用。添加剂,例如,增塑剂、着色剂、颜料、填充剂反逆向和抗静电剂,例如,硬脂酸镁、二氧化钛、滑石并且其它添加剂还可包含于分离层中。
当将任选分离层涂覆至核心材料时,其可构成可变厚度。分离层的最大厚度通常仅受限于处理条件。分离层可充当扩散隔膜且可充当pH缓冲区。可选涂布的分离层对于本发明不是必不可少的。但是,分离层可提高活性物质的活血稳定性及/或新颖多元药片剂型的物理属性。
或者,可通过涂布于核心材料上的肠溶包衣聚合物层与核心材料中的碱性反应化合物之间的反应而原位形成分离层。因此,所形成的分离层包括在肠溶包衣层聚合物与在形成盐位置的碱性反应化合物之间形成的水溶性盐
一或多个肠溶包衣层通过合适的包衣技术涂布于核心材料上或覆盖有分离层的核心材料上。肠溶包衣层材料可在水中或合适有机溶剂中分解或溶解。作为肠溶包衣层聚合物,可单独或组合使用下列各者的一种或多种:例如,溶解或分散甲基丙烯酸共聚物、邻苯二甲酸乙酸纤维素、羟丙甲纤维素酞酸醋、醋酸羟丙基甲基纤维素琥珀酸酯、三苯六甲酸乙酸纤维素、羧甲基乙基纤维素、虫胶或其它合适肠溶包衣聚合物。
肠溶包衣层含有医药学上可接受增塑剂以获得所要机械属性,例如,肠溶包衣层的弹性和硬度。此类增塑剂为(例如)但不局限于三乙酸甘油酯、柠檬酸酯、邻苯二甲酸酯、癸二酸二丁酯、鲸蜡酯、聚乙二醇、聚山梨酯或其它增塑剂。
增塑剂的量针对每一肠溶包衣层配方,关于所选肠溶包衣层聚合物、所选增塑剂和所述聚合物的所施用量来优化,以此方式,机械属性(即,肠溶包衣层的弹性和硬度,例如,以Vickers硬度为例)经调整以使得当需要药片时,覆盖有肠溶包衣层的药丸的耐酸性在将药丸压缩成药片期间不明显降低。增塑剂的量通常高于肠溶包衣层聚合物的5重量%,例如,15至50重量%且进一步例如20至50重量%。还可将例如分散剂、着色剂、颜料聚合物(例如,聚(丙烯乙酯、甲基丙烯酸甲酯))、抗粘结和消泡剂的添加剂包含于肠溶包衣中。可添加其它化合物以增加膜厚度并降低酸性胃液扩散到酸敏感材料中。所涂布包衣层的最大厚度通常由加工条件及所要溶解特性限制。
外包衣层:
覆盖有肠溶包衣层的药丸可以任选地进一步覆盖有一个或多个外包衣层。外包衣层应为水溶性的或在水中迅速地崩解。可通过例如包衣锅、包衣制粒机的合适设备中或将水和/或有机溶剂使用于涂布或成层过程的流化床设备中的涂布或成层流程来将外包衣层涂于肠溶包衣。用于外包衣层的材料选自医药学上可接受化合物,例如,单独使用或以混合物形式使用的糖、聚乙二醇、聚乙烯吡咯烷酮、聚乙烯醇、聚乙酸乙烯酯、羟丙基纤维素、甲基纤维素、乙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠或其它。例如增塑剂、着色剂、色素、填料、防粘着剂或抗静电剂的添加剂,例如硬脂酸镁、二氧化钛、滑石粉及其它添加剂也可包含于外包衣层中。外包衣层可以进一步防止肠溶包衣状药丸的潜在团聚,另外其可以在压实过程期间防止肠溶包衣破裂并且促进压片过程。所涂外包衣层的最大厚度通常由加工条件及所需溶出特性限制。外包衣层还可以用作药片膜包衣层。
软胶胶囊的肠溶包衣可能含有乳液、油、微型乳液、自乳化系统、脂类、三酸甘油酯、聚乙二醇、表面活性剂、其它增溶剂或其类似者,其组合,从而增溶活化剂。软胶胶囊的可塑性由残余水及增塑剂维持。此外,对于胶囊,明胶可以溶入水中,使得喷雾必须在具有相对较低的相对湿度的速率下完成,例如可以在流化床或底喷流化床中完成。另外,应在不去除导致胶囊壳破裂的残余水或增塑剂的情况下完成干燥。经最优化用于例如InstamodelEPD(肠聚合物分散)的软胶胶囊的肠溶包衣的可商购共混物可从Ideal Cures有限公司购得。(印度,孟买)。在实验室规模上,肠溶胶囊可通过以下步骤制备:a)在烧瓶中旋转胶囊,或在最低可能温度下在经温和加热的肠溶包衣材料与增塑剂的溶液中浸渍胶囊或b)在实验室规模下的喷雾器/流化床中浸渍胶囊并且随后进行干燥。
对于水活化剂,可能尤其期望将药物加入乳液的水相中。这类“油包水”乳液为药物提供合适的生物物理环境,且可提供可以保护药物免受pH的不良影响的油水界面或可以降解药物的酶。此外,这类油包水制剂可以提供脂质层,所述脂质层可以顺利地与身体细胞中的脂类相互作用,并且可以增加细胞的细胞膜上的制剂的分区。此分区可增强在循环中的这类制剂中的药物的吸收,且因此可以提高药物的生物利用度。
在一些实施例中,油包水乳液含有由介质、长链羧酸或酯类过其醇组成的油相、表面活化剂或表面活化剂,及主要含有水及活化剂的水相。
介质和长链羧酸为具有多达三个不饱和键(也为分支链)的范围从C8至C22的那些。饱和直链酸的实例为正十二烷酸、正十四烷酸、正十六烷酸、己酸、辛酸、癸酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、花生酸、山嵛酸、褐煤酸及蜂花酸。还可以使用不饱和单烯直链单羧酸。这些的实例为油酸、鳕油酸及芥酸。还可以使用不饱和(多烯)直链单羧酸。这些的实例为亚油酸、蓖麻油酸、亚麻酸、花生四烯酸及二十二炔酸。有用的分支链酸包含(例如)二乙酰酒石酸。不饱和烯链还可经羧基化或经乙氧基化以防止氧化或改变表面性质。
长链羧酸酯的实例包含(但不限于)选自以下群组的那些:甘油单硬脂酸酯;甘油单棕榈酸酯;甘油单硬脂酸酯与甘油单棕榈酸酯的混合物;甘油单亚油酸酯;甘油单油酸酯;甘油单棕酸酯、甘油单硬脂酸酯、甘油单油酸酯及甘油单亚油酸酯的混合物、甘油单亚麻酸酯;甘油单鳕油酸酯;甘油单棕榈酸酯、甘油单硬脂酸酯、甘油单油酸酯、甘油单亚油酸酯、甘油单亚麻酸酯及甘油单鳕油酸酯的混合物;例如蒸馏得来的乙酰化单酸甘油酯的乙酰化甘油酯;丙二醇单酯、蒸馏得来的甘油单酯、硬脂酰乳酸钠及二氧化硅的混合物;d-α生育酚聚乙二醇1000琥珀酸酯;例如非离(Atmul)的甘油单酯及甘油二酯的混合物;硬脂酰乳酸钙;乙氧基化的甘油单酯及甘油二酯;乳酸化的甘油单酯及甘油二酯;甘油及丙二醇的乳酸羧酸酯;长链羧酸的乳酸酯;长链羧酸的聚甘油酯、长链羧酸的丙二醇单酯及二酯;硬脂酰乳酸钠;单硬脂酸山梨醇酐酯;单油酸山梨醇酐酯;长链羧酸的其它山梨糖醇酯;琥珀酸单甘酯;硬脂单甘柠檬酸酯;硬脂庚酸酯;鲸蜡酯;硬酯辛酸酯;C8-C30胆固醇/羊毛固醇酯;及蔗糖长链羧酸酯。自乳化长链羧酸酯的实例包含选自以下群组的那些:硬脂酸酯、棕榈酸酯、蓖麻醇酸酯、油酸酯、山嵛酸酯、蓖麻油酸酯、肉豆蔻酸酯、月桂酸酯、辛酸酯及己酸酯。在一些实施例中,油相可包括长链羧酸或酯类或其醇类中的两者或两者以上的组合。在一些实施例中,可使用介质链表面活性剂且油相可包括辛酸/癸酸甘油三酯与辛酸的C8/C10甘油单酯/甘油二酯的混合物、甘油辛酸酯或丙二醇单辛酸酯或其混合物。
可使用的醇类由上文例示的羧酸的羧基形式以及硬脂醇例示。
表面活化剂或表面活性剂为可以在亲水/疏水(水/油)界面处累积并且降低所述界面处的表面张力的长链分子。作为结果,其可使乳液稳定。在本发明的一些实施例中,表面活性剂可包括:表面活性剂的(聚氧乙烯山梨酸酯)家族;表面活性剂的(山梨聚糖长链羧酸酯)家族;表面活性剂的(环氧乙烷/环氧丙烷嵌段共聚物)家族;表面活性剂的及(聚乙二醇化甘油酯)家族;油酸酯、硬脂酸酯、月桂酸酯或其它长链羧酸的山梨糖醇酯;泊洛沙姆(聚乙-聚丙二醇嵌段共聚物或);其它山梨聚糖或蔗糖长链羧酸酯;甘油单酯及甘油二酯;辛酸/癸酸甘油三脂的PEG衍生物及其混合物,或以上各者中之两者或两者以上的混合物。在一些实施例中,表面活性剂相可包括聚氧乙烯(20)单油酸山梨糖醇酐酯(Tween)与单油酸山梨糖醇酐酯(Span)的混合物。
水相可任选地包括悬浮于水及缓冲液中的活化剂。
在一些实施例中,这类乳液为粗乳液、微乳液及液晶乳液。在其它实施例中,这类乳液可任选地包括渗透增强剂。在其它实施例中,可使用含有经封装微乳液、粗乳液或液晶乳液的喷雾干燥分散体或微粒或纳米粒。
在一些实施例中,本文中所描述的固体剂型为非肠道延时释放剂型。本文中所使用的术语“非肠道延时释放”指代使得可以在肠道中的某一通常可预测位置完成药物释放的递送,所述位置在当无延迟释放改变时将已完成药物释放的位置的较远端。在一些实施例中,用于延迟释放的方法为包衣变得可渗透、溶解、破裂,及/或在所设计时间之后不再完整。延时释放剂型中的包衣可具有在药物释放之前被侵蚀的固定时间(合适的包衣包含例如HPMC、PEO及其类似者的聚合包衣),或具有芯,所述芯由以下各者组成:超级崩解剂或渗透剂或水引诱剂,例如盐、亲水聚合物(典型地聚环氧乙烯或烷基纤维素),盐例如氯化钠、氯化镁、乙酸钠、柠檬酸钠;糖,例如葡萄糖、乳糖、或蔗糖,或其类似者,所述芯将水抽吸通过半透膜或气体生成剂,例如柠檬酸及有或没有例如柠檬酸或包括于剂型中的任一上述酸类的酸的碳酸氢钠。虽然半透膜多半不能渗透药物或者渗透剂,但其可渗透水,水以恒速渗透以进入剂型从而增加压力并且历时期望延迟时间在膨胀压力超过某一阈值后破裂。通过药物的此膜的渗透率应比水小1/10,并且在一个实施例中小于水渗透率的1/100。替代地,可通过历时期望延迟时间浸出可萃取的水使膜变得可渗透。
已在Theeuwes US 3,760,984中描述渗透剂型,且在Baker US 3,952,741中描述渗透破裂剂型。如果使用具有不同定时的不同装置,那么这种渗透破裂剂型可以提供释放的单脉冲或多脉冲。可以通过选择包围含有药物及渗透剂或引诱剂两者的芯的半透膜的聚合物及厚度或面积控制渗透破裂的定时。由于剂型中的压力随着额外渗透水增加,膜伸长直至其断裂点为止,且随后释放药物。替代地,可通过在膜中具有较薄、较弱区域或通过将较弱材料添加到包衣膜的区域中而在膜中产生特定破裂区域。具有高水渗透率的可用作半透膜的一些优选聚合物为乙酸纤维素、乙酸丁酸纤维素、硝酸纤维素、交联聚乙烯、乙醇、聚氨酯、尼龙6、尼龙6.6及芳香尼龙。乙酸纤维素是尤其优选聚合物。
在另一实施例中,在肠溶包衣至少部分地溶解后开始此延迟以释放药物的延时包衣由一旦与水接触就随时间流逝开始逐渐被侵蚀的亲水性、易蚀聚合物组成。这类聚合物的实例包含纤维素聚合物及其衍生物,包含(但不限于):羟烃基纤维素;羟甲基纤维素;羟乙基纤维素;羟丙基纤维素;羟丙基甲基纤维素;羧甲基纤维素;微晶纤维素;多糖及其衍生物;聚环氧烷,例如聚环氧乙烷或聚乙烯二醇,尤其高分子量聚乙烯二醇;聚(乙烯醇);黄原胶;马来酸酐共聚物;聚(乙烯基吡咯烷酮);淀粉及淀粉基聚合物;麦芽糖糊精;聚(2-乙基-2-唑啉);聚(乙撑亚胺);聚氨酯;水凝胶;交联聚丙烯酸;及任何上述者的组合或共混物。
使用于形成易蚀包衣的一些优选易蚀亲水聚合物为聚(环氧乙烷)、羟丙基甲基纤维素、及聚(环氧乙烷)与羟丙基甲基纤维素的组合。聚(环氧乙烷)在本文中用于指代非取代环氧乙烷的线性聚合物。聚(环氧乙烷)聚合物的分子量的范围可从约105道尔顿到约107道尔顿。聚(环氧乙烷)聚合物的优选分子量范围是从约2乘105道尔顿到约2乘106道尔顿,且所述聚合物可从的陶氏化学公司(Dow Chemical Company)(Midland,Mich.)商购,被称作SENTRYR POLYOXTM水溶性树脂,NF(国家药典)品级。当使用聚环氧乙烷的较高分子量时,还包含促进此包衣的侵蚀或崩解的其它亲水剂(例如盐或糖(如葡萄糖、蔗糖或乳糖))。
制剂中公开的化合物的量可在由本领域技术人员采用的全范围内变化。通常,基于重量百分比(wt%),制剂基于总制剂将含有式(I)化合物的约0.01wt%到99.99wt%,其中剩余部分为一种或多种合适的药用辅料。在一个实施例中,化合物呈现约1wt%到80wt%的水平。
本发明的化合物可与疾病治疗或本发明的化合物或其它药物可具有实用性的条件中的一种或多种药物组合使用,其中药物组合到一起比单独使用药物更安全或更有效。可通过途径及以因此常用的量同时或连续地管理这类其它药物及本发明的化合物。当本发明的化合物与一种或多种其它药物同时使用时,含有这类其它药物及本发明的化合物的单位剂型中的药用组合物为优选的。然而,组合疗法还可包含其中本发明的化合物及一种或多种其它药物以不同的重叠时间表被管理的疗法。还预期的是,当与一种或多种活性成分组合使用时,本发明的化合物及其它活性成分可以比各自单独使用时更少的剂量使用。
因此,除本发明的化合物之外,本发明的药用组合物还包含含有一种或多种其它活性成分的那些。
上述组合不仅包含本发明的化合物与一种其它活性化合物的组合,而且包含与两种或两种以上其它活性化合物的组合。同样地,本发明的化合物可与用于预防、治疗、控制、改善或降低疾病风险或本发明的化合物适用的条件的其它药物组合使用。可通过途径及以因此常用的量同时或连续地管理这类其它药物及本发明的化合物。当本发明的化合物与一种或多种其它药物同时使用时,除本发明的化合物外还含有这类其它药物的药用组合物(例如固定组合药物产品)为优选的。因此,除本发明的化合物之外,本发明的药用组合物还包含也含有一种或多种其它活性成分的那些。本发明的化合物与第二活性成分的重量比可为不同的且将取决于每一成分的有效剂量。一般来说,将使用每一者的有效剂量。
在受试者遭受或处于遭受自身免疫性疾病、炎性疾病或过敏性疾病的风险中的情况下,式(I)化合物及/或其医药学上可接受盐可与以下治疗剂中的一者或多种以任意组合的方式一起使用:免疫抑制剂(例如,他克莫司、环孢菌素、雷帕霉素、甲胺喋呤、环磷酰胺、咪唑硫嘌呤、巯基嘌呤、霉酚酸酯或FTY720);糖皮质激素(例如,强的松、乙酸可的松、强的松龙、甲基强的松龙、地塞米松、倍他米松、去炎松、倍氯米松、乙酸氟氢可的松、乙酸脱氧皮质酮、醛固酮);非甾体抗炎药(例如,水杨酸盐、芳基链烷酸、2-芳基丙酸、N-芳基邻氨基苯甲酸、昔康类、昔布类或磺苯胺);Cox-2-特异性抑制剂(例如,伐地考昔、塞来考昔或罗非考昔);来氟米特;硫代葡萄糖金;硫代苹果酸金;奥罗分(aurofin);柳氮磺胺吡啶;羟氯喹(hydroxychloroquinine);米诺环素;TNF-α结合蛋白(例如,英利昔单抗、依那西普或阿达木单抗);阿巴西普;阿那白滞素;干扰素-β;干扰素-γ;白介素-2;变态反应疫苗;抗组胺剂;抗白三烯;β-激动剂;茶碱或抗胆碱能药。
在受试者遭受或处于遭受B细胞增殖性病症(例如,浆细胞骨髓瘤)的风险中时,可以用与一种或多种其它抗癌剂任意组合的式(I)化合物及/或其医药学上可接受盐来治疗受试者。在一些实施例中,一种或多种其它抗癌剂为凋亡诱导剂。抗癌剂的实例包含(但不限于)任一以下各者:棉酚、反义寡核苷酸、多酚E、氯融合素(Chlorofusin)、全反式视黄酸(ATRA)、苔藓抑素、肿瘤坏死因子相关的凋亡诱导配体(TRAIL)、5-氮杂-2'-脱氧胞苷、全反式视黄酸、阿霉素、长春新碱、依托泊苷、吉西他滨、伊马替尼(GleevecTM)、格尔德霉素、17-N-烯丙基氨基-17-脱甲氧基格尔德霉素(17-AAG)、黄酮吡醇、LY294002、硼替佐米、曲妥单抗、BAY 11-7082、PKC412或PD184352、TaxolTM(还被称作“紫杉醇”),其为通过增强及稳定微管形成起作用的著名抗癌药物,及TaxolTM的类似物,例如TaxotereTM。具有基本紫杉烷骨架作为共有结构特征的化合物已经展示能够通过稳定微管从而抑制G2-M期的细胞,并且可用于与本文中所描述的化合物组合以治疗癌症。
与式(I)化合物及/或其医药学上可接受盐结合以供使用的抗癌剂的其他实例包含丝裂原活化蛋白激酶信号的抑制剂(例如,U0126、PD98059、PD184352、PD0325901、ARRY-142886,SB239063、SP600125、BAY 43-9006、渥曼青霉素或LY294002);Syk抑制剂;mTOR抑制剂;及抗体(例如,美罗华)。
可与式(I)化合物及/或其医药学上可接受盐组合使用的其它抗癌剂包含:阿霉素;更生霉素;博来霉素;长春花碱;顺铂;阿西维辛;阿克拉霉素;盐酸阿考达唑;阿克罗宁;阿多来新;阿地白介素;六甲蜜胺;二霉素;乙酸阿美蒽醌;氨鲁米特;安吖啶;阿那曲唑;氨茴霉素;天门冬酰胺酶;曲林菌素;阿扎胞苷;阿扎替派;阿佐霉素;巴马司他;苯佐替派;比卡鲁胺;盐酸比生群;二甲磺酸双奈法德;比折来新;硫酸博来霉素;布喹那钠;溴匹立明;白消安;放线菌素C;二甲睾酮;卡醋胺;卡贝替姆;卡铂;卡莫司汀;盐酸卡柔红霉素;卡折来新;西地芬戈;苯丁酸氮芥;西罗里霉素;克拉屈滨;甲磺酸克立那托;环磷酰胺;阿糖胞苷;达卡巴嗪;盐酸柔红霉素;地西他滨;右奥马铂;地扎胍宁;甲磺酸地扎胍宁;地吖醌;阿霉素;盐酸阿霉素;屈洛昔芬;枸橼酸屈洛昔芬;丙酸屈膜斯酮;达佐霉素;依达曲沙;盐酸依氟鸟氨酸;依沙芦星;恩洛铂;恩普氨酯;依匹哌啶;盐酸表阿霉素;厄布洛唑;盐酸依索比星;雌莫司汀;雌莫司汀磷酸钠;依他硝唑;依托泊苷;磷酸依托泊苷;氯苯乙嘧胺(etoprine);盐酸法屈唑;法扎拉滨;芬维A胺;氟尿苷;磷酸氟达拉滨;氟尿嘧啶;氟西他滨;磷喹酮;福司曲星钠;吉西他滨;盐酸吉西他滨;羟基脲;盐酸伊达比星;异环磷酰胺;伊莫福新;第二型介白素(包含重组白介素II或rIL2);干扰素α-2a;干扰素α-2b;干扰素α-n1;干扰素α-n3;干扰素β-1a;干扰素γ-1b;异丙铂;盐酸伊立替康;乙酸兰瑞肽;来曲唑;乙酸亮丙瑞林;盐酸利阿唑;洛美曲索钠;洛莫司汀;盐酸洛索蒽醌;马索丙考;美登素;盐酸氮芥;乙酸甲地孕酮;乙酸美仑孕酮;苯丙氨酸氮芥;美诺立尔;巯基嘌呤;甲氨喋呤;甲氨喋呤钠;氯苯氨啶;美妥替哌;米丁度胺;米托克星;丝裂红素;米托洁林;丝裂马菌素;丝裂霉素;米托司培;米托坦;盐酸米托蒽醌;麦考酚酸;诺考达唑;诺加霉素;奥马铂;奥昔舒仑;培门冬酶;佩里霉素;奈莫司汀;硫酸匹来霉素;培磷酰胺;溴丙哌嗪;哌泊舒凡;罗蒽醌;普卡霉素;普洛美坦;卟吩姆钠;甲基丝裂霉素;泼尼莫司汀;盐酸甲基苄肼;嘌呤霉素;盐酸嘌呤霉素;吡唑呋喃菌素;利波腺苷;洛太米特;沙芬戈;盐酸沙芬戈;司莫司汀;辛曲秦;磷乙酰天冬氨酸钠;稀疏霉素;盐酸螺旋锗;螺莫司汀;螺铂;链黑菌素;链脲霉素;磺氯苯脲;他利霉素;替可加兰钠;替加氟;盐酸替洛蒽醌;替莫泊芬;替尼泊苷;替罗昔隆;睾丸内脂;硫咪嘌呤;硫代鸟嘌呤;塞替派;噻唑呋林;替拉扎明;柠檬酸托瑞米芬;乙酸曲托龙;曲西立滨磷酸酯;三甲曲沙;葡糖醛酸三甲曲沙;曲普瑞林;盐酸妥布氯唑;乌拉莫司汀;乌瑞替派;伐普肽;维替泊芬;硫酸长春碱;硫酸长春新碱;长春地辛;硫酸长春地辛;硫酸长春匹定;硫酸长春甘酯;硫酸环氧长春碱;酒石酸长春瑞滨;硫酸长春罗定;硫酸长春氮芥;伏氯唑;折尼铂;净司他丁;盐酸佐柔比星。
可与式(I)化合物及/或其医药学上可接受盐组合使用的其它抗癌剂包含:20-epi-1,25二羟维生维D3;5-乙炔基尿嘧啶;阿比特龙;阿柔比星;酰基富烯;腺环戊醇;阿多来新;阿地白介素;ALL-TK拮抗剂;六甲蜜胺;氨莫司汀;二氯苯氧乙酸;氨磷汀;氨基乙酰丙酸;氨柔比星;安吖啶;阿那格雷;阿那曲唑;穿心莲内酯;血管生成抑制剂;拮抗剂D;拮抗剂G;安雷利克斯(antarelix);抗背部化形态发生蛋白-1;抗雄激素;前列腺癌;抗雌激素;抗瘤酮;反义寡核苷酸;甘氨酸阿非科林;细胞凋亡基因调节剂;细胞凋亡调节剂;脱嘌呤核酸;ara-CDP-DL-PTBA;精氨酸脱氨酶;asulacrine;阿他美坦;阿莫司汀;axinastatin 1;axinastatin 2;axinastatin 3;阿扎司琼;阿扎霉素;重氮酪氨酸;浆果赤霉素III衍生物;balanol;巴马司他;BCR/ABL拮抗剂;苯并二氢卟吩;苯甲酰基星状孢子素;β内酰胺衍生物;β-alethine;β-clamycin B;桦木酸;bFGF抑制剂;比卡鲁胺;比生群;双氮丙唳基精胺;双奈法德;bistratene A;比折来新;breflate;溴匹立明;布镀钛;丁硫氨酸硫酸亚胺;卡泊三醇;钙磷酸蛋白C;喜树碱衍生物;金丝雀痘IL-2;卡培他滨;甲酰胺-氨基-三唑;羧胺三唑;CaRest M3;CARN 700;源自软骨的抑制剂;卡折来新;酪蛋白激酶抑制剂(ICOS);栗树精胺;天蚕抗菌肽B;西曲瑞克;二氢卟酚(chlorlns);氯喹喔啉磺胺药物;西卡前列素;顺式卜啉;克拉屈滨;氯米芬类似物;克霉唑;collismycin A;collismycin B;考布他汀A4;考布他汀类似物;conagenin;crambescidin 816;克立那托;自念珠藻环肽8;自念珠藻环肽A衍生物;curacin A;环戍烯蒽醌;cycloplatam;cypemycin;阿糖胞苷烷磷酯;细胞溶解因子;磷酸己烷雌酚;达昔单抗;地西他滨;脱氢膜海鞘素B;地洛瑞林;地塞米松;右异环磷酰胺;右雷佐生;右维拉帕米;地吖醌;膜海鞘素B;didox;二乙基去甲精胺;二氢-5-氮杂胞苷;9-二氧霉素;二苯基螺莫司汀;二十二烷醇;多拉司琼;去氧氟尿苷;屈洛昔芬;屈大麻酚;多卡霉素SA;依布硒;依考莫司汀;依地福新;依决洛单抗;依氟鸟氨酸;榄香烯;乙嘧替氟;表柔比星;依立雄胺;雌莫司汀类似物;雌激素激动剂;雌激素拮抗剂;依他硝唑;磷酸依托泊苷;依西美坦;法倔唑;法扎拉滨;芬维A胺;非格司亭;非那雄胺(fmasteride);夫拉平度;氟卓斯汀;fluasterone;氟达拉滨;盐酸氟代柔红霉素;福酚美克;福美司坦;福司曲星;福莫司汀;德卟啉钆(gadolinium texaphyrin);硝酸镓;加洛他滨;加尼瑞克;明胶酶抑制剂;吉西他滨;谷胱甘肽抑制剂;hepsulfam;调蛋白;六亚甲基二乙酰胺;金丝桃素;伊班膦酸;伊达比星;艾多昔芬;伊决孟酮;伊莫福新;伊洛马司他;咪唑并吖啶酮;咪喹莫特;免疫刺激肽;胰岛素如生长因子-1受体抑制剂;干扰素激动剂;干扰素;白介素;碘苄胍;碘阿霉素;4-甘薯苦醇;伊罗普拉;伊索拉定;isobengazole;isohomohalicondrin B;伊他司琼;jasplakinolide;kahalalide F;片螺素-N三乙酸盐;兰瑞肽;leinamycin;来格司亭;香菇多糖硫酸酯;leptolstatin;来曲唑;白血病抑制因子;白细胞α干扰素;亮丙瑞林+雌激素+黄体酮;亮丙瑞林;左旋咪唑;利阿唑;线性多胺类似物;亲脂性二糖肽;亲脂性铂化合物;lissoclinamide 7;洛铂;蚯蚓磷脂;洛美曲索;氯尼达明;洛索蒽醌;洛伐他汀;洛索立宾;勒托替康;德B卜啉镥(lutetium texaphyrin);lysofylline;溶解肽;美坦辛;制甘糖酶素A(mannostatin A);马立马司他;马索罗酚;乳腺丝抑蛋白;基质溶解因子抑制剂;基质金属蛋白酶抑制剂;美诺立尔;美巴龙;美替瑞林;甲硫氨酸酶;甲氧氯普胺;MIF抑制剂;米非司酮;米替福新;米立司亭;错配的双链RNA;米托胍腙;二溴卫矛醇;丝裂霉素类似物;米托萘胺;迈托毒素成纤维细胞生长因子-皂草素;米托蒽醌;莫法罗汀;莫拉司亭;单克隆抗体;人绒毛膜促性腺激素;单磷酰脂质A+分枝杆菌细胞壁sk;莫哌达醇;多药耐药性基因抑制剂;基于多肿瘤抑制基因1的治疗;氮芥抗癌剂;印度洋海绵B(mycaperoxide B);分枝杆菌细胞壁萃取物;myriaporone;N-乙酰基地那林;N-取代的苯甲酰胺;那法瑞林;nagrestip;纳洛酮+喷他佐辛;napavin;naphterpin;那托司亭;奈达铂;奈莫柔比星;奈立膦酸;中性内肽酶;尼鲁米特;nisamycin;一氧化氮调节剂;硝基氧抗氧化剂;nitrullyn;O6-苄基鸟嘌呤;奥曲肽;okicenone;寡核苷酸;奥那司酮;昂丹司琼;昂丹司琼;oracin;口服细胞因子诱导剂;奥马铂;奥沙特隆;奥沙利铂;oxaunomycin;帕劳胺(palauamine);棕榈酰根霉素;帕米膦酸;人参三醇;帕诺米芬;副细菌素(parabactin);帕折普汀;培门冬酶;培得星;戊聚硫钠;喷司他汀;pentrozole;全氟溴烷;培磷酰胺;紫苏醇;苯连氮霉素(phenazinomycin);乙酸苯酯;磷酸酶抑制剂;毕西巴尼;盐酸毛果芸香碱;吡柔比星;吡曲克辛;placetin A;placetin B;纤溶酶原激活物抑制剂、铂络合物;铂化合物;铂-三胺络合物;叶吩姆钠;泊非霉素;强的松;丙基二-吖啶酮;前列腺素J2;蛋白酶体抑制剂;基于蛋白A的免疫调节剂;蛋白激酶C抑制剂;蛋白激酶C抑制剂;微藻;蛋白酪氨酸磷酸酶抑制剂;嘌呤核苷磷酸化酶抑制剂;红紫素;吡唑啉吖啶;吡醇羟乙酯血红蛋白聚氧化乙烯共轭物;raf拮抗剂;雷替曲塞;雷莫司琼;ras法尼基蛋白转移酶抑制剂;ras抑制剂;ras-GAP抑制剂;脱甲基瑞替普汀;依替膦酸铼Re186;根霉素;核酶;R.sub.11视黄酰胺;罗谷亚胺;罗希吐碱;罗莫肽;罗喹美克;rubiginone B1;ruboxyl;沙芬戈;saintopin;SarCNU;肌植醇A(sarcophytol A);沙格司亭;Sdi 1模拟物;司莫司汀;衰老衍生的1;有义寡核苷酸;信号转导调节剂;信号转导调节剂;单链抗原结合蛋白;西佐喃;索布佐生;硼卡钠;苯基乙酸钠;solverol;生长调节素结合蛋白;索纳明;膦门冬酸;螺旋霉素D(spicamycin D);螺莫司汀;斯耐潘定;海绵素1(spongistatin 1);角鲨胺;干细胞抑制剂;干细胞分裂抑制剂;stipiamide;溶基质素抑制剂;sulf inosine;超活性血管活性肠肽拮抗剂;suradista;苏拉明;苦马豆素;合成多糖;他莫司汀;它莫西芬甲碘化物;牛磺莫司汀;他扎罗汀;替可加兰钠;替加氟;tellurapyrylium;端粒酶抑制剂;替莫泊芬;替莫唑胺;替尼泊苷;四氯癸烷氧化物;tetrazomine;菌体胚素;噻可拉林;血小板生成素;血小板生成素模拟物;胸腺法新;促胸腺生成素受体激动剂;胸腺曲南;促甲状腺激素;乙基本紫红素锡(tin ethyletiopurpurin);替拉扎明;二茂钛二氯化物;topsentin;托瑞米芬;全能干细胞因子;翻译抑制剂;维A酸;三乙酰基尿苷;曲西立滨;三甲曲沙;曲普瑞林;托烷司琼;妥罗雄脲;酪氨酸激酶抑制剂;酪氨酸磷酸化抑制剂;UBC抑制剂;乌苯美司;泌尿生殖窦来源的生长抑制因子;尿激酶受体拮抗剂;伐普肽;variolin B;载体系统;红细胞基因治疗;维拉雷琐;藜芦明;维尔丁(verdins);维替泊芬;长春瑞滨;vinxaltine;vitaxin;伏氯唑;扎诺特隆;折尼铂;亚苄维C(2H)(zilascorb);及净司他丁斯酯。
可与式(I)化合物及/或其医药学上可接受盐组合使用的其它抗癌剂包含烷化剂;抗代谢物;天然产物;或激素,例如氮芥类(例如,氮芥、环磷酰胺、苯丁酸氮芥等);烷基磺酸盐(例如,白消安);亚硝基脲(例如,卡莫司汀、环己亚硝脲等);或三氮烯(氨烯咪胺等)。抗代谢物的实例包含但不限于叶酸类似物(例如,甲胺喋呤)、或嘧啶类似物(例如,阿糖胞苷)、嘌呤类似物(例如,巯嘌呤、巯鸟嘌呤、喷司他汀)。
与式(I)化合物及/或其医药学上可接受盐组合使用的天然产物的实例包含但不限于长春花生物碱类(例如,长春碱、长春新碱)、鬼臼素(例如,依托泊苷)、抗生素(例如,柔红霉素、阿霉素、博来霉素)、酶素(例如,左旋天冬醋胺酸酶),或生物反应调节剂(例如,干扰素α)。
可与式(I)化合物及/或其医药学上可接受盐组合使用的烷化剂的实例包含(但不限于):氮芥类(例如,氮芥、环磷酰胺、苯丁酸氮芥、苯丙氨酸氮芥等)、乙烯亚胺及甲基蜜胺(例如,六甲蜜胺、塞替派)、烷基磺酸盐(例如,白消安)、亚硝基脲(例如,卡莫司汀、环己亚硝脲、司莫司汀、链脲霉素等),或三氮烯(氨烯咪胺等)。抗代谢物的实例包含(但不限于)叶酸类似物(例如,甲胺喋呤)、或嘧啶类似物(例如,氟尿嘧啶、氟尿苷、阿糖胞苷)、嘌呤类似物(例如,巯嘌呤、巯鸟嘌呤、喷司他汀)。
与式(I)化合物及/或其医药学上可接受盐组合使用的激素及对抗剂的实例包含(但不限于):肾上腺皮质类固醇(例如,强的松)、孕激素(例如,己酸孕酮、甲地孕酮、乙酸甲羟孕酮)、雌激素(例如,二乙基己烯雌酚、乙炔雌二醇)、抗雌激素(例如,它莫西芬)、雄激素(例如,丙酸睾酮、氟甲睾酮)、抗雄激素(例如,氟他胺)、促性腺激素释放激素类似物(例如,亮丙瑞林)。可在本文中所描述的用于治疗和预防癌症的方法和组合物中使用的其它试剂包含铂类化合物(例如,顺铂、卡铂)、蒽二酮(例如,米托蒽醌)、取代脲(例如,羟基脲)、甲肼衍生物(例如,甲基苄肼)、肾上腺皮质遏抑剂(例如,米托坦、氨鲁米特)。
通过稳定微管从而抑制G2-M期的细胞且可与本发明的BTK抑制剂化合物组合使用的抗癌剂的实例包含但不限于以下上市药物及开发中药物:厄布洛唑(也称为R-55104);多拉司他汀10(也称为DLS-10和NSC-376128);羟乙基磺酸米伏布林(也称为CI-980);长春新碱;NSC-639829;圆皮海绵内酯(也称为NVP-XX-A-296);ABT-751(Abbott,也称为E-7010);阿托海汀(Altorhyrtins)(例如阿托海汀A和阿托海汀C);海绵素(例如海绵素1、海绵素2、海绵素3、海绵素4、海绵素5、海绵素6、海绵素7、海绵素8和海绵素9);盐酸西马多丁(也称为LU-103793和NSC-D-669356);埃博霉素类(例如埃博霉素A、埃博霉素B、埃博霉素C(也称为脱氧埃博霉素A或dEpoA)、埃博霉素D(也称为KOS-862、dEpoB和脱氧埃博霉素B)、埃博霉素E、埃博霉素F、埃博霉素B N-氧化物、埃博霉素A N-氧化物、16-氮杂-埃博霉素B、21-氨基埃博霉素B(也称为BMS-310705)、21-羟基埃博霉素D(也称为脱氧埃博霉素F和dEpoF)、26-氟代埃博霉素);澳瑞斯他汀PE(也称为NSC-654663);索利多丁(也称为TZT-1027);LS-4559-P(法玛西亚(Pharmacia),也称为LS-4577);LS-4578(法玛西亚,也称为LS-477-P);LS-4477(法玛西亚);LS-4559(法玛西亚);RPR-112378(安内特(Aventis));硫酸长春新碱;DZ-3358(Daiichi);FR-182877(藤泽(Fujisawa);也称为WS-9885B);GS-164(武田制药(Takeda));GS-198(武田制药);KAR-2(匈牙利科学院);BSF-223651(BASF,也称为ILX-651和LU-223651);SAH-49960(Lilly/Novartis);SDZ-268970(Lilly/Novartis);AM-97(Armad/Kyowa Hakko);AM-132(Armad);AM-138(Armad/Kyowa Hakko);IDN-5005(Indena);Cryptophycin 52(也称为LY-355703);AC-7739(味之素(Ajinomoto),也称为AVE-8063A和CS-39.HCI);AC-7700(味之素,也称为AVE-8062、AVE-8062A、CS-39-L-Ser.HCI和RPR-258062A);Vitilevuamide;TubulysinA;Canadensol;矢车菊黄素(也称为NSC-106969);T-138067(Tularik,也称为T-67、TL-138067和TI-138067);COBRA-1(休斯研究院(ParkerHughes Institute),也称为DDE-261和WHI-261)、H10(堪萨斯州立大学(KansasStateUniversity));H16(堪萨斯州立大学);Oncocidin A1(也称为BTO-956和DIME);DDE-313(休斯研究院);Fijianolide B;Laulimalide;SPA-2(休斯研究院);SPA-1(休斯研究院,也称为SPIKET-P);3-IAABU(Cytoskeleton/Mt.西奈山医学院(Sinai School ofMedicine),也称为MF-569);那可丁(也称为NSC-5366);Nascapine;D-24851(AstaMedica);A-105972(雅培(Abbott));Hemiasterlin;3-BAABU(Cytoskeleton/Mt.西奈山医学院,也称为MF-191);TMPN(亚利桑那州立大学(ArizonaState University));乙酸丙酮双钒;T-138026(Tularik);Monsatrol、lnanocine(也称为NSC-698666);3-1AABE(CytoskeIeton/西奈山医学院);A-204197(雅培);T-607(Tuiarik,也称为T-900607);RPR-115781(安内特);软珊瑚醇(例如去甲软珊瑚醇、去乙酰软珊瑚醇、异软珊瑚醇A和Z-软珊瑚醇);Caribaeoside;Caribaeolin;软海绵素B;D-64131(Asta Medica);D-68144(AstaMedica);含氯环肽(Diazonamide)A;A-293620(雅培);NPI-2350(Nereus);根薯酮内酯A;TUB-245(安内特);A-259754(雅培);Diozostatin;(-)-Phenylahistin(也称为NSCL-96F037);D-68838(Asta Medica);D-68836(Asta Medica);肌基质蛋白(Myoseverin)B;D-43411(Zentaris,也称为D-81862);A-289099(雅培);A-318315(雅培);HTI-286(也称为SPA-110,三氟乙酸盐)(惠氏公司(Wyeth));D-82317(Zentaris);D-82318(Zentaris);SC-12983(NCI);力司弗拉司达汀(Resverastatin)磷酸钠;BPR-OY-007(国家卫生研究院(National Health Research Institutes))和SSR-250411(赛诺菲(Sanofi))。
在受试者正遭受或处于遭受血栓栓塞性疾病(例如,中风)的风险中的情况下,可以用与一种或多种其它抗血栓栓塞药剂任意组合的式(I)化合物治疗受试者。抗血栓栓塞药剂的实例包含(但不限于)以下任一者:血栓溶解剂(例如,阿替普酶阿尼普酶、链激酶、尿激酶或组织纤溶酶原激活物);肝素;亭扎肝素;华法林;达比加群(例如,达比加群酯);Xa因子抑制剂(例如,磺达肝素、依达肝素(draparinux)、利伐沙班、DX-9065a、奥米沙班、LY517717或YM150);噻氯匹定;氯吡格雷;CS-747(普拉格雷、LY640315);希美加群或BIBR1048。
实例
给出式(I)化合物及中间物(参考物)的下列制备以使得本领域技术人员能够更清楚地了解并实践本发明。其不应被视为是对本发明的范围的限制,而仅为对本发明的说明及表示。下文化合物中的烯烃碳处的线指示分离出的化合物为(E)和(Z)异构体的未定义混合物。
参考1
叔丁基(R,E)-3-(4-(((二甲氨基)亚甲基)氨基)-2-氧代-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羧酸酯的合成
步骤1
向100mL圆底烧瓶中置入2,4-二氯-3-硝基吡啶(8g,41.45mmol,1.00当量)、N,N-二甲基甲酰胺(50mL)、叔丁基(R)-3-氨基哌啶-1-羧酸酯(8.3g,41.44mmol,1.00当量)和TEA(6.29g,62.16mmol,1.50当量)。将所得溶液在25℃下搅拌过夜。将所得溶液用H2O稀释,用乙酸乙酯萃取,并且合并有机层。将所得混合物用饱和氯化钠洗涤,并用无水硫酸钠进行干燥并浓缩。将残留物涂覆至硅胶柱上并用乙酸乙酯/石油醚(1:1)洗脱,得到8g(51%)呈黄色油状的叔丁基(R)-3-((2-氯-3-硝基吡啶-4-基)氨基)哌啶-1-羧酸酯。
步骤2
向250mL圆底烧瓶中置入叔丁基(R)-3-((2-氯代-3-硝基吡啶-4-基)氨基)哌啶-1-羧酸酯(8g,22.42mmol,1.00当量)、异丙醇(100mL)、双[(4-甲氧苯基)甲基]胺(5.78g,22.46mmol,1.00当量)和TEA(2.955g,29.20mmol,1.30当量)。将所得溶液在95℃下搅拌过夜。使反应混合物冷却并在真空下浓缩。这产生12g(92%)呈黄色油状的叔丁基(R)-3-((2-(双(4-甲氧苄基)氨基)-3-硝基吡啶-4-基)氨基)哌啶-1-羧酸酯。
步骤3
向250mL圆底烧瓶中置入叔丁基(R)-3-((2-(双(4-甲氧苄基)氨基)-3-硝基吡啶-4-基)氨基)哌啶-1-羧酸酯(10g,17.31mmol,1.00当量)、AcOH/MeOH(1:1,100mL)和Fe(9.69g,173.04mmol,10.00当量)。将所得溶液在25℃下搅拌过夜并随后在真空下浓缩。用碳酸氢钠将溶液的pH值调节到8.0至9.0。用二氯甲烷萃取所得溶液,且用碳酸氢钠洗涤有机层,用无水硫酸钠进行过滤并干燥,随后在真空下浓缩,得到8.8g(92.8%)呈黄色油状的叔丁基(R)-3-((3-氨基-2-(双(4-甲氧苄基)-氨基)吡啶-4-基)氨基)哌啶-1-羧酸酯。
步骤4
向250mL圆底烧瓶中置入叔丁基(R)-3-((3-氨基-2-(双(4-甲氧基-苄基)氨基)吡啶-4-基)氨基)哌啶-1-羧酸酯(12g,19.72mmol,1.00当量,90%)、CH3CN(100mL)和CDI(5.336g,32.91mmol,1.50当量)。将所得溶液在80℃下搅拌过夜。冷却并浓缩反应混合物。将残留物涂覆至硅胶柱上,并用乙酸乙酯/石油醚(1:5)洗脱,得到11g(89%)呈黄色固体油状的叔丁基(R)-3-(4-[双[(4-甲氧基-苯基)甲基]-氨基]-2-氧代-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羧酸酯。
步骤5
向50mL圆底烧瓶中置入叔丁基(R)-3-(4-[双[(4-甲氧苯基)-甲基]-氨基]-2-氧代-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羧酸酯(1.5g,2.61mmol,1.00当量)、二氯甲烷(30mL)和三氟乙酸(30mL)。将所得溶液在50℃下搅拌4小时。用碳酸氢钠将溶液的pH值调节到9。用二氯甲烷萃取所得溶液,并且合并有机层并用无水硫酸钠进行干燥。在真空下浓缩所得混合物,得到0.45g(73.7%)呈淡黄色固体的(R)-4-氨基-1-(哌啶-3-基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮。
步骤6
向100mL圆底烧瓶中置入(R)-4-氨基-1-(哌啶-3-基)-1,3-二氢-2H-咪唑并[4,5-c]吡啶-2-酮(1g,4.29mmol,1.00当量)、1,4-二烷/H2O(1:1,50mL)、Boc2O(1.03g,4.72mmol,1.03当量)和碳酸钠(1.5g,14.15mmol,1.50当量)。将所得溶液搅拌在25℃下搅拌1小时,随后用二氯甲烷萃取,并且合并有机层。用水和饱和氯化钠洗涤所得有机层,并且随后在真空下浓缩。将残留物涂覆至硅胶柱上并用二氯甲烷/甲醇(30:1)洗脱,得到1.2g(84%)呈淡黄色固体的叔丁基(R)-3-(4-氨基-2-氧代-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-yl)哌啶-1-羧酸酯。
步骤7
向100mL圆底烧瓶中置入叔丁基(R)-3-(4-氨基-2-氧代-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羧酸酯(6.5g,19.50mmol,1.00当量)和DMF-DMA(50mL)。将所得溶液在40℃下搅拌1小时并随后在真空下浓缩。随后用CH2Cl2溶解所得混合物并用盐水洗涤。合并有机层且在真空下浓缩,并用己烷洗涤。通过过滤收集固体,得到5.0289g(66%)呈固体的叔丁基(R,E)-3-(4-(((二甲氨基)亚甲基)氨基)-2-氧代-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羧酸酯。
LC-MS m/z:389.2(M+1)
参考2
4-氨基-3-(4-苯氧苯基)-1-[(3R)-哌啶-3-基]-1H,2H,3H-咪唑并[4,5-c]吡啶-2-酮的合成
步骤1
向250mL圆底烧瓶中置入叔丁基(R)-3-(4-[双[(4-甲氧苯基)-甲基]-氨基]-2-氧代-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羧酸酯(10g,17.43mmol,1.00当量)、二氯甲烷(100mL)、(4-苯氧苯基)硼酸(7.5g,35.04mmol,2.00当量)、TEMPO(3g,19.20mmol,1.10当量)、和TEA(7g,69.18mmol,4.00当量)、Cu(OAc)2(1.6g,8.81mmol,0.50当量)。在氧气氛围环境压力下将所得溶液在25℃下搅拌过夜。添加(4-苯氧苯基)硼酸(7.5g,35.04mmol,2.00当量),并且使所得溶液在25℃下反应过夜。将残留物涂覆至硅胶柱上,并用乙酸乙酯/石油醚(1:3)洗脱,得到1.5g(12%)呈黄色固体的叔丁基(R)-3-(4-[双[(4-甲氧苯基)甲基]氨基]-2-氧代-3-(4-苯氧苯基)-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羧酸酯。
步骤6
向250mL圆底烧瓶中置入叔丁基(R)-3-(4-[双[(4-甲氧苯基)-甲基]氨基]-2-氧代-3-(4-苯氧苯基)-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羧酸酯(5g,6.07mmol,1.00当量,90%)、二氯甲烷(80mL)和三氟乙酸(80mL)。将所得溶液在50℃下搅拌5小时。在真空下浓缩所得混合物。用碳酸氢钠将溶液的pH值调节到9。用二氯甲烷萃取所得溶液,并且合并有机层并用无水硫酸钠进行干燥。将残留物涂覆至硅胶柱上并用二氯甲烷/甲醇(30:1)洗脱,得到1g(41%)呈淡黄色固体的4-氨基-3-(4-苯氧苯基)-1-[(3R)-哌啶-3-基]-1H,2H,3H-咪唑并[4,5-c]吡啶-2-酮。
实例1
(R)-2-(3-(4-氨基-2-氧代-3-(4-苯氧苯基)-2,3-二氢咪唑[4,5-c]吡啶-1-基)哌啶-1-羰基)-4,4-二甲基戊-2-烯腈的合成
步骤1
向10mL圆底烧瓶中置入4-氨基-3-(4-苯氧苯基)-1-[(3R)-哌啶-3-基]-1H,2H,3H-咪唑并[4,5-c]吡啶-2-酮(79mg,0.20mmol,1.00当量)、N,N-二甲基甲酰胺(2mL)、TEA(0.082mL,1.50当量)、HATU(113mg,0.30mmol,1.50当量),和2-氰基-4,4-二甲基戊-2-烯酸(46mg,0.30mmol,3.00)。将所得溶液在室温下搅拌2.5小时,且随后通过添加水淬灭。使用二氯甲烷萃取所得溶液,并且合并有机层且在真空下浓缩。在以下条件(2#-AnalyseHPLC-SHIMADZU(HPLC-10))下通过制备性HPLC纯化粗制产物:柱,Gemini-NX C18 AXAI Packed,21.2×150mm 5um 11nm;流动相,含有0.05%TFA和ACN的水(20.0%ACN,在8分钟内提高到50.0%);检测器,254nm,得到50mg(47%)呈白色固体的标题化合物。LC-MS m/z:537.2(M+1)
实例2
(R)-2-(3-(4-氨基-2-氧代-3-(4-苯氧苯基)-2,3-二氢咪唑[4,5-c]吡啶-1-基)哌啶-1-羰基)-4-甲基-4-(4-(氧杂环丁-3-基)哌嗪-1-基)戊-2-烯腈的合成
步骤1
向50mL圆底烧瓶中置入叔丁基(R,E)-3-(4-(((二甲氨基)-亚甲基)氨基)-2-氧代-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羧酸酯
(200mg,0.51mmol,1.00当量)、二氯甲烷(20mL)、TEA(208mg,2.06mmol,4.00当量)、TEMPO(88.5mg,0.57mmol,1.10当量),和Cu(OAc)2(46.7mg,0.26mmol,0.50当量)。将所得溶液在25℃下搅拌0.5小时。添加(4-苯氧苯基)硼酸(220mg,1.03mmol,2.00当量),并且使所得溶液在25℃下反应过夜。将残留物涂覆至硅胶柱上,并用二氯甲烷/乙酸乙酯(5:1)洗脱,得到150mg(52%)呈黄色固体的叔丁基(R)-3-[4-[(E)-[双[(二甲氨基)亚甲基]氨基]-2-氧代-3-(4-苯氧苯基)-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羧酸酯。
步骤2
向25mL圆底烧瓶中置入叔丁基(3R)-3-[4-[(E)-[(二甲氨基)-亚甲基]氨基]-2-氧代-3-(4-苯氧苯基)-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羧酸酯(150mg,0.27mmol,1.00当量)、1,4-二烷(6mL)和氯化氢(3mL)。将所得溶液在50℃下搅拌过夜。用水淬灭反应混合物。用碳酸氢钠将溶液的pH调节到9。使用二氯甲烷:CH3OH=10:1萃取所得溶液,并且合并有机层。用氯化钠洗涤所得混合物,并且合并有机层,且用无水硫酸钠干燥并在真空下浓缩。将残留物涂覆至硅胶柱上并用二氯甲烷/甲醇(30:1)洗脱,得到80mg(74%)呈淡黄色固体的4-氨基-3-(4-苯氧苯基)-1-[(3R)-哌啶-3-基]-1H,2H,3H-咪唑并[4,5-c]吡啶-2-酮。
步骤3
向50mL圆底烧瓶中置入4-氨基-3-(4-苯氧苯基)-1-[(3R)-哌啶-3-基]-1H,2H,3H-咪唑并[4,5-c]吡啶-2-酮(2g,4.98mmol,1.00当量)、N,N-二甲基甲酰胺(20mL)、2-氰基乙酸(402.5mg,4.73mmol,0.95当量)、HATU(2.84g,7.47mmol,1.50当量)和TEA(1.51g,14.92mmol,3.00当量)。将所得溶液在室温下搅拌1小时,并且随后用水淬灭。使用乙酸乙酯萃取所得溶液,并且合并有机层。用饱和氯化钠洗涤有机层,并且用无水硫酸钠干燥并在真空下浓缩。将残留物涂覆至具有二氯甲烷/甲醇(30:1)的硅胶柱,得到1.3g(56%)呈淡黄色固体的3-[(3R)-3-[4-氨基-2-氧代-3-(4-苯氧苯基)-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基]哌啶-1-基]-3-溴苯甲酰乙腈。
步骤4
向50-mL圆底烧瓶中置入3-[(3R)-3-[4-氨基-2-氧代-3-(4-苯氧苯基)-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基]哌啶-1-基]-3-溴苯甲酰乙腈(800mg,1.71mmol,1.00当量)、二氯甲烷(20mL)、2-甲基-2-[4-(氧杂环丁-3-基)哌嗪-1-基]丙醛(1.0875g,5.12mmol,3.00当量)、TMSCl(922mg,8.49mmol,4.97当量)和吡咯烷(0.607g)。将所得溶液在室温下搅拌1小时。在真空下浓缩所得混合物。通过制备性TLC,随后在以下条件(2#-AnalyseHPLC-SHIMADZU(HPLC-10))下通过制备性HPLC纯化粗制产物:柱,Gemini-NX C18 AXAI Packed,21.2×150mm 5um 11nm;流动相,含有0.05%TFA和ACN的水(20.0%ACN,在10分钟内提高到40.0%);检测器,uv 254nm,得到0.478g(42%)呈淡黄色固体的标题化合物。LC-MS m/z:663.3(M+1)。
实例3
(R)-1-(1-丙烯酰哌啶-3-基)-4-氨基-3-(4-苯氧苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮的合成
向100mL圆底烧瓶中置入(R)-4-氨基-3-(4-苯氧苯基)-1-(哌啶-3-基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮(150mg,0.37mmol,1.00当量)、DCM-CH3OH(6mL)、TEA(113mg,1.12mmol,3.00当量)。接着在0℃下在5分钟内在搅拌下逐滴添加丙-2-烯酰氯(40.1mg,0.44mmol,1.20当量)。将所得溶液在0℃下搅拌2小时。在真空下浓缩所得混合物。将残留物涂覆至具有二氯甲烷/甲醇(30:1)的硅胶柱上。在以下条件(柱,XBridge制备性C18 OBD柱,5um,19×150mm;流动相,具有0.05%TFA和ACN的水(25.0%ACN,在8分钟内提高到45.0%))下通过制备性HPLC纯化粗制产物(100mg)。得到54.5mg呈白色固体的(R)-1-(1-丙烯哌啶-3-基)-4-氨基-3-(4-苯氧苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮产物。LC-MS m/z:465.2(M+1)
实例4
(R)-4-氨基-1-(1-(丁-2-炔酰基)哌啶-3-基)-3-(4-苯氧苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮的合成
向100mL圆底烧瓶中置入(R)-4-氨基-3-(4-苯氧苯基)-1-(哌啶-3-基]-1H-咪唑并[4,5-c]吡啶-2(3H)-酮(150mg,0.37mmol,1.00当量)、N,N-二甲基甲酰胺(15mL)、丁-2-炔酸(31.42mg,0.37mmol,1.00当量)、HATU(213.2mg,0.56mmol,1.50当量)、TEA(113.4mg,1.12mmol,3.00当量)。将所得溶液在室温下搅拌2小时。随后通过添加50mL水来淬灭反应。使用3×50mL二氯甲烷萃取所得溶液,并且合并有机层。使用50mL盐水来洗涤所得混合物。通过无水硫酸钠干燥混合物并在真空下浓缩。将残留物涂覆至具有二氯甲烷/甲醇(30:1)的硅胶柱上。如实例3所描述的通过制备性HPLC纯化粗制产物(100mg),得到86.5mg(50%)呈白色固体的(R)-4-氨基-1-(1-(丁-2-炔酰基)哌啶-3-基)-3-(4-苯氧苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮。LC-MS m/z:468.2(M+1)。
实例5
(R)-2-(3-(4-氨基-2-氧代-3-(4-苯氧苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羰基)-4-甲基-4-(1-甲基哌啶-4-基)戊-2-烯腈的合成
步骤1
向250-mL3颈圆底烧瓶中置入2-(哌啶-4-基)乙酸甲酯盐酸盐(10g,51.63mmol,1.00当量)、二氯甲烷(100mL)。将所得溶液在0℃下搅拌30分钟。接着添加三乙胺(15.65g,154.66mmol,3当量)、Boc2O(12.4g,56.82mmol,1.1当量)。在搅拌下,使所得溶液在25℃下反应另外14小时。使用柠檬酸(3%)将溶液的pH值调节到7.0。用2×100mL水和2×100mL饱和盐水洗涤所得混合物。将残留物涂覆至具有乙酸乙酯/石油醚(1:10)的硅胶柱上。这产生10g(75.2%)呈无色油状的叔丁基4-(2-甲氧基-2-氧乙基)哌啶-1-羧酸酯。
步骤2
向250mL 3颈圆底烧瓶中置入LDA(46.7mL,3.00当量)、四氢呋喃(80mL)、叔丁基4-(2-甲氧基-2-氧乙基)哌啶-1-羧酸酯(8g,31.1mmol,1.00当量)。将所得溶液在-78℃下搅拌30分钟。随后添加CH3I(22g,155mmol,5.00当量)。在搅拌下,使所得溶液在-78℃下反应另外1小时。在-78℃下添加额外的LDA(46.7mL,3.00当量),并且在0.5小时后添加CH3I(22g,155mmol,5.00当量)。将反应物在室温下搅拌16小时。随后通过添加200mL NH4Cl来淬灭反应物。使用2×200mL乙酸乙酯萃取所得溶液,并且合并有机层。用2×200mL水和2×200mL饱和氯化钠洗涤所得混合物。使用乙酸乙酯/石油醚(1:35)通过硅胶柱层析法纯化残留物。这产生6g(68%)呈淡黄色油状的叔丁基4-(1-甲氧基-2-甲基-1-氧代丙-2-基)哌啶-1-羧酸酯。
步骤3
向100mL 3颈圆底烧瓶中置入LiAlH4(1.6g,42.2mmol,4.00当量)、四氢呋喃(50mL)、叔丁基4-(1-甲氧基-2-甲基-1-氧代丙-2-基)哌啶-1-羧酸酯(3g,10.5mmol,1.00当量)。将所得溶液在-78℃下搅拌3小时。将反应混合物温热至0℃。通过添加1.6mL水淬灭反应物,随后添加1.6mL的15%NaOH,然后添加4.8mL H2O。过滤固体得到1.5g(83%)呈粉红色油状的2-甲基-2-(1-甲基哌啶-4-基)丙-1-醇。
步骤4
向100mL圆底烧瓶中置入草酰氯(440mg,3.47mmol,1.20当量)、二氯甲烷(50mL),在-78℃下置入DMSO(684mg,8.75mmol,3.00当量)、2-甲基-2-(1-甲基哌啶-4-基)丙-1-醇(500mg,2.92mmol,1.00当量)、TEA(1.48g,14.6mmol,5.00当量)。将所得溶液在-78℃下搅拌30分钟。在搅拌下,使所得溶液在25℃下反应另外2小时。随后通过添加水淬灭反应物。用二氯甲烷萃取所得溶液,并且合并有机层并用无水硫酸钠进行干燥,且在真空下浓缩。这产生385mg(88%)呈黄色油状的2-甲基-2-(1-甲基哌啶-4-基)丙醛。
步骤5
向100mL圆底烧瓶中置入(R)-3-(3-(4-氨基-2-氧代-3-(4-苯氧苯基)-2,3-二氢-1H,-咪唑并[4,5-c]吡啶-1-基)哌啶-1-基)-3-溴苯甲酰乙腈(100mg,0.19mmol,1.00当量,90%)、二氯甲烷(50mL)、2-甲基-2-(1-甲基哌啶-4-基)丙醛(108mg,0.57mmol,3.00当量)、TMSCl(115mg,1.01mmol,5.00当量,95%)、吡咯烷(75.8mg,1.01mmol,5.00当量,95%)。将所得溶液在室温下搅拌16小时。在以下条件(柱,Gemini-NX C18 AXAI Packed,21.2×150mm 5um 11nm;流动相,具有0.05%TFA和ACN的水(20.0%ACN,在8分钟内提高到50.0%);检测器,254nm)下通过制备性HPLC纯化粗制产物。这产生15.5mg(12%)呈淡黄色固体的(R)-2-(3-(4-氨基-2-氧代-3-(4-苯氧苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羰基)-4-甲基-4-(1-甲基哌啶-4-基)戊-2-烯腈。LC-MS m/z:620.3(M+1)。
实例6
(R)-2-(3-(4-氨基-2-氧代-3-(4-苯氧苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羰基)-6-羟基-4-(2-羟乙基)己-2-烯腈的合成
步骤1
在用氮气吹扫并维持氮气惰性氛围的250mL 3颈圆底烧瓶中,用乙腈(690mg,16.8mmol)处理-78℃下的干燥THF(20mL)中的HMPA(6.0mL)和LDA(16.8mmol)。将溶液搅拌30分钟,并且逐滴添加THF(15mL)中的(2-溴乙氧基)(叔丁基)二甲基硅烷(3.4g,14.3mmol)。继续搅拌2小时,随后添加第二部分LDA(16.8mmol于20mL THF中)。将溶液搅拌30分钟,并且逐滴添加THF(15mL)中的(2-溴乙氧基)(叔丁基)二甲基硅烷(3.4,14.3mmol)。使反应进行2小时。添加NH4Cl饱和水溶液,并且使混合物达到室温。添加乙醚,进行相分离,并且用乙醚萃取水层。用盐水洗涤经合并有机相,用Na2SO4干燥,并且浓缩。柱层析法[硅,石油醚]得到无色油状物(3.2g,53%)。
步骤2
向用氮气吹扫并维持氮气惰性氛围的250mL 3颈圆底烧瓶中置入甲苯(15mL)中的4-[(叔丁基二甲基硅烷基)氧基]-2-[2-[(叔丁基二甲基硅烷基)氧基]乙基]丁腈(1g,2.80mmol,1.00当量)。在-78℃下添加DIBAL-H(1M)(3.36mL,1.20当量),并且在液氮浴中将所得溶液在-78℃下搅拌1小时。添加水(0.7mL),并且使混合物达到室温。添加NaOH水溶液(0.7mL,4M),并且继续搅拌15分钟。添加水(2.1mL)并且将悬浮液搅拌另外15分钟。用Na2SO4干燥混合物且在真空下浓缩。用PE/EA(20:1)通过硅胶柱纯化残留物。这产生900mg(89%)呈无色油状的4-[(叔丁基二甲基硅烷基)氧基]-2-[2-[(叔丁基二甲基硅烷基)氧基]乙基]丁醛。
步骤3
向8mL小瓶中置入3-[(3R)-3-[4-氨基-2-氧代-3-(4-苯氧苯基)-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基]哌啶-1-基]-3-溴苯甲酰乙腈(150mg,0.32mmol,1.00当量)、4-[(叔丁基二甲基硅烷基)氧基]-2-2-[(叔丁基二甲基硅烷基)氧基]乙基丁醛(346mg,0.96mmol,3.00当量)、TMSCl(173mg,1.59mmol,5.00当量)、吡咯烷(114mg,1.61mmol,5.00当量)、二氯甲烷(2mL)。将所得溶液在室温下搅拌3小时。在真空下浓缩所得混合物。将残留物涂覆至具有二氯甲烷/甲醇(30:1)的硅胶柱上。这产生120mg(46%)呈黄色固体的2-[[(3R)-3-[4-氨基-2-氧代-3-(4-苯氧苯基)-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基]哌啶-1-基]羰基]-6-[(叔丁基二甲基硅烷基)氧基]-4-[2-[(叔丁基二甲基硅烷基)氧基]乙基]己-2-烯腈。
步骤4
将2-[[(3R)-3-[4-氨基-2-氧代-3-(4-苯氧苯基)-1H,2H,3H-咪唑并[4,5-c]吡啶-1-基]哌啶-1-基]羰基]-6-[(叔丁基二甲基硅烷基)氧基]-4-[2-[(叔丁基二甲基硅烷基)氧基]乙基]己-2-烯腈(120mg,0.15mmol,1.00当量)、三氟乙酸(1mL)、二氯甲烷(5mL)放入25-mL圆底烧瓶中。将所得溶液在室温下搅拌2小时。随后通过添加饱和碳酸氢钠来淬灭反应。用3×20mL的DCM/MeOH(10:1)萃取所得溶液,并且合并有机层。用饱和氯化钠洗涤所得混合物。通过无水硫酸钠干燥混合物并在真空下浓缩。用DCM/MeOH(15:1)通过制备性TLC纯化残留物。在以下条件(Atlantis Prep T3 OBD柱,19×150mm 5um 10nm;流动相,具有0.1%FA和MeCN的水(20.0%MeCN,在10分钟内提高到50.0%);检测器,254nm)下通过制备性HPLC纯化粗制产物。这产生7.9mg(9%)呈白色固体的(R)-2-(3-(4-氨基-2-氧代-3-(4-苯氧苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羰基)-6-羟基-4-(2-羟乙基)己-2-烯腈。LC-MS m/z:583.2(M+1)。
实例7
(R)-2-(3-(4-氨基-3-(4-(2,6-二氟苯氧基)苯基)-2-氧代-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羰基)-4-甲基-4-(4-(氧杂环丁-3-基)哌嗪-1-基)戊-2-烯腈的合成
步骤1
向用O2吹扫并维持O2氛围的250mL圆底烧瓶中置入Cu(OAc)2(6.96g,38.3mmol,1.00当量)、吡啶(15.2g,192mmol,5.00当量)和二氯甲烷(100mL)中的分子筛(4A)(5g)。将所得溶液搅拌30分钟,且随后添加2,6-二氟苯酚(5g,38.4mmol,1.00当量)和(4-溴苯基)硼酸(15.4g,76.6mmol,2.00当量)。将所得溶液在室温下搅拌过夜。在真空下浓缩所得混合物。将残留物涂覆至硅胶柱上,并用石油醚洗脱。这产生5.5g(50%)呈黄色油状的2-(4-溴苯氧基)-1,3-二氟苯。
步骤2
向用氮气吹扫并维持氮气惰性氛围的250mL 3颈圆底烧瓶中置入在四氢呋喃(100mL)中的2-(4-溴苯氧基)-1,3-二氟苯(5.5g,19.3mmol,1.00当量)。在-78℃下添加nBuLi在己烷(11.6mL,1.50当量)中的2.5M溶液,并且将所得溶液搅拌30分钟,且随后添加硼酸三甲酯(4.03g,38.8mmol,2.00当量)。将反应温热至室温,且随后将所得溶液在室温下搅拌3小时。随后通过添加氯化氢(2M)淬灭反应。使用3×150mL乙醚萃取所得溶液,并且合并有机层。使用1×200mL氯化钠(饱和)洗涤所得混合物。通过无水硫酸钠干燥混合物并在真空下浓缩。将残留物涂覆于具有二氯甲烷/甲醇(50:1)的硅胶柱。这产生2.15g(45%)呈棕色固体的[4-(2,6-二氟苯氧基)苯基]硼酸。
步骤3
向用O2吹扫并维持O2氛围的100mL圆底烧瓶中置入(R,E)-叔丁基3-(4-(((二甲氨基)亚甲基)氨基)-2-氧代-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羧酸酯(500mg,1.29mmol,1.00当量)、TEA(521mg,5.15mmol,4.00当量)、Cu(OAc)2(117mg,0.64mmol,0.50当量)、TEMPO(221mg,1.41mmol,1.10当量)和二氯甲烷(50mL)中的Ms(4A)(500mg)。将所得溶液搅拌30分钟,且随后添加[4-(2,6-二氟苯氧基)苯基]硼酸(644mg,2.58mmol,2.00当量)。将所得溶液在室温下搅拌过夜。在真空下浓缩所得混合物。将残留物涂覆至具有二氯甲烷/甲醇(30:1)的硅胶柱上。这产生490mg呈棕色固体的(R,E)-叔丁基3-(4-(((二甲氨基)亚甲基)氨基)-2-氧代-3-(4-苯氧苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羧酸酯。
步骤4
将15mL氯化氢(12M)添加到(R,E)-叔丁基3-(4-(((二甲氨基)亚甲基)氨基)-2-氧代-3-(4-苯氧苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羧酸酯(490mg,0.83mmol,1.00当量)在30mL二烷中的溶液中。将所得溶液在油浴中在85℃下搅拌3小时。接着通过添加(饱和)碳酸氢钠淬灭所述反应。用3×100mL的DCM/MeOH(10:1)萃取所得溶液,并且合并有机层。使用1×100mL氯化钠(饱和)洗涤所得混合物。通过无水硫酸钠干燥混合物并在真空下浓缩。这产生360mg(100%)呈棕色固体的4-氨基-3-[4-(2,6-二氟苯氧基)苯基]-1-[(3R)-哌啶-3-基]-1H,2H,3H-咪唑并[4,5-c]吡啶-2-酮。
步骤5
向50mL圆底烧瓶中置入4-氨基-3-[4-(2,6-苯氧苯基)苯基]-1-[(3R)-哌啶-3-基]-1H,2H,3H-咪唑并[4,5-c]吡啶-2-酮(360mg,0.82mmol,1.00当量)、2-氰基乙酸(70mg,0.82mmol,1.00当量)、HATU(470mg,1.24mmol,1.50当量)、TEA(250mg,2.47mmol,3.00当量)、N,N-二甲基甲酰胺(10mL)。将所得溶液在室温下搅拌2小时。用二氯甲烷萃取所得溶液,并且合并有机层。用6×100mL的水来洗涤所得混合物。通过无水硫酸钠干燥混合物并在真空下浓缩。将残留物涂覆至具有二氯甲烷/甲醇(30:1)的硅胶柱上。这产生260mg(63%)呈棕色固体的(R)-3-(3-(4-氨基-3-(4-(2,6-二氟苯氧基)苯基)-2-氧代-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-基)-3-溴苯甲酰乙腈。
遵从实例2的步骤4中的协议得到(R)-2-(3-(4-氨基-3-(4-(2,6-二氟苯氧基)苯基)-2-氧代-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羰基)-4-甲基-4-(4-(氧杂环丁-3-基)哌嗪-1-基)戊-2-烯腈。LC-MS m/z:699.2(M+1)
实例8
(R)-2-(3-(4-氨基-3-(4-(2,3-二氟苯氧基)苯基)-2-氧代-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羰基)-4-甲基-4-(4-(氧杂环丁-3-基)哌嗪-1-基)戊-2-烯腈的合成
步骤1
向用O2吹扫并维持O2氛围的250mL圆底烧瓶中置入Cu(OAc)2(6.96g,38.3mmol,1.00当量)、吡啶(15.2g,192mmol,5.00当量)和二氯甲烷(100mL)中的分子筛(4A)(5g)。将所得溶液搅拌30分钟,且随后添加2,3-二氟苯酚(5g,38.43mmol,1.00当量)和(4-溴苯基)硼酸(15.4g,76.6mmol,2.00当量)。将所得溶液在室温下搅拌过夜。在真空下浓缩所得混合物。将残留物涂覆于具有石油醚的硅胶柱。这产生3.17g(29%)呈无色油状的1-(4-溴苯氧基)-2,3-二氟苯。
步骤2
向用氮气吹扫并维持氮气惰性氛围的250mL 3颈圆底烧瓶中置入在四氢呋喃(100mL)中的1-(4-溴苯氧基)-2,3-二氟苯(3.17g,11.12mmol,1.00当量)。在-78℃下添加nBuLi(6.7mL,1.50当量)的2.5M溶液,并且将所得溶液搅拌30分钟,且随后添加硼酸三甲酯(2.32g,22.3mmol,2.00当量)。将所得溶液在室温下搅拌3小时。随后通过添加HCl(2M)淬灭反应。使用3×150mL乙醚萃取所得溶液,并且合并有机层。使用1×200mL氯化钠(饱和)洗涤所得混合物。通过无水硫酸钠干燥混合物并在真空下浓缩。将残留物涂覆于具有二氯甲烷/甲醇(50:1)的硅胶柱。这产生1g(36%)呈白色固体的[4-(2,3-二氟苯氧基)苯基]硼酸。
遵从实例2中描述的协议但使用[4-(2,3-二氟苯氧基)苯基]硼酸得到标题化合物。LC-MS m/z:699.2(M+1)。
实例9
(R)-2-(3-(4-氨基-3-(3-氟代-4-苯氧苯基)-2-氧代-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羰基)-4-甲基-4-(4-(氧杂环丁-3-基)哌嗪-1-基)戊-2-烯腈的合成
遵从实例7中描述的协议但使用使用实例2中描述的方法用(3-氟代-4-苯氧苯基)硼酸得到标题化合物。LC-MS m/z:681.4(M+1)。
实例10
(R)-2-(3-(4-氨基-3-(2-氟代-4-苯氧苯基)-2-氧代-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)哌啶-1-羰基)-4-甲基-4-(4-(氧杂环丁-3-基)哌嗪-1-基)戊-2-烯腈的合成
遵从实例7中描述的协议但使用(2-氟代-4-苯氧苯基)硼酸(如PCT国际申请案2012158764,22Nov 201中所描述制备)得到标题化合物。LC-MS m/z:681.2(M+1)。
实例11
(S)-2-(2-((4-氨基-2-氧代-3-(4-苯氧苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)甲基)吡咯烷-1-羰基)-4-甲基-4-(4-(氧杂环丁-3-基)哌嗪-1-基)戊-2-烯腈的合成
步骤1
将Et3N(5.2g,51.8mmol)和(S)-叔丁基2-(氨甲基)吡咯烷-1-羧酸酯(5.4g,27.2mmol)添加到2,4-二氯-3-硝基吡啶(5g,25.9mmol)在DMF(50mL)中的溶液中。将所得混合物在室温下搅拌过夜,随后过滤且将滤液浓缩至干燥。用水(150mL)处理残留物,并用DCM(30mL×3)萃取。用盐水(40mL)洗涤经合并有机相,用Na2SO4干燥,并且浓缩至干燥。所得6.9g(S)-叔丁基2-(((2-氯代-3-硝基吡啶-4-基)氨基)甲基)吡咯烷-1-羧酸酯不经进一步纯化即用于下一步骤。
步骤2
将双(4-甲氧苄基)胺(7.5g,29.1mmol)和TEA(5.9g,58.2mmol)添加至(S)-叔丁基2-(((2-氯代-3-硝基吡啶-4-基)氨基)甲基)吡咯烷-1-羧酸酯(6.9g,19.4mmol)在i-PrOH(100mL)中的溶液。使混合物回流过夜。在冷却至室温之后,将混合物浓缩至干燥。通过硅胶层析法(洗脱液:自5:1到2:1的石油醚/乙酸乙酯)纯化残留物,得到4.4g呈淡黄色固体的(S)-叔丁基2-(((2-(双(4-甲氧苄基)氨基)-3-硝基吡啶-4-基)氨基)甲基)吡咯烷-1-羧酸酯。
步骤3
将NH4Cl(2.0g,38.1mmol)和H2O(10mL)添加到(S)-叔丁基2-(((2-(双(4-甲氧苄基)氨基)-3-硝基吡啶-4-基)氨基)甲基)吡咯烷-1-羧酸酯(4.4g,7.6mmol)在EtOH(100mL)中的溶液中,然后在搅拌下分批添加Zn粉(2.5g,38.1mmol)。在通过硅藻土过滤之前使所得混合物回流3小时。浓缩滤液,得到再次溶解于水(50mL)中并用乙酸乙酯(100mL×3)萃取的残留物。用盐水(400mL)洗涤经合并有机相,用Na2SO4干燥,浓缩,得到直接用于下一步骤中的2.9g呈淡黄色固体的(S)-叔丁基2-(((3-氨基-2-(双(4-甲氧苄基)氨基)吡啶-4-基)氨基)甲基)吡咯烷-1-羧酸酯。
步骤4
将CDI(2.6g,15.9mmol)分批加入(S)-叔丁基2-(((3-氨基-2-(双(4-甲氧苄基)氨基)吡啶-4-基)氨基)甲基)吡咯烷-1-羧酸酯(2.9g,5.3mmol)在无水乙腈(30mL)中的溶液中。在浓缩之前使所得混合物回流2小时,得到通过其中PE:EtOAc=2:1的硅胶层析法纯化的残留物,从而得到直接用于下一步骤中的2.6g呈淡黄色固体的(S)-叔丁基2-((4-(双(4-甲氧苄基)氨基)-2-氧代-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)甲基)吡咯烷-1-羧酸酯。
步骤5
将Cu(OAc)2(2.2g,12.4mmol)、TEMPO(2.1g,13.4mmol)、4A分子筛(20g)和Et3N(20g,196mmol)添加到(S)-叔丁基2-((4-(双(4-甲氧苄基)氨基)-2-氧代-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)甲基)吡咯烷-1-羧酸酯(7g,12.2mmol)在无水DCM(100mL)中的溶液中,然后在搅拌下分批加入4-苯氧基苯硼酸(10.5g,48.9mmol)。在O2氛围下将混合物在室温下搅拌78小时。浓缩溶剂,并通过其中PE:EtOAc=2:1的硅胶柱纯化残留物,产生呈淡黄色固体的(S)-叔丁基2-((4-(双(4-甲氧苄基)氨基)-2-氧代-3-(4-苯氧苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)甲基)吡咯烷-1-羧酸酯(3.2g,36%)。
步骤5
将(S)-叔丁基2-((4-(双(4-甲氧苄基)氨基)-2-氧代-3-(4-苯氧苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)甲基)吡咯烷-1-羧酸酯(2g,2.7mmol)溶于TFA(10mL)中,并在室温下搅拌过夜。浓缩反应,且使用H2O(50mL)稀释残留物并用EtOAc萃取。用NaOH水溶液将水相调节至pH=13且用EtOAc(2×100mL)萃取,并且浓缩有机相,得到不经进一步纯化即用于下一步骤中的870mg(S)-4-氨基-3-(4-苯氧苯基)-1-(吡咯烷-2-亚甲基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮。
步骤6
将Et3N(150mg,1.5mmol)、2-氰基乙酸(47mg,0.55mmol)和HATU(284mg,0.75mmol)添加到(S)-4-氨基-3-(4-苯氧苯基)-1-(吡咯烷-2-亚甲基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮(200mg,0.5mmol)在0℃下于DMF(10mL)中的溶液中。在0℃下搅拌30分钟后,将反应物倾入水(20mL)中并用EtOAc(两次30mL)萃取,浓缩有机相并且通过用PE:EtOAc=1:1洗脱的硅胶层析法纯化残留物,得到70mg呈白色固体的(S)-3-(2-((4-氨基-2-氧代-3-(4-苯氧苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)甲基)吡咯烷-1-基)-3-溴苯甲酰乙腈。
步骤7
将氯(三甲基)硅烷(69mg,0.68mmol)逐滴缓慢添加到在室温下的(S)-3-(2-((4-氨基-2-氧代-3-(4-苯氧苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)甲基)吡咯烷-1-基)-3-溴苯甲酰乙腈(80mg,0.17mmol)、2-甲基-2-(4-(氧杂环丁-3-基)哌嗪-1-基)丙醛(72mg,0.34mmol)和吡咯烷(120mg,1.7mmol)在DCM(2mL)中的溶液中。在30分钟之后,用DCM(20mL)稀释反应,并用NaHCO3水溶液(20mL)洗涤。用无水Na2SO4干燥有机层,过滤并浓缩,得到粗制残留物,所述粗制残留物通过制备性TLC纯化,得到呈白色固体的(S)-2-(2-((4-氨基-2-氧代-3-(4-苯氧苯基)-2,3-二氢-1H-咪唑并[4,5-c]吡啶-1-基)甲基)吡咯烷-1-羰基)-4-甲基-4-(4-(氧杂环丁-3-基)哌嗪-1-基)戊-2-烯腈(10mg,9%)。LC-MS m/z:662.8(M+1)。
实例12
(S)-1-((1-丙烯酰基吡咯烷-2-基)甲基)-4-氨基-3-(4-苯氧苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮的合成
在0℃下将丙烯酰氯(45mg,0.50mmol)逐滴缓慢添加到(S)-4-氨基-3-(4-苯氧苯基)-1-(吡咯烷-2-亚甲基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮(200mg,0.17mmol)和DIPEA(129mg,1.0mmol)在DCM(2mL)中的溶液中。在30分钟之后,用DCM(20mL)稀释反应,并用NaHCO3水溶液(20mL)洗涤。通过无水Na2SO4干燥有机层,过滤并浓缩,得到粗制残留物,所述粗制残留物通过制备性TLC纯化得到70mg呈白色固体的(S)-1-((1-丙烯酰基吡咯烷-2-基)甲基)-4-氨基-3-(4-苯氧苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮。LC-MS m/z:455.9(M+1)。
实例13
(S)-4-氨基-1-((1-(丁-2-炔酰基)吡咯烷-2-基)甲基)-3-(4-苯氧苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮的合成
在0℃下将丁-2-炔酰氯(50mg,0.50mmol)逐滴缓慢添加到(S)-4-氨基-3-(4-苯氧苯基)-1-(吡咯烷-2-亚甲基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮(200mg,0.17mmol)和DIPEA(129mg,1.0mmol)在DCM(10mL)中的溶液中。0.5小时后,用DCM(20mL)稀释反应,并用NaHCO3水溶液(20mL)洗涤。通过无水Na2SO4干燥有机层,过滤并浓缩,得到粗制残留物,所述粗制残留物通过制备性TLC纯化得到50mg呈白色固体的(S)-4-氨基-1-((1-(丁-2-炔酰基)吡咯烷-2-基)甲基)-3-(4-苯氧苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮。LC-MS m/z:467.9(M+1)。
实例14
(R)-4-氨基-1-(1-(2-氟丙烯酰基)哌啶-3-基)-3-(4-苯氧苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮的合成
将二异丙基乙胺(0.2mL,1.1mmol)添加到(R)-4-氨基-3-(4-苯氧苯基)-1-(哌啶-3-基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮(154mg,0.38mmol,1.0当量)在2mL DMF中的溶液中。添加2-氟丙-2-烯酸(51.8mg,0.580mmol),然后添加HATU(97mg,1.1mmol)。在搅拌1小时后,通过制备性HPLC(Shimadzu,C18柱;流动相,具有0.05%TFA和ACN(10%,用20分钟提高到90%)的水)直接纯化材料。用饱和碳酸氢钠稀释经纯化部分,且分离DCM和层。用MgSO4干燥有机层,过滤并浓缩。其溶入于最少量的水和乙腈中,并且经冻干以得到65mg呈白色固体的(R)-4-氨基-1-(1-(2-氟丙烯酰基)哌啶-3-基)-3-(4-苯氧苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮。LC-MS m/z:474.1(M+1)。
生物学实例
实例1
BTK酶活性检定
将基于测径器的激酶检定(Caliper Life Sciences,Hopkinton,MA)用于测量本发明的化合物的BTK激酶活性抑制。用人类重组BTK(0.5nM)、ATP(16μM)和磷酸受体肽底物FAM-GEEPLYWSFPAKKK-NH2(1μM)将受试化合物的系列稀释物在室温下培养3小时。随后用EDTA终止反应,终浓度为20mM,且在Caliper Desktop Profiler(Caliper LabChip 3000)上量化磷酸化反应产物。计算出每一化合物稀释物的抑制百分数,并且计算出产生50%抑制的浓度。这个值表示为IC50。在下文提供本发明的某些化合物的IC50。
实例2
测量BTK在人类外周血单核细胞中的占有率
可通过使化合物与含有BTK的人类外周血单核细胞(PBMC)中的目标结合来评估化合物抑制BTK活性的效力。在用化合物处理细胞并且通过用探针结合(R,E)-N-(2-(4-(4-(3-(4-氨基-3-(2-氟代-4-苯氧苯基)-1H-吡唑并[3,4-d]嘧啶-1-基)哌啶-1-基)-4-氧代丁-2-烯-1-基)哌嗪-1-基)乙基)-3-(5,5-二氟-7,9-二甲基-5H-4l4,5l4-二吡咯并[1,2-c:2',1'-f][1,3,2]二硫唑嘌呤硼-2-基)丙酰胺的占有率之后测量BTK占有率的范围。
简单地说,从健康志愿者得到人血,并且向9个分离的15ml管中的每一者中分入5ml。添加经测试效力的化合物的系列稀释物,使得终浓度开始于10uM且针对总共9个系列稀释物连续稀释3倍。使化合物与血液反应1小时。随后使用聚蔗糖从每一管分离PBMC。经分离PBMC随后再悬浮于1ml RPMI1640培养液中,且将占有率探针添加到浓度1uM的每一样本1小时。用SDS-PAGE洗涤、裂解和评估PBMC。将凝胶内荧光用于测量结合至BTK的BTK占有率探针的抑制范围。随后,通过具有BTK抗体(BD Bioscience Cat#611117)的Western blotting测定每一样本中的全部BTK。
此检定还经修改以测量结合于PBMC中的BTK的耐久性。在此,将浓度2uM的化合物加入人全血中1小时。使用聚蔗糖分离PBMC,并且在37℃下在培养液中再悬浮4小时或18小时。将占有率探针加入浓度1uM的每一样本1小时,且随后以上文所描述的同一方式测定BTK占有率。
实例3
人全血样本中的CD69表达的阻断
B细胞受体的激活导致增加的BTK活性、钙动员和B细胞激活(参见HonigbergL.A.,等人,Proc Natl Acad Sci U S A.107:13075-80.2010)。已表明BTK抑制剂阻断如CD69表达测量的B细胞激活(参见Karp,R.,等人,Inhibition of BTK with AVL-292Translates to Protective Activity in Animal Models of RheumatoidArthritis.Inflammation Research Association Meeting,2010年9月)。在B细胞激活后将CD69表达为全血中的BTK活性测量。全血的等分试样用受试化合物的系列稀释物预培养30分钟,然后用抗IgM(羊Fab’2,50μg/ml)激活。将样本在37℃下培养过夜,且随后根据制造商说明书用PE标记的抗CD20和APC标记的抗CD69(BD Pharmingen)染色30分钟。随后裂解全血,且通过FACS针对CD 69表达量化门控于CD20表达上的细胞。基于针对无抑制的DMSO对照计算抑制百分数,且将其标绘为可借以计算IC50值的受试化合物浓度的函数。
实例4
小鼠胶原诱导性关节炎的抑制
小鼠胶原诱导性关节炎(mCIA)的抑制为类风湿性关节炎的标准动物疾病模型。先前研究已表明,BTK的抑制在阻断mCIA中有效(参见Honigberg L.A.,等人Proc Natl AcadSci U S A.107:13075-80.2010)。从第0天开始,向DBA/1小鼠注射II型胶原在完全弗氏佐剂(Complete Freund’s Adjuvant)中的乳剂。在21天后对小鼠进行加强以同步疾病的发展。在发展轻度疾病之后,将动物纳入研究并随机化。口服给药,通常每天四次持续11天,其中受试化合物或地塞米松(0.2mg/kg)作为对照。一组仅接受载体。临床得分(0–4)是基于肿胀程度和关节炎的严重性。所有四个爪的得分相加的最大得分为16。在研究结束时通过Elisa(Bolder BioPath,Boulder,CO)测量每一动物的抗胶原抗体和总Ig。
实例5
在透析以评估不可逆vs.可逆共价结合之后恢复激酶活性
将在比其IC50值大10倍的浓度下的本发明的化合物及/或医药学上可接受的盐添加到蛋白激酶(5nM)在含有20mM Hepes[pH 7.5]、5mM MgCl2、0.01%Triton X-100和1mM二硫苏糖醇的缓冲液中的溶液中。在22℃下60分钟后,反应转移到透析盒(0.1–0.5mL Slide-A-Lyzer,MWCO 10kDa,Pierce),并且在22℃下相对于1L缓冲液(20mM Hepes[pH 7.5],5mMMgCl2,0.01%Triton X-100,和1mM二硫苏糖醇)透析。每天更换透析缓冲液两次,直到实验结束为止。每24小时从透析盒移除等分试样并分析蛋白激酶活性。每一样本的激酶活性经归一化为那个时间点的DMSO对照并表达为平均值±SD。可以观察到,激酶活性在Ra为氰基的情况下将返回本发明化合物的透析,且在Ra为氢或氟基的情况下将不返回本发明化合物。
实例6
质谱分析
通过本发明的化合物及/或医药学上可接受的盐抑制的蛋白激酶可经受质谱分析以评估永久性的、不可逆的共价加合物的形成。用于检验经由蛋白激酶的胰蛋白酶切割生成的全蛋白或肽片段的合适的分析方法通常为此项技术中已知的(参见Lipton,Mary S.,Ljiljana,Pasa-Tolic,Eds.Mass Spectrometry of Proteins and Peptides,Methodsand Protocols,第二版,Humana Press.2009)。这类方法通过观察对应于对照样本的质量加上不可逆加合物的质量的质量峰来识别永久性、不可逆共价蛋白加合物。下文描述两种这类方法。
全激酶的质谱分析
方法:
在室温下将蛋白激酶(5μM)(例如BTK)在缓冲液(20mM Hepes[pH 8.0],100mMNaCl,10mM MgCl2)中用本发明的化合物(25μM,5当量)培养1h。还制备不具有本发明的化合物的对照样本。通过添加等体积的0.4%甲酸停止反应,且通过液相色谱法(Microtrap C18蛋白柱[Michrom Bioresources],5%MeCN,0.2%甲酸,0.25mL/min;用95%MeCN、0.2%甲酸洗脱)和线内ESI质谱法(LCT Premier,Waters)分析样本。可以用MassLynx去卷积软件测定蛋白激酶和任何加合物的分子量(参见专利申请案WO2014 011900和PCT/US2010/048916)。
结果:在Ra为氰基的情况下对由本发明的化合物抑制的蛋白激酶(例如BTK)的高分辨率全质谱分析将显示与缺乏抑制剂的激酶(例如,对照样本)相似的频谱。质谱中将不会形成对应于激酶的分子量加上化合物的分子量的新的峰。相反地,在Ra为氢或氟基的情况下对由本发明的化合物抑制的蛋白激酶的高分辨率全质谱分析将显示在质谱中形成对应于激酶的分子量加上不可逆激酶抑制剂的分子量的新的峰(例如,不存在于无抑制剂的对照样本中的峰)。在此实验的基础上,不可逆蛋白加合物对本领域的技术人员来说将显而易见。
对激酶胰蛋白酶消化的质谱分析
方法:
在胰蛋白酶消化之前将蛋白(10pmol至100pmol)用本发明的化合物及/或医药学上可接受的盐(100pmol至1000pmol,10当量)培养3小时。在化合物培养之后可将碘乙酰胺用作烷化剂。还制备不利用本发明的化合物及/或医药学上可接受的盐的对照样本。对于胰蛋白酶消化,在微型C18 Zip Tipping直接在将α氰基-4-氢氧基-肉桂酸用作解吸基质(5mg/mol的0.1%TFA:Acetonitrile 50:50)或将芥子酸用作解吸基质(10mg/mol的0.1%TFA:Acetonitrile 50:50)的MALDI目标上之前用10μl 0.1%TFA稀释1μl等分试样(3.3pmol)(参见PCT/US2010/048916)。
结果:在Ra为氰基的情况下对由本发明的化合物及/或医药学上可接受的盐抑制的激酶的胰蛋白酶化片段的高分辨率质谱分析将显示与缺乏抑制剂的激酶(例如,对照样本)相似的频谱。将没有任何经改性肽不存在于对照样本中的证据。在此实验的基础上,无永久性、不可逆蛋白加合物对本领域的技术人员来说将显而易见。
相反地,在Ra为氢或氟基的情况下对由本发明的化合物抑制的激酶的胰蛋白酶化片段的高分辨率质谱分析将显示含有不存在于对照样本中的经改性肽的频谱。在此实验的基础上,不可逆的蛋白加合物对本领域的技术人员来说将显而易见。此外,在精确质量和MS-MS片段化模式的基础上,可通过定义为共价修饰的位点的半胱氨酸残基确定经改性肽的序列。
实例7
测定激酶药物的停留时间
下文为协议,所述协议可用于将化合物显示缓慢裂解速率或不存在裂解速率与BTK区分开来,例如通常将在共价键形成于化合物与目标之间时发生。缓慢裂解的读出为所感兴趣的化合物阻断高亲和荧光追踪分子与激酶活性位点的结合的能力,如使用时间分辨的荧光共振能量转移(TR-FRET)所检测到的。在由50mM Hepes pH 7.5、10mM MgCl2、0.01%Triton X-100和1mM EGTA组成的缓冲液中进行实验。
程序的第一步骤为在体积10μL中用1.5μM的本发明化合物将500nM BTK(Invitrogen Cat.#PV3587)培养30分钟。随后通过添加40μL缓冲液将混合物稀释5倍。随后将体积为10μL的经稀释激酶/化合物溶液添加到小容量384孔板(例如Greiner Cat.#784076)的孔中。为了探查激酶化合物结合反应的可逆性,制备含有高亲和荧光追踪剂和耦合到铕的抗体两者的竞争溶液。对于BTK,竞争溶液含有1.5μM追踪剂178(InvitrogenCat.#PV5593),所述追踪剂为耦合到荧光团AlexaFluor 647的BTK的专有高亲和配体。竞争溶液还含有耦合到铕的80nM抗多组氨酸抗体(Invitrogen Cat.#PV5596),所述抗体经设计结合到BTK中的多组氨酸纯化标签。
在将10μL竞争溶液添加到Greiner板之后,将混合物培养一个小时或更长时间,以允许非共价抑制剂的裂解和高亲和追踪剂的结合的时间。预期共价及缓慢裂解抑制剂将阻断追踪剂的结合,而快速裂解非共价抑制剂将不会。在半抗组氨酸抗体的铕与追踪剂178的AlexaFluor 647基团之间使用TR-FRET检测到追踪剂结合到BTK。使用与LANCE-type TR-FRET实验相容的装备有过滤器和镜子的Perkin Elmer Envision仪器(模型2101)评估结合。将数据标绘在缺少竞争化合物时得到的信号的百分比处。通过从反应遗漏BTK得到背景信号。如果化合物为不可逆共价抑制剂,那么贯穿整个实验过程追踪剂将完全阻断与目标的结合。如果化合物为可逆共价抑制剂,那么追踪剂将在化合物从目标分离时与目标结合。对于耐久性测量,下文展示本文中公开的化合物在1小时、6小时和24小时的冲刷下的占有率范围。
实例8
结合的可逆性
以下方法经开发以确定化合物与其目标形成不可逆共价键还是可逆共价键。在比所感兴趣化合物高的浓度下用蛋白目标制备反应。不可逆和可逆共价化合物都与目标结合且在溶液中耗尽。随后用包含使用5M盐酸胍的变性且使用胰蛋白酶的消化两者的扰动处理反应,从而扰乱目标的适当折叠。应发现,归因于从目标裂解扰动将可逆共价化合物返回到溶液,而不可逆共价化合物保持与目标结合。在扰动之前和之后都使用耦合到串联质谱法的高效液相色谱法来评估化合物在溶液中的浓度。使用此技术,其可表明在Ra为氢或氟基的情况下本发明的不可逆共价化合物在原始状态和扰动状态两者下在溶液中耗尽,而在Ra为氰基的情况下本文中所公开的化合物在折叠状态下耗尽但在目标扰动表明这类化合物形成可逆共价键之后返回到溶液。
制剂实例
下文为含有式(I)化合物的代表性药物制剂。
药片制剂
以下成分经密切混合且被压成单刻痕药片。
胶囊制剂
以下成分经密切混合且充入硬壳明胶胶囊中。
注射制剂
本发明的化合物(例如,化合物1)在2%HPMC中,1%Tween 80在DI水中,pH 2.2的MSA,至少20mg/mL的q.s.
出于清楚和理解的目的,已借助于说明和实例以一些细节描述前述内容。因此,应了解,以上描述意图为说明性的而并非限制性的。因此,本发明的范围不应参考以上描述而确定,而应替代地参考以下随附权利要求书以及这类权利要求书所授权的等效物的全部范围来确定。
Claims (51)
1.一种式(I)化合物:
其中:
R1和R2独立地为氢、烷基、烷氧基、卤代烷基或卤代基;
X为-O-、-CONR-、-NRCO-或-NR-CO-NR’,其中R和R’独立地为氢或烷基;
Ar为杂芳基或苯基,其中杂芳基和苯基任选地由独立地选自烷基、卤代基、卤代烷基、烷氧基和羟基的一个、两个或三个取代基取代;
A为-N-或CR3-,其中R3为氢、烷基、环丙基、卤代基、卤代烷基、卤代烷氧基、烷氧基或氰基;
Y为化学键或亚烷基;
环Z为任选地由独立地选自烷基、羟基、烷氧基和氟代基的一个或两个取代基取代的杂环氨基;
R5为式(i)、(ii)、(iii)或(iv)的基团:
其中:
Ra为氢、氟代基或氰基;其限制条件是当Ra为氰基时,那么Rb为氢且Rc不为氢;
Rb为氢或烷基;且
Rc为氢、羟烷基、烷氧烷基、烷基(其任选地由独立地选自羟基、羟烷基、杂芳基(其任选地由独立地选自烷基和杂环基的一个或两个取代基取代,其中杂环基任选地由独立地选自卤代基和烷基的一个或两个取代基取代)和-CONR9R10(其中R9及R10独立地为氢或烷基,或R9和R10与其附接到的氮原子一起形成任选地由选自烷基和杂环基的一个或两个取代基取代的杂环基)的一个或两个取代基取代)、环烷基(其任选地由独立地选自卤代基、烷基、烷氧烷基和芳基的一个或两个取代基取代;或其中所述环烷基的两个相邻取代基与其附接到的碳原子一起形成杂环基)、杂环基烷基、杂环基(其中杂环基和杂环基烷基中的杂环基任选地由一个、两个或三个取代基取代,其中两个可选取代基独立地选自烷基、烷氧基、羟基、卤代基、氨基和氧代基,且一个可选取代基为烷基、羟烷基、烷氧基、烷氧烷基、酰基、卤代烷基、烷基磺酰基、烷氧羰基或杂环基,其中所述杂环基经由独立地选自氢、烷基、卤代基、羟基和烷氧基的一个或两个取代基取代),或-(亚烷基)-NR6R7(其中R6和R7独立地为氢、烷基、卤代烷基、羟烷基、烷氧烷基、环烷基或杂环基,其中所述杂环基任选地由独立地选自烷基、卤代基、羟基、羟烷基、烷氧烷基、酰基和烷氧羰基的一个或两个取代基取代;或R6和R7与其附接到的氮原子一起形成其中X1、X2和X3中的一个或两个为氮,且其余为碳,并且环任选地由独立地选自烷基、卤代烷基和卤代基的一个或两个取代基取代);及/或
其医药学上可接受的盐,其限制条件是:
当A为-N-时,那么Ra为氰基且Rc为杂环氨基烷基,其中杂环氨基烷基中的杂环氨基任选地由独立地选自烷基、烷氧基、羟基、卤代基、氨基和氧代基的一个或两个取代基取代,且杂环氨基的氮原子任选地由杂环基取代,其中所述杂环基经由独立地选自氢、烷基、卤代基、羟基和烷氧基的一个或两个取代基取代。
2.根据权利要求1所述的化合物及/或其医药学上可接受的盐,其中A为-CR3-。
3.根据权利要求2所述的化合物及/或其医药学上可接受的盐,其中R3为氢、甲基、乙基、异丙基、氟代基或氯代基。
4.根据权利要求3所述的化合物及/或其医药学上可接受的盐,其中R3为氢。
5.根据权利要求1所述的化合物及/或其医药学上可接受的盐,其中A为-N-。
6.根据权利要求1至5中任一项所述的化合物及/或其医药学上可接受盐,其中-X-Ar在苯环的4位置处附接至碳原子,所述苯环附接至环状脲环的N的碳原子为位置1。
7.根据权利要求1至6中任一项所述的化合物及/或其医药学上可接受的盐,其中X为-O-。
8.根据权利要求7所述的化合物及/或其医药学上可接受的盐,其中Ar为吡啶基、嘧啶基、噻吩基或吡嗪基,其任选地由独立地选自烷基、卤代基、卤代烷基、烷氧基和羟基的一个、两个或三个取代基取代。
9.根据权利要求7所述的化合物及/或其医药学上可接受的盐,其中Ar为苯基,其中苯基任选地由独立地选自烷基、卤代基、卤代烷基、烷氧基和羟基的一个、两个或三个取代基取代。
10.根据权利要求1至9中任一项所述的化合物及/或其医药学上可接受的盐,其中R1及R2独立地选自氢或卤代基,优选地氢或氟代基。
11.根据权利要求10所述的化合物及/或其医药学上可接受的盐,其中R1及R2为氢或R1为氢且R2为氟代基。
12.根据权利要求1至11中任一项所述的化合物及/或其医药学上可接受的盐,其中Y为键且环Z为哌啶基,其中在哌啶环的3位置处的碳原子附接到环状脲环的氮原子。
13.根据权利要求12所述的化合物及/或其医药学上可接受的盐,其中附接到所述环状脲氮的所述哌啶基的碳处的立体化学为(R)。
14.根据权利要求1至4及6至13中任一项所述的化合物及/或其医药学上可接受的盐,其中Ra为氢。
15.根据权利要求13或14所述的化合物及/或其医药学上可接受的盐,其中为R5式(i)的基团。
16.根据权利要求13所述的化合物及/或其医药学上可接受的盐,其中R5为式(iv)的基团。
17.根据权利要求14或15所述的化合物及/或其医药学上可接受的盐,其中Rb及Rc为氢。
18.根据权利要求14所述的化合物或其医药学上可接受的盐,其中Rb为氢且Rc为烷基或-(烯烃基)-NR6R7(其中R6和R7独立地为氢、烷基、卤代烷基、羟烷基、烷氧烷基、环烷基或杂环基,其中杂环基任选地由独立地选自烷基、卤代基、烷氧基、羟烷基、烷氧烷基、酰基和烷氧羧基的一个或两个取代基取代),优选地R6和R7独立地为氢或烷基。
19.根据权利要求1至13中任一项所述的化合物及/或其医药学上可接受的盐,其中Ra为氰基。
20.根据权利要求19所述的化合物及/或其医药学上可接受的盐,其中R5为式(i)的基团。
21.根据权利要求20所述的化合物及/或其医药学上可接受的盐,其中Rc为杂环烷基,其中杂环烷基中的杂环基任选地由一个、两个或三个取代基取代,其中可选取代基中的两个独立地选自烷基、烷氧基、羟基、卤代基、氨基和氧代基,并且可选取代基中的一者为烷基、羟烷基、烷氧烷基、酰基、卤代烷基、烷基磺酰、烷氧羰基或另一杂环基,其中所述另一杂环基任选地由独立地选自烷基、卤代基、羟基和烷氧基的一个或两个取代基取代。
22.根据权利要求21所述的化合物及/或其医药学上可接受的盐,其中Rc为-C(CH3)2吗啉-4-基、-C(CH3)2-4-(2,2,2-三氟代乙基)哌嗪-1-基、-C(CH3)2-4-(1-甲基)哌嗪-1-基、-C(CH3)2-4-乙基-3-氧代哌嗪-1-基、C(CH3)2四氢吡喃-4-基、-C(CH3)2-4-甲氧羧基哌嗪-1-基、-C(CH3)2-4-(氧杂环丁-4-基)哌嗪-1-基、-C(CH3)2-4-(3-甲基氧杂环丁-4-基)哌嗪-1-基、-C(CH3)2-4-t-丁氧羧基哌嗪-1-基、-C(CH3)2-4-乙酰哌嗪-1-基、-C(CH3)2-4-甲氧羧基哌嗪-1-基、-C(CH3)2-哌嗪-1-基、-C(CH3)2-3,3-二氟代吡咯烷-1-基、-C(CH3)2-(S)-3-甲氧吡咯烷-1-基、-C(CH3)2(R)-3-甲氧吡咯-1-基、-C(CH3)2-(S)-2-(甲氧甲基)吡咯烷-1-基、-C(CH3)2-(R)-2-(甲氧甲基)吡咯烷-1-基、-C(CH3)2-4-甲基哌嗪-1-基、-C(CH3)2-4-乙基哌嗪-1-基、-C(CH3)2-4-异丙基哌嗪-1-基、-C(CH3)2-4-(2-甲氧乙基)哌嗪-1-基、-C(CH3)2-4-乙酰基哌嗪-1-基、-C(CH3)2-4-(3R,5S)-3,4,5-三甲基哌嗪-1-基、-C(CH3)2-4-(3R,5S)-3,5-二甲基哌嗪-1-基、-C(CH3)2-4-(3R,5S)-二甲基吗啉-4-基、-C(CH3)2-哌啶-1-基、-C(CH3)2-吡咯烷-1-基、-C(CH3)2-3-氧代-哌嗪-1-基或-C(CH3)2-(3-氧代-4-甲基哌嗪-1-基)。
23.根据权利要求20所述的化合物及/或其医药学上可接受的盐,其中Rc为未取代的烷基。
24.根据权利要求23所述的化合物及/或其医药学上可接受的盐,其中Rc为叔丁基。
25.根据权利要求20所述的化合物及/或其医药学上可接受的盐,其中Rc为环烷基,其任选地由独立地选自卤代基、烷基、烷氧烷基和芳基的一个或两个取代基取代;或其中所述环烷基的两个相邻取代基与其附接到的碳原子一起形成杂环基基团。
27.根据权利要求20所述的化合物及/或其医药学上可接受的盐,其中Rc为杂环基,其中杂环基任选地由一个、两个或三个取代基取代,其中任选取代基中的两个独立地选自烷基、烷氧基、羟基、卤代基、氨基和氧代基,并且任选取代基中的一者为烷基、羟烷基、烷氧基、烷氧烷基、酰基、卤代烷基、烷基磺酰基、烷氧羰基或杂环基,其中杂环基任选地由独立地选自氢、烷基、卤代基、羟基和烷氧基的一个或两个取代基取代。
29.根据权利要求20所述的化合物及/或其医药学上可接受的盐,其中Rc为任选地由独立地选自羟基、羟烷基和杂芳基的一个或两个取代基取代的烷基,所述杂芳基经由独立选自烷基和杂环基的一个或两个取代基所取代,其中杂环基任选地由独立地选自卤代基和烷基的一个或两个取代基取代。
30.根据权利要求29所述的化合物及/或其医药学上可接受的盐,其中Rc为经由一种或两种羟基取代基取代的烷基。
32.根据权利要求20所述的化合物及/或其医药学上可接受的盐,其中Rc为由杂芳基取代的烷基,所述杂芳基任选地由独立地选自烷基和杂环基的一个或两个取代基取代,其中杂环基由独立地选自卤代基和烷基的一个或两个取代基取代。
34.根据权利要求20所述的化合物及/或其医药学上可接受的盐,其中Rc为由-CONR9R10、取代的烷基,其中R9和R10独立地为氢或烷基,或R9和R10与其附接到的氮原子一起形成由选自烷基和杂环基的一个或两个取代基可选取代的杂环基。
35.根据权利要求34所述的化合物及/或其医药学上可接受的盐,其中R9及R10为氢或烷基两者。
36.根据权利要求35所述的化合物及/或其医药学上可接受的盐,其中
Rc为-C(CH3)2-CONH2或C(CH3)2-CON(CH3)2。
37.根据权利要求34所述的化合物及/或其医药学上可接受的盐,其中R9和R10与其附接到的氮原子一起形成任选地由选自烷基和杂环基的一个或两个取代基取代的杂环基。
38.根据权利要求37所述的化合物及/或其医药学上可接受的盐,其中由R9和R10与其附接到的氮原子一起形成的杂环基为4-甲基哌嗪基或4-(氧杂环丁-3-基)哌嗪-1-基。
39.根据权利要求1至11中任一项所述的化合物及/或其医药学上可接受的盐,其中Y为亚烷基且环Z为吡咯烷基。
40.根据权利要求39所述的化合物及/或其医药学上可接受的盐,其中Y为亚甲基且环Z为2-吡咯烷基。
41.根据权利要求40所述的化合物及/或其医药学上可接受的盐,其中R5为式(i)或(iv)的基团。
42.根据权利要求1、5和6至13中任一项所述的化合物及/或其医药学上可接受的盐,其中R5为式(i)的基团,Ra为氰基,Rb为氢且Rc为杂环烷基,其中杂环烷基中的杂环基任选地由一个、两个或三个取代基取代,其中任选取代基中的两个独立地选自烷基、烷氧基、羟基、卤代基、氨基和氧代基,并且任选取代基中的一者为烷基、羟烷基、烷氧基、烷氧烷基、酰基、卤代烷基、烷基磺酰基、烷氧羰基或杂环基,其中杂环基任选地由独立选自烷基、卤代基、羟基和烷氧基的一个或两个取代基取代。
45.一种药学组合物,其包括根据权利要求1至44中任一项所述的化合物及/或医药学上可接受的盐及医药学上可接受的赋形剂。
46.一种抑制有此需要的哺乳动物中的BTK的方法,所述方法包括给予需要此治疗的所述哺乳动物(例如人类)药学组合物,所述药学组合物包括根据权利要求1至44中任一项所述的化合物、或其(E)或(Z)异构体、及/或任何前述化合物的医药学上可接受的盐及医药学上可接受的赋形剂的医药学上有效的量。
47.一种治疗有此需要的哺乳动物中的自身免疫性疾病、炎性疾病或癌症的方法,所述方法包括给予需要此治疗的所述哺乳动物(例如人类)药学组合物,所述药学组合物包括根据权利要求1至44中任一项所述的化合物、或其(E)或(Z)异构体、及/或任何前述化合物的医药学上可接受的盐及医药学上可接受的赋形剂的医药学上有效的量。
48.根据权利要求47所述的方法,其中所述疾病为急性坏死出血性脑白质炎、急性播散性脑脊髓炎、自身免疫性内耳病(AIED)、自身免疫性视网膜病、轴突及神经元神经病、慢性炎性脱髓鞘性多神经病(CIDP)、脱髓鞘神经病、德维克病(视神经脊髓炎)、实验性变应性脑脊髓炎、巨细胞性动脉炎(颞动脉炎)、格林-巴利综合征、肌无力综合征、慢性美尼尔氏病、重症肌无力、神经性肌强直、视眼阵挛-肌阵挛综合征、视神经炎、副肿瘤性小脑变性、周围神经病、静脉周脑脊髓炎、不宁腿综合征、僵人综合征、交感性眼炎、高安氏动脉炎、颞动脉炎/巨细胞性动脉炎、横贯性脊髓炎、多发性硬化症、自主神经功能异常、老年性黄斑变性(湿性或干性)、角膜移植、脑炎、脑膜炎、血管炎和系统性红斑狼疮(SLE)。
49.根据权利要求47所述的方法,其中所述疾病为类风湿性关节炎、银屑病性关节炎、狼疮、葡萄膜炎、重症肌无力、温抗体型自身免疫性溶血性贫血、韦格纳肉芽肿、休格兰氏疾病、休格兰氏干眼症、非休格兰氏干眼症、银屑病、天疱疮、荨麻疹或哮喘。
50.根据权利要求47所述的方法,其中所述疾病为弥漫性大B细胞淋巴瘤、滤泡性淋巴瘤、慢性淋巴细胞性淋巴瘤、慢性淋巴细胞性白血病、B细胞前淋巴细胞性白血病、小淋巴细胞淋巴瘤(SLL)、多发性骨髓瘤、B细胞非霍奇金淋巴瘤、淋巴浆细胞淋巴瘤/原发性巨球蛋白血症、脾边缘带淋巴瘤、浆细胞骨髓瘤、浆细胞瘤、淋巴结外边缘区B细胞淋巴瘤、节点淋巴结边缘区B细胞淋巴瘤、套细胞淋巴瘤、纵隔(胸腺)大B细胞淋巴瘤、血管内大B细胞淋巴瘤、原发性渗出性淋巴瘤、伯基特淋巴瘤/白血病和淋巴瘤样肉芽肿。
51.根据权利要求46至50中任一项所述的方法,其中所述化合物及/或其医药学上可接受的盐与一种或多种抗癌或抗炎剂组合给予。
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