CN102227424A - 囊性纤维化跨膜传导调节因子的调节剂 - Google Patents
囊性纤维化跨膜传导调节因子的调节剂 Download PDFInfo
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Abstract
本发明涉及囊性纤维化跨膜传导调节因子(“CFTR”)的调节剂、其组合物及其方法。本发明还涉及使用CFTR的调节剂(I)或其药学上可接受的盐治疗疾病的方法其中,环A选自:
Description
相关申请的交叉参考
根据35U.S.C.§119,本申请要求2008年10月23日提交的题为“囊性纤维化跨膜传导调节因子的调节剂”的美国临时申请US 61/107,830的优先权,将该文献的全部内容引入本文参考。
本发明的技术领域
本发明涉及囊性纤维化跨膜传导调节因子(“CFTR”)的调节剂、其组合物及其方法。本发明还涉及使用CFTR调节剂治疗疾病的方法。
发明背景
ATP盒转运体是一族膜转运蛋白,其调节范围广泛的药物、可能的毒性药物和外源性化学物质和阴离子的转运。它们是同源膜蛋白,由于结合和使用细胞的三磷腺苷(ATP)来实现它们的特异性活性。人们发现,这些转运体中的一些是多药抗药性蛋白质类(例如MDR1-P糖蛋白,或多药抗药性蛋白MRP1),保护恶性癌细胞免于化疗剂的影响。迄今为止,已经鉴定出了48种这样的转运体,基于它们的序列同一性和功能分为7族。
通常与疾病有关的ATP盒转运体家族的一个成员是cAMP/ATP-介导的阴离子通道,CFTR。CFTR在多种细胞类型(包括吸收和分泌上皮细胞)中表达,其中它调节跨膜的阴离子流通,并调节其他离子通道和蛋白质的活性。在上皮细胞中,CFTR的正常功能对于维持包括呼吸和消化组织在内的整个身体的电解质转运是非常关键的。CFTR是由约1480个氨基酸构成的,这些氨基酸编码由跨膜区的串联重复体构成的蛋白质,每个重复体包含6个跨膜螺旋和1个核苷酸结合区。2个跨膜区通过一个具有多个磷酸化位点的大的、极性的、调节性(R)-区相连,所述磷酸化位点调节通道活性和细胞运输。
已经鉴定出了编码CFTR的基因并测定了其序列(参见Gregory,R.J.等人(1990)Nature 347:382-386;Rich,D.P.等人(1990)Nature347:358-362),Riordan,J.R.等人(1989)Science 245:1066-1073)。这个基因的缺陷引起CFTR突变,导致囊性纤维化(“CF”),是人体最常致命的遗传性疾病。在美国,囊性纤维化影响约2,500分之一的婴儿。在一般的美国人口中,高达1千万的人携带有单独1份这样的缺陷基因,但没有明显的不良效果。与此不同的是,具有2份与CF有关的基因的个体会发生CF的致虚弱和致命作用,包括慢性肺病。
在患囊性纤维化的患者中,在呼吸上皮中内源性表达的CFTR突变导致顶膜的阴离子分泌减少,使离子和液体转运失衡。所导致的阴离子转运的减少使得CF患者的肺粘液蓄积增加并伴随最终导致死亡的微生物感染。除了呼吸性疾病,CF患者典型地具有胃肠方面的问题和胰功能不全,如果不治疗的话,会导致死亡。此外,大部分患有囊性纤维化的男性都不能生育,而患囊性纤维化的女性则生育力降低。与2份和CF有关的基因所带来的严重后果不同的是,携带有一份与CF有关的基因的个体显示出对霍乱和腹泻导致的脱水的抵抗力增强——可能解释了CF基因在这个人群中的相对高频率出现。
CF染色体的CFTR基因的序列分析显示了很多导致疾病的突变(Cutting,G.R.等人(1990)Nature 346:366-369;Dean,M.等人(1990)Cell 61:863:870;和Kerem,B-S.等人(1989)Science 245:1073-1080;Kerem,B-S等人(1990)Proc.Natl.Acad.Sci.USA 87:8447-8451)。迄今为止,已经鉴定出了1000种以上的引起疾病的CF基因突变(http://www.genet.sickkids.on.ca/cftr/)。最常见的突变是在CFTR氨基酸序列的508位上苯丙氨酸的缺失,一般称作ΔF508-CFTR。这种突变在约70%的囊性纤维化病例中都会发生,与严重的疾病有关。
ΔF508-CFTR中残基508的缺失妨碍了初生蛋白正确折叠。这导致该突变蛋白不能退出ER,和通过质膜。结果,膜中存在的通道数量远小于表达野生型CFTR的细胞中所观察到的数量。除了运输受损,该突变导致通道门控缺陷。这样加起来,膜中通道数量减少和门控缺陷导致通过上皮的阴离子转运减少,导致离子和液体转运出现缺陷(Quinton,P.M.(1990),FASEB J.4:2709-2727)。但是,研究已经显示出,尽管比野生型CFTR少,膜中ΔF508-CFTR的数量减少是有用的。(Dolmans等人(1991),Nature Lond.354:526-528;Denning等人,出处同前;Pasyk和Foskett(1995),J.Cell.Biochem.270:12347-50)。除了ΔF508-CFTR、R117H-CFTR和G551D-CFTR以外,导致运输、合成和/或通道门控缺陷的其他的引起疾病的CFTR突变可以被向上或向下调节,以改变阴离子分泌并改变疾病进程和/或严重性。
尽管除了阴离子外CFTR还转运多种分子,但是显然,这种作用(转运阴离子)代表了跨上皮细胞转运离子和水的重要机制中的一个要素。其他要素包括上皮Na+通道、ENaC、Na+/2Cl-/K+共转运体、Na+-K+-ATP酶泵和基底外侧膜K+通道,它们负责将氯离子吸收到细胞中。
这些要素一起运作,以通过它们在细胞中的选择性表达和定位实现跨上皮细胞的定向转运。通过存在于顶膜上的ENaC和CFTR与在细胞的基底外侧表面上表达的Na+-K+-ATP酶泵和Cl通道之间的协调性活性,发生了氯离子的吸收。氯离子从腔侧的继发性主动转运导致细胞内的氯离子蓄积,接着被动地通过Cl-通道离开细胞,导致矢量转运。基底外侧表面上的Na+/2Cl-/K+共转运体、Na+-K+-ATP酶泵和基底外侧膜K+通道和腔侧上的CFTR的排列,通过腔侧上的CFTR来协调氯离子的分泌。由于水可能从不自己主动转运,因此它依靠钠和氯离子的总体流量产生的微小的跨上皮渗透梯度流过上皮。
推定因CFTR中的突变导致的碳酸氢盐转运缺陷导致一些分泌功能缺陷。例如,参见“Cystic fibrosis:impaired bicarbonatesecretion and mucoviscidosis”,Paul M.Quinton,Lancet 2008;372:415-417。
与中度CFTR功能障碍相关的CFTR中的突变还在与CF共有一些疾病表现、但不满足CF诊断标准的疾病的患者中明显。它们包括先天性双侧输精管缺失、特发性慢性胰腺炎、慢性支气管炎和慢性鼻窦炎。认为突变体CFTR与修饰基因或环境因素一起是危险因素的其他疾病包括原发性硬化性胆管炎、变应性支气管肺曲菌病和哮喘。
还显示吸香烟、缺氧和诱导含氧量低信号的环境因素损害CFTR功能并且可以贡献一些呼吸道疾病的形式,例如慢性支气管炎。可能因缺陷性CFTR功能、但不满足CF诊断标准的疾病的特征为CFTR-相关疾病。
除了囊性纤维化,调节CFTR活性还有益于并非是CFTR突变直接导致的其他疾病,例如CFTR介导的分泌性疾病和其他蛋白质折叠性疾病。CFTR调节氯离子和碳酸氢盐流过许多细胞上皮,以控制流体运动、蛋白质增溶、粘液粘度和酶活性。CFTR中的缺陷可以导致气道或许多器官包括肝和胰腺中的导管阻塞。增强剂是增强于细胞膜中存在的CFTR的门控活性的化合物。牵连粘液浓稠、流体调节受损、粘液清除受损或导致炎症和组织破坏的阻塞导管的任何疾病可以是增强剂的候选者。
这些疾病包括但不限于慢性阻塞性肺病(COPD)、哮喘、吸烟诱发的COPD、慢性支气管炎、鼻窦炎、便秘、干眼病、斯耶格伦综合征、胃食管返流病、胆石、直肠脱垂和炎性肠病。COPD的特征在于渐进性和非完全可逆性的气流受限。气流受限是由于粘液分泌过多、肺气肿和细支气管炎。突变体或野生型CFTR的活化剂为COPD中常见的粘液分泌过多和粘膜纤毛清除受损提供了潜在的治疗。具体地,增加跨CFTR的阴离子的分泌会促进流体转运到气道表面液体中,以水化粘液且优化纤周流体粘度。这会导致增强粘膜纤毛清除并减轻与COPD有关的症状。此外,通过预防因气道清除改善导致的进行性感染和炎症,CFTR调节剂可以预防或减缓特征在于肺气肿的气道实质毁坏和减少或逆转粘液细胞数量和大小增加,其以气道疾病中的粘液分泌过多为基础。干眼病的特征在于泪水产生减少以及泪液膜液体、蛋白质和粘蛋白性质异常。干眼有很多种原因,其中一些包括年龄、Lasik眼科手术、关节炎、药物、化学/热灼伤、变态反应和疾病,例如囊性纤维化和斯耶格伦综合征。通过CFTR的阴离子分泌增加可以增加由眼周围的角膜内皮细胞和分泌腺中的流体转运,以增强角膜水合。这有助于减轻与干眼病有关的症状。斯耶格伦综合征是一种自身免疫性疾病,其中免疫系统攻击全身的产生液体的腺体,包括眼、口、皮肤、呼吸组织、肝、阴道和消化道。症状包括眼、口和阴道干燥,以及肺病。该病也与类风湿性关节炎、系统性红斑狼疮、系统性硬化病和多肌炎/皮肌炎有关。蛋白质运输缺陷据认为会导致该疾病,由此限制了治疗选择。CFTR活性的调节剂可以使受该疾病影响的各种器官水合并有助于缓解相关的症状。具有囊性纤维化的个体存在肠梗阻反复发作和直肠脱垂、胆石、胃食管返流病、GI恶性肿瘤和炎性肠病的高发病率,显示CFTR功能可能在预防这类疾病中起重要作用。
如上所述,据认为,ΔF508-CFTR中残基508的缺失会妨碍初生蛋白正确折叠,导致该突变蛋白不能退出ER,并通过质膜。结果,质膜中存在的成熟蛋白量不足,上皮组织内的氯离子转运显著减少。事实上,经由ER机制加工CFTR的ER缺陷的这种细胞现象已经显示出,其不仅是CF疾病的潜在基础,也是范围广泛的其他独立和遗传疾病的潜在基础。导致ER机制障碍的两种途径是,通过丧失与蛋白质的ER出口偶合而导致降解,或者是通过这些缺陷/错误折叠蛋白质的ER蓄积[Aridor M.等人,Nature Med.,5(7),pp 745-751(1999);Shastry,B.S.等人,Neurochem.International,43,pp 1-7(2003);Rutishauser,J.等人,Swiss Med Wkly,132,pp 211-222(2002);Morello,JP等人,TIPS,21,pp.466-469(2000);Bross P.等人,Human Mut.,14,pp.186-198(1999)]。与第一类ER障碍有关的疾病是囊性纤维化(由如上所述的错误折叠的ΔF508-CFTR导致)、遗传性肺气肿(由α1-抗胰蛋白酶;非Piz变体导致)、遗传性血色病、凝血-纤溶缺陷,例如蛋白质C缺乏症、1型遗传性血管性水肿、脂质加工缺陷,例如家族性高胆固醇血症、1型乳糜微粒血症、无β脂蛋白血症、溶酶体贮积症,例如I-细胞病/假性-赫尔勒综合症(pseudo-Hurler)、粘多糖症(由溶酶体加工酶导致)、桑霍夫病/泰-萨病(由β-氨基己糖苷酶导致)、克-纳综合征(Crigler-Najjar)II型(由UDP-葡糖醛酸-唾液酸-转移酶导致)、多内分泌腺病/高胰岛素血症、糖尿病(由胰岛素受体导致)、拉伦侏儒症(由生长激素受体导致)、髓过氧化物酶缺乏症、原发性甲状旁腺功能减退(由前甲状旁腺激素原导致),黑素瘤(由酪氨酸酶导致)。与后一类ER障碍有关的疾病是聚糖病(Glycanosis)CDG 1型、遗传性肺气肿(由α1-抗胰蛋白酶(PiZ变体)导致)、先天性甲状腺功能亢进症、成骨不全(由I、II、IV型前胶原导致)、遗传性低纤维蛋白原血症(由纤维蛋白原导致)、ACT缺乏症(由α1-抗胰凝乳蛋白酶导致)、尿崩症(DI)、神经生长性DI(由加压素激素/V2-受体导致)、肾性DI(由水通道蛋白-II导致)、夏-马-图综合征(由周围髓磷脂蛋白22导致)、佩-梅病、神经变性疾病,例如阿尔茨海默病(由βAPP和衰老蛋白导致)、帕金森病、肌萎缩性侧索硬化、进行性核上性麻痹、皮克病、若干聚谷氨酰胺神经性障碍,例如亨廷顿病、I型脊髓小脑性共济失调、脊髓与延髓肌肉萎缩症、齿状核红核苍白球丘脑下部核萎缩,和肌强直性营养不良,以及海绵状脑病,例如遗传性克雅病(由朊病毒蛋白加工缺陷导致)、法布里病(由溶酶体α-半乳糖苷酶A导致)、格-斯-施综合征(由Prp加工缺陷导致)、不育症胰腺炎、胰腺功能不全、骨质疏松症、骨质减少、戈勒姆(Gorham)综合征、氯化物通道病变、先天性肌强直(汤姆森(Thomson)和贝克尔(Becker)型)、巴特综合征III型、登特(Dent)病、过度惊跳症、癫痫症、过度惊跳症、溶酶体贮存病、安格曼(Angelman)综合征、原发性纤毛运动障碍(PCD)、具有左右转位的PCD(也称作卡特金纳综合征)、没有左右转位和纤毛发育不良的PCD和肝病。
CFTR中突变牵连的其他疾病包括因输精管先天性双侧缺失(CBAVD)导致的男性不育症、轻度肺病、特发性胰腺炎和变应性支气管肺曲菌病(ABPA)。参见“CFTR-opathies:disease phenotypesassociated with cystic fibrosis transmembrane regulator genemutations”,Peader G.Noone和Michael R.Knowles,Respir.Res.2001,2:328-332(引入本文参考)。
除了向上调节CFTR活性以外,CFTR调节剂导致的阴离子分泌减少对于治疗分泌性腹泻可能是有益的,其中由于促分泌性活化的氯离子转运,上皮细胞的水转运显著增加。该机制包括提高cAMP和刺激CFTR。
尽管腹泻有很多原因,但由氯离子转运过量引起的腹泻性疾病的主要后果是共同的,包括脱水、酸中毒、发育受损和死亡。急性和慢性腹泻代表了世界上很多地区的主要医学问题。腹泻是营养不良的重要因素,并且是导致5岁以下儿童死亡的主要原因(每年死亡5,000,000人)。
分泌性腹泻也是获得性免疫缺陷综合征(AIDS)和慢性炎性肠病(IBD)患者的一种危险的症状。每年都有1600万从发达国家到发展中国家的旅行者会发生腹泻,腹泻病例的严重性和数量随着所旅行的国家和地区而变化。
因此,对人CFTR野生型和突变型的有效和选择性CFTR增强剂存在需求,这些突变型CFTR包括、但不限于ΔF508del、G551D、R117H、2789+5G->A。
对CFTR活性调节剂及其组合物也存在需求,它们可以用于调节哺乳动物细胞膜中的CFTR活性。
对使用这种CFTR活性调节剂治疗因CFTR中突变导致的疾病的方法存在需求。
对调节哺乳动物离体细胞膜中CFTR活性的方法存在需求。
发明概述
现在已经发现,本发明的化合物及其药学上可接受的组合物用作CFTR活性的调节剂。这些化合物具有式(I):
或其药学上可接受的盐,其中R1、R2、R3和A如下文一般所述和分类乃至亚类所述。
这些化合物和药学上可接受的组合物用于治疗以下各种与CFTR中的突变相关的疾病、障碍或病症或者减轻所述疾病、障碍或病症的严重性。
发明详述
本发明化合物的一般描述:
本发明涉及用作CFTR活性调节剂的式(I)的化合物:
或其药学上可接受的盐,其中:
环A选自:
R1是-CF3、-CN或-C≡CCH2N(CH3)2;
R2是氢、-CH3、-CF3、-OH或-CH2OH;
R3是氢、-CH3、-OCH3或-CN;
条件是R2和R3不同时为氢。
化合物和定义:
本发明的化合物包括上文一般性描述的那些,通过本文所述的类、亚类和种类进一步说明。在本文中使用时,除非另有说明,适用下列定义。
本文使用的术语“ABC-转运体”是指ABC-转运蛋白或其包含至少一个结合区的片段,其中所述蛋白或其片段存在于体内或体外。本文使用的术语“结合区域”是指可以与调节剂结合的ABC-转运体上的一个区域。参见,例如,Hwang,T.C.等人,J.Gen.Physiol.(1998):111(3),477-90。
本文使用的术语“CFTR”是指囊性纤维化跨膜传导调节因子或其具有调节活性的突变体,包括但不限于ΔF508 CFTR、R117H CFTR和G551D CFTR(例如,参见http://www.genet.sickkids.on.ca/cftr/,CFTR突变体)。
本文使用的术语“调节”是指以可测定量增加或减少。
本文所用的术语“正常CFTR”或“正常CFTR功能”是指类似于CFTR这样的不具有任何因环境因素导致损伤的野生型,所述的环境因素例如吸烟、污染或任何在肺中产生炎症的情况。
本文所用的术语“降低的CFTR”或“降低的CFTR功能”是指低于正常CFTR或低于正常CFTR功能。
为了本发明的目的,根据元素周期表,CAS版,Handbook ofChemistry and Physics,第75版来鉴定化学元素。此外,在“OrganicChemistry”,Thomas Sorrell,University Science Books,Sausalito:1999,以及“March′s Advanced Organic Chemistry”,第5版,Ed.:Smith,M.B.和March,J.,John Wiley & Sons,New York:2001中描述了有机化学的一般原理,将其全部内容通过参考引入本文。
本发明关注的取代基组合优选是导致形成稳定或化学上切实可行的化合物这样的取代基组合。本文所用的术语“稳定的”意指在接触能够进行其生产、检测且优选其回收、纯化和用于本文公开的一个或多个目的的条件时基本上不改变的化合物。在一些实施方案中,稳定或化学上切实可行的化合物是在保持在40℃以下的温度、在没有湿度或其他化学反应条件的存在下保持至少1周不改变的化合物。
本文所用的术语“保护基”是指暂时用于打断多官能化合物上的一个或多个期望反应位置的试剂。在一些实施方案中,保护基具有一个或多个或优选全部如下特征:a)以良好收率选择性反应,得到被保护的底物,在一个或多个其他反应位置上发生反应时它保持稳定;和b)用不攻击再生官能团的试剂以良好收率选择性除去。典型保护基详细描述在Greene,T.W.,Wuts,P.G的“Protective Groups in OrganicSynthesis”,第3版John Wiley & Sons,New York:1999和该书的其他版本中,将这些文献的全部内容引入本文参考。
除非另作陈述,否则本文描述的结构也指包括该结构的所有异构体(例如对映体、非对映异构体和几何异构体(或构象))形式;例如每一不对称中心的R和S构型、(Z)和(E)双键异构体和(Z)和(E)构象异构体。因此,本发明化合物的单一立体化学异构体和对映体、非对映异构体和几何(构象)混合物属于本发明的范围。除非另作陈述,否则本发明的所有互变体形式均属于本发明的范围;例如,式(I)的化合物可以作为互变体存在:
另外,除非另作陈述,否则本文描述的结构也指包括仅在一个或多个富合同位素的原子的存在下不同的化合物。例如,具有本发明结构的化合物,除氢被氘或氚替代或碳被富含13C-或14C-的碳替代外,都属于本发明的范围。例如,这种化合物用作生物试验中的分析工具或探针。这种化合物、特别是包含氘原子的化合物可以显示改进的代谢特性。
典型化合物的描述:
本发明提供式(I)的化合物:
或其药学上可接受的盐,其中:
环A选自:
R1是-CF3、-CN或-C≡CCH2N(CH3)2;
R2是氢、-CH3、-CF3、-OH或-CH2OH;
R3是氢、-CH3、-OCH3或-CN;
条件是R2和R3不同时为氢。
在另一个实施方案中,环A是
在一个实施方案中,R1是-CF3。
在另一个实施方案中,R1是-CN。
在另一个实施方案中,R1是-C≡CCH2N(CH3)2。
在一个实施方案中,R2是-CH3。
在另一个实施方案中,R2是-CF3。
在另一个实施方案中,R2是-OH。
在另一个实施方案中,R2是-CH2OH。
在一个实施方案中,R3是-CH3。
在一个实施方案中,R3是-OCH3。
在另一个实施方案中,R3是-CN。
在一个实施方案中,R2是氢;R3是-CH3、-OCH3或-CN。
在另一个实施方案中,R2是-CH3、-CF3、-OH或-CH2OH;R3是氢。
在本发明的几个实施方案中,环A是R1是-CF3,R2是氢;R3是-CH3、-OCH3或-CN。在其他实施方案中,R1是-CN。在其他实施方案中,R1是-C≡CCH2N(CH3)2。在一个实施方案中,R3是-CH3。或R3是-OCH3。或R3是-CN。
在本发明的其他实施方案中,环A是R1是-CF3,R2是-CH3、-CF3、-OH或-CH2OH,R3是氢。在其他实施方案中,R1是-CN。在其他实施方案中,R1是-C≡CCH2N(CH3)2。在一个实施方案中,R2是-CH3。或R2是-CF3。或R2是-OH。或R2是-CH2OH。
在本发明的几个实施方案中,环A是R1是-CF3,R2是氢;R3是-CH3、-OCH3或-CN。在其他实施方案中,R1是-CN。在其他实施方案中,R1是-C≡CCH2N(CH3)2。在一个实施方案中,R3是-OCH3。或R3是-CH3。或R3是-CN。
在本发明的其他实施方案中,环A是R1是-CF3,R2是-CH3、-CF3、-OH或-CH2OH,R3是氢。在其他实施方案中,R1是-CN。在其他实施方案中,R1是-C≡CCH2N(CH3)2。在一个实施方案中,R2是-CH3。或R2是-CF3。或R2是-OH。或R2是-CH2OH。
在本发明的几个实施方案中,环A是R1是-CF3,R2是氢;R3是-CH3、-OCH3或-CN。在其他实施方案中,R1是-CN。在其他实施方案中,R1是-C≡CCH2N(CH3)2。在一个实施方案中,R3是-CH3。或R3是-OCH3。或R3是-CN。
在本发明的其他实施方案中,环A是R1是-CF3,R2是-CH3、-CF3、-OH或-CH2OH,R3是氢。在其他实施方案中,R1是-CN。在其他实施方案中,R1是-C≡CCH2N(CH3)2。在一个实施方案中,R2是-CH3。或R2是-CF3。或R2是-OH。或R2是-CH2OH。
在本发明的几个实施方案中,环A是R1是-CF3,R2是氢;R3是-CH3、-OCH3或-CN。在其他实施方案中,R1是-CN。在其他实施方案中,R1是-C≡CCH2N(CH3)2。在一个实施方案中,R3是-CH3。或R3是-OCH3。或R3是-CN。
在本发明的其他实施方案中,环A是R1是-CF3,R2是-CH3、-CF3、-OH或-CH2OH,R3是氢。在其他实施方案中,R1是-CN。在其他实施方案中,R1是-C≡CCH2N(CH3)2。在一个实施方案中,R2是-CH3。或R2是-CF3。或R2是-OH。或R2是-CH2OH。
本发明有代表性的化合物在下表1中举出。
表1
一般合成路线
本发明的化合物易于通过本领域公知的方法方法制备,如合成路线1-3中所述。
合成路线1.式(I)化合物的制备
a)(CO2R)2CH=CH(OR),甲苯,加热;b)道氏热载体(Dowtherm)或二苯基醚,回流,N2气氛;c)如果存在,除去卤素阻断基(例如-Cl),Pd/C,H2,EtOH;d)用碱或酸除去保护基;e)CH3CN,Et3N,加热;f)Pd/C,H2,EtOH;g)HATU,Et3N,DMF或丙基膦酸环酐吡啶,2-甲基四氢呋喃。
合成路线1描述了由取代的苯衍生物1a和2a制备式(I)化合物的集合性方法。在最终的转化中,可以使用在N,N-二甲基甲酰胺(DMF)中的O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸盐(HATU)和三乙胺或者在2-甲基四氢呋喃中的丙基磺酸(sulfronicacid)环酐和吡啶通过使羧酸1d与胺2c偶合形成酰胺得到式(I)化合物。由相应的取代的苯衍生物1a制备羧酸1d,通过从加热-介导的1a与适合的丙二酸酯(CO2R)2CH=CH(OR)的缩合开始的次序进行,其中R是烷基,例如甲基、乙基等,得到1b。
通过三步次序将化合物1b转化成羧酸1d,包括在回流状态下加热时在道氏热载体或二苯基醚中的分子内环化(步骤b),然后在钯催化的脱卤化条件下除去(如果需要)阻断卤代基团(步骤c)和酸-或碱-催化的皂化(步骤d)。脱保护和皂化次序可以颠倒;即步骤c可以在步骤d之前或之后进行,如合成路线1所述。
再涉及到合成路线1,通过三步次序由硝基苯2a制备苯胺衍生物2c。因此,如本文所定义的在三乙胺的存在下硝基苯2a与环胺3偶合得到化合物2b。钯催化的2b还原得到胺2c。
合成路线2.式(I)化合物的制备
DMSO,K2CO3,80℃;b)N,N-二甲基丙-2-炔-1-胺,Pd(PPh3)2Cl2,CuI,DMF,TEA,80℃;c)Fe,FeSO4,H2O或Zn,AcOH,H2O;d)HATU,Et3N,DMF或丙基膦酸环酐吡啶,2-甲基四氢呋喃。
合成路线2描述了具有丙炔基胺侧链的式(I)化合物的合成。因此,如在碳酸钾的存在下在DMSO中硝基苯2a,其中Hal是溴、氯等,与如本文所定义的3偶合得到化合物4。钯催化化合物4与N,N-二甲基丙-2-炔-1-胺偶合,然后铁或锌催化硝基部分还原,得到胺5。胺5与羧酸1d偶合得到化合物6,其为式(I)的化合物。
合成路线3.式(I)化合物的制备,其中R是H或OH
DMSO,K2CO3,加热或CH3CN,TEA,加热;b)PGX,例如TBDMSCl,碱,例如咪唑,DMF;c)H2,Pd/C,EtOH;d)HATU,Et3N,DMF或丙基膦酸环酐吡啶,2-甲基四氢呋喃;e)PG脱保护,例如HCl,EtOH。PG=保护基;X=离去基。
合成路线3描述式(I)化合物的合成,其中3是7-氮杂二环[2.2.1]庚烷,其在2-位上任选地带有外或内羟基。使用如Fletcher,S.R.等人在“Total Synthesis and Determination of the AbsoluteConfiguration of Epibatidine”,J.Org.Chem,59,pp.1771-1778(1994)中所述的方法制备羟基-取代的加合物(+)-内-7-氮杂二环[2.2.1]庚-2-醇、(-)-内-7-氮杂二环[2.2.1]庚-2-醇、(+)-外-7-氮杂二环[2.2.1]庚-2-醇和(-)-外-7-氮杂二环[2.2.1]庚-2-醇。7-氮杂二环[2.2.1]庚烷自身购自Tyger Scientific Inc.324Stokes Avenue Ewing,NJ,08638 USA。
因此,与合成路线1和2中概述的系列转化一样,化合物2a与二环[2.2.1]胺7偶合得到化合物8。如果羟基存在于化合物8上,则有必要用保护基保护羟基,然后进行转化。因此,用叔丁基二甲基甲硅烷基氯、使用已知条件处理化合物8得到被保护的化合物9,然后还原硝基部分,得到胺10。与1d(参见合成路线3)形成酰胺并除去羟基保护基(根据需要)得到化合物11,其为式(I)的化合物。
应用、制剂和给药
药学上可接受的组合物
在本发明的一个方面中提供了药学上可接受的组合物,其中这些组合物包含如本文所述的任意化合物且任选包含药学上可接受的载体、佐剂或媒介物。在一些实施方案中,这些组合物任选还包含一种或多种另外的治疗剂。
也应认识到,本发明的某些化合物可以以游离形式存在用于治疗,或者如果适当可以以其药学上可接受的衍生物或前药的形式存在。根据本发明,药学上可接受的衍生物或前药包括但不限于,药学上可接受的盐、酯、这些酯的盐或者在施用于有此需要的患者时能直接或间接提供本文所述的化合物或其代谢产物或残留物的任何另外的加合物或衍生物。
本文使用的术语“药学上可接受的盐”是指在合理的医学判断的范围内,适用于与人和低级动物的组织接触而没有异常毒性、刺激性、过敏反应等的那些盐,而且具有合理的收益/风险比。“药学上可接受的盐”是指本发明化合物的任何无毒性的盐或酯盐,当施用于接受者时,能够直接或间接提供本发明的化合物或其具有抑制活性的代谢产物或残留物。
药学上可接受的盐是本领域公知的。例如S.M.Berge等人在J.Pharmaceutical Sciences,1977,66,1-19中详细描述了药学上可接受的盐,将其引入本文作参考。本发明化合物的药学上可接受的盐包括由适当的无机和有机的酸和碱衍生的盐。药学上可接受的无毒性的酸加成盐的例子是与无机酸例如盐酸、氢溴酸、磷酸、硫酸和高氯酸形成的氨基盐,或是与有机酸例如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸形成的氨基盐,或通过使用本领域使用的其他方法例如离子交换法而形成的氨基盐。
其他药学上可接受的盐包括己二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、十二烷基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等。由适当的碱产生的适当的盐包括碱金属、碱土金属、铵和N+(C1-4烷基)4盐。本发明也包括本文所述的化合物的任何碱性含氮基团的四价化形式。通过这种四价化可以获得水或油溶性或可分散于水或油中的产物。代表性的碱或碱土金属盐类包括钠、锂、钾、钙、镁盐等。当适当时,药学上可接受的盐还包括无毒的铵盐、季铵盐,以及使用抗衡离子形成的胺阳离子盐,例如卤化物、氢氧化物、羧酸盐、硫酸盐、磷酸盐、硝酸盐、低级烷基磺酸盐和芳基磺酸盐。
如上所述,本发明的药学上可接受的组合物还包含药学上可接受的载体、佐剂或赋形物,其在本文中使用时,包括任何和所有的溶剂、稀释剂或其他液体载体、助分散剂或助悬剂、表面活性剂、等渗剂、增稠或乳化剂、防腐剂、固体粘合剂、润滑剂等,其适合所需的特定剂型。Remington的Pharmaceutical Sciences,第16版,E.W.Martin(Mack Publishing Co.,Easton,Pa.,1980)描述了在配制药学上可接受的组合物中使用的各种载体和已知的制备技术。除了例如由于产生任何不希望的生物学效应或以有害的方式干扰该药学上可接受的组合物的任何其他组分而与本发明化合物不相容的任何常规的载体介质以外,其使用也涵盖在本发明的范围内。可以用作药学上可接受的载体的物质的一些例子包括但不限于,离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白质例如人血清白蛋白、缓冲物质例如磷酸盐、甘氨酸、山梨酸或山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质,例如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段共聚物、羊毛脂、糖,例如乳糖、葡萄糖和蔗糖;淀粉例如玉米淀粉和马铃薯淀粉;纤维素及其衍生物例如羧甲基纤维素钠、乙基纤维素和醋酸纤维素;西黄蓍胶粉;麦芽;明胶;滑石粉;赋形剂,例如可可脂和栓剂用蜡;油,例如花生油、棉籽油;红花油;芝麻油;橄榄油;玉米油和豆油;二醇类;例如丙二醇或聚乙二醇;酯类例如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,例如氢氧化镁和氢氧化铝;海藻酸;无热原的水;等渗盐水;林格液;乙醇,和磷酸盐缓冲溶液,以及其他无毒性的相容性润滑剂,例如十二烷基硫酸钠和硬脂酸镁,此外根据配制者的判断,该组合物中也可以存在着色剂、释放剂、包衣剂、甜味剂、调味剂和芳香剂、防腐剂和抗氧化剂。
化合物和药学上可接受的组合物的应用
在另一个方面,本发明提供一种治疗与CFTR突变牵连的病症、疾病或障碍或减轻所述病症、疾病或障碍严重性的方法。在一些实施方案中,本发明提供一种治疗与CFTR活性缺陷牵连的病症、疾病或障碍的方法,该方法包括给有此需要的受试者,优选哺乳动物施用包含式(I)化合物的组合物。
在一些实施方案中,本发明提供一种治疗与因编码CFTR的基因中的突变或环境因素(例如吸烟)导致的CFTR功能降低相关的疾病的方法。这些疾病包括囊性纤维化、慢性支气管炎、复发性支气管炎、急性支气管炎、先天性双侧输精管缺失(CBAVD)导致的男性不育症、子宫和阴道先天性缺失(CAUV)导致的女性不育症、特发性慢性胰腺炎(ICP)、特发性复发性胰腺炎、特发性急性胰腺炎、慢性鼻窦炎、原发性硬化性胆管炎、变应性支气管肺曲菌病、糖尿病、干眼、便秘、变应性支气管肺曲菌病(ABPA)、骨疾病(例如骨质疏松症)和哮喘。
在一些实施方案中,本发明提供一种治疗与正常CFTR功能降低相关的疾病的方法。这些疾病包括慢性阻塞性肺病(COPD)、慢性支气管炎、复发性支气管炎、急性支气管炎、鼻窦炎、便秘、胰腺炎包括慢性胰腺炎、复发性胰腺炎和急性胰腺炎、胰腺功能不全、先天性双侧输精管缺失(CBAVD)导致的男性不育症、轻度肺病、特发性胰腺炎、肝病、遗传性肺气肿、胆石、胃食管返流病、胃肠道恶性肿瘤、炎性肠病、便秘、糖尿病、关节炎、骨质疏松症和骨质减少。
在一些实施方案中,本发明提供一种治疗与正常CFTR功能降低相关的疾病的方法,包括:遗传性血色病、凝血-纤溶缺陷,例如蛋白质C缺乏症、1型遗传性血管性水肿、脂质加工缺陷,例如家族性高胆固醇血症、1型乳糜微粒血症、无β脂蛋白血症、溶酶体贮积症,例如I-细胞病/假性赫尔勒综合征、粘多糖症、桑德霍夫/泰-萨克斯病、克-纳综合征I I型、多内分泌腺病/高胰岛素血症、糖尿病、拉伦侏儒症、髓过氧化物酶缺乏症、原发性甲状旁腺功能减退、黑素瘤、聚糖病CDG1型、先天性甲状腺功能亢进症、成骨不全、遗传性低纤维蛋白原血症、ACT缺乏症、尿崩症(DI)、神经生长性DI、肾性DI、夏-马-图综合征、佩-梅病、神经变性疾病,例如阿尔茨海默病、帕金森病、肌萎缩性侧索硬化、进行性核上性麻痹、皮克病、若干聚谷氨酰胺神经性障碍,例如亨廷顿病、I型脊髓小脑性共济失调、脊髓与延髓肌肉萎缩症、齿状核红核苍白球丘脑下部核萎缩,和肌强直性营养不良,以及海绵状脑病,例如遗传性克雅病(由朊病毒蛋白加工缺陷导致)、法布里病、格-斯-施综合征、戈勒姆综合征、氯化物通道病变、先天性肌强直(汤姆森和贝克尔型)、巴特综合征III型、登特病、过度惊跳症、癫痫症、过度惊跳症、溶酶体贮存病、安格曼综合征、原发性纤毛运动障碍(PCD)、具有左右转位的PCD(也称作卡特金纳综合征)、没有左右转位和纤毛发育不良的PCD或斯耶格仑综合征,该方法包括对所述哺乳动物施用有效量的包含本发明化合物的组合物的步骤。
根据一个可替代的优选实施方案,本发明提供一种治疗囊性纤维化的方法,所述方法包括给所述哺乳动物施用组合物的步骤,该组合物包含本发明化合物。
根据本发明,化合物或药学上可接受的组合物的“有效量”是有效治疗如上所述一种或多种疾病、障碍或病症或减轻所述疾病、障碍或病症严重性的用量。
根据本发明的方法,化合物和组合物可以使用能有效治疗如上所述的一种或多种疾病或减轻所述疾病严重性的任何用量和任何给药途径来施用。
在一些实施方案中,本发明的化合物和组合物可以用于治疗患者的囊性纤维化或减轻患者的囊性纤维化的严重性,该患者的呼吸上皮或非呼吸上皮的顶膜中显示残留的CFTR活性。使用本领域已知的方法,例如标准的电生理学、生化或组织化学技术可以容易地检测上皮细胞表面残留的CFTR活性的存在。这些方法使用体外或离体的电生理技术、汗液或唾液的Cl-浓度测定或者离体生化或组织化学技术来监测细胞表面密度,以鉴定CFTR活性。使用这些方法,可以容易地在各种不同突变体的杂合或纯合的患者,包括最常见的突变体ΔF508的杂合或纯合的患者中检测残留的CFTR活性。
在另一个实施方案中,本发明的化合物和组合物可以用于治疗患者的囊性纤维化或减轻患者的囊性纤维化的严重性,该患者具有用药理学方法或基因疗法诱导或增强的残留CFTR活性。这些方法增加细胞表面上存在的CFTR的量,因此在患者中诱导迄今不存在的CFTR活性或在患者中提高残留CFTR活性的现存水平。
在一个实施方案中,本发明的化合物和组合物可以用于治疗患者的囊性纤维化或减轻患者的囊性纤维化的严重性,该患者具有某些显示残留CFTR活性的基因型,例如,III类突变(调节或门控受损)、IV类突变(传导改变)或V类突变(合成减少)(Lee R.Choo-Kang,PamelaL.,Zeitlin,Type I,II,III,IV,and V cystic fibrosisTansmembrane Conductance Regulator Defects and Opportunitiesof Therapy;Current Opinion in Pulmonary Medicine 6:521-529,2000)。显示残留CFTR活性的其他患者基因型包括这些类型之一的纯合或任何其他类型突变体的杂合的患者,所述其他类型的突变包括I类突变、II类突变或无分类的突变。
在一个实施方案中,本发明的化合物和组合物可以用于治疗患者的囊性纤维化或减轻患者的囊性纤维化的严重性,该患者具有某些临床显型,例如,典型地与上皮细胞顶膜上的残留CFTR活性的量相关的轻度至中度临床显型。这些显型包括显示胰腺充足的患者或者诊断为特发性胰腺炎和输精管的先天性双侧缺失或者轻度肺病的患者。
所需的确切的量对于不同的受治疗者而言是不同的,这取决于受治疗者的种类、年龄和一般状况、感染的严重度、具体的药物、其给药方式等。本发明的化合物优选配制成易于给药和剂量均匀的剂量单位形式。本文使用的表述“剂量单位形式”是指适合所要治疗的患者的药物的物理上分离的单位。但是,应当理解,本发明的化合物和组合物的每日总使用量将由主治医师在合理的医学判断范围内决定。任何具体的患者或生物体的具体有效剂量水平将取决于多种因素,包括所要治疗的疾病和该疾病的严重性;所使用的具体化合物的活性;所使用的具体组合物;患者的年龄、体重、一般健康状况、性别和饮食;给药时间、给药途径和所使用的具体化合物的排泄率;治疗的持续时间;与所使用的具体化合物联合或同时使用的药物等,以及医学领域公知的其它因素。本文使用的术语“患者”是指动物,优选哺乳动物,最优选人。
本发明的药学上可接受的组合物可以通过口服、直肠、胃肠外、脑池内、阴道内、腹膜内、局部(如通过粉剂、软膏或滴剂)、经颊以及作为口腔或鼻喷雾剂等方式施用于人和其它动物,这取决于所要治疗的感染的严重性。在一些实施方案中,本发明的化合物可以以每日约0.01mg/kg-约50mg/kg,优选约0.5mg/kg-约25mg/kg患者体重的剂量水平经口服或胃肠外施用,每日一次或多次,以获得期望的治疗效果。
用于口服给药的液体剂型包括但不限于,药学上可接受的乳剂、微乳、溶液、混悬液、糖浆和酏剂。除了活性化合物以外,该液体剂型可以包含本领域常用的惰性稀释剂,例如水或其它溶剂、增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(特别是,棉籽油、花生油、玉米油、胚油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃醇、聚乙二醇和脱水山梨糖醇脂肪酸酯,以及它们的混合物。除了惰性稀释剂,该口服组合物也可以包含佐剂,例如湿润剂、乳化剂和助悬剂、甜味剂、调味剂和芳香剂。
可以根据已知的技术,使用适当的分散或湿润剂和助悬剂配制可注射制剂,例如无菌注射用水或油性混悬液。无菌注射制剂也可以是在无毒性的胃肠外可接受的稀释剂或溶剂中的无菌注射溶液、混悬液或乳剂,例如在1,3-丁二醇中的溶液。可以使用的可接受的载体或溶剂是水、林格液,U.S.P.和等渗氯化钠溶液。此外,无菌的不挥发性油一般也用作溶剂或助悬介质。为此目的,可以使用任何温和的不挥发性油,包括合成的甘油单酯或甘油二酯。此外,脂肪酸例如油酸可以用于注射制剂中。
注射制剂可以通过例如细菌截留性过滤器过滤或通过掺入无菌固体组合物形式的灭菌剂来灭菌,其中所述无菌固体组合物可以在临用前溶解或分散于无菌水或其它无菌可注射介质中。
为了延长本发明化合物的效果,经常需要缓慢地吸收皮下或肌内注射的化合物。这可以通过使用水溶性差的晶体或无定形物质的液体混悬液来实现。那么,化合物的吸收速率将取决于其溶出速度,溶出速度又可能取决于晶体大小和晶型。可替代地,延迟胃肠外给药的化合物形式的吸收可以通过将该化合物溶解或混悬于油性载体中来实现。制备可注射的储库型(长效型)剂型,包括在生物可降解的聚合物例如聚乳酸-聚乙醇酸交酯中形成化合物的微囊基质。根据化合物与聚合物的比例和所使用的具体聚合物的性质,可以控制化合物的释放速率。其它生物可降解的聚合物的例子包括聚(正酯)和聚(酸酐)。储库型注射剂也可以通过将化合物包埋在与机体组织相容的脂质体或微乳中来制备。
直肠或阴道施用的组合物优选是栓剂,其可以通过将本发明的化合物与适当的非刺激性赋形剂或载体例如可可脂、聚乙二醇或栓剂用蜡混合来制备,其中所述赋形剂或载体在环境温度下是固体,但在体温下是液体,因此在直肠或阴道腔中融化并释放出活性化合物。
口服给药的固体剂型包括胶囊、片剂、丸剂、粉剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种惰性的、药学上可接受的赋形剂或载体混合,所述赋形剂或载体例如为柠檬酸钠或磷酸二钙、和/或a)填充剂或增充剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸,b)粘合剂,例如,羧甲基纤维素、海藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶,c)保湿剂,例如甘油,d)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠,e)溶解阻滞剂,例如石蜡,f)吸收促进剂,例如季铵类化合物,g)湿润剂,例如十六醇和单硬脂酸甘油酯,h)吸收剂,例如高岭土和膨润土,和i)润滑剂,例如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,及它们的混合物。在胶囊、片剂和丸剂的情况下,该剂型也可以包含缓冲剂。
相似类型的固体组合物也可以在软和硬的填充性明胶胶囊中用作填充剂,胶囊使用例如乳糖或奶糖,以及高分子聚乙二醇等赋形剂。可以用包衣和壳例如肠溶衣和药物配制领域公知的其它包衣材料来制备片剂、锭剂、胶囊、丸剂和颗粒剂等固体剂型。它们任选可以包含遮光剂,也可以是这样一种组合物:它们只在或优选在肠道的某一部分(任选地以延迟方式)释放一种或多种活性成分。可以使用的包埋组合物的例子包括聚合物质和蜡。相似类型的固体组合物也可以在软和硬的填充性明胶胶囊中用作填充剂,胶囊所用赋形剂例如为乳糖或奶糖,以及高分子量聚乙二醇等。
活性化合物也可以存在于具有一种或多种上述赋形剂的微囊中。可以用包衣和壳例如药物配制领域公知的肠溶衣和其它包衣材料来制备片剂、糖衣片、胶囊、丸剂和颗粒等固体剂型。在这些固体剂型中,活性化合物可以与至少一种惰性稀释剂,例如蔗糖、乳糖或淀粉混合。这些剂型也可以例如如一般实践,包含惰性稀释剂以外的其它物质,例如压片润滑剂和其它压片助剂,例如硬脂酸镁和微晶纤维素。在胶囊、片剂和丸剂的情况中,该剂型也可以包含缓冲剂。它们任选可以包含遮光剂,也可以是这样一种组合物:它们只在或优选在肠道的某一部分任选地以延迟方式释放一种或多种活性成分。可以使用的包埋组合物的例子包括聚合物和蜡。
本发明化合物的局部或经皮给药的剂型包括软膏、糊剂、乳剂、洗剂、凝胶剂、粉剂、溶液、喷雾剂、吸入剂或贴剂。活性组分在无菌条件下与药学上可接受的载体和任何需要的防腐剂或可能需要的缓冲剂混合。眼用制剂、滴耳剂和滴眼剂也涵盖在本发明的范围内。此外,本发明涵盖透皮贴剂的使用,它的附加优点在于向机体可控地递送化合物。这类剂型可以通过将化合物溶解或分散于适当的介质中来制备。也可以使用吸收增强剂来增加化合物通过皮肤的流量。可以通过提供速率控制膜或通过将化合物分散于聚合物基质或凝胶中来控制速率。
可以根据本领域一般描述和本文实施例中所述的方法测定用于本发明作为CFTR调节剂的化合物的活性。
也应当认识到,本发明的化合物和药学上可接受的组合物可以用在联合治疗中,也就是说,本发明的化合物和药学上可接受的组合物可以在一种或多种另外的所需治疗或医学操作的同时、之前或之后施用。在联合治疗方案中使用的治疗(治疗或操作)的具体组合将考虑所需的治疗和/或操作与所要实现的所需治疗效果之间的相容性。也应当认识到,所使用的治疗可以对相同的疾病达到期望的效果(例如,本发明的化合物可以与另一种用于治疗相同疾病的药物同时施用),或者它们可以实现不同的效果(例如,控制任何不良反应)。本文所用的通过正常给药来治疗或预防特定疾病或病症的另外的治疗剂被称作“适合所要治疗的疾病或病症”。
在一个实施方案中,另外的活性剂选自溶粘蛋白剂、支气管扩张剂、抗生素、抗感染剂、抗炎剂、本发明化合物以外的CFTR调节剂或营养剂。在另一个实施方案中,另外的活性剂是非本发明化合物的CFTR调节剂。
在一个实施方案中,另外的活性剂是抗生素。本文所用的典型抗生素包括妥布霉素包括妥布霉素吸入粉末(TIP)、阿奇霉素、氨曲南包括氨曲南的气雾剂形式、阿米卡星包括其脂质体制剂、环丙沙星包括其适合于通过吸入给药的制剂、左氧氟沙星包括其气雾剂制剂和两种抗生素的组合,例如磷霉素和妥布霉素。
在另一个实施方案中,另外的活性剂是黏液溶解药。本文所用的典型黏液溶解药包括
在另一个实施方案中,另外的活性剂是支气管扩张剂。典型支气管扩张剂包括沙丁胺醇、硫酸奥西那林(metaprotenerol sulfate)、醋酸吡布特罗、沙美特罗或硫酸tetrabuline。
在另一个实施方案中,另外的活性剂有效恢复肺气道表面液体。这种活性剂改善盐在细胞内和外的运动,使得肺气道中的粘液更易于水化且由此更易于被清除。典型的这种活性剂包括高张生理盐水、地纽福索钠([[(3S,5R)-5-(4-氨基-2-氧代嘧啶-1-基)-3-羟基氧戊环-2-基]甲氧基-羟基磷酰基][[[(2R,3S,4R,5R)-5-(2,4-二氧代嘧啶-1-基)-3,4-二羟基氧戊环-2-基]甲氧基-羟基磷酰基]氧基-羟基磷酰氯]磷酸氢盐)或bronchitol(甘露糖醇的吸入制剂)。
在另一个实施方案中,另外的活性剂是抗炎药,即可以减轻肺中的炎症的活性剂。本文所用的典型的这种活性剂包括布洛芬、二十二碳六烯酸(DHA)、西地那非、吸入谷胱甘肽、吡格列酮、羟氯喹或斯伐他汀。
在另一个实施方案中,另外的活性剂降低上皮钠通道阻滞剂(ENaC)的活性(通过阻断通道直接或通过调节导致ENaC活性增加的蛋白酶(例如丝氨酸蛋白酶、通道活化蛋白酶间接)。典型的这种活性剂包括卡莫司他(胰蛋白酶样蛋白酶抑制剂)、QAU145、552-02、GS-9411、INO-4995、Aerolytic和阿米洛利。降低上皮钠通道阻滞剂(ENaC)活性的另外的活性剂可以在例如PCT公开号WO2009/074575中找到,将该文献的全部内容完整性引入本文参考。
在本文所述的其他疾病中,CFTR调节剂例如式I的化合物与降低ENaC活性的活性剂的组合用于治疗Liddle综合征、炎性或过敏性病症包括囊性纤维化、原发性纤毛运动障碍、慢性支气管炎、慢性阻塞性肺病、哮喘、呼吸道感染、肺癌、口腔干燥和角结膜炎、呼吸道感染(急性和慢性;病毒和细菌性)和肺癌。
CFTR调节剂例如式I的化合物与降低ENaC活性的活性剂的组合还用于治疗阻断上皮钠通道介导的疾病,包括并非呼吸系统疾病的疾病,它们与通过上皮的流体调节异常相关,可能涉及其表面上的保护表面液体的生理学异常,例如口腔干燥(口干燥)或角结膜炎(干眼)。此外,阻断肾中的上皮钠通道可以用于促进多尿且由此诱导降血压效应。
哮喘包括内源性(非过敏性)哮喘和外源性(过敏性)哮喘、轻度哮喘、中度哮喘、重度哮喘、支气管哮喘、运动诱发哮喘、职业性哮喘和细菌感染后诱发的哮喘。对哮喘的治疗还应理解为包括治疗显示例如哮鸣症状的低于4或5岁和诊断或可诊断为″喘鸣婴儿″的受试者、具有主要医学关注的确立的患者类别和目前通常鉴定为初始或早期哮患者(为便利起见,这种特定哮喘病症称作“喘鸣婴儿综合征”)。治疗消除的预防性功效通过例如急性哮喘或支气管收缩发作症状发作频率或严重性下降、肺功能改善或气道高反应性改善得到证实。可以进一步通过对其他治标疗法的需求减少得到证实,即用于或预期在发作时限制或中断针对症状的攻击的疗法,例如抗炎(例如皮质类固醇)或支气管扩张。特别地,哮喘中的预防有益性对易于“晨降”的受试者而言显而易见。“晨降”是公认的哮喘综合征,常见于较大百分比的哮喘患者且特征在于哮喘发作,例如在约4-6am之间的几小时,即每次通常基本上远离任何预先给予的症状性哮喘疗法。
慢性阻塞性肺病包括慢性支气管炎或与之相关的呼吸困难、肺气肿以及其他药物疗法特别是其他吸入药物疗法之后的气道高反应性加剧。在一些实施方案中,CFTR调节剂例如式I的化合物与降低ENaC活性的活性剂的组合用于治疗无论何种类型或起源的支气管炎,包括,例如急性、结核性支气管炎、卡他性、格鲁布性、慢性或结核性支气管炎。
在另一个实施方案中,另外的活性剂是非式I化合物的CFTR调节剂,即具有调节CFTR活性的效应。典型的这种活性剂包括ataluren(3-[5-(2-氟苯基)-1,2,4-噁二唑-3-基]苯甲酸)、西那普肽、兰考韦泰、地来司他(人重组中性白细胞弹性蛋白酶)、cobiprostone(7-{(2R,4aR,5R,7aR)-2-[(3S)-1,1-二氟-3-甲基戊基]-2-羟基-6-氧代八氢环戊[b]吡喃-5-基}庚酸)或(3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸。在另一个实施方案中,另外的活性剂是(3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸。
其他治疗剂在本发明组合物中的含量将不超过在包含该治疗剂作为唯一活性成分的组合物中通常的给药量。优选地,其他治疗剂在目前所公开的组合物中的量将是通常的包含该药物作为唯一治疗活性剂的组合物中的含量的约50%-100%。
本发明化合物或其药学上可接受的组合物也可以引入到涂覆可植入医药装置的组合物中,如假肢、人工瓣膜、脉管移植物、斯坦特印模和导管。因此,本发明在另一方面包括涂覆可植入装置的组合物,其包含如上一般性描述和在本文的大类与小类中所述的本发明化合物,和适合于涂覆所述可植入装置的载体。在另一方面,本发明包括涂有组合物的可植入装置,所述组合物包含如上一般性描述和在本文大类与小类中所述的本发明化合物,和适合于涂覆所述可植入装置的载体。适合的涂料和涂覆可植入装置的一般制备方法描述在美国专利US6,099,562、5,886,026和5,304,121中。涂料通常是生物可相容的聚合材料,如水凝胶聚合物、聚甲基二硅氧烷、聚己内酯、聚乙二醇、聚乳酸、乙烯乙酸乙烯酯共聚物和它们的混合物。涂料可以可选地进一步被适合的氟硅酮、多糖、聚乙二醇、磷脂或其组合的表层所覆盖,以赋予组合物的控释特征。
本发明的另一方面涉及在生物样品或患者中调节CFTR活性(例如体外或体内),该方法包括对患者给予式(I)化合物或包含所述化合物的组合物或者使所述生物样品与式I化合物或包含所述化合物的组合物接触。本文所用的术语“生物样品”非限制性地包括细胞培养物及其提取物;从哺乳动物或其提取物获得的活组织检查材料;和血液、唾液、尿、粪便、精液、泪液或其他体液或者其提取物。
在生物样品中调节CFTR可用于本领域技术人员已知的多种目的。这类目的的实例包括但不限于CFTR在生物学与病理学现象中的研究;和新型CFTR调节剂的对比评价。
在另一个实施方案中,提供了体外或体内调节阴离子通道活性的方法,所述方法包括使所述通道与式(I)化合物接触的步骤。在优选的实施方案中,该阴离子通道是氯离子通道或碳酸氢根通道。在其他优选的实施方案中,该阴离子通道是氯离子通道。
按照可替代选择的实施方案,本发明提供增加细胞膜中功能性CFTR数量的方法,所述方法包括使所述细胞与式(I)化合物接触的步骤。
根据另一种优选的实施方式,通过测定跨膜电压电位来测定CFTR的活性。测定生物样品中跨膜电压电位的手段可以采用本领域的任意已知方法,如光学膜电位测定法或其他电生理学方法。
光学膜电位测定法采用如Gonzalez和Tsien所述的电压-敏感性FRET传感器(参见Gonzalez,J.E.和R.Y.Tsien(1995)“Voltagesensing by fluorescence resonance energy transfer in singlecells.”Biophys J 69(4):1272-80;和Gonzalez,J.E.和R.Y.Tsien(1997);“Improved indicators of cell membrane potentialthat use fluorescence resonance energy transfer”Chem Biol4(4):269-77)与测定荧光变化的仪器的组合,如电压/离子探针读数器(VIPR)(参见Gonzalez,J.E.,K.Oades等人(1999)“Cell-basedassays and instrumentation for screening ion-channel targets”Drug Discov Today 4(9):431-439)。
这些电压敏感性测定法基于膜溶性、电压敏感性染料DiSBAC2(3)与荧光磷脂CC2-DMPE之间荧光共振能量转移(FRET)的变化,所述荧光磷脂连接于质膜的外部小叶,充当FRET供体。膜电位(Vm)的变化导致带负电的DiSBAC2(3)跨越质膜重新分布,从CC2-DMPE转移的能量相应地改变。荧光发射的变化可以利用VIPRTMII监测,它是一种整合的液体处理器和荧光检测器,被设计用来在96-或384-孔微量滴定板中进行基于细胞的筛选。
在另一方面中,本发明提供试剂盒,用于体外或体内测定生物样品中CFTR或其片段的活性,所述试剂盒包括:(i)包含式(I)化合物或任意上述实施方案的组合物;和(ii)关于下列内容的说明书:a)使该组合物与该生物样品接触;和b)测定所述CFTR或其片段的活性。在一个实施方案中,试剂盒进一步包含关于下列内容的说明书:a)使另外的组合物与该生物样品接触;b)测定在所述另外的化合物的存在下所述CFTR或其片段的活性;和c)比较在另外的化合物的存在下CFTR活性与在式(I)组合物的存在下CFTR的密度。在优选的实施方案中,所述试剂盒用于测定CFTR的密度。
为了可以更加充分地理解本文所述发明,提供下列实施例。应当理解,这些实施例仅供说明,不以任何方式被解释为限制本发明。
制备式(I)化合物的方法和中间体
本发明的另一个方面涉及式(Ic)化合物或其药学上可接受的盐的制备方法:
其中该方法包括:
使式1d的酸与式2c的胺反应,得到式(Ic)的化合物
其中:
环A选自:
其中
R1是-CF3、-CN或-C≡CCH2N(CH3)2;
R2是氢、-CH3、-CF3、-OH或-CH2OH;
R3是氢、-CH3、-OCH3或-CN;
条件是R2和R3不同时为氢,且
Ra是氢或甲硅烷基保护基,所述甲硅烷基保护基选自三甲基甲硅烷基(TMS)、叔丁基二苯基甲硅烷基(TBDPS)、叔丁基二甲基甲硅烷基(TBDMS)、三异丙基甲硅烷基(TIPS)和[2-(三甲基甲硅烷基)乙氧基]甲基(SEM)。
在一个实施方案中,式1d的酸与式2c的胺的反应在溶剂中、在O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸盐(HATU)和三乙胺的存在下或在溶剂中、在丙基膦酸环酐和吡啶的存在下进行。更具体地说,溶剂包括N,N-二甲基甲酰胺、乙酸乙酯或2-甲基四氢呋喃。
在另一个实施方案中,Ra是氢或TBDMS。
在另一个实施方案中,Ra是TBDMS。
在另一个实施方案中,该方法还包括脱保护步骤;例如,当环A是时,其中Ra是甲硅烷基保护基,生成式(Ic)的化合物,其中环A是典型地,除去甲硅烷基保护基需要用酸例如乙酸或稀无机酸等处理,不过,可以使用其他试剂例如氟离子源(例如氟化四丁基铵)。
在该方法中,式2c的胺由式2a的化合物制备,所述方法包括下列步骤:
使式2a的化合物与式3的胺反应,得到式2b的化合物
其中:
Hal是F、Cl、Br或I;且
将式2b的化合物还原成式2c的胺
在式2c制备方法的一个实施方案中,步骤(a)中的式3的胺在原位由相应季铵盐例如胺盐酸盐生成,不过,也可以使用其他铵盐(例如三氟乙酸盐)。
在另一个实施方案中,步骤(a)在极性非质子溶剂中、在叔胺碱的存在下进行。可以使用的叔胺类的实例包括三乙胺、二异丙基乙胺、1,5-二氮杂二环[4.3.0]壬-5-烯(DBN)、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、1,4-二氮杂二环[2.2.2]辛烷(DABCO)和吡啶。可以使用的溶剂的实例包括N,N-二甲基甲酰胺、二甲亚砜或乙腈。
在一个实施方案中,叔胺碱是三乙胺。
在另一个实施方案中,步骤(a)在乙腈中、在三乙胺的存在下进行。
在另一个实施方案中,步骤(a)的反应温度为约75℃-约85℃。
在另一个实施方案中,步骤(a)的反应时间为约2-约30小时。
在式2c的胺的制备方法的一个实施方案中,步骤(b)在极性质子溶剂或极性质子溶剂混合物中、在钯催化剂的存在下进行。当钯是催化剂时,步骤(b)中的溶剂典型地是极性质子溶剂,例如醇。更具体地说,溶剂包括甲醇或乙醇。
在另一个实施方案中,步骤(b)在极性质子溶剂例如水中、在Fe和FeSO4或Zn和AcOH的存在下进行。
本发明的另一个方面涉及式(Ic)的化合物或其药学上可接受的盐的制备方法:
所述方法包括下列步骤:
使式2a的化合物与式3的胺反应,得到式2b的化合物
通过还原将式2b的化合物转化成式2c的胺
使式2c的胺与式1d的酸反应,得到式(Ic)的化合物
其中Hal是F、Cl、Br或I;
环A选自:
其中
R1是-CF3、-CN或-C≡CCH2N(CH3)2;
R2是氢、-CH3、-CF3、-OH或-CH2OH;
R3是氢、-CH3、-OCH3或-CN;
条件是R2和R3不同时为氢,且
Ra是氢或甲硅烷基保护基,所述甲硅烷基保护基选自三甲基甲硅烷基(TMS)、叔丁基二苯基甲硅烷基(TBDPS)、叔丁基二甲基甲硅烷基(TBDMS)、三异丙基甲硅烷基(TIPS)和[2-(三甲基甲硅烷基)乙氧基]甲基(SEM)。
在一个实施方案中,步骤(a)中式3的胺在原位由相应季铵盐例如胺乙酸盐生成,不过,也可以使用其他铵盐(例如三氟乙酸盐)。
在形成式2c的胺的步骤(a)的一个实施方案中,当式3的胺是时,Ra是氢或TBDMS。更具体地说,Ra是TBDMS。
在另一个实施方案中,步骤(a)在极性非质子溶剂中、在叔胺碱的存在下进行。可以使用的叔胺类的实例包括三乙胺、二异丙基乙胺、1,5-二氮杂二环[4.3.0]壬-5-烯(DBN)、1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)、1,4-二氮杂二环[2.2.2]辛烷(DABCO)和吡啶。
在一个实施方案中,叔胺碱是三乙胺。
在另一个实施方案中,步骤(a)在乙腈中、在三乙胺的存在下进行。
在另一个实施方案中,步骤(a)的反应温度为75℃-约85℃。
在另一个实施方案中,步骤(a)的反应时间为约2-约30小时。
在式2c的胺的制备方法的一个实施方案中,步骤(b)在极性质子溶剂或极性质子溶剂混合物中、在钯催化剂的存在下进行。当钯是催化剂时,步骤(b)中的溶剂典型地是极性质子溶剂,例如醇。更具体地说,溶剂包括甲醇或乙醇。
在另一个实施方案中,步骤(b)在极性质子溶剂例如水中、在Fe和FeSO4或Zn和AcOH的存在下进行。
在步骤(c)的一个实施方案中,式1d的酸与式2c的胺发反应在溶剂中、在的存在下O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸盐(HATU)和三乙胺或在溶剂中、在丙基膦酸环酐和吡啶的存在下进行。更具体地说,溶剂包括N,N-二甲基甲酰胺、乙酸乙酯或2-甲基四氢呋喃。
在另一个实施方案中,Ra是氢或TBDMS。
在另一个实施方案中,Ra是TBDMS。
在另一个实施方案中,该方法还包括脱保护步骤;例如当环A是时,其中Ra是甲硅烷基保护基,生成式(I)的化合物,其中环A是典型地,除去甲硅烷基保护基需要用酸例如乙酸或稀无机酸等处理,不过,可以使用其他试剂,例如氟离子源(例如氟化四丁基铵)。
其中
R1是-CF3、-CN或-C≡CCH2N(CH3)2,且
Ra是甲硅烷基保护基,所述甲硅烷基保护基选自三甲基甲硅烷基(TMS)、叔丁基二苯基甲硅烷基(TBDPS)、叔丁基二甲基甲硅烷基(TBDMS)、三异丙基甲硅烷基(TIPS)和[2-(三甲基甲硅烷基)乙氧基]甲基(SEM)。
本发明的另一个方面涉及化合物,其为其中环A是
其中
R1是-CF3、-CN或-C≡CCH2N(CH3)2,且
Ra是甲硅烷基保护基,所述甲硅烷基保护基选自三甲基甲硅烷基(TMS)、叔丁基二苯基甲硅烷基(TBDPS)、叔丁基二甲基甲硅烷基(TBDMS)、三异丙基甲硅烷基(TIPS)和[2-(三甲基甲硅烷基)乙氧基]甲基(SEM)。
本发明的另一个方面涉及式(IA)的化合物:
或其药学上可接受的盐,其中:
R1是-CF3、-CN或-C≡CCH2N(CH3)2;
R2是氢、-CH3、-CF3、-OH或-CH2OH;
R3是氢、-CH3、-OCH3或-CN;
条件是R2和R3不同时为氢,且
Ra是甲硅烷基保护基,所述甲硅烷基保护基选自三甲基甲硅烷基(TMS)、叔丁基二苯基甲硅烷基(TBDPS)、叔丁基二甲基甲硅烷基(TBDMS)、三异丙基甲硅烷基(TIPS)和[2-(三甲基甲硅烷基)乙氧基]甲基(SEM)。
本发明的另一个方面涉及式(I)的化合物
或其药学上可接受的盐,其中:
环A选自:
其中
R1是-CF3、-CN或-C≡CCH2N(CH3)2;
R2是氢、-CH3、-CF3、-OH或-CH2OH;
R3是氢、-CH3、-OCH3或-CN;
条件是R2和R3不同时为氢;
所述化合物通过本文公开的任意方法制备。
本发明的另一个方面涉及选自如下的化合物:
所述化合物通过本文公开的任意方法制备。
实施例
中间体1:4-氧代-5-(三氟甲基)-1,4-二氢喹啉-3-甲酸(17)。标题化合物的合成如合成路线4所示。
合成路线4
2-((2-氯-5-(三氟甲基)苯基氨基)亚甲基)丙二酸二乙酯(14)的制备。在安装迪安-斯达克(Dean-Stark)冷凝器的3-颈1-L圆底烧瓶中在氮气气氛下合并2-氯-5-(三氟甲基)苯胺12(200g,1.023mol)、2-(乙氧基亚甲基)丙二酸二乙酯13(276g,1.3mol)和甲苯(100mL)。将该溶液在搅拌下加热至140℃,将温度维持4h。将该反应混合物冷却至70℃,缓慢加入己烷(600mL)。搅拌得到的淤浆,将其温至室温。通过过滤收集固体,用10%乙酸乙酯的己烷溶液(2x400mL)洗涤,然后真空干燥,得到白色固体(350g,94%收率),为期望的缩合产物2-((2-氯-5-(三氟甲基)苯基氨基)亚甲基)丙二酸二乙酯14。1HNMR(400MHz,DMSO-d6)δ11.28(d,J=13.0Hz,1H),8.63(d,J=13.0Hz,1H),8.10(s,1H),7.80(d,J=8.3Hz,1H),7.50(dd,J=1.5,8.4Hz,1H),4.24(q,J=7.1Hz,2H),4.17(q,J=7.1Hz,2H),1.27(m,6H)。
8-氯-4-氧代-5-(三氟甲基)-1,4-二氢喹啉-3-甲酸乙酯(15)的制备。向3-颈1-L烧瓶中加入道氏热载体(200mL,8mL/g),在200℃脱气1h。将溶剂加热至260℃,在10min内分部分加入2-((2-氯-5-(三氟甲基)苯基氨基)亚甲基)丙二酸二乙酯14(25g,0.07mol)。将得到的混合物在260℃搅拌6.5小时(h),通过蒸馏除去得到的乙醇副产物。将该混合物缓慢冷却至80℃。在30分钟(min)内缓慢加入己烷(150mL),然后再一次加入200mL己烷。搅拌淤浆至其达到室温。过滤固体,用己烷(3x150mL)洗涤,然后真空干燥,得到8-氯-4-氧代-5-(三氟甲基)-1,4-二氢喹啉-3-甲酸乙酯15,为黄褐色固体(13.9g,65%收率)。1H NMR(400MHz,DMSO-d6)δ11.91(s,1H),8.39(s,1H),8.06(d,J=8.3Hz,1H),7.81(d,J=8.4Hz,1H),4.24(q,J=7.1Hz,2H),1.29(t,J=7.1Hz,3H)。
4-氧代-5-(三氟甲基)-1H-喹啉-3-甲酸乙酯(16)的制备。向3-颈5-L烧瓶中加入8-氯-4-氧代-5-(三氟甲基)-1,4-二氢喹啉-3-甲酸乙酯15(100g,0.3mol)、乙醇(1250mL,12.5mL/g)和三乙胺(220mL,1.6mol)。然后在5℃向容器中加入10g 10%Pd/C(50%湿)。将该反应体系在5℃在氢气气氛中剧烈搅拌20h,此后将该反应混合物浓缩至约150mL体积。将作为具有Pd/C的淤浆的产物4-氧代-5-(三氟甲基)-1H-喹啉-3-甲酸乙酯16直接用于下一步。
4-氧代-5-(三氟甲基)-1,4-二氢喹啉-3-甲酸(17)的制备。在带有回流冷凝器的1-L烧瓶中将4-氧代-5-(三氟甲基)-1H-喹啉-3-甲酸乙酯16(58g,0.2mol,包含Pd/C的粗反应淤浆)混悬于NaOH(814mL,5M,4.1mol),在80℃加热18h,然后在100℃再加热5h。将该反应体系通过填充的C盐温热过滤以除去Pd/C,用1N NaOH冲洗C盐。将滤液酸化至约pH 1,得到浓稠白色沉淀。过滤沉淀,然后用水和冷乙腈冲洗。然后真空干燥固体,得到4-氧代-5-(三氟甲基)-1,4-二氢喹啉-3-甲酸17,为白色固体(48g,92%收率)。1H NMR(400.0MHz,DMSO-d6)δ15.26(s,1H),13.66(s,1H),8.98(s,1H),8.13(dd,J=1.6,7.8Hz,1H),8.06-7.99(m,2H)。
中间体2:4-(7-氮杂二环[2.2.1]庚-7-基)-2-(三氟甲基)苯胺(21)。标题化合物的合成如合成路线5中所示。
合成路线5
7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚烷(20)的制备。在氮气气氛下向包含7-氮杂二环[2.2.1]庚烷盐酸盐7a(4.6g,34.43mmol,获自Tyger Scientific Inc.,324 Stokes Avenue,Ewing,NJ,08638 USA)的烧瓶中加入4-氟-1-硝基-2-(三氟甲基)苯18(6.0g,28.69mmol)和三乙胺(8.7g,12.00mL,86.07mmol)在乙腈(50mL)中的溶液。将反应烧瓶在80℃在氮气气氛下加热16h。将该反应混合物冷却,然后使其分配在水与二氯甲烷之间。用1M HCl洗涤有机层,用Na2SO4干燥,过滤,浓缩至干。通过硅胶色谱法纯化(0-10%乙酸乙酯的己烷溶液),得到7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚烷19(7.2g,88%收率),为黄色固体。1H NMR(400.0MHz,DMSO-d6)δ8.03(d,J=9.1Hz,1H),7.31(d,J=2.4Hz,1H),7.25(dd,J=2.6,9.1Hz,1H),4.59(s,2H),1.69-1.67(m,4H),1.50(d,J=7.0Hz,4H)。
4-(7-氮杂二环[2.2.1]庚-7-基)-2-(三氟甲基)苯胺(20)的制备。将加入7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚烷19(7.07g,24.70mmol)和10%Pd/C(0.71g,6.64mmol)的烧瓶抽真空,然后充氮气。加入乙醇(22mL),给反应烧瓶安装氢气囊。剧烈搅拌12h后,用氮气净化该反应混合物,通过过滤除去Pd/C。减压浓缩滤液至得到深棕色油状物,通过硅胶色谱法纯化残余物(0-15%乙酸乙酯的己烷溶液),得到4-(7-氮杂二环[2.2.1]庚-7-基)-2-(三氟甲基)苯胺20,为紫色固体(5.76g,91%收率)。1H NMR(400.0MHz,DMSO-d6)δ6.95(dd,J=2.3,8.8Hz,1H),6.79(d,J=2.6Hz,1H),6.72(d,J=8.8Hz,1H),4.89(s,2H),4.09(s,2H),1.61-1.59(m,4H)和1.35(d,J=6.8Hz,4H)。
中间体3:2-氨基-5-(7-氮杂二环[2.2.1]庚-7-基)苄腈(23)。标题化合物的合成如合成路线6中所示。
合成路线6
5-(7-氮杂二环[2.2.1]庚-7-基)-2-硝基苄腈(22)的制备。向5-氟-2-硝基苄腈21(160mg,0.96mmol)在乙腈(1mL)中的溶液中缓慢加入7-氮杂二环[2.2.1]庚烷盐酸盐7a(129mg,0.96mmol)和三乙胺(244mg,335.7μL,2.41mmol)。将该反应体系在60℃搅拌4h。用水使反应停止,用1N HCl酸化至pH 1,用二氯甲烷(3x10mL)萃取。用水洗涤合并的有机层,用MgSO4干燥,过滤,浓缩,得到5-(7-氮杂二环[2.2.1]庚-7-基)-2-硝基苄腈22(205mg,87%收率)。LC/MS m/z244.3[M+H]+,保留时间1.69min(RP-C18,10-99%CH3CN/0.05%TFA,3min内)。
2-氨基-5-(7-氮杂二环[2.2.1]庚-7-基)苄腈(23)的制备。给加入5-(7-氮杂二环[2.2.1]庚-7-基)-2-硝基苄腈22(205mg,0.8427mmol)和10%Pd/C(41mg,0.39mmol)的烧瓶充氮气,然后抽真空。在氮气气氛下加入甲醇(4mL),给反应烧瓶安装氢气囊。搅拌15min后,通过过滤除去Pd/C,减压除去溶剂,得到2-氨基-5-(7-氮杂二环[2.2.1]庚-7-基)苄腈23(170mg,95%收率)。1H NMR(400.0MHz,DMSO-d6)δ7.02(dd,J=2.8,9.0Hz,1H),6.87(d,J=2.7Hz,1H),6.68(d,J=9.0Hz,1H),5.36(s,2H),4.09(s,2H),1.59(d,J=6.8Hz,4H),1.34(d,J=6.8Hz,4H)。
中间体4:4-(7-氮杂二环[2.2.1]庚-7-基)-2-(3-(二甲基氨基)丙-1-炔基)苯胺(27)。标题化合物的合成如合成路线7中所示。
合成路线7
7-(3-溴-4-硝基苯基)-7-氮杂二环[2.2.1]庚烷(25)的制备。向2-溴-4-氟-1-硝基-苯24(1.1g,4.8mmol)和K2CO3(2.0g,14.3mmol)在DMSO(8.400mL)中的溶液中逐步加入7-氮杂二环[2.2.1]庚烷7a(765.4mg,5.7mmol)。将该反应体系在80℃搅拌24h。用水稀释该反应体系,以沉淀产物。将固体再溶于二氯甲烷,用1.0N HCl洗涤,用MgSO4干燥,过滤,浓缩,得到7-(3-溴-4-硝基苯基)-7-氮杂二环[2.2.1]庚烷25(1.1g,78%收率)。将粗产物直接用于下一步。LC/MSm/z 299.1[M+H]+,保留时间1.97min(RP-C18,10-99%CH3CN/0.05%TFA,3min内)。
3-[5-(7-氮杂二环[2.2.1]庚-7-基)-2-硝基-苯基]-N,N-二甲基-丙-2-炔-1-胺(26)的制备。向7-(3-溴-4-硝基-苯基)-7-氮杂二环[2.2.1]庚烷25(500mg,1.683mmol)、Pd(PPh3)2Cl2(59mg,0.08mmol)和碘化亚铜(9.616mg,1.708μL,0.05049mmol)中加入N,N-二甲基丙-2-炔-1-胺(420mg,538μL,5.05mmol)在脱气的DMF(5mL)和三乙胺(5mL)中的溶液。将该反应混合物在100℃在N2气氛下微波照射10min。用乙酸乙酯稀释该反应体系,用50%饱和碳酸氢钠溶液(2x20mL)、水和盐水洗涤。用无水Na2SO4干燥该溶液,过滤,得到红色固体。通过硅胶色谱法纯化(0-50%二氯甲烷的乙酸乙酯溶液),得到3-[5-(7-氮杂二环[2.2.1]庚-7-基)-2-硝基-苯基]-N,N-二甲基-丙-2-炔-1-胺26(400mg,79%收率)。LC/MS m/z 300.5[M+H]+,保留时间1.11min(RP-C18,10-99%CH3CN/0.05%TFA,3min内)。
4-(7-氮杂二环[2.2.1]庚-7-基)-2-(3-二甲基氨基丙-1-炔基)苯胺(27)的制备。将3-[5-(7-氮杂二环[2.2.1]庚-7-基)-2-硝基-苯基]-N,N-二甲基-丙-2-炔-1-胺26(340mg,1.14mmol)、铁(634mg,11.36mmol)和七水硫酸亚铁(316mg,1.136mmol)混悬于水(1mL),回流20min。过滤该反应体系,用甲醇和二氯甲烷洗涤固体。浓缩滤液,通过使用(0-5%甲醇的二氯甲烷溶液)的硅胶色谱法纯化,得到4-(7-氮杂二环[2.2.1]庚-7-基)-2-(3-二甲基氨基丙-1-炔基)苯胺27(148mg,48%收率)。LC/MS m/z 270.3[M+H]+,保留时间0.25min(RP-C18,10-99%CH3CN/0.05%TFA,3min内)。
中间体5:外-4-(2-(叔丁基二甲基甲硅烷基氧基)-7-氮杂二环[2.2.1]庚-7-基)-2-(三氟甲基)苯胺(30)。标题化合物的合成如合成路线8中所示。
合成路线8
外-7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚-5-醇(28)的制备。在氮气气氛下向包含外-7-氮杂二环[2.2.1]庚-2-醇7b(0.86g,5.74mmol)的烧瓶中加入4-氟-1-硝基-2-(三氟甲基)苯18(1g,4.78mmol)和三乙胺(1.45g,2.0mL,14.35mmol)在乙腈(8mL)中的溶液。将该反应体系在84℃、在氮气气氛下加热22h。将该反应混合物冷却,然后使其分配在水与乙酸乙酯之间。分离各层,用乙酸乙酯将水层萃取两次、用Na2SO4干燥合并的有机层,过滤,浓缩至干。通过硅胶色谱法纯化(0-50%乙酸乙酯的己烷溶液),得到外-7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚-5-醇28,为黄色固体(0.67g,46%收率)。LC/MS m/z 303.3[M+H]+,保留时间1.51min(RP-C18,10-99%CH3CN/0.05%TFA,3min内)。
外-叔丁基-二甲基-[[7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚-5-基]氧基]硅烷29的制备。将叔丁基-氯-二甲基-硅烷(197mg,1.267mmol)加入到4H-咪唑(144mg,2.11mmol)在DMF(0.5mL)中的溶液中。该溶液停止发泡后,加入作为在DMF(0.6mL)中的溶液的外-7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚-5-醇28(255mg,0.84mmol),在室温搅拌14h。用水使反应停止,用乙醚萃取两次,用MgSO4干燥,过滤,浓缩至得到无水油状物。通过硅胶色谱法纯化(0-40%二氯甲烷的己烷溶液),得到外-叔丁基-二甲基-[[7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚-5-基]氧基]硅烷29(318mg,90%收率),为黄色油状物。1H NMR(400.0MHz,DMSO-d6)δ8.01(d,J=9.2Hz,1H),7.29(d,J=2.4Hz,1H),7.19(dd,J=2.6,9.2Hz,1H),4.60(t,J=4.4Hz,1H),4.47(d,J=5.2Hz,1H),4.07(dd,J=2.0,6.8Hz,1H),1.94(dd,J=6.4,12.8Hz,1H),1.71-1.47(m,3H),1.39-1.32(m,2H),0.65(s,9H),0.03(s,6H)。
外-4-[5-[叔丁基(二甲基)甲硅烷基]氧基-7-氮杂二环[2.2.1]庚-7-基]-2-(三氟甲基)苯胺(30)的制备。将包含钯/活性炭(10wt%,30mg,0.28mmol)的烧瓶抽真空,用N2净化,加入外-叔丁基-二甲基-[[7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚-5-基]氧基]硅烷29(301mg,0.72mmol)在乙醇(3mL)中的溶液。将烧瓶抽真空,然后安装H2气囊,在室温搅拌4h。过滤该混合物,浓缩至干,得到外-4-[5-[叔丁基(二甲基)甲硅烷基]氧基-7-氮杂二环[2.2.1]庚-7-基]-2-(三氟甲基)苯胺30(268mg,96%收率),为黄白色固体。1HNMR(400.0MHz,DMSO-d6)δ6.92(dd,J=2.4,8.8Hz,1H),6.77(d,J=2.6Hz,1H),6.70(d,J=8.8Hz,1H),4.84(s,2H),4.11(t,J=4.4Hz,1H),3.91-3.89(m,2H),1.82(dd,J=7.1,12.3Hz,1H),1.54-1.39(m,3H),1.20-1.16(m,2H),0.79(s,9H),0.02(s,6H)。
中间体6:内-4-(2-(叔丁基二甲基甲硅烷基氧基)-7-氮杂二环[2.2.1]庚-7-基)-2-(三氟甲基)苯胺(34)。标题化合物的制备描述在合成路线9中。
合成路线9
7-氮杂二环[2.2.1]庚-5-酮(31)的制备。在-78℃、在氮气气氛下向草酰二氯(165mg,113μL,1.27mmol)在二氯甲烷(3mL)中的溶液中滴加DMSO(199mg,180μL,2.54mmol)在二氯甲烷(0.7mL)中的溶液。将该反应混合物搅拌30min,然后滴加外-7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚-5-醇28(320mg,1.06mmol)在二氯甲烷(2.5mL)中的溶液。将该反应体系在-78℃再搅拌1小时,然后滴加三乙胺(536mg,738μL,5.30mmol),将该反应体系温至室温。用二氯甲烷稀释该反应混合物,使其分配在二氯甲烷与水之间,分离各层。用二氯甲烷将水层萃取一次以上。用Na2SO4干燥合并的有机层,过滤,浓缩至得到黄色油状物。通过硅胶色谱法纯化(0-30%乙酸乙酯的己烷溶液),得到7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚-5-酮31(266mg,84%收率),为黄色固体。1H NMR(400.0MHz,DMSO-d6)δ8.06(d,J=9.1Hz,1H),7.47(d,J=2.4Hz,1H),7.39(dd,J=2.6,9.1Hz,1H),4.98(t,J=4.5Hz,1H),4.84(d,J=5.4Hz,1H),2.44(d,J=3.1Hz,1H),2.23(d,J=16Hz,1H),2.00-1.92(m,1H),1.88-1.70(m,2H),1.66-1.60(m,1H)。
内-7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚-5-醇(32)的制备。在-55℃、在氮气气氛下向7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚-5-酮31(261mg,0.87mmol)在THF(11mL)中的溶液中滴加三仲丁基-硼氢化锂溶液(1.04mL的1M,1.04mmol)。30min后,将该反应混合物转入冰水浴,持续搅拌。在0℃用甲醇(1.2mL)使该反应混合物猝灭。使该反应混合物分配在二氯甲烷/水之间,分离,用二氯甲烷将水层萃取两次以上。用Na2SO4干燥合并的有机层,浓缩至干。通过硅胶色谱法纯化(0-50%乙酸乙酯的己烷溶液),得到内-7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚-5-醇32(222mg,84%收率),为黄色固体。1H NMR(400.0MHz,DMSO-d6)δ8.01(d,J=9.1Hz,1H),7.27(d,J=3.0Hz,1H),7.22(dd,J=2.6,9.1Hz,1H),5.17(d,J=4.4Hz,1H),4.49(t,J=4.9Hz,1H),4.44(t,J=4.5Hz,1H),4.16-4.10(m,1H),2.20-2.06(m,2H),1.67-1.44(m,3H),1.09(dd,J=3.5,12.4Hz,1H)。
内-叔丁基-二甲基-[[7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚-5-基]氧基]硅烷(33)的制备。将叔丁基氯二甲基硅烷(168mg,1.08mmol)加入到4H-咪唑(122mg,1.80mmol)在DMF(425.3μL)中的溶液中。在该溶液停止发泡后,将作为在DMF(1mL)中的溶液的内-7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚-5-醇32(217mg,0.72mmol)加入,在室温搅拌14h。用水使反应停止,用乙醚将其萃取两次,用MgSO4干燥,过滤,浓缩至得到无水油状物。通过硅胶色谱法纯化(0-40%二氯甲烷的己烷溶液),得到内-叔丁基-二甲基-[[7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚-5-基]氧基]硅烷33(251mg,84%收率),为黄色油状物。1H NMR(400.0MHz,DMSO-d6)δ8.01(d,J=9.1Hz,1H),7.32(d,J=2.3Hz,1H),7.26(dd,J=2.5,9.1Hz,1H),4.54-4.51(m,2H),4.29-4.26(m,1H),2.20-2.11(m,2H),1.67-1.45(m,3H),1.08(dd,J=3.2,12.4Hz,1H),0.88(s,9H),0.07(d,J=2.6Hz,6H)。
内-4-[5-[叔丁基(二甲基)甲硅烷基]氧基-7-氮杂二环[2.2.1]庚-7-基]-2-(三氟甲基)苯胺(34)的制备。将包含钯/活性炭(10wt%,24mg,0.23mmol)的烧瓶抽真空,然后在氮气气氛下净化。向其中加入内-叔丁基-二甲基-[[7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚-5-基]氧基]硅烷33(240mg,0.58mmol)在乙醇(5mL)中的溶液。将该反应混合物抽真空,然后安装H2气囊,在室温搅拌4h。过滤该混合物,浓缩至干,得到内-4-[5-[叔丁基(二甲基)甲硅烷基]氧基-7-氮杂二环[2.2.1]庚-7-基]-2-(三氟甲基)苯胺34(222mg,100%收率),为黄白色固体。1H NMR(400.0MHz,DMSO-d6)δ6.95(dd,J=2.4,8.8Hz,1H),6.79(d,J=2.6Hz,1H),6.72(d,J=8.8Hz,1H),4.91(s,2H),4.24-4.19(m,1H),4.06-4.03(m,2H),2.12-1.99(m,2H),1.55-1.53(m,1H),1.42-1.36(m,2H),0.96(dd,J=3.2,12.2Hz,1H),0.87(s,9H),0.05(s,6H)。
实施例化合物3:N-(4-(7-氮杂二环[2.2.1]庚-7-基)-2-(三氟甲基)苯基)-4-氧代-5-(三氟甲基)-1,4-二氢喹啉-3-甲酰胺。标题化合物的制备描述在合成路线10。
合成路线10
在室温向4-氧代-5-(三氟甲基)-1H-喹啉-3-甲酸17(9.1g,35.39mmol)和4-(7-氮杂二环[2.2.1]庚-7-基)-2-(三氟甲基)苯胺20(9.2g,35.74mmol)在2-甲基四氢呋喃(91.00mL)中的溶液中加入丙基膦酸环酐(T3P,50%的乙酸乙酯溶液,52.68mL,88.48mmol)和吡啶(5.6g,5.73mL,70.78mmol)。将反应烧瓶在65℃、在氮气气氛下加热10h。冷却至室温后,用乙酸乙酯稀释该反应体系,用Na2CO3饱和溶液(50mL)使反应停止。分离各层,用乙酸乙酯将水层萃取两次。用水洗涤合并的有机层,用Na2SO4干燥,过滤,浓缩至得到黄褐色固体、将粗固体产物在乙酸乙酯/乙醚(2∶1)中搅拌成淤浆,通过真空过滤收集,用乙酸乙酯/乙醚(2∶1)洗涤两次以上,得到产物,为淡黄色结晶粉末。将该粉末溶于温乙酸乙酯,吸附在C盐上。通过硅胶色谱法纯化(0-50%乙酸乙酯的二氯甲烷溶液),得到N-(4-(7-氮杂二环[2.2.1]庚-7-基)-2-(三氟甲基)苯基)-4-氧代-5-(三氟甲基)-1,4-二氢喹啉-3-甲酰胺,为白色结晶固体(13.5g,76%收率)。LC/MS m/z 496.0[M+H]+,保留时间1.48min(RP-C18,10-99%CH3CN/0.05%TFA,3min内)。1H NMR(400.0MHz,DMSO-d6)δ13.08(s,1H),12.16(s,1H),8.88(s,1H),8.04(dd,J=2.1,7.4Hz,1H),7.95-7.88(m,3H),7.22(dd,2.5,8.9Hz,1H),7.16(d,J=2.5Hz,1H),4.33(s,2H),1.67(d,J=6.9Hz,4H),1.44(d,J=6.9Hz,4H)。
实施例化合物3晶型A HCl盐N-(4-(7-氮杂二环[2.2.1]庚-7-基)-2-(三氟甲基)苯基)-4-氧代-5-(三氟甲基)-1,4-二氢喹啉-3-甲酰胺盐酸盐(晶型A-HCl)。
7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚烷(19)的制备。将4-氟-1-硝基-2-(三氟甲基)苯(18)(901g)加入30L夹套容器。加入碳酸钠(959.1g)和5L二甲亚砜(DMSO),将该混合物在氮气气氛下搅拌。将7-氮杂二环[2.2.1]庚烷盐酸盐(7a)(633.4g)分部分加入到容器中。使该混合物的温度逐步升至55℃,通过HPLC监测反应体系。当底物少于1%AUC时,反应被视为完成。然后用10vol.2-甲基四氢呋喃稀释该混合物,用5.5vol.水洗涤三次,直到无DMSO保留在水层中,正如通过HPLC测定的,得到在2-甲基四氢呋喃中的7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚烷(19)(约95%收率)。
4-(7-氮杂二环[2.2.1]庚-7-基)-2-(三氟甲基)苯胺(20·HCl)盐酸盐的制备。在氮气气氛下将钯/碳(150g,5%w/w)加入步琪(Büchi)氢化器(20L容量),然后添加7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚烷(19)(1500g)和2-甲基四氢呋喃(10.5L,7vol)。将氢气加入封闭的氢化器至0.5巴压力。施加真空约2min,然后导入氢气至0.5巴压力。将该过程重复2次。然后持续将氢气以0.5巴压力加入到混合物中。然后通过冷却容器夹套将该混合物在18-23℃温度搅拌。施加真空给容器,此时再无氢气消耗且不再放热。然后将氮气以0.5巴加入容器,再施加真空,然后加入第二次0.5巴氮气。当过滤的等分部分的HPLC显示无7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚烷(19)保留(例如≤0.5%)时,将该反应混合物在氮气气氛下通过使用C盐滤膜的过滤漏斗转入接收烧瓶。用2-甲基四氢呋喃(3L,2vol)洗涤C盐滤饼。将洗涤液和滤液加入配有搅拌、温度控制和氮气的容器。在20℃将4M HCl的1,4-二噁烷溶液(1vol)在1h内持续加入容器。将该混合物再搅拌10h(或过夜),过滤,用2-甲基四氢呋喃(2vol)洗涤,干燥至生成1519g的4-(7-氮杂二环[2.2.1]庚-7-基)-2-(三氟甲基)苯胺盐酸盐(20·HCl),为白色结晶固体(约97%收率)。
7-[4-氨基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚烷盐酸盐(20·HCl)的可替代选择的制备。
在步琪氢化器(20L容量)中,在氮气气氛下导入钯/碳(5%w/w)(150g),然后添加7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚烷19(1500g)和2-甲基四氢呋喃(10.5L,7vol)。将氢气加入封闭的氢化器至0.5巴压力。单纯施加真空约(2min),然后导入氢气至0.5巴压力。将该过程重复2次。然后持续将氢气以0.5巴压力持续加入到氢化器中,开始搅拌。然后通过冷却容器夹套将该混合物维持在18-23℃温度。施加真空给容器,此时再无氢气消耗且不再放热。然后将氮气以0.5巴加入容器,再施加真空,然后以0.5巴加入氮气。认为反应完成,此时过滤的等分部分的HPLC显示未检测到7-[4-硝基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚烷(≤0.5%)。然后通过C盐过滤该反应混合物。将剩余的淤浆在氮气气氛下通过包含C盐滤膜的过滤漏斗转入接收烧瓶。用2-甲基四氢呋喃(3L,2vol)洗涤C盐滤饼。将洗涤液和滤液加入配有搅拌、温度控制和氮气的容器。在20℃将4M HCl的1,4-二噁烷溶液(1vol)在1h内持续加入容器。将该混合物再搅拌10h,过滤,用2-甲基四氢呋喃(2vol)洗涤,干燥至生成1519g的7-[4-氨基-3-(三氟甲基)苯基]-7-氮杂二环[2.2.1]庚烷盐酸盐(20·HCl),为白色结晶固体。
N-(4-(7-氮杂二环[2.2.1]庚-7-基)-2-(三氟甲基)苯基)-4-氧代-5-(三氟甲基)-1,4-二氢喹啉-3-甲酰胺盐酸盐(晶型A-HCl)。将2-甲基四氢呋喃(0.57L,1.0vol)加入30L加套反应容器,然后添加4-(7-氮杂二环[2.2.1]庚-7-基)-2-(三氟甲基)苯胺盐酸盐(20·HCl)(791g,2.67mol)和4-氧代-5-(三氟甲基)-1,4-二氢喹啉-3-甲酸(17)(573g,2.23mol),再加入5.2L(9.0vol)2-甲基四氢呋喃。开始搅拌,在15min内将在2-甲基四氢呋喃中的T3P(2.84kg,4.46mol)加入到反应混合物中。然后通过加液漏斗在30min内加入吡啶(534.0g,546.0mL,6.68mol)。将该混合物在约30min内温至45℃,搅拌12-15h。HPLC分析显示存在低于2%量的4-氧代-5-(三氟甲基)-1,4-二氢喹啉-3-甲酸。然后将该混合物冷却至室温。加入2-甲基四氢呋喃(4vol,2.29L),然后加入水(6.9vol,4L),同时将温度维持在低于30℃。除去水层,用NaHCO3饱和水溶液将有机层谨慎洗涤两次。然后用10%w/w柠檬酸(5vol)、最终用水(7vol)洗涤有机层。精滤该混合物,转入另一干燥容器。加入来自上一批的N-(4-(7-氮杂二环[2.2.1]庚-7-基)-2-(三氟甲基)苯基)-4-氧代-5-(三氟甲基)-1,4-二氢喹啉-3-甲酰胺盐酸盐(晶型A-HCl)晶种(3.281g,5.570mmol)。在2h内使HCl(g)(10eq)发泡,将该混合物搅拌过夜,过滤得到的混悬液,用2-甲基四氢呋喃(4vol)洗涤,抽干,在60℃烘箱干燥至恒重,得到868gN-(4-(7-氮杂二环[2.2.1]庚-7-基)-2-(三氟甲基)苯基)-4-氧代-5-(三氟甲基)-1,4-二氢喹啉-3-甲酰胺盐酸盐(晶型A-HCl)。
实施例化合物3晶型B HCl盐N-(4-(7-氮杂二环[2.2.1]庚-7-基)-2-(三氟甲基)苯基)-4-氧代-5-(三氟甲基)-1,4-二氢喹啉-3-甲酰胺盐酸盐(晶型B-HCl)。
实施例化合物3 实施例化合物3
晶型A盐酸盐 晶型B盐酸盐
(晶型A-HCl) (晶型B-HCl)
将2-甲基四氢呋喃(100mL)加入到安装搅拌器的具有氮气气氛的3颈烧瓶中。将实施例化合物3晶型A-HCl(实施例3B,55g,0.103mol)加入到烧瓶中,然加入349mL 2-甲基四氢呋喃,开始搅拌。将28mL水加入烧瓶,将烧瓶温至内部温度60℃,搅拌48h。将烧瓶冷却至室温,搅拌1h。真空过滤该反应混合物,直到滤饼干燥为止。用2-甲基四氢呋喃(4vol)洗涤滤饼两次。将固体滤饼保持在抽真空中约30分钟期限,转入干燥盘。将滤饼在60℃真空干燥至恒重,得到实施例化合物3晶型B-HCl,为白色结晶固体(49g)(约90%收率)。
实施例化合物6:N-(4-(7-氮杂二环[2.2.1]庚-7-基)-2-氰基苯基)-5-甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺的制备。标题化合物的制备描述在合成路线11。
合成路线11
向5-甲基-4-氧代-1,4-二氢喹啉-3-甲酸35(162mg,0.80mmol)和2-氨基-5-(7-氮杂二环[2.2.1]庚-7-基)苄腈23(170mg,0.80mmol)在2-甲基四氢呋喃(1.5mL)中的溶液中加入丙基膦酸环酐(50%的乙酸乙酯溶液,949.5μL,1.605mmol)和吡啶(126mg,129μL,1.60mmol)。封盖该反应体系,在100℃、在微波照射中加热65min。将该反应体系冷却至室温,用乙酸乙酯(10mL)稀释,用饱和Na2CO3溶液(6mL)使反应停止。用Na2SO4干燥有机层,过滤,浓缩。通过硅胶色谱法纯化(0-35%乙酸乙酯的二氯甲烷溶液),得到N-(4-(7-氮杂二环[2.2.1]庚-7-基)-2-氰基苯基)-5-甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺(157mg,49%收率)。LC/MS m/z 399.3[M+H]+,保留时间1.47min(RP-C18,10-99%CH3CN/0.05%TFA,3min内)。1H NMR(400.0MHz,DMSO-d6)δ12.77(s,1H),12.75(s,1H),8.77(s,1H),8.11(d,J=9.1Hz,1H),7.64-7.60(m,1H),7.55(d,J=8.0Hz,1H),7.34(d,J=2.8Hz,1H),7.27(dd,J=2.8,9.1Hz,1H),7.23(d,J=7.2Hz,1H),4.32(s,2H),2.91(s,3H),1.65(d,J=7.2Hz,4H),1.42(d,J=6.8Hz,4H)。
实施例化合物13:N-[4-(7-氮杂二环[2.2.1]庚-7-基)-2-(3-二甲基氨基丙-1-炔基)苯基]-4-氧代-5-(三氟甲基)-1H-喹啉-3-甲酰胺。标题化合物的制备描述在合成路线12中。
合成路线12
向4-氧代-5-(三氟甲基)-1H-喹啉-3-甲酸17(19mg,0.07mmol)和4-(7-氮杂二环[2.2.1]庚-7-基)-2-(3-二甲基氨基丙-1-炔基)苯胺27(20mg,0.07mmol)在2-甲基四氢呋喃(190.9μL)中的溶液中加入T3P(118mg,0.19mmol)和吡啶(12mg,12μL,0.15mmol)。将该反应体系在100℃、在微波照射中加热30min。用EtOAc稀释该反应体系,用饱和水溶液NaHCO3(50mL)使反应停止。分离各层,用EtOAc将水层萃取两次。用将合并的有机层萃取一次,用Na2SO4干燥,过滤,浓缩。通过反相HPLC(0-99%CH3CN/0.05%TFA)纯化残余物,得到N-[4-(7-氮杂二环[2.2.1]庚-7-基)-2-(3-二甲基氨基丙-1-炔基)苯基]-4-氧代-5-(三氟甲基)-1H-喹啉-3-甲酰胺(8mg,17%收率)。LC/MS m/z 509.7[M+H]+,保留时间1.06min(RP-C18,10-99%CH3CN/0.05%TFA,3min内)。1H NMR(400.0MHz,DMSO-d6)δ13.23(d,J=6.8Hz,1H),12.40(s,1H),10.31(s,1H),8.96(d,J=6.6Hz,1H),8.40(d,J=9.0Hz,1H),8.08-8.06(m,H),8.07(dd,J=1.5Hz,8.1Hz,1H),8.00-7.95(m,2H),7.15-7.09(m,2H),4.49(s,2H),4.29(s,2H),2.94(s,6H),1.67(d,J=7.2Hz,4H),1.44(d,J=7.0Hz,4H)。
实施例化合物5:内-N-[4-[(5S)-5-[叔丁基(二甲基)甲硅烷基]氧基-7-氮杂二环[2.2.1]庚-7-基]-2-(三氟甲基)苯基]-4-氧代-5-(三氟甲基)-1H-喹啉-3-甲酰胺。标题化合物的制备描述在合成路线13中。
合成路线13
内-N-[4-[(5S)-5-[叔丁基(二甲基)甲硅烷基]氧基-7-氮杂二环[2.2.1]庚-7-基]-2-(三氟甲基)苯基]-4-氧代-5-(三氟甲基)-1H-喹啉-3-甲酰胺的制备。向4-氧代-5-(三氟甲基)-1H-喹啉-3-甲酸17(148mg,0.58mmol)、O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基脲六氟磷酸盐(HATU)(306mg,0.81mmol)在2-甲基四氢呋喃(2.2mL)中的溶液中加入内-4-[5-[叔丁基(二甲基)甲硅烷基]氧基-7-氮杂二环[2.2.1]庚-7-基]-2-(三氟甲基)苯胺34(222mg,0.58mmol),然后加入三乙胺(146mg,201μL,1.44mmol)。将该反应混合物在62℃加热16h。将该反应混合物冷却至室温,使其分配在2-甲基四氢呋喃/水之间,分离,用2-甲基四氢呋喃将水层萃取一次以上,合并有机层,用Na2SO4干燥,过滤,浓缩至干。通过硅胶色谱法纯化(0-30%乙酸乙酯的二氯甲烷溶液),得到内-N-[4-[(5S)-5-[叔丁基(二甲基)甲硅烷基]氧基-7-氮杂二环[2.2.1]庚-7-基]-2-(三氟甲基)苯基]-4-氧代-5-(三氟甲基)-1H-喹啉-3-甲酰胺(285mg,79%收率)。1H NMR(400.0MHz,DMSO-d6)δ13.07(s,1H),12.16(s,1H),8.88(s,1H),8.04(dd,J=2.2,7.3Hz,1H),7.95-7.89(m,3H),7.22(dd,J=2.4,8.9Hz,1H),7.16(d,J=2.6Hz,1H),4.29(m,3H),2.16-2.07(m,2H),1.62-1.43(m,3H),1.05-1.01(m,1H),0.89(s,9H),0.08(d,J=1.4Hz,6H)。
内-N-[4-[(5S)-5-羟基-7-氮杂二环[2.2.1]庚-7-基]-2-(三氟甲基)苯基]-4-氧代-5-(三氟甲基)-1H-喹啉-3-甲酰胺的制备。将内-N-[4-[(5S)-5-[叔丁基(二甲基)甲硅烷基]氧基-7-氮杂二环[2.2.1]庚-7-基]-2-(三氟甲基)苯基]-4-氧代-5-(三氟甲基)-1H-喹啉-3-甲酰胺(281mg,0.45mmol)溶于1%HCl/乙醇(2mL,1%w/w)溶液,将其在室温搅拌16h,得到白色沉淀。用乙醚稀释该反应体系,过滤。将收集的固体溶于乙酸乙酯/饱和NaHCO3水溶液。分离各层,用乙酸乙酯将水层萃取一次以上。用水将有机层洗涤两次,用Na2SO4干燥,过滤,浓缩至干,得到内-N-[4-[(5S)-5-羟基-7-氮杂二环[2.2.1]庚-7-基]-2-(三氟甲基)苯基]-4-氧代-5-(三氟甲基)-1H-喹啉-3-甲酰胺(190mg,83%)。1H NMR(400.0MHz,DMSO-d6)δ13.07(s,1H),12.15(s,1H),8.88(s,1H),8.04(dd,J=2.2,7.4Hz,1H),7.95-7.88(m,3H),7.19(dd,J=2.4,9.0Hz,1H),7.12(d,J=2.6Hz,1H),5.00(d,J=4.2Hz,1H),4.25-4.13(m,1H),4.21-4.19(m,1H),4.16-4.13(m,1H),2.15-2.08(m,2H),1.61-1.55(m,1H),1.47-1.44(m,2H)和1.03(dd,J=3.4,12.3Hz,1H)。
表1化合物的分析数据如下所示:
表2
a保留时间
用于检测和测量化合物的ΔF508-CFTR增强特性的分析
用于测定化合物的ΔF508-CFTR调节性质的跨膜电位光学方法
该分析使用荧光电压传感染料以使用荧光板读出器测定跨膜电位改变(例如FLIPR III,Molecular Devices,Inc.)作为NIH 3T3细胞中功能性ΔF508-CFTR增加的读出值。对该响应的驱动力在于在预先用化合物处理细胞、然后加载电压传感染料后,通过单一液体添加步骤生成与通道活化相关的氯离子梯度。
增强剂化合物的鉴定
为了鉴定ΔF508-CFTR增强剂,研发了双重添加HTS分析形式。该HTS分析使用荧光电压传染染料以测定FLIPR III上跨膜电位改变作为温度校准的ΔF508 CFTR NIH 3T3细胞中ΔF508 CFTR门控增加的测量值(电导)。对该响应的驱动力在于在预先用增强剂化合物(或DMSO媒介物对照品)处理细胞、然后加载再分布染料后,与使用荧光板读出器例如FLIPR III进行通道活化相关的Cl-离子梯度。
溶液
浴溶液#1:(以mM计)NaCl 160,KCl 4.5,CaCl2 2,MgCl2 1,HEPES10,pH 7.4,含有NaOH。
不含氯离子的浴溶液:用葡糖酸盐取代浴溶液#1中的盐酸盐
细胞培养
将稳定表达ΔF508-CFTR的NIH3T3小鼠成纤维细胞用于跨膜电位的光学测量。将细胞维持在37℃、5%CO2和90%湿度中的在175cm2培养烧瓶中的Dulbecco改进的Eagle培养基内,该培养基补充了2mM谷氨酰胺、10%胎牛血清、1XNEAA、β-ME、1X pen/strep和25mMHEPES。就全部光学分析而言,将细胞以~20,000/孔接种在384-孔基质胶-包被的培养板上,在37℃培养2,然后在27℃培养24h,以进行增强剂分析。为了进行校准分析,在27℃或37℃与和不与化合物一起培养细胞16-24小时。用于分析化合物的ΔF508-CFTR调节特性的电生理分析。
Using室分析
对表达ΔF508-CFTR的极化气道上皮细胞进行Ussing室实验,以进一步表征在光学测定法中鉴别的ΔF508-CFTR调节剂。从支气管组织中分离非-CF和CF气道上皮,如上所述培养(Galietta,L.J.V.,Lantero,S.,Gazzolo,A.,Sacco,O.,Romano,L.,Rossi,G.A.,& Zegarra-Moran,O.(1998)In Vitro Cell.Dev.Biol.34,478-481),在用NIH3T3-条件培养基预包被的SnapwellTM滤器上铺。4天后,除去顶部培养基,使细胞在空气液体界面上生长>14天,然后使用。这产生单层完全分化的柱状细胞,它们具纤毛、特征在于气道上皮特征。从没有已知任何肺病的不吸烟者中分离非-CF HBE。从对ΔF508-CFTR而言纯合的患者中分离CF-HBE。
将生长在SnapwellTM细胞培养插入物上的HBE固定在Ussing室(Physiologic Instruments,Inc.,San Diego,CA)上,使用电压钳系统(Department of Bioengineering,University of Iowa,IA)测定在基底外侧到顶端Cl-梯度(ISC)的存在下的经上皮电阻和短路电流。简言之,在电压钳记录条件下(V保持=0mV)、在37℃检验HBE。基底外侧溶液包含(以mM计)145NaCl、0.83K2HPO4、3.3KH2PO4、1.2MgCl2、1.2CaCl2、10葡萄糖、10HEPES(用NaOH将pH调整至7.35),顶端溶液包含(以mM计)145葡糖酸钠、1.2MgCl2、1.2CaCl2、10葡萄糖、10HEPES(用NaOH将pH调整至7.35)。
增强剂化合物的鉴定
典型的方案使用基底外侧至顶端膜的Cl-浓度梯度。为了产生该梯度,对基底外侧膜使用正常的林格液(ringer),并且使用制霉菌素进行可渗透处理,另外,通过用等摩尔的葡糖酸钠(用NaOH滴定至pH 7.4)代替顶膜的NaCl,以得到跨上皮的大幅的Cl-浓度梯度。将福斯柯林(10μM)和所有受试化合物加入到细胞培养嵌入物的两侧。比较推测的ΔF508-CFTR增强剂与已知增强剂染料木黄酮的效果。
膜片钳记录
如上所述使用穿孔的膜片记录监测ΔF508-NIH3T3细胞中的总Cl-电流(Rae,J.,Cooper,K.,Gates,P.,& Watsky,M.(1991)J.Neurosci.Methods 37,15-26)。使用Axopatch 200B膜片钳放大器(Axon Instruments Ine.,Foster City,CA)在22℃进行电压钳记录。移取管溶液包含(以mM计)150N-甲基-D-葡萄糖胺(NMDG)-Cl、2MgCl2、2CaCl2、10EGTA、10HEPES和240μg/ml两性霉素-B(用HCl将pH调整至7.35)。胞外培养基包含(以mM计)150NMDG-Cl、2MgCl2、2CaCl2、10HEPES(用HCl将pH调整至7.35)。使用安装了Digidata 1320A/D界面与Clampex 8(Axon Instruments Inc.)的PC进行脉冲发生、数据采集和分析。为了活化ΔF508-CFTR,向浴中加入ΔF508-CFTR、10μM福司柯林和20μM染料木黄酮,每隔30秒监测一次电流-电压相关性。
增强剂化合物的鉴定
还用穿孔膜片记录技术研究了ΔF508-CFTR强化剂增加稳定表达ΔF508-CFTR的NIH3T3细胞中宏观ΔF508-CFTR Cl-电流(IΔF508)的能力。从光学测定法中鉴别的强化剂引起与在光学测定法中观察到的类似效力和功效的IΔF508剂量依赖性增加。在所有检验的细胞中,施加强化剂前和过程中的逆转电位约为-30mV,它是计算的ECl(-28mV)。
细胞培养
将稳定表达ΔF508-CFTR的NIH3T3小鼠成纤维细胞用于全细胞记录。将细胞维持在37℃、在5%CO2和90%湿度中的在175cm2培养烧瓶中的改进的Eagle培养基中,该培养基补充了2mM谷氨酰胺、10%胎牛血清、1XNEAA、β-ME、1Xpen/strep和25mM HEPES。为了进行全细胞记录,将2,500-5,000个细胞接种在聚-L-赖氨酸-包被的玻璃盖玻片上并且在27℃培养24-48h后用于测试强化剂的活性;且与或不与纠正化合物一起在37℃孵育,以便测定纠正剂的活性。
单通道记录
如上所述使用切下的膜内侧翻外膜片(Dalemans,W.,Barbry,P.,Champigny,G.,Jallat,S.,Dott,K.,Dreyer,D.,Crystal,R.G.,Pavirani,A.,Lecocq,J-P.,Lazdunski,M.(1991)Nature 354,526-528)、应用Axopatch 200B膜片钳放大器(Axon Instruments Inc.)观察在NIH3T3细胞中稳定表达的经过wt-CFTR和温度校正的ΔF508-CFTR的门控活性。移取管包含(以mM计):150NMDG、150天冬氨酸、5CaCl2、2MgCl2和10HEPES(用Tris碱将pH调整至7.35)。浴包含(以mM计):150NMDG-Cl、2MgCl2、5EGTA、10TES和14Tris碱(用HCl将pH调整至7.35)。切下后,通过添加1mM Mg-ATP、75nMcAMP-依赖性蛋白激酶催化亚单位(PKA;Promega Corp.Madison,WI)和10mM NaF以抑制蛋白磷酸酶活化wt-和ΔF508-CFTR,这防止了电流下降。将移取管电位维持在80mV。从包含≤2活性通道的膜片中分析通道活性。同时开放的最大数量确定了实验过程中活性通道的数量。为了测定单通道电流振幅,在100Hz“离线”过滤从120秒ΔF508-CFTR活性记录的数据,然后用于构建所有点的振幅直方图,使用Bio-Patch分析软件(Bio-Logic Comp.France)拟合多高斯函数。从120秒的通道活性确定总微观电流和开放概率(Po)。使用Bio-Patch软件或根据关系式Po=I/i(N)确定Po,其中I=平均电流,i=单通道电流振幅,N=膜片中活性通道的数量。
细胞培养
将稳定表达ΔF508-CFTR的NIH3T3小鼠成纤维细胞用于切下膜的膜片钳记录。将细胞维持在37℃、在5%CO2和90%湿度中的在175cm2培养烧瓶中的改进的Eagle培养基中,该培养基补充了2mM谷氨酰胺、10%胎牛血清、1XNEAA、β-ME、1X pen/strep和25mM HEPES。为了进行单通道记录,将2,500-5,000个细胞接种在聚-L-赖氨酸-包被的玻璃盖玻片上并且在27℃培养24-48h后使用。
本发明的化合物用作ATP结合盒转运体的调节剂。式(I)化合物的活性和效力的实例如下表3中所示。如果将活性测定为低于2.0μM,则使用“+++”示例化合物活性;如果将活性测定为2μM-5.0μM,则使用“++”示例化合物活性;如果将活性测定为大于5.0μM,则使用“+”示例化合物活性;如果未得到数据,则表示为“-”。如果将效力计算为大于100%,则使用“+++”示例效力,如果将效力计算为100%-25%,则使用“++”示例效力,如果将效力计算为低于25%,则使用“+”示例效力,如果未得到数据,则使用“-”表示。应注意100%效力是使用4-甲基-2-(5-苯基-1H-吡唑-3-基)苯酚得到的最大响应。
表3
实施例化合物编号 | 活性EC50(μm) | %效力 |
1 | +++ | ++ |
2 | +++ | ++ |
3 | +++ | ++ |
4 | +++ | ++ |
5 | +++ | +++ |
6 | +++ | +++ |
7 | +++ | ++ |
8 | +++ | ++ |
9 | +++ | ++ |
10 | +++ | +++ |
11 | +++ | ++ |
12 | +++ | ++ |
13 | +++ | ++ |
14 | +++ | ++ |
Claims (71)
6.权利要求2-5任一项的化合物,其中R1是-CF3。
7.权利要求2-5任一项的化合物,其中R1是-CN。
8.权利要求2-5任一项的化合物,其中R1是-C≡CCH2N(CH3)2。
9.权利要求6-8任一项的化合物,其中R2是氢。
10.权利要求6-8任一项的化合物,其中R2是-CH3。
11.权利要求6-8任一项的化合物,其中R2是-CF3。
12.权利要求6-8任一项的化合物,R2是-OH。
13.权利要求6-8任一项的化合物,其中R2是-CH2OH。
14.权利要求10-13任一项的化合物,其中R3是氢。
15.权利要求9-13任一项的化合物,其中R3是-CH3。
16.权利要求9-13任一项的化合物,其中R3是-OCH3。
17.权利要求9-13任一项的化合物,其中R3是-CN。
19.药物组合物,所述组合物包含权利要求1-18任一项的化合物和药学上可接受的载体或佐剂。
20.权利要求19的药物组合物,所述组合物还包含另外的活性剂,所述另外的活性剂选自溶粘蛋白剂、支气管扩张剂、抗生素、抗感染剂、抗炎剂、式(I)化合物以外的CFTR调节剂或营养剂。
21.权利要求20的药物组合物,其中所述另外的活性剂是式(I)化合物以外的CFTR调节剂。
22.治疗患者疾病或减轻所述疾病严重性的方法,其中所述疾病选自囊性纤维化、哮喘、吸烟诱发的COPD、慢性支气管炎、鼻窦炎、便秘、胰腺炎、胰腺功能不全、先天性双侧输精管缺失(CBAVD)导致的男性不育症、轻度肺病、特发性胰腺炎、变应性支气管肺曲菌病(ABPA)、肝病、遗传性肺气肿、遗传性血色病、凝血-纤溶缺陷,例如蛋白质C缺乏症、1型遗传性血管性水肿、脂质加工缺陷,例如家族性高胆固醇血症、1型乳糜微粒血症、无β脂蛋白血症、溶酶体贮积症,例如I-细胞病/假性赫尔勒综合征、粘多糖症、桑德霍夫/泰-萨克斯病、克-纳综合征II型、多内分泌腺病/高胰岛素血症、糖尿病、拉伦侏儒症、髓过氧化物酶缺乏症、原发性甲状旁腺功能减退、黑素瘤、聚糖病CDG1型、先天性甲状腺功能亢进症、成骨不全、遗传性低纤维蛋白原血症、ACT缺乏症、尿崩症(DI)、神经生长性DI、肾性DI、夏-马-图综合征、佩-梅病、神经变性疾病,例如阿尔茨海默病、帕金森病、肌萎缩性侧索硬化、进行性核上性麻痹、皮克病、若干聚谷氨酰胺神经性障碍,例如亨廷顿病、I型脊髓小脑性共济失调、脊髓与延髓肌肉萎缩症、齿状核红核苍白球丘脑下部核萎缩,和肌强直性营养不良,以及海绵状脑病,例如遗传性克雅病(由朊病毒蛋白加工缺陷导致)、法布里病、格-斯-施综合征、COPD、干眼病、胰腺功能不全、骨质疏松症、骨质减少、戈勒姆综合征、氯化物通道病变、先天性肌强直(汤姆森和贝克尔型)、巴特综合征III型、登特病、过度惊跳症、癫痫症、过度惊跳症、溶酶体贮存病、安格曼综合征、原发性纤毛运动障碍(PCD)、具有左右转位的PCD(也称作卡特金纳综合征)、没有左右转位和纤毛发育不良的PCD或斯耶格仑病,该方法包括对所述患者给予有效量的权利要求1-18任一项的化合物的步骤。
23.权利要求22的方法,其中所述疾病是囊性纤维化。
24.治疗患者疾病或减轻所述疾病严重性的方法,其中所述疾病与因编码CFTR的基因中的突变或环境因素导致的CFTR功能下降相关,该方法包括对所述患者给予有效量的权利要求1-18任一项的化合物的步骤。
25.权利要求24的方法,其中所述疾病是囊性纤维化、慢性支气管炎、复发性支气管炎、急性支气管炎、先天性双侧输精管缺失(CBAVD)导致的男性不育症、子宫和阴道先天性缺失(CAUV)导致的女性不育症、特发性慢性胰腺炎(ICP)、特发性复发性胰腺炎、特发性急性胰腺炎、慢性鼻窦炎、原发性硬化性胆管炎、变应性支气管肺曲菌病、糖尿病、干眼、便秘、变应性支气管肺曲菌病(ABPA)、骨疾病和哮喘。
26.治疗患者疾病或减轻所述疾病严重性的方法,其中所述疾病与CFTR正常功能相关,该方法包括对所述患者给予有效量的权利要求1-18任一项的化合物的步骤。
27.权利要求26的方法,其中所述疾病是慢性阻塞性肺病(COPD)、慢性支气管炎、复发性支气管炎、急性支气管炎、鼻窦炎、便秘、慢性胰腺炎、复发性胰腺炎和急性胰腺炎、胰腺功能不全、先天性双侧输精管缺失(CBAVD)导致的男性不育症、轻度肺病、特发性胰腺炎、肝病、遗传性肺气肿、胆石、胃食管返流病、胃肠道恶性肿瘤、炎性肠病、便秘、糖尿病、关节炎、骨质疏松症或骨质减少。
28.权利要求26的方法,其中所述疾病是遗传性血色病、凝血-纤溶缺陷,例如蛋白质C缺乏症、1型遗传性血管性水肿、脂质加工缺陷,例如家族性高胆固醇血症、1型乳糜微粒血症、无β脂蛋白血症、溶酶体贮积症,例如I-细胞病/假性赫尔勒综合征、粘多糖症、桑德霍夫/泰-萨克斯病、克-纳综合征II型、多内分泌腺病/高胰岛素血症、糖尿病、拉伦侏儒症、髓过氧化物酶缺乏症、原发性甲状旁腺功能减退、黑素瘤、聚糖病CDG 1型、先天性甲状腺功能亢进症、成骨不全、遗传性低纤维蛋白原血症、ACT缺乏症、尿崩症(DI)、神经生长性DI、肾性DI、夏-马-图综合征、佩-梅病、神经变性疾病,例如阿尔茨海默病、帕金森病、肌萎缩性侧索硬化、进行性核上性麻痹、皮克病、若干聚谷氨酰胺神经性障碍,例如亨廷顿病、I型脊髓小脑性共济失调、脊髓与延髓肌肉萎缩症、齿状核红核苍白球丘脑下部核萎缩,和肌强直性营养不良,以及海绵状脑病,例如遗传性克雅病(由朊病毒蛋白加工缺陷导致)、法布里病、格-斯-施综合征、戈勒姆综合征氯化物通道病变、先天性肌强直(汤姆森和贝克尔型)、巴特综合征III型、登特病、过度惊跳症、癫痫症、过度惊跳症、溶酶体贮存病、安格曼综合征、原发性纤毛运动障碍(PCD)、具有左右转位的PCD(也称作卡特金纳综合征)、没有左右转位和纤毛发育不良的PCD或斯耶格仑病。
29.用于体外或体内测定生物样品中CFTR或其片段活性的试剂盒,所述试剂盒包括:
(i)包含权利要求1的式(I)化合物的组合物;
(ii)关于下列内容的说明书:
a)使该组合物与该生物样品接触;
b)测定所述CFTR或其片段的活性。
30.权利要求29的试剂盒,所述试剂盒还包括关于如下的说明书:
a)使另外的组合物与该生物样品接触;
b)测定在所述另外的化合物的存在下所述CFTR或其片段的活性;和
c)比较在另外的化合物的存在下CFTR活性与在式(I)组合物的存在下CFTR的密度。
31.调节生物样品中CFTR活性的方法,所述方法包括使所述CFTR接触权利要求1-18任一项的化合物的步骤。
34.权利要求33的方法,其中所述溶剂包括N,N-二甲基甲酰胺、乙酸乙酯或2-甲基四氢呋喃。
35.权利要求32的方法,其中Ra是氢或TBDMS。
36.权利要求32的方法,其中Ra是TBDMS。
39.权利要求38的方法,其中步骤(a)中的式3的胺在原位由胺盐酸盐生成。
40.权利要求38的方法,其中Ra是氢或TBDMS。
41.权利要求38的方法,其中Ra是TBDMS。
42.权利要求38的方法,其中步骤(a)在极性非质子溶剂中、在叔胺碱的存在下进行。
43.权利要求42的方法,其中步骤(a)在乙腈中、在三乙胺的存在下进行。
44.权利要求38的方法,其中步骤(a)的反应温度是约75℃-约85℃。
45.权利要求38的方法,其中反应时间是约2-约30小时。
46.权利要求38的方法,其中步骤(b)在极性质子溶剂中、在钯催化剂的存在下进行。
47.权利要求46的方法,其中步骤(b)中的溶剂包括甲醇或乙醇。
48.权利要求38的方法,其中步骤(b)在极性质子溶剂中、在Fe和FeSO4或Zn和AcOH的存在下进行。
49.权利要求48的方法,其中极性质子溶剂是水。
50.式(Ic)化合物或其药学上可接受的盐的制备方法
所述方法包括下列步骤:
(a)使式2a的化合物与式3的胺反应,得到式2b的化合物
(b)通过还原将式2b的化合物转化成式2c的胺
(c)使式2c的胺与式1d的酸反应,得到式(Ic)的化合物
其中Hal是F、Cl、Br或I;
其中
R1是-CF3、-CN或-C≡CCH2N(CH3)2;
R2是氢、-CH3、-CF3、-OH或-CH2OH;
R3是氢、-CH3、-OCH3或-CN;
条件是R2和R3不同时为氢;且
Ra是氢或甲硅烷基保护基,所述甲硅烷基保护基选自三甲基甲硅烷基(TMS)、叔丁基二苯基甲硅烷基(TBDPS)、叔丁基二甲基甲硅烷基(TBDMS)、三异丙基甲硅烷基(TIPS)和[2-(三甲基甲硅烷基)乙氧基]甲基(SEM)。
51.权利要求50的方法,其中步骤(a)中的式3的胺在原位由胺盐酸盐生成。
52.权利要求51的方法,其中Ra是氢或TBDMS。
53.权利要求52的方法,其中Ra是TBDMS。
54.权利要求50的方法,其中步骤(a)在极性非质子溶剂中、在叔胺碱的存在下进行。
55.权利要求54的方法,其中步骤(a)在乙腈中、在三乙胺的存在下进行。
56.权利要求50的方法,其中步骤(a)的反应温度是约75℃-约85℃。
57.权利要求50的方法,其中反应时间是约2-约30小时。
58.权利要求50的方法,其中步骤(b)在极性质子溶剂中、在钯催化剂的存在下进行。
59.权利要求58的方法,其中步骤(b)中的溶剂包括甲醇或乙醇。
60.权利要求50的方法,其中步骤(b)在极性质子溶剂中、在Fe和FeSO4或Zn和AcOH的存在下进行。
61.权利要求50的方法,其中所述极性溶剂是水。
63.权利要求62的方法,其中步骤(c)中的溶剂包括N,N-二甲基甲酰胺(DMF)、乙酸乙酯或2-甲基四氢呋喃。
64.权利要求62的方法,其中Ra是氢或TBDMS。
65.权利要求64的方法,其中Ra是TBDMS。
70.式(I)的化合物
或其药学上可接受的盐,其中:
环A选自:
其中
R1是-CF3、-CN或-C≡CCH2N(CH3)2;
R2是氢、-CH3、-CF3、-OH或-CH2OH;
R3是氢、-CH3,-OCH3或-CN;
条件是R2和R3不同时为氢;
所述化合物通过权利要求45-61任一项的方法制备。
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TWI828358B (zh) * | 2018-02-15 | 2024-01-01 | 美商維泰克斯製藥公司 | 囊性纖維化跨膜傳導調節因子之調節劑、醫藥組合物、治療方法及製造該調節劑之方法 |
US11866450B2 (en) | 2018-02-15 | 2024-01-09 | Vertex Pharmaceuticals Incorporated | Modulators of Cystic Fibrosis Transmembrane Conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulators |
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