CN101374849A - 作为abc转运蛋白调控剂的喹啉-4-酮衍生物 - Google Patents
作为abc转运蛋白调控剂的喹啉-4-酮衍生物 Download PDFInfo
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- CN101374849A CN101374849A CNA2006800530016A CN200680053001A CN101374849A CN 101374849 A CN101374849 A CN 101374849A CN A2006800530016 A CNA2006800530016 A CN A2006800530016A CN 200680053001 A CN200680053001 A CN 200680053001A CN 101374849 A CN101374849 A CN 101374849A
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Abstract
本发明涉及ABC转运蛋白、特别是CFTR的调控剂的前体药物、其组合物和相关方法。本发明也涉及使用这类调控剂治疗ABC转运蛋白介导疾病的方法。
Description
技术领域
[001]本发明涉及ABC转运蛋白、特别是CFTR的调控剂的前体药物、其组合物和相关方法。本发明也涉及使用这类前体药物治疗ABC转运蛋白介导疾病的方法。
背景技术
[002]ABC转运蛋白是膜转运蛋白家族,调节多种药理成分、潜在毒性药物和异生素以及阴离子的转运。ABC转运蛋白是同源性膜蛋白,它们结合和利用细胞三磷酸腺苷(ATP)供它们的特异性活性。这些转运蛋白中有些被发现是多药耐受性蛋白(象MDR1-P糖蛋白或多药耐受性蛋白MRP1),为恶性癌细胞防御化学治疗剂。迄今已经鉴别了48种ABC转运蛋白,基于它们的序列同源性和功能分为7个家族。
[003]ABC转运蛋白在体内调节多种重要的生理角色,并且提供对有害环境化合物的防御。因为如此,它们代表重要的潜在药物靶,用于治疗与该转运蛋白缺陷有关的疾病,防止药物从靶细胞中转运除去,和干预其他其中ABC转运蛋白活性的调控可能是有益的疾病。
[004]普遍与疾病有关的一种ABC转运蛋白家族成员是cAMP/ATP-介导的阴离子通道CFTR。CFTR在多种细胞类型中被表达,包括吸收性和分泌性上皮细胞,在那里它调节阴离子的跨膜流动以及其他离子通道和蛋白质的活性。在上皮细胞中,CFTR的正常功能发挥是维持电解质在体内各处转运的关键,包括呼吸和消化组织。CFTR由大约1480个氨基酸组成,它们编码由跨膜结构域的串联重复要素所构成的蛋白质,各自含有六个跨膜螺旋和一个核苷酸结合结构域。两个跨膜结构域通过大型极性调节性(R)-结构域连接,具有多个调节通道活性和细胞运输的磷酸化位点。
[005]编码CFTR的基因已被鉴别和测序(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)。这种基因的缺陷引起CFTR突变,导致囊性纤维化(“CF”),这是人类最常见的致命性遗传疾病。囊性纤维化影响大约两千五百分之一的美国新生儿。在全部美国人口中,多达一千万人携带有缺陷基因的单一副本,没有明显的疾病效应。相反,带有两个CF相关基因副本的个体患有CF的衰弱与致命性效应,包括慢性肺疾病。
[006]在囊性纤维化患者中,在呼吸道上皮中被内源性表达的CFTR的突变引起顶端阴离子分泌减少,导致离子和体液转运的失衡。所致阴离子转运疾病对肺中粘液蓄积增强和伴随微生物感染有贡献,最终导致CF患者死亡。除了呼吸疾病以外,CF患者通常患有胃肠问题和胰腺机能不全,如果不加治疗则导致死亡。另外,大多数囊性纤维化男性是不育的,囊性纤维化女性的生育力降低。与两个CF相关基因副本的严重效应相反,带有单一CF相关基因副本的个体表现对霍乱和腹泻所致脱水的抗性增加——这也许解释了人群内相对高频率的CF基因的原因。
[007]CF染色体CFTR基因的序列分析已经揭示了多种致病性突变(Cutting,G.R.等人(1990)Nature 346:366-369;Dean,M.等人(1990)Cell 61:863:870;and Kerem,B-S.等人(1989)Science245:1073-1080;Kerem,B-S等人(1990)Proc.Natl.Acad.Sci.USA87:8447-8451)。迄今已经鉴别了1000种以上致病性CF基因突变(http://www.genet.sickkids.on.ca/cftr/)。最常见的突变是CFTR氨基酸序列508位苯丙氨酸的缺失,普遍被称为ΔF508-CFTR。这种突变发生在大约70%的囊性纤维化病例中,与严重的疾病有关。
[008]ΔF508-CFTR中508残基的缺失防止初生蛋白正确地折叠。这导致该突变蛋白不能退出ER和运输至质膜。其结果是,膜中通道数量远远少于表达野生型CFTR的细胞。除了运输减低以外,突变还导致有缺陷的通道门控。总之,膜中通道数量减少和有缺陷的门控引起跨越上皮的阴离子转运减少,引起有缺陷的离子和体液转运(Quinton,P.M.(1990),FASEB J.4:2709-2727)。不过,研究已经显示,膜中ΔF508-CFTR的数量减少是功能性的,尽管少于野生型CFTR(Dalemans等人(1991),Nature Lond.354:526-528;Denning等人,supra;Pasyk and Foskett(1995),J.Cell.Biochem.270:12347-50)。除了ΔF508-CFTR以外,其他导致有缺陷的运输、合成和/或通道门控的致病性CFTR突变可能被增量或减量调节,以改变阴离子分泌和修改疾病进展和/或严重性。
[009]尽管CFTR除了阴离子以外还转运多种分子,不过显然这种角色(阴离子的转运)代表了跨越上皮转运离子和水的重要机理中的一种要素。其他要素包括上皮Na+通道、ENaC、Na+/2Cl-/K+共同转运蛋白、Na+-K+-ATP酶泵和基底外侧膜K+通道,它们负责摄取氯化物进入细胞。
[0010]这些要素一起发挥作用,经由它们在细胞内的选择性表达和定位实现跨越上皮的定向转运。借助存在于顶端膜上的ENaC与CFTR和在细胞基底外侧表面上表达的Na+-K+-ATP酶泵与Cl-通道的协调活性,发生氯化物的吸收。氯化物从腔侧的次级主动转运引起细胞内氯化物的蓄积,然后可以被动地经由Cl-通道离开细胞,导致向量转运。Na+/2Cl-/K+共同转运蛋白、Na+-K+-ATP酶泵和基底外侧膜K+通道在基底外侧表面上的排列和腔侧上的CFTR协调氯化物经由腔侧上CFTR的分泌。因为水可能从不主动转运自己,它跨越上皮的流动依赖于由钠和氯的大量流动所生成的微小跨上皮渗透梯度。
[0011]除了囊性纤维化以外,CFTR活性的调控也可以有益于其他不直接由CFTR突变所导致的疾病,例如分泌性疾病和其他由CFTR介导的蛋白质折叠疾病。这些疾病包括但不限于慢性阻塞性肺疾病(COPD)、干眼病和斯耶格伦氏综合征。COPD是以气流受限为特征的,它是进行性的,不是完全可逆的。气流受限是由于粘液分泌过多、肺气肿和细支气管炎。突变或野生型CFTR的活化剂提供COPD常见的粘液分泌过多和粘液纤毛廓清率减低的潜在治疗。具体而言,增加跨越CFTR的阴离子分泌可以有利于体液转运进入气道表面液体,以水化粘液,优化纤毛周围的体液粘度。这将引起粘液纤毛廓清率增强和与COPD有关的症状减少。干眼病是以泪水产生降低和异常泪膜脂质、蛋白质与粘蛋白行为为特征的。干眼有很多原因,其中一些包括年龄、Lasik眼手术、关节炎、药物治疗、化学/热灼伤、变态反应和疾病,例如囊性纤维化和斯耶格伦氏综合征。增加经由CFTR的阴离子分泌将增强体液从角膜内皮细胞和眼周围分泌腺体的转运,以增加角膜的水化作用。这将有助于缓解与干眼病有关的症状。斯耶格伦氏综合征是一种自身免疫疾病,其中免疫系统攻击体内各处产生水分的腺体,包括眼、口、皮肤、呼吸组织、肝、阴道和肠。症状包括眼、口和阴道干燥以及肺疾病。该疾病也与类风湿性关节炎、全身性红斑狼疮、系统性硬化和多肌炎/皮肤肌炎有关。有缺陷的蛋白质运输据信会导致该疾病,治疗选择是有限的。CFTR活性调控剂可以水化各种受疾病影响的器官,帮助改善有关症状。
[0012]正如上文所讨论的,据信ΔF508-CFTR中508残基的缺失防止初生蛋白正确地折叠,导致这种突变蛋白不能退出ER和运输至质膜。其结果是,存在于质膜的成熟蛋白数量不足,上皮组织内氯化物的转运显著减少。事实上,这种ABC转运蛋白被ER机构有缺陷的ER加工的细胞现象已被显示不仅是CF疾病的基础,而且是广泛的其他孤立性与遗传性疾病的基础。ER机构可能发生故障的两种方式要么是与蛋白质的ER输出的偶联丧失,引起降解,要么是这些有缺陷/误折叠的蛋白质的ER蓄积[Aridor M,等人,NatureMed.,5(7),pp 745-751(1999);Shastry,B.S.,等人,Neurochem.International,43,pp1-7(2003);Rutishauser,J.,等人,Swiss Med Wkly,132,pp211-222(2002);Morello,JP等人,TIPS,21,pp.466-469(2000);Bross P.,等人,Human Mut.,14,pp.186-198(1999)]。与前一类ER故障有关的疾病有囊性纤维化(由误折叠的ΔF508-CFTR引起,正如上文所讨论的)、遗传性肺气肿(由a1-抗胰蛋白酶非Piz变体引起)、遗传性血色素沉着、凝血-纤维蛋白溶解缺陷(例如C蛋白缺陷)、1型遗传性血管水肿、脂质加工缺陷(例如家族性高胆固醇血)、1型乳糜微粒血、无β脂蛋白血症、溶酶体贮存疾病(例如I-细胞疾病/假性Hurler)、粘多糖病(由溶酶体加工酶引起)、Sandhof/Tay-Sachs(由β-己糖胺酶引起)、Crigler-Najjar II型(由UDP-葡糖醛基-sialyc-转移酶引起)、多内分泌病/高胰岛素血、糖尿病(由胰岛素受体引起)、拉伦侏儒症(由生长激素受体引起)、髓过氧化物酶缺陷、原发性甲状旁腺机能减退(由前促甲状旁腺激素引起)、黑素瘤(由酪氨酸酶引起)。与后一类ER故障有关的疾病有聚糖病CDG 1型、遗传性肺气肿(由α1-抗胰蛋白酶PiZ变体引起)、先天性甲状腺机能亢进、成骨不全(由I、II、IV型前胶原引起)、遗传性低纤维蛋白原血(由纤维蛋白原引起)、ACT缺陷(由α1-抗凝乳蛋白酶引起)、尿崩症(DI)、后叶激素运载蛋白性DI(由加压素/V2-受体引起)、肾原性DI(由水通道蛋白II引起)、夏-马-图三氏综合征(由外周髓磷脂蛋白22引起)、佩-梅二氏病、神经变性疾病(例如阿尔茨海默氏病(由βAPP和早老蛋白引起)、帕金森氏病、肌萎缩性侧索硬化、进行性核上性麻痹、皮克氏病)、若干聚谷氨酰胺神经病学疾患(例如亨廷顿氏病、I型脊髓小脑性共济失调、脊髓与延髓肌肉萎缩、齿状核苍白球丘脑下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-雅二氏病(由朊病毒蛋白加工缺陷引起)、法布里氏病(由溶酶体α-半乳糖苷酶A引起)和斯-施二氏综合征(由Prp加工缺陷引起))。
[0013]除了CFTR活性的增量调节以外,减少CFTR分泌阴离子也可以有益于分泌性腹泻的治疗,其中作为促分泌性活化的氯化物转运的结果,上皮水转运戏剧性地增加。该机理牵涉cAMP的升高和CFTR的刺激。
[0014]尽管腹泻有大量原因,不过由过量氯化物转运所致腹泻性疾病的主要后果是共同的,包括脱水、酸中毒、生长减退和死亡。
[0015]急性与慢性腹泻在世界很多地区代表了主要的医学问题。腹泻在不到五岁的儿童中既是营养不良的显著因素,又是死亡的主导原因(5,000,000例死亡/年)。
[0016]分泌性腹泻也是获得性免疫缺陷综合征(AIDS)和慢性炎性肠疾病(IBD)患者中的危险病症。每年从工业化国家到发展中国家旅行的人中有一千六百万人患上腹泻,腹泻病例的严重性和数量因旅行的国家和地区而异。
[0017]牲畜和宠物、例如牛、猪、马、绵羊、山羊、猫和狗的腹泻也称为家畜腹泻病,是这些动物死亡的主要原因。腹泻可以由任何重大转变所致,例如断奶或身体运动,以及响应于多种细菌或病毒感染,一般发生在动物寿命的前几个小时内。
[0018]最常见的致腹泻性细菌是肠毒原性大肠杆菌(ETEC),具有K99毛发抗原。腹泻的常见病毒原因包括轮状病毒和冠形病毒。其他感染性成分包括隐孢子虫、兰伯氏贾第虫和沙门氏菌等等。
[0019]轮状病毒感染的症状包括水样便的排泄、脱水和虚弱。冠形病毒导致更严重的新生动物疾病,具有比轮状病毒感染更高的死亡率。不过经常是年幼动物可能同时感染有一种以上病毒或者病毒与细菌微生物的组合。这戏剧性地增加疾病的严重性。
[0020]因此,需要CFTR活性的调控剂及其组合物,它们能够用于调控哺乳动物细胞膜中CFTR的活性。
[0021]需要这类调控剂的前体药物,它们体内提供治疗上足量的调控剂。
发明简要内容
[0022]现已发现,本发明化合物及其药学上可接受的组合物可用作CFTR活性调控剂的前体药物。这些化合物具有通式I:
[0023]这些化合物提高了水溶性,所以具备治疗上相关的优点,例如提高了生物利用度、适合于制剂等。结果,这些化合物及其药学上可接受的组合物可用于治疗多种疾病、疾患或病症或者减轻其严重性,包括但不限于囊性纤维化、遗传性肺气肿、遗传性血色素沉着、凝血-纤维蛋白溶解缺陷(例如C蛋白缺陷)、1型遗传性血管水肿、脂质加工缺陷(例如家族性高胆固醇血)、1型乳糜微粒血、无β脂蛋白血症、溶酶体贮存疾病(例如I-细胞疾病/假性Hurler)、粘多糖病、Sandhof/Tay-Sachs、Crigler-Najjar II型、多内分泌病/高胰岛素血、糖尿病、拉伦侏儒、髓过氧化物酶缺陷、原发性甲状旁腺机能减退、黑素瘤、聚糖病CDG 1型、遗传性肺气肿、先天性甲状腺机能亢进、成骨不全、遗传性低纤维蛋白原血、ACT缺陷、尿崩症(DI)、后叶激素运载蛋白性DI、肾原性DI、夏-马-图三氏综合征、佩-梅二氏病、神经变性疾病(例如阿尔茨海默氏病、帕金森氏病、肌萎缩性侧索硬化、进行性核上性麻痹、皮克氏病)、若干聚谷氨酰胺神经病学疾患(例如亨廷顿氏病、I型脊髓小脑性共济失调、脊髓与延髓肌肉萎缩、齿状核红核苍白球丘脑下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-雅二氏病、法布里氏病和斯-施二氏综合征)、COPD、干眼病和斯耶格伦氏病。
发明详细内容
[0024]I.本发明化合物的一般说明:
[0025]按照一种实施方式,本发明提供式I化合物:
或其药学上可接受的盐;
X是价键或者是可选被取代的C1-C6亚烷基链,其中X的至多两个亚甲基单元可选地和独立地被-CO-、-CS-、-COCO-、-CONR′-、-CONR′NR′-、-CO2-、-OCO-、-NR′CO2-、-O-、-NR′CONR′-、-OCONR′-、-NR′NR′、-NR′NR′CO-、-NR′CO-、-S-、-SO、-SO2-、-NR′-、-SO2NR′-、NR′SO2-或-NR′SO2NR′-代替;
RX独立地是R′、卤代基、NO2、CN、CF3或OCF3;
y是0-4;
每个R1和R2独立地选自氢、CN、CF3、卤代基、C1-C6直链或支链烷基、3-12元环脂族基、苯基、C5-C10杂芳基或C3-C7杂环基,其中所述杂芳基或杂环基具有至多3个选自O、S或N的杂原子,其中所述R1和R2独立地和可选地被至多三个选自如下的取代基取代:-OR′、-CF3、-OCF3、SR′、S(O)R′、SO2R′、-SCF3、卤代基、CN、-COOR′、-OC(O)R′、-COR′、-O(CH2)2N(R′)(R′)、-O(CH2)N(R′)(R′)、-CON(R′)(R′)、-(CH2)2OR′、-(CH2)3OR′、CH2CN、可选被取代的苯基或苯氧基、-N(R′)(R′)、-NR′C(O)OR′、-NR′C(O)R′、-(CH2)2N(R′)(R′)或-(CH2)N(R′)(R′);
R3是氢;
RXY是选自如下的基团:
其中在基团(A)和基团(B)中:
每个wA、wB、wC和wD独立地是0或1;
每个M独立地选自氢、Li、Na、K、Mg、Ca、Ba、-N(R7)4、C1-C12-烷基、C2-C12-链烯基或-R6;其中该烷基或链烯基的1至4个-CH2原子团、除了与Z键合的-CH2以外,可选地被选自O、S、S(O)、S(O)2或N(R7)的杂原子基团代替;其中所述烷基、链烯基或R6中的任意氢可选地被选自如下的取代基取代:氧代基、OR7、R7、N(R7)2、N(R7)3、(C1-C4亚烷基)-OH、CN、CO2R7、C(O)N(R7)2、S(O)2-N(R7)2、N(R7)-C(O)-R7、C(O)R7、-S(O)n-R7、OCF3、-S(O)n-R6、N(R7)-S(O)2(R7)、卤代基、-CF3或-NO2;
n是0-2;
M′是H、C1-C12-烷基、C2-C12-链烯基或-R6;其中该烷基或链烯基的1至4个-CH2原子团可选地被选自O、S、S(O)、S(O)2或N(R7)的杂原子基团代替;其中所述烷基、链烯基或R6中的任意氢可选地被选自如下的取代基取代:氧代基、-OR7、-R7、-N(R7)2、N(R7)3、-R7OH、-CN、-CO2R7、-C(O)-N(R7)2、-S(O)2-N(R7)2、-N(R7)-C(O)-R7、-C(O)R7、-S(O)n-R7、-OCF3、-S(O)n-R6、-N(R7)-S(O)2(R7)、卤代基、-CF3或-NO2;
Z是-CH2-、-O-、-S-、-N(R7)2-;或者,
若M不存在,则Z是氢、=O或=S;
Y是P或S,其中若Y是S,则Z不是S;
X是O或S;
每个R7独立地选自氢或C1-C4脂族基,可选地被至多两个Q1取代;
每个Q1独立地选自3-7元饱和、部分饱和或不饱和的碳环环系;或者4-7元饱和、部分饱和或不饱和的杂环,含有一个或多个选自O、N、NH、S、SO或SO2的杂原子或杂原子基团;其中Q1可选地被至多三个选自如下的取代基取代:氧代基、-OH、-O(C1-C4脂族基)、-C1-C4脂族基、-NH2、NH(C1-C4脂族基)、-N(C1-C4脂族基)2、-N(C1-C4脂族基)-C(O)-C1-C4脂族基、-(C1-C4脂族基)-OH、-CN、-CO2H、-CO2(C1-C4脂族基)、-OCO(C1-C4脂族基)、-C(O)-NH2、-C(O)-NH(C1-C4脂族基)、-C(O)-N(C1-C4脂族基)2、卤代基或-CF3;
R6是4-6元饱和、部分饱和或不饱和的碳环或杂环环系,或者8-10元饱和、部分饱和或不饱和的二环环系;其中任意所述杂环环系含有一个或多个选自O、N、S、S(O)n或N(R7)的杂原子;其中任意所述环系可选地含有1至4个独立选自OH、C1-C4烷基、O-(C1-C4烷基)或O-C(O)-(C1-C4烷基)的取代基;
R9是C(R7)2、O或N(R7);
其中在基团(C)中:
R8选自C1-C6烷基;
每个R4和R5选自可选被Q1取代的C1-C6脂族基;
R′独立地选自氢或者可选被取代的基团,选自C1-C8脂族基团,3-8元饱和、部分不饱和或完全不饱和的单环,具有0-3个独立选自氮、氧或硫的杂原子,或者8-12元饱和、部分不饱和或完全不饱和的二环环系,具有0-5个独立选自氮、氧或硫的杂原子;或者两次出现的R′与它们所键合的原子一起构成可选被取代的3-12元饱和、部分不饱和或完全不饱和的单环或二环,具有0-4个独立选自氮、氧或硫的杂原子;以及
每个RU独立地是氢或者可选被至多四个卤素取代基取代的C1-C6烷基。
[001]化合物和定义:
[0026]本文所用的下列定义应当适用,另有指示除外。
[0027]本文所用的术语“ABC-转运蛋白”表示包含至少一个结合结构域的ABC-转运蛋白或其片段,其中所述蛋白质或其片段是体内或体外存在的。本文所用的术语“结合结构域”表示ABC-转运蛋白上能够与调控剂结合的结构域。例如参见Hwang,T.C.等人,J.Gen.Physiol.(1998):111(3),477-90。
[0028]本文所用的术语“CFTR”表示囊性纤维化跨膜传导调节剂或其有调节剂活性的突变体,包括但不限于△F508CFTR和G551DCFTR(例如参见http://www.genet.sickkids.on.ca/cftr/关于CFTR突变)。
[0029]本文所用的术语“调控”表示增加或降低达到可测量的量。
[0030]出于本发明的目的,化学元素符合Periodic Table of theElements,CAS版本,Handbook of Chemistry and Physics,75thEd。另外,有机化学的一般原理参见"Organic Chemistry",ThomasSorrell,University Science Books,Sausalito:1999,and"March′s Advanced Organic Chemistry",5thEd.,Ed.:Smith,M.B.and March,J.,John Wiley & Sons,New York:2001,其完整内容引用在此作为参考。
[0031]如本文所述,本发明化合物可以可选地被一个或多个取代基取代,例如上文所一般性阐述的,或者如本发明的特定大类、小类和品种所例证的。将被领会到,措辞“可选被取代的”与措辞“取代或未取代的”可互换使用。一般而言,术语“取代”无论前面有无术语“可选”,都表示给定结构中的氢原子团被指定取代基的原子团所代替。除非另有指示,可选被取代的基团可以在该基团每个可取代的位置上具有取代基,若任意给定结构中一个以上位置可以被一个以上选自指定组的取代基所取代,则取代基可以在每个位置上是相同或不同的。本发明所关注的取代基组合优选地是生成稳定的或化学上可行的化合物的那些。本文所用的措辞“稳定”表示在受到用于它们制备、检测、优选回收、纯化的条件和用于一种或多种本文所公开的目的时基本上不变的化合物。在有些实施方式中,稳定的化合物或化学上可行的化合物是在没有水分或其他化学反应性条件的存在下、在40℃或以下的温度下保持至少一周而基本上不发生变化的化合物。
[0032]本文所用的术语“脂族基”或“脂族基团”表示直链(即未分支)或支链的取代或未取代的烃链,其是完全饱和的或者含有一个或多个不饱和单元,或者表示单环烃或二环烃,其是完全饱和的或者含有一个或多个不饱和单元,但是不是芳族的(本文也称之为“碳环”、“环脂族基”或“环烷基”),其具有单一的与分子其余部分连接的点。除非另有说明,脂族基团含有1-20个脂族碳原子。在有些实施方式中,脂族基团含有1-10个脂族碳原子。在其他实施方式中,脂族基团含有1-8个脂族碳原子。在其他实施方式中,脂族基团含有1-6个脂族碳原子,在其他实施方式中,脂族基团含有1-4个脂族碳原子。在有些实施方式中,“环脂族基”(或者“碳环”或“环烷基”)表示单环C3-C8烃或二环或三环C8-C14烃,其是完全饱和的或者含有一个或多个不饱和单元,但不是芳族的,其具有单一的与分子其余部分连接的点,其中所述二环环系中任意单一的环是3-7元环。适合的脂族基团包括但不限于直链或支链的取代或未取代的烷基、链烯基、炔基及其杂合物,例如(环烷基)烷基、(环烯基)烷基或(环烷基)链烯基。适合的环脂族基团包括环烷基、二环烷基(例如十氢萘)、桥连二环烷基(例如降冰片基或[2.2.2]二环辛基)、桥连三环基(例如金刚烷基)。
[0033]本文所用的术语“杂脂族基”表示脂族基团,其中一个或两个碳原子独立地被一个或多个氧、硫、氮、磷或硅代替。杂脂族基团可以是取代或未取代的,分支或未分支的,环状或无环的,包括“杂环”、“杂环基”、“杂环脂族”或“杂环的”基团。
[0034]本文所用的术语“杂环”、“杂环基”、“杂环脂族”或“杂环的”表示非芳族的、单环、二环或三环环系,其中一个或多个环成员是独立选择的杂原子。在有些实施方式中,“杂环”、“杂环基”、“杂环脂族”或“杂环的”基团具有三至十四个环成员,其中一个或多个环成员是独立选自氧、硫、氮或磷的杂原子,该系统中每个环含有3至7个环成员。
[0035]术语“杂原子”表示一个或多个氧、硫、氮、磷或硅(包括氮、硫、磷或硅的任意氧化形式;任意碱性氮或杂环可取代氮的季铵化形式,例如N(如在3,4-二氢-2H-吡咯基中)、NH(如在吡咯烷基中)或NR+(如在N-取代的吡咯烷基中))。
[0036]本文所用的术语“不饱和的”意味着该部分具有一个或多个不饱和单元。
[0037]本文所用的术语“烷氧基”或“硫代烷基”表示如前文所定义的烷基,通过氧(“烷氧基”)或硫(“硫代烷基”)原子与分子其余部分连接。
[0038]本文所用的“卤代脂族基”和“卤代烷氧基”表示被一个或多个卤原子取代的脂族基或烷氧基,视情况而定。术语“卤素”或“卤代基”表示F、Cl、Br或I。卤代脂族基的实例包括-CHF2、-CH2F、-CF3、-CF2-,或者全卤代烷基,例如-CF2CF3。
[0039]单独或者作为更大部分“芳烷基”、“芳烷氧基”或“芳氧基烷基”的一部分使用的术语“芳基”表示具有总计五至十四个环成员的单环、二环和三环环系,其中该系统中至少一个环是芳族的,并且其中该系统中每个环含有3至7个环成员。术语“芳基”可以与术语“芳基环”互换使用。术语“芳基”也表示如下所定义的杂芳基环系。
[0040]单独或者作为更大部分“杂芳烷基”或“杂芳基烷氧基”的一部分使用的术语“杂芳基”表示具有总计五至十四个环成员的单环、二环和三环环系,其中该系统中至少一个环是芳族的,该系统中至少一个环含有一个或多个杂原子,并且其中该系统中每个环含有3至7个环成员。术语“杂芳基”可以与术语“杂芳基环”或术语“杂芳族”互换使用。
[0041]芳基(包括芳烷基、芳烷氧基、芳氧基烷基等)或杂芳基(包括杂芳烷基和杂芳烷氧基等)可以含有一个或多个取代基,因而可以是“可选被取代的”。除非上文和本文另有定义,芳基或杂芳基的不饱和碳原子上适合的取代基一般选自卤素、-Ro、-ORo、-SRo、1,2-亚甲二氧基、1,2-亚乙二氧基、可选被Ro取代的苯基(Ph)、可选被Ro取代的-O(Ph)、可选被Ro取代的-(CH2)1-2(Ph)、可选被Ro取代的-CH=CH(Ph)、-NO2、-CN、-N(Ro)2、-NRoC(O)Ro、-NRoC(O)N(Ro)2、-NRoCO2Ro、-NRoNRoC(O)Ro、-NRoNRoC(O)N(Ro)2、-NRoNRoCO2Ro、-C(O)C(O)Ro、-C(O)CH2C(O)Ro、-CO2Ro、-C(O)Ro、-C(O)N(Ro)2、-OC(O)N(Ro)2、-S(O)2Ro、-SO2N(Ro)2、-S(O)Ro、-NRoSO2N(Ro)2、-NRoSO2Ro、-C(=S)N(Ro)2、-C(=NH)-N(Ro)2、或-(CH2)0-2NHC(O)Ro;其中每次独立出现的Ro选自氢、可选被取代的C1-6脂族基、未取代的5-6元杂芳基或杂环、苯基、-O(Ph)或-CH2(Ph),或者尽管有如上定义,在相同取代基或不同取代基上的两次独立出现的Ro与每个Ro基团所键合的原子一起构成3-8元环烷基、杂环基、芳基或杂芳基环,具有0-3个独立选自氮、氧或硫的杂原子。Ro的脂族基团上可选的取代基选自NH2、NH(C1-4脂族基)、N(C1-4脂族基)2、卤素、C1-4脂族基、OH、O(C1-4脂族基)、NO2、CN、CO2H、CO2(C1-4脂族基)、-O(卤代C1-4脂族基)或卤代C1-4脂族基,其中Ro的每个上述C1-4脂族基团是未取代的。
[0042]脂族或杂脂族基团或者非芳族杂环可以含有一个或多个取代基。脂族或杂脂族基团或者非芳族杂环的饱和碳原子上适合的取代基选自上面关于芳基或杂芳基不饱和碳所列举的那些,并且另外包括下列基团:=O、=S、=NNHR*、=NN(R*)2、=NNHC(O)R*、=NNHCO2(烷基)、=NNHSO2(烷基)或=NR*,其中每个R*独立地选自氢或者可选被取代的C1-6脂族基。R*的脂族基团上可选的取代基选自NH2、NH(C1-4脂族基)、N(C1-4脂族基)2、卤素、C1-4脂族基、OH、O(C1-4脂族基)、NO2、CN、CO2H、CO2(C1-4脂族基)、0(卤代C1-4脂族基)或卤代C1-4脂族基,其中R*的每个上述C1-4脂族基团是未取代的。
[0043]非芳族杂环氮上可选的取代基选自-R+、-N(R+)2、-C(O)R+、-CO2R+、-C(O)C(O)R+、-C(O)CH2C(O)R+、-SO2R+、-SO2N(R+)2、-C(=S)N(R+)2、-C(=NH)-N(R+)2或-NR+SO2R+;其中R+是氢、可选被取代的C1-6脂族基、可选被取代的苯基、可选被取代的-O(Ph)、可选被取代的-CH2(Ph)、可选被取代的-(CH2)1-2(Ph)、可选被取代的-CH=CH(Ph)、或者具有一至四个独立选自氧、氮或硫的杂原子的未取代的5-6元杂芳基或杂环,或者尽管有如上定义,在相同取代基或不同取代基上的两次独立出现的R+与每个R+基团所键合的原子一起构成3-8元环烷基、杂环基、芳基或杂芳基环,具有0-3个独立选自氮、氧或硫的杂原子。R+的脂族基团或苯基环上可选的取代基选自NH2、NH(C1-4脂族基)、N(C1-4脂族基)2、卤素、C1-4脂族基、OH、O(C1-4脂族基)、NO2、CN、CO2H、CO2(C1-4脂族基)、O(卤代C1-4脂族基)或卤代C1-4脂族基团,其中R+的每个上述C1-4脂族基团是未取代的。
[0044]术语“亚烷基链”表示直链或支链碳链,它可以是完全饱和的或者具有一个或多个不饱和单元,并且具有两个与分子其余部分连接的点。术语“亚螺环烷基”表示这样一种碳环的环,它可以是完全饱和的或者具有一个或多个不饱和单元,并且同一碳原子具有两个与分子其余部分连接的点。
[0045]如上所述,在有些实施方式中,两次独立出现的Ro(或者R+或本文相似定义的任意其他变量)与它们所键合的原子一起构成3-8元环烷基、杂环基、芳基或杂芳基环,具有0-3个独立选自氮、氧或硫的杂原子。两次独立出现的Ro(或者R+或本文相似定义的任意其他变量)与每个变量所键合的原子一起所构成的示范性环包括但不限于下列:a)两个独立出现的Ro(或者R+或本文相似定义的任意其他变量)键合于同一原子,并且与该原子一起构成一个环,例如N(Ro)2,其中出现的两个Ro与氮原子一起构成哌啶-1-基、哌嗪-1-基或吗啉-4-基;和b)两个独立出现的Ro(或者R+或本文相似定义的任意其他变量)键合于不同原子,并且与这些原子一起构成一个环,例如其中苯基被两次出现的ORo取代这两次出现的Ro与它们所键合的氧原子一起构成稠合的6-元含氧环:将被领会到,两次独立出现的Ro(或者R+或本文相似定义的任意其他变量)与每个变量所键合的原子一起可以构成多种其他环,上述详细实例不打算是限制性的。
[0046]不言而喻,在上述RXY的基团(A)和(B)中,若M是二价阳离子,例如Mg或Ca,则wC是0,以满足化合价。
[0047]除非另有规定,本文所描绘的结构也意味着包括该结构的所有异构(例如对映异构、非对映异构和几何异构(或构象异构))形式;例如每一不对称中心的R与S构型,(Z)与(E)双键异构体,和(Z)与(E)构象异构体。因此,这些化合物的单一立体化学异构体以及对映异构、非对映异构和几何异构(或构象异构)混合物都属于本发明的范围。除非有相反规定,本发明化合物的所有互变异构形式都属于本发明的范围。例如,当式I化合物中的R3是氢时,式I化合物可以存在互变体:
另外,除非另有规定,本文所描绘的结构也意味着包括仅在一个或多个同位素富集原子的存在上有所不同的化合物。例如,除了氢被氘或氚代替或者碳被13C-或14C-富集的碳代替以外具有本发明结构的化合物都属于本发明的范围。这类化合物例如可用作生物学测定法中的分析工具或探针。
[0048]3.示范性化合物的说明:
[0049]按照一种实施方式,本发明提供式I化合物:
或其药学上可接受的盐;
X是价键或者是可选被取代的C1-C6亚烷基链,其中X的至多两个亚甲基单元可选地和独立地被-CO-、-CS-、-COCO-、-CONR′-、-CONR′NR′-、-CO2-、-OCO-、-NR′CO2-、-O-、-NR′CONR′-、-OCONR′-、-NR′NR′、-NR′NR′CO-、-NR′CO-、-S-、-SO、-SO2-、-NR′-、-SO2NR′-、NR′SO2-或-NR′SO2NR′-代替;
RX独立地是R′、卤代基、NO2、CN、CF3或OCF3;
y是0-4;
每个R1和R2独立地选自氢、CN、CF3、卤代基、C1-C6直链或支链烷基、3-12元环脂族基、苯基、C5-C10杂芳基或C3-C7杂环基,其中所述杂芳基或杂环基具有至多3个选自O、S或N的杂原子,其中所述R1和R2独立地和可选地被至多三个选自如下的取代基取代:-OR′、-CF3、-OCF3、SR′、S(O)R′、SO2R′、-SCF3、卤代基、CN、-COOR′、-OC(O)R′、-COR′、-O(CH2)2N(R′)(R′)、-O(CH2)3N(R′)(R′)、-CON(R′)(R′)、-(CH2)2OR′、-(CH2)OR′、CH2CN、可选被取代的苯基或苯氧基、-N(R′)(R′)、-NR′C(O)OR′、-NR′C(O)R′、-(CH2)2N(R′)(R′)或-(CH2)N(R′)(R′);
R3是氢;
RXY是选自如下的基团:
其中在基团(A)和基团(B)中:
每个wA、wB、wC和wD独立地是0或1;
每个M独立地选自氢、Li、Na、K、Mg、Ca、Ba、-N(R7)4、C1-C12-烷基、C2-C12-链烯基或-R6;其中该烷基或链烯基的1至4个-CH2原子团、除了与Z键合的-CH2以外,可选地被选自O、S、S(O)、S(O)2或N(R7)的杂原子基团代替;其中所述烷基、链烯基或R6中的任意氢可选地被选自如下的取代基取代:氧代基、-OR7、-R7、N(R7)2、N(R7)3、R7OH、-CN、-CO2R7、-C(O)-N(R7)2、S(O)2-N(R7)2、N(R7)-C(O)-R7、C(O)R7、-S(O)n-R7、OCF3、-S(O)n-R6、N(R7)-S(O)2(R7)、卤代基、-CF3或-NO2;
n是0-2;
M′是H、C1-C12-烷基、C2-C12-链烯基或-R6;其中该烷基或链烯基的1至4个-CH2原子团可选地被选自O、S、S(O)、S(O)2或N(R7)的杂原子基团代替;其中所述烷基、链烯基或R6中的任意氢可选地被选自如下的取代基取代:氧代基、-OR7、-R7、-N(R7)2、N(R7)3、-R7OH、-CN、-CO2R7、-C(O)-N(R7)2、-S(O)2-N(R7)2、-N(R7)-C(O)-R7、-C(O)R7、-S(O)n-R7、-OCF3、-S(O)n-R6、-N(R7)-S(O)2(R7)、卤代基、-CF3或-NO2;
Z是-CH2-、-O-、-S-、-N(R7)2-;或者,
若M不存在,则Z是氢、=O或=S;
Y是P或S,其中若Y是S,则Z不是S;
X是O或S;
每个R7独立地选自氢或C1-C4脂族基,可选地被至多两个Q1取代;
每个Q1独立地选自3-7元饱和、部分饱和或不饱和的碳环环系;或者4-7元饱和、部分饱和或不饱和的杂环的环,含有一个或多个选自O、N、NH、S、SO或SO2的杂原子或杂原子基团;其中Q1可选地被至多三个选自如下的取代基取代:氧代基、-OH、-O(C1-C4脂族基)、-C1-C4脂族基、-NH2、NH(C1-C4脂族基)、-N(C1-C4脂族基)2、-N(C1-C4脂族基)-C(O)-C1-C4脂族基、-(C1-C4脂族基)-OH、-CN、-CO2H、-CO2(C1-C4脂族基)、-C(O)-NH2、-C(O)-NH(C1-C4脂族基)、-C(O)-N(C1-C4脂族基)2、卤代基或-CF3;
R6是4-6元饱和、部分饱和或不饱和的碳环或杂环环系,或者8-10元饱和、部分饱和或不饱和的二环环系;其中任意所述杂环环系含有一个或多个选自O、N、S、S(O)n或N(R7)的杂原子;其中任意所述环系可选地含有1至4个独立选自OH、C1-C4烷基、O-C1-C4烷基或O-C(O)-C1-C4烷基的取代基;
R9是C(R7)2、O或N(R7);
其中在基团(C)中:
R8选自C1-C6烷基;
每个R4和R5选自可选被Q1取代的C1-C6脂族基;
R′独立地选自氢或者可选被取代的基团,选自C1-C8脂族基团,3-8元饱和、部分不饱和或完全不饱和的单环,具有0-3个独立选自氮、氧或硫的杂原子,或者8-12元饱和、部分不饱和或完全不饱和的二环环系,具有0-5个独立选自氮、氧或硫的杂原子;或者两次出现的R′与它们所键合的原子一起构成可选被取代的3-12元饱和、部分不饱和或完全不饱和的单环或二环,具有0-4个独立选自氮、氧或硫的杂原子;以及
每个RU独立地是氢或者可选被至多四个卤素取代基取代的C1-C6烷基。
[0050]在一种实施方式中,y是0-2。在一种实施方式中,y是0。
[0051]在一种实施方式中,X是价键,RX是氢。
[0052]在一种实施方式中,R′是氢。
[0053]在一种实施方式中,R′是C1-C8脂族基团,可选地被至多3个选自卤代基、CN、CF3、CHF2、OCF3或OCHF2的取代基取代,其中所述C1-C8脂族基的至多两个亚甲基单元可选地被-CO-、-CONH(C1-C4烷基)-、-CO2-、-OCO-、-N(C1-C4烷基)CO2-、-O-、-N(C1-C4烷基)CON(C1-C4烷基)-、-OCON(C1-C4烷基)-、-N(C1-C4烷基)CO-、-S-、-N(C1-C4烷基)-、-SO2N(C1-C4烷基)-、N(C1-C4烷基)SO2-或-N(C1-C4烷基)SO2N(C1-C4烷基)-代替。在另一种实施方式中,R′是C1-C6烷基。示范性R′包括甲基、乙基、丙基、丁基等。
[0054]在一种实施方式中,R′是3-8元饱和、部分不饱和或完全不饱和的单环,具有0-3个独立选自氮、氧或硫的杂原子,其中R′可选地被至多3个选自卤代基、CN、CF3、CHF2、OCF3、OCHF2或C1-C6烷基的取代基取代,其中所述C1-C6烷基的至多两个亚甲基单元可选地被-CO-、-CONH(C1-C4烷基)-、-CO2-、-OCO-、-N(C1-C4烷基)CO2-、-O-、-N(C1-C4烷基)CON(C1-C4烷基)-、-OCON(C1-C4烷基)-、-N(C1-C4烷基)CO-、-S-、-N(C1-C4烷基)-、-SO2N(C1-C4烷基)-、N(C1-C4烷基)SO2-或-N(C1-C4烷基)SO2N(C1-C4烷基)-代替。
[0055]在一种实施方式中,R′是8-12元饱和、部分不饱和或完全不饱和的二环环系,具有0-5个独立选自氮、氧或硫的杂原子;其中R′可选地被至多3个选自卤代基、CN、CF3、CHF2、OCF3、OCHF2或C1-C6烷基的取代基取代,其中所述C1-C6烷基的至多两个亚甲基单元可选地被-CO-、-CONH(C1-C4烷基)-、-CO2-、-OCO-、-N(C1-C4烷基)CO2-、-O-、-N(C1-C4烷基)CON(C1-C4烷基)-、-OCON(C1-C4烷基)-、-N(C1-C4烷基)CO-、-S-、-N(C1-C4烷基)-、-SO2N(C1-C4烷基)-、N(C1-C4烷基)SO2-或-N(C1-C4烷基)SO2N(C1-C4烷基)-代替。
[0056]在一种实施方式中,两次出现的R′与它们所键合的原子一起构成可选被取代的3-12元饱和、部分不饱和或完全不饱和的单环或二环,具有0-4个独立选自氮、氧或硫的杂原子,其中R′可选地被至多3个选自卤代基、CN、CF3、CHF2、OCF3、OCHF2或C1-C6烷基的取代基取代,其中所述C1-C6烷基的至多两个亚甲基单元可选地被-CO-、-CONH(C1-C4烷基)-、-CO2-、-OCO-、-N(C1-C4烷基)CO2-、-O-、-N(C1-C4烷基)CON(C1-C4烷基)-、-OCON(C1-C4烷基)-、-N(C1-C4烷基)CO-、-S-、-N(C1-C4烷基)-、-SO2N(C1-C4烷基)-、N(C1-C4烷基)SO2-或-N(C1-C4烷基)SO2N(C1-C4烷基)-代替。
[0057]在一种实施方式中,两个RU都是氢。或者,两个RU都是C1-C6烷基,可选地被至多4个卤代基取代。在另一种实施方式中,两个RU都是C1-C3烷基。示范性RU包括甲基、乙基或丙基。
[0058]在另一种实施方式中,一个RU是氢,另一个RU是C1-C6烷基,可选地被至多4个卤代基取代。或者,一个RU是氢,另一个RU是C1-C3烷基。示范性RU包括甲基、乙基或丙基。
[0059]在一种实施方式中,每个R1和R2独立地选自氢、CN、CF3、卤代基、C1-C6直链或支链烷基、3-12元环脂族基或苯基,其中所述R1和R2独立地和可选地被至多三个选自如下的取代基取代:-OR′、-CF3、-OCF3、-SCF3、卤代基、-COOR′、-COR′、-O(CH2)2N(R′)(R′)、-O(CH2)N(R′)(R′)、-CON(R′)(R′)、-(CH2)2OR′、-(CH2)OR′、可选被取代的苯基、-N(R′)(R′)、-NC(O)OR′、-NC(O)R′、-(CH2)2N(R′)(R′)或-(CH2)N(R′)(R′)。
[0060]在一种实施方式中:
R1是苯基环,可选地被至多三个选自如下的取代基取代:-OR′、-CF3、-OCF3、SR′、S(O)R′、SO2R′、-SCF3、卤代基、CN、-COOR′、-COR′、-O(CH2)2N(R′)(R′)、-O(CH2)N(R′)(R′)、-CON(R′)(R′)、-(CH2)2OR′、-(CH2)3OR′、CH2CN、可选被取代的苯基或苯氧基、-N(R′)(R′)、-NR′C(O)OR′、-NR′C(O)R′、-(CH2)2N(R′)(R′)或-(CH2)N(R′)(R′);且
R2是C1-C6直链或支链烷基。
[0061]在一种实施方式中,每个R1和R2独立地选自CF3或卤代基。在一种实施方式中,每个R1和R2独立地选自氢或者可选被取代的C1-C6直链或支链烷基。在某些实施方式中,每个R1和R2独立地选自可选被取代的正丙基、异丙基、正丁基、仲丁基、叔丁基、1,1-二甲基-2-羟基乙基、1,1-二甲基-2-(乙氧基羰基)-乙基、1,1-二甲基-3-(叔丁氧基羰基-氨基)丙基或正戊基。
[0062]在一种实施方式中,每个R1和R2独立地选自可选被取代的3-12元环脂族基。这类环脂族基的示范性实施方式包括环戊基、环己基、环庚基、降冰片基、金刚烷基、[2.2.2.]二环-辛基、[2.3.1.]二环-辛基或[3.3.1]二环-壬基。
[0063]在某些实施方式中,R1是氢,R2是C1-C6直链或支链烷基。在某些实施方式中,R2选自甲基、乙基、丙基、正丁基、仲丁基或叔丁基。
[0064]在一种实施方式中,R1是氢,R2是CF3。
[0065]在某些实施方式中,R2是氢,R1是C1-C6直链或支链烷基。在某些实施方式中,R1选自甲基、乙基、丙基、正丁基、仲丁基、叔丁基或正戊基。
[0066]在某些实施方式中,每个R1和R2是C1-C6直链或支链烷基。在某些实施方式中,每个R1和R2选自甲基、乙基、丙基、正丁基、仲丁基、叔丁基或戊基。在一种实施方式中,两个R1和R2都是叔丁基。
[0067]在一种实施方式中,式I化合物具有一种、优选多种、或者更优选全部下列特性:
i)R1是氢;
ii)R2是C1-C6直链或支链烷基或者C6-C10环脂族基,可选地被至多3个选自C1-C4烷基或-O(C1-C4烷基)的取代基取代;以及
iii)RXY是:
其中R8是C1-C3亚烷基;
每个R4和R5是C1-C4烷基。
[0068]在一种实施方式中,式I化合物具有一种、优选多种、或者更优选全部下列特性:
i)R1是氢;
ii)R2是C3-C5环脂族基,可选地被至多3个选自C1-C4烷基或-O(C1-C4烷基)的取代基取代;以及
iii)RXY是:
其中R8是C1-C3亚烷基;
每个R4和R5是C1-C4烷基。
[0069]在一种实施方式中,式I化合物具有一种、优选多种、或者更优选全部下列特性:
i)R1是氢;
ii)R2是CF3;以及
iii)RXY是:
其中R8是C1-C3亚烷基;且
每个R4和R5是C1-C4烷基。
[0070]在一种实施方式中,式I化合物具有一种、优选多种、或者更优选全部下列特性:
i)R1是卤代基、C1-C6直链或支链烷基、CF3、CN或苯基,可选地被至多3个选自C1-C4烷基、-O(C1-C4烷基)或卤代基的取代基取代;
ii)R2是CF3、卤代基、C1-C6烷基或C6-C10环脂族基;以及
iii)RXY是:
其中R8是C1-C3亚烷基;
每个R4和R5是C1-C4烷基。
[0071]在一种实施方式中,式I化合物具有一种、优选多种、或者更优选全部下列特性:
i)R1是卤代基、C1-C6直链或支链烷基、CF3、CN或苯基,可选地被至多3个选自C1-C4烷基、-O(C1-C4烷基)或卤代基的取代基取代;
ii)R2是C3-C5环脂族基,可选地被至多3个选自C1-C4烷基或-O(C1-C4烷基)的取代基取代;以及
iii)RXY是:
其中R8是C1-C3亚烷基;以及
每个R4和R5是C1-C4烷基。
[0072]在一种实施方式中,式I化合物具有一种、优选多种、或者更优选全部下列特性:
i)R1是氢;
ii)R2是C1-C6直链或支链烷基或者C6-C10环脂族基,可选地被至多3个选自C1-C4烷基或-O(C1-C4烷基)的取代基取代;以及
iii)RXY是:
其中:
wB是0;
wC是0或1;
M独立地选自Na、K或Ca。
[0073]在一种实施方式中,式I化合物具有一种、优选多种、或者更优选全部下列特性:
i)R1是卤代基、C1-C6烷基、CF3、CN或苯基,可选地被至多3个选自C1-C4烷基、-O(C1-C4烷基)或卤代基的取代基取代;
ii)R2是CF3、卤代基、C1-C6烷基或C6-C10环脂族基;以及
iii)RXY是:
其中:
wB是0;
wC是0或1;
M独立地选自Na、K或Ca。
[0074]在一种实施方式中,式I化合物具有一种、优选多种、或者更优选全部下列特性:
i)R1是卤代基、C1-C6烷基、CF3、CN或苯基,可选地被至多3个选自C1-C4烷基、-O(C1-C4烷基)或卤代基的取代基取代;
ii)R2是C3-C5环脂族基,可选地被至多3个选自C1-C4烷基或-O(C1-C4烷基)的取代基取代;以及
iii)RXY是:
其中:
wB是0;
wC是0或1;
M独立地选自Na、K或Ca。
[0075]在一种实施方式中,式I化合物具有一种、优选多种、或者更优选全部下列特性:
i)R1是氢;
ii)R2是C3-C5环脂族基,可选地被至多3个选自C1-C4烷基或-O(C1-C4烷基)的取代基取代;以及
iii)RXY是:
其中:
wB是0;
wC是0或1;
M独立地选自Na、K或Ca。
[0076]在一种实施方式中,式I化合物具有一种、优选多种、或者更优选全部下列特性:
i)R1是氢;
ii)R2是CF3;以及
iii)RXY是:
wB是0;
wC是0或1;
M独立地选自Na、K或Ca。
[0077]在一种实施方式中,式I化合物具有一种、优选多种、或者更优选全部下列特性:
i)R1是氢;
ii)R2是C1-C6直链或支链烷基或者C6-C10环脂族基,可选地被至多3个选自C1-C4烷基或-O(C1-C4烷基)的取代基取代;以及
iii)RXY是:
其中:
wD是0或1;
wA是0或1;
R9是-CH2-、O或NH;
M′是C1-C8烷基,其中至多3个-CH2-原子团可选地被O、NH或NMe代替。
[0078]在一种实施方式中,式I化合物具有一种、优选多种、或者更优选全部下列特性:
i)R1是卤代基、C1-C6烷基、CF3、CN或苯基,可选地被至多3个选自C1-C4烷基、-O(C1-C4烷基)或卤代基的取代基取代;
ii)R2是CF3、卤代基、C1-C6烷基或C6-C10环脂族基;以及
iii)RXY是:
其中:
wD是0或1;
wA是0或1;
R9是-CH2-、O或NH;
M′是C1-C8烷基,其中至多3个-CH2-原子团可选地被O、NH或NMe代替。
[0079]在一种实施方式中,式I化合物具有一种、优选多种、或者更优选全部下列特性:
i)R1是卤代基、C1-C6烷基、CF3、CN或苯基,可选地被至多3个选自C1-C4烷基、-O(C1-C4烷基)或卤代基的取代基取代;
ii)R2是C3-C5环脂族基,可选地被至多3个选自C1-C4烷基或-O(C1-C4烷基)的取代基取代;以及
iii)RXY是:
其中:
wD是0或1;
wA是0或1;
R9是-CH2-、O或NH;
M′是C1-C8烷基,其中至多3个-CH2-原子团可选地被O、NH或NMe代替。
[0080]在一种实施方式中,式I化合物具有一种、优选多种、或者更优选全部下列特性:
i)R1是氢;
ii)R2是C3-C5环脂族基,可选地被至多3个选自C1-C4烷基或-O(C1-C4烷基)的取代基取代;以及
iii)RXY是:
其中:
wD是0或1;
wA是0或1;
R9是-CH2-、O或NH;
M′是C1-C8烷基,其中至多3个-CH2-原子团可选地被O、NH或NMe代替。
[0081]在一种实施方式中,式I化合物具有一种、优选多种、或者更优选全部下列特性:
i)R1是氢;
ii)R2是CF3;以及
iii)RXY是:
其中:
wD是0或1;
wA是0或1;
R9是-CH2-、O或NH;
M′是C1-C8烷基,其中至多3个-CH2-原子团可选地被O、NH或NMe代替。
[0082]在一种实施方式中,RXX位于喹啉基环的6-位。在某些实施方式中,RXX一起是C1-C6烷基、-O-(C1-C6烷基)或卤代基。
[0083]在一种实施方式中,RXX位于喹啉基环的5-位。在某些实施方式中,RXX一起是-OH。
[0084]在另外一种实施方式中,RXY是:
或其药学上可接受的盐。
[0085]在一种实施方式中,R8是C1-C3亚烷基。示范性实施方式包括亚甲基或亚乙基。
[0086]在另一种实施方式中,R4和R5都是C1-C6脂族基。或者,R4和R5是C1-C4烷基。或者,R4和R5都是乙基。
[0087]在另外一种实施方式中,RXY选自:
[0088]在一种实施方式中:
wB是0。
[0089]在另一种实施方式中,每个M独立地选自Na、K或Ca。或者,每个M独立地选自Na或Ca。或者,每个M是Na。或者,M是Ca。
[0090]在另一种实施方式中:
wB是0;
wC是1;以及
每个M是Na。
[0091]在另一种实施方式中:
wB是0;
wC是0;以及
M是Ca。
[0092]在另外一种实施方式中,RXY选自:
-(L)-赖氨酸、-PO3Na2、-(L)-酪氨酸、-(L)-丝氨酸、-SO3Na2、 乙酰基、-(L)-缬氨酸、-(L)-谷氨酸、-(L)-天冬氨酸、-(L)-γ-叔丁基-天冬氨酸、-(L)-3-吡啶基丙氨酸、-(L)-组氨酸、-CHO、 PO3K2、PO3Ca、PO3-精胺、PO3-(精脒)2或PO3-(葡甲胺)2。
[0093]在另外一种实施方式中,RXY选自:
[0094]在另一种实施方式中,本发明提供式II化合物:
其中:
X、y、RX、R1、R2、R3、R4、R5和R8定义如上;以及
Y是药学上可接受的阴离子。
[0095]本文所用的术语“药学上可接受的阴离子”表示适合于药物用途的阴离子。本领域技术人员完全知晓这类阴离子。
[0096]适合于本发明的药学上可接受的阴离子包括卤离子、羧酸根(例如甲酸根、乙酸根等)、硫酸根、甲磺酸根、甲苯磺酸根等。
[0097]在一种实施方式中,Y是卤离子。或者,Y是氯离子或溴离子。
[0098]在另一种实施方式中,Y是羧酸根。或者,Y是甲酸根。
[0099]式II化合物中X、y、RX、R1、R2、R3、R4、R5和R8的实施方式如上式I化合物所述。
[00100]本发明的代表性化合物如下表1所述。
表1
[00101]本领域技术人员将领会到,可以采用本领域熟知的方法制备本发明化合物。下面阐述制备本发明化合物的示范性方法。
[00102]5.用途、制剂和给药
[00103]药学上可接受的组合物
[00104]正如上文所讨论的,本发明提供可用作ABC转运蛋白、例如CFTR的调控剂的前体药物。这些化合物提高了水溶性,所以提供治疗上相关的优点,例如提高了生物利用度、适合于制剂等。所以,本发明化合物可用于治疗疾病、疾患或病症,例如囊性纤维化、遗传性肺气肿、遗传性血色素沉着、凝血-纤维蛋白溶解缺陷(例如C蛋白缺陷)、1型遗传性血管水肿、脂质加工缺陷(例如家族性高胆固醇血)、1型乳糜微粒血、无β脂蛋白血症、溶酶体贮存疾病(例如I-细胞疾病/假性Hurler)、粘多糖病、Sandhof/Tay-Sachs、Crigler-Najjar II型、多内分泌病/高胰岛素血、糖尿病、拉伦侏儒、髓过氧化物酶缺陷、原发性甲状旁腺机能减退、黑素瘤、聚糖病CDG 1型、遗传性肺气肿、先天性甲状腺机能亢进、成骨不全、遗传性低纤维蛋白原血、ACT缺陷、尿崩症(DI)、后叶激素运载蛋白性DI、肾原性DI、夏-马-图三氏综合征、佩-梅二氏病、神经变性疾病(例如阿尔茨海默氏病、帕金森氏病、肌萎缩性侧索硬化、进行性核上性麻痹、皮克氏病)、若干聚谷氨酰胺神经病学疾患(例如亨廷顿氏病、I型脊髓小脑性共济失调、脊髓与延髓肌肉萎缩、齿状核红核苍白球丘脑下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-雅二氏病(由朊病毒蛋白加工缺陷引起)、法布里氏病和斯-施二氏综合征)、COPD、干眼病或斯耶格伦氏病。
[00105]因此,在本发明的另一方面,提供药学上可接受的组合物,其中这些组合物包含任意如本文所述的化合物,并且可选地包含药学上可接受的载体、助剂或赋形剂。在某些实施方式中,这些组合物可选地进一步包含一种或多种附加治疗剂。
[00106]也将被领会到,某些本发明化合物能够以游离形式存在供治疗,或者酌情为其药学上可接受的衍生物。按照本发明,药学上可接受的衍生物包括但不限于药学上可接受的盐、酯、这类酯的盐、或者任意其他加合物或衍生物,一旦对需要的患者给药即能够直接或间接提供如本文所述的化合物或者其代谢产物或残余物。
[00107]本文所用的术语“药学上可接受的盐”表示这样的盐,在合理的医学判断范围内,它们适合用于与人体和低等动物组织接触,没有不适当的毒性、刺激性、变态反应等,与合理的利益/风险比相称。“药学上可接受的盐”表示本发明化合物的任意无毒性盐或酯盐,一旦对接受者给药,即能够直接或间接提供本发明化合物或者其抑制活性代谢产物或残余物。
[00108]药学上可接受的盐是本领域熟知的。例如,S.M.Berge等在J.Pharmaceutical Sciences,1977,66,1-19中详细描述了药学上可接受的盐,引用在此作为参考。本发明化合物的药学上可接受的盐包括从适合的无机与有机酸与碱衍生的那些。药学上可接受的无毒性酸加成盐的实例是与无机酸或有机酸生成的氨基盐,无机酸例如盐酸、氢溴酸、磷酸、硫酸和高氯酸,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,或者利用本领域所用的其他方法,例如离子交换形成的盐。其他药学上可接受的盐包括己二酸盐、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、葡庚酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、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、十一烷酸盐、戊酸盐等。从适当的碱衍生的盐包括碱金属、碱土金属、铵和N+(C1-4烷基)4盐。本发明也涵盖如本文所公开的化合物的任意碱性含氮基团的季铵化作用。借助这类季铵化作用可以得到可溶于水或油或可分散在水或油中的产物。代表性碱金属或碱土金属盐包括钠、锂、钾、钙、镁等。当适当的时候,其他药学上可接受的盐包括无毒的铵盐、季铵盐和胺阳离子盐,利用抗衡离子生成,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。
[00109]如上所述,本发明的药学上可接受的组合物另外包含药学上可接受的载体、助剂或赋形剂,正如本发明中所述,它们包括适合于所需的特定剂型的任意和所有溶剂、稀释剂或其他液体赋形剂、分散或悬浮助剂、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。Remington′s Pharmaceutical Sciences,Sixteenth Edition,E.W.Martin(Mack Publishing Co.,Easton,Pa.,1980)公开了用于配制药学上可接受的组合物的各种载体和用于其制备的已知技术。除了任何常规载体介质与本发明化合物不相容以外,例如产生任何不可取的生物学效应或者以有害方式相互作用于药学上可接受的组合物的任何其他组分,它的使用涵盖在本发明的范围内。能够充当药学上可接受的载体的材料的一些实例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;蜡类;聚乙烯-聚氧化丙烯-嵌段聚合物;羊毛脂;糖类,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、乙基纤维素和乙酸纤维素;粉碎的黄蓍胶;麦芽;明胶;滑石;赋形剂,例如可可脂和栓剂用蜡;油类,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇,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;藻酸;无热原的水;等渗盐水;林格氏溶液;乙醇;磷酸盐缓冲溶液;以及其他无毒的可相容的润滑剂,例如月桂基硫酸钠和硬脂酸镁;根据制剂人员的判断,在组合物中也可以存在着色剂、释放剂、包衣剂、甜味剂、调味剂和香料、防腐剂和抗氧化剂。
[00110]化合物和药学上可接受的组合物的用途
[00111]另一方面,本发明提供治疗牵涉ABC转运蛋白、例如CFTR活性的病症、疾病或疾患的方法。在某些实施方式中,本发明提供治疗牵涉ABC转运蛋白活性缺陷的病症、疾病或疾患的方法,该方法包含对有此需要的受治疗者、优选哺乳动物给予包含式(I)化合物的组合物。
[00112]在某些实施方式中,本发明提供治疗如下疾病的方法:囊性纤维化、遗传性肺气肿、遗传性血色素沉着、凝血-纤维蛋白溶解缺陷(例如C蛋白缺陷)、1型遗传性血管水肿、脂质加工缺陷例如家族性高胆固醇血、1型乳糜微粒血、无β脂蛋白血症、溶酶体贮存疾病(例如I-细胞疾病/假性Hurler)、粘多糖病、Sandhof/Tay-Sachs、Crigler-Najjar II型、多内分泌病/高胰岛素血、糖尿病、拉伦侏儒、髓过氧化物酶缺陷、原发性甲状旁腺机能减退、黑素瘤、聚糖病CDG1型、先天性甲状腺机能亢进、成骨不全、遗传性低纤维蛋白原血、ACT缺陷、尿崩症(DI)、后叶激素运载蛋白性DI、肾原性DI、夏-马-图三氏综合征、佩-梅二氏病、神经变性疾病(例如阿尔茨海默氏病、帕金森氏病、肌萎缩性侧索硬化、进行性核上性麻痹、皮克氏病)、若干聚谷氨酰胺神经病学障碍(例如亨廷顿氏病、I型脊髓小脑性共济失调、脊髓与延髓肌肉萎缩、齿状核红核苍白球丘脑下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-雅二氏病(由朊病毒蛋白加工缺陷引起)、法布里氏病和斯-施二氏综合征)、COPD、干眼病或斯耶格伦氏病,包含对所述哺乳动物给予有效量的包含本发明化合物的组合物的步骤。
[00113]按照替代的优选实施方式,本发明提供治疗囊性纤维化的方法,包含对所述哺乳动物给予有效量的包含本发明化合物的组合物的步骤。
[00114]按照本发明,化合物或药学上可接受的组合物的“有效量”是有效治疗一种或多种如下疾病或者减轻其严重性的量:囊性纤维化、遗传性肺气肿、遗传性血色素沉着、凝血-纤维蛋白溶解缺陷(例如C蛋白缺陷)、1型遗传性血管水肿、脂质加工缺陷(例如家族性高胆固醇血)、1型乳糜微粒血、无β脂蛋白血症、溶酶体贮存疾病(例如I-细胞疾病/假性Hurler)、粘多糖病、Sandhof/Tay-Sachs、Crigler-Najjar II型、多内分泌病/高胰岛素血、糖尿病、拉伦侏儒、髓过氧化物酶缺陷、原发性甲状旁腺机能减退、黑素瘤、聚糖病CDG1型、先天性甲状腺机能亢进、成骨不全、遗传性低纤维蛋白原血、ACT缺陷、尿崩症(DI)、后叶激素运载蛋白性DI、肾原性DI、夏-马-图三氏综合征、佩-梅二氏病、神经变性疾病(例如阿尔茨海默氏病、帕金森氏病、肌萎缩性侧索硬化、进行性核上性麻痹、皮克氏病)、若干聚谷氨酰胺神经病学障碍(例如亨廷顿氏病、I型脊髓小脑性共济失调、脊髓与延髓肌肉萎缩、齿状核红核苍白球丘脑下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-雅二氏病(由朊病毒蛋白加工缺陷引起)、法布里氏病和斯-施二氏综合征)、COPD、干眼病或斯耶格伦氏病。
[00115]按照本发明的方法,化合物和组合物可以使用就治疗一种或多种如下疾病或者减轻其严重性而言有效的任意量和任意给药途径给药:囊性纤维化、遗传性肺气肿、遗传性血色素沉着、凝血-纤维蛋白溶解缺陷(例如C蛋白缺陷)、1型遗传性血管水肿、脂质加工缺陷(例如家族性高胆固醇血)、1型乳糜微粒血、无β脂蛋白血症、溶酶体贮存疾病(例如I-细胞疾病/假性Hurler)、粘多糖病、Sandhof/Tay-Sachs、Crigler-Najjar II型、多内分泌病/高胰岛素血、糖尿病、拉伦侏儒、髓过氧化物酶缺陷、原发性甲状旁腺机能减退、黑素瘤、聚糖病CDG 1型、先天性甲状腺机能亢进、成骨不全、遗传性低纤维蛋白原血、ACT缺陷、尿崩症(DI)、后叶激素运载蛋白性DI、肾原性DI、夏-马-图三氏综合征、佩-梅二氏病、神经变性疾病(例如阿尔茨海默氏病、帕金森氏病、肌萎缩性侧索硬化、进行性核上性麻痹、皮克氏病)、若干聚谷氨酰胺神经病学障碍(例如亨廷顿氏病、I型脊髓小脑性共济失调、脊髓与延髓肌肉萎缩、齿状核红核苍白球丘脑下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-雅二氏病(由朊病毒蛋白加工缺陷引起)、法布里氏病和斯-施二氏综合征)、COPD、干眼病或斯耶格伦氏病。
[00116]在一种实施方式中,本发明的化合物和组合物可用于治疗患者的囊性纤维化或者减轻其严重性。
[00117]在某些实施方式中,本发明的化合物和组合物可用于治疗囊性纤维化或者减轻其严重性,其中患者在呼吸与非呼吸上皮顶膜中表现残留ABC转运蛋白活性。残留ABC转运蛋白活性在上皮表面上的存在可以利用本领域已知的方法方便地检测,例如标准电生理学、生物化学或组织化学技术。这类方法利用体内或来自体内的电生理技术、汗液或唾液Cl-浓度测量或者来自体内的监测细胞表面密度的生物化学或组织化学技术来鉴定ABC转运蛋白活性。例如,利用这类方法,可以在多种不同突变杂合或纯合的患者中容易地检测残留ABC转运蛋白活性,包括最常见突变ΔF508杂合或纯合的患者。
[00118]在另一种实施方式中,本发明的化合物和组合物可用于治疗患者囊性纤维化或者减轻其严重性,所述患者因为采用药理方法或基因疗法而诱导或增加残留CFTR活性。这类方法增加存在于细胞表面上的CFTR量,由此诱导患者中尚不存在的CFTR活性或者增加患者中残留CFTR活性的现有水平。
[00119]在一种实施方式中,本发明的化合物和组合物可用于治疗患者囊性纤维化或者减轻其严重性,所述患者处于某些表现残留CFTR活性的遗传型内,例如III类突变(调节或门控减低)、IV类突变(电导改变)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)。其他表现残留CFTR活性的患者遗传型包括这些种类之一纯合或者任意其他突变种类杂合的患者,包括I类突变、II类突变或未分类的突变。
[00120]在一种实施方式中,本发明的化合物和组合物可用于治疗患者囊性纤维化或者减轻其严重性,所述患者处于某些临床遗传型内,例如通常与上皮顶膜中残留CFTR活性的量相关的适中至轻微的临床遗传型。这类遗传型包括表现胰腺功能充足的患者或者被诊断为特发性胰腺炎和先天性两侧输精管缺乏或轻微肺疾病的患者。
[00121]所需确切的量将因受治疗者而异,取决于受治疗者的种类、年龄与一般状态、感染的严重性、特定药物、其给药的方式等。本发明化合物优选地被配制成剂量单元形式,有易于给药和剂量的一致性。本文所用的表达方式“剂量单元形式”表示物理离散的药物单元,对所治疗的患者而言是适当的。不过将被理解的是,本发明化合物和组合物的总每日用量将由主治医师在合理的医学判断范围内决定。任意特定患者或生物体的具体有效剂量水平将依赖于多种因素,包括所治疗的病症和病症的严重性;所采用的具体化合物的活性;所采用的具体组合物;患者的年龄、体重、一般健康状况、性别和饮食;给药的时间、给药的途径和所采用的具体化合物的排泄速率;治疗的持续时间;与所采用的具体化合物联合或同时使用的药物;和医药领域熟知的其他因素。本文所用的术语“患者”表示动物,优选哺乳动物,最优选人。
[00122]本发明的药学上可接受的组合物可以对人和其他动物口服、直肠、肠胃外、脑池内、阴道内、腹膜内、局部(以粉剂、软膏剂或滴剂)、颊、以口用或鼻用喷雾剂等方式给药,这依赖于所治疗感染的严重性。在某些实施方式中,本发明化合物可以被口服或肠胃外给药,剂量水平为每天约0.01mg/kg至约50mg/kg、优选约1mg/kg至约25mg/kg受治疗者体重,一天一次或多次,以获得所需的治疗效果。
[00123]口服给药的液体剂型包括但不限于药学上可接受的乳剂、微乳剂、溶液、悬液、糖浆剂和酏剂。除了活性化合物以外,液体剂型可以含有本领域常用的惰性稀释剂,例如水或其他溶剂,增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄基酯、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、麦胚油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脱水山梨醇的脂肪酸酯,和它们的混合物。除了惰性稀释剂以外,口服组合物还可以包括助剂,例如湿润剂、乳化与悬浮剂、甜味剂、矫味剂和香料。
[00124]使用适合的分散或湿润剂和悬浮剂,可以按照已知技术配制可注射制剂,例如无菌可注射的水性或油性悬液。无菌可注射制剂也可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液、悬液或乳液,例如在1,3-丁二醇中的溶液。可以采用的可接受的载体和溶剂有水、林格氏溶液、U.S.P.和等渗氯化钠溶液。另外,常规上采用无菌的不挥发油作为溶剂或悬浮介质。为此,可以采用任何温和的不挥发油,包括合成的单-或二-甘油酯。另外,在注射剂的制备中也可以使用脂肪酸,例如油酸。
[00125]可注射制剂可以这样进行灭菌,例如通过细菌截留性滤器过滤,或者掺入无菌固体组合物形式的灭菌剂,可以在使用前将其溶解或分散在无菌的水或其他无菌可注射介质中。
[00126]为了延长本发明化合物的作用,经常需要延缓化合物在皮下或肌内注射后的吸收。这可以利用水溶性差的结晶性或无定形物质的液体悬液来实现。化合物的吸收速率取决于它的溶解速率,后者又可能取决于晶体大小和晶型。作为替代选择,将化合物溶解或悬浮在油类载体中,实现肠胃外给药化合物形式的延迟吸收。可注射的储库形式是这样制备的,在生物可降解的聚合物中,例如聚乳酸-聚乙醇酸交酯,生成化合物的微囊包封基质。根据化合物与聚合物的比例和所采用特定聚合物的属性,可以控制化合物的释放速率。其他生物可降解聚合物的实例包括聚(原酸酯)和聚(酸酐)。储库型可注射制剂也可以将化合物包合在与机体组织相容的脂质体或微乳中来制备。
[00127]直肠或阴道给药组合物优选地是栓剂,它们可以这样制备,将本发明化合物与适合的无刺激性赋形剂或载体混合,例如可可脂、聚乙二醇或栓剂用蜡,它们在环境温度下是固体,但是在体温下是液体,因此在直肠或阴道腔中融化,释放出活性化合物。
[00128]口服给药的固体剂型包括胶囊剂、片剂、丸剂、粉剂和颗粒剂。在这类固体剂型中,将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,例如柠檬酸钠或磷酸二钙,和/或a)填充剂或增容剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露糖醇和硅酸,b)粘合剂,例如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶,c)润湿剂,例如甘油,d)崩解剂,例如琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、某些硅酸盐和碳酸钠,e)溶解迟延剂,例如石蜡,f)吸收促进剂,例如季铵化合物,g)湿润剂,例如鲸蜡醇和甘油单硬脂酸酯,h)吸收剂,例如高岭土和膨润土,和i)润滑剂,例如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠及其混合物。在胶囊剂、片剂和丸剂的情况下,该剂型还可以包含缓冲剂。
[00129]也可以采用相似类型的固体组合物作为软或硬的填充的明胶胶囊剂中的填充剂,胶囊所用赋形剂例如乳糖或奶糖以及高分子聚乙二醇等。片剂、锭剂、胶囊剂、丸剂和颗粒剂等固体剂型可以带有包衣和外壳,例如肠溶衣和药物配制领域熟知的其他包衣。它们可以可选地含有遮光剂,也可以是仅仅或优先在肠道某一部分释放活性成分的组合物,可选地为延迟的方式。可以使用的包埋组合物的实例包括聚合物质和蜡类。也可以采用相似类型的固体组合物作为软与硬的填充的明胶胶囊剂中的填充剂,胶囊所用赋形剂例如乳糖或奶糖以及高分子聚乙二醇等。
[00130]活性化合物也可以是微囊包封的形式,其中含有一种或多种上述赋形剂。片剂、锭剂、胶囊剂、丸剂和颗粒剂等固体剂型可以带有包衣和外壳,例如肠溶衣、释放控制性包衣和药物配制领域熟知的其他包衣。在这类固体剂型中,可以将活性化合物与至少一种惰性稀释剂混合,例如蔗糖、乳糖或淀粉。在正常情况下,这类剂型还可以包含除惰性稀释剂以外的其他物质,例如压片润滑剂和其他压片助剂,例如硬脂酸镁和微晶纤维素。在胶囊剂、片剂和丸剂的情况下,剂型还可以包含缓冲剂。它们可以可选地含有遮光剂,也可以是仅仅或优先在肠道某一部分释放活性成分的组合物,可选地为延迟的方式。可以使用的包埋组合物的实例包括聚合物质和蜡类。
[00131]本发明化合物的局部或透皮给药剂型包括软膏剂、糊剂、霜剂、洗剂、凝胶剂、粉剂、溶液、喷雾剂、吸入剂或贴剂。将活性组分在无菌条件下与药学上可接受的载体和任何必需的防腐剂或缓冲剂混合,根据需要而定。眼科制剂、滴耳剂和滴眼剂也被涵盖在本发明的范围内。另外,本发明涵盖透皮贴剂的使用,它们具有控制化合物向机体递送的附加优点。这类剂型可以通过将化合物溶解或分散在恰当的介质中来制备。还可以使用吸收增强剂以增加化合物穿过皮肤的通量。可以通过提供速率控制膜或者将化合物分散在聚合物基质或凝胶中来控制速率。
[00132]正如上文一般性描述的,本发明化合物可用作ABC转运蛋白的调控剂。因而,不希望受任意特定理论所限,化合物和组合物特别可用于治疗疾病、病症或疾患或者减轻其严重性,其中ABC转运蛋白的活性过高或无活性在该疾病、病症或疾患中有牵连。当ABC转运蛋白的活性过高或无活性在特定疾病、病症或疾患中有牵连时,该疾病、病症或疾患也可以被称为“ABC转运蛋白-介导的疾病、病症或疾患”。因此,在另一方面,本发明提供治疗疾病、病症或疾患或者减轻其严重性的方法,其中ABC转运蛋白的活性过高或无活性在该疾病状态中有牵连。在一种实施方式中,所述ABC转运蛋白是CFTR。
[00133]也将被领会到,本发明的前体药物和药学上可接受的组合物可以用在联合疗法中,也就是说,化合物和药学上可接受的组合物可以在一种或多种其他所需治疗剂或医药程序同时、之前或随后给药。用在联合方案中的特定疗法组合(治疗剂或程序)将考虑所需治疗剂和/或程序与所要达到的所需治疗效果的可相容性。也将被领会的是,所用疗法可以对同一病症达到所需效果(例如,本发明化合物可以与另一种用于治疗同一病症的药物同时给药),或者它们可以达到不同的效果(例如控制任何副作用)。正如本文所用的,在正常情况下给药以治疗或预防特定疾病或病症的附加治疗剂被称为“就所治疗的疾病或病症而言是适当的”。
[00134]在一种实施方式中,附加成分选自粘液溶解剂、支气管扩张剂、抗生素、抗感染剂、抗炎剂、除本发明化合物以外的ABC转运蛋白调控剂或者营养剂。
[00135]附加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,附加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成分的组合物中的含量的约50%至100%。
[00136]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,例如假肢、人工瓣膜、脉管移植物、支架和导管。因此,本发明在另一方面包括涂覆可植入装置的组合物,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。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6,099,562、5,886,026和5,304,121中。涂料通常是生物可相容的聚合材料,例如水凝胶聚合物、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。
[00137]为了可以更加充分地理解本文所述发明,描述下列实施例。应当理解,这些实施例仅供阐述目的,不被解释为以任何方式限制本发明。
实施例
[00286]通用流程:
[00287]实施例1:
[5-[(4-氧代-1H-喹啉-3-基)羰基氨基]-2,4-二叔丁基-苯氧基]膦酸二苄基酯
将四唑(0.45M CH3CN溶液,12.4mL,0.56mmol)加入到N-(5-羟基-2,4-二叔丁基-苯基)-4-氧代-1H-喹啉-3-酰胺(78mg,0.2mmol)与二苄基二异丙基氨基亚磷酸酯(184μL,0.56mmol)在二氯甲烷(2mL)中的混合物中。将反应在室温下搅拌2h,然后加入叔丁基过氧化氢(5.5M癸烷溶液,102μL,0.56mmol),将反应在室温下搅拌过夜。然后使反应混合物在乙酸乙酯与饱和NaHCO3溶液之间分配。将有机层用盐水洗涤,经MgSO4干燥,浓缩。使残余物吸附上硅胶,经过柱色谱纯化(硅胶,50-100%乙酸乙酯-己烷),得到[5-[(4-氧代-1H-喹啉-3-基)羰基氨基]-2,4-二叔丁基-苯氧基]膦酸二苄基酯,为澄清的油(80mg,61%)。1H-NMR(400MHz,d-DMSO)δ 13.04(br s,1H),12.05(s,1H),8.91(s,1H),8.35(dd,J=8.1,1.0 Hz,1H),7.88(s,1H),7.82(m,1H),7.77(d,J=7.7 Hz,1H),7.53(m,1H),7.37-7.31(m,11H),5.19(m,4H),1.44(s,9H),1.33(s,9H);HPLC保留时间3.77min,30-99% CH3CN,运行5min;ESI-MS 653.4m/z[M+H]+。
[5-[(4-氧代-1H-喹啉-3-基)羰基氨基]-2,4-二叔丁基-苯氧基]膦酸
将[5-[(4-氧代-1H-喹啉-3-基)羰基氨基]-2,4-二叔丁基-苯氧基]膦酸二苄基酯(65mg,0.1mmol)溶于乙醇(2mL),用N2(g)冲洗反应烧瓶。然后加入Pd-C(5%wt,20mg),再次用N2(g)冲洗烧瓶。然后用H2(g)冲洗反应烧瓶,然后在H2(g,atm)和室温下搅拌3h。通过硅藻土过滤反应,然后再次通过0.2μm滤片过滤。浓缩溶液,得到[5-[(4-氧代-1H-喹啉-3-基)羰基氨基]-2,4-二叔丁基-苯氧基]膦酸,为白色固体(40mg,85%)。1H-NMR(400MHz,d-DMSO)δ 13.37(br s,1H),11.85(s,1H),8.93(s,1H),8.31(d,J=8.0 Hz,1H),7.79-7.74(m,3H),7.49(m,1H),7.26(s,1H),1.37(m,18H);HPLC保留时间3.07min,10-99%CH3CN,运行5min;ESI-MS473.0m/z[M+H]+。
[5-[(4-氧代-1H-喹啉-3-基)羰基氨基]-2,4-二叔丁基-苯氧基]膦酸二钠盐
向[5-[(4-氧代-1H-喹啉-3-基)羰基氨基]-2,4-二叔丁基-苯氧基]膦酸(300mg,0.635mmol)的去离子水(15mL)悬液加入NaOH溶液(0.1024N,12.4mL,1.27mmol)。超声混合物,加入更多的水(15mL),使固体溶解。水溶液然后冷冻干燥,得到二钠盐,为绒毛状白色固体。1H-NMR(400MHz,d-DMSO)δ 13.27(s,1H),8.95(s,1H),8.22(d,J=8.0 Hz,1H),7.74(s,1H),7.58(d,J=8.1 Hz,1H),7.45(m,1H),7.20-7.16(m,2H),1.40(s,9H),1.38(s,9H);HPLC保留时间3.11min,10-99%CH3CN,运行5min;ESI-MS 473.3m/z[M+H]+。
[00288]实施例2:
[4-(3-乙氧基苯基)-5-[(4-氧代-1H-喹啉-3-基)羰基氨基]-2-叔丁基-苯氧基]膦酸二苄基酯
将四唑(0.45M CH3CN溶液,12.4mL,5.6mmol)加入到在冰水浴中冷却的N-[2-(3-乙氧基苯基)-5-羟基-4-叔丁基-苯基]-4-氧代-1H-喹啉-3-酰胺(912mg,2mmol)与二苄基二异丙基氨基亚磷酸酯(1.84mL,5.6mmol)在二氯甲烷(2mL)中的混合物中。将反应搅拌2h,同时升温至室温,然后加入更多的二苄基二异丙基氨基亚磷酸酯(1.00mL,3.0mmol),将反应加热至回流达3h。然后将反应在冰水浴中冷却,同时加入叔丁基过氧化氢(5.5M癸烷溶液,1.02mL,5.6mmol),在室温下搅拌过夜。然后使反应混合物在二氯甲烷与饱和NaHCO3溶液之间分配。将有机层用盐水洗涤,经MgSO4干燥,浓缩。使残余物吸附上硅藻土,经过反相柱色谱纯化(C-18,30-50%乙腈-水洗脱副产物,然后50-95%洗脱产物),得到磷酸二苄基酯5-叔丁基-3′-乙氧基-2-[(4-氧代-1,4-二氢-喹啉-3-羰基)-氨基]-联苯-4-基酯,为白色固体(1.2g,83%)。1H-NMR(400MHz,d-DMSO)δ 12.17(s,1H),8.86(s,1H),8.68(s,1H),8.11(dd,J=8.2,1.1 Hz,1H),7.77(m,1H),7.71(d,J=7.8 Hz,1H),7.49-7.34(m,12H),7.18(d,J=1.3 Hz,1H),6.99-6.96(m,3H),5.24(m,4H),4.10(q,J=7.0 Hz,2H),1.34(s,9H),1.30(t,J=7.0 Hz,3H);HPLC保留时间4.20min,30-99%CH3CN,运行5min;ESI-MS 717.3m/z[M+H]+。
[4-(3-乙氧基苯基)-5-[(4-氧代-1H-喹啉-3-基)羰基氨基]-2-叔丁基-苯氧基]膦酸
将[4-(3-乙氧基苯基)-5-[(4-氧代-1H-喹啉-3-基)羰基氨基]-2-叔丁基-苯氧基]膦酸二苄基酯(50mg,0.07mmol)溶于乙醇(2mL),用N2(g)冲洗反应烧瓶。然后加入Pd-C(5%wt,5mg),再次用N2(g)冲洗烧瓶。然后用H2(g)冲洗反应烧瓶,然后在H2(g,atm)和室温下搅拌2.5h。过滤反应,浓缩,得到[4-(3-乙氧基苯基)-5-[(4-氧代-1H-喹啉-3-基)羰基氨基]-2-叔丁基-苯氧基]膦酸,为白色固体(35mg,93%)。1H-NMR(400MHz,d-DMSO)δ 13.21(br s,1H),11.95(s,1H),8.87(d,J=6.5 Hz,1H),8.48(s,1H),8.10(d,J=8.0 Hz,1H),7.75-7.67(m,2H),7.44(m,1H),7.32(m,1H),7.10(s,1H),6.92-6.90(m,3H),4.06(q,J=7.0 Hz,2H),1.39(s,9H),1.28(t,J=7.0 Hz,3H);HPLC保留时间3.20min,10-99%CH3CN,运行5min;ESI-MS 537.4m/z[M+H]+。
[4-(3-乙氧基苯基)-5-[(4-氧代-1H-喹啉-3-基)羰基氨基]-2-叔丁基-苯氧基]膦酸二钠盐
向[4-(3-乙氧基苯基)-5-[(4-氧代-1H-喹啉-3-基)羰基氨基]-2-叔丁基-苯氧基]膦酸(28mg,0.052mmol)的去离子水(2mL)悬液加入NaOH溶液(0.1024N,1.02mL,0.104mmol)。将混合物用声波处理,使固体溶解。水溶液然后冷冻干燥,得到二钠盐,为绒毛状白色固体。1H-NMR(400MHz,d-DMSO)δ 13.32(s,1H),8.91(s,1H),8.25(s,1H),8.06(d,J=6.9 Hz,1H),7.53(d,J=8.0 Hz,1H),7.41(m,1H),7.26(t,J=7.9 Hz,1H),7.13(m,1H),7.02-7.01(m,2H),6.96(d,J=7.7 Hz,1H),6.82(dd,J=8.2,2.0Hz,1H),4.10(q,J=7.0 Hz,2H),1.40(s,9H),1.26(t,J=7.0Hz,3H);HPLC保留时间3.22min,10-99%CH3CN,运行5min;ESI-MS 537.5m/z[M+H]+。
[00289]通用流程:
[00290]实施例3:
[5-[(4-氧代-1H-喹啉-3-基)羰基氨基]-2,4-二叔丁基-苯基]2-二乙基氨基乙酸酯.HCl
向N-(5-羟基-2,4-二叔丁基-苯基)-4-氧代-1H-喹啉-3-酰胺(3.92g,10mmol)、DMAP(8.54g,70mmol)与二乙基氨基-乙酸(2.62g,20mmol)在二氯甲烷(35mL)中的混合物加入N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺(5.75g,30mmol)。将反应在室温下搅拌3天。将反应混合物用水洗涤,经MgSO4干燥,浓缩。将残余物溶于DMSO,经过反相HPLC纯化(10-99%CH3CH-H2O,含有0.5% TFA),得到产物,为TFA盐。将一部分该产物(130mg)溶于二氯甲烷,用饱和NaHCO3溶液萃取,经MgSO4干燥,浓缩,得到游离碱。1H-NMR(400MHz,d-DMSO)δ 12.93(br s,1H),12.05(s,1H),8.87(s,1H),8.33(dd,J=8.2,1.1 Hz,1H),7.82(m,1H),7.75(d,J=7.8 Hz,1H),7.52(m,1H),7.42(s,1H),7.39(s,1H),3.63(s,2H),2.66(q,J=7.1 Hz,4H),1.45(s,9H),1.32(s,9H),1.02(t,J=7.1 Hz,6H);HPLC保留时间2.99min,10-99%CH3CN,运行5min;ESI-MS506.5m/z(MH+)。然后将游离碱溶于二乙醚,加入HCl溶液(2M二乙醚溶液,2当量),浓缩溶液,得到[5-[(4-氧代-1H-喹啉-3-基)羰基氨基]-2,4-二叔丁基-苯基]2-二乙基氨基乙酸酯盐酸盐,为浅粉红色固体。1H-NMR(400MHz,d-DMSO)δ 13.15(d,J=6.8Hz,1H),12.09(s,1H),10.13(s,1H),8.83(d,J=6.8 Hz,1H),8.33(d,J=7.6 Hz,1H),7.85-7.78(m,2H),7.58(s,1H),7.53(m,1H),7.44(s,1H),4.66(m,2H),3.28(m,4H),1.46(s,9H),1.34(s,9H),1.27(t,J=7.3Hz,6H);HPLC保留时间3.01min,10-99% CH3CN,运行5min;ESI-MS 506.5m/z[M+H]+。
[00291]实施例4:
[4-(4-乙氧基苯基)-5-[(4-氧代-1H-喹啉-3-基)羰基氨基]-2-叔丁基-苯基]2-二乙基氨基乙酸酯.HCl
向N-[2-(3-乙氧基苯基)-5-羟基-4-叔丁基-苯基]-4-氧代-1H-喹啉-3-酰胺(228mg,0.5mmol)、DMAP(610mg,5mmol)与二乙基氨基-乙酸(328mg,2.5mmol)在二氯甲烷(2.5mL)中的混合物加入N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺(480mg,2.5mmol)。将反应在室温下搅拌过夜。除去溶剂后,残余物经过反相柱色谱纯化(10-50%CH3CN-H2O,含有1.0% HCOOH),得到产物,为甲酸盐。1H-NMR(400MHz,d-DMSO)δ 12.14(bs,1H),11.68(s,1H),8.84(s,1H),8.33(s,1H),8.26(s,1H),8.20-8.18(m,1H),7.48(t,J=7.7Hz,1H),7.35-7.23(m,4H),6.93-6.90(m,1H),6.85-6.83(m,2H),4.02(q,J=7.0Hz,2H),3.98(s,2H),3.07(q,J=7.2Hz,4H),1.37-1.34(m,12H),1.26(t,J=7.2 Hz,6H);HPLC保留时间3.05min,10-99% CH3CN,运行5min;ESI-MS 570.4m/z[M+H]+。将一部分该产物(5mg)溶于氯仿(200μL),加入HCl溶液(2M二乙醚溶液,12μL)。将溶液浓缩,重新溶于氯仿(200μL),加入HCl溶液(2M二乙醚溶液,12μL)。蒸发溶液至干,得到[4-(4-乙氧基苯基)-5-[(4-氧代-1H-喹啉-3-基)羰基氨基]-2-叔丁基-苯基]2-二乙基氨基乙酸酯盐酸盐。1H-NMR(400MHz、CD3CN)δ 12.17(bs,1H),11.31-11.29(m,1H),8.76(s,1H),8.38(s,1H),8.14(d,J=8.0Hz,1H),7.75-7.70(m,2H),7.41(t,J=7.8Hz,2H),7.33(s,1H),7.04-6.99(m,3H),4.36(s,2H),4.12(q,J=7.0Hz,2H),3.42(m,4H),2.15-1.96(m,18H);HPLC保留时间3.07min,10-99% CH3CN,运行5min;ESI-MS 570.4m/z[M+H]+。
[00292]表1化合物的鉴别数据如下表2所示。
表2
化合物# | LC/MSM+1 | LC/RTMin | 1H NMR |
1 | 570.4 | 3.07 | 1H-NMR(400MHz、CD3CN)δ 12.17(bs,1H),11.31-11.29(m,1H),8.76(s,1H),8.38(s,1H),8.14(d,J=8.0 Hz,1H),7.75-7.70(m,2H),7.41(t,J=7.8 Hz,2H),7.33(s,1H),7.04-6.99(m,3H),4.36(s,2H),4.12(q,J=7.0 Hz,2H),3.42(m,4H),2.15-1.96(m,18H) |
2 | 537.5 | 3.22 | 1H-NMR(400MHz,DMSO-d6)13.32(s,1H),8.91(s,1H),8.25(s,1H),8.06(d,J=6.9 Hz,1H),7.53(d,J=8.0 Hz,1H),7.41(m,1H),7.26(t,J=7.9 Hz,1H),7.13(m,1H),7.02-7.01(m,2H),6.96(d,J=7.7 Hz,1H),6.82(dd,J=8.2,2.0 Hz,1H),4.10(q,J=7.0 Hz,2H),1.40(s,9H),1.26(t,J=7.0 Hz,3H) |
3 | 506.5 | 3.01 | 1H-NMR(400 MHz,DMSO-d6)13.15(d,J=6.8 Hz,1H),12.09(s,1H),10.13(s,1H),8.83(d,J=6.8 Hz,1H),8.33(d,J=7.6 Hz,1H),7.85-7.78(m,2H),7.58(s,1H),7.53(m,1H),7.44(s,1H),4.66(m,2H),3.28(m,4H),1.46(s,9H),1.34(s,9H),1.27(t,J=7.3 Hz,6H) |
4 | 473 | 3.07 | 1H-NMR(400MHz,DMSO-d6)13.27(s,1H),8.95(s, |
1H),8.22(d,J=8.0Hz,1H),7.74(s,1H),7.58(d,J=8.1Hz,1H),7.45(m,1H),7.20-7.16(m,2H),1.40(s,9H),1.38(s,9H) | |||
5 | 478.4 | 2.89 | H NMR(400MHz,DMSO-d6)13.11(d,J=6.7Hz,1H),12.09(s,1H),10.35(br s,1H),8.86(d,J=6.8Hz,1H),8.34(d,J=8.1Hz,1H),7.83(m,1H),7.77(d,J=7.7Hz,1H),7.59(s,1H),7.54(m,1H),7.44(s,1H),4.64(s,2H),2.93(s,6H),1.46(s,9H),1.34(s,9H). |
[00293]检测和测量化合物的ΔF508-CFTR活性的测定法
[00294]I)测定化合物ΔF508-CFTR调控性质的膜电位光学 方法
[00295]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.and R.Y.Tsien(1995)"Voltage sensing by fluorescence resonance energytransfer in single cells"Biophys J 69(4):1272-80,andGonzalez,J.E.and R.Y.Tsien(1997)"Improved indicatorsof cell membrane potential that use fluorescence resonanceenergy transfer"Chem Biol 4(4):269-77)与测量荧光变化的仪器的组合,例如电压/离子探针读数器(VIPR)(参见,Gonzalez,J.E.,K.Oades,等人(1999)"Cell-based assays andinstrumentation for screening ion-channel targets"Drug Discov Today 4(9):431-439)。
[00296]这些电压敏感性测定法基于膜溶性、电压敏感性染剂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,它是一种集成的液体处理器和荧光检测器,被设计用来在96-或384-孔微量滴定平板中进行细胞类筛选。
[00297]强化化合物的鉴定
[00298]为了鉴定ΔF508-CFTR的强化剂,开发了双加入HTS测定形式。在第一加入期间,向每孔加入含有或没有供试化合物的无Cl-培养基。22秒后,进行含有2-10μM福司扣林的无Cl-培养基的第二加入,以活化ΔF508-CFTR。两次加入后的细胞外Cl-浓度为28mM,这促进响应于ΔF508-CFTR活化的Cl-流出,使用FRET类电压-传感染剂光学监测所致膜的去极化。
溶液
浴溶液#1(mM):NaCl 160,KCl 4.5,CaCl2 2,MgCl2 1,HEPES10,用NaOH调至pH7.4。
无氯浴溶液:浴溶液#1中的氯化物盐用葡糖酸盐取代。
CC2-DMPE:在DMSO中制成10mM储备溶液,贮存在-20℃下。
DiSBAC2(3):在DMSO中制成10mM储备溶液,贮存在-20℃下。
[00299]细胞培养
[00300]使用稳定表达ΔF508-CFTR的NIH3T3小鼠成纤维细胞进行膜电位的光学测量。在175cm2培养烧瓶中,将细胞供养在37℃下、在5%CO2和90%湿度中、和Dulbecco氏改性Eagle氏培养基中,其中补充有2mM谷氨酰胺、10%胎牛血清、1X NEAA,β-ME、1X青霉素/链霉素和25mM HEPES。就全部光学测定而言,将细胞按30,000/孔接种在384-孔涂有基质胶的平板中,在37℃下培养2小时,然后在27℃下培养24小时,供强化剂测定。就纠正测定而言,在27℃或37℃下将细胞用和不用化合物培养16-24小时。
[00302]B)测定化合物ΔF508-CFTR调控性质的电生理测定 法
[00303]II.Ussing室测定法
[00304]对表达ΔF508-CFTR的极化上皮细胞进行Ussing室实验,以进一步鉴定在光学测定法中鉴别的ΔF508-CFTR调控剂。将生长在Costar Snapwell细胞培养插件上的FRTΔF508-CFTR上皮细胞固定在Ussing室内(Physiologic Instruments,Inc.,SanDiego,CA),利用电压钳系统(Department of Bioengineering,University ofIowa,IA,and,Physiologic Instruments,Inc.,San Diego,CA)连续使单层短路。施加2mV脉冲测量跨上皮电阻。在这些条件下,FRT上皮证明有4KΩ/cm2或以上的电阻。将溶液维持在27℃下,通入空气。利用无电池插件纠正电极偏移电位和流体电阻。在这些条件下,电流反映顶端膜中Cl-通过ΔF508-CFTR的流动。利用MP100A-CE界面和AcqKnowledge软件(v3.2.6;BIOPAC Systems,Santa Barbara,CA)数字式获取的ISC。
[00305]强化化合物的鉴定
[00306]典型的方案采用基底外侧至顶端膜Cl-浓度梯度。为了建立这种梯度,对基底外侧膜使用正常的套环,用制霉菌素(360μg/ml)可渗透化,而顶端NaCl被等摩尔葡糖酸钠代替(用NaOH滴定至pH7.4),得到跨越上皮的大幅Cl-浓度梯度。所有实验均是在制霉菌素可渗透化后30分钟进行的。向细胞培养插件两侧加入福司扣林(10μM)和所有供试化合物。比较假定ΔF508-CFTR强化剂与已知强化剂染料木素的功效。
[00307]溶液
基底外侧溶液(mM):NaCl(135),CaCl2(1.2),MgCl2(1.2),K2HPO4(2.4),KHPO4(0.6),N-2-羟基乙基哌嗪-N′-2-乙磺酸(HEPES)(10),葡萄糖(10)。用NaOH滴定溶液至pH7.4。
顶端溶液(mM):与基底外侧溶液相同,NaCl用葡糖酸钠(135)代替。
[00308]细胞培养
[00309]使用表达ΔF508-CFTR的Fisher大鼠上皮(FRT)细胞(FRTΔF508-CFTR),对从我们的光学测定法鉴定的假定ΔF508-CFTR调控剂进行Ussing室实验。在Costar Snapwell细胞培养插件上培养细胞,在37℃下和5%CO2中,在Coon氏改性Ham氏F-12培养基中培养5天,其中补充有5%胎牛血清、100U/ml青霉素和100μg/ml链霉素。在用于鉴定化合物的强化性质之前,将细胞在27℃下温育16-48小时,以纠正ΔF508-CFTR。为了测定纠正化合物的活性,在27℃或37℃下将细胞用和不用化合物温育24小时。
[00310]III.全细胞记录
[00311]利用开孔-碎片全细胞记录,监测经过温度和供试化合物纠正的稳定表达ΔF508-CFTR的NIH3T3细胞中的宏观ΔF508-CFTR电流(IΔF508)。简而言之,利用Axopatch 200B碎片-钳放大器(AxonInstruments Inc.,Foster City,CA),在室温下进行IΔF508的电压钳记录。在10kHz的取样频率下获取所有记录,在1kHz下低通滤波。吸移管在充满细胞内溶液时具有5-6MΩ的电阻。在这些记录条件下,计算室温下的Cl-反向电位(EC1)为-28mV。所有记录具有>20GΩ的密封电阻和<15MΩ的串联电阻。利用装有Digidata 1320 A/D界面连接Clampex 8(Axon Instruments Inc.)的PC进行脉冲发生、数据获取和分析。浴液含有<250μL盐水,利用重力灌注系统连续灌注,速率2ml/min。
[00312]也利用开孔-碎片-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。从光学测定法鉴定的强化剂引起IΔF508的剂量-依赖性增加,效力和功效与光学测定法相似。在所有所检查的细胞中,强化剂施加之前和期间的反向电位为-30mV左右,它是所计算的EC1(-28mV)。
[00313]溶液
细胞内溶液(mM):Cs-天冬氨酸盐(90),CsCl(50),MgCl2(1),HEPES(10)和240μg/ml两性霉素-B(用CsOH调节pH至7.35)。
细胞外溶液(mM):N-甲基-D-葡糖胺(NMDG)-C1(150),MgCl2(2),CaCl2(2),HEPES(10)(用HCl调节pH至7.35)。
[00314]细胞培养
[00315]使用稳定表达ΔF508-CFTR的NIH3T3小鼠成纤维细胞进行全细胞记录。在175cm2培养烧瓶中,将细胞供养在37℃下、在5%CO2和90%湿度中、和Dulbecco氏改性Eagle氏培养基中,其中补充有2mM谷氨酰胺、10%胎牛血清、1X NEAA,β-ME、1X青霉素/链霉素和25mM HEPES。就全细胞记录而言,将2,500-5,000细胞接种在涂有聚-L-赖氨酸的玻璃盖片上,在27℃下培养24-48小时,然后用于测试强化剂活性;用或不用纠正化合物在37℃下温育,用于测量纠正剂的活性。
[00316]IV.单通道记录
[00317]利用所切除的内侧外翻膜碎片观察在NIH3T3细胞中稳定表达的经过温度纠正的ΔF508-CFTR的单通道活动和强化化合物的活性。简而言之,利用Axopatch 200B碎片-钳放大器(AxonInstruments Inc.),在室温下进行单通道活动的电压钳记录。在10kHz的取样频率下获取所有记录,在400Hz下低通滤波。将碎片吸移管改造成Corning Kovar Sealing#7052玻璃(World PrecisionInstruments,Inc.,Sarasota,FL),在充满细胞外溶液时具有5-8MΩ的电阻。在切除后加入1mM Mg-ATP和75nM cAMP-依赖性蛋白激酶催化性亚单位(PKA;Promega Corp.Madison,WI),活化ΔF508-CFTR。通道活动稳定后,利用重力微量灌注系统灌注碎片。将流入物置于碎片附近,导致1-2秒内溶液交换完全。为了维持迅速灌注期间的ΔF508-CFTR活性,向浴溶液加入非特异性磷酸酶抑制剂F-(10mM NaF)。在这些记录条件下,通道活动在整个碎片记录期间(长达60分钟)保持恒定。由正电荷从细胞内溶液向细胞外溶液运动(阴离子向相反方向运动)所产生的电流以正电流显示。吸移管电位(Vp)维持在80mV。
[00318]分析含有≤2个活动通道的膜碎片的通道活动。在实验过程期间同时开放的最大数量决定了活动通道的数量。为了测定单通道电流幅度,在100Hz下“离线”过滤从120秒ΔF508-CFTR活性记录的数据,然后用于构建全点幅度直方图,利用Bio-Patch分析软件(Bio-Logic Comp.France)带入多高斯函数。从120秒通道活动测定总微观电流和开放概率(P0)。P0是利用Bio-Patch软件或者从P0=I/i(N)测定的,其中I=平均电流,i=单通道电流幅度,N=碎片中活动通道的数量。
[00319]溶液
细胞外溶液(mM):NMDG(150),天冬氨酸(150),CaCl2(5),MgCl2(2)和HEPES(10)(用Tris碱调节pH至7.35)。
细胞内溶液(mM):NMDG-C1(150),MgCl2(2),EGTA(5),TES(10)和Tris碱(14)(用HCl调节pH至7.35)。
[00320]细胞培养
[00321]使用稳定表达ΔF508-CFTR的NIH3T3小鼠成纤维细胞进行切除膜碎片钳记录。在175cm2培养烧瓶中,将细胞供养在37℃下、在5%CO2和90%湿度中、和Dulbecco氏改性Eagle培养基中,其中补充有2mM谷氨酰胺、10%胎牛血清、1X NEAA,β-ME、1X青霉素/链霉素和25mM HEPES。就单通道记录而言,将2,500-5,000细胞接种在涂有聚-L-赖氨酸的玻璃盖片上,在27℃下培养24-48小时备用。
[00322]利用一种或多种上述测定法,发现本发明化合物强化CFTR的活性。
不言而喻,尽管已经结合详细的说明描述了发明,不过上述说明仅供举例说明,并不限制发明的范围,发明范围受到权利要求范围的限定。其他方面、优点和修改也在下列权利要求的范围内。
Claims (56)
1.式I化合物:
或其药学上可接受的盐;
X是价键或者是可选被取代的C1-C6亚烷基链,其中X的至多两个亚甲基单元可选地和独立地被-CO-、-CS-、-COCO-、-CONR′-、-CONR′NR′-、-CO2-、-OCO-、-NR′CO2-、-O-、-NR′CONR′-、-OCONR′-、-NR′NR′、-NR′NR′CO-、-NR′CO-、-S-、-SO、-SO2-、-NR′-、-SO2NR′-、NR′SO2-或-NR′SO2NR′-代替;
RX独立地是R′、卤代基、NO2、CN、CF3或OCF3;
y是0-4;
每个R1和R2独立地选自氢、CN、CF3、卤代基、C1-C6直链或支链烷基、3-12元环脂族基、苯基、C5-C10杂芳基或C3-C7杂环基,其中所述杂芳基或杂环基具有至多3个选自O、S或N的杂原子,其中所述R1和R2独立地和可选地被至多三个选自如下的取代基取代:-OR′、-CF3、-OCF3、SR′、S(O)R′、SO2R′、-SCF3、卤代基、CN、-COOR′、-OC(O)R′、-COR′、-O(CH2)2N(R′)(R′)、-O(CH2)N(R′)(R′)、-CON(R′)(R′)、-(CH2)2OR′、-(CH2)3OR′、CH2CN、可选被取代的苯基或苯氧基、-N(R′)(R′)、-NR′C(O)OR′、-NR′C(O)R′、-(CH2)2N(R′)(R′)或-(CH2)N(R′)(R′);
R3是氢;
RXY是选自如下的基团:
其中在基团(A)和基团(B)中:
每个wA、wB、wC和wD独立地是0或1;
每个M独立地选自氢、Li、Na、K、Mg、Ca、Ba、-N(R7)4、C1-C12-烷基、C2-C12-链烯基或-R6;其中该烷基或链烯基的1至4个-CH2原子团、除了与Z键合的-CH2以外,可选地被选自O、S、S(O)、S(O)2或N(R7)的杂原子基团代替;其中所述烷基、链烯基或R6中的任意氢可选地被选自如下的取代基取代:氧代基、OR7、R7、N(R7)2、N(R7)3、(C1-C4亚烷基)-OH、CN、CO2R7、C(O)N(R7)2、S(O)2-N(R7)2、N(R7)-C(O)-R7、C(O)R7、-S(O)n-R7、OCF3、-S(O)n-R6、N(R7)-S(O)2(R7)、卤代基、-CF3或-NO2;
n是0-2;
M′是H、C1-C12-烷基、C2-C12-链烯基或-R6;其中该烷基或链烯基的1至4个-CH2原子团可选地被选自O、S、S(O)、S(O)2或N(R7)的杂原子基团代替;其中所述烷基、链烯基或R6中的任意氢可选地被选自如下的取代基取代:氧代基、-OR7、-R7、-N(R7)2、N(R7)3、-R7OH、-CN、-CO2R7、-C(O)-N(R7)2、-S(O)2-N(R7)2、-N(R7)-C(O)-R7、-C(O)R7、-S(O)n-R7、-OCF3、-S(O)n-R6、-N(R7)-S(O)2(R7)、卤代基、-CF3或-NO2;
Z是-CH2-、-O-、-S-、-N(R7)2-;或者,
若M不存在,则Z是氢、=O或=S;
Y是P或S,其中若Y是S,则Z不是S;
X是O或S;
每个R7独立地选自氢或C1-C4脂族基,可选地被至多两个Q1取代;
每个Q1独立地选自3-7元饱和、部分饱和或不饱和的碳环环系;或者4-7元饱和、部分饱和或不饱和的杂环的环,含有一个或多个选自O、N、NH、S、SO或SO2的杂原子或杂原子基团;其中Q1可选地被至多三个选自如下的取代基取代:氧代基、-OH、-O(C1-C4脂族基)、-C1-C4脂族基、-NH2、NH(C1-C4脂族基)、-N(C1-C4脂族基)2、-N(C1-C4脂族基)-C(O)-C1-C4脂族基、-(C1-C4脂族基)-OH、-CN、-CO2H、-CO2(C1-C4脂族基)、-OCO(C1-C4脂族基)、-C(O)-NH2、-C(O)-NH(C1-C4脂族基)、-C(O)-N(C1-C4脂族基)2、卤代基或-CF3;
R6是4-6元饱和、部分饱和或不饱和的碳环或杂环环系,或者8-10元饱和、部分饱和或不饱和的二环环系;其中任意所述杂环环系含有一个或多个选自O、N、S、S(O)n或N(R7)的杂原子;其中任意所述环系可选地含有1至4个独立选自OH、C1-C4烷基、O-(C1-C4烷基)或O-C(O)-(C1-C4烷基)的取代基;
R9是C(R7)2、O或N(R7);
其中在基团(C)中:
R8选自C1-C6烷基;
每个R4和R5选自可选被Q1取代的C1-C6脂族基;
R′独立地选自氢或者可选被取代的基团,选自C1-C8脂族基团,3-8元饱和、部分不饱和或完全不饱和的单环,具有0-3个独立选自氮、氧或硫的杂原子,或者8-12元饱和、部分不饱和或完全不饱和的二环环系,具有0-5个独立选自氮、氧或硫的杂原子;或者两次出现的R′与它们所键合的原子一起构成可选被取代的3-12元饱和、部分不饱和或完全不饱和的单环或二环,具有0-4个独立选自氮、氧或硫的杂原子;
每个RU独立地是氢或者可选被至多四个卤素取代基取代的C1-C6烷基。
3.根据权利要求2的化合物,其中y是0。
4.根据权利要求1的化合物,其中每个R1和R2独立地选自氢、CN、CF3、卤代基、C1-C6直链或支链烷基、3-12元环脂族基或苯基,其中所述R1和R2独立地和可选地被至多三个选自如下的取代基取代:-OR′、-CF3、-OCF3、-SCF3、卤代基、-COOR′、-OCOR′、-COR′、-O(CH2)2N(R′)(R′)、-O(CH2)N(R′)(R′)、-CON(R′)(R′)、-(CH2)2OR′、-(CH2)OR′、可选被取代的苯基、-N(R′)(R′)、-NC(O)OR′、-NC(O)R′、-(CH2)2N(R′)(R′)或-(CH2)N(R′)(R′)。
5.根据权利要求5的化合物,其中R1是苯基环,可选地被至多三个选自如下的取代基取代:-OR′、-CF3、-OCF3、SR′、S(O)R′、SO2R′、-SCF3、卤代基、CN、-COOR′、-OCOR′、-COR′、-O(CH2)2N(R′)(R′)、-O(CH2)N(R′)(R′)、-CON(R′)(R′)、-(CH2)2OR′、-(CH2)3OR′、CH2CN、可选被取代的苯基或苯氧基、-N(R′)(R′)、-NR′C(O)OR′、-NR′C(O)R′、-(CH2)2N(R′)(R′)或-(CH2)N(R′)(R′);R2是C1-C6直链或支链烷基。
6.根据权利要求4的化合物,其中每个R1和R2独立地选自CF3或卤代基。
7.根据权利要求4的化合物,其中每个R1和R2独立地选自氢或者可选被取代的C1-C6直链或支链烷基。
8.根据权利要求5的化合物,其中每个R1和R2独立地选自可选被取代的正丙基、异丙基、正丁基、仲丁基、叔丁基、1,1-二甲基-2-羟基乙基、1,1-二甲基-2-(乙氧基羰基)-乙基、1,1-二甲基-3-(叔丁氧基羰基-氨基)丙基或正戊基。
9.根据权利要求4的化合物,其中R1是氢,R2是C1-C6直链或支链烷基。
10.根据权利要求4的化合物,其中R2是氢,R1是C1-C6直链或支链烷基。
11.根据权利要求4的化合物,其中每个R1和R2是C1-C6直链或支链烷基。
12.根据权利要求4的化合物,其中两个R1和R2都是叔丁基。
13.根据权利要求4的化合物,其中R1是氢或者C1-C6直链或支链烷基,R2是CF3。
14.根据权利要求1的化合物,其中两个RU都是氢。
15.根据权利要求1的化合物,其中两个RU都是C1-C6烷基,可选地被至多4个卤素取代基取代。
16.根据权利要求1的化合物,其中一个RU是氢,另一个RU是C1-C6烷基,可选地被至多4个卤代基取代。
23.根据权利要求1的化合物,其中所述式I化合物具有一种、优选多种、或者更优选全部下列特性:
i)R1是卤代基、C1-C6烷基、CF3、CN或苯基,可选地被至多3个选自C1-C4烷基、-O(C1-C4烷基)或卤代基的取代基取代;
ii)R2是CF3、卤代基、C1-C6烷基或C6-C10环脂族基;以及
iii)RXY是:
wB是0;
wC是0或1;
M独立地选自Na、K或Ca。
23.根据权利要求1的化合物,其中所述式I化合物具有一种、优选多种、或者更优选全部下列特性:
i)R1是氢;
ii)R2是C3-C5环脂族基,可选地被至多3个选自C1-C4烷基或-O(C1-C4烷基)的取代基取代;以及
iii)RXY是:
其中:
wB是0;
wC是0或1;
M独立地选自Na、K或Ca。
33.根据权利要求1的化合物,其中RXX位于喹啉基环的6-位。
34.根据权利要求33的化合物,其中RXX一起是C1-C6烷基、-O-(C1-C6烷基)或卤代基。
35.根据权利要求1的化合物,其中RXX位于喹啉基环的5-位。
36.根据权利要求33或35的化合物,其中RXX一起是-OH。
38.根据权利要求37的化合物,其中R8是C1-C3亚烷基。
39.根据权利要求37的化合物,其中R4和R5都是C1-C6脂族基。
40.根据权利要求39的化合物,其中R4和R5都是C1-C4烷基。
41.根据权利要求40的化合物,其中R4和R5都是甲基或乙基。
43.根据权利要求42的化合物,其中wB是0。
44.根据权利要求42的化合物,其中每个M独立地选自Na、K或Ca。
45.根据权利要求42的化合物,其中:
wB是0;
wC是1;以及
每个M是Na。
46.根据权利要求42的化合物,其中:
wB是0;
wC是0;以及
M是Ca。
50.根据权利要求49的化合物,其中所述Y选自卤离子、羧酸根、硫酸根、甲磺酸根或甲苯磺酸根。
51.根据权利要求50的化合物,其中所述Y是氯离子或溴离子。
52.根据权利要求1的化合物,其中所述化合物选自表1。
53.药物组合物,包含根据权利要求1的化合物和药学上可接受的载体、助剂或赋形剂。
54.根据权利要求53的药物组合物,其中所述组合物包含附加成分,选自粘液溶解剂、支气管扩张剂、抗生素、抗感染剂、抗炎剂、CFTR调控剂或营养剂。
55.治疗患者疾病或者减轻其严重性的方法,其中所述疾病选自囊性纤维化、遗传性肺气肿、遗传性血色素沉着、凝血-纤维蛋白溶解缺陷(例如C蛋白缺陷)、1型遗传性血管水肿、脂质加工缺陷(例如家族性高胆固醇血)、1型乳糜微粒血、无β脂蛋白血症、溶酶体贮存疾病(例如I-细胞疾病/假性Hurler)、粘多糖病、Sandhof/Tay-Sachs、Crigler-Najjar II型、多内分泌病/高胰岛素血、糖尿病、拉伦侏儒症、髓过氧化物酶缺陷、原发性甲状旁腺机能减退、黑素瘤、聚糖病CDG 1型、先天性甲状腺机能亢进、成骨不全、遗传性低纤维蛋白原血、ACT缺陷、尿崩症(DI)、后叶激素运载蛋白性DI、肾原性DI、夏-马-图三氏综合征、佩-梅二氏病、神经变性疾病(例如阿尔茨海默氏病、帕金森氏病、肌萎缩性侧索硬化、进行性核上性麻痹、皮克氏病)、若干聚谷氨酰胺神经病学障碍(例如亨廷顿氏病、I型脊髓小脑性共济失调、脊髓与延髓肌肉萎缩、齿状核红核苍白球丘脑下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-雅二氏病(由朊病毒蛋白加工缺陷引起)、法布里氏病和斯-施二氏综合征)、COPD、干眼病或斯耶格伦氏病,所述方法包含对所述患者给予有效量的根据权利要求1的式I化合物的步骤。
56.用于体外或体内测量生物样品中CFTR或其片段活性的药盒,包含:
(i)包含根据权利要求1的式(I)化合物的组合物;
(ii)关于如下内容的说明书:
a)使该组合物与该生物样品接触;
b)测量所述CFTR或其片段的活性。
57.根据权利要求56的药盒,进一步包含关于如下内容的说明书:
a)使附加组合物与该生物样品接触;
b)在所述附加化合物的存在下测量所述CFTR或其片段的活性;和
c)比较在该附加化合物存在下的CFTR或其片段的活性与在式(I)组合物存在下的CFTR密度。
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CN103228632A (zh) * | 2010-09-14 | 2013-07-31 | 波兰科学院生物化学与生物物理研究所 | 作为突变cftr蛋白的调节剂的化合物及其在治疗与cftr蛋白失常相关的疾病中的用途 |
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US9670163B2 (en) | 2005-12-28 | 2017-06-06 | Vertex Pharmaceuticals Incorporated | Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
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Families Citing this family (42)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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ZA200604578B (en) * | 2003-11-14 | 2008-05-28 | Vertex Pharma | Thiazoles and oxazoles.useful as modulators of ATP Binding cassette transporters |
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US10022352B2 (en) | 2006-04-07 | 2018-07-17 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
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US7645789B2 (en) | 2006-04-07 | 2010-01-12 | Vertex Pharmaceuticals Incorporated | Indole derivatives as CFTR modulators |
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JP5497633B2 (ja) | 2007-05-09 | 2014-05-21 | バーテックス ファーマシューティカルズ インコーポレイテッド | Cftrのモジュレーター |
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ES2552990T3 (es) | 2008-03-31 | 2015-12-03 | Vertex Pharmaceuticals Incorporated | Derivados de piridilo como moduladores del CFTR |
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WO2011127241A2 (en) | 2010-04-07 | 2011-10-13 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyriodin-2-yl)benzoic acid and administration thereof |
US9035072B2 (en) | 2010-04-22 | 2015-05-19 | Vertex Pharmaceuticals Incorporated | Process of producing cycloalkylcarboxamido-indole compounds |
EP2560649A1 (en) | 2010-04-22 | 2013-02-27 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions and administrations thereof |
WO2011133953A1 (en) | 2010-04-22 | 2011-10-27 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions and administrations thereof |
US8563593B2 (en) | 2010-06-08 | 2013-10-22 | Vertex Pharmaceuticals Incorporated | Formulations of (R)-1-(2,2-difluorobenzo[D] [1,3] dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide |
JP5525612B2 (ja) * | 2010-07-23 | 2014-06-18 | 国立大学法人 東京大学 | 含窒素複素環誘導体 |
HUE047354T2 (hu) | 2011-05-18 | 2020-04-28 | Vertex Pharmaceuticals Europe Ltd | Ivacaftor deuterizált származékai |
CN102816175B (zh) * | 2011-06-09 | 2015-12-16 | 上海汇伦生命科技有限公司 | 一种杂环并吡啶酮类化合物,其中间体、制备方法和用途 |
MX357328B (es) | 2011-11-08 | 2018-07-05 | Vertex Pharma | Moduladores de trasportadores de casete enlazante de atp. |
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US9012496B2 (en) | 2012-07-16 | 2015-04-21 | Vertex Pharmaceuticals Incorporated | Pharmaceutical compositions of (R)-1-(2,2-difluorobenzo[D][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide and administration thereof |
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WO2016081556A1 (en) | 2014-11-18 | 2016-05-26 | Vertex Pharmaceuticals Incorporated | Process of conducting high throughput testing high performance liquid chromatography |
WO2017053711A2 (en) | 2015-09-25 | 2017-03-30 | Concert Pharmaceuticals, Inc. | Deuterated cftr potentiators |
CN117924170A (zh) | 2017-12-01 | 2024-04-26 | 弗特克斯药品有限公司 | 用于制备囊性纤维化跨膜传导调节因子的调节剂的方法 |
Family Cites Families (76)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5874424A (en) * | 1995-12-20 | 1999-02-23 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β converting enzyme |
US3524858A (en) * | 1967-05-18 | 1970-08-18 | Warner Lambert Pharmaceutical | 1,4 - dihydro-1-substituted alkyl-6,7-methylenedioxy - 4 - oxoquinoline-3-carboxylic acid |
FR2281761A1 (fr) * | 1974-08-13 | 1976-03-12 | Roussel Uclaf | Nouveaux derives de l'acide 3-quinoleine carboxylique, leur procede de preparation et leur application comme medicament |
FR2340735A1 (fr) * | 1976-02-11 | 1977-09-09 | Roussel Uclaf | Nouveaux derives de l'acide 3-quinoleine carboxylique, leur procede de preparation et leur application comme medicament |
US4312870A (en) * | 1979-06-21 | 1982-01-26 | Ciba-Geigy Corporation | Pyrazoloquinolines |
HU190796B (en) * | 1981-06-12 | 1986-11-28 | Roussel Uclaf,Fr | Process for producing n-dihydrothiazolyl-3-quinoline-carboxamide derivatives |
FR2509728A1 (fr) * | 1981-07-17 | 1983-01-21 | Roussel Uclaf | Nouveaux derives de la quinoleine, leurs sels, procede de preparation, application a titre de medicaments et compositions les renfermant |
US4845105A (en) * | 1984-10-30 | 1989-07-04 | Roussel Uclaf | 4-OH-quinoline carboxylic acid amides having analgesic and anti-inflammatory activity |
DE3702393A1 (de) * | 1987-01-28 | 1988-08-11 | Bayer Ag | 8-cyano-1-cyclopropyl-1,4-dihydro-4-oxo- 3-chinolincarbonsaeuren, verfahren zu ihrer herstellung und diese enthaltende antibakterielle mittel |
US4777252A (en) * | 1987-08-13 | 1988-10-11 | E. R. Squibb & Sons, Inc. | 2-oxo-1-[[(substituted sulfonyl)amino]-carbonyl]azetidines |
DE3811341A1 (de) * | 1987-10-09 | 1989-04-27 | Bayer Ag | In 7-stellung c-verknuepfte chinolon- und 1,8-naphthyridin-4-on-carbonsaeure und ein verfahren zu ihrer herstellung |
US4786644A (en) * | 1987-11-27 | 1988-11-22 | Hoechst-Roussel Pharmaceuticals Inc. | 1-aryl-3-quinolinecarboxamide |
DK273689A (da) * | 1988-06-06 | 1989-12-07 | Sanofi Sa | 4-amino-3-carboxyquinoliner og -naphthyridiner, fremgangsmaade til deres fremstilling og anvendelse deraf i laegemidler |
US5491139A (en) * | 1988-10-24 | 1996-02-13 | The Procter & Gamble Company | Antimicrobial quinolonyl lactams |
LU87611A1 (fr) * | 1989-10-20 | 1991-05-07 | Oreal | Composition tinctoriale pour fibres keratiniques contenant des precurseurs de colorants par oxydation et des coupleurs amino indoliques,procedes de teinture mettant en oeuvre ces compositions et composes nouveaux |
FR2662713B1 (fr) * | 1990-05-29 | 1994-04-08 | Oreal | Procede de teinture de fibres keratiniques avec un aminoindole associe a un derive quinonique. |
US5175151A (en) * | 1990-09-07 | 1992-12-29 | Schering Corporation | Antiviral compounds and antihypertensive compounds |
WO1992004328A1 (en) * | 1990-09-07 | 1992-03-19 | Schering Corporation | Antiviral compounds and antihypertensive compounds |
WO1992004327A1 (en) * | 1990-09-07 | 1992-03-19 | Schering Corporation | Antiviral compounds and antihypertensive compounds |
CA2075154A1 (en) * | 1991-08-06 | 1993-02-07 | Neelakantan Balasubramanian | Peptide aldehydes as antithrombotic agents |
JPH05345780A (ja) * | 1991-12-24 | 1993-12-27 | Kumiai Chem Ind Co Ltd | ピリミジンまたはトリアジン誘導体及び除草剤 |
AU668180B2 (en) * | 1992-05-20 | 1996-04-26 | Merck & Co., Inc. | 17-ethers and thioethers of 4-aza-steroids |
US5610162A (en) * | 1992-05-20 | 1997-03-11 | Merck & Co., Inc. | Ester derivatives of 4-aza-steroids |
US5352690A (en) * | 1992-07-01 | 1994-10-04 | Eli Lilly And Company | 1,2,4-trioxygenated benzene derivatives useful as leukotriene antagonists |
DE69310367T2 (de) * | 1992-07-10 | 1997-08-14 | Glaxo Lab Sa | Anilide-derivate |
US5322847A (en) * | 1992-11-05 | 1994-06-21 | Pfizer Inc. | Azabenzimidazoles in the treatment of asthma, arthritis and related diseases |
US5750754A (en) * | 1993-03-29 | 1998-05-12 | Zeneca Limited | Heterocyclic compounds |
JP3760474B2 (ja) * | 1993-04-22 | 2006-03-29 | ダイキン工業株式会社 | 電気エネルギーを発生させる方法、装置およびそれに用いるn−f結合を有する化合物 |
IL111266A (en) * | 1993-10-22 | 2002-03-10 | Zeneca Ltd | 2-HETEROARYL OR 2-ARYLPYRIDAZINO [4,5-b] QUINOLINE - 1, 10 - DIONES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
ATE179422T1 (de) * | 1994-02-25 | 1999-05-15 | Aranda Lab Sa De Cv | Chinolonylcarboxamidocephalosporin-derivate und diese enthaltende arzneimittel |
FR2720397B1 (fr) * | 1994-05-24 | 1996-08-23 | Laphal Laboratoires Sa | Nouveaux oxathiolanes, leur procédé de préparation et les compositions pharmaceutiques qui en renferment. |
EP0940391B1 (en) * | 1994-05-27 | 2004-08-18 | GlaxoSmithKline S.p.A. | Quinoline derivatives as tachykinin NK3 receptor antagonists |
GB9501567D0 (en) * | 1995-01-26 | 1995-03-15 | Pharmacia Spa | Hydrosoluble 3-arylidene-2-oxindole derivatives as tyrosine kinase inhibitors |
PT841929E (pt) * | 1995-08-02 | 2003-09-30 | Darwin Discovery Ltd | Quinolonas e sua utilizacao terapeutica |
AU695132B2 (en) * | 1995-08-02 | 1998-08-06 | Darwin Discovery Limited | Quinolones and their therapeutic use |
ATE223902T1 (de) * | 1995-10-19 | 2002-09-15 | Takeda Chemical Industries Ltd | Chinolinderivate als gnrh antagonisten |
US6215016B1 (en) * | 1996-03-27 | 2001-04-10 | Toray Industries, Inc. | Ketone derivatives and medical application thereof |
DE19615262A1 (de) * | 1996-04-18 | 1997-10-23 | Bayer Ag | Heteroverknüpfte Phenylglycinolamide |
JP2000510866A (ja) * | 1996-05-20 | 2000-08-22 | ダーウィン・ディスカバリー・リミテッド | Tnfとpde―ivのインヒビターとしてのキノリンスルホンアミド |
RU2170730C2 (ru) * | 1996-05-20 | 2001-07-20 | Дарвин Дискавери Лимитед | Хинолиновые карбоксамиды и фармацевтическая композиция на их основе |
HUP9904567A3 (en) * | 1996-06-20 | 2001-10-29 | Univ Texas | Use of azo, thioalkyl, thiocarbonyl derivatives substituted by fused heterocycles and/or phenyl group for the preparation of pharmaceutical compositions stimulating bone growth |
WO1998003494A1 (en) * | 1996-07-23 | 1998-01-29 | Neurogen Corporation | Certain amido- and amino-substituted benzylamine derivatives; a new class of neuropeptite y1 specific ligands |
GB9717576D0 (en) * | 1997-08-19 | 1997-10-22 | Xenova Ltd | Pharmaceutical compounds |
US6069151A (en) * | 1996-11-06 | 2000-05-30 | Darwin Discovery, Ltd. | Quinolines and their therapeutic use |
US6258822B1 (en) * | 1997-08-06 | 2001-07-10 | Abbott Laboratories | Urokinase inhibitors |
US6429207B1 (en) * | 1997-11-21 | 2002-08-06 | Nps Pharmaceuticals, Inc. | Metabotropic glutamate receptor antagonists and their use for treating central nervous system diseases |
DE19818614A1 (de) * | 1998-04-20 | 1999-10-21 | Basf Ag | Neue substituierte Amide, deren Herstellung und Anwendung |
EP1101758A4 (en) * | 1998-07-28 | 2002-04-03 | Nihon Nohyaku Co Ltd | DICARBOXYLIC DIAMIDE DERIVATIVES WITH CONDENSED HETEROCYCLE OR SALTS THEREOF, HERBICIDES AND THEIR USE |
KR100624239B1 (ko) * | 1998-08-03 | 2006-09-13 | 어플라이드 리서치 시스템스 에이알에스 홀딩 엔.브이. | (1h)-벤조〔c〕퀴놀리진-3-온 유도체의 합성방법 |
FR2786483B1 (fr) * | 1998-12-01 | 2001-02-16 | Rhodia Chimie Sa | Procede de preparation de 4-hydroxyquinoleines et/ou formes tautomeres |
EP1177177B1 (en) * | 1999-05-06 | 2005-02-23 | Neurogen Corporation | Substituted 4-oxo-quinoline-3-carboxamides: gaba brain receptor ligands |
RS51019B (sr) * | 1999-10-25 | 2010-10-31 | Active Biotech Ab. | Lekovi za lečenje malignih tumora |
DOP2000000107A (es) * | 1999-12-01 | 2002-09-16 | Agouron Pharmaceutical Inc | Compuestos, composiciones y metodos para estimular el crecimiento y alongamiento de las neuronas |
GB0011409D0 (en) * | 2000-05-11 | 2000-06-28 | Smithkline Beecham Plc | Novel compounds |
PL360398A1 (en) * | 2000-07-13 | 2004-09-06 | Takeda Chemical Industries, Ltd. | Lipid-rich plaque inhibitors |
EP1310488A4 (en) * | 2000-08-09 | 2005-08-10 | Mitsubishi Pharma Corp | CONDENSED BICYCLIC AMIDE COMPOUNDS AND MEDICAL USES THEREOF |
GB0102687D0 (en) * | 2001-02-02 | 2001-03-21 | Pharmacia & Upjohn Spa | Oxazolyl-pyrazole derivatives active as kinase inhibitors,process for their preparation and pharmaceutical compositions comprising them |
TWI243164B (en) * | 2001-02-13 | 2005-11-11 | Aventis Pharma Gmbh | Acylated indanyl amines and their use as pharmaceuticals |
DE10108271A1 (de) * | 2001-02-21 | 2002-08-22 | Schering Ag | Chinolin-, Isochinolin- und Phthalazinderivate als Antagonisten des Gonadotropin freisetzenden Hormons |
US6515001B2 (en) * | 2001-03-05 | 2003-02-04 | Chemokine Therapeutic Corporation | IL-8 receptor ligands-drugs for inflammatory and autoimmune diseases |
DE10110750A1 (de) * | 2001-03-07 | 2002-09-12 | Bayer Ag | Neuartige Aminodicarbonsäurederivate mit pharmazeutischen Eigenschaften |
US6878713B2 (en) * | 2001-04-25 | 2005-04-12 | Wockhardt Limited | Generation triple-targeting, chiral, broad-spectrum antimicrobial 7-substituted piperidino-quinolone carboxylic acid derivatives, their preparation, compositions and use as medicaments |
BR0213233A (pt) * | 2001-10-12 | 2005-01-04 | Warner Lambert Co | Alcinos inibidores de metaloproteinase de matriz |
AU2002352878B2 (en) * | 2001-11-27 | 2007-11-22 | Merck Sharp & Dohme Corp. | 2-Aminoquinoline compounds |
WO2003049702A2 (en) * | 2001-12-10 | 2003-06-19 | Amgen Inc. | Vanilloid receptor ligands and their use in treatments |
DE10211413A1 (de) * | 2002-03-15 | 2003-09-25 | Wella Ag | Quinolinium-Salze enthaltende Färbemittel |
US6930131B2 (en) * | 2002-04-10 | 2005-08-16 | Wyeth | Aryl substituted 3-ethoxy phenyl trifluoromethane sulfonamides for the treatment of non-insulin dependent diabetes mellitus (NIDDM) |
US7037913B2 (en) * | 2002-05-01 | 2006-05-02 | Bristol-Myers Squibb Company | Bicyclo 4.4.0 antiviral derivatives |
CN100349888C (zh) * | 2002-05-14 | 2007-11-21 | 埃克森诺瓦有限公司 | 药物化合物 |
CA2484308A1 (en) * | 2002-05-14 | 2003-11-27 | The Regents Of The University Of California | Substituted quinolone carboxylic acids, their derivatives, site of action, and uses thereof |
CA2492593A1 (en) * | 2002-07-15 | 2004-01-22 | Myriad Genetics, Inc. | Compounds, compositions, and methods employing same |
US20040033959A1 (en) * | 2002-07-19 | 2004-02-19 | Boehringer Ingelheim Pharmaceuticals, Inc. | Pharmaceutical compositions for hepatitis C viral protease inhibitors |
WO2004014377A1 (en) * | 2002-08-13 | 2004-02-19 | Warner-Lambert Company Llc | 4-hydroxyquinoline derivatives as matrix metalloproteinase inhibitors |
WO2005009971A1 (ja) * | 2003-07-24 | 2005-02-03 | Astellas Pharma Inc. | キノロン誘導体又はその塩 |
EP1765347A4 (en) | 2004-06-04 | 2008-10-01 | Univ California | COMPOUNDS WITH ION TRANSPORTER HEALING EFFECT BY MUTANT CFTR AND ITS USE |
EP2489659B1 (en) * | 2004-06-24 | 2017-12-13 | Vertex Pharmaceuticals Incorporated | Modulators of ATP-binding cassette transporters |
-
2006
- 2006-12-21 JP JP2008547552A patent/JP2009521468A/ja active Pending
- 2006-12-21 AU AU2006331614A patent/AU2006331614A1/en not_active Abandoned
- 2006-12-21 WO PCT/US2006/048810 patent/WO2007075901A2/en active Application Filing
- 2006-12-21 EP EP06848958A patent/EP1979367A2/en not_active Withdrawn
- 2006-12-21 CA CA002634113A patent/CA2634113A1/en not_active Abandoned
- 2006-12-21 CN CNA2006800530016A patent/CN101374849A/zh active Pending
- 2006-12-21 US US11/643,634 patent/US20090105272A1/en not_active Abandoned
-
2013
- 2013-07-10 US US13/938,768 patent/US20130303484A1/en not_active Abandoned
-
2014
- 2014-05-02 US US14/268,756 patent/US20140243289A1/en not_active Abandoned
-
2015
- 2015-08-04 US US14/817,633 patent/US20150336898A1/en not_active Abandoned
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US9670163B2 (en) | 2005-12-28 | 2017-06-06 | Vertex Pharmaceuticals Incorporated | Solid forms of N-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
US11291662B2 (en) | 2005-12-28 | 2022-04-05 | Vertex Pharmaceuticals Incorporated | Solid forms of n-[2,4-bis(1,1-dimethylethyl)-5-hydroxyphenyl]-1,4-dihydro-4-oxoquinoline-3-carboxamide |
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US9751839B2 (en) | 2009-03-20 | 2017-09-05 | Vertex Pharmaceuticals Incorporated | Process for making modulators of cystic fibrosis transmembrane conductance regulator |
CN102361856A (zh) * | 2009-03-20 | 2012-02-22 | 沃泰克斯药物股份有限公司 | 囊性纤维化跨膜传导调节因子的调节剂 |
CN103228632B (zh) * | 2010-09-14 | 2016-08-31 | 波兰科学院生物化学与生物物理研究所 | 作为突变cftr蛋白的调节剂的化合物及其在治疗与cftr蛋白失常相关的疾病中的用途 |
CN104496840A (zh) * | 2010-09-14 | 2015-04-08 | 波兰科学院生物化学与生物物理研究所 | 作为突变cftr蛋白的调节剂的化合物及其在治疗与cftr蛋白失常相关的疾病中的用途 |
CN103228632A (zh) * | 2010-09-14 | 2013-07-31 | 波兰科学院生物化学与生物物理研究所 | 作为突变cftr蛋白的调节剂的化合物及其在治疗与cftr蛋白失常相关的疾病中的用途 |
US10272046B2 (en) | 2012-02-27 | 2019-04-30 | Vertex Pharmaceuticals Incorporated | Pharmaceutical composition and administrations thereof |
US11147770B2 (en) | 2012-02-27 | 2021-10-19 | Vertex Pharmaceuticals Incorporated | Pharmaceutical composition and administrations thereof |
US11752106B2 (en) | 2012-02-27 | 2023-09-12 | Vertex Pharmaceuticals Incorporated | Pharmaceutical composition and administrations thereof |
WO2014135096A1 (zh) * | 2013-03-06 | 2014-09-12 | 上海特化医药科技有限公司 | Ivacaftor 的制备方法及其中间体 |
CN104030981A (zh) * | 2013-03-06 | 2014-09-10 | 上海特化医药科技有限公司 | Ivacaftor的制备方法及其中间体 |
US9701639B2 (en) | 2014-10-07 | 2017-07-11 | Vertex Pharmaceuticals Incorporated | Co-crystals of modulators of cystic fibrosis transmembrane conductance regulator |
CN105237414B (zh) * | 2015-09-30 | 2017-03-22 | 浙江永宁药业股份有限公司 | ivacaftor中间体及其制备方法和用途 |
CN105237414A (zh) * | 2015-09-30 | 2016-01-13 | 浙江永宁药业股份有限公司 | ivacaftor中间体及其制备方法和用途 |
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US20090105272A1 (en) | 2009-04-23 |
AU2006331614A1 (en) | 2007-07-05 |
EP1979367A2 (en) | 2008-10-15 |
JP2009521468A (ja) | 2009-06-04 |
CA2634113A1 (en) | 2007-07-05 |
US20130303484A1 (en) | 2013-11-14 |
US20150336898A1 (en) | 2015-11-26 |
WO2007075901A2 (en) | 2007-07-05 |
US20140243289A1 (en) | 2014-08-28 |
WO2007075901A3 (en) | 2007-10-11 |
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