CN103382201B - 作为cftr调节剂的杂芳基衍生物 - Google Patents
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- CN103382201B CN103382201B CN201310274774.9A CN201310274774A CN103382201B CN 103382201 B CN103382201 B CN 103382201B CN 201310274774 A CN201310274774 A CN 201310274774A CN 103382201 B CN103382201 B CN 103382201B
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- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical class CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 208000013464 vaginal disease Diseases 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical class CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000002676 xenobiotic agent Substances 0.000 description 1
- 208000005494 xerophthalmia Diseases 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- SJCALMUTSZRVSS-UHFFFAOYSA-M zinc;methanidylcyclohexane;bromide Chemical compound Br[Zn+].[CH2-]C1CCCCC1 SJCALMUTSZRVSS-UHFFFAOYSA-M 0.000 description 1
Classifications
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Abstract
本发明涉及作为CFTR调节剂的杂芳基衍生物,具体涉及ATP结合盒(“ABC”)转运蛋白或其片段的调控剂,包括囊性纤维化跨膜传导调节剂(“CFTR”)、其组合物和及其使用方法。本发明还涉及使用这类调控剂治疗ABC转运蛋白介导的疾病的方法。
Description
本申请是申请号为200980111324.X、申请日为2009年2月25日、发明名称为“作为CFTR调节剂的杂芳基衍生物”的专利申请的分案申请。
技术领域
本发明涉及ATP结合盒(ATP-Binding Cassette)(“ABC”)转运蛋白或其片段的调控剂,包括囊性纤维化跨膜传导调节剂(“CFTR”)、其组合物及其使用方法。本发明也涉及使用这类调控剂治疗ABC转运蛋白介导的疾病的方法。
背景技术
ABC转运蛋白是膜转运蛋白家族,调节广泛多种药理学物质、潜在毒性药物和外源物以及阴离子的转运。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(如MDR1-P糖蛋白或多药耐受性蛋白MRP1),为恶性癌细胞防御抵抗化学治疗剂。迄今,已经鉴别了48种ABC转运蛋白,并基于它们的序列同一性和功能将它们分为7个家族。
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出去并干预其它其中ABC转运蛋白活性的调控可能是有益的疾病。
普遍与疾病有关的一个ABC转运蛋白家族的成员是cAMP/ATP-介导的阴离子通道CFTR。CFTR在多种细胞类型(包括吸收性和分泌性上皮细胞)中被表达,在其中它调节阴离子的跨膜流动以及其它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(包括呼吸和消化组织)转运的关键。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所构成的蛋白质,其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。
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)Nature 347:358-362);(Riordan,J.R.等人(1989)Science245:1066-1073)。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。在美国,囊性纤维化影响大约两千五百分之一的新生儿。在全部美国人口中,多达一千万人携带有一个拷贝的缺陷基因,没有明显的疾病效应。相反,带有两个拷贝的CF相关基因的个体患有CF的衰弱与致命性效应,包括慢性肺疾病。
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,导致离子和流体转运的失衡。所致阴离子转运的减少对肺中粘液蓄积增强和伴随的微生物感染有贡献,所述感染最终导致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,胰腺机能不全则导致死亡。另外,大多数囊性纤维化男性是不育的,并且囊性纤维化女性的生育力降低。与两个拷贝的CF相关基因的严重效应相反,带有一个拷贝的CF相关基因的个体表现出对霍乱和腹泻所致脱水的抗性增加—这也许解释了人群中CF基因的相对高频率的原因。
CF染色体的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;以及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,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,并且普遍将其称为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。
ΔF508-CFTR中508残基的缺失阻止初新生蛋白正确地折叠。这导致该突变蛋白不能退出内质网(“ER”)和运输至质膜。其结果是,膜中存在的通道数量远远少于表达野生型CFTR的细胞中所观察到的数量。除了运输受损以外,该突变还导致缺陷性通道门控。总之,膜中通道数量减少和缺陷性门控引起阴离子穿过上皮的转运减少,导致缺陷性离子和流体转运(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),NatureLond.354:526-528;Denning等人,上文;Pasyk和Foskett(1995),J.Cell.Biochem.270:12347-50)。除了ΔF508-CFTR以外,其它导致缺陷性运输、合成和/或通道门控的致病性CFTR突变可能被上调或下调,以改变阴离子分泌和改变疾病进展和/或严重性。
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)代表了穿过上皮转运离子和水的重要机理中的一种要素。其它要素包括上皮Na+通道、ENaC、Na+/2Cl-/K+协同转运蛋白、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。
这些要素一起发挥作用,以经由它们在细胞内的选择性表达和定位实现穿过上皮的定向转运。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+协同转运蛋白、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以及腔侧上的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,所以它穿过上皮的流动依赖于由钠和氯化物的大量流动所生成的微小跨上皮渗透梯度。
除了囊性纤维化以外,CFTR活性的调控也可以有益于其它不直接由CFTR突变所导致的疾病,例如分泌性疾病和其它由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的特征在于气流受限,它是进行性的,不是完全可逆的。气流受限是因为粘液分泌过多、肺气肿和细支气管炎。突变CFTR或野生型CFTR的活化剂提供COPD中常见的粘液分泌过多和粘液纤毛清除减少的潜在治疗。具体而言,增加穿过CFTR的阴离子分泌可以有利于流体转运进入气道表面液体,以水化粘液,优化纤毛周围的流体粘度。这将引起粘液纤毛清除增强以及与COPD有关的症状减少。干眼病的特征在于泪水产生减少和异常泪膜脂质、蛋白质与粘蛋白特征。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流体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、全身性狼疮、系统性硬化和多肌炎/皮肤肌炎有关。缺陷性蛋白质运输据信会导致该疾病,用于它的治疗选择是有限的。CFTR活性的调控剂可以水化各种受该疾病影响的器官,帮助改善有关症状。
正如上文所讨论的,据信ΔF508-CFTR中508残基的缺失阻止新生蛋白正确地折叠,导致这种突变蛋白不能退出ER并运输至质膜。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机构缺陷性ER加工的细胞现象已被显示不仅是CF疾病的潜在础,而且是广泛的其它孤立性与遗传性疾病的潜在础。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,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功能障碍有关的疾病有囊性纤维化(正如上文所讨论的,其由误折叠的ΔF508-CFTR引起)、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、溶酶体贮积病(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)、II型Crigler-Najjar(由UDP-葡糖醛基-唾液酰基-转移酶引起)、多内分泌腺病/高胰岛素血、糖尿病(由胰岛素受体引起)、拉伦(Laron)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功能障碍有关的疾病有1型聚糖病CDG、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)、神经生长性(neurophyseal)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(Charcot-Marie-Tooth)综合征(由外周髓磷脂蛋白22引起)、佩-梅二氏(Perlizaeus-Merzbacher)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(Creutzfeldt-Jakob)病(由朊病毒蛋白加工缺陷引起)、法布里氏(Fabry)病(由溶酶体α-半乳糖苷酶A引起)和斯-施二氏(Straussler-Scheinker)综合征、慢性阻塞性肺疾病(COPD)、干眼病和斯耶格伦氏综合征。
除了CFTR活性的上调以外,通过CFTR调控剂来减少阴离子分泌也可以有益于分泌性腹泻的治疗,其中作为促分泌素活化的氯化物转运的结果,上皮水转运显著地增加。该机理牵涉cAMP的升高和CFTR的刺激。
尽管腹泻有许多原因,不过由过量氯化物转运所致腹泻性疾病的主要后果是所有原因所共有的,包括脱水、酸中毒、生长减退和死亡。
急性腹泻与慢性腹泻在世界很多地区代表了主要的医学问题。在小于五岁的儿童中,腹泻既是营养不良的显著因素,又是死亡的主要原因(5,000,000例死亡/年)。
在获得性免疫缺陷综合征(AIDS)和慢性炎性肠疾病(IBD)患者中,分泌性腹泻也是危险的病况。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。
圈养动物和宠物,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。
最常见的致腹泻性细菌是肠毒原性大肠杆菌(ETEC),其具有K99菌毛抗原。腹泻的常见病毒原因包括轮状病毒和冠状病毒。其它感染性因子包括隐孢子虫、兰伯氏贾第虫和沙门氏菌等等。
轮状病毒感染的症状包括水样便的排泄、脱水和虚弱。在新生动物中,冠状病毒导致更严重的疾病,具有比轮状病毒感染更高的死亡率。不过经常,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。这显著地增加疾病的严重性。
因此,需要ABC转运蛋白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ABC转运蛋白的活性。
需要用ABC转运蛋白的这类调控剂来治疗ABC转运蛋白介导的疾病的方法。
需要在离体的哺乳动物细胞膜中调控ABC转运蛋白活性的方法。
需要CFTR活性调控剂,其可以用于调控哺乳动物细胞膜中CFTR的活性。
需要用这类CFTR活性调控剂治疗CFTR介导疾病的方法。
需要在离体的哺乳动物细胞膜中调控CFTR活性的方法。
发明内容
现发现,本发明的化合物及其药学上可接受的组合物可用作ABC转运蛋白活性(特别是CFTR活性)的调控剂。这些化合物具有通式I:
或其药学上可接受的盐,其中Ar1、RN、A环、B环和J如下所述。
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、障碍或病况或者减轻其严重性,所述疾病、障碍或病况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症)、1型乳糜微粒血症、无β脂蛋白血症、溶酶体贮积病(例如I-细胞疾病/假性Hurler)、粘多糖病、Sandhof/Tay-Sachs、Crigler-Najjar II型、多内分泌腺病/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)、神经生长性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、法布里氏病和斯-施二氏综合征、COPD、干眼病和斯耶格伦氏病。
本发明的详细说明
本发明化合物的一般性描述:
本发明涉及式I的化合物:
或其药学上可接受的盐,其中:
Ar1是:
Ar1任选被w个-W-RW取代;其中
W独立地是键或任选被取代的(C1-C6)亚烷基链,其中W的至多两个亚甲基单元独立地被-CO-、-O-、-S-、-SO2-或-NR'-替代;
R'独立地是H、烷基、芳基、杂芳基、芳烷基、环烷基或杂环烷基;以及
RW独立地是H、卤素、CN、NO2,NH2、CF3、OCF3、OH、烷氧基或任选被取代的脂肪族基、环烷基、杂环烷基、芳基或杂芳基,其中,当被取代时,Rw被至多两个R2取代;
R2是卤素、CN、NO2、CF3、OCF3、OR、-(C1-C6)亚烷基-OH、-(C1-C6)亚烷基-N(R)2、OC(O)R、OC(O)N(R)2、SR、S(O)R、SO2R、SO2N(R)2、SO3R、C(O)R、CO2R、C(O)N(R)2、N(R)2、NRC(O)R、NRCO2R、NRC(O)N(R)2、NRSO2R、B(OR)2或NRSO2N(R)2;
R独立地是H、烷基、环烷基、杂环基、芳基或杂芳基;
RN是H、烷基、芳基、杂芳基、芳烷基、环烷基或杂环烷基;
A是任选被取代的3-7元单环;
B任选与5-7元环稠合,所述环选自脂环族基、芳基、杂环基和杂芳基;
J选自CH2、CF2、C(CH3)2、C(O)、C(苯基)2、B(OH)和CH(OEt);以及
w是包括端值在内的0至5的整数;
条件是,当Ar1是时,W独立地是任选被取代的(C1-C6)亚烷基链,其中W的至多两个亚甲基单元独立地被-CO-、-O-、-S-、-SO2-或-NR'-替代。
组合物和定义:
本发明化合物包括上文一般性描述的那些,并通过本文公开的类型、小类和品种进一步阐述。在本文中使用下列定义时,除非另有说明,否则应当适用。
本文所用的术语“ABC-转运蛋白”意指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”意指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。
本文所用的术语“CFTR”意指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ΔF508CFTR和G551D CFTR(关于CFTR突变,例如参见http:// www.genet.sickkids.on.ca/cftr/)。
本文所用的术语“调控”意指增加或降低可测量的量。
出于本发明的目的,根据元素周期表CAS版Handbook of Chemistry andPhysics,第75版鉴定化学元素。另外,有机化学的一般原理描述在“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito:1999和“March's AdvancedOrganic Chemistry”,第5版,Ed.:Smith,M.B.和March,J.,John Wiley&Sons,New York:2001中,通过引用将其全部内容并入本说明书。
正如本文所述,本发明的化合物可以任选地被一个或多个取代基取代,例如上文一般性阐述的,或者如通过本发明的特定类型、小类和品种所例证的。将被领会到,短语“任选被取代的”与短语“被取代或未被取代的”是可互换使用的。一般而言,术语“被取代的”无论其前面有无术语“任选”,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。除非另有说明,任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能形成稳定的或化学上可行的化合物的那些。本文所用的短语“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。在有些实施方案中,稳定的化合物或化学上可行的化合物是在没有水分或其它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。
本文所用的术语“脂肪族基”或“脂肪族基团”意指直链(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,或者意指单环烃或二环烃,其是完全饱和的或者含有一个或多个不饱和单元,但不是芳族的(本文也称之为“碳环”、“脂环族基”或“环烷基”),其具有单一的与分子其余部分连接的点。除非另有指定,脂肪族基团含有1-20个脂肪族碳原子。在有些实施方案中,脂肪族基团含有1-10个脂肪族碳原子。在其它实施方案中,脂肪族基团含有1-8个脂肪族碳原子。在其它实施方案中,脂肪族基团含有1-6个脂肪族碳原子,在其它实施方案中,脂肪族基团含有1-4个脂肪族碳原子。在有些实施方案中,“脂环族基”(或者“碳环”或“环烷基”)表示单环C3-C8烃或二环C8-C12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。适合的脂肪族基团包括但不限于直链或支链的取代或未取代的烷基、烯基、炔基及其杂合基,例如(环烷基)烷基、(环烯基)烷基或(环烷基)烯基。
本文所用的术语“杂脂肪族基”意指脂肪族基团,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。杂脂肪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“杂环烷基”、“杂环基”、“杂脂环族”或“杂环的”基团。
本文所用的术语“杂环烷基”、“杂环基”、“杂脂环族”或“杂环的”等意指非芳族的单环、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。在有些实施方案中,所述“杂环烷基”、“杂环基”、“杂脂环族”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、氮和磷的杂原子,该系统中每个环含有3至7个环成员。
术语“杂原子”意指一个或多个硼、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))。
本文所用的术语“不饱和的”意指该部分具有一个或多个不饱和单元。
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,其通过氧(“烷氧基”)或硫(“硫代烷基”)原子与主碳链连接。
术语“卤代脂肪族基”和“卤代烷氧基”意指被一个或多个卤原子取代的脂肪族基或烷氧基,视情况而定。术语“卤素”表示F、Cl、Br或I。卤代脂肪族基的实例包括-CHF2、-CH2F、-CF3、-CF2-或全卤代烷基,比如,-CF2CF3。
单独使用或者作为更大部分“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一环含有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”也表示如下定义的杂芳基环系。
单独使用或者作为更大部分“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一环含有3至7个环成员。术语“杂芳基”可以与术语“杂芳基环”或术语“杂芳族基”互换使用。
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。芳基或杂芳基基团的不饱和碳原子上的适宜取代基选自卤素、-R°、-OR°、-SR°、1,2-亚甲二氧基、1,2-亚乙二氧基、任选被R°取代的苯基(Ph)、任选被R°取代的-O(Ph)、任选被R°取代的-(CH2)1-2(Ph)、任选被R°取代的-CH=CH(Ph)、-NO2、-CN、-N(R°)2、-NR°C(O)R°、-NR°C(O)N(R°)2、-NR°CO2R°、-NR°NR°C(O)R°、-NR°NR°C(O)N(R°)2、-NR°NR°CO2R°、-C(O)C(O)R°、-C(O)CH2C(O)R°、-CO2R°、-C(O)R°、-C(O)N(R°)2、-OC(O)N(R°)2、-S(O)2R°、-SO2N(R°)2、-S(O)R°、-NR°SO2N(R°)2、-NR°SO2R°、-C(=S)N(R°)2、-C(=NH)-N(R°)2和-(CH2)0-2NHC(O)R°,其中每次独立出现的R°选自氢、任选被取代的C1-6脂肪族基、未取代的5-6元杂芳基环或杂环、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,其具有0-3个独立选自氮、氧和硫的杂原子。R°的脂肪族基团上任选的取代基选自NH2、NH(C1-4脂肪族基)、N(C1-4脂肪族基)2、卤素、C1-4脂肪族基、OH、O(C1-4脂肪族基)、NO2、CN、CO2H、CO2(C1-4脂肪族基)、O(卤代C1-4脂肪族基)和卤代C1-4脂肪族基,其中R°的每个上述C1-4脂肪族基团是未取代的。
脂肪族或杂脂肪族基团或者非芳族杂环可以含有一个或多个取代基。脂肪族或杂脂肪族基团或者非芳族杂环的饱和碳原子上的适合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)和=NR*,其中每个R*独立地选自氢和任选被取代的C1-6脂肪族基。R*的脂肪族基团上的任选取代基选自NH2、NH(C1-4脂肪族基)、N(C1-4脂肪族基)2、卤素、C1-4脂肪族基、OH、O(C1-4脂肪族基)、NO2、CN、CO2H、CO2(C1-4脂肪族基)、O(卤代C1-4脂肪族基)和卤代C1-4脂肪族基,其中R*的每个上述C1-4脂肪族基团是未取代的。
非芳族杂环的氮上的任选取代基选自-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和-NR+SO2R+;其中R+是氢、任选被取代的C1-6脂肪族基、任选被取代的苯基、任选被取代的-O(Ph)、任选被取代的-CH2(Ph)、任选被取代的-(CH2)1-2(Ph)、任选被取代的-CH=CH(Ph)、或者具有一至四个独立选自氧、氮和硫的杂原子的未取代的5-6元杂芳基环或杂环,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,其具有0-3个独立选自氮、氧和硫的杂原子。R+的脂肪族基团或苯基环上的任选取代基选自NH2、NH(C1-4脂肪族基)、N(C1-4脂肪族基)2、卤素、C1-4脂肪族基、OH、O(C1-4脂肪族基)、NO2、CN、CO2H、CO2(C1-4脂肪族基)、O(卤代C1-4脂肪族基)和卤代(C1-4脂肪族基团),其中R+的每个上述C1-4脂肪族基团是未取代的。
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,它可以是完全饱和的或者具有一个或多个不饱和单元,并且同一环碳原子具有两个与分子其余部分连接的点。
如上所述,在有些实施方案中,两次独立出现的R°(或者R+或本文相似定义的任意其它变量)与每个变量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,其具有0-3个独立选自氮、氧和硫的杂原子。两次独立出现的R°(或者R+或本文相似定义的任意其它变量)与每个变量所键合的原子结合在一起时所构成的示范性环包括但不限于下列:a)两个独立出现的R°(或者R+或本文相似定义的任意其它变量)键合于同一原子,并且与该原子一起构成一个环,例如N(R°)2,其中出现的两个R°与氮原子一起构成哌啶-1-基、哌嗪-1-基或吗啉-4-基;以及b)两个独立出现的R°(或者R+或本文相似定义的任意其它变量)键合于不同原子,并且与这两个原子一起构成一个环,例如其中苯基被两次出现的OR°取代这两次出现的R°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R°(或者R+或本文相似定义的任意其它变量)与每个变量所键合的原子结合在一起时可以构成多种其它环,上述详细实例不打算是限制性的。
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。除非另有规定,本发明化合物的所有互变异构形式都属于本发明的范围。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。
举例性化合物的描述:
在一个实施方案中,本发明涉及式I的化合物:
或其药学上可接受的盐,其中:
Ar1是:
Ar1任选被w个-W-RW取代;其中
W独立地是键或任选被取代的(C1-C6)亚烷基链,其中W的至多两个亚甲基单元独立地被-CO-、-O-、-S-、-SO2-或-NR'-替代;
R'独立地是H、烷基、芳基、杂芳基、芳烷基、环烷基或杂环烷基;以及
RW独立地是H、卤素、CN、NO2,NH2、CF3、OCF3、OH、烷氧基或任选被取代的脂肪族基、环烷基、杂环烷基、芳基或杂芳基,其中,当被取代时,Rw被至多两个R2取代;
R2是卤素、CN、NO2、CF3、OCF3、OR、-(C1-C6)亚烷基-OH、-(C1-C6)亚烷基-N(R)2、OC(O)R、OC(O)N(R)2、SR、S(O)R、SO2R、SO2N(R)2、SO3R、C(O)R、CO2R、C(O)N(R)2、N(R)2、NRC(O)R、NRCO2R、NRC(O)N(R)2、NRSO2R,B(OH)2或NRSO2N(R)2;
R独立地是H、烷基、环烷基、杂环基、芳基或杂芳基;
RN是H、烷基、芳基、杂芳基、芳烷基、环烷基或杂环烷基;
A是任选被取代的3-7元单环;
B任选与5-7元环稠合,所述环选自脂环族基、芳基、杂环基和杂芳基;
J选自CH2、CF2、C(CH3)2、C(O)、 C(苯基)2、B(OH)和CH(OEt);以及
w是包括端值在内的0至5的整数;
条件是,当Ar1是时,W独立地是任选被取代的(C1-C6)亚烷基链,其中W的至多两个亚甲基单元独立地被-CO-、-O-、-S-、-SO2-或-NR'-替代。
在另一个实施方案中,本发明涉及式I的化合物和伴随的定义,其中A选自:
R3是烷基、烷芳基、芳基或杂芳基;以及q是包括端值在内的0至4的整数。在另一个实施方案中,A是在另一个实施方案中,A是
在另一个实施方案中,本发明涉及式I的化合物和伴随的定义,其中J是CH2。在另一个实施方案中,J是CF2。
在另一个实施方案中,本发明涉及式I的化合物和伴随的定义,其中RN是H、芳基或杂芳基。在另一个实施方案中,RN是H或杂芳基。在另一个实施方案中,RN是杂芳基。在另一个实施方案中,RN是H。
在另一个实施方案中,本发明涉及式I的化合物和伴随的定义,其中Ar1与5-7元单环或9-11双环稠合,所述环选自脂环族基、芳基、杂环基和杂芳基。
在另一个实施方案中,本发明涉及式I的化合物和伴随的定义,其中任选被取代的Ar1是在另一个实施方案中,任选被取代的Ar1是在另一个实施方案中,任选被取代的Ar1是在另一个实施方案中,任选被取代的Ar1是在另一个实施方案中,任选被取代的Ar1是在另一个实施方案中,任选被取代的Ar1是
在另一个实施方案中,本发明涉及式I的化合物和伴随的定义,其中w是0。在另一个实施方案中,w是1。在另一个实施方案中,w是2。
在另一个实施方案中,本发明涉及式I的化合物和伴随的定义,其中W是键。在另一个实施方案中,W是任选被取代的(C1-C6)亚烷基链。在另一个实施方案中,W是-CH2-。在另一个实施方案中,W是-NH-。在另一个实施方案中,W是-O-。在另一个实施方案中,W是-SO2-。
在另一个实施方案中,本发明涉及式I的化合物和伴随的定义,其中Rw是H。在另一个实施方案中,Rw是OH。在另一个实施方案中,Rw是芳基。在另一个实施方案中,Rw是苯基。在另一个实施方案中,Rw是杂芳基。在另一个实施方案中,Rw是吡啶基。在另一个实施方案中,Rw是烷氧基。在另一个实施方案中,Rw是甲氧基。在另一个实施方案中,Rw是三氟甲氧基。在另一个实施方案中,Rw是环烷基。在另一个实施方案中,Rw是环己基。在另一个实施方案中,Rw是杂环烷基。在另一个实施方案中,Rw是未饱和的杂环烷基。在另一个实施方案中,Rw是吡啶酮。在另一个实施方案中,Rw是-(C1-C6)亚烷基-N(R)2。在另一个实施方案中,Rw是-(C1-C6)亚烷基-OH。在另一个实施方案中,Rw是-CH2OH。
在另一个实施方案中,本发明涉及式I的化合物和伴随的定义,其中Ar1被无环-W-Rw取代。
在另一个实施方案中,本发明涉及式I的化合物和伴随的定义,其中Ar1被-W-Rw取代,所述-W-Rw是芳基、杂芳基或环烷基。
在另一个实施方案中,本发明涉及式I的化合物和伴随的定义,其中Ar1被至少一个-W-Rw取代,所述-W-Rw具有下式
其中,
W是直链或支链(C1-C6)亚烷基,其中亚甲基可以被-O-、-SO2-或-NR’-替代;
R’是H或烷基;
C是芳基或杂芳基;
R4是卤素、-(C1-C6)烷基、CN、NO2、CF3、OCF3、OR、-(C1-C6)亚烷基-OH、SO2N(R)2、NRSO2R、C(O)R、CO2R、C(O)N(R)2、N(R)2或NRC(O)R;以及
q是包括端值在内的0至5的整数。
在另一个实施方案中,Ar1被至少一个-W-Rw取代,所述-W-Rw选自下列基团:
-OH,-CH3,-OMe,-CN,-CF3,
在另一个实施方案中,本发明涉及式I的化合物和伴随的定义,其中Ar1被至少一个-W-Rw取代,所述-W-Rw选自下列基团:
在另一个实施方案中,本发明涉及具有式Ia的化合物:
其中:
J是CH2或CF2;
RN是H、烷基、芳基或杂芳基;
Ar1是
Ar1任选被w个-W-RW取代;其中
W独立地是键或任选被取代的(C1-C6)亚烷基链,其中W的至多两个亚甲基单元独立地被-O-、-SO2-或-NR'-替代;
R'独立地是H、烷基或芳基;以及
RW独立地是H、卤素、CN、CF3、OH、烷氧基或任选被取代的脂肪族基、环烷基、杂环烷基、芳基或杂芳基,其中,当被取代时,Rw被至多两个R2取代;
R2是卤素、CF3、OR、-(C1-C6)亚烷基-OH、SO2N(R)2、CO2R、C(O)N(R)2、B(OH)2或N(R)2;
R独立地是H、烷基、环烷基、杂环基、芳基或杂芳基;以及
w是包括端值在内的0至5的整数;
条件是,当Ar1是时,W独立地是任选被取代的(C1-C6)亚烷基链,其中W的至多两个亚甲基单元独立地被-CO-、-O-、-S-、-SO2-或-NR'-替代。
在另一个实施方案中,本发明涉及式Ia的化合物和伴随的定义,其中J是CH2。在另一个实施方案中,J是CF2。
在另一个实施方案中,本发明涉及式Ia的化合物和伴随的定义,其中RN是H或杂芳基。在另一个实施方案中,RN是杂芳基。在另一个实施方案中,RN是H。
在另一个实施方案中,Ar1选自下列基团:
在另一个实施方案中,本发明涉及式Ia的化合物和伴随的定义,其中Ar1被无环-W-Rw取代。
在另一个实施方案中,本发明涉及式Ia的化合物和伴随的定义,其中Ar1被-W-Rw取代,所述-W-Rw是芳基、杂芳基或环烷基环。在另一个实施方案中,本发明涉及式Ia的化合物和伴随的定义,其中Ar1被-W-Rw取代,所述-W-Rw是未被取代的杂环烷基。在还一个实施方案中,-W-Rw是吡啶酮。
在另一个实施方案中,本发明涉及式Ia的化合物和伴随的定义,其中Ar1被至少一个-W-Rw取代,所述-W-Rw选自下列基团:
–OH,-CH3,-OMe,-CN,-CF3,
在另一个实施方案中,本发明涉及式Ia的化合物和伴随的定义,其中Ar1被至少一个-W-Rw取代,所述-W-Rw选自下列基团:
在另一个实施方案中,本发明涉及式Ia的化合物和伴随的定义,其中Ar1选自下列基团:
在另一个实施方案中,本发明涉及具有式Ib的化合物:
或其药学上可接受的盐,其中:
Ar1选自下列基团:
在另一个实施方案中,本发明涉及具有式Ic的化合物:
或其药学上可接受的盐,其中:
Ar1选自下列基团:
在另一个实施方案中,本发明涉及举例性化合物,其选自表1。
表1.
在另一个实施方案中,本发明涉及药物组合物,其包含(i)本发明的化合物;以及(ii)药学上可接受的载体。在另一个实施方案中,药物组合物还包含另外的药剂,该另外的药剂选自黏液溶解药、支气管扩张药、抗生素、抗感染药、抗炎药、CFTR矫正剂和营养剂。
在另一个实施方案中,本发明涉及一种调控细胞膜中ABC转运蛋白的方法,该方法包括使所述的细胞与本发明化合物接触的步骤。在另一个实施方案中,所述ABC转运蛋白是CFTR。
在另一个实施方案中,本发明涉及一种治疗患者中涉及ABC转运蛋白活性的病况、疾病或障碍的方法,其包括将本发明的化合物给予所述患者的步骤。在另一个实施方案中,所述ABC转运蛋白是CFTR。在另一个实施方案中,所述的病况、疾病或障碍选自囊性纤维化、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症、1型乳糜微粒血症、无β脂蛋白血症、溶酶体贮积病例如I-细胞疾病/假性Hurler、粘多糖病、Sandhof/Tay-Sachs、Crigler-NajjarII型、多内分泌腺病/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)、神经生长性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、法布里氏病、斯-施二氏综合征、COPD、干眼病和斯耶格伦氏病。
在另一个实施方案中,本发明涉及一种用于在体外或体内测量生物样品中ABC转运蛋白或其片段的活性的试剂盒,该试剂盒包含:(i)包含本发明的化合物的第一组合物;以及(ii)关于如下内容的说明书:a)使所述组合物与生物样品接触;以及b)测定所述ABC转运蛋白或其片段的活性。
一般性合成方案
可以通过本领域中众所周知的方法,制备式I的化合物。下面举例说明的是用于制备式I化合物的典型方法。下面的方案I举例说明了用于式I化合物的典型合成方法。
合成方案
可以通过已知的方法和方案I-III中举例说明的方法,制备本发明的化合物。
方案I–环烷基酸的制备。
a)X=Br,I;Pd(PPh3)4,CO,MeOH;b)LiAlH4;c)SOCl2;d)NaCN;e)ClCH2CH2Br,NaOH,ΔT;f)ClCH2CH2Br,NaOH;g)NaOH,ΔT。
方案II–Amid偶联。
a)SOCl2,DMF;b)Ar1NRNH,Et3N,CH2Cl2;或
a)HATU,DMF,Et3N,X-Ar1NRNH(X=卤化物)。
方案III–杂芳基卤的衍生化
a)Rw-W-B(OR’)2(R’=H,Me),Pd(0),碱,DMF,H2O;b)Rw-CH2ZnX,(dppf)2PdCl2,CH2Cl2,THF(X=Cl,Br);c)(dppf)2PdCl2,Xantphos,KtOBu,二氧杂环己烷,Et3N,Rw-NH2。
本领域的技术人员轻易地理解,适合于本发明各种取代基的合成途径适合于上述反应条件和步骤。
应用、制剂和给药
药学上可接受的组合物
如前文所讨论,本发明提供可用作ABC转运蛋白调控剂并因此可用于治疗疾病、障碍或病况的化合物,比如囊性纤维化、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症、1型乳糜微粒血症、无β脂蛋白血症、溶酶体贮积病例如I-细胞疾病/假性Hurler、粘多糖病、Sandhof/Tay-Sachs、Crigler-Najjar II型、多内分泌腺病/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)、神经生长性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(由于朊病毒蛋白质处理缺陷)、法布里氏病、斯-施二氏综合征、COPD、干眼病和斯耶格伦氏病。
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如本文所述的任意化合物,并且任选地包含药学上可接受的载体、助剂或赋形剂。在某些实施方案中,这些组合物任选地进一步包含一种或多种附加治疗剂。
也将被领会到,某些本发明化合物能够以游离形式存在,用于治疗,或者需要时,以其药学上可接受的衍生物形式存在。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、或者任意其它加合物或衍生物,其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。
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,没有过度的毒性、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”表示任意无毒性的本发明化合物的盐或本发明化合物的酯的盐,其一旦对接受者给药,即能够直接或间接提供本发明化合物或者其抑制活性的代谢产物或残余物。如本文所用,术语“其抑制活性的代谢产物或残余物”表示其代谢产物或残余物也是ATP结合盒转运蛋白的抑制剂。
药学上可接受的盐是本领域熟知的。例如,S.M.Berge等人在J.PharmaceuticalSciences,1977,66,1-19中详细描述了药学上可接受的盐,通过引用将其并入本说明书。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盐。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的盐,所述无机酸例如盐酸、氢溴酸、磷酸、硫酸和高氯酸,所述有机酸例如乙酸、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它方法,例如离子交换形成的盐。其它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、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。在适当时,其它药学上可接受的盐包括无毒的铵盐、季铵盐和胺阳离子盐,其利用抗衡离子生成,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。
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、稀释剂或其它液体介质、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,第16版,E.W.Martin(MackPublishing 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,例如产生任何不需要的生物学效应或者以有害方式其它相互作用于药学上可接受的组合物的任何其它组分,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;以及其它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。
化合物和药学上可接受的组合物的用途
在另一方面,本发明提供治疗牵涉ABC转运蛋白活性的病况、疾病或障碍的方法。在某些实施方案中,本发明提供治疗牵涉ABC转运蛋白活性缺陷的病况、疾病或障碍的方法,该方法包括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。
在某些优选实施方案中,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(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症、1型乳糜微粒血症、无β脂蛋白血症、溶酶体贮积病例如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)、多内分泌腺病/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)、神经生长性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)、斯-施二氏综合征、慢性阻塞性肺病(COPD)、干眼病和斯耶格伦氏综合征,该方法包括对所述哺乳动物给予有效量的包含式(I)化合物的组合物的步骤,或如前文所述的其优选实施方案。
按照可替代的优选实施方案,本发明提供治疗囊性纤维化的方法,其包括对所述哺乳动物给予有效量的包含式(I)化合物的组合物的步骤,或如前文所述的其优选实施方案。
按照本发明,化合物或药学上可接受的组合物的“有效量”是有效治疗如下疾病中的一种或多种或者减轻其严重性的量:囊性纤维化、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症、1型乳糜微粒血症、无β脂蛋白血症、溶酶体贮积病例如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)、多内分泌腺病/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)、神经生长性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)、斯-施二氏综合征、慢性阻塞性肺病(COPD)、干眼病和斯耶格伦氏综合征。
根据本发明方法的化合物和组合物可以利用有效用于治疗如下疾病或者减轻其严重性的任意量和任意给药途径进行给药:囊性纤维化、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症、1型乳糜微粒血症、无β脂蛋白血症、溶酶体贮积病例如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)、多内分泌腺病/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)、神经生长性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)、斯-施二氏综合征、慢性阻塞性肺病(COPD)、干眼病和斯耶格伦氏综合征。
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”表示物理上离散的药物单元,对所治疗的患者而言是适当的。不过将被理解到,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,包括所治疗的病况和病况的严重性;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;以及医药领域熟知的其它因素。本文所用的术语“患者”表示动物,优选哺乳动物,最优选人。
本发明的药学上可接受的组合物可以对人和其它动物口服、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)、口腔、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。在某些实施方案中,本发明化合物可以口服或肠胃外给药,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。
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,口服组合物也可以包括助剂,例如湿润剂、乳化与悬浮剂、甜味剂、矫味剂和香料。
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备物,例如无菌可注射的水性或油性悬液。无菌可注射制备物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,常规采用无菌的固定油作为溶剂或悬浮介质。为此,可以采用任何温和的固定油,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。
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它无菌可注射介质中。
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,而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,例如聚交酯-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。其它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埋在与机体组织相容的脂质体或微乳中来制备。
用于直肠或阴道给药的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。
用于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,所述剂型也可以包含缓冲剂。
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量聚乙二醇等。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它包衣。它们可以任选地含有遮光剂,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,任选地为延迟的方式。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量聚乙二醇等。
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它包衣。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,这类剂型也可以包含除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。在胶囊剂、片剂和丸剂的情况下,剂型也可以包含缓冲剂。它们可以任选地含有遮光剂,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,任选地为延迟的方式。可以使用的包埋组合物的实例包括聚合物质和蜡类。
用于局部或透皮给予本发明化合物的剂型包括软膏剂、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。也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。
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、病况或障碍或者减轻其严重性,其中ABC转运蛋白的活性过高或无活性在该疾病、病况或障碍中有牵连。当在特定的疾病、病况或障碍中涉及ABC转运蛋白的活性过高或无活性时,该疾病、病况或障碍也可以被称为“ABC转运蛋白介导的疾病、病况或障碍”。因此,在另一方面,本发明提供治疗疾病、病况或障碍或者减轻其严重性的方法,其中在该疾病状态中涉及ABC转运蛋白的活性过高或无活性。
在本发明中用作ABC转运蛋白调控剂的化合物的活性可以按照本领域中和本文实施例中一般描述的方法来测定。
也将被领会到,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它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况达到所需效果(例如,本发明化合物可以与另一种用于治疗同一病况的药物同时给药),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况的附加治疗剂被称为“就所治疗的疾病或病况而言是适当的”。
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%。
本发明化合物或其药学上可接受的组合物也可以引入到用于涂覆可植入医疗器械(例如假肢、人工瓣膜、脉管移植物、支架和导管)的组合物中。因此,在另一方面,本发明包括用于涂覆可植入器械的组合物,其包含如上一般性描述和在本文类型与小类中所述的本发明化合物,以及适合于涂覆所述可植入器械的载体。在另一方面,本发明包括涂有组合物的可植入器械,所述组合物包含如上一般性描述和在本文类型与小类中所述的本发明化合物,以及适合于涂覆所述可植入器械的载体。适合的涂料和被涂覆可植入的器械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。涂料可以任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。
本发明的另一个方面涉及调控生物样品或患者中(例如,体外或体内)的ABC转运蛋白活性,该方法包括向患者给药或使所述生物样品接触式I化合物或包含所述化合物的组合物。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;以及血液、唾液、尿、粪便、精液、泪液或其它流体或者其提取物。
生物样品中ABC转运蛋白活性的调控可用于本领域技术人员已知的多种目的。上述目的的实例包括,但不限于,在生物和病理现象中研究ABC转运蛋白;以及新ABC转运蛋白调控剂的对比评价。
在又一个实施方案中,提供在体外或体内调控阴离子通道活性的方法,其包括将所述通道与式(I)化合物接触的步骤。在优选实施方案中,该阴离子通道是氯化物通道或碳酸氢根通道。在其它优选实施方案中,该阴离子通道是氯化物通道。
按照可替代的实施方案,本发明提供增加细胞膜中的功能性ABC转运蛋白的数量的方法,其包括将所述细胞与式(I)化合物接触的步骤。本文所用术语“功能性ABC转运蛋白”表示具有转运活性的ABC转运蛋白。在优选实施方案中,所述功能性ABC转运蛋白是CFTR。
按照另一个优选实施方案,通过测量跨膜电压电位来测量ABC转运蛋白的活性。在生物样品中测量跨膜电压电位的手段可以借助本领域中的任意已知方法,比如光学膜电位测定法或其它电生理学方法。
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)"Voltage sensing by fluorescence resonanceenergy transfer in single cells"Biophys J 69(4):1272-80,以及Gonzalez,J.E.和R.Y.Tsien(1997)"Improved indicators of cell membrane potential that usefluorescence resonance energy 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 and instrumentation for screening ion-channeltargets"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)穿过质膜重新分布,从CC2-DMPE转移的能量相应地改变。荧光发射的变化可以利用VIPRTM II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。
在另一方面,本发明提供用于在体外或体内测量生物样品中ABC转运蛋白或其片段活性的试剂盒,其包含(i)包含式(I)化合物的组合物或者任意上述实施方案;以及(ii)关于如下内容的说明书:a)将该组合物与生物样品接触和b)测量所述ABC转运蛋白或其片段的活性。在一个实施方案中,所述试剂盒进一步包含关于如下内容的说明书:a)将附加组合物与生物样品接触;b)在所述附加化合物存在下测量ABC转运蛋白或其片段的活性,以及c)比较附加化合物存在下的ABC转运蛋白的活性与式(I)组合物存在下的ABC转运蛋白的密度。在优选实施方案中,所述试剂盒用于测量CFTR的密度。
具体实施方式
为了可以更加充分地理解本文所述的发明,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
1-苯并[1,3]二氧杂环戊烯-5-基-环丙烷甲酸的制备
在70℃,加热2-(苯并[d][1,3]二氧杂环戊烯)乙腈(5.10g 31.7mmol)、1-溴-2-氯-乙烷(9.00mL 109mmol)和氯化苄基三乙铵(0.181g,0.795mmol)的混合物,然后向混合物中缓慢添加50%(wt./wt.)氢氧化钠水溶液(26mL)。在70℃,将反应搅拌24小时,然后在130℃加热48小时。将深棕色的反应混合物用水(400mL)稀释,用等体积的乙酸乙酯萃取一次并用等体积的二氯甲烷萃取一次。用浓盐酸酸化碱性水溶液至pH小于1,过滤沉淀物并用1M盐酸洗涤。将固体物质溶于二氯甲烷(400mL),用等体积的1M盐酸萃取两次并用饱和的氯化钠水溶液萃取一次。将有机溶液用硫酸钠干燥并蒸发至干,得到白色至淡灰白色固体(5.23g,80%)ESI-MS m/z计算值为206.1,实测值为207.1(M+1)+。保留时间2.37分钟。1HNMR(400MHz,DMSO-d6)δ1.07-1.11(m,2H),1.38-1.42(m,2H),5.98(s,2H),6.79(m,2H),6.88(m,1H),12.26(s,1H)。
1-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基)-环丙烷甲酸的制备
步骤a:2,2-二氟-苯并[1,3]二氧杂环戊烯-5-甲酸甲酯
在一氧化碳气氛(55PSI)下,在75℃(油浴温度),将5-溴-2,2-二氟-苯并[1,3]二氧杂环戊烯(11.8g,50.0mmol)和四(三苯基膦)钯(0)[Pd(PPh3)4,5.78g,5.00mmol]在含有乙腈(30mL)和三乙胺(10mL)的甲醇(20mL)中的溶液搅拌15小时。将冷却的反应混合物过滤并将滤液蒸发至干。通过硅胶柱色谱法纯化残余物,得到粗制的2,2-二氟-苯并[1,3]二氧杂环戊烯-5-甲酸甲酯(11.5g),将其直接用于下一步骤中。
步骤b:(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基)-甲醇
在0℃,将溶于20mL无水四氢呋喃(THF)中的粗制2,2-二氟-苯并[1,3]二氧杂环戊烯-5-甲酸甲酯(11.5g)缓慢添加至氢化铝锂(4.10g,106mmol)在无水THF(100mL)中的悬浮液中。然后,将混合物温热至室温。在室温搅拌1小时后,将反应混合物冷却至0℃并用水(4.1g)处理,接着用氢氧化钠(10%水溶液,4.1mL)处理。将得到的於浆过滤并用THF洗涤。将合并的滤液蒸发至干并通过硅胶柱色谱法纯化残余物,得到(2,2-二氟-苯并[1,3]二氧杂环戊烯)-甲醇(7.2g,38mmol,76%,两步),为无色的油。
步骤c:5-氯甲基-2,2-二氟-苯并[1,3]二氧杂环戊烯
在0℃,将亚硫酰氯(45g,38mmol)缓慢添加至(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基)-甲醇(7.2g,38mmol)在二氯甲烷(200mL)中的溶液中。在室温,将得到的混合物搅拌过夜,然后蒸发至干。将残余物分配在饱和的碳酸氢钠水溶液(100mL)和二氯甲烷(100mL)之间。用二氯甲烷(150mL)萃取分离的水层并将有机层用硫酸钠干燥,过滤,并蒸发至干,得到粗制的5-氯甲基-2,2-二氟-苯并[1,3]二氧杂环戊烯(4.4g),在不进一步纯化的情况下,将其直接用于下一步骤中。
步骤d:(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基)-乙腈
在室温,将粗制的5-氯甲基-2,2-二氟-苯并[1,3]二氧杂环戊烯(4.4g)和氰化钠(1.36g,27.8mmol)在二甲亚砜(50mL)中的混合物搅拌过夜。将反应混合物倒入冰中并用乙酸乙酯(300mL)萃取。将有机层用硫酸钠干燥并蒸发至干,得到粗制的(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基)-乙腈(3.3g),将其直接用于下一步骤中。
步骤e:1-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基)-环丙腈
在70℃,将氢氧化钠(50%水溶液,10mL)缓慢添加至粗制的(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基)-乙腈、氯化苄基三乙铵(3.00g,15.3mmol)和1-溴-2-氯乙烷(4.9g,38mmol)的混合物中。在70℃,将混合物搅拌过夜,然后将反应混合物用水(30mL)稀释并用乙酸乙酯萃取。将合并的有机层用硫酸钠干燥并蒸发至干,得到粗制的1-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基)-环丙腈,将其直接用于下一步骤中。
步骤f:1-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基)-环丙烷甲酸
将1-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基)-环丙腈(来自上一步骤的粗制品)在10%氢氧化钠水溶液(50mL)中回流2.5小时。用乙醚(100mL)洗涤冷却的反应混合物并用2M盐酸将水相酸化至pH 2。将沉淀出的固体过滤,得到1-(2,2-二氟-苯并[1,3]二氧杂环戊烯-5-基)-环丙烷甲酸,为白色固体(0.15g,1.6%,四步)。ESI-MS m/z计算值为242.04,实测值为241.58(M+1)+;1H NMR(CDCl3)δ7.14-7.04(m,2H),6.98-6.96(m,1H),1.74-1.64(m,2H),1.26-1.08(m,2H)。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-溴-6-甲基吡啶-3-基)环丙烷甲酰
胺的制备
在氮气下,将1-苯并[1,3]二氧杂环戊烯-5-基-环丙烷甲酸(2.76g,13.4mmol)置于烘箱干燥的烧瓶中。添加亚硫酰氯(3.0mL)和N,N-二甲基甲酰胺(0.3mL)并在室温让溶液搅拌10分钟。在真空下除去过量的亚硫酰氯并将得到的固体悬浮在10mL无水二氯甲烷中。然后将该溶液缓慢地添加到5-溴-6-甲基吡啶-3-胺(2.50g,13.4mmol)在10mL含有三乙胺(5.64mL,40.2mmol)的无水二氯甲烷中的溶液中。在室温,让得到的混合物搅拌10分钟。然后将粗制的产物用饱和的碳酸氢钠水溶液洗涤三次,接着用饱和的氯化钠水溶液洗涤两次。将有机层用硫酸钠干燥,蒸发至干,并在没有进一步纯化的情况下使用得到的黄色粉末(3.62g,9.65mmol,72.0%)。ESI-MS m/z计算值为374.0,实测值;375.1(M+1)+保留时间2.30分钟。1H NMR(400MHz,CD3CN)δ8.38(d,J=2.2Hz,1H),8.14(d,J=2.2Hz,1H),7.80-7.60(m,1H),7.08-6.95(s,2H),6.89(dd,J=1.2,7.3Hz,1H),6.01(s,2H),2.54(s,3H),1.59-1.50(m,2H),1.19-1.09(m,2H)。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-甲基-5-苯基吡啶-3-基)环丙烷甲
酰胺的制备
将1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-溴-6-甲基吡啶-3-基)环丙烷甲酰胺(38mg,0.10mmol)溶于1mL含有0.2mL 2M碳酸钾水溶液和12mg Fibre-Cat 1007的N,N-二甲基甲酰胺(DMF)中。然后将反应混合物加热至80℃持续16小时。将得到的物质冷却至室温,过滤,并使用含有0.05%三氟乙酸的0-99%乙腈水溶液的梯度,通过反相制备型液相色谱法纯化,得到纯产物。ESI-MS m/z计算值为372.2,实测值为373.2(M+1)+。保留时间1.80分钟。
4-(5-(1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-2-甲基吡啶-3-
基)苯甲酰胺的制备
以与制备1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-甲基-5-苯基吡啶-3-基)环丙烷甲酰胺类似的方式,由4-氨基甲酰基苯基硼酸和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-溴-6-甲基吡啶-3-基)环丙烷甲酰胺,制备4-(5-(1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-2-甲基吡啶-3-基)苯甲酰胺。
4-(5-(1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-2-甲基吡啶-3-
基)-N-甲基苯甲酰胺的制备
以与制备1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-甲基-5-苯基吡啶-3-基)环丙烷甲酰胺类似的方式,由4-(甲基氨基甲酰基)苯基硼酸和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-溴-6-甲基吡啶-3-基)环丙烷甲酰胺,制备4-(5-(1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-2-甲基吡啶-3-基)-N-甲基苯甲酰胺。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-(3-(羟甲基)苯基)-6-甲基吡啶-3-
基)环丙烷甲酰胺的制备
以与制备1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-甲基-5-苯基吡啶-3-基)环丙烷甲酰胺类似的方式,由3-(羟甲基)苯基硼酸和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-溴-6-甲基吡啶-3-基)环丙烷甲酰胺,制备1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-(3-(羟甲基)苯基)-6-甲基吡啶-3-基)环丙烷甲酰胺。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-甲基-5-(4-(N-甲基氨磺酰基)苯
基)吡啶-3-基)环丙烷甲酰胺的制备
以与制备1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-甲基-5-苯基吡啶-3-基)环丙烷甲酰胺类似的方式,由4-(N-甲基氨磺酰基)苯基硼酸和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-溴-6-甲基吡啶-3-基)环丙烷甲酰胺,制备1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-甲基-5-(4-(N-甲基氨磺酰基)苯基)吡啶-3-基)环丙烷甲酰胺。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-(3-(N,N-二甲基氨磺酰基)苯基)-
6-甲基吡啶-3-基)环丙烷甲酰胺的制备
以与制备1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-甲基-5-苯基吡啶-3-基)环丙烷甲酰胺类似的方式,由3-(N,N-二甲基氨磺酰基)苯基硼酸和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-溴-6-甲基吡啶-3-基)环丙烷甲酰胺,制备1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-(3-(N,N-二甲基氨磺酰基)苯基)-6-甲基吡啶-3-基)环丙烷甲酰胺。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-(4-(N,N-二甲基氨磺酰基)苯基)-
6-甲基吡啶-3-基)环丙烷甲酰胺的制备
以与制备1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-甲基-5-苯基吡啶-3-基)环丙烷甲酰胺类似的方式,由4-(N,N-二甲基氨磺酰基)苯基硼酸和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-溴-6-甲基吡啶-3-基)环丙烷甲酰胺,制备1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-(4-(N,N-二甲基氨磺酰基)苯基)-6-甲基吡啶-3-基)环丙烷甲酰胺。
3-(5-(1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-2-甲基吡啶-3-
基)苯甲酰胺的制备
以与制备1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-甲基-5-苯基吡啶-3-基)环丙烷甲酰胺类似的方式,由3-氨基甲酰基苯基硼酸和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-溴-6-甲基吡啶-3-基)环丙烷甲酰胺,制备3-(5-(1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-2-甲基吡啶-3-基)苯甲酰胺。
3-(5-(1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-2-甲基吡啶-3-
基)苯甲酸的制备
以与制备1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-甲基-5-苯基吡啶-3-基)环丙烷甲酰胺类似的方式,由3-二羟硼基苯甲酸和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-溴-6-甲基吡啶-3-基)环丙烷甲酰胺,制备3-(5-(1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-2-甲基吡啶-3-基)苯甲酸。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-(4-(羟甲基)苯基)-6-甲基吡啶-3-
基)环丙烷甲酰胺的制备
以与制备1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-甲基-5-苯基吡啶-3-基)环丙烷甲酰胺类似的方式,由4-(羟甲基)苯基硼酸和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-溴-6-甲基吡啶-3-基)环丙烷甲酰胺,制备1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-(4-(羟甲基)苯基)-6-甲基吡啶-3-基)环丙烷甲酰胺。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-甲基-5-(3-氨磺酰基苯基)吡啶-3-
基)环丙烷甲酰胺的制备
以与制备1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-甲基-5-苯基吡啶-3-基)环丙烷甲酰胺类似的方式,由3-氨磺酰基苯基硼酸和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-溴-6-甲基吡啶-3-基)环丙烷甲酰胺,制备1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-甲基-5-(3-氨磺酰基苯基)吡啶-3-基)环丙烷甲酰胺。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-异丙基吡啶-3-基)环丙烷甲酰胺的
制备
将1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酸(20.6mg,0.100mmol)和6-异丙基吡啶-3-胺(13.6g,0.100mmol)溶于含有三乙胺(0.042mL,0.300mmol)的N,N-二甲基甲酰胺(DMF,1mL)中。添加六氟磷酸O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲(HATU,39.9mg,0.105mmol)并让溶液搅拌3小时。然后通过反相制备型液相色谱法,使用含有0.05%三氟乙酸的0-99%乙腈水溶液的梯度纯化混合物,得到纯产物。ESI-MS m/z计算值为324.2,实测值为325.3(M+1)+。保留时间2.14分钟。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-甲氧基苄基)吡啶-3-基)环丙烷
甲酰胺的制备
步骤a:1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-溴吡啶-3-基)环丙烷甲酰胺
向1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酸(9.50g,46.00mmol)中添加亚硫酰氯(10.00mL,138.00mmol)和DMF(4滴),搅拌混合物并在60℃加热30分钟。在减压下蒸发过量的亚硫酰氯。将一部分酰氯(23.20mmol)溶于吡啶(15mL)中并缓慢添加至在吡啶(10mL)中的6-溴吡啶-3-胺(23.20mmol)中。在110℃,将反应混合物搅拌1小时30分钟。在减压下蒸发吡啶。将得到的混合物溶于二氯甲烷(200mL)并用1N NaOH(4x 50mL)洗涤。将有机层用无水Na2SO4干燥并在减压下蒸发。通过硅胶柱色谱法纯化粗制的产物,得到1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-溴吡啶-3-基)环丙烷甲酰胺(4g,48%)。
步骤b:1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-甲氧基苄基)吡啶-3-基)环丙烷甲酰胺
在室温,将氯化(2-甲氧基苄基)锌(II)(4.44mL,0.5M,2.20mmol)在THF和(DPPF)2PdCl2.CH2Cl2(45mg,0.056mmol)中的溶液搅拌20分钟。向该溶液中添加1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-溴吡啶-3-基)环丙烷甲酰胺(200mg,0.56mmol)在THF(4mL)中的於浆并在微波反应器中将反应混合物加热至150℃持续10分钟。将得到的物质冷却至室温。将Na2EDTA和饱和的NH4Cl水溶液添加至反应中并在室温将混合物搅拌30分钟。使用二氯甲烷萃取产物。将有机层用无水Na2SO4干燥并在减压下蒸发。通过硅胶柱色谱法纯化粗制的产物,得到1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-甲氧基苄基)吡啶-3-基)环丙烷甲酰胺(152mg,68%)。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-氯苄基)吡啶-3-基)环丙烷甲酰
胺的制备
使用1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-甲氧基苄基)吡啶-3-基)环丙烷甲酰胺的程序,由氯化(2-氯苄基)锌(II)和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-溴吡啶-3-基)环丙烷甲酰胺,合成1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-氯苄基)吡啶-3-基)环丙烷甲酰胺。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-苄基吡啶-3-基)环丙烷甲酰胺的制
备
使用1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-甲氧基苄基)吡啶-3-基)环丙烷甲酰胺的程序,使用溴化苄基锌(II)和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-溴吡啶-3-基)环丙烷甲酰胺,合成1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-苄基吡啶-3-基)环丙烷甲酰胺。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-苯基吡啶-3-基)环丙烷甲酰胺的制
备
向1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-溴吡啶-3-基)环丙烷甲酰胺(72mg,0.20mmol)、苯基硼酸(16mg,0.13mmol)、K2CO3(19mg,0.14mmol)和(DPPF)2PdCl2.CH2Cl2(6mg,0.007mmol)中添加乙醇(545uL)和水(55uL)。在微波反应器中,将反应混合物加热至150℃持续10分钟。将得到的物质冷却至室温。将反应混合物用二氯甲烷稀释,过滤,并浓缩滤液。将粗制的产物溶于DMSO(1mL),过滤,并通过反相制备型HPLC纯化,得到1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-苯基吡啶-3-基)环丙烷甲酰胺,为TFA盐(8.5mg,0.018mmol,13%)。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-甲氧基苯基)吡啶-3-基)环丙烷
甲酰胺的制备
使用1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-苯基吡啶-3-基)环丙烷甲酰胺的程序,由2-甲氧基苯基硼酸和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-溴吡啶-3-基)环丙烷甲酰胺,合成1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-甲氧基苯基)吡啶-3-基)环丙烷甲酰胺。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-氯苯基)吡啶-3-基)环丙烷甲酰
胺的制备
使用1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-苯基吡啶-3-基)环丙烷甲酰胺的程序,由2-氯苯基硼酸和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-溴吡啶-3-基)环丙烷甲酰胺,合成1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-氯苯基)吡啶-3-基)环丙烷甲酰胺。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-甲氧基苯基氨基)吡啶-3-基)环
丙烷甲酰胺的制备
向在二氧杂环己烷(0.400mL)中的1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-溴吡啶-3-基)环丙烷甲酰胺(72mg,0.2mmol)中添加XANTPHOS(2.3mg,0.004mmol)、KtBuO(31mg,0.28mmol)、(DPPF)2PdCl2.CH2Cl2(3.00mg,0.004mmol)和2-甲氧基苯胺(30mg,0.24mmol)和Et3N(0.200mL)。在微波反应器中,将反应混合物加热至150℃持续10分钟。将得到的物质冷却至室温。通过硅胶柱色谱法纯化粗制的产物,得到1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-甲氧基苯基氨基)吡啶-3-基)环丙烷甲酰胺,然后将其用含HCl的MeOH处理,形成HCl盐(2.3mg,0.0053mmol,2.7%)。ESI-MS m/z计算值为403.2,实测值;404.5(M+1)+保留时间2.29分钟。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-苄基吡嗪-2-基)环丙烷甲酰胺的制
备
向溴化苄基锌(II)在THF(0.8mL,0.4mmol)的0.5M溶液中添加[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)(8mg,0.01mmol)并在氮气下将反应搅拌20分钟。添加1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-氯吡嗪-2-基)环丙烷甲酰胺(32mg,0.1mmol)并在150℃,在微波反应器中将反应照射10分钟。用饱和的氯化铵溶液(2mL)和饱和的乙二胺四乙酸二钠盐溶液(2mL)淬灭反应。将混合物搅拌30分钟,然后将其用二氯甲烷(3x 4mL)萃取。将有机物用Na2SO4干燥并蒸发。将粗制的产物溶于DMSO(1mL)并使用含有0.05%三氟乙酸的0-99%乙腈水溶液的梯度,通过反相制备型液相色谱法纯化,得到纯产物(2.0mg,0.0054mmol,5.4%)。ESI-MS m/z计算值为373.14,实测值为374.1(M+1)+;保留时间3.32分钟。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-甲氧基苄基)吡嗪-2-基)环丙烷
甲酰胺的制备
以与关于1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-苄基吡嗪-2-基)环丙烷甲酰胺所报道的相似程序,由氯化(2-甲氧基苄基)锌(II)和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-氯吡嗪-2-基)环丙烷甲酰胺,制备了标题化合物。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-氯苄基)吡嗪-2-基)环丙烷甲酰
胺的制备
使用关于1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-苄基吡嗪-2-基)环丙烷甲酰胺所报道的相似程序,由氯化(2-氯苄基)锌(II)和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-氯吡嗪-2-基)环丙烷甲酰胺,制备了标题化合物。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-(2-氯苄基)吡嗪-2-基)环丙烷甲酰
胺的制备
向氯化(2-氯苄基)锌(II)在THF(0.8mL,0.4mmol)中的0.5M溶液中添加[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)(8mg,0.01mmol)并在氮气下将反应搅拌20分钟。添加1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-溴吡嗪-2-基)环丙烷甲酰胺(36mg,0.10mmol)并在150℃,在微波中将反应照射10分钟。用饱和的氯化铵溶液(2mL)和饱和的乙二胺四乙酸二钠盐溶液(2mL)淬灭反应。将混合物搅拌30分钟,然后将其用二氯甲烷(3x 4mL)萃取。将有机物用Na2SO4干燥并蒸发。将粗制的产物溶于DMSO(1mL)并使用含有0.05%三氟乙酸的0-99%乙腈水溶液的梯度,通过反相制备型液相色谱法纯化,得到纯产物(16mg,0.039mmol,39%)。ESI-MS m/z计算值为407.1,实测值为408.2(M+1)+;保留时间3.82分钟。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-(2-甲氧基苄基)吡嗪-2-基)环丙烷
甲酰胺的制备
使用关于1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-(2-氯苄基)吡嗪-2-基)环丙烷甲酰胺所述的相似程序,由氯化(2-甲氧基苄基)锌(II)和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-溴吡嗪-2-基)环丙烷甲酰胺,制备了标题化合物。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-苄基吡嗪-2-基)环丙烷甲酰胺的制
备
使用关于1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-(2-氯苄基)吡嗪-2-基)环丙烷甲酰胺所报道的相似程序,由溴化苄基锌(II)和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-溴吡嗪-2-基)环丙烷甲酰胺,制备了标题化合物。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-(2-甲氧基苯基氨基)吡嗪-2-基)环
丙烷甲酰胺的制备
向1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-溴吡嗪-2-基)环丙烷甲酰胺(72mg,0.2mmol)、2-甲氧基苯胺(30mg,0.24mmol)和叔丁醇钾(31mg,0.28mmol)在2:1二氧杂环己烷:Et3N(1.8mL)中的溶液中添加[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)(1.6mg,0.0020mmol)和XANTPHOS(1.2mg,0.0020mmol)。将反应混合物加热至80℃持续18小时。将反应混合物过滤并使用含有0.05%三氟乙酸的0-99%乙腈水溶液的梯度,通过反相制备型液相色谱法纯化,得到纯产物(32mg,0.079mmol,39%)。ESI-MS m/z计算值为404.1,实测值为405.3(M+1)+;保留时间3.61分钟。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-甲氧基苄基)哒嗪-3-基)环丙烷
甲酰胺的制备
向氯化(2-甲氧基苄基)锌(II)在THF(0.8mL,0.4mmol)中的0.5M溶液中添加[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)(8mg,0.01mmol)并在氮气下将反应搅拌20分钟。添加1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-氯哒嗪-3-基)环丙烷甲酰胺(32mg,0.1mmol)并在150℃,在微波中将反应照射10分钟。用饱和的氯化铵溶液(2mL)和饱和的乙二胺四乙酸二钠盐溶液(2mL)淬灭反应。将混合物搅拌30分钟,然后将其用二氯甲烷(3x4mL)萃取。将有机物用Na2SO4干燥并蒸发。将粗制的产物溶于DMSO(1mL)并使用含有0.05%三氟乙酸的0-99%乙腈水溶液的梯度,通过反相制备型液相色谱法纯化,得到纯产物(21mg,0.052mmol,52%)。ESI-MS m/z计算值为379.2,实测值为380.3(M+1)+;保留时间3.54分钟。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-氯苄基)哒嗪-3-基)环丙烷甲酰
胺的制备
使用关于1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-甲氧基苄基)哒嗪-3-基)环丙烷甲酰胺所报道的相似程序,由氯化(2-氯苄基)锌(II)和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-氯哒嗪-3-基)环丙烷甲酰胺,制备了标题化合物。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(环己基甲基)哒嗪-3-基)环丙烷甲
酰胺的制备
以与关于1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-甲氧基苄基)哒嗪-3-基)环丙烷-甲酰胺所报道的相似程序,由溴化(环己基甲基)锌(II)和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-氯哒嗪-3-基)环丙烷甲酰胺,制备了标题化合物。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-苄基哒嗪-3-基)环丙烷甲酰胺的制
备
使用关于1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2-甲氧基苄基)哒嗪-3-基)环丙烷甲酰胺所报道的相似程序,由溴化苄基锌(II)和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-氯哒嗪-3-基)环丙烷甲酰胺,制备了标题化合物。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(2-苄基吡啶-4-基)环丙烷甲酰胺的制
备
步骤a:1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(2-氯吡啶-4-基)环丙烷-甲酰胺
向含1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酸(1.5g,7.3mmol)的亚硫酰氯(1.6mL,21.8mmol)中添加N,N-二甲基甲酰胺(100μL)。在室温,将反应混合物搅拌30分钟,然后将其蒸发至干,得到期望的酰氯。将该酰氯添加到2-氯吡啶-4-胺(0.94g,7.3mmol)在吡啶(10mL)中的溶液中。将反应加热至100℃持续12小时。将反应用二氯甲烷(30mL)稀释并用1N NaOH(3x 20mL)洗涤。将有机物用Na2SO4干燥并蒸发至干。通过硅胶色谱法(用含0-50%乙酸乙酯的己烷洗脱)纯化粗制的物质,得到期望的产物。ESI-MS m/z计算值为316.06,实测值为317.1(M+1)+。保留时间2.97分钟。
步骤b:1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(2-苄基吡啶-4-基)环丙烷-甲酰胺
向溴化苄基锌(II)在THF(0.8mL,0.4mmol)中的0.5M溶液中添加[1,1’-双(二苯基膦基)二茂铁]二氯钯(II)(8mg,0.01mmol)并在氮气下将反应搅拌20分钟。添加1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(2-氯吡啶-4-基)环丙烷甲酰胺(32mg,0.10mmol)并在150℃,在微波中将反应照射10分钟。用饱和的氯化铵溶液(2mL)和饱和的乙二胺四乙酸二钠盐溶液(2mL)淬灭反应。将混合物搅拌30分钟,然后将其用二氯甲烷(3x 4mL)萃取。将有机物用Na2SO4干燥并蒸发。将粗制的产物溶于DMSO(1mL)并使用含有0.05%三氟乙酸的0-99%乙腈水溶液的梯度,通过反相制备型液相色谱法纯化,得到纯产物(18mg,0.048mmol,48%)。ESI-MS m/z计算值为372.1,实测值为373.3(M+1)+;保留时间2.44分钟。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(2-(2-甲氧基苄基)吡啶-4-基)环丙烷
甲酰胺的制备
使用关于1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(2-苄基吡啶-4-基)环丙烷甲酰胺所报道的相似程序,由氯化(2-甲氧基苄基)锌(II)和1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(2-氯吡啶-4-基)环丙烷-甲酰胺,制备了标题化合物。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(4-羟基-6-甲基嘧啶-2-基)环丙烷甲
酰胺的制备
向含1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷碳酰氯(45mg,0.2mmol)的吡啶(2mL)中添加2-氨基-6-甲基嘧啶-4-醇(25mg,0.2mmol)并在115℃将反应混合物搅拌15小时。将溶剂蒸发至干并将残余物再溶于DMF,过滤并使用含有0.05%三氟乙酸的0-99%乙腈水溶液的梯度,通过反相制备型液相色谱法纯化,得到纯产物。ESI-MS m/z计算值为313.1,实测值为314.1(M+1)+。保留时间2.31分钟。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(4-甲基嘧啶-2-基)环丙烷甲酰胺的制
备
向含1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷碳酰氯(45mg,0.2mmol)的吡啶(2mL)中添加4-甲基嘧啶-2-胺(22mg,0.2mmol)并在115℃将反应混合物搅拌15小时。将溶剂蒸发至干并将残余物再溶于DMF,过滤并使用含有0.05%三氟乙酸的0-99%乙腈水溶液的梯度,通过反相制备型液相色谱法纯化,得到纯产物。ESI-MS m/z计算值为297.3,实测值为298.3(M+1)+。保留时间2.14分钟。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-氰基吡啶-3-基)环丙烷甲酰胺的制
备
向含1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷碳酰氯(45mg,0.2mmol)的吡啶(2mL)中添加5-氨基吡啶甲腈(24mg,0.2mmol)并在115℃将反应混合物搅拌15小时。将溶剂蒸发至干并将残余物再溶于DMF,过滤并使用含有0.05%三氟乙酸的0-99%乙腈水溶液的梯度,通过反相制备型液相色谱法纯化,得到纯产物。ESI-MS m/z计算值为307.3,实测值为308.3(M+1)+。保留时间2.87分钟。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(2,6-二甲氧基嘧啶-4-基)环丙烷甲酰
胺的制备
向含1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷碳酰氯(45mg,0.2mmol)的吡啶(2mL)中添加2,6-二甲氧基嘧啶-4-胺(31mg,0.2mmol)并在115℃将反应混合物搅拌15小时。将溶剂蒸发至干并将残余物再溶于DMF,过滤并使用含有0.05%三氟乙酸的0-99%乙腈水溶液的梯度,通过反相制备型液相色谱法纯化,得到纯产物。ESI-MS m/z计算值为343.3,实测值为344.1(M+1)+。保留时间2.87分钟。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(6-(2,3-二甲基苯氧基)吡啶-3-基)环
丙烷甲酰胺的制备
向含1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷碳酰氯(45mg,0.2mmol)的吡啶(2mL)中添加6-(2,3-二甲基苯氧基)吡啶-3-胺(43mg,0.2mmol)并在115℃将反应混合物搅拌15小时。将溶剂蒸发至干并将残余物再溶于DMF,过滤并使用含有0.05%三氟乙酸的0-99%乙腈水溶液的梯度,通过反相制备型液相色谱法纯化,得到纯产物。ESI-MS m/z计算值为402.4,实测值为403.1(M+1)+。保留时间3.11分钟。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(4-(1-(4-氯苯氧基)乙基)嘧啶-2-基)
环丙烷甲酰胺的制备
向含1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷碳酰氯(45mg,0.2mmol)的吡啶(2mL)中添加4-(1-(4-氯苯氧基)乙基)嘧啶-2-胺(50mg,0.2mmol)并在115℃将反应混合物搅拌15小时。将溶剂蒸发至干并将残余物再溶于DMF,过滤并使用含有0.05%三氟乙酸的0-99%乙腈水溶液的梯度,通过反相制备型液相色谱法纯化,得到纯产物。ESI-MS m/z计算值为437.9,实测值为438.1(M+1)+。保留时间3.16分钟。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(吡啶-2-基)-N-(2-(三氟甲基)吡啶-
4-基)环丙烷甲酰胺的制备
向含1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷碳酰氯(45mg,0.2mmol)的吡啶(2mL)中添加N-(2-(三氟甲基)吡啶-4-基)吡啶-2-胺(48mg,0.2mmol)并在115℃将反应混合物搅拌15小时。将溶剂蒸发至干并将残余物再溶于DMF,过滤并使用含有0.05%三氟乙酸的0-99%乙腈水溶液的梯度,通过反相制备型液相色谱法纯化,得到纯产物。ESI-MS m/z计算值为427.4,实测值为428.1(M+1)+。保留时间2.91分钟。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5,6-二氢呋喃并[2,3-h]喹唑啉-2-
基)环丙烷甲酰胺的制备
向含1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷碳酰氯(45mg,0.2mmol)的吡啶(2mL)中添加5,6-二氢呋喃并[3,2-f]喹唑啉-3-胺(37mg,0.2mmol)并在115℃将反应混合物搅拌15小时。将溶剂蒸发至干并将残余物再溶于DMF,过滤并使用含有0.05%三氟乙酸的0-99%乙腈水溶液的梯度,通过反相制备型液相色谱法纯化,得到纯产物。ESI-MS m/z计算值为375.4,实测值为375.1(M+1)+。保留时间2.61分钟。
1-(苯并[d][1,3]二氧杂环戊烯-5-基)-N-(2-甲苯磺酰基吡啶-3-基)环丙烷甲酰
胺的制备
向1-(苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷碳酰氯(45mg,0.2mmol)的吡啶(2mL)中添加2-甲苯磺酰基吡啶-3-胺(50mg,0.2mmol)并在115℃将反应混合物搅拌15小时。将溶剂蒸发至干并将残余物再溶于DMF,过滤并使用含有0.05%三氟乙酸的0-99%乙腈水溶液梯度,通过反相制备型液相色谱法纯化,得到纯产物。ESI-MS m/z计算值为436.5,实测值为437.1(M+1)+。保留时间3.16分钟。
3-(2-(1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-5-甲基
嘧啶-4-基)苯甲酸的制备
步骤a:5-甲基异胞嘧啶
在室温,将新制备的甲醇钠(10.8g,200mmol)悬浮在丙酸乙酯(15.3g,150mmol)的DMF(20mL)溶液中。在1小时期间,添加甲酸甲酯(6.0g,100mmol)。搅拌30分钟后,快速添加盐酸胍(9.6g g,100mmol)的MeOH(35mL)溶液并将反应混合物回流12小时。冷却至30℃并用浓盐酸将pH调节至6.0后,将於浆在5℃保持30分钟。收集固体,用甲醇洗涤,从水中结晶并在真空中干燥,得到5-甲基异胞嘧啶(7.3g,58.4%收率)。1H NMR(300MHz,DMSO):δ10.83(br s,2H),7.38(s,1H),6.26(br s,2H),1.72(s,3H)。
步骤b:4-氯-2-氨基-5-甲基嘧啶
将5-甲基异胞嘧啶(3g,24.0mmol)和POCl3(20mL)的混合物回流45分钟。减压下除去过量的POCl3并将残余物倒在冰上。在10℃,将得到的混合物用氨变成碱性。将沉淀物过滤并从乙醇中结晶,得到4-氯-2-氨基-5-甲基嘧啶(1g 29.0%收率)。1H NMR(400MHz,DMSO):δ8.11(s,1H),6.81(br s,2H),2.04(s,3H)。
步骤c:3-(2-氨基-5-甲基嘧啶-4-基)苯甲酸叔丁酯
向4-氯-5-甲基嘧啶-2-胺(150mg,1.04mmol)、四三苯基膦钯(0)(60mg,0.052mmol)和3-(叔丁氧羰基)苯基硼酸(347mg,1.56mmol)中添加1,2-DME(3mL)和Na2CO3(1.04mL,2M,2.08mmol)并在微波反应器中加热至120℃持续30分钟。使用EtOAc将反应混合物过滤,将滤液用无水Na2SO4干燥并在减压下蒸发。通过硅胶柱色谱法纯化粗制的产物,得到3-(2-氨基-5-甲基嘧啶-4-基)苯甲酸叔丁酯(148mg,50%)。ESI-MS m/z计算值为285.1,实测值为286.5(M+1)+。保留时间1.33分钟。
步骤d:3-(2-(1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-5-甲基嘧啶-4-基)苯甲酸叔丁酯
向1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷碳酰氯(91mg,0.35mmol)和3-(2-氨基-5-甲基嘧啶-4-基)苯甲酸叔丁酯(50mg,0.175mmol)中添加吡啶(2mL)。在90℃,将反应加热24小时。在减压下蒸发吡啶。得到的混合物溶于乙酸乙酯并过滤。用饱和的NaHCO3水溶液(x 3)洗涤滤液。将有机层用无水Na2SO4干燥并在减压下蒸发。通过硅胶柱色谱法纯化粗制的产物,得到3-(2-(1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-5-甲基嘧啶-4-基)苯甲酸叔丁酯。ESI-MS m/z计算值为509.18,实测值为510.5(M+1)+。保留时间2.22分钟
步骤e:3-(2-(1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-5-甲基嘧啶-4-基)苯甲酸
向3-(2-(1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-5-甲基嘧啶-4-基)苯甲酸叔丁酯(48mg,0.094mmol)中添加二氯甲烷(1mL)和TFA(726μL)并在室温搅拌4小时。在减压下蒸发二氯甲烷和TFA。将粗制的产物溶于DMSO(1mL),过滤并通过反相制备型HPLC纯化,得到3-(2-(1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-5-甲基嘧啶-4-基)苯甲酸。ESI-MS m/z计算值为453.11,实测值为454.3(M+1)+。保留时间1.63分钟。
4-(2-(1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-5-甲基
嘧啶-4-基)苯甲酸的制备
步骤a:4-(2-氨基-5-甲基嘧啶-4-基)苯甲酸叔丁酯
向4-氯-5-甲基嘧啶-2-胺(150mg,1.04mmol)、四三苯基膦钯(0)(60mg,0.052mmol)和4-(叔丁氧羰基)苯基硼酸(347mg,1.56mmol)中添加1,2-DME(3mL)和Na2CO3(1.04mL,2M,2.08mmol)并在微波反应器中加热至120℃持续30分钟。使用EtOAc过滤反应混合物,将滤液用水Na2SO4干燥并在减压下蒸发。通过硅胶柱色谱法纯化粗制的产物,得到4-(2-氨基-5-甲基嘧啶-4-基)苯甲酸叔丁酯(149mg,50%)。ESI-MS m/z计算值为285.1,实测值为286.3(M+1)+。保留时间1.36分钟。
步骤b:4-(2-(1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-5-甲基嘧啶-4-基)苯甲酸叔丁酯
向1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷碳酰氯(91mg,0.35mmol)和4-(2-氨基-5-甲基嘧啶-4-基)苯甲酸叔丁酯(50mg,0.175mmol)中添加吡啶(2mL)。在90℃,将反应加热24小时。在减压下蒸发吡啶。将得到的混合物溶于EtOAc并过滤。用饱和的NaHCO3水溶液(x3)洗涤滤液。将有机层用无水Na2SO4干燥并在减压下蒸发。通过硅胶柱色谱法纯化粗制的产物,得到4-(2-(1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-5-甲基嘧啶-4-基)苯甲酸叔丁酯。ESI-MS m/z计算值为509.2,实测值为510.5(M+1)+。保留时间2.18分钟。
步骤c:4-(2-(1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-5-甲基嘧啶-4-基)苯甲酸
向4-(2-(1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-5-甲基嘧啶-4-基)苯甲酸叔丁酯(68mg,0.13mmol)中添加DCM(1.42mL)和TFA(1.00mL)并在室温搅拌1小时。在减压下蒸发DCM和TFA。将粗制的产物溶于DMSO(1mL),过滤并通过反相制备型HPLC纯化,得到4-(2-(1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷甲酰氨基)-5-甲基嘧啶-4-基)苯甲酸。ESI-MS m/z计算值为453.1,实测值为454.3(M+1)+。保留时间1.62分钟。
1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)-N-(4-(6-甲氧基吡啶-3-基)-5-
甲基嘧啶-2-基)环丙烷甲酰胺的制备
步骤a:4-(6-甲氧基吡啶-3-基)-5-甲基嘧啶-2-胺
向4-氯-5-甲基嘧啶-2-胺(250mg,1.74mmol)、四三苯基膦钯(0)(100mg,0.087mmol)和6-甲氧基吡啶-3-基硼酸(398mg,2.60mmol)中添加1,2-DME(6mL)和Na2CO3(1.74mL,2M,3.47mmol)并在微波反应器中加热至120℃持续30分钟。使用乙腈过滤反应混合物并将滤液用无水Na2SO4干燥并在减压下蒸发。通过硅胶柱色谱法纯化粗制的产物,得到4-(6-甲氧基吡啶-3-基)-5-甲基嘧啶-2-胺(160mg,43%)。ESI-MS m/z计算值为216.10,实测值为217.5(M+1)+。保留时间0.52分钟。
步骤b:1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)-N-(4-(6-甲氧基吡啶-3-基)-5-甲基嘧啶-2-基)环丙烷甲酰胺
向1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)环丙烷碳酰氯(369mg,1.42mmol)和4-(6-甲氧基吡啶-3-基)-5-甲基嘧啶-2-胺(153mg,0.71mmol)中添加吡啶(4mL)。在90℃,将反应加热3.5小时。在减压下蒸发吡啶。将得到的混合物溶于乙酸乙酯并过滤。用饱和的NaHCO3水溶液(x 3)洗涤滤液。将有机层用无水Na2SO4干燥并在减压下蒸发。通过硅胶柱色谱法纯化粗制的产物,得到1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)-N-(4-(6-甲氧基吡啶-3-基)-5-甲基嘧啶-2-基)环丙烷甲酰胺。ESI-MS m/z计算值为440.13,实测值为441.5(M+1)+。保留时间1.72分钟。
1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-甲基-4-(6-氧代-1,6-二
氢吡啶-3-基)嘧啶-2-基)环丙烷甲酰胺的制备
向1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)-N-(4-(6-甲氧基吡啶-3-基)-5-甲基嘧啶-2-基)环丙烷甲酰胺(126mg,0.286mmol)的1,4-二氧杂环己烷(1.50mL)溶液中添加4M HCl水溶液(775μL,3.10mmol)并在90℃搅拌1小时。将反应冷却至室温,用Et3N淬灭并浓缩。将得到的混合物溶于EtOAc并过滤。将固体溶于水并使用乙酸乙酯(x 3)萃取产物。将合并的有机层用无水Na2SO4干燥并在减压下蒸发。将粗制的产物溶于DMSO(1mL),过滤并通过反相制备型HPLC纯化,得到1-(2,2-二氟苯并[d][1,3]二氧杂环戊烯-5-基)-N-(5-甲基-4-(6-氧代-1,6-二氢吡啶-3-基)嘧啶-2-基)环丙烷甲酰胺。ESI-MS m/z计算值为426.11,实测值为427.3(M+1)+。保留时间1.34分钟。
下面列出的是根据上述实施例制备的本发明化合物的表征数据。
表2.
检测和测量化合物的△F508-CFTR纠正性质的测定法
测定化合物的△F508-CFTR调控性质的膜电位光学方法。
该测定法采用荧光电压敏感性染料来测量膜电位变化,用荧光板读取器(例如,FLIPR III,Molecular Devices,Inc.)来读出NIH 3T3细胞中的功能性ΔF508-CFTR的增加。该响应的驱动力是氯离子梯度的形成,与预先用化合物处理细胞并随后载入电压敏感性染料之后通过单独的液体添加步骤的通道活化有关。
纠正化合物的鉴定
为了鉴定纠正有关△F508-CFTR的运输缺陷的小分子,开发了单加入HTS测定格式。在组织培养温育器中,在37℃、5%CO2、90%湿度下温育含有细胞的测定板约2-4小时。在附着于测定板底部后,细胞即准备好进行化合物暴露。
在组织培养温育器中,在37℃、5%CO2、90%湿度下,在试验化合物存在或不存在(阴性对照)下,在不含血清的培养基中温育细胞16-24小时。随后用Krebs Ringers溶液冲洗上述细胞3次,并载入电压敏感再分布染料。为了活化ΔF508-CFTR,将10μM福司扣林和CFTR强化剂染料木素(20μM)与无Cl-培养基一起加入各孔。无Cl-培养基的加入促进响应于ΔF508-CFTR活化的Cl-流出,使用电压-传感染剂来光学监测所致膜的去极化。
强化剂化合物的鉴定
为了鉴定ΔF508-CFTR的强化剂,开发了双加入HTS测定形式。该HTS测试法采用荧光电压敏感性染料来在FLIPR III上测量膜电位变化,它是在温度纠正的ΔF508CFTR NIH3T3细胞中的ΔF508CFTR门控(传导)增加的度量。该响应的驱动力是Cl-离子梯度,与预先用强化剂化合物(或DMSO介质对照)处理细胞并随后载入再分布染料之后在使用荧光板读取器如FLIPR III的单独液体添加步骤中用福司扣林的通道活化有关。
溶液:
浴溶液#1:(mM)NaCl 160,KCl 4.5,CaCl2 2,MgCl2 1,HEPES 10,用NaOH调至pH7.4。
无氯化物的浴溶液:用葡萄糖酸盐代替浴溶液#1中的氯化物盐。
细胞培养
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,将细胞按约20,000/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。
测定化合物ΔF508-CFTR调控性质的电生理测定法。
1.Ussing室测试法
对表达ΔF508-CFTR的极化导气管上皮细胞进行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。非CF和CF导气管上皮分离自支气管组织,按先前的描述(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)来培养,并覆盖至预涂NIH3T3条件培养基的SnapwellTM过滤器上。四天后,除去顶端培养基,在使用前在空气液体界面生长细胞>14天。获得完全分化的纤毛柱状细胞单层,这正是导气管上皮的特征。非CF HBE分离自无任何已知肺病的不吸烟者。CF-HBE分离自对△F508-CFTR纯合的患者。
将生长在SnapwellTM细胞培养插件上的HBE固定在Ussing室内(Physiologic Instruments,Inc.,San Diego,CA),利用电压钳系统(Department ofBioengineering,University of Iowa,IA)来测量在基底外侧到顶端的Cl-梯度(ISC)存在下的经上皮电阻和短路电流。简言之,在37℃下于电压钳记录条件下(Vhold=0mV)检验HBE。基底外侧溶液包含(mM)145NaCl,0.83K2HPO4,3.3KH2PO4,1.2MgCl2,1.2CaCl2,10葡萄糖,10HEPES(用NaOH调至pH为7.35),而顶端溶液包含(mM)145葡萄糖酸钠,1.2MgCl2,1.2CaCl2,10葡萄糖,10HEPES(用NaOH调至pH为7.35)。
纠正化合物的鉴定
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,而顶端NaCl被等摩尔葡糖酸钠代替(用NaOH滴定至pH为7.4),得到穿过上皮的大幅Cl-浓度梯度。全部实验都是用完好的单层进行的。为了完全活化ΔF508-CFTR,将福司扣林(10μM)、PDE抑制剂、IBMX(100μM)和CFTR强化剂染料木素(50μM)加至顶端一侧。
如在其它细胞类型中所观察到的,在低温下温育FRT细胞和分离自患病CF患者的人支气管上皮细胞(CF-HBE)表明ΔF508-CFTR增加在质膜中的CFTR功能性密度。为确定纠正化合物的活性,在37℃下将细胞与试验化合物一起温育24-48小时,并随后在记录前洗涤3次。将cAMP和染料木素介导的经化合物处理的细胞中的ISC归一至37℃对照,并表达为野生型HBE的CFTR活性的百分比活性。相比37℃对照,用纠正化合物预温育细胞显著增加了所述cAMP和染料木素介导的ISC。
强化剂化合物的鉴定
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,而顶端NaCl被等摩尔葡糖酸钠代替(用NaOH滴定至pH 7.4),得到穿过上皮的大幅Cl-浓度梯度。向细胞培养插件顶端侧加入福司扣林(10μM)和所有供试化合物。比较假定△F508-CFTR强化剂与已知强化剂染料木素的功效。
2.膜片钳记录
利用如先前所描述的(Rae,J.,Cooper,K.,Gates,P.,&Watsky,M.(1991)J.Neurosci.Methods 37,15-26)开孔-碎片记录技术,监测△F508-NIH3T3细胞中的总Cl-电流。利用Axopatch 200B碎片-钳放大器(Axon Instruments Inc.,Foster City,CA),在22℃下进行电压钳记录。吸移管溶液包含(mM)150N-甲基-d-葡萄糖胺(NMDG)-Cl、2MgCl2、2CaCl2、10EGTA、10HEPES和240μg/ml两性霉素-B(用HCl调节至pH为7.35)。细胞外培养基包含(mM)150NMDG-Cl、2MgCl2、2CaCl2、10HEPES(用HCl调节至pH为7.35)。利用装有Digidata1320A/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。为了活化△F508-CFTR,将10μM福司扣林和20μM染料木素加至所述浴中,并每30秒监测一次电流-电压关系。
纠正化合物的鉴定
为了确定纠正化合物在质膜中增加功能性ΔF508-CFTR密度的活性,在用所述纠正化合物处理24小时之后使用上述开孔-钳记录技术来测量电流密度。为了完全活化ΔF508-CFTR,将10μM福司扣林和20μM染料木素加至所述细胞。在该记录条件下,在27℃下温育24小时后的电流密度高于在37℃下温育24小时后观察到的电流密度。这些结果与低温温育对质膜中的ΔF508-CFTR密度的已知效果相符。为了确定纠正化合物对CFTR电流密度的效果,将所述细胞与10μM试验化合物在37℃下温育24小时,将电流密度与27℃和37℃的对照比较(%活性)。在记录之前用细胞外记录培养基洗涤细胞3次,除去任何余留的试验化合物。相比所述37℃对照,用10μM纠正化合物预温育显著增加所述cAMP和染料木素决定的电流。
强化化合物的鉴定
也利用开孔-碎片-记录技术研究了△F508-CFTR强化剂增加稳定表达△F508-CFTR的NIH3T3细胞中宏观△F508-CFTR Cl-电流(I△F508)的能力。从光学测定法鉴定的强化剂引起I△F508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ECl(-28mV)。
细胞培养
使用稳定表达△F508-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25mMHEPES。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。
3.单通道记录
借助在先描述的切除的内侧外翻的膜片记录(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)用Axopatch 200B碎片钳放大器(AxonInstruments Inc.)来观察表达于NIH3T3细胞中的野生型CFTR和温度纠正的△F508-CFTR的门控活性。吸移管包含(mM):150NMDG、150天冬氨酸、5CaCl2、2MgCl2和10HEPES(用Tris碱将pH调至7.35)。浴包含(mM):150NMDG-Cl、2MgCl2、5EGTA、10TES和14Tris碱(用HCl将pH调至7.35)。切除后加入1mM Mg-ATP、75nM cAMP-依赖性蛋白激酶催化性亚单位(PKA;PromegaCorp.Madison,WI)和10mM NaF,活化野生型CFTR和△F508-CFTR,抑制阻止电流减少的蛋白磷酸酶。吸移管电位维持在80mV。分析含有≤2个活动通道的膜片的通道活动。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△F508-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)用多高斯函数拟合。从120秒通道活动测定总微观电流和开放概率(PO)。PO是利用Bio-Patch软件或者从PO=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。
细胞培养
使用稳定表达△F508-CFTR的NIH3T3小鼠成纤维细胞进行切除膜片钳记录。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。
发现表1的化合物在上文所描述的测定法中测定时显示纠正活性。
本发明化合物可用作ATP结合盒转运蛋白的调控剂。使用前文描述的方法,测定了本发明化合物的活性,即EC50,并将其显示于表3。
表3.
Claims (37)
1.式I的化合物:
或其药学上可接受的盐,其中:
Ar1是
Ar1任选被w个-W-RW取代;其中
W独立地是任选被取代的C1-C6亚烷基链,其中W的至多两个亚甲基单元独立地被-CO-、-O-、-S-、-SO2-或-NR'-替代;
R'独立地是H、烷基、芳基、杂芳基、芳烷基、环烷基或杂环烷基;以及
RW独立地是H、卤素、CN、NO2、NH2、CF3、OCF3、OH、烷氧基或者任选被取代的脂肪族基、脂环族基、杂环烷基、芳基或杂芳基,其中,当被取代时,Rw被至多两个R2取代;
R2是卤素、CN、NO2、CF3、OCF3、OR、-C1-C6亚烷基-OH、-C1-C6亚烷基-NR2、OC(O)R、O C(O)NR2、SR、S(O)R、SO2R、SO2NR2、SO3R、C(O)R、CO2R、C(O)NR2、NR2、NRC(O)R、NRCO2R、NRC(O)NR2、NRSO2R、B(OR)2或NRSO2NR2;
R独立地是H、烷基、环烷基、杂环烷基、芳基或杂芳基;
RN是H、烷基、芳基、杂芳基、芳烷基、环烷基或杂环烷基;
A是任选被取代的3-7元单环;
B任选与5-7元环稠合,该环选自脂环族基、芳基、杂环烷基和杂芳基;
J选自CH2、CF2、C(CH3)2、C(O)、C(苯基)2、B(OH)和CH(OEt);以及
w独立地是包括端值在内的1至5的整数;
其中单独使用或者作为更大部分“芳烷基”、“烷氧基”的一部分使用的术语“烷基”具有1-6个碳原子;
单独使用或者作为更大部分“芳烷基”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一环含有3至7个环成员;
单独使用或者作为更大部分“杂芳烷基”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一环含有3至7个环成员;
术语“杂环烷基”意指非芳族的单环、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,其具有三至十四个环成员,该系统中每个环含有3至7个环成员;
术语“杂原子”是独立选自氧、硫、氮和磷的杂原子;
所述“脂肪族基”意指直链或支链的取代或未取代的烃链,其含有1-20个脂肪族碳原子,其是完全饱和的或者含有一个或多个不饱和单元,或者意指单环烃或二环烃,其是完全饱和的或者含有一个或多个不饱和单元,但不是芳族的,其具有单一的与分子其余部分连接的点;
“脂环族基”或“环烷基”表示单环C3-C8烃或二环C8-C12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。
2.权利要求1的化合物,其中A是
3.权利要求1的化合物,其中A是
4.权利要求1的化合物,其中J是CH2。
5.权利要求1的化合物,其中J是CF2。
6.权利要求1的化合物,其中RN是H。
7.权利要求1的化合物,其中W是任选被取代的C1-C6亚烷基链。
8.权利要求1的化合物,其中W是-CH2-。
9.权利要求1的化合物,其中W是-NH-。
10.权利要求1的化合物,其中W是-O-。
11.权利要求1的化合物,其中W是-SO2-。
12.权利要求1的化合物,其中Rw是H。
13.权利要求1的化合物,其中Rw是OH。
14.权利要求1的化合物,其中Rw是芳基。
15.权利要求1的化合物,其中Rw是苯基。
16.权利要求1的化合物,其中Rw是杂芳基。
17.权利要求1的化合物,其中Rw是吡啶基。
18.权利要求1的化合物,其中Rw是烷氧基。
19.权利要求1的化合物,其中Rw是甲氧基。
20.权利要求1的化合物,其中Rw是三氟甲氧基。
21.权利要求1的化合物,其中Rw是环烷基。
22.权利要求1的化合物,其中Rw是环己基。
23.权利要求1的化合物,其中Rw是杂环烷基。
24.权利要求1的化合物,其中Rw是未被取代的杂环烷基。
25.权利要求1的化合物,其中Rw是吡啶酮。
26.权利要求1的化合物,其中Ar1被至少一个-W-Rw取代,该-W-Rw选自下列基团:
-OH、-CH3、-OMe、-CF3,
27.选自表1的化合物:
表1.
28.药物组合物,其包含
(i)权利要求1-27任一项所述的化合物;以及
(ii)药学上可接受的载体。
29.权利要求28的组合物,其还包含另外的药剂,该另外的药剂选自黏液溶解药、支气管扩张药、抗生素、抗感染药、抗炎药、CFTR矫正剂和营养剂。
30.权利要求1-27任一项所述的化合物在制备用于调控细胞膜中ABC转运蛋白的制剂中的用途。
31.权利要求30的用途,其中所述ABC转运蛋白是CFTR。
32.权利要求1-27任一项所述的化合物在制备用于治疗患者中涉及ABC转运蛋白活性的病况、疾病或障碍的药物中的用途。
33.权利要求32的用途,其中所述ABC转运蛋白是CFTR。
34.权利要求32的用途,其中所述的病况、疾病或障碍选自囊性纤维化;遗传性肺气肿;遗传性血色素沉着;凝血-纤维蛋白溶解缺陷;1型遗传性血管水肿;脂质加工缺陷;1型乳糜微粒血;无β脂蛋白血症;溶酶体贮积病;粘多糖病;Sandhof/Tay-Sachs;II型Crigler-Najjar;多内分泌腺病/高胰岛素血症;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;1型聚糖病CDG;先天性甲状腺机能亢进;成骨不全;遗传性低纤维蛋白原血症;ACT缺陷;尿崩症;夏-马-图三氏综合征;佩-梅二氏病;神经变性疾病;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;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;法布里氏病;斯-施二氏综合征;COPD;干眼病和斯耶格伦氏病。
35.权利要求32的用途,其中所述的病况、疾病或障碍选自C蛋白缺陷;家族性高胆固醇血症;I-细胞疾病/假性Hurler;阿尔茨海默氏病;亨廷顿氏病;遗传性克-雅二氏病。
36.权利要求34的用途,其中所述的病况、疾病或障碍选自神经生长性尿崩症和肾原性尿崩症。
37.用于在体外或体内测定生物样品中ABC转运蛋白或其片段的活性的试剂盒,该试剂盒包含:
(i)包含权利要求1-27任一项所述的化合物的第一组合物;以及
(ii)关于如下内容的说明书:
a)使所述组合物与所述生物样品接触;
b)测定所述ABC转运蛋白或其片段的活性。
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