CN103626744A - 3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的固体形式 - Google Patents
3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的固体形式 Download PDFInfo
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Abstract
本发明涉及式(I)的3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸(晶型I)的基本上结晶和游离固态形式、其药物组合物和使用它们的治疗方法。
Description
本申请是申请日为2008年12月04日、申请号为200880123888.0、发明名称为“3-(6-(1-(2,2-二氟苯并[D][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的固体形式”的专利申请的分案申请。
相关申请的交叉参考
本申请根据35U.S.C.§119要求2007年12月7日提交的美国临时专利申请顺序号US61/012,162的利益,将该文献的全部内容引入本文参考。
本发明的技术领域
本发明涉及3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的固态形式例如晶型、其药物组合物及其使用方法。
发明背景
CFTR是在多种细胞类型包括吸收性和分泌上皮细胞中表达的cAMP/ATP-介导的阴离子通道,其中它调节通过膜的阴离子流量和其他离子通道和蛋白的活性。在上皮细胞中,CFTR的正常概念对维持遍布体内包括呼吸和消化组织的电解质运输而言是关键的。CFTR由约1480个氨基酸组成,这些氨基酸编码由跨膜结构域的串联重复单元构成的蛋白质,所述跨膜结构域各自包含六个跨膜螺旋和核苷酸结合结构域。两个跨膜结构域通过大的极性调节(R)-结构域连接,所述大的极性调节(R)-结构域具有调节通道活性和细胞运输的多个磷酸化位点。
编码CFTR的基因已被鉴别和测序(参见Gregory,R.J.等人,(1990)Nature347:382-386;Rich,D.P.等人,(1990)Nature347:358-362;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。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遭受CF的衰弱与致命性效应,包括慢性肺病。
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,导致离子和体液转运的失衡。所致阴离子转运降低导致肺中粘液蓄积增强和伴随的微生物感染,最终导致CF患者死亡。除了呼吸疾病以外,CF患者通常经历胃肠问题和胰腺机能不全,如果不加治疗则导致死亡。另外,大多数患有囊性纤维化的男性是不育的,患有囊性纤维化的女性的生育力降低。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出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。
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)Nature346:366-369;Dean,M.等人,(1990)Cell61:863:870;和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,其普遍被称为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。
ΔF508-CFTR中残基508的缺失阻止初生蛋白正确地折叠。这导致该突变蛋白不能退出ER并运输至质膜。其结果是,膜中通道数量远远少于表达野生型CFTR的细胞中所观察到的。除了运输受损以外,突变还导致有缺陷的通道门控。同时,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,见上;Pasyk和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减缓疾病进展和/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。
这些要素一起工作,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化物的大量流动所生成的微小跨上皮渗透梯度。
正如上文所讨论的,据信ΔF508-CFTR中残基508的缺失阻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囊性纤维化疾病的基础,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,Nature Med.,5(7),pp745-751(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)]。
盐形式的3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸作为CFTR活性调节剂公开在国际PCT公开号WO2007056341中(将该公开文献的全部内容引入本文参考)且由此用于治疗CFTR-介导的疾病例如囊性纤维化。然而,对准备用于适合于用作治疗剂的药物组合物的所述化合物的稳定固体形式存在需求。
发明概述
本发明涉及3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸(下文的“化合物1”)的固体形式,它具有如下结构:
化合物1及其药学上可接受的组合物用于治疗囊性纤维化或减轻其严重性。在一个方面中,化合物1为基本上结晶且不含盐(salt free)的形式,被称为如下文所述和表征的晶型I。
本文描述了可以用于制备包含晶型I的本发明组合物的的方法。用于该方法的成分的量和特征如本文所述。
附图简述
图1是根据化合物1的晶型I的单晶结构计算的X-射线衍射图案。
图2是化合物1的晶型I的实际X-射线粉末衍射图案。
图3是根据化合物1的晶型I的单晶结构计算的X-射线衍射图案和化合物1的晶型I的实际X-射线粉末衍射图案的覆盖图。
图4是化合物1的晶型I的差示扫描量热(DSC)扫迹(trace)。
图5是基于单晶X-射线分析的化合物1的晶型I的构象照片。
图6是基于作为通过羧酸基团形成的二聚体的单晶X-射线分析的化合物1的晶型I的构象照片。
图7是基于显示分子彼此叠加的单晶X-射线分析的化合物1的晶型I的构象照片。
图8是显示不同视图的基于单晶X-射线分析的化合物1的晶型I的构象照片(a向下)。
图9是化合物1的晶型I的50mg/mL、0.5甲基纤维素-聚山梨醇酯80混悬液在T(0)的1HNMR分析。
图10是贮存在室温24小时的化合物1的晶型I的50mg/mL、0.5甲基纤维素-聚山梨醇酯80混悬液在T(0)的1HNMR分析。
图11是化合物1·HCl标准品的1HNMR分析。
发明概述
定义
除非另作陈述,否则下列定义应适用。
本文所用的术语“CFTR”表示囊性纤维化跨膜传导调节剂或其具有调节剂活性的突变体,包括但不限于ΔF508CFTR和G551D CFTR(参见例如http://www.genet.sickkids.on.ca/cftr/,关于CFTR突变)。
本文所用的“结晶”意指化合物或组合物,其中结构单元以固定几何模式或晶格排列,使得结晶固体具有刚性长程序。构成晶体结构的结构单元可以是原子、分子或离子。结晶固体显示确定的熔点。
本文所用的术语“调节”表示以可测量的量增加或降低例如活性。
本发明在一个方面中的特征在于3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的晶型,其特征为晶型I。
在另一个实施方案中,晶型I的特征在于使用Cu Kα射线得到的在X-射线粉末衍射中在15.2-15.6度、16.1-16.5度和14.3-14.7度的一个或多个峰。
在另一个实施方案中,晶型I的特征在于在15.4、16.3和14.5度的一个或多个峰。
在另一个实施方案中,晶型I的特征还在于在14.6-15.0度的峰。
在另一个实施方案中,晶型I的特征还在于在14.8度的峰。
在另一个实施方案中,晶型I的特征还在于在17.6-18.0度的峰。
在另一个实施方案中,晶型I的特征还在于在17.8度的峰。
在另一个实施方案中,晶型I的特征还在于在16.4-16.8度的峰。
在另一个实施方案中,晶型I的特征还在于在16.4-16.8度的峰。
在另一个实施方案中,晶型I的特征还在于在16.6度的峰。
在另一个实施方案中,晶型I的特征还在于在7.6-8.0度的峰。
在另一个实施方案中,晶型I的特征还在于在7.8度的峰。
在另一个实施方案中,晶型I的特征还在于在25.8-26.2度的峰。
在另一个实施方案中,晶型I的特征还在于在26.0度的峰。
在另一个实施方案中,晶型I的特征还在于在21.4-21.8度的峰。
在另一个实施方案中,晶型I的特征还在于在21.6度的峰。
在另一个实施方案中,晶型I的特征还在于在23.1-23.5度的峰。
在另一个实施方案中,晶型I的特征还在于在23.3度的峰。
在一些实施方案中,晶型I的特征在于基本上与图1的衍射图案类似的衍射图案。
在一些实施方案中,晶型I的特征在于基本上与图2的衍射图案类似的衍射图案。
在一些实施方案中,晶型I的D90的粒度分布为约82μm或更小。
在一些实施方案中,晶型I的D50的粒度分布为约30μm或更小。
本发明在一个方面中的特征在于包含晶型I和药学上可接受的载体的药物组合物。
在一个方面中,本发明的特征在于治疗人CFTR介导的疾病的方法,该方法包括对该人给予有效量的晶型I。
在一些实施方案中,该方法包括给予另一种治疗剂。
在一些实施方案中,所述疾病选自囊性纤维化、遗传性肺气肿、遗传性血色素沉着症、凝血-纤维蛋白溶解缺陷症例如C蛋白缺陷症、1型遗传性血管水肿、脂质加工缺陷症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/假性赫尔勒(Hurler)病、粘多糖病、桑德霍夫/泰-萨克斯(Sandhof/Tay-Sachs)病、克里格勒-纳贾尔(Crigler-Najjar)综合症II型、多内分泌腺病/高胰岛素血症(hyperinsulemia)、糖尿病、拉伦(Laron)侏儒症、髓过氧化物酶(myleoperoxidase)缺乏症、原发性甲状旁腺机能减退症、黑色素瘤、聚糖病(glycanosis)CDG1型、遗传性肺气肿、先天性甲状腺机能亢进症、成骨不全、遗传性低纤维蛋白原血症、ACT缺乏症、尿崩症(DI)、后叶激素运载蛋白性(neurophyseal)DI、肾性DI、夏-马-图(Charcot-Marie Tooth)综合征、佩-梅(Perlizaeus-Merzbacher)病、神经变性疾病例如阿尔茨海默病、帕金森病、肌萎缩性侧索硬化、进行性核上性麻痹、皮克病、若干聚谷氨酰胺神经障碍例如亨廷顿病、I型脊髓小脑性共济失调(spinocerebullar ataxia type I)、脊髓与延髓肌肉萎缩、齿状核红核(dentatorubal)苍白球丘脑下部核萎缩和肌强直性营养不良以及海绵状脑病例如遗传性克-雅病、法布里病和斯-施综合征、COPD、干眼病和斯耶格仑病。
在一个实施方案中,本发明提供了治疗人囊性纤维化的方法,该方法包括对该人给予有效量的晶型I。
在一个方面中,本发明的特征在于包含晶型I及其使用说明书的试剂盒。
在一个方面中,本发明的特征在于晶型I的制备方法,该方法包括将3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的HCl盐分散于或溶于适合溶剂有效量的时间。
在一个实施方案中,本发明的特征在于晶型I的制备方法,该方法包括将3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的HCl盐分散于适合溶剂有效量的时间。
在一些实施方案中,适合溶剂是水或醇/水混合物。
在一些实施方案中,适合溶剂是水或50%甲醇/水混合物。
在一些实施方案中,适合溶剂是水。
在一些实施方案中,适合溶剂是包含50%甲醇和50%水的混合物。
在一些实施方案中,有效量的时间是约2-约1天。在一些实施方案中,有效量的时间是约2-约18小时。在一些实施方案中,有效量的时间是约2-约12小时。在一些实施方案中,有效量的时间是约2-约6小时。
本发明在一个方面中的特征在于3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的晶型,它具有单斜晶系、P21/n空间群和如下晶胞大小: α=90°、β=93.938(9)°和γ=90°。
晶型I的制备方法
在一个实施方案中,通过将3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的盐形式例如HCL分散于或溶于适合溶剂有效量的时间制备晶型I。在另一个实施方案中,通过将3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的盐形式例如HCL分散于适合溶剂有效量的时间制备晶型I。在另一个实施方案中,由3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)-叔丁基苯甲酸酯和适宜酸例如甲酸直接形成晶型I。在一个实施方案中,3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的HCl盐形式是起点,且在一个实施方案中,可以根据反应路线1-3通过使酰氯结构部分与胺结构部分偶合来制备。
反应路线1.酰氯结构部分的合成
反应路线2.胺结构部分的合成
反应路线3.3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的酸盐的形成
使用例如3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的HCl盐形式作为起点,可以通过将3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的HCl盐形式分散于或溶于适合溶剂有效量的时间以高收率形成晶型I。可以使用3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的其他盐形式例如其他无机酸或有机酸形式。其他盐形式由叔丁酯与相应酸的水解产生。其他酸/盐形式包括硝酸、硫酸、磷酸、硼酸、乙酸、苯甲酸、丙二酸等。3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的盐形式可以根据所用溶剂的不同是可溶的或不溶的,但溶解度低不会妨碍晶型I形成。例如,在一个实施方案中,适合溶剂可以是水或醇/水混合物例如50%甲醇/水混合物,即使3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的HCl盐形式仅仅微溶于水。在一个实施方案中,适合溶剂是水。
由3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的盐形式形成晶型I的有效量的时间可以是2-24小时之间的任意时间或更长。一般而言,24小时以上不一定得到高收率(~98%),但一些溶剂可能需要更长时间。还认为所需时间的量与温度成反比。即温度越高,则所需影响酸解离形成晶型I的时间越短。当溶剂是水时,在室温将该混悬液搅拌约24小时得到约98%收率的晶型I。如果3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的盐形式的溶液是方法目的所期望的,则可以使用高温。将该溶液在高温下搅拌有效量的时间后,在冷却时重结晶得到基本上纯形式的晶型I。在一个实施方案中,基本上纯的含义是高于约90%的纯度。在另一个实施方案中,基本上纯的含义是高于约95%的纯度。在另一个实施方案中,基本上纯的含义是高于约98%的纯度。在另一个实施方案中,基本上纯的含义是高于约99%的纯度。选择的温度部分取决于所用的溶剂并且属于本领域技术人员决定能力的范围。在一个实施方案中,温度是室温-约80℃。在另一个实施方案中,温度是室温-约40℃。在另一个实施方案中,温度是约40℃-约60℃。在另一个实施方案中,温度是约60℃-约80℃。
在一些实施方案中,可以通过从有机溶剂中重结晶进一步纯化晶型I。有机溶剂的实例包括但不限于甲苯、枯烯、茴香醚、1-丁醇、乙酸异丙酯、乙酸丁酯、乙酸异丁酯、甲基叔丁基醚、甲基异丁基酮或1-丙醇/水(以不同比例)。可以如上所述使用温度。例如,在一个实施方案中,将晶型I在75℃溶于1-丁醇至完全溶解。将该溶液以0.2℃/min的速率冷却至10℃得到晶型I的晶体,其可以通过过滤分离。
用途、制剂和给药
药学上可接受的组合物
在本发明的另一个方面中提供了药学上可接受的组合物,其中这些组合物包含如本文所述的晶型I且任选包含药学上可接受的载体、佐剂或媒介物。在一些实施方案中,这些组合物任选还包含一种或多种其他治疗剂。
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、佐剂或媒介物,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。在Remington's Pharmaceutical Sciences,第16版,E.W.Martin(Mack Publishing Co.,Easton,Pa.,1980)中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,将这些文献的内容引入本文参考。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成分,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。
化合物和药学上可接受的组合物的用途
本发明在另一个方面中提供了治疗涉及CFTR的病症、疾病或障碍的方法。在一些实施方案中,本发明提供了治疗涉及CFTR活性缺陷的病症、疾病或障碍的方法,该方法包括对有此需要的受试者、优选哺乳动物给予本文所述的晶型I的固态形式。
本文所用的“CFTR-介导的疾病”是选自如下的疾病:囊性纤维化、遗传性肺气肿、遗传性血色素沉着症、凝血-纤维蛋白溶解缺陷症(例如C蛋白缺陷症)、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/假性赫尔勒病)、粘多糖病、桑德霍夫/泰-萨克斯病、克里格勒-纳贾尔(Crigler-Najjar)综合症II型、多内分泌腺病/高胰岛素血症、糖尿病、拉伦侏儒症、髓过氧化物酶缺乏症、原发性甲状旁腺机能减退症、黑色素瘤、聚糖病CDG1型、遗传性肺气肿、先天性甲状腺机能亢进症、成骨不全、遗传性低纤维蛋白原血症、ACT缺乏症、尿崩症(DI)、后叶激素运载蛋白性DI、肾性DI、夏-马-图综合征、佩-梅病、神经变性疾病(例如阿尔茨海默病、帕金森病、肌萎缩性侧索硬化、进行性核上性麻痹、皮克病)、若干聚谷氨酰胺神经障碍(例如亨廷顿病、I型脊髓小脑性共济失调、脊髓与延髓肌肉萎缩、齿状核红核苍白球丘脑下部核萎缩和肌强直性营养不良)以及海绵状脑病(例如遗传性克-雅二病、法布里病和斯-施综合征、COPD、干眼病和斯耶格仑病。
在一些实施方案中,本发明提供了治疗人CFTR-介导的疾病的方法,该方法包括对该人给予有效量的包含本文所述的晶型I的组合物的步骤。
根据可选择的优选实施方案,本发明提供了治疗人囊性纤维化的方法,该方法包括对该人给予有效量的包含本文所述的晶型I的组合物的步骤。
本发明的晶型I或其药学上可接受的组合物的“有效量”是用于治疗上述任意疾病或减轻其严重性的用量。
可以使用有效治疗一种或多种上述疾病或减轻其严重性的任意量和任意给药途径给予晶型I或其药学上可接受的组合物。
在一些实施方案中,本文所述的晶型I或其药学上可接受的组合物用于治疗患者囊性纤维化或减轻其严重性,所述患者显示在呼吸和非呼吸上皮顶膜中的残留CFTR活性。易于使用本领域公知的方法例如标准电生理、生化或组织化学技术检测上皮表面上存在的残留CFTR活性。这种方法使用体内或离体电生理技术、测量汗液或唾液Cl-浓度或离体生化或组织化学技术鉴定CFTR活性,以监测细胞表面密度。使用这种方法易于在各种不同突变的杂合或纯合的患者包括对最常见突变ΔF508纯合或杂合的患者中检测残留CFTR活性。
在一个实施方案中,本文所述的晶型I或其药学上可接受的组合物用于治疗患者囊性纤维化或减轻其严重性,所述患者在一些基因型中显示残留CFTR活性,例如III型突变(调节或门控受损)、IV型突变(传导改变)或V型突变(合成减少)(Lee R.Choo-Kang,Pamela L.,Zeitlin,Type I,II,III,IV,and V cystic fibrosis TansmembraneConductance Regulator Defects and Opportunities of Therapy;Current Opinion in Pulmonary Medicine6:521-529,2000)。其他显示残留CFTR活性的患者基因型包括对这些类型之一纯合的患者或对任意其他类型突变杂合的患者,所述其他类型突变包括I型突变、II型突变或缺乏分类的突变。
在一个实施方案中,本文所述的晶型I或其药学上可接受的组合物用于治疗具有一些临床表型内患者囊性纤维化或减轻其严重性,在所述患者的一些临床表型例如为典型地与上皮顶膜中残留CFTR活性量相关的中度到轻度临床表型。这种表型包括显示胰腺功能不全的患者或诊断为特发性胰腺炎和先天性双侧输精管缺失或轻度肺病的患者。
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。
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。在一些实施方案中,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-约50mg/kg、优选约1mg/kg-约25mg/kg受治疗者体重,一天一次或多次,以获得期望的治疗效果。
在一些实施方案中,晶型I在单位剂量晶型I中的剂量是100mg-1,000mg。在另一个实施方案中,晶型I的剂量是200mg-900mg。在另一个实施方案中,晶型I的剂量是300mg-800mg。在另一个实施方案中,晶型I的剂量是400mg-700mg。在另一个实施方案中,晶型I的剂量是500mg-600mg。
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他无菌可注射介质中。
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。
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)填充剂或增充剂,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。
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,这类剂型也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。
也将被领会的是,本文所述的晶型I及其药学上可接受的组合物可以用在联合疗法中,也就是说,晶型I及其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其他治疗剂被称为“就所治疗的疾病或病症而言是适当的”。
在一个实施方案中,另一种活性剂选自溶粘蛋白剂、支气管扩张药、抗生物素药、抗感染药、抗炎药、非本发明化合物的CFTR调节剂或营养剂。
在另一个实施方案中,另一种活性剂是选自如下的化合物:庆大霉素、姜黄素、环磷酰胺、4-苯基丁酸酯、麦格司他、非洛地平、尼莫地平、Philoxin B、染料木黄酮(geniestein)、芹菜配基、cAMP/cGMP调节剂例如咯利普兰、西地那非、米力农、他达拉非、氨力农、异丙肾上腺素、沙丁胺醇和沙美特罗(almeterol)、脱氧精胍菌素、HSP90抑制剂、HSP70抑制剂、蛋白体抑制剂例如epoxomicin、乳胞素等。
在另一个实施方案中,另一种活性剂是公开在WO2004028480、WO2004110352、WO2005094374、WO2005120497或WO2006101740中的化合物。
在另一个实施方案中,另一种活性剂是显示CFTR调节活性的苯并[c]喹嗪(benzo(c)quinolizinium)衍生物或显示CFTR调节活性的苯并吡喃衍生物。
在另一个实施方案中,另一种活性剂是公开在US7202262、US6992096、US20060148864、US20060148863、US20060035943、US20050164973、WO2006110483、WO2006044456、WO2006044682、WO2006044505、WO2006044503、WO2006044502或WO2004091502中的化合物。
在另一个实施方案中,另一种活性剂是公开在WO2004080972、WO2004111014、WO2005035514、WO2005049018、WO2006002421、WO2006099256、WO2006127588或WO2007044560中的化合物。
在另一个实施方案中,另一种活性剂选自公开在如下文献中的化合物:美国专利申请顺序号US11/165,818、作为2005年6月24日提交的美国公开专利申请号US2006/0074075公布,将其全部内容引入本文参考。在另一个实施方案中,另一种活性剂是N-(5-羟基-2,4-二叔丁基-苯基)-4-氧代-1H-喹啉-3-甲酰胺。它们的组合用于治疗本文所述的疾病包括囊性纤维化。这些组合物还用于本文所述的试剂盒。
其他治疗剂在本发明组合物中的含量将不超过在包含该治疗剂作为唯一活性成分的组合物中通常的给药量。优选地,其他治疗剂在目前所公开的组合物中的量将是通常的包含该药物作为唯一治疗活性成分的组合物中的含量的约50%-100%。
本文所述的晶型I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。涂料可以选择性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。
为了更完整地理解本文所述的本发明,举出下列实施例。应理解这些实施例仅用于示例目的,而不以任何方式限定本发明。
实施例
方法和材料
差示扫描量热法(DSC)
使用DSC Q100V9.6Build290(TA Instruments,New Castle,DE)采集晶型I的差示扫描量热法(DSC)数据。使用铟校准温度并且使用蓝宝石校准热容。将3-6mg样品称量入用带有1个针孔的盖覆盖的铝盘。从25℃-350℃以1.0℃/min的加热速率和50ml/min的氮气吹扫来扫描样品。用Thermal Advantage Q SeriesTM2.2.0.248版软件采集数据并且用Universal Analysis软件4.1D版(TAInstruments,New Castle,DE)分析。报道的数值表示单一分析。
XRPD(X-射线粉末衍射)
用带有HI-STAR2-维检测器和扁平石墨单色镜的Bruker D8DISCOVER粉末衍射计采集晶型I的X-射线衍射(XRD)数据。在40kV,35mA使用带有Kα射线的Cu密封试管。在25℃将样品置于零背景的硅晶片上。对每一样品而言,各自以2个不同的θ2角在120秒采集两个数据范围:8°和26°。用GADDS软件给数据积分并且用DIFFRACT+EVA软件进行数据合并。报道的峰位的不确定值是±0.2度。
2,2-二氟-1,3-苯并间二氧杂环戊烯-5-甲酸购自Saltigo(并入Lanxess Corporation)。
在本申请中化合物名称不能正确描述该化合物结构的任何地方,结构替代名称并且以其为准。
3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸·HCl的合成
酰氯结构部分
(2,2-二氟-1,3-苯并间二氧杂环戊烯-5-基)-甲醇的合成
将商购2,2-二氟-1,3-苯并间二氧杂环戊烯-5-甲酸(1.0eq)在甲苯(10vol)中搅拌成淤浆。以维持温度在15-25℃的速率通过滴液漏斗加入(2eq)。在添加结束时,使温度增加至40℃2h,然后通过滴液漏斗谨慎加入10%(w/w)NaOH(4.0eq)水溶液,维持温度在40-50℃。再搅拌30分钟后,使各层在40℃分离。将有机相冷却至20℃,然后用水(2x1.5vol)洗涤,干燥(Na2SO4),过滤,浓缩至得到粗(2,2-二氟-1,3-苯并间二氧杂环戊烯-5-基)-甲醇,将其直接用于下一步。
5-氯甲基-2,2-二氟-1,3-苯并间二氧杂环戊烯的合成
将(2,2-二氟-1,3-苯并间二氧杂环戊烯-5-基)-甲醇(1.0eq)溶于MTBE(5vol)。加入催化量的DMAP(1mol%),通过滴液漏斗加入SOCl2(1.2eq)。以维持反应器中在15-25℃温度的速率加入SOCl2。使温度增加至30℃1小时,冷却至20℃,然后通过滴液漏斗加入水(4vol),维持温度低于30℃。再搅拌30分钟后,使各层分离。搅拌有机层,加入10%(w/v)NaOH水溶液(4.4vol)。搅拌15-20分钟后,使各层分离。然后干燥有机相(Na2SO4),过滤,浓缩,得到粗5-氯甲基-2,2-二氟-1,3-苯并间二氧杂环戊烯,将其直接用于下一步。
(2,2-二氟-1,3-苯并间二氧杂环戊烯-5-基)-乙腈的合成
将5-氯甲基-2,2-二氟-1,3-苯并间二氧杂环戊烯(1eq)在DMSO(1.25vol)中的溶液加入到NaCN(1.4eq)在DMSO(3vol)中的淤浆中,维持温度在30-40℃。将该混合物搅拌1小时,然后加入水(6vol),然后加入MTBE(4vol)。搅拌30min后,分离各层。用MTBE(1.8vol)萃取水层。用水(1.8vol)洗涤合并的有机层,干燥(Na2SO4),过滤,浓缩,得到粗(2,2-二氟-1,3-苯并间二氧杂环戊烯-5-基)-乙腈(95%),将其直接用于下一步。
(2,2-二氟-1,3-苯并间二氧杂环戊烯-5-基)-环丙烷腈的合成
将(2,2-二氟-1,3-苯并间二氧杂环戊烯-5-基)-乙腈(1.0eq)、50wt%KOH水溶液(5.0eq)、1-溴-2-氯乙烷(1.5eq)和Oct4NBr(0.02eq)的混合物在70℃加热1h。冷却该反应混合物,然后用MTBE和水进行后处理。用水和盐水洗涤有机相,然后除去溶剂,得到(2,2-二氟-1,3-苯并间二氧杂环戊烯-5-基)-环丙烷腈。
1-(2,2-二氟-1,3-苯并间二氧杂环戊烯-5-基)-环丙烷甲酸的合成
在80℃使用6M NaOH(8当量)的乙醇(5vol)溶液水解(2,2-二氟-1,3-苯并间二氧杂环戊烯-5-基)-环丙烷腈过夜。将该混合物冷却至室温,真空蒸发乙醇。将残余物溶于水和MTBE,加入1M HCl,分离各层。然后用二环己基胺(0.97当量)处理MTBE层。将该淤浆冷却至0℃,过滤,用庚烷洗涤,得到相应的DCHA盐。将该盐溶于MTBE和10%柠檬酸,搅拌至全部固体溶解。分离各层,用水和盐水洗涤MTBE层。将溶剂交换成庚烷,然后过滤,在50℃、在真空烘箱内干燥过夜后得到1-(2,2-二氟-1,3-苯并间二氧杂环戊烯-5-基)-环丙烷甲酸。
1-(2,2-二氟-1,3-苯并间二氧杂环戊烯-5-基)-环丙烷羰基氯的合成
将1-(2,2-二氟-1,3-苯并间二氧杂环戊烯-5-基)-环丙烷甲酸(1.2eq)在甲苯(2.5vol)中搅拌成淤浆,将该混合物加热至60℃。通过滴液漏斗加入SOCl2(1.4eq)。30分钟后从反应混合物中蒸馏甲苯和SOCl2。再加入甲苯(2.5vol),再蒸馏。
胺结构部分
叔丁基-3-(3-甲基吡啶-2-基)苯甲酸酯的合成
将2-溴-3-甲基吡啶(1.0eq)溶于甲苯(12vol)。加入K2CO3(4.8eq),然后加入水(3.5vol),在N2气流中将该混合物加热至65℃1小时。然后加入3-(叔丁氧羰基)苯基硼酸(1.05eq),然后加入Pd(dppf)Cl2·CH2Cl2(0.015eq),将该混合物加热至80℃。2小时后,停止加热,加入水(3.5vol),使各层分离。然后用水(3.5vol)洗涤有机相,用10%甲磺酸水溶液(2eq MsOH,7.7vol)萃取。用50%NaOH水溶液(2eq)使水相呈碱性,用EtOAc(8vol)萃取。浓缩有机层,得到粗叔丁基-3-(3-甲基吡啶-2-基)苯甲酸酯(82%),将其直接用于下一步。
2-(3-(叔丁氧羰基)苯基)-3-甲基吡啶-1-氧化物的合成
将叔丁基-3-(3-甲基吡啶-2-基)苯甲酸酯(1.0eq)溶于EtOAc(6vol)。加入水(0.3vol),然后加入脲-过氧化氢(3eq)。逐步加入作为固体的邻苯二甲酸酐(3eq),维持反应器内部温度低于45℃。邻苯二甲酸酐添加完成后,将该混合物加热至45℃。再搅拌4小时后,停止加热。通过滴液漏斗加入10%w/w Na2SO3水溶液(1.5eq)。Na2SO3添加完成后,将该混合物再搅拌30分钟,分离各层。搅拌有机层,加入10%w/w Na2CO3水溶液(2eq)。搅拌30分钟后,使各层分离。用13%w/vNaCl水溶液洗涤有机相。然后过滤有机相,浓缩,得到粗2-(3-(叔丁氧羰基)苯基)-3-甲基吡啶-1-氧化物(95%),将其直接用于下一步。
叔丁基-3-(6-氨基-3-甲基吡啶-2-基)苯甲酸酯的合成
将2-(3-(叔丁氧羰基)苯基)-3-甲基吡啶-1-氧化物(1eq)和吡啶(4eq)在MeCN(8vol)中的溶液加热至70℃。在50min内通过滴液漏斗加入甲磺酸酐(1.5eq)在MeCN(2vol)中的溶液,维持温度低于75℃。添加完成后将该混合物再搅拌0.5小时。然后将该混合物冷却至环境温度。通过滴液漏斗加入乙醇胺(10eq)。搅拌2小时后,加入水(6vol),将该混合物冷却至10℃。搅拌NLT3小时后,通过过滤收集固体,用水(3vol)、2:1MeCN/水(3vol)和MeCN(2x1.5vol)洗涤。在50℃、在通少许N2的真空烘箱内干燥固体至恒重(<1%差异),得到叔丁基-3-(6-氨基-3-甲基吡啶-2-基)苯甲酸酯,为红-黄色固体(53%收率)。
3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)-叔丁基苯甲酸酯的合成
将粗的酰氯溶于甲苯(基于酰氯2.5vol),通过滴液漏斗加入到叔丁基-3-(6-氨基-3-甲基吡啶-2-基)苯甲酸酯(1eq)、二甲氨基吡啶(DMAP,0.02eq)和三乙胺(3.0eq)在甲苯(基于叔丁基-3-(6-氨基-3-甲基吡啶-2-基)苯甲酸酯4vol)中的混合物中。2小时后,向该反应混合物中加入水(基于叔丁基-3-(6-氨基-3-甲基吡啶-2-基)苯甲酸酯4vol)。搅拌30分钟后,分离各层。然后过滤有机相,浓缩至得到3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)-叔丁基苯甲酸酯的粘稠油(定量粗收率)。加入MeCN(基于粗产物3vol),蒸馏至出现结晶。加入水(基于粗产物2vol),将该混合物搅拌2h。通过过滤收集固体,用1:1(按体积计)MeCN/水(基于粗产物2x1vol)洗涤,在真空下在过滤器上部分干燥。在60℃、在通少许N2的真空烘箱内干燥固体至恒重(<1%差异),得到3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)-叔丁基苯甲酸酯,为棕色固体。
3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸·HCL盐的合成
向3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)-叔丁基苯甲酸酯(1.0eq)在MeCN(3.0vol)中的淤浆中加入水(0.83vol),然后加入浓HCl水溶液(0.83vol)。将该混合物加热至45±5℃。搅拌24-48小时后,反应完成,将该混合物冷却至环境温度。加入水(1.33vol),搅拌该混合物。通过过滤收集固体,用水(2x0.3vol)洗涤,在真空下在过滤器上部分干燥。在60℃、在通少许N2的真空烘箱内干燥固体至恒重(<1%差异),得到3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸·HCl,为黄白色固体。
3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸(晶型I)的合成
在环境温度搅拌3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸·HCl(1eq)在水(10vol)中的淤浆。搅拌24小时后取样。过滤样品,用水(2x)洗涤固体。对固体样品进行DSC分析。当DSC分析显示完全转化成晶型I时,通过过滤收集固体,用水(2x1.0vol)洗涤,在真空下在过滤器上部分干燥。在60℃、在通少许N2的真空烘箱内干燥固体至恒重(<1%差异),得到晶型I,为黄白色固体(98%收率)。1H NMR(400MHz,DMSO-d6)9.14(s,1H),7.99-7.93(m,3H),7.80-7.78(m,1H),7.74-7.72(m,1H),7.60-7.55(m,2H),7.41-7.33(m,2H),2.24(s,3H),1.53-1.51(m,2H),1.19-1.17(m,2H)。
使用水和碱合成3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸(晶型I)。
向在环境温度搅拌的3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸·HCl(1eq)在水(10vol)中的淤浆中加入50%w/w NaOH水溶液(2.5eq)。将该混合物搅拌NLT15min或直到得到均匀溶液。加入浓HCl(4eq)以使晶型I结晶。如果需要,将该混合物加热至60℃或90℃,以降低叔丁基苯甲酸酯的水平。加热该混合物至HPLC分析显示NMT0.8%(AUC)叔丁基苯甲酸酯。然后将该混合物滤器至环境温度,通过过滤收集固体,用水(3x3.4vol)洗涤,在真空下在过滤器上部分干燥。在60℃、在通少许N2的真空烘箱内干燥固体至恒重(<1%差异),得到晶型I,为黄白色固体(97%收率)。
直接由苯甲酸酯合成3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸(晶型I)。
将3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)叔丁基苯甲酸酯(1.0eq)在甲酸(3.0vol)中的溶液加热至70±10℃。将反应持续至反应完成(NMT1.0%AUC3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)-叔丁基苯甲酸酯)或加热至NMT8h。将该混合物冷却至环境温度。将该溶液加入到水(6vol)中,在50℃加热,搅拌该混合物。然后将该混合物加热至70±10℃直到3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)-叔丁基苯甲酸酯的水平是NMT0.8%(AUC)。通过过滤收集固体,用水(2x3vol)洗涤,在真空下在过滤器上部分干燥。在60℃、在通少许N2的真空烘箱内干燥固体至恒重(<1%差异),得到化合物1的晶型I,为黄白色固体。
根据化合物1的晶型I的单晶结构计算的X-射线衍射图案如图1所示。表1举出了计算的图1的峰。
表1.
峰等级(Peak Rank) | 2θ角[度] | 相对强度[%] |
11 | 14.41 | 48.2 |
8 | 14.64 | 58.8 |
1 | 15.23 | 100.0 |
2 | 16.11 | 94.7 |
3 | 17.67 | 81.9 |
7 | 19.32 | 61.3 |
4 | 21.67 | 76.5 |
5 | 23.40 | 68.7 |
9 | 23.99 | 50.8 |
6 | 26.10 | 67.4 |
10 | 28.54 | 50.1 |
化合物1的晶型I的实际X-射线粉末衍射图案如图2所示。表2举出了图2的实际峰。
表2.
峰等级 | 2θ角[度] | 相对强度[%] |
7 | 7.83 | 37.7 |
3 | 14.51 | 74.9 |
4 | 14.78 | 73.5 |
1 | 15.39 | 100.0 |
2 | 16.26 | 75.6 |
6 | 16.62 | 42.6 |
5 | 17.81 | 70.9 |
9 | 21.59 | 36.6 |
10 | 23.32 | 34.8 |
11 | 24.93 | 26.4 |
8 | 25.99 | 36.9 |
化合物1的晶型I的单晶结构计算是X-射线衍射图案和化合物1的晶型I的实际X-射线粉末衍射图案的重叠图如图3所示。这种重叠图显示计算与实际峰位之间的良好一致性,其中差异仅为约0.15度。
化合物1的晶型I的DSC扫迹如图4所示。化合物1的晶型I的熔化在约204℃出现。
基于单晶X-射线分析的化合物1的晶型I的构象照片如图5-8所示。图6-8显示二聚体羧酸基团之间的氢键与得到的晶体中出现的堆积。该晶体结构揭示出分子的紧密堆积。化合物1的晶型I是单斜晶系,P21/n,其具有如下晶胞大小: β=93.938(9)°,Z=4。根据结构数据计算的化合物1的晶型I的密度是在100K1.492g/cm3。
化合物1的1HNMR光谱如图9-11所示(图9和10描述了化合物1的晶型I的50mg/mL、0.5甲基纤维素-聚山梨醇酯80的混悬液,图11描述了化合物1的HCl盐)。
下表3描述了化合物1的其他分析数据。
表3.
试验
用于检测和测定化合物的ΔF508-CFTR纠正(Correction)性质的试验
用于测定化合物的ΔF508-CFTR调节特性的膜电位光学方法
光学膜电位测定法采用如Gonzalez和Tsien所述的电压-敏感性FRET传感器(参见,Gonzalez,J.E.和R.Y.Tsien(1995)“Voltagesensing by fluorescence resonance energy transfer in singlecells”Biophys J69(4):1272-80;和Gonzalez,J.E.和R.Y.Tsien(1997)“Improved indicators of cell membrane potentialthat use fluorescence resonance energy transfer”Chem Biol4(4):269-77)与测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 screeningion-channel targets”Drug Discov Today4(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)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VIPRTM II监测,它是一种整合的液体处理器和荧光检测器,被设计用来在96-或384-孔微量滴定平板中进行基于细胞的筛选。
1.纠正化合物的鉴别
为了鉴别纠正与ΔF508-CFTR相关的运输缺陷的小分子,研发了单一-添加HTS测定方式。在37℃将细胞在有或没有(阴性对照)测试化合物的存在下在不含血清的培养基中孵育16h。作为阳性对照,将在384-孔培养板上铺板的细胞在27℃孵育至“温度-校准”ΔF508-CFTR。然后用3X Krebs林格液冲洗细胞并且加载电压敏感性染料。为了活化ΔF508-CFTR,加入10μM福司柯林和CFTR增强剂染料木黄酮(20μM)与不含Cl-的培养基到各孔中。添加不含Cl-的培养基促进了Cl-流出量作为对ΔF508-CFTR活化的响应,且使用基于FRET的电压敏感器染料以光学方式监测产生的膜去极化。
2.增强剂化合物的鉴别
为了鉴别ΔF508-CFTR增强剂,研发了双重一-添加HTS测定方式。第一次添加过程中,向各孔中添加不含Cl-的培养基与或不与测试化合物。22秒后,第二次添加不含Cl-的包含2-10μM福司柯林的培养基以活化ΔF508-CFTR。两次添加后的胞外Cl-浓度是28mM,这促进了Cl-流出量作为对ΔF508-CFTR活化的响应,且使用基于FRET的电压敏感器染料以光学方式监测产生的膜去极化。
3.溶液
浴溶液#1:(以mM计)NaCl160,KCl4.5,CaCl22,MgCl21,HEPES10,pH7.4与NaOH。
不含氯化物的浴溶液:浴溶液#1中的氯化物盐被葡糖酸盐取代。
CC2-DMPE:制备成10mM的DMSO储备溶液并且贮存在-20℃下。
DiSBAC2(3):制备成10mM的DMSO储备溶液并且贮存在-20℃下。
4.细胞培养
将稳定表达ΔF508-CFTR的NIH3T3小鼠成纤维细胞用于膜电位的光学测定。将细胞维持在37℃、在5%CO2和90%湿度中的在175cm2培养烧瓶中的改进的Eagle培养基中,该培养基补充了2mM谷氨酰胺、10%胎牛血清、1X NEAA、β-ME、1X pen/strep和25mM HEPES。就所有光学测定而言,以30,000/孔将细胞接种在384-孔基质胶包被的培养板上并且在37℃培养2h,然后在27℃培养24h,以用于增强剂测定。就纠正测定而言,将细胞在27℃或37℃与和不与化合物一起培养16-24小时。
用于测定化合物的ΔF508-CFTR调节性质的电生理测定法
1.Using室测定
对表达ΔF508-CFTR的极化上皮细胞进行Using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CostarSnapwell细胞培养插件上的FRTΔF508-CFTR上皮细胞固定在Ussing室内(Physiologic Instruments,Inc.,San Diego,CA),利用电压箝系统(Department of Bioengineering,University of Iowa,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)获取数字方式的ISC。
2.纠正化合物的鉴别
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pH7.4),得到跨越上皮的大幅Cl-浓度梯度。所有实验均是用完整单层进行的。为了充分活化ΔF508-CFTR,施加福司柯林(10μM)和PDE抑制剂IBMX(100μM),继之以加入CFTR增强剂染料木黄酮(50μM)。
正如在其他细胞类型中所观察到的,在低温下孵育稳定表达ΔF508-CFTR的FRT细胞会增加CFTR在质膜中的功能密度。为了测定纠正化合物的活性,将细胞与10μM供试化合物在37℃下孵育24小时,随后洗涤3次,然后记录。将cAMP-和染料木黄酮-介导的化合物-处置细胞ISC正常化为27℃和37℃对照,以活性百分比表示。与37℃对照相比,细胞用纠正化合物预孵育显著增加cAMP-和染料木黄酮-介导的ISC。
3.增强剂化合物的鉴别
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并且用制霉菌素(360μg/ml)可渗透化处理,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。所有实验均在制霉菌素可渗透化处理后30min进行。向细胞培养插入物两侧施加福司柯林(10μM)和测试化合物。将推定的ΔF508-CFTR增强剂功效与已知增强剂染料木黄酮的功效进行比较。
4.溶液
基底外侧溶液(以mM计):NaCl(135)、CaCl2(1.2)、MgCl2(1.2)、K2HPO4(2.4)、KHPO4(0.6)、N-2-羟乙基哌嗪-N'-2-乙磺酸(HEPES)(10)和葡萄糖(10)。用NaOH将该溶液滴定至pH7.4。
顶部溶液(以mM计):与基底外侧溶液相同,但NaCl被葡糖酸Na(135)替代。
5.细胞培养
将表达ΔF508-CFTR(FRTΔF508-CFTR)的Fisher大鼠上皮(FRT)细胞用于从我们的光学测定法鉴别的推定ΔF508-CFTR调节剂的Ussing室实验。在Costar Snapwell细胞培养插入物上培养细胞并且在37℃和5%CO2、在Coon改进的Ham's F-12培养基中培养5天,该培养基补充了5%胎牛血清、100U/ml青霉素和100μg/ml链霉素。在用于表征化合物增强剂活性钳,将细胞在27℃孵育16-48h以校准ΔF508-CFTR。为了测定纠正化合物的活性,将细胞在27℃或37℃与和不与化合物一起孵育24小时。
6.全细胞记录
使用穿孔的膜片全细胞记录监测温度和测试化合物校准的NIH3T3细胞中的宏观ΔF508-CFTR电流(IΔF508)。简言之,在室温用Axopatch200B膜片钳放大器(Axon Instruments Inc.,Foster City,CA)对IΔF508进行电压钳记录。全部记录均在10kHz采样频率下获取并且在1kHz低通过滤。移取管在充满胞内溶液时具有5-6MΩ电阻。在这些记录条件下,在室温计算的Cl-逆转电位(ECl)是-28mV。全部记录均具有>20GΩ的密封电阻和<15MΩ的串联电阻。使用安装了Digidata1320A/D界面与Clampex8(Axon Instruments Inc.)的PC进行脉冲发生、数据采集和分析。浴包含<250μl的盐水并且使用重力驱动的灌注系统以2ml/min的速率连续灌注。
7.纠正化合物的鉴别
为了测定纠正化合物增加质膜中功能性ΔF508-CFTR密度的活性,我们利用上述开孔-碎片-记录技术测量纠正化合物处理24小时后的电流密度。为了充分活化ΔF508-CFTR,向细胞加入10μM福司柯林和20μM染料木黄酮。在我们的记录条件下,在27℃下孵育24小时后的电流密度高于在37℃下孵育24小时后的观测值。这些结果与低温孵育对质膜中ΔF508-CFTR密度的已知影响是一致的。为了测定纠正化合物对CFTR电流密度的影响,将细胞与10μM供试化合物在37℃下孵育24小时,与27℃和37℃对照比较电流密度(活性%)。在记录之前,将细胞用细胞外记录介质洗涤3次,以除去任何剩余的供试化合物。与37℃对照相比,用10μM纠正化合物预孵育显著增加cAMP-和染料木黄酮-依赖性电流。
8.增强剂化合物的鉴别
还用穿孔膜片记录技术研究了ΔF508-CFTR增强剂增加稳定表达ΔF508-CFTR的NIH3T3细胞中宏观ΔF508-CFTR Cl-电流(IΔF508)的能力。从光学测定法中鉴别的增强剂引起与在光学测定法中观察到的类似效力和功效的IΔF508剂量依赖性增加。在所有检验的细胞中,施加增强剂前和过程中的逆转电位为约-30mV,它是计算的ECl(-28mV)。
9.溶液
胞内溶液(以mM计):天冬氨酸Cs(90)、CsCl(50)、MgCl2(1)、HEPES(10)和240μg/ml两性霉素-B(用CsOH将pH调节至7.35)。
胞外溶液(以mM计):N-甲基-D-葡萄糖胺(NMDG)-Cl(150)、MgCl2(2)、CaCl2(2)、HEPES(10)(用HCl将pH调节至7.35)。
10.细胞培养
将稳定表达ΔF508-CFTR的NIH3T3小鼠成纤维细胞用于全细胞记录。将细胞维持在37℃、在5%CO2和90%湿度中的在175cm2培养烧瓶中的改进的Eagle培养基中,该培养基补充了2mM谷氨酰胺、10%胎牛血清、1X NEAA、β-ME、1X pen/strep和25mM HEPES。为了进行全细胞记录,将2,500-5,000个细胞接种在聚-L-赖氨酸-包被的玻璃盖玻片上并且在27℃培养24-48h后用于测试增强剂的活性;且与或不与纠正化合物一起在37℃孵育,以便测定纠正剂的活性。
11.单通道记录
使用切下的膜内侧翻外膜片观察稳定表达NIH3T3细胞中温度校准的ΔF508-CFTR的单通道活性和强化即化合物的活性。简言之,在室温用Axopatch200B膜片钳放大器(Axon Instruments Inc.)对单通道活性进行电压钳记录。全部记录均在10kHz采样频率下获取并且在400Hz低通过滤。膜片移取管由Corning Kovar Sealing#7052玻璃制成(World Precision Instruments,Inc.,Sarasota,FL)并且在充满胞外溶液时具有5-8MΩ电阻。在切下后通过添加1mM Mg-ATP和75nM cAMP-依赖性蛋白激酶催化亚单位(PKA;Promega Corp.Madison,WI)活化ΔF508-CFTR。在通道活性稳定后,使用重力驱动的微量灌注系统灌注膜片。使流入量接近膜片,导致在1-2sec内完全交换溶液。为了维持快速灌注过程中的ΔF508-CFTR活性,将非特异性磷酸酶抑制剂F-(10mM NaF)加入到浴溶液中。在这些记录条件下,通道活性在整个膜片记录期间保持恒定(至多60min)。从胞内溶液运动至胞外溶液(阴离子以相反方向运动)的正电荷产生的电流显示为正电流。将移取管电位(Vp)维持在80mV。
分析来自包含≤2活性通道的膜片中通道活性。同时开放的最大值确定了实验过程中活性通道的数量。为了测定单通道电离振幅,在100Hz“离线”过滤从120secΔF508-CFTR活性记录的数据,然后用于构建所有点的振幅直方图,使用Bio-Patch Analysis软件(Bio-LogicComp.France)与多高斯函数拟合。根据120sec的通道活性确定总微型电流和开放概率(Po)。使用Bio-Patch软件或根据相关性Po=I/i(N)测定Po,其中I=平均电流,i=单通道电流振幅,且N=膜片中活性通道的数量。
12.溶液
胞外溶液(以mM计):NMDG(150)、天冬氨酸(150)、CaCl2(5)、MgCl2(2)和HEPES(10)(用Tris碱将pH调节至7.35)。
胞内溶液(以mM计):NMDG-Cl(150)、MgCl2(2)、EGTA(5)、TES(10)和Tris碱(14)(用HCl将pH调节至7.35)。
13.细胞培养
将稳定表达ΔF508-CFTR的NIH3T3小鼠成纤维细胞用于切下膜的膜片钳记录。将细胞维持在37℃、在5%CO2和90%湿度中的在175cm2培养烧瓶中的改进的Eagle培养基中,该培养基补充了2mM谷氨酰胺、10%胎牛血清、1X NEAA、β-ME、1X pen/strep和25mM HEPES。为了进行单通道记录,将2,500-5,000个细胞接种在聚-L-赖氨酸-包被的玻璃盖玻片上并且在27℃培养24-48h后使用。
使用上述方法测定了化合物1的活性即EC50并且如表4所示。
表4.
Claims (32)
1.3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸,其特征为晶型I。
2.权利要求1的晶型I,其中晶型I的特征在于在使用Cu Kα射线得到的X-射线粉末衍射中在15.2-15.6度、16.1-16.5度和14.3-14.7度的一个或多个峰。
3.权利要求2的晶型I,其中晶型I的特征在于在15.4、16.3和14.5度的一个或多个峰。
4.权利要求2的晶型I,其中晶型I的特征还在于在14.6-15.0度的峰。
5.权利要求4的晶型I,其中晶型I的特征还在于在14.8度的峰。
6.权利要求4的晶型I,其中晶型I的特征还在于在17.6-18.0度的峰。
7.权利要求6的晶型I,其中晶型I的特征还在于在17.8度的峰。
8.权利要求6的晶型I,其中晶型I的特征还在于在16.4-16.8度的峰。
9.权利要求8的晶型I,其中晶型I的特征还在于在16.4-16.8度的峰。
10.权利要求9的晶型I,其中晶型I的特征还在于在16.6度的峰。
11.权利要求9的晶型I,其中晶型I的特征还在于在7.6-8.0度的峰。
12.权利要求11的晶型I,其中晶型I的特征还在于在7.8度的峰。
13.权利要求11的晶型I,其中晶型I的特征还在于在25.8-26.2度的峰。
14.权利要求13的晶型I,其中晶型I的特征还在于在26.0度的峰。
15.权利要求13的晶型I,其中晶型I的特征还在于在21.4-21.8度的峰。
16.权利要求15的晶型I,其中晶型I的特征还在于在21.6度的峰。
17.权利要求15的晶型I,其中晶型I的特征还在于在23.1-23.5度的峰。
18.权利要求17的晶型I,其中晶型I的特征还在于在23.3度的峰。
19.权利要求1的晶型I,其中晶型I的特征在于基本上与图1的衍射图案类似的衍射图案。
20.权利要求1的晶型I,其中晶型I的特征在于基本上与图2的衍射图案类似的衍射图案.
21.权利要求1的晶型I,其中D90的粒度分布为约82μm或更小。
22.权利要求1的晶型I,其中D50的粒度分布为约30μm或更小。
23.药物组合物,包含权利要求1的晶型I和药学上可接受的载体。
24.治疗哺乳动物囊性纤维化的方法,该方法包括对哺乳动物给予有效量的权利要求1的晶型I。
25.权利要求24的方法,其中该方法包括给予另一种治疗剂。
26.试剂盒,该试剂盒包含权利要求1的晶型I及其使用说明书。
27.权利要求1的晶型I的制备方法,该方法包括将3-(6-(1-(2,2-二氟苯并[d][1,3]间二氧杂环戊烯-5-基)环丙烷甲酰氨基)-3-甲基吡啶-2-基)苯甲酸的HCl盐混悬于或溶于适合溶剂有效量的时间。
28.权利要求27的方法,其中适合溶剂是水或50%甲醇/水混合物。
29.权利要求27的方法,其中适合溶剂是水。
30.权利要求27的方法,其中有效量的时间是2-24小时。
31.权利要求27的方法,其中有效量的时间是2-6小时。
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