CN108135897B - 稠合的苯甲酰胺 - Google Patents
稠合的苯甲酰胺 Download PDFInfo
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- CN108135897B CN108135897B CN201580083607.3A CN201580083607A CN108135897B CN 108135897 B CN108135897 B CN 108135897B CN 201580083607 A CN201580083607 A CN 201580083607A CN 108135897 B CN108135897 B CN 108135897B
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Abstract
本发明涉及式(I)的化合物,其中,R1、R2和Z‑具有说明书所述的一种含义,或其可药用盐,还涉及式(I)的化合物作为药物的用途、含有至少一种式(I)的化合物的药物组合物以及含有一或多种式(I)的化合物的药物组合。
Description
本发明的领域
本发明涉及式(I)的化合物,
其中,R1、R2和Z-具有说明书所述的一种含义,或其可药用盐,还涉及式(I)的化合物作为药物的用途、含有至少一种式(I)的化合物的药物组合物以及含有一或多种式(I)的化合物的药物组合。
发明背景
WO2011079087、WO2015007516、WO2015007519和WO2015007517公开了显示出ENaC(上皮钠通道)抑制剂活性的相关结构的3,5-二氨基-6-卤代-吡嗪-2-甲酸的酰胺。
Venanzi认为,阿米洛利和其类似物的吡嗪部分上的5位氨基,对于与ENaC的阻断复合体的稳定性是必不可少的(Venanzi等人,Journal of Medicinal Chemistry,1992,Vol.35(9),1643-1649)。
本发明的问题是,提供用于治疗能够通过阻断上皮钠通道来治疗的病理生理学过程的其它治疗化合物,尤其用于肺和呼吸道的治疗。
这种化合物应该是ENaC的有效抑制剂。Ussing室试验所测定的合适的IC50值典型地低于30nM。
另外,这种化合物应该显示出低渗透性,这对于局部的肺治疗有利。CALU-3细胞试验所测定的合适的渗透率值典型地低于6x 10-7cm/s。
另外,这种化合物在水介质中应该具有高溶解度,这有利于通过吸入液剂的方式给药。在具有生理学可接受的pH值的缓冲剂水溶液中的合适的溶解度数值是2%或更高。
另外,这种化合物在水介质中应该具有高水解稳定性,这有利于通过吸入液剂的方式给药。
另外,局部给予肺部后,这种化合物应该体内抑制水的再吸收。局部给予肺部药理学活性剂量的本发明化合物,不应该提高血浆醛固酮水平,或仅仅低程度地提高血浆醛固酮水平。
意外地发现,所主张的、在吡嗪部分的5位没有氨基的3-氨基-6-氯-吡嗪-2-甲酸衍生物是有效的ENaC抑制剂,并且进一步具有上面列出的其它特征。
本发明的详细说明
本发明涉及式(I)的化合物,
其中
R1和R2独立地选自氢和C1-C6-烷基,其中,所述C1-C6-烷基可以携带1至5个选自羟基、氨基、C1-C4-烷基氨基、二-C1-C4-烷基氨基、吗啉-4-基和二甲基膦酰基甲氧基的取代基,条件是,R1和R2中的至少一个不是氢、未取代的C1-C6-烷基和携带1个羟基取代基的C1-C6-烷基;或
R1和R2与它们相连接的氮原子一起形成选自哌啶、哌嗪和1,4-二氮杂环庚烷的杂环部分,其中,所述杂环部分可以携带1或2个选自C1-C4-烷基、二甲基膦酰基-C1-C4-烷基和NRaRb的取代基,其中,Ra和Rb独立地选自氢、C1-C4-烷基和-C(O)CH2NRcRd,其中,Rc和Rd独立地选自氢和C1-C4-烷基;
Z-选自氯离子、溴离子、碘离子、氢氧根、硫酸氢根、硫酸根、硝酸根、磷酸根、甲酸根、乙酸根、三氟乙酸根、富马酸根、柠檬酸根、酒石酸根、草酸根、琥珀酸根、扁桃酸根、甲磺酸根和对甲苯磺酸根;
或其可药用盐。
本文所定义的式(I)化合物或其可药用盐尤其适合于治疗能够通过阻断上皮钠通道治疗的病理生理学过程,尤其用于肺和呼吸道的治疗。
相应地,本发明进一步涉及用作药物的本文所定义的式(I)化合物或其可药用盐。
本发明进一步涉及本文所定义的式(I)化合物或其可药用盐,用于治疗选自下列的疾病:呼吸***疾病或障碍和呼吸道的***反应性疾病。
本发明进一步本文所定义的式(I)化合物或其可药用盐,用于治疗选自下列的疾病:慢性支气管炎(chronic bronchitis)、急性支气管炎(acute bronchitis)、细菌或病毒感染或真菌或蠕虫所引起的支气管炎(bronchitis caused by bacterial or viralinfection or fungi or helminths)、过敏性支气管炎(allergic bronchitis)、毒性支气管炎(toxic bronchitis)、慢性阻塞性支气管炎(chronic obstructive bronchitis)(COPD)、哮喘(固有的或过敏性的)(asthma(intrinsic or allergic))、儿童哮喘(pediatric asthma)、支气管扩张症(bronchiectasis)、过敏性的肺泡炎(allergicalveolitis)、过敏性或非过敏性鼻炎(allergic or non-allergic rhinitis)、慢性窦炎(chronic sinusitis)、囊性纤维化或囊肿性纤维化(cystic fibrosis ormucoviscidosis)、α1抗胰蛋白酶缺乏(alpha-1-antitrypsin deficiency)、咳嗽(cough)、肺气肿(pulmonary emphysema)、间质性肺疾病(interstitial lung diseases)、肺泡炎(alveolitis)、呼吸道反应过度(hyperreactive airways)、鼻息肉(nasal polyps)、肺水肿(pulmonary oedema)、各种原因的肺炎(pneumonitis of different origins)和干眼(dry eyes)。
本发明进一步涉及含有至少一种本文所定义的式(I)化合物或其可药用盐以及可药用载体的药物组合物。
本发明进一步涉及药物组合,除了一或多种本文所定义的式(I)化合物或其可药用盐之外,作为其它活性物质,所述药物组合还含有一或多种选自下列类型的化合物:其它ENaC抑制剂、β模拟剂、抗胆碱能药、皮质类甾醇、PDE4抑制剂、LTD4拮抗剂、EGFR抑制剂、多巴胺激动剂、H1抗组胺剂、PAF拮抗剂、MAP激酶抑制剂、MPR4抑制剂、iNOS抑制剂、SYK抑制剂、校正囊性纤维化横跨膜的调节剂(CFTR)和CFTR增效剂或其两种或三种的药物组合。
术语和定义
本文没有具体定义的术语应该给出了本领域技术人员根据公开内容和背景所能够给出的含义。然而,除非具体说明相反的意思,否则本说明书使用的下列术语具有指定含义,并且给出下列惯例∶
在下面定义的基团、原子团或部分中,通常在基团前面列出碳原子数目,例如,C1-6-烷基是指具有1至6个碳原子的烷基基团或原子团。
通常,在单个基团中,所述基团例如,HO、H2N、OS、O2S、NC(氰基)、HOOC、F3C,等等,技术人员可以从所述基团本身的自由价了解原子团与分子的连接点。对于包含两个或多个子基团的组合基团,末端的词条表明原子团连接点,例如,取代基“芳基-C1-3-烷基”是指与C1-3-烷基-基团键合的芳基,后面的基团与该取代基连接的核或基团键合。
如果用化学名称和化学式描述本发明的化合物,在存在任何差异的情况下,以化学式为准。
在化学式或基团的定义中,许多下列术语可以反复地使用,并且在每种情况下,彼此独立地具有一种上面给出的含义。
除非具体表明,否则,按照本发明,给出的化学式或名称应包括互变异构体和所有的立体、旋光和几何异构体(例如,对映异构体、非对映异构体、E/Z异构体,等等)和其外消旋体,以及单独的对映异构体的不同比例的混合物、非对映异构体的混合物或任何上述形式的混合物(在存在这种异构体和对映异构体的情况下),以及盐,包括其可药用盐,其溶剂化物,例如,水合物,包括游离化合物的溶剂化物或所述化合物的盐的溶剂化物。
本文使用的术语“取代的”是指在指定原子上的任何一个或多个氢被选自指定的基团取代,条件是:不超过所指定原子的正常化合价,并且这种取代能够得到稳定化合物。
应该理解,本文使用的表述“防止”、“预防”、“预防性治疗”或预防性处理”的意义相同,从此意义来说,形成上述病症的风险降低,特别是具有所述病症或相应病史的高风险,例如形成代谢病(例如,糖尿病或肥胖症)或其它本文提到的病症的高风险的患者中。由此,本文使用的表述“预防疾病”是指在临床发病之前管理和护理处于发展疾病的危险之中的个体。预防的目的是抵御疾病、症状或病症的发展,并且包括给予活性化合物,从而防止或延迟症状或并发症的发作,防止或延迟相关疾病、病症或失调的发展。与没有进行预防性治疗的同等患者人群相比,通过所述病症在处于这种病症危险之中的患者人群的发病率的降低,统计上反映所述预防性治疗的成功。
表述“处理”或“治疗”是指对于已经发展成急性或慢性形式的一或多种所述病症的患者进行治疗,包括:为了减轻具体适应症的症状进行对症疗法,或为了逆转或部分逆转所述病症或延迟适应症的发展,进行病因治疗,只要这些治疗是可行的,这取决于所述病症和其严重程度。由此,本文使用的表述“治疗疾病”是指管理和护理已经发展成疾病、病症或失调的患者。治疗的目的是抵御疾病、病症或失调。治疗包括:给予活性化合物,消除或控制疾病、病症或失调,以及减轻与所述疾病、病症或失调相关的症状或并发症。
本文使用的术语“可药用”是指:在可靠的医学判断范围内,那些化合物、原料、组合物和/或剂型适合与人类和动物的组织接触,没有过度的毒性、刺激性、***反应或其它问题或并发症,与合理的收益/风险比相称。
本文使用的“可药用盐”指的是所公开的化合物的衍生物,其中,通过制备其酸式或碱式盐来修饰母体化合物。可药用盐的例子包括但不局限于:碱性残基(例如,胺)的无机或有机酸盐;酸性残基(例如,羧酸)的碱金属或有机盐;等等。例如,这种盐包括得自于下列的盐:氨、L-精氨酸、甜菜碱、苯乙苄胺、苄星青霉素(benzathine)、氢氧化钙、胆碱、丹醇、二乙醇胺(2,2'-亚氨基二(乙醇))、二乙胺、2-(二乙基氨基)-乙醇、乙醇胺、乙二胺、N-乙基-葡糖胺、哈胺(hydrabamine)、1H-咪唑、赖氨酸、氢氧化镁、4-(2-羟乙基)-吗啉、哌嗪、氢氧化钾、1-(2-羟乙基)-吡咯烷、氢氧化钠、三乙醇胺(2,2',2”-次氮基三(乙醇))、氨丁三醇、氢氧化锌、乙酸、2.2-二氯-乙酸、己二酸、褐藻酸、抗环血酸、L-门冬氨酸、苯磺酸、苯甲酸、2,5-二羟基苯甲酸、4-乙酰氨基-苯甲酸、(+)-樟脑酸、(+)-樟脑-10-磺酸、碳酸、肉桂酸、柠檬酸、环拉酸、癸酸、十二烷基硫酸、乙-1,2-二磺酸、乙磺酸、2-羟基-乙磺酸、乙二胺四乙酸、甲酸、富马酸、粘酸、龙胆酸、D-葡庚糖酸、D-葡糖酸、D-葡糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、甘氨酸、羟基乙酸、己酸、N-苯甲酰甘氨酸、氢溴酸、盐酸、异丁酸、DL-乳酸、乳糖酸、月桂酸、赖氨酸、马来酸、(-)-L-苹果酸、丙二酸、DL-扁桃酸、甲磺酸、粘酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、硝酸、辛酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸(扑酸)、磷酸、丙酸、(-)-L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、鞣酸、(+)-L-酒石酸、硫氰酸、对甲苯磺酸和十一碳烯酸。其它可药用盐可以与金属阳离子形成,例如,铝、钙、锂、镁、钾、钠、锌,等等(也参见Pharmaceutical salts,Berge,S.M.等人,J.Pharm.Sci.,(1977),66,1-19)。
本发明的可药用盐,可以通过常规的化学方法,由含有阳离子基团和任选其它碱性或酸性部分的母体化合物合成。通常,这种盐可以通过这些化合物的其它盐形式在水或有机稀释剂(例如,醚、乙酸乙酯、乙醇、异丙醇或乙腈,或其混合物)中与足够量的合适的碱或酸进行反应来制备。此外,反离子通常可以通过离子交换色谱来互换。
除了上述那些酸的其它酸的盐,例如,用于纯化或分离本发明的化合物的盐(例如,三氟乙酸盐),也构成本发明的一部分。
术语“C1-n-烷基”(其中,n是1至n的整数,单独或与其它原子团组合),表示具有1至n个C原子的非环状的饱和支链或直链烃原子团。例如,本文使用的术语C1-4-烷基,包括下列原子团:H3C-、H3C-CH2-、H3C-CH2-CH2-、H3C-CH(CH3)-、H3C-CH2-CH2-CH2-、H3C-CH2-CH(CH3)-、H3C-CH(CH3)-CH2-和H3C-C(CH3)2-。
在结构和它们的名称之间存在矛盾的所有情况下,以结构为准。
优选实施方案
本发明的一个具体实施方案涉及按照权利要求1的化合物,或其可药用盐,其中,R1和R2独立地选自氢、甲基、异丁基、2-氨基乙基、3-氨基丙基、2-(甲基氨基)乙基、2-(二甲基氨基)乙基、3-(甲基氨基)丙基、3-(二甲基氨基)丙基、2-(吗啉-4-基)乙基、2-(二甲基膦酰基甲氧基)乙基和2,3,4,5,6-五羟基己-1-基。
本发明的另一个具体实施方案涉及式(I)的化合物或其可药用盐,其中,R1和R2与它们相连接的氮原子一起形成选自下列的部分:
本发明的另一个具体实施方案涉及式(I)的化合物或其可药用盐,其中,R1和R2中的至少一个选自C1-C6-烷基,其中,C1-C6-烷基带有1或2个选自氨基、C1-C4-烷基氨基、二-C1-C4-烷基氨基和吗啉-4-基的取代基。
本发明的另一个具体实施方案涉及式(I)的化合物或其可药用盐,其中,R1和R2与它们相连接的氮原子一起形成选自哌啶、哌嗪和1,4-二氮杂环庚烷的杂环部分,其中,哌啶带有1或2个选自NRaRb的取代基,其中,Ra和Rb独立地选自氢、C1-C4-烷基和-C(O)CH2NRcRd,其中,Rc和Rd独立地选自氢和C1-C4-烷基,其中,哌嗪或1,4-二氮杂环庚烷带有1或2个选自C1-C4-烷基、二甲基膦酰基-C1-C4-烷基的取代基。
本发明的另一个具体实施方案涉及式(I)的化合物或其可药用盐,其中,R1和R2中的至少一个是C1-C6-烷基,其中,C1-C6-烷基携带有1或2个选自二-C1-C4-烷基氨基和吗啉-4-基的取代基。
本发明的另一个具体实施方案涉及式(I)的化合物或其可药用盐,其中,R1和R2与它们相连接的氮原子一起形成选自哌啶、哌嗪和1,4-二氮杂环庚烷的杂环部分,其中,哌啶携带有1或2个选自NRaRb的取代基,其中,Ra和Rb独立地选自C1-C4-烷基和-C(O)CH2NRcRd,其中,Rc和Rd独立地选自C1-C4-烷基,其中,哌嗪或1,4-二氮杂环庚烷携带有氮键合的选自C1-C4-烷基和二甲基膦酰基-C1-C4-烷基的取代基。
本发明的另一个具体实施方案涉及式(I)的化合物或其可药用盐,其中,R1和R2中的至少一个选自C2-C6-烷基,其中,C2-C6-烷基携带有二甲基膦酰基甲氧基取代基。
本发明的另一个具体实施方案涉及式(I)的化合物或其可药用盐,其中,R1和R2与它们相连接的氮原子一起形成选自哌啶、哌嗪和1,4-二氮杂环庚烷的杂环部分,其中,所述杂环部分携带有二甲基膦酰基-C1-C4-烷基取代基。
本发明的另一个具体实施方案涉及式(I)的化合物或其可药用盐,其中,Z-选自氯离子和三氟乙酸根。
本发明的另一个具体实施方案涉及式(I)的化合物或其可药用盐,选自
本发明的另一个具体实施方案涉及式(I)的化合物,其特征在于:拓扑极性表面积值(TPSA)至少为150。本文使用的术语“拓扑极性表面积”是指,基于PSA的片段所公开的计算值,如Ertl P.等人,J.Med.Chem,43(2000),3714-3717所公开。合适的式(I)的化合物的TPSA值通常在150至250范围内。这种化合物尤其为选自如下的化合物:
上面定义的任何取代基可以彼此组合,形成上面没有具体举例说明的其它化合物。尤其优选的是式(I)的化合物或其可药用盐,其中,至少2、3或4个本文定义的取代基具有一个本文所定义的具体或优选的含义。
制备
下列方法适合于制备通式(I)的化合物。
使用本领域技术人员已知的以及有机合成文献所描述的合成方法,可以获得按照本发明的化合物。官能团保护和脱保护步骤的一般方法描述在下列文献中∶例如,Greene,T.W.and Wuts,P.G.M.(eds.):Protective Groups in Organic Synthesis,thirdedition 1999;John Wiley and Sons,Inc。优选地,类似于下文更详细解释的制备方法,尤其是实验部分中描述的制备方法,获得所述化合物。
利用标准酰胺化方法,例如,使用偶合试剂HATU,由酸中间体(IV.1)(下文描述其合成方法)和通式(II)的胺,可以制备通式(I)的化合物。本领域技术人员很清楚,根据合成和纯化的条件,(IV.1)和(I)中的反离子Z-可以不同。此外,可选地,可以使用化合物(IV.1)的两性离子形式(即,羧酸酯基团去质子化,并且没有反离子Z-)。
使用本领域技术人员已知的和有机合成文献所描述的合成方法,可以制备胺(II)。胺(II)的取代基R1和R2的范围可以超出通式(I)化合物所要求的范围。在酰胺化步骤中,化合物(II)中的R1和R2可以例如携带必要或有利的保护基。在随后的合成步骤中,例如,脱保护和/或酰胺化反应,可以改变R1和R2。
上文所定义的式(I)的化合物是包含阴离子Z-的盐。这些阴离子Z-可以衍生自合成或纯化过程,或通过本领域技术人员已知的方法,从一种阴离子物种改变为另一种合适的阴离子物种。这种方法的例子是使用例如离子交换树脂进行离子交换,或使用另一种酸(通常是强酸),将它的盐用酸反离子替代。例如,在Z-是CF3COO-的情况下,在合适的溶剂(例如,水、甲醇或***)中,用HCl处理上文所定义的式(I)化合物,可以制备上文所定义的式1的化合物,其中,Z-是Cl-。
某些上文所定义的式(I)化合物,可以包含能够进一步转变为其盐的基团,对于药物应用来说,尤其与无机或有机酸和碱一起转变为可药用盐。可以用于该目的的酸包括,例如,盐酸、氢溴酸、硫酸、甲磺酸、磷酸、富马酸、琥珀酸、乳酸、柠檬酸、酒石酸或马来酸。技术人员了解相应的方法。
此外,在可存在一或多种立体异构体的情况下,可以获得通式(I)化合物或合成通式(I)化合物过程中的中间体的混合物,而后拆分为它们的立体异构体,例如,对映异构体和/或非对映异构体。由此,例如,可以将顺式/反式混合物拆分为它们的顺反异构体,可以将外消旋化合物分离成它们的对映异构体。
由此,例如,可以利用色谱,将顺式/反式混合物拆分为顺反异构体。以外消旋体形式出现的通式(I)的化合物或合成通式(I)化合物过程中的中间体,其可以利用本来已知的方法(参见Allinger N.L.and Eliel E.L.,“Topics in Stereochemistry”,Vol.6,WileyInterscience,1971),分离为它们的旋光对映体,并且具有至少2个不对称碳原子的通式(I)化合物或合成通式(I)化合物过程中的中间体,可以基于它们的物理-化学差异,使用本来已知的方法,例如,色谱和/或分步结晶,拆分为它们的非对映异构体,如果获得外消旋形式的这些化合物,则随后可以将它们拆分为如上所述的对映异构体。
优选地,如下拆分外消旋体:利用在手性相上进行柱色谱,或利用旋光性的溶剂结晶,或使光学活性物质与外消旋化合物反应,形成盐或衍生物例如酯或酰胺。对于碱性化合物来说,可以与对映体纯的酸形成盐,对于酸性化合物来说,可以与对映体纯的碱形成盐。与对映体纯的辅助化合物,例如,酸、它们的活化衍生物或醇,形成非对映的衍生物。利用它们的不同的理化性质,例如,溶解度差异,可以将由此获得的盐或衍生物的非对映混合物分离;在合适的试剂的作用下,可以从纯的非对映的盐或衍生物中释放出游离对映体。这种目的通常使用的旋光性的酸是,例如,D和L型酒石酸、二苯甲酰基酒石酸、二甲苯酰基酒石酸、苹果酸、扁桃酸、樟脑磺酸、谷氨酸、门冬氨酸或奎尼酸。适合作为辅助残基的旋光性的醇可以是,例如,(+)或(-)-薄荷醇,酰胺中的旋光性的酰基可以是,例如,(+)-或(-)-甲氧羰基。
利用本来已知的方式分离和纯化按照本发明的物质,例如,减压蒸出溶剂,利用合适的溶剂将残余物重结晶,或进行一种常规纯化方法,例如,柱色谱(在合适的载体物质上)。
有利地,使用下面实施例所描述的方法,获得按照本发明的化合物,为此目的,也可以将这些方法与技术人员通过他们的专业知识所了解的方法组合。同样,下面实施例没有明确描述制备方法的按照本发明的其它化合物,可以按照近似或类似于所述实施例的方法来制备。
实施例
下列实施例举例说明本发明,不限制本发明的范围。
通过下列更详细的实施例,本发明的其它特征和优点变得更明显,其举例说明本发明的原理。
在没有列举化合物的盐形式的情况下,根据化学结构、合成条件和所使用的后处理和纯化方法,化合物可以以游离碱或盐或两性离子形态存在。技术人员可以理解,所述化合物不局限于某些盐形式。在列举化合物的盐形式的情况下,通常省略反离子的化学计量。在多电荷反离子的情况下,技术人员可以理解,所得到的盐形式是不带电荷的,得出相应的化学计量。技术人员可以理解,所述化合物不局限于单盐形式,还可以是以二盐、三盐的形式、或其它化合物∶反离子的化学计量形式存在。此外,技术人员可以理解,根据使用的合成条件以及后处理和纯化方法,这种化合物还可以预料不到地作为与各种反离子形成的盐形式存在。仅仅为了进行收率测定,要对反离子和化合物∶反离子化学计量的性质进行评估(如所给出的化学式所表明的那样)。
合成中间体
按照表中给出的文献所描述的方法,可以制备下列中间体I∶
中间体II.1
将中间体I.1(6.00g;19.6mmol)、中间体I.2(6.46g;19.6mmol)和DMF(20mL)的混合物在室温下搅拌过夜。蒸发该混合物,将残余物溶于DCM中,并用盐水提取。干燥(Na2SO4)有机层,并蒸发。将得到的固体与***一起研磨,过滤,并干燥。
中间体III.1
向中间体II.1(7.57g;16.7mmol)和ACN(70mL)的混合物中分批次加入碘乙烷(66.7mL;835mmol)。将该混合物加热至90℃过夜,然后蒸干。将残余物悬浮在甲苯中,并再次蒸发至干。
中间体IV.1
将中间体III.1(6.00g;10.0mmol)和盐酸(4M,在二噁烷中;75mL;300mmol)的混合物在90℃下搅拌过夜,然后蒸干。将残余物悬浮在甲苯中,并再次蒸发至干。
中间体V.1
步骤1∶
向酸中间体IV.1(100mg;0.455mmol)、胺4-叔丁氧羰基氨基-哌啶(110mg;0.549mmol)、三乙胺(170μl;1.23mmol)和DMF(4.0mL)的混合物中加入HATU(215mg;0.565mmol)。将该混合物在室温下搅拌2小时,然后蒸发。用RP-HPLC(C18;水-ACN-TFA)纯化残余物。
步骤2∶
在室温下,将步骤1获得的中间体在DCM/TFA(3:1)中搅拌1小时,然后蒸发。
步骤3∶
将步骤2获得的中间体吸收在甲醇化的HCl中,并蒸干。
C23H30ClN8O2 x HCl x Cl ESI质谱∶m/z=485[M]+
HPLC分析∶RT=0.51min(HPLC方法A)
合成实施例
按照合成中间体V.1所描述的方法,由相应的酸和指定的胺,制备下列实施例化合物。根据所使用的条件,可以意想不到地合成得到其它化学计量的反离子或其它盐形式。
(a)用RP-HPLC(水-ACN-甲酸铵)纯化
分析方法和制备色谱
通常,已经获得所制备化合物的1H-NMR和质谱。给出的质量峰(例如,(M)+、(M+H)+、(M+HCOO)-)指的是单一同位素的分子量。
制备HPLC∶
固定相(除非另有说明)∶XBridge C18,10μm;或SunFire C18,10μm(两者都得自于Waters,www.waters.com)
分析HPLC/MS方法
在下列参数下测定所给的HPLC保留时间。
HPLC方法A
HPLC方法B
HPLC方法C
柱∶Atlantis dC18 5μm 4,6x 50mm,温度:35℃
流动相∶A=H2O 90%+10%CH3CN+CF3COOH 0,05%
B=CH3CN 90%+10%H2O
HPLC方法D
HPLC方法E
HPLC方法F
上文和下文使用下列缩写∶
ACN 乙腈
Aq. 水溶液
BOC 叔丁氧羰基
Cbz 苄氧羰基
CH 环己烷
DCM 二氯甲烷
DIPEA 二异丙基-乙胺
DMAP 4-二甲基氨基吡啶
DMF N,N-二甲基甲酰胺
DPPF 1,1'-双(二苯基膦基)二茂铁
EDC 1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐
EE 乙酸乙酯
Eq. 摩尔当量
ESI 电喷射离子化
h 小时
HATU O-(7-氮杂苯并***-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸盐
HCl 盐酸
KOH 氢氧化钾
l 升
LiHMDS 二(三甲基甲硅烷基)酰胺锂
M mol/l
Min 分钟
Mp 熔点
NaOH 氢氧化钠
n.d. 没有测定
NMP N-甲基吡咯烷酮
Pd/C 钯/炭
r.t. 环境温度(大约20℃)
RT 保留时间
TBME 甲基叔丁基醚
TBTU 2-(1H-苯并***-1-基)-1,1,3,3-四甲基脲鎓-四氟硼酸盐
TEA 三乙胺
TFA 三氟乙酸
THF 四氢呋喃
TLC 薄层色谱
TMS 三甲基甲硅烷基
药理学试验方法
利用Ussing室试验,测定上面给出的实施例化合物的IC50值。
Ussing室∶在聚酯transwell过滤器上,在包含5%FCS和5μM***的DMEM中,培养小鼠肾脏M-1细胞10至12天。将过滤器***到适合于Ussing室***的特氟隆涂渍的多孔板中。在测定之前,用Caco-2转移缓冲液(Invitrogen,Germany)代替M-1细胞的培养基。在测定期间,使Ussing室温度保持在37℃。利用电压钳模式,使用数据收集和分析的软件包Lab View,测定短路电流(I_sc)。每5秒钟施加±5mV的阶跃电压(voltage steps),测定跨膜电阻(TEER)。将化合物给予到顶部的溶液中,最后浓度为3μM,或浓度递增(1-3-10μM)。每个实验结束时,将3μM阿米洛利加入到顶部的室中,测定阿米洛利敏感的I_SC。用阿米洛利效果的抑制百分数来表示结果,或用IC50值表示。
对于上面给出的实施例化合物,利用Ussing室试验,测定下列IC50值∶
实施例 | 1.01 | 1.02 | 1.03 | 1.04 | 1.05 | 1.06 | 1.07 | 1.08 | 1.09 | 1.10 | 1.11 |
IC<sub>50</sub>[nM] | 7 | 4 | 7 | 3 | 8 | 4 | 5 | 6 | 6 | 4 | 5 |
实施例 | 1.12 | 1.13 | 1.14 | 1.15 | 1.16 | 1.17 | 1.18 | 1.19 | 1.20 | 1.21 | 1.22 |
IC<sub>50</sub>[nM] | 4 | 7 | 4 | 6 | 12 | 7 | 5 | 4 | 6 | 5 | 13 |
在CALU-3细胞中的渗透性∶
穿过极化的融合的CALU-3细胞单层(在渗透性的滤网支撑器上生长)的渗透性,用于提供有关化合物通过肺上皮的潜力的信息。按照顶端至基底端(AB)和基底端至顶端(BA)的转移方向,测定化合物穿过CALU-3细胞单层的表观渗透系数(Papp)(pH 7.4,37℃)。AB渗透性(Papp,AB)代表药物从肺腔吸收到血液中,BA渗透性(Papp,BA)代表药物主要通过被动渗透从血液转运到肺腔中,这是由于Calu-3细胞以及肺上皮细胞不表达外排转运体,例如,P-gp,同时可以表达吸收转运体。
将CALU-3细胞(1-2x 105个细胞/1cm2面积)播种在滤器芯子(Costar transwell聚碳酸酯过滤器,0.4μm孔径)上,并进行培养(10-12天,DMEM),直到形成紧密的单层为止。将目标化合物溶于合适的溶剂(DMSO,10mM储备溶液)中。用HTP-4缓冲液(128.13mM NaCl,5.36mM KCl,1mM MgSO4,1.8mM CaCl2,4.17mM NaHCO3,1.19mM Na2HPO4 x 7H2O,0.41mMNaH2PO4xH2O,15mM HEPES,20mM葡萄糖,0.25%BSA,pH7.4)稀释储备溶液,制备转移溶液(10μM化合物,最终DMSO<=0.5%)。将转移溶液(TL)施加到顶端或基底外侧供体侧,分别测定A-B或B-A渗透性(3个过滤器平行测定)。接受侧包含与供体侧相同的缓冲液。适应30分钟之后,在实验起始t0=0分钟和实验结束tn=90分钟,从供体收集样品,并且在0、30、60和90分钟,也从接受室收集样品。用HTP-4缓冲液补充所除去的体积。利用HPLC-MS/MS或闪烁计数,测定样品中的化合物浓度。按照Papp[cm/s]=(接受浓度[nM]*接受体积[mL]/时间间隔[秒])*(1/过滤器面积)*(1/供体浓度[nM]),计算渗透系数(Papp)和排出率。
对于上面给出的实施例化合物,利用CALU-3细胞试验,测定下列渗透率值∶
适应症
正如所发现的那样,式(I)的化合物的特征在于:它们广泛应用于治疗领域。基于按照本发明的式(I)化合物作为ENaC抑制剂的药物效果,特别提及更适合它们的那些应用。实例包括:呼吸***疾病或障碍、呼吸道的***反应性疾病或干眼。
特别提及预防和治疗伴随有呼吸道的粘液多、炎症和/或阻塞疾病的呼吸道和肺疾病。实例包括:急性、过敏性或慢性支气管炎、慢性阻塞性支气管炎(COPD)、咳嗽、肺气肿、过敏性或非过敏性鼻炎或窦炎、慢性鼻炎或窦炎、哮喘、肺泡炎、农夫病、呼吸道反应过度、传染性支气管炎或肺炎、儿童哮喘、支气管扩张、肺纤维化、ARDS(急性成人呼吸窘迫综合征)、支气管水肿、肺水肿、支气管炎、肺炎或各种原因(例如,吸入有毒气体)引起的间质性肺炎,或由于心力衰竭、辐射、化学治疗、囊性纤维化或囊肿性纤维化引起的支气管炎、肺炎或间质性肺炎,或α1抗胰蛋白酶缺乏。
尤其优选地,本发明涉及式(I)化合物用于制备药物组合物的用途,所述药物组合物用于治疗上下呼吸道的炎性或阻塞性疾病,包括肺,例如,过敏性鼻炎、慢性鼻炎、支气管扩张症、囊性纤维化、COPD、慢性支气管炎、慢性窦炎和哮喘。
最优选式(I)的化合物用于治疗炎性和阻塞性疾病的用途,例如,COPD、慢性支气管炎、慢性窦炎、哮喘、囊性纤维化,尤其是COPD、慢性支气管炎、哮喘和囊性纤维化。
实际的药学有效量或治疗剂量当然取决于本领域技术人员已知的因素,例如,患者的年龄和体重、给药途径和疾病的严重程度。在任何情况下,基于患者的独特病症,以递送的药学有效量允许的剂量和方式给予药物组合。
药物组合
按照本发明,式(I)的化合物可以单独使用,或与式(I)的其它活性物质结合使用。如果需要的话,式(I)的化合物也可以与其它药理学活性物质联用。
因此,本发明进一步涉及药物组合,优选地,除了一或多种式(I)的化合物或其盐之外,所述药物组合还包含其它活性物质,一或多种选自下列类型的化合物:其它ENaC抑制剂、β模拟剂、抗胆碱能药、皮质类甾醇、PDE4抑制剂、LTD4拮抗剂、EGFR抑制剂、多巴胺激动剂、H1抗组胺剂、PAF拮抗剂、MAP激酶抑制剂、MPR4抑制剂、iNOS抑制剂、SYK抑制剂、校正囊性纤维化横跨膜的调节剂(CFTR)和CFTR增效剂,或其两种或三种的药物组合。
制剂
合适的给药形式是,例如,吸入式粉剂或气雾剂。在所有情况下,药学有效化合物的含量应该在整个组合物的0.2至50wt%的范围,优选0.5至25wt%,即,足以获得下文所列举的剂量范围的量。
吸入给予的活性物质药物组合可以是粉剂、水化或水化-乙醇化的溶液剂或使用气体推进剂的制剂。
因此,优选地,药物制剂的特征在于:它们包含一或多种按照上面优选实施方案的式(I)的化合物。
还优选地,吸入给予式(I)的化合物,尤其优选地,一天给予一次或两次。为此目的,必须将式(I)的化合物制备为适合于吸入的形式。吸入式制剂包括:吸入式粉剂、包含发射剂的定量气雾剂或不含发射剂的吸入式溶液剂,任选与常规生理学可接受的赋形剂混合。
在本发明范围内,术语“不含发射剂的吸入式溶液剂”还包括浓缩物,或无菌备用的吸入式溶液剂。在接下来的说明书部分中,更详细地描述了可以按照本发明使用的制剂。
吸入式粉剂
如果式(I)的活性物质存在于与生理学可接受的赋形剂的混合物中,则下列生理学可接受的赋形剂可以用于制备按照本发明的吸入式粉剂∶单糖(例如,葡萄糖或***糖)、二糖(例如,乳糖、蔗糖、麦芽糖)、寡糖和多糖(例如,葡聚糖)、多元醇(例如,山梨糖醇、甘露糖醇、木糖醇)、盐(例如,氯化钠、碳酸钙)或这些赋形剂彼此的混合物。优选地,使用单糖或二糖,同时优选使用乳糖或葡萄糖,尤其(但不仅仅是)它们的水合物形式。为了本发明的目的,乳糖是尤其优选的赋形剂,同时最尤其优选乳糖一水合物。从现有技术可以了解制备按照本发明的吸入式粉剂的方法:将组分碾磨和粉碎,并将所述组分最终混合在一起。
含有发射剂的吸入式气雾剂
可以按照本发明使用的含有发射剂的吸入式气雾剂,可以含有溶于气体推进剂中的或分散形式的式(I)化合物。现有技术已知可以用于制备按照本发明的吸入式气雾剂的气体推进剂。合适的气体推进剂选自:烃,例如,正丙烷、正丁烷或异丁烷,卤代烃,例如,优选甲烷、乙烷、丙烷、丁烷、环丙烷或环丁烷的氟化的衍生物。上述气体推进剂可以单独使用,或使用它们的混合物。尤其优选的气体推进剂是氟化的烷烃衍生物,选自TG134a(1,1,1,2-四氟乙烷)、TG227(1,1,1,2,3,3,3-七氟丙烷)和其混合物。在按照本发明的用途范围内使用的发射剂驱动的吸入式气雾剂还可以含有其它组分,例如,共溶剂、稳定剂、表面活性剂、抗氧化剂、润滑剂和pH值调节剂。所有这些组分在本领域是已知的组分。
不含发射剂的吸入式溶液剂
优选地,按照本发明的式(I)化合物用于制备不含发射剂的吸入式溶液剂和吸入式混悬剂。用于该目的的溶剂包括:水化的或醇化的溶液,优选乙醇化的溶液。溶剂可以是水本身,或是水和乙醇的混合物。使用合适的酸,将溶液剂或混悬剂调节pH为3至7。使用选自无机或有机酸的酸,可以调节pH值。尤其合适的无机酸的例子包括盐酸、氢溴酸、硝酸、硫酸和/或磷酸。尤其合适的有机酸的例子包括抗环血酸、柠檬酸、苹果酸、酒石酸、马来酸、琥珀酸、富马酸、乙酸、甲酸和/或丙酸,等等。优选的无机酸是盐酸和硫酸。还可以使用已经与一种活性物质形成酸加成盐的酸。有机酸当中,优选抗环血酸、富马酸和柠檬酸。如果需要的话,还可以使用上述酸的混合物,尤其是在酸除了具有酸化性质之外还具有其它性能的情况下,例如,作为调味剂、抗氧化剂或络合剂,例如,柠檬酸或抗环血酸。按照本发明,尤其优选地,使用盐酸调节pH值。
为了按照本发明的目的,可以将共溶剂和/或其它赋形剂加入到所使用的不含发射剂的吸入式溶液剂中。优选的共溶剂是含有羟基或其它极性基团的那些共溶剂,例如,醇,尤其是异丙醇;二醇,尤其是丙二醇、聚乙二醇、聚丙二醇、乙二醇醚、丙三醇、聚氧乙烯醇和聚氧乙烯脂肪酸酯。关于这点,术语“赋形剂”和“添加剂”表示任何可药用物质,它们不是活性物质,但为了提高活性物质制剂的质量,可以将它们与活性物质配制在药理学合适的溶剂中。优选地,这些物质没有药理学效果,或与目标治疗无关,没有明显的或至少没有不合乎需要的药理学效果。赋形剂和添加剂包括,例如,表面活性剂,例如,大豆卵磷脂、油酸,脱水山梨醇酯,例如,聚山梨酸酯,聚乙烯吡咯烷酮、保证或延长最终药物制剂的保存期限的其它稳定剂、络合剂、抗氧化剂和/或防腐剂,调味剂、维生素和/或本领域已知的其它添加剂。添加剂还包括可药用盐,例如,作为等渗试剂的氯化钠。优选的赋形剂包括抗氧化剂,例如,抗环血酸,条件是,它不是用于调节pH值,还包括维生素A、维生素E、生育酚和存在于人体中的类似的维生素或前维生素。防腐剂可以用于保护制剂免受病原体的污染。合适的防腐剂是本领域已知的那些防腐剂,尤其是氯化十六烷基呲啶、苯扎氯铵或苯甲酸或苯甲酸盐,例如,苯甲酸钠,从现有技术可以了解其浓度。
对于上述治疗形式,提供了用于治疗呼吸疾病的备用的药物包装,其包括:装入的说明书(包括,例如,措辞呼吸***疾病、COPD或哮喘)、按照本发明的化合物和一或多种选自上述那些的药物组合。
Claims (36)
1.式(I)的化合物,
其中
R1和R2独立地选自氢和C1-C6-烷基,其中,C1-C6-烷基可以携带1至5个选自羟基、氨基、C1-C4-烷基氨基、二-C1-C4-烷基氨基、吗啉-4-基和二甲基膦酰基甲氧基的取代基,条件是,R1和R2中的至少一个不是氢、未取代的C1-C6-烷基和携带1个羟基取代基的C1-C6-烷基;或
R1和R2与它们相连接的氮原子一起形成选自哌啶、哌嗪和1,4-二氮杂环庚烷的杂环部分,其中,所述杂环部分可以携带1或2个选自C1-C4-烷基、二甲基膦酰基-C1-C4-烷基和NRaRb的取代基,其中,Ra和Rb独立地选自氢、C1-C4-烷基和-C(O)CH2NRcRd,其中,Rc和Rd独立地选自氢和C1-C4-烷基;和
Z-选自氯离子、溴离子、碘离子、氢氧根、硫酸氢根、硫酸根、硝酸根、磷酸根、甲酸根、乙酸根、三氟乙酸根、富马酸根、柠檬酸根、酒石酸根、草酸根、琥珀酸根、扁桃酸根、甲磺酸根和对甲苯磺酸根;
或其可药用盐。
2.按照权利要求1的化合物或其可药用盐,其中,R1和R2独立地选自氢、甲基、异丁基、2-氨基乙基、3-氨基丙基、2-(甲基氨基)乙基、2-(二甲基氨基)乙基、3-(甲基氨基)丙基、3-(二甲基氨基)丙基、2-(吗啉-4-基)乙基、2-(二甲基膦酰基甲氧基)乙基和2,3,4,5,6-五羟基己-1-基。
4.按照权利要求1的化合物或其可药用盐,其中,Z-选自氯离子和三氟乙酸根。
7.合成按照权利要求6所述的化合物的可药用盐的方法,其中含有阳离子基团的母体化合物通过常规化学方法反应。
8.合成按照权利要求6所述的化合物的可药用盐的方法,其中含有阳离子基团的母体化合物与足量的适宜的碱或酸在水或有机稀释剂中反应。
9.按照权利要求6所述化合物1.01的母体化合物的可药用盐。
10.按照权利要求6所述化合物1.02的母体化合物的可药用盐。
11.按照权利要求6所述化合物1.03的母体化合物的可药用盐。
12.按照权利要求6所述化合物1.04的母体化合物的可药用盐。
13.按照权利要求6所述化合物1.05的母体化合物的可药用盐。
14.按照权利要求6所述化合物1.06的母体化合物的可药用盐。
15.按照权利要求6所述化合物1.07的母体化合物的可药用盐。
16.按照权利要求6所述化合物1.08的母体化合物的可药用盐。
17.按照权利要求6所述化合物1.09的母体化合物的可药用盐。
18.按照权利要求6所述化合物1.10的母体化合物的可药用盐。
19.按照权利要求6所述化合物1.11的母体化合物的可药用盐。
20.按照权利要求6所述化合物1.12的母体化合物的可药用盐。
21.按照权利要求6所述化合物1.13的母体化合物的可药用盐。
22.按照权利要求6所述化合物1.14的母体化合物的可药用盐。
23.按照权利要求6所述化合物1.15的母体化合物的可药用盐。
24.按照权利要求6所述化合物1.16的母体化合物的可药用盐。
25.按照权利要求6所述化合物1.17的母体化合物的可药用盐。
26.按照权利要求6所述化合物1.18的母体化合物的可药用盐。
27.按照权利要求6所述化合物1.19的母体化合物的可药用盐。
28.按照权利要求6所述化合物1.20的母体化合物的可药用盐。
29.按照权利要求6所述化合物1.21的母体化合物的可药用盐。
30.按照权利要求1至6或9至29中任一项所述的化合物或可药用盐,其用作药物。
31.按照权利要求1至6或9至29中任一项所述的化合物或其可药用盐,用于治疗选自下列的疾病:呼吸***疾病或障碍和呼吸道的***反应性疾病。
32.按照权利要求1至6或9至29中任一项所述的化合物或其可药用盐,用于治疗选自下列的疾病:慢性支气管炎、急性支气管炎、细菌或病毒感染或真菌或蠕虫所引起的支气管炎、过敏性支气管炎、毒性支气管炎、慢性阻塞性支气管炎(COPD)、哮喘、支气管扩张症、过敏性或非过敏性鼻炎、慢性窦炎、特发性肺纤维化、囊性纤维化或囊肿性纤维化、α1抗胰蛋白酶缺乏、咳嗽、肺气肿、间质性肺疾病、肺泡炎、呼吸道反应过度、鼻息肉、肺水肿、各种原因的肺炎和干眼。
33.按照权利要求32所述的化合物或其可药用盐,其中所述哮喘为儿童哮喘。
34.按照权利要求32所述的化合物或其可药用盐,其中所述肺泡炎为过敏性的肺泡炎。
35.药物组合物,其包含至少一种按照权利要求1至6或9至29中任一项所述的化合物或其可药用盐,以及可药用载体。
36.药物组合,其除了含有一或多种按照权利要求1至6或9至29中任一项所述的化合物或其可药用盐之外,作为其它活性物质,还含有一或多种选自下列类型的化合物:其它ENaC抑制剂、β模拟剂、抗胆碱能药、皮质类甾醇、PDE4抑制剂、LTD4拮抗剂、EGFR抑制剂、多巴胺激动剂、H1抗组胺剂、PAF拮抗剂、MAP激酶抑制剂、MPR4抑制剂、iNOS抑制剂、SYK抑制剂、校正囊性纤维化横跨膜的调节剂(CFTR)和CFTR增效剂,或其两种或三种的药物组合。
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