CN107072976A - 用于治疗传染性疾病的包含Danirixin的药物组合物 - Google Patents
用于治疗传染性疾病的包含Danirixin的药物组合物 Download PDFInfo
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- CN107072976A CN107072976A CN201580038007.5A CN201580038007A CN107072976A CN 107072976 A CN107072976 A CN 107072976A CN 201580038007 A CN201580038007 A CN 201580038007A CN 107072976 A CN107072976 A CN 107072976A
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4462—Non condensed piperidines, e.g. piperocaine only substituted in position 3
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
提供了化合物和其药学上可接受的盐以及化合物的组合、其药物组合物、其制备方法和其用于治疗或预防传染性疾病的方法。
Description
相关专利和专利申请的交叉引用
这是专利合作条约申请,且要求享有于2014年5月12日申请的美国临时专利申请号61/991,754;2015年4月20日申请的美国临时专利申请号62/149,893;和2015年4月22日申请的美国临时专利申请号62/151,013的权益;所述申请均在此以其全文通过引用并入本文。
发明领域
本发明涉及某些化合物、方法和药物组合物,其用于治疗传染性疾病,诸如病毒和细菌感染。还公开了制备这样的化合物的方法和使用所述化合物的方法。具体而言,公开了治疗诸如由副粘病毒科(Paramyxoviridae)、正粘病毒科(Orthomyxoviridae)、黄病毒科(Flaviviridae)、小核糖核酸病毒科(Picornaviridae)和冠状病毒科(Coronaviridae)引起的那些病毒感染。
发明背景
CXCR2是一种趋化因子受体,其在嗜中性粒细胞中高度表达,且通过该受体的信号传导引起炎性细胞募集至受伤组织(1-2)。例如,已注意到,RSV-感染的婴儿肺中的嗜中性粒细胞升高(3-6)。此外,使CXCR2配体IL-8的生成增加的遗传单核苷酸多态性(SNP)与RSV细支气管炎和气喘相关联(7,8)。嗜中性粒细胞也是一种突出细胞类型,其在流毒感染期间募集至肺,并在小鼠中的流感感染期间CXCR2的清除可显著减少嗜中性粒细胞浸润至肺中(9,10)。
已知RSV感染期间过度生成黏液对婴儿有害,因为其阻塞肺的小呼吸道,并阻碍正常氧气交换。在RSV感染的小鼠模型中,经由CXCR2的信号传导有助于过度生成黏液和呼吸道高反应性。用抗CXCR2抗体进行免疫中和,且CXCR2 -/-小鼠显示显著减少在RSV感染后肺中的黏液(11)。还据报导,用CXCR2配体抗体(MIP-2)治疗的流感感染小鼠表明减少的肺嗜中性粒细胞计数,同时改善肺病理,而不影响病毒复制和清除(12)。总之,已显示,CXCR2和其一些配体(例如,IL-8)在人类呼吸道感染期间显著上调。
因此,能够结合至CXCR2受体和抑制CXCR2配体(例如,IL-8)结合的化合物可帮助治疗与CXCR2配体生成增加相关的状况。因此,这样的化合物可治疗与CXCR2配体诱导的嗜中性粒细胞趋化性相关的炎性状况。急性病毒和细菌肺感染引起显著免疫炎症和黏液生成,其通常导致呼吸道阻塞、呼吸困难和住院治疗。在症状开始后不久施用时,当前抗病毒治疗和抗生素作用可取得不同程度的成功。尽管传染剂在疾病和致病性方面发挥作用,但针对感染的过度免疫反应也显著促进严重呼吸道疾病的病因。
流感病毒是全球性健康问题,其为从1900年以来已杀死全世界范围内超过五千万人的三大流行病的原因。最近,世界卫生组织(World Health Organization)已估计,每年有三至五百万严重流感病例,且这些个体中每年有多达五十万由于并发症而死亡。参见WHO, Fact sheet N°211, (2009)。流感的特征在于突发高烧、咳嗽、头痛、肌肉和关节痛、严重不适、咽喉痛和流鼻涕。这些症状据信为免疫系统的过度或非特异性反应的结果。大多数人无需就医就可在一周内从发烧和其它症状恢复。然而,流感可引起高风险人的严重疾病或死亡。同上。实际上,小于两岁的儿童、年龄为65岁或更年长的成人和患有某些医学状况(诸如慢性心脏、肺(即COPD和哮喘)、肾脏、肝脏、血液或代谢疾病(即糖尿病))的任何年龄的人或具有弱化免疫系统的那些中出现并发症的最高风险。
当前针对各种流感病毒感染的治疗剂聚焦于干扰神经氨酸酶的作用。在流感病毒至其它细胞的传播可发生之前,需要用病毒蛋白神经氨酸酶切割细胞表面上的唾液酸。Tamiflu®(磷酸奥司他韦)是经口施用的神经氨酸酶抑制剂,且Relenza®(扎那米韦)是由口吸入的神经氨酸酶抑制剂。其它批准的治疗剂(如金刚烷胺和金刚烷乙胺)是靶向病毒离子通道(M2蛋白)和抑制病毒脱壳。不幸的是,Tamiflu®已报导具有严重副作用,包括恶心、呕吐和神经或精神系统的异常。而且,还已报导耐Tamiflu®病毒和耐金刚烷胺病毒的爆发,包括出现耐药性病毒的人传人(human-to-human)传播。事实上,美国CDC已建议,不再开金刚烷胺和金刚烷乙胺处方来治疗流感,因为如此高比例的最近季节性毒株已显示出对该作用的耐药性。另一缺点在于,许多这些治疗剂如果未在症状开始四十八小时内开始治疗,则效力小很多。尽管可预防性地服用针对某些流感毒株的疫苗,但美国CDC和疫苗制造商必须精确地预测在即将到来的季节将传播的特定毒株,而该预测难以进行。
因此,需要可有益地靶向呼吸道感染的多个方面(包括,例如过度生成黏液、呼吸道高反应性)且也可抑制潜在传染剂复制的额外医学疗法。
发明概述
根据本发明的一个实施方案,提供治疗患有呼吸道感染的受试者的呼吸道感染的新型方法,其包括向所述受试者施用式(I)化合物,
式(I)
或者其药学上可接受的盐,其单独施用或与抗微生物剂或其药学上可接受的盐组合施用。式(I)化合物与抗微生物剂(诸如,例如任何神经氨酸酶抑制剂)的这样的“组合”可作为在相同剂量中的固定剂量组合施用于患有呼吸道感染的受试者,或者这样的组合可以多个独立剂量施用。
还提供组合物,其包含式(I)化合物:
式(I)
和神经氨酸酶抑制剂化合物的组合。
还提供组合物,其包含式(I)化合物:
式(I)
和利巴韦林的组合。
还提供药物组合物,其包含药学上可接受的载体或赋形剂和式(I)化合物或其药学上可接受的盐,与抗微生物剂或其药学上可接受的盐组合。
还提供预防受试者的呼吸道感染的方法,其包括向具有呼吸道感染风险或易于呼吸道感染、获得呼吸道感染的受试者施用式(I)化合物或其药学上可接受的盐,其单独施用或与抗微生物剂或其药学上可接受的盐组合施用。
还提供药物组合物,其包含药学上可接受的载体或赋形剂,和单独的式(I)化合物或其药学上可接受的盐或者其与抗微生物剂或其药学上可接受的盐的组合。
还提供制备式(I)化合物或其药学上可接受的盐与抗微生物剂的组合和其组合物的方法以及该组合的治疗用途。
代表性实施方案的详述
在整个本申请中,参考关于化合物、组合物和方法的各个实施方案。所述各个实施方案意在提供各种说明性实例,且不应解释为描述替代性物质。反而,应注意,本文提供的各个实施方案的描述可以具有重叠范围。本文讨论的实施方案仅仅是说明性的,且意不在于限制本发明的范围。
应理解,本文所用的术语用于仅描述特定实施方案的目的,而不意在限制本发明的范围。在本说明书和后面的权利要求中,将参考应定义为具有以下含义的许多术语。
如本文所用,“抗微生物剂”是指杀死微生物或抑制其生长或预防或阻碍其致病作用的试剂,其为化合物或生物实体。抗微生物剂可根据其主要针对其作用的微生物分类,诸如抗病毒剂或抗细菌剂。
如本文所用的“一种/多种化合物”、“化学品”和“化学化合物”是指本文公开的通式、那些通式的任何亚属涵盖的化合物和通式和亚通式内的任何形式的化合物,包括一种或多种化合物的外消旋物、立体异构体和互变异构体。
“外消旋物”是指对映异构体的混合物。在本发明的一个实施方案中,式(I)化合物或其药学上可接受的盐用一种对映异构体对映异构富集,其中所有提及的手性碳均呈一种构型。一般而言,提及对映异构富集的化合物或盐意在表明指定的对映异构体将占所述化合物或盐的所有对映异构体的总重量的超过50重量%。
化合物的“一种或多种溶剂化物”是指结合至化学计量或非化学计量的溶剂的如上所定义的那些化合物。化合物的溶剂化物包括该化合物的所有形式的溶剂化物。在某些实施方案中,溶剂是挥发性、无毒和/或对于以痕量施用于人可接受的。合适的溶剂化物包括水,其中溶剂化物是水合物。
“一种或多种立体异构体”是指一个或多个立构中心的手性不同的化合物。立体异构体包括对映异构体和非对映异构体。
“互变异构体”是指质子位置不同的化合物的替代形式,诸如烯醇-酮和亚胺-烯胺互变异构体,或者含有同时附接至环-NH-部分和环=N-部分的环原子的杂芳基的互变异构形式,诸如吡唑类、咪唑类、苯并咪唑类、三唑类和四唑类。
“药学上可接受的盐”是指衍生自本领域中熟知的各种有机和无机抗衡离子的药学上可接受的盐,且包括(仅示例性地),钠盐、钾盐、钙盐、镁盐、铵盐和四烷基铵盐,和当分子含有碱性官能度时,有机酸或无机酸的盐,诸如盐酸盐、氢溴酸盐、酒石酸盐、甲磺酸盐、乙酸盐、马来酸盐和草酸盐。合适的盐包括P. Heinrich Stahl, Camille G. Wermuth(编), Handbook of Pharmaceutical Salts Properties, Selection, and Use; 2002中描述的那些。
在一个实施方案中,所述药学上可接受的盐是式(I)化合物的氢溴酸盐。
“患者”或“受试者”是指哺乳动物,且包括人和非人哺乳动物。
“治疗”患者的疾病是指1)预防易患或尚未显示该疾病症状的患者出现该疾病;2)抑制该疾病或阻止其发展;或3)改善该疾病或引起其消退。
根据本发明的一个实施方案,提供针对呼吸道系统的传染性疾病的医学疗法和治疗。在一个实施方案中,本发明可用于治疗由病毒感染所引起的症状,所述病毒包括但不限于流感病毒、人鼻病毒、其它肠道病毒、呼吸道合胞病毒、副流感病毒、偏肺病毒、冠状病毒、疱疹病毒或腺病毒。还应注意,本文治疗的呼吸道病毒感染也可与后续继发性细菌感染相关联。
CXCR2是一种趋化因子受体,其在嗜中性粒细胞高度表达,且通过该受体的信号传导引起炎性细胞募集至受伤组织。预期细胞因子信号传导以减少嗜中性粒细胞趋化性的化学拮抗作用可通过经由减少嗜中性粒细胞浸润来控制、减少和减轻许多所得症状而使患有呼吸道感染的受试者受益。因此,本发明提供新型治疗,其包含单独或与抗微生物剂组合的拮抗CXCR2受体的式(I)化合物。例如,预期本发明减少病原体滴度,和防止重复炎性细胞信号传导并浸润至受感染患者的肺,其可减轻疾病症状和肺病理。本发明还提供减少过度炎性免疫反应和病毒或细菌复制的治疗组合物和方法。
在一个实施方案中,预期CXCR2拮抗剂化合物(例如,式I化合物)与抗微生物剂的组合治疗靶向病毒/细菌和疾病的免疫方面,从而加速疾病恢复和消退,速度快于任一单独治疗。
在其它实施方案中,可向式I的CXCR2拮抗剂化合物与抗微生物剂的组合疗法添加额外制剂。这样的额外制剂可包括有效地减少一种或多种症状(包括,例如高烧、咳嗽、头痛、肌肉和关节痛、不适、咽喉痛和流鼻涕)的任何其它呼吸道感染疗法。
式I化合物也可与抗微生物剂组合使用,用于治疗人中由细菌引起的感染(具体而言呼吸道感染)的症状。具体细菌包括但不限于细菌性肺炎的病原体,诸如肺炎链球菌(Streptococcus pneumoniae)、金黄色葡萄球菌(Staphylococcus aureus)、流感嗜血杆菌(Haemophilus influenza)、肺炎克雷伯氏菌(Klebsiella pneumoniae)、嗜肺军团菌(Legionella pneumophila)、牙龈卟啉单胞菌(Porphyromonas gingivalis)和鲍曼不动杆菌(Acinetobacter baumanii)。此外,本发明涉及加剧潜在慢性状况(诸如哮喘、慢性支气管炎、慢性阻塞性肺病、中耳炎和窦炎)的呼吸道感染。在该情况下,感染可引发病情恶化,且用本发明控制症状会减少出现恶化的可能性。
根据本发明,已发现,可以通过向受试者施用单独或与一种或多种抗微生物剂组合的式(I)化合物而治疗和预防所述受试者的传染性疾病和传染性疾病相关并发症。出于本发明的目的,包含与至少一种抗微生物剂组合的式(I)化合物的新型组合疗法也可用于预防和治疗需要这样的预防或治疗的受试者的传染性疾病和传染性疾病相关并发症的目的。因此,本发明组合疗法将可用于例如减少患有这样的症状的受试者的这样的传染性疾病症状,诸如例如咳嗽、鼻漏、呼吸困难、呼吸短促、疼痛、炎症、眼睛瘙痒和/或流泪、流鼻涕、鼻充血、面部压力、打喷嚏、咽喉痛、咳嗽、头痛、发烧、不适、疲劳、虚弱和/或肌肉疼痛。本发明组合疗法也可用于预防出现这样的症状。
本发明方法和组合物也可用于减少患有传染性疾病的受试者的住院治疗的数量,或预防或延迟受试者发展与传染性疾病相关的并发症,其最终可由具有慢性或复发性传染性疾病而引起。式(I)化合物与抗微生物剂的组合疗法也可用于降低所需独立剂量的数量,因此可能提高患者顺应性。施用式(I)化合物用于预防和治疗传染性疾病和传染性疾病相关并发症是意料之外地有效的治疗和预防性疗法。这样的施用有效改善传染性疾病和传染性疾病相关并发症的症状,同时避免或减少当前治疗的某些缺点。此外,施用式(I)化合物与抗微生物剂的组合可有效治疗传染性疾病或传染性疾病相关并发症或症状,且在一些实施方案中,可优于使用任一单独试剂。例如,组合疗法可有效降低通常作为单一疗法开处方的抗微生物剂的剂量。施用较低剂量的常规治疗剂可减少这样的常规制剂相应的副作用。包含式(I)化合物和抗微生物剂的组合疗法不仅可用于改善传染性疾病症状和缩短恢复时间,而且也可减少通常所需的抗微生物剂的剂量。
如本文所用,当指组合使用式(I)化合物与抗微生物剂时,短语“组合疗法”、“共同施用”、“与...一起施用”、“施用”、“组合”或“共同疗法”意欲包括在将提供药物组合的有益效果的方案中以依次方式施用各制剂,且同样意欲包括以实质上同时的方式共同施用这些制剂。因此,式(I)化合物和抗微生物剂可以一种治疗剂型施用,诸如以单一胶囊、锭剂、注射剂或输注剂,或以两个分开治疗剂型,诸如以分开胶囊、片剂、注射剂或输注剂。在其它实施方案中,当式(I)化合物以相对于抗微生物剂的分开剂型施用时,这样的分开给药可在类似或不同时间段内进行,这取决于患者的治疗需求。本领域技术人员将理解如何适当地定时这样的分开给药时段。
依次施用这样的治疗涵盖施用本方法各药物之间的相对短和相对长时段。然而,在本发明的一些实施方案中,施用第二药物,同时第一药物仍对受试者具有有效效果。因此,在一个实施方案中,本发明利用如下事实:受试者中同时存在式(I)化合物与抗微生物剂的组合具有大于施用任一单独试剂的临床疗效。或者,在本发明的一些实施方案中,施用第二药物,同时第一药物已对受试者没有有效效果。
在一个实施方案中,两种药物中的第二种应当在待施用的第一药物的治疗反应时间内给予受试者。例如,本发明涵盖向受试者施用式(I)化合物,和随后施用抗微生物剂,只要将抗微生物剂施用于受试者,同时式(I)化合物仍以一定水平存在于受试者中,所述水平与抗微生物剂的水平组合是治疗有效的,且反之亦然。
如本文所用,术语“治疗反应时间”意指化合物在受试者体内以治疗浓度存在或可检测的持续时间。
如本文所用,术语“单一疗法”意欲包括向患有传染性疾病或传染性疾病相关并发症的受试者作为单一治疗处理施用式(I)化合物,而无包含抗微生物剂的额外治疗处理。然而,式(I)化合物仍可以多个剂型施用。因此,式(I)化合物可以一个治疗剂型施用,诸如以单一胶囊、片剂、注射剂或输注剂,或以两个分开治疗剂型施用,诸如以分开胶囊、锭剂、注射剂或输注剂。
将选择本文所述的式(I)化合物或其盐和其它药学活性剂的量以及相对施用时机,以达到所需组合疗效。
在其它实施方案中,本发明化合物可与一种或多种可用于预防或治疗病毒性疾病或相关联病理生理的抗微生物剂组合使用。因此,本发明化合物和其盐、溶剂化物或其药学上可接受的其它衍生物可单独使用或与其它抗微生物剂组合使用。本发明化合物和任何其它药学活性剂可一起或分开施用,且当分开施用时可同时或以任何顺序依次进行施用。将选择本发明化合物和其它药学活性剂的量以及相对施用时机,以达到所需组合疗效。本发明化合物和其盐、溶剂化物或其它药学上可接受的衍生物与其它治疗剂的组合施用可以如下组合同时施用:(1)包括两种化合物的整体药物组合物;或(2)各自包括所述化合物之一的分开药物组合物。可选地,该组合可以依次方式分开施用,其中首先施用一种治疗剂,然后施用另一第二治疗剂,或反之亦然。这样的依次施用可以时间接近或时间较远。
在一个实施方案中,本发明涵盖用于预防受试者的传染性疾病的方法,所述方法包括向所述受试者施用单独或与抗微生物剂组合的式(I)化合物。
如本文所用,术语“预防”是指受试者发展传染性疾病或传染性疾病相关并发症的倾向或风险的任何下降,无论多么轻微。出于本发明的目的,所述受试者是任何受试者,且优选为具有发展传染性疾病或传染性疾病相关并发症的风险或倾向的受试者。术语“预防”包括在具有风险受试者中完全预防临床明显的传染性疾病的发作,或预防临床前明显的传染性疾病的发作。
在另一个实施方案中,本发明涵盖用于治疗受试者的传染性疾病或传染性疾病相关并发症的方法,所述方法包括向所述受试者施用单独或与抗微生物剂组合的式(I)化合物。
如本文所用,术语“治疗”意指减轻症状、暂时或永久地消除病因、或改变或减缓症状出现或症状恶化。这些术语还包括减轻或消除与本文所述的任何传染性疾病或传染性疾病相关并发症相关联(但不限于此)的症状起因。这样的术语还包括减少受试者的传染性疾病或传染性疾病相关并发症的持续时间。
不受此或任何其它理论束缚,据信包含式(I)化合物的疗法可有效削弱呼吸道感染期间肺内的炎症进程,因此预防或治疗传染性疾病症状且因而预防或治疗传染性疾病相关并发症。此外,在优选实施方案中,式(I)化合物与抗微生物剂的组合可提供协同效果,其可减少与传染性疾病和传染性疾病相关并发症相关的症状,其程度大于基于使用任一种所预期的程度。
术语“协同”是指式(I)化合物与抗微生物剂的组合作为组合疗法的预防和治疗传染性疾病的疗效可大于其各自效果的总和。本发明组合疗法的某些实施方案的协同效果可涵盖治疗和预防传染性疾病的额外意料之外的优势。这样的额外优势可包括但不限于降低抗微生物剂所需剂量、减少抗微生物剂副作用和使那些制剂对经历传染性疾病疗法的受试者更耐受。
而且,本发明单一疗法和组合疗法可通过治疗自身潜在的呼吸道传染性疾病来治疗或预防可由具有呼吸道传染性疾病间接引起的传染性疾病相关并发症。例如,如果受试者患有病毒性呼吸道疾病相关并发症(诸如继发性呼吸道细菌感染(例如肺炎)),则通过本发明方法和组合物治疗潜在病毒性传染性疾病(诸如病毒性流感)可预防出现相关的细菌性感染并发症和其症状。本发明涉及预防或治疗需要这样的预防或治疗的受试者的传染性疾病和传染性疾病相关并发症的新型方法,其包括向所述受试者施用式(I)化合物。本发明还涉及预防或治疗需要这样的预防或治疗的受试者的传染性疾病和传染性疾病相关并发症的新型方法,其包括向所述受试者施用式(I)化合物和一种或多种抗微生物剂。
根据本发明的一个实施方案,提供具有式I结构的化合物:
式(I)
在其它实施方案中,式(I)化合物也可以所示其立体化学描绘。因此,式(I)化合物也是具有以下结构的手性化合物:
。
式(I)化合物是目前在美国用于慢性阻塞性肺病(COPD)的2期临床试验中的CXCR2抑制剂,且称为“Danirixin”,且化学名为:N-[4-氯-2-羟基-3-(3-哌啶基磺酰基)-苯基]-N′-(3-氟-2-甲基苯基)脲,其中所有都在本文中可互换。式(I)化合物描述于美国专利号7,893,089中,所述专利以其全文通过引用并入本文。
在一个替代实施方案中,还提供氢溴酸盐形式且作为独立新型化合物的式(I)化合物。此外,这样的式(I)化合物的氢溴酸盐可与本发明的新型疗法和组合一起使用。
在本发明的另一个实施方案中,提供包含式(I)化合物与抗微生物剂的组合的组合治疗或预防疗法。在本发明的一个实施方案中,所述抗微生物剂为神经氨酸酶抑制剂。在本发明的另一个实施方案中,所述抗微生物剂选自扎那米韦、奥司他韦、拉尼米韦和帕拉米韦。在本发明的另一个实施方案中,所述抗微生物剂为扎那米韦。在本发明的另一个实施方案中,所述抗微生物剂为奥司他韦。在本发明的一个实施方案中,所述抗微生物剂为利巴韦林。
扎那米韦是市售的流感病毒神经氨酸酶抑制剂,称为Relenza®,且被美国FDA批准用于治疗和预防流感。参见Ryan, D. M.等人, Antimicrob. Agents Chemother. 1994,38, 2270。扎那米韦是作为用于Diskhaler™装置中的吸入粉末以5 mg强度给药于患者。随后扎那米韦结合至流感神经氨酸酶的活性位点,因此使得流感病毒不能逃离其宿主细胞并感染其它细胞。尽管如此,本发明涵盖扎那米韦的替代施用模式和替代剂量,诸如例如静脉内给药。
扎那米韦具有如下化学结构:
。
在其它实施方案中,扎那米韦也可以所示其真实立体化学描绘。这样的立体化学指示扎那米韦是具有以下结构的手性化合物:
。
扎那米韦描述于美国专利号5,360,817(von Izstein等人);美国专利号5,597,933;美国专利号5,495,027;和美国专利号6,156,544中,所述专利在此以其全文通过引用并入本文。除这些专利中的公开内容以外,已报导另一种制造扎那米韦的合成途径。参见Zhu等人,Tetrahedron, 68(8), 2041-2044 (2012)。
奥司他韦是市售的流感病毒神经氨酸酶抑制剂,称为Tamiflu®,且被美国FDA批准用于治疗和预防流感。参见Lew等人,Curr. Med. Chem., 7(6): 663-72 (2000)。
奥司他韦作为胶囊(含有98.5 mg磷酸奥司他韦,其相当于75 mg奥司他韦)且作为用于口服悬浮剂的粉末(磷酸奥司他韦,其相当于奥司他韦,6mg/mL)给药于患者。随后奥司他韦结合至流感神经氨酸酶的活性位点,使得流感病毒无法逃离其宿主细胞并感染其它细胞。Tamiflu®也可得自于含有30mg或45mg奥司他韦的胶囊中。
奥司他韦具有如下化学结构:
。
在其它实施方案中,奥司他韦也可以所示其真实立体化学描绘。这样的立体化学指示奥司他韦是具有以下结构的手性化合物:
。
奥司他韦描述于美国专利号5,763,483;5,866,601和5,952,375中;所述专利在此以其全文通过引用并入本文。除这些专利中的公开内容以外,已报导另一种制造奥司他韦的合成途径。参见Ishikawa等人,Angew. Chem. Int. Ed., 48: 1304-1307 (2009)。
因此,根据本发明的一个实施方案,提供用于呼吸道感染的新型组合治疗疗法。
本发明还提供包含式(I)化合物与扎那米韦的组合的新型组合物。在另一个实施方案中,本发明提供包含式(I)化合物与奥司他韦的组合的新型组合物。在另一个实施方案中,本发明提供包含式(I)化合物与拉尼米韦的组合的新型组合物。在另一个实施方案中,本发明提供包含式(I)化合物与帕拉米韦的组合的新型组合物。在另一个实施方案中,本发明提供包含式(I)化合物与法匹拉韦(T-705)的组合的新型组合物。
进一步提供治疗患有呼吸道感染的受试者的呼吸道感染的新型方法,其包括向所述受试者施用式(I)化合物或其药学上可接受的盐和扎那米韦或其药学上可接受的盐的组合。这样的式(I)化合物和扎那米韦的“组合”可作为相同剂量中的固定剂量组合施用于患有呼吸道感染的受试者,或者这样的组合可以两个分开剂量施用。
还提供包含药学上可接受的载体或赋形剂和式(I)化合物或其药学上可接受的盐和扎那米韦或其药学上可接受的盐的组合的药物组合物。
还提供预防受试者的呼吸道感染的方法,其包括向具有呼吸道感染风险或易感呼吸道感染、获得呼吸道感染的受试者施用式(I)化合物或其药学上可接受的盐与扎那米韦或其药学上可接受的盐的组合。
进一步提供治疗患有病毒性呼吸道感染的受试者的病毒性呼吸道感染的新型方法,其包括向所述受试者施用式(I)化合物或其药学上可接受的盐与扎那米韦或其药学上可接受的盐的组合。
进一步提供治疗患有流感感染的受试者的流感感染的新型方法,其包括向所述受试者施用式(I)化合物或其药学上可接受的盐与扎那米韦或其药学上可接受的盐的组合。
进一步提供用于治疗患有RSV感染的受试者的RSV感染的新型组合物和/或方法,其包括向所述受试者施用式(I)化合物或其药学上可接受的盐与利巴韦林或其药学上可接受的盐的组合。
本发明的这样的化合物可以特定几何或立体异构形式存在。本发明涵盖所有这样的化合物,包括顺式-和反式-异构体、(-)-和(+)-对映异构体、(R)-和(S)-对映异构体、非对映异构体、(D)-异构体、(L)-异构体、其外消旋混合物和其其它混合物(诸如对映异构或非对映异构富集的混合物),如同落入本发明范围内一样。取代基(诸如烷基)中可存在额外不对称碳原子。意欲所有这样的异构体和其混合物包括于本发明中。
可使用手性合成子或手性试剂来制备或使用常规技术来拆分光学活性(R)-和(S)-异构体以及d和I异构体。如果,例如,需要本发明化合物的特定对映异构体,则可通过不对称合成或通过用手性助剂衍生化来制备,其中分离所得非对映异构体混合物,并切割助剂基团,以提供纯净所需对映异构体。可选地,当分子含有碱性官能团(诸如氨基)或酸性官能团(诸如羧基)时,可用适当光学活性酸或碱形成非对映异构盐,随后通过本领域中已知的分级结晶或层析方式拆分因此形成的非对映异构体,和随后回收纯对映异构体。此外,通常使用层析法,利用手性固定相,任选地组合化学衍生化(例如,从胺形成氨基甲酸酯),实现对映异构体和非对映异构体的分离。
在本发明的另一个实施方案中,提供式(I)化合物与抗微生物剂的组合,其中所述化合物和抗微生物剂用于制造用于治疗人的病毒感染的药剂。
在本发明的另一个实施方案中,提供包含药学上可接受的稀释剂和治疗有效量的如式(I)所定义的化合物与抗微生物剂的组合的药物组合物。
在一个实施方案中,本发明涉及具有作为病毒感染的新型治疗和/或预防性疗法的效用的化合物、组合物和药物组合物。在另一个实施方案中,本发明涉及具有作为呼吸道病毒感染的新型治疗和/或预防性疗法的效用的化合物、组合物和药物组合物。在另一个实施方案中,本发明涉及具有作为细菌呼吸道感染的新型治疗和/或预防性疗法的效用的化合物、组合物和药物组合物。
病毒通过评估几种特性(包括病毒基因组的类型)分类。病毒基因组可由DNA或RNA构成,可以是双链或单链的(其可进一步为正义或反义的),且大小和基因组织形式可大大不同。
RNA病毒是具有RNA(核糖核酸)作为其遗传物质的病毒。该核酸通常是单链RNA(ssRNA)。RNA病毒可根据其RNA的正义或反义(sense)或极性进一步分为反义和正义。正义病毒RNA类似于mRNA,且因此可由宿主细胞立即翻译。反义病毒RNA与mRNA互补,且因此必须在翻译前由RNA聚合酶转化为正义RNA。因此,正义病毒的纯化RNA可直接引起感染,尽管其传染性可小于全病毒颗粒。反义病毒的纯化RNA本身不是传染性的,因为其需要转录成正义RNA;各病毒颗粒可转录成几种正义RNA。
正义、单链RNA病毒(“正链RNA病毒”)构成来自许多不同亚家族的病毒的大型超家族。这些病毒横跨植物和动物界,引起范围为轻度表型至重度衰竭性疾病的病理。正链RNA病毒聚合酶超群的组合物包括至少以下家族:轻小病毒、裸露核糖核酸病毒(narnavirus)、小核糖核酸病毒、双顺反子病毒、海洋RNA病毒(marnavirus)、伴生病毒、豇豆花叶病毒、马铃薯y病毒、杯状病毒、星状病毒、诺达病毒、四病毒、黄矮病毒、番茄丛矮病毒、冠状病毒、动脉炎病毒、若尼病毒(ronivirus)、黄病毒、披膜病毒、雀麦花叶病毒、芜菁黄花叶病毒、线性病毒、弯曲病毒(flexivirus)、塞科病毒(secovirus)、杆菌状核糖核酸病毒、软腐病病毒、温州蜜柑矮缩病毒、樱桃锉叶病毒、肝炎病毒、南方菜豆花叶病毒、幽影病毒、烟草花叶病毒、烟草脆裂病毒、大麦病毒、真菌传杆状病毒、马铃薯帚顶病毒、花生丛簇病毒、甜菜坏死黄脉病毒、欧尔蜜病毒和悬钩子病毒。
反义、单链RNA病毒(“反链RNA病毒”)必须通过RNA-依赖性RNA聚合酶复制其基因组,以形成正义RNA。这意味着该病毒必须使其携带RNA复制酶。然后,正义RNA分子充当病毒mRNA,其通过宿主核糖体翻译为蛋白。所得蛋白继续引导合成新的病毒颗粒,诸如衣壳蛋白和RNA复制酶,其用于产生新的反义RNA分子。
反义单链RNA病毒群中识别有八个科,且一些未指定为特定科。
˙ 单股反链病毒目(Oder Mononegavirales)
˙博纳病毒科(Bornaviridae)-博纳(Borna)病病毒
˙丝状病毒科(Filoviridae)-包括埃博拉(Ebola)病毒、马尔堡(Marburg)病毒
˙副粘病毒科(Paramyxoviridae)-包括麻疹(Measles)病毒、腮腺炎(Mumps)病毒、尼帕(Nipah)病毒、亨德拉(Hendra)病毒
˙弹状病毒科(Rhabdoviridae)-包括狂犬病(Rabies)病毒
˙未指定科:
˙沙粒病毒科(Areaaviridae)-包括拉沙(Lassa)病毒
˙布尼亚病毒科(Bunyaviridae)-包括汉坦病毒(Hantavirus)、克里米亚-刚果(Crimean-Congo)出血热
˙蛇形病毒科(Ophioviridae)
˙正粘病毒科(Orthomyxoviridae)-包括流感病毒
˙未指定属:
˙δ病毒属(Deltavirus)-包括丁型肝炎病毒
˙Dichorhavirus属
˙Emaravirus属
˙尼亚病毒属(Nyavirus)-包括尼亚玛尼病毒(Nyamanini virus)和Midway病毒
˙纤细病毒属(Tenuivirus)
˙叶脉曲张病毒属(Varicosavirus)
˙未指定种:
˙Taastrup病毒。
因此,意欲本发明可涵盖治疗或预防本文所引用的任何病毒或者病毒科或属以及本文未引用但将为本领域技术人员所知的其它病毒。
在本发明的一个实施方案中,本文所述化合物可用于预防或治疗受试者中由单链RNA病毒所引起的病毒感染。
在本发明的一个实施方案中,本文所述化合物可用于预防或治疗受试者中由正义、单链RNA病毒所引起的病毒感染。
在本发明的一个实施方案中,本文所述化合物可用于预防或治疗受试者中由反义、单链RNA病毒所引起的病毒感染。
在一些实施方案中,提供治疗受试者中至少部分由网巢病毒目(Nidovirale)、小核糖核酸病毒目(picornavirale)、芜菁黄花叶病毒目(tymovirale)、单股反链病毒目(mononegavirale)、呼肠孤病毒科(reoviridae)、pycobirnaviridae、小DNA病毒科(parvoviridae)、腺病毒科(adenoviridae)、痘病毒科(poxviridae)、多瘤病毒科(polyomaviridae)、疱疹病毒科(herpesviridae)、副粘病毒科的病毒介导的病毒感染的方法,其包括向所述受试者施用包含任一式(I)化合物与抗微生物剂的组合的组合物。
治疗患有病毒感染的受试者的病毒感染的方法,其包括向所述受试者施用式(I)化合物与抗微生物剂的组合。
预防受试者的病毒感染的方法,其包括向所述受试者施用任一式(I)化合物与抗微生物剂的组合。
在其它实施方案中,本文所述化合物可用于预防或治疗受试者的病毒感染,其中所述感染由属于以下家族的病毒所引起:轻小病毒、裸露核糖核酸病毒(narnavirus)、小核糖核酸病毒、双顺反子病毒、海洋RNA病毒、伴生病毒、豇豆花叶病毒、马铃薯y病毒、杯状病毒、星状病毒、诺达病毒、四病毒、黄矮病毒、番茄丛矮病毒、冠状病毒、动脉炎病毒、ronivirus、黄病毒、披膜病毒、雀麦花叶病毒、芜菁黄花叶病毒、线性病毒、弯曲病毒、塞科病毒、杆菌状核糖核酸病毒、软腐病病毒、温州蜜柑矮缩病毒、樱桃锉叶病毒、肝炎病毒、南方菜豆花叶病毒、幽影病毒、烟草花叶病毒、烟草脆裂病毒、大麦病毒、真菌传杆状病毒、马铃薯帚顶病毒、花生丛簇病毒、甜菜坏死黄脉病毒、欧尔蜜病毒和悬钩子病毒。
公开了化合物、方法和药物组合物,其用于通过向患有所述病毒感染的受试者施用单独或与本文所述的抗微生物剂组合的式(I)化合物来治疗呼吸道病毒感染。还公开了制备这样的化合物的方法和使用所述化合物和其药物组合物的方法。具体而言,公开了病毒感染诸如由RNA或DNA病毒所引起的病毒感染的治疗和预防。
在其它实施方案中,本文所述的化合物可用于治疗受试者的病毒感染,其中所述感染由属于小核糖核酸病毒科、丝状病毒科、副粘病毒科或冠状病毒科的病毒所引起。在其它实施方案中,本文所述的化合物可用于治疗受试者的病毒感染,其中所述感染由属于小核糖核酸病毒科的病毒所引起。在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由属于冠状病毒科的病毒所引起。
在其它实施方案中,本文所述的化合物可用于预防或治疗受试者的病毒感染,其中所述感染由任一种或多种选自以下的病毒所引起:脊髓灰质炎病毒、鼻病毒、柯萨奇病毒、甲型流感病毒、乙型流感病毒、腺病毒、冠状病毒、甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、戊型肝炎病毒、埃博拉病毒、马尔堡病毒、严重急性呼吸道综合征(SARS)病毒、沙粒病毒、裂谷热病毒、黄热病毒、呼吸道合胞体病毒(RSV)、丙型肝炎病毒、西尼罗河病毒、登革热病毒、爱知病毒、肠病毒、风疹病毒、鼠脑脊髓炎病毒、副流感病毒、偏肺病毒、口蹄疫病毒、禽流感病毒和中东呼吸道综合征(MERS)。
在其它实施方案中,本文所述的化合物可用于预防或治疗由下表1中所列任何系统发生目、属、科或特定种所引起的病毒感染。
表1
正义单链RNA病毒 |
˙网巢病毒目 |
o 动脉炎病毒科 |
o 冠状病毒科 - 包括冠状病毒、SARS |
o 杆套病毒科 |
˙小核糖核酸病毒目 |
o Bacillariornaviridae科 |
o 杯状病毒科- 包括Norwalk病毒 |
o二顺反子病毒科 |
o 黄病毒科 |
o Labyrnaviridae科 |
o 海洋RNA病毒科 |
o 小核糖核酸病毒科-包括脊髓灰质炎病毒、“感冒”病毒(鼻病毒)、甲型肝炎病毒、柯萨奇病毒 |
o 马铃薯y病毒科 |
o 伴生豇豆病毒科包括豇豆花叶病毒亚科 |
o 随伴病毒科 |
˙芜菁黄花叶病毒目 |
o α线形病毒科 |
o β线形病毒科 |
o γ线形病毒科 |
o 芜菁黄花叶病毒科 |
˙未指定 |
o 蜂窝状病毒科 |
o 星状病毒科 |
o 杆菌状核糖核酸病毒科 |
o 雀麦花叶病毒科 |
o 修道院病毒科 |
o黄病毒科 - 包括黄热病毒、西尼罗河病毒、丙型肝炎病毒、登革热病毒 |
o 光滑病毒科 |
o 黄症病毒科 |
o 裸露核糖核酸病毒 |
o 野田病毒科 |
o 逆转录病毒科 - 包括人类免疫缺陷病毒1和2 |
o 四抗病毒科 |
o 披膜病毒科 - 包括风疹病毒、罗斯河病毒、辛德毕斯病毒、基孔肯雅病毒 |
o 番茄丛矮病毒科 |
o 帚状病毒科 |
反义单链RNA病毒 |
˙单股反链病毒目 |
o博纳病毒科 - 博纳病病毒 |
o 丝状病毒科 - 包括埃博拉病毒、马尔堡病毒 |
o 副粘病毒科 - 包括麻疹病毒、腮腺炎病毒、尼帕病毒、亨德拉病毒、呼吸道合胞体病毒(RSV)、人类副流感病毒(PIVs)、人类偏肺病毒(hMPV) |
o 弹状病毒科 - 包括狂犬病病毒 |
˙未指定科: |
o 沙粒病毒科 - 包括拉沙病毒、胡宁病毒 |
o 布尼亚病毒科 -包括汉坦病毒、克里米亚-刚果出血热 |
o 蛇形病毒科 |
o正粘病毒科 - 包括流感病毒 |
˙未指定属: |
oδ病毒属 |
o Emaravirus属 |
o Nyavirus属 –包括Nyamanini和Midway病毒 |
双链RNA病毒 |
o 呼肠孤病毒科 - 包括轮状病毒 |
o Pycobirnaviridae科 – 包括人类pycobirnavirus |
DNA病毒 |
o 细小病毒科 – 包括细小病毒B19 |
o 腺病毒科 - 包括腺病毒 |
o 痘病毒科 - 包括猴痘 |
o 多瘤病毒科 - 包括BK病毒 |
o 疱疹病毒科 - 包括单纯疱疹病毒 |
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由属于副粘病毒科、小核糖核酸病毒科或黄病毒科的病毒所引起。在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由属于副粘病毒科的病毒所引起。在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由属于黄病毒科的病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由属于小核糖核酸病毒科的病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由任一种或多种选自以下的病毒所引起:脊髓灰质炎病毒、鼻病毒、柯萨奇病毒、甲型流感病毒、乙型流感病毒、丙型流感病毒、腺病毒、冠状病毒、甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、戊型肝炎病毒、埃博拉病毒、马尔堡病毒、严重急性呼吸道综合征(SARS)病毒、沙粒病毒、裂谷热病毒、黄热病毒、呼吸道合胞体病毒(RSV)、西尼罗河病毒、登革热病毒、爱知病毒、肠病毒、风疹病毒、泰莱氏鼠脑脊髓炎病毒(TMEV)、口蹄疫病毒(FMDV)、人类免疫缺陷病毒(HIV)、呼吸道合胞体病毒(RSV)、副流感病毒(PIV)、人类PIV、人类偏肺病毒(hMPV)、禽流感病毒和中东呼吸道综合征(MERS)。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由人类肠道病毒A至D中任一种所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由肠道病毒A71所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由人类鼻病毒A-C中任一种所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由人类鼻病毒A所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由人类鼻病毒B所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由人类鼻病毒C所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由人类呼吸道合胞病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由人类呼吸道合胞病毒A所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由人类呼吸道合胞病毒B所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由爱知病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由脊髓灰质炎病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由柯萨奇病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由埃可病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由甲型肝炎病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由严重急性呼吸道综合征病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由胡宁病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由猴痘病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由裂谷热病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由乙型肝炎病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由丙型肝炎病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由人类免疫缺陷病毒(HIV)所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由流感病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由甲型流感病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由乙型流感病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由丙型流感病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由冠状病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由属于丝状病毒科的病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由属于沙状病毒科的病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由属于布尼亚病毒科的病毒所引起。
在其它实施方案中,本文所述化合物可用于治疗受试者的病毒感染,其中所述感染由人类免疫缺陷病毒1和/或人类免疫缺陷病毒2所引起。
式(I)化合物的合成
以下实例用来更完全地描述制造式(I)化合物的方式。本领域技术人员在阅读美国专利号7,893,089后将理解如何合成式(I)化合物,所述专利通过引用完全并入本文。
应理解,该实例绝不用来限制本发明的真实范围,而是出于说明目的提供。
如果需要,可通过任何合适分离或纯化程序,诸如例如,过滤、萃取、结晶、柱层析、薄层层析或厚层层析或这些程序的组合来实现本文所述的化学实体和中间体的分离和纯化。可通过参考下文实例来获得合适的分离和分离程序的具体说明。然而,也可使用其它等效分开或分离程序。
当需要时,(R)-和(S)-异构体可通过本领域技术人员已知的方法拆分,例如通过形成可例如通过结晶分离的非对映异构体盐或复合物;经由形成可例如通过结晶、气-液或液相层析分离的非对映异构体衍生物;选择性地使一种对映异构体与对映异构体特异性试剂反应(例如酶促氧化或还原),随后分离修饰和未修饰的对映异构体;或在手性环境中(例如在手性支持物(诸如具有结合的手性配体的二氧化硅)上或在手性溶剂存在的情况下)进行气-液或液相层析。或者,可通过不对称合成,使用光学活性试剂、底物、催化剂或溶剂,或通过不对称转换将一种对映异构体转化为另一种来合成特定对映异构体。
这些实例不意在限制本发明的范围,而是为技术人员制备和使用本发明化合物、组合物和方法提供指导。尽管描述了本发明的具体实施方案,但技术人员将理解,可在不背离本发明的精神和范围的情况下作出各种改变和修改。
对醚的所有提及是指乙醚;盐水是指饱和NaCl水溶液,DCM是指二氯甲烷,THF是指四氢呋喃,EtOAc是指乙酸乙酯,Hex和Hx是指己烷,IMS是指工业用甲基化酒精,TBME是指叔丁基甲醚,DMF是指二甲基甲酰胺,BOC和Boc是指叔丁氧羰基。除非另有指示,否则所有温度都以℃(摄氏度)表示。除非另有指明,否则所有反应都在室温下惰性气氛下进行。
1H NMR光谱记录在Jeol Delta2 (300 MHz)光谱仪上。化学位移以百万分率(ppm,δ单位)表示。分裂模式描述表观多重性,且命名为s(单峰)、d(双峰)、t(三重峰)、q(四重峰)、quint(五重峰)、m(多重峰)、br(宽峰)。
除非另有说明,否则“快速”且“柱层析”是指在二氧化硅上使用所述溶剂系统进行的快速柱层析。LC-MS数据在与Shimadzu LC系统(SCL-10A控制器和双UV检测器)组合的PESciex Single Quadrupole LC/MS API-150上或与Waters 2695分离模块组合的Watersmicromass ZQ上获得。
起始物质1:
N-(3,4-二氯苯基)-2,2-二甲基丙酰胺:
将3,4-二氯苯胺(150 g)溶解于1.0 L TBME中,并将溶液冷却至10℃。在机械搅拌下添加氢氧化钠(140.7g的30%水溶液)。逐滴添加新戊酰氯(125.9 mL),同时将内部温度保持在35℃以下。添加之后,将反应温度在30至35℃下再维持30分钟。然后使反应混合物冷却至室温,随后在0-5℃下维持1小时。过滤所得沉淀物,并用600 mL水/MeOH(90/10)洗涤,然后用900 mL水洗涤。将所得固体在55℃下在真空烘箱中干燥4天。得率:162g。1H-NMR (DMSO-d6)δ 9.46(s, 1H), 8.04 (d, J= 2.4 Hz, 1H), 7.65 (dd, J= 9.0. 2.4 Hz, 1H), 7.54(d, J= 9.0 Hz, 1H), 1.22 (9H, s)。
起始物质2:
6-氯-2-(1,1-二甲基乙基)-1,3-苯并噁唑-7-磺酰氯:
将N-(3,4-二氯苯基)-2,2-二甲基丙酰胺(121 g)溶解于720 mL THF中,并将溶液冷却至-50℃。添加丁基锂(433 mL,2.5N,在hex中),同时将内部温度维持在-45℃和-35℃之间。(最终温度:-35℃)。在-25℃下保持40分钟。反应混合物的HPLC检查揭示残留5-10%起始物质。在-30℃下再添加35 mL丁基锂,并在-30至-25℃下再反应30分钟(HPLC:无明显变化)。将反应混合物冷却至-45℃,并使SO2鼓泡通过溶液,直至看起来已经达到饱和。随后,将反应混合物在-10至0℃下搅拌45分钟。使氩气(2倍气球体积)鼓泡通过溶液,其后将反应混合物冷却至-5℃。添加硫酰氯(58.8 mL),同时将温度保持在22℃以下。随后,将反应混合物维持在10至15℃下1小时(HPLC:完全)。添加EtOAc,并浓缩混合物,用水、饱和碳酸氢纳水溶液和盐水洗涤,经MgSO4干燥,并在真空中蒸发溶剂。结晶出粗物质,并用热己烷研磨。得率:87.2g。 1H-NMR (DMSO-d6) δ 7.60(d, J= 8.4Hz, 1H), 7.34(d, J= 8.4Hz, 1H), 1.43(9H, s)。
中间体1:
在氩气气氛下将起始物质1 N-(3,4-二氯苯基)-2,2-二甲基丙酰胺(根据WO01/68033A2制备,其在其教导也在上文描述的起始物质1的合成的程度上通过引用并入本文)溶解于干燥THF(400 mL)中,然后冷却至-75℃。逐滴添加n-BuLi(160 mL,2.5M,在己烷中,5当量),同时将温度维持在-60℃以下。一旦添加所有n-BuLi,就将反应物在-5℃下搅拌1.5小时,然后冷却至-70℃,并添加硫(“硫华”)(13g),随后在-70℃至室温下搅拌过夜。在-10℃下搅拌反应混合物之后,溶液颜色从黄色变为棕色/橙色。将反应混合物冷却至0℃,然后用2N HCl溶液(200 mL)淬灭,并搅拌10分钟。分离有机层,并用2N NaOH溶液碱化至pH 12-13,然后用EtOAc洗涤。将水层用2M HCl溶液再酸化至约pH 1,并用二氯甲烷(2X)萃取,其用水洗涤,经Na2SO4干燥并浓缩。通过柱层析使用1:5 (EtOAc/Hex)纯化粗产物。得率:6g(30%,橙色油状物)。1H-NMR (CDCl3) δ 7.39-7.30 (m, 2H), 4.08 (s, 1H), 1.50 (9H,s)。
可选地,以如下方式制备中间体1:将三苯基膦(89g)溶解于DCM(200 mL)和DMF(2.2 mL)中。将溶液在冰/甲醇浴中冷却至-1℃。经30分钟向其中添6-氯-2-(1,1二甲基乙基)-1,3-苯并噁唑-7-磺酰氯(起始物质2)(根据WO01/68033A2制备,其在其教导也在上文描述的起始物质2的合成的程度上通过引用并入本文)(35g)于DCM(100 mL)中的溶液,并将温度保持在15℃以下。将反应混合物在室温下在氮气下搅拌18小时。使用2N盐酸(200 mL)将反应混合物淬灭。分离各相并在真空中蒸发有机层。将残余物悬浮于2N氢氧化钠(400mL)中,并快速搅拌3小时。通过过滤移除固体,并用水洗涤。将合并的滤液和洗液在冰/水浴中冷却,并用5N盐酸酸化至~pH 1。将其使用TBME(400 mL)萃取。将有机相经硫酸镁干燥,并在真空中蒸发以得到作为棕色固体的中间体1(22.85g)。
中间体2:(一般程序A)
在0℃下向(R)-(+)-3-羟基哌啶盐酸盐(1g)于DCM(20 mL)中的悬浮液中添加Et3N(3.04 mL),随后添加BOC2O (1.75 g),将其放过周末。添加水(50 mL),并用DCM(100 mL)萃取。将合并的有机物用水(2 x 50 mL)洗涤,然后用盐水(50 mL)洗涤,干燥(Na2SO4)并浓缩。将残余物进行柱层析(快速层析,用0 – 10% MeOH/DCM的梯度洗脱)。得率:1.55g。1HNMR(CDCl3) δ 3.74-3.69 (2H, m), 3.56-3.48 (1H, m), 3.18-3.03 (2H, m), 1.92-1.83(1H, m), 1.79-1.71(2H, m), 1.55-1.45 (1H, m), 1.43 (9H, s)。
中间体3:(一般程序B)
在0℃下向中间体2(1g)于DCM(10 mL)中的溶液中逐滴添加Et3N (1.38 mL),随后逐滴添加MsCl(0.46 mL)。在0℃下搅拌1小时之后,将反应物温热至室温,用水(10 mL)淬灭并分离。用DCM (2 x 20 mL)萃取水层。将合并的有机物用水(40 mL)洗涤,添加二氧化硅刮刀,干燥(NaSO4)并浓缩。得率:1.4148g。1H-NMR (CDCl3) δ 4.71 (1H, br s), 3.62 (2H, brd), 3.49-3.27 (2H, m), 3.04 (3H, s), 2.01-1.76 (3H, m), 1.791.71(2H, m),1.55-1.45 (1H, m), 1.45 (9H, s)。
中间体4:(一般程序C)
向NaH(0.30g)于THF(20 mL)中的悬浮液中逐滴添加中间体1(使用起始物质1)(1.22g)。搅拌1小时之后,添加THF中的中间体3(1.41g),并将反应物加热至80℃,并放置过夜。将反应混合物冷却至室温,然后用饱和NaHCO3水溶液(50 mL)淬灭。用DCM(2 x 50 mL)萃取反应混合物。用水(100 mL)洗涤合并的有机物,干燥(Na2SO4)并浓缩。将残余物进行柱层析(快速层析,20% EtOAC/Hx,二氧化硅)。得率:946.9mg。1H-NMR (CDCl3) δ 7.50 (d, J= 7.9Hz, 1H), 7.38 (d, J= 7.9Hz, 1H), 3.82 (d, J= 13.4Hz, 1H), 3.55-3.45 (m,1H), 3.00-2.80 (m, 2H)。
中间体5:(一般程序D)
在-10℃下向中间体4(946.9mg)于DCM(10 mL)中的溶液中添加DCM(10 mL)中的mCPBA(2.31g)。将反应物在-10℃下搅拌1小时,然后温热至室温。将反应混合物用饱和NaHCO3水溶液(50 mL)淬灭,然后用DCM(2 x 70 mL)萃取。将合并的有机物用水(50 mL)洗涤,干燥(Na2SO4)并浓缩。将残余物进行柱层析(快速层析,30% EtOAc/Hx,二氧化硅)。得率353.6mg(35%,黄色油状物)。MS (m/z, ES+, M+H): 457.08。
中间体6:(一般程序E)
向中间体5 (353mg)于IMS (5 mL)中的溶液中添加浓HCl水溶液(5 mL)。然后将反应物加热至80℃,并放置过夜。将反应混合物冷却至室温,并浓缩以移除IMS。将残余物用饱和NaOH水溶液碱化至pH 12,在0℃下添加EtOAc(30 mL)、BOC2O (1当量,0.17g)并放置过夜。分离反应混合物,并用EtOAc (2 x 30 mL)萃取水层。(用Na2SO4)干燥合并的有机物并浓缩。将残余物进行柱层析(快速层析,用10%-30% EA/Hx的梯度洗脱)。得率:分离两种含有产物的级分:58.0mg和180.9mg。MS (m/z, ES+, M+H): 291.01。
中间体7:(一般程序F)
在氩气气氛下,在室温下将3-氟-2-甲基苯胺(7.4g)溶解于DCM(220 mL)中。冷却至0℃之后,添加饱和NaHCO3水溶液(220 mL),随后添加三光气(5.85g)。将反应物在0℃下搅拌1小时。此后,用DCM(2 x 50 mL)萃取产物。将有机级分合并,经MgSO4干燥,并在真空中移除溶剂,以得到黄色油状物。添加己烷,允许沉淀白色盐,将其过滤出。在真空中移除己烷,得到黄色油状物(7.69g,86%)。1H-NMR (CDCl3) δ 7.09 (dd, 1H), 6.92-6.85 (m, 2H),2.24 (s, 3H)。
中间体8:(一般程序G)
向中间体6(60mg)于DCM(3 mL)中的溶液中添加中间体7(70mg),并将反应物放过周末。浓缩反应混合物,并将残余物进行柱层析(快速层析,用20%-30% EtOAc/Hx的梯度洗脱)。得率:56.2mg。MS (m/z, ES+, M+H): 542.01。
实施例1 N-{4-氯-2-羟基-3-[(3S)-3-哌啶基磺酰基]苯基}-N'-(3-氟-2甲基苯基)脲。(一般程序H)
将中间体8 (56.2 mg)和4N HCl/二氧杂环己烷(3 mL)在室温下一起搅拌,并放置过夜。如上所述制备中间体6、5、4、3和2。使用起始物质1制备中间体1,用于合成实例1。浓缩反应混合物,并将残余物溶解于最少量MeOH中,并添加Et2O。固体析出(crashed out),将其过滤并干燥。粗品得率:28.4mg。将粗产物溶解于最少量MeOH中,并添加Et2O。固体析出,倾析出溶剂并干燥固体。得率:18.8mg。MS (m/z, ES+, M+H): 441.98. NMR (MeOD) δ 8.40(1H, d, ArH), 7.46 (1H, d, ArH), 7.19-7.15 (2H, m, ArH), 6.85 (1H, t, ArH),4.14 (1H, dt, CH), 3.66 (1H, dd, CH), 3.37 (2H, d, CH2), 3.04 (1H, dt, CH),2.19 (3H, S, ArCH3), 2.14-1.69 (4H, m, 2xCH2)。
本发明的一个实施方案涵盖包含单独和/或与一种或多种额外治疗剂组合的式(I)化合物的组合。例如,在一个实施方案中,本发明涵盖包含与选自表2、表3和/或表4中的那些的一种或多种抗微生物剂组合的式(I)化合物的组合。在一个实施方案中,所述抗微生物剂选自存在于表2中的抗病毒剂。
表2
在本发明的其它实施方案中,抗病毒剂选自阿昔洛韦、更昔洛韦、干扰素、硫汞(thimerasol)、碘苷(idoxuridine)、阿糖腺苷、曲氟尿苷、泛昔洛韦、伐昔洛韦、喷昔洛韦、更昔洛韦、双嘧达莫、依姆帕辛(impulsin)、普利康纳利(pleconaril)、膦甲酸(foscarnet)、西多福韦、ICI 130,685、缬更昔洛韦(valganciclovir)、阿昔洛韦、碘苷、阿糖腺苷或伐昔洛韦。
在本发明的一个实施方案中,所述抗微生物剂为扎那米韦。
扎那米韦是一种市售的有效流感病毒神经氨酸酶抑制剂,称为Relenza®,且被美国FDA批准用于治疗和预防流感。
扎那米韦的合成描述于von Izstein等人的美国专利号5,360,817的实施例3中,所述专利以其全文通过引用并入本文。例如,其中将扎那米韦的制备方法描述为:用三氟化硼合乙醚(boron trifluoride ethearate)将式(II)的5-乙酰胺基-4-乙酰氧基-6-(l,2,3-三乙酰氧基丙基)-5,6-二氢-4H-吡喃-2-甲酸酯脱乙酰基,得到式(III)的5-乙酰胺基-4-羟基-6(l,2,3-三乙酰氧基丙基)-5,6-二氢-4H-吡喃-2-甲酸酯,其进一步用三氟甲磺酸酐和叠氮化钠处理,得到式(IV)的5-乙酰胺基-4-叠氮基6-(l,2,3-三乙酰氧基丙基)-5,6-二氢-4H-吡喃-2-甲酸酯。在吡啶中用硫化氢使式(IV)的中间体化合物还原,得到相应的式(V)的5-乙酰胺基-4-氨基-6-(l,2,3-三乙酰氧基丙基)-5,6-二氢-4H-吡喃-2-甲酸酯中间体,最后与S-甲基异硫脲在水中缩合,并通过Dowex 50W在氢氧化铵水溶液中皂化来得到扎那米韦。
在本发明的其它实施方案中,所述抗微生物剂为抗生素。出于本发明的目的,式(I)化合物与抗微生物剂(诸如抗生素)的组合为患有呼吸道细菌传染性疾病的受试者提供有效治疗疗法。本文中可互换使用的术语“抗细菌剂”或“抗生素”意指具有杀死或抑制或阻止生物细胞生长的效果的天然或合成化学品。本发明组合方法和组合物所涵盖的抗细菌剂的实例包括那些在下表3中所列的抗生素和抗生素类别。参见Todar, K.,Todar的Textbookof Bacteriology, University of Wisconsin-Madison, Department of Bacteriology(2002)和The Merck Manual, Sec. 13. 章节153., "Antibacterial Drugs," 第17版(1999)。
表3
表4
在其它实施方案中,本发明涵盖包含式(I)化合物与一种或多种选自表2、表3和/或表4中的那些试剂的抗微生物剂组合和还任选地与一种或多种其它常规呼吸道治疗剂组合的组合。
如本文所用,术语“常规呼吸道治疗剂”包括治疗或缓和(无论如何轻微)由患有呼吸道传染性疾病引起的任何症状且并非式(I)化合物或抗微生物剂的任何这样的呼吸道传染性疾病治疗。
出于本发明的目的,合适的常规呼吸道治疗剂可包含一种或多种选自以下的试剂:抗炎剂(例如,Cox-2抑制剂、Cox-2/Cox-1抑制剂、NSAID)、抗组胺、抗胆碱药(特别是M1/M2/M3受体拮抗剂)、β2-肾上腺素能受体激动剂、类固醇(例如,皮质类固醇)、PDE4抑制剂(例如,罗氟司特)、解除充血剂。
在本文中可互换使用的术语“环氧合酶-2抑制剂”或“Cox-2抑制剂”包括抑制Cox-2酶的化合物,无论对Cox-1酶的抑制程度,且包括那些化合物的药学上可接受的盐。因此,出于本发明的目的,将化合物视为Cox-2抑制剂,不论该化合物抑制Cox-2酶的程度是否等于、大于或小于Cox-1酶。在本发明的一个实施方案中,Cox-2抑制剂优选为非类固醇抗炎药(NSAID)。因此,可充当本发明Cox-2抑制剂的优选物质包括非类固醇抗炎药化合物、其药学上可接受的盐或其纯(-)或(+)光学异构形式。
抗炎剂的实例包括非类固醇抗炎药(NSAID)。可用于本发明的合适NSAID化合物包括阿西美辛、乙酰水杨酸、阿氯芬酸、阿明洛芬、阿扎丙宗、苯乐来、苯恶洛芬、布氯酸、卡洛芬、三水杨酸胆碱镁、环氯茚酸、氯吡酸(clopinac)、氨苯砜、双氯芬酸、双氟尼酸、屈昔康、依托度酸、非诺洛芬、苯布芬、fenclofenec、芬替酸(fentiazac)、夫洛非宁(floctafenine)、氟苯柳、氟比洛芬、(r)-氟比洛芬、(s)-氟比洛芬、呋罗芬酸、非普拉宗、氟芬那酸、氟洛芬、异丁芬酸、伊布洛芬(ibuprofen)、吲哚美辛(indometacin)、茚甲新(indomethacin)、吲哚布洛芬、伊索克酸、伊索昔康、酮洛芬、酮洛酸、咪洛芬、吡罗昔康、美洛昔康、甲芬那(mefenamic)、甲灭酸(mefenamic acid)、甲氯芬那酸、甲氯芬(meclofen)、萘丁美酮、萘普生、尼氟酸、奥沙普秦、oxipinac、羟基保泰松、苯基丁氮酮、鬼臼毒素衍生物、丙谷美辛、piprofen、比丙芬、prapoprofen、水杨酸、水杨酸酯、舒多昔康、舒洛芬、舒林酸(sulindac)、替诺昔康、噻洛芬酸、硫平酸、硫恶洛芬、托芬那酸、托美丁、齐多美辛、佐美酸(zomepirac)和2-氟-a-甲基[1 ,1 '-联苯]-4-乙酸、4-(硝基氧基)丁酯。
其它合适的NSAID化合物包括伊布洛芬、萘普生、舒林酸、酮洛芬(ketoporfen)、非诺洛芬、噻洛芬酸、舒洛芬、依托度酸、卡洛芬、酮洛酸(ketrolac)、piprofen、吲哚布洛芬、水杨酸和氟比洛芬。
在一个实施方案中,本发明涵盖包含式I化合物与β2-肾上腺素能受体激动剂的组合。
β2-肾上腺素能受体激动剂的实例包括维兰特罗、沙美特罗(其可以是外消旋物或单一对映异构体,诸如R-对映异构体)、沙丁胺醇(其可以是外消旋物或单一对映异构体,诸如R-对映异构体)、福莫特罗(其可以是外消旋物或单一对映异构体,诸如R,R-非对映异构体)、沙甲胺醇、非诺特罗、卡莫特罗、依坦特罗、那明特罗、克伦特罗、吡布特罗、氟丁特罗(flerbuterol)、瑞普特罗、班布特罗、茚达特罗、特布他林和其盐,例如沙美特罗的羟萘甲酸(1-羟基-2-萘甲酸盐)盐、沙丁胺醇的硫酸盐或游离碱或福莫特罗的富马酸盐。在一个实施方案中,β2-肾上腺素能受体激动剂是长效β2-肾上腺素能受体激动剂,例如提供有效扩张支气管约12小时或更长时间的化合物。
其它β2-肾上腺素能受体激动剂包括WO2002/066422、WO2002/070490、WO2002/076933、WO2003/024439、WO2003/072539、WO2003/091204、WO2004/016578、WO2004/022547、WO2004/037807、WO2004/037773、WO2004/037768、WO2004/039762、WO2004/039766、WO2001/42193和WO2003/042160中描述的那些。
β2-肾上腺素能受体激动剂的其它实例包括:
3-(4-{[6-({(2R)-2-羟基-2-[4-羟基-3(羟基甲基)苯基]乙基}氨基)己基] 氧基} 丁基) 苯磺酰胺;
3-(3-{[7-({(2R)-2-羟基-2-[4-羟基-3-羟基甲基) 苯基] 乙基}-氨基) 庚基] 氧基} 丙基) 苯磺酰胺;
4-{(1R)-2-[(6-{2-[(2, 6-二氯苄基) 氧基] 乙氧基} 己基) 氨基]-1-羟基乙基}2-(羟基甲基)苯酚;
4-{(1R)-2-[(6-{4-[3-(环戊基磺酰基)苯基]丁氧基}己基)氨基]-1羟基乙基}-2-(羟基甲基)苯酚;
N-[2-羟基l-5-[(1R)-1-羟基-2-[[2-4-[[(2R)-2-羟基-2苯基乙基]氨基]苯基]乙基]氨基]乙基]苯基]甲酰胺;
N-2{2-[4-(3-苯基-4-甲氧基苯基)氨基苯基]乙基}-2-羟基-2-(8-羟基2(1H)-喹啉酮-5-基)乙胺;和
5-[(R)-2-(2-{4-[4-(2-氨基-2-甲基-丙氧基)-苯基氨基]-苯基}-乙基氨基)1-羟基-乙基]-8-羟基-1H-喹啉-2-酮。
β2-肾上腺素能受体激动剂可呈与选自以下的药学上可接受的酸形成的盐的形式:硫酸、盐酸、富马酸、羟基萘甲酸(例如1-或3-羟基-2-萘甲酸)、肉桂酸、取代的肉桂酸、三苯基乙酸、氨基磺酸、磺胺酸、萘丙烯酸、苯甲酸、4-甲氧基苯甲酸、2-或4-羟基苯甲酸、4-氯苯甲酸和4-苯基苯甲酸。
合适的抗炎剂包括皮质类固醇。可与本发明式I化合物组合使用的皮质类固醇的实例为那些口服和吸入皮质类固醇和其具有抗炎活性的前药。实例包括甲基泼尼松龙、泼尼松龙、地塞米松、氟替卡松丙酸酯、6α,9α-二氟-11β-羟基-16α-甲基-17α-[(4-甲基-1,3-噻唑-5-羰基)氧基]-3-氧代-雄甾-1,4-二烯-17β-羧硫代酸S-氟甲酯、6α,9α-二氟-17α-[(2-呋喃基羰基)氧基]-11β-羟基-16α-甲基-3-氧代-雄甾-1,4-二烯-17β-羧硫代酸S-氟甲酯(糠酸氟替卡松)、6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-丙酰基氧基-雄甾-1,4-二烯-17β-羧硫代酸S-(2-氧代-四氢-呋喃-3S-基)酯、6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-(2,2,3,3-四甲基环丙基羰基)氧基-雄甾-1,4-二烯-17β-甲酸氰基甲酯和6α,9α-二氟-11β-羟基-16α-甲基-17α-(1-甲基环丙基羰基)氧基-3-氧代-雄甾-1,4-二烯-17β-羧硫代酸S-氟甲酯、倍氯米松酯(例如17-丙酸酯或17,21-二丙酸酯)、布地奈德、氟尼缩松、莫米他松酯(例如糠酸莫米他松)、曲安奈德(triamcinolone acetonide)、罗氟奈德、环索奈德(16α,17-[[(R)-环己基亚甲基]双(氧基)]-11β,21-二羟基-孕甾-1,4-二烯-3,20-二酮)、丙酸布替可特(butixocort)、RPR-106541和ST-126。在一个实施方案中,皮质类固醇包括氟替卡松丙酸酯、6α,9α-二氟-11β-羟基-16α-甲基-17α-[(4-甲基-1,3-噻唑-5-羰基)氧基]-3-氧代-雄甾-1,4-二烯-17β-羧硫代酸S-氟甲酯、6α,9α-二氟-17α-[(2-呋喃基羰基)氧基]-11β-羟基-16α-甲基-3-氧代-雄甾-1,4-二烯-17β-羧硫代酸S-氟甲酯、6α,9α-二氟-11β-羟基-16α-甲基-3-氧代-17α-(2,2,3,3-四甲基环丙基羰基)氧基-雄甾-1,4-二烯-17β-甲酸氰基甲酯和6α,9α-二氟-11β-羟基-16α-甲基-17α-(1-甲基环丙基羰基)氧基-3-氧代-雄甾-1,4-二烯-17β-羧硫代酸S-氟甲酯。在一个实施方案中,皮质类固醇为6α,9α-二氟-17α-[(2-呋喃基羰基)氧基]-11β-羟基-16α-甲基-3-氧代-雄甾-1,4-二烯-17β-羧硫代酸S-氟甲酯。
皮质类固醇的实例可包括WO2002/088167、WO2002/100879、WO2002/12265、WO2002/12266、WO2005/005451、WO2005/005452、WO2006/072599和WO2006/072600中描述的那些。
对可具有转录抑制的选择性可强于转录激活的选择性且可用于组合疗法中的具有糖皮质激素激动作用的非类固醇化合物包括以下公开专利申请和专利中覆盖的那些:WO1998/54159、WO2000/66590、WO2001/16128、WO2002/02565、WO2003/059899、WO2003/061651、WO2003/082280、WO2003/082787、WO2003/082827、WO2003/086294、WO2003/101932、WO2003/104195、WO2004/005229、WO2004/009017、WO2004/018429、WO2004/026248、WO2006/000398、WO2006/000401、WO2006/015870、WO2006/108699、WO2007/000334、WO2007/054294、WO2007/122165、WO2007/144327和WO2008/000777。
在一个实施方案中,本发明使用式(I)化合物与磷酸二酯酶4(PDE4)抑制剂的组合,例如在适用于吸入的制剂的情况下。可用于本发明的该方面的PDE4抑制剂可以是已知或发现充当PDE4抑制剂(例如PDE4B和/或PDE4D的抑制剂)的任何化合物。
PDE4抑制剂化合物包括顺-4-氰基-4-(3-环戊基氧基-4甲氧基苯基)环己-1-甲酸、2-甲氧甲酰基-4-氰基-4-(3-环丙基甲氧基-4-二氟甲氧基苯基)环己-1-酮和顺-[4-氰基-4-(3环丙基甲氧基-4-二氟甲氧基苯基)环己-1-醇]。还有,1996年9月3日授权的美国专利5,552,438中描述的顺-4-氰基-4-[3(环戊基氧基)-4-甲氧基苯基]环己烷-1-甲酸(也称为西洛司特)和其盐、酯、前药或物理形式;该专利和其公开的化合物全部通过引用并入本文。
其它PDE4抑制化合物包括AWD-12-281(N-(3,5-二氯-4-吡啶基)-1-[4-氟苯基)甲基]-5-羟基-α-氧代-1H-吲哚-3-乙酰胺),其来自Elbion(Hofgen, N.等人.15th EFMC IntSymp Med Chem(9月6-10日,Edinburgh)1998,Abst P.98;CAS索引号247584020-9);命名为NCS-613的9-苄基腺嘌呤衍生物(INSERM);来自Chiroscience and Schering-Plough的D-4418;鉴定为CI-1018且归属于Pfizer的苯并二氮杂䓬PDE4抑制剂(PD-168787);KyowaHakko在WO99/16766中公开的苯并二氧杂环戊烯衍生物;来自Kyowa Hakko的K-34;V-11294A,其来自Napp(Landells, L.J.等人Eur Resp J[Annu Cong Eur Resp Soc(9月19-23日,Geneva)1998]1998,12(增刊28):Abst P.2393);罗氟司特(3-(环丙基甲氧基)-N-(3,5-二氯-4-吡啶基)-4-(二氟甲氧基)苯甲酰胺)(参见Byk Gulden Lomberg的EP 0 706 513B1,例如参见其实施例5);来自Byk-Gulden的杂环聚芳醚(WO1999/47505);Pumafentrine,(-)-p-[(4aR*,10bS*)-9-乙氧基-1,2,3,4,4a,10b-六氢-8-甲氧基-2-甲基苯并[c][1,6]萘啶-6-基]-N,N-二异丙基苯甲酰胺,其为由Byk-Gulden(现为Altana)制备和公开的混合PDE3/PDE4抑制剂;Almirall-Prodesfarma正在开发的阿罗茶碱(arofylline);来自Vernalis的VM554/UM565;或T-440(Tanabe Seiyaku;Fuji, K.等人,J Pharmacol ExpTher, 1998, 284(1):162)和T2585。
其它PDE4抑制化合物公开于公开的国际专利申请WO2004/024728、WO2004/056823、WO2004/103998(例如其中公开的实施例399或544)、WO2005/058892、WO2005/090348、WO2005/090353和WO2005/090354,其全部在Glaxo Group Limited名下。
抗胆碱药的实例是充当蕈毒碱受体的拮抗剂的那些化合物,具体而言作为M1或M3受体的拮抗剂、M1/M3或M2/M3受体的双重拮抗剂或M1/M2/M3受体的泛拮抗剂的那些化合物。经由吸入施用的示例性化合物包括异丙托铵(ipratropium)(例如,作为溴化物,CAS22254-24-6,以名称Atrovent销售)、氧托溴铵(oxitropium)(例如,作为溴化物,CAS30286-75-0)和噻托溴铵(tiotropium)(例如,作为溴化物,CAS 136310-93-5,以名称Spiriva销售)。还感兴趣的是瑞伐托酯(revatropate)(例如,作为氢溴化物,CAS 262586-79-8)和WO2001/04118中所公开的LAS-34273。用于口服施用的示例性化合物包括哌仑西平(CAS 28797-61-7)、达非那新(CAS 133099-04-4或对于以名称Enablex销售的氢溴化物的CAS 133099-07-7)、奥昔布宁(CAS 5633-20-5,以名称Ditropan销售)、特罗地林(CAS15793-40-5)、托特罗定(CAS 124937-51-5或对于名称Detrol销售的酒石酸盐的CAS124937-52-6)、奥替溴铵(例如,作为溴化物,CAS 26095-59-0,以名称Spasmomen销售)、曲司氯铵(trospium chloride)(CAS 10405-02-4)和索利那新(CAS 242478-37-1或对于也称为YM-905且以名称Vesicare销售的琥珀酸盐的CAS 242478-38-2)。
其它化合物公开在WO 2005/037280、WO 2005/046586和WO 2005/104745中,其通过引用并入本文。本发明组合包括但不限于:
(3-内)-3-(2,2-二-2-噻吩基乙烯基)-8,8-二甲基-8-氮鎓二环[3.2.1]辛烷碘化物;
(3-内)-3-(2-氰基-2,2-二苯基乙基)-8,8-二甲基-8-氮鎓二环[3.2.1]辛烷溴化物;
4-[羟基(二苯基)甲基]-1-{2-[(苯基甲基)氧基]乙基}-1-氮鎓二环[2.2.2]辛烷溴化物;和
(1R,5S)-3-(2-氰基-2,2-二苯基乙基)-8-甲基-8-{2-[(苯基甲基)氧基]乙基}-8-氮鎓二环[3.2.1]辛烷溴化物。
在一个实施方案中,本发明提供包含式(I)化合物或其药学上可接受的盐连同抗组胺(诸如H1拮抗剂)的组合。合适的H1拮抗剂的实例包括但不限于苯海拉明、amelexanox、阿司咪唑、阿扎他啶、氮卓斯汀、阿伐斯汀、溴苯那敏、西替利嗪、左旋西替利嗪、乙氟利嗪、氯苯那敏、克立马丁、赛克利嗪、卡瑞斯汀、赛庚啶、卡比沙明、去羧乙氧基氯雷他定、多西拉敏、二甲茚定、依巴斯汀、依匹斯汀、乙氟利嗪、非索非那定、羟嗪、酮替芬、氯雷他定、左卡巴斯汀、咪唑斯汀、美喹他嗪、米安色林、诺白拉斯啶、氯苯甲嗪、诺阿司咪唑、奥洛他定、哌香豆司特、吡拉明、异丙嗪、特非那定、曲吡那敏、泰美拉斯、异丁嗪和曲普利啶,尤其是氮卓斯汀、西替利嗪、左旋西替利嗪、乙氟利嗪和非索非那定。
在另一个实施方案中,本发明提供包含式(I)化合物或其药学上可接受的盐连同H3拮抗剂(和/或反向激动剂)的组合。H3拮抗剂的实例包括例如WO2004/035556、WO2006/045416、WO2006/090142、WO2006/125665、WO2007/009739和WO2007/009741中公开的那些化合物。在另一个实施方案中,本发明提供包含式(I)化合物或其药学上可接受的盐连同H1/H3双重拮抗剂(和/或反向激动剂)的组合。H1/H3双重拮抗剂的实例包括例如WO2004/035556、WO2007/071691、WO2007/122156和WO2007/135081中公开的那些化合物。在另一个实施方案中,本发明提供包含式(I)化合物或其药学上可接受的盐连同选自3-(4-{[4-(4-{[3-(3,3-二甲基-1-哌啶基)丙基]氧基}苯基)-1-哌啶基]羰基}-1萘基) 丙酸和4-[(4-氯苯基)甲基]-2-({(2R)-1-[4-(4-{[3-(六氢-1H氮杂䓬-1-基)丙基]氧基}苯基)丁基]-2-吡咯烷基}甲基)-1(2H)-杂环聚芳醚的H1/H3双重拮抗剂的组合。可与本发明化合物组合使用的其它组胺受体拮抗剂包括H4受体的拮抗剂(和/或反向激动剂),例如公开Jablonowski等人,J. Med. Chem. 46: 3957-3960(2003)中公开的化合物。
其它合适的常规呼吸道治疗剂包括色甘酸钠、奈多罗米钠、磷酸二酯酶(PDE)抑制剂(例如,茶碱、PDE4抑制剂或混合PDE3/PDE4抑制剂)、白三烯拮抗剂、白三烯合成抑制剂(例如孟鲁司特)、iNOS抑制剂、类胰蛋白酶和弹性蛋白酶抑制剂、β-2整联蛋白拮抗剂和腺苷受体激动剂或拮抗剂(例如腺苷2a激动剂)、细胞因子拮抗剂(例如趋化因子拮抗剂,诸如CCR3拮抗剂)或细胞因子合成抑制剂或者5-脂氧化酶抑制剂。在一个实施方案中,本发明涵盖用于口服施用的iNOS(诱导型一氧化氮合成酶)抑制剂。iNOS抑制剂的实例包括WO1993/13055、WO1998/30537、WO2002/50021、WO1995/34534和WO1999/62875中公开的那些。CCR3抑制剂的实例包括WO2002/26722中公开的那些。
在本发明的其它实施方案中,常规呼吸道治疗剂可选自:芬那酯(fenamate)、吡咯烷酸、吡唑啉酮衍生物、昔康类、普莫卡因(pramoxine)、阿扎他啶、氯苯甲嗪、异丙嗪溴苯海拉明、溴苯那敏、马来酸溴苯那敏、卡比沙明、氯苯那敏、右旋氯苯那敏(dexchlorpheniramine)、苯海拉明、多西拉敏、苯茚胺(phenindamine)、非尼拉敏(pheniramine)、苯托沙敏、吡拉明、曲普利啶、克立马丁、茶苯海明(dimenhydrinate)、西替利嗪、特非那定、阿司咪唑、氯雷他定、阿伐斯汀、羟嗪、美克洛嗪(meclozine)、丙氯拉嗪(compazine)、丙咪嗪(imipramine)、多昔平(doxopin)、阿米替林(amitryptoline)、曲吡那敏、非索非那定、阿扎他啶、麻黄碱(ephedrine)、肾上腺素(ephinephrine)、左旋脱氧麻黄碱(levodesoxyephedrine)、羟甲唑啉、萘甲唑啉、苯肾上腺素(phenylephrine)、苯丙醇胺、环己丙甲胺、假麻黄碱、丁苄唑啉、氯己定、红汞、聚维酮碘、聚羟碘(polyhyroxineiodine)、甲酚盐、氢化可的松、强的松、氟泼尼龙、地塞米松、倍他米松、戊酸倍他米松、甲泼尼龙、氟轻松(fluocinolone acetonide)、丙酮缩氟氢羟龙(flurandrenoloneacetonide)、氟米龙、可的松、泼尼松龙、阿氯米松、安西奈德、倍他米松、氯倍他索、氯可托龙、地奈德、去羟米松、双氟拉松、醋酸氟轻松、氟氢缩松、氟替卡松、哈西奈德、乌倍他索、莫米他松、氟甲松、泼尼卡酯、曲安西龙、克霉唑、灰黄霉素、十一碳烯(undecylenic)、益康唑、咪康唑、酮康唑、硫康唑、奥昔康唑、氟康唑、伊曲康唑、制霉菌素、奈替芬、特比萘芬、环匹罗司、布替萘芬、卤普罗近、托萘酯、妥布霉素加上地塞米松、乙酸间甲苯酯、双-(2-吡啶基-1-氧化物)二硫化物、乙酰胺酚、磺胺米隆和其混合物。
因此,在本发明的一个实施方案中,提供包含Danirixin与神经氨酸酶抑制剂化合物的组合的组合物。
在本发明的另一个实施方案中,提供包含danirixin与扎那米韦的组合的组合物。
在本发明的另一个实施方案中,提供包含danirixin与奥司他韦的组合的组合物。
在本发明的另一个实施方案中,提供包含danirixin与利巴韦林的组合的组合物。
在本发明的另一个实施方案中,提供包含danirixin与法匹拉韦的组合的组合物。
在本发明的另一个实施方案中,提供包含danirixin与一种或多种选自表4的抗微生物剂的组合的组合物。
在本发明的另一个实施方案中,提供包含danirixin与神经氨酸酶抑制剂化合物的组合和药学上可接受的赋形剂的药物组合物。
在本发明的另一个实施方案中,提供包含danirixin与扎那米韦的组合和药学上可接受的赋形剂的药物组合物。
在本发明的另一个实施方案中,提供包含danirixin与奥司他韦的组合和药学上可接受的赋形剂的药物组合物。
在本发明的另一个实施方案中,提供包含danirixin与利巴韦林的组合和药学上可接受的赋形剂的药物组合物。
在本发明的另一个实施方案中,提供包含danirixin与一种或多种选自表4的抗微生物剂的组合和药学上可接受的赋形剂的组合物。
在本发明的另一个实施方案中,提供治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin与神经氨酸酶抑制剂化合物的组合。
在本发明的另一个实施方案中,提供治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin与扎那米韦的组合。
在本发明的另一个实施方案中,提供治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin与奥司他韦的组合。
在本发明的另一个实施方案中,提供治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin与利巴韦林的组合。
在本发明的另一个实施方案中,提供治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin与法匹拉韦的组合。
在本发明的另一个实施方案中,提供治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin与一种或多种选自表4的抗微生物剂的组合。
在本发明的另一个实施方案中,提供治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin与神经氨酸酶抑制剂化合物的组合,其中所述呼吸道传染性疾病为流感。
在本发明的另一个实施方案中,提供治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin与神经氨酸酶抑制剂化合物的组合,其中所述danirixin与神经氨酸酶抑制剂化合物的组合以相同剂型施用。
在本发明的另一个实施方案中,提供治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin与神经氨酸酶抑制剂化合物的组合,其中所述danirixin与神经氨酸酶抑制剂化合物的组合同时施用。
在本发明的另一个实施方案中,提供治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin与神经氨酸酶抑制剂化合物的组合,其中所述danirixin与神经氨酸酶抑制剂化合物的组合分开施用。
在本发明的另一个实施方案中,提供治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin与神经氨酸酶抑制剂化合物的组合,其中所述danirixin与神经氨酸酶抑制剂化合物的组合以相同剂型施用。
在本发明的另一个实施方案中,提供治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin与神经氨酸酶抑制剂化合物的组合,其中所述danirixin化合物与神经氨酸酶抑制剂化合物的组合同时施用。
在本发明的另一个实施方案中,提供治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin与利巴韦林的组合。
在本发明的另一个实施方案中,提供治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin与利巴韦林的组合,其中所述danirixin化合物与利巴韦林的组合同时施用。
在本发明的另一个实施方案中,提供治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin与利巴韦林的组合,其中所述danirixin与利巴韦林的组合以相同剂型施用。
在本发明的另一个实施方案中,提供治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin与利巴韦林的组合,其中所述danirixin化合物与利巴韦林的组合同时施用。
在本发明的另一个实施方案中,提供治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin与利巴韦林的组合,其中所述danirixin与利巴韦林的组合分开施用。
用于治疗受试者的流感的方法,所述方法包括向患有流感的受试者施用danirixin。
用于治疗受试者的RSV的方法,所述方法包括向患有RSV的受试者施用danirixin。
用于静脉内施用的药物组合物,其包含:水溶液中作为氢溴酸盐的danirixin。
用于静脉内施用的药物组合物,其包含:水溶液中作为氢溴酸盐的danirixin和药学上可接受的赋形剂。
用于静脉内施用的药物组合物,其包含:水溶液中作为氢溴酸盐的danirixin和药学上可接受的赋形剂,其中所述药学上可接受的赋形剂包含环糊精。
用于静脉内施用的药物组合物,其包含:水溶液中作为氢溴酸盐的danirixin和药学上可接受的赋形剂,其中所述药学上可接受的赋形剂包含β-环糊精。
用于静脉内施用的药物组合物,其包含:水溶液中作为氢溴酸盐的danirixin和药学上可接受的赋形剂,其中所述药学上可接受的赋形剂包含磺基丁醚。
用于静脉内施用的药物组合物,其包含:水溶液中作为氢溴酸盐的danirixin和药学上可接受的赋形剂,其中所述药学上可接受的赋形剂包含β-环糊精和磺基丁醚。
用于静脉内施用的药物组合物,其包含:水溶液中作为氢溴酸盐的danirixin和药学上可接受的赋形剂,其中所述药学上可接受的赋形剂包含Captisol®。
用于治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用用于静脉内施用的药物组合物,其包含:水溶液中作为氢溴酸盐的danirixin和药学上可接受的赋形剂。
用于治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用用于静脉内施用的药物组合物,其包含:水溶液中作为氢溴酸盐的danirixin和药学上可接受的赋形剂,其中所述药学上可接受的赋形剂包含环糊精。
用于治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用用于静脉内施用的药物组合物,其包含:水溶液中作为氢溴酸盐的danirixin和药学上可接受的赋形剂,其中所述药学上可接受的赋形剂包含β-环糊精。
施用和制剂
在另一个实施方案中,提供包含单独或者与抗微生物剂和/或常规呼吸道治疗剂组合的药学上可接受的稀释剂以及治疗有效量的式(I)化合物或其药学上可接受的盐的药物组合物。
本发明化合物可以药学上可接受的盐形式提供。术语“药学上可接受的盐”是指从药学上可接受的无机和有机酸和碱制备的盐。因此,“化合物或其药学上可接受的盐”的上下文中的词语“或”应当理解为是指化合物或其药学上可接受的盐(可选地)或化合物或其药学上可接受的盐(组合地)。
如本文所用,术语“药学上可接受的”是指在合理医药判断的范围内适于与人类和动物组织接触而无过度毒性、刺激性或其它问题或并发症的那些化合物、物质、组合物和剂型。技术人员将理解,可制备根据式I、II或III的化合物的药学上可接受的盐。这些药学上可接受的盐可在分离和纯化化合物期间原位制备,或通过分别使呈其游离酸或游离碱形式的纯化化合物分别与合适碱或酸反应制备。
本发明化合物的说明性药学上可接受的酸式盐可由以下酸制备,包括但不限于甲酸、乙酸、丙酸、苯甲酸、琥珀酸、乙醇酸、葡萄糖酸、乳酸、马来酸、苹果酸、酒石酸、柠檬酸、硝酸、抗坏血酸、葡糖醛酸、马来酸、富马酸、丙酮酸、天冬氨酸、谷氨酸、苯甲酸、盐酸、氢溴酸、氢碘酸、异柠檬酸、三氟乙酸、双羟萘酸、丙酸、邻氨基苯甲酸、甲磺酸(mesylic)、草酰乙酸、油酸、硬脂酸、水杨酸、对羟基苯甲酸、烟碱酸、苯乙酸、扁桃酸、恩贝酸(双羟萘酸)、甲磺酸、磷酸、膦酸、乙磺酸、苯磺酸、泛酸、甲苯磺酸、2-羟乙磺酸、磺胺酸、硫酸、水杨酸、环己胺基磺酸、海藻酸、β-羟基丁酸、粘酸和半乳糖醛酸。优选的药学上可接受的盐包括盐酸和三氟乙酸的盐。
本发明化合物的说明性药学上可接受的无机碱式盐包括金属离子。更优选的金属离子包括但不限于适当碱金属盐、碱土金属盐和其它生理上可接受的金属离子。衍生自无机碱的盐包括其常见价态的铝盐、铵盐、钙盐、铜盐、三价铁盐、二价铁盐、锂盐、镁盐、三价锰盐、二价锰盐、钾盐、钠盐、锌盐等。示例性碱式盐包括铝盐、钙盐、锂盐、镁盐、钾盐、钠盐和锌盐。其它示例性碱式盐包括铵盐、钙盐、镁盐、钾盐和钠盐。还有其它示例性碱式盐包括例如氢氧化物、碳酸盐、氢化物和醇盐,包括NaOH、KOH、Na2CO3、K2CO3、NaH和叔丁醇钾。
衍生自药学上可接受的有机无毒性碱的盐包括以下物质的盐:伯胺、仲胺和叔胺(部分包括三甲胺、二乙胺、N, N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、葡甲胺(N-甲基葡糖胺)和普鲁卡因;取代的胺(包括天然存在的取代的胺);环状胺;季铵阳离子;和碱性离子交换树脂,诸如精氨酸、甜菜碱、咖啡因、胆碱、N,N-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、葡萄糖胺、组氨酸、海巴明(hydrabamine)、异丙胺、赖氨酸、甲基葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。
所有上述盐均可由本领域技术人员通过常规方式从本发明相应化合物制备。例如,可通过常规化学方法从含有碱性或酸性部分的母体化合物合成本发明的药学上可接受的盐。通常,这样的盐可通过使这些化合物的游离酸或碱形式与化学计量的适当碱或酸在水或有机溶剂或者两者的混合物中反应而制备;通常,非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈是优选的。所述盐可以从溶液中沉淀出,且可通过过滤收集或可通过蒸发溶剂来回收。盐中的电离度可从完全电离至几乎不电离变化。合适盐的列表可见于Remington's Pharmaceutical Sciences, 第17版, Mack Publishing Company, Easton,Pa., 1985, 第1418页,其公开内容仅关于合适盐的列表通过引用并入本文。
本发明化合物可以非溶剂化和溶剂化形式存在。本文使用术语“溶剂化物”来描述包含本发明化合物和一种或多种药学上可接受的溶剂分子(例如乙醇)的分子复合物。当所述溶剂为水时,采用术语“水合物”。药学上可接受的溶剂化物包括水合物和其它溶剂化物,其中结晶的溶剂可进行同位素取代,例如D2O、d6-丙酮、d6-DMSO。
含有一个或多个不对称碳原子的式(I)化合物可以作为两种或更多种立体异构体存在。当式(I)化合物(或抗微生物剂和/或常规呼吸道治疗剂)含有烯基或亚烯基或环烷基时,几何顺式/反式(或Z/E)异构体是可能的。当所述化合物含有例如酮基或肟基或芳族部分时,可存在互变异构现象(“互变异构性”)。结果是,单一化合物可表现出超过一种类型的异构性。
本发明范围内包括式(I)化合物(或抗微生物剂和/或常规呼吸道治疗剂)(包括表现出超过一种类型的异构性的化合物和其一种或多种的混合物)的所有立体异构体、几何异构体和互变异构体形式。还包括酸加成盐或碱式盐,其中抗衡离子是光学活性的,例如,D-乳酸根或L-赖氨酸,或外消旋的,例如,DL-酒石酸根或DL-精氨酸。
顺式/反式异构体可通过本领域技术人员熟知的常规技术分离,例如层析或分级结晶。
用于制备/分离个别对映异构体的常规技术包括从合适光学纯前体手性合成或者使用例如手性高压液相层析(HPLC)拆分外消旋物(或者盐或衍生物的外消旋物)。
本发明手性化合物(和其手性前体)可以对映异构富集的形式获得,其使用树脂上的层析,通常为HPLC,其具有不对称固定相和由含有0至50%异丙醇(通常2至20%)和0至5%烷胺(通常0.1%二乙胺)的烃(通常为庚烷或己烷)组成的流动相。洗脱液的浓缩得到富集的混合物。
可通过本领域技术人员已知的常规技术分离立体异构体的混合物。[参见例如E LEliel的“Stereochemistry of Organic Compounds” (Wiley, New York, 1994)]。
本发明包括所有药学上可接受的同位素标记的化合物,其中一个或多个原子可被具有相同原子序数、但原子质量或质量数不同于自然界中常见的原子质量或质量数的原子置换。
适合包括于本发明化合物中的同位素的实例包括以下元素的同位素:氢(诸如2H和3H)、碳(诸如11C、13C和14C)、氯(诸如36Cl)、氟(诸如18F)、碘(诸如123I和125I)、氮(诸如13N和15N)、氧(诸如15O、17O和18O)、磷(诸如32P)和硫(诸如35S)。
包括本发明的某些同位素标记的化合物,包括例如掺入放射性同位素的那些,可用于药物和/或底物组织分布研究。鉴于掺入便利性和已有的检测方式,放射性同位素氚(即3H)和碳-14(即14C)特别可用于该目的。
被较重同位素(诸如氘(即2H))取代可提供由更大代谢稳定性导致的某些治疗优点(例如体内半衰期增加或剂量要求降低),且因此在一些情形下可以是优选的。
通常,可通过本领域技术人员已知的常规技术或通过与本文所述的那些类似的方法使用适当同位素标记的试剂代替先前使用的非标记的试剂来制备同位素标记的化合物。
本发明化合物可作为前药施用。因此,当施用于人体时,本发明化合物的某些衍生物(其本身可具有极小或无药理活性)可例如通过水解裂解转化为具有所需活性的化合物。这样的衍生物称为“前药”。
一般而言,本发明组合物由至少一种本文所述的化学实体与至少一种药学上可接受的赋形剂的组合组成。可接受的赋形剂是无毒的,有助于施用,且不会不利地影响至少一种本文所述的化学实体的治疗益处。这样的赋形剂可以是任何固体、液体、半固体或(在气雾剂组合物的情况下)气态赋形剂,这是本领域技术人员通常可得的。
本文的化合物、其药学上可接受的盐和包含其的药物组合物可便利地通过任何常规用于药物施用的途径进行施用。本文的化合物可以通过根据常规程序将式(I)化合物与标准药物载体组合在一起制备的常规剂型施用。本文的化合物也可以常规剂量与已知的第二治疗活性化合物组合施用。
本文所述的化学实体可经由任何对起到类似效用的试剂而言可接受的施用模式施用,所述模式包括但不限于经口、全身(例如,经皮、鼻内或经栓剂)或肠胃外(例如,肌肉内、静脉内或皮下)、舌下、局部、腹膜内、肺内、阴道内、直肠或眼内。在一些实施方案中,经口肠胃外施用式(I)化合物。在其它实施方案中,通过肺内途径施用式(I)化合物。在其它实施方案中,通过肺内途径施用抗微生物剂。
在其它实施方案中,静脉内施用式(I)化合物。在一个实施方案中,将式(I)化合物作为含有注射用水中的0.1至10mg/mL的作为游离碱的式(I)化合物且包含β-环糊精和磺基丁醚的溶液进行静脉内施用。在另一个实施方案中,将式(I)化合物作为含有注射用水中的2mg/mL的作为游离碱的式(I)化合物且包含β环糊精和磺基丁醚的溶液进行静脉内施用。在其它实施方案中,将式(I)化合物作为含有注射用水中的2mg/mL的作为游离碱的式(I)化合物且包含β环糊精和磺基丁醚的溶液进行静脉内施用,且其中式(I)化合物的静脉内溶液的每个小瓶含有13 mL的2mg/mL式(I)化合物。
药物组合物或制剂包括固体、半固体、液体和气雾剂剂型,诸如例如,片剂、胶囊、粉剂、液体、悬浮液、栓剂、气雾剂等。化学实体也可以缓释或控释剂型施用,包括以预定速率长时间和/或定时脉冲施用的储库注射液、渗透活性泵、丸剂、经皮(包括电转移)贴片等。在某些实施方案中,所述组合物以适合单次施用精确剂量的单位剂型提供。
本文所述的化学实体可单独施用或更通常与常规载体、赋形剂等(例如,甘露糖醇、乳糖、淀粉、硬脂酸镁、糖精钠、滑石、纤维素、交联羧甲基纤维素钠、葡萄糖、明胶、蔗糖、碳酸镁等)组合施用。如果需要,所述药物组合物也可含有少量无毒辅助物质,诸如润湿剂、乳化剂、增溶剂、pH缓冲剂等(例如,乙酸钠、柠檬酸钠、环糊精(cyclodextrin)、环状糊精(cyclodextrine)、环糊精衍生物和环状糊精衍生物、脱水山梨糖醇单月桂酸酯、三乙醇胺乙酸盐、三乙醇胺油酸盐)。通常,根据预期施用模式,所述药物组合物将含有约0.005重量%至95重量%;在某些实施方案中,约0.5重量%至50重量%的化学实体。制备这样的剂型的实际方法是本领域技术人员已知或将显而易见的;例如参见 Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania。
在某些实施方案中,所述组合物将采取丸剂或片剂的形式,因此所述组合物将连同活性成分含有稀释剂,诸如乳糖、蔗糖、磷酸二钙等;润滑剂,诸如硬脂酸镁等;和粘合剂,诸如淀粉、阿拉伯树胶、聚乙烯基吡咯烷、明胶、纤维素、纤维素衍生物等。在另一种固体剂型中,将粉末、颗粒(marume)、溶液或悬浮液(例如,在碳酸丙烯酯、植物油或甘油三酯)包封于明胶胶囊中。
液体药物可施用的组合物可例如通过如下制备:将至少一种化学实体和任选的药物佐剂溶解、分散等于载体(例如,水、盐水、水性右旋糖、甘油、二醇类、乙醇等)中,以形成溶液或悬浮液。注射剂可制备成常规形式,作为液体溶液或悬浮液,作为乳液或为适合于注射前溶解或悬浮于液体中的固体形式。这样的肠胃外组合物中含有的化学实体的百分比高度取决于其具体性质以及化学实体的活性和受试者的需求。然而,可采用溶液中的活性成分的0.01%至10%的百分比,且如果组合物是随后将稀释至上述百分比的固体,则百分比将更高。在某些实施方案中,所述组合物将包含溶液中的约0.2至2%的活性剂。
本文所述的化学实体的药物组合物也可作为用于喷雾器的气雾剂或溶液、或作为用于吸入的微细粉末施用于呼吸道,其单独施用或与惰性载体诸如乳糖组合施用。在这样的情况下,所述药物组合物的颗粒具有小于50微米,在某些实施方案中,小于10微米的直径。
这些程序可涉及根据需要将成分混合、粒化和压缩或溶解成所需制备物。应理解,药学上可接受的载体或稀释剂的形式和特性由待与其组合的活性成分的量、施用途径和其它熟知变量来决定。所述载体必须在与制剂的其它成分相容的意义上是“可接受的”且对其受体不会有害。
所用药物载体可以是例如固体或液体。固体载体的实例为乳糖、白土、蔗糖、滑石、明胶、琼脂、果胶、阿拉伯胶、硬脂酸镁、硬脂酸等。液体载体的实例为糖浆、花生油、橄榄油、水等。类似地,所述载体或稀释剂可包括本领域熟知的延时材料,诸如单独或与蜡组合的甘油单硬脂酸酯或甘油二硬脂酸酯。可采用各种各样的药物形式。因此,如果使用固体载体,可将制备物压片,以粉末或丸粒形式或者片剂或锭剂的形式置于硬明胶胶囊中。固体载体的量将大大不同,但优选为约25mg至约1g。当使用液体载体时,制备物将为糖浆、乳液、软明胶胶囊、无菌可注射液诸如安瓿剂或非水性液体悬浮液的形式。
一般而言,所提供的化学实体将通过任一对起到类似效用的试剂而言接受的施用模式以治疗有效量施用。化学实体(即活性成分)的实际量将取决于许多因素,诸如待治疗疾病的严重性、受试者的年龄和相对健康、所用化学实体的效力、施用的途径和形式和其它因素。所述药物可一天施用超过一次,诸如一天施用一次或两次。
本文所述的化学实体的治疗有效量可范围为约0.01至200mg/千克受体体重/天;诸如约0.01至100mg/kg/天,例如约0.1至50mg/kg/天。因此,对于施用于70kg的人,剂量范围可以是约1至2000mg/天。
施用所提供的化学实体的另一方式是吸入。制剂的选择取决于各种因素,诸如药物施用模式和药物物质的生物利用度。对于经由吸入递送,所述化学实体可配制成液体溶液、悬浮液、气雾剂推进剂或干燥粉末,并装载于合适的用于施用的分配器中。有几种药物吸入装置-喷雾吸入器、计量剂量吸入器(MDI)和干粉吸入器(DPI)。喷雾器装置产生高速空气流,其引起治疗剂(配制成液体形式)作为被携带进入患者呼吸道的薄雾喷雾。MDI通常为包装有压缩气体的制剂。致动后,装置通过压缩气体释放测量的量的治疗剂,因此得到施用固定量的制剂的可靠方法。DPI分配自由流动粉末形式的治疗剂,其可在患者呼吸期间通过该装置分配于吸气气流中。为了获得自由流动粉末,用赋形剂诸如乳糖配制治疗剂。测量的量的治疗剂以胶囊形式储存,并经由每次致动进行分配。
本文的化合物可局部施用,即通过非全身性施用。这包括将式(I)化合物外部施加至表皮或颊腔和将这样的化合物滴注于耳、眼和鼻,使得该化合物不会显著进入血流。相比之下,全身性施用是指经口、静脉内、腹膜内和肌肉内施用。适合于局部施用的制剂包括适合于通过皮肤渗透至炎症部位的液体或半液体制备物,诸如擦剂、洗剂、乳膏、油膏或糊膏和适合于施用于眼、耳或鼻的滴剂。对于局部施用,所述活性成分可占制剂的0.001% w/w至10% w/w,例如1重量%至2重量%。然而,其可占制剂的多达10% w/w,但优选将占小于5% w/w,更优选0.1% w/w至1% w/w。
根据本发明的洗剂包括适合于施加至皮肤或眼的那些。眼用洗剂可包含任选地含有杀细菌剂的无菌水溶液,且可通过类似于用于制备滴剂的方法的方法制备。用于施加至皮肤的洗剂或擦剂也可包括加速干燥和冷却皮肤的试剂(诸如乙醇或丙酮)和/或保湿剂(诸如甘油)或油(诸如蓖麻油或花生油)。
根据本发明的乳膏、油膏或糊膏是用于外用的活性成分的半固体制剂。它们可通过如下制备:用油脂性或非油脂性基质,在合适机器的帮助下,单独或在水性或非水性液体中的溶液或悬浮液中,混合细分散或粉末形式的活性成分。该基质可包含烃类,诸如硬、软或液体石蜡、甘油、蜂腊、金属皂;粘质物;天然来源的油,诸如杏仁油、玉米油、落花生油、蓖麻油或橄榄油;羊毛脂或其衍生物或脂肪酸,诸如硬脂酸或油酸;以及醇(诸如丙二醇)或大粒凝胶。所述制剂可并入任何合适的表面活性剂,诸如阴离子、阳离子或非离子表面活性剂,诸如脱水山梨糖醇酯或其聚氧乙烯衍生物。还可包括悬浮剂(诸如天然树胶)、纤维素衍生物或无机材料(诸如火成二氧化硅(silicaceous silicas))、15和其它成分(诸如羊毛脂)。
根据本发明的滴剂可包含无菌水溶液或油性溶液或悬浮液,且可通过将活性成分溶解于合适的杀细菌剂和/或杀真菌剂和/或任何合适防腐剂的水溶液中且优选包括表面活性剂来制备。然后可以将所得溶液通过过滤澄清,转移至合适容器中,随后将其密封并通过高压灭菌或在98-100℃维持半小时来灭菌。可选地,所述溶液可以通过过滤灭菌,并通过无菌技术转移至容器。适合于包括于滴剂中的杀细菌剂和杀真菌剂的实例为硝酸苯汞或乙酸苯汞(0.002%)、苯扎氯铵(0.01%)和醋酸氯己定(0.01%)。适合于制备油性溶液的溶剂包括甘油、稀酒精和丙二醇。
本文所述的化合物也可通过吸入来施用,即通过鼻内且经口吸入施用。用于这样的施用的适当剂型(诸如气雾剂制剂或计量剂量吸入剂)可通过常规技术制备。在本发明的一个实施方案中,本发明的试剂经由经口吸入或鼻内施用来递送。用于这样的施用的适当剂型(诸如气雾剂制剂或计量剂量吸入剂)可通过常规技术来制备。
对于通过吸入的施用,所述化合物可借助使用合适推进剂(例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、氢氟烷(诸如四氟乙烷或六氟丙烷)、二氧化碳或其它合适气体)以喷雾剂喷雾呈现形式从加压包装或喷雾器递送。在加压气雾剂的情况下,剂量单位可通过提供递送计量的量的阀来确定。可配制用于吸入器或吹入器的例如明胶的胶囊和滤筒,其含有本发明化合物和合适粉末基质(诸如乳糖或淀粉)的粉末混合物。
用于通过吸入局部递送至肺的干粉组合物可例如呈现于用于吸入器或吹入器的例如明胶的胶囊和药筒或者例如层压铝箔的泡罩(blister)中。粉末共混制剂通常含有本发明化合物和合适粉末基质(载体/稀释剂/赋形剂物质)诸如单糖、二糖或多糖(例如乳糖或淀粉)的用于吸入的粉末混合物。优选使用乳糖。
各胶囊或滤筒通常可含有20μg-1000mg式(I)化合物,其任选地与另一治疗活性剂(诸如抗微生物剂)组合。可选地,本发明化合物可在无赋形剂的情况下呈现。合适地,包装/药剂分配器具有选自以下的类型:储库干粉吸入器(RDPI)、多剂量粉末吸入器(MDPI)和计量剂量吸入器(MDI)。储库干粉吸入器(RDPI)意指具有适用于包含多剂(非计量剂量)干粉形式的药剂的储库形式包装且包括用于将药剂剂量从储库计量至递送位置的装置的吸入器。计量装置可例如包含计量杯,其可从所述杯可用来自储库的药剂填充的第一位置移动至患者可吸入计量药剂剂量的第二位置。多剂量干粉吸入器(MDPI)意指适合于分配干粉形式的药剂的吸入器,其中所述药剂包含于含有(或以其它方式携带)多个确定剂量(或其部分)的药剂的多剂量包装内。在一个优选方面,所述载体具有泡罩包装形式,但其也可例如包含基于胶囊的包装形式或其上已通过任何合适方法(包括印刷、涂漆和真空闭塞)施加药剂的载体。
在多剂量递送的情况下,所述制剂可预先计量(例如,如在Diskus中,参见美国专利号6,632,666、5,860,419、5,873,360、5,622,166和5,590,645,或在Diskhaler中,参见美国专利号4,627,432、4,778,054、4,811,731、5,035,237,其公开内容通过引用并入本文)或在使用时计量(例如,如在Turbuhaler中,参见US 4,524,769,或在美国专利号6,321,747中所述的装置中,其公开内容通过引用并入本文)。单位剂量装置的实例为(Rotahaler(参见美国专利号4,353,656和5,724,959,其公开内容通过引用并入本文)。
Diskus吸入装置包含由具有多个沿着其长度间隔开的凹穴的基片形成的细长条带以及气密性、但可剥离地密封至细长条带,以定义多个容器的盖片,各容器在其中具有含有式(I)化合物(优选与乳糖组合)的可吸入制剂。优选地,该条带具有足够柔性,以绕成卷。所述盖片和基片优选将具有未彼此密封的引导端部分,且所述引导端部分中的至少一个被构建为附接至缠绕构件。还有,优选地,基片与盖片之间的气密性密封件延伸越过其完整宽度。该盖片优选可在长度方向上由所述基片的第一端从基片剥离。在一个方面,多剂量包装是泡罩包装,其包含多个用于含有干粉形式的药剂的泡罩。所述泡罩通常以规则方式排列,以易于从其释放药剂。在一个方面,多剂量泡罩包装包含多个通常以环形方式排列在盘形泡罩包装上的泡罩。在另一个方面,多剂量泡罩包装是细长形式,例如包含条带或胶带。在一个方面,多剂量泡罩包装限定在两个彼此可剥离固定的膜之间。美国专利号5,860,419、5,873,360和5,590,645描述该一般类型的药剂泡罩。在该方面,该装置通常提供有开放平台,其包含用于将部件剥离开以接触各药剂剂量的剥离构件。合适地,该装置适合用于其中可剥离部件是细长片材的情况,所述细长片材限定多个沿着其长度间隔开的药剂容器,该装置提供有用于依次指引各容器的指引构件。更优选地,该装置适合用于其中片材之一是其中具有多个口袋的基片且另一个片材是盖片的情况,各口袋和盖片的相邻部分限定各个容器,该装置包括用于在开放平台上使盖片与基片拉开的驱动构件。
计量剂量吸入器(MDI)意指适合于分配气雾剂形式的药剂的药剂分配器,其中该药剂包含在适用于含有基于推进剂的气雾剂药剂制剂的气雾剂容器中。该气雾剂容器通常提供有用于将气雾剂形式药剂制剂释放至患者的计量阀,例如滑动阀。该气雾剂容器通常设计为在每次借助阀致动后递送预定剂量的药剂,其可通过在容器保持静止的同时降低阀或者在阀保持静止的同时降低容器而开放。当该药剂容器为气雾剂容器时,该阀通常包含具有药剂喷雾剂制剂可通过其进入所述阀体的入口、气雾剂可通过其离开阀体的出口和可通过其控制流过所述出口的流的开放/关闭机制的阀体。该阀可以是滑动阀,其中该开放/关闭机制包含密封环和可由密封环接受的具有分配通道的阀杆,该阀杆可在该环内从阀关闭位置滑移动至阀开放位置,其中该阀体的内部与经由该分配通道与该阀体的外部连通。
通常该阀是计量阀。计量体积通常为10至100μl,诸如25μl、50μl或63μl。合适地,该阀体限定用于计量药剂制剂的量的计量室和可借助其控制通过入口流至该计量室的流的开放/关闭机制。优选地,该阀体具有经由第二入口与该计量室连通的取样室,所述入口可借助开放/关闭机制控制,从而调节进入该计量室的药剂制剂流。
该阀也可包含“自由流动气雾剂阀”,其具有室和延伸进入该室且可相对于该室在分配与非分配位置之间移动的阀杆。该阀杆具有一定结构,且该室具有内部结构,使得在其之间限定计量体积,且使得在其之间移动期间是非分配和分配位置,该阀杆依次:(i)容许气雾剂制剂自由流动至该室中,(ii)在该阀杆外表面和该室内表面之间为加压气雾剂制剂限定密闭计量体积,和(iii)随着该室内的密闭计量体积移动而不会减少密闭计量体积的体积,直至剂量体积与出口通道连通,从而允许分配计量体积的加压气雾剂制剂。美国专利号5,772,085中描述了此类阀。此外,本发明化合物的鼻内递送是有效的。
为了配制有效药物鼻用组合物,药剂必须容易地递送至鼻腔的其发挥其药理功能的所有部分(目标组织)。此外,药剂应当保持与目标组织接触相对长时间段。药剂与目标组织保持接触时间越长,药剂必须能够抵抗鼻道内发挥功能以从鼻子移除颗粒作用的那些力。此类力(称为“黏液纤毛清除”)被认为在以快速方式从鼻子移除颗粒中极其有效,例如,在从颗粒进入鼻子的时间开始10-30分钟内。
鼻用组合物的其它所需特征是,其必须不含引起使用者不适的成分,其具有令人满意的稳定性和保质期性质,且其不包括被视为对环境有害的成分,例如臭氧耗竭剂。当施用于鼻子时,就患者而言,本发明制剂的合适给药方案将是在清洁鼻腔后深深吸气。在吸入过程中,将所述制剂施加至一个鼻孔,同时用手压着另一个。然后将对另一鼻孔重复该程序。一种用于将本发明制剂施加至鼻道的方式是使用预压泵。最优选地,该预压泵将是由Valois SA制造的VP7型号。这样的泵是有益的,因为其将确保制剂直到施加足够力时才释放,否则可施加较小剂量。预压泵的另一优势在于确保喷雾的雾化,因为其直到达到使喷雾有效雾化的阈值压力时才释放制剂。通常,VP7型号可与可容纳10-50 ml制剂的瓶子一起使用。每次喷雾通常将递送50-100μl这种制剂;因此,VP7型号能够提供至少100个计量剂量。
用于通过吸入局部递送至肺的喷雾组合物可例如配制成水溶液或悬浮液或者借助使用合适液化推剂剂从加压包(诸如计量剂量吸入器)递送的气雾剂。适合吸入的气雾剂组合物可以是悬浮液或溶液,且通常含有任选地与另一种治疗活性成分和合适推进剂组合的式I化合物,所述合适推进剂诸如氟碳化合物或含氢的氟氯碳化物或者其混合物,具体地氢氟烷,例如二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷,特别是1,1,1,2-四氟乙烷、1,1,1,2,3,3,3-七氟正丙烷或其混合物。二氧化碳或其它合适气体也可用作推进剂。该气雾剂组合物可不含赋形剂或可任选地含有本领域中熟知的其它制剂赋形剂,诸如表面活性剂(例如油酸或卵磷脂)和共溶剂(例如乙醇)。加压制剂通常将保存在用阀(例如计量阀)密封并装入提供有喷嘴的致动器中的药罐(例如铝罐)中。用于通过吸入施用的药剂合意地具有受控粒径。用于吸入支气管系统的最佳粒径通常为1-10μm,优选2-5μm。当吸入到达小呼吸道时,尺寸大于20μm的颗粒通常太大。为了达到这些粒径,所产生的活性成分颗粒可通过常规方式(例如通过微粒化)减小尺寸。所需部分可通过风选或筛分来分离。合适地,所述颗粒将是结晶形式。当采用赋形剂诸如乳糖时,赋形剂的粒径通常将比本发明内的吸入药剂大得多。当赋形剂是乳糖时,其通常将作为研磨乳糖存在,其中不超过85%的乳糖颗粒将具有60-90μm的MMD,且不少于15%的乳糖颗粒将具有小于15μm的MMD。鼻内喷雾剂可用水性或非水性媒介物,通过添加试剂诸如增稠剂、调节pH的缓冲盐或酸或碱、渗透性调节剂或抗氧化剂来配制。
用于通过雾化吸入的溶液可用水性媒介物,通过添加试剂诸如酸或碱、缓冲盐、渗透性调节剂或抗氧化剂来配制。它们可通过过滤或在高压釜中灭菌或呈现为未灭菌产品。合适地,通过吸入施用可优选地靶向呼吸道疾病的目标器官,即肺,且这么做可减少需递送至患者所需的有效剂量。此外,通过吸入施用可减少化合物的全身接触,因此避免化合物在肺以外的效应。
最近,基于可通过增加表面积(即减小粒径)来提高生物利用度的原理,已经为显示较差生物利用度的药物开发出药物组合物。例如,美国专利号4,107,288描述了具有10至1,000nm的尺寸范围的颗粒的药物制剂,其中活性物质支持于大分子的交联基质上。美国专利号5,145,684描述了药物组合物的产生,其中药物物质在表面修饰剂存在的情况下粉碎成纳米颗粒(平均粒径为400nm),然后分散于液体介质中,以得到展现极高生物利用度的药物制剂。
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Claims (42)
1.组合物,其包含danirixin和神经氨酸酶抑制剂化合物的组合。
2.组合物,其包含danirixin和扎那米韦的组合。
3.组合物,其包含danirixin和奥司他韦的组合。
4.组合物,其包含danirixin和利巴韦林的组合。
5.组合物,其包含danirixin和法匹拉韦的组合。
6.组合物,其包含danirixin和一种或多种选自表4的抗微生物剂的组合。
7.药物组合物,其包含danirixin和神经氨酸酶抑制剂化合物的组合以及药学上可接受的赋形剂。
8.药物组合物,其包含danirixin和扎那米韦的组合以及药学上可接受的赋形剂。
9.药物组合物,其包含danirixin和奥司他韦的组合以及药学上可接受的赋形剂。
10.药物组合物,其包含danirixin和利巴韦林的组合以及药学上可接受的赋形剂。
11.药物组合物,其包含danirixin和一种或多种选自表4的抗微生物剂的组合以及药学上可接受的赋形剂。
12.用于治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin和神经氨酸酶抑制剂化合物的组合。
13.用于治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin和扎那米韦的组合。
14.用于治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin和奥司他韦的组合。
15.用于治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin和利巴韦林的组合。
16.用于治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin和法匹拉韦的组合。
17.用于治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用danirixin和一种或多种选自表4的抗微生物剂的组合。
18.根据权利要求12-17所述的方法,其中所述呼吸道传染性疾病是流感。
19.根据权利要求12-17所述的方法,其中所述呼吸道传染性疾病是RSV。
20.根据权利要求12-17所述的方法,其中以相同剂型施用danirixin和神经氨酸酶抑制剂化合物的组合。
21.根据权利要求12-17所述的方法,其中同时施用danirixin和神经氨酸酶抑制剂化合物的组合。
22.根据权利要求12-17所述的方法,其中分开施用danirixin和神经氨酸酶抑制剂化合物的组合。
23.根据权利要求12-17所述的方法,其中以相同剂型施用danirixin和神经氨酸酶抑制剂化合物的组合。
24.根据权利要求12-17所述的方法,其中同时施用danirixin的化合物和神经氨酸酶抑制剂化合物的组合。
25.根据权利要求12-17所述的方法,其中分开施用danirixin和神经氨酸酶抑制剂化合物的组合。
26.根据权利要求15所述的方法,其中以相同剂型施用danirixin和利巴韦林的组合。
27.根据权利要求15所述的方法,其中同时施用danirixin的化合物和利巴韦林的组合。
28.根据权利要求15所述的方法,其中分开施用danirixin和利巴韦林的组合。
29.用于治疗受试者的流感的方法,所述方法包括向患有流感的受试者施用danirixin。
30.用于治疗受试者的RSV的方法,所述方法包括向患有RSV的受试者施用danirixin。
31.用于静脉内施用的药物组合物,其包含:水溶液中的作为氢溴酸盐的danirixin。
32.用于静脉内施用的药物组合物,其包含:水溶液中的作为氢溴酸盐的danirixin和药学上可接受的赋形剂。
33.根据权利要求32所述的药物组合物,其中所述药学上可接受的赋形剂包含β-环糊精。
34.根据权利要求32所述的药物组合物,其中所述药学上可接受的赋形剂包含磺基丁醚。
35.根据权利要求32所述的药物组合物,其中所述药学上可接受的赋形剂包含β-环糊精和磺基丁醚。
36.根据权利要求32所述的药物组合物,其中所述药学上可接受的赋形剂包含Captisol®。
37.用于治疗受试者的呼吸道传染性疾病的方法,所述方法包括向患有呼吸道传染性疾病的受试者施用根据权利要求31-36中任一项所述的药物组合物。
38.用于治疗受试者的RSV的方法,所述方法包括向患有RSV的受试者施用根据权利要求31-36中任一项所述的药物组合物。
39.用于治疗受试者的流感的方法,所述方法包括向患有流感的受试者施用根据权利要求31-36中任一项所述的药物组合物。
40.用于治疗受试者的RSV的方法,所述方法包括向患有RSV的受试者施用danirixin和帕利珠单抗的组合。
41.根据权利要求40所述的方法,其中同时施用danirixin和帕利珠单抗的组合。
42.根据权利要求40所述的方法,其中分开施用danirixin和帕利珠单抗的组合。
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- 2015-05-08 KR KR1020167034634A patent/KR20170003673A/ko unknown
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- 2015-05-08 EP EP15721878.5A patent/EP3142694A2/en not_active Withdrawn
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- 2015-05-08 CN CN201580038007.5A patent/CN107072976A/zh active Pending
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EP3142694A2 (en) | 2017-03-22 |
EA201692111A1 (ru) | 2017-08-31 |
AU2015260841A1 (en) | 2016-12-01 |
WO2015173701A2 (en) | 2015-11-19 |
ZA201607729B (en) | 2018-11-28 |
IL248779A0 (en) | 2017-01-31 |
UY36117A (es) | 2016-01-08 |
PH12016502243A1 (en) | 2017-01-09 |
CL2016002879A1 (es) | 2017-02-24 |
WO2015173701A3 (en) | 2016-02-18 |
SG11201609276RA (en) | 2016-12-29 |
PE20170185A1 (es) | 2017-04-01 |
KR20170003673A (ko) | 2017-01-09 |
DOP2016000297A (es) | 2016-12-31 |
US20180207145A1 (en) | 2018-07-26 |
TW201625247A (zh) | 2016-07-16 |
AU2018203911A1 (en) | 2018-06-21 |
JP2017515840A (ja) | 2017-06-15 |
CA2948441A1 (en) | 2015-11-19 |
MX2016014859A (es) | 2017-06-27 |
US20170100385A1 (en) | 2017-04-13 |
CR20160529A (es) | 2017-01-02 |
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