CN112457291A - 苯并硫代吡喃酮类化合物的盐及其制备方法和用途 - Google Patents
苯并硫代吡喃酮类化合物的盐及其制备方法和用途 Download PDFInfo
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- CN112457291A CN112457291A CN201910849215.3A CN201910849215A CN112457291A CN 112457291 A CN112457291 A CN 112457291A CN 201910849215 A CN201910849215 A CN 201910849215A CN 112457291 A CN112457291 A CN 112457291A
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- Prior art keywords
- benzothiopyran
- cyclohexylmethyl
- trifluoromethyl
- nitro
- salt
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Abstract
本发明公开了苯并硫代吡喃酮类化合物的盐,具体为式(I)所示的2‑(4‑(环己基甲基)哌嗪‑1‑基)‑6‑(三氟甲基)‑8‑硝基‑苯并硫代吡喃‑4‑酮的盐、其制备方法及在治疗和/或预防结核分枝杆菌引起的感染性疾病药物中的应用。具体地说,本发明涉及式(I)药学可接受的盐以及包含本发明化合物的药物组合物。本发明旨在制备一种药代性质和理化性质显著改善并具有强抗结核分枝杆菌活性的2‑(4‑(环己基甲基)哌嗪‑1‑基)‑6‑(三氟甲基)‑8‑硝基‑苯并硫代吡喃‑4‑酮的盐,其作为潜在的新药物,可用于由细菌引起的感染性疾病,特别是由结核分枝杆菌引起的肺结核(TB)疾病的治疗或预防性治疗,同时可用于克服与结核分枝杆菌耐药相关的问题。
Description
技术领域
本发明属于医药技术领域。特别涉及苯并硫代吡喃酮类化合物的盐:式(I)所示的2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的盐,其制备方法,以该盐为活性成分的药物组合物,以及它们在治疗和/或预防由结核分枝杆菌引起的感染性疾病中的应用。
背景技术
结核病(Tuberculosis,TB)是由结核分枝杆菌引起的一种慢性致死性疾病,是危害人类健康和导致人类死亡的重大传染性疾病。据WHO估算,2017年全球的结核病潜伏感染人群约为17亿,潜伏感染率为23%。全球新发结核病患者约1000万,死亡患者约140万,结核病发病率为133/10万,其中小于15岁的儿童患者和艾滋病病毒感染者分别占新发患者的10%和9%。在2017年的结核病患者中,耐药结核病例55.8万,82%为多重耐药结核病(MDR-TB),同时广泛耐药(XDR-TB)结核病上升速率亦较快,耐药结核的治愈率全球仅为55%。
结核分枝杆菌特有的细胞壁具有多层次的结构,这些独特成分的生物合成途径是潜在药物靶标的丰富来源,例如一线药物异烟肼和乙胺丁醇分别作用于霉菌酸和阿拉伯聚糖层的合成,干扰结核分枝杆菌细胞壁的形成。结核分枝杆菌细胞壁外膜的阿拉伯半乳聚糖层及阿拉伯甘露聚糖层的主要组成部分是一种以DPA为重要前体的阿拉伯糖,研究表明,DPA主要是由DPR在DprE1和DprE2的共同作用下差向异构化得到,因此抑制DprE1的活性可阻碍细胞壁的合成最终达到杀灭结核分枝杆菌的目的(Decaprenylphosphorylarabinofuranose,the donor of the D-arabinofuranosyl residues of mycobacterialarabinan,is formed via a two-step epimerization of decaprenylphosphorylribose.Journal of bacteriology 2005,187(23),8020-8025)。
目前,DprE1抑制剂还没有药物上市,其中共价结合型化合物PBTZ169已进入II期临床的研究。近年来,本申请发明人针对具有良好研发前景的靶标DprE1,进行了深入的研究,通过活性、毒性和早期成药性评价,确定了苯并硫代吡喃酮母核结构为优势骨架,并申请了专利(专利号:201810092333.X和PCT/CN2018/080787),通过系统深入的研究,获得了具有显著抗结核及耐药结核活性和低毒性的苯并硫代吡喃酮类化合物6b(2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮)(Identification of novelbenzothiopyranone compounds against Mycobacterium tuberculosis throughscaffold morphing from benzothiazinones[J].Eur.J.Med.Chem.,2018,160,157-170)。
专利201810092333.X和PCT/CN2018/080787公开了2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮及其盐酸盐的实施例,但未公开其它药学上可接受盐的具体实施例和实验结果。
发明内容
本发明要解决的技术问题是提供一种药代性质和理化性质显著改善并具有强抗结核分枝杆菌活性的2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的盐。本发明发现,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的盐具有强的抗结核分枝杆菌作用,可用于由细菌引起的感染性疾病,特别是由结核分枝杆菌引起的肺结核疾病的治疗或预防性治疗,同时在药代性质和理化性质等成药性方面相比游离碱和盐酸盐具有了明显的改善。本发明基于以上发现而得以完成。
发明概述
为此,本发明第一方面提供式(I)所示2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的药学上可接受的盐,
其中,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的盐不包括盐酸盐。
本发明第一方面任一项的盐,其特征在于,其为2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的马来酸盐、富马酸盐、枸橼酸盐以及L-苹果酸盐。
本发明第一方面任一项的盐,其特征在于,其为2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1马来酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1/2马来酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2马来酸盐;2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1富马酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1/2富马酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2富马酸盐;2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1枸橼酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1/2枸橼酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2枸橼酸盐或2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1L-苹果酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1/2L-苹果酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2L-苹果酸盐。
本发明第二方面提供了制备本发明第一方面任一项所述的盐的方法,其包括以下步骤:
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮与酸(例如药学上的常见酸,优选马来酸、富马酸、枸橼酸以及L-苹果酸)反应,在合适的溶剂(例如甲醇、乙醇、丙酮、乙腈,优选甲醇)中,于20-140℃下反应2-8小时,优选20-100℃条件下反应2-5小时,经过成盐反应得到式(I)所示的化合物的盐。
本发明第三方面提供了一种药物组合物,其包括治疗和/或预防有效量的本发明第一方面任一项所述的化合物的药学上可接受的盐,以及任选的一种或多种药学上可接受的载体、赋形剂、稀释剂、辅料和媒介物。
本发明第四方面提供了本发明第一方面任一项所述化合物的药学可接受的盐,或者本发明第三方面任一项所述药物组合物在制备治疗和/或预防由结核分枝杆菌引起的感染性疾病的药物中的应用。
前面所述内容只概述了本发明的某些方面,但并不限于这方面。这些方面及其他的方面内容将在下面做更加具体完整的描述。
发明详述
下面对本发明的各个方面和特点作进一步的描述。
本发明所引述的所有文献,它们的全部内容通过引用并入本文,并且如果这些文献所表达的含义与本发明不一致时,以本发明的表述为准。此外,本发明使用的各种术语和短语具有本领域技术人员公知的一般含义,即便如此,本发明仍然希望在此对这些术语和短语作更详尽的说明和解释,提及的术语和短语如有与公知含义不一致的,以本发明所表述的含义为准。下面是本发明所用多种术语的定义,这些定义适用于本申请整个说明书中所用的术语,除非在具体情况中另作说明。
本发明中“室温”指的是温度由10℃到40℃。在一些实施例中,“室温”指的是温度由20℃到30℃;在另一些实施例中,室温指的是25℃。
如本文所述的,术语“有效量”是指可在受试者中实现所期望的治疗本发明所述疾病或病症的药物用量。
如本文所述的,术语“药学可接受的”例如在描述“药学可接受的盐”时,表示该盐不但是受试者生理学上可接受,而且还可指在药学上有使用价值的合成物质。
如本文所述的,术语“药物组合物”,其还可以是指“组合物”,其可用于在受试者特别是哺乳动物中实现治疗本发明所述疾病或病症。
疾病的“治疗”包括:
(1)预防该疾病,即,使暴露至或易感染该疾病但未经历或显示该疾病症状的哺乳动物不发生该疾病的临床症状,
(2)抑制该疾病,即,阻止或减少该疾病或其临床症状的进展,
(3)减轻该疾病,即,引起该疾病或其临床症状的复原。
“治疗有效量”指为了治疗疾病向哺乳动物施用时足以实现对该疾病的治疗的化合物的量。治疗有效量将根据化合物、待治疗的疾病及其严重性以及哺乳动物的年龄、体重、性别等因素而变化。治疗有效量还可指足以实现所需的有益效果的化合物的任何量,该有益效果包括如以上(1)-(3)所述的预防疾病、抑制疾病或减轻疾病。例如化合物的量可以介于0.1-250mg/kg,或优选地,0.5-100mg/kg,或更优选地,1-50mg/kg,或甚至更优选地,2-20mg/kg。优选地,所述量的化合物每天两次向哺乳动物施用。更优选地,所述量的化合物每天一次向哺乳动物施用。
如本文所述的,术语“疾病和/或病症”是指所述受试者的一种身体状态,该身体状态与本发明所述疾病和/或病症有关。例如,本发明所述疾病和/或病症指结核分枝杆菌感染性疾病。
如本文所述的,术语“受试者”可以指患者或者其它接受本发明式(I)化合物的盐或其药物组合物以治疗本发明所述疾病或病症的动物,特别是哺乳动物,例如人、狗、猴、牛、马等。
本发明再一方面还涉及以本发明中的化合物作为活性成份的药物组合物。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合,制成适于人或动物使用的任何剂型。
本发明中的化合物或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明化合物制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助溶剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;润湿剂可以是水、乙醇、异丙醇等;粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助溶剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成分本发明化合物与稀释剂、助溶剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助溶剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调节剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;pH调节剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的,增强治疗效果,本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明的化合物或组合物可单独服用,或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时,应根据实际情况调整它的剂量。
有益技术效果
本发明的发明人经过广泛的研究,合成式(I)所示化合物的盐,并通过MABA(Microplate alamar blue assay)法以M.tuberculosis H37Rv菌株进行最低抑菌浓度MIC(Minimum inhibitory concentration)测定,显示出较强的抗结核分枝杆菌活性,其中获得MIC<0.016μg/mL的盐5个,显著强于抗结核一线药物异烟肼。本发明的式(I)化合物的马来酸盐、富马酸盐、枸橼酸盐以及L-苹果酸盐在细胞渗透性上优于式(I)化合物的盐酸盐,预示本发明的盐具有更优的吸收性质。在小鼠药代动力学试验结果显示,式(I)化合物的马来酸盐和L-苹果酸盐的生物利用度相比化合物(I)显著提高。大鼠药代动力学实验结果显示,式(I)化合物的马来酸盐相比式(I)化合物及其盐酸盐,体内暴露量(AUC)和生物利用度均显著提高,预示本发明的盐具有相比游离碱和盐酸盐更优的药代动力学性质。影响因素试验考察结果显示,在光照、高温及高湿条件下放置十天,式(I)化合物的马来酸盐非常稳定,尤其是光照条件下,稳定性显著优于化合物(I),预示本发明的盐在光照稳定性方面有明显改善。本发明提供了一类抗结核活性强、药代动力学性质和理化性质显著改善的苯并硫代吡喃酮类化合物的盐,可用于由细菌引起的感染性疾病,特别是由结核分枝杆菌引起的结核病的治疗或预防性治疗,同时也可用于克服与耐药性有关的问题。
具体实施方式
通过下面的实施例可以对本发明进行详细描述,但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明,其中也公开了其具体实施例,对本领域的技术人员而言,在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进是显而易见的。
对于以下全部实施例,可使用本领域技术人员已知的标准操作和纯化方法。除非另有说明,所有温度以℃(摄氏度)表示。化合物的结构是通过核磁共振谱(NMR)来确定的。
制备实施例部分
化合物的结构是通过核磁共振氢谱(1H NMR)来确定的。核磁共振氢谱化学位移(δ)以百万分之一(ppm)的单位给出。耦合常数(J)以赫兹(Hz)为单位。核磁共振谱用Mercury-400型核磁共振仪测定,氘代甲醇(CD3OD)和氘代二甲基亚砜(DMSO-d6)作溶剂,四甲基硅烷(TMS)为内标。
电子天平采用日本Yanaco LY-300型电子天平。
无水溶剂均通过标准方法处理。其它试剂均为市售分析纯。
本发明采用下述缩略词:
MIC为最小抑菌浓度
Papp为表观渗透系数
po为口服给药
iv为静脉给药
AUC为药物浓度-时间曲线下面积
F为生物利用度
t1/2β为消除半衰期
Cmax为达峰浓度
Tmax为达峰时间
对比例
对比例1
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮(化合物(I))
化合物(I)参照专利201810092333.X和PCT/CN2018/080787实施例11(化合物11)合成。
对比例2
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1盐酸盐(化合物(I)·1盐酸盐)
化合物(I)·1盐酸盐参照专利201810092333.X和PCT/CN2018/080787实施例15(化合物22)合成。
实施例
实施例1
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1马来酸盐(化合物1)
合成路线:
将化合物(I)(1.14g,2.5mmol)加入100mL三口瓶中,加入21mL无水甲醇,室温搅拌均匀,常温缓慢加入马来酸(0.348g,3.0mmol),加完2-3min后,溶液开始析出黄色固体,保持常温搅拌3小时后,抽滤,滤饼用5mL甲醇冲洗,干燥得到黄色粉末状固体1.23g,收率:86%。
1H NMR(400MHz,CD3OD)δ:9.02(d,J=2.2Hz,1H),8.90(d,J=2.2Hz,1H),6.40(s,1H),6.27(s,2H),3.98(brs,4H),3.32(brs,4H),2.94-2.92(m,2H),1.86-1.79(m,5H),1.76-1.72(m,1H),1.39-1.21(m,3H),1.12-1.03(m,2H).
实施例2
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2富马酸盐(化合物2)
合成路线:
将化合物(I)(0.228g,0.5mmol)加入25mL单口瓶中,加入6mL无水甲醇,室温搅拌均匀,加入富马酸(0.232g,2.0mmol),加完后,保持80℃回流搅拌3小时后,自然冷却至室温,冰浴10min后抽滤,滤饼用1mL甲醇冲洗,干燥得到黄色粉末状固体0.25g,收率:79%。
1H NMR(400MHz,DMSO-d6)δ:13.08(brs,2H),8.85-8.83(m,2H),6.62(s,3H),6.30(s,1H),3.66-3.64(m,4H),2.48(brs,4H),2.16-2.14(m,2H),1.76-1.65(m,5H),1.54-1.48(m,1H),1.27-1.12(m,3H),0.90-0.82(m,2H).
实施例3
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1枸橼酸盐(化合物3)
合成路线:
将化合物(I)(0.2g,0.44mmol)加入25mL单口瓶中,加入5mL无水甲醇,室温搅拌均匀,加入枸橼酸(0.127g,0.66mmol),保持80℃回流搅拌3小时后,自然冷却至室温,室温搅拌5min后抽滤,滤饼用1mL甲醇冲洗,干燥得到黄色粉末状固体0.27g,收率:83%。
1H NMR(400MHz,DMSO-d6)δ:8.85-8.84(m,2H),6.61(s,1H),3.69-3.66(m,4H),2.74(d,J=15.4Hz,2H),2.64(d,J=15.4Hz,2H),2.57(brs,4H),2.24-2.22(m,2H),1.77-1.62(m,5H),1.56-1.50(m,1H),1.27-1.13(m,3H),0.91-0.82(m,2H).
实施例4
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2枸橼酸盐(化合物4)
合成路线:
将化合物(I)(0.2g,0.44mmol)加入25mL单口瓶中,加入5mL无水甲醇,室温搅拌均匀,加入枸橼酸(0.42g,2.2mmol),保持80℃回流搅拌4小时后,自然冷却至室温过夜,抽滤,滤饼用1mL甲醇冲洗,干燥得到黄色固体0.25g,收率:76%。
1H NMR(400MHz,DMSO-d6)δ:8.83(brs,2H),6.29(s,1H),3.67(brs,4H),2.74(d,J=15.4Hz,3H),2.64(d,J=15.4Hz,3H),2.58(brs,4H),2.24-2.22(m,2H),1.76-1.62(m,5H),1.55-1.50(m,1H),1.24-1.12(m,3H),0.91-0.82(m,2H).
实施例5
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1L-苹果酸盐(化合物5)
合成路线:
将化合物(I)(0.228g,0.5mmol)加入25mL单口瓶中,加入6mL无水甲醇,室温搅拌均匀,加入L-苹果酸(0.268g,2.0mmol),加完后,保持80℃回流搅拌5小时后,自然冷却至室温,滤除不溶物,滤液冰浴下缓慢加入6mL冰水,保持冰浴搅拌30min后抽滤,干燥得到土黄色固体0.1g,收率:34%。
1H NMR(400MHz,CD3OD)δ:9.00(s,1H),8.87(s,1H),6.33(s,1H),4.46-4.43(m,1H),3.81(brs,4H),2.82-2.77(m,5H),2.65-2.59(m,1H),2.40-2.38(m,2H),1.86-1.64(m,6H),1.37-1.21(m,3H),1.01-0.92(m,2H).
生物活性测试
1、体外抗结核活性测试
测定方法:Microplate Alamar Blue Assay(MABA)法测定体外抗结核活性。
实验原理:Alamar Blue加入培养基可作为氧化还原指示剂,颜色由蓝色向红色转变,反映所研究的微生物对氧分子的消耗。Alamar Blue的颜色改变可用光度计测定,其发射波长为590nm。
实验方法:参照文献(专利201810092333.X和Antimicrob Agents Chemother,2011,55,5185-5193.)进行。
表1、本发明部分化合物体外抗结核分枝杆菌H37Rv活性
由表1数据可知,本发明中的化合物具有很强的体外抗结核分枝杆菌活性。
2、Caco-2细胞渗透性测试实验方法:参照文献(Advanced drug deliveryreviews,2001,46,27-43.)进行。
Caco-2细胞是一种人克隆结肠腺癌细胞,结构和功能类似于分化的上皮细胞,具有微绒毛等结构,广泛地被用于体外模拟药物在肠道的渗透和吸收。化合物的表观渗透系数(Papp)通过下式计算:
Papp=(dQ/dt)/(C0×A)
其中dQ/dt是药物分子过膜渗透速率,C0为药物初始浓度,A为单分子层的面积。
表2、本发明部分化合物的Caco-2细胞渗透性数据
由表2数据可知,本发明的化合物相比化合物(I)·1盐酸盐具有更好的渗透性,预示本发明的化合物具有更好的吸收性质。
3、小鼠体内药代动力学试验
实验方法:
每组采用三只重量为23-25克的Balb/c小鼠(雄性)进行化合物1、2、3和5的药代动力学研究。化合物1、2、3和5分别以0.5%羧甲基纤维素配置成5mg/mL悬液,口服给予50mg/kg的剂量。化合物1、2、3和5分别以20%HP-β-CD和1N盐酸配置成1mg/mL溶液,静脉给予5mg/kg的剂量。
在口服和静脉给药后5,15,30分钟,以及1,2,4,7,24小时收集血浆样本。收集的血浆样本储存在-80℃直到用于分析。血浆样本用含有特非那丁内标的乙腈进行提取,提取剂与血浆比率为20:1。通过LC/TSQ Quantum Access质谱仪(AB Sciex 5500)进行分析物定量。色谱条件:色谱柱:Kinetex C18 100A(30mm×3.0mm,2.6μm);柱温:室温,流动相:乙腈/水(80:20,v/v)(含0.1%甲酸);流速:0.8mL/min。质谱仪上的化合物检测以电喷雾正离子化模式进行。应用WinNonlin软件(6.3Pharsight Corporation,Mountain View,USA)计算药代动力学参数。
表3、小鼠血浆药代动力学参数
由表3可知本发明的化合物1、2、3和5生物利用度(F)为18.9-28.0%。对比文件(Eur.J.Med.Chem.,2018,160,157-170)中报道的化合物1、2、3和5的游离碱6b(化合物(I))生物利用度为13.1%。相比游离碱,化合物1、2、3和5的生物利用度提高,其中化合物1和5提高了1倍左右,预示本发明的化合物具有更优的药代动力学性质。
4、大鼠体内药代动力学试验
实验方法:
每组采用三只重量为223-245克的SD大鼠(雄性)进行化合物1,化合物(I)及其盐酸盐的药代动力学研究。化合物1,化合物(I)及其盐酸盐分别以0.5%羧甲基纤维素配置成5mg/mL悬液,口服给予50mg/kg的剂量。化合物1,化合物(I)及其盐酸盐分别以20%HP-β-CD和1N盐酸配置成1mg/mL溶液,静脉给予5mg/kg的剂量。
在口服和静脉给药后5,15,30分钟,以及1,2,4,7,12,24小时收集血浆样本。收集的血浆样本储存在-80℃直到用于分析。应用WinNonlin软件(6.3Pharsight Corporation,Mountain View,USA)计算药代动力学参数。
表4、大鼠血浆药代动力学参数
由表4可知本发明的化合物1,在相同剂量下,较化合物(I)及其盐酸盐,口服Cmax,AUC及生物利用度(F)均明显提高,预示化合物1具有更优的药代动力学性质。
5、稳定性考察
采用HPLC考察化合物1和化合物(I)及其盐酸盐在光照、高温、高湿条件下放置10天的稳定性,结果如表5所示。
表5、稳定性考察结果
采用Waters e2695-PDA HPLC系统检测化合物纯度。色谱条件:色谱柱:KromasilC18(250mm×4.6mm,5μm);柱温:30℃,流动相:乙腈/水(84:16,v/v)等梯度;流速:1.0mL/min。由表5可知本发明的化合物1在光照、高温及高湿条件下非常稳定。专利(201810092333.X)中报道的化合物11(式(I)所示化合物)为本专利化合物1的游离碱,在光照条件下,外观发生变化并且纯度降低,因此,本发明的化合物1具有更优的理化性质。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (9)
2.根据权利要求1所述的盐,其特征在于,其为2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的马来酸盐。
3.根据权利要求1所述的盐,其特征在于,其为2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的富马酸盐。
4.根据权利要求1所述的盐,其特征在于,其为2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的枸橼酸盐。
5.根据权利要求1所述的盐,其特征在于,其为2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮的L-苹果酸盐。
6.根据权利要求1-5任一项的盐,其特征在于,其为2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1马来酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1/2马来酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2马来酸盐;2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1富马酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1/2富马酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2富马酸盐;2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1枸橼酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1/2枸橼酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2枸橼酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1L-苹果酸盐,2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·1/2L-苹果酸盐,或2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮·3/2L-苹果酸盐。
7.制备权利要求1至6任一项所述的盐的方法,其包括以下步骤:
2-(4-(环己基甲基)哌嗪-1-基)-6-(三氟甲基)-8-硝基-苯并硫代吡喃-4-酮与药学上的常见酸反应,在醇类或丙酮,乙腈中,于常温或回流条件下反应2-8小时,经过成盐反应得到式(I)所示的化合物的盐。
8.一种药物组合物,其包括治疗和/或预防有效量的权利要求1至6任一项所述的药学上可接受的盐,以及任选的一种或多种药学上可接受的载体、赋形剂、稀释剂、辅料和媒介物。
9.权利要求1-6任一项所述的药学可接受的盐或者权利要求8所述组合物在制备治疗和/或预防由结核分枝杆菌引起的感染性疾病的药物中的应用。
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