CN112020356A - 作为抗疟疾药物组合的喹啉-4-甲酰胺类和苯并萘啶衍生物的组合 - Google Patents
作为抗疟疾药物组合的喹啉-4-甲酰胺类和苯并萘啶衍生物的组合 Download PDFInfo
- Publication number
- CN112020356A CN112020356A CN201980024772.XA CN201980024772A CN112020356A CN 112020356 A CN112020356 A CN 112020356A CN 201980024772 A CN201980024772 A CN 201980024772A CN 112020356 A CN112020356 A CN 112020356A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutically acceptable
- acceptable salt
- quinoline
- combination
- pyronaridine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- LEWDKQKVAFOMPI-UHFFFAOYSA-N quinoline-4-carboxamide Chemical class C1=CC=C2C(C(=O)N)=CC=NC2=C1 LEWDKQKVAFOMPI-UHFFFAOYSA-N 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 67
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- DJUFPMUQJKWIJB-UHFFFAOYSA-N pyronaridine Chemical compound C12=NC(OC)=CC=C2N=C2C=C(Cl)C=CC2=C1NC(C=C(CN1CCCC1)C=1O)=CC=1CN1CCCC1 DJUFPMUQJKWIJB-UHFFFAOYSA-N 0.000 claims abstract description 39
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Abstract
本发明涉及包含6‑氟‑2‑(4‑吗啉‑4‑基甲基‑苯基)‑喹啉‑4‑甲酸(2‑吡咯烷‑1‑基‑乙基)‑酰胺或其前药或药学上可接受的盐作为第一活性成分和咯萘啶或其前药或药学上可接受的盐作为第二活性成分的组合。本发明也涉及三种抗疟疾活性成分即6‑氟‑2‑(4‑吗啉‑4‑基甲基‑苯基)‑喹啉‑4‑甲酸(2‑吡咯烷‑1‑基‑乙基)‑酰胺或其前药或盐、咯萘啶或其药学上可接受的盐、以及青蒿素或其衍生物的组合。本发明进一步涉及包含这样的组合的药物组合物及其在疟疾的治疗和/或预防中的用途。
Description
本发明涉及包含6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺或其前药或药学上可接受的盐作为第一活性成分和咯萘啶(pyronaridine)或其前药或药学上可接受的盐作为第二活性成分的组合。本发明也涉及三种抗疟疾活性成分即6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺或其前药或盐、咯萘啶或其药学上可接受的盐、以及青蒿素或其衍生物的组合。本发明进一步涉及包含这样的组合的药物组合物及其在疟疾的治疗和/或预防中的用途。
背景技术
在进化现象的驱使下,对抗疟疾药物的抗性一直是药物开发的挑战,并已导致一线疗法诸如氯喹、氯胍、乙胺嘧啶、磺胺多辛-乙胺嘧啶和甲氟喹的连续消失,它们不能在许多已经密集采用它们的地区产生90%的临床反应(Mita T,Tanabe K,Kita K:Spread andevolution of Plasmodium falciparum drug resistance.Parasitol Int.2009,58:201-209;World Health Organization:Global report on antimalarial drug efficacy anddrug resistance:2000-2010.2010,WHO,Geneva,121)。随着复方蒿甲醚-苯芴醇(arthemeter-lumefantrine)的批准,此后基于青蒿素的疗法(ACTs)已经被采用,并已成为护理标准。在3天内每天都施用所有ACT,并且在每个地区都已经观察到患者顺应性问题。开发基于青蒿素的组合疗法的基本原理是将一种非常速效的化合物(一种青蒿素衍生物)与长效化合物诸如4-氨基喹啉组合,所述非常速效的化合物将在最初的24小时内杀死超过80%的寄生物(parasite)(迅速减轻症状),所述长效化合物为防止再感染提供一定保护(治疗后预防)。目前,对青蒿素的抗性在东南亚的出现相对缓慢。就目前而言,这转化为寄生物清除时间的减少,例如在泰国报道(Phyo AP,Nkhoma S,Stepniewska K,Ashley EA,Nair S,McGready R,Ler Moo C,Al-Saai S,Dondorp AM,Lwin KM,Singhasivanon P,DayNPJ,White NJ,Anderson TJC,Nosten F:Emergence of artemisinin-resistant malariaon the western border of Thailand:a longitudinal study.Lancet.2012,379:1960-1966)。
根据WHO推荐,应将新的抗疟药开发为固定剂量组合。寄生物疾病诸如疟疾的药物联合治疗的目标是防止抗性的出现,同时通过提高治愈率为治疗提供额外益处。原理是,只要两种组分具有不同的作用模式,那么对组合的一种组分具有抗性的任何生物都会被另一种组分消除。因此增加了抗性的障碍,因为寄生物随后必须同时获得两种抗性,假设突变事件是随机的,这是一个不太可能的情况(White N,Olliaro PL:Strategies for theprevention of antimalarial drug resistance:Rationale for combinationchemotherapy for malaria.Parasitol Today.1996,12:399-401)。值得注意的是,影响抗药性出现的其它因素也应考虑在内,例如药物对其它寄生物生命周期阶段的影响,诸如配子体发生(gametocytogenesis)和配子体生存力、药物半衰期、临床寄生物减少率或药物剂量(Xavier C Ding,David Ubben and Timothy NC Wells,A framework for assessingthe risk of resistance for anti-malarials in development,Malaria Journal2012,11:292)。
在过去的十年中,高通量表型筛选运动使人们发现了新型的抗疟疾药物,因此增加了用于治疗疟疾的潜在新组合疗法的数量,并加强了对最有前途的药物的合理选择和优先处理的需求,包括但不限于两种化学实体的有益抗寄生物作用以及与每种化合物和每种组合相关的产生抗性的风险的早期评估(Canfield C.J.,Pudney M.,GutteridgeW.E.Interactions of atovaquone with other antimalarial drugs againstPlasmodium falciparum in vitro.Exp Parasitol.1995,80:373-81;Fivelman,Q.L.,Adagu I.S.,Warhurst,D.C.Modified fixed-ratio isobologram method for studyingin vitro interactions between atovaquone and proguanil or dihydroartemisininagainst drug-resistant strains of Plasmodium falciparum.Antimicrob AgentsChemother.2004,48:4097-4102)。
发明内容
本发明提供了包含6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺或其前药或药学上可接受的盐作为第一活性成分和咯萘啶或其前药或药学上可接受的盐作为第二活性成分的组合,优选地用于用在疟疾的治疗和/或预防中。
在这样的组合中,6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺可以呈游离碱的形式(如下面所示),但是也可以呈药学上可接受的盐(诸如尤其是琥珀酸盐)的形式:
此外,在这样的组合中,咯萘啶可以呈游离碱的形式或呈药学上可接受的盐诸如尤其是下面显示的咯萘啶四磷酸盐的形式:
根据本发明的上述组合显示出累加的寄生物性能(additive parasitologicalproperties),并且除此以外,令人惊奇地发现6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺(和它的盐中的任一种)通过P-gp流出,而作为P-gp抑制剂(Qi J,Yang CZ,Wang CY,Wang SB,Yang M,Wang JH.Function and mechanism ofpyronaridine:a new inhibitor of P-glycoprotein-mediated multidrugresistance.Acta Pharmacol Sin.2002,23:544-50)的咯萘啶(不同于许多其它抗疟药)可以积极地影响6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺(和它的盐中的任一种)以较低剂量穿过肠壁,从而积极地影响治疗窗口。
本发明也涉及这样的组合,其进一步包含青蒿素或其衍生物或药学上可接受的盐作为第三活性成分。
在根据本发明的这样的组合的一个非常重要的实施方案中,青蒿素衍生物选自二氢青蒿素、蒿甲醚和青蒿琥酯。
就本发明的目的而言,术语“青蒿琥酯”用于青蒿酸(artesunic acid):
在本发明的一个具体实施方案中,第三活性成分是青蒿琥酯或青蒿琥酯的药学上可接受的盐(优选青蒿琥酯钠或形成的碱金属碳酸盐例如碳酸钠或碳酸钾)。
药用盐和其它形式
在组合中包含的上述化合物可以呈其最终的非盐形式使用。另一方面,本发明还涉及这些化合物以其药学上可接受的盐的形式的用途,所述盐可用本领域已知的方法从各种有机的和无机的酸和碱制备得到。在组合中包含的化合物的药学上可接受的盐形式通常通过常规方法制备。如果在组合中包含的化合物含有酸性中心(例如青蒿酸)诸如羧基,则可以通过使化合物与合适的碱反应生成相应的碱加成盐来形成其合适的盐之一。这样的碱是例如碱金属氢氧化物,包括氢氧化钾和氢氧化钠;碱土金属氢氧化物,诸如氢氧化镁和氢氧化钙;碱金属碳酸盐(诸如碳酸钠和碳酸钾);和各种有机碱,诸如哌啶、二乙醇胺和N-甲基-还原葡糖胺(葡甲胺)、苄星青霉素、胆碱、二乙醇胺、乙二胺、苯乙苄胺、二乙胺、哌嗪、赖氨酸、L-精氨酸、氨、三乙醇胺、甜菜碱、乙醇胺、吗啉和氨丁三醇。
在组合中包含的化合物含有碱性中心的情况下(例如6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺和咯萘啶),通过用药学上可接受的有机和无机酸(例如卤化氢,诸如氯化氢或溴化氢,其它无机酸及其相应的盐)处理这些化合物,可以形成酸加成盐。
在本发明的一个具体实施方案中,可以在用于治疗和/或预防疟疾的组合、药物组合物(下文描述)和/或方法(下文描述)中使用的咯萘啶的药学活性盐是选自以下的盐:乙酸盐、苯甲酸盐、苯磺酸盐、溴化物盐(bromide salts)、樟脑磺酸盐、碳酸盐、柠檬酸盐、氯化物盐(chloride salts)、乙二磺酸盐、依托酸盐(estolate)、富马酸盐、葡庚糖酸盐、葡萄糖酸盐、葡糖醛酸盐、马尿酸盐、碘化物盐(iodide salts)、羟乙基磺酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、甲磺酸盐、甲基硫酸盐、萘磺酸盐(napsylate)、硝酸盐、草酸盐、扑酸盐、磷酸盐(诸如尤其是四磷酸盐)、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐和甲苯磺酸盐;优选地,咯萘啶的药学活性盐是选自以下的盐:乙酸盐、苯甲酸盐、苯磺酸盐、柠檬酸盐、氯化物盐、乙二磺酸盐、富马酸盐、乳酸盐(诸如尤其是L-乳酸盐)、苹果酸盐(诸如尤其是L-苹果酸盐)、马来酸盐、甲磺酸盐、萘磺酸盐、草酸盐、磷酸盐(包括尤其是四磷酸盐)、琥珀酸盐、硫酸盐、酒石酸盐(诸如尤其是L-酒石酸盐)和甲苯磺酸盐;和甚至更优选地咯萘啶的药学活性盐是选自以下的盐:氯化物盐、富马酸盐、马来酸盐、甲磺酸盐、磷酸盐(诸如尤其是四磷酸盐)、硫酸盐和甲苯磺酸盐。
在本发明的另一个具体实施方案中,可以在用于治疗和/或预防疟疾的组合、药物组合物(下文描述)和/或方法(下文描述)中使用的6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺的药学活性盐是选自以下的盐:乙酸盐、苯甲酸盐、苯磺酸盐、溴化物盐、樟脑磺酸盐、碳酸盐、柠檬酸盐、氯化物盐、乙二磺酸盐、依托酸盐、富马酸盐、葡庚糖酸盐、葡萄糖酸盐、葡糖醛酸盐、马尿酸盐、碘化物盐、羟乙基磺酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、甲磺酸盐、甲基硫酸盐、萘磺酸盐、硝酸盐、草酸盐、扑酸盐、磷酸盐(诸如尤其是四磷酸盐)、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐和甲苯磺酸盐;优选地咯萘啶的药学活性盐是选自以下的盐:乙酸盐、苯甲酸盐、苯磺酸盐、柠檬酸盐、氯化物盐、乙二磺酸盐、富马酸盐、乳酸盐(诸如尤其是L-乳酸盐)、苹果酸盐(诸如尤其是L-苹果酸盐)、马来酸盐、甲磺酸盐、萘磺酸盐、草酸盐、磷酸盐、琥珀酸盐、硫酸盐、酒石酸盐(诸如尤其是L-酒石酸盐)和甲苯磺酸盐;和甚至更优选地咯萘啶的药学活性盐是选自以下的盐:氯化物盐、富马酸盐、马来酸盐、甲磺酸盐、磷酸盐、硫酸盐和甲苯磺酸盐。
在本发明的另一个具体实施方案中,可以在用于治疗和/或预防疟疾的组合、药物组合物(下文描述)和/或方法(下文描述)中使用的青蒿琥酯的药学活性盐是选自以下的盐:钠盐和钾盐。
本发明的一个特定实施方案涉及组合,其包含(a)6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺(游离碱)或6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺琥珀酸盐和(b)咯萘啶四磷酸盐或咯萘啶(游离碱)。在甚至更具体的实施方案中,所述组合包含(a)6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺(游离碱)或6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺琥珀酸盐和(b)咯萘啶四磷酸盐。
在另一个实施方案中,所述组合包含a)6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺(游离碱)或6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺琥珀酸盐,b)咯萘啶(游离碱)或咯萘啶四磷酸盐和c)青蒿琥酯或青蒿琥酯钠。
在非常具体的实施方案中,所述组合包含a)6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺(游离碱)或6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺琥珀酸盐,b)咯萘啶四磷酸盐和c)青蒿琥酯钠。
同时或依次施用根据本发明的组合的活性成分(随时间分布)。
在同时进行活性成分的施用的情况下,可以将两种或三种活性成分组合在单一药物形式(固定组合,例如片剂或药囊(sachet))内。与活性成分的施用是同时还是不同时(或者在三种活性成分的情况下,部分同时)无关,两种或三种活性成分可以以不同的药物形式存在。在该情况下,根据本发明的组合可以呈试剂盒的形式。
本发明的另一个方面涉及本文公开的药物组合。此外,本发明涉及本文所述的组合在疟疾的治疗和/或预防中的用途。本发明还包括本文所述的组合在制备用于治疗和/或预防疟疾的药物中的用途。
药物组合物
本发明也涉及一种药物组合物,优选地用于治疗和/或预防疟疾,其包含6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺或其前药或药学上可接受的盐作为第一活性成分和咯萘啶或其药学上可接受的盐活性成分作为第二活性成分,两种活性成分优选地以治疗活性剂量使用。
本发明进一步涉及一种药物组合物,优选地用于治疗和/或预防疟疾,其包含6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺或其前药或药学上可接受的盐作为第一活性成分、咯萘啶或其药学上可接受的盐活性成分作为第二活性成分、和青蒿素或其衍生物作为第三活性成分。优选地,这样的组合物包含治疗有效量的所有三种活性成分。在一个优选的实施方案中,所述第三活性成分是青蒿琥酯或其药学上可接受的盐(例如青蒿琥酯钠)。
本发明也涉及一种用于治疗和/或预防疟疾的药物组合物,其包含作为活性成分的治疗活性剂量的6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺或其前药或药学上可接受的盐和咯萘啶或其药学上可接受的盐以及还有至少一种药学上可接受的赋形剂。这样的药物组合物的一个具体实施方案包含治疗活性剂量的青蒿素或其衍生物或药学上可接受的盐作为另一种活性成分。
药物组合物可以以剂量单位(dosage unit)的形式施用,每个剂量单位包含预定量的活性成分。根据所治疗的疾病状况、施用方法以及患者的年龄、体重和状况,这样的单位可以包含不同剂量的根据本发明的组合,或者可以以剂量单位的形式施用药物组合物,每个剂量单位包含预定量的活性成分。优选的剂量单位制剂是包含如上面指出的每日剂量或分份剂量(part-dose)或活性成分的其相应部分。此外,可以使用制药领域中通常已知的方法来制备这种类型的药物组合物。
药物组合物可适于通过任何期望的合适方法施用,例如通过口服(包括含服或舌下)、直肠、鼻、局部(包括含服、舌下或透皮)或胃肠外(包括皮下、肌肉内、静脉内或真皮内)方法。使用药学领域已知的所有方法,例如通过将活性成分与赋形剂或辅助剂组合,可以制备这样的组合物。
适于口服施用的药物组合物可以作为单独的单位施用,例如,胶囊剂或片剂;粉末(powder)或颗粒;在水性或非水性液体中的溶液或混悬剂;可食用的泡沫或泡沫食物;或水包油液体乳剂或油包水液体乳剂。因此,例如,就以片剂或胶囊剂形式的口服施用而言,可以将活性成分组分与口服的、无毒的且药学上可接受的惰性赋形剂如乙醇、甘油、水等混合。如下制备粉末:将化合物粉碎至合适的细小尺寸并将它与以类似方式粉碎的药物赋形剂组合,所述药物赋形剂是例如可食用的碳水化合物,例如,淀粉或甘露醇。同样可以存在矫味剂、防腐剂、分粉末和染料。
通过如上所述制备粉末混合物,并将其填充到成型的明胶壳中,制备胶囊剂。在填充操作前,可以向粉末混合物中加入助流剂和润滑剂,如高度分散的硅酸、滑石、硬脂酸镁、硬脂酸钙或固体形式的聚乙二醇。同样可以加入崩解剂或增溶剂,例如,琼脂、碳酸钙或碳酸钠,以便在服用胶囊后提高药物的利用率。此外,如果需要或必要,同样可以向混合物中掺入适宜的粘合剂、润滑剂和崩解剂以及染料。合适的粘合剂包括淀粉、明胶、天然糖(例如,葡萄糖或β-乳糖)、由玉米制成的甜味剂、天然的和合成的橡胶(例如,阿拉伯胶、黄蓍胶或海藻酸钠)、羧甲纤维素、聚乙二醇、蜡类等。在这些剂型中所用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括,且不限于,淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。如下配制片剂:例如,制备粉末混合物,将该混合物制粒或干压,加入润滑剂和崩解剂,并将整个混合物压成片剂。如下制备粉末混合物:将以适当方式粉碎的化合物与如上所述的稀释剂或碱混合,以及任选地与粘合剂(例如羧甲纤维素、海藻酸盐、明胶或聚乙烯基吡咯烷酮)、溶出延缓剂(dissolution retardant)(例如,石蜡)、吸收促进剂(例如,季盐)和/或吸附剂(例如,膨润土、高岭土或磷酸二钙)混合。可以如下将粉末混合物制粒:用粘合剂如糖浆、淀粉糊、acadia胶浆或者纤维素或聚合物材料的溶液润湿它,并压迫它穿过筛。作为制粒的替代方法,可以使粉末混合物穿过压片机,得到不均匀形状的块,将其破碎以形成颗粒。通过加入硬脂酸、硬脂酸盐、滑石或矿物油,可以润滑颗粒,以防止粘附在片剂铸模上。然后,将被润滑的混合物压成片剂。活性成分也可以与自由流动的惰性赋形剂组合,然后直接压制得到片剂,而无需进行制粒或干压步骤。可以存在透明的或不透明的保护层,其由紫胶密封层、糖或聚合物材料层和蜡的光泽层组成。可以向这些包衣中加入染料,以便能区分不同的剂量单位。
可以以剂量单位的形式制备口服液,例如,溶液、糖浆剂和酏剂,使得给定量包含预定量的化合物。可以通过将化合物溶解在含有合适矫味剂(flavor)的水溶液中来制备糖浆剂,而酏剂则使用无毒的醇媒介物来制备。可以通过将化合物分散在无毒的媒介物中来配制混悬剂。同样可以添加增溶剂和乳化剂,例如,乙氧基化的异硬脂醇和聚氧乙烯山梨醇醚,防腐剂,矫味剂添加剂,例如,薄荷油或天然的甜味剂或糖精或其它人工甜味剂等。如果需要,可以将用于口服施用的剂量单位制剂包封于微胶囊中。还可以以延长或延迟释放的方式来制备制剂,例如,通过将微粒材料用聚合物、蜡等进行包衣,或者将其包埋于聚合物、蜡等中。
根据本发明的组合的活性成分及其盐、溶剂合物和生理学功能衍生物以及其它活性成分也可以以脂质体递送系统的形式施用,例如,小单层囊泡、大单层囊泡和多层囊泡。可以从各种磷脂如胆固醇、硬脂胺或磷脂酰胆碱形成脂质体。
适于透皮施用的药物组合物可以作为独立的硬膏剂施用,以与接受者的表皮长期紧密接触。因而,例如,如在Pharmaceutical Research,3(6),318(1986)中的概括描述的,可以通过离子透入法从硬膏剂递送活性成分。适于局部施用的药物化合物可以配制成软膏剂、乳膏剂、混悬剂、洗剂、粉末、溶液剂、糊剂、凝胶剂、喷雾剂、气雾剂或油。适用于直肠施用的药物组合物可以以栓剂或灌肠剂的形式施用。按照处方制备的注射溶液和混悬剂可以从无菌粉末、颗粒和片剂制备。
不言而喻,除了以上特别提到的组分外,就特定类型的制剂而言,组合物还可以包含本领域中常用的其它试剂;因而,例如,适合口服施用的组合物可以包含矫味剂。
根据本发明的药物组合物/制剂可以用作人类和兽医学中的药物。
根据本发明的组合的每种活性成分和其它活性成分的治疗有效量或治疗活性剂量取决于许多因素,包括例如动物的年龄和体重、需要治疗的精确疾病状况及其严重程度、制剂的性质和施用方法,并最终由主治医生或兽医来决定。
对于含有6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺琥珀酸盐和咯萘啶四磷酸盐作为活性成分的根据本发明的组合的口服施用,这两种活性成分的每日剂量如下:
6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺琥珀酸盐:每个个体每天30mg至1000mg,优选地100mg至700mg,甚至更优选地300mg至600mg(单剂量)。
咯萘啶四磷酸盐:每个个体每天180mg至1000mg,优选地300-800mg,甚至更优选地400mg至600mg(单剂量)。
对于含有6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺琥珀酸盐、咯萘啶四磷酸盐和青蒿琥酯作为活性成分的根据本发明的组合的口服施用,这三种活性成分中的每一种的每日剂量如下:
6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺琥珀酸盐:每个个体每天30mg至1000mg,优选地100mg至700mg,甚至更优选地300mg至600mg(单剂量)。
咯萘啶四磷酸盐:每个个体每天180-1000mg,优选地300-800mg,甚至更优选地400mg至600mg(单剂量)。
青蒿琥酯:每个个体每天20-200mg,优选地100-200mg,甚至更优选地150mg至180mg(单剂量)。
根据本发明的组合/药物组合物可以用作人类和兽医学中的药物。
在另一个方面,本发明涉及一种在有此需要的患者中治疗和/或预防疟疾的方法,所述方法包括给这样的患者施用6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺(第一活性成分)和咯萘啶(第二活性成分)或前述任一种的前药或药学上可接受的盐的治疗活性量的组合(包括它们的所有比例的混合物)。在根据本发明的这样的方法的一个具体实施方案中,也将青蒿素或其衍生物或药学上可接受的盐施用给患者(作为第三活性成分)。
在另一个方面,本发明涉及一种用于治疗疟疾的试剂盒(由单独包组成),其首先包含6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺或其药学活性盐,其次包含咯萘啶或其药学活性盐。
另一个实施方案涉及如上所述的试剂盒,其中所述试剂盒第三进一步包含青蒿素或其衍生物或药学上可接受的盐(优选地所述试剂盒进一步包含青蒿酸的青蒿琥酯(优选青蒿琥酯钠))。
为了本发明的目的,表述“有效量”表示药物或药学上的活性成分的量,其在组织、系统、动物或人中造成例如研究人员或医师所寻求或期望的生物学或医学响应。
此外,表述“治疗有效量”表示与未接受该量的相应个体相比具有如下结果的量:改善治疗、治愈、预防或消除疾病、综合症、状况、病患、病症或副作用,或也减少疾病、病患或病症的发展。表述“治疗有效量”还包括有效增加正常生理功能的量。
如本文所用并除非另有说明,术语“前药”是指活性成分的衍生物,其可以在生物条件(体外或体内)下水解、氧化或以其它方式反应以提供活性化合物。前药的例子包括、但不限于活性成分的衍生物和代谢物,其包括生物可水解的部分例如生物可水解的酰胺、生物可水解的酯、生物可水解的氨基甲酸酯、生物可水解的碳酸酯、生物可水解的酰脲和生物可水解的磷酸酯类似物。在某些实施方案中,带有羧基官能团的化合物的前药是羧酸的低级烷基酯。羧酸酯通过使分子上存在的任何羧酸基团酯化而方便地形成。可通常使用熟知的方法制备前药,所述方法例如在Burger’s Medicinal Chemistry and Drug Discovery第6版(Donald J.Abraham编,2001,Wiley)和Design and Application of Prodrugs(H.Bundgaard编,1985,Harwood Academic Publishers Gmfh)中描述的那些。
实施例
除非另外指出,否则所有起始原料都得自商业供应商,且不经进一步纯化地使用。除非另外指出,否则所有温度都以℃表示,且所有实验都在室温进行。
缩写
ACT 基于青蒿素的疗法
Ci 居里
Cpm 每分钟计数
CsA 环孢菌素A
DMEM Dulbecco 氏改良的伊格尔培养基
DMSO 二甲亚砜
HBSS 汉克氏缓冲盐溶液
HEPES 4-(2-羟基乙基)哌嗪-1-乙磺酸
HESI 加热电喷射电离
LC 液相色谱法
M1 6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺琥珀酸盐
MS 质谱法
P.falciparum 恶性疟原虫(Plasmodium falciparum)
P-gp P-糖蛋白
po 经口(口服)
PYRO 咯萘啶四磷酸盐
RT 室温
RPMI Roswell Park Memorial Institute培养基
SCID 严重联合免疫缺陷
将参考在下述实施例中描述的具体实施方案举例说明本发明(但不限于此)。
I.体外等效线图解法
使用由补充了0.5%II、25mM HEPES、25mM NaHCO3(pH 7.3)、0.36mM次黄嘌呤和100μg/ml新霉素的RPMI 1640组成的混合物作为培养基,如Desjardins,R.E.,Canfield,C.J.,Haynes,J.D.和Chulay,J.D.Quantitative assessment ofantimalarial activity in vitro by a semiautomatic microdilutiontechnique.Antimicrob.Agents Chemother.1979,16:710-718以及Matile,H.和Pink,J.R.L.Plasmodium falciparum malaria parasite cultures and their use inimmunology.Immunological Methods IV,221-234Academia Press(1990)中所述,针对实验室菌株NF54(来源不明的Schiphol机场菌株)的异步储备培养物所衍生出的恶性疟原虫(P.falciparum)的红细胞内形式试验了化合物。人A+型红细胞充当宿主细胞。将培养物在控湿的模块化培养箱中于3%O2、4%CO2和93%N2的气氛中保持在37℃。在96-孔微量滴定板中进行每种药物的试验。将化合物溶解在DMSO(10mg/ml)中,在无次黄嘌呤的培养基中预先稀释,并在64倍范围内在100μl重复液(duplicates)中滴定。在2.5%的红细胞悬浮液中加入等体积的含有0.3%的寄生物血症(parasitemia)的寄生物培养物,将试验板在上述条件下温育24h、48h或72h。通过在试验终止前8h(对于24h测定持续时间)或24h(对于48h和72h测定持续时间)加入的放射性标记的[3H]次黄嘌呤(0.25μCi在50μl体积的无次黄嘌呤的培养基中)的掺入来测量寄生物生长。将培养物收获到玻璃纤维过滤器上,并用蒸馏水洗涤。使用MicroBetaplate液体闪烁计数器(Wallac,Zürich,瑞士)对放射性进行计数,并将结果记录为在每种药物浓度的每孔每分钟计数,并表示为未处理对照的百分比。通过线性插值确定50%抑制浓度(IC50)(Huber,W.,Hurt,N.,Mshinda,H.,Jaquet,C.,Koella,J.C.,Tanner,M.Sensitivity of Plasmodium falciparum field-isolates from Tanzania tochloroquine,mefloquine and pyrimethamine during in vitro cultivation.ActaTrop.1993,52:313-6)。
如在Canfield C.J.,Pudney M.,Gutteridge W.E.Interactions of atovaquonewith other antimalarial drugs against Plasmodium falciparum in vitro.ExpParasitol.1995,80:373-81和Fivelman,Q.L.,Adagu I.S.,Warhurst,D.C.ModifiedFixed-ratio isobologram method for studying in vitro interactions betweenatovaquone and proguanil or dihydroartemisinin against drug-resistant strainsof Plasmodium falciparum.Antimicrob Agents Chemother.2004,48:4097-4102中所述进行药物相互作用研究。最初,确定单独试验药物的IC50(参见上面)。随后,将药物溶液用不含次黄嘌呤的培养基稀释至为预定IC50的10倍的初始浓度。将溶液(都在10xIC50)以1+3、1+1或3+1的比率组合。然后将单一药物溶液和组合药物溶液引入96-孔平板中以产生重复行。其余操作如上所述。关于数据解释,将组合药物的IC50表示为单独药物的IC50的分数(fraction)。这些分数分别被称为药物A和药物B的“分数抑制浓度”(FIC)。
FIC Drug A:分数抑制浓度
IC50 A(B):在有药物B存在下药物A的50%抑制浓度
IC50 A:单独药物A的50%抑制浓度
获得相互作用的数值,并表示为FICA和FICB的总和。FIC值的总和如下指示相互作用的类型:
当ΣFIC>4.0时有拮抗作用,当ΣFIC>0.5-4.0时无有害相互作用(Odds,F.C.,Antimicrob Agents Chemother.2003,52:1)。
表1.M1+PYRO的体外药物组合测定.
ΣFIC(分数抑制浓度),当ΣFIC>4.0时有拮抗作用,当ΣFIC>0.5-4.0时无有害相互作用。所述值分别显示K1和NF54的≥3个独立测定的平均值。
将M1与PYRO单独组合。对于具有三种不同测定持续时间(24h、48h和标准的72h)的NF54恶性疟原虫菌株,从≥3个独立实验计算出ΣFIC50值。它们在1.3-1.7的范围内,从而提示,在给定的试验条件下M1和PYRO之间的相互作用是无害的(表1)。
II.体内SCID小鼠模型
针对体内恶性疟原虫菌株Pf3D70087/N9评估了化合物效力。在第0天,用带寄生物的红血细胞静脉内感染小鼠。通常在感染后第3、4、5和6天用口服剂量的化合物(单次或4天口服给药方案)治疗实验小鼠,并关于在第7天寄生物血症的减少与感染的对照组进行对比(María Belen Jimenez-Díaz,Teresa Mulet,Sara Viera,Vanessa Gomez,Helen Garuti,Javier Ibanez,Angela Alvarez-Doval,Leonard D.Shultz,Antonio Martínez,DomingoGargallo-Viola,and Inigo Angulo-Barturen,Improved Murine Model of MalariaUsing Plasmodium falciparum Competent Strains and Non-Myelodepleted NOD-scidIL2Rgammanull Mice Engrafted with Human Erythrocytes,Antimicrob AgentsChemother.2009,53:4533)。
媒介物
将PYRO和M1溶解在由70%吐温-80和30%乙醇组成的媒介物中,然后在H2O中稀释10倍。所有制备物产生黄色液体和澄清溶液。
药代动力学分析
评价试验化合物的血液水平以便确定效力研究的个体中的标准药代动力学参数。在不同的时间(参见以下方案)采集外周血样品(20μl),与20μl H2O Milli Q混合并立即在干冰上冷冻。将冷冻样品保存在-80℃直至分析。来自对照小鼠的血液用于校准和QC目的。将血液样品在标准液-液萃取条件下处理,并通过LC-MS/MS(在阳离子模式下通过HESI电离进行定量)进行分析。
表2.在SCID小鼠中在4天给药期间咯萘啶对恶性疟原虫Pf3D70087/N9的口服治疗效果.
1无治疗;2平均值;3每组小鼠数目;LLQ=定量下限(<0.01%寄生物血症)。
从表2可以看出,在感染后第7天,口服9mg/kg的咯萘啶表现出>99.9%活性,在第7天没有寄生物。与未处理的对照小鼠相比,3mg/kg表现出99.6%活性,1mg/kg的其余剂量表现出微小活性(17%)。在完全相同的实验系统中,PYRO诱导的外周血寄生物清除率与50mg/kg氯喹相当。由于有限的剂量数目而无法准确确定ED90(即相对于未处理的对照小鼠,在感染后第7天使寄生物血症降低90%的以mg/kg计的M1剂量),但可以缩小到在1-3mg/kg之间的范围。
表3.在SCID小鼠中在4天给药期间M1对恶性疟原虫Pf3D70087/N9的口服治疗效果.
1无治疗;2平均值;3每组小鼠数目;LLQ=定量下限(<0.01%寄生物血症)。
从表3可以看出,在感染后第7天,口服1.2mg/kg的M1表现出>99.9%活性。与未处理的对照小鼠相比,0.6和0.4mg/kg分别显示出99.7%和94.9%活性,而0.2mg/kg的其余剂量显示出微小活性(28.3%)。
在相同的实验系统中,M1诱导的寄生物清除率与50mg/kg氯喹相当(但更低)。ED90计算为0.37mg/kg(游离碱)(María Belen Jimenez-Díaz,Teresa Mulet,Sara Viera,Vanessa Gomez,Helen Garuti,Javier Ibanez,Angela Alvarez-Doval,LeonardD.Shultz,Antonio Martínez,Domingo Gargallo-Viola,and Inigo Angulo-Barturen,Improved Murine Model of Malaria Using Plasmodium falciparum CompetentStrains and Non-Myelodepleted NOD-scid IL2Rgammanull Mice Engrafted withHuman Erythrocytes,Antimicrob Agents Chemother.2009,53:4533)。
表4.在4天给药期间M1+PYRO组合对恶性疟原虫Pf3D70087/N9的口服治疗效果.
1对照;2平均值;3每组小鼠数目;LLQ=定量下限(<0.01%寄生物血症);ND=未测定。
表4总结了在相同实验体内系统中将M1和咯萘啶组合时的药效学数据(%寄生物血症)。
当未经治疗的组(对照组)在感染后第7天使寄生物血症达到总红细胞的12%时,条目1显示了%寄生物血症。条目2显示了在最大寄生物学浓度(MPC)时M1的%寄生物血症,并且在寄生物清除率在第10天有效达到LLQ之前,可以观察到48h的滞后阶段。
如PYRO条目3和4、5和6、以及7和8中指示的,基于组合组相对于单独组的%寄生物血症之比,当需要快速杀死寄生物时,M1似乎不会影响在第4和5天由PYRO诱导的寄生物清除率。
III.在Caco-2细胞中的体外渗透性
将Caco-2细胞在8.5%CO2气氛下维持在DMEM中。对于运输实验,将0.125×106个细胞/孔接种在聚碳酸酯滤芯上,并使其生长并分化14±1天,然后将细胞单层用于实验。使用混合液(cocktail)方法在四维环境下进行药物转运实验。在存在和不存在CsA作为转运蛋白抑制剂的情况下,确定A(顶侧)→B(基底外侧)和B→A方向的表观渗透系数。将多达五种试验物质和参照化合物溶解在pH 7.4的汉克平衡盐溶液中,达到1μM的终浓度。在5%CO2的气氛中在37℃在含有25mM HEPES的HBSS(pH 7.4)中进行测定。在研究之前,将单层在预热的HBSS中洗涤。在实验开始时,将包含试验物质的预热HBSS添加到单层的供体侧,将没有试验物质的HBSS添加到接收器侧。在实验期间,将平板在150rpm在37℃摇动。2小时后,小心取出含单层的Transwell插入物,并将其放在新板中,以及取出接收器侧和供体侧的等分试样,并用等体积的含有内部标准品的乙腈稀释。离心混合物,并通过LC-MS/MS分析上清液。使用以下公式计算表观渗透系数(Papp):
Papp=[Vrec/(A×C0,供体)](dCrec/dt)×106
其中dCrev/dt是接收器隔室中的浓度随时间的变化,Vrec是接收器隔室中样品的体积,C0是在时间0时在供体隔室中的供体浓度,而A是具有细胞的隔室的面积。
表7.在有或没有环孢菌素A存在下Caco-2单层中M1的渗透系数和比率.
1在顶侧/基底外侧腔室中的pH为7.4/7.4。2在10μM温育的环孢菌素A。
在Caco-2单层细胞中,M1通过P-gp转运蛋白流出,比率为18.2(表7)。随着比例降至1.53,渗透率可以借助于P-gp抑制剂(如CsA)恢复,从而使M1以相似的速率从Caco-2单层的顶侧到基底外侧以及从基底外侧到顶侧。
表8.在有或没有PYRO存在下M1在Caco-2单层中的渗透系数和比率.
1在顶侧/基底外侧腔室中的pH为7.4/7.4。2顶侧至基底外侧。3基底外侧至顶侧
当PappA-B=2.00(无PYRO)时,M1的渗透性随PYRO浓度的增加而增加,在100μMPYRO时达到19.3。流出比从没有PYRO时的15.44降低到具有100μM咯萘啶时的2.42。
在大于10μM的浓度,PYRO抑制Pgp介导的M1流出。
Claims (13)
1.组合,其包含6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺或其前药或药学上可接受的盐作为第一活性成分和咯萘啶或其前药或药学上可接受的盐作为第二活性成分。
2.根据权利要求1的组合,其包含青蒿素或其衍生物或药学上可接受的盐作为第三活性成分。
3.根据权利要求2的组合,其中所述青蒿素衍生物选自:二氢青蒿素和蒿甲醚、青蒿琥酯。
4.根据权利要求3的组合,其中所述第三活性成分是青蒿琥酯或其药学上可接受的盐。
5.根据权利要求4的组合,其中所述青蒿琥酯的药学上可接受的盐为选自以下的盐:钠盐和钾盐。
6.根据权利要求2-5中的任一项的组合,其中所述组合包含6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺、咯萘啶四磷酸盐和青蒿琥酯钠。
7.根据权利要求1-6中的任一项的组合,其中同时或依次施用所述活性成分。
8.根据权利要求1-7中的任一项的组合,其用于治疗和/或预防疟疾。
9.用于治疗和/或预防疟疾的药物组合物,其包含治疗活性剂量的6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺或其前药或药学上可接受的盐和咯萘啶或其药学上可接受的盐作为活性成分,以及至少一种药学上可接受的赋形剂。
10.根据权利要求9的药物组合物,其包含治疗活性剂量的青蒿素或其衍生物或药学上可接受的盐作为另一种活性成分。
11.用于治疗疟疾的试剂盒,其首先包含6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺或其药学活性盐,且其次包含咯萘啶或其药学活性盐。
12.根据权利要求11的试剂盒,其进一步包含青蒿素或其衍生物或药学上可接受的盐。
13.在有此需要的患者中治疗和/或预防疟疾的方法,所述方法包括给这样的患者施用6-氟-2-(4-吗啉-4-基甲基-苯基)-喹啉-4-甲酸(2-吡咯烷-1-基-乙基)-酰胺和咯萘啶或前述任一种的前药或药学上可接受的盐的治疗活性量的组合,包括它们的所有比例的混合物。
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BEATRIZ BARAGANA ET AL.: "Anovel multiple-stage antimalarial agent that inhibits protein synthesis" * |
RITA PIEDADE ET AL.: "The pharmacogenetics of antimalaria artemisinin combination therapy" * |
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CN112020356B (zh) | 2024-04-05 |
US20210023087A1 (en) | 2021-01-28 |
AU2019252324A1 (en) | 2020-10-01 |
KR20200143703A (ko) | 2020-12-24 |
MX2020009711A (es) | 2020-10-07 |
EP3773549A1 (en) | 2021-02-17 |
IL277409A (en) | 2020-11-30 |
US11491162B2 (en) | 2022-11-08 |
WO2019197367A1 (en) | 2019-10-17 |
SG11202009956WA (en) | 2020-11-27 |
CA3096721A1 (en) | 2019-10-17 |
BR112020020656A2 (pt) | 2021-01-12 |
JP2021521147A (ja) | 2021-08-26 |
JP7391036B2 (ja) | 2023-12-04 |
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