CN106580982B - 一种治疗药物流产后子宫出血的药物 - Google Patents
一种治疗药物流产后子宫出血的药物 Download PDFInfo
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- Pharmacology & Pharmacy (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种治疗药物流产后子宫出血的药物，所述药物包含：有效量的本文所述结构式化合物及其药学上可接受的盐、酯或前药；和药学上可接受的载体，其中R1是氢、C1‑6烷基、单或多卤代C1‑6烷基、被一个或两个羟基基团取代的C1‑6烷基、或被一个取代基取代的C1‑6烷基，该取代基选自下组，该组由以下各项组成：氰基和C1‑4烷基氧基；R2是氢、C1‑6烷基、单或多卤代C1‑6烷基、被一个或两个羟基基团取代的C1‑6烷基、或被一个取代基取代的C1‑6烷基，该取代基选自下组，该组由以下各项组成：氰基和C1‑4烷基氧基；R3是氢、C1‑4烷基氧基、羟基、氰基、C1‑4烷基或卤素；R4是氢、C1‑4烷基氧基、羟基、氰基、C1‑4烷基或卤素。本发明的药物对流产后的子宫出血具有止血作用。
Description
技术领域
本发明涉及医药领域，具体的说，本发明涉及一种治疗药物流产后子宫出血的药物。
背景技术
药物流产是指通过服用药物而非手术终止妊娠的方法，因其方便、痛苦小、疗效显著，受到广大育龄期妇女的欢迎，在临床上广泛应用。但药物流产后出血时间延长、出血量增多为其主要并发症，成为临床函待解决的问题。
发明内容
本发明的目的在于提供一种治疗药物流产后子宫出血的药物。
为了实现本发明的目的，本发明提供一种治疗药物流产后子宫出血的药物，所述药物包含：有效量的具有下列结构式化合物及其药学上可接受的盐、酯或前药；和药学上可接受的载体：
其中
R1是氢、C1-6烷基、单或多卤代C1-6烷基、被一个或两个羟基基团取代的C1-6烷基、或被一个取代基取代的C1-6烷基，该取代基选自下组，该组由以下各项组成：氰基和C1-4烷基氧基；
R2是氢、C1-6烷基、单或多卤代C1-6烷基、被一个或两个羟基基团取代的C1-6烷基、或被一个取代基取代的C1-6烷基，该取代基选自下组，该组由以下各项组成：氰基和C1-4烷基氧基；
R3是氢、C1-4烷基氧基、羟基、氰基、C1-4烷基或卤素；
R4是氢、C1-4烷基氧基、羟基、氰基、C1-4烷基或卤素。
优选地，R1是氢。
优选地，R2是氢。
优选地，R3是氢。
优选地，R4是氢。
本发明还提供具有下列结构式的化合物在制备治疗药物流产后子宫出血的药物中的用途：
其中
R1是氢、C1-6烷基、单或多卤代C1-6烷基、被一个或两个羟基基团取代的C1-6烷基、或被一个取代基取代的C1-6烷基，该取代基选自下组，该组由以下各项组成：氰基和C1-4烷基氧基；
R2是氢、C1-6烷基、单或多卤代C1-6烷基、被一个或两个羟基基团取代的C1-6烷基、或被一个取代基取代的C1-6烷基，该取代基选自下组，该组由以下各项组成：氰基和C1-4烷基氧基；
R3是氢、C1-4烷基氧基、羟基、氰基、C1-4烷基或卤素；
R4是氢、C1-4烷基氧基、羟基、氰基、C1-4烷基或卤素。
优选地，R1是氢。
优选地，R2是氢。
优选地，R3是氢。
优选地，R4是氢。
在进一步描述本发明之前，应理解，本发明不限于所述的具体实施方式，因为它们当然可能变化。还应理解，本文所用术语的目的仅是描述具体实施方式，不用来构成限制，因为本发明的范围仅受所附权利要求书的限制。
除非另有说明，本文所用的所有科技术语与本发明所属领域普通技术人员所理解的通常含义相同。本文中引用的所有专利、申请、公开申请和其他出版物都全文参考结合于本文。如果该部分中的定义与引用纳入本文的专利、申请和其他出版物中所列的定义相反或不一致，该部分中的定义将压倒引用纳入本文的定义。
本文和所附权利要求书所用的单数形式“一个”、“一种”和“所述”包括复数指示物，除非上下文另有明确说明。还应注意到，权利要求书可撰写成排除任何任选要素。同样，这种说明应用作引用权利要求元素相关地使用这类排除性术语，如“只有”、“仅仅”等，或使用“负”限制的前提基础。
本文所用术语“包含”、“含有”和“包括”以其开放、非限定的含义使用。
为提供更简明的描述，本文中的一些定量表达前不使用术语“约”。应理解无论是否明确地使用术语“约”，本文中的每个含量均表示实际给定的数值，且其还表示基于本领域普通技术所能合理推断的给定数值的近似值，包括由于实验和/或测量条件产生的这类给定数值的等同值和近似值。无论何时以百分比表示产率时，这类产率表示在特定的化学计量比条件下用于计算产率的实体质量与同一实体所能获得的最大量的比值。百分比形式的浓度表示质量比率，除非另有说明。
除非另有说明，本文所用的所有科技术语与本发明所属领域普通技术人员所理解的通常含义相同。虽然也可采用与本文所述类似或等 同的任何方法和材料实施或测试本发明，但以下描述优选的方法和材料。本文提及的所有出版物均通过引用纳入本文，与所引用出版物相关联来公开和描述这些方法和/或材料。
除非另有说明，本发明实施方式的方法和技术一般遵循本领域熟知的传统方法进行并如若干一般的或更特定的参考文献中所述，所述参考文献贯穿本说明书引用和讨论。参见，例如，Loudon，OrganicChemistry(《有机化学》)，第四版；纽约：牛津大学出版社(OxfordUniversityPress)，2002，第360-361、1084-1085页；Smith和March，March′sAdvancedOrganicChemistry：Reactions，Mechanisms，andStructure(《麻尺高级有机化学：反应、机制和结构》)，第五版，韦利科学公司(Wiley-Interscience)，2001。
本文用于命名主题化合物的命名法在本文的实施例中说明。该命名法一般采用市售可得的AutoNom软件(加利福尼亚州圣里安德鲁的MDL公司)，版本12.0.2获得。
应理解，为清楚起见，在单独的各实施方式的内容中描述的本发明的一些特征还可以合并在单个的实施方式中提供。反之，在单个实施方式的内容中简短描述的本发明的各个特征也可以单独提供或以任何合适的子组合的形式提供。与由可变形式代表的化学基团相关的实施方式的所有组合均特定包含在本发明范围内并由本文公开，形同本文单独且明确地公开每个和各个组合以至此类组合包含自身为稳定化合物的化合物(即，可分离、表征和检测生物学活性的化合物)。此外，描述此类可变形式的实施方式中所列的化学基团的所有子组合也具体包含在本发明范围内并由本文公开，形同本文单独且明确地公开化学基团的每个和各个此类子组合。
“药学上可接受的盐”旨在表示本文所示化合物的游离酸或碱的盐，其没有毒性、生物学上可以容忍或者生物学上适于向对象给药。通常参见，S.M.Berge等，“PharmaceuticalSalts(《药用盐》)”J.Pharm.Sci.， 1977，66，1-19。优选的药学上可接受的盐是药学上有效并且适于接触对象组织而没有过多的毒性、刺激、或过敏反应的那些。本文所述的化合物可具有足够酸性的基团、足够碱性的基团、两种类型的官能团、或超过一种各类型，并且因此与多种无机或有机碱，以及无机和有机酸反应以形成药学上可接受的盐。
药学上可接受的盐的示例包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、己酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、1，4-丁炔二酸盐、1，6-己炔二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、磺酸盐、甲基磺酸盐、丙基磺酸盐、苯磺酸盐、二甲苯磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、苯基乙酸盐、苯基丙酸盐、苯基丁酸盐、柠檬酸盐、乳酸盐、γ-羟基丁酸盐、乙醇酸盐、酒石酸盐和扁桃酸盐。其它合适的药学上可接受的盐的列表可见于Remington′sPharmaceuticalSciences(《雷明顿药物科学》)，第17版，宾夕法尼亚州伊斯顿的马克出版公司(MackPublishingCompany)，1985。
为治疗目的，包括本文所述化合物的药物组合物还可包括一种或多种药学上可接受的赋形剂。药学上可接受的赋形剂指没有毒性且生物学上适于向对象给药的物质。这类赋形剂促进本文所述化合物的给药过程且与活性成分相容。药学上可接受的赋形剂的示例包括稳定剂、润滑剂、表面活性剂、稀释剂、抗氧化剂、粘结剂、着色剂、膨胀剂、乳化剂或调味剂。在优选实施方式中，该发明的药物组合物是无菌组合物。可使用本领域技术人员已知或可以使用的复合技术制备药物组合物。
本发明也涉及无菌组合物，包括符合决定该组合物的国家和当地规定的组合物。
根据本领域中用于多种剂型制备的常规方法，本文所述药物组合物和化合物可配制为适当药物溶剂或载剂中的溶液剂、乳剂、混悬剂或分散剂，或者丸剂、片剂、锭剂、栓剂、囊剂、糖衣剂、颗粒剂、粉末剂、用于重建的粉末剂或连同固态载剂的胶囊剂。本发明的药物组合物可以通过适当的递送途径给予，如口服、胃肠外、直肠、经鼻、局部或经眼途径，或通过吸入。优选地，该组合物配制为用于静脉内或口服给药。
对于口服给药，本发明的化合物可以固体形式(如片剂或胶囊剂)或溶液剂、乳剂或混悬剂的形式提供。为制备口服组合物，可配制本发明的化合物以形成例如每天约0.01至约50mg/kg、或每天约0.05至约20mg/kg、或每天约0.1至约10mg/kg的剂量。其他剂量包括每天约0.1mg至1g，每天约1mg至约10mg，每天约10mg至约50mg，每天约50mg至约250mg、或每天约250mg至1g。口服片剂可包括与相容的药学上可接受的赋形剂(如稀释剂、崩解剂、粘结剂、润滑剂、甜味剂、调味剂、着色剂和防腐剂)混合的活性成分。合适的惰性填料包括碳酸钠和碳酸钙、磷酸钠和磷酸钙、乳糖、淀粉、糖、葡萄糖、甲基纤维素、硬脂酸镁、甘露醇、山梨糖醇等。示例性液体口服赋形剂包括乙醇、甘油、水等。淀粉、聚乙烯吡咯烷酮(PVP)、淀粉乙醇酸钠、微晶纤维素和海藻酸是示例性崩解剂。结合剂可包括淀粉和明胶。如果存在，润滑剂可以是硬脂酸镁、硬脂酸或滑石。如果需要，可以使用某种材料(如单硬脂酸甘油酯或二硬脂酸甘油酯)包被片剂以延缓胃肠道中的吸收，或者使用肠溶衣包被。
用于口服给药的胶囊包括硬和软明胶胶囊。为制备硬明胶胶囊，可将活性成分与固体、半固体或液体稀释剂混合。软明胶胶囊可以通过将活性成分与水、油(如花生油或橄榄油)、液体石蜡、短链脂肪酸 的单和二甘油酯的混合物、聚乙二醇400或丙二醇混合的方式制备。
用于口服给药的液体可以是混悬剂、溶液剂、乳剂或糖浆剂的形式，或者可以是临用前用水或其他合适载剂重建的干燥产品。这类液体组合物可选包含：药学上可接受的赋形剂，如助悬剂(例如山梨糖醇、甲基纤维素、藻酸钠、明胶、羟乙基纤维素、羧甲基纤维素、硬脂酸铝凝胶等)；非水性载剂，例如油(例如杏仁油或分级椰子油)、丙二醇、乙醇或水；防腐剂(例如对羟基苯甲酸甲酯或对羟基苯甲酸丙酯或山梨酸)；润湿剂(如卵磷脂)；以及(如果需要)调味剂或着色剂。
本发明的组合物可配制为栓剂用于直肠给药。对于胃肠外使用(包括静脉内、肌肉内、腹膜内、鼻内或皮下途径)，本发明的试剂可以无菌水性溶液剂或混悬剂，缓冲至合适pH和等渗性或者以胃肠道外可接受的油的形式提供。合适的水性载剂包括林格氏溶液和等渗氯化钠。这类形式可以是单位剂量形式(如安瓿或一次性注射设备)、多剂量形式(如可以从中取出合适剂量的药瓶)或固体形式或可用于制备可注射制剂的预浓缩液。在数分钟至数天的时间内，示范性输注剂量的范围是约1至1000μg/kg/分钟的与药物运载体混合的试剂。
对于经鼻、吸入或口服给药，可使用例如也包含合适运载体的喷雾制剂给予本发明的药物组合物。
对于局部使用，优选将本发明的化合物配制为乳膏或软膏或适用于局部给药的类似载剂。对于局部给药，可将本发明的化合物与药物运载体混合，浓度为药物占载剂的约0.1％至约10％。另一个给予本发明的试剂的模式是利用贴片制剂以达到透皮递送的效果。
本文所用术语“治疗”或“处理”包括“预防性”和“治疗性”治疗。“预防性”治疗指推迟疾病、疾病症状或医学病症的发展、抑制可能出现的症状或降低疾病或症状发展或复发的风险。“治疗性”治疗包括降低已有疾病、症状或病症的严重程度或抑制其恶化。因此，治疗包括改善或防止已有疾病症状的恶化、防止出现其他症状、改善 或防止症状的根本性系统原因、抑制失调或疾病，例如阻止失调或疾病的发展、减轻失调或疾病、促使失调或疾病退行、减轻疾病或失调引起的病症或停止疾病或失调的症状。
术语“对象”指需要该治疗的哺乳动物患者，例如人。
在根据本发明的治疗方法中，“有效量”指足以使需要这类治疗的对象获得所需治疗益处的量或剂量。本发明的化合物的有效量或剂量可通过常规方法(如建模、剂量递增或临床试验)确定，其中考虑常规因素，例如给药或药物递送的模式或途径、试剂的药代动力学、感染的严重程度和过程、对象的健康状态、病情和体重以及主治医生的判断。示例性剂量的范围为每天每千克对象体重约1ug至2mg活性试剂，优选约0.05至100mg/kg/天、或约1至35mg/kg/天、或约0.1至10mg/kg/天。在其他实施方式中，示例性剂量的范围是约1mg至约1g/天，或约1-500、1-250、1-100、1-50、50-500、或250-500mg/天。总剂量可以单个或分开的剂量单元(例如BID、TID、QID)给予。
一旦患者的疾病出现改善，即可调节剂量用于预防性或维持治疗。例如，给药的剂量或频率或两者可以随着症状变化降至保持所需治疗或预防效果的水平。当然，如果症状已减轻至合适水平，可以停止治疗。但任何症状复发时，患者可以要求长期基础上的间歇治疗。患者可能还需要长时程基础上的长期治疗。
通过参考用于本文中通用制备方法的示意性合成方案和之后的具体实施例来描述本发明的方法中有用的示例性化学实体。本领域技术人员应认识到，为获得本文中的多种化合物，可对起始材料进行适当选择，从而通过适当地带有或不带有保护的反应方案使用最终所需的取代基以生成所需的产物。或者，可能需要或想要在最终所需的取代基位置上采用可通过反应方案携带并在适当时可被所需取代基替代的合适基团。此外，本领域技术人员应认识到，以下方案中显示的转化可以任意与特定侧基功能相容的顺序进行。通用方案中描述的各 反应均优选在约0℃至所用有机溶剂的回流温度下进行。所有材料通常可从市场供应商处购得。
本发明的药物能缩短流产大鼠的凝血酶原时间、凝血酶时间，血浆纤维蛋白原增加，表明对流产后的子宫出血具有止血作用。
附图说明
图1是大鼠子宫囊胚形态，其中A：正常妊娠组；B：模型对照组；C：阳性对照组；D、E、F：本发明药物低、中、高剂量组。
具体实施方式
以下通过具体实施方式的描述对本发明作进一步说明，但这并非是对本发明的限制，本领域技术人员根据本发明的基本思想，可以做出各种修改或改进，但是只要不脱离本发明的基本思想，均在本发明的范围之内。
实验例
本发明药物化合物的结构式为：
将健康未孕的SD雌性大鼠90只与雄性大鼠按2:1比例合笼，次日上午进行阴道涂片检查，以发现有精子为妊娠第1天。选取交配成功雌鼠60只，按体质量随机分为6组，每组10只，分别为正常妊娠组、模型对照组、阳性对照组(宫血宁胶囊，购自云南白药药业股份有限公司)及本发明药物低、中、高剂量组。除正常妊娠组外，其余各组均于妊娠第7天分别灌胃米非司酮12.50mg/kg(9:00)和米索前列醇0.12mg/kg(17:00)，同时于阴道内置入定量棉球一个(棉球重90mg)。次日分别于9:00和17:00将棉球取出，以保鲜膜包裹，放入塑料袋中密闭冷藏保存；同时置换一个新棉球于阴道内，连续至第14天。造模成功后，次日(第8天)，阳性对照组每日灌胃给予宫血宁胶囊内容物0.15g/kg，本发明药物低、中、高剂量组每日灌胃给予1.2mg/kg、2.4mg/kg和4.8mg/kg，正常妊娠组和模型对照组给予蒸馏水，给药体积为2mL/100g。各组均每天1次，连续7d。
在末次给药24h后以3％的戊巴比妥钠0.5ml/只腹腔注射麻醉，经腹主动脉取全血(加抗凝剂)，1500r/min离心15min，取上清液。采用全自动凝血分析仪测定凝血酶原时间(PT)、凝血酶时间(TT)、血浆纤维蛋白原(FIB)。用SPSS 17.0软件进行统计分析。数据以均数±标准差表示，多组间差异采用方差分析，两组组间差异用Dunnett-t检验。P<0.05表示差异有统计学意义。结果见下表。
取血后将大鼠子宫完整剪下，进行大鼠子宫形态学肉眼观察，结果见图1。观察结果显示，正常妊娠组子宫呈结节状膨大，色泽红，血供丰富，胚胎数5～10个，解剖后见胚胎完好；模型组子宫宫腔内见淤血，胚胎不完整，有残留，为不完全流产；给药组子宫除个别充血外未见胚胎或明显淤血。
注：与正常妊娠组比较，*P<0.05；与模型对照组比较，**P<0.05；与阳性对照组比较，ΔP<0.05。
Claims (1)
1.具有下列结构式的化合物在制备治疗药物流产后子宫出血的药物中的用途：
，其中R1是氢；R2是氢；R3是氢；R4是氢。
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