CN110063947A - 苯酚衍生物用于制备麻醉药物中的用途 - Google Patents
苯酚衍生物用于制备麻醉药物中的用途 Download PDFInfo
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- CN110063947A CN110063947A CN201811304158.2A CN201811304158A CN110063947A CN 110063947 A CN110063947 A CN 110063947A CN 201811304158 A CN201811304158 A CN 201811304158A CN 110063947 A CN110063947 A CN 110063947A
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Abstract
本发明涉及一种式(I)化合物或者其立体异构体、药学上可接受的盐或前药用于哺乳动物结肠镜检查的新用途。
Description
技术领域
本发明涉及一种含苯酚衍生物在制备结肠镜检查的药物中的用途,以及其联合用药在制备 全身麻醉或者全麻诱导的药物中的用途。
背景技术
丙泊酚可激活多种GABAA受体亚型,是一个临床上成熟的静脉麻醉药,广泛用于全身 麻醉的诱导和维持,具有起效快、易苏醒等优点。然而,丙泊酚也有显而易见的局限性和缺点。 据报道,约70%的病人在注射丙泊酚时有一定程度的疼痛或不适(Pascale Picard(2000).Anesthesia&Analgesia,90,963-969)。虽然有报道用其他药物预处理或联合用药的方法可 降低丙泊酚注射疼痛的发生率和严重程度(C.H.Tan等(1998).Anaesthesia,53,302–305),但 这种疼痛仍难以避免。15给药剂量一般为2.0~2.5mg/kg,一般与止痛剂配合使用,用于麻醉 诱导部分的丙泊酚注射液,可以以大于20∶1的比例与0.5W/V%或1W/V%的利多卡因注射 液混合使用,来减少注射疼痛。丙泊酚已被证明可降低收缩压,舒张压和平均动脉血压,因此 在临床上会引起低血压。同时,呼吸抑制也是使用丙泊酚时不可忽视的风险。20这些不良反 应很大程度上阻碍了丙泊酚在一些临床病例中的应用,如心血管疾病,脑损伤和慢性低血压。
国际专利申请WO2014180305公开了丙泊酚类似物,其是一种高脂溶性物质,直接给予 到血流中,可引起麻醉的迅速起效,特别是式(1)化合物等相关结构具有良好的麻醉效果, 式(1)化合物结构如下所示:
结肠镜是通过手术能顺次地、清晰地观察肛管、直肠、乙状结肠、结肠、回盲部黏膜状态, 而且可以进行活体的病理学和细胞学检查。肠镜检查的术前用药对保障顺利插镜、仔细观察及 寻找病变、准确活检和精细的内镜下治疗均十分重要,且对一些精神紧张的患者术前用药还有 助于减少痛苦,能更好的配合检查。为了更好的满足临床需求,本发明了提供了一种结肠镜检 查用药新用途以及一种全身麻醉用药新用途。
发明内容
本发明提供了一种稳定性好、药效高、用量少、安全性好、副作用少、减少注射疼痛、顺 应性好或成本低的结肠镜检查的新用途。
本发明提供了一种稳定性好、药效高、用量少、安全性好、副作用少、减少注射疼痛、顺 应性好或成本低的全身麻醉用药的新用途。
本发明提供一种式(I)化合物或者其立体异构体、药学上可接受的盐或前药在制备结肠镜检 查的药物中的用途。
本发明关于一种式(I)化合物或者其立体异构体、药学上可接受的盐或前药在制备结肠镜检 查的药物中的用途,所述的用途包括对该哺乳动物给药有效剂量的式(I)化合物或者其立体异构 体、药学上可接受的盐或前药,其中所述的有效剂量为负荷剂量和/或维持剂量。
本发明关于一种式(I)化合物或者其立体异构体、药学上可接受的盐或前药在制备结肠镜检 查的药物中的用途,包括对哺乳动物给药有效剂量的式(I)化合物或者其立体异构体、药学上可 接受的盐或前药,其中所述式(I)化合物的有效剂量选自0.1mg/kg至20mg/kg的范围内、0.1 mg/(kg·h)至20.0mg/(kg·h)的范围内,所述式(I)化合物的药学上可接受的盐或前药的有效 剂量均通过式(I)化合物的有效剂量折算。
本发明优选方案,其中所述的有效剂量包括负荷剂量和/或维持剂量。
本领域技术人员将理解:许多因素会影响给药的负荷剂量和/或维持剂量。例如,在患者 体内诱导或维持全身麻醉或镇静可能与患者是人还是除人以外的其他哺乳动物有关;它也可能 与患者的年龄、体重、性别、饮食、健康状态或心理状态等有关。实际应用中,麻醉医生、兽 医或其他本领域的医药学科或者保健从业技术人员依据上述的影响因素以及患者的反应性变 化选定并调整负荷剂量和/或维持剂量,实现相对稳定的血药浓度,达到麻醉深度稳定、可控 性强、苏醒质量好和生命体征平稳的目的。
可以选择一系列的剂量,很大程度上取决于结肠镜检查所要到达的麻醉或镇静的水平和深 度。
本发明关于哺乳动物结肠镜检查的用途,在一种变化方案中,式(I)化合物结肠镜检查的有 效剂量任选地选自0.2mg/kg至15.0mg/kg的范围内、0.2mg/kg至10.0mg/kg的范围内、任选 地选自0.2mg/kg至12.0mg/kg的范围内、任选地选自0.2mg/kg至10.0mg/kg的范围内、任 选地选自0.2mg/kg至8.0mg/kg的范围内、任选地选自0.2mg/kg至6.0mg/kg的范围内、任 选地选自0.2mg/kg至5.0mg/kg的范围内、任选地选自0.2mg/kg至4.0mg/kg的范围内、任 选地选自0.2mg/kg至3.0mg/kg的范围内、任选地选自0.2mg/kg至2.0mg/kg的范围内、任 选地选自0.2mg/kg至1.0mg/kg的范围内、任选地选自0.2mg/kg至0.8mg/kg的范围内、任 选地选自0.2mg/kg至0.6mg/kg的范围内、任选地选自0.2mg/kg至0.5mg/kg的范围内或者 任选地选自0.2mg/kg至0.3mg/kg的范围内。
本发明关于哺乳动物结肠镜检查的用途,在一种变化方案中,式(I)化合物结肠镜检查的有 效剂量任选地选自0.2mg/kg至15.0mg/kg的范围内、0.2mg/kg至10.0mg/kg的范围内、 0.2mg/kg至5.0mg/kg的范围内、0.2mg/kg至2.0mg/kg的范围内或者0.2mg/kg至1.0mg/kg 的范围内的范围内。
本发明关于哺乳动物结肠镜检查的用途,在一种变化方案中,式(I)化合物结肠镜检查的有 效剂量任选地选自0.1mg/kg、0.2mg/kg、0.3mg/kg、0.4mg/kg或者0.5mg/kg。
本发明关于哺乳动物结肠镜检查的用途,在一种变化方案中,式(I)化合物结肠镜检查的有 效剂量任选地选自0.2mg/(kg·h)至20.0mg/(kg·h)的范围内、任选地选自0.2mg/(kg·h)至15.0 mg/(kg·h)的范围内、任选地选自0.2mg/(kg·h)至10.0mg/(kg·h)的范围内、任选地选自0.2 mg/(kg·h)至6.0mg/(kg·h)的范围内、任选地选自0.2mg/(kg·h)至6.0mg/(kg·h)的范围内、任选 地选自0.2mg/(kg·h)至5.0mg/(kg·h)的范围内、任选地选自0.2mg/(kg·h)至4.0mg/(kg·h)的范围 内、任选地选自0.2mg/(kg·h)至4.0mg/(kg·h)的范围内、任选地选自0.2mg/(kg·h)至3.0mg/(kg·h) 的范围内、任选地选自0.2mg/(kg·h)至2.0mg/(kg·h)的范围内或任选地选自0.2mg/(kg·h)至 1.0mg/(kg·h)的范围内。
本发明关于哺乳动物结肠镜检查的用途,在一种变化方案中,式(I)化合物结肠镜检查的有 效剂量任选地选自0.1mg/(kg·h)、0.2mg/(kg·h)、0.3mg/(kg·h)、0.4mg/(kg·h)或者0.5mg/(kg·h)。
本发明关于哺乳动物结肠镜检查的用途,在一种变化方案中,式(I)化合物或其前药的有效 剂量给药时间为在10分钟内,优选为2分钟内。或有效剂量的给药时间根据维持哺乳动物结 肠镜检查的时间而决定。并且,式(I)化合物或者其立体异构体、药学上可接受的盐或前药的给 药形式任选地选自单次给药、多次给药、连续给药和靶控输注中的一种或多种,优选给药形式 为靶控输注。
根据临床用药的特点,诱导全身麻醉或镇静的负荷剂量给药多采用单次注射给药。维持全 身麻醉或镇静的维持剂量可采用多次注射给药,但是此方法血药浓度会出现锯齿样波动,病人 的麻醉深浅也会因此而波动。所以临床实践中维持剂量多采用连续输注给药或靶控输注,避免 了分次给药后血药浓度高峰和低谷的跌宕波动,麻醉深度易于控制、麻醉过程平稳。
式(I)化合物或者其立体异构体、药学上可接受的盐或前药用于哺乳动物结肠镜检查的方 法,可以通过广泛多样的给药途径进行给药,该给药途径包括,但不限于选自如下的给药途径: 静脉内注射、动脉内注射、肌肉内注射、透皮吸收、含服吸收、肠胃外腹膜内、直肠、透颊、 鼻内、吸入、通过局部递送、皮下、脂肪内、关节内、腹膜内和鞘内。在一种特定的变化方案 中,通过静脉内注射进行给药。
式(I)化合物是一种GABAA受体增强剂,GABAA受体被激动后,受体在细胞膜上发生构 型改变,受体通道开放,氯阴离子可顺着电势和浓度梯度通过离子通道,使细胞超极化,以至 于弱化了激动性神经递质的去极化效果和产生动作电位的可能。因此,该受体主要发挥抑制性 作用,减少神经元的活动。GABAA受体增强剂通常能够产生抗焦虑、抗惊厥、失忆症、镇静、 催眠、麻醉、欣快以及肌肉松弛等效果。在一种特定的变化方案中,进行给药以诱导或维持哺 乳动物的全身麻醉或者镇静状态。
本发明还提供一种哺乳动物结肠镜检查的用途,所述的方法包括对该哺乳动物同时给予有 效剂量的式(I)化合物和一种或多种除式(I)化合物以外的其它活性成分,所述的其它活性成分选 自具有镇静催眠或麻醉辅助作用的药物,所述的有效剂量包括负荷剂量和/或维持剂量。在一 种变化方案中,其中式(I)化合物负荷剂量任选地选自0.2mg/kg至15.0mg/kg的范围内、0.2 mg/kg至10.0mg/kg的范围内、任选地选自0.2mg/kg至12.0mg/kg的范围内、任选地选自0.2 mg/kg至10.0mg/kg的范围内、任选地选自0.2mg/kg至8.0mg/kg的范围内、任选地选自0.2 mg/kg至6.0mg/kg的范围内、任选地选自0.2mg/kg至5.0mg/kg的范围内、任选地选自0.2 mg/kg至4.0mg/kg的范围内、任选地选自0.2mg/kg至3.0mg/kg的范围内、任选地选自0.2 mg/kg至2.0mg/kg的范围内、任选地选自0.2mg/kg至1.0mg/kg的范围内、任选地选自0.2 mg/kg至0.8mg/kg的范围内、任选地选自0.2mg/kg至0.6mg/kg的范围内、任选地选自0.2 mg/kg至0.5mg/kg的范围内、任选地选自0.2mg/kg至0.3mg/kg的范围内或任选地选自0.2 mg/kg至0.2mg/kg的范围内;任选地选自0.1mg/kg、0.2mg/kg、0.3mg/kg、0.4mg/kg或者 0.5mg/kg;式(I)化合物的维持剂量任选地选自0.2mg/(kg·h)至20.0mg/(kg·h)的范围内、任选地 选自0.2mg/(kg·h)至15.0mg/(kg·h)的范围内、任选地选自0.2mg/(kg·h)至10.0mg/(kg·h)的范 围内、任选地选自0.2mg/(kg·h)至6.0mg/(kg·h)的范围内、任选地选自0.2mg/(kg·h)至6.0 mg/(kg·h)的范围内、任选地选自0.2mg/(kg·h)至5.0mg/(kg·h)的范围内、任选地选自0.2mg/(kg·h) 至4.0mg/(kg·h)的范围内、任选地选自0.2mg/(kg·h)至4.0mg/(kg·h)的范围内、任选地选自0.2 mg/(kg·h)至3.0mg/(kg·h)的范围内、任选地选自0.2mg/(kg·h)至2.0mg/(kg·h)的范围内或任 选地选自0.2mg/(kg·h)至1.0mg/(kg·h)的范围内,任选地选自0.1mg/(kg·h)、0.2mg/(kg·h)、 0.3mg/(kg·h)、0.4mg/(kg·h)或者0.5mg/(kg·h)。
本发明关于哺乳动物结肠镜检查的用途,在一种变化方案中,所述的用途进一步包括对该 哺乳动物同时给予一种或多种除式(I)化合物以外的其它活性成分,所述的其它活性成分选自具 有镇静催眠或麻醉辅助作用的药物。
本发明关于哺乳动物结肠镜检查的用途,在一种变化方案中,所述的其它活性成分选自γ -氨基丁酸受体激动剂、γ-氨基丁酸受体增强剂、M受体拮抗剂、N2受体拮抗剂、5-羟色胺3 (5-HT3)受体拮抗剂、钠离子通道拮抗剂或阿片受体激动剂。
本发明关于哺乳动物全结肠镜检查的用途,在一种变化方案中,所述的其它活性成分选自 静脉麻醉药、吸入麻醉药或麻醉辅助剂。
本发明关于哺乳动物全结肠镜检查的用途,在一种特定的变化方案中,所述的静脉麻醉药 任选地选自丙泊酚、磷丙泊酚钠、咪达唑仑、氯胺酮、硫喷妥钠、羟丁酸钠或依托咪酯,包括 他们的药学上可接受的盐;
所述的吸入麻醉药任选地选自七氟烷、异氟烷、恩氟烷、地氟烷、甲氧氟烷或氧化亚氮;
所述的麻醉辅助剂任选地选自镇静催眠药、抗胆碱药、肌松药、止吐药、局部麻醉药或镇 痛药。
本发明关于哺乳动物结肠镜检查的用途,在一种特定的变化方案中,所述的镇静催眠药任 选地选自地西泮、氟西泮、氯氮卓、艾司唑仑、氯硝西泮、格鲁米特、甲丙氨酯、丁螺环酮、 咪达唑仑、右美托咪定、氟哌利多、异丙嗪、氯丙嗪、巴比妥、苯巴比妥、戊巴比妥、异戊巴 比妥、司可巴比妥或硫喷妥钠,包括他们的药学上可接受的盐;优选地西泮、氟西泮、咪达唑 仑、右美托咪定、异丙嗪或氯丙嗪,包括他们的药学上可接受的盐;
所述的抗胆碱药任选地选自阿托品或东莨菪碱,包括他们的药学上可接受的盐;
所述的肌松药任选地选自维库溴铵、罗库溴铵、泮库溴铵、哌库溴铵、米库氯铵、阿曲库 铵或琥珀酰胆碱,包括他们的药学上可接受的盐;优选维库溴铵、罗库溴铵、泮库溴铵或哌库 溴铵,包括他们的药学上可接受的盐;
所述的止吐药任选地选自托烷司琼、帕洛诺司、格拉司琼、多拉司琼、东莨菪碱、赛克力 嗪或甲氧氯普胺,包括他们的药学上可接受的盐;优选托烷司琼或东莨菪碱,包括他们的药学 上可接受的盐;
所述的局部麻醉药任选地选自利多卡因、罗哌卡因、丙胺卡因、布比卡因、阿替卡因或达 克罗宁,包括他们的药学上可接受的盐;优选利多卡因或罗哌卡因,包括他们的药学上可接受 的盐;
所述的镇痛药任选地选自芬太尼、瑞芬太尼、舒芬太尼、阿芬太尼、吗啡、哌替啶、地佐 辛、布托啡诺、羟考酮或奈福泮,包括他们的药学上可接受的盐;优选芬太尼、瑞芬太尼、舒 芬太尼、阿芬太尼或哌替啶,包括他们的药学上可接受的盐;更优选芬太尼或瑞芬太尼,包括 他们的药学上可接受的盐。
本发明关于哺乳动物结肠镜检查的用途,在一种变化方案中,式(I)化合物与阿芬太尼、芬 太尼或瑞芬太尼,包括其药学上可接受的盐联合给药。
上述每一个关于哺乳动物结肠镜检查的用途的方案、优选方案和变化方案中,所述的式(I) 化合物药学上可接受的盐选自碱金属盐或碱土金属盐,其中所述的碱金属选自Na、K或Li, 所述的碱土金属选自Ca。
本发明还提供一种式(I)化合物或者其立体异构体、药学上可接受的盐或前药,在制备 用于全身麻醉或者全麻诱导的药物中的用途。
本发明关于一种式(I)化合物或者其立体异构体、药学上可接受的盐或前药在制备全身麻醉 或者全麻诱导的药物中的用途,所述的用途包括对该哺乳动物给药有效剂量的式(I)化合物或者 其立体异构体、药学上可接受的盐或前药,其中所述的有效剂量为负荷剂量和/或维持剂量。
本发明关于一种式(I)化合物或者其立体异构体、药学上可接受的盐或前药在制备全身麻醉 或者全麻诱导的药物中的用途,包括对哺乳动物给药有效剂量的式(I)化合物或者其立体异构 体、药学上可接受的盐或前药,其中所述式(I)化合物的有效剂量选自0.01mg/kg至20.0mg/kg 的范围内、0.01mg/(kg·h)至20.0mg/(kg·h)的范围内,所述式(I)化合物的药学上可接受的 盐或前药的有效剂量均通过式(I)化合物的有效剂量折算。
本发明关于哺乳动物全身麻醉或者全麻诱导的用途,在一种变化方案中,式(I)化合物全身 麻醉或者全麻诱导的有效剂量任选地选自0.01mg/kg至15.0mg/kg的范围内、0.01mg/kg至10.0 mg/kg的范围内、任选地选自0.01mg/kg至12.0mg/kg的范围内、任选地选自0.01mg/kg至 10.0mg/kg的范围内、任选地选自0.01mg/kg至8.0mg/kg的范围内、任选地选自0.01mg/kg 至6.0mg/kg的范围内、任选地选自0.01mg/kg至5.0mg/kg的范围内、任选地选自0.01mg/kg 至4.0mg/kg的范围内、任选地选自0.01mg/kg至3.0mg/kg的范围内、任选地选自0.01mg/kg 至2.0mg/kg的范围内、任选地选自0.01mg/kg至1.0mg/kg的范围内、任选地选自0.01mg/kg 至0.8mg/kg的范围内、任选地选自0.01mg/kg至0.6mg/kg的范围内、任选地选自0.01mg/kg 至0.5mg/kg的范围内、任选地选自0.01mg/kg至0.3mg/kg的范围内。
本发明关于哺乳动物全身麻醉或者全麻诱导的用途,在一种变化方案中,式(I)化合物全身 麻醉或者全麻诱导的有效剂量任选地选自0.016mg/kg、0.064mg/kg、0.128mg/kg、0.192mg/kg、 0.288mg/kg、0.432mg/kg、0.3mg/kg、0.4mg/kg、0.5mg/kg、0.540mg/kg、0.6mg/kg、0.648mg/kg、 0.7mg/kg、0.8mg/kg、、0.81mg/kg或者0.9mg/kg。
本发明关于哺乳动物全身麻醉或者全麻诱导的用途,在一种变化方案中,式(I)化合物全身 麻醉或者全麻诱导的有效剂量任选地选自0.01mg/kg至15.0mg/kg的范围内、0.01mg/kg至10.0 mg/kg的范围内、0.01mg/kg至5.0mg/kg的范围内、0.01mg/kg至2.0mg/kg的范围内、0.01mg/kg 至1.0mg/kg的范围内。
本发明关于哺乳动物全身麻醉或者全麻诱导的用途,在一种变化方案中,式(I)化合物全身 麻醉的有效剂量任选地选自0.016mg/kg、0.064mg/kg、0.128mg/kg、0.192mg/kg、0.288mg/kg、 0.432mg/kg、0.540mg/kg、0.648mg/kg或者0.81mg/kg。
本发明关于哺乳动物全身麻醉或者全麻诱导的用途,在一种变化方案中,式(I)化合物全身 麻醉或者全麻诱导的有效剂量任选地选自0.01mg/(kg·h)至20.0mg/(kg·h)的范围内、任选地选 自0.01mg/(kg·h)至15.0mg/(kg·h)的范围内、任选地选自0.01mg/(kg·h)至10.0mg/(kg·h)的范 围内、任选地选自0.01mg/(kg·h)至6.0mg/(kg·h)的范围内、任选地选自0.01mg/(kg·h)至6.0 mg/(kg·h)的范围内、任选地选自0.01mg/(kg·h)至5.0mg/(kg·h)的范围内、任选地选自 0.01mg/(kg·h)至4.0mg/(kg·h)的范围内、任选地选自0.01mg/(kg·h)至4.0mg/(kg·h)的范围内、 任选地选自0.01mg/(kg·h)至3.0mg/(kg·h)的范围内、任选地选自0.01mg/(kg·h)至2.0mg/(kg·h) 的范围内或任选地选自0.01mg/(kg·h)至1.0mg/(kg·h)的范围内。
本发明关于哺乳动物全身麻醉或者全麻诱导的用途,在一种变化方案中,式(I)化合物全身 麻醉或者全麻诱导的的有效剂量任选地选自0.016mg/(kg·h)、0.064mg/(kg·h)、0.128mg/(kg·h)、 0.192mg/(kg·h)、0.288mg/(kg·h)、0.432mg/(kg·h)、0.540mg(kg·h)、0.648mg/(kg·h)或者 0.81mg/(kg·h)。
本发明关于哺乳动物全身麻醉或者全麻诱导的用途,在一种变化方案中,所述的方法进一 步包括对该哺乳动物同时给予一种或多种除式(I)化合物以外的其它活性成分,所述的其它活性 成分选自具有镇静催眠或麻醉辅助作用的药物。
本发明关于哺乳动物全身麻醉或者全麻诱导的用途,在一种变化方案中,所述的其它活性 成分选自γ-氨基丁酸受体激动剂、γ-氨基丁酸受体增强剂、M受体拮抗剂、N2受体拮抗剂、 5-羟色胺3(5-HT3)受体拮抗剂、钠离子通道拮抗剂或阿片受体激动剂。
本发明关于哺乳动物全身麻醉的用途,在一种变化方案中,所述的其它活性成分选自静脉 麻醉药、吸入麻醉药或麻醉辅助剂。
本发明关于哺乳动物全身麻醉或者全麻诱导的用途,在一种特定的变化方案中,所述的静 脉麻醉药任选地选自丙泊酚、磷丙泊酚钠、咪达唑仑、氯胺酮、硫喷妥钠、羟丁酸钠或依托咪 酯,包括他们的药学上可接受的盐;所述的吸入麻醉药任选地选自七氟烷、异氟烷、恩氟烷、 地氟烷、甲氧氟烷或氧化亚氮;所述的麻醉辅助剂任选地选自镇静催眠药、抗胆碱药、肌松药、 止吐药、局部麻醉药或镇痛药。
本发明关于哺乳动物结肠镜检查的用途,在一种特定的变化方案中,所述的镇静催眠药任 选地选自地西泮、氟西泮、氯氮卓、艾司唑仑、氯硝西泮、格鲁米特、甲丙氨酯、丁螺环酮、 咪达唑仑、右美托咪定、氟哌利多、异丙嗪、氯丙嗪、巴比妥、苯巴比妥、戊巴比妥、异戊巴 比妥、司可巴比妥或硫喷妥钠,包括他们的药学上可接受的盐;优选地西泮、氟西泮、咪达唑 仑、右美托咪定、异丙嗪或氯丙嗪,包括他们的药学上可接受的盐;所述的抗胆碱药任选地选 自阿托品或东莨菪碱,包括他们的药学上可接受的盐;所述的肌松药任选地选自维库溴铵、罗 库溴铵、泮库溴铵、哌库溴铵、米库氯铵、阿曲库铵或琥珀酰胆碱,包括他们的药学上可接受 的盐;优选维库溴铵、罗库溴铵、泮库溴铵或哌库溴铵,包括他们的药学上可接受的盐;所述 的止吐药任选地选自托烷司琼、帕洛诺司、格拉司琼、多拉司琼、东莨菪碱、赛克力嗪或甲氧 氯普胺,包括他们的药学上可接受的盐;优选托烷司琼或东莨菪碱,包括他们的药学上可接受 的盐;所述的局部麻醉药任选地选自利多卡因、罗哌卡因、丙胺卡因、布比卡因、阿替卡因或 达克罗宁,包括他们的药学上可接受的盐;优选利多卡因或罗哌卡因,包括他们的药学上可接 受的盐;所述的镇痛药任选地选自芬太尼、瑞芬太尼、舒芬太尼、阿芬太尼、吗啡、哌替啶、 地佐辛、布托啡诺、羟考酮或奈福泮,包括他们的药学上可接受的盐;优选芬太尼、瑞芬太尼、 舒芬太尼、阿芬太尼或哌替啶,包括他们的药学上可接受的盐;更优选芬太尼或瑞芬太尼,包 括他们的药学上可接受的盐。
本发明关于哺乳动物全身麻醉或者全麻诱导的用途,在一种变化方案中,式(I)化合物与阿 芬太尼、芬太尼或瑞芬太尼,包括其药学上可接受的盐联合给药。
上述每一个关于哺乳动物全身麻醉或者全麻诱导的用途的方案、优选方案和变化方案中, 所述的式(I)化合物药学上可接受的盐选自碱金属盐或碱土金属盐,其中所述的碱金属选自Na、 K或Li,所述的碱土金属选自Ca。
本发明关于哺乳动物全身麻醉或者全麻诱导的用途,在一种变化方案中,式(I)化合物与依托 咪酯、咪达唑仑、舒芬太尼、七氟醚中的一种或多种联合用药。
本发明关于哺乳动物全身麻醉或者全麻诱导的用途,在一种变化方案中,依托咪酯的有效剂 量为0.01mg/kg至20.0mg/kg的范围内,式(I)化合物的有效剂量为0.01-20mg/kg的范围内, 所述式(I)化合物的药学上可接受的盐或前药的有效剂量均通过式(I)化合物的有效剂量折 算。
本发明关于哺乳动物全身麻醉或者全麻诱导的用途,在一种变化方案中,依托咪酯的有效剂 量选自0.01mg/kg至15.0mg/kg的范围内、0.01mg/kg至10.0mg/kg的范围内、0.01mg/kg至 5.0mg/kg的范围内、0.01mg/kg至2.0mg/kg的范围内、0.01mg/kg至1.0mg/kg的范围内;式 (I)化合物的有效剂量选自0.01mg/kg至15.0mg/kg的范围内、0.01mg/kg至10.0mg/kg的范围 内、0.01mg/kg至5.0mg/kg的范围内、0.01mg/kg至2.0mg/kg的范围内、0.01mg/kg至1.0mg/kg 的范围内,本发明关于哺乳动物全身麻醉或者全麻诱导的用途,在一种变化方案中,依托咪酯的 有效剂量选自0.1mg/kg、0.15mg/kg或者0.2mg/kg,所述式(I)化合物的药学上可接受的盐或 前药的有效剂量均通过式(I)化合物的有效剂量折算。
本发明关于哺乳动物全身麻醉或者全麻诱导的用途,在一种变化方案中,联合使用式(I)化合 物与依托咪酯,其中给药式(I)化合物的剂量选0.216mg/kg、0.324mg/kg或者0.432mg/kg,给 药依托咪酯的剂量选自0.1mg/kg、0.15mg/kg或者0.2mg/kg。
本发明关于哺乳动物全身麻醉或者全麻诱导的用途,在一种变化方案中,其中给药形式选 自单次给药、多次给药、连续给药和靶控输注中的一种或多种。
本发明关于哺乳动物全身麻醉或者全麻诱导的用途,在一种变化方案中,其中给药途径选 自静脉内注射、动脉内注射、肌肉内注射、透皮吸收、含服吸收、肠胃外腹膜内、直肠、透颊、 鼻内、吸入、通过局部递送、皮下、脂肪内、关节内、腹膜内或鞘内中的一种或多种。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
“全身麻醉”是指药物经呼吸道吸入、静脉或肌肉注射进入体内,产生中枢神经系统的暂 时抑制,临床表现为神志消失、全身痛觉消失、遗忘、反射抑制和骨骼肌松弛。对中枢神经系 统抑制的程度与血液内药物浓度有关,并且可以控制和调节。这种抑制是完全可逆的,当药物 被代谢或从体内排出后,病人的神志及各种反射逐渐恢复。
“镇静”是指药物给药后精神兴奋的平静或生理功能的减轻。
“哺乳动物”是全身披毛、运动快速、恒温胎生、体内有膈的脊椎动物,是脊椎动物中躯 体结构、功能行为最为复杂的最高级动物类群,因能通过乳腺分泌乳汁来给幼体哺乳而得名。 包括但不限于小鼠、大鼠、牛、猪、羊、水牛、犬、猫、马、类人猿、猴子、大猩猩和人,优 选人。
“有效剂量”是指给药时足以诱导或维持麻醉或镇静的药量。
“负荷剂量”是指药物单次给药后麻醉或镇静效应迅速达到峰效应的药量。
“维持剂量”是维持在麻醉或镇静作用下所需的药量,该药量以给药速率mg/(kg.h)或 mg/(m2.h)表示。
“单次给药”是指一次注入一定剂量的药物,以快速达到适宜的麻醉或镇静深度,多用于 麻醉或镇静诱导和短小手术。
“多次给药”是指先静脉注射一定剂量的药物,使达到适宜的麻醉深度或镇静后,再根据 麻醉或镇静对象的反应和手术的需要分次追加药物,以维持一定的麻醉或镇静深度。
“连续给药”是指麻醉或镇静对象在麻醉或镇静诱导后,采用不同的速度连续滴入或泵入 药物的方法来维持麻醉或镇静深度。给药速度包括人工设置和计算机设置。借助药代动力学模 型和理论,可以计算出达到满意和期望的血药浓度时间过程的所需给药剂量。
“靶控输注”是在输注静脉药物时,以药代动力学和药效动力学理论为依据,利用计算机 对药物在体内过程、效应过程进行模拟,并寻找到最合理的用药方案,继而控制药物注射泵, 实现血药浓度或效应部位浓度稳定于预期值(靶浓度值),从而控制麻醉或镇静深度,并根据 临床需要可随时调整给药系统。
“静脉麻醉药”是指静脉注射进入体内,通过血液循环作用于中枢神经系统而产生全身麻 醉作用的药物,非限制性实施例包括丙泊酚、磷丙泊酚钠、咪达唑仑、氯胺酮、硫喷妥钠、丙 泊酚、羟丁酸钠和依托咪酯,包括他们的药学上可接受的盐。
“吸入麻醉药”是指经过呼吸道吸入,产生中枢神经系统抑制而产生全身麻醉作用的药物, 非限制性实施例包括七氟烷、异氟烷、恩氟烷、地氟烷、甲氧氟烷和氧化亚氮。
“麻醉辅助剂”是指用于复合麻醉中辅助全身麻醉药更好发挥作用的药物,非限制性实施 例包括镇静催眠药、抗胆碱药、肌松药、止吐药、局部麻醉药和镇痛药。
“镇静催眠药”是指能够引起镇静和近似生理睡眠的药物,小剂量产生镇静作用,较大剂 量可产生催眠作用,非限制性实施例包括地西泮、氟西泮、氯氮卓、艾司唑仑、氯硝西泮、格 鲁米特、甲丙氨酯、丁螺环酮、咪达唑仑、右美托咪定、氟哌利多、巴比妥、苯巴比妥、戊巴 比妥、异戊巴比妥、司可巴比妥和硫喷妥钠,包括他们的药学上可接受的盐。
“抗胆碱药”是指具有阻滞胆碱受体,使递质乙酰胆碱不能与受体结合而呈现与拟胆碱药 相反的作用的药物,非限制性实施例包括阿托品、东莨菪碱、戊乙奎醚和格隆溴铵,包括他们 的药学上可接受的盐。
“肌松药”是指能选择性地作用于运动神经终板膜上的N2受体而产生的可逆性骨骼肌松 弛的药物,非限制性实施例包括维库溴铵、罗库溴铵、泮库溴铵、哌库溴铵、米库氯铵、阿曲 库铵和琥珀酰胆碱,包括他们的药学上可接受的盐。
“止吐药”是指防止或减轻恶心和呕吐的药物,非限制性实施例包括烷司琼、帕洛诺司、 格拉司琼、多拉司琼、东莨菪碱、赛克力嗪和甲氧氯普胺,包括他们的药学上可接受的盐。
“局部麻醉药”是指在用药局部可逆性的阻断感觉神经冲动发生与传递的药物,非限制性 实施例包括普鲁卡因、氯普鲁卡因、丁卡因、苯佐卡因、利多卡因、罗哌卡因、丙胺卡因、布 比卡因、依替卡因、甲哌卡因和阿替卡因,包括他们的药学上可接受的盐。
“镇痛药”是指主要作用于中枢神经系统,选择性消除或缓解疼痛,对其他感觉(如听觉、 视觉及触觉)无明显影响,并保持清醒的药物,非限制性实施例选自芬太尼、瑞芬太尼、舒芬 太尼、阿芬太尼、哌替啶、吗啡、地佐辛、布托啡诺、羟考酮和奈福泮,包括他们的药学上可 接受的盐。
“阿片类镇痛剂”是指能激动阿片受体从而消除或减轻疼痛并改变对疼痛的情绪反应的药 物,非限制性实施例选自阿法罗定、芬太尼、瑞芬太尼、舒芬太尼、阿芬太尼、哌替啶、吗啡、 地佐辛、布托啡诺、羟考酮、烯丙罗定、阿尼利定、苄吗啡、丁丙诺啡、布托啡诺、氯尼他秦、 环佐辛、地索吗啡、右吗拉胺、地佐辛、地恩丙胺、二醋吗啡、双氢可待因、双氢吗啡、地美 沙朵、地美庚醇、二甲噻丁、吗苯丁酯、地匹哌酮、依他佐辛、依索庚嗪、乙甲噻丁、乙基吗 啡、依托尼嗪、海洛因、氢吗啡酮、羟哌替啶、美普他酚、美他佐辛、美沙酮、美托酮、麦罗 啡、纳布啡、尼可吗啡、去甲左啡诺、去甲美沙酮、烯丙吗啡、去甲吗啡、羟吗啡酮、喷他佐 辛、非那佐辛、曲马多、替利定、右丙氧芬和丙哌利定,包括他们的药学上可接受的盐。
“药物组合物”是指本发明式(I)化合物或者其立体异构体、药学上可接受的盐或前药和其 它化学组分形成的混合物,其中,“其它化学组分”是指药学上可接受的载体、赋形剂和/或一 种或多种其它药物。
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材 料。
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括 碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、 稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。
“药学上可接受的盐”是指安全、无毒的并且既不在生物学上也不再其它方面不合乎需要, 并且包括其对于兽医使用以及人类药物使用上药学可接受的,并且具有所期望的药理学活性的 盐,这样的盐包括,但不限于与无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等等形成的酸加成 盐;或者与有机酸如乙酸、三氟乙酸、丙酸、己酸、庚酸、环戊烷丙酸、丙酮酸、乳酸、丙二 酸、琥珀酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、o-(4-羟基苯甲酰基)苯甲 酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、三氟甲磺酸、1,2-乙二磺酸、苯磺酸、对氯苯磺酸、 2-萘磺酸、对甲苯磺酸、樟脑磺酸、4-甲基二环[2.2.2]辛-2-烯-1-羧酸、葡萄糖醛酸、葡庚糖酸、 3-苯基丙酸、三甲基乙酸、叔丁基乙酸、十二烷基硫酸、谷氨酸、羟基萘甲酸、水杨酸、硬脂 酸、枸橼酸、赖氨酸、精氨酸、门冬氨酸、2-羟基丙酸、草酸和黏糠酸等等形成的酸加成盐。
药学上可接受的盐也包括,但不限于碱加成盐,当存在的酸性质子能够与无机碱或有机碱 起反应时,可以形成碱加成盐,所述的盐选自Al、Ca、Li、Mg、K、Na和Zn。可接受的无 机碱包括,但不限于氢氧化钠、碳酸氢钠、碳酸钠、氢氧化钾、碳酸氢钾、碳酸钾、氢氧化锂、 碳酸锂、磷酸钾、磷酸钠、磷酸氢二钠、磷酸氢二钾、氢氧化钙和氢氧化铝;可接受的无机碱 包括,但不限于氨、异丙基胺、三甲基胺、二乙胺、三乙胺、三丙基胺、四甲基胺、二乙醇胺、 乙醇胺、二甲基乙醇胺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己基胺、咖啡碱、普鲁 卡因、胆碱、甜菜碱、苯明青霉素、乙二胺、葡萄糖胺、N-甲基葡糖胺、可可碱、三乙醇胺、 氨丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶和聚胺树脂。
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本 发明化合物中的酚基团来制备,该修饰可以通过常规的操作或者在体内被除去,而得到母体化 合物。当本发明的前药被施予哺乳动物个体时,前药被割裂形成游离的羟基。
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体,包括顺反异构 体、对映异构体和构象异构体。
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发 生,该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如,“选择性地被烷基 取代的杂环基”是指该烷基可以但未必存在,该描述包括其中杂环基被烷基取代的情况,及其 中杂环基未被烷基取代的情况。
具体实施方式
以下实施例详细说明本发明的技术方案,但本发明的保护范围包括但是不限于此。
丙泊酚、七氟醚、舒芬太尼、咪达唑仑为购买,式(I)化合物及其制剂参考专利WO2016034079可以制备得到。
1、结肠镜临床实验
试验方案:
进行诊断性结肠镜检查的患者64名,随机分为7组,其中1、2、4、5、6、7组每组10名,第3组4名,具体见表1。每组麻醉前注射用药芬太尼50μg,组1和组2分别用不同剂量的丙泊酚麻醉诱导,组3至组7分别用不同剂量的式(I)化合物麻醉诱导,1/2初始计量用于麻醉维持。
表1:结肠镜检查研究情况
结论:式(I)化合物的0.2~0.5mg/kg剂量组的结肠镜检查成功率均为100%,其等效剂量 是Propofol的1/4~1/5,式(I)化合物各组呼吸暂停发生率低于丙泊酚,式(I)化合物各组注 射痛明显低于丙泊酚。
2、全麻诱导实验
试验方案:
需全麻下行气管插管的≤3h的非急诊、非心胸、非脑外择期手术的住院患者45名,随机分为 5组,其中1、2每组10名,第3组9名,第4、5组每组10名,具体见表2。每组麻醉前注射用 药咪达唑仑和舒芬太尼,组1和组2分别用不同剂量的丙泊酚麻醉诱导,组3至组5分别用不同 剂量的式(I)化合物麻醉诱导,七氟醚用于麻醉维持。
表2:全身麻醉研究情况
结论:式(I)化合物成功用于全身麻醉,且注射痛发生率为0。
3、式(I)化合物与依托咪酯联合用药安全性、耐受性
受试者:18-49周岁,健康男性
试验方案:
序号 | 式(I)化合物剂量 | 依托咪酯剂量 | 入组人数 |
1 | 0.324mg/kg | 0.15mg/kg | 5 |
2 | 0.216mg/kg | 0.2mg/kg | 5 |
3 | 0.432mg/kg | 0.1mg/kg | 5 |
结论:式(I)化合物与依托咪酯联用后,具有更好的安全性和耐受性。
Claims (18)
1.式(I)化合物或者其立体异构体、药学上可接受的盐或前药,在制备用于结肠镜检查的药物中的用途
2.根据权利要求1所述的用途,包括对哺乳动物给药有效剂量的式(I)化合物或者其立体异构体、药学上可接受的盐或前药,其中所述式(I)化合物的有效剂量为0.2mg/kg至20mg/kg的范围内,所述式(I)化合物的药学上可接受的盐或前药的有效剂量均通过式(I)化合物的有效剂量折算。
3.根据权利要求2所述的用途,式(I)化合物的有效剂量任选自0.2mg/kg至15.0mg/kg的范围内、0.2mg/kg至10.0mg/kg的范围内、0.2mg/kg至5.0mg/kg的范围内、0.2mg/kg至2.0mg/kg的范围内或者0.2mg/kg至1.0mg/kg的范围内。
4.根据权利要求2所述的用途,式(I)化合物或其前药的有效剂量给药时间为在10分钟内。
5.根据权利要求4所述的用途,式(I)化合物或其前药的有效剂量给药时间为在2分钟内。
6.根据权利要求2所述的用途,其中给药形式为单次给药、多次给药、连续给药和靶控输注中的一种或多种。
7.根据权利要求2所述的用途,其中通过选自如下的途径进行给药:静脉内注射、动脉内注射、肌肉内注射、透皮吸收、含服吸收、肠胃外腹膜内、直肠、透颊、鼻内、吸入、通过局部递送、皮下、脂肪内、关节内、腹膜内或鞘内。
8.根据权利要求7所述的用途,其中通过静脉内注射进行给药。
9.根据权利要求1-8任意一项所述的用途,进一步包括对该哺乳动物同时给予一种或多种除式(I)化合物以外的其它活性成分,所述的其它活性成分选自具有镇静催眠或麻醉辅助作用的药物。
10.根据权利要求9所述的用途,所述的其它活性成分选自γ-氨基丁酸受体激动剂、γ-氨基丁酸受体增强剂、M受体拮抗剂、N2受体拮抗剂、5-羟色胺3受体拮抗剂、钠离子通道拮抗剂或阿片受体激动剂。
11.根据权利要求9所述的用途,所述的其它活性成分选自静脉麻醉药、吸入麻醉药或麻醉辅助剂。
12.式(I)化合物或者其立体异构体、药学上可接受的盐或前药,在制备用于全身麻醉的药物中的用途
13.根据权利要求12所述的用途,其中包括对哺乳动物给药有效剂量的式(I)化合物或者其立体异构体、药学上可接受的盐或前药其中,式(I)化合物的有效剂量为0.01mg/kg至20.0mg/kg的范围内,所述式(I)化合物的药学上可接受的盐或前药的有效剂量均通过式(I)化合物的有效剂量折算。
14.根据权利要求13所述的用途,其中进一步包括对哺乳动物给药有效剂量的依托咪酯、咪达唑仑、舒芬太尼、七氟醚中的一种或多种。
15.根据权利要求14所述的用途,其中,依托咪酯的有效剂量为0.01mg/kg至20.0mg/kg的范围内,所述式(I)化合物的药学上可接受的盐或前药的有效剂量均通过式(I)化合物的有效剂量折算。
16.根据权利要求15所述的用途,其中式(I)化合物的有效剂量为0.01-5mg/kg的范围内,依托咪酯的有效剂量为0.01-5mg/kg的范围内。
17.根据权利要求16所述的用途,其中给药形式选自单次给药、多次给药、连续给药和靶控输注中的一种或多种。
18.根据权利要求17所述的用途,其中给药途径选自静脉内注射、动脉内注射、肌肉内注射、透皮吸收、含服吸收、肠胃外腹膜内、直肠、透颊、鼻内、吸入、通过局部递送、皮下、脂肪内、关节内、腹膜内或鞘内中的一种或多种。
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CN115708819A (zh) * | 2022-11-24 | 2023-02-24 | 中国科学院深圳先进技术研究院 | 丙泊酚的抗焦虑制药用途及抗焦虑药物制剂 |
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