CN116135833A - 一种芳基丙酸衍生物及其用途 - Google Patents
一种芳基丙酸衍生物及其用途 Download PDFInfo
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- CN116135833A CN116135833A CN202211435001.XA CN202211435001A CN116135833A CN 116135833 A CN116135833 A CN 116135833A CN 202211435001 A CN202211435001 A CN 202211435001A CN 116135833 A CN116135833 A CN 116135833A
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
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- C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
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Abstract
本发明公开了一种R‑氟比洛芬盐及其制备方法、药物组合物和用途。本发明中R‑氟比洛芬与胺或氨基酸成盐制备的衍生物在溶液状态下具有相对较高的粘度,在制备眼用及皮肤外用药物及其应用中具有显著优势。
Description
技术领域
本发明涉及但不限于医药技术领域及化妆品领域,尤其涉及一种由R-氟比洛芬盐或溶剂化物,及其用途。
背景技术
氟比洛芬是临床上常用的非甾体抗炎类药物,自1977年投放市场以来,广泛用于风湿性关节炎、类风湿关节炎、骨关节炎、变形关节炎、强直性脊柱炎等,也可用于软组织病(如扭伤及劳损)以及轻中度疼痛(如痛经和手术后疼痛、牙痛等)的对症治疗。主要通过抑制前列腺素合成酶起作用,是目前已知的丙酸类非甾体抗炎药中作用最强的一种,氟比洛芬抗炎效果和镇痛效果分别为阿司匹林的250倍和50倍,药效和耐受性比同类布洛芬更强,且毒性低。
但氟比洛芬溶解度小,脂溶性较强,生物利用度低,因此,可寻求一种溶解度好的氟比洛芬有机胺盐来提高药物吸收效果。以消旋氟比洛芬与有机胺形成的盐,溶解性大幅度提高,但由于其是PH依赖型溶解型的盐类,其溶解度受pH影响较大,所以在一些pH条件下其溶解度提高并不明显,此外由于氟比洛芬固有活性的限制,所以溶解度提高的同时并不必然导致其生物利用度的提高,甚至在某些剂型中会有所下降这类盐,这都影响了其应用。
氟比洛芬是手性药物,分子中存在手性中心,具有S型和R型一对对映体。目前临床应用的是它的外消旋体,虽然专利(WO2010001103、WO2015145163、US3959364A、CN201680057083.5)报道了S-氟比洛芬拆分和合成的方法。但是目前为止,并未有拆分的S-氟比洛芬或R-氟比洛芬制剂上市,目前已公开的专利都是以氟比洛芬为主药,如专利CN1387842A、专利CN1205631A、专利CN101119716A。
文献报道氟比洛芬的消炎活性主要来自其(S)-对映体,而(R)-对映体则缺乏显著的环氧合酶抑制活性(日本专利特开平8-119859)。通过文献调研及相关的研究,本发明人发现R构型氟比洛芬盐虽然没有抗炎活性,但依然有镇痛活性,且R构型氟比洛芬盐对胃肠道的刺激性极弱。
本发明人在对氟比洛芬及其单一构型的异构体研究时,意外的发现R-氟比洛芬盐类化合物对人膀胱癌细胞株具有很强的抑制作用。说明此类化合物有显著的抑制膀胱癌细胞的作用。
这些优势促使我们对其进行了进一步的研究。
发明内容
本发明提供了R-氟比洛芬胺或氨基酸盐及其制备方法、药物组合物。
本发明中R-氟比洛芬与胺或氨基酸成盐制备的衍生物具有高水溶性的特点,意外地发现该类盐在溶液状态下具有相对较高的黏度,在制备眼用及皮肤外用药物及化妆品应用中具有显著优势。本发明化合物具有较好的镇痛的效果,进一步研究表明本发明化合物有显著的抑制膀胱癌细胞的作用。
本发明提供了一种R-氟比洛芬与胺或氨基酸形成的盐或溶剂化物及其药物组合物和用途。
一方面,本发明提供了一种如式(I)所示的R-氟比洛芬盐或溶剂化物;
式(I)中,R-氟比洛芬与M成盐,M选自下列结构:三乙醇胺、二乙醇胺、乙醇胺、二乙胺、乙二胺、三乙胺、哌嗪、L-精氨酸、D-精氨酸、L-赖氨酸、D-赖氨酸、L-组氨酸、D-组氨酸、L-鸟氨酸和D-鸟氨酸。
进一步地,所述的R-氟比洛芬盐具有如下结构:
本发明化合物红外光谱显示成盐后羰基伸缩振动峰向低波数移动,这表明化合物已成盐。
在本申请的实施方案中,所述的溶剂化物是指化合物与药学上可接受的溶剂相互作用形成的络合物,药学上可接受的溶剂包括水、乙醇,异丙醇、丁醇、乙酸。
进一步地,所述R-氟比洛芬盐,其制剂为R-氟比洛芬盐加入药学上所需的辅料做成的制剂。
进一步地,所述的R-氟比洛芬盐制剂剂型包括但不限于:片剂、胶囊、散剂、颗粒剂、丸剂、混悬剂、糖浆剂、滴丸、软膏、硬膏、巴布膏、贴片、贴剂、膜剂、注射液、滴眼液、或喷雾剂。
进一步地,所述的R-氟比洛芬盐制剂中,R-氟比洛芬衍生物的含量范围为:0.001%~80%(W/W%)。
进一步地,所述的R-氟比洛芬盐及药物组合物用于轻度至中度疼痛或术后疼痛,如痛经、牙痛、眼部疼痛、眼部手术后的疼痛等的用途。
进一步地,所述R-氟比洛芬盐及药物组合物用于治疗膀胱癌等疾病。
本发明化合物与未成盐的R-氟比洛芬或氟比洛芬氨丁三醇盐相比,溶解度显著提高。
本发明化合物与R-氟比洛芬钠相比,其水溶液和醇溶液中具有更高的粘度。
本发明化合物体外透皮研究中,具有较好的透过皮肤的能力,这可能与其高粘度和结构中存在多处氢键供体或受体及形成离子键的基团有关,预期在眼用及皮肤外用制剂中有助于提高生物利用度。
本发明化合物在镇痛药效模型中(醋酸扭体法)表现出较好的镇痛效果;进一步地,本发明化合物可显著抑制膀胱癌细胞的增殖。
本发明化合物具有较好的溶解性,与R-氟比洛芬相比具有更好的溶液剂应用前景;在溶液中有较高的粘度及透皮吸收的能力,结合其较好的镇痛效果,预期在皮肤外用镇痛或滴眼用镇痛方面具有较好的应用前景。
文献及本发明相关研究也表明,本发明化合物对于胃肠道功能的影响较小或基本没有影响。
本发明化合物与氟比洛芬钠相比具有更高的活性,与未成盐的R-氟比洛芬具有更高的水溶解性,在临床应用中可显著降低给药剂量并减少副作用。
附图说明
图1表示的是本发明R(+)-氟比洛芬盐的饱和水溶液在大鼠皮肤上的相对累积释放试验结果。
具体实施方式:
下面具体实施例中如无特殊说明,采用的制备与精制方法均为本领域的常规方法:
实施例一:氟比洛芬中R-氟比洛芬异构体的拆分
将消旋的氟比洛芬(3.0kg)装入20L的夹套玻璃反应器中。加入甲醇(2.0L)和甲苯(8.0L)。加热混合物以溶解固体。将R-1-苯基乙胺(0.76kg)溶于甲苯(1.87L)中,并在60℃下搅拌约30分钟将溶液加到20L反应器中。将混合物逐渐冷却至0至5℃以引起结晶。滤出晶体,用甲苯(3L)洗涤,并在55℃的真空烘箱中干燥以形成粗制的R-氟比洛芬/R-1-苯基乙胺盐(1.4kg)。
将R-氟比洛芬/R-1-苯基乙胺盐(1.4kg)粗品加入20L夹套玻璃反应器中。加入甲苯(12.0L)和甲醇(2.5L),搅拌混合物并加热至60℃以溶解固体。将该溶液逐渐冷却至0至5℃以引起结晶。滤出晶体,用甲苯(4L)洗涤,并在55℃的真空烘箱中干燥以形成纯的R-氟比洛芬/R-1-苯乙胺盐(1.2kg)。
将纯的R-氟比洛芬/R-1-苯基乙胺盐(1.2kg)加入到10L带夹套的玻璃反应瓶中。在搅拌下加入甲苯(4L)。加入水(1.0L)和浓盐酸(0.5L),并将混合物在60℃下搅拌。分离出下部水层,并保留上部有机层。重复盐酸洗涤,然后用水洗涤甲苯溶液。加入另外的甲苯(0.7L),然后蒸出甲苯(2.0L)以确保溶液不含水。将该甲苯溶液逐渐冷却至-10℃以引起结晶。滤出晶体,用正庚烷(1.0L)洗涤并在40℃的真空烘箱中干燥,得R-氟比洛芬(0.6kg)。收率20%(以氟比洛芬计)。纯度:99.2%。1H NMR(300MHz,CDCl3)δ7.45-7.56(m,2H),7.29-7.47(m,4H),7.12-7.26(m,2H),3.75-3.84(m,1H),1.38-1.59(d,3H)。
实施例二:R-氟比洛芬精氨酸盐AMX9301的制备
取R-氟比洛芬(2.44g,10.0mmol)加入至25.0mL乙醇与水混合溶剂中(20:1,V/V),向其中加入精氨酸(化合物1,1.91g,11.0mmol),加热至回流全溶,继续回流2.0h,冷却析晶,有白色固体析出,降为室温后过滤,所得滤饼用乙醇淋洗(5.0mL×2),所得固体于50℃下真空干燥12.0h得1.70g产物AMX9301,收率:35%,纯度:98.7%。1H NMR(300MHz,CDCl3)δ7.72-7.74(m,1H),7.31-7.57(m,7H),3.74-3.82(m,1H),3.38-3.40(m,1H),3.24-3.26(m,2H),1.70-1.72(m,2H),1.49-1.64(m,2H),1.46(d,J=13.2Hz,3H)。
实施例三:R-氟比洛芬赖氨酸盐AMX9303的制备
取R-氟比洛芬(2.44g,10.0mmol)加入至25.0mL乙醇与水混合溶剂中(4:1,V/V),向其中加入赖氨酸(化合物3,1.62g,11.0mmol),加热至回流全溶,继续回流2.0h,冷却析晶,有白色固体析出,降为室温后过滤,所得滤饼用水淋洗(5.0mL×2),所得固体于50℃下真空干燥12.0h得2.47g产物AMX9303,收率:63%,纯度:98.4%。1H NMR(300MHz,CDCl3)δ7.75-7.77(m,1H),7.39-7.56(m,6H),7.31-7.37(m,1H),3.81-4.06(m,2H),2.67-2.70(m,2H),1.70-1.89(m,2H),1.36-1.65(m,7H)。
实施例四:R-氟比洛芬组氨酸盐AMX9306的制备
取R-氟比洛芬(2.44g,10.0mmol)加入至100mL无水乙醇中,向其中加入组氨酸(化合物6,1.70g,11.0mmol),加热至回流全溶,继续回流5.0h,冷却析晶,有白色固体析出,降为室温后过滤,所得滤饼用无水乙醇淋洗(5.0mL×2),所得固体于50℃下真空干燥12.0h得3.24g产物AMX9306。收率:79%。纯度:98.1%。1H NMR(300MHz,CDCl3)δ8.72(d,J=4.2Hz,1H),7.70-7.80(m,1H),7.65(d,J=4.2Hz,1H),7.34-7.55(m,7H),3.82-4.06(m,1H),3.71-3.74(m,1H),3.10-3.13(m,2H),1.46(d,J=13.2Hz,3H)。
实施例五:R-氟比洛芬鸟氨酸盐AMX9308的制备
R-氟比洛芬(2.44g,10.0mmol)加入至20.0mL乙醇与水混合溶剂中(4:1,V/V),向其中加入鸟氨酸(化合物8,1.45g,11.0mmol),加热至回流全溶,继续回流2.0h,冷却析晶,有白色固体析出,降为室温后过滤,所得滤饼用无水乙醇淋洗(5.0mL×2),所得固体于50℃下真空干燥12.0h得2.67g产物AMX9308。收率:71%。纯度:98.5%。1H NMR(300MHz,CDCl3)δ7.71-7.79(m,1H),7.36–7.56(m,7H),3.83-4.02(m,2H),2.70-2.73(m,2H),1.64-1.90(m,2H),1.38-1.60(m,5H)。
实施例六:R-氟比洛芬三乙醇胺盐AMX9310的制备
取R-氟比洛芬(2.44g,10.0mmol)加入至50ml异丙醇中,向其中加入三乙醇胺(化合物10,1.49g,10.0mmol),加热至70℃-80℃,继续回流5.0h,冷却析晶,有白色固体析出,降为室温后过滤,所得滤饼用异丙醇淋洗,所得固体于50℃下真空干燥12.0h得3.57g产物AMX9310。收率:91%。纯度:99.3%。1H-NMR(300MHz,CDCl3)δ7.68-7.76(m,1H),7.59-7.61(m,1H),7.36-7.54(m,6H),4.45(s,3H),4.31(q,1H),3.69-3.71(m,4H),3.50-3.55(m,4H),1.44(d,3H)。
实施例七:R-氟比洛芬二乙醇胺盐AMX9311的制备
取R-氟比洛芬(2.44g,10.0mmol)加入至50mL无水乙醇中,向其中加入二乙醇胺(化合物11,1.05g,10.0mmol),加热回流5.0h,冷却析晶,有白色固体析出,降为室温后过滤,所得滤饼用无水乙醇淋洗,所得固体于50℃下真空干燥12.0h得3.04g产物AMX9311。收率:87%。纯度:98.9%。1H NMR(300MHz,CDCl3)δ7.78-7.73(m,1H),7.36-7.58(m,7H),4.32(q,1H),3.66-3.70(m,4H),3.50-3.54(m,4H),1.43(d,J=13.1Hz,3H)。
实施例八:R-氟比洛芬哌嗪盐AMX9314的制备
取R-氟比洛芬(2.44g,10.0mmol)加入至50mL无水乙醇中,向其中加入哌嗪(化合物14,0.86g,10.0mmol),加热至回流全溶,继续回流5.0h,冷却析晶,有白色固体析出,降为室温后过滤,所得滤饼用无水乙醇淋洗,所得固体于50℃下真空干燥12.0h得1.75g产物AMX9314。收率:53%。纯度:98.5%。1H NMR(300MHz,CDCl3)δ7.64-7.69(m,1H),7.30-7.49(m,7H),4.25(q,1H),3.38-3.46(m,4H),3.24-3.33(m,4H),1.43(d,J=13.0Hz,3H)。
对比例一:R-氟比洛芬氨丁三醇盐AMX01的制备
R-氟比洛芬(2.44g,10mmol)和1-氯丁烷(25mL)的溶液加热至70℃,溶解后,滴加氨丁三醇(化合物9,1.21g,10mmol)、甲醇(10mL)和1-氯丁烷(25mL)的混合溶液。搅拌2h后,冷却结晶。抽滤,将其在50℃减压干燥过夜得到1.5g白色固体产物AMX01收率:41%。1H NMR(300MHz,CDCl3)δ7.72-7.77(m,1H),7.56-7.61(m,1H),7.38-7.54(m,6H),4.24-4.32(m,1H),3.64-3.67(m,6H),1.45(d,J=13.2Hz,3H)。
对比例二:S(+)-氟比洛芬D-鸟氨酸盐AMX02的制备
S(+)-氟比洛芬(2.44g,10.0mmol)加入至20.0mL乙醇与水混合溶剂中(4:1,V/V),向其中加入D-鸟氨酸(1.45g,11.0mmol),加热至回流全溶,继续回流2.0h,冷却析晶,有白色固体析出,降为室温后过滤,所得滤饼用无水乙醇淋洗(5.0mL×2),所得固体于50℃下真空干燥12h得2.67g产物AMX02。收率:71%,纯度:98.5%。1H-NMR(400MHz,H2O)δ7.44-7.54(m,2H),7.32-7.42(m,4H),7.09-7.17(m,2H),3.52-3.58(m,2H),2.70-2.73(m,2H),1.64-1.90(m,2H),1.28-1.32(m,5H)。
对比例三:S(+)-氟比洛芬L-赖氨酸盐(AMX3)的制备
取S(+)-氟比洛芬(2.44g,10.0mmol)加入至25.0mL乙醇与水混合溶剂中(4:1,V/V),向其中加入L-赖氨酸(1.62g,11.0mmol),加热至回流全溶,继续回流2.0h,冷却析晶,有白色固体析出,降为室温后过滤,所得滤饼用水淋洗(5.0mL×2),所得固体于50℃下真空干燥12h得2.47g产物AMX3,收率:63%,纯度:98.4%。1H-NMR(400MHz,H2O)δ7.49(m,2H),7.35-7.42(m,4H),7.12(m,2H),3.59-3.64(m,2H),2.91(m,2H),1.79(m,2H),1.60-1.62(m,2H),1.30-1.40(m,5H)。对比例四:RS-氟比洛芬-L-赖氨酸盐(AMX04)的合成
完全按照AMX03的合成方法,以外消旋的氟比洛芬(RS-氟比洛芬)为原料,合成RS-氟比洛芬-L-赖氨酸盐(AMX04)
按照与上述实施例同样的方法,使用市售化合物或由市售化合物适当合成的中间体化合物,合成了下列实施例化合物。
实施例九:R-氟比洛芬盐在水中的溶解度测试
溶解度结果显示,相比于R-氟比洛芬,本发明R-氟比洛芬盐水溶性显著提高;甚至相比于对比例化合物AMX01,本发明R-氟比洛芬盐水溶性也提高约2~6倍。
实施例十:R-氟比洛芬盐溶液粘度测试
使用Ubbelohde毛细管粘度计测量粘度,以水作为标准溶液,其密度和粘度值均取自兰氏化学手册。首先将粘度计放入超声波中清洗干净,用二次蒸馏水洗涤,再用丙酮冲洗三遍,然后放入烘箱中烘干。将预先配好的溶液移入粘度计,并将粘度计垂直放入恒温水浴中,待粘度计中液体的温度达到待测温度并恒温20分钟后,开始测定流动时间。溶液流过粘度计毛细管的时间由精度为0.01s的电子秒表读取。被测液样在毛细管流动过程中不能有气泡,以免形成气阻。每个数据点至少进行5次重复实验,可重复性误差为±0.06s,取其平均值为最终实验结果。待测溶液的粘度η按公式[η/ηw=(ρt)/(ρwtw)]计算,式中,η、ρ、t、ηw、ρw、tw分别表示待测溶液和标准溶液的粘度、密度和溶液流过毛细管的时间。粘度结果如下表1所示。
表1:乙醇溶液中粘度测试结果(mPa·s)
*DB1为R-氟比洛芬钠
从上表可以看出,各样品在乙醇溶液的粘度不同。在温度为298.15K时,相比于DB1(R-氟比洛芬钠),对比例化合物AMX01粘度有微弱的增加,但本发明化合物粘度增加较大;温度为313.15K时,表现出了相似的结果。这说明本发明化合物在溶液状态下具有更高的粘度,预期在作为滴眼液或皮肤外用制剂使用时具有更好的效果。
实施例十一:体外透皮释放试验
健康小鼠(体重20~25g),用8%硫化钠溶液脱去背部毛,温水洗净,24h后颈部脱臼处死。取下背部皮肤,除去皮下组织,洗净,于解剖镜下检查无损伤,浸入生理盐水中,置冰箱低温保存备用。
采用Franz扩散池进行实验,将小鼠活性皮肤固定于释放池一端,角质层面向释放池,释放面积为3.8cm2。配置AMX01、AMX9301、AMX9303的过饱和水溶液,加入释放池时摇匀,以保证整个体外透皮释药实验过程中供给液始终呈过饱和状态,浓度保持恒定。接受池中加入10.0mL的生理盐水作为接受液,使皮肤另一面与生理盐水紧密接触,37℃恒温水浴,定速搅拌,于0.25h,0.5h,1h,2h,4h,6h各取接受液1.0mL,同时向接受池中加入等量同温的生理盐水。将所取接受液经微孔滤膜滤过,进行HPLC测定,各点空白对测定均无干扰。
将药物的透皮累积释药量与37℃饱和溶液浓度的比值为纵坐标(相对释放),以时间为横坐标做图,其斜率即为药物的渗透系数Ps(cm.h-1)。结果见图1。实验结果可知,相比于对比例AMX01,本发明化合物AMX9301、AMX9303的渗透系数明显较高。
实施例十二:抑制膀胱癌细胞作用
人膀胱癌细胞5637细胞以5×104个/孔接种于96孔板中,每孔加入培养基100ul,置于37℃、5%CO2培养箱中培养,细胞贴壁后弃去原培养基,实验组加入分别含有受试化合物的培养基200ul,其浓度别为100ug/ml,阴性对照组加入含有与受试化合物中相同浓度的DMSO的培养基200ul,每组设3个复孔。加入受试化合物48h后,弃上清液,PBS洗涤3遍,再加入200ul培养基,同时向每孔加入5mg/ml的MTT溶液20ul,继续培养4h。小心吸去孔内培养液,每孔加入150ul DMSO,置摇床上低速振荡10min,使结晶物充分溶解。酶标仪测定在570m波长下的吸光值(OD值)。按公式计算生长抑制率,生长抑制率(%)=(1-实验组平均OD值/对照组平均OD值)×100%,结果如表2所示。
表2:对膀胱癌细胞的抑制作用
分组 | 抑制率(%) | 分组 | 抑制率(%) |
AMX9301 | 88.5 | AMX9310 | 90.1 |
AMX9302 | 90.3 | AMX9311 | 88.2 |
AMX9303 | 90.7 | AMX9312 | 88.9 |
AMX9304 | 92.2 | AMX9313 | 90.1 |
AMX9305 | 91.8 | AMX9314 | 91.5 |
AMX9306 | 86.7 | AMX9315 | 92.4 |
AMX9307 | 89.5 | AMX02 | 18.9 |
AMX9308 | 94.2 | AMX04 | 39.2 |
结果显示,在100ug/m1浓度下,相比于对比例AMX02和AMX04,本发明化合物均表现出了很好的对人膀胱癌细胞5637的抑制作用。
实施例十三:对大鼠体重及胃肠道功能的影响实验
50只SD大鼠(180~220g,雄性)适应性饲养3天后,随机分成5组,每组10只。组1~4组分别灌胃给予供试品混悬液(AMX9303、AMX9307、R-氟比洛芬、AMX04,分别用1%的甲基纤维素水溶液混悬)0.4ml,样品等摩尔给药,以氟比洛芬计7.2mg/kg,组5为溶媒组,灌胃给予同体积的甲基纤维素水溶液。各组每天给药或给溶媒1次,连续给药30天,分别在第15天和第30天称重,然后与各组第1天体重对照分析,评估体重变化量。结果如表3所示。
表3:给药30天后大鼠体重变化量(单位:g)
分组 | 15天动物数 | 15天体重变化量 | 30天动物数 | 30天体重变化量 |
AMX9303 | 10 | 16.5±5.6 | 10 | 22.5±5.1 |
AMC9307 | 10 | 15.3±5.4 | 10 | 23.2±5.7 |
AMX04 | 10 | 6.6±6.2 | 8 | 10.2±4.1 |
R-氟比洛芬 | 10 | 14.3±6.9 | 10 | 19.4±6.5 |
溶媒组 | 10 | 14.1±6.6 | 10 | 22.1±6.6 |
从上表可以看出,给药15天后,所有各组动物均存活,对比例化合物AMX04组的体重增加量相对较小,而其它各组体重的增加高于或与溶媒组持平;给药30天后,对比例化合物AMX04给药组2只动物死亡,其它各组动物均存活。在给药30天后,对比例化合物AMX04组动物体重增加最小,R-氟比洛芬组动物体重增加量也低于溶媒组,而本发明化合物AMX9303组和AMX9307组的动物体重增加最大,且有大于R-氟比洛芬的趋势。这说明消旋氟比洛芬(AMX04)组大鼠体重增加量明显较低,因此可判断消旋氟比洛芬对大鼠胃肠道功能的影响较大,而R-氟比洛芬及本发明化合物对大鼠胃肠道功能的基本无影响。
实施例十四醋酸扭体法镇痛药效实验
取12只18-22g SPF级雌性KM小鼠(厂家:斯贝福(北京)生物技术有限公司;许可证号码:SCXK(京)2019-0010),随机分成4组,每组3只动物。每组分别用1mL注射器吸取待注射溶液(组1为无菌注射用水,其余3组样品用无菌注射用水溶解)0.2ml,给药剂量如表4所示,在两腿之间动物腹中线左部2-3mm部位进针,针头进入腹腔后进行回抽,确认是真空的状态下进行溶液注射。于末次给药30min后,每鼠腹腔注射0.6%冰醋酸0.2mL,详细记录各鼠出现每一次扭体反应(腹部收缩成“S”形、身体扭曲、后肢伸展及蠕行等)的时间及20min内小鼠的扭体次数。结果如表4所示。
表4:镇痛药效实验结果
分组 | 动物 | 给药途径 | 剂量 | 给药体积 | 扭体平均值 |
阴性对照组 | KM小鼠 | 腹腔注射 | 0mg/kg,溶媒 | 0.2ml | 19.7 |
AMX 9303-高剂量组 | KM小鼠 | 腹腔注射 | 7.2mg/kg | 0.2ml | 7.0 |
AMX 9303-中剂量组 | KM小鼠 | 腹腔注射 | 3.6mg/kg | 0.2ml | 8.0 |
AMX 9303-低剂量组 | KM小鼠 | 腹腔注射 | 1.8mg/kg | 0.2ml | 6.0 |
从表4可以看出,相比于溶媒组,本发明化合物AMX 9303表现出来明显的镇痛活性。
本申请描述了多个实施例,但是该描述是示例性的,而不是限制性的,并且对于本领域的普通技术人员来说显而易见的是,在本申请所描述的实施例包含的范围内可以有更多的实施例和实现方案。
Claims (6)
3.一种药物组合物,其包含权利要求1~2所述R-氟比洛芬盐或溶剂化物以及药学上所需的辅料。
4.根据权利要求书3所述的药物组合物,该药物组合物包括但不限于片剂、胶囊、散剂、颗粒剂、丸剂、混悬剂、糖浆剂、滴丸、软膏、硬膏、巴布膏、贴片、贴剂、膜剂、注射液、滴眼液、或喷雾剂的剂型形式。
5.权利要求1~2中任一项所述的R-氟比洛芬盐或溶剂化物,或者权利要求3~4中任一项所述的药物组合物在制备治疗疼痛相关疾病的药物中的应用,所述的疼痛相关疾病包括痛经、牙痛、眼部疼痛、眼部手术后的疼痛。
6.权利要求1~2中任一项所述的R-氟比洛芬盐或溶剂化物,或者权利要求3~4中任一项所述的药物组合物在制备治疗膀胱癌的药物中的用途。
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