CN106083980A - 头孢克洛的药物组合物及其对急性肺损伤的保护作用 - Google Patents
头孢克洛的药物组合物及其对急性肺损伤的保护作用 Download PDFInfo
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- A—HUMAN NECESSITIES
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- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/888—Araceae (Arum family), e.g. caladium, calla lily or skunk cabbage
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Abstract
本发明公开了头孢克洛的药物组合物及其对急性肺损伤的保护作用,本发明提供的头孢克洛的药物组合物中含有头孢克洛和一种从石菖蒲的干燥根茎中分离得到的结构新颖的天然产物化合物(Ⅰ),头孢克洛和该天然产物单独作用时,对肺损伤具有防治作用;二者联合作用时,对肺损伤的防治作用进一步提高,可以开发成防治肺损伤的药物。本发明与现有技术相比具有突出的实质性特点和显著的进步。
Description
技术领域
本发明属于生物医药领域,涉及头孢克洛的新用途,具体涉及一种头孢克洛的药物组合物及其对急性肺损伤的保护作用。
背景技术
头孢克洛属第二代口服头孢菌素,对多种革兰氏阳性菌和革兰氏阴性菌均具有很强的杀灭作用。本品为广谱半合成头孢菌素类抗生素。对产青霉素酶金黄色葡萄球菌、A组溶血性链球菌、草绿色链球菌和表皮葡萄球菌的活性与头孢羟氨苄相同,对不产酶金黄色葡萄球菌和肺炎球菌的抗菌作用较头孢羟氨苄强2~4倍。对革兰阴性杆菌包括对大肠埃希菌和肺炎克雷伯菌等的活性较头孢氨苄强,与头孢羟氨苄相仿,对奇异变形杆菌、沙门菌属和志贺菌属的活性较头孢羟氨苄强。
该品的作用机制是抑制细菌细胞壁的合成。
目前尚未见头孢克洛与肺损伤防治的相关报道。
发明内容
本发明的目的在于提供一种头孢克洛的药物组合物,该药物组合物中含有头孢克洛和一种从石菖蒲中分离得到的结构新颖的天然产物,头孢克洛和该天然产物可以协同治疗肺损伤。
本发明的上述目的是通过下面的技术方案得以实现的:
一种具有下述结构式的化合物(Ⅰ),
一种头孢克洛的药物组合物,包括头孢克洛、如上所述的化合物(Ⅰ)和药学上可以接受的载体。
如上所述的化合物(Ⅰ)的制备方法,包含以下操作步骤:(a)将石菖蒲的干燥根茎粉碎,用85~95%乙醇热回流提取,合并提取液,浓缩至无醇味,依次用石油醚、乙酸乙酯和水饱和的正丁醇萃取,分别得到石油醚萃取物、乙酸乙酯萃取物和正丁醇萃取物;(b)步骤(a)中正丁醇萃取物用大孔树脂除杂,先用8%乙醇洗脱10个柱体积,再用70%乙醇洗脱12个柱体积,收集70%洗脱液,减压浓缩得70%乙醇洗脱浓缩物;(c)步骤(b)中70%乙醇洗脱浓缩物用正相硅胶分离,依次用体积比为40:1、20:1、10:1和5:1的二氯甲烷-甲醇梯度洗脱得到4个组分;(d)步骤(c)中组分4用正相硅胶进一步分离,依次用体积比为8:1、5:1和2:1的二氯甲烷-甲醇梯度洗脱得到3个组分;(e)步骤(d)中组分2用十八烷基硅烷键合的反相硅胶分离,用体积百分浓度为75%的甲醇水溶液等度洗脱,收集8~14个柱体积洗脱液,洗脱液减压浓缩得到化合物(Ⅰ)。
进一步地,步骤(a)中用90%乙醇热回流提取,合并提取液。
进一步地,所述大孔树脂为AB-8型大孔吸附树脂。
如上所述的化合物(Ⅰ)在制备治疗肺损伤的药物中的应用。
如上所述的头孢克洛的药物组合物在制备治疗肺损伤的药物中的应用。
本发明的优点:
本发明提供的头孢克洛的药物组合物中含有头孢克洛和一种从石菖蒲中分离得到的结构新颖的天然产物,头孢克洛和该天然产物单独作用时,对肺损伤具有防治作用;二者联合作用时,对肺损伤的防治作用进一步提高,可以开发成防治肺损伤的药物。本发明与现有技术相比具有突出的实质性特点和显著的进步。
具体实施方式
下面结合实施例进一步说明本发明的实质性内容,但并不以此限定本发明保护范围。尽管参照较佳实施例对本发明作了详细说明,本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的实质和范围。
实施例1:化合物(Ⅰ)分离制备及结构确证
分离方法:(a)将石菖蒲的干燥根茎(2kg)粉碎,用90%乙醇热回流提取(20L×3次),合并提取液,浓缩至无醇味(4L),依次用石油醚(4L×3次)、乙酸乙酯(4L×3次)和水饱和的正丁醇(4L×3次)萃取,分别得到石油醚萃取物、乙酸乙酯萃取物和正丁醇萃取物;(b)步骤(a)中正丁醇萃取物用AB-8型大孔树脂除杂,先用8%乙醇洗脱10个柱体积,再用70%乙醇洗脱12个柱体积,收集70%洗脱液,减压浓缩得70%乙醇洗脱浓缩物;(c)步骤(b)中70%乙醇洗脱浓缩物用正相硅胶分离,依次用体积比为40:1(8个柱体积)、20:1(8个柱体积)、10:1(8个柱体积)和5:1(10个柱体积)的二氯甲烷-甲醇梯度洗脱得到4个组分;(d)步骤(c)中组分4用正相硅胶进一步分离,依次用体积比为8:1(8个柱体积)、5:1(10个柱体积)和2:1(5个柱体积)的二氯甲烷-甲醇梯度洗脱得到3个组分;(e)步骤(d)中组分2用十八烷基硅烷键合的反相硅胶分离,用体积百分浓度为75%的甲醇水溶液等度洗脱,收集8~14个柱体积洗脱液,洗脱液减压浓缩得到化合物(Ⅰ)(395mg,HPLC归一化纯度大于98%)。
结构确证:白色无定形粉末,HR-ESI-MS显示[M+H]+为m/z 469.3243,结合核磁特征可得分子式为C30H44O4,不饱和度为9。核磁共振氢谱数据δH(ppm,CDCl3,600MHz):H-1(1.49,m),H-1(2.91,ddd,J=13.3,7.0,4.2Hz),H-2(2.41,ddd,J=15.4,6.8,4.2Hz),H-2(2.65,ddd,J=15.4,11.2,7.0Hz),H-5(1.34,d,J=11.2Hz),H-6(1.48,m),H-6(1.63,m),H-7(1.68,m),H-7(1.87,m),H-9(2.47,s),H-16(2.21,d,J=13.1Hz),H-16(2.43,d,J=13.1Hz),H-18(2.46,d,J=8.4Hz),H-19(1.41,m),H-20(1.10,m),H-21(1.28,m),H-21(1.48,m),H-22(1.36,m),H-22(1.51,m),H-23(1.02,s),H-24(0.82,s),H-25(1.19,s),H-26(1.22,s),H-27(1.36,s),H-28(0.87,s),H-29(0.85,d,J=6.3Hz),H-30(0.93,d,J=6.1Hz),OH-12(6.38,s);核磁共振碳谱数据δC(ppm,CDCl3,125MHz):39.2(CH2,1-C),34.3(CH2,2-C),215.6(C,3-C),47.5(C,4-C),55.2(CH,5-C),19.7(CH2,6-C),38.4(CH2,7-C),46.5(C,8-C),54.7(CH,9-C),37.2(C,10-C),196.2(C,11-C),140.8(C,12-C),143.2(C,13-C),58.6(C,14-C),209.4(C,15-C),54.3(CH2,16-C),53.4(C,17-C),48.0(CH,18-C),39.9(CH,19-C),40.5(CH,20-C),30.8(CH2,21-C),38.8(CH2,22-C),26.6(CH3,23-C),15.7(CH3,24-C),13.7(CH3,25-C),19.7(CH3,26-C),14.3(CH3,27-C),19.3(CH3,28-C),17.2(CH3,29-C),20.4(CH3,30-C)。红外波谱表明该化合物含有α,β-不饱和羰基(1705cm-1),羟基(3425cm-1),羰基(1760cm-1),双键(1663cm-1)和偕二甲基(1380cm-1)基团。13C-NMR、DEPT和HSQC谱中显示有30个碳信号,包括八个甲基,七个亚甲基,五个次甲基,三个羰基,一对四取代烯烃碳,以及五个季碳,以上功能结构再结合不饱和数表明该化合物为五环三萜结构。1H-NMR谱结合HSQC谱显示的六个叔甲基质子信号δH 1.02(3H,s),0.82(3H,s),1.19(3H,s),1.22(3H,s),1.36(3H,s)和0.87(3H,s),两个仲甲基质子信号δH 0.85(3H,d,J=6.3Hz),0.93(3H,d,J=6.1Hz)以及1H-NMR数据表明该化合物为乌苏烷型三萜类化合物。在该乌苏烷型化合物中,C-3、C-11和C-15位形成酮基,C-12与C-13形成双键结构。HMBC谱中H3-23和H3-24与C-3,H2-16和H3-27与C-15的相关性以及它们的碳化学位移进一步确证C-3和C-15位形成酮基。另HMBC谱中H-9和H-18与C-12,H-18和H3-27与C-13以及OH-12与C-12相关信号以及它们的碳化学位移表明该化合物存在烯醇式结构,羟基连接在C-12位与C-12和C-13形成的双键构成烯醇式结构。此外,OH-12和H-9与C-11的相关信号以及碳化学位移确认C-11位形成羰基。综合氢谱、碳谱、HMBC谱和NOESY谱,以及文献关于相关类型核磁数据,可基本确定该化合物如下所示,立体构型进一步通过ECD试验确定,理论值与实验值基本一致。化学结构式和碳原子编号如下:
实施例2:药理作用
1、材料与方法
1.1动物
选用健康雄性清洁级SD大鼠,体重320-370g(由南京军区总医院动物实验中心提供)。动物饲养在温度(22±1)℃、相对湿度55%~65%、12h光照周期的通风干燥环境中,采用大小鼠维持料1022饲养。
1.2试剂与样品
头孢克洛购自中国药品生物制品检定所。化合物(Ⅰ)自制,制备方法见实施例1。大鼠肿瘤坏死因子-α(TNF-α)、白细胞介素-6(IL-6)、白细胞介素-10(IL-10),酶联免疫吸附法(ELISA)检测试剂盒购自美国Biosource International公司;大鼠HMGB1ELISA检测试剂盒购自日本Shino-Test公司产品。
1.3大鼠分组及模型制备
采用盲肠结扎穿孔法(CLP)建立脓毒血症模型,术前禁食12h,以乌拉坦(1250mg/kg)腹腔注射剂量麻醉,沿腹正中线做一2cm长的切口,进腹找到盲肠,以4-0丝线环形结扎盲肠根部,以18G针头在游离端对穿1次后挤出粪便少许,送回腹腔,随后依次缝合腹膜和皮肤。Sham组仅做剖腹、分离盲肠远端、关腹手术。术后立即皮下注射生理盐水1mL补充术中液体丢失。大鼠随机分为5组,每组10只,分别为假手术组(Sham组)、模型对照组(CLP组)、头孢克洛组(10mg·kg-1)、化合物(Ⅰ)组(10mg·kg-1)、头孢克洛与化合物(Ⅰ)组合物组【5mg·kg-1头孢克洛+5mg·kg-1化合物(Ⅰ)】。CLP+药物组于CLP后即时及6h后腹腔分别注射药物;Sham组于假手术后即时及6h后、CLP组于CLP后0及6h腹腔分别注射生理盐水1mL。
1.4检测指标及方法
各组动物均于CLP后24h取股静脉血2mL,离心10min后取血清-80℃保存。采用ELISA法检测血清中TNF-α、HMGB1及IL-10的水平。此外,CLP 24h后检测肺组织干湿重比(W/D)、髓过氧化物酶活性(MPO)。
1.5统计学方法
采用SPSS13.0统计软件进行统计分析,计量资料以均数±标准差(x±s)表示,多组间比较采用单因素方差分析,P<0.05为差异有统计学意义。
2、实验结果
2.1对脓毒血症大鼠TNF-α、HMGB1及IL-10水平的影响
与Sham组比较,CLP明显增加血浆TNF-α、HMGB1及IL-10水平。CLP+药物组CLP后24h时的TNF-α和HMGB1水平低于CLP组;与模型对照组比较,头孢克洛与化合物(Ⅰ)组合物组血浆TNF-α、HMGB1及IL-10水平明显降低(P<0.01);与模型对照组比较,头孢克洛组、化合物(Ⅰ)组血浆TNF-α、HMGB1及IL-10水平降低(P<0.05)。结果如下。
2.2对脓毒血症大鼠肺组织W/D及MPO活性的影响
与Sham组比较,CLP明显增加肺组织W/D及MPO活性,(P<0.05);而CLP+药物组肺组织W/D及MPO活性低于CLP组。与模型对照组比较,头孢克洛与化合物(Ⅰ)组合物组肺组织W/D及MPO活性明显降低(P<0.01);与模型对照组比较,头孢克洛组、化合物(Ⅰ)组肺组织W/D及MPO活性降低(P<0.05)。结果见下表。
上述结果表明,头孢克洛与化合物(Ⅰ)组合物可以显著降低脓毒血症引发的肺损伤,且效果优于头孢克洛或化合物(Ⅰ)单独作用的结果,可以开发成治疗急性肺损伤的药物。
上述实施例的作用在于说明本发明的实质性内容,但并不以此限定本发明的保护范围。本领域的普通技术人员应当理解,可以对本发明的技术方案进行修改或者等同替换,而不脱离本发明技术方案的实质和保护范围。
Claims (7)
1.一种具有下述结构式的化合物(Ⅰ),
2.一种头孢克洛的药物组合物,其特征在于:包括头孢克洛、如权利要求1所述的化合物(Ⅰ)和药学上可以接受的载体。
3.权利要求1所述的化合物(Ⅰ)的制备方法,其特征在于,包含以下操作步骤:(a)将石菖蒲的干燥根茎粉碎,用85~95%乙醇热回流提取,合并提取液,浓缩至无醇味,依次用石油醚、乙酸乙酯和水饱和的正丁醇萃取,分别得到石油醚萃取物、乙酸乙酯萃取物和正丁醇萃取物;(b)步骤(a)中正丁醇萃取物用大孔树脂除杂,先用8%乙醇洗脱10个柱体积,再用70%乙醇洗脱12个柱体积,收集70%洗脱液,减压浓缩得70%乙醇洗脱浓缩物;(c)步骤(b)中70%乙醇洗脱浓缩物用正相硅胶分离,依次用体积比为40:1、20:1、10:1和5:1的二氯甲烷-甲醇梯度洗脱得到4个组分;(d)步骤(c)中组分4用正相硅胶进一步分离,依次用体积比为8:1、5:1和2:1的二氯甲烷-甲醇梯度洗脱得到3个组分;(e)步骤(d)中组分2用十八烷基硅烷键合的反相硅胶分离,用体积百分浓度为75%的甲醇水溶液等度洗脱,收集8~14个柱体积洗脱液,洗脱液减压浓缩得到化合物(Ⅰ)。
4.根据权利要求3所述的化合物(Ⅰ)的制备方法,其特征在于:步骤(a)中用90%乙醇热回流提取,合并提取液。
5.根据权利要求3所述的化合物(Ⅰ)的制备方法,其特征在于:所述大孔树脂为AB-8型大孔吸附树脂。
6.权利要求1所述的化合物(Ⅰ)在制备治疗肺损伤的药物中的应用。
7.权利要求2所述的头孢克洛的药物组合物在制备治疗肺损伤的药物中的应用。
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