吲哚美辛吗啉酯衍生物的系列合成及相关脂水分配系数和活性的测定
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摘要
一、目的
利用环氧合酶两种同工异构酶(即COX-1和COX-2)的结构差异设计合成对COX-2抑制选择性适当增强,同时抑制5-脂氧合酶(5-LOX)的系列吲哚美辛吗啉酯衍生物,其主要针对吲哚美辛结构中的羧基进行修饰,以期能寻求到同时减少胃肠道和心血管等方面不良反应的药物；以COX-2选择性抑制剂代表药物塞来昔布为参考对象,考察其对COX-1与COX-2活性的抑制作用,筛选对两种同工异构酶活性抑制更理想的吲哚美辛吗啉酯衍生物；模拟理想条件下的体内环境,测定系列吲哚美辛吗啉酯衍生物在不同pH缓冲溶液下的表观油水分配系数,为预测其稳定性并为今后拟开展的相关性药动学研究提供有意义的实验数据。
二、方法
以草酰氯为酰氯化试剂,干燥后的二氯甲烷作溶剂,将吲哚美辛的羧基改造成活性增强的酰氯基,再以极性非质子试剂四氢呋喃为反应溶剂,将吲哚美辛酰氯与不同取代基的吗啉醇发生酯化反应,获得吲哚美辛2-芳基吗啉乙酯类的系列化合物；以塞来昔布为对照品,测定系列吲哚美辛吗啉酯衍生物的优选化合物对小鼠腹腔巨噬细胞的抑制率,考察其对COX-1与COX-2活性的抑制作用；在理想条件下模拟人体内的胃肠道环境,采用摇瓶法,利用高效液相色谱仪与紫外分光光度仪测定优选的吲哚美辛吗啉酯衍生物在不同pH值磷酸盐缓冲溶液的表观油水分配系数。
三、结果
1讨论了9种吲哚美辛2-芳基吗啉乙酯系列衍生物及其盐的制备合成方法,并通过核磁共振氢谱图确定了其结构。
2测定吲哚美辛吗啉酯衍生物优选化合物的COX-1与COX-2活性的抑制作用,并与塞来昔布的活性进行比较,发现吲哚美辛2-[2-(4-丁氧基苯基)吗啉基]乙酯盐酸盐和吲哚美辛2-[2-(2,4-二氯-5-氟苯基)吗啉基]乙酯盐酸盐IC50COX-1/COX-2的比值最接近塞来昔布的IC50 COX-1/COX-2的比值。
3脂水分配系数测定实验发现系列吲哚美辛吗啉酯衍生物盐酸盐在pH为4时,其表观脂水分配系数为最大,当空间构型增大与引入的基团分子量增大时,吲哚美辛吗啉酯衍生物的表观油水分配系数也随着增大。
四、结论
1通过吲哚美辛2-芳基吗啉乙酯系列合成实验,为其他吲哚美辛衍生物及其盐酸盐的合成提供了新的方法。
2抑制COX-1和COX-2活性实验考察发现了接近塞来昔布IC50 COX-1/COX-2比值的吲哚美辛2-芳基吗啉乙酯衍生物,为后续筛选对两种同工异构酶活性抑制更理想的吲哚美辛吗啉酯衍生物提供了参考依据。
3吲哚美辛2-芳基吗啉乙酯衍生物在正辛醇磷酸盐缓冲液中的表观油水分配系数的测定显示其log p不仅取决于药物本身的分子结构,还与药物在不同pH条件下所处的分子型比例有关,并且与引入基团的空间构型和引入的基团分子量有关。
Objective
In order to find a proper drug that COX-2 inhibitory function is appropriately enhanced and 5-LOX is also inhibited, a series of new produrgs of indomethacin are synthetized based on the structural difference of isoenzyme of COX (COX-1 and COX-2). The attetion is mainly focused on the hydroxy of the indomethacin, hoping to find a satisfying drug that gastrointestinal and cadiovascular side effect can be reduced at the same time. Compared with celecoxib, a tropical COX-2 selective inhibitory drug, the inhibitory functions of COX-1 and COX-2 are determined to find an ideal prodrug with a better inhibit ritio of COX-1/COX-2. In order to ultivily provide meaningful data for it's further stability forcast and relative PK study, the ideal condition of the vivo environment is simulated to determine the apparent oil/water partition coefficient in buffer solvents under different pH.
Methods
Oxalyl chloride is used as chloroformylating agent to sustitude the hydroxyl of indomethacin into a more active acyl chloride in solvent of after-dried dichloromethane. And then, esterification between the product of last step and different substituted morpholinols is happened in polar aprotic solveni of tetrahydrofuran, obtaining a serious product of indomethacin 2-aryl morpholine ethyl ester. Considering celecoxin as referece substance, the macrophage inhibition ratios in mice enterocoelia of these optimized products are determined to see their inhibitory function to COX-land COX-2. Gastrointestinal environment in vivo under ideal condition is imulated via shaking flask method to determine the apparent oil/water partition coefficient of these optimized products by HPLC and ultraviolet spectrophotometer under different pH phosphate buffer solution systems.
Results
1 The synthesis methods of 9 indomethacin 2-aryl morpholine ethyl esters and relative muriatics are discussed, and their conformations are confirmed through'H-NMR structures.
2 The inhibitory functions to COX-1 and COX-2 of these optimized compounds are determined, and the outcome shows that the IC50 COX-1/COX-2 ratio of indomethacin 2-[2-(4-butoxy phenyl morpholinyl] ethyl ester muriate and 2-[2-(2,4-Dichloro-5-phenyl fluoride) morpholinyl] ethyl ester muriate have a most close ratio to celecoxib.
3 The result of apparent oil/water partition coefficient determining experiment suggest that these indomethacin 2-aryl morpholine ethyl esters own a highest partition coefficient in n-octanol/pH4 buffer solution system, and apparent oil/water partition coefficient increases along with structrural conformation and the molecular weight of inductive groups.
Conclusions:
1 New method is provided to other indomethacin derivatives and relative muriates through the synthesis experiment of indomethacin 2-aryl morpholine ethyl esters series.
2 The compounds is found that IC50 COX-1/COX-2 ratio most close to celecoxib through activity inhibition experiment, which provide reference evidence to screen a ideal indomethacin morpholine esters further that suppress COX-1/COX-2 more reasonable.
3 The apparent oil/water partition coefficient determining experiment of the series of indomethacin 2- aryl morpholine ethyl esters in n-octanol phosphate buffer system shown that logP depends on not only the molecular structure of the drug, but also molecular ratio under different pH and the conformation and molecular weight of inductiv groups.
利用环氧合酶两种同工异构酶(即COX-1和COX-2)的结构差异设计合成对COX-2抑制选择性适当增强,同时抑制5-脂氧合酶(5-LOX)的系列吲哚美辛吗啉酯衍生物,其主要针对吲哚美辛结构中的羧基进行修饰,以期能寻求到同时减少胃肠道和心血管等方面不良反应的药物；以COX-2选择性抑制剂代表药物塞来昔布为参考对象,考察其对COX-1与COX-2活性的抑制作用,筛选对两种同工异构酶活性抑制更理想的吲哚美辛吗啉酯衍生物；模拟理想条件下的体内环境,测定系列吲哚美辛吗啉酯衍生物在不同pH缓冲溶液下的表观油水分配系数,为预测其稳定性并为今后拟开展的相关性药动学研究提供有意义的实验数据。
二、方法
以草酰氯为酰氯化试剂,干燥后的二氯甲烷作溶剂,将吲哚美辛的羧基改造成活性增强的酰氯基,再以极性非质子试剂四氢呋喃为反应溶剂,将吲哚美辛酰氯与不同取代基的吗啉醇发生酯化反应,获得吲哚美辛2-芳基吗啉乙酯类的系列化合物；以塞来昔布为对照品,测定系列吲哚美辛吗啉酯衍生物的优选化合物对小鼠腹腔巨噬细胞的抑制率,考察其对COX-1与COX-2活性的抑制作用；在理想条件下模拟人体内的胃肠道环境,采用摇瓶法,利用高效液相色谱仪与紫外分光光度仪测定优选的吲哚美辛吗啉酯衍生物在不同pH值磷酸盐缓冲溶液的表观油水分配系数。
三、结果
1讨论了9种吲哚美辛2-芳基吗啉乙酯系列衍生物及其盐的制备合成方法,并通过核磁共振氢谱图确定了其结构。
2测定吲哚美辛吗啉酯衍生物优选化合物的COX-1与COX-2活性的抑制作用,并与塞来昔布的活性进行比较,发现吲哚美辛2-[2-(4-丁氧基苯基)吗啉基]乙酯盐酸盐和吲哚美辛2-[2-(2,4-二氯-5-氟苯基)吗啉基]乙酯盐酸盐IC50COX-1/COX-2的比值最接近塞来昔布的IC50 COX-1/COX-2的比值。
3脂水分配系数测定实验发现系列吲哚美辛吗啉酯衍生物盐酸盐在pH为4时,其表观脂水分配系数为最大,当空间构型增大与引入的基团分子量增大时,吲哚美辛吗啉酯衍生物的表观油水分配系数也随着增大。
四、结论
1通过吲哚美辛2-芳基吗啉乙酯系列合成实验,为其他吲哚美辛衍生物及其盐酸盐的合成提供了新的方法。
2抑制COX-1和COX-2活性实验考察发现了接近塞来昔布IC50 COX-1/COX-2比值的吲哚美辛2-芳基吗啉乙酯衍生物,为后续筛选对两种同工异构酶活性抑制更理想的吲哚美辛吗啉酯衍生物提供了参考依据。
3吲哚美辛2-芳基吗啉乙酯衍生物在正辛醇磷酸盐缓冲液中的表观油水分配系数的测定显示其log p不仅取决于药物本身的分子结构,还与药物在不同pH条件下所处的分子型比例有关,并且与引入基团的空间构型和引入的基团分子量有关。
Objective
In order to find a proper drug that COX-2 inhibitory function is appropriately enhanced and 5-LOX is also inhibited, a series of new produrgs of indomethacin are synthetized based on the structural difference of isoenzyme of COX (COX-1 and COX-2). The attetion is mainly focused on the hydroxy of the indomethacin, hoping to find a satisfying drug that gastrointestinal and cadiovascular side effect can be reduced at the same time. Compared with celecoxib, a tropical COX-2 selective inhibitory drug, the inhibitory functions of COX-1 and COX-2 are determined to find an ideal prodrug with a better inhibit ritio of COX-1/COX-2. In order to ultivily provide meaningful data for it's further stability forcast and relative PK study, the ideal condition of the vivo environment is simulated to determine the apparent oil/water partition coefficient in buffer solvents under different pH.
Methods
Oxalyl chloride is used as chloroformylating agent to sustitude the hydroxyl of indomethacin into a more active acyl chloride in solvent of after-dried dichloromethane. And then, esterification between the product of last step and different substituted morpholinols is happened in polar aprotic solveni of tetrahydrofuran, obtaining a serious product of indomethacin 2-aryl morpholine ethyl ester. Considering celecoxin as referece substance, the macrophage inhibition ratios in mice enterocoelia of these optimized products are determined to see their inhibitory function to COX-land COX-2. Gastrointestinal environment in vivo under ideal condition is imulated via shaking flask method to determine the apparent oil/water partition coefficient of these optimized products by HPLC and ultraviolet spectrophotometer under different pH phosphate buffer solution systems.
Results
1 The synthesis methods of 9 indomethacin 2-aryl morpholine ethyl esters and relative muriatics are discussed, and their conformations are confirmed through'H-NMR structures.
2 The inhibitory functions to COX-1 and COX-2 of these optimized compounds are determined, and the outcome shows that the IC50 COX-1/COX-2 ratio of indomethacin 2-[2-(4-butoxy phenyl morpholinyl] ethyl ester muriate and 2-[2-(2,4-Dichloro-5-phenyl fluoride) morpholinyl] ethyl ester muriate have a most close ratio to celecoxib.
3 The result of apparent oil/water partition coefficient determining experiment suggest that these indomethacin 2-aryl morpholine ethyl esters own a highest partition coefficient in n-octanol/pH4 buffer solution system, and apparent oil/water partition coefficient increases along with structrural conformation and the molecular weight of inductive groups.
Conclusions:
1 New method is provided to other indomethacin derivatives and relative muriates through the synthesis experiment of indomethacin 2-aryl morpholine ethyl esters series.
2 The compounds is found that IC50 COX-1/COX-2 ratio most close to celecoxib through activity inhibition experiment, which provide reference evidence to screen a ideal indomethacin morpholine esters further that suppress COX-1/COX-2 more reasonable.
3 The apparent oil/water partition coefficient determining experiment of the series of indomethacin 2- aryl morpholine ethyl esters in n-octanol phosphate buffer system shown that logP depends on not only the molecular structure of the drug, but also molecular ratio under different pH and the conformation and molecular weight of inductiv groups.
引文
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[41]Dogne J M,Supuran C T,Pratico D.Adverse cardiovascular effects of the coxibs.[J]Med.Chem.2005,48(9):565-569.
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