CN101550119B - 芳基(乙)丙酸抗坏血酸酯,其制备方法及含有它们的药物 - Google Patents

芳基(乙)丙酸抗坏血酸酯,其制备方法及含有它们的药物 Download PDF

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CN101550119B
CN101550119B CN2009100266979A CN200910026697A CN101550119B CN 101550119 B CN101550119 B CN 101550119B CN 2009100266979 A CN2009100266979 A CN 2009100266979A CN 200910026697 A CN200910026697 A CN 200910026697A CN 101550119 B CN101550119 B CN 101550119B
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xitix
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ascorbyl ester
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CN101550119A (zh
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汤鲁宏
戴阿娟
王择
孙阳
刘信宁
徐玲燕
方鑫
邱爽
曹雅晴
徐晓敏
姜瑞霞
吴超
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Tang Luhong
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WUXI HONGRUI BIO-PHARM TECHNOLOGY Co Ltd
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Abstract

本发明设计并合成布洛芬、酮洛芬、萘普生等芳基(乙)丙酸类非甾类抗炎药物的抗坏血酸酯类衍生物以及其与可药用酸或碱的加成盐。以布洛芬为代表的非甾类抗炎药物是一类常用的解热镇痛药物。除抗炎作用外，又具显著的镇痛、退热作用及很好的安全性，不仅适于成年人同样适用于老年人和婴、幼儿服用。将其转化为抗坏血酸酯类衍生物及其与可药用酸或碱的加成盐，可改善其水溶性，便于静脉给药，缩短起效时间，提高生物利用度，减轻其对肠胃道的刺激作用，增强其血脑屏障的穿透能力，作为新型药物用于消炎、解热、镇痛、治疗关节炎、痛经、多发性硬化症、囊性纤维化肺炎、早产儿动脉导管未闭、预防和治疗脑卒中、缺血性脑损伤、老年痴呆症和某些癌症。

Description

芳基(乙)丙酸抗坏血酸酯,其制备方法及含有它们的药物
技术领域
本发明涉及新的非甾类抗炎药物的酯类衍生物，其制备方法以及含有它们的药物组合物。具体地讲是属于芳基(乙)丙酸的抗坏血酸酯类衍生物以及其与可药用酸或碱的加成盐，其制备方法以及含有它们的药物组合物。
背景技术
以布洛芬为代表的非甾类抗炎药物是近年来发展最为成功的解热镇痛药物之一。它们除抗炎作用外，又具显著的镇痛、退热作用及很好的安全性；不仅适于成年人同样适用于老年人和婴幼儿服用。在国外布洛芬已成为解热镇痛药的主要品种，广泛用于安全性要求很高的非处方药(OTC)，被视为比扑热息痛、阿司匹林更具有发展前景的品种之一。
但这类药物普遍存在水溶性较差、刺激肠胃道、吸收慢、生物利用度低、起效相对较慢等不足，对儿童、老年人和不能吞服固体制剂的患者也带来诸多不便。
为改进制剂的产品溶解性及给药途径问题，提高产品的稳定性和生物利用度，加快起效速度，现有技术中已公开了大量的各种改良技术。CN99800474.X公开了一种含有水溶性酮基布洛芬盐的药用制剂及其应用；CN00807563.8公开了一种可饮用布洛芬药物悬浮液；CN02109536.1公开了一种布洛芬三氮唑核苷酯及制备方法和用途；CN02110476.X公开了酮基布洛芬与β-环糊精或其衍生物包合物的制备方法；CN02115459.7公开了聚己内酯-布洛芬组合物及其制法和用途；CN02821502.8公开了布洛芬盐乳化剂和包含其的霜剂制剂；CN03139116.8公开了一种布洛芬糖缀合物及其制备方法和应用；CN03144095.9公开了含有布洛芬和盐酸伪麻黄碱的液态软胶囊；CN03145504.2公开了精氨酸-布洛芬混合物的制法和用途；CN03805774.3公开了用于硬壳胶囊的布洛芬溶液；CN200410014369.4公开了一种新的制备布洛芬精氨酸盐的方法；CN200410021005.9公开了布洛芬酯、可药用盐及其制备工艺以及它的药物组合物；CN200410021590.2公开了丁香酚布洛芬酯药用化合物及其制剂和制备方法；CN200510024043.4公开了一种布洛芬糖衍生物及其制备方法和应用；CN200510026269.8公开了一种制备2-芳基乳酸酯及萘普生、布洛芬的方法；CN200510040242.4公开了苯氧布洛芬钙的清洁生产方法；CN200510060924.1公开了一种水分散性纳米级布洛芬注射制剂及其制备方法；CN200510096990.4公开了右布洛芬氨基酸盐制备方法和应用；CN200610038794.6公开了含葡萄糖酸锌、布洛芬和马来酸氯苯那敏的软胶囊组合物；CN200610044134.9公开了含有布洛芬的注射剂及其制备方法；CN200610044528.4公开了含有酮基布洛芬的注射剂及其制备方法；CN200610090025.0公开了一种儿童适用的精氨酸布洛芬药剂；CN200610129620.0公开了一种精氨酸布洛芬盐的制备方法；CN200610130587.3公开了布洛芬口腔溶解片及其制备方法；CN200610170923.7公开了布洛芬输液制剂及其制备方法；CN200680001752.3公开了包含右布洛芬作为有效成分的糖浆剂组合物及其制备方法；CN200680016935.2公开了增溶的布洛芬；CN200710004659.4公开了具有改善溶出性能的右旋布洛芬药物组合物及其制备方法；CN200810000637.5公开了一种布洛芬氨基酸盐注射液及其制备方法；CN200810102110.3公开了一种布洛芬精氨酸盐的制备方法；CN200810105086.9公开了一种右旋布洛芬的氨基酸盐及其药用组合物。
但将布洛芬类非甾类抗炎药物与抗坏血酸结合，转化为抗坏血酸酯，利用其与可药用酸或碱形成的盐来改善其溶解特性、起效速度、生物利用度以及血脑屏障穿透性能的研究尚未见任何报道。
发明内容
本发明发明了一种布洛芬类非甾类抗炎药物的酯类衍生物新品种，布洛芬类非甾类抗炎药物的抗坏血酸酯，及其与可药用酸或碱的加成盐。本发明化合物具有新的结构，因此是新颖的，尤其是具有溶解性好、生物利用度高、起效快、血脑屏障穿透性能强等有价值的药代动力学特性和能够作为治疗早产儿动脉导管未闭、脑卒中、缺血性脑损伤、老年痴呆症和某些癌症的药物的有价值的药理学特性。
更具体的说，本发明涉及式(I)化合物，其对映体、外消旋混合物和非对映异构体，以及其与可药用酸或碱的加成盐：
其中R代表：
Figure G2009100266979D00022
在可药用酸中，能以非限制性方式提及的是：磷酸，三偏磷酸，三聚磷酸等。
在可药用碱中，能以非限制性方式提及的是：氢氧化钠，氢氧化钾，氨水，氢氧化锌，氢氧化镁，氢氧化钙等。
本发明的优选化合物是这样一些化合物：
L-抗坏血酸-6-O-(S)-布洛芬酯
L-抗坏血酸-6-O-(S)-酮洛芬酯
L-抗坏血酸-6-O-(S)-萘普生酯
L-抗坏血酸-6-O-(S)-吲哚美辛酯
本发明优选化合物的对映体、外消旋混合物、非对映异构体及其与可药用酸或碱的加成盐也构成本发明的一个重要部分。
本发明还涉及式(I)化合物的制备方法，其特征在于以L-抗坏血酸为底物，在脂肪酶的催化下，在特定的反应体系中，跟另一底物，式(II)化合物
RCOOH    (II)
式中R如上文定义。按照下面的反应方程式发生酯化反应制得：
Figure G2009100266979D00023
该方法由下列步骤组成：
(1)以脂肪酶为催化剂，在特定的反应体系中，使L-抗坏血酸的6-羟基和式(II)化合物发生酯化反应，生成L-抗坏血酸的6-O-酯，得到一个由反应物L-抗坏血酸、式(II)化合物和反应产物-L-抗坏血酸的6-O-酸酯以及水构成的平衡混合物。
(2)对该平衡混合物进行分离提取，得到目的产物，式(I)化合物。
我们发现，可供用作催化剂的脂肪酶可以是Novozym435，胰脂肪酶等市场上可以买到的常见脂肪酶品种；反应介质可以是丙酮、叔丁醇(2-甲基-2-丙醇)、叔戊醇(2-甲基-2-丁醇)、己烷、辛烷、环己烷、苯、甲苯、二甲苯、离子液体、超临界流体等可供脂肪酶在其中催化该反应进行的液体或流体；酯化反应应当在反应温度为-30-200℃，反应压力为0.0001-0.5MPa的条件下进行；分离提取，包括萃取、结晶、柱层析、溶剂回收以及其他任何必要的从反应混合物中得到纯物质的常规操作过程，应当在温度为-30-200℃，压力为0.0001-3.5MPa的条件下进行。
式(I)化合物具有重要的药代动力学性能和药理学性能。它们的可药用酸或碱的加成盐具有良好的水溶解性、极佳的生物利用度和血脑屏障穿透性能，起效快，有效剂量低，能够在中枢神经系统中和脑血管中发挥作用，这些性能使得它们可以在医疗上用于消炎、解热、镇痛、治疗关节炎、痛经、多发性硬化症、囊性纤维化肺炎、早产儿动脉导管未闭、预防和治疗脑卒中、缺血性脑损伤、老年痴呆症和某些癌症。
本发明还涉及含有式(I)化合物、其对映体或其与可药用酸或碱的加成盐本身或者与一种或多种惰性、无毒的赋形剂或载体结合的药物组合物。
在本发明的药物组合物中，尤其值得一提的是适于口服、肠胃外、经鼻、直肠、经舌、经眼或经呼吸给药的那些，尤其是片剂或糖衣丸、舌下片剂、扁囊剂、扇形剂(paquet)、明胶胶囊、舌含片(glossette)、锭剂、栓剂、膏霜剂、油膏剂、皮肤用凝胶、可注射或可饮用制剂、气雾剂、滴眼或滴鼻剂。
有用剂量根据患者的年龄和体重、给药途径、治疗适应症的性质及任何相关治疗而定，范围是从0.1mg/天至800mg/天，分一次或多次给药。
具体实施方式
为了更好地理解本发明，下面以实施例说明之，但并不限止本发明的内容。
实施例1，L-抗坏血酸-6-O-(S)-布洛芬酯
在一个500ml具塞三角瓶中加入0.85g L-抗坏血酸和60ml 25％(w/v)的(S)-布洛芬叔戊醇溶液，然后放入恒温空气浴振荡器中加热，使物料达到55℃，然后加入Novozym 435lg，在200rpm的震摇速度下让体系反应12hrs，然后加入1g分子筛A4，在同样条件下继续震摇12hrs，得到反应混合物。
趁热过滤，除去未反应的反应物和酶，得到澄清的滤液。滤液用等量的饱和食盐水洗4-5次，并在减压条件下49℃，旋蒸出叔戊醇，称量得到的固体，按10％的量加入环己烷，在45℃水浴上微热，充分搅拌溶解，然后放入4℃冰箱中过夜，得到结晶。过滤，用环己烷冲洗滤饼多次，回收滤饼，室温干燥滤饼，得到标题化合物。
熔点：145～146℃
元素微量分析：
计算值％：C：62.64；H：6.63
实测值％：C：62.68；H：6.69
实例2，实施例1的标题化合物的结构确认
经结构确认，所得产物为L-抗坏血酸-6-O-(S)-布洛芬酯。其特征的理化及结构分析参数为：
m.p.145～146℃
[α]D＝+21.8°(c＝0.00232g/ml，CH3OH)。0.1003g、50ml(c＝0.00611g/ml，CH3OH)
IR(KBr，cm-1)：3395.52，3222.26，3022.03，2954.93，2876.59，2954.93，2876.59，1761.60，1709.72，1665.92，1665.92，1510.01，1463.13，1382.85
1H NMR(400MHz，CD3OD)：7.20(d，2H)，7.11(d，2H)，4.39(d，1H)，4.12(t，2H)，3.99(t，1H)，3.75(t，1H)，2.44(d，2H)，1.82(t，1H)，1.47(d，3H)，0.88(t，6H)
13C NMR(400MHz，CD3OD)：δ(ppm)18.8533(C8)，22.8453，22.7906(C1+C1’)，31.6083(C3)，46.3302，46.1564(C9+C2)，65.7436(C12)，67.7221(C11)，76.8915(C13)，120.1202(C15)，128.4167(C5+C5’)，130.5936(C6+C6’)，141.9723，139.4376(C7+C4)，154.1888(C14)，173.2871，176.1047(C10+C16)
MS(m/z)：365.4(M+H+)，363.3(M-1)。
Figure G2009100266979D00041
溶解性：易溶于甲醇，乙醇，丙二醇，难溶于氯仿，环己烷，水
实施例3，L-抗坏血酸-6-O-布洛芬酯
Figure G2009100266979D00042
方法与实施例1中所用的相同，只是用外消旋的布洛芬替代(S)-布洛芬。
熔点：145～146℃
元素微量分析：
计算值％：C：62.64；H：6.63
实测值％：C：62.65；H：6.70
[α]D＝0°(c＝0.00611g/ml，CH3OH)
实施例4，L-抗坏血酸-6-O-(S)-酮洛芬酯
Figure G2009100266979D00043
方法与实施例1中所用的相同，只是用(S)-酮洛芬替代(S)-布洛芬。
熔点：165～166℃
元素微量分析：
计算值％：C：64.07；H：4.88
实测值％：C：64.15；H：4.90
[α]D＝+20.3°(c＝0.00311g/ml，CH3OH)
实施例5，L-抗坏血酸-6-O-落索洛芬酯
Figure G2009100266979D00044
方法与实施例1中所用的相同，只是用外消旋的落索洛芬替代(S)-布洛芬。
熔点：168～169℃
元素微量分析：
计算值％：C：62.36；H：5.98
实测值％：C：62.45；H：6.13
[α]D＝0°(c＝0.00231g/ml，CH3OH)
实施例6，L-抗坏血酸-6-O-普拉洛芬酯
Figure G2009100266979D00051
方法与实施例1中所用的相同，只是用外消旋的普拉洛芬替代(S)-布洛芬。
熔点：198～199℃
元素微量分析：
计算值％：C：61.01；H：4.63；N：3.39
实测值％：C：61.05；H：4.73；N：3.41
[α]D＝0°(c＝0.00231g/ml，CH3OH)
实施例7，L-抗坏血酸-6-O-(S)-萘普生酯
Figure G2009100266979D00052
方法与实施例1中所用的相同，只是用(S)-萘普生替代(S)-布洛芬。
熔点：215～216℃
元素微量分析：
计算值％：C：61.85；H：5.15
实测值％：C：61.87；H：5.18
[α]D＝+18.5°(c＝0.00511g/ml，CH3OH)
实施例8，L-抗坏血酸-6-O-依托度酸酯
Figure G2009100266979D00053
方法与实施例1中所用的相同，只是用依托度酸替代(S)-布洛芬。
熔点：218～219℃
元素微量分析：
计算值％：C：62.01；H：6.06；N：3.14
实测值％：C：62.07；H：6.10；N：3.21
[α]D＝0°(c＝0.00201g/ml，CH3OH)
实施例9，L-抗坏血酸-6-O-(S)-布洛芬酯钠盐的制备
在连续搅拌的条件下，取0.05mol/L的L-抗坏血酸-6-O-(S)-布洛芬酯甲醇溶液100ml与等体积等摩尔浓度的氢氧化钠甲醇溶液混合，然后置旋转蒸发仪上真空浓缩至原体积的三分之一，4℃下放置过夜，过滤，得到标题化合物1.8g。
经测定，其在水中的溶解度为12.8g。
实例10，L-抗坏血酸-6-O-(S)-布洛芬酯钠盐：动静脉环路血栓
正常大鼠，雌雄各半，按表1随机分组，灌胃给药L-抗坏血酸-6-O-(S)-布洛芬酯钠盐水溶液(pH 7.4)及空白对照组(等pH生理盐水)，连续给药3d。末次给药后1h腹腔注射8％水合氯醛350mgkg-1麻醉，仰卧位固定，分离右侧颈总动脉和左侧颈外静脉。在10cm长的聚乙烯管中段放入一根提前称重的7号手术线(长约8cm)并充满生理盐水，其两端连接充满肝素的插管(长约3cm)，一端插入颈静脉，另一端插入颈总动脉。打开动脉夹后，形成体外环路血流。15min后中断血流，迅速取出血栓称重，该重量减去丝线重量即得血栓湿重。
血栓抑制率：(空白组血栓湿重-给药组血栓湿重)/空白组血栓湿重
统计学处理：实验数据以x±s表示，用单因素方差分析判断差异的显著性。t表示空白对照组和L-抗坏血酸-6-O-(S)-布洛芬酯钠盐之间的t检验结果。
表1血栓抑制率
Figure G2009100266979D00061
方差分析，P＜0.05；与空白组比较**P＜0.01，*P＜0.05
由表1可知，L-抗坏血酸-6-O-(S)-布洛芬酯钠盐的血栓抑制率与对照组的差异具有显著性(P＜0.01)，L-抗坏血酸-6-O-(S)-布洛芬酯钠盐能抑制血栓形成，增强其抗凝血功能。L-抗坏血酸-6-O-(S)-布洛芬酯钠盐血栓抑制率达12.9％。
实例11，每片包含300mg L-抗坏血酸-6-O-(S)-布洛芬酯的片剂
用于制备1000片的配方：
L-抗坏血酸-6-O-(S)-布洛芬酯            300g
小麦淀粉                               300g
土豆淀粉                               300g
乳糖                                   1000g
硬脂酸镁                               50g
二氧化硅                               20g
羟丙基纤维素                           30g
实例12，每支含200mg L-抗坏血酸-6-O-(S)-布洛芬酯钠的针剂
用于制备1000支的配方：
L-抗坏血酸-6-O-(S)-布洛芬酯钠          200g
乳糖                                   200g

Claims (10)

1.一类芳基(乙)丙酸抗坏血酸酯，其特征为符合式(I)的化合物，以及其与可药用酸或碱的加成盐：
Figure FDA0000138182590000011
其中R代表：
Figure FDA0000138182590000012
2.如权利要求1所述的式(I)化合物，它是L-抗坏血酸-6-O-(S)-布洛芬酯，其外消旋混合物L-抗坏血酸-6-O-布洛芬酯，以及其与可药用酸或碱的加成盐。
3.如权利要求1所述的芳基(乙)丙酸抗坏血酸酯的制备方法，其特征是以L-抗坏血酸为底物，在脂肪酶的催化下，在特定的反应介质中，跟另一底物，式(II)化合物
RCOOH    (II)
式中R如上文定义，
按照下面的反应方程式发生酯化反应制得：
Figure FDA0000138182590000013
该方法由下列步骤组成：
(1)以脂肪酶为催化剂，在特定的反应介质中，使L-抗坏血酸的6-羟基和式(II)化合物发生酯化反应，生成L-抗坏血酸的6-O-酸酯，得到一个由反应物L-抗坏血酸、式(II)化合物和反应产物-L-抗坏血酸的6-O-酸酯以及水构成的平衡混合物，
(2)对该平衡混合物进行分离提取，得到目的产物式(I)化合物。
4.如权利要求3所述的制备方法，其特征是脂肪酶系指Novozym435或胰脂肪酶。
5.如权利要求3所述的芳基(乙)丙酸抗坏血酸酯的制备方法，其特征是反应介质系指丙酮、叔丁醇(2-甲基-2-丙醇)、叔戊醇(2-甲基-2-丁醇)、己烷、辛烷、环己烷、苯、甲苯、二甲苯、离子液体、超临界流体以及其他任何可供脂肪酶在其中催化该反应进行的液体或流体。
6.如权利要求3所述的芳基(乙)丙酸抗坏血酸酯的制备方法，其特征是酯化反应系指反应体系在反应温度为-30-200℃，反应压力为0.0001-0.5MPa的条件下进行的，利用脂肪酶催化底物发生化学变化生成反应产物的过程。
7.如权利要求3所述的芳基(乙)丙酸抗坏血酸酯的制备方法，其特征是分离提取为萃取、结晶、柱层析、溶剂回收以及其他任何必要的从反应混合物中得到纯物质的操作过程。
8.如权利要求7所述的芳基(乙)丙酸抗坏血酸酯的制备方法，其特征是分离提取在温度为-30-200℃，压力为0.0001-3.5MPa的条件下进行。
9.药物组合物，它包含作为活性成分的至少一种按照权利要求1-2任一项所述的化合物本身或其与一种或多种惰性、无毒的可药用赋形剂或载体的组合。 
10.如权利要求9所述的药物组合物，它包含至少一种活性成分：按照权利要求1-2任一项所述的化合物，用于消炎、解热、镇痛、治疗关节炎、痛经、多发性硬化症、囊性纤维化肺炎、早产儿动脉导管未闭、预防和治疗脑卒中、缺血性脑损伤、老年痴呆症和某些癌症。 
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