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    Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate
    6.
    发明公开
    Positively charged water-soluble prodrugs of n-arylanthranilic acids with very fast skin penetration rate 审中-公开
    阳离子胶原蛋白，wasserlöslicheProdrugs vonArylanthranilsäurenmit sehr schneller Hautpenetrationsrate

    公开(公告)号：EP2623495A1

    公开(公告)日：2013-08-07

    申请号：EP13153470.3

    申请日：2006-09-03

    申请人： Techfields Biochem Co. Ltd ,  Yu, Chongxi

    发明人： Yu, Chongxi ,  Xu, Lina

    IPC分类号： C07D213/80 ,  C07C237/34 ,  C07C327/30 ,  A61K31/245 ,  A61K31/44 ,  A61P29/00

    CPC分类号： C07D213/80 ,  C07C237/34 ,  C07C327/30

    摘要： The novel positively charged pro-drugs of arylanthranilic acids in the general formula (1) 'Structure 1' were designed and synthesized. The compounds of the general formula (1) 'Structure 1' indicated above can be prepared from mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds, by reaction with suitable alcohols, thiols, or amines and coupling reagents, such as N, N'-Dicyclohexylcarbodiimide, N, N'-Diisopropylcarbodiimide, O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, Benzotriazol-1-yl-oxy-tris (dimethylamino)phosphonium hexafluorophosphate, et al. The positively charged amino groups of these pro-drugs not only largely increases the solubility of the drugs, but also bonds to the negative charge on the phosphate head group of membranes and pushes the pro-drug into the cytosol. The results suggest that the pro-drugs diffuses through human skin -200 times faster than does mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds. It takes 2-4 hours for mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about -50 minutes to reach the peak plasma level when they are taken transdermally. In plasma, more than 90% of these pro-drugs can change back to the parent drugs in a few minutes. The prodrugs can be used medicinally in treating any NSAIAs-treatable conditions in humans or animals. The prodrugs can be administered not only orally, but also transdermally for any kind of medical treatments and thus avoid most of the side effects of NSAIAs, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enables mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.

    摘要翻译： 设计并合成了通式（1）“结构1”中芳基邻氨基苯甲酸新型带正电荷的前药。 上述通式（1）“结构1”的化合物可以通过与合适的醇，硫醇或胺反应而由甲芬那酸，甲氯芬那酸，氟芬那酸，尼氟酸，氟尼克辛和相关化合物制备，偶联试剂 ，N，N'-二异丙基碳二亚胺，O-（苯并三唑-1-基）-N，N，N'，N'-四甲基脲四氟硼酸盐，O-（苯并三唑-1-基） - N，N，N'，N'-四甲基脲六氟磷酸盐，苯并三唑-1-基 - 氧 - 三（二甲基氨基）鏻六氟磷酸盐等。 这些前药的带正电荷的氨基不仅大大增加药物的溶解度，而且还与磷酸盐头基上的负电荷键合，并将前药推入细胞溶质中。 结果表明，前药通过人体皮肤扩散比美芬那酸，甲氯芬那酸，氟芬那酸，尼氟酸，氟尼辛和相关化合物快200倍。 甲灭酸，甲氯芬那酸，氟芬那酸，尼氟菌酸，氟尼昔康及相关化合物口服后达到峰值血浆水平需要2-4小时，但这些前药只需要约-50分钟才能达到峰值血浆 当他们经皮摄取时。 在血浆中，超过90％的这些前药可以在几分钟内恢复到母体药物。 前药可以在医学上用于治疗人或动物中任何NSAIAs可治疗的病症。 前药可以不仅口服给药，而且可以经皮给予任何种类的医学治疗，从而避免NSAIAs的大部分副作用，特别是GI紊乱如消化不良，胃十二指肠出血，胃溃疡和胃炎。 前药的控制透皮给药系统使得甲芬那酸，甲氯芬那酸，氟芬那酸，尼氟酸，氟尼昔康及相关化合物达不到最佳的治疗血液水平，以提高效力，减少甲芬那酸，甲氯芬那酸，氟芬那酸， 尼氟酸，氟尼昔康和相关化合物。 这些前药的透皮给药的另一大好处是给予药物，尤其是给儿童服用的药物将容易得多。

    POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF N-ARYLANTHRANILIC ACIDS WITH VERY FAST SKIN PENETRATION RATE
    9.
    发明公开
    POSITIVELY CHARGED WATER-SOLUBLE PRODRUGS OF N-ARYLANTHRANILIC ACIDS WITH VERY FAST SKIN PENETRATION RATE 审中-公开
    带正电的N-ARYLANTHRANILSÄUREN的水溶性前药具有非常快的皮肤渗透速率

    公开(公告)号：EP2084132A4

    公开(公告)日：2010-05-26

    申请号：EP06795893

    申请日：2006-09-03

    申请人： TECHFIELDS BIOCHEM CO LTD ,  YU CHONGXI

    发明人： YU CHONGXI ,  XU LINA

    IPC分类号： C07D213/74 ,  A61K31/245 ,  A61K31/44 ,  A61P29/00 ,  C07C237/34 ,  C07C327/30

    CPC分类号： C07D213/80 ,  C07C237/34 ,  C07C327/30

    摘要： The novel positively charged pro-drugs of arylanthranilic acids in the general formula (1) 'Structure 1' were designed and synthesized. The compounds of the general formula (1) 'Structure 1' indicated above can be prepared from mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds, by reaction with suitable alcohols, thiols, or amines and coupling reagents, such as N, N'-Dicyclohexylcarbodiimide, N, N'-Diisopropylcarbodiimide, O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, Benzotriazol-1-yl-oxy-tris (dimethylamino)phosphonium hexafluorophosphate, et al. The positively charged amino groups of these pro-drugs not only largely increases the solubility of the drugs, but also bonds to the negative charge on the phosphate head group of membranes and pushes the pro-drug into the cytosol. The results suggest that the pro-drugs diffuses through human skin -200 times faster than does mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds. It takes 2-4 hours for mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds to reach the peak plasma level when they are taken orally, but these prodrugs only took about -50 minutes to reach the peak plasma level when they are taken transdermally. In plasma, more than 90% of these pro-drugs can change back to the parent drugs in a few minutes. The prodrugs can be used medicinally in treating any NSAIAs-treatable conditions in humans or animals. The prodrugs can be administered not only orally, but also transdermally for any kind of medical treatments and thus avoid most of the side effects of NSAIAs, most notably GI disturbances such as dyspepsia, gastroduodenal bleeding, gastric ulcerations, and gastritis. Controlled transdermal administration systems of the prodrug enables mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds to reach constantly optimal therapeutic blood levels to increase effectiveness and reduce the side effects of mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, flunixin, and related compounds. Another great benefit of transdermal administration of these pro-drugs is that administering medication, especially to children, will be much easier.

    摘要翻译： 新颖的带正电荷的氨基酸arylanthranilic前药，通式（1）“结构1”，设计并合成英寸 上面所示的通式（1）“结构1”的化合物可以从甲芬那酸，甲氯灭酸，氟芬那酸，尼氟灭酸，氟尼辛，和相关的化合物与合适的醇，硫醇，或cardamines和偶联试剂被下载，由反应 ，：如N，N'-二环己基，N，N'-二异丙基，O-（苯并三唑-1-基）-N，N，N”，N'-四甲基脲四氟硼酸盐，O-（苯并三唑-1-基） - N，N，N”，N'-四甲基脲六氟磷酸盐，苯并三唑-1-基 - 氧基 - 三（二甲氨基）鏻六氟磷酸盐等。 毕业论文前药带正电荷的氨基不仅大大增加了药物的溶解度，因此而债券对磷酸头基膜的负电荷和推动有利于药物进入细胞质。 结果表明确实亲药物通过人体皮肤扩散速度-200倍呢甲灭酸，甲氯灭酸，氟芬那酸，尼氟灭酸，氟尼辛，和相关的化合物。 这需要2-4小时为甲芬那酸，甲氯灭酸，氟芬那酸，尼氟灭酸，氟尼辛，和相关的化合物达到峰值血浆水平的时候都口服，但只有论文前药大约过了-50分钟达到峰值血浆 水平时，他们采取了皮。 在血浆中，90％以上的合成前体药物可以在几分钟内变回母体药物。 前体药物可药用治疗人或动物的任何NSAIAs可治疗的条件下使用。 前体药物可施用不仅在口头上，但如此透皮任何形式的药物治疗，从而避免大多数的NSAIAs的副作用，最明显的是胃肠功能紊乱：如消化不良，胃十二指肠出血，胃溃疡，和胃炎。 前药的控制透皮给药系统启用甲芬那酸，甲氯灭酸，氟芬那酸，尼氟灭酸，氟尼辛，和相关的化合物以达到不断最佳治疗血液水平来提高效率和降低甲芬那酸，甲氯灭酸，氟芬那酸的副作用， 尼氟灭酸，氟尼辛，和相关化合物。 毕业论文的前体药物透皮给药的另一大好处是没有管理的药物，尤其是爱孩子，会容易得多。