CN1052472C - 结合有烟酰胺和锌的乙酰水杨酸衍生物 - Google Patents
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Abstract
本发明涉及一种结合有烟酰胺和锌的乙酰水杨酸衍生物，结构为：
Description
本发明涉及的是一种可供药用的乙酰水杨酸衍生物，具体讲是一种结合有烟酸衍生物和金属成分的乙酰水杨酸衍生物。
乙酰水杨酸(阿斯匹林)作为经典而至今仍有效的解热镇痛抗炎药物已应用一百多年了，并且近期又不断发现其还具有治疗心血管疾病和某些抗癌疗效，更扩大了其应用范围。但由于其酸性强，对胃肠道刺激易导致的胃出血，甚至溃疡症等副作用也一直是困扰人们并设法解决的问题。为降低其酸性，目前除作成酯类和酰胺等前体药物外，形成复盐也是一个已多有报道的途径。如J55141438，DT2909829等文献都报道了阿斯匹林铝化合物；DT2925718介绍的是阿斯匹林与锌所成的化合物；US4294819介绍的是阿斯匹林与钙、镁所成的盐；US3284489介绍了钙和氨基酸与阿斯匹林结合形式的盐；J56022748介绍了阿斯匹林与碱性氨基酸所成的盐；US3318892介绍了阿斯匹林与烟酸和铝相结合的形式；EP200628A，EP233459A，FR2492368和FR2638742A等文献分别介绍了阿斯匹林与脲、钙和/或镁相结合的形式。从这些文献所介绍的内容可以了解，上述阿斯匹林的衍生物均能降低酸性，并增加水溶性，但在药理学上并未产生更多或新的有价值的积极作用。
针对上述问题，本发明首先的一个目的是提供一种结合有锌和烟酰胺的新结构的乙酰水杨酸衍生物。本发明的再一个目的是提供一种不仅可降低临床使用中的酸性，增大水溶性，而且可以对乙酰水杨酸在药理学上产生有价值的积极作用的结合有锌和烟酰胺的乙酰水杨酸衍生物。
本发明的乙酰水杨酸衍生物由两个乙酰水杨酸分别以羧基，以及两个烟酰胺分别以吡啶环N同时与一个锌相结合的形式，其结构为
本发明所述此衍生物(I)的合成一般并不复杂，可参照如US3318892，EP233459A，EP200628A或其它类似文献所报道的方法进行，也可以参照下述方法进行。其中所用的溶剂可以为甲醇、乙醇、异丙醇，或丙酮、丁酮等C1-C5的小分子醇或酮。锌可以使用氯化锌硫酸锌、硝酸锌等无机酸锌盐，或乳酸锌、乙酸锌、十一烯酸锌等有机酸的锌盐。制备时各原料成分的用量可按乙酰水杨酸∶烟酰胺∶锌盐＝(1.8～2.4)∶(1.8～2.4)∶(0.9～1.2)[摩尔比]。例如：将乙酰水杨酸36克在搅拌下溶解于200毫升丙酮中。另将烟酰胺22克和硫酸锌30克溶解于40毫升水中。在搅拌下将上述水溶液滴入丙酮溶液中，室温下搅拌5小时。过滤所得沉淀，用无水丙酮洗涤。60℃烘干后，得该衍生物产物(I)40克(收率60％)，mp142～145℃，纯度检测含量不低于98％。产物(I)中的乙酰水杨酸含量比例约为54％。该产物在水中易溶，溶解度为5～8％，在乙醇、丙酮中略溶，在乙醚、氯仿、乙酸乙酯中几乎不溶。产物制成5％水溶液中测得pH为6.4。除此方法以外，也可以采用分步法制备，例如，先制备成烟酰胺锌后，再与乙酰水杨酸合成产物(I)，或先制备成乙酰水杨酸锌后再与烟酰胺合成产物(I)。
该衍生产物(I)的化学式为C30H26N4O10Zn，元素分析理论值应为：C：53.95％，H：3.92％，N：8.39％，Zn：9.79％。上述产物(I)的元素分析实测值为：C：54.19％，H：4.01％，N：8.07％，Zn：9.95％。
上述产物(I)的红外吸收光谱图如附图所示。其中特征吸收峰的归属为：3340(波数，以下同)(NH)，1750(C＝O)，1625(C＝N)，1600(C＝C)，1370(C-H)，1220(C-N)。
取上述产物(I)样品适量，分别置50℃烘箱中5天和室温放置18个月后，检查样品中游离水杨酸含量均小于0.2％，表明本发明上述产物(I)有很好的稳定性。
对本发明上述产物(I)作急性毒性动物试验：取体重19～23克雌雄各半的小鼠60只，随机分成两批共六组，试验组与对照组各为一批三组。将产物(I)与对照用的阿斯匹林均用西黄蓍胶配成混悬剂后口服给药，根据72小时内动物死亡情况所得半数致死量(LD50)结果：阿斯匹林为972.7(文献值1050)，产物(I)为1456(毫克/公斤)。
有关药理学实验的结果如下：
对胃的刺激性试验：取体重为210～230克雌雄兼有的SD大鼠70只，随机分组。禁食24小时后，将上述产物(I)和阿斯匹林对照品分别用西黄蓍胶配成不同剂量的混悬剂，另用等量西黄蓍胶液作空白对照，均以灌胃形式给药6小时后处死，作胃溃疡指数检查。将结果作线性回归处理后的半数致溃疡量(UD50)结果为：阿斯匹林215.7，产物(I)631.1(其中相当于阿斯匹林340.8)(毫克/公斤)。
镇痛活性试验：取样重18～22克雌雄各半的小鼠70只随机分组。实验前禁食禁水。产物(I)配成水溶液，对照用阿斯匹林用西黄蓍胶配成混悬剂，空白对照为等量生理盐水。口服给药30分钟后，按10毫升/公斤体重的量腹腔注射0.6％醋酸液，5分钟后开始计数在15分钟内动物扭体反应次数。根据致痛反应抑制率的线性回归所得的半数致痛有效量(ED50)结果：阿斯匹林为368.2，产物(I)为216.5(其中相当于阿斯匹林116.9)(毫升/公斤)。表明产物(I)的镇痛作用相当于阿斯匹林的3.2倍。
抗炎活性试验：同样取上述小鼠70只随机分组。实验前禁食禁水。试验药物配制及空白对照品与镇痛活性试验相同。口服给药30分钟后，用微量加样器在动物左耳滴加二甲苯0.03毫升致炎30分钟后，处死动物，用打孔器取耳片称重，计算两耳片重量差所示的肿胀度。根据致炎反应抑制率作线性回归所得的抑制率达15％时的抗炎有效量(ED15)结果：阿斯匹林682.8，产物(I)为138.2(其中相当于阿斯匹林74.6)(毫克/公斤)。表明产物(I)的抗炎作用相当于阿斯匹林的9.2倍。
这些实验结果已充分表明，本发明上述产物(I)的水溶液为中性，口服后对胃粘膜刺激小，而同时又使镇痛作用和抗炎作用有了明显和大幅度提高，在相同疗效下大大减少了阿斯匹林的实际用量。
此外，烟酰胺作为水溶性维生素，是辅酶I的主要成分，在参与机体新陈代谢方面有重要作用。锌元素为人体必需的微量元素，与体内数十种酶的活性有关，特别是在维持细胞完整性与反应性方面有重要作用。近来用锌作为治疗胃溃疡的新方法已进入临床实验阶段，已显示出在对抗阿斯匹林所致胃肠刺激副作用方面有卓越的优越性。本发明的上述乙酰水杨酸衍生物(I)通过烟酰胺和锌元素与阿斯匹林相结合，在补充对人体有益的元素和成分和可明显对抗阿斯匹林的副作用的同时，还显著改善了传统阿斯匹林药物的药理学性能。随着阿斯匹林新用途和适用领域范围的不断发现和扩展，本发明上述衍生物(I)所显示出的积极意义和价值也将日益明显和重要。
Claims (1)
1、一种结合有烟酸衍生物和金属成分的乙酰水杨酸衍生物，其特征在于其中的烟酸衍生物为烟酰胺，金属成分为锌，并具有如下结构
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| JP6033041B2 (ja) * | 2012-10-31 | 2016-11-30 | 株式会社オハラ | 光学ガラス母材の自動品質検査装置及び光学ガラス母材の自動品質検査方法 |
| CN116063356A (zh) * | 2023-01-18 | 2023-05-05 | 广东电网有限责任公司 | 一种烷基水杨酸异质金属衍生物及其制备方法与应用 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0200628A1 (fr) * | 1985-04-19 | 1986-11-05 | Rhone-Poulenc Sante | Nouveau dérivé de l'acide acétylsalicylique, sa préparation et les compositions pharmaceutiques qui le contiennent |
| EP2333459A2 (en) * | 2009-11-30 | 2011-06-15 | Sanyo Electric Co., Ltd. | Refrigerating apparatus |
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1994
- 1994-11-16 CN CN94111976A patent/CN1052472C/zh not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0200628A1 (fr) * | 1985-04-19 | 1986-11-05 | Rhone-Poulenc Sante | Nouveau dérivé de l'acide acétylsalicylique, sa préparation et les compositions pharmaceutiques qui le contiennent |
| EP2333459A2 (en) * | 2009-11-30 | 2011-06-15 | Sanyo Electric Co., Ltd. | Refrigerating apparatus |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1107140A (zh) | 1995-08-23 |
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