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1. 发明授权

US06255324B1 Amino-and mercurio-substituted 4′,5'-dihydropsoralens and therapeutical uses thereof 有权
标题翻译：氨基和巯基取代的4'，5'-二氢补骨脂素及其治疗用途
公开(公告)号：US06255324B1
公开(公告)日：2001-07-03
申请号：US09199552
申请日：1998-11-25
申请人： Ned D. Heindel , Jeffrey D. Laskin , Diane E. Heck , Robert D. Rapp , Marilyn S. Whittemore , Thomas E. McNeel , Ivan Jabin
发明人： Ned D. Heindel , Jeffrey D. Laskin , Diane E. Heck , Robert D. Rapp , Marilyn S. Whittemore , Thomas E. McNeel , Ivan Jabin
IPC分类号： A61K314709
CPC分类号： C07D493/04 , C07D311/44 , C07D311/56 , C07F3/14
摘要： 5′-substituted, 4′,5′-dihydropsoralen compounds (5) bearing tertiary amines (and salts thereof), quaternary ammonium moieties or organomercurial moieties are described. Also described are 2-substituted mercurimethyl-2-3-dihydro-benzofurans of forumla (7): Also reported are versatile direct syntheses through a hitherto unknown compounds such as 3-R-4,8-dimethyl-4′,5′-dihydro-5′-bromomethylpsoralen or a 3-R-4,8-dimethyl-4′, 5′-dihydro-5′-iodomethylpsoralen to prepare a structurally diverse array of partially reduced psoralens and benzofurans. The presence of a permanent ammonium charge in these psoralens precludes membrane passage and the mono-unsaturation precludes the cross-linking of nuclear DNA, thereby minimizing the mutagenic/carcinogenic side effects long associated with psoralen-derived therapies. The presence of a mercury functionality provides a reactive cell-binding group on these psoralens with unique cytotoxicity without light activation and an enhancement of cytotoxicity activity upon light activation. The invention also relates to These partially reduced and quaternized psoralens, amino-substituted psoralens, and mercurio psoralens display impressive pharmacology against PAM 212 keratinocytes, a model cell line employed as a test system to indicate epidermal cytotoxicity and cancer. The compounds of the invention also have antimicrobicidal activity useful in pharmacologic agents for mammals (e.g. the treatment of tuberculosis) as well as in controlling the growth of microorganisms on substrates and in aqueous systems.
摘要翻译：描述了含有叔胺（及其盐），季铵部分或有机聚合物部分的5'取代的4'，5'-二氢补骨脂素化合物（5）。还描述了2-取代的缩水甘油二甲基-2,3-二氢 - 苯并呋喃论坛（7）：还报道了通过迄今为止未知的化合物如3-R-4,8-二甲基-4'，5'-二氢-5'-溴甲基口服或3-R-4,8- 二甲基-4'，5'-二氢-5'-碘甲基肌醇，以制备结构不同的部分还原的补骨脂素和苯并呋喃的阵列。在这些补骨脂素中存在永久铵电荷排除了膜通过，并且单不饱和度排除了核DNA的交联，从而使与补骨脂素衍生疗法长期相关的诱变/致癌副作用最小化。汞功能的存在在这些补骨脂素上提供了具有独特细胞毒性的反应性细胞结合基团，而没有光活化，并且在光活化时增强细胞毒性活性。本发明还涉及这些部分还原和季铵化的补骨脂素，氨基取代的补骨脂素和补骨脂素，对PAM 212角质形成细胞，用作指示表皮细胞毒性和癌症的测试系统的模型细胞系显示令人印象深刻的药理学。本发明的化合物还具有用于哺乳动物的药理学（例如治疗结核病）以及控制底物和水系统中的微生物生长的抗除菌活性。

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