公开(公告)号：EP3201201A1

公开(公告)日：2017-08-09

申请号：EP15778052.9

申请日：2015-09-30

申请人： biolitec unternehmensbeteiligungs II AG ,  Freie Universität Berlin

发明人： GOLF, Hartwig Richard Arthur ,  WIEHE, Arno ,  GRÄFE, Susanna ,  ALBRECHT, Volker ,  REISSIG, Hans-ulrich

IPC分类号： C07D487/22 ,  C07F5/02 ,  A61K31/409 ,  A61P35/00

CPC分类号： A61K31/409 ,  A61K31/03 ,  C07D487/22 ,  C07F5/02

摘要： Biologically active compounds that can be used as photosensitizers for diagnostic and therapeutic applications, particularly for PDT of cancer, infections and other hyperproliferative diseases, fluorescence diagnosis and PDT treatment of a non-tumorous indication such as arthritis, inflammatory diseases, viral or bacterial infections, dermatological, opthamological or urological disorders are provided as well as providing methods to obtain them in pharmaceutical quality. One embodiment consists of a method to synthesize a porphyrin with a defined arrangement of meso-substituents and then converting this porphyrin system to a chlorin system by dihydroxylation or reduction, and if more than one isomer is formed separate them by chromatography either on normal or reversed phase silica. In another embodiment the substituents on the porphyrin are selected to direct the reduction or dihydroxylation to the chlorin so that a certain isomer is selectively formed. Another embodiment is to provide amphiphilic compounds with a higher membrane affinity and increased PDT-efficacy. In other embodiments the nucleophilic substitution on pentafluorophenyl-substituted tetrapyrroles is used to obtain compounds with a high PDT-efficacy. In another embodiment substituents are identified that via their steric and/or electronic influence direct the dihydroxylation or reduction with diimine so that one isomer is favored. Another embodiment consists of formulating the desired tetrapyrrole photosensitizer into a pharmaceutical formulation to be injected into the body avoiding undesirable effects like solubility problems or delayed pharmacokinetics of the tetrapyrrole systems.

摘要翻译： 可用作诊断和治疗应用的光敏剂的生物活性化合物，特别是用于癌症的PDT，感染和其他过度增殖性疾病，非肿瘤性适应症如关节炎，炎性疾病，病毒或细菌感染的荧光诊断和PDT治疗， 提供皮肤病，眼科或泌尿系统疾病以及提供获得药物质量的方法。 一个实施方案由合成具有确定的中位取代基的卟啉并随后通过二羟基化或还原将该卟啉体系转化为二氢卟吩体系的方法组成，并且如果形成多于一种异构体，则通过色谱法将其分离为正常或反转 相二氧化硅。 在另一个实施方案中，选择卟啉上的取代基以指导还原或二羟基化成二氢卟酚，从而选择性形成某种异构体。 另一个实施方案是提供具有较高膜亲和性和增加的PDT-功效的两亲化合物。 在其他实施方案中，使用五氟苯基取代的四吡咯上的亲核取代来获得具有高PDT效力的化合物。 在另一个实施方案中，鉴定取代基是通过它们的空间和/或电子影响直接用二亚胺进行二羟基化或还原，以使一种异构体受到青睐。 另一个实施方案包括将所需的四吡咯光敏剂配制成药物制剂以注射到体内，避免不希望的效应，例如四吡咯系统的溶解度问题或延迟的药代动力学。