SYNTHESIS OF NEW 2(1H) QUINOLONE ANTICONVULSANT DRUGS

描述：（改编自申请人的摘要）PI 建议 设计并合成了几种新的3,4-二氢-2(1H)-喹诺酮类药物 潜在的抗惊厥候选药物，基于观察到的 两种先导化合物的抗惊厥活性，表现出良好的抗惊厥活性 MES（主动抗电诱发癫痫）和抗 PTZ（主动抗癫痫） 对抗戊四氮引起的癫痫发作）活动。 阶段中 研究中，PI 建议测试增强的可行性， 适当的结构操作和合理的合成， 新3-取代和3,3-二取代3,4-的抗惊厥活性 二氢-2(1H)-喹诺酮类。 他计划利用独特且方便的新 合成方法，基于生成和区域选择性 衍生自3,4-二氢-2(1H)-喹诺酮类的N,C3-二价阴离子的反应， 他声称这代表了新的化学技术。 拟议的商业应用： 鉴于受癫痫影响的人数众多 以及有限数量的批准治疗药物 治疗方面，迫切需要开发新的治疗方法 新一代抗癫痫药物（AED），疗效更佳 抗癫痫发作、降低神经毒性和减少有害副作用 影响。正如本 STTR 第一阶段提案中最初概述的那样 项目中，我们目前正在制备多个3,4-的衍生物 二氢-2(1H)-喹诺酮，以评估其潜力 抗惊厥候选药物。这些化合物的生物学筛选 有望让人们对结构有更清晰的了解 其抗惊厥特性所需的要求，以及 其作用机制的可能线索。这反过来又会更加 明确我们的第二阶段研究的综合目标 新型潜在的 AED。我们设计的合成方法 提供低成本、随时获取这些喹诺酮衍生物的途径 生产规模从毫克到公斤，使该技术适合 商业化生产。如果这些新颖、结构简单、易于使用 改良化合物被证明是有效的，具有商业潜力 申请将包括该过程的专利考虑因素和 药物本身及其大规模生产。

DESCRIPTION: (adapted from applicant's abstract) The PI proposes to design and synthesize several new 3,4-dihydro-2(1H)-quinolones as potential anticonvulsant drug candidates, based upon the observed anticonvulsant activity of two lead compounds, which exhibit good anti- MES (active against electrically-induced seizures) and anti-PTZ (active against pentylenetetrazol-induced seizures) activities. In the Phase studies, the PI proposes to test the feasibility of enhancing, by appropriate structural manipulation and rational synthesis, the anticonvulsant activity of new 3-substituted and 3,3-disubstituted 3,4- dihydro-2(1H)-quinolones. He plans to utilize unique and convenient new synthetic methodology, based upon the generation and regioselective reaction of N,C3-dianions derived from 3,4-dihydro-2(1H)-quinolones, which he claims represents new chemical technology. PROPOSED COMMERCIAL APPLICATION: In light of the significant number of people affected by epilepsy as well as the limited number of approved therapeutic agents available for treatment, there is an urgent need to pursue the development of new generation antiepileptic drugs (AEDs) which exhibit greater efficacy against seizures, lower neurotoxicity and fewer deleterious side effects. As originally outlined in the proposal for this STTR Phase I project, we are currently preparing a number of derivatives of 3,4- dihydro-2(1H)-quinolone in order to evaluate their potential as anticonvulsant drug candidates. Biological screening of these compounds is expected to provide a clearer understanding of the structural requirements necessary for their anticonvulsant properties, as well as possible clues to their mechanism of action. This, in turn, will more sharply define our synthetic goals for Phase II investigations of this new class of potential AEDs. The synthetic methodology we have devised provides low-cost, ready access to these quinolone derivatives on any production scale, from mg to kg, making this technology amenable to commercial production. If these novel, structurally simple, and readily modified compounds prove to be efficacious, potential commercial applications would include patent considerations for the process and the drugs themselves, as well as their large-scale manufacture.