SYNTHESIS OF NEW 2(1H) QUINOLONE ANTICONVULSANT DRUGS

新型2(1H)喹诺酮类抗惊厥药物的合成

• 批准号: 2536876
• 负责人: Thomas Piccariello
• 金额: $ 10万
• 依托单位: SYNTHONS, INC.
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2536876
• 关键词: anticonvulsants; chemical structure; chemical synthesis; drug design /synthesis /production; heterocyclic compounds; quinoline

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.

描述：(改编自申请人的摘要)私人投资公司建议 新型3，4-二氢-2(1H)-喹诺酮类化合物的设计合成 基于观察到的潜在抗惊厥药物候选 两种具有良好抗惊厥活性的先导化合物 MES(主动抗电诱导癫痫)和ANT-PTZ(主动 抗戊四氮诱发的癫痫发作)活动。在阶段中 在研究中，私人投资委员会建议通过以下方式测试加强 适当的结构操纵和合理的综合， 新的3-取代和3，3-二取代3，4-二取代物的抗惊厥活性 二氢-2(1H)-喹诺酮类药物。他计划利用独特而方便的新技术 综合方法论，基于世代和区域选择 由3，4-二氢-2(1H)-喹诺酮衍生的N，C3-二阴离子的反应， 他声称这代表了新的化学技术。 建议的商业应用： 鉴于受癫痫影响的人数相当多， 以及可用于治疗的经批准的治疗剂数量有限 治疗方面，迫切需要追求新的发展 产生更有效的抗癫痫药物(AEDs) 抗癫痫，更低的神经毒性和更少的有害副作用 效果。正如最初在本STTR第一阶段的提案中所概述的那样 项目，我们目前正在准备一些3，4- 二氢-2(1H)-喹诺酮类药物 抗惊厥药物候选药物。这些化合物的生物筛选 预计将提供对结构的更清晰的理解 对其抗惊厥性能的必要要求，以及 关于它们的作用机制的可能线索。反过来，这将比 明确定义我们的第二阶段调查的综合目标 新一类潜在的AEDs。我们设计的综合方法论 提供低成本、方便的访问这些喹诺酮类衍生物的任何 生产规模，从毫克到公斤，使这项技术符合 商业化生产。如果这些新奇的、结构简单的、容易的 事实证明，改性化合物是有效的，具有潜在的商业价值 申请将包括对该方法的专利考虑和 毒品本身以及它们的大规模制造。