3,4-bis(N-fumaryl-N-(n-butyl)amino)-2,5-diketopiperazine | 294659-59-9

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 3,4-bis(N-fumaryl-N-(n-butyl)amino)-2,5-diketopiperazine
• 英文别名: FDKP；2,5-diketo-3,6-di(4-fumarylaminobutyl)piperazine；Fumaryldiketopiperazine；(E)-4-[4-[5-[4-[[(E)-3-carboxyprop-2-enoyl]amino]butyl]-3,6-dioxopiperazin-2-yl]butylamino]-4-oxobut-2-enoic acid
• CAS: 294659-59-9
• 化学式: C₂₀H₂₈N₄O₈
• 分子量: 452.464
• InChiKey: BBNKIRVUCQNAQR-FIFLTTCUSA-N

物化性质

• 沸点：
  945.5±65.0 °C(Predicted)
• 密度：
  1.281±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.9
• 重原子数：
  32
• 可旋转键数：
  14
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  191
• 氢给体数：
  6
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  、 3,4-bis(N-fumaryl-N-(n-butyl)amino)-2,5-diketopiperazine 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 生成
  参考文献：
  名称：

  [EN] FUMARYL DIKETOPIPERIDINE PRODRUGS OF TREPROSTINIL
  [FR] PROMÉDICAMENTS À BASE DE FUMARYLE DICÉTOPIPÉRIDINE DE TRÉPROSTINIL

  摘要：

  Provided are novel treprostinil based compounds, methods of treatment using the same, and their methods of making.

  公开号：

  WO2021252446A1
• 作为产物：
  描述：

  三氟乙酰赖氨酸 在 N-羟基丁二酰亚胺 、 四磷十氧化物 、 水 、 sodium hydroxide 作用下， 以 N-甲基吡咯烷酮 、 甲醇 为溶剂， 反应 31.5h， 生成 3,4-bis(N-fumaryl-N-(n-butyl)amino)-2,5-diketopiperazine
  参考文献：
  名称：

  Azithromycin-loaded respirable microparticles for targeted pulmonary delivery for the treatment of pneumonia

  摘要：

  Pneumonia is a major contributor to infection-based hospitalizations and deaths in the United States. Antibiotics such as azithromycin (AZM), although effective at managing pneumonia, often suffer from off-target diffusion and poor bioavailability when administered orally or via intravenous injection. The formation of biofilms at the disease sites makes the treatment more complicated by protecting bacteria from antimicrobial agents and thus necessitating a much higher dosage of antibiotics to eradicate the biofilms. As such, targeted pulmonary delivery of antibiotics has emerged as a promising alternative by providing direct access to the lung while also allowing higher local therapeutic concentrations but minimal systemic exposure. In this study, AZM was encapsulated in N-fumaroylated diketopiperazine (FDKP) microparticles for efficient pulmonary delivery. Both in vitro and in vivo results demonstrated that AZM@FDKP-MPs administered via intratracheal insufflation achieved at least a 3.4 times higher local concentration and prolonged retention times compared to intravenous injection and oral administration, suggesting their potential to better manage bacterial pneumonia. (C) 2018 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.biomaterials.2018.01.022

文献信息

• Pulmonary delivery of inhibitors of phosphodiesterase type 5
  申请人：Cheatham Wendell Wayman

  公开号：US20060099269A1

  公开（公告）日：2006-05-11

  Provided herein are compositions of 1) diketopiperazine salts of PDE5 inhibitors, and 2) DKP microparticles having a PDE5 inhibitors thereon, as well as methods for the pulmonary delivery of these compositions for the treatment of pulmonary hypertension and sexual dysfunction(s).

  本文提供了1）磷酸二酮肽盐的PDE5抑制剂组合物，以及2）DKP微粒具有PDE5抑制剂，以及用于将这些组合物经肺部递送以治疗肺动脉高压和性功能障碍的方法。
• Methods for the synthesis of activated ethylfumarates and their use as intermediates
  申请人：Kraft Kelly Sullivan

  公开号：US20130289278A1

  公开（公告）日：2013-10-31

  Disclosed embodiments relate to improved methods for the synthesis of activated fumarate intermediates and their use in chemical synthesis. Disclosed embodiments describe the synthesis of activated fumarate esters including those derived from activating groups including: 4-nitrophenyl, diphenylphosphoryl azide, pivaloyl chloride, chlorosulfonyl isocyanate, p-nitrophenol, MEF, trifluoroacetyl and chlorine, for example, ethyl fumaroyl chloride and the subsequent use of the activated ester in situ. Further embodiments describe the improved synthesis of substituted aminoalkyl-diketopiperazines from unisolated and unpurified intermediates allowing for improved yields and reactor throughput.

  揭示的实施例涉及改进的方法，用于合成活性富马酸中间体，并将其用于化学合成。揭示的实施例描述了活化富马酸酯的合成，包括那些来自激活基团的酯，例如：4-硝基苯基、二苯基磷酸酰叠氮化物、皮瓦酰氯、氯磺酰异氰酸酯、对硝基苯酚、MEF、三氟乙酰和氯等，例如，乙酰基富马酰氯和随后在原位使用活化酯。进一步的实施例描述了从未分离和未纯化的中间体改进合成取代氨基烷基二酮哌嗪，从而实现了更高的产量和反应器吞吐量。
• HEAT-STABLE DRY POWDER PHARMACEUTICAL COMPOSITIONS AND METHODS
  申请人：MANNKIND CORPORATION

  公开号：US20160158156A1

  公开（公告）日：2016-06-09

  Disclosed herein are heat-stable dry powders which include peptides or protein such as oxytocin for use as a pharmaceutical composition. The composition is highly stable at increased temperatures and relatively high humid environments, and are intended for storage at room temperature with an improved shelf-life. In particular, the dry powders are intended for inhalation, however, other routes of administration can be used when reconstituted in solution.

  本文披露了一种热稳定的干粉，其中包括肽或蛋白质，例如催产素，用作药物组合物。该组合物在高温和相对高湿度环境下非常稳定，并且旨在在室温下存储，具有改进的保质期。特别是，这些干粉旨在用于吸入，但是在溶液中重构时可以使用其他给药途径。
• A dry powder inhaler and system for drug delivery
  申请人：MannKind Corporation

  公开号：EP2567723A1

  公开（公告）日：2013-03-13

  A breath powered dry powder inhaler configured to deliver particles to the pulmonary circulation of a subject comprises a chamber for containing the particles and a mouthpiece. Portions of the inhaler define a flow path leading from at least one inlet (119) to said chamber through said chamber and through at least one outlet (127) from said chamber to the mouthpiece. The at least one inlet and the at least one outlet are further configured so that air from the at least one inlet is directed across said at least one outlet and controls exit from the chamber of powder entrained within the flow. In embodiments the at least one inlet (119), the at least one outlet (127) and the chamber are configured so that in use air entering the chamber circulates within the chamber for promoting entrainment and lifting of a powder in the chamber. In these embodiments the inlet may define a first direction for air entry into the chamber, the outlet may define a second direction generally perpendicular to the first direction for air and powder leaving the chamber, and the inlet (119), outlet (127) and chamber may be configured so that in use air within the chamber circulates about an axis directed generally perpendicular to the first and generally perpendicular to the second direction. The chamber may contain a cohesive powder e.g. a diketopiperazine, and the powder may contain insulin or another medicament.

  一种呼吸驱动的干粉吸入器配置用于将微粒输送到受试者的肺循环中，该吸入器包括一个用于容纳微粒的腔室和一个口罩。吸入器的部分限定了一条流路，从至少一个入口（119）通过所述腔室，并从至少一个出口（127）通过所述腔室到达口罩。至少一个入口和至少一个出口进一步配置成使来自至少一个入口的空气穿过所述至少一个出口，并控制气流中夹带的粉末从腔室中流出。在实施例中，至少一个入口 (119)、至少一个出口 (127) 和腔室被配置成在使用中使进入腔室的空气在腔室内循环，以促进腔室内粉末的夹带和提升。在这些实施例中，进气口可确定空气进入腔室的第一方向，出气口可确定空气和粉末离开腔室的大致垂直于第一方向的第二方向，进气口 (119)、出气口 (127) 和腔室可配置成在使用中使腔室内的空气围绕大致垂直于第一方向和大致垂直于第二方向的轴线循环。腔体内可含有粘性粉末，例如二酮哌嗪，粉末中可含有胰岛素或其他药物。
• METHOD FOR CRYOGRANULATING A PHARMACEUTICAL COMPOSITION
  申请人：MannKind Corporation

  公开号：EP3533517A1

  公开（公告）日：2019-09-04

  Cryogranulation systems with improved dispenser assemblies are provided for use in manufacturing frozen pellets of pharmaceutical substances in a fluid medium. Methods of cryogranulating the pharmaceutical substance in the fluid medium are also provided. In particular embodiments, the dispenser assembly is used with suspensions or slurries of pharmaceutical compositions including biodegradable substances, such as proteins, peptides, and nucleic acids. In certain embodiments, the pharmaceutical substance can be adsorbed to any pharmaceutically acceptable carrier particles suitable for making pharmaceutical powders. In one embodiment, the pharmaceutical carrier can be, for example, diketopiperazine-based microparticles. The dispenser assembly improves the physical characteristics of the cryopellets formed and minimizes product loss during processing.

  冷冻造粒系统具有改进的分配器组件，可用于制造流体介质中药物的冷冻颗粒。此外，还提供了在流体介质中冷冻药物的方法。在特定的实施例中，分配器组件用于药物组合物的悬浮液或浆液，包括可生物降解的物质，如蛋白质、肽和核酸。在某些实施例中，可将药物物质吸附到任何适合制作药粉的药学上可接受的载体颗粒上。在一个实施例中，药用载体可以是例如基于二酮哌嗪的微颗粒。分配器组件可改善所形成的冷冻颗粒的物理特性，并最大程度地减少加工过程中的产品损失。