(4R,5S,6S,7R)-5,6-二羟基-1,3-二[[4-(羟基甲基)苯基]甲基]-4,7-二(苯基甲基)-1,3-二氮杂环庚-2-酮 | 151867-81-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: (4R,5S,6S,7R)-5,6-二羟基-1,3-二[[4-(羟基甲基)苯基]甲基]-4,7-二(苯基甲基)-1,3-二氮杂环庚-2-酮
• 英文名称: DMP 323
• 英文别名: DMP323；DMP-323；[4R-(4α, 5α, 6β, 7β)]-hexahydro-5,6-bis (hydroxy)-1,3-bis ([(4-hydroxymethyl)phenyl]methyl)-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one；(4r,5s,6s,7r)-4,7-Dibenzyl-5,6-dihydroxy-1,3-bis[4-(hydroxymethyl)benzyl]-1,3-diazepan-2-one；(4R,5S,6S,7R)-4,7-dibenzyl-5,6-dihydroxy-1,3-bis[[4-(hydroxymethyl)phenyl]methyl]-1,3-diazepan-2-one
• CAS: 151867-81-1
• 化学式: C₃₅H₃₈N₂O₅
• 分子量: 566.697
• InChiKey: XCVGQMUMMDXKCY-WZJLIZBTSA-N

物化性质

• 沸点：
  798.6±60.0 °C(Predicted)
• 密度：
  1.294±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  42
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  105
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (4R,5S,6S,7R)-5,6-二羟基-1,3-二[[4-(羟基甲基)苯基]甲基]-4,7-二(苯基甲基)-1,3-二氮杂环庚-2-酮 在 四氮唑 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 0.83h， 生成 Phosphoric acid di-tert-butyl ester 4-{(4R,5S,6S,7R)-4,7-dibenzyl-3-[4-(di-tert-butoxy-phosphoryloxymethyl)-benzyl]-5,6-dihydroxy-2-oxo-[1,3]diazepan-1-ylmethyl}-benzyl ester
  参考文献：
  名称：

  Synthesis of water soluble prodrug of DMP323

  摘要：

  A water soluble bisphosphate prodrug of DMP323 was synthesized from DMP323. Pharmacokinetic studies of the prodrug indicate that it is orally absorbed as the parent drug, after hydrolysis of the phosphate ester in the gastrointestinal tract. Copyright (C) 1996 The DuPont Merck Pharmaceutical Company. Published by Elsevier Science Ltd

  DOI：

  10.1016/0960-894x(96)00391-5
• 作为产物：
  描述：

  N-苄氧羰基-D-苯丙氨酸 在 palladium dihydroxide N-甲基吗啉 、 盐酸 、 lithium aluminium tetrahydride 、 [VCl3(thf)3] 、 铜 、 sodium hydride 、 N,N-二异丙基乙胺 、 锌 、 环己烯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 97.25h， 生成 (4R,5S,6S,7R)-5,6-二羟基-1,3-二[[4-(羟基甲基)苯基]甲基]-4,7-二(苯基甲基)-1,3-二氮杂环庚-2-酮
  参考文献：
  名称：

  Preparation and Structure−Activity Relationship of Novel P1/P1‘-Substituted Cyclic Urea-Based Human Immunodeficiency Virus Type-1 Protease Inhibitors

  摘要：

  A series of novel P1/P1'-substituted cyclic urea-based HIV-1 protease inhibitors was prepared. Three different synthetic schemes were used to assemble these compounds. The first approach uses amino acid-based starting materials and was originally used to prepare DMP 323. The other two approaches use L-tartaric acid or L-mannitol as the starting material. The required four contiguous R,S,S,R centers of the cyclic urea scaffold are introduced using substrate control methodology. Each approach has specific advantages based on the desired P1/P1' substituent. Designing analogs based on the enzyme's natural substrates provided compounds with reduced activity. Attempts at exploiting hydrogen bond sites in the S1/S1' pocket, suggested by molecular modeling studies, were not fruitful. Several analogs had better binding affinity compared to our initial leads. Modulating the compound's physical properties led to a 10-fold improvement in translation resulting in better overall antiviral activity.

  DOI：

  10.1021/jm960083n

文献信息

• Stereoselective Synthesis of HIV-1 Protease Inhibitor, DMP 323
  作者：Michael E. Pierce、Gregory D. Harris、Qamrul Islam、Lilian A. Radesca、Louis Storace、Robert E. Waltermire、Ed Wat、Prabhakar K. Jadhav、George C. Emmett

  DOI：10.1021/jo951847u

  日期：1996.1.1

  DMP 323, a potent HIV-1 protease inhibitor, has been synthesized by an efficient stereoselective process, amenable to large scale preparations. The core C(2) symmetric diol was synthesized by a stereoselective pinacol coupling of CBZ protected D-phenylalanine. Judicious selection of protecting groups allowed cyclic urea formation under mild conditions, enhanced the ease of bis-alkylation, and led to

  DMP 323是一种有效的HIV-1蛋白酶抑制剂，已经通过有效的立体选择性方法合成，适用于大规模制备。核心的C（2）对称二醇是由CBZ保护的D-苯丙氨酸的立体选择性频哪醇偶联合成的。明智地选择保护基团可以在温和条件下形成环状脲，增强了双烷基化的难度，并导致了无需色谱即可轻松纯化的中间体。另外，开发了一种单锅高产率方法，以从1，4-苯二甲醇制备烷基化剂4-[（（三苯基甲氧基）甲基]苄基氯。
• Cyclic HIV Protease Inhibitors:  Synthesis, Conformational Analysis, P2/P2‘ Structure−Activity Relationship, and Molecular Recognition of Cyclic Ureas
  作者：Patrick Y. S. Lam、Yu Ru、Prabhakar K. Jadhav、Paul E. Aldrich、George V. DeLucca、Charles J. Eyermann、Chong-Hwan Chang、George Emmett、Edward R. Holler、Wayne F. Daneker、Liangzhu Li、Pat N. Confalone、Robert J. McHugh、Qi Han、Renhua Li、Jay A. Markwalder、Steven P. Seitz、Thomas R. Sharpe、Lee T. Bacheler、Marlene M. Rayner、Ronald M. Klabe、Linyee Shum、Dean L. Winslow、David M. Kornhauser、David A. Jackson、Susan Erickson-Viitanen、C. Nicholas Hodge

  DOI：10.1021/jm9602571

  日期：1996.1.1

  X-ray structures of the complexes of HIV-1 protease (HIV-1PR) with peptidomimetic inhibitors reveal the presence of a structural water molecule which is hydrogen bonded to both the mobile flaps of the enzyme and the two carbonyls flanking the transition-state mimic of the inhibitors. Using the structure-activity relationships of C2-symmetric diol inhibitors, computed-aided drug design tools, and first

  HIV-1蛋白酶（HIV-1PR）与拟肽抑制剂的复合物的高分辨率X射线结构揭示了结构水分子的存在，该结构水分子氢键合到酶的可移动侧翼和过渡过渡带两侧的两个羰基上态的抑制剂。利用C2对称二醇抑制剂的结构活性关系，计算机辅助药物设计工具和第一原理，我们设计并合成了新型的环状脲，其结合了该结构水并将侧链残基预先组织为最佳结合构象。构象分析表明对伪双轴苄基和伪二季基羟基取代基的偏爱和对RSSR立体化学的对映体偏爱。HIV-1PR和一种环状尿素DMP323的配合物的X射线和溶液NMR结构证实了结构水的置换。另外，结合的和“未结合的”（小分子X射线）配体具有相似的构象。提出了高度的预组织，互补性和水置换的熵增益，以解释这些小分子对酶的高度亲和力。小尺寸可能有助于在动物中观察到良好的口服生物利用度。基于结构优化的侧链填充酶的S2和S2'口袋产生了DMP323，该药物已在I期临床试验中进行了研究，但发现其
• [EN] PROCESS FOR THE PREPARATION OF ALDEHYDES<br/>[FR] PROCÉDÉ DE PRÉPARATION D'ALDÉHYDES
  申请人：LONZA AG

  公开号：WO2009003661A1

  公开（公告）日：2009-01-08

  The present invention is related to a method for the production of an aldehyde by reducing an ester of a carboxylic acid with H-DIBAL (diisobutylaluminium hydride).

  本发明涉及一种通过使用H-DIBAL（双异丁基铝氢化物）还原羧酸酯来生产醛的方法。
• Solid pharmaceutical dosage form
  申请人：Abbott Laboratories

  公开号：US08268349B2

  公开（公告）日：2012-09-18

  A solid pharmaceutical dosage form providing improved oral bioavailability is disclosed for inhibitors of HIV protease. In particular, the dosage form comprises a solid dispersion of at least one HIV protease inhibitor and at least one pharmaceutically acceptable water-soluble polymer and at least one pharmaceutically acceptable surfactant, said pharmaceutically acceptable water-soluble polymer having a Tg of at least about 50° C. Preferably, the pharmaceutically acceptable surfactant has an HLB value of from about 4 to about 10.

  本发明揭示了一种提供改善口服生物利用度的固体制剂，用于HIV蛋白酶抑制剂。特别地，该制剂包括至少一种HIV蛋白酶抑制剂和至少一种药用可接受的水溶性聚合物以及至少一种药用可接受的表面活性剂的固态分散体，其中所述的药用可接受的水溶性聚合物具有至少约50°C的Tg。优选地，所述的药用可接受的表面活性剂具有约4至约10的HLB值。
• Solid Pharmaceutical Dosage Form
  申请人：Rosenberg Jöerg

  公开号：US20120202858A1

  公开（公告）日：2012-08-09

  A solid pharmaceutical dosage form providing improved oral bioavailability is disclosed for inhibitors of HIV protease. In particular, the dosage form comprises a solid dispersion of at least one HIV protease inhibitor and at least one pharmaceutically acceptable water-soluble polymer and at least one pharmaceutically acceptable surfactant, said pharmaceutically acceptable water-soluble polymer having a Tg of at least about 50° C. Preferably, the pharmaceutically acceptable surfactant has an HLB value of from about 4 to about 10.

  本发明揭示了一种用于HIV蛋白酶抑制剂的固体制剂，提供了改善口服生物利用度的效果。特别地，该剂型包括至少一种HIV蛋白酶抑制剂和至少一种药用可接受的水溶性聚合物以及至少一种药用可接受的表面活性剂的固体分散体，其中所述药用可接受的水溶性聚合物具有至少约50℃的Tg。优选地，所述药用可接受的表面活性剂的HLB值在约4到约10之间。