(4-(2,4-dichlorophenyl)piperazin-1-yl)(morpholino)methanone | 1548116-54-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (4-(2,4-dichlorophenyl)piperazin-1-yl)(morpholino)methanone
• 英文别名: [4-(2,4-Dichlorophenyl)piperazin-1-yl]-morpholin-4-ylmethanone；[4-(2,4-dichlorophenyl)piperazin-1-yl]-morpholin-4-ylmethanone
• CAS: 1548116-54-6
• 化学式: C₁₅H₁₉Cl₂N₃O₂
• 分子量: 344.241
• InChiKey: ZVSJDUNUGMVNIL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  36
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  4-吗啉碳酰氯 在 palladium diacetate 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 18.5h， 生成 (4-(2,4-dichlorophenyl)piperazin-1-yl)(morpholino)methanone
  参考文献：
  名称：

  Morpholylureas are a new class of potent and selective inhibitors of the type 5 17-β-hydroxysteroid dehydrogenase (AKR1C3)

  摘要：

  Inhibitors of the aldo-keto reductase enzyme AKR1C3 are of interest as potential drugs for leukemia and hormone-related cancers. A series of non-carboxylate morpholino(phenylpiperazin-1-yl)methanones were prepared by palladium-catalysed coupling of substituted phenyl or pyridyl bromides with the known morpholino(piperazin-1-yl)methanone, and shown to be potent (IC50 similar to 100 nM) and very isoform-selective inhibitors of AKR1C3. Lipophilic electron-withdrawing substituents on the phenyl ring were positive for activity, as was an H-bond acceptor on the other terminal ring, and the ketone moiety (as a urea) was essential. These structure-activity relationships are consistent with an X-ray structure of a representative compound bound in the AKR1C3 active site, which showed H-bonding between the carbonyl oxygen of the drug and Tyr55 and His117 in the 'oxyanion hole' of the enzyme, with the piperazine bridging unit providing the correct twist to allow the terminal benzene ring to occupy the lipophilic pocket and align with Phe311. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.12.050

文献信息

• [EN] PRODRUG COMPOUNDS ACTIVATED BY AKR1C3 AND THEIR USE FOR TREATING HYPERPROLIFERATIVE DISORDERS<br/>[FR] COMPOSÉS DE TYPE PROMÉDICAMENTS ACTIVÉS PAR AKR1C3 ET LEUR UTILISATION POUR LE TRAITEMENT DE TROUBLES HYPERPROLIFÉRATIFS
  申请人：ACHILLES MEDICAL LTD

  公开号：WO2019190331A1

  公开（公告）日：2019-10-03

  AKR1C3-activated prodrugs of Formula (I), pharmaceutical compositions comprising prodrugs of Formula (I), and their use in the treatment of hyperproliferative diseases such as cancer and for cell ablation. The compounds of the invention are able to penetrate neoplasm tissue and be selectively reduced to an active (cytotoxic) form by contact with an AKR1C3 enzyme found in the neoplasm. This active form is therefore able to ablate AKR1C3-expressing target cells of the neoplasm and therefore has particular utility in the treatment of cancer and other hyperproliferative disorders.

  AKR1C3激活的Formula (I)的前药，包括Formula (I)的前药的药物组合物，以及它们在治疗癌症等高增殖性疾病和细胞消融中的用途。该发明的化合物能够穿透肿瘤组织，并通过与肿瘤中发现的AKR1C3酶接触而选择性地还原为活性（细胞毒性）形式。因此，这种活性形式能够消灭肿瘤中表达AKR1C3的靶细胞，因此在癌症和其他高增殖性疾病的治疗中具有特殊的实用性。
• PRODRUG COMPOUNDS ACTIVATED BY AKR1C3 AND THEIR USE FOR TREATING HYPERPROLIFERATIVE DISORDERS
  申请人：ACHILLES MEDICAL LIMITED

  公开号：US20210115002A1

  公开（公告）日：2021-04-22

  AKR1C3-activated prodrugs of Formula (I), pharmaceutical compositions comprising prodrugs of Formula (I), and their use in the treatment of hyperproliferative diseases such as cancer and for cell ablation. The compounds of the invention are able to penetrate neoplasm tissue and be selectively reduced to an active (cytotoxic) form by contact with an AKR1C3 enzyme found in the neoplasm. This active form is therefore able to ablate AKR1C3-expressing target cells of the neoplasm and therefore has particular utility in the treatment of cancer and other hyperproliferative disorders.
• FLUORINE-CONTAINING COMPOUND AND ANTI-CANCER MEDICAL USE THEREOF
  申请人：ASCENTAWITS PHARMACEUTICALS, LTD.

  公开号：US20220119429A1

  公开（公告）日：2022-04-21

  The present invention provides a fluorine-containing compound shown in Formula II/III and its anti-cancer medical use.
• ANTI-CANCER COMPOUNDS ACTING AS NON-PGP SUBSTRATE
  申请人：ASCENTAWITS PHARMACEUTICALS, LTD.

  公开号：US20220387345A1

  公开（公告）日：2022-12-08

  Provided are anti-cancer compounds which act as a non-PGP substrate, same being compounds of formula I-1, or a pharmaceutically acceptable salt, a prodrug or a solvate thereof, and the medical use of these compounds in the treatment of cancers, tumors, conditions caused by cancers or tumors, or cell proliferative diseases. Also provided is a method for treating cancers, tumors, conditions caused by cancers or tumors, or cell proliferative diseases using the anti-cancer compounds which act as non-PGP substrates as described above.
• Morpholylureas are a new class of potent and selective inhibitors of the type 5 17-β-hydroxysteroid dehydrogenase (AKR1C3)
  作者：Jack U. Flanagan、Graham J. Atwell、Daniel M. Heinrich、Darby G. Brooke、Shevan Silva、Laurent J.M. Rigoreau、Elisabeth Trivier、Andrew P. Turnbull、Tony Raynham、Stephen M.F. Jamieson、William A. Denny

  DOI：10.1016/j.bmc.2013.12.050

  日期：2014.2

  Inhibitors of the aldo-keto reductase enzyme AKR1C3 are of interest as potential drugs for leukemia and hormone-related cancers. A series of non-carboxylate morpholino(phenylpiperazin-1-yl)methanones were prepared by palladium-catalysed coupling of substituted phenyl or pyridyl bromides with the known morpholino(piperazin-1-yl)methanone, and shown to be potent (IC50 similar to 100 nM) and very isoform-selective inhibitors of AKR1C3. Lipophilic electron-withdrawing substituents on the phenyl ring were positive for activity, as was an H-bond acceptor on the other terminal ring, and the ketone moiety (as a urea) was essential. These structure-activity relationships are consistent with an X-ray structure of a representative compound bound in the AKR1C3 active site, which showed H-bonding between the carbonyl oxygen of the drug and Tyr55 and His117 in the 'oxyanion hole' of the enzyme, with the piperazine bridging unit providing the correct twist to allow the terminal benzene ring to occupy the lipophilic pocket and align with Phe311. (C) 2013 Elsevier Ltd. All rights reserved.