5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(4-formylphenyl)isoxazole-3-carboxylic acid ethylamide | 747414-23-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(4-formylphenyl)isoxazole-3-carboxylic acid ethylamide
• 英文别名: 5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-N-ethyl-4-(4-formylphenyl) isoxazole-3-carboxamide；5-[2,4-Bis(benzyloxy)-5-isopropylphenyl]-N-ethyl-4-(4-formylphenyl)isoxazole-3-carboxamide；5-[2,4-bis(phenylmethoxy)-5-propan-2-ylphenyl]-N-ethyl-4-(4-formylphenyl)-1,2-oxazole-3-carboxamide
• CAS: 747414-23-9
• 化学式: C₃₆H₃₄N₂O₅
• 分子量: 574.676
• InChiKey: JDINHIFHEFLORE-UHFFFAOYSA-N

物化性质

• 沸点：
  722.5±60.0 °C(Predicted)
• 密度：
  1.187±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  43
• 可旋转键数：
  12
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  90.7
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(4-formylphenyl)isoxazole-3-carboxylic acid ethylamide 在 N-羟基-7-氮杂苯并三氮唑 、 sodium cyanoborohydride 、 溶剂黄146 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成
  参考文献：
  名称：

  Design, synthesis and pharmacological evaluation of ALK and Hsp90 dual inhibitors bearing resorcinol and 2,4-diaminopyrimidine motifs

  摘要：

  Rather than by directly focusing on the ever-changing ALK mutants, here we report an alternative strategy to overcome the drug resistance caused by treatment of ALK inhibitors by developing ALK and Hsp90 dual targeting inhibitors. Since Hsp90 is a molecular chaperone that regulates the maturation, activation and stability of numerous "client proteins" including ALK, dual targeting ALK and Hsp90 may bring more benefits and efficacy against drug resistance of ALK inhibitors. By using our previously developed ALK inhibitor 6 and the clinical Hsp90 inhibitors AUY922 or AT13387 as the templates, we developed several series of resorcinol tethered 2,4-diaminopyrimidines as ALK/Hsp90 dual inhibitors bearing various linkers at different linking sites. Compound 10h and 10j showed high potency against ALK (173 vs 9.8 nM) and Hsp90 alpha (100 vs 40 nM). They also have high potency against ALK resistant mutants, especially the gatekeeper mutation ALK(L1196M). Both compounds showed strong antiproliferative activity against the ALK-addictive H3122 cells (11 vs 13 nM). The dual functioning mechanism is further confirmed by their down-regulation of the Hsp90 clients ALK and AICT, and up-regulation of the chaperone protein Hsp70 in H3122 cells. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.04.019
• 作为产物：
  描述：

  4-异丙基苯-1,3-二醇 在 bis-triphenylphosphine-palladium(II) chloride 、 N-溴代丁二酰亚胺(NBS) 、 ammonium cerium (IV) nitrate 、 三氟化硼乙醚 、 盐酸羟胺 、 sodium ethanolate 、 sodium hydride 、 碳酸氢钠 、 potassium carbonate 作用下， 以 甲醇 、 乙醇 、 水 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， 生成 5-(2,4-bis(benzyloxy)-5-isopropylphenyl)-4-(4-formylphenyl)isoxazole-3-carboxylic acid ethylamide
  参考文献：
  名称：

  通过实时 19F NMR 在人细胞中进行基于配体的竞争结合

  摘要：

  开发更有效的药物需要直接在天然细胞环境中了解其生物利用度和结合功效。细胞内核磁共振 （NMR） 波谱是直接研究活细胞中配体-靶标相互作用的强大工具。然而，由于与细胞成分的相互作用，靶分子可能是 NMR 不可见的，而由于细胞背景，通过 1H NMR 观察配体是不切实际的。当氟化配体与细胞内靶标结合时，可以通过 19F 细胞内 NMR 观察它们来克服这些限制。在这里，我们报道了一种基于实时细胞内 19F NMR 的新方法，该方法允许使用氟化化合物作为参考，通过竞争结合来测量人细胞中的配体结合亲和力。研究了一组化合物与 Hsp90α 的结合。原则上，这种方法可以应用于其他药理学相关靶点，从而有助于在药物开发的早期阶段设计更有效的化合物。

  DOI：

  10.1021/acs.jmedchem.3c01600

文献信息

• HSP90 INHIBITORS CONTAINING A ZINC BINDING MOIETY
  申请人：Qian Changgeng

  公开号：US20090076006A1

  公开（公告）日：2009-03-19

  The present invention relates to HSP90 inhibitors containing a zinc binding moiety and their use in the treatment of cell proliferative diseases such as cancer. The said derivatives may further act as HDAC inhibitors.

  本发明涉及含有锌结合基团的HSP90抑制剂及其在治疗细胞增殖性疾病如癌症中的应用。所述衍生物还可能作为HDAC抑制剂。
• [EN] ISOXAZOLE COMPOUNDS AS INHIBITORS OF HEAT SHOCK PROTEINS<br/>[FR] COMPOSES D'ISOXAZOLE UTILES COMME INHIBITEURS DES PROTEINES DE CHOC THERMIQUE
  申请人：VERNALIS CAMBRIDGE LTD

  公开号：WO2004072051A1

  公开（公告）日：2004-08-26

  Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: (A), (B) wherein R1, is a group of formula (IA): -Ar1-(Alk1)p-(Z)r-(Alk2)S-Q, wherein in any compatible combination Ar1 is an optionally substituted aryl or heteroaryl radical, Alk1and Alk2 are optionally substituted divalent Cl-C6 alkylene or C2-C6 alkenylene radicals, p, r and s are independently 0 or 1, Z is -0-, -S-, -(C=O)-, -(C=S)-, -SO2-, -C(=O)O-, -C(=O)NRA-, -C(=S)NRA-, - SO2NRA-, -NRAC(=O)-, -NRASO2- or -NRA- wherein RA is hydrogen or Cl-C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R2 is (i) a group of formula (IA) above or (ii) a carboxamide radical; or (iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk1)p-(Z)r-(Alk2)s-Q wherein Q, Alk1, Alk2, Z, p, r and s are as defined above in relation to group (IA); and R3 is hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

  式(A)或(B)的异唑唑烷是HSP90活性的抑制剂，可用于治疗癌症等疾病：其中R1是式(IA)的一个基团：-Ar1-(Alk1)p-(Z)r-(Alk2)S-Q，其中在任何兼容的组合中，Ar1是可选择地取代的芳基或杂环基团，Alk1和Alk2是可选择地取代的二价Cl-C6烷基或C2-C6烯基基团，p、r和s独立地为0或1，Z是-0-，-S-，-(C=O)-，-(C=S)-，-SO2-，-C(=O)O-，-C(=O)NRA-，-C(=S)NRA-，-SO2NRA-，-NRAC(=O)-，-NRASO2-或-NRA-，其中RA是氢或Cl-C6烷基，Q是氢或一个可选择地取代的脂环或杂环基团；R2是(i)上述式(IA)的一个基团或(ii)一个羧酰胺基团；或(iii)一个非芳香的脂环或杂环环，其中一个环碳原子可选择地取代，和/或一个环氮原子可选择地被一个式-(Alk1)p-(Z)r-(Alk2)s-Q的基团取代，其中Q、Alk1、Alk2、Z、p、r和s如上所述与式(IA)相关的基团定义；R3是氢，可选择地取代的环烷基、环烯烃基、C1-C6烷基、C1-C6烯基或C1-C6炔基；或一个羧基、羧酰胺基或羧酸酯基团。
• Isozazole Compounds As Inhibitors Of Heat Shock Proteins
  申请人：Drysdale Martin James

  公开号：US20100179138A1

  公开（公告）日：2010-07-15

  Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: wherein R 1 , is a group of formula (IA): —Ar 1 -(Alk 1 ) p -(Z) r -(Alk 2 ) s -Q, wherein in any compatible combination Ar 1 is an optionally substituted aryl or heteroaryl radical, Alk 1 and Alk 2 are optionally substituted divalent C 1 -C 6 alkylene or C 2 -C 6 alkenylene radicals, p, r and s are independently 0 or 1, Z is -0-, —S—, —(C═O)—, —(C═S)—, —SO.sub.2-, —C(═O)O—, —C(═O)NR A —, —C(═S)NR A —, —SO 2 NR A —, —NR A C(═O)—, —NR A SO 2 —or —NR A — wherein R A is hydrogen or C 1 -C 6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R 2 is (i) a group of formula (IA) above or (ii) a carboxamide radical; or (iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk 1 ) p -(Z) r -(Alk 2 ) s -Q wherein Q, Alk 1 , Alk 2 , Z, p, r and s are as defined above in relation to group (IA); and R 3 is hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, or C 1 -C 6 alkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

  式（A）或（B）的异噁唑是HSP90活性的抑制剂，可用于治疗癌症，例如：其中R1是以下式（IA）的基团：—Ar1-(Alk1)p-(Z)r-(Alk2)s-Q，其中在任何兼容的组合中，Ar1是可选取代的芳基或杂环芳基基团，Alk1和Alk2是可选取代的二价C1-C6烷基或C2-C6烯基基团，p，r和s独立地为0或1，Z为-0-，—S—，—（C═O）—，—（C═S）—，—SO.sub.2-，—C（═O）O—，—C（═O）NRA—，—C（═S）NRA—，—SO2NRA—，—NRAC（═O）—，—NRASO2—或—NRA—，其中RA为氢或C1-C6烷基，并且Q为氢或可选取代的碳环或杂环基团；R2为（i）上述式（IA）的基团或（ii）一个羧酰胺基团；或（iii）一个非芳香碳环或杂环环，其中一个环碳原子可选取代，和/或一个环氮原子可选取代为以下式的基团-(Alk1)p-(Z)r-(Alk2)s-Q，其中Q，Alk1，Alk2，Z，p，r和s如上所述定义于基团（IA）；和R3为氢，可选取代的环烷基，环烯基，C1-C6烷基，C1-C6烯基或C1-C6炔基；或羧基，羧酰胺基或羧酸酯基。
• Isoxazole compounds as inhibitors of heat shock proteins
  申请人：Vernalis (R&D) Ltd.

  公开号：US10413550B2

  公开（公告）日：2019-09-17

  Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: wherein R1, is a group of formula (IA): —Ar1-(Alk1)p-(Z)r-(Alk2)s-Q, wherein in any compatible combination Ar1 is an optionally substituted aryl or heteroaryl radical, Alk1 and Alk2 are optionally substituted divalent C1-C6 alkylene or C2-C6 alkenylene radicals, p, r and s are independently 0 or 1, Z is —O—, —S—, —(C═O)—, —(C═S)—, —SO.sub.2-, —C(═O)O—, —C(═O)NRA—, —C(═S)NRA—, —SO2NRA—, —NRAC(═O)—, —NRASO2— or —NRA— wherein RA is hydrogen or C1-C6 alkyl, and Q is hydrogen or an optionally substituted carbocyclic or heterocyclic radical; R2 is (i) a group of formula (IA) above or (ii) a carboxamide radical; or (iii) a non aromatic carbocyclic or heterocyclic ring wherein a ring carbon is optionally substituted, and/or a ring nitrogen is optionally substituted by a group of formula -(Alk1)p-(Z)r-(Alk2)s-Q wherein Q, Alk1, Alk2, Z, p, r and s are as defined above in relation to group (IA); and R3 is hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C1-C6 alkyl, C1-C6 alkenyl, or C1-C6 alkynyl; or a carboxyl, carboxamide, or carboxyl ester group.

  式（A）或（B）的异噁唑是 HSP90 活性的抑制剂，可用于治疗癌症等： -C(═O)O-、-C(═O)NRA-、-C(═S)NRA-、-SO2NRA-、-NRAC(═O)-、-NRASO2- 或 -NRA-，其中 RA 是氢或 C1-C6 烷基，Q 是氢或任选取代的碳环或杂环基；R2 是 (i) 上式 (IA) 的基团或 (ii) 羧酰胺基；或 (iii) 非芳香碳环或杂环，其中环碳任选被式-(Alk1)p-(Z)r-(Alk2)s-Q 的基团取代，和/或环氮任选被式-(Alk1)p-(Z)r-(Alk2)s-Q 的基团取代，其中 Q、Alk1、Alk2、Z、p、r 和 s 如上文有关基团 (IA) 的定义；和 R3 是氢、任选取代的环烷基、环烯基、C1-C6 烷基、C1-C6 烯基或 C1-C6 烷炔基；或羧基、羧酰胺或羧基酯基团。
• 4,5-Diarylisoxazole Hsp90 Chaperone Inhibitors: Potential Therapeutic Agents for the Treatment of Cancer
  作者：Paul A. Brough、Wynne Aherne、Xavier Barril、Jenifer Borgognoni、Kathy Boxall、Julie E. Cansfield、Kwai-Ming J. Cheung、Ian Collins、Nicholas G. M. Davies、Martin J. Drysdale、Brian Dymock、Suzanne A. Eccles、Harry Finch、Alexandra Fink、Angela Hayes、Robert Howes、Roderick E. Hubbard、Karen James、Allan M. Jordan、Andrea Lockie、Vanessa Martins、Andrew Massey、Thomas P. Matthews、Edward McDonald、Christopher J. Northfield、Laurence H. Pearl、Chrisostomos Prodromou、Stuart Ray、Florence I. Raynaud、Stephen D. Roughley、Swee Y. Sharp、Allan Surgenor、D. Lee Walmsley、Paul Webb、Mike Wood、Paul Workman、Lisa Wright

  DOI：10.1021/jm701018h

  日期：2008.1.1

  Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.