[2,4-bis(benzyloxy)-5-isopropenylphenyl]-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone | 1019890-18-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: [2,4-bis(benzyloxy)-5-isopropenylphenyl]-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone
• 英文别名: (2,4-bis(benzyloxy)-5-(prop-1-en-2-yl)phenyl)(5-((4-methylpiperazin-1-yl)methyl)isoindolin-2-yl)methanone；2-(2,4-bis-benzyloxy-5-isopropenylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone；(2,4-Bis-benzyloxy-5-isopropenyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl]-methanone；[2,4-bis(phenylmethoxy)-5-prop-1-en-2-ylphenyl]-[5-[(4-methylpiperazin-1-yl)methyl]-1,3-dihydroisoindol-2-yl]methanone
• CAS: 1019890-18-6
• 化学式: C₃₈H₄₁N₃O₃
• 分子量: 587.762
• InChiKey: QLEJCRVDQBVASY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  44
• 可旋转键数：
  10
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  45.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  [2,4-bis(benzyloxy)-5-isopropenylphenyl]-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone 在 palladium 10% on activated carbon 氢气 、 potassium carbonate 作用下， 以 水 、 异丙醇 为溶剂， 反应 1.17h， 以94%的产率得到[1,3-二氢-5-[(4-甲基-1-哌嗪基)甲基]-2H-异吲哚-2-基][2,4-二羟基-5-(1-甲基乙基)苯基]甲酮
  参考文献：
  名称：

  PHARMACEUTICAL COMPOUNDS

  摘要：

  本发明提供了一种用于药物中的化合物，该化合物是式(VI0)的化合物或其盐、溶剂化物、互变异构体或N-氧化物：其中双环基团：选自结构C1、C5和C6：其中n为0、1、2或3；R1为氢、羟基或O—Rz；R2a为羟基、甲氧基或O—Rz；条件是R1和R2a中至少一个是O—Rz；Rz为Lp-Rp1；SO3H；一个葡萄糖苷酸残基；一个单、二或三肽残基；或Lp为键、C═O、(C═O)O、(C═O)NRp1或S(O)xNRp1；x为1或2；Rp1为氢或一个可选地取代的含0、1或2个碳环和0、1、2、3、4、5或6个碳-碳多重键的C1-25烃基团，条件是当Lp为键、C═O或(C═O)O时，Rp1不是氢；并且还条件是O—Rz不包含O—O部分；并排除R1为羟基且R2a为甲氧基的化合物；Rp2和Rp3相同或不同，且各自为Rp1基团；R3、R4a、R8和R10如权利要求中定义。式(VI0)的化合物是其中R1和/或R2a为羟基的母化合物的前药，其中母化合物具有Hsp90抑制活性。

  公开号：

  US20100152184A1
• 作为产物：
  描述：

  benzyl 2,4-bis(benzyloxy)-5-bromobenzoate 在 4-二甲氨基吡啶 、 水 、 palladium diacetate 、 1-羟基苯并三唑 、 caesium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 lithium hydroxide 、 tri tert-butylphosphoniumtetrafluoroborate 、 2-二环己基磷-2,4,6-三异丙基联苯 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 41.0h， 生成 [2,4-bis(benzyloxy)-5-isopropenylphenyl]-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone
  参考文献：
  名称：

  The succinct synthesis of AT13387, a clinically relevant Hsp90 inhibitor

  摘要：

  AT13387 is an orally bioavailable clinical candidate developed to inhibit heat shock protein 90 (Hsp90). This article describes a modified synthetic route for the multi-gram production of AT13387 in 46% overall yield. The modified synthetic route is short, avoids stringent reaction conditions and difficult purifications, which led to an increase in overall yield.

  DOI：

  10.1080/00397911.2019.1602654

文献信息

• [EN] COMBINATION THERAPY FOR TREATING CANCER<br/>[FR] TRAITEMENT D'ASSOCIATION POUR LE TRAITEMENT DU CANCER
  申请人：PLEX PHARMACEUTICALS INC

  公开号：WO2019014600A1

  公开（公告）日：2019-01-17

  A method of treating cancer comprising administering an effective amount of each of a chemotherapeutic agent and an Hsp90 inhibitor, either separately or as a covalent conjugate of the two, to provide a combination therapy having an enhanced therapeutic effect is described. The Hsp90 inhibitor is capable of also inhibiting TRAP1. Also disclosed are compositions including a chemotherapeutic agent and an Hsp90 inhibitor for nasal delivery.

  一种治疗癌症的方法包括分别或作为两者的共价结合物的方式，向患者施用足够量的化疗药物和Hsp90抑制剂，以提供具有增强治疗效果的联合疗法。Hsp90抑制剂还能抑制TRAP1。还公开了包含化疗药物和Hsp90抑制剂用于鼻腔给药的组合物。
• HYDROBENZAMIDE DERIVATIVES AS INHIBITORS OF HSP90
  申请人：Frederickson Martyn

  公开号：US20110046155A1

  公开（公告）日：2011-02-24

  The invention provides an acid addition salt of a compound of the formula (1) Also provided by the invention are processes for preparing the compound of formula (1) and alkyl analogues thereof, novel intermediates for use in the process and methods for preparing the intermediates. The invention also provides new medical uses of compounds of the formula (1) and its ethyl analogue.

  该发明提供了化合物（1）的酸加成盐。该发明还提供了制备化合物（1）及其烷基类似物的方法，用于该过程的新型中间体以及制备中间体的方法。该发明还提供了化合物（1）及其乙基类似物的新医药用途。
• PHARMACEUTICAL COMBINATIONS
  申请人：Gallagher Neil James

  公开号：US20100092474A1

  公开（公告）日：2010-04-15

  The invention provides combinations comprising (or consisting essentially of) one or more ancillary compound(s) and a compound of the formula (I): or salts, tautomers, solvates and N-oxides thereof; wherein R 1 is hydroxy or hydrogen; R 2 is hydroxy; methoxy or hydrogen; provided that at least one of R 1 and R 2 is hydroxy; R 3 is selected from hydrogen; halogen; cyano; optionally substituted C 1-5 hydrocarbyl and optionally substituted C 1-5 hydrocarbyloxy; R 4 is selected from hydrogen; a group —(O) n —R 7 where n is 0 or 1 and R 7 is an optionally substituted acyclic C 1-5 hydrocarbyl group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and optionally substituted mono- or di-C 1-5 hydrocarbyl-amino; or R 3 and R 4 together form a monocyclic carbocyclic or heterocyclic ring of 5 to 7 ring members; and NR 5 R 6 forms an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 ring members are heteroatoms selected from oxygen, nitrogen and sulphur. The combinations have activity as Hsp90 inhibitors.

  本发明提供的组合物包括（或者基本上由）一种或多种辅助化合物和一个式（I）的化合物组成，或其盐，互变异构体，溶剂化物和N-氧化物；其中R1是羟基或氢原子；R2是羟基，甲氧基或氢原子；至少R1和R2中的一个是羟基；R3选自氢原子，卤素，氰基，可选取代的C1-5烃基和可选取代的C1-5烃氧基；R4选自氢原子，一个—（O）n—R7基团，其中n为0或1，R7是一个可选取代的无环C1-5烃基基团或一个具有3至7个环成员的单环碳环或杂环基团；卤素，氰基，羟基，氨基和可选取代的单一或二元C1-5烃基氨基；或者R3和R4共同形成一个有5至7个环成员的单环碳环或杂环；并且NR5R6形成一个有8至12个环成员的可选取代的双环杂环基团，其中最多有5个环成员是从氧，氮和硫中选取的杂原子。这些组合物具有作为Hsp90抑制剂的活性。
• Pharmaceutical combinations
  申请人：Astex Therapeutics Limited

  公开号：US08277807B2

  公开（公告）日：2012-10-02

  The invention provides combinations comprising (or consisting essentially of) one or more ancillary compound(s) and a compound of the formula (I): or salts, tautomers, solvates and N-oxides thereof; wherein R1 is hydroxy or hydrogen; R2 is hydroxy; methoxy or hydrogen; provided that at least one of R1 and R2 is hydroxy; R3 is selected from hydrogen; halogen; cyano; optionally substituted C1-5 hydrocarbyl and optionally substituted C1-5 hydrocarbyloxy; R4 is selected from hydrogen; a group —(O)n—R7 where n is 0 or 1 and R7 is an optionally substituted acyclic C1-5 hydrocarbyl group or a monocyclic carbocyclic or heterocyclic group having 3 to 7 ring members; halogen; cyano; hydroxy; amino; and optionally substituted mono- or di-C1-5 hydrocarbyl-amino; or R3 and R4 together form a monocyclic carbocyclic or heterocyclic ring of 5 to 7 ring members; and NR5R6 forms an optionally substituted bicyclic heterocyclic group having 8 to 12 ring members of which up to 5 ring members are heteroatoms selected from oxygen, nitrogen and sulphur. The combinations have activity as Hsp90 inhibitors.

  本发明提供了组合物，包括(或基本上由)一个或多个辅助化合物和式(I)的化合物组成：或其盐、互变异构体、溶剂化物和N-氧化物；其中R1是羟基或氢；R2是羟基、甲氧基或氢；但至少其中之一为羟基；R3选择自氢、卤素、氰基、可选取代的C1-5烃基和可选取代的C1-5烃氧基；R4选择自氢、—(O)n—R7基团，其中n为0或1，R7是可选取代的无环C1-5烃基团或具有3至7个环成员的单环碳环或杂环基团；卤素、氰基、羟基、氨基和可选取代的单或双C1-5烃基氨基；或R3和R4共同形成5至7个环成员的单环碳环或杂环环；NR5R6形成8至12个环成员的可选取代的双环杂环基团，其中最多5个环成员为氧、氮和硫的杂原子。这些组合物具有作为Hsp90抑制剂的活性。
• Hydrobenzamide derivatives as inhibitors of Hsp90
  申请人：Frederickson Martyn

  公开号：US08653084B2

  公开（公告）日：2014-02-18

  The invention provides an acid addition salt of a compound of the formula (1) Also provided by the invention are processes for preparing the compound of formula (1) and alkyl analogues thereof, novel intermediates for use in the process and methods for preparing the intermediates. The invention also provides new medical uses of compounds of the formula (1) and its ethyl analogue.

  本发明提供了一种化合物的酸加成盐，该化合物的化学式为（1）。本发明还提供了制备化合物（1）及其烷基类似物的方法，用于该过程的新型中间体以及制备中间体的方法。本发明还提供了化合物（1）及其乙基类似物的新医疗用途。