2-(4-hydroxy-3-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinoline | 912998-98-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 2-(4-hydroxy-3-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinoline
• 英文别名: (3,4-dihydro-1H-isoquinolin-2-yl)-(4-hydroxy-3-isopropyl-phenyl)-methanone；3,4-dihydro-1H-isoquinolin-2-yl-(4-hydroxy-3-propan-2-ylphenyl)methanone
• CAS: 912998-98-2
• 化学式: C₁₉H₂₁NO₂
• 分子量: 295.381
• InChiKey: VMHRONMVQTZRED-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  40.5
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  四氢异喹啉 、 3-异丙基-4-羟基苯甲酸 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 2-(4-hydroxy-3-isopropylbenzoyl)-1,2,3,4-tetrahydroisoquinoline
  参考文献：
  名称：

  Fragment-Based Drug Discovery Applied to Hsp90. Discovery of Two Lead Series with High Ligand Efficiency

  摘要：

  Inhibitors of the chaperone Hsp90 are potentially useful as chemotherapeutic agents in cancer. This paper describes an application of fragment screening to Hsp90 using a combination of NMR and high throughput X-ray crystallography. The screening identified an aminopyrimidine with affinity in the high micromolar range and subsequent structure-based design allowed its optimization into a low nanomolar series with good ligand efficiency. A phenolic chemotype was also identified in fragment screening and was found to bind with affinity close to 1 mM. This fragment was optimized using structure based design into a resorcinol lead which has subnanomolar affinity for Hsp90, excellent cell potency, and good ligand efficiency. This fragment to lead campaign improved affinity for Hsp90 by over 1,000,000-fold with the addition of only six heavy atoms. The companion paper (DOI: 10.1021/jm100060b) describes how the resorcinol lead was optimized into a compound that is now in clinical trials for the treatment of cancer.

  DOI：

  10.1021/jm100059d

文献信息

• PHARMACEUTICAL COMPOUNDS
  申请人：Congreve Miles Stuart

  公开号：US20100152184A1

  公开（公告）日：2010-06-17

  The invention provides a compound for use in medicine, the compound being a compound of the formula (VI 0 ) or a salt, solvate, tautomer or N-oxide thereof: wherein the bicyclic group: is selected from the structures C1, C5 and C6: wherein n is 0, 1, 2 or 3; R 1 is hydrogen, hydroxy, or O—R z ; R 2a is hydroxy, methoxy or O—R z ; provided that at least one of R 1 and R 2a is O—R z ; R z is L p -R p1 ; SO 3 H; a glucuronide residue; a mono-, di- or tripeptide residue; or L p is a bond, C═O, (C═O)O, (C═O)NR p1 or S(O) x NR p1 ; x is 1 or 2; R p1 is hydrogen or a an optionally substituted C 1-25 hydrocarbyl group containing 0, 1 or 2 carbocyclic rings and 0, 1, 2, 3, 4, 5 or 6 carbon-carbon multiple bonds, provided that R p1 is not hydrogen when L p is a bond, C═O or (C═O)O; and provided also that O—R z does not contain an O—O moiety; and excluding compounds wherein R 1 is hydroxy and R 2a is methoxy; R p2 and R p3 are the same or different and each is a group R p1 ; and R 3 , R 4a , R 8 and R 10 are defined in the claims. The compounds of formula (VI 0 ) are pro-drugs of parent compounds wherein R 1 and/or R 2a are hydroxy, wherein the parent compounds have Hsp90 inhibiting activity.

  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。
• Hydroxybenzamide derivatives and their use as inhibitors of HSP90
  申请人：Chessari Gianni

  公开号：US20090215772A1

  公开（公告）日：2009-08-27

  The invention provides compounds 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 hydrocarbylamino; 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 compounds have activity as Hsp90 inhibitors.

  该发明提供了公式（I）的化合物：或其盐，互变异构体，溶剂化合物和N-氧化物；其中R1为羟基或氢；R2为羟基，甲氧基或氢；但至少其中一个为羟基；R3选自氢，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选自氢，一个群组-（O）n-R7，其中n为0或1，R7为可选取代的无环C1-5烃基或具有3至7个环成员的单环碳环或杂环基；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；NR5R6形成一个具有8至12个环成员的可选取代的双环杂环基，其中最多5个环成员为氧，氮和硫的杂原子。这些化合物具有作为Hsp90抑制剂的活性。
• DIHYDROXYPHENYL ISOINDOLYLMETHANONES
  申请人：Chessari Gianni

  公开号：US20070259886A1

  公开（公告）日：2007-11-08

  Compounds having the formula (I): and in particular, those of subgenus VIIa are disclosed as inhibits or modulators of the activity of the heat shock protein Hsp90. As such they are useful for treating cancer, particularly hematopoietic tumors of lymphoid or myeloid lineage, prostate cancer, lung cancer, gastrointestinal stromal tumor, breast cancer and melanoma.

  具有公式(I)的化合物，特别是VIIa亚属的化合物，被披露为热休克蛋白Hsp90的抑制剂或调节剂。因此，它们可用于治疗癌症，特别是淋巴或骨髓系的造血肿瘤、前列腺癌、肺癌、胃肠间质瘤、乳腺癌和黑色素瘤。
• Hydroxybenzamide Derivatives And Their Use As Inhibitors Of HSP90
  申请人：Chessari Gianni

  公开号：US20070259871A1

  公开（公告）日：2007-11-08

  The invention provides compounds 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 compounds have activity as Hsp90 inhibitors.

  该发明提供了式(I)的化合物或其盐、互变异构体、溶剂合物和N-氧化物；其中R1为羟基或氢；R2为羟基、甲氧基或氢；但至少其中一个为羟基；R3选择氢、卤素、氰基、可选取代的C1-5烃基或可选取代的C1-5烃氧基；R4选择氢、—(O)n—R7基团，其中n为0或1，R7为可选取代的非环C1-5烃基或有3至7个环成员的单环碳环或杂环基团；还可以选择卤素、氰基、羟基、氨基和可选取代的单基或双基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；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个环成员为氧、氮和硫的杂原子。这些化合物具有作为Hsp90抑制剂的活性。
• Therapeutic Combinations Of Hydroxybenzamide Derivatives As Inhibitors Of HSP90
  申请人：Chessari Gianni

  公开号：US20120251545A1

  公开（公告）日：2012-10-04

  The invention provides a combination comprising an Hsp90 inhibitor compound of the formula (VII): or tautomer or salt thereof and one or more therapeutic agents selected from topoisomerase I inhibitors; antimetabolites; tubulin targeting agents; DNA binder and topoisomerase II inhibitors; alkylating agents; monoclonal antibodies; anti-hormones; signal transduction inhibitors; proteasome inhibitors; DNA methyl transferases; cytokines; retinoids and HDAC or HAT modulators.

  本发明提供了一种组合物，包括式（VII）的Hsp90抑制剂化合物或其互变异构体或盐，以及从拓扑异构酶I抑制剂、抗代谢物、微管靶向剂、DNA结合剂和拓扑异构酶II抑制剂、烷化剂、单克隆抗体、抗激素、信号转导抑制剂、蛋白酶体抑制剂、DNA甲基转移酶、细胞因子、视黄醇和HDAC或HAT调节剂中选择一个或多个治疗剂。