6-chloro-7-hydroxy-3-(4-methoxyphenyl)-2-methyl-4H-chromen-4-one | 558643-26-8

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 异黄酮类化合物
• 英文名称: 6-chloro-7-hydroxy-3-(4-methoxyphenyl)-2-methyl-4H-chromen-4-one
• 英文别名: 6-chloro-7-hydroxy-3-(4-methoxyphenyl)-2-methylchromen-4(1H)-one；6-chloro-7-hydroxy-3-(4-methoxy-phenyl)-2-methyl-chromen-4-one；6-chloro-7-hydroxy-3-(4-methoxyphenyl)-2-methylchromen-4-one
• CAS: 558643-26-8
• 化学式: C₁₇H₁₃ClO₄
• 分子量: 316.741
• InChiKey: KAYSWUQXABPRMH-UHFFFAOYSA-N

物化性质

• 沸点：
  499.9±45.0 °C(Predicted)
• 密度：
  1.367±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  55.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  6-chloro-7-hydroxy-3-(4-methoxyphenyl)-2-methyl-4H-chromen-4-one 在 一水合肼 作用下， 以 乙醇 为溶剂， 反应 1.0h， 以223.6 mg的产率得到4-chloro-6-(4-(4-methoxyphenyl)-5-methyl-1H-pyrazol-3-yl)benzene-1,3-diol
  参考文献：
  名称：

  Repurposing Hsp90 inhibitors as antibiotics targeting histidine kinases

  摘要：

  To address the growing need for new antimicrobial agents, we explored whether inhibition of bacterial signaling machinery could inhibit bacterial growth. Because bacteria rely on two-component signaling systems to respond to environmental changes, and because these systems are both highly conserved and mediated by histidine kinases, inhibiting histidine kinases may provide broad spectrum antimicrobial activity. The histidine kinase ATP binding domain is conserved with the ATPase domain of eukaryotic Hsp90 molecular chaperones. To find a chemical scaffold for compounds that target histidine kinases, we leveraged this conservation. We screened ATP competitive Hsp90 inhibitors against CckA, an essential histidine kinase in Caulobacter crescentus that controls cell growth, and showed that the diaryl pyrazole is a promising scaffold for histidine kinase inhibition. We synthesized a panel of derivatives and found that they inhibit the histidine kinases C. crescentus CckA and Salmonella PhoQ but not C. crescentus DivJ; and they inhibit bacterial growth in both Gram-negative and Gram-positive bacterial strains. (C) 2017 The Authors. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2017.10.036
• 作为产物：
  描述：

  4-氯间苯二酚 在 三氟化硼乙醚 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 6-chloro-7-hydroxy-3-(4-methoxyphenyl)-2-methyl-4H-chromen-4-one
  参考文献：
  名称：

  Novel, Potent Small-Molecule Inhibitors of the Molecular Chaperone Hsp90 Discovered through Structure-Based Design

  摘要：

  The crystal structure of a previously reported screening hit 1 (CCT018159) bound to the N terminal domain of molecular chaperone Hsp90 has been used to design 5-amide analogues. These exhibit enhanced potency against the target in binding and functional assays with accompanying appropriate cellular pharmaeodynamic changes. Compound 11 (VER-49009) compares favorably with the clinically evaluated 17-AAG.

  DOI：

  10.1021/jm050355z

文献信息

• [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。
• [EN] 3,4-DIARYLPYRAZOLES AND THEIR USE IN THE THERAPY OF CANCER<br/>[FR] 3,4-DIARYLPYRAZOLES ET LEUR UTILISATION EN THERAPIE ANTI-CNCEREUSE
  申请人：RIBOTARGETS LTD

  公开号：WO2003055860A1

  公开（公告）日：2003-07-10

  The present invention pertains to the use of certain 3,4-diarylpyrazoles of formula (I), both in vitro and in vivo, to inhibit heat shock protein 90 (HSP90), and in the treatment of conditions mediated by HSP90, including, for example, cancer; wherein: Ar3 is independently: a C5-20aryl group, and is optionally substituted; Ar4 is independently: a C5-20aryl group, and is optionally substituted; R5 is independently: hydrogen; halo; hydroxy; ether; formyl; acyl; carboxy; ester; acyloxy; oxycarbonyloxy; amido; acylamido; aminocarbonyloxy; tetrazolyl; amino; nitro; cyano; azido; sulfhydryl; thioether; sulfonamido; C1-7alkyl; C3-20heterocycyl; or C5-20aryl; RN is independently: -H; C1-7alkyl; C3-20heterocycyl; or, C5-20aryl; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof. The present invention also pertains to such compounds, pharmaceutical compositions comprising such compounds, such compounds for medical use, such compounds for use in the treatment of conditions mediated by HSP90, including, for example, cancer, and use of such compounds in the preparation of medicaments for such treatments.

  本发明涉及使用式(I)的特定3,4-二芳基吡唑化合物，无论是体外还是体内，以抑制热休克蛋白90（HSP90）的作用，并用于治疗由HSP90介导的疾病，例如癌症；其中：Ar3独立地表示：C5-20芳基基团，且可选地被取代；Ar4独立地表示：C5-20芳基基团，且可选地被取代；R5独立地表示：氢；卤素；羟基；醚；甲酰基；酰基；羧基；酯基；酰氧基；氧羰基氧基；酰胺基；酰胺氧基；氨基羰氧基；四唑基；氨基；硝基；氰基；偶氮基；硫醇基；硫醚基；磺酰胺基；C1-7烷基；C3-20杂环基；或C5-20芳基；RN独立地表示：-H；C1-7烷基；C3-20杂环基；或C5-20芳基；以及其药学上可接受的盐，溶剂化合物，酰胺，酯，醚，化学保护形式和前药。本发明还涉及这些化合物，包含这些化合物的制药组合物，用于医疗用途的这些化合物，用于治疗由HSP90介导的疾病，例如癌症的这些化合物，以及使用这些化合物制备此类治疗药物的用途。
• 3,4-diarylpyrazoles and their use in the therapy of cancer
  申请人：Drysdale James Martin

  公开号：US20050222230A1

  公开（公告）日：2005-10-06

  The present invention pertains to the use of certain 3,4-diarylpyrazoles of formula (I), both in vitro and in vivo, to inhibit heat shock protein 90 (HSP90), and in the treatment of conditions mediated by HSP90, including, for example, cancer; wherein: Ar 3 is independently: a C 5-20 aryl group, and is optionally substituted; Ar 4 is independently: a C 5-20 aryl group, and is optionally substituted; R 5 is independently: hydrogen; halo; hydroxy; ether; formyl; acyl; carboxy; ester, acyloxy; oxycarbonyloxy; amido; acylamido; aminocarbonyloxy; tetrazolyl; amino; nitro; cyano; azido; sulfhydryl; thioether; sulfonamido; C 1-7 alkyl; C 3-20 heterocycyl; or C 5-20 aryl; RN is independently: —H; C 1-7 alkyl; C 3-20 heterocycyl; or, C 5-20 aryl; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof. The present invention also pertains to such compounds, pharmaceutical compositions comprising such compounds, such compounds for medical use, such compounds for use in the treatment of conditions mediated by HSP90, including, for example, cancer, and use of such compounds in the preparation of medicaments for such treatments.

  本发明涉及使用公式（I）中的某些3,4-二芳基吡唑化合物，无论是在体内还是体外，用于抑制热休克蛋白90（HSP90），以及用于治疗由HSP90介导的疾病，包括癌症等；其中：Ar3独立地表示：C5-20芳基基团，可选地取代；Ar4独立地表示：C5-20芳基基团，可选地取代；R5独立地表示：氢；卤素；羟基；醚；甲酰基；酰基；羧基；酯，酰氧基；氧羰酰氧基；酰胺；酰胺基；氨基羰酰氧基；四唑基；氨基；硝基；氰基；偶氮基；磺酰基；硫醚基；磺酰胺基；C1-7烷基；C3-20杂环基；或C5-20芳基；R N 独立地表示：-H；C1-7烷基；C3-20杂环基；或C5-20芳基；以及其药学上可接受的盐，溶剂化合物，酰胺，酯，醚，化学保护形式和前药。本发明还涉及这种化合物，包含这种化合物的制药组合物，用于医学用途的这种化合物，用于治疗由HSP90介导的疾病，包括癌症的这种化合物，以及使用这种化合物制备这种治疗药物的用途。
• Isoxazole compounds as inhibitors of heat shock proteins
  申请人：Drysdale James Martin

  公开号：US20060241106A1

  公开（公告）日：2006-10-26

  Isoxazoles of formula (A) or (B) are inhibitors of HSP90 activity, and useful for treatment of, for example cancers: (A), (B) 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 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，可用于治疗癌症等疾病：(A)、(B)其中R1是以下式子的基团：-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是独立的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C1-C6烷基，Q是氢或可选取代的碳环或杂环基团；R2是(i)上述式(Ia)的基团，或(ii)羧酰胺基团，或(iii)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子的基团：-(Alk1)p-(Z)r-(Alk2)s-Q，其中Q、Alk1、Alk2、Z、p、r和s如上所述；R3是氢、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团。
• Isoxazole Compounds As Inhibitors Of Heat Shock Proteins
  申请人：Drysdale Martin James

  公开号：US20120252797A1

  公开（公告）日：2012-10-04

  Isoxazoles of formula (A) or (B) wherein R 1 is a group of formula (IB) The isoxazoles are inhibitors of HSP90 activity, and useful for the treatment of, for example, cancers.

  化合物的式子为(A)或(B)，其中R1为式子(IB)所代表的基团。这些异噁唑是HSP90活性的抑制剂，可用于治疗癌症等疾病。