(E)-3-{3,4-dihydro-3-methyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4'-piperidin]-6-yl}-acrylic acid methyl ester hydrochloride | 1192127-64-2

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: (E)-3-{3,4-dihydro-3-methyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4'-piperidin]-6-yl}-acrylic acid methyl ester hydrochloride
• 英文别名: methyl (E)-3-(3-methyl-4-oxospiro[1,3-benzoxazine-2,4'-piperidine]-6-yl)prop-2-enoate;hydrochloride
• CAS: 1192127-64-2
• 化学式: C₁₇H₂₀N₂O₄*ClH
• 分子量: 352.818
• InChiKey: QYBDYCYUPJJJBU-CVDVRWGVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.84
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  67.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (E)-3-{3,4-dihydro-3-methyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4'-piperidin]-6-yl}-acrylic acid methyl ester hydrochloride 在 盐酸 、 水 、 sodium cyanoborohydride 、 1-羟基苯并三唑 、 溶剂黄146 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 为溶剂， 反应 15.0h， 生成 (E)-3-{1'-benzyl-3,4-dihydro-3-methyl-4-oxospiro[2H-(1,3)-benzoxazine-2,4'-piperidin]-6-yl}-N-hydroxyacrylamide hydrochloride
  参考文献：
  名称：

  Synthesis and biological characterization of spiro[2H-(1,3)-benzoxazine-2,4′-piperidine] based histone deacetylase inhibitors

  摘要：

  Histone Deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases. In previous studies we described the development of novel spirocyclic HDAC inhibitors based on the combination of privileged structures with hydroxamic acid moieties as zinc binding group. Herein, we report further explorations, which resulted in the discovery of a new class of spiro[2H-(1,3)-benzoxazine-2,4'-piperidine] derivatives. Several compounds showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC50 values when tested against tumour cell lines and a remarkable stability in human and mouse microsomes. Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumour growth inhibition. In addition, the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogues. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.03.061
• 作为产物：
  描述：

  5-溴水杨酰胺 在 四氢吡咯 、 盐酸 、 palladium diacetate 、 sodium hydride 、 三乙胺 、 三(邻甲基苯基)磷 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 15.67h， 生成 (E)-3-{3,4-dihydro-3-methyl-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4'-piperidin]-6-yl}-acrylic acid methyl ester hydrochloride
  参考文献：
  名称：

  Synthesis and biological characterization of spiro[2H-(1,3)-benzoxazine-2,4′-piperidine] based histone deacetylase inhibitors

  摘要：

  Histone Deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases. In previous studies we described the development of novel spirocyclic HDAC inhibitors based on the combination of privileged structures with hydroxamic acid moieties as zinc binding group. Herein, we report further explorations, which resulted in the discovery of a new class of spiro[2H-(1,3)-benzoxazine-2,4'-piperidine] derivatives. Several compounds showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC50 values when tested against tumour cell lines and a remarkable stability in human and mouse microsomes. Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumour growth inhibition. In addition, the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogues. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.03.061

文献信息

• Spirocyclic derivatives as histone deacetylase inhibitors
  申请人：Varasi Mario

  公开号：US08592444B2

  公开（公告）日：2013-11-26

  This invention is related to new histone deacetylase inhibitors according to the general formula (I) wherein: the dotted line is an optional additional bond; n is zero or an integer from 1 to 4; R1 is hydrogen; C1-C6 alkyl, optionally substituted by cycloalkyl, aryl or by heteroaryl; (CO)R3; (SO2)R4; cycloalkyl; aryl; or heteroaryl; R2 is C1-C6 alkyl, optionally substituted by aryl or by heteroaryl; aryl; heteroaryl; or (CO)R5; X is CH2, oxygen or NR6; Y is a bond, CHR7 or NR8; Z is oxygen, CR9R10 or C═R11; and R3, R4, R5, R6, R7, R8, R9, R10 and R11 are as further defined in the specification; and pharmaceutical acceptable salts thereof.

  本发明涉及新的组蛋白去乙酰化酶抑制剂，其通式为（I），其中：虚线为可选的附加键；n为零或1至4的整数；R1为氢、C1-C6烷基，可选地被环烷基、芳基或杂芳基取代；（CO）R3；（SO2）R4；环烷基；芳基；或杂芳基；R2为C1-C6烷基，可选地被芳基或杂芳基取代；芳基；杂芳基；或（CO）R5；X为CH2、氧或NR6；Y为键、CHR7或NR8；Z为氧、CR9R10或C═R11；R3、R4、R5、R6、R7、R8、R9、R10和R11如规范中进一步定义；以及其药学上可接受的盐。
• SPIROCYCLIC DERIVATIVES AS HISTONE DEACETYLASE INHIBITORS
  申请人：Varasi Mario

  公开号：US20140080823A1

  公开（公告）日：2014-03-20

  This invention is related to new histone deacetylase inhibitors according to the general formula (I) wherein: the dotted line is an optional additional bond; n is zero or an integer from 1 to 4; R 1 is hydrogen; C 1 -C 6 alkyl, optionally substituted by cycloalkyl, aryl or by heteroaryl; (CO)R 3 ; (SO 2 )R 4 ; cycloalkyl; aryl; or heteroaryl; R 2 is C 1 -C 6 alkyl, optionally substituted by aryl or by heteroaryl; aryl; heteroaryl; or (CO)R 5 ; X is CH 2 , oxygen or NR 6 ; Y is a bond, CHR 7 or NR 8 ; Z is oxygen, CR 9 R 10 or C═R 11 ; and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as further defined in the specification; and pharmaceutical acceptable salts thereof.

  本发明涉及新的组蛋白去乙酰化酶抑制剂，其通式为(I)，其中：虚线是可选的额外键；n为零或1至4的整数；R1为氢；C1-C6烷基，可选地被环烷基、芳基或杂芳基取代；(CO)R3；(SO2)R4；环烷基；芳基；或杂芳基；R2为C1-C6烷基，可选地被芳基或杂芳基取代；芳基；杂芳基；或(CO)R5；X为CH2、氧或NR6；Y为键、CHR7或NR8；Z为氧、CR9R10或C═R11；而R3、R4、R5、R6、R7、R8、R9、R10和R11如规范中所进一步定义的；以及其药学上可接受的盐。
• US8592444B2
  申请人：——

  公开号：US8592444B2

  公开（公告）日：2013-11-26
• US9115148B2
  申请人：——

  公开号：US9115148B2

  公开（公告）日：2015-08-25
• [EN] SPIROCYCLIC DERIVATIVES AS HISTONE DEACETYLASE INHIBITORS<br/>[FR] DÉRIVÉS SPIROCYCLIQUES SERVANT D'INHIBITEURS DE L'HISTONE DÉSACÉTYLASE
  申请人：DAC SRL

  公开号：WO2009127609A1

  公开（公告）日：2009-10-22

  This invention is related to new histone deacetylase inhibitors according to the general formula (I) wherein: the dotted line is an optional additional bond; n is zero or an integer from 1 to 4; R1 is hydrogen; C1-C6 alkyl, optionally substituted by cycloalkyl, aryl or by heteroaryl; (CO)R3; (SO2)R4; cycloalkyl; aryl; or heteroaryl; R2 is C1-C6 alkyl, optionally substituted by aryl or by heteroaryl; aryl; heteroaryl; or (CO)R5; X is CH2, oxygen or NR6; Y is a bond, CHR7 or NR8; Z is oxygen, CR9R10 or C=R11; and R3, R4, R5, R6, R7, R8, R9, R10 and R11 are as further defined in the specification; and pharmaceutical acceptable salts thereof.