(R)-2-[7-(3,5-Dimethoxy-benzyloxy)-1,1-dioxo-1,3,4,5-tetrahydro-1λ⁶-benzo[f][1,2,5]thiadiazepin-2-yl]-pentanedioic acid 1-tert-butyl ester 5-methyl ester | 1053636-00-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (R)-2-[7-(3,5-Dimethoxy-benzyloxy)-1,1-dioxo-1,3,4,5-tetrahydro-1λ⁶-benzo[f][1,2,5]thiadiazepin-2-yl]-pentanedioic acid 1-tert-butyl ester 5-methyl ester
• 英文别名: 1-O-tert-butyl 5-O-methyl (2R)-2-[7-[(3,5-dimethoxyphenyl)methoxy]-1,1-dioxo-4,5-dihydro-3H-1lambda6,2,5-benzothiadiazepin-2-yl]pentanedioate；1-O-tert-butyl 5-O-methyl (2R)-2-[7-[(3,5-dimethoxyphenyl)methoxy]-1,1-dioxo-4,5-dihydro-3H-1λ6,2,5-benzothiadiazepin-2-yl]pentanedioate
• CAS: 1053636-00-2
• 化学式: C₂₇H₃₆N₂O₉S
• 分子量: 564.657
• InChiKey: RZYISTLUDCUSGR-HSZRJFAPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  39
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  138
• 氢给体数：
  1
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  (R)-2-[7-(3,5-Dimethoxy-benzyloxy)-1,1-dioxo-1,3,4,5-tetrahydro-1λ⁶-benzo[f][1,2,5]thiadiazepin-2-yl]-pentanedioic acid 1-tert-butyl ester 5-methyl ester 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 (R)-2-[7-(3,5-Dimethoxy-benzyloxy)-1,1-dioxo-1,3,4,5-tetrahydro-1λ⁶-benzo[f][1,2,5]thiadiazepin-2-yl]-pentanedioic acid 5-methyl ester
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of Benzothiadiazepine Hydroxamates as Selective Tumor Necrosis Factor-α Converting Enzyme Inhibitors

  摘要：

  Elevated levels of tumor necrosis factor-alpha (TNF-alpha) have been associated with several inflammatory diseases, and therefore, strategies for its suppression have become important targets in drug discovery. Our efforts to suppress TNF-alpha have centered on the inhibition of TNF-alpha converting enzyme (TACE) through the use of hydroxamate inhibitors. Starting from broad-spectrum matrix metalloproteinase (MMP) inhibitors, we have designed and synthesized novel benzothiadiazepines as potent and selective TACE inhibitors. The benzothiadiazepines were synthesized with variation in P1 and P1' in order to effect potency and selectivity. The inhibitors were evaluated versus porcine TACE (pTACE), and the initial selectivity was assessed with counterscreens of MMP-1, -2, and -9. Several potent and selective inhibitors were discovered with compound 41 being the most active against pTACE (K-i = 5 nM) while still maintaining good selectivity versus the MMP's (at least 75-fold). Most compounds were assessed in the human peripheral blood mononuclear cell assay (PBMC) and the human whole blood assay (WBA) to determine their ability to suppress TNF-alpha. Compound 32 was the most potent compound in the PBMC assay (IC50 = 0.35 muM), while compound 62 was the most active in the WBA (IC50 = 1.4 muM).

  DOI：

  10.1021/jm020475w
• 作为产物：
  描述：

  4-苄氧基-2-硝基苯胺 在 palladium on activated charcoal N-甲基吗啉 、 盐酸 、 potassium tert-butylate 、 氢气 、 铁粉 、 溶剂黄146 、 N,N-二异丙基乙胺 、 三苯基膦 、 三氟乙酸 、 sodium nitrite 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 叔丁醇 为溶剂， 80.0 ℃ 、344.74 kPa 条件下， 反应 15.66h， 生成 (R)-2-[7-(3,5-Dimethoxy-benzyloxy)-1,1-dioxo-1,3,4,5-tetrahydro-1λ⁶-benzo[f][1,2,5]thiadiazepin-2-yl]-pentanedioic acid 1-tert-butyl ester 5-methyl ester
  参考文献：
  名称：

  Design, Synthesis, and Evaluation of Benzothiadiazepine Hydroxamates as Selective Tumor Necrosis Factor-α Converting Enzyme Inhibitors

  摘要：

  Elevated levels of tumor necrosis factor-alpha (TNF-alpha) have been associated with several inflammatory diseases, and therefore, strategies for its suppression have become important targets in drug discovery. Our efforts to suppress TNF-alpha have centered on the inhibition of TNF-alpha converting enzyme (TACE) through the use of hydroxamate inhibitors. Starting from broad-spectrum matrix metalloproteinase (MMP) inhibitors, we have designed and synthesized novel benzothiadiazepines as potent and selective TACE inhibitors. The benzothiadiazepines were synthesized with variation in P1 and P1' in order to effect potency and selectivity. The inhibitors were evaluated versus porcine TACE (pTACE), and the initial selectivity was assessed with counterscreens of MMP-1, -2, and -9. Several potent and selective inhibitors were discovered with compound 41 being the most active against pTACE (K-i = 5 nM) while still maintaining good selectivity versus the MMP's (at least 75-fold). Most compounds were assessed in the human peripheral blood mononuclear cell assay (PBMC) and the human whole blood assay (WBA) to determine their ability to suppress TNF-alpha. Compound 32 was the most potent compound in the PBMC assay (IC50 = 0.35 muM), while compound 62 was the most active in the WBA (IC50 = 1.4 muM).

  DOI：

  10.1021/jm020475w