4-<<<(phenylamino)carbonyl>amino>methyl>benzoic acid

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-<<<(phenylamino)carbonyl>amino>methyl>benzoic acid
• 英文别名: 4-[(Phenylcarbamoylamino)methyl]benzoic acid
• 化学式: C₁₅H₁₄N₂O₃
• 分子量: 270.288
• InChiKey: DVSAMBUWUFZMHX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  78.4
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-(bromomethyl)-1,2-benzisothiazol-3(2H)-one-1,1-dioxide 、 4-<<<(phenylamino)carbonyl>amino>methyl>benzoic acid 在 N,N-二异丙基乙胺 作用下， 以 乙腈 为溶剂， 反应 12.0h， 生成 (1,1,3-Trioxo-1,2-benzothiazol-2-yl)methyl 4-[(phenylcarbamoylamino)methyl]benzoate
  参考文献：
  名称：

  1,2-Benzisothiazol-3-one 1,1-Dioxide Inhibitors of Human Mast Cell Tryptase

  摘要：

  A library of compounds were prepared by reacting 2-(bromomethyl)-1,2-benzisothiazol-3(2N) one 1,1-dioxide (5) with commercially available carboxylic acids in the presence of potassium carbonate or a tertiary amine base. From this library, (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(SH)-yl)methyl N-[(phenylmethoxy)carbonyl]-beta-alanate (7b) emerged as a potent inhibitor of human mast cell tryptase (IC50 = 0.85 mu M) Extension of the side chain of 7b by two carbons gave (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methyl 5-[[(phenylmethoxy)carbonyl]amino]-pentanoate (7d) which was an 8-fold more potent inhibitor (IC50 = 0.1 mu M). Further modification of this series produced benzoic acid derivative (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)-methyl 4-[[(phenylmethoxy)carbonyl] amino]benzo ate (7n) which is the most potent inhibitor identified in this series (IC50 = 0.064 mu M). These compounds exhibit time-dependent inhibition consistent with mechanism-based inhibition. For 7b, the initial enzyme velocity is not a saturable function of the inhibitor concentration and the initial Ki could not be determined (K-i > 10 mu M). The steady-state rate constant, K-i*, was determined to be 396 nM. On the other hand, compounds 7d and 7n are time-dependent inhibitors with a saturable initial complex. From these studies, an initial rate constant, K-i, for 7d and 7n was found to be 345 and 465 nM, respectively. The steady-state inhibition constants, K-i*, for 7d and 7n were calculated to be 60 and 52 nM, respectively. Compound 7n is a 13-fold more potent inhibitor than 7b, and these kinetic studies indicate that the increase in inhibitory activity is due to an increase in initial affinity toward the enzyme and not an increase in chemical reactivity. These inhibitors generally show high selectivity for tryptase, being 40-fold weaker inhibitors of elastase, being 100-fold weaker against trypsin, and showing no inhibition against thrombin. These compounds are not inhibitors of thrombin, plasmin t-PA, urokinase and factor Xa (IC50 > 33 mu M). In the delayed-type hypersensitivity (DTH) mouse model, a model of skin inflammation, a 5% solution of 7d reduced edema by 69% compared to control animals.

  DOI：

  10.1021/jm9804580
• 作为产物：
  描述：

  4-氨甲基苯甲酸 、 异氰酸苯酯 在 sodium hydroxide 作用下， 反应 1.0h， 以96%的产率得到4-<<<(phenylamino)carbonyl>amino>methyl>benzoic acid
  参考文献：
  名称：

  1,2-Benzisothiazol-3-one 1,1-Dioxide Inhibitors of Human Mast Cell Tryptase

  摘要：

  A library of compounds were prepared by reacting 2-(bromomethyl)-1,2-benzisothiazol-3(2N) one 1,1-dioxide (5) with commercially available carboxylic acids in the presence of potassium carbonate or a tertiary amine base. From this library, (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(SH)-yl)methyl N-[(phenylmethoxy)carbonyl]-beta-alanate (7b) emerged as a potent inhibitor of human mast cell tryptase (IC50 = 0.85 mu M) Extension of the side chain of 7b by two carbons gave (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methyl 5-[[(phenylmethoxy)carbonyl]amino]-pentanoate (7d) which was an 8-fold more potent inhibitor (IC50 = 0.1 mu M). Further modification of this series produced benzoic acid derivative (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)-methyl 4-[[(phenylmethoxy)carbonyl] amino]benzo ate (7n) which is the most potent inhibitor identified in this series (IC50 = 0.064 mu M). These compounds exhibit time-dependent inhibition consistent with mechanism-based inhibition. For 7b, the initial enzyme velocity is not a saturable function of the inhibitor concentration and the initial Ki could not be determined (K-i > 10 mu M). The steady-state rate constant, K-i*, was determined to be 396 nM. On the other hand, compounds 7d and 7n are time-dependent inhibitors with a saturable initial complex. From these studies, an initial rate constant, K-i, for 7d and 7n was found to be 345 and 465 nM, respectively. The steady-state inhibition constants, K-i*, for 7d and 7n were calculated to be 60 and 52 nM, respectively. Compound 7n is a 13-fold more potent inhibitor than 7b, and these kinetic studies indicate that the increase in inhibitory activity is due to an increase in initial affinity toward the enzyme and not an increase in chemical reactivity. These inhibitors generally show high selectivity for tryptase, being 40-fold weaker inhibitors of elastase, being 100-fold weaker against trypsin, and showing no inhibition against thrombin. These compounds are not inhibitors of thrombin, plasmin t-PA, urokinase and factor Xa (IC50 > 33 mu M). In the delayed-type hypersensitivity (DTH) mouse model, a model of skin inflammation, a 5% solution of 7d reduced edema by 69% compared to control animals.

  DOI：

  10.1021/jm9804580

文献信息

• A Facile Synthesis of <i>N</i>-Carbamoylamino Acids
  作者：Sergey Ryabukhin、Andrey Bogolubsky、Gennadiy Pakhomov、Eugeniy Ostapchuk、Alexander Shivanyuk、Andrey Tolmachev

  DOI：10.1055/s-2008-1078017

  日期：——

  N-Carbamoylamino acids were obtained through the alkylation of monosubstituted parabanic acids followed by hydro­lysis of the intermediate products. This new methodology furnishes structurally and functionally diverse N-carbamoylamino acids in high preparative yields and excellent purity.

  通过对单取代对位氨基甲酸酯进行烷基化，然后水解中间产物，获得了 N-氨基甲酰基氨基甲酸酯。这种新方法可提供结构和功能多样化的 N-氨基甲酰基氨基酸，制备收率高，纯度极佳。
• 1,2-Benzisothiazol-3-one 1,1-Dioxide Inhibitors of Human Mast Cell Tryptase
  作者：Keith D. Combrink、H. Belgin Gülgeze、Nicholas A. Meanwell、Bradley C. Pearce、Pi Zulan、Gregory S. Bisacchi、Daniel G. M. Roberts、Paul Stanley、Steven M. Seiler

  DOI：10.1021/jm9804580

  日期：1998.11.1

  A library of compounds were prepared by reacting 2-(bromomethyl)-1,2-benzisothiazol-3(2N) one 1,1-dioxide (5) with commercially available carboxylic acids in the presence of potassium carbonate or a tertiary amine base. From this library, (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(SH)-yl)methyl N-[(phenylmethoxy)carbonyl]-beta-alanate (7b) emerged as a potent inhibitor of human mast cell tryptase (IC50 = 0.85 mu M) Extension of the side chain of 7b by two carbons gave (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methyl 5-[[(phenylmethoxy)carbonyl]amino]-pentanoate (7d) which was an 8-fold more potent inhibitor (IC50 = 0.1 mu M). Further modification of this series produced benzoic acid derivative (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)-methyl 4-[[(phenylmethoxy)carbonyl] amino]benzo ate (7n) which is the most potent inhibitor identified in this series (IC50 = 0.064 mu M). These compounds exhibit time-dependent inhibition consistent with mechanism-based inhibition. For 7b, the initial enzyme velocity is not a saturable function of the inhibitor concentration and the initial Ki could not be determined (K-i > 10 mu M). The steady-state rate constant, K-i*, was determined to be 396 nM. On the other hand, compounds 7d and 7n are time-dependent inhibitors with a saturable initial complex. From these studies, an initial rate constant, K-i, for 7d and 7n was found to be 345 and 465 nM, respectively. The steady-state inhibition constants, K-i*, for 7d and 7n were calculated to be 60 and 52 nM, respectively. Compound 7n is a 13-fold more potent inhibitor than 7b, and these kinetic studies indicate that the increase in inhibitory activity is due to an increase in initial affinity toward the enzyme and not an increase in chemical reactivity. These inhibitors generally show high selectivity for tryptase, being 40-fold weaker inhibitors of elastase, being 100-fold weaker against trypsin, and showing no inhibition against thrombin. These compounds are not inhibitors of thrombin, plasmin t-PA, urokinase and factor Xa (IC50 > 33 mu M). In the delayed-type hypersensitivity (DTH) mouse model, a model of skin inflammation, a 5% solution of 7d reduced edema by 69% compared to control animals.