N2-(4-叔丁基苯甲酰基)-4-甲氧羰基-1,2-苯二胺 | 104224-96-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: N2-(4-叔丁基苯甲酰基)-4-甲氧羰基-1,2-苯二胺
• 英文名称: methyl 4-amino-3-[(4-tert-butylbenzoyl)amino]benzoate
• 英文别名: N²-(4-tert-butylbenzoyl)-4-methoxycarbonyl-1,2-benzenediamine；N2-(4-t-Butylbenzoyl)-4-methoxycarbonyl-1,2-benzenediamine；methyl 4-amino-3-(p-t-butylbenzamido)benzoate；4-methoxycarbonyl-N2-(4-t-butylbenzoyl)-1,2-benzenediamine
• CAS: 104224-96-6
• 化学式: C₁₉H₂₂N₂O₃
• 分子量: 326.395
• InChiKey: KYGZJNHCAONBGA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  81.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N2-(4-叔丁基苯甲酰基)-4-甲氧羰基-1,2-苯二胺 在 吡啶 、 lithium hydroxide 、 potassium carbonate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 27.0h， 生成 N¹-(3-cyanobenzoyl)-N²-(4-tert-butylbenzoyl)-4-benzyloxycarbonyl-1,2-benzenediamine
  参考文献：
  名称：

  Structure-Based Design of Potent, Amidine-Derived Inhibitors of Factor Xa:  Evaluation of Selectivity, Anticoagulant Activity, and Antithrombotic Activity

  摘要：

  To enhance the potency of 1,2-dibenzamidobenzene-derived inhibitors of factor Xa (fXa), an amidine substituent was incorporated on one of the benzoyl side chains to interact with Asp189 in the S1 specificity pocket. Lead molecule 1 was docked into the active site of Ma to facilitate inhibitor design. Subsequently, iterative SAR studies and molecular modeling led to a 1000-fold increase in Ma affinity and a refined model of the new inhibitors in the Ma active site. Strong support for the computational model was achieved through the acquisition of an X-ray crystal structure using thrombin as a surrogate protein. The amidines in this series show high levels of selectivity for the inhibition of Ma relative to other trypsin-like serine proteases. Furthermore, the Ma affinity of compounds in this series (K-ass = 50-500 x 10(6) L/mol) translates effectively into both anticoagulant activity in vitro and antithrombotic activity in vivo.

  DOI：

  10.1021/jm9903287
• 作为产物：
  描述：

  3,4-二氨基苯甲酸甲酯 、 对叔丁基苯甲酰氯 在 三乙胺 作用下， 以 乙醚 为溶剂， 生成 N2-(4-叔丁基苯甲酰基)-4-甲氧羰基-1,2-苯二胺
  参考文献：
  名称：

  Benzo (b) thiophene carboxylate derivatives and pharmaceutical

  摘要：

  芳香杂环衍生物的化学式为##STR1##其中R.sub.1表示##STR2##其中R.sub.3表示氢，-OR.sub.4其中R.sub.4表示氢，具有1-20个碳原子的烷基或单糖基或多糖基烷基或R.sub.3表示##STR3##其中r'和r"表示氢，较低的烷基或一起形成杂环，R.sub.2表示氢或-CH.sub.3，Ar表示##STR4##其中Z为O或S，##STR5##其中R.sub.5为较低的烷基或##STR6##其中R.sub.6为氢或具有1-10个碳原子的烷基，R.sub.7表示具有4-12个碳原子的烷基或环烷基，Y为CH或氮原子，X表示氧、硫或-N-R.sub.8，当R.sub.8表示氢、较低的烷基或较低的烷氧羰基时，条件是(i)当Y为CH且X为氧或硫时，Ar与C不同，(ii)当Y为氮且X为氧时，Ar与(C)或(D)不同，其中R.sub.6为具有1-4个碳原子的烷基，R.sub.7为具有4-12个碳原子的支链烷基，用于兽医或人类治疗和化妆品配方中。

  公开号：

  US04740519A1

文献信息

• Antithrombotic agents
  申请人：Eli Lilly and Company

  公开号：US06372759B1

  公开（公告）日：2002-04-16

  This application relates to a compound of formula (I), a pharmaceutically acceptable salt of the compound, or a prodrug thereof, as defined herein, pharmaceutical compositions thereof, and its use as an inhibitor of factor Xa, as well as a process for its preparation and intermediates therefor.

  该申请涉及公式(I)的化合物，该化合物的药学上可接受的盐，或者其前药，如本文所定义的，以及其药物组合物，以及其用作因子Xa抑制剂的用途，以及其制备过程和中间体。
• Benzo (b) thiophene carboxylate derivatives and pharmaceutical
  申请人：Centre International de Recherches Dermatologiques C.I.R.D.

  公开号：US04740519A1

  公开（公告）日：1988-04-26

  Aromatic heterocyclic derivatives have the formula ##STR1## wherein R.sub.1 represents ##STR2## wherein R.sub.3 represents hydrogen, --OR.sub.4 wherein R.sub.4 represents hydrogen, alkyl having 1-20 carbon atoms or mono- or polyhydroxyalkyl or R.sub.3 represents ##STR3## wherein r' and r" represent hydrogen, lower alkyl or together form a heterocycle, R.sub.2 represents hydrogen or --CH.sub.3 and Ar represents ##STR4## wherein Z is O or S, ##STR5## wherein R.sub.5 is lower alkyl or ##STR6## wherein R.sub.6 is hydrogen or alkyl having 1-10 carbon atoms and R.sub.7 represents alkyl having 4-12 carbon atoms or cycloalkyl, Y is CH or a nitrogen atom and X represents oxygen, sulfur or --N--R.sub.8 when R.sub.8 represents hydrogen, lower alkyl or lower alkoxycarbonyl, with the proviso that (i) when Y is CH and X is oxygen or sulfur Ar is other than C and (ii) when Y is nitrogen and X is oxygen, Ar is other than (C) or (D) in which R.sub.6 is alkyl having 1-4 carbon atoms and R.sub.7 is branched alkyl having 4-12 atoms useful in veterinary or human therapy and in cosmetic formulations.

  芳香杂环衍生物的化学式为##STR1##其中R.sub.1表示##STR2##其中R.sub.3表示氢，-OR.sub.4其中R.sub.4表示氢，具有1-20个碳原子的烷基或单糖基或多糖基烷基或R.sub.3表示##STR3##其中r'和r"表示氢，较低的烷基或一起形成杂环，R.sub.2表示氢或-CH.sub.3，Ar表示##STR4##其中Z为O或S，##STR5##其中R.sub.5为较低的烷基或##STR6##其中R.sub.6为氢或具有1-10个碳原子的烷基，R.sub.7表示具有4-12个碳原子的烷基或环烷基，Y为CH或氮原子，X表示氧、硫或-N-R.sub.8，当R.sub.8表示氢、较低的烷基或较低的烷氧羰基时，条件是(i)当Y为CH且X为氧或硫时，Ar与C不同，(ii)当Y为氮且X为氧时，Ar与(C)或(D)不同，其中R.sub.6为具有1-4个碳原子的烷基，R.sub.7为具有4-12个碳原子的支链烷基，用于兽医或人类治疗和化妆品配方中。
• [EN] ANTITHROMBOTIC AGENTS<br/>[FR] AGENTS ANTITHROMBOTIQUES
  申请人：ELI LILLY AND COMPANY

  公开号：WO1999000121A1

  公开（公告）日：1999-01-07

  (EN) This application relates to a compound of formula (I) (or a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug thereof) as defined herein, pharmaceutical compositions thereof, and its use as an inhibitor of factor Xa, as well as a process for its preparation and intermediates therefor.(FR) Cette invention traite d'un composé de la formule (I), telle que définie dans le descriptif, (ou bien d'un promédicament de ce composé ou bien d'un sel pharmaceutiquement acceptable de ce composé ou d'un promédicament de ce composé), de compositions pharmaceutiques contenant ce composé, de l'utilisation de ce composé en tant qu'inhibiteur du facteur Xa, d'un procédé permettant de préparer ce composé et d'intermédiaires utilisés pour produire ledit composé.

  该申请涉及公式（I）的化合物（或其前药或化合物或前药的药学上可接受的盐），其药物组成，以及其作为因子Xa的抑制剂的用途，以及其制备过程和中间体。
• 1,2-Dibenzamidobenzene Inhibitors of Human Factor Xa
  作者：David K. Herron、Theodore Goodson、Michael R. Wiley、Leonard C. Weir、Jeffrey A. Kyle、Ying K. Yee、Ann Louise Tebbe、Jennifer M. Tinsley、David Mendel、John J. Masters、Jeffry B. Franciskovich、J. Scott Sawyer、Douglas W. Beight、Andrew M. Ratz、Guy Milot、Steven E. Hall、Valentine J. Klimkowski、James H. Wikel、Brian J. Eastwood、Richard D. Towner、Donetta S. Gifford-Moore、Trelia J. Craft、Gerald F. Smith

  DOI：10.1021/jm990326m

  日期：2000.3.1

  High-throughput screening of a combinatorial library of diamidophenols yielded lead compounds with the ability to inhibit human factor Xa (fXa) at micromolar concentrations (e.g. compound 4, fXa apparent K-ass = 0.64 x 10(6) L/mol). SAR studies in this novel structural series of fXa inhibitors showed that the phenolic hydroxyl group was not essential for activity. The best activity was found in substituted 1,2-dibenzamidobenzenes in which the phenyl group of one benzoyl group (A-ring) was substituted in the 4-position with relatively small lipophilic or polarizable groups such as methoxy, vinyl, or chloro and the phenyl group of the other benzoyl group (B-ring) was substituted in the 4-position with larger lipophilic groups such as tert-butyl or dimethylamino. The central phenyl ring (C-ring) tolerated a wide variety of substituents, but methoxy, methanesulfonamido, hydroxyl, and carboxyl substitution produced slightly higher levels of activity than other substituents when present in combination with favorable B-ring substitution. Methylation of the amide nitrogen atoms was found to greatly decrease activity. Compound 12 is the highest affinity fXa inhibitor in this group of compounds, having fXa apparent K-ass = 25.5 x 10(6) L/mol, about 40x more active than the original lead. This lead series does not show potent inhibition of human thrombin. A model for the binding of these ligands to the fXa active site is proposed. The model is consistent with the observed SAR and can serve to guide future SAR studies.
• ——
  作者：SHROOT B.、 EUSTACHE J.、 BERNARDON J. -M.

  DOI：——

  日期：——