Toluene-4-sulfonic acid 2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethyl ester | 192810-56-3

• 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: Toluene-4-sulfonic acid 2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethyl ester
• 英文别名: 2-[(2-methylpropan-2-yl)oxycarbonyl-pyridin-4-ylamino]ethyl 4-methylbenzenesulfonate
• CAS: 192810-56-3
• 化学式: C₁₉H₂₄N₂O₅S
• 分子量: 392.476
• InChiKey: VIKYPHJAWPFDTF-UHFFFAOYSA-N

物化性质

• 沸点：
  533.8±35.0 °C(Predicted)
• 密度：
  1.243±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  27
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  94.2
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  Toluene-4-sulfonic acid 2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethyl ester 在 sodium hydride 、 苯甲醚 、 三乙胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 72.75h， 生成 4-methyl-N-(4-methylphenyl)sulfonyl-N-[3-[2-(pyridin-4-ylamino)ethoxy]phenyl]benzenesulfonamide
  参考文献：
  名称：

  Generation of Ligand Conformations in Continuum Solvent Consistent with Protein Active Site Topology:  Application to Thrombin

  摘要：

  Using the crystal structure of an inhibitor complexed with the serine protease thrombin (PDB code 1UVT) and the functional group definitions contained within the Catalyst software, a representation of the enzyme's active site was produced (structure-based pharmacophore model). A training set of 16 homologous non-peptide inhibitors whose conformations had been generated in continuum solvent (MacroModel) and clustered into conformational. families (XCluster) was regressed against this pharmacophore so as to obtain a 3D-QSAR model. To test the robustness of the resulting QSAR model, the synthesis of a series of non-peptide thrombin inhibitors based on arylsuphonyl derivatives of an aminophenol ring linked to a pyridyl-based S1 binding group was undertaken. These compounds served as a test set (20-24). The crystal structure for the novel symmetrical disulfonyl compound 24, in complex with thrombin, has been solved. Its calculated binding mode is in general agreement with the crystallographically observed one, and the predicted K-i value is in close accord with the experimental value.

  DOI：

  10.1021/jm021028j
• 作为产物：
  描述：

  二碳酸二叔丁酯 在 sodium hydride 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.5h， 生成 Toluene-4-sulfonic acid 2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethyl ester
  参考文献：
  名称：

  Generation of Ligand Conformations in Continuum Solvent Consistent with Protein Active Site Topology:  Application to Thrombin

  摘要：

  Using the crystal structure of an inhibitor complexed with the serine protease thrombin (PDB code 1UVT) and the functional group definitions contained within the Catalyst software, a representation of the enzyme's active site was produced (structure-based pharmacophore model). A training set of 16 homologous non-peptide inhibitors whose conformations had been generated in continuum solvent (MacroModel) and clustered into conformational. families (XCluster) was regressed against this pharmacophore so as to obtain a 3D-QSAR model. To test the robustness of the resulting QSAR model, the synthesis of a series of non-peptide thrombin inhibitors based on arylsuphonyl derivatives of an aminophenol ring linked to a pyridyl-based S1 binding group was undertaken. These compounds served as a test set (20-24). The crystal structure for the novel symmetrical disulfonyl compound 24, in complex with thrombin, has been solved. Its calculated binding mode is in general agreement with the crystallographically observed one, and the predicted K-i value is in close accord with the experimental value.

  DOI：

  10.1021/jm021028j

文献信息

• Benzamide derivatives as thrombin inhibitors
  申请人：Glaxo Group Limited

  公开号：US06326386B1

  公开（公告）日：2001-12-04

  The invention relates to a novel class of amide derivatives which act as thrombin inhibitors as described by formula (I), where R1 and R2, independently represent a group (a) or R1 and R2 together form a C3-7 heterocycloalkyl or heterocycloalkenyl group which may be optionally substituted by C1-6 alkyl, C1-4 alkoxy, halogen, carboxylic acid or a C1-4 carboxylic acid ester group; R3 represents hydrogen, C1-3 alkyl, halogen, or C1-2 alkoxy; R4, R5 and R6 independently represent hydrogen, or halogen; R7 represents hydrogen or C1-6 alkyl; R8 represents hydrogen, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, aryl or heteroaryl, which groups are optionally substituted by one or more groups selected from halogen, hydroxy, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 acyloxy, NR9R10, NHCOR11, NHSO2R12, COR13, CO2R14, CONR15R16, and SO2NHR17; X represents a bond, a C1-6 alkyl chain, or a C3-6 alkenyl chain, where one or two nitrogen, oxygen, or sulfur atoms may be optionally contained within each chain, and the chains are optionally substituted by one or more groups selected from halogen, hydroxy, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 acyloxy, NR9R10, NHCOR11, NHSO2R12, COR13, CO2R14, CONR15R16, and SO2NHR17; R9-R17 represent hydrogen, C1-6 alkyl, or R9 and R10 or R15 and R16 form a C3-7 heterocycloalkyl ring, or R12 additionally may represent trifluoromethyl; and pharmaceutically acceptable derivatives or solvates thereof, to processes for their preparation; and their use in the treatment of clinical conditions susceptible to amelioration by administration of a thrombin inhibitor.

  本发明涉及一种新型酰胺衍生物，作为一种抑制凝血酶的药物。其化学式为（I），其中R1和R2独立地代表一个群（a）或R1和R2共同形成一个C3-7杂环烷基或杂环烯基基团，该基团可以被C1-6烷基，C1-4烷氧基，卤素，羧酸或C1-4羧酸酯基团进行选择性取代；R3代表氢，C1-3烷基，卤素或C1-2烷氧基；R4，R5和R6独立地代表氢或卤素；R7代表氢或C1-6烷基；R8代表氢，C3-7环烷基，C3-7环烯基，C3-7杂环烷基，C3-7杂环烯基，芳基或杂芳基，该基团可以选择性地被一个或多个从卤素，羟基，CN，C1-6烷基，C1-6烷氧基，C1-6酰氧基，NR9R10，NHCOR11，NHSO2R12，COR13，CO2R14，CONR15R16和SO2NHR17中选择的基团所取代；X代表一个键，一个C1-6烷基链或一个C3-6烯基链，其中每个链内可以选择性地包含一个或两个氮，氧或硫原子，并且这些链可以选择性地被一个或多个从卤素，羟基，CN，C1-6烷基，C1-6烷氧基，C1-6酰氧基，NR9R10，NHCOR11，NHSO2R12，COR13，CO2R14，CONR15R16和SO2NHR17中选择的基团所取代；R9-R17代表氢，C1-6烷基，或R9和R10或R15和R16形成一个C3-7杂环烷基环，或R12还可以表示三氟甲基；以及其药学上可接受的衍生物或溶剂，制备它们的方法，以及它们在治疗临床状况中的应用，该状况可以通过给予凝血酶抑制剂进行改善。
• BENZAMIDE DERIVATIVES AS THROMBIN INHIBITORS
  申请人：GLAXO GROUP LIMITED

  公开号：EP1021411A1

  公开（公告）日：2000-07-26
• US6326386B1
  申请人：——

  公开号：US6326386B1

  公开（公告）日：2001-12-04
• [EN] BENZAMIDE DERIVATIVES AS THROMBIN INHIBITORS<br/>[FR] DERIVES BENZAMIDES A TITRE D'INHIBITEURS DE THROMBINE
  申请人：GLAXO GROUP LIMITED

  公开号：WO1997022589A1

  公开（公告）日：1997-06-26

  (EN) The invention relates to a novel class of amide derivatives which act as thrombin inhibitors as described by formula (I), where R1 and R2, independently represent a group (a) or R1 and R2 together form a C3-7 heterocycloalkyl or heterocycloalkenyl group which may be optionally substituted by C1-6 alkyl, C1-4 alkoxy, halogen, carboxylic acid or a C1-4 carboxylic acid ester group; R3 represents hydrogen, C1-3 alkyl, halogen, or C1-2 alkoxy; R4, R5 and R6 independently represent hydrogen, or halogen; R7 represents hydrogen or C1-6 alkyl; R8 represents hydrogen, C3-7 cycloalkyl, C3-7 cycloalkenyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, aryl or heteroaryl, which groups are optionally substituted by one or more groups selected from halogen, hydroxy, CN, C1-6 alkyl, C1-6 alkoxy, C1-6 acyloxy, NR9R10, NHCOR11, NHSO2R12, COR13, CO2R14, CONR15R16, and SO2NHR17; X represents a bond, a C1-6 alkyl chain, or a C3-6 alkenyl chain, where one or two nitrogen, oxygen, or sulfur atoms may be optionally contained within each chain, and the chains are optionally substituted by one or more groups selected from halogen, hydroxy, CN, C1-6alkyl, C1-6alkoxy, C1-6acyloxy, NR9R10, NHCOR11, NHSO2R12, COR13, CO2R14, CONR15R16, and SO2NHR17; R9-R17 represent hydrogen, C1-6 alkyl, or R9 and R10 or R15 and R16 form a C3-7 heterocycloalkyl ring, or R12 additionally may represent trifluoromethyl; and pharmaceutically acceptable derivatives or solvates threreof, to processes for their preparation; and their use in the treatment of clinical conditions susceptible to amelioration by administration of a thrombin inhibitor.(FR) Nouvelle classe de dérivés amidés servant d'inhibiteurs de thrombine et répondant à la formule (I), dans laquelle R1 et R2, indépendamment l'un de l'autre, représentent un groupe (a), ou R1 et R2, pris ensemble, forment un groupe hétérocycloalkyle ou hétérocycloalcényle C3-7 éventuellement substitué par alkyle C1-6, alcoxy C1-4, un halogène, un acide carboxylique ou un groupe ester d'acide carboxylique C1-4; R3 représente hydrogène, alkyle C1-3, halogène ou alcoxy C1-2; R4, R5 et R6, indépendamment les uns des autres, représentent hydrogène ou halogène; R7 représente hydrogène ou alkyle C1-6; R8 représente hydrogène, cycloalkyle C3-7, cycloalcényle C3-7, hétérocycloalkyle C3-7, hétérocycloalcényle C3-7, aryle ou hétéroaryle, ces groupes étant éventuellement substitués par un ou plusieurs groupes choisis parmi halogène, hydroxy, CN, alkyle C1-6, alcoxy C1-6, acyloxy C1-6, NR9R10, NHCOR11, NHSO2R12, COR13, CO2R14, CONR15R16 et SO2NHR17; X représente une liaison, une chaîne alkyle C1-6 ou une chaîne alcényle C3-6, où un ou deux atomes d'azote, d'oxygène ou de soufre sont éventuellement compris dans chaque chaîne, et les chaînes sont éventuellement substituées par un ou plusieurs groupes choisis parmi halogène, hydroxy, CN, alkyle C1-6, alcoxy C1-6, acyloxy C1-6, NR9R10, NHCOR11, NHSO2R12, COR13, CO2R14, CONR15R16 et SO2NHR17; R9 à R17 représentent hydrogène ou alkyle C1-6, ou R9 et R10 ou R15 et R16 forment un cycle hétérocycloalkyle C3-7, ou R12 peut en outre représenter trifluorométhyle; et leurs dérivés ou solvates pharmaceutiquement acceptables; leurs procédés de préparation; et leur application au traitement des états cliniques susceptibles d'être améliorés par l'administration d'un inhibiteur de thrombine.