2,5-dichlorophenyl 6-(chloromethyl)-2-oxo-2H-chromene-3-carboxylate | 217081-33-9

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 香豆素及其衍生物
• 英文名称: 2,5-dichlorophenyl 6-(chloromethyl)-2-oxo-2H-chromene-3-carboxylate
• 英文别名: (2,5-dichlorophenyl) 6-(chloromethyl)-2-oxochromene-3-carboxylate
• CAS: 217081-33-9
• 化学式: C₁₇H₉Cl₃O₄
• 分子量: 383.615
• InChiKey: OZKMBTRSTVYGMK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  52.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-羟基-5-(羟基甲基)苯甲醛 在 哌啶 、 吡啶 、 盐酸 、 氯化亚砜 、 溶剂黄146 作用下， 以 乙醇 为溶剂， 反应 25.0h， 生成 2,5-dichlorophenyl 6-(chloromethyl)-2-oxo-2H-chromene-3-carboxylate
  参考文献：
  名称：

  3,6-Disubstituted Coumarins as Mechanism-Based Inhibitors of Thrombin and Factor Xa

  摘要：

  In this work, coumarins were screened on thrombin (THR) and factor Xa (FXa), two of the most promising targets for the development of anticoagulant drugs. This allowed us to highlight compound 30, characterized by a 2,5-dichlorophenyl ester in the 3-position and a chloromethyl moiety in the 6-position, as a very potent THR inhibitor (k(i)/K-I, = 37 000 M-1 s(-1)). Moreover, this compound exhibits good selectivity over FXa (168-fold) and trypsin (54-fold). The mechanism of inactivation was investigated in this series and significantly differs from that previously observed with (x-chymotrypsin. Indeed, the addition of hydrazine on the THR-inhibitor complex promotes a partial induced THR reactivation. This reactivation, confirmed by LC/MS, showed the resurgence of the native THR and a new dihydrazide complex. Docking experiments were then efficiently used to explain the trends observed in the enzymatic assays as well as to corroborate the postulated inhibition mechanism. Finally, the cell permeability of our derivatives was estimated using a computational approach.

  DOI：

  10.1021/jm050448g

文献信息

• Coumarinic derivatives as mechanism-based inhibitors of α-chymotrypsin and human leukocyte elastase
  作者：Lionel Pochet、Caroline Doucet、Georges Dive、Johan Wouters、Bernard Masereel、Michèle Reboud-Ravaux、Bernard Pirotte

  DOI：10.1016/s0968-0896(00)00071-7

  日期：2000.6

  inhibitory potency toward alpha-CT and HLE. Cycloalkyl esters and amides were found to be essentially inactive on both enzymes. On the opposite, aromatic esters strongly inactivated alpha-CT whereas HLE was less efficiently inhibited with dichlorophenyl ester derivatives (kinact/K(I) = 4000 M(-1) s(-1) for 36). Representative examples of amide, ester, thioester and ketone derivatives were prepared in order

  合成了新型香豆素衍生物，并测试了其对α-CT和HLE的抑制作用。发现环烷基酯和酰胺对两种酶基本上无活性。相反，芳香族酯强烈地使α-CT失活，而二氯苯基酯衍生物对HLE的抑制作用较弱（36的动力学/ K（I）= 4000 M（-1）s（-1））。制备酰胺，酯，硫代酯和酮衍生物的代表性实例，以评估香豆素环与苯基侧链之间的连接的影响。如修饰的胰凝乳蛋白酶的氨基酸分析所示，6-氯甲基衍生物不可逆地使α-CT失活是由于组氨酸残基的烷基化。相反，对HLE的抑制是短暂的。香豆素的内在反应性已使用配体与甲醇-水对之间的亲核反应模型进行了计算。从该计算看来，这些分子表达的抑制能力的差异不能仅通过内酯羰基对亲核攻击的反应性差异来解释。
• [EN] USE OF COUMARIN DERIVATIVES FOR THE PREPARATION OF DRUGS FOR TREATING SKIN DISEASES<br/>[FR] UTILISATION DE DÉRIVÉS DE COUMARINE POUR LA PRÉPARATION DE MÉDICAMENTS POUR LE TRAITEMENT DE MALADIES DE LA PEAU
  申请人：UNIV PARIS CURIE

  公开号：WO2013010963A1

  公开（公告）日：2013-01-24

  The invention relates to a compound of formula (I-1) wherein n equals 0 or 1, Z represents O or S, R1 represents one group chosen among the group consisting ofhydrogen, C1-C7 alkyl, substituted, or not, by a halogen, a hydroxyl or a O-R12 group, wherein R12 is a C1-C7 alkyl, a group CH2OCOR5 wherein R5 is chosen among a hydrogen atom and a C1-C7 alkyl, substituted or not by at least one halogen, a group O-R13, wherein R13 is chosen among hydrogen and a C1-C7 alkyl, an amine or a CH2-amine, R1 represents a group chosen among hydrogen and O-R14, wherein R14 is chosen among hydrogen and a C1-C7 alkyl, and R2 is chosen among the group consisting of a C1-C7 alkyl, a C3-C6 cycloalkyl, an aryl group, and an heteroaryl group for its use for the treatment of pathologies involving an excess of activity of at least one member of the kallikrein family.

  该发明涉及一种化合物，其化学式为（I-1），其中n等于0或1，Z代表O或S，R1代表在羟基、C1-C7烷基、经取代或未取代的氢、卤素、羟基或O-R12基团中选择的一种基团，其中R12是C1-C7烷基、CH2OCOR5基团中的一种，其中R5选择在氢原子和C1-C7烷基之间，经取代或未取代，至少含有一个卤素，O-R13基团中选择在氢和C1-C7烷基之间，胺或CH2-胺，R1代表在氢和O-R14之间选择的一种基团，其中R14选择在氢和C1-C7烷基之间，R2选择在C1-C7烷基、C3-C6环烷基、芳基和杂环芳基之间的一种基团，用于治疗涉及卡利克雷因家族至少一成员活性过量的病理。
• Use of coumarin derivatives for the preparation of drugs for treating skin diseases
  申请人：Université Pierre et Marie Curie - Paris 6

  公开号：EP2545916A1

  公开（公告）日：2013-01-16

  The invention relates to a compound of formula (I) wherein n equals 0 or 1, and wherein, if n=1, Z represents O or S, R1 represents at least one group chosen among the group consisting of hydrogen, a linear or branched, saturated or not, C1-C7 alkyl, substituted, or not, by a halogen, a group -CH2-O-CO-R5 wherein R5 is chosen among a hydrogen atom, and a linear or branched, saturated or not, C1-C7 alkyl, substituted or not by at least one halogen, and an amine, and R2 is chosen among the group consisting of a linear or branched, saturated or not C1-C7 alkyl, a C3-C6 cycloalkyl, an aryl group, and an heteroaryl group for its use for the treatment of pathologies involving an excess of activity of at least one member of the kallikrein family.

  该发明涉及一种具有公式（I）的化合物，其中n等于0或1，如果n=1，则Z代表O或S，R1代表至少选择自氢、一种线性或支链、饱和或非饱和的C1-C7烷基中的一种，该烷基可以被卤素取代或不取代，一个基团-CH2-O-CO-R5，其中R5选择自氢原子，以及一种线性或支链、饱和或非饱和的C1-C7烷基，该烷基可以被至少一个卤素取代或不取代，以及一种胺，R2选择自线性或支链、饱和或非饱和的C1-C7烷基中的一种，C3-C6环烷基，芳基和杂环芳基，用于治疗涉及至少一种卡利克雷因家族成员活性过高的病理的用途。
• USE OF COUMARIN DERIVATIVES FOR THE PREPARATION OF DRUGS FOR TREATING SKIN DISEASES
  申请人：UNIVERSITE PIERRE ET MARIE CURIE (PARIS 6)

  公开号：US20140148480A1

  公开（公告）日：2014-05-29

  A compound of formula (I-1) wherein n equals 0 or 1, Z represents O or S, R1 represents one group chosen among the group consisting of hydrogen, C1-C7 alkyl, substituted, or not, by a halogen, a hydroxyl or a —O—R12 group, wherein R12 is a C1-C7 alkyl, a group —CH 2 —O—CO—R5 wherein R5 is chosen among a hydrogen atom and a C1-C7 alkyl, substituted or not by at least one halogen, a group —O—R13, wherein R13 is chosen among hydrogen and a C1-C7 alkyl, an amine or a —CH 2 — amine, R′1 represents a group chosen among hydrogen and —O—R14, wherein R14 is chosen among hydrogen and a C1-C7 alkyl, and R2 is chosen among the group consisting of a C1-C7 alkyl, a C3-C6 cycloalkyl, an aryl group, and an heteroaryl group for the treatment of pathologies involving excess activity of at least one member of the kallikrein family.

  化合物的公式（I-1），其中n等于0或1，Z代表O或S，R1代表从以下组中选择的一组基团，该组基团由氢，C1-C7烷基组成，被卤素，羟基或—O—R12基团取代或未取代，其中R12是C1-C7烷基，一个基团—CH2—O—CO—R5，其中R5选择氢原子和C1-C7烷基，被至少一个卤素取代或未取代，一个基团—O—R13，其中R13选择氢和C1-C7烷基，胺或—CH2—胺，R'1代表选择氢和—O—R14之一的基团，其中R14选择氢和C1-C7烷基，而R2选择在由C1-C7烷基，C3-C6环烷基，芳基和杂芳基组成的一组中，用于治疗涉及至少一种卡利克雷因家族成员过度活性的病理情况。
• US6355658B1
  申请人：——

  公开号：US6355658B1

  公开（公告）日：2002-03-12