7-氨基-3-(2-溴乙氧基)异色烯-1-酮 | 913837-02-2

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 异香豆素及其衍生物
• 中文名称: 7-氨基-3-(2-溴乙氧基)异色烯-1-酮
• 英文名称: 7-amino-3-(2-bromoethoxy)-isocoumarin
• 英文别名: 7-Amino-3-(2-bromoethoxy)-1H-2-benzopyran-1-one；7-amino-3-(2-bromoethoxy)isochromen-1-one
• CAS: 913837-02-2
• 化学式: C₁₁H₁₀BrNO₃
• 分子量: 284.109
• InChiKey: OPBJLBJYBIRHFP-UHFFFAOYSA-N

物化性质

• 熔点：
  >280 °C(Solv: dichloromethane (75-09-2); methanol (67-56-1))
• 沸点：
  472.8±45.0 °C(Predicted)
• 密度：
  1?+-.0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  61.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-乙酸基-4-硝基苯甲酸 在 硫酸 、 palladium 10% on activated carbon 、 氢气 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 5.0h， 生成 7-氨基-3-(2-溴乙氧基)异色烯-1-酮
  参考文献：
  名称：

  Further characterization of a putative serine protease contributing to the γ-secretase cleavage of β-amyloid precursor protein

  摘要：

  The 3-alkoxy-7-amino-4-chloro-isocoumarins JLK-6 and JLK-2 have been shown to markedly reduce the production of Amyloid beta-peptide (A beta) by Amyloid-beta Precursor Protein (APP) expressing HEK293 cells by affecting the gamma-secretase cleavage of APP, with no effect on the cleavage of the Notch receptor. This suggested that these compounds do not directly inhibit the presenilin-dependent gamma-secretase complex but more likely interfere with an upstream target involved in gamma-secretase-associated pathway. The mechanism of action of these compounds is unknown and there are high fundamental and therapeutical interests to unravel their target. Isocoumarin compounds were previously shown to behave as potent mechanism-based irreversible inhibitors of serine proteases, suggesting that the JLK-directed target could belong to such enzyme family. To get further insight into structure-activity relationships and to develop more potent isocoumarin derivatives, we have synthesized and evaluated a series of isocoumarin analogues with modifications at positions 3, 4 and 7. In particular, the 7-amino group was substituted with either acyl, urethane, alkyl or aryl groups, which could represent additional interaction sites. Altogether, the results highlighted the essential integrity of the 3-alkoxy-7-amino-4-chloro-isocoumarin scaffold for A beta-lowering activity and supported the involvement of a seri ne protease, or may be more generally, a serine hydrolase. The newly reported 7-N-alkyl series produced the most active compounds with an IC50 between 10 and 30 mu M. Finally, we also explored peptide boronates, a series of reversible serine protease inhibitors, previously shown to also lower cellular A beta production. The presented data suggested they could act on the same target or interfere with the same pathway as isocoumarins derivatives. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.11.045

文献信息

• Isocoumarin-based inhibitors of urokinase-type plasminogen activator
  申请人：Deck M. Lorraine

  公开号：US20060252823A1

  公开（公告）日：2006-11-09

  The present invention relates to chemical compounds, pharmaceutical compositions and methods for treating tumors and cancer and diseases which involve angiogenesis including retinopathy, age-related macular degeneration, angiogenic skin disorders and inflammation, including chronic inflammatory diseases, such as psoriasis, acne, rosacea, warts, eczema, hemangiomas, lymphangiogenesis, arthritis, lupus and scleroderma, among others. Compounds according to the present invention have the chemical structure: Where X is O or S, preferably O; Y is O, S, or N, preferably O; R 3 is an optionally substituted C 1 -C 7 alkyl group, an optionally substituted (CH 2 ) n R b group or an OR group; R b is a guanidino group or a thioguanidino group; R is an optionally substituted C 1 -C 7 alkyl group or an optionally substituted (CH 2 ) n R′ group; n is 0, 1, 2, 3, 4, 5, 6, or 7 (preferably 2, 3 or 4); R′ is F, Cl, Br or I (preferably Br), NO 2 , an R″ group, an OR″ group or an SR″ group, where R″ is an optionally substituted C 1 -C 6 alkyl group, a guanidino group or a thioguanidino group; R 4 is H, F, Cl, Br, I, NO 2 , OH, R 1 or OR 1 , where R 1 is an optionally substituted C 1 -C 7 alkyl group or an optionally substituted C 2 -C 11 acyl group; R 6 is H, an optionally substituted C 1 -C 6 alkyl group, or together with R 7 forms an optionally substituted 5-7 membered saturated or unsaturated carbocyclic group, an optionally substituted 5-7 membered saturated or unsaturated heterocyclic group, or an optionally substituted aromatic or heteroaromatic group; R 7 is H, F, Cl, Br, I, NO 2 , NR a′ R b′ or NHR b , where R a′ and R b′ are independently H or a C 1 -C 3 alkyl group and R b is a C 2 -C 11 acyl group which is optionally substituted, or together with R 6 or R 8 forms an optionally substituted 5-7 membered saturated or unsaturated carbocyclic group, an optionally substituted 5-7 membered saturated or unsaturated heterocyclic group, or an optionally substituted aromatic or heteroaromatic group; R 8 is H, an optionally substituted C 1 -C 6 alkyl group, or together with R 7 forms an optionally substituted 5-7 membered saturated or unsaturated carbocyclic group, an optionally substituted 5-7 membered saturated or unsaturated heterocyclic group, or an optionally substituted aromatic or heteroaromatic group; and pharmaceutically acceptable salts, thereof.

  本发明涉及化合物、药物组合物和治疗肿瘤、癌症以及涉及血管生成的疾病，包括视网膜病变、年龄相关性黄斑变性、血管生成性皮肤疾病和炎症，包括慢性炎症性疾病，如银屑病、痤疮、酒渣鼻、疣、湿疹、血管瘤、淋巴管生成、关节炎、狼疮和硬皮病等。根据本发明的化合物具有以下化学结构：其中X为O或S，优选为O；Y为O、S或N，优选为O；R3为可选择取代的C1-C7烷基基团、可选择取代的(CH2)nRb基团或OR基团；Rb为胍基团或硫胍基团；R为可选择取代的C1-C7烷基基团或可选择取代的(CH2)nR'基团；n为0、1、2、3、4、5、6或7（优选为2、3或4）；R'为F、Cl、Br或I（优选为Br）、NO2、R″基团、OR″基团或SR″基团，其中R″为可选择取代的C1-C6烷基基团、胍基团或硫胍基团；R4为H、F、Cl、Br、I、NO2、OH、R1或OR1，其中R1为可选择取代的C1-C7烷基基团或可选择取代的C2-C11酰基基团；R6为H、可选择取代的C1-C6烷基基团，或与R7一起形成可选择取代的5-7成员饱和或不饱和碳环基团、可选择取代的5-7成员饱和或不饱和杂环基团，或可选择取代的芳香基或杂芳基；R7为H、F、Cl、Br、I、NO2、NRa′Rb′或NHRb，其中Ra′和Rb′独立地为H或C1-C3烷基基团，Rb为可选择取代的C2-C11酰基基团，或与R6或R8一起形成可选择取代的5-7成员饱和或不饱和碳环基团、可选择取代的5-7成员饱和或不饱和杂环基团，或可选择取代的芳香基或杂芳基；R8为H、可选择取代的C1-C6烷基基团，或与R7一起形成可选择取代的5-7成员饱和或不饱和碳环基团、可选择取代的5-7成员饱和或不饱和杂环基团，或可选择取代的芳香基或杂芳基；以及其药学上可接受的盐。
• Isocoumarin-based inhibitors of pancreatic cholesterol esterase
  作者：Justin J. Heynekamp、Lucy A. Hunsaker、Thomas A. Vander Jagt、Robert E. Royer、Lorraine M. Deck、David L. Vander Jagt

  DOI：10.1016/j.bmc.2008.03.016

  日期：2008.5

  Pancreatic cholesterol esterase (CEase), which is secreted from the exocrine pancreas, is a serine hydrolase that aids in the bile salt-dependent hydrolysis of dietary cholesteryl esters and contributes to the hydrolysis of triglycerides and phospholipids. Additional roles for CEase in intestinal micelle formation and in transport of free cholesterol to the enterocyte have been suggested. There also are studies that point to a pathological role(s) for CEase in the circulation where CEase accumulates in atherosclerotic lesions and triggers proliferation of smooth muscle cells. Thus, there is interest in CEase as a potential drug target. 4-Chloro-3-alkoxyisocoumarins are a class of haloenol lactones that inhibit serine hydrolases and serine proteases and have the potential to be suicide inhibitors. In the present study, we have developed 3-alkoxychloroisocoumarins that are potent inhibitors of CEase. These inhibitors were designed to have a saturated cycloalkane ring incorporated into a 3-alkoxy substituent. The size of the ring as well as the length of the tether holding the ring was found to be important contributors to binding to CEase. 4-Chloro-3-(4-cyclohexylbutoxy) isocoumarin and 4-chloro-3-(3-cyclopentylpropoxy) isocoumarin were demonstrated to be potent reversible inhibitors of CEase, with dissociation constants of 11 nM and 19 nM, respectively. The kinetic results are consistent with predictions from molecular modeling. (C) 2008 Elsevier Ltd. All rights reserved.
• Further characterization of a putative serine protease contributing to the γ-secretase cleavage of β-amyloid precursor protein
  作者：Marine Peuchmaur、Marie-Agnès Lacour、Jean Sévalle、Vincent Lisowski、Youness Touati-Jallabe、Fabien Rodier、Jean Martinez、Frédéric Checler、Jean-François Hernandez

  DOI：10.1016/j.bmc.2012.11.045

  日期：2013.2

  The 3-alkoxy-7-amino-4-chloro-isocoumarins JLK-6 and JLK-2 have been shown to markedly reduce the production of Amyloid beta-peptide (A beta) by Amyloid-beta Precursor Protein (APP) expressing HEK293 cells by affecting the gamma-secretase cleavage of APP, with no effect on the cleavage of the Notch receptor. This suggested that these compounds do not directly inhibit the presenilin-dependent gamma-secretase complex but more likely interfere with an upstream target involved in gamma-secretase-associated pathway. The mechanism of action of these compounds is unknown and there are high fundamental and therapeutical interests to unravel their target. Isocoumarin compounds were previously shown to behave as potent mechanism-based irreversible inhibitors of serine proteases, suggesting that the JLK-directed target could belong to such enzyme family. To get further insight into structure-activity relationships and to develop more potent isocoumarin derivatives, we have synthesized and evaluated a series of isocoumarin analogues with modifications at positions 3, 4 and 7. In particular, the 7-amino group was substituted with either acyl, urethane, alkyl or aryl groups, which could represent additional interaction sites. Altogether, the results highlighted the essential integrity of the 3-alkoxy-7-amino-4-chloro-isocoumarin scaffold for A beta-lowering activity and supported the involvement of a seri ne protease, or may be more generally, a serine hydrolase. The newly reported 7-N-alkyl series produced the most active compounds with an IC50 between 10 and 30 mu M. Finally, we also explored peptide boronates, a series of reversible serine protease inhibitors, previously shown to also lower cellular A beta production. The presented data suggested they could act on the same target or interfere with the same pathway as isocoumarins derivatives. (C) 2012 Elsevier Ltd. All rights reserved.