2-(2-bromo-ethoxycarbonylmethyl)-5-nitro-benzoic acid | 141468-58-8

• 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: 2-(2-bromo-ethoxycarbonylmethyl)-5-nitro-benzoic acid
• 英文别名: 2-[2-(2-bromoethoxy)-2-oxoethyl]-5-nitrobenzoic acid
• CAS: 141468-58-8
• 化学式: C₁₁H₁₀BrNO₆
• 分子量: 332.107
• InChiKey: XYRQGEZLLZCOSK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  19
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  109
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-(2-bromo-ethoxycarbonylmethyl)-5-nitro-benzoic acid 在 五氯化磷 、 palladium on activated charcoal 、 氢气 作用下， 以 四氢呋喃 、 氯仿 、 甲苯 为溶剂， 生成 7-氨基-3-(2-溴乙氧基)-4-氯异苯并吡喃-1-酮
  参考文献：
  名称：

  异香豆素的炔烃衍生物作为丝氨酸蛋白酶的可点击的基于活性的探针

  摘要：

  基于活动的探针（ABP）已发现在功能蛋白质组学研究中的使用越来越多。近来，可与点击化学结合使用的ABP由于其在体内和体外的灵活应用而受到了特别的关注。此外，持续需要针对小部分酶的新ABP。我们在此报告基于4-氯-异香豆素（IC）亲电子体的新型可点击ABP，这是一种基于机理的抑制剂骨架，与丝氨酸蛋白酶共价结合。我们描述了一个IC ABPs小库的合成，该库包含炔烃功能和一组不同的选择性元素。IC结构上的不同取代基决定结合哪些蛋白酶，与优选的底物偏好表现出良好的相关性。IC ABP可以以敏感的方式（低至总蛋白的0.007％）在蛋白质组背景中检测其目标蛋白酶。此外，我们显示了组织蛋白质组中内源蛋白酶的活性依赖性和选择性标记。因此，这些IC代表了对丝氨酸蛋白酶已经存在的ABP的宝贵扩展，并且可能在将来阐明丝氨酸蛋白酶功能方面发挥了作用。

  DOI：

  10.1016/j.bmc.2011.03.014
• 作为产物：
  描述：

  邻羧基苯乙酸 在 硫酸 、 硝酸 作用下， 反应 6.12h， 生成 2-(2-bromo-ethoxycarbonylmethyl)-5-nitro-benzoic acid
  参考文献：
  名称：

  Synthesis of new 3-alkoxy-7-amino-4-chloro-isocoumarin derivatives as new β-amyloid peptide production inhibitors and their activities on various classes of protease

  摘要：

  A series of new 7-substituted-4-chloro-3-alkoxy isocoumarin derivatives were synthesized and evaluated as inhibitors of representative classes of proteases: serine protease (alpha-chymotrypsin, trypsin), cysteine protease (Caspase-3), and aspartyl protease (HIV-protease), 20S proteasome and also as inhibitors of amyloid peptide gamma-secretase-mediated production. Protease inhibition selectivity is directly related to the structure of the substituent at the 7-position of the isocoumarin nucleus. 7-Nitro-isocoumarin derivatives (4c, 4d 4f) are potent alpha-chymotrypsin inhibitors but slightly active or inactive on HIV-protease, as well as on cysteine protease. In contrast.. only derivatives bearing a free amino (5d, 5f) or a substituted amino group (6f) at the 7-position of the isocoumarin nucleus, were found weakly active or inactive on alpha-chymotrypsin, trypsin, Caspase-3 and HIV-protease, but prevent gamma-secretase-mediated production of Abeta 40/42 amyloid peptides, which is known to be involved in Alzheimer's disease. Moreover, the most active compounds on beta-amyloid peptide production [JLK6 (5d), JLK2 (5f) and JLK7 (6f)] show only weak or moderate inhibitory activity on the 20S proteasome. The obtained results suggest that the described new isocoumarin analogues could be of interest, since compounds like JLK6 (5d), JLK2 (5f) and JLK7 (6f) can be considered as possible hits for the development of new agents directed towards Alzheimer's disease. (C) 2003 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00235-9

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。
• Mechanism-Based Isocoumarin Inhibitors for Blood Coagulation Serine Proteases. Effect of the 7-Substituent in 7-Amino-4-chloro-3-(isothioureidoalkoxy)isocoumarins on Inhibitory and Anticoagulant Potency
  作者：Chih-Min Kam、John E. Kerrigan、R. Richard Plaskon、Edward J. Duffy、Pete Lollar、F. L. Suddath、James C. Powers

  DOI：10.1021/jm00035a009

  日期：1994.4

  7-amino-4-chloro-3-(3-isothioureidopropoxy)isocoumarin (NH2-CiTPrOIC) derivatives with various substituents at the 7- and 3-positions have been synthesized as inhibitors of several blood coagulation enzymes. Isocoumarins substituted with basic groups such as guanidino or isothioureidoalkoxy groups were previously shown to be potent irreversible inhibitors of blood coagulation enzymes [Kam et al. Biochemistry

  已经合成了在7位和3位带有各种取代基的一系列7-氨基-4-氯-3-（3-异硫脲基丙氧基）异香豆素（NH2-CiTPrOIC）衍生物，它们是几种凝血酶的抑制剂。先前已显示被诸如胍基或异硫脲基烷氧基等碱性基团取代的异香豆素是有效的不可逆的凝血酶抑制剂[Kam et al。生物化学1988，27，2547-2557]。与NH2-CiTPrOIC（4）相比，在3位具有异硫脲基乙氧基和在7位具有大疏水基团的取代的香豆素是更好的凝血酶，VIIa，Xa，XIa，IIa和IXa抑制剂。PhNHCONH-CiTEtOIC（14），（S）-Ph（CH3）CHNHCONH-CiTEtOIC（25），和（R）-Ph（CH3）CHNHCONH-CiTEtOIC（26）非常有效地抑制凝血酶，并且kobs / [I]值为（1-4）x 10（4）M-1 s-1。与人α-凝血酶非共价复合的几种异香豆素的结构模型表明，7位取代基与Lys-60F
• 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.
• Alkyne derivatives of isocoumarins as clickable activity-based probes for serine proteases
  作者：Ute Haedke、Markus Götz、Philipp Baer、Steven H.L. Verhelst

  DOI：10.1016/j.bmc.2011.03.014

  日期：2012.1

  detect their target proteases in a proteome background in a sensitive manner (down to 0.007% of total protein). Furthermore, we show activity-dependent and selective labeling of endogenous proteases in a tissue proteome. These ICs therefore represent a valuable extension to already existing ABPs for serine proteases and may be instrumental in future elucidation of serine protease functions.

  基于活动的探针（ABP）已发现在功能蛋白质组学研究中的使用越来越多。近来，可与点击化学结合使用的ABP由于其在体内和体外的灵活应用而受到了特别的关注。此外，持续需要针对小部分酶的新ABP。我们在此报告基于4-氯-异香豆素（IC）亲电子体的新型可点击ABP，这是一种基于机理的抑制剂骨架，与丝氨酸蛋白酶共价结合。我们描述了一个IC ABPs小库的合成，该库包含炔烃功能和一组不同的选择性元素。IC结构上的不同取代基决定结合哪些蛋白酶，与优选的底物偏好表现出良好的相关性。IC ABP可以以敏感的方式（低至总蛋白的0.007％）在蛋白质组背景中检测其目标蛋白酶。此外，我们显示了组织蛋白质组中内源蛋白酶的活性依赖性和选择性标记。因此，这些IC代表了对丝氨酸蛋白酶已经存在的ABP的宝贵扩展，并且可能在将来阐明丝氨酸蛋白酶功能方面发挥了作用。
• Synthesis of new 3-alkoxy-7-amino-4-chloro-isocoumarin derivatives as new β-amyloid peptide production inhibitors and their activities on various classes of protease
  作者：Frédéric Bihel、Gilles Quéléver、Hugues Lelouard、Agnès Petit、Cristine Alvès da Costa、Olivier Pourquié、Frédéric Checler、Annie Thellend、Philippe Pierre、Jean-Louis Kraus

  DOI：10.1016/s0968-0896(03)00235-9

  日期：2003.7

  A series of new 7-substituted-4-chloro-3-alkoxy isocoumarin derivatives were synthesized and evaluated as inhibitors of representative classes of proteases: serine protease (alpha-chymotrypsin, trypsin), cysteine protease (Caspase-3), and aspartyl protease (HIV-protease), 20S proteasome and also as inhibitors of amyloid peptide gamma-secretase-mediated production. Protease inhibition selectivity is directly related to the structure of the substituent at the 7-position of the isocoumarin nucleus. 7-Nitro-isocoumarin derivatives (4c, 4d 4f) are potent alpha-chymotrypsin inhibitors but slightly active or inactive on HIV-protease, as well as on cysteine protease. In contrast.. only derivatives bearing a free amino (5d, 5f) or a substituted amino group (6f) at the 7-position of the isocoumarin nucleus, were found weakly active or inactive on alpha-chymotrypsin, trypsin, Caspase-3 and HIV-protease, but prevent gamma-secretase-mediated production of Abeta 40/42 amyloid peptides, which is known to be involved in Alzheimer's disease. Moreover, the most active compounds on beta-amyloid peptide production [JLK6 (5d), JLK2 (5f) and JLK7 (6f)] show only weak or moderate inhibitory activity on the 20S proteasome. The obtained results suggest that the described new isocoumarin analogues could be of interest, since compounds like JLK6 (5d), JLK2 (5f) and JLK7 (6f) can be considered as possible hits for the development of new agents directed towards Alzheimer's disease. (C) 2003 Elsevier Science Ltd. All rights reserved.