2-(4-hydroxyphenoxy)acetyl chloride | 115384-99-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: 2-(4-hydroxyphenoxy)acetyl chloride
• 英文别名: 2-(4-Hydroxyphenoxy)acetyl chloride
• CAS: 115384-99-1
• 化学式: C₈H₇ClO₃
• 分子量: 186.595
• InChiKey: YOHSTDWUQIJMBU-UHFFFAOYSA-N

物化性质

• 沸点：
  308.9±17.0 °C(Predicted)
• 密度：
  1.363±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  12
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  7-氨基-3-氯-3-头孢环-4-羧酸 、 2-(4-hydroxyphenoxy)acetyl chloride 在 碳酸氢钠 作用下， 以 水 、 乙腈 为溶剂， 生成 7-[(4-hydroxyphenoxy)acetamido]-3-chloro-3-cephem-4-carboxylic acid
  参考文献：
  名称：

  Oral absorption of cephalosporin antibiotics. 1. Synthesis, biological properties and oral bioavailability of 7-arylacetamido-3-chloro cephalosporins in animals

  摘要：

  A number of 7-(arylacetamido)-3-substituted cephalosporins were prepared and tested in animals for oral absorbability. Bioavailability in mice, rats, dogs, and monkeys was determined after oral or parenteral administration. Oral bioavailability of five compounds selected for more intensive study was generally higher than that of penicillin V in all species tested. The results of ED50 testing against experimental infections in mice generally supported the bioavailability studies. Antibiotic activities were evaluated against Gram-positive and Gram-negative organisms with some derivatives expressing in vitro activity similar to cefaclor. The plasma half-life in rats was relatively short and the plasma curves were strongly influenced by probenecid, indicating rapid renal secretion. Some 7-(arylacetamido)-3-chloro cephalosporins are orally absorbed in animals to a greater extent than penicillin V, and antibacterial agent of proven clinical utility.

  DOI：

  10.1021/jm00118a022
• 作为产物：
  描述：

  4-羟基苯氧乙酸 在 氯化亚砜 作用下， 以 苯 为溶剂， 反应 3.0h， 以91%的产率得到2-(4-hydroxyphenoxy)acetyl chloride
  参考文献：
  名称：

  恶二唑-异丙基酰胺作为有效的非共价蛋白酶体抑制剂

  摘要：

  对 50 000 ChemBridge 化合物库的筛选导致鉴定出恶二唑-异丙基酰胺1 (PI-1833)，其抑制胰凝乳蛋白酶样 (CT-L) 活性（IC 50 = 0.60 μM），对其他两种主要蛋白酶体几乎没有影响蛋白水解活性，胰蛋白酶样 (TL) 和谷氨酰肽水解样 (PGPH-L)。LC-MS/MS 和透析表明1是一种非共价且快速可逆的 CT-L 抑制剂。集中文库合成为11ad (PI-1840) 提供了 CT-L 活性 (IC 50= 27 纳米）。详细的 SAR 研究表明酰胺部分和两个苯环对修饰敏感。疏水性残基，如在对位丙基或丁基（未邻位或间位）的A环和一个的米-吡啶基团作为B环，显著提高活性。化合物11ad (IC 50 = 0.37 μM)在抑制完整 MDA-MB-468 人乳腺癌细胞中的 CT-L 活性和抑制其存活方面比1 (IC 50 = 3.5 μM)更有效。11ad的活

  DOI：

  10.1021/jm400221d

文献信息

• PROTEASOME CHYMOTRYPSIN-LIKE INHIBITION USING PI-1833 ANALOGS
  申请人：H. Lee Moffitt Cancer Center and Research Institute, Inc

  公开号：US20140073650A1

  公开（公告）日：2014-03-13

  Focused library synthesis and medicinal chemistry on an oxadiazole-isopropylamide core proteasome inhibitor provided the lead compound that strongly inhibits CT-L activity. Structure activity relationship studies indicate the amide moiety and two phenyl rings are sensitive toward synthetic modifications. Only para-substitution in the A-ring was important to maintain potent CT-L inhibitory activity. Hydrophobic residues in the A-ring's para-position and meta-pyridyl group at the B-ring significantly improved inhibition. The meta-pyridyl moiety improved cell permeability. The length of the aliphatic chain at the para position of the A-ring is critical with propyl yielding the most potent inhibitor, whereas shorter (i.e. ethyl, methyl or hydrogen) or longer (i.e. butyl, propyl and hexyl) chains demonstrating progressively less potency. Introduction of a stereogenic center next to the ether moiety (i.e. substitution of one of the hydrogens by methyl) demonstrated chiral discrimination in proteasome CT-L activity inhibition (the S-enantiomer was 35-40 fold more potent than the R-enantiomer).

  聚焦于氧代二唑-异丙酰胺核心蛋白酶体抑制剂的合成和药物化学，提供了一种强烈抑制CT-L活性的先导化合物。结构活性关系研究表明，酰胺基团和两个苯环对合成修饰非常敏感。只有在A环上的对位取代对维持强效的CT-L抑制活性至关重要。A环对位的疏水基团和B环的间吡啶基团显著提高了抑制作用。间吡啶基团提高了细胞渗透性。A环对位的脂肪链长度是关键，丙基产生了最有效的抑制剂，而较短（即乙基，甲基或氢）或较长（即丁基，异丙基和己基）的链逐渐表现出较少的效力。在醚基团旁引入一个立体异构中心（即将一个氢原子取代为甲基）表明在蛋白酶体CT-L活性抑制中具有手性歧视（S-对映体比R-对映体更有效，效力提高了35-40倍）。
• Proteasome chymotrypsin-like inhibition using PI-1833 analogs
  申请人：H. Lee Moffitt Cancer Center and Research Institute, Inc.

  公开号：US10662180B2

  公开（公告）日：2020-05-26

  Focused library synthesis and medicinal chemistry on an oxadiazole-isopropylamide core proteasome inhibitor provided the lead compound that strongly inhibits CT-L activity. Structure activity relationship studies indicate the amide moiety and two phenyl rings are sensitive toward synthetic modifications. Only para-substitution in the A-ring was important to maintain potent CT-L inhibitory activity. Hydrophobic residues in the A-ring's para-position and meta-pyridyl group at the B-ring significantly improved inhibition. The meta-pyridyl moiety improved cell permeability. The length of the aliphatic chain at the para position of the A-ring is critical with propyl yielding the most potent inhibitor, whereas shorter (i.e. ethyl, methyl or hydrogen) or longer (i.e. butyl, propyl and hexyl) chains demonstrating progressively less potency. Introduction of a stereogenic center next to the ether moiety (i.e. substitution of one of the hydrogens by methyl) demonstrated chiral discrimination in proteasome CT-L activity inhibition (the S-enantiomer was 35-40 fold more potent than the R-enantiomer).

  通过对一种噁二唑-异丙基酰胺核心蛋白酶体抑制剂进行重点文库合成和药物化学研究，获得了能强烈抑制 CT-L 活性的先导化合物。结构活性关系研究表明，酰胺分子和两个苯基环对合成修饰很敏感。只有 A 环中的对位取代对保持 CT-L 的强效抑制活性非常重要。A 环的对位疏水残基和 B 环的元吡啶基能显著改善抑制作用。偏吡啶基提高了细胞渗透性。A 环对位脂肪族链的长度至关重要，丙基产生的抑制作用最强，而较短的链（即乙基、甲基或氢基）或较长的链（即丁基、丙基和己基）的抑制作用则逐渐减弱。在醚分子旁边引入一个立体中心（即用甲基取代其中一个氢）可在蛋白酶体 CT-L 活性抑制方面显示出手性差异（S-对映体的效力比 R-对映体高 35-40 倍）。
• US9878999B2
  申请人：——

  公开号：US9878999B2

  公开（公告）日：2018-01-30
• [EN] COMPOUNDS<br/>[FR] COMPOSÉ
  申请人：SENEXIS LTD

  公开号：WO2008107677A2

  公开（公告）日：2008-09-12

  [EN] A compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof: wherein X is an oxygen or sulphur atom A is CH(R⁶)-, -O- or NR⁷ or when A is NR⁷, then R¹ and NR⁷ can together form a ring such that R¹ and R⁷ are (CH₂)_n, where n is 2-4, preferably 2-3; Y is a bond, CH(R⁶)-, -O- or NR⁷ or A and Y together form a single bond between the aromatic group and the carbonyl group but when A is-O- then Y is not -O-; R¹ and R² are independently hydrogen, halogen, OR⁸, NR⁹R¹⁰, NR⁹COR¹¹, NR⁹SO₂R¹¹ or C_1-6 alkyl optionally substituted by fluorine, hydroxyl, C_1-6 alkoxy or NR⁹R¹⁰; R³ is C_1-6 alkyl, C_3-8 cycloalkyl C_4-10 alkylcycloalkyl optionally substituted by hydroxyl, C_1-6 alkoxy or NR⁹R¹⁰; R⁴ is hydrogen, halogen, CF₃, OR⁹, NR⁹R¹⁰, NR⁹COR¹¹, NR⁹SO₂R¹¹ or C_1-6 alkyl optionally substituted by hydroxyl, C_1-6 alkoxy or NR⁹R¹⁰; R⁵ is hydrogen, halogen, CF₃, OR⁸, COOR⁹, CONR⁹R¹⁰ or SO₂R¹¹; R⁶ is hydrogen, C_1-6 alkyl, C_3-8 cycloalkyl C_4-10 alkylcycloalkyl, C_1-6 alkyl optionally substituted by hydroxyl, C_1-6 alkoxy or NR⁹R¹⁰, C_1-6 alkoxy or NR⁹R¹⁰; R⁷ is hydrogen, C_1-6 alkyl optionally substituted by C_1-6 alkoxy or NR⁹R¹⁰, phenyl wherein said phenyl group is optionally substituted by one or more substituents selected from halogen, C_1-6 alkyl, CF₃, OCF₃ or OR⁹; R⁸ is hydrogen or C_1-6 alkyl optionally substituted by fluorine, C_1-6 alkoxy or NR⁹R¹⁰; R⁹ is hydrogen, C_1-6 alkyl or C_1-3 alkylphenyl wherein said phenyl group is optionally substituted by one or more substituents selected from halogen, C_1-6 alkyl optionally substituted by fluorine, OR⁸, NR⁹R¹⁰; R¹⁰ is hydrogen, C_1-6 alkyl, C_3-8 cycloalkyl C_4-10 alkylcycloalkyl, C_1-6 alkenyl, phenyl or C_1-3 alkylphenyl wherein said phenyl groups are optionally substituted by one or more substituents selected from halogen, C_1-6 alkyl optionally substituted by fluorine, OR⁸; or the groups R⁹ and R¹⁰ when they are attached to a nitrogen atom may together form a 5- or 6-membered ring which optionally contains one further heteroatom selected from NR9, S and O; and R¹¹ is C_1-6 alkyl or a phenyl group optionally substituted by one or more substituents selected from halogen, C_1-6 alkyl, CF₃, OCF₃ or OR⁸; with the provisos that when A is -O- or NR⁷ and Y is CH(R⁶) then R⁶ is not C_1-6 alkoxy or NR⁹R¹⁰; when
  [FR] L'invention porte sur un composé de formule (I) ou un sel pharmaceutiquement acceptable ou un promédicament de celui-ci : où X est un atome d'oxygène ou de soufre, A représente CH(R⁶)-, -O- ou NR⁷ ou lorsque A est NR⁷, R¹ et NR⁷ peuvent former ensemble un cycle tel que R¹ et NR⁷ sont (CH₂)_n, où n est 2-4, de préférence 2-3 ; Y est une liaison, CH(R⁶)-, -O- ou NR⁷ ou A et Y forment ensemble une simple liaison entre le groupe aromatique et le groupe carbonyle, mais, lorsque A est -O-, alors Y n'est pas -O- ; R¹ et R² sont indépendamment hydrogène, halogène, OR⁸, NR⁹R¹⁰, NR⁹COR¹¹, NR⁹SO₂R¹¹ ou alkyle en C_1-6 facultativement substitué par fluor, hydroxyle, alcoxy en C_1-6 ou NR⁹R¹⁰ ; R³ représente alkyle en C_1-6, cycloalkyle en C_3-8, alkylcycloalkyle en C_4-10, facultativement substitué par hydroxyle, alcoxy en C_1-6 ou NR⁹R¹⁰ ; R⁴ représente hydrogène, halogène, CF₃, OR⁹, NR⁹R¹⁰, NR⁹COR¹¹, NR⁹SO₂R¹¹ ou alkyle en C_1-6 facultativement substitué par hydroxyle, alcoxy en C_1-6 ou NR⁹R¹⁰ ; R⁵ représente hydrogène, halogène, CF₃, OR⁸, COOR⁹, CONR⁹R¹⁰ ou SO₂R¹¹ ; R⁶ représente hydrogène, alkyle en C_1-6, cycloalkyle en C_3-8, alkylcycloakyle en C_4-10, alkyle en C_1-6 facultativement substitué par hydroxyle, alcoxy en C_1-6 ou NR⁹R¹⁰, alcoxy en C_1-6 ou NR⁹R¹⁰ ; R⁷ représente hydrogène, alkyle en C_1-6 facultativement substitué par alcoxy en C_1-6 ou NR⁹R¹⁰, phényle dans lequel ledit groupe phényle est facultativement substitué par un ou plusieurs substituants choisis parmi halogène, alkyle en C_1-6, CF₃, OCF₃ ou OR⁹ ; R⁸ représente hydrogène ou alkyle en C_1-6 facultativement substitué par fluor, alcoxy en C_1-6 ou NR⁹R¹⁰ ; R⁹ représente hydrogène, alkyle en C_1-6 ou alkyle en C_1-3-phényle, dans lequel ledit groupe phényle est facultativement substitué par un ou plusieurs substituants choisis parmi halogène, alkyle en C_1-6 facultativement substitué par fluor, OR⁸, NR⁹R¹⁰; R¹⁰ représente hydrogène, alkyle en C_1-6, cycloalkyle en C_3-8, alkylcycloalkyle en C_4-10, alcényle en C_1-6, phényle ou alkyle en C_1-3-phényle, dans lequel lesdits groupes phényle sont facultativement substitués par un ou plusieurs substituants choisis parmi halogène, alkyle en C_1-6 facultativement substitué par fluor, OR⁸ ; ou les groupes R⁹ et R¹⁰ lorsqu'ils sont attachés à un atome d'azote peuvent former ensemble un noyau à 5 ou 6 chaînons qui contient facultativement un autre hétéroatome choisi par
• [EN] PROTEASOME CHYMOTRYPSIN-LIKE INHIBITION USING PI-1833 ANALOGS<br/>[FR] INHIBITION DE CHYMOTRYPSINE-LIKE DU PROTÉASOME À L'AIDE D'ANALOGUES DE PI-1833
  申请人：H LEE MOFFITT CANCER CT & RES

  公开号：WO2012129564A2

  公开（公告）日：2012-09-27

  Focused library synthesis and medicinal chemistry on an oxadiazole-isopropylamide core proteasome inhibitor provided the lead compound that strongly inhibits CT-L activity. Structure activity relationship studies indicate the amide moiety and two phenyl rings are sensitive toward synthetic modifications. Only para-substitution in the A-ring was important to maintain potent CT-L inhibitory activity. Hydrophobic residues in the A-ring's para-position and meta-pyridyl group at the B-ring significantly improved inhibition. The meta-pyridyl moiety improved cell permeability. The length of the aliphatic chain at the para position of the A-ring is critical with propyl yielding the most potent inhibitor, whereas shorter (i.e. ethyl, methyl or hydrogen) or longer (i.e. butyl, propyl and hexyl) chains demonstrating progressively less potency. Introduction of a stereogenic center next to the ether moiety (i.e. substitution of one of the hydrogens by methyl) demonstrated chiral discrimination in proteasome CT-L activity inhibition (the S-enantiomer was 35-40 fold more potent than the R-enantiomer).