ethyl 5-[2-(3-ethoxy-3-oxopropyl)-3-hydroxyphenoxy]pentanoate | 152608-80-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: ethyl 5-[2-(3-ethoxy-3-oxopropyl)-3-hydroxyphenoxy]pentanoate
• 英文别名: 5-[2-(2-ethoxycarbonylethyl)-3-hydroxyphenoxy]-pentanoic acid ethyl ester；ethyl 3-(2-hydroxy-6-(4-ethoxycarbonylbutyloxy)phenyl)propionate
• CAS: 152608-80-5
• 化学式: C₁₈H₂₆O₆
• 分子量: 338.401
• InChiKey: JYEDLGKEXVBSCP-UHFFFAOYSA-N

物化性质

• 沸点：
  457.8±40.0 °C(Predicted)
• 密度：
  1.127±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  24
• 可旋转键数：
  13
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  82.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl 5-[2-(3-ethoxy-3-oxopropyl)-3-hydroxyphenoxy]pentanoate 在 sodium hydroxide 、 potassium carbonate 、 二甲基亚砜 、 potassium iodide 作用下， 以 四氢呋喃 、 甲醇 、 丁酮 为溶剂， 反应 19.0h， 生成 3-<2-<3-<5-(benzyloxy)-2-ethyl-4-(4-fluorophenyl)phenoxy>propoxy>-6-<(4-carboxybutyl)oxy>phenyl>propanoic acid
  参考文献：
  名称：

  Synthetic and Structure/Activity Studies on Acid-Substituted 2-Arylphenols: Discovery of 2-[2-Propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]- propoxy]phenoxy]benzoic Acid, a High-Affinity Leukotriene B4 Receptor Antagonist

  摘要：

  Structural derivatives of LY255283 have been studied as receptor antagonists of leukotriene B-4. Substitution of the 2-hydroxyacetophenone subunit of 1 (LY255283) with a 2-arylphenol group provided entry into several new series that feature various mono- and diacidic core functionality. These new analogues, the subject of a broad structure-activity investigation, displayed significantly increased in vitro and in vivo activity as receptor antagonists of LTB(4). A series of diaryl ether carboxylic acids demonstrated especially interesting activity and led to the discovery of compound 43b, 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]- propoxy]phenoxy]benzoic acid (LY293111), a 2-arylphenol-substituted diaryl ether carboxylic acid which displayed potent binding to human neutrophils (IC50 = 17 +/- 14.6 nM) and guinea pig lung membranes (IC50 6.6 +/- 0.71 nM), inhibition of LTB(4)-induced expression of the CD11b/CD18 receptor on human neutrophils (IC50 - 3.3 +/- 0.81 nM), and inhibition of LTB(4)-induced contraction of guinea pig lung parenchyma (pK(B) = 8.7 +/- 0.16). In vivo, 43b demonstrated potent activity in inhibiting LTB(4)-induced airway obstruction in the guinea pig when dosed by the oral (ED(50) = 0.40 mg/kg) or intravenous (ED(50) = 0.014 mg/kg) routes. A specific LTB(4) receptor antagonist, 43b had little effect on inhibiting contractions of guinea pig lung parenchyma induced by leukotriene D-4 (LTD(4)), histamine, carbachol, or U46619. Compound 43b has been chosen as a clinical candidate and is currently in phase I studies for a variety of inflammatory diseases.

  DOI：

  10.1021/jm00022a006
• 作为产物：
  描述：

  5-溴戊酸乙酯 在 盐酸 、 potassium carbonate 、 三甲基乙酸 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 41.0h， 生成 ethyl 5-[2-(3-ethoxy-3-oxopropyl)-3-hydroxyphenoxy]pentanoate
  参考文献：
  名称：

  Synthetic and Structure/Activity Studies on Acid-Substituted 2-Arylphenols: Discovery of 2-[2-Propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]- propoxy]phenoxy]benzoic Acid, a High-Affinity Leukotriene B4 Receptor Antagonist

  摘要：

  Structural derivatives of LY255283 have been studied as receptor antagonists of leukotriene B-4. Substitution of the 2-hydroxyacetophenone subunit of 1 (LY255283) with a 2-arylphenol group provided entry into several new series that feature various mono- and diacidic core functionality. These new analogues, the subject of a broad structure-activity investigation, displayed significantly increased in vitro and in vivo activity as receptor antagonists of LTB(4). A series of diaryl ether carboxylic acids demonstrated especially interesting activity and led to the discovery of compound 43b, 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]- propoxy]phenoxy]benzoic acid (LY293111), a 2-arylphenol-substituted diaryl ether carboxylic acid which displayed potent binding to human neutrophils (IC50 = 17 +/- 14.6 nM) and guinea pig lung membranes (IC50 6.6 +/- 0.71 nM), inhibition of LTB(4)-induced expression of the CD11b/CD18 receptor on human neutrophils (IC50 - 3.3 +/- 0.81 nM), and inhibition of LTB(4)-induced contraction of guinea pig lung parenchyma (pK(B) = 8.7 +/- 0.16). In vivo, 43b demonstrated potent activity in inhibiting LTB(4)-induced airway obstruction in the guinea pig when dosed by the oral (ED(50) = 0.40 mg/kg) or intravenous (ED(50) = 0.014 mg/kg) routes. A specific LTB(4) receptor antagonist, 43b had little effect on inhibiting contractions of guinea pig lung parenchyma induced by leukotriene D-4 (LTD(4)), histamine, carbachol, or U46619. Compound 43b has been chosen as a clinical candidate and is currently in phase I studies for a variety of inflammatory diseases.

  DOI：

  10.1021/jm00022a006

文献信息

• Leukotriene antagonists for use in the treatment or prevention of alzheimer's disease
  申请人：ELI LILLY AND COMPANY

  公开号：EP0743064A1

  公开（公告）日：1996-11-20

  This invention provides methods for the treatment or prevention of Alzheimer's disease which comprises administering to a mammal in need thereof an effective amount of a compound having activity as a leukotriene antagonist.

  这项发明提供了治疗或预防阿尔茨海默病的方法，包括向需要的哺乳动物施用具有白三烯拮抗活性的化合物的有效量。
• Synthesis of structural analogues of leukotriene B4 and their receptor binding activity
  作者：Mitoshi Konno、Takahiko Nakae、Shigeru Sakuyama、Minoru Nishizaki、Yoshihiko Odagaki、Hisao Nakai、Nobuyuki Hamanaka

  DOI：10.1016/s0968-0896(97)00090-4

  日期：1997.8

  [3H] LTB4 binding to human neutrophils, and by a secondary intact human neutrophil functional assay for agonist/antagonist activity. The first analogues prepared, compounds 2-7, demonstrated moderate potency in the LTB4 receptor binding assay. The modification of these compounds by the introduction of another substituent into the aromatic ring produced a marked increase in receptor binding (28c, IC50

  白三烯B4（LTB4）的结构类似物是根据LTB4的合理构象设计的（1）。将构象体A或B的C-7-C-9连接到芳香环系统中，导致发现苯类似物2、4和6a。将构象体C或D的C-4-C-9连接到芳香环系统中，导致发现类似物3、5和7。评估了本研究中化合物对[3H] LTB4结合的抑制作用人类嗜中性粒细胞，并通过第二次完整的人类嗜中性粒细胞功能测定来确定激动剂/拮抗剂活性。制备的第一个类似物化合物2-7在LTB4受体结合试验中显示出中等效力。通过将另一个取代基引入芳环对这些化合物进行修饰，可显着提高受体结合力（28c，IC50 = 0.020 microM; 38c，IC50 = 0。020微米; 52a，IC 50 ＝0.020μM；52b，IC 50 ＝0.018μM。LTB4的大多数这些结构类似物表现出激动剂活性。在这项研究中制备的类似物中，只有化合物57在10 microM时显示出弱的LTB4受体拮抗剂活性。
• Convenient approach for the synthesis of ONO-LB-457, a potent leukotriene B4 receptor antagonist
  作者：Salha Hamri、Jabrane Jouha、Asmaa Oumessaoud、M.D. Pujol、Mostafa Khouili、Gérald Guillaumet

  DOI：10.1016/j.tet.2020.131740

  日期：2021.1

  This study reports a new approach for the synthesis of 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl)-(5E)-hexen-1-yloxy]phenoxy]pentanoic acid V (ONO-LB-457), previously described by Konno and col. and which is considered a highly potent and orally active LTB4 receptor antagonist. This compound acts as an inhibitor of aggregation and chemotaxis, in addition to LTB4-induced human neutrophil degranulation

  这项研究报告了一种合成5- [2-（2-羧乙基）-3- [6-（4-甲氧基苯基）-（5 E）-己烯-1-基氧基]苯氧基]戊酸V（ONO）的新方法-LB-457），先前由Konno和col。并被认为是一种高效且口服的LTB 4受体拮抗剂。除了LTB 4诱导的人类嗜中性粒细胞脱粒之外，该化合物还用作聚集和趋化性抑制剂。 在这项工作中，通过集中于两个片段的制备的收敛合成提出了ONO-LB-457的制备。首先，由2,6-二甲氧基苯甲醛和丙二酸制备5-羟基苯并二氢吡喃酮（4），涉及Knoevenagel反应，然后还原烯烃，并用路易斯酸（三溴化物）催化分子内环化。总产率为57％。第二，由5-维戊酸（15）制备（E）-6-（4-甲氧基苯基）己-5-烯-1-基-甲磺酸酯（18），涉及维蒂希反应。通过（E的亲核取代获得所需的化合物V（ONO-LB-457）带有开环的酚二酯14的）-6-（4-甲氧基苯基）己-
• An Efficient Method for the Synthesis of a Novel Leukotriene B₄ Receptor Antagonist, ONO-4057, via Michael Reaction of Dihydroresorcinol
  作者：Mitoshi Konno、Takahiko Nakae、Shigeru Sakuyama、Katsuhiro Imaki、Hisao Nakai、Nobuyuki Hamanaka

  DOI：10.1055/s-1997-1079

  日期：——

  A practical method for the synthesis of ONO-4057, a highly potent and orally active leukotriene B4 (LTB4) receptor antagonist, was developed. This method includes improved synthesis of a key intermediate, 1,3-dioxo-2-(2-ethoxycarbonylethyl)cyclohexane (6).

  开发了一种合成 ONO-4057（一种高效且具有口服活性的白三烯 B4 (LTB4) 受体拮抗剂）的实用方法。该方法包括改进关键中间体 1,3-二氧代-2-(2-乙氧基羰基乙基)环己烷 (6) 的合成。
• [DE] NEUE LEUKOTRIEN-B4-ANTAGONISTEN, VERFAHREN ZU IHRER HERSTELLUNG UND IHRE VERWENDUNG ALS ARZNEIMITTEL<br/>[EN] NEW LEUKOTRIENE-B4 ANTAGONISTS, PROCESS FOR PREPARING THE SAME AND THEIR USE AS MEDICAMENTS<br/>[FR] NOUVEAUX ANTAGONISTES DES LEUCOTRIENES B4, LEUR PROCEDE DE PREPARATION ET LEUR UTILISATION COMME MEDICAMENTS
  申请人：SCHERING AKTIENGESELLSCHAFT

  公开号：WO1994004522A1

  公开（公告）日：1994-03-03

  (DE) Die Erfindung betrifft Leukotrien-B4-Antagonisten der Formel (I), worin n eine ganze Zahl von 2 bis 5; X eine direkte Bindung, 1 bis 6 Methyleneinheiten, ein ortho-, meta- oder para-substituierter Phenylring oder ein meta- oder para-substituierter Pyridinring; Y eine Bindung zu einem Wasserstoffatom und gleichzeitig zu einer Hydroxygruppe, ein doppelt gebundenes Sauerstoffatom oder -O-CH2-CH2-O-; R1 und R2 den Rest OH, -O-(C1-C4)-Alkyl, O-(C3-C6)-Cycloalkyl, -O-(C6-C10)-Aryl, -O-(C7-C12)-Aralkyl, O-(CH2)-CO-(C6-C10)-Aryl oder den Rest NHR3 mit R3 in der Bedeutung Wasserstoff, (C1-C4)-Alkyl, (C3-C6)-Cycloalkyl oder (C7-C12)-Aralkyl darstellen sowie deren Salze mit physiologisch verträglichen Basen und deren Cyclodextrinclathrate.(EN) Antagonists of the leukotrienes-B4 have formula (I), in which n is an integer between 2 and 5, X is a direct bond, 1 to 6 methylene units, an ortho-, meta- or para-substituted phenyl ring or a meta- or para-substituted pyridin ring; Y is a bond to a hydrogen atom and at the same time to a hydroxy group, an oxygen atom with a double bond or -O-CH2-CH2-O-; R1 and R2 stand for the rest OH, -O-(C1-C4)-alkyl, O-(C3-C6)-cycloalkyl, -O-(C6-C10)-aryl, -O-(C7-C12)-aralkyl, O-(CH2)-CO-(C6-C10)-aryl or the residue NHR3, in which R3 stands for hydrogen, (C1-C4)-alkyl, (C3-C6)-cycloalkyl or (C7-C12)-aralkyl. Also disclosed are the salts of said antagonists with physiologically tolerable bases and their cyclodextrin clathrates.(FR) Des antagonistes des leucotriènes B4 ont la formule (I), dans laquelle n est un nombre entier entre 2 et 5, X est une liaison directe, 1 à 6 unités de méthylène, un cycle phényle substitué en ortho, méta ou para ou un cycle pyridine substitué en méta ou para; Y est une liaison avec un atome d'hydrogène et en même temps avec un groupe hydroxyle, un atome d'oxygène doublement lié ou -O-CH2-CH2-O-; R1 et R2 désignent le résidu OH, -O-(C1-C4)-alkyle, O-(C3-C6)-cycloalkyle, -O-(C6-C10)-aryle, -O-(C7-C12)-aralkyle, O-(CH2)-CO-(C6-C10)-aryle ou le résidu NHR3, où R3 désigne hydrogène, (C1-C4)-alkyle, (C3-C6)-cycloalkyle ou (C7-C12)-aralkyle. L'invention concerne également les sels de ces antagonistes avec des bases physiologiquement tolérables et leurs clathrates de cyclodextrine.

  此发明涉及Leukotrien-B4的抗竞争性拮抗剂，其化学式为(I)，其中n为整数，取值范围为2至5；X表示直接键合，由1至6个甲ylene单元构成的基团，或者带有正位、间位或对位取代基的苯环，或带有对位或间位取代基的吡啶环；Y表示与一个氢原子键合，同时与一个羟基、氧原子双键或-O-CH2- -O-羟基相连；R1和R2分别表示羟基、-(C1-C4)-烷基氧基、-(C3-C6)-环烷基氧基、-(C6-C10)-苯基氧基、-(C7-C12)-联苯基氧基、- -羰基-(C6-C10)-苯基氧基或NHR3基团，其中R3基团表示氢、-(C1-C4)-烷基、-(C3-C6)-环烷基或-(C7-C12)-联苯基；其中所述抗竞争性拮抗剂及其与耐受碱的盐，以及它们的环状多糖笼合物也被披露。