4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzoic acid | 189365-92-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzoic acid
• 英文别名: 4-(1,2,4-oxadiazol-5(4H)-one)benzoic acid；4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzoic acid；4-(5-Oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzoic acid；4-(5-oxo-4H-1,2,4-oxadiazol-3-yl)benzoic acid
• CAS: 189365-92-2
• 化学式: C₉H₆N₂O₄
• 分子量: 206.158
• InChiKey: AIHHXKBESQKXFV-UHFFFAOYSA-N

物化性质

• 熔点：
  > 219° C (dec.)
• 密度：
  1.60±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少量，超声处理）

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  88
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzoic acid 在 palladium 10% on activated carbon 、 氢气 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 15.0h， 生成 (S)-ethyl 1-(4-(5-((4-carbamimidoylbenzamido)methyl)-2-oxooxazolidin-3-yl)phenyl)piperidine-4-carboxylate acetate
  参考文献：
  名称：

  Low molecular weight dual inhibitors of factor Xa and fibrinogen binding to GPIIb/IIIa with highly overlapped pharmacophores

  摘要：

  Dual antithrombotic agents acting as anticoagulants and aggregation inhibitors could have substantial advantages over currently prescribed combinations of antithrombotic drugs. Herein, we report compounds with moderate inhibitory activity for factor Xa and fibrinogen GPIIb/IIIa binding (both in the micromolar range). These compounds resulted from our efforts to merge the pharmacophores of selective factor Xa inhibitor rivaroxaban with a mimic of the Arg-Gly-Asp (RGD) sequence of fibrinogen to obtain designed multiple ligands with potential antithrombotic activity. Resulting from this study, a structurally novel class of submicromolar fibrinogen GPIIb/IIIa binding inhibitor bearing 1,2,4-oxadiazol-5(4H)-one moiety is also described. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.03.056
• 作为产物：
  描述：

  ethyl 4-(N'-((ethoxycarbonyl)oxy)carbamimidoyl)benzoate 在 水 、 sodium hydroxide 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 15.25h， 生成 4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)benzoic acid
  参考文献：
  名称：

  Low molecular weight dual inhibitors of factor Xa and fibrinogen binding to GPIIb/IIIa with highly overlapped pharmacophores

  摘要：

  Dual antithrombotic agents acting as anticoagulants and aggregation inhibitors could have substantial advantages over currently prescribed combinations of antithrombotic drugs. Herein, we report compounds with moderate inhibitory activity for factor Xa and fibrinogen GPIIb/IIIa binding (both in the micromolar range). These compounds resulted from our efforts to merge the pharmacophores of selective factor Xa inhibitor rivaroxaban with a mimic of the Arg-Gly-Asp (RGD) sequence of fibrinogen to obtain designed multiple ligands with potential antithrombotic activity. Resulting from this study, a structurally novel class of submicromolar fibrinogen GPIIb/IIIa binding inhibitor bearing 1,2,4-oxadiazol-5(4H)-one moiety is also described. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.03.056

文献信息

• [EN] FACTOR XIa INHIBITORS<br/>[FR] INHIBITEURS DU FACTEUR XIA
  申请人：MERCK SHARP & DOHME

  公开号：WO2015164308A1

  公开（公告）日：2015-10-29

  The present invention provides a compound of Formula (I) and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing thromboses, embolisms, hypercoagulability or fibrotic changes. The compounds are selective Factor XIa inhibitors or dual inhibitors of Factor XIa and plasma kallikrein.

  本发明提供了一种化合物(I)及包含一种或多种所述化合物的药物组合物，以及使用所述化合物用于治疗或预防血栓、栓塞、高凝血性或纤维变化的方法。这些化合物是选择性因子XIa抑制剂或因子XIa和血浆激肽原的双重抑制剂。
• Design and synthesis of novel platelet fibrinogen receptor antagonists with 2H-1,4-benzoxazine-3(4H)-one scaffold. A systematic study
  作者：Marko Anderluh、Jožko Cesar、Petra Štefanič、Danijel Kikelj、Damjan Janeš、Jernej Murn、Kristina Nadrah、Mojca Tominc、Elisabeth Addicks、Athanassios Giannis、Mojca Stegnar、Marija Sollner Dolenc

  DOI：10.1016/j.ejmech.2004.09.004

  日期：2005.1

  New platelet glycoprotein IIb/IIIa (GP IIb/IIIa, integrin alpha(IIb)beta3) antagonists were prepared on a 2H-1,4-benzoxazine-3(4H)-one scaffold. Their anti-aggregatory activities in human platelet rich plasma and their affinity towards alpha(IIb)beta3 and alpha(V)beta3 integrins were assessed. Various substitution positions and side chain variations were studied. In contrast to the generally accepted

  在2H-1,4-苯并恶嗪-3（4H）-一个支架上制备了新的血小板糖蛋白IIb / IIIa（GP IIb / IIIa，整联蛋白alpha（IIb）beta3）拮抗剂。评估了它们在富含人血小板的血浆中的抗聚集活性以及它们对alpha（IIb）beta3和alpha（V）beta3整联蛋白的亲和力。研究了各种取代位置和侧链变化。与普遍接受的模型相反，含有乙酯作为天冬氨酸盐模拟物的化合物通常比相应的游离酸更具活性。我们建议对这些新化合物的观察行为进行解释。
• Orally Active GPIIb/IIIa Antagonists. Synthesis and Biological Activities of Masked Amidines as Prodrugs of 2-[(3S)-4-[(2S)-2-(4-Amidinobenzoylamino)-3-(4-methoxyphenyl)propanoyl]-3-(2-methoxy-2-oxoethyl)-2-oxopiperazinyl] acetic Acid.
  作者：Shuji KITAMURA、Hideto FUKUSHI、Toshio MIYAWAKI、Masaki KAWAMURA、Zen-ichi TERASHITA、Takehiko NAKA

  DOI：10.1248/cpb.49.268

  日期：——

  To improve the in vivo potency of the potent GPIIb/IIIa antagonist 2-[(3S)-4-[(2S)-2-(4-amidinobenzoylamino)-3-(4-methoxyphenyl)propanoyl]-3-(2-methoxy-2-oxoethyl)-2-oxopiperazinyljacetic acid (4), the amidino group was converted to an oxadiazole ring, thiadiazole ring or substituted amidoxime group. These groups were expected to be metabolized to an amidino group in vivo. The compounds synthesized

  提高有效的GPIIb / IIIa拮抗剂2-[（（3S）-4-[（2S）-2-（4-4-基苯甲酰氨基）-3-（4-甲氧基苯基）丙酰基] -3-（2-甲氧基-2-氧代乙基）-2-氧代哌嗪基j乙酸（4），将mid基转化为恶二唑环，噻二唑环或取代的mid肟基。预期这些组在体内被代谢为an基组。评价合成的化合物抑制离体腺苷5'-二磷酸（ADP）诱导的豚鼠血小板聚集的能力。在所研究的化合物中，甲氧羰基氧基am8a表现出最有效的离体抑制活性，口服后起效快，作用时间长。
• [EN] PIPERAZINONES USEFUL AS INHIBITORS OF PLATELET AGGREGATION<br/>[FR] PIPERAZINONES UTILES COMME INHIBITEURS D'AGREGATION PLAQUETTAIRE
  申请人：TAKEDA CHEMICAL INDUSTRIES, LTD.

  公开号：WO1996033982A1

  公开（公告）日：1996-10-31

  (EN) The present invention provides compounds and medicines effective for prophylaxis and therapy of various diseases by controlling or inhibiting cell-adhesion. Especially, the compounds of this invention perform platelet aggregation action without remarkable elongation of hemorrhagic period and can be used as a safe and long-acting antithrombotic drug as compared with known substances showing the same activity. Compounds of this invention are piperazinones of formula (I) wherein A1 and A2 independently are a proton-accepting group or a group convertible into the proton-accepting group; D is a spacer having a 2 to 6 atomic chain optionally bonded through a hetero-atom and/or a 5- or 6-membered ring (provided that the 5- or 6-membered ring is, depending on its bonding position, counted as 2- or 3-atomic chains); R1 is hydrogen atom or a hydrocarbon group; R2 is hydrogen atom or a residual group formed by removing -CH(NH2)COOH from an alpha-amino acid, or R1 and R2 may be combined to form a 5- or 6-membered ring; P is a spacer having a 1- to 10- atomic chain optionally bonded through a hetero-atom and/or a 5- or 6-membered ring (provided that the 5- or 6-membered ring is, depending on its bonding position, counted as 2- or 3-atomic chains); Y is an optionally esterified or amidated carboxyl group; and n is a number ranging 0 to 8, and salts thereof.(FR) La présente invention concerne des composés et des médicaments efficaces pour la prophylaxie ou la thérapie de diverses maladies par la maîtrise ou l'inhibition de l'adhésion cellulaire. En particulier, les composés selon l'invention effectuent l'agrégation plaquettaire sans allongement sensible de la période d'hémorragie et peuvent s'utiliser comme médicaments antithrombotiques sûrs et à action prolongée par rapport aux substances connues pour leur activité similaire. Les composés selon l'invention sont des piperazinones correspondant à la formule (I) dans laquelle A1 et A2 représentent, indépendamment l'un de l'autre, un groupe accepteur de protons ou un groupe convertible en groupe accepteur de protons; D représente un espaceur ayant une chaîne de 2 à 6 atomes, éventuellement liée par un hétéro-atome et/ou un cycle à 5 ou à 6 éléments (à condition que le noyau à 5 ou à 6 chaînons soit compté, en fonction de sa position de liaison, comme des chaînes à 2 ou à 3 atomes); R1 représente un atome d'hydrogène ou un groupe hydrocarbure; R2 représente un atome d'hydrogène ou un groupe résiduel formé par l'élimination de -CH(NH2)COOH à partir d'un acide alpha-amino, ou R1 et R2 peuvent être combinés pour former un cycle à 5 ou à 6 éléments; P représente un espaceur ayant une chaîne de 1 à 10 atomes, éventuellement liée par un hétéro-atome et/ou par un cycle à 5 ou à 6 éléments (à condition que le cycle à 5 ou à 6 éléments soit compté, en fonction de sa position de liaison, comme des chaînes à 2 ou à 3 atomes); Y représente un groupe carboxyle éventuellement estérifié ou amidaté; et n représente un nombre compris entre 0 et 8, ainsi que les sels dérivés.

  本发明提供了控制或抑制细胞粘附的化合物和药物，用于预防和治疗各种疾病。特别地，本发明的化合物可以进行血小板聚集作用，而不会明显延长出血期，并且与具有相同活性的已知物质相比，可以用作安全和长效的抗血栓药物。本发明的化合物是式（I）的哌嗪酮，其中A1和A2独立地表示质子受体基团或可转化为质子受体基团的基团；D是具有2至6个原子链的间隔物，可以通过杂原子和/或5或6元环键合（在5或6元环根据其键合位置，被计算为2或3原子链）；R1是氢原子或烃基团；R2是氢原子或通过从α-氨基酸中去除-CH（NH2）COOH形成的残基基团，或者R1和R2可以结合形成5或6元环；P是具有1至10个原子链的间隔物，可以通过杂原子和/或5或6元环键合（在5或6元环根据其键合位置，被计算为2或3原子链）；Y是可选酯化或酰胺化的羧基团；n是0至8之间的数字，以及其盐。
• Substituted (aminoiminomethyl or aminomethyl) benzoheteroaryl compounds
  申请人：Aventis Pharmaceuticals Inc.

  公开号：US20030153604A1

  公开（公告）日：2003-08-14

  This invention is directed to an (aminoiminomethyl or aminomethyl)benzoheteroaryl compound of formula I which is useful for inhibiting the activity of Factor Xa by combining said compound with a composition containing Factor Xa. The present invention is also directed to compositions containing compounds of the formula I, methods for their preparation, their use, such as in inhibiting the formation of thrombin or for treating a patient suffering from, or subject to, a disease state associated with a physiologically detrimental excess amount of thrombin.

  本发明涉及一种公式I的(氨基亚甲基或氨基甲基)苯并杂环化合物，该化合物通过与含有Xa因子的组合物结合来抑制Xa因子的活性。本发明还涉及含有公式I化合物的组合物、它们的制备方法以及它们的用途，例如抑制凝血酶的形成或治疗患有或受到与生理上有害的过量凝血酶相关的疾病状态的患者。