(2S,5R)-2-[5-(5-chlorothiophen-2-yl)isoxazol-3-ylmethyl]-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine | 1182728-03-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩类
• 英文名称: (2S,5R)-2-[5-(5-chlorothiophen-2-yl)isoxazol-3-ylmethyl]-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine
• 英文别名: (2S,5R)-2-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-5-isopropyl-3,6-dimethoxy-2,5-dihydro-pyrazine；5-(5-chlorothiophen-2-yl)-3-[[(2S,5R)-3,6-dimethoxy-5-propan-2-yl-2,5-dihydropyrazin-2-yl]methyl]-1,2-oxazole
• CAS: 1182728-03-5
• 化学式: C₁₇H₂₀ClN₃O₃S
• 分子量: 381.883
• InChiKey: MUFSMHOJWAXUOO-XHDPSFHLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  97.4
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (2S,5R)-2-[5-(5-chlorothiophen-2-yl)isoxazol-3-ylmethyl]-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine 在 水 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 三氟乙酸 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 生成 N-{(S)-2-azepan-1-yl-1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-oxo-ethyl}-2-ethyl-3-(3-oxo-morpholin-4-yl)-benzenesulfonamide
  参考文献：
  名称：

  [EN] CHLOROTHIOPHENE-ISOXAZOLES AS INHIBITORS OF COAGULATION FACTORS XA AND THROMBIN
  [FR] CHLOROTHIOPHÈNE-ISOXAZOLES UTILISÉS COMME INHIBITEURS DES FACTEURS DE COAGULATION XA ET DE LA THROMBINE

  摘要：

  本发明涉及具有式（I）的化合物，其中R1; R2; R3; R4; R5, R16, X和M在索赔中指示的含义。式I的化合物是有价值的药理活性化合物。它们表现出强大的抗血栓作用，例如，适用于治疗和预防心血管疾病，如血栓栓塞疾病或再狭窄。它们是血凝酶因子Xa和凝血酶的可逆抑制剂，通常可用于存在因子Xa和/或凝血酶不良活性或需要抑制因子Xa和凝血酶的治疗或预防的情况。此外，该发明涉及制备式（I）化合物的方法，它们的使用，特别是作为药物中的活性成分，并包含它们的制剂。

  公开号：

  WO2009103439A1
• 作为产物：
  描述：

  (R)-2,5-二氢-3,6-二甲氧基-2-异丙基吡嗪 、 3-(溴甲基)-5-(5-氯噻吩-2-基)-1,2-恶唑 在 正丁基锂 作用下， 以 四氢呋喃 、 hexanes 为溶剂， 以80%的产率得到(2S,5R)-2-[5-(5-chlorothiophen-2-yl)isoxazol-3-ylmethyl]-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine
  参考文献：
  名称：

  [EN] CHLOROTHIOPHENE-ISOXAZOLES AS INHIBITORS OF COAGULATION FACTORS XA AND THROMBIN
  [FR] CHLOROTHIOPHÈNE-ISOXAZOLES UTILISÉS COMME INHIBITEURS DES FACTEURS DE COAGULATION XA ET DE LA THROMBINE

  摘要：

  本发明涉及具有式（I）的化合物，其中R1; R2; R3; R4; R5, R16, X和M在索赔中指示的含义。式I的化合物是有价值的药理活性化合物。它们表现出强大的抗血栓作用，例如，适用于治疗和预防心血管疾病，如血栓栓塞疾病或再狭窄。它们是血凝酶因子Xa和凝血酶的可逆抑制剂，通常可用于存在因子Xa和/或凝血酶不良活性或需要抑制因子Xa和凝血酶的治疗或预防的情况。此外，该发明涉及制备式（I）化合物的方法，它们的使用，特别是作为药物中的活性成分，并包含它们的制剂。

  公开号：

  WO2009103439A1

文献信息

• CHLOROTHIOPHENE-ISOXAZOLES AS INHIBITORS OF COAGULATION FACTORS XA AND THROMBIN
  申请人：FOLLMANN Markus

  公开号：US20110112074A1

  公开（公告）日：2011-05-12

  The present invention relates to compounds of the formula I, wherein R1; R2; R3; R4; R5, R16, X and M have the meanings indicated in the claims. The compounds of formula I are valuable pharmacologically active compounds. They exhibit a strong anti-thrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardio-vascular disorders like thromboembolic diseases or restenoses. They are reversible inhibitors of the blood clotting enzymes factor Xa and thrombin and can in general be applied in conditions in which an undesired activity of factor Xa and/or thrombin are present or for the cure or prevention of which an inhibition of factor Xa and thrombin are intended. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.

  本发明涉及式I的化合物，其中R1; R2; R3; R4; R5, R16, X和M具有所述权利要求中指出的含义。公式I的化合物是有价值的药理活性化合物。它们表现出强烈的抗血栓作用，例如，适用于治疗和预防心血管疾病，如血栓栓塞病或再狭窄。它们是血凝酶因子Xa和凝血酶的可逆抑制剂，通常可应用于存在血凝酶因子Xa和/或凝血酶不良活性的情况，或者用于治疗或预防需要抑制血凝酶因子Xa和凝血酶的情况。此外，本发明还涉及制备式I化合物的方法，它们的用途，特别是作为药物中的活性成分，以及包含它们的制药制剂。
• Chlorothiophene-isoxazoles as inhibitors of coagulation factors Xa and thrombin
  申请人：Follmann Markus

  公开号：US08835653B2

  公开（公告）日：2014-09-16

  The present invention relates to compounds of the formula I, wherein R1; R2; R3; R4; R5, R16, X and M have the meanings indicated in the claims. The compounds of formula I are valuable pharmacologically active compounds. They exhibit a strong anti-thrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardio-vascular disorders like thromboembolic diseases or restenoses. They are reversible inhibitors of the blood clotting enzymes factor Xa and thrombin and can in general be applied in conditions in which an undesired activity of factor Xa and/or thrombin are present or for the cure or prevention of which an inhibition of factor Xa and thrombin are intended. The invention furthermore relates to processes for the preparation of compounds of the formula I, their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.

  本发明涉及式I的化合物，其中R1; R2; R3; R4; R5, R16, X和M具有所述索引中指示的含义。式I的化合物是有价值的药理活性化合物。它们表现出强烈的抗血栓作用，适用于治疗和预防心血管疾病，如血栓栓塞性疾病或再狭窄。它们是血凝酶Xa和凝血酶的可逆抑制剂，通常可应用于存在不良血凝酶Xa和/或凝血酶活性的情况下，或者用于治疗或预防需要抑制血凝酶Xa和凝血酶的情况。此外，本发明还涉及制备式I的化合物的方法，它们的使用，特别是作为药物中的活性成分，并包括它们的制药制剂。
• US8835653B2
  申请人：——

  公开号：US8835653B2

  公开（公告）日：2014-09-16
• 5-Chlorothiophene-2-carboxylic Acid [(<i>S</i>)-2-[2-Methyl-3-(2-oxopyrrolidin-1-yl)benzenesulfonylamino]-3-(4-methylpiperazin-1-yl)-3-oxopropyl]amide (SAR107375), a Selective and Potent Orally Active Dual Thrombin and Factor Xa Inhibitor
  作者：Jerome Meneyrol、Markus Follmann、Gilbert Lassalle、Volkmar Wehner、Guillaume Barre、Tristan Rousseaux、Jean-Michel Altenburger、Frederic Petit、Zsolt Bocskei、Herman Schreuder、Nathalie Alet、Jean-Pascal Herault、Laurence Millet、Frederique Dol、Peter Florian、Paul Schaeffer、Freddy Sadoun、Sylvie Klieber、Christophe Briot、Françoise Bono、Jean-Marc Herbert

  DOI：10.1021/jm4005835

  日期：2013.12.12

  Compound 15 (SAR107375), a novel potent dual thrombin and factor Xa inhibitor resulted from a rational optimization process. Starting from compound 14, with low factor Xa and modest anti-thrombin inhibitory activities (IC50's of 3.5 and 0.39 mu M, respectively), both activities were considerably improved, notably through the incorporation of a neutral chlorothiophene PI fragment and tuning of P2 and P3-P4 fragments. Final optimization of metabolic stability with microsomes led to the identification of 15, which displays strong activity in vitro vs factor Xa and thrombin (with K-i's of 1 and 8 nM, respectively). In addition 15 presents good selectivity versus related serine proteases (roughly 300-fold), including trypsin (1000-fold), and is very active (0.39 mu M) in the thrombin generation time (TGT) coagulation assay in human platelet rich plasma (PRP). Potent in vivo activity in a rat model of venous thrombosis following iv and, more importantly, po administration was also observed (ED50 of 0.07 and 2.8 mg/kg, respectively). Bleeding liability was reduced in the rat wire coil model, more relevant to arterial thrombosis, with 15 (blood loss increase of 2-fold relative to the ED80 value) compared to rivaroxaban 2 and dabigatran etexilate 1a.
• [EN] CHLOROTHIOPHENE-ISOXAZOLES AS INHIBITORS OF COAGULATION FACTORS XA AND THROMBIN<br/>[FR] CHLOROTHIOPHÈNE-ISOXAZOLES UTILISÉS COMME INHIBITEURS DES FACTEURS DE COAGULATION XA ET DE LA THROMBINE
  申请人：SANOFI AVENTIS

  公开号：WO2009103439A1

  公开（公告）日：2009-08-27

  The present invention relates to compounds of the formula (I), wherein R1; R2; R3; R4; R5, R16, X and M have the meanings indicated in the claims. The compounds of formula I are valuable pharmacologically active compounds. They exhibit a strong anti-thrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardio-vascular disorders like thromboembolic diseases or restenoses. They are reversible inhibitors of the blood clotting enzymes factor Xa and thrombin and can in general be applied in conditions in which an undesired activity of factor Xa and/or thrombin are present or for the cure or prevention of which an inhibition of factor Xa and thrombin are intended. The invention furthermore relates to processes for the preparation of compounds of the formula (I), their use, in particular as active ingredients in pharmaceuticals, and pharmaceutical preparations comprising them.

  本发明涉及具有式（I）的化合物，其中R1; R2; R3; R4; R5, R16, X和M在索赔中指示的含义。式I的化合物是有价值的药理活性化合物。它们表现出强大的抗血栓作用，例如，适用于治疗和预防心血管疾病，如血栓栓塞疾病或再狭窄。它们是血凝酶因子Xa和凝血酶的可逆抑制剂，通常可用于存在因子Xa和/或凝血酶不良活性或需要抑制因子Xa和凝血酶的治疗或预防的情况。此外，该发明涉及制备式（I）化合物的方法，它们的使用，特别是作为药物中的活性成分，并包含它们的制剂。