(2S,4S)-4-fluoro-1-{[(2-hydroxy-1,1-dimethylethyl)amino]acetyl}pyrrolidine-2-carbonitrile | 625110-37-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (2S,4S)-4-fluoro-1-{[(2-hydroxy-1,1-dimethylethyl)amino]acetyl}pyrrolidine-2-carbonitrile
• 英文别名: (2S,4S)-2-cyano-4-fluoro-1-[(2-hydroxy-1,1-dimethyl)ethylamino]acetylpyrrolidine；Dpp-IV-IN-1；(2S,4S)-4-fluoro-1-[2-[(1-hydroxy-2-methylpropan-2-yl)amino]acetyl]pyrrolidine-2-carbonitrile
• CAS: 625110-37-4
• 化学式: C₁₁H₁₈FN₃O₂
• 分子量: 243.281
• InChiKey: XJGUWEAPKPNAID-IUCAKERBSA-N

物化性质

• 沸点：
  472.3±45.0 °C(Predicted)
• 密度：
  1.20±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  -0.4
• 重原子数：
  17
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  76.4
• 氢给体数：
  2
• 氢受体数：
  5

安全信息

• 储存条件：
  2-8℃，请密封保存并在干燥处存放。

制备方法与用途

DPP-IV-IN-1 是一种有效的抑制剂，其值为 4.6 nM；而 DPP-IV 则是一种特异性的丝氨酸蛋白酶。

反应信息

• 作为反应物：
  描述：

  (2S,4S)-4-fluoro-1-{[(2-hydroxy-1,1-dimethylethyl)amino]acetyl}pyrrolidine-2-carbonitrile 在 盐酸 作用下， 以 甲醇 、 乙酸乙酯 为溶剂， 生成 (2S,4S)-4-fluoro-1-[N-(2-hydroxy-1,1-dimethylethyl)glycyl]pyrrolidine-2-carbonitrile hydrochloride
  参考文献：
  名称：

  EP1535907

  摘要：

  公开号：
• 作为产物：
  描述：

  (2S,4S)-1-(bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile 、 2-氨基-2-甲基-1-丙醇 以 四氢呋喃 为溶剂， 生成 (2S,4S)-4-fluoro-1-{[(2-hydroxy-1,1-dimethylethyl)amino]acetyl}pyrrolidine-2-carbonitrile
  参考文献：
  名称：

  有效的4-氟-2-氰基吡咯烷二肽基肽酶IV抑制剂的合成及其构效关系。

  摘要：

  二肽基肽酶IV（DPP-IV）抑制剂是有前途的抗糖尿病药物，并且几种药物都处于开发阶段。我们先前曾报道，将氟引入2-氰基吡咯烷的4-位可增强DPP-IV的抑制作用。在本报告中，我们研究了2-氰基-4-氟吡咯烷与1位上的N-取代甘氨酸的结构-活性关系（SAR）。我们报告鉴定出具有长期持续的血浆药物浓度和有效的降血糖活性的有效和稳定的DPP-IV抑制剂（TS-021）。

  DOI：

  10.1016/j.bmc.2008.01.016

文献信息

• PROCESS FOR PRODUCTION OF CIS-4-FLUORO-L-PROLINE DERIVATIVES
  申请人：Taisho Pharmaceutical Co. Ltd.

  公开号：EP1657237A1

  公开（公告）日：2006-05-17

  The present invention provides a safer method for production of a cis-4-fluoro-L-proline derivative under milder conditions and in good yield to give a product of high purity on an industrial scale at low cost. Namely, the present invention provides a method for producing a cis-4-fluoro-L-proline derivative, which comprises reacting a trans-4-hydroxy-L-proline derivative of the following Formula [I]: (wherein R1 represents a protecting group for an α-amino group, and R2 represents a protecting group for a carboxyl group) with N,N-diethyl-N-(1,1,2,3,3,3-hexafluoropropyl)amine in the presence of a hydrogen fluoride-scavenger.

  本发明提供了一种更安全的方法，用于在较温和的条件下且高产率地生产cis-4-氟-L-脯氨酸衍生物，以在工业规模下以低成本提供高纯度的产品。换句话说，本发明提供了一种生产cis-4-氟-L-脯氨酸衍生物的方法，包括将以下式[I]的trans-4-羟基-L-脯氨酸衍生物（其中R1代表α-氨基的保护基，R2代表羧基的保护基）与N,N-二乙基-N-(1,1,2,3,3,3-六氟丙基)胺在氢氟酸清除剂的存在下反应。
• [EN] MODULATORS OF THE GPR119 RECEPTOR AND THE TREATMENT OF DISORDERS RELATED THERETO<br/>[FR] MODULATEURS DU RÉCEPTEUR GPR119 ET TRAITEMENT DE TROUBLES ASSOCIÉS
  申请人：ARENA PHARM INC

  公开号：WO2013055910A1

  公开（公告）日：2013-04-18

  The present invention relates to compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, and N-oxides thereof,that are useful as single pharmaceutical agents or in combination with one or more additional pharmaceutical agents, such as, an inhibitor of DPP-IV, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, or an anti-diabetic peptide analogue, in the treatment of, for example, a disorder selected from: a GPR119-receptor-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; obesity; and complications related thereto.

  本发明涉及式(I)的化合物及其药学上可接受的盐、溶剂化合物、水合物和N-氧化物，这些化合物可作为单一药物代理或与一个或多个额外的药物代理结合使用，例如DPP-IV的抑制剂、双胍类药物、α-葡萄糖苷酶抑制剂、胰岛素类似物、磺脲类药物、SGLT2抑制剂、噻嗪二酮类药物或抗糖尿病肽类似物，用于治疗例如从以下选择的疾病中选择的疾病：GPR119受体相关疾病；通过增加促胰高血糖素分泌而改善的状况；通过增加血液促胰高血糖素水平而改善的状况；低骨量状况；神经系统疾病；与代谢相关的疾病；2型糖尿病；肥胖症；以及相关并发症。
• [EN] MODULATORS OF GPR119 AND THE TREATMENT OF DISORDERS RELATED THERETO<br/>[FR] MODULATEURS DE GPR119 ET TRAITEMENT DE TROUBLES ASSOCIÉS À CEUX-CI
  申请人：ARENA PHARM INC

  公开号：WO2014074668A1

  公开（公告）日：2014-05-15

  The present invention relates to compounds of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof, Formula (I), that are useful as single pharmaceutical agents or in combination with one or more additional pharmaceutical agents, such as, an inhibitor of DPP-IV, a biguanide, an alpha-glucosidase inhibitor, an insulin analogue, a sulfonylurea, an SGLT2 inhibitor, a meglitinide, a thiazolidinedione, an anti-diabetic peptide analogue, or a DGAT-1 inhibitor, in the treatment of, for example, a disorder selected from: a GPR119-related disorder; a condition ameliorated by increasing secretion of an incretin; a condition ameliorated by increasing a blood incretin level; a condition characterized by low bone mass; a neurological disorder; a metabolic-related disorder; type 2 diabetes; obesity; and complications related thereto.

  本发明涉及化合物的公式(I)及其药学上可接受的盐、溶剂化合物和水合物，公式(I)可作为单一药物代理或与一个或多个其他药物代理结合使用，例如DPP-IV抑制剂、双胍类药物、α-葡萄糖苷酶抑制剂、胰岛素类似物、磺脲类药物、SGLT2抑制剂、胰岛素分泌促进剂、噻唑烷二酮类药物、抗糖尿病肽类似物或DGAT-1抑制剂，用于治疗例如GPR119相关疾病；通过增加内分泌物分泌改善的疾病；通过增加血液内分泌物水平改善的疾病；低骨量疾病；神经系统疾病；与代谢相关的疾病；2型糖尿病；肥胖及相关并发症。
• MODIFIED-RELEASE DOSAGE FORMS OF 5-HT2C AGONISTS USEFUL FOR WEIGHT MANAGEMENT
  申请人：Arena Pharmaceuticals, Inc.

  公开号：EP3485878A1

  公开（公告）日：2019-05-22

  The present invention relates to methods for weight management that utilize modified-release dosage forms comprising (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine salts and crystalline forms thereof. The present invention further relates to (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine salts, crystalline forms thereof and modified-release dosage forms comprising them.

  本发明涉及利用含有(R)-8-氯-1-甲基-2,3,4,5-四氢-1H-3-苯并哌啶盐及其结晶形式的改良释放剂型的体重管理方法。本发明还涉及(R)-8-氯-1-甲基-2,3,4,5-四氢-1H-3-苯并哌啶盐、其结晶形式以及含有它们的改良释放剂型。
• Process for production of cis-4-fluoro-l-proline derivatives
  申请人：Tomisawa Kazuyuki

  公开号：US20060281927A1

  公开（公告）日：2006-12-14

  The present invention provides a safer method for production of a cis-4-fluoro-L-proline derivative under milder conditions and in good yield to give a product of high purity on an industrial scale at low cost. Namely, the present invention provides a method for producing a cis-4-fluoro-L-proline derivative, which comprises reacting a trans-4-hydroxy-L-proline derivative of the following Formula [I]: (wherein R 1 represents a protecting group for an α-amino group, and R 2 represents a protecting group for a carboxyl group) with N,N-diethyl-N-(1,1,2,3,3,3-hexafluoropropyl)amine in the presence of a hydrogen fluoride-scavenger.

  本发明提供了一种更安全的方法，在较温和的条件下并且高产率地生产cis-4-氟-L-脯氨酸衍生物，以在工业规模下低成本地得到高纯度的产物。即，本发明提供了一种制备cis-4-氟-L-脯氨酸衍生物的方法，该方法包括将以下式[I]的trans-4-羟基-L-脯氨酸衍生物（其中R1表示α-氨基保护基，R2表示羧基保护基）与N,N-二乙基-N-(1,1,2,3,3,3-六氟丙基)胺在氢氟酸清除剂的存在下反应。