(S)-2-((tert-butoxycarbonyl)amino)-3-(1-fluorocyclopentyl)propanoic acid | 1232365-63-7

• 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: (S)-2-((tert-butoxycarbonyl)amino)-3-(1-fluorocyclopentyl)propanoic acid
• 英文别名: (S)-2-(tert-butoxycarbonylamino)-3-(1-fluorocyclopentyl)propanoic acid；2-tert-butoxycarbonylamino-3-(1-fluorocyclopentyl)propionic acid；(2S)-3-(1-fluorocyclopentyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid
• CAS: 1232365-63-7
• 化学式: C₁₃H₂₂FNO₄
• 分子量: 275.32
• InChiKey: BFGVRJYKSHKFPJ-VIFPVBQESA-N

物化性质

• 沸点：
  408.7±20.0 °C(Predicted)
• 密度：
  1.16±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  19
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  75.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (S)-2-((tert-butoxycarbonyl)amino)-3-(1-fluorocyclopentyl)propanoic acid 在 盐酸 、 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-) 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.74h， 生成 [1-[1-(carbamoyl-hydroxy-methyl)-cyclobutylcarbamoyl]-2-(1-fluorocyclopentyl)-ethyl]-carbamic acid ethyl ester
  参考文献：
  名称：

  [EN] NEW CATHEPSIN S PROTEASE INHIBITORS, USEFUL IN THE TREATMENT OF E.G. AUTOIMMUNE DISORDERS, ALLERGY AND CHRONIC PAIN CONDITIONS
  [FR] NOUVEAUX INHIBITEURS DE CATHEPSINE S PROTÉASE, UTILES DANS LE TRAITEMENT, PAR EX., DE MALADIES AUTO-IMMUNES, D'ALLERGIES ET DE DOULEURS CHRONIQUES

  摘要：

  式（I）的化合物，其中R2a和R2b分别为H、卤素、C1-C4烷基、C1-C4卤代烷基或C1-C4烷氧基，或者R2a和R2b与它们连接的碳原子一起形成C3-C6环烷基；R3为C5-C10烷基，可选择地用1-3个卤素、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基取代；或者R3为至少有2个氯或3个氟取代基的C2-C4烷基链；或者R3为C3-C7环烷基甲基，可选择地用1-3个C1-C4烷基、卤素、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基取代；R4为C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C6烷基氨基、C1-C6二烷基氨基或者；R4为Het或Carbocyclyl，其中任一者可选择地用1-3个取代基取代；n为1、2或3；用于预防或治疗以胰蛋白酶S的不适当表达或活化为特征的疾病。

  公开号：

  WO2011158197A1

文献信息

• [EN] CYSTEINE PROTEASE INHIBITORS<br/>[FR] INHIBITEURS DES CYSTÉINE PROTÉASES
  申请人：MEDIVIR UK LTD

  公开号：WO2011070539A1

  公开（公告）日：2011-06-16

  Compounds of Formula (II) wherein R1a is H; and R1b is C1-C6alkyl, Carbocyclyl or Het; or R1a and R1b together define a saturated cyclic amine with 3-6 ring atoms; R2a and R2b are independently H, halo, C1-C4alkyl, C1-C4haloalkyl or C1-C4alkoxy, or R2a and R2b together with the carbon atom to which they are attached form a C3-C6cycloalkyl; R3 is a branched C5-C10 alkyl chain, C2-C4haloalkyl or -CH2C3-C7 cycloalkyl; R4' is C1-C6alkyl, C1-C6haloalkyl or oxetany-3-yl. for use in the prophylaxis or treatment of a disorder characterised by inappropriate expression or activation of cathepsin S.

  式（II）中的化合物，其中R1a为H；R1b为C1-C6烷基，碳环烷基或杂环基；或者R1a和R1b一起定义具有3-6个环原子的饱和环胺；R2a和R2b独立地为H，卤素，C1-C4烷基，C1-C4卤代烷基或C1-C4烷氧基，或者R2a和R2b与它们连接的碳原子一起形成C3-C6环烷基；R3为支链C5-C10烷基链，C2-C4卤代烷基或-CH2C3-C7环烷基；R4'为C1-C6烷基，C1-C6卤代烷基或氧杂环丙基。用于预防或治疗由于cathepsin S的不恰当表达或激活而特征化的疾病。
• Selective Cathepsin S Inhibition with MIV-247 Attenuates Mechanical Allodynia and Enhances the Antiallodynic Effects of Gabapentin and Pregabalin in a Mouse Model of Neuropathic Pain
  作者：E. Hewitt、T. Pitcher、B. Rizoska、K. Tunblad、I. Henderson、B.-L. Sahlberg、U. Grabowska、B. Classon、C. Edenius、M. Malcangio、E. Lindstrom

  DOI：10.1124/jpet.116.232926

  日期：2016.8.1

  Cathepsin S inhibitors attenuate mechanical allodynia in preclinical neuropathic pain models. The current study evaluated the effects when combining the selective cathepsin S inhibitor MIV-247 with gabapentin or pregabalin in a mouse model of neuropathic pain. Mice were rendered neuropathic by partial sciatic nerve ligation. MIV-247, gabapentin, or pregabalin were administered alone or in combination via oral gavage. Mechanical allodynia was assessed using von Frey hairs. Neurobehavioral side effects were evaluated by assessing beam walking. MIV-247, gabapentin, and pregabalin concentrations in various tissues were measured. Oral administration of MIV-247 (100-200 µ mol/kg) dose-dependently attenuated mechanical allodynia by up to approximately 50% reversal when given as a single dose or when given twice daily for 5 days. No behavioral deficits were observed at any dose of MIV-247 tested. Gabapentin (58-350 µ mol/kg) and pregabalin (63-377 µ mol/kg) also inhibited mechanical allodynia with virtually complete reversal at the highest doses tested. The minimum effective dose of MIV-247 (100 µ mol/kg) in combination with the minimum effective dose of pregabalin (75 µ mol/kg) or gabapentin (146 µ mol/kg) resulted in enhanced antiallodynic efficacy without augmenting side effects. A subeffective dose of MIV-247 (50 µ mol/kg) in combination with a subeffective dose of pregabalin (38 µ mol/kg) or gabapentin (73 µ mol/kg) also resulted in substantial efficacy. Plasma levels of MIV-247, gabapentin, and pregabalin were similar when given in combination as to when given alone. Cathepsin S inhibition with MIV-247 exerts significant antiallodynic efficacy alone, and also enhances the effect of gabapentin and pregabalin without increasing side effects or inducing pharmacokinetic interactions.

  猫肽酶 S 抑制剂在临床前神经病理性疼痛模型中减轻机械性异痛。本研究评估了在小鼠神经病理性疼痛模型中，将选择性猫肽酶 S 抑制剂 MIV-247 与加巴喷丁或普瑞巴林结合使用的效果。通过部分坐骨神经结扎使小鼠出现神经病理性疼痛。MIV-247、加巴喷丁或普瑞巴林以单独或组合的方式通过口服灌胃给药。使用冯·弗雷毛发评估机械性异痛。通过评估走杆实验来评价神经行为副作用。测量了 MIV-247、加巴喷丁和普瑞巴林在各种组织中的浓度。口服给药 MIV-247（100-200 µ mol/kg）能够剂量依赖性地减轻机械性异痛，单次给药或每日两次连续给药 5 天时最多可逆转约 50%。在测试的任何剂量下未观察到 MIV-247 的行为缺陷。加巴喷丁（58-350 µ mol/kg）和普瑞巴林（63-377 µ mol/kg）也能抑制机械性异痛，在测试的最高剂量下几乎完全逆转。MIV-247 的最低有效剂量（100 µ mol/kg）与普瑞巴林的最低有效剂量（75 µ mol/kg）或加巴喷丁（146 µ mol/kg）联合使用后，增强了抗异痛效果而未增加副作用。MIV-247 的亚有效剂量（50 µ mol/kg）与普瑞巴林的亚有效剂量（38 µ mol/kg）或加巴喷丁（73 µ mol/kg）联合使用后也产生了显著的效果。MIV-247、加巴喷丁和普瑞巴林在联合使用时的血浆水平与单独使用时相似。使用 MIV-247 抑制猫肽酶 S 能显著提高单独的抗异痛效果，并且增强了加巴喷丁和普瑞巴林的效果，而不增加副作用或引发药代动力学相互作用。
• [EN] CYSTEINE PROTEASE INHIBITORS<br/>[FR] INHIBITEURS DE CYSTÉINE PROTÉASE
  申请人：MEDIVIR UK LTD

  公开号：WO2010070615A1

  公开（公告）日：2010-06-24

  Compounds of the formula I wherein R1a is H; and R1b is C1-C6 alkyl, Carbocyclyl or Het; or R1a and R1b together define a saturated cyclic amine with 3-6 ring atoms; R2a and R2b are H, halo, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy; or R2a and R2b together with the carbon atom to which they are attached form a C3-C6cycloalkyl; R is a branched C5-C10alkyl chain, C2-C4haloalkyl or C3-C7cycloalkylmethyl, R4 is Het, Carbocyclyl, optionally substituted as defined in the specification and pharmaceutically acceptable salts, hydrates and N-oxides thereof; are inhibitors of cathepsin S and have utility in the treatment of psoriasis, autoimmune disorders and other disorders such as asthma, arteriosclerosis, COPD and chronic pain

  式I的化合物，其中R1a为H；R1b为C1-C6烷基，碳环烷基或杂环基；或者R1a和R1b一起定义为具有3-6个环原子的饱和环胺；R2a和R2b为H，卤素，C1-C4烷基，C1-C4卤代烷基，C1-C4烷氧基；或者R2a和R2b与它们连接的碳原子一起形成C3-C6环烷基；R为支链C5-C10烷基链，C2-C4卤代烷基或C3-C7环烷基甲基，R4为杂环基，碳环烷基，如规范中定义的可选择取代基和药用盐、水合物及N-氧化物；是cathepsin S的抑制剂，用于治疗银屑病、自身免疫性疾病以及其他疾病，如哮喘、动脉硬化、慢性阻塞性肺疾病和慢性疼痛。
• CYSTEINE PROTEASE INHIBITORS
  申请人：Ayesa Susana

  公开号：US20130172232A1

  公开（公告）日：2013-07-04

  Compounds of the formula I wherein R 2a and R 2b are independently H, halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl or C 1 -C 4 alkoxy, or R 2a and R 2b together with the carbon atom to which they are attached form a C 3 -C 6 cycloalkyl; R 3 is a C 5 -C 10 alkyl, optionally substituted with 1-3 substituents independently selected from halo, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy; or R 3 is a C 2 -C 4 alkyl chain with at least 2 chloro or 3 fluoro substituents; or R 3 is C 3 -C 7 cycloalkylmethyl, optionally substituted with 1-3 substituents independently selected from C 1 -C 4 alkyl, halo, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy; R 4 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino or; R 4 is Het or Carbocyclyl, either of which is optionally substituted with 1-3 substituents R 4 is Het, carbocyclyl, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy or C 1 -C 6 haloalkoxy; n is 1, 2 or 3; for the use in the prophylaxis or treatment of a disorder characterised by inappropriate expression or activation of cathepsin S.

  化合物的公式为I，其中R2a和R2b独立地为H、卤素、C1-C4烷基、C1-C4卤代烷基或C1-C4烷氧基，或者R2a和R2b与它们连接的碳原子一起形成C3-C6环烷基；R3是C5-C10烷基，可选地被1-3个卤素、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基独立地取代；或者R3是具有至少2个氯或3个氟取代基的C2-C4烷基链；或者R3是C3-C7环烷基甲基，可选地被1-3个C1-C4烷基、卤素、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基独立地取代；R4是C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基、C1-C6烷基氨基、C1-C6二烷基氨基或者R4是Het或Carbocyclyl，它们中的任意一个可选地被1-3个取代基取代，其中R4是Het、carbocyclyl、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基或C1-C6卤代烷氧基；n为1、2或3；用于预防或治疗由于cathepsin S不适当的表达或激活而表现出的障碍。
• Cysteine protease inhibitors
  申请人：Medivir UK Ltd

  公开号：EP2752404A1

  公开（公告）日：2014-07-09

  There is provided a process for the preparation of a compound of formula III, comprising the step of oxidising the compound of formula 2b wherein n is 2; R2a and R2b are independently H or F; R3 is 1-methylcyclopentylmethyl or 1-fluorocyclopentylmethyl; R3' is CH3 or F; R4 is C1-C6alkyl, C1-C6haloalkyl or C3-C6cycloalkyl, wherein C3-C6cycloalkyl is optionally substituted with methyl, CF3 or one or two fluoro. Compounds and processes used in the preparation of a compound of formula III are also provided.

  提供了一种制备式 III 化合物的工艺，包括氧化式 2b 化合物的步骤 其中 n 为 2；R2a 和 R2b 独立地为 H 或 F；R3 为 1-甲基环戊基甲基或 1-氟环戊基甲基；R3' 为 CH3 或 F；R4 为 C1-C6 烷基、C1-C6 卤代烷基或 C3-C6 环烷基，其中 C3-C6 环烷基任选被甲基、CF3 或一或二氟取代。还提供了用于制备式 III 化合物的化合物和工艺。