tert-butyl (2S)-4-oxo-2-(pyrrolidinocarbonyl)pyrrolidine-1-carboxylate | 401564-40-7

• 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: tert-butyl (2S)-4-oxo-2-(pyrrolidinocarbonyl)pyrrolidine-1-carboxylate
• 英文别名: 1-((S)-1-tert-butoxycarbonyl-4-oxo-2-pyrrolidinylcarbonyl)pyrrolidine；tert-butyl (2S)-4-oxo-2-(pyrrolidin-1-yl-carbonyl)pyrrolidine-1-carboxylate；1,1-Dimethylethyl (2S)-4-oxo-2-(1-pyrrolidinylcarbonyl)-1-pyrrolidinecarboxylate；tert-butyl (2S)-4-oxo-2-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylate
• CAS: 401564-40-7
• 化学式: C₁₄H₂₂N₂O₄
• 分子量: 282.34
• InChiKey: CHFSTLOSOOLPFC-NSHDSACASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  66.9
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl (2S)-4-oxo-2-(pyrrolidinocarbonyl)pyrrolidine-1-carboxylate 在 甲次磺酰胺,N,N-二乙基-1,1,1-三氟- 作用下， 以 苯 为溶剂， 以52%的产率得到tert-butyl (2S)-4,4-difluoro-2-(pyrrolidinocarbonyl)pyrrolidine-1-carboxylate
  参考文献：
  名称：

  Prolyl Oligopeptidase Inhibition by N-Acyl-pro-pyrrolidine-type Molecules

  摘要：

  Three novel, N-acyl-pro-pyrrolidine-type, inhibitors of prolyl oligopeptidase (POP) with nanomolar activities were synthesized and their binding analyzed to the host enzyme in the light of X-ray diffraction and molecular modeling studies. We were interested in the alteration in the binding affinity at the S3 site as a function of the properties of the N-terminal group of the inhibitors. Our studies revealed that, for inhibitors with flat aromatic terminal groups, the optimal length of the linker chain is three C-C bonds, but this increases to four C-C bonds if there is a bulky group in the terminal position. Molecular dynamics calculations indicate that this is due to the better fit into the binding pocket. A 4-fold enhancement of the inhibitor activity upon replacement of the 4-CH2 group of the proline ring by CF2 is a consequence of a weak hydrogen bond formed between the fluorine atom and the hydroxy group of Tyr473 of the host enzyme. There is notably good agreement between the calculated and experimental free energies of binding; the average error in the IC50 values is around 1 order of magnitude.

  DOI：

  10.1021/jm800944x
• 作为产物：
  描述：

  tert-butyl (2S,4R)-4-hydroxy-2-(pyrrolidine-1-carbonyl)pyrrolidine-1-carboxylate 在 草酸氯化物 、 二甲基亚砜 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 以79.7%的产率得到tert-butyl (2S)-4-oxo-2-(pyrrolidinocarbonyl)pyrrolidine-1-carboxylate
  参考文献：
  名称：

  Prolyl Oligopeptidase Inhibition by N-Acyl-pro-pyrrolidine-type Molecules

  摘要：

  Three novel, N-acyl-pro-pyrrolidine-type, inhibitors of prolyl oligopeptidase (POP) with nanomolar activities were synthesized and their binding analyzed to the host enzyme in the light of X-ray diffraction and molecular modeling studies. We were interested in the alteration in the binding affinity at the S3 site as a function of the properties of the N-terminal group of the inhibitors. Our studies revealed that, for inhibitors with flat aromatic terminal groups, the optimal length of the linker chain is three C-C bonds, but this increases to four C-C bonds if there is a bulky group in the terminal position. Molecular dynamics calculations indicate that this is due to the better fit into the binding pocket. A 4-fold enhancement of the inhibitor activity upon replacement of the 4-CH2 group of the proline ring by CF2 is a consequence of a weak hydrogen bond formed between the fluorine atom and the hydroxy group of Tyr473 of the host enzyme. There is notably good agreement between the calculated and experimental free energies of binding; the average error in the IC50 values is around 1 order of magnitude.

  DOI：

  10.1021/jm800944x

文献信息

• Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
  申请人：Akritopoulou-Zanze Irini

  公开号：US20050215603A1

  公开（公告）日：2005-09-29

  The present invention relates to compounds of formula (I), which inhibit dipeptidyl peptidase IV (DPP-IV) and are useful for the prevention or treatment of diabetes, especially type II diabetes, as well as hyperglycemia, syndrome X, hyperinsulinemia, obesity, atherosclerosis, and various immunomodulatory diseases.

  本发明涉及一种化合物，其化学式为(I)，能够抑制二肽基肽酶IV（DPP-IV），并且可用于预防或治疗糖尿病，特别是2型糖尿病，以及高血糖、X综合征、高胰岛素血症、肥胖、动脉粥样硬化和各种免疫调节性疾病。
• [EN] ANTIDIABETIC COMPOUNDS<br/>[FR] COMPOSES ANTI-DIABETIQUES
  申请人：PFIZER PROD INC

  公开号：WO2006008644A1

  公开（公告）日：2006-01-26

  The invention provides compounds of formula (I), prodrugs and stereoisomers thereof, and the pharmaceutically acceptable salts of the compounds, prodrugs, and stereoisomers, wherein R1 is hydrogen, -(C1-C6)alkyl, -(C1-C6)alkoxy, -(C1-C6)arylalkyl, -NRaRb, hydroxy, cyano, arly or heteroaryl, wherein said -(C1-C6)alkyl, said aryl, or said heteroaryl is optionally substituted independently with one to three -COOH, -C(O)(C1-C6)alkyl, -C(O)NRaRb cyano, halogen, nitro, trifluoromethyl, -(C1-C6)alkyl, --(C1-C6)alkoxy, -(C3-C6)cycloalkyl or phenyl, wherein: Ra and Rb are, independently, hydrogen, -(C1-C6)alkyl, aryl or heteroaryl or Ra and Rb, taken together with the nitrogen atom to which they are attached, form a four- to six- membered heterocyclic ring, wherein said ring optionally incorporates an additional one or two nitrogen, oxygen or sulfur ring heteroatoms; R2 and R3 are, independently, hydrogen, halogen, -(C1-C6)alkyl, or -(C3-C8)cycloalkyl; R4 is (i) hydrogen, (ii) - COOH, (iii) -C(O)(C1-C6)alkoxy, (iv) -C(O)(C1-C6)alkyl, (v) -C(O)NRaRb, (vi) cyano or (vii) -(C1-C6)alkyl, optionally substituted with one to six halogen atoms, -(C1-C6)alkoxy, cyano, hydroxy, or -NRaRb, (viii) -(C3-C6)cycloalkyl, (ix) -(C1-C6)arylalkyl, (x) aryl, or (xi) heteroaryl; Q is a covalent bond, -C(O)-, or -SO2-; HET is heterocycloalkyl ring, moiety, optionally substituted independently with: (A) one to four -(C1-C6)alkyl optionally substituted with one to six halogen atoms, -(C1-C6)alkoxy, cyano, halogen, hydroxy, or -NRaRb, or (B) -(C1-C6)aralkyl, optionally substituted with on to six halogen atoms, -(C1-C6)alkoxy, cyano, halogen, hydroxy, or -NRaRb; n is zero or one; X is hydrogen or cyano; and Y is -CH2-, -S-, -S(O)-, or -SO2; provided that R2, R3 and R4 are not all hydrogen; compositions thereof; and uses thereof in treating diabetic complications including diabetic neuropathy diabetic nephropathy, diabetic microangiopathy, and the like.

  该发明提供了式（I）化合物，它们的前药和立体异构体，以及所述化合物，前药和立体异构体的药学上可接受的盐，其中R1为氢，-(C1-C6)烷基，-(C1-C6)烷氧基，-(C1-C6)芳基烷基，-NRaRb，羟基，氰基，芳基或杂环芳基，其中所述-(C1-C6)烷基，所述芳基或所述杂环芳基可以独立地取代一个至三个-COOH，-C（O）（C1-C6）烷基，-C（O）NRaRb，氰基，卤素，硝基，三氟甲基，-(C1-C6)烷基，-(C1-C6)烷氧基，-(C3-C6)环烷基或苯基，其中：Ra和Rb独立地为氢，-(C1-C6)烷基，芳基或杂环芳基，或Ra和Rb与它们连接的氮原子一起形成四至六元杂环，其中所述环可以选择地包含一个或两个额外的氮，氧或硫环杂原子；R2和R3独立地为氢，卤素，-(C1-C6)烷基或-(C3-C8)环烷基；R4为（i）氢，（ii）-COOH，（iii）-C（O）（C1-C6）烷氧基，（iv）-C（O）（C1-C6）烷基，（v）-C（O）NRaRb，（vi）氰基或（vii）-(C1-C6)烷基，可以选择地取代一个至六个卤素原子，-(C1-C6)烷氧基，氰基，羟基或-NRaRb，（viii）-(C3-C6）环烷基，（ix）-(C1-C6）芳基烷基，（x）芳基或（xi）杂环芳基；Q为共价键，-C（O）-或-SO2-；HET为杂环环烷基，基团，可以独立地取代：（A）一个至四个-(C1-C6)烷基，可以选择地取代一个至六个卤素原子，-(C1-C6)烷氧基，氰基，卤素，羟基或-NRaRb，或（B）-(C1-C6）芳基烷基，可以选择地取代一个至六个卤素原子，-(C1-C6)烷氧基，氰基，卤素，羟基或-NRaRb；n为零或一；X为氢或氰基；Y为-CH2-，-S-，-S（O）-或-SO2；前提是R2，R3和R4不全为氢；其组成；以及在治疗糖尿病并发症，包括糖尿病神经病变，糖尿病肾病，糖尿病微血管病等方面的用途。
• Proline derivatives and use thereof as drugs
  申请人：Kitajima Hiroshi

  公开号：US20050245538A1

  公开（公告）日：2005-11-03

  The present invention aims at providing compounds having therapeutic effects due to a DPP-IV inhibitory action, and satisfactory as pharmaceutical products. The present inventors have found that derivatives having a substituent introduced into the γ-position of proline represented by the formula (I) wherein each symbol is as defined in the specification, have a potent DPP-IV inhibitory activity, and completed the present invention by increasing the stability.

  本发明旨在提供具有治疗效果的化合物，其作用是通过DPP-IV的抑制作用，并且作为药物产品具有令人满意的效果。本发明人发现，在丙氨酸的γ位上引入取代基的衍生物具有强效的DPP-IV抑制活性，并通过增加稳定性完成了本发明。
• Proline derivatives and the use thereof as drugs
  申请人：——

  公开号：US20040106655A1

  公开（公告）日：2004-06-03

  The present invention aims at providing compounds having therapeutic effects due to a DPP-IV inhibitory action, and satisfactory as pharmaceutical products. The present inventors have found that derivatives having a substituent introduced into the &ggr;-position of proline represented by the formula (I) 1 wherein each symbol is as defined in the specification, have a potent DPP-IV inhibitory activity, and completed the present invention by increasing the stability.

  本发明旨在提供具有治疗作用的化合物，由于DPP-IV抑制作用而具有满意的药物产品。本发明人发现，具有引入取代基的脯氨酸γ-位置的衍生物，其化学式为(I)1，其中每个符号如规范中所定义，具有强效的DPP-IV抑制活性，并通过增加稳定性完成了本发明。
• PHARMACEUTICAL COMPOSITIONS AS INHIBITORS OF DIPEPTIDYL PEPTIDASE-IV (DPP-IV)
  申请人：Akritopoulou-Zanze Irini

  公开号：US20080119464A1

  公开（公告）日：2008-05-22

  The present invention relates to compounds of formula (I), which inhibit dipeptidyl peptidase IV (DPP-IV) and are useful for the prevention or treatment of diabetes, especially type II diabetes, as well as hyperglycemia, syndrome X, hyperinsulinemia, obesity, atherosclerosis, and various immunomodulatory diseases.

  本发明涉及公式(I)的化合物，其抑制二肽基肽酶IV（DPP-IV），并且可用于预防或治疗糖尿病，特别是II型糖尿病，以及高血糖，X综合症，高胰岛素血症，肥胖症，动脉粥样硬化和各种免疫调节性疾病。