(S)-2-(3,3-difluoropyrrolidine-1-carbonyl)-4-oxopyrrolidine-1-carboxylic acid tert-butyl ester | 869488-91-5

• 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-(3,3-difluoropyrrolidine-1-carbonyl)-4-oxopyrrolidine-1-carboxylic acid tert-butyl ester
• 英文别名: tert-butyl-(2S)-2-[(3,3-difluoropyrrolidin-1-yl)carbonyl]-4-oxopyrrolidine-1-carboxylate；tert-butyl (2S)-2-(3,3-difluoropyrrolidine-1-carbonyl)-4-oxopyrrolidine-1-carboxylate
• CAS: 869488-91-5
• 化学式: C₁₄H₂₀F₂N₂O₄
• 分子量: 318.321
• InChiKey: VAUAJWPEBZXSES-JTQLQIEISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  22
• 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：
  6

反应信息

• 作为反应物：
  描述：

  (S)-2-(3,3-difluoropyrrolidine-1-carbonyl)-4-oxopyrrolidine-1-carboxylic acid tert-butyl ester 在 sodium tetrahydroborate 作用下， 以 甲醇 为溶剂， 生成
  参考文献：
  名称：

  (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone: A potent, selective, orally active dipeptidyl peptidase IV inhibitor

  摘要：

  A series of 4-substituted proline amides was synthesized and evaluated as inhibitors of dipeptidyl pepdidase IV for the treatment of type 2 diabetes. (3,3-Difluoro-pyrrolidin-1-yl)-[(2S,4S)-(4-(4-pyrimidin-2-yl-piperazin-1-yl)-pyrrolidin-2-yl]-methanone (5) emerged as a potent (IC(50) = 13 nM) and selective compound, with high oral bioavailability in preclinical species and low plasma protein binding. Compound 5, PF-00734200, was selected for development as a potential new treatment for type 2 diabetes.

  DOI：

  10.1016/j.bmcl.2009.02.041
• 作为产物：
  描述：

  3,3-二氟吡咯烷盐酸 在 三乙胺 、 三甲基乙酰氯 、 盐酸 、 碳酸氢钠 作用下， 以 二氯甲烷 、 dixhloroethane 为溶剂， 反应 1.67h， 以79%的产率得到(S)-2-(3,3-difluoropyrrolidine-1-carbonyl)-4-oxopyrrolidine-1-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Therapeutic compounds

  摘要：

  该发明提供了式（I）的化合物，其前药和立体异构体，以及该化合物、前药和立体异构体的药用可接受盐，其中R1、R2、R3、HET、n、Q、X、Y和Z如本文所述；它们的组合物；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、糖尿病微血管病变等方面的用途。

  公开号：

  US20050256310A1

文献信息

• Metabolism, Excretion, and Pharmacokinetics of ((3,3-Difluoropyrrolidin-1-yl)((2<i>S</i>,4<i>S</i>)-4-(4-(pyrimidin-2-yl)piperazin-1-yl)pyrrolidin-2-yl)methanone, a Dipeptidyl Peptidase Inhibitor, in Rat, Dog and Human
  作者：Raman Sharma、Hao Sun、David W. Piotrowski、Tim F. Ryder、Shawn D. Doran、Haiqing Dai、Chandra Prakash

  DOI：10.1124/dmd.112.047316

  日期：2012.11

  The disposition of 3,3-difluoropyrrolidin-1-yl(2 S ,4 S )-4-[4-(pyrimidin-2-yl)piperazin-1-yl]pyrrolidin-2-yl}methanone (PF-00734200), a dipeptidyl peptidase IV inhibitor that progressed to phase 3 for the treatment of type 2 diabetes, was examined in rats, dogs, and humans after oral administration of a single dose of [14C]PF-00734200. Mean recoveries of administered radioactivity were 97.1, 92.2, and 87.2% in rats, dogs, and humans, respectively. The majority of radioactive dose was detected in the urine of dogs and humans and in the feces of rats. Absorption of PF-00734200 was rapid in all species, with maximal plasma concentrations of radioactivity achieved within 1 h after the dose. Circulating radioactivity was primarily composed of the parent drug (79.9, 80.2, and 94.4% in rat, dog, and human, respectively). The major route of metabolism was due to hydroxylation at the 5′ position of the pyrimidine ring (M5) in all species. In vitro experiments with recombinant cytochrome P450 isoforms suggested that the formation of M5 was catalyzed both by CYP2D6 and CYP3A4. Molecular docking simulations showed that the 5′ position of the pyrimidine moiety of PF-00734200 can access the heme iron-oxo of both CYP3A4 and CYP2D6 in an energetically favored orientation. Other metabolic pathways included amide hydrolysis (M2), N-dealkylation at the piperazine nitrogen (M3) and an unusual metabolite resulting from scission of the pyrimidine ring (M1). Phase II metabolic pathways included the following: carbamoyl glucuronidation (M9), glucosidation (M15) on the pyrrolidine nitrogen, and conjugation with creatinine to form an unusual metabolite/metabonate (M16). The data from these studies suggest that PF-00734200 is eliminated by both metabolism and renal clearance.

  3,3-二氟吡咯烷-1-基(2 S, 4 S)-4-[4-(氟嘧啶-2-基)哌嗪-1-基]吡咯烷-2-基}甲酮（PF-00734200）是一种二肽基肽酶IV抑制剂，已进入阶段3用于治疗2型糖尿病。研究在口服单剂量[14C]PF-00734200后，对大鼠、犬和人类进行了药物分布的观察。大鼠、犬和人类的放射性药物的平均回收率分别为97.1%、92.2%和87.2%。大部分放射性剂量在犬和人类的尿液中以及大鼠的粪便中被检测到。PF-00734200在所有物种中的吸收速度较快，在给药后1小时内达到了最大血浆浓度。循环中的放射性主要由母药组成（大鼠、犬和人类分别为79.9%、80.2%和94.4%）。所有物种的主要代谢途径是通过在嘧啶环的5'位置进行羟基化（M5）。与重组细胞色素P450同种型的体外实验表明，M5的形成是由CYP2D6和CYP3A4催化的。分子对接模拟显示PF-00734200的嘧啶部分的5'位置可以以有利的能量取向接触CYP3A4和CYP2D6的血红素铁氧。其他代谢途径包括酰胺水解（M2）、在哌嗪氮处的N-去烷基化（M3）以及由嘧啶环裂解产生的非典型代谢物（M1）。II期代谢途径包括以下内容：氨基甲基葡萄糖醛化（M9）、在吡咯烷氮处的葡萄糖苷化（M15）以及与肌酐结合形成非典型代谢物/代謝酸（M16）。这些研究数据表明PF-00734200的排除主要通过代谢和肾脏清除。
• THERAPEUTIC COMPOUNDS
  申请人：Hulin Bernard

  公开号：US20070161664A1

  公开（公告）日：2007-07-12

  The invention provides compounds of formula (I), or a pharmaceutically acceptable salt of said compound, or a solvate of said compound or salt, wherein R 1 , R 2 , R 3 , HET, n, Q, X, Y, and Z are as described herein; compositions thereof; and uses thereof including treating Type 2 diabetes.

  本发明提供了式(I)的化合物，或其药学上可接受的盐，或该化合物或盐的溶剂结晶体，其中R1、R2、R3、HET、n、Q、X、Y和Z如本文所述；以及包括治疗2型糖尿病在内的其使用方法和组合物。
• (2S,4S)-4-(piperazin-1-yl)pyrrolidine-2-methanone derivatives
  申请人：Pfizer Inc

  公开号：US07465732B2

  公开（公告）日：2008-12-16

  The invention provides compounds of formula (I), or a pharmaceutically acceptable salt of said compound, or a solvate of said compound or salt, wherein R1, R2, R3, HET, n, Q, X, Y, and Z are as described herein; compositions thereof; and uses thereof including treating Type 2 diabetes.

  本发明提供以下化合物（I）的化合物，或其药学上可接受的盐，或其化合物或盐的溶剂，其中R1，R2，R3，HET，n，Q，X，Y和Z如本文所述；以及其组合物；和使用它们治疗2型糖尿病。
• PROLINE DERIVATIVES AND THEIR USE AS DIPEPTIDYL PEPTIDASE IV INHIBITORS
  申请人：Pfizer Products Inc.

  公开号：EP1753748A1

  公开（公告）日：2007-02-21
• Proline derivatives and their use as dipeptidyl peptidase IV inhibitors
  申请人：Pfizer Products Inc.

  公开号：EP2116541B1

  公开（公告）日：2015-02-25