(2R,3R,4S)-1-(benzyloxycarbonyl)-2-(hydroxymethyl)pyrrolidine-3,4-diol 3,4-O-isopropylidene acetal | 111265-96-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (2R,3R,4S)-1-(benzyloxycarbonyl)-2-(hydroxymethyl)pyrrolidine-3,4-diol 3,4-O-isopropylidene acetal
• 英文别名: (2R,3R,4S)-1-(benzyloxycarbonyl)-2-(hydroxymethyl)pyrrolidine-3,4-diol-3,4-O-isopropylidene acetal；(2R,3R,4S)-1-benzyloxycarbonyl-2-hydroxymethylpyrrolidine-3,4-diol-3,4-isopropylidene acetal；(2R,3R,4S)-1-benzyloxycarbonyl-3,4-isopropylidenedioxy-2-pyrrolidinyl methanol；benzyl (3aR,4R,6aS)-4-(hydroxymethyl)-2,2-dimethyl-3a,4,6,6a-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole-5-carboxylate
• CAS: 111265-96-4
• 化学式: C₁₆H₂₁NO₅
• 分子量: 307.346
• InChiKey: BAKQOXPWCAOVAA-HZSPNIEDSA-N

物化性质

• 沸点：
  447.8±45.0 °C(Predicted)
• 密度：
  1.222±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  68.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2R,3R,4S)-1-(benzyloxycarbonyl)-2-(hydroxymethyl)pyrrolidine-3,4-diol 3,4-O-isopropylidene acetal 在 palladium on activated charcoal 氢气 、 三氟乙酸 作用下， 以 乙醇 、 水 为溶剂， 35.0 ℃ 、172.37 kPa 条件下， 反应 20.25h， 生成 (2R,3R,4S)-2-(羟基甲基)吡咯烷-3,4-二醇
  参考文献：
  名称：

  由（2S）-3,4-脱氢脯氨酸衍生物合成（2R，3R，4S）-2-羟甲基吡咯烷-3,4-二醇。

  摘要：

  由N-保护的（2S）-3,4经五步合成（2R，3R，4S）-2-羟甲基吡咯烷-3,4-二醇（1,4-二脱氧-1,4-亚氨基-D-核糖醇） -脱氢脯氨酸甲酯。四氧化与脱氢脯氨酸衍生物的立体选择反应得到高产率的（2S，3R，4S）-3,4-二羟基脯氨酸（2,3-trans-3,4-cis-3,4-二羟基-L-脯氨酸）伴随少量（<15％）的非对映异构体（2S，3S，4R）-3,4-二羟基脯氨酸（2,3-cis-3,4-cis-3,4-二羟基-L-脯氨酸）。将非对映异构二醇的混合物转化为异亚丙基乙缩醛，并且异构体在制备规模上有效分离。将得到的受保护的（2S，3R，4S）-3,4-二羟基脯氨酸甲酯还原（LiBH4）成2-羟基甲基吡咯烷并脱保护，从而产生（2R，3R，4S）-2-羟基甲基吡咯烷-3，高产高纯度的4-二醇。产品的1H和13C NMR信号已使用二维NMR技术进行了明确分配，并且标题吡咯烷的

  DOI：

  10.1016/0008-6215(94)84059-8
• 作为产物：
  描述：

  反式-4-羟基-L-脯氨酸甲酯 在 四氧化锇 锂硼氢 作用下， 以 乙醚 、 水 、 丙酮 、 叔丁醇 为溶剂， 生成 (2R,3R,4S)-1-(benzyloxycarbonyl)-2-(hydroxymethyl)pyrrolidine-3,4-diol 3,4-O-isopropylidene acetal
  参考文献：
  名称：

  Synthesis of hydroxylated pyrrolidines derivatives as potential inhibitors of SAH/MTA nucleosidase.

  摘要：

  DOI：

  10.1016/s0040-4039(00)95775-7

文献信息

• 4-(Pyrrolidinyl)methoxybenzoic Acid Derivatives as a Potent, Orally Active VLA-4 Antagonist
  作者：Jun Chiba、Shin Iimura、Yoshiyuki Yoneda、Yuichi Sugimoto、Takao Horiuchi、Fumito Muro、Yuichi Ochiai、Tomomi Ogasawara、Masao Tsubokawa、Yutaka Iigou、Gensuke Takayama、Tomoe Taira、Yoshimi Takata、Mika Yokoyama、Tohru Takashi、Atsushi Nakayama、Nobuo Machinaga

  DOI：10.1248/cpb.54.1515

  日期：——

  A novel series of benzoic acid derivatives as VLA-4 antagonists were synthesized. Optimization, focusing on activity and lipophilicity needed for cell permeability, resulted in the identification of 15b and 15e with good activity (IC50=1.6 nM each) and moderate lipophilicity (Log D=2.0, 1.8). Furthermore, 15e demonstrated efficacy in murine asthma model by an oral dose of 30 mg/kg.

  合成了一系列苯甲酸衍生物作为VLA-4拮抗剂。优化侧重于活性和细胞通透性所需的亲脂性，最终鉴定出活性良好（IC50分别为1.6纳摩尔）和适度亲脂性（Log D=2.0，1.8）的化合物15b和15e。此外，化合物15e在30毫克/千克口服剂量下对小鼠哮喘模型显示出疗效。
• VLA-4 inhibitor compounds
  申请人：Daiichi Pharmaceutical Co., LTD.

  公开号：US20030078249A1

  公开（公告）日：2003-04-24

  Compounds that selectively inhibit the binding of ligands to &agr;4&bgr;1 integrin (VLA-4) and methods for their preparation are disclosed. In one embodiment, compounds of the invention are represented by Formula I: 1 As selective inhibitors of VLA-4 mediated cell adhesion, compounds of the present invention are useful in the treatment of conditions associated with such adhesion, including, but not limited to, such conditions as inflammatory and autoimmune responses, diabetes, asthma, psoriasis, inflammatory bowel disease, transplantation rejection, and tumor metastasis. Also disclosed are pharmaceutical compositions, methods of inhibiting VLA-4 mediated cell adhesion and methods of treating conditions associated with LA-4 mediated cell adhesion, which involve compounds of Formula I.

  本发明公开了选择性抑制配体与α4β1整合素（VLA-4）结合的化合物及其制备方法。在一个实施例中，本发明的化合物由式I表示： 1 作为VLA-4介导的细胞粘附的选择性抑制剂，本发明的化合物可用于治疗与该粘附相关的疾病，包括但不限于炎症和自身免疫反应、糖尿病、哮喘、银屑病、炎症性肠病、移植排斥和肿瘤转移。还公开了包含式I化合物的药物组合物、抑制VLA-4介导的细胞粘附的方法以及治疗与VLA-4介导的细胞粘附相关疾病的方法。
• Synthesis and cancer growth inhibitory activities of 2-fatty-alkylated pyrrolidine-3,4-diol derivatives
  作者：Pilar Elías-Rodríguez、Elena Moreno-Clavijo、Sebastián Carrión-Jiménez、Ana T. Carmona、Antonio J. Moreno-Vargas、Irene Caffa、Fabrizio Montecucco、Michele Cea、Alessio Nencioni、Inmaculada Robina

  DOI：10.3998/ark.5550190.p008.492

  日期：——

  of new amphiphilic pyrrolidines containing dodecyl and oleyl apolar side chains were prepared and evaluated for their ability to inhibit the growth of pancreatic ductal adenocarcinoma cells in vitro. The new compounds are shown to exhibit anticancer activity at concentrations in the M range.

  制备了一系列含有十二烷基和油基非极性侧链的新型两亲性吡咯烷，并评估了它们在体外抑制胰腺导管腺癌细胞生长的能力。新化合物在 M 范围内的浓度显示出抗癌活性。
• SAR Analysis of Adenosine Diphosphate (Hydroxymethyl)pyrrolidinediol Inhibition of Poly(ADP-ribose) Glycohydrolase
  作者：David W. Koh、Donna L. Coyle、Nimish Mehta、Sushma Ramsinghani、Hyuntae Kim、James T. Slama、Myron K. Jacobson

  DOI：10.1021/jm020541u

  日期：2003.9.1

  Polyadenosine diphosphoribose glycohydrolase (PARG) catalyzes the intracellular hydrolysis of adenosine diphosphoribose polymers. Because structure-activity data are lacking for PARG, the specific inhibitor adenosine diphosphate (hydroxymethyl)pyrrolidinediol (ADP-HPD) was utilized to determine the effects of structure on inhibitor potency using PARG isolated from bovine thymus (bPARG) and recombinant bovine PARG catalytic fragment (rPARG-CF). Both enzymes were strongly inhibited by submicromolar levels of ADP-HPD, but ADP and the phosphorylated pyrrolidine displayed no activity. Utilizing ADP-HPD analogues containing 2-, N-6, or 8-adenosyl substituents or guanine instead of adenine, the importance of adenine ring recognition as well as a correlation between loss of PARG inhibition and the length and bulkiness of 8-adenosyl substituents was shown. Utilization of ADP-HPD analogues lacking one or both pyrrolidine cis-hydroxyls demonstrated their importance for inhibitor binding. Last, the similarity between naturally occurring bPARG and heterologously expressed rPARG-CF was demonstrated. Therefore, readily available rPARG-CF is suitable for use in future studies to determine the structural aspects of PARG.
• Specific Inhibition of Poly(ADP-ribose) Glycohydrolase by Adenosine Diphosphate (Hydroxymethyl)pyrrolidinediol
  作者：James T. Slama、Nasreen Aboul-Ela、Deepa M. Goli、Bruce V. Cheesman、Anne M. Simmons、Myron K. Jacobson

  DOI：10.1021/jm00002a021

  日期：1995.1

  Adenosine diphosphate (hydroxymethyl)pyrrolidinediol (ADP-HPD), an NH analog of ADP-ribose, was chemically synthesized and shown to be a potent and specific inhibitor of poly(ADP-ribose) glycohydrolase. The synthetic starting material was the protected pyrroidine, (2R,3R,4S)-1-(benzyloxycarbonyl)-2-(hydroxymethyl)pyrrolidine-3,4-diol 3,4-O-isopropylidene acetal. This starting pyrrolidine was phosphorylated, coupled to adenosine 5'-monophosphate, and deprotected, yielding the title inhibitor ADP-HPD. ADP-HDP was shown to inhibit the activity of poly(ADP-ribose) glycohydrolase by 50% (IC50) at 0.12 mu M, a value 1000-times lower than the IC50 of the product, ADP-ribose. The NAD glycohydrolase from Bungarus fasciatus venom was less sensitive to inhibition by ADP-HPD,exhibiting an IC50 of 260 mu M. ADP-HPD did not inhibit either poly(ADP-ribose) polymerase or NAD:arginine mono(ADP-ribosyl)-transferase A at inhibitor concentrations up to 1 mM. At low ADP-HPD concentration, inhibition was therefore shown to be highly specific for poly(ADP-ribose) glycohydrolase,the hydrolytic enzyme in the metabolism of ADP-ribose polymers.