benzyl (S)-(-)-2-isocyanato-3-methylbutyrate | 55565-28-1

• 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: benzyl (S)-(-)-2-isocyanato-3-methylbutyrate
• 英文别名: benzyl (2S)-2-isocyanato-3-methylbutanoate
• CAS: 55565-28-1
• 化学式: C₁₃H₁₅NO₃
• 分子量: 233.267
• InChiKey: WNUXNPJUFUXAEJ-LBPRGKRZSA-N

物化性质

• 沸点：
  314.2±25.0 °C(Predicted)
• 密度：
  1.07±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  17
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  55.7
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  benzyl (S)-(-)-2-isocyanato-3-methylbutyrate 、 7-乙基-10-羟基喜树碱 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 生成
  参考文献：
  名称：

  Synthesis and Biological Evaluation of Novel 10-Substituted-7-ethyl-10-hydroxycamptothecin (SN-38) Prodrugs

  摘要：

  为了提高伊立替康（irinotecan, 2）的抗肿瘤活性并减少其副作用，研究人员通过羧酸酯链接将氨基酸或二肽与SN-38（3）的10-羟基结合，制备了新型的SN-38前药。这些合成的化合物在pH 7.4的缓冲液或人血浆中能够完全生成SN-38，同时在酸性条件下保持稳定。所有前药化合物在体外对HeLa细胞和SGC-7901细胞的抗肿瘤活性都明显高于伊立替康。最活跃的化合物5h、7c、7d和7f，在HeLa细胞中的IC50值比伊立替康低1000倍，而在SGC-7901细胞中的IC50值低30倍，同时这些前药对乙酰胆碱酯酶（AchE）的抑制活性显著降低，IC50值比伊立替康高出6.8倍。此外，化合物5e在体内的人类结肠异种移植模型中表现出与伊立替康（CPT-11相同的肿瘤生长抑制活性。

  DOI：

  10.3390/molecules191219718
• 作为产物：
  描述：

  三光气 、 L-缬氨酸苄酯对甲苯磺酸盐 在 碳酸氢钠 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 0.5h， 生成 benzyl (S)-(-)-2-isocyanato-3-methylbutyrate
  参考文献：
  名称：

  Synthesis and Biological Evaluation of Novel 10-Substituted-7-ethyl-10-hydroxycamptothecin (SN-38) Prodrugs

  摘要：

  为了提高伊立替康（irinotecan, 2）的抗肿瘤活性并减少其副作用，研究人员通过羧酸酯链接将氨基酸或二肽与SN-38（3）的10-羟基结合，制备了新型的SN-38前药。这些合成的化合物在pH 7.4的缓冲液或人血浆中能够完全生成SN-38，同时在酸性条件下保持稳定。所有前药化合物在体外对HeLa细胞和SGC-7901细胞的抗肿瘤活性都明显高于伊立替康。最活跃的化合物5h、7c、7d和7f，在HeLa细胞中的IC50值比伊立替康低1000倍，而在SGC-7901细胞中的IC50值低30倍，同时这些前药对乙酰胆碱酯酶（AchE）的抑制活性显著降低，IC50值比伊立替康高出6.8倍。此外，化合物5e在体内的人类结肠异种移植模型中表现出与伊立替康（CPT-11相同的肿瘤生长抑制活性。

  DOI：

  10.3390/molecules191219718

文献信息

• NOVEL CARBAMATE AMINO ACID AND PEPTIDE PRODRUGS OF OPIOIDS AND USES THEREOF
  申请人：Franklin Richard

  公开号：US20110015182A1

  公开（公告）日：2011-01-20

  Carbamate linked prodrugs of meptazinol and other opioid analgesics are provided. The prodrug moiety may comprise a single amino acid or short peptide. Additionally, the present invention relates to methods for reducing gastrointestinal side effects in a subject, the gastrointestinal side effects being associated with the administration of an opioid analgesic. The methods comprise orally administering an opioid prodrug or pharmaceutically acceptable salt thereof to a subject, wherein the opioid prodrug is comprised of an opioid analgesic covalently bonded through a carbamate linkage to a prodrug moiety, and wherein upon oral administration, the prodrug or pharmaceutically acceptable salt minimizes at least one gastrointestinal side effect associated with oral administration of the opioid analgesic alone. Compositions for use with the method are also provided.

  本发明提供了与咪哌唑酮和其他阿片类镇痛剂相关的氨基甲酸酯前药。前药基团可以包括单个氨基酸或短肽。此外，本发明涉及减少受试者胃肠道副作用的方法，其中胃肠道副作用与阿片类镇痛剂的给药有关。该方法包括口服给受试者阿片类前药或其药学上可接受的盐，其中阿片类前药由阿片类镇痛剂通过氨基甲酸酯键共价结合到前药基团上，且在口服给药时，前药或药学上可接受的盐至少减少与单独口服阿片类镇痛剂有关的一个胃肠道副作用。本发明还提供了用于该方法的组合物。
• AMINO ACID PEPTIDE PRO-DRUGS OF PHENOLIC ANALGESICS AND USES THEREOF
  申请人：Franklin Richard

  公开号：US20090186832A1

  公开（公告）日：2009-07-23

  Prodrugs of meptazinol and other phenolic analgesics exhibiting low oral bioavailability with amino acids or lower peptides, pharmaceutical compositions containing such prodrugs and a method for providing pain relief with such prodrugs are provided. In addition, the present invention relates to methods for increasing the oral bioavailability of a phenolic analgesic. The method comprises orally administering a phenolic analgesic prodrug, wherein the phenolic analgesic is bound to an amino acid or peptide via a carbamate linkage, to a subject in need thereof. Prodrugs having side chains of valine, leucine, isoleucine and glycine amino acids and mono-, di- and tripeptides thereof are preferred.

  本发明提供了美托津诺尔及其他表现出口服生物利用度低的酚类镇痛剂的前药，其与氨基酸或较低的肽结合，以及含有这种前药的制药组合物和使用这种前药提供缓解疼痛的方法。此外，本发明还涉及提高酚类镇痛剂口服生物利用度的方法。该方法包括口服给予酚类镇痛剂前药，其中酚类镇痛剂通过氨基酸或肽的氨甲酰基链接结合到前药中，并给予需要的受试者。具有缬氨酸、亮氨酸、异亮氨酸和甘氨酸氨基酸和其单、二、三肽的侧链的前药是首选。
• Toward the Back-Up of Boceprevir (SCH 503034): Discovery of New Extended P₄-Capped Ketoamide Inhibitors of Hepatitis C Virus NS3 Serine Protease with Improved Potency and Pharmacokinetic Profiles
  作者：Stéphane L. Bogen、Weidong Pan、Sumei Ruan、Latha G. Nair、Ashok Arasappan、Frank Bennett、Kevin X. Chen、Edwin Jao、Srikanth Venkatraman、Bancha Vibulbhan、Rong Liu、Kuo-Chi Cheng、Zhuyan Guo、Xiao Tong、Anil K. Saksena、Viyyoor Girijavallabhan、F. George Njoroge

  DOI：10.1021/jm801632a

  日期：2009.6.25

  Hepatitis C is the most prevalent liver disease. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically an estimated 300 million people worldwide. Results of Phase I clinical studies with our first generation HCV inhibitor Boceprevir, SCH 503034 (1), presented at the 56th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) were encouraging, and thus, additional human clinical studies are underway. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P-4 pocket and optimization of the P-1' capping led to the discovery of new ketoamide inhibitors of the HCV NS3 serine protease with improved in vitro potency. In addition to being potent inhibitors of HCV subgenomic RNA replication, some of the new P-4-capped inhibitors were also found to have improved PK profile.
• Total Synthesis of Syringolin A
  作者：Chunhui Dai、Corey R. J. Stephenson

  DOI：10.1021/ol101252y

  日期：2010.8.6

  A convergent, efficient synthesis of syringolin A has been accomplished in 13 steps from commercially available materials, Garner's aldehyde and L-valine. The unnatural 3,4-dehydrolysine fragment was prepared using successive Johnson-Claisen/Curtius rearrangement reactions. The macrolactamization and late-stage introduction of the side chain will provide convenient access to analogues of this promising proteasome Inhibitor.
• AMINO ACID AND PEPTIDE PRODRUGS OF OPIOID ANALGESICS WITH REDUCED GI SIDE-EFFECTS
  申请人：Franklin Richard

  公开号：US20090192095A1

  公开（公告）日：2009-07-30

  The present invention relates to methods for reducing gastrointestinal side effects in a subject, the gastrointestinal side effects being associated with the administration of an opioid analgesic. The methods comprise orally administering an opioid prodrug or pharmaceutically acceptable salt thereof to a subject, wherein the opioid prodrug is comprised of an opioid analgesic covalently bonded through a carbamate linkage to a peptide of 1-5 amino acids in length, and wherein upon oral administration, the prodrug or pharmaceutically acceptable salt minimizes at least one gastrointestinal side effect associated with oral administration of the opioid analgesic alone. Compositions for use with the method are also provided.