tert-butyl 4-(3-amino-4-hydroxyphenyl)piperidine-1-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: tert-butyl 4-(3-amino-4-hydroxyphenyl)piperidine-1-carboxylate
• 英文别名: Tert-butyl 4-(3-amino-4-hydroxyphenyl)piperidine-1-carboxylate
• 化学式: C₁₆H₂₄N₂O₃
• 分子量: 292.378
• InChiKey: DLDYCGIFBGTCQP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  75.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-(3-amino-4-hydroxyphenyl)piperidine-1-carboxylate 在 盐酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 乙腈 为溶剂， 反应 5.5h， 生成 N-isobutyl-2-oxo-5-(4-piperidyl)-1,3-benzoxazole-3-carboxamide hydrochloride
  参考文献：
  名称：

  Lead Optimization of Benzoxazolone Carboxamides as Orally Bioavailable and CNS Penetrant Acid Ceramidase Inhibitors

  摘要：

  Sphingolipids (SphLs) are a diverse class of molecules that are regulated by a complex network of enzymatic pathways. A disturbance in these pathways leads to lipid accumulation and initiation of several SphL-related disorders. Acid ceramidase is one of the key enzymes that regulate the metabolism of ceramides and glycosphingolipids, which are important members of the SphL family. Herein, we describe the lead optimization studies of benzoxazolone carboxamides resulting in piperidine 22m, where we demonstrated target engagement in two animal models of neuropathic lysosomal storage diseases (LSDs), Gaucher's and Krabbe's diseases. After daily intraperitoneal administration at 90 mg kg(-1), 22m significantly reduced the brain levels of the toxic lipids glucosylsphingosine (GluSph) in 4L;C* mice and galactosylsphingosine (GalSph) in Twitcher mice. We believe that 22m is a lead molecule that can be further developed for the correction of severe neurological LSDs where GluSph or GalSph play a significant role in disease pathogenesis.

  DOI：

  10.1021/acs.jmedchem.9b02004
• 作为产物：
  描述：

  4-溴-2-硝基苯酚 在 甲醇 、 二氯双(三邻甲苯膦)合钯(II) 、 环己烷 、 palladium 10% on activated carbon 、 sodium carbonate 作用下， 以 1,4-二氧六环 为溶剂， 反应 4.0h， 生成 tert-butyl 4-(3-amino-4-hydroxyphenyl)piperidine-1-carboxylate
  参考文献：
  名称：

  Lead Optimization of Benzoxazolone Carboxamides as Orally Bioavailable and CNS Penetrant Acid Ceramidase Inhibitors

  摘要：

  Sphingolipids (SphLs) are a diverse class of molecules that are regulated by a complex network of enzymatic pathways. A disturbance in these pathways leads to lipid accumulation and initiation of several SphL-related disorders. Acid ceramidase is one of the key enzymes that regulate the metabolism of ceramides and glycosphingolipids, which are important members of the SphL family. Herein, we describe the lead optimization studies of benzoxazolone carboxamides resulting in piperidine 22m, where we demonstrated target engagement in two animal models of neuropathic lysosomal storage diseases (LSDs), Gaucher's and Krabbe's diseases. After daily intraperitoneal administration at 90 mg kg(-1), 22m significantly reduced the brain levels of the toxic lipids glucosylsphingosine (GluSph) in 4L;C* mice and galactosylsphingosine (GalSph) in Twitcher mice. We believe that 22m is a lead molecule that can be further developed for the correction of severe neurological LSDs where GluSph or GalSph play a significant role in disease pathogenesis.

  DOI：

  10.1021/acs.jmedchem.9b02004

文献信息

• SUBSTITUTED N-HETEROCYCLIC CARBOXAMIDES AS ACID CERAMIDASE INHIBITORS AND THEIR USE AS MEDICAMENTS
  申请人：Bial - R&D Investments, S.A.

  公开号：US20220402901A1

  公开（公告）日：2022-12-22

  The invention provides substituted N-heterocyclic carboxamides and related compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat a medical disorder, e.g., cancer, lysosomal storage disorder, neurodegenerative disorder, inflammatory disorder, in a patient.
• Lead Optimization of Benzoxazolone Carboxamides as Orally Bioavailable and CNS Penetrant Acid Ceramidase Inhibitors
  作者：Simona Di Martino、Piero Tardia、Vincenzo Cilibrasi、Samantha Caputo、Marco Mazzonna、Debora Russo、Ilaria Penna、Natalia Realini、Natasha Margaroli、Marco Migliore、Daniela Pizzirani、Giuliana Ottonello、Sine Mandrup Bertozzi、Andrea Armirotti、Duc Nguyen、Ying Sun、Ernesto R. Bongarzone、Peter Lansbury、Min Liu、Renato Skerlj、Rita Scarpelli

  DOI：10.1021/acs.jmedchem.9b02004

  日期：2020.4.9

  Sphingolipids (SphLs) are a diverse class of molecules that are regulated by a complex network of enzymatic pathways. A disturbance in these pathways leads to lipid accumulation and initiation of several SphL-related disorders. Acid ceramidase is one of the key enzymes that regulate the metabolism of ceramides and glycosphingolipids, which are important members of the SphL family. Herein, we describe the lead optimization studies of benzoxazolone carboxamides resulting in piperidine 22m, where we demonstrated target engagement in two animal models of neuropathic lysosomal storage diseases (LSDs), Gaucher's and Krabbe's diseases. After daily intraperitoneal administration at 90 mg kg(-1), 22m significantly reduced the brain levels of the toxic lipids glucosylsphingosine (GluSph) in 4L;C* mice and galactosylsphingosine (GalSph) in Twitcher mice. We believe that 22m is a lead molecule that can be further developed for the correction of severe neurological LSDs where GluSph or GalSph play a significant role in disease pathogenesis.