(S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one | 1110642-47-1

• 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: (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one
• 英文别名: (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one；(6S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(1S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl]-1,3-oxazinan-2-one
• CAS: 1110642-47-1
• 化学式: C₂₈H₃₈BNO₅
• 分子量: 479.424
• InChiKey: BXQWRZYOOZPLBJ-MMTVBGGISA-N

物化性质

• 沸点：
  643.7±55.0 °C(Predicted)
• 密度：
  1.15±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.95
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.54
• 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：

  (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 sodium carbonate 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.42h， 生成 5-(4-{(S)-1-[(S)-6-(2-Hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]-ethyl}-phenyl)-pyridine-2-carboxylic acid ethylamide
  参考文献：
  名称：

  INHIBITORS OF 11beta-HYDROXYSTEROID DEHYDROGENASE 1

  摘要：

  这项发明涉及公式（I）、（Ia1-10）、（Ib1-10）、（Ic1-10）、（Id1-7）、（Ie1-5）的新化合物，其药学上可接受的盐，以及其药物组合物，这些化合物对于治疗与哺乳动物中11β-HSD1的调节或抑制相关的疾病是有用的。该发明还涉及这些新化合物的药物组合物和它们在细胞中减少或控制皮质醇的产生或抑制皮质醇酮转化为皮质醇的方法的用途。

  公开号：

  US20120108578A1
• 作为产物：
  描述：

  (R)-6-allyl-3-((S)-1-(4-bromophenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 氧气 、 potassium acetate 、 copper(l) chloride 、 palladium dichloride 作用下， 以 四氢呋喃 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 21.0h， 生成 (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one
  参考文献：
  名称：

  Discovery of BI 135585, an in vivo efficacious oxazinanone-based 11β hydroxysteroid dehydrogenase type 1 inhibitor

  摘要：

  A potent, in vivo efficacious 11 beta hydroxysteroid dehydrogenase type 1 (11 beta HSD1) inhibitor (11j) has been identified. Compound 11j inhibited 11 beta HSD1 activity in human adipocytes with an IC50 of 4.3 nM and in primary human adipose tissue with an IC80 of 53 nM. Oral administration of 11j to cynomolgus monkey inhibited 11 beta HSD1 activity in adipose tissue. Compound 11j exhibited >1000x selectivity over other hydroxysteroid dehydrogenases, displays desirable pharmacodynamic properties and entered human clinical trials in 2011. (C) 2017 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2017.04.033

文献信息

• CYCLIC INHIBITORS OF 11BETA-HYDROXYSTEROID DEHYDROGENASE 1
  申请人：Renz Martin

  公开号：US20100331320A1

  公开（公告）日：2010-12-30

  This invention relates to novel compounds of the Formula Ik, Im 1 , Im 2 , Im 5 , In 1 , In 2 , In 5 , Io 1 , Io 2 , Io 5 , Ip 1 , Ip 3 , pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful for the therapeutic treatment of diseases associated with the modulation or inhibition of 11β-HSD1 in mammals. The invention further relates to pharmaceutical compositions of the novel compounds and methods for their use in the reduction or control of the production of cortisol in a cell or the inhibition of the conversion of cortisone to cortisol in a cell.

  这项发明涉及到Ik、Im1、Im2、Im5、In1、In2、In5、Io1、Io2、Io5、Ip1、Ip3的新化合物，以及其药学上可接受的盐和药物组合物，这些化合物对于治疗与哺乳动物中11β-HSD1的调节或抑制相关的疾病是有用的。该发明还涉及这些新化合物的药物组合物和它们在细胞中减少或控制皮质醇的产生或抑制皮质醇酮转化为皮质醇的方法。
• [EN] SUBSTITUTED 5-,6- AND 7-MEMBERED HETEROCYCLES, MEDICAMENTS CONTAINING SUCH COMPOUNDS, AND THEIR USE<br/>[FR] HÉTÉROCYCLES À 5, 6 ET 7 CHAÎNONS SUBSTITUÉS, MÉDICAMENTS CONTENANT CES COMPOSÉS ET LEUR UTILISATION
  申请人：VITAE PHARMACEUTICALS INC

  公开号：WO2011159760A1

  公开（公告）日：2011-12-22

  The present invention relates to compounds defined by formula I: wherein the variables A1, A2, Cy1 Cy2, Cy3, E, R1a, R1b, R2, R3, n, and Q are as defined herein, possessing valuable pharmacological activity. Particularly, the compounds are inhibitors of 11 β-hydroxysteroid dehydrogenase (HSD) 1 and thus are suitable for treatment and prevention of diseases which can be influenced by inhibition of this enzyme, such as metabolic diseases, in particular diabetes type 2, obesity, and dyslipidemia.

  本发明涉及由以下式I定义的化合物：其中变量A1、A2、Cy1、Cy2、Cy3、E、R1a、R1b、R2、R3、n和Q如本文所定义，具有有价值的药理活性。特别地，这些化合物是11β-羟基类固醇脱氢酶（HSD）1的抑制剂，因此适用于治疗和预防可以受到该酶抑制影响的疾病，如代谢性疾病，特别是2型糖尿病、肥胖症和血脂异常。
• [EN] SYNTHESIS OF INHIBITORS OF 11BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1<br/>[FR] SYNTHÈSE D'INHIBITEURS DE LA 11?-HYDROXYSTÉROÏDE DÉHYDROGÉNASE DE TYPE 1
  申请人：BOEHRINGER INGELHEIM INT

  公开号：WO2010010150A1

  公开（公告）日：2010-01-28

  Disclosed are syntheses of 11β-HSD1 inhibitors and corresponding intermediates that are promising for the treatment of a variety of disease states including diabetes, metabolic syndrome, obesity, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hypertension-related cardiovascular disorders, hyperlipidemia, deleterious gluco-corticoid effects on neuronal function (e.g. cognitive impairment, dementia, and/or depression), elevated intra-ocular pressure, various forms of bone disease (e.g., osteoporosis), tuberculosis, leprosy (Hansen's disease), psoriasis, and impaired wound healing (e.g., in patients that exhibit impaired glucose tolerance and/or type 2 diabetes).

  披露了合成11β-HSD1抑制剂及相应中间体的方法，这些方法对治疗包括糖尿病、代谢综合征、肥胖、葡萄糖耐量不良、胰岛素抵抗、高血糖、高血压、与高血压相关的心血管疾病、高脂血症、糖皮质激素对神经功能的有害影响（例如认知障碍、痴呆症和/或抑郁症）、眼内压升高、各种骨病（例如骨质疏松症）、结核病、麻风病（汉森病）、牛皮癣以及伤口愈合受损（例如在表现出糖耐量不良和/或2型糖尿病的患者中）等多种疾病状态具有前景。
• SYNTHESIS OF INHIBITORS OF 11BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1
  申请人：Fandrick Keith R.

  公开号：US20110269957A1

  公开（公告）日：2011-11-03

  Disclosed are syntheses of 11β-HSD1 inhibitors and corresponding intermediates that are promising for the treatment of a variety of disease states including diabetes, metabolic syndrome, obesity, glucose intolerance, insulin resistance, hyperglycemia, hypertension, hypertension-related cardiovascular disorders, hyperlipidemia, deleterious gluco-corticoid effects on neuronal function (e.g. cognitive impairment, dementia, and/or depression), elevated intra-ocular pressure, various forms of bone disease (e.g., osteoporosis), tuberculosis, leprosy (Hansen's disease), psoriasis, and impaired wound healing (e.g., in patients that exhibit impaired glucose tolerance and/or type 2 diabetes).

  本文披露了11β-HSD1抑制剂及相应中间体的合成方法，这些方法非常适用于治疗多种疾病状态，包括糖尿病、代谢综合征、肥胖症、葡萄糖不耐受、胰岛素抵抗、高血糖、高血压、高血压相关心血管疾病、高脂血症、糖皮质激素对神经功能的有害影响（例如认知障碍、痴呆和/或抑郁症）、眼内压升高、各种骨病（例如骨质疏松症）、结核病、麻风病（汉森病）、牛皮癣和受损伤口愈合不良（例如在表现出糖耐量受损和/或2型糖尿病的患者中）。
• DERIVATIVES OF [1,3]OXAZIN-2-ONE USEFUL FOR THE TREATMENT OF METABOLIC DISEASES SUCH AS LIPID DISORDERS
  申请人：Claremon David A.

  公开号：US20120040973A1

  公开（公告）日：2012-02-16

  This invention relates to novel compounds of an 11 β-HSD1 inhibitor disclosed herein, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful for the therapeutic treatment of diseases associated with the modulation or inhibition of 11/3-HSD1 in mammals. The invention further relates to pharmaceutical compositions of the novel compounds and methods for their use in the reduction or control of the production of Cortisol in a cell or the inhibition of the conversion of cortisone to Cortisol in a cell.

  本发明涉及一种11β-HSD1抑制剂的新化合物、其药学上可接受的盐以及药物组合物，用于治疗与哺乳动物中11β-HSD1的调节或抑制相关的疾病。本发明还涉及这些新化合物的药物组合物和它们在细胞中减少或控制皮质醇的产生或抑制皮质酮转化为皮质醇的方法。