6-((2R,5R)-2-methyl-5-phenylmorpholino)-2H-pyrido[3,2-b]-[1,4]oxazin-3(4H)-one | 1349829-77-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 恶嗪烷类
• 英文名称: 6-((2R,5R)-2-methyl-5-phenylmorpholino)-2H-pyrido[3,2-b]-[1,4]oxazin-3(4H)-one
• 英文别名: 6-((2R,5R)-2-methyl-5-phenylmorpholino)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one；6-[(2R,5R)-2-methyl-5-phenylmorpholin-4-yl]-4H-pyrido[3,2-b][1,4]oxazin-3-one
• CAS: 1349829-77-1
• 化学式: C₁₈H₁₉N₃O₃
• 分子量: 325.367
• InChiKey: NDBQYPUELRHJBZ-OCCSQVGLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  63.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6-((2R,5R)-2-methyl-5-phenylmorpholino)-2H-pyrido[3,2-b]-[1,4]oxazin-3(4H)-one 在 四(三苯基膦)钯 N-溴代丁二酰亚胺(NBS) 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 6-((2R,5R)-2-methyl-5-phenylmorpholino)-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-7-carbonitrile
  参考文献：
  名称：

  MORPHOLINE COMPOUNDS

  摘要：

  矿物皮质激素受体拮抗剂（MRa），含有这类抑制剂的药物组合物以及利用这类抑制剂治疗哺乳动物，包括人类，例如糖尿病肾病和高血压。

  公开号：

  US20110281854A1
• 作为产物：
  描述：

  N-(6-氯吡啶-2-基)-2,2-二甲基丙酰胺 在 盐酸 、 正丁基锂 、 四甲基乙二胺 、 过氧化脲素 、 potassium carbonate 、 N,N-二异丙基乙胺 、 sodium iodide 、 sodium hydroxide 作用下， 以 2-甲基四氢呋喃 、 甲醇 、 水 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 66.5h， 生成 6-((2R,5R)-2-methyl-5-phenylmorpholino)-2H-pyrido[3,2-b]-[1,4]oxazin-3(4H)-one
  参考文献：
  名称：

  Synthesis of a cis 2,5-Disubstituted Morpholine by De-epimerization: Application to the Multigram Scale Synthesis of a Mineralocorticoid Antagonist

  摘要：

  A convergent route to multigram quantities of a mineralocorticoid antagonist 3 is described. Starting from (R)-phenylglycinol, the synthesis of cis 2,5-morpholine 2 is accomplished utilizing a de-epimerization to install the second stereogenic center. The multigram synthesis of 3 was completed through a sequence of an SNAr reaction, Dakin oxidation, alkylation, and cyclization to provide a crystalline solid.

  DOI：

  10.1021/op400101p

文献信息

• Identification of Morpholino-2<i>H</i>-pyrido[3,2-<i>b</i>][1,4]oxazin-3(4<i>H</i>)-ones as Nonsteroidal Mineralocorticoid Antagonists
  作者：David W. Piotrowski、Kentaro Futatsugi、Agustin Casimiro-Garcia、Liuqing Wei、Matthew F. Sammons、Michael Herr、Wenhua Jiao、Sophie Y. Lavergne、Steven B. Coffey、Stephen W. Wright、Kun Song、Paula M. Loria、Mary Ellen Banker、Donna N. Petersen、Jonathan Bauman

  DOI：10.1021/acs.jmedchem.7b01515

  日期：2018.2.8

  A novel series of morpholine-based non steroidal mineralocorticoid receptor antagonists is reported. Starting from a pyrrolidine HTS hit 9 that possessed modest potency but excellect selectivity versus related nuclear hormone receptors, a series of libraries led to identification of morpholine lead 10. After further optimization, cis disubstituted morpholine 22 was discovered, which showed a 45-fold boost in binding affinity and corresponding functional potency compared to 13. While 22 had high clearance in rat, it provided sufficient exposure at high doses to favorably assess in vivo efficacy (increased urinary Na+/K+ ratio) and safety. In contrast to rat, the dog and human MetID and PK profiles of 22 were adequate, suggesting that it could be suitable as a potential clinical asset.
• MORPHOLINE COMPOUNDS AS MINERALOCORTICOID RECEPTOR ANTAGONISTS
  申请人：Pfizer Inc.

  公开号：EP2569310A1

  公开（公告）日：2013-03-20
• METHODS AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF CHOROIDAL NEOVASCULARISATION
  申请人：INSERM (Institut National de la Santé et de la Recherche Médicale)

  公开号：EP3362095B1

  公开（公告）日：2020-11-25
• PHARMACEUTICAL COMPOSITIONS FOR PREVENTING GLUCOCORTICOID-INDUCED CORNEAL OR SKIN THINNING
  申请人：INSERM (INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE)

  公开号：US20160136183A1

  公开（公告）日：2016-05-19

  The present invention relates to method and pharmaceutical compositions for preventing glucocorticoid-induced corneal or skin thinning. In particular, the present invention relates to a mineralocorticoid receptor antagonist for topical use in a method for preventing or reducing glucocorticoid-induced corneal or skin thinning in a subject in need thereof. The invention also relates to a topical pharmaceutical composition comprising an amount of at least one glucocorticoid and an amount of at least one mineralocorticoid receptor antagonist or inhibitor of MR expression for use in a method for treating an inflammatory skin disease or an inflammatory disease of the cornea or of the anterior segment of the eye in a subject in need thereof.
• ANTAGONIST OF MINERALOCORTICOID RECEPTOR FOR THE TREATMENT OF OSTEOARTHRITIS
  申请人：INSERM (INSTITUT NATIONAL DE LA SANTÉ ET DE LA RECHERCHE MÉDICALE

  公开号：US20190262363A1

  公开（公告）日：2019-08-29

  The present invention relates to methods and pharmaceutical compositions for the treatment of osteoarthritis. The inventors showed that accumulated metabolic risk factors, hypertension, obesity, dyslipidemia, insulin resistance (known as metabolic syndrome), lead to severe osteoarthritis articular phenotype. They showed in rats that preventive and chronic mineralocorticoid receptor antagonist eplerenone treatment can improve the metabolic syndrome related osteoarthritis. In particular, the present invention relates to an antagonist of mineralocorticoid receptor for use in a method for the treatment of osteoarthritis in a subject in need thereof.