6-dipropargylamino-1-isopropyl-4-(4-isopropylphenyl)-1H-quinazolin-2-one | 478963-45-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 6-dipropargylamino-1-isopropyl-4-(4-isopropylphenyl)-1H-quinazolin-2-one
• 英文别名: 6-Dipropargylamino-1-isopropyl-4-(4-isopropyl-phenyl)-1Hquinazolin-2-one；6-[bis(prop-2-ynyl)amino]-1-propan-2-yl-4-(4-propan-2-ylphenyl)quinazolin-2-one
• CAS: 478963-45-0
• 化学式: C₂₆H₂₇N₃O
• 分子量: 397.52
• InChiKey: LDTKJMBKBTVMFK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  35.9
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  6-氨基-1-异丙基-4-(4-异丙基苯基)-1H-喹唑啉-2-酮 、 3-溴丙炔 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 以48%的产率得到6-dipropargylamino-1-isopropyl-4-(4-isopropylphenyl)-1H-quinazolin-2-one
  参考文献：
  名称：

  1-Alkyl-4-phenyl-6-alkoxy-1H-quinazolin-2-ones: A Novel Series of Potent Calcium-Sensing Receptor Antagonists

  摘要：

  Parathyroid hormone (PTH) is an effective bone anabolic agent. However, only when administered by daily sc injections exposure of short duration is achieved, a prerequisite for an anabolic response. Instead of applying exogenous PTH, mobilization of endogenous stores of the hormone can be envisaged. The secretion of PTH stored in the parathyroid glands is mediated by a calcium Sensing receptor (CaSR) a GPCR localized at the cell surface. Antagonists of CaSR (calcilytics) mimic a state of hypocalcaemia and stimulate PTH release to the bloodstream. Screening of the internal compound collection for inhibition of CaSR signaling function afforded 2a. In vitro potency Could be improved > 1000 fold by optimization of its chemical structure. The binding mode of our compounds was predicted based oil molecular modeling and confirmed by testing with Mutated receptors. While the Compounds readily induced PTH release after iv application a special formulation was needed for oral activity. The required profile was achieved by using microemulsions. Excellent PK/PD correlation was found in rats and dogs. High levels of PTH were reached in plasma within Minutes which reverted to baseline in about 1-2 h in both species.

  DOI：

  10.1021/jm901811v

文献信息

• QUINAZOLINE DERIVATIVES WHICH PROMOTE THE RELEASE OF PARATHYROID HORMONE
  申请人：Novartis AG

  公开号：EP2191832A1

  公开（公告）日：2010-06-02

  Use of a compound of formula I wherein is and wherein the symbols are as defined, or a pharmaceutically-acceptable and -cleavable ester, or acid addition salt thereof, for the preparation of a medicament for promoting the release of parathyroid hormone, e.g. for preventing or treating bone conditions which are associated with increased calcium depletion or resorption or in which stimulation of bone formation and calcium fixation in the bone is desirable.

  使用式 I 的化合物 式中 是 其中符号如定义、 或其药学上可接受和可清除的酯或酸加成盐，用于制备促进甲状旁腺激素释放的药物，例如用于预防或治疗与钙消耗或钙吸收增加有关的骨病，或希望刺激骨形成和钙在骨中固定的骨病。
• US8476286B2
  申请人：——

  公开号：US8476286B2

  公开（公告）日：2013-07-02
• 1-Alkyl-4-phenyl-6-alkoxy-1<i>H</i>-quinazolin-2-ones: A Novel Series of Potent Calcium-Sensing Receptor Antagonists
  作者：Leo Widler、Eva Altmann、René Beerli、Werner Breitenstein、Rochdi Bouhelal、Thomas Buhl、Rainer Gamse、Marc Gerspacher、Christine Halleux、Markus R. John、Hansjoerg Lehmann、Oskar Kalb、Michaela Kneissel、Martin Missbach、Irene R. Müller、Sibylle Reidemeister、Johanne Renaud、Agnes Taillardat、Ruben Tommasi、Sven Weiler、Romain M. Wolf、Klaus Seuwen

  DOI：10.1021/jm901811v

  日期：2010.3.11

  Parathyroid hormone (PTH) is an effective bone anabolic agent. However, only when administered by daily sc injections exposure of short duration is achieved, a prerequisite for an anabolic response. Instead of applying exogenous PTH, mobilization of endogenous stores of the hormone can be envisaged. The secretion of PTH stored in the parathyroid glands is mediated by a calcium Sensing receptor (CaSR) a GPCR localized at the cell surface. Antagonists of CaSR (calcilytics) mimic a state of hypocalcaemia and stimulate PTH release to the bloodstream. Screening of the internal compound collection for inhibition of CaSR signaling function afforded 2a. In vitro potency Could be improved > 1000 fold by optimization of its chemical structure. The binding mode of our compounds was predicted based oil molecular modeling and confirmed by testing with Mutated receptors. While the Compounds readily induced PTH release after iv application a special formulation was needed for oral activity. The required profile was achieved by using microemulsions. Excellent PK/PD correlation was found in rats and dogs. High levels of PTH were reached in plasma within Minutes which reverted to baseline in about 1-2 h in both species.