8-hydroxy-4-(N-methylphenylamino)-2-<(2-methylphenyl)amino>quinazoline | 133412-81-4

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 8-hydroxy-4-(N-methylphenylamino)-2-<(2-methylphenyl)amino>quinazoline
• 英文别名: 4-(Methyl-phenyl-amino)-2-o-tolylamino-quinazolin-8-ol；4-(N-methylanilino)-2-(2-methylanilino)quinazolin-8-ol
• CAS: 133412-81-4
• 化学式: C₂₂H₂₀N₄O
• 分子量: 356.427
• InChiKey: ZIIVYURONGRZQL-UHFFFAOYSA-N

物化性质

• 沸点：
  593.5±60.0 °C(Predicted)
• 密度：
  1.294±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  61.3
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  8-hydroxy-4-(N-methylphenylamino)-2-<(2-methylphenyl)amino>quinazoline 在 lithium aluminium tetrahydride 、 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 反应 12.0h， 生成 2-[4-(Methyl-phenyl-amino)-2-o-tolylamino-quinazolin-8-yloxy]-ethanol
  参考文献：
  名称：

  Reversible Inhibitors of the Gastric (H+/K+)-ATPase. 5. Substituted 2,4-Diaminoquinazolines and Thienopyrimidines

  摘要：

  Quinazolines bearing a secondary 4-(arylamino) substituent demonstrate an SAR for inhibition of the gastric (H+/K+)-ATPase different from the previously described 3-acylquinolines, suggesting that, although these compounds are also K+-competitive, they probably bind to the enzyme in a different orientation. Compounds bearing a tertiary 4-(arylamino) substituent, however, in particular 4-(N-methylarylamino), appear to possess an SAR quite similar to the 3-acylquinolines. We show that this arises from the effect of the N-methylation, which is to orientate the 4-(arylamino) substituent syn to C-5, analogous to the 3-acylquinolines. Compounds possessing both a 4-(N-methylarylamino) substituent and a 2-(arylamino) substituent proved to be very potent, K+-competitive inhibitors of K+-stimulated ATPase activity with K-i values down to 12 nM. Some compounds also proved to be effective inhibitors of stimulated acid secretion in both the rat and dog when dosed intravenously. However, although a number of these demonstrated activity after oral administration in the dog, the level and variability precluded further evaluation.

  DOI：

  10.1021/jm00014a027
• 作为产物：
  描述：

  4-(N-methylphenylamino)-2-(2-methylphenylamino)-8-methoxy quinazoline 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 以38%的产率得到8-hydroxy-4-(N-methylphenylamino)-2-<(2-methylphenyl)amino>quinazoline
  参考文献：
  名称：

  Reversible Inhibitors of the Gastric (H+/K+)-ATPase. 5. Substituted 2,4-Diaminoquinazolines and Thienopyrimidines

  摘要：

  Quinazolines bearing a secondary 4-(arylamino) substituent demonstrate an SAR for inhibition of the gastric (H+/K+)-ATPase different from the previously described 3-acylquinolines, suggesting that, although these compounds are also K+-competitive, they probably bind to the enzyme in a different orientation. Compounds bearing a tertiary 4-(arylamino) substituent, however, in particular 4-(N-methylarylamino), appear to possess an SAR quite similar to the 3-acylquinolines. We show that this arises from the effect of the N-methylation, which is to orientate the 4-(arylamino) substituent syn to C-5, analogous to the 3-acylquinolines. Compounds possessing both a 4-(N-methylarylamino) substituent and a 2-(arylamino) substituent proved to be very potent, K+-competitive inhibitors of K+-stimulated ATPase activity with K-i values down to 12 nM. Some compounds also proved to be effective inhibitors of stimulated acid secretion in both the rat and dog when dosed intravenously. However, although a number of these demonstrated activity after oral administration in the dog, the level and variability precluded further evaluation.

  DOI：

  10.1021/jm00014a027

文献信息

• Substituted quinazoline derivatives for use in gastrointestinal diseases
  申请人：Smithkline Beecham Intercredit B.V.

  公开号：US05064833A1

  公开（公告）日：1991-11-12

  2,4-diaminoquinazoline compounds are inhibitors of the H.sup.+ K.sup.+ ATPase enzyme and useful for the treatment of diseases of the stomach based on excessive gastric acid secretion. A compound of the invention is 2-[2-methyl-4-fluorophenyl)amino]-4-(N-methylphenylamino)quinazoline.

  2,4-二氨基喹嗪化合物是H.sup.+ K.sup.+ ATPase酶的抑制剂，可用于治疗基于胃酸分泌过多的胃病。本发明的一种化合物是2-[2-甲基-4-氟苯基)氨基]-4-(N-甲基苯基氨基)喹嗪。
• Quinazoline derivatives
  申请人：SMITHKLINE BEECHAM INTERCREDIT B.V.

  公开号：EP0404322A1

  公开（公告）日：1990-12-27

  Compounds of structure in which R1 is hydroxy, hydroxyC1-4alkyl, hydroxyC1-4alkoxy, carboxyC1-4 alkoxy, C1-4 alkoxyC1-4alkoxy, O(CH2)mHet, C1-4alkyINR6R7 or O(CH2)mNR6R7 in which m is 2 to 4 and R6 and R7 are the same or different and are each hydrogen, C1-4alkyl, Het, or -(CH2)nAr where n is 0 to 4, Ar is an optionally substituted phenyl ring, m is 2 to 4 and Het is an optionally substituted heterocyclic ring, or R6 and R7 together with the nitrogen to which they are attached form a saturated or unsaturated ring optionally containing one or more further heteroatoms; R2 and R3 and R4 and R5 are the same, or different and, are each hydrogen, C1-4alkyl, -(CH2)nAr in which n is 0 to 4 and Ar is an optionally substituted phenyl ring, or R2 and R3 together with the nitrogen atom to which they are attached form a saturated or unsaturated ring optionally containing one or more further heteroatoms process for their preparation, pharmaceutical compositions containing them and their use in therapy as inhibitors of gastric acid secretion.

  结构如下的化合物 其中 R1 为羟基、羟基 C1-4 烷基、羟基 C1-4 烷氧基、羧基 C1-4 烷氧基、C1-4 烷氧基 C1-4 烷氧基、O(CH2)mHet、C1-4 烷基 INR6R7 或 O(CH2)mNR6R7，其中 m 为 2 至 4，R6 和 R7 相同或不同，且各自为氢、C1-4 烷基、Het 或-(CH2)nAr，其中 n 为 0 至 4、Ar 是任选取代的苯基环，m 是 2 至 4，Het 是任选取代的杂环，或 R6 和 R7 与它们所连接的氮一起形成任选含有一个或多个杂原子的饱和或不饱和环；R2和R3以及R4和R5相同或不同，且各自为氢、C1-4烷基、-(CH2)nAr，其中n为0至4，Ar为任选取代的苯基环，或R2和R3与它们所连接的氮原子一起形成任选含有一个或多个杂原子的饱和或不饱和环。
• JPH0317068A
  申请人：——

  公开号：JPH0317068A

  公开（公告）日：1991-01-25
• US5064833A
  申请人：——

  公开号：US5064833A

  公开（公告）日：1991-11-12
• Reversible Inhibitors of the Gastric (H+/K+)-ATPase. 5. Substituted 2,4-Diaminoquinazolines and Thienopyrimidines
  作者：Robert J. Ife、Thomas H. Brown、Peter Blurton、David J. Keeling、Colin A. Leach、Malcolm L. Meeson、Michael E. Parsons、Colin J. Theobald

  DOI：10.1021/jm00014a027

  日期：1995.7

  Quinazolines bearing a secondary 4-(arylamino) substituent demonstrate an SAR for inhibition of the gastric (H+/K+)-ATPase different from the previously described 3-acylquinolines, suggesting that, although these compounds are also K+-competitive, they probably bind to the enzyme in a different orientation. Compounds bearing a tertiary 4-(arylamino) substituent, however, in particular 4-(N-methylarylamino), appear to possess an SAR quite similar to the 3-acylquinolines. We show that this arises from the effect of the N-methylation, which is to orientate the 4-(arylamino) substituent syn to C-5, analogous to the 3-acylquinolines. Compounds possessing both a 4-(N-methylarylamino) substituent and a 2-(arylamino) substituent proved to be very potent, K+-competitive inhibitors of K+-stimulated ATPase activity with K-i values down to 12 nM. Some compounds also proved to be effective inhibitors of stimulated acid secretion in both the rat and dog when dosed intravenously. However, although a number of these demonstrated activity after oral administration in the dog, the level and variability precluded further evaluation.