7,8-dihydro-7-methyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxylic acid | 170640-09-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 7,8-dihydro-7-methyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxylic acid
• 英文别名: 7-Methyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxylic acid
• CAS: 170640-09-2
• 化学式: C₁₇H₁₄N₂O₃
• 分子量: 294.31
• InChiKey: LADQHJLUXXKNMT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  70.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  7,8-dihydro-7-methyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxylic acid 在 氯化亚砜 、 三乙胺 、 N,N-二甲基甲酰胺 作用下， 以 二氯甲烷 、 1,2-二氯乙烷 为溶剂， 反应 4.0h， 生成 7-Methyl-8-oxo-5-p-tolyl-7,8-dihydro-[1,7]naphthyridine-6-carboxylic acid [(R)-1-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-amide
  参考文献：
  名称：

  轴向手性N-苄基-N，7-二甲基-5-苯基-1，7-萘啶-6-羧酰胺衍生物作为速激肽NK1受体拮抗剂：绝对立体化学要求的测定。

  摘要：

  一种有效的，口服活性的NK1拮抗剂，反式-N- [3,5-双（三氟甲基）苄基] -7,8-二氢-N，7-二甲基-5-（4-甲基苯基）-8-oxo-1， 7-萘啶-6-羧酰胺（1t）已显示为可分离和稳定的（R）-和（S）-阻转异构体（1t-A和1t-B）的混合物，其起源于围绕-C的受限旋转（6）-C（＝ O）-键；1t-A的拮抗活性约为。比1t-B高6-13倍。制备了在1t的苄基亚甲基部分具有（S）-和（R）-甲基的1t（3）的类似物，并将其分离为非对映异构的阻转异构体3a-A，3a-B和3b-A，3b -B，对映体纯形式。在3的四个异构体中，（aR，S）-对映异构体（3a-A）表现出最强的拮抗活性，IC50值为0。80 nM（在体外抑制人IM-9细胞中[125I] BH-SP的结合）和ED50值分别为9.3微克/千克（iv）和67.7微克/千克（po）（体内抑制辣椒素诱导的血浆外渗在豚鼠气

  DOI：

  10.1021/jm980042m
• 作为产物：
  描述：

  2,3-吡啶二羧酸酐 在 盐酸 、 sodium hydroxide 、 三氯化铝 、 氯化亚砜 、 溶剂黄146 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 、 N,N-二甲基甲酰胺 、 sodium nitrite 作用下， 以 四氢呋喃 、 乙醇 、 甲苯 为溶剂， 反应 27.17h， 生成 7,8-dihydro-7-methyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxylic acid
  参考文献：
  名称：

  Novel, Potent, and Orally Active Substance P Antagonists: Synthesis and Antagonist Activity of N-Benzylcarboxamide Derivatives of Pyrido[3,4-b]pyridine

  摘要：

  A series of 4-phenylisoquinolone derivatives were synthesized and evaluated for NK1 (substance P) antagonist activity. Highly potent antagonists, 4-phenyl-3-isoquinolone-N-benzylcarboxamides (11), were discovered from the structure-activity relationship studies on the isoquinolone-urea lead la. Optimization of the activity in this series resulted in the development of 5-phenyl-6-pyrido[3,4-b]pyridine-N-benzylcarboxamides (30) which are highly potent orally active NK1 antagonists. Among the compounds synthesized, N-[3,5-bis(trifluoromethyl)benzyl]7,8-dihydro-N, 7-dimethyl-8-oxo-5-(substituted phenyl)6-pyrido[3,4-b]pyridinecarboxamides (30a,f,g) showed excellent antagonist activities with IC50 values (in vitro inhibition of [I-125]- BH-SP binding in human IM-9 cells) of 0.21-0.34 nM and ED(50) values (in vivo inhibition of capsaicin-induced plasma extravasation in guinea-pig trachea, iv) of 0.017-0.030 mg/kg. These compounds exhibited significantly potent activity upon oral administration with ED(50) values of 0.068-0.17 mg/kg. Conformational studies on 30g indicated that the two stable conformers of 30g are quite similar to those of CP-99,994.

  DOI：

  10.1021/jm00016a014

文献信息

• Novel, Potent, and Orally Active Substance P Antagonists: Synthesis and Antagonist Activity of N-Benzylcarboxamide Derivatives of Pyrido[3,4-b]pyridine
  作者：Hideaki Natsugari、Yoshinori Ikeura、Yutaka Kiyota、Yuji Ishichi、Takenori Ishimaru、Osamu Saga、Hideo Shirafuji、Toshimasa Tanaka、Izumi Kamo

  DOI：10.1021/jm00016a014

  日期：1995.8

  A series of 4-phenylisoquinolone derivatives were synthesized and evaluated for NK1 (substance P) antagonist activity. Highly potent antagonists, 4-phenyl-3-isoquinolone-N-benzylcarboxamides (11), were discovered from the structure-activity relationship studies on the isoquinolone-urea lead la. Optimization of the activity in this series resulted in the development of 5-phenyl-6-pyrido[3,4-b]pyridine-N-benzylcarboxamides (30) which are highly potent orally active NK1 antagonists. Among the compounds synthesized, N-[3,5-bis(trifluoromethyl)benzyl]7,8-dihydro-N, 7-dimethyl-8-oxo-5-(substituted phenyl)6-pyrido[3,4-b]pyridinecarboxamides (30a,f,g) showed excellent antagonist activities with IC50 values (in vitro inhibition of [I-125]- BH-SP binding in human IM-9 cells) of 0.21-0.34 nM and ED(50) values (in vivo inhibition of capsaicin-induced plasma extravasation in guinea-pig trachea, iv) of 0.017-0.030 mg/kg. These compounds exhibited significantly potent activity upon oral administration with ED(50) values of 0.068-0.17 mg/kg. Conformational studies on 30g indicated that the two stable conformers of 30g are quite similar to those of CP-99,994.
• Axially Chiral <i>N</i>-Benzyl-<i>N</i>,7-dimethyl-5-phenyl-1,7-naphthyridine-6-carboxamide Derivatives as Tachykinin NK₁ Receptor Antagonists:  Determination of the Absolute Stereochemical Requirements
  作者：Yoshinori Ikeura、Yuji Ishichi、Toshimasa Tanaka、Akira Fujishima、Mika Murabayashi、Mitsuru Kawada、Takenori Ishimaru、Izumi Kamo、Takayuki Doi、Hideaki Natsugari

  DOI：10.1021/jm980042m

  日期：1998.10.1

  this series of antagonists indicate that the (R)-configuration at the axial bond and the stacking (or stacking-like) conformation between the two phenyl rings as shown in 1t-A and 3a-A are essential for high-affinity binding and suggest that the amide moiety functions as a hydrogen bond acceptor in the interaction with the receptor.

  一种有效的，口服活性的NK1拮抗剂，反式-N- [3,5-双（三氟甲基）苄基] -7,8-二氢-N，7-二甲基-5-（4-甲基苯基）-8-oxo-1， 7-萘啶-6-羧酰胺（1t）已显示为可分离和稳定的（R）-和（S）-阻转异构体（1t-A和1t-B）的混合物，其起源于围绕-C的受限旋转（6）-C（＝ O）-键；1t-A的拮抗活性约为。比1t-B高6-13倍。制备了在1t的苄基亚甲基部分具有（S）-和（R）-甲基的1t（3）的类似物，并将其分离为非对映异构的阻转异构体3a-A，3a-B和3b-A，3b -B，对映体纯形式。在3的四个异构体中，（aR，S）-对映异构体（3a-A）表现出最强的拮抗活性，IC50值为0。80 nM（在体外抑制人IM-9细胞中[125I] BH-SP的结合）和ED50值分别为9.3微克/千克（iv）和67.7微克/千克（po）（体内抑制辣椒素诱导的血浆外渗在豚鼠气