3-<<<3,5-bis(trifluoromethyl)benzyl>oxy>methyl>-2-methyl-4-phenyl-1(2H)-isoquinolinone

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 3-<<<3,5-bis(trifluoromethyl)benzyl>oxy>methyl>-2-methyl-4-phenyl-1(2H)-isoquinolinone
• 英文别名: 3-(3,5-Bis-trifluoromethyl-benzyloxymethyl)-2-methyl-4-phenyl-2H-isoquinolin-1-one；3-[[3,5-bis(trifluoromethyl)phenyl]methoxymethyl]-2-methyl-4-phenylisoquinolin-1-one
• 化学式: C₂₆H₁₉F₆NO₂
• 分子量: 491.433
• InChiKey: VUMATGNDCCCSSB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  35
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  1,2-dihydro-2-methyl-1-oxo-4-phenyl-3-isoquinolinecarboxylic acid 在 sodium tetrahydroborate 、 草酰氯 、 sodium hydride 、 三乙胺 、 N,N-二甲基甲酰胺 作用下， 以 四氢呋喃 、 乙二醇二甲醚 、 二氯甲烷 为溶剂， 反应 3.25h， 生成 3-<<<3,5-bis(trifluoromethyl)benzyl>oxy>methyl>-2-methyl-4-phenyl-1(2H)-isoquinolinone
  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

• Condensed heterocyclic compounds, their production and use
  申请人：TAKEDA CHEMICAL INDUSTRIES, LTD.

  公开号：EP0585913A2

  公开（公告）日：1994-03-09

  Novel compound represented by the formula: wherein ring A may be substituted; ring B represents an optionally substituted benzene ring; either X or Y represents -NR¹- (R¹ represents a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted hydroxyl group or an optionally substituted amino group), -O- or -S-, the other representing -CO-, -CS- or -C(R²)R2a- (R² and R2a independently represent a hydrogen atom or an optionally substituted hydrocarbon group), or either X or Y represents -N=, the other representing =CR³- (R³ represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group , an optionally substituted amino group, a substituted hydroxyl group or a mercapto group substituted by an optionally substituted hydrocarbon group); ........ represents a single or double bond; when ........ is a single bond, Z represents -CR⁴- (R⁴ represents a hydrogen atom, hydroxyl group or an optionally substituted hydrocarbon group) or a nitrogen atom, or (ii) when ........ is a double bond, Z represents a carbon atom; D represents a C₁₋₃ alkylene group which may be substituted by an oxo group or a thioxo group, or D and Y, taken together, may form a 5- to 7-membered ring which may be substituted by an oxo group or a thioxo group; E represents -NR⁵- (R⁵ represents a hydrogen atom or an optionally substituted hydrocarbon group), -O- or -S(O)n- (n is 0,1 or 2), or R⁵ and Y, taken together, may form a 5- to 7- membered ring which may be substituted by an oxo group or a thioxo group; G represents a bond or a C₁₋₃ alkylene group; Ar represents an optionally substituted aryl group or an optionally substituted heterocyclic group, provided that (1) when (i) -X-Y- represents - O-CO- or -CO-O-, (ii) D represents -CO- and (iii) E represents -NR⁵-, either (a) G represents a C₁₋₃ alkylene group and Ar represents a substituted aryl group or a substituted heterocyclic group, or (b) G represents a bond and R⁵ represents an optionally substituted hydrocarbon group, and (2) when -X-Y- represents -NH-CO-, D represents -CO-, or a salt thereof having an excellent activity of inhibiting ACAT, lowering chlesterol in blood and inhibiting tachykinin recepter, or a salt thereof, their production and use.

  由式表示的新型化合物： 其中环 A 可被取代 环 B 代表任选取代的苯环； X或Y代表-NR¹-（R¹代表氢原子、任选取代的烃基、任选取代的羟基或任选取代的氨基）、-O-或-S-，另一个代表-CO-、-CS-或-C(R²)R2a-（R²和R2a独立地代表氢原子或任选取代的烃基）、或 X 或 Y 代表-N=，另一个代表 =CR³-（R³ 代表氢原子、卤素原子、任选取代的烃基、任选取代的氨基、取代的羟基或被任选取代的烃基取代的巯基）； ........ 代表单键或双键； 当 ........ 为单键时，Z 代表-CR⁴-（R⁴ 代表氢原子、羟基或任选取代的烃基）或氮原子；或 (ii) 当 ........ 为双键时，Z 代表碳原子； D 代表可被氧代基团或硫代基团取代的 C₁₋₃亚烷基，或 D 和 Y 合在一起可形成可被氧代基团或硫代基团取代的 5-7 元环； E 代表-NR⁵-（R⁵ 代表氢原子或任选取代的烃基）、-O-或-S(O)n-（n 为 0、1 或 2），或 R⁵ 和 Y 合在一起可形成可被氧代基团或硫代基团取代的 5-7 分子环； G 代表键或 C₁₋₃ 亚烷基； Ar 代表任选取代的芳基或任选取代的杂环基，条件是 (1) 当(i)-X-Y-代表-O-CO-或-CO-O-，(ii)D 代表-CO-和(iii)E 代表-NR⁵-时， (a) G 代表 C₁₋₃亚烷基，Ar 代表取代的芳基或取代的杂环基、(2) 当-X-Y-代表-NH-CO-时，D代表-CO-，或其盐具有抑制 ACAT、降低血液中胆固醇和抑制速激肽受体的优异活性，或其盐的生产和使用。
• US5482967A
  申请人：——

  公开号：US5482967A

  公开（公告）日：1996-01-09
• US5700810A
  申请人：——

  公开号：US5700810A

  公开（公告）日：1997-12-23
• 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.