4-(pyridin-4-yl)methyl-5,6,7,8-tetrahydro-2H-phthalazin-1-one | 212142-89-7

• 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: 4-(pyridin-4-yl)methyl-5,6,7,8-tetrahydro-2H-phthalazin-1-one
• 英文别名: 4-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1(2H)-one；4-(4-Pyridylmethyl)-5,6,7,8-tetrahydro-1(2H)-phthalazinone；4-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydro-2H-phthalazin-1-one
• CAS: 212142-89-7
• 化学式: C₁₄H₁₅N₃O
• 分子量: 241.293
• InChiKey: VLHRCDZMDBOSMW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  54.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  对氯苯胺 、 4-(pyridin-4-yl)methyl-5,6,7,8-tetrahydro-2H-phthalazin-1-one 在 phosphorus pentoxide 、 三乙胺盐酸盐 作用下， 以68%的产率得到N-(4-chlorophenyl)-4-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydrophthalazin-1-amine
  参考文献：
  名称：

  新的苯胺酞嗪作为有效的和口服吸收良好的VEGF受体酪氨酸激酶抑制剂，可用作肿瘤驱动的血管生成的拮抗剂。

  摘要：

  要使任何实体瘤长到足以引起威胁生命的疾病，新血管的萌发或血管新生都是必不可少的。血管内皮生长因子（VEGF）是肿瘤诱导的血管生成的关键启动子之一。VEGF受体，酪氨酸激酶Flt-1和KDR在血管内皮细胞上表达，并在被VEGF激活后启动血管生成。1-Anilino-（4-吡啶基甲基）-酞嗪，例如CGP 79787D（或PTK787 / ZK222584），可逆地抑制Flt-1和KDR，IC（50）值<0.1 microM。CGP 79787D还可以在异位表达KDR受体的CHO细胞中阻断VEGF诱导的受体自磷酸化（ED（50）= 34 nM）。与相关受体酪氨酸激酶PDGF-R和c-Kit相比，对1-苯胺基部分的修饰提供了对VEGF受体酪氨酸激酶Flt-1和KDR具有更高选择性的衍生物。由于这些1-苯胺基-（4-吡啶基甲基）酞嗪口服吸收良好，因此这些化合物可用于进一步的分析，并可作为临床评估的候选药物。

  DOI：

  10.1021/jm9909443
• 作为产物：
  描述：

  4,5,6,7-tetrahydro-3H-isobenzofuran-1-one 在 sodium methylate 、 一水合肼 作用下， 以 甲醇 为溶剂， 反应 10.0h， 生成 4-(pyridin-4-yl)methyl-5,6,7,8-tetrahydro-2H-phthalazin-1-one
  参考文献：
  名称：

  新的苯胺酞嗪作为有效的和口服吸收良好的VEGF受体酪氨酸激酶抑制剂，可用作肿瘤驱动的血管生成的拮抗剂。

  摘要：

  要使任何实体瘤长到足以引起威胁生命的疾病，新血管的萌发或血管新生都是必不可少的。血管内皮生长因子（VEGF）是肿瘤诱导的血管生成的关键启动子之一。VEGF受体，酪氨酸激酶Flt-1和KDR在血管内皮细胞上表达，并在被VEGF激活后启动血管生成。1-Anilino-（4-吡啶基甲基）-酞嗪，例如CGP 79787D（或PTK787 / ZK222584），可逆地抑制Flt-1和KDR，IC（50）值<0.1 microM。CGP 79787D还可以在异位表达KDR受体的CHO细胞中阻断VEGF诱导的受体自磷酸化（ED（50）= 34 nM）。与相关受体酪氨酸激酶PDGF-R和c-Kit相比，对1-苯胺基部分的修饰提供了对VEGF受体酪氨酸激酶Flt-1和KDR具有更高选择性的衍生物。由于这些1-苯胺基-（4-吡啶基甲基）酞嗪口服吸收良好，因此这些化合物可用于进一步的分析，并可作为临床评估的候选药物。

  DOI：

  10.1021/jm9909443

文献信息

• Fused pyridazine derivative compounds and drugs containing the compounds as the active ingredient
  申请人：Seko Takuya

  公开号：US20050085476A1

  公开（公告）日：2005-04-21

  Fused pyridazine derivatives represented by formula (I) or pharmaceutically acceptable salts thereof (wherein each symbol has the meaning as defined in the specification.). Because of inhibiting poly(ADP-ribose)polymerase, the compounds represented by formula (I) are useful as preventives and/or remedies for various ischemic diseases (in brain, cord, heart, digestive tract, skeletal muscle, retina, etc.), inflammatory diseases (inflammatory bowel disease, multiple cerebrosclerosis, arthritis, etc.), neurodegenerative diseases (extrapyramidal disorder, Alzheimer's disease, muscular dystrophy, lumbar spinal canal stenosis, etc.), diabetes, shock, head trauma, renal failure, hyperalgesia, etc. Moreover, these compounds are useful as agents against retroviruses (HIV etc.), sensitizers in treating cancer and immunosuppressants.

  公式(I)所代表的融合吡啶嗪衍生物或其药学上可接受的盐（其中每个符号的含义如说明书所定义）。由于抑制多聚腺苷酸核苷酸聚合酶，公式（I）所代表的化合物可用作各种缺血性疾病（在大脑、脊髓、心脏、消化道、骨骼肌、视网膜等处）、炎症性疾病（炎症性肠病、多发性硬化症、关节炎等）、神经退行性疾病（锥体外系障碍、阿尔茨海默病、肌萎缩症、腰椎管狭窄等）、糖尿病、休克、头部创伤、肾功能衰竭、高痛感等的预防和/或治疗剂。此外，这些化合物可用作抗逆转录病毒剂（HIV等）、癌症治疗敏感剂和免疫抑制剂。
• Phthalazines with angiogenesis inhibiting activity
  申请人：——

  公开号：US20030191129A1

  公开（公告）日：2003-10-09

  The invention relates to compounds of formula I, 1 wherein r is 0 to 2, n is 0 to 2; m is 0 to 4; R 1 and R 2 (i) are in each case a lower alkyl, or (ii) together form a bridge in subformula I* 2 (I*) or (iii) together form a bridge in subformula I** 3 (I**), wherein one or two of the ring members T 1 , T 2 , T 3 , and T 4 are nitrogen, and the remainder are in each case CH; A, B, D, and E are N or CH, wherein not more than 2 of these radicals are N; G is lower alkylene, acyloxy- or hydroxy-lower alkylene, —CH 2 —O—, —CH 2 —S—, —CH 2 —NH—, oxa, thia, or imino; Q is methyl; R is H or lower alkyl; X is imino, oxa, or thia; Y is aryl, pyridyl, or (un)substituted cycloalkyl; and Z is mono- or disubstited amino, halogen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amidino, guanidino, mercapto, sulfo, phenylthio, phenyl-lower alkylthio, alkylphenylthio, phenyisulfinyl, phenyl-lower alkylsulfinyl, alkylphenylsulfinyl, phenylsulfonyl, phenyl-lower alkylsulfonyl, or alkylphenylsulfony; and wherein the bonds characterized by a wavy line are either single or double bonds; or an N-oxide of said compound with the stipulation that, if Y is pyridyl or unsubstituted cycloalkyl, X is imino, and the remaining radicals are as defined, then G is selected from the group comprising lower alkylene, —CH 2 —O—, —CH 2 —S—, oxa and thia; or a salt thereof. The compounds inhibit angiogenesis.

  该发明涉及公式I的化合物，其中r为0至2，n为0至2，m为0至4；R1和R2（i）分别为较低的烷基，或（ii）在亚公式I*2（I*）中形成桥，或（iii）在亚公式I**3（I**）中形成桥，其中环成员T1、T2、T3和T4中的一个或两个为氮，其余的为CH; A、B、D和E为N或CH，其中不超过2个基团为N；G为较低的烷基，酰氧基或羟基较低的烷基，-CH2-O-，-CH2-S-，-CH2-NH-，氧杂环，硫杂环或亚氨基；Q为甲基；R为H或较低的烷基；X为亚氨基，氧杂环或硫杂环；Y为芳基，吡啶基或（未）取代的环烷基；Z为单取代或双取代的氨基，卤素，烷基，取代烷基，羟基，醚化或酯化羟基，硝基，氰基，羧基，酯化羧基，烷酰基，氨基甲酰基，N-单取代或N，N-双取代的氨基甲酰基，氨基甲酰基，胍基，巯基，磺酰基，苯基硫基，烷基苯基硫基，苯基亚磺酰基，苯基烷基亚磺酰基，苯基磺酰基，苯基较低的烷基磺酰基或烷基苯基磺酰基；其中由波浪线表示的键是单键或双键；或该化合物的N-氧化物，规定如果Y为吡啶基或未取代的环烷基，则X为亚氨基，并且其余基团如定义，则G选自较低的烷基，-CH2-O-，-CH2-S-，氧杂环和硫杂环；或其盐。这些化合物抑制血管生成。
• FUSED PYRIDAZINE DERIVATIVE COMPOUNDS AND DRUGS CONTAINING THESE COMPOUNDS AS THE ACTIVE INGREDIENT
  申请人：Seko Takuya

  公开号：US20080261947A1

  公开（公告）日：2008-10-23

  Fused pyridazine derivatives represented by formula (I) or pharmaceutically acceptable salts thereof (wherein each symbol has the meaning as defined in the specification.). Because of inhibiting poly(ADP-ribose)polymerase, the compounds represented by formula (I) are useful as preventives and/or remedies for various ischemic diseases (in brain, cord, heart, digestive tract, skeletal muscle, retina, etc.), inflammatory diseases (inflammatory bowel disease, multiple cerebrosclerosis, arthritis, etc.), neurodegenerative diseases (extrapyramidal disorder, Alzheimer's disease, muscular dystrophy, lumbar spinal canal stenosis, etc.), diabetes, shock, head trauma, renal failure, hyperalgesia, etc. Moreover, these compounds are useful as agents against retroviruses (HIV etc.), sensitizers in treating cancer and immunosuppressants.

  式（I）所表示的融合吡嗪衍生物或其药学上可接受的盐（其中每个符号的含义如规范中所定义）。由于抑制了聚(ADP-核糖)聚合酶，式（I）所表示的化合物可用作预防和/或治疗各种缺血性疾病（在大脑、脊髓、心脏、消化道、骨骼肌、视网膜等部位），炎症性疾病（炎症性肠病、多发性硬化症、关节炎等），神经退行性疾病（锥体外系障碍、阿尔茨海默病、肌萎缩症、腰椎管狭窄等），糖尿病、休克、头部创伤、肾功能衰竭、高痛感等。此外，这些化合物还可用作抗逆转录病毒剂（HIV等）、治疗癌症的增敏剂和免疫抑制剂。
• Pyrido-, pyrimido-, pyridazo- and pyrazo- pyridazines having angiogenesis inhibiting activity
  申请人：Novartis AG

  公开号：US06514974B2

  公开（公告）日：2003-02-04

  The invention relates to compounds of formula I, wherein r is 0 to 2, n is 0 to 2; m is 0 to 4; R1 and R2 (i) are in each case a lower alkyl, or (ii) together form a bridge in subformula I* or (iii) together form a bridge in subformula I** wherein one or two of the ring members T1, T2, T3, and T4 are nitrogen, and the remainder are in each case CH; A, B, D, and E are N or CH, wherein not more than 2 of these radicals are N; G is lower alkylene, acyloxy- or hydroxy-lower alkylene, —CH2—O—, —CH2—S—, —CH2—NH—, oxa, thia, or imino; Q is methyl; R is H or lower alkyl; X is imino, oxa, or thia; Y is aryl, pyridyl, or (un)substituted cycloalkyl; and Z is mono- or disubstited amino, halogen, alkyl, substituted alkyl, hydroxy, etherified or esterified hydroxy, nitro, cyano, carboxy, esterified carboxy, alkanoyl, carbamoyl, N-mono- or N,N-disubstituted carbamoyl, amidino, guanidino, mercapto, sulfo, phenylthio, phenyl-lower alkylthio, alkylphenylthio, phenylsulfinyl, phenyl-lower alkylsulfinyl, alkylphenylsulfinyl, phenylsulfonyl, phenyl-lower alkylsulfonyl, or alkylphenylsulfony; and wherein the bonds characterized by a wavy line are either single or double bonds; or an N-oxide of said compound with the stipulation that, if Y is pyridyl or unsubstituted cycloalkyl, X is imino, and the remaining radicals are as defined, then G is selected from the group comprising lower alkylene, —CH2—O—, —CH2—S—, oxa and thia; or a salt thereof. The compounds inhibit angiogenesis.

  本发明涉及式I的化合物，其中r为0至2，n为0至2；m为0至4；R1和R2（i）分别为较低的烷基，或（ii）在子式I*中形成桥，或（iii）在子式I**中形成桥，其中环成员T1、T2、T3和T4中的一个或两个为氮，其余的都是CH；A、B、D和E为N或CH，其中不超过2个基团为N；G为较低的烷基，酰氧基或羟基较低的烷基，-CH2-O-，-CH2-S-，-CH2-NH-，氧杂环、硫杂环或亚胺基；Q为甲基；R为H或较低的烷基；X为亚胺基、氧杂环或硫杂环；Y为芳基、吡啶基或（未）取代的环烷基；Z为单取代或双取代的氨基、卤素、烷基、取代烷基、羟基、醚化或酯化的羟基、硝基、氰基、羧基、酯化的羧基、脂肪酰基、氨基甲酰、N-单取代或N，N-双取代的氨基甲酰、氨基甲酸酰、胍基、硫脲基、苯硫醇基、苯基较低烷基硫醇基、烷基苯基硫醇基、苯基亚磺酸基、苯基较低烷基亚磺酸基、烷基苯基亚磺酸基、苯基磺酰基、苯基较低烷基磺酰基或烷基苯基磺酰基；其中由波浪线标识的键要么是单键，要么是双键；或该化合物的N-氧化物，条件是，如果Y为吡啶基或未取代的环烷基，X为亚胺基，并且其余基团如定义的那样，则G从包括较低的烷基、-CH2-O-、-CH2-S-、氧杂环和硫杂环的群中选择；或其盐。该化合物抑制血管生成。
• Fused pyridazine derivative compounds and drugs containing these compounds as the active ingredient
  申请人：ONO PHARMACEUTICAL CO., LTD.

  公开号：EP2281818A1

  公开（公告）日：2011-02-09

  Fused pyridazine derivatives represented by formula (I) or pharmaceutically acceptable salts thereof (wherein each symbol has the meaning as defined in the specification.). Because of inhibiting poly(ADP-ribose)polymerase, the compounds represented by formula (I) are useful as preventives and/or remedies for various ischemic diseases (in brain, cord, heart, digestive tract, skeletal muscle, retina, etc.), inflammatory diseases (inflammatory bowel disease, multiple cerebrosclerosis, arthritis, etc.), neurodegenerative diseases (extrapyramidal disorder, Alzheimer's disease, muscular dystrophy, lumbar spinal canal stenosis, etc.), diabetes, shock, head trauma, renal failure, hyperalgesia, etc. Moreover, these compounds are useful as agents against retroviruses (HIV etc.), sensitizers in treating cancer and immunosuppressants.

  式 (I) 所代表的融合哒嗪衍生物或其药学上可接受的盐（其中各符号的含义如说明书中所定义）。 由于能抑制多（ADP-核糖）聚合酶，式（I）代表的化合物可作为各种缺血性疾病（脑、脊髓、心脏、消化道、骨骼肌、视网膜等）、炎症性疾病（炎症性肠病）的预防和/或治疗药物。炎症性疾病（炎症性肠病、多发性脑硬化症、关节炎等）、神经退行性疾病（锥体外系障碍、阿尔茨海默病、肌肉萎缩症、腰椎管狭窄症等）、糖尿病、休克、头部创伤、肾功能衰竭、痛觉减退等。此外，这些化合物还可用作抗逆转录病毒（HIV 等）的药物、治疗癌症的增敏剂和免疫抑制剂。