4-(2-acetylhydrazino)-phthalazinone | 65846-18-6

• 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: 4-(2-acetylhydrazino)-phthalazinone
• 英文别名: acetic acid N'-(4-oxo-3,4-dihydro-phthalazin-1-yl)-hydrazide；N'-(4-oxo-3H-phthalazin-1-yl)acetohydrazide
• CAS: 65846-18-6
• 化学式: C₁₀H₁₀N₄O₂
• 分子量: 218.215
• InChiKey: RIHRITBAKWRQDD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  82.6
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-(2-acetylhydrazino)-phthalazinone 以 N,N-二甲基甲酰胺 为溶剂， 生成 3-methyl-[1,2,4]triazolo[3,4-a]phthalazin-6(5H)-one
  参考文献：
  名称：

  3-Phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazines and Analogues:  High-Affinity γ-Aminobutyric Acid-A Benzodiazepine Receptor Ligands with α2, α3, and α5-Subtype Binding Selectivity over α1

  摘要：

  Studies with our screening lead 5 and the literature compound 6 led to the identification of 6-benzyloxy-3-(4-methoxy)phenyl-1,2,4-triazolo[3,4-a]phthalazine 8 as a ligand with binding selectivity for the gamma-aminobutyric acid-A (GABA-A) alpha3- and alpha5-containing receptor subtypes over the GABA-A alpha1 subtype (K-i: alpha2 = 850 nM, alpha3 = 170 nM, alpha5 = 72 nM, alpha1 = 1400 nM). Early optimization studies identified the close analogue 10 (Ki: alpha2 = 16 nM, alpha3 = 41 nM, alpha5 = 38 nM, alpha1 = 280 nM) as a suitable lead for further study. High-affinity ligands were identified by replacing the 6-benzyloxy group of compound 10 with 2-pyridylmethoxy (compound 29), but binding selectivity was not enhanced (K-i: alpha2 = 1.7 nM, alpha3 = 0.71 nM, alpha5 = 0.33 nM, alpha1 = 2.7 nM). Furthermore, on evaluation in xenopus oocytes,(22) 29 was discovered to be a weak to moderate inverse agonist at all four receptor subtypes (alpha1, -7%; alpha2, -5%; alpha3, -16%; alpha5, -5%). Replacement of the 3-phenyl group of 29 with alternatives led to reduced affinity, and smaller 3-substituents led to reduced efficacy. Methyl substitution of the benzo-fused ring of 29 at the 7-, 8-, and 10-positions resulted in increased efficacy although selectivity was abolished. Increased efficacy and retention of selectivity for alpha3 over alpha1 was achieved with the 7,8,9,10-tetrahydro-(7,10-ethano)-phthalazine 62. Compound 62 is currently one of the most binding selective GABA-A alpha3-benzodiazepine-site partial agonists known, and although its selectivity is limited, its good pharmacokinetic profile in the rat (33% oral bioavailability after a 3 mg/kg dose, reaching a peak plasma concentration of 179 ng/mL; half-life of I h) made it a useful pharmacological tool to explore the effect of a GABA-A alpha2/alpha3 agonist in vivo.

  DOI：

  10.1021/jm031020p
• 作为产物：
  描述：

  4-hydrazino-phthalazin-1(2H)-one 、 乙酰氯 在 三乙胺 作用下， 以 1,4-二氧六环 为溶剂， 生成 4-(2-acetylhydrazino)-phthalazinone
  参考文献：
  名称：

  3-Phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazines and Analogues:  High-Affinity γ-Aminobutyric Acid-A Benzodiazepine Receptor Ligands with α2, α3, and α5-Subtype Binding Selectivity over α1

  摘要：

  Studies with our screening lead 5 and the literature compound 6 led to the identification of 6-benzyloxy-3-(4-methoxy)phenyl-1,2,4-triazolo[3,4-a]phthalazine 8 as a ligand with binding selectivity for the gamma-aminobutyric acid-A (GABA-A) alpha3- and alpha5-containing receptor subtypes over the GABA-A alpha1 subtype (K-i: alpha2 = 850 nM, alpha3 = 170 nM, alpha5 = 72 nM, alpha1 = 1400 nM). Early optimization studies identified the close analogue 10 (Ki: alpha2 = 16 nM, alpha3 = 41 nM, alpha5 = 38 nM, alpha1 = 280 nM) as a suitable lead for further study. High-affinity ligands were identified by replacing the 6-benzyloxy group of compound 10 with 2-pyridylmethoxy (compound 29), but binding selectivity was not enhanced (K-i: alpha2 = 1.7 nM, alpha3 = 0.71 nM, alpha5 = 0.33 nM, alpha1 = 2.7 nM). Furthermore, on evaluation in xenopus oocytes,(22) 29 was discovered to be a weak to moderate inverse agonist at all four receptor subtypes (alpha1, -7%; alpha2, -5%; alpha3, -16%; alpha5, -5%). Replacement of the 3-phenyl group of 29 with alternatives led to reduced affinity, and smaller 3-substituents led to reduced efficacy. Methyl substitution of the benzo-fused ring of 29 at the 7-, 8-, and 10-positions resulted in increased efficacy although selectivity was abolished. Increased efficacy and retention of selectivity for alpha3 over alpha1 was achieved with the 7,8,9,10-tetrahydro-(7,10-ethano)-phthalazine 62. Compound 62 is currently one of the most binding selective GABA-A alpha3-benzodiazepine-site partial agonists known, and although its selectivity is limited, its good pharmacokinetic profile in the rat (33% oral bioavailability after a 3 mg/kg dose, reaching a peak plasma concentration of 179 ng/mL; half-life of I h) made it a useful pharmacological tool to explore the effect of a GABA-A alpha2/alpha3 agonist in vivo.

  DOI：

  10.1021/jm031020p

文献信息

• Stable pharmaceutical compositions
  申请人：——

  公开号：US20030212272A1

  公开（公告）日：2003-11-13

  Pharmaceutical compounds having the general formula: 1 or compounds having the formula: 2 where R 1 and R 2 are independently H, branched or straight chain alkyl having from 1 to about 7 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl, substituted or unsubstituted alkylcycloalkyl, lower alkenyl or R 1 and R 2 together form part of a substituted or unsubstituted cycloalkyl having from about 4 of about 7 carbon atoms; where R 3 is a branched or straight chain alkyl having from 1 to about 7 carbon atoms, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted cycloalkyl, aralkyl, substituted or unsubstituted alkylcycloalkyl or a group having the formula (CH 2 ) n COOH where n is from 1 to about 7.

  具有一般式的制药化合物：1或具有式的化合物：2其中R1和R2分别为H、支链或直链烷基，其碳原子数为1至约7，取代或未取代芳基，取代或未取代环烷基，取代或未取代芳基烷基，取代或未取代烷基环烷基，较低的烯基或R1和R2共同形成碳原子数约为4至7的取代或未取代环烷基的一部分；其中R3为支链或直链烷基，其碳原子数为1至约7，取代或未取代芳基，取代或未取代芳基烷基，取代或未取代环烷基，芳基烷基，取代或未取代烷基环烷基或具有式（CH2）nCOOH的基团，其中n为1至约7。
• Schmid; Kueng; Riess, Arzneimittel-Forschung/Drug Research, 1981, vol. 31, # 7, p. 1143 - 1147
  作者：Schmid、Kueng、Riess、Dollery、Harland

  DOI：——

  日期：——
• STABLE PHARMACEUTICAL COMPOSITIONS
  申请人：Barbeau, Donald L.

  公开号：EP1480649A2

  公开（公告）日：2004-12-01
• EP1480649A4
  申请人：——

  公开号：EP1480649A4

  公开（公告）日：2006-04-26
• US6821974B2
  申请人：——

  公开号：US6821974B2

  公开（公告）日：2004-11-23