5-{3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]-2-propynyl}-phenanthridin-6(5H)-one | 125030-71-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 5-{3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]-2-propynyl}-phenanthridin-6(5H)-one
• 英文别名: 5-{3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepin-2-yl]-2-propynyl}phenanthridin-6(5H)-one；5-{3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2 yl]-2 propynyl}-phenanthridin-6(5H)-one；5-{3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]-2-propynyl}phenanthridin-6(5H)-one；5-(3-(4-(2-Chlorophenyl)-9-methyl-6H-thieno(3,2-f)(1,2,4)triazolo(4,3-a)(1,4)diazepin-2-yl)-2-propynyl)phenanthridin-6(5H)-one；5-[3-[7-(2-chlorophenyl)-13-methyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-4-yl]prop-2-ynyl]phenanthridin-6-one
• CAS: 125030-71-9
• 化学式: C₃₁H₂₀ClN₅OS
• 分子量: 546.052
• InChiKey: MPMZSZMDCRPSRF-UHFFFAOYSA-N

物化性质

• 熔点：
  247-249 °C
• 沸点：
  819.6±75.0 °C(Predicted)
• 密度：
  1.41±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  39
• 可旋转键数：
  3
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  91.6
• 氢给体数：
  0
• 氢受体数：
  5

制备方法与用途

生物活性

Ro 24-4736 是一种长效的选择性血小板活化因子 (PAF) 拮抗剂。

靶点

PAF

体外研究

Ro 24-4736 能与狗血小板上的 [³H]PAF 竞争其受体位点，半数抑制浓度（IC₅₀）为 9.8±1.0 nM，并且选择性地抑制豚鼠、狗和人类的 PA 引起的血小板聚集，具有剂量依赖性。

体内研究

Ro 24-4736 剂量依赖性地抑制豚鼠体内的支气管收缩（ID₅₀ 为 0.006 mg/kg p.o.）和外周血小板聚集（ID₅₀ 为 0.004 mg/kg p.o.）。时间进程研究显示，单次口服剂量为 0.03 mg/kg 后，Ro 24-4736 可完全阻断 PAF 引起的血小板聚集长达 8 小时，并且体内作用具有较长持续时间（长达 30 小时）。其体内 PAF 抗拮抗活性非常具体，即使在高剂量下 (最高 10 mg/kg) 也不会抑制白三烯 D₄ 或组胺的支气管收缩效果。与其他已评估的 PAF 拮抗剂相比，在豚鼠模型中，Ro 24-4736 在口服效力、生物利用度和口服作用时间方面表现更优。

此外，还对 Ro 24-4736 进行了其他体内实验研究。通过口服给予致敏豚鼠后，该药物可减轻吸入抗原诱导的气道高反应性而不影响支气管肺泡灌洗白细胞积聚。¹⁴C-Ro 24-4736 单次静脉注射 1.0 mg/kg 在雄性大鼠体内的组织分布研究表明，肝脏、肾脏、心脏和消化道均有明显摄取。血浆及组织中的峰值浓度分别在给药后 5 分钟（除小肠为 4 小时外）和 48 小时内出现。48 小时时，仅 3.5% 的剂量存在于组织中，而胃肠道管腔中有 6.1%。

反应信息

• 作为反应物：
  描述：

  5-{3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]-2-propynyl}-phenanthridin-6(5H)-one 在 间氯过氧苯甲酸 作用下， 以 二氯甲烷 为溶剂， 以79%的产率得到5-[3-[7-(2-Chlorophenyl)-13-methyl-8-oxido-3-thia-1,11,12-triaza-8-azoniatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-4-yl]prop-2-ynyl]phenanthridin-6-one
  参考文献：
  名称：

  Triazolobenzo- and triazolothienodiazepines as potent antagonists of platelet activating factor

  摘要：

  A series of [1,2,4]triazolo[4,3-alpha][1,4]benzodiazepines bearing an ethynyl functionality at the 8-position and the isosteric thieno[3,2-f][1,2,4]triazolo[4,3-alpha][1,4]diazepines were prepared and evaluated as antagonists of platelet activating factor. The effects of substitution were explored in in vitro and in vivo test systems designed to measured PAF-antagonistic activity. Results are discussed and compared with previously published data. Many of the compounds had activity superior to WEB 2086, compound 1. In general, the thieno analogues exhibited better oral activity than the corresponding benzodiazepines. The duration of activity upon oral administration was modulated by the substitution on the acetylenic side chain. Compounds 71 and 81 were selected for further pharmacological evaluation as a result of their good oral potency and exceptionally long duration of action.

  DOI：

  10.1021/jm00107a048
• 作为产物：
  描述：

  6(5H)-菲啶酮 在 copper(l) iodide 、 potassium tert-butylate 、 palladium diacetate 、 三乙胺 、 三苯基膦 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 72.67h， 生成 5-{3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-2-yl]-2-propynyl}-phenanthridin-6(5H)-one
  参考文献：
  名称：

  Triazolobenzo- and triazolothienodiazepines as potent antagonists of platelet activating factor

  摘要：

  A series of [1,2,4]triazolo[4,3-alpha][1,4]benzodiazepines bearing an ethynyl functionality at the 8-position and the isosteric thieno[3,2-f][1,2,4]triazolo[4,3-alpha][1,4]diazepines were prepared and evaluated as antagonists of platelet activating factor. The effects of substitution were explored in in vitro and in vivo test systems designed to measured PAF-antagonistic activity. Results are discussed and compared with previously published data. Many of the compounds had activity superior to WEB 2086, compound 1. In general, the thieno analogues exhibited better oral activity than the corresponding benzodiazepines. The duration of activity upon oral administration was modulated by the substitution on the acetylenic side chain. Compounds 71 and 81 were selected for further pharmacological evaluation as a result of their good oral potency and exceptionally long duration of action.

  DOI：

  10.1021/jm00107a048

文献信息

• Triazolo(4,3-A)(1,4)benzodiazepines and thieno
  申请人：Hoffmann-La Roche Inc.

  公开号：US04959361A1

  公开（公告）日：1990-09-25

  The invention relates to compounds of the formula ##STR1## wherein X is --CH.dbd.CH-- or S; R.sub.1 is lower alkyl, lower alkoxy or trifluoromethyl; R.sub.2 is hydrogen, lower alkyl, lower alkoxy, hydroxy or alkanoyloxy; R.sub.3 and R.sub.4, independently, are hydrogen, chlorine, fluorine, lower alkyl or lower alkoxy; s is an integer from 0 to 1, provided that when s is 1, R.sub.2 cannot be hydroxy, lower alkoxy or alkanoyloxy; R.sub.5 is a radical of the formula R.sub.6 --(CH.sub.2).sub.n -- or R.sub.7 --O--(CH.sub.2).sub.m -- wherein R.sub.6 and R.sub.7 are aryl or a heterocyclic radical, n is an integer of from 0 to 2 and m is an integer of from 1 to 2, provided that, when n is 0, R.sub.6 must be attached through a carbon to carbon bond, and provided that R.sub.7 is always attached through a carbon to oxygen bond, and, when at least one asymmetric carbon is present, its enantiomers and racemates, and pharmaceutically acceptable acid addition salts thereof. The compounds of formula I exhibit activity as platelet activating factor (PAF) antagonists and are, therefore, useful in disease states characterized by excess platelet activating factor or for the prevention and treatment of cardiovascular diseases, pulmonary diseases, immunological disorders, inflammatory diseases, dermatological disorders, shock or transplant rejection.

  本发明涉及通式##STR1##的化合物，其中X为--CH=CH--或S；R1为低级烷基、低级烷氧基或三氟甲基；R2为氢、低级烷基、低级烷氧基、羟基或烷酰氧基；R3和R4各自独立地为氢、氯、氟、低级烷基或低级烷氧基；s为0至1的整数，但当s为1时，R2不能为羟基、低级烷氧基或烷酰氧基；R5为通式R6--(CH2)n--或R7--O--(CH2)m--的基团，其中R6和R7为芳基或杂环基团，n为0至2的整数，m为1至2的整数，但当n为0时，R6必须通过碳-碳键连接，且R7始终通过碳-氧键连接，当存在至少一个不对称碳时，包括其对映体和外消旋体，以及药学上可接受的酸加成盐。通式I的化合物表现出作为血小板活化因子（PAF）拮抗剂的活性，因此可用于治疗以过量血小板活化因子为特征的疾病状态，或用于预防和治疗心血管疾病、肺部疾病、免疫紊乱、炎症性疾病、皮肤病、休克或移植排斥反应。
• Pharmaceutical composition for controlled release
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：EP0662322A2

  公开（公告）日：1995-07-12

  An erodible pharmaceutical composition providing a unique zero order controlled release profile contains a therapeutically active substance having a water solubility not greater than 80 mg/mL in water at 25°C, a hydroxypropyl methylcellulose derivative and erosion modifiers depending on drug solubility and drug loading, such as lactose and polyoxyalkylene derivatives of propylene glycol, as well as other inert materials such as binders and lubricants.

  一种可侵蚀的药物组合物具有独特的零阶控释特性，其中包含一种治疗活性物质（在 25°C 水中的水溶性不大于 80 毫克/毫升）、羟丙基甲基纤维素衍生物和侵蚀调节剂（取决于药物溶解度和药物负载量），如乳糖和丙二醇的聚氧亚烷基衍生物，以及其他惰性材料，如粘合剂和润滑剂。
• J. Med. Chem. 1991, 34, 1209-1221
  作者：

  DOI：——

  日期：——
• Antiallergic combination
  申请人：F. HOFFMANN-LA ROCHE AG

  公开号：EP0469477B1

  公开（公告）日：1995-09-20
• WALSER, ARMIN
  作者：WALSER, ARMIN

  DOI：——

  日期：——