オピカポン

危険有害性情報のコード(GHS)

• 絵表示(GHS)

  

• 注意喚起語

  Warning

• 危険有害性情報

  H302：飲み込むと有害

  H315：皮膚刺激

  H319：強い眼刺激

  H335：呼吸器への刺激のおそれ

• 注意書き

  P261：粉じん/煙/ガス/ミスト/蒸気/スプレーの吸入を避ける こと。

  P305+P351+P338：眼に入った場合：水で数分間注意深く洗うこと。次にコ ンタクトレンズを着用していて容易に外せる場合は外す こと。その後も洗浄を続けること。

オピカポン 化学特性,用途語,生産方法

• 効能

  パーキンソン病治療薬, COMT阻害薬

• 説明

  Opicapone is a selective and reversible catechol O-methyltransferase (COMT) inhibitor that was developed by the Portuguese pharmaceutical firm Bial and sold to Neurocrine Biosciences. The drug was approved by the USFDA as adjunctive treatment to levodopa (L-Dopa)/ dopa-decarboxylase inhibitor (DDCI) therapy in adults with Parkinson’s disease (PD) and end-of-dose motor fluctuations that cannot be stabilized on those combinations. In 14- to 15- week double-blind multinational trials and in one-year openlabel extension studies in this patient population, opicapone was an effective and generally well-tolerated adjunctive therapy to L-Dopa plus a DDCI and other PD therapies. During the double-blind phase, adjunctive opicapone (50 mg once daily) provided significantly greater improvements in motor fluctuations than placebo, and no new unexpected safety concerns were identified after treatment with opicapone over a 1.4 year period. Furthermore, no serious cases of hepatotoxicity were reported in clinical trials, which represents a significant safety profile improvement over existing standard-of-care COMT inhibitors enticapone, tolcapone, and nebicapone.

• 使用

  Opicapone, is used for the synthesis of novel nitrocatechol-substituted heterocycles, having the ability to inhibit catechol-O-methyltransferase (COMT), used for the treatment of Parkinson`s diseases.

• 合成

  Although several synthetic approaches to opicapone or opicapone subunits have been disclosed, a synthetic approach described by Bial was exemplified on a scale capable of producing 14.4 kg of the active pharmaceutical ingredient (API). Commercial 2,4-pentanedione (114) was condensed with cyanoacetamide in warm methanol to give rise to cyanopyridone 115 in excellent yield. Chlorination with sulfuryl chloride in chilled acetonitrile followed by treatment with phosphorus oxychloride resulted in dichloropyridine 117. Next, treatment with hydroxylamine in aqueous methanol converted nitrile 117 to the corresponding Nhydroxyamidine 118, and this was followed by exposure to pyridine and acid chloride 119. These operations facilitated a cyclization reaction, which furnished the key oxadiazole 120 in good yield. Subjection of 120 to urea hydrogen peroxide (UHP) in dichloromethane to establish the pyridine N-oxide functionality within opicapone preceded methyl ether cleavage through the use of aluminum trichloride in warm pyridine to furnish opicapone (X) in 53% yield for the two-step sequence.
  The preparation of acid chloride 119 involved the nitration of commercially available benzoic acid 121 followed by thionyl chloride-mediated conversion of the resulting nitrobenzoic acid 122 to acid chloride 119. Interestingly, although the nitration step is low-yielding and involves nitric acid, the authors report an operationally simple isolation method that has been exemplified on multiple kilogram scale. No yield was reported for the conversion of 122 to 119.

  

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