ジフェリケファリン

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

• 注意書き

  P264：取扱い後は皮膚をよく洗うこと。

  P264：取扱い後は手や顔をよく洗うこと。

  P270：この製品を使用する時に、飲食または喫煙をしないこ と。

  P280：保護手袋/保護衣/保護眼鏡/保護面を着用するこ と。

  P302+P352：皮膚に付着した場合：多量の水と石鹸で洗うこと。

  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。

  P332+P313：皮膚刺激が生じた場合：医師の診断/手当てを受けるこ と。

  P337+P313：眼の刺激が続く場合：医師の診断/手当てを受けること。

  P501：内容物/容器を．．．に廃棄すること。

ジフェリケファリン 化学特性,用途語,生産方法

• 効能

  鎮痛薬, オピオイド受容体作動薬

• 使用

  Difelikefalin is used in the formation of oral formulations of kappa opioid receptor agonists for the treatment of variety of kappa opioid receptor-assocd. diseases and conditions such as pain, pruritus and inflammation.

• 合成

  Chromatography-free hydrochloride synthesis of Difelikefalin:
  Firstly, the piperidine amino acid 21.1 was coupled with the fully protected d-lysine analogue 21.2 under conventional EDCI/HOBt peptide coupling conditions to produce the fully protected dipeptide 21.3 in 97% yield. Conventional hydrogenation reduction was used to remove the N-terminal benzyloxycarbonyl protection to afford the amine 21.4 in 91% yield. Subsequent treatment of dipeptide 21.4 with protected d-leucine (21.5) and the same peptide coupling method followed by deprotection of the benzyl protecting group afforded tripeptide 21.6 in yields of 99% and 48%, respectively. Notably, the lower yield of tripeptide 21.6 may be due to crystallisation implemented during purification using cyclohexane and ethyl acetate rather than failure of the reaction to complete. Pure tripeptide 21.6 was then treated with protected d-phenylalanine and subjected to the same peptide coupling method followed by deprotection of the benzyl protecting group to give tetrapeptide 21.8 in 99% yield at each step. Treatment of tetrapeptide 21.8 with d-BocPhe under conventional peptide coupling conditions yielded a fully protected pentapeptide in 99% yield. The pentapeptide methyl ester 21.10 was precipitated in 99% yield by deprotection of the global Boc protecting group using 6N hydrochloric acid in isopropanol and addition of toluene to the reaction mixture. Next, the methyl ester 21.10 was treated under standard saponification conditions and the reaction was burst with 1N hydrochloric acid to obtain the pentapeptide 21.11 as a hydrochloride salt. although not disclosed, it is conceivable that the saponification reaction of 21.10 was burst with acetic acid to obtain its difelikefalin as a commercially available acetate salt (Compound No. 21).
  

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