アジルサルタンカメドキソミル

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。

  P280：保護手袋/保護衣/保護眼鏡/保護面を着用するこ と。

  P301+P312：飲み込んだ場合：気分が悪い時は医師に連絡する 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。

アジルサルタンカメドキソミル 化学特性,用途語,生産方法

• 効能

  血圧降下薬, アンジオテンシンII受容体拮抗薬

• 定義

  ChEBI: An organic potassium salt that is the monopotassium salt of azilsartan medoxomil. A prodrug for azilsartan, it is used for treatment of hypertension.

• 臨床応用

  Azilsartan kamedoxomil, developed by Takeda Pharmaceuticals, was approved for the treatment of hypertension and launched in the U.S. under the brand name Edarbi. Edarbi is a prodrug that undergoes rapid hydrolysis to liberate azilsartan, the active ingredient (TAK-536, 39). As the 8th angiotensin receptor blocker (ARB) to enter the world market, azilsartan kamedoxomil can function as monotherapy or in combination with other antihypertensive agents. In several clinical studies, monotherapeutic azilsartan kamedoxomil showed superior antihypertensive activity and a favorable safety/tolerability profile in patients compared with other established therapeutics, including valsartan, olmesartan medoxomil, candesartan, and telmisartan.In late 2011,Takeda announced that FDA also approved the fixed-dose combination tablet of azilsartan kamedoxomil with chlorthalidone under the trade name of Edarbyclor.

• 合成

  Based on the synthesis of azilsartan, the process-scale approach to azilsartan kamedoxomil is described in the scheme. The synthesis started with commercially available methyl 2-[(tert-butoxycarbonyl)amino]-3-nitrobenzoate (30), which can also be prepared by several different routes.41,42 Alkylation of 30 with diaryl bromide 31 gave benzylamine 32 in 78% yield, which was followed by deprotection with 30% ethanolic HCl and alkalinization to produce amine 33 in 77% yield. The nitro group within 33 was reduced with hydrazine hydrate and a catalytic amount of ferric chloride to afford 2,3-diaminobenzoate 34 in 64% yield. Ring formation was achieved by treatment of 34 with tetraethoxymethane and acetic acid to produce benzimidazole 35 in 91% yield.37 The addition of hydroxylamine to the cyano group of 35 provided amidoxime 36 in 55% yield, which underwent immediate cyclization upon treatment with 2-ethylhexyl chloroformate 37 in refluxing xylenes to give oxadiazolone 38 in 52% yield. Hydrolysis of 38 gave azilsartan (39, TAK-536) in 94% yield. In the presence of perchlorobenzoyl chloride 40 and triethylamine, carboxylic acid 39 was converted to the mixed acid anhydride intermediate, which when condensed with alcohol 41 furnished benzoate 42 in 50% yield. Salt preparation of 42 was accomplished with potassium 2-ethylhexyl carboxylate 43 affording azilsartan kamedoxomil (V) in 63% yield.

  

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