JP2011236170A - 電位依存性カチオンチャネル抑制剤 - Google Patents
電位依存性カチオンチャネル抑制剤 Download PDFInfo
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- JP2011236170A JP2011236170A JP2010110194A JP2010110194A JP2011236170A JP 2011236170 A JP2011236170 A JP 2011236170A JP 2010110194 A JP2010110194 A JP 2010110194A JP 2010110194 A JP2010110194 A JP 2010110194A JP 2011236170 A JP2011236170 A JP 2011236170A
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- Japan
- Prior art keywords
- carbon atoms
- alkylene group
- alkyl group
- group
- adamantane
- Prior art date
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- Granted
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Abstract
【解決手段】下記式(1)
〔式中、R1及びR2は、各々同一又は異なって、水素原子又は炭素数1〜6のアルキル基であり、Xは、−OH、−R3−OH(ここで、R3は炭素数1〜6のアルキレン基を示す)、−NH、−R4−NH2(ここで、R4は炭素数1〜6のアルキレン基を示す)、−COOH、−R5−COOH(ここで、R5は炭素数1〜6のアルキレン基を示す)、−CO−R6(ここで、R6は炭素数1〜6のアルキル基を示す)、−CO−R7−COO−R8(ここで、R7は炭素数1〜6のアルキレン基を示し、R8は炭素数1〜6のアルキル基を示す)又はNHCO−R9(ここで、R9は炭素数1〜6のアルキル基を示す)を示す〕で表されるアダマンタン誘導体を有効成分とする電位依存性カチオンチャネル阻害剤又はマスキング剤。
【選択図】なし
Description
感覚は、皮膚感覚や深部感覚等の体性感覚、内臓痛等の内臓感覚、視覚、聴覚、味覚、嗅覚等の特殊感覚に分類することができる。感覚の情報は、例えば、皮膚の各種受容器、筋紡錘、網膜、嗅粘膜、味蕾、蝸牛の有毛細胞等の末梢の感覚受容器等によって受容され、知覚感覚において神経インパルスに変換された後、電気信号として中枢まで伝達される。
従って、電位依存性カチオンチャネルの活性化を阻害すれば、感覚を抑制することが可能である。実際、電位依存性カチオンチャネル阻害剤を利用して感覚を抑制させる方法は、従来から医療現場等で使用されている。例えば、局所麻酔剤や抗不整脈薬として使用されるリドカイン(例えばキロシカイン(登録商標))は、電位依存性ナトリウムチャネル阻害剤である。電位依存性カルシウムチャネル阻害剤であるガバペンチン(例えば、ガバペン(登録商標)、ニューロンチン(登録商標))、は抗痙攣剤或いは鎮痛補助薬として使用されている。また、電位依存性カルシウムチャネル又はナトリウムチャネルのインヒビター(例えば、バラパミル)が、外的攻撃に対する皮膚の耐性閾値を増加させ、皮膚の過敏症に適用できることが報告されている(特許文献1)。
そこで、例えば、ヒト嗅覚器CNGチャネルタンパク質の作用機序を利用して、嗅細胞イオンチャネル阻害が強いものを不快臭のマスキング素材として探索することが試みられている(特許文献2)。
しかしながら、未だ満足の行く不快臭のマスキング素材を得るまでには至っていない。
しかしながら、アダマンタン誘導体に電位依存性チャネル阻害作用や不快臭のマスキング効果があることは知られていない。
1)本発明は、下記式(1)
ここで、R1及びR2で示される炭素数1〜6のアルキル基としては、直鎖又は分岐鎖のものが包含されるが、炭素数1〜4のアルキル基が好ましく、例えば、メチル基、エチル基、プロピル基、ブチル基、イソプロピル基、イソブチル基、sec−ブチル基及びtert−ブチル基等が挙げられる。
上記R1及びR2としては、このうち、水素原子及び直鎖のアルキル基が好ましく、より水素原子、メチル基、エチル基及びプロピル基が好ましく、更に水素原子及びメチル基が好ましい。
更に、上記R3で示されるアルキレン基のうち、炭素数1〜2の直鎖又は分岐鎖のアルキレン基が好ましく、よりメチレン基及びエチレン基が好ましい。
また、上記R4で示されるアルキレン基のうち、炭素数1〜2の直鎖又は分岐鎖のアルキレン基が好ましく、よりメチレン基及びメチルメチレン基が好ましい。
また、上記R5及びR7で示されるアルキレン基のうち、炭素数1〜2の直鎖又は分岐鎖のアルキレン基が好ましく、よりメチレン基が好ましい。
(1)Xが−OHの場合、アダマンタンから次亜塩素酸やオゾンなど適当な酸化剤を用いて酸化することにより合成することが出来る(特開2000−219646号公報、特開2004−26778号公報)
(2)Xが−NH2の場合、アダマンタンをフッ素及びルイス酸存在下、アセトニトリルと反応させることによりN−(1ーアダマンチル)アセトアミドを合成し、これを酸または塩基と接触させることによって合成する事が出来る(WO 01/053234)。
(3)Xが−R3−OHの場合、対応するアダマンチル基を有するカルボン酸又はカルボン酸エステルを適当な還元剤を用いて還元することにより得ることが出来る。例えば、1−アダマンチル酢酸をボラン/THF錯体と反応させることにより、1−アダマンタンエタノールを合成することが出来る。(Angew. Chem., 72, 628(1960) )
(4)Xが−R3−NH2の場合、対応するアルキル基末端にハロゲン基を有するアダマンタン誘導体をアジ化ナトリウムと反応させて、アジ化物を合成し、これを水素添加反応することにより得ることが出来る。例えば、1−(2−ブロモエチル)アダマンタンにアジ化ナトリウムを作用させて1−(2−アジドエチル)アダマンタンを合成し、これをプラチナ触媒存在下水素と接触させることにより、1−(2−アミノエチル)アダマンタンを得ることが出来る。(Journal of Medicinal Chemistry, 1971, Vol. 14, No. 6 535)
また、「外部刺激」とは、例えば界面活性剤や防腐剤、又は香料など刺激性を有する化合物、及び環境、食物、風、摩擦、シェービング、石鹸、カルシウム濃度の高い硬水、温度変化、毛糸などを意味するものである。
なお、皮膚痛覚過敏とは、痛みの感覚が亢進し、痛みとなる刺激をより強く感じる感覚異常のことを、異痛症とは通常では疼痛をもたらさない刺激でも全て疼痛として認識される感覚異常のことを、痒み過敏とは普段であれば痒みを感じない刺激に対しても痒みを感じる感覚異常のことをいう。
投与形態としては、経口投与及び非経口投与が挙げられる。経口投与のための剤型としては、錠剤、被覆錠剤、顆粒剤、散剤、カプセル剤のような固形投薬形態、あるいはエリキシル、シロップおよび懸濁液のような液体投薬形態が挙げられる。非経口投与のための経路としては、注射、輸液、経皮、経粘膜、経鼻、経腸、吸入、坐剤、ボーラス等が挙げられ、剤型としては、錠剤、カプセル、液体、粉末、顆粒、軟膏、スプレー、ミスト、クリーム、乳液、ジェル、ペースト、ローション、パップ、プラスター、スティック、シート等が挙げられる。
食品や飼料の形態としては、特に限定されないが、液状、半固体状、固体状の他、上記の経口投与製剤と同様の、錠剤、丸剤、カプセル剤、液剤、シロップ剤、粉末剤、顆粒剤等の形態であってもよい。
表1に示すように、アダマンタン、1,3−ジメチルアダマンタン、1−アダマンタノール、1−アダマンタンメタノール、1−アダマンタンエタノール、3,5−ジメチルアダマンタン−1−メタノール、1−アダマンタンメチルアミン、1−アダマンチルメチルケトン、1−アダマンタン酢酸、エチル−3−(1−アダマンチル)−3−オキソプロピオネート、1−アセトアミドアダマンタン又は1−アダマンタンメタンアミンは、全てシグマアルドリッチジャパンから購入した物を用いた。
1.嗅細胞の単離
アカハライモリより公知の方法(Kurahashiら, J. Physiol. (1989), vol.419: 177-192)に従って嗅細胞を単離し、正常リンガー液に浸した。単離方法を簡単に示すと、氷水中で冬眠状態にしたイモリにダブルピスを施し、頭蓋を切開し嗅粘膜を取り出す。取り出した嗅粘膜を0.1%コラゲナーゼ溶液中で37℃にて5分間インキュベートし、コラゲナーゼを洗い流したあと、ガラスピペットにて組織を粉砕し細胞を単離した。正常リンガー液としては、NaCl 110mM、KCl 3.7 mM、CaCl2 3 mM、MgCl2 1 mM、グルコース 15 mM、ピルビン酸ナトリウム 1 mM、HEPES 10 mM、フェノールレッド 0.001%(w/v)、pH 7.4(NaOHで調整)を用いた。
〔A.設定〕 単離した嗅細胞を全細胞記録法により膜電位を固定し、膜電流の計測を行った(Kawaiら, J. Gen. Physiol. (1997), vol.109: 265-272)。電極は、ホウケイ酸ガラスキャピラリー(直径1.2mm)を用い、電極作成用プラー(P-97, SUTTER INSTRUMENT CO.)にて作製した(電極抵抗6.0MΩ前後)。電極内には、電極内溶液と銀塩化銀線を挿入し、銀塩化銀線はパッチクランプアンプ(EPC10, HEKA)と接続し、膜電位の固定、脱分極刺激を行った。電極内溶液としては、CsCl 119 mM、HEPES 10 mM、CaCl2 1mM、EGTA 5mM、フェノールレッド 0.001%(w/v)、pH7.4(CsOHで調整)を用いた。膜電流の記録は、パッチクランプアンプに接続したコンピュータ(IBM互換機)にて行い(Sampling frequency, 1kHz)、測定、解析にはPatch Masterソフトウェア(HEKA)を用いた。試験物質の添加(吹きかけ)には、圧力制御装置を用いた。圧力制御装置とは、エアーコンプレッサーより送り込まれた圧縮空気を、コンピューター制御にて任意の圧力まで減圧し、設定した時間、その圧縮空気を試験物質を充填したガラスピペット尾部へ送り込む装置である(Itoら、日本生理学雑誌, 1995,vol.57,127-133)。
尚、試験中、稀に試験物質添加に伴い、嗅覚受容体が応答し、CNGチャネルに由来する内向き電流が観察される場合が起きるが、このようなケースは除外した。このケースは、試験物質が試験に用いた嗅細胞上の嗅覚受容体のアゴニストとして作用することにより生じたと考えられる。CNGチャネル電流は、その強度、ピーク形状、持続時間などから電位依存性チャネル電流と容易に区別することができる
官能評価の嗅覚マスキング試験をパネラー10名に対して実施した。悪臭物質として10%へキサン酸を用い、悪臭 20μLと50%濃度のアダマンタン誘導体(1-アダマンタン酢酸は25%濃度)の試験溶液20μLを同一の綿球(直径 1cm)にしみこませ、50mL容器内で一晩、室温で揮発させた。
評価は、パネラー自身が容器内の匂いを嗅ぎ、ヘキサン酸単体の匂い強度を21段階評価(0:臭わない、10:臭いが強い)の中間点である5.0に設定した時のアダマンタン誘導体添加によるヘキサン酸のマスキング強度を判定することにより行った。
〔結果〕
ヘキサン酸単体に対する匂い強度変化を図2に、匂い強度抑制率を表2に示した。各アダマンタン誘導体添加により嗅覚マスキング作用が認知された。
図3及び表3に示すように、種々のサンプルを用いた結果から、内向き電流抑制率(%)とマスキングスコアとに相関関係が認められたことから、電位依存性カチオンチャネル阻害作用のある成分は不快臭のマスキング素材として有用である。
〔官能評価試験〕
官能評価の嗅覚マスキング試験をパネラー20名に対して実施した。悪臭物質として1%イソ吉草酸を、対照として悪臭に対する嗅覚感度低下効果が知られている1,8−シネオールを用いた。
悪臭 2μLと、表3に示す 0.1%濃度の評価化合物の試験溶液 4μLを別々の綿球(直径 1cm)にしみこませ、別々の 50mL注射筒内で12時間、室温で揮発させた。注射筒内で気化したイソ吉草酸と評価化合物をフタ付きのPP容器(容積 500mL)内へ注入し、混和させた。
評価は、パネラー自身がPP容器のフタをわずかに開け、容器内の匂いを嗅ぎ、イソ吉草酸の匂いに対するマスキング強度を判定した。
マスキング強度の評価は、気化したイソ吉草酸のみを注入したPP容器内の臭気強度と比較し、以下の6段階のマスキングスコアにより行った。この結果を表3に示した。
0:マスキングされていない
1:マスキング効果がごくわずかに認められる
2:マスキング効果がやや認められる
3:マスキング効果が十分認められる
4:ほとんどマスキングされている
5:完全にマスキングされている
Claims (10)
- 下記式(1)
- 上記R1及びR2は、各々同一又は異なって、水素原子又はメチル基である請求項1記載の電位依存性カチオンチャネル阻害剤。
- 上記R3、R4、R5及びR7が炭素数1〜4のアルキレン基であり、上記R6、R8及びR9が炭素数1〜4のアルキル基である請求項1又は2記載の電位依存性カチオンチャネル阻害剤。
- 上記Xが、−OH、−R3−OH(ここで、R3は炭素数1〜2のアルキレン基を示す)、−R4−NH2(ここで、R4は炭素数1〜2のアルキレン基を示す)、−R5−COOH(ここで、R5は炭素数1〜2のアルキレン基を示す)、−CO−R6(ここで、R6は炭素数1〜2のアルキル基を示す)、−CO−R7−COO−R8(ここで、R7は炭素数1〜2のアルキレン基を示し、R8は炭素数1〜2のアルキル基を示す)、又はNHCO−R9(ここで、R9は炭素数1〜2のアルキル基を示す)である請求項1〜3の何れか1項記載の電位依存性カチオンチャネル阻害剤。
- 上記式(1)で表される化合物が、1−アダマンタノール、1−アダマンタンメタノール、1−アダマンタンエタノール、3,5−ジメチルアダマンタン−1−メタノール、1−アダマンタンメチルアミン、1−アダマンチルメチルケトン、1−アダマンタン酢酸、エチル−3−(1−アダマンチル)−3−オキソプロピオネート、1−アセトアミドアダマンタン又は1−アダマンタンメタンアミンである請求項1〜4の何れか1項記載の電位依存性カチオンチャネル阻害剤。
- 下記式(1)
- 上記R1及びR2は、各々同一又は異なって、水素原子又はメチル基である請求項6記載のマスキング剤。
- 上記R3、R4、R5及びR7が炭素数1〜4のアルキレン基であり、上記R6、R8及びR9が炭素数1〜4のアルキル基である請求項6又は7記載のマスキング剤。
- 上記Xが、−OH、−R3−OH(ここで、R3は炭素数1〜2のアルキレン基を示す)、−R4−NH2(ここで、R4は炭素数1〜2のアルキレン基を示す)、−R5−COOH(ここで、R5は炭素数1〜2のアルキレン基を示す)、−CO−R6(ここで、R6は炭素数1〜2のアルキル基を示す)、−CO−R7−COO−R8(ここで、R7は炭素数1〜2のアルキレン基を示し、R8は炭素数1〜2のアルキル基を示す)、又はNHCO−R9(ここで、R9は炭素数1〜2のアルキル基を示す)である請求項6〜8の何れか1項記載のマスキング剤。
- 上記式(1)で表される化合物が、1−アダマンタノール、1−アダマンタンメタノール、1−アダマンタンエタノール、3,5−ジメチルアダマンタン−1−メタノール、1−アダマンタンメチルアミン、1−アダマンチルメチルケトン、1−アダマンタン酢酸、エチル−3−(1−アダマンチル)−3−オキソプロピオネート、1−アセトアミドアダマンタン又は1−アダマンタンメタンアミンである請求項6〜9の何れか1項記載のマスキング剤。
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