JP2021516228A - 固定中の筋力低下の防止に使用する植物エクジソン - Google Patents
固定中の筋力低下の防止に使用する植物エクジソン Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
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Abstract
Description
・肢の骨折又は損傷による外部固定装置の装着(頸部カラー又はつり包帯型の非ギプスサポータ、固定包帯、金属又は膝ブレース、肢の完全又は不完全固定を行う合指又はギプスサポータ)、
・外科的介入を必要とするか、又は必要としない部分又は完全靭帯断裂による外部固定装置の装着、
・人工股関節の装着、
・人工膝関節の装着、
・直接支持を行わない整形外科的装具、
・疼痛期間の骨盤骨折、
・手術又は未手術、安定又は不安定な大腿骨頸部の骨折、
・外傷による部分的末梢神経攻撃、
・外傷による脊髄の部分的攻撃、
・長期間臥位の患者、である。
R1は(C1−C6)W(C1−C6)基;(C1−C6)W(C1−C6)W(C1−C6)基;(C1−C6)W(C1−C6)CO2(C1−C6)基;(C1−C6)A基;CH2Brから選択され、Aは任意にOH、OMe、(C1−C6)、N(C1−C6)、CO2(C1−C6)から選択される基で置換される複素環を表し;
WはN、O及びSから選択されるヘテロ原子であり、好ましくはO、さらにいっそう優先的にはSである。
1:(2S,3R,5R,10R,13R,14S,17S)−2,3,14−トリヒドロキシ−10,13−ジメチル−17−(2−モルホリノアセチル)−2,3,4,5,9,11,12,15,16,17−デカヒドロ−1H−シクロペンタ[a]フェナントレン−6−オン、
2:(2S,3R,5R,10R,13R,14S,17S)−2,3,14−トリヒドロキシ−17−[2−(3−ヒドロキシピロリジン−1−イル)アセチル]−10,13−ジメチル−2,3,4,5,9,11,12,15,16,17−デカヒドロ−1H−シクロペンタ[a]フェナントレン−6−オン;
3:(2S,3R,5R,10R,13R,14S,17S)−2,3,14−トリヒドロキシ−17−[2−(4−ヒドロキシ−1−ピペリジル)アセチル]−10,13−ジメチル−2,3,4,5,9,11,12,15,16,17−デカヒドロ−1H−シクロペンタ[a]フェナントレン−6−オン;
4:(2S,3R,5R,10R,13R,14S,17S)−2,3,14−トリヒドロキシ−17−[2−[4−(2−ヒドロキシエチル)−1−ピペリジル]アセチル]−10,13−ジメチル−2,3,4,5,9,11,12,15,16,17−デカヒドロ−1H−シクロペンタ[a]フェナントレン−6−オン;
5:(2S,3R,5R,10R,13R,14S,17S)−17−[2−(3−ジメチルアミノプロピル(メチル)アミノ)アセチル]−2,3,14−トリヒドロキシ−10,13−ジメチル−2,3,4,5,9,11,12,15,16,17−デカヒドロ−1H−シクロペンタ[a]フェナントレン−6−オン;
6:エチル2−[2−オキソ−2−[(2S,3R,5R,10R,13R,14S,17S)−2,3,14−トリヒドロキシ−10,13−ジメチル−6−オキソ−2,3,4,5,9,11,12,15,16,17−デカヒドロ−1H−シクロペンタ[a]フェナントレン−17−イル]エチル]スルファニルアセタート;
7:(2S,3R,5R,10R,13R,14S,17S)−17−(2−エチルスルファニルアセチル)−2,3,14−トリヒドロキシ−10,13−ジメチル−2,3,4,5,9,11,12,15,16,17−デカヒドロ−1H−シクロペンタ[a]フェナントレン−6−オン;
8:(2S,3R,5R,10R,13R,14S,17S)−2,3,14−トリヒドロキシ−17−[2−(2−ヒドロキシエチルスルファニル)アセチル]−10,13−ジメチル−2,3,4,5,9,11,12,15,16,17−デカヒドロ−1Hシクロペンタ[a]フェナントレン−6−オン。
本明細書の残部で言及する式(II)の化合物は以下の通りである。
・20−ヒドロキシエクジソンの側鎖を炭素C20からC22の間で酸化切断してポストステロンを得る工程と、
・C21位に臭素原子を導入する工程と、
・臭素誘導体をエタンチオールと反応させる工程と、を含む。
C57BL/6J遺伝的背景マウスの後足を固定したモデルは、管を用いて実行した(Langら、2012年)。
前脛骨筋の組織学研究は、ヘマトキシリン及びエオシン(HE)で着色した切片で実施する。筋繊維面積は、コントロールマウスの筋肉、或いは溶剤又は式(II)の化合物で処理した筋肉について評価する。すべての例の筋肉は健康な筋組織の組織構造を呈し(図1A〜C);一方で、予想されるように、固定14日後、繊維の平均面積は固定されていないコントロール動物と比較して、溶剤で処理した動物では大きく低減する(−24.4%、p=0.006)。式(II)の化合物で処理した群の筋繊維面積もコントロール群と比較して低減する(−26.8%、p=0.002)。
AT筋(図2A)及び腓腹筋(図2B)の重量は、無固定(コントロール)マウス、及び14日間の固定中に溶剤又は式(II)の化合物のどちらかで処理したマウスで固定14日後に評価した。
AT筋の生体位での収縮性評価は、プロトコールの異なる時間で、無固定のコントロールマウス(J0)、14日間、後足を固定したマウス(J14)、14日間固定後に1週間リモビライゼーション(J21)したマウス、並びに14日間固定後に2週間リモビライゼーション(J28)したマウスに実施される。
2つ目の研究は、後足を固定する同じ方法を用い、同年齢(13週)及び先に記載した同じ遺伝的背景(C57BL/6J)マウスに実施したが、固定7日後に分析点を追加した。従って、分析点はJ0、J7、J14及びJ28である。
AT(図4A)及び腓腹(図4B)筋重量を無固定マウス(コントロール群)、並びに固定の継続期間を通して溶剤又は化合物BIO101のどちらかで処理したマウスで固定14日後に評価した。予想通り、固定することで、溶剤で処理したマウスにおけるATの筋肉量は、無固定のコントロール群と比較して低減することが観察される(−21.7%、p<0.001)(図4A)。
AT筋の生体位での収縮性評価は、プロトコールの異なる時間で、無固定のコントロールマウス(コントロール群、J0)、7日間(J7)、14日間(J14)後足を固定したマウス、14日間固定後に2週間リモビライゼーション(J28)したマウスに実施する。
従って、固定された哺乳動物の筋機能に対する植物エクジソン及びその誘導体の性質により、特に筋力に関して、筋機能を保存するため、結果として固定による筋機能の低下を遅らせるため、植物エクジソン及びその誘導体の使用を提案することができる。
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Claims (10)
- 固定中の筋力低下を防止するために哺乳動物に使用する、少なくとも1つの植物エクジソン及び少なくとも1つの植物エクジソンの半合成誘導体を含む組成物。
- 20−ヒドロキシエクジソン又は20−ヒドロキシエクジソンの半合成誘導体を含む、請求項1に記載の使用する組成物。
- 以下の化合物:
1:(2S,3R,5R,10R,13R,14S,17S)−2,3,14−トリヒドロキシ−10,13−ジメチル−17−(2−モルホリノアセチル)−2,3,4,5,9,11,12,15,16,17−デカヒドロ−1H−シクロペンタ[a]フェナントレン−6−オン、
2:(2S,3R,5R,10R,13R,14S,17S)−2,3,14−トリヒドロキシ−17−[2−(3−ヒドロキシピロリジン−1−イル)アセチル]−10,13−ジメチル−2,3,4,5,9,11,12,15,16,17−デカヒドロ−1H−シクロペンタ[a]フェナントレン−6−オン;
3:(2S,3R,5R,10R,13R,14S,17S)−2,3,14−トリヒドロキシ−17−[2−(4−ヒドロキシ−1−ピペリジル)アセチル]−10,13−ジメチル−2,3,4,5,9,11,12,15,16,17−デカヒドロ−1H−シクロペンタ[a]フェナントレン−6−オン;
4:(2S,3R,5R,10R,13R,14S,17S)−2,3,14−トリヒドロキシ−17−[2−[4−(2−ヒドロキシエチル)−1−ピペリジル]アセチル]−10,13−ジメチル−2,3,4,5,9,11,12,15,16,17−デカヒドロ−1H−シクロペンタ[a]フェナントレン−6−オン;
5:(2S,3R,5R,10R,13R,14S,17S)−17−[2−(3−ジメチルアミノプロピル(メチル)アミノ)アセチル]−2,3,14−トリヒドロキシ−10,13−ジメチル−2,3,4,5,9,11,12,15,16,17−デカヒドロ−1H−シクロペンタ[a]フェナントレン−6−オン;
6:エチル2−[2−オキソ−2−[(2S,3R,5R,10R,13R,14S,17S)−2,3,14−トリヒドロキシ−10,13−ジメチル−6−オキソ−2,3,4,5,9,11,12,15,16,17−デカヒドロ−1H−シクロペンタ[a]フェナントレン−17−イル]エチル]スルファニルアセタート;
7:(2S,3R,5R,10R,13R,14S,17S)−17−(2−エチルスルファニルアセチル)−2,3,14−トリヒドロキシ−10,13−ジメチル−2,3,4,5,9,11,12,15,16,17−デカヒドロ−1H−シクロペンタ[a]フェナントレン−6−オン;
8:(2S,3R,5R,10R,13R,14S,17S)−2,3,14−トリヒドロキシ−17−[2−(2−ヒドロキシエチルスルファニル)アセチル]−10,13−ジメチル−2,3,4,5,9,11,12,15,16,17−デカヒドロ−1Hシクロペンタ[a]フェナントレン−6−オン;
から選択される化合物を含む、請求項1に記載の使用する組成物。 - 経口投与に好適である薬学的に許容可能な製剤に組み込まれる形態である、請求項1から請求項5のいずれか一項に記載の使用する組成物。
- 前記植物エクジソンは、ヒトに1日あたり50から1000ミリグラムの用量で投与される、請求項1から請求項6のいずれか一項に記載の使用する組成物。
- 固定中に投与される、請求項1から請求項7のいずれか一項に記載の使用する組成物。
- 固定が終わるまで投与される、請求項1から請求項8のいずれか一項に記載の使用する組成物。
- 固定終了後の所定期間中にも投与される、請求項8又は9に記載の使用する組成物。
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