JP6407974B2 - 炎症性腸疾患の処置のためのチアゾロピリミジノンの使用 - Google Patents
炎症性腸疾患の処置のためのチアゾロピリミジノンの使用 Download PDFInfo
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- JP6407974B2 JP6407974B2 JP2016513452A JP2016513452A JP6407974B2 JP 6407974 B2 JP6407974 B2 JP 6407974B2 JP 2016513452 A JP2016513452 A JP 2016513452A JP 2016513452 A JP2016513452 A JP 2016513452A JP 6407974 B2 JP6407974 B2 JP 6407974B2
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- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229940074545 sodium dihydrogen phosphate dihydrate Drugs 0.000 description 1
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- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
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Classifications
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- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicinal Preparation (AREA)
Description
以下のパラグラフは、本発明の様々な態様を詳述する。疑義を避けるため、特に、任意のこれらのパラグラフの1つ(またはその一部)に個別に記載された任意の特定の特徴(複数可)は、1つまたはそれ以上の残りのパラグラフ(またはその一部)に記載された1つまたはそれ以上の他の特徴と組み合わせてよいことが意図されている。言い換えれば、各パラグラフ(またはその一部)において以下で個別に記載される特徴は、単独で採用されてもよいし、実施例および図面を含む本明細書全体内の他の場所に記載される本発明の他の重要な側面と組み合わせてもよい、本発明の重要な側面を表すことが明示的に意図されている。当業者は、本発明がそのような特徴の組み合わせにも拡張されること、および、簡潔にするため、これらは本明細書では詳細に記載されていないことを理解するであろう。
TNBS(2,4,6トリニトロベンゼンスルホン酸)誘発性大腸炎を有する動物は、IBDの確立されたモデルである。雄のBALB/cマウスは、16時間の絶食を維持され、イソフルラン麻酔下で可撓性のポリエチレンカテーテルを使って、肛門内側の直腸内4cmに0.1mlのTNBS溶液(50%エタノール中の1.5mgのTNBSを含む)を投与された。TNBS投与後直ちに、動物の結腸内でのTNBS溶液の保持および分布を確保するために、マウスは、さらに45〜60秒間、頭位で垂直に保持された。 (Fiorucci et al, Immunity, 2002; Vol. 17; 769-780)
化合物Aを含む医薬組成物は、化合物Aの1mg/kgの1日2回の用量で、腹腔内経路および経口経路で投与量10ml/kgで、TNBS誘発性大腸炎(例3に従って発現したように)を有するマウスに投与された。投与は、TNBS大腸炎の誘導(1日目)の前日に開始された。処置された動物の血液サンプルは、5回目の投与前(0分)および5回目の投与後の様々な時点で採取された。血液サンプルは、4000rpmで収集した1時間以内に4℃で10分間、遠心分離され、血漿を分離した。これらの血漿サンプルはLC−MS/MS法を用いて、化合物Aの濃度を分析した。化合物Aの薬物動態パラメーターは、Phoenix WinNolin version 6.2を用いて、非コンパートメント解析法により算出された。薬物動態の結果は、表2にまとめられている。
医薬組成物を含む化合物Aは、1日2回、化合物Aの1mg/kgの用量で、10ml/kgの投与量で、TNBS誘発性大腸炎(例3に従って発現したように)を有するマウスに経口投与された。投与は、TNBS大腸炎の誘導(1日目)の前日に開始された。処置に関する体重減少の減衰、疾患活動性指数の改善(DAI、体重減少、糞便の硬さおよび糞便中の潜血の有無を考慮した0から最大12までの範囲の集成値)、大腸の健康状態(肉眼検査スコア)および生存率は、化合物Aの有効性を確認するため、6日間処置した動物(1日目から4日目まで)において確立された。体重は、毎日モニターされ、DAIは、2日目および4日目に記録され、その一方で、大腸損傷(肉眼検査スコアおよび病理組織学的スコア)に対し、大腸損傷の程度に基づいてスコア化された。大腸損傷の病理組織学的評価は、試験終了後、Leica(登録商標)DM2500顕微鏡を用いて10倍の倍率で、ヘマトキシリンおよびエオシンで染色した、ホルマリン固定された大腸の組織切片で行われた。プラセボ群は、化合物Aなしの同様の組成物が与えられた。結果は、図1a〜図1d (*P<0.05、対プラセボ/ビヒクル{化合物Aなしの組成物})、図5および図8で与えられる。
例5の上で与えられた手順と同様に、化合物Aの医薬組成物は、腹腔内経路および口腔経路を介して、TNBS誘発性大腸炎を有するマウスにおいて、1日2回投与された。処置された動物は、疾患活動性指数の改善および大腸の健康状態(肉眼検査スコア)について分析された。結果は図6aおよび6bにまとめられている。
飲用水に溶解された5%のDSS(MW−36000〜50000)は、11日間、雌のBALB/cマウスに提供され(Gunther et al, The Journal of Pharmacology and Experimental Therapeutics, 1999; Vol. 292, No. 1; 22-30)、その後、14日目までの期間はDSSなしであった。化合物Aを含む医薬組成物は、5日目から14日目まで、化合物Aの1および2.5mg/kgの用量で、1日2回、10ml/kgの投与量で口腔経路(PO)によって、これらの動物に投与された。プラセボ群には、化合物Aなしの同様の組成物が与えられた。プラセボ(化合物Aなしの組成物)は健康な動物にも投与され、これは飲用水のみを与えられ、プラセボ(水)として表された。体重減少における処置関連の減衰、疾患活性指数の改善(DAI、体重減少、糞便の硬さおよび糞便中の潜血の有無を考慮した0から最大12までの範囲の集成値)、および大腸組織病理学(スコア)は、化合物Aの有効性を確認するため、10日間処置された動物(5日目から14日目に)において確立された。体重は、毎日モニターされ、1日おきにDAIは記録され、その一方で、例5と同様に、大腸損傷の病理組織学的評価は、試験終了後にホルマリン固定された大腸組織で行われた。結果は、図2a〜図2c(*P<0.05 対プラセボ(5%DSS))および図4にまとめられている。
飲用水に溶解した5%のDSS(MW−36000〜50000)を7日間の雌のBALB/cマウスに提供した。化合物Aを含む医薬組成物は、10ml/kgの投与量で、経口で化合物Aの1mg/kgの用量で、腹腔内で化合物Aの0.25mg/kgの用量で、これらの動物に5日目から1日2回投与された。
飲用水に溶解させた、5%DSS(MW−36000〜50000)を、9日間の試験期間を通じて雌のBALB/cマウスに提供した。化合物Aの1mg/kgの用量での化合物Aを含む医薬組成物の単回投与は、10ml/kgの投与量で、5日目に、経口的に行われた。糞便は、組成物の投与96時間後に回収された。集めた糞便は、LC−MS/MS法を用いて、化合物Aの濃度について分析した。結果は、表3にまとめられている。
HSP70の発現に対する化合物Aの医薬組成物の経口投与の効果を、大腸炎のDSSモデルにおいて確認した。飲用水に溶解した5%のDSS(MW−36000〜50000)を5日間雌のBALB/cマウスに提供した。化合物Aの単回投与は、5日目にこれらの動物に投与された。化合物Aを含む組成物は、口腔経路(PO)10ml/kgの投与量で、2.5mg/kgの用量で投与された。プラセボ群は、化合物Aなしで同様の組成物を与えられた。投与6時間後、動物をサクリファイスし、結腸を全組織抽出物の調製のために処理した。タンパク質は、SDS−PAGEで分離され、その後、HSP70抗体を用いて、イムノブロッティングされた。結果は図2dに示される。
インターロイキン(IL)−10、TNF−α、およびインターフェロン(INF)−γのmRNAの発現に対する化合物Aの医薬組成物の経口投与の効果は、大腸炎のDSSモデルで評価された。
Claims (9)
- 2.5mg〜60mgの量の[(2−ヒドロキシ−4−オキソ−6,7,8,9−テトラヒドロ−4H−,5H−10−チア−l,4a−ジアザ−ベンゾ[a]アズレン−3−カルボニル)−アミノ]−酢酸またはその薬学的に許容し得る塩、および、希釈剤、結合剤、崩壊剤、pH調整剤および潤滑剤から選択される少なくとも1つの薬学的に許容し得る担体を含む低用量医薬組成物であって、該組成物が炎症性腸疾患の処置に有効である、前記低用量医薬組成物。
- [(2−ヒドロキシ−4−オキソ−6,7,8,9−テトラヒドロ−4H,5H−10−チア−l,4a−ジアザ−ベンゾ[a]アズレン−3−カルボニル)−アミノ]−酢酸またはその薬学的に許容し得る塩、および、希釈剤、結合剤、崩壊剤、pH調整剤および潤滑剤から選択される少なくとも1つの薬学的に許容し得る担体を含む低用量医薬組成物であって、該組成物が炎症性腸疾患の処置に、1日あたり2.5mg〜60mgの用量範囲で有効である、前記低用量医薬組成物。
- 非腸管外投与のための、請求項1または2に記載の低用量医薬組成物。
- 非腸管外投与が口腔である、請求項3に記載の低用量医薬組成物。
- ヒトにおける炎症性腸疾患の処置のための低用量医薬組成物の製造のための2.5mg〜60mgの範囲における[(2−ヒドロキシ−4−オキソ−6,7,8,9−テトラヒドロ−4H,5H−10−チア−l,4a−ジアザ−ベンゾ[a]アズレン−3−カルボニル)−アミノ]−酢酸またはその薬学的に許容し得る塩の使用。
- 低用量医薬組成物が1日あたり2.5mg〜60mgの用量範囲で有効である、請求項5に記載の使用。
- 低用量医薬組成物が、希釈剤、結合剤、崩壊剤、pH調整剤および潤滑剤から選択される少なくとも1つの薬学的に許容し得る担体をさらに含む、請求項5または6に記載の使用。
- ヒトにおける炎症性腸疾患を処置するための、2.5mg〜60mgの量の[(2−ヒドロキシ−4−オキソ−6,7,8,9−テトラヒドロ−4H−,5H−10−チア−l,4a−ジアザ−ベンゾ[a]アズレン−3−カルボニル)−アミノ]−酢酸またはその薬学的に許容し得る塩を含む低用量医薬組成物。
- 希釈剤、結合剤、崩壊剤、pH調整剤および/または潤滑剤から選択される少なくとも1つの薬学的に許容し得る担体をさらに含む、請求項8に記載の低用量医薬組成物。
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IN1718/MUM/2013 | 2013-05-14 | ||
IN2309MU2013 | 2013-07-09 | ||
IN2309/MUM/2013 | 2013-07-09 | ||
PCT/IB2014/000707 WO2014184631A1 (en) | 2013-05-14 | 2014-05-12 | Use of a thiazolo pyrimidinone for the treatment of inflammatory bowel disease |
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