JP6042436B2 - 二重活性H1インバースアゴニスト/5−HT2Aアンタゴニストとしての(チエノ[2,3−b][1,5]ベンゾオキサゼピン−4−イル)ピペラジン−1−イル化合物 - Google Patents
二重活性H1インバースアゴニスト/5−HT2Aアンタゴニストとしての(チエノ[2,3−b][1,5]ベンゾオキサゼピン−4−イル)ピペラジン−1−イル化合物 Download PDFInfo
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- JP6042436B2 JP6042436B2 JP2014528453A JP2014528453A JP6042436B2 JP 6042436 B2 JP6042436 B2 JP 6042436B2 JP 2014528453 A JP2014528453 A JP 2014528453A JP 2014528453 A JP2014528453 A JP 2014528453A JP 6042436 B2 JP6042436 B2 JP 6042436B2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Epidemiology (AREA)
- Anesthesiology (AREA)
- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
またはその薬学的に許容される塩を提供する。すなわち、3−[4−(2,8−ジメチルチエノ[2,3−b][1,5]ベンゾオキサゼピン−4−イル)ピペラジン−1−イル]−2,2−ジメチルプロパン酸またはその薬学的に許容される塩である。
「ブライン」は飽和NaCl水溶液を意味する。
「DMEM」はDulbeccoの最小Eagle培地を意味する。
「DMSO」はジメチルスルホキシドを意味する。
「EDTA」はエチレンジアミン四酢酸を意味する。
「equiv」は当量を意味する。
「FBS」はウシ胎仔血清を意味する。
「HEPES」は4−(2−ヒドロキシエチル)−1−ピペラジンエタンスルホン酸を意味する。
「HPLC」は高圧液体クロマトグラフィーを意味する。
「hr.」は時間を意味する。
「IC50」は、最大阻害の50%が達成される濃度を意味する。
「LC−MS」はHPLC−質量分析法を意味する。
「MeOH」はメタノールを意味する。
「min.」は分を意味する。
「MS」は質量分析法を意味する。
「MS(ES+)」はエレクトロスプレーイオン化を使用する質量分析法を意味する。
「NMR」は核磁気共鳴を意味する。
「RO」は受容体占有を意味する。
「THF」はテトラヒドロフランを意味する。
本発明の化合物は以下の合成例に従って調製することができる。
H1競合結合アッセイ
[3H]−ピリラミン結合実験をSPA(シンチレーション近接アッセイ)96ウェル形式において実行する。このアッセイにおいて使用する膜を組換えH1受容体(ヒト)を安定的に発現するHEK−293細胞から調製する。インキュベーションは、3.5nMの[3H]−ピリラミンおよび変動する濃度の試験化合物(濃度応答曲線の10点)を含有するアッセイバッファー(67mMトリス;pH7.6)へ、WGA PVT SPAビーズ(1mg/ウェル、Perkin Elmer(MA、USA)RPNQ0001)および3μgの膜混合物を添加することによって開始する。非特異的結合は10μMのトリプロリジンの存在下において決定する。サンプルを室温(22℃)で4時間インキュベーションし、次いでMicrobeta Triluxにおいて読み取る。
[3H]−ケタンセリン結合実験をSPA 96ウェル形式において実行する。このアッセイにおいて使用する膜を組換え5−HT2A受容体(ヒト)を安定的に発現するAV−12細胞から調製する。インキュベーションは、3.1nMの[3H]−ケタンセリンおよび変動する濃度の試験化合物(10ポイント濃度応答曲線)を含有するアッセイバッファー(67mMトリス、0.5mM EDTA;pH7.6)へ、WGA YSi SPAビーズ(1mg/ウェル、Perkin Elmer(MA、USA)RPNQ0011)および2μgの膜混合物を添加することによって開始する。非特異的結合は20μMの1−(1−ナフチル)ピペラジンの存在下において決定する。サンプルを室温(22℃)で4時間インキュベーションし、次いでMicrobeta Triluxにおいて読み取る。
[125I]−(±)DOI結合実験をSPA 96ウェル形式において実行する。このアッセイにおいて使用する膜を組換え5−HT2C受容体(ヒト)を安定的に発現するAV−12細胞から調製する。インキュベーションは、0.2nM[[125I]−(±)DOIおよび変動する濃度の試験化合物(10ポイント濃度応答曲線)を含有するアッセイバッファー(50mMトリスHCl、10mM MgCl2、0.5mM EDTA、10μMパルギリン、0.1%アスコルビン酸、pH7.4)へ、WGA PVT SPAビーズ(0.5mg/ウェル、Perkin Elmer(MA、USA)、RPNQ0001)および2.5μgの膜混合物の添加によって開始する。非特異的結合は20μMの1−(1−ナフチル)ピペラジンの存在下において決定する。サンプルを室温(22℃)で4時間インキュベーションし、次いでMicrobeta Triluxにおいて読み取る。
4パラメータのロジスティック非線形方程式を使用して曲線を評価して、放射性リガンド結合の50%阻害を引き起こす競合物の濃度(IC50)を得る。平衡解離定数(Ki)を方程式Ki=IC50/(1+L/Kd)に従って計算し、式中、Lは実験において使用される放射性リガンドの濃度と等しく、Kdは受容体について放射性リガンドの一定の平衡解離と等しく、標準的な飽和分析または相同な競合実験から決定される。Kiについて報告された値は、n値が示される場合、nによって示される重複した決定の数により幾何平均値±標準誤差(SEM)として示される。幾何平均値は、方程式GeoMean=10^(Average(log Ki 1+ log Ki 2 +...log Ki n)/sqrt n)によって計算される。
ネイティブGABAA受容体に対する化合物の活性は、96ウェルフォーマットFLIPR(登録商標)システム(蛍光イメージングプレートリーダー(FLIPR(登録商標))、Molecular Devices)を使用して、カルシウムフラックスをモニタリングすることによって評価する。簡潔には、胚性皮質ニューロンをE18ラット胚から分離し、黒色壁で囲まれた透明底のポリ−D−リジンコート96ウェルFLIPR(登録商標)プレートの中へ最適の密度でプレーティングする。カルシウム感受性色素(Fluo4−AM、Molecular Devices)と共に細胞をロードした後に、細胞を低塩化物含有溶液(塩化物をグルコン酸塩によって置き換える)中に入れる。これらの条件下で、GABAA受容体の活性化は塩化物イオンの流出を引き起こし(化学勾配の方向において)、電位関門型カルシウムチャンネル(VGCC)の膜脱分極およびしたがって活性化をもたらす。VGCCを介するカルシウム流入を記録し、FLIPR(登録商標)システムを使用してオフラインで分析する。アッセイの薬理学的検証のために、標準的なアゴニスト(GABA)および標準的なアンタゴニスト(ギャバジン)について濃度応答曲線(CRC)を記録する。任意の効果は10μMのアゴニストGABAの固定した濃度(EC90GABA応答と等価)に対するCRCモードにおいて決定される。
化合物のアンタゴニスト効果を、化合物の存在および非存在下におけるアゴニストGABAに対するピーク蛍光応答を比較することによって、10ポイント用量応答曲線を使用して定量化する。アッセイウィンドウは、ギャバジンの完全阻害濃度(50μM)によって得られた応答を引いた、あらかじめ決定したEC90濃度でのGABAによって得られた最大応答として定義される。アンタゴニスト効果はアッセイウィンドウのパーセントとして計算される。すべてのデータは、4パラメータのロジスティック曲線フィッティングプログラム(Prism Graphpad(登録商標)3.01)を使用して、相対的IC50値として計算される。すべての化合物についてのアンタゴニスト効力は、各アッセイランにおける3つの重複測定によりギャバジンに対して比較される。
研究は以下のように行なわれる。
・累積睡眠:分における、処理後最初の6時間にわたるもの(「全睡眠」はNREM睡眠+REM睡眠を示す)。
・平均睡眠バウト:ベヒクル対照に対してn倍増加として表現される、処理後最初の6時間のにわたる1時間ごとの平均化された睡眠バウトの平均。
・最長睡眠バウト:ベヒクル対照に対してn倍増加として表現される、処理後最初の6時間のにおける最長睡眠バウト。
・反跳性不眠症:点灯期間の最初の3時間の間の(すなわち処理後7、8および9時間目)NREM+REM睡眠の累積分。
・REM阻害:処理後最初の12時間の間のREM睡眠の累積分。
・自発運動活性(LMA)強度:処理後最初の6時間にわたって平均化した、EEGで定義した覚醒の1分あたりのカウントをLMAとして表現したもの。
実施例 クリアランス(ml/分/Kg)
ラット イヌ
2 27(±7.3、n=3) 2.8(±1.2、n=3)
以下に、本願の当初の特許請求の範囲に記載された発明を付記する。
[1] 以下の式の化合物
またはその薬学的に許容される塩。
[2] HCl塩である、[1]に記載の化合物。
[3] トシル酸塩である、[1]に記載の化合物。
[4] [1]に記載の化合物またはその薬学的に許容される塩を、少なくとも1つの薬学的に許容される担体、希釈剤または賦形剤と組み合わせて含む、医薬組成物。
[5] 効果的な量の[1]に記載の化合物またはその薬学的に許容される塩を、かかる治療を必要とする哺乳類へ投与することを含む、哺乳類において不眠症を治療する方法。
[6] 前記哺乳類がヒトである、[5]に記載の方法。
[7] 前記不眠症が睡眠開始もしくは睡眠維持の困難またはその両方によって特徴づけられる、[5]に記載の方法。
[8] 前記哺乳類がヒトである、[7]に記載の方法。
[9] 治療法における使用のための[1]に記載の化合物またはその薬学的に許容される塩。
[10] 不眠症の治療における使用のための[1]に記載の化合物またはその薬学的に許容される塩。
[11] 前記不眠症が睡眠開始もしくは睡眠維持の困難またはその両方によって特徴づけられる、[10]に記載の使用のための化合物またはその薬学的に許容される塩。
[12] ヒトにおける[10]または[11]に記載の使用のための化合物。
[13] 不眠症の治療のための医薬品の製造における、[1]に記載の化合物またはその薬学的に許容される塩の使用。
[14] 前記不眠症が、哺乳類における睡眠開始もしくは睡眠維持の困難またはその両方によって特徴づけられる、[13]に記載の使用。
[15] [1]に記載の化合物またはその薬学的に許容される塩を、少なくとも1つの薬学的に許容される担体、賦形剤または希釈剤、および任意に他の治療成分と組み合わせて含む、医薬組成物。
[16] 前記他の治療成分が選択的セロトニン再取込み阻害剤を含む、[15]に記載の医薬組成物。
Claims (9)
- 以下の式の化合物
またはその薬学的に許容される塩。 - HCl塩である、請求項1に記載の化合物。
- トシル酸塩である、請求項1に記載の化合物。
- 請求項1に記載の化合物またはその薬学的に許容される塩を、少なくとも1つの薬学的に許容される担体、希釈剤または賦形剤と組み合わせて含む、医薬組成物。
- 請求項1に記載の化合物またはその薬学的に許容される塩を、少なくとも1つの薬学的に許容される担体、賦形剤または希釈剤、および選択的セロトニン再取込み阻害剤と組み合わせて含む、医薬組成物。
- 請求項1に記載の化合物またはその薬学的に許容される塩を含む、不眠症の治療のための医薬組成物。
- 前記不眠症が睡眠開始もしくは睡眠維持の困難またはその両方によって特徴づけられる、請求項6に記載の医薬組成物。
- 不眠症の治療のための医薬品の製造における、請求項1に記載の化合物またはその薬学的に許容される塩の使用。
- 前記不眠症が哺乳類における睡眠開始もしくは睡眠維持の困難またはその両方によって特徴づけられる、請求項8に記載の使用。
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