JP6200561B2 - 統合失調症を処置するための環状アミド誘導体の使用の方法 - Google Patents
統合失調症を処置するための環状アミド誘導体の使用の方法 Download PDFInfo
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Classifications
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
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- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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Description
陽性症状は一般に、通常は存在するはずのない意識中の何かの経験を含む。例えば、幻覚および妄想は、通常は経験するはずのない知覚または信念を表す。幻覚および妄想に加えて、統合失調症を有する患者は頻繁に彼らの思考の論理プロセスにおいて顕著な乱れを有する。具体的には、精神病性の思考プロセスは特徴的に散漫、無秩序、非論理的、または奇妙である。思考プロセスにおけるこれらの乱れは、やはり無秩序で奇妙である人目を引く行動のパターンを頻繁にもたらす。陽性症状を構成する思考の内容およびプロセスの重篤な乱れは、しばしば統合失調症の最も認識できる目立つ特徴である。
陽性症状が通常は経験しない何かの存在を表す一方で、陰性症状はそうでなければ期待されたであろう思考および行動が存在しないことを反映し、従って通常の機能の低下もしくは喪失または通常の行動の低下もしくは喪失を反映する。統合失調症の陰性症状には、例えば平担な情動または情動鈍麻、明確な思考(concrete thoughts)、快感消失(楽しさを経験することができないこと)、乏しい動機付け、自発性、およびイニシアチブが含まれる。思考の硬直性または堅さは、抽象的に考える能力の欠陥を表す。情動の鈍麻は、感情を表現する能力の全般的な低減を意味する。動機付けの失敗および活動を開始できないことは、統合失調症における長期の能力障害の重要な源を意味する。快感消失は、楽しみを経験する能力および楽しい状況に適切に反応する能力における欠陥を反映している。
“BACS”は統合失調症認知機能簡易評価(Brief Assessment of Cognition in Schizophrenia)試験を意味する。
“HAMA”はハミルトン不安尺度(Hamilton Anxiety Scale)を意味する。
“PSQI”はピッツバーグ睡眠質指数(Pittsburgh Sleep Quality Index)を意味する。
一態様において、それを必要とする対象に療法上有効量の上記で述べたような式(I)の化合物または医薬的に許容できる塩を投与することを含む、対象において統合失調症の少なくとも1種類の陰性症状を処置するための方法が提供される。一態様において、その化合物が式IIで示した化合物である方法が提供される。別の態様において、その化合物が式IIIで示した化合物である方法が提供される。
(例えば、外部刺激により生成されたのではない、聴覚的、視覚的、嗅覚的、または肉体的領域において生じる可能性のある知覚を示す、言葉での報告または行動)、活動亢進および興奮(例えば、速められた運動挙動、刺激に対する高められた反応性、過覚醒、または過剰な気分の易変性)、誇大的態度(非凡な能力、富、知識、名声、力、および道徳的正しさの妄想を含む、誇張された自己評価および非現実的な優越の確信)、疑い深さ/迫害(例えば、用心深さ、邪推深い態度、疑い深い過覚醒、または他人が自分に危害を加えようとしているという露骨な妄想において反映されるような、非現実的または誇張された迫害の観念)、ならびに敵意(例えば、嫌味、受動的−攻撃的行動、暴言、および攻撃性が含まれる、言語による、および言語によらない怒りおよび憤慨の表現)が含まれるが、それらに限定されない。他の陽性症状およびその例は、例えば上記で参照したPANSS尺度において見つけることができる。
本発明に従う療法的投与に関して、式Iの化合物はその遊離塩基の形で用いることができるが、好ましくは医薬的に許容できる塩、典型的には塩酸塩の形で用いられる。
一態様において、式Iの化合物またはその医薬的に許容できる塩は、効率的2D6代謝者である対象に投与される。当業者には理解されるであろうように、効率的2D6代謝者は、平均的な2D6代謝活性を有する、または平均的な2D6代謝活性より大きい2D6代謝活性を有する対象である。
別の態様において、式Iの化合物またはその医薬的に許容できる塩は、1種類以上の他の薬物療法と合わせて投与される。そのような他の薬物療法は、当技術で既知の形態および投与量で、または代替策において、上記で式Iの化合物の投与に関して記述したように投与または同時投与されてよい。
一態様において、式Iの化合物は、患者に少なくとも1種類の神経遮断薬と合わせて、または既に少なくとも1種類の神経遮断薬を用いた処置を受けている患者に、統合失調症の陰性症状、統合失調症の陽性症状、統合失調症の一般症状のあらゆる組み合わせの向上した処置、または統合失調症自体の処置を提供するために投与されてよい。1態様において、式Iの化合物の投与はその神経遮断薬の療法上有効量を達成するのに必要なその神経遮断薬の濃度を低くする。一観点において、式Iの化合物はその神経遮断薬に相乗作用を提供する。
統合失調症および統合失調症の症状の処置への有効性を調べるため、式IIの化合物を用いて試験を実施した。その試験は、DSM−IV統合失調症を有する患者における、多施設での、入院患者および通院患者の、2相の、二重盲検の、ランダム化された、プラセボを対照とした式IIの化合物の概念実証試験であった。その試験は3つの異なる国にわたって21の施設を用いた。
その試験の目的には、以下のことが含まれていた:
1.主要:処置の1ヵ月後のPANSS総スコアおよびサブスコア。
2.二次的:処置の3ヵ月後のPANSS総スコアおよびサブスコア、CGI−Sスコア、DAI−10スコア、PSQIスコア、BACS試験スコア、MADRS総スコア、およびHAMA総スコア、退院準備質問票(Readiness of Discharge Questionnaire)(RDQ)。
4.安全性:12誘導ECG、有害事象(AE)の記録、生命徴候、身体検査、体重および腹囲、安全性実験室試験、錐体外路系症状の評価(シンプソン・アンガス尺度により測定)、ならびにプロラクチンレベル。
用いた統計的方法は以下の通りである:
1.主要有効性変数:完全分析セット(FAS)に対する、処置の1ヶ月後の、PANSS総スコアおよびサブスコアに関するベースラインからの変化についての、処置および施設を固定効果、ならびにベースラインの値を共変数とした共分散分析(ANCOVA)。
その結果は、錐体外路系症状の出現または悪化に関して、CYR−101およびプラセボグループの間で有意な差を示さなかった。3件の統計的に重要な有害事象(SAE)があり、その内の2件はプラセボグループにおいてであった。有効処置グループにおける1件のSAEは、患者の病歴に基づいて、CYR−101に関連するとは考えられなかった。
処置の1ヵ月後の(D28における)PANSS総スコアにおけるベースラインからの変化は、有効性の主要な基準である。D28において、FASにおいて、PANSS総スコア、PANSS一般精神病理学サブスコアおよびPANSS陽性サブスコアは、両方のグループにおいて減少を示し、プラセボおよびCYR−101グループの間での処置による差はない。
PSQIの結果は、FASにおいて、睡眠の質が両方のグループに関してその試験の終了時によりよかったことを示している。この向上は、プラセボグループ(−1.4ポイント±6.6)と比較してCYR−101グループ(−4ポイント±4.9)においてより大きかった。FASの結果と同様に、PPCのデータは、睡眠の質が両方のグループに関してその試験の終了時によりよかったことを示している。この向上は、プラセボグループ(−1.2ポイント±6.2)と比較してCYR−101グループ(−4.6ポイント±4.3)においてより大きかった。
D28およびD84において、FASにおいて、結果は両方のグループにおけるわずかなHAMA総スコアの低減を示しており、ベースラインからの統計的に有意な変化はない。PPCにおける時間経過パターンはD28において異なっており、両グループの間に統計的に有意な処置による差はないにもかかわらず、データはプラセボおよびCYR−101に関してそれぞれ−1.6(p=0.1000)および−1.0(p=0.2920)の有意な低減を示している。D84において、CYR−101を支持する転換がある。両方のグループが数値の低減を示し、それはCYR−101グループにおいてプラセボグループと比較してより大きい:−2.2(p=0.1523)および−2.9(p=0.0642)。
本明細書にそのまま援用する米国特許第7,166,617号は、CYR−101のシグマ2受容体部位への優先的な結合を説明している。米国特許第7,166,617号の実施例1の試験化合物がCYR−101である。米国特許第7,166,617号の表3で説明されているように、CYR−101はシグマ2受容体に関して13nMの親和性を有する。このデータは、CYR−101はシグマ2に選択的な受容体結合を示すことを説明している。さらに、CYR−101は5−HT2A/シグマ2拮抗薬であり、ドーパミン結合特性を欠いていることが知られている。
CYR−101の睡眠への作用の試験はCYR−101が統合失調症の患者において睡眠を改善すること示唆しており、それはより一般的に睡眠障害の処置に有用である可能性がある。
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