JP2020520964A - Apoe4アレルを有する患者亜集団におけるアルツハイマー病の治療での使用のための5−ht6受容体アンタゴニストとアセチルコリンエステラーゼ阻害剤の組み合わせ - Google Patents
Apoe4アレルを有する患者亜集団におけるアルツハイマー病の治療での使用のための5−ht6受容体アンタゴニストとアセチルコリンエステラーゼ阻害剤の組み合わせ Download PDFInfo
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Abstract
Description
本発明の発明者らは、驚くべきことに、軽度から中等度のアルツハイマー病を有する患者におけるアセチルコリンエステラーゼ阻害剤に対する追加治療としてのイダロピルジンが、ドネペジル単独療法と比較して認知能力の有意な改善を全く生み出さなかったが、ドネペジル単独療法と比較した認知能力の有意な改善が、軽度から中等度のアルツハイマー病(MMSE 12〜22)を有するAPOE4ホモ接合体患者及びAPOE4ヘテロ接合体患者においてドネペジルに対する追加治療としてのイダロピルジンにより達成されたことを見いだした。
下記において、本発明の実施形態が開示される。第1の実施形態はE1と表され、第2の実施形態はE2と表されるなどである。
本明細書全体で、用語「5−HT6受容体アンタゴニスト」並びにイダロピルジン、AVN−211、又はRVT−101などのあらゆる特異的な5−HT6受容体アンタゴニストは、特記されない限り、遊離塩基及び薬学的に許容できる塩など、その化合物のあらゆる形態を含むものとする。遊離塩基及び薬学的に許容できる塩は、無水の形態及び水和物などの溶媒和された形態を含む。無水の形態は非晶形及び結晶形を含み、溶媒和物は結晶形を含む。さらに、特記されない限り、用語「5−HT6受容体アンタゴニスト」はヒト5−HT6受容体アンタゴニスト(「h5−HT6受容体アンタゴニスト」とも示され得る)を含む。
本発明は、5−HT6受容体アンタゴニストの塩、典型的には薬学的に許容できる塩も含む。そのような塩には薬学的に許容できる酸付加塩がある。酸付加塩は、無機酸並びに有機酸の塩を含む。
本発明は、治療上有効な量の5−HT6受容体アンタゴニスト及び薬学的に許容できる担体又は希釈剤を含む医薬組成物をさらに提供する。本発明は、治療上有効な量の1種の5−HT6受容体アンタゴニスト及び薬学的に許容できる担体又は希釈剤を含む医薬組成物も提供する。
5−HT6アンタゴニストの投与レジメンはアンタゴニストの実際の薬物動態プロファイルによるだろうが、一般的に投与量範囲は1日1回又は2回投与される5〜200mg/日だろう。イダロピルジンでは、好ましい投与量範囲は、1日1回又は2回、好ましくは1日1回投与される10〜120mg/日である。イダロピルジンの好ましい投与量範囲は、BID又はQD投与される60〜120mg/日である。
実施例1:イダロピルジンの結合親和性、アッセイ及び結果
以前に、イダロピルジンの5−HT結合親和性は、Arnt J,et al.Lu AE58054,a 5−HT6 receptor antagonist,reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats.Int J Neuropsychopharmacol 2010;13:1021−1033に記載のとおり決定された。報告された結果は、N−(2−(6−フルオロ−1H−インドール−3−イル)−エチル)−3−(2,2,3,3−テトラフルオロプロポキシ)−ベンジルアミンが、ヒト5−HT6受容体及び他のヒト5−HT受容体サブタイプに対して以下の親和性を有する強力で選択的なヒト5−HT6受容体アンタゴニストであることを示す。
第III相プログラムは、H.Lundbeck A/S(HLu)により資金調達され、軽度から中等度のAD(スクリーニング時にMMSE 12〜22)を有する50才以上の患者におけるAChEIに対する追加治療としてのイダロピルジンの3つの24週二重盲検並行群プラセボ対照固定用量(10、30、及び60mg QD)試験からなっていた。
以下の表において、ADAS−cog及びNPIの負の効果値は良好な治療効果を反映する一方で、ADL及びMMSEでは正の効果値が良好な治療効果を反映する。
Claims (16)
- アルツハイマー病の、アセチルコリンエステラーゼ阻害剤の使用をさらに含む治療での使用のための5−HT6受容体アンタゴニスト又はその薬学的に許容できる塩であって、アルツハイマー病患者が1又は2つのApoE4アレルを有する使用のための5−HT6受容体アンタゴニスト又はその薬学的に許容できる塩。
- 前記5−HT6受容体アンタゴニストが、N−(2−(6−フルオロ−1H−インドール−3−イル)−エチル)−3−(2,2,3,3−テトラフルオロプロポキシ)−ベンジル−アミン、3−ベンゼンスルホニル−5,7−ジメチル−2−メチルスルファニル−ピラゾロ[1,5−a]ピリミジン及び3−フェニルスルホニル−8−ピペラジン−1−イル−キノリン又はその薬学的に許容できる塩からなる群から選択される、請求項1に記載の使用のための5−HT6受容体アンタゴニスト又はその薬学的に許容できる塩。
- 前記5−HT6受容体アンタゴニストが、N−(2−(6−フルオロ−1H−インドール−3−イル)−エチル)−3−(2,2,3,3−テトラフルオロプロポキシ)−ベンジルアミンの薬学的に許容できる塩である、請求項1に記載の使用のための5−HT6受容体アンタゴニスト又はその薬学的に許容できる塩。
- 前記5−HT6受容体アンタゴニストが、N−(2−(6−フルオロ−1H−インドール−3−イル)−エチル)−3−(2,2,3,3−テトラフルオロプロポキシ)−ベンジルアミンの塩酸塩である、請求項1に記載の使用のための5−HT6受容体アンタゴニスト又はその薬学的に許容できる塩。
- 前記アセチルコリンエステラーゼ阻害剤が、ドネペジル、リバスチグミン及びガランタミン又はその薬学的に許容できる塩からなる群から選択される、請求項1に記載の使用のためのアセチルコリンエステラーゼ阻害剤。
- 前記アセチルコリンエステラーゼ阻害剤がドネペジルの塩酸塩である、請求項1に記載の使用のためのアセチルコリンエステラーゼ阻害剤。
- 前記5−HT6受容体アンタゴニストがN−(2−(6−フルオロ−1H−インドール−3−イル)−エチル)−3−(2,2,3,3−テトラフルオロプロポキシ)−ベンジルアミンの塩酸塩であり、前記アセチルコリンエステラーゼ阻害剤がドネペジルの塩酸塩である、請求項1に記載の使用のための5−HT6受容体アンタゴニスト及びアセチルコリンエステラーゼ阻害剤。
- 投薬範囲が60mg/日〜120mg/日である、請求項3〜7のいずれか一項に記載の使用のための5−HT6受容体アンタゴニスト。
- 前記アルツハイマー病患者がAPOE4ヘテロ接合体患者である、請求項1〜8のいずれか一項に記載の使用のための5−HT6受容体アンタゴニスト。
- 前記アルツハイマー病患者がAPOE4/4ホモ接合体患者である、請求項1〜8のいずれか一項に記載の使用のための5−HT6受容体アンタゴニスト。
- 前記アルツハイマー病患者が、軽度から中等度のアルツハイマー病と診断されたAPOE4/4ホモ接合体患者である、請求項1〜8のいずれか一項に記載の使用のための5−HT6受容体アンタゴニスト。
- 前記アルツハイマー病患者が、軽度から中等度のアルツハイマー病と診断されたAPOE4ヘテロ接合体患者である、請求項1〜8のいずれか一項に記載の使用のための5−HT6受容体アンタゴニスト。
- 5−HT6受容体アンタゴニスト又はその薬学的に許容できる塩及びアセチルコリンエステラーゼ阻害剤又はその薬学的に許容できる塩を含む医薬組成物。
- 前記5−HT6受容体アンタゴニストがN−(2−(6−フルオロ−1H−インドール−3−イル)−エチル)−3−(2,2,3,3−テトラフルオロプロポキシ)−ベンジルアミン又はその薬学的に許容できる塩であり、前記アセチルコリンエステラーゼ阻害剤がドネペジル又はその薬学的に許容できる塩である、請求項13に記載の医薬組成物。
- 前記5−HT6受容体アンタゴニストがN−(2−(6−フルオロ−1H−インドール−3−イル)−エチル)−3−(2,2,3,3−テトラフルオロプロポキシ)−ベンジルアミンの塩酸塩であり、前記アセチルコリンエステラーゼ阻害剤がドネペジルの塩酸塩である、請求項13に記載の医薬組成物。
- アルツハイマー病を治療する方法であって、アルツハイマー病患者が1又は2つのApoE4アレルを有し、前記患者がアセチルコリンエステラーゼ阻害剤で治療されており、前記方法がさらなる投与5−HT6受容体アンタゴニスト又はその薬学的に許容できる塩を含む方法。
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