JP2019530711A - アピリモド組成物およびそれをアルツハイマー病の処置に使用するための方法 - Google Patents
アピリモド組成物およびそれをアルツハイマー病の処置に使用するための方法 Download PDFInfo
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- JP2019530711A JP2019530711A JP2019519652A JP2019519652A JP2019530711A JP 2019530711 A JP2019530711 A JP 2019530711A JP 2019519652 A JP2019519652 A JP 2019519652A JP 2019519652 A JP2019519652 A JP 2019519652A JP 2019530711 A JP2019530711 A JP 2019530711A
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Abstract
Description
[14] 本明細書中で用いる用語“医薬的に許容できる塩”は、たとえば酸と本明細書に記載する化合物(たとえば、2−[2−ピリジン−2−イル)−エトキシ]−4−N’−(3−メチル−ベンジリデン)−ヒドラジノ]−6−(モルホリン−4−イル)−ピリミジン)の塩基性基から形成される塩である。具体的な塩類には下記のものが含まれるが、それらに限定されない:硫酸塩、クエン酸塩、酢酸塩、シュウ酸塩、クロリド、ブロミド、ヨージド、硝酸塩、硫酸水素塩、リン酸塩、酸性リン酸塩、イソニコチン酸塩、乳酸塩、サリチル酸塩、酸性クエン酸塩、酒石酸塩、オレイン酸塩、タンニン酸塩、パントテン酸塩、酒石酸水素塩、アスコルビン酸塩、コハク酸塩、マレイン酸塩、ベシル酸塩、ゲンチシン酸塩、フマル酸塩、グルコン酸塩、グルカロネート(glucaronate)、サッカリン酸塩、ギ酸塩、安息香酸塩、グルタミン酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、p−トルエンスルホン酸塩、およびパモ酸塩(たとえば、1,1’−メチレン−ビス−(2−ヒドロキシ−3−ナフトエ酸塩)。好ましい態様において、アピリモドの塩はメタンスルホン酸塩を含む。用語“医薬的に許容できる塩”は、酸性官能基、たとえばカルボン酸官能基をもつ本明細書に記載する化合物(たとえば、2−[2−ピリジン−2−イル)−エトキシ]−4−N’−(3−メチル−ベンジリデン)−ヒドラジノ]−6−(モルホリン−4−イル)−ピリミジン)と、医薬的に許容できる無機塩基または有機塩基から製造される塩をも表わす。
[26] 本開示は、その必要がある対象において、対象に療法有効量のアピリモド、またはその医薬的に許容できる塩、溶媒和物、包接化合物、水和物、多型、代謝産物、プロドラッグ、アナログもしくは誘導体を投与することにより、アルツハイマー病を含めた認知症を処置するための方法を提供する。本開示はさらに、アルツハイマー病の処置に有用な医薬を製造するための、アピリモド、またはその医薬的に許容できる塩、溶媒和物、包接化合物、水和物、多型、代謝産物、プロドラッグ、アナログもしくは誘導体の使用を提供する。
[49] 本開示は、ある量のアピリモド、またはその医薬的に許容できる塩、溶媒和物、包接化合物、水和物、多型、代謝産物、プロドラッグ、アナログもしくは誘導体を、少なくとも1種類の医薬的に許容できる賦形剤またはキャリヤーと組み合わせて含む医薬組成物を提供し、その量は疾患または障害を処置するために有効である。複数の態様において、疾患または障害は認知症およびアルツハイマー病から選択される。
[62] 医薬組成物は、非経口投与に適した無菌、水性の液剤または分散液剤の形態であってもよい。本明細書中で用いる非経口という用語には、皮下、皮内、静脈内、筋肉内、関節内、動脈内、滑液包内、胸骨内、クモ膜下、病巣内、および頭蓋内の注射または注入法が含まれる。
[68] アミロイド前駆体タンパク質(APP)を、プロテアーゼにより、まずベータセクレターゼ(BACE1)、続いてガンマセクレターゼにより処理して、アミロイドベータ(Ab)と命名される40および42アミノ酸のサイズのもの、たとえばAb 1−40およびAb 1−42を含むペプチドフラグメントを生成させることができる。APP遺伝子における家族性アルツハイマー病関連の幾つかの変異およびトランケート型変異が、インビトロおよびインビボでのAPPからAbへのプロセシングの研究に記載されている。ここに提示するデータは、インビトロモデル系においてアピリモド処理によってAbが用量依存症で低減することを立証する。要約すると、2つの構築体を用いてAbを生成させた:(1)695アミノ酸APP構築体におけるAPP Swedish/Indiana二重変異体(APPSw−I)は、Swedish変異体APP K670N、M671L(Mullan M et al, A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet., 1992 Aug;1(5):345-7)とIndiana変異体APP V717F(Suzuki N et al, An increased percentage of long amyloid beta protein secreted by familial amyloid beta protein precursor (beta APP717) mutants. Science, 1994 May 27; 264(5163):1336-40)を組み合わせたものである;および(2)APP 695の最後の99アミノ酸をコードするC99 APPトランケート型変異体(C99)フラグメント:この構築体は、Aβの主Asp+1部位におけるBACE1開裂APPを模倣して、C99を生成させたものである。
実施例2:コンピューター法により同定したアピリモドについての有望な適応症としてのアルツハイマー病
[74] コンピューターによる薬物再開発(drug repurposing)法を用いてアピリモドについて新規適応症を同定した。この解析のコアアルゴリズムにより、多数の細胞株において種々の濃度のアピリモドによって種々の時点で誘導される遺伝子発現プロフィールを、多数の疾患の遺伝子発現シグネチャーと比較した。この比較を実施するために、210の疾患発現シグネチャーから構成される疾患データベースを作成した;それには、種々の組織タイプにおいて対照/正常試料と患者試料の間で有意に変化した遺伝子が含まれていた。そのデータベースには疾患当たり多数の発現シグネチャー、および多数の疾患カテゴリーが含まれていた(図3)。
Claims (17)
- 認知症の処置を必要とする対象において認知症を処置するための方法であって、対象の細胞においてアミロイド前駆体タンパク質(APP)がプロセシングされてアミロイドベータ(Ab)ペプチドになるのを阻害するのに有効な量のアピリモドを含む医薬組成物を対象に投与することを含む方法。
- 細胞が神経細胞である、請求項1に記載の方法。
- 医薬組成物が経口剤形である、請求項1に記載の方法。
- さらに、少なくとも1種類の追加薬剤を対象に投与することを含む、請求項1に記載の方法。
- 少なくとも1種類の追加薬剤が療法薬である、請求項4に記載の方法。
- 療法薬がコリンエステラーゼ阻害薬である、請求項5に記載の方法。
- 少なくとも1種類の追加薬剤がアピリモドと同じ剤形で投与される、請求項4〜6のいずれか1項に記載の方法。
- 少なくとも1種類の追加薬剤がアピリモドと異なる剤形で投与される、請求項4〜6のいずれか1項に記載の方法。
- 剤形が経口剤形である、請求項7または8に記載の方法。
- 認知症がアルツハイマー病である、請求項1〜9のいずれか1項に記載の方法。
- その方法が患者においてアルツハイマー病の少なくとも1つの症状を軽減するのに有効であるか、あるいは患者においてアルツハイマー病の進行を遅延させるのに有効である、請求項10に記載の方法。
- アピリモドが2−[2−ピリジン−2−イル)−エトキシ]−4−N’−(3−メチル−ベンジリデン)−ヒドラジノ]−6−(モルホリン−4−イル)−ピリミジン(IUPAC名:(E)−4−(6−(2−(3−メチルベンジリデン)ヒドラジニル)−2−(2−ピリジン−2−イル)エトキシ)ピリミジン−4−イル)モルホリン)である、請求項1〜11のいずれか1項に記載の方法。
- 細胞においてアミロイド前駆体タンパク質(APP)がプロセシングされてアミロイドベータ(Ab)ペプチドになるのを阻害するための方法であって、その細胞をAPPがプロセシングされてAbペプチドになるのを阻害するのに有効な量のアピリモドと接触させることを含む方法。
- 細胞がインビトロまたはインビボにある、請求項13に記載の方法。
- 細胞が組織の一部である、請求項14に記載の方法。
- 組織が神経組織である、請求項15に記載の方法。
- アピリモドが2−[2−ピリジン−2−イル)−エトキシ]−4−N’−(3−メチル−ベンジリデン)−ヒドラジノ]−6−(モルホリン−4−イル)−ピリミジン(IUPAC名:(E)−4−(6−(2−(3−メチルベンジリデン)ヒドラジニル)−2−(2−ピリジン−2−イル)エトキシ)ピリミジン−4−イル)モルホリン)である、請求項13〜16のいずれか1項に記載の方法。
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