JP2020528938A - ガラクトース血症を処置するための組成物および方法 - Google Patents
ガラクトース血症を処置するための組成物および方法 Download PDFInfo
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- JP2020528938A JP2020528938A JP2020527861A JP2020527861A JP2020528938A JP 2020528938 A JP2020528938 A JP 2020528938A JP 2020527861 A JP2020527861 A JP 2020527861A JP 2020527861 A JP2020527861 A JP 2020527861A JP 2020528938 A JP2020528938 A JP 2020528938A
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- galactosemia
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- aldose reductase
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- 229910052725 zinc Inorganic materials 0.000 description 1
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Abstract
Description
本出願は、2017年7月28日に出願された米国仮出願第62/538,443号(これは、その全体が参照により本明細書に組み込まれる)の利益を主張する。
ガラクトース血症は、ガラクトースを代謝する能力の低下または不能に起因する代謝障害である。前記疾患は、典型的には、ガラクトース−1−リン酸ウリジルトランスフェラーゼ(GALT)、ガラクトキナーゼ(GALK)およびガラクトース−6−リン酸エピメラーゼ(GALE)を含む、ルロワール経路に関与する1つまたはそれを超える酵素の欠損により引き起こされる。これらの酵素の1つまたはそれよりも多くの欠損は、ルロワール経路の破壊、ならびにガラクトースおよび特定のガラクトース代謝産物、例えばガラクトース1−リン酸(G1P)およびガラクトネートの蓄積をもたらす。加えて、ガラクトースが蓄積すると、それは、グルコース代謝のポリオール経路の酵素であるアルドースレダクターゼ(AR)の基質になり得る。ARは、通常、ソルビトールへのグルコースの還元(ポリオール経路の最初の段階)を触媒するが、ガラクトースレベルが上昇すると、ガラクトースをガラクチトールに変換することもできる。ガラクトースおよびガラクトース代謝産物の蓄積は、肝臓、中枢神経系(例えば、脳)、腎臓、目および他の身体系への損傷を引き起こし得る(Quan−Maら、Am J Dis Child.,112(5):477−478,1966)。
したがって、ガラクトース血症の処置および/または管理のための方法に対する認識されているが満たされていない必要性がある。
本開示は、ガラクトース血症の処置およびガラクトース血症の合併症の処置または予防を必要とする被験体に治療有効量のAR阻害剤を投与することにより、ガラクトース血症を処置し、ガラクトース血症の合併症を処置または予防するための方法に関する。いかなる特定の理論にも縛られるものではないが、本明細書に記載されるように、ARの阻害は、ガラクチトールの蓄積およびその結果として生じるガラクトース血症に関連する病状を軽減または予防し得ると考えられる。
(a)式I〜VIの化合物および薬学的に許容され得る担体を含む第1の医薬組成物;ならびに
(b)アルポナルレスタット、エパルレスタット、ソルビニルまたはソルビノール、イミレスタット、AND−138、CT−112、ゾポルレスタット、ゼナレスタット、BAL−AR18、AD−5467、M−79175、トルレスタット、アルコニル、スタチル、ベルベリンまたはSPR−210および薬学的に許容され得る担体を含む第2の医薬組成物
を投与することを含む方法に関する。
詳細な説明
I.方法
II.AR阻害剤
式IおよびIIのAR阻害剤
式IV、VおよびVIの化合物
III.組成物
IV.併用療法
V.診断用途
実施例1
結果
結論および考察
実施例2
実施例3
実施例4
本発明は、例えば、以下の項目を提供する。
(項目1)
ガラクトース血症を処置するかまたはガラクトース血症に関連する合併症を予防する方法であって、それを必要とする被験体に治療有効量のアルドースレダクターゼ阻害剤を投与することを含む、方法。
(項目2)
ガラクトース血症を有する被験体におけるガラクチトールの量またはレベルを減少させる方法であって、前記被験体に治療有効量のアルドースレダクターゼ阻害剤を投与することを含む、方法。
(項目3)
白内障を処置するための方法であって、それを必要とする被験体に治療有効量のアルドースレダクターゼ阻害剤を投与することを含む、方法。
(項目4)
前記それを必要とする被験体がガラクトース血症を有する、項目3に記載の方法。
(項目5)
ガラクトース血症に関連する認知的または神経学的な機能不全を処置または予防するための方法であって、ガラクトース血症を有する被験体に治療有効量のアルドースレダクターゼ阻害剤を投与することを含む、方法。
(項目6)
ガラクトース血症に関連する前記認知的または神経学的な機能不全が発話機能障害である、項目5に記載の方法。
(項目7)
ガラクトース血症に関連する前記認知的または神経学的な機能不全が運動失調である、項目5に記載の方法。
(項目8)
ガラクトース血症に関連する前記認知的または神経学的な機能不全が認知機能障害である、項目5に記載の方法。
(項目9)
ガラクトース血症に関連する前記認知的または神経学的な機能不全が偽脳腫瘍である、項目5に記載の方法。
(項目10)
ガラクトース血症に関連する前記認知的または神経学的な機能不全が痙攣である、項目5に記載の方法。
(項目11)
前記アルドースレダクターゼ阻害剤が式I〜VIのいずれか1つの化合物またはそれらの塩である、項目1〜10のいずれか一項に記載の方法。
(項目12)
前記アルドースレダクターゼ阻害剤がゾポルレスタットもしくはその塩またはエパルレスタットもしくはその塩である、項目1〜10のいずれか一項に記載の方法。
(項目13)
前記アルドースレダクターゼ阻害剤が式(II)の化合物またはその塩である、項目1〜10のいずれか一項に記載の方法。
(項目14)
前記アルドースレダクターゼ阻害剤が、以下
またはそれらの塩から選択される、項目13に記載の方法。
(項目15)
前記アルドースレダクターゼ阻害剤が式IIIの化合物である、項目1〜10のいずれか一項に記載の方法。
(項目16)
前記アルドースレダクターゼ阻害剤が、以下
またはそれらの塩から選択される、項目15に記載の方法。
(項目17)
前記被験体がヒトである、項目1〜16のいずれか一項に記載の方法。
(項目18)
前記ガラクトース血症が、血液、尿または眼内液中のアルジトールレベルの増加として前記被験体において現れる、項目1〜17のいずれか一項に記載の方法。
(項目19)
前記アルジトールがガラクチトール、ミオイノシトールまたはソルビトールである、項目18に記載の方法。
(項目20)
前記ガラクトース血症が、肝硬変、網膜障害、黄斑浮腫、目の白内障、卵巣機能障害、筋肉または神経の機能障害、網膜症、ニューロパチー、神経伝導障害または精神遅滞の増加として前記被験体において現れる、項目1〜19のいずれか一項に記載の方法。
(項目21)
前記ガラクトース血症がI型ガラクトース血症(GALT欠損症)である、項目1〜20のいずれか一項に記載の方法。
(項目22)
前記ガラクトース血症がII型ガラクトース血症(GALK欠損症)である、項目1〜20のいずれか一項に記載の方法。
(項目23)
前記ガラクトース血症がIII型ガラクトース血症(GALE欠損症)である、項目1〜10のいずれか一項に記載の方法。
(項目24)
前記アルドースレダクターゼ阻害剤が化合物Aまたはその塩である、前述の項目のいずれか一項に記載の方法。
(項目25)
前記アルドースレダクターゼ阻害剤が化合物Bまたはその塩である、前述の項目のいずれか一項に記載の方法。
Claims (25)
- ガラクトース血症を処置するかまたはガラクトース血症に関連する合併症を予防する方法であって、それを必要とする被験体に治療有効量のアルドースレダクターゼ阻害剤を投与することを含む、方法。
- ガラクトース血症を有する被験体におけるガラクチトールの量またはレベルを減少させる方法であって、前記被験体に治療有効量のアルドースレダクターゼ阻害剤を投与することを含む、方法。
- 白内障を処置するための方法であって、それを必要とする被験体に治療有効量のアルドースレダクターゼ阻害剤を投与することを含む、方法。
- 前記それを必要とする被験体がガラクトース血症を有する、請求項3に記載の方法。
- ガラクトース血症に関連する認知的または神経学的な機能不全を処置または予防するための方法であって、ガラクトース血症を有する被験体に治療有効量のアルドースレダクターゼ阻害剤を投与することを含む、方法。
- ガラクトース血症に関連する前記認知的または神経学的な機能不全が発話機能障害である、請求項5に記載の方法。
- ガラクトース血症に関連する前記認知的または神経学的な機能不全が運動失調である、請求項5に記載の方法。
- ガラクトース血症に関連する前記認知的または神経学的な機能不全が認知機能障害である、請求項5に記載の方法。
- ガラクトース血症に関連する前記認知的または神経学的な機能不全が偽脳腫瘍である、請求項5に記載の方法。
- ガラクトース血症に関連する前記認知的または神経学的な機能不全が痙攣である、請求項5に記載の方法。
- 前記アルドースレダクターゼ阻害剤が式I〜VIのいずれか1つの化合物またはそれらの塩である、請求項1〜10のいずれか一項に記載の方法。
- 前記アルドースレダクターゼ阻害剤がゾポルレスタットもしくはその塩またはエパルレスタットもしくはその塩である、請求項1〜10のいずれか一項に記載の方法。
- 前記アルドースレダクターゼ阻害剤が式(II)の化合物またはその塩である、請求項1〜10のいずれか一項に記載の方法。
- 前記アルドースレダクターゼ阻害剤が、以下
- 前記アルドースレダクターゼ阻害剤が式IIIの化合物である、請求項1〜10のいずれか一項に記載の方法。
- 前記アルドースレダクターゼ阻害剤が、以下
- 前記被験体がヒトである、請求項1〜16のいずれか一項に記載の方法。
- 前記ガラクトース血症が、血液、尿または眼内液中のアルジトールレベルの増加として前記被験体において現れる、請求項1〜17のいずれか一項に記載の方法。
- 前記アルジトールがガラクチトール、ミオイノシトールまたはソルビトールである、請求項18に記載の方法。
- 前記ガラクトース血症が、肝硬変、網膜障害、黄斑浮腫、目の白内障、卵巣機能障害、筋肉または神経の機能障害、網膜症、ニューロパチー、神経伝導障害または精神遅滞の増加として前記被験体において現れる、請求項1〜19のいずれか一項に記載の方法。
- 前記ガラクトース血症がI型ガラクトース血症(GALT欠損症)である、請求項1〜20のいずれか一項に記載の方法。
- 前記ガラクトース血症がII型ガラクトース血症(GALK欠損症)である、請求項1〜20のいずれか一項に記載の方法。
- 前記ガラクトース血症がIII型ガラクトース血症(GALE欠損症)である、請求項1〜10のいずれか一項に記載の方法。
- 前記アルドースレダクターゼ阻害剤が化合物Aまたはその塩である、前述の請求項のいずれか一項に記載の方法。
- 前記アルドースレダクターゼ阻害剤が化合物Bまたはその塩である、前述の請求項のいずれか一項に記載の方法。
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