JP2022518632A - マイトフュージン活性化物質及びその使用方法 - Google Patents
マイトフュージン活性化物質及びその使用方法 Download PDFInfo
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- JP2022518632A JP2022518632A JP2021566929A JP2021566929A JP2022518632A JP 2022518632 A JP2022518632 A JP 2022518632A JP 2021566929 A JP2021566929 A JP 2021566929A JP 2021566929 A JP2021566929 A JP 2021566929A JP 2022518632 A JP2022518632 A JP 2022518632A
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Abstract
Description
本願は、2019年1月28日出願の米国仮出願第62/797,513号の優先権を主張する。
から選択される。
が挙げられる。
が挙げられる。
が挙げられる。
から選択される化合物ではない。
「アルコール」は、第1級、第2級又は第3級アルコールであり得る。
(i)水素結合が親和性に寄与する可能性が高い、より親水性のヒットが得られる(エンタルピーによって駆動される結合)。一般に、疎水性基を付加することによって親和性を高めることは、かなり容易である(エントロピーによって駆動される結合)。親水性リガンドから開始することで、最終的に最適化されたリガンドが疎水性になりすぎない(logP<5)確率が上がる。
(ii)リガンド効率が高いため、最終的に最適化されるリガンドの分子量が比較的小さくなる可能性が高くなる(MW<500Da)。
(iii)理論上は2~3個のフラグメントを組み合わせることにより、最適化されたリガンドが形成され得るので、N個の化合物のフラグメントライブラリーのスクリーニングは、従来のライブラリーにおけるN2~N3個の化合物のスクリーニングに等しい。
マイトフュージン活性化物質又はその薬学的に許容され得る塩のうちの1つ以上を含む治療有効量の組成物を被験体に投与する工程を含み、マイトフュージン活性化物質は、ミトコンドリアの融合を刺激し、ミトコンドリアの細胞内移送を増強する、方法。
R1は、非置換、一置換又は多置換のC3-8シクロアルキル、C3-8ヘテロアリール及びC3-8ヘテロシクリルから選択され、R2は、非置換、一置換又は多置換のC3-8シクロアルキル、C3-8ヘテロアリール及びC3-8ヘテロシクリルから選択される、条項1に記載の方法。
R1又はR2が、必要に応じてさらに、1つ以上のアセトアミド、アルコキシ、アミノ、アゾ、Br、C1-8アルキル、カルボニル、カルボキシル、Cl、シアノ、C3-8シクロアルキル、C3-8ヘテロアリール、C3-8ヘテロシクリル、ヒドロキシル、F、ハロ、インドール、N、ニトリル、O、フェニル、S、スルホキシド、二酸化硫黄及び/又はチオフェンで置換され、アルキル、シクロアルキル、ヘテロアリール、ヘテロシクリル、インドール又はフェニル置換基のうちの1つ以上は、必要に応じてさらに、以下の置換基:アセトアミド、アルコキシ、アミノ、アゾ、Br、C1-8アルキル、カルボニル、カルボキシル、Cl、シアノ、C3-8シクロアルキル、C3-8ヘテロアリール、C3-8ヘテロシクリル、ヒドロキシル、F、ハロ、インドール、N、ニトリル、O、フェニル、S、スルホキシド、二酸化硫黄及びチオフェンのうちの1つ以上で置換される、条項2又は3に記載の方法。
から選択される、条項1~4のいずれか1項に記載の方法。
Xは、シクロアルキル、ヘテロシクロアルキル、アリール及びヘテロアリールから選択され、
Zは、シクロアルキル、ヘテロシクロアルキル、アリール及びヘテロアリールから選択され、
R1及びR2は、独立して、H、F、アルキル及びC3-7シクロアルキルから選択されるか、又はR1とR2とが一体となって、C3-7シクロアルキル又はヘテロシクロアルキルを形成し、
R3及びR4は、独立して、H、F、アルキル、COR7、C3-7シクロアルキルから選択されるか、又はR3とR4とが一体となって、C3-7シクロアルキル又はヘテロシクロアルキルを形成し、
Yは、O、CR5R6、CR7=CR8、三重結合、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、NR7、S、SO2、SONR8、-NR8SO2-、-NR7CO-、-CONR7-及び-NR7CONR8-から選択され、
R5及びR6は、独立して、H、F、アルキル及びシクロアルキルから選択されるか、又はR5とR6とが一体となって、C3-7シクロアルキル又はヘテロシクロアルキルを形成し、
R7は、H、アルキル及びC3-7シクロアルキルから選択され、
R8は、H、アルキル、COR7及びC3-7シクロアルキルから選択され、
oは、0、1、2、3、4又は5であり、
pは、0又は1であり、
qは、0、1、2、3、4又は5であり、oが、1以上であるとき、Y=NR7、S、SO2、SONR8、-NR8SO2-、-NR7CO-、-CONR7-、-NR7CONR8-であり、o+p+qの合計は、3以上又は7以下である、
条項1~5のいずれかに記載の方法。
Zが、シクロアルキル、ヘテロシクロアルキル、アリール及びヘテロアリールから選択され、
Yが、O、CR5R6、シクロアルキル及びアリールから選択され、
R1、R2、R3、R4、R5、R6及びR7が、それぞれ独立して、H及びアルキルから選択され、
oが、0、1、2、3、4又は5であり、
pが、0又は1であり、
qが、0、1、2、3、4又は5であり、oが、1以上であるとき、Yは、S又はSOであり、
o+p+qの合計は、3以上又は7以下である、
条項6に記載のマイトフュージン活性化物質又はその薬学的に許容され得る塩。
Zが、アリール及びヘテロアリールから選択され、
Yが、O、CH2及びシクロアルキルから選択され、
R1、R2、R3及びR4が、それぞれHであり、
R7が、H、アルキル及びC3-7シクロアルキルから選択され、
R8が、H、アルキル及びC3-7シクロアルキルから選択され、
oが、0、1、2、3、4又は5であり、
pが、0又は1であり、
qが、0、1、2、3、4又は5であり、oが、1以上であるとき、Yは、S又はSO2であり、
o+p+qの合計は、3以上又は5以下である、
条項6若しくは7に記載のマイトフュージン活性化物質又はその薬学的に許容され得る塩。
Zが、アリール及びヘテロアリールから選択され、
Yが、シクロプロピル及びシクロブチルから選択され、
R1、R2、R3及びR4が、それぞれHであり、
R7が、H、アルキル及びC3-7シクロアルキルから選択され、R8が、H、アルキル、COR7及びC3-7シクロアルキルから選択されるか、又はR7とR8とが一体となって、C3-7シクロアルキルを形成し、
oが、0、1、2又は3であり、
pが、1であり、
qが、0、1、2又は3であり、o+p+qの合計は、3以上又は5以下である、
条項6~8のいずれかに記載のマイトフュージン活性化物質又はその薬学的に許容され得る塩。
Zが、アリール及びヘテロアリールから選択され、
Yが、O及びCH2から選択され、
R1、R2、R3及びR4が、それぞれHであり、
R7及びR8が、独立して、H、アルキル及びC3-7シクロアルキルから選択されるか、又はR7とR8とが一体となって、C3-7シクロアルキルを形成し、
oが、0、1、2、3又は4であり、
pが、1であり、
qが、0、1、2、3又は4であり、o+p+qの合計は、5である、
条項6~9のいずれかに記載のマイトフュージン活性化物質又はその薬学的に許容され得る塩。
Zが、アリール及びヘテロアリールから選択され、
Yが、O及びCH2から選択され、
R1、R2、R3及びR4が、それぞれHであり、
oが、0、1、2、3又は4であり、
pが、1であり、
qが、0、1、2、3又は4であり、o+p+qの合計は、5である、
条項6~10のいずれかに記載のマイトフュージン活性化物質又はその薬学的に許容され得る塩。
Zが、フェニル及びヘテロアリールから選択され、これらの各々は、R7、OR7、Cl、F、-CN、CF3、-NR7R8、-SO2NR7R8、-NR7SO2R9、-SO2R9、-CONR7R8、-NR7COR9、C3-7シクロアルキル及びヘテロシクロアルキルから独立して選択される0~4個の置換基を有し、ヘテロアリールは、窒素、酸素及び硫黄から独立して選択される1~4個の原子を含み、フェニル又は複素環部分、
Yが、O及びCH2から選択され、
R1、R2、R3及びR4が、それぞれHであり、
R7が、H、アルキル及びC3-7シクロアルキルから選択され、R8が、H、アルキル、COR7及びC3-7シクロアルキルから選択されるか、又はR7とR8とが一体となって、C3-7シクロアルキルを形成し、
R9が、アルキル及びC3-7シクロアルキルから選択され、
oが、0、1、2、3又は4であり、
pが、1であり、
qが、0、1、2、3又は4であり、
o+p+qの合計は、5である、
条項6~11のいずれかに記載のマイトフュージン活性化物質又はその薬学的に許容され得る塩。
Zが、フェニル及びヘテロアリールから選択され、複素環式部分は、窒素、酸素及び硫黄から独立して選択される1~3個の原子を含み、フェニル又は複素環式部分は、R7、OR7、Cl、F、-CN、CF3、-NR7R8、-SO2R9、-CONR7R8、-NR7COR9、C3-7シクロアルキル及びヘテロシクロアルキルから独立して選択される0~3個の置換基を有し、
Yが、O及びCH2から選択され、
R1、R2、R3及びR4が、それぞれHであり、
R7が、H、アルキル及びC3-7シクロアルキルから選択され、R8が、H、アルキル、COR7及びC3-7シクロアルキルから選択されるか、又はR7とR8とが一体となって、C3-7シクロアルキルを形成し、
R9が、アルキル及びC3-7シクロアルキルから選択され、
oが、0、1、2、3又は4であり、
pが、1であり、
qが、0、1、2、3又は4であり、o+p+qの合計は、5である、
条項6~12のいずれかに記載のマイトフュージン活性化物質又はその薬学的に許容され得る塩。
Zが、フェニル、2-ピリジニル、3-ピリジニル、4-ピリジニル、6-ピリミジニル、5-ピリミジニル、4-ピリミジニル及び2-ピリミジニルから選択され、フェニル、ピリジニル及びピリミジニル部分は、R7、OR7、Cl、F、-CN、CF3、-NR7R8、-SO2R9、-CONR7R8及び-NR7COR9からなる群より独立して選択される0~2個の置換基を有し、
Yが、O又はCH2であり、
R1、R2、R3及びR4が、それぞれHであり、
R7が、H、アルキル及びC3-7シクロアルキルから選択され、R8が、H、アルキル、COR7及びC3-7シクロアルキルから選択されるか、又はR7とR8とが一体となって、C3-7シクロアルキルを形成し、
R9が、アルキル及びC3-7シクロアルキルから選択され、
oが、0、1、2、3又は4であり、
pが、1であり、
qが、0、1、2、3又は4であり、o+p+qの合計は、5である、
条項6~13のいずれかに記載のマイトフュージン活性化物質又はその薬学的に許容され得る塩。
Xは、シクロアルキル、ヘテロシクロアルキル、アリール及びヘテロアリールから選択され、
Zは、シクロアルキル、ヘテロシクロアルキル、アリール及びヘテロアリールから選択され、
R1及びR2は、独立して、H、F、アルキル及びC3-7シクロアルキルから選択されるか、又はR1とR2とが一体となって、C3-7シクロアルキル又はヘテロシクロアルキルを形成し、
R3及びR4は、独立して、H、F、アルキル、COR7及びC3-7シクロアルキルから選択されるか、又はR3とR4とが一体となって、C3-7シクロアルキル又はヘテロシクロアルキルを形成し、
Yは、O、CR5R6、CR7=CR8、三重結合、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、NR7、S、SO2、SONR8、-NR8SO2-、-NR7CO-、-CONR7-及び-NR7CONR8-から選択され、
R5及びR6は、独立して、H、F、アルキル及びシクロアルキルから選択されるか、又はR5とR6とが一体となって、C3-7シクロアルキル又はヘテロシクロアルキルを形成し、
R7は、H、アルキル及びC3-7シクロアルキルから選択され、
R8は、H、アルキル、COR7及びC3-7シクロアルキルから選択され、
oは、0、1、2、3、4又は5であり、
pは、0又は1であり、
qは、0、1、2、3、4又は5であり、oが、1以上であるとき、Y=NR7、S、SO2、SONR8、-NR8SO2-、-NR7CO-、-CONR7-、-NR7CONR8-であり、o+p+qの合計は、3以上又は7以下である、
方法。
ミトコンドリアの融合、健康状態又は輸送が損なわれている慢性神経変性状態、
マイトフュージン1(MFN1)又はマイトフュージン2(MFN2)の機能不全に関連する疾患又は障害、
ミトコンドリアの断片化、機能不全又は運動不全に関連する疾患、
シャルコー・マリー・トゥース病、筋萎縮性側索硬化症、ハンチントン病、アルツハイマー病、パーキンソン病などの変性神経筋状態、
遺伝性運動感覚性ニューロパチー、自閉症、常染色体優性視神経萎縮症(ADOA)、筋ジストロフィー、ルー・ゲーリッグ病、癌、ミトコンドリアミオパチー、聴覚消失を伴う真性糖尿病(DAD)、レーベル遺伝性視神経症(LHON)、リー症候群、亜急性硬化性脳症、ニューロパチー・運動失調・網膜色素変性症・眼瞼下垂(NARP)、筋神経胃腸管性脳症(MNGIE)、赤色ぼろ線維・ミオクローヌスてんかん症候群(MERRF)、ミトコンドリアミオパチー・脳筋症・乳酸アシドーシス・脳卒中様症状(MELAS)、mtDNA枯渇、ミトコンドリア神経性胃腸管系脳筋症(MNGIE)、自律神経障害性ミトコンドリアミオパチー、ミトコンドリアチャネル病又はピルビン酸脱水素酵素複合体欠損症(PDCD/PDH)、
糖尿病性ニューロパチー、
化学療法誘発性末梢神経障害、並びに/又は
挫滅傷、脊髄傷害(SCI)、外傷性脳傷害(TBI)、脳卒中、視神経傷害、及び軸索切断を伴う関連状態
のうちのいずれか1つ又は組み合わせから選択される、条項1~15のいずれかに記載の方法。
から選択されないという条件の、条項1~16のいずれかに記載の方法。
ミトコンドリアの融合、健康状態又は輸送が損なわれている慢性神経変性状態、
マイトフュージン1(MFN1)又はマイトフュージン2(MFN2)の機能不全に関連する疾患又は障害、
ミトコンドリアの断片化、機能不全又は運動不全に関連する疾患、
シャルコー・マリー・トゥース病、筋萎縮性側索硬化症、ハンチントン病、アルツハイマー病、パーキンソン病などの変性神経筋状態、
遺伝性運動感覚性ニューロパチー、自閉症、常染色体優性視神経萎縮症(ADOA)、筋ジストロフィー、ルー・ゲーリッグ病、癌、ミトコンドリアミオパチー、聴覚消失を伴う真性糖尿病(DAD)、レーベル遺伝性視神経症(LHON)、リー症候群、亜急性硬化性脳症、ニューロパチー・運動失調・網膜色素変性症・眼瞼下垂(NARP)、筋神経胃腸管性脳症(MNGIE)、赤色ぼろ線維・ミオクローヌスてんかん症候群(MERRF)、ミトコンドリアミオパチー・脳筋症・乳酸アシドーシス・脳卒中様症状(MELAS)、mtDNA枯渇、ミトコンドリア神経性胃腸管系脳筋症(MNGIE)、自律神経障害性ミトコンドリアミオパチー、ミトコンドリアチャネル病又はピルビン酸脱水素酵素複合体欠損症(PDCD/PDH)、
糖尿病性ニューロパチー、
化学療法誘発性末梢神経障害、並びに/又は
挫滅傷、脊髄傷害(SCI)、外傷性脳傷害(TBI)、脳卒中、視神経傷害、及び軸索切断を伴う関連状態
と診断されている又は有すると疑われる、条項19に記載の方法。
(i)遺伝的に定義された様式で種々の組み合わせのMFN1又はMFN2を発現している細胞において、光スイッチ可能なミトコンドリア標的化フルオロフォアを恒常的に発現させる工程、
(ii)光スイッチ可能なミトコンドリア標的化フルオロフォアを一過性に又は恒常的に発現している細胞において、ミトコンドリア標的化フルオロフォアをマイクロマトリックスパターンで光スイッチする工程、及び
(iii)光スイッチされたミトコンドリアにおいてマージ/オーバーレイ蛍光を計測する工程
を含む、方法。
Claims (23)
- 末梢神経系(PNS)又は中枢神経系(CNS)の遺伝性障害、物理的損傷及び/又は化学的傷害を治療する方法であって、
マイトフュージン活性化物質又はその薬学的に許容され得る塩のうちの1つ以上を含む治療有効量の組成物を被験体に投与する工程を含み、前記マイトフュージン活性化物質は、ミトコンドリアの融合を刺激し、ミトコンドリアの細胞内移送を増強する、方法。 - R1又はR2が、必要に応じて、アセトアミド、C1-8アルコキシ、アミノ、アゾ、Br、C1-8アルキル、カルボニル、カルボキシル、Cl、シアノ、C3-8シクロアルキル、C3-8ヘテロアリール、C3-8ヘテロシクリル、ヒドロキシル、F、ハロ、インドール、N、ニトリル、O、フェニル、S、スルホキシド、二酸化硫黄及びチオフェンから選択される1つ以上の置換基で置換され、
R1又はR2が、必要に応じてさらに、1つ以上のアセトアミド、アルコキシ、アミノ、アゾ、Br、C1-8アルキル、カルボニル、カルボキシル、Cl、シアノ、C3-8シクロアルキル、C3-8ヘテロアリール、C3-8ヘテロシクリル、ヒドロキシル、F、ハロ、インドール、N、ニトリル、O、フェニル、S、スルホキシド、二酸化硫黄又はチオフェンで置換され、
前記アルキル、シクロアルキル、ヘテロアリール、ヘテロシクリル、インドール及びフェニル置換基のうちの1つ以上は、必要に応じて、アセトアミド、アルコキシ、アミノ、アゾ、Br、C1-8アルキル、カルボニル、カルボキシル、Cl、シアノ、C3-8シクロアルキル、C3-8ヘテロアリール、C3-8ヘテロシクリル、ヒドロキシル、F、ハロ、インドール、N、ニトリル、O、フェニル、S、スルホキシド、二酸化硫黄及びチオフェンから選択される1つ以上の置換基で置換される、
請求項2又は3に記載の方法。 - 前記マイトフュージン活性化物質が、
から選択される、請求項1~4のいずれか1項に記載の方法。 - 前記マイトフュージン活性化物質が、式:
Xは、シクロアルキル、ヘテロシクロアルキル、アリール及びヘテロアリールから選択され、
Zは、シクロアルキル、ヘテロシクロアルキル、アリール及びヘテロアリールから選択され、
R1及びR2は、独立して、H、F、アルキル及びC3-7シクロアルキルから選択されるか、又はR1とR2とが一体となって、C3-7シクロアルキル又はヘテロシクロアルキルを形成し、
R3及びR4は、独立して、H、F、アルキル、COR7、C3-7シクロアルキルから選択されるか、又はR3とR4とが一体となって、C3-7シクロアルキル又はヘテロシクロアルキルを形成し、
Yは、O、CR5R6、CR7=CR8、三重結合、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、NR7、S、SO2、SONR8、-NR8SO2-、-NR7CO-、-CONR7-及び-NR7CONR8-から選択され、
R5及びR6は、独立して、H、F、アルキル及びシクロアルキルから選択されるか、又はR5とR6とが一体となって、C3-7シクロアルキル又はヘテロシクロアルキルを形成し、
R7は、H、アルキル及びC3-7シクロアルキルから選択され、
R8は、H、アルキル、COR7及びC3-7シクロアルキルから選択され、
oは、0、1、2、3、4又は5であり、
pは、0又は1であり、
qは、0、1、2、3、4又は5であり、oが、1以上であるとき、Y=NR7、S、SO2、SONR8、-NR8SO2-、-NR7CO-、-CONR7-、-NR7CONR8-であり、o+p+qの合計は、3以上又は7以下である、
請求項1に記載の方法。 - Xが、シクロアルキル及びヘテロシクロアルキルから選択され、
Zが、シクロアルキル、ヘテロシクロアルキル、アリール及びヘテロアリールから選択され、
Yが、O、CR5R6、シクロアルキル及びアリールから選択され、
R1、R2、R3、R4、R5、R6及びR7が、それぞれ独立して、H及びアルキルから選択され、
oが、0、1、2、3、4又は5であり、
pが、0又は1であり、
qが、0、1、2、3、4又は5であり、oが、1以上であるとき、Yは、S又はSO2であり、
o+p+qの合計は、3以上又は7以下である、
請求項6に記載のマイトフュージン活性化物質又はその薬学的に許容され得る塩。 - Xが、R7、OR7、NR7R8、フッ素及びCF3から独立して選択される1、2又は3個の置換基を有するシクロアルキル、並びにO、NR7及びSから独立して選択される1又は2個の必要に応じて置換されるヘテロ原子を含むヘテロシクロアルキルから選択され、
Zが、アリール及びヘテロアリールから選択され、
Yが、O、CH2及びシクロアルキルから選択され、
R1、R2、R3及びR4が、それぞれHであり、
R7が、H、アルキル及びC3-7シクロアルキルから選択され、
R8が、H、アルキル及びC3-7シクロアルキルから選択され、
oが、0、1、2、3、4又は5であり、
pが、0又は1であり、
qが、0、1、2、3、4又は5であり、oが、1以上であるとき、Yは、S又はSO2であり、
o+p+qの合計は、3以上又は5以下である、
請求項6に記載のマイトフュージン活性化物質又はその薬学的に許容され得る塩。 - Xが、R7、OR7、NR7R8、フッ素及びCF3からなる群より独立して選択される1、2又は3個の置換基を有するシクロアルキルであるか、又はXが、O、NR7及びSから独立して選択される1又は2個の必要に応じて置換されるヘテロ原子を含むヘテロシクロアルキルであり、
Zが、アリール及びヘテロアリールから選択され、
Yが、シクロプロピル及びシクロブチルから選択され、
R1、R2、R3及びR4が、それぞれHであり、
R7が、H、アルキル及びC3-7シクロアルキルから選択され、R8が、H、アルキル、COR7及びC3-7シクロアルキルから選択されるか、又はR7とR8とが一体となって、C3-7シクロアルキルを形成し、
oが、0、1、2又は3であり、
pが、1であり、
qが、0、1、2又は3であり、o+p+qの合計は、3以上又は5以下である、
請求項6に記載のマイトフュージン活性化物質又はその薬学的に許容され得る塩。 - Xが、R7、OR7、NR7R8、フッ素及びCF3からなる群より独立して選択される1、2又は3個の置換基を有するシクロアルキルであるか、又はXが、O、NR7及びSから独立して選択される1又は2個の必要に応じて置換されるヘテロ原子を含むヘテロシクロアルキルであり、
Zが、アリール及びヘテロアリールから選択され、
Yが、O及びCH2から選択され、
R1、R2、R3及びR4が、それぞれHであり、
R7及びR8が、独立して、H、アルキル及びC3-7シクロアルキルから選択されるか、又はR7とR8とが一体となって、C3-7シクロアルキルを形成し、
oが、0、1、2、3又は4であり、
pが、1であり、
qが、0、1、2、3又は4であり、o+p+qの合計は、5である、
請求項6に記載のマイトフュージン活性化物質又はその薬学的に許容され得る塩。 - Xが、4-ヒドロキシルシクロヘキシル、4-アミノシクロヘキシル、4-(N-メチル)アミノシクロヘキシル、4-(N,N-ジメチル)アミノシクロヘキシル、4-(N-アセチルアミノ)シクロヘキシル、4,4-ジフルオロシクロヘキシル、テトラヒドロピラニル、テトラヒドロチオピラニル、ピペリジニル、N-メチル-ピペリジニル及びN-アセチル-ピペリジニルから選択され、
Zが、アリール及びヘテロアリールから選択され、
Yが、O及びCH2から選択され、
R1、R2、R3及びR4が、それぞれHであり、
oが、0、1、2、3又は4であり、
pが、1であり、
qが、0、1、2、3又は4であり、o+p+qの合計は、5である、
請求項6に記載のマイトフュージン活性化物質又はその薬学的に許容され得る塩。 - Xが、シクロアルキル、ヘテロシクロアルキル、アリール及びヘテロアリールから選択され、これらの各々は、独立して、R7、OR7、Cl、F、-CN、CF3、-NR7R8、-SO2NR7R8、-NR7SO2R9、-SO2R9、-CONR7R8、-NR7COR9、C3-7シクロアルキル及びヘテロシクロアルキルから独立して選択される0~4個の置換基を有し、前記ヘテロシクロアルキル及びヘテロアリールは、独立して、窒素、酸素及び硫黄からなる群より選択される1~4個のヘテロ原子を含み、
Zが、フェニル及びヘテロアリールから選択され、これらの各々は、R7、OR7、Cl、F、-CN、CF3、-NR7R8、-SO2NR7R8、-NR7SO2R9、-SO2R9、-CONR7R8、-NR7COR9、C3-7シクロアルキル及びヘテロシクロアルキルから独立して選択される0~4個の置換基を有し、前記ヘテロアリールは、窒素、酸素及び硫黄から独立して選択される1~4個の原子を含み、前記フェニル又は複素環部分、
Yが、O及びCH2から選択され、
R1、R2、R3及びR4が、それぞれHであり、
R7が、H、アルキル及びC3-7シクロアルキルから選択され、R8が、H、アルキル、COR7及びC3-7シクロアルキルから選択されるか、又はR7とR8とが一体となって、C3-7シクロアルキルを形成し、
R9が、アルキル及びC3-7シクロアルキルから選択され、
oが、0、1、2、3又は4であり、
pが、1であり、
qが、0、1、2、3又は4であり、
o+p+qの合計は、5である、
請求項6に記載のマイトフュージン活性化物質又はその薬学的に許容され得る塩。 - Xが、4-ヒドロキシルシクロヘキシル、4-アミノシクロヘキシル、4-(N-メチル)アミノシクロヘキシル、4-(N,N-ジメチル)アミノシクロヘキシル、4-(N-アセチルアミノ)シクロヘキシル、4,4-ジフルオロシクロヘキシル、テトラヒドロピラニル、テトラヒドロチオピラニル、ピペリジニル、N-メチル-ピペリジニル及びN-アセチル-ピペリジニルから選択され、
Zが、フェニル及びヘテロアリールから選択され、前記複素環式部分は、窒素、酸素及び硫黄から独立して選択される1~3個の原子を含み、前記フェニル又は複素環式部分は、R7、OR7、Cl、F、-CN、CF3、-NR7R8、-SO2R9、-CONR7R8、-NR7COR9、C3-7シクロアルキル及びヘテロシクロアルキルから独立して選択される0~3個の置換基を有し、
Yが、O及びCH2から選択され、
R1、R2、R3及びR4が、それぞれHであり、
R7が、H、アルキル及びC3-7シクロアルキルから選択され、R8が、H、アルキル、COR7及びC3-7シクロアルキルから選択されるか、又はR7とR8とが一体となって、C3-7シクロアルキルを形成し、
R9が、アルキル及びC3-7シクロアルキルから選択され、
oが、0、1、2、3又は4であり、
pが、1であり、
qが、0、1、2、3又は4であり、o+p+qの合計は、5である、
請求項6に記載のマイトフュージン活性化物質又はその薬学的に許容され得る塩。 - Xが、4-ヒドロキシルシクロヘキシル、4-アミノシクロヘキシル、4-(N-メチル)アミノシクロヘキシル、4-(N,N-ジメチル)アミノシクロヘキシル、4-(N-アセチルアミノ)シクロヘキシル、4,4-ジフルオロシクロヘキシル、テトラヒドロピラニル、テトラヒドロチオピラニル、ピペリジニル、4-N-メチル-ピペリジニル及び4-N-アセチル-ピペリジニルから選択され、
Zが、フェニル、2-ピリジニル、3-ピリジニル、4-ピリジニル、6-ピリミジニル、5-ピリミジニル、4-ピリミジニル及び2-ピリミジニルから選択され、前記フェニル、ピリジニル及びピリミジニル部分は、R7、OR7、Cl、F、-CN、CF3、-NR7R8、-SO2R9、-CONR7R8及び-NR7COR9からなる群より独立して選択される0~2個の置換基を有し、
Yが、O又はCH2であり、
R1、R2、R3及びR4が、それぞれHであり、
R7が、H、アルキル及びC3-7シクロアルキルから選択され、R8が、H、アルキル、COR7及びC3-7シクロアルキルから選択されるか、又はR7とR8とが一体となって、C3-7シクロアルキルを形成し、
R9が、アルキル及びC3-7シクロアルキルから選択され、
oが、0、1、2、3又は4であり、
pが、1であり、
qが、0、1、2、3又は4であり、o+p+qの合計は、5である、
請求項6に記載のマイトフュージン活性化物質又はその薬学的に許容され得る塩。 - マイトフュージン活性化物質の必要を示す疾患を治療する方法であって、前記方法は、それを必要とする哺乳動物に、治療有効量の式:
Xは、シクロアルキル、ヘテロシクロアルキル、アリール及びヘテロアリールから選択され、
Zは、シクロアルキル、ヘテロシクロアルキル、アリール及びヘテロアリールから選択され、
R1及びR2は、独立して、H、F、アルキル及びC3-7シクロアルキルから選択されるか、又はR1とR2とが一体となって、C3-7シクロアルキル又はヘテロシクロアルキルを形成し、
R3及びR4は、独立して、H、F、アルキル、COR7及びC3-7シクロアルキルから選択されるか、又はR3とR4とが一体となって、C3-7シクロアルキル又はヘテロシクロアルキルを形成し、
Yは、O、CR5R6、CR7=CR8、三重結合、シクロアルキル、ヘテロシクロアルキル、アリール、ヘテロアリール、NR7、S、SO2、SONR8、-NR8SO2-、-NR7CO-、-CONR7-及び-NR7CONR8-から選択され、
R5及びR6は、独立して、H、F、アルキル及びシクロアルキルから選択されるか、又はR5とR6とが一体となって、C3-7シクロアルキル又はヘテロシクロアルキルを形成し、
R7は、H、アルキル及びC3-7シクロアルキルから選択され、
R8は、H、アルキル、COR7及びC3-7シクロアルキルから選択され、
oは、0、1、2、3、4又は5であり、
pは、0又は1であり、
qは、0、1、2、3、4又は5であり、oが、1以上であるとき、Y=NR7、S、SO2、SONR8、-NR8SO2-、-NR7CO-、-CONR7-、-NR7CONR8-であり、o+p+qの合計は、3以上又は7以下である、
方法。 - 前記PNS又はCNS障害が、
ミトコンドリアの融合、健康状態又は輸送が損なわれている慢性神経変性状態、
マイトフュージン1(MFN1)又はマイトフュージン2(MFN2)の機能不全に関連する疾患又は障害、
ミトコンドリアの断片化、機能不全又は運動不全に関連する疾患、
シャルコー・マリー・トゥース病、筋萎縮性側索硬化症、ハンチントン病、アルツハイマー病、パーキンソン病などの変性神経筋状態、
遺伝性運動感覚性ニューロパチー、自閉症、常染色体優性視神経萎縮症(ADOA)、筋ジストロフィー、ルー・ゲーリッグ病、癌、ミトコンドリアミオパチー、聴覚消失を伴う真性糖尿病(DAD)、レーベル遺伝性視神経症(LHON)、リー症候群、亜急性硬化性脳症、ニューロパチー・運動失調・網膜色素変性症・眼瞼下垂(NARP)、筋神経胃腸管性脳症(MNGIE)、赤色ぼろ線維・ミオクローヌスてんかん症候群(MERRF)、ミトコンドリアミオパチー・脳筋症・乳酸アシドーシス・脳卒中様症状(MELAS)、mtDNA枯渇、ミトコンドリア神経性胃腸管系脳筋症(MNGIE)、自律神経障害性ミトコンドリアミオパチー、ミトコンドリアチャネル病又はピルビン酸脱水素酵素複合体欠損症(PDCD/PDH)、
糖尿病性ニューロパチー、
化学療法誘発性末梢神経障害、並びに/又は
挫滅傷、脊髄傷害(SCI)、外傷性脳傷害、脳卒中、視神経傷害、及び軸索切断を伴う関連状態
のうちのいずれか1つ又は組み合わせから選択される、請求項1又は15に記載の方法。 - 前記マイトフュージン活性化物質が、以下の化合物:
から選択されないという条件の、請求項1に記載の方法。 - 前記組成物が、薬学的に許容され得る賦形剤をさらに含む、前述の請求項のいずれか1項に記載の方法。
- CNS又はPNSの遺伝性又は非遺伝性の神経変性状態、傷害、損傷又は外傷を治療する方法であって、治療有効量の請求項2~18のいずれか1項に記載のマイトフュージン活性化物質を前記被験体に投与する工程を含む、方法。
- 前記被験体が、
ミトコンドリアの融合、健康状態又は輸送が損なわれている慢性神経変性状態、
マイトフュージン1(MFN1)又はマイトフュージン2(MFN2)の機能不全に関連する疾患又は障害、
ミトコンドリアの断片化、機能不全又は運動不全に関連する疾患、
シャルコー・マリー・トゥース病、筋萎縮性側索硬化症、ハンチントン病、アルツハイマー病、パーキンソン病などの変性神経筋状態、
遺伝性運動感覚性ニューロパチー、自閉症、常染色体優性視神経萎縮症(ADOA)、筋ジストロフィー、ルー・ゲーリッグ病、癌、ミトコンドリアミオパチー、聴覚消失を伴う真性糖尿病(DAD)、レーベル遺伝性視神経症(LHON)、リー症候群、亜急性硬化性脳症、ニューロパチー・運動失調・網膜色素変性症・眼瞼下垂(NARP)、筋神経胃腸管性脳症(MNGIE)、赤色ぼろ線維・ミオクローヌスてんかん症候群(MERRF)、ミトコンドリアミオパチー・脳筋症・乳酸アシドーシス・脳卒中様症状(MELAS)、mtDNA枯渇、ミトコンドリア神経性胃腸管系脳筋症(MNGIE)、自律神経障害性ミトコンドリアミオパチー、ミトコンドリアチャネル病又はピルビン酸脱水素酵素複合体欠損症(PDCD/PDH)、
糖尿病性ニューロパチー、
化学療法誘発性末梢神経障害、並びに/又は
挫滅傷、脊髄傷害、外傷性脳傷害、脳卒中、視神経傷害、及び軸索切断を伴う関連状態
と診断されている又は有すると疑われる、請求項19に記載の方法。 - 1つ以上の候補分子をミトコンドリア融合の調節活性についてスクリーニングする方法であって、
(i)遺伝的に定義された様式で種々の組み合わせのMFN1又はMFN2を発現している細胞において、光スイッチ可能なミトコンドリア標的化フルオロフォアを恒常的に発現させる工程、
(ii)光スイッチ可能なミトコンドリア標的化フルオロフォアを一過性に又は恒常的に発現している細胞において、ミトコンドリア標的化フルオロフォアをマイクロマトリックスパターンで光スイッチする工程、及び
(iii)光スイッチされたミトコンドリアにおいてマージ/オーバーレイ蛍光を計測する工程
を含む、方法。 - 前記試験混合物のマージ/オーバーレイ蛍光を前記コントロール混合物のマージ/オーバーレイ蛍光と比較する工程をさらに含み、前記試験混合物のマージ/オーバーレイ蛍光が、前記コントロール混合物のマージ/オーバーレイ蛍光よりも大きいとき、前記試験混合物中の1つ以上の候補分子が、ミトコンドリア融合の活性化物質と同定される、請求項21に記載の方法。
- 野生型、MFN1又はMFN2を発現している細胞における候補作用物質の試験混合物のマージ/オーバーレイ蛍光を、MFN1とMFN2の両方を欠く細胞(MFNヌル細胞)における候補作用物質のマージ/オーバーレイ蛍光と比較する工程をさらに含み、MFN発現細胞における前記混合物のマージ/オーバーレイ蛍光が、MFNヌル細胞における前記混合物のマージ/オーバーレイ蛍光より大きいとき、前記試験混合物中の1つ以上の候補分子が、マイトフュージン活性化物質と同定される、請求項21に記載の方法。
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CA3127590A1 (en) | 2020-08-06 |
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