JP2022116328A - 線維症疾患の治療及び/又は予防用アミノナフトキノン化合物 - Google Patents
線維症疾患の治療及び/又は予防用アミノナフトキノン化合物 Download PDFInfo
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- JP2022116328A JP2022116328A JP2022092059A JP2022092059A JP2022116328A JP 2022116328 A JP2022116328 A JP 2022116328A JP 2022092059 A JP2022092059 A JP 2022092059A JP 2022092059 A JP2022092059 A JP 2022092059A JP 2022116328 A JP2022116328 A JP 2022116328A
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- Prior art keywords
- methyl
- dihydronaphthalen
- dioxo
- chloro
- benzamide
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Abstract
Description
ここで、
R1は、ハロゲン、C1-10アルキル、C2-10アルケニル、C2-10アルキニル、NH2、NO2、OH又はCNであり、
各R2は同一又は異なり、H、C1-10アルキル、C2-10アルケニル、C2-10アルキニル、NH2、NO2、C1-10アルコキシ、C1-10アルキルチオ、C1-10アルキルアミノ、C1-10アルコキシ、C1-10アルキル、OH若しくはCN、C6-10アリール、又はN、O及びSからなる群から選択される1~3個のヘテロ原子を有するC5-7複素環を表し、
R3は、H、C1-10アルキル、C2-10アルケニル、C2-10アルキニル、NH2、NO2、OH又はCNであり、
R4は、H、C1-10アルキル、C2-10アルケニル、C2-10アルキニル、NH2、NO2、OH若しくはCNであり、又は、R4はそれに結合している窒素原子及びR5と一緒に、O、N及びSから選択される0~3個のヘテロ原子を有する縮合二環を形成し、
R5は存在していないか、OH、C3-10シクロアルキル、C6-10アリール、C5-7複素環(O、N及びSから選択される0~3個のヘテロ原子を有する)、又はC10-12縮合複素環(O、N及びSから選択される0~3個のヘテロ原子を有する)であり、シクロアルキル、アリール、複素環及び縮合複素環の各々は、未置換であるか、又は、OH、ハロゲン、NH2、NO2、CN、C1-10アルキル、C2-10アルケニル、C2-10アルキニル、C1-10アルコキシ、C5-10ヘテロアリール(N、O及びSからなる群から選択される1~3個のヘテロ原子を有し、未置換であるか又はC1-10アルキル、C2-10アルケニル、C2-10アルキニル、OH、ハロゲン、CN、NH2若しくはNO2で置換されている)、-S(O)2-フェニル(フェニルは未置換であるか、又はハロゲン、OH、CN、NH2、NO2、C1-10アルキル、C2-10アルケニル、C2-10アルキニル若しくはC1-10アルコキシで置換されている)、-C(O)NHOH、-C(O)NH2、-C(O)-フェニル(フェニルは未置換であるか、又はOH、ハロゲン、CN、NH2、NO2、C1-10アルキル、C2-10アルケニル、C2-10アルキニル若しくはC1-10アルコキシからなる群から選択される1~5個の同一又は異なる置換基で置換されている)、-C(O)NRaRb、NHS(O)2フェニル(フェニルは未置換であるか、又は場合によりOH、ハロゲン、CN、NH2、NO2、C1-10アルキル、C2-10アルケニル、C2-10アルキニル若しくはC1-10アルコキシで置換されている)、C1-10アルキレン-ヘテロアリール、-S(O)2-ヘテロアリール、-S(O)2-複素環、-S(O)2N(H)-ヘテロアリール、-アルキレン-N(H)-ヘテロアリール、複素環(未置換であるか、又はC1-10アルキルで置換されている)の中の1~3個で置換され、又は、R5はアルキレン-R6であり、R6はOH、NO2、CN、アルキル、アルケニル、アルキニル、NRaRb、シクロアルキル、アリール、O、N及びSから選択される0~3個のヘテロ原子を有する複素環又はO、N及びSから選択される0~3個のヘテロ原子を有する縮合複素環であり、シクロアルキル、アリール、複素環及び縮合複素環の各々は、未置換であるか、又はOH、ハロゲン、NH2、NO2、CN、アルキル、アルケニル、アルキニル、アルコキシ、ヘテロアリール(N、O及びSからなる群から選択される1~3個のヘテロ原子を有し、未置換であるか又はアルキル、アルケニル、アルキニル、OH、ハロゲン、CN、NH2若しくはNO2で置換されている)の中の1~3個で置換され、
RaとRbは同一又は異なり、独立してH、OH、アルキル、アルケニル、アルキニル、アルコキシ、シクロアルキル、ヘテロシクリロ、アルキレンアミノ、アルキレン-N-(アルキル)2、アリール(未置換であるか、又はOH、ハロゲン、CN、NH2、NO2、アルキル、アルケニル、アルキニル、アルコキシ若しくはヘテロアリールで置換されている)、ヘテロアリール(未置換であるか、又はOH、ハロゲン、CN、NH2、NO2、アルキル、アルケニル、アルキニル若しくはアルコキシで置換されている)、アルキレン-ヘテロアリール、又はアルキレン-ヘテロシクリロ(未置換であるか、又はアルキルで置換されている)を表し、
Xは、-C(O)、-S(O)2又は-NH-C(O)-であり、
Yは、-C-又は-N-であり、
mは、0~3の整数であり、
nは、0~7の整数である。
スキーム1
*試薬及び条件
(a)4-アミノメチル安息香酸、TEA、EtOH、還流
(b)EDC、HCl、HOBt、NMM、DMF、NH2OTHP、室温。1に対し、次いで10%のTFA(aq.)、MeOH、室温。
(c)2~5、9~26、28~42に対し、置換アミン、HBTU、DIPEA、DMF、室温。
スキーム2
*試薬及び条件
(a)4-アミノメチル安息香酸、TEA、EtOH、還流
(b)27、43、44に対し、置換アミン、HBTU、DIPEA、DMF、室温。
(c)45~49に対し、置換アミン、EDC、HCl、HOBt、NMM、DMF、室温。
実施例44 4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(ピリジン-4-イルメチル)ベンズアミド(27)
実施例46 N-(2-(1H-インドール-3-イル)エチル)-4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)ベンズアミド(44)
細胞培養
正常なヒト胎児肺線維芽細胞株であるWI-38細胞をアメリカ培養細胞系統保存機関(Manassas、VA)から得た。細胞を、10%のFCS、2mMのL-グルタミン、0.1mMのNEAA、1mMのピルビン酸ナトリウム、50U/mlのペニシリンG、及び100μg/mlのストレプトマイシンを含むMEM栄養混合物中で、加湿した37℃の5%のCO2を有するインキュベーターで増殖させた。すべての実験において継代18~30の間で細胞を使用した。コンフルエンスに達した後、イムノブロッティングのために細胞を6cmの皿に播種した。
化合物4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(ピリジン-4-イル)ベンズアミド(ここで使用されるMPT0L056又はL056)を本明細書に記載のアッセイで使用した。
ウエスタンブロット解析は、以前に記載されているように行った(ChenBC,ChangYS,KangJC,HsuMJ,SheuJR,ChenTL,etal.Peptidoglycaninducesnuclearfactor-kappaBactivationandcyclooxygenase-2expressionviaRas,Raf-1,andERKinRAW264.7macrophages.JBiolChem2004;279:20889-97)。簡潔に言うと、WI-38肺線維芽細胞を6cmの皿で培養した。コンフルエンスに達した後、細胞を30分間表示したように特異的阻害剤(E028及びG009)で前処理し、次いでビヒクル(H2O)又は10ng/mlのTGF-βで2時間(CTGFアッセイ)又は24時間(コラーゲンIアッセイ)処理した。全細胞溶解物(30μg)を12%(CTGF)又は8%(コラーゲンI)のSDS-PAGEに供し、ポリビニリデンジフルオリド膜上に移し、次いで5%のBSAを含有するTBSTバッファー(150mMのNaCl、20mMのTris-HCl、及び0.02%のTween20、pH7.4)でインキュベートした。タンパク質を特異的な一次抗体によって視覚化し、次いでHRP標識された二次抗体と共にインキュベートした。免疫反応性は、製造者の指示に従って増強化学発光(ECL)を用いて検出した。定量データは、科学的イメージングシステム(Kodak、Rochester、NY)を備えた計算密度計を使用して得た。
結果は、示された別個の実験の数に対する平均±SEMとして表される。t検定を用いて平均の統計学的差異を調べ、P値<0.05を有意と見なした。
プロ線維形成性メディエーター(TGF-β、トロンビン、及びET-1)に対する化合物MPT0L056の阻害効果が、CTGF及びコラーゲンI産生の調節に関連するか否かを決定するために、ウエスタンブロット解析を行った。まず、WI-38肺線維芽細胞を、TGF-β(10ng/mL)で2時間インキュベートする前及びその間に、異なる濃度のMPT0L056(0.3、1、3又は10μM)で30分間インキュベートした。L056は、濃度依存的にWI-38肺線維芽細胞からのTGF-β誘導性CTGFの産生を大幅に阻害した(図1)。さらに、他のプロ線維形成性メディエーターに対するMPT0L056の効果を調べた。MPT0L0560はまた、それぞれ図2及び3に示されるように、ET-1-及びトロンビン誘導性CTGF発現形態WI-38肺線維芽細胞を阻害した。さらに、図4に示されるように、MPT0L056はまた、WI-38細胞におけるTGF-β誘導性コラーゲン発現を阻害した。これらの結果は、MPT0L056がプロ線維形成性メディエーター誘導性CTGF発現及びコラーゲン産生を明らかに阻害したことを示した。
MTT-アッセイ前に、WI-38肺線維芽細胞を異なる濃度のMPT0L056(0.3、1、3又は10μM)で2時間インキュベートした。
WI38細胞における細胞生存率に対するL056の効果を示す。これらのデータは、L056が細胞生存率に影響しなかったことを示唆した。
実施例3 インビボ有効性ブレオマイシン(BLM)誘発性肺線維症マウスモデルアッセイ
腹腔内注射によりCCl4(1μl/μg/BW、q.w.)又はPBS(1μl/μg/BW、q.w.)でC57BL/6JNarlマウス(8週)を6週間処置した。CCl4を注射したマウスに、MPT0L056(25、50及び100mg/kg/日、q.d.)及びシリマリン(200mg/kg/日、q.d.)を2週間~6週間経口投与した。43日目に、マウスを犠牲にし、IHC染色(元の倍率、×100)によって、肺組織のα-SMA解析を行った(図11を参照)。図10は、マウスのCCl4誘導性肝線維症に対するMPT0L056及びシリマリンの抗線維化効果を示す。図10(A)は、シリウスレッド染色の結果を示す。図10(B)に示されるように、CCl4誘導性肝線維症に対するMPT0L056の阻害は用量依存的であり、阻害におけるMPT0L056の有効性はシリマリンより高い。線維症スコアの低減におけるMPT0L056の結果は、以下の表に示される。
Claims (28)
- 対象の線維症疾患の予防及び/又は治療のための方法であって、有効量の式(I)の化合物又は薬学的に許容される塩、溶媒和化合物若しくはプロドラッグを活性成分として対象に投与することを含み、
ここで、
R1は、ハロゲン、C1-10アルキル、C2-10アルケニル、C2-10アルキニル、NH2、NO2、OH又はCNであり、
各R2は同一又は異なり、H、C1-10アルキル、C2-10アルケニル、C2-10アルキニル、NH2、NO2、C1-10アルコキシ、C1-10アルキルチオ、C1-10アルキルアミノ、C1-10アルコキシ、C1-10アルキル、OH若しくはCN、C6-10アリール、又はN、O及びSからなる群から選択される1~3個のヘテロ原子を有するC5-7複素環を表し、
R3は、H、C1-10アルキル、C2-10アルケニル、C2-10アルキニル、NH2、NO2、OH又はCNであり、
R4は、H、C1-10アルキル、C2-10アルケニル、C2-10アルキニル、NH2、NO2、OH又はCNであり、
R5は存在していないか、OH、C3-10シクロアルキル、C6-10アリール、C5-7複素環(O、N及びSから選択される0~3個のヘテロ原子を有する)、又はC10-12縮合複素環(O、N及びSから選択される0~3個のヘテロ原子を有する)であり、シクロアルキル、アリール、複素環及び縮合複素環の各々は、未置換であるか、又は、OH、ハロゲン、NH2、NO2、CN、C1-10アルキル、C2-10アルケニル、C2-10アルキニル、C1-10アルコキシ、C5-10ヘテロアリール(N、O及びSからなる群から選択される1~3個のヘテロ原子を有し、未置換であるか又はC1-10アルキル、C2-10アルケニル、C2-10アルキニル、OH、ハロゲン、CN、NH2若しくはNO2で置換されている)、-S(O)2-フェニル(フェニルは未置換であるか、又はハロゲン、OH、CN、NH2、NO2、C1-10アルキル、C2-10アルケニル、C2-10アルキニル若しくはC1-10アルコキシで置換されている)、-C(O)NHOH、-C(O)NH2、-C(O)-フェニル(フェニルは未置換であるか、又はOH、ハロゲン、CN、NH2、NO2、C1-10アルキル、C2-10アルケニル、C2-10アルキニル若しくはC1-10アルコキシからなる群から選択される1~5個の同一又は異なる置換基で置換されている)、-C(O)NRaRb、NHS(O)2フェニル(フェニルは未置換であるか、又は場合によりOH、ハロゲン、CN、NH2、NO2、C1-10アルキル、C2-10アルケニル、C2-10アルキニル若しくはC1-10アルコキシで置換されている)、C1-10アルキレン-ヘテロアリール、-S(O)2-ヘテロアリール、-S(O)2-複素環、-S(O)2N(H)-ヘテロアリール、-アルキレン-N(H)-ヘテロアリール、複素環(未置換であるか、又はC1-10アルキルで置換されている)の中の1~3個で置換され、
RaとRbは同一又は異なり、独立してH、OH、アルキル、アルケニル、アルキニル、アルコキシ、シクロアルキル、ヘテロシクリロ、アルキレンアミノ、アルキレン-N-(アルキル)2、アリール(未置換であるか、又はOH、ハロゲン、CN、NH2、NO2、アルキル、アルケニル、アルキニル、アルコキシ若しくはヘテロアリールで置換されている)、ヘテロアリール(未置換であるか、又はOH、ハロゲン、CN、NH2、NO2、アルキル、アルケニル、アルキニル若しくはアルコキシで置換されている)、アルキレン-ヘテロアリール、又はアルキレン-ヘテロシクリロ(未置換であるか、又はアルキルで置換されている)を表し、
Xは、-C(O)、-S(O)2又は-NH-C(O)-であり、
Yは、-C-又は-N-であり、
mは、0~3の整数であり、
nは、0~7の整数である、ことを特徴とする方法。 - mは0であり、R1はハロゲンであり、nは1~4の任意の整数であり、R3はHであり、Xは-C(O)-であり、R4はHであり、R5は、OH、C3-8シクロアルキル、フェニル(未置換であるか、又はOH、CN、ハロゲン、NH2若しくはC1-4アルキルピペラジニルから選択される1~3個の同一又は異なる置換基で置換されている)、C1-6アルキルピペラジニル、C1-6アルキルピリジニル、C1-6アルキルピロリジニル、ピリジニル、ピリミジニル、ピラジニル、ピペラジニル、ピロリジニル、チアゾリル、ベンゾイミダゾリル、ピラゾリル、インダゾリル、ピラゾリル、キノリニル、インドリル、C1-4インドリル、インダゾリル、アザインドリル、アザインダゾリル、デアザプリニル、インダニル、モルホリノイル又はC1-4アルキルモルホリノイルであり、これらの各々は、未置換であるか、又はOH、CN、ハロゲン若しくはNH2から選択される1、2又は3個の基で置換されている、ことを特徴とする請求項1に記載の方法。
- mは0であり、R1はハロゲンであり、nは1~2の任意の整数であり、R3はHであり、Xは-C(O)であり、R4はHであり、R5は、OH、C3-8シクロアルキル、ピリジニル、又は、NH2、ハロゲン、OH、CN若しくはC1-4アルキルピペラジニルの中の1~3個で置換されているフェニル、ピリニジニル(pyrinidinyl)(未置換であるか、又はNO2、NH2若しくはC1-4アルキルで置換されている)、ピラジニル(未置換であるか、又はNO2、NH2若しくはC1-4アルキルで置換されている)、チアゾリル(未置換であるか、又はNO2、NH2若しくはC1-4アルキルで置換されている)、ベンズイミダゾリル(未置換であるか、又はNO2、NH2若しくはC1-4アルキルで置換されている)、ピラゾリル(未置換であるか、又はNO2、NH2若しくはC1-4アルキルで置換されている)、インダゾリル(未置換であるか、又はNO2、NH2若しくはC1-4アルキルで置換されている)、チアゾリル(未置換であるか、又はNO2、NH2若しくはC1-4アルキルで置換されている)、キノリニル(未置換であるか、又はNO2、NH2若しくはC1-4アルキルで置換されている)、インドリル(未置換であるか、又はNO2、NH2若しくはC1-4アルキルで置換されている)、インダゾリル(未置換であるか、又はNO2、NH2若しくはC1-4アルキルで置換されている)、アザインダゾリル(未置換であるか、又はNO2、NH2若しくはC1-4アルキルで置換されている)、デアザプリニル(未置換であるか、又はNO2、NH2若しくはC1-4アルキルで置換されている)、インダニル(未置換であるか、又はNO2、NH2若しくはC1-4アルキルで置換されている)、又はモルホリノイル(未置換であるか、又はNO2,NH2又はC1-4アルキルで置換されている)である、ことを特徴とする請求項1に記載の方法。
- mは0であり、nは0であり、Xは-C(O)であり、Yは-N-であり、R1はハロゲン又はC1-4アルキルであり、R3はHであり、R4はH又はC1-4アルキルであり、R5はピリジニル、ピラジニル、又はピリミジニルである、ことを特徴とする請求項1に記載の方法。
- mは0であり、nは0であり、Xは-C(O)であり、Yは-N-であり、R1はハロゲンであり、R3はHであり、R4はHであり、R5はピリジニル、ピラジニル、又はピリミジニルである、ことを特徴とする請求項1に記載の方法。
- mは0であり、nは0であり、XはS(O)2であり、Yは-N-であり、R1はハロゲン又はC1-4アルキルであり、R3はHであり、R4はそれに結合している窒素原子及びR5と一緒に縮合二環を形成し、好ましくは、前記縮合二環はインドリル又はアザインドリルである、ことを特徴とする請求項1に記載の方法。
- mは0であり、R1はハロゲンであり、nは1~4の任意の整数であり、R3はHであり、XはC(O)であり、R4はHであり、R5はアルキレン-R6であり、ここで、R6は、NRaRb、O、N及びSから選択される0~3個のヘテロ原子を有するC5-7複素環、又はO、N及びSから選択される0~3個のヘテロ原子を有するC10-12縮合複素環であり、Ra及びRbはアルキルである、ことを特徴とする請求項1に記載の方法。
- mは0であり、R1はハロゲンであり、nは1~2の任意の整数であり、R3はHであり、XはC(O)であり、R4はHであり、R5は(CH2)1-4R6であり、ここで、R6は未置換又は置換のピロリジニル、オキソラニル、チオラニル、ピロリル、フラニル、チオフェニル、ピペリジニル、オキサニル、チアニル、モルホリノイル、ピリジニル、ピペリジニル、ピペラジニル、チオピラニル、ピラジニル、ピリミジニル、ピリダジニル、チアゾリル、ベンゾイミダゾリル、ピラゾリル、インダゾリル、ピラゾリル、キノリニル、インドリル、インダゾリル、アザインドリル、アザインダゾリル、デアザプリニル、又はインダニルである、ことを特徴とする請求項1に記載の方法。
- mは0であり、R1はハロゲンであり、nは1~2の任意の整数であり、R3はHであり、XはC(O)であり、R4はHであり、R5は(CH2)1-4R6であり、ここで、R6は未置換又は置換のピロリジニル、モルホリノイル、ピリジニル、ピペリジニル、ピペラジニル、又はインドリルである、ことを特徴とする請求項1に記載の方法。
- 前記化合物は、
4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-ヒドロキシベンズアミド、
4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(ピリジン-2-イル)ベンズアミド、
N-(2-アミノフェニル)-4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)ベンズアミド、
4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(ピリジン-3-イル)ベンズアミド、
4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(ピリジン-3-イル)ベンズアミド、
4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(3-フルオロフェニル)ベンズアミド、
4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(4-フルオロフェニル)ベンズアミド、
4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-フェニルベンズアミド、
4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(2-フルオロフェニル)ベンズアミド、
4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(チアゾール-2-イル)ベンズアミド、
N-(1H-ベンゾ[d]イミダゾール-2-イル)-4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)ベンズアミド、
4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(4-ヒドロキシフェニル)ベンズアミド、
4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(3-エチニルフェニル)ベンズアミド、
4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(2-フルオロ-4-ヨードフェニル)ベンズアミド、
N-(1H-ベンゾ[d]イミダゾール-5-イル)-4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)ベンズアミド、
2-(4-(3-アミノ-1H-ピラゾール-1-カルボニル)ベンジルアミノ)-3-クロロナフタレン-1,4-ジオン、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-シクロプロピルベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-シクロペンチルベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(1H-インダゾール-5-イル)ベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(5-メチルチアゾール-2-イル)ベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(5-メチル-3H-ピラゾール-3-イル)ベンズアミド、
2-(4-(3-アミノ-5-メチル-1H-ピラゾール-1-カルボニル)ベンジルアミノ)-3-クロロナフタレン-1,4-ジオン、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(3-ニトロピリジン-4-イル)ベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(キノリン-6-イル)ベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(キノリン-8-イル)ベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(キノリン-3-イル)ベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(キノリン-5-イル)ベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(2-メチルキノリン-4-イル)ベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(1H-インドール-5-イル)ベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(2-メチル-1H-インドール-5-イル)ベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(1H-インドール-5-イル)ベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(1H-インドール-4-イル)ベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(4-(4-エチルピペラジン-1-イル)フェニル)ベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(1H-インダゾール-6-イル)ベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(1H-ピロロ[2,3-b]ピリジン-5-イル)ベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(1H-ピラゾロ[3,4-b]ピリジン-5-イル)ベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(7-メチル-7H-ピロロ[2,3-d]ピリミジン-4-イル)ベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(2,3-ジヒドロ-1H-インデン-4-イル)ベンズアミド、
4-(((3-ブロモ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(ピリジン-2-イル)ベンズアミド、
4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(ピリミジン-4-イル)ベンズアミド、
4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(ピラジン-2-イル)ベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(ピリジン-4-イルメチル)ベンズアミド、
4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)-N-(2-モルホリノエチル)ベンズアミド、
N-(2-(1H-インドール-3-イル)エチル)-4-((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イルアミノ)メチル)ベンズアミド、
4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(2-(ジメチルアミノ)エチル)ベンズアミド、
4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(2-(ピロリジン-1-イル)エチル)ベンズアミド、
4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(2-(ジエチルアミノ)エチル)ベンズアミド、
4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(2-(ピペリジン-1-イル)エチル)ベンズアミド、及び
4-(((3-クロロ-1,4-ジオキソ-1,4-ジヒドロナフタレン-2-イル)アミノ)メチル)-N-(2-(4-メチルピペラジン-1-イル)エチル)ベンズアミドから選択される、ことを特徴とする請求項1に記載の方法。 - 前記方法に使用される前記活性成分の前記有効量は、約1.5mg/kg/日~約20mg/kg/日の範囲にある、ことを特徴とする請求項1に記載の方法。
- 治療のための前記有効量は、約5.0mg/kg/日~約15mg/kg/日である、ことを特徴とする請求項1に記載の方法。
- 治療のための前記有効量は、約1.5mg/kg/日~約8mg/kg/日である、ことを特徴とする請求項1に記載の方法。
- 前記活性成分は、さらに、第2抗線維症剤と共投与される、ことを特徴とする請求項1に記載の方法。
- 前記第2抗線維症剤は、ピルフェニドン、ニンテダニブ、LOXL2抗体、シムツズマブ、IL-13抗体、レブリキズマブ、αVβ6抗体、STX-100、CTGF抗体、FG-3019、タイペルカスト、MN-001、エアロゾルのピルフェニドン又はGP-101である、ことを特徴とする請求項15に記載の方法。
- 前記共投与は、同時投与、個別投与又は逐次投与である、ことを特徴とする請求項15に記載の方法。
- 前記線維症疾患は、皮膚線維症、肺線維症、腎線維症、肝線維症、腸管線維症、嚢胞性繊維症、心線維症、子宮平滑筋腫又は腺筋症である、ことを特徴とする請求項1に記載の方法。
- 前記肺線維症は、特発性肺線維症である、ことを特徴とする請求項18に記載の方法。
- 前記肺線維症又は特発性肺線維症の治療は、肺移植、高圧酸素療法(HBOT)又は肺リハビリテーションと共投与された療法をさらに含む、ことを特徴とする請求項18に記載の方法。
- 医薬組成物であって、約1日量の請求項1で定義された式(I)の化合物又は薬学的に許容される塩、溶媒和化合物若しくはプロドラッグを活性成分として1つ又は複数の単位剤形で含む、ことを特徴とする医薬組成物。
- 前記化合物は約100mg~約1,400mgの範囲にある、ことを特徴とする請求項21に記載の医薬組成物。
- 1つ以上のカプセル形態又は錠剤形態である、ことを特徴とする請求項21に記載の医薬組成物。
- 約140mg~約1,050mgの前記活性成分を1つ又は複数の単位剤形で含むことを特徴とする請求項21に記載の医薬組成物。
- 約100mg~約300mgの前記活性成分を単一の錠剤に含む、ことを特徴とする請求項21に記載の医薬組成物。
- 約100mg~約500mgの前記活性成分を単一のカプセルに含む、ことを特徴とする請求項21に記載の医薬組成物。
- 第2抗線維症剤を更に含む、ことを特徴とする請求項21に記載の医薬組成物。
- 前記第2抗線維症剤は、ピルフェニドン、ニンテダニブ、LOXL2抗体、シムツズマブ、IL-13抗体、レブリキズマブ、αVβ6抗体、STX-100、CTGF抗体、FG-3019、タイペルカスト、MN-001、エアロゾルのピルフェニドン又はGP-101である、ことを特徴とする請求項27に記載の医薬組成物。
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JP2008522981A (ja) * | 2004-12-07 | 2008-07-03 | プロテオリックス, インコーポレイテッド | プロテアソームを阻害するための組成物 |
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JP2008522981A (ja) * | 2004-12-07 | 2008-07-03 | プロテオリックス, インコーポレイテッド | プロテアソームを阻害するための組成物 |
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TW201720433A (zh) | 2017-06-16 |
EP3377062A1 (en) | 2018-09-26 |
KR20180096609A (ko) | 2018-08-29 |
JP7085994B2 (ja) | 2022-06-17 |
EP3377062B1 (en) | 2023-09-06 |
WO2017087695A1 (en) | 2017-05-26 |
EP3377062A4 (en) | 2019-07-03 |
JP2019501126A (ja) | 2019-01-17 |
EP3377062C0 (en) | 2023-09-06 |
CA3005614A1 (en) | 2017-05-26 |
US11833122B2 (en) | 2023-12-05 |
US20180325845A1 (en) | 2018-11-15 |
US20240130984A1 (en) | 2024-04-25 |
TWI673049B (zh) | 2019-10-01 |
CN108697697A (zh) | 2018-10-23 |
ES2955665T3 (es) | 2023-12-05 |
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