JP7422737B2 - 神経変性疾患を治療するためのPpargc1a活性化剤としての2‐アリールベンゾイミダゾール - Google Patents
神経変性疾患を治療するためのPpargc1a活性化剤としての2‐アリールベンゾイミダゾール Download PDFInfo
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- JP7422737B2 JP7422737B2 JP2021506624A JP2021506624A JP7422737B2 JP 7422737 B2 JP7422737 B2 JP 7422737B2 JP 2021506624 A JP2021506624 A JP 2021506624A JP 2021506624 A JP2021506624 A JP 2021506624A JP 7422737 B2 JP7422737 B2 JP 7422737B2
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Description
筋萎縮性側索硬化症(ALS)は、運動ニューロンの消失を特徴とし、運動機能が徐々に低下して最終的には死に至る、重篤な神経変性疾患である。ALSの運動症状には筋力低下、筋攣縮及び筋肉消耗があり、このため発話、嚥下及び呼吸が困難となる。ALSにおける運動ニューロン死の原因は不明であり、ALS症例の5~10%は遺伝性である。
アルツハイマー病(AD)は、記憶、認知、論理的思考、判断力及び情動安定性に加えて運動機能が進行性に失われることを臨床的な特徴とし、徐々に深刻な精神機能低下をもたらし最終的には死に至る、退行性脳障害である。酸化ストレスの形のニューロン代謝機能不全が、ADにおける神経変性の根本原因であるという説が示されている(Friedland-Leuner ら, Progress in Molecular Biology and Translational Science, (オランダ), 2014, Vol.127, p.183-201)。
特発性又は一次性パーキンソン症候群としても知られるパーキンソン病(PD)は、中枢神経系の神経変性疾患である。PDの運動症状は、中脳の一部である黒質のドーパミン生成細胞の死に起因するが、この細胞死の原因は不明である。この疾患の経過の初期に最も明白な症状は運動に関連する症状であり、振動、強剛、動作緩慢、並びに微細運動技能、歩行及び歩容の障害が挙げられる。後期には、この疾患の進行期によく生じる認知症と共に思考及び行動上の問題が発生する場合があるが、一方で抑うつが最も一般的な精神医学的症状である。他の症状には、感覚、睡眠及び情緒の障害が挙げられる。
ハンチントン舞踏病(HD)は、ハンチンチン遺伝子に変異が生じている、常染色体優性遺伝形式の中枢神経系の変性疾患である。HDは、脳内の神経細胞の進行性の破壊(変性)を引き起こす遺伝病である。HDは人間の機能的能力に広く影響を及ぼし、通常は運動、思考(認知)及び精神の障害をもたらす。
前頭側頭型変性症(FTD)は、脳の前頭葉及び側頭葉に進行性の変性が生じる、ADと密接に関係する疾患である。グリオーシス及びミクログリアの炎症性活性化が、FTD患者及びFTD動物モデルにおいて報告されている(Cagnin ら, Annals of Neurology, (米), 2004, Vol.6, p.894-897; Yi ら, Journal of Experimental Medicine (米),2010, Vol.1, p.117-128)。FTD患者には行動及び言語の緩徐な低下が認められるが、記憶は通常は比較的維持される。疾患が進行するにつれて、罹患者は系統立てて活動し、適切に行動し、自立することが次第に困難になる。この疾患の進行を遅らせるか又は止める治療は目下存在しない。
レビー小体型認知症(DLB)はPDに関係する認知症の一種である。この疾患の顕著な特徴は、罹患者の脳内にαシヌクレイン凝集物が存在することである。この患者には、PDのような症状、例えば前傾姿勢、筋強剛、引きずり足歩行及び運動開始困難、加えて論理的思考及び思考の変化、記憶障害(ただしADほど顕著ではない)が認められる。レビー小体はPDにも存在するので、これら2つの疾患は脳がαシヌクレインタンパク質をどのように処理するかという点で同じ根本的異常に関連づけることができる。さらに、PDと同様に、ミクログリアに関連した神経炎症がDLB患者の脳内に存在するが、ただしこの病理学的特徴がより広範囲に生じている(Iannaccone ら, Parkinsonism and Related Disorders, (オランダ), 2013, Vol.19, p.47-52)。
運動ニューロン疾患(MND)は、発話、歩行、嚥下、及び自発運動などの随意筋活動を制御する細胞である運動ニューロンを選択的に侵す、ALSに類似の神経学的障害である。MNDに有効な治療は存在しない。この疾患は本質的に神経変性疾患であり、進行性の身体障害及び死を引き起こす。さらに、プログラニュリンと呼ばれる特定の経路がMNDの動物モデルにおいてミクログリアの炎症性活性化を誘発する可能性があり、この経路の遺伝的除去により疾患の進行を遅らせることができる(Philips ら, Journal of neuropathology and experimental neurology, (英), 2010, Vol.69, p.1191-200)。
ギラン・バレー症候群及び多発性硬化症(MS)のような脱髄疾患は、ニューロンの髄鞘が損なわれる変性疾患である。この損傷は、患部神経におけるシグナル伝導を害し、その結果として感覚、運動、認知、又はその他の機能の欠損を引き起こす。これらの疾患を治す方法は存在しない。該疾患の最もよく知られた病型は、免疫系の細胞サブセットが関与している疾患のMSである。例えば、進行中の脱髄は、血液循環からのT細胞及びマクロファージの浸潤、並びにミクログリアの炎症性活性化と関係していることが多い(Kutzelnigg ら, Handbook of Clinical Neurology, (オランダ), 2014, Vol.122, p.15-58)。
W2はN又はC‐R2であり;
W3はN又はC‐R3であり;
W4はN又はC‐R4であり;
W5はN又はC‐R5であり;
W6はN又はC‐R6であり;
W7はN又はC‐R7であり;
W8はN又はC‐R8であり;
上記式中、
R1は、‐CH2OC(=O)R30、‐CH2OP(=O)OR40OR41、-C(=O)OR42、及び-C(=O)R43から選択され;
上記式中、
R30は、(C1‐C10)ヒドロカルビル、アミノで置換された(C1‐C10)ヒドロカルビル、(C1‐C4)アルコキシカルボニルで置換された(C1‐C10)ヒドロカルビル、カルボキシルで置換された(C1‐C10)ヒドロカルビル、カルボキシ、(C1‐C6)アルコキシカルボニル、(C1‐C6)アルコキシカルボニルアミノ、メチルチオ、ヘテロシクリル、(C1‐C10)オキサアルキル、CHR44NHR45、及びグアニジノから選択され;
上記式中、
R44は任意の天然に存在するアミノ酸側鎖から選択され;
R45はH、メチル、及び(C1‐C4)アルコキシカルボニルから選択され;
R40及びR41は、水素及び(C1‐C6)ヒドロカルビルから独立に選択され;
R42は(C1‐C5)アルキルであり;
R43は(C1‐C3)アルキルであり;
R2、R3、R4及びR5は、水素、重水素、ハロゲン、ペルフルオロ(C1‐C4)アルキル、(C1‐C4)アルキル、(C1‐C4)アルコキシ、ペルフルオロ(C1‐C4)アルコキシ、(C1‐C4)アシル、(C1‐C4)アルコキシ(C1‐C4)アルキル、ヒドロキシ(C1‐C4)アルキル、ヒドロキシ、カルボキシ、(C1‐C4)アルコキシカルボニルアミノ[‐HNC(=O)O‐アルキル]、カルボキサミド[‐C(=O)NH2]、(C1‐C4)アルキルアミノカルボニル[‐C(=O)NH‐アルキル]、シアノ、アセトキシ、ニトロ、アミノ、(C1‐C4)アルキルアミノ、ジ(C1‐C4)アルキルアミノ、メルカプト、(C1‐C4)アルキルチオ、アミノスルホニル、(C1‐C4)アルキルスルホニル、及び(C1‐C4)アシルアミノから独立に選択され;
R6及びR10は、水素、重水素、ハロ、(C1‐C3)アルキル、ペルフルオロ(C1‐C3)アルキル、ヒドロキシ、(C1‐C3)アルコキシ、ペルフルオロ(C1‐C3)アルコキシ、及びアミノから独立に選択され;
R7及びR9は、水素、重水素、ヒドロキシ、シアノ、アミノ、ハロゲン、ハロ(C1‐C4)アルキル、(C1‐C4)アルキル、(C1‐C4)アルコキシ、及びハロ(C1‐C4)アルコキシから独立に選択され;
R8は、水素、重水素、ハロゲン、ハロ(C1‐C4)アルキル、(C1‐C4)アルキル、(C1‐C4)アルコキシ、ハロ(C1‐C4)アルコキシ、シアノ、フェニル、フェノキシ、ベンジルオキシ、及びアミノから選択される。
Arは
W1は、O、S、及びN‐R1から選択されるか、又は、W9がNである場合にW1はさらにC‐R50であってよく;
W2はN又はC‐R2であり;
W3はN又はC‐R3であり;
W4はN又はC‐R4であり;
W5はN又はC‐R5であり;
W9はCであるか、又は、W1がC‐R50である場合にW9はNであってよく;
上記式中、
R1は、H、(C1‐C3)アルキル、‐CH2OC(=O)R30、‐CH2OP(=O)OR40OR41、‐C(=O)OR42、及び‐C(=O)R43から選択され;
上記式中、
R30は、(C1‐C10)ヒドロカルビル、アミノで置換された(C1‐C10)ヒドロカルビル、(C1‐C4)アルコキシカルボニルで置換された(C1‐C10)ヒドロカルビル、カルボキシルで置換された(C1‐C10)ヒドロカルビル、カルボキシ、(C1‐C6)アルコキシカルボニル、(C1‐C6)アルコキシカルボニルアミノ、メチルチオ、ヘテロシクリル、(C1‐C10)オキサアルキル、CHR44NHR45、及びグアニジノから選択され;
上記式中、
R44は任意の天然に存在するアミノ酸側鎖から選択され;
R45はH、メチル、及び(C1‐C4)アルコキシカルボニルから選択され;
R40及びR41は、水素及び(C1‐C6)ヒドロカルビルから独立に選択され;
R42は(C1‐C5)アルキルであり;
R43は(C1‐C3)アルキルであり;
R50は、H又は(C1‐C3)アルキルであり;
R2、R3、R4及びR5は、水素、重水素、ハロゲン、ペルフルオロ(C1‐C4)アルキル、(C1‐C4)アルキル、(C1‐C4)アルコキシ、ペルフルオロ(C1‐C4)アルコキシ、(C1‐C4)アシル、(C1‐C4)アルコキシ(C1‐C4)アルキル、ヒドロキシ(C1‐C4)アルキル、ヒドロキシ、カルボキシ、(C1‐C4)アルコキシカルボニルアミノ[‐HNC(=O)O‐アルキル]、カルボキサミド[‐C(=O)NH2]、(C1‐C4)アルキルアミノカルボニル[‐(C(=O)NH‐アルキル]、シアノ、アセトキシ、ニトロ、アミノ、(C1‐C4)アルキルアミノ、ジ(C1‐C4)アルキルアミノ、メルカプト、(C1‐C4)アルキルチオ、アミノスルホニル、(C1‐C4)アルキルスルホニル、及び(C1‐C4)アシルアミノから独立に選択され;
ただし、Arは、
W9がCであり;
W1がN‐R1であり;かつ
R1がHでも(C1‐C3)アルキルでもない
という場合に限り、
W1は、O、S、及びN‐R1から選択されるか、又は、W9がNである場合にW1はさらにC‐R50であってよく;
W2はN又はC‐R2であり;
W3はN又はC‐R3であり;
W4はN又はC‐R4であり;
W5はN又はC‐R5であり;
W6はN又はC‐R6であり;
W7はN又はC‐R7であり;
W8はN又はC‐R8であり;
W9はCであるか、又は、W1がC‐R50である場合にW9はNであってよく;
上記式中、
R1は、H、(C1‐C3)アルキル、‐CH2OC(=O)R30、‐CH2OP(=O)OR40OR41、‐C(=O)OR42、及び‐C(=O)R43から選択され;
上記式中、
R30は、(C1‐C10)ヒドロカルビル、アミノで置換された(C1‐C10)ヒドロカルビル、(C1‐C4)アルコキシカルボニルで置換された(C1‐C10)ヒドロカルビル、カルボキシルで置換された(C1‐C10)ヒドロカルビル、カルボキシ、(C1‐C6)アルコキシカルボニル、(C1‐C6)アルコキシカルボニルアミノ、メチルチオ、ヘテロシクリル、(C1‐C10)オキサアルキル、CHR44NHR45、及びグアニジノから選択され;
上記式中、
R44は任意の天然に存在するアミノ酸側鎖から選択され;
R45はH、メチル、及び(C1‐C4)アルコキシカルボニルから選択され;
R40及びR41は、水素及び(C1‐C6)ヒドロカルビルから独立に選択され;
R42は(C1‐C5)アルキルであり;
R43は(C1‐C3)アルキルであり;
R50は、H又は(C1‐C3)アルキルであり;
R2、R3、R4及びR5は、水素、重水素、ハロゲン、ペルフルオロ(C1‐C4)アルキル、(C1‐C4)アルキル、(C1‐C4)アルコキシ、ペルフルオロ(C1‐C4)アルコキシ、(C1‐C4)アシル、(C1‐C4)アルコキシ(C1‐C4)アルキル、ヒドロキシ(C1‐C4)アルキル、ヒドロキシ、カルボキシ、(C1‐C4)アルコキシカルボニルアミノ[‐HNC(=O)O‐アルキル]、カルボキサミド[‐C(=O)NH2]、(C1‐C4)アルキルアミノカルボニル[‐(C(=O)NH‐アルキル]、シアノ、アセトキシ、ニトロ、アミノ、(C1‐C4)アルキルアミノ、ジ(C1‐C4)アルキルアミノ、メルカプト、(C1‐C4)アルキルチオ、アミノスルホニル、(C1‐C4)アルキルスルホニル、及び(C1‐C4)アシルアミノから独立に選択され;
R6及びR10は、水素、重水素、ハロ、(C1‐C3)アルキル、ペルフルオロ(C1‐C3)アルキル、ヒドロキシ、(C1‐C3)アルコキシ、ペルフルオロ(C1‐C3)アルコキシ、及びアミノから独立に選択され;
R7及びR9は、水素、重水素、ヒドロキシ、シアノ、アミノ、ハロゲン、ハロ(C1‐C4)アルキル、(C1‐C4)アルキル、(C1‐C4)アルコキシ、及びハロ(C1‐C4)アルコキシから独立に選択され;
R8は、水素、重水素、ハロゲン、ハロ(C1‐C4)アルキル、(C1‐C4)アルキル、(C1‐C4)アルコキシ、ハロ(C1‐C4)アルコキシ、シアノ、フェニル、フェノキシ、ベンジルオキシ、及びアミノから選択され;
ただし、R8は、
(a)W1がN‐R1であり;
(b)R1が水素であり;
(c)W2、W3、W4、W5、W6、及びW7がC‐Hであり;
(d)W8がC‐R8であり;
(e)W9がCであり;かつ
(f)R9及びR10が水素である
という場合には、水素でも(C1‐C4)アルキルでもない。
化合物の調製は、様々な化学基の保護及び脱保護を伴う可能性がある。保護及び脱保護の必要性、並びに適切な保護基の選択は、当業者であれば容易に決定することができる。その目的に適した基については、化学分野の標準的な教科書、例えばT.W.Greene and P.G.M.Wuts, “Protective Groups in Organic Synthesis”, (米), John Wiley and Sons, New York, 1999; Jeremy Robertson, “Protecting Group Chemistry”, 1st Ed., (英), Oxford University Press, 2000及びMichael B. Smith, “March's Advanced Organic chemistry: Reactions, Mechanisms, and Structure”, 5th Ed., (米), Wiley-Interscience Publication, 2001において議論されている。
実施例1. 2‐(4‐(tert‐ブチル)フェニル)‐1H‐ベンゾ[d]イミダゾール
実施例2. 2‐(4‐(tert‐ブチル)フェニル)‐1H‐イミダゾ[4,5‐c]ピリジン
実施例3. 2‐(4‐tert‐ブチルフェニル)‐1,3‐ベンゾチアゾール
実施例4. 2‐(4‐tert‐ブチルフェニル)‐1,3‐ベンゾオキサゾール
実施例5. 2‐(4‐tert‐ブチルフェニル)イミダゾ[1,2‐a]ピリジン
1‐アルキル‐ベンゾイミダゾールは、重炭酸ナトリウム又は炭酸ナトリウムの存在下でハロゲン化アルキルを滴下して添加することにより合成した。
実施例6. 2‐(4‐tert‐ブチルフェニル)‐1‐メチル‐ベンゾ[d]イミダゾール
ベンゾイミダゾールのプロドラッグは、還流中のアセトンの中でヨウ化ナトリウム及び炭酸ナトリウムの存在下にてベンゾイミダゾールをクロロメチルエステルとともに加熱することにより調製するが、又は別例として、還流中のアセトンの中でヨウ化ナトリウム及び炭酸ナトリウムの存在下にてベンゾイミダゾールをクロロメチルカルボナートとともに加熱することにより調製することも可能である(実施例6‐P~9‐P及び11‐P)。
実施例1‐P. (2‐(4‐(tert‐ブチル)フェニル)‐1H‐ベンゾ[d]イミダゾール‐1‐イル)メチルアセタート
実施例2‐P. (2‐(4‐(tert‐ブチル)フェニル)‐1H‐ベンゾ[d]イミダゾール‐1‐イル)メチルブチラート
実施例3‐P. (2‐(4‐(tert‐ブチル)フェニル)‐1H‐ベンゾ[d]イミダゾール‐1‐イル)メチルイソブチラート
実施例4‐P. (2‐(4‐(tert‐ブチル)フェニル)‐1H‐ベンゾ[d]イミダゾール‐1‐イル)メチルピバラート
実施例5‐P. tert‐ブチル((2‐(4‐(tert‐ブチル)フェニル)‐1H‐ベンゾ[d]イミダゾール‐1‐イル)メチル)スクシナート
この混合物を周囲温度まで冷却し、フィルタ処理し、溶媒を減圧下で蒸発させた。
残渣をフラッシュクロマトグラフィ(ヘキサン‐EtOAc、100:0→70:30)により精製するとろう状の固体が得られ、この固体をヘキサンでトリチュレーションして白色固体を得た(487mg、28%)。1H NMR (500 MHz, CDCl3): δ 7.83-7.80 (3H, m, overlapping), 7.61-7.59 (1H, m), 7.57 (2H, d, J = 8.4 Hz), 7.35-7.33 (2H, m), 6.20 (2H, s), 2.69 (2H, t, J = 6.5 Hz), 2.60 (2H, t, J= 6.5 Hz), 1.41 (9H, s), 1.38 (9H, s); LCMS: rt 3.80-3.90 min, +ve ESI m/z 437.1 ([M + H]+, 100%).
実施例6‐P. 4‐((2‐(4‐(tert‐ブチル)フェニル)‐1H‐ベンゾ[d]イミダゾール‐1‐イル)メトキシ)‐4‐オキソブタン酸
実施例7‐P. (2‐(4‐(tert‐ブチル)フェニル)‐1H‐ベンゾ[d]イミダゾール‐1‐イル)メチル4‐(((tert‐ブトキシカルボニル)アミノ)メチル)ベンゾアート
実施例8‐P. (4‐(((2‐(4‐(tert‐ブチル)フェニル)‐1H‐ベンゾ[d]イミダゾール‐1‐イル)メトキシ)カルボニル)‐フェニル)メチルアンモニウムヒドロクロリド
ベンゾイミダゾールのプロドラッグは、ベンゾイミダゾールを過剰量の水素化ナトリウムで処理した後にジアルキルクロロメチルホスファートで処理することにより調製する。ジtert‐ブチルクロロメチルホスファートの場合には、得られた生成物を酸加水分解に供してジヒドロゲンホスファートのプロドラッグを得ることができる。上記の手法は、Chassaingら(Journal of Medicinal Chemistry, (米), 2008, Vol.51, p.1111)及びFlores-Ramosら(Bioorganic & Medicinal Chemistry Letters, (オランダ), 2014, Vol.24, p.5814)が報告した手法の変法である。
実施例10‐P. ジヒドロゲン((2‐(4‐(tert‐ブチル)フェニル)‐1H‐ベンゾ[d]イミダゾール‐1‐イル)メチル)ホスファート
実施例11‐P. ジソディウム((2‐(4‐(tert‐ブチル)フェニル)‐1H‐ベンゾ[d]イミダゾール‐1‐イル)メチル)ホスファート
実施例12‐P. (2‐(4‐(tert‐ブチル)フェニル)‐1H‐ベンゾ[d]イミダゾール‐1‐イル)メチル(tert‐ブトキシカルボニル)‐L‐アラニナート
酸化的代謝は骨髄性細胞の表現型に抗炎症性の作用を及ぼし(O'Neill LA, Frontiers in Immunology, (スイス), 2014, Vol.5, 420)、Ppargc1aはこのエネルギー代謝経路を促進する可能性がある(Spiegelman BM, Novartis Foundation Symposium, (米) 2007)。よって、Ppargc1aの薬理学的活性化は骨髄性細胞の炎症反応を阻害すると予想された。この現象はTNF‐α阻害試験により培養物中で測定可能である。
ネズミ動物の骨髄性細胞株BV2又はヒト末梢血単核細胞(PBMC)を、10%ウシ胎児血清及び1%L‐グルタミン1%ペニシリンを補足したRPMI1640培地(カタログ番号11875119、ギブコ)で培養する。これらの細胞を次に、100ng/mlのリポポリサッカライド(LPS、O111:B4、カタログ番号L2630、シグマ)で24時間刺激する。LPS刺激の結果、BV2細胞又はPBMCによって炎症性サイトカインTNF‐αが分泌されるが、その量は、製造業者の実施手順書(BV2はカタログ番号558273、PBMCはカタログ番号558299、BDバイオサイエンス)に従って培養上清試料中でELISAによって定量可能である。実施例の化合物1~78がBV2細胞又はPBMCによるTNF‐α産生を阻害するかどうか判定するために、細胞を様々な濃度の化合物が存在する状態で培養し、ジメチルスルホキシド(ビヒクル対照)が存在する状態で培養された同じ細胞によるTNF‐α産生に対してTNF‐α産生が何倍低減されるかを決定した。結果を表2に示す。
ヒト肝臓ミクロソーム(コーニング#452117、ロット38291)又はマウス肝臓ミクロソーム(コーニング#452701、ロット番号6328004)を個別に、終濃度11.25mgタンパク質/化合物として、KxPO4、pH7.4(100mM)、MgCl2(10mM)、及び被験化合物(1μM)と組み合わせ、プレインキュベートした(10分、37℃)。次に、NADPH(1mM)を添加して反応を開始させた(全容積100μL)。様々な時点(0、10、20、及び40分)において、アセトニトリル中のClem停止溶液(100μL、625ng/mL)(シプロテクス)で反応を停止させた。試料を4000gで20分間遠心分離処理し、希釈し(75μLを75μLの0.1%ギ酸水溶液に添加)、LC‐MS/MSで分析した。結果を表3に示す。
Caco‐2細胞を、5%CO2の雰囲気中DMEMで維持した。輸送実験のために細胞5×105個/ウェルをポリカーボネート製フィルタのインサート上に播種し、21±4日間増殖及び分化させてから細胞単層を実験に使用した。見かけの透過係数を、輸送体阻害剤としてのエラクリダールの存在下及び非存在下において、A→B方向及びB→A方向について決定した。最大3種の被験物及び参照化合物をpH7.4のハンクス平衡塩類溶液に溶解して終濃度10μMとした。試験は、25mMのHEPES(pH7.4)を含有するHBSS中にて37℃で実施した。この試験に先立ち、単層を予め暖めたHBSS中で洗った。実験の最初に、被験物を含有している予め暖めたHBSSを単層のドナー側に添加し、被験物を含まないHBSSをレシーバ側に添加した。レシーバ側のアリコートは2時間のインキュベーション期間にわたって採取し;ドナー側のアリコートは0時間及び2時間で採取した。アリコートを、内部標準を含有する0.1%のギ酸を含む等体積のメタノール/水で希釈した。該混合物をLC‐MS/MSで分析した。見かけの透過係数(Papp)を、式:Papp=(dCrec/dt)/(A×C0,donor)]×106を使用して計算したが、前記式中、dCrev/dtはレシーバ側区画内の経時的な濃度変化であり、C0,donorは時間0におけるドナー側区画内の濃度であり、Aは細胞が存在する区画の面積である。結果を表3に示す。
図2は、プロドラッグの実施例6‐P、8‐P、及び11‐PのAPIの脳中レベルを示す。
図3は、プロドラッグの実施例6‐P、8‐P、及び11‐PのAPIの肝臓中レベルを示す。
Claims (5)
- 式(III):
上記式中、
W1は、N‐R1 であり;
W2 はC‐R2であり;
W3 はC‐R3であり;
W4 はC‐R4であり;
W5 はC‐R5であり;
W6 はC‐R6であり;
W7 はC‐R7であり;
W8 はC‐R8であり;
W9はCであり;
上記式中、
R1は、H、又は(C1‐C3)アルキルであり;
R 2、R3、R4及びR5は、水素、重水素、ハロゲン、ペルフルオロ(C1‐C4)アルキル、(C1‐C4)アルキル、(C1‐C4)アルコキシ、ペルフルオロ(C1‐C4)アルコキシ、(C1‐C4)アシル、(C1‐C4)アルコキシ(C1‐C4)アルキル、ヒドロキシ(C1‐C4)アルキル、ヒドロキシ、カルボキシ、(C1‐C4)アルコキシカルボニルアミノ[‐HNC(=O)O‐アルキル]、カルボキサミド[‐C(=O)NH 2 ]、(C1‐C4)アルキルアミノカルボニル[‐(C(=O)NH‐アルキル]、シアノ、アセトキシ、ニトロ、アミノ、(C1‐C4)アルキルアミノ、ジ(C1‐C4)アルキルアミノ、メルカプト、(C1‐C4)アルキルチオ、アミノスルホニル、(C1‐C4)アルキルスルホニル、及び(C1‐C4)アシルアミノから独立に選択され;
R6及びR10は、水素、重水素、ハロ、(C1‐C3)アルキル、ペルフルオロ(C1‐C3)アルキル、ヒドロキシ、(C1‐C3)アルコキシ、ペルフルオロ(C1‐C3)アルコキシ、及びアミノから独立に選択され;
R7及びR9は、水素、重水素、ヒドロキシ、シアノ、アミノ、ハロゲン、ハロ(C1‐C4)アルキル、(C1‐C4)アルキル、(C1‐C4)アルコキシ、及びハロ(C1‐C4)アルコキシから独立に選択され;
R8は、tert-ブチルであり;
ただし、前記化合物は
でない、医薬組成物。 - 前記神経変性疾患は、筋萎縮性側索硬化症(ALS)、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、前頭側頭型変性症、レビー小体型認知症、運動ニューロン疾患、及び脱髄疾患からなる群から選択される、請求項1に記載の医薬組成物。
- 老齢化に関連する認知障害及び神経炎症の治療用である、請求項1に記載の医薬組成物。
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