JP2015506995A - グリコーゲンシンターゼキナーゼ3ベータ阻害剤としての1h−インダゾール−3−カルボキサミド化合物の使用 - Google Patents
グリコーゲンシンターゼキナーゼ3ベータ阻害剤としての1h−インダゾール−3−カルボキサミド化合物の使用 Download PDFInfo
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- JP2015506995A JP2015506995A JP2014556994A JP2014556994A JP2015506995A JP 2015506995 A JP2015506995 A JP 2015506995A JP 2014556994 A JP2014556994 A JP 2014556994A JP 2014556994 A JP2014556994 A JP 2014556994A JP 2015506995 A JP2015506995 A JP 2015506995A
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Abstract
Description
であって、式中、
RaおよびRa’は、互いに同じまたは異なるが、水素原子;ハロゲン原子;任意でハロゲン、ヒドロキシ、−NH2、およびC1〜C3アルコキシからなる群から選択される1つ以上の置換基により置換される、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニルおよびC1〜C6アルコキシ基;任意でハロゲン、ヒドロキシ、C1〜C6アルキル、C1〜C6アルコキシ、−NR1R2、−C(O)OH、−C(O)OR1および−C(O)NR1R2からなる群から選択される1つ以上の置換基により置換される、3〜12員を有する脂肪族または芳香族炭素または複素環であり;
Yは、結合、任意でハロゲン、ヒドロキシ、−NH2、およびC1〜C3アルコキシからなる群から選択される1つ以上の置換基により置換される、C1〜C6アルキル、C2〜C6アルケニルまたはC2〜C6アルキニル基であり;
Rbはハロゲン、ヒドロキシ、ニトロ、シアノ、−CF3、C1〜C6アルコキシ、ベンジルオキシ、C1〜C4アルキル、C2〜C4アルケニル、C2〜C4アルキニル、−NHSO2CH3、−SO2NH2、Zがσ結合または(C1〜C3)アルキルである−Z−C(O)OH、−Z−C(O)OR1および−Z−C(O)NR1R2からなる群から選択される1つ以上の置換基により置換される、3〜12員を有する脂肪族または芳香族炭素または複素環であり;
R1およびR2は独立して水素原子、C1〜C4アルキル基、C2〜C4アルケニル基、C2〜C4アルキニル基、およびフェニル基である、式
を有する1H−インダゾール−3−カルボキサミド化合物、ならびに医薬的に許容可能な有機および無機酸および塩基を添加したその塩の使用に関する。
であって、式中、
RaおよびRa’は、互いに同じまたは異なるが、水素原子;ハロゲン原子;任意でハロゲン、ヒドロキシ、−NH2、およびC1〜C3アルコキシからなる群から選択される1つ以上の置換基により置換される、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニルおよびC1〜C6アルコキシ基;任意でハロゲン、ヒドロキシ、C1〜C6アルキル、C1〜C6アルコキシ、−NR1R2、−C(O)OH、−C(O)OR1および−C(O)NR1R2からなる群から選択される1つ以上の置換基により置換される、3〜12員を有する脂肪族または芳香族炭素または複素環であり;
Yは、結合、任意でハロゲン、ヒドロキシ、−NH2、およびC1〜C3アルコキシからなる群から選択される1つ以上の置換基により置換される、C1〜C6アルキル、C2〜C6アルケニルまたはC2〜C6アルキニル基であり;
Rbはハロゲン、ヒドロキシ、ニトロ、シアノ、−CF3、C1〜C6アルコキシ、ベンジルオキシ、C1〜C4アルキル、C2〜C4アルケニル、C2〜C4アルキニル、−NHSO2CH3、−SO2NH2、Zがσ結合または(C1〜C3)アルキルである−Z−C(O)OH、−Z−C(O)OR1および−Z−C(O)NR1R2からなる群から選択される1つ以上の置換基により置換される、3〜12員を有する脂肪族または芳香族炭素または複素環であり;
R1およびR2は独立して水素原子、C1〜C4アルキル基、C2〜C4アルケニル基、C2〜C4アルキニル基、およびフェニル基である、式
を有する1H−インダゾール−3−カルボキサミド、ならびに医薬的に許容可能な有機および無機酸および塩基を添加したその塩の投与による、治療方法に関する。
− N−{[1−(2,4−ジクロロベンジル)ピペリジン−4−イル]メチル}−5−メトキシ−1H−インダゾール−3−カルボキサミドおよび
− N−({1−[4−(ベンジルオキシ)ベンジル]ピペリジン−4−イル}メチル)−5−メトキシ−1H−インダゾール−3−カルボキサミド
の1H−インダゾール−3−カルボキサミド化合物に関する。
式(I)の化合物は、当業者に知られる方法により、例えば下記の方法A〜Dにより得ることができる。
第1ステップ:
第1ステップ:
−3’:T1=160℃、T2=130℃;最大電力300W
−45’:T1=160℃、T2=130℃;最大電力300W
−5’;T1=20℃、T2=15℃。
方法A〜Dの1つに従って得られた式(I)の化合物は、下記の技術(a)〜(c)の1つで精製することができる。
20〜45μMシリカカートリッジ上のBiotage Flash Master Personalシステム、または40μMシリカカートリッジを用いるGrace Revelerisフラッシュクロマトグラフィーシステムでフラッシュクロマトグラフィーを行った。
精製する化合物に応じて異なる結晶化溶媒を用いた。溶媒は下記の表2に示す。
LC/MSシステムは、Waters2767サンプルマネージャ、Waters2478デュアルλ吸光検出器およびエレクトロスプレーイオン化(ESI)源を用いるWaters Micromass ZQシングル四重極型質量分析計で構成される。用いたカラムは、X−Bridge Prep C18 5μmと19×10mm(Waters)プレカラムだった。分画回収はシステムソフトウェアMassLynx(商標)v.4.1から得ることができた。検出波長は230nmおよび温度は25℃に設定した。
チャネルA=CH3CN+0.1%ギ酸(溶離液A)
チャネルB=H2O+0.1%ギ酸(溶離液B)
フロー=40ml/分
勾配=15分で達する溶離液Aの最小および最大パーセントはそれぞれ2〜20および25〜55の範囲である。
7a)4−({[(5−メトキシ−1H−インダゾール−3−イル)カルボニル]アミノ}メチル)ピペリジン−カルボン酸tert−ブチル
1−ヒドロキシベンゾトリアゾール(HOBt、24.3g、142ミリモル)およびN,N’−ジシクロヘキシルカルボジイミド(DCC、29.3g、142ミリモル)を、DMF(400mL)中の5−メトキシ−1H−インダゾ−ル−3−カルボン酸(30g、129ミリモル)の溶液に0℃で添加した。1時間後、DMF(250mL)中の[4−(アミノメチル)ピペリジン−1−イル]酢酸エチル(26g、129ミリモル)の溶液を同じ温度で添加した。混合物を0℃で2時間撹拌した後、夜間室温に達するまで放置した。混合物をEtOAcで希釈し、固体を濾過により除去した。溶液を塩酸(HCl)2Nで3回抽出した。酸相のpHを5NのNaOHで増加させ(約13)、溶液をジクロロメタン(DCM)で3回抽出した。有機相を無水Na2SO4で乾燥させ、溶媒を濾過し、減圧下で蒸発させ、4−({[(5−メトキシ−1H−インダゾール−3−イル)カルボニル]アミノ}メチル)ピペリジン−カルボン酸tert−ブチル7a(96%収率)をもたらした。
Et2O(1.8L)中の2MのHClを、MeOH(500mL)中の化合物7a(92.8g、0.24モル)の溶液に添加した。混合物を3時間室温で撹拌した後、得られた固体を濾過し、乾燥させ、5−メトキシ−N−(ピペリジン−4−イルメチル)−1H−インダゾール−3−カルボキサミド塩酸塩7b(61.1g、89%収率)を得た。
MeOH(10mL)中の化合物7(1.85ミリモル)の溶液に、1Mの水性NaOH(3.7mL)を添加した。溶液を一晩還流した後、有機溶媒を真空下で除去し、残渣をH2Oで希釈し、1MのHClを添加することによりpHを5に調節した。混合物を一晩4℃で保持した後、得られた固体を濾過し、清浄水で洗浄し、真空下で乾燥させ、2−{[4−({[(5−メトキシ−1H−インダゾール−3−イル)カルボニル]アミノ}メチル)ピペリジン−1−イル]メチル}−1,3−チアゾール−4−カルボン酸8(43%収率)を得た。
2−{[4−({[(5−メトキシ−1H−インダゾール−3−イル)カルボニル]アミノ}メチル)ピペリジン−1−イル]メチル}−1,3−オキサゾール−4−カルボン酸メチル9を、化合物7について記載した手順に従い、2−(クロロメチル)−1,3−オキサゾール−4−カルボン酸メチルを用いて調製した。収率:410mg、45%。
2−{[4−({[(5−メトキシ−1H−インダゾール−3−イル)カルボニル]アミノ}メチル)ピペリジン−1−イル]メチル}−1,3−オキサゾール−4−カルボン酸水和物10を、化合物8について記載した手順に従い、化合物9から出発して調製した。収率:238mg、82%。
11a)4−({[(5−ブロモ−1H−インダゾール−3−イル)カルボニル]アミノ}メチル)ピペリジン−1−カルボン酸tert−ブチル
4−({[(5−ブロモ−1H−インダゾール−3−イル)カルボニル]アミノ}メチル)ピペリジン−1−カルボン酸tert−ブチル11aを、化合物7について記載した手順に従い、5−ブロモ−1H−インダゾール−3−カルボン酸および4−(アミノメチル)ピペリジン−1−カルボン酸tert−ブチルから調製した。収率:40.6g、87%。
Et2O(1.8L)中の2MのHClを、MeOH(500mL)中の4−(アミノメチル)ピペリジン−1−カルボン酸tert−ブチル11a(0.24モル)の溶液に添加した。混合物を3時間室温で撹拌した後、得られた固体を濾過し、乾燥させ、5−ブロモ−N−(ピペリジン−4−イルメチル)−1H−インダゾール−3−カルボキサミド塩酸塩11b(76%収率)を得た。
1,4−ジオキサンおよび水(3:1比、8mL)中の化合物11(0.44ミリモル)、(2,3−ジフルオロフェニル)ボロン酸(1.77ミリモル)、[1,1’−ビス(ジフェニルホスフィノ)フェロセン]−ジクロロ−パラジウム(II)[Pd(dppf)Cl2](81mg、0.11ミリモル)および炭酸セシウム(575mg、1.76ミリモル)の溶液に、下記のとおりマイクロ波照射を行った:
時間=3’;T1=160℃、T2=130℃;最大電力300W
時間=45’;T1=160℃、T2=130℃;最大電力300W
時間=5’;T1=20℃、T2=15℃。
4−{[4−({[(5−メトキシ−1H−インダゾール−3−イル)カルボニル]アミノ}メチル)ピペリジン−1−イル]メチル}−1,3−チアゾール−2−カルボン酸エチル13を、化合物7について記載した手順に従い、4−(クロロメチル)−1,3−チアゾール−2−カルボン酸エチルを用いて調製した。収率:45mg、11%。
2−{[4−({[(5−メトキシ−1H−インダゾール−3−イル)カルボニル]アミノ}メチル)ピペリジン−1−イル]メチル}フラン−3−カルボン酸メチル14を、化合物7について記載した手順に従い、2−(クロロメチル)フラン−3−カルボン酸メチルを用いて調製した。収率:120mg、13%。
5−{[4−({[(5−ブロモ−1H−インダゾール−3−イル)カルボニル]アミノ}メチル)ピペリジン−1−イル]メチル}フラン−2−カルボン酸エチル15を、化合物7について記載した手順に従い、11bおよび5−(クロロメチル)フラン−2−カルボン酸エチルから調製した。収率:300mg、62%。
5−({4−[({[5−(2−メトキシピリジン−3−イル)−1H−インダゾール−3−イル]カルボニル}アミノ)メチル]ピペリジン−1−イル}メチル)フラン−2−カルボン酸水和物16を、化合物12について記載した手順に従い、化合物15および(2−メトキシピリジン−3−イル)ボロン酸から、精製に下記の予備HPLCパラメーターを用いて調製した:チャネルA=CH3CN+0.1%ギ酸;チャネルB=H2O+0.1%ギ酸;フロー=40ml/分;勾配=15分で溶離液Aの10%〜45%。収率:14mg、5%。
5−({4−[({[5−(6−メトキシピリジン−3−イル)−1H−インダゾール−3−イル]カルボニル}アミノ)メチル]ピペリジン−1−イル}メチル)フラン−2−カルボン酸水和物17を、化合物12について記載した手順に従い、化合物15および(6−メトキシピリジン−3−イル)ボロン酸から、精製に下記の予備HPLCパラメーターを用いて調製した:チャネルA=CH3CN+0.1%ギ酸;チャネルB=H2O+0.1%ギ酸;フロー=40ml/分;勾配=15分で溶離液Aの10%〜45%。収率:23mg、8%。
5−({4−[({[5−(4−メトキシフェニル)−1H−インダゾール−3−イル]カルボニル}アミノ)メチル]ピペリジン−1−イル}メチル)フラン−2−カルボン酸水和物18を、化合物12について記載した手順に従い、化合物15および(4−メトキシフェニル)ボロン酸から、精製に下記の予備HPLCパラメーターを用いて調製した:チャネルA=CH3CN+0.1%ギ酸;チャネルB=H2O+0.1%ギ酸;フロー=40ml/分;勾配=15分で溶離液Aの10%〜50%。収率:14mg、5%。
5−({4−[({[5−(2,3−ジフルオロフェニル)−1H−インダゾール−3−イル]カルボニル}アミノ)メチル]ピペリジン−1−イル}メチル)フラン−2−カルボン酸19を、化合物12について記載した手順に従い、化合物15および(2,3−ジフルオロフェニル)ボロン酸から、精製に下記の予備HPLCパラメーターを用いて調製した:チャネルA=CH3CN+0.1%ギ酸;チャネルB=H2O+0.1%ギ酸;フロー=40ml/分;勾配=15分で溶離液Aの15%〜50%。収率:32mg、11%。
5−({4−[({[5−(2−フルオロフェニル)−1H−インダゾール−3−イル]カルボニル}アミノ)メチル]ピペリジン−1−イル}メチル)フラン−2−カルボン酸水和物20を、化合物12について記載した手順に従い、化合物15および(2−フルオロフェニル)ボロン酸から、精製に下記の予備HPLCパラメーターを用いて調製した:チャネルA=CH3CN+0.1%ギ酸;チャネルB=H2O+0.1%ギ酸;フロー=40ml/分;勾配=15分で溶離液Aの10%〜45%。収率:20mg、7%。
5−({4−[({[5−(4−メトキシピリジン−3−イル)−1H−インダゾール−3−イル]カルボニル}アミノ)メチル]ピペリジン−1−イル}メチル)フラン−2−カルボン酸ギ酸塩21を、化合物12について記載した手順に従い、化合物15および(4−メトキシピリジン−3−イル)ボロン酸から、精製に下記の予備HPLCパラメーターを用いて調製した:チャネルA=CH3CN+0.1%ギ酸;チャネルB=H2O+0.1%ギ酸;フロー=40ml/分;勾配=15分で溶離液Aの2%〜40%。収率:40mg、14%。
5−{[4−({[(5−ブロモ−1H−インダゾール−3−イル)カルボニル]アミノ}メチル)ピペリジン−1−イル]メチル}フラン−2−カルボン酸22を、化合物8について記載した手順に従い、化合物15から出発し、EtOHを溶媒として用いて調製した。収率:264mg、98%。
5−{[4−({[(5−メトキシ−1H−インダゾール−3−イル)カルボニル]アミノ}メチル)ピペリジン−1−イル]メチル}フラン−2−カルボン酸エチル23を、化合物7について記載した手順に従い、5−(クロロメチル)フラン−2−カルボン酸エチルから出発して調製した。収率:290mg、71%。
5−{[4−({[(5−メトキシ−1H−インダゾール−3−イル)カルボニル]アミノ}メチル)ピペリジン−1−イル]メチル}フラン−2−カルボン酸24を、化合物8について記載した手順に従い、化合物23から出発し、EtOHを溶媒として用いて調製した。収率:64mg、84%。
アセトン(250mL)中の化合物7b(8g、24.6ミリモル)および炭酸カリウム(17g、123ミリモル)の混合物を1時間還流した後、(2R,6S)−4−(2−クロロエチル)−2,6−ジメチルモルホリン(25.9ミリモル)を滴下した。混合物を一晩還流した後、冷却し、濾過した。得られた固体を乾燥させ、予備HPLC(チャネルA=CH3CN+0.1%ギ酸;チャネルB=H2O+0.1%ギ酸;フロー=40ml/分;勾配=15分で溶離液Aの10%〜45%)によって精製し、N−[(1−{2−[(2R,6S)−2,6−ジメチルモルホリン−4−イル]エチル}ピペリジン−4−イル)メチル]−5−メトキシ−1H−インダゾール−3−カルボキサミド25(48.3%収率)をもたらした。
N−[(1−{3−[(2R,6S)−2,6−ジメチルモルホリン−4−イル]プロピル}ピペリジン−4−イル)メチル]−5−メトキシ−1H−インダゾール−3−カルボキサミド26を、化合物25について記載した手順に従い、(2R,6S)−4−(3−クロロプロピル)−2,6−ジメチルモルホリンおよびメタノールを溶媒として用いて調製した。収率=91mg(59.1%)。
DMF(45ml)およびトリエチルアミン(0.61ml、4.4mmol)中の化合物11b(420mg、1.46mmol)の溶液を80℃で1時間撹拌した後、1−(2−ブロモエチル)−3−メチルシクロヘキサン(300mg、1.46mmol)で処理した。混合物を一晩同じ温度で撹拌した。反応物を次に室温まで冷却し、溶媒を減圧下で蒸発により除去した。粗5−メトキシ−N−({1−[2−(3−メチルシクロヘキシル)エチル]ピペリジン−4−イル}メチル)−1H−インダゾール−3−カルボキサミド27を、シリカゲル上でのフラッシュクロマトグラフィーにより、CH3Cl/CH3OHの9/1混合物を溶離液として用いて精製した。収率=45mg(18.0%)。
4−{[4−({[(5−メトキシ−1H−インダゾール−3−イル)カルボニル]アミノ}メチル)ピペリジン−1−イル]メチル}ピリジン−2−カルボン酸28を、化合物25について記載した手順に従い、4−(クロロメチル)ピリジン−2−カルボン酸メチルを試薬として、CH3CNを溶媒として用いて調製した。収率=335mg(16%)。
29a)5−{[4−({[(5−メトキシ−1H−インダゾール−3−イル)カルボニル]アミノ}メチル)ピペリジン−1−イル]メチル}ピリジン−2−カルボン酸メチル
5−{[4−({[(5−メトキシ−1H−インダゾール−3−イル)カルボニル]アミノ}メチル)ピペリジン−1−イル]メチル}ピリジン−2−カルボン酸メチル29aを、化合物25について記載した手順に従い、5−(クロロメチル)ピリジン−2−カルボン酸メチルを試薬として、CH3CNを溶媒として用いて調製し、その後のステップにさらなる精製なしで用いた。
N−({1−[(5−カルバモイル−1,2,4−オキサジアゾール−3−イル)メチル]ピペリジン−4−イル}メチル)−5−メトキシ−1H−インダゾール−3−カルボキサミド30を、化合物25について記載した手順に従い、3−(クロロメチル)−1,2,4−オキサジアゾール−5−カルボン酸エチルを試薬として、CH3CNを溶媒として用いて調製した。収率=80mg(4%)。
トルエン(300ml)中の7H,14H−ピラジノ[1,2−b:4,5−b’]ジインダゾール−7,14−ジオン(8.2g、28.5mmol)、1−{1−[2−(4−ニトロフェニル)エチル]ピペリジン−4−イル}メタンアミン(15g、57mmol)の混合物を室温で一晩撹拌した。こうして得られた固体を濾過し、2NのHCl(100ml)で溶解し、ジエチルエーテル(3×150ml)で洗浄した。酸相をNaOHで塩基性化し、DCM(3×200ml)で抽出した。溶媒を真空により除去し、残渣を次にTHF(30ml)中に注ぎ、MeOH中の1.25MのHClで処理した。こうして得られた粗固体N−({1−[2−(4−ニトロフェニル)エチル]ピペリジン−4−イル}メチル)−1H−インダゾール−3−カルボキサミド塩酸塩31を濾過し、EtOHから結晶化した。
本発明において有用な式(I)の化合物の薬理学的特性を下記のセクションに記載する方法により評価した。
ヒトGSK−3βに対する活性を(Meijer et al., Chem.Biol.,2003−10:1255−1266に従って)下記の方法を用いて評価した。
(a)化合物1を、その選択性を評価するため、60キナーゼのパネルに対して試験した。アッセイはアッセイファミリーの多様性を考慮して選択した。
−タンパク質−セリン/スレオニンキナーゼ;
−タンパク質−チロシンキナーゼ;
−その他のキナーゼ;および
−異型キナーゼ。
Claims (13)
- (i)インスリン抵抗性障害;(ii)神経変性疾患;(iii)気分障害;(iv)統合失調症;(v)癌性障害;(vi)炎症;(vii)物質乱用障害;および(viii)てんかんからなる群から選択される、GSK−3βの無制御活性化および/または過剰発現に起因する疾患の治療のための、下記の一般式(I):
であって、式中、
RaおよびRa’は、互いに同じまたは異なるが、水素原子;ハロゲン原子;任意でハロゲン、ヒドロキシ、−NH2、およびC1〜C3アルコキシからなる群から選択される1つ以上の置換基により置換される、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニルおよびC1〜C6アルコキシ基;任意でハロゲン、ヒドロキシ、C1〜C6アルキル、C1〜C6アルコキシ、−NR1R2、−C(O)OH、−C(O)OR1および−C(O)NR1R2からなる群から選択される1つ以上の置換基により置換される、3〜12員を有する脂肪族または芳香族炭素または複素環であり;
Yは、結合、任意でハロゲン、ヒドロキシ、−NH2、およびC1〜C3アルコキシからなる群から選択される1つ以上の置換基により置換される、C1〜C6アルキル、C2〜C6アルケニルまたはC2〜C6アルキニル基であり;
Rbはハロゲン、ヒドロキシ、ニトロ、シアノ、−CF3、C1〜C6アルコキシ、ベンジルオキシ、C1〜C4アルキル、C2〜C4アルケニル、C2〜C4アルキニル、−NHSO2CH3、−SO2NH2、Zがσ結合または(C1〜C3)アルキルである−Z−C(O)OH、−Z−C(O)OR1および−Z−C(O)NR1R2からなる群から選択される1つ以上の置換基により置換される、3〜12員を有する脂肪族または芳香族炭素または複素環であり;
R1およびR2は独立して水素原子、C1〜C4アルキル基、C2〜C4アルケニル基、C2〜C4アルキニル基、およびフェニル基である、式
を有する1H−インダゾール−3−カルボキサミド化合物、ならびに医薬的に許容可能な有機および無機酸および塩基を添加したその塩の使用。 - 前記インスリン抵抗性障害が2型糖尿病、X症候群、肥満および多嚢胞性卵巣症候群からなる群から選択される、請求項1に記載の1H−インダゾール−3−カルボキサミドの使用。
- 前記神経変性疾患がパーキンソン病、アルツハイマー病、ハンチントン病、および脊髄性神経変性障害からなる群から選択される、請求項1に記載の1H−インダゾール−3−カルボキサミドの使用。
- 前記脊髄性神経変性障害が筋萎縮性側索硬化症、多発性硬化症、脊髄性筋萎縮症および脊髄損傷による神経変性からなる群から選択される、請求項3に記載の1H−インダゾール−3−カルボキサミドの使用。
- 前記気分障害が双極性障害およびうつ病性障害からなる群から選択される、請求項1に記載の1H−インダゾール−3−カルボキサミドの使用。
- 前記双極性障害がI型双極性、II型双極性、気分循環性および特定不能の双極性障害(BD−NOS)からなる群から選択される、請求項5に記載の1H−インダゾール−3−カルボキサミドの使用。
- 前記うつ病性障害が大うつ病性障害(MDD)、非定型うつ病(AD)、メランコリー型うつ病、精神病性大うつ病(PMD)、緊張病性うつ病、産後うつ病(PPD)、季節性情動障害(SAD)、気分変調症、および特定不能のうつ病性障害(DD−NOS)からなる群から選択される、請求項5に記載の1H−インダゾール−3−カルボキサミドの使用。
- 前記物質乱用障害が精神刺激薬による乱用障害の群から選択される、請求項1に記載の1H−インダゾール−3−カルボキサミドの使用。
- 前記統合失調症が妄想型統合失調症、解体型統合失調症、緊張型統合失調症、単純型統合失調症、残遺型統合失調症、および未分化型統合失調症からなる群から選択される、請求項1に記載の1H−インダゾール−3−カルボキサミドの使用。
- 前記癌性障害が前立腺、膵臓、卵巣、および大腸癌ならびにMLL関連白血病からなる群から選択される、請求項1に記載の1H−インダゾール−3−カルボキサミドの使用。
- (i)インスリン抵抗性障害;(ii)神経変性疾患;(iii)気分障害;(iv)統合失調症;(v)癌性障害;(vi)炎症;(vii)物質乱用障害;および(viii)てんかんからなる群から選択される、GSK−3βの無制御活性化および/または過剰発現に起因する病理状態の治療方法であって、それを必要とするヒトへの効果的な量の、下記の一般式(I):
であって、式中、
RaおよびRa’は、互いに同じまたは異なるが、水素原子;ハロゲン原子;任意でハロゲン、ヒドロキシ、−NH2、およびC1〜C3アルコキシからなる群から選択される1つ以上の置換基により置換される、C1〜C6アルキル、C2〜C6アルケニル、C2〜C6アルキニルおよびC1〜C6アルコキシ基;任意でハロゲン、ヒドロキシ、C1〜C6アルキル、C1〜C6アルコキシ、−NR1R2、−C(O)OH、−C(O)OR1および−C(O)NR1R2からなる群から選択される1つ以上の置換基により置換される、3〜12員を有する脂肪族または芳香族炭素または複素環であり;
Yは、結合、任意でハロゲン、ヒドロキシ、−NH2、およびC1〜C3アルコキシからなる群から選択される1つ以上の置換基により置換される、C1〜C6アルキル、C2〜C6アルケニルまたはC2〜C6アルキニル基であり;
Rbはハロゲン、ヒドロキシ、ニトロ、シアノ、−CF3、C1〜C6アルコキシ、ベンジルオキシ、C1〜C4アルキル、C2〜C4アルケニル、C2〜C4アルキニル、−NHSO2CH3、−SO2NH2、Zがσ結合または(C1〜C3)アルキルである−Z−C(O)OH、−Z−C(O)OR1および−Z−C(O)NR1R2からなる群から選択される1つ以上の置換基により置換される、3〜12員を有する脂肪族または芳香族炭素または複素環であり;
R1およびR2は独立して水素原子、C1〜C4アルキル基、C2〜C4アルケニル基、C2〜C4アルキニル基、およびフェニル基である、式
を有する1H−インダゾール−3−カルボキサミド化合物、ならびに医薬的に許容可能な有機および無機酸および塩基を添加したその塩の投与による、治療方法。 - (i)2型糖尿病、X症候群、肥満および多嚢胞性卵巣症候群のような、インスリン抵抗性障害;(ii)パーキンソン病、アルツハイマー病、ハンチントン病および脊髄性神経変性障害のような、神経変性疾患;(iii)双極性障害およびうつ病性障害のような、気分障害;(iv)統合失調症;(v)前立腺、膵臓、卵巣、および大腸癌ならびにMLL関連白血病のような、癌性障害;(vi)炎症;(vii)物質乱用障害;ならびに(viii)てんかんからなる群から選択される、GSK−3βの無制御活性化および/または過剰発現に起因する病理状態の治療に用いられる、効果的な量の少なくとも1つの請求項1において定義した式(I)の化合物、医薬的に許容可能な有機もしくは無機酸もしくは塩基を含むその塩、またはそのプロドラッグ、および少なくとも1つの不活性で医薬的に許容可能な賦形剤を含む医薬組成物。
- 式:
− N−{[1−(2,4−ジクロロベンジル)ピペリジン−4−イル]メチル}−5−メトキシ−1H−インダゾール−3−カルボキサミド、および
− N−({1−[4−(ベンジルオキシ)ベンジル]ピペリジン−4−イル}メチル)−5−メトキシ−1H−インダゾール−3−カルボキサミド
の1H−インダゾール−3−カルボキサミド化合物。
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JP2021523134A (ja) * | 2018-05-07 | 2021-09-02 | アジェンデ・キミケ・リウニテ・アンジェリニ・フランチェスコ・ア・チ・エレ・ア・エフェ・ソシエタ・ペル・アチオニAziende Chimiche Riunite Angelini Francesco A.C.R.A.F.Societa Per Azioni | グリコーゲンシンターゼキナーゼ3ベータ阻害剤としての1h−インダゾール−3−カルボキサミド化合物 |
JP7411574B2 (ja) | 2018-05-07 | 2024-01-11 | アジェンデ・キミケ・リウニテ・アンジェリニ・フランチェスコ・ア・チ・エレ・ア・エフェ・ソシエタ・ペル・アチオニ | グリコーゲンシンターゼキナーゼ3ベータ阻害剤としての1h-インダゾール-3-カルボキサミド化合物 |
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