JP2017528493A - イミダゾ[4,5‐c]ピリジン由来のssao阻害剤 - Google Patents
イミダゾ[4,5‐c]ピリジン由来のssao阻害剤 Download PDFInfo
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- JP2017528493A JP2017528493A JP2017515166A JP2017515166A JP2017528493A JP 2017528493 A JP2017528493 A JP 2017528493A JP 2017515166 A JP2017515166 A JP 2017515166A JP 2017515166 A JP2017515166 A JP 2017515166A JP 2017528493 A JP2017528493 A JP 2017528493A
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- JP
- Japan
- Prior art keywords
- pyridin
- imidazo
- methylpyridin
- disease
- amine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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- 239000003112 inhibitor Substances 0.000 title description 16
- 101710132836 Membrane primary amine oxidase Proteins 0.000 title description 13
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Abstract
Description
R−CH2−NH2+O2→R−CHO+H2O2+NH3
に従う一級アミンのアルデヒド、過酸化水素、およびアンモニアへの酸化的脱アミノ化において銅(II)イオンおよびタンパク質誘導トパキノン(TPQ)補酵素を用いる。
Yは、水素、ヒドロキシル、−NH2、−NH−C1−4アルキル、−NH−ハロ‐C1−4アルキル、または−C1−4アルコキシから選択され;
Zは、水素、ハロゲン、ヒドロキシル、シアノ、C1−4アルキル、ハロ‐C1−4アルキル、C1−4アルコキシ、ハロ‐C1−4アルコキシ、−CONH2、−SO2NH2、−NH2、−NHC1−4アルキル、または−NHハロ‐C1−4アルキルから選択され;
R1は、フェニル環または5員もしくは6員のヘテロアリール環であり、いずれの環も、ハロゲン、シアノ、C1−4アルキル、ハロ‐C1−4アルキル、シアノ‐C1−4アルキル、3員〜7員のシクロアルキル環、−OR5、−NR6C(O)OR5、−NR6C(O)R5、−NR6C(O)NR4AR4B、−C(O)NR4AR4B、−C(O)R5、−C(O)OR5、および−NR6S(O)2R5から選択される1または複数の置換基によって置換されていてもよく;ここで
R4A、R4B、R5、およびR6は、それぞれ独立に、水素、C1−4アルキル、もしくはハロ‐C1−4アルキルから選択されるか、または
R4AおよびR4Bは、それらが結合している窒素と共に、ハロゲン、ヒドロキシル、シアノ、C1−4アルキル、ハロ‐C1−4アルキル、C1−4アルコキシ、ハロ‐C1−4アルコキシ、−CONH2、−SO2NH2、−NH2、−NHC1−4アルキル、−NHハロ‐C1−4アルキルから選択される1または複数の置換基によって置換されていてもよい、3員〜7員の環状アミノ基を形成し;
Xは、−N=であり;
Wは、フェニル環、またはピリジニル、ピリダジニル、ピラジニル、ピリミジニル、オキサゾリル、チアゾリル、もしくはイミダゾリルから選択される5員もしくは6員のヘテロアリール環であり、いずれの環も、ハロゲン、シアノ、オキソ、C1−4アルキル、ハロ‐C1−4アルキル、シアノ‐C1−4アルキル、−OR5、−NR7AR7B、−NR6C(O)OR5、−NR6C(O)R5、−NR6C(O)NR7AR7B、−C(O)NR7AR7B、−C(O)R5、−C(O)OR5、−SO2R5、−SO2NR7AR7B、および−NR6S(O)2R5から選択される1または複数の置換基によって置換されていてもよく;
R7AおよびR7Bは、独立して、水素、C1−4アルキル、またはハロ‐C1−4アルキルであり、
Vは、結合、−O−、−N(R6)−、−(C=O)−、−CONR6−、−NR6C(O)−、または−C1−4アルキレン−から選択され、ここで、前記C1−4アルキレン基はハロゲンによって置換されていてもよく、前記C1−4アルキレン基の炭素原子はいずれも−O−または−N(R6)−によって置き換えられていてもよく;
R3は、水素、−C1−4アルキル、−C1−4アルキル−C1−4アルコキシ、または3員〜7員の複素環、または3員〜7員のシクロアルキル環、または5員もしくは6員のヘテロアリール環から選択され、いずれの環も、ハロゲン、オキソ、ヒドロキシル、シアノ、C1−4アルキル、ハロ‐C1−4アルキル、シアノ‐C1−4アルキル、−OR5、−NR4AR4B、−NR6C(O)OR5、−NR6C(O)R5、−NR6C(O)NR4AR4B、−C(O)NR4AR4B、−C(O)R5、−C(O)OR5、−SO2R5、−SO2NR4AR4B、および−NR6S(O)2R5から選択される1または複数の置換基によって置換されていてもよい。
ただし、−WVR3基および/またはR1基が、以下の基ではない。
nは、0、1、または2であり;
R’およびR’’は、独立して、H、−C1‐C6アルキル、−(C=O)−C1‐C6アルキル、および−(C=O)OC(CH3)3から成る群より選択され;且つ
R’’’は、H、OH、またはC1‐C6アルキルである。
Yは、水素、ヒドロキシル、−NH2、−NH−C1−4アルキル、−NH−ハロ‐C1−4アルキル、または−C1−4アルコキシから選択され;
Zは、水素、ハロゲン、ヒドロキシル、シアノ、C1−4アルキル、ハロ‐C1−4アルキル、C1−4アルコキシ、ハロ‐C1−4アルコキシ、−CONH2、−SO2NH2、−NH2、−NHC1−4アルキル、または−NHハロ‐C1−4アルキルから選択され;
R1は、フェニル環または5員もしくは6員のヘテロアリール環であり、いずれの環も、ハロゲン、シアノ、C1−4アルキル、ハロ‐C1−4アルキル、シアノ‐C1−4アルキル、−OR5、−NR6C(O)OR5、−NR6C(O)R5、−NR6C(O)NR4AR4B、−C(O)NR4AR4B、−C(O)R5、−C(O)OR5、および−NR6S(O)2R5から選択される1または複数の置換基によって置換されていてもよく;ここで
R4A、R4B、R5、およびR6は、それぞれ独立に、水素、C1−4アルキル、もしくはハロ‐C1−4アルキルから選択されるか、または
R4AおよびR4Bは、それらが結合している窒素と共に、ハロゲン、ヒドロキシル、シアノ、C1−4アルキル、ハロ‐C1−4アルキル、C1−4アルコキシ、ハロ‐C1−4アルコキシ、−CONH2、−SO2NH2、−NH2、−NHC1−4アルキル、−NHハロ‐C1−4アルキルから選択される1または複数の置換基によって置換されていてもよい、3員〜7員の環状アミノ基を形成し;
Xは、−N=であり;
Wは、フェニル環または5員もしくは6員のヘテロアリール環であり、いずれの環も、ハロゲン、シアノ、C1−4アルキル、ハロ‐C1−4アルキル、シアノ‐C1−4アルキル、−OR5、−NR7AR7B、−NR6C(O)OR5、−NR6C(O)R5、−NR6C(O)NR7AR7B、−C(O)NR7AR7B、−C(O)R5、−C(O)OR5、−SO2R5、−SO2NR7AR7B、および−NR6S(O)2R5から選択される1または複数の置換基によって置換されていてもよく;
R7AおよびR7Bは、独立して、水素、C1−4アルキル、またはハロ‐C1−4アルキルである。
R3は、水素、または3員〜7員の複素環、またはシクロプロピル、シクロペンチル、もしくはシクロヘキシルから選択される3員〜7員のシクロアルキル環、または5員もしくは6員のヘテロアリール環であり、いずれの環も、ハロゲン、オキソ、ヒドロキシル、シアノ、C1−4アルキル、ハロ‐C1−4アルキル、シアノ‐C1−4アルキル、−OR5、−NR4AR4B、−NR6C(O)OR5、−NR6C(O)R5、−NR6C(O)NR4AR4B、−C(O)NR4AR4B、−C(O)R5、−C(O)OR5、−SO2R5、−SO2NR4AR4B、および−NR6S(O)2R5から選択される1または複数の置換基によって置換されていてもよい。
4‐{5‐[3‐(5‐フルオロピリジン‐2‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン‐2‐イル}モルホリン;
4‐{5‐[3‐(2,4‐ジフルオロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐4‐メチルピリジン‐2‐イル}モルホリン;
5‐[3‐(2,4‐ジフルオロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐N‐(オキサン‐4‐イル)ピリミジン‐2‐アミン;
N,N‐ジエチル‐5‐[3‐(6‐メチルピリジン‐3‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリミジン‐2‐アミン;
N,N‐ジエチル‐5‐[3‐(4‐フルオロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリミジン‐2‐アミン;
N,N‐ジエチル‐5‐[3‐(4‐メチルフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリミジン‐2‐アミン;
N,N‐ジエチル‐5‐[3‐(5‐メチルピリジン‐2‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリミジン‐2‐アミン;
4‐{5‐[3‐(2‐フルオロ‐4‐メチルフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐4‐メチルピリジン‐2‐イル}モルホリン;
4‐{5‐[3‐(4‐クロロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐4‐メチルピリジン‐2‐イル}モルホリン;
5‐[3‐(4‐メチルフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐N‐(オキサン‐4‐イル)ピリジン‐2‐アミン;
2‐(4,4‐ジフルオロピペリジン‐1‐イル)‐5‐[3‐(4‐メチルフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン;
4‐{5‐[3‐(5‐クロロピリジン‐2‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐4‐メチルピリジン‐2‐イル}モルホリン;
4‐{4‐メチル‐5‐[3‐(5‐メチルピリジン‐2‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン‐2‐イル}モルホリン;
4‐{5‐[3‐(5‐フルオロピリジン‐2‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐4‐メチルピリジン‐2‐イル}モルホリン;
5‐[3‐(4‐フルオロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐N‐(オキサン‐4‐イル)ピリジン‐2‐アミン;
4‐{5‐[3‐(4‐フルオロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン‐2‐イル}チオモルホリン;
N‐シクロプロピル‐5‐[3‐(4‐メチルフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン‐2‐アミン;
5‐[3‐(6‐メチルピリジン‐3‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐2‐(ピロリジン‐1‐イル)ピリジン;
2‐(4‐フルオロピペリジン‐1‐イル)‐5‐[3‐(6‐メチルピリジン‐3‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン;
5‐[3‐(4‐フルオロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐N‐[2‐(モルホリン‐4‐イル)エチル]ピリジン‐2‐アミン;
5‐[3‐(4‐メチルフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐N‐[2‐(モルホリン‐4‐イル)エチル]ピリジン‐2‐アミン;
N‐シクロプロピル‐5‐[3‐(4‐フルオロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン‐2‐アミン;
N‐シクロプロピル‐5‐[3‐(6‐メチルピリジン‐3‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン‐2‐アミン;
5‐[3‐(4‐メチルフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐N‐(プロパン‐2‐イル)ピリジン‐2‐アミン
5‐[3‐(6‐メチルピリジン‐3‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐2‐(ピロリジン‐1‐イル)ピリミジン;
5‐[3‐(5‐メチルピリジン‐2‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐2‐(ピロリジン‐1‐イル)ピリミジン;
5‐[3‐(5‐フルオロピリジン‐2‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐2‐(ピロリジン‐1‐イル)ピリミジン;
4‐{4‐[3‐(6‐メチルピリジン‐3‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]フェニル}モルホリン;
5‐[3‐(4‐メチルフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐2‐(ピロリジン‐1‐イル)ピリミジン;
4‐{4‐[3‐(5‐メチルピリジン‐2‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]フェニル}モルホリン;
2‐メチル‐5‐{2‐[4‐(ピロリジン‐1‐イル)フェニル]‐3H‐イミダゾ[4,5‐c]ピリジン‐3‐イル}ピリジン;
5‐{2‐[2‐フルオロ‐4‐(ピロリジン‐1‐イル)フェニル]‐3H‐イミダゾ[4,5‐c]ピリジン‐3‐イル}‐2‐メチルピリジン;
4‐{3‐フルオロ‐4‐[3‐(6‐メチルピリジン‐3‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]フェニル}モルホリン;
5‐{2‐[3‐フルオロ‐4‐(ピロリジン‐1‐イル)フェニル]‐3H‐イミダゾ[4,5‐c]ピリジン‐3‐イル}‐2‐メチルピリジン;
N‐{4‐[3‐(6‐メチルピリジン‐3‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]フェニル}オキサン‐4‐アミン;
5‐メチル‐2‐{2‐[4‐(ピロリジン‐1‐イル)フェニル]‐3H‐イミダゾ[4,5‐c]ピリジン‐3‐イル}ピリジン;
5‐{2‐[4‐(4‐フルオロピペリジン‐1‐イル)フェニル]‐3H‐イミダゾ[4,5‐c]ピリジン‐3‐イル}‐2‐メチルピリジン;
2‐クロロ‐5‐[3‐(4‐クロロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン
2‐クロロ‐5‐[3‐(4‐フルオロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン。
以下の定義は、特に断りのない限り、本明細書および添付の特許請求の範囲を通して適用されるものとする。
本発明の現時点で好ましい実施形態は、本発明の化合物を、1種または複数種の医薬的に許容可能な担体および/または賦形剤と共に含む医薬組成物である。
以下の略語を用いた。
実験方法
特に断りのない限り、反応は室温で行った。マイクロ波反応は、Biotageマイクロ波反応器により、アルミニウムキャップおよび隔壁を備えたプロセスバイアルを用いて行った。水素化は、Thales H‐Cubeを用いて行った。分取用低圧クロマトグラフィーは、RediSepまたはGraceResolvシリカおよびC18逆相カラムを備えたCombiFlash CompanionまたはCombiflash RFシステムを用いて行った。分取用逆相HPLCは、ACE‐5AQ、100×21.20mm、5mmカラムまたはPhenomenex Synergi Hydro‐RP 80A AXIA、100×21.20mm、4mmカラムを備えた紫外線検出器を用いてGilsonシステムで行った。最も純粋な画分を集収し、濃縮し、真空乾燥した。化合物は、通常は、40℃から60℃の真空オーブン中で乾燥した後、純度分析を行った。
5‐フルオロ‐N‐(4‐ニトロピリジン‐3‐イル)ピリジン‐2‐アミン
N‐(5‐クロロピリジン‐2‐イル)‐4‐ニトロピリジン‐3‐アミン
N‐(5‐メチルピリジン‐2‐イル)‐4‐ニトロピリジン‐3‐アミン
3‐[(2,4‐ジフルオロフェニル)アミノ]‐4‐ニトロピリジン‐1‐イウム‐1‐オレート
中間体5〜7は、3‐フルオロ‐4‐ニトロピリジンN‐オキシドを適切なアニリンとカップリングすることによって、中間体4と同様に調製した。以下の表1を参照されたい。
3‐[(4‐クロロフェニル)アミノ]‐4‐ニトロピリジン‐1‐イウム‐1‐オレート
3‐[(4‐フルオロフェニル)アミノ]‐4‐ニトロピリジン‐1‐イウム‐1‐オレート
3‐N‐(2,4‐ジフルオロフェニル)ピリジン‐3,4‐ジアミン
中間体11〜16を、中間体1および5〜9をヒドラジン水和物またはギ酸アンモニウムと共にラネーニッケルで還元することにより、中間体10と同様に調製した。以下の表2を参照されたい。
3‐N‐(5‐クロロピリジン‐2‐イル)ピリジン‐3,4‐ジアミン
N‐(5‐メチルピリジン‐2‐イル)‐4‐ニトロピリジン‐3‐アミン
4‐メチル‐6‐(モルホリン‐4‐イル)ピリジン‐3‐カルボン酸
2‐[(オキサン‐4‐イル)アミノ]ピリミジン‐5‐カルボン酸
2‐(ジエチルアミノ)ピリミジン‐5‐カルボン酸
N‐{3‐[(5‐フルオロピリジン‐2‐イル)アミノ]ピリジン‐4‐イル}‐6‐(モルホリン‐4‐イル)ピリジン‐3‐カルボキシアミド
中間体23〜30を、中間体10、12〜16、および18を適切なカルボン酸とカップリングさせることにより、中間体22と同様に調製した。以下の表3を参照されたい。
N‐{3‐[(5‐クロロピリジン‐2‐イル)アミノ]ピリジン‐4‐イル}‐6‐フルオロ‐4‐メチルピリジン‐3‐カルボキシアミド
中間体32〜36を、中間体11、14〜16、および18のカルボン酸活性化ならびにカップリングにより、中間体31と同様に調製した。以下の表4を参照されたい。
4‐ブロモ‐N‐{3‐[(6‐メチルピリジン‐3‐イル)アミノ]ピリジン‐4‐イル}ベンズアミド
中間体38〜40を、中間体14および18を適切な酸塩化物とカップリングさせることにより、中間体37と同様に調製した。以下の表5を参照されたい。
5‐[2‐(4‐ブロモフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐3‐イル]‐2‐メチルピリジン
に溶解し、得られた溶液を、マイクロ波反応器中、120℃で15分間加熱した。この反応混合物を、水(40mL)およびDCM(40mL)で希釈し、固体Na2CO3で約pH9まで塩基性化した。有機相を鹹水(40mL)で洗浄し、乾燥し(MgSO4)、溶媒を真空蒸発させて、表題の化合物をオフホワイト色の固体として得た(664mg、75.5%)。LCMS(ES+):364.9、366.9[M+H]+。UPLC:保持時間2.16分、純度98.6%。
中間体42〜44を、中間体38〜40の酸媒介環化により、中間体41と同様に調製した。以下の表6を参照されたい。
6‐クロロ‐N‐{3‐[(4‐クロロフェニル)アミノ]ピリジン‐4‐イル}ピリジン‐3‐カルボキシアミド
4‐{5‐[3‐(5‐フルオロピリジン‐2‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン‐2‐イル}モルホリン
実施例2〜7を、中間体23および26〜30の酸媒介環化により、実施例1と同様に調製した。以下の表7を参照されたい。
4‐{5‐[3‐(2‐フルオロ‐4‐メチルフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐4‐メチルピリジン‐2‐イル}モルホリン
実施例9〜11を、中間体25および35の適切なアミンとのSnArおよび環化により、実施例8と同様に調製した。以下の表8を参照されたい。
4‐{5‐[3‐(5‐クロロピリジン‐2‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐4‐メチルピリジン‐2‐イル}モルホリン
実施例13〜24を、中間体32〜36の適切なアミンとのSnArおよび環化、ならびにそれに続く酸媒介環化により、実施例12と同様に調製した。以下の表9を参照されたい。
5‐[3‐(6‐メチルピリジン‐3‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐2‐(ピロリジン‐1‐イル)ピリミジン
実施例26〜30を、中間体11、14、16、および18の適切なアルデヒドとの還元縮合により、実施例25と同様に調製した。以下の表10を参照されたい。
2‐メチル‐5‐{2‐[4‐(ピロリジン‐1‐イル)フェニル]‐3H‐イミダゾ[4,5‐c]ピリジン‐3‐イル]ピリジン
実施例32〜37を、中間体41〜44の適切なアミンとのブッフバルト・ハートウィッグカップリングにより、実施例31と同様に調製した。以下の表11を参照されたい。
2‐クロロ‐5‐[3‐(4‐クロロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン
2‐クロロ‐5‐[3‐(4‐フルオロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン
SSAO酵素阻害剤の生物学的アッセイ
すべての一次アッセイは、精製された組換え発現ヒトSSAOを用いて室温で行った。酵素は、本質的にOhman et al.(Protein Expression and Purification 46 (2006) 321-331)に記載の通りに調製した。加えて、様々な組織から調製したSSAOまたは精製されたラット組換えSSAOを使用して二次アッセイおよび選択性アッセイを実施した。ベンジルアミンを基質として用いて、14C標識基質を用いてベンズアルデヒド生成を測定するか、または西洋ワサビペルオキシダーゼ(HRP)共役反応における過酸化水素の産生を利用することによって、酵素活性を分析した。簡潔に説明すると、試験化合物をジメチルスルホキシド(DMSO)中に溶解して10mMの濃度とした。DMSO中の1:10の段階希釈物を作製し7点曲線を作成するか、またはDMSO中の1:3の段階希釈物を作製して11点曲線を作成することによって、用量応答測定値を分析した。化合物の効力に応じて最大濃度を調節し、その後の反応緩衝液中への希釈により、最終DMSO濃度を2%以下とした。
西洋ワサビペルオキシダーゼ(HRP)共役反応では、10‐アセチル‐3,7‐ジヒドロキシフェノキサジンの過酸化水素酸化により、高蛍光化合物であるレゾルフィン(Zhout and Panchuk-Voloshina. Analytical Biochemistry 253 (1997) 169-174;Amplex(登録商標)Red過酸化水素/ペルオキシダーゼアッセイキット、Invitrogen A22188)が産生した。50mM リン酸ナトリウム、pH7.4中の酵素および化合物を、平底マイクロタイタープレート中に配置しておよそ15分間プレインキュベートした後、HRP、ベンジルアミン、およびAmplex試薬の混合物を添加することによって反応を開始した。標準的な手順を用いて決定したミカエリス定数に対応する濃度にベンジルアミン濃度を固定した。次に、544nmでの励起および590nmでの発光の読み取りにより、1〜2時間の間の複数の時間で蛍光強度を測定した。ヒトSSAOアッセイの場合、アッセイウェル中の試薬の最終濃度は、SSAO酵素 1ug/mL、ベンジルアミン 100uM、Amplex試薬 20uM、HRP 0.1U/mL、および様々な濃度の試験化合物であった。阻害剤を含まない対照(希釈DMSOのみ)と比較したシグナルの減少率(%)として阻害を測定した。SSAO酵素を含まない試料に由来するバックグラウンドシグナルを、すべてのデータポイントから減算した。データを4パラメータロジスティックモデルに適合させ、GraphPad Prism 4プログラムまたはXLfit 4プログラムを用いてIC50値を計算した。
14C標識ベンジルアミンを用いて、且つ放射性ベンズアルデヒドを測定することによってSSAO活性をアッセイした。白色の96ウェルoptiplate(Packard)内で、20uLの希釈試験化合物を20uL SSAO酵素と共におよそ15分間、連続的に撹拌しながら室温でプレインキュベートした。希釈はすべて、PBSを用いて行った。[7‐14C]ベンジルアミン塩酸塩(CFA589、GE Healthcare)を含有する20uLのベンジルアミン基質溶液を添加することによって反応を開始した。プレートを上記のように1時間インキュベートし、その後、酸性化(10uLの1M HCl水溶液)によって反応を停止した。次に、90uLのMicro Scint‐E溶液(Perkin−Elmer)を各ウェルに添加し、プレートの混合を15分間継続した。直ちに相分離が発生し、Topcountシンチレーションカウンター(Perkin−Elmer)で活性を読み取った。最終反応ウェルにおいて、ヒト組換えSSAO濃度は、10ug/mLであった。感度を最適化する目的で、高い放射性生成物の画分を得るために、HRP共役アッセイと比較して基質濃度を低下させた。ヒトSSAOアッセイでは、ベンジルアミン濃度は、40uM(0.2uCi/mL)であった。上記の通りにデータ分析を行った。
IonWorksパッチクランプ電気生理学法を用いて、ヒト遅延整流性カリウムイオンチャネル遺伝子(hERG)K+チャネルの阻害について、本発明の化合物を試験した。最大アッセイ濃度(11uM)からの3倍段階希釈物を用い、2回の試験について、8点濃度応答曲線を作成した。全長hERGチャネルを安定に発現するチャイニーズハムスター肺細胞株からの電気生理学的記録を行った。IonWorks Quattro装置を用いて、穿孔パッチクランプ構成(100ug/mL アンホテロシン(amphoterocin))において、室温で単一細胞イオン電流を測定した。内部溶液は、140mM KCl、1mM MgCl2、1mM EGTA、および20mM HEPESを含み、pH7.3に緩衝された。外部溶液は、138mM NaCl、2.7mM KCl、0.9mM CaCl2、0.5mM MgCl2、8mM Na2HPO4、および1.5mM KH2PO4を含み、pH7.3に緩衝された。70mVの保持電位で30秒間細胞を固定し、次に細胞に1秒間の+40mVまでの電位ステップを与えた。この後、1秒間の30mVまでの過分極ステップを与えてhERGのテール電流を引き起こした。この一連の工程を、0.25Hzの周波数で5回繰り返した。5回目のパルスでのテールステップから電流を測定し、それらの電流を保持電流に対して参照した。化合物を6〜7分間インキュベートした後、同一のパルス手順を用いてhERGシグナルの2回目の測定を行った。各pIC50曲線フィッティングに対して、少なくとも17個の細胞が必要であった。対照化合物(キニジン)を用いた(以下の表13を参照のこと)。
Claims (7)
- 以下から成る群より選択される化合物、およびその医薬的に許容可能な塩。
4‐{5‐[3‐(5‐フルオロピリジン‐2‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン‐2‐イル}モルホリン;
4‐{5‐[3‐(2,4‐ジフルオロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐4‐メチルピリジン‐2‐イル}モルホリン;
5‐[3‐(2,4‐ジフルオロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐N‐(オキサン‐4‐イル)ピリミジン‐2‐アミン;
N,N‐ジエチル‐5‐[3‐(6‐メチルピリジン‐3‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリミジン‐2‐アミン;
N,N‐ジエチル‐5‐[3‐(4‐フルオロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリミジン‐2‐アミン;
N,N‐ジエチル‐5‐[3‐(4‐メチルフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリミジン‐2‐アミン;
N,N‐ジエチル‐5‐[3‐(5‐メチルピリジン‐2‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリミジン‐2‐アミン;
4‐{5‐[3‐(2‐フルオロ‐4‐メチルフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐4‐メチルピリジン‐2‐イル}モルホリン;
4‐{5‐[3‐(4‐クロロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐4‐メチルピリジン‐2‐イル}モルホリン;
5‐[3‐(4‐メチルフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐N‐(オキサン‐4‐イル)ピリジン‐2‐アミン;
2‐(4,4‐ジフルオロピペリジン‐1‐イル)‐5‐[3‐(4‐メチルフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン;
4‐{5‐[3‐(5‐クロロピリジン‐2‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐4‐メチルピリジン‐2‐イル}モルホリン;
4‐{4‐メチル‐5‐[3‐(5‐メチルピリジン‐2‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン‐2‐イル}モルホリン;
4‐{5‐[3‐(5‐フルオロピリジン‐2‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐4‐メチルピリジン‐2‐イル}モルホリン;
5‐[3‐(4‐フルオロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐N‐(オキサン‐4‐イル)ピリジン‐2‐アミン;
4‐{5‐[3‐(4‐フルオロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン‐2‐イル}チオモルホリン;
N‐シクロプロピル‐5‐[3‐(4‐メチルフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン‐2‐アミン;
5‐[3‐(6‐メチルピリジン‐3‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐2‐(ピロリジン‐1‐イル)ピリジン;
2‐(4‐フルオロピペリジン‐1‐イル)‐5‐[3‐(6‐メチルピリジン‐3‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン;
5‐[3‐(4‐フルオロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐N‐[2‐(モルホリン‐4‐イル)エチル]ピリジン‐2‐アミン;
5‐[3‐(4‐メチルフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐N‐[2‐(モルホリン‐4‐イル)エチル]ピリジン‐2‐アミン;
N‐シクロプロピル‐5‐[3‐(4‐フルオロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン‐2‐アミン;
N‐シクロプロピル‐5‐[3‐(6‐メチルピリジン‐3‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン‐2‐アミン;
5‐[3‐(4‐メチルフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐N‐(プロパン‐2‐イル)ピリジン‐2‐アミン
5‐[3‐(6‐メチルピリジン‐3‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐2‐(ピロリジン‐1‐イル)ピリミジン;
5‐[3‐(5‐メチルピリジン‐2‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐2‐(ピロリジン‐1‐イル)ピリミジン;
5‐[3‐(5‐フルオロピリジン‐2‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐2‐(ピロリジン‐1‐イル)ピリミジン;
4‐{4‐[3‐(6‐メチルピリジン‐3‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]フェニル}モルホリン;
5‐[3‐(4‐メチルフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]‐2‐(ピロリジン‐1‐イル)ピリミジン;
4‐{4‐[3‐(5‐メチルピリジン‐2‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]フェニル}モルホリン;
2‐メチル‐5‐{2‐[4‐(ピロリジン‐1‐イル)フェニル]‐3H‐イミダゾ[4,5‐c]ピリジン‐3‐イル}ピリジン;
5‐{2‐[2‐フルオロ‐4‐(ピロリジン‐1‐イル)フェニル]‐3H‐イミダゾ[4,5‐c]ピリジン‐3‐イル}‐2‐メチルピリジン;
4‐{3‐フルオロ‐4‐[3‐(6‐メチルピリジン‐3‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]フェニル}モルホリン;
5‐{2‐[3‐フルオロ‐4‐(ピロリジン‐1‐イル)フェニル]‐3H‐イミダゾ[4,5‐c]ピリジン‐3‐イル}‐2‐メチルピリジン;
N‐{4‐[3‐(6‐メチルピリジン‐3‐イル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]フェニル}オキサン‐4‐アミン;
5‐メチル‐2‐{2‐[4‐(ピロリジン‐1‐イル)フェニル]‐3H‐イミダゾ[4,5‐c]ピリジン‐3‐イル}ピリジン;
5‐{2‐[4‐(4‐フルオロピペリジン‐1‐イル)フェニル]‐3H‐イミダゾ[4,5‐c]ピリジン‐3‐イル}‐2‐メチルピリジン;
2‐クロロ‐5‐[3‐(4‐クロロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン
2‐クロロ‐5‐[3‐(4‐フルオロフェニル)‐3H‐イミダゾ[4,5‐c]ピリジン‐2‐イル]ピリジン。 - 請求項1に記載の化合物を、1種または複数種の医薬的に許容可能な担体および/または賦形剤と共に含む医薬組成物。
- 炎症、炎症性疾患、免疫異常もしくは自己免疫異常の治療、または腫瘍増殖の阻害に用いるための請求項1に記載の化合物。
- 炎症、炎症性疾患、免疫異常もしくは自己免疫異常の治療、または腫瘍増殖の阻害のための組成物の製造における、請求項1に記載の化合物の使用。
- 炎症、炎症性疾患、免疫異常もしくは自己免疫異常の治療、または腫瘍増殖の阻害のための、そのような疾患に罹患している対象に請求項1に記載の化合物を有効量投与することを含む方法。
- 前記炎症、または炎症性疾患、または免疫異常もしくは自己免疫異常が、関節炎(関節リウマチ、若年性関節リウマチ、骨関節炎、および乾癬性関節炎を含む)、滑膜炎、血管炎、シェーグレン病、腸の炎症に伴う症状(クローン病、潰瘍性大腸炎、炎症性腸疾患、および過敏性腸症候群を含む)、アテローム性動脈硬化症、多発性硬化症、アルツハイマー病、血管性認知症、パーキンソン病、脳アミロイド血管症、皮質下梗塞と白質脳症を伴う常染色体優性脳動脈症、肺炎症性疾患(喘息、慢性閉塞性肺疾患、および急性呼吸窮迫症候群を含む)、線維性疾患(特発性肺線維症、心臓線維症、肝線維症、および全身性硬化症(強皮症)を含む)、皮膚の炎症性疾患(接触皮膚炎、アトピー性皮膚炎、および乾癬を含む)、眼の炎症性疾患(加齢性黄斑変性症、ぶどう膜炎、および糖尿病性網膜症を含む)、全身性炎症反応症候群、敗血症、肝臓の炎症性および/または自己免疫性の症状(自己免疫性肝炎、原発性胆汁性肝硬変、アルコール性肝疾患、硬化性胆管炎、および自己免疫性胆管炎を含む)、糖尿病(I型またはII型)および/またはその合併症、慢性心不全、うっ血性心不全、虚血性疾患(脳卒中および虚血再灌流障害を含む)、または心筋梗塞および/またはその合併症、またはてんかんである、請求項1に記載の化合物、または請求項4に記載の使用、または請求項5に記載の方法。
- 関節リウマチ、骨関節炎、肝線維症、慢性閉塞性肺疾患、多発性硬化症、シェーグレン病、アルツハイマー病、パーキンソン病、炎症性腸疾患、または血管性認知症から選択される疾患の治療のための、請求項1に記載の化合物、または請求項4に記載の使用、または請求項5に記載の方法。
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GBGB1416446.1A GB201416446D0 (en) | 2014-09-17 | 2014-09-17 | New enzyme inhibitor compounds |
PCT/GB2015/052690 WO2016042331A1 (en) | 2014-09-17 | 2015-09-17 | Imidazo[4,5-c]pyridine derived ssao inhibitors |
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GB (1) | GB201416446D0 (ja) |
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GB201304526D0 (en) * | 2013-03-13 | 2013-04-24 | Proximagen Ltd | New compounds |
GB201416446D0 (en) * | 2014-09-17 | 2014-10-29 | Proximagen Ltd | New enzyme inhibitor compounds |
CN108084191A (zh) * | 2017-12-23 | 2018-05-29 | 广东赛博科技有限公司 | 一种三唑类ssao抑制剂、制备方法及其用途 |
CN108003170A (zh) * | 2017-12-23 | 2018-05-08 | 广东赛博科技有限公司 | 含吗啉和哌嗪三唑类衍生物及其用途 |
CN108003167A (zh) * | 2017-12-23 | 2018-05-08 | 广东赛博科技有限公司 | 乙丙哌嗪的哌嗪三唑结构化合物及其用途 |
CN108084189A (zh) * | 2017-12-23 | 2018-05-29 | 广东赛博科技有限公司 | 含氟苯和哌嗪三唑类化合物、制备方法及其用途 |
CN108003166A (zh) * | 2017-12-23 | 2018-05-08 | 广东赛博科技有限公司 | 含哌嗪基和哌嗪三唑类结构化合物、制备方法及其用途 |
CN108164533A (zh) * | 2017-12-23 | 2018-06-15 | 广东赛博科技有限公司 | 含胺基苯的哌嗪三唑结构的化合物及其用途 |
CN107936026A (zh) * | 2017-12-23 | 2018-04-20 | 广东赛博科技有限公司 | 三唑类ssao抑制剂、制备方法及其用途 |
CN107936027A (zh) * | 2017-12-23 | 2018-04-20 | 广东赛博科技有限公司 | 含哌嗪基和哌嗪三唑类结构化合物、制备方法及其用途 |
CN108148066A (zh) * | 2017-12-23 | 2018-06-12 | 广东赛博科技有限公司 | 含异丙哌嗪和哌嗪三唑类结构化合物、制备方法及其用途 |
CN108084190A (zh) * | 2017-12-23 | 2018-05-29 | 广东赛博科技有限公司 | 哌嗪三唑类ssao抑制剂、制备方法及其用途 |
CN108003169A (zh) * | 2017-12-23 | 2018-05-08 | 广东赛博科技有限公司 | 一种含吗啉和哌嗪三唑类化合物及其用途 |
CN107936028A (zh) * | 2017-12-23 | 2018-04-20 | 广东赛博科技有限公司 | 一种哌嗪三唑类化合物、制备方法及其用途 |
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DK3194388T3 (da) | 2019-09-23 |
IL251164A0 (en) | 2017-04-30 |
EP3194388A1 (en) | 2017-07-26 |
AU2015316610A1 (en) | 2017-04-06 |
US10065954B2 (en) | 2018-09-04 |
HUE045626T2 (hu) | 2020-01-28 |
US20170362218A1 (en) | 2017-12-21 |
IL251164B (en) | 2020-10-29 |
BR112017005314A2 (pt) | 2017-12-05 |
GB201416446D0 (en) | 2014-10-29 |
CA2961422A1 (en) | 2016-03-24 |
WO2016042331A1 (en) | 2016-03-24 |
EP3194388B1 (en) | 2019-08-14 |
PT3194388T (pt) | 2019-09-27 |
AU2015316610B2 (en) | 2019-05-30 |
CN107074854B (zh) | 2019-07-19 |
ES2745824T3 (es) | 2020-03-03 |
PL3194388T3 (pl) | 2019-12-31 |
JP6556838B2 (ja) | 2019-08-07 |
CN107074854A (zh) | 2017-08-18 |
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