JP5812541B2 - 8−ヒドロキシキノリン誘導体 - Google Patents
8−ヒドロキシキノリン誘導体 Download PDFInfo
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- JP5812541B2 JP5812541B2 JP2013508559A JP2013508559A JP5812541B2 JP 5812541 B2 JP5812541 B2 JP 5812541B2 JP 2013508559 A JP2013508559 A JP 2013508559A JP 2013508559 A JP2013508559 A JP 2013508559A JP 5812541 B2 JP5812541 B2 JP 5812541B2
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- methyl
- quinolin
- compound
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- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000013595 supernatant sample Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 239000008399 tap water Substances 0.000 description 1
- 235000020679 tap water Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
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Description
R1は、水素原子、低級アルキル基、低級アルケニル基、低級シクロアルキル基、アリール基、アラルキル基又は複素環基であり、これらの基は、オルト、メタ及び/又はパラ位において1、2、3又は4つの電子求引基又は電子供与基で任意に置換されていてもよく、
R2は、水素原子、低級アルキル基、アリール基、アラルキル基又は複素環基であり、これらの基は、1以上のハロゲン原子で任意に置換されていてもよく、
R3は、低級アルキル基、アリール基、アラルキル基又は複素環基であり、これらの基は、オルト、メタ又はパラ位において1、2、3又は4つの電子求引基又は電子供与基で任意に置換されていてもよく、
R4は、水素原子、低級アルキル基又は酸性官能基であり、
nは1又は2である。)
R1が、パラ位において電子求引基で置換された基、メタ位において電子求引基で置換された基又はオルト、メタ又はパラ位において電子供与基で置換された前記基であるか、メタ及びパラ位において電子求引基で置換された基であるか、オルト及びパラ位において電子求引基で置換された前記基であるか、置換又は非置換の複素環基であり、
R3が、パラ位において電子求引基で置換された芳香族基であるか、オルト、メタ又はパラ位においてアルキル基及び/又は電子求引基で置換されていてもよい芳香族複素環基又は脂環基であり、
R2及びR4が水素原子であり、
nが1である誘導体である。
R1が、ニトロ基、トリフルオロメチル基、水酸基、フッ素原子又はイソプロポキシ基で任意に一置換又は二置換されたフェニル基又はピリジル基であり、
R2が水素原子であり、
R3が、トリフルオロメチル基又はメトキシカルボニル基で任意に一置換又は二置換されたフェニル基、メチル基、フッ素原子又はニトロ基で任意に一置換又は二置換されたピリジル基、ピリミジル基、ピロリジニル基、オキサゾリジニル基又はピラゾリル基であり、
R4が水素原子であり、
nが1である誘導体である。
1mmolのアルデヒドを2倍量(体積)の水に懸濁又は溶解させ、1.1当量の第一アミンを反応混合物に添加する。混合物を60℃で1時間保持した後、水の2倍量(体積)のアセトニトリル又はアセトンに溶解させた0.6当量の8−ヒドロキシキノリンの溶液を、加熱した混合物に滴下する。混合物を室温まで冷却した後、沈殿が生じるまで混合物を撹拌する。HPLC及びTLCによって反応を監視する。沈殿物を濾過し、アセトニトリルで洗浄し、乾燥する。
1mmolのアルデヒドを3倍量(体積)のアセトニトリルに溶解させ、1当量のアミン、0.6当量の8−ヒドロキシキノリン及び1V/V%ギ酸を反応混合物に添加する。沈殿が生じるか、キノリンのスポットが消失するまで混合物を撹拌する。混合物を濾過し、アセトニトリルで洗浄した後、ヘキサン(異性体混合物)/酢酸エチルの混合物を使用してクロマトグラフィーを行い、アルコール又はアセトニトリルから再結晶させる。
化学的実施例
水(20mL)を10.1g(18.5mmol、Sigma)の4−ニトロベンズアルデヒドに滴下した後、2−アミノ−6−ピコリン(7.95g、1.1当量、Aldrich)を得られたレモンイエロー色の懸濁液に激しく撹拌しながら添加した。懸濁液の色がレモンイエローからオレンジイエローに変化した後、5.82gの8−ヒドロキシキノリン(0.6当量、Sigma)を20mLのアセトン(Molar)に溶解させた溶液を懸濁液に添加し、反応容器を60℃で4時間加熱した後、溶液を室温まで冷却した。沈殿した黄色の粉末を濾過し(7.87g、50.8%)、少量のアセトンで洗浄した。その後、HPLCによって純度を調べた(≧99.5%)。
4−ニトロベンズアルデヒド(2.8g、18.5mmol、Sigma)を無水アセトニトリル(15mL、Molar)に溶解させた後、2−アミノ−6−ピコリン(2g、1当量、Aldrich)を得られたレモンイエロー色の溶液に撹拌しながら添加した。1.61gの8−ヒドロキシキノリン(0.6当量、Sigma)を混合物に添加し、得られた混合物を室温で4日間撹拌した。沈殿した生成物を濾過し(4.2g、27.1%)、質量分光分析法によって生成物の分子量を測定し、NMRによって生成物の構造を確認し(MW:386.1)、HPLCによって純度を調べた(≧99.6%)。
C22H18N4O3(MW:386.1);m.p.:157−160℃;HPLC(CH3CN/H2O 70:30 Phenomenex C18 282nm):Tr=7.14min
1H NMR 1(DMSO)δ2.2(3H,s,CH3),6.37(1H,d,J=7.0Hz),6.49(1H,d,J=7.9Hz),6.98(1H,d,J=8.8Hz,NHCH),7.28(1H,t,J=7.9Hz),7.40(2H,t,J=7.9,8.8Hz),7.50−7.55(1H,m),7.59−7.66(3H,m),8.16(2H,d,J=8.8Hz),8.28(1H,d,J=7.9Hz),10.1(1H,wide s,OH).
13C NMR 1(DMSO)δ24.2(CH3),51.5(CH),105.6(CH),111.6(CH),117.7(CH),121.9(CH),123.5(2×CH),124.5(Cq),126.7(CH),127.7(Cq),128.2(2×CH),136.1(CH),137.3(CH),138.2(Cq),146.2(Cq),148.4(CH),149.8(Cq),152.0,155.7,157.3(Cq).
1H NMR 5(DMSO)δ6.31(1H,d,J=7.1Hz),6.79(1H,d,J=7.6Hz),7.27(1H,t,J=5.1Hz),7.29−7.37(4H,m),7.47−7.54(3H,m),7.75(1H,t,J=7.2Hz),7.74(1H,d,J=8.5Hz),8.24(1H,d,J=8.3Hz),8.55(1H,d,J=4.1Hz),8.85(1H,d,J=3.2Hz),10.24(1H,wide s).
1H NMR 8(DMSO)δ2.18(3H,s,CH3),6.41(1H,d,J=5.1Hz),6.44(1H,s,NH),6.49(1H,d,J=4.9Hz),7.07(1H,d,J=9.2Hz),7.39(1H,d,J=8.9Hz),7.49−7.54(1H,m),7.58(2H,d,J=7.9Hz),7.63(2H,d,J=8.3Hz),7.73(1H,d,J=7.9Hz),7.85(2H,d,J=7.9Hz),8.03−8.08(1H,m),8.12(2H,d,J=8.5Hz),8.27(1H,d,J=8.2Hz),8.81−8.86(1H,m)
13C−NMR 8(DMSO)δ23.5(CH3),51.8(NHCH),109.5(CH),117.6(CH),121.8(CH),124.5(Cq),125.1(CH),125.6(2×CH),126.8(CH),127.7(2×CH),127.8(Cq),130.1(CH),134.7(Cq),136.1(CH),138.1(Cq),148.2(Cq),148.5(CH),149.6(Cq),157.7(CH),161.6(Cq),166.3(Cq).
1H NMR 9(DMSO)δ2.14(3H,s,CH3),6.35(1H,d,J=5.8Hz),6.55(1H,s),7.00(1H,d,J=8.0Hz),7.36−7.43(2H,m),7.50−7.55(1H,m),7.56(1H,d,J=7.5Hz),7.60(1H,d,J=8.5Hz),7.79(1H,d,J=5.5Hz),8.15(2H,d,J=8.5Hz),8.28(1H,d,J=8.5Hz),8.84(s,1H),10.1(s,1H)
13C NMR 9(DMSO)δ20.6(CH3),51.6(NHCH),109.0(CH),114.2(CH),117.7(CH),121.9(CH),123.5(2×CH),124.6(Cq),126.7(CH),127.7(Cq),128.2(2×CH),136.1(CH),138.2(Cq),146.2(Cq),147.1(Cq),147.2(CH),148.5(CH),149.8,152.0,157.9(3 Cq).
1H NMR 10(DMSO)δ2.24(3H,s,CH3),6.49(1H,d,J=5.1Hz),7.07(1H,d,J=9.0Hz,NHCH)),7.39(1H,d,J=8.5Hz),7.49−7.55(1H,m),7.58(2H,d,J=7.7Hz),7.64(2H,d,J=7.9Hz),7.74(1H,d,J=8.5Hz),8.07(1H,d,J=8.9Hz),8.14(1H,d,J=4.9Hz),8.28(1H,d,J=7.7Hz),8.83(1H,s),10.08(1H,wide s).
13C NMR 10(DMSO)δ23.6(CH3),51.7(NHCH),110.4(CH),117.6(CH),121.8(CH),124.6(Cq),125.2(2×CH),126.8(CH),127.2(Cq),127.4(Cq),127.7(Cq),127.8(2×CH),136.1(CH),138.1(Cq),148.2(Cq),148.4(CH),149.8,149.6,161.6,167.6(4 Cq).
1H NMR 11(DMSO)δ2.21(3H,s,CH3),6.39−6.46(2H,m),6.69(1H,t,J=6.4Hz),6.75(1H,d,J=7.7Hz),7.23(1H,d,J=7.0Hz),7.32(1H,d,J=8.4Hz),7.44−7.51(2H,m),7.57(2H,d,J=8.0Hz),8.09(1H,d,J=5.4Hz),8.25(1H,d,J=8.0Hz),8.79(1H,wide s),9.47(1H,wide s,OH),9.80(1H,wide s,OH).
1H NMR 13(DMSO)δ2.23(3H,s),6.34(1H,d,J=6.0Hz),6.38(1H,d,J=7.1Hz),6.69(1H,t,J=7.2Hz),6.80(2H,m),7.02(2H,m),7.18(1H,d,J=6.2Hz),7.25(1H,d,J=6.8Hz),7.36(1H,d,J=7.4Hz),7.42−7.54(1H,m),7.64(1H,d,J=7.9Hz),8.25(1H,d,J=7.1Hz),8.80(1H,s),9.85(1H,s).
13C NMR 13(DMSO)δ23.9(CH3),47.8(CHNH),111.1(CH),115.7(CH),116.7(CH),118.7(CH),121.5(CH),125.3(Cq),127.2(CH),127.4(Cq),127.8(CH),128.3(CH),129.2(Cq),135.9(CH),137.5(CH),138.2(Cq),148.1(CH),149.7,155.1,155.6,157.6(4×Cq).
概要:ドナーの心臓をルイスラットに移植した。虚血保護を4℃で1時間行った後、ドナーの心臓の大動脈及び肺動脈をレシピエントラットの腹部大動脈又は大静脈に接続した。ラットのケアは「Principles of Laboratory Animal Care」(National Society of Medical Research and the Guide for the Care and Use of Laboratory Animals prepared by the National Academy of Sciences、発行者:National Institutes of Health(NIH Publication No.86−23,1996年改訂))の要件に準拠して行った。
7−((4−ニトロフェニルアミノ)(フェニル)メチル)キノリン−8−オール(曲線B)
4−{[(8−ヒドロキシキノリン−7−イル)フェニルメチル]アミノ}安息香酸エチル(曲線C、実施例3)
7−((4−フェニルピペラジン−1−イル)(チオフェン−2−イル)メチル)キノリン−8−オール(曲線D)
7−((6−メチルピリジン−2−イルアミノ)(4−(トリフルオロメチル)フェニル)メチル)キノリン−8−オール(曲線E)
7−((4−フルオロフェニル)(チアゾール−2−イルアミノ)メチル)キノリン−8−オール(曲線F)
7−(フェニルアミノピリジン−2−イルメチル)キノリン−8−オール(曲線G、実施例4)
7−[(4−フルオロフェニル)(ピロリジン−1−イル)メチル]キノリン−8−オール(曲線H、実施例14)
7−((6−メチルピリジン−2−イルアミノ)(4−ニトロフェニル)メチル)キノリン−8−オール(曲線L、実施例1)
7−[(6−メチルピリジン−2−イルアミノ)(4−トリフルオロメチルフェニル)メチル)]キノリン−8−オール(曲線M、実施例7)
4−((8−ヒドロキシキノリン−7−イル)(4−ニトロフェニル)メチルアミノ)安息香酸エチル(曲線N、実施例2)
7−((4−メチルピリミジン−2−イルアミノ)(4−(トリフルオロメチル)フェニル)メチル)キノリン−8−オール(曲線O、実施例10)
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Claims (8)
- 前記一般式(I)で表される化合物が、
7−((4−メチルピリミジン−2−イルアミノ)(4−ニトロフェニル)メチル)キノリン−8−オール、7−((4−メチルピリミジン−2−イルアミノ)(4−(トリフルオロメチル)フェニル)メチル)キノリン−8−オール、7−[(2−ヒドロキシフェニル)(4−メチルピリミジン−2−イルアミノ)メチル]キノリン−8−オール又は7−[(4,6−ジメチルピリミジン−2−イルアミノ)(4−トリフルオロメチルフェニル)メチル)]キノリン−8−オールである、請求項1に記載の化合物。 - 下記一般式(I)で表される化合物の製造方法であって、
R1は、オルト、メタ及び/又はパラ位において水酸基、トリフルオロメチル基又はニトロ基で任意に置換されていてもよいフェニル基であるか、オルト、メタ及び/又はパラ位においてハロゲン原子、水酸基、トリフルオロメチル基、ニトロ基又は低級アルキル基で任意に置換されていてもよいピリジル基であり、
R2は、水素原子であり、
R3は、オルト、メタ又はパラ位においてハロゲン原子、トリフルオロメチル基、ニトロ基又は低級アルキル基で任意に置換されていてもよいピリミジル基であり、
R4は、水素原子又はメチル基であり、
nは1である。)
下記一般式(II)で表される8−ヒドロキシキノリン誘導体を、下記一般式(III)で表されるオキソ化合物及び下記一般式(IV)で表されるアミンと反応させ、得られた前記一般式(I)で表される化合物を、必要に応じてその薬学的に許容し得る酸付加塩に転化及び/又はその塩から単離することを特徴とする製造方法。
(式中、置換基は上述した通りであり、R3'は、R3について定義した基からR3とは独立して選択され、R3'は水素原子であってもよく、R3及びR3'は、互いに結合して環状第二アミンを形成していてもよい。) - 請求項1又は2に記載の化合物と、薬学的に許容し得る固体又は液体の担体及び/又は賦形剤と、を含む医薬組成物。
- 請求項1又は2に記載の化合物を、不活性な薬学的に許容し得る固体又は液体の担体及び/又は賦形剤と混合することを特徴とする、請求項4に記載の医薬組成物の製造方法。
- 虚血、再潅流障害、心臓血管疾患、神経変性障害、外傷、神経精神疾患、肝臓、腎臓及び肺損傷から選択される疾患の治療又は予防のために使用される、請求項4に記載の医薬組成物。
- 前記神経変性障害がアルツハイマー病及びハンチントン病から選択される、請求項6に記載の医薬組成物。
- 前記神経精神疾患が鬱病及び不安障害から選択される、請求項6に記載の医薬組成物。
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Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
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R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |