JP2017529333A - 2−アルコキシベンゾイル芳香族アミン化合物及びその薬物の用途 - Google Patents
2−アルコキシベンゾイル芳香族アミン化合物及びその薬物の用途 Download PDFInfo
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Abstract
Description
1)2−(2−フルオロベンジルオキシ)−N−(ピリジン−3−基)ベンズアミド(式I−1)は5μM下の抑制率は53.8%である。
1)2−ベンジルオキシ安息香酸メチル(化合物3a)の合成
4)2−ヒドロキシ−N−(ピリジン−3−基)ベンズアミド(化合物7)の合成
5)2−((2,6−ジクロロ)ベンジルオキシ)−N−(ピリジン−3−基)ベンズアミド(式I−17)の合成
2−ヒドロキシ−N−(ピリジン−3−基)ベンズアミド(化合物7) 0.21 g(1.0 mmol,1.0 eq)を6 mlアセトンの中に溶解し、炭酸カリウム0.28 g(2.0 mmol,2.0 eq)を加え、続いて2,6−ジクロロベンジル臭化物0.24 g(1.0 mmol,1.0 eq)を加え、1.0時間反応した。反応終了後、蒸留でアセトンを除去し、水を加え、EAで抽出した。次は,有機層を飽和食塩水で2回洗って、無水硫酸ナトリウムで乾燥し、濃縮して0.34 g浅黄色オイルを得た。粗生成物をカラムクロマトグラフィーで精製し、流動性相はPE:EA=2:1である。0.24 g浅黄色の固体(式I−17)を得た。収率は64.9%である。検測結果は以下の通り:m.p 115.0−116.4 oC. MS(ESI) (m/z): 373.0(M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.16 (s, 1H), 8.51 (d, J = 2.4 Hz, 1H), 8.25 (dd, J = 4.7, 1.4 Hz, 1H), 8.05 − 7.98 (m, 1H), 7.71 (dd, J = 7.6, 1.6 Hz, 1H), 7.63 − 7.53 (m, 3H), 7.47 (dd, J = 9.0, 7.0 Hz, 2H), 7.33 (dd, J = 8.3, 4.7 Hz, 1H), 7.18 (t, J = 7.3 Hz, 1H), 5.43 (s, 2H).
実施例2:化合物I−1,I−2,I−3,I−4,I−5,I−6,I−7,I−8,I−9,I−10,I−11,I−12,I−13,I−14,I−15,I−16,I−18,I−19,I−20の合成
式I−1 m.p 101.6−102.5oC. MS(ESI) (m/z): 323.2(M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.56 (s, 1H), 8.86 (d, J = 1.8 Hz, 1H), 8.39 (dd, J = 4.9, 1.1 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.68 (dd, J = 7.6, 1.7 Hz, 1H), 7.66 − 7.61 (m, 1H), 7.60 − 7.53 (m, 2H), 7.44 − 7.34 (m, 2H), 7.25 (dd, J = 9.8, 8.9 Hz, 1H), 7.19 (td, J = 7.5, 0.8 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 5.33 (s, 2H).
式I−2 m.p 102.8−104.2oC. MS(ESI) (m/z): 323.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.40 (s, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.29 (dd, J = 4.7, 1.4 Hz, 1H), 8.18 − 8.10 (m, 1H), 7.67 (dd, J = 7.6, 1.6 Hz, 1H), 7.57 − 7.50 (m, 1H), 7.45 − 7.34 (m, 4H), 7.27 (d, J = 8.3 Hz, 1H), 7.19 − 7.09 (m, 2H), 5.27 (s, 2H).
式I−3 m.p 138.2−141.1oC. MS(ESI) (m/z): 350.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.43 (s, 1H), 8.79 (s, 1H), 8.27 (d, J = 4.6 Hz, 1H), 8.19 (d, J = 7.3 Hz, 2H), 8.14 (d, J = 7.2 Hz, 1H), 7.75 (d, J = 7.8 Hz, 2H), 7.62 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.36 (dd, J = 7.7, 4.8 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 5.39 (s, 2H).
式I−4 m.p 150.2−152.6oC. MS(ESI) (m/z): 330.1 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.41 (s, 1H), 8.80 (s, 1H), 8.27 (d, J = 4.1 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 7.97 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.59 - 7.47 (m, 2H), 7.36 (dd, J = 8.1, 4.7 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 5.27 (s, 2H).
式I−5 m.p 114.9−118.4oC. MS(ESI) (m/z): 335.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.34 (s, 1H), 8.63 (s, 1H), 8.25 (d, J = 4.6 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.9 Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.34 (dd, J = 8.3, 4.7 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.91 (d, J = 8.5 Hz, 2H), 5.15 (s, 2H), 3.72 (s, 3H).
式I−6 m.p 122.8−125.2oC. MS(ESI) (m/z): 330.1 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.32 (s, 1H), 8.67 (s, 1H), 8.25 (d, J = 4.2 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.78 (t, J = 10.8 Hz, 1H), 7.67 (dd, J = 12.1, 7.0 Hz, 2H), 7.53 (dd, J = 9.0, 4.4 Hz, 2H), 7.33 (dd, J = 12.6, 6.5 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H), 5.41 (s, 2H).
式I−7 m.p 125.1−125.6oC. MS(ESI) (m/z): 339.2 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.40 (s, 1H), 8.79 (d, J = 2.4 Hz, 1H), 8.29 (dd, J = 4.7, 1.4 Hz, 1H), 8.20 - 8.07 (m, 1H), 7.66 (dd, J = 7.7, 1.6 Hz, 2H), 7.58 − 7.50 (m, 1H), 7.50 − 7.44 (m, 1H), 7.43 − 7.33 (m, 3H), 7.28 (d, J = 8.3 Hz, 1H), 7.12 (t, J = 7.4 Hz, 1H), 5.25 (s, 2H).
式I−8 m.p 151.4−152.4oC. MS(ESI) (m/z): 384.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.39 (s, 1H), 8.78 (s, 1H), 8.26 (d, J = 4.6 Hz, 1H), 8.11 (d, J = 8.2 Hz, 1H), 7.77 (s, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.51 (dd, J = 14.6, 7.6 Hz, 3H), 7.35 (dd, J = 8.2, 4.8 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 5.22 (s, 2H).
式I−9 m.p 147.2−148.7oC. MS(ESI) (m/z): 384.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.36 (s, 1H), 8.72 (d, J = 2.3 Hz, 1H), 8.26 (d, J = 4.6 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 8.3 Hz, 2H), 7.48 (t, J = 8.9 Hz, 3H), 7.35 (dd, J = 8.3, 4.7 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 5.21 (s, 2H).
式I−10 m.p 151.9−153.6oC. MS(ESI) (m/z): 319.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.37 (s, 1H), 8.68 (s, 1H), 8.26 (d, J = 4.7 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.34 (t, J = 6.4 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 7.22 (t, J = 7.5 Hz, 1H), 7.10 (dd, J = 12.8, 6.3 Hz, 2H), 5.18 (s, 2H), 2.20 (s, 3H).
式I−11 m.p 95.9−98.0oC. MS(ESI) (m/z): 319.2 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.37 (s, 1H), 8.61 (d, J = 2.4 Hz, 1H), 8.27 (dd, J = 4.7, 1.4 Hz, 1H), 8.09 − 8.02 (m, 1H), 7.69 (dd, J = 7.6, 1.7 Hz, 1H), 7.58 − 7.52 (m, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.39 − 7.32 (m, 2H), 7.28 − 7.21 (m, 2H), 7.15 (ddd, J = 17.3, 11.2, 4.7 Hz, 2H), 5.26 (s, 2H), 2.34 (s, 3H).
式I−12 m.p 110.7−112.9oC. MS(ESI) (m/z): 350.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.42 (s, 1H), 8.76 (d, J = 2.3 Hz, 1H), 8.28 (dd, J = 4.7, 1.4 Hz, 1H), 8.13 (dt, J = 8.2, 2.0 Hz, 2H), 7.84 (d, J = 7.5 Hz, 1H), 7.69 − 7.54 (m, 3H), 7.52 − 7.45 (m, 1H), 7.36 (dd, J = 8.3, 4.7 Hz, 1H), 7.24 (d, J = 8.3 Hz, 1H), 7.11 (td, J = 7.5, 0.7 Hz, 1H), 5.60 (s, 2H).
式I−13 m.p 142.4−144.6oC. MS(ESI) (m/z): 350.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.43 (s, 1H), 8.79 (s, 1H), 8.27 (d, J = 4.6 Hz, 1H), 8.19 (d, J = 7.3 Hz, 2H), 8.14 (d, J = 7.2 Hz, 1H), 7.75 (d, J = 7.8 Hz, 2H), 7.62 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.36 (dd, J = 7.7, 4.8 Hz, 1H), 7.23 (d, J = 8.3 Hz, 1H), 7.10 (t, J = 7.4 Hz, 1H), 5.39 (s, 2H).
式I−14 m.p 133.3−137.6oC. MS(ESI) (m/z): 319.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.35 (s, 1H), 8.66 (s, 1H), 8.26 (d, J = 4.6 Hz, 1H), 8.08 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.41 (d, J = 7.2 Hz, 2H), 7.34 (dd, J = 7.9, 4.6 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.15 (d, J = 7.2 Hz, 2H), 7.08 (t, J = 7.4 Hz, 1H), 5.18 (s, 2H), 2.27 (s, 3H).
式I−15 m.p 139.1−140.5oC. MS(ESI) (m/z): 330.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.40 (s, 1H), 8.76 (s, 1H), 8.27 (d, J = 4.7 Hz, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.85 − 7.78 (m, 2H), 7.68 (d, J = 7.8 Hz, 2H), 7.62 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.36 (dd, J = 8.2, 4.6 Hz, 1H), 7.22 (d, J = 8.3 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 5.33 (s, 2H).
式I−16 m.p 118.0−119.2oC. MS(ESI) (m/z): 357.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.41 (s, 1H), 8.76 (d, J = 2.4 Hz, 1H), 8.29 (dd, J = 4.7, 1.4 Hz, 1H), 8.17 - 8.11 (m, 1H), 7.66 (dd, J = 7.5, 1.6 Hz, 1H), 7.59 − 7.48 (m, 3H), 7.38 (dd, J = 8.3, 4.7 Hz, 1H), 7.31 (d, J = 8.3 Hz, 1H), 7.25 (td, J = 8.5, 3.1 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H), 5.30 (s, 2H). 式I−16の塩酸塩m.p 167.3−169.0oC.
式I−18 m.p 149.8−150.6oC. MS(ESI) (m/z): 357.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.33 (s, 1H), 8.72 (d, J = 2.4 Hz, 1H), 8.28 (dd, J = 4.7, 1.4 Hz, 1H), 8.14 − 8.08 (m, 1H), 7.66 (dd, J = 7.6, 1.7 Hz, 1H), 7.63 − 7.51 (m, 3H), 7.39 − 7.32 (m, 2H), 7.21 (t, J = 7.9 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 5.36 (s, 2H).
式I−19 m.p 93.7−97.0oC. MS(ESI) (m/z): 377.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.42 (s, 1H), 8.76 (d, J = 1.8 Hz, 1H), 8.27 (d, J = 4.2 Hz, 1H), 8.18 - 8.12 (m, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.67 − 7.60 (m, 3H), 7.54 − 7.47 (m, 1H), 7.35 (dd, J = 8.3, 4.7 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 5.31 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H).
式I−20 m.p 144.6−147.8oC. MS(ESI) (m/z): 373.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.41 (s, 1H), 8.77 (d, J = 2.1 Hz, 1H), 8.27 (d, J = 4.6 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.76 − 7.67 (m, 4H), 7.67 − 7.61 (m, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.35 (dd, J = 8.3, 4.7 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 7.5 Hz, 1H), 5.34 (s, 2H).
実施例3:化合物I−21、I−22、I−23、I−24、I−25およびI−26の合成
1)化合物8−2a〜8−2dの合成
式I−21 m.p 156.2−157.7oC. MS(ESI) (m/z): 337.0 (M+H)+. 1H NMR (600 MHz, DMSO−d6) δ ppm 11.05 (d, J = 6.3 Hz, 1H), 9.21 (s, 1H), 8.59 (d, J = 5.3 Hz, 1H), 8.47 (d, J = 7.7 Hz, 1H), 7.90 (dt, J = 9.1, 4.7 Hz, 1H), 7.63 (dd, J = 7.5, 1.7 Hz, 1H), 7.60 - 7.55 (m, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.28 (dd, J = 10.0, 2.7 Hz, 1H), 7.23 (dd, J = 8.2, 6.0 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 7.02 (td, J = 8.5, 2.8 Hz, 1H), 5.24 (s, 2H), 2.28 (s, 3H). 式I−21の塩酸塩m.p 156.2−157.7oC.
式I−23 m.p 168.6−171.0oC. MS(ESI) (m/z): 335.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.37 (s, 1H), 8.72 (d, J = 2.3 Hz, 1H), 8.28 (dd, J = 4.7, 1.3 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 7.6, 1.6 Hz, 1H), 7.59 - 7.48 (m, 1H), 7.36 (dd, J = 8.3, 4.7 Hz, 1H), 7.29 (dd, J = 12.8, 5.0 Hz, 2H), 7.18 − 7.03 (m, 3H), 6.89 (dd, J = 8.1, 2.2 Hz, 1H), 5.23 (s, 2H), 3.67 (s, 3H).
式I−24 m.p 136.4−137.6oC. MS(ESI) (m/z): 335.0 (M+H)+. 1H NMR (600 MHz, DMSO−d6) δ ppm 10.34 (s, 1H), 8.59 (d, J = 2.4 Hz, 1H), 8.28 (dd, J = 4.7, 1.4 Hz, 1H), 8.09 − 8.01 (m, 1H), 7.76 (dd, J = 7.6, 1.7 Hz, 1H), 7.56 − 7.50 (m, 2H), 7.38 − 7.31 (m, 3H), 7.14 − 7.06 (m, 2H), 6.93 (td, J = 7.4, 0.7 Hz, 1H), 5.26 (s, 2H), 3.78 (s, 3H).
式I−25 MS(ESI) (m/z): 365.1 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.38 (s, 1H), 8.65 (s, 1H), 8.26 (d, J = 4.1 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.34 (dd, J = 8.0, 4.7 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.11 (dd, J = 15.2, 4.9 Hz, 2H), 6.96 (d, J = 8.9 Hz, 1H), 6.86 (dd, J = 8.9, 2.6 Hz, 1H), 5.19 (s, 2H), 3.71 (s, 3H), 3.55 (s, 3H).
3)化合物8−2eと8−2fの合成
式I−22 MS(ESI) (m/z): 407.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 11.11 (s, 1H), 9.27 (s, 1H), 8.61 (d, J = 5.3 Hz, 1H), 8.54 (d, J = 7.8 Hz, 1H), 7.97 (dd, J = 8.5, 5.5 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 7.26 (dt, J = 10.4, 5.9 Hz, 2H), 7.13 − 7.04 (m, 3H), 6.82 (d, J = 6.9 Hz, 1H), 5.21 (s, 2H), 4.71 (s, 2H), 4.11 (q, J = 7.1 Hz, 2H), 1.16 (t, J = 7.1 Hz, 3H).
式I−26 MS(ESI) (m/z): 411.2 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 11.10 (s, 1H), 9.21 (s, 1H), 8.61 (d, J = 5.1 Hz, 1H), 8.44 (d, J = 8.5 Hz, 1H), 7.95 (dd, J = 8.3, 5.5 Hz, 1H), 7.67 (d, J = 7.4 Hz, 1H), 7.49 (dd, J = 13.5, 7.0 Hz, 2H), 7.38 (d, J = 7.2 Hz, 2H), 7.31 − 7.21 (m, 5H), 7.08 (t, J = 8.3 Hz, 2H), 6.89 (t, J = 7.4 Hz, 1H), 5.29 (s, 2H), 5.13 (s, 2H).
実施例4:化合物I−27,I−28,I−29,I−30,I−31,I−32和I−33の合成
1)化合物8−3aから8−3gまでの合成
式I−27 MS(ESI) (m/z): 333.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 11.06 (s, 1H), 9.18 (d, J = 1.6 Hz, 1H), 8.60 (d, J = 5.3 Hz, 1H), 8.44 (d, J = 8.5 Hz, 1H), 7.94 (dd, J = 8.5, 5.4 Hz, 1H), 7.64 (dd, J = 7.6, 1.6 Hz, 1H), 7.61 − 7.55 (m, 1H), 7.49 (d, J = 7.4 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.26 (dt, J = 13.9, 6.5 Hz, 2H), 7.19 − 7.10 (m, 2H), 5.27 (s, 2H), 2.68 (q, J = 7.5 Hz, 2H), 1.12 (t, J = 7.5 Hz, 3H).
式I−28 m.p 164.8−167.1oC. MS(ESI) (m/z): 333.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 11.17 (s, 1H), 9.27 (s, 1H), 8.64 (d, J = 5.3 Hz, 1H), 8.57 (d, J = 8.6 Hz, 1H), 8.00 (dd, J = 8.4, 5.6 Hz, 1H), 7.63 (d, J = 6.7 Hz, 1H), 7.52 (t, J = 7.8 Hz, 1H), 7.40 (d, J = 7.8 Hz, 2H), 7.27 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 7.8 Hz, 2H), 7.08 (t, J = 7.5 Hz, 1H), 5.19 (s, 2H), 2.54 (q, J = 7.5 Hz, 2H), 1.11 (t, J = 7.6 Hz, 3H).
式I−29 MS(ESI) (m/z): 333.1 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 11.07 (s, 1H), 9.08 (d, J = 1.8 Hz, 1H), 8.57 (d, J = 5.2 Hz, 1H), 8.30 (d, J = 8.6 Hz, 1H), 7.91 (dd, J = 8.5, 5.5 Hz, 1H), 7.58 (dd, J = 13.8, 4.6 Hz, 2H), 7.45 (d, J = 8.2 Hz, 1H), 7.11 (dd, J = 13.3, 7.1 Hz, 2H), 7.00 (d, J = 7.5 Hz, 2H), 5.18 (s, 2H), 2.31 (s, 6H). 式I−29の塩酸塩m.p 145.7−148.5oC.
式I−30 MS(ESI) (m/z): 349.2 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.34 (s, 1H), 8.53 (d, J = 1.7 Hz, 1H), 8.25 (d, J = 4.5 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.77 (dd, J = 7.6, 1.4 Hz, 1H), 7.57 − 7.47 (m, 2H), 7.32 (dd, J = 12.9, 6.2 Hz, 3H), 7.10 (t, J = 7.5 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.90 (t, J = 7.4 Hz, 1H), 5.24 (s, 2H), 3.99 (q, J = 6.9 Hz, 2H), 1.20 (t, J = 6.9 Hz, 3H).
式I−31 m.p 119.0−122.8oC. MS(ESI) (m/z): 369.1 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.39 (s, 1H), 8.74 (d, J = 2.2 Hz, 1H), 8.27 (dd, J = 4.7, 1.3 Hz, 1H), 8.11 (ddd, J = 8.3, 2.3, 1.5 Hz, 1H), 7.67 (dd, J = 7.6, 1.6 Hz, 1H), 7.56 − 7.48 (m, 2H), 7.38 − 7.31 (m, 2H), 7.27 (d, J = 8.3 Hz, 1H), 7.10 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 5.18 (s, 2H), 3.77 (s, 3H).
式I−32 MS(ESI) (m/z): 357.0 (M+H)+. 1H NMR (600 MHz, DMSO−d6) δ ppm 10.87 (s, 1H), 9.11 (s, 1H), 8.57 (d, J = 4.8 Hz, 1H), 8.38 (s, 1H), 7.90 (s, 1H), 7.66 − 7.58 (m, 2H), 7.50 − 7.44 (m, 2H), 7.36 (d, J = 8.1 Hz, 1H), 7.28 (t, J = 8.9 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 5.33 (s, 2H). 式I−32の塩酸塩m.p 177.3−179.1oC.
式I−33 MS(ESI) (m/z): 372.9 (M+H)+. 1H NMR (600 MHz, DMSO−d6) δ ppm 11.18 − 11.07 (m, 1H), 9.26 (s, 1H), 8.65 - 8.48 (m, 2H), 7.94 (d, J = 4.7 Hz, 1H), 7.70 − 7.63 (m, 2H), 7.62 − 7.56 (m, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.42 (dd, J = 8.5, 2.5 Hz, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 5.30 (s, 2H). 式I−33の塩酸塩m.p 185.0−186.9oC.
実施例5:化合物I−34,I−35,I−36,I−37,I−38,I−39及びI−40の合成
1)化合物8−4aから8−4eまでの合成
式I−34 MS(ESI) (m/z): 411.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.96 (s, 1H), 9.15 (d, J = 1.8 Hz, 1H), 8.60 (d, J = 5.1 Hz, 1H), 8.40 (d, J = 8.7 Hz, 1H), 7.93 (dd, J = 8.5, 5.4 Hz, 1H), 7.72 (dd, J = 7.6, 1.7 Hz, 1H), 7.61 − 7.54 (m, 1H), 7.50 − 7.45 (m, 1H), 7.31 (dd, J = 10.2, 5.0 Hz, 2H), 7.13 (t, J = 7.3 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.91 (t, J = 7.3 Hz, 1H), 5.26 (s, 2H), 4.03 (t, J = 5.7 Hz, 2H), 3.64 (t, J = 6.1 Hz, 2H), 1.88 − 1.72 (m, 4H). 式I−34の塩酸塩m.p 127.4−128.1oC.
式I−35 MS(ESI) (m/z): 425.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.95 (s, 1H), 9.14 (d, J = 1.7 Hz, 1H), 8.60 (d, J = 5.1 Hz, 1H), 8.39 (d, J = 9.2 Hz, 1H), 7.93 (dd, J = 8.5, 5.4 Hz, 1H), 7.73 (dd, J = 7.6, 1.6 Hz, 1H), 7.61 − 7.54 (m, 1H), 7.47 (d, J = 6.3 Hz, 1H), 7.32 (dd, J = 10.7, 4.8 Hz, 2H), 7.14 (t, J = 7.4 Hz, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.91 (t, J = 7.4 Hz, 1H), 5.26 (s, 2H), 3.99 (t, J = 6.2 Hz, 2H), 3.58 (t, J = 6.6 Hz, 2H), 1.76 − 1.62 (m, 4H), 1.52 − 1.42 (m, 2H).
式I−36 MS(ESI) (m/z): 439.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.90 − 10.79 (m, 1H), 9.06 (d, J = 12.3 Hz, 1H), 8.56 (d, J = 5.2 Hz, 1H), 8.31 (d, J = 8.5 Hz, 1H), 7.87 (t, J = 9.5 Hz, 1H), 7.76 (d, J = 7.6 Hz, 1H), 7.62 − 7.55 (m, 1H), 7.48 (d, J = 7.4 Hz, 1H), 7.33 (t, J = 7.1 Hz, 2H), 7.14 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 6.92 (t, J = 7.4 Hz, 1H), 5.27 (s, 2H), 3.98 (t, J = 6.3 Hz, 2H), 3.57 (t, J = 6.6 Hz, 2H), 1.64 (dd, J = 13.1, 6.5 Hz, 4H), 1.43 - 1.31 (m, 4H). 式I−36の塩酸塩m.p 113.7−115.4oC.
式I−37 MS(ESI) (m/z): 405.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 11.04 (s, 1H), 9.18 (s, 1H), 8.62 (s, 1H), 8.42 (d, J = 6.6 Hz, 1H), 7.97 (s, 1H), 7.71 (d, J = 6.8 Hz, 1H), 7.60 − 7.42 (m, 2H), 7.25 (d, J = 7.6 Hz, 2H), 7.17 − 6.83 (m, 3H), 5.22 (s, 2H), 3.92 (s, 2H), 1.59 (s, 2H), 1.27 (dd, J = 17.1, 8.5 Hz, 2H), 1.18 (d, J = 21.4 Hz, 4H), 0.76 (s, 3H).
式I−38 MS(ESI) (m/z): 419.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 11.00 (s, 1H), 9.16 (s, 1H), 8.61 (d, J = 5.1 Hz, 1H), 8.40 (d, J = 8.4 Hz, 1H), 7.95 (dd, J = 8.4, 5.5 Hz, 1H), 7.72 (dd, J = 7.6, 1.4 Hz, 1H), 7.54 (t, J = 7.1 Hz, 1H), 7.46 (d, J = 6.8 Hz, 1H), 7.27 (t, J = 7.7 Hz, 2H), 7.10 (t, J = 7.4 Hz, 1H), 7.01 (d, J = 8.2 Hz, 1H), 6.88 (t, J = 7.4 Hz, 1H), 5.23 (s, 2H), 3.93 (t, J = 6.3 Hz, 2H), 1.66 − 1.54 (m, 2H), 1.34 − 1.23 (m, 2H), 1.23 − 1.06 (m, 6H), 0.78 (t, J = 6.9 Hz, 3H).
3)化合物8−4fと8−4gの合成
式I−39 MS(ESI) (m/z): 439.2 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 11.18 (s, 1H), 9.27 (d, J = 1.8 Hz, 1H), 8.64 (d, J = 5.4 Hz, 1H), 8.56 (d, J = 8.7 Hz, 1H), 8.00 (dd, J = 8.6, 5.5 Hz, 1H), 7.65 (dd, J = 7.6, 1.5 Hz, 1H), 7.58 − 7.51 (m, 1H), 7.45 (d, J = 2.6 Hz, 1H), 7.26 (dd, J = 12.2, 5.7 Hz, 2H), 7.11 (t, J = 7.5 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 5.17 (s, 2H), 3.95 (t, J = 6.4 Hz, 2H), 1.68 − 1.58 (m, 2H), 1.32 (dd, J = 14.4, 7.1 Hz, 2H), 1.22 (dt, J = 7.1, 4.7 Hz, 4H), 0.80 (t, J = 7.0 Hz, 3H). 式I−39の塩酸塩m.p 155.3−158.0oC.
式I−40 MS(ESI) (m/z): 453.3 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 11.16 (s, 1H), 9.26 (d, J = 2.0 Hz, 1H), 8.64 (d, J = 5.3 Hz, 1H), 8.54 (d, J = 8.7 Hz, 1H), 7.99 (dd, J = 8.6, 5.5 Hz, 1H), 7.66 (dd, J = 7.6, 1.6 Hz, 1H), 7.58 − 7.52 (m, 1H), 7.46 (d, J = 2.6 Hz, 1H), 7.26 (dd, J = 12.4, 5.8 Hz, 2H), 7.12 (t, J = 7.5 Hz, 1H), 7.02 (d, J = 8.9 Hz, 1H), 5.17 (s, 2H), 3.95 (t, J = 6.4 Hz, 2H), 1.69 − 1.57 (m, 2H), 1.38 − 1.28 (m, 2H), 1.27 − 1.11 (m, 6H), 0.80 (t, J = 6.9 Hz, 3H).I−40の塩酸塩m.p 156.9−159.2oC.
実施例6:化合物I−41,I−42,I−43,I−44及びI−45の合成
1)化合物13uの合成
3)化合物I−42,I−43及びI−44の合成
式I−42 m.p 73.6−75.1oC. MS(ESI) (m/z): 373.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.37 (s, 1H), 8.67 (d, J = 2.4 Hz, 1H), 8.28 (dd, J = 4.7, 1.4 Hz, 1H), 8.13 − 8.07 (m, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.71 − 7.61 (m, 2H), 7.61 − 7.52 (m, 2H), 7.36 (dd, J = 8.3, 4.7 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 5.40 (s, 2H).
式I−43 MS(ESI) (m/z): 353.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 11.20 (s, 1H), 9.26 (s, 1H), 8.62 (d, J = 5.3 Hz, 1H), 8.54 (d, J = 8.6 Hz, 1H), 7.97 (dd, J = 8.5, 5.5 Hz, 1H), 7.60 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.47 (s, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.24 − 7.17 (m, 2H), 7.12 (t, J = 7.5 Hz, 1H), 5.20 (s, 2H), 2.27 (s, 3H). 式I−43の塩酸塩m.p 177.8−178.9oC.
式I−44 m.p 98.6−100.5oC. MS(ESI) (m/z): 353.1 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.37 (s, 1H), 9.00 (s, 1H), 8.66 (d, J = 1.9 Hz, 1H), 8.26 (d, J = 4.1 Hz, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.64 − 7.57 (m, 2H), 7.39 (d, J = 7.9 Hz, 1H), 7.37 − 7.31 (m, 2H), 7.15 (t, J = 7.8 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 5.27 (s, 2H), 2.33 (s, 3H).
4)化合物I−45の合成
実施例6のスッテプ2の化合物I−41の合成条件を参照し、2−ヒドロキシ−N−(ピリジン−3−基)ベンズアミド(化合物7)と1−ナフトールメタノールと反応させて、化合物2−((ナフトール−1−基)メトキシ)−N−(ピリジン−3−基) ベンズアミド(式I−45)を得た。
実施例7:化合物I−46,I−47及びI−48の合成
1)化合物I−46とI−48の合成
2)化合物I−47の合成
実施例8:化合物I−49,I−50及びI−51の合成
1)化合物8−6aと8−6bの合成
式I−49 MS(ESI) (m/z): 427.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.36 (s, 1H), 8.67 (d, J = 2.3 Hz, 1H), 8.26 (dd, J = 4.7, 1.4 Hz, 1H), 8.12 - 8.06 (m, 1H), 7.70 (dd, J = 7.6, 1.7 Hz, 1H), 7.53 (dd, J = 12.3, 2.2 Hz, 2H), 7.37 − 7.30 (m, 2H), 7.28 (d, J = 8.3 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 5.19 (s, 2H), 4.01 (t, J = 6.2 Hz, 2H), 3.36 (t, J = 6.2 Hz, 2H), 3.13 (s, 3H), 1.87 (p, J = 6.2 Hz, 2H).
式I−50 MS(ESI) (m/z): 413.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.35 (s, 1H), 8.71 (d, J = 2.3 Hz, 1H), 8.27 (dd, J = 4.7, 1.4 Hz, 1H), 8.10 (ddd, J = 8.3, 2.4, 1.5 Hz, 1H), 7.69 (dd, J = 7.6, 1.7 Hz, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.53 − 7.49 (m, 1H), 7.37 − 7.34 (m, 1H), 7.32 (dd, J = 8.9, 2.6 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 7.07 (d, J = 8.9 Hz, 1H), 5.19 (s, 2H), 4.11 (t, J = 4.4 Hz, 2H), 3.59 (t, J = 4.4 Hz, 2H), 3.21 (s, 3H).
3)化合物I−51の合成
実施例9:化合物I−52とI−53の合成
式I−52 m.p 112.3−114.9oC. MS(ESI) (m/z): 305.2 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.58 (s, 1H), 8.30 (dd, J = 4.8, 1.0 Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 7.86 (dd, J = 7.7, 1.7 Hz, 1H), 7.84 − 7.77 (m, 1H), 7.53 (dd, J = 13.9, 4.5 Hz, 3H), 7.39 − 7.28 (m, 4H), 7.12 (dt, J = 12.3, 4.1 Hz, 2H), 5.34 (s, 2H).
式I−53 m.p 145.3−148.9oC. MS(ESI) (m/z): 306.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.53 (s, 1H), 9.00 (s, 2H), 8.88 (s, 1H), 7.68 (dd, J=7.6, 1.6, 1H), 7.57 − 7.45 (m, 3H), 7.33 (ddd, J=16.5, 10.5, 5.3, 4H), 7.10 (t, J=7.5, 1H), 5.24 (s, 2H).
実施例10:化合物I−54,式I−55,式I−56,式I−57,式I−58,式I−59及びI−60の合成
式I−54 m.p 129.2−131.9oC. MS(ESI) (m/z): 407.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.27 (s, 1H), 8.54 (d, J = 2.3 Hz, 1H), 8.24 (dd, J = 4.6, 1.2 Hz, 1H), 7.99 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 2.6 Hz, 1H), 7.61 (dd, J = 8.7, 2.7 Hz, 1H), 7.53 − 7.40 (m, 4H), 7.31 (dd, J = 8.3, 4.7 Hz, 1H), 5.37 (s, 2H).
式I−55 m.p 153.3−154.7oC. MS(ESI) (m/z): 391.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.51 (s, 1H), 8.75 (d, J = 1.4 Hz, 1H), 8.29 (d, J = 4.2 Hz, 1H), 8.11 (d, J = 8.3 Hz, 1H), 7.65 (d, J = 2.5 Hz, 1H), 7.57 (dd, J = 8.8, 2.6 Hz, 1H), 7.52 (dd, J = 8.8, 5.1 Hz, 1H), 7.45 (dd, J = 9.4, 2.9 Hz, 1H), 7.36 (dd, J = 8.3, 4.8 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 7.21 (td, J = 8.5, 3.0 Hz, 1H), 5.27 (s, 2H).
式I−56 m.p 117.6−121.7oC. MS(ESI) (m/z): 373.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.32 (s, 1H), 8.62 (d, J = 2.3 Hz, 1H), 8.26 (dd, J = 4.6, 1.1 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 1.5 Hz, 1H), 7.40 - 7.27 (m, 3H), 7.19 (dd, J = 8.2, 1.5 Hz, 1H), 5.34 (s, 2H).
式I−57 m.p 175.7−177.9oC. MS(ESI) (m/z): 384.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.56 (s, 1H), 8.69 (d, J = 2.3 Hz, 1H), 8.46 (d, J = 2.9 Hz, 1H), 8.42 (dd, J = 9.1, 2.9 Hz, 1H), 8.31 - 8.27 (m, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.67 - 7.61 (m, 1H), 7.55 (d, J = 9.2 Hz, 1H), 7.50 (d, J = 7.9 Hz, 1H), 7.37 (dd, J = 7.8, 5.6 Hz, 2H), 7.31 (t, J = 7.4 Hz, 1H), 5.45 (s, 2H).
式I−58 m.p 117.6−120.1oC. MS(ESI) (m/z): 417.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.32 (s, 1H), 8.62 (d, J = 2.3 Hz, 1H), 8.26 (dd, J = 4.7, 1.4 Hz, 1H), 8.05 (ddd, J = 8.3, 2.3, 1.5 Hz, 1H), 7.64 (dd, J = 7.6, 1.5 Hz, 1H), 7.59 (t, J = 5.2 Hz, 2H), 7.49 (dd, J = 7.9, 1.1 Hz, 1H), 7.34 (qdd, J = 15.9, 7.5, 1.4 Hz, 4H), 5.33 (s, 2H).
式I−59 m.p 97.3−99.8oC. MS(ESI) (m/z): 369.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.36 (s, 1H), 8.64 (d, J = 2.3 Hz, 1H), 8.29 - 8.23 (m, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 6.4 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.39 - 7.22 (m, 5H), 7.10 (dd, J = 9.0, 3.1 Hz, 1H), 5.25 (s, 2H), 3.75 (s, 3H).
式I−60 m.p 122.1−124.4oC. MS(ESI) (m/z): 369.0 (M+H)+. 1H NMR (400 MHz, DMSO−d6) δ ppm 10.05 (s, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.23 (dd, J = 4.7, 1.3 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.82 - 7.76 (m, 1H), 7.71 (dd, J = 7.4, 1.3 Hz, 1H), 7.53 (dd, J = 7.9, 1.0 Hz, 1H), 7.41 (td, J = 7.7, 1.7 Hz, 1H), 7.35 (td, J = 7.5, 1.1 Hz, 1H), 7.30 (dd, J = 8.3, 4.7 Hz, 1H), 6.86 (d, J = 2.1 Hz, 1H), 6.71 (dd, J = 8.7, 2.2 Hz, 1H), 5.37 (s, 2H), 3.84 (s, 3H).
実施例11:化合物I−16,I−21,I−24,I−27,I−29,I−32,I−33,I−34,I−36,I−39,I−40及びI−43の塩酸塩の合成
1)化合物I−24の塩酸塩の合成
化合物(I−24) 0.33 g(1.0 mmol, 1.0 eq)を10 ml乾燥した酢酸エチルの中に溶解し、アイスバスでそれに1.2 ml(1.5 mmol, 1.5 eq) HCl(g)を含んだ酢酸エチル溶液(c =1.25 mol/L)を滴下し、10 分間反応し、濾過し、乾燥してから0.24 g白い粉末状固体を得た。収率は64.9%であった。式I−24の塩酸塩m.p 154.4−157.2oC.
2)化合物I−27の塩酸塩の合成
化合物(I−27) 0.42 g(1.26 mmol, 1.0 eq)を13 ml乾燥した酢酸エチルの中に溶解し、アイスバスでそれに1.5 ml(1.75 mmol, 1.5 eq) HCl(g)を含んだ酢酸エチル溶液(c =1.25 mol/L)を滴下し、10 分間反応し、濾過し、乾燥してから0.33 g白い粉末状固体を得た。収率は70.8%であった。式I−27の塩酸塩m.p 158.0−161.3oC.
3)化合物I−40の塩酸塩の合成
化合物(I−40) 0.23 g(0.5 mmol, 1.0 eq)を5 ml乾燥した酢酸エチルの中に溶解し、アイスバスでそれに0.6 ml(0.75 mmol, 1.5 eq) HCl(g) を含んだ酢酸エチル溶液(c =1.25 mol/L)を滴下し、10分間反応し、濾過し、乾燥してから0.16 g白い粉末状固体を得た。収率は64.0%であった。式I−40の塩酸塩m.p 156.9−159.2 oC.
以上の方法を参照し、それぞれ反応しれから、化合物I−16,I−21,I−29,I−32,I−33,I−34,I−36,I−39及びI−43の塩酸塩を得た。
実験器具と材料
1. エレクトリックヒートサモスタッチク水浴(上海一恒科技有限公司)
2. 渦混合器(上海精科実業有限公司XW−80A)
3. 高速遠心機(Eppendorf 5804R)
4. HPLC Agilent 1100 (Agilent Technologies, Palo Alto, CA, USA)、四次ポンプ、真空脱気,FLD蛍光検出器。
250 μL三重蒸留水、30 μL Buffer2、4 μL SMS2高表現の昆虫細胞ホモゲネート(総蛋白質含有量は0.5 μg/μLである)及び10 μLテスト化合物のDMSO溶液または空白のDMSO溶液を、1.5 mLのeppendorf管の中に加え、30秒渦振動し、37 ℃の水浴の中で半時間抱卵した。それから、3 μL DMPCのエタノール溶液(40 mM)と3 μL C6−NBD−Ceramideのエタノール溶液(1.16 mM)を加え、30秒渦振動してから、37 ℃の水浴の中で2時間抱卵した。取り出してから、加入600 μLの無水エタノールを加え、1分間渦振動した。10 分間10000 rpmで遠心し、取り出してから、4 ℃で600 μLの上清液は貯蔵し、HPLC分析の為に備えた。
テスト化合物6 mMのDMSO貯蔵溶液を階段式希釈し、五つの濃度段階の溶液を調製し、それぞれに10 μLを取って実施例12のステップ1の測定システムの中に加え、実施例12のステップ1の方法でサンプルを製造し、そしてHPLC方法で五つの濃度でのAsm値を測定し、五つの濃度での抑制率をそれぞれ計算し、整合して半数抑制濃度IC50を得て、化合物毎は3グループを平行測定した。化合物式I−1〜I−60のSMS2の半数抑制濃度(IC50)は表1で表す。
Claims (7)
- 式(I)の構造で表される2−アルコキシベンゾイル芳香族アミン化合物またはその薬学的に許容される塩;
X、YおよびZはC原子またはN原子から選択され、且つX、YおよびZは同時にC原子から選択されることがなく;
Gはフェニル基、置換のフェニル基とナフチル基から選択され、YおよびXまたはYおよびZはC原子から選択された場合、Gは置換のフェニル基またはナフチル基から選択され、
Rは水素、ハロゲン、ニトロ基またはC1〜C4のアルコキシ基から選択される。 - 前記Gは置換のフェニル基である場合、その置換基がハロゲン、ニトロ基、シアノ基、トリフルオロメトキシ基、カルボキシル基、エステル基、ベンジルオキシ基、C1〜C7のアルキル基またはC1〜C7のアルコキシ基から選択される一つまたは二つである、請求項1に記載の2−アルコキシベンゾイル芳香族アミン化合物またはその薬学的に許容される塩。
- 前記薬学的に許容される塩が塩酸塩、臭化水素酸塩である、請求項1または2に記載の2−アルコキシベンゾイル芳香族アミン化合物またはその薬学的に許容される塩。
- 請求項1〜3のいずれか1項に記載の2−アルコキシベンゾイル芳香族アミン化合物またはその薬学的に許容される塩と、医学的に許容される担体とからなる薬物組成物。
- 請求項1〜3のいずれか1項に記載の2−アルコキシベンゾイル芳香族アミン化合物またはその薬学的に許容される塩の、スフィンゴミエリンシンターゼ低分子の阻害剤の製造のための使用。
- 請求項1〜3のいずれか1項に記載の2−アルコキシベンゾイル芳香族アミン化合物またはその薬学的に許容される塩の、スフィンゴミエリンのレベル異常増加による疾患の予防と治療の薬物の製造のための使用。
- 前記スフィンゴミエリンのレベル異常増加による疾患は、アテローム性動脈硬化症、脂肪肝、肥満またはII型糖尿病及びそれらの関連の代謝症候群である、請求項6に記載の使用。
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