JPWO2013108800A1 - 置換フェニルアゾール誘導体 - Google Patents
置換フェニルアゾール誘導体 Download PDFInfo
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Abstract
Description
(1)一般式(I):
(2)環Aが、
(3)環Aが
(4)環Aが、
(5)環Aが、
(6)環Aが、
(7)一般式(II):
(8)一般式(III):
(9)以下:
1-[4-(4-{1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-2H-1,2,3-トリアゾール-2-イル)-2-フルオロフェニル]-3-(2-ヒドロキシエチル)ウレア;
4-{4-[(1R)-1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル]-2H-1,2,3-トリアゾール-2-イル}-N-[(1R,2R)-2,3-ジヒドロキシ-1-メチルプロピル]-2-フルオロベンズアミド;
1-(4-{4-[(1R)-1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル]-2H-1,2,3-トリアゾール-2-イル}-2-フルオロフェニル)-3-(2-ヒドロキシエチル)ウレア;
4-(5-{1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-2H-テトラゾール-2-イル)-2-フルオロ-N-[(1R)-2-ヒドロキシ-1-メチルエチル]ベンズアミド;
4-(5-{1-[4-(シクロプロピルカルボニル)フェノキシ]エチル}-1,3-チアゾール-2-イル)-2-フルオロ-N-[(1R)-2-ヒドロキシ-1-メチルエチル]ベンズアミド;
4-[4-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,3-オキサゾール-2-イル]-2-フルオロ-N-[(1R)-2-ヒドロキシ-1-メチルエチル]ベンズアミド;
N-シクロプロピル-4-[4-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,3-オキサゾール-2-イル]-2-フルオロベンズアミド;
1-{4-[4-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,3-オキサゾール-2-イル]-2-フルオロフェニル}-3-(2-ヒドロキシエチル)ウレア;
4-{5-[(1R)-1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル]-1,2,4-オキサジアゾール-3-イル}-2-フルオロ-N-[(1R)-2-ヒドロキシ-1-メチルエチル]ベンズアミド;
1-{4-[5-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,2,4-オキサジアゾール-3-イル]-2-フルオロフェニル}-3-(2-ヒドロキシエチル)ウレア;
4-[3-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,2,4-オキサジアゾール-5-イル]-2-フルオロ-N-[2-ヒドロキシ-1-(ヒドロキシメチル)エチル]ベンズアミド;および
1-{4-[3-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,2,4-オキサジアゾール-5-イル]-2-フルオロフェニル}-3-(2-ヒドロキシエチル)ウレア
からなる群より選択される化合物またはその薬学的に許容され得る塩;
(10)前記(1)〜(9)いずれか1項に記載の化合物またはその薬学的に許容され得る塩を有効成分として含有する医薬組成物;
(11)1型糖尿病、2型糖尿病または肥満を治療するための、前記(10)に記載の医薬組成物;
(12)β細胞または膵臓を保護するための、前記(10)に記載の医薬組成物;
(13)医薬組成物を製造するための、前記(1)〜(9)いずれか1項に記載の化合物またはその薬学的に許容され得る塩の使用;
(14)前記(1)〜(9)いずれか1項に記載の化合物またはその薬学的に許容され得る塩を哺乳動物に投与することを含む、疾病を治療する方法;ならびに
(15)哺乳動物がヒトである前記(14)に記載の方法;
を提供する。
1H-NMR (400MHz, CDCl3) δppm:
8.27 (1H, s), 8.13-7.98 (3H, m), 4.49 (2H, q, J = 7 Hz), 3.97 (3H, s), 1.45 (3H, t, J = 7 Hz).
1H-NMR (400MHz, DMSO-d6) δppm:
13.80 (1H, m), 8.63 (1H, s), 8.16-7.92 (3H, m), 3.90 (3H, s).
1H-NMR (400MHz, CDCl3) δppm:
8.25 (1H, s), 8.13-7.95 (3H, m), 3.97 (3H, s), 3.85 (3H, s), 3.46 (3H, br s).
1H-NMR (400MHz, CDCl3) δppm:
8.27 (1H, s), 8.14-8.10 (1H, m), 8.02-7.95 (2H, m), 3.98 (3H, s), 3.16-3.11 (2H, m), 1.29-1.25 (3H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.09-8.05 (1H, m), 7.93-7.85 (2H, m), 7.81 (1H, s), 4.94-4.89 (1H, m), 3.96 (3H, s), 2.20-2.19 (1H, m), 2.01-1.88 (2H, m), 1.05-1.02 (3H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.10-8.06 (1H, m), 7.98-7.86 (4H, m), 7.76 (1H, s), 7.01-6.99 (2H, m), 5.52-5.49 (1H, m), 3.96 (3H, s), 2.62-2.56 (1H, m), 2.21-2.07 (2H, m), 1.20-1.17 (2H, m), 1.10-1.06 (3H, m), 1.00-0.97 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.19-8.15 (1H, m), 7.99-7.89 (4H, m), 7.78 (1H, s), 7.03-6.99 (2H, m), 5.53-5.50 (1H, m), 2.63-2.56 (1H, m), 2.22-2.06 (2H, m), 1.21-1.17 (2H, m), 1.11-1.07 (3H, m), 1.01-0.96 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.26 (1H, s), 8.15-8.11 (1H, m), 8.03-7.95 (2H, m), 3.98 (3H, s), 2.71 (3H, s).
1H-NMR (400MHz, CDCl3) δppm:
8.10-8.05 (1H, m), 7.93-7.86 (2H, m), 7.83 (1H, s), 5.19-5.12 (1H, m), 3.96 (3H, s), 1.65 (3H, d, J = 7 Hz).
1H-NMR (400MHz, CDCl3) δppm:
8.10-8.06 (1H, m), 7.99-7.97 (2H, m), 7.93-7.86 (2H, m), 7.80 (1H, s), 7.04-7.00 (2H, m), 5.77-5.73 (1H, m), 3.96 (3H, s), 2.63-2.57 (1H, m), 1.80 (3H, d, J = 7 Hz), 1.21-1.18 (2H, m), 1.01-0.96 (2H, m).
1H-NMR (400MHz, DMSO-d6) δppm:
8.32 (1H, s), 8.12-8.01 (3H, m), 7.94-7.85 (2H, m), 7.18-7.16 (2H, m), 6.02-5.97 (1H, m), 2.87-2.80 (1H, m), 1.75 (3H, d, J = 6 Hz), 0.98-0.96 (4H, m).
1H-NMR (400MHz, DMSO-d6) δppm:
13.54 (1H, br s), 8.67 (1H, s), 8.15-8.11 (1H, m), 8.04-7.97 (2H, m), 3.16-3.10 (2H, m), 1.15-1.12 (3H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.26 (1H, s), 8.06-8.02 (1H, m), 7.98-7.90 (2H, m), 3.14 (2H, q, J = 7 Hz), 1.62 (9H, s), 1.27 (3H, t, J = 7 Hz).
1H-NMR (400MHz, CDCl3) δppm:
8.00-7.96 (1H, m), 7.89-7.81 (3H, m), 7.80 (3H, s), 4.93-4.89 (1H, m), 2.21-2.20 (1H, m), 2.01-1.88 (2H, m), 1.61 (9H, s), 1.06-1.02 (3H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.00-7.96 (1H, m), 7.89-7.81 (3H, m), 7.80 (3H, s), 4.93-4.89 (1H, m), 2.17-2.16 (1H, m), 2.00-1.90 (2H, m), 1.62 (9H, s), 1.06-1.02 (3H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.02-7.94 (3H, m), 7.89-7.81 (2H, m), 7.75 (1H, s), 7.03-6.99 (2H, m), 5.52-5.49 (1H, m), 2.62-2.56 (1H, m), 2.21-2.07 (2H, m), 1.62 (9H, s), 1.20-1.17 (2H, m), 1.10-1.07 (3H, m), 1.00-0.96 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.19-8.15 (1H, m), 7.99-7.89 (4H, m), 7.78 (1H, s), 7.03-6.99 (2H, m), 5.53-5.50 (1H, m), 2.63-2.56 (1H, m), 2.22-2.06 (2H, m), 1.21-1.17 (2H, m), 1.11-1.07 (3H, m), 1.01-0.96 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.26 (1H, s), 8.15-8.11 (1H, m), 8.03-7.95 (2H, m), 3.98 (3H, s).
1H-NMR (400MHz, CDCl3) δppm:
8.26 (1H, s), 8.06-7.91 (3H, m), 2.71 (3H, s), 1.63 (9H, s).
1H-NMR (400MHz, CDCl3) δppm:
8.01-7.97 (1H, m), 7.89-7.81 (3H, m), 5.18-5.12 (1H, m), 1.65 (3H, d, J = 6 Hz), 1.62 (9H, s).
1H-NMR (400MHz, CDCl3) δppm:
1H-NMR (CDCl3) δ: 8.01-7.97 (1H, m), 7.89-7.81 (3H, m), 5.18-5.12 (1H, m), 1.65 (4H, d, J = 6.4 Hz), 1.62 (9H, s).
1H-NMR (400MHz, CDCl3) δppm:
8.46 (1H, dd, J = 3, 1 Hz), 7.65 (1H, dd, J = 9, 1 Hz), 7.45 (1H, dd, J = 9, 3 Hz), 5.28 (2H, s), 3.50 (3H, s).
1H-NMR (400MHz, CDCl3) δppm:
8.32 (1H, dd, J = 3, 1 Hz), 8.00 (1H, d, J = 9, 1 Hz), 7.27 (1H, dd, J = 9, 3 Hz), 3.43-3.35 (1H, m), 1.26-1.21 (2H, m), 1.12-1.06 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.42 (1H, d, J = 3 Hz), 8.02-7.98 (2H, m), 7.89-7.81 (3H, m), 7.37-7.34 (1H, m), 5.81-5.76 (1H, m), 3.45-3.38 (1H, m), 1.84 (3H, d, J= 7 Hz), 1.62 (9H, s), 1.22-1.18 (2H, m), 1.08-1.03 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.45 (1H, d, J = 3 Hz), 8.18-8.14 (1H, m), 8.01 (1H, d, J= 9 Hz), 7.97-7.89 (2H, m), 7.85 (1H, s), 7.38-7.35 (1H, m), 5.83-5.78 (1H, m), 3.43-3.37 (1H, m), 1.85 (3H, d, J= 6 Hz), 1.22-1.19 (2H, m), 1.09-1.04 (2H, m).
上記の混合物(0.610g)のジクロロメタン(12mL)溶液に、室温にてトリフルオロ酢酸(6mL)を加えた。室温にて2時間攪拌後、反応液中の溶媒を減圧下、留去した。得られた残渣に飽和炭酸水素ナトリウム水溶液および水を加え、ジクロロメタンで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥した。ろ別後、減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(25% 酢酸エチル/ヘキサン)で精製することにより、標記化合物(242mg、収率:52%)を得た。
1H-NMR (400MHz, CDCl3) δppm:
7.97-7.93 (2H, m), 7.72-7.69 (1H, m), 7.64-7.61 (2H, m), 7.03-6.99 (2H, m), 6.86-6.82 (1H, m), 5.49-5.45 (1H, m), 3.85 (2H, br s), 2.62-2.56 (1H, m), 2.20-2.04 (2H, m), 1.20-1.16 (2H, m), 1.09-1.05 (3H, m), 1.00-0.95 (2H, m).
上記の混合物(0.282g)のジクロロメタン(6mL)溶液に、室温にてトリフルオロ酢酸(3mL)を加えた。室温にて1時間攪拌後、反応液中の溶媒を減圧下、留去した。得られた残渣に飽和炭酸水素ナトリウム水溶液および水を加え、ジクロロメタンで抽出した。得られた有機層を無水硫酸ナトリウムで乾燥した。ろ別後、減圧下溶媒を留去し、得られた残渣をシリカゲルカラムクロマトグラフィー(30% 酢酸エチル/ヘキサン)で精製することにより、標記化合物(190mg、収率:99%)を得た。
1H-NMR (400MHz, CDCl3) δppm:
8.42 (1H, d, J = 3 Hz), 8.00-7.98 (1H, m), 7.72-7.68 (2H, m), 7.64-7.61 (1H, m), 7.39-7.36 (1H, m), 6.87-6.83 (1H, m), 5.78-5.73 (1H, m), 3.44-3.37 (1H, m), 1.82 (3H, d, J = 6 Hz), 1.21-1.18 (2H, m), 1.08-1.03 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.22-8.18 (1H, m), 8.13-8.06 (2H, m), 4.62-4.57 (2H, m), 3.99 (3H, s), 1.52-1.49 (3H, m).
1H-NMR (400MHz, DMSO-d6) δppm:
8.23-8.10 (3H, m), 3.92 (3H, s).
1H-NMR (400MHz, CDCl3) δppm:
8.21-8.18 (1H, m), 8.11-8.02 (2H, m), 3.99 (3H, s), 3.93 (3H, s), 3.46 (3H, br s).
1H-NMR (400MHz, CDCl3) δppm:
8.22-8.18 (1H, m), 8.13-8.06 (2H, m), 4.00 (3H, s), 3.30-3.25 (2H, m), 1.34-1.31 (3H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.18-8.14 (1H, m), 8.05-7.97 (2H, m), 5.11-5.06 (1H, m), 3.99 (3H, s), 2.65-2.63 (1H, m), 2.18-1.99 (2H, m), 1.08-1.05 (3H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.17-8.13 (1H, m), 8.03-7.95 (4H, m), 7.08-7.05 (2H, m), 5.67-5.64 (1H, m), 3.98 (3H, s), 2.62-2.56 (1H, m), 2.38-2.21 (2H, m), 1.20-1.16 (2H, m), 1.13-1.09 (3H, m), 1.00-0.97 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.25-8.21 (1H, m), 8.06-7.96 (4H, m), 7.08-7.06 (2H, m), 5.68-5.65 (1H, m), 2.62-2.56 (1H, m), 2.39-2.22 (2H, m), 1.21-1.17 (2H, m), 1.13-1.10 (3H, m), 1.00-0.97 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.23-8.06 (3H, m), 4.00 (3H, s), 2.86 (3H, s).
1H-NMR (400MHz, CDCl3) δppm:
8.19-8.15 (1H, m), 8.05-7.97 (2H, m), 5.34-5.28 (1H, m), 3.99 (3H, s), 1.76 (3H, d, J = 7 Hz).
1H-NMR (400MHz, CDCl3) δppm:
8.47-8.46 (1H, m), 8.18-8.14 (1H, m), 8.03-7.95 (3H, m), 7.45-7.42 (1H, m), 5.96-5.91 (1H, m), 3.98 (3H, s), 3.45-3.38 (1H, m), 1.97 (3H, d, J = 7 Hz), 1.21-1.18 (2H, m), 1.08-1.03 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.49 (1H, d, J = 3 Hz), 8.24-8.20 (1H, m), 8.06-7.98 (3H, m), 7.45 (1H, dd, J = 9, 3 Hz), 5.97-5.92 (1H, m), 3.42-3.36 (1H, m), 1.98 (3H, d, J = 7 Hz), 1.23-1.19 (2H, m), 1.09-1.04 (2H, m).
1H-NMR (500MHz, DMSO-d6) δppm:
10.21 (1H, s), 9.75 (1H, s), 7.94-7.90 (1H, m), 7.79-7.72 (2H, m), 3.88-3.87 (3H, m).
1H-NMR (500MHz, DMSO-d6) δppm:
10.12 (1H, m), 8.86-8.85 (1H, m), 8.05-8.02 (3H, m), 3.90-3.89 (3H, m).
1H-NMR (500MHz, CDCl3) δppm:
8.01-7.98 (1H, m), 7.73-7.71 (3H, m), 5.25-5.20 (1H, m), 3.96-3.95 (3H, m), 2.34-2.32 (1H, m), 1.67-1.65 (3H, m).
1H-NMR (500MHz, CDCl3) δppm:
8.01-7.96 (3H, m), 7.82 (1H, m), 7.72-7.71 (1H, m), 7.70-7.69 (1H, m), 7.02-6.98 (2H, m), 5.81-5.77 (1H, m), 3.95 (3H, s), 2.63-2.57 (1H, m), 1.83 (3H, d, J = 6 Hz), 1.21-1.18 (2H, m), 1.02-0.97 (2H, m).
1H-NMR (400MHz, DMSO-d6) δppm:
13.44 (1H, br s), 8.10 (1H, s), 8.02-7.93 (3H, m), 7.83-7.79 (2H, m), 7.19-7.15 (2H, m), 6.20-6.15 (1H, m), 2.86-2.80 (1H, m), 1.75-1.74 (3H, m), 0.98-0.96 (4H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.40 (1H, d, J = 3 Hz), 8.03-7.97 (2H, m), 7.84 (1H, s), 7.73-7.69 (2H, m), 7.32 (1H, dd, J = 9, 3 Hz), 5.82 (1H, q, J = 6 Hz), 3.95 (3H, s), 3.45-3.37 (1H, m), 1.86 (4H, d, J = 6 Hz), 1.22-1.17 (2H, m), 1.09-1.03 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
10.03 (1H, s), 7.94 (2H, d, J = 9 Hz), 7.31 (2H, d, J = 9 Hz), 7.26 (1H, s), 2.54 (3H, s).
1H-NMR (500MHz, CDCl3) δppm:
7.83 (2H, d, J = 9 Hz), 7.64 (1H, s), 7.28 (2H, d, J = 9 Hz), 4.90 (1H, dd, J = 7, 6 Hz), 2.52 (3H, s), 2.18 (1H, br s), 1.97-1.84 (2H, m), 1.00 (3H, t, J = 7 Hz).
1H-NMR (500MHz, CDCl3) δppm:
7.73 (1H, dd, J = 9, 1 Hz), 7.66 (1H, dd, J = 8, 1 Hz), 7.61 (1H, dd, J = 8, 6 Hz), 4.95 (1H, dd, J = 11, 8 Hz), 4.72 (1H, dd, J = 9, 8 Hz), 4.62 (1H, dd, J = 11, 9 Hz), 3.83 (3H, s).
1H-NMR (400MHz, CDCl3) δppm:
8.31 (1H, s), 7.87 (1H, dd, J = 9, 2 Hz), 7.80 (1H, td, J = 8, 2 Hz), 7.68 (1H, dd, J = 8, 7 Hz), 3.97 (3H, s).
1H-NMR (500MHz, CDCl3) δppm:
7.78 (1H, dd, J = 9, 2 Hz), 7.71 (1H, dd, J = 8, 2 Hz), 7.68 (1H, s), 7.65 (1H, dd, J = 8, 7 Hz), 4.69 (2H, d, J = 6 Hz), 2.06 (1H, br s).
1H-NMR (500MHz, CDCl3) δppm:
7.78 (1H, dd, J = 9, 2 Hz), 7.71 (1H, dd, J = 8, 2 Hz), 7.64 (1H, dd, J = 8, 7 Hz), 7.61 (1H, s), 4.95-4.88 (1H, m), 2.27 (1H, br s), 1.58 (3H, d, J = 6 Hz).
1H-NMR (500MHz, CDCl3) δppm:
8.03 (1H, dd, J = 8, 7 Hz), 7.87 (1H, dd, J = 8, 1 Hz), 7.81 (1H, dd, J = 11, 1 Hz), 7.65 (1H, s), 4.97-4.90 (1H, m), 3.96 (3H, s), 2.27 (1H, d, J = 5 Hz), 1.59 (3H, d, J= 8 Hz).
1H-NMR (400MHz, CDCl3)δppm:
8.18-8.05 (1H, m), 8.00 (2H, d, J = 9 Hz), 7.95-7.80 (2H, m), 7.66 (1H, s), 7.02 (2H, d, J = 9 Hz), 5.55 (1H, q, J = 6 Hz), 2.66-2.57 (1H, m), 1.76 (3H, d, J= 7 Hz), 1.23-1.18 (2H, m), 1.03-0.98 (2H, m).
1H-NMR (500MHz, CDCl3) δppm:
8.45 (1H, d, J = 3 Hz), 8.12 (1H, dd, J = 8, 7 Hz), 8.02 (1H, d, J = 9 Hz), 7.90 (1H, dd, J = 8, 2 Hz), 7.84 (1H, dd, J = 11, 2 Hz), 7.71 (1H, d, J = 1 Hz), 7.37 (1H, dd, J = 9, 3 Hz), 5.58 (1H, q, J = 7 Hz), 3.45-3.37 (1H, m), 1.81 (3H, d, J = 7 Hz), 1.24-1.19 (2H, m), 1.10-1.04 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
7.98 (2H, d, J = 9 Hz), 7.67-7.61 (2H, m), 7.51 (1H, s), 7.02 (2H, d, J = 7 Hz), 6.81 (1H, dd, J = 9, 8 Hz), 5.52 (1H, q, J = 6 Hz), 3.27 (2H, bs), 2.64-2.56 (1H, m), 1.74 (3H, d, J= 6 Hz), 1.22-1.18 (2H, m), 1.02-0.96 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
8.49-8.48 (1H, m), 8.02 (1H, d, J = 9 Hz), 7.65-7.60 (2H, m), 7.57 (1H, s), 7.43-7.39 (1H, m), 6.81 (1H, dd, J = 9, 9 Hz), 5.57 (1H, q, J = 6 Hz), 3.45-3.38 (1H, m), 1.78 (3H, d, J = 6 Hz), 1.25-1.20 (2H, m), 1.10-1.06 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
7.97 (1H, t, J = 8 Hz), 7.90 (1H, d, J = 8 Hz), 7.84 (1H, d, J = 5 Hz), 5.18 (1H, q, J = 7 Hz), 1.73 (4H, d, J = 7 Hz), 1.60 (9H, s);
MS (FAB) m/z: 309 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.48 (1H, d, J = 3 Hz), 8.13 (1H, dd, J = 8, 7 Hz), 8.04 (1H, d, J = 9 Hz), 7.95 (1H, dd, J = 8, 2 Hz), 7.90 (1H, dd, J = 11, 2 Hz), 7.40 (1H, dd, J = 9, 3 Hz), 5.80 (1H, q, J = 7 Hz), 3.44-3.37 (1H,m), 1.97 (3H, d, J = 7 Hz), 1.24-1.19 (2H, m), 1.11-1.05 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.31 (1H, d, J = 3 Hz), 8.00 (1H, d, J = 9 Hz), 7.31 (1H, dd, J = 9, 3 Hz), 4.05-3.98 (1H, m), 1.20 (6H, d, J = 7 Hz).
1H-NMR (400MHz, CDCl3) δppm:
8.35 (1H, d, J = 3 Hz), 8.05 (1H, d, J = 9 Hz), 7.26 (1H, d, J = 9, 3 Hz), 4.74 (1H, dd, J = 7, 5 Hz), 4.04-3.95 (1H, m), 2.17-2.03 (2H, m), 1.19 (6H, d, J = 7 Hz), 1.14 (3H, t, J = 7 Hz).
1H-NMR (500MHz, CDCl3) δppm:
8.42 (1H, d, J = 3 Hz), 8.05 (1H, dd, J = 8, 7 Hz), 8.03 (1H, d, J= 9 Hz), 7.92 (1H, dd, J = 8, 2 Hz), 7.86 (1H, dd, J = 11, 2 Hz), 7.36 (1H, dd, J = 9, 3 Hz), 5.54 (1H, dd, J = 7, 6 Hz), 4.07-4.00 (1H, m), 3.97 (3H, s), 2.38-2.24 (2H, m), 1.18 (6H, d, J = 7 Hz), 1.16 (3H, t, J = 7 Hz).
1H-NMR (500MHz, CDCl3) δppm:
8.45 (1H, d, J = 3 Hz), 8.14 (1H, dd, J = 8, 7 Hz), 8.05 (1H, d, J = 9 Hz), 7.96 (1H, dd, J = 8, 1 Hz), 7.90 (1H, dd, J = 11, 1 Hz), 7.38 (1H, dd, J = 9, 3 Hz), 5.56 (1H, dd, J = 7, 6 Hz), 4.08-3.98 (1H, m), 2.41-2.23 (2H, m), 1.18 (6H, d, J = 7 Hz), 1.17 (3H, t, J = 7 Hz).
1H-NMR (500MHz, CDCl3) δppm:
8.41 (1H, d, J = 3 Hz), 8.03 (1H, d, J = 9 Hz), 7.44 (1H, dd, J = 9, 3 Hz), 5.27 (2H, s), 3.50 (3H, s), 3.05 (2H, d, J = 7 Hz), 2.36-2.26 (1H, m), 0.99 (6H, d, J = 6 Hz).
1H-NMR (500MHz, CDCl3) δppm:
8.42 (1H, d, J = 3 Hz), 7.56 (1H, d, J = 9 Hz), 7.43 (1H, dd, J = 9, 3 Hz), 5.23 (2H, s), 3.50 (3H, s), 2.22 (2H, td, J = 18, 7 Hz), 1.93-1.84 (1H, m), 0.95 (6H, d, J= 7 Hz).
(500MHz, CDCl3) δppm:
8.27 (1H, d, J = 2 Hz), 7.54 (1H, d, J = 9 Hz), 7.25 (1H, dd, J = 9, 2 Hz), 2.20 (2H, td, J = 18, 7 Hz), 1.92-1.83 (1H, m), 0.94 (6H, d, J = 7 Hz).
1H-NMR (400MHz, CDCl3)δppm:
5.00 (1H, m), 2.15 (3H, s), 1.94-1.90 (2H, m), 1.03 (3H, t, J = 7 Hz);
MS (FAB) m/z: 147 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
7.96 (1H, t, J = 8 Hz), 7.90 (1H, dd, J = 8, 2 Hz), 7.84 (1H, dd, J = 11, 2 Hz), 5.92 (1H, t, J = 7 Hz), 2.21 (3H, s), 2.16-2.08 (2H, m), 1.62 (9H, s), 1.05 (3H, t, J = 7 Hz);
MS (FAB) m/z: 365 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
7.97 (1H, t, J = 8 Hz), 7.91 (1H, d, J = 8 Hz), 7.85 (1H, d, J = 11 Hz), 4.98 (1H, q, J = 6 Hz), 2.54 (1H, brs), 2.14-1.96 (2H, m), 1.62 (9H, s), 1.08 (3H, t, J = 7 Hz);
MS (FAB+) m/z: 323 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.46 (1H, d, J = 3 Hz), 8.12 (1H, dd, J = 8, 7 Hz), 7.96 (1H, d, J = 8 Hz), 7.90 (1H, d, J = 11 Hz), 7.58 (1H, d, J = 9 Hz), 7.37 (1H, dd, J = 9, 3 Hz), 5.49 (1H, dd, J = 7, 6 Hz), 2.38-2.13 (4H, m), 1.91-1.82 (1H, m), 1.16 (3H, t, J = 7 Hz), 0.94 (6H, d, J = 7 Hz).
1H-NMR (500MHz, DMSO-d6)δppm:
9.35 (1H, s), 7.27 (1H, dd, J = 13, 2 Hz), 7.21 (1H, dd, J = 8, 2 Hz), 6.71 (1H, dd, J = 9, 8 Hz), 5.63 (2H, s), 5.33 (2H, s).
1H-NMR (500MHz, CDCl3) δppm:
7.74-7.66 (2H, m), 6.82 (1H, dd, J = 9, 8 Hz), 5.90 (1H, dd, J = 7, 6 Hz), 4.03 (1H, s), 2.19 (3H, d, J= 4 Hz), 2.16-2.04 (2H, m), 1.03 (2H, t, J= 8 Hz).
1H-NMR (500MHz, CDCl3) δppm:
7.74-7.66 (2H, m), 6.83 (1H, dd, J = 9, 8 Hz), 4.92 (1H, dd, J = 7, 6 Hz), 4.04 (2H, br s), 2.64 (1H, br s), 2.11-1.93 (2H, m), 1.06 (3H, t, J = 8 Hz).
1H-NMR (500MHz, CDCl3) δppm:
7.98 (2H, d, J = 9 Hz), 7.72-7.65 (2H, m), 7.03 (2H, d, J = 9 Hz), 6.81 (1H, dd, J = 9, 8 Hz), 5.47 (1H, dd, J = 7, 6 Hz), 4.04 (2H, s), 2.62-2.56 (1H, m), 2.33-2.16 (2H, m), 1.22-1.17 (2H, m), 1.12 (3H, t, J = 7 Hz), 1.01-0.96 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.38 (1H, d, J = 3 Hz), 8.03 (1H, d, J = 9 Hz), 7.26 (1H, dd, J = 9, 2 Hz), 4.93 (1H, q, J = 7 Hz), 3.41-3.35 (1H, m), 1.74 (3H, d, J = 7 Hz), 1.25-1.20 (2H, m), 1.10-1.05 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.46 (1H, d, J = 3 Hz), 8.02 (1H, d, J = 9 Hz), 7.69 (1H, dd, J = 12, 2 Hz), 7.67 (1H, dd, J = 8, 2), 7.38 (1H, dd, J = 9, 3 Hz), 6.82 (1H, dd, J = 9, 8 Hz), 5.73 (1H, q, J = 7 Hz), 4.06 (2H, s), 3.46-3.93 (1H, m), 1.93 (3H, d, J = 7 Hz), 1.23-1.19 (2H, m), 1.10-1.04 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
8.03 (2H, d, J= 9 Hz), 7.76-7.68 (2H, m), 7.10 (2H, d, J= 9 Hz), 6.85 (1H, dd, J = 9, 8 Hz), 5.49 (1H, t, J = 7 Hz), 4.08 (2H, bs), 3.34-3.24 (m, 1H), 2.38-2.20 (2H, m), 1.47 (6H, d, J = 7 Hz), 1.13 (3H, t, J = 8 Hz).
1H-NMR (400MHz, CDCl3)δppm:
8.00 (2H, d, J= 9 Hz), 7.73-7.65 (2H, m), 7.06 (2H, d, J= 9 Hz), 6.81 (1H, dd, J = 9, 8 Hz), 5.46 (1H, t, J = 7 Hz), 3.30-3.19 (m, 1H), 2.32-2.17 (2H, m), 1.43 (6H, d, J= 7 Hz), 1.13 (3H, t, J = 8 Hz).
1H-NMR (400MHz, CDCl3) δppm:
10.0 (1H, d, J = 2 Hz), 8.01 (1H, dd, J = 8, 7 Hz), 7.69 (1H, d, J = 8, 2 Hz), 7.61 (1H, dd, J = 10, 2 Hz), 1.61 (9H, s).
1H-NMR (400MHz, CDCl3) δppm:
7.97-7.89 (2H, m), 7.83 (1H, dd, J = 11, 1 Hz), 1.62 (9H, s).
1H-NMR (400MHz, CDCl3)δppm:
8.01-7.99 (2H, m), 6.95-6.93 (2H, m), 4.88 (2H, q, J = 7 Hz), 2.65-2.59 (1H, m), 1.70 (3H, d, J = 7 Hz), 1.24-1.20 (2H, m), 1.03-1.01 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
8.06 (2H, d, J= 9 Hz), 7.06 (2H, d, J = 9 Hz), 4.99 (1H, q, J = 7 Hz), 2.67-2.58 (1H, m), 1.84 (3H, d, J= 7 Hz), 1.39-1.32 (2H, m), 1.06-1.01 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
8.00 (2H, d, J= 9 Hz), 7.06 (2H, d, J = 9 Hz), 4.87 (1H, q, J =7 Hz), 4.68 (2H, bs), 2.64-2.57 (2H, m), 1.64 (3H, d, J = 7 Hz), 1.25-1.18 (2H, m), 1.04-0.98 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
8.20-8.14 (1H, m), 8.03-7.92 (4H, m), 7.08 (2H, d, J = 9 Hz), 5.72 (1H, q, J = 7 Hz), 2.63-2.56 (1H, m), 1.87 (3H, d, J = 6 Hz), 1.21-1.17 (2H, m), 1.01-0.96 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
7.98 (2H, d, J = 9 Hz), 7.76-7.72 (2H, m), 7.08 (2H, d, J = 9 Hz), 6.82 (1H, t, J = 9 Hz), 5.66 (1H, q, J = 7 Hz), 2.64-2.57 (1H, m), 1.84 (3H, d, J = 6 Hz), 1.21-1.17 (2H, m), 1.02-0.95 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
8.02 (2H, d, J= 9 Hz), 6.99 (2H, d, J = 9 Hz), 6.28 (1H, bs), 5.74 (1H, bs), 4.62 (1H, dd, J = 6, 5 Hz), 2.66-2.52 (1H, m), 2.10-1.95 (2H, m), 1.25-1.20 (2H, m), 1.10-1.00 (5H, m).
1H-NMR (400MHz, CDCl3)δppm:
8.05 (2H, d, J = 9 Hz), 7.07 (2H, d, J = 9 Hz), 4.83 (1H, t, J = 6 Hz), 2.67-2.60 (1H, m), 2.19-2.12 (2H, m), 1.28-1.17 (5H, m), 1.06-0.97 (2H, m).
1H-NMR (500MHz, CDCl3)δppm:
7.98 (2H, d, J= 9 Hz), 7.07 (2H, d, J = 9 Hz), 4.70 (2H, s), 4.62-4.55 (1H, m), 3.72 (1H, dq, J = 7, 6 Hz), 2.64-2.53 (1H, m), 2.08-1.82 (2H, m), 1.23-1.17 (2H, m), 1.09-0.92 (5H, m).
1H-NMR (400MHz, CDCl3)δppm:
8.02-7.92 (4H, m), 7.88 (1H, d, J= 9 Hz), 7.08 (2H, d, J = 9 Hz), 5.46 (1H, t, J = 7 Hz), 2.65-2.56 (1H, m), 2.36-2.12 (2H, m), 1.61 (9H, s), 1.23-1.17 (2H, m), 1.11 (3H, t, J = 7 Hz), 1.02-0.96 (2H, m).
1H-NMR (500MHz, CDCl3)δppm:
8.17 (1H, dd, J= 8, 7 Hz), 8.03-7.92 (4H, m), 7.08 (2H, d, J = 9 Hz), 5.47 (1H, t, J= 7 Hz), 2.63-2.56 (1H, m), 2.34-2.10 (2H, m), 1.22-1.15 (2H, m), 1.11 (3H, t, J = 8 Hz), 1.02-0.95 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
7.995 (2H, d, J = 9 Hz), 7.80-7.73 (2H, m), 7.08 (2H, d, J = 9 Hz), 6.82 (1H, t, J = 9 Hz), 5.39 (1H, t, J = 7 Hz), 4.24 (2H, s), 2.64-2.56 (1H, m), 2.34-2.10 (2H, m), 1.24-1.20 (2H, m), 1.09 (1H, t, J = 7 Hz), 1.04-0.96 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.48 (1H, d, J = 3 Hz), 8.17 (1H, dd, J = 8, 7 Hz), 8.02 (1H, d, J = 9 Hz), 8.01 (1H, dd, J = 8, 2 Hz), 7.95 (1H, dd, J = 10, 2 Hz), 7.43 (1H, dd, J = 9, 3 Hz), 5.75 (1H, q, J = 6.5 Hz), 3.45-3.38 (1H,m), 1.91 (3H, d, J = 7 Hz), 1.22-1.17 (2H,m), 1.09-1.03 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
8.47 (1H, d, J = 3 Hz), 8.34 (1H, t, J = 8 Hz), 8.00 (1H, d, J = 9 Hz), 7.90 (1H, dd, J = 8, 2 Hz), 7.83 (1H, dd, J = 11, 2 Hz), 7.42 (1H, dd, J = 9, 3 Hz), 6.98-6.94 (1H, m), 5.70 (1H, q, J = 7 Hz), 3.45-3.39 (1H, m), 1.89 (3H, d, J = 7 Hz), 1.54 (9H, s), 1.22-1.17 (2H, m), 1.09-1.03 (2H, m).
H-NMR (400MHz, CDCl3) δppm:
8.47 (1H, d, J = 3 Hz), 8.00 (1H, d, J = 9 Hz), 7.77-7.71 (2H, m), 7.42 (1H, dd, J = 9, 3 Hz), 6.82 (1H, t, J = 9 Hz), 5.67 (1H, q, J = 7 Hz), 4.25 (2H, s), 3.46-3.39 (1H, m), 1.87 (3H, d, J= 7 Hz), 1.22-1.17 (2H, m), 1.08-1.03 (2H, m).
1H-NMR (400MHz, CDCl3) δppm:
6.95-6.84 (4H, m), 6.49-6.35 (1H, m), 5.53-5.36 (1H, m), 4.45 (1H, dd, J = 7, 4 Hz), 3.80 (3H, s), 2.06-1.90 (2H, m), 1.08 (3H, t, J= 7 Hz).
1H-NMR (500MHz, CDCl3)δppm:
7.01 (2H, d, J= 9 Hz), 6.90 (2H, d, J = 9 Hz), 4.65 (1H, t, J = 7 Hz), 3.82 (3H, s), 2.10 (2H, dq, J = 7, 7 Hz), 1.22 (3H, t, J = 7 Hz).
1H-NMR (400MHz, CDCl3)δppm:
6.95 (2H, d, J= 9 Hz), 6.83 (2H, d, J = 9 Hz), 4.70 (2H, bs), 4.38 (1H, dd, J= 7, 6 Hz), 3.77 (3H, s), 2.02-1.80 (2H, m), 1.06 (3H, t, J = 7 Hz).
1H-NMR (400MHz, CDCl3)δppm:
8.03-7.89 (3H, m), 6.97 (2H, d, J = 9 Hz), 6.81 (2H, d, J = 9 Hz), 5.25 (1H, dd, J = 7, 6 Hz), 3.76 (3H, s), 2.30-2.07 (2H, m), 1.63 (9H, s), 1.10 (3H, t, J= 7 Hz).
1H-NMR (400MHz, CDCl3)δppm:
8.02 (1H, dd, J= 8, 7 Hz), 7.95 (1H, dd, J = 8, 2 Hz), 7.89 (1H, dd, J = 11, 1 Hz), 4.92-4.86 (1H, m), 2.40-2.32 (1H, m), 2.08-1.95 (2H, m), 1.62 (9H, s), 1.05 (3H, t, J = 7 Hz).
1H-NMR (400MHz, CDCl3)δppm:
8.20-8.13 (1H, m), 8.04-7.92 (4H, m), 7.08 (2H, d, J = 8 Hz), 5.50-5.44 (1H, m), 2.85-2.55 (1H, m), 2.38-2.10 (2H, m), 1.22-1.16 (2H, m), 1.11 (3H, t, J = 7 Hz), 1.04-0.96 (2H, m).
1H-NMR (400MHz, CDCl3)δppm:
8.02 (2H, d, J =9 Hz), 6.96 (2H, d, J =9 Hz), 5.39 (1H, br s).
1H-NMR (400MHz, CDCl3)δppm:
8.02 (2H, m), 7.02 (2H, d, J = 9 Hz).
1H-NMR (400MHz, CDCl3) δppm:
7.37-7.29 (4H, m), 7.28-7.21 (1H, m), 4.05-3.98 (2H, m), 3.93-3.85 (2H, m), 3.74 (1H, d, J = 13 Hz), 2.89-2.80 (1H, m), 1.71-1.29 (10H, m), 1.10 (3H, d, J = 6 Hz).
1H-NMR (400MHz, CDCl3) δppm:
3.99 (1H, dd, J = 7, 6 Hz), 3.93 (1H, td, J = 6, 5 Hz), 3.80 (1H, dd, J = 7, 6 Hz), 3.07 (1H, qd, J = 7, 5 Hz), 1.67-1.30 (10H, m), 1.07 (3H, dd, J = 7 Hz).
1H-NMR (400MHz, CDCl3) δppm:
8.42 (1H, d, J = 2.7 Hz), 8.24-8.20 (1H, m), 8.01-7.97 (2H, m), 7.89-7.85 (1H, m), 7.83 (1H, s), 7.37-7.34 (1H, m), 6.88-6.83 (1H, m), 5.81-5.76 (1H, m), 4.26-4.21 (1H, m), 3.73-3.65 (2H, m), 3.51-3.47 (1H, m), 3.44-3.38 (1H, m), 3.23-3.19 (1H, m), 2.83-2.81 (1H, m), 1.84 (3H, d, J= 6.3 Hz), 1.42 (3H, d, J = 7.0 Hz), 1.22-1.18 (2H, m), 1.08-1.03 (2H, m);
MS (ES) m/z: 484 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.23-8.19 (1H, m), 7.95 (2H, d, J= 8.6 Hz), 7.80-7.75 (2H, m), 7.67 (1H, s), 7.09 (1H, br s), 7.01 (2H, d, J = 9.0 Hz), 5.52-5.46 (2H, m), 3.81-3.78 (2H, m), 3.48-3.44 (2H, m), 2.63-2.56 (2H, m), 2.22-2.02 (2H, m), 1.19-1.16 (2H, m), 1.09-1.05 (3H, m), 0.99-0.97 (2H, m);
MS (ES) m/z: 468 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.42 (1H, d, J = 2.7 Hz), 8.25-8.21 (1H, m), 7.99 (1H, d, J= 8.6 Hz), 7.82-7.76 (2H, m), 7.74 (1H, s), 7.38-7.35 (1H, m), 6.89 (1H, br s), 5.79-5.74 (1H, m), 5.28-5.24 (1H, m), 3.82-3.80 (2H, m), 3.50-3.46 (2H, m), 3.44-3.38 (1H, m), 2.35 (1H, m), 1.83 (3H, d, J = 6.7 Hz), 1.21-1.18 (2H, m), 1.08-1.03 (2H, m);
MS (ES) m/z: 455 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.32-8.28 (1H, m), 8.08-8.05 (1H, m), 7.99-7.93 (3H, m), 7.09-7.05 (2H, m), 6.92-6.87 (1H, m), 5.67-5.64 (1H, m), 4.35 (1H, m), 3.85-3.80 (1H, m), 3.72-3.66 (1H, m), 2.62-2.56 (1H, m), 2.39-2.19 (3H, m), 1.33 (3H, d, J = 6.6 Hz), 1.20-1.16 (2H, m), 1.13-1.09 (3H, m), 1.01-0.96 (2H, m);
MS (FAB) m/z: 468 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.16-8.12 (1H, m), 8.00-7.97 (2H, m), 7.81 (1H, s), 7.74 (1H, s), 7.72-7.71 (1H, m), 7.02-6.98 (2H, m), 6.93-6.88 (1H, m), 5.81-5.77 (1H, m), 4.35-4.31 (1H, m), 3.83-3.78 (1H, m), 3.70-3.65 (1H, m), 2.63-2.56 (2H, m), 1.83 (3H, d, J = 6.6 Hz), 1.31 (3H, d, J = 7.0 Hz), 1.21-1.18 (2H, m), 1.02-0.97 (2H, m).
MS (ES) m/z: 469 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.40 (1H, d, J = 3 Hz), 8.15 (1H, t, J = 8 Hz), 8.00 (1H, d, J = 9 Hz), 7.83 (1H, s), 7.75-7.71 (2H, m), 7.32 (1H, dd, J = 9, 3 Hz), 6.93-6.85 (1H, m), 5.82 (1H, q, J= 6 Hz), 4.38-4.29 (1H, m), 3.83-3.77 (1H, m), 3.71-3.64 (1H, m), 3.45-3.37 (1H, m), 2.53 (1H, t, J = 6 Hz), 1.86 (3H, d, J = 6 Hz), 1.32 (3H, d, J = 7 Hz), 1.22-1.17 (2H, m), 1.09-1.03 (2H, m);
MS (ES) m/z: 470 [M+H]+.
1H-NMR (500MHz, CDCl3) δppm:
8.09 (2H, d, J = 8 Hz), 7.99 (2H, d, J = 8 Hz), 7.97 (2H, d, J = 9 Hz), 7.82 (1H, s), 7.02 (2H, d, J = 9 Hz), 5.49 (1H, dd, J = 7, 6 Hz), 3.28-3.22 (1H, m), 3.07 (3H, s), 2.26-2.17 (1H, m), 2.09-2.00 (1H, m), 1.43 (6H, d, J = 7 Hz), 1.09 (3H, t, J = 7 Hz).
MS (ES) m/z: 484 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.43 (1H, d, J = 2 Hz), 8.19 (1H, t, J = 8 Hz), 8.01 (1H, d, J = 9 Hz), 7.92 (1H, dd, J = 8, 1 Hz), 7.80 (1H, dd, J = 12, 1 Hz), 7.68 (1H, s), 7.36 (1H, dd, J = 9, 2 Hz), 6.96-6.88 (1H, m), 5.56 (1H, q, J = 7 Hz), 4.39-4.30 (1H, m), 3.84-3.78 (1H, m), 3.71-3.65 (1H, m), 3.45-3.40 (1H, m), 2.51 (1H, t, J = 5 Hz), 1.80 (3H, d, J = 7 Hz), 1.32 (3H, d, J = 7 Hz), 1.22-1.19 (2H, m), 1.09-1.04 (2H, m).
MS (ES) m/z: 454 [M+H]+.
1H-NMR (400MHz, CDCl3)δppm:
8.42 (1H, d, J = 3 Hz), 8.21 (1H, dd, J = 8, 8 Hz), 8.01 (1H, d, J = 9 Hz), 7.91 (1H, dd, J = 8, 2 Hz), 7.78 (1H, dd, J = 13, 2 Hz), 7.67 (1H, s), 7.36 (1H, dd, J = 9, 3 Hz), 6.90-6.80 (1H, m), 5.56 (1H, q, J = 7 Hz), 3.47-3.40 (1H, m), 3.00-2.92 (1H, m), 1.79 (3H, d, J = 6 Hz), 1.23-1.18 (2H, m), 1.10-1.04 (2H, m), 0.93-0.88 (2H, m), 0.68-0.62 (2H, m).
MS (ES) m/z: 436 [M+H]+.
1H-NMR (400MHz, CDCl3)δppm:
8.42 (1H, d, J = 2 Hz), 8.27 (1H, dd J = 9, 8 Hz), 8.00 (1H, d, J = 9 Hz), 7.76 (1H, d, J = 9 Hz), 7.70 (1H, dd, J = 12, 2 Hz), 7.58 (1H, s), 7.36 (1H, dd, J = 9, 3 Hz), 7.15-7.04 (1H, m), 5.53 (1H, q, J = 6 Hz), 5.42-5.36 (1H, m), 3.85-3.76 (2H, m), 3.50-3.38 (3H, m), 2.46-2.39 (1H, m), 1.78 (3H, d, J = 7 Hz), 1.23-1.17 (2H, m), 1.09-1.02 (2H, m).
MS (FAB) m/z: 455 [M+H]+.
1H-NMR (400MHz, CDCl3) δppm:
8.47 (1H, d, J = 3 Hz), 8.21 (1H, t, J = 8 Hz), 8.03 (1H, d, J = 9 Hz), 7.98 (1H, dd, J = 8, 1 Hz), 7.85 (1H, dd, J = 12, 1 Hz), 7.39 (1H, dd, J = 9, 3 Hz), 6.97-6.85 (1H, m), 5.78 (1H, J = 7 Hz), 4.40-4.29 (1H, m), 3.81 (1H, dd, J = 11, 3 Hz), 3.68 (1H, dd, J = 11, 6 Hz), 3.47-3.37 (1H, m), 2.49 (1H, br s), 1.95 (3H, d, J = 7 Hz), 1.32 (3H, d, J = 7 Hz), 1.24-1.18 (2H, m), 1.10-1.04 (2H, m);
MS (ES) m/z: 455 [M+H]+.
1H-NMR (400MHz, DMSO-d6) δppm:
8.76 (1H, d, J = 3 Hz), 8.57 (1H, d, J = 3 Hz), 8.39 (1H, dd, J = 9, 8 Hz), 7.97 (1H, d, J = 9 Hz), 7.75-7.68 (3H, m), 6.93 (1H, t, J = 6 Hz), 6.28 (1H, q, J = 7 Hz), 4.79 (1H, t, J = 5 Hz), 3.46 (2H, q, J = 5 Hz), 3.43-3.38 (1H, m), 3.18 (2H, td, J = 6, 5 Hz), 1.84 (3H, d, J = 7 Hz), 1.09-0.98 (4H, m).
MS (ES) m/z: 456 [M+H]+.
(400MHz, CDCl3) δppm:
8.47 (1H, d, J = 3 Hz), 8.26 (1H, dd, J = 9, 8 Hz), 8.04 (1H, dd, J = 8, 1 Hz), 8.01 (1H, d, J = 9 Hz), 7.93 (1H, dd, J = 12, 1 Hz), 7.57-7.46 (1H, m), 7.43 (1H, dd, J= 9, 3 Hz), 5.74 (1H, q, J = 7 Hz), 4.28-4.22 (1H, m), 4.04-3.99 (2H, m), 3.97-3.91 (2H, m), 3.45-3.39 (1H, m), 2.46 (2H, dd, J = 7, 5 Hz), 1.91 (3H, d, J = 7 Hz), 1.22-1.17 (2H, m), 1.09-1.03 (2H, m);
MS (ES) m/z: 471 [M+H]+.
1H-NMR (400MHz, DMSO-d6) δppm:
8.92 (1H, d, J = 3 Hz), 8.52 (1H, d, J= 3 Hz), 8.48 (1H, t, J = 8 Hz), 7.94 (1H, d, J = 9 Hz), 7.91-7.85 (2H, m), 7.67 (1H, dd, J = 9, 3 Hz), 7.01 (1H, t, J = 5 Hz), 6.08 (1H, q, J = 7 Hz), 4.80 (1H, t, J = 5 Hz), 3.6 (2H, td, J = 6, 5 Hz), 3.42-3.37 (1H, m), 3.19 (2H, td, J = 6, 5 Hz), 1.77 (3H, d, J = 7 Hz), 1.07-0.98 (4H, m);
MS (ES) m/z: 456 [M+H]+.
実施例で得られた化合物5g、乳糖90g、トウモロコシデンプン34g、結晶セルロース20gおよびステアリン酸マグネシウム1gをブレンダーで混合した後、打錠機で打錠することにより、錠剤が得られる。
化合物の投与液は、0.5w/v%メチルセルロース溶液を用い、メノウ乳鉢で粉砕しながら1mg/mLの濃度になるように懸濁液を調製した。動物は、雄性C57/BL6Jマウス(日本チャールスリバー株式会社)を6週齢から8週齢で入荷し、9週齢から13週齢で使用した。試験日前日の17時から18時の間を目安に絶食を開始し、16時間から17時間程度の絶食下で試験を開始した。各群5匹ずつを用いた。尾静脈から採血を行った後、化合物懸濁液を10mg/kgとなるように経口投与した。陰性対照群には0.5w/v%メチルセルロース溶液を投与した。経口投与から25分後に尾静脈から採血を行い、経口投与から30分後に30w/v%グルコース溶液を10mL/kgで経口投与した。グルコース負荷から15分、30分、60分、120分後に尾静脈から採血を行った。採取した血液を遠心して血漿を分取し、Glucoroder-GXT(株式会社エイアンドティー)で血漿血糖値(mg/dL)を測定した。個体毎に、糖負荷5分前、糖負荷15分、30 分、60分、120分後の血糖値を用いてAUC(mg/dL・min)を算出した。群毎におけるAUC平均値を算出し、陰性対照群と比較したAUC低下率(%)を算出し、薬効の指標とした。
化合物を秤量し、溶媒(0.5w/v%メチルセルロースまたは20w/v%シクロデキストリン)中で1〜10mg/mLの濃度になるように懸濁し、投与液を調製する。必要に応じ、調製した投与液を前記溶媒を用いて順次希釈し、複数の用量の投与液を調製する。動物はZucker fatty ラット(日本チャールスリバー)またはZucker diabetic fatty(ZDF) ラット(日本チャールスリバー)、雄10〜18週齢を使用する。試験の2日前に血糖値、体重、血中インスリン値を測定し、各パラメータが均等になるように各群n=5から8に割り付ける。試験実施日の前日15時頃に絶食を行う。試験当日、ラットに前述の方法によって調製される化合物投与液を1〜5mL/kgで経口投与し、その30分後に25〜50w/v%グルコース溶液を4〜5mL/kgで経口投与する。採血は化合物投与前、グルコース投与5分前、グルコース投与30、60、120および180分後に、ラット尾静脈より行う。得られた血液を遠心後、プラズマを分離し、プラズマ血糖値をGlucoroder-GXT(株式会社エイアンドティー)で測定する。各群におけるグルコース投与後の血糖値のAUCを算出し、vehicle投与群の血糖値AUCに対する低下率(%)を化合物の薬効として表記する。
Junko Ogawa, et al., Life Sciences Vol.65, No.12 pp.1287-1296 (1999) に記載の方法を参照して被検化合物のβ細胞(膵臓)保護作用を確認することができる。
Claims (15)
- 一般式(I):
(式中、
環Aは、
であり、
*はベンゼン環との結合位置であり、
Xは、CHまたはNであり、
R1は、-C(=O)-NH-R5、-NH-C(=O)-NH-R5または-S(=O)2-R5であり、
R2は、-Fまたは-Hであり、
R3は、-CH3または-C2H5であり、
R4は、
であり、
R5は、-H、あるいは、1〜3個の-OHで置換されていてもよい、C1〜C6アルキル基、C3〜C6シクロアルキル基または
である)
で表される化合物またはその薬学的に許容され得る塩。 - 環Aが、
であり、
R1が、-C(=O)-NH-R5または-NH-C(=O)-NH-R5であり、
R2が、-Fであり、
R4が、
である、
請求項1に記載の化合物またはその薬学的に許容され得る塩。 - 環Aが
であり、
R1が-C(=O)-NH-R5であり、
R2が-Fであり、
R4が
であり、
R5がヒドロキシイソプロピル基またはシクロプロピル基である、
請求項1に記載の化合物またはその薬学的に許容され得る塩。 - 環Aが、
であり、
R1が、-C(=O)-NH-R5または-S(=O)2-R5であり、
R3が、-CH3であり、
R4が、
であり、
R5が、1〜3個の-OHで置換されていてもよいC1〜C6アルキル基である、
請求項1に記載の化合物またはその薬学的に許容され得る塩。 - 環Aが、
であり、
R1が、-C(=O)-NH-R5または-NH-C(=O)-NH-R5であり、
R2が、-Fであり、
R3が、-CH3であり、
R4が、
であり、
R5が、-H、あるいは、1〜3個の-OHで置換されていてもよい、C1〜C6アルキル基またはC3〜C6シクロアルキル基である、
請求項1に記載の化合物またはその薬学的に許容され得る塩。 - 環Aが、
であり、
R1が、-C(=O)-NH-R5または-NH-C(=O)-NH-R5であり、
R2が、-Fであり、
R4が、
であり、
R5が、-H、あるいは、1〜3個の-OHで置換されていてもよい、C1〜C6アルキル基またはC3〜C6シクロアルキル基である、
請求項1に記載の化合物またはその薬学的に許容され得る塩。 - 一般式(II):
(式中、
R3は、-CH3または-C2H5であり、
R6は、1〜3個の-OHで置換されていてもよい、C1〜C6アルキル基またはC3〜C6シクロアルキル基であり、
R7は、
である)
で表される化合物またはその薬学的に許容され得る塩。 - 一般式(III):
(式中、
Xは、CHまたはNであり、
R3は、-CH3または-C2H5であり、
R8は、-H、または、置換基群αから選択される1〜3個の置換基で置換されていてもよいC1〜C6アルキル基であり、
R9は、
であり、
置換基群αは、-OH、-O-C(=O)-O-CH3または-O-C(=O)-NH-C2H5である)
で表される化合物またはその薬学的に許容され得る塩。 - 以下:
1-[4-(4-{1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-2H-1,2,3-トリアゾール-2-イル)-2-フルオロフェニル]-3-(2-ヒドロキシエチル)ウレア;
4-{4-[(1R)-1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル]-2H-1,2,3-トリアゾール-2-イル}-N-[(1R,2R)-2,3-ジヒドロキシ-1-メチルプロピル]-2-フルオロベンズアミド;
1-(4-{4-[(1R)-1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル]-2H-1,2,3-トリアゾール-2-イル}-2-フルオロフェニル)-3-(2-ヒドロキシエチル)ウレア;
4-(5-{1-[4-(シクロプロピルカルボニル)フェノキシ]プロピル}-2H-テトラゾール-2-イル)-2-フルオロ-N-[(1R)-2-ヒドロキシ-1-メチルエチル]ベンズアミド;
4-(5-{1-[4-(シクロプロピルカルボニル)フェノキシ]エチル}-1,3-チアゾール-2-イル)-2-フルオロ-N-[(1R)-2-ヒドロキシ-1-メチルエチル]ベンズアミド;
4-[4-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,3-オキサゾール-2-イル]-2-フルオロ-N-[(1R)-2-ヒドロキシ-1-メチルエチル]ベンズアミド;
N-シクロプロピル-4-[4-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,3-オキサゾール-2-イル]-2-フルオロベンズアミド;
1-{4-[4-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,3-オキサゾール-2-イル]-2-フルオロフェニル}-3-(2-ヒドロキシエチル)ウレア;
4-{5-[(1R)-1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル]-1,2,4-オキサジアゾール-3-イル}-2-フルオロ-N-[(1R)-2-ヒドロキシ-1-メチルエチル]ベンズアミド;
1-{4-[5-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,2,4-オキサジアゾール-3-イル]-2-フルオロフェニル}-3-(2-ヒドロキシエチル)ウレア;
4-[3-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,2,4-オキサジアゾール-5-イル]-2-フルオロ-N-[2-ヒドロキシ-1-(ヒドロキシメチル)エチル]ベンズアミド;および
1-{4-[3-(1-{[6-(シクロプロピルカルボニル)ピリジン-3-イル]オキシ}エチル)-1,2,4-オキサジアゾール-5-イル]-2-フルオロフェニル}-3-(2-ヒドロキシエチル)ウレア
からなる群より選択される化合物またはその薬学的に許容され得る塩。 - 請求項1〜9いずれか1項に記載の化合物またはその薬学的に許容され得る塩を有効成分として含有する医薬組成物。
- 1型糖尿病、2型糖尿病または肥満を治療するための、請求項10に記載の医薬組成物。
- β細胞または膵臓を保護するための、請求項10に記載の医薬組成物。
- 医薬組成物を製造するための、請求項1〜9いずれか1項に記載の化合物またはその薬学的に許容され得る塩の使用。
- 請求項1〜9いずれか1項に記載の化合物またはその薬学的に許容され得る塩を哺乳動物に投与することを含む、疾病を治療する方法。
- 哺乳動物がヒトである請求項14に記載の方法。
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