Quinoline derivatives for treatment of inflammatory diseases
A quinoline and drug technology, applied in the field of quinoline derivatives, can solve problems such as low activity, and achieve the effects of low affinity and favorable safety limit
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Embodiment 1
[0146] 6-Chloro-N-{[(1S,3S)-1-hydroxy-3-methylcyclohexyl]methyl}-2-[(3S)-3-hydroxypyrrolidin-1-yl]quinoline-5 -Formamide
[0147]
[0148] a) (3S,5S)-5-methyl-1-oxaspiro[2.5]octane
[0149] The subtitle compound was prepared according to the literature procedure (Weijers, C.A.G.M.et al., JOC.2005, 70, 6639-6646) as follows: potassium tert-butoxide (7.84 g) in dimethyl sulfoxide (200 ml) was mixed with (3S)- 3-Methylcyclohexanone (4.0 g, >98% ee) (Alexakis, A. et al., Synlett 2001, No. 9, 1375 and Hiemstra, H and Wynberg, H., Tetrahedron Lett., 1977, 2183 ) and a mixture of trimethylsulfoxonium iodide (15.4g) in dimethylsulfoxide (100ml) gave the subtitled compound (3.5g).
[0150] 1 H NMR 2.62(2H,m), 1.86-1.56(5H,m), 1.26(2H,m), 0.99(1H,m), 0.92(3H,d), 0.86(1H,m).
[0151] b) (1S,3S)-1-[(benzylamino)methyl]-3-methylcyclohexanol
[0152] A solution of benzylamine (5.9g) and (3S,5S)-5-methyl-1-oxaspiro[2.5]octane (3.5g) in methanol (1ml) was heated in a microwave (100W...
Embodiment 2
[0166] 6-Chloro-N-{[(1S,3S)-1-hydroxy-3-methylcyclohexyl]methyl}-2-[(3R)-3-hydroxypyrrolidin-1-yl]quinoline-5 -Formamide
[0167]
[0168] The title compound was prepared according to the method of Example 1, step e) by combining (R)-3-hydroxypyrrolidine (80 mg) (in place of (S)-3-hydroxypyrrolidine) with the product of Example 1, step d) (0.2g) was reacted with diisopropylethylamine (300[mu]l) in acetonitrile (3ml) to give the title compound as a cream solid (190mg). Melting point 222-223°C (acetonitrile).
[0169] m / z 418 (M+H, 100%).
[0170] 1 H NMR 7.92(1H,d), 7.65(1H,d), 7.49(1H,d), 6.94(1H,d), 4.54(1H,d), 3.69(3H,m), 3.62(1H,m), 3.41 (2H, s), 2.15(1H, m), 2.10(1H, m), 1.86-1.53(6H, br.m), 1.40(1H, m), 1.12(1H, t), 0.89(3H, d ), 0.85(1H,q).
Embodiment 3
[0172] 6-Chloro-N-{[(1S,3S)-1-hydroxy-3-methylcyclohexyl]methyl}-2-(4-hydroxypiperidin-1-yl)quinoline-5-carboxamide
[0173]
[0174]The title compound was prepared according to the method of Example 1, step e) by combining piperidin-4-ol (28 mg) (instead of (S)-3-hydroxypyrrolidine) with the product of Example 1, step d) (0.10 g ) and diisopropylethylamine (0.11 g) in acetonitrile (2 ml) gave the title compound as a white solid (99 mg). Melting point120℃dec.
[0175] m / z 432(M+H, 100%), 430(M-H, 100%)
[0176] 1 H NMRδ (DMSO) 8.46(1H,t), 7.79(1H,d), 7.52(1H,d), 7.49(1H,d), 7.32(1H,d), 4.71(1H,d), 4.18(2H,m), 4.13 (1H, s), 3.73 (1H, m), 3.37-3.20 (4H, m), 1.84-1.21 (11H, m), 1.02 (1H, t), 0.82 (3H, d), 0.73 (1H, m )
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