Hydantoin derivatives used as mmp inhibitors
A methyl and phenyl technology, applied in the field of novel hydantoin derivatives, can solve problems hindering the development of matrix metalloproteinase inhibitor drug candidates
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Embodiment 1
[0175] 1-[(4S)-4-cyclopropyl-2,5-dioxoimidazolidin-4-yl]-N-methyl-N-{[4-(pyrimidin-5-yloxy)phenyl ]Methyl}methanesulfonamide trifluoroacetate
[0176]
[0177] N-Methyl-N-{[4-(pyrimidin-5-yloxy)phenyl]methyl}amine (0.043 g, 0.20 mmol) was stirred in NMP (1.0 mL). The mixture was cooled using a cold water bath, and DIPEA (36 μL, 0.22 mmol) was added, followed by the addition of (4S)-(4-cyclopropyl-2,5-dioxoimidazolidin-4-yl in portions over 5 minutes ) methanesulfonyl chloride (WO 2006 / 065215; 0.051 g, 0.20 mmol). After 10 minutes, water was added and the product was extracted three times with EtOAc. The extract was washed with brine, dried and concentrated. The product was purified by preparative HPLC (0.1% TFA in eluent) to afford 0.057 g (66%) of the title compound as the trifluoroacetate salt.
[0178] APCI-MS m / z: 432 (M+1).
[0179] 1 H NMR (DMSO-d 6 ): δ0.12-0.26(m, 1H), 0.35-0.58(m, 3H), 1.12-1.22(m, 1H), 2.67(s, 3H), 3.60(d, 2H), 4.25(q, 2H ), 7.28 (q, 4H), ...
Embodiment 2
[0196] 1-[(4S)-4-cyclopropyl-2,5-dioxoimidazolidin-4-yl]-N-({4-[(2-cyclopropylpyrimidin-5-yl)oxy] Phenyl}methyl)-N-methylmethanesulfonamide
[0197]
[0198] Crude {4-[(2-cyclopropylpyrimidin-5-yl)oxy]benzyl}methanamine dihydrochloride (0.115 g, 0.35 mmol) was dissolved in NMP (2.0 mL), THF (2.0 mL) and DIPEA (0.30 mL, 1.8 mmol) to give a yellow solution. (4S)-(4-Cyclopropyl-2,5-dioxoimidazolidin-4-yl)methanesulfonyl chloride (WO 2006 / 065215; 0.070 g, 0.28 mmol) was added in portions over 5 minutes, and the reaction The mixture was stirred for 1 hour. The solvent was removed by evaporation, the residue was diluted with water and extracted twice with EtOAc. The combined organic phases were washed with water and concentrated. The crude product was purified by HPLC using a 35 min gradient of 20% to 90% MeCN in water to afford 0.081 g (61% yield) of the title compound as a colorless powder.
[0199] APCI-MS m / z 472.1 (M+1); Rt = 1.93 min.
[0200] 1 H-NMR (DMSO-d 6 ): δ0....
Embodiment 3
[0219] 1-[(4S)-4-cyclopropyl-2,5-dioxoimidazolidin-4-yl]-N-methyl-N-({4-[(2-methylpyrimidin-5-yl )oxy]phenyl}methyl)methanesulfonamide
[0220]
[0221] The preparation was carried out as in Example 1, but starting from N-methyl-1-{4-[(2-methylpyrimidin-5-yl)oxy]-phenyl}methanamine on a scale of 0.50 mmol and after purification The rate is 61%.
[0222] APCI-MS m / z 446 (M+1).
[0223] 1 H NMR (DMSO-d 6 ): δ0.13-0.24(m, 1H), 0.33-0.57(m, 3H), 1.15(ddd, 1H), 2.61(d, 3H), 2.66(s, 3H), 3.60(dd, 2H), 4.23 (dd, 2H), 7.11 (dd, 2H), 7.35 (dd, 2H), 7.97 (s, 1H), 8.52 (s, 2H), 10.74 (s, 1H) ppm.
[0224] The starting material was prepared as follows:
[0225] a) 2-methyl-5-[(phenylmethyl)oxy]pyrimidine
[0226] The preparation was carried out according to Example 2(a), the scale was 15 mmol, and the yield after purification was 73%.
[0227] APCI-MS m / z: 201 (M+1).
[0228] 1 H NMR (CDCl 3 ): δ2.67 (s, 3H), 5.13 (s, 2H), 7.31-7.50 (m, 5H), 8.37 (s, 2H) ppm.
[0229] b) 2-...
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