Hydroxamic acid compound used as histone deacetylase inhibitor and application thereof
A compound and pharmaceutical technology, applied in the field of hydroxamic acid-type histone deacetylase inhibitors, can solve the problems of high toxicity, inaccurate curative effect, few types of deacetylase inhibitors, etc.
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Embodiment 1
[0069] Example 1 Preparation of 7-(3-phenyl-1,2,4-oxadiazol-5-yl)heptanoic acid methyl ester
[0070]
[0071] Aniline oxime (5g, 36.7mmol) was dissolved in 15mL of pyridine, and 8-chloro-8-oxooctanoic acid methyl ester (9.11g, 44.1mmol) was added dropwise within 30min at room temperature, and the reflux reaction was completed. After the reaction of aniline oxime is complete, cool to room temperature, add ethyl acetate and water for distribution, and wash the organic layer with 2M aqueous hydrochloric acid solution, saturated sodium bicarbonate solution and saturated brine successively, dry the organic layer with magnesium sulfate, and pass through a silica gel column layer. A colorless oily liquid was obtained by analysis. Yield 65%. Heptanoic acid methyl esters of other substituents were synthesized in the same way, and the yield was 52-70%. 1 H-NMR (500Hz, CDCl 3 )δ: 8.06-8.08 (m, 2H), 7.28-7.49 (m, 3H), 3.66 (s, CO 2 CH 3 , 3H), 2.94(t, J=7.5Hz, het-CH 2 CH 2 , 2...
Embodiment 2
[0072] Example 2 Preparation of 7-(3-phenyl-1,2,4-oxadiazol-5-yl)heptanoic acid
[0073]
[0074] Dissolve 15 mmol of methyl 7-(3-phenyl-1,2,4-oxadiazol-5-yl)heptanoate in 30 mL of tetrahydrofuran, add 30 mL of 0.6 M lithium hydroxide aqueous solution, and stir overnight at room temperature. Add 150 mL of water, extract with ethyl acetate, discard the organic layer, acidify the lower aqueous solution to a pH equal to 3, extract with ethyl acetate (3×50 mL), combine the organic layers, wash with saturated brine, dry over anhydrous magnesium sulfate, and evaporate the solvent under reduced pressure. That is, 7-(3-phenyl-1,2,4-oxadiazol-5-yl)heptanoic acid was obtained with a yield of 70-95%. Mp: 100-101°C.
Embodiment 3
[0075] Example 3 Preparation of N-hydroxyl-7-(3-phenyl-1,2,4-oxadiazol-5-yl)heptanamide (compound 1)
[0076]
[0077] At 0°C, a tetrahydrofuran solution of ethyl chloroformate (1.3g, 12mmol) was added dropwise to 7-(3-phenyl-1,2,4-oxadiazol-5-yl)heptanoic acid (2.74g, 10mmol) and N-methylmorpholine (1.3g, 13mmol) in THF solution, the mixture was reacted for 30min. The generated salt was removed by filtration, and the filtrate was added dropwise to a methanol solution of hydroxylamine, and the reaction mixture was stirred at room temperature for 30 min. The solvent was distilled off, ethyl acetate and saturated ammonium chloride solution were added for partitioning, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 2.31 g of white solid with a yield of 80%. Mp: 84-86°C. 1 H-NMR (300Hz, DMSO-d6) δ: 10.36(s, -NHOH), 8.66(s, -NHOH), 7.99-8.02(m, 2H), 7.56-7.58(m, 3H), 2.99(t, J = 7.45Hz, CH 2 CH 2 CO 2 NHOH, 2H), 1....
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