Compounds for treatment of inflammation, diabetes and related disorders
A compound and selected technology, applied in the field of compounds, can solve problems such as hindering the protective effect of COX-1
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Embodiment 1
[0205] 3-(3,5-dimethoxyphenyl)-2-{4-[4-(3-oxo-3-ureidopropyl)-phenoxy]-phenyl]-methyl acrylate ( 1) Synthesis [see scheme I]
[0206] Step 1: Synthesis of 3-(3,5-dimethoxyphenyl)-2-(4-hydroxyphenyl)-acrylic acid (2).To a mixture of 3,5-dimethoxybenzaldehyde (120 g, 0.72 mol) and p-hydroxyphenylacetic acid (110 g, 0.72 mol) was added acetic anhydride (240 mL) and triethylamine (161 mL, 1.6 equiv.). This heterogeneous solution became homogeneous at ~70°C upon heating. After stirring at 130 °C for 4 hrs, the mixture was cooled to room temperature. HCl (15%, 500 mL) was slowly added to the reaction mixture over 30 min to keep the temperature below 5-10 °C. The solid was dissolved in 3N aqueous NaOH (1.2 L) and stirred for 0.5 hr. The filtrate was acidified to pH 1 with concentrated HCl (-700 mL), maintaining the temperature at 25-30 °C. The precipitated product was filtered and washed with water to give the crude product (-300 g, wet cake). The crude product was dissolved b...
Embodiment 2
[0213] 3-(3,5-dimethoxyphenyl)-2-{4-[4-(3-ethoxycarbonylamino-3-oxo-propyl)-phenoxy]-phenyl}- Synthesis of Methyl Acrylate (8)
[0214] Proceeding essentially as shown in PCT / US99 / 09982 (WO 99 / 58127), 3-(3,5-dimethoxy-phenyl)-2-{4-[4-(2,4-diox In the synthesis of thiazolidin-5-ylmethyl)-phenoxy]-phenyl}-methyl acrylate, 2-{4-[4-(2-carbamoyl-ethyl)-benzene Oxy]-phenyl}-3-(3,5-dimethoxyphenyl)-methyl acrylate (7). 7 (460 mg, 1.0 mmol) was taken up in dry THF (6 mL) and cooled to -78 °C. To this solution, lithium diisopropylamide (LDA) (2M, 0.55 mL, 1.1 mmol) was added and stirred for 10 min. Ethyl chloroformate (0.11 mL, 1.2 mmol) was added and stirred at room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride, then ethyl acetate (50 mL) was added. The organic layer was washed with brine (2x20 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The crude product was purified by chromatography on silica ...
Embodiment 3
[0218] 2-{4-[4-(3-Benzoyloxycarbonylamino-3-oxo-propyl)-phenoxy]-phenyl]-3-(3,5-dimethoxyphenyl )-Synthesis of methyl acrylate (9)
[0219]7 (1.38, 3.0 mmol) as prepared in Example 2 was taken up in dry THF (20 mL) and cooled to -78 °C. To this solution, LDA (2M, 1.8 mL, 3.6 mmol) was added and stirred for 10 min. Benzyl chloroformate (0.67 g, 39 mmol) was added and stirred overnight at room temperature. The reaction was quenched with saturated aqueous ammonium chloride and added ethyl acetate (150 mL). The organic layer was washed with brine (2 x 25 mL), dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The crude product was purified by silica gel chromatography and eluted with hexane-ethyl acetate (7:3). Yield: 0.68 g, 37.3%.
[0220]
[0221] analyze: 1 HNMR (DMSO-d 6 ): δ10.65(s, 1H), 7.72(s, 1H), 7.38-7.39(m, 5H), 7.25(d, J=8.4Hz, 2H), 7.18(d, J=8.4Hz, 2H) , 7.00(d, J=8.4Hz, 2H), 6.94(d, J=8.4Hz, 2H), 6.41(t, J=2.0Hz, 1H), 6.28(d, J=...
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