Thiadiazine derivatives
A technology of thiadiazine and compounds, applied in the field of thiadiazine derivatives, can solve the problem of suboptimal clinical curative effect, etc.
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Embodiment 1
[0314]
[0315] 5-(3,4-Dimethoxyphenyl)-2-methyl-N-(3-methylphenyl)-1,1-dioxo-2H-1λ 6 ,2,6-Thiadiazine-3-carboxamide
[0316] Under an inert atmosphere, m-toluidine (0.46 mL, 4.3 mmol) and N,N-diisopropylethylamine (1.48 mL, 8.50 mmol) were added to intermediate 65 (5-(3, 4-dimethoxyphenyl)-2-methyl-1,1-dioxo-2H-1λ 6 ,2,6-thiadiazine-3-carboxylic acid, 700mg, 2.15mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b] A suspension of pyridinium oxide hexafluorophosphate (HATU, 1.06 g, 2.79 mmol) in N,N-dimethylformamide (20 mL), and the resulting solution was stirred at room temperature for 2 days. 10% HCl solution (100 mL) was added, and the mixture was extracted with ethyl acetate, the combined organic layers were washed with water, washed with Na 2 SO 4 Dry and evaporate to dryness. The residue was purified by flash column chromatography on silica gel using a gradient with 0 to 2.5% V / V ethyl acetate-dichloromethane mixture as eluent and subsequent cryst...
Embodiment 53
[0327]
[0328] 2-Ethyl-1,1-dioxo-5-[(1r,4r)-4-(trifluoromethyl)cyclohexyl]-N-[6-(trifluoromethyl)pyridin-2-yl ]-2H-1λ 6 ,2,6-Thiadiazine-3-carboxamide
[0329] A solution of oxalyl chloride (0.24 mL, 2.82 mmol) in dichloromethane (10 mL) was added dropwise to intermediate 75 (2-ethyl-1,1-dioxo-5- [(1r,4r)-4-(trifluoromethyl)cyclohexyl]-2H-1λ 6 , 2,6-thiadiazine-3-carboxylic acid; 500 mg, 1.41 mmol) and N,N-dimethylformamide (3 drops) in dichloromethane (20 mL). After stirring at room temperature for 15 minutes, the reaction mixture was evaporated to dryness, dichloromethane (20 mL) was added, and it was evaporated to dryness again. The residue (carbonyl chloride) was dissolved in tetrahydrofuran under an inert atmosphere, cooled to 0 °C, and tripotassium phosphate (375 mg, 1.76 mmol) and 2-amino-6-(trifluoromethyl)pyridine (229 mg, 1.41 mmol), and the mixture was stirred at room temperature for 3 hours.
[0330] The inorganic salts were filtered off, the filtrate was ...
Embodiment 85
[0339]
[0340] 5-(3,4-Dimethoxyphenyl)-2-methyl-1,1-dioxo-N-(1-propyl-1H-pyrazol-3-yl)-2H-1λ 6 ,2,6-Thiadiazine-3-carboxamide
[0341] 1-Propyl-1H-pyrazol-3-amine (99 mg, 0.79 mmol) and 4-(dimethylamino)pyridine (209 mg, 1.71 mmol) were added to intermediate 65 (5-( 3,4-dimethoxyphenyl)-2-methyl-1,1-dioxo-2H-1λ 6 , 2,6-thiadiazine-3-carboxylic acid; 210mg, 0.64mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC, 248mg, 1.29 mmol) in N,N-dimethylformamide (9 mL), and the mixture was stirred at room temperature for 4 days. Another portion of 1-propyl-1H-pyrazol-3-amine (85 mg, 0.68 mmol) in N,N-dimethylformamide (2 mL) was added, and the mixture was further stirred for two days. 10% HCl solution was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water, washed with Na 2 SO 4 Dry and evaporate to dryness. The residue was purified by column chromatography on silica gel using a mixture of ethyl a...
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