Sulfonyl containing compounds as cysteine protease inhibitors
a cysteine protease inhibitor and sulfonyl containing technology, which is applied in the direction of drug compositions, immunological disorders, metabolism disorders, etc., can solve the problems of pathological consequences and the activeness of cysteine proteases
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example 6
Synthesis of N-(1-cyanocyclopropyl)-1-3-(cyclopropylmethanesulfonyl)2(R)-[2,2,3,3,3-pentafluoro-1(S)-(4-fluorophenyl)propylamino]propionamide
Compound 54
[0435]
Step 1
[0436]To a solution of 1-bromo-4-fluorobenzene (16.5 mL, 0.15 mol) in anhydrous THF (200 mL) at −78° C., 2,2,3,3,3-pentafluoropropionic acid ethyl ether (14.4 g, 75 mmol) was slowly added. After stirring for 4 h at −78° C., ethyl ether (200 mL) and sat. sol. of NH4Cl (100 mL) were added. The resulting mixture was placed in a sep. funnel, shaken and the organic phase separated. After washing with brine, the solution was dried over magnesium sulfate. The solution was concentrated in a rotary vapor and the residue was purified by distillation to give 2,2,3,3,3-pentafluoro-1-(4-fluorophenyl)propan-1-one.
Step 2
[0437]To a solution of 2,2,3,3,3-pentafluoro-1-(4-fluorophenyl)propan-1-one (13.0 g, 53 mmol) in a mixture 1:1 of dichloromethane and toluene (160 mL) at room temperature, 1M solution of S-methyl-CBS-oxazaborolidine in t...
example 7
Synthesis of N-(1-cyanocyclopropyl)-3-(pyridin-2-ylmethanesulfonyl)-2(R)-[2,2,3,3,3-pentafluoro-1(S)-(4-fluorophenyl)propylamino]propionamide
Compound 50
[0444]
Step 1
[0445]To a 0.2 M stock solution of 3-mercapto-2(R)-[2,2,3,3,3-pentafluoro-1-(S)-(4-fluorophenyl)propylamino]-propionic acid in NaOH (10 mL, 2 mmol), 2-chloromethylpyridine (0.328 g, 2 mmol) and 1N solution of NaOH (1 mL) were added. After stirring the reaction mixture for 5 h at room temperature, 1M HCl solution was added until pH 5-6. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine and dried over sodium sulfate and concentrated to give N-(1-cyanocyclopropyl)-3-(pyridin-2-ylmethanesulfanyl)-2(R)-[3,3,3,2,2-pentafluoro-1(S)-(4-fluorophenyl)propylamino]-propionamide as a foam (0.692 g) which was converted to the title compound as described in Example 6 above.
[0446]1HNMR (DMSO-d6): δ 8.97 (1H, s), 8.60 (1H, m), 7.88 (1H, m), 7.47 (4H, m), 7.24 (2H, t), 4.74 (2H, s), 4.58 ...
example 8
Synthesis of N-(1-cyanocyclopropyl)-3-(2-trifluoromethylphenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)-propionamide
Compound 35
[0451]
[0452]2-(Trifluoromethyl)benzyl bromide (0.50 mmol) was dissolved in dioxane (3 mL) and a 0.16 M stock solution of 3-mercapto-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-propionic acid (4.7 mL, 0.75 mmol) in 1.0 M aqueous sodium hydroxide / 0.032 M tris(2-carboxyethyl)phosphine hydrochloride was added. After stirring overnight, the reaction mixture was concentrated to half the volume and then diluted with water and washed with heptane. Ethyl acetate (5 mL) was added and the two phase mixture was placed in an ice / water bath and the pH was adjusted to 3 with 3.0 M hydrochloric acid. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with brine, dried over MgSO4, and concentrated. The residue was dissolved in DMF (2 mL) and 1-aminocyclopropanecarbonitrile hydrochloride (64 mg, 0.54...
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