Novel compounds and compositions as cathepsin inhibitors
a technology of cathepsin and compound, applied in the field of peptidases, can solve the problems of pathological consequences and the activeness of cysteine proteases
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example 1
2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-N-[(S)-1-(5-phenyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide
[0204]
[0205] A suspension of PS-bound N-cyclohexylcarbodiimide (HL 200-400 mesh cross linked with 2% DVB) from Novabiochem (436 mg, 0.841 mmol, 1.93 mmol / g loading) in methylene chloride (6 mL) was treated with 2-(2-Methyl-propane-1-sulfonylmethyl)-4-morpholin-4-yl-4-oxo-butyric acid (154 mg, 0.480 mmol) in methylene chloride (3 mL) and stirred at room temperature for 10 minutes. A solution of (S)-2-Amino-1-(5-phenyl-1,2,4-oxadiazol-3-yl)-butan-1-ol (96 mg, 0.412 mmol) in methylene chloride (3 mL) was added and the reaction mixture was stirred at room temperature for 3 h. The mixture was filtered and the filtrate was evaporated under reduced pressure. Crude purified by flash chromatography eluting with a mixture of ethyl acetate and heptane to give N-{(S)-1-[Hydroxy-(5-phenyl-1,2,4-oxadiazol-3-yl)-methyl]-propyl}-2-(2-methyl-propane-1-sulfonylmethyl)-4-morp...
example 2
(R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-N-[(S)-1-(5-trifluoromethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-butyramide
[0210]
[0211] A solution of (R)-2-Cyclohexylmethyl-4-morpholin-4-yl-4-oxo-butyric acid (223 mg, 0.788 mmol) in dimethylformamide (10 ml) was treated successively with (S)-2-Amino-1-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol; compound with trifluoroacetic acid (267 mg, 0.788 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (299 mg, 0.787 mmol) and diisopropylethylamine (0.274 ml, 1.576 mmol). Reaction stirred at room temperature overnight. Solvent evaporated under reduced pressure. Residue taken up in ethyl acetate and washed with 1N hydrochloric acid, saturated aqueous bicarbonate solution and water, dried over Na2SO4 and solvent evaporated under reduced pressure to give (R)-2-Cyclohexylmethyl-N-{(S)-1-[hydroxy-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-methyl]-propyl}-4-morpholin-4-yl-4-oxo-butyramide as a yellow solid (32...
example 3
(R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid [(S)-1-(5-trifluoromethyl-1,2,4-oxadiazole-3-carbonyl)-propyl]-amide
[0216]
[0217] It is similarly prepared according to general procedure given for Example 2 above but using (R)-4,4-Dimethyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-pentanoic acid and (S)-2-Amino-1-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-butan-1-ol; compound with trifluoroacetic acid,
[0218]1H NMR (CDCl3): 6.79 (d, J=5 Hz, 1H), 5.16 (m, 1H), 3.86-3.51 (m, 6H), 3.51-3.28 (m, 2H), 2.96 (m, 1H), 2.72 (dd, J=16 Hz & 10 Hz, 1H), 2.28 (dd, J=16 HZ & 3 Hz, 1H), 2.15-1.96 (m, 1H), 1.96-1.72 (m, 2H), 1.14 (m, 1H), 1.00 (t, J=7 Hz, 3H), 0.88 (s, 9H).
[0219] MS: 463 (MH+).
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