Novel compounds and compositions as cathepsin inhibitors
A technology of compounds, alkyls, applied in the field of compounds and compositions
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[0073] Although the broadest definition of the invention is set forth in the Summary of the Invention, certain aspects of the invention are preferred. For example, X 1 Yes-NHC (R 1 )(R 2 )X 2 or - NHX 3 ;X 2 is cyano, -C(O)X 3 ,-C(O)CF 3 ,-C(O)CF 2 CF 2 R 9 ,-CH=CHS(O) 2 R 5 ,-C(O)CF 2 C(O)NR 5 R 5 , -C(O)C(O)NR 5 R 6 , -C(O)C(O)OR 5 ,-C(O)CH 2 OR 5 ,-C(O)CH 2 N(R 6 ) SO 2 R 5 or -C(O)C(O)R 5 ; where R 5 and R 6 As above; X 3 Including heteromonocyclic rings containing 4-6 ring atoms or fused heterobicyclic ring systems containing 8-14 ring atoms, and any carbocyclic ketone, imino ketone or thione derivatives thereof; wherein in R 5 、X 2 or X 3 In, any alicyclic or aromatic ring system can be further independently selected from 1-5 (C 1-6 ) alkyl, or -X 4 OC(O)R 12 and / or substituted by a group selected from -R14 ,-X 4 C(O)R 14 or -X 4 OC(O)R 14 The group substitution; where X 4 , R 12 and R 14 As above; R 1 is hydrogen or (C 1-6 ) alky...
Embodiment 1
[0238] 2-Butyl-N-cyanomethyl-N'-phenylmalonamide (compound 1)
[0239]
[0240] A DMF (5.0 mL) solution composed of 2-phenylcarbamoylcaproic acid (188 g, 0.8 mmol) prepared in reference 1 was mixed with PyBOP_ (425 mg, 0.8 mmol), aminoacetonitrile hydrogensulfate (140 mg, 0.9 mmol ) and triethylamine (600 μl, 4.3 mmol). The mixture was stirred for 3 hours, then partitioned between water (20 mL) and ethyl acetate (50 mL). The organic layer was separated and washed with 1M saturated sodium bicarbonate solution, 1M hydrochloric acid solution and water, dried (MgSO 4 ) and concentrate. The product, 2-butyl-N-cyanomethyl-N'-phenylmalonamide (125 mg, Yield 57%).
[0241] 1 H NMR: (DMSO) 10.01(s, 1H), 7.59(d, J=8Hz, 2H), 7.31(t, J=7Hz, 2H), 7.06(t, J=7Hz, 1H), 4.13(d, J=6Hz, 2H), 3.32(t, J=8Hz, 1H), 1.80(m, 2H), 1.25(m, 4H), 0.86(t, J=7Hz, 3H). MS: m / e 273.9.
Embodiment 2
[0243] N-cyanomethyl-2-cyclohexylmethyl-N'-phenylmalonamide (Compound 2)
[0244]
[0245] A solution consisting of 2-cyclohexylmethyl-N-phenylpropionamic acid (350 mg, 1.2 mmol) prepared in reference 2 in N,N-dimethylpyrrolidone (5 ml) ), EDCI (250 mg, 1.3 mmol), HOBt hydrate (199 mg, 1.3 mmol), aminoacetonitrile bisulfate (200 mg, 1.3 mmol) and N-methylmorpholine (0.30 ml, 2.7 mmol mol), stirred at ambient temperature for 15 hours. The reaction mixture was poured into cold 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with saturated aqueous sodium bicarbonate solution, then brine (50 mL each), dried over magnesium sulfate and evaporated. The residue was purified by radial chromatography using 50% ethyl acetate / hexane as eluent to give N-cyanomethyl-2-cyclohexylmethyl-N'-phenylmalonamide (179 mg, Yield 48%). 1 h
[0246] NMR: (DMSO) 10.01(s, 1H), 8.47(t, J=5Hz, 1H), 7.59(d, J=7Hz, 2H), 7.31(t, J=8Hz, 2H), 7.07(t, J =7Hz, 1H), 4.1...
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