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US 5,670,494 AGranted
N-(pyrimidinyl)-aspartic acid analogs as interleukin-1.beta. converting enzyme inhibitors
AssigneeSanoft
InventorsRoland E. Dolle, Catherine P. Prouty, Prasad V. Chaturvedula, Stanley J. Schmidt
Life of this patent
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Abstract
Disclosed are compounds, compositions and methods for inhibiting interleukin-1.beta. (1L-.beta.) protease activity. The compounds, N-(pyrimidinyl)-aspartic acid .alpha.-substituted methyl ketones and aspartic acid aldehydes, have the formula (I) set out herein. These compounds are inhibitors of 1.beta.-converting enzyme and as such are useful whenever such inhibition is desired. For example, they may be used as research tools in pharmacological, diagnostic and related studies and in the treatment of diseases in mammals in which IL-.beta. protease activity is implicated.
Claims2
A compound selected from the group consisting of:
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(4-fluorophenyl)-1, 6-dihydro-1-pyrimidinyl-acetoyl!-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- N-2-(5-thiomethyl-benzoylamino-6-oxo-2-(4-fluorophenyl)-1, 6-dihyro-1-pyrirnidinyl) acetoyl!-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(4-fluorophenyl)-1, 6-dihydro-1-pyrimidinyl)acetoyl!-L-aspartic acid diphenylphosphinoxymethyl ketone;
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(4-fluorophenyl-1, 6-dihydro- 1-pyrimidinyl)acetoyl!-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl) pyrazoloxymethyl ketone
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(4-fluorophenyl)-1, 6-dihydro-1-pyrimidinyl)acetoyl!-L-aspartic acid 5-(3-pheny)coumarinyloxymethyl ketone;
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(4-fluorophenyl)-1, 6-dihydro-1-pyrimidinyl)acetoyl!-L-aspartic acid 5-(1-phenyl-3-fluoromethyl)-pyrazoloxymethyl ketone;
- N-2-(5-isopropyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl) acetoyl!-L-aspartic acid 5-(1-phenyl-3-trifluoromethyl)pyrazoloxymethyl ketone;
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(3-pyridinyl)-1, 6-dihydro-1-pyrimidinyl)acetoyl!-L-aspartic acid 5-(1-phenyl-3-trifluoromethyl)pyrazoloxymethyl ketone;
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidiny l) acetoyl!-L-aspartic acid 5-(1-phenyl-3-trifluoromethyl)pyrazoloxymethyl ketone;
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-methyl-1, 6-dihydro-1-pyrimidinyl)-acetoyl!-L-aspartic acid 5-(1-phenyl-3-trifluoromethyl)pyrazoloxymethyl ketone;
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidiny l) acetoyl!-L-aspartic acid 5-(1-(2-pyridinyl)-3-trifluoromethyl)pyrazoloxymethyl ketone;
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidiny l) acetoyl!-L-aspartic acid 5-(1-(4-chlorophenyl-3-trifluoromethyl)pyrazoloxymethyl ketone;
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidiny l) acetoyl!-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- and
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidiny l) acetoyl!-L-aspartic acid aldehyde.
12 more elements
A pharmaceutical composition for inhibiting interleukin-1.beta. protease comprising a compound selected from the group consisting of:
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrim idinyl) acetoyl!-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- N-2-(5-thiomethylbenzoylamino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrim idinyl) acetoyl!-L-aspartic acid 2,6-dichlorobenzoyloxymethyl ketone;
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrim idinyl) acetoyl!-L-aspartic acid diphenylphosphinoxymethyl ketone;
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(4-fluorophenyl-1,6-dihydro-1-pyrimi dinyl) acetoyl!-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl)pyrazoloxymethyl ketone;
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(4-fluorophenyl)-1, 6-dihydro-1-pyrimidinyl)-acetoyl!-L-aspartic acid 5-(3-pheny)coumarinyloxymethyl ketone;
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(4-fluorophenyl)-1,6-dihydro-1-pyrim idinyl) acetoyl!-L-aspartic acid 5-(1-phenyl-3-trifluoromethyl)pyrazoloxymethyl ketone;
- N-2-(5-isopropyloxycarbonylamino-6-oxo-2-phenyl-1,6-dihydro-1-pyrimidinyl) acetoyl!-L-aspartic acid 5-(1-phenyl-3-trifluoromethyl)pyrazoloxymethyl ketone;
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(3-pyridinyl)-1,6-dihydro-1-pyrimidi nyl) acetoyl!-L-aspartic acid 5-(1-phenyl-3-trifluoromethyl)pyrazoloxymethyl ketone;
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidiny l) acetoyl!-L-aspartic acid 5-(1-phenyl-3-trifluoromethyl)pyrazoloxymethyl ketone;
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-methyl-1,6-dihydro-1-pyrimidinyl) acetoyl!-L-aspartic acid 5-(1-phenyl-3-trifluoromethyl)pyrazoloxymethyl ketone;
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidiny l) acetoyl!-1,6-dihydro-1-pyrimidinyl)acetoyl!-L-aspartic acid 5-(1-(2-pyridinyl)-3-trifluoromethyl)pyrazoloxymethyl ketone;
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidiny l) acetoyl-L-aspartic acid 5-(1-(4-chlorophenyl)-3-trifluoromethyl)pyrazoloxymethyl ketone;
- N-2-(5-benzyloxycarbonylamino-6-oxo-2-(2-thienyl)-L-aspartic acid 2, 6-dichlorobenzoyloxymethyl ketone;
- and
- N-2-(5-benzyloxycarbonyl-amino-6-oxo-2-(2-thienyl)-1,6-dihydro-1-pyrimidin yl) acetoyl!-L-aspartic acid aldehyde.
12 more elements
Dependencies are inferred from the claim text.