Claims
- 1. A compound of the formula (I) or a pharmaceutically acceptable salt thereof:
wherein
16and when R6 is OH, then Y can also be:
17R5 is H or deuterium; R6 is OR8 or NHOH where R8 is independently H, alkyl, or aralkyl; R3 and R4=independently H, alkyl or aralkyl; R2=H, alkyl, -(CH2)0-4-cycloalkyl,
18aryl, aralkyl, or -(CH2)2-4-R10; where n=1-3; R10=alkoxy, CH2F, CHF2, CF3, CF2CF3, OH, COOR11, CONR9R11, or NR9R11; R9 is independently H, alkyl, aryl, aralkyl, -CH2CH2O-alkyl or C(O)—R12; R11 is independently H, alkyl, aryl, or aralkyl; and when R9 and R11 are taken together, they can equal a five, six or seven membered ring of the type:
19where n=1-3 and m=0-1; and R12 is alkyl, aryl, or aralkyl; R7=H, CH2F, CHR13O(CO)0-1-aryl, CHR13OP(O)(R14)R15,
20wherein: R13=H or alkyl R14=H, alkyl or aryl R15=H, alkyl or aryl R16=H, alkyl, aryl or aralkyl; R17=H, alkyl, CF3, CF2CF3, aryl, aralkyl, COOR11, or CONR9R11 R18=H, alkyl, CF3, CF2CF3, aryl, or aralkyl; R1 is defined as: R19-R2, R19-R20, R19-R21, or R19-NR9R11 where R19=(CR3R4)-0-4;
21R22O- where R22 is alkyl, aryl, aralkyl, R19-cycloalkyl, R19-R21, R23-R10 or R23-R20; wherein R23=(CR3R4)-2-4, R9 R11N- or R24R11N- where R24=R19-cycloalkyl, R19-R21, R23-R10, R23-R20, CR3R4COOR11 or CR3CR4CONR9R11.
- 2. A pharmaceutical composition for inhibiting interleukin-1βprotease comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof:
22wherein
23and when R6 is OH, then Y can also be:
24R5 is H or deuterium; R6 is OR8 or NHOH where R8 is independently H, alkyl, or aralkyl; R3 and R4=independently H, alkyl or aralkyl; R2=H, alkyl, -(CH2)0-4-cycloalkyl,
25aryl, aralkyl, or-(CH2)2-4-R10; where n=1-3; R10=alkoxy, CH2F, CHF2, CF3, CF2CF3, OH, COOR11, CONR9R11, or NR9R11; R9 is independently H, alkyl, aryl, aralkyl, -CH2CH2O-alkyl or C(O)-R12; R11 is independently H, alkyl, aryl, or aralkyl; and when R9 and R11 are taken together, they can equal a five, six or seven membered ring of the type:
26where n=1-3 and m=0-1; and R12 is alkyl, aryl or aralkyl; R7=H, CH2F, CHR13O(CO)0-1-aryl, CHR13OP(O)(R14)R15,
27wherein: R13=H or alkyl; R14=H, alkyl or aryl; R15=H, alkyl or aryl; R16=H, alkyl, aryl or aralkyl; R17=H, alkyl, CF3, CF2CF3, aryl, aralkyl, COOR11, or CONR9R11; R18=H, alkyl, CF3, CF2CF3, aryl, or aralkyl; R1 is defined as:
R19-R2, R19-R20, R19-R21, or R19-NR9R11 where R19=(CR3R4)-0-4;
28R22O- where R22 is alkyl, aryl, aralkyl, R19-cycloalkyl, R19-R21, R23-R20, or R23-R20; wherein R23=(CR3R4)-2-4; R9 R11N- or R24R11N- where R24=R19-cycloalkyl, R19-R21, R23-R10, R23-R20, CR3R4COOR11 or CR3CR4CONR9R11 in combination with a pharmaceutically acceptable carrier.
- 3. A method of inhibiting interleukin-1βprotease activity in a mammal in need of such treatment comprising administering to said mammal an effective inhibitory amount of a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof:
29wherein
30and when R6 is OH, then Y can also be:
31R5 is H or deuterium; R6 is OR8 or NHOH where R8 is independently H, alkyl, or aralkyl; R3 and R4=independently H, alkyl or aralkyl; R2=H, alkyl, -(CH2)2-4-cycloalkyl, -(CH2),
32aryl, aralkyl, or -(CH2)2-4-R10; where n=1-3; R10=alkoxy, CH2F, CHF2, CF3, CF2CF3, OH, COOR11, CONR9R11, or NR9R11; R9 is independently H, alkyl, aryl, aralkyl, -CH2CH2O-alkyl or C(O)-R12; R11 is independently H, alkyl, aryl or aralkyl; and when R9 and R11 are taken together, they can equal a five, six or seven membered ring of the type:
33where n=0-3 and m=0-1; and R12 is alkyl, aryl or aralkyl; R7=H, CH2F, CHR13O(CO)0-1-aryl, CHR13OP(O)(R14)R15,
34wherein: R13=H or alkyl; R14=H, alkyl or aryl; R15 H, alkyl or aryl; R16=H, alkyl, aryl or aralkyl; R17=H, alkyl, CF3, CF2CF3, aryl, aralkyl, COOR11, or CONR9R11; R18=H, alkyl, CF3, CF2CF3, aryl or aralkyl; R1 is defined as:
R19-R2, R19-R20, R19-R21, or R19-NR9R11; where R19=(CR3R4)-0-4;
35R22O- where R22 is alkyl, aryl or aralkyl; wherein R23=(CR3R4)-2-4; R9R11N- or R24R11N-; where R24=R19-cycloalkyl, R19-R21, R23-R10, R23-R20, CR3R4COOR11 or CR3CR4CONR9R11.
- 4. The compound according to claim 1 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, 6dichlorobenzoyloxymethyl ketone; N-[2-(5- thiomethylbenzoylamino-6-oxo-2-(4-fluorophenyl)-1, 6-dihyro-1 -pyrimidinyl)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- 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-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-pyrimidinyl)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-pyrimidinyl)acetoyl]-L-aspartic acid 5-(1-(2-pyridinyl)-3- trifluoromethyl)pyrazoloxymethyl ketone; N-[2-(5-benzyloxycarbonylamino-6-oxo-2-(2- thienyl)-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-pyrimidinyl)acetoyl]-L-aspartic acid aldehyde.
- 5. The pharmaceutical composition of claim 3 wherein said compound is 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-thiomethylbenzoylamino-6-oxo-2-(4- fluorophenyl)-1, 6-dihyro-1-pyrimidinyl)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)acetoyi]-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- 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-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-pyrimidinyl)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-pyrimidinyl)acetoyl]-L-aspartic acid 5-(1-(2-pyridinyl)-3- trifluoromethyl)pyrazoloxymethyl ketone; N-[2-(5-benzyloxycarbonylamino-6-oxo-2-(2- thienyl)-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- thienyi)-1, 6-dihydro-1-pyrimidinyl)acetoyl]-L-aspartic acid aidehyde.
- 6. The method of claim 5 wherein said compound is 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- thiomethylbenzoylamino-6-oxo-2-(4-fluorophenyl)-1, 6-dihyro-1-pyrimidinyl)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- trifluoromethyl)pyrazoloxymethyl ketone; N-[2-(5-isopropyloxycarbony-lamino-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-pyrimidinyl)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-benzyloxycarbonyl-amino-6-oxo-2- (2-thienyl)-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)-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-benzyloxycarbonylamino-6-oxo-2-(2- thienyl)-1, 6-dihydro-1-pyrimidinyl)acetoyl]-L-aspartic acid aldehyde.
Parent Case Info
[0001] This application is a continuation-in-part of application Ser. No. 08/221,712, filed Mar. 31, 1994.
Divisions (1)
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Number |
Date |
Country |
Parent |
08877380 |
Jun 1997 |
US |
Child |
09740623 |
Dec 2000 |
US |
Continuations (1)
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Number |
Date |
Country |
Parent |
08559870 |
Nov 1995 |
US |
Child |
08877380 |
Jun 1997 |
US |
Continuation in Parts (1)
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Number |
Date |
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Parent |
08221712 |
Mar 1994 |
US |
Child |
08559870 |
Nov 1995 |
US |