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US 2004/0023945 A1Published application
Cyclic amp-specific phosphodiesterase inhibitors
AssigneeICOS Corporation
InventorsTimothy J. Martins, Kerry W. Fowler, Joshua Odingo, Edward A. Kesicki, Amy Oliver, Laurence E. Burgess, John J. Gaudino, Zachary S. Jones, Bradley J. Newhouse, Stephen T. Schlachter
Life of this patent
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Abstract
Novel pyrrolidine compounds that are potent and selective inhibitors of PDE4, as well as methods of making the same, are disclosed. Use of the compounds in the treatment of inflammatory diseases and other diseases involving elevated levels of cytokines, as well as central nervous system (CNS) disorders, also is disclosed.
Claims46
A compound having a formula:
- 308
- wherein R1 is selected from the group consisting of hydrogen, lower alkyl, bridged alkyl, aryl, cycloalkyl, a 4-, 5-, or 6-membered saturated heterocycle, heteroaryl, C1-4alkylenearyl, C1-4alkyleneOaryl, C1-4alkyleneheteroaryl, C1-4alkyleneHet, C2-4alkylenearylOaryl, C1-4alkylene bridged alkyl, C1-4alkylenecycloalkyl, substituted or unsubstituted propargyl, substituted or unsubstituted allyl, and halocycloalkyl;
- R2 is selected from the group consisting of hydrogen, methyl, and halo-substituted methyl, e.g., CHF2;
- R3 is selected from the group consisting of C(═O)OR7, C(═O)R7, NHC(═O)OR7, C1-3alkyleneC(═O)OR8, C1-3alkyleneC(═O)R8, C(═NH)NR8R9, C(═O)NR8R9, C(═O)—C(═O)NR8R9, C(═O)C(═O)OR8, C1-4alkyleneOR8, aryl, C1-3alkylenearyl, C1-4alkyleneheteroaryl, SO2heteroaryl, Het, and heteroaryl;
- R4 is selected from the group consisting of hydrogen, lower alkyl, haloalkyl, cycloalkyl, and aryl;
- R5 is selected from the group consisting of hydrogen, lower alkyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, and aryl;
- R6 is selected from the group consisting of hydrogen, lower alkyl, and C(═O)R7;
- R7 is selected from the group consisting of lower alkyl, branched or unbranched, C1-4alkylenearyl, cycloalkyl, Het, C1-4alkylenecycloalkyl, heteroaryl, and aryl, each optionally substituted with one or more of OC(═O)R8, C(═O)OR8, OR8, NR8R9, or SR8;
- R8 and R9, same or different, are selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, C(═O)Oalkyl, C(═O)—Oaryl, C(═O)alkyl, alkylSO2, haloalkylSO2, C(═O)—C1-3alkylenearyl, C(═O)OC1-4alkylenearyl, C1-4alkylenearyl, and Het, or R8 and R9 together form a 4-membered to 7-membered ring;
- R10 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, C(═O)alkyl, C(═O)cycloalkyl, C(═O)aryl, C(═O)Oalkyl, C(═O)Ocycloalkyl, C(═O)aryl, CH2OH, CH2Oalkyl, CHO, CN, NO2, and SO2R11;
- R11 is selected from the group consisting of alkyl, cycloalkyl, trifluoromethyl, aryl, aralkyl, and NR8R9;
- and
- salts and solvates thereof.
10 more elements
A compound having a formula:
- 324
- wherein R1 is selected from the group consisting of hydrogen, lower alkyl, bridged alkyl, aryl, cycloalkyl, a 4-, 5-, or 6-membered saturated heterocycle, heteroaryl, C1-4alkylenearyl, C1-4alkyleneOaryl, C1-4alkyleneheteroaryl, C1-4alkyleneHet, C2-4alkylenearylOaryl, C1-4alkylene bridged alkyl, C1-4alkylenecycloalkyl, substituted or unsubstituted propargyl, substituted or unsubstituted allyl, and halocycloalkyl;
- R2 is selected from the group consisting of hydrogen, methyl, and halo-substituted methyl;
- R3 is selected from the group consisting of hydrogen, C1-4alkylenearyl, and C(═O)C1-3alkyleneOC1-3-alkylenearyl;
- R4 is selected from the group consisting of hydrogen, lower alkyl, haloalkyl, cycloalkyl, and aryl;
- R5 is selected from the group consisting of hydrogen, lower alkyl, alkynyl, haloalkyl, hydroxyalkyl, cycloalkyl, and aryl;
- R6 is selected from the group consisting of hydrogen, lower alkyl, and C(═O)R7;
- R7 is selected from the group consisting of lower alkyl, branched or unbranched, C1-4alkylenearyl, cycloalkyl, Het, C1-4alkylenecycloalkyl, heteroaryl, and aryl, each optionally substituted with one or more of OC(═O)R8, C(═O)OR8, OR8, NR8R9, and SR8;
- and
- R8 and R9, same or different, are selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, C(═O)Oalkyl, C(═O)alkyl, C(═O)Oaryl, alkylSO2, haloalkylSO2, C(═O)C1-3alkylenearyl, C(═O)OC1-4alkylenearyl, C1-4alkylenearyl, and Het, or R8 and R9 together form a 4-membered to 7-membered ring;
- R10 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl, aryl, C(═O)alkyl, C(═O)cycloalkyl, C(═O)aryl, C(═O)Oalkyl, C(═O)Ocycloalkyl, C(═O)aryl, CH2OH, CH2Oalkyl, CHO, CN, NO2, and SO2R11;
- and
- R11 is selected from the group consisting of alkyl, cycloalkyl, trifluoromethyl, aryl, aralkyl, and NR8R9;
- and
- salts and solvates thereof.
12 more elements
Dependencies are inferred from the claim text.