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US 6,486,186 B2Granted
Thiazole compounds as cyclic AMP-specific phosphodiesterase inhibitors and method of using the same
AssigneeICOS Corporation
InventorsKerry W. Fowler, Joshua Odingo
Life of this patent
Estimating the term…
Abstract
Novel 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.
Claims5
A method of inhibiting IL-1β release by monocytes in a mammal comprising administering to said mammal a therapeutically effective amount of a compound having a formula:
- wherein R1 is lower alkyl, bridged alkyl, aralkyl, cycloalkyl, a 5- or 6-membered saturated heterocycle, C1-3alkylenecycloalkyl, aryl- or heteroaryl-substituted propargyl, aryl- or heteroaryl-substituted allyl, or halocycloalkyl;
- R2 is hydrogen, methyl, or halo-substituted methyl;
- R3 is selected from the group consisting of C(═O)OR7, C(═O)R7, C(═NH)NR8R9, C(═O)NR8R9, lower alkyl, bridged alkyl, cycloalkyl, haloalkyl, halocycloalkyl, C1-3alkylenecycloalkyl, a substituted or unsubstituted 5- or 6-membered saturated heterocycle, aryl, heteroaryl, heteroarylSO2, aralkyl, alkaryl, heteroaralkyl, heteroalkaryl, C1-3alkyleneC(═O)OR7, C(═O)C1-3alkyleneC(═O)OR7, C1-3alkyleneheteroaryl, C(═O)C(═O)OR7, C(═O)C1-3alkyleneC(═O)OR7, C(═O)C1-3alkyleneNHC(═O)OR7, C(═O)C1-3alkyleneNH2, and NHC(═O)OR7;
- R4 is hydrogen, lower alkyl, haloalkyl, cycloalkyl, aryl, C(═O)R7, OR8, NR8R9, or SR8;
- R5 is hydrogen, lower alkyl, haloalkyl, cycloalkyl, or aryl;
- R7 is selected from the group consisting of cycloalkyl, branched or unbranched lower alkyl, heteroaryl, aryl, a substituted or unsubstituted heterocycle, and substituted or unsubstituted aralkyl, and R7 is optionally substituted with one or more of RO8, NR8R9, or SR8;
- and
- R8 and R9, same or different, are selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, alkaryl, heteroaralkyl, heteroalkaryl, and aralkyl, or R8 and R9 are taken together form a 4-membered to 7-membered ring;
- R10 is 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, or SO2R11;
- and
- R11 is alkyl, cycloalkyl, trifluoromethyl, aryl, aralkyl, or NR8R9.
8 more elements
A method of inhibiting activation of human T-lymphocytes in a mammal comprising administering to said mammal a therapeutically effective amount of a compound having a formula:
- wherein R1 is lower alkyl, bridged alkyl, aralkyl, cycloalkyl, a 5- or 6-membered saturated heterocycle, C1-3alkylenecycloalkyl, aryl- or heteroaryl-substituted propargyl, aryl- or heteroaryl-substituted allyl, or halocycloalkyl;
- R2 is hydrogen, methyl, or halo-substituted methyl;
- R3 is selected from the group consisting of C(═O)OR7, C(═O)R7, C(═NH)NR8R9, C(═O)NR8R9, lower alkyl, bridged alkyl, cycloalkyl, haloalkyl, halocycloalkyl, C1-3alkylenecycloalkyl, a substituted or unsubstituted 5- or 6-membered saturated heterocycle, aryl, heteroaryl, heteroarylSO2, aralkyl, alkaryl, heteroaralkyl, heteroalkaryl, C1-3 alkyleneC(═O)OR7, C(═O)C1-3alkyleneC(═O)OR7, C1-3alkyleneheteroaryl, C(═O)C(═O)OR7, C(═O)C1-3alkyleneC(═O)OR7, C(═O)C1-3alkyleneNHC(═O)OR7, C(═O)C1-3alkyleneNH2, and NHC(═O)OR7;
- R4 is hydrogen, lower alkyl, haloalkyl, cycloalkyl, aryl, C(═O)R7, OR8, NR8R9, or SR8;
- R5 is hydrogen, lower alkyl, haloalkyl, cycloalkyl, or aryl;
- R7 is selected from the group consisting of cycloalkyl, branched or unbranched lower alkyl, heteroaryl, aryl, a substituted or unsubstituted heterocycle, and substituted or unsubstituted aralkyl, and R7 is optionally substituted with one or more of RO8, NR8R9, or SR8;
- and
- R8 and R9, same or different, are selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, alkaryl, heteroaralkyl, heteroalkaryl, and aralkyl, or R8 and R9 are taken together form a 4-membered to 7-membered ring;
- R10 is 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, or SO2R11;
- and
- R11 is alkyl, cycloalkyl, trifluoromethyl, aryl, aralkyl, or NR8R9.
8 more elements
A pharmaceutical composition comprising
- (a) a compound having a formula
- wherein R1 is lower alkyl, bridged alkyl, aralkyl, cycloalkyl, a 5- or 6-membered saturated heterocycle, C1-3alkylenecycloalkyl, aryl- or heteroaryl-substituted propargyl, aryl- or heteroaryl-substituted allyl, or halocycloalkyl;
- R2 is hydrogen, methyl, or halo-substituted methyl;
- R3 is selected from the group consisting of C(═O)OR7, C(═O)R7, C(═NH)NR8R9, C(═O)NR8R9, lower alkyl, bridged alkyl, cycloalkyl, haloalkyl, halocycloalkyl, C1-3alkylenecycloalkyl, a substituted or unsubstituted 5- or 6-membered saturated heterocycle, aryl, heteroaryl, heteroarylSO2, aralkyl, alkaryl, heteroaralkyl, heteroalkaryl, C1-3 alkylenec(═O)OR7, C(═O)C1-3alkyleneC(═O)OR7, C1-3alkyleneheteroaryl, C(═O)C(═O)OR7, C(═O)C1-3alkyleneC(═O)OR7, C(═O)C1-3alkyleneNHC(═O)OR7, C(═O)C1-3alkyleneNH2, and NHC(═O)OR7;
- R4 is hydrogen, lower alkyl, haloalkyl, cycloalkyl, aryl, C(═O)R7, OR8, NR8R9, or SR8;
- R5 is hydrogen, lower alkyl, haloalkyl, cycloalkyl, or aryl;
- R7 is selected from the group consisting of cycloalkyl, branched or unbranched lower alkyl, heteroaryl, aryl, a substituted or unsubstituted heterocycle, and substituted or unsubstituted aralkyl, and R7 is optionally substituted with one or more of RO8, NR8R9, or SR8;
- and
- R8 and R9, same or different, are selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, alkaryl, heteroaralkyl, heteroalkaryl, and aralkyl, or R8 and R9 are taken together form a 4-membered to 7-membered ring;
- R10 is 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, or SO2R11;
- and
- R11 is alkyl, cycloalkyl, trifluoromethyl, aryl, aralkyl, or NR8R9;
- (b) a pharmaceutically acceptable carrier, and
- (c) a second therapeutic agent having utility in the treatment of rheumatoid arthritis.
11 more elements
Dependencies are inferred from the claim text.