Derivatives of 1-phenyl-2-pyridinyl alkyl alcohols as phosphodiesterase inhibitors

摘要

Compounds, pyridine N-oxides, and pharmaceutically acceptable salts of formula (I) are useful as inhibitors of the phosphodiesterase 4 (PDE4) enzyme and for preventing and/or treating diseases of the respiratory tract characterized by airway obstruction, such as asthma or COPD.

主权项

1. A compound of formula (I): wherein: R1 and R2, which can be the same or different, are each independently:
(C1-C6) alkyl, optionally substituted by (C3-C7) cycloalkyl;(C1-C6) haloalkyl;(C3-C7) cycloalkyl; or(C3-C7) heterocycloalkyl; R3 is hydrogen, (C1-C6) alkyl, or (C1-C3) alkylthio(C1-C6) alkyl; A is a partially unsaturated or unsaturated bicyclic ring system consisting of two fused monocyclic ring systems B and C as represented below: wherein ring B contains a nitrogen atom which represents the point of attachment for ring A to the rest of the molecule through a —(CHR3)— group and wherein ring B and C may optionally contain further heteroatoms; p is an integer from zero to 3; Y is an oxo group; n is an integer from zero to 3; K is:
(C1-C6) alkyl, optionally substituted by one or more (C3-C7) cycloalkyl groups;(C3-C7) heterocycloalkyl(C1-C4) alkyl;(C3-C7) heterocycloalkyl, optionally substituted by one or more (C1-C6) alkyl groups;(C1-C4) haloalkyl;a group —OR4 wherein R4 is:
H; or(C1-C10) alkyl, optionally substituted by (C3-C7) cycloalkyl or heteroaryl;halogen;—CN;—NO2;NR5R6 wherein R5 and R6, which can be the same or different, are each independently:
H;a group —OH;NR7R8(C1-C4)alkyl wherein R7 and R8, which can be the same or different, are each independently: H; (C1-C6) alkyl, optionally substituted with (C1-C6) alkoxyl; or NR9R10(C1-C6)alkyl wherein R9 and R10, which can be the same or different, are H or (C1-C6) alkyl; or they form with the nitrogen atom to which they are linked a (C3-C7) heterocycloalkyl ring optionally substituted by (C1-C6)alkyl or a group (C1-C6) alkylcarbonyl;(C1-C6) alkyl, optionally substituted by (C1-C6) alkoxyl or heteroaryl, (C3-C7) heterocycloalkylcarbonyl, heteroarylcarbonyl, all of them being optionally further substituted by one or more groups (C1-C6) alkyl, (C1-C6) haloalkyl or (C1-C6) alkoxyl, which may be the same or different and are independently selected;a group —SO2R11, wherein R11 is (C1-C6) alkyl; ora group —C(O)R12, wherein R12 is (C1-C6) alkyl optionally substituted by (C1-C6) alkoxyl;NR13R14(C1-C4)alkyl; wherein R13 and R14, which can be the same or different, are each independently: —SO2(C1-C6) alkyl, H, (C1-C6) alkyl, or (C3-C7)heterocycloalkyl(C1-C4) alkyl; or—SO2NR15R16, wherein R15 and R16, which can be the same or different, are each independently H or (C1-C6) alkyl;wherein groups R4 to R16 may have the same or different meanings at each occurrence, if present in more than one group;or a pyridine N-oxide or a pharmaceutically acceptable salt thereof;and wherein the compound of formula (I) is not 3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetoxy)ethyl)pyridine or the pyridine N-oxide thereof.