Nicotinamide derivatives for selective inhibition of phosphodiesterase type 4 (PDE4) and the production of tumour necrosis factor (TNF) useful for the treatment of respiratory, rheumatoid and allergic diseases

摘要

A compound of Formula (I) useful in the treatment of respiratory, allergic, rheumatoid, body weight regulation, inflammatory and central nervous system disorders such as asthma, chronic obstructive pulmonary disease, adult respiratory diseases syndrome, shock, fibrosis, pulmonary hypersensitivity, allergic rhinitis, atopic dermatitis, psoriasis, weight control, rheumatoid arthritis, cachexia, crohn's disease, ulcerative colitis, arthritic conditions and other inflammatory diseases, depression, multi-infarct dementia and AIDS. Wherein; The broken line represents an optional double bond; m is 0 or 1; n is 0 or 1; o is 0, 1, 2, 3 or 4; p is 0 or 1; q is 0, 1, 2 or 3; r is 0, 1, 2, 3, or 4; t is 0 or 1; A is oxygen, NH or sulfur; B is oxygen or NH; D is oxygen or NR9, wherein R9 is hydrogen or C1-6alkyl; E is CH2, O, NH or S(O)a wherein a is 0, 1 or 2; R1 is hydrogen, C1-6alkyl, C3-7cycloalkyl, C3-7cycloalkenyl, C6-10aryl, bridgedC7-9bicycloalkyl or a saturated or unsaturated cyclic or bicyclicC3-7heterocyclic group; or R1 cycloalkyl, cycloalkenyl, aryl, bicycloalkyl and heterocyclic groups are additionally optionally independently substituted with from one to three substituents of the Formula (II) wherein R10 is hydrogen, C1-6alkyl, C1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkenyl, C6-10arylamino, C6-10aryl, bridgedC7-9bicycloalkyl or a saturated or unsaturated cyclic or bicyclic C3-7heterocycle; wherein R10 saturated or unsaturated cyclic or bicyclicC3-7heterocycle contains from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR9, or R1 is a group of the Formula (III), wherein u is 0 or 1; and G, J, K and L are each independently oxygen, sulfur, nitrogen, NR9, carbonyl or CHR16; wherein the dashed lines represent optional double bonds and where it is understood that when a double bond exists between G and J, J and K or K and L that R9 is absent, CHR16 is CR16 and G, J, K or L cannot be carbonyl; wherein R16 is hydrogen, halo, cyano, carboxy, amino, nitro, hydroxy, C1-6alkylC1-6alkoxy, C3-7cycloalkyl, hydroxyC1-6alkyl, hydroxyC1-6alkylamino, C1-6alkoxy, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, C1-6acyl, C1-6acylamino, C1-6acyloxy, C1-6alkylamino, C1-6alkyl)amino, aminosulfonyl, C1-6alkylaminosulfonyl, or a saturated or unsaturated cyclic or bicyclic C3-7heterocycle containing one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR9.