Patent EA-003528-B1 (EA)
Title: Nicotinamide derivatives, use thereof, pharmaceutical composition, method of treatment and method for selective inhibition of pde4 d isoenzymes
Inventor: MARFAT ANTHONY
IPC: C07D213/82
Filed: 1998-03-10
Abstract: 1. A compound of the formula (I) or the pharmaceutically acceptable salt thereof, wherein: t is 0 or 1; A is oxygen or NH; R<1> is (C3-C6)cycloalkyl, (C6-C10)aryl or saturated or unsaturated cyclic or bicyclic (C3-C7)heterocyclic group containing from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR<9>, wherein R<9> is hydrogen or (C1-C6)alkyl; wherein said cycloalkyl, cycloalkenyl, cycloalkanone, aryl, bicycloalkyl and heterocyclic groups are optionally substituted by one to three substituents independently selected from the substituents consisting of halo, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino or hydroxy(C1-C6)alkylamino; R<2> is hydrogen or (C1-C6)alkyl; R<5> is a group of the formula wherein R<11>, R<12>, R<13>, R<14> and R<15> are each substituents independently selected from the group consisting of hydrogen, halo, cyano, carboxy, amino, nitro, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, hydroxy(C1-C6)alkyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino; wherein the alkyl, alkoxy or cycloalkyl groups of said R<11>, R<12>, R<13>, R<14> and R<15> groups are optionally substituted by one to three substituents independently selected from halo, cyano, nitro, trifluoromethyl and trifluoromethoxy; or R<12> and R<13> can be taken together with the carbon atoms to which they are attached to form a group of the formula wherein u is 0 or 1; and G, J, K and L are each independently oxygen, sulfur, nitrogen and NR<9>, wherein R<9> is as defined above, carbonyl or CHR<16>, wherein R<16> is hydrogen, carboxy or (C1-C6)alkyl; 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 R<9> is absent, >CHR<16> is >CR<16> and G, J, K or L cannot be carbonyl; R<6>, R<7>, and R<8> are each independently selected from the group consisting of hydrogen, halo, nitro, trifluoromethyl and trifluoromethoxy; with the proviso that when A is oxygen, R<2> is hydrogen, R<1> is phenyl substituted by methyl, methoxy, chloro or fluoro; and R<5> is phenyl optionally substituted by one or two fluoro or chloro; then R<1> must be at least di - substituted by at least one substituent other than methyl, methoxy or halo; with the proviso that when t is one that the compound of formula (I) is a zwitterionic N-oxide, with the proviso that adjacent positions defined by G, J, K and L cannot both be defined by oxygen; and with the proviso that when A is oxygen; R<2>, R<6>, R<7> and R<8> are hydrogen and R<1> is phenyl optionally substituted by one or two substituents selected from (C1-C4)alkyl, (C1-C4)alkoxy and halo, then R<5> is not a group of the formula wherein R<11>, R<12>, R<13>, R<14> and R<15> are hydrogen, and R<14> is selected from halo and trifluoromethyl. 2. The compound according to claim 1, wherein R<2> is hydrogen; R<1> is (C6-C10)aryl optionally substituted by halo, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino or hydroxy(C1-C6)alkylamino. 3. The compound according to claim 2, wherein R<1> is (C6-C10)aryl optionally substituted by hydroxy(C1-C6)alkyl. 4. The compound according to claim 1, wherein A is oxygen; R<2> is hydrogen; R<1> is (C6-C10)aryl optionally substituted by hydroxy(C1-C6)alkyl. 5. Use the compound of the formula (I) or the pharmaceutically acceptable salt thereof, wherein: t is 0 or 1; A is oxygen or NH; R<1> is (C3-C6)cycloalkyl, (C6-C10)aryl or saturated or unsaturated cyclic or bicyclic (C3-C7)heterocyclic group containing from one to four heteroatoms independently selected from the group consisting of oxygen, sulfur, nitrogen and NR<9>, wherein R<9> is hydrogen or (C1-C6)alkyl; wherein said cycloalkyl, cycloalkenyl, cycloalkanone, aryl, bicycloalkyl and heterocyclic groups are optionally substituted by one to three substituents independently selected from the substituents consisting of halo, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino or hydroxy(C1-C6)alkylamino; R<2> is hydrogen or (C1-C6)alkyl; R<5> is a group of the formula wherein R<11>, R<12>, R<13>, R<14> and R<15> are each substituents independently selected from the group consisting of hydrogen, halo, cyano, carboxy, amino, nitro, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, hydroxy(C1-C6)alkyl, difluoromethyl, trifluoromethyl, difluoromethoxy, trifluoromethoxy, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino; wherein the alkyl, alkoxy or cycloalkyl groups of said R<11>, R<12>, R<13>, R<14> and R<15> groups are optionally substituted by one to three substituents independently selected from halo, cyano, nitro, trifluoromethyl and trifluoromethoxy; or R<12> and R<13> can be taken together with the carbon atoms to which they are attached to form a group of the formula wherein u is 0 or 1; and G, J, K and L are each independently oxygen, sulfur, nitrogen and NR<9>, wherein R<9> is as defined above, carbonyl or CHR<16>, wherein R<16> is hydrogen, carboxy or (C1-C6)alkyl; 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 R<9> is absent, >CHR<16> is >CR<16> and G, J, K or L cannot be carbonyl; R<6>, R<7>, and R<8> are each independently selected from the group consisting of hydrogen, halo, nitro, trifluoromethyl and trifluoromethoxy; with the proviso that when A is oxygen, R<2> is hydrogen, R<1> is phenyl substituted by methyl, methoxy, chloro or fluoro; and R<5> is phenyl optionally substituted by one or two fluoro or chloro; then R<1> must be at least di - substituted by at least one substituent other than methyl, methoxy or halo; with the proviso that when t is one that the compound of formula (I) is a zwitterionic N-oxide, with the proviso that adjacent positions defined by G, J, K and L cannot both be defined by oxygen; as a medicament for the treatment of respiratory, allergic, rheumatoid, body weight regulation and inflammatory disorders. 6. A pharmaceutical composition for the treatment of respiratory, allergic, rheumatoid, body weight regulation and inflammatory 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 in a mammal including a human, comprising an amount of the compound of the formula (I) wherein the radical values are as defined in claim 5, or a pharmaceutically acceptable salt thereof, effective in such preventions or treatment and a pharmaceutically acceptable carrier. 7. A method for the treatment of respiratory, allergic, rheumatoid, body weight regulation and inflammatory 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 in a mammal, including a human, comprising administering to said mammal an amount of the compound of the formula (I) wherein the radical values are as defined in claim 5 or a pharmaceutically acceptable salt thereof, effective in such treatment. 8. A pharmaceutical composition for selective inhibition of PDE4 D isozymes which regulate the activation and degranulation of human eosinophils 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, in a mammal, including a human, comprising an effective amount of a PDE4 D isozyme inhibiting compound of the formula (I) wherein the radical values are as defined in claim 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 9. A method for selective inhibition of PDE4 D isozymes which regulate the activation and degranulation of human eosinophils 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 in a mammal, including a human, comprising administering to said mammal a PDE4 D isozyme inhibiting effective amount of a compound of the formula (I) wherein the radical values are as defined in claim 5 or a pharmaceutically acceptable salt thereof.