Patent DE-102005018025-A1 (DE)
Title: New heterocyclic compounds which are cytokine interleukin-8 inhibitors useful for treating e.g., chronic obstructive lung disease, bronchitis, rheumatoid arthritis, psoriasis, gastrointestinal disease and Crohn's disease
Inventor: MENGEL ANNE
IPC: C07D311/68
Filed: 2005-04-14
Abstract: Heterocyclic compounds (I) and their stereoisomers and/or salts, are new. Heterocyclic compounds of formula (I) and their stereoisomers and/or salts, are new. Either R1>,R2>H, OH, halo, optionally substituted 1-10C alkyl, 1-10C alkoxy, 1-10C alkylthio, 1-5C perfluoroalkyl, CN, NO2 or NR9>R-9a; or R1>+R2>-O-(CH2)n-O, -O(CH2)n-CH2, -O-CH=CH, -(CH2)n+2-, -NH(CH2)n+1-, -N(1-3C alkyl)-(CH2)n+1- or -NH-N=CH- (where the final constant O, C or N is linked directly with the neighbouring carbon atoms of the ring); R11>H,OH, halo, CN, optionally substituted 1-10C alkyl, 1-10C alkoxy, 1-10C alkylthio or 1-5C perfluoroalkyl; R12>H, OH, halo, CN, optionally substituted 1-10C alkyl or 1-10C alkoxy; R3>1-10C alkyl (optionally substituted by 1-3 OH, 1-3 halo or 1-3 1-5C alkoxy), 3-7C cycloalkyl, heterocyclyl, aryl (all optionally substituted by 1-5C alkyl (optionally substituted by 1-3 OH or 1-3 COOR13>)), 1-5C alkoxy, halo, OH, NR9>R-9a or exomethylene (optionally substituted by 1-4N, 1-2O, 1-2S or 1-2 keto containing mono or bicyclic group of hetero aryl), where the groups at any position with the group X to be linked is optionally hydrogenated; R4>OH, -OR10>- or -O(CO)R10>-; R5>1-10C alkyl (optionally partially or completely fluorinated), 3-7C cycloalkyl, 1-8C alkyl-(3-7C) cycloalkyl, 2-8C alkenyl-(3-7C) cycloalkyl, heterocyclyl, 1-8C alkylheterocyclyl, 2-8C alkenylheterocyclyl, aryl, 1-8C alkyl aryl, 2-8C alkenylaryl, 2-8C alkynylaryl (optionally substituted by 1-2 keto, 1-2 1-5C alkyl, 1-2 1-5C alkoxy, 1-3 halo, 1-2 exomethylene, 1-3N or 1-2 O or 1-2S containing mono or bicyclic group of hetero aryl), 1-8C alkyl heteroaryl, 2-8C alkenyl heteroaryl or 2-8C alkynylheteroaryl, where the groups at any position with the tetrahydronaphthaline system is optionally hydrogenated; R6>H, halo or optionally substituted 1-10C alkyl; R9>, R-9a : H, 1-5C alkyl or -(CO)-1-5C alkyl; R10>1-10C alkyl or hydroxy protecting group; R13>H or 1-5C alkyl; X : a bond, -C(=O), -C(=S), -C(=O)-NH, -C(=S)-NH, -S(O)m, -C(=O)-O, -C(=S)-O or -(CH2)p; Y1>O, S(O)q or NR13>; p : 1-3; m, n : 1-2; and q : 0-2. When X contains a carbonyl- or thiocarbonyl function, the function is bound at the group -NH- in (I). Independent claims are included for: (1) the preparation of (I); and (2) a heterocyclic-amide compound of formula (II). [Image] [Image] ACTIVITY : Antiinflammatory; Respiratory-Gen.; Antiallergic; Antiarthritic; Antirheumatic; Antipsoriatic; Nephrotropic; Hepatotropic; Gastrointestinal-Gen.; Antiulcer; Ophthalmological; Neuroprotective; Vasotropic; Cytostatic; Endocrine-Gen.; Antithyroid; Antiemetic; Analgesic; Gynecological. MECHANISM OF ACTION : Cytokine interleukin-8 inhibitor. The ability of (I) to inhibit cytokine interleukin-8 was tested. The results showed that 8-methoxy-4-[(pyrazolo[1,5-a]pyridin-3-ylmethyl)-amino]-3-trifluoromethyl-chroman-3-ol exhibited an IC50 value of 15 nM.