| 摘要 |
<p>1-Aminotetrahydronaphthalene derivatives (I) are new. 1-Amino-tetrahydronaphthalene derivatives of formula (I) are new. [Image] R 1, R 2 : H, hydroxy, halo, 1-10C alkyl or alkoxy (both optionally substituted), 1-10C alkylthio, 1-5C perfluoroalkyl, cyano, nitro or NR 8R 9; or R 1+R 2 on adjacent ring atoms : O(CH 2) n-O, O(CH 2) n-CH 2, O-CH=CH, (CH 2) n+2, NH(CH 2) n+1, N(1-3C alkyl)(CH 2) n+1 or NH-N=CH; n : 1 or 2; R 8, R 9 : H, 1-5C alkyl or 1-5C alkylcarbonyl; R 3 : 1-10C alkyl (optionally substituted by 1-3 hydroxy, halo or 1-5C alkoxy), 3-7C cycloalkyl, heterocyclyl or aryl (all optionally substituted) or mono- or bi-cyclic heteroaryl containing 1-4 N, 1-2 O, 1-2 S and/or 1-2 keto groups and/or optionally substituted by one or more 1-5C alkyl (optionally substituted by 1-3 hydroxy or C(O)OR 13), 1-5C alkoxy, halo, hydroxy, NR 8R 9, exo-methylene or oxygen, and these groups are linked to tetrahydronaphthyl through any appropriate position and/or hydrogenated at one or more positions; R 4 : OH, OR 10 or OC(O)R 10; R 10 : 1-10C alkyl or hydroxy protecting group; R 11 : H, OH, halogen, CN, optionally substituted 1-10C alkyl, 1-10C alkoxy, 1-10C alkylthio or 1-5C perfluoroalkyl; R 12 : H, OH, halogen, CN, optionally substituted 1-10C alkyl or 1-10C alkoxy; R 13 : H or 1-5C alkyl; R 5 : 1-10C alkyl (optionally partly or fully fluorinated), 3-7C cycloalkyl (optionally substituted by 1-8C alkyl or 2-8C alkenyl), heterocyclyl (optionally substituted by 1-8C alkyl or 2-8C alkenyl), aryl (optionally substituted by 1-8C alkyl, 2-8C alkenyl or 2-8C alkynyl), mono- or bi-cyclic heteroaryl (containing 1-3 N, 1-2 O and/or 1-2 S and/or optionally substituted by 1-2 keto, 1-5C alkyl or alkoxy, exomethylene or 1-3 halo) or heteroaryl substituted by 1-8C alkyl, 2-8C alkenyl or 2-8C alkynyl, and these groups are linked to tetrahydronaphthyl through any appropriate position and may be hydrogenated at one or more positions; R 6, R 7 : H, methyl or ethyl; or CR 6R 7 : 3-6C spirocycloalkyl ring. Independent claims are also included for: (1) stereoisomers of (I), provided that at least three of R 1, R 2, R 11 and R 12 are not H; (2) stereoisomers of formula (II); and (3) method for preparing (I) by cyclization of imine (III), optionally with addition of (in)organic or Lewis acids. [Image] R 1a, R 2a : H, hydroxy, halo, 1-10C alkyl or alkoxy, 1-10C alkylthio, 1-5C perfluoroalkyl, cyano, nitro or NR 8R 9; or R 1a+R 2a on adjacent C : O(CH 2) n-O, O(CH 2) n-CH 2, OCH=CH or (CH 2) n+2; R 3a : 1-10C alkyl (optionally substituted by 1-3 hydroxy or halo), phenyl (optionally substituted) or mono- or bi-cyclic heteroaryl, containing 1-3 N, 1-2 O, and /or 1-2 S and optionally substituted by 1-2 keto, 1-5C alkyl or alkoxy, exo-methylene or by 1-3 halo, linked to tetrahydronaphthyl through any appropriate position and optionally hydrogenated at one or more positions; R 4a : hydroxy; R 5a : 1-5C alkyl (optionally partly or fully fluorinated), 3-7C cycloalkyl or aryl (both optionally substituted by 1-8C alkyl or 2-8C alkenyl). ACTIVITY : Antiinflammatory; Antiallergic; Antirheumatic; Immunosuppressive; Dermatological; Vasotropic; Antipsoriatic; Cytostatic; Neuroprotective; Gastrointestinal; Antiulcer; Nephrotropic; Hepatotropic; Ophthalmological; Cerebroprotective; Antianemic; Antithyroid; Thyromimetic; Antibacterial; Analgesic. No details of tests for these activities are given. MECHANISM OF ACTION : (I) bind to the glucocorticoid receptors (GR), so inhibit GR-mediated transcription of cytokines, adhesion molecules, enzymes and other proinflammatory factors. 7-Fluoro-1-[(1H-indazol-4-yl)amino]-4,4-dimethyl-2-trifluoromethyl-1,2,3,4-tetrahydronaphthalene-2,5-diol showed IC 50 for GR of 95 nM and for the progesterone receptor 460 nM.</p> |
