New tetrahydroquinoxaline urea derivatives are 11 beta-hydroxysteroid dehydrogenase type 1 modulators useful to treat/prevent e.g. obesity, diabetes, insulin resistance, metabolic syndrome, glaucoma, Cushing's syndrome and hypertension

摘要

Tetrahydroquinoxaline urea derivatives (I) and their acid or base addition salts, hydrates or solvates are new. Tetrahydroquinoxaline urea derivatives of formula (I) and their acid or base addition salts, hydrates or solvates are new. A : a bond, O or -O-CH 2-; Ar 1phenyl or heteroaryl; Ar 2phenyl, heteroaryl or heterocycloalkyl; R1a-R1c, R2a-R2c : H or halo, alkyl, -OR 5, hydroxy-alkyl, alkoxy-alkyl, alkoxy-alkoxy, haloalkyl, -O-haloalkyl, oxo, -CO-alkyl, -CO-haloalkyl, -COOR 5, alkyl-COOR 5, -O-alkyl-COOR 5, -SO 2-alkyl, -SO 2-haloalkyl, alkyl-SO 2-alkyl, -SO 2-NR 6R 7, -CONR 6R 7, -alkyl-CONR 6R 7or -O-alkyl-NR 6R 7; R 3H or alkyl; R 4H, halo, CN, -OR 5, hydroxy-alkyl, -COOR 5, -NR 6R 7, -CONR 6R 7, -SO 2-alkyl or -SO 2-NR 6R 7; R 5-R 7H or alkyl; R 8H or -B 1-Het; B 1absent or a bond, O, -CO- or -SO 2-; and Het : heterocycloalkyl (optionally substituted by 1-3 groups of alkyl, -SO 2-alkyl or -COOR 5). Independent claims are included for: (1) the preparations of (I); (2) a substituted tetrahydroquinoxaline compound of formulae (II) and (IV); and (3) adamantanamine substituted tetrahydroquinoxaline compound of formula (XXVII). Lg, V1 : leaving group. [Image] [Image] [Image] ACTIVITY : Anorectic; Antidiabetic; Analgesic; Antianginal; Endocrine-Gen.; Hypotensive; Antiarteriosclerotic; Nootropic; Ophthalmological; Osteopathic; Antimicrobial. MECHANISM OF ACTION : 11beta -Hydroxysteroid dehydrogenase type 1 modulator. The ability of (I) to inhibit 11beta -hydroxysteroid dehydrogenase type 1 enzyme was tested using scintillation proximity assay. The result showed that trans-4-[4-(4-methanesulfonyl-piperazin-1-yl)-phenyl]-3,4-dihydro-2H-quinoxaline-1-carboxylic acid (5-hydroxy-adamantan-2-yl)-amide exhibited an IC 5 0value of 0.052 mu M.