Patent EP-2058308-A1 (EP)
Inventor: BOTTON GERARD
IPC: C07D417/04
Filed: 2007-11-12
Abstract: Benzimidazoledihydrothiadiazinone derivatives (I) and their crystalline forms, tautomers, enantiomers, diastereoisomers, epimers and/or salts, are new. Benzimidazoledihydrothiadiazinone derivatives of formula (I) and their crystalline forms, tautomers, enantiomers, diastereoisomers, epimers and/or salts, are new. R 1alkyl, alkoxyalkyl, alkenyl, alkynyl (all optionally substituted by Y 1), aryl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, arylthioalkyl, arylalkylthioalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylalkyloxyalkyl, heteroarylthioalkyl, heteroarylalkylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, cycloalkylthioalkyl, cycloalkylalkylthioalkyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxyalkyl, heterocycloalkylalkyloxyalkyl, heterocycloalkylthioalkyl, heterocycloalkylalkylthioalkyl or A-B 1group comprising two cycles A and B 1linked by a bond (where each of the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is optionally substituted by Y 1); A, B 1aryl, heteroaryl, cycloalkyl or heterocycloalkyl (all optionally substituted by Y 1); R 2, R 3alkyl, alkoxyalkyl, alkenyl, alkynyl (all optionally substituted by Y 1), aryl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, arylthioalkyl, arylalkylthioalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylalkyloxyalkyl, heteroarylthioalkyl, heteroarylalkylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, cycloalkylthioalkyl, cycloalkylalkylthioalkyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxyalkyl, heterocycloalkylalkyloxyalkyl, heterocycloalkylthioalkyl, heterocycloalkylalkylthioalkyl (where each of the aryl, heteroaryl, cycloalkyl or heterocycloalkyl is optionally substituted by Y 1) or H; R 4, R 5H or W1; Y 1OH, thio, halo, trifluoromethoxy, trifluoromethyl, alkyloxy, carboxyl, alkoxycarbonyl, carbamoyl, sulfamoyl, nitro, guanidino, amidino, aryl, heteroarylimidazolone, amino or -C(=O)-R 8; R 8W 1or -S(=O) p-R 9; R 9W 1or -(CH 2) n-O-R 10; p : 0-2; n : 0-8; R 10H, W 1or -N(R 11)-C(=O)-N(R 12)-R 13; either R 11-R 13H, W 1or -N(R 11)-C(=O)-R 14; or R 12R 13optionally saturated 3-10 mono- or bicyclic system comprising 1-3 heteroatoms; R 14W 1or -N(R 11)-S(=O) p-R 15; R 15W 1or -N(R a1)(R b1); R a1, R b1H or W 1; and W 1alkyl, alkenyl, alkynyl, aryl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, arylthioalkyl, arylalkylthioalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylalkyloxyalkyl, heteroarylthioalkyl, heteroarylalkylthioalkyl, cycloalkyl, cycloalkylalkyl, cycloalkyloxyalkyl, cycloalkylalkyloxyalkyl, cycloalkylthioalkyl, cycloalkylalkylthioalkyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkyloxyalkyl, heterocycloalkylalkyloxyalkyl, heterocycloalkylthioalkyl or heterocycloalkylalkylthioalkyl (all optionally substituted by Y 1). An independent claim is included for the preparation of (I). [Image] ACTIVITY : Antidiabetic; Antilipemic; Anorectic; Hypotensive; Antiarteriosclerotic; Ophthalmological; Neuroprotective; Cardiant; Vasotropic; Nephrotropic. MECHANISM OF ACTION : Fructose-1,6-bisphosphatase inhibitor. The ability of (I) to inhibit fructose-1,6-bisphosphatase was tested in recombinant human liver enzyme. The results showed that 5-[2-(3-fluoro-phenyl)-1-methyl-1H-benzoimidazol-5-yl]-3-isopropyl-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one exhibited an IC 50value of mu M.