Treating or preventing diabetes or diabetic complications, using kynurenine 3-hydroxylase inhibitors, preferably thiazole derivatives or new or known keto-acid compounds

摘要

The use of kynurenine 3-hydroxylase inhibitor(s) (I) is claimed in the production of medicaments for prevention and/or treatment of diabetes and diabetic complications. (I) include new thio-substituted 4-oxo-butanoic acid derivatives (I'). Independent claims are included for: (1) new ketoacid compounds of formula (I') (including their geometric and/or optical isomers, tautomers, solvates, hydrates, acid or base addition salts or prodrugs); (2) the production of medicaments for treatment and/or prevention of diabetes, diabetic complications and/or associated disorders by increasing the number of islet of Langerhans cells, comprising screening test compounds for kynurenine 3-hydroxylase inhibiting activity in vitro and preparing pharmaceutical compositions containing compounds showing positive results in the test; and (3) the above screening procedure. R1 = optionally substituted (os) 1-14C alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; R2 = H, halo, OH, SH, COOH, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; R3 = H, halo, OH, SH, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, aryl, heteroaryl, cycloalkyl or heterocyclyl; or R2 + R3 = =C(R16)(R17) or group completing a cycloalkyl or heterocyclyl ring; R4 = OH, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, NR12R121, N(R12)OR13, os 1-14C alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl; R12, R121 = H, alkyl, alkenyl, alkynyl, alkylcarbonyl, aryl or heteroaryl; or NR12R121 = 5-10 membered mono- or bicyclic heterocycle, containing 1-4 of N, O or S, optionally containing 1-4 double bonds and os by one or more of OH, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, heterocyclyl, aryl, heteroaryl or CF3; R13 = H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, NR12R121 or N(R12)OR13; R14 = H, halo, OH, SH, COOH, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylcarbonyl, alkoxycarbonyl, aryl, aralkyl, heteroaryl, cycloalkyl or heterocyclyl; or R14 + R2 = additional C-C bond or group forming a 3-7 membered ring (optionally containing 1-3 N, O or S heteroatoms, optionally containing one or more double bonds and os by one or more of =O, alkoxy, alkoxycarbonyl or alkylcarbonyloxy); R151 = SH, alkylthio, alkenylthio, alkynylthio, arylthio, cycloalkylthio, heteroarylthio or heterocyclylthio; R16, R17 = H, halo, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl; or CR16R17 = cycloalkyl or heterocyclyl ring; provided that if R2-R4 = H, then R151 is other than SH or alkylthio.