Derivatives of 2H-pyridazin-3-ones, their preparation and their use as SCD-1 inhibitors.

Abstract

The invention is related to the prepn. of title compds. I [R1 = ≥1 groups selected from CF3, F, Cl, Br, NO2, etc.; X = (CH2)n; Z = (CH2)m; when n = m = 1, W = CH, then Y = O, CH2N(Me), NHCH2, or W = N, then Y = CO; when n = m = 0, W = CH, then Y = O, OCH2; when n = 1 and m = 0, W = CH, then Y = OCH2; U = COCH2O and can be attached at position (4) or (5) of the pyridazinone and R2 = H; or U = COCHR4NR5 in which R4 = R5 = H or independently of each other, can be H or Me, and if U is attached at position (4) of pyridazinone then R2 is at position (5) and represents H or OMe, and if U is attached at position (5) of pyridazinone then R2 = H; or U = CONH and can be branched at position (4) or (5) or (6) of pyridazinone and R2 = H; or U = COCONH, COCH=CH, COCH2CH2, and can be attached at position (4) of pyridazinone, then R2 = H; R3 = H, C1-6 linear or branched alkyl, or a C1-3 alkyl substituted by CF3, Ph or C3 alkynyl], their pharmaceutically acceptable acid and base addn. salts, and their stereoisomers, as inhibitors of stearoyl-CoA desaturase-1 (SCD-1). Thus, a multi-step synthesis starting from 4,5-dichloro-2H-pyridazin-3-one was given for pyridazinone II (m.p. = 160°). II inhibited the enzymic activity of human SCD-1 from microsomes of HepG2 cells with IC50 = 0.003 μM. I are useful for treating diseases requiring inhibitors of SCD-1 enzyme activity such as obesity, , type-2 diabetes, lipid diseases of the skin, etc. [on SciFinder(R)]