New thiadiazole and oxadiazole derivatives are triglycerides biosynthesis inhibitors useful to treat or prevent e.g. obesity, dyslipidemia, metabolic acidosis, ketosis, hepatic steatosis, insulin resistance, type 2 diabetes, and cancer

摘要

Thiadiazole and oxadiazole derivatives (I) and their acid, base, or addition salts with acid or base are new. Thiadiazole and oxadiazole derivatives of formula (I) and their acid, base, or addition salts with acid or base are new. U1 : O or N, provided that when U1 is O then R5 is absent; n : 0-3; p : 0-2; D : O, -NH- group or bond; W1 : C or N; X : heteroatom comprising O or S; either R1-R4 : H or 1-6C alkyl; or CR1R2, CR3R4 : 3-10C cycloalkyl; Y1 : H, -1-6C alkyl, 3-10C cycloalkyl, 3-10C cycloalkyloxy-, 3-10C cycloalkyl-1-6C alkyloxy-, heterocycloalkyl-1-6C alkyloxy-, -COOR1, aryl, arylalkyl, heteroaryl, heterocycloalkyl, aryloxy, -C(O)-heterocycloalkyl, -C(O)aryl, -CH(OH) aryl, or -NH-cycloalkyl (all optionally substituted by one or more substituents of halo, hydroxyl group, (1-6C) alkyl, (1-6C)alkoxy, aryloxy or heterocycloalkyl); R : H or halo; Z1 : absent, S, -NH-, -NHC(O)-, -S(O)-CH 2-, -SCH 2-, methylene or ethylene group; either Z2 : methylene, cycloalkyl, absent, -CH(CH 3)- or =CH-; and Z3 : methylene, cycloalkyl, absent, O, -CH(CH 3)- or =CH-, provided that Z2 is -CH-, when Z3 is present (i.e. =CH-); or Z2Z3 : double bond; Z4 : H, C (which optionally forms 3-10C cycloalkyl with Z3 (when Z3 is -CH(CH 3)-)) or absent (when Z3 is a =CH- group that forms a double bond with the carbon which is adjacent to cyclohexyl); and R5 : H, alkyl optionally substituted by at least one OH, heterocyclo-1-6C alkyl, amine or alkyloxy. Independent claims are included for: (1) the preparation of (I); (2) 4-(4-methoxycarbonylmethyl-cyclohexyl)-benzoic acid compounds of formula (III); (3) [4-(4-carbamoyl-phenyl)-cyclohexyl]-acetic acid methyl ester compounds of formula (V); (4) 4-[4-(4H-pyrazol-3-ylcarbamoyl)-phenoxy]-cyclohexanecarboxylic acid methyl ester compounds of formula (XXIII); and (5) 4-(4-methoxycarbonyl-cyclohexyloxy)-benzoic acid compounds of formula (XXI). R : -C(R1R2) n-Y1; and R1a, R2a : protecting group. [Image] [Image] [Image] ACTIVITY : Anorectic; Antilipemic; Antidiabetic; Vasotropic; Metabolic; Hepatotropic; Cardiant; Hypotensive; Dermatological; Neuroprotective; Nootropic; Immunomodulator; Anti-HIV; Antiinflammatory; Gastrointestinal-Gen.; Cytostatic. MECHANISM OF ACTION : Triglycerides biosynthesis inhibitor. The ability of (I) to inhibit triglyceride biosynthesis was tested in vitro. The result showed that (4-{4-[5-(3-fluoro-benzyl)-[1,3,4]thiadiazol-2-ylcarbamoyl]-phenyl}-cyclohexyl)-acetic acid exhibited the IC 5 0value of 0.046 mu M.