C10-C20 AULKYL FUROYLACETIC ACID DERIVATIVES AS HYPOLIPIDEMIC AGENTS

摘要

1417103 Furoyl-acetic acid derivatives RICHARDSON-MERRELL Inc 26 March 1974 [2 April 1973] 13298/74 Heading C2C Novel compounds I in which Y is O or S, R is a C 10-20 alkyl or alkenyl (containing 1 to 4 double bonds) group, R1 is hydrogen, C 1-6 alkyl, benzyl, phenethyl, pyridylmethyl, a group -(CH 2 ) n -NR2R3 (where n is 2 or 3; R2 and R3 are C 1-4 alkyl or R2 is (C 1-4 alkyl)carbonyl and R3 is hydrogen; or NR2R3 represents pyrrolidino piperidino, morpholino or piperazino) or a group of Formula V (where m+p is 3 to 5 and R4 is C 1-4 alkyl) and the salts thereof when R 1 is hydrogen or a basic group are prepared by reacting an appropriately R-Y- substituted furyl methyl ketone with magnesium methyl carbonate in dimethyl acetamide or dimethyl formamide and treating the resulting complex with water and a mineral acid to form a compound I (R 1 =H) which may be converted to esters of Formula I by (i) treatment with trifluoroacetic anhydride, N,N1 - dicyclohexylcarbodiimide, N,N1 - carbonylimidazole or a thionyl halide followed by aleoholysis with R1OH, (ii) reaction with diazomethane to form the methyl ester which may be transesterified. Compounds I in which R1 is other than hydrogen are also prepared by (1) condensing a compound III in which X is halogen, imidazole or OR5 (where R5 is lower alkyl) with either an ester of acetoacetic acid followed by alkaline hydrolysis of the furoylacetoacetate produced or an ester of acetic acid and a basic catalyst or (2) acylation of a compound III in which X is halogen or 1- imidazole with a magnesium complex of R 1 OOC-CH 2 -COOH. R-Y- substituted furyl methyl ketones (R-Y-=tetradecyloxy, cis-9-octadecenyloxy, 9,12,15-octadecatrienyloxy) are prepared by reaction of MeMgBr and the imidazole derivative of an R-Y- substituted furoic acid or by acetylating an R-Y- substituted furan by Friedel-Crafts. R-Y- substituted furans are prepared from R-Y furoic acids by decarboxylation. R-Y- substituted furoic acids are prepared by reaction of R-Y-H with bromofuroic acid in the presence of base. Compounds I are hypolipidemic agents and form with a carrier a pharmaceutical composition which may be administered orally or parenterally.