Kojic amine--a novel gamma-aminobutyric acid analogue

A series of compounds containing the 3-hydroxy-4H-pyran-4-one nucleus has been synthesized and tested as potential skeletal muscle relaxants. Reduction of 2-(azidomethyl)-5-hydroxy-4H-pyran-4-one (4) with HBr in HOAc--phenol yielded 2-(aminomethyl)-5-hydroxy-4H-pyran-4-one (kojic amine, 3) in 81% yield. Reaction of 2-[(tosyloxy)-methyl]-5-(benzyloxy)-4H-pyran-4-one (5) with NH3 gave a 40% yield of the O-benzyl ether of kojic amine, which was N-acylated with a series of carbobenzyloxy-protected amino acids. Complete deprotection with HBr--HOAc gave the following amino acid amides of kojic amine: glycyl (23), alpha-alanyl (24), beta-alanyl (25), gamma-aminobutyryl (26), and glycylglycyl (27). Among the analogues of kojic amine prepared was a series of one-carbon homologues: 2-[(methylamino)methyl]-5-hydroxy-4H-pyran-4-one (7a), 2-(1-aminoethyl)-5-hydroxy-4H-pyran-4-one (8), 6-(aminomethyl)-3-hydroxy-2-methyl-4H-pyran-4-one (12), and 2-(2-aminoethyl)-5-hydroxy-4H-pyran-4-one (16). Kojic amine (3) has been found to possess certain of the properties to be expected in a gamma-aminobutyric acid mimetic agent, notably skeletal muscle relaxant activity. In the chronic spinal cat preparation, ED70 values for reduction of flexor spasms of 2.2 and 4.0 mg/kg by iv and po routes of administration, respectively, were observed for kojic amine, which was the most potent of the various hydroxypyrone derivatives investigated.