Microbial synthesis of three metabolites of a tachykinin receptor antagonist, TAK-637

The compound TAK-637 ((aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11- tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthy ridine-6,13-dione), a tachykinin receptor antagonist, has been shown to be converted into three metabolites in rats and guinea pigs. It was difficult to isolate the metabolites from rats and guinea pigs administered TAK-637 a nd elucidate the structures. A total of 100 actinomycete strains were scree ned for the ability to convert TAK-637 into its metabolites. Three strains, Streptomyces subrutilus IFO13388, Streptomyces tanashiensis subsp. cephalo myceticus IFO13929 and Streptomyces lavenduligriseus IFO13405, were found t o convert TAK-637 into the metabolites consistent with the metabolites form ed in rats and guinea pigs as determined by HPLC analyses. The metabolites were synthesized by microbial conversion using the actinomycetes. The struc tures of the metabolites were elucidated by spectral analyses. It was found that the methyl group at the C-(5)-phenyl group of TAK-637 was hydroxylate d and the resulting alcohol was converted to carboxylic acid via aldehyde. One of the metabolites (hydroxylated TAK-637) was obtained using a 200-l fe rmentor in a large-scale cultivation to evaluate its biological activity.