Drug development of ribonucleotide reductase inhibitors 3-AP and 3-AMP

摘要

The present invention relates to novel prodrug forms of ribonucleoside diphosphate reductase inhibitors 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) 3-amino-4-methylpyridine-2-carboxaldehyde thiosemicarbazone (3-AMP) which have increased water solubility, bioavailablity and resistance to in vivo acetylation of their amino functions. Novel compounds according to the present invention relate to those of the formula: IMAGE where R4 is H or CH3 and R5 is CHR, benzyl or ortho or para substituted benzyl; R is H, CH3, CH2CH3, CH2CH2CH3or IMAGE R' is a free acid phosphate, phosphate salt or an -S-S-R'' group; R'' is CH2CH2NHR6, CH2CH2OH, CH2COOR7, an ortho or para substituted alkylphenyl and ortho or para substituted nitro-phenyl; R6 is H, C1-C4 acyl group, trifluoroacetyl, benzoyl or substituted benzoyl group, and R7 is H, C1-C4 alkyl or a benzyl or substituted benzyl.