Prodrug forms of ribonucleotide reductase inhibitors 3-AP and 3-AMP
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: ##STR1## where R.sup.4 is H or CH.sub.3 and PA1 R.sup.5 is CHR, benzyl or ortho or para substituted benzyl; PA1 R is H, CH.sub.3, CH.sub.2 CH.sub.3, CH.sub.2 CH.sub.2 CH.sub.3 or ##STR2## R' is a free acid phosphate, phosphate salt or an --S--S--R" group; R" is CH.sub.2 CH.sub.2 NHR.sup.6, CH.sub.2 CH.sub.2 OH, CH.sub.2 COOR.sup.7, an ortho or para substituted alkylphenyl and ortho or para substituted nitro-phenyl; PA1 R.sup.6 is H, C.sub.1 -C.sub.4 acyl group, trifluoroacetyl, benzoyl or substituted benzoyl group, and PA1 R.sup.7 is H, C.sub.1 -C.sub.4 alkyl or a benzyl or substituted benzyl.
Vion Pharmaceuticals, Inc.
C C A A
C07D C07F A61P A61P
inventional inventional inventional inventional
Jun Shu-Hui Chuan-Sheng Terrence W. Xiuyan
Li Chen Niu Doyle Li