Rifaldehyde derivative

The most numerous C-25 substitution products are those derived from the 25-aminomethyl derivatives (46) (76) of rifamycin SV obtained by the Mannich reaction of rifamycin S with secondary amines in the presence of formaldehyde (Fig. 19). The aminomethyl derivatives upon oxidation in acidic medium give 25-formylrifamycin SV (rifaldehyde), the starting point for preparation of many of the best rifamycin derivatives (47—52) (28, 78, 126). The most active rifaldehyde derivatives are generally N,N-disubstituted hydrazones (48) and O-alkyl oximes (49), such as those shown in Fig. 19 (21). The O-methyl oxime and the hydrazone formed from N-amino-N -methylpiperazine were especially potent and... 

Many of the rifaldehyde derivatives have also been screened for inhibition of the RNA-directed DNA polymerases (reverse transcriptases) of murine sarcoma virus (MSV) and Rauscher murine leukemia virus (RLV) and the purified DNA polymerases from human normal and leukemic lymphoblasts (40,163). Surprisingly perhaps, the best compounds shown in Fig. 19 (48, 49, rifampicin) were inactive. Further testing of derivatives of rifaldehyde indicated tl at a longer, bulkier side chain is needed at C-25 for inhibition of viral polymerases. 

A number of oxime derivatives of rifaldehyde have been prepared. Many of these derivatives exhibit good activity against rifampicin-resistant organisms (151,152). 

Treatment of rifamycin S with formaldehyde and secondary amines yields the 3-aminomethyl derivatives (38, X = CH2NR2) which are not of therapeutic interest (125). However, upon oxidation in acidic medium, the aminomethyl derivatives yield 3-formylrifamycin SV, also known as rifaldehyde [13292-22-3] (38, X = CHO), C3gH47N023. Treatment of rifaldehyde with amines, hydrazines, hydroxylamines, and hydrazides yields a number of derivatives of the 3-fomiyl group having exceUent biological activity (109,126—128). The most therapeuticaUy usehjl derivative is the A/-amino-iV-methylpiperazine hydrazone of rifaldehyde known as rifampin in the United States and rifampicin elsewhere. 

Condensation of rifaldehyde with larger hydrazines produces the rifazacyclo (146) and the rifazone (6, 146) series of derivatives. Of these, rifazacyclo-16 (48, R + R = -(CH2)i5-) is one of the most potent and rifazone-82 (48, R = R = n —CsHi7 —) one of the most selective inhibitors of the viral polymerase in vitro. 

Other compounds of interest have been obtained by acylating N-demethylrifampicin (see Fig. 19) and rifaldehyde hydrazone with diacid derivatives to give a series of rifamycin dimers (26,145). A simpler dimeric material, the azine of rifaldehyde (from two moles of rifaldehyde and... 

---