N-salicylidene derivatives of pirarubicin.

Abstract

The preparation and biological evaluation of Ar-salicylidene derivatives of pirarubicin are described. Pirarubicin was treated with various kinds ofaryl aldehydes. Most of compounds synthesized here were more active than pirarubicin in vitro. Someof themshowedsignificant prolongation of the survival period in experimental mice by oral administration. Interestingly, a derivative containing forphenicine exhibited the broadest dose-response range by intraperitoneal administration. In the search for useful and orally absorbable analogues, we found that iV-salicylidene derivatives of pirarubicin were therapeutically superior to doxorubicin in murine models. Someof them showed the possibility of being orally absorbable agents in in vivo tests.Wewish to demonstrate here the synthesis of sixteen TV-salicylidene derivatives (3~5 and 7~19) of pirarubicin (1) and their biological evaluation in vivo and in vitro. Chemistry Pirarubicin (1) was treated with various kinds of aryl aldehydes in chloroform or in a mixture of chloroform and methanol. At first, 1 was converted into its iV-salicylidene derivative (3) by treatment with salicylaldehyde in a good yield after chromatographic separation on silica gel with chloroformmethanol containing triethylamine. The Schiff base-methine proton of 3 in 2H NMRspectrum resonated clearly at d 8.35. A similar treatment of 1 with benzaldehyde did not afford a benzylidene derivative of 1 because of the lability of the product. 7V_Salicylideneadriamycin (2) was prepared by Arcamoneet alP as an intermediate of the synthesis of doxorubicin from daunorubicin, but they did not describe any biological data of 2. Compound3 was acylated with valeryl and decanoyl chlorides in pyridine and re-salicylidenated to give 14-0-valeryl and 14-0-decanoyl derivatives (4 and 5). To comparethe biological activities of Schiff base derivative (3) with 7V-alkyl derivative, compound6 was prepared by Borch reduction of 1 with salicylaldehyde and NaB(CN)H3in acidic medium. Since the reductive alkylation of the amino group of 1 competed with the reduction of the 13-carbonyl group, the yield of 6 was poor.iV-Salicylidene derivatives of 1 having electron-donating group(s) on the aryl ring were synthesized.Reaction of 1 with substituted-aldehydes (3-, 4-and 5-hydroxy, 3,4-dihydroxy, 4-and 5-methoxy-A part of this work was presented at the 243rd JARAResearch Meeting in Tokyo on Dec. 13. 1988.

Synthesis and physical properties of novel liquid crystals containing pyranobenzopyrans as a core structure

“…14 Methoxycarbonylsalicylaldehyde 18 was prepared by selective reduction of the 1 position of methyl ester of 16 with excess sodium borohydride 15 to give alcohol 17, followed by oxidation with active manganese dioxide. 16 Bromosalicylaldehyde 20 was synthesized by Reimer-Tiemann reaction in 18% yield. 17a-b Sulfide 13 was prepared from the known 8 in four steps (coupling reaction, decarboxylation, 18 radical addition of thiophenol, 19 and LiAlH 4 reduction) as 1 : 1 mixture of (E) and (Z) isomers.…”