SYNTHESIS AND ANTITUMOR-ACTIVITY OF 4-SUBSTITUTED AND 5-SUBSTITUTED DERIVATIVES OF ISOQUINOLINE-1-CARBOXALDEHYDE THIOSEMICARBAZONE

Various substituted isoquinoline-1-carboxaldehyde thiosemicarbazones ( 12 compounds) have been synthesized and evaluated for antineoplastic a ctivity in mice bearing the L1210 leukemia. Condensation of 4-bromo-1- methylisoquinoline (4) with ammonium hydroxide, methylamine, ethylamin e, and N-acetylethylenediamine gave the corresponding 4-amino, 4-methy lamino, 4-ethylamino, and 4-N-(acetylethyl)amino derivatives, which we re then converted to amides and subsequently oxidized to aldehydes fol lowed by condensation with thiosemicarbazide to yield thiosemicarbazon es 8a-c, 9a-c, and 16. Nitration of 4, followed by oxidation with sele nium dioxide, produced aldehyde 18, which was then converted to the cy clic ethylene acetal 19. Condensation of 19 with morpholine followed b y catalytic reduction of the nitro group and treatment with thiosemica rbazide afforded 5-amino-4-morpholinoisoquinoline-1-carboxaldehyde thi osemicarbazone (22). N-Oxidation of 1,5-dimethylisoquinoline, followed by rearrangement with acetic anhydride, gave, after acid hydrolysis, 1,5-dimethyl-4-hydroxyisoquinoline, which was converted to its acetate and then oxidized to yield 1-acetoxy-5-methylisoquinoline-1-carboxald ehyde (32). Sulfonation of 1,4-dimethylisoquinoline, followed by react ion with potassium hydroxide, acetylation, and oxidation, gave 5-aceto xy-4-methylisoquinoline-1-carboxaldehyde (40). Condensation of compoun ds 32 and 39 with thiosemicarbazide afforded the respective 4- and g-a cetoxy(5- and 4-methyl)thiosemicarbazones 33 and 40, which were then c onverted to their respective 4- and 5-hydroxy derivatives 34 and 41 by acid hydrolysis. The most active compounds synthesized were 4-aminois oquinoline-1-carboxaldehyde thiosemicarbazone (9a) and 4-(methylamino) isoquinoline-1-carboxaldehyde thiosemicarbazone (9b), which both produ ced optimum % T/C values of 177 against the L1210 leukemia in mice whe n used at a daily dosage of 40 mg/kg for 6 consecutive days. Furthermo re, when 9a was given twice daily at a dosage of 40 mg/kg for 6 consec utive days, a T/C value of 165 was obtained and 60% of the mice were 6 0-day long-term survivors.