3'-Deamino-3'-(3-cyano-4-morpholinyl)doxorubicin is a new analogue that is 100 to 1000 times more potent than doxorubicin against tumors in cell culture or in mice, that is active by intraperitoneal, intravenous, or oral dosing, and that does not produce chronic myocardial lesions in mice. This analogue was encountered in studies on the reductive alkylation of doxorubicin and daunorubicin with 2,2' - oxybis [acetaldehyde], which constructs a morpholino ring incorporating the amino N. The morpholinyl nitrile byproducts are separated by virtue of their nonbasicity from the expected morpholino derivatives. The 13-dihydro and 5-imino derivatives are also described in this important new class of anthracyclines.

Treatment of daunorubicin with methanolic ammonia affords 5-iminodaunorubicin, the first quinone-modified analogue of either daunorubicin or adriamycin. This product retains antileukemic activity in mice, is less cardiotoxic by electrocardiographic measurements in rats, and is nonmutagenic in Salmonella typhimurium (Ames test).

Reaction of daunorubicin (1) and adriamycin (2) with aldehydes and ketones in the presence of NaCNBH3 afforded N-alkyl- and N,N-dialkylanthracyclines along with their 13-dihydro derivatives. Product ratios depended upon the nature of the carbonyl reagent and the starting drug. The majority of these analogues retained in vivo antitumor activity comparable to 1 and 2. However, unlike the parent compounds, which inhibit DNA and RNA synthesis at comparable concentrations, several of these analogues inhibit RNA synthesis at markedly lower concentrations than required to inhibit DNA synthesis. In addition, in some cases the ability to bind to DNA in vitro was reduced while antitumor activity was retained. N,N-Dibenzyldaunorubicin was especially notable for increased efficacy (T/C 259, qd 1--9) against P388 leukemia in mice, despite reduction of DNA binding in vitro. It showed almost complete loss of mutagenicity vs S. typhimurium (Ames test) and it was tenfold less cardiotoxic by electrocardiographic measurements (Zbinden test) in the rat.

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A 15% aqueous solution of KMn04 was slowly added to a stirred solution of 11 g of the arylcyclohexylamino alcohol, 75 mL of H20, and 20 mL of 5 N HC1 at room temperature. The solution was examined periodically to determine if the pH was acidic, if there was an excess of KMn04, and if any starting material remained (via HPLC). After the addition of 24 g (0.15 mol) of KMn04 over 2 h, the reaction was quenched with 100 mL of isopropyl alcohol. Solid NaHS03 was then added with stirring until the brown color of the Mn02 had been dissipated. The mixture was filtered then the filtrate was concentrated to a thick slurry by evaporation at 40 °C under vacuum. To form the methyl ester and to aid in the removal of water, 3 X 75 mL portions of anhydrous methanol were added to the highly acidic residue and then evaporated at 40 °C to dryness. The crude product was chromatographed on a 3 X 30 cm silica gel column (Woelm, 0.05-0.2 mm) using 300 mL of CH2C12, 300 mL of 5% CH3OH in CH2C12, and 300 mL of 10% CH3OH in CH2C12 for elution to give 4.2 g of the crude methyl ester. A diethyl ether solution of the product was washed with an aqueous NH4OH solution and dried with Na2S04, and then the HC1 salt of the product was precipitated with HCl-ether. The final product (2) was recrystallized from methanol-ethyl acetate (2:75) to give fine colorless needles: mp 189-191 °C; NMR (HC1 salt, CDC13) 7.2-7.S (phenyl, 5), 3.37 (OCH3, 3, s), 1.1-2.8 (br m); 13C NMR (HC1 salt, CDClg) 173.2 (C=0, s), 135.4 (l'-phenyl, s), 129.4 (phenyl, d), 129.0 (phenyl, d), 128.4 (phenyl, s), 64.6 (l'-cyclohexyl, s), 51.5 (OCH3, q), 41.5 (t), 33.5 (t), 33.3 (t), 26.1 (5), 25.2 (t), 22.4 (t); IR (KBr disk) 1726 (C=0), 1272, 774 (phenyl), 706 cm"1 (phenyl); mass spectrum (70 eV), m/e (relative intensity), 289 (M+, 3.7), 246 (42), 159 (26), 115 (38), 91 (100). Anal. (CígH^ClNOs) C, , N. 5-[N-(l'-Phenylcyclohexyl)amino]pentanoic Acid (1).