Podophyllotoxins and peltatins

摘要

Novel compounds of Formula I in which either one of the symbols R1 signifies the radical -OCOAm and the other symbol signifies a hydrogen atom, and R2 signifies a methoxy radical or the radical -OCOAm, or each of the two symbols R1 signifies a hydrogen atom and R2 signifies the radical -OCOAm, Am signifying the amino radical, a C1- 4 alkyl-, C2- 4 alkanoyl-, phenyl-, benzyl-, or, except when R1 in the 1-position signifies OCOAm, a di-(C1- 4)-alkyl-amino radical, are prepared (1) when one of the symbols R1 represents -OCONH2 and the other symbols represents a hydrogen atom, and R2 represents a methoxy radical, by reacting a compound of Formula II in which one of the symbol R11 signifies hydroxyl, and the other represents hydrogen, and R12 represents a methoxy radical, with cyanic acid in an anhydrous inert solvent at a temperature between -10 DEG and 60 DEG C., (2) when one of the symbols R1 represents -OCOAm11, and the other represents hydrogen, and R2 represents a methoxy radical or the radical -OCOAm11, or both symbols R1 signify hydrogen and R2 represents -OCOAm11, Am11 signifying a C1- 4 alkyl-, C2- 4 alkanoyl-phenyl- or benzyl-amino radical, by reacting a compound of Formula II above in which one of the symbols R11 represents hydroxyl, and the other represents hydrogen, and R12 represents a methoxy or hydroxyl radical, or both symbols R11 represent hydrogen atoms and R12 is hydroxyl, with an isocyanate of formula R3NCO, wherein R3 is a C1- 4 alkyl, C2- 4 alkanoyl, phenyl, or benzyl radical, in an anhydrous solvent at a temperature of -10 DEG to 60 DEG C., (3) when one of the symbols R1 represents -OCOAm111 and the other is hydrogen and R2 is the methoxy radical or a radical -OCOAm111, or both symbols R1 represent hydrogen, and R2 is -OCOAm111, Am111 signifying the amino radical, or a C1- 4 alkyl-, phenyl- or benzyl-amino radical, by reacting a compound of Formula II above in which R11 and R12 have the significance given under (2) above, with a compound of formula X-CO-Am111, wherein X is a chlorine or bromine atom, in an anhydrous solvent in the presence of a tertiary base at a temperature of - 20 DEG to 60 DEG C., or, wherein X is a lower alkoxy radical, in an anhydrous solvent in the presence of a metal alcoholate as catalyst at a temperature symbols R1 represent hydrogen, and R2 is -OCOAm1111, or the symbol R1 in position 8 represents -OCOAm1111, the symbol R1 in position 1 represents hydrogen and R2 is a methoxy radical or the radical -OCOAm1111, Am1111 signifying an amino, C1- 4 alkyl-, phenyl-, benzyl- or di-(C1- 4) alkyl-amino radical, by reacting a compound of Formula V in which R4 is hydrogen and R5 is -OCOY, or R4 is -OCOY and R5 is -OCOY or methoxy, Y signifying a chlorine or bromine atom, with a compound H-Am1111 in an anhydrous inert solvent at a temperature of - 20 DEG to 30 DEG C. Diphenylurea, phenyl- and benzyl-carbamic acid alkyl esters are obtained as by-products in process (2) above. Chloroformic acid esters of Formula V above are obtained by treating the corresponding hydroxy compound with phosgene. Therapeutic compositions, which have a cytostatic and antimitotic effect and inhibit experimental tumours, and which may be administered enterally or parenterally, contain as active ingredient a compound of Formula I above.