ANALOGIFORFARANDE FOR FRAMSTELLNING AV AMINDERIVAT AV VINBLASTIN, LEUROSIDIN OCH LEUROKRISTIN

摘要

1463575 Novel amides, azides and hydrazides of vinca alkaloids ELI LILLY & CO 25 March 1974 [2 April 1973] 13101/74 Heading C2C Novel compounds of the Formula I wherein R is NH 2 , NH.NH 2 , N(CH 3 ) 3 , NHalk-X, NH(C 3-8 )cycloalkyl, NHalkAm, NHalk(OH) 1-3 or N 3 ; wherein alk is C 1-6 alkylene, Am is NH 2 , NHCH 3 or N(CH 3 ) 2 , X is hydrogen, CN, optionally substituted phenyl, carboxy, carbo- (C 1-3 )-alkoxy, or carboxamido; R1 is H, alkanoyl or chloroalkanoyl; R11 is hydrogen, C 1-3 alkyl, formyl or alkanoyl; and one of R111 and R1111 is hydroxy and the other is ethyl, in which alkanoyl groups have 1-3 carbon atoms in the alkane moiety, and salts thereof, may be prepared by reacting a compound of the Formula I wherein R is OCH 3 , R1 is hydrogen or acetyl and R11, R111 and R1111 are as defined above with ammonia, methylamine or hydrazine to obtain a compound of Formula I wherein R is NH 2 , NHCH 3 or NH.NH 2 , and R1 is hydrogen and, if desired, when R is NHNH 2 (a) reacting said compound with a nitrosating agent to form an azide in where R 3 N 3 and then reacting said azide with ammonia, an amine of the formula HN(CH 3 ) 2 , NH 2 alk-X, NH 2 -(C 3-8 )cycloalkyl, NH 2 alkAm or NH 2 alk(OH) 1-3 to obtain the corresponding compound of Formula I or (b) hydrogenolysing said compound with Raney nickel in an inert solvent to yield a compound of the Formula I wherein R is NH 2 , and/or, if desired, acylating a product in which R1 is hydrogen to introduce an alkanoyl or chloroalkanoyl group at R1, and, if in the starting material R11 is hydrogen, to introduce an alkanoyl or chloroalkanoyl at R11. Various by-products having the same ring systems as I are formed during some of the above reactions. Pharmaceutical compositions of the compounds I or salts thereof with the usual excipients may be administered orally or parenterally for treating neoplastic disease. The compounds also show antivral activity in vitro against herpes virus.