analogiforfarande for framstellning of aminderivat of vinblastine, leurosidin and 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; RSP1/SP is H, alkanoyl or chloroalkanoyl; RSP11/SP is hydrogen, C 1-3 alkyl, formyl or alkanoyl; and one of RSP111/SP and RSP1111/SP 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 , RSP1/SP is hydrogen or acetyl and RSP11/SP, RSP111/SP and RSP1111/SP 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 RSP1/SP 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 RSP1/SP is hydrogen to introduce an alkanoyl or chloroalkanoyl group at RSP1/SP, and, if in the starting material RSP11/SP is hydrogen, to introduce an alkanoyl or chloroalkanoyl at RSP11/SP. 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.