Synthesis and Cytostatic Activity of N-[2-(Phosphonomethoxy)alkyl] Derivatives of N6-Substituted Adenines, 2,6-Diaminopurines and Related Compounds

Abstract

N 6 -Substituted adenine and 2,6-diaminopurine derivatives of 9-[2-(phosphonomethoxy)- ethyl] (PME), 9-[( R )-2-(phosphonomethoxy)propyl] [( R )-PMP] and enantiomeric ( S )-PMP series were synthesized by reactions of primary or secondary amines with 6-chloro-9-{[2-(diisopropoxyphosphoryl)methoxy]alkyl}purines ( 26 - 28 ) or 2-amino-6-chloro-9-{[2-(diisopropoxy- phosphoryl)methoxy]alkyl}purines ( 29 - 31 ) followed by treatment of the diester intermediates 32 with bromo(trimethyl)silane and hydrolysis. Diesters 32 were also obtained by reaction of N 6 -substituted purines with synthons 23 - 25 bearing diisopropoxyphosphoryl group. Alkylation of 2-amino-6-chloropurine ( 9 ) with diethyl [2-(2-chloroethoxy)ethyl]phosphonate ( 148 ) gave the diester 149 which was analogously converted to N 6 -substituted 2,6-diamino- 9-[2-(2-phosphonoethoxy)ethyl]purines 151 - 153 . Alkylation of N 6 -substituted 2,6-diaminopurines with ( R )-[(trityloxy)methyl]oxirane ( 155 ) followed by reaction of thus-obtained intermediates 156 with dimethylformamide dimethylacetal and condensation with diisopropyl [(tosyloxy)methyl]phosphonate ( 158 ) followed by deprotection of the intermediates 159 gave N 6 -substituted 2,6-diamino-9-[( S )-3-hydroxy-2-(phosphonomethoxy)propyl]purines 160 - 163 . The highest cytostatic activity in vitro was exhibited by the following N 6 -derivatives of 2,6-diamino-9-[2-(phosphonomethoxy)ethyl]purine (PMEDAP): 2,2,2-trifluoroethyl ( 53 ), allyl ( 54 ), [(2-dimethylamino)ethyl] ( 68 ), cyclopropyl ( 75 ) and dimethyl ( 91 ). In CCRF-CEM cells, the cyclopropyl derivative 75 is deaminated to the guanine derivative PMEG ( 3 ) which is then converted to its diphosphate.