O2,2-ANHYDRO-1- BETA-D-ARABINO-FURANOSYL-CYTOSINE DERIVATIVES METHODS FOR THEIR PREPARATION AND RELATED PROCEDURES

摘要

1422214 0SP2/SP,2SP1/SP-Anhydro-1-(#-D-arabinofuranosyl) - cylosines and azacytosines SYNTEX CORP 2 March 1973 [3 March 1972] 10166/73 Heading C2C Novel compounds I in which R 1 and R 2 are hydrogen, C 1-6 alkyl aryl or C 7-30 arylalkyl; R 3 is C 1-6 alkyl, C 3-6 cycloalkyl or heterocyclic ring having 5 to 7 ring atoms and 1 or 2 heteroatoms selected from oxygen, nitrogen and sulphur; R 4 and R 5 are C 1-6 alkyl, aryl or C 5-30 arylalkyl (wherein when one of R 4 and R 5 is aryl or arylalkyl the other can be hydrogen) or RSP4/SP and RSP5/SP together with the C atom to which they are joined represent C 4-8 cycloalkyl or a heterocyclic ring as defined above, Z is -C(RSP6/SP) = CH-, -N=CH- or -C(RSP7/SP)=N- (in which RSP6/SP is hydrogen, halo, C 1-6 alkyl, C 1-6 hydroxyalkyl, CF 3 , N 3 , NO 2 , amino which may be mono- or di-C 1-6 alkylated or RSP1/SP-CO-NH- (in which RSP1/SP is hydrogen, C 1-10 alkyl, aryl or C 7-30 aralkylaryl) and R 7 is hydrogen or methyl) and X is a pharmaceutically acceptable anion with the proviso that when Z is -N = CH- or then RSP1/SP and RSP2/SP are hydrogen or C 1-6 alkyl are prepared by reaction of a compound A with an α-acyloxy acyl halide B in which XSP1/SP is chlorine or bromine and, if desired, forming other salts by use of an ionexchange resin. Compounds B used are α- acetoxyisobutyl chloride, α-propionyloxyisobutyryl chloride, α-butyryloxyisobutyryl chloride and 1-acetoxycyclohexane carbonyl chloride or the corresponding bromides. The 5SP1/SP-O-substituent is hydrolysed by treatment in a hydroxylic solvent containing a mineral or strong organic acid sufficient to provide a 0À01 to 0À5 molar acid solution at a temperature from 0‹ to 40‹ C. for ¢ to 5 hr. to form the corresponding OSP2/SP,2SP1/SP-anhydro-1-(3SP1/SP- O - acyl - # - D - arabinofuranosyl) - cytosine derivative salt. Prolonged treatment for 36 to 96 hr. causes deacylation at the 3SP1/SP-position to form the corresponding 0SP2/SP,2SP1/SP-cyclocytidine salt. Base hydrolysis of compounds I at a pH of 10 to 14 and at a temperature of 0‹ to 100‹ C. for 1 to 24 hr. hydrolysis the 5SP1/SP-O-substituent and the 3SP1/SP-O-acyl group and cleaves the OSP2/SP,2SP1/SP- anhydro bridge to produce the corresponding 1 - (# - D - arabinofuranosyl) cytosine nucleoside. Compounds I exhibit anti-viral and cytotoxic activity and form with a carrier a pharmaceutical composition which may be administered orally or parenterally.