Tetrazolyl-(phenoxy and phenoxyalkyl)-piperidinylpyridazines as antiviral agents

DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS As used herein the term halogen means fluorine, chlorine, bromine and iodine.
The term C.
sub.
1 -C.
sub.
6 alkylene refers to divalent straight or branched hydrocarbon radicals having from one to six carbon atoms and thus includes methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1,6-hexylene, 1-methyl-1,4-butylene and the like.
DEAD refers to diethyl azodicarboxylate.
DIPEA refers to diisopropylethylamine.
THF, NMP and DMF are tetrahydrofuran, N-methylpyrrolidine and N,N-dimethylformamide, respectively.
Compounds of formula I are made by two general procedures outlined below.
In the formulas below, unless specifically defined otherwise, R.
sub.
1, R.
sub.
2, R.
sub.
3, R.
sub.
4 and Y, have the meanings given above in formula I.
METHOD A The compounds of formula I are prepared by reacting phenol ##STR8## with a suitable piperidine IV ##STR9## in the presence of triphenylphosphine and diethyl azodicarboxylate (DEAD) in a noninteracting solvent at a temperature in the range of about -50.
degree.
C.
to 48.
degree.
C.
preferably at about 0.
degree.
C.
PREPARATION OF INTERMEDIATES The tetrazolyl phenol III is prepared by reacting an appropriate R.
sub.
2 -R.
sub.
3 -4-cyanophenol preferably protected, e.
g.
as the benzyl ether, with sodium azide in a noninteracting solvent, e.
g.
DMF preferably under an inert atmosphere at a temperature between 100.
degree.
and 150.
degree.
C.
for about 15-25 hours.
The resulting tetrazole which can exist in two tautomeric forms (Va, Vb, Bz=benzyl): ##STR10## is then reacted with an alkylating agent, e.
g.
an alkyl halide, R.
sub.
4 X, preferably under inert atmosphere.
Alkylation can occur at either available nitrogen atom and the desired isomer can be separated by conventional means, e.
g.
fractional crystallization or chromatography.
Deprotection, e.
g.
reacting the benzyl ether with a strong acid such as HCL in acetic acid, affords III.
Intermediate IV is prepared from 4-hydroxypiperidine or 4-(hydroxyalkyl)piperidine and the substituted or unsubstituted halopyridazine VI (X is halogen, preferably chloro or bromo): ##STR11## by reacting them in the presence of diisopropylethylamine (DIPEA) in a noninteracting solvent (e