An entire new field of therapeutics arose with the serendipitous discovery
of the effect of sildefanil, far better known as Viagra, on erectile function.
The almost predictable wild success of that drug has led to the search for
other inhibitors of phosphodiesterase 5, the enzyme responsible for this
activity. The structures of many follow-on agents hewed fairly close to
the original PDE 5 inhibitor. Others, such asavanafil( 107 ), differ markedly
in structure from sildefanil. The synthesis of agent 107 in effect consist of a
series of displacement reactions. Thus, reaction of the benzylamine ( 99 )
with chloropyrimidine ( 100 ) leads to displacement of chlorine and for-
mation of the coupling product ( 101 ). The inert methylthio ether on the pyr-
imidine ring is made labile by conversion to a sulfoxide ( 102 ) by means
of m-chloroperbenzoic (MCPBA) acid. Reaction of that product with
L-prolinol ( 103 ) leads to the replacement of the sulfoxide by the basic nitro-
gen in 103 and formation of coupling product 104. The ester group in this
last intermediate is then hydrolyzed to afford the corresponding acid ( 105 ).
Reaction of this acid with 1-aminomethylpyrimidine ( 106 ) in the presence
of a carbodiimide leads to the amide ( 107 ).^15
ClSCH3CO 2 CH 3NH 2
CH 3 OCl99 100+SCH 3CH 3 O CO^2 CH^3Cl N
HMCPBASO 2 CH 3CH 3 O CO^2 CH^3Cl N
HNH OH101 102103CH CO^2 CH^3
3 OCl N
HNOHCH 3 O CO^2 HCl N
HNOHNaOH105 104NN NN NNNN NN NNCH 3 OCl N
HNOHN
H 2 N NO
NN N
H106107The duration of action of venerable antitumor antimetabolite 5-
fluoruracyl (5-FU, 108 ) is limited by its relatively fast destruction by liver
enzymes. One approach to extending the half-life of the drug involves a
prodrug in which the sites where degradation occurs are covered by moi-
eties known to inhibit the metabolism of other uracils. The majority
of the drug in circulation would then consist of the prodrug. Slow loss of
these protecting groups would then lead to extended therapeutic levels of
active 5-FU. The first few steps in preparingemitefur( 116 ) involves a
scheme analogous to that used to prepare the prodrug tegafur. In this
- COMPOUNDS WITH TWO HETEROATOMS 127