nitrite in the presence of acid converts the amino group at the 4 position to
the corresponding hydroxyl derivative. Saponification then leads to the free
carboxylic acid, shown as its keto tautomer ( 107 ). The acid is next esteri-
fied with trifluoroacetyl nitrophenol ( 108 ) in order to provide that function
with a good leaving group ( 109 ). Ester–amide interchange with ethyl
p-benzoate ( 110 ) displaces nitrophenol to form the corresponding benza-
mide. Base hydrolysis of the terminal ester then affordsleteprinim( 111 ).^16
The xanthine theophylline has been used for well over a century for
treating asthmatic episodes by relaxing the constricted bronchioles that
are part of attacks. The discovery of the role of the phosphodiesterase
enzyme (PDE) by Sutherland in the early 1960s helped explain the
mode of action of this drug. Research over the past few decades has led
to the identification of a large number of subtypes of PDE receptors.
Theophylline, for one, was found to interact mainly with PDE IV recep-
tors. The relatively narrow therapeutic index of this drug has led to the con-
tinued search for better tolerated agents. The synthesis of a recent example
starts with nitrosation of the pyrimidinedione ( 112 ) with sodium nitrite in
the presence of acid to yield 113. Reduction of the newly introduced
nitroso group with sodium dithionite leads to the 1,2-diamine ( 114 ).
Reaction of 114 with formamide closes the fused imidazole ring. Thus,
the PDE IV inhibitorarofylline( 115 ) is obtained.^17
ClNNOO NH 2112NaNO 2
HCO 2 HClNNOO NH 2113NO
NaS 2 O 2ClNNOO NH 2114NH 2ClNNOO N115HN
HCONH 2Replacing the hydrogen atom on the imidazole ring of a purine with a
large lipophillic group effects a major change in the biological activity.
The resulting compounds are no longer PDE inhibitors, but instead act as
adenosine receptor antagonists. The first of these,istradefylline( 120 ), selec-
tively blocks A(2A) receptors and in addition inhibit monoamine oxidase B
(MAO-B). The neuroprotective action of this agent in animal models for
Parkinson’s disease has been attributed to this mixed activity. Reaction of
the diamine ( 116 ), with the dimethoxy cinnamic acid ( 117 ) in the presence
of a diimide leads to the formation of a mixture of the amides formed
between the acid and one of the two amines on the pyrimidine (only one,
118 , is shown). Heating that mixture with sodium hydroxide leads to cycli-
zation, forming the xanthine ( 119 ). The free amine on the fused imidazole is
then alkylated with methyl iodide in the presence of base to afford 120.^18
202 BICYCLIC FUSED HETEROCYCLES