Organic Chemistry of Drug Synthesis. Volume 7

serious limitations. The benzodiazepines that came along in the 1960s were
better tolerated though these too had their drawbacks, such as drug hangover
and the propensity to induce dependence. These have now been largely
replaced by drugs, such as zolpidem. The structures of these drugs share the
purine 6–5 fused rings system found in purines; the placement of ring nitro-
gens atoms is usually quite different from that found in purines. The synthesis
of a recent example begins with the condensation of the substituted acetophe-
none ( 25 ) with DMF acetal. This reaction affords the chain-extended enamide
( 26 ). The amide nitrogen is then alkylated ( 27 ). Reaction of this intermediate
with the aminopyrrazole ( 28 ) leads to formation of the fused pyrimidinopyr-
razole ( 29 ). For bookkeeping purposes, the transform may be visualized to
involve addition–elimination of the enamide diethylamino group by the
amine on the pyrrazole. Imine formation between the carbonyl and pyrrazole
ring nitrogen then closes the fused ring. The product ( 29 ) is next acylated with
thiazole-carboxylic acid ( 30 ) inthe presenceofaluminum chloride ( 31 ). Thus,
indiplon( 31 ) is obtained.^5

O

HN

O

25

(H 3 C) 2 N

OCH 3

O

HN

O CH 3 I

NaH

N(CH 3 ) 2

O

N

O

N(CH 3 ) 2

CH 3

N

HN

H 2 N

(^2627)
28
N
O
CH 3
N
N N
29
ClOC S
30
AlCl 3
N
O
CH 3
N
N N
O
S
31
The enzyme, purine nucleoside phosphorylase (PNP), is directly
involved with blood levels of T-cells. Low levels of this enzyme will
inhibit T-cell proliferation. Drugs that inhibit the enzyme can also be
expected to act against proliferation of malignant T-cells. The PNP inhibi-
torforodesine( 36 ) has shown early activity against T-cell malignancies.
Treatment of the deazapurine ( 32 ) with lithium leads to derivative 33
192 BICYCLIC FUSED HETEROCYCLES