CHAPTER 4
CARBOCYCLIC COMPOUNDS
FUSED TO A BENZENE RING
The nucleus of a modest number of new compounds comprise a two- or
three-ring fused system, one of which consists of a benzene ring. As was
the case for free-standing benzene rings in Chapter 3, the annelated
rings in most instances serve merely as supports for the pharmacophoric
substituents.
1. INDENES
Imidazolines have a venerable history asa-adrenergic agents. Compounds
that include this group variously act asa 1 - anda 2 -agonists or antagonists
depending on the substitution pattern in the rest of the molecule. The
indene fadolmidine ( 5 ), is an effective a 2 -agonist that blocks pain
responses. The compound does not cross the blood–brain barrier as a
result of its hydrophobic character; it has as a consequence been developed
as a drug for use as a spinal analgesic. Preparation of the compound starts
with a crossed version of the McMurray reaction. Thus treatment of a
mixture of the indanone ( 1 ) withN-benzyl protected imidazolecarbox-
aldehyde ( 2 ) in the presence of TiCl 2 , preformed from TiCl 4 and zinc
powder, gives the coupling product 3. Catalytic hydrogenation serves to
The Organic Chemistry of Drug Synthesis, Volume 7. By Daniel Lednicer
Copyright#2008 John Wiley & Sons, Inc.
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