caused by the presence of the preexisting adjacent chiral center. The free car-
boxylic acid is condensed with piperidine to form 132. The remaining ester
is then hydrolyzed in acid to afford the acid ( 133 ). Reaction of 133 with
O-benzylhydroxylamine followed by hydrogenolysis of the benzyl group
then leads to the hydroxamic acid. Thus, the collagenase inhibitorcipema-
stat( 134 ) is obtained.^20
The discovery of canabinol receptors has led to the search for synthetic
agonists and antagonists based on different structures from the hemp-
related product. One of the first antagonists to come out of those programs,
rimonabant( 140 ) has shown activity as an appetite suppressant weight
loss agent. Addition of the anion from the propiophenone ( 135 )tothe
anion from ethyl oxalate gives the enolate ( 136 ). Condensation of that
with 2,4-dichlorophenylhydrazine ( 147 ) results in formation of
imines between carbonyl groups and the basic nitrogen thus forming the
pyrrazole ring ( 138 ). Saponification of the ester affords the corresponding
acid ( 139 ). This is then reacted withN-aminopiperidine in the presence of
DCC to form the amide 140.^21
ClO135(CO 2 C 2 H 5 ) 2
BuLi ClOLi136C 2 H 5 O 2 CO+ H^2 N NHCl ClClClCl137C 2 H 5 O 2 CClClClHO 2 C139 138NN NN NaOH N NClClClHN
N
O
140C 6 H 10 NHNH 2C. Thiazoles
A relatively simple thiazole has been shown to be a quite potent antiinfla-
matory agent.Darbufelone( 143 ), which is quite different in structure from
all preceding NSAIDs inhibits both arms of the arachidonic acid cascade at
the very inception of the process. This in effect shuts off production of both
prostaglandins and leukotrienes. This agent is prepared in a single step by
condensation of substituted benzaldehyde 141 with the enolate from
thiazolone ( 142 ).^22
- COMPOUNDS WITH TWO HETEROATOMS 99