is used to alkylate the phenol group onp-hydroxybenzaldehyde ( 23 ).
Condensation of the aldehyde group in 24 with glycine methyl ester
leads to the corresponding imine. Reduction of that function with boro-
hydride yields the intermediate 25. Acylation of the amino group in 25
compound withp-anisyl chloroformate ( 26 ) yieldsmuraglitazar( 27 ).^5
A very simple triketone has proven useful for treating the rare genetic
disease tyrosinemia. The drug alternately known asnitisinone ( 30 )or
orfadinactually bears a very close relation to a pesticide. The analogue
in which methylsulfonyl replaces the trifluoromethyl group, mesotrione,
is an important corn herbicide. Acylation of cyclohexan-1,3-dione,
shown as an enol ( 28 ) with acid chloride ( 29 ), leads in a single step
to 30.^6
OOH CF 3NO 2ClO+OOH CF 3O NO 228 29 30Et 3 N2. BIPHENYLS
Excision of malignant tumors comprises first line treatment for cancer of
solid tissues. This procedure not infrequently misses small fragments of
the tumor that may have broken off before surgery from the principal
site of the disease. These fragments, metasteses, often proliferate at quite
remote locations where they cause much of the pathology of cancer. A
series of proteolytic enzymes present in tumor cells, known as matrix
metalloproteinases, help establish growth of these metasteses at the
newly invaded sites; these proteases are also involved in the formation
of new blood vessels that will nourish the invasive cell masses.
Consequently, considerable research has been devoted to matrix metallo-
proteinases as a target for anticancer drugs. Clinical results with these
compounds have to date produced equivocal results.^7
Construction of one biphenyl-based metaloproteinase inhibitor starts with
the Friedel–Crafts acylation of 4-chlorobiphenyl ( 31 ) with itaconic anhydride
( 32 ). Attack proceeds on the less inactivated ring to give the acylated product
( 33 ). Michael addition of phenylmercaptan to the exomethylene group gives
the proteinase inbitortanomastat( 34 ).^8
- BIPHENYLS 47