H

Figure 1.21. Synthesis of dihydropyridine libraries.

Many more examples could be covered, but this gives a representative flavor of the field. By now most of the heterocyclic ring systems have been produced in library form. Particular emphasis has been placed on libraries of molecules with interesting pharmacological properties. Rather extensive reviews of this work exist for the interested reader to consult. [The

Captopril
Figure 1.22. Captopril library results.

reviews of Dolle (36-40) and of Thompson and Ellman (41) are particularly useful in this context.]

Recently, focused libraries explore the SAR properties of series of contemporary interest where no drugs have yet emerged or where the first of a promising series has been marketed. An example of this is the oxazolidinones. One example of this class, linezolid, has recently been marketed as an orally effective anti-infective, and most large firms have extensive analog programs in progress in attempts to improve on its properties (Fig. 1.24).Combi-natorial chemistry plays a significant role in this work. A Pharmacia group has shown that alteration of the morpholine function to a methylated pyrazole moiety produces a broad spectrum analog with oral activity. Palladium coupling of the iodoaromatic moiety of the starting material allows construction of the trimethylsilylacetylene side-chain. Hydrolysis of this group with formic acid produces a methyl ketone, which after a mixed aldol reaction to the dimethylenamine, reacts with methylhydrazine to produce a mixture of the two possible methylated pyrazole isomers. These are separated by chromatography to produce the best of a large series of analogs produced by these and other reaction se

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