Synthesis of chiral pharmaceutical intermediates by biocatalysis

ATP-sensitive potassium channels (K(ATP) channels) are heteromeric complexes of pore-forming inwardly rectifying potassium channel subunits and regulatory sulfonylurea receptor subunits. K(ATP) channels were identified in a variety of tissues including muscle cells, pancreatic beta-cells, and various neurons. They are regulated by the intracellular ATP/ADP ratio; ATP induces channel inhibition and MgADP induces channel opening. Functionally, K(ATP) channels provide a means of linking the electrical activity of a cell to its metabolic state. Shortening of the cardiac action potential, smooth muscle relaxation, inhibition of both insulin secretion, and neurotransmitter release are mediated via K(ATP) channels. Given their many physiological functions, K(ATP) channels represent promising drug targets. Sulfonylureas like glibenclamide block K(ATP) channels; they are used in the therapy of type 2 diabetes. Openers of K(ATP) channels (KCOs), for example, relax smooth muscle and induce hypotension. KCOs are chemically heterogeneous and include as different classes as the benzopyrans, cyanoguanidines, thioformamides, thiadiazines, and pyridyl nitrates. Examples for new chemical entities more recently developed as KCOs include cyclobutenediones, dihydropyridine related structures, and tertiary carbinols.

KATP channel openers: structure-activity relationships and therapeutic potential.

A convenient and biogenetic type synthesis of few naturally occurring chromeno dihydrochalcones and their in vitro antileishmanial activity

Improved synthesis of aryl 1,1-dimethylpropargyl ethers

Efficient and general method for the synthesis of benzopyrans by ethylenediamine diacetate-catalyzed reactions of resorcinols with α,β-unsaturated aldehydes. One step synthesis of biologically active (±)-confluentin and (±)-daurichromenic acid

By aldol condensation of 4-chromanones with paraformaldehyde, 3-alkylenechromanones 10 were obtained which gave 3-alkylchromenes following reduction and dehydration. Subsequent 3-chloroperbenzoic acid oxidation produced the versatile epoxide intermediates 15, from which 3,4-epoxy-3,4-dihydro-2,2,3-trimethyl-2H-1-benzopyran-6-carbonitrile (15a) was resolved into its enantiomers by entrainment. In addition to the methyl group, the benzyl, alkyloxymethyl, and 2-nitroethyl residues could be introduced in the 3-position. Treatment of 15a with 2-pyridone simultaneously gave N- and O-substituted products 19a and 20. 19a easily gave 4-(1,2-dihydro-2-oxo-1-pyridyl)chromene 21 by treatment with base. The corresponding pyrrolidinone compounds 26 and 27 were obtained by a slightly modified procedure. Reaction with 2,4-dihydroxypyridine or 3,6-pyridazinediol resulted in the exclusive formation of 4-(heterocyclyloxy)chromanols (31 and 32). Treatment of 15a with 3-amino-6-pyridazinol gave 4-(3-amino-1,6-dihydro-6-oxo-1-pyridazinyl)chromanol derivative 34 lacking an NH bridge. This could be established after methylation of the ring-nitrogen atom (----35). Trans-configurated 3-methyl-4-pyridone compound 36 was obtained by addition of methyllithium to chromene 3. Hyperpolarizing and antispasmodic or relaxing effects of the compounds were determined in organ bath studies using pig coronary arteries precontracted with acetylcholine or rabbit main pulmonary arteries precontracted with noradrenaline. In the 3-methyl series the classical pyridone and pyrrolidinone structures (9, 21, 26, 27) were only weakly active or inactive, but the corresponding 4-(heterocyclyloxy) and 4-(heterocyclylamino) derivatives (31, 32, 35) were even more potent than the demethyl analogues. In conformation/activity investigations it was found that the activity of the 4-substituted benzopyran derivatives seems to be dependent on the relative orientation of their ring systems.

Juergen Harting

Papers

3-Methyl-2H-1-benzopyran potassium channel activators