K. S. Keshava Murthy

Synthesis of pyrimido[1,4]diazepin-2-one analogs and their evaluation as anticonvulsant agents

5‐Benzyloxycarbonylaminomethylcarbonyl(N‐methyl)amino‐4‐[2‐chloro(2‐fluoro or 2‐hydrogen)benzoyl]pyrimidines (compound 14) in which the chlorophenyl moiety of dipeptidoaminochlorobenzophenones (1) is replaced by a pyrimido ring, and 1,3‐dihydro‐1‐methyl‐5‐[2‐chloro (2‐fluoro or 2‐hydrogen)phenyl]‐2H‐pyrimido[5,4‐e][1,4]diazepin‐2‐ones (16) in which the chlorophenyl moiety of 7‐chloro‐5‐aryl‐benzo[1,4]diazepin‐2‐one (3) is replaced by a pyrimido ring, were synthesized and evaluated as anticonvulsants by using the subcutaneous metrazol‐ (Met) and maximal electroshock– (MES) induced seizure screening tests. Structure‐activity studies showed these two classes of compounds (14, 16) are generally more potent in the Met screen relative to the MES screen. The effect which the nature of the benzoyl C‐4 ortho‐substituent (Cl, F, H) in compound 14, or the ortho‐phenyl C‐5 substituent (Cl, F. H) in compounds 16, has upon anticonvulsant activity was small with the potency profile generally being Cl ≅ F > H. It is proposed that 5‐benzyloxycarbonylaminocarbonyl(N‐methyl)amino‐4‐(2‐fluorobenzoyl)pyrimidine (14b) may act as a prodrug, at least in part, to 1,3‐dihydro‐1‐methyl‐5‐(2‐fluorophenyl)‐2H‐pyrimido[5,4‐e][1,4]diazepin‐2‐one (16b), because 14b does not bind to the benzodiazepine receptor binding site(s), yet it is approximately equipotent to 16b in the Met and MES screens. Compounds 14b and 16b are less active than clonazepam but more active than valproic acid in the Met screen, and less active than phenytoin but more active than clonazepam and valproic acid in the MES screen. Drug Dev. Res. 46:155–162, 1999.

Chemical synthesis of 3-ethylcompactin, an inhibitor of 3-hydroxy-3-methylglutarylcoenzyme A reductase

A method is described for stereocontrolled synthesis of (+)-3-ethylcompactin (1c), a compound that inhibits rat liver HMG CoA reductase with a similar potency to mevinolin. The synthetic approach is a general one and involves linking a pent-4-enal (3) with a substituted cyclohexenone (2). Evans asymmetric alkylation was used (Scheme 2) to prepare the oxazolidinone (6). Ozonolysis, acetalization, and reduction (LiAlH4) then gave the alcohol (9), and this was transformed by Swern oxidation, Wittig methylenation, and acid hydrolysis into (R)-3-ethylpent-4-enal (12). Aldol condensation (Scheme 3) of the cyclohexenone (2) with the aldehyde (12), followed by triethylsilylation, and ozonolysis gave the enone aldehyde (15). A modified McMurry reaction, requiring an excess of a reagent prepared from C8K and TiCl3(2:1 molar ratio) in 1,2-dimethoxyethane, then produced the hexahydronaphthyl ether (16), which was converted into (+)-3-ethylcompactin by appropriate modification of the oxygen functionality.