Paul Barraclough

A simple synthesis of a stable thromboxane A2 analogue

Abstract A simple synthetic route, which appears to have some general utility, has been used to obtain a Bicyclo[2.2.1]heptane analogue of Thromboxane A 2 .

Synthesis of kainoid analogues

Abstract 4-oxoproline has been used as a chiral template in a synthesis of kainoid analogues which are epimeric with the parent compound at C-3.

Synthesis of hexahydrocyclopentimidazol-2-(1H)-one derivatives displaying selective DP-receptor agonist properties

The rationale for investigating conformationally restricted analogues of BW245C as DP-receptor ligands and the syntheses of three such racemic bicyclic imidazolidinone analogues are described. Compounds 7 (BW587C), 8 (BW480C85), and 9 (BW572C85) were found to be potent inhibitors of human platelet aggregation and selective DP-receptor agonists in washed platelet and jugular vein isolated tissue assays.

An adventitious synthesis of a 5-methylimidazo[4,5-c]pyridine derivative

Abstract At 210° in the melt 2-(4-Cyano-2-methoxyphenyl)-1 H -imidazo[4,5- c ]pyridine( 2 ) undergoes isomerization to give 2-(4-cyano-2-hydroxyphenyl)-5-methylimidazo[4,5- c ]pyridine ( 3a ).

Two separate and distinct syntheses of stereospecifically deuteriated samples of (2S)-proline

Two distinct syntheses of samples of the amino acid L-proline which are stereospecifically deuteriated on the beta-carbon atom are reported. In the first of these, the labelled diazoketones 6, prepared by a chemico-enzymatic synthesis, have been photolysed in alkaline conditions to give the corresponding labelled methyl pyroglutamates 10 via hydrolysis and intramolecular trapping of the resultant ketene intermediates 9. These were then converted into (2S,3S)-[3-(2)H1]- and (2S,3R)-[2,3-(2)H2]-proline, 1a and 1b respectively. The second synthesis provides (2S)-[3,3-(2)H2]-, (2S,3S)- and (2S,3R)-[3-(2)H1]-proline, 1d, 1a and 1c respectively, and has as its key step the highly stereoselective hydrolysis of the silylenol ethers 14 and 14a respectively in which deuteriation or protonation occurs from the re-face of the enol ether.

Conjugative and homoconjugative effects in 2-heterobicyclo[3.2.1]octa-3,6-dienes

Abstract The 1 H-NMR, 13 C-NMR and photoelectron spectra of a variety of 2-heterobicyclo[3.2.1]octa-3,6-dienes 6 give evidence of conjugative and homoeonjugative effects in these compounds, but there is no suggestion from the data of any special contribution from the (4n+2)π neutral bishomoaromatic system. Reaction of the dienes 6 with TCNE invariably yielded the product of [2+2] addition in cases where a fully characterisable product was obtained.

Synthesis and pharmacological properties of BW315c and other inotropic 2-arylimidazo[1,2-a]pyrazines

A series of 2-aryl imidazo[1,2-a]pyrazines has been prepared and evaluated for inotropic activity. Sulphoxide 12, BW315C, displayed potent inotropic effects having comparable in vitro and vivo inotropic potencies to those of isomazole. Structure-activity relationships are discussed.

Synthesis and platelet aggregation inhibiting activity of 1'-carboxyl modified hydantoin prostaglandin analogues

A series of hydantoin prostaglandin analogues, in which the 1′-carboxy group was replaced by tetrazole, amine, alcohol, amide, cyanamide, or sulphonamide functionalities, was prepared and evaluated for platelet aggregation inhibiting activity. The 2′-decarboxy-2′-(tetrazol-5-yl) analogue (30) proved to have interesting activity, being approximately equipotent (ca. 17 × PGE1) to BW245C (1). Activity was often lost when the carboxy group was replaced by neutral or basic moieties. Substitution of the carboxy terminus by other groups of similar acidity gave rise to reduced activity. These results suggest that the platelet receptor which mediates these effects possesses a cationic site requiring binding of an anionic group at the agonist 1′-position. However, additional factors are clearly involved in determining agonist potency.

Synthesis of 2-heterobicyclo[3.2.1]octanes and the corresponding monoenes and dienes

Abstract Synthesis of the theoretically interesting 2-heterobicyclo[3.2.1.]octa-3,6-dienes and their dihydro-and tetrahydro-derivatives has been achieved in the oxygen, nitrogen and sulphur series. The parent compound of the nitrogen series appears to exist as 2-azabicyclo[3.2.1]octa-2,6-diene rather than as the enamine (3, R=H). The Cope rearrangement equilibrium ( 2 , X=NR)⇌( 3 ) lies more to the side of the diene 3 when nitrogen is substituted with an electron withdrawing group than when an alkyl substituent is present. These effects seem to suggest no special bishomoconjugative stabilisation in the dienes 3.

Synthesis of

The base-catalysed hydrolysis of oxazolidin-2-one 15 gives an oxypropanolamine 7 and 4,5-dihydro-1H-imidazo[4,5-c]pyridin-4-ones (17–19) and may occur by a B AL mechanism.