Stephen L. Condon

Synthesis and Structure Determination of (3S, 5S)-2,3,5,6-Tetrahydro-3,5-dialkyl-N-(tert-butyloxycarbonyl)-4H-1,4-oxazine-2-ones

Abstract (5S)-2,3,5,6-Tetrahydro-5-alkyl-N-(tert-butyloxycarbonyl)-4H-1,4-oxazine-2-ones, which are readily prepared from optically pure 2-amino alcohols alkylate selectively at the C-3 position to give (3S, 5S)-dialkyl-2,3,5,6-tetrahydro-5-alkyl-N-(tert-butyloxycarbonyl)-4H-1,4-oxazine-2-ones in good yield. The structures of compounds 3e, 5c, 5g, 6h, and 5h (p-bromobenzoate) were determined by single crystal X-ray analysis. The structure of 5b was determined by conversion to optically active diols 6 and 7 and the structure of 5f was determined by correlation to 5c.

A Practical Synthesis of the Dihydroxyethylene Dipeptide Isostere, (2S, 3R, 4S) 2-[(tert-Butyloxycarbonyl)amino]-1-cyclohexyl-3,4-dihydroxy-6-methylheptane, from D-Isoascorbic Acid

Abstract The N-Boc dihydroxyethylene dipeptide isostere 7 and its N-Boc 3-(thiazol-4-yl)alanyl derivative 8 were synthesized, without purification of intermediates, from (4S,5R)-2,2-dimethyl-4-(2-methylpropyl)-5-hydroxymethyl-1,3-dioxolane ( 3b ), in 24 and 32% overall yield, respectively. Alcohol 3b was readily prepared from inexpensive and commercially available D-isoascorbic acid in four steps. The synthesis featured a stereoselective addition of cyclohexylmethyllithium to the dimethyl hydrazone of (4S,5S)-2,2-dimethyl-4-(2-methylpropyl)-5-formyl-1,3-dioxolane ( 4 ).

Conformationally restricted peptide isosteres. 2.1 Synthesis and in vitro potency of dipeptide renin inhibitors employing a 2-alkylsulfonyl-3-phenylcyclopropane carboxamide as a P3 amino acid replacement ☆

Abstract A series of dipeptide renin inhibitors employing a 2,3-disubstituted cyclopropane carboxamide at the P3 position of the molecule were prepared by coupling racemic(IS,2R,3R) 2-alkylsulfonyl-3-phenyl(or cyclohexyl)cyclopropanecarboxylic acid with the amino acid derivatives 11a–d. The individual diastereomers were separated and tested for in vitro potency. IC50 values ranged from 0.37 to 1.4 nM and 5.8 to 29 nm against purified, pH 6.0 and plasma, pH 7.4 human renin, respectively. In all examples, the more polar diastereomer was the most potent.

Synthesis and In Vitro evaluation of fused ring heterocyle-containing angiotensin II antagonists.

Abstract Fused ring heterocyclic analogs of A-81080 (pA2= 9.9) were synthesized and their activities in the rabbit aorta in vitro assay were measued. The best compounds (pA2 = 8.6) in series 1 had R1 = Et, R2 = H, W = X = Z = C-H, and Y = C-OMe or C-COOH. In series 2, the best compound (pA2 = 8.3) had R1 = Et, R2 = H, W = N-Me, X = C-H, and Y = N.

Synthesis of the Nonpeptide Renin Inhibitor A-68064 and the ACE Inhibitor Methyl Enalaprilat from (5S)-2,3,5,6-Tetrahydro-5-alkyl-N-(tert-butyloxycarbonyl-4H-1,4-oxazine-2-ones

Abstract The nonpeptide renin inhibitor, A-68064, and the ACE inhibitor methyl enalaprilat were synthesized from (5S) 2,3,5,6-tetrahydro-5-benzyl(butyl)-N-(tert-butoxycarbonyl)-4H-1,4-oxazine-2-ones 7a and 7b, and (5S) 2,3,5,6-tetrahydro-5-methyl-N-(tert-butoxycarbonyl)-4H-1,4-oxazine-2-one 12, respectively.

Slow, tight binding to human renin of some nonpeptidic renin inhibitors containing a 4‐methoxymethoxypiperidinylamide at the P4 position

A series of nonpeptidic human renin inhibitors with a 4‐methoxymethoxypiperidinylamide at the P4 position of the molecule exhibited slow tight binding to the enzyme. Replacement of the methoxymethoxy moiety on the piperidine ring with H, OH, methoxyethyl, propyloxy or n‐butyl eliminated the effect. The inhibition was partially reversed by prolonged dialysis at 4°C, arguing against formation of a covalent bond in the tightened complex.