Triazolinones as nonpeptide angiotensin II antagonists. 1. Synthesis and evaluation of potent 2,4,5-trisubstituted triazolinones.

A series of 2,4-dihydro-2,4,5-trisubstituted-3H-1,2,4-triazol-3-ones was prepared via several synthetic routes and evaluated as AII receptor antagonists in vitro and in vivo. The preferred compounds contained a [2'-(5-tetrazolyl)biphenyl-4-yl]methyl side chain at N4 and an n-butyl group at C5. A number of these bearing an alkyl or aralkyl substituent at N2 showed in vitro potency in the nanomolar range (rabbit aorta membrane receptor), and several of these, e.g., the 2,2-dimethyl-1-propyl analogue (54, IC50 = 2.1 nM), effectively blocked the AII pressor response in conscious rats with significant duration (2.5 h at 1 mg/kg orally for 54). Among analogues possessing aryl substituents at N2, ortho substitution on the phenyl moiety resulted in several derivatives with in vitro potency in the low nanomolar range. One of these, featuring a 2-(trifluoromethyl)phenyl substituent at N2 (25, IC50 = 1.2 nM), was effective at 1 mg/kg orally in the rat model, with a duration of > 6 h. Implications for hydrophobic and hydrogen-bonding interactions with the AT1 receptor are discussed.

Nonpeptide angiotensin II antagonists derived from 4H-1,2,4-triazoles and 3H-imidazo[1,2-b][1,2,4]triazoles.

By a variety of synthetic routes, we have synthesized a series of 3,4,5-trisubstituted 4H-1,2,4-triazoles and a related series of 3H-imidazo[1,2-b][1,2,4]triazoles and evaluated them in vitro and in vivo as angiotensin II (AII) antagonists. Principal efforts focused on triazoles bearing an n-alkyl substitutent at C3 and a 4-[(2-carboxybenzoyl)amino]benzyl, (2'-carboxybiphenyl-4-yl)methyl, or [2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl side chain at N4. Among numerous variations at C5, benzylthio groups gave the best potency. Particularly noteworthy was 3-n-butyl-5-[(2-carboxybenzyl)thio]-4-[[2'-(1H-tetrazol-5-yl )biphenyl-4 - yl]methyl]-4H-1,2,4-triazole (71, IC50 1.4 nM), which blocked the AII pressor response in conscious rats at 0.3 mg/kg iv with a duration of action of approximately 6 h, similar to that of DuP 753. Although 71 was active orally only at a 10-fold higher dose level, good oral bioavailability was demonstrated for a monoacidic analogue 62. Most potent among the bicyclic derivatives was 2-n-butyl-5,6-dimethyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]meth yl]- 3H-imidazo[1,2-b][1,2,4]triazole (93, IC50 7.8 nM). The effects of hydrophobic, hydrogen-bonding, and ionic interactions with the AT1 receptor are considered.

Antibacterial N-[omega,omega'-bis(alicyclic and aryl)-sec-alkyl]-1,3-diamino-2-propanol dihydrochloride salts.

A series of 14 antibacterial N-[omega,omega'-bis(cycloalkyl, bicyclo[2.2.1]heptyl, and substituted phenyl)-sec-alkyl]-1,3-diamino-2-propanol dihydrochloride salts were synthesized as potential topical antiseptics and disinfectants. Four derivatives which were particularly effective against Pseudomonas aeruginosa encompassed the three diverse ring-type substituents and an 8-n-pentadecyl moiety. The calculated Hansch hydrophobic parameter (pi) for the N-substituents of the more efficient compounds were in the range 7.0--9.0 and correlated with minimal inhibitory activity as a parabola for all of the products under the assay conditions. The potencies against Gram-positive and other Gram-negative bacteria were comparable to benzalkonium chloride and chlorhexidine.

Antibacterial N-[omega, omega'-bis(alicyclic and aryl)-sec-alkyl]poly(methylene)triamine and -tetramine hydrochloride salts.

A series of antibacterial N-(omega, omega'-(cycloalkyl, bicyclo[2.2.1]heptyl, and alkyl-substituted phenyl)-sec-alkyl]poly(methylene)triamine and -tetramine hydrochloride salts were synthesized in an effort to develop efficient, nonsystemic inhibitors, particularly for Pseudomonas aeruginosa. In the 1,5,9-triazanonane group, 3 of 16 compounds were effective at 8--10 micrograms/mL against pseudomonads. Efficiency appeared more dependent upon lipophilicity of the nitrogen substituent than other characteristics represented by the three types of rings. A parabolic relationship was observed for the entire set between the hydrophobic parameter, pi, of the lipoidal moiety and minimal inhibitory concentration. One of 16 tetramines, 1-[1,5-bis(3,3-dimethyl-2-norbornyl)-3-pentyl]-1,5,9,13-tetraazatridecane tetrahydrochloride (26f), ranked similarly. An additional two compounds in each series were superior to several commercial cationic detergents in the control of the Gram-negative bacteria. None was inhibitory at up to 200 micrograms/mL for Proteus vulgaris.

Synthesis and biological evaluation of 1-(4-hydroxy-2-oxo-2H-1-benzopyran-3-yl)pyridinium hydroxide inner salt derivatives.

Eight 1-(4-hydroxy-2-oxo-2H-1-benzopyran-3-yl)pyridinium hydroxide inner salts were synthesized, and the antibacterial, antifungal, anticoccidial, and anthelmintic activities were determined against different microorganisms, the protozoan Eimeria tenella, and trichostrongyle nematodes. All were noninhibitory to Gram-negative bacteria and the parasites. The pyridine, 4-benzylpyridine, and 2-isoquinoline inner salt derivatives controlled only Rhizoctonia solani of the four genera of fungi challenged.