Preparation and antiinflammatory activity of 2- and 4-pyridones.

Several N-alkyl- and N-arylacetoacetamides have been self-condensed to form pyridones. N-Alkylacetoacetamides give 2-pyridones, while N-arylacetoacetamides give 4-pyridones. In an attempt to develop nonacidic, nonsteroidal antiinflammatory agents, the pyridones were tested in a carrageenan-induced pedal edema assay in rats. While the 2-pyridones were not active, 9 of 17 4-pyridones tested were active, and one compound (4g) had antiinflammatory efficacy in a dose-response assay (ED50 values). Most compounds were considered nontoxic by determination of approximate LD50 values in mice by a standard multidimensional observational assay.

Effect of structural change on acute toxicity and antiinflammatory activity in a series of imidazothiazoles and thiazolobenzimidazoles.

The effect of structural change on the biological activity of a series of imidazothiazoles and thiazolobenzimidazoles is described. It was found that compounds with polar substituents at the 2 or 3 position of the ring system are less acutely toxic while maintaining antiinflammatory activity. Other structural changes, such as the incorporation of a gem-dimethyl substituent in the 6 position, increase acute toxicity and eliminate antiinflammatory activity. The compound with the best activity/toxicity ratio contains an alkyl sulfonyl substituent on the thiazole ring. The thiazolobenzimidazole analogues are more potent than the imidazole analogues.

Antihypertensive 5,6-diarylpyridazin-3-ones.

The synthesis of a series of 5,6-diarylpyridazinones is described. Some members of this series display an antihypertensive effect in both the spontaneously hypertensive rat (SHR) model and the deoxycorticosteroid (DOCA) model of hypertension. The most potent compounds in the series have halogen substituents on the 5,6-diphenyl rings, a beta-substituted alkyl group at the 2 position of the ring, and acetyl or cyano substituent at the 4 position.

Synthesis and anti-inflammatory evaluation of 3-methylthio-1,2,4-triazines, 3-alkoxy-1,2,4-triazines, and 3-aryloxy-1,2,4-triazines.

To develop nonacidic, nonsteroidal anti-inflammatory agents without GI complications, a series of asymmetric triazines was synthesized and evaluated for anti-inflammatory efficacy in the carrageenan-induced pedal edema assay. Toxicity was estimated by determination of approximate LD50 values in mice. Twenty-five compounds possessed activity comparable to the standard, indomethacin. Thirteen of the 25 compounds were selected for dose-response evaluation in the carrageenan assay based on their relative toxicity and anti-inflammatory activity. Neurotoxicity of the 13 triazines was estimated by determination of NTD50 values in mice. Five of the 13 compounds tested in the dose-response assay were active in terms of anti-inflammatory efficacy (ED50 values) and lack of overt neurotoxicity (NTD50 values) when compared to indomethacin. To determine the effect of these five developmental triazines on chronic inflammation, they were evaluated in the adjuvant-induced polyarthritis assay. One was comparable to indomethacin in reducing adjuvant-induced inflammation in this assay.

Synthesis and antihypertensive activity of novel 3-hydrazino-5-phenyl-1,2,4-triazines.

In an effort to develop antihypertensive agents with peripheral vasodilator activity, a series of 40 novel 3-hydrazino-5-phenyl-1,2,4-triazines (II) were synthesized and evaluated in the spontaneously hypertensive rat assay (SHR assay). Based on the performance of the structurally related standard, hydralazine (I), 15 triazines were active. Thirteen of these hypotensive triazines possessed LD50 values in the mouse greater than I (LD50 = 100 mg/kg); only one active triazine had an LD50 value greater than 300 mg/kg (11d). Four asymmetric triazines had moderate antihypertensive activity and LD50 values greater than 300 mg/kg (6b, 7c, 8f, and 9g). Based on the relationship between toxicity and antihypertensive activity, three triazines (8f, 9g, and 11d) were chosen for dose-responses studies in the SHR assay. None were as efficacious as I, but all three were less toxic, resulting in similar therapeutic indices relative to I.