Novel antiallergic agents. Part I: Synthesis and pharmacology of pyrimidine amide derivatives.

We have synthesized many pyrimidine amide derivatives. Novel pyrimidine bis-glycolic amide derivatives showed moderate inhibition in the rat passive cutaneous anaphylaxis (PCA) assay by oral administration. Among these compounds, 2,4-bis(methoxyacetylamino)-6-piperidinopyrimidine (2i) exhibited significant inhibition. However the compound (2i) did not inhibit antigen-induced histamine or SRS-A release from lung fragments of the guinea-pig at less than 10(-4) M. Derivatives of 2i have also notable or moderate activity in the rat PCA assay. Compound 2h which has no oxygen atom at the alpha-position of the amide carbonyl group and, compound 17 which has no amide carbonyl group, showed no inhibition in the rat PCA assay. We supposed that both the amide carbonyl group and the oxygen atom at alpha-position of the amide carbonyl group play an important role in inhibiting the rat PCA reaction. These pyrimidine bis-glycolic amide derivatives have a novel structure and unique activity which suggests they may be potentially useful in the treatment of allergic diseases.

Novel antiallergic and antiinflammatory agents. Part I: Synthesis and pharmacology of glycolic amide derivatives.

A series of mono-glycoloylamino derivatives was synthesized by treatment of the corresponding aromatic monoamine derivatives with glycoloyl chloride derivatives in pyridine or dichloromethane, in the presence of a base such as triethylamine or pyridine. Hydrolysis of acetoxy compounds in aqueous ammonia and methanol solution produced hydroxy derivatives with ease. These compounds were tested in the rat PCA (passive cutaneous anaphylaxis) assay by oral administration. Thiazole and thiadiazole derivatives showed moderate inhibition in this assay. In contrast, benzothiazole and benzonitrile derivatives exhibited marked inhibition. In particular, compound 5t also showed marked inhibition of eosinophil adhesion to TNF (tumor necrosis factor) -alpha-treated HUVEC (human umbilical vein endothelial cells) in the range of 10(-8)-10(-5) M.

Novel antiallergic and antiinflammatory agents. Part II: Synthesis and pharmacology of TYB-2285 and its related compounds.

A series of m-bis(glycoloylamino)benzene derivatives was synthesized by treatment of the corresponding m-diaminobenzene derivatives with glycoloyl chloride derivatives in pyridine. Hydrolysis of acetyl compounds gave hydroxy derivatives, from which other acyl derivatives could be synthesized. These compounds were tested in the rat PCA (passive cutaneous anaphylaxis) assay by oral administration. Benzonitrile derivatives (4c, 5c, 6c, 4h, 5h) exhibited notable inhibition in this assay. Compounds 5c and 6c also showed remarkable inhibition of eosinophil adhesion to TNF- (tumor necrosis factor) alpha-treated HUVEC (human umbilical vein endothelial cells) in the range of 10(-8)-10(-5) M. Compound 5c is now under investigation in Japan as TYB-2285 (Figure 1) for asthma and atopic dermatitis in phase II clinical studies.

Structure-activity relationships of 8-cycloalkyl-1,3-dipropylxanthines as antagonists of adenosine receptors.

8-Substituted xanthines currently represent the most potent class of adenosine-receptor antagonists. A series of 8-substituted 1,3-dipropylxanthines was prepared and their potency as antagonists of A1 and A2 adenosine receptors of human platelets and rat adipocytes, respectively, were determined. No agents studied were as potent as 8-cyclopentyl-1,3-dipropylxanthine as antagonists of the A1 adenosine receptor, but 8-(2-methylcyclopropyl)-1,3-dipropylxanthine was at least 1000-fold more potent as an antagonist of A1 than of A2 adenosine receptors. While most substitutions on the 8-cycloalkyl moiety caused decreased potency to inhibit both A1 and A2 adenosine receptors, 8-[trans-4-(acetamidomethyl)cyclohexyl]-1,3-dipropylxanthine was nearly equipotent as an antagonist of the two receptors and appeared to be the most potent antagonist of A2 adenosine receptors reported to date.