Inhibitory Activities of Novel Pyrimidine Derivatives on the Contact Hypersensitivity Reaction.

Abstract

We recently found that a novel pyrimidine derivative, CX-659S (1) [(S)-6-amino-5-(6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxamido)-3-methyl-1-phenyl-2,4(1H,3H)-pyrimidinedione] ( Fig. 1), had inhibitory activities against a variety of acute and chronic inflammation models when topically applied. [2][3][4] This compound, having a tocopherol-related moiety with a non-steroidal structure, exerted a potent radical scavenging activity and inhibitory effects on lipid peroxidation both in vitro and in vivo. 5)Generally, a chiral compound such as CX-659S has many difficulties for the development of it as a new drug candidate. For example, we must establish an efficient, low cost, synthetic method to prepare it, and conduct a comparative study on its pharmacology and toxicology and so on by using each isomer (R or S) and racemate. Moreover, from the viewpoint of pharmacokinetics, we must confirm whether one isomer converts into the other one in the body or not.In the present study, to avoid the problems mentioned above, we sought to find a new type of compound with a simple structure without chirality. Typical antioxidants without chirality are the polyphenols such as pyrogallol 6) and methoxyphenol.7) So, we synthesized compounds 2a 2) and 2b, having partial antioxidant structures, and evaluated their inhibitory activities toward picryl chloride (PC)-induced contact hypersensitivity reaction (CHR) in mice by the topical administration. The anti-inflammatory activities of 2a and 2b were almost equipotent with that of 1 (Table 1). Compounds 2a and 2b were evaluated as their acetate form, because their free acids were poorly soluble in application solvents such as acetone, ethyl acetate, and EtOH, and could not be used for the evaluation of anti-inflammatory activity in this study. Moreover, as both compounds were found to be unstable due to mainly their deacetylation under the moisture condition (data not shown), we judged that compounds 2a and 2b were not suitable as lead compounds. On the other hand, 2c, 2) having a di-tert-butylphenol moiety, showed a moderate inhibitory activity (ED 50 ϭ0.81 mg/ear), which was 3-fold weaker than that of 1. The di-tert-butylphenol moiety is also well-known to have an anti-oxidative activity, 8) and is widely used as an inexpensive anti-oxidative moiety without chirality. In the present study, we report and discuss our preliminary structure-activity relationship (SAR) study on 2c derivatives as a new type anti-inflammatory drug. ChemistryThe compounds described in this study are shown in Table 1, and their synthetic methods are outlined in Charts 1, 2. The syntheses of analogues were accomplished by the following pathway using the reported methods. Nitrosation of 14 with sodium nitrite followed by catalytic hydrogenation of the nitroso group furnished 15. 9,10) Compounds (2-5, 12, 13) were obtained by the coupling of 15 with the corresponding carboxylic acids by using diphenylphosphoryl chloride (DPP-Cl) as a condensation reagent. Compound 8 was afforded by the reaction of 14 with 2...

Synthesis of Pyrimidine Derivatives Possessing an Antioxidative Property and Their Inhibitory Effects on Picryl Chloride-Induced Contact Hypersensitivity Reaction

“…6-Amino-5-(3,5-di-t-butyl-4-hydroxybenzyl)uracil (3) was synthesized by the reaction of 6-aminouracil (2) with 3,5-di-t-butyl-4-hydroxybenzyl chloride as previously reported. 10) For the synthesis of 5-(3,5-di-tbutyl-4-hydroxybenzyl)barbituric acids (6a-d), first, several N-substituted barbituric acids (4a-d), which were easily prepared 10) by acid-hydrolysis of the corresponding 6-aminouracils, 11) were condensed 12) with 3,5-di-t-butyl-4-hydroxybenzaldehyde to give the 5-benzylidenebarbituric acids (5a-d) in moderate yields. The NMR analysis of an unsymmetrical product (5a) possessing different substituents at the 1,3-N-positions indicates them to be a mixture of E-and Zisomers.…”