Synthesis of Pyrimidine Derivatives Possessing an Antioxidative Property and Their Inhibitory Effects on Picryl Chloride-Induced Contact Hypersensitivity Reaction
Chemical and pharmaceutical bulletin
Recently, patients suffering from allergic cutaneous disorders such as atopic dermatitis and allergic contact dermatitis have been increasing in number. T cell-mediated delayed type hypersensitivity (DTH) reactions are thought to be involved in these diseases. 1) Many antiallergic drugs are clinically used for treatment of these dermatitis, but they are not very efficacious because these drugs are not effective against DTH reactions. Glucocorticoids have a suppressive effect against DTH
... against DTH reactions, and are widely used for the treatment of these disorders. However, long-time use of glucocorticoids is limited because of its many side effects, such as atrophia cutis and infections. Therefore, development of non-steroidal agents having inhibitory activity against DTH reactions and low toxicity has been ardently desired. In the pathogenesis of many inflammatory skin diseases, there are both direct and indirect evidences implicating a reactive oxygen species (ROS) such as superoxide and hydrogen peroxide. 2) Overproduction of ROS has also been postulated for immune-mediated skin diseases such as atopic dermatitis, contact dermatitis, and psoriasis. 3) Monocytes or neutrophils of these patients show an increased capacity to release ROS. 4,5) Therefore, compounds having inhibitory activity on the production and/or scavenging of ROS may be effective against DTH reactions. For example, tocopherol was reported to show a suppressive effect on chemical hapten-induced contact hypersensitivity reaction (CHR), one of the DTH models, 6) and showed efficacy against atopic dermatitis in clinic. 7, 8) In a previous paper, we described antiallergic activities against DTH reaction of various 5-acylamido-6-aminouracil derivatives, which originated from the lead compound (1) with an antioxidative activity. 9) We describe herein the synthesis and suppressive effects against picryl chloride (PC)-induced CHR of novel pyrimidine derivatives, such as barbituric acids and uracils, having a 2,6-di-t-butylphenol moiety at the side chain of the C(5) or C(6)-position of the pyrimidine ring. We conducted a preliminary structure-activity relationship (SAR) study of some barbituric acid and uracil derivatives against the picryl chloride-induced contact hypersensitivity reaction. The introduction of an antioxidative moiety to the side chain of the C(6)-position of uracil was effective against this model. The introduction of dimethoxyphenol (8b) or dimethylphenol (8c) instead of di-t-butylphenol (8a) as an antioxidative moiety gave diminished activities, so, the reactive oxygen would contribute to the inflammation of this model, and an antioxidative activity was required for exhibiting the inhibitory activity. The inhibitory activity was significantly affected by the substituent at the N(1)-phenyl moiety.