- Synthesis and structure-activity relationships of phenothiazine carboxylic acids having pyrimidine-dione as novel histamine H1 antagonists
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A series of phenothiazine carboxylic acid derivatives, having 6-amino-pyrimidine-2,4(1H,3H)-dione moiety via a appropriate linker, were synthesized and evaluated for their affinity toward human histamine H1 receptor and Caco-2 cell permeability. Selected compounds were further evaluated for their oral anti-histaminic activity in mice and bioavailability in rats. Finally, promising compounds were examined for their anti-inflammatory potential in mice OVA-induced biphasic cutaneous reaction model. Among the compounds tested, phenothiazineacetic acid compound 27 showed both histamine H1-receptor antagonistic activity and anti-inflammatory activity in vivo model.
- Kubota, Katsumi,Kurebayashi, Hirotaka,Miyachi, Hirotaka,Tobe, Masanori,Onishi, Masako,Isobe, Yoshiaki
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scheme or table
p. 2766 - 2771
(2009/12/31)
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- Compounds
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The invention provides compounds of general formula (I) wherein: R1represents optionally substituted, C1-C12alkyl or optionally substituted 3- to 10-membered saturated or unsaturated ring system comprising up to two ring carbon atoms that form carbonyl groups and comprising up to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulfur; m is 0-1; Q represents OCH2, C1-C4alkylene or C2-C4alkenylene; T represents C(O)NH, or when m is 0, T may additionally represent a bond or NH, or when m is 1 and Q represents C1-C4alkylene, T may additionally represent NH; n is 1-4; each R2and R3independently represents H or C1-C4alkyl; V represents N, and W represents N or CH; X represents O, C(O), CH(OH), SO2, NH or N(C1-C6alkyl), provided that when W represents N, then X represents either C(O) or SO2and when W represents CH, then X is other than SO2; R4represents optionally substituted phenyl; R5and R6each independently represent H, C1-C6alkyl or hydroxyC1-C6alkyl, or R5and R6together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R7and R8each independently represent H or C1-C6alkyl; and R9represents OH or —NR7R8; processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
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