Equilibrium Studies on 2-(5-Methylthien-3-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (S-135) in n-Octanol

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The partition equilibrium of 2-(5-methylthien-3-yl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (S-135) in n-octanol (n-OcOH)-water system was studied. S-135,which was developed as a drug for activating depressed brain function, could be easily partitioned into n-OcOH from water with a coefficient (p) of about 40 as the ratio of the concentration in the organic phase to the aqueous phase. In alkaline solution above pH 11,S-135 with a pK_a, value of 9.44 decreased the parition ratio up to about 5 with an increase in nuextractable sodium salt dissociated in the aqueous phase. When extracted in more alkaline solution above pH 13,the distribution increased to p=15,in spite of the fact that sodium salt alone was present. The distribution ratio increased as the concentrations of n-OcOH and NaOH increased in the mixed solvent system of n-OcOH, n-hexane and aqueous alkaline solution. The acid-base equilibrium in n-OcOH and the partition equilibrium between n-OcOH and the strongly alkaline system were examined to determine the species extracted in n-OcOH. The extracted species of S-135 was not a monosodium salt but a complex salt associated with both the solvent molecule and NaOH. The salt isolated from the 5 N NaOH solution containing NaOH in its structure differed in physico-chemical character from the monosodium salt, thus supporting the validity of the partition equilibrium.
公益社団法人日本薬学会の論文
1993-01-15