Syntheses and interferon inducing acitivites are reported for 137 relatives of 1,3-dimethyl-4-(3-dimethylamino-propylamino)-1H-pyrazolo[3,4-b]quinoline (1). Three different generalized synthetic schemes for the preparation of pyrazolo[3,4-b]quinolines are presented and limitations contrasted. Other heterocyclic nuclei containing the 3-dimethylaminopropylamino side chain include pyridine, quinoline, acridine, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-B][1,8]naphthyridine, pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine, dipyrazolo[3,4-b:4',3'-e]pyridine, pyrrolo-[2,3-b]quinoline, isothiazolo[5,4-b]quinoline, and pyrido[2,3-h]pyrazolo[3,4-b]quinoline. Structural requirements for interferon induction in this series are discussed and two of the more active compounds (172 and 196) are compared directly with tilorone.
Procedure.-A 1-ml. aliquot of the reaction mixture was pipeted into a 50-ml. volumetric flask containing a 5-ml. aliquot of aqueous sodium hydroxide (20 g. per 100 ml. of water) and the flask was heated for 10 min. on a steam bath. The flask was cooled and 2.3 ml. of concentrated hydrochloric acid was added in portions with intermittent cooling. A 25-ml. aliquot of aqueous ferric chloride solution (>0.5 g. per 300 ml. of water plus several drops of concentrated hydrochloric acid) was added and the flask diluted to the mark with distilled water. The absorption of the solution was then immediately measured with a Klett-Summerson photoelectric colorimeter; the blank solution consisted of a 25-ml. aliquot of the ferric chloride solution diluted to 50 ml. The same ferric chloride solution was used throughout a kinetic run.The recorded time of the aliquot is that of complete drainage of the 1-ml. pipet.The absorbancy (A) reading of the colorimeter is directly proportional to the concentration of the original sodium benzoyl aliphatic hydroxamate. The first-order rate equation then is20 _ log (A -A") = 2353 + lo8
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