The Chemsitry of Drugs. III. Acid Hydrolysis of Antimalarial 5-Alkoxy-6,6-dimethyl-5,6-dihydro-s-triazines

S-Alkoxy-6,6-dime~hyl-5,6-dihyd~o-s-triii undergo a fragmentation reaction in refluxing IN HC~.me hydralyric degradation of the antimalarial m 99210 belonging to this class of compovnds was investigatedStudy of the chunicel compatibility of synthetic or natural drugs may provide useful informtion regarding purity.stability, mode of action and alternate synthesis.We considered the anri-malarial& an interesting candidare to explore the validiry of chis concept and report here on the results obtained in srudyinp its acid hydrolysis end its base catalyzed ismerizetion.Arylmethoay-substituted biguanides and their dihydrorriarines obtained in their condensation with acetone, shaved considerable antimicrobial activity virro.3'4Chlorophenoxyalkoxy-substifured represenfafives described showed besides antimicrobial properties also marked antimalarial activity.In particular the 2.4.5-rrichlorophenoxy-subbtituredcompound shared marked suppressive activity againsr Plasmodium berghei infections in mice.6 Compound is an entifalare,' effective against the drug-sensitive N strain, the cycloguanil-resistant B line, a pyrimethamine-resistanr line of P. berghei,' and was found to be not mutagenic in the Ames test. 9 Compound &HC1was for this reason selected by the Walter Reed Army InsLirvte of Research for a human bioavailability s t u d y .' ' in this study &.HC1 shoved pronounced gas~ro-intestinal intolerance and poor bioavailability, and additional human studies were therefore not carried our.The excellent antimalarial properties of la, together wirh its poor bioavailability, poor 3 stability at pH >8 and its rather unappealing structural features, made & an interesting candidate compound to investigate, hoping that such an endeavour would ultimately lead to the development of improved drugs.c , R = H Chemistry: Reflvxing k.HC1 in 1N HC1 for 24 hours gave beside ammonium chloride as the water solvble product and probably originating from gvanylurea by further hydrolysis, the acetone mime ether 2a in 64% yield.The structure of & is in agreement with ire spectral properties, and is secvred by its conversion into the c-substituted hydroxylamine g, isolated as irs HC1 Reduction of 2 with pyridine-borane complex,'' afforded the N-isopropylated hydroxylamine ether &.Conden- sarian af and 5 with dicyanodiamide by the Beecham pr~cedure,~ gave the biguanides 2 and &.Condensation of the biguanide 2 virh acetone in methanol in the presence of conc.HC1 gave the s-dihydrotriazine &.HCl, readily isomerized ra &.HCl virh trieth~lamine.~A similar isomeriracion from into & is snoicahle when ethanolic NaOH is added t o an ethanolic salvtion of &.HCl, and rhe pH of the solution brought >8.The N,O-substituted hydroxylamine & could not be cyelired with acetone vnder similar reaction conditions.A comparison of the original dihydrotriarine hydrochloride (mp 187-189•‹C) with ~.H C 1 prepared here (mp 205-207'C) by tlc revealed fhaf the former sample was conraminaced with about 10-20% of the isomer ~.H c ~.