IDENTIFICATION BY DISTRIBUTION STUDIES. IX. APPLICATION TO METABOLIC STUDIES OF 4-AMINOQUINOLINE ANTIMALARIALS¹

Abstract

Although the capacity of the animal organism for causing transformations of drugs has been recognized, many studies of the pharmacological or therapeutic activities of various substances appear in which this factor has not been taken into consideration. Thus frequently, the observed effect has been related to the dosage of a given drug or to drug levels in various parts of the body as determined spectrophotometrically. By the latter method, confusion may occur between the identification of the drug administered and metabolic products of the drug which, while actually being the active agent or agents, still sholy spectrographic properties closely similar to the drug itself. Often this has been the only feasible approach because of the difficulty in the detection, isolation and identification of the small amounts of the transformation products carried in the complicated mixture present in the biological fluids. The need for such information, often realized in the past, is obvious for the proper evaluation or interpretation of the underlying cause of the desired effect.The method of counter-current distribution (1) is an approach which should prove helpful for the problem as stated, because of the quantitative nature of the process and other advantages mentioned in previous publications (2). An excellent opportunity to test this thesis came with the appraisal of the 4-aminoquinoline group of drugs as among the most effective suppressive antimalarials, and the need for knowledge of the fate and physiological disposition of representative members of the series. It was thought that information on the mechanism of detoxification of the drugs could prove of value both as a guide to more efficient administration of the substances and as a source of leads for the synthesis of perhaps even more highly useful drugs.In the present investigation, the metabolic fate of three typical 4-aminoquinolines as indicated by the nature of the degradation products isolated from the urine of normal human volunteers receiving the drugs has been the subject of a preliminary study. Unfortunately, termination of hostilities prevented accumulation of sufficient material to enable the studies to be carried as far as might have been desired. The drugs investigated were 4-(4-diethylamino-1-methylbutylamino)-7-chloroquinoline (chloroquine) (SN-7618) (I),2 4-(3-di-

Chain extenders for polyesters. V. Reactivities of hydroxyl-addition-type chain extender; 2,2′-bis(4h-3,1-benzoxazin-4-one)

“…We have calculated the number of coupled hydroxyl groups (HV,) after 5 min reaction, and plotted it vs. HV, as shown in Figure 6. We have approximated HV, to the "decrease of total terminal groups," which can be calculated by measurement of the number-average molecular weight: (5) where N, means N of the resulting polymer.…”

An ANTIMALARIAL ALKALOID FROM HYDRANGEA. VII. 3-[Β-Keto-Γ-(5-Hydroxy-2-Piperidyl)propyl]-4-Quinazolone, AN ISOMER

“…The green copper derivative was collected and washed with alcohol until the washings were colorless; yield, 113 g. (34%). The use of purified epoxypropylphthalimide (7) gave the same yield. When the reaction wras run at 25°for 16 hours the yield was also the same.…”

“…of methanol and 1.85 cc. of 1 N methanolic sodium methoxide was added 420 mg. of epoxypropylphthalimide (7).…”

Simple Synthesis of β-Acetoxy Thiocyanates from Oxiranes

“…At first, the ring opening of epoxides 1a, b was investigated. The known epoxide 1a [26] was prepared from potassium phthalimide and epichlorohydrin (66%), whereas epoxide 1b [27] from N-hydroxyphthalimide [28] and epibromohydrin (55%). In our experiments, 18-crown-6 was Scheme 1.…”