A new series of radiopaque compounds; further notes on the cholecystographic uses of certain iodinated hydroxyphenyl fatty acids.

Abstract

A recent paper by Jones, Grohowski, Robertson, Ramsey, Schilling, and Strain on the use of 2-(4-hydroxy-3, 5-diiodobenzyl) benzoic acid for the visualization of the gallbladder and extrahepatic biliary ducts in dogs (1) prompted us to review our notes on a similar project upon which we are still engaged (2). Our results with the use of certain 3,5-diiodo-4-hydroxyphenyl aliphatic and alicyclic acids were reported in 1946. In this series we studied but did not report on the compound described by Jones and his co-workers. This compound was prepared and tested by us on ten normal human subjects. It was then abandoned because the resulting gallbladder visualization twelve hours after the oral ingestion of doses of 3 and 5 gm. was considered less satisfactory than that obtained with related compounds. The material was well tolerated but was excreted rapidly through the urinary tract. Iodine excretion studies in four patients showed that 4.6 to 4.8 gm. were recovered from the urine and stool in forty-eight hours after the intake of 5 gm. No visualization of the extrahepatic biliary ducts was noted at that time or on recent re-examination of the films. For human gallbladder visualization compounds are required which are relatively more fat-soluble, and the freedom from toxicity encountered in the series we reported encouraged us to proceed with our investigations. At the time of our original communication we had found that the product which afforded the best visualization was alpha-(3,5-diiodo-4-hydroxybenzyl) caproic acid. When this substance was prepared in the laboratory and used soon thereafter, there was practically no reaction after oral ingestion, and studies on laboratory animals with intravenous administration showed correspondingly low toxicity (3). It was found, nevertheless, that on standing for several months the compound became instable, causing diarrhea and epigastric distress in many patients. We therefore directed our search for a better cholecystographic medium to its related compounds. One of the lines of investigation was to modify 2(4-hydroxy-3,5-diiodobenzyl)benzoic acid so as to make it more fat-soluble. This was accomplished in two ways: first, by adding two methyl groups to the benzoic acid part of the molecule, as shown in Compound II below; and second, by preparing a compound with a reduced benzoic acid residue so as to produce a cyclohexyl group instead of a phenyl group (Compound III). Both of these compounds were found superior to the patent compound for use in the human subject. Of these, the preparation of Compound III is easier and it has been selected, therefore, for more intensive investigation, the results of which will be reported later (4). It was believed that the relatively low melting point (98–100° C.) of the alpha(3,5-diiodo-4-hydroxybenzyl)caproic acid might have been in some way related to the relative instability of the substance.