Excavations in drug chirality: 1. Cyclothiazide

Abstract

There is a great deal of current interest in the role and importance of chirality in the development of new drugs, but little attention is being paid to the stereochemistry of older drugs. Indeed, many older chiral drugs were introduced without adequate information on their stereochemical identity or composition. We have examined one such drug, the antihypertensive diuretic agent cyclothiazide. Standard sources of drug information and the research literature do not provide data on the stereochemical composition of clinically used cyclothiazide, although scattered reports indicate that the drug may consist of "several stereoisomers." Inspection of the chemical structure of the drug, 6-chloro-3,4-dihydro-3-(5-norbornen-2-yl)-2H-1,2,4-benzothiadiazin e-7- sulfonamide 1,1-dioxide, shows that it can exist as eight stereoisomers that may form four racemates. Using synthesis, fast-atom-bombardment mass spectrometry, gas-liquid chromatography, chiral and nonchiral high-performance liquid chromatography, and nuclear magnetic resonance spectroscopy, we determined that pharmaceutical cyclothiazide is in fact a mixture of the eight stereoisomers in the form of the four racemates. The two racemates with endo configuration at the norbornene moiety predominate over the exo racemates, and small but significant differences in isomer distribution between different batches of the drug were observed. We urge that in studies of older drugs the stereochemical details be considered.

Pharmaceuticals that contain polycyclic hydrocarbon scaffolds

“…139 Still, the process was costly and possibly not environmentally sustainable. Attempts to develop a total synthesis for this diterpene class commenced in the 1980s and it was recognised that development of a synthetic approach for ingenol (45) 140 would allow synthesis of multiple analogues, including ingenol mebutate. However, it has only been recently, with the publication by Baran et al of a 14 step synthesis of (+)-ingenol (45) from (+)-3-carene (46), that fully synthetic commercial production has become a potentially viable option.…”

“…Scheme 9 Key stages in the final synthesis of ingenol (45). Paclitaxel is the original pharmaceutical taxane.…”

“…[40][41][42][43][44] Information about the stereochemical consistency of this drug is very limited. A report by Gal 45 determined, using a range of modern analytical techniques, that, of the eight possible stereochemical isomers (i.e. four racemates), all are present in the marketed drug.…”

“…Semi-synthesis from the commercially available natural product ingenol (45), extracted from E. lathyris seeds, 137 has been explored as an avenue to obtain commercially relevant amounts of ingenol mebutate. 138 However, only 275 mg of ingenol ( 45) could be extracted per kg of seeds and further synthesis was still required.…”

“…138 However, only 275 mg of ingenol ( 45) could be extracted per kg of seeds and further synthesis was still required. 137 In 2013, a new extraction process was patented claiming an extraction of 750 mg of ingenol (45) per kg of seeds. 139 Still, the process was costly and possibly not environmentally sustainable.…”