HLö 7 dimethanesulfonate, a potent bispyridinium-dioxime against anticholinesterases

HLo 7 dimethanesulfonate (1-[[[4-(aminocarbonyl)pyridinio] methoxy] methyl] -2,4-bis [(hydroxyimino) methyl]pyridinium dimethanesulfonate) is a broad-spectrum reactivator against highly toxic organophosphorus compounds. The compound was synthesized by a new route with the carcinogenic bis(chloromethyl)ether being substituted by the non-mutagenic bis(methylsulfonoxymethyl)ether. The very soluble dimethanesulfonate of obidoxime was also prepared by this way. HLo 7 dimethanesulfonate is the first water-soluble salt of HLo 7 that should be suitable for the wet/dry autoinjector technology, because aqueous solutions of HLo 7 are not very stable (calculated shelf-life 0.2 years when stored at 8°C, 1 M solution, pH 2.5). The crystalline preparation contains 96% of thesyn/syn-isomer, less than 2% of thesyn/anti-isomer and some minor identified by-products. HLo 7 was very efficient in reactivating acetylcholinesterase (AChE) blocked by organophosphates as long as ageing did not prevent dephosphylation. HLo 7 was superior to HI 6 (1-[[[4-(aminocarbonyl)pyridinio]methoxy]methyl]-2-[(hydroxyimino)methyl]pyridinium dichloride) in reactivating soman and sarin-inhibited AChE from erythrocytes, and literature data indicate that HLo 7 exceeds HI 6 by far in reactivating tabun-inhibited AChE. In atropine-protected, soman-poisoned mice HLo 7 was three times more potent than HI 6 (protective ratio 5 versus 2.5), and in sarin-poisoned mice HLo 7 was 10 times more potent than HI 6 (protective ratio 8 for both oximes). In atropine-protected guinea-pigs HLo 7 was less effective than HI 6 (protective ratio: 2.3 versus 5.2 for soman; 5.2 versus 6.8 for sarin; 4.3 versus 3.8 for tabun). The mean survival time of anaesthetized guinea-pigs exposed to 5 LD50 soman (6.3 min) was increased by atropine (27 min) and atropine + HLo 7 (57 min). HLo 7 alone did not prolong the survival. The most impressive effect of HLo 7 was on respiration: 3 min after i.v. injection of HLo 7 and atropine, the depressed respiration increased rapidly to 60% of control and remained at that level during the observation period (60 min). With atropine alone, respiration recovered only slowly. Behavioural and physiologic parameters were determined in atropine-protected mice exposed to a sublethal soman dose. The running performance was significantly improved by HLo 7. Even central symptoms, e.g. hypothermia and convulsions, were decreased markedly by HLo 7 (evaluation 60 min after poisoning). The pharmacokinetic data for HLo 7 in male beagle dogs are similar to those of HI 6. After i.v. injection: t1/2α = 5 min; t1/2s = 46 min; VD = 0.24 1/kg; Clp1 = 3.7 ml x min−1 x kg−1; Clren= 3.2 ml x min−1 x kg−1; renal excretion of unchanged HLo 7 = 86%. After i. m. injection: t1/2abs = 14 min; t1/2s = 48 min; Vd = 0.27 1/kg; Clp1= 3.9 ml x min−1 x kg−1; Clren= 2.7 ml x min−1 x kg−1; renal excretion of unchanged HLo 7 = 76%; bioavailability >95%. Plasma protein binding was