HLö 7 dimethanesulfonate, a potent bispyridinium-dioxime against anticholinesterases

Abstract

HLö 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. HLö 7 dimethanesulfonate is the first water-soluble salt of HLö 7 that should be suitable for the wet/dry autoinjector technology, because aqueous solutions of HLö 7 are not very stable (calculated shelf-life 0.2 years when stored at 8 degrees C, 1 M solution, pH 2.5). The crystalline preparation contains 96% of the syn/syn-isomer, less than 2% of the syn/anti-isomer and some minor identified by-products. HLö 7 was very efficient in reactivating acetylcholinesterase (AChE) blocked by organophosphates as long as ageing did not prevent dephosphylation. HLö 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 HLö 7 exceeds HI 6 by far in reactivating tabun-inhibited AChE. In atropine-protected, soman-poisoned mice HLö 7 was three times more potent than HI 6 (protective ratio 5 versus 2.5), and in sarin-poisoned mice HLö 7 was 10 times more potent than HI 6 (protective ratio 8 for both oximes). In atropine-protected guinea-pigs HLö 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 + HLö (57 min). HLö 7 alone did not prolong the survival. The most impressive effect of HLö 7 was on respiration: 3 min after i.v. injection of HLö 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 HLö 7. Even central symptoms, e.g. hypothermia and convulsions, were decreased markedly by HLö 7 (evaluation 60 min after poisoning). The pharmacokinetic data for HLö 7 in male beagle dogs are similar to those of HI 6.(ABSTRACT TRUNCATED AT 400 WORDS)

HLö-7 - A REVIEW OF ACETYLCHOLINESTERASE REACTIVATOR AGAINST ORGANOPHOSPHOROUS INTOXICATION

“…The overall yield for ion-exchange was 95%. 32 The 1 H NMR spectrum of prepared HLö-7 dimethanesulfonate was measured in D 2 O and DMSO confirming the structure acquiring similar data to HLö-7 diiodide (Table 1). 32 HPLC analysis of HLö-7 dimethanesulfonate gave information about formation of five major by-products.…”

“…32 The 1 H NMR spectrum of prepared HLö-7 dimethanesulfonate was measured in D 2 O and DMSO confirming the structure acquiring similar data to HLö-7 diiodide (Table 1). 32 HPLC analysis of HLö-7 dimethanesulfonate gave information about formation of five major by-products. These were identified as de-aminated by-product of HLö-7 ("HLö-7 acid"; (1-[[[4-(carboxy)pyridinio]methoxy]methyl]-2,4-bis[(hydroxyimino)methyl]pyridinium dimethanesulfonate).…”

“…Its substitution to non-mutagenic bis(methylsulfonoxymethyl)ether not only solved this problem but also led to water-soluble hybrid HLö-7 dimethanesulfonate. 32 Accordingly, HLö-7 dimethanesulfonate can be prepared by two different routes either from pyridine-2,4-dialdoxime and isonicotinamid in reaction with bis(methylsulfonoxomethyl)ether or from HLö-7 diiodide by ion exchange (Fig. 13).…”

“…The structure of last impurity has not been elucidated. 32 Figure 14. Side-products identified during HPLC analysis of HLö-7 dimethanesulfonate…”

“…injection of HLö-7 dimethanesulfonate was established proposing that the distribution period ( l t 1/2 about 5 minutes) and terminal elimination was found to be first-order throughout ( e t 1/2 about 45 minutes). 32 HLö-7 dimethanesulfonate was administered into the gluteal muscles to four male beagles. Absorption halftime was about 14 minutes, maximum plasma concentrations were found about 30 minutes after injection and elimination fits the kinetics observed after i.v.…”