Sodium channel modulators

Choi etal, US Patent 6,646,012 (November 11, 2003) Assignee Theravance, Inc. 

To o-cresol (0.14 mol) dissolved in 200 ml water containing NaOH (0.125 mol) was added 2-chloromethyl-2-methyloxirane (0.188 mol) and the mixture stirred for 1 hour in an ice bath. Thereafter the mixture stirred 24 hours at ambient temperature and the mixture extracted with 300 ml diethyl ether/hexane, 2 5. The extract was washed twice with 150 ml 1 M NaOH, dried, concentrated, purified by chromatography with hexane/EtOAc with a gradient of 8 1 to 5 1, and the product isolated as an oil. H-MNR data supplied. 

The product from Step 1 (0.063 mol) was dissolved in 130 ml cold 2-ethoxyethanol to which was added 30 ml water containing sodium azide (0.127 mol) and (NH4)2S04 (0.076 mol). The mixture stirred in an ice bath 2 hours and then 36 hours at ambient temperature. The product was extracted twice with 300 ml diethyl ether, washed with brine, dried, and evaporated to dryness giving a colorless oil. The oil was dissolved in 100 ml acetonitrile to which was slowly added triphenylphosphine (0.053 mol) dissolved in 100 ml acetonitrile. Thereafter the mixture stirred 3 hours at ambient temperature, heated to 90 °C 6 hours, cooled, and concentrated in vacuo yielding a white semi-solid. The product was purified by chromatography on silica gel using EtOAc/hexane, 1 1, to 5% methyl alcohol in EtOAc/hexane, 1 1, and isolated as an oil. H-MNR data supplied. 

The product from Step 2 (0.2 mmol), 2-chlorophenol (0.2 mmol) and BF3 Et20 (0.2 mmol) were dissolved in 0.5 ml toluene and heated to 90°C for 24 hours. After cooling to ambient temperature it was treated with 1 ml 5% trifluoroacetic acid dissolved in 50% aqueous acetonitrile. The product was purified by preparative reverse HPLC and isolated as a TEA salt. Mass spectra data supplied. 

H-NMR data of azido alcohols were supplied by the author. 

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It blocks voltage-sensitive sodium channels, modulates the voltage-activated Ca currents, and increases potassium conductance. 

Ion channel modulation represents another approach to positive inotropy [13]. Sodium channel modulators increase Na+ influx and prolong the plateau phase of the action potential sodium/calcium exchange then leads to an increase in the level of calcium available to the contractile elements, thus increasing the force of cardiac contraction [13,14]. Synthetic compounds such as DPI 201-106 and BDF 9148 (Figure 1) increase the mean open time of the sodium channel by inhibiting channel inactivation [15]. Importantly, BDF 9148 remains an effective positive inotropic compound even in severely failing human myocardium [16] and in rat models of cardiovascular disease [17]. Modulators of calcium and potassium channel activities also function as positive inotropes [13], but in the remainder of this article we shall focus on sodium channel modulators. 

Nay 1 channels have been purified from mammalian brain and skeletal muscle [11-13]. In these tissues, sodium channels are a complex of a large a-subunit ( 260kDa) and one or two smaller (3-subunils (30-40 kDa). The a-subunit contains the pore that sodium ions pass through and, when expressed alone, forms functional channels that display sodium selectivity, voltage-dependent activation and rapid inactivation. Nine distinct a-subunits (Nayl.l-Navl.9) have been identified, cloned, and functionally expressed (Table 1). Homology between these Nayl subtypes is high (>50% amino acid identity) within the membrane-spanning domains and extracellular loops. A tenth, more distantly related, subunit, Nax, has been identified but not yet functionally expressed. All sodium channel modulators known to date interact with the a-subunit. 

Lactones, (IV), effective as NMDA antagonists prepared by Sundermann (4) and aryl pyrazole sodium channel modulators, (V), prepared by Hogenkamp (5) were effective in treating chronic pain sensations perceived by patients afflicted with tinnitus and related disorders. 

Rein, K.S., Baden, D.G., and Gawley, R.E. 1994. Conformational analysis of the sodium-channel modulator brevetoxin-A, comparison with brevetoxin-B conformations, and a hypothesis about the common pharmacophore of the site-5 toxins. Journal of Organic Chemistry 59, 2101-2106. 

Anticonvulsant, voltage-sensitive sodium channel modulator... 

Anticonvulsant, voltage-sensitive sodium channel modulator T-type calcium channel modulator structurally a sulfonamide... 

Warmke JW, Reenan RA, Wang P et al 1997 Functional expression of Drosophila para sodium channels. Modulation by the membrane protein TipE and toxin pharmacology. J Gen Physiol 110 119-133... 

Pharmacology and Mechanism of Action. Lamotrigine blocks voltage-sensitive sodium channels, modulates or decreases glutamate and aspartate release, and has antikindling properties (see Table 68-10)." 2 " ... 

M. Huchet, P. Chabrier, D. Bigg, Bioorg. Med. Chem. Lett. 2004, 14, 3521-3523. 2-Alkyl-4-arylimidazoles stucturally novel sodium channel modulators, (b) D. W. Cheung, E. E. Daniel, Nature 1980, 283,485-486. Imidazole inhibits a temperature-dependent component of mammalian skeletal muscle action potential. 

Pyrethroid insecticides are widely used because of their high activity as an insecticide and low mammalian toxicity. Pyrethroids are in group 3, sodium channel modulators. The pyrethroids have a highly nonpolar nature, low water solubility, and high affinity to soil and sediment particulate matter. Natural pyrethrin is extracted from the flowers of Chrysanthemum spp., and its use was already known in China in the first century A.D. Pyrethroids, synthetic analogues of pyrethrin, have been produced since 1940 [26]. 

Mironov SL, Richter DW. Intracellular signalling pathways modulate K(ATP) channels in inspiratory brainstem neurones and their hypoxic activation involvement of metabotropic receptors, G-proteins and cytoskeleton. Brain Res 2000 853 60-67. Cummins TR, Jiang C, Haddad GG. Human neocortical excitability is decreased during anoxia via sodium channel modulation. J Clin Invest 1993 91 608-615. Mironov SL, Richter DW. Cytoskeleton mediates inhibition of the fast Na+ current in respiratory brainstem neurons during hypoxia. Eur J Neurosci 1999 11 1831-1834. Mironov SL, Richter DW. Oscillations and hypoxic changes of mitochondrial variables in neurons of the brainstem respiratory centre of mice. J Physiol 2001 533 227-236. Mazza E Jr, Edelman NH, Neubauer JA. Hypoxic excitation in neurons cultured fi om the rostral ventrolateral medulla of the neonatal rat. J Appl Physiol 2000 88 2319-2329. 

Cummins TR, Jiang C, Haddad GG. Human neocortical excitability is decreased during anoxia via sodium channel modulation. J Clin Invest 1993 91 608-615. 

Servant, G. Brust, P Ray, S. Hung, N. Improved cell-based fluorescent assays for identifying a and5 epithelial sodium channel modulators. PCX Int. Appl. WO 2008013969, 2008 Chem. Abstr. 2008,148, 222369. 

Navi.8 sodium channel modulator Fray etaL Org. Process Res. Dev. 2010, N, 263-271... 

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