Login Register Cart 0
Generic placeholder image

Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe Translate in Chinese
Review Article

Voltage-Gated Sodium Channel Blockers: Synthesis of Mexiletine Analogues and Homologues

Author(s): Alessia Catalano*, Carlo Franchini and Alessia Carocci

Volume 28, Issue 8, 2021

Published on: 04 May, 2020

Page: [1535 - 1548] Pages: 14

DOI: 10.2174/0929867327666200504080530

Price: $65

Abstract

Mexiletine is an antiarrhythmic drug belonging to IB class, acting as sodium channel blocker. Besides its well-known activity on arrhythmias, its usefulness in the treatment of myotonia, myotonic dystrophy and amyotrophic lateral sclerosis is now widely recognized. Nevertheless, it has been retired from the market in several countries because of its undesired effects. Thus, several papers were reported in the last years about analogues and homologues of mexiletine being endowed with a wider therapeutic ratio and a more selectivity of action. Some of them showed sodium channel blocking activity higher than the parent compound. It is noteworthy that mexiletine is used in therapy as a racemate even though a difference in the activities of the two enantiomers was widely demonstrated, with (–)-(R)-enantiomer being more active: this finding led several research groups to study mexiletine and its analogues and homologues in their optically active forms. This review summarizes the different synthetic routes used to obtain these compounds. They could represent an interesting starting point to new mexiletine-like compounds without common side effects related to the use of mexiletine.

Keywords: Antiarrhythmic agents, antimyotonic agents, sodium channel blockers, mexiletine analogues, mexiletine homologues, amyotrophic lateral sclerosis (ALS).

« Previous Next »
[1]
Catalano, A.; Carocci, A. Antiarrhythmic mexiletine: a review on synthetic routes to racemic and homochiral mexiletine and its enantioseparation. Curr. Med. Chem., 2016, 23(29), 3227-3244.
[http://dx.doi.org/10.2174/0929867323666160517120234] [PMID: 27183983]
[2]
Carocci, A.; Corbo, F.; Lentini, G.; Cavalluzzi, M.M.; Franchini, C.; Catalano, A. A focus on the synthesis and pharmacokinetics of tocainide and its analogues. Curr. Med. Chem., 2018, 25(42), 5822-5834.
[http://dx.doi.org/10.2174/0929867325666180327104320] [PMID: 29589531]
[3]
Podrid, P.J.; Lown, B. Mexiletine for ventricular arrhythmias. Am. J. Cardiol., 1981, 47(4), 895-902.
[http://dx.doi.org/10.1016/0002-9149(81)90191-0] [PMID: 6782850]
[4]
Badri, M.; Patel, A.; Patel, C.; Liu, G.; Goldstein, M.; Robinson, V.M.; Xue, X.; Yang, L.; Kowey, P.R.; Yan, G.X. Mexiletine prevents recurrent torsades de pointes in acquired long QT syndrome refractory to conventional measures. JACC Clin. Electrophysiol., 2015, 1(4), 315-322.
[http://dx.doi.org/10.1016/j.jacep.2015.05.008] [PMID: 29759319]
[5]
Phillips, L.; Trivedi, J.R. Skeletal muscle channelopathies. Neurotherapeutics, 2018, 15(4), 954-965.
[http://dx.doi.org/10.1007/s13311-018-00678-0] [PMID: 30341599]
[6]
Hahn, C.; Salajegheh, M.K. Myotonic disorders: a review article. Iran. J. Neurol., 2016, 15(1), 46-53.
[PMID: 27141276]
[7]
D’Mello, S.; Shum, L. A review of the use of mexiletine in patients with myotonic dystrophy and non-dystrophic myotonia. Eur. J. Hosp. Pharm. Sci. Pract., 2016, 23(6), 359-363.
[http://dx.doi.org/10.1136/ejhpharm-2015-000839] [PMID: 31156883]
[8]
Snedecor, S.J.; Sudharshan, L.; Cappelleri, J.C.; Sadosky, A.; Mehta, S.; Botteman, M. Systematic review and meta-analysis of pharmacological therapies for painful diabetic peripheral neuropathy. Pain Pract., 2014, 14(2), 167-184.
[http://dx.doi.org/10.1111/papr.12054] [PMID: 23534696]
[9]
Zuliani, V.; Rivara, M.; Fantini, M.; Costantino, G. Sodium channel blockers for neuropathic pain. Expert Opin. Ther. Pat., 2010, 20(6), 755-779.
[http://dx.doi.org/10.1517/13543771003774118] [PMID: 20384535]
[10]
Gao, Y.; Xue, X.; Hu, D.; Liu, W.; Yuan, Y.; Sun, H.; Li, L.; Timothy, K.W.; Zhang, L.; Li, C.; Yan, G-X. Inhibition of late sodium current by mexiletine: a novel pharmotherapeutical approach in timothy syndrome. Circ Arrhythm Electrophysiol, 2013, 6(3), 614-622.
[http://dx.doi.org/10.1161/CIRCEP.113.000092] [PMID: 23580742]
[11]
Noto, Y.; Shibuya, K.; Vucic, S.; Kiernan, M.C. Novel therapies in development that inhibit motor neuron hyperexcitability in amyotrophic lateral sclerosis. Expert Rev. Neurother., 2016, 16(10), 1147-1154.
[http://dx.doi.org/10.1080/14737175.2016.1197774] [PMID: 27314534]
[12]
Oskarsson, B.; Moore, D.; Mozaffar, T.; Ravits, J.; Wiedau-Pazos, M.; Parziale, N.; Joyce, N.C.; Mandeville, R.; Goyal, N.; Cudkowicz, M.E.; Weiss, M.; Miller, R.G.; McDonald, C.M. Mexiletine for muscle cramps in amyotrophic lateral sclerosis: A randomized, double-blind crossover trial. Muscle Nerve, 2018, 58(1), 42-48.
[http://dx.doi.org/10.1002/mus.26117] [PMID: 29510461]
[13]
Bruno, C.; Carocci, A.; Catalano, A.; Cavalluzzi, M.M.; Corbo, F.; Franchini, C.; Lentini, G.; Tortorella, V. Facile, alternative route to lubeluzole, its enantiomer, and the racemate. Chirality, 2006, 18(4), 227-231.
[http://dx.doi.org/10.1002/chir.20240] [PMID: 16521088]
[14]
Camerino, D.C.; Tricarico, D.; Desaphy, J-F. Ion channel pharmacology. Neurotherapeutics, 2007, 4(2), 184-198.
[http://dx.doi.org/10.1016/j.nurt.2007.01.013] [PMID: 17395128]
[15]
Remme, C.A.; Wilde, A.A.M. Targeting sodium channels in cardiac arrhythmia. Curr. Opin. Pharmacol., 2014, 15, 53-60.
[http://dx.doi.org/10.1016/j.coph.2013.11.014] [PMID: 24721654]
[16]
Yang, Y.; Wang, Y.; Li, S.; Xu, Z.; Li, H.; Ma, L.; Fan, J.; Bu, D.; Liu, B.; Fan, Z.; Wu, G.; Jin, J.; Ding, B.; Zhu, X.; Shen, Y. Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia. J. Med. Genet., 2004, 41(3), 171-174.
[http://dx.doi.org/10.1136/jmg.2003.012153] [PMID: 14985375]
[17]
Akıncı, E.; Yüzbaşıoglu, Y.; Coşkun, F. Hemodialysis as an alternative treatment of mexiletine intoxication. Am. J. Emerg. Med., 2011, 29(9), 1235.e5-1235.e6.
[http://dx.doi.org/10.1016/j.ajem.2010.08.027] [PMID: 20971596]
[18]
Chrestian, N.; Puymirat, J.; Bouchard, J-P.; Dupré, N. Myotonia congenita--a cause of muscle weakness and stiffness. Nat. Clin. Pract. Neurol., 2006, 2(7), 393-399.
[http://dx.doi.org/10.1038/ncpneuro0239] [PMID: 16932590]
[19]
Eijkelkamp, N.; Linley, J.E.; Baker, M.D.; Minett, M.S.; Cregg, R.; Werdehausen, R.; Rugiero, F.; Wood, J.N. Neurological perspectives on voltage-gated sodium channels. Brain, 2012, 135(Pt 9), 2585-2612.
[http://dx.doi.org/10.1093/brain/aws225] [PMID: 22961543]
[20]
Finnerup, N.B.; Attal, N.; Haroutounian, S.; McNicol, E.; Baron, R.; Dworkin, R.H.; Gilron, I.; Haanpää, M.; Hansson, P.; Jensen, T.S.; Kamerman, P.R.; Lund, K.; Moore, A.; Raja, S.N.; Rice, A.S.; Rowbotham, M.; Sena, E.; Siddall, P.; Smith, B.H.; Wallace, M. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol., 2015, 14(2), 162-173.
[http://dx.doi.org/10.1016/S1474-4422(14)70251-0] [PMID: 25575710]
[21]
Cashman, J.R.; Ryan, D.J.; Okolotowicz, K. Compounds as inhibitors of sodium channels. WO Patent 2017/210371/A2., 2017.
[22]
Catalano, A.; Carocci, A.; Fracchiolla, G.; Franchini, C.; Lentini, G.; Tortorella, V.; De Luca, A.; De Bellis, M.; Desaphy, J-F.; Conte Camerino, D. Stereospecific synthesis of “para-hydroxymexiletine” and sodium channel blocking activity evaluation. Chirality, 2004, 16(2), 72-78.
[http://dx.doi.org/10.1002/chir.10307] [PMID: 14712469]
[23]
De Bellis, M.; De Luca, A.; Rana, F.; Cavalluzzi, M.M.; Catalano, A.; Lentini, G.; Franchini, C.; Tortorella, V.; Conte Camerino, D. Evaluation of the pharmacological activity of the major mexiletine metabolites on skeletal muscle sodium currents. Br. J. Pharmacol., 2006, 149(3), 300-310.
[http://dx.doi.org/10.1038/sj.bjp.0706867] [PMID: 16921388]
[24]
Cavalluzzi, M.M.; Catalano, A.; Bruno, C.; Lovece, A.; Carocci, A.; Corbo, F.; Franchini, C.; Lentini, G.; Tortorella, V. Synthesis of (R)-, (S)-, and (RS)-hydroxymethylmexiletine, one of the major metabolites of mexiletine. Tetrahedron Asymmetry, 2007, 18(20), 2409-2417.
[http://dx.doi.org/10.1016/j.tetasy.2007.10.002]
[25]
Cavalluzzi, M.M.; Bruno, C.; Lentini, G.; Lovece, A.; Catalano, A.; Carocci, A.; Franchini, C. One-step synthesis of homochiral O-aryl and O-heteroaryl mandelic acids and their use as efficient 1H NMR chiral solvating agents. Tetrahed. Asym., 2009, 20(17), 1984-1991.
[http://dx.doi.org/10.1016/j.tetasy.2009.08.002]
[26]
Catalano, A.; Desaphy, J-F.; Lentini, G.; Carocci, A.; Di Mola, A.; Bruno, C.; Carbonara, R.; De Palma, A.; Budriesi, R.; Ghelardini, C.; Perrone, M.G.; Colabufo, N.A.; Conte Camerino, D.; Franchini, C. Synthesis and toxicopharmacological evaluation of m-hydroxymexiletine, the first metabolite of mexiletine more potent than the parent compound on voltage-gated sodium channels. J. Med. Chem., 2012, 55(3), 1418-1422.
[http://dx.doi.org/10.1021/jm201197z] [PMID: 22191686]
[27]
Catalano, A.; Carocci, A.; Lentini, G.; Defrenza, I.; Cavalluzzi, M.M.; Franchini, C. An improved synthesis of m-hydroxymexiletine, a potent mexiletine metabolite. Drug Metab. Lett., 2012, 6(2), 124-128.
[http://dx.doi.org/10.2174/1872312811206020124] [PMID: 22849704]
[28]
Catalano, A.; Carocci, A.; Lentini, G.; Defrenza, I.; Bruno, C.; Franchini, C. Stereospecific synthesis of m-Hydroxymexiletine enantiomers. Drug Metab. Lett., 2012, 6(3), 182-186.
[http://dx.doi.org/10.2174/1872312811206030005] [PMID: 23140556]
[29]
Desaphy, J-F.; Dipalma, A.; Costanza, T.; Carbonara, R.; Dinardo, M.M.; Catalano, A.; Carocci, A.; Lentini, G.; Franchini, C.; Camerino, D.C. Molecular insight into the local anesthetic receptor within voltage-gated sodium channels using hydroxylated analogs of mexiletine. Front. Pharmacol., 2012, 3, 17.
[http://dx.doi.org/10.3389/fphar.2012.00017] [PMID: 22403541]
[30]
Catalano, A.; Carocci, A.; Cavalluzzi, M.M.; Di Mola, A.; Lentini, G.; Lovece, A.; Dipalma, A.; Costanza, T.; Desaphy, J.F.; Conte Camerino, D.; Franchini, C. Hydroxylated analogs of mexiletine as tools for structural-requirements investigation of the sodium channel blocking activity. Arch. Pharm. (Weinheim), 2010, 343(6), 325-332.
[http://dx.doi.org/10.1002/ardp.200900218] [PMID: 20509146]
[31]
Catalano, A.; Budriesi, R.; Bruno, C.; Di Mola, A.; Defrenza, I.; Cavalluzzi, M.M.; Micucci, M.; Carocci, A.; Franchini, C.; Lentini, G. Searching for new antiarrhythmic agents: evaluation of meta-hydroxymexiletine enantiomers. Eur. J. Med. Chem., 2013, 65, 511-516.
[http://dx.doi.org/10.1016/j.ejmech.2013.05.008] [PMID: 23777871]
[32]
Catalano, A.; Carocci, A.; Sinicropi, M.S. Mexiletine metabolites: a review. Curr. Med. Chem., 2015, 22(11), 1400-1413.
[http://dx.doi.org/10.2174/0929867322666150227145412] [PMID: 25723511]
[33]
Catalano, A.; Carocci, A.; Corbo, F.; Franchini, C.; Muraglia, M.; Scilimati, A.; De Bellis, M.; De Luca, A.; Camerino, D.C.; Sinicropi, M.S.; Tortorella, V. Constrained analogues of tocainide as potent skeletal muscle sodium channel blockers towards the development of antimyotonic agents. Eur. J. Med. Chem., 2008, 43(11), 2535-2540.
[http://dx.doi.org/10.1016/j.ejmech.2008.01.023] [PMID: 18342401]
[34]
Muraglia, M.; De Bellis, M.; Catalano, A.; Carocci, A.; Franchini, C.; Carrieri, A.; Fortugno, C.; Bertucci, C.; Desaphy, J.F.; De Luca, A.; Conte Camerino, D.; Corbo, F. N-aryl-2,6-dimethylbenzamides, a new generation of tocainide analogues as blockers of skeletal muscle voltage-gated sodium channels. J. Med. Chem., 2014, 57(6), 2589-2600.
[http://dx.doi.org/10.1021/jm401864b] [PMID: 24568674]
[35]
De Luca, A.; De Bellis, M.; Corbo, F.; Franchini, C.; Muraglia, M.; Catalano, A.; Carocci, A.; Camerino, D.C. Searching for novel anti-myotonic agents: pharmacophore requirement for use-dependent block of skeletal muscle sodium channels by N-benzylated cyclic derivatives of tocainide. Neuromuscul. Disord., 2012, 22(1), 56-65.
[http://dx.doi.org/10.1016/j.nmd.2011.07.001] [PMID: 21802953]
[36]
Franchini, C.; Carocci, A.; Catalano, A.; Cavalluzzi, M.M.; Corbo, F.; Lentini, G.; Scilimati, A.; Tortorella, P.; Camerino, D.C.; De Luca, A. Optically active mexiletine analogues as stereoselective blockers of voltage-gated Na(+) channels. J. Med. Chem., 2003, 46(24), 5238-5248.
[http://dx.doi.org/10.1021/jm030865y] [PMID: 14613326]
[37]
De Bellis, M.; De Luca, A.; Desaphy, J-F.; Carbonara, R.; Heiny, J.A.; Kennedy, A.; Carocci, A.; Cavalluzzi, M.M.; Lentini, G.; Franchini, C.; Camerino, D.C. Combined modifications of mexiletine pharmacophores for new lead blockers of Na(v)1.4 channels. Biophys. J., 2013, 104(2), 344-354.
[http://dx.doi.org/10.1016/j.bpj.2012.11.3830] [PMID: 23442856]
[38]
Huang, K.; Ortiz-Marciales, M.; Stepanenko, V.; De Jesús, M.; Correa, W. A practical and efficient route for the highly enantioselective synthesis of mexiletine analogues and novel β-thiophenoxy and pyridyl ethers. J. Org. Chem., 2008, 73(17), 6928-6931.
[http://dx.doi.org/10.1021/jo801181d] [PMID: 18690744]
[39]
Jin, K.B.; Kim, H.E.; Hyun, M.H. Liquid chromatographic resolution of mexiletine and its analogs on crown ether-based chiral stationary phases. Chirality, 2014, 26(5), 272-278.
[http://dx.doi.org/10.1002/chir.22318] [PMID: 24677299]
[40]
Ortiz-Marciales, M.; Huang, K.; Stepanenko, V.; De Jesus, M.; Correa, W. Method of synthesizing enantiopure mexiletine analogues and novel β-thiophenoxy and pyridyl ethers. US Patent 8012901 B1., 2011.
[41]
Carrieri, A.; Muraglia, M.; Corbo, F.; Pacifico, C. 2D- and 3D-QSAR of tocainide and mexiletine analogues acting as Na(v)1.4 channel blockers. Eur. J. Med. Chem., 2009, 44(4), 1477-1485.
[http://dx.doi.org/10.1016/j.ejmech.2008.10.005] [PMID: 19027197]
[42]
Roselli, M.; Carocci, A.; Budriesi, R.; Micucci, M.; Toma, M.; Di Cesare Mannelli, L.; Lovece, A.; Catalano, A.; Cavalluzzi, M.M.; Bruno, C.; De Palma, A.; Contino, M.; Perrone, M.G.; Colabufo, N.A.; Chiarini, A.; Franchini, C.; Ghelardini, C.; Habtemariam, S.; Lentini, G. Synthesis, antiarrhythmic activity, and toxicological evaluation of mexiletine analogues. Eur. J. Med. Chem., 2016, 121, 300-307.
[http://dx.doi.org/10.1016/j.ejmech.2016.05.046] [PMID: 27267000]
[43]
Carocci, A.; Catalano, A.; Corbo, F.; Duranti, A.; Amoroso, R.; Franchini, C.; Lentini, G.; Tortorella, V. Stereospecific synthesis of mexiletine and related compounds: Mitsunobu versus Williamson reaction. Tetrahed. Asym., 2000, 11(17), 3619-3634.
[http://dx.doi.org/10.1016/S0957-4166(00)00332-3]
[44]
Talwar, D.; Salguero, N. P.; Robertson, C. M.; Xiao, J. Primary amines by transfer hydrogenative reductive amination of ketones by using cyclometalated IrIII catalysts. Chemistry– A Eur. J., 2014, 20(1), 245-252.
[http://dx.doi.org/10.1002/chem.201303541] [PMID: 24516890]
[45]
Liu, H.; Gao, Z.B.; Yao, Z.; Zheng, S.; Li, Y.; Zhu, W.; Tan, X.; Luo, X.; Shen, J.; Chen, K.; Hu, G.Y.; Jiang, H. Discovering potassium channel blockers from synthetic compound database by using structure-based virtual screening in conjunction with electrophysiological assay. J. Med. Chem., 2007, 50(1), 83-93.
[http://dx.doi.org/10.1021/jm060414o] [PMID: 17201412]
[46]
De Luca, A.; Talon, S.; De Bellis, M.; Desaphy, J.F.; Franchini, C.; Lentini, G.; Catalano, A.; Corbo, F.; Tortorella, V.; Conte-Camerino, D. Inhibition of skeletal muscle sodium currents by mexiletine analogues: specific hydrophobic interactions rather than lipophilia per se account for drug therapeutic profile. Naunyn Schmiedebergs Arch. Pharmacol., 2003, 367(3), 318-327.
[http://dx.doi.org/10.1007/s00210-002-0669-0] [PMID: 12644906]
[47]
Mátyus, P.; Varga, I.; Rettegi, T.; Simay, A.; Kállay, N.; Károlyházy, L.; Kocsis, A.; Varró, A.; Pénzes, I.; Papp, J.G. Novel antiarrhythmic compounds with combined class IB and class III mode of action. Curr. Med. Chem., 2004, 11(1), 61-69.
[http://dx.doi.org/10.2174/0929867043456232] [PMID: 14754426]
[48]
Carocci, A.; Catalano, A.; Bruno, C.; Lentini, G.; Franchini, C.; De Bellis, M.; De Luca, A.; Conte Camerino, D. Synthesis and in vitro sodium channel blocking activity evaluation of novel homochiral mexiletine analogs. Chirality, 2010, 22(3), 299-307.
[http://dx.doi.org/10.1002/chir.20741] [PMID: 19544349]
[49]
Vazzana, I.; Budriesi, R.; Terranova, E.; Ioan, P.; Ugenti, M.P.; Tasso, B.; Chiarini, A.; Sparatore, F. Novel quinolizidinyl derivatives as antiarrhythmic agents. J. Med. Chem., 2007, 50(2), 334-343.
[http://dx.doi.org/10.1021/jm060878m] [PMID: 17228875]
[50]
Tasso, B.; Budriesi, R.; Vazzana, I.; Ioan, P.; Micucci, M.; Novelli, F.; Tonelli, M.; Sparatore, A.; Chiarini, A.; Sparatore, F. Novel quinolizidinyl derivatives as antiarrhythmic agents: 2. Further investigation. J. Med. Chem., 2010, 53(12), 4668-4677.
[http://dx.doi.org/10.1021/jm100298d] [PMID: 20509610]
[51]
De Bellis, M.; Sanarica, F.; Carocci, A.; Lentini, G.; Pierno, S.; Rolland, J.F.; Conte Camerino, D.; De Luca, A. Dual action of mexiletine and its pyrroline derivatives as skeletal muscle sodium channel blockers and anti-oxidant compounds: toward novel therapeutic potential. Front. Pharmacol., 2018, 8, 907.
[http://dx.doi.org/10.3389/fphar.2017.00907] [PMID: 29379434]
[52]
Williams, A.J.; Tortella, F.C. Neuroprotective effects of the sodium channel blocker RS100642 and attenuation of ischemia-induced brain seizures in the rat. Brain Res., 2002, 932(1-2), 45-55.
[http://dx.doi.org/10.1016/S0006-8993(02)02275-8] [PMID: 11911860]
[53]
Batcioglu, K.; Uyumlu, A.B.; Satilmis, B.; Yildirim, B.; Yucel, N.; Demirtas, H.; Onkal, R.; Guzel, R.M.; Djamgoz, M.B. Oxidative stress in the in vivo DMBA rat model of breast cancer: suppression by a voltage-gated sodium channel inhibitor (RS100642). Basic Clin. Pharmacol. Toxicol., 2012, 111(2), 137-141.
[http://dx.doi.org/10.1111/j.1742-7843.2012.00880.x] [PMID: 22429688]
[54]
Kamisli, S.; Basaran, C.; Batcioglu, K.; Oztanir, M.N.; Gul, M.; Satilmis, B.; Uyumlu, A.B.; Kayhan, B.; Genc, M. Neuroprotective effects of the new Na channel blocker rs100642 in global ischemic brain injury. Arch. Med. Sci., 2019, 15(2), 467-474.
[http://dx.doi.org/10.5114/aoms.2017.72550] [PMID: 30899300]
[55]
Loughhead, D.G.; Flippin, L.A.; Weikert, R.J. Synthesis of mexiletine stereoisomers and related compounds via SNAr nucleophilic substitution of a Cr(CO)3-complexed aromatic fluoride. J. Org. Chem., 1999, 64(9), 3373-3375.
[http://dx.doi.org/10.1021/jo982287c] [PMID: 11674449]
[56]
Mitsunobu, O. The use of diethyl azodicarboxylate and triphenylphosphine in synthesis and transformation of natural products. Synthesis, 1981, 1-28.
[http://dx.doi.org/10.1055/s-1981-29317]
[57]
Duranti, A.; Franchini, C.; Lentini, G.; Loiodice, F.; Tortorella, V.; De Luca, A.; Pierno, S.; Conte Camerino, D. Homologation of mexiletine alkyl chain and stereoselective blockade of skeletal muscle sodium channels. Eur. J. Med. Chem., 2000, 35(1), 147-156.
[http://dx.doi.org/10.1016/S0223-5234(00)00115-X] [PMID: 10733611]
[58]
Ryan, D.A.; Okolotowicz, K.J.; Mercola, M.; Cashman, J.R. Stereoselective synthesis of mexiletine and structural analogs with chiral tert-butanesulfinamide. Tetrahedron Lett., 2015, 56(28), 4195-4199.
[http://dx.doi.org/10.1016/j.tetlet.2015.05.041]

Rights & Permissions Print Cite
Article Metrics
14
1
© 2024 Bentham Science Publishers | Privacy Policy