A Medicinal Chemistry Investigation of 3,4-Methylenedioxymethamphetamine(MDMA) Katie D. Lewis B. Sc. (Hons) Chemistry School of Biomedical, Biomolecular and Chemical Sciences This thesis is presented for the degree of Doctor of Philosophy of The University of Western Australia 2011 Candidate Declaration The work described in this thesis was carried out by the author in the School of Biomedical, supervision of Professor Robert Stick, Professor Allan McKinley and Associate Professor Matthew Piggott. Unless duly referenced, the work described is original. Katie D. Lewis April 2011 Contents Summary Acknowledgements Glossary Introduction Chapter One "The Synthesis of Some a-Substituted Analogues of MDMA" Introduction Results and Discussion General Experimental Experimental Chapter Two "The Synthesis of Some ^-Modified Analogues of MDMA" Introduction Results and Discussion Experimental Chapter Three "The Synthesis of Some Optically-Active Analogues of MDMA' Introduction Results and Discussion Experimental v Chapter Four 129 "MDMA Analogues as Putative Monoamine Oxidase Inhibitors " Introduction 130 Results and Discussion 140 Experimental 150 Epilogue 157 References 161 Appendix 171 vi Summary 3,4-Memylenedioxymethamphetamine (MDMA) 1, the active chemical constituent of the illicit drug ecstasy, is a psychotropic agent whose effects are primarily modulated through the serotonergic system. In recent years numerous researchers have identified MDMA as possessing therapeutic activity towards a variety of disease states. MDMA 1 Parkinson's disease (PD) is a common and disabling neurodegenerative disorder. The primary symptomatic treatment of PD utilises the dopamine precursor levodopa. Long-term levodopa therapy typically elicits deleterious side-effects, the most significant being levodopa-induced dyskinesia (LED), the severity of which may negate the therapeutic benefit of levodopa. MDMA has been demonstrated in primate models to possess both anti-parkinsonian and anti-LED activity. Burkitt's lymphoma (BL) is a malignant disease of the lymphatic system, affecting B-cell lymphocytes in particular. Recent characterisation of a functioning immunoreactive serotonin reuptake transporter (SERT) in B-cell lines has been impetus for the investigation of SERT as a target for drug therapy in BL. MDMA, a known SERT substrate, exhibitss an anti-proliferative and pro-apoptotic response in a BL cell line (L3055). This thesis, prompted by recent reports of the therapeutic activity of MDMA in various disease states, details a medicinal chemistry investigation of MDMA, Chapters One, Two and Three document the analogues synthesised. These analogues were intended for evaluation as anti-neoplasties for Burkitt's lymphoma and for evaluation as therapeutics for the treatment of PD. This work was conducted in collaboration with Prof. John Gordon and coworkers (MRC viii Centre for Immune Regulation at The University of Birmingham), and Dr Jonathan Brotchie and coworkers (Toronto Western Research Institute). Additionally a series of putative monoamine oxidase (MAO; EC 1.4.3.4) inhibitors was conceived, synthesised and assayed (Chapter Four). These compounds were structurally analogous to selegiline 10, a clinically useful MAO-B inhibitor. Selegiline 10 ix Acknowledgements I would like to thank my supervisor Professor Robert Stick, whose support and guidance have been invaluable. I would also like to thank my supervisor Professor Allan McKinley for his commitment to assisting my graduate studies. I am also indebted to the following staff members: Dr Lindsay Byrne for his always friendly assistance with NMR spectroscopy, Dr Tony Reeder for acquiring mass spectra on my behalf, and Dr Brian Skelton for performing X-ray crystallography on my compounds. Many thanks must go to my fellow research group members for their friendship and assistance, in particular Katie Punch, Matthew Mclldowie and Blake Nguyen. The financial support of an Australian Postgraduate Award, Jean Rogerson Postgraduate Supplementary Scholarship, Geoffrey Kennedy Postgraduate Research Travel Award and Australian Federation of University Women (WA) Inc. Foundation Bursary is gratefully acknowledged. Thank you to Dr Lindsay Allet for his assistance during my candidature. Your professionalism is inspiring. Finally I wish to thank my parents and my partner Jakub for their unwavering love, support and care through the triumphs and despair of this PhD candidature. Without whom my successes would not be possible. There is nothing I can write here to truly express my gratitude, excepting to say I love you. XI Glossary Abbreviations 5-HT 5-hydroxytryptamine (serotonin) abs absolute anal. analytical aq aqueous ap. apparent br broad calcd calculated CI confidence interval d doublet DA dopamine DAT dopamine transporter dt doublet of triplets dd doublet of doublets ddd doublet of doublet of doublets ddq doublet of doublet of quartets DEPT distortionless enhancement by polarisation transfer DME 1,2-dimethoxyethane DMF dimethylformamide EI electron impact ESI electrospray ionisation equiv equivalent eV electron volt FAB fast atom bombardment g gram(s) GC-MS gas chromatography mass spectrometry h hour(s) Hz Hertz HR-MS high resolution mass spectrometry half maximal inhibitory concentration IC50 IR infrared spectroscopy ^m Michaelis-Menten constant Ki inhibition constant LID levodopa-induced dyskinesia lit. literature m multiplet mg milligram(s) min minute(s) mL milliliter(s) XIII mmol millimole(s) moi mole(s) mp melting point MPTP 1 -methyl-4-phenyl-1,2,3,6-tetrahydropyridine NE norepinephrine NET norepinephrine transporter NIE no inhibitory effect NMR nuclear magnetic resonance PD Parkinson's disease PEA phenethylamine q quartet quant. quantitative rsf rapid suction filtration rt room temperature SAR structure activity relationship sat. saturated SEM standard error of the mean sept septet SERT serotonin reuptake transporter sext sextet st strong s singlet sh sharp si slightly t triplet tic thin layer chromatography THF tetrahydrofuran v maximum rate r max 5 chemical shift (parts per million) Functional Groups Ac acetyl Ar aryl Bn benzyl Bu butyl r-Bu ter/-butyl Des 2,5 -dichlorobenzenesulfonyl Et ethyl c-Hx cyclohexyl XIV Me methyl Ph phenyl Pr propyl c-Pr cyclopropyl f-Pr isopropyl Py pyridyl Ts £>-toluenesulfonyl (tosyl) XV Introduction Introduction Introduction 3,4-Methylenedioxymethamphetamine (MDMA) 1 is a psychotropic drug and the active chemical constituent of the illicit drug ecstasy.* It is a ring-substituted derivative of methamphetamine 2, a similarly notorious substance of abuse. Both MDMA and methamphetamine belong to the entirely synthetic class of compounds, the amphetamines, all members of which possess the amphetamine scaffold 3. Amphetamines have been extensively studied and reported in the literature. They are most remarkable for their • 10 diverse and potent central nervous system (CNS) activity. ' O^/^/^-NH Z /^/^NHj o- -^ MDMA 1 Methamphetamine 2 Amphetamine 3 The social history of MDMA has been documented in many texts.1'3"6 In 1914 MDMA entered the chemical literature as an intermediate published in a Merck patent. There was little interest in MDMA until many decades later. By the late 1970s MDMA was being used in clinical settings in California, developing a reputation amongst psychotherapists as a useful adjunct to psychotherapy. Concurrently there were increasing numbers of recreational users consuming MDMA under the newly minted name ecstasy. The burgeoning appetite for ecstasy in the 1980s coincided with the growing popularity of the dance music counterculture, in particular with dance music events called raves, where ecstasy was the drug of choice. In 1985, after a series of alarmist reports on ecstasy surfaced, the United States Drug Enforcement Agency listed MDMA on Schedule I of the Controlled Substances Act, for dangerous and addictive drugs without medical use.1'* The scheduling of MDMA as a * More accurately the active chemical found in ecstasy is the hydrochloride of MDMA, MDMA.HCI. f Methamphetamine is the active chemical constituent of the illicit drug commonly known as ice or speed. * Australian regulatory bodies rapidly followed suit and restrictively scheduled MDMA in 1986. 2 Introduction controlled substance has not curtailed its popularity. The United Nations report on ecstasy production and consumption, Ecstasy and Amphetamines Global Survey 2003, declared 'the huge increase in ecstasy consumption has continued globally over the past years'. The survey reported estimated worldwide ecstasy production at 125 tonnes a year, with eight million users.7 Subjective Effects The phenomenal popularity of MDMA as a drug of abuse derives from the combination of effects that it elicits. As the name ecstasy implies, MDMA is both a euphoriant and an empathogen. In humans the effective dose range is between 100-160 mg (~2 mg/kg).8 A person who has consumed ecstasy is reported to experience feelings of intense pleasure, a lack of inhibition and heightened empathy and awareness.§ Indeed it is these subjective effects that some have argued lend MDMA so well to the role of an adjunct to psychotherapy.10 MDMA's unique psychotropic properties prompted Nichols and coworkers to propose that it belonged to a novel drug class, designated the enactogens.11 Pharmacology The pharmacology of MDMA has been studied extensively in vitro and in vivo and consequently has been the subject of periodic review. Recent noteworthy contributions include those by Green et al.12 (2003) and by Baumann