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Syntheses of Nipecotic Acid Derivatives with New N-Arylalkenyl

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Syntheses of Nipecotic Acid Derivatives with New N-Arylalkenyl Dissertation zur Erlangung des Doktorgrades Fakultät für Chemie und Pharmazie Ludwig-Maximilians-Universität München Syntheses of nipecotic acid derivatives with new N-arylalkenyl and N-arylalkynyl substituents and with new photoswitchable residues as mGAT1 inhibitors Toni Alexander Lutz aus München 2017 Erklärung Diese Dissertation wurde im Sinne von § 7 Abs. 1 bzw. 2 der Promotionsordnung vom 28. November 2011 von Herrn Prof. Dr. Klaus T. Wanner betreut. Eidesstattliche Versicherung Diese Dissertation wurde eigenständig und ohne unerlaubte Hilfe erarbeitet. München, den 11.04.2017 .................................................. (Toni Lutz) Dissertation eingereicht am …………………………12.04.2017 1. Gutachter Prof. Dr. Klaus T. Wanner 2. Gutachter Prof. Dr. Franz Paintner Mündliche Prüfung am …………………………05.05.2017 Die vorliegende Arbeit entstand in der Zeit von August 2011 bis März 2017 am Department Pharmazie – Zentrum für Pharmaforschung – der Ludwig-Maximilians-Universität München auf Anregung und unter Leitung von Herrn Prof. Dr. Klaus T. Wanner Für die engagierte, ausgezeichnete und sehr hilfreiche Betreuung und Förderung meiner Arbeit sowie die hervorragenden Forschungsbedingungen danke ich Herrn Prof. Dr. Klaus T. Wanner sehr herzlich. Herrn Prof. Dr. Paintner danke ich herzlich für die Übernahme des Korreferats. Danksagung Für die gute Zusammenarbeit und die schöne gemeinsame Zeit möchte ich mich bei allen aktuellen und ehemaligen Mitarbeiterinnen und Mitarbeitern des Arbeitskreises bedanken. Besonderer Dank gilt meinen ehemaligen Laborkollegen Ludwig Angermeier, Tobias Hauke und Tim (Hölle) Hellenbrand für die super Zeit im und rund ums Labor, wie beispielsweise vieler Schafkopfrunden und gemeinsamer Treffen und Unternehmungen außerhalb der Uni. Meinen Bachelor-Studenten Patrick Spanner und Thomas Ackermann sowie meinem Wahlpflichtpraktikanten Florian Schanzer danke ich für ihre Mithilfe im Labor und die durchgeführten Synthesen im Rahmen ihrer Arbeiten. Die Zusammenarbeit mit euch hat mir sehr Spaß gemacht und ich wünsche euch alles Gute für eure jeweilige Zukunft! Dr. Georg Höfner sowie dem gesamten Team der biologischen Prüfabteilung, insbesondre Silke Duensing-Kropp und Ljiljana Galogaza, danke ich sehr für die Testung der von mir synthetisierten Verbindungen, v.a. für die aufwendige Testung meiner photoschaltbaren Verbindungen und die dabei jeweils erforderliche gute Abstimmung im zeitlichen Ablauf. Dr. Lars Allmendinger und den Mitarbeiterinnen der analytischen Abteilung, insbesondere Claudia Glas und Ursula Groß gilt besonderer Dank für die Messung all meiner IR-, MS- und NMR-Spektren, v.a. aber für das Möglichmachen der Messung sehr vieler NMR-Kinetik- Experimente und die stets sehr gute zeitliche Koordination dafür. Den Mitarbeitern des AK Trauners, v.a. Dr. Martin Sumser, danke ich für die andauernde Bereitstellung ihrer Messgeräte, v.a. des Monochromators und des UV-Spektrometers und für das Ermöglichen unzähliger (Kinetik)-Messungen an diesen Geräten. Katharina Heimberger und Annerose Kärtner danke ich für die Unterstützung bei allen organisatorischen Aufgaben sowie die Versorgung mit Büro- und Labormaterialien. Für die hervorragende Organisation der von mir betreuten Studentenpraktika möchte ich Herrn Dr. Jörg Pabel und Elisabeth Zoller herzlich danken. Dr. Jörg Pabel und Dr. Thejavathi Renukappa-Gutke danke ich außerdem für das Korrekturlesen meiner Publikationen. Besonderer Dank gilt auch all meinen Münchener, Holzkirchner und Uni-Freunden für die zeitliche Begleitung durch meine Promotionszeit und die vielen gemeinsamen Erlebnisse. Größter Dank geht an meine Familie, an meine Schwester, an meine Eltern und meine Tante, für die bedingungslose Unterstützung und den Rückhalt von zu Hause und vor allem dafür, dass ihr zu jedem Zeitpunkt an mich geglaubt habt und immer für mich da wart! Ihr habt mir diese Doktorarbeit erst möglich gemacht. This cumulative thesis is based on the following original publications and manuscripts: 2013: Miriam Sindelar, Toni A. Lutz, Marilena Petrera, Georg Höfner, and Klaus T. Wanner; Journal of Medicinal Chemistry 2013, 56, 1323-1340. "Focused Pseudostatic Hydrazone Libraries Screened by Mass Spectrometry Binding Assay – Optimizing Affinities towards -Aminobutyric Acid Transporter 1" 2015: Toni A. Lutz, Patrick Spanner, and Klaus T. Wanner; Tetrahedron 2016, 72, 1579-1589. A geeal appoah to sustituted dipheyldiazees 2016: Toni A. Lutz, Thomas Wein, Georg Höfner, and Klaus T. Wanner; ChemMedChem 2017, 12, 362-371. Development of highly potent GAT1 Inhibitors: Synthesis of Nipecotic Acids Derivatives with N-arylalkinyl substituents 2017: Toni A. Lutz, Thomas Wein, Georg Höfner, and Klaus T. Wanner; Manuscript to be submitted to Journal of Medicinal Chemistry. Development of new photoswitchable azobenzene bound GABA uptake inhibitors with distinctly enhanced potency upon photoactivation Copyright of the publications belong to the publishers. Table of contents 1 Introduction ......................................................................................................................................... 1 1.1 CNS diseases and the physiologic significance of GABA ............................................................... 2 1.1.1 GABA Neurotransmission .................................................................................................... 2 1.1.2 Pathology and Therapy ........................................................................................................ 4 1.2 GABA Transporters ...................................................................................................................... 5 1.2.1 The SLC6 transporter family ................................................................................................ 5 1.2.2 Classification of GABA transporters ..................................................................................... 9 1.2.3 GABA transporters as pharmacolocical targets ................................................................. 10 1.2.4 Binding modes of GABA and GAT1 inhibitors .................................................................... 13 1.3 Cross-coupling reactions as synthetic tool in medicinal chemistry ............................................ 16 1.4 The use of light for the activity control of ligands ...................................................................... 18 1.4.1 Photochromism and photoswitchable compounds ........................................................... 18 1.4.2 Establishments of photoswitchable ligands ....................................................................... 20 2 Aims and Scope .................................................................................................................................. 21 2.1 Nipecotic acid derivatives with N-arylalkenyl and N-arylalkinyl substituents ............................ 21 2.2 Nipecotic acid derivatives with photoswitchable N-substituents .............................................. 23 3 Summary of manuscripts and published results ................................................................................ 25 3.1 Focused Pseudostatic Hydrazone Libraries Screened by MS Binding Assay – Optiizig Affiities towards γ-Aminobutyric Acid Transporter 1 .................................................... 25 3.2 Development of highly potent GAT1 Inhibitors: Synthesis of Nipecotic Acids Derivatives with N-arylalkynyl substituents .......................................... 27 3.3 Development of new photoswitchable azobenzene bound GABA uptake inhibitors with distinctly enhanced potency upon photoactivation ................................................................... 29 3.4 A general approach to substituted diphenyldiazenes ................................................................. 31 4 Conclusions ........................................................................................................................................ 33 5 Further experiments .......................................................................................................................... 35 6 List of Abbreviations .......................................................................................................................... 67 7 Literature ........................................................................................................................................... 68 8 Publications and Manuscripts ............................................................................................................ 72 INTRODUCTION 1 1 Introduction The investigation of the relationships between chemical structures and their biological effect is the principal aim of medicinal chemical research. Active compounds may be found in a library of various different chemical structures by means of high-throughput screening. Identified hits can then be used as lead structure for the design of further drugs. However, since this common method is time-consuming and expensive, nowadays the computer based design represents a wide spread and established method. In this context, drug development in pharmaceutical research mostly begins with the identification and characterization of a biological target which may be an enzyme or a membrane bound protein like receptors or transporters that mediate a physiological effect. In general, two different strategies can be pursued: The taget ased dug desig euies the knowledge of the exact 3D structure of the target in presence of the ligand that may be generated
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