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Design, Synthesis, and Evaluation of Antiepileptic Compounds Based on Β-Alanine and Isatin

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Design, Synthesis, and Evaluation of Antiepileptic Compounds Based on Β-Alanine and Isatin Design, Synthesis, and Evaluation of Antiepileptic Compounds Based on β-Alanine and Isatin by Robert Philip Colaguori A thesis submitted in conformity with the requirements for the degree of Master of Science Department of Pharmaceutical Sciences University of Toronto © Copyright by Robert Philip Colaguori, 2016 ii Design, Synthesis, and Evaluation of Antiepileptic Compounds Based on β-Alanine and Isatin Robert Philip Colaguori Master of Science Department of Pharmaceutical Sciences University of Toronto 2016 Abstract Epilepsy is the fourth-most common neurological disorder in the world. Approximately 70% of cases can be controlled with therapeutics, however 30% remain pharmacoresistant. There is no cure for the disorder, and patients affected are subsequently medicated for life. Thus, there is a need to develop compounds that can treat not only the symptoms, but also delay/prevent progression. Previous work resulted in the discovery of NC-2505, a substituted β-alanine with activity against chemically induced seizures. Several N- and α-substituted derivatives of this compound were synthesized and evaluated in the kindling model and 4-AP model of epilepsy. In the kindling model, RC1-080 and RC1-102 were able to decrease the mean seizure score from 5 to 3 in aged mice. RC1-085 decreased the interevent interval by a factor of 2 in the 4-AP model. Future studies are focused on the synthesis of further compounds to gain insight on structure necessary for activity. iii Acknowledgments First and foremost, I would like to thank my supervisor Dr. Donald Weaver for allowing me to join the lab as a graduate student and perform the work ultimately resulting in this thesis. His guidance and support, not just on medicinal chemistry, but life in general, is something that I will always remember and try to impart upon others. I would also like to thank my committee members Dr. Robert Batey and Dr. Jack Uetrecht for their assistance in the completion of this work. To all members of the Weaver group, thank you for not only being exceptional scientists, but even more exceptional human beings. In particular Usman, Brendan, Elena, Pete, and Braden, thank you for the countless discussions about everything from reaction work-up to fish tacos. I can say with confidence that I have gained friendships that will last for life. I would especially like to thank Kurt, who aided in much of the animal work presented in this thesis, which could not have been completed without his expertise and patience while teaching an organic chemist how to handle a mouse. Finally, I would like to thank my family, whose constant love and emotional support made this thesis possible. Thank you for all the cups of tea and rides downtown when the subway was delayed, they mean more than you know. iv Acknowledgments ........................................................................................................................ iii List of Figures .............................................................................................................................. vii List of Schemes .............................................................................................................................. x List of Tables ............................................................................................................................... xii Chapter 1 – Introduction .............................................................................................................. 1 1.1 History of Epilepsy .......................................................................................................... 1 1.2 Epilepsy In Its Current State .......................................................................................... 1 1.2.1 Seizure Classification .................................................................................................. 2 1.2.2 Ictogenesis and Epileptogenesis .................................................................................. 3 1.3 Available Anticonvulsants: Discovery, Use, and Limitations ...................................... 6 1.3.1 Problems Currently Hampering Effective AED Development ................................. 11 1.4 Endogenous Platforms for Antiepileptic Drug Development .................................... 15 1.4.1 Beta-Alanine as a Lead Molecule ............................................................................. 15 1.4.2 Isatin as a Lead Molecule .......................................................................................... 17 1.5 Research Goals ............................................................................................................... 18 Chapter 2 – Synthesis of Disubstituted Beta-Amino Acids ..................................................... 20 2.1 Previous Synthesis of Lead Molecule NC-2505 ........................................................... 20 2.2 Retrosynthesis of NC-2505 ............................................................................................ 21 2.3 Improved Synthesis of NC-2505 ................................................................................... 22 2.4 Synthesis of N-substituted Derivatives of NC-2505 .................................................... 23 2.4.1 Buchwald-Hartwig Amination Route ........................................................................ 24 2.4.2 Nucleophilic Aromatic Substitution Route .................................................................. 25 2.4.3 Reductive Amination Route ...................................................................................... 25 2.5 Synthesis of α-substituted Derivatives of NC-2505 ..................................................... 30 2.5.1 Fráter-Seebach-type Enolate Alkylation ................................................................... 30 2.5.2 Lithium-amide Conjugate Addition to Trisubstituted (E)-α,β-Unsaturated Esters .. 33 2.5.3 Palladium-Catalyzed α-Arylation of Esters .............................................................. 34 2.5.4 Ellman Mannich-Type Reaction ............................................................................... 35 2.6 Experimental .................................................................................................................. 36 2.6.1 Knoevenagel condensation procedure for the synthesis of α,β-unsaturated ester 10 37 v 2.6.2 General procedure for the synthesis of benzylated-aminoester 11 and 22 ................ 38 2.6.3 Hydrogenation procedure for the synthesis of aminoester 12 ................................... 39 2.6.4 General reductive amination procedure for the synthesis of N-substituted derivatives of NC-2505 tert-butyl esters ................................................................................................. 40 2.6.5 General procedure for the synthesis of N-substituted derivatives of NC-2505 via tert- butyl ester cleavage ............................................................................................................... 46 2.6.6 Procedure for the Boc-protection of aminoester 12 .................................................. 49 2.6.7 General procedure for the enolate alkylation of Boc-aminoester 15 ......................... 50 2.6.8 General procedure for global Boc-deprotection of 16a/b to furnish α-substituted derivatives of NC-2505 17a/b ............................................................................................... 51 2.6.9 Procedure for the synthesis of N-sulfinylimine 24 .................................................... 52 2.6.10 Procedure for the enolate addition to N-sulfinylimine 24 ......................................... 53 Chapter 3 – In vivo and Ex vivo Evaluation of Substituted Derivatives of NC-2505 ............ 55 3.1 In vivo Methods for Compound Evaluation ................................................................ 55 3.2 Critical Analysis of the MES and scPTZ Tests ........................................................... 55 3.3 The Kindling Model of Epilepsy .................................................................................. 56 3.4 Route of Administration ................................................................................................ 58 3.5 Evaluation of Compounds in the Kindling Model ...................................................... 59 3.5.1 Vehicle Selection ......................................................................................................... 59 3.5.2 Compound Activity in Aged Kindled Mice .............................................................. 59 3.6 Evaluation of Compounds in the 4-Aminopyridine Ex Vivo Epilepsy Model .......... 64 3.7 Experimental .................................................................................................................. 66 3.7.1 Surgical Implantation of Electrodes .......................................................................... 66 3.7.2 Kindling Protocol ...................................................................................................... 67 3.7.3 Video-EEG Recordings ............................................................................................. 67 3.7.4 Assessment of Seizure Score ..................................................................................... 67 3.7.5 Compound Administration ........................................................................................ 67 3.7.6 Limbic Slice Preparation ..........................................................................................
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