The Design and Synthesis of Novel Barbiturates of Pharmaceutical Interest

University of New Orleans ScholarWorks@UNO University of New Orleans Theses and Dissertations Dissertations and Theses 5-21-2004 The Design and Synthesis of Novel Barbiturates of Pharmaceutical Interest Donna Neumann University of New Orleans Follow this and additional works at: https://scholarworks.uno.edu/td Recommended Citation Neumann, Donna, "The Design and Synthesis of Novel Barbiturates of Pharmaceutical Interest" (2004). University of New Orleans Theses and Dissertations. 1040. https://scholarworks.uno.edu/td/1040 This Dissertation is protected by copyright and/or related rights. It has been brought to you by ScholarWorks@UNO with permission from the rights-holder(s). You are free to use this Dissertation in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s) directly, unless additional rights are indicated by a Creative Commons license in the record and/ or on the work itself. This Dissertation has been accepted for inclusion in University of New Orleans Theses and Dissertations by an authorized administrator of ScholarWorks@UNO. For more information, please contact [email protected]. THE DESIGN AND SYNTHESIS OF NOVEL BARBITURATES OF PHARMACEUTICAL INTEREST A Dissertation Submitted to the Graduate Faculty of the University of New Orleans in partial fulfillment of the requirements for the degree of Doctor of Philosophy in The Department of Chemistry by Donna M. Neumann B. A. University of New Orleans, 2000 May 2004 Dedicated to: My daughter, Madeline Megan Jenkins ii ACKNOWLEDGEMENTS I would like to express my utmost gratitude to my advisor, Professor Branko S. Jursic, for his unwavering support, advice and education for which I am forever indebted. I would also like to extend sincere gratitude to my committee members, Professors Bruce Gibb, Paul Hanson, Guijun Wang, and Mark Trudell, each for their patience and sound advice that enabled me to complete my goals set forth. My fellow peers and laboratory group members, Ms. Katharine L. Bowdy, Ms. Sarada Raju, Mr. Paresh Patel, Ms. Jessica Campbell and Ms. Joni D. Swenson are acknowledged for their continuing support, help, and insight into all aspects of my research. I would like to extend special thanks to Professor Edwin Stevens and Professor Kenneth Martin, whose expertise in X- ray crystallography proved essential to my successful research, Professor Ronald Evilia, whose advice and support are irreplaceable, Dr. Lee Roy Morgan and Dekk Tec, Inc. for providing biological results necessary for my research, and Dr. Edith Banner, for whose friendship I am forever grateful. Lastly, I would like to thank the Louisiana Board of Regents, the University of New Orleans, and the Cancer Association of Greater New Orleans for their financial support for this work. iii TABLE OF CONTENTS LIST OF FIGURES vii LIST OF TABLES xiv ABSTRACT xvi INTRODUCTION 1 Ia. History of Barbituric Acid 1 Ia.1. Modifications to original barbituric acid 2 Ia.2. Effects of subsequent barbituric acid modification 4 Ib. Classifications of Barbiturates 5 Ic. Physical Properties of barbituric acids 6 Id. Pharmacological effects of barbiturates and barbituric acids as building blocks for large heterocycles with pharmaceutical value 7 Id.1. The traditional barbiturate target: The GABAa-ion Receptor Complex 8 Id.2. Discovery of Benzodiazepines 11 Id.3. Other possible physiological targets for barbiturates: Histone deacetylase enzymes 12 Id.4. Barbiturates as Potential Immuno-Modulating Compounds 17 RESULTS AND DISCUSSION 25 IIa. Condensation Products 25 IIa.1. Preamble 25 IIa.2. Results and Discussion 27 IIb. Reductive C-5 alkylation and C-5 benzylation of barbituric acids 34 iv IIb.1. Preamble 34 IIb.2. Results and Discussion 36 IIb.2.1 Alkylation 36 IIb.2.2 Benzylation 39 IIb.2.3 C-5 dibenzylation of barbituric acid 42 IIb.2.4 Unsymmetrical C-5 alkylation of barbituric acid 43 IIc. Development of 5-cyclohexylmethyl barbituric acids- Precursors for asymmetric synthesis 44 IIc.1. Preamble 44 IIc.2. Results and Discussion 44 IId. Preparation of 5-Formyl and 5-Acetyl Barbiturates and Corresponding Schiff Base Products 50 IId.1. Preamble 50 IId.2. Results and Discussion 52 IId.3. Preparation of ω-aminoalkanoic acid Schiff Base Products 53 IId.3.1 Physical properties of Schiff base products with ω-aminoalkanoic acid 55 IId.4. Preparations of Phenylhydrazones of 5-Formyl and 5-Acetyl barbiturates 58 IIe. Aromatic-dibarbiturates- Pyridine and Quinoline Derivatives 61 IIe.1. Preamble 61 IIe.2. Results and Discussion 62 IIf. Unique Molecules: Charge Separated Pyridinium-Barbiturate Zwitterions 76 IIf.1. Preamble 76 IIf.2. Results and Discussion 78 IIf.3. Physical properties of Pyridinium-barbituric acid Zwitterion F1 84 IIg. Syntheses of Heteroaromatic, Electron Rich, and Aliphatic Bis-barbiturate Ammonium Salts 88 IIg.1. Preamble 88 IIg.2. Results and Discussion 89 IIh. Syntheses of Substituted and Unsubstituted 5-benzoylbarbituric acids and Corresponding Phenylhydrazones 99 IIh.1. Preamble 99 v IIh.2. Synthesis of benzoyl barbiturates 100 IIh.2.1 Physical properties 102 IIh.3. Hydroxy-benzoyl barbiturate precursors 106 IIi. A Barbituric Acid Initiated Rearrangement Reaction: Formation of 5-5’-(2-pyrilidine)bis barbituric acids 120 IIi.1. Preamble 120 IIi.2. Results and Discussion 121 BIOLOGICAL EVALUATIONS OF NOVEL BARBITURATES 126 IIIa. Introduction 126 IIIb. Biology Methods 126 IIIc. Results and Discussion 127 CONCLUSIONS 134 REFERENCES 136 EXPERIMENTALS 145 APPENDIX 261 VITA 316 vi LIST OF FIGURES Figure I.1 Synthesis of barbituric acid 1 Figure I.2 Original synthesis of Veronal (5,5’-diethylbarbituric acid) (3) 2 Figure I.3 Structure of the active anti-epileptic Phenobarbital (4) 3 Figure I.4 Substitutions of the original barbituric acid at either C-5 or C-2 4 Figure I.5 Acidic properties of barbituric acids 6 Figure I.6 Cartoon of the GABAa receptor 9 Figure I.7 Cartoon of protein subunits of GABAa that traverse the cell membrane 10 Figure I.7a Benzodiazepines commonly used today 11 Figure I.8 Cartoon of targets for post-translational histone modification via acetylation of lysine residues (K). 13 Figure I.9 Several known histone deacetylase inhibitors 14 Figure I.10 HDLP Enzyme catalytic site with suberylanilido hydroxamic acid (19) bound 16 Figure I.11 Pharmacophore of potential histone deacetylase inhibitors 17 Figure I.12 Antigen initiated human immune response 20 Figure I.13 Structural crystallography characteristics of A-007 20 Figure I.14 Postulated interactions of A-007 with the CD45 receptor 23 vii Figure IIa.1 Villemin et al. preparation of Knoevenagel condensation products 26 Figure IIa.2 Formation of Knoevenagel products from solid state reactions 27 Figure IIa.3 General procedure for obtaining Knoevenagel condensation products 28 Figure IIa.4 Spectroscopically detected products in reaction between barbituric acid and aliphatic aldehydes 31 Figure IIa.5 Products of described reactions in Table IIa.1 33 Figure IIb.1 Examples of asymmetric barbiturates 35 Figure IIb.2 Trost utilization of mono C-5 alkylated barbiturates 36 Figure IIb.3 General reaction for synthesis of mono C-5 alkylated barbiturates 38 Figure IIb.4 Products of mono C-5 benzylation after hydrogenation 40 Figure IIb.5 General synthesis of mono C-5-benzylated products 41 Figure IIb.6 Two representative structures of barbituric acid C-5 dibenzylation 42 Figure IIb.7 Representative synthesis of unsymmetrical double alkylation products 43 Figure IIc.1 Reaction methodology for 5-cyclohexylmethyl barbiturates 46 Figure IIc.2 One pot synthesis of 5-cyclohexylmethyl barbiturates 47 Figure IIc.3 Ortep drawing of compound C4 (courtesy of Prof.s E. D. Stevens and K. L. Martin) 49 Figure IId.1 Inanaga method for introduction of a masked formyl group 50 Figure IId.2 Example of (–C) masked nucleophile to introduce formyl group 51 Figure IId.3 Example of direct formylation via Vilsmeier-Haack reaction 51 viii Figure IId.4 Synthesis of 5-formyl and 5-acetyl barbiturates 52 Figure IId.5 Formyl barbiturates designed as potential HDACI’s 54 Figure IId.6 Synthesis of ω-aminoalkanoic acid Schiff bases 54 Figure IId.7 1H-NMR following the change of equilibrium for two structural isomers of D13. (A) Two isomers isolated from methanol reaction mixture. (B) Ratio of isomers after heating DMSO-d6 solution for 1 min. (C) 3 min heating. (D) 5 min heating then standing at room temperature for 8 h 57 Figure IId.8 Synthesis of traditional Schiff bases of phenylhydrazines and barbituric acids 59 Figure IIe.1 Possible starting materials for the preparation of heterocyclic dibarbiturates 62 Figure IIe.2 Two different products of barbituric acid (R=H) and 1,3- dimethylbarbituric acid (R=CH3) condensation with 2- pyridinecarbaldehyde 63 Figure IIe.3 1H-NMR (500 MHz) reaction following for 1-naphthaldehyde (1 mM) condensation with barbituric acid (5 mM) in CF3COOH to produce A7 64 Figure IIe.4 The 1H-NMR (500 MHz) reaction following of 4- dimethylaminobenzaldehyde condensation with barbituric acid in DMSO (a, b, and c) to yield A1 and CF3COOH (d, e, and f) to yield E1 66 Figure IIe.5 1H-NMR reaction following of 4-hydroxybenzaldehyde ix condensation with barbituric acid in CF3CO2H yielding A16 68 1 Figure IIe.6 H-NMR reaction following in DMSO-d6 -300 MHz Varian Unity and CF3COOH with electron-deficient aromatic aldehydes to yield E2 69 1 Figure IIe.7 The H-NMR (DMSO-d6 -300 MHz Varian Unity, 500 MHz) reaction following for 4-quinolinecarboxaldehyde condensation with barbituric acid to yield E3 70 Figure IIe.8 All reactive intermediates that were detected in our 1H-NMR following experiments of the barbituric acid addition to 2,2’-dipyridine-4,4’-dicarboxaldehyde 72 Figure IIe.9 1H-NMR (500 MHz) following of barbituric acid (10 mM) condensation with 2,2’-bipyridine-4,4’-carboxaldehyde (2.5 mM) in TFA-DMSO (3:1) at room temperature yielding E4 72 Figure IIe.10 Preparation of heteroaromatic dibarbiturates 73 Figure IIe.11 Ortep Drawing of compound E3 (courtesy of E.

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