Solid phase synthesis and biological evaluation of 1, 3, 5 triazine derivatives

SOLID-PHASE SYNTHESIS AND BIOLOGICAL EVALUATION OF 1, 3, 5-TRIAZINE DERIVATIVES KONG KAH HOE (B.Sc (Hons.), NUS) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY NATIONAL UNIVERSITY OF SINGAPORE 2009 ACKNOWLEDGEMENTS I would like to thank my supervisor, A/P Lam Yulin, for giving me a chance to pursue my interest in organic synthesis I am very grateful to her for accepting me into her research group and be trained as an organic chemist She is always very patient in giving me time to surmount the difficult synthetic transformations that are presented in this thesis I also like to express my immense graditiude to Mrs Ting Wee Lee from the Department of Pharmacology Her invaluable help have been critical to the biological study that is presented in this thesis I would like to also acknowledge Prof Peter Wong and A/P Chui Wai Keong for their valuable inputs during the development of the assay and the optimization of the various substrates To all my past and present group members, Dr Fu Han, Dr He Rongjun, Madam Liang Eping, Dr Makam Shantha Kumar Raghavendra, Dr Chen Yu, Fang Zhanxiong, Tan Chong Kiat, Lin Xijie, Chen Yanjun, Wong Ling Kai, Dr Gao Yongnian, Dr Soh Chai Hoon, Ching Shimin, Che Jun, Gao Yaojun and Sanjay Samanta, thank you for all the helpful hints and kind assistances I want to express my appreciation to CMMAC staff for their assistance in the spectroscopic analysis I would thank my family members and wife for their unlimited support during all these years I would also like to thank the National University of Singapore for awarding me a research scholarship to pursue my doctorate degree i TABLE OF CONTENTS TABLE OF CONTENTS SUMMARY LIST OF TABLES LIST OF FIGURES LIST OF SCHEME LIST OF ABBREVIATIONS ii vi vii viii xi xiv Chapter 1: Introduction 1.1.1 Solid-Phase Synthesis 1.1.2 Solid Supports 1.1.3 Linkers 1.1.3.1 Acid Labile Linkers 1.1.3.2 Base Labile Linkers 1.1.3.3 Traceless Linkers 1.1.3.4 Safety Catch Linkers 10 1.2.1 1,3,5-Triazine Derivatives 11 1.2.2 Synthesis of 1,3,5-Triazine Derivatives 14 1.2.2.1 Solution phase synthesis of 2,4,6-trisubtituted-1,3,5-triazine 14 1.2.2.2 Solid-Phase Synthesis of 1,3,5-Triazine Derivatives 17 Purpose of the Research Work in this Thesis 19 1.3 Chapter 2: Traceless Solid-Phase Synthesis of 6-Amino- and 6-Hydroxyimino1,3,5-triazine-2,4-diones and 1,3,5-Triazine-2,4,6-triones 2.1 Introduction 21 2.2 Results and Discussion 22 2.2.1 Solution-Phase Synthesis 22 ii 2.2.2 Solid-Phase Synthesis 25 2.3 Conclusion 30 2.4 Experimental Section 30 Chapter 3: Development of a Novel Solid-Phase Traceless Synthetic Strategy for the Syntheses of Diverse Libraries with 1,3,5-Triazine Template 3.1 Introduction 54 3.1.1 Synthesis of 1,3,5-Triazine Heterocycles 54 3.2 Outline of Synthetic Strategy 56 3.3 Results and Discussion for the Synthesis of 2,5,6-Trisubsituted-4phenylimino-4,5-dihydro-1,3,5-triazine-2-amine 57 3.3.1 Synthesis of 2-benzylisothiourea 3-1 and 3-2 57 3.3.2 Synthesis of (E)-2-benzyl-1-(N'-alkyl-Nphenylcarbamimidoyl)isothiourea 3-4 58 3.3.3 Revised Synthesis of (E)-2-benzyl-1-(N'-alkyl-Nphenylcarbamimidoyl) isothiourea 3-4 59 3.3.4 Oxidation and cleavage of 3-7 62 3.3.5 Solid-phase Synthesis of 3-7 63 3.3.6 Experimental Section 65 3.4 Synthesis of 1,3,5-triazine Analogs via Guanidium Azolides 80 3.5 Synthesis of 1,3,5-traizine-2,4-diones 3-17 81 3.5.1 Solution-Phase synthesis of 3-17 81 3.5.2 Solid-Phase Synthesis of 3-Benzyl-6-(butylamino)-1,3,5triazine-2,4(1H,3H)-dione 3-17 83 3.5.3 Experimental Section 88 3.5.3.1 Solution phase synthesis 88 3.5.3.2 Solid-Phase Synthesis 91 iii 3.6 Synthesis of 2-(Methylamino)-6,7,8,9-tetrahydropyrimido [1,2a][1,3,5]triazin-4-ones 103 3.6.1 Solution Phase Synthesis of 2-(Methylamino)-6,7,8,9 103 -tetrahydropyrimido [1,2-a][1,3,5]triazin-4-ones 3-28 3.6.2 Solid phase synthesis of 2-(methylamino)-6,7,8,9- 105 tetrahydropyrimido [1,2-a][1,3,5]triazin-4-ones 3-28 3.6.3 Microwave assisted cleavage of 3-28 3.6.4 Solution-Phase Synthesis 114 Acid catalysed cyclization to yield 1,3,5-traizine analogs 3-38, 3-39, 3-44, 3-45 and 3-47 123 3.7.1 Solution phase synthesis of 3-36 124 3.7.2 Solid-Phase library synthesis of 3-38, 3-39, 3-44, 4-45 and 3-47 126 3.7.3 Experimental Section 132 3.7.3.1 Solution Phase Synthesis 132 3.7.3.2 Solid-Phase synthesis 134 Traceless cleavage via Liebeskind-Srogl cross coupling on solid phase 145 3.8.1 Traceless cleavage via Liebeskind-Srogl Cross Coupling on 3.8 111 3.6.5 Solid-phase synthesis 3.7 107 147 3-40 and 3-41 3.8.2 Traceless cleavage via Liebeskind-Srogl Cross Coupling on 150 3-11 3.8.3 Experimental Section 3.8.3.1 Solution phase synthesis of 3-48, 3-49 and 3-50 3.9 152 152 Conclusion 156 iv Chapter 4: Biological Evaluation of 1,3,5-Triazines Derivatives on Neuronal Nitric Oxide Synthase 4.1 Nitric Oxide Synthase 157 4.2 NOS inhibitors 159 4.3 Structure Activity Relationship of Cofactor H4Bip 160 4.4 Screening 1,3,5-triazine Derivatives 161 4.5 Experimental Methods 162 4.6 Results and Discussion 164 4.7 Conclusion 168 Chapter 5: References 169 v SUMMARY This thesis reports on the development of novel methodologies for the solid-phase synthesis of 1,3,5-triazine derivatives and biological evalution of the synthesized 1,3,5triazine derivatives as nNOS inhibitors In the first project, a small library consisting of trisubstituted 1,3,5-triazine-2,4(1H,3H)diones were synthesized using solid phase synthetic methodology that is amenable to KBr FTIR monitoring to afford the compounds Key steps of the reaction are (i) S-alkylation of substituted ethyl carbomothioylcarbamate onto a bromomethyl resin, (ii) cyclization using various isocyanates, (iii) oxidation using dimethyl dioxirane, and (iv) nucleophilic substitution using various primary amines, ammonium hydroxide or hydroxylamine In addition microwave assisted cleavage was used to cleave the substrate whenever possible The second project works on developing a new synthetic strategy for the analogs of 1,3,5traizines In this new synthetic route, S-alkylation of bromomethyl resin generates the solid supported thiouronium salt as the primary precursor for cyclization reactions to yield the corresponding solid supported triazine derivatives Afterwhich the triazine compounds were released from the solid support via either oxidative activation and cleavage or microwave assisted cleavage In addition, we developed a general Liebeskind-Srogl coupling condition for the cleavage for three sets of triazine substrates The third project reports on the nNOS inhibition studies on 45 triazine derivatives The preliminary results show that triazinetriones are potential candidates for futher development as inhibitors of nNOS enzyme vi LIST OF TABLES Table 1.1 Representative examples of functional group and acid labile linkers combinations Table 2.1 Synthesis of 2-7 from 2-6 and Isocynates R2NCO 24 Table 3.1 Optimized reaction conditions for the one pot synthesis of 3-5 60 Table 3.2 Conditions for the oxidation of 3-5 62 Table 3.3 Reaction Conditions for the synthesis of 3-14 82 Table 3.4 Yields of microwave assisted cleavage and safety catch cleavage 85 Table 3.5 Conditions of various attempts to obtain 3-28 from 3-33 under 108 sealed tube microwave irradiation Table 3.6 Presence of hydrolysed product 3-38 vs reaction conditions 128 Table 3.7 Yields of 3-48 and 3-49 on solution phase 148 Table 3.8 Yields of 3-44a under various reaction conditions 149 Table 3.9 Solid-phase yields of 3-48 and 3-49 150 Table 3.10 Yields of 3-50 from the Liebeskind-Srogl coupling on resin 3-29 151 Table 4.1 Structures and inhibition values of 2-1 164 Table 4.2 Structures and inhibition values of 3-17 165 Table 4.3 Structures and inhibition values of 2-2 165 Table 4.4 Structures and inhibition values of 3-38 and 3-45 166 Table 4.5 Structures and inhibition values of 3-28 and 3-29 167 vii LIST OF FIGURES Figure 1.1 Three key elements of solid-phase synthesis Figure 1.2 Structure of various solid supports Figure 1.3 General representation of nucleophile-labile ester linker cleavage Figure 1.4 Synthesis of indolyl diketopiperazine alkaloids Figure 1.5 Generic representative of base labile cleavage process Figure 1.6 Kroll’s solid-phase synthesis of trialkyl-ammonium salt via base promoted cleavage Figure 1.7 Ellman’s traceless synthesis of benzodiazepine via silicon linker Figure 1.8 Ellman’s traceless synthesis of benzodiazepine via germanium linker Figure 1.9 Houghten and associates’ traceless synthesis of triazinedione 10 Figure 1.10 Kenner’s safety catch approach for solid phase peptide synthesis 10 Figure 1.11 Villalgordo’s safety catch synthesis of 4-alkoxy-substituted 11 pyrimidines Figure 1.12 General structure of 1,3,5-triazine 12 Figure 1.13 Self-assembly network by means of hydrogen bonds 12 Figure 1.14 Structure of common herbicides with 1,3,5-triazine structures 13 Figure 1.15 Structures of pharmaceutically active 1,3,5-triazines 13 Figure 2.1 27 Figure 3.1 Library of 2-1 and 2-2 obtained from the direct substitution and peroxy acid oxidation of resin 2-10 Library of 2-1 obtained by the oxidative activation followed by the nucleophilic substitution of resin 2-10 Steric interaction between the R1 and R2 substituents Figure 3.2 ORTEP plot of 3-5c 62 Figure 2.2 29 61 viii 65 Figure 3.4 Library of 3-7 obtained via oxidative activation followed by the nucleophilic substitution of resin 3-12 Reaction of 3-12 with primary amines under basic condition Figure 3.5 Structure and yields of 3-17 obtained from solid phase synthesis 87 Figure 3.6 Structure and yields of 2-1c synthesized via alkylation of 3-20 88 Figure 3.7 Hydrolysis of 3-27 to 3-29 105 Figure 3.8 Structures of small library 3-28 synthesized from 3-34 110 Figure 3.9 Structures of compound 3-29 110 Figure 3.10 ORTEP diagram of 3-28h 111 Figure 3.11 Structures of triazine cyclized with orthoformate and orthoacetate 123 Figure 3.12 Examples of antibacterial DHFR inhibitors 124 Figure 3.13 ORTEP diagram of 3-35 125 Figure 3.14 ORTEP diagram of 3-38a 126 Figure 3.15 Yields of 3-39 131 Figure 3.16 Yields of 3-38 131 Figure 3.17 Yields of 3-44 131 Figure 3.18 Yields of 3-45 132 Figure 3.19 Yields of 3-47 132 Figure 3.20 ORTEP diagram of 3-50a 152 Figure 4.1 NOS catalyzed oxidation of L-arginine 158 Figure 4.2 Schematic presentation of NOS primary structure 158 Figure 4.3 Structure of cofactor H4Bip 160 Figure 4.4 Possible interaction in the H4Bip binding site 161 Figure 4.5 Comparison of H4Bip and 1,3,5-triazine derivatives 162 Figure 3.3 82 ix The tabulated results presented in Table 4.3 shows that compounds 2-2 with R1 = Me and R2 = Bn, alkyl or allyl (Table 4.3, entry 1, and 4) inhibit nNOS activity by more than 50% Changing the either R1 or R2 to phenyl (Table 4.3, entry 5-6) is detrimental to the inhibitory properties of 2-2 Changing the substituent X from O to oxime leads to a 10% decrease in activity for R2 = Bn (Table 4.3, entry and 9), however, for R2 = Ph changing X from O to oxime lead to a 27% increase in inhibition of nNOS (Table 4.3, entry and entry 11) O HN O R3 N R2 N R2 H R1 R 3-38 / 3-45 R1 R2 R3 H Cl OMe Cl OMe Me Me cyclohexyl cyclohexyl Cyclohexyl H H H H OMe Entry Compound 3-38a 3-38c 3-45b 3-45c 3-45d Average Inhibition, % -2 24 17 16 Table 4.4 Structures and inhibition values of 3-38 and 3-45 Results tabulated in Table 4.4 show that switching from a carbonyl to two R2 alkyl substituents on the triazine hetercyclic template is resulted in inhibition of only -2 to 24% inhibition of nNOS activity O N O O O N N H 3-38a 9% inhibition HN HN N N N O 3-17b 34% inhibition N OH O N O N H 2-1a1 49% inhibition N N O O N H 2-2a 59% inhibition Figure 4.6 Comparison of inhibition values of structurally similar 1,3,5-triazine derivatives Based on the results of the biological assay on the monocyclic 1,3,5-triazine analogs we deduced that triazinetriones 2-2 are potential candidate for further development as inhibitors 166 of nNOS In addition, changing from the substituent at the 6th position from amino to hydroxyamino to carbonyl results in increase of inhibition from 34% to 59% O O N R1 Entry Compound 3-28e 3-28f 3-28g 3-28h 3-28a 3-28b 3-28c 3-28d 3-28i 10 3-28j 11 3-28k 12 3-28m 13 3-28l 14 3-28n 15 3-29a 16 3-29b R1 H H H H H H Me Me Me - A N N N R2 3-28 B N n H HN O N A B N n N H 3-29 R2 Bu Me Piperidine Morpholine Bu Me Piperidine Morpholine Me Morpholine Piperidine Me Me Me - n 1 1 2 2 3 3 % Inhibition* 14 27 17 19 17 19 23 36 27 37 13 -2 30 46 Table 4.5 Structures and inhibition values of 3-28 and 3-29 The nNOS inhibition assay results of 3-28 and 3-29 shows a correlation between the size of the B ring and the inhibition values For smaller B ring size of five and six (n = 1-2, Table 4.4, entry 1-8, 12 and 15) the inhibition ranges between 5% to 27% Increasing the B ring size to seven (n = 3, Table 4.4, entry 9-11, 14 and 16) the inhibition values are increased to between 27% to 46% However, despite the structural similarities of 3-28 and 3-29 with H4Bip, the bicyclic triazines not significantly inhibit activity of nNOS 167 4.7 Conclusion Among the 45 triazine compounds evaluated for inhibition of nNOS, three compounds bearing the triazinetriones substructure 2-2 (Figure 4.7) exhibited significant inhibition nNOS activity O R O O N N N H 2-2 R O O O N N N O O N H 2-2h 68% inhibition O N N O N H 2-2i 60% inhibition N O O N H 2-2a 59% inhibition Figure 4.7 Structures of compound with more than 50% inhibitions The preliminiary results show that potential nNOS inhibitors should possess a N,N’disubstituted triazinetrione substructure with R1 as a small substituent like methyl or a proton and R2 can be alkyl, benzyl or allyl In order to elucidate a more detailed structure activity relationshiip, more derivatives with different diversity on R1 and R2 should be generated for further biological evaluations 168 Chapter 5: References (1) Merrifield, R B J Am Chem Soc 1963, 85, 2149-54 (2) 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synthesis of