Privileged Structures in Drug Discovery
Medicinal Chemistry and Synthesis
Inbunden, Engelska, 2018
Av Larry Yet
2 769 kr
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Fri frakt för medlemmar vid köp för minst 249 kr.A comprehensive guide to privileged structures and their application in the discovery of new drugs The use of privileged structures is a viable strategy in the discovery of new medicines at the lead optimization stages of the drug discovery process. Privileged Structures in Drug Discovery offers a comprehensive text that reviews privileged structures from the point of view of medicinal chemistry and contains the synthetic routes to these structures. In this text, the author—a noted expert in the field—includes an historical perspective on the topic, presents a practical compendium to privileged structures, and offers an informed perspective on the future direction for the field.The book describes the up-to-date and state-of-the-art methods of organic synthesis that describe the use of privileged structures that are of most interest. Chapters included information on benzodiazepines, 1,4-dihydropyridines, biaryls, 4-(hetero)arylpiperidines, spiropiperidines, 2-aminopyrimidines, 2-aminothiazoles, 2-(hetero)arylindoles, tetrahydroisoquinolines, 2,2-dimethylbenzopyrans, hydroxamates, and bicyclic pyridines containing ring-junction nitrogen as privileged scaffolds in medicinal chemistry. Numerous, illustrative case studies document the current use of the privileged structures in the discovery of drugs. This important volume: Describes the drug compounds that have successfully made it to the marketplace and the chemistry associated with themOffers the experience from an author who has worked in many therapeutic areas of medicinal chemistryDetails many of the recent developments in organic chemistry that prepare target moleculesIncludes a wealth of medicinal chemistry case studies that clearly illustrate the use of privileged structuresDesigned for use by industrial medicinal chemists and process chemists, academic organic and medicinal chemists, as well as chemistry students and faculty, Privileged Structures in Drug Discovery offers a current guide to organic synthesis methods to access the privileged structures of interest, and contains medicinal chemistry case studies that document their application.
Produktinformation
- Utgivningsdatum2018-05-15
- Mått221 x 274 x 33 mm
- Vikt1 497 g
- FormatInbunden
- SpråkEngelska
- Antal sidor560
- FörlagJohn Wiley & Sons Inc
- ISBN9781118145661
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Larry Yet, PhD, is an Assistant Professor in the Department of Chemistry at the University of South Alabama. He has authored or coauthored more than 40 publications, is an inventor on several non-provisional and issued patents, and has written multiple invited book chapters and review articles in synthetic organic and medicinal chemistry.
- 1 Introduction 11.1 The Original Definition of Privileged Structures 11.2 The Role of Privileged Structures in the Drug Discovery Process 11.3 The Loose Definitions of “Privileged Structures” 21.4 Synthesis and Biological Activities of Carbocyclic and Heterocyclic Privileged Structures 21.4.1 Synthesis and Biological Activities of Three] and Four]Membered Ring Privileged Structures 21.4.2 Synthesis and Biological Activities of Five-Membered Ring Privileged Structures 21.4.3 Synthesis and Biological Activities of Six-Membered Ring Privileged Structures 41.4.4 Synthesis and Biological Activities of Bicyclic 5/5 and 6/5 Ring Privileged Structures 41.4.5 Synthesis and Biological Activities of Bicyclic 6/6 and 6/7 Ring Privileged Structures 41.4.6 Synthesis and Biological Activities of Tricyclic and Tetracyclic Ring Privileged Structures 41.5 Combinatorial Libraries of “Privileged Structures” 41.6 Scope of this Monograph 9References 102 Benzodiazepines 152.1 Introduction 152.2 Marketed BDZ Drugs 152.2.1 1,4-Benzodiazepine Marketed Drugs 152.2.2 1,5-Benzodiazepine Marketed Drugs 162.2.3 Linearly Fused BDZ Marketed Drugs 162.2.4 Angularly Fused-1,4-Benzodiazepine Marketed Drugs 172.3 Medicinal Chemistry Case Studies 172.3.1 Cardiovascular Applications 172.3.2 Central Nervous System Applications 192.3.3 Gastrointestinal Applications 232.3.4 Infectious Diseases Applications 242.3.5 Inflammation Applications 252.3.6 Metabolic Diseases Applications 272.3.7 Oncology Applications 282.4 Synthesis of BDZs 302.4.1 Condensation of o-Phenylenediamines to 1,5-Benzodiazepines 312.4.1.1 Condensation of o-Phenylenediamines with Ketones 312.4.1.2 Condensation of o-Phenylenediamines with α,β-Unsaturated Ketones 332.4.1.3 Condensation of o-Phenylenediamines with Alkynes 342.4.2 Reductive Condensation of α-Substituted Nitrobenzenes with Ketones and α,β-Unsaturated Ketones 352.4.3 Intramolecular Cyclizations to 1,4-Benzodiazepines 352.4.3.1 Intramolecular Cyclizations—Path A 362.4.3.2 Intramolecular Cyclizations—Path B 372.4.3.3 Intramolecular Cyclizations—Path C 392.4.3.4 Intramolecular Cyclizations—Path D 402.4.3.5 Intramolecular Cyclizations—Path E 422.4.3.6 Intramolecular Cyclizations—Path F 422.4.3.7 Intramolecular Cyclizations—Path G 422.4.3.8 Intramolecular Cyclizations—Path H 422.4.4 Ugi Multicomponent Synthesis 422.4.5 Elaboration of 1,4-Benzodiazepines 442.4.6 Pyrrolo[2,1-c]benzodiazepines 452.4.7 Fused BDZ Ring Systems 452.4.8 Solid-Phase Synthesis of BDZs 47References 473 1,4-Dihydropyridines 593.1 Introduction 593.2 Marketed 1,4-Dihyropyridine Drugs 593.3 Medicinal Chemistry Case Studies 593.3.1 Cardiovascular Applications 593.3.2 Central Nervous System Applications 613.3.3 Infectious Diseases Applications 623.3.4 Inflammation Applications 633.3.5 Men’s and Women’s Health Issues Applications 643.3.6 Metabolic Diseases Applications 653.3.7 Oncology Applications 653.4 Synthesis of 1,4-Dihydropyridines 663.4.1 Classical Hantzsch Synthesis 663.4.2 Modified Hantzsch Conditions 663.4.3 1,4-Disubstituted-1,4-Dihydropyridines 693.4.4 Organometallic Additions to Pyridinium Salts 693.4.5 From Imines and Enamino Compounds 713.4.6 Multicomponent Synthesis 723.4.6.1 Three-Component Synthesis of 1,4-Dihydropyridines 723.4.6.2 Four-Component Synthesis of 1,4-Dihydropyridines 743.4.7 Organocatalytic Synthesis of 1,4-Dihydropyridines 743.4.8 Miscellaneous Preparations 753.4.9 Elaboration of 1,4-Dihydropyridines 76References 774 Biaryls 834.1 Introduction 834.2 Marketed Biaryl Drugs 834.3 Medicinal Chemistry Case Studies 874.3.1 Cardiovascular Applications 874.3.2 Central Nervous System Applications 894.3.3 Infectious Diseases Applications 954.3.4 Inflammation Applications 984.3.5 Men’s and Women’s Health Issues Applications 1024.3.6 Metabolic Diseases Applications 1034.3.7 Oncology Applications 1094.4 Synthesis of Biaryls 1144.4.1 Transition Metal-Catalyzed Cross‑Coupling Synthesis 1144.4.1.1 Suzuki–Miyaura Cross-Coupling Reactions with Boronic Acids 1144.4.1.2 Suzuki–Miyaura Cross-Coupling Reactions with Boronate Esters 1144.4.1.3 Metal-Catalyzed Homocoupling Reactions 1214.4.1.4 Uhlmann Coupling Reactions 1224.4.1.5 Kumada–Tamao–Corriu Cross-Coupling Reactions 1234.4.1.6 Negishi Cross-Coupling Reactions 1244.4.1.7 Hiyama Cross-Coupling Reactions 1244.4.1.8 Stille Cross-Coupling Reactions 1254.4.1.9 Miscellaneous Cross-Coupling Reactions 1264.4.1.10 Metal-Catalyzed Functional Group Removal Cross-Coupling Reaction 1274.4.2 C„ŸH Functionalization Reactions 1274.4.2.1 Oxidative Coupling Reactions 1274.4.2.2 Direct C„ŸH Arylations 1274.4.2.3 C„ŸH Functionalization with Directing Groups 1274.4.3 Cycloaddition Reactions 1324.4.3.1 [3+3] Cycloaddition Reactions 1324.4.3.2 [4+2] Cycloaddition Reactions 1324.4.3.3 [2+2+2] Cycloaddition Reactions 1334.4.3.4 Tandem Cycloaddition Reactions 1334.4.4 Biaryl Phenol Syntheses 1334.4.5 Miscellaneous Syntheses 134References 1355 4-(Hetero)Arylpiperidines 1555.1 Introduction 1555.2 Marketed 4-(Hetero)Arylpiperidine Drugs 1555.3 Medicinal Chemistry Case Studies 1595.3.1 Cardiovascular Applications 1595.3.2 Central Nervous System Applications 1595.3.3 Infectious Diseases Applications 1685.3.4 Inflammation Applications 1695.3.5 Men’s and Women’s Health Applications 1745.3.6 Metabolic Diseases Applications 1755.3.7 Oncology Applications 1775.4 Synthesis of 4-(Hetero)Arylpiperidines 1795.4.1 Preparation from 4-Piperidinones 1795.4.2 Preparation from 4-Prefunctionalized-3-alkenylpiperidines 1805.4.3 Preparation from Negishi Cross-Coupling of 3-Zincated Piperidines 1805.4.4 Preparation from 4-Funtionalized Piperidines 1815.4.5 Conjugated Addition to Unsaturated Piperidines 1815.4.6 Miscellaneous Syntheses 183References 1856 Spiropiperidines 1946.1 Introduction 1946.2 Marketed Spiropiperidine Drugs 1946.3 Medicinal Chemistry Case Studies 1956.3.1 Cardiovascular Applications 1956.3.2 Central Nervous System Applications 1976.3.3 Infectious Diseases Applications 2036.3.4 Inflammation Applications 2056.3.5 Men’s and Women’s Health Applications 2106.3.6 Metabolic Diseases Applications 2116.3.7 Oncology Applications 2166.4 Synthesis of Spiropiperidines 2186.4.1 Quinolinylspiropiperidines 2180003364809.INDD 7 12/18/2017 9:40:53 PMviii Contents6.4.2 Azaspiro[5.5]alkane Systems 2186.4.3 Diazaspiro[5.5]alkane Derivatives 2216.4.4 1,4-Benzodioxinylspiropiperidines 2226.4.5 Spirobenzooxazinylspiropiperidines 2236.4.6 (Iso)Quinolinylspiropiperidines 2236.4.7 Indenospiropiperidines 2256.4.8 Indolin(on)ylspiropiperidines 2256.4.9 Cyclohexadienonylspiropiperidines 2266.4.10 Cyclopenta[b]pyrrolospiropiperidines 2266.4.11 Chromanylspiropiperidines 2266.4.12 (Iso)Benzofuran(on)ylspiropiperidines 2276.4.13 Indenospiropiperidines 227References 2287 2-Aminopyrimidines 2377.1 Introduction 2377.2 Marketed 2-Aminopyrimidine Drugs 2377.3 Medicinal Chemistry Case Studies 2397.3.1 Cardiovascular Applications 2397.3.2 Central Nervous System Applications 2417.3.3 Infectious Diseases Applications 2457.3.4 Inflammation Applications 2487.3.5 Metabolic Diseases Applications 2547.3.6 Miscellaneous Applications 2557.3.7 Oncology Applications 2567.4 Synthesis of 2-Aminopyrimidines 2677.4.1 Aminations with 2-Halo or 2,4-Dihalopyrimidines 2677.4.2 Cross-Coupling Reactions with 2-Aminopyrimidines 2707.4.3 Aminations with 2-Sulfonylpyrimidines 2707.4.4 Cyclizations with Guanidines 272References 2728 2-Aminothiazoles 2848.1 Introduction 2848.2 Marketed 2-Aminothiazole Drugs 2848.3 Medicinal Chemistry Case Studies 2868.3.1 Cardiovascular Diseases Applications 2868.3.2 Central Nervous System Applications 2888.3.3 Infectious Diseases Applications 2928.3.4 Inflammation Applications 2968.3.5 Metabolic Diseases Applications 2998.3.6 Oncology Applications 3018.3.7 Miscellaneous Applications 3058.4 Synthesis of 2-Aminothiazoles 3068.4.1 Hantzsch Synthesis from α-Functionalized Ketones and Thioureas 3068.4.2 Hantzsch Synthesis from Ketones and Thioureas 3068.4.3 Synthesis from α-Haloketones and Thiocyanates 3088.4.4 Synthesis from Vinyl Azides and Thiocyanates 3088.4.5 Synthesis from Amidines and Thiocyanates 3098.4.6 Synthesis from Alkenyl and Alkynyl Compounds with Thiocyanates or Thioureas 3098.4.7 Miscellaneous Syntheses 3098.4.8 Elaboration of 2-Aminothiazoles 311References 3119 2-(Hetero)Arylindoles 3219.1 Introduction 3219.2 Marketed 2-Arylindole Drugs 3219.3 Medicinal Chemistry Case Studies 3219.3.1 Cardiovascular Applications 3219.3.2 Central Nervous System Applications 3229.3.3 Infectious Diseases Applications 3239.3.4 Inflammation Applications 3259.3.5 Men’s and Women’s Health Applications 3269.3.6 Metabolic Diseases Applications 3289.3.7 Miscellaneous Applications 3289.3.8 Oncology Applications 3289.4 Synthesis of 2-(Hetero)Arylindoles 3329.4.1 Functionalization to the Preformed Indole System 3329.4.1.1 2-Functionalized Metallated Indoles with Aryl Halides (Strategy 1) 3329.4.1.2 2-Halogenated or 2-Triflated Indoles with Functionalized Arenes (Strategy 1) 3329.4.1.3 Direct Arylation of Indole with Functionalized Arenes (Strategy 2) 3349.4.1.4 Direct Oxidative Coupling of Indoles with (Hetero)Arenes (Strategy 3) 3349.4.2 Fischer Indole Synthesis 3349.4.3 Bischler–Mohlau Indole Synthesis 3349.4.4 Metal-Catalyzed Approach with Alkynes 3349.4.4.1 Intramolecular Cyclizations of o-Alkynylanilines (Strategy A) 3369.4.4.2 Intramolecular Cyclizations of o-Alkynylanilines with Other Groups (Strategy B) 3369.4.4.3 Intramolecular Cyclizations of o-Haloanilines with Alkynes (Strategy C) 3379.4.4.4 Intramolecular Cyclizations of o-Alkynylhaloarenes with Primary Amines (Strategy D) 3409.4.4.5 Miscellaneous Transition Metal-Catalyzed Reactions 3409.4.4.6 Reductive Cyclizations of o-Nitroalkynylarenes 3429.4.5 Intracmolecular Reductive Cyclizations of o-Nitro (or Azido)alkenylarenes 3429.4.6 Cyclizations of Arylamido and Arylimine Precursors 3439.4.7 Cyclizations of o-Vinylaminoarenes 3449.4.8 Cyclizations with N-Arylenamines or N-Arylenaminones 3449.4.9 Multicomponent Synthesis 3459.4.10 Radical Cyclization Reactions 3469.4.11 Miscellaneous Cyclizations with o-Substituted Anilines 346References 34810 Tetrahydroisoquinolines 35610.1 Introduction 35610.2 Marketed THIQ Drugs 35610.3 Medicinal Chemistry Case Studies 35710.3.1 Cardiovascular Applications 35710.3.2 Central Nervous System Applications 35910.3.3 Infectious Diseases Applications 36510.3.4 Inflammation Applications 36610.3.5 Men’s and Women’s Health Applications 36910.3.6 Metabolic Diseases Applications 36910.3.7 Miscellaneous Applications 37010.3.8 Oncology Applications 37210.4 Synthesis of THIQs 37610.4.1 Pictet–Spengler Reactions 37610.4.1.1 Classical Pictet–Spengler Reactions 37610.4.1.2 Pictet–Spengler Reactions with Masked Carbonyl Compounds 37710.4.1.3 Modified Pictet–Spengler Reactions 37710.4.1.4 Pictet–Spengler-Type Reactions 37710.4.1.5 Pictet–Spengler Synthesis of Tic 37810.4.2 Transition Metal-Catalyzed Reactions 37910.4.2.1 Intramolecular α-Arylation Reactions 37910.4.2.2 Intramolecular Cyclizations of N-Propargylbenzylamines 37910.4.2.3 Intramolecular Heck Cyclizations 37910.4.2.4 Intramolecular Nucleophilic Additions 37910.4.2.5 One-Pot Multistep Metal-Catalyzed Cyclization Reactions 38010.4.3 Multicomponent Synthesis of THIQs 38210.4.4 Synthesis of 3-Aryltetrahydroisoquinolines 38210.4.5 Synthesis of 4-Aryltetrahydroisoquinolines 38310.4.6 Miscellaneous Intramolecular Cyclizations 38610.4.7 Asymmetric Reduction of 1-Substituted-3,4-Dihydroisoquinolines 38710.4.7.1 Iridium-Catalyzed Hydrogenations of Dihydroisoquinolines, Isoquinoline Salts, and Isoquinolines 38810.4.7.2 Ruthenium- and Rhodium-Catalyzed Reductions of Dihydroisoquinolines 38910.4.7.3 Asymmetric Additions to Dihydroisoquinolines, DihydroisoquinolineSalts, and Dihydroisoquinoline N-Oxides 38910.4.7.4 Asymmetric Intramolecular Cyclizations 39110.4.7.5 Asymmetric Intramolecular Cyclizations with Chiral Sulfoxides 39110.4.7.6 Miscellaneous Asymmetric Preparations 39210.4.8 Arylations of THIQs 39310.4.9 C„ŸH Functionalization of THIQs 39510.4.9.1 Direct C-1 (Hetero)Arylations of THIQs 39510.4.9.2 Oxidative C-1 CDC Reactions 39510.4.9.3 Oxidative C-1 CDC with β-Ketoesters 39610.4.9.4 Oxidative C-1 CDC with Ketones 39710.4.9.5 Oxidative C-1 CDC with Indoles 39710.4.9.6 Oxidative C-1 CDC with Aliphatic Nitro Compounds 39810.4.9.7 Oxidative C-1 CDC with Alkynes 39910.4.9.8 Oxidative C-1 CDC with Alkenes 39910.4.9.9 Oxidative C-1 Cross-Dehydrogenative Phosphonations 40010.4.9.10 Miscellaneous Oxidative C-1 CDC Reactions 400References 40111 2,2-Dimethylbenzopyrans 41411.1 Introduction 41411.2 Marketed 2,2-Dimethylopyran Drugs 41411.3 Medicinal Chemistry Case Studies 41511.3.1 Cardiovascular Applications 41511.3.2 Central Nervous System Applications 41611.3.3 Infectious Diseases Applications 41811.3.4 Inflammation Applications 41911.3.5 Metabolic Diseases Applications 41911.3.6 Oncology Applications 41911.3.7 Cannabinoid Receptors 42111.4 Synthesis of 2,2-Dimethylbenzopyrans 42311.4.1 Annulations of Phenol Derivatives with Unsaturated Systems 42311.4.1.1 Annulations of Phenol Derivatives with Simple Alkenes 42311.4.1.2 Annulations of Phenol Derivatives with α,β-Unsaturated Systems 42411.4.1.3 Annulations of Phenol Derivatives with Nitroalkenes 42411.4.1.4 Annulations of Phenol Derivatives with Allylic Alcohols 42411.4.1.5 Annulations of Phenol Derivatives with Propargyl Alcohols 42511.4.2 Replacement of the Methyl Group of 2,2-Dimethylbenzopyrans 42511.4.3 Functionalization of 2,2,-Dimethylbenzopyrans 42611.4.4 Fused 2,2-Dimethylbenzopyran Ring Systems 42811.4.5 Solid-Phase Synthesis of 2,2-Dimethylbenzopyrans 428References 42912 Hydroxamates 43512.1 Introduction 43512.2 Marketed Hydroxame Drugs 43512.3 Medicinal Chemistry Case Studies 43612.3.1 Central Nervous System Applications 43612.3.2 Infectious Diseases Applications 43612.3.3 Inflammation Applications 43912.3.4 Men’s and Women’s Health Applications 45212.3.5 Metabolic Diseases Applications 45312.3.6 Oncology Applications 45312.4 Synthesis of Hydroxamates 46612.4.1 Synthesis of Hydroxamates from Carboxylic Acids 46612.4.2 Synthesis of Hydroxamates from Carboxylic Acid Derivatives 46612.4.2.1 Synthesis of Hydroxamates from Esters 46612.4.2.2 Synthesis of Hydroxamates from Acid Chlorides 46812.4.2.3 Synthesis of Hydroxamates from Oxazolidinones 46812.4.3 Miscellaneous Syntheses of Hydroxamates 46912.4.4 Solid-Phase Synthesis of Hydroxamates 469References 47013 Bicyclic Pyridines Containing Ring-Junction Nitrogen 48113.1 Introduction 48113.2 Marketed Bicyclic Ring-Junction Pyridine Drugs 48113.3 Medicinal Chemistry Case Studies 48213.3.1 Cardiovascular Applications 48213.3.2 Central Nervous System Applications 48313.3.3 Gastrointestinal Applications 48713.3.4 Infectious Diseases Applications 48813.3.5 Inflammation Applications 49113.3.6 Metabolic Diseases Applications 49313.3.7 Miscellaneous Applications 49413.3.8 Oncology Applications 49413.4 Synthesis of Pyrazolo[1,5-a]pyridines 49813.4.1 [3+2] Dipolar Cycloadditions 49813.4.2 Intramolecular Cyclizations 49913.4.3 From N-Aminopyridinium Ylides 50013.4.4 From 2-Substituted Pyridines 50013.4.5 Thermal and Radical Cyclizations 50013.5 Synthesis of Imidazo[1,5-a]pyridines 50113.5.1 From 2-Methylaminopyridines 50113.5.2 From 2-Methylaminopyridine Amides 50213.5.3 From 2-Methylaminopyridine Thioamides or Thioureas 50313.5.4 From Pyridine-2-Carbaldehydes (Picolinaldehydes) 50313.5.5 From 2-Cyanopyridines 50313.5.6 From Pyridine-2-Esters 50413.5.7 From Di-2-Pyridyl Ketones 50413.5.8 From Pyridotriazoles 50413.5.9 Miscellaneous Syntheses 50413.5.10 Chemical Elaborations of Imidazo[1,5-a]pyridines 50513.6 Synthesis of Imidazo[1,2-a]pyridines 50713.6.1 Ugi Three-Component Reactions 50713.6.1.1 Classical Ugi Three-Component Reactions of 2-Aminopyridines, Aldehydes, and (Iso)Nitriles 50713.6.1.2 Modified Ugi Three-Component Reactions 50713.6.2 From 2-Aminopyridines and Carbonyl Compounds 50913.6.2.1 From 2-Aminopyridines and Methyl Ketones 50913.6.2.2 From 2-Aminopyridines and β-Ketoesters 50913.6.2.3 From 2-Aminopyridines and Miscellaneous Ketones 51013.6.2.4 From Pyridines and 2-Aminopyridines with α-Haloketones or α-Haloaldehydes 51113.6.3 From 2-Aminopyridines and Alkynes 51213.6.3.1 From 2-Aminopyridines and Alkynes 51213.6.3.2 From 2-Aminopyridines, Alkynes, and Aldehydes 51313.6.4 From 2-Aminopyridines and α,β-Unsaturated Systems 51313.6.5 From 2-Aminopyridines and Nitroolefins 51513.6.6 Cyclizations from 2-Aminopropargylpyridines 51513.6.7 Cyclizations from Pyridyl Enamines(ones) 51713.6.8 From Other Heterocycles 51713.6.9 Miscellaneous Syntheses 51813.6.10 Chemical Elaboration of Imidazo[1,2-a]pyridines 52013.6.10.1 Cross-Coupling Reactions of Pre-functionalized Imidazo[1,2-a]pyridines 52013.6.10.2 C„ŸH Functionalization of Imidazo[1,2-a]pyridines 52113.6.11 Fused Imidazo[1,2-a]pyridine Ring Systems 523References 525Index