491

Index

a – structure–activity relationships 321 absorption, distribution, metabolism and – subclasses 315 excretion (ADME) 162, 211 – synthesis 317 ACCORD trial 44 amino amides 29 acetaminophen 27, 30, 33 amino ester group 29 acetate ester of 2-hydroxy TP prasugrel 57 aminocyclopyrachlor 285, 286 acetic acid derivatives 221 aminopyralid 284–286, 288, 290 acetochlor 293, 295, 296 amisulpride acetohydroxyacid synthase (AHAS) 339 – dopamine antagonist 8 acetolactate synthase (ALS) 306 anagliptin 180, 183 acetyl ester group (OCOCH3)59 androgen receptor (AR) 262 acifluorfen-sodium 347 Angiomax 104 acrivastine 239, 241, 243 angiotensin II (AII)-induced hemodynamic activator protein 1 (AP-1) 259 pathway 87 active pharmaceutical ingredient (API) 92 angiotensin II receptor blockers 88 activity-based protein profiling (ABPP) 205 angiotensin receptor blockers (ARB’s) 87, 98 acute coronary syndrome (ACS) 59, 66 angiotensin-converting enzyme (ACE) acyl-coA oxidase (ACOX) 49 inhibitor 89, 95 adrenocorticotropic hormone (ACTH) 259 antedrug 251, 252 Advil 223 anthranilamides 479, 485–488 alachlor 293, 295 anthranilic acid derivatives 221 alfentanil 28, 35 antifungal ketoconazole alkylamines 242 – CYP3A4 inhibitor 66 alkylated pyridinium salt 31 antihistamines 237 allidochlor 295 – generation of drugs 237, 238 Almirall-Hermal GmbH 212 – mode of action 241 alogliptin 180 – structure–activity relationships 241 (3α,5α)-3-hydroxy-androstan-17-one – synthesis 239 (androsterone) 43 antioxidant response element (ARE) 214 2′-α-fluoro-2′-β-methyl analogs 174 antiplatelet thienopyridines 60 9α-fluorohydrocortisone, nonnatural steroid arachidonic acid (AA) 271 analog 250 argatroban 104, 105 alveolar mucosa 245 – discovery and optimization 106 Amberlite-IRA 400 (OH−) resin 137 – pioneering work 109 Amias® 87 ArylexTM 286, 288, 291 amino acid herbicides aryloxyphenoxypropionate herbicides – biological activity 320 – biological activity 330 – mode of action 319 – ester replacements 332

Bioactive Carboxylic Compound Classes: Pharmaceuticals and Agrochemicals, First Edition. Edited by Clemens Lamberth and Jürgen Dinges. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2016 by Wiley-VCH Verlag GmbH & Co. KGaA. 492 Index

aryloxyphenoxypropionate herbicides (contd.) – halogenation 439 – mode of action 329 –synthesis – structure–activity relationships 331 – – 2,6-difluoro-4-nitro-phenol 444 – structures 326, 327 – – benzonitriles/benzamides 443 arylpyridinecarboxylic acid auxin herbicides – – benzoylisocyanates 442, 444 286, 288, 291 – – flucycloxuron 444 Asperfillus terreus 73 – – flufenoxuron 445 aspirin 221, 222, 224 – – halogen-substituted nitro- or – reaction mechanism of 230 amino-phenols 444 – synthesis of 224 benzovindiflupyr 413, 417 Atacand® 87 β-lactam 18 atorvastatin 3, 73, 75 betamethasone (BM) 250 – industrial production of 78 bezafibrate 41, 47, 51 atrial fibrillation (AF) 103 biaryl ring system 163 atromid 43 bifenox 349 attention deficit disorder (ADD) 15 bilanafos 315, 320 attention deficit hyperactivity disorder bilastine 239, 240 (ADHD) 15 bimatoprost 271, 275 auxin mimic herbicides 283 BioCryst Pharmaceuticals 135 – biological activity 289 Biogen 212 – mode of action 289 bioisostere 6 – synthesis 287 bioprecursors 4 Avapro® 87 Biota, Australian biotechnology company azilsartan medoxomil 88, 95 135 azoxystrobin 3, 371, 372, 374–376 bistrifluron 448 bivalirudin 104 b bixafen 408, 411 B cell receptors (BCRs) 202 blood coagulation cascade 103 Bacillus anthracis 121 Blopress® 87 Bargellini reaction 45, 47 Boc-protection 185 Barton ester formation 258 Bontima® 416 basipetal movement 2 Boots Company 224 benalaxyl 361 boron-dipyrromethene (BODIPY) Benicar® 87 fluorescence probe 204 N-benyzl-5-imidazole acetic acids 89 boronic acids 181 benzfendizone 347 boscalid 405 benzoic acid auxin herbicide 284, 287 BPUs, see N-benzoyl-N′-phenyl ureas, 2-(1-benzyl-1H-imidazol-5-yl)acetic acid 87 acaricides and termiticides N-benzoyl-N′-phenyl ureas, acaricides and Br-alkyl intermediate 61 termiticides Breo®ElliptaTM 246 – biological activity Broad-band spectrum antibiotics 117 – – bistrifluron 448 brufen 223 – – chlorfluazuron 447 Bruton’s tyrosine kinase (Btk) 199 – – diflubenzuron 447 – critical role of 202 – – flucycloxuron 447 – inhibition in oncology 203 – – flufenoxuron 447 – mechanism of action 202 – – hexaflumuron 448 – structure–activity relationships (SAR) 203 ––logKow -values 446 butachlor 293 – – lufenuron 448 butafenacil 349, 350 – – novaluron 447 – – noviflumuron 448 c – – physico-chemical properties 446 C-20 ketone 250 – – teflubenzuron 447 C-7-fluorotetracycline derivative 123 – – triflumuron 448 Caco-2 cell system 218 Index 493 cAMP (cyclic adenosine monophosphate) cerivastatin 81 concentration 63 – lipophilic statin 83 candesartan cilexetil 88 cetirizine 238, 240 candesartan pro-drug 92 chelating agents 128 captopril 89 chelation sites 128 carbonyl diimidazole (CDI) 108 chiral resolution 153 carboxamide moiety 200 chlorantraniliprole 479, 480, 485 carboxin 405, 406, 408 chlorfluazuron 447 carboxylic acid 1, 7, 133 chloroacetamide herbicides 294 –bioisostere 6 – biological activity 299 – moiety 135, 237, 240 – invention pathway 295 – pharmacophore 3 – mode of action 297 –prodrug 4 – structure–activity relationships 300 –scaffold 8 – structures 294 – solubilizer 1 – synthesis 296 carboxylic acid amide (CAA) fungicides 2-chloropyridine 17 – agrochemical active ingredients 395 chlorsulfuron 308 – benthiavalicarb 395 chlortetracycline 120 – central amide linkage 395 cholesterol biosynthesis 80 – cinnamic 397, 398, 401 chromafenozide 467 – dimethomorph 395 – biological activity 473 – flumorph 395 – history 467 – general structure 401 – synthesis 469 – history 395 chromanones 387 – mandelamide mandipropamid 395 chronic inflammatory skin disease 211 – – biological activity 400 chronic lymphocytic leukemia (CLL) 199 – – structure–activity 401 cinidon-ethyl 350 – – synthesis 398, 399 ciprofibrate 41, 51 – pyrimorph 395 citrinin 72 – valifenalate 395 Claisen condensation 79 – valinamide iprovalicarb 395 Claisen cyclization 126 – – biological activity 400 clodinafop 330 – – structure–activity 401, 402 clofibrate 41 ––synthesis 398 – primary prevention trial 43 Carboxylic acid ester, see Sovaldi clofibric acid esterification 47 carboxylic acid-based statins 71 clopidogrel 57, 58 –historyof 72 – activation and metabolic pathways of 63 – structure–activity relationship 81 – antithrombotic drug 6 –synthesis 73 – pharmacological properties in humans 67 carfentanil 28, 32 clopyralid 284, 285, 288, 290 carfentrazone-ethyl 347 coagulation cascade pathway 108 carpropamid cocaine abuse treatment agents 23 – history 385, 386 compactin 73 – mode of action 390 Congo red azo dye 134 – synthesis 389 Corey lactone 273, 275 catalytic asymmetric hydrogenation 226 coronary heart disease (CHD) 43 cathepsin A (CatA) 172 cortexolone acetate 255 Caucasian population 211 coumoxystrobin 372 150-cavity, N1-nueraminidase inhibitors 145 Cozaar® 87 Celanese process patent 33 Crohn’s disease 246 celecoxib 223, 232 Cubist Pharmaceuticals 152 Celera Genomics 200 Cunninghamella blakeskeeana 250 cell-based assays 173 Curvularia lunata 255 CentedrinTM 15, 16 Cushing’s syndrome 251 494 Index

cyanoacrylamide based covalent inhibitors ––history 467 206 – – synthesis 469, 470 cyantraniliprole 485 – (history) 467 cyclaniliprole 480 – methoxyfenozide 467 cyclohexyl 1-hydroxyethyl carbonate (cilexetil) – – biological activity 473 ester 92 ––history 467 cyclooxygenase COX1/2 isoforms 221 – – synthesis 468, 469 cyclopentane ring 272 – (mode of action) 471 cyclopropyl congener 173, 174 – N-tert-butyl dicarbonyl hydrazine backbone cyhalofop-butyl 330 473 cyhalothrinic acid 455 – new structural types 476 cytochrome P450 218 – non-steroidal ecdysone agonists 467 cytochrome-mediated activation 57 – pharmacophore model 473 – tebufenozide 467 d – – biological activity 473 D-homoannulation 253 ––history 467 D-Phe-Pro-Arg sequence 105 – – synthesis 469, 470 dabigatran 104 dicamba 284, 287, 290 – historic path 112 2,4-dichlorophenoxyacetic acid 283, 284 – synthesis 108 2,4-dichlorophenoxybutyric acid 283, 284 dabigatran etexilate (Pro-1) 103, 104, 113 dichlorprop 284 – Daiichi Sankio synthesis pathway 60 diclocymet Danishefsky’s diene 140 – history 387 deep vein thrombosis (DVT) 103 – synthesis 389 deltamethrin 455 diclofenac 221, 223, 227, 233 deoxycycline 121 diclofop 330 2-deoxy-2, 3-didehydro-N-acetylneuraminic diclofop-methyl 325–328 acid (DANA, 6) 134 Diels-Alder cycloaddition 126 deoxyribose-5-phosphate aldolase (DERA) Diels-Alder reaction 140 80 diester 246 detoxification 387 (3R,5R)-3,5-dihydroxypentanoic acid 72 Dexamethasone (DX) 256 diisobutylaluminium hydride (DIBAL) 275 diamides insecticides dimethenamid 293, 300 – anthranilamides 479 N,N-dimethylthiocarbamoyl chloride, – biological activity 485 thioesterification agent 256 – history 479 dimethyl fumarate (DMF) 212 – mode of action 485 – approved drugs 212 – phthalamides 479 – immumodulatory, anti-inflammatory effects – structure–activity relationship 486 215 – synthesis 481 – mode of action 213 diasteroconvergent approach 431 – oral formulation of 213 dibenzoyl hydrazine insecticides dimoxystrobin 373 – A-ring or B-ring replacement 475 diofenolan 436 – bicyclic systems 476 diosgenin 250 – chromafenozide 467 Diovan® 87 – – biological activity 473 dipeptidyl peptidase-4 (DPP-4 DPP-IV, CD26) – – history 467 179 – – synthesis 469 – immunomodulating agents 180 – fufenozide 467 – history 179 – – biological activity 473 – mode of action 187 – – history 467 – structure–activity relationships 188 – – synthesis 470 DNA-binding domain (DBD) 48 – halofenozide 467 dopamine transporter (DAT) 15 – – biological activity 473 Dowex resin 137 Index 495

DPX KZ165 382 fluazifop-butyl 327 drug induced liver injury (DILI) 106 fluazifop-P-butyl 326 DuPont 480 fluazolate 347 – oxazolidinone program 151 flubendiamide 479, 485 – pharmaceuticals division 89 flucycloxuron 444, 447 flufenoxuron 445, 447 e flufenoxystrobin 372 Edarbi® 87 flufenpyr-ethyl 350 Effient® 59 flumiclorac-pentyl 350 electrophilic reactivity 216 fluocinolone acetonide (FC) 251 Emergency Use Authorization (EUA) 136 fluocinonide 258 5-enolpyruvyl shikimate 3-phosphate synthase fluopyram 417, 421 (EPSPS) 319 fluoroglycofen-ethyl 349 enoxastrobin 372 fluorophenyl moiety 163 Enterococcus faecalis, vancomycin-resistant fluoxastrobin 382 149 flupropacil 347 enzymatic lactam pathway 161 flurbiprofen 3 eperezolid 151, 155 fluroxypyr 285, 287, 291 eprosartan 88, 94, 98 fluthiacet-methyl 350 Escherichia coli 118 fluticasone 252 Ester hydrolysis 136 fluticasone furoate (FTF) 246 ethoxyfen-ethyl 349 fluticasone propionate (FTP) 246, 255, 256 3-ethyllutaryl-coenzyme A (HMG-CoA) fluvastatin 76 reductase 71 – industrial production of 77 (±)-ethylphenidate ((±)-4) 15 fluvastatin statin 73 European Medicines Agency (EMA) 182 fluxapyroxad 417 ex-chiral pool approach 432 Focalin® 15 fomesafen 349 f Food and Drug Administration (FDA) 182 famciclovir 4 fop herbicides, (see) aryloxyphenoxypropionate fenaminostrobin 373 herbicides fenofibrate 41, 44, 51 Friedel–Crafts reaction 240 fenoxanil Friedel–Crafts acylation 226 – history 387 Friedel–Crafts alkylation 45, 227 – synthesis 389 Friedel–Crafts conditions 224 fenoxycarb 433, 434, 436 fufenozide 467 fentanyl 27 – biological activity 473 – derivatives in 29 – history 467 –discoveryof 29 Fumaderm® 212, 217 – important drug analogs 28 fumaric acid esters (FAE) 211, 213 –modeofaction 33 – basic structure of 212 – structure–activity relationships 34 – history of 211 –synthesis 30 Fungicide Resistance Action Committee fexofenadine 239, 240 (FRAC) 405, 406 fibrates acids 41 – clofibrate 41 g – generic versions of 41 G-protein coupled receptors (GPCRs) 63 –historyof 42 GAL4 transactivation assays 50 – treatment of hyperlipidemia 41 gastrointestinal irritation 223 Fischer esterification 45 gemfibrozil 41, 44, 46, 50 Fischer Indole synthesis 227 gemigliptin 180, 183 Flavobacterium dehydrogenans 250 Gilead Sciences 138, 139 fluacrypyrim 382 Glaxo compound 263 fluazifop 328, 333 Glaxo Wellcome 258 496 Index

GlaxoSmithKline 135, 137 Hoffman-La Roche Ltd 135 gliptins 179, 187 Horner Wadsworth Emmons and Witting glucagon-like peptide-1 (GLP-1, GLP-1(7–36) reactions 241 amide) 179 Horner–Wadsworth–Emmons (HWE) glucocorticoid esters, intranasal agents 260 reaction 76, 273 glucocorticoid receptors (GRs) 258 human whole-blood (HWB) assay 231 glucocorticoid-responsive elements (GREs) Humoryl® 149 258 Hunig’s base 186 glucocorticoids carboxylic acid esters hydrocortisone monoesters 246 – approved/marketed 247 hydrofluoroalkane propellants 246 glucocorticosteroid carboxylic acid esters hydrolysis reaction 173 (GCE) analogs 245 hydrophilic inositol-1,4,5-triphosphate (IP3) – history of 249 63 – mode of action 258 hydrophobic diacylglycerol (DAG) 63 – synthesis of 252 hydroxyisothiazoles 7 glufosinate 316 hydroxyisoxazole 7 – biological activity 321 20-hydroxy-ecdysone 468 – structure–activity relationships 322 (4R,6R)-4-hydroxy-tetrahydro-2H-pyran-2-one – synthesis 318, 319 72 glutamine272 3 hydroxyzine 2 glutathione 216 hypothalamic-pituitary-adrenal (HPA) axis glycine-based inhibitors mimic 179 259 glyoxaline ring 90 glyphosate 315, 316 i – biological activity 321 ibrutinib – mode of action 319 – alternate synthesis of 202 – structure–activity relationships 322 – chemical structure of 200 – synthesis 317, 318 – commercialized Btk inhibitor 199 Gram-positive bacteria 149 – synthesis 201 Grignard reaction 60, 62 ibuprofen 221, 222, 224 Grignard reagent 225 – boots synthesis of 225 Groupe Fournier French company 44 – Hoechst synthesis of 225 guanidine moiety 144 ICM PocketFinder 233 imazamethabenz methyl 340, 341, 342, 344, h 345 H1N1, influenza A virus 135 imazamox 340, 342, 343 Haemophilus influenza 118, 159 imazapic 340 halofenozide 467 imazapyr 340, 342 – biological activity 473 imazaquin 340, 343, 345 – history 467 imazethapyr 340, 341 – synthesis 469, 470 Imbruvica® 199 haloperidol 28 imidazole ring modifications 97 halopredone acetate 254 imidazolinone herbicides halosafen 349 – biological activity 342 hemagglutinin (HA) 142 – carboxylic acid mimics 344 heparin-induced thrombocytopenia (HIT) – invention pathway 340 105 – mode of action 342 hexaflumuron 448 – structure–activity relationship 344 high-throughput screening (HTS) 179 – synthesis 341 hirudin 104 imidazoyl-methylbiphenyl-tetrazole scaffold hirudin analogue bivalirudin 105 90 histamine 237 Imperial Chemical Industries (ICI) 41 HMG-CoA reductase 72 IMPROVE-IT trial 71 Hoechst synthesis 225 in vitro studies 169 Index 497 in vivo studies 169 L-valine-pyrrolidide 182 indomethacin 222, 223 lactofen 349 – Fischer Indole synthesis-based route 227 lactone pathway 71, 161 inhaled/intranasal corticosteroids (ICS) 245, laninamivir (Inavir 3), 133, 136 252 latanoprost 271, 274, 278 insect growth regulators (IGRs) 439 Lederle Laboratories 120 Insecticide Resistance Action Committee Lewis-acid 253 (IRAC) 439 LG Life Sciences 183 Integrated Pest Management (IPM) 439 lidocaine 27, 29, 34 intramolecular amine nitrile cyclization ligand binding domain (LBD) 48, 259 deactivation pathway 183 linagliptin 180 intramolecular cyclization 189 Lindlar’s catalyst 137 intraocular pressure (IOP) 271, 278 linezolid 151, 157 invention pathway 169 – enantioselective syntheses of 155 iprovalicarb 390 – international surveillance programs 159 irbesartan 92 – metabolic pathways of 160 irebesartan 88 Linezolid Experience and Accurate isobutyric acid 46 Determination of Resistance (LEADER) isofetamid 421 159 isopyrazam 408, 412 Lipinski Rule of five 211 – succinate dehydrogenase inhibitor 8 lipophilicity 50 isoxapyrifop 330, 331 lipoprotein lipase (LPL) 49 liver fatty acid binding protein (L-FABP) 49 j liver S9 fraction 216 juvenile hormone mimics long-acting β2-adrenoceptor agonist (LABA) – biological activity 434 246 – diofenolan 436 losartan 4, 6, 88, 89, 90 – fenoxycarb 429, 436 lovastatin 73, 81 – history 429 –biosynthesisof 74 – hydroprene 429 lufenuron 448 – kinoprene 429 Lumiracoxib 221, 224, 232 – methoprene 429 lysine735 3 – mode of action 433 – non-crop application 429 m – SAR exploration program 434 M2 protein inhibitors 133 – synthetic chemistry of 431 Magnaporthe oryzae 385 mandestrobin 371, 373 k mandipropamid kadethrin 455 – cellulose synthase inhibitor 8 Keap1Nrf2pathway 214 mantle cell lymphoma (MCL) 199 keto-enol tautomerism 61, 128 Mayo clinic 249 ketoreductase (KERD) 79 mecoprop 284, 325, 326 (S)-kinoprene 434 melagatran 104, 105 Kirkpatrick Chemical Engineering – historic path 110 Achievement Award 225 – synthesis of 107 Knoevenagel-type condensation 79, 94, 256 melanin biosynthesis inhibitors-dehydratase kresoxim-methyl 373–375, 377 (MBI-D) Kyoto grain shop 73 – Magnaporthe oryzae 385 – amide motif 385 l – amino-quinazoline melanin biosynthesis L-threo-isoleucine thiazolidide 182 inhibitor 386 L-amino acids 169 – biological activity 391 l-phosphinothricin – carpropamid – enantioselective synthesis 320 ––tert-butyl terminus 388 498 Index

melanin biosynthesis inhibitors-dehydratase methyl tert-butyl ether (MTBE) 275 (MBI-D) (contd.) methylphenidate 15, 17 – – history 385, 386 metofluthrin 455 – – mode of action 390 metolachlor 293, 295, 296, 297, 300, 362 – – synthesis 389 – stereosiomers of 301 – diclocymet metominostrobin 373 – – history 387 metsulfuron-methyl 308 – DuPont 388 mevalonate pathway 80 – fenoxanil mevastatin 73 – – history 387 MeyerSchuster (MS) rearrangement 273, 274 – halo-cyclobutanes 388 Micardis® 87 – structure–activity relationships 392 Michael type addition reactions 141, 211 – tolprocarb 390 Michael–Dieckmann reaction 127 melanin biosynthesis pathway 385 Michael-type addition reaction 216 Meldrum’s acid 186 Micobacterium fortuitum mutant 253 meperidine 28 mineralcorticoid receptors (MRs) 259 Merck synthesis 250 minimum inhibitory concentration (MIC90) mesosulfuron-methyl 304 159 metalaxyl 360, 361 Mitsubishi Chemical Industry 105, 106 – alkylthio analogue of 367 – Mitsunobu reaction 138, 201 – invention pathway 360 mometasone furoate 245 metalaxyl-M (R)-(1) 361 momfluorothrin 457 – chiral pool synthesis 362 mono ethyl fumarate (MEF) 212 – enantioselective hydrogenation routes 363, mono ethylester 212 364 Mono methyl fumarate 213 – invention pathway 360 monoamine oxidase (MAO) inhibitors 149 metamifop 330, 331 monocyte chemoattractant protein-1 (MCP-1) metazachlor 293 260 metered-dose aerosol inhalation 246 monohydroxylated adamantyl ring 190 methano bridge 190 Moraxella catarrhalis 159 methanoprolinamide 184 morphine 27 methicillin-resistant Staphylococcu Motrin 223 epidermidis (MRSE) 159 Mount Sinai School of Medicine and Ferring methicillin-resistant Staphylococcus aureus Research 181 (MRSA) 159 multiple sclerosis (MS) therapy 213 methoprene 431, 432 Muxfeldt’s synthesis 126 methoxyacrylate strobilurin fungicides 372 Mycobacterium fortuitum 251 methoxycarbamate strobilurin fungicides Mycobacterium tuberculosis, multidrug 374 resistant 149 methoxyfenozide 467 – biological activity 473 n – history 467 N-α-tosyl-L-arginine methyl ester (TAME) – synthesis 468, 469 110 methoxyiminoacetamide strobilurin fungicides N-(2,5-dichlorophenyl)chloroacetamide 294 373 N-benzoyl-N′-phenyl ureas, acaricides and methoxyiminoacetate strobilurin fungicides termiticides 373 – biological activity N-methylacetamido group 149 ––biologicalprofiles 442 methyl carboxylate (COOCH3)group 58 – – structure–activity relationship 448 2-methyl-4-chlorophenoxyacetic acid 283, – mode of action 445 284 – history 439 2-methyl-4-chlorophenoxybutyric acid 283, –synthesis 284 – – benzoylisocyanates 443 16β-methyl corticosteroid synthesis 253 – – methods I, and II 445 Index 499

N-Boc-D-threo-methylphenidate 21 orysastrobin 373 N-terminal domain 48 oseltamivir 4, 135, 136, 143 naphthacene ring system 118 – H5N1 NA 146 naphthyl ring 24 – synthesis of 138 Naprosyn 223 oseltamivir (Tamiflu® 2) 133 naproxen 221–223, 225 oxadiazolone ring 7, 95 – catalytic asymmetric hydrogenation oxadiazon 347, 348 synthesis 226 oxadixyl 361, 367 – commercial synthetic route 225 oxalate blocking method 255 – Zambon process 226 oxazolidinones 149 neuraminidase (NA) 142 – DuPont synthesis of 153 Neuraminidase inhibitors (NAI’S) 133, 134, – history of 150 142 – mechanism of action 156 – mode of action 142 – structure–activity relationships 162 – structure–activity relationships 143 oxodihydroindenyl oxazolidinones 151 neurotransmitters 21 oxytetracycline 120 nicosulfuron 304 nicotinic acid 50 p Nihon Nohyaku 480 Paal–Knorr pyrrole synthesis 78 nitrofen 347, 348 palladium metal catalyst 121 non-natural D-amino acids 174 palladium tetrakistriphenylphosphine 91 non-peptidic angiotensin II receptor blockers para-nitrophenol acetoxycarbonate 108 87 paracrine-acting autacoids 271 –modeofaction 95 paraoxonase-1 (PON-1) 65 Nonsteroidal anti-inflammatory drugs Paratek Pharmaceuticals, Inc. 123 (NSAIDs) 9, 221 Penicillium chrysogenum 75 – history of 222 Penicillium citrinum Pen-51 73 – HWB activity of 231 peptidyl transferase center (PTC) 157, 158 – selected examples of 222 peramivir 135, 136 – structure–activity relationships 230 – facile synthesis of 142 norepinephrine transporter (NET) 15 peramivir (Rapivap 4) 133 Norepinephrine-dopamine reuptake inhibitors peripheral blood mononuclear cells (PBMC’s) (NDRIs) 15 205 novaluron 447 peroxisome proliferator activated receptors Novartis 182 (PPARs) 41, 48 noviflumuron 448 pethoxamid 293, 297 Noyori hydrogenation conditions 226 pharmacophore model 3, 474 nucleophilic attack 189 phenoxy-carboxylic acid auxin herbicides S. litura nucleopolyhedrovirus (SINPV) 450 287, 290 Nurofen 223 phenyl rings replacement 474 phenylacetonitrile 17 o phenylamide fungicides olapatadine 239 – biological activity 365 olefin precursor 226 – classes 359 olmesartan medoxomil 88, 92, 93 – mode of action 364 Olmetec® 87 – structure–activity relationship 365 olopatadine 241 – structures 360 omarigliptin 180 – synthesis 362 one-pot domino-reaction sequence 141 phenylamido piperidine 27 Oomycetes diseases 400 phenylbenzyl (PPB) protecting group 275 opioids 27 2-phenylethyl side chain 27 organic anion transfer protein 83 phloem mobility 2 organic anion transporting polypeptides 243 phosphinothricin 315, 316, 318 Orthomyxovirdae family 142 phthalamides 479, 486, 488 500 Index

phthaldiamides 479 ––synthesis 272 picloram 284, 288, 290 protease activating receptor PAR1 103 picoxystrobin 372 protoporphyrinogen-IX-oxidase inhibiting pinoxaden 329 herbicides (Protox herbicides) piperazine moiety 2, 152 – biological activity 352 piperazine ring oxidation 192 – chemical structures 348 piperazines 242 – mode of action 351 piperazinyl 3-fluorophenyl oxazolidinones – structure activity relationship 352 151 – synthesis 350 piperidine group 201 prynachlor 293 piperidines 243 Psoriasis vulgaris, chronic inflammatory skin pirinixic acid 52 disease 211 pitavastatin 82 purinergic receptor P2Y12 57 Plasmodium falciparum 121 pydiflumetofen 421 polar surface area 213 pyraclostrobin 374, 378 ponasteron 472 pyraflufen-ethyl 350 positron-emission tomography (PET) 17 pyrametostrobin 374 posizolid 149, 152 pyraoxystrobin 372 AR response elements (PPRE)I pyrethroid esters 49 – alkenyl substituents 464 AR subtype selectivityI – B. Thuringiensis 453 53 – benzyl ester substituents 463 ARα ligand binding cavityI – bioactive candidates 462 51 – biological activity 461 prasugrel 58, 64, 66 – carboxylic ester motif 453 – activation and metabolic pathways of 65 – class B compound esfenvalerate 459 –majorriskin 66 – classification 453, 454 –synthesis 60 – deltamethrin 453, 458 – structure–activity relationships 67 – halogen substituents 463 prasugrel antiplatelet agents 59 –history prasugrel pharmacological properties in – – alcohol variation 455 humans 67 – – carboxylic acid moiety 455 pravastatin – manufacturing route 75 – – cyhalothrinic acid 455 – production of 76 ––discoveryof 456 Presidential Green Chemistry Challenge ––fenvalerate 455 Award 75, 186, 225 ––metofluthrin 455 pretilachlor 293 – – momfluorothrin 457 probiodrug 182, 183 ––pyrethrinI 454 prodrug 4 ––pyrethrinsII 454 progesterone receptor (PR) 262 – – stereochemistry 457 propachlor 293, 295 – – structural features 454 propionic acid derivatives 221 ––Tanacetum cinerariaefolium 454 propionylation 32 – insecticidal activity 463 Proprotein Convertase Subtilisin Kexin 9 – lambda cyhalothrin 453, 457 (PCSK9) inhibitors 72 – mode of action 459 prostaglandin biosynthesis 223 – natural 462 prostaglandin-endo peroxide synthases – physicochemical properties 464 (PTGS/ PGHS) 228 – prenyl alcohol 457 prostaglandins (PGs) –racemictrans chrysanthemic acid 458 – treatment of glaucoma (PGF2α) 271 – stereochemistry 462, 464 – – mode of action 276 – (Syngenta) and deltamethrin 453 – – structure–activity relationship 278 – synthetic 462 – – structure of 272 pyribencarb 371, 374 Index 501 pyridinecarboxylic acid auxin herbicides 284, saralasin 89 288, 291 sartans 87 pyridyloxy-carboxylic acid auxin herbicides saxagliptin 182, 184, 185, 190 285, 287 scaffold 8 pyrimidinecarboxylic acid auxin herbicide Schiff base intermediates 263 285, 286 scytalone dehydratase pyrrolidine analogs 24 – MBI-D, see melanin biosynthesis inhibitors + dehydratase (MBI-D) q – melanin biosynthesis pathway 385 quinclorac 285, 291 seasonal influenza 133 (-)-quinic acid 139 sedaxane 413 quinolinecarboxylic acid auxin herbicide selective serotonin reuptake inhibitors (SSRIs) 285, 286 161 quinolone antibiotic ciprofloxacin 2 Ser630 hydroxyl group 181 serotonin transporter (SERT) 15 r sethoxydim 329, 331 radezolid 149, 152, 156 (-)-shikimic acid 139 ragaglitazar 7 sialic acid 134, 137, 142 ranitidine sialidase inhibitors 133 – CYP3A4 inhibitor 66 Simmons–Smith cyclopropanation 185 Rapivap 136 simvastatin 74, 81 Ratacand®,87 sitagliptin 180, 183, 186, 191 reactive oxygen species (ROS) 213, 214 Sivextro® 149 Red-Al reduction 32 Smith Kline Beecham Pharmaceuticals 94 Relenza 135 solubility 2 remifentanil 28, 36 Sovaldi renin 95 – history 168 Renin-Angiotensin System (RAS) pathway – mode of action 172 87, 95, 96 – prodrugs 167 retinoid X receptor (RXR) 48 – ProTide-based antiviral agents 167, 168 retro-aldol reaction 124 – soft drugs 167 Rhizopus nigricans 250 – structure–activity relationships 173, 174 Rib-X 152 –synthesis Rib-X Pharmaceuticals 156 – – discovery stage 170 ring-opening reaction 64 – – large-scale 170, 171 ring-opening route 64 – – stereoselective preparation 170, 171 RinskorTM 286, 288, 291 spirotetramat insecticide 4 Ritalin® 15, 16 Staphylococcus aureus, methicillin-resistant rituximab 199 149 rivaroxaban 163 Streptococcus pneumonia, penicillin-resistant rofecoxib 221, 223 149 rosiglitazone antidiabetic drug 7 statin therapy 41 rosuvastatin 77 statins 71 – industrial production 77 Staudinger reduction 138 ryanodine receptor (RyR), see diamides stent thrombosis 66 insecticides sterling drug 45 Stetter reaction 79 s stigmasterol 250 saflufenacil 347 Storck’s total synthesis 126 salicin 222 stratum corneum 245 salicyclic acid 221, 222 Strecker reaction 185, 319 Salix alba 222 Strecker synthesis 31 Sankyo Research Laboratories 72 Streptomyces bacteria 117 saponification 185 Streptomyces strain 120 502 Index

striatal cells 22 – tied-up cinnamate esters 311 strobilurin A 371, 374, 375 – tied-up phenylacetic esters 310 strobilurin fungicides sulfonylurea receptor (SUR) protein 446 – biological activity 380 sulfoxide-sulfenate rearrangement 254 – general structural requirements 381 sulfoximine 488 – mode of action 379 sulphosate 315 – pharmacophore 382 sutezolid 149, 152, 156 – structure–activity relationship 381 Suzuki coupling technology 91, 156, 202, 412 – synthesis 375 Swern conditions 155 structure activity relationships (SAR) 162, Swern oxidation 185 215 succinate dehydrogenase (SDH) 405 t succinate dehydrogenase inhibitor (SDHI) tafluprost 271, 277 – carboxamides Takeda Chemical Industries 87, 98 – – aromatic amines 422 Tamiflu® 135, 138 – – BASF’s protecting group approach 411 tebufenozide 467 – – benzovindiflupyr 413 – biological activity 473 ––β-ketoester 409 – history 467 – – biological activity 416 – synthesis 469, 470 – – bixafen 411 Tecfidera® 213, 215 – – boscalid 405, 420 tedizolid phosphate 149, 152 – – carboxin 405 teflubenzuron 447 – – 2-difluoroacyl-3-aminoacrylic acid 411 telmisartan 88, 94, 98 – – 3-difluoromethylpyrazole-1-methyl-4- teneligliptin 179, 183 carboxylic acid 409 terfenadine 239 – – fluopyram 421 terramycin 120 – – FRAC 405, 406 tert-butyl group 139 – – history 406 tert. butyl carbamate (Boc) group 107 – – isofetamid 421 tetracycline antibiotics – – isopyrazam 412 – chemical sensitivity 123, 124 – – market impact 416 – generations of 119 – – 5-membered ring 421 – historic development of 121, 122 – – mode of action 415 – mode of action 127 – – phenylbenzamides 420 – stereochemical complexity 123 – – pydiflumetofen 421 – structure–activity relationships 128 – – pyraziflumid 420 – structural requirements 128 – – pyrazole-4-carboxamides 407 – synthesis 123 – – respiration inhibitors 415 – resistance 122 – – sedaxane 413 tetracyclines amide antibiotics 117 – – structures 405 – fully synthetic 119 – – Suzuki coupling technology 412 – history of 120 – – Syngenta patent 421 – natural products 118 – – thifluzamide 420 – semi-synthetic 119 – – Zymoseptoria leaf blotch 419 tetraphase pharmaceuticals 123 sufentanil 28 Teveten® 87 sulfonylurea herbicides therapeutic index (TI) 249 – ALS biochemical pathway 306, 307 thiadiazolidinediones 7 – biological activity 308 Thienopyridine (TP) 57 – general structure 304 thifluzamide 420 – mode of action 306 thrombin 103 – ortho-carboxylate derivative 305 thromboembolic diseases 103 – structure activity relationship 309 ticagrelor antiplatelet agents 59 – synthesis 307 Ticlid® 58 – tied-back ester strategy 311 Ticlopidine 57 Index 503 tolprocarb 390 vancomycin-resistant Enterococcus Faecium tosylhydrazone 18 (VRE) 159 TradjentaTM 180 venous thromboembolism (VTE) 149 transactivation agonistic mechanism 259 very long-chain fatty acids (VLCFAs) 297, – travoprost synthesis 271, 276 298 triamcinolone acetate (TCA) 257 vildagliptin 182, 184 triamcinolone acetonide (TC) 251 Vilsmeier–Haack conditions 91 triazolopiperazine HCl salt 186 triclopyr 285, 291 w triclopyricarb 374 Waldenström’s macroglobulinemia (WM) trifloxystrobin 373 199 triflumuron 448 Wilkinson’s catalyst 258 trilipix 44 Wittig condensation 273, 276 Trius Therapeutics 152 Wittig coupling 275 tropone fluorophenyl oxazolidinones 151 Wittig reaction 76, 241 Trypan blue azo dye 134 Woodward’s synthesis 124, 125 Tufts University School of Medicine 123 type 2 diabetes (T2D) 179 x tyrosine355 3 X-linked agammaglobulinemia (XLA) 199 Xarelto® 149 u ximelagatran 105, 107, 108 Ugi reaction 32 ximelagatran (Pro-3) 103, 104 ultraviolet visible spectroscopy (UV vis) 120 University of Copenhagen 182 z unoprostone 271 Zambon process 226 unoprostone isopropyl ester synthesis 277 zanamivir 135, 136 unsaturated carboxylic ester moiety 211 – optimized scalable synthesis of 138 Upjohn company 151 – synthetic preparation of 136 Upjohn synthesis pathway 154 zanamivir (Relenza 1), 133 Zuckerfa/fa rats 182, 191 v zwitterions 2 valsartan 88, 91 Zyvox®Antimicrobial Potency Study (ZAPS) – Suzuki coupling reaction 92 149, 159 van der Waals-type interactions 259