Bioactive Heterocyclic Compound Classes: Pharmaceuticals

354 Pages·2012·3.66 MB·English

EditedbyJu¨rgenDingesand
ClemensLamberth
BioactiveHeterocyclicCompoundClasses
RelatedTitles
Lamberth,C.,Dinges,J.(eds.) Brahmachari,G.
Bioactive Heterocyclic Handbook ofPharmaceutical
CompoundClasses Natural Products
Agrochemicals
2010
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Edited by Ju¨rgen Dinges and Clemens Lamberth
Bioactive Heterocyclic Compound Classes
Pharmaceuticals
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V
Contents
Preface XI
ListofContributors XIII
Introduction 1
1 TheSignificanceofHeterocyclesforPharmaceuticals
andAgrochemicals 3
ClemensLamberthandJu¨rgenDinges
1.1 Introduction 3
1.2 HeterocyclesasFrameworkofBiologicallyActiveCompounds 4
1.3 Fine-TuningthePhysicochemicalPropertieswithHeterocycles 6
1.4 HeterocyclesasProdrugs 6
1.5 HeterocyclesasPeptidomimetics 7
1.6 HeterocyclesasIsostericReplacementofFunctionalGroups 8
1.7 HeterocyclesasIsostericReplacementofAlicyclicRings 11
1.8 HeterocyclesasIsostericReplacementofotherHeterocyclicRings 13
References 16
PartI NeurologicalDisorders 21
2 Tropane-BasedAlkaloidsasMuscarinicAntagonists
fortheTreatmentofAsthma,ObstructivePulmonaryDisease,
andMotionSickness 23
MichaelL.SchulteandCraigW.Lindsley
2.1 Introduction 23
2.2 History 23
2.3 Synthesis 25
2.4 ModeofAction 29
2.5 Structure–ActivityRelationships 32
References 34
VI Contents
3 Morphinone-BasedOpioidReceptorAgonistAnalgesics 37
StephanieM.Ng
3.1 Introduction 37
3.2 History 37
3.3 Synthesis 40
3.4 ModeofAction 43
3.5 Structure–ActivityRelationship 44
References 48
4 BarbituricAcid-BasedGABA(A)ReceptorModulatorsfortheTreatment
ofSleepDisorderandEpilepsyandasAnesthetics 51
IngoJanserandRomyJanser
4.1 Introduction 51
4.2 History 52
4.2.1 BarbituratesintheTreatmentofSleepDisorders 55
4.2.2 BarbituratesintheTreatmentofEpilepsy 55
4.2.3 BarbituratesasAnesthetics 56
4.3 Synthesis 57
4.4 ModeofAction 60
4.5 Structure–ActivityRelationship 62
4.5.1 5,5-Disubstitution 62
4.5.2 SubstitutionattheNitrogens 63
References 63
5 Phenothiazine-BasedDopamineD AntagonistsfortheTreatment
2
ofSchizophrenia 65
CristianaA.Zaharia
5.1 Introduction 65
5.2 History 65
5.3 Synthesis 70
5.4 ModeofAction 72
5.5 Structure–ActivityRelationships 76
References 77
6 Arylpiperazine-Based5-HT1AReceptorPartialAgonistsand5-HT2A
AntagonistsfortheTreatmentofAutism,Depression,Anxiety,Psychosis,
andSchizophrenia 81
IriniAkritopoulou-Zanze
6.1 Introduction 81
6.2 History 81
6.3 Synthesis 85
6.4 ModeofAction 88
6.5 Structure–ActivityRelationship 89
References 96
Contents VII
7 Arylpiperidine-BasedDopamineD2Antagonists/5-HT2AAntagonists
fortheTreatmentofAutism,Depression,Schizophrenia,and
BipolarDisorder 99
YingWang
7.1 Introduction 99
7.2 History 99
7.3 Synthesis 106
7.4 ModeofAction 109
7.5 Structure–ActivityRelationship 111
References 113
8 Dibenzazepine-BasedSodiumChannelBlockers
fortheTreatmentofNeuropathicPain 115
DerekW.Nelson
8.1 Introduction 115
8.2 History 115
8.3 Synthesis 119
8.4 ModeofAction 124
8.5 Structure–ActivityRelationships 128
References 130
PartII CardiovascularDiseases 135
9 Dihydropyridine-BasedCalciumChannelBlockers
fortheTreatmentofAnginaPectorisandHypertension 137
MilanBruncko
9.1 Introduction 137
9.2 History 139
9.3 Synthesis 141
9.4 ModeofAction 144
9.5 Structure–ActivityRelationship 148
References 149
10 Tetrazole-BasedAngiotensinIIType1(AT )Antagonists
1
fortheTreatmentofHeartFailureandCongestive
Hypertension 153
EdwardC.Lawson,BrianC.Shook,andJamesC.Lanter
10.1 Introduction 153
10.2 History 154
10.3 Synthesis 157
10.4 ModeofAction 159
10.5 Structure–ActivityRelationship 161
References 163
VIII Contents
11 Thiazide-BasedDiureticsfortheTreatmentofHypertension
andGenitourinaryDisorders 169
Ju¨rgenDinges
11.1 Introduction 169
11.2 History 169
11.3 Synthesis 174
11.4 ModeofAction 177
11.5 Structure–ActivityRelationship 179
References 180
12 Tetrahydropyranone-BasedHMG-CoAReductaseInhibitors
fortheTreatmentofArterialHypercholesterolemia 183
HongyuZhao
12.1 Introduction 183
12.2 History 183
12.3 Synthesis 188
12.4 ModeofAction 191
12.5 Structure–ActivityRelationship 192
12.5.1 TheHydrophilicDihydroxypentanoicAcidPortion 192
12.5.2 TheSARofNaturalStatins 192
12.5.3 SARofSyntheticStatins 195
12.5.4 Liver-SelectiveHMGCoAInhibitors 197
12.5.5 X-RayCrystalStructures 197
References 198
PartIII InfectiousDiseases 201
13 Adenine-BasedReverseTranscriptaseInhibitorsasAnti-HIV
Agents 203
AlastairDonald
13.1 Introduction 203
13.2 History 203
13.3 Synthesis 209
13.4 ModeofAction 212
13.5 Structure–ActivityRelationship 212
References 214
14 Guanine-BasedNucleosideAnalogsasAntiviralAgents 217
MaurizioFranzini
14.1 Introduction 217
14.2 History 219
14.3 Synthesis 221
14.4 ModeofAction 227
14.5 Structure–ActivityRelationship 229
References 232
Contents IX
15 PenicillinandCephalosporinAntibiotics 237
MichaelZ.Hoemann
15.1 Introduction 237
15.2 History 237
15.3 Synthesis 239
15.3.1 TotalSyntheses 239
15.3.2 CoreModifications 243
15.4 ModeofAction 248
15.5 Structure–ActivityRelationships 250
References 251
PartIV Oncology 255
16 Pyrimidine-BasedKinaseInhibitorsinCancerChemotherapy 257
RobertMah
16.1 Introduction 257
16.2 History 257
16.3 Synthesis 261
16.4 ModeofAction 264
16.5 Structure–ActivityRelationship 266
References 269
17 BenzylTriazole-BasedAromataseInhibitorsfortheTreatment
ofBreastCancer 275
DawnGeorgeandStacyVanEpps
17.1 Introduction 275
17.2 History 275
17.3 Synthesis 277
17.4 ModeofAction 281
17.5 Structure–ActivityRelationship 282
References 286
PartV InflammationandGastrointestinalDiseases 289
18 Acetonide-BasedGlucocorticoidsfortheTreatmentofAsthma,Skin
Inflammation,andDiseasesoftheEye 291
KevinP.Cusack,VikramG.Kalthod,RajarathnamE.Reddy,
andSanjayR.Chemburkar
18.1 Introduction 291
18.2 History 293
18.3 Synthesis 297
18.4 ModeofAction 304
18.4.1 Asthma 306
18.4.2 SkinInflammation 307
18.4.3 EyeDisease 307
X Contents
18.5 Structure–ActivityRelationship 308
References 311
19 Benzimidazole-BasedH+/K+-ATPaseInhibitorsfortheTreatment
ofGastroesophagealRefluxDisease 313
SteveSwann
19.1 Introduction 313
19.2 History 313
19.3 Synthesis 316
19.4 ModeofAction 319
19.5 Structure–ActivityRelationships 320
References 324
PartVI MetabolicDiseases 327
20 Thiazolidinedione-BasedInsulinSensitizers:PPAR-γ Agonistsforthe
TreatmentofType2Diabetes 329
StevenRichards
20.1 Introduction 329
20.2 History 329
20.3 Synthesis 337
20.4 ModeofAction 343
20.5 Structure–ActivityRelationship 344
References 345
Index 349