Significant Pharmaceuticals Reported in US Patents (eBook)
700 Seiten
Elsevier Science (Verlag)
978-0-08-048091-6 (ISBN)
Pharmaceuticals are reported for 27 separate classes of illness, including,
AIDS, Alzheimer's Disease, Cardiovascular Disorders, Diabetes, Epilepsy, Hepatitis C, Osteoporosis, Obesity and Sleep Disorders.
Significant Pharmaceuticals Reported in US Patents has been designed to be used as both a reference and synthetic guide for pharmaceutical, medicinal and organic chemists and graduate students.
Researchers working in other areas will also find the information valuable as in many instances intermediates or the next generation pharmaceutical are readily convertible into other industrial products including: anti-oxidants, chemical additives, herbicides, polymer precursors, water purification agents. Clear structural depictions of reagents and chemical transformations have been supplied to permit the identification of other future applications.
* Identifies next generation pharmaceuticals
* Provides practical preparation methods for each active agent and derivatives
* Documents the analytical characterization and biological testing results of active agents
Significant Pharmaceuticals Reported in US Patents identifies the next generation of pharmaceuticals reported in US Patents. This "e;hands-on"e; title provides explicit laboratory methods for preparing the most recent and effective medications. Each entry documents the biological testing protocols used to evaluate a drug and the significance of the current treatment agent over previous methods. Pharmaceuticals are included in this review only if at least two of the following criteria were met: Effectiveness in treating an illness, Innovative, ease of preparation, synergy with existing Medications. Pharmaceuticals are reported for 27 separate classes of illness, including: AIDS, Alzheimer's Disease, Cardiovascular Disorders, Diabetes, Epilepsy, Hepatitis C, Osteoporosis, Obesity and Sleep Disorders. Significant Pharmaceuticals Reported in US Patents has been designed to be used as both a reference and synthetic guide for pharmaceutical, medicinal and organic chemists and graduate students. Researchers working in other areas will also find the information valuable as in many instances intermediates or the next generation pharmaceutical are readily convertible into other industrial products including: anti-oxidants, chemical additives, herbicides, polymer precursors, water purification agents. Clear structural depictions of reagents and chemical transformations have been supplied to permit the identification of other future applications. - Identifies next generation pharmaceuticals- Provides practical preparation methods for each active agent and derivatives- Documents the analytical characterization and biological testing results of active agents
Front Cover 1
Significant Pharmaceuticals Reported in US Patents 4
Copyright Page 5
Table of Contents 8
Introduction 20
Chapter I. Acquired Immune Deficiency Syndrome 22
I. Antioxidants, Preparation Methods, and Uses 22
II. Azole-based Fungicides 28
III. Human Immunodeficiency Virus Replication Inhibitor 33
Chapter II. Addiction Disorders 40
I. Alcohol Addiction 40
II. Cocaine Addiction 45
III. Opioid Addiction 52
a) Delta Receptor Antagonists 52
b) Kappa Opioid Receptor Antagonists 58
Chapter III. Alzheimer’s Disease 64
I. Beta-Amyloid Inhibitory Agents 64
a) Beta-Secretase Enzyme Inhibitors 64
b) Transthyretin Stabilizers 71
II. Calbindin D28Kd Inducing Agents 76
III. Metabotropic Glutamate 5a Receptor Antagonists 80
a) Phenylethynyl and Styryl Imidazole Antagonists 80
b) Metabotropic Glutamate Receptor Agonists/Antagonists 85
IV. Nerve Growth Factors/Neuroprotectants 90
V. Nicotinic Acetylcholinergic Receptor Subtype Alpha7 Antagonists 94
VI. Selective Nicotinic Acetylcholine Receptors Agonists 100
Chapter IV. Analgesics 106
I. Cannabinoid CB1 and CB2 Receptor Modulators 106
II. Cyclooxygenase-II Inhibitors 112
III. Enkephalin Delivery Agents 118
IV. ORL1 Inhibitors 123
Chapter V. Antibacterial Agents 128
I. Aminoglycoside-modifying Enzyme Inhibitors Targeting Ribosomal RNA 128
II. Bacterial DNA Gyrase Inhibitors 134
III. Methionyl t-RNA Synthetase Inhibitors 141
Chapter VI. Anti-inflammatory Agents 146
I. Anti-inflammatory Cytokine Inhibitors 146
II. Bradykinin B1 Receptor Antagonists 153
III. CCR1/CCR3 Chemokine Antagonists 159
IV. Cyclooxygenase-II Inhibitors 165
a) Trifluoromethyl Pyrazoline Medicaments 165
b) Aryl Nitrone Medicaments 170
V. Interleukins-1 and -6 and Tumor Necrosis Factor Cytokine Inhibitors 175
VI. Interleukin-12 Inhibitors 180
VII. Interleukin-1Beta-converting Enzyme Inhibitors 184
VIII. Alpha4 Integrin Antagonists 193
IX. Monocyte Chemoattractant Protein-1 Antagonists 200
X. Nitric Oxide Synthase Inhibitors 206
XI. P38 Protein Kinase Inhibitors 210
XII. Secretory Phospholipase A2 Inhibitors 215
a) N-Benzyl Tetracyclic-based Medicaments 215
b) N-Benzyl Cyclopent[G]indole-based Medicaments 222
Chapter VII. Autoimmune Disorders 230
I. Jun N-terminal Kinase Inhibitors 230
II. Macrophage Inflammatory Protein-1Alpha Chemokine Receptor Antagonists 235
Chapter VIII. Cardiovascular Disorders 242
I. Anticoagulants 242
a) Blood Clotting Enzyme Factor Xa, FXa, or Factor VIIa, FVIIa Inhibitors 242
b) Factor Xa Inhibitions 248
c) Serine Protease Inhibitors 254
d) Thrombin Receptor, PAR-1, Inhibitor 264
II. Arrhythmia 271
a) Potassium Channel Blockers of the Kv1.5 Channel 271
b) Ultrarapidly Activating Potassium Channel Blockers of the Kv1.5 Channel 277
III. Atherosclerosis 284
a) Cholesterol Absorption Inhibitors 284
b) Hypolipidemia and Hypocholesterolemia Treatment Agents 289
IV. Cardiac Hypertrophy: Angiotensin-(1–7) Receptor Agonists 294
V. Cardiac Infarction: Chymase Inhibitors 301
VI. Cell Proliferation Diseases: Phosphorylation Kinase Inhibitors 307
VII. Vasodilators: Cyclic Guanosine 3',5'-Monophosphate-Specific Phosphodiesterase, PDE5, Inhibitors 313
VIII. Vasorelaxants: Cyclic Guanosine Monophosphate Formation Stimulators 317
Chapter IX. Diabetes 324
Type I Diabetes 324
I. Insulin-dependent Enzyme Stimulants: Inositolphosphoglycan Mimics 324
Type II Diabetes 331
I. Blood Glucose-Lowering Agents 331
a) Dipeptidyl Peptidase-IV Inhibitors 331
b) Glycogen Synthase Kinase 3 Inhibitors 339
c) Dipeptidyl Peptidase IV Inhibitors 344
II. Insulin Resistance Syndrome: Cyclic Nucleotide Phosphodiesterase-9 Inhibitors 350
Chapter X. Diagnostics 356
I. Urea Nucleosides as Diagnostic and Therapeutic Agents 356
Chapter XI. Epilepsy 364
I. Calcium Channel Alpha2delta Subunit Antagonists 364
II. N-Methyl-D-Aspartic Acid Receptor Antagonists 370
Chapter XII. Gastrointestinal Disorders 374
I. Somatostatin Receptor Agonists: Treatment of Excess Gastrointestinal Secretion 374
Chapter XIII. Hepatitis C 380
I. Hepatitis C Virus Protease Inhibitors: Macrocyclic NS3 Serine Protease Inhibitors 380
Chapter XIV. Hormonal Disorders 388
I. Growth Hormone Releaser: Benzimidazolidinones 388
II. Nonsteroidal Selective Androgen Receptor Modulators: 4-Nitro-3-(Trifluoromethyl)phenyl Propionamides 394
Chapter XV. Immunosuppressants 398
I. Immunosuppressants Mediated by Lymphocyte Interactions with EDG Receptor-Mediated Signal Transduction 398
II. Inosine-5'-monophosphate Dehydrogenase Inhibitors 405
Chapter XVI. Improved Synthetic Methods 412
I. Antineoplastic Agents 412
a) Distamycin Derivative 412
b) Psorospermin Derivative 417
II. Macular Degeneration Treatment Agent 424
III. Urinary Incontinence Treatment Agent 431
Chapter XVII. Incontinence 434
I. Alpha1L-Adrenoreceptor Agonists 434
Chapter XVIII. Irritable Bowel Syndrome 440
I. Nonpeptidyl Motilin Antagonists 440
Chapter XIX. Malaria 448
I. Intracellular Protein-Degradation Inhibitors 448
II. Treatment of Protozoal Infections Using Gem-Dihydroperoxides 452
Chapter XX. Migraine Headaches 458
I. KCNQ Potassium Channels Modulators 458
Chapter XXI. Obesity 464
I. Peroxisome Proliferator Receptor-Gamma Inhibitor and Peroxisome Proliferator Receptor-Alpha Stimulator 464
II. Subtype NPY-5 Receptor Antagonists 470
Chapter XXII. Ocular Disorders 476
I. Glaucoma: Serotonergic 5-HT2 Receptor Agonists 476
II. Retinopathy: Platelet-activating Factor Antagonists 481
III. Short-Term Treatment of Ocular Hypertension 485
a) Thromboxane A2 Receptor Agonists 485
b) Prostanoic Acid Derivatives as EP4 Agonists 491
Chapter XXIII. Osteoporosis 496
I. Estrogen Receptor, ER-Beta, Agonists 496
II. Vitronectin AlphavBeta3 Receptor Antagonists 502
Chapter XXIV. Parkinson’s Disease 508
I. Blood–Brain Barrier Crossing Nerve Growth Factor Stimulators 508
II. Selective Serotonin-to-Dopamine Monoamine Transporters 512
Chapter XXV. Proliferative Disorders 518
I. Antiangiogenic Agents 518
a) Kinase Growth Factor VEGFR-2 and FGFR-1 Inhibitors 518
b) Tyrosine Kinase-2 Receptor Inhibitors 522
c) Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors 526
d) Vascular Endothelial Growth Factor Tyrosine Kinase Receptor Inhibitors 531
II. Antineoplastic Agents 536
a) Bifunctional Cytotoxic DNA Crosslinking Agents 536
b) Cyclin-dependent Kinase-2/Cyclin Kinase Inhibitors 542
c) Mustard-based Alkylating Chemotherapeutic Agents 546
d) Yujungamycin-based Alkylating Chemotherapeutic Agents 553
III. Antineovascularization Agents: Combretastatin A-1 and A-4 Inhibitors 562
IV. Brain, Head, and Neck Cancer: Cyclin-dependent Kinase-4 or -6 Kinase Inhibitors 569
V. Breast Cancer: Human Epidermal Growth Factor Tyrosine Kinase Inhibitors 576
VI. Breast and Prostate Cancer: TrkA, TrkB, and TrkC Protein Tyrosine Kinase Inhibitors 582
VII. Cell Growth Regulators: Eg5 Motor Protein Inhibitors 586
VIII. Cervical Cancer: Immune Response Modifiers as Antineoplastic Agents 593
IX. Colon Cancer 598
a) Immune Response Modifiers as Antineoplastic Agents 598
b) MAPK/ERK Kinase Inhibitors 603
c) Renal Dipeptidase Inhibitors 610
X. Leukemia 614
a) Inducible Nitric Oxide Synthase Inhibitors 614
b) Topoisomerase II Inhibitors 618
XI. Prostate Cancer: Nonsteroidal Antiandrogenic Antagonists 623
Chapter XXVI. Psychiatric 630
I. Major Depression 630
a) 5-HT1A Agonists 630
b) Noradrenaline Reuptake Inhibitors 637
c) Repotentiating Alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid and Kainic Acid Glutamate Receptors 642
d) Tachykinin Neurokinin-1 Receptor Antagonists 648
Chapter XXVII. Skin Disorders 654
I. Inflammatory Skin Diseases: Interleukin-2 Inhibitors 654
II. Treatment of Pruritus: Opioid Receptor Antagonists 660
III. Treatment of Skin Aging: Leukocyte Elastase Inhibitor 664
Chapter XXVIII. Sleep Disorders 668
I. Treatment of Circadian Rhythm Disorders Using 5HT7 Receptor Agonists 668
Chapter XXIX. Thyroid Disorders 674
I. Nongenomic Thyroid Disorders: T3 Thyroid Hormone Receptor Agonists 674
Chapter XXX. Tinnitus 682
I. Gabapentin Analogs as Antagonists of the Alpha2Beta Subunit of a Calcium Channel 682
Appendix: Patent Assignees 690
I. Academic 690
II. Industrial 690
Index 694
Acquired Immune Deficiency Syndrome
I Antioxidants, Preparation Methods, and Uses
Title Antioxidants, Preparation Methods and Uses
J. Oiry et al., US Patent 6,989,372 (January 24, 2006)
Assignee Centre National de la Recherche Scientifique and Commissariat a l'Engergie Atomique
Utility Treatment of Pathologies Associated with Glutathione Depletion
Invention Significance Reactive oxygen species play an important role in human pathologies and are particularly associated with retroviral infections such as human immunodeficiency virus (HIV). Intracellular defense against oxidative species is controlled by glutathione. To contain these reactive oxygen species effects, free radical scavengers have been prepared that increase glutathione reserves.
Reaction
Eq. 1
i- N-Methylmorpholine, isobutyl chloroformate, EtOAc, S-acetylcysteamine · HCl
ii- Methyl alcohol, CHCl3, silver nitrate, pyridine
iii- CHCl3, hydrochloric acid
Experimental
1. Preparation of N-(N-acetyl-S-trityl-l-cysteinyl)-S-acetylcysteamine
A solution of N-acetyl-S-trityl-l-cysteine (0.71 mmol) and 80μ1 N-methylmorpholine dissolved in 5 ml of EtOAc was stirred at–15°C, then treated with 93μl isobutyl chloroformate. After 15 minutes, S-acetylcysteamine hydrochloride (0.71 mmol) and an additional 80μl N-methyl-morpholine were added and the mixture stirred for 15 minutes at – 15°C and then 3 hours at ambient temperature. N-Methylmorpholine hydrochloride was then filtered off and the mixture was washed twice with 2.5 ml of EtOAc and concentrated. The gummy residue was purified by flash chromatography with silica gel using EtOAc/30% petroleum ether and the product isolated in 55% yield as a colorless powder, mp=111−113°C.
Rf = 0.41, EtOAc/petroleum ether, 9:1
[α]D20=+10.5° (c. 0.8, CHCl3
1H NMR (CDCl3) δ (ppm) 1.90 (s, 3H, NCOCH3), 2.29 (s, 3H, SCOCH3), 2.48 (dd, J = 5.7, 12.9Hz, 1H, β Ha cys), 2.82 (dd, J = 6.4, 12.9Hz, 1H, β Hb cys), 2.92–3.01 (m, 2H, NCH2CH2S), 3.32–3.42 (m, 2H, NCH2CH2S), 4.07–4.20 (m, 1H, α H cys), 5.70 (d, J = 7.6Hz, 1H, NH cys), 6.34 (t, J = 5.5Hz, 1H, NHCH2), 7.19–7.35 and 7.40–7.47 (2m, 15H, aromatic H)
MS (FAB +/NBA + K +) m/z 545 (M + K)+, 507 (M + H)+; (FAB-/NRA) m/z 505 (M-H)−
Analysis Calc. for C28H30N2O3S2 (506): C, 66.40; H, 5.93; N, 5.53. Found: C, 66.17; H, 6.00; N, 5.81
2. Preparation of N-(N-acetyl-l-cysteinyl)-S-acetylcysteamine, silver
While protected from light, a saturated solution of the Step 1 product (2.49 mmol) in 20 ml methyl alcohol and 1.5 ml of CHCl3 stirred at ambient temperature was treated with a light-protected mixture of silver nitrate (2.64 mmol) and 213μl pyridine in 13 ml methyl alcohol. When a precipitate was formed, stirring was stopped and mixture left overnight at ambient temperature. The solid was isolated, then washed twice with 10 ml apiece methyl alcohol and CHCl3, and the product isolated.
Analysis Calc. for C9H15N2O3S2Ag (371): Ag, 29.11. Found: Ag, 29.16
3. Preparation of N-(N-acetyl-l-cysteinyl)-S-acetylcysteamine
While protected from light, a stirred suspension of the Step 2 product in 15 ml CHCl3 at ambient temperature was treated with 400μl 12 M HCl, then stirred 2 hours at ambient temperature and 2 minutes at 30–35°C. The mixture was diluted with 70 ml CHCl3, then filtered to remove AgCl, and the combined organic phase washed three times with 10 ml ice-cold water. The solution was then dried with Na2SO4 and concentrated. A semicrystalline paste was collected, which was recrystallized using EtOAc/petroleum ether, and the product isolated in 56% yield as colorless microcrystals, mp=121−122°C.
[α]D20 = − 39.1° (c. 0.9, CHCl3).
Derivatives
Table 1
Selected Step 3 cysteamine derivatives and their associated mass spectral data
| I-152 | CH3 | CH3 | 247 |
| I-188 | CH3 | CH(CH3)2 | 293 |
| I-198 | CH3 | C6H5 | 327 |
| I-203 | CH(CH3)2 | C6H5 | 293 |
| I-208 | CH(CH3)2 | CH(CH3)2 | 321 |
| I-219 | CH(CH3)2 | C6H5 | 355 |
1H MS data for products and intermediates supplied by author.
Table 2
Selected S-acetated cysteamine derivatives and associated physical properties
| I-189 | CH3 | CH(CH3)2 | COCH3 | 335 |
| I-197 | CH3 | C(CH3)3 | COC6H5 | 411 |
| I-204 | CH(CH3)2 | CH3 | COCH3 | 335 |
| I-207 | CH(CH3)2 | CH3 | COC6H5 | 397 |
| I-210 | CH(CH3)2 | CH(CH3)2 | COCH(CH3)2 | 391 |
| I-223 | CH(CH3)2 | C6H5 | COC6H5 | 459 |
1H NMR data for products and intermediates supplied by author.
Testing
I. Antiviral Effectiveness of I–152 in Spleen Monocytes and Macrophages
The spleen was dissected, sieved, and mononuclear cells isolated using a density gradient. Monocytes/macrophages were isolated by adherence to plastic and differentiated into macrophages for 7 days. Thereafter, they were infected with HIV-1/Ba-L and evaluated. Testing results are provided in Table 3.
Table 3
Antiviral activity of the preferred experimental agent, I-152, N-(N-acetyl-l-cysteinyl)-S-acetylcysteamine, in spleen MDMs infected with 10 000 TCID50s of the HIV-1/Ba-L isolate at 50, 70 and 90% effective doses
| I-152 | 38 | 54 | 97 |
II. Anti-HIV Effectiveness Using Macrophages Derived from Human Blood Monocytes
Synergistic effects of anti-oxidant agents when used in conjunction with AZT using macrophages derived from human blood monocytes infected by the HIV-1/Ba-L strain were evaluated according to the method of Chou (1). Testing results are provided in Table 4.
Table 4
Comparison of the antiviral activities of selected derivatives in MDM cultures infected with 10 000 TCID50s of the HIV-1/Ba-L isolate at 50, 70, and 90% effective doses
| I-152 | 43 | 58 | 141 |
| I-203 | 74 | 93 | 132 |
| I-204 | 74 | 91 | 127 |
| I-207 | 43 | 63 | 112 |
| I-208 | 36 | 50 | 88 |
| I-209 | 51 | 71 | 118 |
The preferred agent is I-152, N-(N-acetyl-l-cysteinyl)-S-acetylcysteamine.
Notes
1. Additional S-acetylcysteamine derivatives, (I), were prepared by the author (2) and were effective in increasing the intracellular and/or extracellular glutathione levels.
(I)
2. The use of glutathione as a free radical scavenger in treating oxidative stress improved fetal and neonatal outcome of preterm birth and is described by Buhimschi (3).
3. Lipolal aldol condensation derivatives, (II), prepared by Haj-Yehia (4) were effective as reactive oxygen species scavengers and used in treating conditions associated with oxidative stress or free radical injury including mitochondrial cytopathies...
| Erscheint lt. Verlag | 7.7.2010 |
|---|---|
| Sprache | englisch |
| Themenwelt | Sachbuch/Ratgeber |
| Medizin / Pharmazie ► Gesundheitsfachberufe | |
| Medizin / Pharmazie ► Medizinische Fachgebiete ► Pharmakologie / Pharmakotherapie | |
| Naturwissenschaften ► Chemie ► Analytische Chemie | |
| Naturwissenschaften ► Chemie ► Organische Chemie | |
| Technik | |
| Wirtschaft | |
| ISBN-10 | 0-08-048091-8 / 0080480918 |
| ISBN-13 | 978-0-08-048091-6 / 9780080480916 |
| Haben Sie eine Frage zum Produkt? |
EPUB (Adobe DRM)Kopierschutz: Adobe-DRM
Adobe-DRM ist ein Kopierschutz, der das eBook vor Mißbrauch schützen soll. Dabei wird das eBook bereits beim Download auf Ihre persönliche Adobe-ID autorisiert. Lesen können Sie das eBook dann nur auf den Geräten, welche ebenfalls auf Ihre Adobe-ID registriert sind.
Details zum Adobe-DRM
Dateiformat: EPUB (Electronic Publication)
EPUB ist ein offener Standard für eBooks und eignet sich besonders zur Darstellung von Belletristik und Sachbüchern. Der Fließtext wird dynamisch an die Display- und Schriftgröße angepasst. Auch für mobile Lesegeräte ist EPUB daher gut geeignet.
Systemvoraussetzungen:
PC/Mac: Mit einem PC oder Mac können Sie dieses eBook lesen. Sie benötigen eine
eReader: Dieses eBook kann mit (fast) allen eBook-Readern gelesen werden. Mit dem amazon-Kindle ist es aber nicht kompatibel.
Smartphone/Tablet: Egal ob Apple oder Android, dieses eBook können Sie lesen. Sie benötigen eine
Geräteliste und zusätzliche Hinweise
Buying eBooks from abroad
For tax law reasons we can sell eBooks just within Germany and Switzerland. Regrettably we cannot fulfill eBook-orders from other countries.
aus dem Bereich
