WO2011071996A1 - Faah inhibitors - Google Patents
Faah inhibitors Download PDFInfo
- Publication number
- WO2011071996A1 WO2011071996A1 PCT/US2010/059428 US2010059428W WO2011071996A1 WO 2011071996 A1 WO2011071996 A1 WO 2011071996A1 US 2010059428 W US2010059428 W US 2010059428W WO 2011071996 A1 WO2011071996 A1 WO 2011071996A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pain
- disease
- pharmaceutically acceptable
- acceptable salt
- ring
- Prior art date
Links
- 239000003940 fatty acid amidase inhibitor Substances 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 229
- 238000000034 method Methods 0.000 claims abstract description 77
- 238000011282 treatment Methods 0.000 claims abstract description 58
- 230000002265 prevention Effects 0.000 claims abstract description 36
- -1 methoxy, trifluoromethoxy, ethoxy, propyloxy Chemical group 0.000 claims description 128
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 103
- 208000002193 Pain Diseases 0.000 claims description 101
- 150000003839 salts Chemical class 0.000 claims description 88
- 230000036407 pain Effects 0.000 claims description 87
- 239000008194 pharmaceutical composition Substances 0.000 claims description 61
- 125000001931 aliphatic group Chemical group 0.000 claims description 54
- 208000035475 disorder Diseases 0.000 claims description 54
- 125000000217 alkyl group Chemical group 0.000 claims description 51
- 239000003814 drug Substances 0.000 claims description 50
- 201000010099 disease Diseases 0.000 claims description 49
- 229910052736 halogen Inorganic materials 0.000 claims description 49
- 150000002367 halogens Chemical class 0.000 claims description 49
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 46
- 125000004432 carbon atom Chemical group C* 0.000 claims description 42
- 239000003795 chemical substances by application Substances 0.000 claims description 41
- 125000003545 alkoxy group Chemical group 0.000 claims description 35
- 238000002648 combination therapy Methods 0.000 claims description 35
- 125000001424 substituent group Chemical group 0.000 claims description 35
- 208000003251 Pruritus Diseases 0.000 claims description 30
- 125000000623 heterocyclic group Chemical group 0.000 claims description 30
- 208000014674 injury Diseases 0.000 claims description 30
- 229940079593 drug Drugs 0.000 claims description 28
- 208000011231 Crohn disease Diseases 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- 206010012289 Dementia Diseases 0.000 claims description 24
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 22
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 22
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- 208000010412 Glaucoma Diseases 0.000 claims description 21
- 208000004296 neuralgia Diseases 0.000 claims description 21
- 239000007787 solid Substances 0.000 claims description 21
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- 239000000126 substance Substances 0.000 claims description 20
- 208000024891 symptom Diseases 0.000 claims description 20
- 229940124597 therapeutic agent Drugs 0.000 claims description 20
- 208000011580 syndromic disease Diseases 0.000 claims description 19
- 230000008733 trauma Effects 0.000 claims description 18
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 17
- 206010012601 diabetes mellitus Diseases 0.000 claims description 17
- 201000008482 osteoarthritis Diseases 0.000 claims description 17
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 16
- 230000004054 inflammatory process Effects 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 241000282414 Homo sapiens Species 0.000 claims description 15
- 208000006011 Stroke Diseases 0.000 claims description 15
- 208000025865 Ulcer Diseases 0.000 claims description 15
- 230000001154 acute effect Effects 0.000 claims description 15
- 208000006673 asthma Diseases 0.000 claims description 15
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 201000004624 Dermatitis Diseases 0.000 claims description 14
- 241001465754 Metazoa Species 0.000 claims description 14
- 230000006378 damage Effects 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 201000006417 multiple sclerosis Diseases 0.000 claims description 14
- 210000001519 tissue Anatomy 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 208000001640 Fibromyalgia Diseases 0.000 claims description 13
- 208000012902 Nervous system disease Diseases 0.000 claims description 13
- 208000025966 Neurological disease Diseases 0.000 claims description 13
- 125000001188 haloalkyl group Chemical group 0.000 claims description 13
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- 208000015181 infectious disease Diseases 0.000 claims description 13
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 13
- 208000021722 neuropathic pain Diseases 0.000 claims description 13
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 13
- 238000001356 surgical procedure Methods 0.000 claims description 13
- 208000024827 Alzheimer disease Diseases 0.000 claims description 12
- 208000023275 Autoimmune disease Diseases 0.000 claims description 12
- 206010020751 Hypersensitivity Diseases 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical group C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 12
- 201000004810 Vascular dementia Diseases 0.000 claims description 12
- 208000027418 Wounds and injury Diseases 0.000 claims description 12
- 206010003246 arthritis Diseases 0.000 claims description 12
- 230000001684 chronic effect Effects 0.000 claims description 12
- 201000006292 polyarteritis nodosa Diseases 0.000 claims description 12
- 208000017604 Hodgkin disease Diseases 0.000 claims description 11
- 206010028980 Neoplasm Diseases 0.000 claims description 11
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 claims description 11
- 239000005557 antagonist Substances 0.000 claims description 11
- 230000004770 neurodegeneration Effects 0.000 claims description 11
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 11
- 206010010904 Convulsion Diseases 0.000 claims description 10
- 206010061218 Inflammation Diseases 0.000 claims description 10
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 10
- 241000700159 Rattus Species 0.000 claims description 10
- 208000025747 Rheumatic disease Diseases 0.000 claims description 10
- 206010008118 cerebral infarction Diseases 0.000 claims description 10
- 201000006549 dyspepsia Diseases 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 229960002715 nicotine Drugs 0.000 claims description 10
- SNICXCGAKADSCV-UHFFFAOYSA-N nicotine Natural products CN1CCCC1C1=CC=CN=C1 SNICXCGAKADSCV-UHFFFAOYSA-N 0.000 claims description 10
- 208000020431 spinal cord injury Diseases 0.000 claims description 10
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims description 9
- 208000028185 Angioedema Diseases 0.000 claims description 9
- 208000019901 Anxiety disease Diseases 0.000 claims description 9
- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 9
- 208000020925 Bipolar disease Diseases 0.000 claims description 9
- 206010048962 Brain oedema Diseases 0.000 claims description 9
- 208000015943 Coeliac disease Diseases 0.000 claims description 9
- 208000020401 Depressive disease Diseases 0.000 claims description 9
- 206010019233 Headaches Diseases 0.000 claims description 9
- 208000018737 Parkinson disease Diseases 0.000 claims description 9
- 208000004550 Postoperative Pain Diseases 0.000 claims description 9
- 208000028017 Psychotic disease Diseases 0.000 claims description 9
- 206010039085 Rhinitis allergic Diseases 0.000 claims description 9
- 206010039710 Scleroderma Diseases 0.000 claims description 9
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 9
- 206010046851 Uveitis Diseases 0.000 claims description 9
- 201000010105 allergic rhinitis Diseases 0.000 claims description 9
- 208000003455 anaphylaxis Diseases 0.000 claims description 9
- 208000006752 brain edema Diseases 0.000 claims description 9
- 201000001981 dermatomyositis Diseases 0.000 claims description 9
- 231100000869 headache Toxicity 0.000 claims description 9
- 208000024714 major depressive disease Diseases 0.000 claims description 9
- 206010028417 myasthenia gravis Diseases 0.000 claims description 9
- 230000000926 neurological effect Effects 0.000 claims description 9
- 208000020016 psychiatric disease Diseases 0.000 claims description 9
- 208000011117 substance-related disease Diseases 0.000 claims description 9
- 231100000397 ulcer Toxicity 0.000 claims description 9
- 230000003612 virological effect Effects 0.000 claims description 9
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 8
- 206010013935 Dysmenorrhoea Diseases 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 208000004454 Hyperalgesia Diseases 0.000 claims description 8
- 206010065390 Inflammatory pain Diseases 0.000 claims description 8
- 206010030113 Oedema Diseases 0.000 claims description 8
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 8
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 8
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 8
- 206010047700 Vomiting Diseases 0.000 claims description 8
- 239000000556 agonist Substances 0.000 claims description 8
- 239000012472 biological sample Substances 0.000 claims description 8
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 claims description 8
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 claims description 8
- 230000002496 gastric effect Effects 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 230000003902 lesion Effects 0.000 claims description 8
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 8
- 208000019116 sleep disease Diseases 0.000 claims description 8
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 8
- 208000009935 visceral pain Diseases 0.000 claims description 8
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 7
- 201000001320 Atherosclerosis Diseases 0.000 claims description 7
- 206010003645 Atopy Diseases 0.000 claims description 7
- 201000006474 Brain Ischemia Diseases 0.000 claims description 7
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 7
- 208000000094 Chronic Pain Diseases 0.000 claims description 7
- 206010012442 Dermatitis contact Diseases 0.000 claims description 7
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 7
- 208000005171 Dysmenorrhea Diseases 0.000 claims description 7
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 7
- 208000003456 Juvenile Arthritis Diseases 0.000 claims description 7
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 claims description 7
- 208000019695 Migraine disease Diseases 0.000 claims description 7
- 208000008589 Obesity Diseases 0.000 claims description 7
- 208000022873 Ocular disease Diseases 0.000 claims description 7
- 201000002661 Spondylitis Diseases 0.000 claims description 7
- 208000005298 acute pain Diseases 0.000 claims description 7
- 208000010877 cognitive disease Diseases 0.000 claims description 7
- 208000010247 contact dermatitis Diseases 0.000 claims description 7
- 208000021302 gastroesophageal reflux disease Diseases 0.000 claims description 7
- 238000007917 intracranial administration Methods 0.000 claims description 7
- 230000004410 intraocular pressure Effects 0.000 claims description 7
- 239000004090 neuroprotective agent Substances 0.000 claims description 7
- 235000020824 obesity Nutrition 0.000 claims description 7
- 210000000056 organ Anatomy 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 239000000018 receptor agonist Substances 0.000 claims description 7
- 229940044601 receptor agonist Drugs 0.000 claims description 7
- 201000003068 rheumatic fever Diseases 0.000 claims description 7
- 238000002054 transplantation Methods 0.000 claims description 7
- 230000009529 traumatic brain injury Effects 0.000 claims description 7
- 210000003932 urinary bladder Anatomy 0.000 claims description 7
- 239000003981 vehicle Substances 0.000 claims description 7
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 6
- 208000035285 Allergic Seasonal Rhinitis Diseases 0.000 claims description 6
- 206010002199 Anaphylactic shock Diseases 0.000 claims description 6
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 6
- 206010010741 Conjunctivitis Diseases 0.000 claims description 6
- 208000020406 Creutzfeldt Jacob disease Diseases 0.000 claims description 6
- 208000003407 Creutzfeldt-Jakob Syndrome Diseases 0.000 claims description 6
- 208000010859 Creutzfeldt-Jakob disease Diseases 0.000 claims description 6
- 201000011240 Frontotemporal dementia Diseases 0.000 claims description 6
- 208000007882 Gastritis Diseases 0.000 claims description 6
- 208000007465 Giant cell arteritis Diseases 0.000 claims description 6
- 208000015023 Graves' disease Diseases 0.000 claims description 6
- 208000035895 Guillain-Barré syndrome Diseases 0.000 claims description 6
- 208000031886 HIV Infections Diseases 0.000 claims description 6
- 208000037357 HIV infectious disease Diseases 0.000 claims description 6
- 208000030836 Hashimoto thyroiditis Diseases 0.000 claims description 6
- 208000010496 Heart Arrest Diseases 0.000 claims description 6
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 claims description 6
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 claims description 6
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 6
- 206010021143 Hypoxia Diseases 0.000 claims description 6
- 201000009906 Meningitis Diseases 0.000 claims description 6
- 206010049567 Miller Fisher syndrome Diseases 0.000 claims description 6
- 208000005314 Multi-Infarct Dementia Diseases 0.000 claims description 6
- 241000699666 Mus <mouse, genus> Species 0.000 claims description 6
- 206010029164 Nephrotic syndrome Diseases 0.000 claims description 6
- 208000025047 Non-histaminic angioedema Diseases 0.000 claims description 6
- 208000000609 Pick Disease of the Brain Diseases 0.000 claims description 6
- 208000007048 Polymyalgia Rheumatica Diseases 0.000 claims description 6
- 201000004681 Psoriasis Diseases 0.000 claims description 6
- 206010063837 Reperfusion injury Diseases 0.000 claims description 6
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 6
- 206010039966 Senile dementia Diseases 0.000 claims description 6
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 6
- 208000016247 Soft tissue disease Diseases 0.000 claims description 6
- 208000010040 Sprains and Strains Diseases 0.000 claims description 6
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 claims description 6
- 201000009594 Systemic Scleroderma Diseases 0.000 claims description 6
- 206010042953 Systemic sclerosis Diseases 0.000 claims description 6
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 claims description 6
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 6
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 6
- 208000026935 allergic disease Diseases 0.000 claims description 6
- 230000007815 allergy Effects 0.000 claims description 6
- 239000000935 antidepressant agent Substances 0.000 claims description 6
- 229940005513 antidepressants Drugs 0.000 claims description 6
- 239000003435 antirheumatic agent Substances 0.000 claims description 6
- 230000036506 anxiety Effects 0.000 claims description 6
- 208000002399 aphthous stomatitis Diseases 0.000 claims description 6
- 230000036528 appetite Effects 0.000 claims description 6
- 235000019789 appetite Nutrition 0.000 claims description 6
- 208000027625 autoimmune inner ear disease Diseases 0.000 claims description 6
- 230000001580 bacterial effect Effects 0.000 claims description 6
- 230000003542 behavioural effect Effects 0.000 claims description 6
- 229940049706 benzodiazepine Drugs 0.000 claims description 6
- 125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 claims description 6
- 208000020670 canker sore Diseases 0.000 claims description 6
- 239000000544 cholinesterase inhibitor Substances 0.000 claims description 6
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 6
- 230000003412 degenerative effect Effects 0.000 claims description 6
- 239000002988 disease modifying antirheumatic drug Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 208000024732 dysthymic disease Diseases 0.000 claims description 6
- 230000002124 endocrine Effects 0.000 claims description 6
- 208000007565 gingivitis Diseases 0.000 claims description 6
- 208000006454 hepatitis Diseases 0.000 claims description 6
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 claims description 6
- 208000008384 ileus Diseases 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical group C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 239000000367 immunologic factor Substances 0.000 claims description 6
- 229940125721 immunosuppressive agent Drugs 0.000 claims description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 6
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 claims description 6
- 208000019423 liver disease Diseases 0.000 claims description 6
- 206010025135 lupus erythematosus Diseases 0.000 claims description 6
- 230000003547 miosis Effects 0.000 claims description 6
- 239000003604 miotic agent Substances 0.000 claims description 6
- 208000029766 myalgic encephalomeyelitis/chronic fatigue syndrome Diseases 0.000 claims description 6
- 206010035653 pneumoconiosis Diseases 0.000 claims description 6
- 208000005987 polymyositis Diseases 0.000 claims description 6
- 230000002685 pulmonary effect Effects 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 208000002574 reactive arthritis Diseases 0.000 claims description 6
- 229940044551 receptor antagonist Drugs 0.000 claims description 6
- 239000002464 receptor antagonist Substances 0.000 claims description 6
- 102000005962 receptors Human genes 0.000 claims description 6
- 108020003175 receptors Proteins 0.000 claims description 6
- 201000000306 sarcoidosis Diseases 0.000 claims description 6
- 201000009032 substance abuse Diseases 0.000 claims description 6
- 231100000736 substance abuse Toxicity 0.000 claims description 6
- 206010043207 temporal arteritis Diseases 0.000 claims description 6
- 206010043778 thyroiditis Diseases 0.000 claims description 6
- 208000010392 Bone Fractures Diseases 0.000 claims description 5
- 241000283690 Bos taurus Species 0.000 claims description 5
- 206010058019 Cancer Pain Diseases 0.000 claims description 5
- 208000019454 Feeding and Eating disease Diseases 0.000 claims description 5
- 241000282326 Felis catus Species 0.000 claims description 5
- 201000005569 Gout Diseases 0.000 claims description 5
- 208000006877 Insect Bites and Stings Diseases 0.000 claims description 5
- 208000005615 Interstitial Cystitis Diseases 0.000 claims description 5
- 241000283973 Oryctolagus cuniculus Species 0.000 claims description 5
- 206010033645 Pancreatitis Diseases 0.000 claims description 5
- 210000003169 central nervous system Anatomy 0.000 claims description 5
- 239000003246 corticosteroid Substances 0.000 claims description 5
- 229960001334 corticosteroids Drugs 0.000 claims description 5
- 229940111134 coxibs Drugs 0.000 claims description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 5
- 230000003111 delayed effect Effects 0.000 claims description 5
- 206010015037 epilepsy Diseases 0.000 claims description 5
- 208000024908 graft versus host disease Diseases 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 238000002483 medication Methods 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 208000005264 motor neuron disease Diseases 0.000 claims description 5
- 208000031225 myocardial ischemia Diseases 0.000 claims description 5
- 230000002093 peripheral effect Effects 0.000 claims description 5
- 230000006641 stabilisation Effects 0.000 claims description 5
- 238000011105 stabilization Methods 0.000 claims description 5
- 230000000472 traumatic effect Effects 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 4
- 208000006820 Arthralgia Diseases 0.000 claims description 4
- 208000000659 Autoimmune lymphoproliferative syndrome Diseases 0.000 claims description 4
- 208000032841 Bulimia Diseases 0.000 claims description 4
- 206010006550 Bulimia nervosa Diseases 0.000 claims description 4
- 241000700199 Cavia porcellus Species 0.000 claims description 4
- 208000011038 Cold agglutinin disease Diseases 0.000 claims description 4
- 206010012735 Diarrhoea Diseases 0.000 claims description 4
- 241000283073 Equus caballus Species 0.000 claims description 4
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 4
- 206010019196 Head injury Diseases 0.000 claims description 4
- 208000035154 Hyperesthesia Diseases 0.000 claims description 4
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 claims description 4
- 208000019693 Lung disease Diseases 0.000 claims description 4
- 206010025323 Lymphomas Diseases 0.000 claims description 4
- 206010027476 Metastases Diseases 0.000 claims description 4
- 208000019022 Mood disease Diseases 0.000 claims description 4
- 208000029549 Muscle injury Diseases 0.000 claims description 4
- 206010028813 Nausea Diseases 0.000 claims description 4
- 206010029240 Neuritis Diseases 0.000 claims description 4
- 235000002637 Nicotiana tabacum Nutrition 0.000 claims description 4
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 4
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 4
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical group C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 4
- 206010040070 Septic Shock Diseases 0.000 claims description 4
- 206010042496 Sunburn Diseases 0.000 claims description 4
- 241000282898 Sus scrofa Species 0.000 claims description 4
- 208000000491 Tendinopathy Diseases 0.000 claims description 4
- 206010043255 Tendonitis Diseases 0.000 claims description 4
- 208000007536 Thrombosis Diseases 0.000 claims description 4
- 208000024780 Urticaria Diseases 0.000 claims description 4
- 239000002671 adjuvant Substances 0.000 claims description 4
- 206010053552 allodynia Diseases 0.000 claims description 4
- 208000022531 anorexia Diseases 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 208000010668 atopic eczema Diseases 0.000 claims description 4
- 229940125717 barbiturate Drugs 0.000 claims description 4
- 239000002876 beta blocker Substances 0.000 claims description 4
- 229940097320 beta blocking agent Drugs 0.000 claims description 4
- 206010006451 bronchitis Diseases 0.000 claims description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 229960001948 caffeine Drugs 0.000 claims description 4
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 210000004027 cell Anatomy 0.000 claims description 4
- 208000015114 central nervous system disease Diseases 0.000 claims description 4
- 229960003920 cocaine Drugs 0.000 claims description 4
- 125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 0.000 claims description 4
- 208000007784 diverticulitis Diseases 0.000 claims description 4
- 208000007475 hemolytic anemia Diseases 0.000 claims description 4
- 239000003018 immunosuppressive agent Substances 0.000 claims description 4
- 230000002757 inflammatory effect Effects 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 208000017169 kidney disease Diseases 0.000 claims description 4
- 239000003589 local anesthetic agent Substances 0.000 claims description 4
- 229960005015 local anesthetics Drugs 0.000 claims description 4
- 208000025036 lymphosarcoma Diseases 0.000 claims description 4
- 230000001404 mediated effect Effects 0.000 claims description 4
- 230000002503 metabolic effect Effects 0.000 claims description 4
- 230000008693 nausea Effects 0.000 claims description 4
- 230000002474 noradrenergic effect Effects 0.000 claims description 4
- 230000000750 progressive effect Effects 0.000 claims description 4
- 150000003222 pyridines Chemical class 0.000 claims description 4
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
- 230000036303 septic shock Effects 0.000 claims description 4
- 230000000862 serotonergic effect Effects 0.000 claims description 4
- 239000003369 serotonin 5-HT3 receptor antagonist Substances 0.000 claims description 4
- 201000004415 tendinitis Diseases 0.000 claims description 4
- 239000003053 toxin Substances 0.000 claims description 4
- 231100000765 toxin Toxicity 0.000 claims description 4
- 108700012359 toxins Proteins 0.000 claims description 4
- 230000008673 vomiting Effects 0.000 claims description 4
- 239000005541 ACE inhibitor Substances 0.000 claims description 3
- 208000030507 AIDS Diseases 0.000 claims description 3
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 3
- 208000008190 Agammaglobulinemia Diseases 0.000 claims description 3
- 208000008811 Agoraphobia Diseases 0.000 claims description 3
- 208000007848 Alcoholism Diseases 0.000 claims description 3
- 206010057380 Allergic keratitis Diseases 0.000 claims description 3
- 208000035939 Alveolitis allergic Diseases 0.000 claims description 3
- 229920000856 Amylose Polymers 0.000 claims description 3
- 206010002198 Anaphylactic reaction Diseases 0.000 claims description 3
- 102000008873 Angiotensin II receptor Human genes 0.000 claims description 3
- 108050000824 Angiotensin II receptor Proteins 0.000 claims description 3
- 206010002660 Anoxia Diseases 0.000 claims description 3
- 241000976983 Anoxia Species 0.000 claims description 3
- 208000003343 Antiphospholipid Syndrome Diseases 0.000 claims description 3
- 206010003267 Arthritis reactive Diseases 0.000 claims description 3
- 208000033116 Asbestos intoxication Diseases 0.000 claims description 3
- 206010003805 Autism Diseases 0.000 claims description 3
- 208000020706 Autistic disease Diseases 0.000 claims description 3
- 206010003827 Autoimmune hepatitis Diseases 0.000 claims description 3
- 208000000412 Avitaminosis Diseases 0.000 claims description 3
- 208000008035 Back Pain Diseases 0.000 claims description 3
- 208000023328 Basedow disease Diseases 0.000 claims description 3
- 208000009137 Behcet syndrome Diseases 0.000 claims description 3
- 208000009299 Benign Mucous Membrane Pemphigoid Diseases 0.000 claims description 3
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 3
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 3
- 206010006002 Bone pain Diseases 0.000 claims description 3
- 206010006482 Bronchospasm Diseases 0.000 claims description 3
- 206010006811 Bursitis Diseases 0.000 claims description 3
- 208000007596 Byssinosis Diseases 0.000 claims description 3
- 201000002829 CREST Syndrome Diseases 0.000 claims description 3
- 206010006895 Cachexia Diseases 0.000 claims description 3
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 3
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 3
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 3
- 208000001387 Causalgia Diseases 0.000 claims description 3
- 206010008111 Cerebral haemorrhage Diseases 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 206010008748 Chorea Diseases 0.000 claims description 3
- 208000002691 Choroiditis Diseases 0.000 claims description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
- 208000030939 Chronic inflammatory demyelinating polyneuropathy Diseases 0.000 claims description 3
- 206010009868 Cold type haemolytic anaemia Diseases 0.000 claims description 3
- 241000272201 Columbiformes Species 0.000 claims description 3
- 206010010744 Conjunctivitis allergic Diseases 0.000 claims description 3
- 206010011224 Cough Diseases 0.000 claims description 3
- 241000699800 Cricetinae Species 0.000 claims description 3
- 208000019707 Cryoglobulinemic vasculitis Diseases 0.000 claims description 3
- 206010063057 Cystitis noninfective Diseases 0.000 claims description 3
- 208000006313 Delayed Hypersensitivity Diseases 0.000 claims description 3
- 206010012335 Dependence Diseases 0.000 claims description 3
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 3
- 201000003066 Diffuse Scleroderma Diseases 0.000 claims description 3
- 206010013654 Drug abuse Diseases 0.000 claims description 3
- 208000012661 Dyskinesia Diseases 0.000 claims description 3
- 208000014094 Dystonic disease Diseases 0.000 claims description 3
- 206010014561 Emphysema Diseases 0.000 claims description 3
- 206010015226 Erythema nodosum Diseases 0.000 claims description 3
- 208000020564 Eye injury Diseases 0.000 claims description 3
- 208000027445 Farmer Lung Diseases 0.000 claims description 3
- 208000028387 Felty syndrome Diseases 0.000 claims description 3
- 206010016654 Fibrosis Diseases 0.000 claims description 3
- 206010017076 Fracture Diseases 0.000 claims description 3
- 239000003691 GABA modulator Substances 0.000 claims description 3
- 206010017740 Gas poisoning Diseases 0.000 claims description 3
- 208000012671 Gastrointestinal haemorrhages Diseases 0.000 claims description 3
- 241000699694 Gerbillinae Species 0.000 claims description 3
- 206010018498 Goitre Diseases 0.000 claims description 3
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 claims description 3
- 208000003807 Graves Disease Diseases 0.000 claims description 3
- 208000001204 Hashimoto Disease Diseases 0.000 claims description 3
- 206010019280 Heart failures Diseases 0.000 claims description 3
- 206010019799 Hepatitis viral Diseases 0.000 claims description 3
- 229940122957 Histamine H2 receptor antagonist Drugs 0.000 claims description 3
- 208000023105 Huntington disease Diseases 0.000 claims description 3
- 206010020853 Hypertonic bladder Diseases 0.000 claims description 3
- 206010020983 Hypogammaglobulinaemia Diseases 0.000 claims description 3
- 208000013016 Hypoglycemia Diseases 0.000 claims description 3
- 206010021135 Hypovitaminosis Diseases 0.000 claims description 3
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 3
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 claims description 3
- 208000010159 IgA glomerulonephritis Diseases 0.000 claims description 3
- 206010021263 IgA nephropathy Diseases 0.000 claims description 3
- 208000001718 Immediate Hypersensitivity Diseases 0.000 claims description 3
- 206010061598 Immunodeficiency Diseases 0.000 claims description 3
- 208000029462 Immunodeficiency disease Diseases 0.000 claims description 3
- 206010021750 Infantile Spasms Diseases 0.000 claims description 3
- 102000004877 Insulin Human genes 0.000 claims description 3
- 108090001061 Insulin Proteins 0.000 claims description 3
- 102000001399 Kallikrein Human genes 0.000 claims description 3
- 108060005987 Kallikrein Proteins 0.000 claims description 3
- 208000007914 Labor Pain Diseases 0.000 claims description 3
- 208000035945 Labour pain Diseases 0.000 claims description 3
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 claims description 3
- 206010067125 Liver injury Diseases 0.000 claims description 3
- 206010026749 Mania Diseases 0.000 claims description 3
- 208000027530 Meniere disease Diseases 0.000 claims description 3
- 208000037093 Menstruation Disturbances Diseases 0.000 claims description 3
- 206010027339 Menstruation irregular Diseases 0.000 claims description 3
- 206010027951 Mood swings Diseases 0.000 claims description 3
- 208000026072 Motor neurone disease Diseases 0.000 claims description 3
- 208000012192 Mucous membrane pemphigoid Diseases 0.000 claims description 3
- 208000008238 Muscle Spasticity Diseases 0.000 claims description 3
- 208000023178 Musculoskeletal disease Diseases 0.000 claims description 3
- 102000004129 N-Type Calcium Channels Human genes 0.000 claims description 3
- 108090000699 N-Type Calcium Channels Proteins 0.000 claims description 3
- 206010051606 Necrotising colitis Diseases 0.000 claims description 3
- 208000036110 Neuroinflammatory disease Diseases 0.000 claims description 3
- 102000019315 Nicotinic acetylcholine receptors Human genes 0.000 claims description 3
- 108050006807 Nicotinic acetylcholine receptors Proteins 0.000 claims description 3
- 208000000224 Night Terrors Diseases 0.000 claims description 3
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 3
- 208000001294 Nociceptive Pain Diseases 0.000 claims description 3
- 206010067013 Normal tension glaucoma Diseases 0.000 claims description 3
- 208000021384 Obsessive-Compulsive disease Diseases 0.000 claims description 3
- 206010030216 Oesophagitis Diseases 0.000 claims description 3
- 102000003840 Opioid Receptors Human genes 0.000 claims description 3
- 108090000137 Opioid Receptors Proteins 0.000 claims description 3
- 208000001132 Osteoporosis Diseases 0.000 claims description 3
- 206010033078 Otitis media Diseases 0.000 claims description 3
- 208000009722 Overactive Urinary Bladder Diseases 0.000 claims description 3
- 102100040460 P2X purinoceptor 3 Human genes 0.000 claims description 3
- 101710189970 P2X purinoceptor 3 Proteins 0.000 claims description 3
- 208000016222 Pancreatic disease Diseases 0.000 claims description 3
- 208000030852 Parasitic disease Diseases 0.000 claims description 3
- 206010034277 Pemphigoid Diseases 0.000 claims description 3
- 208000031845 Pernicious anaemia Diseases 0.000 claims description 3
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 claims description 3
- 206010036018 Pollakiuria Diseases 0.000 claims description 3
- 206010065159 Polychondritis Diseases 0.000 claims description 3
- 208000004880 Polyuria Diseases 0.000 claims description 3
- 208000003971 Posterior uveitis Diseases 0.000 claims description 3
- 102000004257 Potassium Channel Human genes 0.000 claims description 3
- 208000006399 Premature Obstetric Labor Diseases 0.000 claims description 3
- 206010036600 Premature labour Diseases 0.000 claims description 3
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 3
- 208000024777 Prion disease Diseases 0.000 claims description 3
- 206010037660 Pyrexia Diseases 0.000 claims description 3
- 208000012322 Raynaud phenomenon Diseases 0.000 claims description 3
- 208000033464 Reiter syndrome Diseases 0.000 claims description 3
- 206010038910 Retinitis Diseases 0.000 claims description 3
- 206010038923 Retinopathy Diseases 0.000 claims description 3
- 208000034189 Sclerosis Diseases 0.000 claims description 3
- 201000010001 Silicosis Diseases 0.000 claims description 3
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 claims description 3
- 206010041010 Sleep terror Diseases 0.000 claims description 3
- 206010041243 Social avoidant behaviour Diseases 0.000 claims description 3
- 206010041250 Social phobia Diseases 0.000 claims description 3
- 206010041347 Somnambulism Diseases 0.000 claims description 3
- 208000007156 Spondylarthritis Diseases 0.000 claims description 3
- 206010072148 Stiff-Person syndrome Diseases 0.000 claims description 3
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 claims description 3
- 231100000643 Substance intoxication Toxicity 0.000 claims description 3
- 206010042742 Sympathetic ophthalmia Diseases 0.000 claims description 3
- 208000001106 Takayasu Arteritis Diseases 0.000 claims description 3
- 201000002015 Thyroid Crisis Diseases 0.000 claims description 3
- 206010043784 Thyroiditis subacute Diseases 0.000 claims description 3
- 206010043786 Thyrotoxic crisis Diseases 0.000 claims description 3
- 208000009205 Tinnitus Diseases 0.000 claims description 3
- 206010043903 Tobacco abuse Diseases 0.000 claims description 3
- 206010070863 Toxicity to various agents Diseases 0.000 claims description 3
- 206010048873 Traumatic arthritis Diseases 0.000 claims description 3
- 206010044565 Tremor Diseases 0.000 claims description 3
- 229940123445 Tricyclic antidepressant Drugs 0.000 claims description 3
- 206010045240 Type I hypersensitivity Diseases 0.000 claims description 3
- 206010046543 Urinary incontinence Diseases 0.000 claims description 3
- 206010047642 Vitiligo Diseases 0.000 claims description 3
- 208000000208 Wet Macular Degeneration Diseases 0.000 claims description 3
- 206010047924 Wheezing Diseases 0.000 claims description 3
- 238000012084 abdominal surgery Methods 0.000 claims description 3
- 208000010638 acquired aplastic anemia Diseases 0.000 claims description 3
- 230000009692 acute damage Effects 0.000 claims description 3
- 231100000354 acute hepatitis Toxicity 0.000 claims description 3
- 208000012826 adjustment disease Diseases 0.000 claims description 3
- 239000000048 adrenergic agonist Substances 0.000 claims description 3
- 206010064930 age-related macular degeneration Diseases 0.000 claims description 3
- 230000032683 aging Effects 0.000 claims description 3
- 201000007930 alcohol dependence Diseases 0.000 claims description 3
- 208000029650 alcohol withdrawal Diseases 0.000 claims description 3
- 208000010002 alcoholic liver cirrhosis Diseases 0.000 claims description 3
- 201000009961 allergic asthma Diseases 0.000 claims description 3
- 208000002205 allergic conjunctivitis Diseases 0.000 claims description 3
- 208000004631 alopecia areata Diseases 0.000 claims description 3
- 208000028462 aluminosis Diseases 0.000 claims description 3
- 230000036783 anaphylactic response Effects 0.000 claims description 3
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 3
- 230000007953 anoxia Effects 0.000 claims description 3
- 208000010123 anthracosis Diseases 0.000 claims description 3
- 230000003178 anti-diabetic effect Effects 0.000 claims description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 3
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 3
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 3
- 229940124604 anti-psychotic medication Drugs 0.000 claims description 3
- 239000003472 antidiabetic agent Substances 0.000 claims description 3
- 239000002111 antiemetic agent Substances 0.000 claims description 3
- 229940125683 antiemetic agent Drugs 0.000 claims description 3
- 229940006133 antiglaucoma drug and miotics carbonic anhydrase inhibitors Drugs 0.000 claims description 3
- 229940030600 antihypertensive agent Drugs 0.000 claims description 3
- 239000002220 antihypertensive agent Substances 0.000 claims description 3
- 229960005475 antiinfective agent Drugs 0.000 claims description 3
- 239000004599 antimicrobial Substances 0.000 claims description 3
- 239000002830 appetite depressant Substances 0.000 claims description 3
- 206010003230 arteritis Diseases 0.000 claims description 3
- 230000002917 arthritic effect Effects 0.000 claims description 3
- 206010003441 asbestosis Diseases 0.000 claims description 3
- 208000010216 atopic IgE responsiveness Diseases 0.000 claims description 3
- 208000024998 atopic conjunctivitis Diseases 0.000 claims description 3
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 claims description 3
- 208000036923 autoimmune primary adrenal insufficiency Diseases 0.000 claims description 3
- 231100000871 behavioral problem Toxicity 0.000 claims description 3
- 208000028683 bipolar I disease Diseases 0.000 claims description 3
- 208000025307 bipolar depression Diseases 0.000 claims description 3
- 208000010217 blepharitis Diseases 0.000 claims description 3
- 239000003914 blood derivative Substances 0.000 claims description 3
- 208000019664 bone resorption disease Diseases 0.000 claims description 3
- 230000007177 brain activity Effects 0.000 claims description 3
- 208000025698 brain inflammatory disease Diseases 0.000 claims description 3
- 208000029028 brain injury Diseases 0.000 claims description 3
- 206010006514 bruxism Diseases 0.000 claims description 3
- 239000000480 calcium channel blocker Substances 0.000 claims description 3
- 229940121376 cannabinoid receptor agonist Drugs 0.000 claims description 3
- 239000003537 cannabinoid receptor agonist Substances 0.000 claims description 3
- 239000003489 carbonate dehydratase inhibitor Substances 0.000 claims description 3
- 206010007776 catatonia Diseases 0.000 claims description 3
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 239000000064 cholinergic agonist Substances 0.000 claims description 3
- 208000012601 choreatic disease Diseases 0.000 claims description 3
- 208000019069 chronic childhood arthritis Diseases 0.000 claims description 3
- 201000005795 chronic inflammatory demyelinating polyneuritis Diseases 0.000 claims description 3
- 208000013507 chronic prostatitis Diseases 0.000 claims description 3
- 201000010002 cicatricial pemphigoid Diseases 0.000 claims description 3
- 230000027288 circadian rhythm Effects 0.000 claims description 3
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 3
- 230000007370 cognitive improvement Effects 0.000 claims description 3
- 208000018631 connective tissue disease Diseases 0.000 claims description 3
- 230000008602 contraction Effects 0.000 claims description 3
- 239000002872 contrast media Substances 0.000 claims description 3
- 238000007887 coronary angioplasty Methods 0.000 claims description 3
- 235000019788 craving Nutrition 0.000 claims description 3
- 201000003278 cryoglobulinemia Diseases 0.000 claims description 3
- 239000003260 cyclooxygenase 1 inhibitor Substances 0.000 claims description 3
- 230000003247 decreasing effect Effects 0.000 claims description 3
- 230000006806 disease prevention Effects 0.000 claims description 3
- 230000035619 diuresis Effects 0.000 claims description 3
- 230000003291 dopaminomimetic effect Effects 0.000 claims description 3
- 208000010118 dystonia Diseases 0.000 claims description 3
- 230000002500 effect on skin Effects 0.000 claims description 3
- 206010014599 encephalitis Diseases 0.000 claims description 3
- 201000002491 encephalomyelitis Diseases 0.000 claims description 3
- 208000030172 endocrine system disease Diseases 0.000 claims description 3
- 201000003104 endogenous depression Diseases 0.000 claims description 3
- 208000006881 esophagitis Diseases 0.000 claims description 3
- 208000024695 exercise-induced bronchoconstriction Diseases 0.000 claims description 3
- 208000030533 eye disease Diseases 0.000 claims description 3
- 208000022195 farmer lung disease Diseases 0.000 claims description 3
- 230000027950 fever generation Effects 0.000 claims description 3
- 230000004761 fibrosis Effects 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 235000013305 food Nutrition 0.000 claims description 3
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims description 3
- 208000030304 gastrointestinal bleeding Diseases 0.000 claims description 3
- 208000037870 generalized anxiety Diseases 0.000 claims description 3
- 210000003714 granulocyte Anatomy 0.000 claims description 3
- 238000001631 haemodialysis Methods 0.000 claims description 3
- 239000000380 hallucinogen Substances 0.000 claims description 3
- 210000003128 head Anatomy 0.000 claims description 3
- 208000014951 hematologic disease Diseases 0.000 claims description 3
- 230000000322 hemodialysis Effects 0.000 claims description 3
- 231100000753 hepatic injury Toxicity 0.000 claims description 3
- 231100000283 hepatitis Toxicity 0.000 claims description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 230000004402 high myopia Effects 0.000 claims description 3
- 229960001340 histamine Drugs 0.000 claims description 3
- 239000003485 histamine H2 receptor antagonist Substances 0.000 claims description 3
- 229940088597 hormone Drugs 0.000 claims description 3
- 239000005556 hormone Substances 0.000 claims description 3
- 201000001421 hyperglycemia Diseases 0.000 claims description 3
- 230000002218 hypoglycaemic effect Effects 0.000 claims description 3
- 230000007954 hypoxia Effects 0.000 claims description 3
- 230000007813 immunodeficiency Effects 0.000 claims description 3
- 230000002458 infectious effect Effects 0.000 claims description 3
- 206010022437 insomnia Diseases 0.000 claims description 3
- 229940125396 insulin Drugs 0.000 claims description 3
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 3
- 201000010659 intrinsic asthma Diseases 0.000 claims description 3
- 238000011835 investigation Methods 0.000 claims description 3
- 201000004614 iritis Diseases 0.000 claims description 3
- 208000028867 ischemia Diseases 0.000 claims description 3
- 239000003199 leukotriene receptor blocking agent Substances 0.000 claims description 3
- 201000007270 liver cancer Diseases 0.000 claims description 3
- 210000005229 liver cell Anatomy 0.000 claims description 3
- 201000002978 low tension glaucoma Diseases 0.000 claims description 3
- 206010027175 memory impairment Diseases 0.000 claims description 3
- 231100000544 menstrual irregularity Toxicity 0.000 claims description 3
- 230000004060 metabolic process Effects 0.000 claims description 3
- 208000027061 mild cognitive impairment Diseases 0.000 claims description 3
- 208000037890 multiple organ injury Diseases 0.000 claims description 3
- 230000004118 muscle contraction Effects 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 201000003631 narcolepsy Diseases 0.000 claims description 3
- 239000003887 narcotic antagonist Substances 0.000 claims description 3
- 208000004995 necrotizing enterocolitis Diseases 0.000 claims description 3
- 201000008383 nephritis Diseases 0.000 claims description 3
- 230000001272 neurogenic effect Effects 0.000 claims description 3
- 230000003959 neuroinflammation Effects 0.000 claims description 3
- 230000002981 neuropathic effect Effects 0.000 claims description 3
- 208000025319 neurotic depression Diseases 0.000 claims description 3
- 208000015238 neurotic disease Diseases 0.000 claims description 3
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 3
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 3
- 208000007892 occupational asthma Diseases 0.000 claims description 3
- 229940005483 opioid analgesics Drugs 0.000 claims description 3
- 230000000399 orthopedic effect Effects 0.000 claims description 3
- 239000002337 osmotic diuretic agent Substances 0.000 claims description 3
- 206010033072 otitis externa Diseases 0.000 claims description 3
- 208000020629 overactive bladder Diseases 0.000 claims description 3
- 208000024691 pancreas disease Diseases 0.000 claims description 3
- 208000019906 panic disease Diseases 0.000 claims description 3
- 230000003071 parasitic effect Effects 0.000 claims description 3
- 239000004031 partial agonist Substances 0.000 claims description 3
- 230000037361 pathway Effects 0.000 claims description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 3
- 201000006195 perinatal necrotizing enterocolitis Diseases 0.000 claims description 3
- 229950010883 phencyclidine Drugs 0.000 claims description 3
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 claims description 3
- 208000022131 polyp of large intestine Diseases 0.000 claims description 3
- 208000028173 post-traumatic stress disease Diseases 0.000 claims description 3
- 108020001213 potassium channel Proteins 0.000 claims description 3
- 208000026440 premature labor Diseases 0.000 claims description 3
- 230000002062 proliferating effect Effects 0.000 claims description 3
- 201000007094 prostatitis Diseases 0.000 claims description 3
- 201000001474 proteinuria Diseases 0.000 claims description 3
- 229940126409 proton pump inhibitor Drugs 0.000 claims description 3
- 239000000612 proton pump inhibitor Substances 0.000 claims description 3
- 230000001107 psychogenic effect Effects 0.000 claims description 3
- 230000000306 recurrent effect Effects 0.000 claims description 3
- 239000002461 renin inhibitor Substances 0.000 claims description 3
- 229940086526 renin-inhibitors Drugs 0.000 claims description 3
- 208000037803 restenosis Diseases 0.000 claims description 3
- 230000000552 rheumatic effect Effects 0.000 claims description 3
- 201000000980 schizophrenia Diseases 0.000 claims description 3
- 208000012672 seasonal affective disease Diseases 0.000 claims description 3
- 230000004799 sedative–hypnotic effect Effects 0.000 claims description 3
- 229940124834 selective serotonin reuptake inhibitor Drugs 0.000 claims description 3
- 230000035939 shock Effects 0.000 claims description 3
- 208000004003 siderosis Diseases 0.000 claims description 3
- 239000003195 sodium channel blocking agent Substances 0.000 claims description 3
- 208000018198 spasticity Diseases 0.000 claims description 3
- 201000007497 subacute thyroiditis Diseases 0.000 claims description 3
- 208000020408 systemic-onset juvenile idiopathic arthritis Diseases 0.000 claims description 3
- 231100000886 tinnitus Toxicity 0.000 claims description 3
- 235000019505 tobacco product Nutrition 0.000 claims description 3
- 208000004371 toothache Diseases 0.000 claims description 3
- 239000003860 topical agent Substances 0.000 claims description 3
- 231100000331 toxic Toxicity 0.000 claims description 3
- 230000002588 toxic effect Effects 0.000 claims description 3
- 239000003029 tricyclic antidepressant agent Substances 0.000 claims description 3
- 230000005747 tumor angiogenesis Effects 0.000 claims description 3
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 claims description 3
- 239000005483 tyrosine kinase inhibitor Substances 0.000 claims description 3
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 claims description 3
- 230000002485 urinary effect Effects 0.000 claims description 3
- 230000036325 urinary excretion Effects 0.000 claims description 3
- 208000022934 urinary frequency Diseases 0.000 claims description 3
- 208000014001 urinary system disease Diseases 0.000 claims description 3
- 230000036318 urination frequency Effects 0.000 claims description 3
- 210000004291 uterus Anatomy 0.000 claims description 3
- 208000019553 vascular disease Diseases 0.000 claims description 3
- 229940124549 vasodilator Drugs 0.000 claims description 3
- 239000003071 vasodilator agent Substances 0.000 claims description 3
- 201000001862 viral hepatitis Diseases 0.000 claims description 3
- 208000030401 vitamin deficiency disease Diseases 0.000 claims description 3
- KWIVRAVCZJXOQC-UHFFFAOYSA-N 3h-oxathiazole Chemical group N1SOC=C1 KWIVRAVCZJXOQC-UHFFFAOYSA-N 0.000 claims description 2
- 206010013980 Dyssomnias Diseases 0.000 claims description 2
- 208000009329 Graft vs Host Disease Diseases 0.000 claims description 2
- GVGLGOZIDCSQPN-PVHGPHFFSA-N Heroin Chemical compound O([C@H]1[C@H](C=C[C@H]23)OC(C)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4OC(C)=O GVGLGOZIDCSQPN-PVHGPHFFSA-N 0.000 claims description 2
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical group C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Chemical group C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 2
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical group C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 claims description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 2
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 2
- 206010009887 colitis Diseases 0.000 claims description 2
- 229960002069 diamorphine Drugs 0.000 claims description 2
- 238000002670 nicotine replacement therapy Methods 0.000 claims description 2
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 claims description 2
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 2
- 208000020685 sleep-wake disease Diseases 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 150000003536 tetrazoles Chemical group 0.000 claims description 2
- 229930192474 thiophene Chemical group 0.000 claims description 2
- 150000003852 triazoles Chemical group 0.000 claims description 2
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 claims 1
- 102100027297 Fatty acid 2-hydroxylase Human genes 0.000 claims 1
- 101000937693 Homo sapiens Fatty acid 2-hydroxylase Proteins 0.000 claims 1
- 101000918494 Homo sapiens Fatty-acid amide hydrolase 1 Proteins 0.000 claims 1
- 241000208125 Nicotiana Species 0.000 claims 1
- 241000009328 Perro Species 0.000 claims 1
- 229940025084 amphetamine Drugs 0.000 claims 1
- 125000000068 chlorophenyl group Chemical group 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 240000004308 marijuana Species 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 90
- 102100029111 Fatty-acid amide hydrolase 1 Human genes 0.000 abstract description 23
- 108010046094 fatty-acid amide hydrolase Proteins 0.000 abstract description 23
- 239000003112 inhibitor Substances 0.000 abstract description 5
- FNEQHKCQXDKYEO-UHFFFAOYSA-N 1-benzylpyrrole Chemical class C1=CC=CN1CC1=CC=CC=C1 FNEQHKCQXDKYEO-UHFFFAOYSA-N 0.000 abstract description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 56
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 125000003118 aryl group Chemical group 0.000 description 39
- 125000004429 atom Chemical group 0.000 description 31
- 238000009472 formulation Methods 0.000 description 30
- 238000005481 NMR spectroscopy Methods 0.000 description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- 210000004556 brain Anatomy 0.000 description 20
- 235000019439 ethyl acetate Nutrition 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 239000002904 solvent Substances 0.000 description 18
- 239000013078 crystal Substances 0.000 description 16
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 15
- 239000004480 active ingredient Substances 0.000 description 15
- 239000000463 material Substances 0.000 description 15
- 239000012453 solvate Substances 0.000 description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 14
- 239000010410 layer Substances 0.000 description 14
- 239000000546 pharmaceutical excipient Substances 0.000 description 14
- 229940002612 prodrug Drugs 0.000 description 14
- 239000000651 prodrug Substances 0.000 description 14
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000002621 endocannabinoid Substances 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- 125000003342 alkenyl group Chemical group 0.000 description 11
- 239000000969 carrier Substances 0.000 description 11
- 125000004122 cyclic group Chemical group 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- 239000003995 emulsifying agent Substances 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 239000006071 cream Substances 0.000 description 10
- 239000002552 dosage form Substances 0.000 description 10
- 125000005647 linker group Chemical group 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 229920001223 polyethylene glycol Polymers 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 9
- 150000001200 N-acyl ethanolamides Chemical class 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 235000014113 dietary fatty acids Nutrition 0.000 description 9
- 239000003085 diluting agent Substances 0.000 description 9
- 239000000194 fatty acid Substances 0.000 description 9
- 229930195729 fatty acid Natural products 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 239000001301 oxygen Chemical group 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- LGEQQWMQCRIYKG-DOFZRALJSA-N anandamide Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NCCO LGEQQWMQCRIYKG-DOFZRALJSA-N 0.000 description 8
- 125000002619 bicyclic group Chemical group 0.000 description 8
- 150000004665 fatty acids Chemical class 0.000 description 8
- 239000012528 membrane Substances 0.000 description 8
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- 239000003755 preservative agent Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000002202 Polyethylene glycol Substances 0.000 description 7
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 235000019441 ethanol Nutrition 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 231100000252 nontoxic Toxicity 0.000 description 7
- 230000003000 nontoxic effect Effects 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 125000006413 ring segment Chemical group 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- 239000011593 sulfur Chemical group 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 6
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 6
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000007900 aqueous suspension Substances 0.000 description 6
- 125000003710 aryl alkyl group Chemical group 0.000 description 6
- 239000002270 dispersing agent Substances 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 239000011539 homogenization buffer Substances 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 238000002955 isolation Methods 0.000 description 6
- 239000004530 micro-emulsion Substances 0.000 description 6
- 125000002950 monocyclic group Chemical group 0.000 description 6
- 239000002674 ointment Substances 0.000 description 6
- 239000008188 pellet Substances 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 230000000069 prophylactic effect Effects 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 6
- 108090000623 proteins and genes Proteins 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 239000003381 stabilizer Substances 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- 238000002560 therapeutic procedure Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 239000004215 Carbon black (E152) Substances 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Natural products OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 5
- 229930006000 Sucrose Natural products 0.000 description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 125000004104 aryloxy group Chemical group 0.000 description 5
- 230000037396 body weight Effects 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 235000003599 food sweetener Nutrition 0.000 description 5
- 239000000499 gel Substances 0.000 description 5
- 235000011187 glycerol Nutrition 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 229930195733 hydrocarbon Natural products 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 229960004063 propylene glycol Drugs 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 238000006467 substitution reaction Methods 0.000 description 5
- 239000005720 sucrose Substances 0.000 description 5
- 239000000375 suspending agent Substances 0.000 description 5
- 230000000699 topical effect Effects 0.000 description 5
- 239000000080 wetting agent Substances 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 4
- 238000003556 assay Methods 0.000 description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 4
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000002512 chemotherapy Methods 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 235000019197 fats Nutrition 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 239000006210 lotion Substances 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- 229910001629 magnesium chloride Inorganic materials 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- YBIAQTPXONLBJG-UHFFFAOYSA-N methyl 6h-thieno[2,3-b]pyrrole-5-carboxylate Chemical compound C1=CSC2=C1C=C(C(=O)OC)N2 YBIAQTPXONLBJG-UHFFFAOYSA-N 0.000 description 4
- 239000003094 microcapsule Substances 0.000 description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 210000005036 nerve Anatomy 0.000 description 4
- 239000004006 olive oil Substances 0.000 description 4
- 125000004430 oxygen atom Chemical group O* 0.000 description 4
- 150000003141 primary amines Chemical class 0.000 description 4
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 239000001993 wax Substances 0.000 description 4
- AHOUBRCZNHFOSL-YOEHRIQHSA-N (+)-Casbol Chemical compound C1=CC(F)=CC=C1[C@H]1[C@H](COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-YOEHRIQHSA-N 0.000 description 3
- WSEQXVZVJXJVFP-HXUWFJFHSA-N (R)-citalopram Chemical compound C1([C@@]2(C3=CC=C(C=C3CO2)C#N)CCCN(C)C)=CC=C(F)C=C1 WSEQXVZVJXJVFP-HXUWFJFHSA-N 0.000 description 3
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- 101150015280 Cel gene Proteins 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 3
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 3
- 108010036949 Cyclosporine Proteins 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- 108010008165 Etanercept Proteins 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 3
- 244000061176 Nicotiana tabacum Species 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- AHOUBRCZNHFOSL-UHFFFAOYSA-N Paroxetine hydrochloride Natural products C1=CC(F)=CC=C1C1C(COC=2C=C3OCOC3=CC=2)CNCC1 AHOUBRCZNHFOSL-UHFFFAOYSA-N 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical group [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- LGEQQWMQCRIYKG-UHFFFAOYSA-N arachidonic acid ethanolamide Natural products CCCCCC=CCC=CCC=CCC=CCCCC(=O)NCCO LGEQQWMQCRIYKG-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 235000019445 benzyl alcohol Nutrition 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 235000019437 butane-1,3-diol Nutrition 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 229960001265 ciclosporin Drugs 0.000 description 3
- 229960001653 citalopram Drugs 0.000 description 3
- 229960002896 clonidine Drugs 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 239000007859 condensation product Substances 0.000 description 3
- 238000013270 controlled release Methods 0.000 description 3
- 230000001804 emulsifying effect Effects 0.000 description 3
- 239000003623 enhancer Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 125000005553 heteroaryloxy group Chemical group 0.000 description 3
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 238000011065 in-situ storage Methods 0.000 description 3
- 239000003701 inert diluent Substances 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 239000007972 injectable composition Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 229960004503 metoclopramide Drugs 0.000 description 3
- TTWJBBZEZQICBI-UHFFFAOYSA-N metoclopramide Chemical compound CCN(CC)CCNC(=O)C1=CC(Cl)=C(N)C=C1OC TTWJBBZEZQICBI-UHFFFAOYSA-N 0.000 description 3
- 239000002480 mineral oil Substances 0.000 description 3
- 235000010446 mineral oil Nutrition 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 3
- 201000001119 neuropathy Diseases 0.000 description 3
- 230000000269 nucleophilic effect Effects 0.000 description 3
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 125000004043 oxo group Chemical group O=* 0.000 description 3
- 229960002296 paroxetine Drugs 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 239000006072 paste Substances 0.000 description 3
- 208000033808 peripheral neuropathy Diseases 0.000 description 3
- 235000019271 petrolatum Nutrition 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Chemical group 0.000 description 3
- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 235000010356 sorbitol Nutrition 0.000 description 3
- 125000003003 spiro group Chemical group 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 239000000829 suppository Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- 206010044652 trigeminal neuralgia Diseases 0.000 description 3
- FELGMEQIXOGIFQ-CYBMUJFWSA-N (3r)-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-2,3-dihydro-1h-carbazol-4-one Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FELGMEQIXOGIFQ-CYBMUJFWSA-N 0.000 description 2
- ZEUITGRIYCTCEM-KRWDZBQOSA-N (S)-duloxetine Chemical compound C1([C@@H](OC=2C3=CC=CC=C3C=CC=2)CCNC)=CC=CS1 ZEUITGRIYCTCEM-KRWDZBQOSA-N 0.000 description 2
- REGAJTKYVCJGQB-UHFFFAOYSA-N 2-(2-oxopropyl)cyclooctan-1-one Chemical compound CC(=O)CC1CCCCCCC1=O REGAJTKYVCJGQB-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- DDYUBCCTNHWSQM-UHFFFAOYSA-N 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(1,3-dioxoisoindol-2-yl)propanamide Chemical compound COC1=CC=C(C(CC(N)=O)N2C(C3=CC=CC=C3C2=O)=O)C=C1OC1CCCC1 DDYUBCCTNHWSQM-UHFFFAOYSA-N 0.000 description 2
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 2
- FXPCGHUTBCPZHN-UHFFFAOYSA-N 3-phenylhexane-2,5-dione Chemical compound CC(=O)CC(C(C)=O)C1=CC=CC=C1 FXPCGHUTBCPZHN-UHFFFAOYSA-N 0.000 description 2
- 125000001397 3-pyrrolyl group Chemical group [H]N1C([H])=C([*])C([H])=C1[H] 0.000 description 2
- HBIGGKYQZGKYCU-UHFFFAOYSA-N 5-methyl-6h-thieno[2,3-b]pyrrole Chemical compound C1=CSC2=C1C=C(C)N2 HBIGGKYQZGKYCU-UHFFFAOYSA-N 0.000 description 2
- YZQRFCAMVCFEFE-UHFFFAOYSA-N 6-benzyl-5-methylthieno[2,3-b]pyrrole Chemical compound CC1=CC=2C=CSC=2N1CC1=CC=CC=C1 YZQRFCAMVCFEFE-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 239000005995 Aluminium silicate Substances 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 244000105624 Arachis hypogaea Species 0.000 description 2
- 239000004475 Arginine Substances 0.000 description 2
- 102100034605 Atrial natriuretic peptide receptor 3 Human genes 0.000 description 2
- 238000009010 Bradford assay Methods 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 2
- 241000218236 Cannabis Species 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 2
- 206010010774 Constipation Diseases 0.000 description 2
- 229930105110 Cyclosporin A Natural products 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
- 208000030814 Eating disease Diseases 0.000 description 2
- 241000792859 Enema Species 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000007995 HEPES buffer Substances 0.000 description 2
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 2
- 101000924488 Homo sapiens Atrial natriuretic peptide receptor 3 Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 102000003996 Interferon-beta Human genes 0.000 description 2
- 108090000467 Interferon-beta Proteins 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 2
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 2
- 208000008930 Low Back Pain Diseases 0.000 description 2
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 2
- 239000004472 Lysine Substances 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 2
- MITFXPHMIHQXPI-UHFFFAOYSA-N Oraflex Chemical compound N=1C2=CC(C(C(O)=O)C)=CC=C2OC=1C1=CC=C(Cl)C=C1 MITFXPHMIHQXPI-UHFFFAOYSA-N 0.000 description 2
- 241001494479 Pecora Species 0.000 description 2
- 239000004264 Petrolatum Substances 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- 229920001214 Polysorbate 60 Polymers 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- SYCBXBCPLUFJID-UHFFFAOYSA-N Pramoxine hydrochloride Chemical compound Cl.C1=CC(OCCCC)=CC=C1OCCCN1CCOCC1 SYCBXBCPLUFJID-UHFFFAOYSA-N 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- 208000008765 Sciatica Diseases 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 2
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 2
- ZZHLYYDVIOPZBE-UHFFFAOYSA-N Trimeprazine Chemical compound C1=CC=C2N(CC(CN(C)C)C)C3=CC=CC=C3SC2=C1 ZZHLYYDVIOPZBE-UHFFFAOYSA-N 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 229960001466 acetohexamide Drugs 0.000 description 2
- VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000011149 active material Substances 0.000 description 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 2
- 125000005082 alkoxyalkenyl group Chemical group 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 235000012211 aluminium silicate Nutrition 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000002431 aminoalkoxy group Chemical group 0.000 description 2
- 125000004103 aminoalkyl group Chemical group 0.000 description 2
- 229960000836 amitriptyline Drugs 0.000 description 2
- KRMDCWKBEZIMAB-UHFFFAOYSA-N amitriptyline Chemical compound C1CC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 KRMDCWKBEZIMAB-UHFFFAOYSA-N 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 239000003125 aqueous solvent Substances 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 229960003121 arginine Drugs 0.000 description 2
- 125000003435 aroyl group Chemical group 0.000 description 2
- 125000005110 aryl thio group Chemical group 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 230000001363 autoimmune Effects 0.000 description 2
- 239000011324 bead Substances 0.000 description 2
- 235000013871 bee wax Nutrition 0.000 description 2
- 239000012166 beeswax Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- BLGXFZZNTVWLAY-UHFFFAOYSA-N beta-Yohimbin Natural products C1=CC=C2C(CCN3CC4CCC(O)C(C4CC33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-UHFFFAOYSA-N 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000000133 brain stem Anatomy 0.000 description 2
- 210000005013 brain tissue Anatomy 0.000 description 2
- 229960001058 bupropion Drugs 0.000 description 2
- SNPPWIUOZRMYNY-UHFFFAOYSA-N bupropion Chemical compound CC(C)(C)NC(C)C(=O)C1=CC=CC(Cl)=C1 SNPPWIUOZRMYNY-UHFFFAOYSA-N 0.000 description 2
- DQXBYHZEEUGOBF-UHFFFAOYSA-N but-3-enoic acid;ethene Chemical compound C=C.OC(=O)CC=C DQXBYHZEEUGOBF-UHFFFAOYSA-N 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229930003827 cannabinoid Natural products 0.000 description 2
- 239000003557 cannabinoid Substances 0.000 description 2
- 229960002504 capsaicin Drugs 0.000 description 2
- 229960000623 carbamazepine Drugs 0.000 description 2
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 2
- 125000004452 carbocyclyl group Chemical group 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 239000012876 carrier material Substances 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 229960000541 cetyl alcohol Drugs 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 239000000812 cholinergic antagonist Substances 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 239000007822 coupling agent Substances 0.000 description 2
- 125000004966 cyanoalkyl group Chemical group 0.000 description 2
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 2
- 229930182912 cyclosporin Natural products 0.000 description 2
- 206010061428 decreased appetite Diseases 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 208000010643 digestive system disease Diseases 0.000 description 2
- 235000014632 disordered eating Nutrition 0.000 description 2
- AUZONCFQVSMFAP-UHFFFAOYSA-N disulfiram Chemical compound CCN(CC)C(=S)SSC(=S)N(CC)CC AUZONCFQVSMFAP-UHFFFAOYSA-N 0.000 description 2
- ODQWQRRAPPTVAG-GZTJUZNOSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=C/CCN(C)C)/C2=CC=CC=C21 ODQWQRRAPPTVAG-GZTJUZNOSA-N 0.000 description 2
- 229960004242 dronabinol Drugs 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 229960002866 duloxetine Drugs 0.000 description 2
- 239000003221 ear drop Substances 0.000 description 2
- 229940047652 ear drops Drugs 0.000 description 2
- 239000008387 emulsifying waxe Substances 0.000 description 2
- 229940073621 enbrel Drugs 0.000 description 2
- 239000007920 enema Substances 0.000 description 2
- 229940088598 enzyme Drugs 0.000 description 2
- 239000005038 ethylene vinyl acetate Substances 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 231100000318 excitotoxic Toxicity 0.000 description 2
- 230000003492 excitotoxic effect Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000003889 eye drop Substances 0.000 description 2
- 229940012356 eye drops Drugs 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 229960002870 gabapentin Drugs 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 208000018685 gastrointestinal system disease Diseases 0.000 description 2
- 239000003365 glass fiber Substances 0.000 description 2
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229940075507 glyceryl monostearate Drugs 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- JUMYIBMBTDDLNG-OJERSXHUSA-N hydron;methyl (2r)-2-phenyl-2-[(2r)-piperidin-2-yl]acetate;chloride Chemical compound Cl.C([C@@H]1[C@H](C(=O)OC)C=2C=CC=CC=2)CCCN1 JUMYIBMBTDDLNG-OJERSXHUSA-N 0.000 description 2
- 125000005113 hydroxyalkoxy group Chemical group 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 229940057995 liquid paraffin Drugs 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- RDOIQAHITMMDAJ-UHFFFAOYSA-N loperamide Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(C(=O)N(C)C)CCN(CC1)CCC1(O)C1=CC=C(Cl)C=C1 RDOIQAHITMMDAJ-UHFFFAOYSA-N 0.000 description 2
- WGFOBBZOWHGYQH-MXHNKVEKSA-N lubiprostone Chemical compound O1[C@](C(F)(F)CCCC)(O)CC[C@@H]2[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]21 WGFOBBZOWHGYQH-MXHNKVEKSA-N 0.000 description 2
- 201000001268 lymphoproliferative syndrome Diseases 0.000 description 2
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000007257 malfunction Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Chemical class 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- VSDAHAYSJGVXCV-DAXSKMNVSA-N methyl (z)-2-azido-3-thiophen-3-ylprop-2-enoate Chemical compound COC(=O)C(\N=[N+]=[N-])=C\C=1C=CSC=1 VSDAHAYSJGVXCV-DAXSKMNVSA-N 0.000 description 2
- PUVPNBQYYYYQCY-UHFFFAOYSA-N methyl 2-chloro-6h-thieno[2,3-b]pyrrole-5-carboxylate Chemical compound C1=C(Cl)SC2=C1C=C(C(=O)OC)N2 PUVPNBQYYYYQCY-UHFFFAOYSA-N 0.000 description 2
- 229960001033 methylphenidate hydrochloride Drugs 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229960005181 morphine Drugs 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 2
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 2
- 229960002009 naproxen Drugs 0.000 description 2
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 2
- 230000007823 neuropathy Effects 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 239000003883 ointment base Substances 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 229960005343 ondansetron Drugs 0.000 description 2
- 229960005489 paracetamol Drugs 0.000 description 2
- 239000012188 paraffin wax Substances 0.000 description 2
- AQIXEPGDORPWBJ-UHFFFAOYSA-N pentan-3-ol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 description 2
- 239000002304 perfume Substances 0.000 description 2
- 229940066842 petrolatum Drugs 0.000 description 2
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 description 2
- 229960002702 piroxicam Drugs 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 2
- 229920000747 poly(lactic acid) Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 108010029667 pramlintide Proteins 0.000 description 2
- NRKVKVQDUCJPIZ-MKAGXXMWSA-N pramlintide acetate Chemical compound C([C@@H](C(=O)NCC(=O)N1CCC[C@H]1C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@@H](N)CCCCN)[C@@H](C)O)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NRKVKVQDUCJPIZ-MKAGXXMWSA-N 0.000 description 2
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 description 2
- 229960001233 pregabalin Drugs 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- 229940127293 prostanoid Drugs 0.000 description 2
- 150000003814 prostanoids Chemical class 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229940116176 remicade Drugs 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 150000003873 salicylate salts Chemical class 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 229910052710 silicon Inorganic materials 0.000 description 2
- 239000010703 silicon Substances 0.000 description 2
- 208000017520 skin disease Diseases 0.000 description 2
- 229940126586 small molecule drug Drugs 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 2
- 229960001967 tacrolimus Drugs 0.000 description 2
- RMMXLENWKUUMAY-UHFFFAOYSA-N telmisartan Chemical compound CCCC1=NC2=C(C)C=C(C=3N(C4=CC=CC=C4N=3)C)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(O)=O RMMXLENWKUUMAY-UHFFFAOYSA-N 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical compound CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 2
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 2
- 238000011287 therapeutic dose Methods 0.000 description 2
- OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 2
- 239000012049 topical pharmaceutical composition Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 229960005486 vaccine Drugs 0.000 description 2
- 231100000611 venom Toxicity 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- WJJYZXPHLSLMGE-UHFFFAOYSA-N xaliproden Chemical compound FC(F)(F)C1=CC=CC(C=2CCN(CCC=3C=C4C=CC=CC4=CC=3)CC=2)=C1 WJJYZXPHLSLMGE-UHFFFAOYSA-N 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- KDGDTPNBDMVKHC-XIAWMOHYSA-N (1ar,7bs)-5-[[[(2s,3s,6s)-6-ethyl-2-phenylpiperidin-3-yl]amino]methyl]-6-methoxy-3-methyl-1a,7b-dihydro-1h-cyclopropa[c]quinolin-2-one Chemical compound C1([C@H]2[C@@H](NCC=3C(=CC=4[C@H]5C[C@H]5C(=O)N(C)C=4C=3)OC)CC[C@@H](N2)CC)=CC=CC=C1 KDGDTPNBDMVKHC-XIAWMOHYSA-N 0.000 description 1
- OELFLUMRDSZNSF-OFLPRAFFSA-N (2R)-2-[[oxo-(4-propan-2-ylcyclohexyl)methyl]amino]-3-phenylpropanoic acid Chemical compound C1CC(C(C)C)CCC1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-OFLPRAFFSA-N 0.000 description 1
- CBQGYUDMJHNJBX-OALUTQOASA-N (2S)-2-[(S)-(2-ethoxyphenoxy)-phenylmethyl]morpholine Chemical compound CCOC1=CC=CC=C1O[C@@H](C=1C=CC=CC=1)[C@H]1OCCNC1 CBQGYUDMJHNJBX-OALUTQOASA-N 0.000 description 1
- VLPIATFUUWWMKC-SNVBAGLBSA-N (2r)-1-(2,6-dimethylphenoxy)propan-2-amine Chemical compound C[C@@H](N)COC1=C(C)C=CC=C1C VLPIATFUUWWMKC-SNVBAGLBSA-N 0.000 description 1
- RJMIEHBSYVWVIN-LLVKDONJSA-N (2r)-2-[4-(3-oxo-1h-isoindol-2-yl)phenyl]propanoic acid Chemical compound C1=CC([C@H](C(O)=O)C)=CC=C1N1C(=O)C2=CC=CC=C2C1 RJMIEHBSYVWVIN-LLVKDONJSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical compound OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- VHKVKWTWHZUFIA-DGOKBZBKSA-N (2s)-1-phenylpropan-2-amine;(2s,3s,4s,5r)-2,3,4,5-tetrahydroxyhexanedioic acid Chemical compound C[C@H](N)CC1=CC=CC=C1.OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O VHKVKWTWHZUFIA-DGOKBZBKSA-N 0.000 description 1
- RDJGLLICXDHJDY-NSHDSACASA-N (2s)-2-(3-phenoxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](C)C1=CC=CC(OC=2C=CC=CC=2)=C1 RDJGLLICXDHJDY-NSHDSACASA-N 0.000 description 1
- GUHPRPJDBZHYCJ-SECBINFHSA-N (2s)-2-(5-benzoylthiophen-2-yl)propanoic acid Chemical compound S1C([C@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CC=C1 GUHPRPJDBZHYCJ-SECBINFHSA-N 0.000 description 1
- MDKGKXOCJGEUJW-VIFPVBQESA-N (2s)-2-[4-(thiophene-2-carbonyl)phenyl]propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C(=O)C1=CC=CS1 MDKGKXOCJGEUJW-VIFPVBQESA-N 0.000 description 1
- XMQUEQJCYRFIQS-YFKPBYRVSA-N (2s)-2-amino-5-ethoxy-5-oxopentanoic acid Chemical compound CCOC(=O)CC[C@H](N)C(O)=O XMQUEQJCYRFIQS-YFKPBYRVSA-N 0.000 description 1
- BIDNLKIUORFRQP-XYGFDPSESA-N (2s,4s)-4-cyclohexyl-1-[2-[[(1s)-2-methyl-1-propanoyloxypropoxy]-(4-phenylbutyl)phosphoryl]acetyl]pyrrolidine-2-carboxylic acid Chemical compound C([P@@](=O)(O[C@H](OC(=O)CC)C(C)C)CC(=O)N1[C@@H](C[C@H](C1)C1CCCCC1)C(O)=O)CCCC1=CC=CC=C1 BIDNLKIUORFRQP-XYGFDPSESA-N 0.000 description 1
- OQANPHBRHBJGNZ-FYJGNVAPSA-N (3e)-6-oxo-3-[[4-(pyridin-2-ylsulfamoyl)phenyl]hydrazinylidene]cyclohexa-1,4-diene-1-carboxylic acid Chemical compound C1=CC(=O)C(C(=O)O)=C\C1=N\NC1=CC=C(S(=O)(=O)NC=2N=CC=CC=2)C=C1 OQANPHBRHBJGNZ-FYJGNVAPSA-N 0.000 description 1
- LVGMMVAWLISWJD-MRVPVSSYSA-N (3r)-1-pyridin-3-ylpyrrolidin-3-amine Chemical compound C1[C@H](N)CCN1C1=CC=CN=C1 LVGMMVAWLISWJD-MRVPVSSYSA-N 0.000 description 1
- YMVFJGSXZNNUDW-UHFFFAOYSA-N (4-chlorophenyl)methanamine Chemical compound NCC1=CC=C(Cl)C=C1 YMVFJGSXZNNUDW-UHFFFAOYSA-N 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
- 239000001211 (E)-4-phenylbut-3-en-2-one Substances 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- RTHCYVBBDHJXIQ-MRXNPFEDSA-N (R)-fluoxetine Chemical compound O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=C(C(F)(F)F)C=C1 RTHCYVBBDHJXIQ-MRXNPFEDSA-N 0.000 description 1
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 description 1
- PYHRZPFZZDCOPH-QXGOIDDHSA-N (S)-amphetamine sulfate Chemical compound [H+].[H+].[O-]S([O-])(=O)=O.C[C@H](N)CC1=CC=CC=C1.C[C@H](N)CC1=CC=CC=C1 PYHRZPFZZDCOPH-QXGOIDDHSA-N 0.000 description 1
- RKUNBYITZUJHSG-FXUDXRNXSA-N (S)-atropine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@H]3CC[C@@H](C2)N3C)=CC=CC=C1 RKUNBYITZUJHSG-FXUDXRNXSA-N 0.000 description 1
- NWIUTZDMDHAVTP-KRWDZBQOSA-N (S)-betaxolol Chemical compound C1=CC(OC[C@@H](O)CNC(C)C)=CC=C1CCOCC1CC1 NWIUTZDMDHAVTP-KRWDZBQOSA-N 0.000 description 1
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 description 1
- QBWLKDFBINPHFT-UHFFFAOYSA-L 1,3,2$l^{2}-benzodioxabismin-4-one;hydrate Chemical compound O.C1=CC=C2C(=O)O[Bi]OC2=C1 QBWLKDFBINPHFT-UHFFFAOYSA-L 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- 125000003363 1,3,5-triazinyl group Chemical group N1=C(N=CN=C1)* 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 0.000 description 1
- HJPRDDKCXVCFOH-UHFFFAOYSA-N 1,3-dibutyl-7-(2-oxopropyl)purine-2,6-dione Chemical compound O=C1N(CCCC)C(=O)N(CCCC)C2=C1N(CC(C)=O)C=N2 HJPRDDKCXVCFOH-UHFFFAOYSA-N 0.000 description 1
- AICIYIDUYNFPRY-UHFFFAOYSA-N 1,3-dihydro-2H-imidazol-2-one Chemical compound O=C1NC=CN1 AICIYIDUYNFPRY-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- VCPMZDWBEWTGNW-UHFFFAOYSA-N 1-(4-benzhydrylpiperazin-1-yl)-3,3-diphenylpropan-1-one Chemical compound C1CN(C(C=2C=CC=CC=2)C=2C=CC=CC=2)CCN1C(=O)CC(C=1C=CC=CC=1)C1=CC=CC=C1 VCPMZDWBEWTGNW-UHFFFAOYSA-N 0.000 description 1
- KQNBRMUBPRGXSL-UHFFFAOYSA-N 1-(bromomethyl)-4-chlorobenzene Chemical compound ClC1=CC=C(CBr)C=C1 KQNBRMUBPRGXSL-UHFFFAOYSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- YJUFGFXVASPYFQ-UHFFFAOYSA-N 2,3-dihydro-1-benzothiophene Chemical compound C1=CC=C2SCCC2=C1 YJUFGFXVASPYFQ-UHFFFAOYSA-N 0.000 description 1
- WXTMDXOMEHJXQO-UHFFFAOYSA-N 2,5-dihydroxybenzoic acid Chemical compound OC(=O)C1=CC(O)=CC=C1O WXTMDXOMEHJXQO-UHFFFAOYSA-N 0.000 description 1
- KLIVRBFRQSOGQI-UHFFFAOYSA-N 2-(11-oxo-6h-benzo[c][1]benzothiepin-3-yl)acetic acid Chemical compound S1CC2=CC=CC=C2C(=O)C2=CC=C(CC(=O)O)C=C12 KLIVRBFRQSOGQI-UHFFFAOYSA-N 0.000 description 1
- JHVHEDNLONERHY-UHFFFAOYSA-N 2-(2-chloro-5-methylsulfanylphenyl)-1-methyl-1-(3-methylsulfanylphenyl)guanidine Chemical compound CSC1=CC=CC(N(C)C(N)=NC=2C(=CC=C(SC)C=2)Cl)=C1 JHVHEDNLONERHY-UHFFFAOYSA-N 0.000 description 1
- MYQXHLQMZLTSDB-UHFFFAOYSA-N 2-(2-ethyl-2,3-dihydro-1-benzofuran-5-yl)acetic acid Chemical compound OC(=O)CC1=CC=C2OC(CC)CC2=C1 MYQXHLQMZLTSDB-UHFFFAOYSA-N 0.000 description 1
- UJSZNPKZSFYPBL-UHFFFAOYSA-N 2-(2-oxopropyl)cycloheptan-1-one Chemical compound CC(=O)CC1CCCCCC1=O UJSZNPKZSFYPBL-UHFFFAOYSA-N 0.000 description 1
- YNZFFALZMRAPHQ-SYYKKAFVSA-N 2-[(1r,2r,5r)-5-hydroxy-2-(3-hydroxypropyl)cyclohexyl]-5-(2-methyloctan-2-yl)phenol Chemical compound OC1=CC(C(C)(C)CCCCCC)=CC=C1[C@H]1[C@H](CCCO)CC[C@@H](O)C1 YNZFFALZMRAPHQ-SYYKKAFVSA-N 0.000 description 1
- KRQUFUKTQHISJB-YYADALCUSA-N 2-[(E)-N-[2-(4-chlorophenoxy)propoxy]-C-propylcarbonimidoyl]-3-hydroxy-5-(thian-3-yl)cyclohex-2-en-1-one Chemical compound CCC\C(=N/OCC(C)OC1=CC=C(Cl)C=C1)C1=C(O)CC(CC1=O)C1CCCSC1 KRQUFUKTQHISJB-YYADALCUSA-N 0.000 description 1
- DCXHLPGLBYHNMU-UHFFFAOYSA-N 2-[1-(4-azidobenzoyl)-5-methoxy-2-methylindol-3-yl]acetic acid Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(N=[N+]=[N-])C=C1 DCXHLPGLBYHNMU-UHFFFAOYSA-N 0.000 description 1
- FZXHGKCGHKXDNK-UHFFFAOYSA-N 2-[1-[(2,4-dichlorophenyl)methyl]-2,5-dimethylpyrrol-3-yl]-n-(2-methoxypyridin-4-yl)-2-oxoacetamide Chemical compound C1=NC(OC)=CC(NC(=O)C(=O)C2=C(N(CC=3C(=CC(Cl)=CC=3)Cl)C(C)=C2)C)=C1 FZXHGKCGHKXDNK-UHFFFAOYSA-N 0.000 description 1
- VEIQAYXYJZLWJP-UHFFFAOYSA-N 2-[1-[(4-chlorophenyl)methyl]-2,5,5-trimethyl-6,7-dihydro-4h-indol-3-yl]-n-(2-methoxypyridin-4-yl)-2-oxoacetamide Chemical compound C1=NC(OC)=CC(NC(=O)C(=O)C=2C=3CC(C)(C)CCC=3N(CC=3C=CC(Cl)=CC=3)C=2C)=C1 VEIQAYXYJZLWJP-UHFFFAOYSA-N 0.000 description 1
- HLKIWHMRRSLUES-UHFFFAOYSA-N 2-[1-[(4-chlorophenyl)methyl]-2,5-dimethyl-4-phenylpyrrol-3-yl]-n-(2-methoxypyridin-4-yl)-2-oxoacetamide Chemical compound C1=NC(OC)=CC(NC(=O)C(=O)C=2C(=C(C)N(CC=3C=CC(Cl)=CC=3)C=2C)C=2C=CC=CC=2)=C1 HLKIWHMRRSLUES-UHFFFAOYSA-N 0.000 description 1
- DUVOXTRXMBJHGW-UHFFFAOYSA-N 2-[1-[(4-chlorophenyl)methyl]-2,5-dimethylpyrrol-3-yl]-2-oxo-n-pyridin-4-ylacetamide Chemical compound CC=1N(CC=2C=CC(Cl)=CC=2)C(C)=CC=1C(=O)C(=O)NC1=CC=NC=C1 DUVOXTRXMBJHGW-UHFFFAOYSA-N 0.000 description 1
- FYVLKUMHNORNQA-UHFFFAOYSA-N 2-[1-[(4-chlorophenyl)methyl]-2,5-dimethylpyrrol-3-yl]-n-(2-methoxypyridin-4-yl)-2-oxoacetamide Chemical compound C1=NC(OC)=CC(NC(=O)C(=O)C2=C(N(CC=3C=CC(Cl)=CC=3)C(C)=C2)C)=C1 FYVLKUMHNORNQA-UHFFFAOYSA-N 0.000 description 1
- FPHGZBXZIMYKCP-UHFFFAOYSA-N 2-[1-[(4-chlorophenyl)methyl]-2-methyl-5-phenylpyrrol-3-yl]-n-(2-methoxypyridin-4-yl)-2-oxoacetamide Chemical compound C1=NC(OC)=CC(NC(=O)C(=O)C2=C(N(CC=3C=CC(Cl)=CC=3)C(C=3C=CC=CC=3)=C2)C)=C1 FPHGZBXZIMYKCP-UHFFFAOYSA-N 0.000 description 1
- NZHTUGLIEWGYPX-UHFFFAOYSA-N 2-[1-[(4-fluorophenyl)methyl]-2,5-dimethylpyrrol-3-yl]-n-(2-methoxypyridin-4-yl)-2-oxoacetamide Chemical compound C1=NC(OC)=CC(NC(=O)C(=O)C2=C(N(CC=3C=CC(F)=CC=3)C(C)=C2)C)=C1 NZHTUGLIEWGYPX-UHFFFAOYSA-N 0.000 description 1
- RVKBNASTZRSVRS-UHFFFAOYSA-N 2-[1-[(4-methoxyphenyl)methyl]-2,5-dimethylpyrrol-3-yl]-n-(2-methoxypyridin-4-yl)-2-oxoacetamide Chemical compound C1=CC(OC)=CC=C1CN1C(C)=C(C(=O)C(=O)NC=2C=C(OC)N=CC=2)C=C1C RVKBNASTZRSVRS-UHFFFAOYSA-N 0.000 description 1
- APBSKHYXXKHJFK-UHFFFAOYSA-N 2-[2-(4-chlorophenyl)-1,3-thiazol-4-yl]acetic acid Chemical compound OC(=O)CC1=CSC(C=2C=CC(Cl)=CC=2)=N1 APBSKHYXXKHJFK-UHFFFAOYSA-N 0.000 description 1
- ZKLPARSLTMPFCP-OAQYLSRUSA-N 2-[2-[4-[(R)-(4-chlorophenyl)-phenylmethyl]-1-piperazinyl]ethoxy]acetic acid Chemical compound C1CN(CCOCC(=O)O)CCN1[C@@H](C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-OAQYLSRUSA-N 0.000 description 1
- OUEKLNJUMVZULZ-UHFFFAOYSA-N 2-[4-(2-aminoethoxy)-3-methoxyphenyl]-n-[3-(3,4-dimethylphenyl)propyl]acetamide;hydron;chloride Chemical compound Cl.C1=C(OCCN)C(OC)=CC(CC(=O)NCCCC=2C=C(C)C(C)=CC=2)=C1 OUEKLNJUMVZULZ-UHFFFAOYSA-N 0.000 description 1
- JIEKMACRVQTPRC-UHFFFAOYSA-N 2-[4-(4-chlorophenyl)-2-phenyl-5-thiazolyl]acetic acid Chemical compound OC(=O)CC=1SC(C=2C=CC=CC=2)=NC=1C1=CC=C(Cl)C=C1 JIEKMACRVQTPRC-UHFFFAOYSA-N 0.000 description 1
- WLURMFFKHVMPGQ-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-5-methylthieno[3,2-b]pyrrol-6-yl]-n-(2-methoxypyridin-4-yl)-2-oxoacetamide Chemical compound C1=NC(OC)=CC(NC(=O)C(=O)C=2C=3SC=CC=3N(CC=3C=CC(Cl)=CC=3)C=2C)=C1 WLURMFFKHVMPGQ-UHFFFAOYSA-N 0.000 description 1
- VXYDHPDQMSVQCU-UHFFFAOYSA-N 2-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)piperidin-1-yl]-n-hydroxyacetamide Chemical compound COC1=CC=C(C2(CCN(CC(=O)NO)CC2)C#N)C=C1OC1CCCC1 VXYDHPDQMSVQCU-UHFFFAOYSA-N 0.000 description 1
- WGDADRBTCPGSDG-UHFFFAOYSA-N 2-[[4,5-bis(4-chlorophenyl)-1,3-oxazol-2-yl]sulfanyl]propanoic acid Chemical compound O1C(SC(C)C(O)=O)=NC(C=2C=CC(Cl)=CC=2)=C1C1=CC=C(Cl)C=C1 WGDADRBTCPGSDG-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-IVMDWMLBSA-N 2-amino-2-deoxy-D-glucopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O MSWZFWKMSRAUBD-IVMDWMLBSA-N 0.000 description 1
- SPCKHVPPRJWQRZ-UHFFFAOYSA-N 2-benzhydryloxy-n,n-dimethylethanamine;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 SPCKHVPPRJWQRZ-UHFFFAOYSA-N 0.000 description 1
- BFSVOASYOCHEOV-UHFFFAOYSA-N 2-diethylaminoethanol Chemical compound CCN(CC)CCO BFSVOASYOCHEOV-UHFFFAOYSA-N 0.000 description 1
- 229940013085 2-diethylaminoethanol Drugs 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
- ILYSAKHOYBPSPC-UHFFFAOYSA-N 2-phenylbenzoic acid Chemical class OC(=O)C1=CC=CC=C1C1=CC=CC=C1 ILYSAKHOYBPSPC-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 1
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- FSUYMKXZLQOFQY-UHFFFAOYSA-N 3,4-dihydro-1,2-benzodithiine Chemical compound C1=CC=C2SSCCC2=C1 FSUYMKXZLQOFQY-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- XKFMBGWHHBCWCD-QMMMGPOBSA-N 3-[[(2s)-azetidin-2-yl]methoxy]pyridine Chemical compound C([C@H]1NCC1)OC1=CC=CN=C1 XKFMBGWHHBCWCD-QMMMGPOBSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 description 1
- JKHPOPCIKQQRPU-UHFFFAOYSA-N 3-chloro-2-(methoxymethoxy)prop-1-ene Chemical compound COCOC(=C)CCl JKHPOPCIKQQRPU-UHFFFAOYSA-N 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- RBIGKSZIQCTIJF-UHFFFAOYSA-N 3-formylthiophene Chemical compound O=CC=1C=CSC=1 RBIGKSZIQCTIJF-UHFFFAOYSA-N 0.000 description 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 description 1
- MWVTWFVJZLCBMC-UHFFFAOYSA-N 4,4'-bipyridine Chemical compound C1=NC=CC(C=2C=CN=CC=2)=C1 MWVTWFVJZLCBMC-UHFFFAOYSA-N 0.000 description 1
- UTUUPXBCDMQYRR-HSZRJFAPSA-N 4-[(2r)-2-(3-cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine Chemical compound COC1=CC=C([C@H](CC=2C=CN=CC=2)C=2C=CC=CC=2)C=C1OC1CCCC1 UTUUPXBCDMQYRR-HSZRJFAPSA-N 0.000 description 1
- YPELFRMCRYSPKZ-UHFFFAOYSA-N 4-amino-5-chloro-2-ethoxy-N-({4-[(4-fluorophenyl)methyl]morpholin-2-yl}methyl)benzamide Chemical compound CCOC1=CC(N)=C(Cl)C=C1C(=O)NCC1OCCN(CC=2C=CC(F)=CC=2)C1 YPELFRMCRYSPKZ-UHFFFAOYSA-N 0.000 description 1
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 1
- SYCHUQUJURZQMO-UHFFFAOYSA-N 4-hydroxy-2-methyl-1,1-dioxo-n-(1,3-thiazol-2-yl)-1$l^{6},2-benzothiazine-3-carboxamide Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=CS1 SYCHUQUJURZQMO-UHFFFAOYSA-N 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 description 1
- GPXAWLDGWSBLKM-MWLCHTKSSA-N 5-[(1r,5s)-3,6-diazabicyclo[3.2.0]heptan-6-yl]pyridine-3-carbonitrile Chemical compound N#CC1=CN=CC(N2[C@@H]3CNC[C@@H]3C2)=C1 GPXAWLDGWSBLKM-MWLCHTKSSA-N 0.000 description 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- CWDWFSXUQODZGW-UHFFFAOYSA-N 5-thiazolyl Chemical group [C]1=CN=CS1 CWDWFSXUQODZGW-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 1
- XDBHURGONHZNJF-UHFFFAOYSA-N 6-[2-(3,4-diethoxyphenyl)-1,3-thiazol-4-yl]pyridine-2-carboxylic acid Chemical compound C1=C(OCC)C(OCC)=CC=C1C1=NC(C=2N=C(C=CC=2)C(O)=O)=CS1 XDBHURGONHZNJF-UHFFFAOYSA-N 0.000 description 1
- DHSSDEDRBUKTQY-UHFFFAOYSA-N 6-prop-2-enyl-4,5,7,8-tetrahydrothiazolo[4,5-d]azepin-2-amine Chemical compound C1CN(CC=C)CCC2=C1N=C(N)S2 DHSSDEDRBUKTQY-UHFFFAOYSA-N 0.000 description 1
- SEPXFZLYPWFMSY-UHFFFAOYSA-N 6h-thieno[2,3-b]pyrrole-5-carboxylic acid Chemical compound C1=CSC2=C1C=C(C(=O)O)N2 SEPXFZLYPWFMSY-UHFFFAOYSA-N 0.000 description 1
- ILOIOIGZFHGSMS-UHFFFAOYSA-N 7-phenyl-1-(5-pyridin-2-yl-1,3-oxazol-2-yl)heptan-1-one Chemical compound N=1C=C(C=2N=CC=CC=2)OC=1C(=O)CCCCCCC1=CC=CC=C1 ILOIOIGZFHGSMS-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- 206010063409 Acarodermatitis Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- UXOWGYHJODZGMF-QORCZRPOSA-N Aliskiren Chemical compound COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC UXOWGYHJODZGMF-QORCZRPOSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- XYLJNLCSTIOKRM-UHFFFAOYSA-N Alphagan Chemical compound C1=CC2=NC=CN=C2C(Br)=C1NC1=NCCN1 XYLJNLCSTIOKRM-UHFFFAOYSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 235000003911 Arachis Nutrition 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 206010003399 Arthropod bite Diseases 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 206010003497 Asphyxia Diseases 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 208000025978 Athletic injury Diseases 0.000 description 1
- 206010003791 Aura Diseases 0.000 description 1
- 208000037157 Azotemia Diseases 0.000 description 1
- KPYSYYIEGFHWSV-UHFFFAOYSA-N Baclofen Chemical compound OC(=O)CC(CN)C1=CC=C(Cl)C=C1 KPYSYYIEGFHWSV-UHFFFAOYSA-N 0.000 description 1
- XPCFTKFZXHTYIP-PMACEKPBSA-N Benazepril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C2=CC=CC=C2CC1)=O)CC1=CC=CC=C1 XPCFTKFZXHTYIP-PMACEKPBSA-N 0.000 description 1
- BWHOZHOGCMHOBV-UHFFFAOYSA-N Benzalacetone Natural products CC(=O)C=CC1=CC=CC=C1 BWHOZHOGCMHOBV-UHFFFAOYSA-N 0.000 description 1
- ZBJJDYGJCNTNTH-UHFFFAOYSA-N Betahistine mesilate Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.CNCCC1=CC=CC=N1 ZBJJDYGJCNTNTH-UHFFFAOYSA-N 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-N Betaine Natural products C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 description 1
- 206010005063 Bladder pain Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010065417 Brachial plexopathy Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 239000004358 Butane-1, 3-diol Substances 0.000 description 1
- 239000002083 C09CA01 - Losartan Substances 0.000 description 1
- 239000002080 C09CA02 - Eprosartan Substances 0.000 description 1
- 239000004072 C09CA03 - Valsartan Substances 0.000 description 1
- 239000002947 C09CA04 - Irbesartan Substances 0.000 description 1
- 239000002053 C09CA06 - Candesartan Substances 0.000 description 1
- 239000005537 C09CA07 - Telmisartan Substances 0.000 description 1
- 102000009132 CB1 Cannabinoid Receptor Human genes 0.000 description 1
- 108010073366 CB1 Cannabinoid Receptor Proteins 0.000 description 1
- 102000009135 CB2 Cannabinoid Receptor Human genes 0.000 description 1
- 108010073376 CB2 Cannabinoid Receptor Proteins 0.000 description 1
- KORNTPPJEAJQIU-KJXAQDMKSA-N Cabaser Chemical compound C1=CC([C@H]2C[C@H](CN(CC=C)[C@@H]2C2)C(=O)N(CCCN(C)C)C(=O)NCC)=C3C2=CNC3=C1 KORNTPPJEAJQIU-KJXAQDMKSA-N 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 208000009132 Catalepsy Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 208000035484 Cellulite Diseases 0.000 description 1
- 206010064012 Central pain syndrome Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- ZKLPARSLTMPFCP-UHFFFAOYSA-N Cetirizine Chemical compound C1CN(CCOCC(=O)O)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZKLPARSLTMPFCP-UHFFFAOYSA-N 0.000 description 1
- 206010008631 Cholera Diseases 0.000 description 1
- OIRAEJWYWSAQNG-UHFFFAOYSA-N Clidanac Chemical compound ClC=1C=C2C(C(=O)O)CCC2=CC=1C1CCCCC1 OIRAEJWYWSAQNG-UHFFFAOYSA-N 0.000 description 1
- GDLIGKIOYRNHDA-UHFFFAOYSA-N Clomipramine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCN(C)C)C2=CC=CC=C21 GDLIGKIOYRNHDA-UHFFFAOYSA-N 0.000 description 1
- 208000006561 Cluster Headache Diseases 0.000 description 1
- ACTIUHUUMQJHFO-UHFFFAOYSA-N Coenzym Q10 Natural products COC1=C(OC)C(=O)C(CC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UHFFFAOYSA-N 0.000 description 1
- 101001008801 Conus marmoreus Mu-conotoxin MrVIB Proteins 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- 206010012468 Dermatitis herpetiformis Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 102000015554 Dopamine receptor Human genes 0.000 description 1
- 108050004812 Dopamine receptor Proteins 0.000 description 1
- CYQFCXCEBYINGO-DLBZAZTESA-N Dronabinol Natural products C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@H]21 CYQFCXCEBYINGO-DLBZAZTESA-N 0.000 description 1
- 206010013786 Dry skin Diseases 0.000 description 1
- 108010061435 Enalapril Proteins 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 1
- RBBWCVQDXDFISW-UHFFFAOYSA-N Feprazone Chemical compound O=C1C(CC=C(C)C)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 RBBWCVQDXDFISW-UHFFFAOYSA-N 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- 208000004262 Food Hypersensitivity Diseases 0.000 description 1
- 206010016946 Food allergy Diseases 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 206010064147 Gastrointestinal inflammation Diseases 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- 108010072051 Glatiramer Acetate Proteins 0.000 description 1
- 208000021965 Glossopharyngeal Nerve disease Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 206010018634 Gouty Arthritis Diseases 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010019133 Hangover Diseases 0.000 description 1
- 208000003698 Heroin Dependence Diseases 0.000 description 1
- 206010019973 Herpes virus infection Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- RKUNBYITZUJHSG-UHFFFAOYSA-N Hyosciamin-hydrochlorid Natural products CN1C(C2)CCC1CC2OC(=O)C(CO)C1=CC=CC=C1 RKUNBYITZUJHSG-UHFFFAOYSA-N 0.000 description 1
- 206010020850 Hyperthyroidism Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- ZJVFLBOZORBYFE-UHFFFAOYSA-N Ibudilast Chemical compound C1=CC=CC2=C(C(=O)C(C)C)C(C(C)C)=NN21 ZJVFLBOZORBYFE-UHFFFAOYSA-N 0.000 description 1
- 206010021333 Ileus paralytic Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 238000012695 Interfacial polymerization Methods 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 201000005081 Intestinal Pseudo-Obstruction Diseases 0.000 description 1
- 206010022971 Iron Deficiencies Diseases 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 1
- BHBOSTKQCZEAJM-UHFFFAOYSA-N JNJ-1661010 Chemical compound C1CN(C=2SN=C(N=2)C=2C=CC=CC=2)CCN1C(=O)NC1=CC=CC=C1 BHBOSTKQCZEAJM-UHFFFAOYSA-N 0.000 description 1
- UETNIIAIRMUTSM-UHFFFAOYSA-N Jacareubin Natural products CC1(C)OC2=CC3Oc4c(O)c(O)ccc4C(=O)C3C(=C2C=C1)O UETNIIAIRMUTSM-UHFFFAOYSA-N 0.000 description 1
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 1
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 1
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 1
- 206010024453 Ligament sprain Diseases 0.000 description 1
- 108010007859 Lisinopril Proteins 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 239000004907 Macro-emulsion Substances 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 241000422980 Marietta Species 0.000 description 1
- SBDNJUWAMKYJOX-UHFFFAOYSA-N Meclofenamic Acid Chemical compound CC1=CC=C(Cl)C(NC=2C(=CC=CC=2)C(O)=O)=C1Cl SBDNJUWAMKYJOX-UHFFFAOYSA-N 0.000 description 1
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Meloxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 244000097724 Mesua ferrea Species 0.000 description 1
- 235000010931 Mesua ferrea Nutrition 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- FQISKWAFAHGMGT-SGJOWKDISA-M Methylprednisolone sodium succinate Chemical compound [Na+].C([C@@]12C)=CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)[C@@](O)(C(=O)COC(=O)CCC([O-])=O)CC[C@H]21 FQISKWAFAHGMGT-SGJOWKDISA-M 0.000 description 1
- 241001448624 Miliaria Species 0.000 description 1
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 1
- UCHDWCPVSPXUMX-TZIWLTJVSA-N Montelukast Chemical compound CC(C)(O)C1=CC=CC=C1CC[C@H](C=1C=C(\C=C\C=2N=C3C=C(Cl)C=CC3=CC=2)C=CC=1)SCC1(CC(O)=O)CC1 UCHDWCPVSPXUMX-TZIWLTJVSA-N 0.000 description 1
- 206010061296 Motor dysfunction Diseases 0.000 description 1
- 206010028116 Mucosal inflammation Diseases 0.000 description 1
- 201000010927 Mucositis Diseases 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 201000002481 Myositis Diseases 0.000 description 1
- HSHXDCVZWHOWCS-UHFFFAOYSA-N N'-hexadecylthiophene-2-carbohydrazide Chemical compound CCCCCCCCCCCCCCCCNNC(=O)c1cccs1 HSHXDCVZWHOWCS-UHFFFAOYSA-N 0.000 description 1
- KWIUHFFTVRNATP-UHFFFAOYSA-O N,N,N-trimethylglycinium Chemical compound C[N+](C)(C)CC(O)=O KWIUHFFTVRNATP-UHFFFAOYSA-O 0.000 description 1
- IJHNSHDBIRRJRN-UHFFFAOYSA-N N,N-dimethyl-3-phenyl-3-(2-pyridinyl)-1-propanamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=CC=C1 IJHNSHDBIRRJRN-UHFFFAOYSA-N 0.000 description 1
- GZNIYOXWFCDBBJ-UHFFFAOYSA-N N,N-dimethyl-5-[(4-phenylphenyl)methyl]-1-tetrazolecarboxamide Chemical compound CN(C)C(=O)N1N=NN=C1CC1=CC=C(C=2C=CC=CC=2)C=C1 GZNIYOXWFCDBBJ-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- QQQIECGTIMUVDS-UHFFFAOYSA-N N-[[4-[2-(dimethylamino)ethoxy]phenyl]methyl]-3,4-dimethoxybenzamide Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)NCC1=CC=C(OCCN(C)C)C=C1 QQQIECGTIMUVDS-UHFFFAOYSA-N 0.000 description 1
- 150000007945 N-acyl ureas Chemical class 0.000 description 1
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 description 1
- HTLZVHNRZJPSMI-UHFFFAOYSA-N N-ethylpiperidine Chemical compound CCN1CCCCC1 HTLZVHNRZJPSMI-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229940124635 NMED-160 Drugs 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- OJNSNSZTGUACNI-IBFUIWIBSA-N N[C@H](CC(O)=O)C(O)=O.CC(N)CC1=CC=CC=C1.CC(N)CC1=CC=CC=C1 Chemical compound N[C@H](CC(O)=O)C(O)=O.CC(N)CC1=CC=CC=C1.CC(N)CC1=CC=CC=C1 OJNSNSZTGUACNI-IBFUIWIBSA-N 0.000 description 1
- WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 description 1
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 description 1
- 206010029174 Nerve compression Diseases 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 208000001738 Nervous System Trauma Diseases 0.000 description 1
- 208000005890 Neuroma Diseases 0.000 description 1
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 206010062501 Non-cardiac chest pain Diseases 0.000 description 1
- 239000006057 Non-nutritive feed additive Substances 0.000 description 1
- 239000008913 Normacol Substances 0.000 description 1
- 206010068106 Occipital neuralgia Diseases 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000005480 Olmesartan Substances 0.000 description 1
- 235000005704 Olneya tesota Nutrition 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- HBMSIPLIFIVUKZ-UHFFFAOYSA-N Palmitinsaeure-propylamid Natural products CCCCCCCCCCCCCCCC(=O)NCCC HBMSIPLIFIVUKZ-UHFFFAOYSA-N 0.000 description 1
- 241000282577 Pan troglodytes Species 0.000 description 1
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 208000000450 Pelvic Pain Diseases 0.000 description 1
- BYPFEZZEUUWMEJ-UHFFFAOYSA-N Pentoxifylline Chemical compound O=C1N(CCCCC(=O)C)C(=O)N(C)C2=C1N(C)C=N2 BYPFEZZEUUWMEJ-UHFFFAOYSA-N 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- BDABGOLMYNHHTR-UHFFFAOYSA-N Perzinfotel Chemical compound OP(O)(=O)CCN1CCCNC2=C1C(=O)C2=O BDABGOLMYNHHTR-UHFFFAOYSA-N 0.000 description 1
- 208000004983 Phantom Limb Diseases 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002732 Polyanhydride Polymers 0.000 description 1
- 229920002556 Polyethylene Glycol 300 Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 206010036105 Polyneuropathy Diseases 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 1
- 206010054048 Postoperative ileus Diseases 0.000 description 1
- TVQZAMVBTVNYLA-UHFFFAOYSA-N Pranoprofen Chemical compound C1=CC=C2CC3=CC(C(C(O)=O)C)=CC=C3OC2=N1 TVQZAMVBTVNYLA-UHFFFAOYSA-N 0.000 description 1
- 235000008198 Prosopis juliflora Nutrition 0.000 description 1
- 102100038280 Prostaglandin G/H synthase 2 Human genes 0.000 description 1
- 108050003267 Prostaglandin G/H synthase 2 Proteins 0.000 description 1
- 208000036741 Pruritus generalised Diseases 0.000 description 1
- 206010038419 Renal colic Diseases 0.000 description 1
- 206010038490 Renal pain Diseases 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 241000447727 Scabies Species 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 229940121991 Serotonin and norepinephrine reuptake inhibitor Drugs 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 208000004078 Snake Bites Diseases 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 208000003589 Spider Bites Diseases 0.000 description 1
- 206010041738 Sports injury Diseases 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 0.000 description 1
- 208000007107 Stomach Ulcer Diseases 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- QLYKJCMUNUWAGO-GAJHUEQPSA-N Taranabant Chemical compound N([C@@H](C)[C@@H](CC=1C=CC(Cl)=CC=1)C=1C=C(C=CC=1)C#N)C(=O)C(C)(C)OC1=CC=C(C(F)(F)F)C=N1 QLYKJCMUNUWAGO-GAJHUEQPSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 208000004760 Tenosynovitis Diseases 0.000 description 1
- 208000008548 Tension-Type Headache Diseases 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- DHCOPPHTVOXDKU-UHFFFAOYSA-N Tofimilast Chemical compound C1CN2C(C=3SC=CC=3)=NN=C2C2=C1C(CC)=NN2C1CCCC1 DHCOPPHTVOXDKU-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- UFLGIAIHIAPJJC-UHFFFAOYSA-N Tripelennamine Chemical compound C=1C=CC=NC=1N(CCN(C)C)CC1=CC=CC=C1 UFLGIAIHIAPJJC-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- ROFVXGGUISEHAM-UHFFFAOYSA-N URB597 Chemical compound NC(=O)C1=CC=CC(C=2C=C(OC(=O)NC3CCCCC3)C=CC=2)=C1 ROFVXGGUISEHAM-UHFFFAOYSA-N 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- 208000010285 Ventilator-Induced Lung Injury Diseases 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 208000003728 Vulvodynia Diseases 0.000 description 1
- 206010069055 Vulvovaginal pain Diseases 0.000 description 1
- HQVHOQAKMCMIIM-HXUWFJFHSA-N WIN 55212-2 Chemical compound C([C@@H]1COC=2C=CC=C3C(C(=O)C=4C5=CC=CC=C5C=CC=4)=C(N1C3=2)C)N1CCOCC1 HQVHOQAKMCMIIM-HXUWFJFHSA-N 0.000 description 1
- 206010047853 Waxy flexibility Diseases 0.000 description 1
- BLGXFZZNTVWLAY-CCZXDCJGSA-N Yohimbine Natural products C1=CC=C2C(CCN3C[C@@H]4CC[C@@H](O)[C@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-CCZXDCJGSA-N 0.000 description 1
- YEEZWCHGZNKEEK-UHFFFAOYSA-N Zafirlukast Chemical compound COC1=CC(C(=O)NS(=O)(=O)C=2C(=CC=CC=2)C)=CC=C1CC(C1=C2)=CN(C)C1=CC=C2NC(=O)OC1CCCC1 YEEZWCHGZNKEEK-UHFFFAOYSA-N 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 1
- YPFLFUJKZDAXRA-UHFFFAOYSA-N [3-(carbamoylamino)-2-(2,4-dichlorobenzoyl)-1-benzofuran-6-yl] methanesulfonate Chemical compound O1C2=CC(OS(=O)(=O)C)=CC=C2C(NC(N)=O)=C1C(=O)C1=CC=C(Cl)C=C1Cl YPFLFUJKZDAXRA-UHFFFAOYSA-N 0.000 description 1
- YKKPYMXANSSQCA-UHFFFAOYSA-N [3-[4-(aminomethyl)-6-(trifluoromethyl)pyridin-2-yl]oxyphenyl]-(3-pyrazol-1-ylazetidin-1-yl)methanone Chemical compound N1(N=CC=C1)C1CN(C1)C(=O)C1=CC(=CC=C1)OC1=NC(=CC(=C1)CN)C(F)(F)F YKKPYMXANSSQCA-UHFFFAOYSA-N 0.000 description 1
- SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 229940124532 absorption promoter Drugs 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- AFCGFAGUEYAMAO-UHFFFAOYSA-N acamprosate Chemical compound CC(=O)NCCCS(O)(=O)=O AFCGFAGUEYAMAO-UHFFFAOYSA-N 0.000 description 1
- 229960004047 acamprosate Drugs 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000035508 accumulation Effects 0.000 description 1
- 229960004892 acemetacin Drugs 0.000 description 1
- FSQKKOOTNAMONP-UHFFFAOYSA-N acemetacin Chemical compound CC1=C(CC(=O)OCC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 FSQKKOOTNAMONP-UHFFFAOYSA-N 0.000 description 1
- 229960000571 acetazolamide Drugs 0.000 description 1
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 208000017733 acquired polycythemia vera Diseases 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 229960005142 alclofenac Drugs 0.000 description 1
- ARHWPKZXBHOEEE-UHFFFAOYSA-N alclofenac Chemical compound OC(=O)CC1=CC=C(OCC=C)C(Cl)=C1 ARHWPKZXBHOEEE-UHFFFAOYSA-N 0.000 description 1
- 125000003158 alcohol group Chemical group 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 229960003790 alimemazine Drugs 0.000 description 1
- 229960004601 aliskiren Drugs 0.000 description 1
- 125000005083 alkoxyalkoxy group Chemical group 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 125000005157 alkyl carboxy group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 229960004663 alminoprofen Drugs 0.000 description 1
- FPHLBGOJWPEVME-UHFFFAOYSA-N alminoprofen Chemical compound OC(=O)C(C)C1=CC=C(NCC(C)=C)C=C1 FPHLBGOJWPEVME-UHFFFAOYSA-N 0.000 description 1
- 229960003550 alosetron Drugs 0.000 description 1
- FLZQKRKHLSUHOR-UHFFFAOYSA-N alosetron Chemical compound CC1=NC=N[C]1CN1C(=O)C(C=2C(=CC=CC=2)N2C)=C2CC1 FLZQKRKHLSUHOR-UHFFFAOYSA-N 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 229940000806 amaryl Drugs 0.000 description 1
- JBDGDEWWOUBZPM-XYPYZODXSA-N ambroxol Chemical compound NC1=C(Br)C=C(Br)C=C1CN[C@@H]1CC[C@@H](O)CC1 JBDGDEWWOUBZPM-XYPYZODXSA-N 0.000 description 1
- 229960005174 ambroxol Drugs 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- ONNOFKFOZAJDHT-UHFFFAOYSA-N amineptine Chemical compound C1CC2=CC=CC=C2C(NCCCCCCC(=O)O)C2=CC=CC=C21 ONNOFKFOZAJDHT-UHFFFAOYSA-N 0.000 description 1
- 229960000959 amineptine Drugs 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000005021 aminoalkenyl group Chemical group 0.000 description 1
- 229940040386 amitiza Drugs 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 229940052327 amphetamine aspartate Drugs 0.000 description 1
- PYHRZPFZZDCOPH-UHFFFAOYSA-N amphetamine sulfate Chemical compound OS(O)(=O)=O.CC(N)CC1=CC=CC=C1.CC(N)CC1=CC=CC=C1 PYHRZPFZZDCOPH-UHFFFAOYSA-N 0.000 description 1
- 229940008238 amphetamine sulfate Drugs 0.000 description 1
- 238000002266 amputation Methods 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 229940051880 analgesics and antipyretics pyrazolones Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 229960002469 antazoline Drugs 0.000 description 1
- REYFJDPCWQRWAA-UHFFFAOYSA-N antazoline Chemical compound N=1CCNC=1CN(C=1C=CC=CC=1)CC1=CC=CC=C1 REYFJDPCWQRWAA-UHFFFAOYSA-N 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 230000002424 anti-apoptotic effect Effects 0.000 description 1
- 230000001142 anti-diarrhea Effects 0.000 description 1
- 230000001910 anti-glutamatergic effect Effects 0.000 description 1
- 239000003911 antiadherent Substances 0.000 description 1
- 229940065524 anticholinergics inhalants for obstructive airway diseases Drugs 0.000 description 1
- 229940124572 antihypotensive agent Drugs 0.000 description 1
- 229940111133 antiinflammatory and antirheumatic drug oxicams Drugs 0.000 description 1
- 229940111131 antiinflammatory and antirheumatic product propionic acid derivative Drugs 0.000 description 1
- 229940027983 antiseptic and disinfectant quaternary ammonium compound Drugs 0.000 description 1
- 229960002610 apraclonidine Drugs 0.000 description 1
- IEJXVRYNEISIKR-UHFFFAOYSA-N apraclonidine Chemical compound ClC1=CC(N)=CC(Cl)=C1NC1=NCCN1 IEJXVRYNEISIKR-UHFFFAOYSA-N 0.000 description 1
- IMOZEMNVLZVGJZ-QGZVFWFLSA-N apremilast Chemical compound C1=C(OC)C(OCC)=CC([C@@H](CS(C)(=O)=O)N2C(C3=C(NC(C)=O)C=CC=C3C2=O)=O)=C1 IMOZEMNVLZVGJZ-QGZVFWFLSA-N 0.000 description 1
- GVTLDPJNRVMCAL-UHFFFAOYSA-N arofylline Chemical compound C1=2N=CNC=2C(=O)N(CCC)C(=O)N1C1=CC=C(Cl)C=C1 GVTLDPJNRVMCAL-UHFFFAOYSA-N 0.000 description 1
- 229950009746 arofylline Drugs 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 229940072107 ascorbate Drugs 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- GXDALQBWZGODGZ-UHFFFAOYSA-N astemizole Chemical compound C1=CC(OC)=CC=C1CCN1CCC(NC=2N(C3=CC=CC=C3N=2)CC=2C=CC(F)=CC=2)CC1 GXDALQBWZGODGZ-UHFFFAOYSA-N 0.000 description 1
- LUCXVPAZUDVVBT-UNTBIKODSA-N atomoxetine hydrochloride Chemical compound Cl.O([C@H](CCNC)C=1C=CC=CC=1)C1=CC=CC=C1C LUCXVPAZUDVVBT-UNTBIKODSA-N 0.000 description 1
- 229960002828 atomoxetine hydrochloride Drugs 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- AAMATCKFMHVIDO-UHFFFAOYSA-N azane;1h-pyrrole Chemical compound N.C=1C=CNC=1 AAMATCKFMHVIDO-UHFFFAOYSA-N 0.000 description 1
- WOIIIUDZSOLAIW-NSHDSACASA-N azapropazone Chemical compound C1=C(C)C=C2N3C(=O)[C@H](CC=C)C(=O)N3C(N(C)C)=NC2=C1 WOIIIUDZSOLAIW-NSHDSACASA-N 0.000 description 1
- 229960001671 azapropazone Drugs 0.000 description 1
- 229960000383 azatadine Drugs 0.000 description 1
- SEBMTIQKRHYNIT-UHFFFAOYSA-N azatadine Chemical compound C1CN(C)CCC1=C1C2=NC=CC=C2CCC2=CC=CC=C21 SEBMTIQKRHYNIT-UHFFFAOYSA-N 0.000 description 1
- RNOAANRGEYCUQZ-UHFFFAOYSA-N azido acetate Chemical compound CC(=O)ON=[N+]=[N-] RNOAANRGEYCUQZ-UHFFFAOYSA-N 0.000 description 1
- UEQYFPCXXRUPKQ-UHFFFAOYSA-N azidoethene Chemical compound C=CN=[N+]=[N-] UEQYFPCXXRUPKQ-UHFFFAOYSA-N 0.000 description 1
- 229960000794 baclofen Drugs 0.000 description 1
- 230000006399 behavior Effects 0.000 description 1
- 229960004530 benazepril Drugs 0.000 description 1
- 229960005430 benoxaprofen Drugs 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical compound C=1C=CC=CC=1CNCCNCC1=CC=CC=C1 JUHORIMYRDESRB-UHFFFAOYSA-N 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229960001950 benzethonium chloride Drugs 0.000 description 1
- UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WGNZRLMOMHJUSP-UHFFFAOYSA-N benzotriazol-1-yloxy(tripyrrolidin-1-yl)phosphanium Chemical compound C1CCCN1[P+](N1CCCC1)(N1CCCC1)ON1C2=CC=CC=C2N=N1 WGNZRLMOMHJUSP-UHFFFAOYSA-N 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 125000006515 benzyloxy alkyl group Chemical group 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 229960003237 betaine Drugs 0.000 description 1
- 229960002537 betamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-DVTGEIKXSA-N betamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-DVTGEIKXSA-N 0.000 description 1
- NWIUTZDMDHAVTP-UHFFFAOYSA-N betaxolol Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1CCOCC1CC1 NWIUTZDMDHAVTP-UHFFFAOYSA-N 0.000 description 1
- 229960004324 betaxolol Drugs 0.000 description 1
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 229920000080 bile acid sequestrant Polymers 0.000 description 1
- 229940096699 bile acid sequestrants Drugs 0.000 description 1
- AQOKCDNYWBIDND-FTOWTWDKSA-N bimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 description 1
- 229960002470 bimatoprost Drugs 0.000 description 1
- 230000002715 bioenergetic effect Effects 0.000 description 1
- HUTDDBSSHVOYJR-UHFFFAOYSA-H bis[(2-oxo-1,3,2$l^{5},4$l^{2}-dioxaphosphaplumbetan-2-yl)oxy]lead Chemical compound [Pb+2].[Pb+2].[Pb+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O HUTDDBSSHVOYJR-UHFFFAOYSA-H 0.000 description 1
- 229960000782 bismuth subsalicylate Drugs 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 201000006431 brachial plexus neuropathy Diseases 0.000 description 1
- 229960003679 brimonidine Drugs 0.000 description 1
- HCRKCZRJWPKOAR-JTQLQIEISA-N brinzolamide Chemical compound CCN[C@H]1CN(CCCOC)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 HCRKCZRJWPKOAR-JTQLQIEISA-N 0.000 description 1
- 229960000722 brinzolamide Drugs 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- OZVBMTJYIDMWIL-AYFBDAFISA-N bromocriptine Chemical compound C1=CC(C=2[C@H](N(C)C[C@@H](C=2)C(=O)N[C@]2(C(=O)N3[C@H](C(N4CCC[C@H]4[C@]3(O)O2)=O)CC(C)C)C(C)C)C2)=C3C2=C(Br)NC3=C1 OZVBMTJYIDMWIL-AYFBDAFISA-N 0.000 description 1
- 229960002802 bromocriptine Drugs 0.000 description 1
- ZDIGNSYAACHWNL-UHFFFAOYSA-N brompheniramine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Br)C=C1 ZDIGNSYAACHWNL-UHFFFAOYSA-N 0.000 description 1
- 229960000725 brompheniramine Drugs 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000000168 bronchodilator agent Substances 0.000 description 1
- 229950005608 bucloxic acid Drugs 0.000 description 1
- IJTPQQVCKPZIMV-UHFFFAOYSA-N bucloxic acid Chemical compound ClC1=CC(C(=O)CCC(=O)O)=CC=C1C1CCCCC1 IJTPQQVCKPZIMV-UHFFFAOYSA-N 0.000 description 1
- 229960004436 budesonide Drugs 0.000 description 1
- 239000012512 bulk drug substance Substances 0.000 description 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N butyl alcohol Substances CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- 229960004596 cabergoline Drugs 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 229940062007 camphor / menthol Drugs 0.000 description 1
- 239000012830 cancer therapeutic Substances 0.000 description 1
- 229960000932 candesartan Drugs 0.000 description 1
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 description 1
- 235000017663 capsaicin Nutrition 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 125000004181 carboxyalkyl group Chemical group 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 208000003295 carpal tunnel syndrome Diseases 0.000 description 1
- 229960003184 carprofen Drugs 0.000 description 1
- IVUMCTKHWDRRMH-UHFFFAOYSA-N carprofen Chemical compound C1=CC(Cl)=C[C]2C3=CC=C(C(C(O)=O)C)C=C3N=C21 IVUMCTKHWDRRMH-UHFFFAOYSA-N 0.000 description 1
- 229960001222 carteolol Drugs 0.000 description 1
- LWAFSWPYPHEXKX-UHFFFAOYSA-N carteolol Chemical compound N1C(=O)CCC2=C1C=CC=C2OCC(O)CNC(C)(C)C LWAFSWPYPHEXKX-UHFFFAOYSA-N 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 230000036232 cellulite Effects 0.000 description 1
- 229940047525 cepastat Drugs 0.000 description 1
- 239000000919 ceramic Substances 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- 229940081733 cetearyl alcohol Drugs 0.000 description 1
- 229960001803 cetirizine Drugs 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- CFBUZOUXXHZCFB-OYOVHJISSA-N chembl511115 Chemical compound COC1=CC=C([C@@]2(CC[C@H](CC2)C(O)=O)C#N)C=C1OC1CCCC1 CFBUZOUXXHZCFB-OYOVHJISSA-N 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 229940099062 chloraseptic Drugs 0.000 description 1
- SOYKEARSMXGVTM-UHFFFAOYSA-N chlorphenamine Chemical compound C=1C=CC=NC=1C(CCN(C)C)C1=CC=C(Cl)C=C1 SOYKEARSMXGVTM-UHFFFAOYSA-N 0.000 description 1
- 229960003291 chlorphenamine Drugs 0.000 description 1
- 229960001761 chlorpropamide Drugs 0.000 description 1
- 201000001352 cholecystitis Diseases 0.000 description 1
- 230000001587 cholestatic effect Effects 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
- 229950001653 cilomilast Drugs 0.000 description 1
- 229960001380 cimetidine Drugs 0.000 description 1
- CCGSUNCLSOWKJO-UHFFFAOYSA-N cimetidine Chemical compound N#CNC(=N/C)\NCCSCC1=NC=N[C]1C CCGSUNCLSOWKJO-UHFFFAOYSA-N 0.000 description 1
- KSPYMJJKQMWWNB-UHFFFAOYSA-N cipamfylline Chemical compound O=C1N(CC2CC2)C(=O)C=2NC(N)=NC=2N1CC1CC1 KSPYMJJKQMWWNB-UHFFFAOYSA-N 0.000 description 1
- 229950002405 cipamfylline Drugs 0.000 description 1
- 229940001468 citrate Drugs 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229960002881 clemastine Drugs 0.000 description 1
- YNNUSGIPVFPVBX-NHCUHLMSSA-N clemastine Chemical compound CN1CCC[C@@H]1CCO[C@@](C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 YNNUSGIPVFPVBX-NHCUHLMSSA-N 0.000 description 1
- 229950010886 clidanac Drugs 0.000 description 1
- 208000018912 cluster headache syndrome Diseases 0.000 description 1
- 238000005354 coacervation Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 229940110767 coenzyme Q10 Drugs 0.000 description 1
- 235000017471 coenzyme Q10 Nutrition 0.000 description 1
- ACTIUHUUMQJHFO-UPTCCGCDSA-N coenzyme Q10 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CC\C=C(/C)CCC=C(C)C)=C(C)C1=O ACTIUHUUMQJHFO-UPTCCGCDSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 230000001447 compensatory effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940038717 copaxone Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000005159 cyanoalkoxy group Chemical group 0.000 description 1
- WZHCOOQXZCIUNC-UHFFFAOYSA-N cyclandelate Chemical compound C1C(C)(C)CC(C)CC1OC(=O)C(O)C1=CC=CC=C1 WZHCOOQXZCIUNC-UHFFFAOYSA-N 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- IIRFCWANHMSDCG-UHFFFAOYSA-N cyclooctanone Chemical compound O=C1CCCCCCC1 IIRFCWANHMSDCG-UHFFFAOYSA-N 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960001140 cyproheptadine Drugs 0.000 description 1
- JJCFRYNCJDLXIK-UHFFFAOYSA-N cyproheptadine Chemical compound C1CN(C)CCC1=C1C2=CC=CC=C2C=CC2=CC=CC=C21 JJCFRYNCJDLXIK-UHFFFAOYSA-N 0.000 description 1
- PCCPERGCFKIYIS-AWEZNQCLSA-N daxalipram Chemical compound C1=C(OC)C(OCCC)=CC([C@@]2(C)OC(=O)NC2)=C1 PCCPERGCFKIYIS-AWEZNQCLSA-N 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 description 1
- 229950004687 denbufylline Drugs 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 229960003314 deracoxib Drugs 0.000 description 1
- WAZQAZKAZLXFMK-UHFFFAOYSA-N deracoxib Chemical compound C1=C(F)C(OC)=CC=C1C1=CC(C(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 WAZQAZKAZLXFMK-UHFFFAOYSA-N 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 231100000223 dermal penetration Toxicity 0.000 description 1
- 229960001271 desloratadine Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 229960003957 dexamethasone Drugs 0.000 description 1
- UREBDLICKHMUKA-CXSFZGCWSA-N dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 description 1
- SSQJFGMEZBFMNV-PMACEKPBSA-N dexanabinol Chemical compound C1C(CO)=CC[C@@H]2C(C)(C)OC3=CC(C(C)(C)CCCCCC)=CC(O)=C3[C@H]21 SSQJFGMEZBFMNV-PMACEKPBSA-N 0.000 description 1
- SOYKEARSMXGVTM-HNNXBMFYSA-N dexchlorpheniramine Chemical compound C1([C@H](CCN(C)C)C=2N=CC=CC=2)=CC=C(Cl)C=C1 SOYKEARSMXGVTM-HNNXBMFYSA-N 0.000 description 1
- 229960001882 dexchlorpheniramine Drugs 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 229940052370 dextroamphetamine saccharate Drugs 0.000 description 1
- 229940119751 dextroamphetamine sulfate Drugs 0.000 description 1
- XLMALTXPSGQGBX-GCJKJVERSA-N dextropropoxyphene Chemical compound C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 XLMALTXPSGQGBX-GCJKJVERSA-N 0.000 description 1
- 229960004193 dextropropoxyphene Drugs 0.000 description 1
- QMQBBUPJKANITL-MYXGOWFTSA-N dextropropoxyphene hydrochloride Chemical compound [H+].[Cl-].C([C@](OC(=O)CC)([C@H](C)CN(C)C)C=1C=CC=CC=1)C1=CC=CC=C1 QMQBBUPJKANITL-MYXGOWFTSA-N 0.000 description 1
- 229940089126 diabeta Drugs 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229960001259 diclofenac Drugs 0.000 description 1
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 1
- CURUTKGFNZGFSE-UHFFFAOYSA-N dicyclomine Chemical compound C1CCCCC1C1(C(=O)OCCN(CC)CC)CCCCC1 CURUTKGFNZGFSE-UHFFFAOYSA-N 0.000 description 1
- 229960002777 dicycloverine Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 229960000520 diphenhydramine Drugs 0.000 description 1
- OWQUZNMMYNAXSL-UHFFFAOYSA-N diphenylpyraline Chemical compound C1CN(C)CCC1OC(C=1C=CC=CC=1)C1=CC=CC=C1 OWQUZNMMYNAXSL-UHFFFAOYSA-N 0.000 description 1
- 229960000879 diphenylpyraline Drugs 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960002563 disulfiram Drugs 0.000 description 1
- FGXWKSZFVQUSTL-UHFFFAOYSA-N domperidone Chemical compound C12=CC=CC=C2NC(=O)N1CCCN(CC1)CCC1N1C2=CC=C(Cl)C=C2NC1=O FGXWKSZFVQUSTL-UHFFFAOYSA-N 0.000 description 1
- 229960001253 domperidone Drugs 0.000 description 1
- XWAIAVWHZJNZQQ-UHFFFAOYSA-N donepezil hydrochloride Chemical compound [H+].[Cl-].O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 XWAIAVWHZJNZQQ-UHFFFAOYSA-N 0.000 description 1
- 229960003135 donepezil hydrochloride Drugs 0.000 description 1
- 229940052760 dopamine agonists Drugs 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 229940052764 dopaminergic anti-parkinson drug mao b inhibitors Drugs 0.000 description 1
- IAVUPMFITXYVAF-XPUUQOCRSA-N dorzolamide Chemical compound CCN[C@H]1C[C@H](C)S(=O)(=O)C2=C1C=C(S(N)(=O)=O)S2 IAVUPMFITXYVAF-XPUUQOCRSA-N 0.000 description 1
- 229960003933 dorzolamide Drugs 0.000 description 1
- ODQWQRRAPPTVAG-UHFFFAOYSA-N doxepin Chemical compound C1OC2=CC=CC=C2C(=CCCN(C)C)C2=CC=CC=C21 ODQWQRRAPPTVAG-UHFFFAOYSA-N 0.000 description 1
- 229960005426 doxepin Drugs 0.000 description 1
- OMFNSKIUKYOYRG-MOSHPQCFSA-N drotaverine Chemical compound C1=C(OCC)C(OCC)=CC=C1\C=C/1C2=CC(OCC)=C(OCC)C=C2CCN\1 OMFNSKIUKYOYRG-MOSHPQCFSA-N 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 230000037336 dry skin Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 238000007345 electrophilic aromatic substitution reaction Methods 0.000 description 1
- 238000007336 electrophilic substitution reaction Methods 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- PWVXXGRKLHYWKM-LJQANCHMSA-N eletriptan Chemical compound CN1CCC[C@@H]1CC(C1=C2)=CNC1=CC=C2CCS(=O)(=O)C1=CC=CC=C1 PWVXXGRKLHYWKM-LJQANCHMSA-N 0.000 description 1
- 229960002472 eletriptan Drugs 0.000 description 1
- 230000004406 elevated intraocular pressure Effects 0.000 description 1
- 239000003974 emollient agent Substances 0.000 description 1
- GBXSMTUPTTWBMN-XIRDDKMYSA-N enalapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(O)=O)CC1=CC=CC=C1 GBXSMTUPTTWBMN-XIRDDKMYSA-N 0.000 description 1
- 229960000873 enalapril Drugs 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- QVDKSPUZWYTNQA-UHFFFAOYSA-N enprofylline Chemical compound O=C1NC(=O)N(CCC)C2=NC=N[C]21 QVDKSPUZWYTNQA-UHFFFAOYSA-N 0.000 description 1
- 229950000579 enprofylline Drugs 0.000 description 1
- 230000001787 epileptiform Effects 0.000 description 1
- OROAFUQRIXKEMV-LDADJPATSA-N eprosartan Chemical compound C=1C=C(C(O)=O)C=CC=1CN1C(CCCC)=NC=C1\C=C(C(O)=O)/CC1=CC=CS1 OROAFUQRIXKEMV-LDADJPATSA-N 0.000 description 1
- 229960004563 eprosartan Drugs 0.000 description 1
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 description 1
- 229960004770 esomeprazole Drugs 0.000 description 1
- 229950008247 esreboxetine Drugs 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 229960004945 etoricoxib Drugs 0.000 description 1
- MNJVRJDLRVPLFE-UHFFFAOYSA-N etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 1
- 239000000374 eutectic mixture Substances 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 1
- 229960000815 ezetimibe Drugs 0.000 description 1
- PCOBBVZJEWWZFR-UHFFFAOYSA-N ezogabine Chemical compound C1=C(N)C(NC(=O)OCC)=CC=C1NCC1=CC=C(F)C=C1 PCOBBVZJEWWZFR-UHFFFAOYSA-N 0.000 description 1
- 229960001596 famotidine Drugs 0.000 description 1
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 229940065410 feldene Drugs 0.000 description 1
- OJSFTALXCYKKFQ-YLJYHZDGSA-N femoxetine Chemical compound C1=CC(OC)=CC=C1OC[C@@H]1[C@@H](C=2C=CC=CC=2)CCN(C)C1 OJSFTALXCYKKFQ-YLJYHZDGSA-N 0.000 description 1
- 229950003930 femoxetine Drugs 0.000 description 1
- ZWJINEZUASEZBH-UHFFFAOYSA-N fenamic acid Chemical class OC(=O)C1=CC=CC=C1NC1=CC=CC=C1 ZWJINEZUASEZBH-UHFFFAOYSA-N 0.000 description 1
- 229950006236 fenclofenac Drugs 0.000 description 1
- IDKAXRLETRCXKS-UHFFFAOYSA-N fenclofenac Chemical compound OC(=O)CC1=CC=CC=C1OC1=CC=C(Cl)C=C1Cl IDKAXRLETRCXKS-UHFFFAOYSA-N 0.000 description 1
- 229950011481 fenclozic acid Drugs 0.000 description 1
- 229960001419 fenoprofen Drugs 0.000 description 1
- 229960002679 fentiazac Drugs 0.000 description 1
- 229960000489 feprazone Drugs 0.000 description 1
- 229960003592 fexofenadine Drugs 0.000 description 1
- RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- STTRYQAGHGJXJJ-LICLKQGHSA-N filaminast Chemical compound COC1=CC=C(C(\C)=N\OC(N)=O)C=C1OC1CCCC1 STTRYQAGHGJXJJ-LICLKQGHSA-N 0.000 description 1
- 229950006884 filaminast Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 229960002053 flibanserin Drugs 0.000 description 1
- PPRRDFIXUUSXRA-UHFFFAOYSA-N flibanserin Chemical compound FC(F)(F)C1=CC=CC(N2CCN(CCN3C(NC4=CC=CC=C43)=O)CC2)=C1 PPRRDFIXUUSXRA-UHFFFAOYSA-N 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 229960002464 fluoxetine Drugs 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 229960004038 fluvoxamine Drugs 0.000 description 1
- CJOFXWAVKWHTFT-XSFVSMFZSA-N fluvoxamine Chemical compound COCCCC\C(=N/OCCN)C1=CC=C(C(F)(F)F)C=C1 CJOFXWAVKWHTFT-XSFVSMFZSA-N 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 229960002490 fosinopril Drugs 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 229950010931 furofenac Drugs 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 239000004083 gastrointestinal agent Substances 0.000 description 1
- 229940125695 gastrointestinal agent Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229940080856 gleevec Drugs 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- BOVGTQGAOIONJV-UHFFFAOYSA-N gliclazide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CC2CCCC2C1 BOVGTQGAOIONJV-UHFFFAOYSA-N 0.000 description 1
- 229960004346 glimepiride Drugs 0.000 description 1
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 1
- 201000005442 glossopharyngeal neuralgia Diseases 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940120105 glynase Drugs 0.000 description 1
- MFWNKCLOYSRHCJ-BTTYYORXSA-N granisetron Chemical compound C1=CC=C2C(C(=O)N[C@H]3C[C@H]4CCC[C@@H](C3)N4C)=NN(C)C2=C1 MFWNKCLOYSRHCJ-BTTYYORXSA-N 0.000 description 1
- 229960003727 granisetron Drugs 0.000 description 1
- SCMLRESZJCKCTC-KMYQRJGFSA-N gtpl8173 Chemical compound C12=CC=C(CSCC)C=C2C2=C(CNC3=O)C3=C3C4=CC(CSCC)=CC=C4N4C3=C2N1[C@]1(C)[C@@](O)(C(=O)OC)C[C@H]4O1 SCMLRESZJCKCTC-KMYQRJGFSA-N 0.000 description 1
- LHGVFZTZFXWLCP-UHFFFAOYSA-N guaiacol Chemical class COC1=CC=CC=C1O LHGVFZTZFXWLCP-UHFFFAOYSA-N 0.000 description 1
- 125000000262 haloalkenyl group Chemical group 0.000 description 1
- 235000015220 hamburgers Nutrition 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000002489 hematologic effect Effects 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004475 heteroaralkyl group Chemical group 0.000 description 1
- 125000005114 heteroarylalkoxy group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000001320 hippocampus Anatomy 0.000 description 1
- 239000003906 humectant Substances 0.000 description 1
- 229940048921 humira Drugs 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000008309 hydrophilic cream Substances 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229920001600 hydrophobic polymer Polymers 0.000 description 1
- 125000005020 hydroxyalkenyl group Chemical group 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 229960000930 hydroxyzine Drugs 0.000 description 1
- ZQDWXGKKHFNSQK-UHFFFAOYSA-N hydroxyzine Chemical compound C1CN(CCOCCO)CCN1C(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 ZQDWXGKKHFNSQK-UHFFFAOYSA-N 0.000 description 1
- 229930005342 hyoscyamine Natural products 0.000 description 1
- 229960003210 hyoscyamine Drugs 0.000 description 1
- 239000005555 hypertensive agent Substances 0.000 description 1
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 1
- 230000002631 hypothermal effect Effects 0.000 description 1
- 208000003532 hypothyroidism Diseases 0.000 description 1
- 230000002989 hypothyroidism Effects 0.000 description 1
- 229960002491 ibudilast Drugs 0.000 description 1
- 229950009183 ibufenac Drugs 0.000 description 1
- CYWFCPPBTWOZSF-UHFFFAOYSA-N ibufenac Chemical compound CC(C)CC1=CC=C(CC(O)=O)C=C1 CYWFCPPBTWOZSF-UHFFFAOYSA-N 0.000 description 1
- 229960002411 imatinib Drugs 0.000 description 1
- YLMAHDNUQAMNNX-UHFFFAOYSA-N imatinib methanesulfonate Chemical compound CS(O)(=O)=O.C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 YLMAHDNUQAMNNX-UHFFFAOYSA-N 0.000 description 1
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 description 1
- BCGWQEUPMDMJNV-UHFFFAOYSA-N imipramine Chemical compound C1CC2=CC=CC=C2N(CCCN(C)C)C2=CC=CC=C21 BCGWQEUPMDMJNV-UHFFFAOYSA-N 0.000 description 1
- 229960004801 imipramine Drugs 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 229940095970 imodium Drugs 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 229950002473 indalpine Drugs 0.000 description 1
- SADQVAVFGNTEOD-UHFFFAOYSA-N indalpine Chemical compound C=1NC2=CC=CC=C2C=1CCC1CCNCC1 SADQVAVFGNTEOD-UHFFFAOYSA-N 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 229960004187 indoprofen Drugs 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 229960001388 interferon-beta Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 238000000752 ionisation method Methods 0.000 description 1
- 229960002198 irbesartan Drugs 0.000 description 1
- YCPOHTHPUREGFM-UHFFFAOYSA-N irbesartan Chemical compound O=C1N(CC=2C=CC(=CC=2)C=2C(=CC=CC=2)C=2[N]N=NN=2)C(CCCC)=NC21CCCC2 YCPOHTHPUREGFM-UHFFFAOYSA-N 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 229950011455 isoxepac Drugs 0.000 description 1
- QFGMXJOBTNZHEL-UHFFFAOYSA-N isoxepac Chemical compound O1CC2=CC=CC=C2C(=O)C2=CC(CC(=O)O)=CC=C21 QFGMXJOBTNZHEL-UHFFFAOYSA-N 0.000 description 1
- 229950002252 isoxicam Drugs 0.000 description 1
- YYUAYBYLJSNDCX-UHFFFAOYSA-N isoxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC=1C=C(C)ON=1 YYUAYBYLJSNDCX-UHFFFAOYSA-N 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 229960005302 itopride Drugs 0.000 description 1
- 229940084418 kaopectate Drugs 0.000 description 1
- DKYWVDODHFEZIM-UHFFFAOYSA-N ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 description 1
- 229960000991 ketoprofen Drugs 0.000 description 1
- 229960002623 lacosamide Drugs 0.000 description 1
- VPPJLAIAVCUEMN-GFCCVEGCSA-N lacosamide Chemical compound COC[C@@H](NC(C)=O)C(=O)NCC1=CC=CC=C1 VPPJLAIAVCUEMN-GFCCVEGCSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001848 lamotrigine Drugs 0.000 description 1
- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 description 1
- 201000010901 lateral sclerosis Diseases 0.000 description 1
- 239000008141 laxative Substances 0.000 description 1
- 229940125722 laxative agent Drugs 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 229960000681 leflunomide Drugs 0.000 description 1
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 1
- 229960004771 levobetaxolol Drugs 0.000 description 1
- IXHBTMCLRNMKHZ-LBPRGKRZSA-N levobunolol Chemical compound O=C1CCCC2=C1C=CC=C2OC[C@@H](O)CNC(C)(C)C IXHBTMCLRNMKHZ-LBPRGKRZSA-N 0.000 description 1
- 229960000831 levobunolol Drugs 0.000 description 1
- 229960001508 levocetirizine Drugs 0.000 description 1
- 208000028454 lice infestation Diseases 0.000 description 1
- 201000011486 lichen planus Diseases 0.000 description 1
- 229960004194 lidocaine Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- KXGCNMMJRFDFNR-WDRJZQOASA-N linaclotide Chemical compound C([C@H](NC(=O)[C@@H]1CSSC[C@H]2C(=O)N[C@H]3CSSC[C@H](N)C(=O)N[C@H](C(N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N2)=O)CSSC[C@H](NC(=O)[C@H](C)NC(=O)[C@@H]2CCCN2C(=O)[C@H](CC(N)=O)NC3=O)C(=O)N[C@H](C(NCC(=O)N1)=O)[C@H](O)C)C(O)=O)C1=CC=C(O)C=C1 KXGCNMMJRFDFNR-WDRJZQOASA-N 0.000 description 1
- 229960000812 linaclotide Drugs 0.000 description 1
- 108010024409 linaclotide Proteins 0.000 description 1
- 239000000865 liniment Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 238000005567 liquid scintillation counting Methods 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- 229950008462 lirimilast Drugs 0.000 description 1
- 229960002394 lisinopril Drugs 0.000 description 1
- CZRQXSDBMCMPNJ-ZUIPZQNBSA-N lisinopril dihydrate Chemical compound O.O.C([C@H](N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(O)=O)C(O)=O)CC1=CC=CC=C1 CZRQXSDBMCMPNJ-ZUIPZQNBSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 229960001571 loperamide Drugs 0.000 description 1
- 229960003088 loratadine Drugs 0.000 description 1
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229960000345 lubiprostone Drugs 0.000 description 1
- 230000001926 lymphatic effect Effects 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 239000012931 lyophilized formulation Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 229960003803 meclofenamic acid Drugs 0.000 description 1
- 229960003464 mefenamic acid Drugs 0.000 description 1
- HYYBABOKPJLUIN-UHFFFAOYSA-N mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 1
- 229960001929 meloxicam Drugs 0.000 description 1
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 description 1
- 229960004640 memantine Drugs 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 229960000582 mepyramine Drugs 0.000 description 1
- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 description 1
- 238000003808 methanol extraction Methods 0.000 description 1
- FLOSMHQXBMRNHR-DAXSKMNVSA-N methazolamide Chemical compound CC(=O)\N=C1/SC(S(N)(=O)=O)=NN1C FLOSMHQXBMRNHR-DAXSKMNVSA-N 0.000 description 1
- 229960004083 methazolamide Drugs 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- RXYCUKSOYJWGPE-UHFFFAOYSA-N methyl 2-azidoacetate Chemical compound COC(=O)CN=[N+]=[N-] RXYCUKSOYJWGPE-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 229960004584 methylprednisolone Drugs 0.000 description 1
- BQIPXWYNLPYNHW-UHFFFAOYSA-N metipranolol Chemical compound CC(C)NCC(O)COC1=CC(C)=C(OC(C)=O)C(C)=C1C BQIPXWYNLPYNHW-UHFFFAOYSA-N 0.000 description 1
- 229960002704 metipranolol Drugs 0.000 description 1
- 229960003404 mexiletine Drugs 0.000 description 1
- 210000001589 microsome Anatomy 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 229940042472 mineral oil Drugs 0.000 description 1
- 229960003632 minoxidil Drugs 0.000 description 1
- OJGQFYYLKNCIJD-UHFFFAOYSA-N miroprofen Chemical compound C1=CC(C(C(O)=O)C)=CC=C1C1=CN(C=CC=C2)C2=N1 OJGQFYYLKNCIJD-UHFFFAOYSA-N 0.000 description 1
- 229950006616 miroprofen Drugs 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- 229960005285 mofebutazone Drugs 0.000 description 1
- REOJLIXKJWXUGB-UHFFFAOYSA-N mofebutazone Chemical compound O=C1C(CCCC)C(=O)NN1C1=CC=CC=C1 REOJLIXKJWXUGB-UHFFFAOYSA-N 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 201000005518 mononeuropathy Diseases 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229960005127 montelukast Drugs 0.000 description 1
- 229960004085 mosapride Drugs 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 208000013465 muscle pain Diseases 0.000 description 1
- RTGDFNSFWBGLEC-SYZQJQIISA-N mycophenolate mofetil Chemical compound COC1=C(C)C=2COC(=O)C=2C(O)=C1C\C=C(/C)CCC(=O)OCCN1CCOCC1 RTGDFNSFWBGLEC-SYZQJQIISA-N 0.000 description 1
- 229960004866 mycophenolate mofetil Drugs 0.000 description 1
- 229940043348 myristyl alcohol Drugs 0.000 description 1
- BGTBRDJUHRMBQB-UHFFFAOYSA-N n,n-dimethylmethanamine;n,n-dipropylpropan-1-amine Chemical compound CN(C)C.CCCN(CCC)CCC BGTBRDJUHRMBQB-UHFFFAOYSA-N 0.000 description 1
- HSQAARMBHJCUOK-UHFFFAOYSA-N n-(1-adamantylmethyl)-2-chloro-5-[3-(3-hydroxypropylamino)propyl]benzamide Chemical compound OCCCNCCCC1=CC=C(Cl)C(C(=O)NCC23CC4CC(CC(C4)C2)C3)=C1 HSQAARMBHJCUOK-UHFFFAOYSA-N 0.000 description 1
- IIBSHMFXVWTQSJ-UHFFFAOYSA-N n-(2-chloropyrimidin-5-yl)-3,4-difluorobenzamide Chemical compound C1=C(F)C(F)=CC=C1C(=O)NC1=CN=C(Cl)N=C1 IIBSHMFXVWTQSJ-UHFFFAOYSA-N 0.000 description 1
- PNMJVSYIKZYBDB-UHFFFAOYSA-N n-(3-chlorophenyl)-2-[1-[(4-chlorophenyl)methyl]-2,5,5-trimethyl-6,7-dihydro-4h-indol-3-yl]-2-oxoacetamide Chemical compound C1=2CC(C)(C)CCC=2N(CC=2C=CC(Cl)=CC=2)C(C)=C1C(=O)C(=O)NC1=CC=CC(Cl)=C1 PNMJVSYIKZYBDB-UHFFFAOYSA-N 0.000 description 1
- SMLZRMZBUWYSKX-UHFFFAOYSA-N n-(3-chlorophenyl)-2-[1-[(4-chlorophenyl)methyl]-2,5-dimethylpyrrol-3-yl]-2-oxoacetamide Chemical compound CC=1N(CC=2C=CC(Cl)=CC=2)C(C)=CC=1C(=O)C(=O)NC1=CC=CC(Cl)=C1 SMLZRMZBUWYSKX-UHFFFAOYSA-N 0.000 description 1
- DOLGAQVFXJZFLQ-UHFFFAOYSA-N n-(3-chlorophenyl)-2-[4-[(4-chlorophenyl)methyl]-5-methylthieno[3,2-b]pyrrol-6-yl]-2-oxoacetamide Chemical compound C1=2SC=CC=2N(CC=2C=CC(Cl)=CC=2)C(C)=C1C(=O)C(=O)NC1=CC=CC(Cl)=C1 DOLGAQVFXJZFLQ-UHFFFAOYSA-N 0.000 description 1
- YUTIXVXZQIQWGY-UHFFFAOYSA-N n-[4-[6-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl]oxy-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=CC=C2SC(NC(=O)C)=NC2=C1OC(N=CN=1)=CC=1C1=CC=C(C(F)(F)F)C=C1 YUTIXVXZQIQWGY-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960005297 nalmefene Drugs 0.000 description 1
- 229960003086 naltrexone Drugs 0.000 description 1
- 239000002088 nanocapsule Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- UNHGSHHVDNGCFN-UHFFFAOYSA-N naratriptan Chemical compound C=12[CH]C(CCS(=O)(=O)NC)=CC=C2N=CC=1C1CCN(C)CC1 UNHGSHHVDNGCFN-UHFFFAOYSA-N 0.000 description 1
- 229960005254 naratriptan Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 201000009240 nasopharyngitis Diseases 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- 230000003880 negative regulation of appetite Effects 0.000 description 1
- 230000031990 negative regulation of inflammatory response Effects 0.000 description 1
- 210000000478 neocortex Anatomy 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 208000028412 nervous system injury Diseases 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000003040 nociceptive effect Effects 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005593 norbornanyl group Chemical group 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 235000018343 nutrient deficiency Nutrition 0.000 description 1
- GYCKQBWUSACYIF-UHFFFAOYSA-N o-hydroxybenzoic acid ethyl ester Natural products CCOC(=O)C1=CC=CC=C1O GYCKQBWUSACYIF-UHFFFAOYSA-N 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- KVWDHTXUZHCGIO-UHFFFAOYSA-N olanzapine Chemical compound C1CN(C)CCN1C1=NC2=CC=CC=C2NC2=C1C=C(C)S2 KVWDHTXUZHCGIO-UHFFFAOYSA-N 0.000 description 1
- 229960005017 olanzapine Drugs 0.000 description 1
- FATBGEAMYMYZAF-KTKRTIGZSA-N oleamide Chemical compound CCCCCCCC\C=C/CCCCCCCC(N)=O FATBGEAMYMYZAF-KTKRTIGZSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- FATBGEAMYMYZAF-UHFFFAOYSA-N oleicacidamide-heptaglycolether Natural products CCCCCCCCC=CCCCCCCCC(N)=O FATBGEAMYMYZAF-UHFFFAOYSA-N 0.000 description 1
- BOWVQLFMWHZBEF-KTKRTIGZSA-N oleoyl ethanolamide Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)NCCO BOWVQLFMWHZBEF-KTKRTIGZSA-N 0.000 description 1
- 210000000956 olfactory bulb Anatomy 0.000 description 1
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 1
- 229960005117 olmesartan Drugs 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 210000001328 optic nerve Anatomy 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 229960002739 oxaprozin Drugs 0.000 description 1
- OFPXSFXSNFPTHF-UHFFFAOYSA-N oxaprozin Chemical compound O1C(CCC(=O)O)=NC(C=2C=CC=CC=2)=C1C1=CC=CC=C1 OFPXSFXSNFPTHF-UHFFFAOYSA-N 0.000 description 1
- 229960000649 oxyphenbutazone Drugs 0.000 description 1
- CNDQSXOVEQXJOE-UHFFFAOYSA-N oxyphenbutazone hydrate Chemical compound O.O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=C(O)C=C1 CNDQSXOVEQXJOE-UHFFFAOYSA-N 0.000 description 1
- LXCFILQKKLGQFO-UHFFFAOYSA-N p-hydroxybenzoic acid methyl ester Natural products COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 1
- 229940124583 pain medication Drugs 0.000 description 1
- HXYVTAGFYLMHSO-UHFFFAOYSA-N palmitoyl ethanolamide Chemical compound CCCCCCCCCCCCCCCC(=O)NCCO HXYVTAGFYLMHSO-UHFFFAOYSA-N 0.000 description 1
- 229960005019 pantoprazole Drugs 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 201000007620 paralytic ileus Diseases 0.000 description 1
- 229960004662 parecoxib Drugs 0.000 description 1
- TZRHLKRLEZJVIJ-UHFFFAOYSA-N parecoxib Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 TZRHLKRLEZJVIJ-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 208000035824 paresthesia Diseases 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 229960001476 pentoxifylline Drugs 0.000 description 1
- 229940101070 pepto-bismol Drugs 0.000 description 1
- YEHCICAEULNIGD-MZMPZRCHSA-N pergolide Chemical compound C1=CC([C@H]2C[C@@H](CSC)CN([C@@H]2C2)CCC)=C3C2=CNC3=C1 YEHCICAEULNIGD-MZMPZRCHSA-N 0.000 description 1
- 229960004851 pergolide Drugs 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 210000000578 peripheral nerve Anatomy 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 229960001190 pheniramine Drugs 0.000 description 1
- 229960002895 phenylbutazone Drugs 0.000 description 1
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- RRRUXBQSQLKHEL-UHFFFAOYSA-N piclamilast Chemical compound COC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OC1CCCC1 RRRUXBQSQLKHEL-UHFFFAOYSA-N 0.000 description 1
- 229950005184 piclamilast Drugs 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- PIDSZXPFGCURGN-UHFFFAOYSA-N pirprofen Chemical compound ClC1=CC(C(C(O)=O)C)=CC=C1N1CC=CC1 PIDSZXPFGCURGN-UHFFFAOYSA-N 0.000 description 1
- 229960000851 pirprofen Drugs 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920000768 polyamine Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 208000037244 polycythemia vera Diseases 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920002338 polyhydroxyethylmethacrylate Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 230000007824 polyneuropathy Effects 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 150000004804 polysaccharides Chemical class 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 description 1
- 229960003611 pramlintide Drugs 0.000 description 1
- DQKXQSGTHWVTAD-UHFFFAOYSA-N pramocaine Chemical compound C1=CC(OCCCC)=CC=C1OCCCN1CCOCC1 DQKXQSGTHWVTAD-UHFFFAOYSA-N 0.000 description 1
- 229960001896 pramocaine Drugs 0.000 description 1
- 229940096058 prandin Drugs 0.000 description 1
- 229960004583 pranlukast Drugs 0.000 description 1
- UAJUXJSXCLUTNU-UHFFFAOYSA-N pranlukast Chemical compound C=1C=C(OCCCCC=2C=CC=CC=2)C=CC=1C(=O)NC(C=1)=CC=C(C(C=2)=O)C=1OC=2C=1N=NNN=1 UAJUXJSXCLUTNU-UHFFFAOYSA-N 0.000 description 1
- 229960003101 pranoprofen Drugs 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 229960004618 prednisone Drugs 0.000 description 1
- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011324 primary prophylaxis Methods 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- 150000005599 propionic acid derivatives Chemical class 0.000 description 1
- 229960004134 propofol Drugs 0.000 description 1
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical compound CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical class O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002206 pyridazin-3-yl group Chemical group [H]C1=C([H])C([H])=C(*)N=N1 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- BHJIBOFHEFDSAU-LBPRGKRZSA-N ralfinamide Chemical compound C1=CC(CN[C@@H](C)C(N)=O)=CC=C1OCC1=CC=CC=C1F BHJIBOFHEFDSAU-LBPRGKRZSA-N 0.000 description 1
- NTHPAPBPFQJABD-LLVKDONJSA-N ramosetron Chemical compound C12=CC=CC=C2N(C)C=C1C(=O)[C@H]1CC(NC=N2)=C2CC1 NTHPAPBPFQJABD-LLVKDONJSA-N 0.000 description 1
- 229950001588 ramosetron Drugs 0.000 description 1
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 229960000620 ranitidine Drugs 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- RUOKEQAAGRXIBM-GFCCVEGCSA-N rasagiline Chemical compound C1=CC=C2[C@H](NCC#C)CCC2=C1 RUOKEQAAGRXIBM-GFCCVEGCSA-N 0.000 description 1
- 229960000245 rasagiline Drugs 0.000 description 1
- BLGXFZZNTVWLAY-DIRVCLHFSA-N rauwolscine Chemical compound C1=CC=C2C(CCN3C[C@H]4CC[C@H](O)[C@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-DIRVCLHFSA-N 0.000 description 1
- CBQGYUDMJHNJBX-RTBURBONSA-N reboxetine Chemical compound CCOC1=CC=CC=C1O[C@H](C=1C=CC=CC=1)[C@@H]1OCCNC1 CBQGYUDMJHNJBX-RTBURBONSA-N 0.000 description 1
- 229960003770 reboxetine Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229940100618 rectal suppository Drugs 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 208000000029 referred pain Diseases 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000009256 replacement therapy Methods 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 229960003312 retigabine Drugs 0.000 description 1
- 210000001525 retina Anatomy 0.000 description 1
- 229940110294 revia Drugs 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- 229960000371 rofecoxib Drugs 0.000 description 1
- RZJQGNCSTQAWON-UHFFFAOYSA-N rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 description 1
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 1
- 229960002586 roflumilast Drugs 0.000 description 1
- HJORMJIFDVBMOB-UHFFFAOYSA-N rolipram Chemical compound COC1=CC=C(C2CC(=O)NC2)C=C1OC1CCCC1 HJORMJIFDVBMOB-UHFFFAOYSA-N 0.000 description 1
- 229950005741 rolipram Drugs 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 208000005687 scabies Diseases 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- MEZLKOACVSPNER-GFCCVEGCSA-N selegiline Chemical compound C#CCN(C)[C@H](C)CC1=CC=CC=C1 MEZLKOACVSPNER-GFCCVEGCSA-N 0.000 description 1
- 229960003946 selegiline Drugs 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 239000000387 serotonin 5-HT4 receptor agonist Substances 0.000 description 1
- 229960002073 sertraline Drugs 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- UNAANXDKBXWMLN-UHFFFAOYSA-N sibutramine Chemical compound C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UNAANXDKBXWMLN-UHFFFAOYSA-N 0.000 description 1
- 229960004425 sibutramine Drugs 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 210000000273 spinal nerve root Anatomy 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- SFVFIFLLYFPGHH-UHFFFAOYSA-M stearalkonium chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 SFVFIFLLYFPGHH-UHFFFAOYSA-M 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 229950005175 sudoxicam Drugs 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-UHFFFAOYSA-N sulfasalazine Natural products C1=C(O)C(C(=O)O)=CC(N=NC=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-UHFFFAOYSA-N 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 229960000894 sulindac Drugs 0.000 description 1
- MLKXDPUZXIRXEP-MFOYZWKCSA-N sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
- 229960003708 sumatriptan Drugs 0.000 description 1
- 229960004492 suprofen Drugs 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 229940099093 symlin Drugs 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229950008160 tanezumab Drugs 0.000 description 1
- 229950005022 taranabant Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000001138 tear Anatomy 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- 229960000351 terfenadine Drugs 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229950002896 tetomilast Drugs 0.000 description 1
- MHXBHWLGRWOABW-UHFFFAOYSA-N tetradecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC MHXBHWLGRWOABW-UHFFFAOYSA-N 0.000 description 1
- 150000004685 tetrahydrates Chemical class 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- CFMYXEVWODSLAX-QOZOJKKESA-N tetrodotoxin Chemical compound O([C@@]([C@H]1O)(O)O[C@H]2[C@@]3(O)CO)[C@H]3[C@@H](O)[C@]11[C@H]2[C@@H](O)N=C(N)N1 CFMYXEVWODSLAX-QOZOJKKESA-N 0.000 description 1
- 210000001103 thalamus Anatomy 0.000 description 1
- 229960004559 theobromine Drugs 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000001149 thermolysis Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 229960001312 tiaprofenic acid Drugs 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 229950002345 tiopinac Drugs 0.000 description 1
- 229950006150 tioxaprofen Drugs 0.000 description 1
- 230000000451 tissue damage Effects 0.000 description 1
- 231100000827 tissue damage Toxicity 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 229950003899 tofimilast Drugs 0.000 description 1
- 229960002277 tolazamide Drugs 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- 229960002905 tolfenamic acid Drugs 0.000 description 1
- YEZNLOUZAIOMLT-UHFFFAOYSA-N tolfenamic acid Chemical compound CC1=C(Cl)C=CC=C1NC1=CC=CC=C1C(O)=O YEZNLOUZAIOMLT-UHFFFAOYSA-N 0.000 description 1
- 229940035266 tolinase Drugs 0.000 description 1
- 229960001017 tolmetin Drugs 0.000 description 1
- UPSPUYADGBWSHF-UHFFFAOYSA-N tolmetin Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC=C(CC(O)=O)N1C UPSPUYADGBWSHF-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- BWHOZHOGCMHOBV-BQYQJAHWSA-N trans-benzylideneacetone Chemical compound CC(=O)\C=C\C1=CC=CC=C1 BWHOZHOGCMHOBV-BQYQJAHWSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 210000003901 trigeminal nerve Anatomy 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 229960003223 tripelennamine Drugs 0.000 description 1
- 229960001128 triprolidine Drugs 0.000 description 1
- CBEQULMOCCWAQT-WOJGMQOQSA-N triprolidine Chemical compound C1=CC(C)=CC=C1C(\C=1N=CC=CC=1)=C/CN1CCCC1 CBEQULMOCCWAQT-WOJGMQOQSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 229940102936 tucks hemorrhoidal Drugs 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 229940049669 ulcerease Drugs 0.000 description 1
- 208000009852 uremia Diseases 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 239000006213 vaginal ring Substances 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 239000000003 vaginal tablet Substances 0.000 description 1
- 229960002004 valdecoxib Drugs 0.000 description 1
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- ACWBQPMHZXGDFX-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- BLGXFZZNTVWLAY-SCYLSFHTSA-N yohimbine Chemical compound C1=CC=C2C(CCN3C[C@@H]4CC[C@H](O)[C@@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-SCYLSFHTSA-N 0.000 description 1
- 229960000317 yohimbine Drugs 0.000 description 1
- AADVZSXPNRLYLV-UHFFFAOYSA-N yohimbine carboxylic acid Natural products C1=CC=C2C(CCN3CC4CCC(C(C4CC33)C(O)=O)O)=C3NC2=C1 AADVZSXPNRLYLV-UHFFFAOYSA-N 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- 229960004764 zafirlukast Drugs 0.000 description 1
- BPKIMPVREBSLAJ-QTBYCLKRSA-N ziconotide Chemical compound C([C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]2C(=O)N[C@@H]3C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CSSC2)C(N)=O)=O)CSSC[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CSSC3)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(N1)=O)CCSC)[C@@H](C)O)C1=CC=C(O)C=C1 BPKIMPVREBSLAJ-QTBYCLKRSA-N 0.000 description 1
- 229960002811 ziconotide Drugs 0.000 description 1
- 229950007802 zidometacin Drugs 0.000 description 1
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- 229960005332 zileuton Drugs 0.000 description 1
- OYPPVKRFBIWMSX-SXGWCWSVSA-N zimeldine Chemical compound C=1C=CN=CC=1C(=C/CN(C)C)\C1=CC=C(Br)C=C1 OYPPVKRFBIWMSX-SXGWCWSVSA-N 0.000 description 1
- 229960002791 zimeldine Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- RNWHGQJWIACOKP-UHFFFAOYSA-N zinc;oxygen(2-) Chemical compound [O-2].[Zn+2] RNWHGQJWIACOKP-UHFFFAOYSA-N 0.000 description 1
- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 1
- 229960000607 ziprasidone Drugs 0.000 description 1
- ULSDMUVEXKOYBU-ZDUSSCGKSA-N zolmitriptan Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1C[C@H]1COC(=O)N1 ULSDMUVEXKOYBU-ZDUSSCGKSA-N 0.000 description 1
- 229960001360 zolmitriptan Drugs 0.000 description 1
- 229960003414 zomepirac Drugs 0.000 description 1
- ZXVNMYWKKDOREA-UHFFFAOYSA-N zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 description 1
- 229940083488 zonalon Drugs 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/333—Radicals substituted by oxygen or sulfur atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/337—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Definitions
- the present disclosure relates to N-benzyl pyrrole compounds useful as inhibitors of the enzyme Fatty Acid Amide Hydrolase (FAAH).
- Fatty Acid Amide Hydrolase Fatty Acid Amide Hydrolase
- the disclosure also provides pharmaceutically acceptable compositions comprising the compounds of the disclosure and methods of using the compositions in the treatment of various disorders.
- the endocannabinoid (eCB) system has been implicated in a variety of processes including cell signaling, memory encoding, compensatory mechanisms, and immunosuppressant and anti-inflammatory responses.
- the eCB system comprises at least two receptors: the CB 1 cannabinoid receptor, widely distributed in the brain and present in some peripheral organs, and the CB2 receptor, found principally in the periphery and immune systems and in some regions of the brain.
- the endogenous agonists of these receptors are the endogenous cannabinoids (eCBs), a family of lipids comprising the fatty acid Anandamide (AEA) as well as other fatty acids.
- eCBs cannabinoids
- AEA fatty acid Anandamide
- Endocannabinoid-degrading enzymes including fatty acid amide hydrolase
- FAAH inhibitors may also be useful agents for treating glaucoma.
- ring B is selected from the group consisting of phenyl and a 5-6-membered monocyclic heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S;
- each J is independently selected from the group consisting of halogen, -N0 2 , -CN, Ci. 6 aliphatic, C3.6 cycloaliphatic, C
- p is an integer selected from the group consisting of 0, 1, 2 and 3;
- R is selected from the group consisting of halogen, -N0 2 , -CN, C ⁇ * aliphatic, phenyl, a 5-6- membered heteroaryl ring and a C 3 . 7 cycloalkyl, wherein said Ci_ 6 aliphatic, phenyl, 5-6-membered heteroaryl ring and C 3 . 7 cycloalkyl is optionally substituted by up to three instances of halogen;
- R 5 is selected from the group consisting of hydrogen, halogen, -CN, C
- Ci -6 aliphatic, C 3-7 cycloaliphatic ring, 5-6-membered heteroaryl ring, and phenyl is optionally substituted with up to three instances of halogen, Ci- 4 alkyl, C haloalkyl, Ci -4 alkoxy or C haloalkoxy; or
- cycloaliphatic ring a 5-8-membered heterocyclic ring or a 5-membered heteroaryl ring
- said heterocyclic and heteroaryl ring formed by R 4 and R 5 contain up to three heteroatoms selected from the group consisting of N, O and S, and wherein said cycloaliphatic, heterocyclic and heteroaryl ring formed by R 4 and R 5 is optionally substituted by up to 3 instances of halogen, C
- each R is independently selected from the group consisting of Ci -6 aliphatic, C 3-7
- each R Y is optionally substituted by up to six instances of halogen, C
- the invention also relates to pharmaceutical compositions comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle or adjuvant. Also within the scope of the invention are pharmaceutical compositions further comprising at least one additional therapeutic agent.
- compounds of the invention may optionally be substituted with one or more substituents, such as illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
- substituents such as illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention.
- the phrase "optionally substituted” is used interchangeably with the phrase "substituted or
- the phrase "up to”, as used herein, refers to zero or any integer number that is equal to or less than the number following the phrase.
- optionally substituted with "up to 3" means substituted with 0, 1, 2, or 3 substituents.
- a specified number range of atoms includes any integer therein.
- a group having from 1-4 atoms could have 1, 2, 3 or 4 atoms. It will be understood by one of ordinary skill in the art that when a group is characterized as substituted (as opposed to optionally substituted) with, e.g., "up to 3" substituents, it can only be substituted with 1, 2 or 3 substituents.
- a compound such as the compounds of the invention or other compounds herein disclosed, may be present in its free form (e.g., an amorphous form or polymorphs). Under certain conditions, compounds may also form salts, and/or other multi-component crystalline forms (e.g., solvates (i.e., hydrates), and co-crystals). As used herein, the term co- form is synonymous with the term multi-component crystalline form. When one of the components in the co-form has clearly transferred a proton to the other component, the resulting co-form is referred to as a "salt".
- solvate refers to an association or complex of one or more solvent molecules and a compound disclosed herein (or its salts or co-crystals).
- a "hydrate” is a particular type of solvate in which the solvent is water.
- diastereomeric, atropoisomeric and cis-trans isomeric) forms of the structure for example, the R and S configurations for each asymmetric center, Ra and Sa configurations for each asymmetric axis, (Z) and (E) double bond configurations, and cis and trans conformational isomers. Therefore, single stereochemical isomers as well as racemates, and mixtures of enantiomers, diastereomers, and cis-trans isomers (double bond or conformational) of the present compounds are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the disclosure.
- the present disclosure also embraces isotopically labeled compounds that are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses.
- Tritiated (i.e., 3 H) and carbon-14 (i.e., I4 C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
- Positron-emitting isotopes such as 15 0, 13 N, n C, and 18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
- Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
- aliphatic or "aliphatic group”, as used herein, mean a straight- chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms.
- aliphatic groups contain 1-4 aliphatic carbon atoms and in yet other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms.
- Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Specific examples of aliphatic groups include, but are not limited to: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, sec- butyl, terr-butyl, butenyl, propargyl, acetylene and the like.
- alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group contains 1-20 carbon atoms (e.g., 1-20 carbon atoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1 ⁇ 1 carbon atoms or 1-3 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl and the like.
- alkynyl refers to a linear or branched monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon sp triple bond. Unless otherwise specified, an alkynyl group contains 2-20 carbon atoms (e.g., 2-20 carbon atoms,
- cycloaliphatic refers to a cyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic, and which has a single point of attachment to the rest of the molecule. Unless otherwise specified, a cycloaliphatic group may be monocyclic, bicyclic, tricyclic, fused, spiro or bridged. In one embodiment, the term “cycloaliphatic” refers to a monocyclic C3-C12 hydrocarbon or a bicyclic C 7 -Ci 2 hydrocarbon.
- any individual ring in a bicyclic or tricyclic ring system has 3-7 members.
- Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of aliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,
- cyclohexenyl cycloheptyl, cycloheptenyl, norbornyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
- cycloaliphatic also includes polycyclic ring systems in which the non-aromatic carbocyclic ring can be "fused” to one or more aromatic or non-aromatic carbocyclic or heterocyclic rings or combinations thereof, as long as the radical or point of attachment is on the non-aromatic carbocyclic ring.
- a heterocycle may be monocyclic, bicyclic or tricyclic.
- the heterocycle has 3-18 ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur or nitrogen, and each ring in the system contains 3 to 7 ring members.
- a heterocycle may be a monocycle having 3-7 ring members (2-6 carbon atoms and ⁇ heteroatoms) or a bicycle having 7-10 ring members (4-9 carbon atoms and 1-6 heteroatoms).
- Examples of bicyclic heterocyclic ring systems include, but are not limited to: adamantanyl, 2-oxa- bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl.
- heterocycle also includes polycyclic ring systems wherein the heterocyclic ring is fused with one or more aromatic or non-aromatic carbocyclic or heterocyclic rings, or with combinations thereof, as long as the radical or point of attachment is in the heterocyclic ring.
- heterocyclic rings include, but are not limited to, the following monocycles: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3- tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3- thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1- tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 2-thiazolid
- the term also includes polycyclic ring systems where the aryl ring is fused with one or more aromatic or non-aromatic carbocyclic or heterocyclic rings, or with combinations thereof, as long as the radical or point of attachment is in the aryl ring.
- aryl rings include, but are not limited to, phenyl, naphthyl, indanyl, indenyl, tetralin, fluorenyl, and anthracenyl.
- An optionally substituted "aralkyl” can be substituted on both the alkyl and the aryl portion.
- an optionally substituted aralkyl is attached to the rest of the molecule through the alkyl chain and optionally substituted in the aryl portion.
- the same principle applies, for example, to a substituted aralkoxy, which would be attached to the rest of the molecule through the oxygen of the alkoxy and substituted on the aryl portion.
- a substituted aryloxyalkyl would be attached to the rest of the molecule through the alkyl chain and substituted on the aryl ring, which in turn would be attached to the alkyl chain through an oxygen atom.
- a bicyclic 6,5 heteroaromatic system as used herein, for example, is a six-membered heteroaromatic ring fused to a second five-membered ring wherein the radical or point of attachment is on the six-membered ring.
- Heteroaryl rings include, but are not limited to the following monocycles: 2- furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3- pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5- tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-
- cyclo encompasses mono-, bi- and tri-cyclic ring systems including cycloaliphatic, heterocyclic, aryl or heteroaryl, each of which has been previously defined.
- “Fused” bicyclic ring systems comprise two rings which share two adjoining ring atoms.
- “Bridged” bicyclic ring systems comprise two rings which share three or four adjacent ring atoms.
- the term “bridge” refers to a bond or an atom or a chain of atoms connecting two different parts of a molecule. The two atoms that are connected through the bridge (usually but not always, two tertiary carbon atoms) are referred to as "bridgeheads".
- bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza- bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl.
- ring atom refers to an atom such as C, N, O or S that is part of the ring of an aromatic group, a cycloaliphatic group or a heteroaryl ring.
- a “substitutable ring atom” is a ring carbon or nitrogen atom bonded to at least one hydrogen atom. The hydrogen can be optionally replaced with a suitable substituent group.
- substituted ring atom does not include ring nitrogen or carbon atoms which are shared when two rings are fused.
- substituted does not include ring carbon or nitrogen atoms when the structure depicts that they are already attached to one or more moiety other than hydrogen and no hydrogens are available for substitution.
- Heteroatom refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, including any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocyclic or heteroaryl ring, for example, N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR + (as in N-substituted pyrrolidinyl).
- Exemplary rings that are formed when two independent occurrences of a substituent are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of a substituent that are bound to the same atom and are taken together with that atom to form a ring, where both occurrences of the substituent are taken together with the atom to which they are bound to form a heterocyclyl, heteroaryl, carbocyclyl or aryl ring, wherein the group is attached to the rest of the molecule by a single point of attachment; and b) two independent occurrences of a substituent that are bound to different atoms and are taken together with both of those atoms to form a heterocyclyl, heteroaryl, carbocyclyl or aryl ring, wherein the ring that is formed has two points of attachment with the rest of the molecule.
- a phenyl group is substituted with two occurrences of R 0 as in Formula Dl:
- an alkyl or aliphatic chain can be optionally interrupted with another atom or group. This means that a methylene unit of the alkyl or aliphatic chain can optionally be replaced with said other atom or group.
- the optional replacements form a chemically stable compound.
- Optional interruptions can occur both within the chain and/or at either end of the chain; i.e. both at the point of attachment(s) to the rest of the molecule and/or at the terminal end.
- Two optional replacements can also be adjacent to each other within a chain so long as it results in a chemically stable compound.
- the replacement or interruption occurs at a terminal end of the chain, the replacement atom is bound to an H on the terminal end. For example, if
- a C3 aliphatic can be optionally replaced by -N(R S )-, -C(O)-, and -N(R $ )- to form -N(R $ )C(0)N(R s )- (a urea).
- the term "vicinal” refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to adjacent carbon atoms.
- terminal refers to the location of a group within a substituent.
- a group is terminal when the group is present at the end of the substituent not further bonded to the rest of the chemical structure.
- Carboxyalkyl i.e., R x O(0)C-alkyl is an example of a carboxy group used terminally.
- a group is internal when the group is present in the middle of a substituent at the end of the substituent bound to the rest of the chemical structure.
- Alkylcarboxy e.g., alkyl-C(0)0- or alkyl-O(CO)-
- alkylcarboxyaryl e.g., alkyl-C(0)0-aryl- or alkyl-O(CO)-aryl-
- carboxy groups used internally are examples of carboxy groups used internally.
- alkoxy or “alkylthio” refer to an alkyl group, as previously defined, attached to the molecule, or to another chain or ring, through an oxygen (“alkoxy,” e.g., -O-alkyl) or a sulfur (“alkylthio,” e.g., -S-alkyl) atom.
- alkoxy e.g., -O-alkyl
- sulfur e.g., -S-alkyl
- C n-m alkoxyalkyl
- C n-m alkoxyalkenyl
- C n . m alkoxyaliphatic
- alkoxyalkoxy mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more alkoxy groups, wherein the total number of carbons between the alky and alkoxy, alkenyl and alkoxy, aliphatic and alkoxy or alkoxy and alkoxy, as the case may be, is between the values of n and m.
- these moieties are optionally substituted they can be substituted in either of the portions on both sides of the oxygen or sulfur.
- an optionally substituted C 4 alkoxyalkyl could be, for instance, -CH 2 CH 2 OCH 2 (Me)CH 3 or -CH 2 (OH)0 CH 2 CH 2 CH 3 ;
- aryloxy refers to an aryl or benzyl group attached to the molecule, or to another chain or ring, through an oxygen (“aryloxy” “benzyloxy,” e.g., -O-Ph, -OCH 2 Ph) or sulfur (“arylthio,” e.g., -S-Ph, -S- CH 2 Ph) atom.
- aryloxyalkyl means alkyl, alkenyl or aliphatic, as the case may be, substituted with one or more aryloxy or benzyloxy groups, as the case may be.
- the number of atoms for each aryl, aryloxy, alkyl, alkenyl or aliphatic will be indicated separately.
- a 5-6-membered is a 5-6 membered aryl ring, attached via an oxygen atom to a C alkyl chain, which, in turn, is attached to the rest of the molecule via the terminal carbon of the C
- an optionally substituted "aralkyl” can potentially be substituted on both the alkyl and the aryl portion. Unless otherwise indicated, as used in this disclosure, an optionally substituted aralkyl is attached to the rest of the molecule through the alkyl chain and optionally substituted in the aryl portion. The same principle applies to, for example, substituted aralkoxy, which would be attached to the rest of the molecule through the oxygen of the alkoxy and substituted on the aryl portion. A substituted aryloxyalkyl would be attached to the rest of the molecule through the alkyl chain and substituted on the aryl ring, which in turn would be attached to the alkyl chain through an oxygen atom. For example, an optionally substituted 6-membered aryloxy(C3alkyl) group could be, for instance,
- an optionally substituted 6-membered heteroaryloxy(C 4 alkyl) could, for instance, be -CH 2 CH 2 CH 2 -0-(3-F-2-pyrydyl) or -CH(CH 3 )-0-CH 2 CH 2 -(5,6- dimethyl-l,3-pyrimidine). If the alkyl chain on the "aralkyl" group is also substituted that will be specifically indicated. For instance, an optionally substituted 6-membered
- heteroaryloxy(C 4 alkyl) that is also optionally substituted on the alkyl, would be referred to as "an optionally substituted 6-membered heteroaryloxy(C 4 alkyl), wherein said C 4 alkyl chain is optionally substituted".
- An example of this latter group could be 5, 6-dimethyl-l,3- pyrimidine-0-CF(CH 3 )-CH(OH)CH 2 -, wherein the alkyl chain is substituted with F and with -OH.
- haloalkyl means alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more halogen atoms.
- a Ci -3 haloalkyl could be -CFHCH 2 CHF 2 and a Q -2 haloalkoxy could be -OC(Br)HCHF 2 .
- This term includes perfluorinated alkyl groups, such as -CF 3 and -CF 2 CF 3 .
- cyano refers to -CN or -C ⁇ N.
- cyanoalkoxy mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more cyano groups.
- . cyanoalkyl could be -C(CN) 2 CH 2 CH 3 and a C
- -2 cyanoalkenyl could be CHC(CN)H 2 .
- amino refers to -NH 2 .
- aminoalkyl aminoalkenyl
- aminoaliphatic aminoalkyl
- aminoalkoxy mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more amino groups.
- a Ci -3 aminoalkyl could be -CH(NH 2 )CH 2 CH 2 NH 2 and a Ci. 2 aminoalkoxy could be -OCH 2 CH 2 NH 2 .
- hydroxyl or "hydroxy” refers to -OH.
- hydroxyalkyl means alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more -OH groups.
- -3 hydroxyalkyl could be
- -CH 2 (CH 2 OH)CH 3 and a C 4 hydroxyalkoxy could be -OCH 2 C(CH 3 )(OH)CH 3 .
- an “aroyl” or “heteroaroyl” refers to a -C(0)-aryl or a -C(O)- heteroaryl.
- the aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined.
- An aliphatic chain can be optionally interrupted by a carbonyl group or can optionally be substituted by an oxo group, and both expressions refer to the same: e.g., -CH 2 - C(0)-CH 3 .
- linker refers to a bifunctional chemical moiety attaching a compound to a solid support or soluble support.
- a linker can be a C
- An alternative way to define the same -CH 2 -NH-CH 2 -C(0)-CH 2 - and - CH 2 -NH-C(0)-CH 2 - groups is as a C 3 alkyl chain optionally interrupted by up to two -C(O)- or -NH- moieties.
- Cyclic groups can also form linkers: e.g., a 1,6-cyclohexanediyl R
- protecting group refers to an agent used to temporarily block one or more desired reactive sites in a multifunctional compound.
- a protecting group has one or more, or preferably all, of the following characteristics: a) reacts selectively in good yield to give a protected substrate that is stable to the reactions occurring at one or more of the other reactive sites; and b) is selectively removable in good yield by reagents that do not attack the regenerated functional group.
- Exemplary protecting groups are detailed in Greene, T. W., Wuts, P. G in Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
- nitrogen protecting group refers to an agents used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound.
- Preferred nitrogen protecting groups also possess the characteristics exemplified above, and certain exemplary nitrogen protecting groups are also detailed in Chapter 7 in Greene, T. W., Wuts, P. G in Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
- amide coupling agent or "amide coupling reagent” means a compound that reacts with the hydroxyl moiety of a carboxy moiety thereby rendering it susceptible to nucleophilic attack.
- exemplary amide coupling agents include DIC
- the compounds of the invention are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
- ring B is selected from the group consisting of phenyl and a 5-6-membered monocyclic
- heteroaryl ring wherein said monocyclic heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S;
- n is an integer selected from the group consisting of 0, 1, 2 and 3;
- each J is independently selected from the group consisting of halogen, -N0 2 , -CN, C
- each J C1 is independently selected from the group consisting of halogen, -N0 2 , -CN, C
- p is an integer selected from the group consisting of 0, 1, 2 and 3;
- R 2 is selected from the group consisting of halogen, -N0 2 , -CN, C ⁇ aliphatic, phenyl, a 5-6- membered heteroaryl ring and a C 3-7 cycloalkyl, wherein said Ci -6 aliphatic, phenyl, 5-6-membered heteroaryl ring and C 3-7 cycloalkyl is optionally substituted by up to three instances of halogen;
- R 4 is selected from the group consisting of hydrogen, halogen, -CN, C )-6 aliphatic, a C 3- cycloaliphatic ring, a 5-6-membered heteroaryl ring, phenyl, -OR Y and -SR Y ;
- R 5 is selected from the group consisting of hydrogen, halogen, -CN, Ci -6 aliphatic, a C 3-7 cycloaliphatic ring, a 5-6-membered heteroaryl ring, phenyl, -OR Y and -SR Y ;
- Ci -6 aliphatic, C 3 . 7 cycloaliphatic ring, 5-6-membered heteroaryl ring, and phenyl is optionally substituted with up to three instances of halogen, Ci -4 alkyl, CM alkoxy or Ci -4 haloalkoxy; or
- cycloaliphatic ring a 5-8-membered heterocyclic ring or a 5-membered heteroaryl ring
- said heterocyclic and heteroaryl ring formed by R 4 and R 5 contains up to three heteroatoms selected from the group consisting of N, O and S, and wherein said cycloaliphatic, heterocyclic and heteroaryl rings formed by R 4 and R 5 is optionally substituted by up to 3 instances of halogen, C alkyl, Q -4 haloalkyl, Q -4 alkoxy or CM haloalkoxy; and
- each R is independently selected from the group consisting of C
- each R is optionally substituted by up to six instances of halogen, C alkyl, Ci -4 haloalkyl, C alkoxy or CM haloalkoxy;
- ring B is an optionally substituted ring selected from the group consisting of phenyl, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, imidazole, pyrazole, furan, thiophene, triazole, tetrazole, thiazole, oxathiazole and oxazole.
- ring B is an optionally substituted pyridine or an optionally substituted phenyl. In still further embodiments, ring B is an optionally substituted pyridine. In other embodiments, ring B is an optionally substituted phenyl. [00169] In some embodiments, n is selected from the group consisting of 0 and 1.
- the invention relates to a compound of Formula III or a pharmaceutically acceptable salt thereof,
- a method for the treatment or prevention of autoimmune disorders comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of the pharmaceutical composition.
- the autoimmune disorder is selected from the group consisting of alopecia areata (also known as systemic sclerosis (SS)), amyloses, amyotrophic lateral sclerosis, ankylosing spondylarthritis, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune
- vascular dementia including multi-infarct dementia and dementia associated with intracranial space-occupying lesions, infections and related conditions such as HIV infection
- Guillain-Barre syndrome myasthenia gravis
- stroke and various forms of seizures (such as nodding spasms)
- blood diseases such as acquired hemolytic anemia, aplastic anemia, and idiopathic thrombocytopenia
- tumor diseases such as acute lymphatic leukemia, Hodgkin's disease, malignant lymphoma, lymphogranulomatoses, lymphosarcoma, solid malignant tumors, colorectal polyps, extensive metastases and other proliferative disorders such as diabetic retinopathy and tumor angiogenesis (e.g., wet macular degeneration); endocrine diseases such as endocrine opthalmopathy, endocrine orbitopathia, thyrotoxic crisis, Thyroiditis de
- endocrine diseases such as endocrine opthalmopathy, endocrine orbito
- a method for the treatment or prevention of pruritus comprises administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition discussed above.
- the pruritus is dermal pruritus, neuropathic pruritus, neurogenic pruritus or psychogenic pruritus.
- a method is provided for the treatment or prevention of substance abuse-related syndromes, disorders, diseases or withdrawal symptoms comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition discussed above.
- the method of treating substance abuse-related syndromes, disorders,, diseases or withdrawal symptoms are chosen from the group consisting of drug abuse and drug withdrawal, wherein the abused substances include alcohol, amphetamines,
- amphetamitte-1 ike substances caffeine, cannabis, cocaine, hallucinogens, inhalants, opioids, nicotine (and/or tobacco products), heroin abuse, barbiturates, phencyclidine (or
- dementia dementia, anxiety, psychosis, social affective disorders, and/or cognitive disorders
- manic-depressive psychoses bipolar disorders
- extreme psychotic states such as mania, schizophrenia, and excessive mood swings where behavioral stabilization is desired
- post-traumatic stress disorder panic disorder
- obsessive compulsive disorder psychiatric tremors such as dyskinesias, dystonia, and spasticity
- attention disorders such as ADHD (attention deficit hyperactivity disorders), autism, anxiety states, generalized anxiety, agoraphobia, as well as those behavioral states characterized by social withdrawal
- a method for the treatment or prevention of appetite-related disorders comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a
- the methods above are provided for the treatment of a human patient.
- the patient is a companion animal, exotic animal or a farm animal such as a dog, cat, mouse, rat, hamster, gerbil, guinea pig, rabbit, horse, pig or cow.
- a method for inhibiting FAAH in a biological sample comprising contacting said biological sample with a composition discussed herein.
- pharmaceutically acceptable salt refers to pharmaceutically acceptable organic or inorganic salts of a compound of Formula I.
- the salts of the compounds of Formula I will be pharmaceutically acceptable salts.
- Other salts may, however, be useful in the preparation of the compounds of Formula I or of their pharmaceutically acceptable salts.
- a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion.
- the counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.
- a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions.
- a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
- salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particular embodiments include ammonium, calcium, magnesium, potassium and sodium salts.
- Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.
- basic ion exchange resins such as arginine
- Particular embodiments include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.
- Other exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,
- benzenesulfonate p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3- naphthoate)) salts.
- the term "pharmaceutically acceptable solvate,” is a solvate formed from the association of one or more pharmaceutically acceptable solvent molecules to one of the compounds described herein.
- the term “hydrate” means a compound described herein or a salt thereof that further includes a stoichiometric or non- stoichiometric amount of water bound by non-covalent intermolecular forces.
- the term solvate includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).
- compositions to treat or prevent the disorders identified herein.
- pro-drug encompasses a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound described herein.
- pro-drugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of the invention that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues.
- pro-drugs include derivatives of compounds described herein that comprise -NO, -N0 2 , -ONO, or -ON0 2 moieties.
- Pro-drugs can typically be prepared using well-known methods, such as those described by Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed.).
- compositions and methods of administration are provided.
- a typical formulation is prepared by mixing a compound of Formula I, or a pharmaceutically acceptable salt, solvate, co-crystal or pro-drug thereof, and a carrier, diluent or excipient.
- Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
- the particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of Formula I is being formulated.
- Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (e.g., GRAS-Generally Regarded as Safe) to be administered to a mammal.
- safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
- Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc., and mixtures thereof.
- the formulations may also include other types of excipients such as one or more buffers, stabilizing agents, antiadherents, surfactants, wetting agents, lubricating agents, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g., enteric or slow release) preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of Formula I or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
- excipients such as one or more buffers, stabilizing agents, antiadherents, surfactants, wetting agents, lubricating agents, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g., enteric or slow release
- the formulations may be prepared using conventional dissolution and mixing procedures.
- the bulk drug substance i.e., compound of Formula I, a
- compositions such as a complex with a cyclodextrin derivative or other known complexation agent
- a compound having the desired degree of purity is optionally mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers, in the form of a lyophilized formulation, milled powder, or an aqueous solution.
- Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers.
- the pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8.
- the compound of Formula I or a pharmaceutically acceptable salt, solvate, co- crystal or pro-drug thereof is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.
- Pharmaceutical formulations of compounds of Formula I, or a pharmaceutically acceptable salt, solvate, co-crystal or pro-drug thereof may be prepared for various routes and types of administration. Various dosage forms may exist for the same compound, since different medical conditions may warrant different routes of administration.
- the amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the subject treated and the particular mode of administration.
- the initial pharmaceutically effective amount of the inhibitor administered will be in the range of about 0.01-100 mg/kg per dose, namely about 0.1 to 20 mg kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
- therapeutically effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
- the therapeutically or pharmaceutically effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to ameliorate, cure or treat the disease or disorder or one or more of its symptoms.
- compositions of Formula I will be formulated, dosed, and administered in a fashion, i.e., the amounts, concentrations, schedules, courses, vehicles, and route(s) of administration, consistent with good medical practice.
- Factors for consideration in this context include the particular disorder being treated, the particular human or other mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners, such as the age, weight, and response of the individual patient.
- Acceptable diluents, carriers, excipients, and stabilizers are those that are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride;
- hexamethonium chloride benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol;
- proteins such as serum albumin, gelatin, or immunoglobulins
- hydrophilic polymers such as polyvinylpyrrolidone
- amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine
- chelating agents such as EDTA
- sugars such as sucrose, mannitol, trehalose or sorbitol
- salt-forming counter-ions such as sodium
- metal complexes e.g., Zn-protein complexes
- non-ionic surfactants such as TWEENTM, PLURONICSTM or polyethylene glycol (PEG).
- Remington's The Science and Practice of Pharmacy, 21 st Edition, University of the Sciences in Philadelphia, Eds., 2005 (hereafter "Remington's”).
- Controlled drug delivery systems supply the drug to the body in a manner precisely controlled to suit the drug and the conditions being treated.
- the primary aim is to achieve a therapeutic drug concentration at the site of action for the desired duration of time.
- controlled release is often used to refer to a variety of methods that modify release of drug from a dosage form. This term includes preparations labeled as "extended release”, “delayed release”, “modified release” or “sustained release”.
- sustained-release preparations are the most common applications of controlled release. Suitable examples of sustained-release preparations include
- sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl- methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, and poly-D-(-)-3-hydroxybutyric acid.
- immediate-release preparations may also be prepared.
- the objective of these formulations is to get the drug into the bloodstream and to the site of action as rapidly as possible. For instance, for rapid dissolution, most tablets are designed to undergo rapid disintegration to granules and subsequent disaggregation to fine particles. This provides a larger surface area exposed to the dissolution medium, resulting in a faster dissolution rate.
- Implantable devices coated with a compound of this invention are another embodiment of the present invention.
- the compounds may also be coated on implantable medical devices, such as beads, or co-formulated with a polymer or other molecule, to provide a "drug depot", thus permitting the drug to be released over a longer time period than administration of an aqueous solution of the drug.
- implantable medical devices such as beads, or co-formulated with a polymer or other molecule
- the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
- the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
- the formulations include those suitable for the administration routes detailed herein.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
- administer in reference to a compound, composition or formulation of the invention mean introducing the compound into the system of the animal in need of treatment.
- administration and its variants are each understood to include concurrent and/or sequential introduction of the compound and the other active agents.
- compositions described herein may be administered systemically or locally, e.g.: orally (e.g., using capsules, powders, solutions, suspensions, tablets, sublingual tablets and the like), by inhalation (e.g., with an aerosol, gas, inhaler, nebulizer or the like), to the ear (e.g., using ear drops), topically (e.g., using creams, gels, liniments, lotions, ointments, pastes, transdermal patches, etc.), ophthalmically (e.g., with eye drops, ophthalmic gels, ophthalmic ointments), rectally (e.g., using enemas or suppositories), nasally, buccally, vaginally (e.g., using douches, intrauterine devices, vaginal suppositories, vaginal rings or tablets, etc.), via an implanted reservoir or the like, or parenterally depending on the severity and
- parenteral includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
- the compositions are administered orally, intraperitoneally or intravenously.
- the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
- Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
- the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl
- Tablets may be uncoated or may be coated by known techniques including microencapsulation to mask an unpleasant taste or to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
- a time-delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
- a water soluble taste-masking material such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose may be employed.
- compositions may be prepared as discrete units such as tablets, pills, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs.
- Formulations of a compound intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
- Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
- an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
- water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
- the active compounds can also be in microencapsulated form with one or more excipients as noted above.
- aqueous suspensions When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
- sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
- Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
- Sterile injectable forms of the compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- sterile, fixed oils are conventionally employed as a solvent or suspending medium.
- any bland fixed oil may be employed including synthetic mono- or di- glycerides.
- Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
- These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
- surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of injectable formulations.
- Oily suspensions may be formulated by suspending the compound of Formula I in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
- the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation.
- These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha- tocopherol.
- Aqueous suspensions of compounds of Formula I contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients include a suspending agent, such as sodium carboxymethylcellulose,
- croscarmellose povidone, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
- a naturally occurring phosphatide e.g., lecithin
- a condensation product of an alkylene oxide with a fatty acid e.g., polyoxyethylene stearate
- the aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
- the injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
- the rate of compound release can be controlled.
- biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot-injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
- the injectable solutions or microemulsions may be introduced into a patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound.
- a continuous intravenous delivery device may be utilized.
- An example of such a device is the Deltec CADD-PLUSTM model 5400 intravenous pump.
- compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax that are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax that are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax that are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
- Other formulations suitable for vaginal administration may be presented as pes
- compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the ear, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
- Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
- the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
- Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention.
- the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body.
- Such dosage forms can be made by dissolving or dispensing the compound in the proper medium.
- Absorption enhancers can also be used to increase the flux of the compound across the skin.
- the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
- Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.
- Topically-transdermal patches may also be used.
- the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers.
- Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
- the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
- Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.
- compositions may be formulated in an ointment such as petrolatum.
- an ointment such as petrolatum
- the formulations may be applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w.
- the active ingredients may be employed with either an oil-based, paraffinic or a water-miscible ointment base.
- the active ingredients may be formulated in a cream with an oil- in-water cream base.
- the aqueous phase of the cream base may include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
- the topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.
- the oily phase of emulsions prepared using compounds of Formula I may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. A hydrophilic emulsifier may be included together with a lipophilic emulsifier which acts as a stabilizer. In some embodiments, the emulsifier includes both an oil and a fat.
- Emulgents and emulsion stabilizers suitable for use in the formulation of compounds of Formula I include Tween -60, Span -80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
- Formulations suitable for intrapulmonary or nasal administration have a mean particle size, for example, in the range of 0.1 to 500 microns (including particles with a mean particle size in a range between 0.1 and 500 microns in micron increments such as 0.5, 1, 30, 35 microns, etc.), and are administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
- the pharmaceutical composition may be packaged in a variety of ways depending upon the method used for administering the drug.
- an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form.
- Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like.
- the container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package.
- the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
- the formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use.
- sterile liquid carrier for example water
- Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
- Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as recited herein above, or an appropriate fraction thereof of the active ingredient.
- a compound of Formula I or a pharmaceutically acceptable salt, co-crystal, solvate or pro-drug thereof may be formulated in a veterinary composition comprising a veterinary carrier.
- Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials that are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.
- the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit).
- a farm animal e.g., a horse, cow, pig or sheep
- a pet e.g., a dog, cat, guinea pig or rabbit
- the subject is a "human”.
- biological sample includes, without limitation, in vivo or ex vivo cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; blood, saliva, urine, feces, semen, tears, lymphatic fluid, ocular fluid, vitreous humor or other body fluids or extracts thereof.
- Neuralgia is also involved in disorders such as sciatica and brachial plexopathy with neuropathia. Neuralgias that do not involve the trigeminal nerve are occipital neuralgia and glossopharyngeal neuralgia. Neuropathic pain also includes referred pain.
- alopecia areata also known as systemic sclerosis (SS)
- amyloses amyotrophic lateral sclerosis
- ankylosing spondylarthritis ankylosing spondylitis
- neurodegenerative diseases include dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease, prion disease and Creutzfeldt-Jakob disease, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); dementia in Parkinson's disease; metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with aging, particularly Age-Associated Memory Impairment.
- dementia particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease, prion disease and Creutzfeldt-Jakob disease, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); dementia in Parkinson's disease; metabolism; toxins;
- Compounds and compositions of the invention are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including, without limitation, dogs, cats, mice, rats, hamsters, gerbils, guinea pigs, rabbits, horses, pigs and cattle.
- the terms “in combination” or “co-administration” can be used interchangeably to refer to the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents).
- the use of the terms does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject.
- a first therapy e.g., a prophylactic or therapeutic agent such as a compound described herein
- a first therapy can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks subsequent to) the administration of a second therapy (e.g., a prophylactic or therapeutic agent such as an anticancer agent) to a subject.
- a second therapy e.g., a prophylactic or therapeutic agent such as an anticancer agent
- Additional therapeutic agents that can be combined with compounds described herein include, without limitation:
- fenamic acid derivatives meclofenamic acid, mefe-namic acid, and tolfenamic acid
- oxicams isoxicam, meloxicam, piroxicam, sudoxicam and tenoxican
- salicylates acetyl salicylic acid, sulfasalazine
- pyrazolones azolones
- sodium channel blockers such as carbamazepine, mexiletine, lamotrigine, pregabalin, tectin, NW-1029, CGX-1002;
- N-type calcium channel blockers such as Ziconotide, NMED-160, SPI-860; serotonergic and noradrenergic modulators such as SR-57746, paroxetine, duloxetine, clonidine, amitriptyline, citalopram;
- VR1 agonists and antagonists such as NGX-4010, WL-1002, ALGRX-4975, WL-10001, AMG-517;
- anti-inflammatory and/or immunosuppressive agents such as methotrexate, cyclosporin A (including, for example, cyclosporin microemulsion), tacrolimus,
- ADD/ADHD agents e.g., RitalinTM (methylphenidate hydrochloride), StratteraTM (atomoxetine hydrochloride), ConcertaTM (methylphenidate hydrochloride) and AdderallTM (amphetamine aspartate; amphetamine sulfate; dextroamphetamine saccharate; and dextroamphetamine sulfate);
- agents to treat alcoholism such as opioid antagonists (e.g., naltrexone (also known under the tradename ReVia M) and nalmefene), disulfiram (also known under the tradename AntabuseTM), and acamprosate (also known under the tradename CampralTM));
- opioid antagonists e.g., naltrexone (also known under the tradename ReVia M) and nalmefene
- disulfiram also known under the tradename AntabuseTM
- acamprosate also known under the tradename CampralTM
- agents used to treat glaucoma e.g., direct- acting Miotics (cholinergic agonists), indirect acting Miotics (cholinesterase inhibitors), Carbonic anhydrase inhibitors (e.g., Acetazolamide, Methazolamide, Brinzolamide, Dorzolamide), Selective adrenergic agonists (e.g., Apraclonidine, Brimonidine), Beta-blockers (Timolol, Betaxolol, Carteolol, Levobetaxolol, Levobunolol, Metipranolol), Osmotic diuretics (e.g., Glycerin, Mannitol);
- anti-emetic agents e.g., 5HT3 antagonists such as ondansetron, granisetron, metoclopramide;
- antipsychotic medications e.g., ziprasidone (GeodonTM), risperidone
- PDE4 inhibitors such as theophylline, drotaverine hydrochloride, cilomilast, roflumilast, denbufylline, rolipram, tetomilast, enprofylline, arofylline, cipamfylline, tofimilast, filaminast, piclamilast, (R)-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2- phenylethyl]pyridine, mesopram, N-(3,5-dichloro-4-pyridinyl)-2-[ l-(4-fluorobenzyl)-5- hydroxy-lH- -indol-3-yl]-2-oxoacetamide, CDC-801 (Celgene), CC-1088 (Celgene), Lirimilast, ONO-6126 (Ono), CC-10004 (Ce
- corticosteroids such as betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone;
- histamine HI receptor antagonists such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdiazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, desloratadine, fexofenadine and levocetirizine;
- histamine H2 receptor antagonists such as cimetidine, famotidine and ranitidine;
- leukotriene antagonists and 5-lipoxygenase inhibitors such as zafirlukast, montelukast, pranlukast and zileuton;
- P2X3 receptor antagonists such as A-317491 , ISIS- 13920, AZD-9056;
- NGF agonists and antagonists such as RI-724, RI-1024, AMG-819, AMG- 403, PPH 207;
- NMDA antagonist such as NER-MD-1 1, CNS-5161, EAA-090, AZ-756, CNP-3381; potassium channel modulators such as CL-888, ICA-69673, retigabine;
- GABA modulators such as lacosamide and propofol
- anti-cancer agents such as tyrosine kinase inhibitors imatinib (Gleevec Glivec) and gefitinib (Iressa);
- anti hyperlipidemia drugs such as statins, ezetimibe, niacin and bile acid sequestrants;
- appetite suppressing agents e.g., sibutramine, taranabant, rimobamant;
- anti-diabetic medications such as insulin, tolbutamide (Orinase),
- GI agents e.g., laxatives (e.g., Lubiprostone (Amitiza), Fybogel®, Regulan®, Normacol® and the like), a gastrointestinal agent used for the treatment of idiopathic chronic constipation and constipation-predominant IBS, GI motility stimulants (e.g., domperidone, metoclopramide, mosapride, itopride), antispasmodic drugs (e.g., anticholinergics such as hyoscyamine or dicyclomine); anti-diarrheal medicines such loperamide (Imodium) and bismuth subsalicylate (as found in Pepto Bismol and Kaopectate), GCC (Guanylate Cyclase C) agonists (e.g., Linaclotide), 5HT4 agonists (e.g., Tegasarod), 5HT3 antagonists (e.g.,
- the compounds of Formula I may be prepared according to the schemes and examples depicted and described below. Unless otherwise specified, the starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available compounds or prepared using well-known synthetic methods.
- a compound of Formula 3 can be synthesized by the alkylation of a compound of Formula 2a by reaction with the appropriate protected (trapped) enolate compound of Formula 2b, wherein X is a leaving group and PG is an oxygen protecting group (Scheme la). Deprotection of the alcohol functionality (e.g., under acidic conditions), then releases the enolate, which tautomerizes in situ to the carbonyl compound of Formula 3.
- a compound of Formula 5 can be prepared from a compound of Formula 4 via the magnesium-mediated radical reduction of the ⁇ , ⁇ -unsaturation in the presence of trimethylsilyl chloride, followed by nucleophilic attack of the resulting ⁇ -carbanion onto an electrophile such as an acid chloride or anhydride. (Scheme lb).
- a compound of Formula 7 can be synthesized by the condensation reaction of a primary amine of general formula R 6 NH 2 , and a 1 ,4-dicarbonyl moiety of Formula 3 (Scheme 2).
- a compound of Formula 8 can then be obtained from the intermediate of Formula 7 by electrophilic aromatic substitution at position three of the pyrrole ring using oxalyl chloride. This creates an intermediate a-keto acid chloride, which is subsequently aminated by a primary amine of general formula R 6 NH 2 to produce a pyrrole of Formula 8.
- a compound of Formula 10 can be synthesized by the condensation of a
- the pyrrole nitrogen of a compound of Formula 12 can be alkylated to form the corresponding compound of Formula 13 using an appropriate alkylating agent. As in
- LC/MS was run on a Waters Acquity system using a Polar CI 8 column, and 5 to 60% acetonitrile/water over 5 min.
- the ionization method for the MS was electrospray.
- Microwave reactions were run on a Personal Chemistry Optimizer, at 0-240 °C, a power of 0-300 W and a pressure of 0-21 bar.
- Solvent A 0.1% Trifluoroacetic acid in water
- Solvent B 0.1% Trifluoroacetic acid in acetonitrile
- I- 10 was prepared according to Schemes la and 2. ⁇ NMR (CDCl 3 /400 MHz) ⁇ 8.81 (s, IH), 7.82 (d, IH), 7.50 (d, IH), 7.30 (d, 2H), 7.14 (d, IH), 6.88 (d, 2H), 5.01 (s, 2H), 2.78 (t, 2H), 2.57-2.54 (m, 2H), 2.36 (s, 3H), 1.68-1.60 (m, 2H), 1.42-1.34 (m, 6H); MS m/z: 468 (M + 1).
- resuspension buffer 50 mM Tris-HCl buffer, pH 7.4, containing 1 mM EDTA and 3 mM MgCl 2 .
- a Bradford Protein assay was performed to determine protein
- the protein was aliquotted into screw cap Cryo tubes each containing ⁇ 400iL, flash frozen in liquid nitrogen and stored at -80 °C until used for the assay. A similar protocol was used to obtain brain membrane homogenates from mice.
- mice housed at the animal care facility of Ironwood Pharmaceuticals were anesthetized by isoflurane anesthesia and rapidly decapitated using a small decapitator (Harvard Apparatus part # PY8 SS-0012, Holliston, Massachusetts).
- Whole brain tissue from these mice was collected (approximately 9.4 g total) and placed on aluminum foil sitting on dry ice to flash freeze the tissue. Tissue was thawed and used to prepare microsomes as described above for rat brain homogenates.
- RBM rat brain membrane
- Assay of FAAH activity in rat brain membrane (RBM) homogenates RBM homogenates (7 ⁇ g protein in 20 pL final volume of 10 mM Tris pH 6.5) were mixed with 180 ⁇ _, of a mixture of the following: 2.0 ⁇ unlabelled anandamide, 0.03 ⁇ ' radio labeled anandamide [ethanolamine 1- H] (40-60 Cis/mmol, product number ART- 626, American Radiolabeled Chemicals, St.
- Bovine Serum Albumin fatty acid-free BSA, electrophoresis grade, Sigma, St. Louis, MO
- 10 mM Tris-HCl pH 6.5
- 1 mM EDTA in the presence and absence of test compounds (vehicle was DMSO at a final concentration of 1%) and incubated for 10 minutes at 37 °C. Samples were placed on ice to terminate the reactions.
- Radioactivity (corresponding to FAAH-catalyzed breakdown of 3 H-anandamide) found in aliquots (0.2 mL) of the aqueous phase was determined by liquid scintillation counting with quench correction. IC50 values were determined as described by Jonsson et al. (2001 Br. J Pharmacol. 133: 1263). Alternatively, reactions were purified using a modification of the solid-phase extraction method described by Wilson et al (2003 Anal. Biochem. 318 : 270). This method was modified as follows: after reactions were incubated at 37 °C for 10 minutes and chilled on ice, the reaction mixtures were acidified by adding 10 ⁇ . of sodium phosphate solution [0.5M (pH 2.0)].
- the known FAAH inhibitors 3'-(aminocarbonyl)biphenyl-3-yl cyclohexylcarbamate (URB597), [ l-(4- chlorobenzoyl)-5-methoxy-2-methyl-lH-indol-3-yl]acetic acid (indomethacin) and 5- benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylic acid (Ketorolac) were used as controls in these assays.
- Example 6 Whole cell anandamide hydrolysis assay:
- cDNA expression clone for human FAAH-1 (in pcDNA3 vector) (Genbank Accession U82535; obtained from Benjamin Cravatt, Scripps Research Institute, La Jolla, California) was linearized by digestion with BglH (New England Biolabs) and transfected by calcium phosphate into human HeLa cells (ATCC catalog #CCL-2).
- the HeLa cell line was selected as a host because it does not express FAAH or exhibit FAAH activity such that all subsequent activity can be attributed to the transfected gene.
- Clone 5c5 (50,000 cells in 150 ⁇ ) was seeded into 96- well plates and incubated overnight (5% C0 2 , 37 °C). Media was carefully replaced with 180
- the charcoal glass fiber filter plates were pre-washed with methanol by centrifugation 650 x g for 10 min). Next, 80 ⁇ . of water was added to the wells of the pre-washed 96-well charcoal filter plate. Then, 90 ⁇ , of the acidified reaction mixture was added to the water in the wells of the charcoal plate. The samples were centrifuged as above. The substrate remained bound to the charcoal, whereas the [ H]-ethanolamine product formed flowed through and was transferred to the microplates containing scintillation cocktail and quantified in a micro-plate scintillation counter (Perkin-Elmer Microbeta).
- the LC/MS MS method used a Waters 2777 sample manager, 1525 binary pump, and Quattro micro mass spectrometer. The separation was performed on a Waters Xterra MS C8, 5 ⁇ ⁇ ⁇ , 2.1 x 20 mm analytical LC column with a Thermo Electron Javelin Basic 8, 2 x 10 mm guard column at a flow rate of 0.30 mL/min and a 25 ⁇ _ injection volume. A binary linear gradient of mobile phase A (10 mM ammonium acetate in water (pH 9.5)) and mobile phase B (80:20 acetonitrile:methanol) was used from 2.0 to 2.2 minutes from 25% to 90% B, with a total run time of 6.0 minutes per sample injection.
- mobile phase A (10 mM ammonium acetate in water (pH 9.5)
- mobile phase B 80:20 acetonitrile:methanol
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present disclosure relates to N-benzyl pyrrole compounds of formula (I) useful as inhibitors of the enzyme Fatty Acid Amide Hydrolase (FAAH). The disclosure also provides pharmaceutically acceptable compositions comprising the compounds of the disclosure and methods of using the compositions in the treatment or prevention of various disorders.
Description
FAAH Inhibitors
PRIORITY CLAIM
[00100] This application claims priority to U.S. Provisional Application No.
61/267,696, filed on December 8, 2009. The entire contents of the aforementioned application are incorporated herein by reference.
TECHNICAL FIELD
[00101] The present disclosure relates to N-benzyl pyrrole compounds useful as inhibitors of the enzyme Fatty Acid Amide Hydrolase (FAAH). The disclosure also provides pharmaceutically acceptable compositions comprising the compounds of the disclosure and methods of using the compositions in the treatment of various disorders.
BACKGROUND
[00102] The endocannabinoid (eCB) system has been implicated in a variety of processes including cell signaling, memory encoding, compensatory mechanisms, and immunosuppressant and anti-inflammatory responses. The eCB system comprises at least two receptors: the CB 1 cannabinoid receptor, widely distributed in the brain and present in some peripheral organs, and the CB2 receptor, found principally in the periphery and immune systems and in some regions of the brain. The endogenous agonists of these receptors are the endogenous cannabinoids (eCBs), a family of lipids comprising the fatty acid Anandamide (AEA) as well as other fatty acids.
[00103] Endocannabinoid-degrading enzymes, including fatty acid amide hydrolase
(FAAH), are responsible for cleaving and deactivating eCBs in vivo. FAAH is an integral membrane protein that is expressed in high levels in several brain regions, especially in the neurons of the hippocampus, cerebellum, neocortex and olfactory bulb. FAAH is the principal enzyme responsible for the hydrolysis of AEA in vivo and is also capable of hydrolyzing a wide variety of other substrates. It is known that inhibiting FAAH can lead to increases in fatty acids, including AEA, which could enhance cannabinoid signals within the eCB system. It has also been demonstrated that a number of fatty acid amides can induce analgesia in acute and chronic animal models of pain. Thus, increasing the level of AEA and
other fatty acid amides (e.g., N-palmitoyl ethanolamide, N-oleoylethanol amide and oleamide) by inhibiting FAAH may lead to an increase in the nociceptive threshold. For these reasons, inhibitors of FAAH are useful in the treatment of pain. Inhibitors of FAAH might also be useful in the treatment of other disorders involving deregulation of the eCB system (e.g., anxiety, eating disorders, gastrointestinal and cardiovascular disorders, inflammation, excitotoxic insult, brain trauma and gastrointestinal diseases), and may avoid some of the side effects typically associated with CB receptor agonists (e.g., catalepsy or hypothermia).
[00104] In addition, there is evidence that when FAAH activity is reduced or absent, AEA acts as a substrate for COX-2, which can convert it to a prostamide. Thus, certain prostamides may be elevated in the presence of an FAAH inhibitor. Given that certain prostamides are associated with reduced intraocular pressure and ocular hypotensivity, FAAH inhibitors may also be useful agents for treating glaucoma.
SUMMARY
[00105] The compounds of the instant disclosure, and their pharmaceutically acceptable salts thereof, are useful as FAAH inhibitors. They are represented by the general formula I,
Formula I
wherein:
ring B is selected from the group consisting of phenyl and a 5-6-membered monocyclic heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S;
n is an integer selected from the group consisting of 0, 1 , 2 and 3;
each JB1 is independently selected from the group consisting of halogen, -N02, -CN, C|-6 aliphatic, C3-6 cycloaliphatic, Ci-6 haloaliphatic, Ci-6 alkoxy, Ci-6 haloalkoxy and C3-6 cycloalkoxy;
each J is independently selected from the group consisting of halogen, -N02, -CN, Ci.6 aliphatic, C3.6 cycloaliphatic, C|-6 haloaliphatic, C|-6 alkoxy, C|-6 haloalkoxy and C3-6 cycloalkoxy;
p is an integer selected from the group consisting of 0, 1, 2 and 3;
R is selected from the group consisting of halogen, -N02, -CN, C\* aliphatic, phenyl, a 5-6- membered heteroaryl ring and a C3.7 cycloalkyl, wherein said Ci_6 aliphatic, phenyl, 5-6-membered heteroaryl ring and C3.7 cycloalkyl is optionally substituted by up to three instances of halogen;
R4 is selected from the group consisting of hydrogen, halogen, -CN, C|.6 aliphatic, a C3-7 cycloaliphatic ring, a 5-6-membered heteroaryl ring, phenyl, -ORY and -SRY;
R5 is selected from the group consisting of hydrogen, halogen, -CN, C|-6 aliphatic, a C3.7
Y Y
cycloaliphatic ring, a 5-6-membered heteroaryl ring, phenyl, -OR and -SR ;
wherein said Ci-6 aliphatic, C3-7 cycloaliphatic ring, 5-6-membered heteroaryl ring, and phenyl is optionally substituted with up to three instances of halogen, Ci-4 alkyl, C haloalkyl, Ci-4 alkoxy or C haloalkoxy; or
R4 and R5, together with the two carbon atoms to which they are attached, form a C5-8
cycloaliphatic ring, a 5-8-membered heterocyclic ring or a 5-membered heteroaryl ring; wherein said heterocyclic and heteroaryl ring formed by R4 and R5 contain up to three heteroatoms selected from the group consisting of N, O and S, and wherein said cycloaliphatic, heterocyclic and heteroaryl ring formed by R4 and R5 is optionally substituted by up to 3 instances of halogen, C|-4 alkyl, CM haloalkyl, C1.4 alkoxy or Ci-4 haloalkoxy; and
each R is independently selected from the group consisting of Ci-6 aliphatic, C3-7
cycloaliphatic, a 5-6-membered heteroaryl ring and phenyl, wherein each RY is optionally substituted by up to six instances of halogen, C|-4 alkyl, CM haloalkyl, C]-4 alkoxy or CM haloalkoxy; provided that the compound is not:
[00106] The invention also relates to pharmaceutical compositions comprising a compound according to formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle or adjuvant. Also within the scope of the invention are pharmaceutical compositions further comprising at least one additional therapeutic agent.
[00107] The invention also relates to methods for the treatment or prevention of pain; autoimmune disorders; disease-states or indications that are accompanied by inflammatory processes; gastrointestinal diseases or disorders; pruritus; substance abuse related syndromes, disorders, diseases or withdrawal symptoms; psychiatric disorders; neurological or neurodegenerative disorders; ocular disorders; appetite-related disorders; gynecological disorders and sleep disorders.
DETAILED DESCRIPTION
[00108] Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulae. While the invention will be described in conjunction with the disclosed embodiments, it will be understood that they are not intended to limit the invention to those embodiments. Rather, the invention is intended to cover all alternatives, modifications and equivalents that may be included within the scope of the present invention as defined by the claims. The present invention is not limited to the methods and materials described herein but include any methods and materials similar or equivalent to those described herein that could be used in the practice of the present invention. In the event that one or more of the incorporated literature references, patents or similar materials differ from or contradict this application, including but not limited to defined terms, term usage, described techniques or the like, this application controls.
Description of Exemplary Compounds:
Definitions and general terminology
[00109] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Ed. 1994. Additionally, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry, 5th Ed., Smith, M. B. and March, J., eds. John Wiley & Sons, New York: 2001, which are herein incorporated by reference in their entirety.
[00110] As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention. The phrase "optionally substituted" is used interchangeably with the phrase "substituted or
unsubstituted." In general, the term "substituted" refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. If a substituent radical or structure is not
identified or defined as "optionally substituted", the substituent radical or structure is not substituted. As it will be apparent to one of ordinary skill in the art, groups such as -H, halogen, -N02, -CN, -OH, -NH2 or -OCF3 would not be substitutable groups.
[00111] The phrase "up to", as used herein, refers to zero or any integer number that is equal to or less than the number following the phrase. For example, optionally substituted with "up to 3" means substituted with 0, 1, 2, or 3 substituents. As described herein, a specified number range of atoms includes any integer therein. For example, a group having from 1-4 atoms could have 1, 2, 3 or 4 atoms. It will be understood by one of ordinary skill in the art that when a group is characterized as substituted (as opposed to optionally substituted) with, e.g., "up to 3" substituents, it can only be substituted with 1, 2 or 3 substituents.
[00112] When any variable occurs more than one time at any position, its definition on each occurrence is independent from every other occurrence.
[00113] Selection of substituents and combinations envisioned by this disclosure are only those that result in the formation of stable or chemically feasible compounds. Such choices and combinations will be apparent to those of ordinary skill in the art and may be determined without undue experimentation. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions that allow for their production, detection, and, in some embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 25°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
[00114] A compound, such as the compounds of the invention or other compounds herein disclosed, may be present in its free form (e.g., an amorphous form or polymorphs). Under certain conditions, compounds may also form salts, and/or other multi-component crystalline forms (e.g., solvates (i.e., hydrates), and co-crystals). As used herein, the term co- form is synonymous with the term multi-component crystalline form. When one of the components in the co-form has clearly transferred a proton to the other component, the resulting co-form is referred to as a "salt". When both compounds in a multi-component crystalline form are independently solids at room temperature, the resulting co-form is referred to as a "co-crystal". In co-crystals no proton transfer takes place between the different components of the co-form. The formation of a salt or a co-crystal is determined by
how large is the difference in the pKas between the partners that form the mixture. As used herein, a "solvate" refers to an association or complex of one or more solvent molecules and a compound disclosed herein (or its salts or co-crystals). A "hydrate" is a particular type of solvate in which the solvent is water. Examples of solvents that can form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, dimethyl sulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, tetrahydrofuran (THF), dichloromethane (DCM), NJV-dimethylformamide (DMF).
[00115] Unless only one of the isomers is drawn or named specifically, structures depicted herein are also meant to include all stereoisomeric (e.g., enantiomeric,
diastereomeric, atropoisomeric and cis-trans isomeric) forms of the structure; for example, the R and S configurations for each asymmetric center, Ra and Sa configurations for each asymmetric axis, (Z) and (E) double bond configurations, and cis and trans conformational isomers. Therefore, single stereochemical isomers as well as racemates, and mixtures of enantiomers, diastereomers, and cis-trans isomers (double bond or conformational) of the present compounds are within the scope of the present disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the present disclosure are within the scope of the disclosure.
[00116] The present disclosure also embraces isotopically labeled compounds that are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, ¾, nC, ,3C, ,4C, l3N, 15N, ,50, 170, ,80, 32P, 33P, 35S, 18F, 36C1, ,23I, and 125I, respectively. Certain isotopically labeled compounds of the present invention (e.g., those labeled with 3H and l4C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., I4C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron-emitting isotopes such as 150, 13N, nC, and 18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy.
Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
[00117] The terms "aliphatic" or "aliphatic group", as used herein, mean a straight- chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms and in yet other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Specific examples of aliphatic groups include, but are not limited to: methyl, ethyl, propyl, butyl, isopropyl, isobutyl, vinyl, sec- butyl, terr-butyl, butenyl, propargyl, acetylene and the like.
[00118] The term "alkyl", as used herein, refers to a saturated linear or branched-chain monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group contains 1-20 carbon atoms (e.g., 1-20 carbon atoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, 1^1 carbon atoms or 1-3 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, heptyl, octyl and the like.
[00119] The term "alkenyl" refers to a linear or branched-chain monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon, sp1 double bond, wherein the alkenyl radical includes radicals having "cis" and "trans" orientations, or alternatively, Έ" and "Z" orientations. Unless otherwise specified, an alkenyl group contains 2-20 carbon atoms (e.g., 2-20 carbon atoms, 2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms or 2-3 carbon atoms). Examples include, but are not limited to, vinyl, allyl and the like.
[00120] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical with at least one site of unsaturation, i.e., a carbon-carbon sp triple bond. Unless otherwise specified, an alkynyl group contains 2-20 carbon atoms (e.g., 2-20 carbon atoms,
2-10 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, 2-4 carbon atoms or 2-3 carbon atoms). Examples include, but are not limited to, ethynyl, propynyl, and the like.
[00121] The term "carbocyclic" refers to a ring system formed only by carbon and hydrogen atoms. Unless otherwise specified, throughout this disclosure, carbocycle is used as a synonym of "non-aromatic carbocycle" or "cycloaliphatic"). In some instances, the term can be used in the phrase "aromatic carbocycle", and in this case it refers to an "aryl group" as defined below.
[00122] The term "cycloaliphatic" (or "non-aromatic carbocycle", "non-aromatic carbocyclyl", "non-aromatic carbocyclic") refers to a cyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation but which is not aromatic, and which has a single point of attachment to the rest of the molecule. Unless otherwise specified, a cycloaliphatic group may be monocyclic, bicyclic, tricyclic, fused, spiro or bridged. In one embodiment, the term "cycloaliphatic" refers to a monocyclic C3-C12 hydrocarbon or a bicyclic C7-Ci2 hydrocarbon. In some embodiments, any individual ring in a bicyclic or tricyclic ring system has 3-7 members. Suitable cycloaliphatic groups include, but are not limited to, cycloalkyl, cycloalkenyl, and cycloalkynyl. Examples of aliphatic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,
cyclohexenyl, cycloheptyl, cycloheptenyl, norbornyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.
[00123] The term "cycloaliphatic" also includes polycyclic ring systems in which the non-aromatic carbocyclic ring can be "fused" to one or more aromatic or non-aromatic carbocyclic or heterocyclic rings or combinations thereof, as long as the radical or point of attachment is on the non-aromatic carbocyclic ring.
[00124] The term "heterocycle" (or "heterocyclyl" or "heterocyclic), as used herein, refers to a ring system in which one or more ring members are an independently selected heteroatom, which is completely saturated or that contains one or more units of unsaturation but which is not aromatic, and which has a single point of attachment to the rest of the molecule. Unless otherwise specified, through this disclosure, heterocycle is used as a synonym of "non-aromatic heterocycle"). In some instances the term can be used in the phrase "aromatic heterocycle", and in this case it refers to a "heteroaryl group" as defined below. The term heterocycle also includes fused, spiro or bridged heterocyclic ring systems. Unless otherwise specified, a heterocycle may be monocyclic, bicyclic or tricyclic. In some embodiments, the heterocycle has 3-18 ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur or nitrogen, and each ring in the system contains 3 to 7 ring members. In other embodiments, a heterocycle may be a
monocycle having 3-7 ring members (2-6 carbon atoms and Ι^ heteroatoms) or a bicycle having 7-10 ring members (4-9 carbon atoms and 1-6 heteroatoms). Examples of bicyclic heterocyclic ring systems include, but are not limited to: adamantanyl, 2-oxa- bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl.
[00125] As used herein, the term "heterocycle" also includes polycyclic ring systems wherein the heterocyclic ring is fused with one or more aromatic or non-aromatic carbocyclic or heterocyclic rings, or with combinations thereof, as long as the radical or point of attachment is in the heterocyclic ring.
[00126] Examples of heterocyclic rings include, but are not limited to, the following monocycles: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3- tetrahydrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino, 2-thiomorpholino, 3- thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1- tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3-tetrahydropiperazinyl, 1-piperidinyl, 2- piperidinyl, 3-piperidinyl, 1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-thiazolidinyl, 3 -thiazolidinyl, 4- thiazolidinyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl; and the following bicycles: 3-lH-benzimidazol-2-one, 3-(l-alkyl)-benzimidazol-2-one, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane, benzodithiane, and 1,3-dihydro- imidazol-2-one.
[00127] As used herein, the term "aryl" (as in "aryl ring" or "aryl group"), used alone or as part of a larger moiety, as in "aralkyl", "aralkoxy", "aryloxyalkyl", refers to a carbocyclic ring system wherein at least one ring in the system is aromatic and has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aryl group may be monocyclic, bicyclic or tricyclic and contain 6-18 ring members. The term also includes polycyclic ring systems where the aryl ring is fused with one or more aromatic or non-aromatic carbocyclic or heterocyclic rings, or with combinations thereof, as long as the radical or point of attachment is in the aryl ring. Examples of aryl rings include, but are not limited to, phenyl, naphthyl, indanyl, indenyl, tetralin, fluorenyl, and anthracenyl. An optionally substituted "aralkyl" can be substituted on both the alkyl and the aryl portion. For instance, unless otherwise indicated, as used in this disclosure, an optionally substituted aralkyl is attached to the rest of the molecule through the alkyl chain and optionally substituted in the aryl portion. The same principle applies, for example, to a substituted aralkoxy, which would be attached to the rest of the molecule through the oxygen of the
alkoxy and substituted on the aryl portion. A substituted aryloxyalkyl would be attached to the rest of the molecule through the alkyl chain and substituted on the aryl ring, which in turn would be attached to the alkyl chain through an oxygen atom.
[00128] The term "heteroaryl" (or "heteroaromatic" or "heteroaryl group" or "aromatic heterocycle") used alone or as part of a larger moiety as in "heteroaralkyl" or
"heteroarylalkoxy" refers to a ring system wherein at least one ring in the system is aromatic and contains one or more heteroatoms, wherein each ring in the system contains 3 to 7 ring members and which has a single point of attachment to the rest of the molecule. Unless otherwise specified, a heteroaryl ring system may be monocyclic, bicyclic or tricyclic and have a total of five to fourteen ring members. In one embodiment, all rings in a heteroaryl system are aromatic. Also included in this definition are heteroaryl radicals where the heteroaryl ring is fused with one or more aromatic or non-aromatic carbocyclic or
heterocyclic rings, or combinations thereof, as long as the radical or point of attachment is in the heteroaryl ring. A bicyclic 6,5 heteroaromatic system, as used herein, for example, is a six-membered heteroaromatic ring fused to a second five-membered ring wherein the radical or point of attachment is on the six-membered ring.
[00129] Heteroaryl rings include, but are not limited to the following monocycles: 2- furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4- isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3- pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5- tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g., 2- pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3- triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, and the following bicycles: benzimidazolyl, benzofuryl, benzothiophenyl, benzopyrazinyl, benzopyranonyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl).
[00130] As used herein, "cyclo" (or "cyclic", or "cyclic moiety") encompasses mono-, bi- and tri-cyclic ring systems including cycloaliphatic, heterocyclic, aryl or heteroaryl, each of which has been previously defined.
[00131] "Fused" bicyclic ring systems comprise two rings which share two adjoining ring atoms.
[00132] "Bridged" bicyclic ring systems comprise two rings which share three or four adjacent ring atoms. As used herein, the term "bridge" refers to a bond or an atom or a chain of atoms connecting two different parts of a molecule. The two atoms that are connected through the bridge (usually but not always, two tertiary carbon atoms) are referred to as "bridgeheads". Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.2.3]nonyl, 2-oxa-bicyclo[2.2.2]octyl, l-aza-bicyclo[2.2.2]octyl, 3-aza- bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl.
[00133] "Spiro" bicyclic ring systems share only one ring atom (usually a quaternary carbon atom).
[00134] The term "ring atom" refers to an atom such as C, N, O or S that is part of the ring of an aromatic group, a cycloaliphatic group or a heteroaryl ring. A "substitutable ring atom" is a ring carbon or nitrogen atom bonded to at least one hydrogen atom. The hydrogen can be optionally replaced with a suitable substituent group. Thus, the term "substitutable ring atom" does not include ring nitrogen or carbon atoms which are shared when two rings are fused. In addition, "substitutable ring atom" does not include ring carbon or nitrogen atoms when the structure depicts that they are already attached to one or more moiety other than hydrogen and no hydrogens are available for substitution.
[00135] "Heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon, including any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocyclic or heteroaryl ring, for example, N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in N-substituted pyrrolidinyl).
[00136] In some embodiments, two independent occurrences of a variable may be taken together with the atom(s) to which each variable is bound to form a 5-8-membered, heterocyclyl, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring. Exemplary rings that are formed when two independent occurrences of a substituent are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of a substituent that are bound to the same atom and are taken together with that atom to form a ring, where both occurrences of the substituent are taken together with the atom to which they are bound to form a heterocyclyl, heteroaryl, carbocyclyl or aryl ring, wherein the group is attached to the rest of the molecule by a single point of attachment; and b) two independent occurrences of a substituent that are bound to
different atoms and are taken together with both of those atoms to form a heterocyclyl, heteroaryl, carbocyclyl or aryl ring, wherein the ring that is formed has two points of attachment with the rest of the molecule. For example, where a phenyl group is substituted with two occurrences of R0 as in Formula Dl:
Di these two occurrences of R0 are taken together with the oxygen atoms to which they are bound to form a fused 6-membered oxygen containing ring as in Formula D2:
[00137] It will be appreciated that a variety of other rings can be formed when two independent occurrences of a substituent are taken together with the atom(s) to which each substituent is bound and that the examples detailed above are not intended to be limiting.
[00138] In some embodiments, an alkyl or aliphatic chain can be optionally interrupted with another atom or group. This means that a methylene unit of the alkyl or aliphatic chain can optionally be replaced with said other atom or group. Unless otherwise specified, the optional replacements form a chemically stable compound. Optional interruptions can occur both within the chain and/or at either end of the chain; i.e. both at the point of attachment(s) to the rest of the molecule and/or at the terminal end. Two optional replacements can also be adjacent to each other within a chain so long as it results in a chemically stable compound. Unless otherwise specified, if the replacement or interruption occurs at a terminal end of the chain, the replacement atom is bound to an H on the terminal end. For example, if
-CH2CH2CH3 were optionally interrupted with -0-, the resulting compound could be
-OCH2CH3, -CH2OCH3, or -CH2CH2OH. In another example, if the divalent linker
-CH2CH2CH2- were optionally interrupted with -0-, the resulting compound could be
-OCH2CH2-, -CH2OCH2-, or -CH2CH2O-. The optional replacements can also completely replace all of the carbon atoms in a chain. For example, a C3 aliphatic can be optionally replaced by -N(RS)-, -C(O)-, and -N(R$)- to form -N(R$)C(0)N(Rs)- (a urea).
[00139] In general, the term "vicinal" refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to adjacent carbon atoms.
[00140] In general, the term "geminal" refers to the placement of substituents on a group that includes two or more carbon atoms, wherein the substituents are attached to the same carbon atom.
[00141] The terms "terminally" and "internally" refer to the location of a group within a substituent. A group is terminal when the group is present at the end of the substituent not further bonded to the rest of the chemical structure. Carboxyalkyl, i.e., RxO(0)C-alkyl is an example of a carboxy group used terminally. A group is internal when the group is present in the middle of a substituent at the end of the substituent bound to the rest of the chemical structure. Alkylcarboxy (e.g., alkyl-C(0)0- or alkyl-O(CO)-) and alkylcarboxyaryl (e.g., alkyl-C(0)0-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally.
[00142] As described herein, a bond drawn from a substituent to the center of one ring within a multiple-ring system (as shown below), represents substitution of the substituent at any substitutable position in any of the rings within the multiple ring system. For example, formula D3 represents possible substitution in any of the positions shown in formula D4:
D3 D4
[00143] This also applies to multiple ring systems fused to optional ring systems (which would be represented by dotted lines). For example, in Formula D5, X is an optional substituent both for ring A and ring B.
[00144] If, however, two rings in a multiple ring system each have different substituents drawn from the center of each ring, then, unless otherwise specified, each substituent only represents substitution on the ring to which it is attached. For example, in Formula D6, Y is an optional substituent for ring A only, and X is an optional substituent for
ring B only.
D6
[00145] As used herein, the terms "alkoxy" or "alkylthio" refer to an alkyl group, as previously defined, attached to the molecule, or to another chain or ring, through an oxygen ("alkoxy," e.g., -O-alkyl) or a sulfur ("alkylthio," e.g., -S-alkyl) atom. The terms Cn-m "alkoxyalkyl", Cn-m "alkoxyalkenyl", Cn.m "alkoxyaliphatic", and Cn.m "alkoxyalkoxy" mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more alkoxy groups, wherein the total number of carbons between the alky and alkoxy, alkenyl and alkoxy, aliphatic and alkoxy or alkoxy and alkoxy, as the case may be, is between the values of n and m. When these moieties are optionally substituted they can be substituted in either of the portions on both sides of the oxygen or sulfur. For example, an optionally substituted C4 alkoxyalkyl could be, for instance, -CH2CH2OCH2(Me)CH3 or -CH2(OH)0 CH2CH2CH3; a C5 alkoxyalkenyl could be, for instance, =CHCH20 CH2CH2CH3 or =CHCH2 CH2 O
CH2CH3.
[00146] The terms "aryloxy", "arylthio", "benzyloxy" or "benzylthio", refer to an aryl or benzyl group attached to the molecule, or to another chain or ring, through an oxygen ("aryloxy" "benzyloxy," e.g., -O-Ph, -OCH2Ph) or sulfur ("arylthio," e.g., -S-Ph, -S- CH2Ph) atom. For instance, the terms "aryloxyalkyl", "benzyloxyalkyl" "aryloxyalkenyl" and "aryloxyaliphatic" mean alkyl, alkenyl or aliphatic, as the case may be, substituted with one or more aryloxy or benzyloxy groups, as the case may be. In this case, the number of atoms for each aryl, aryloxy, alkyl, alkenyl or aliphatic will be indicated separately. Thus, a 5-6-membered
is a 5-6 membered aryl ring, attached via an oxygen atom to a C alkyl chain, which, in turn, is attached to the rest of the molecule via the terminal carbon of the C|.4 alkyl chain.
[00147] An optionally substituted "aralkyl" can potentially be substituted on both the alkyl and the aryl portion. Unless otherwise indicated, as used in this disclosure, an optionally substituted aralkyl is attached to the rest of the molecule through the alkyl chain and optionally substituted in the aryl portion. The same principle applies to, for example, substituted aralkoxy, which would be attached to the rest of the molecule through the oxygen
of the alkoxy and substituted on the aryl portion. A substituted aryloxyalkyl would be attached to the rest of the molecule through the alkyl chain and substituted on the aryl ring, which in turn would be attached to the alkyl chain through an oxygen atom. For example, an optionally substituted 6-membered aryloxy(C3alkyl) group could be, for instance,
-(CH3)2CH2- [ >-(MeO)-Ph]; an optionally substituted 6-membered heteroaryloxy(C4alkyl) could, for instance, be -CH2CH2CH2-0-(3-F-2-pyrydyl) or -CH(CH3)-0-CH2CH2-(5,6- dimethyl-l,3-pyrimidine). If the alkyl chain on the "aralkyl" group is also substituted that will be specifically indicated. For instance, an optionally substituted 6-membered
heteroaryloxy(C4alkyl) that is also optionally substituted on the alkyl, would be referred to as "an optionally substituted 6-membered heteroaryloxy(C4alkyl), wherein said C4 alkyl chain is optionally substituted". An example of this latter group could be 5, 6-dimethyl-l,3- pyrimidine-0-CF(CH3)-CH(OH)CH2-, wherein the alkyl chain is substituted with F and with -OH.
[00148] As used herein, the terms "halogen" or "halo" mean F, CI, Br, or I.
[00149] The terms "haloalkyl", "haloalkenyl", "haloaliphatic", and "haloalkoxy" mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more halogen atoms. For example, a Ci-3 haloalkyl could be -CFHCH2CHF2 and a Q-2 haloalkoxy could be -OC(Br)HCHF2. This term includes perfluorinated alkyl groups, such as -CF3 and -CF2CF3.
[00150] As used herein, the term "cyano" refers to -CN or -C≡N.
[00151] The terms "cyanoalkyl", "cyanoalkenyl", "cyanoaliphatic", and
"cyanoalkoxy" mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more cyano groups. For example, a C|. cyanoalkyl could be -C(CN)2CH2CH3 and a C|-2 cyanoalkenyl could be =CHC(CN)H2.
[00152] As used herein, an "amino" group refers to -NH2.
[00153] The terms "aminoalkyl", "aminoalkenyl", "aminoaliphatic", and
"aminoalkoxy" mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more amino groups. For example, a Ci-3 aminoalkyl could be -CH(NH2)CH2CH2NH2 and a Ci.2 aminoalkoxy could be -OCH2CH2NH2.
[00154] The term "hydroxyl" or "hydroxy" refers to -OH.
[00155] The terms "hydroxyalkyl", "hydroxyalkenyl", "hydroxyaliphatic", and
"hydroxyalkoxy" mean alkyl, alkenyl, aliphatic or alkoxy, as the case may be, substituted with one or more -OH groups. For example, a C|-3 hydroxyalkyl could be
-CH2(CH2OH)CH3 and a C4 hydroxyalkoxy could be -OCH2C(CH3)(OH)CH3.
[00156] As used herein, an "aroyl" or "heteroaroyl" refers to a -C(0)-aryl or a -C(O)- heteroaryl. The aryl and heteroaryl portion of the aroyl or heteroaroyl is optionally substituted as previously defined.
[00157] As used herein, a "carbonyl", used alone or in connection with another group refers to -C(O)- or -C(0)H. For example, as used herein, an "alkoxycarbonyl," refers to a group such as -C(0)0(alkyl).
[00158] As used herein, an "oxo" refers to =0, wherein oxo is usually, but not always, attached to a carbon atom (e.g, it can also be attached to a sulfur atom forming a sulfoxide or a sulfone). An aliphatic chain can be optionally interrupted by a carbonyl group or can optionally be substituted by an oxo group, and both expressions refer to the same: e.g., -CH2- C(0)-CH3.
[00159] As used herein, in the context of resin chemistry (e.g., using solid resins or soluble resins or beads), the term "linker" refers to a bifunctional chemical moiety attaching a compound to a solid support or soluble support.
[00160] In all other situations, a "linker", as used herein, refers to a divalent group in which the two free valences are on different atoms (e.g., carbon or heteroatom) or are on the same atom but can be substituted by two different substituents. For example, a methylene group can be a C| alkyl linker (-CH2-), which can be substituted by two different groups, one for each of the free valences (e.g., as in Ph-CH2-Ph, wherein methylene acts as a linker between two phenyl rings). Ethylene can be a C2 alkyl linker (-CH2CH2-) wherein the two free valences are on different atoms. The amide group, for example, can act as a linker when placed in an internal position of a chain (e.g., -CONH- ). A linker can be the result of interrupting an aliphatic chain by certain functional groups or of replacing methylene units on said chain by said functional groups. E.g., a linker can be a C|.6 aliphatic chain in which up to two methylene units are substituted by -C(O)- or -NH- (as in -CH2-NH-CH2-C(0)-CH2- or -CH2-NH-C(0)-CH2-). An alternative way to define the same -CH2-NH-CH2-C(0)-CH2- and - CH2-NH-C(0)-CH2- groups is as a C3 alkyl chain optionally interrupted by up to two -C(O)- or -NH- moieties. Cyclic groups can also form linkers: e.g., a 1,6-cyclohexanediyl
R
can be a linker between two R groups, as in
[00161] Divalent groups of the type =CH-R or =C-R2, wherein both free valences are in the same atom and are attached the same substituent, are also possible. In this case, they will be referred to by their IUPAC accepted names. For instance, an alkylidene (such as, for example, a methylidene (=CH2) or an ethylidene (=CH-CH3» would not be encompassed by the definition of a linker in this disclosure.
[00162] The term "protecting group", as used herein, refers to an agent used to temporarily block one or more desired reactive sites in a multifunctional compound. In certain embodiments, a protecting group has one or more, or preferably all, of the following characteristics: a) reacts selectively in good yield to give a protected substrate that is stable to the reactions occurring at one or more of the other reactive sites; and b) is selectively removable in good yield by reagents that do not attack the regenerated functional group. Exemplary protecting groups are detailed in Greene, T. W., Wuts, P. G in Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference. The term "nitrogen protecting group", as used herein, refers to an agents used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound. Preferred nitrogen protecting groups also possess the characteristics exemplified above, and certain exemplary nitrogen protecting groups are also detailed in Chapter 7 in Greene, T. W., Wuts, P. G in Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.
[00163] As used herein, the term "displaceable moiety" or "leaving group" refers to a group that is associated with an aliphatic or aromatic group as defined herein and is subject to being displaced by nucleophilic attack by a nucleophile.
[00164] As used herein, "amide coupling agent" or "amide coupling reagent" means a compound that reacts with the hydroxyl moiety of a carboxy moiety thereby rendering it susceptible to nucleophilic attack. Exemplary amide coupling agents include DIC
(diisopropylcarbodiimide), EDCI (l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide), DCC (dicyclohexylcarbodiimide), BOP (Benzotriazol-l-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate), pyBOP ((Benzotriazol- 1 -yloxy)tripyrrolidinophosphonium
Hexafluorophosphate), etc.
[00165] The compounds of the invention are defined herein by their chemical
structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the chemical structure and chemical name conflict, the chemical structure is determinative of the compound's identity.
[00166] In one aspect, the invention relates to a compound of Formula I, or a pharmaceutically acceptable salt thereof,
Formula I
wherein:
ring B is selected from the group consisting of phenyl and a 5-6-membered monocyclic
heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S;
n is an integer selected from the group consisting of 0, 1, 2 and 3;
each J is independently selected from the group consisting of halogen, -N02, -CN, C|.6 aliphatic, C3-6 cycloaliphatic, Ci-6 haloaliphatic, C1.6 alkoxy, Ci-6 haloalkoxy and C3-6 cycloalkoxy;
each JC1 is independently selected from the group consisting of halogen, -N02, -CN, C|.6 aliphatic, C3-6 cycloaliphatic, Ci-6 haloaliphatic, C|-6 alkoxy, C|-6 haloalkoxy and C3-6 cycloalkoxy;
p is an integer selected from the group consisting of 0, 1, 2 and 3;
R2 is selected from the group consisting of halogen, -N02, -CN, C^ aliphatic, phenyl, a 5-6- membered heteroaryl ring and a C3-7 cycloalkyl, wherein said Ci-6 aliphatic, phenyl, 5-6-membered heteroaryl ring and C3-7 cycloalkyl is optionally substituted by up to three instances of halogen;
R4 is selected from the group consisting of hydrogen, halogen, -CN, C)-6 aliphatic, a C3- cycloaliphatic ring, a 5-6-membered heteroaryl ring, phenyl, -ORY and -SRY;
R5 is selected from the group consisting of hydrogen, halogen, -CN, Ci-6 aliphatic, a C3-7 cycloaliphatic ring, a 5-6-membered heteroaryl ring, phenyl, -ORY and -SRY;
wherein said Ci-6 aliphatic, C3.7 cycloaliphatic ring, 5-6-membered heteroaryl ring,
and phenyl is optionally substituted with up to three instances of halogen, Ci-4 alkyl,
CM alkoxy or Ci-4 haloalkoxy; or
R4 and R5, together with the two carbon atoms to which they are attached, form a Cs.g
cycloaliphatic ring, a 5-8-membered heterocyclic ring or a 5-membered heteroaryl ring; wherein said heterocyclic and heteroaryl ring formed by R4 and R5 contains up to three heteroatoms selected from the group consisting of N, O and S, and wherein said cycloaliphatic, heterocyclic and heteroaryl rings formed by R4 and R5 is optionally substituted by up to 3 instances of halogen, C alkyl, Q-4 haloalkyl, Q-4 alkoxy or CM haloalkoxy; and
each R is independently selected from the group consisting of C|-6 aliphatic, C3-7
, Y
cycloaliphatic, a 5-6-membered heteroaryl ring and phenyl, wherein each R is optionally substituted by up to six instances of halogen, C alkyl, Ci-4 haloalkyl, C alkoxy or CM haloalkoxy;
provided that the compound is not:
[00167] In some embodiments, ring B is an optionally substituted ring selected from the group consisting of phenyl, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, imidazole, pyrazole, furan, thiophene, triazole, tetrazole, thiazole, oxathiazole and oxazole.
[00168] In other embodiments, ring B is an optionally substituted pyridine or an optionally substituted phenyl. In still further embodiments, ring B is an optionally substituted pyridine. In other embodiments, ring B is an optionally substituted phenyl.
[00169] In some embodiments, n is selected from the group consisting of 0 and 1.
[00170] In some embodiments, each JB I is independently selected from the group consisting of halogen, C|-4 alkyl, cyclopropyl, cyclopropyloxy, Ci-4 haloalkyl, C 4 alkoxy and C|-4 haloalkoxy.
[00171] In other embodiments, each JB I is independently selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy,
trifluoromethoxy, ethoxy, propyloxy and isopropyloxy.
[00172] In some embodiments, the moiety represented by
is selected from the group consisting of phenyl, 3-chlorophenyl, 3-pyridine, 4-pyridine and 3-methoxy- 4-pyridine.
[00173] In some embodiments, p is selected from the group consisting of 0, 1 and 2.
[00174] In some embodiments, each J is independently selected from the group consisting of halogen, Ci-4 alkyl, C|-4 haloalkyl, cyclopropyl, cyclopropyloxy, Ci-4 alkoxy and C|-4 haloalkoxy. In other embodiments, each J is independently selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, propyloxy and isopropyloxy. In still further embodiments, each JCI is halogen. In still further embodiments, JC1 is chlorine and p is 1 or 2. In some
embodiments, JCI is fluorine and p is 1. In still other embodiments, JC1 is methoxy and p is 1.
[00175] In some embodiments, R" is selected from the group consisting of halogen, -NO2, -CN, Ci^ aliphatic and phenyl, wherein each C|.6 aliphatic and phenyl is optionally substituted with up to three instances of halogen. In other embodiments, R2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, /-butyl, pentyl or hexyl. In still further embodiments, R2 is methyl. In other embodiments, R2 is phenyl.
[00176] In some embodiments, R4 is hydrogen, C alkyl, a 5-6-membered heteroaryl or phenyl. In further embodiments, R4 is hydrogen. In other embodiments, R4 is phenyl.
[00177] In some embodiments, R5 is a C|-4 alkyl, a 5-6-membered heteroaryl or phenyl. In further embodiments, R5 is methyl. In other embodiments, R5 is phenyl.
[00178] In some embodiments, R4 and R5, together with the two carbon atoms to which they are attached, form a C5.8 cycloaliphatic ring, a 5-8-membered heterocyclic ring or a 5-membered heteroaryl ring, wherein said cycloaliphatic, heterocyclic and heteroaryl ring
formed by R4 and R5 is optionally substituted with up to 3 instances of halogen, C|-2 alkyl, Cj. 2 haloalkyI, C[-2 alkoxy or C(-2 haloalkoxy. In further embodiments, R4 and R5, together with the two carbon atoms to which they are attached, form an optionally substituted Cs.g cycloaliphatic ring. In other embodiments, R4 and R5, together with the two carbon atoms to
which they are attached, form the fused ring:
or
. In other embodiments, R4 and R5, together with the two carbon atoms to which they are attached, form an optionally substituted 5-membered heteroaryl ring. In some other embodiments, R4 and R5, together with the two carbon atoms to which they are attached, form an optionally substituted thiophene ring. In some other embodiments, R4 and R5, together with the pyrrole ring to which they are attached and its substituents, form
[00179] In another aspect, the invention relates to a compound of Formula II or a pharmaceutically acceptable salt thereof,
Formula II
wherein each X is independently selected from the group consisting of C and N.
[00180] In another aspect, the invention relates to a compound of Formula III or a pharmaceutically acceptable salt thereof,
Formula III
wherein: n is selected from the group consisting of 0 and 1 and wherein JB I is selected from the group consisting of halogen and methoxy.
[00181] In another aspect, the invention relates to a compound of Formula IV or a pharmaceutically acceptable salt thereof,
Formula IV
wherein ring CI is an optionally substituted C5-8 cycloaliphatic ring. In some embodiments, CI is optionally substituted with up to two instances of methyl.
[00182] In another aspect, the invention relates to a compound of Formula V or a pharmaceutically acceptable salt thereof,
Formula V
wherein ring C2 is an optionally substituted 5-membered heteroaryl ring. In other embodiments, C2 is an optionally substituted thiophene ring. In some other
embodiments, C2 is optionally substituted with up to two instances of methyl or halogen.
[00183] In some embodiments, the compound is selected from the group consisting of:
1-10 1 11 1-13
1-14 M5 1-16
1-12
[00184] In another aspect, the invention comprises a pharmaceutical composition comprising a compound discussed above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle or adjuvant. In a further embodiment, the pharmaceutical composition further comprises at least one additional therapeutic agent.
[00185] In other embodiments, the pharmaceutical composition further comprises an additional therapeutic agent which is chosen from the group consisting of painkillers, nonsteroidal anti-inflammatory drugs (NSAIDs), cannabinoid receptor agonists, opiate receptor agonists, anti-infective agents, sodium channel blockers, N-type calcium channel blockers, local anesthetics, VR1 agonists and antagonists, agents used for migraines, topical agents used in the treatment of localized pruritus, anti-inflammatory and/or immunosuppressive agents, agents designed to treat tobacco abuse (e.g., nicotine receptor partial agonists and nicotine replacement therapies), ADD/ADHD agents, agents to treat alcoholism, such as opioid antagonists, agents for reducing alcohol withdrawal symptoms such as
benzodiazepines and beta-blockers, antihypertensive agents such as ACE inhibitors and Angiotensin II Receptor blockers, Renin inhibitors, vasodilators, agents used to treat glaucoma such as direct-acting Miotics (cholinergic agonists), indirect-acting Miotics (cholinesterase inhibitors), Carbonic anhydrase inhibitors, selective adrenergic agonists, Osmotic diuretics, antidepressants such as SSRIs, tricyclic antidepressants, and dopaminergic antidepressants, cognitive improvement agents, acetylcholinesterase inhibitors, anti-emetic agents (e.g., 5HT3 antagonists), neuroprotective agents, neuroprotective agents currently under investigation, antipsychotic medications, agents used for multiple sclerosis, disease- modifying anti-rheumatic drugs (DMARDS), biological response modifiers (BRMs), COX-2 selective inhibitors, COX-1 inhibitors, immunosuppressives, PDE4 inhibitors, corticosteroids, histamine HI receptor antagonists, histamine H2 receptor antagonists, proton pump inhibitors, leukotriene antagonists, 5-lipoxygenase inhibitors, nicotinic acetylcholine receptor agonists, P2X3 receptor antagonists, NGF agonists and antagonists, NK1 and NK2 antagonists, NMDA antagonist, potassium channel modulators, GABA modulators, anti-
cancer agents such as tyrosine kinase inhibitors, anti-hyperlipidemia drugs, appetite suppressing agents, anti-diabetic medications such as insulin, gastrointestinal (GI) agents, and serotonergic and noradrenergic modulators.
[00186] In another aspect, the invention provides a method for the treatment or prevention of pain comprising administering, alone or in combination therapy, to a patient in need thereof, a therapeutically or prophylactically acceptable dose of a pharmaceutical composition discussed above.
[00187] In some embodiments, the method of treatment for pain is selected from chronic pain, acute pain, perioperative pain (e.g., associated with surgery), postoperative pain, visceral pain, inflammatory pain, cancer pain, headache pain, pain associated with a cough, neuropathic pain, deafferentation pain, chronic nociceptive pain, dental pain (such as odontalgia), bone pain, joint pain (e.g., osteoarthritis or rheumatoid arthritis), myofascial pain (e.g., muscular injury, fibromyalgia), labor pain, pain associated with injuries, pain resulting from trauma, pain resulting from allergies, pain resulting from dermatitis, pain resulting from immunodeficiency, pain resulting from Hodgkin's disease, pain resulting from Myasthenia gravis, pain resulting from nephrotic syndrome, pain resulting from scleroderma, pain resulting from thyroiditis, central and peripheral pathway mediated pain, menstrual pain, neurogenic pain, dental pain, dysmenorrheal pain, visceral pain, neuropathic pain, post operative pain, headache, migraines, allodynia, hyperalgesia, post operative pain (e.g., associated with orthopedic surgery, gynecological surgery, abdominal surgery, incisions, or oral surgery), back pain, pain caused by inflammation (e.g., arthritis, osteoarthritis, spondylitis, rheumatoid arthritis, Crohn's disease and irritable bowel syndrome), and pain associated with injury, burns or trauma.
[00188] In some embodiments, a method is provided for the treatment or prevention of autoimmune disorders comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of the pharmaceutical composition. In further embodiments, the autoimmune disorder is selected from the group consisting of alopecia areata (also known as systemic sclerosis (SS)), amyloses, amyotrophic lateral sclerosis, ankylosing spondylarthritis, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune
lymphoproliferative syndrome (ALPS), autoimmune thrombocytopenic purpura (ATP), Behcet's disease, cardiomyopathy, celiac sprue-dermatitis hepetiformis; chronic fatigue
immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy (CEPD), cicatricial pemphigoid, cold agglutinin disease, connective tissue diseases, crest syndrome, Crohn's disease, Degos' disease, dermatomyositis-juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, graft vs. host disease, transplantation rejection, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin-dependent diabetes mellitus, juvenile chronic arthritis (Still's disease), juvenile rheumatoid arthritis, lupus erythematosus, Meniere's disease, multiple sclerosis, myasthenia gravis, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomena, reactional arthritis, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma (progressive systemic sclerosis (PSS)), Sjogren's syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, undifferentiated spondylarthritis, uveitis, vitiligo, and Wegener's granulomatosis.
[00189] In other embodiments, a method is provided for the treatment or prevention of disease states or indications that are accompanied by inflammatory processes, which comprises administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition discussed above. In further embodiments, the disease states or indications that are accompanied by inflammatory processes are chosen from the group consisting of: lung diseases such as asthma, bronchitis, allergic rhinitis, emphysema, adult respiratory distress syndrome (ARDS), pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease (COPD), asthma including allergic asthma (atopic or non-atopic) as well as exercise- induced bronchoconstriction, occupational asthma, viral or bacterial exacerbation of asthma, other non-allergic asthmas and "wheezy-infant syndrome", pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis; rheumatic diseases or autoimmune diseases or musculoskeletal diseases such as all forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, and polymyalgia rheumatica; reactive arthritis; rheumatic soft tissue diseases; inflammatory soft tissue diseases of other genesis; arthritic symptoms in degenerative joint diseases (arthroses); tendinitis, bursitis, osteoarthritis, traumatic arthritis, gout (metabolic arthritis); collagenoses of any genesis, e.g., systemic lupus erythematosus, scleroderma, polymyositis,
dermatomyositis, Sjogren syndrome, Still disease, Felty syndrome; and osteoporosis and
other bone resorption diseases; allergic diseases including all forms of allergic reactions, (e.g., allergic rhinitis, allergic conjunctivitis infectious parasitic, angioneurotic edema, hay fever, insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc.), anaphylactic shock (anaphylaxis), urticaria, angioneurotic edema, delayed or immediate hypersensitivity, and contact dermatitis; vascular diseases such as panarteritis nodosa, polyarteritis nodosa, periarteritis nodosa, arteritis temporalis, Wegner granulomatosis, giant cell arthritis, atherosclerosis, reperfusion injury, myocardial ischemia, thrombosis and erythema nodosum; dermatological diseases such as dermatitis, psoriasis, sunburn, burns, and eczema; renal, urinary and pancreatic diseases such as nephrotic syndrome and all types of nephritis (such as glomerulonephritis), pancreatitis, bladder hyperrelexia following bladder inflammation, urinary incontinence or vesicle inflammation, uresesthesia urgency, overactive bladder, urinary frequency, interstitial cystitis or chronic prostatitis; hepatic diseases such as acute liver cell disintegration; acute hepatitis of various genesis (such as viral, toxic, drug- induced) and chronically aggressive and/or chronically intermittent hepatitis, liver fibrosis associated with liver injury or disease, including fibrosis caused or exacerbated by alcoholic liver cirrhosis, chronic viral hepatitis, non-alcoholic steatohepatitis and primary liver cancer; gastrointestinal diseases such as ulcers, inflammatory bowel diseases, regional enteritis (Crohn's disease), ulcerated colitis, gastritis, aphthous ulcer, celiac disease, regional ileitis, ileus, esophagitis, NSAED-induced ulcer, non-ulcerative dyspepsia and gastroesophageal reflux disease; neurodegenerative diseases such as the neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, cerebral ischemia, seizures, spinal cord injury or the like; eye diseases such as allergic keratitis, uveitis, or iritis, conjunctivitis, blepharitis, neuritis nervi optici, choroiditis, glaucoma and sympathetic ophthalmia; diseases of the ear, nose, and throat (ENT) area such as tinnitus, allergic rhinitis or hay fever, gingivitis, otitis externa, caused by contact eczema, infection, etc., and otitis media;
progressive central nervous system or neurological diseases such as brain edema, particularly tumor-related brain edema, multiple sclerosis, acute encephalomyelitis, meningitis, acute spinal cord injury, trauma, dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Parkinson's disease and Creutzfeldt-Jacob disease,
Huntington's chorea, Pick's disease, amyotrophic lateral sclerosis (ALS)), vascular dementia (including multi-infarct dementia and dementia associated with intracranial space-occupying lesions, infections and related conditions such as HIV infection), Guillain-Barre syndrome, myasthenia gravis, stroke, and various forms of seizures (such as nodding spasms); blood diseases such as acquired hemolytic anemia, aplastic anemia, and idiopathic
thrombocytopenia; tumor diseases such as acute lymphatic leukemia, Hodgkin's disease, malignant lymphoma, lymphogranulomatoses, lymphosarcoma, solid malignant tumors, colorectal polyps, extensive metastases and other proliferative disorders such as diabetic retinopathy and tumor angiogenesis (e.g., wet macular degeneration); endocrine diseases such as endocrine opthalmopathy, endocrine orbitopathia, thyrotoxic crisis, Thyroiditis de
Quervain, Hashimoto thyroiditis, Morbus Basedow, granulomatous thyroiditis, struma lymphomatosa, Graves disease, type I diabetes (such as insulin-dependent diabetes); organ and tissue transplantations and graft- versus-host diseases; severe states of shock such as septic shock, anaphylactic shock, and systemic inflammatory response syndrome (SIRS); viral or bacterial parasitic infectious disease: for example ADDS and meningitis; and various other disease states or conditions including, restenosis following percutaneous transluminal coronary angioplasty, acute and chronic pain, atherosclerosis, reperfusion injury, congestive heart failure, myocardial infarction, thermal injury, multiple organ injury secondary to trauma, necrotizing enterocolitis and syndromes associated with hemodialysis, leukopheresis, granulocyte transfusion, sarcoidosis, gingivitis, pyrexia, Edema resulting from trauma associated with burns, sprains or fracture, cerebral edema and angioedema, and diabetes (such as diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, post capillary resistance and diabetic symptoms associated with insulitis (e.g., Hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion)).
[00190] In some embodiments, a method is proved for the treatment or prevention of gastrointestinal diseases or disorders comprises administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition discussed above. In further embodiments, the gastrointestinal disease or disorder is chosen from the group consisting of: functional gastrointestinal disorders, ulcers, inflammatory bowel diseases (IBD), regional enteritis (Crohn's disease), ulcerative colitis, diarrhea, gastritis, aphthous ulcer, celiac disease, regional ileitis, ileus, functional dyspepsia, diverticulitis, gastrointestinal bleeding, irritable bowel syndrome (IBS), non-ulcerative dyspepsia and gastroesophageal reflux disease.
[00191] In some embodiments, a method is provided for the treatment or prevention of pruritus, comprises administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition discussed above. In further embodiments, the pruritus is dermal pruritus, neuropathic pruritus, neurogenic pruritus or psychogenic pruritus.
[00192] In some embodiments, a method is provided for the treatment or prevention of substance abuse-related syndromes, disorders, diseases or withdrawal symptoms comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition discussed above. In further embodiments, the method of treating substance abuse-related syndromes, disorders,, diseases or withdrawal symptoms are chosen from the group consisting of drug abuse and drug withdrawal, wherein the abused substances include alcohol, amphetamines,
amphetamitte-1 ike substances, caffeine, cannabis, cocaine, hallucinogens, inhalants, opioids, nicotine (and/or tobacco products), heroin abuse, barbiturates, phencyclidine (or
pheneyeiidine-like compounds), sedative-hypnotics, benzodiazepines, or combinations of any of the foregoing; and the withdrawal symptoms, include tobacco craving or nicotine dependency, addiction., or withdrawal.
(00193] in some embodiments, a method is provided for the treatment or prevention of psychiatric disorders comprises administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition as discussed herein. In further embodiments, the psychiatric disorders are chosen from the group consisting of depressions (including major depressive disorder, bipolar depression, unipolar depression, single or recurrent major depressive episodes (e.g., with or without psychotic features, catatonic features, and/or melancholic features), postpartum onset, seasonal affective disorder, dysthymic disorders (e.g., with early or late onset and with or without atypical features), neurotic depression and social phobia, depression
accompanying dementia, anxiety, psychosis, social affective disorders, and/or cognitive disorders), manic-depressive psychoses, bipolar disorders, extreme psychotic states (such as mania, schizophrenia, and excessive mood swings where behavioral stabilization is desired), post-traumatic stress disorder, panic disorder, obsessive compulsive disorder, psychiatric tremors such as dyskinesias, dystonia, and spasticity, attention disorders such as ADHD (attention deficit hyperactivity disorders), autism, anxiety states, generalized anxiety, agoraphobia, as well as those behavioral states characterized by social withdrawal
[00194] In some embodiments, a method is provided for the treatment or prevention of neurological or neurodegenerative disorders, which comprises administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition discussed herein, h further embodiments, the neurological or neurodegenerative disorders are chosen from the group consisting of
dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease, prion disease and Creutzfeldt-Jakob disease and motor neuron disease); vascular dementia (including multi-infarct dementia); dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); dementia in Parkinson's disease; metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with aging, particularly Age-Associated Memory Impairment; amyotrophic lateral sclerosis (ALS), multiple sclerosis, epilepsy, ischemia, traumatic head or brain injury, brain inflammation, eye injury, stroke and neuroinflammation; and neurodegeneration or decreased brain activity associated with stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, hypoxia, hypoglycemia, gas poisoning, drug intoxication, diabetes mellitus, edema, spinal cord injury, cerebral ischemia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, seizures or the like.
[00195] In some embodiments, a method is provided for the treatment or prevention of ocular disorders comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition discussed above. In further embodiments, the ocular disorder is chosen from the group consisting of glaucoma (such as normal tension glaucoma), glaucoma-associated intraocular pressure retinitis, retinopathies, uveitis, acute injury to the eye tissue (e.g., conjunctivitis), high intraocular pressure, family history of glaucoma, glaucoma in the contralateral eye and high myopia.
[00196] In some embodiments, a method is provided for the treatment or prevention of appetite-related disorders comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a
pharmaceutical composition discussed above. In further embodiments, the appetite-related disorder is chosen from the group consisting of: emesis, vomiting and nausea, food behavioral problems or feeding disorders such as anorexias, cachexias, wasting conditions and bulimia; and obesity or obesity-related disorders such as diabetes type II, hyperlipidemia.
[00197] In some embodiments, a method is provided for the treatment or prevention of gynecological disorders comprising administering, alone or in combination, a therapeutically acceptable dose of a pharmaceutical composition discussed above. In further embodiments, the gynecological disorder is uterus contraction caused by hormones, or prostanoid-induced muscle contraction such as premature labor, menstrual cramps, menstrual irregularity or
dysmenorrhea.
[00198] In some embodiments, a method is provided for the treatment or prevention of sleep disorders comprising administering, alone or in combination, a pharmaceutically acceptable dose of a pharmaceutical composition discussed herein. In further embodiments, the sleep disorder is chosen from the group consisting of: insomnia, night terrors, bruxism, somnambulism, narcolepsy, circadian rhythm adjustment disorders, and sleep disorders associated with neurological or mental disorders or with pain.
[00199] In some embodiments, the methods above are provided for the treatment of a human patient. In other embodiments, the patient is a companion animal, exotic animal or a farm animal such as a dog, cat, mouse, rat, hamster, gerbil, guinea pig, rabbit, horse, pig or cow.
[00200] In some embodiments, a method is provided for inhibiting FAAH in a biological sample, comprising contacting said biological sample with a composition discussed herein.
Pharmaceutically acceptable salts, co-forms and pro-drues:
[00201] The phrase "pharmaceutically acceptable salt," as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of Formula I. For use in medicine, the salts of the compounds of Formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of Formula I or of their pharmaceutically acceptable salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.
[00202] Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. In some embodiments, the salts can be prepared in situ during the final isolation and purification of the compounds. In other embodiments the salts can be prepared from the free form of the compound in a separate synthetic step.
[00203] When the compound of Formula I is acidic or contains a sufficiently acidic bioisostere, suitable pharmaceutically acceptable salts are salts prepared from
pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particular embodiments include ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.
[00204] When the compound of Formula I is basic or contains a sufficiently basic bioisostere, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particular embodiments include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. Other exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3- naphthoate)) salts.
[00205] The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berg et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977:66: 1-19, incorporated herein by reference in its entirety.
[00206] In addition to the compounds described herein and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g., hydrates) and co-crystals of these compounds and salts may also be employed in compositions to treat or prevent the disorders identified herein.
[00207] As used herein, the term "pharmaceutically acceptable solvate," is a solvate formed from the association of one or more pharmaceutically acceptable solvent molecules to one of the compounds described herein. As used herein, the term "hydrate" means a compound described herein or a salt thereof that further includes a stoichiometric or non- stoichiometric amount of water bound by non-covalent intermolecular forces. The term solvate includes hydrates (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and the like).
[00208] "Pharmaceutically acceptable co-crystals" result when a pharmaceutically active compound crystallizes with another material (e.g., a carboxylic acid, a 4,4'-bipyridine or an excipient) that is also a solid at room temperature. Some pharmaceutically acceptable excipients are described in the next section. Other pharmaceutically acceptable substances that can be used to form co-crystals are exemplified by the GRAS (Generally regarded as safe) list of the U.S. Food and Drug Administration (FDA).
[00209] In addition to the compounds described herein, pharmaceutically acceptable pro-drugs of these compounds may also be employed in compositions to treat or prevent the disorders identified herein.
[00210] A "pharmaceutically acceptable pro-drug" includes any pharmaceutically acceptable ester, salt of an ester or other derivative or salt thereof of a compound described herein which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound described herein. Particularly favored pro-drugs are those that increase the bioavailability of the compounds when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. The term "pro-drug" encompasses a derivative of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to provide a compound described herein. Examples of pro-drugs contemplated in this invention include, but are not limited to, analogs or derivatives of compounds of the invention that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates,
biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of pro-drugs include derivatives of compounds described herein that comprise -NO, -N02, -ONO, or -ON02 moieties. Pro-drugs can typically be prepared using well-known methods, such as those described by Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed.).
Pharmaceutical compositions and methods of administration:
[00211] The compounds disclosed herein, and their pharmaceutically acceptable salts, solvates, co-crystals and pro-drugs thereof, may be formulated as pharmaceutical
compositions or "formulations".
[00212] A typical formulation is prepared by mixing a compound of Formula I, or a pharmaceutically acceptable salt, solvate, co-crystal or pro-drug thereof, and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like. The particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of Formula I is being formulated. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (e.g., GRAS-Generally Regarded as Safe) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc., and mixtures thereof. The formulations may also include other types of excipients such as one or more buffers, stabilizing agents, antiadherents, surfactants, wetting agents, lubricating agents, emulsifiers, binders, suspending agents, disintegrants, fillers, sorbents, coatings (e.g., enteric or slow release) preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of Formula I or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
[00213] The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound of Formula I, a
pharmaceutically acceptable salt, solvate, co-crystal or pro-drug thereof, or a stabilized form
of the compound, such as a complex with a cyclodextrin derivative or other known complexation agent) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. A compound having the desired degree of purity is optionally mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers, in the form of a lyophilized formulation, milled powder, or an aqueous solution. Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers. The pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8.
[00214] The compound of Formula I or a pharmaceutically acceptable salt, solvate, co- crystal or pro-drug thereof is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen. Pharmaceutical formulations of compounds of Formula I, or a pharmaceutically acceptable salt, solvate, co-crystal or pro-drug thereof, may be prepared for various routes and types of administration. Various dosage forms may exist for the same compound, since different medical conditions may warrant different routes of administration. The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the subject treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% of the total composition (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur. As a general proposition, the initial pharmaceutically effective amount of the inhibitor administered will be in the range of about 0.01-100 mg/kg per dose, namely about 0.1 to 20 mg kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day.
[00215] The term "therapeutically effective amount" as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. The therapeutically or pharmaceutically effective amount
of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to ameliorate, cure or treat the disease or disorder or one or more of its symptoms.
[00216] The pharmaceutical compositions of Formula I will be formulated, dosed, and administered in a fashion, i.e., the amounts, concentrations, schedules, courses, vehicles, and route(s) of administration, consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular human or other mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners, such as the age, weight, and response of the individual patient.
[00217] The term "prophylactically effective amount" refers to an amount effective in preventing or substantially lessening the chances of acquiring a disease or disorder or in reducing the severity of the disease or disorder or one or more of its symptoms before it is acquired or before the symptoms develop. Roughly, prophylactic measures are divided between primary prophylaxis (to prevent the development of a disease) and secondary prophylaxis (whereby the disease has already developed and the patient is protected against worsening of its severity).
[00218] Acceptable diluents, carriers, excipients, and stabilizers are those that are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride;
hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol;
cyclohexanol; 3-pentanol; and m-cresol); proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). The active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, e.g., hydroxymethylcellulose or gelatin-
microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano- particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in
Remington's: The Science and Practice of Pharmacy, 21st Edition, University of the Sciences in Philadelphia, Eds., 2005 (hereafter "Remington's").
[00219] "Controlled drug delivery systems" supply the drug to the body in a manner precisely controlled to suit the drug and the conditions being treated. The primary aim is to achieve a therapeutic drug concentration at the site of action for the desired duration of time. The term "controlled release" is often used to refer to a variety of methods that modify release of drug from a dosage form. This term includes preparations labeled as "extended release", "delayed release", "modified release" or "sustained release".
[00220] "Sustained-release preparations" are the most common applications of controlled release. Suitable examples of sustained-release preparations include
semipermeable matrices of solid hydrophobic polymers containing the compound, wherein the matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl- methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers, and poly-D-(-)-3-hydroxybutyric acid.
[00221] "Immediate-release preparations" may also be prepared. The objective of these formulations is to get the drug into the bloodstream and to the site of action as rapidly as possible. For instance, for rapid dissolution, most tablets are designed to undergo rapid disintegration to granules and subsequent disaggregation to fine particles. This provides a larger surface area exposed to the dissolution medium, resulting in a faster dissolution rate.
[00222] Implantable devices coated with a compound of this invention are another embodiment of the present invention. The compounds may also be coated on implantable medical devices, such as beads, or co-formulated with a polymer or other molecule, to provide a "drug depot", thus permitting the drug to be released over a longer time period than administration of an aqueous solution of the drug. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562;
5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be
further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.
[00223] The formulations include those suitable for the administration routes detailed herein. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
[00224] The terms "administer", "administering" or "administration" in reference to a compound, composition or formulation of the invention mean introducing the compound into the system of the animal in need of treatment. When a compound of the invention is provided in combination with one or more other active agents, "administration" and its variants are each understood to include concurrent and/or sequential introduction of the compound and the other active agents.
[00225] The compositions described herein may be administered systemically or locally, e.g.: orally (e.g., using capsules, powders, solutions, suspensions, tablets, sublingual tablets and the like), by inhalation (e.g., with an aerosol, gas, inhaler, nebulizer or the like), to the ear (e.g., using ear drops), topically (e.g., using creams, gels, liniments, lotions, ointments, pastes, transdermal patches, etc.), ophthalmically (e.g., with eye drops, ophthalmic gels, ophthalmic ointments), rectally (e.g., using enemas or suppositories), nasally, buccally, vaginally (e.g., using douches, intrauterine devices, vaginal suppositories, vaginal rings or tablets, etc.), via an implanted reservoir or the like, or parenterally depending on the severity and type of the disease being treated. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.
[00226] The pharmaceutical compositions described herein may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. Liquid dosage forms for oral administration include, but are not
limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[00227] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. Tablets may be uncoated or may be coated by known techniques including microencapsulation to mask an unpleasant taste or to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. A water soluble taste-masking material such as hydroxypropyl-methylcellulose or hydroxypropyl-cellulose may be employed.
[00228] Formulations of a compound of Formula I that are suitable for oral
administration may be prepared as discrete units such as tablets, pills, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs. Formulations of a compound intended for oral use may be prepared according to any method known to the art for the manufacture of
pharmaceutical compositions.
[00229] Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent.
[00230] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water soluble carrier such as polyethyleneglycol or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
[00231] The active compounds can also be in microencapsulated form with one or more excipients as noted above.
[00232] When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring agents may be added. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, flavoring and coloring agents and antioxidant.
[00233] Sterile injectable forms of the compositions described herein (e.g., for parenteral administration) may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di- glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically
acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of injectable formulations.
[00234] Oily suspensions may be formulated by suspending the compound of Formula I in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as butylated hydroxyanisol or alpha- tocopherol.
[00235] Aqueous suspensions of compounds of Formula I contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose,
croscarmellose, povidone, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
[00236] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
[00237] In order to prolong the effect of a compound described herein, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline
form. Alternativel , delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsuled matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot-injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.
[00238] The injectable solutions or microemulsions may be introduced into a patient's bloodstream by local bolus injection. Alternatively, it may be advantageous to administer the solution or microemulsion in such a way as to maintain a constant circulating concentration of the instant compound. In order to maintain such a constant concentration, a continuous intravenous delivery device may be utilized. An example of such a device is the Deltec CADD-PLUS™ model 5400 intravenous pump.
[00239] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing the compounds described herein with suitable non-irritating excipients or carriers such as cocoa butter, beeswax, polyethylene glycol or a suppository wax that are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. Other formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays.
[00240] The pharmaceutical compositions described herein may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the ear, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
[00241] Dosage forms for topical or transdermal administration of a compound described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the
compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
[00242] For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.
[00243] For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or, preferably, as solutions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as
benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical
compositions may be formulated in an ointment such as petrolatum. For treatment of the eye or other external tissues, e.g., mouth and skin, the formulations may be applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w. When formulated in an ointment, the active ingredients may be employed with either an oil-based, paraffinic or a water-miscible ointment base.
[00244] Alternatively, the active ingredients may be formulated in a cream with an oil- in-water cream base. If desired, the aqueous phase of the cream base may include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.
[00245] The oily phase of emulsions prepared using compounds of Formula I may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. A hydrophilic emulsifier may be included together with a lipophilic emulsifier which acts as a stabilizer. In some embodiments, the emulsifier includes both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulations. Emulgents and emulsion stabilizers suitable for use in the formulation of compounds of Formula I include Tween -60, Span -80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
[00246] The pharmaceutical compositions may also be administered by nasal aerosol or by inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance
bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. Formulations suitable for intrapulmonary or nasal administration have a mean particle size, for example, in the range of 0.1 to 500 microns (including particles with a mean particle size in a range between 0.1 and 500 microns in micron increments such as 0.5, 1, 30, 35 microns, etc.), and are administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
[00247] For use, the pharmaceutical composition (or formulation) may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well-known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.
[00248] The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized)
condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as recited herein above, or an appropriate fraction thereof of the active ingredient.
[00249] In another aspect, a compound of Formula I or a pharmaceutically acceptable salt, co-crystal, solvate or pro-drug thereof may be formulated in a veterinary composition comprising a veterinary carrier. Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials that are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.
Therapeutic Methods:
[00250] The terms, "disease", "disorder", and "condition" may be used
interchangeably here to refer to a condition where an increase in the concentration of an endogenous cannabinoid (eCB) might be beneficial or a condition that can be treated by a FAAH inhibitor.
[00251] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to an animal (e.g., a bird such as a chicken, quail or turkey, or a mammal), preferably a "mammal" including a non-primate (e.g., a cow, pig, horse, sheep, rabbit, guinea pig, rat, cat, dog, and mouse) and a primate (e.g., a monkey, chimpanzee and a human), and more preferably a human. In one embodiment, the subject is a non-human animal such as a farm animal (e.g., a horse, cow, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit). In a preferred embodiment, the subject is a "human".
[00252] The term "biological sample", as used herein, includes, without limitation, in vivo or ex vivo cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; blood, saliva, urine, feces, semen, tears, lymphatic fluid, ocular fluid, vitreous humor or other body fluids or extracts thereof.
[00253] "Treat", "treating" or "treatment" with regard to a disorder or disease refers to alleviating or abrogating the cause and/or the effects of the disorder or disease. As used herein, the terms "treat", "treatment" and "treating" refer to the reduction or amelioration of
the progression, severity and/or duration of a condition wherein an increase in the concentration of eCB might be beneficial or that can be treated with a FAAH inhibitor, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of said condition, resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a compound or composition of the invention). In specific embodiments, the terms "treat", "treatment" and "treating" refer to the amelioration of at least one measurable physical parameter of condition wherein an increase in the
concentration of eCB might be beneficial or a condition that can be treated with a FAAH inhibitor. In other embodiments the terms "treat", "treatment" and "treating" refer to the inhibition of the progression of said condition, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both.
[00254] As used herein, the terms "prevent", "preventing" and "prevention" with regard to a disorder or disease refer to averting the cause and/or effects of a disease or disorder prior to the disease or disorder manifesting itself. The terms "prophylaxis" or "prophylactic use", as used herein, refer to any medical or public health procedure whose purpose is to prevent, rather than treat or cure a disease. As used herein, the terms "prevent", "prevention" and "preventing" refer to the reduction in the risk of acquiring or developing a given condition, or the reduction or inhibition of the recurrence or said condition in a subject who is not ill, but who has been or may be near a person with the disease.
[00255] The term "chemotherapy" refers to the use of medications, e.g., small molecule drugs (rather than e.g., "vaccines") for treating a disorder or disease.
[00256] The term "chemoprophylaxis" refers to the use of medications, e.g., small molecule drugs (rather than e.g.," vaccines") for the prevention of a disorder or disease.
[00257] In one embodiment, the methods of the invention are a preventative or "preemptive" measure to a patient, preferably a human, having a predisposition to developing a condition or symptom that can be improved by an increase in the concentration of an eCB or treated with a FAAH inhibitor.
[00258] Also described are methods for treating or preventing various disorders with a composition that includes any of the various embodiments of the compound of Formula I. Among the disorders or symptoms that can be treated or prevented are: pain (e.g., acute pain, chronic pain, neurogenic pain, dental pain, menstrual pain, dysmenorrheal pain, visceral pain, neuropathic pain, post operative pain, headache, migraines, allodynia, hyperalgesia, post
operative pain (e.g., associated with orthopedic surgery, gynecological surgery, abdominal surgery, incisions, oral surgery), back pain, pain caused by inflammation (e.g., arthritis, osteoarthritis, spondylitis, rheumatoid arthritis, Crohn's disease and irritable bowel syndrome) and pain associated with injury, burns or trauma), anxiety, depression, an eating disorder (e.g., anorexia and bulimia), obesity (e.g., by appetite suppression), elevated intraocular pressure (e.g., glaucoma), a cardiovascular disorder (e.g., hypertension), an inflammatory disorder (e.g., allergy (e.g., food allergy-, respiratory inflammation, inflammation of the skin and gastrointestinal inflammation), asthma, Crohn's disease), emesis (e.g., as a side effect of chemotherapy), some cancers, excitotoxic insult (e.g., in cerebral ischemia, seizure and edema due to traumatic brain injury), asphyxia, addictive behaviors, sleep disorders, epilepsy, epileptiform-induced damage, progressive CNS diseases (e.g., Parkinson's, motor neuron disorders, ALS (amyotropic lateral sclerosis), Huntington's and motor dysfunction), gastrointestinal disorders (e.g., attenuation of cholera induced fluid accumulation, nausea, vomiting, gastric ulcers, diarrhea, paralytic ileus, IBS, and gastroesophageal reflux conditions) and autoimmune disorders (e.g., Multiple Sclerosis).
[00259] The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of pain. The pain can be chronic pain, acute pain, perioperative pain (e.g., associated with surgery), postoperative pain, visceral pain, inflammatory pain, cancer pain, headache pain, pain associated with cough, neuropathic pain, deafferentation pain, chronic nociceptive pain, dental pain (such as odontalgia), bone pain, joint pain (e.g., osteoarthritis or rheumatoid arthritis), myofascial pain (e.g., muscular injury, fibromyalgia), labor pain, pain associated with injuries, trauma, allergies, dermatitis, immunodeficiency, Hodgkin's disease, Myasthenia gravis, nephrotic syndrome, scleroderma, or thyroiditis, central and peripheral pathway mediated pain, or pain associated with or the result of injury or age.
[00260] Neuropathic pain is initiated or caused by a primary lesion or dysfunction in the peripheral or central nervous systems. It can occur in the peripheral nerves, dorsal roots, spinal cord and certain regions of the brain. It can also result from a peripheral nerve disorder such as neuroma, nerve compression, nerve crush, nerve stretch or incomplete nerve transsection. It can be associated with neuronal lesions, such as those induced by diabetes, HIV, herpes infection, nutritional deficiencies or a stroke. Chronic neuropathic pain can result from injury and/or inflammation such as chronic lower back pain. Acute neuropathic pain includes, for example, traumatic pain (e.g., bone fracture pain, sprains, strains and soft
tissue damage), muscle pain, burn pain, and sun burn pain. Neuropathic pain can also be associated with, for example, nerve injury, head trauma, hyperalgesia, allodynia,
dysesthesias, sciatica, amputation (e.g., phantom limb syndrome, stump pain), fibromyalgia, chemotherapeutic neuropathy, cancer pain (e.g., tumors of the brainstem, thalamus or cortex), AIDS-related neuropathy, painful traumatic mononeuropathy, painful polyneuropathy, multiple sclerosis, root avulsions, post-thoracotomy syndrome. It can be the result of a central nervous system injury (such as pain in stroke or spinal cord injury patients).
Neuropathic pain also includes lower back pain, toxin induced pain, neurogenic pain, thalamic pain syndrome, repetitive motion pain (e.g., carpal tunnel syndrome) or pain induced by post mastectomy syndrome, by surgery or by radiation. Neuralgia is a type of neuropathic pain that is thought to be linked to four possible mechanisms: ion gate
malfunctions; a nerve becoming mechanically sensitive and creating an ectopic signal; cross signals between large and small fibers; and malfunction due to damage in the central processor. Under the general heading of neuralgia are trigeminal neuralgia (TN), atypical trigeminal neuralgia (ATN), and post-herpetic neuralgia (caused by shingles or herpes).
Neuralgia is also involved in disorders such as sciatica and brachial plexopathy with neuropathia. Neuralgias that do not involve the trigeminal nerve are occipital neuralgia and glossopharyngeal neuralgia. Neuropathic pain also includes referred pain.
[00261] Visceral pain includes, for example, pain associated with pancreatitis, peptic ulcers, interstitial cystitis, renal colic, angina, dysmenorrhea, menstrual cramps, menstruation, irritable bowel syndrome (IBS), myocardial ischemia, and non-ulcer dyspepsia. Visceral pain also includes gynecological pain, urinary bladder pain, kidney pain, non-cardiac chest pain, and chronic pelvic pain.
[00262] Inflammatory pain includes both inflammatory pain that is a significant component of a disorder or disease and that that is considered a minor component or symptom. For example, inflammatory pain induced by or associated with disorders such as osteoarthritis, rheumatic fever, rheumatoid arthritis, rheumatic disease, tendonitis, juvenile arthritis, spondylitis, gouty arthritis, psoriatic arthritis, interstitial cystitis, peripheral neuritis, mucositis, fibromyalgia, pancreatitis, enteritis, diverticulitis, cellulites, bone fractures, postoperative ileus, Crohn's Disease, ulcerative colitis, cholecystitis, teno-synovitis, gout, vulvodynia, fibromyalgia, sprains and strains, systemic lupus erythematosus, myositis, bronchitis and influenza and other viral infections such as the common cold. Inflammatory pain also includes sympathetically maintained pain, pain due to venomous and non- venomous
snake bite, spider bite or insect sting, sports injury pain, sprain pain, joint pain, myofascial pain (muscular injury, fibromyalgia), muscoskeletal pain, and pain due to inflammatory bowel diseases. Among the inflammatory pain disorders that can be treated are included some autoimmune disorders or diseases.
[00263] Cancer pain can be induced by or associated with tumors such as lymphatic leukemia, Hodgkin's disease, malignant lymphoma, osteosarcoma, bone cancer,
lymphogranulomatoses, lymphosarcoma, solid malignant tumors, and extensive metastases. Chemotherapy pain is a side effect of chemotherapy treatments.
[00264] Headache pain includes cluster headache, migraines with and without aura, tension type headache, headaches caused by injury or infection, hangovers, and headaches with unknown origins.
[00265] The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of inflammatory disorders, including, for example, chronic and acute inflammatory disorders. Examples of disorders with inflammatory components include asthma, atopic allergy, allergy,
atherosclerosis, bronchial asthma, eczema, glomerulonephritis, graft vs. host disease, hemolytic anemia, osteoarthritis, sepsis, septic shock (e.g., as antihypovolemic and/or antihypotensive agents), systemic lupus erythematosus, stroke, transplantation of tissue and organs, vasculitis, diabetic retinopathy and ventilator induced lung injury. The compounds and pharmaceutical compositions described herein can also be used alone or in combination therapy for the treatment or prevention of disease states or indications that are accompanied by inflammatory processes such as:
[00266] (1) Lung diseases: e.g., asthma, bronchitis, allergic rhinitis, emphysema, adult respiratory distress syndrome (ARDS), pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease (COPD), asthma including allergic asthma (atopic or non- atopic) as well as exercise-induced bronchoconstriction, occupational asthma, viral or bacterial exacerbation of asthma, other non-allergic asthmas and "wheezy-infant syndrome", pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis;
[00267] (2) Rheumatic diseases or autoimmune diseases or musculoskeletal diseases: e.g., all forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, and polymyalgia rheumatica; reactive arthritis; rheumatic soft tissue diseases; inflammatory
soft tissue diseases of other genesis; arthritic symptoms in degenerative joint diseases (arthroses); tendinitis, bursitis, osteoarthritis, traumatic arthritis, gout (metabolic arthritis); collagenoses of any genesis, e.g., systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, Sjogren syndrome, Still disease, Felty syndrome; and osteoporosis and other bone resorption diseases;
[00268] (3) Allergic diseases including all forms of allergic reactions, e.g., allergic rhinitis, allergic conjunctivitis, infectious parasitic, angioneurotic edema, hay fever, insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc., anaphylactic shock (anaphylaxis), urticaria, angioneurotic edema, delayed or immediate hypersensitivity, and contact dermatitis;
[00269] (4) Vascular diseases: e.g., panarteritis nodosa, polyarteritis nodosa, periarteritis nodosa, arteritis temporalis, Wegner granulomatosis, giant cell arthritis, atherosclerosis, reperfusion injury and erythema nodosum, myocardial ischemia, thrombosis.
[00270] (5) Dermatological diseases: e.g., dermatitis, psoriasis, sunburn, burns, and eczema;
[00271] (6) Renal, urinary and pancreatic diseases: e.g., nephrotic syndrome and all types of nephritis (such as glomerulonephritis); pancreatitis; bladder hyperrelexia following bladder inflammation; other renal diseases that can be treated by the compounds and compositions herein described include urinary incontinence or vesicle inflammation, uresesthesia urgency, overactive bladder, urinary frequency, interstitial cystitis or chronic prostatitis;
[00272] (7) Hepatic diseases: e.g., acute liver cell disintegration; acute hepatitis of various genesis (such as viral, toxic, drug-induced) and chronically aggressive and/or chronically intermittent hepatitis, liver fibrosis associated with liver injury or disease, including fibrosis caused or exacerbated by alcoholic liver cirrhosis, chronic viral hepatitis, non alcoholic steatohepatitis and primary liver cancer;
[00273] (8) Gastrointestinal diseases: e.g., ulcers, inflammatory bowel diseases, regional enteritis (Crohn's disease), ulcerative colitis, gastritis, aphthous ulcer, celiac disease, regional ileitis, ileus, esophagitis, NSAID-induced ulcer, non-ulcerative dyspepsia and gastroesophageal reflux disease;
[00274] (9) Neurodegenerative diseases: e.g., treatment/reduction of
neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury,
edema, spinal cord injury, cerebral ischemia, seizures or the like;
[00275] (10) Eye diseases: e.g., allergic keratitis, uveitis, or iritis, conjunctivitis, blepharitis, neuritis nervi optici, choroiditis, glaucoma and sympathetic ophthalmia;
[00276] (1 1) Diseases of the ear, nose, and throat (ENT) area: e.g., tinnitus, allergic rhinitis or hay fever, gingivitis, otitis externa, caused by contact eczema, infection, etc., and otitis media;
[00277] (12) Progressive central nervous system or neurological diseases: e.g., brain edema, particularly tumor-related brain edema, multiple sclerosis, acute encephalomyelitis, meningitis, acute spinal cord injury, trauma; cognitive disorders such as dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Parkinson's disease and Creutzfeldt- Jacob disease, Huntington's chorea, Pick's disease, amyotrophic lateral sclerosis (ALS)), vascular dementia (including multi-infarct dementia and dementia associated with intracranial space occupying lesions, infections and related conditions such as HIV infection); Guillain-Barre syndrome, myasthenia gravis, stroke, and various forms of seizures (such as nodding spasms);
[00278] (13) Blood diseases: e.g., acquired hemolytic anemia, aplastic anemia, and idiopathic thrombocytopenia;
[00279] (14) Tumor diseases: e.g., acute lymphatic leukemia, Hodgkin's disease, malignant lymphoma, lymphogranulomatoses, lymphosarcoma, solid malignant tumors, colorectal polyps, and extensive metastases; other proliferative disorders such as diabetic retinopathy and tumor angiogenesis (e.g., wet macular degeneration).
[00280] (15) Endocrine diseases: e.g., endocrine opthalmopathy, endocrine orbitopathia, thyrotoxic crisis, Thyroiditis de Quervain, Hashimoto thyroiditis, Morbus Basedow, granulomatous thyroiditis, struma lymphomatosa, Graves disease, type I diabetes (such as insulin-dependent diabetes); organ and tissue transplantations and graft vs. host diseases;
[00281] (16) Severe states of shock: e.g., septic shock, anaphylactic shock, and systemic inflammatory response syndrome (SIRS);
[00282] (17) Viral or bacterial parasitic infectious disease: for example AIDS and meningitis; and
[00283] (18) various other disease-states or conditions including, restenosis following
percutaneous transluminal coronary angioplasty, acute and chronic pain, atherosclerosis, reperfusion injury, congestive heart failure, myocardial infarction, thermal injury, multiple organ injury secondary to trauma, necrotizing enterocolitis and syndromes associated with hemodialysis, leukopheresis, granulocyte transfusion, sarcoidosis, gingivitis, pyrexia; edema resulting from trauma associated with burns, sprains or fracture, cerebral edema and angioedema, and diabetes (such as diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, post capillary resistance and diabetic symptoms associated with insulitis (e.g., hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion)).
[00284] The compounds and compositions herein described can be used alone or in combination therapy for the treatment of gastrointestinal (GI) diseases or disorders: e.g., functional gastrointestinal disorders, ulcers, inflammatory bowel diseases (IBD), regional enteritis (Crohn's disease), ulcerative colitis, diarrhea, gastritis, aphthous ulcer, celiac disease, regional ileitis, ileus, functional dyspepsia, diverticulitis, gastrointestinal bleeding, irritable bowel syndrome (IBS), non-ulcerative dyspepsia and gastroesophageal reflux disease.
[00285] The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of pruritus (itch). For example, pruritus originated in the skin (dermal pruritus), neuropathic pruritus, neurogenic or psychogenic pruritus would all be included. Pruritus (itching) can be a symptom of primary skin diseases or of systemic disease. Skin diseases notorious for causing intense pruritus include scabies, pediculosis, insect bites, urticaria, atopic and contact dermatitis, lichen planus, miliaria, and dermatitis herpetiformis. In other cases pruritus is prominent without any identifiable skin lesions: e.g., dry skin (especially in elderly people), systemic disease, and use of certain drugs can generate pruritus. Systemic diseases that cause generalized pruritus include cholestatic diseases, uremia, polycythemia vera, and hematologic
malignancies. Pruritus may also occur during the later months of pregnancy. Barbiturates, salicylates, morphine and cocaine can cause pruritus. Less well-defined causes of pruritus include hyper- and hypothyroidism, diabetes, iron deficiency, and internal cancers of many types.
[00286] The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of substance abuse related syndromes, disorders or diseases include, including, for example, drug abuse and drug withdrawal. Abused substances can include alcohol, amphetamines, amphetamine-like
substances, caffeine, cannabis, cocaine, hallucinogens, inhalants, opioids, nicotine (and/or tobacco products), heroin, barbiturates, phencyclidine (or phencyclidine-Hke compounds), sedative-hypnotics, benzodiazepines, or combinations of any of the foregoing. The compounds and pharmaceutical compositions can also be used to treat withdrawal symptoms and substance-induced anxiety or mood disorder. In addition, they can be used to reduce tobacco craving; treat nicotine dependency, addiction, or withdrawal; or aid in the cessation or lessening of tobacco in a subject in need thereof.
[00287] The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of psychiatric disorders, such as depressions (including major depressive disorder, bipolar depression, unipolar depression, single or recurrent major depressive episodes (e.g., with or without psychotic features, catatonic features, and/or melancholic features), postpartum onset, seasonal affective disorder, dysthymic disorders (e.g., with early or late onset and with or without atypical features), neurotic depression and social phobia, depression accompanying dementia, anxiety, psychosis, social affective disorders, and/or cognitive disorders); manic-depressive psychoses; bipolar disorders; extreme psychotic states (such as mania, schizophrenia, and excessive mood swings where behavioral stabilization is desired),\; Post-traumatic stress disorder; panic disorder; obsessive compulsive disorder. The compounds and pharmaceutical compositions described herein can also be used alone or in combination therapy for the treatment or prevention of attention disorders such as ADHD (attention deficit hyperactivity disorders), autism, anxiety states, generalized anxiety, agoraphobia, as well as those behavioral states characterized by social withdrawal. They can also be used for the treatment of psychiatric tremors (e.g., dyskinesias, dystonia, spasticity).
[00288] The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of an autoimmune disease or disorder or at least one symptom associated with said disease or disorder, including, for example, alopecia areata (also known as systemic sclerosis (SS)), amyloses, amyotrophic lateral sclerosis, ankylosing spondylarthritis, ankylosing spondylitis,
antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune
lymphoproliferative syndrome (ALPS), autoimmune thrombocytopenic purpura (ATP), Behcet's disease, cardiomyopathy, celiac sprue-dermatitis hepetiformis; chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating
polyneuropathy (CIPD), cicatricial pemphigoid, cold agglutinin disease, connective tissue diseases, crest syndrome, Crohn's disease, Degos' disease, dermatomyositis-juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, graft vs. host disease, transplantation rejection, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin-dependent diabetes mellitus, juvenile chronic arthritis (Still's disease), juvenile rheumatoid arthritis, lupus erythematosus, Meniere's disease, multiple sclerosis, myasthenia gravis, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomena, reactional arthritis, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma (progressive systemic sclerosis (PSS), Sjogren's syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, undifferentiated spondylarthritis, uveitis, vitiligo, and Wegener's granulomatosis.
[00289] The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of neurological or neurodegenerative disorders. Examples of neurodegenerative diseases include dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease, prion disease and Creutzfeldt-Jakob disease, motor neuron disease); vascular dementia (including multi-infarct dementia); as well as dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); dementia in Parkinson's disease; metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with aging, particularly Age-Associated Memory Impairment. Examples of neurological disorders include amyotrophic lateral sclerosis (ALS), multiple sclerosis, epilepsy, ischemia, traumatic head or brain injury, brain inflammation, eye injury, stroke and neuroinflammation. The compounds and compositions here described can also be used for the treatment/reduction of neurodegeneration or decreased brain activity associated with stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, hypoxia, hypoglycemia, gas poisoning, drug intoxication, diabetes mellitus, edema, spinal cord injury, cerebral ischemia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, seizures or the like.
[00290] The compounds and pharmaceutical compositions described herein can be used alone or in combination therapy for the treatment or prevention of ocular disorders
including, for example, glaucoma (such as normal tension glaucoma), glaucoma-associated intraocular pressure retinitis, retinopathies, uveitis, and acute injury to the eye tissue (e.g., conjunctivitis). Ocular disorders also include neurodegenerative disease conditions of the retina and the optic nerve, for example, in patients presenting risk factors for glaucoma, such as high intraocular pressure, family history of glaucoma, glaucoma in the contralateral eye and high myopia.
[00291] The compounds and compositions described herein can also be used, alone or in combination therapy, to treat or prevent appetite related disorders such as emesis, vomiting and nausea, food behavioral problems or feeding disorders (e.g., anorexias, cachexias, wasting conditions and bulimia) and obesity or obesity-related disorders (e.g., diabetes type II, hyperlipidemia).
[00292] Certain gynecological disorders can be treated by inhibition of uterus contraction caused by hormones and prostanoid-induced muscle contraction using compounds or compositions described herein, for example, premature labor, menstrual cramps, menstrual irregularity, dysmenorrhea.
[00293] Some sleep disorders can be treated with compounds or compositions described herein, for example, insomnia, night terrors, bruxism, somnambulism, narcolepsy, circadian rhythm adjustment disorders, and the like. Also contemplated are sleep disorders associated with neurological or mental disorders or with pain.
[00294] Cardiovascular diseases that can be treated with the compounds and compositions described herein include myocardial ischemia, thrombosis, hypertension or cardiac arrhythmias.
[00295] Compounds and compositions of the invention are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including, without limitation, dogs, cats, mice, rats, hamsters, gerbils, guinea pigs, rabbits, horses, pigs and cattle.
[00296] In another embodiment, the invention provides a method of inhibiting FAAH in a biological sample, comprising contacting said biological sample with a compound or composition of the invention. Use of a FAAH inhibitor in a biological sample is useful for a variety of purposes known to one of skill in the art. Examples of such purposes include, without limitation, biological assays and biological specimen storage.
Combination Therapies:
[00297] The compounds and pharmaceutical compositions described herein can be used in combination therapy with one or more additional therapeutic agents. For combination treatment with more than one active agent, where the active agents are in separate dosage formulations, the active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of the other agent.
[00298] When co-administered with other agents, e.g., when co-administered with another pain medication, an "effective amount" of the second agent will depend on the type of drug used. Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound described herein being used. In cases where no amount is expressly noted, an effective amount should be assumed. For example, compounds described herein can be administered to a subject in a dosage range from between about 0.001 to about 100 mg/kg body weight/day, from about 0.001 to about 50 mg/kg body weight/day, from about 0.001 to about 30 mg/kg body weight/day, from about 0.001 to about 10 mg/kg body weight/day.
[00299] When combination therapy is employed, an effective amount can be achieved using a first amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate (e.g., hydrate), co-crystal or pro-drug thereof and a second amount of an additional suitable therapeutic agent (e.g., an agent to treat pain).
[00300] In one embodiment of this invention, the compound of Formula I and the additional therapeutic agent, are each administered in an effective amount (i.e., each in an amount which would be therapeutically effective if administered alone). In another embodiment, the compound of Structural Formula I and the additional therapeutic agent, are each administered in an amount which alone does not provide a therapeutic effect (a subtherapeutic dose). In yet another embodiment, the compound of Structural Formula I can be administered in an effective amount, while the additional therapeutic agent is administered in a sub-therapeutic dose. In still another embodiment, the compound of Structural Formula I can be administered in a sub-therapeutic dose, while the additional therapeutic agent, for example, a suitable cancer-therapeutic agent is administered in an effective amount.
[00301] As used herein, the terms "in combination" or "co-administration" can be used
interchangeably to refer to the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). The use of the terms does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject.
[00302] Co-administration encompasses administration of the first and second amounts of the compounds in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, capsule or tablet having a fixed ratio of first and second amounts, or in multiple, separate capsules or tablets for each. In addition, such coadministration also encompasses use of each compound in a sequential manner in either order. When coadministration involves the separate administration of a first amount of a compound of Formula I and a second amount of an additional therapeutic agent, the compounds are administered sufficiently close in time to have the desired therapeutic effect. For example, the period of time between each administration that can result in the desired therapeutic effect can range from minutes to hours and can be determined taking into account the properties of each compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile. For example, a compound of Formula I and the second therapeutic agent can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other or within about 30 minutes of each other.
[00303] More specifically, a first therapy (e.g., a prophylactic or therapeutic agent such as a compound described herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks prior to), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks subsequent to) the administration of a second therapy (e.g., a prophylactic or therapeutic agent such as an anticancer agent) to a subject.
[00304] Additional therapeutic agents that can be combined with compounds described herein include, without limitation:
[00305] FAAH inhibitors: e.g., OL-135, LY2183240, URB-597, CAY-10402, PF-750,
BMS-469908, SSR-411298, TK-25, PF-04457845, PF-3845, SA-47, JNJ-245, JNJ-28833155 and JNJ-1661010;
[00306] painkillers such as acetaminophen or paracetamol;
[00307] non-steroidal anti-inflammatory drugs (NSAIDs) such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenhufen, fenoprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives
(indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (meclofenamic acid, mefe-namic acid, and tolfenamic acid), biphenyl-carboxylic acid derivatives, oxicams (isoxicam, meloxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone), and COX-2 inhibitors, such as the coxibs (celecoxib, deracoxib, valdecoxib, rofecoxib, parecoxib and etoricoxib);
[00308] other pain relieving agents such as gabapentin, topical capsaicin, tanezumab, esreboxetine;
[00309] opiate receptor agonists such as morphine, propoxyphene (Darvon), tramadol, buprenorphin;
[00310] cannabinoid receptor agonists such as Dronabinol, A9-THC, CP-55940, WIN- 55212-2, HU-210;
[00311] anti- infective agents;
[00312] sodium channel blockers such as carbamazepine, mexiletine, lamotrigine, pregabalin, tectin, NW-1029, CGX-1002;
[00313] N-type calcium channel blockers such as Ziconotide, NMED-160, SPI-860; serotonergic and noradrenergic modulators such as SR-57746, paroxetine, duloxetine, clonidine, amitriptyline, citalopram;
[00314] local anesthetics such as ambroxol, lidocaine;
[00315] VR1 agonists and antagonists such as NGX-4010, WL-1002, ALGRX-4975, WL-10001, AMG-517;
[00316] agents used for migraines, such as sumatriptan, zolmitriptan, naratriptan, eletriptan, rauwolscine, yohimbine, metoclopramide;
[00317] topical agents used in the treatment of localized pruritus: e.g.,
camphor/menthol lotions or creams containing 0.125 to 0.25% menthol, doxepin (e.g., Sinequan, Zonalon), phenol (e.g., Cepastat, Chloraseptic gargle, Ulcerease), 0.5 to 2%, pramoxine (e.g., Anusol ointment, Proctofoam-NS, Tronolane Cream, Tucks Hemorrhoidal), eutectic mixture of local anesthetics (EMLA), and corticosteroids;
[00318] anti-inflammatory and/or immunosuppressive agents such as methotrexate, cyclosporin A (including, for example, cyclosporin microemulsion), tacrolimus,
corticosteroids, statins, interferon beta, Remicade (Infliximab), Enbrel (Etanercept) and Humira (Adalimumab);
[00319] agents designed to treat tobacco abuse: e.g., nicotine receptor partial agonists, bupropion hypochloride (also known under the tradename Zyban™) and nicotine
replacement therapies;
[00320] ADD/ADHD agents: e.g., Ritalin™ (methylphenidate hydrochloride), Strattera™ (atomoxetine hydrochloride), Concerta™ (methylphenidate hydrochloride) and Adderall™ (amphetamine aspartate; amphetamine sulfate; dextroamphetamine saccharate; and dextroamphetamine sulfate);
[00321] agents to treat alcoholism, such as opioid antagonists (e.g., naltrexone (also known under the tradename ReVia M) and nalmefene), disulfiram (also known under the tradename Antabuse™), and acamprosate (also known under the tradename Campral™));
[00322] agents for reducing alcohol withdrawal symptoms such as benzodiazepines, beta-blockers, clonidine, carbamazepine, pregabalin, and gabapentin (Neurontin™);
[00323] antihypertensive agents: e.g., ACE inhibitors and Angiotensin II Receptor blockers such as benazepril , captopril , enalapril , fosinopril , lisinopril, candesartan , eprosartan, Irbesartan, losartan, olmesartan, telmisartan, valsartan, Renin inhibitors such as aliskiren, vasodilators such as minoxidil;
[00324] agents used to treat glaucoma: e.g., direct- acting Miotics (cholinergic agonists), indirect acting Miotics (cholinesterase inhibitors), Carbonic anhydrase inhibitors (e.g., Acetazolamide, Methazolamide, Brinzolamide, Dorzolamide), Selective adrenergic agonists (e.g., Apraclonidine, Brimonidine), Beta-blockers (Timolol, Betaxolol, Carteolol, Levobetaxolol, Levobunolol, Metipranolol), Osmotic diuretics (e.g., Glycerin, Mannitol);
[00325] antidepressants: e.g., SSRIs (e.g., fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline, zimeldine), tricyclic antidepressants (e.g., imipramine, amitriptiline, chlomipramine and nortriptiline), dopaminergic antidepressants
(e.g., bupropion and amineptine), SNRIs (e.g., venlafaxine and reboxetine);
[00326] cognitive improvement agents: e.g., donepezil hydrochloride (Aricept™) and other acetylcholinesterase inhibitors;
[00327] anti-emetic agents: e.g., 5HT3 antagonists such as ondansetron, granisetron, metoclopramide;
[00328] neuroprotective agents: e.g., memantine, L-dopa, bromocriptine, pergolide, talipexol, pramipexol, cabergoline, neuroprotective agents currently under investigation including anti-apoptotic drugs (CEP 1347 and CTCT346), lazaroids, bioenergetics, antiglutamatergic agents and dopamine receptors. Other clinically evaluated neuroprotective agents are, e.g., the monoamine oxidase B inhibitors selegiline and rasagiline, dopamine agonists, and the complex I mitochondrial fortifier coenzyme Q10;
[00329] antipsychotic medications: e.g., ziprasidone (Geodon™), risperidone
(Risperdal™), and olanzapine (Zyprexa™);
[00330] agents used for multiple sclerosis such as beta-interferon (e.g., Avonex™, Betaseron™) Baclofen and Copaxone;
[00331] disease-modifying anti-rheumatic drugs (DMARDS) such as methotrexate, azathioptrine, leflunomide, pencillinamine, gold salts, mycophenolate mofetil,
cyclophosphamide, CP-690,550; biological response modifiers (BRMs) such as Enbrel, Remicade, IL-1 antagonists; NSAEDS such as piroxicam, naproxen, indomethacin, ibuprofen and the like; COX-2 selective inhibitors such as Celebrex™; COX-1 inhibitors such as Feldene; immunosuppressives such as steroids, cyclosporine, Tacrolimus, rapamycin and the like;
[00332] PDE4 inhibitors such as theophylline, drotaverine hydrochloride, cilomilast, roflumilast, denbufylline, rolipram, tetomilast, enprofylline, arofylline, cipamfylline, tofimilast, filaminast, piclamilast, (R)-(+)-4-[2-(3-cyclopentyloxy-4-methoxyphenyl)-2- phenylethyl]pyridine, mesopram, N-(3,5-dichloro-4-pyridinyl)-2-[ l-(4-fluorobenzyl)-5- hydroxy-lH- -indol-3-yl]-2-oxoacetamide, CDC-801 (Celgene), CC-1088 (Celgene), Lirimilast, ONO-6126 (Ono), CC-10004 (Celgene) and MN-001 (Kyorin), ibudilast and pentoxifylline, for use in treating inflammation, lung disorders and as bronchodilators;
[00333] corticosteroids such as betamethasone, budesonide, cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, prednisone and triamcinolone;
[00334] histamine HI receptor antagonists such as bromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdiazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, desloratadine, fexofenadine and levocetirizine;
[00335] histamine H2 receptor antagonists such as cimetidine, famotidine and ranitidine;
[00336] proton pump inhibitors such as omeprazole, pantoprazole and esomeprazole;
[00337] leukotriene antagonists and 5-lipoxygenase inhibitors such as zafirlukast, montelukast, pranlukast and zileuton;
[00338] nicotinic acetylcholine receptor agonists such as ABT-202, A-366833, ABT- 594; BTG-102, A-85380, CGX1204;
[00339] P2X3 receptor antagonists such as A-317491 , ISIS- 13920, AZD-9056;
[00340] NGF agonists and antagonists such as RI-724, RI-1024, AMG-819, AMG- 403, PPH 207;
[00341] NK1 and NK2 antagonists such as DA-5018, R-l 16301 ; CP-728663, ZD- 2249;
[00342] NMDA antagonist such as NER-MD-1 1, CNS-5161, EAA-090, AZ-756, CNP-3381; potassium channel modulators such as CL-888, ICA-69673, retigabine;
[00343] GABA modulators such as lacosamide and propofol;
[00344] anti-cancer agents such as tyrosine kinase inhibitors imatinib (Gleevec Glivec) and gefitinib (Iressa);
[00345] anti hyperlipidemia drugs such as statins, ezetimibe, niacin and bile acid sequestrants;
[00346] appetite suppressing agents: e.g., sibutramine, taranabant, rimobamant;
[00347] anti-diabetic medications such as insulin, tolbutamide (Orinase),
acetohexamide (Dymelor), tolazamide (Tolinase), chlorpropamide (Diabinese), glipizide (Glucotrol), glyburide (Diabeta, Micronase, Glynase), glimepiride (Amaryl), gliclazide (Diamicron), repaglinide (Prandin), nateglinide (Starlix), pramlintide (Symlin) and exanatide (Byetla);
[00348] serotonergic and noradrenergic modulators such as SR-57746, paroxetine, duloxetine, clonidine, amitriptyline, citalopram, flibanserin; and
[00349] GI agents: e.g., laxatives (e.g., Lubiprostone (Amitiza), Fybogel®, Regulan®, Normacol® and the like), a gastrointestinal agent used for the treatment of idiopathic chronic constipation and constipation-predominant IBS, GI motility stimulants (e.g., domperidone, metoclopramide, mosapride, itopride), antispasmodic drugs (e.g., anticholinergics such as hyoscyamine or dicyclomine); anti-diarrheal medicines such loperamide (Imodium) and bismuth subsalicylate (as found in Pepto Bismol and Kaopectate), GCC (Guanylate Cyclase C) agonists (e.g., Linaclotide), 5HT4 agonists (e.g., Tegasarod), 5HT3 antagonists (e.g., Alosetron, Ramosetron, Ondansetron).
Methods of preparing the compounds:
[00350] The compounds of Formula I may be prepared according to the schemes and examples depicted and described below. Unless otherwise specified, the starting materials and various intermediates may be obtained from commercial sources, prepared from commercially available compounds or prepared using well-known synthetic methods.
General Synthetic methods and General Synthetic Schemes
[00351] General synthetic procedures for the compounds of this invention are described below. The synthetic schemes are presented as examples and do not limit the scope of the invention in any way.
Scheme
Formula 2a Formula 2b Formula 3
[00352] A compound of Formula 3 can be synthesized by the alkylation of a compound of Formula 2a by reaction with the appropriate protected (trapped) enolate compound of Formula 2b, wherein X is a leaving group and PG is an oxygen protecting group (Scheme la). Deprotection of the alcohol functionality (e.g., under acidic conditions), then releases the enolate, which tautomerizes in situ to the carbonyl compound of Formula 3.
Formula 4 Formula 5
[00353] A compound of Formula 5 can be prepared from a compound of Formula 4 via the magnesium-mediated radical reduction of the α,β-unsaturation in the presence of trimethylsilyl chloride, followed by nucleophilic attack of the resulting β-carbanion onto an electrophile such as an acid chloride or anhydride. (Scheme lb).
Scheme 2
ormu a Formula 8
[00354] A compound of Formula 7 can be synthesized by the condensation reaction of a primary amine of general formula R6NH2, and a 1 ,4-dicarbonyl moiety of Formula 3 (Scheme 2). A compound of Formula 8 can then be obtained from the intermediate of Formula 7 by electrophilic aromatic substitution at position three of the pyrrole ring using
oxalyl chloride. This creates an intermediate a-keto acid chloride, which is subsequently aminated by a primary amine of general formula R6NH2 to produce a pyrrole of Formula 8.
Formula 9 Formula 10 Formula 11 Formula 12
[00355] A compound of Formula 10 can be synthesized by the condensation of a
compound of Formula 9 with an azidoacetate of general formula N3CH2C(0)OR in the
presence of a strong alkaline base such as sodium methoxide (Scheme 3). In this scheme, W, Y and Z are independently selected from C, N, O or S. The alkylation of the aldehyde of formula 9 produces a β-hydroxy ester intermediate (not shown), which, upon subsequent in situ dehydration produces the vinyl azide of Formula 10. The resulting compound of formula 10 can be transformed to a [5,5] bicyclic product of Formula 11 via a Hemetsberger-Rees thermolysis reaction in toluene. Reduction of the ester functionality of a compound of
Formula 11 to a methyl, using a reducing agent such as Lithium Aluminum Hydride,
produces a compound of general Formula 12.
Scheme 4
Formula 14
[00356] The pyrrole nitrogen of a compound of Formula 12 can be alkylated to form the corresponding compound of Formula 13 using an appropriate alkylating agent. As in
Scheme 2, subsequent aromatic electrophilic substitution at position three of the pyrrole ring by oxalyl chloride creates an intermediate a-keto acid chloride, which can subsequently be aminated by a primary amine of the general formula R6NH2, to produce an a-keto amide compound of general Formula 14.
General analytical techniques
[00357] LC/MS was run on a Waters Acquity system using a Polar CI 8 column, and 5 to 60% acetonitrile/water over 5 min. The ionization method for the MS was electrospray.
[00358] Automated column chromatography was run using an ISCO system. One of the Companion, Combiflash, or Combiflash Rf was used in each case.
[00359] Microwave reactions were run on a Personal Chemistry Optimizer, at 0-240 °C, a power of 0-300 W and a pressure of 0-21 bar.
[00360] HPLC for purification was run on a Varian Prepstar instrument using the following conditions:
Solvent A: 0.1% Trifluoroacetic acid in water
Solvent B: 0.1% Trifluoroacetic acid in acetonitrile
EXAMPLES
[00361] All references provided in the Examples are herein incorporated by reference in their entirety. As used herein, all abbreviations, symbols and conventions are consistent with those used in the contemporary scientific literature. See, e.g., Janet S. Dodd, ed., The ACS Style Guide: A Manual for Authors and Editors, 2nd Ed., Washington, D.C.: American Chemical Society, 1997, herein incorporated by reference in its entirety.
Synthetic procedures:
[00362] In a 50 mL round-bottomed flask equipped with a stir bar, NaH (484 mg, 12.1 mmol) was added to DMF (20 mL) under a nitrogen atmosphere. Cyclooctanone (1.39 g, 11 mmol) was added and the mixture was stirred at room temperature (RT) for 20 minutes. Then, 3-chloro-2-(methoxymethoxy)prop-l-ene (1.65 g, 12.1 mmol) was added, and the reaction mixture was heated at 120 °C for 2 hours, then allowed to cool to RT. Ice water (10 mL) was added, followed by EtOAc (50 mL). The layers were separated and the EtOAc layer was extracted with water (10 mL). The organic layers were combined, washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The crude mixture was dissolved in dioxane (5 mL), and H2S04 (1%, 5 mL) was added. The reaction mixture was heated at 60 °C for 1 hour, followed by cooling to RT. Ice water (10 mL) was added, followed by EtOAc (50 mL). The layers were separated and the EtOAc layer was extracted with water (10 mL). The organic layers were combined, washed with brine, dried over Na2S04, filtered and concentrated to afford 2-(2-oxopropyl)cyclooctanone which was used without further purification.
Example lb: Synthesis of 3-phenylhexane-2,5-dione (See Scheme lb).
[00363] In a 250 mL round-bottomed flask equipped with a stir bar, (E)-4-phenylbut-3- en-2-one (1.4 g, 10 mmol) was dissolved in DMF (100 mL) under a nitrogen atmosphere. Acetic anhydride (2.8 mL, 30 mmol) and magnesium (0.72 g, 30 mmol) were added, followed by the dropwise addition of trimethylsilylchloride (3.78 ml, 30 mmol). The reaction was stirred overnight at RT, and ice water (10 mL) was then added, followed by EtOAc (50 mL). The layers were separated and the EtOAc layer was extracted with water (10 mL). The organic layers were combined, washed with brine, dried over Na2S04, filtered and
concentrated to afford 3-phenylhexane-2,5-dione as an oil. The product was used without further purification.
Example 2: Synthesis of 2-(l-(4-chlorobenzyl)-2-methyl-l,4,5,6,7,8- hexahydrocyclohepta[b]pyrrol-3-yl)-N-(3-chlorophenyl)-2-oxoacetamide (1-12) (See Scheme 2).
1-12
[00364] In a 50 mL round-bottomed flask equipped with a stir bar, 4- chlorobenzylamine (1.3 mL, 11 mmol) and 2-(2-oxopropyl)cycloheptanone (1.84 g, 11 mmol) was stirred at ambient temperature. EtOAc (20 mL) was added and the organic layer was washed with water (3 x 50 mL). The organic layers were combined, washed with brine, dried over Na2S04, filtered and concentrated. The crude mixture was subjected to flash chromatography on silica gel (0 to 50% EtOAc in hexanes) resulting in isolation of l-(4- chlorobenzyl)-2-methyl-l,4,5,6,7,8-hexahydrocyclohepta[b]pyrrole. This was used directly in the next step without further purification.
[00365] In a 50 mL round-bottomed flask equipped with a stir bar was stirred l-(4-
chlorobenzyl)-2-methyl-l, 4,5,6,7, 8-hexahydrocyclohepta[b]pyrrole (800 mg, 2.9 mmol) in DCM (10 mL) at -60 °C under a nitrogen atmosphere. Oxalyl chloride (1.46 mL of a 2M DCM solution, 2.93 mmol) was added, the mixture warmed to RT and stirred at this temperature for 15 minutes then concentrated under vacuum. The resulting crude acid chloride (530 mg, 1.46 mmol) was placed under high vacuum for 2 hours, and was then dissolved in DCM (5 mL), and cooled to -10 °C under a nitrogen atmosphere.
[00366] Triethylamine (0.49 mL, 3.5 mmol) and 3-chloroaniline (259 mg, 2.04 mmol) were added to the above solution and the reaction mixture was stirred at RT for 3 hours. Water (20 mL) was added and the DCM layer was separated. Water (15 mL) and DCM (10 mL) were added and the water layer was extracted with more DCM (10 mL). The organic layers were combined, washed with brine, dried over Na2S04, filtered and concentrated. The crude mixture was subjected to flash chromatography on silica gel (0 to 50% EtOAc in hexanes) resulting in isolation of Compound 1-12 as a yellow solid. 1H NMR (CDCI3/4OO MHz) δ 8.80 (s, IH), 7.80 (t, IH), 7.46 (d, IH), 7.28 (m, 3H), 7.12 (d, IH), 6.87 (d, 2H), 4.90 (s, 2H), 2.68-2.65 (m, 2H), 2.50-2.45 (m, 2H), 2.35 (s, 3H), 1.80-1.50 (m, 6H) ; MS m/z: 454 (M + 1).
[00367] In a 3L round-bottomed flask equipped with a stir bar, methanol (1.49 L), thiophene-3-carboxaldehyde (50 g, 446 mmol) and methyl 2-azidoacetate (205 g, 1783 mmol) were combined and the resulting mixture cooled to -25 °C. Sodium methoxide (385 mL, 1783 mmol, 25% w/w methanol) was added dropwise at this temperature over 3.5 hours. The reaction mixture was allowed to warm to RT over the course of 2 h, then it was poured over ammonium chloride (95 g) in ice water. This mixture was stored in the freezer overnight. Methanol was removed in vacuo, water (500 mL) was added, followed by EtOAc (500 mL). The layers were separated and the EtOAc layer was further extracted with water (10 mL). The organic layers were combined, washed with brine, dried over Na2S04, filtered through a pad of celite and concentrated. The product (Z)-methyl 2-azido-3(thiophen-3- yl)acrylate was used in the next step without further purification.
[00368] In a 2L round-bottomed flask equipped with a stir bar, (Z -methyl-2-azido-3-
(thiophen-3-yl)acrylate (36.3 g, 173 mmol) in toluene (450 mL) was heated at reflux for 75 minutes. The mixture was concentrated, and a 4: 1 hexanes/DCM mixture was added until a product had precipitated from the solution. The solid was collected, dissolved in minimal DCM and flushed through a pad of silica gel to yield methyl 6H-thieno[2,3-b]pyrrole-5- carboxylate as a tan solid. This was used in the next step without further purification.
[00369] In a 200 mL round-bottomed flask equipped with a stir bar, 6H-thieno[2,3- b]pyrrole-5-carboxylate (20.2 g, 1 11 mmol) was dissolved in THF (50 mL) and cooled to 0 °C. Lithium aluminum hydride (1.0 N in THF, 330 mL, 330 mmol) was added slowly (caution, gas evolution can be intense). The resulting mixture was heated at reflux for 22 hours, then was cooled to 0 °C and quenched by slow addition of water (12 mL), 4N NaOH (12 mL), and water (36 mL). This mixture was stirred for 30 minutes, followed by addition of MgSC (4 g) and stirring for an additional 30 minutes. The mixture was filtered, concentrated and the resulting crude product was dissolved in EtOAc, dried over MgSC>4, filtered and concentrated. The product was azeotroped with toluene (3 x 50 mL) resulting in isolation of 5-methyl-6H-thieno[2,3-b]pyrrole as a light brown solid.
Example 4: Synthesis of 2-(6-(4-chlorobenzyl)-5-methyl-6H-thieno[2,3-b]pyrrol-4-yl)-N- (3-chlorophenyl)-2-oxoacetami -08) (See Scheme 4).
1-08
[00370] In a 50 mL round-bottomed flask equipped with a stir bar was stirred DMF (10 mL) and NaH (80 mg, 2.0 mmol, 60%) under a nitrogen atmosphere. Then, 5-methyl-6H- thieno[2,3-b]pyrrole (274 mg, 2.0 mmol) was added and the mixture stirred for 15 minutes at 0 °C. Next, 4-chlorobenzylbromide (493 mg, 2.4 mmol) was added, then the reaction stirred for 2 hours at 0 °C, followed by stirring at RT overnight. Ice water (10 mL) was added, followed by EtOAc (20 mL). The layers were separated and the EtOAc layer was extracted with water (10 mL). The organic layers were combined, washed with brine, dried over Na2S04, filtered and concentrated. The crude mixture was subjected to flash chromatography on silica gel (0 to 50% EtOAc in hexanes) resulting in isolation of 6-benzyl-5-methyl-6H- thieno[2,3-b]pyrrole as a yellow solid. This intermediate was used directly in the next step without further purification.
[00371] In a 50 mL round-bottomed flask equipped with a stir bar was stirred 6- benzyl-5-methyl-6H-thieno[2,3-b]pyrrole (522 mg, 1.0 mmol) and DCM (10 mL) at -60 °C, under a nitrogen atmosphere. Oxalyl chloride ( 1 mL of a 2M DCM solution, 2 mmol) was added and the solution was stirred at RT for 15 minutes, then it was concentrated under vacuum. The resulting crude acid chloride (243 mg, 1 mmol) was placed under high vacuum for 2 hours and was then dissolved in DCM (5 mL) and cooled to -10 °C under a nitrogen atmosphere.
[00372] Triethylamine (0.335 mL, 2.4 mmol) and 3-chloroaniline (127 mg, 1 mmol) were added to the above solution and the reaction mixture was stirred at RT for 3 hours. Water (20 mL) was added and the DCM layer was separated. Water (15 mL) and DCM (10 mL) were added again and the water layer was extracted with DCM (10 mL) once more. The organic layers were combined, washed with brine, dried over Na2S04, filtered and concentrated. The crude mixture was subjected to flash chromatography over silica gel (0 to
50% EtOAc in hexanes) resulting in isolation of Compound 1-08 (100 mg, 23%) as a yellow solid. 1H NMR (CDCl3/400 MHz) δ 9.15 (s, IH), 7.90 (t, IH), 7.60 (d, IH), 7.53 (d, IH), 7.30 (m, 3H), 7.16 (d, IH), 7.08 (d, 2H), 6.94 (d, 2H), 5.20 (s, 2H), 2.74 (s, 3H); MS m/z: 443 (M + 1).
The foUovying compounds were prepared according to Schemes 1A or IB and Scheme 2:
2-(l-(4-chlorobenzyl)-2-methyI-4,5,6,7,8,9-hexahydro-lH-cycIoocta[b]pyrroi-3-yl)-N-(3- chlorophenyl)-2-oxoacetamid -10).
1-10
[00373] I- 10 was prepared according to Schemes la and 2. Ή NMR (CDCl3/400 MHz) δ 8.81 (s, IH), 7.82 (d, IH), 7.50 (d, IH), 7.30 (d, 2H), 7.14 (d, IH), 6.88 (d, 2H), 5.01 (s, 2H), 2.78 (t, 2H), 2.57-2.54 (m, 2H), 2.36 (s, 3H), 1.68-1.60 (m, 2H), 1.42-1.34 (m, 6H); MS m/z: 468 (M + 1).
2-(l-(4-chlorobenzyl)-2-methyl-4,5,6,7,8,9-hexahydro-lH-cycloocta[b]pyrroi-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (1-11).
I ll
[00374] 1-11 was prepared according to Schemes la and 2. 1H NMR (CDCl3/400 MHz) δ 8.82 (s, IH), 8.10 (d, IH), 7.29 (d, 2H), 7.18 (d, IH), 7.10 (d, 2H), 6.85 (d, 2H), 5.02 (s, 2H), 3.84 (s, 3H), 2.78-2.70 (m, 2H), 2.59-2.51 (m, 2H), 2.34 (s, 3H), 1.68-1.60 (m, 2H),
1.40-1.30 (m, 6H) ; MS m/z: 466 (M + 1).
2-(l-(4-chlorobenzyl)-2-methyl-l,4,5,6,7,8-hexahydrocyclohepta[b]pyrrol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (1-13).
1-13
[00375] 1-13 was prepared according to Schemes la and 2. Ή NMR (CDCl3/400 MHz) δ 8.94 (s, IH), 8.03 (d, IH), 7.28 (d, 2H), 7.19 (d, IH), 7.15 (d, 2H), 6.84 (d, 2H), 5.0 (s, 2H), 3.92 (s, 3H), 2.70-2.65 (m, 2H), 2.50-2.45 (m, 2H), 2.30 (s, 3H), 1.78-1.70 (m, 2H), 1.68-1.62 (m, 2H), 1.60-1.55 (m, 2H); MS m/z: 451 (M + 1).
2-(l-(4-chlorobenzyl)-2,5,5-trimethyl-4,5,6,7-tetrahydro-lH-indol-3-yl)-N-(3- chlorophenyl)-2-oxoacetamid -14).
1-14
[00376] 1-14 was prepared according to Schemes la and 2. Ή NMR (CDCl3/400 MHz) δ 8.76 (s, IH), 7.80 (t, IH), 7.48 (d, IH), 7.28 (m, 3H), 7.12 (d, IH), 6.85 (d, 2H), 4.90 (s, 2H), 2.47 (s, 2H), 2.38 (s, 3H), 2.32 (t, 2H), 1.52 (t, 2H), 0.92 (s, 6H); MS m/z: 468 (M + 1).
2-(l-(4-chlorobenzyl)-2,5,5-trimethyl-4,5,6,7-tetrahydro-lH-indol-3-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (1-15).
1-15
[00377] 1-15 was prepared according to Schemes la and 2. Ή NMR (CDCl3/400 MHz) 6 8.76 (s, IH), 8.04 (d, IH)., 7.23 (d, 2H), 7.13 (d, IH), 7.04 (d, 2H), 6.81 (d, 2H), 4.93 (s, 2H), 3.88 (s, 2H), 2.40 (s, 3H), 2.28 (t, 2H), 1.49 (t, 2H), 0.86 (s, 6H); MS m/z: 465 (M + 1).
2-(l-(4-chIorobenzyl)-2-methyl-4,5,6,7-tetrahydro-lH-indol-3-yI)-N-(3-chlorophenyl)-2- oxoacetamide (1-16).
1-16
[00378] 1-16 was prepared according to Schemes la and 2. Ή NMR (CDCl3/400 MHz) δ 8.79 (s, IH), 7.80 (t, IH)., 7.48 (d, IH), 7.28 (m, 3H), 7.12 (d, IH), 6.87 (d, 2H), 4.90 (s, 2H), 2.66 (t, 2H), 2.39 (s, 3H), 2.35 (t, 2H), 1.80-1.74 (m, 2H), 1.70-1.64 (m, 2H); MS m z: 440 (M + 1).
2-(l-(4-chIorobenzyl)-2-methyl-4,5,6,7-tetrahydro-lH-indol-3-yl)-N-(2-methoxypyridin- 4-yl)-2-oxoacetamide (1-18).
[00379] 1-18 was prepared according to Schemes la and 2. Ή NMR (CDCl3/400 MHz) δ 8.94 (s, IH), 8.03 (d, IH), 7.28 (d, 2H), 7.19 (d, IH), 7.15 (d, 2H), 6.86 (d, 2H), 4.90 (s, 2H), 3.90 (s, 3H), 2.62 (t, 2H), 2.38 (s, 3H), 2.32 (t, 2H), 1.78-1.72 (m, 2H), 1.68-1.62 (m, 2H); MS m z: 438 (M + 1).
2-(l-(4-fluorobenzyl)-2,5-dimethyl-lH-pyrrol-3-yl)-N-(2-methoxypyridin-4-yl)-2- oxoacetamide (1-17).
1-17
[00380] 1-17 was prepared according to Scheme 2. Ή NMR (CD3OD/400 MHz) δ 8.02 (dd, IH), 7.31 (d, IH), 7.24 (dd, IH), 7.08-7.04 (m, 2H) , 6.98-6.94 (m, 2H), 6.74 (d, IH), 5.17 (s, 2H), 3.89( s, 3H), 2.51 (s, 3H), 2.14 (s, 3H).
2-(l-(4-chlorobenzyl)-2,5-dimethyl-4-phenyl-lH-pyrrol-3-yl)-N-(2-methoxypyridin-4- yl)-2-oxoacetamide (1-19).
1-19
[00381] 1-19 was prepared according to Schemes lb and 2. Ή NMR (CDCI3/400 MHz) δ 7.82 (d, IH), 7.43 (m, 3H)., 7.35 (d, 2H), 7.29 (d, 2H), 7.09 (s, IH), 6.88 (d, 2H), 6.57 (d, IH), 6.42 (d, IH), 5.14 (s, 2H), 3.81 (s, 3H), 2.57 (s, 3H), 2.0 (s, 3H); MS m/z: 474 (M + 1).
2-(l-(4 hlorobenzyl)-2,5-dimethyl-4-phenyI-lH-pyrrol-3-yl)-N-(3-chlorophenyl)-2- oxoacetamide (1-20).
1-20
[00382] 1-20 was prepared according to Schemes lb and 2. 1 H NMR (CDCl3/400 MHz) 5 7.35-7.25 (m, 9H), 7.40 (d, 2H), 6.88 (d, 2H), 5.08 (s, 2H), 4.42 (s, 1H), 2.49 (s, 3H), 2.0 (s, 3H); MS m/z: 476 (M + 1).
2-(l-(2,4-dichlorobenzyl)-2,5-dimethyl-lH-pyrrol-3-yl)-N-(2-methoxypyridin-4-yl)-2- oxoacetamide (1-21).
1-21
[00383] 1-21 was prepared according to Scheme 2.
2-(l-(4-methoxybenzyl)-2,5-dimethyl-lH-pyrrol-3-yl)-N-(2-methoxypyridin-4-yl)-2- oxoacetamide (1-22).
[00384] 1-22 was prepared according to Scheme 2. Ή NMR (CDCl3/400 MHz) δ 9.23 (s, lH), 8.10 (d, IH), 7.17-7.16 (m, IH), 7.14-7.11 (m, 2H) , 6.824-6.79 (m, 5H), 4.99 (s, 2H), 3.90 (s, 3H), 3.74( d, 3H), 2.51 (s, 3H), 2.13 (s, 3H).
2-(l-(4-chlorobenzyI)-5-methyl-2-phenyl-lH-pyrrol-3-yl)-N-(2-methoxypyridin-4-yl)-2- oxoacetamide (1-23).
1-23
[00385] 1-23 was prepared according to Schemes la and 2. Ή NMR (CDCl3/400 MHz) δ 9.13 (s, IH), 8.08 (d, IH), 7.40-7.03 (m, 10H), 6.79 (d, 2H), 4.92 (s, 2H), 3.93 (s, 3H), 2.16 (s, 3H).
2-(l-(4-chlorobenzyI)-5-methyl-2-phenyl-lH-pyrrol-3-yl)-N-(3-chIorophenyl)-2- oxoacetamide (1-24).
1-24
[00386] 1-24 was prepared according to Schemes la and 2. Ή NMR (CDCl3/400 MHz) δ 9.08 (s, IH), 7.80 (m, IH), 7.40-7.10 (m, 1 IH), 6.79 (d, 2H), 4.92 (s, 2H), 3.93 (s, 3H), 2.16 (s, 3H).
1-25
[00387] 1-25 was prepared according to Scheme 2. Ή NMR (CDCl3/400 MHz) 6 9.24 (s, IH), 7.87 (s, IH), 7.55(s, IH), 7.49 (d, IH), 7.33-7.25 (m, 8H), 7.12 (d, IH), 6.86 (d, 2H), 5.14 (s, 2H), 2.54 (s, 3H).
2-(l-(4-chIorobenzyl)-2-methyl-5-phenyl-lH-pyrrol-3-yl)-2-oxo-N-(pyridin-4- yl)acetamide (1-26).
1-26
[00388] 1-26 was prepared according to Scheme 2. Ή NMR (CDCl3/400 MHz) δ 9.41 (s, IH), 8.55 (d, 2H), 7..64-7.62 (m, 2H), 7.51 (s, IH), 7.34-7.25, (m, 7H), 6.84 (d, 2H), 5.13 (s, 2H), 2.54 (3H).
2-(l-(4-chlorobenzyl)-2-methyl-5-phenyl-lH-pyrrol-3-yl)-N-(2-methoxypyridin-4-yl)-2- oxoacetamide (1-27).
1-27
[00389] 1-27 was prepared according to Scheme 2. Ή NMR (CDCl3/400 MHz) δ 9.40 (bs, IH), 8.13 (d, IH), 7.50 (s, IH), 7.34-7.25 (m, 8H), 7.18 (d, IH), 6.85 (d, 2H), 5.14 (s, 2H), 3.99 (s, 3H), 2.54 (s, 3H).
2-(l-(4-chlorobenzyl)-2,5-dimethyI-lH-pyrrol-3-yl)-N-(2-chIoropyridin-4-yl)-2- oxoacetamide (1-28).
1-28
1-28 was prepared according to scheme 2. Ή NMR (CDCl3/400 MHz) δ 9.45 (bs, IH), 8.31 (d, IH), 7.81 (s, H), 7.46 (d, IH), 7.29 (d, 2H), 7.17 (s, IH), 6.84 (d, 2H), 5.06 (s, 2H), 2.52 (s, 3H), 2.15 (s, 3H).
2-(l-(4-chlorobenzyl)-2,5-dimethyl-lH-pyrrol-3-yl)-N-(3-chlorophenyl)-2-oxoacetamide (1-29).
1-29
[00390] 1-29 was prepared according to Scheme 2. Ή NMR (CDCl3/400 MHz) δ 9.24 (bs, IH), 7.87 (s, IH), 7.48 (d, IH), 7.31-7.22 (m, 4H), 7.12 (d, IH), 6.84 (d, 2H), 5.06 (s, 2H), 2.53 (s, 3H), 2.15 (s, 3H).
1-30
[00391] 1-30 was prepared according to Scheme 2. Ή NMR (CDCl3/400 MHz) δ 9.38 (bs, IH), 8.56 (m, 2H), 7.61 (d, 2H), 7.29 (d, 2H), 6.84 (d, 2H), 5.06 (s, 2H), 2.53 (s, 3H), 2.15 (s, 3H).
2-(l-(4-chlorobenzyI)-2,5-dimethyl-lH-pyrrol-3-yl)-2-oxo-N-(pyridin-3-yl)acetamide (I-
31).
1-31
[00392] 1-31 was prepared according to Scheme 2. 1 H NMR (CDCl3/400 MHz) 5 9.32 (bs, IH), 8.78 (bs, IH), 8.40 (d, IH), 8.29 (d, IH), 7.35-7.21 (m, 4H), 6.84 (d, 2H), 5.06 (s, 2H), 2.54 (s, 3H), 2.15 (s, 3H);
2-(l-(4-chIorobenzyl)-2,5-diraeth I-lH-pyrrol-3-yl)-2-oxo-N-phenylacetamide (1-32).
1-32
[00393] 1-32 was prepared according to Scheme 2. Ή NMR (CDCl3/400 MHz) δ 9.20 (bs, IH), 7.69 (dd, 2H), 7.39-7.35 (m, 2H), 7.30-7.23 (m, 3H), 7.20-7.15 (m, IH), 6.85 (d,
2H), 5.05 (s, 2H), 2.54 (s, 3H), 2.14 (d, 3H)
2-(l-(4-chlorobenzyl)-2,5-dimethyl-lH-pyrrol-3-yl)-N-(2-methoxypyridin-4-yl)-2- oxoacetamide (1-01).
1-01
[00394] 1-01 was prepared according to Scheme 2. Ή NMR (CDCl3/400 MHz) δ 9.27 (bs, IH), 8.10 (d, IH), 7.29-7.27 (m, 2H), 7.18 (bs, 2H), 7.13 (dd, IH), 6.83 (d, 2H), 5.05 (s, 2H), 3.93 (s, 3H), 2.52 (s, 3H), 2.14 (d, 3H).
The following compounds were prepared according to Scheme 3 and Scheme 4:
2-(4-(4-chlorobenzyI)-2,5-dimethyl-4H-thieno[3,2-b]pyrrol-6-yl)-2-oxo-N-(pyridin-4- yl)acetamide (1-04).
1-04
[00395] 1H NMR (CDCl3/400 MHz) 6 9.50 (s, IH), 8.58 (d, 2H), 7.68 (d, 2H), 7.30 (d, 2H), 7.00 (d, 2H), 6.55 (s, IH), 5.22 (s, 2H), 2.72 (s, 3H), 2.50 (s, 3H); MS m/z: 424 (M + 1).
2-(4-(4-chlorobenzyl)-2,5-dimethyl-4H-thieno[3,2-b]pyrrol-6-yI)-N-(2-methoxypyridin- 4-yl)-2-oxoacetamide (1-05).
1-05
[00396] Ή NMR (CDCl3/400 MHz) 6 9.40 (s, IH), 8.12 (d, IH), 7.30 (d, 2H), 7.22 (m, 2H), 6.98 (d, 2H), 6.54 (s, IH), 5.20 (s, 2H), 3.90 (s, 3H), 2.70 (s, 3H), 2.50 (s, 3H); MS m/z: 454 (M + 1).
2-(4-(4-chlorobenzyl)-5-methyl-4H-thieno[3,2-b]pyrrol-6-yl)-N-(3-chlorophenyl)-2- oxoacetamide (1-06).
1-06
[00397] Ή NMR (CDCl3/400 MHz) 6 9.40 (s, IH), 7.58 (d, IH)., 7.34-7.30 (m, 3H), 7.22 (m, 2H), 7.22-7.15 (m, 3H), 7.07 (t, IH), 7.01 (d, 2H), 6.86 (d, IH), 5.31 (s, 2H), 2.76 (s, 3H); MS m/z: 443 (M + l).
2-(4-(4-chlorobenzyl)-5-methyl-4H-thieno[3,2-b]pyrrol-6-yl)-N-(2-methoxypyridin-4-yl)- 2-oxoacetamide (1-07).
1-07
[00398] Ή NMR (CDCl3/400 MHz) 6 9.42 (s, IH), 8.20 (d, IH), 7.39 (d, 3H), 7.30-
7.20 (m, 3H), 7.09 (d, 2H), 6.88 (d, 1H), 5.38 (s, 2H), 4.00 (s, 3H), 3.80 (s, 3H); MS m/z: 440 (M + 1).
2-(6-(4-chlorobenzyl)-5-methyl-6H-thieno[2,3-b]pyrrol-4-yl)-N-(2-methoxypyridin-4-yI)- 2-oxoacetamide (1-09).
1-09
[00399] Ή NMR (CDCl3/400 MHz) 6 9.20 (s, 1H), 8.12 (d, 1H), 7.59 (d, 1H), 7.32 (d, 2H), 7.26 (d, 2H), 7.18 (d, 1H), 7.09 (d, 2H), 6.95 (d, 2H), 5.20 (s, 2H), 3.92 (s, 3H), 2.72 (s, 3H); MS m/z: 440 (M + 1).
The following compounds were prepared according to Scheme 4:
2-(2-chloro-6-(4-chIorobenzyl)-5-methyl-6H-thieno[2,3-b]pyrrol-4-yl)-2-oxo-N-(pyridin- 4-\ Ijacetamide (1-02).
1-02
[00400] 1-02 was prepared according to Scheme 4 with the exception that methyl 6H- thieno[2,3-b]pynOle-5-carboxylate was chlorinated under the following general conditions:
[00401] Methyl 6H-thieno[2,3-b]pyrrole-5-carboxylate (1.0 equiv) and N- chlorosuccinimide (1.05 equiv.) were dissolved in CHC13 and stirred overnight. The mixture was neutralized to pH 7 with 4N NaOH (aq.), followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated to give
methyl 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylate. 1H NMR (CDCl3/400 MHz) δ 9.25 (s, IH), 8.60 (d, 2H), 7.64 (d, 2H), 7.55 (s, IH), 7.38 (d, 2H), 7.10 (d, 2H), 5.18 (s, 2H), 2.75 (s, 3H); MS m z: 444 (M + 1).
2-(2-chIoro-6-(4-chlorobenzyl)-5-methyl-6H-thieno[2,3-b]pyrrol-4-yl)-N-(2- methoxypyridin-4-yl)-2-oxoacetamide (1-03).
1-03
[00402] 1-03 was prepared according to Scheme 4 with the exception that methyl 6H- thieno[2,3-b]pyrrole-5-carboxylate was chlorinated under the following gerenal conditions:
[00403] Methyl 6H-thieno[2,3-b]pyrrole-5-carboxylate ( 1.0 equiv) and N- chlorosuccinimide (1.05 equiv.) were dissolved in CHC13 and stirred overnight. The mixture was neutralized to pH 7 with 4N NaOH (aq.), followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na2SC<4, filtered and concentrated to give methyl 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylate. Ή NMR (CDCl3/400 MHz) δ 9.20 (s, IH), 8.18 (d, IH), 7.52 (s, IH), 7.34 (d,2H), 7.24 (d, IH), 7.14 (m, IH), 7.08 (d, 2H), 5.18 (s, 2H), 3.90 (s, 3H), 2.70 (s, 3H); MS m/z: 474 (M + 1).
Biological Assays:
Example 5: FAAH Inhibition Using Rat, Mouse and Human Brain Homogenate Assays.
[00404] The ability of compounds to inhibit FAAH was measured in human whole cell and human and rodent brain homogenates as described herein.
A. FAAH Rat Brain Membrane (RBM) Homogenate Preparation
[00405] Adult rats (Charles River CD strain, female, 200 g) were anaesthetized with isofluorane and rapidly decapitated. Each brain was quickly removed and chilled in tubes (3 brains per tube) on ice. About 25 mL of "homogenization buffer" (20 mM HEPES buffer,
pH 7.0, with 1 mM MgCl2) was added to 15 to 20 g of brain. The brains were homogenized on ice for 1 minute using an Omni GLH homogenizer (Omni International, Marietta,
Georgia). The homogenates were then transferred to three centrifuge tubes and centrifuged at 36,500 g for 20 minutes at 4 °C. The supernatant was discarded and each pellet was re- suspended in 25 mL homogenization buffer. The re-suspended material was again centrifuged (36,500 g, 20 minutes at 4 °C). Pellets were combined by resuspension in 10 mL of homogenization buffer and incubated in a 37 °C water bath for 15 minutes. The tubes were then placed on ice for 5 minutes followed by centrifugation at 36,500 g for 20 minutes at 4 °C. The supernatant was discarded and the membrane pellets were then re-suspended in 40 mL of "resuspension buffer" (50 mM Tris-HCl buffer, pH 7.4, containing 1 mM EDTA and 3 mM MgCl2). A Bradford Protein assay was performed to determine protein
concentration. The protein was aliquotted into screw cap Cryo tubes each containing ~ 400iL, flash frozen in liquid nitrogen and stored at -80 °C until used for the assay. A similar protocol was used to obtain brain membrane homogenates from mice.
B. FAAH Human Brain Membrane (HBM) Homogenate Preparation.
[00406] About 10 g of frozen normal human brain cortex tissue was obtained (e.g., from Analytical Biological Services (ABS), Inc. (Wilmington, DE)). The brain tissue was thawed and transferred to a large ceramic mortar on ice. 50 mL of ice-cold "homogenization buffer" (20 mM HEPES buffer, pH 7.0, with 1 mM MgCl2) was added to the mortar and the tissue was homogenized with a pestle. The homogenate was centrifuged at 36,500 g for 20 minutes at 4 °C. The supematants were discarded and the pellets were re-suspended in homogenization buffer and centrifuged as before. The supematants were again discarded and the pellets were re-suspended in 30 mL homogenization buffer and incubated in a 37 °C water bath for 20 minutes. The homogenate was then centrifuged as before. The supernatant was discarded and the membrane pellets were re-suspended in 30 mL "resuspension buffer" (50 mM Tris-HCl buffer, pH 7.4, containing 1 mM EDTA and 3 mM MgCl2). A Bradford Protein assay was performed to determine protein concentration. The protein was aliquotted into screw cap Cryo tubes each containing ~ 200 ί, flash frozen in liquid nitrogen and stored at -80 °C until used for the assay.
C. FAAH Mouse Brain Membrane (MBM) Homogenate Preparation.
[00407] Eighteen 10 to 12 week old female CD-I mice housed at the animal care facility of Ironwood Pharmaceuticals were anesthetized by isoflurane anesthesia and rapidly
decapitated using a small decapitator (Harvard Apparatus part # PY8 SS-0012, Holliston, Massachusetts). Whole brain tissue from these mice was collected (approximately 9.4 g total) and placed on aluminum foil sitting on dry ice to flash freeze the tissue. Tissue was thawed and used to prepare microsomes as described above for rat brain homogenates.
D. Determination of FAAH Activity
[00408] FAAH activity was assayed in the respective homogenates described herein
(Rat brain, Mouse brain or Human brain) for certain exemplary substrate compounds using a modification of the method of Omeir et al. (1995 Life Sci 56: 1999) and Fowler et al. (1997 J. Pharmacol Exp Ther 283:729). For assay of FAAH activity in rat brain membrane (RBM) homogenates, RBM homogenates (7 μg protein in 20 pL final volume of 10 mM Tris pH 6.5) were mixed with 180 μΙ_, of a mixture of the following: 2.0 μΜ unlabelled anandamide, 0.03 μθι' radio labeled anandamide [ethanolamine 1- H] (40-60 Cis/mmol, product number ART- 626, American Radiolabeled Chemicals, St. Louis, MO), 1 mg/mL Bovine Serum Albumin (fatty acid-free BSA, electrophoresis grade, Sigma, St. Louis, MO), 10 mM Tris-HCl (pH 6.5), and 1 mM EDTA in the presence and absence of test compounds (vehicle was DMSO at a final concentration of 1%) and incubated for 10 minutes at 37 °C. Samples were placed on ice to terminate the reactions.
[00409] 3H-ethanolamine product and un-reacted 3H-anandamide substrate were then separated either: (1) by using chloroform/ methanol extraction or (2) by passing the reaction mixture through a glass fiber filter containing activated charcoal. Samples were extracted with chloroform/methanol by adding 0.4 mL of chloroform/methanol (1 : 1 v/v), vigorously mixing the samples, and separating the aqueous and organic phases by centrifugation.
Radioactivity (corresponding to FAAH-catalyzed breakdown of 3H-anandamide) found in aliquots (0.2 mL) of the aqueous phase was determined by liquid scintillation counting with quench correction. IC50 values were determined as described by Jonsson et al. (2001 Br. J Pharmacol. 133: 1263). Alternatively, reactions were purified using a modification of the solid-phase extraction method described by Wilson et al (2003 Anal. Biochem. 318 : 270). This method was modified as follows: after reactions were incubated at 37 °C for 10 minutes and chilled on ice, the reaction mixtures were acidified by adding 10 μΐ. of sodium phosphate solution [0.5M (pH 2.0)]. Next, 90 μΐ^ aliquots of the acidified reaction mixtures were applied to activated charcoal (that had been previously washed with methanol as described by Wilson et al. (supra)) containing 80 μί. of water on top of a glass fiber filter, centrifuged, and the radioactivity in the eluate was counted as described previously by Wilson et al. (supra).
[00410] Table 1 provides activity data for certain compounds tested for inhibition of FAAH using the FAAH rat, mouse and human brain homogenate assays. The known FAAH inhibitors, 3'-(aminocarbonyl)biphenyl-3-yl cyclohexylcarbamate (URB597), [ l-(4- chlorobenzoyl)-5-methoxy-2-methyl-lH-indol-3-yl]acetic acid (indomethacin) and 5- benzoyl-2,3-dihydro-lH-pyrrolizine-l-carboxylic acid (Ketorolac) were used as controls in these assays.
Example 6: Whole cell anandamide hydrolysis assay:
[00411] FAAH activity was assayed in whole cells using methods disclosed previously (Maccarone et al. 1998 J Biol.Chem. 273:32332 and Bisogno et al. 1997 J Biol. Chem.
272:3315). In addition to the cell lines described in Maccarone et al. and Bisogno et al., MCF7 (ATCC designation HTB-22) and T84 (ATCC designation CCL-248) cell lines were also used in these assays.
A. HeLa cell transfection with human FAAH-1
[00412] cDNA expression clone for human FAAH-1 (in pcDNA3 vector) (Genbank Accession U82535; obtained from Benjamin Cravatt, Scripps Research Institute, La Jolla, California) was linearized by digestion with BglH (New England Biolabs) and transfected by calcium phosphate into human HeLa cells (ATCC catalog #CCL-2). The HeLa cell line was selected as a host because it does not express FAAH or exhibit FAAH activity such that all subsequent activity can be attributed to the transfected gene. Following transfection, a stable HeLa-derived clone, designated 5c5, was isolated by single colony purification and expanded and maintained in modified Eagles medium (MEM; VWR catalog # 45000-300) containing 10% fetal bovine serum (FBS), 2 mM L-glutamine, and 0.5 mg/mL G-418 (Sigma catalog # G5013).
B. FAAH activity assay
[00413] Clone 5c5 (50,000 cells in 150 μί) was seeded into 96- well plates and incubated overnight (5% C02, 37 °C). Media was carefully replaced with 180
DMEM/F12 medium (VWR catalog # 45000-350) containing 15 mM HEPES, pH 7.4 and
0.1% fatty acid free BSA (Sigma catalog # A0281). Then, 2 μί of lOOx desired final concentrations of certain exemplary compounds described herein were made up in DMSO, added to wells containing cells, and plates were incubated at 37 °C for 10 min. Next, 20 xL of 5 uM anandamide (Cayman catalog # 90050) spiked with 8 uCi of anandamide-
(ethanolamine-l-[3H]) (American Radiolabeled Chemicals, Inc., catalog #ART 626) was added to the cells and the plates were incubated for an additional 15 min at 37 °C. The reactions were terminated by chilling the plates on ice and adding 20 μΐ- of 0.5 M of potassium phosphate buffer (adjusted to pH 2.1 with phosphoric acid).
[00414] The acidified reactions were transferred to 96-well filter plates (0.25 mL capacity/well, 1.2 micron glass fiber pre-filter packed above 0.65 micron pore-size PVDF membrane, Millipore catalog MSFCN6B50) containing 25 μL· charcoal (neutral activated carbon, Fisher Scientific catalog CI 70-500) per well. Prior to assay, charcoal was measured and loaded onto the plate using an aluminum 96-well column loading device (Millipore catalog MACL09625). The filter plate was assembled over empty 96-well plate (Costar) using a centrifuge alignment frame (Millipore catalog MACF09604) to allow collection of the filtrate in the receiver plate. The charcoal glass fiber filter plates were pre-washed with methanol by centrifugation 650 x g for 10 min). Next, 80 μΐ. of water was added to the wells of the pre-washed 96-well charcoal filter plate. Then, 90 μί, of the acidified reaction mixture was added to the water in the wells of the charcoal plate. The samples were centrifuged as above. The substrate remained bound to the charcoal, whereas the [ H]-ethanolamine product formed flowed through and was transferred to the microplates containing scintillation cocktail and quantified in a micro-plate scintillation counter (Perkin-Elmer Microbeta).
Control reactions with either no cells or cells treated with DMSO alone were performed in triplicate and used to define background (no cells) and 100% activity (DMSO alone).
[00415] Following subtraction of background radioactivity, data were expressed as percent inhibition relative to 100% activity and fit with a nonlinear regression curve using GraphPad Prism Software (GraphPad Software Inc). IC50 values were calculated from the resulting dose-response curves constrained at top and bottom to 100% and 0%, respectively.
Example 7: Determination of Endogenous and Exogenous Anandamide Levels in Rat Plasma and Brain Tissue:
[00416] The effects of some exemplary compounds described herein on endogenous and exogenously dosed anandamide (AEA) levels were measured. Rats dosed with test compound were sacrificed at various time points to determine the levels of anandamide both circulating and within the brain tissue. For experiments measuring exogenous levels of anandamide, the anandamide (Cayman Chemical, Ann Arbor, MI or Sigma Chemical, St.
Louis, MO) was dosed (in the range of 3-30 mg/kg) post dosing of test compound. Animals were sacrificed at 5, 15, 30, or 60 minutes after anandamide administration with anesthesia administration followed by decapitation. Brains were removed immediately and the plasma was recovered from the blood for analysis of anandamide levels.
[00417] Flash frozen whole brain (e.g., from rat or mouse) samples were first transferred to clean 50 mL conical tubes and the wet brain weight was recorded. Fifteen mL of 9: 1 ethyl acetate:hexane and 40 ng of deuterated anandamide (d8AEA) were added to the brain samples. The samples were then homogenized with an Omni GLH homogenizer until the solution was an uniform slurry, and 5.0 mL of water was added just prior to completion. Upon completion of the homogenization the tubes were held on ice. The chilled tubes were then vortexed and centrifuged at 4 °C at 3500 rpm for 10 minutes. One milliliter of the aqueous layer was sampled for use in a Bradford assay of protein content (Bradford, M.M. Anal. Biochem. 1976, 72: 248). The ethyl acetate layer was recovered, placed in a 15-mL glass tube, and evaporated under nitrogen in a TurboVac. Once dry, samples were reconstituted in 1 mL of 1:3 (v/v) CHCl3:methanol and vortexed. Prepared brain samples were transferred to a 96-well plate for analysis by LC/MS/MS.
[00418] Stock standards were prepared at 0.0, 0.50, 1.0, 5.0, 10.0, 50.0, 100, 500, and 1000 ng/mL in methanol. Standards for LC/MS/MS were prepared with 0.5 mg Pefabloc, 10 of the stock standard to 90 of stock rat plasma and vortexing.
[00419] Frozen plasma samples containing pefabloc were thawed, and 100 μί of each sample was transferred to a microcentrifuge tube. To each standard and sample tube, 20 ng d8AEA and 100 μL· of ice-cold acetone (for protein precipitation) were added. Tubes were vortexed, and centrifuged at 13,000 rpm for at least 5 minutes. The supernatants were collected in microcentrifuge tubes and the acetone was evaporated off in a TurboVac for 5- 10 minutes. The evaporated supernatant solutions were next extracted with 250 \iL of 1 :2 (v/v) methanol :CHC13 and centrifuged at 13,000 rpm for at least 5 minutes. The CHC13 layer was collected and evaporated under nitrogen (TurboVac) until dry. Standards and samples were then reconstituted in 200 of 1 :3 (v/v) CHC^methanol. Prepared standards and plasma samples were transferred to a 96-well plate for analysis by LC/MS/MS. Similar experiments were performed using human plasma to which test compounds and exogenous anandamide was dosed or not dosed.
[00420] The LC/MS MS method used a Waters 2777 sample manager, 1525 binary
pump, and Quattro micro mass spectrometer. The separation was performed on a Waters Xterra MS C8, 5 μηι, 2.1 x 20 mm analytical LC column with a Thermo Electron Javelin Basic 8, 2 x 10 mm guard column at a flow rate of 0.30 mL/min and a 25 μΙ_ injection volume. A binary linear gradient of mobile phase A (10 mM ammonium acetate in water (pH 9.5)) and mobile phase B (80:20 acetonitrile:methanol) was used from 2.0 to 2.2 minutes from 25% to 90% B, with a total run time of 6.0 minutes per sample injection. AEA and d8- AEA eluted in ~ 3.5 minutes. The Quattro micro was operated in multiple reaction monitoring (MRM) mode with negative electrospray ionization. The mass transitions of 348 m/z - 62 m/z (AEA) and 356 m/z - 62 m/z (d8-AEA) were monitored using optimized collision settings (determined experimentally). Data were analyzed using Micromass QuanLynx software, and standard curves were generated using the ratio of the internal standard (d8-AEA) peak area to AEA peak area in response to AEA concentration. AEA concentration in brain and plasma samples was calculated using the linear regression of the standard curve. AEA concentration in plasma was reported as ng AEA/mL plasma, and AEA concentration in brain was reported as ng AEA/g protein (protein content determined by the Bradford assay).
[00421] The measured increase in endogenous AEA levels in rat brains for the tested compounds was generally between 0.7 and 3.3 fold.
Table 1: Average activity of the compounds of this invention, expressed as IC50 (the concentration of the agent needed to induce 50% inhibition of the enzyme) of FAAH extracted from human, mouse and rat brain homogenates.
Mouse Brain FAAH Rat Brian Extract
Compound # FAAH Extract ICS0
Extract IC50 (μΜ) ICso (uM) (μΜ)
1-06 1.5
1-07 0.018
1-08 0.797 > 5.0
1-09 0.031 0.062
1-10 0.605 >5.0
1-11 0.080 0.192
1-12 0.234 1.09
1-13 0.009 0.003
1-14 0.202 0.516
1-15 0.094 0.007
1-16 0.119 2.08 0.004
1-17 1.22
1-18 0.021 0.009 1.44
1-19 > 5.0 0.005
1-20 > 5.0 1.04
1-21 1.01 0.001
1-22 4.11 1.77
1-23 2.56 0.185
1-24 50+ > 5.0
1-25 50+ 0.028
1-26 50+ >5.0
Human brain
Mouse Brain FAAH Rat Brian Extract
Compound # FAAH Extract IC50
Extract IC50 (μΜ) ICso (uM) (μΜ)
1-27 50+
1-28 0.8969
1-29 5.0
1-30 3.4
1-31 3.2
1-32 >5.0
Claims
1. A compound of Formula I, or a pharmaceutically acceptable salt thereof,
Formula I
wherein:
ring B is selected from the group consisting of phenyl and a 5-6-membered monocyclic heteroaryl ring, wherein said monocyclic heteroaryl ring contains up to 3 ring heteroatoms selected from the group consisting of N, O and S;
n is an integer selected from the group consisting of 0, 1, 2 and 3;
each JBI is independently selected from the group consisting of halogen, -N02, -CN, Cj-6 aliphatic, C3.6 cycloaliphatic, C|.6 haloaliphatic, Ci-6 alkoxy, Ci^ haloalkoxy and C3-6 cycloalkoxy;
each JCI is independently selected from the group consisting of halogen, -N02, -CN, Q.6 aliphatic, C3.6 cycloaliphatic, C|-6 haloaliphatic, Ci.6 alkoxy, Ci^ haloalkoxy and C3-6 cycloalkoxy;
p is an integer selected from the group consisting of 0, 1, 2 and 3;
R2 is selected from the group consisting of halogen, -N02, -CN, Ci^ aliphatic, phenyl, a 5-6 membered heteroaryl ring and a C3-7 cycloalkyl, wherein said Ci-6 aliphatic, phenyl, 5- 6 membered heteroaryl ring and C3-7 cycloalkyl is optionally substituted by up to three instances of halogen;
R4 is selected from the group consisting of hydrogen, halogen, -CN, Ci-6 aliphatic, a C3-7 cycloaliphatic ring, a 5-6 membered heteroaryl ring, phenyl, -ORY and -SRY;
R5 is selected from the group consisting of hydrogen, halogen, -CN, Ci-6 aliphatic, a C3-7 cycloaliphatic ring, a 5-6 membered heteroaryl ring, phenyl, -ORY and -SRY, wherein said C|-6 aliphatic, C3-7 cycloaliphatic ring, 5-6-membered heteroaryl ring, and phenyl is optionally substituted with up to three instances of halogen, Ci^ alkyl, C haloalkyl, Ci-4 alkoxy or C haloalkoxy; or R4 and R5, together with the two carbon atoms to which they are attached, form a C5-8 cycloaliphatic ring, a 5-8-membered heterocyclic ring or a 5-membered heteroaryl ring; wherein said heterocyclic and heteroaryl ring formed by R4 and R5 contains up to three heteroatoms selected from the group consisting of N, O and S, and wherein said cycloaliphatic, heterocyclic and heteroaryl rings formed by R4 and R5 is optionally substituted by up to 3 instances of halogen, Ci-4 alkyl, Ci^ haloalkyl, Ci-4 alkoxy or C|.4 haloalkoxy; and
each R is independently selected from the group consisting of C|-6 aliphatic, C3-7
cycloaliphatic, a 5-6-membered heteroaryl ring and phenyl, wherein each RY is optionally substituted by up to six instances of halogen, Ci-4 alkyl, C 1.4 haloa.kyl, Ci-4 alkoxy or C|-4 haloalkoxy;
provided that the compound is not:
2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring B is an optionally substituted ring selected from the group consisting of phenyl, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, imidazole, pyrazole, furan, thiophene, triazole, tetrazole, thiazole, oxathiazole and oxazole.
3. A compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein ring B is an optionally substituted pyridine or an optionally substituted phenyl.
4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein ring B is an optionally substituted pyridine.
5. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein ring B is an optionally substituted phenyl.
6. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein n is selected from the group consisting of 0 and 1.
7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein each JB 1 is independently selected from the group consisting of halogen, C| -4 alkyl, cyclopropyl, cyclopropyloxy, Q- haloalkyl, C|-4 alkoxy and C|-4 haloalkoxy.
8. A compound according to claim 7, or a pharmaceutically acceptable salt thereof,
B 1
wherein each J is independently selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, propyloxy and isopropyloxy.
wherein the moeity — ' is selected from the group consisting of phenyl, chlorophenyl, 3-pyridine, 4-pyridine and 3-methoxy-4-pyridine.
10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein p is selected from the group consisting of 0, 1 and 2.
11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein each JCI is independently selected from the group consisting of halogen, Ci-4 alkyl, Ci-4 haloalkyl, cyclopropyl, cyclopropyloxy, Q-4 alkoxy and C|-4 haloalkoxy.
12. A compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein each JC1 is independently selected from the group consisting of halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, methoxy, trifluoromethoxy, ethoxy, propyloxy and isopropyloxy.
13. A compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein each J is halogen.
14. A compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein JC1 is chlorine and p is 1 or 2.
15. A compound according to claim 13, or a pharmaceutically acceptable salt thereof, wherein J is fluorine and p is 1.
16. A compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein JC1 is methoxy and p is 1.
17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from the group consisting of halogen, -N02, -CN, Cj« aliphatic and phenyl, wherein each C|-6 aliphatic and phenyl is optionally substituted with up to three instances of halogen.
18. A compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein R2 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl or hexyl.
19. A compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein R2 is methyl.
20. A compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein R is phenyl.
21. A compound according to anyone of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen, C|-4 alkyl, a 5-6-membered heteroaryl or phenyl.
22. A compound according to claim 21, or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen.
23. A compound according to claim 19, or a pharmaceutically acceptable salt thereof, wherein R4 is phenyl.
24. A compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R5 is a Ci-4 alkyl, a 5-6-membered heteroaryl or phenyl.
25. A compound according to claim 24, or a pharmaceutically acceptable salt thereof, wherein R5 is methyl.
26. A compound according to claim 24, or a pharmaceutically acceptable salt thereof, wherein R5 is phenyl.
27. A compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R4 and R5, together with the two carbon atoms to which they are attached, form a C5.8 cycloaliphatic ring, a 5-8-membered heterocyclic ring or a 5-membered heteroaryl ring, wherein said cycloaliphatic, heterocyclic and heteroaryl ring formed by R4 and R5 is optionally substituted with up to 3 instances of halogen, Ci-2 alkyl, C|.2 haloalkyl, Ci-2 alkoxy or Ci-2 haloalkoxy.
28. A compound according to claim 27, or a pharmaceutically acceptable salt thereof, wherein R4 and R5, together with the two carbon atoms to which they are attached, form an optionally substituted C5-8 cycloaliphatic ring.
29. A compound according to claim 28, or a pharmaceutically acceptable salt thereof, wherein R4 and R5, together with the two carbon atoms to which they are attached, form the
30. A compound according to claim 27, or a pharmaceutically acceptable salt thereof , wherein R4 and R5, together with the two carbon atoms to which they are attached, form an optionally substituted 5-membered heteroaryl ring.
31. A compound according to claim 30, or a pharmaceutically acceptable salt thereof, wherein R4 and R5, together with the two carbon atoms to which they are attached, form an optionally substituted thiophene ring.
32. A compound according to claim 31, or a pharmaceutically acceptable salt thereof, wherein R4 and R5, together with the pyrrole ring to which they are attached and its substituents form
33. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, represented by Formula II,
Formula II
wherein each X is independently selected from the group consisting of C and N.
34. A compound according to claim 1 or claim 33, or a pharmaceutically acceptable salt thereof, represented by Formula III,
wherein: n is selected from the group consisting of 0 and 1 and JBI is selected from the group consisting of halogen and methoxy.
35. A compound according to claim 1, represented by Formula IV, or a pharmaceutically acceptable salt thereof,
Formula IV
wherein ring CI is an optionally substituted C5-8 cycloaliphatic ring.
36. A compound according to claim 35, wherein ring CI is optionally substituted with up to two instances of methyl.
37. A compound according to claim 1, represented by Formula V, or a pharmaceutically acceptable salt thereof,
Formula V
wherein ring C2 is an optionally substituted 5 membered heteroaryl ring.
38. A compound according to claim 37, or a pharmaceutically acceptable salt thereof, wherein ring C2 is an optionally substituted thiophene ring.
39. A compound according to claim 38, or a pharmaceutically acceptable salt thereof, wherein ring C2 is optionally substituted with up to two instances of methyl or halogen.
103
1-12
41. A pharmaceutical composition comprising a compound according to any of claims 1 to 40, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, vehicle or adjuvant.
42. The pharmaceutical composition of claim 41, further comprising at least one additional therapeutic agent.
43. The pharmaceutical composition of claim 42, wherein the additional therapeutic agent is chosen from the group consisting of painkillers, non-steroidal anti-inflammatory drugs (NSAIDs), cannabinoid receptor agonists, opiate receptor agonists, anti-infective agents, sodium channel blockers, N-type calcium channel blockers, local anesthetics, VRl agonists and antagonists, agents used for migraines, topical agents used in the treatment of localized pruritus, anti-inflammatory and/or immunosuppressive agents, agents designed to treat tobacco abuse (e.g., nicotine receptor partial agonists and nicotine replacement therapies), ADD/ ADHD agents, agents to treat alcoholism such as opioid antagonists, agents for reducing alcohol withdrawal symptoms such as benzodiazepines and beta-blockers, antihypertensive agents such as ACE inhibitors and Angiotensin II Receptor blockers, Renin inhibitors, vasodilators, agents used to treat glaucoma such as direct-acting Miotics
(cholinergic agonists) or indirect acting Miotics (cholinesterase inhibitors), Carbonic anhydrase inhibitors, selective adrenergic agonists, Osmotic diuretics, antidepressants such as SSRIs, tricyclic antidepressants, dopaminergic antidepressants, cognitive improvement agents, acetylcholinesterase inhibitors, anti-emetic agents (e.g., 5HT3 antagonists), neuroprotective agents, neuroprotective agents currently under investigation, antipsychotic medications, agents used for multiple sclerosis, disease-modifying anti-rheumatic drugs (DMARDS), biological response modifiers (BRMs), COX-2 selective inhibitors, COX-1 inhibitors, immunosuppressives, PDE4 inhibitors, corticosteroids, histamine HI receptor antagonists, histamine H2 receptor antagonists, proton pump inhibitors, leukotriene antagonists, 5-lipoxygenase inhibitors, nicotinic acetylcholine receptor agonists, P2X3 receptor antagonists, NGF agonists and antagonists, NK1 and NK2 antagonists, NMD A antagonist, potassium channel modulators, GABA modulators, anti-cancer agents such as tyrosine kinase inhibitors, anti-hyperlipidemia drugs, appetite suppressing agents, antidiabetic medications such as insulin, GI (gastrointestinal) agents, and serotonergic and noradrenergic modulators.
44. A method for the treatment or prevention of pain comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition according to any of claims 41 to 43.
45. The method according to claim 44, wherein the pain is chronic pain, acute pain, perioperative pain (e.g., associated with surgery), postoperative pain, visceral pain, inflammatory pain, cancer pain, headache pain, pain associated with a cough, neuropathic pain, deafferentation pain, chronic nociceptive pain, dental pain (such as odontalgia), bone pain, joint pain (e.g., osteoarthritis or rheumatoid arthritis), myofascial pain (e.g., muscular injury, fibromyalgia), labor pain, pain associated with injuries, pain resulting from trauma, pain resulting from allergies, pain resulting from dermatitis, pain resulting from
immunodeficiency, pain resulting from Hodgkin's disease, pain resulting from Myasthenia gravis, pain resulting from nephrotic syndrome, pain resulting from scleroderma, pain resulting from thyroiditis, central and peripheral pathway mediated pain, menstrual pain, neurogenic pain, dental pain, dysmenorrheal pain, visceral pain, neuropathic pain, post operative pain, headache, migraines, allodynia, hyperalgesia, post operative pain (e.g., associated with orthopedic surgery, gynecological surgery, abdominal surgery, incisions, oral surgery), back pain, pain caused by inflammation (e.g., arthritis, osteoarthritis, spondylitis, rheumatoid arthritis, Crohn's disease and irritable bowel syndrome), pain associated with injury, burns or trauma.
46. A method for the treatment or prevention of autoimmune disorders comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition according to any of claims 41 to 43.
47. The method according to claim 46, wherein the autoimmune disorder is selected from the group consisting of alopecia areata (also known as systemic sclerosis (SS)), amyloses, amyotrophic lateral sclerosis, ankylosing spondylarthritis, ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune
lymphoproliferative syndrome (ALPS), autoimmune thrombocytopenic purpura (ATP), Behcet's disease, cardiomyopathy, celiac sprue-dermatitis hepetiformis; chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy (CIPD), cicatricial pemphigoid, cold agglutinin disease, connective tissue diseases, crest syndrome, Crohn's disease, Degos' disease, dermatomyositis-juvenile, discoid lupus, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, graft vs. host disease, transplantation rejection, Graves' disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin-dependent diabetes mellitus, juvenile chronic arthritis (Still's disease), juvenile rheumatoid arthritis, lupus erythematosus, Meniere's disease, multiple sclerosis, myasthenia gravis, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis and dermatomyositis, primary agammaglobulinemia, primary biliary cirrhosis, psoriasis, psoriatic arthritis, Raynaud's phenomena, reactional arthritis, Reiter's syndrome, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma (progressive systemic sclerosis (PSS), Sjogren's syndrome, stiff-man syndrome, systemic lupus erythematosus, Takayasu arteritis, temporal arteritis/giant cell arteritis, ulcerative colitis, undifferentiated spondylarthritis, uveitis, vitiligo, and Wegener's granulomatosis.
48. A method for the treatment or prevention of disease states or indications that are accompanied by inflammatory processes comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition according to any of claims 41 to 43.
49. The method according to claim 48, wherein the disease states or indications that are accompanied by inflammatory processes are chosen from the group consisting of:
lung diseases such as asthma, bronchitis, allergic rhinitis, emphysema, adult respiratory distress syndrome (ARDS), pigeon fancier's disease, farmer's lung, chronic obstructive pulmonary disease (COPD), asthma including allergic asthma (atopic or non- atopic) as well as exercise-induced bronchoconstriction, occupational asthma, viral or bacterial exacerbation of asthma, other non-allergic asthmas and "wheezy-infant syndrome", pneumoconiosis, including aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis;
rheumatic diseases or autoimmune diseases or musculoskeletal diseases such as all forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, and polymyalgia rheumatica; reactive arthritis; rheumatic soft tissue diseases; inflammatory soft tissue diseases of other genesis; arthritic symptoms in degenerative joint diseases (arthroses); tendinitis, bursitis, osteoarthritis, traumatic arthritis, gout (metabolic arthritis); collagenoses of any genesis (e.g., systemic lupus erythematosus, scleroderma, polymyositis, dermatomyositis, Sjogren syndrome, Still disease, Felty syndrome); and osteoporosis and other bone resorption diseases;
allergic diseases including all forms of allergic reactions (e.g., allergic rhinitis, allergic conjunctivitis infectious parasitic, angioneurotic edema, hay fever, insect bites, allergic reactions to drugs, blood derivatives, contrast agents, etc.), anaphylactic shock (anaphylaxis), urticaria, angioneurotic edema, delayed or immediate hypersensitivity, and contact dermatitis;
vascular diseases such as panarteritis nodosa, polyarteritis nodosa, periarteritis nodosa, arteritis temporalis, Wegner granulomatosis, giant cell arthritis, atherosclerosis, reperfusion injury, myocardial ischemia, thrombosis and erythema nodosum;
dermatological diseases such as dermatitis, psoriasis, sunburn, burns, and eczema; renal, urinary and pancreatic diseases such as nephrotic syndrome and all types of nephritis (such as glomerulonephritis), pancreatitis, bladder hyperrelexia following bladder inflammation, urinary incontinence or vesicle inflammation, uresesthesia urgency, overactive bladder, urinary frequency, interstitial cystitis or chronic prostatitis;
hepatic diseases such as acute liver cell disintegration; acute hepatitis of various genesis (such as viral, toxic, drug-induced) and chronically aggressive and/or chronically intermittent hepatitis, liver fibrosis associated with liver injury or disease, including fibrosis caused or exacerbated by alcoholic liver cirrhosis, chronic viral hepatitis, non alcoholic steatohepatitis and primary liver cancer;
gastrointestinal diseases such as ulcers, inflammatory bowel diseases, regional enteritis (Crohn's disease), ulcerated colitis, gastritis, aphthous ulcer, celiac disease, regional ileitis, ileus, esophagitis, NSAID-induced ulcer, non-ulcerative dyspepsia and
gastroesophageal reflux disease;
neurodegenerative diseases such as the neurodegeneration following stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, cerebral ischemia, seizures, spinal cord injury or the like;
eye diseases such as allergic keratitis, uveitis, or iritis, conjunctivitis, blepharitis, neuritis nervi optici, choroiditis, glaucoma and sympathetic ophthalmia;
diseases of the ear, nose, and throat (ENT) area such as tinnitus, allergic rhinitis or hay fever, gingivitis, otitis externa, caused by contact eczema, infection, etc., and otitis media;
progressive central nervous system or neurological diseases such as brain edema, particularly tumor-related brain edema, multiple sclerosis, acute encephalomyelitis, meningitis, acute spinal cord injury, trauma, dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Parkinson's disease and Creutzfeldt- Jacob disease, Huntington's chorea, Pick's disease, amyotrophic lateral sclerosis (ALS)), vascular dementia (including multi-infarct dementia and dementia associated with intracranial space occupying lesions, infections and related conditions such as HIV infection), Guillain-Barre syndrome, myasthenia gravis, stroke, and various forms of seizures (such as nodding spasms);
blood diseases such as acquired hemolytic anemia, aplastic anemia, and idiopathic thrombocytopenia;
tumor diseases such as acute lymphatic leukemia, Hodgkin's disease, malignant lymphoma, lymphogranulomatoses, lymphosarcoma, solid malignant tumors, colorectal polyps, extensive metastases and other proliferative disorders such as diabetic retinopathy and tumor angiogenesis (e.g., wet macular degeneration);
endocrine diseases such as endocrine opthalmopathy, endocrine orbitopathia, thyrotoxic crisis, Thyroiditis de Quervain, Hashimoto thyroiditis, Morbus Basedow, granulomatous thyroiditis, struma lymphomatosa, Graves disease, type I diabetes (such as insulin-dependent diabetes); organ and tissue transplantations and graft-versus-host diseases;
severe states of shock such as septic shock, anaphylactic shock, and systemic inflammatory response syndrome (SIRS);
viral or bacterial parasitic infectious disease: for example AIDS and meningitis; and
various other disease-states or conditions including, restenosis following percutaneous transluminal coronary angioplasty, acute and chronic pain, atherosclerosis, reperfusion injury, congestive heart failure, myocardial infarction, thermal injury, multiple organ injury secondary to trauma, necrotizing enterocolitis and syndromes associated with hemodialysis, leukopheresis, granulocyte transfusion, sarcoidosis, gingivitis, pyrexia, edema resulting from trauma associated with burns, sprains or fracture, cerebral edema and angioedema, and diabetes (such as diabetic vasculopathy, diabetic neuropathy, diabetic retinopathy, post capillary resistance and diabetic symptoms associated with insulitis (e.g., Hyperglycemia, diuresis, proteinuria and increased nitrite and kallikrein urinary excretion)).
50. A method for the treatment or prevention of gastrointestinal diseases or disorders comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition according to any of claims 41 to 43.
51. The method of claim 50, wherein the disease or disorder is chosen from the group consisting of: functional gastrointestinal disorders, ulcers, inflammatory bowel diseases (IBD), regional enteritis (Crohn's disease), ulcerative colitis, diarrhea, gastritis, aphthous ulcer, celiac disease, regional ileitis, ileus, functional dyspepsia, diverticulitis, gastrointestinal bleeding, irritable bowel syndrome (IBS), non-ulcerative dyspepsia and gastroesophageal reflux disease.
52. A method for the treatment or prevention of pruritus, comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition according to any of claims 41 to 43.
53. The method according to claim 52, wherein the pruritus is dermal pruritus, neuropathic pruritus, neurogenic pruritus or psychogenic pruritus.
54. A method for the treatment or prevention of substance abuse-related syndromes, disorders, diseases or withdrawal symptoms comprising administering, alone or in
combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition according to any of claims 41 to 43.
55. The method according to claim 54, wherein the substance abuse-related syndromes, disorders, diseases or withdrawal symptoms are chosen from the group consisting of: drug abuse and drug withdrawal, wherein the abused substances include alcohol, amphetamines, amphetamine like substances, caffeine, cannabis, cocaine, hallucinogens, inhalants, opioids, nicotine (and/or tobacco products), heroin, barbiturates, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics, benzodiazepines, or combinations of any of the foregoing; and the withdrawal symptoms include tobacco craving or nicotine dependency, addiction, or withdrawal.
56. A method for the treatment or prevention of psychiatric disorders comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition according to any of claims 41 to 43.
57. The method according to claim 56, wherein the psychiatric disorders are chosen from the group consisting of depressions (including major depressive disorder, bipolar depression, unipolar depression, single or recurrent major depressive episodes (e.g., with or without psychotic features, catatonic features, and/or melancholic features), postpartum onset, seasonal affective disorder, dysthymic disorders (e.g., with early or late onset and with or without atypical features), neurotic depression and social phobia, depression accompanying dementia, anxiety, psychosis, social affective disorders, and/or cognitive disorders), manic- depressive psychoses, bipolar disorders, extreme psychotic states (such as mania,
schizophrenia, and excessive mood swings where behavioral stabilization is desired), posttraumatic stress disorder, panic disorder, obsessive compulsive disorder, psychiatric tremors such as dyskinesias, dystonia and spasticity, attention disorders such as ADHD (attention deficit hyperactivity disorders), autism, anxiety states, generalized anxiety, agoraphobia, as well as those behavioral states characterized by social withdrawal.
58. A method for the treatment or prevention of neurological or neurodegenerative disorders comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition according to any of claims 41 to 43.
59. The method according to claim 58, wherein the neurological or neurodegenerative disorders are chosen from the group consisting of dementia, particularly degenerative dementia (including senile dementia, Alzheimer's disease, Pick's disease, Huntingdon's chorea, Parkinson's disease, prion disease and Creutzfeldt-Jakob disease and motor neuron disease); vascular dementia (including multi-infarct dementia); dementia associated with intracranial space occupying lesions; trauma; infections and related conditions (including HIV infection); dementia in Parkinson's disease; metabolism; toxins; anoxia and vitamin deficiency; and mild cognitive impairment associated with aging, particularly Age- Associated Memory Impairment; amyotrophic lateral sclerosis (ALS), multiple sclerosis, epilepsy, ischemia, traumatic head or brain injury, brain inflammation, eye injury, stroke and neuroinflammation; and neurodegeneration or decreased brain activity associated with stroke, cardiac arrest, pulmonary bypass, traumatic brain injury, hypoxia, hypoglycemia, gas poisoning, drug intoxication, diabetes mellitus, edema, spinal cord injury, cerebral ischemia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, seizures or the like.
60. A method for the treatment or prevention of ocular disorders comprising
administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition according to any of claims 41 to 43.
61. The method according to claim 60, wherein the ocular disorders are chosen from the group consisting of glaucoma (such as normal tension glaucoma), glaucoma-associated intraocular pressure retinitis, retinopathies, uveitis, acute injury to the eye tissue (e.g., conjunctivitis), high intraocular pressure, family history of glaucoma, glaucoma in the contralateral eye and high myopia.
I l l
62. A method for the treatment or prevention of appetite related disorders comprising administering, alone or in combination therapy, to a patient in need thereof a therapeutically or prophylactically acceptable dose of a pharmaceutical composition according to any of claims 41 to 43.
63. The method of claim 62, wherein the appetite related disorder is chosen from the group consisting of: emesis, vomiting and nausea, food behavioral problems or feeding disorders such as anorexias, cachexias, wasting conditions and bulimia; and obesity or obesity-related disorders such as diabetes type II, or hyperlipidemia.
64. A method for the treatment or prevention of gynecological disorders comprising administering, alone or in combination, a therapeutically acceptable dose of a pharmaceutical composition according to any of claims 41 to 43.
65. The method of claim 64, wherein the gynecological disorder is uterus contraction caused by hormones, or prostanoid- induced muscle contraction such as premature labor, menstrual cramps, menstrual irregularity or dysmenorrhea.
66. A method for the treatment or prevention of sleep disorders comprising administering, alone or in combination, a pharmaceutically acceptable dose of a pharmaceutical composition according to any of claims 41 to 43.
67. The method of claim 66, wherein the sleep disorder is chosen from the group consisting of: insomnia, night terrors, bruxism, somnambulism, narcolepsy, circadian rhythm adjustment disorders, and sleep disorders associated with neurological or mental disorders or with pain.
68. The method according to any of claims 44 to 67, wherein the patient is a human.
69. The method according to any of claims 44 to 67, wherein the patient is a companion animal, exotic animal or a farm animal such as a dog, cat, mouse, rat, hamster, gerbil, guinea pig, rabbit, horse, pig or cow.
70. A method of inhibiting FAAH in a biological sample, comprising contacting said biological sample with a pharmaceutical composition according to any of claims 41 to 43.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/514,343 US20130109721A1 (en) | 2009-12-08 | 2010-12-08 | FAAH Inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US26769609P | 2009-12-08 | 2009-12-08 | |
US61/267,696 | 2009-12-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2011071996A1 true WO2011071996A1 (en) | 2011-06-16 |
Family
ID=43513760
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2010/059428 WO2011071996A1 (en) | 2009-12-08 | 2010-12-08 | Faah inhibitors |
Country Status (2)
Country | Link |
---|---|
US (1) | US20130109721A1 (en) |
WO (1) | WO2011071996A1 (en) |
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011123719A3 (en) * | 2010-03-31 | 2011-12-15 | Ironwood Pharmaceuticals, Inc. | Use of faah inhibitors for treating abdominal, visceral and pelvic pain |
WO2012088431A1 (en) * | 2010-12-23 | 2012-06-28 | Ironwood Pharmaceuticals, Inc. | Faah inhibitors |
WO2013079223A1 (en) * | 2011-12-02 | 2013-06-06 | Phenex Pharmaceuticals Ag | Pyrrolo carboxamides as modulators of orphan nuclear receptor rar-related orphan receptor-gamma (rorϒ, nr1f3) activity and for the treatment of chronic inflammatory and autoimmune diseases |
US8507561B2 (en) | 2009-01-22 | 2013-08-13 | Absorption Pharmaceuticals, LLC | Desensitizing drug product |
WO2013180698A1 (en) * | 2012-05-30 | 2013-12-05 | Alcon Research, Ltd. | Use of faah antagonists for treating dry eye and ocular pain |
US8865723B2 (en) | 2012-10-25 | 2014-10-21 | Tetra Discovery Partners Llc | Selective PDE4 B inhibition and improvement in cognition in subjects with brain injury |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115887456A (en) | 2015-03-26 | 2023-04-04 | 杰奎琳·M·艾弗森 | Methods and compositions for inhibiting symptoms associated with hangover |
SG11202011513RA (en) * | 2018-05-22 | 2020-12-30 | Js Innomed Holdings Ltd | Heterocyclic compounds as kinase inhibitors, compositions comprising the heterocyclic compound, and methods of use thereof |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3773919A (en) | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
US5304121A (en) | 1990-12-28 | 1994-04-19 | Boston Scientific Corporation | Drug delivery system making use of a hydrogel polymer coating |
US5886026A (en) | 1993-07-19 | 1999-03-23 | Angiotech Pharmaceuticals Inc. | Anti-angiogenic compositions and methods of use |
US6099562A (en) | 1996-06-13 | 2000-08-08 | Schneider (Usa) Inc. | Drug coating with topcoat |
US20040122074A1 (en) * | 2002-12-12 | 2004-06-24 | Pfizer Inc. | Cannabinoid receptor ligands and uses thereof |
WO2004058249A1 (en) * | 2002-12-24 | 2004-07-15 | Astrazeneca Ab | 1,5-diaryl-pyrrole-3-carboxamide derivatives and their use as cannabinoid receptor modulators |
WO2004060870A1 (en) * | 2003-01-02 | 2004-07-22 | F. Hoffmann-La Roche Ag | Novel cb 1 receptour inverse agonists |
WO2008019357A2 (en) * | 2006-08-07 | 2008-02-14 | Ironwood Pharmaceuticals, Inc. | Indole compounds |
WO2008157740A2 (en) * | 2007-06-20 | 2008-12-24 | Ironwood Pharmaceuticals, Inc. | Faah inhibitors |
-
2010
- 2010-12-08 US US13/514,343 patent/US20130109721A1/en not_active Abandoned
- 2010-12-08 WO PCT/US2010/059428 patent/WO2011071996A1/en active Application Filing
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3773919A (en) | 1969-10-23 | 1973-11-20 | Du Pont | Polylactide-drug mixtures |
US5304121A (en) | 1990-12-28 | 1994-04-19 | Boston Scientific Corporation | Drug delivery system making use of a hydrogel polymer coating |
US5886026A (en) | 1993-07-19 | 1999-03-23 | Angiotech Pharmaceuticals Inc. | Anti-angiogenic compositions and methods of use |
US6099562A (en) | 1996-06-13 | 2000-08-08 | Schneider (Usa) Inc. | Drug coating with topcoat |
US20040122074A1 (en) * | 2002-12-12 | 2004-06-24 | Pfizer Inc. | Cannabinoid receptor ligands and uses thereof |
WO2004058249A1 (en) * | 2002-12-24 | 2004-07-15 | Astrazeneca Ab | 1,5-diaryl-pyrrole-3-carboxamide derivatives and their use as cannabinoid receptor modulators |
WO2004060870A1 (en) * | 2003-01-02 | 2004-07-22 | F. Hoffmann-La Roche Ag | Novel cb 1 receptour inverse agonists |
WO2008019357A2 (en) * | 2006-08-07 | 2008-02-14 | Ironwood Pharmaceuticals, Inc. | Indole compounds |
WO2008157740A2 (en) * | 2007-06-20 | 2008-12-24 | Ironwood Pharmaceuticals, Inc. | Faah inhibitors |
Non-Patent Citations (15)
Title |
---|
"Burger's Medicinal Chemistry and Drug Discovery", vol. 172-178, 1995, pages: 949 - 982 |
"Handbook of Chemistry and Physics", 1994 |
"March's Advanced Organic Chemistry", 2001, JOHN WILEY & SONS |
"Remington's: The Science and Practice of Pharmacy", 2005, UNIVERSITY OF THE SCIENCES IN PHILADELPHIA |
"The ACS Style Guide: A Manual for Authors and Editors", 1997, AMERICAN CHEMICAL SOCIETY |
BERG ET AL., PHARMACEUTICAL SALTS, J. PHARM. SCI., vol. 66, 1977, pages 1 - 19 |
BISOGNO ET AL., J BIOL. CHEM., vol. 272, 1997, pages 3315 |
BRADFORD, M.M., ANAL. BIOCHEM., vol. 72, 1976, pages 248 |
FOWLER ET AL., J. PHARMACOL EXP THER, vol. 283, 1997, pages 729 |
GREENE, T. W.; WUTS, P. G: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY & SONS |
JONSSON ET AL., BR. J PHARMACOL., vol. 133, 2001, pages 1263 |
MACCARONE ET AL., J BIOL. CHEM., vol. 273, 1998, pages 32332 |
OMEIR ET AL., LIFE SCI, vol. 56, 1995, pages 1999 |
THOMAS SORRELL: "Organic Chemistry", 1999, UNIVERSITY SCIENCE BOOKS |
WILSON ET AL., ANAL. BIOCHEM., vol. 318, 2003, pages 270 |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8507561B2 (en) | 2009-01-22 | 2013-08-13 | Absorption Pharmaceuticals, LLC | Desensitizing drug product |
US8563616B2 (en) | 2009-01-22 | 2013-10-22 | Absorption Pharmaceuticals, LLC | Desensitizing drug product |
US8637577B2 (en) | 2009-01-22 | 2014-01-28 | Absorption Pharmaceuticals, LLC | Desensitizing drug product |
WO2011123719A3 (en) * | 2010-03-31 | 2011-12-15 | Ironwood Pharmaceuticals, Inc. | Use of faah inhibitors for treating abdominal, visceral and pelvic pain |
WO2012088431A1 (en) * | 2010-12-23 | 2012-06-28 | Ironwood Pharmaceuticals, Inc. | Faah inhibitors |
WO2013079223A1 (en) * | 2011-12-02 | 2013-06-06 | Phenex Pharmaceuticals Ag | Pyrrolo carboxamides as modulators of orphan nuclear receptor rar-related orphan receptor-gamma (rorϒ, nr1f3) activity and for the treatment of chronic inflammatory and autoimmune diseases |
US9815851B2 (en) | 2011-12-02 | 2017-11-14 | Phenex Pharmaceuticals Ag | Pyrrolo carboxamides as modulators of orphan nuclear receptor RAR-related orphan receptor-gamma (RORγ, NR1F3) activity and for the treatment of chronic inflammatory and autoimmune diseases |
WO2013180698A1 (en) * | 2012-05-30 | 2013-12-05 | Alcon Research, Ltd. | Use of faah antagonists for treating dry eye and ocular pain |
US8865723B2 (en) | 2012-10-25 | 2014-10-21 | Tetra Discovery Partners Llc | Selective PDE4 B inhibition and improvement in cognition in subjects with brain injury |
Also Published As
Publication number | Publication date |
---|---|
US20130109721A1 (en) | 2013-05-02 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2655356B1 (en) | Faah inhibitors | |
WO2012088431A1 (en) | Faah inhibitors | |
US20130178453A1 (en) | Cannabinoid Agonists | |
US20130109721A1 (en) | FAAH Inhibitors | |
TWI444378B (en) | Sulfur containing heterocyclic derivatives having β secretase inhibitory activities and use thereof | |
TWI637949B (en) | Aminotriazine derivative and pharmaceutical composition comprising the same | |
US20130196960A1 (en) | Cannabinoid Receptor Agonists | |
JP5860417B2 (en) | Inhibitors of catechol O-methyltransferase and their use in the treatment of mental disorders | |
US20130029970A1 (en) | CB Receptor Agonists | |
JP5937971B2 (en) | Inhibitors of catechol O-methyltransferase and their use in the treatment of mental disorders | |
EP3194386A2 (en) | Sgc stimulators | |
KR20160055190A (en) | Spirocyclic compounds as tryptophan hydroxylase inhibitors | |
EP2976341A1 (en) | Acyclic cyanoethylpyrazolo pyridones as janus kinase inhibitors | |
WO2012009134A1 (en) | Crth2 modulators | |
WO2012009137A1 (en) | Crth2 modulators | |
US8674115B2 (en) | CRTH2 modulators | |
EP3087060B1 (en) | Pyrimidone carboxamide compounds as pde2 inhibitors | |
CN109988169B (en) | Octahydropyrrolo [3,4-c ] pyrrole derivatives and uses thereof | |
WO2016144860A1 (en) | Faah inhibitors for the treatment or prevention of nausea |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 10798655 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 13514343 Country of ref document: US |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 10798655 Country of ref document: EP Kind code of ref document: A1 |