CN115996930A - 氨基嘧啶基衍生物 - Google Patents
氨基嘧啶基衍生物 Download PDFInfo
- Publication number
- CN115996930A CN115996930A CN202180046561.3A CN202180046561A CN115996930A CN 115996930 A CN115996930 A CN 115996930A CN 202180046561 A CN202180046561 A CN 202180046561A CN 115996930 A CN115996930 A CN 115996930A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutically acceptable
- disease
- compound
- acceptable salt
- pyrazol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- -1 Aminopyrimidinyl Chemical class 0.000 title claims description 64
- 150000001875 compounds Chemical class 0.000 claims abstract description 234
- 150000003839 salts Chemical class 0.000 claims abstract description 76
- 238000000034 method Methods 0.000 claims abstract description 61
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 30
- 239000003814 drug Substances 0.000 claims abstract description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 239000001257 hydrogen Substances 0.000 claims abstract description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 46
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims description 42
- 201000010099 disease Diseases 0.000 claims description 28
- 201000004681 Psoriasis Diseases 0.000 claims description 23
- 208000011580 syndromic disease Diseases 0.000 claims description 19
- 208000003456 Juvenile Arthritis Diseases 0.000 claims description 18
- 208000035475 disorder Diseases 0.000 claims description 18
- 230000000366 juvenile effect Effects 0.000 claims description 18
- 208000006673 asthma Diseases 0.000 claims description 17
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 claims description 16
- 206010003246 arthritis Diseases 0.000 claims description 16
- 201000004624 Dermatitis Diseases 0.000 claims description 14
- 230000000694 effects Effects 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 201000001981 dermatomyositis Diseases 0.000 claims description 12
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 claims description 12
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 12
- 208000019069 chronic childhood arthritis Diseases 0.000 claims description 11
- 206010025135 lupus erythematosus Diseases 0.000 claims description 11
- 208000023275 Autoimmune disease Diseases 0.000 claims description 10
- 206010061218 Inflammation Diseases 0.000 claims description 10
- 230000004054 inflammatory process Effects 0.000 claims description 10
- 102000002227 Interferon Type I Human genes 0.000 claims description 9
- 108010014726 Interferon Type I Proteins 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- 230000009885 systemic effect Effects 0.000 claims description 9
- 206010040070 Septic Shock Diseases 0.000 claims description 8
- 206010052779 Transplant rejections Diseases 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 8
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims description 8
- 206010008609 Cholangitis sclerosing Diseases 0.000 claims description 7
- 206010020751 Hypersensitivity Diseases 0.000 claims description 7
- 206010063837 Reperfusion injury Diseases 0.000 claims description 7
- 208000010668 atopic eczema Diseases 0.000 claims description 7
- 208000005987 polymyositis Diseases 0.000 claims description 7
- 208000010157 sclerosing cholangitis Diseases 0.000 claims description 7
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 7
- 229940116839 Janus kinase 1 inhibitor Drugs 0.000 claims description 6
- 201000002481 Myositis Diseases 0.000 claims description 6
- 206010039710 Scleroderma Diseases 0.000 claims description 6
- 206010047115 Vasculitis Diseases 0.000 claims description 6
- 201000008937 atopic dermatitis Diseases 0.000 claims description 6
- 206010012601 diabetes mellitus Diseases 0.000 claims description 6
- 206010020718 hyperplasia Diseases 0.000 claims description 6
- 230000004770 neurodegeneration Effects 0.000 claims description 6
- 201000005671 spondyloarthropathy Diseases 0.000 claims description 6
- 208000024827 Alzheimer disease Diseases 0.000 claims description 5
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 5
- 208000015943 Coeliac disease Diseases 0.000 claims description 5
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 5
- 206010012438 Dermatitis atopic Diseases 0.000 claims description 5
- 208000003556 Dry Eye Syndromes Diseases 0.000 claims description 5
- 206010013774 Dry eye Diseases 0.000 claims description 5
- 208000024556 Mendelian disease Diseases 0.000 claims description 5
- 241000721454 Pemphigus Species 0.000 claims description 5
- 201000001263 Psoriatic Arthritis Diseases 0.000 claims description 5
- 208000036824 Psoriatic arthropathy Diseases 0.000 claims description 5
- 208000006011 Stroke Diseases 0.000 claims description 5
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 5
- 206010046851 Uveitis Diseases 0.000 claims description 5
- 201000009961 allergic asthma Diseases 0.000 claims description 5
- 208000026935 allergic disease Diseases 0.000 claims description 5
- 230000007815 allergy Effects 0.000 claims description 5
- 208000004631 alopecia areata Diseases 0.000 claims description 5
- 208000007118 chronic progressive multiple sclerosis Diseases 0.000 claims description 5
- 208000026278 immune system disease Diseases 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 201000006417 multiple sclerosis Diseases 0.000 claims description 5
- 208000023504 respiratory system disease Diseases 0.000 claims description 5
- 206010002556 Ankylosing Spondylitis Diseases 0.000 claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims description 4
- 206010003827 Autoimmune hepatitis Diseases 0.000 claims description 4
- 208000009137 Behcet syndrome Diseases 0.000 claims description 4
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 claims description 4
- 208000033222 Biliary cirrhosis primary Diseases 0.000 claims description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
- 208000011231 Crohn disease Diseases 0.000 claims description 4
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 claims description 4
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 4
- 208000012528 Juvenile dermatomyositis Diseases 0.000 claims description 4
- 201000009053 Neurodermatitis Diseases 0.000 claims description 4
- 208000002193 Pain Diseases 0.000 claims description 4
- 206010036030 Polyarthritis Diseases 0.000 claims description 4
- 208000012654 Primary biliary cholangitis Diseases 0.000 claims description 4
- 208000034189 Sclerosis Diseases 0.000 claims description 4
- 208000021386 Sjogren Syndrome Diseases 0.000 claims description 4
- 206010047642 Vitiligo Diseases 0.000 claims description 4
- 210000000988 bone and bone Anatomy 0.000 claims description 4
- 210000000845 cartilage Anatomy 0.000 claims description 4
- 201000010415 childhood type dermatomyositis Diseases 0.000 claims description 4
- 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 4
- 208000015181 infectious disease Diseases 0.000 claims description 4
- 230000002458 infectious effect Effects 0.000 claims description 4
- 208000028774 intestinal disease Diseases 0.000 claims description 4
- 208000028867 ischemia Diseases 0.000 claims description 4
- 201000011486 lichen planus Diseases 0.000 claims description 4
- 210000004698 lymphocyte Anatomy 0.000 claims description 4
- 206010028417 myasthenia gravis Diseases 0.000 claims description 4
- 208000010125 myocardial infarction Diseases 0.000 claims description 4
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims description 4
- 201000006292 polyarteritis nodosa Diseases 0.000 claims description 4
- 208000030428 polyarticular arthritis Diseases 0.000 claims description 4
- 206010063401 primary progressive multiple sclerosis Diseases 0.000 claims description 4
- 201000000742 primary sclerosing cholangitis Diseases 0.000 claims description 4
- 201000003651 pulmonary sarcoidosis Diseases 0.000 claims description 4
- 208000002574 reactive arthritis Diseases 0.000 claims description 4
- 201000000306 sarcoidosis Diseases 0.000 claims description 4
- 201000004384 Alopecia Diseases 0.000 claims description 3
- 206010003267 Arthritis reactive Diseases 0.000 claims description 3
- 208000035143 Bacterial infection Diseases 0.000 claims description 3
- 208000023328 Basedow disease Diseases 0.000 claims description 3
- 206010048962 Brain oedema Diseases 0.000 claims description 3
- 206010006895 Cachexia Diseases 0.000 claims description 3
- 241000222122 Candida albicans Species 0.000 claims description 3
- 206010007134 Candida infections Diseases 0.000 claims description 3
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 3
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 3
- 208000006547 Central Nervous System Lupus Vasculitis Diseases 0.000 claims description 3
- 208000032544 Cicatrix Diseases 0.000 claims description 3
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 3
- 208000005171 Dysmenorrhea Diseases 0.000 claims description 3
- 206010013935 Dysmenorrhoea Diseases 0.000 claims description 3
- 201000009273 Endometriosis Diseases 0.000 claims description 3
- 206010016654 Fibrosis Diseases 0.000 claims description 3
- 208000010412 Glaucoma Diseases 0.000 claims description 3
- 201000005569 Gout Diseases 0.000 claims description 3
- 206010018634 Gouty Arthritis Diseases 0.000 claims description 3
- 206010019280 Heart failures Diseases 0.000 claims description 3
- 208000005777 Lupus Nephritis Diseases 0.000 claims description 3
- 208000000112 Myalgia Diseases 0.000 claims description 3
- 208000036110 Neuroinflammatory disease Diseases 0.000 claims description 3
- 208000008589 Obesity Diseases 0.000 claims description 3
- 208000001132 Osteoporosis Diseases 0.000 claims description 3
- 208000007048 Polymyalgia Rheumatica Diseases 0.000 claims description 3
- 206010037549 Purpura Diseases 0.000 claims description 3
- 241001672981 Purpura Species 0.000 claims description 3
- 206010037575 Pustular psoriasis Diseases 0.000 claims description 3
- 206010037660 Pyrexia Diseases 0.000 claims description 3
- 208000012322 Raynaud phenomenon Diseases 0.000 claims description 3
- 208000017442 Retinal disease Diseases 0.000 claims description 3
- 206010038910 Retinitis Diseases 0.000 claims description 3
- 206010038923 Retinopathy Diseases 0.000 claims description 3
- 208000025747 Rheumatic disease Diseases 0.000 claims description 3
- 201000010001 Silicosis Diseases 0.000 claims description 3
- 208000006045 Spondylarthropathies Diseases 0.000 claims description 3
- 206010042496 Sunburn Diseases 0.000 claims description 3
- 208000007536 Thrombosis Diseases 0.000 claims description 3
- 201000007023 Thrombotic Thrombocytopenic Purpura Diseases 0.000 claims description 3
- 206010044248 Toxic shock syndrome Diseases 0.000 claims description 3
- 231100000650 Toxic shock syndrome Toxicity 0.000 claims description 3
- 208000030886 Traumatic Brain injury Diseases 0.000 claims description 3
- 208000024780 Urticaria Diseases 0.000 claims description 3
- 206010046914 Vaginal infection Diseases 0.000 claims description 3
- 201000008100 Vaginitis Diseases 0.000 claims description 3
- 208000036142 Viral infection Diseases 0.000 claims description 3
- 230000001154 acute effect Effects 0.000 claims description 3
- 208000024340 acute graft versus host disease Diseases 0.000 claims description 3
- 231100000360 alopecia Toxicity 0.000 claims description 3
- 206010003230 arteritis Diseases 0.000 claims description 3
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 3
- 208000006752 brain edema Diseases 0.000 claims description 3
- 201000003984 candidiasis Diseases 0.000 claims description 3
- 230000002612 cardiopulmonary effect Effects 0.000 claims description 3
- 208000011235 central nervous system lupus Diseases 0.000 claims description 3
- 208000017760 chronic graft versus host disease Diseases 0.000 claims description 3
- 230000007850 degeneration Effects 0.000 claims description 3
- 230000004064 dysfunction Effects 0.000 claims description 3
- 208000037902 enteropathy Diseases 0.000 claims description 3
- 230000004761 fibrosis Effects 0.000 claims description 3
- 230000001969 hypertrophic effect Effects 0.000 claims description 3
- 201000004990 juvenile ankylosing spondylitis Diseases 0.000 claims description 3
- 208000019423 liver disease Diseases 0.000 claims description 3
- 208000002780 macular degeneration Diseases 0.000 claims description 3
- 208000024714 major depressive disease Diseases 0.000 claims description 3
- 201000006938 muscular dystrophy Diseases 0.000 claims description 3
- 201000008383 nephritis Diseases 0.000 claims description 3
- 230000003959 neuroinflammation Effects 0.000 claims description 3
- 235000020824 obesity Nutrition 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- 230000001717 pathogenic effect Effects 0.000 claims description 3
- 208000017940 prurigo nodularis Diseases 0.000 claims description 3
- 231100000241 scar Toxicity 0.000 claims description 3
- 230000037387 scars Effects 0.000 claims description 3
- 230000008961 swelling Effects 0.000 claims description 3
- 230000003582 thrombocytopenic effect Effects 0.000 claims description 3
- 230000001732 thrombotic effect Effects 0.000 claims description 3
- 230000003612 virological effect Effects 0.000 claims description 3
- 208000026872 Addison Disease Diseases 0.000 claims description 2
- 206010012455 Dermatitis exfoliative Diseases 0.000 claims description 2
- 206010042033 Stevens-Johnson syndrome Diseases 0.000 claims description 2
- 231100000168 Stevens-Johnson syndrome Toxicity 0.000 claims description 2
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 claims description 2
- 210000000589 cicatrix Anatomy 0.000 claims description 2
- 238000011010 flushing procedure Methods 0.000 claims description 2
- 230000000306 recurrent effect Effects 0.000 claims description 2
- 238000004378 air conditioning Methods 0.000 claims 2
- 230000035939 shock Effects 0.000 claims 1
- 208000020408 systemic-onset juvenile idiopathic arthritis Diseases 0.000 claims 1
- 201000006594 toxic diffuse goiter Diseases 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 17
- 229940122245 Janus kinase inhibitor Drugs 0.000 abstract description 8
- 229940124597 therapeutic agent Drugs 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 82
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
- 210000003491 skin Anatomy 0.000 description 31
- 239000002904 solvent Substances 0.000 description 24
- 108091082332 JAK family Proteins 0.000 description 23
- 102000042838 JAK family Human genes 0.000 description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- 230000002829 reductive effect Effects 0.000 description 21
- 239000007787 solid Substances 0.000 description 21
- 238000005481 NMR spectroscopy Methods 0.000 description 20
- 239000003795 chemical substances by application Substances 0.000 description 20
- 229940079593 drug Drugs 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 238000009472 formulation Methods 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 235000019439 ethyl acetate Nutrition 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 210000004209 hair Anatomy 0.000 description 15
- 210000000003 hoof Anatomy 0.000 description 15
- 239000003112 inhibitor Substances 0.000 description 15
- 210000000282 nail Anatomy 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 14
- 238000003556 assay Methods 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- 101000844245 Homo sapiens Non-receptor tyrosine-protein kinase TYK2 Proteins 0.000 description 12
- 102100032028 Non-receptor tyrosine-protein kinase TYK2 Human genes 0.000 description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 11
- 239000013543 active substance Substances 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- 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 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 210000000078 claw Anatomy 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- 238000011200 topical administration Methods 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 9
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 9
- 229940002612 prodrug Drugs 0.000 description 9
- 239000000651 prodrug Substances 0.000 description 9
- 230000000699 topical effect Effects 0.000 description 9
- KMLMOVWSQPHQME-REOHCLBHSA-N (1s)-2,2-difluorocyclopropane-1-carboxylic acid Chemical compound OC(=O)[C@@H]1CC1(F)F KMLMOVWSQPHQME-REOHCLBHSA-N 0.000 description 8
- 102000004127 Cytokines Human genes 0.000 description 8
- 108090000695 Cytokines Proteins 0.000 description 8
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 8
- 239000000969 carrier Substances 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000002609 medium Substances 0.000 description 8
- 229920001223 polyethylene glycol Polymers 0.000 description 8
- 238000000634 powder X-ray diffraction Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- 239000002502 liposome Substances 0.000 description 7
- 231100000252 nontoxic Toxicity 0.000 description 7
- 230000003000 nontoxic effect Effects 0.000 description 7
- 239000003755 preservative agent Substances 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 7
- 229960001082 trimethoprim Drugs 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 6
- 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 6
- 241000124008 Mammalia Species 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 125000003158 alcohol group Chemical group 0.000 description 6
- 239000000908 ammonium hydroxide Substances 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 239000005557 antagonist Substances 0.000 description 6
- 230000001363 autoimmune Effects 0.000 description 6
- 239000000872 buffer Substances 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- 239000003085 diluting agent Substances 0.000 description 6
- 229940088598 enzyme Drugs 0.000 description 6
- 229960004756 ethanol Drugs 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 108090000765 processed proteins & peptides Proteins 0.000 description 6
- 229940044551 receptor antagonist Drugs 0.000 description 6
- 239000002464 receptor antagonist Substances 0.000 description 6
- 239000002002 slurry Substances 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 229940123371 Tyrosine kinase 2 inhibitor Drugs 0.000 description 5
- 125000004429 atom Chemical group 0.000 description 5
- 239000000460 chlorine Substances 0.000 description 5
- 238000009792 diffusion process Methods 0.000 description 5
- 239000003995 emulsifying agent Substances 0.000 description 5
- 239000003623 enhancer Substances 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 210000003494 hepatocyte Anatomy 0.000 description 5
- 208000027866 inflammatory disease Diseases 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 150000002500 ions Chemical class 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 229960005027 natalizumab Drugs 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- 230000035699 permeability Effects 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 239000000375 suspending agent Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 239000001993 wax Substances 0.000 description 5
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 4
- XORHNJQEWQGXCN-UHFFFAOYSA-N 4-nitro-1h-pyrazole Chemical compound [O-][N+](=O)C=1C=NNC=1 XORHNJQEWQGXCN-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 108010010803 Gelatin Proteins 0.000 description 4
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 4
- 108010024121 Janus Kinases Proteins 0.000 description 4
- 102000015617 Janus Kinases Human genes 0.000 description 4
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000037396 body weight Effects 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 239000002552 dosage form Substances 0.000 description 4
- 238000000132 electrospray ionisation Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 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 4
- 230000002757 inflammatory effect Effects 0.000 description 4
- 230000000968 intestinal effect Effects 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 244000144972 livestock Species 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 208000015122 neurodegenerative disease Diseases 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 150000007530 organic bases Chemical class 0.000 description 4
- 230000035515 penetration Effects 0.000 description 4
- 239000003961 penetration enhancing agent Substances 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 229960004063 propylene glycol Drugs 0.000 description 4
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- 239000000454 talc Substances 0.000 description 4
- 229910052623 talc Inorganic materials 0.000 description 4
- 235000012222 talc Nutrition 0.000 description 4
- 230000037317 transdermal delivery Effects 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000000080 wetting agent Substances 0.000 description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 description 4
- 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 3
- 229920001817 Agar Polymers 0.000 description 3
- 241000416162 Astragalus gummifer Species 0.000 description 3
- 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 3
- 102100025248 C-X-C motif chemokine 10 Human genes 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
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 101000858088 Homo sapiens C-X-C motif chemokine 10 Proteins 0.000 description 3
- 102000014150 Interferons Human genes 0.000 description 3
- 108010050904 Interferons Proteins 0.000 description 3
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 3
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 108091000080 Phosphotransferase Proteins 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- 208000003251 Pruritus Diseases 0.000 description 3
- 208000020410 Psoriasis-related juvenile idiopathic arthritis Diseases 0.000 description 3
- 208000007400 Relapsing-Remitting Multiple Sclerosis Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 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 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 229920001615 Tragacanth Polymers 0.000 description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 229960002964 adalimumab Drugs 0.000 description 3
- 235000010419 agar Nutrition 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 230000004888 barrier function Effects 0.000 description 3
- 235000012216 bentonite Nutrition 0.000 description 3
- 239000000090 biomarker Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 229960004436 budesonide Drugs 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 229960001265 ciclosporin Drugs 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 229930182912 cyclosporin Natural products 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- WDVGNXKCFBOKDF-UHFFFAOYSA-N dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane Chemical compound COC1=CC=C(OC)C(C=2C(=CC(=CC=2C(C)C)C(C)C)C(C)C)=C1P(C1CCCCC1)C1CCCCC1 WDVGNXKCFBOKDF-UHFFFAOYSA-N 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 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 3
- 229960003592 fexofenadine Drugs 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 238000000684 flow cytometry Methods 0.000 description 3
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 3
- 239000003205 fragrance Substances 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 229960000598 infliximab Drugs 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000007972 injectable composition Substances 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 229940079322 interferon Drugs 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 230000037361 pathway Effects 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 102000020233 phosphotransferase Human genes 0.000 description 3
- 239000006187 pill Substances 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 230000011664 signaling Effects 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000007909 solid dosage form Substances 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 239000003765 sweetening agent Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- OEQJOYQHIGIVTN-UHFFFAOYSA-N tert-butyl nonanoate Chemical compound CCCCCCCCC(=O)OC(C)(C)C OEQJOYQHIGIVTN-UHFFFAOYSA-N 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 238000000844 transformation Methods 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- LOCRXNKSDRSSLC-YFKPBYRVSA-N (2S)-1-(4-nitropyrazol-1-yl)propan-2-ol Chemical compound N(=O)(=O)C1=CN(N=C1)C[C@H](C)O LOCRXNKSDRSSLC-YFKPBYRVSA-N 0.000 description 2
- RSQSEMKMQIULTM-RXMQYKEDSA-N (2r)-1-(4-aminopyrazol-1-yl)propan-2-ol Chemical compound C[C@@H](O)CN1C=C(N)C=N1 RSQSEMKMQIULTM-RXMQYKEDSA-N 0.000 description 2
- LOCRXNKSDRSSLC-RXMQYKEDSA-N (2r)-1-(4-nitropyrazol-1-yl)propan-2-ol Chemical compound C[C@@H](O)CN1C=C([N+]([O-])=O)C=N1 LOCRXNKSDRSSLC-RXMQYKEDSA-N 0.000 description 2
- 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 2
- RSQSEMKMQIULTM-YFKPBYRVSA-N (2s)-1-(4-aminopyrazol-1-yl)propan-2-ol Chemical compound C[C@H](O)CN1C=C(N)C=N1 RSQSEMKMQIULTM-YFKPBYRVSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- HEKOSZRTFFCROP-UHFFFAOYSA-N 1-propylpyrazol-4-amine;hydrochloride Chemical compound Cl.CCCN1C=C(N)C=N1 HEKOSZRTFFCROP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- SFYNEVYTYPHPBM-UHFFFAOYSA-N 3-(4-aminopyrazol-1-yl)propan-1-ol Chemical compound NC=1C=NN(CCCO)C=1 SFYNEVYTYPHPBM-UHFFFAOYSA-N 0.000 description 2
- NHCUMCWMHCBXRO-UHFFFAOYSA-N 4-nitro-1-propylpyrazole Chemical compound CCCN1C=C([N+]([O-])=O)C=N1 NHCUMCWMHCBXRO-UHFFFAOYSA-N 0.000 description 2
- LSLYOANBFKQKPT-DIFFPNOSSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-hydroxyphenyl)propan-2-yl]amino]ethyl]benzene-1,3-diol Chemical compound C([C@@H](C)NC[C@H](O)C=1C=C(O)C=C(O)C=1)C1=CC=C(O)C=C1 LSLYOANBFKQKPT-DIFFPNOSSA-N 0.000 description 2
- 102000001381 Arachidonate 5-Lipoxygenase Human genes 0.000 description 2
- 108010093579 Arachidonate 5-lipoxygenase Proteins 0.000 description 2
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
- 241000271566 Aves Species 0.000 description 2
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 102100029391 Cardiotrophin-like cytokine factor 1 Human genes 0.000 description 2
- 101710107109 Cardiotrophin-like cytokine factor 1 Proteins 0.000 description 2
- 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 2
- 206010010744 Conjunctivitis allergic Diseases 0.000 description 2
- 206010012442 Dermatitis contact Diseases 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 2
- 102000003837 Epithelial Sodium Channels Human genes 0.000 description 2
- 108090000140 Epithelial Sodium Channels Proteins 0.000 description 2
- 241000283086 Equidae Species 0.000 description 2
- 108010008165 Etanercept Proteins 0.000 description 2
- 241000206672 Gelidium Species 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
- 208000015023 Graves' disease Diseases 0.000 description 2
- 239000007821 HATU Substances 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 101000845170 Homo sapiens Thymic stromal lymphopoietin Proteins 0.000 description 2
- 206010021143 Hypoxia 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
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 102100030703 Interleukin-22 Human genes 0.000 description 2
- 108090000978 Interleukin-4 Proteins 0.000 description 2
- 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 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
- 102100027998 Macrophage metalloelastase Human genes 0.000 description 2
- 108010000684 Matrix Metalloproteinases Proteins 0.000 description 2
- 102000002274 Matrix Metalloproteinases Human genes 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 206010027982 Morphoea Diseases 0.000 description 2
- JAUOIFJMECXRGI-UHFFFAOYSA-N Neoclaritin Chemical compound C=1C(Cl)=CC=C2C=1CCC1=CC=CN=C1C2=C1CCNCC1 JAUOIFJMECXRGI-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 208000022873 Ocular disease Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 108091007960 PI3Ks Proteins 0.000 description 2
- 206010034277 Pemphigoid Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 102000003993 Phosphatidylinositol 3-kinases Human genes 0.000 description 2
- 108090000430 Phosphatidylinositol 3-kinases Proteins 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- 206010035226 Plasma cell myeloma Diseases 0.000 description 2
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 2
- 102000004005 Prostaglandin-endoperoxide synthases Human genes 0.000 description 2
- 108090000459 Prostaglandin-endoperoxide synthases Proteins 0.000 description 2
- 102000001253 Protein Kinase Human genes 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 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
- 102100031294 Thymic stromal lymphopoietin Human genes 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 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 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 229960001138 acetylsalicylic acid Drugs 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000003463 adsorbent Substances 0.000 description 2
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 208000002205 allergic conjunctivitis Diseases 0.000 description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 2
- 238000010976 amide bond formation reaction Methods 0.000 description 2
- 229940024606 amino acid Drugs 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 125000003277 amino group Chemical group 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000000065 atmospheric pressure chemical ionisation Methods 0.000 description 2
- 229960002170 azathioprine Drugs 0.000 description 2
- LMEKQMALGUDUQG-UHFFFAOYSA-N azathioprine Chemical compound CN1C=NC([N+]([O-])=O)=C1SC1=NC=NC2=C1NC=N2 LMEKQMALGUDUQG-UHFFFAOYSA-N 0.000 description 2
- 229960003270 belimumab Drugs 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-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
- 229940124748 beta 2 agonist Drugs 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
- 230000000975 bioactive effect Effects 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 235000019437 butane-1,3-diol Nutrition 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000036755 cellular response Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 229960001803 cetirizine Drugs 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 208000030949 chronic idiopathic urticaria Diseases 0.000 description 2
- 206010072757 chronic spontaneous urticaria Diseases 0.000 description 2
- 208000024376 chronic urticaria Diseases 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 229940110456 cocoa butter Drugs 0.000 description 2
- 235000019868 cocoa butter Nutrition 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000012084 conversion product Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 235000012343 cottonseed oil Nutrition 0.000 description 2
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 2
- 238000007405 data analysis Methods 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 230000003831 deregulation Effects 0.000 description 2
- 210000004207 dermis Anatomy 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 238000007876 drug discovery Methods 0.000 description 2
- 239000003974 emollient agent Substances 0.000 description 2
- 230000001804 emulsifying effect Effects 0.000 description 2
- 210000002615 epidermis Anatomy 0.000 description 2
- 229960000403 etanercept Drugs 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 2
- 229940093471 ethyl oleate Drugs 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 208000030533 eye disease Diseases 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 229960001022 fenoterol Drugs 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000005755 formation reaction Methods 0.000 description 2
- 229960002848 formoterol Drugs 0.000 description 2
- BPZSYCZIITTYBL-UHFFFAOYSA-N formoterol Chemical compound C1=CC(OC)=CC=C1CC(C)NCC(O)C1=CC=C(O)C(NC=O)=C1 BPZSYCZIITTYBL-UHFFFAOYSA-N 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 238000004108 freeze drying Methods 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 229960001340 histamine Drugs 0.000 description 2
- 239000003906 humectant Substances 0.000 description 2
- 229960000890 hydrocortisone Drugs 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 230000003301 hydrolyzing effect Effects 0.000 description 2
- 230000007954 hypoxia Effects 0.000 description 2
- 229960001680 ibuprofen Drugs 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 206010023332 keratitis Diseases 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000003199 leukotriene receptor blocking agent Substances 0.000 description 2
- 229960001508 levocetirizine Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 239000008297 liquid dosage form Substances 0.000 description 2
- 229960003088 loratadine Drugs 0.000 description 2
- 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 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- KBOPZPXVLCULAV-UHFFFAOYSA-N mesalamine Chemical compound NC1=CC=C(O)C(C(O)=O)=C1 KBOPZPXVLCULAV-UHFFFAOYSA-N 0.000 description 2
- 229960004963 mesalazine Drugs 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229960000485 methotrexate Drugs 0.000 description 2
- 239000004530 micro-emulsion Substances 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 229960005127 montelukast Drugs 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 239000003605 opacifier Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- WYWIFABBXFUGLM-UHFFFAOYSA-N oxymetazoline Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C)=C1CC1=NCCN1 WYWIFABBXFUGLM-UHFFFAOYSA-N 0.000 description 2
- 239000006072 paste Substances 0.000 description 2
- 239000002304 perfume Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 150000003904 phospholipids Chemical class 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 229960004618 prednisone Drugs 0.000 description 2
- 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 2
- 230000002265 prevention Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108060006633 protein kinase Proteins 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 229940044601 receptor agonist Drugs 0.000 description 2
- 239000000018 receptor agonist Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000012552 review Methods 0.000 description 2
- 229960002052 salbutamol Drugs 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229960004017 salmeterol Drugs 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 230000036303 septic shock Effects 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000008247 solid mixture Substances 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 210000000434 stratum corneum Anatomy 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 150000008163 sugars Chemical class 0.000 description 2
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 2
- 229960001940 sulfasalazine Drugs 0.000 description 2
- 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 2
- 230000001629 suppression Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 229960001967 tacrolimus Drugs 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
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 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
- 206010043778 thyroiditis Diseases 0.000 description 2
- 235000010487 tragacanth Nutrition 0.000 description 2
- 239000000196 tragacanth Substances 0.000 description 2
- 229940116362 tragacanth Drugs 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
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 229960004764 zafirlukast Drugs 0.000 description 2
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- ZYZHMSJNPCYUTB-CYBMUJFWSA-N (1r)-n-benzyl-1-phenylethanamine Chemical compound N([C@H](C)C=1C=CC=CC=1)CC1=CC=CC=C1 ZYZHMSJNPCYUTB-CYBMUJFWSA-N 0.000 description 1
- PNSLSBMUJBHQNO-OCAPTIKFSA-N (1s,5r)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane Chemical compound ClC1=NC=CC(N2C[C@H]3CC[C@H](N3)C2)=N1 PNSLSBMUJBHQNO-OCAPTIKFSA-N 0.000 description 1
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- LLPLFCXEXFQWGH-UHFFFAOYSA-N (9,9-dimethylbenzo[c]chromen-1-yl)-diphenylphosphane Chemical compound C1(=CC=CC=C1)P(C1=CC=CC=C1)C1=CC=CC2=C1C=1C(=CO2)C=CC(C=1)(C)C LLPLFCXEXFQWGH-UHFFFAOYSA-N 0.000 description 1
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 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
- 229940095131 (r)- propylene glycol Drugs 0.000 description 1
- 229960004463 (s)- propylene glycol Drugs 0.000 description 1
- 229940058015 1,3-butylene glycol Drugs 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
- PDNHLCRMUIGNBV-UHFFFAOYSA-N 1-pyridin-2-ylethanamine Chemical compound CC(N)C1=CC=CC=N1 PDNHLCRMUIGNBV-UHFFFAOYSA-N 0.000 description 1
- BTTNYQZNBZNDOR-UHFFFAOYSA-N 2,4-dichloropyrimidine Chemical compound ClC1=CC=NC(Cl)=N1 BTTNYQZNBZNDOR-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical group CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- TWBPWBPGNQWFSJ-UHFFFAOYSA-N 2-phenylaniline Chemical group NC1=CC=CC=C1C1=CC=CC=C1 TWBPWBPGNQWFSJ-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- VQMPBTACKKSVFG-UHFFFAOYSA-N 3-(4-nitropyrazol-1-yl)propan-1-ol Chemical compound OCCCN1C=C([N+]([O-])=O)C=N1 VQMPBTACKKSVFG-UHFFFAOYSA-N 0.000 description 1
- RQFUZUMFPRMVDX-UHFFFAOYSA-N 3-Bromo-1-propanol Chemical compound OCCCBr RQFUZUMFPRMVDX-UHFFFAOYSA-N 0.000 description 1
- ALKYHXVLJMQRLQ-UHFFFAOYSA-M 3-carboxynaphthalen-2-olate Chemical compound C1=CC=C2C=C(C([O-])=O)C(O)=CC2=C1 ALKYHXVLJMQRLQ-UHFFFAOYSA-M 0.000 description 1
- LKDMKWNDBAVNQZ-UHFFFAOYSA-N 4-[[1-[[1-[2-[[1-(4-nitroanilino)-1-oxo-3-phenylpropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)NC(C)C(=O)NC(C)C(=O)N1CCCC1C(=O)NC(C(=O)NC=1C=CC(=CC=1)[N+]([O-])=O)CC1=CC=CC=C1 LKDMKWNDBAVNQZ-UHFFFAOYSA-N 0.000 description 1
- 102000004023 5-Lipoxygenase-Activating Proteins Human genes 0.000 description 1
- 108090000411 5-Lipoxygenase-Activating Proteins Proteins 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 206010000748 Acute febrile neutrophilic dermatosis Diseases 0.000 description 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 1
- 208000000884 Airway Obstruction Diseases 0.000 description 1
- 239000012114 Alexa Fluor 647 Substances 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 241000272517 Anseriformes Species 0.000 description 1
- 235000003276 Apios tuberosa Nutrition 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000010777 Arachis hypogaea Nutrition 0.000 description 1
- 235000010744 Arachis villosulicarpa Nutrition 0.000 description 1
- 206010003402 Arthropod sting Diseases 0.000 description 1
- 208000004300 Atrophic Gastritis Diseases 0.000 description 1
- 206010050245 Autoimmune thrombocytopenia Diseases 0.000 description 1
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 description 1
- 208000027496 Behcet disease Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 208000003014 Bites and Stings Diseases 0.000 description 1
- 206010005949 Bone cancer Diseases 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 208000018084 Bone neoplasm Diseases 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-AHCXROLUSA-N Bromine-79 Chemical compound [76Br] WKBOTKDWSSQWDR-AHCXROLUSA-N 0.000 description 1
- 102100021935 C-C motif chemokine 26 Human genes 0.000 description 1
- 102100036166 C-X-C chemokine receptor type 1 Human genes 0.000 description 1
- 102000017925 CHRM3 Human genes 0.000 description 1
- 101150060249 CHRM3 gene Proteins 0.000 description 1
- LERNTVKEWCAPOY-VOGVJGKGSA-N C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 Chemical compound C[N+]1(C)[C@H]2C[C@H](C[C@@H]1[C@H]1O[C@@H]21)OC(=O)C(O)(c1cccs1)c1cccs1 LERNTVKEWCAPOY-VOGVJGKGSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 102100028892 Cardiotrophin-1 Human genes 0.000 description 1
- 102000004173 Cathepsin G Human genes 0.000 description 1
- 108090000617 Cathepsin G Proteins 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 239000004381 Choline salt Substances 0.000 description 1
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 description 1
- 102100024539 Chymase Human genes 0.000 description 1
- 108090000227 Chymases Proteins 0.000 description 1
- LUKZNWIVRBCLON-GXOBDPJESA-N Ciclesonide Chemical compound C1([C@H]2O[C@@]3([C@H](O2)C[C@@H]2[C@@]3(C[C@H](O)[C@@H]3[C@@]4(C)C=CC(=O)C=C4CC[C@H]32)C)C(=O)COC(=O)C(C)C)CCCCC1 LUKZNWIVRBCLON-GXOBDPJESA-N 0.000 description 1
- 108010005939 Ciliary Neurotrophic Factor Proteins 0.000 description 1
- 102100031614 Ciliary neurotrophic factor Human genes 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 208000010007 Cogan syndrome Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 241000699800 Cricetinae Species 0.000 description 1
- 229930105110 Cyclosporin A Natural products 0.000 description 1
- 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 1
- 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 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
- 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 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
- 206010012434 Dermatitis allergic Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 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
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 102000004980 Dopamine D2 Receptors Human genes 0.000 description 1
- 108090001111 Dopamine D2 Receptors Proteins 0.000 description 1
- 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 1
- 206010014201 Eczema nummular Diseases 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 206010014989 Epidermolysis bullosa Diseases 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 206010015278 Erythrodermic psoriasis Diseases 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102100028314 Filaggrin Human genes 0.000 description 1
- 101710088660 Filaggrin Proteins 0.000 description 1
- 239000004606 Fillers/Extenders Substances 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 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
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 208000036495 Gastritis atrophic Diseases 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 241000699694 Gerbillinae Species 0.000 description 1
- 102100031181 Glyceraldehyde-3-phosphate dehydrogenase Human genes 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Polymers OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 1
- 206010018498 Goitre Diseases 0.000 description 1
- 208000024869 Goodpasture syndrome Diseases 0.000 description 1
- 208000009329 Graft vs Host Disease Diseases 0.000 description 1
- 108010017080 Granulocyte Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 206010058898 Hand dermatitis Diseases 0.000 description 1
- 208000030836 Hashimoto thyroiditis Diseases 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 1
- 208000005100 Herpetic Keratitis Diseases 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 229940122236 Histamine receptor antagonist Drugs 0.000 description 1
- 101000897493 Homo sapiens C-C motif chemokine 26 Proteins 0.000 description 1
- 101000577881 Homo sapiens Macrophage metalloelastase Proteins 0.000 description 1
- 101001059454 Homo sapiens Serine/threonine-protein kinase MARK2 Proteins 0.000 description 1
- 101000669447 Homo sapiens Toll-like receptor 4 Proteins 0.000 description 1
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 208000008454 Hyperhidrosis Diseases 0.000 description 1
- 239000003458 I kappa b kinase inhibitor Substances 0.000 description 1
- 108091069211 IL-3 family Proteins 0.000 description 1
- 102000039992 IL-3 family Human genes 0.000 description 1
- 229940127590 IRAK4 inhibitor Drugs 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
- 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 1
- 108010008212 Integrin alpha4beta1 Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 108090000177 Interleukin-11 Proteins 0.000 description 1
- 102000013462 Interleukin-12 Human genes 0.000 description 1
- 108010065805 Interleukin-12 Proteins 0.000 description 1
- 108090000176 Interleukin-13 Proteins 0.000 description 1
- 108090000172 Interleukin-15 Proteins 0.000 description 1
- 108050009288 Interleukin-19 Proteins 0.000 description 1
- 102000013264 Interleukin-23 Human genes 0.000 description 1
- 108010065637 Interleukin-23 Proteins 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 108010067003 Interleukin-33 Proteins 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- 108010018976 Interleukin-8A Receptors Proteins 0.000 description 1
- 108010018951 Interleukin-8B Receptors Proteins 0.000 description 1
- 102000002791 Interleukin-8B Receptors Human genes 0.000 description 1
- 108010002335 Interleukin-9 Proteins 0.000 description 1
- 206010022941 Iridocyclitis Diseases 0.000 description 1
- 208000007766 Kaposi sarcoma Diseases 0.000 description 1
- 208000002260 Keloid Diseases 0.000 description 1
- 206010023330 Keloid scar Diseases 0.000 description 1
- 208000009319 Keratoconjunctivitis Sicca Diseases 0.000 description 1
- 201000002287 Keratoconus Diseases 0.000 description 1
- 206010066295 Keratosis pilaris Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 102000002397 Kinins Human genes 0.000 description 1
- 108010093008 Kinins Proteins 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical class NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 102000016267 Leptin Human genes 0.000 description 1
- 108010092277 Leptin Proteins 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 108090000581 Leukemia inhibitory factor Proteins 0.000 description 1
- 206010024434 Lichen sclerosus Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 101710187853 Macrophage metalloelastase Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 240000003183 Manihot esculenta Species 0.000 description 1
- 235000016735 Manihot esculenta subsp esculenta Nutrition 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 1
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 1
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 1
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 208000024599 Mooren ulcer Diseases 0.000 description 1
- 208000026072 Motor neurone disease Diseases 0.000 description 1
- 208000034578 Multiple myelomas Diseases 0.000 description 1
- 229940122694 Muscarinic M3 receptor antagonist Drugs 0.000 description 1
- 208000002231 Muscle Neoplasms Diseases 0.000 description 1
- 241000282339 Mustela Species 0.000 description 1
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 description 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 1
- 208000014767 Myeloproliferative disease Diseases 0.000 description 1
- GXCLVBGFBYZDAG-UHFFFAOYSA-N N-[2-(1H-indol-3-yl)ethyl]-N-methylprop-2-en-1-amine Chemical compound CN(CCC1=CNC2=C1C=CC=C2)CC=C GXCLVBGFBYZDAG-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical class CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010028703 Nail psoriasis Diseases 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 208000007256 Nevus Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 239000006057 Non-nutritive feed additive Substances 0.000 description 1
- 208000027771 Obstructive airways disease 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
- 108090000630 Oncostatin M Proteins 0.000 description 1
- 206010073938 Ophthalmic herpes simplex Diseases 0.000 description 1
- 241001420836 Ophthalmitis Species 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 241000283903 Ovis aries Species 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 102100028045 P2Y purinoceptor 2 Human genes 0.000 description 1
- 101710096700 P2Y purinoceptor 2 Proteins 0.000 description 1
- 102000016387 Pancreatic elastase Human genes 0.000 description 1
- 108010067372 Pancreatic elastase Proteins 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 208000009675 Perioral Dermatitis Diseases 0.000 description 1
- 208000031845 Pernicious anaemia Diseases 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 229940123263 Phosphodiesterase 3 inhibitor Drugs 0.000 description 1
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 1
- 229940123333 Phosphodiesterase 5 inhibitor Drugs 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000101040 Pityriasis Species 0.000 description 1
- 208000021738 Plummer disease Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004952 Polyamide Substances 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
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 229920002675 Polyoxyl Polymers 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 206010036229 Post inflammatory pigmentation change Diseases 0.000 description 1
- 206010036774 Proctitis Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 108050000258 Prostaglandin D receptors Proteins 0.000 description 1
- 102100024218 Prostaglandin D2 receptor 2 Human genes 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- GOOHAUXETOMSMM-GSVOUGTGSA-N R-propylene oxide Chemical compound C[C@@H]1CO1 GOOHAUXETOMSMM-GSVOUGTGSA-N 0.000 description 1
- 238000002123 RNA extraction Methods 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 208000033464 Reiter syndrome Diseases 0.000 description 1
- 206010063897 Renal ischaemia Diseases 0.000 description 1
- 235000004443 Ricinus communis Nutrition 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 241001303601 Rosacea Species 0.000 description 1
- GOOHAUXETOMSMM-VKHMYHEASA-N S-propylene oxide Chemical compound C[C@H]1CO1 GOOHAUXETOMSMM-VKHMYHEASA-N 0.000 description 1
- 108010017324 STAT3 Transcription Factor Proteins 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 206010039705 Scleritis Diseases 0.000 description 1
- 206010039793 Seborrhoeic dermatitis Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 102100028904 Serine/threonine-protein kinase MARK2 Human genes 0.000 description 1
- 102100024040 Signal transducer and activator of transcription 3 Human genes 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- 206010041955 Stasis dermatitis Diseases 0.000 description 1
- SSZBUIDZHHWXNJ-UHFFFAOYSA-N Stearinsaeure-hexadecylester Natural products CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCCCC SSZBUIDZHHWXNJ-UHFFFAOYSA-N 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
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000010265 Sweet syndrome Diseases 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 102000003141 Tachykinin Human genes 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 1
- JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- 101710195626 Transcriptional activator protein Proteins 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 206010064996 Ulcerative keratitis Diseases 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 206010046751 Urticaria physical Diseases 0.000 description 1
- 208000001445 Uveomeningoencephalitic Syndrome Diseases 0.000 description 1
- SECKRCOLJRRGGV-UHFFFAOYSA-N Vardenafil Chemical compound CCCC1=NC(C)=C(C(N=2)=O)N1NC=2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(CC)CC1 SECKRCOLJRRGGV-UHFFFAOYSA-N 0.000 description 1
- 208000034705 Vogt-Koyanagi-Harada syndrome Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000016807 X-linked intellectual disability-macrocephaly-macroorchidism syndrome Diseases 0.000 description 1
- 206010048222 Xerosis Diseases 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
- 239000001089 [(2R)-oxolan-2-yl]methanol Substances 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000037374 absorbed through the skin Effects 0.000 description 1
- 229940124532 absorption promoter Drugs 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 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
- 150000007960 acetonitrile Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000003449 adenosine A2 receptor antagonist Substances 0.000 description 1
- 239000002465 adenosine A2a receptor agonist Substances 0.000 description 1
- 239000002318 adhesion promoter Substances 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 description 1
- 239000000533 adrenergic alpha-1 receptor agonist Substances 0.000 description 1
- 239000000384 adrenergic alpha-2 receptor agonist Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000036428 airway hyperreactivity Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 208000002029 allergic contact dermatitis Diseases 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 201000004612 anterior uveitis Diseases 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003434 antitussive agent Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000000637 arginyl group Chemical class N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 238000007080 aromatic substitution reaction Methods 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 208000024998 atopic conjunctivitis Diseases 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 210000003719 b-lymphocyte Anatomy 0.000 description 1
- 229940092705 beclomethasone Drugs 0.000 description 1
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- JUHORIMYRDESRB-UHFFFAOYSA-N benzathine Chemical class 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
- 229940050390 benzoate Drugs 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 229960000397 bevacizumab Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 239000012267 brine Substances 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
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000012512 bulk drug substance Substances 0.000 description 1
- 208000000594 bullous pemphigoid Diseases 0.000 description 1
- DLDJFQGPPSQZKI-UHFFFAOYSA-N but-2-yne-1,4-diol Chemical compound OCC#CCO DLDJFQGPPSQZKI-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 235000012241 calcium silicate 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
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 108010041776 cardiotrophin 1 Proteins 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 239000004359 castor oil Substances 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
- 230000024245 cell differentiation Effects 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000009087 cell motility Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 230000008859 change Effects 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
- 235000013330 chicken meat Nutrition 0.000 description 1
- VEXZGXHMUGYJMC-IGMARMGPSA-N chlorine-35 Chemical compound [35ClH] VEXZGXHMUGYJMC-IGMARMGPSA-N 0.000 description 1
- 229960004926 chlorobutanol Drugs 0.000 description 1
- 150000005827 chlorofluoro hydrocarbons Chemical class 0.000 description 1
- 235000019417 choline salt Nutrition 0.000 description 1
- 238000013375 chromatographic separation Methods 0.000 description 1
- 208000016644 chronic atrophic gastritis Diseases 0.000 description 1
- 229960003728 ciclesonide Drugs 0.000 description 1
- 229950001653 cilomilast Drugs 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 230000002508 compound effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 208000010247 contact dermatitis Diseases 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 210000004087 cornea Anatomy 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000007822 coupling agent Substances 0.000 description 1
- 229960000265 cromoglicic acid Drugs 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 208000004921 cutaneous lupus erythematosus Diseases 0.000 description 1
- 229940109275 cyclamate Drugs 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 108010057085 cytokine receptors Proteins 0.000 description 1
- 102000003675 cytokine receptors Human genes 0.000 description 1
- 230000010250 cytokine signaling pathway Effects 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 230000020335 dealkylation Effects 0.000 description 1
- 238000006900 dealkylation reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229960001271 desloratadine Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 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
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical class OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 150000005332 diethylamines Chemical class 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- VLARUOGDXDTHEH-UHFFFAOYSA-L disodium cromoglycate Chemical compound [Na+].[Na+].O1C(C([O-])=O)=CC(=O)C2=C1C=CC=C2OCC(O)COC1=CC=CC2=C1C(=O)C=C(C([O-])=O)O2 VLARUOGDXDTHEH-UHFFFAOYSA-L 0.000 description 1
- 239000003136 dopamine receptor stimulating agent Substances 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000008387 emulsifying waxe Substances 0.000 description 1
- 201000002491 encephalomyelitis Diseases 0.000 description 1
- 208000030172 endocrine system disease Diseases 0.000 description 1
- 206010014801 endophthalmitis Diseases 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 201000001564 eosinophilic gastroenteritis Diseases 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-L ethane-1,2-disulfonate Chemical compound [O-]S(=O)(=O)CCS([O-])(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-L 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 229940093476 ethylene glycol Drugs 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 210000003414 extremity Anatomy 0.000 description 1
- 208000024711 extrinsic asthma Diseases 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 229960002714 fluticasone Drugs 0.000 description 1
- MGNNYOODZCAHBA-GQKYHHCASA-N fluticasone Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(O)[C@@]2(C)C[C@@H]1O MGNNYOODZCAHBA-GQKYHHCASA-N 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 108020004445 glyceraldehyde-3-phosphate dehydrogenase Proteins 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
- 150000002332 glycine derivatives Chemical class 0.000 description 1
- 201000003872 goiter Diseases 0.000 description 1
- 208000024908 graft versus host disease Diseases 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 210000002216 heart Anatomy 0.000 description 1
- 210000002443 helper t lymphocyte Anatomy 0.000 description 1
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 229960001008 heparin sodium Drugs 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 201000010884 herpes simplex virus keratitis Diseases 0.000 description 1
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 239000003276 histone deacetylase inhibitor Substances 0.000 description 1
- 102000057041 human TNF Human genes 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000037315 hyperhidrosis Effects 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 229960002491 ibudilast Drugs 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 230000005965 immune activity Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 208000030603 inherited susceptibility to asthma Diseases 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 229960001388 interferon-beta Drugs 0.000 description 1
- 108090000681 interleukin 20 Proteins 0.000 description 1
- 108010074108 interleukin-21 Proteins 0.000 description 1
- 108010074109 interleukin-22 Proteins 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 201000010659 intrinsic asthma Diseases 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 229960001361 ipratropium bromide Drugs 0.000 description 1
- KEWHKYJURDBRMN-ZEODDXGYSA-M ipratropium bromide hydrate Chemical compound O.[Br-].O([C@H]1C[C@H]2CC[C@@H](C1)[N@@+]2(C)C(C)C)C(=O)C(CO)C1=CC=CC=C1 KEWHKYJURDBRMN-ZEODDXGYSA-M 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 208000001875 irritant dermatitis Diseases 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 210000004153 islets of langerhan Anatomy 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 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 1
- 210000001117 keloid Anatomy 0.000 description 1
- 230000003780 keratinization Effects 0.000 description 1
- 201000010666 keratoconjunctivitis Diseases 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- NRYBAZVQPHGZNS-ZSOCWYAHSA-N leptin Chemical compound O=C([C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(C)C)CCSC)N1CCC[C@H]1C(=O)NCC(=O)N[C@@H](CS)C(O)=O NRYBAZVQPHGZNS-ZSOCWYAHSA-N 0.000 description 1
- 229940039781 leptin Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 208000002741 leukoplakia Diseases 0.000 description 1
- 108010052322 limitin Proteins 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 229940127212 long-acting beta 2 agonist Drugs 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229940049920 malate Drugs 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
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 201000006512 mast cell neoplasm Diseases 0.000 description 1
- 208000008585 mastocytosis Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 201000008350 membranous glomerulonephritis Diseases 0.000 description 1
- 229960005108 mepolizumab Drugs 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 208000021039 metastatic melanoma Diseases 0.000 description 1
- HNJJXZKZRAWDPF-UHFFFAOYSA-N methapyrilene Chemical compound C=1C=CC=NC=1N(CCN(C)C)CC1=CC=CS1 HNJJXZKZRAWDPF-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000006082 mold release agent Substances 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 229960001664 mometasone Drugs 0.000 description 1
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- 230000000510 mucolytic effect Effects 0.000 description 1
- 229940066491 mucolytics Drugs 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 239000003681 muscarinic M3 receptor antagonist Substances 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 210000003098 myoblast Anatomy 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- PVWOIHVRPOBWPI-UHFFFAOYSA-N n-propyl iodide Chemical compound CCCI PVWOIHVRPOBWPI-UHFFFAOYSA-N 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 210000000581 natural killer T-cell Anatomy 0.000 description 1
- 229960004398 nedocromil Drugs 0.000 description 1
- RQTOOFIXOKYGAN-UHFFFAOYSA-N nedocromil Chemical compound CCN1C(C(O)=O)=CC(=O)C2=C1C(CCC)=C1OC(C(O)=O)=CC(=O)C1=C2 RQTOOFIXOKYGAN-UHFFFAOYSA-N 0.000 description 1
- 229960002259 nedocromil sodium Drugs 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 239000012740 non-selective inhibitor Substances 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OIPZNTLJVJGRCI-UHFFFAOYSA-M octadecanoyloxyaluminum;dihydrate Chemical compound O.O.CCCCCCCCCCCCCCCCCC(=O)O[Al] OIPZNTLJVJGRCI-UHFFFAOYSA-M 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229940055577 oleyl alcohol Drugs 0.000 description 1
- XMLQWXUVTXCDDL-UHFFFAOYSA-N oleyl alcohol Natural products CCCCCCC=CCCCCCCCCCCO XMLQWXUVTXCDDL-UHFFFAOYSA-N 0.000 description 1
- 229960000470 omalizumab Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000000668 oral spray Substances 0.000 description 1
- 229940041678 oral spray Drugs 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229960001528 oxymetazoline Drugs 0.000 description 1
- 239000005022 packaging material Substances 0.000 description 1
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 1
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 208000010403 panophthalmitis Diseases 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 208000015385 phacoanaphylactic uveitis Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229960003742 phenol Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
- 229960001802 phenylephrine Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 239000002570 phosphodiesterase III inhibitor Substances 0.000 description 1
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 1
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 238000003566 phosphorylation assay Methods 0.000 description 1
- 201000002881 physical urticaria Diseases 0.000 description 1
- 239000002797 plasminogen activator inhibitor Substances 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 238000002600 positron emission tomography Methods 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 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
- 230000008569 process Effects 0.000 description 1
- 201000007914 proliferative diabetic retinopathy Diseases 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- BHMBVRSPMRCCGG-OUTUXVNYSA-N prostaglandin D2 Chemical compound CCCCC[C@H](O)\C=C\[C@@H]1[C@@H](C\C=C/CCCC(O)=O)[C@@H](O)CC1=O BHMBVRSPMRCCGG-OUTUXVNYSA-N 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 229940043131 pyroglutamate Drugs 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 229960003876 ranibizumab Drugs 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 102000000568 rho-Associated Kinases Human genes 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
- UHSKFQJFRQCDBE-UHFFFAOYSA-N ropinirole Chemical compound CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 description 1
- 229960001879 ropinirole Drugs 0.000 description 1
- 201000004700 rosacea Diseases 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000009738 saturating Methods 0.000 description 1
- 230000037390 scarring Effects 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
- 208000008742 seborrheic dermatitis Diseases 0.000 description 1
- 201000008628 secondary progressive multiple sclerosis Diseases 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229910052708 sodium Inorganic materials 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
- 239000011780 sodium chloride Substances 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
- 229910001415 sodium ion Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000010922 spray-dried dispersion Methods 0.000 description 1
- 206010041823 squamous cell carcinoma Diseases 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000003206 sterilizing agent Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000004808 supercritical fluid chromatography Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 210000000106 sweat gland Anatomy 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 108060008037 tachykinin Proteins 0.000 description 1
- 229960000835 tadalafil Drugs 0.000 description 1
- IEHKWSGCTWLXFU-IIBYNOLFSA-N tadalafil Chemical compound C1=C2OCOC2=CC([C@@H]2C3=C([C]4C=CC=CC4=N3)C[C@H]3N2C(=O)CN(C3=O)C)=C1 IEHKWSGCTWLXFU-IIBYNOLFSA-N 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- OECIBZZKIXVOKZ-PHIMTYICSA-N tert-butyl (1r,5s)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Chemical compound C([C@H]1CC[C@@H](C2)N1C(=O)OC(C)(C)C)N2C1=CC=NC(Cl)=N1 OECIBZZKIXVOKZ-PHIMTYICSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- RZWIIPASKMUIAC-VQTJNVASSA-N thromboxane Chemical compound CCCCCCCC[C@H]1OCCC[C@@H]1CCCCCCC RZWIIPASKMUIAC-VQTJNVASSA-N 0.000 description 1
- ATJFFYVFTNAWJD-OUBTZVSYSA-N tin-120 atom Chemical compound [120Sn] ATJFFYVFTNAWJD-OUBTZVSYSA-N 0.000 description 1
- 229960000257 tiotropium bromide Drugs 0.000 description 1
- 229960005371 tolbutamide Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000008736 traumatic injury Effects 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
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 1
- 229960001661 ursodiol Drugs 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 238000005292 vacuum distillation Methods 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
- 229960002381 vardenafil Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 201000005539 vernal conjunctivitis Diseases 0.000 description 1
- 208000010484 vulvovaginitis Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical group CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 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
- 150000003751 zinc Chemical class 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/18—Bridged systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
式I化合物或其药学上可接受的盐,其中R1和R2各自独立地为氢或羟基;其中R1和R2不都为羟基。本发明亦提供作为Janus激酶抑制剂的治疗方法及含有本发明化合物的药物组合物以及其与其他治疗剂的组合。
Description
技术领域
本发明提供药学上活性的氨基嘧啶基配体(ligand)及类似物。此类化合物有用于抑制Janus激酶(JAK)。此发明亦针对包含所述化合物的组合物、制备所述化合物的方法,以及用于治疗和预防由JAK、且特别是由TYK2/JAK1介导之病症(condition)的方法。
背景技术
蛋白质激酶是催化蛋白质中之特定残基的磷酸化的酶的家族,大致分类为酪氨酸和丝氨酸/苏氨酸激酶。因突变、过度表达、或不适当调节、不良调节或去调节,以及生长因子或细胞因子的过度或不足产生所引起的不适当的激酶活性已牵涉许多疾病,包括但不限于癌症、心血管疾病、过敏、哮喘及其他呼吸疾病、自体免疫性疾病、炎性疾病、骨疾病、代谢紊乱、以及神经和神经退化紊乱,如阿尔茨海默病(Alzheimer’s disease)。不适当的激酶活性引发各种与前述及相关疾病牵涉的细胞生长、细胞分化、细胞功能、存活、细胞凋亡和细胞运动性相关的生物细胞反应(biological cellular response)。
因此,蛋白质激酶已成为一类作为标靶用于治疗性干预(therapeuticintervention)的重要酶。特别是,细胞蛋白质酪氨酸激酶之JAK家族(JAK1、JAK2、JAK3和TYK2)在细胞因子信号传导(signaling)中扮演中心角色(Kisseleva et al.,Gene,2002,285,1;Yamaoka et al.Genome Biology 2004,5,253)。在结合到他们的受体后,细胞因子活化JAK,然后JAK磷酸化细胞因子受体,从而创造信号分子(特别是最终导致基因表达的信号转导因子和转录活化蛋白(STAT)家族的成员)的停泊位点。已知许多细胞因子会活化JAK家族。这些细胞因子包括干扰素(IFN)家族(IFN-α、IFN-β、IFN-ω、限制素(Limitin)、IFN-γ、IL-10、IL-19、IL-20、IL-22)、gp130家族(IL-6、IL-11、OSM、LIF、CNTF、NNT-1/BSF-3、G-CSF、CT-1、瘦素、IL-12、IL-23)、伽马C家族(IL-2、IL-7、TSLP、IL-9、IL-15、IL-21、IL-4、IL-13)、IL-3家族(IL-3、IL-5、GM-CSF)、单链家族(EPO、GH、PRL、TPO)、受体酪氨酸激酶(EGF、PDGF、CSF-1、HGF)、及G-蛋白偶合受体(AT1)。
仍然需要有效且选择性地抑制特定JAK酶的新化合物。已显示JAK酶在炎性疾病和自体免疫性疾病中重要的多种细胞类型的分化和功能中是重要的,包括自然杀伤细胞、B细胞和辅助性T细胞(T helper cell)类型。异常JAK表达与多种自体免疫性或炎性病症相关联。通过抑制JAK1激酶活性调节免疫活性可以在各种免疫紊乱的治疗中证明是有用的(O’Shea JJ,Plenge R,Immunity,36,542-50(2012);Murray,P.J.,J.Immunol.,178,2623-2629(2007);Kisseleva,T.,et al.,Gene,285,1-24(2002))。
本技术领域已知的JAK抑制剂常常具有使得他们通常更适合口服给药而较不适合局部给药的性质。据此,本发明提供新JAK抑制剂,他们既是有效的JAK抑制剂,特别是TYK2/JAK1抑制剂,而且在人类肝细胞中也展现高清除率,因此提供显著改善的全身清除率,从而降低局部给药时的不良副作用的风险,并同时在皮肤中保有效力(efficacy)。
发明内容
本发明提供一种具有式I结构的化合物或其药学上可接受的盐,
其中R1和R2各自独立地为氢或羟基;其中R1和R2不都为羟基。
在其他面上,本发明亦提供:包含药学上可接受的载剂及式I化合物或其药学上可接受的盐的药物组合物。
在其他面上,本发明亦提供治疗包括下列病症或紊乱的方法,
关节炎,包括类风湿关节炎、幼年型关节炎、及银屑病关节炎;
自体免疫性或炎性疾病或紊乱,包括桥本(Hashimoto’s)甲状腺炎、自体免疫性溶血性贫血、恶性贫血的自体免疫性萎缩性胃炎、自体免疫性脑脊髓炎、自体免疫性睪丸炎、Goodpasture病、自体免疫性血小板减少症、交感性眼炎、重症肌无力、毒性弥漫性甲状腺肿(Graves’disease)、原发性胆汁性肝硬化、自体免疫性肝炎、原发性硬化性胆管炎、慢性侵袭性肝炎、非酒精性脂肪肝病、非酒精性脂肪性肝炎、溃疡性结肠炎和膜性肾小球肾病、全身性红斑狼疮、类风湿关节炎、银屑病关节炎、Sjogren综合征、Reiter综合征、多肌炎、皮肌炎、I型干扰素病,包括Aicardi-Goutières综合征和其他过度表达I型干扰素的孟德尔疾病(mendelian diseases)、全身性硬化、结节性多动脉炎、多发性硬化、复发性缓解型多发性硬化、原发性进行性多发性硬化、次发性进行性多发性硬化、及大疱性类天疱疮、以及额外的自体免疫性疾病,其可以是基于O形细胞(体液性)或基于T细胞者,包括Cogan综合征、强直性脊柱炎、Wegener肉芽肿病、自体免疫性脱发、I型或青少年发病型糖尿病、或甲状腺炎;
癌症或肿瘤,包括消化道/胃肠道癌、结肠癌、肝癌、皮肤癌(包括肥大细胞肿瘤和鳞状细胞癌)、乳癌和乳腺癌、卵巢癌、前列腺癌、淋巴瘤、白血病(包括急性骨髓性白血病和慢性骨髓性白血病)、肾癌、肺癌、肌肉癌、骨癌、膀胱癌、脑癌、黑色素瘤(包括口及转移性黑色素瘤)、卡波西肉瘤、骨髓瘤(包括多发性骨髓瘤)、骨髓增生性紊乱、增生性糖尿病视网膜病变、或血管生成相关紊乱,包括实体肿瘤;
糖尿病,包括I型糖尿病或来自糖尿病的并发症;
眼疾病、紊乱或病症,包括眼的自体免疫性疾病、角膜结膜炎、春季结膜炎、葡萄膜炎(包括与Behcet病相关的葡萄膜炎和镜片引起的葡萄膜炎)、角膜炎、疱疹性角膜炎、圆锥形角膜炎、角膜上皮营养不良、角膜白斑、眼天疱疮、蚕蚀性角膜溃疡(Mooren's ulcer)、巩膜炎、格雷夫眼病、伏格特-小柳-原田综合征(Vogt-Koyanagi-Harada syndrome)、干燥性角结膜炎(干眼)、小水疱(phlyctenule)、虹膜睫状体炎、结节病、内分泌性眼病、交感性眼炎、过敏性结膜炎、或眼部新生血管;
肠炎症,包括克罗恩病(Crohn’s disease)、溃疡性结肠炎、炎性肠病、腹腔疾病、直肠炎、嗜酸性胃肠炎、或肥大细胞增多症;
神经退化疾病,包括运动神经元病、阿尔茨海默病、帕金森病、肌萎缩性侧索硬化、亨廷顿病、脑缺血、或由跌打损伤、敲击(strike)、谷氨酸神经毒性或缺氧导致的神经退化疾病;中风、心肌缺血、肾缺血、心脏发作、心脏肥大、动脉粥样硬化及动脉硬化中的缺血/再灌注损伤、器官缺氧、或血小板聚集;
皮肤疾病、病症或紊乱、包括特应性皮炎、手部皮炎、接触性皮炎、过敏性接触性皮炎、刺激性接触性皮炎、神经性皮炎、口周皮炎、郁血性皮炎、多汗性湿疹、干燥性皮炎、钱币状皮炎(nummular dermatitis)、脂溢性皮炎、眼睑皮炎、尿布皮炎、皮肌炎、扁平苔藓、硬化性苔藓、斑秃、白癜风、酒渣鼻、大疱性表皮松解症、毛角化病、白色糠疹、天疱疮、外阴阴道炎、痤疮、慢性自发性荨麻疹、慢性特发性荨麻疹、慢性身体性荨麻疹、伏格特-小柳-原田病、萨顿痣/母斑、发炎后色素过少症、老年性白斑病、化学/药物引起的白斑病、皮肤红斑狼疮、盘状狼疮、瘑疮、类天疱疮、Sweet综合征、化脓性汗腺炎、银屑病、斑块状银屑病、脓疱性银屑病、指甲银屑病、屈侧型银屑病、滴状银屑病、银屑病关节炎、红皮病性银屑病或反转型银屑病;
过敏反应,包括哺乳动物的过敏性皮炎(包括马过敏性疾病,如叮咬超敏反应)、夏季湿疹、马的甜痒病、肺气肿、炎性气道疾病、复发性气道阻塞、气道高反应性、或慢性阻塞性肺病;
哮喘及其他气道阻塞性疾病,包括慢性或顽固性哮喘、晚期哮喘、支气管炎、支气管哮喘、过敏性哮喘、内源性哮喘、外源性哮喘、或粉尘哮喘;以及
移植排斥,包括胰岛移植排斥、骨髓移植排斥、移植物抗宿主病、器官及细胞移植排斥,例如骨髓、软骨、角膜、心脏、椎间盘、胰岛、肾、肢、肝、肺、肌、成肌细胞、神经、胰腺、皮肤、小肠、或气管、或异种移植。
本发明将自仅通过举例方式给出的下文描述得以进一步理解。本发明是针对一类氨基嘧啶基衍生物。特别是,本发明是针对有用于作为JAK之抑制剂的氨基嘧啶基化合物。虽然本发明并不如此受到限制,但本发明的各种面向的理解将通过以下讨论和实例来获得。
术语“经分离”和“呈经分离形式”意指化合物或其盐,对于化合物而言,该术语是指从合成程序例如从反应混合物中分离后的化合物物理状态。因此,对于化合物而言,术语“经分离”和“呈经分离形式”是指从本文所述的或本领域技术人员熟知的一或多种纯化程序(例如,色谱法、再结晶等)获得后的化合物物理状态,有足够的纯度而可通过本文所述或本领域技术人员熟知的标准分析技术示性。例如,本文揭示的纯化技术(例如,LC-MS和LC-MS/MS技术)得到经分离形式的对象化合物。预期此等分离和纯化技术将得到含有以重量计至少约70%、至少约80%、至少约90%、至少约95%、至少约97%或至少约99%的化合物或其盐的产品纯度。
术语“对象”是指哺乳动物,例如人类、家畜或伴侣动物。可互换使用的“患者”、“个体”或“对象”是哺乳动物,更优选是人类。
术语“伴侣动物(companion animal或companion animals)”是指作为宠物或家庭动物饲养的动物。伴侣动物的实例包括狗、猫及啮齿动物(包括仓鼠、豚鼠、沙鼠等)、兔、雪貂和鸟类。
术语“家畜(livestock)”指在农业环境中养殖或饲养以制作产品,诸如食品或纤维,或获得其劳力的动物。在一些实施方案中,家畜适合于由哺乳动物,例如人类消费。家畜动物的实例包括牛、山羊、马、猪、绵羊(包括羊羔)、和兔、以及鸟类,如鸡、鸭及火鸡。
除非本文另有定义,否则与本发明有关的科学和技术术语具有本领域技术人员通常理解的含义。
如果取代基被描述为“独立地选自”一组时,各取代基彼此独立地选择。因此各取代基可与其他一或多个取代基相同或不同。
除非另有指明,否则如本文所用的术语“治疗(treating)”意指逆转(reversing)、减轻(alleviating)、抑制其进展、推迟(delaying)对其应用该术语的紊乱或病症,或一或多种此类紊乱或病症的症状(symptom)的进展、推迟其发作、或预防之。除非另有指明,否则如本文所用的术语“治疗(treatment)”是指治疗的行为,如上文所定义的“治疗(treating)”。
术语“选择性(selective)”,当在本文中用于描述功能上定义(functionally-defined)的受体配体或酶抑制剂时意指与同一家族中的其他受体或酶亚型相比,对该定义的受体或酶亚型具有选择性。例如,选择性TYK2/JAK1抑制剂是比任何其他JAK酶亚型更有效地抑制TYK2/JAK1酶亚型的化合物。在一个实施方案中,此选择性为至少2倍(如使用传统结合测定法(assay)测量),或在另一个实施方案中,为至少10倍,或在另一个实施方案中,为至少100倍。
术语“治疗有效”是指药剂预防紊乱、或减少紊乱的严重程度的能力。短语“治疗有效”应理解为等同于短语“有效治疗、预防或改善(amelioration)”,并且二者都意图定量药剂的量,其将在各药剂以其本身治疗期间实现缓解(mitigating)癌症、心血管疾病、或疼痛及炎症的严重程度及发生频率的目标。
“药学上可接受的”意指适合用于对象。
附图说明
图1提供了针对结晶((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮获得的粉末X射线衍射图,而下表1列出了以2-theta值表示的衍射峰。
图2提供了在根据下文阐述的公开内容中以Th2刺激的离体人类皮肤测定法中局部给药实施例1的1%调配物和化合物2后CXCL10生物标志物的百分比变化。
具体实施方式
本发明关于新化合物,他们是有用于治疗与JAK(特别是TYK2/JAK1)的不良调节相关的疾病和病症的JAK调节剂(modulator)。本发明进一步提供包含此类JAK酶调节剂的药物组合物以及治疗和/或预防此类疾病和病症的方法。
根据本发明的第一方面,提供式I化合物或其药学上可接受的盐,
其中R1和R2各自独立地为氢或羟基;其中R1和R2不都为羟基。下面描述的是本发明的这个第一方面的多个实施方案(E),其中为方便起见,E1与其相同。
E1.如上所定义的式I化合物或其药学上可接受的盐。
E2.如E1所述的化合物或其药学上可接受的盐,其中R1为羟基且R2为氢。
E3.如E1所述的化合物或其药学上可接受的盐,其中R1为氢且R2为羟基。
E4.式IA之如E1所述的化合物或其药学上可接受的盐,
E5.式IB之如E1所述的化合物或其药学上可接受的盐,
E6.式IC之如E1所述的化合物或其药学上可接受的盐,
E7.式ID之如E1所述的化合物或其药学上可接受的盐,
E8.如E1所述的化合物,其选自以下组中:
((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮;
((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-((R)-2-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮;
((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-((S)-2-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮;及,
((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-(3-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮,或,其药学上可接受的盐。
E9.((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮。
E10.((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-((R)-2-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮。
E11.((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-(3-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮。
E12.((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-((S)-2-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮。
E13.如E1至E12中任一项所述的化合物或其药学上可接受的盐,其呈经分离形式。
E14.如E1至E13中任一项所述的化合物或其药学上可接受的盐,其呈结晶形式。
E15.一种药物组合物,其包含如E1至E13中任一项所述的化合物或其药学上可接受的盐,以及药学上可接受的载剂。
E16.一种于有治疗需要的对象中治疗或预防对其指示用药TYK2/JAK1抑制剂的疾病和病症的方法,其包括向所述对象给药治疗有效量之如E1至E14中任一项所述的化合物或其药学上可接受的盐。
E17.一种治疗或预防炎性或免疫性病症的方法,其包括向有此需要的对象给药治疗有效量的如E1至E14中任一项所述的化合物或其药学上可接受的盐。
E18.一种治疗或预防疾病或病症的方法,所述疾病或病症选自下列:炎症、自体免疫性疾病、神经炎症、关节炎、类风湿关节炎、脊椎关节病、全身性红斑狼疮、狼疮性肾炎、骨关节炎、痛风性关节炎、疼痛、发热、肺结节病(pulmonary sarcoidosis)、硅肺病、心血管疾病、动脉粥样硬化、心肌梗塞、血栓形成、充血性心脏衰竭及心脏再灌注损伤、心肌病、中风、局部缺血、再灌注损伤、脑水肿、脑外伤、神经退化、肝病、炎性肠病、克罗恩病、溃疡性结肠炎、肾炎、视网膜炎、视网膜病、黄斑变性、青光眼、糖尿病(1型及2型)、糖尿病性神经病、病毒及细菌感染、肌痛、内毒素休克、中毒性休克综合征、骨质疏松症、多发性硬化、子宫内膜异位、痛经、阴道炎、念珠菌病、癌症、纤维化、肥胖症、肌营养不良症、多肌炎、皮肌炎、自体免疫性肝炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、白癜风、阿尔茨海默病、皮肤潮红、湿疹、银屑病、特应性皮炎、晒伤、蟹足肿(keloid)、肥厚性瘢痕、风湿性疾病、荨麻疹、盘状狼疮、皮肤狼疮、中枢神经系统狼疮、银屑病关节炎、哮喘、过敏性哮喘、I型干扰素病(包括Aicardi-Goutières综合征和其他过度表达I型干扰素的孟德尔疾病)、原发性进行性多发性硬化、复发性缓解型多发性硬化、非酒精性脂肪肝病、非酒精性脂肪性肝炎、硬皮病、斑秃、疤痕性脱发、痒疹、结节性痒疹、CPUO、苔藓疾病、扁平苔藓、史蒂文斯-约翰逊综合征(Steven’s Johnson’s syndrome)、脊椎病、肌炎、血管炎、天疱疮、狼疮、重性抑郁症、过敏、干眼综合征、移植排斥、癌症、感染性休克、心肺功能障碍、急性呼吸疾病、强直性脊柱炎、恶病质、慢性移植物抗宿主病、急性移植物抗宿主病、乳糜泻(Celiac Sprue)、特发性血小板减少性血栓性紫癜、血栓性血小板减少性紫癜、重症肌无力、Sjogren综合征、上皮增生、软骨炎症、骨退化(bone degradation)、幼年型关节炎、幼年型类风湿性关节炎、少关节型幼年型类风湿性关节炎、多关节型幼年型类风湿性关节炎、全身性发病幼年型类风湿性关节炎、幼年型强直性脊柱炎、幼年型肠病性关节炎、幼年型Reter综合征(juvenile Reter’sSyndrome)、SEA综合征、幼年型皮肌炎(juvenile dermatomyositis)、幼年型银屑病关节炎、幼年型硬皮病、幼年型全身性红斑狼疮、幼年型脉管炎、少关节型类风湿性关节炎、多关节型类风湿性关节炎、全身性发病类风湿性关节炎、肠病性关节炎、反应性关节炎、Reter综合征(Reter’s Syndrome)、肌炎、多发性肌炎、皮肌炎、结节性多动脉炎、Wegener肉芽肿病、动脉炎、风湿性多肌痛、结节病、硬化、原发性胆汁性硬化、硬化性胆管炎、皮炎、Still病、慢性阻塞性肺病、Guillain-Barre病、毒性弥漫性甲状腺肿(Graves’disease)、艾迪生病、雷诺现象(Raynaud’s phenomenon)、银屑病上皮增生、斑块型银屑病、滴状银屑病、反向性银屑病、脓疱型银屑病、红皮症银屑病、与致病性淋巴细胞的活动相关或由其引起的免疫紊乱、非传染性葡萄膜炎、Behcet病和伏格特-小柳-原田综合征(Vogt-Koyanagi-Haradasyndrome),该方法包括向有此需要的对象给药治疗有效量之如E1至E14中任一项所述的化合物或其药学上可接受的盐。
E19.如E16至E18中任一项所述的方法,其中所述化合物选自以下组:
((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮;
((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-((R)-2-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮;
((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-((S)-2-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮;及,
((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-(3-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮,或其药学上可接受的盐。
E20.如E16至E18中任一项所述的方法,其中所述化合物为((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮;或其药学上可接受的盐,其呈经分离形式。
E21.如E16至E18中任一项所述的方法,其中所述化合物为((S)-2,2-二氟环丙基))((1R,5S)-3-(2-((1-(3-羟基丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮;或其药学上可接受的盐,其呈经分离形式。
E22.如E16至E19中任一项所述的方法,其中所述疾病或病症为银屑病。
E23.如E16至E19中任一项所述的方法,其中所述疾病或病症为特应性皮炎。
E24.如E16至E19中任一项所述的方法,其中所述疾病或病症为手部湿疹。
E25.如E16至E19中任一项所述的方法,其中所述疾病或病症为瘙痒症(pruritis)。
E26.如E16至E19中任一项所述的方法,其中所述疾病或病症为皮肤狼疮。
E27.如E16至E19中任一项所述的方法,其中所述化合物是局部给药。
E28.如E1至E14中任一项所述的化合物或其药学上可接受的盐在制造用于治疗对其指示用药TYK2/JAK1抑制剂之紊乱的药物中的用途。
E29.如E1至E14中任一项所述的化合物或其药学上可接受的盐,其是用于治疗对其指示用药TYK2/JAK1抑制剂的紊乱。
E30.一种药物组合,其包含如E1至E14中任一项所述的化合物或其药学上可接受的盐,其呈经分离形式,或其药学上可接受的盐;以及一或多种额外的药理活性化合物。
E40.如E4所述的化合物,其呈结晶形式,该结晶形式具有包含在4.6、9.2、18.5、和19.6±0.2°2θ处的衍射峰的粉末X射线衍射图。
在某些实施方案中,根据所述方法使用的治疗有效量为0.01mg/kg体重/天至100mg/kg体重/天。在某些其他实施方案中,根据所述方法使用的治疗有效量为其中该治疗有效量为0.1mg/kg体重/天至10mg/kg体重/天。
在某些实施方案中,本发明提供一种局部药物调配物,其包含以约0.0001%至约10.0%(w/w)浓度存在的活性剂。在另一实施方案中,活性剂以约0.001%至约3.0%(w/w)的浓度存在。在另一实施方案中,活性剂以约0.01%至约3.0%(w/w)的浓度存在。
具有相同分子式但在性质或他们的原子的键合顺序、或他们的原子的空间排列上不同的本发明化合物被称为“异构体”。彼等原子之空间排列不同的异构体被称为“立体异构体”。取决于手性碳原子周围取代基的构型(configuration),这些立体异构体为“R”或“S”。本文所用术语“R”和“S”是如同IUPAC 1974Recommendations for Section E,Fundamental Stereochemistry,Pure Appl.Chem.,1976,45:13-30中定义的构型。由(R)、(S)或*指示的本发明对映异构体(enantiomer)实质上不含其它对映异构体。术语“实质上不含”意指对映体过量(enantiomeric excess)大于约90%,优选大于约95%,且更优选大于约99%。在对映体过量的上下文中,术语“约”意指±1.0%。符号*将手性碳原子指定为(R)或(S)立体化学(取决于手性碳原子周围取代基的构型)。本发明涉及具体包括在本发明范围内的各种立体异构体及其混合物。立体异构体包括对映异构体和对映异构体的混合物。本发明化合物的个别立体异构体可从含有不对称或手性中心的市售起始材料合成制备,或者通过制备外消旋混合物接着通过本领域技术人员熟知的拆分(resolution)来制备。这些拆分方法包括但不限于(1)将手性助剂附接到对映异构体的混合物上,通过再结晶或色谱法分离所得的非对映异构体混合物,并从助剂中释放出光学上纯的产物;或(2)在手性色谱柱上直接分离光学对映异构体混合物。未指定(R)、(S)或*的本发明化合物可呈外消旋物存在(亦即,50%(R)和50%(S))、或呈二种对映异构体的混合物存在,其中一种对映异构体过量。例如,对映异构混合物可包括51%的(R)对映异构体和49%的(S)对映异构体,反之亦然,或者除了50%(R)和50%的(S)的外消旋混合物之外的任何(R)和(S)的组合。
所述化合物的范围内包括本文单独描述的化合物的所有异构体(例如,顺式-、反式-、或非对映异构体)以及任何混合物。所有这些形式,包括对映异构体、非对映异构体、顺式、反式、同式、逆式、溶剂化物(包括水合物)、互变异构体以及其混合物均包括在所述化合物中。立体异构混合物,例如非对映异构体的混合物,可以通过适合的分离方法以已知方式分离成他们的相应异构体。非对映异构体混合物例如可通过分级结晶(fractionatedcrystallization)、色谱法、溶剂分配、及类似的程序分离成他们的个别非对映异构体。此分离可在起始化合物中之一者的层级上或在式I、IA、IB、IC或ID化合物本身发生。对映异构体可通过形成非对映异构体盐,例如通过与对映异构体纯的手性酸形成盐,或通过色谱法装置,例如通过HPLC,使用层析底物与手性配体来分离。本发明包括所有药学上可接受的同位素标记式I、IA、IB、IC或ID化合物或其药学上可接受的盐,其中一个或多个原子被具有相同原子数但原子质量或质量数不同于自然中占优势的原子质量或质量数的原子代替。
适合含括在本发明化合物中的同位素的实例包括氢的同位素,例如2H和3H,碳的同位素,例如11C、13C和14C,氯的同位素,例如36Cl,氟的同位素,例如18F,碘的同位素,例如123I和125I,氮的同位素,例如13N和15N,氧的同位素,例如15O、17O和18O,磷的同位素,例如32P,以及硫的同位素,例如35S。
某些同位素标记的式I、IA、IB、IC或ID化合物或其药学上可接受的盐,例如并入放射性同位素的那些,有用于药物和/或底物组织分布研究中。放射性同位素氚(亦即,3H)和碳-14(亦即,14C)鉴于他们易于并入以及现成的检测装置,特别适用于此目的。
用较重的同位素诸如氘(亦即,2H)取代可提供由更大的代谢稳定性所带来的某些治疗优点,例如,增加的体内半衰期或降低的剂量需求,并因此可能在某些情况下是优选的。用诸如11C、18F、15O和13N的正电子发射同位素取代,可在用于检查底物受体占有率的正电子发射断层显像(PET)研究中是有用的。同位素标记的式I、IA、IB、IC或ID化合物通常可通过本领域技术人员已知的习知技术或通过类似于在所附实施例及制剂中描述的那些方法,使用适当的同位素标记的试剂代替先前采用的非标记的试剂制备。
在用于治疗哺乳动物紊乱的治疗用途中,本发明化合物或其药物组合物可以口服、非消化道、局部、直肠、透黏膜、或肠内给药。非消化道给药包括间接注射以产生全身效果或直接注射到生病区域。局部给药包括治疗易通过局部施用触及的皮肤或器官,例如眼睛或耳朵。其亦包括经皮递送以产生全身效果。直肠给药包括栓剂的形式。优选的给药途径是口服和非消化道。
式I、IA、IB、IC或ID化合物之药学上可接受的盐包括其酸加成盐和碱盐。合适的酸加成盐由形成无毒盐的酸形成。实例包括乙酸盐、己二酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、硼酸盐、樟脑磺酸盐、柠檬酸盐、环己氨基磺酸盐(cyclamate)、乙二磺酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、海苯酸盐、盐酸盐/氯化物、氢溴酸盐/溴化物、氢碘酸盐/碘化物、羟乙基磺酸盐、乳酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、甲基硫酸盐、萘酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、焦谷氨酸盐、糖二酸盐、硬脂酸盐、琥珀酸盐、鞣酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐和羟萘甲酸盐(xinofoate)。
合适的碱盐由形成无毒盐的碱形成。实例包括铝盐、精氨酸盐、苄星盐(benzathine)、钙盐、胆碱盐、二乙胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、镁盐、葡甲胺盐、乙醇胺盐、钾盐、钠盐、氨丁三醇盐和锌盐。
亦可以形成酸和碱的半盐,例如半硫酸盐及半钙盐。对于合适的盐的综述,参见Handbook of Pharmaceutical Salts:Properties,Selection,and Use by Stahl andWermuth(Wiley-VCH,2002)。
式I、IA、IB、IC或ID化合物之药学上可接受的盐可分别通过三种方法中之一者或多者来制备:(i)使式I、IA、IB、IC或ID化合物与所欲的酸反应;(ii)从式I、IA、IB、IC或ID化合物的合适的前体中移除酸不稳定保护基团或碱不稳定保护基团,或使合适的环状前体(例如内酯或内酰胺)开环;或(iii)与适当的酸或碱反应或通过合适的离子交换柱装置将式I、IA、IB、IC或ID化合物的一种盐转化为另一种。所有三种反应典型地在溶液中进行。所得盐可沉淀出来,然后通过过滤收集或可通过蒸发溶剂来回收。所得盐中电离的程度可能会从完全电离到几乎不电离变化。
本发明亦包括下列实施方案:
如本文所述实施方案中之任一者所定义的式I、IA、IB、IC或ID化合物或其药学上可接受的盐,用于作为药物;
如本文所述实施方案中之任一者所定义的式I、IA、IB、IC或ID化合物或其药学上可接受的盐,用于治疗或预防选自下列者:炎症、自体免疫性疾病、神经炎症、关节炎、类风湿关节炎、脊椎关节病、全身性红斑狼疮、狼疮性肾炎、骨关节炎、痛风性关节炎、疼痛、发热、肺结节病、硅肺病、心血管疾病、动脉粥样硬化、心肌梗塞、血栓形成、充血性心脏衰竭及心脏再灌注损伤、心肌病、中风、局部缺血、再灌注损伤、脑水肿、脑外伤、神经退化、肝病、炎性肠病、克罗恩病、溃疡性结肠炎、肾炎、视网膜炎、视网膜病、黄斑变性、青光眼、糖尿病(1型及2型)、糖尿病性神经病、病毒及细菌感染、肌痛、内毒素休克、中毒性休克综合征、骨质疏松症、多发性硬化、子宫内膜异位、痛经、阴道炎、念珠菌病、癌症、纤维化、肥胖症、肌营养不良症、多肌炎、皮肌炎、自体免疫性肝炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、白癜风、阿尔茨海默病、皮肤潮红、湿疹、银屑病、特应性皮炎、晒伤、蟹足肿、肥厚性瘢痕、风湿性疾病、荨麻疹、盘状狼疮、皮肤狼疮、中枢神经系统狼疮、银屑病关节炎、哮喘、过敏性哮喘、I型干扰素病(包括Aicardi-Goutières综合征和其他过度表达I型干扰素的孟德尔疾病)、原发性进行性多发性硬化、复发性缓解型多发性硬化、非酒精性脂肪肝病、非酒精性脂肪性肝炎、硬皮病、斑秃、疤痕性脱发、痒疹、结节性痒疹、CPUO、苔藓疾病、扁平苔藓、史蒂文斯-约翰逊综合征、脊椎病、肌炎、血管炎、天疱疮、狼疮、重性抑郁症、过敏、干眼综合征、移植排斥、癌症、感染性休克、心肺功能障碍、急性呼吸疾病、强直性脊柱炎、恶病质、慢性移植物抗宿主病、急性移植物抗宿主病、乳糜泻、特发性血小板减少性血栓性紫癜、血栓性血小板减少性紫癜、重症肌无力、Sjogren综合征、上皮增生、软骨炎症、骨退化、幼年型关节炎、幼年型类风湿性关节炎、少关节型幼年型类风湿性关节炎、多关节型幼年型类风湿性关节炎、全身性发病幼年型类风湿性关节炎、幼年型强直性脊柱炎、幼年型肠病性关节炎、幼年型Reter综合征、SEA综合征、幼年型皮肌炎、幼年型银屑病关节炎、幼年型硬皮病、幼年型全身性红斑狼疮、幼年型脉管炎、少关节型类风湿性关节炎、多关节型类风湿性关节炎、全身性发病类风湿性关节炎、肠病性关节炎、反应性关节炎、Reter综合征、肌炎、多发性肌炎、皮肌炎、结节性多动脉炎、Wegener肉芽肿病、动脉炎、风湿性多肌痛、结节病、硬化、原发性胆汁性硬化、硬化性胆管炎、皮炎、Still病、慢性阻塞性肺病、Guillain-Barre病、毒性弥漫性甲状腺肿、艾迪生病、雷诺现象、银屑病上皮增生、斑块型银屑病、滴状银屑病、反向性银屑病、脓疱型银屑病、红皮症银屑病、与致病性淋巴细胞的活动相关或由其引起的免疫紊乱、非传染性葡萄膜炎、Behcet病和伏格特-小柳-原田综合征;
于有治疗需要的对象中治疗对其指示用药JAK抑制剂的疾病的方法,其包括向所述对象给药治疗有效量的如本文所述实施方案中之任一者所定义的式I、IA、IB、IC或ID化合物或其药学上可接受的盐;
如本文所述实施方案中之任一者所定义的式I、IA、IB、IC或ID化合物或其药学上可接受的盐在制造用于治疗对其指示用药JAK抑制剂的疾病或病症的药物中的用途;
如本文所述实施方案中之任一者所定义的式I、IA、IB、IC或ID化合物或其药学上可接受的盐,用于治疗对其指示用药JAK抑制剂的疾病或病症;
用于治疗对其指示用药JAK抑制剂的疾病或病症的药物组合物,其包含如本文所述实施方案中之任一者所定义的式I、IA、IB、IC或ID化合物或其药学上可接受的盐。
本发明亦提供如上所定义之用途、方法或组合物中之任一者,其中式I、IA、IB、IC或ID化合物或其药学上可接受的盐是与另一种药理活性化合物,特别是与下面列出的功能上定义的类或具体化合物中之一者组合使用。这些药剂可以根据本领域技术人员已知的标准制药实务,作为相同或分开剂型的一部分,经由相同或不同的给药途径,并以相同或不同的给药时间表给药。
适合用于与式I、IA、IB、IC或ID化合物或其药学上可接受的盐之组合疗法中药剂:柳氮磺吡啶(sulfasalazine)、美沙拉嗪(mesalazine)、泼尼松(prednisone)、咪唑硫嘌呤(azathioprine)、英夫利昔单抗(infliximab)、阿达木单抗(adalimumab)、贝利木单抗(belimumab)、塞妥珠单抗(becertolizumab)、那他珠单抗(natalizumab)、维多珠单抗(vedolizumab)、氢化可的松(hydrocortisone)、布地奈德(budesonide)、环孢菌素(cyclosporin)、他克莫司(tacrolimus)、非索非那定(fexofenadine)、6-巯基嘌呤、甲氨蝶呤(methotrexate)、熊脱氧胆酸(ursodeoxycholic acid)、奥贝胆酸(obeticholic acid)、抗组织胺、利福平(rifampin)、泼尼松(prednisone)、甲氨蝶呤(methotrexate)、咪唑硫嘌呤(azathioprine)、环磷酰胺(cyclophosphamide)、羟氯喹(hydroxychloroquine)、吗替(mofetil)、霉酚酸钠(sodium mycophenolate)、他克莫司(tacrolimus)、来氟米特(leflunomide)、氯奎(chloroquine)和奎纳克林(quinacrine)、沙利度胺(thalidomide)、利妥昔单抗(rituxan)、非甾体抗炎药(NSAID)、甲强龙(solumedrol)、甲基泼尼松龙(depomedrol)和地塞米松(dexamethasone)。
其他适合用于与式I、IA、IB、IC或ID化合物或其药学上可接受的盐之组合疗法中的药剂包括:5-脂氧合酶活化蛋白(FLAP)拮抗剂;白三烯拮抗剂(LTRA),如LTB4、LTC4、LTD4、LTE4、CysLT1或CysLT2的拮抗剂,例如孟鲁司特(montelukast)和扎鲁司特(zafirlukast);组胺受体拮抗剂,诸如组胺1型受体拮抗剂或组胺2型受体拮抗剂,例如氯雷他定(loratidine)、非索非那定(fexofenadine)、地氯雷他定(desloratidine)、左西替利嗪(levocetirizine)、美沙吡林(methapyrilene)或西替利嗪(cetirizine);α1肾上腺素受体激动剂或α2肾上腺素受体激动剂,例如,苯福林、甲氧胺、羟甲唑啉或甲基去甲肾上腺素;毒蕈碱M3受体拮抗剂,例如噻托溴铵或异丙托溴铵;双毒蕈碱M3受体拮抗剂/β2激动剂;PDE抑制剂,诸如PDE3抑制剂、PDE4抑制剂或PDE5抑制剂,如茶碱、西地那非(sildenafil)、伐地那非(vardenafil)、他达拉非(tadalafil)、异丁司特(ibudilast)、西洛司特(cilomilast)或罗氟司特(roflumilast);色甘酸钠或奈多罗米钠(sodium nedocromil);环氧合酶(COX)抑制剂,诸如非选择性抑制剂(例如,阿司匹林(aspirin)和布洛芬(ibuprofen))或选择性抑制剂(例如塞来昔布(celecoxib)或伐地考昔(valdecoxib));糖皮质激素,例如氟替卡松(fluticasone)、莫米松(mometasone)、地塞米松(dexamethasone)、泼尼松龙(prednisolone)、布地奈德(budesonide)、环索奈德(ciclesonide)或倍氯米松(beclamethasone);抗炎单株抗体,例如,英夫利昔单抗(infliximab)、阿达木单抗(adalimumab)、他尼珠(tanezumab)、兰尼单抗(ranibizumab)、贝伐单抗(bevacizumab)或美泊利单抗(mepolizumab);β2激动剂,例如沙美特罗(salmeterol)、沙丁胺醇(albuterol)、舒喘宁(salbutamol)、非诺特罗(fenoterol)或福莫特罗(formoterol),特别是长效β2激动剂;整合素拮抗剂,例如,那他珠单抗(natalizumab);黏附分子抑制剂,如VLA-4拮抗剂;激肽B1或B2受体拮抗剂;免疫抑制剂,如IgE途径的抑制剂(例如,奥马珠单抗(omalizumab))或环孢霉素;基质金属蛋白酶(MMP)抑制剂,如MMP-9或MMP-12的抑制剂;速激肽NK1、NK2或NK3受体拮抗剂;蛋白酶抑制剂,诸如弹性蛋白酶、胃促胰酶或组织蛋白酶G的抑制剂;腺苷A2a受体激动剂;腺苷A2b受体拮抗剂;尿激酶抑制剂;多巴胺受体激动剂(例如,罗匹尼罗(ropinirole)),特别是多巴胺D2受体激动剂(例如,溴隐亭(bromocriptine));NFκB途径的调节剂,诸如IKK抑制剂;细胞因子信号传导途径的另一调节剂,如JAK激酶、syk激酶、p38激酶、SPHK-1激酶、Rho激酶、EGF-R或MK-2的抑制剂;黏液溶解、黏液促动或止咳剂;抗生素;抗病毒剂;疫苗;趋化因子;上皮钠通道(ENaC)阻断剂或上皮钠通道(ENaC)抑制剂;核苷酸受体激动剂,诸如P2Y2激动剂;血栓素抑制剂;烟酸;5-脂氧合酶(5-LO)抑制剂,例如齐留通(Zileuton);黏附因子,如VLAM、ICAM或ELAM;CRTH2受体(DP2)拮抗剂;前列腺素D2受体(DP1)拮抗剂;造血前列腺素D2合酶(HPGDS)抑制剂;β干扰素;可溶性人类TNF受体,例如,依那西普(Etanercept);HDAC抑制剂;磷酸肌醇3-激酶伽玛(PI3Kγ)抑制剂;磷酸肌醇3-激酶δ(PI3Kδ)抑制剂;CXCR-1或CXCR-2受体拮抗剂;IRAK-4抑制剂;以及TLR-4或TLR-9抑制剂,包括特别命名的化合物的药学上可接受的盐。药剂可以与另一活性剂一起给药,其中第二活性剂可口服或局部给药。
据此,本发明提供于对象(诸如人类或非人类哺乳动物)中治疗或预防与JAK相关联的疾病、病症或紊乱的方法,其包括向有此需要的对象给药有效量的一或多种本文所述的化合物。其中选择性靶向JAK途径或调节JAK激酶被认为是治疗上有用的病症尤其包括关节炎、哮喘、自体免疫性疾病、癌症或肿瘤、糖尿病、某些眼疾病、紊乱或病症、炎症、肠炎症、过敏或病症、神经退化疾病、银屑病、和移植排斥。
实施本发明的一种方式是以前药的形式给药式I、IA、IB、IC或ID化合物。因此,本身可能具有很少或没有药理活性的式I、IA、IB、IC或ID化合物的某些衍生物在给药到身体内或身体上时可以转化为具有所希望之活性的式I、IA、IB、IC或ID化合物,例如通过水解断裂(hydrolytic cleavage),特别是通过酯酶或肽酶之酶促进的水解断裂。此等衍生物被称为“前药”。对于前药使用的进一步信息可在‘Pro-drugs as Novel Delivery Systems’,Vol.14,ACS Symposium Series(T.Higuchi and W.Stella)和‘Bioreversible Carriersin Drug Design’,Pergamon Press,1987(Ed.E.B.Roche,American PharmaceuticalAssociation)中找到。也可以参考Nature Reviews/Drug Discovery,2008,7,355,以及Current Opinion in Drug Discovery and Development,2007,10,550。
根据本发明的前药可以例如通过利用本领域技术人员已知的作为“前部分(pro-moieties)”的某些部分,如描述在例如H.Bundgaard的‘Design of Prodrugs’(Elsevier,1985)中者,来替代式I、IA、IB、IC或ID化合物中存在的适当官能性而制备。
因此,根据本发明的前药是:(a)式I、IA、IB、IC或ID化合物中羟基的酯或酰胺衍生物;(b)式I、IA、IB、IC或ID化合物中羟基的酯、碳酸酯、氨基甲酸酯、磷酸酯或醚衍生物;(c)式I、IA、IB、IC或ID化合物形式中氨基的酰胺、亚胺、氨基甲酸酯或胺衍生物;(d)式I、IA、IB、IC或ID化合物中羰基的肟或亚胺衍生物。
一些根据本发明的前药的具体实例包括:
(i)其中式I、IA、IB、IC或ID化合物含有羟基官能性
(ii)其中式I、IA、IB、IC或ID化合物含有醇官能性(-OH)、其酯,诸如其中式I、IA、IB、IC或ID化合物的醇官能性的氢被-CO(C1-C8烷基)(例如,甲基羰基)替代或该醇是用氨基酸酯化的化合物;
(iii)其中式I、IA、IB、IC或ID化合物含有醇官能性(-OH)、其酯,诸如其中式I、IA、IB、IC或ID化合物的醇官能性的氢被(C1-C8烷基)C(=O)OCH2-或-CH2OP(=O)(OH)2替代的化合物;
(iv)其中式I、IA、IB、IC或ID化合物含有醇官能性(-OH)、其磷酸酯,诸如其中式I、IA、IB、IC或ID化合物的醇官能性的氢被-P(=O)(OH)2或-P(=O)(ONa)2或-P(=O)(O-)2Ca2+替代的化合物;
(v)其中式I、IA、IB、IC或ID化合物含有二级氨基官能性(-NHR,其中R≠H)、其酰胺,例如其中式I、IA、IB、IC或ID化合物的氨基官能性的一个氢原子被或二个氢原子都被(视情况而定)(C1-C10)烷酰基、-COCH2NH2替代或该氨基是用氨基酸衍生的化合物;
(vi)其中式I、IA、IB、IC或ID化合物含有二级氨基官能性(-NH2或-NHR,其中R≠H)、其胺,例如其中式I、IA、IB、IC或ID化合物的氨基官能性的一个氢原子被或二个氢原子都被(视情况而定)-CH2OP(=O)(OH)2替代的化合物。
对式I、IA、IB、IC或ID化合物的提及被认为包括化合物本身及其前药。本发明包括此等式I、IA、IB、IC或ID化合物以及此等化合物的药学上可接受的盐。
也包括在本发明范围内的是式I、IA、IB、IC或ID化合物的活性代谢物,亦即给药药物后在体内通常通过氧化或脱烷基化作用形成的化合物。一些根据本发明的代谢物的实例包括:
(i)其中式I、IA、IB、IC或ID化合物含有亚甲基、其羟基亚甲基衍生物(-CH2-->-CHOH):
(ii)其中式I、IA、IB、IC或ID化合物含有三级氨基、其二级氨基衍生物(-NRR’->-NHR或-NHR’);和
(iii)其中式I、IA、IB、IC或ID化合物含有二级氨基、其伯氨基衍生物(-NHR->-NH2)。
药物组合物或调配物
在另一实施方案中,本发明提供药物组合物或调配物,其包含治疗有效量的本发明化合物和药学上可接受的稀释剂或载剂。本发明的药物组合物或调配物可向人类和其他哺乳动物局部、口服、非消化道、脑池内、阴道内、腹膜内、口腔内、作为口喷雾剂、作为鼻喷雾剂、作为栓或以脂质体的形式给药。
典型的药物组合物或调配物是通过将本发明的化合物与载剂或稀释剂混合来制备的。合适的载剂和稀释剂包括诸如碳水化合物、蜡、水溶性和/或可溶胀聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等的材料。所使用的具体载剂或稀释剂将取决于本发明化合物所应用的装置和目的。合适的水性溶剂包括水、乙醇、丙二醇、聚乙二醇(例如PEG400、PEG300)等及其混合物。调配物也可包含一种或多种缓冲剂、稳定剂、表面活性剂、湿润剂、润滑剂、乳化剂、悬浮剂、防腐剂、抗氧化剂、遮光剂、助流剂、加工助剂、着色剂、甜味剂、芳香剂、调味剂和其他已知的添加剂以提供药物(亦即,本发明的化合物或其药物组合物)的精美呈现或有助于药学上产品的制造(亦即,用于制备药物)。
可以使用传统溶解和混合程序来制备调配物。例如,将原料药(bulk drugsubstance)(亦即,本发明化合物或化合物的经稳定形式(例如与环糊精衍生物或其他已知复合剂的复合物))在一种或多种上面描述的载剂的存在下溶解在合适溶剂中。水溶性差的化合物的溶解率可通过使用喷雾干燥的分散体来提高,例如Takeuchi,H.等人在“Enhancement of the dissolution rate of a poorly water-soluble drug(tolbutamide)by a spray-drying solvent deposition method and disintegrants,”J.Pharm.Pharmacol.,39,769-773(1987);和EP0901786B1(US2002/009494)中所述的那些,这些文献通过引用并入本文。本发明的化合物典型地调配成药物剂型以提供易于控制的药物剂量并为患者提供优雅且易于操作的产品。
用于施用的药物组合物或调配物可用各种方式包装,这取决于用于给药药物的方法。通常,用于分配的物品包括容器,容器中存放有适当形式的药物调配物。合适的容器包括诸如瓶子(塑料和玻璃)、小袋、安瓿、塑料袋、金属圆筒等材料。容器也可以包括防破坏总成,以防止不小心触及包装的内容物。另外,容器上还贴有描述容器内容物的标签。标签也可包括适当的警告。
术语“药学上可接受的载剂”是指提供有效量如本文定义的活性剂的适当递送、不干扰活性剂的生物活性有效性的载剂介质,以及对宿主或患者足够无毒的载剂介质。代表性载剂包括水、油、植物油和矿物油、乳膏基质、洗剂基质(lotion base)、软膏基质等。这些基质包括悬浮剂、增稠剂、渗透增强剂等。有关载剂的额外信息可以在以下文献中找到:Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005),其通过引用并入本文。可用作药学上可接受的载剂的材料的进一步实例是糖,诸如乳糖、葡萄糖和蔗糖;淀粉,诸如玉米淀粉和马铃薯淀粉;纤维素及其衍生物,诸如羧甲基纤维素钠、乙基纤维素和乙酸纤维素;粉末化黄蓍胶;麦芽;明胶;滑石;载剂,诸如可可脂和栓剂蜡;油,诸如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和大豆油;二醇,诸如丙二醇;酯,诸如油酸乙酯和月桂酸乙酯;琼脂;缓冲剂,诸如氢氧化镁和氢氧化铝等;海藻酸;无热原水;等渗盐水;林格液(Ringer's solution);乙醇和磷酸盐缓冲溶液,以及其他无毒兼容的润滑剂,诸如月桂基硫酸钠和硬脂酸镁,以及着色剂、脱模剂、包衣剂、甜味剂、调味和芳香剂、防腐剂和抗氧化剂也可以根据调配师的判断存在于组合物中。
术语“药学上可接受的局部载剂”是指适合于局部应用的如上文所述药学上可接受的载剂。能够悬浮或溶解活性剂并且当应用于皮肤、指甲、毛发、爪或蹄时具有无毒和非炎性性质的不活性液体或乳膏载剂是药学上可接受的局部载剂的实例。此术语特别意图涵盖也批准用于局部化妆品的载剂材料。
术语“局部给药”是指将药剂应用于皮肤、指甲、毛发、爪或蹄的外表面,而使得药剂穿过皮肤、指甲、毛发、爪或蹄的外表面并且进入下方组织。局部给药包括将组合物应用于完整无伤的皮肤、指甲、毛发、爪或蹄,或应用于皮肤、指甲、毛发、爪或蹄的破损、露出或开放的伤口。药剂的局部给药可得到药剂向皮肤和周围组织的有限分布,或者当药剂通过血流从治疗区域移除时,可得到药剂的全身分布。
本发明化合物的局部或经皮给药的剂型包括软膏、糊剂、乳膏、洗剂、凝胶、粉末、溶液、喷雾剂、吸入剂或贴剂。活性成分是在无菌条件下与药学上可接受的载剂和任何所需防腐剂或缓冲剂(当可能需要时)混合。挥发性化合物可能需要与特殊调配用剂或与特殊包装材料混合以确保正确的剂量递送。另外,人类皮肤渗透性差的本发明化合物可能需要一或多种渗透性增强剂,而通过皮肤快速吸收的化合物可能需要具有吸收延迟剂或屏障剂的调配物。
除了含有本发明的活性化合物外,用于局部给药的软膏、糊剂、乳膏、洗剂、凝胶、粉末和溶液还可含有药学上可接受的载剂,例如动物和植物脂肪、油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、聚硅氧、膨润土、硅酸、滑石、氧化锌、防腐剂、抗氧化剂、香料、乳化剂、染料、惰性填料、抗刺激剂、增黏剂、香料、不透明剂、抗氧化剂、胶凝剂、稳定剂、表面活性剂、润肤剂、着色剂、防腐剂、缓冲剂、渗透增强剂或其混合物。局部载剂不应干扰活性剂的生物活性有效性,并且不应对上皮细胞或它们的功能有害。
术语“渗透性增强剂”或“渗透增强剂”是关于增加皮肤、指甲、毛发、爪或蹄对药物的渗透性,以兹增加药物渗透通过皮肤、指甲、毛发、爪或蹄的速率。例如,可以通过使用扩散单元设备测量药物扩散通过动物或人类的皮肤、指甲、毛发、爪或蹄的速率来观察通过使用此类增强剂致效的增强渗透。扩散单元系由Merritt et al.Diffusion Apparatus forSkin Penetration,J of Controlled Release,1(1984)pp.161-162描述。术语“渗透性增强剂”或“渗透增强剂”意图使药剂或药剂的混合物,单独或组合地作用来增加皮肤、指甲、毛发、爪或蹄对药物的渗透性。
术语“经皮递送”是指因组合物的局部给药或其他应用所致药剂扩散跨越皮肤、指甲、毛发、爪或蹄的屏障。角质层充当屏障,且很少有药剂够渗透完整无伤的皮肤。相反地,表皮和真皮对许多溶质是可渗透的,因此药物的吸收更容易通过磨损或以其他方式剥离角质层而暴露表皮的皮肤、指甲、毛发、爪或蹄发生。经皮递送包括注射或其他递送通过皮肤、指甲、毛发、爪或蹄或黏膜的任何部分的以及通过剩余部分的吸收或渗透。通过完整无伤的皮肤、指甲、毛发、爪或蹄的吸收可以通过在应用于皮肤、指甲、毛发、爪或蹄之前将活性剂放在合适的药学上可接受的媒剂中来增强。被动局部给药可由将活性剂与润肤剂或渗透增强剂组合直接应用于治疗部位所组成。如本文所用,经皮递送意图包括通过渗透或穿过体被,亦即皮肤、指甲、毛发、爪或蹄的递送。
除了含有本发明的化合物之外,粉末和喷雾剂还可以含有乳糖、滑石、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末,或这些物质的混合物。喷雾剂可以额外含有常用的推进剂,例如氯氟烃。
用于口服给药的固体剂型包括胶囊、片剂、丸剂、粉末和颗粒。在此等固体剂型中,活性化合物与至少一种诸如柠檬酸钠或磷酸钙的惰性药学上可接受的载剂和/或a)填料或增量剂,如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和水杨酸;b)黏合剂,如羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和阿拉伯胶;c)保湿剂,如甘油;d)崩解剂,如琼脂、碳酸钙、马铃薯或木薯淀粉、海藻酸、某些硅酸盐和碳酸钠;e)溶解阻滞剂,如石蜡;f)吸收促进剂,如季铵化合物;g)湿润剂,如鲸蜡醇和单硬脂酸甘油酯;h)吸附剂,如高岭土和膨润土;i)润滑剂,如滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、月桂基硫酸钠、及其混合物混合。在胶囊、片剂和丸剂的情况下,剂型还可包含缓冲剂。
类似类型的固体组合物也可用作使用乳糖或牛奶糖以及高分子量聚乙二醇等的软和硬填充明胶胶囊中的填料。
片剂、糖衣丸、胶囊、丸剂和颗粒的固体剂型可以制备有包衣和外壳,例如肠溶包衣和药学制剂领域熟知的其他包衣。他们可视需要地含有不透明剂并且也可以是仅释放或优选在肠道的某部分以延迟方式释放活性成分的组合物。可以使用的包埋组合物的例子包括聚合物质和蜡。
用于口服给药的液体剂型包括药学上可接受的乳液、微乳液、溶液、悬浮液、糖浆和酏剂。除含有活性化合物外,液体剂型可含有本领域常用的惰性稀释剂,例如水或其他溶剂、增溶剂和乳化剂,诸如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄基醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、二甲基甲酰胺、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢糠醇、聚乙二醇和脱水山梨糖醇的脂肪酸酯、及其混合物。
除了惰性稀释剂外,口服组合物也可以包括佐剂,例如润湿剂、乳化和悬浮剂、甜味、调味、和芳香剂。
如本文所用的术语“非消化道”是指给药模式,其包括静脉内、肌肉内、腹膜内、胸骨内、皮下、关节内注射和输注。用于非消化道注射的本发明药物组合物包含药学上可接受的无菌水性或非水性溶液、分散液、悬浮液或乳液以及用于重构成无菌可注射溶液或分散液的无菌粉末。合适的水性和非水性载剂、稀释剂、溶剂或媒剂的实例包括水、乙醇、多元醇(丙二醇、聚乙二醇、甘油等)、其合适混合物、植物油(诸如橄榄油)和可注射有机酯,诸如油酸乙酯。例如,可通过使用诸如卵磷脂的包衣、在分散液的情况下通过保持所需的粒度、以及通过使用表面活性剂来保持适当的流动性。
通过在生物可降解的聚合物(诸如聚丙交酯-聚乙交酯)中形成药物的微胶囊化基质来制作可注射的贮库形式。取决于药物与聚合物的比率和所用特定聚合物的性质,可以控制药物释放的速率。其他生物可降解聚合物的实例包括聚(原酸酯)和聚(酸酐),贮库可注射调配物也可通过将药物裹在与身体组织兼容的脂质体或微乳液中来制备。
可注射调配物可被灭菌,例如,通过过滤通过细菌截留过滤器或在无菌固体组合物形式中通过并入灭菌剂,该无菌固体组合物可以在刚要使用前溶解或分散在无菌水或其他无菌可注射介质中。
可使用合适的分散剂或润湿剂和悬浮剂来调配可注射制剂,例如无菌可注射水性或油性悬浮液。无菌可注射制剂也可为在无毒、非消化道可接受的稀释剂或溶剂中的无菌可注射溶液、悬浮液或乳液,诸如在1,3-丁二醇中的溶液。可使用的可接受媒剂和溶剂中尤其是水、林格氏液、U.S.P.和等渗氯化钠溶液。另外,无菌固定油传统上用作溶剂或悬浮介质。为此,可以使用任何温和的固定油,包括合成的甘油单酯或甘油二酯。另外,诸如油酸的脂肪酸是用于注射剂的制备。
用于直肠或阴道给药的药物组合物、或调配物优选为栓剂,其可以通过将本发明的化合物与合适的无刺激性载剂诸如可可脂、聚乙二醇或在环境温度下为固体但在体温下为液体的栓剂蜡混合来制备,并因此在直肠或阴道腔中融化并释放活性化合物。
本发明的化合物也可呈脂质体的形式给药。脂质体通常衍生自磷脂或其他脂质物质并通过分散在水性介质中的单层或多层水合液晶形成。可使用能够形成脂质体的任何无毒、生理上可接受且可代谢的脂质。除了含有本发明的化合物之外,呈脂质体形式的本发明组合物还可含有稳定剂、防腐剂等。优选的脂质是单独或一起使用的天然和合成磷脂和磷脂酰胆碱(卵磷脂)。形成脂质体的方法是本技术领域已知的。例如参见:Prescott,Ed.,Methods in Cell Biology,Volume XIV,Academic Press,New York,N.Y.(1976),p 33etseq。
本发明的药物组合物、或调配物也可含有佐剂,诸如防腐剂、湿润剂、乳化剂和分散剂。可通过各种抗菌剂和抗真菌剂,例如对羟基苯甲酸酯、氯丁醇、苯酚、山梨酸等来确保预防微生物的作用。包括诸如糖、氯化钠等的等渗剂也可能是希望的。延长可注射药物形式的吸收可通过使用诸如单硬脂酸铝和明胶的延迟吸收剂来实现。
本发明的药物组合物或调配物可为悬浮液。除了含有活性化合物外,悬浮液还可含有悬浮剂,例如乙氧基化异硬脂基醇、聚氧乙烯山梨糖醇和脱水山梨糖醇酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂、黄蓍胶、及其混合物。
药物组合物也包括本发明化合物的溶剂化物和水合物。术语“溶剂化物”是指由式I、IA、IB、IC或ID表示的化合物,包括其药学上可接受的盐,与一种或多种溶剂分子的分子复合物。此等溶剂分子是医药领域常用的那些,并且已知对接受者无害,例如水、乙醇、乙二醇、(S)-丙二醇、(R)-丙二醇等。术语“水合物”是指其中溶剂分子为水的复合物。溶剂化物和/或水合物优选呈结晶形式存在。其他溶剂可用作制备更合乎所希望的溶剂化物的中间溶剂化物。中间溶剂包括但不限于甲醇、甲基叔丁基醚、乙酸乙酯、乙酸甲酯、1,4-丁炔二醇等。
本发明药物组合物中活性成分的实际剂量水平可有变化,以获得对特定患者、组合物、和给药模式有效达成所欲治疗反应的活性化合物的量。所选剂量水平将取决于特定化合物的活性、给药途径、所治疗病症的严重程度、以及所治疗患者的病症和既往病史。然而,以低于达成所希望的治疗效果所需的水平开始化合物的剂量并逐渐增加剂量直至达成所希望的效果是在本技术领域的通常知识范围内。
向人类或较低等动物给药本发明化合物的总每日剂量可在范围约0.000001至约10mg/kg/天。为了口服给药,更优选的剂量可以在约0.001至约1mg/kg/天的范围内。对于局部给药,更优选的剂量可以在0.00001mg/kg/天至约5mg/kg/天的范围内。如果希望,为了给药,有效每日剂量可以分成多个剂量,例如每天二到四个单独的剂量。
合成方法
以下反应路线及书面的描述提供关于制备本发明化合物的一般细节。本发明的化合物可通过本技术领域中已知的用于制备类似结构化合物的任何方法来制备。具体而言,本发明化合物可以通过参考以下反应路线中描述的方法,或通过实施例中描述的具体方法,或通过上述任一者的类似方法来制备。
本领域技术人员将理解,阐述在以下反应路线中的实验条件是说明用于实现所示转变之合适的条件,并且可能有必要或所希望的是改变用于制备式I、IA、IB、IC或ID化合物的精确条件。
另外,本领域技术人员将理解,可能有必要或所希望的是在本发明化合物的合成中的任何阶段保护一个或多个敏感基团,以便预防非所希望的副反应。具体而言,可能有必要或所希望的是保护氨基或羧酸基团。在制备本发明化合物中使用的保护基团是可以常规方式使用。参见,例如,在Theodora W.Greene及Peter G.M.Wuts之‘Greene’s ProtectiveGroups in Organic Synthesis’的3版(John Wiley and Sons,1999),特别是第7章(“Protection for the Amino Group”)及第5章(“Protection for the CarboxylGroup”)中所述的那些,通过引用并入本文中,其亦描述脱除这些基团的方法。
所有式I的衍生物可以通过在下面给出的一般方法中描述的方法或通过其常规变型来制备。本发明也涵盖用于制备式I、IA、IB、IC或ID衍生物的这些方法中之任何一者或多者,除了涵盖其中使用的任何新颖中间体之外。本领域技术人员将理解,下列反应可在用热或在微波照射下加热。应当进一步理解,可能有必要或所希望的是以反应路线中所描述的不同顺序进行变换,或者修改所述变换中之一者或多者,以提供所希望的本发明化合物。
本领域技术人员亦认知到本发明的一些化合物是手性的,并因此可制备呈对映异构体的外消旋或内消旋混合物。有几种方法可得并且是本领域技术人员熟知的用于分离对映异构体的方法。优选分离对映异构体的常规方法是使用手性固定相的超临界流体色谱法。
如反应路线A所示,式I、IA、IB、IC或ID化合物可从化合物A-1、A-2和C-3(A=正丙基、1-羟基丙基或2-羟基丙基、或其受保护形式)制备。式A-1、A-2和C-3化合物是市售或可由本领域技术人员根据文献或本文所描述的制法合成。为此,PG是保护基且典型地是叔丁氧基羰基。式A-3化合物可根据程序步骤(i),而从式A-1和A-2化合物之在有机碱的存在下的芳族取代反应制备。优选的条件包括:三乙胺,在甲醇中,在0℃至室温下。式A-5化合物可根据工艺步骤(ii)和(iii),而从式A-3化合物与式C-3化合物在Buchwald-Hartwig交叉偶合条件或由酸及升高温度所介导下的亲核取代反应,接着由无机或有机酸所介导的去保护反应制备。典型的Buchwald-Hartwig条件包括:合适的钯催化剂与合适的螯合膦配体与无机碱,在合适的有机溶剂中,在用热或在微波照射下之升高温度下。优选的条件包括:a)醋酸钯(II)及2-二环己基膦基-2’,4’,6’-三异丙基联苯或XantphosTM与叔丁醇钠;b)磷酸钾或碳酸铯,在DMA中,在120-140℃于微波照射下;或c)BrettPhosTMPd G3与作为碱的碳酸铯及作为溶剂的DMA或二噁烷,在40℃下。典型的酸性条件包括:合适的无机酸,在合适的醇溶剂中,在用热或微波照射下之升高温度下。优选的条件包括:浓盐酸,在异丙醇中,在140℃于微波照射下。替代地,去保护在工艺步骤(ii)期间原位发生。式A-6化合物(A=正丙基、1-羟基丙基或2-羟基丙基、或其受保护形式)可根据工艺步骤(iv),而从式A-5化合物与式BC(O)X化合物的酰胺键形成反应制备,其中X可为氯、羟基、合适的离去基团或酸酐(例如,(S)-2,2-二氟环丙烷-1-甲酸)。其中式BC(O)X的化合物是酰氯,优选的条件包括:三乙胺,在二氯甲烷中,在室温下。其中式BC(O)X的化合物是羧酸,使用合适的有机碱和合适的偶合剂来活化羧酸。优选的条件包括:DIPEA或三乙胺与HATU,在二氯甲烷或DMF中,在室温下。
反应路线A
替代地,如反应路线B所示,式I、IA、IB、IC或ID化合物可从化合物A-3和C-3制备。如反应路线A所示制备了式A-3化合物。式C-3化合物是市售或可由本领域技术人员根据文献或本文所描述的制法合成。式B-1化合物可根据工艺步骤(i),而从式A-3化合物之由无机或有机酸(在合适的有机溶剂中)所介导的去保护反应制备。优选的条件包括:盐酸或TFA,在二噁烷或DCM中。式B-2化合物可根据工艺步骤(ii),而从式B-1和BC(O)X的化合物的酰胺键形成反应(如反应路线A所示)制备。式A-6化合物可根据工艺步骤(iii),而从式B-2化合物与式C-3化合物在Buchwald-Hartwig交叉偶合条件或由酸及高温所介导下的亲核取代反应(如反应路线A所示)制备。
反应路线B
如反应路线C所示,反应路线A和反应路线B所用式C-3化合物可从式C-1化合物制备。式C-1化合物是市售或可由本领域技术人员根据文献或本文所描述的制法合成。式C-2化合物可根据工艺步骤(i),而从式C-1化合物与式AX(其中X为Cl、Br或I)之适当经取代的卤烷在无机或有机碱和诸如DMF的溶剂存在下的烷基化反应,或式C-1化合物向环氧化物在无机或有机碱的存在下的加成反应制备。式C-3化合物可根据步骤(ii),而从式C-2化合物之典型在诸如钯或镍的金属催化剂、在1-50大气压的压力下的氢气、和诸如甲醇的质子溶剂存在下进行的还原制备。
反应路线C
制备和实施例
以下非限制性制备和实施例说明了本发明化合物和盐的制备。在下面清楚列出的实施例和制备中,以及在上述反应路线中,可能将提及以下缩写、定义和分析方法。也可以使用本技术领域常见的其他缩写。本发明的化合物使用Chemdraw ProfessionalTM的18.0版(Perkin Elmer)命名或给出与IUPAC命名法一致的名称。
1H核磁共振(NMR)光谱在所有情况下是与所提出的结构相符合。特征性化学位移(δ)是以偏离四甲基硅烷之低场的百万分率,使用指定主要峰的常规缩写:例如s,单峰;d,双峰;t,三重峰;q,四重峰;m,多重峰;br,宽峰给出。以下缩写已用于常见NMR溶剂:CD3CN,氘代乙腈;CDCl3,氘代氯仿;DMSO-d6,氘代二甲基亚砜;以及CD3OD,氘代甲醇。在适当处,互变异构体可记录在NMR数据中;且一些可交换的质子可能不可见。NMR光谱中的一些共振显示为复杂的多重峰,这是因为分离物是二种构形异构体(conformer)的混合物。
质谱是使用电子碰撞电离(EI)、电喷雾电离(ESI)或大气压化学电离(APCI)记录。观察到的离子是以MS m/z报告,并且可能是化合物的正离子[M]+、化合物加质子[MH]+、或化合物加钠离子[MNa]+。在一些情况下,仅观察到的离子可能是以[MH-(片段丢失)]+报告的片段离子。当有相关时,所报告的离子被标定为氯的同位素(35Cl和/或37Cl)、溴的同位素(79Br和/或81Br)和锡的同位素(120Sn)。
其中TLC、色谱法或HPLC已用于纯化化合物者,本领域技术人员可选择任何适当的溶剂或溶剂组合来纯化所希望的化合物。除非另有说明,否则色谱分离(排除HPLC)均使用硅胶吸附剂进行。
除非另有说明,否则所有反应均在氮气或氩气气氛下使用连续搅拌进行。在一些情况下,在反应起始之前用氮气或氩气吹扫反应。在这些情况下,氮气或氩气鼓泡通过混合物的液相大约指定的时间。使用的溶剂是商业无水等级。所有起始材料均为市售产品。在某些情况下,起始材料是根据报导的文献方法制备的。对于本领域技术人员将清楚明了的是,本文所用的“浓缩”一词通常是指在减压下蒸发溶剂的实践,其典型是通过使用旋转蒸发器来完成。
本文中使用以下缩写:
ACN:乙腈;
ATM:大气压
BrettPhosTMPd G3:[(2-二-环己基膦基-3,6-二甲氧基-2’,4’,6’-三异丙基-1,1’-联苯)-2-(2’-氨基-1,1’-联苯)]钯(II)甲磺酸盐;
c:浓度
CDI:1,1’-羰基二咪唑;
Cs2CO3:碳酸铯;
DCM:二氯甲烷
DIPEA:N,N-二异丙基乙胺;
DMA:N,N-二甲基乙酰胺;
DMF:N,N-二甲基甲酰胺;
ESI:电喷雾电离;
EtOAc:乙酸乙酯;
HATU:N-[(二甲基氨基)-1H-1,2,3-三唑并-[4,5-b]吡啶-1-基亚甲基]-N-甲基甲铵六氟磷酸N-氧化物;
HCl:盐酸;
HPLC:高压液相色谱法;
HRMS:高分辨率质谱;
H2SO4:硫酸;
kg:千克或公斤
KOH:氢氧化钾;
MeOH:甲醇;
MIBK:甲基异丁基酮;
mg:毫克;
mL:毫升;
mmol:毫摩尔;
Mpa:兆帕;
MTBE:甲基叔丁基醚;
NMT:不超过;
Pd/C:钯碳;
TBAB:溴化四丁基铵;
TFA:三氟乙酸;
THF:四氢呋喃;
TLC:薄层色谱法;
T3P:2,4,6-三丙基-1,3,5,2,4,6-三氧杂三磷杂环己烷-2,4,6-三氧化物;
Xantphos:4,5-双(二苯基膦基)-9,9-二甲基二苯并哌喃。
制备1:(S)-2,2-二氟环丙烷-1-甲酸2,2’,2”-氮基三(乙-1-醇)盐。
向100mL反应器中添加ACN(50.0mL)和三乙醇胺(12.2g,1.0当量)。将溶液加热至45℃,并以100分钟逐滴添加如US专利9,663,526的制备68所述般制备的(S)-2,2-二氟环丙烷-1-甲酸(10.1g,1.0当量)在MTBE(50.0mL,~20%w/w)中的预混合溶液。添加后,将反应在45℃下保持30分钟,然后以0.25℃/min的速率冷却至20℃。将混合物造粒30分钟,然后过滤并用MTBE(40.0mL)清洗,并在50℃真空下干燥。1H NMR(400MHz,DMSO-d6)δ6.85(s,4H),3.61(t,J=5.7Hz,6H),2.97(t,J=5.7Hz,6H),2.38(ddd,J=15.4,10.8,7.9Hz,1H),1.84-1.62(m,2H)。13C NMR(101MHz,DMSO-d6)δ169.0,115.9,113.1(dd,J=285.9,281.2Hz),113.1,110.3,57.4,56.5,27.7,27.6(dd,J=12.0,9.2Hz),27.6,27.5,16.2,16.1(t,J=9.8Hz),16.0。mp:82.4℃。
制备2:2,2-二氟环丙烷-1-(S)-甲酸(R)-N-苄基-1-苯基乙烷-1-铵盐
向250mL容器中添加MTBE(134mL)、(S)-2,2-二氟环丙烷-1-甲酸2,2’,2”-氮基三(乙-1-醇)盐(20.0g,1.0当量)、和硫酸(4.3mL,1.1当量)在水(86.0mL)中的预混溶液。搅拌混合物直至所有固体溶解,然后允许各层沉降。层分离,且用MTBE(58mL)反萃取底层(水性)。合并的有机层经由共沸蒸馏干燥,以达到在MTBE中~15%(w/w)的(S)-2,2-二氟环丙烷-1-甲酸的最终浓度。以~1小时向该溶液中逐滴添加手性胺(R)-(+)-N-苄基-α-甲基苄基胺(13.0g,0.85当量)。添加~25%的该胺后,反应用先前纯化的(R)-N-苄基-1-苯基乙烷-1-胺(S)-2,2-二氟环丙烷-1-甲酸(50mg,0.002当量)种晶。添加该胺后,允许浆液造粒,然后过滤,并用已预冷至10℃的MTBE(12.0mL)清洗,且固体在50℃真空下干燥。使粗制固体(10.57g)回到同一容器中并添加ACN(35.0mL)。将浆液加热至80℃以完全溶解固体。以0.2℃/min的速率将溶液冷却至22℃并允许其造粒。通过过滤收集产物并用ACN(13.0mL)清洗,然后在50℃真空下干燥。1H NMR(400MHz,DMSO-d6)δ9.25(s,2H),7.46(d,J=6.9Hz,2H),7.43-7.24(m,9H),4.00(q,J=6.7Hz,1H),3.74(d,J=13.3Hz,1H),3.65(s,1H),2.50-2.39(m,1H),1.90-1.66(m,2H),1.43(d,J=6.7Hz,3H)。13C NMR(101MHz,DMSO-d6)δ168.5,142.4,137.1,129.3,129.0,128.7,128.0,127.9,127.6,116.0,113.2,113.1(dd,J=286.1,281.3Hz),110.3,57.2,49.8,27.6,27.5,27.5(dd,J=12.0,9.3Hz),27.4,22.5,16.2,16.1(t,J=9.8Hz),16.07。mp:138.6℃。
实施例1:((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮(IA)
步骤1A.4-硝基-1-丙基-1H-吡唑。此步骤以二个平行批次进行。将碳酸钾(1.38g,9.99mmol)一次性添加到4-硝基-1H-吡唑(360g,3.18mol)在ACN(3L)中的25℃搅拌混合物中,并将混合物加热至约50-60℃。以约20min的时间期将1-碘丙烷(595.3g,3.5mol)添加到混合物中。将所得反应混合物在50-60℃下搅拌约2小时。将反应混合物冷却至约25℃。合并这二批次的反应混合物,用水(3L)稀释并在减压下浓缩以移除大部分ACN。所得水性层用EtOAc(4L,3x2L)萃取。合并的有机萃取物用硫酸钠干燥并过滤。在减压下浓缩滤液而得到980.0g(99%)油状的标题化合物。1H NMR(400MHz,CDCl3)δ8.15(s,1H),7.99(s,1H),4.08(t,J=7.2Hz,2H),1.92-1.83(m,2H),0.88(t,J=7.2Hz,2H)。
步骤1B.1-丙基-1H-吡唑-4-胺盐酸盐。向4-硝基-1-丙基-1H-吡唑(1.04kg,9.93mol)在MeOH(5L)中的混合物添加Pd/C(10%Pd,71.06g,66.77mmol)。将混合物脱气并用氩气(3x)重新填充。将混合物回温至35℃并在氢气气氛下在2Mpa左右搅拌约48小时。必要时重新填充氢气以将压力保持在2Mpa左右。过滤反应混合物。将滤液浓缩成溶液(2.5kg)。向在5-10℃左右之HCl的MeOH(5.99mol,2.35L)溶液分次添加该溶液并搅拌约1小时。在减压下浓缩混合物而得到浆液(~1L)。添加EtOAc(500mL),并将混合物搅拌约5min。过滤混合物,且用EtOAc(4x500mL)清洗滤饼。在减压下干燥滤饼而得到550g呈固体的标题化合物。MS m/z 126.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ10.35(br s,3H),7.94(s,1H),7.51(s,1H),4.05(t,J=8.0Hz,2H),1.78-1.69(m,2H),0.79(t,J=8.0Hz,3H)。
步骤1C.(1R,5S)-3-(2-氯嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁基酯。标题化合物购自STA Pharmaceutical Hong Kong Limited。
步骤1D.4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-N-(1-丙基-1H-吡唑-4-基)嘧啶-2-胺。向进料有50mL异丙醇和375mL水的1L OptiMaxTM反应容器中添加呈固体的(1R,5S)-3-(2-氯嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸叔丁基酯(50.00g,153.9mmol)和1-丙基-1H-吡唑-4-胺盐酸盐(49.76g,1.20当量,184.7mmol)。悬浮液在65℃下搅拌约2小时,之后冷却至45℃。向混合物中添加50%KOH水溶液(77mL,6.0当量)并在35℃下搅拌约20小时。然后将悬浮液冷却至15℃,并通过过滤收集固体而得到43.51g(90%)呈灰白色固体的标题化合物。MS m/z 314[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),7.86(d,J=5.9Hz,1H),7.74(s,1H),7.44(s,1H),6.00(d,J=6.1Hz,1H),3.98(t,J=6.9Hz,2H),3.84(s,2H),3.48(d,J=4.7Hz,2H),2.93(d,J=11.8Hz,2H),2.39(s,1H),1.83-1.44(m,6H),0.82(t,J=7.4Hz,3H)。
步骤1E.(S)-2,2-二氟环丙烷-1-甲酸。在2.0L OptiMaxTM反应容器中进料2,2-二氟环丙烷-1-(S)-甲酸(R)-N-苄基-1-苯基乙烷-1-铵盐(如制剂2中所述般制备)(150g,450mmol)、MTBE(1L)、和浓硫酸(27.2mL,0.495mol)的水(945mL)溶液。混合物在25℃下搅拌约1小时。分离水层并用MTBE(630mL)萃取。将合并的有机层浓缩而得到56.7g(95%)油状的标题化合物。
步骤1F.((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮。向进料有THF(595mL)的1.0LOptiMax反应容器中添加(S)-2,2-二氟环丙烷-1-甲酸(43.7g,1.25当量,331mmol)。将溶液冷却至0℃,之后以小量分次添加呈固体的CDI(59.7g,1.35当量,357mmol)。在0℃下搅拌约90分钟后,以5分钟经由加料漏斗添加水(17.0g,17.0mL,944mmol)。混合物在0℃下搅拌约20分钟。向反应混合物中添加呈固体的2-羟基吡啶N-氧化物(1.47g,0.05当量,13.2mmol)和4-((1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-3-基)-N-(1-丙基-1H-吡唑-4-基)嘧啶-2-胺(85.0g,264mmol)。反应混合物在0℃下搅拌约12小时。反应混合物用600mL的MIBK稀释并过滤通过CeliteTM薄层以移除固体杂质。将滤液转移到分液漏斗中,依次用50%饱和碳酸氢钠溶液、50%饱和氯化铵溶液和50%饱和盐水清洗。将有机相转移到2L OptiMaxTM反应器中,并在70℃下通过真空蒸馏移除THF。在70℃下向溶液中缓慢添加庚烷(600mL),且将其在70℃下搅拌约2小时而形成白色悬浮液。以1小时时间期使用计量泵向悬浮液中进料另外600mL庚烷。所得悬浮液在70℃下搅拌约2小时,之后以约3小时冷却至25℃。混合物在25℃下再搅拌8小时。过滤悬浮液而得到97.6g(88%)呈白色固体的标题化合物。针对C20H25F2N7O计算的HRMS(LC-ESI)[(M+H)+]m/z 418.2162,实测值418.2159。1H NMR(400MHz,DMSO-d6)δ8.87(s,1H),7.93(d,J=5.9Hz,1H),.7.75(s,1H),7.46(d,J=8.5Hz,1H),6.11(dd,J=10.6,6.0Hz,1H),4.75-4.51(m,2H),4.00(t,J=6.9Hz,4H),3.28-2.85(m,3H),2.02-1.57(m,8H),0.82(t,J=7.4Hz,3H)。
粉末X射线衍射分析
使用配备有铜辐射源的Bruker AXS D8 Endeavor衍射仪进行粉末X射线衍射分析。发散狭缝设在15mm连续照明。经衍射辐射由PSD-Lynx Eye检测器检测,利用检测器PSD开口设在4.129度。X射线管电压和安培数分别设成40kV和40mA。使用0.00997度的步进大小和1.0秒的步进时间,在3.0至40.0度2-Theta的Cu波长下在Theta-Theta测角仪中收集数据。防散射屏设成1.5mm的固定距离。样品在收集期间以15次/min的速度旋转。通过将他们放在硅低背景样品架中并在收集期间旋转来准备样品。使用Bruker DIFFRACTMPlus软件收集数据,并通过EVA diffract plus软件(v.5.0.0.22)进行分析。通常,阈值1和宽度值0.235用于作出初步峰标定(peak assignment)。目视检查自动标定的输出并将峰位置调整到峰最大值。通常选择相对强度≥3%的峰。未解析或与噪声一致的峰没被选择。在USP中说明之与来自PXRD的结晶材料之峰位置相关的典型误差是高达+/-0.2°2-Theta(USP-941)。
表1:化合物1A的PXRD峰列表
图1是结晶((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮的粉末X射线衍射分析。基于表1,结晶化合物IA的特征在于具有在4.6、9.2、18.5、和19.6±0.2度2θ的特征衍射峰的粉末X射线衍射图。
实施例2:((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-((R)-2-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮(IB)
步骤2A.(R)-1-(4-硝基-1H-吡唑-1-基)丙烷-2-醇。向进料有(R)-(+)-环氧丙烷(12mL)的烧瓶中添加4-硝基-1H-吡唑(4.0g,40mmol),随后添加Cs2CO3(6.92g,21.2mmol)。所得混合物在15℃下搅拌约32小时。添加水(30mL),且混合物用EtOAc(3x40ml)萃取。合并的有机层用硫酸钠干燥并过滤。在减压下浓缩滤液。所得残余物通过硅胶色谱法纯化,用EtOAc:石油醚(1:1)溶剂混合物洗提,而得到5.3g(90%)浅黄色油状的标题化合物。MS m/z171.9[M+H]+。1H NMR(400MHz,CDCl3)δ8.23(d,J=0.6Hz,1H),8.09(s,1H),4.34-4.26(m,1H),4.25(dd,J=13.8,2.6Hz,1H),4.06(dd,J=13.7,7.9Hz,1H),2.47(d,J=3.8Hz,1H),1.28(d,J=6.3Hz,3H)。
步骤2B.(R)-1-(4-氨基-1H-吡唑-1-基)丙烷-2-醇。向(R)-1-(4-硝基-1H-吡唑-1-基)丙烷-2-醇(5.3g,31.0mmol)的MeOH(60mL)溶液中添加Pd/C(10%Pd,659mg,0.02当量)。所得悬浮液在1atm的氢气压力和室温下搅拌约16小时。过滤反应混合物,且在减压下浓缩滤液而得到4.3g(98%)深色油状的标题化合物。MS m/z 142.1[M+H]+。1H NMR(400MHz,CDCl3)δ7.17(d,J=0.9Hz,1H),7.03(d,J=0.9Hz,1H),4.21-4.12(m,1H),4.01(dd,J=13.8,2.8Hz,1H),3.85(dd,J=13.8,8.0Hz,1H),3.47(s,1H),1.18(d,J=6.4Hz,3H)。[α]20 D=-10.862(c=0.2g/100mL,MeOH)。
步骤2C.(1R,5S)-3-(2-氯嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸第三丁基酯。向(1R,5S)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸第三丁基酯(6.0g,28.3mmol)在MeOH(121mL)中的冰溶液添加三乙胺(7.9ml,56.5mmol)。约10分钟后,向混合物中以约二均等份添加2,4-二氯嘧啶(4.6g,31.1mmol)。所得混合物在15℃左右搅拌约5小时。在减压下浓缩混合物而得到浆液。将浆液溶解在二氯甲烷(150mL)中,用水(2x50mL)清洗,用硫酸钠干燥并过滤。在减压下浓缩滤液。残余物通过硅胶色谱法纯化,用0-50%在石油醚中的EtOAc洗提,而得到8.3g(90%)呈白色固体的标题化合物。MS m/z 325.1[M+H]+。
步骤2D.(1R,5S)-3-(2-氯嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷。向(1R,5S)-3-(2-氯嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-甲酸第三丁基酯(10.3g,31.7mmol)的MeOH(160mL)溶液添加HCl的MeOH(60mL,4.0M)溶液。添加后,混合物在15℃左右搅拌约3小时。在减压下浓缩反应。向所得固体中添加水(40mL)并在冰浴中冷却。向搅拌的反应混合物中缓慢添加氢氧化钠水溶液,直至达到10左右的pH。所得浆液用二氯甲烷(2x100mL)萃取。合并的有机萃取物用硫酸钠干燥并过滤。在减压下浓缩滤液而得到6.6g(87%)呈白色固体的标题化合物。MS m/z 225.0[M+H]+。
步骤2E.(1R,5S)-3-(2-氯嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)((S)-2,2-二氟环丙基)甲酮。向T3P(8.86g,13.9mmol,50%的EtOAc溶液)中缓慢添加(1R,5S)-3-(2-氯嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷(1.56g,6.96mmol)、如制备1中所述般制备的(S)-2,2-二氟环丙烷-1-甲酸2,2’,2”-氮基三(乙-1-醇)盐(1.9g,6.96mmol)和三乙胺(4.9mL,34.8mmol)在ACN(4mL)中的冰浴冷却溶液。所得反应混合物在冰浴中搅拌约2小时。向冰浴冷却混合物中添加NaHCO3水溶液(100mL)。然后混合物用水(500mL)和EtOAc(500mL)稀释。分离有机层,用盐水(2x500mL)清洗,用硫酸钠干燥并过滤。浓缩滤液而得到2.3g(100%)呈黄色固体的标题化合物。MS m/z 329.1[M+H]+。[α]25 D=+38.010(c=0.2g/100mL,MeOH)。
步骤2F.((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-((R)-2-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮。向((1R,5S)-3-(2-氯嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)((S)-2,2-二氟环丙基)甲酮(500mg,1.52mmol)的异丙醇(19.6ml)溶液中添加(R)-1-(4-氨基-1H-吡唑-1-基)丙烷-2-醇(258mg,1.83mmol,1.2当量),随后添加浓盐酸(0.05mL)。所得溶液在76℃下搅拌约16小时。在减压下浓缩反应混合物。将残余物溶于水(20mL)中,在冰水浴中冷却,并通过添加氢氧化铵中和至pH>7。溶液用二氯甲烷(2x30mL)萃取。合并的有机萃取物用硫酸钠干燥并过滤。在减压下浓缩滤液。所得粗制产物通过制备型HPLC(Welch XtimateTMC18,25mm i.d.x 150mm;水(0.05%氢氧化氨v/v)-ACN;13-43%,7分钟)纯化,而得到297.4mg(45%)的标题化合物(冻干后呈白色固体)。MS m/z 434.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.90(s,1H),7.93(d,J=5.9Hz,1H),7.79(s,1H),7.44(d,J=6.4Hz,1H),6.14-6.10(m,1H),4.88(d,J=3.9Hz,1H),4.73-4.51(m,2H),4.14(br s,1H),3.95-3.90(m,3H),3.33-2.75(m,3H),2.10-1.50(m,7H),1.02(d,J=4.6Hz,3H)。[α]20 D=+52.807(c=0.2g/100mL,MeOH)。
实施例3:((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-((S)-2-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮(IC)
步骤3A.(S)-1-(4-硝基-1H-吡唑-1-基)丙烷-2-醇。向进料有(S)-(-)-环氧丙烷(6mL)的烧瓶中添加4-硝基-1H-吡唑(2.0g,20mmol),随后添加Cs2CO3(5.76g,17.7mmol)。所得混合物在15℃下搅拌约32小时。添加水(30mL),且混合物用EtOAc(3x40ml)萃取。合并的有机层用硫酸钠干燥并过滤。在减压下浓缩滤液。所得残余物在硅胶色谱法上纯化,用EtOAc:石油醚(1:1)溶剂混合物洗提,而得到2.2g(70%)浅黄色油状的标题化合物。MS m/z171.9[M+H]+。1H NMR(400MHz,CDCl3)δ8.23(s,1H),8.09(s,1H),4.31-4.24(m,1H),4.22(dd,J=13.8,2.5Hz,1H),4.06(dd,J=13.7,7.8Hz,1H),2.49(d,J=3.8Hz,1H),1.28(d,J=6.3Hz,3H)。
步骤3B.(S)-1-(4-氨基-1H-吡唑-1-基)丙烷-2-醇。向(S)-1-(4-硝基-1H-吡唑-1-基)丙烷-2-醇(2.0g,11.7mmol)的MeOH(60mL)溶液中添加Pd/C(10%Pd,249mg,0.2当量)。所得悬浮液在1atm的氢气和室温下搅拌约16小时。过滤反应混合物,且在减压下浓缩滤液而给出1.5g(91%)深色油状的标题化合物。MS m/z 142.1[M+H]+。1H NMR(400MHz,CDCl3)δ7.19(d,J=0.9Hz,1H),7.03(d,J=0.8Hz,1H),4.18-4.10(m,1H),4.02(dd,J=13.8,2.8Hz,1H),3.86(dd,J=13.8,7.9Hz,1H),3.47(s,1H),1.21(d,J=6.4Hz,3H)。[α]20 D=+38.201(c=0.2g/100mL,MeOH)。
步骤3C.((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-((S)-2-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮。向如步骤2E中所述般制备的((1R,5S)-3-(2-氯嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)((S)-2,2-二氟环丙基)甲酮(500mg,1.52mmol)的异丙醇(21.7mL)溶液中添加(S)-1-(4-氨基-1H-吡唑-1-基)丙烷-2-醇(258mg,1.83mmol,1.2当量),随后添加浓盐酸(1mL)。所得溶液在76℃下搅拌约16小时。然后在减压下浓缩反应混合物。将残余物溶于水(20mL)中,用冰水浴冷却,并通过添加氢氧化铵中和并调整至pH>7。溶液混合物用二氯甲烷(2x30ml)萃取。合并的有机萃取物用硫酸钠干燥并过滤。在减压下浓缩滤液。所得残余物通过制备型HPLC(WelchXtimateTMC18,25mm i.d.x 150mm;水(0.05%氢氧化氨v/v)-ACN;14-44%,7分钟)纯化,而得到296.4mg(45%)的标题化合物(冻干后呈白色固体)。MS m/z 434.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.90(s,1H),7.93(d,J=5.6Hz,1H),7.80(s,1H),7.44(d,J=5.6Hz,1H),6.13-6.09(m,1H),4.88(d,J=3.9Hz,1H),4.69-4.58(m,2H),4.14(br s,1H),3.95-3.92(m,3H),3.32-2.90(m,3H),2.00-1.65(m,7H),1.01(d,J=6.0Hz,3H)。[α]20 D=+56.761(c=0.2g/100mL,MeOH)。
实施例4:((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-(3-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮(ID)
步骤4A.3-(4-硝基-1H-吡唑-1-基)丙烷-1-醇。向4-硝基-1H-吡唑(1.13g,9.9mmol)在二甲基甲酰胺(20mL)中混合物添加3-溴丙醇(1.67g,12mmol)和碳酸钾(1.38g,9.99mmol)。混合物加热至60℃约16h。在减压下浓缩混合物。向残余物中添加水(100mL),且混合物用EtOAc(3x100mL)萃取。合并的有机萃取物用硫酸钠干燥并过滤。在减压下浓缩滤液而得到1.7g(99%)的标题化合物。MS m/z 171.9[M+H]+。
步骤4B.3-(4-氨基-1H-吡唑-1-基)丙烷-1-醇。向3-(4-硝基-1H-吡唑-1-基)丙烷-1-醇(1.70g,9.93mmol)在MeOH(19.0mL)中的混合物添加Pd/C(10%Pd,0.60g,0.06mmol)。混合物在1atm的氢气和室温下搅拌16h。过滤混合物,且浓缩滤液而得到1.4g(100%)的标题化合物。1H NMR(400MHz,CDCl3)δ7.19-7.12(m,1H),7.07-6.99(m,1H),4.15(t,J=6.5Hz,2H),3.60(t,J=5.9Hz,2H),2.04-1.95(m,2H)。
步骤4C.((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-(3-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮。向如步骤2E中所述般制备的((1R,5S)-3-(2-氯嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)((S)-2,2-二氟环丙基)甲酮(600mg,1.8mmol)在异丙醇(24mL)中混合物添加3-(4-氨基-1H-吡唑-1-基)丙烷-1-醇(515mg,3.6mmol)和浓盐酸(1mL)。混合物加热至70℃约16小时。在减压下浓缩混合物。将残余物溶解在水(20mL)中,并在冰水浴中冷却的同时用氢氧化铵将pH值调整至>7。混合物用二氯甲烷(2x30mL)萃取。有机萃取物用硫酸钠干燥并过滤。浓缩滤液。残余物通过制备型HPLC(Welch XtimateTMC18,25mm i.d.x 150mm;水(0.05%氢氧化氨v/v)-ACN;14-42%,7分钟)纯化,而得到432mg(55%)的标题化合物,冻干后呈白色固体。MS m/z 434.3[M+H]+。1HNMR(400MHz,DMSO-d6)δ8.90(s,1H),7.93(d,J=5.6Hz,1H),7.75(s,1H),7.46(d,J=4.8Hz,1H),6.14-6.10(m,1H),4.71-4.56(m,3H),4.19(br,1H),4.10(t,J=6.9Hz,2H),3.38(q,J=5.9Hz,2H),3.27-2.90(m,3H),2.00-1.64(m,9H)。
测定流程
JAK家族Caliper酶测定法
通过活体外方法评价本发明化合物以测定其各自抑制JAK激酶(TYK2、JAK1、JAK2、JAK3)的能力。抑制活性是如下测定的:使用微流体测定法(LabChip 3000TM迁移率偏移技术,Caliper Life Science)来监测JAK家族的四个成员--JAK1、JAK2、JAK3和TYK2中各成员的重组人类激酶结构域对合成肽的磷酸化。反应混合物含有1μM的荧光标记的合成肽(浓度低于表观Km),以及1mM ATP。
将化合物的DMSO溶液添加到384孔板中。反应混合物含有10mM HEPES,pH7.4、10mMMgCl2、0.01%BSA、0.0005%Tween 20TM、1mM ATP和1μM肽底物。JAK1和TYK2测定法含有1μM的IRStide肽(5FAM-KKSRGDYMTMQID),而JAK2和JAK3测定法含有1μM的JAKtide肽(FITC-KGGEEEEYFELVKK)。所述测定法通过添加20nM JAK1、1nM JAK2、1nM JAK或1nM TYK2酶开始并在室温下针对JAK1培养三小时,针对JAK2培养60分钟,针对JAK3培养75分钟或针对TYK2培养135分钟。酶浓度和培养时间针对各新的酶制剂优化,并且均随时间略有修改,以确保20%至30%的磷酸化。所述测定法用15μL的180mM HEPES,pH 7.4、20mM EDTA、和0.2%Coating Reagent3停止。将测定法板置于Caliper Life Science LC3000仪器上,并使用适当的分离条件对各孔取样以测量未磷酸化肽和磷酸化肽。
数据分析
使用来自Caliper Life Sciences的HTS孔分析软件收集数据。数据分析的数据输出为基于峰高计算的转化产物百分比(等式1)。
等式1:%转化产物=100*((产物)/(产物+底物))
基于各测定法板内含有的阳性及阴性对照孔,计算在各化合物浓度下的效果百分比(等式2)。阳性对照孔含有会产生与背景相当(亦即,完全抑制的JAK1、JAK2、JAK3或TYK2)的磷酸化水平之饱和浓度的对照化合物。阴性对照孔仅含有DMSO(浓度与化合物孔相同),其用于设定在测定法中的基线活性(即,未受抑制的JAK1、JAK2、JAK3或TYK2)。
等式2:%效果=100*((样品孔-阴性对照)/(阳性对照-阴性对照))
效果百分比是相对于化合物浓度化合物作图。使用4参数逻辑模型拟合非约束S形曲线并测定50%抑制所需的化合物浓度(IC50)(等式3)。
等式3:y=((max-min)/(1+((x/IC50)^s)))+min
其中max是最大渐近线(完全抑制),min是最小渐近线(无抑制),以及s是斜率因子。各化合物的IC50值以nM报告在表1中:
表1
HWB INFα诱导的STAT3磷酸化测定法
在人类全血流式细胞计量术测定法中评估本发明化合物抑制干扰素α信号传导的能力。干扰素α经由TYK2及JAK1发信号。测试品是制备成在100%DMSO中的30mM的原液,然后稀释成10mM。在DMSO中创建11点3稀释系列,其中最高浓度为5mM。通过添加4μL上述测试品溶液到96μL的PBS中作出进一步稀释,其中最高浓度为400μM。人类全血(HWB)是经由静脉穿刺流到含有肝素钠的VacutainerTM收集管(目录号366480;Becton Dickinson,FranklinLakes,NJ)中而从健康供体收集。使用之前血液回温至37℃。向96孔聚丙烯板(VWR 10755-246)中每孔添加90μL的HWB,随后添加5μL上面所制备的测试品而给出最高浓度20μM。将板混合并在37℃下培养60分钟。向各孔中添加5μL的人类IFNα(Universal Type I IFN,R&DSystems#11200-2;最终浓度为5000U/ml)或D-PBS(未受刺激的对照),混合并在37℃下培养15分钟。通过以700μL/孔向所有孔中添加裂解/固定缓冲液[BD Phosflow 5x Lyse/FixBuffer(BD#558049)]来淬灭反应并在37℃下培养20分钟;用FACS缓冲液[含有0.1%BSA和0.1%迭氮化钠的D-PBS(Invitrogen cat#14190)]清洗后,向各孔添加400μL的冰90%甲醇/水并在4℃下培养30分钟。用FACS冲液再作一次清洗且将所有样品最终再悬浮于150μL/孔的Alexa Fluor 647缀合抗磷酸-STAT3(pY705)抗体(BD#557815)(以1:150稀释于FACS冲液中)中。样品在4℃下培养过夜。
流式细胞计量术
将样品转移至96孔U底板(Falcon#353077),并在配备HTS板装载器(BDBiosciences)的LSRFortessa上进行流式细胞计量术分析。为了pSTAT3的直方图分析对淋巴细胞群体进行门控。使用未受刺激的细胞定义背景荧光并将门控放在峰的脚,以包括~0.5%的经门控群体。使用FACSDiva的8.0版(BD Biosciences)软件进行直方图统计分析。测量磷酸STAT水平的相对荧光单位(RFU)是通过将阳性群体百分比乘上其平均荧光计算的。来自11个化合物浓度(各浓度单个)的数据是基于下式标准化成对照的百分比:
对照的%=100x(A-B)/(C-B)
其中A是来自含有化合物和细胞因子的孔的RFU,B是来自没有细胞因子和化合物的孔的RFU(最小荧光),以及C是来自仅含有细胞因子的孔的RFU(最大荧光)。使用Prism的7版软件(GraphPad,La Jolla,CA)测定抑制曲线和IC50值。
表2
以Th2刺激的离体人类皮肤测定法中的生物标志物调节
评估本发明化合物在局部应用后调节以Th2刺激的离体人类皮肤中的CXCL10生物标志物的能力。
将化合物溶解在由以下所构成的调配物中:
10%w/w白凡士林,
5%w/w矿物油,
10%w/w乳化蜡,
2%w/w油醇,
46%w/w水,
15%w/w二乙二醇单乙醚,
10%w/w聚乙二醇(PEG)400,和
1%w/w 2-聚氧乙醇(pehoxyethanol)。
从手术试样中新鲜切出的人类皮肤用皮刀切割成750μm厚,并安装在7mm静态Franz槽中以进行组织培养,而使得皮肤的上表面暴露于在Franz槽供体室中的空气,而底部(真皮)则暴露于角化培养基。总共使用了二个皮肤供体(每个供体每个治疗n=6)。培养是在标准组织培养箱中进行。将化合物以1%w/w的浓度溶解在所指调配物中,并向皮肤以每个样品10μL(每cm2大约18μL)且在每个供体4-6重复下顶端地添加。16h后,培养基更换为含有抗CD3 mAb、抗CD28 mAb、IL-2、IL-4、IL-33和TSLP的刺激鸡尾酒。在37℃下继续培养额外24小时。然后收获皮肤,用RNALater溶液处理并加工以供RNA提取和qPCR,其以双份重复运行。可测量MMP12、CCL26、CXCL10和聚丝蛋白。各样品的结果都用其自身的GAPDH内标准品标准化,该内标准品不会明显受刺激或化合物影响。将倍数变化用未处理的样品标准化。结果总结在下表3和图2中。
表3
体外人类肝细胞清除率测定法
高通量人类肝细胞底物耗尽测定法是在如先前所述般配制的384孔中进行[Di etal.,Eur.J.Med.Chem.,2012,57,441]。简言之,将冷冻保存的人类肝细胞解冻并重新悬浮在补充有HEPES和Na2CO3的Williams’E培养基中。使用台盼蓝排除法将细胞计数。向悬浮在Williams’E培养基缓冲液中的人类肝细胞中添加测试化合物,并在37℃下的加湿CO2培养箱(75%相对湿度,5%CO2/空气)中培养4小时。最终培养以总体积15μL(具有0.1%DMSO)含有50万个细胞/mL和1μM的测试化合物。在各种时间点(0、3、10、30、60、120和240分钟),取出等分样品并用含有内标准品的冷乙腈淬灭。样品在4℃下以3000rpm离心10分钟,将上清液转移到新板中,在进行LC-MS/MS分析前将其密封。表观代谢内在清除率(CLint,met,app)是基于底物耗尽半衰期测定的,该半衰期是从各化合物的峰面积反应与内标准品峰面积反应的比值估算的,如早先所述般[Di et al.,Eur.J.Med.Chem.,2012,57,441]。结果总结在下表4中。
表4
Claims (21)
2.根据权利要求1所述的化合物或其药学上可接受的盐,其中R1为羟基且R2为氢。
3.根据权利要求1所述的化合物或其药学上可接受的盐,其中R1为氢且R2为羟基。
8.根据权利要求1所述的化合物,其选自以下组中:
((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮;
((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-((R)-2-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮;
((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-((S)-2-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮;及
((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-(3-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮;
或其药学上可接受的盐。
9.((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮。
10.((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-((R)-2-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮。
11.((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-(3-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮。
12.((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-((S)-2-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮。
13.根据权利要求1至12中任一项所述的化合物或其药学上可接受的盐,其呈经分离形式。
14.根据权利要求1至13中任一项所述的化合物或其药学上可接受的盐,其呈结晶形式。
15.药物组合物,其包含根据权利要求1至14中任一项所述的化合物或其药学上可接受的盐,以及药学上可接受的载剂。
16.治疗或预防选自下列之疾病或病症的方法:炎症、自体免疫性疾病、神经炎症、关节炎、类风湿关节炎、脊椎关节病、全身性红斑狼疮、狼疮性肾炎、骨关节炎、痛风性关节炎、疼痛、发热、肺结节病、硅肺病、心血管疾病、动脉粥样硬化、心肌梗塞、血栓形成、充血性心脏衰竭和心脏再灌注损伤、心肌病、中风、局部缺血、再灌注损伤、脑水肿、脑外伤、神经退化、肝病、炎性肠病、克罗恩病、溃疡性结肠炎、肾炎、视网膜炎、视网膜病、黄斑变性、青光眼、糖尿病(1型及2型)、糖尿病性神经病、病毒和细菌感染、肌痛、内毒素休克、中毒性休克综合征、骨质疏松症、多发性硬化、子宫内膜异位、痛经、阴道炎、念珠菌病、癌症、纤维化、肥胖、肌营养不良、多肌炎、皮肌炎、自体免疫性肝炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、白癜风、阿尔茨海默病、皮肤潮红、湿疹、银屑病、特应性皮炎、晒伤、蟹足肿、肥厚性瘢痕、风湿性疾病、荨麻疹、盘状狼疮、皮肤狼疮、中枢神经系统狼疮、银屑病关节炎、哮喘、过敏性哮喘、包括Aicardi-Goutières综合征和其他过度表达I型干扰素的孟德尔疾病的I型干扰素病、原发性进行性多发性硬化、复发性缓解型多发性硬化、非酒精性脂肪肝病、非酒精性脂肪性肝炎、硬皮病、斑秃、疤痕性脱发、痒疹、结节性痒疹、CPUO、苔藓疾病、扁平苔藓、史蒂文斯-约翰逊综合征、脊椎病、肌炎、血管炎、天疱疮、狼疮、重性抑郁症、过敏、干眼综合征、移植排斥、癌症、感染性休克、心肺功能障碍、急性呼吸疾病、强直性脊柱炎、恶病质、慢性移植物抗宿主病、急性移植物抗宿主病、乳糜泻、特发性血小板减少性血栓性紫癜、血栓性血小板减少性紫癜、重症肌无力、Sjogren综合征、上皮增生、软骨炎症、骨退化、幼年型关节炎、幼年型类风湿性关节炎、少关节型幼年型类风湿性关节炎、多关节型幼年型类风湿性关节炎、全身性发病幼年型类风湿性关节炎、幼年型强直性脊柱炎、幼年型肠病性关节炎、幼年型Reter综合征、SEA综合征、幼年型皮肌炎、幼年型银屑病关节炎、幼年型硬皮病、幼年型全身性红斑狼疮、幼年型脉管炎、少关节型类风湿性关节炎、多关节型类风湿性关节炎、全身性发病类风湿性关节炎、肠病性关节炎、反应性关节炎、Reter综合征、肌炎、多发性肌炎、皮肌炎、结节性多动脉炎、Wegener肉芽肿病、动脉炎、风湿性多肌痛、结节病、硬化、原发性胆汁性硬化、硬化性胆管炎、皮炎、Still病、慢性阻塞性肺病、Guillain-Barre病、毒性弥漫性甲状腺肿、艾迪生病、雷诺现象、银屑病上皮增生、斑块型银屑病、滴状银屑病、反向性银屑病、脓疱型银屑病、红皮症银屑病、与致病性淋巴细胞的活动相关或由其引起的免疫紊乱、非传染性葡萄膜炎、Behcet病和伏格特-小柳-原田综合征,
所述方法包括向有此需要的对象给药治疗有效量之根据权利要求1至14中任一项所述的化合物或其药学上可接受的盐。
17.根据权利要求16所述的方法,其中所述化合物是选自以下组中:
((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮;
((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-((R)-2-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮;
((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-((S)-2-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮;及
((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-(3-羟基丙基)-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮;
或其药学上可接受的盐。
18.根据权利要求16所述的方法,其中所述化合物为((S)-2,2-二氟环丙基)((1R,5S)-3-(2-((1-丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮,或其药学上可接受的盐,其呈经分离形式。
19.根据权利要求16所述的方法,其中所述化合物为((S)-2,2-二氟环丙基))((1R,5S)-3-(2-((1-(3-羟基丙基-1H-吡唑-4-基)氨基)嘧啶-4-基)-3,8-二氮杂双环[3.2.1]辛烷-8-基)甲酮,或其药学上可接受的盐,其呈经分离形式。
20.根据权利要求1至14中任一项所述的化合物或其药学上可接受的盐在制造用于治疗对其指示用药JAK1抑制剂之紊乱的药物中的用途。
21.药物组合,其包含根据权利要求1至14中任一项所述的化合物或其药学上可接受的盐,其呈经分离形式;以及一或多种额外的药理活性化合物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202063047606P | 2020-07-02 | 2020-07-02 | |
US63/047,606 | 2020-07-02 | ||
PCT/IB2021/055851 WO2022003583A1 (en) | 2020-07-02 | 2021-06-30 | Aminopyrimidinyl derivatives |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115996930A true CN115996930A (zh) | 2023-04-21 |
Family
ID=76829589
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202180046561.3A Pending CN115996930A (zh) | 2020-07-02 | 2021-06-30 | 氨基嘧啶基衍生物 |
Country Status (14)
Country | Link |
---|---|
US (1) | US11655252B2 (zh) |
EP (1) | EP4175959A1 (zh) |
JP (1) | JP2023531992A (zh) |
KR (1) | KR20230018459A (zh) |
CN (1) | CN115996930A (zh) |
AR (1) | AR122860A1 (zh) |
AU (1) | AU2021301417B2 (zh) |
BR (1) | BR112022024929A2 (zh) |
CA (1) | CA3190243A1 (zh) |
IL (1) | IL299603A (zh) |
MX (1) | MX2022015986A (zh) |
TW (1) | TWI782599B (zh) |
UY (1) | UY39308A (zh) |
WO (1) | WO2022003583A1 (zh) |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107074867A (zh) * | 2014-08-21 | 2017-08-18 | 辉瑞公司 | 作为jak抑制剂的氨基嘧啶基化合物 |
WO2019173676A1 (en) * | 2018-03-09 | 2019-09-12 | Children's Hospital Medical Center | Compositions and methods for the treatment of macrophage activation syndrome |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2287971T3 (es) | 1997-08-11 | 2007-12-16 | Pfizer Products Inc. | Dispersiones farmaceuticas solidas con biodisponibilidad incrementada. |
CN103298794A (zh) * | 2010-11-09 | 2013-09-11 | 塞尔卓姆有限公司 | 作为tyk2抑制剂的吡啶化合物及其氮杂类似物 |
US9187453B2 (en) * | 2012-03-28 | 2015-11-17 | Takeda Pharmaceutical Company Limited | Heterocyclic compound |
GB201303109D0 (en) * | 2013-02-21 | 2013-04-10 | Domainex Ltd | Novel pyrimidine compounds |
MX361770B (es) * | 2014-01-24 | 2018-12-17 | Bayer Cropscience Ag | Método para la preparación de 1-alquil-3-difluorometil-5-fluor-1h- pirazol-4-carbaldehídos y 1-alquil-3-difluorometil-5-fluor-1h-pira zol-4-carboxilatos. |
CN112142743A (zh) * | 2019-06-28 | 2020-12-29 | 广州诺诚健华医药科技有限公司 | 杂环类化合物、其制备方法及其在医药学上的应用 |
-
2021
- 2021-06-29 TW TW110123811A patent/TWI782599B/zh active
- 2021-06-30 KR KR1020227046012A patent/KR20230018459A/ko unknown
- 2021-06-30 AU AU2021301417A patent/AU2021301417B2/en active Active
- 2021-06-30 CN CN202180046561.3A patent/CN115996930A/zh active Pending
- 2021-06-30 BR BR112022024929A patent/BR112022024929A2/pt unknown
- 2021-06-30 EP EP21739446.9A patent/EP4175959A1/en active Pending
- 2021-06-30 JP JP2022579799A patent/JP2023531992A/ja active Pending
- 2021-06-30 CA CA3190243A patent/CA3190243A1/en active Pending
- 2021-06-30 WO PCT/IB2021/055851 patent/WO2022003583A1/en active Application Filing
- 2021-06-30 US US17/363,494 patent/US11655252B2/en active Active
- 2021-06-30 MX MX2022015986A patent/MX2022015986A/es unknown
- 2021-06-30 IL IL299603A patent/IL299603A/en unknown
- 2021-07-01 AR ARP210101853A patent/AR122860A1/es unknown
- 2021-07-01 UY UY0001039308A patent/UY39308A/es unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107074867A (zh) * | 2014-08-21 | 2017-08-18 | 辉瑞公司 | 作为jak抑制剂的氨基嘧啶基化合物 |
WO2019173676A1 (en) * | 2018-03-09 | 2019-09-12 | Children's Hospital Medical Center | Compositions and methods for the treatment of macrophage activation syndrome |
Also Published As
Publication number | Publication date |
---|---|
WO2022003583A1 (en) | 2022-01-06 |
AU2021301417A1 (en) | 2023-01-19 |
US20220002301A1 (en) | 2022-01-06 |
US11655252B2 (en) | 2023-05-23 |
EP4175959A1 (en) | 2023-05-10 |
BR112022024929A2 (pt) | 2023-01-31 |
AU2021301417B2 (en) | 2023-09-28 |
AR122860A1 (es) | 2022-10-12 |
JP2023531992A (ja) | 2023-07-26 |
TW202208371A (zh) | 2022-03-01 |
TWI782599B (zh) | 2022-11-01 |
MX2022015986A (es) | 2023-02-01 |
CA3190243A1 (en) | 2022-01-06 |
KR20230018459A (ko) | 2023-02-07 |
UY39308A (es) | 2022-01-31 |
IL299603A (en) | 2023-03-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11479543B2 (en) | Heterocyclic RIP1 kinase inhibitors | |
CN109311851B (zh) | 二氢嘧啶基苯并氮杂䓬甲酰胺化合物 | |
EP3183247B9 (en) | Aminopyrimidinyl compounds as jak inhibitors | |
JP6800969B2 (ja) | 呼吸器疾患の処置のためのjakキナーゼ阻害剤化合物 | |
US10626116B2 (en) | Crystalline form of BTK kinase inhibitor and preparation method thereof | |
RU2493157C2 (ru) | ПРОИЗВОДНЫЕ ПИРРОЛО[2,3-d]ПИРИМИДИНА | |
US10875847B2 (en) | Aminopyrazoles as selective janus kinase inhibitors | |
US20210292340A1 (en) | Cell necrosis inhibitor, preparation method therefor and use thereof | |
JP2009528296A (ja) | Val−4によって媒介される白血球の接着を阻害するピリミジニルスルホンアミド化合物 | |
EP4083038A1 (en) | Pyridazinyl thiazolecarboxamide compound | |
US20230227469A1 (en) | Rip1k inhibitors | |
US20170217897A1 (en) | Quinolone derivatives as antibacterials | |
CN110997657A (zh) | 咪唑烷化合物 | |
US20220411383A1 (en) | AMINOPYRAZINE DERIVATIVES AS PI3K-y INHIBITORS | |
US20240190904A1 (en) | Heteroaryl compounds as inhibitors of RIP2 kinase, composition and application thereof | |
US10550125B2 (en) | Prodrugs of imidazotriazine compounds as CK2 inhibitors | |
US11655252B2 (en) | Aminopyrimidinyl derivatives | |
RU2817349C1 (ru) | Производные аминопиримидинила | |
US20230303534A1 (en) | Preparation method for novel rho-related protein kinase inhibitor and intermediate in preparation method | |
KR20230100919A (ko) | 아미노피리미디닐 유도체 | |
WO2024062360A1 (en) | Heterocyclic sik inhibitors | |
US20230278993A1 (en) | Novel tricyclic aromatic heterocyclic compound and preparation method therefor, pharmaceutical composition and use thereof | |
WO2023244946A1 (en) | Prodrugs of stat3 inhibitors | |
CN115677831A (zh) | 拟肽类stat降解药物、组合物及应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 40087373 Country of ref document: HK |