EA034914B1 - Соединения ингибитора jak-киназы для лечения респираторного заболевания - Google Patents
Соединения ингибитора jak-киназы для лечения респираторного заболевания Download PDFInfo
- Publication number
- EA034914B1 EA034914B1 EA201891091A EA201891091A EA034914B1 EA 034914 B1 EA034914 B1 EA 034914B1 EA 201891091 A EA201891091 A EA 201891091A EA 201891091 A EA201891091 A EA 201891091A EA 034914 B1 EA034914 B1 EA 034914B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- alkyl
- compound
- ethyl
- formula
- imidazo
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 280
- 208000023504 respiratory system disease Diseases 0.000 title claims abstract description 27
- 238000011282 treatment Methods 0.000 title claims description 15
- 229940043355 kinase inhibitor Drugs 0.000 title abstract description 5
- 239000003757 phosphotransferase inhibitor Substances 0.000 title abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 59
- 150000003839 salts Chemical class 0.000 claims abstract description 53
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 38
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 18
- 230000003176 fibrotic effect Effects 0.000 claims abstract description 15
- 241000124008 Mammalia Species 0.000 claims abstract description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 165
- 125000000217 alkyl group Chemical group 0.000 claims description 136
- -1 tetrahydropyran-4yl Chemical group 0.000 claims description 105
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 92
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 72
- 229910052739 hydrogen Inorganic materials 0.000 claims description 58
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 57
- 239000001257 hydrogen Substances 0.000 claims description 57
- 239000000725 suspension Substances 0.000 claims description 56
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 42
- 229910052757 nitrogen Inorganic materials 0.000 claims description 35
- 208000006673 asthma Diseases 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 29
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 28
- 125000001424 substituent group Chemical group 0.000 claims description 28
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 27
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 26
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- 239000003814 drug Substances 0.000 claims description 19
- 125000002947 alkylene group Chemical group 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 15
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 14
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 14
- 125000006239 protecting group Chemical group 0.000 claims description 13
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims description 11
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 10
- 201000003883 Cystic fibrosis Diseases 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 10
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 9
- 239000003937 drug carrier Substances 0.000 claims description 9
- 125000003566 oxetanyl group Chemical group 0.000 claims description 9
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 claims description 9
- 206010035664 Pneumonia Diseases 0.000 claims description 7
- 206010035742 Pneumonitis Diseases 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 6
- 206010014561 Emphysema Diseases 0.000 claims description 6
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims description 6
- ABVFPTCSUWNAEA-UHFFFAOYSA-N O.CCc1cc(O)c(F)cc1-c1ccc2c(n[nH]c2c1)-c1nc2CCN(Cc2[nH]1)C1CCN(C)CC1 Chemical compound O.CCc1cc(O)c(F)cc1-c1ccc2c(n[nH]c2c1)-c1nc2CCN(Cc2[nH]1)C1CCN(C)CC1 ABVFPTCSUWNAEA-UHFFFAOYSA-N 0.000 claims description 6
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 6
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 6
- 206010006451 bronchitis Diseases 0.000 claims description 6
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 206010006448 Bronchiolitis Diseases 0.000 claims description 4
- 206010029888 Obliterative bronchiolitis Diseases 0.000 claims description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 4
- 201000003848 bronchiolitis obliterans Diseases 0.000 claims description 4
- 208000023367 bronchiolitis obliterans with obstructive pulmonary disease Diseases 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 229940011051 isopropyl acetate Drugs 0.000 claims description 4
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 3
- YXKUPJSJNAKRLQ-UHFFFAOYSA-N CN(CCN1CC2=C(CC1)NC(=N2)C1=NNC2=CC(=CC=C12)C1=CC(=C(C=C1CC)O)F)C Chemical compound CN(CCN1CC2=C(CC1)NC(=N2)C1=NNC2=CC(=CC=C12)C1=CC(=C(C=C1CC)O)F)C YXKUPJSJNAKRLQ-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 206010069351 acute lung injury Diseases 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 claims description 2
- HGQQGQFLBDQYCO-UHFFFAOYSA-N N1CC(C1)N1CC2=C(CC1)NC(=N2)C1=NNC2=CC(=CC=C12)C1=CC(=C(C=C1CC)O)F Chemical compound N1CC(C1)N1CC2=C(CC1)NC(=N2)C1=NNC2=CC(=CC=C12)C1=CC(=C(C=C1CC)O)F HGQQGQFLBDQYCO-UHFFFAOYSA-N 0.000 claims description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 230000004907 flux Effects 0.000 claims description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- YKKSLFAFHDNXRX-UHFFFAOYSA-N C(C)C=1C(=CC(=C(C=1)O)F)C1=CC=C2C(=NNC2=C1)C=1NC2=C(CN(CC2)C2CN(C2)C(C)C)N=1 Chemical compound C(C)C=1C(=CC(=C(C=1)O)F)C1=CC=C2C(=NNC2=C1)C=1NC2=C(CN(CC2)C2CN(C2)C(C)C)N=1 YKKSLFAFHDNXRX-UHFFFAOYSA-N 0.000 claims 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims 1
- 229940126214 compound 3 Drugs 0.000 claims 1
- 230000003993 interaction Effects 0.000 claims 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 52
- 102000042838 JAK family Human genes 0.000 abstract description 7
- 108091082332 JAK family Proteins 0.000 abstract description 7
- 230000008569 process Effects 0.000 abstract description 2
- 239000011541 reaction mixture Substances 0.000 description 102
- 239000000203 mixture Substances 0.000 description 67
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 63
- 239000007787 solid Substances 0.000 description 56
- 239000000243 solution Substances 0.000 description 52
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 51
- 238000004458 analytical method Methods 0.000 description 47
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 38
- 210000004072 lung Anatomy 0.000 description 38
- 239000000047 product Substances 0.000 description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 238000002360 preparation method Methods 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- 230000005764 inhibitory process Effects 0.000 description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- 230000014759 maintenance of location Effects 0.000 description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 238000003556 assay Methods 0.000 description 23
- 108090000176 Interleukin-13 Proteins 0.000 description 22
- 102000003816 Interleukin-13 Human genes 0.000 description 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 22
- 238000002953 preparative HPLC Methods 0.000 description 22
- 239000012065 filter cake Substances 0.000 description 21
- 239000000843 powder Substances 0.000 description 21
- 238000004128 high performance liquid chromatography Methods 0.000 description 20
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 19
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 19
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 19
- 235000019439 ethyl acetate Nutrition 0.000 description 19
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical group O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000012360 testing method Methods 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 17
- 230000000694 effects Effects 0.000 description 17
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 17
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 201000010099 disease Diseases 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 14
- 238000005516 engineering process Methods 0.000 description 14
- 239000010410 layer Substances 0.000 description 14
- 238000010898 silica gel chromatography Methods 0.000 description 14
- 238000005481 NMR spectroscopy Methods 0.000 description 13
- 229940124597 therapeutic agent Drugs 0.000 description 13
- 102000004127 Cytokines Human genes 0.000 description 12
- 108090000695 Cytokines Proteins 0.000 description 12
- 241001465754 Metazoa Species 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 238000002390 rotary evaporation Methods 0.000 description 12
- 239000003981 vehicle Substances 0.000 description 12
- ZTQVHAJNEIOLPB-UHFFFAOYSA-N 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]phenol Chemical compound CCC1=CC(O)=C(F)C=C1C1=CC=C(C(=NN2)C=3NC=4CCNCC=4N=3)C2=C1 ZTQVHAJNEIOLPB-UHFFFAOYSA-N 0.000 description 11
- 150000001721 carbon Chemical group 0.000 description 11
- 239000006199 nebulizer Substances 0.000 description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 10
- 239000012458 free base Substances 0.000 description 10
- 229940071648 metered dose inhaler Drugs 0.000 description 10
- 239000000546 pharmaceutical excipient Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 238000002411 thermogravimetry Methods 0.000 description 10
- 241000223600 Alternaria Species 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 210000003979 eosinophil Anatomy 0.000 description 9
- 150000003840 hydrochlorides Chemical class 0.000 description 9
- 239000003921 oil Substances 0.000 description 9
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 8
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 8
- 241000699666 Mus <mouse, genus> Species 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 125000006299 oxetan-3-yl group Chemical group [H]C1([H])OC([H])([H])C1([H])* 0.000 description 8
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 8
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 8
- 210000001519 tissue Anatomy 0.000 description 8
- SLHPSNWCMGCQLB-UHFFFAOYSA-N 5-benzyl-2-(6-bromo-1H-indazol-3-yl)imidazo[4,5-c]pyridine Chemical compound C(C1=CC=CC=C1)N1C=C2C(C=C1)=NC(=N2)C1=NNC2=CC(=CC=C12)Br SLHPSNWCMGCQLB-UHFFFAOYSA-N 0.000 description 7
- 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 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 7
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 7
- 239000013543 active substance Substances 0.000 description 7
- 125000000753 cycloalkyl group Chemical group 0.000 description 7
- 208000035475 disorder Diseases 0.000 description 7
- 239000008101 lactose Substances 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 230000003285 pharmacodynamic effect Effects 0.000 description 7
- 229910052700 potassium Inorganic materials 0.000 description 7
- 239000011591 potassium Substances 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 230000002829 reductive effect Effects 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 6
- 229940122245 Janus kinase inhibitor Drugs 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 108010011005 STAT6 Transcription Factor Proteins 0.000 description 6
- 102100023980 Signal transducer and activator of transcription 6 Human genes 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 125000004429 atom Chemical group 0.000 description 6
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- 231100000673 dose–response relationship Toxicity 0.000 description 6
- 125000000623 heterocyclic group Chemical group 0.000 description 6
- 230000004054 inflammatory process Effects 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 230000026731 phosphorylation Effects 0.000 description 6
- 238000006366 phosphorylation reaction Methods 0.000 description 6
- 230000003389 potentiating effect Effects 0.000 description 6
- 239000003380 propellant Substances 0.000 description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
- 238000001179 sorption measurement Methods 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 102100032028 Non-receptor tyrosine-protein kinase TYK2 Human genes 0.000 description 5
- 108010010057 TYK2 Kinase Proteins 0.000 description 5
- 239000000443 aerosol Substances 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 230000001413 cellular effect Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 231100000135 cytotoxicity Toxicity 0.000 description 5
- 230000003013 cytotoxicity Effects 0.000 description 5
- 230000001419 dependent effect Effects 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 150000005828 hydrofluoroalkanes Chemical class 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- 230000000670 limiting effect Effects 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- VBKNTGMWIPUCRF-UHFFFAOYSA-M potassium;fluoride;hydrofluoride Chemical compound F.[F-].[K+] VBKNTGMWIPUCRF-UHFFFAOYSA-M 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- 238000005292 vacuum distillation Methods 0.000 description 5
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 4
- LTBNCMZYOOIWFC-UHFFFAOYSA-N 1-benzyl-4-iminopyridin-3-amine Chemical compound C1=CC(=N)C(N)=CN1CC1=CC=CC=C1 LTBNCMZYOOIWFC-UHFFFAOYSA-N 0.000 description 4
- RKSHRDUFWGVQSL-UHFFFAOYSA-N 1-bromo-2-ethyl-5-fluoro-4-phenylmethoxybenzene Chemical compound C(C1=CC=CC=C1)OC1=C(C=C(C(=C1)CC)Br)F RKSHRDUFWGVQSL-UHFFFAOYSA-N 0.000 description 4
- GGGMBSBQEAELRI-UHFFFAOYSA-N 2-(2-ethyl-5-fluoro-4-phenylmethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Chemical compound C(C1=CC=CC=C1)OC1=CC(=C(C=C1F)B1OC(C(O1)(C)C)(C)C)CC GGGMBSBQEAELRI-UHFFFAOYSA-N 0.000 description 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 4
- UPJNSCOYLNAEKD-UHFFFAOYSA-N C(C1=CC=CC=C1)N1CC2=C(CC1)NC(=N2)C1=NNC2=CC(=CC=C12)Br Chemical compound C(C1=CC=CC=C1)N1CC2=C(CC1)NC(=N2)C1=NNC2=CC(=CC=C12)Br UPJNSCOYLNAEKD-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 102000015696 Interleukins Human genes 0.000 description 4
- 108010063738 Interleukins Proteins 0.000 description 4
- 208000029523 Interstitial Lung disease Diseases 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 108091000080 Phosphotransferase Proteins 0.000 description 4
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 229910052796 boron Inorganic materials 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- 230000006698 induction Effects 0.000 description 4
- 229940047122 interleukins Drugs 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 102000020233 phosphotransferase Human genes 0.000 description 4
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 description 3
- HUUPVABNAQUEJW-UHFFFAOYSA-N 1-methylpiperidin-4-one Chemical compound CN1CCC(=O)CC1 HUUPVABNAQUEJW-UHFFFAOYSA-N 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- 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
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 3
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 3
- 238000007126 N-alkylation reaction Methods 0.000 description 3
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 3
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000001154 acute effect Effects 0.000 description 3
- 238000003016 alphascreen Methods 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 239000012131 assay buffer Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000002327 eosinophilic effect Effects 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 3
- 238000004020 luminiscence type Methods 0.000 description 3
- 231100000516 lung damage Toxicity 0.000 description 3
- 238000004949 mass spectrometry Methods 0.000 description 3
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 3
- 238000010172 mouse model Methods 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- 238000001144 powder X-ray diffraction data Methods 0.000 description 3
- 230000000770 proinflammatory effect Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 239000000080 wetting agent Substances 0.000 description 3
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 description 2
- 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 2
- JOAKNMHVZBHWFI-UHFFFAOYSA-N 3-methylcyclobutan-1-one Chemical compound CC1CC(=O)C1 JOAKNMHVZBHWFI-UHFFFAOYSA-N 0.000 description 2
- AGPCZZAYJRAENV-UHFFFAOYSA-N 4-bromo-5-ethyl-2-fluorophenol Chemical compound CCC1=CC(O)=C(F)C=C1Br AGPCZZAYJRAENV-UHFFFAOYSA-N 0.000 description 2
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 2
- 241000223602 Alternaria alternata Species 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- YEGFDJOAFMPJSE-UHFFFAOYSA-N C(C)C=1C(=CC(=C(C=1)O)F)C1=CC=C2C(=NNC2=C1)C=1NC2=C(CN(CC2)C2CCN(CC2)C)N=1 Chemical compound C(C)C=1C(=CC(=C(C=1)O)F)C1=CC=C2C(=NNC2=C1)C=1NC2=C(CN(CC2)C2CCN(CC2)C)N=1 YEGFDJOAFMPJSE-UHFFFAOYSA-N 0.000 description 2
- HMKKFNNTFKDYLF-UHFFFAOYSA-N C(C1=CC=CC=C1)N1CC2=C(CC1)NC(=N2)C1=NNC2=CC(=CC=C12)C1=C(C=C(C(=C1)F)OCC1=CC=CC=C1)CC Chemical compound C(C1=CC=CC=C1)N1CC2=C(CC1)NC(=N2)C1=NNC2=CC(=CC=C12)C1=C(C=C(C(=C1)F)OCC1=CC=CC=C1)CC HMKKFNNTFKDYLF-UHFFFAOYSA-N 0.000 description 2
- PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 description 2
- 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 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- 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 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
- 239000012981 Hank's balanced salt solution Substances 0.000 description 2
- 206010062016 Immunosuppression Diseases 0.000 description 2
- 108010002350 Interleukin-2 Proteins 0.000 description 2
- 108010002616 Interleukin-5 Proteins 0.000 description 2
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- CONJUINEIXHPID-UHFFFAOYSA-N N1N=C(C2=CC=CC=C12)C=1NC2=C(CNCC2)N=1 Chemical compound N1N=C(C2=CC=CC=C12)C=1NC2=C(CNCC2)N=1 CONJUINEIXHPID-UHFFFAOYSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 101710140204 Signal transducer and transcription activator Proteins 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- 102100031294 Thymic stromal lymphopoietin Human genes 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 208000037883 airway inflammation Diseases 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- OYTKINVCDFNREN-UHFFFAOYSA-N amifampridine Chemical compound NC1=CC=NC=C1N OYTKINVCDFNREN-UHFFFAOYSA-N 0.000 description 2
- 229960004012 amifampridine Drugs 0.000 description 2
- 230000003092 anti-cytokine Effects 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000004567 azetidin-3-yl group Chemical group N1CC(C1)* 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
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 2
- 210000000424 bronchial epithelial cell Anatomy 0.000 description 2
- 239000006172 buffering agent Substances 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000012054 celltiter-glo Methods 0.000 description 2
- 230000005754 cellular signaling Effects 0.000 description 2
- 238000012512 characterization method Methods 0.000 description 2
- HJWLJNBZVZDLAQ-HAQNSBGRSA-N chembl2103874 Chemical compound C1C[C@@H](CS(=O)(=O)NC)CC[C@@H]1N(C)C1=NC=NC2=C1C=CN2 HJWLJNBZVZDLAQ-HAQNSBGRSA-N 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 102000003675 cytokine receptors Human genes 0.000 description 2
- 108010057085 cytokine receptors Proteins 0.000 description 2
- 238000004807 desolvation Methods 0.000 description 2
- 238000003795 desorption Methods 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000009585 enzyme analysis Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 2
- 230000003090 exacerbative effect Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 230000001506 immunosuppresive effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- 229940125369 inhaled corticosteroids Drugs 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229960002725 isoflurane Drugs 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- MXQOYLRVSVOCQT-UHFFFAOYSA-N palladium;tritert-butylphosphane Chemical compound [Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C MXQOYLRVSVOCQT-UHFFFAOYSA-N 0.000 description 2
- 230000007310 pathophysiology Effects 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 125000003367 polycyclic group Chemical group 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000003586 protic polar solvent Substances 0.000 description 2
- 201000009732 pulmonary eosinophilia Diseases 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 238000005932 reductive alkylation reaction Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 229960005322 streptomycin Drugs 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- VMKIXWAFFVLJCK-UHFFFAOYSA-N tert-butyl 3-oxoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(=O)C1 VMKIXWAFFVLJCK-UHFFFAOYSA-N 0.000 description 2
- ACNRTYKOPZDRCO-UHFFFAOYSA-N tert-butyl n-(2-oxoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCC=O ACNRTYKOPZDRCO-UHFFFAOYSA-N 0.000 description 2
- 238000002076 thermal analysis method Methods 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 108010029307 thymic stromal lymphopoietin Proteins 0.000 description 2
- 238000011200 topical administration Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000013518 transcription Methods 0.000 description 2
- 230000035897 transcription Effects 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- BZMMRNKDONDVIB-UHFFFAOYSA-N (1-ethoxycyclopropyl)oxy-trimethylsilane Chemical compound CCOC1(O[Si](C)(C)C)CC1 BZMMRNKDONDVIB-UHFFFAOYSA-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
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- SAVGSSSLZPLNLG-UHFFFAOYSA-N 1-(2-bromoethyl)pyrrolidine Chemical compound BrCCN1CCCC1 SAVGSSSLZPLNLG-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BAXOFTOLAUCFNW-UHFFFAOYSA-N 1H-indazole Chemical compound C1=CC=C2C=NNC2=C1 BAXOFTOLAUCFNW-UHFFFAOYSA-N 0.000 description 1
- OGFKTAMJLKHRAZ-UHFFFAOYSA-N 2,2-dimethoxyacetaldehyde Chemical compound COC(OC)C=O OGFKTAMJLKHRAZ-UHFFFAOYSA-N 0.000 description 1
- 125000003562 2,2-dimethylpentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- FOCKIYZLSZKVDH-UHFFFAOYSA-N 2,3,3a,4-tetrahydro-1h-imidazo[4,5-b]pyridine Chemical group N1C=CC=C2NCNC21 FOCKIYZLSZKVDH-UHFFFAOYSA-N 0.000 description 1
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
- UKFTXWKNVSVVCJ-UHFFFAOYSA-N 2-[(6-hydrazinylpyridazin-3-yl)-(2-hydroxyethyl)amino]ethanol;hydron;dichloride Chemical class Cl.Cl.NNC1=CC=C(N(CCO)CCO)N=N1 UKFTXWKNVSVVCJ-UHFFFAOYSA-N 0.000 description 1
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- LZKSSLYIICHJEO-UHFFFAOYSA-N 3-methoxycyclobutan-1-one Chemical compound COC1CC(=O)C1 LZKSSLYIICHJEO-UHFFFAOYSA-N 0.000 description 1
- UBOOKRVGOBKDMM-UHFFFAOYSA-N 3h-imidazo[4,5-c]pyridine Chemical compound C1=NC=C2NC=NC2=C1 UBOOKRVGOBKDMM-UHFFFAOYSA-N 0.000 description 1
- MDHKCIIEVIPVLU-JERHFGHZSA-M 4-[(1r)-2-[6-[2-[(2,6-dichlorophenyl)methoxy]ethoxy]hexylamino]-1-hydroxyethyl]-2-(hydroxymethyl)phenol;diphenyl-[1-(2-phenylmethoxyethyl)-1-azoniabicyclo[2.2.2]octan-4-yl]methanol;bromide Chemical compound [Br-].C1=C(O)C(CO)=CC([C@@H](O)CNCCCCCCOCCOCC=2C(=CC=CC=2Cl)Cl)=C1.C=1C=CC=CC=1C(C12CC[N+](CCOCC=3C=CC=CC=3)(CC1)CC2)(O)C1=CC=CC=C1 MDHKCIIEVIPVLU-JERHFGHZSA-M 0.000 description 1
- DWOZNANUEDYIOF-UHFFFAOYSA-L 4-ditert-butylphosphanyl-n,n-dimethylaniline;dichloropalladium Chemical compound Cl[Pd]Cl.CN(C)C1=CC=C(P(C(C)(C)C)C(C)(C)C)C=C1.CN(C)C1=CC=C(P(C(C)(C)C)C(C)(C)C)C=C1 DWOZNANUEDYIOF-UHFFFAOYSA-L 0.000 description 1
- BKIYTAHLOFDKNE-UHFFFAOYSA-N 4-ethyl-1-fluoro-2-phenylmethoxybenzene Chemical compound C(C1=CC=CC=C1)OC1=C(C=CC(=C1)CC)F BKIYTAHLOFDKNE-UHFFFAOYSA-N 0.000 description 1
- MHGSGAMJZBVTNG-UHFFFAOYSA-N 5-ethyl-2-fluorophenol Chemical compound CCC1=CC=C(F)C(O)=C1 MHGSGAMJZBVTNG-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- HROWLWGDTOBEDM-UHFFFAOYSA-N C(C)C=1C(=CC(=C(C=1)O)F)C1=CC=C2C(=NNC2=C1)C=1NC2=C(CN(CC2)C2CN(C2)C)N=1 Chemical compound C(C)C=1C(=CC(=C(C=1)O)F)C1=CC=C2C(=NNC2=C1)C=1NC2=C(CN(CC2)C2CN(C2)C)N=1 HROWLWGDTOBEDM-UHFFFAOYSA-N 0.000 description 1
- FLPXNQWEAODYRF-UHFFFAOYSA-N CN(CC(CN1CC2=C(CC1)NC(=N2)C1=NNC2=CC(=CC=C12)C1=CC(=C(C=C1CC)O)F)F)C Chemical compound CN(CC(CN1CC2=C(CC1)NC(=N2)C1=NNC2=CC(=CC=C12)C1=CC(=C(C=C1CC)O)F)F)C FLPXNQWEAODYRF-UHFFFAOYSA-N 0.000 description 1
- YIQXKPVJSARNPK-UHFFFAOYSA-N COC(CN1CC2=C(CC1)NC(=N2)C1=NNC2=CC(=CC=C12)C1=CC(=C(C=C1CC)O)F)OC Chemical compound COC(CN1CC2=C(CC1)NC(=N2)C1=NNC2=CC(=CC=C12)C1=CC(=C(C=C1CC)O)F)OC YIQXKPVJSARNPK-UHFFFAOYSA-N 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
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 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
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 208000014085 Chronic respiratory disease Diseases 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 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-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
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 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
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 1
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000579425 Homo sapiens Proto-oncogene tyrosine-protein kinase receptor Ret Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 108090000177 Interleukin-11 Proteins 0.000 description 1
- 108010065637 Interleukin-23 Proteins 0.000 description 1
- 108010066979 Interleukin-27 Proteins 0.000 description 1
- 108010002386 Interleukin-3 Proteins 0.000 description 1
- 101710181613 Interleukin-31 Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- 108010002335 Interleukin-9 Proteins 0.000 description 1
- 230000004163 JAK-STAT signaling pathway Effects 0.000 description 1
- 102000008986 Janus Human genes 0.000 description 1
- 108050000950 Janus Proteins 0.000 description 1
- 108010024121 Janus Kinases Proteins 0.000 description 1
- 102000015617 Janus Kinases Human genes 0.000 description 1
- 108010074338 Lymphokines Proteins 0.000 description 1
- 102000008072 Lymphokines Human genes 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 101100335081 Mus musculus Flt3 gene Proteins 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
- LTVSONONTKMPLM-UHFFFAOYSA-N NCC(CN1CC2=C(CC1)NC(=N2)C1=NNC2=CC(=CC=C12)C1=CC(=C(C=C1CC)O)F)F Chemical compound NCC(CN1CC2=C(CC1)NC(=N2)C1=NNC2=CC(=CC=C12)C1=CC(=C(C=C1CC)O)F)F LTVSONONTKMPLM-UHFFFAOYSA-N 0.000 description 1
- 101150111783 NTRK1 gene Proteins 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
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 102100032341 PCNA-interacting partner Human genes 0.000 description 1
- 101710196737 PCNA-interacting partner Proteins 0.000 description 1
- 101150034459 Parpbp gene Proteins 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- VQDBNKDJNJQRDG-UHFFFAOYSA-N Pirbuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=N1 VQDBNKDJNJQRDG-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 108010044012 STAT1 Transcription Factor Proteins 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 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 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- 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 1
- 229930006000 Sucrose Natural products 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 238000006161 Suzuki-Miyaura coupling reaction Methods 0.000 description 1
- 239000004012 Tofacitinib Substances 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 108050007918 Transcription factor STAT Proteins 0.000 description 1
- 102000000887 Transcription factor STAT Human genes 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 239000002250 absorbent Substances 0.000 description 1
- 230000002745 absorbent Effects 0.000 description 1
- 239000003655 absorption accelerator Substances 0.000 description 1
- 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
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- YAJCHEVQCOHZDC-QMMNLEPNSA-N actrapid Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3N=CNC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@H](C)CC)[C@H](C)CC)[C@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C(N)=O)C1=CNC=N1 YAJCHEVQCOHZDC-QMMNLEPNSA-N 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000013567 aeroallergen Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 230000002009 allergenic effect Effects 0.000 description 1
- 208000026935 allergic disease Diseases 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
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 238000011230 antibody-based therapy Methods 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 125000005101 aryl methoxy carbonyl group Chemical group 0.000 description 1
- 125000005002 aryl methyl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229940098165 atrovent Drugs 0.000 description 1
- CREXVNNSNOKDHW-UHFFFAOYSA-N azaniumylideneazanide Chemical group N[N] CREXVNNSNOKDHW-UHFFFAOYSA-N 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
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000008004 cell lysis buffer Substances 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- KEWHKYJURDBRMN-XSAPEOHZSA-M chembl2134724 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-XSAPEOHZSA-M 0.000 description 1
- 239000013000 chemical inhibitor Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 238000007796 conventional method Methods 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
- 229910052593 corundum Inorganic materials 0.000 description 1
- 239000010431 corundum Substances 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- USVZFSNDGFNNJT-UHFFFAOYSA-N cyclopenta-1,4-dien-1-yl(diphenyl)phosphane (2,3-dichlorocyclopenta-1,4-dien-1-yl)-diphenylphosphane iron(2+) Chemical compound [Fe++].c1cc[c-](c1)P(c1ccccc1)c1ccccc1.Clc1c(cc[c-]1Cl)P(c1ccccc1)c1ccccc1 USVZFSNDGFNNJT-UHFFFAOYSA-N 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 238000007405 data analysis Methods 0.000 description 1
- 238000013480 data collection Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000011903 deuterated solvents Substances 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 125000004427 diamine group Chemical group 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical compound CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000013024 dilution buffer Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000007580 dry-mixing Methods 0.000 description 1
- 238000000132 electrospray ionisation Methods 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 238000001952 enzyme assay Methods 0.000 description 1
- 201000009580 eosinophilic pneumonia Diseases 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- FCZCIXQGZOUIDN-UHFFFAOYSA-N ethyl 2-diethoxyphosphinothioyloxyacetate Chemical compound CCOC(=O)COP(=S)(OCC)OCC FCZCIXQGZOUIDN-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229940085861 flovent Drugs 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate 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)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 239000000017 hydrogel Substances 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 230000009610 hypersensitivity Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 230000007365 immunoregulation Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000035990 intercellular signaling Effects 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000000021 kinase assay Methods 0.000 description 1
- 150000002617 leukotrienes Chemical class 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 229940125389 long-acting beta agonist Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 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
- 230000003211 malignant effect Effects 0.000 description 1
- 230000013011 mating Effects 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000013160 medical therapy Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- GTCAXTIRRLKXRU-UHFFFAOYSA-N methyl carbamate Chemical compound COC(N)=O GTCAXTIRRLKXRU-UHFFFAOYSA-N 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002969 oleic acid Drugs 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 150000002892 organic cations Chemical class 0.000 description 1
- 230000001151 other effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 238000002733 pharmacodynamic assay Methods 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002206 pro-fibrotic effect Effects 0.000 description 1
- 230000004647 pro-inflammatory pathway Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- ZZYXNRREDYWPLN-UHFFFAOYSA-N pyridine-2,3-diamine Chemical compound NC1=CC=CN=C1N ZZYXNRREDYWPLN-UHFFFAOYSA-N 0.000 description 1
- NYCVCXMSZNOGDH-UHFFFAOYSA-N pyrrolidine-1-carboxylic acid Chemical compound OC(=O)N1CCCC1 NYCVCXMSZNOGDH-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940090585 serevent Drugs 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 238000002336 sorption--desorption measurement Methods 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
- 238000010561 standard procedure Methods 0.000 description 1
- 238000011272 standard treatment Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- YDBPZCVWPFMBDH-UHFFFAOYSA-N tert-butyl 2-formylpyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1C=O YDBPZCVWPFMBDH-UHFFFAOYSA-N 0.000 description 1
- MSWTVSDFEYSRMQ-UHFFFAOYSA-N tert-butyl n-methyl-n-(2-oxoethyl)carbamate Chemical compound O=CCN(C)C(=O)OC(C)(C)C MSWTVSDFEYSRMQ-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000001757 thermogravimetry curve Methods 0.000 description 1
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
- 229960000257 tiotropium bromide Drugs 0.000 description 1
- 229960001350 tofacitinib Drugs 0.000 description 1
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
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
- C07D471/02—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 two hetero rings
- C07D471/04—Ortho-condensed 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Pulmonology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201562250113P | 2015-11-03 | 2015-11-03 | |
| PCT/US2016/059999 WO2017079205A1 (en) | 2015-11-03 | 2016-11-02 | Jak kinase inhibitor compounds for treatment of respiratory disease |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EA201891091A1 EA201891091A1 (ru) | 2018-12-28 |
| EA034914B1 true EA034914B1 (ru) | 2020-04-06 |
Family
ID=57442794
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EA201891091A EA034914B1 (ru) | 2015-11-03 | 2016-11-02 | Соединения ингибитора jak-киназы для лечения респираторного заболевания |
Country Status (22)
| Country | Link |
|---|---|
| US (6) | US10100049B2 (OSRAM) |
| EP (1) | EP3371186A1 (OSRAM) |
| JP (1) | JP6800969B2 (OSRAM) |
| KR (1) | KR20180073687A (OSRAM) |
| CN (1) | CN108349972B (OSRAM) |
| AU (1) | AU2016350816B2 (OSRAM) |
| BR (1) | BR112018008966B1 (OSRAM) |
| CA (1) | CA3001542C (OSRAM) |
| CL (1) | CL2018001145A1 (OSRAM) |
| CO (1) | CO2018005640A2 (OSRAM) |
| EA (1) | EA034914B1 (OSRAM) |
| HK (1) | HK1252685A1 (OSRAM) |
| IL (1) | IL258772B (OSRAM) |
| MX (1) | MX374605B (OSRAM) |
| MY (1) | MY195427A (OSRAM) |
| NZ (1) | NZ741737A (OSRAM) |
| PH (1) | PH12018500828B1 (OSRAM) |
| SA (1) | SA518391470B1 (OSRAM) |
| TW (1) | TWI710560B (OSRAM) |
| UA (1) | UA123633C2 (OSRAM) |
| WO (1) | WO2017079205A1 (OSRAM) |
| ZA (1) | ZA201802496B (OSRAM) |
Families Citing this family (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2016350816B2 (en) | 2015-11-03 | 2020-06-25 | Theravance Biopharma R&D Ip, Llc | JAK kinase inhibitor compounds for treatment of respiratory disease |
| PT3371185T (pt) | 2015-11-03 | 2020-12-28 | Topivert Pharma Ltd | Derivados de 4,5,6,7-tetrahidro-1h-imidazo[4,5-c]piridina e 1,4,5,6,7,8-hexahidroimidazo[4,5-d]azepina como inibidores de janus quinase |
| US10851097B2 (en) | 2015-11-03 | 2020-12-01 | Topivert Pharma Limited | 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepine derivatives as janus kinase inhibitors |
| EA037261B1 (ru) * | 2017-03-09 | 2021-03-01 | ТЕРЕВАНС БАЙОФАРМА Ар энд Ди АйПи, ЭлЭлСи | Ингибиторы jak, содержащие 4-членный гетероциклический амид |
| KR20200003121A (ko) | 2017-05-01 | 2020-01-08 | 세라밴스 바이오파마 알앤디 아이피, 엘엘씨 | Jak 저해제 화합물의 결정형 |
| CA3059785A1 (en) * | 2017-05-01 | 2018-11-08 | Theravance Biopharma R&D Ip, Llc | Methods of treatment using a jak inhibitor compound |
| AR111495A1 (es) | 2017-05-01 | 2019-07-17 | Theravance Biopharma R&D Ip Llc | Compuestos de imidazo-piperidina fusionada como inhibidores de jak |
| US20200281857A1 (en) | 2017-11-22 | 2020-09-10 | Dauntless 1, Inc. | Therapeutic compound formulations |
| EP3810094A1 (en) | 2018-06-20 | 2021-04-28 | Progenity, Inc. | Treatment of a disease of the gastrointestinal tract with a jak or other kinase inhibitor |
| SI3837258T1 (sl) | 2018-09-04 | 2024-09-30 | Theravance Biopharma R&D Ip, Llc | Dimetil amino azetidin amidi, ki se uporabljajo kot JAK zaviralci |
| CA3108848A1 (en) * | 2018-09-04 | 2020-03-12 | Theravance Biopharma R&D Ip, Llc | Process for preparing jak inhibitors and intermediates thereof |
| ES2955717T3 (es) | 2018-09-04 | 2023-12-05 | Theravance Biopharma R&D Ip Llc | Amidas heterocíclicas de 5 a 7 elementos como inhibidores de JAK |
| EP3853229A1 (en) * | 2018-10-29 | 2021-07-28 | Theravance Biopharma R&D IP, LLC | 2-azabicyclo hexane compound as jak inhibitor |
| JP2022509152A (ja) * | 2018-11-19 | 2022-01-20 | ニューヨーク ユニバーシティ | 治療薬としてのＧｌｉ１の阻害剤開示の背景 |
| JP7514025B2 (ja) * | 2019-02-25 | 2024-07-10 | ホーナン メディノ ファーマシューティカル テクノロジー カンパニー リミテッド | Ｊａｋ阻害剤化合物及びその使用 |
| CN114075200A (zh) * | 2020-08-14 | 2022-02-22 | 河南迈英诺医药科技有限公司 | 用于治疗重症肺炎的jak抑制剂化合物 |
| MX2021010545A (es) | 2019-03-05 | 2021-11-17 | Incyte Corp | Inhibidores de la vía de cinasa janus 1 (jak1) para el tratamiento de la disfunción crónica del aloinjerto pulmonar. |
| JP2022526713A (ja) | 2019-03-21 | 2022-05-26 | オンクセオ | がんの処置のための、キナーゼ阻害剤と組み合わせたＤｂａｉｔ分子 |
| KR20220098759A (ko) | 2019-11-08 | 2022-07-12 | 인쎄름 (엥스띠뛰 나씨오날 드 라 쌍떼 에 드 라 흐쉐르슈 메디깔) | 키나제 억제제에 대해 내성을 획득한 암의 치료 방법 |
| WO2021136345A1 (zh) * | 2019-12-30 | 2021-07-08 | 路良 | Jak抑制剂化合物及其用途 |
| WO2021148581A1 (en) | 2020-01-22 | 2021-07-29 | Onxeo | Novel dbait molecule and its use |
| TW202144343A (zh) | 2020-03-02 | 2021-12-01 | 美商施萬生物製藥研發 Ip有限責任公司 | Jak抑制劑化合物之結晶水合物 |
| WO2022178215A1 (en) | 2021-02-19 | 2022-08-25 | Theravance Biopharma R&D Ip, Llc | Amino amide tetrahydro imidazo pyridines as jak inhibitors |
| TW202304902A (zh) * | 2021-03-26 | 2023-02-01 | 美商施萬生物製藥研發 Ip有限責任公司 | Jak抑制劑化合物之二鹽酸鹽之結晶形式 |
| EP4359402A1 (en) * | 2021-06-25 | 2024-05-01 | Theravance Biopharma R&D IP, LLC | Imidazolo indazole compounds as jak inhibitors |
| CN114181055A (zh) * | 2021-12-21 | 2022-03-15 | 苏州楚凯药业有限公司 | 1-苄氧基-4-溴-5-乙基-2-氟苯的制备方法 |
| WO2023215478A1 (en) | 2022-05-05 | 2023-11-09 | Theravance Biopharma R&D Ip, Llc | Nezulcitinib for delivery by nebulized oral inhalation |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013014567A1 (en) * | 2011-07-27 | 2013-01-31 | Pfizer Limited | Indazoles |
Family Cites Families (33)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI262914B (en) | 1999-07-02 | 2006-10-01 | Agouron Pharma | Compounds and pharmaceutical compositions for inhibiting protein kinases |
| AU2004259012C1 (en) | 2003-07-23 | 2012-08-02 | Exelixis, Inc. | Anaplastic lymphoma kinase modulators and methods of use |
| US20050090529A1 (en) | 2003-07-31 | 2005-04-28 | Pfizer Inc | 3,5 Disubstituted indazole compounds with nitrogen-bearing 5-membered heterocycles, pharmaceutical compositions, and methods for mediating or inhibiting cell proliferation |
| US7884109B2 (en) | 2005-04-05 | 2011-02-08 | Wyeth Llc | Purine and imidazopyridine derivatives for immunosuppression |
| CA2673125C (en) | 2006-10-19 | 2015-04-21 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
| US8648069B2 (en) | 2007-06-08 | 2014-02-11 | Abbvie Inc. | 5-substituted indazoles as kinase inhibitors |
| KR20110033223A (ko) | 2008-06-20 | 2011-03-30 | 제넨테크, 인크. | 트리아졸로피리딘 ｊａｋ 억제제 화합물 및 방법 |
| US20110184013A1 (en) | 2008-10-01 | 2011-07-28 | Shelley Allen | Imidazo[1,2-a]Pyridine Compounds As Receptor Tyrosine Kinase Inhibitors |
| CL2009001884A1 (es) * | 2008-10-02 | 2010-05-14 | Incyte Holdings Corp | Uso de 3-ciclopentil-3-[4-(7h-pirrolo[2,3-d]pirimidin-4-il)-1h-pirazol-1-il)propanonitrilo, inhibidor de janus quinasa, y uso de una composición que lo comprende para el tratamiento del ojo seco. |
| JP2010111624A (ja) | 2008-11-06 | 2010-05-20 | Shionogi & Co Ltd | Ｔｔｋ阻害作用を有するインダゾール誘導体 |
| WO2010114971A1 (en) | 2009-04-03 | 2010-10-07 | Sepracor Inc. | Compounds for treating disorders mediated by metabotropic glutamate receptor 5, and methods of use thereof |
| CA2768543C (en) | 2009-07-28 | 2017-06-20 | Rigel Pharmaceuticals, Inc. | Compositions and methods for inhibition of the jak pathway |
| WO2011084486A1 (en) * | 2009-12-21 | 2011-07-14 | Epitherix, Llc | 1h-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
| EP2338888A1 (en) | 2009-12-24 | 2011-06-29 | Almirall, S.A. | Imidazopyridine derivatives as JAK inhibitors |
| JP5808818B2 (ja) | 2010-11-25 | 2015-11-10 | ラツィオファーム・ゲーエムベーハー | アファチニブの新規塩及び多形形態 |
| PH12017500997A1 (en) | 2012-04-04 | 2018-02-19 | Samumed Llc | Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof |
| TW201513861A (zh) * | 2013-01-17 | 2015-04-16 | Galapagos Nv | 用於治療退化性及發炎疾病之新穎化合物 |
| ME02883B (me) | 2013-12-05 | 2018-04-20 | Pfizer | PIROLO[2,3-d]PIRIMIDINIL-, PIROLO[2,3-b]PIRAZINIL- I PIROLO[2,3-d] PIRIDINILAKRILAMIDI |
| CR20160525A (es) | 2014-05-14 | 2016-12-20 | Pfizer | Pirazolopiridinas y pirazolopirimidinas |
| WO2016026078A1 (en) | 2014-08-19 | 2016-02-25 | Changzhou Jiekai Pharmatech Co., Ltd. | Heterocyclic compounds as erk inhibitors |
| KR101663277B1 (ko) | 2015-03-30 | 2016-10-06 | 주식회사 녹십자 | TNIK, IKKε 및 TBK1 억제제로서의 피라졸계 유도체 및 이를 포함하는 약학적 조성물 |
| US10851097B2 (en) | 2015-11-03 | 2020-12-01 | Topivert Pharma Limited | 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine and 1,4,5,6,7,8-hexahydroimidazo[4,5-d]azepine derivatives as janus kinase inhibitors |
| PT3371185T (pt) | 2015-11-03 | 2020-12-28 | Topivert Pharma Ltd | Derivados de 4,5,6,7-tetrahidro-1h-imidazo[4,5-c]piridina e 1,4,5,6,7,8-hexahidroimidazo[4,5-d]azepina como inibidores de janus quinase |
| AU2016350816B2 (en) | 2015-11-03 | 2020-06-25 | Theravance Biopharma R&D Ip, Llc | JAK kinase inhibitor compounds for treatment of respiratory disease |
| EA037261B1 (ru) | 2017-03-09 | 2021-03-01 | ТЕРЕВАНС БАЙОФАРМА Ар энд Ди АйПи, ЭлЭлСи | Ингибиторы jak, содержащие 4-членный гетероциклический амид |
| AR111495A1 (es) | 2017-05-01 | 2019-07-17 | Theravance Biopharma R&D Ip Llc | Compuestos de imidazo-piperidina fusionada como inhibidores de jak |
| CA3059785A1 (en) | 2017-05-01 | 2018-11-08 | Theravance Biopharma R&D Ip, Llc | Methods of treatment using a jak inhibitor compound |
| KR20200003121A (ko) | 2017-05-01 | 2020-01-08 | 세라밴스 바이오파마 알앤디 아이피, 엘엘씨 | Jak 저해제 화합물의 결정형 |
| CA3108848A1 (en) | 2018-09-04 | 2020-03-12 | Theravance Biopharma R&D Ip, Llc | Process for preparing jak inhibitors and intermediates thereof |
| ES2955717T3 (es) | 2018-09-04 | 2023-12-05 | Theravance Biopharma R&D Ip Llc | Amidas heterocíclicas de 5 a 7 elementos como inhibidores de JAK |
| SI3837258T1 (sl) | 2018-09-04 | 2024-09-30 | Theravance Biopharma R&D Ip, Llc | Dimetil amino azetidin amidi, ki se uporabljajo kot JAK zaviralci |
| EP3853229A1 (en) | 2018-10-29 | 2021-07-28 | Theravance Biopharma R&D IP, LLC | 2-azabicyclo hexane compound as jak inhibitor |
| TW202304902A (zh) | 2021-03-26 | 2023-02-01 | 美商施萬生物製藥研發 Ip有限責任公司 | Jak抑制劑化合物之二鹽酸鹽之結晶形式 |
-
2016
- 2016-11-02 AU AU2016350816A patent/AU2016350816B2/en not_active Ceased
- 2016-11-02 NZ NZ741737A patent/NZ741737A/en unknown
- 2016-11-02 MY MYPI2018701385A patent/MY195427A/en unknown
- 2016-11-02 JP JP2018522556A patent/JP6800969B2/ja not_active Expired - Fee Related
- 2016-11-02 KR KR1020187015680A patent/KR20180073687A/ko not_active Withdrawn
- 2016-11-02 EP EP16804947.6A patent/EP3371186A1/en not_active Withdrawn
- 2016-11-02 EA EA201891091A patent/EA034914B1/ru unknown
- 2016-11-02 MX MX2018005446A patent/MX374605B/es active IP Right Grant
- 2016-11-02 HK HK18111992.5A patent/HK1252685A1/zh unknown
- 2016-11-02 CA CA3001542A patent/CA3001542C/en active Active
- 2016-11-02 UA UAA201806062A patent/UA123633C2/uk unknown
- 2016-11-02 WO PCT/US2016/059999 patent/WO2017079205A1/en not_active Ceased
- 2016-11-02 TW TW105135436A patent/TWI710560B/zh not_active IP Right Cessation
- 2016-11-02 PH PH1/2018/500828A patent/PH12018500828B1/en unknown
- 2016-11-02 US US15/341,226 patent/US10100049B2/en active Active
- 2016-11-02 CN CN201680063886.1A patent/CN108349972B/zh not_active Expired - Fee Related
- 2016-11-02 BR BR112018008966-4A patent/BR112018008966B1/pt not_active IP Right Cessation
-
2018
- 2018-04-16 ZA ZA2018/02496A patent/ZA201802496B/en unknown
- 2018-04-17 IL IL258772A patent/IL258772B/en active IP Right Grant
- 2018-04-30 CL CL2018001145A patent/CL2018001145A1/es unknown
- 2018-04-30 SA SA518391470A patent/SA518391470B1/ar unknown
- 2018-05-29 CO CONC2018/0005640A patent/CO2018005640A2/es unknown
- 2018-07-18 US US16/038,424 patent/US10183942B2/en active Active
- 2018-12-10 US US16/215,194 patent/US10526330B2/en active Active
-
2019
- 2019-11-20 US US16/689,706 patent/US10913740B2/en not_active Expired - Fee Related
-
2021
- 2021-01-05 US US17/248,015 patent/US11299492B2/en active Active
-
2022
- 2022-03-07 US US17/688,001 patent/US11718616B2/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013014567A1 (en) * | 2011-07-27 | 2013-01-31 | Pfizer Limited | Indazoles |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11718616B2 (en) | JAK kinase inhibitor compounds for treatment of respiratory disease | |
| US10640506B2 (en) | Cyclobutyl substituted pyrrolopyridine and pyrrolopyrimidines derivatives as JAK inhibitors | |
| EP3464245B1 (en) | Benzazepine dicarboxamide compounds with tertiary amide function | |
| US11958837B2 (en) | Quinazolinones as PARP14 inhibitors | |
| JP5369302B2 (ja) | Ｐｄｅ４阻害剤としてのピリドピリミジンジオン類 | |
| CN103328472A (zh) | 作为呼吸道合胞病毒抗病毒剂的咪唑并吡啶 | |
| EP3768272B1 (en) | Jak inhibitors | |
| HK1177741B (en) | Piperidin-4-yl azetidine derivatives as jak1 inhibitors |