JP6793658B2 - Tnf阻害剤として有用な三環式ヘテロ環式化合物 - Google Patents
Tnf阻害剤として有用な三環式ヘテロ環式化合物 Download PDFInfo
- Publication number
- JP6793658B2 JP6793658B2 JP2017549093A JP2017549093A JP6793658B2 JP 6793658 B2 JP6793658 B2 JP 6793658B2 JP 2017549093 A JP2017549093 A JP 2017549093A JP 2017549093 A JP2017549093 A JP 2017549093A JP 6793658 B2 JP6793658 B2 JP 6793658B2
- Authority
- JP
- Japan
- Prior art keywords
- phenyl
- pyridazine
- imidazo
- difluoromethoxy
- tetrahydropyrido
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 5
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 title description 3
- 239000002451 tumor necrosis factor inhibitor Substances 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 345
- -1 methoxyphenyl Chemical group 0.000 claims description 267
- 150000003839 salts Chemical class 0.000 claims description 110
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 70
- JPMJNVODBLZHLR-UHFFFAOYSA-N 5h-imidazo[1,2-b]pyridazin-6-one Chemical compound N1C(=O)C=CC2=NC=CN21 JPMJNVODBLZHLR-UHFFFAOYSA-N 0.000 claims description 58
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 46
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 37
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 33
- VTVRXITWWZGKHV-UHFFFAOYSA-N imidazo[1,2-b]pyridazine Chemical compound N1=CC=CC2=NC=CN21 VTVRXITWWZGKHV-UHFFFAOYSA-N 0.000 claims description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims description 22
- 208000023275 Autoimmune disease Diseases 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 201000010099 disease Diseases 0.000 claims description 19
- 238000004519 manufacturing process Methods 0.000 claims description 19
- 208000027866 inflammatory disease Diseases 0.000 claims description 17
- 239000003814 drug Substances 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- 230000002757 inflammatory effect Effects 0.000 claims description 13
- 125000002757 morpholinyl group Chemical group 0.000 claims description 13
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 13
- 125000004076 pyridyl group Chemical group 0.000 claims description 13
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 8
- ZJEAUBBRDBFKCO-UHFFFAOYSA-N 3-[2-(difluoromethoxy)phenyl]-12-[4-(2-hydroxypropan-2-yl)phenyl]-4-oxa-1,8,13-triazatricyclo[7.4.0.02,7]trideca-2(7),8,10,12-tetraen-6-ol Chemical compound FC(OC1=C(C=CC=C1)C1OCC(C=2N=C3N(N=C(C=C3)C3=CC=C(C=C3)C(C)(C)O)C=21)O)F ZJEAUBBRDBFKCO-UHFFFAOYSA-N 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 239000003937 drug carrier Substances 0.000 claims description 7
- OLQONTXLRKBPMD-UHFFFAOYSA-N 3-[2-(difluoromethoxy)phenyl]-12-[4-(2-hydroxypropan-2-yl)phenyl]-6-pyridin-4-yl-4-oxa-1,8,13-triazatricyclo[7.4.0.02,7]trideca-2(7),8,10,12-tetraen-6-ol Chemical compound FC(OC1=C(C=CC=C1)C1OCC(C=2N=C3N(N=C(C=C3)C3=CC=C(C=C3)C(C)(C)O)C=21)(O)C1=CC=NC=C1)F OLQONTXLRKBPMD-UHFFFAOYSA-N 0.000 claims description 6
- 208000002193 Pain Diseases 0.000 claims description 5
- LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 claims description 5
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 5
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 4
- 201000005569 Gout Diseases 0.000 claims description 4
- 108060008683 Tumor Necrosis Factor Receptor Proteins 0.000 claims description 4
- 102000003298 tumor necrosis factor receptor Human genes 0.000 claims description 4
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
- 208000011231 Crohn disease Diseases 0.000 claims description 3
- 206010016207 Familial Mediterranean fever Diseases 0.000 claims description 3
- 208000015023 Graves' disease Diseases 0.000 claims description 3
- 206010059176 Juvenile idiopathic arthritis Diseases 0.000 claims description 3
- 208000005777 Lupus Nephritis Diseases 0.000 claims description 3
- 206010052779 Transplant rejections Diseases 0.000 claims description 3
- 230000000735 allogeneic effect Effects 0.000 claims description 3
- 208000006673 asthma Diseases 0.000 claims description 3
- UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims description 3
- 208000011580 syndromic disease Diseases 0.000 claims description 3
- 208000020408 systemic-onset juvenile idiopathic arthritis Diseases 0.000 claims description 3
- 208000023328 Basedow disease Diseases 0.000 claims description 2
- 206010009900 Colitis ulcerative Diseases 0.000 claims description 2
- 206010018634 Gouty Arthritis Diseases 0.000 claims description 2
- 102100022691 NACHT, LRR and PYD domains-containing protein 3 Human genes 0.000 claims description 2
- 101710126825 NACHT, LRR and PYD domains-containing protein 3 Proteins 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 201000006704 Ulcerative Colitis Diseases 0.000 claims description 2
- 206010025135 lupus erythematosus Diseases 0.000 claims description 2
- 201000001119 neuropathy Diseases 0.000 claims description 2
- 230000007823 neuropathy Effects 0.000 claims description 2
- 230000000737 periodic effect Effects 0.000 claims description 2
- 208000025487 periodic fever syndrome Diseases 0.000 claims description 2
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 2
- VERTYDKHQFEQMO-UHFFFAOYSA-N 12-[4-(2-hydroxypropan-2-yl)phenyl]-3-[2-(trifluoromethoxy)phenyl]-1,4,8,13-tetrazatricyclo[7.4.0.02,7]trideca-2(7),8,10,12-tetraen-6-ol Chemical compound OC(C)(C)C1=CC=C(C=C1)C=1C=CC=2N(N=1)C1=C(N=2)C(CNC1C1=C(C=CC=C1)OC(F)(F)F)O VERTYDKHQFEQMO-UHFFFAOYSA-N 0.000 claims 2
- PQXVMEVPQIXYQE-UHFFFAOYSA-N 3-methoxyazetidine-1-carbaldehyde Chemical compound COC1CN(C=O)C1 PQXVMEVPQIXYQE-UHFFFAOYSA-N 0.000 claims 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims 2
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims 2
- FZQQHPGRNQKJSY-NQIIRXRSSA-N (3S,6R)-3-[2-(difluoromethoxy)phenyl]-12-[4-(2-hydroxypropan-2-yl)phenyl]-1,4,8,13-tetrazatricyclo[7.4.0.02,7]trideca-2(7),8,10,12-tetraen-6-ol Chemical compound FC(OC1=C(C=CC=C1)[C@@H]1NC[C@H](C=2N=C3N(N=C(C=C3)C3=CC=C(C=C3)C(C)(C)O)C=21)O)F FZQQHPGRNQKJSY-NQIIRXRSSA-N 0.000 claims 1
- 208000026326 Adult-onset Still disease Diseases 0.000 claims 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 claims 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 123
- 235000002639 sodium chloride Nutrition 0.000 description 107
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 84
- 239000000203 mixture Substances 0.000 description 83
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 80
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 75
- 238000000034 method Methods 0.000 description 70
- 125000003118 aryl group Chemical group 0.000 description 65
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 65
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 63
- 238000004128 high performance liquid chromatography Methods 0.000 description 59
- 125000000623 heterocyclic group Chemical group 0.000 description 45
- 239000000543 intermediate Substances 0.000 description 43
- 239000000243 solution Substances 0.000 description 41
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 40
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 40
- 239000002904 solvent Substances 0.000 description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- 229910052799 carbon Inorganic materials 0.000 description 32
- 230000014759 maintenance of location Effects 0.000 description 32
- 235000019439 ethyl acetate Nutrition 0.000 description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 235000019441 ethanol Nutrition 0.000 description 28
- 229910052739 hydrogen Inorganic materials 0.000 description 28
- 239000007787 solid Substances 0.000 description 27
- 238000011282 treatment Methods 0.000 description 25
- 125000000217 alkyl group Chemical group 0.000 description 24
- 125000004093 cyano group Chemical group *C#N 0.000 description 24
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 23
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 21
- 229910052757 nitrogen Inorganic materials 0.000 description 21
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 20
- 150000001721 carbon Chemical group 0.000 description 20
- 125000002950 monocyclic group Chemical group 0.000 description 20
- 125000004452 carbocyclyl group Chemical group 0.000 description 19
- 230000002829 reductive effect Effects 0.000 description 19
- 208000035475 disorder Diseases 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 17
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 17
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 16
- 239000005695 Ammonium acetate Substances 0.000 description 16
- 125000003545 alkoxy group Chemical group 0.000 description 16
- 235000019257 ammonium acetate Nutrition 0.000 description 16
- 229940043376 ammonium acetate Drugs 0.000 description 16
- 125000005843 halogen group Chemical group 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- 125000001072 heteroaryl group Chemical group 0.000 description 15
- 238000010898 silica gel chromatography Methods 0.000 description 15
- 239000012453 solvate Substances 0.000 description 15
- 239000000725 suspension Substances 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 125000005842 heteroatom Chemical group 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 239000012267 brine Substances 0.000 description 13
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 13
- 125000003709 fluoroalkyl group Chemical group 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 229910052760 oxygen Inorganic materials 0.000 description 12
- 206010028980 Neoplasm Diseases 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 230000001363 autoimmune Effects 0.000 description 11
- 230000015572 biosynthetic process Effects 0.000 description 11
- 229920000728 polyester Polymers 0.000 description 11
- 239000000651 prodrug Substances 0.000 description 11
- 229940002612 prodrug Drugs 0.000 description 11
- 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 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 235000019341 magnesium sulphate Nutrition 0.000 description 10
- 239000002245 particle Substances 0.000 description 10
- 239000002002 slurry Substances 0.000 description 10
- 238000003786 synthesis reaction Methods 0.000 description 10
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 238000003556 assay Methods 0.000 description 9
- 239000003995 emulsifying agent Substances 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 229910052721 tungsten Inorganic materials 0.000 description 9
- 229910052727 yttrium Inorganic materials 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 8
- 101150003085 Pdcl gene Proteins 0.000 description 8
- 102100040247 Tumor necrosis factor Human genes 0.000 description 8
- 239000002671 adjuvant Substances 0.000 description 8
- 125000002619 bicyclic group Chemical group 0.000 description 8
- 239000003755 preservative agent Substances 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 8
- DTXVKPOKPFWSFF-UHFFFAOYSA-N 3(S)-hydroxy-13-cis-eicosenoyl-CoA Chemical compound NC1=CC=C(Cl)N=N1 DTXVKPOKPFWSFF-UHFFFAOYSA-N 0.000 description 7
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000006069 Suzuki reaction reaction Methods 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- 239000000654 additive Substances 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- 235000014113 dietary fatty acids Nutrition 0.000 description 7
- 239000000194 fatty acid Substances 0.000 description 7
- 229930195729 fatty acid Natural products 0.000 description 7
- 150000004665 fatty acids Chemical class 0.000 description 7
- 239000000796 flavoring agent Substances 0.000 description 7
- 238000007429 general method Methods 0.000 description 7
- 239000001301 oxygen Substances 0.000 description 7
- 239000003643 water by type Substances 0.000 description 7
- MSBJCEKFIIGEOW-UHFFFAOYSA-N 1h-pyridazine-2-carboxylic acid Chemical compound OC(=O)N1NC=CC=C1 MSBJCEKFIIGEOW-UHFFFAOYSA-N 0.000 description 6
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 235000003599 food sweetener Nutrition 0.000 description 6
- 125000001188 haloalkyl group Chemical group 0.000 description 6
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 6
- 150000002576 ketones Chemical class 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 239000000463 material Substances 0.000 description 6
- 208000030159 metabolic disease Diseases 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 229910052763 palladium Inorganic materials 0.000 description 6
- 230000036961 partial effect Effects 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- 239000000080 wetting agent Substances 0.000 description 6
- QQWLQUMNZBPDRS-UHFFFAOYSA-N 1h-pyridazine-2-carbaldehyde Chemical compound O=CN1NC=CC=C1 QQWLQUMNZBPDRS-UHFFFAOYSA-N 0.000 description 5
- ZTAVJSHQCLFIHB-UHFFFAOYSA-N 3-[2-(difluoromethoxy)phenyl]-12-[4-(2-hydroxypropan-2-yl)phenyl]-6-methyl-4-oxa-1,8,13-triazatricyclo[7.4.0.02,7]trideca-2(7),8,10,12-tetraen-6-ol Chemical compound FC(OC1=C(C=CC=C1)C1OCC(C=2N=C3N(N=C(C=C3)C3=CC=C(C=C3)C(C)(C)O)C=21)(O)C)F ZTAVJSHQCLFIHB-UHFFFAOYSA-N 0.000 description 5
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 5
- 208000024172 Cardiovascular disease Diseases 0.000 description 5
- 229920000858 Cyclodextrin Polymers 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 241000124008 Mammalia Species 0.000 description 5
- 208000012902 Nervous system disease Diseases 0.000 description 5
- 208000025966 Neurological disease Diseases 0.000 description 5
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 125000006620 amino-(C1-C6) alkyl group Chemical group 0.000 description 5
- 239000007900 aqueous suspension Substances 0.000 description 5
- 125000005605 benzo group Chemical group 0.000 description 5
- 230000033228 biological regulation Effects 0.000 description 5
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- PREAJPIKNPDDON-APAIHEESSA-N dideuterio-[dichloro(deuterio)methyl]-lambda3-chlorane Chemical compound C(Cl([2H])[2H])(Cl)(Cl)[2H] PREAJPIKNPDDON-APAIHEESSA-N 0.000 description 5
- 208000030533 eye disease Diseases 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 125000001153 fluoro group Chemical group F* 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 208000015122 neurodegenerative disease Diseases 0.000 description 5
- 230000000926 neurological effect Effects 0.000 description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 description 5
- 231100000252 nontoxic Toxicity 0.000 description 5
- 230000003000 nontoxic effect Effects 0.000 description 5
- 230000002265 prevention Effects 0.000 description 5
- 150000004892 pyridazines Chemical class 0.000 description 5
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 229910052717 sulfur Inorganic materials 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 5
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 4
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical compound OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 description 4
- QPBNHDFPMRENBC-UHFFFAOYSA-N 2-(difluoromethoxy)benzaldehyde Chemical compound FC(F)OC1=CC=CC=C1C=O QPBNHDFPMRENBC-UHFFFAOYSA-N 0.000 description 4
- HLSNOMZQZYVRSL-UHFFFAOYSA-N 2-[4-[3-[2-(difluoromethoxy)phenyl]-4-oxa-1,8,13-triazatricyclo[7.4.0.02,7]trideca-2(7),8,10,12-tetraen-12-yl]phenyl]propan-2-ol Chemical compound FC(OC1=C(C=CC=C1)C1OCCC=2N=C3N(N=C(C=C3)C3=CC=C(C=C3)C(C)(C)O)C=21)F HLSNOMZQZYVRSL-UHFFFAOYSA-N 0.000 description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 235000019483 Peanut oil Nutrition 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 201000001263 Psoriatic Arthritis Diseases 0.000 description 4
- 208000036824 Psoriatic arthropathy Diseases 0.000 description 4
- 208000017442 Retinal disease Diseases 0.000 description 4
- 206010038923 Retinopathy Diseases 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- DPIDNFWCDMXMDY-UHFFFAOYSA-N [4-(2-hydroxypropan-2-yl)phenyl]boronic acid Chemical compound CC(C)(O)C1=CC=C(B(O)O)C=C1 DPIDNFWCDMXMDY-UHFFFAOYSA-N 0.000 description 4
- 230000000996 additive effect Effects 0.000 description 4
- 230000000172 allergic effect Effects 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
- 239000003963 antioxidant agent Substances 0.000 description 4
- 235000006708 antioxidants Nutrition 0.000 description 4
- 206010003246 arthritis Diseases 0.000 description 4
- 125000004429 atom Chemical group 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 238000004166 bioassay Methods 0.000 description 4
- 230000005587 bubbling Effects 0.000 description 4
- 238000001023 centrifugal evaporation Methods 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 125000004428 fluoroalkoxy group Chemical group 0.000 description 4
- 235000013355 food flavoring agent Nutrition 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 150000002460 imidazoles Chemical class 0.000 description 4
- 125000002883 imidazolyl group Chemical group 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000312 peanut oil Substances 0.000 description 4
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 125000003373 pyrazinyl group Chemical group 0.000 description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
- 125000003003 spiro group Chemical group 0.000 description 4
- 125000004434 sulfur atom Chemical group 0.000 description 4
- 238000004808 supercritical fluid chromatography Methods 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 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 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 206010018364 Glomerulonephritis Diseases 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 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 3
- WZWKXDDZPSSOMR-UHFFFAOYSA-N OC(C)(C)C1=CC=C(C=C1)OB(O)O Chemical compound OC(C)(C)C1=CC=C(C=C1)OB(O)O WZWKXDDZPSSOMR-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000003377 acid catalyst Substances 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 208000007502 anemia Diseases 0.000 description 3
- 208000010668 atopic eczema Diseases 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 239000003638 chemical reducing agent Substances 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 125000004966 cyanoalkyl group Chemical group 0.000 description 3
- 125000000392 cycloalkenyl group Chemical group 0.000 description 3
- 239000006185 dispersion Substances 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000003925 fat Substances 0.000 description 3
- 235000019197 fats Nutrition 0.000 description 3
- 235000019634 flavors Nutrition 0.000 description 3
- 230000005714 functional activity Effects 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 235000010445 lecithin Nutrition 0.000 description 3
- 239000000787 lecithin Substances 0.000 description 3
- 229940067606 lecithin Drugs 0.000 description 3
- 229940057995 liquid paraffin Drugs 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 239000004530 micro-emulsion Substances 0.000 description 3
- 201000006417 multiple sclerosis Diseases 0.000 description 3
- 230000003040 nociceptive effect Effects 0.000 description 3
- 125000006574 non-aromatic ring group Chemical group 0.000 description 3
- 239000000346 nonvolatile oil Substances 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 3
- 230000002335 preservative effect Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- 125000006583 (C1-C3) haloalkyl group Chemical group 0.000 description 2
- 125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 2
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- ONTXCMXICQNNNO-UHFFFAOYSA-N 2-(3-oxobutyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCC(=O)C)C(=O)C2=C1 ONTXCMXICQNNNO-UHFFFAOYSA-N 0.000 description 2
- PTPZBCHKQSHXQZ-UHFFFAOYSA-N 2-(4-bromo-3-oxobutyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCC(=O)CBr)C(=O)C2=C1 PTPZBCHKQSHXQZ-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 2
- KYRWZLQHRWNMCN-UHFFFAOYSA-N 3-[2-(difluoromethoxy)phenyl]-12-(1-methylpyrazol-4-yl)-4-oxa-1,8,13-triazatricyclo[7.4.0.02,7]trideca-2(7),8,10,12-tetraene Chemical compound FC(OC1=C(C=CC=C1)C1OCCC=2N=C3N(N=C(C=C3)C=3C=NN(C=3)C)C=21)F KYRWZLQHRWNMCN-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- VJXRKZJMGVSXPX-UHFFFAOYSA-N 4-ethylpyridine Chemical compound CCC1=CC=NC=C1 VJXRKZJMGVSXPX-UHFFFAOYSA-N 0.000 description 2
- 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 2
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- 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 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- 208000017701 Endocrine disease Diseases 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 229920000084 Gum arabic Polymers 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 208000003456 Juvenile Arthritis Diseases 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 2
- 239000005642 Oleic acid Substances 0.000 description 2
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical class OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 201000002661 Spondylitis Diseases 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical class OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 101710187830 Tumor necrosis factor receptor superfamily member 1B Proteins 0.000 description 2
- 102100033733 Tumor necrosis factor receptor superfamily member 1B Human genes 0.000 description 2
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 2
- 208000026723 Urinary tract disease Diseases 0.000 description 2
- JJAUYEZYAXAERE-UHFFFAOYSA-N [2-(difluoromethoxy)phenyl]methanol Chemical compound OCC1=CC=CC=C1OC(F)F JJAUYEZYAXAERE-UHFFFAOYSA-N 0.000 description 2
- 235000010489 acacia gum Nutrition 0.000 description 2
- 239000000205 acacia gum Substances 0.000 description 2
- 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 2
- 235000010443 alginic acid Nutrition 0.000 description 2
- 229920000615 alginic acid Polymers 0.000 description 2
- 239000000783 alginic acid Substances 0.000 description 2
- 229960001126 alginic acid Drugs 0.000 description 2
- 150000004781 alginic acids Chemical class 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 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
- 239000011230 binding agent Substances 0.000 description 2
- FUSUHKVFWTUUBE-UHFFFAOYSA-N buten-2-one Chemical compound CC(=O)C=C FUSUHKVFWTUUBE-UHFFFAOYSA-N 0.000 description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 description 2
- 235000010216 calcium carbonate Nutrition 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 235000011010 calcium phosphates Nutrition 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 229940125877 compound 31 Drugs 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 239000002270 dispersing agent Substances 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- MGDWUTQKXCZNAJ-UHFFFAOYSA-N ethyl 4-bromo-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CBr MGDWUTQKXCZNAJ-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 125000004438 haloalkoxy group Chemical group 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 201000006747 infectious mononucleosis Diseases 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 2
- 230000000366 juvenile effect Effects 0.000 description 2
- 201000002215 juvenile rheumatoid arthritis Diseases 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- JHBZAAACZVPPRQ-UHFFFAOYSA-L lithium;magnesium;2,2,6,6-tetramethylpiperidin-1-ide;dichloride Chemical compound [Li+].[Cl-].[Cl-].CC1(C)CCCC(C)(C)N1[Mg+] JHBZAAACZVPPRQ-UHFFFAOYSA-L 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 230000000873 masking effect Effects 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 2
- PQIOSYKVBBWRRI-UHFFFAOYSA-N methylphosphonyl difluoride Chemical group CP(F)(F)=O PQIOSYKVBBWRRI-UHFFFAOYSA-N 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- 230000000414 obstructive effect Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 2
- 239000012285 osmium tetroxide Substances 0.000 description 2
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 2
- 230000003248 secreting effect Effects 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 230000011664 signaling Effects 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000010413 sodium alginate Nutrition 0.000 description 2
- 239000000661 sodium alginate Substances 0.000 description 2
- 229940005550 sodium alginate Drugs 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000011069 sorbitan monooleate Nutrition 0.000 description 2
- 239000001593 sorbitan monooleate Substances 0.000 description 2
- 229940035049 sorbitan monooleate Drugs 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 150000003509 tertiary alcohols Chemical class 0.000 description 2
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 description 2
- 229960000984 tocofersolan Drugs 0.000 description 2
- AOBORMOPSGHCAX-DGHZZKTQSA-N tocofersolan Chemical compound OCCOC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C AOBORMOPSGHCAX-DGHZZKTQSA-N 0.000 description 2
- 230000001256 tonic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 239000013638 trimer Substances 0.000 description 2
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 2
- 235000019798 tripotassium phosphate Nutrition 0.000 description 2
- 208000014001 urinary system disease Diseases 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 238000012800 visualization Methods 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- 239000002076 α-tocopherol Substances 0.000 description 2
- 235000004835 α-tocopherol Nutrition 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- DQSSGOPJTOULIF-PSLIRLAXSA-N (3S,6S)-12-chloro-3-[2-(difluoromethoxy)phenyl]-4-oxa-1,8,13-triazatricyclo[7.4.0.02,7]trideca-2(7),8,10,12-tetraen-6-ol Chemical compound ClC=1C=CC=2N(N=1)C1=C(N=2)[C@@H](CO[C@H]1C1=C(C=CC=C1)OC(F)F)O DQSSGOPJTOULIF-PSLIRLAXSA-N 0.000 description 1
- SJXXZKCSMLZFEH-UHFFFAOYSA-N (6-chloro-2-ethenylimidazo[1,2-b]pyridazin-3-yl)-[2-(difluoromethoxy)phenyl]methanol Chemical compound OC(C1=C(C=C)N=C2C=CC(Cl)=NN12)C1=C(OC(F)F)C=CC=C1 SJXXZKCSMLZFEH-UHFFFAOYSA-N 0.000 description 1
- DHADXDMPEUWEAS-UHFFFAOYSA-N (6-methoxypyridin-3-yl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=N1 DHADXDMPEUWEAS-UHFFFAOYSA-N 0.000 description 1
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 description 1
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 1
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N (R)-alpha-Tocopherol Natural products OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
- ZYZCALPXKGUGJI-DDVDASKDSA-M (e,3r,5s)-7-[3-(4-fluorophenyl)-2-phenyl-5-propan-2-ylimidazol-4-yl]-3,5-dihydroxyhept-6-enoate Chemical compound C=1C=C(F)C=CC=1N1C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C(C)C)N=C1C1=CC=CC=C1 ZYZCALPXKGUGJI-DDVDASKDSA-M 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- JLDMOSFOHYDVMP-UHFFFAOYSA-N 1,4,8,13-tetrazatricyclo[7.4.0.02,7]trideca-2(7),3,5,8-tetraene Chemical compound N1N2C(CCC1)=NC1=C2C=NC=C1 JLDMOSFOHYDVMP-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 1
- JPAFJCUNYQLDIH-UHFFFAOYSA-N 1-[6-chloro-3-[[2-(difluoromethoxy)phenyl]-hydroxymethyl]imidazo[1,2-b]pyridazin-2-yl]ethane-1,2-diol Chemical compound OCC(O)C1=C(C(O)C2=C(OC(F)F)C=CC=C2)N2N=C(Cl)C=CC2=N1 JPAFJCUNYQLDIH-UHFFFAOYSA-N 0.000 description 1
- PZNPLUBHRSSFHT-RRHRGVEJSA-N 1-hexadecanoyl-2-octadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[C@@H](COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCCCCCCCCCC PZNPLUBHRSSFHT-RRHRGVEJSA-N 0.000 description 1
- UCNGGGYMLHAMJG-UHFFFAOYSA-N 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole Chemical compound C1=NN(C)C=C1B1OC(C)(C)C(C)(C)O1 UCNGGGYMLHAMJG-UHFFFAOYSA-N 0.000 description 1
- VUZPGEIXNYGDJN-UHFFFAOYSA-N 1-nitroethanol Chemical compound CC(O)[N+]([O-])=O VUZPGEIXNYGDJN-UHFFFAOYSA-N 0.000 description 1
- DQSSGOPJTOULIF-UHFFFAOYSA-N 12-chloro-3-[2-(difluoromethoxy)phenyl]-4-oxa-1,8,13-triazatricyclo[7.4.0.02,7]trideca-2(7),8,10,12-tetraen-6-ol Chemical compound ClC=1C=CC=2N(N=1)C1=C(N=2)C(COC1C1=C(C=CC=C1)OC(F)F)O DQSSGOPJTOULIF-UHFFFAOYSA-N 0.000 description 1
- MKZIDLGSXBWJBX-UHFFFAOYSA-N 12-chloro-3-[2-(difluoromethoxy)phenyl]-6-methyl-4-oxa-1,8,13-triazatricyclo[7.4.0.02,7]trideca-2(7),8,10,12-tetraen-6-ol Chemical compound ClC=1C=CC=2N(N=1)C1=C(N=2)C(COC1C1=C(C=CC=C1)OC(F)F)(O)C MKZIDLGSXBWJBX-UHFFFAOYSA-N 0.000 description 1
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- MBGHBWMXGQDOQO-UHFFFAOYSA-N 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)ethanol Chemical compound OCCC1=CN2N=C(Cl)C=CC2=N1 MBGHBWMXGQDOQO-UHFFFAOYSA-N 0.000 description 1
- ZDJURXUJJAGERM-UHFFFAOYSA-N 2-[5-[3-[2-(difluoromethoxy)phenyl]-4-oxa-1,8,13-triazatricyclo[7.4.0.02,7]trideca-2(7),8,10,12-tetraen-12-yl]pyrimidin-2-yl]propan-2-ol Chemical compound FC(OC1=C(C=CC=C1)C1OCCC=2N=C3N(N=C(C=C3)C=3C=NC(=NC=3)C(C)(C)O)C=21)F ZDJURXUJJAGERM-UHFFFAOYSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 description 1
- OCVXSFKKWXMYPF-UHFFFAOYSA-N 2-chloroimidazole Chemical compound ClC1=NC=CN1 OCVXSFKKWXMYPF-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
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000006088 2-oxoazepinyl group Chemical group 0.000 description 1
- 125000004638 2-oxopiperazinyl group Chemical group O=C1N(CCNC1)* 0.000 description 1
- 125000004637 2-oxopiperidinyl group Chemical group O=C1N(CCCC1)* 0.000 description 1
- 125000006087 2-oxopyrrolodinyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- 125000005917 3-methylpentyl group Chemical group 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- RTLUPHDWSUGAOS-UHFFFAOYSA-N 4-iodopyridine Chemical compound IC1=CC=NC=C1 RTLUPHDWSUGAOS-UHFFFAOYSA-N 0.000 description 1
- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- 208000009304 Acute Kidney Injury Diseases 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 206010003827 Autoimmune hepatitis Diseases 0.000 description 1
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 208000020084 Bone disease Diseases 0.000 description 1
- 206010065687 Bone loss Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 description 1
- 108010029697 CD40 Ligand Proteins 0.000 description 1
- 101150013553 CD40 gene Proteins 0.000 description 1
- 102100032937 CD40 ligand Human genes 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 206010007572 Cardiac hypertrophy Diseases 0.000 description 1
- 208000006029 Cardiomegaly Diseases 0.000 description 1
- 206010008685 Chondritis Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 206010012438 Dermatitis atopic Diseases 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 206010012688 Diabetic retinal oedema Diseases 0.000 description 1
- 206010012689 Diabetic retinopathy Diseases 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 206010013801 Duchenne Muscular Dystrophy Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 108010008165 Etanercept Proteins 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010072579 Granulomatosis with polyangiitis Diseases 0.000 description 1
- 208000003807 Graves Disease Diseases 0.000 description 1
- 206010019196 Head injury Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010021245 Idiopathic thrombocytopenic purpura Diseases 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 208000029523 Interstitial Lung disease Diseases 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 208000001344 Macular Edema Diseases 0.000 description 1
- 206010025415 Macular oedema Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000001145 Metabolic Syndrome Diseases 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010028372 Muscular weakness Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 1
- 102000003945 NF-kappa B Human genes 0.000 description 1
- 108010057466 NF-kappa B Proteins 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 206010029260 Neuroblastoma Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 208000002389 Pouchitis Diseases 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000033626 Renal failure acute Diseases 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 206010038933 Retinopathy of prematurity Diseases 0.000 description 1
- 206010038934 Retinopathy proliferative Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 208000021386 Sjogren Syndrome Diseases 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 201000009594 Systemic Scleroderma Diseases 0.000 description 1
- 206010042953 Systemic sclerosis Diseases 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 208000031981 Thrombocytopenic Idiopathic Purpura Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 101710187743 Tumor necrosis factor receptor superfamily member 1A Proteins 0.000 description 1
- 102100033732 Tumor necrosis factor receptor superfamily member 1A Human genes 0.000 description 1
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 1
- 108091005956 Type II transmembrane proteins Proteins 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 206010047115 Vasculitis Diseases 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- WERKSKAQRVDLDW-ANOHMWSOSA-N [(2s,3r,4r,5r)-2,3,4,5,6-pentahydroxyhexyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO WERKSKAQRVDLDW-ANOHMWSOSA-N 0.000 description 1
- ZUSWDTWYONAOPH-UHFFFAOYSA-N [2-(trifluoromethyl)phenyl]hydrazine;hydrochloride Chemical group [Cl-].[NH3+]NC1=CC=CC=C1C(F)(F)F ZUSWDTWYONAOPH-UHFFFAOYSA-N 0.000 description 1
- RRDHQJAQWOGHGP-NAKRPHOHSA-N [Si](C1=CC=CC=C1)(C1=CC=CC=C1)(C(C)(C)C)O[C@@H]1CN[C@H](C2=C1N=C1N2N=C(C=C1)Cl)C1=C(C=CC=C1)OC(F)F Chemical compound [Si](C1=CC=CC=C1)(C1=CC=CC=C1)(C(C)(C)C)O[C@@H]1CN[C@H](C2=C1N=C1N2N=C(C=C1)Cl)C1=C(C=CC=C1)OC(F)F RRDHQJAQWOGHGP-NAKRPHOHSA-N 0.000 description 1
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- LPQOADBMXVRBNX-UHFFFAOYSA-N ac1ldcw0 Chemical compound Cl.C1CN(C)CCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN3CCSC1=C32 LPQOADBMXVRBNX-UHFFFAOYSA-N 0.000 description 1
- UGZICOVULPINFH-UHFFFAOYSA-N acetic acid;butanoic acid Chemical compound CC(O)=O.CCCC(O)=O UGZICOVULPINFH-UHFFFAOYSA-N 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 201000011040 acute kidney failure Diseases 0.000 description 1
- 229960002964 adalimumab Drugs 0.000 description 1
- 206010064930 age-related macular degeneration Diseases 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 125000005001 aminoaryl group Chemical group 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 aspartame Drugs 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 239000000305 astragalus gummifer gum Substances 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 201000008937 atopic dermatitis Diseases 0.000 description 1
- 201000003710 autoimmune thrombocytopenic purpura Diseases 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 1
- 229940043253 butylated hydroxyanisole Drugs 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000000845 cartilage Anatomy 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000024245 cell differentiation Effects 0.000 description 1
- 229920001727 cellulose butyrate Polymers 0.000 description 1
- 229940082500 cetostearyl alcohol Drugs 0.000 description 1
- 229960000541 cetyl alcohol Drugs 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 125000004617 chromonyl group Chemical group O1C(=CC(C2=CC=CC=C12)=O)* 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000024207 chronic leukemia Diseases 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 1
- 229960004316 cisplatin Drugs 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 201000000159 corneal neovascularization Diseases 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 238000012937 correction Methods 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
- 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000010779 crude oil Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 125000005508 decahydronaphthalenyl group Chemical group 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 239000012024 dehydrating agents 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
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 201000011190 diabetic macular edema Diseases 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000005906 dihydroxylation reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- FSBVERYRVPGNGG-UHFFFAOYSA-N dimagnesium dioxido-bis[[oxido(oxo)silyl]oxy]silane hydrate Chemical compound O.[Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O FSBVERYRVPGNGG-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- CDNAUIUELRAXBC-UHFFFAOYSA-L disodium sulfate tetrahydrate Chemical compound O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O CDNAUIUELRAXBC-UHFFFAOYSA-L 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000008387 emulsifying waxe Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 229960000403 etanercept Drugs 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000004403 ethyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010228 ethyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229940043351 ethyl-p-hydroxybenzoate Drugs 0.000 description 1
- NUVBSKCKDOMJSU-UHFFFAOYSA-N ethylparaben Chemical compound CCOC(=O)C1=CC=C(O)C=C1 NUVBSKCKDOMJSU-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000003176 fibrotic effect Effects 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000012025 fluorinating agent Substances 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940074045 glyceryl distearate Drugs 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- 229960002449 glycine Drugs 0.000 description 1
- 229960001743 golimumab Drugs 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 230000002324 hematogenic effect Effects 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- UBHWBODXJBSFLH-UHFFFAOYSA-N hexadecan-1-ol;octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO.CCCCCCCCCCCCCCCCCCO UBHWBODXJBSFLH-UHFFFAOYSA-N 0.000 description 1
- 102000057041 human TNF Human genes 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 230000005934 immune activation Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 description 1
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 229960000598 infliximab Drugs 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 208000028867 ischemia Diseases 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
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 238000002955 isolation Methods 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 206010023332 keratitis Diseases 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000000527 lymphocytic effect Effects 0.000 description 1
- 208000002780 macular degeneration Diseases 0.000 description 1
- 201000010230 macular retinal edema Diseases 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 235000012245 magnesium oxide Nutrition 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 206010027191 meningioma Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 201000006938 muscular dystrophy Diseases 0.000 description 1
- 230000036473 myasthenia Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 229940043348 myristyl alcohol Drugs 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 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
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 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
- 201000008383 nephritis Diseases 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 235000014593 oils and fats Nutrition 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 230000000771 oncological effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 125000001979 organolithium group Chemical group 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000001991 pathophysiological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 125000005543 phthalimide group Chemical group 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 208000005987 polymyositis Diseases 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 208000005069 pulmonary fibrosis Diseases 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000006085 pyrrolopyridyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 201000000306 sarcoidosis Diseases 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
- 235000015424 sodium Nutrition 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000008347 soybean phospholipid Substances 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000011301 standard therapy Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000004083 survival effect Effects 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
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000006092 tetrahydro-1,1-dioxothienyl group Chemical group 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000006090 thiamorpholinyl sulfone group Chemical group 0.000 description 1
- 125000006089 thiamorpholinyl sulfoxide group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 206010043778 thyroiditis Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 239000002452 tumor necrosis factor alpha inhibitor Substances 0.000 description 1
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
- C07D471/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
- C07D487/14—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
- C07D491/14—Ortho-condensed systems
- C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Epidemiology (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Description
本出願は、2015年3月18日出願の米国出願番号62/134,779号の利益を主張し、その全体を、引用により本明細書に包含させる。
本発明は、一般にTNFαシグナル伝達のモジュレーターとして有用な三環式ヘテロ環式化合物に関する。ここに提供されるのは、三環式ヘテロ環式化合物、そのような化合物を含む組成物およびそれらの使用法である。本発明は、さらに、炎症性および自己免疫性障害を含む、TNFα活性と関連する状態の処置に有用な、少なくとも一つの本発明の化合物を含む、医薬組成物に関する。
本発明は、TNF阻害剤αとして有用であり、かつ炎症性および自己免疫性障害、神経および神経変性障害、心血管障害、代謝障害、眼障害ならびに腫瘍障害の処置に有用な式(I)の化合物またはその立体異性体、互変異性体、薬学的に許容される塩、溶媒和物もしくはプロドラッグを提供する。
本発明の第一の側面は、少なくとも一つの式(I)
XはNであり;
Wは
(i)−(CR3R3)2−5−;
(ii)−(CR3R3)x−Y−(CR3R3)y−;または
(iii)−Y−(CR3R3)2−3−Y−、−CR3R3−Y−(CR3R3)2−Y−または−Y−(CR3R3)2−Y−CR3R3−であり;
各Yは独立してO、NR4またはS(O)pであり;
xは0、1、2、3または4であり;
yは0、1、2、3または4であるが、ただし(x+y)は1、2、3または4であり;
R1はH、R1a、C1−6ハロアルキル、0〜6個のR1aで置換されているC2−6アルケニル、0〜4個のR1aで置換されているC2−6アルキニル、−(CRgRg)r(0〜3個のR1aで置換されている3〜14員カルボシクリル)、−(CRgRg)r(0〜3個のR1aで置換されているアリール)、−(CRgRg)r(0〜3個のR1aで置換されている5〜7員ヘテロシクリル)または−(CRgRg)r(0〜3個のR1aで置換されている単環または二環式ヘテロアリール)であり;
R2はH、ハロ、−CN、−CF3、−OCF3、−NO2、0〜6個のR1aで置換されているC1−6アルキル、−(CRgRg)rORe、−(CRgRg)rNRcRc、−(CRgRg)rS(O)pRb、−(CRgRg)r(0〜3個のR1aで置換されている3〜14員カルボシクリル)、−(CRgRg)r(0〜3個のR1aで置換されているアリール)、−(CRgRg)r(0〜3個のR1aで置換されている5〜7員ヘテロシクリル)または−(CRgRg)r(0〜3個のR1aで置換されている単環式ヘテロアリール)であり;
各R3は独立してH、ハロ、−CN、−OH、−OCF3、C1−6アルキル、C1−6ハロアルキル、C2−6アルケニル、C2−6アルキニル、−(CRgRg)rC(O)Rb、−(CRgRg)rC(O)ORb、−(CRgRg)rC(O)NRcRc、−(CRgRg)rORe、−(CRgRg)rOC(O)Rb、−(CRgRg)rOC(O)NRcRc、−(CRgRg)rOC(O)ORd、−(CRgRg)rNRcRc、−(CRgRg)rNRbC(O)Rd、−(CRgRg)rNRbC(O)ORd、−(CRgRg)rNRbC(O)NRcRc、−(CRgRg)rNRbS(O)pRd、−(CRgRg)rS(O)pRb、−(CRgRg)rS(O)pNRcRc、−(CRgRg)r(0〜3個のR1aで置換されている3〜14員カルボシクリル)、−(CRgRg)r(0〜3個のR1aで置換されているアリール)、−(CRgRg)r(0〜3個のR1aで置換されている5〜7員ヘテロシクリル)または−(CRgRg)r(0〜3個のR1aで置換されている単環または二環式ヘテロアリール)であるか;または2個のR3は、それらが結合している炭素原子と一体となってC=O、C=NORb、スピロカルボシクリル基またはスピロヘテロシクリル基を形成し;
各R4は独立してH、0〜6個のR1aで置換されているC1−6アルキル、0〜6個のR1aで置換されているC3−7シクロアルキル、−C(O)Rb、−C(O)NRcRc、−C(O)ORb、−S(O)2Rb、−S(O)2NRcRc、−S(O)2ORb、−(CRgRg)r(0〜3個のR1aで置換されている3〜14員カルボシクリル)、−(CRgRg)r(0〜3個のR1aで置換されているアリール)、−(CRgRg)r(0〜3個のR1aで置換されている5〜7員ヘテロシクリル)または−(CRgRg)r(0〜3個のR1aで置換されている単環式ヘテロアリール)であり;
R5は−(CRgRg)r(0〜3個のR1aで置換されている3〜14員カルボシクリル)、−(CRgRg)r(0〜3個のR1aで置換されているアリール)、−(CRgRg)r(0〜3個のR1aで置換されている5〜10員ヘテロシクリル)または−(CRgRg)r(0〜3個のR1aで置換されている単環または二環式ヘテロアリール)であり;
R6はH、C1−6アルキルまたはC1−6ハロアルキルであるか;
またはR5およびR6は、それらが結合している炭素原子と一体となって5〜6員スピロカルボシクリル環またはスピロヘテロシクリル環を形成し、各々0〜6個のR5aで置換されており;
各R5aは独立してH、ハロ、−CN、−OH、C1−3アルキル、C1−3フルオロアルキルおよびC1−3アルコキシから選択されるか;またはスピロ炭素環式またはスピロヘテロ環式環の隣接炭素原子に結合している2個のR5aは、それらが結合している炭素原子と一体となってベンゾ環を形成し、該ベンゾは、0〜4個のRfで置換されているか;またはスピロ炭素環式環またはスピロヘテロ環式環の同じ炭素原子に結合した2個のR5aは=Oを形成し;
R8はH、ハロ、−CN、C1−6ハロアルキルまたはC1−3アルコキシであり;
各R1aは独立してF、Cl、−CN、0〜6個のRaで置換されているC1−6アルキル、0〜6個のRaで置換されているC3−6シクロアルキル、0〜6個のRaで置換されているC1−6アルコキシ、C1−3ハロアルコキシ、0〜6個のRaで置換されているヘテロシクロアルキル、0〜6個のRaで置換されているアリール、0〜6個のRaで置換されている単環もしくは二環式ヘテロアリール、−OCH2(0〜6個のRaで置換されているアリール)、−C(O)Rb、−C(O)ORb、−C(O)NRcRc、−OC(O)Rb、−OC(O)NRcRc、−OC(O)ORd、−NRcRc、−NRbC(O)Rd、−NRbC(O)ORd、−NRbS(O)pRd、−NRbC(O)NRcRc、−NRbS(O)pNRcRc、−S(O)pRb、−S(O)pNRcRcまたは−C(O)NRb(CH2)1−3NRcRcであり;
各Raは独立してハロ、−CN、−OH、−NO2、−NH2、C1−3アルキル、C1−3フルオロアルキル、C2−4アルケニル、C2−4アルキニル、C1−3アルコキシ、C1−3フルオロアルコキシ、−C(O)OH、−CH2C(O)OH、−C(O)(C1−3アルキル)、−C(O)O(C1−4アルキル)、−OC(O)(C1−3アルキル)、−NH(C1−3アルキル)、−N(C1−3アルキル)2、−C(O)NH(C1−3アルキル)、−OC(O)NH(C1−3アルキル)、−NHC(O)NH(C1−3アルキル)、−C(=NH)(NH2)、C3−7カルボシクリル、アリール、5〜7員ヘテロシクリル、単環または二環式ヘテロアリール、−O(アリール)、−O(ベンジル)、−O(ヘテロシクリル)、−S(C1−3アルキル)、−S(アリール)、−S(ヘテロシクリル)、−S(O)(アリール)、−S(O)(ヘテロシクリル)、S(O)2(アリール)、−S(O)2(ヘテロシクリル)、−NHS(O)2(アリール)、−NHS(O)2(ヘテロシクリル)、−NHS(O)2NH(アリール)、−NHS(O)2NH(ヘテロシクリル)、−NH(アリール)、−NH(ヘテロシクリル)、−NHC(O)(アリール)、−NHC(O)(C1−3アルキル)、−NHC(O)(ヘテロシクリル)、−OC(O)(アリール)、−OC(O)(ヘテロシクリル)、−NHC(O)NH(アリール)、−NHC(O)NH(ヘテロシクリル)、−OC(O)O(C1−3アルキル)、−OC(O)O(アリール)、−OC(O)O(ヘテロシクリル)、−OC(O)NH(アリール)、−OC(O)NH(ヘテロシクリル)、−NHC(O)O(アリール)、−NHC(O)O(ヘテロシクリル)、−NHC(O)O(C1−3アルキル)、−C(O)NH(アリール)、−C(O)NH(ヘテロシクリル)、−C(O)O(アリール)、−C(O)O(ヘテロシクリル)、−N(C1−3アルキル)S(O)2(アリール)、−N(C1−3アルキル)S(O)2(ヘテロシクリル)、−N(C1−3アルキル)S(O)2NH(アリール)、−N(C1−3アルキル)S(O)2NH(ヘテロシクリル)、−N(C1−3アルキル)(アリール)、−N(C1−3アルキル)(ヘテロシクリル)、−N(C1−3アルキル)C(O)(アリール)、−N(C1−3アルキル)C(O)(ヘテロシクリル)、−N(C1−3アルキル)C(O)NH(アリール)、−(CH2)0−3C(O)NH(ヘテロシクリル)、−OC(O)N(C1−3アルキル)(アリール)、−OC(O)N(C1−3アルキル)(ヘテロシクリル)、−N(C1−3アルキル)C(O)O(アリール)、−N(C1−3アルキル)C(O)O(ヘテロシクリル)、−C(O)N(C1−3アルキル)(アリール)、−C(O)N(C1−3アルキル)(ヘテロシクリル)、−NHS(O)2N(C1−3アルキル)(アリール)、−NHS(O)2N(C1−3アルキル)(ヘテロシクリル)、−NHP(O)2N(C1−3アルキル)(アリール)、−NHC(O)N(C1−3アルキル)(アリール)、−NHC(O)N(C1−3アルキル)(ヘテロシクリル)、−N(C1−3アルキル)S(O)2N(C1−3アルキル)(アリール)、−N(C1−3アルキル)S(O)2N(C1−3アルキル)(ヘテロシクリル)、−N(C1−3アルキル)C(O)N(C1−3アルキル)(アリール)、−N(C1−3アルキル)C(O)N(C1−3アルキル)(ヘテロシクリル)または−Si(C1−3アルキル)3であり;
各Rbは独立してH、0〜6個のRfで置換されているC1−6アルキル、0〜6個のRfで置換されているC3−7シクロアルキル、0〜6個のRfで置換されているヘテロシクロアルキル、0〜3個のRfで置換されているアリールまたは0〜3個のRfで置換されている単環もしくは二環式ヘテロアリールであり;
各Rcは独立してH、0〜6個のRfで置換されているC1−6アルキル、0〜6個のRfで置換されているC3−7シクロアルキル、0〜6個のRfで置換されているヘテロシクロアルキル、0〜3個のRfで置換されているアリールまたは0〜3個のRfで置換されている単環もしくは二環式ヘテロアリールであるか;または同じ窒素に結合しているとき、2個のRcは、それらが結合している窒素原子とともに、場合によりRgで置換されていてよい4〜8員ヘテロ環式環を形成し;
各Rdは独立してH、0〜6個のRfで置換されているC1−6アルキル、0〜6個のRfで置換されているC3−7シクロアルキル、0〜6個のRfで置換されているヘテロシクロアルキル、0〜3個のRfで置換されているアリールまたは0〜3個のRfで置換されている単環もしくは二環式ヘテロアリールであり;
各Reは独立してH、0〜6個のRfで置換されているC1−6アルキル、C1−3ハロアルキル、0〜6個のRfで置換されているC3−7シクロアルキル、0〜6個のRfで置換されているヘテロシクロアルキル、0〜3個のRfで置換されているアリールまたは0〜3個のRfで置換されている単環もしくは二環式ヘテロアリールであり;
各Rfは独立してH、ハロ、−OH、−CN、0〜6個のRaで置換されているC1−6アルキル、C1−3アルコキシ、0〜6個のRaで置換されているC3−7シクロアルキル、0〜6個のRaで置換されているヘテロシクロアルキル、0〜3個のRaで置換されているアリールまたは0〜3個のRaで置換されている単環もしくは二環式ヘテロアリールであり;
各Rgは独立してH、F、−OH、−CN、C1−3アルキル、−CF3またはフェニルであり;
各pは独立して0、1または2であり;
各rは独立して0、1、2、3または4である。〕
の化合物またはその塩を提供する。
−b]ピリダジン−6−オール(51);(+/−)−trans−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシ−2−メチルプロポキシ)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(52);(+/−)−trans−9−(2,5−ジメチルフェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(53);(+/−)−cis−9−(5−クロロ−2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(54);(+/−)−trans−9−(5−クロロ−2−(トリフルオロメチル)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(55);(+/−)−trans−9−(5−クロロ−2−メトキシフェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(56);rac−(6S,9S)−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−7,9−ジヒドロ−6H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(57);cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,9−ジヒドロ−7H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(58);9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6−メチル−6,9−ジヒドロ−7H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(59);9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6−(ピリジン−4−イル)−6,9−ジヒドロ−7H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(60);cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−5−イル)−6,9−ジヒドロ−7H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(61);2−(4−(9−(2−(ジフルオロメトキシ)フェニル)−7,9−ジヒドロ−6H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)フェニル)プロパン−2−オール(62);2−(5−(9−(2−(ジフルオロメトキシ)フェニル)−7,9−ジヒドロ−6H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)ピリミジン−2−イル)プロパン−2−オール(63);または9−(2−(ジフルオロメトキシ)フェニル)−2−(1−メチル−1H−ピラゾール−4−イル)−7,9−ジヒドロ−6H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン(64)である。
本発明の特性および利点は、次の詳細な説明により、当業者にはより容易に理解され得る。明確性の理由のために、上におよび下に別々の態様の文脈で記載する、本発明のある複数特性を組み合わせて、一つの態様を形成してもよいことは認識される。逆に、簡潔性のために、単一の態様の文脈で記載されている本発明の種々の特性を組み合わせて、その下位の組み合わせを形成してもよい。ここで例示的または好ましいとして特定する態様は、説明的であることを意図し、限定的ではない。
用語“シアノ”は基−CNを指す。
用語“アミノ”は基−NH2を指す。
用語“オキソ”は基=Oを指す。
a) Wermuth, C.G. et al., The Practice of Medicinal Chemistry, Chapter 31, Academic Press (1996);
b) Bundgaard, H. ed., Design of Prodrugs, Elsevier (1985);
c) Bundgaard, H., Chapter 5: “Design and Application of Prodrugs”, A Textbook of Drug Design and Development, pp. 113-191, Krogsgaard-Larsen, P. et al., eds., Harwood Academic Publishers (1991);および
d) Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism, Wiley-VCH (2003)
に記載される。
本発明の化合物はTNFαの活性を調節する。したがって、式(I)の化合物は、TNFαの調節と関係する状態の処置における有用性がある。
心血管障害は、血栓症、心肥大、高血圧、心臓の不規則収縮(例えば、心不全による)および心筋梗塞を含む。
代謝障害は、糖尿病(インスリン依存性糖尿病および若年性糖尿病を含む)、異脂肪血症およびメタボリック症候群を含む。
本発明の化合物は、有機化学の当業者に利用可能な多くの方法により合成できる。本発明の化合物を製造するための一般的合成スキームを下に記載する。これらのスキームは説明的であり、当業者がここに開示する化合物の製造に使用し得る可能性のある技術を限定する意図はない。本発明の化合物を製造するための異なる方法が、当業者には明らかである。さらに、所望の化合物または化合物群を得るために、合成における種々の工程を別の順番で実施してよい。一般的スキームに記載した方法により製造した本発明の化合物の例を、以下の製造および例示部分において示す。ホモキラル例の製造は、当業者に知られる技術により実施し得る。例えば、ホモキラル化合物は、キラル相分取HPLCによる、ラセミ生成物の分離により製造し得る。あるいは、例示化合物を、エナンチオマー的に富化させた生成物をもたらすことが知られる方法により製造し得る。
条件A:カラム:YMC COMBISCREEN(登録商標)ODS-A 4.6×50mm (4分);4分かけて0〜100%溶媒Bに直線勾配と1分100%Bで保持;220nmでUV可視化;溶媒A=10%MeOH、90%H2O、0.2%H3PO4;溶媒B=90%MeOH、10%H2O、0.2%H3PO4;流速:4mL/分。
条件B:カラム:Waters Acquity UPLC BEH C18、2.1×50mm、1.7μm粒子;移動相A:5:95アセトニトリル:10mM酢酸アンモニウム含有水;移動相B:95:5アセトニトリル:10mM酢酸アンモニウム含有水;温度:50℃;勾配:3分かけて0〜100%B、次いで100%Bで0.75分保持;流速:1.11mL/分。
条件C:カラム:Waters Acquity UPLC BEH C18、2.1×50mm、1.7μm粒子;移動相A:5:95アセトニトリル:0.05%TFA含有水;移動相B:95:5アセトニトリル:0.05%TFA含有水;温度:50℃;勾配:3分かけて0〜100%B、次いで100%Bで0.75分保持;流速:1.11mL/分。
条件D:カラム:XBridge Phenyl、4.6×150mm、3.5μ;移動相A:5:95アセトニトリル:0.05%TFA含有水;移動相B:95:5アセトニトリル:0.05%TFA含有水;勾配:25分かけて10〜100%B、次いで100%Bに5分保持;流速:1mL/分。
条件E:カラム:ZORBAX(登録商標)CN、4.6×150mm、5μ;移動相A:5:95アセトニトリル:10mM酢酸アンモニウム含有水;移動相B:95:5アセトニトリル:10mM酢酸アンモニウム含有水;勾配:25分かけて10〜100%B、次いで100%Bに5分保持;流速:1mL/分。
条件F:カラム:SunFire C18、4.6×150mm、3.5μ;移動相A:5:95アセトニトリル:0.05%TFA含有水;移動相B:95:5アセトニトリル:0.05%TFA含有水;勾配:25分かけて10〜100%B、次いで100%Bに5分保持;流速:1mL/分。
条件G:カラム:Ascentis Express C18(4.6×50)mm、2.7μm;移動相A:5:95アセトニトリル:10mM酢酸アンモニウム含有水;移動相B:95:5アセトニトリル:10mM酢酸アンモニウム含有水;温度:45℃;勾配:4分かけて0〜100%B;流速:4.00mL/分。
条件I:Waters Acquity UPLC BEH C18(2.1×50)mm、1.7μm粒子;移動相A:5:95アセトニトリル:0.05%TFA含有水;移動相B:95:5アセトニトリル:0.05%TFA含有水;温度:50℃;勾配:1分かけて2〜98%B、次いで98%Bで0.5分保持;流速:0.80mL/分。
条件J:カラム:XBridge Phenyl、3.0×150mm、3.5μ;移動相A:5:95アセトニトリル:0.05%TFA含有水;移動相B:95:5アセトニトリル:0.05%TFA含有水;勾配:12分かけて10〜100%B、次いで100%Bで3分保持;流速:1mL/分。
条件K:カラム:PHENOMENEX(登録商標)Kinetex、C18(2.1×50)mm、2.6μ;移動相A:10:90アセトニトリル:0.1%TFA含有水;移動相B:90:10アセトニトリル:0.1%TFA含有水;勾配:1.5分かけて0〜100%B、次いで100%Bで0.5分保持;流速:1mL/分。
条件L:カラム:SunFire C18、3.0×150mm、3.5μ;移動相A:5:95アセトニトリル:0.05%TFA含有水;移動相B:95:5アセトニトリル:0.05%TFA含有水;勾配:12分かけて10〜100%B、次いで100%Bで3分保持;流速:1mL/分。
条件M:カラム:Waters Acquity UPLC BEH C18、2.1×50mm、1.7μm粒子;移動相A:水;移動相B:アセトニトリル;温度:50℃;勾配:1分かけて2〜98%B、次いで98%Bで0.75分保持;流速:0.8mL/分。
条件N:カラム:YMC Pro C18 S5 ODS 4.6×50mm;4分かけて0〜100%溶媒Bに直線勾配と1分100%Bで保持;220nmでUV可視化;溶媒A=10%MeOH、90%H2O、0.2%H3PO4;溶媒B=90%MeOH、10%H2O、0.2%H3PO4;流速:4mL/分。
条件O:Waters Acquity UPLC BEH C18、2.1×50mm、1.7μm粒子;移動相A:5:95アセトニトリル:0.1%トリフルオロ酢酸含有水;移動相B:95:5アセトニトリル:0.1%トリフルオロ酢酸含有水;温度:50℃;勾配:3分かけて0〜100%B、次いで100%Bで0.75分保持;流速:1.0mL/分。
(+/−)−9−(2−(ジフルオロメトキシ)フェニル)−2−(6−メトキシピリジン−3−イル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン
反応バイアルに(+/−)−2−クロロ−9−(2−(ジフルオロメトキシ)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン(15mg、0.043mmol)、(6−メトキシピリジン−3−イル)ボロン酸(8.50mg、0.056mmol)、2Mリン酸三カリウム水溶液(0.064mL、0.128mmol)およびジオキサン(0.3mL)を仕込んだ。この混合物に、窒素を約5分間通してバブリングすることにより脱酸素した。次に、PdCl2(dppf)(1.565mg、2.138μmol)を添加し、バイアルに蓋をして、混合物を90℃で45分加熱した。室温に冷却後、反応混合物を真空下濃縮し、粗物質を、次の条件を用いる分取LC/MSで精製した:カラム:XBridge C18、19×200mm、5μm粒子;移動相A:5:95アセトニトリル:0.1%トリフルオロ酢酸含有水;移動相B:95:5アセトニトリル:0.1%トリフルオロ酢酸含有水;勾配:19分かけて10〜50%B、次いで100%Bに5分保持;流速:20mL/分。所望の生成物を含むフラクションを合わせ、遠心蒸発により乾燥させた。
物質を次の条件の分取LC/MSでさらに精製した:カラム:XBridge C18、30×150mm、5μm粒子;移動相A:5:95アセトニトリル:10mM酢酸アンモニウム含有水;移動相B:95:5アセトニトリル:10mM酢酸アンモニウム含有水;勾配:20分かけて10〜60%B、次いで100%Bに2分保持;流速:40mL/分。生成物含有フラクションを合わせ、遠心蒸発により乾燥させて、6.8g(38%)の(+/−)−9−(2−(ジフルオロメトキシ)フェニル)−2−(6−メトキシピリジン−3−イル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]−イミダゾ[1,2−b]ピリダジンを得た。1H NMR (500MHz, DMSO-d6):δ 8.50 (s, 1H), 8.09 (d, J = 9.4 Hz, 1H), 7.89 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 9.4 Hz, 1H), 7.44-7.33 (m, 1H), 7.32-7.23 (m, 1H), 7.14-7.06 (m, 1H), 6.90 (d, J = 7.4 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 5.71 (s, 1H), 3.87 (s, 3H), 3.47 (br. s., 1H), 3.21-3.00 (m, 2H), 2.98-2.76 (m, 2H)。LC保持時間:1.12分(分析的HPLC方法A)。LC/MS (M+H):424
(+/−)−2−(4−(9−(2−(ジフルオロメトキシ)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)フェニル)プロパン−2−オール
(+/−)−2−(5−(9−(2−(ジフルオロメトキシ)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)ピリミジン−2−イル)プロパン−2−オール
(+/−)−Cisおよびtrans−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール
純粋ジアステレオマーは、次の条件を使用するSFCクロマトグラフィーにより分割できた:分取カラム:4−エチルピリジン(5×25cm、5μm、#16664);BPR圧:100バール;温度:40℃;流速:250mL/分;移動相:CO2/MeOH w 0.1%NH4OH(90/10);検出器波長:220nm;分離プログラム:スタック注入;注入:次のサイクル時間の0.5mL:2.5分;サンプル調製:1.05g/20mL MeOH、52.5mg/mL;スループット:630mg/時間。
反応バイアルに(+/−)−cis−6−((tert−ブチルジフェニルシリル)オキシ)−2−クロロ−9−(2−(ジフルオロ−メトキシ)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン(10mg、0.027mmol)、(4−(2−ヒドロキシプロパン−2−イル)フェニル)ボロン酸(6.38mg、0.035mmol)、2Mリン酸三カリウム水溶液(0.041mL、0.082mmol)およびジオキサン(0.3mL)を仕込んだ。得られた混合物に、窒素を約5分間通してバブリングすることにより脱酸素し、次いでPdCl2(dppf)(0.998mg、1.363μmol)を添加し、バイアルに蓋をして、混合物を105℃で2時間加熱した。反応混合物を冷却し、MeOHで希釈し、ミリポア(0.45μm)フィルターで濾過し、次の条件の分取LC/MSでさらに精製し(カラム:XBridge C18、19×200mm、5μm粒子;移動相A:5:95アセトニトリル:10mM酢酸アンモニウム含有水;移動相B:95:5アセトニトリル:10mM酢酸アンモニウム含有水;勾配:20分かけて10〜50%B、次いで100%Bに5分保持;流速:20mL/分)、生成物含有フラクションの濃縮後、(+/−)−cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オールを得た。1H NMR (500MHz, DMSO-d6):δ 8.09 (d, J = 9.6 Hz, 1H), 7.69 (d, J = 9.6 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 7.41-7.34 (m, 1H), 7.34-7.29 (m, 1H), 7.22 (br. s., 1H), 7.14-7.06 (m, 1H), 7.02 (d, J = 7.5 Hz, 1H), 5.61 (s, 1H), 4.71 (br. s., 1H), 3.18-3.04 (m, 1H), 2.99 (dd, J = 14.2, 4.8 Hz, 1H), 1.39 (s, 6H)。LC保持時間1.41分(方法E)。LC/MS (M+H):467
実施例5の化合物を、trans−6−((tert−ブチルジフェニルシリル)オキシ)−2−クロロ−9−(2−(ジフルオロメトキシ)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジンから、実施例4に記載する一般的方法に従い製造した。1H NMR (500MHz, DMSO-d6) δ 8.13 (d, J = 9.5 Hz, 1H), 7.70 (d, J = 9.6 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.38-7.32 (m, 1H), 7.29-7.24 (m, 1H), 7.43-7.09 (m, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.75 (d, J = 7.4 Hz, 1H), 5.70 (s, 2H), 5.37 (d, J = 6.1 Hz, 1H), 5.14 (s, 1H), 4.74 (br. s., 1H), 3.13 (d, J = 11.4 Hz, 1H), 2.85 (d, J = 9.1 Hz, 1H), 1.41 (s, 6H)。LC保持時間1.44分(方法E)。LC/MS (M+H):467
Cis−(6R,9R)−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オールおよび
Cis−(6S,9S)−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール
(+/−)−Cis−2−(4−((6S,9S)−9−(2−(ジフルオロメトキシ)フェニル)−6−フルオロ−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)フェニル)プロパン−2−オール
実施例8の化合物を、(+/−)−cis−2−クロロ−9−(2−(ジフルオロメトキシ)フェニル)−6−フルオロ−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジンおよび(4−(2−ヒドロキシプロパン−2−イル)フェニル)ボロン酸から、実施例4について記載する方法を使用して製造した。1H NMR (500MHz, DMSO-d6) δ 8.21 (d, J = 9.6 Hz, 1H), 7.80 (d, J = 9.7 Hz, 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.45-7.10 (m, 3H), 7.01 (t, J = 7.3 Hz, 1H), 6.55 (d, J = 7.5 Hz, 1H), 5.83 (d, J = 3.8 Hz, 1H), 5.75-5.55 (m, 1H), 3.35-3.00 (m, 2H), 1.40 (s, 6H)。LC保持時間1.50分(方法E)。LC/MS (M+H):469
Rac−(6S,9S)−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−7,9−ジヒドロ−6H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール
エチル6−クロロイミダゾ[1,2−b]ピリダジン−2−カルボキシレート(6.5g、28.8mmol)のテトラヒドロフラン(150mL)中の透明淡黄褐色溶液を、アセトン/ドライアイス浴で−78℃に冷却し、淡黄褐色スラリーを形成した。1Mリチウムマグネシウム2,2,6,6−テトラメチルピペリジン−1−イドジクロライドのテトラヒドロフラン/トルエン溶液(36.0mL、36.0mmol)を滴加して、透明淡黄褐色溶液を得た。−78℃で3時間撹拌後、2−(ジフルオロメトキシ)ベンズアルデヒド(5.21g、30.2mmol)のテトラヒドロフラン(20mL)溶液をシリンジから添加した。得られた混合物を−78℃で5撹拌した。メタノール(10mL)で反応を停止させ、混合物を室温に温めた。褐色沈殿を濾過し、テトラヒドロフラン(10mL)で洗浄した。濾液を濃縮した。残渣を酢酸エチル(200mL)で希釈し、水(20mL)、塩水(20mL)で洗浄し、乾燥させ(硫酸マグネシウム)、濾過し、減圧下濃縮した。20〜60%酢酸エチルのヘキサン溶液で溶出するシリカゲルクロマトグラフィーにより、メチル6−クロロ−3−((2−(ジフルオロメトキシ)フェニル)(ヒドロキシ)メチル)イミダゾ[1,2−b]ピリダジン−2−カルボキシレート(2.40g、22%収率)を得た。LC/MS (M+1): 284.1;HPLC保持時間:0.81分(分析的HPLC方法C);1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 9.7 Hz, 1H), 7.60 (dd, J = 7.7, 1.5 Hz, 1H), 7.37-7.26 (m, 1H), 7.25-7.13 (m, 2H), 7.09 (dd, J = 8.0, 1.0 Hz, 1H), 6.90 (d, J = 11.7 Hz, 1H), 6.74-6.17 (m, 1H), 5.78 (d, J = 11.7 Hz, 1H), 4.03 (s, 3H)
trans−2−クロロ−9−(2−(ジフルオロメトキシ)フェニル)−7,9−ジヒドロ−6H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(6mg、0.016mmol)、(4−(2−ヒドロキシプロパン−2−イル)フェニル)ボロン酸(3.52mg、0.020mmol)、PdCl2(dppf)−CH2Cl2付加物(2.66mg、3.26μmol)および2.0Mリン酸カリウム水溶液(0.016mL、0.033mmol)のN,N−ジメチルホルムアミド(0.8mL)中の混合物を、密閉バイアル中、窒素で脱気し、90℃で2時間加熱した。混合物を室温に冷却し、次の条件の分取LC/MSで精製した:カラム:Waters XBridge C18、19×200mm、5μm粒子;移動相A:5:95アセトニトリル:10mM酢酸アンモニウム含有水;移動相B:95:5アセトニトリル:10mM酢酸アンモニウム含有水;勾配:20分かけて25〜100%B、次いで100%Bに5分保持;流速:20mL/分。生成物含有フラクションを合わせ、遠心蒸発により乾燥させて、rac−(6S,9S)−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−7,9−ジヒドロ−6H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(2.6mg、34%収率)を得た。LC/MS (M+1): 468.1;HPLC RT=1.48分(分析的HPLC方法A)。1H NMR (500 MHz, DMSO-d6) δ 8.18 (d, J = 9.6 Hz, 1H), 7.76 (d, J = 9.7 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.55-7.42 (m, 3H), 7.42-7.20 (m, 2H), 7.20-7.10 (m, 1H), 6.93 (d, J = 7.3 Hz, 1H), 6.44 (s, 1H), 4.87 (d, J = 4.6 Hz, 1H), 4.11-3.98 (m, 1H), 3.73 (dd, J = 11.9, 5.2 Hz, 1H), 1.41 (s, 6H)
Cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,9−ジヒドロ−7H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール
9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6−メチル−6,9−ジヒドロ−7H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール
実施例59の化合物を、実施例57の製造について記載する一般的方法に従い製造した。2−クロロ−9−(2−(ジフルオロメトキシ)フェニル)−6−メチル−6,9−ジヒドロ−7H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(6mg、0.016mmol)を(4−(2−ヒドロキシプロパン−2−イル)フェニル)ボロン酸(3.39mg、0.019mmol)で処理して、9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6−メチル−6,9−ジヒドロ−7H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オールを、2ジアステレオマーの3:2混合物として得た(4.6mg、49%収率)。LC/MS (M+1): 482.1;HPLC RT=0.74分(分析的HPLC方法C);1H NMR (400 MHz, CD3OD) δ 8.46-8.22 (m, 1H), 8.20-8.01 (m, 1H), 7.76-7.64 (m, 2H), 7.64-7.46 (m, 3H), 7.46-7.32 (m, 2H), 7.32-7.14 (m, 2H), 7.12-6.68 (m, 1H), 6.53 (d, J = 12.1 Hz, 1H), 4.24-3.86 (m, 2H), 1.86-1.65 (m, 3H), 1.55 (d, J = 2.6 Hz, 6H)
9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6−(ピリジン−4−イル)−6,9−ジヒドロ−7H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール
Cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−5−イル)−6,9−ジヒドロ−7H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール
2−(4−(9−(2−(ジフルオロメトキシ)フェニル)−7,9−ジヒドロ−6H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)フェニル)プロパン−2−オール
2−クロロ−9−(2−(ジフルオロメトキシ)フェニル)−7,9−ジヒドロ−6H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン(10mg、0.028mmol)、(4−(2−ヒドロキシプロパン−2−イル)フェニル)ボロン酸(6.14mg、0.034mmol)、PdCl2(dppf)−CH2Cl2付加物(4.64mg、5.69μmol)および2.0Mリン酸カリウム水溶液(0.028mL、0.057mmol)のN,N−ジメチルホルムアミド(0.8mL)中の混合物を、密閉バイアル中、窒素で脱気し、90℃で2時間加熱した。混合物を室温に冷却し、次の条件の分取LC/MSで精製した:カラム:Waters XBridge C18、19×200mm、5μm粒子;移動相A:5:95アセトニトリル:10mM酢酸アンモニウム含有水;移動相B:95:5アセトニトリル:10mM酢酸アンモニウム含有水;勾配:20分かけて25〜100%B、次いで100%Bに5分保持;流速:20mL/分。所望の生成物を含むフラクションを合わせ、遠心蒸発により乾燥させて、2−(4−(9−(2−(ジフルオロメトキシ)フェニル)−7,9−ジヒドロ−6H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)フェニル)プロパン−2−オール(11.8mg、90%収率)を得た。LC/MS (M+1): 452.0;HPLC RT=1.60分(分析的HPLC方法B)。1H NMR (500 MHz, DMSO-d6) δ 8.11 (d, J = 9.5 Hz, 1H), 7.71 (d, J = 9.4 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.55-7.41 (m, 3H), 7.41-7.22 (m, 2H), 7.22-7.06 (m, 2H), 6.40 (s, 1H), 4.18 (d, J = 11.1 Hz, 1H), 4.00 (m, 1H), 3.11 (d, J = 16.6 Hz, 1H), 3.01-2.81 (m, 1H), 1.42 (s, 6H)
2−(5−(9−(2−(ジフルオロメトキシ)フェニル)−7,9−ジヒドロ−6H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)ピリミジン−2−イル)プロパン−2−オール
9−(2−(ジフルオロメトキシ)フェニル)−2−(1−メチル−1H−ピラゾール−4−イル)−7,9−ジヒドロ−6H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン
本発明の化合物の薬理学的性質を、多数の生物学的アッセイにより確認し得る。次の例示的生物学的アッセイを、本発明の化合物を用いて実施している。
DMSO中連続希釈した試験化合物を、アッセイプレート(Labcyte, Cat. #LP-0200)に、0.004μM〜25μM範囲の最終濃度でプレーティングした。アッセイ緩衝液[DMEM、4.5g/lグルコース(Gibco, Cat. 21063-029)、10%FBS(Sigma、F4135)、1%ペニシリン−ストレプトマイシン(Gibco, Cat. 15140-122)、1%Anti-Anti(Gibco, Cat. 15240-112)および2mM L−グルタミン(Gibco, Cat. 25030-081)]中のTNFα(最終濃度0.5ng/ml)またはCD40L(最終濃度30ng/ml)を、次いでアッセイプレートに添加した。37℃および5%CO2での30分プレインキュベーション後、NF−κB駆動分泌型アルカリホスファターゼレポーター遺伝子を含むHEK−Blue−CD40L細胞(InvivoGen, Cat. Code hkb-cd40)を、20,000細胞/ウェル密度でアッセイプレートに播種した。このプレートを、18時間、37℃および5%CO2でインキュベートした。分泌型アルカリホスファターゼ発現を、製造業者の明細に従いQUANTI-Blue(InvivoGen, Cat. Code rep-qb1)を使用して測定し、アッセイプレートをPerkinElmer Envisionで620nmで読んだ。
Claims (6)
- 式(I)
Xは、Nであり;
Wは、−CH 2 CH 2 O−、−CH(OH)CH 2 O−、−C(CH 3 )(OH)CH 2 O−、−C(OH)(ピリジニル)CH 2 O−、−CH 2 CH 2 NH−、−CHFCH 2 NH−、または−CH(OH)CH 2 NH−であり;
R 1 は、フェニル、ピラゾリル、ピリジニル、またはピリミジニルであり、各々Cl、−CH 3 、−C(CH 3 ) 2 OH、−C(CH 2 CH 3 ) 2 OH、−C(CH 3 )(CH 2 CH 3 )OH、−CH(CH 3 )OCH 2 CH 3 、−OCH 3 、−OCH 2 CH 3 、−OCH 2 CH 2 CH 3 、−OCH(CH 3 ) 2 、−OCH 2 C(CH 3 ) 3 、−OCH 2 CH(CH 3 ) 2 、−OCH 2 CH 2 OCH 3 、−OCH 2 C(CH 3 ) 2 OH、−OCH 2 (メトキシフェニル)、−S(O) 2 CH 3 、−S(O) 2 NH 2 、−S(O) 2 NH(CH 3 )、−C(O)NH 2 、−C(O)(モルホリニル)、−C(O)(メトキシアゼチジニル)、−C(O)NH(シクロプロピル)、ヒドロキシシクロプロピル、モルホリニル、およびカルボキシメチルピペラジニルから独立して選択される1〜2置換基で置換されており;
R 2 は、Hであり;
R 5 は、F、Cl、−CH 3 、−CH 2 CH 3 、−CF 3 、−OCH 3 、−OCHF 2 、および−OCF 3 から独立して選択される1〜2置換基で置換されているフェニルであり;
R 6 は、Hであり;および
R 8 は、Hである、〕
の化合物またはその塩。 - (+/−)−9−(2−(ジフルオロメトキシ)フェニル)−2−(6−メトキシピリジン−3−イル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン(1);(+/−)−2−(4−(9−(2−(ジフルオロメトキシ)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)フェニル)プロパン−2−オール(2);(+/−)−2−(5−(9−(2−(ジフルオロメトキシ)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)ピリミジン−2−イル)プロパン−2−オール(3);(+/−)−cisおよびtrans−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(4および5);cis−(6R,9R)−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(6);cis−(6S,9S)−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(7);(+/−)−cis−2−(4−((6S,9S)−9−(2−(ジフルオロメトキシ)フェニル)−6−フルオロ−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)フェニル)プロパン−2−オール(8);(+/−)−trans−2−(4−(9−(2−(ジフルオロメトキシ)フェニル)−6−フルオロ−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)フェニル)プロパン−2−オール(9);(+/−)−cis−2−(5−(9−(2−(ジフルオロメトキシ)フェニル)−6−フルオロ−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)ピリミジン−2−イル)プロパン−2−オール(10);(+/−)−cis−9−(2−(ジフルオロメトキシ)フェニル)−6−フルオロ−2−(6−メトキシピリジン−3−イル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン(11);cis−(1S,4S)−2−(4−(9−(2−(ジフルオロメトキシ)フェニル)−6−フルオロ−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)フェニル)プロパン−2−オール(12);cis−(1R,4R)−2−(4−(9−(2−(ジフルオロメトキシ)フェニル)−6−フルオロ−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)フェニル)プロパン−2−オール(13);trans−(6R,9S)−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(14);trans−(6S,9R)−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(15);cis−(6R,9S)−9−(2−(ジフルオロメトキシ)フェニル)−2−(6−メトキシピリジン−3−イル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(16);9−(2−(ジフルオロメトキシ)フェニル)−2−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−5−イル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(17);(4−(9−(2−(ジフルオロメトキシ)フェニル)−6−ヒドロキシ−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)フェニル)(3−メトキシアゼチジン−1−イル)メタノン(18);(4−(9−(2−(ジフルオロメトキシ)フェニル)−6−ヒドロキシ−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)フェニル)(モルホリノ)メタノン(19);N−シクロプロピル−4−(9−(2−(ジフルオロメトキシ)フェニル)−6−ヒドロキシ−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)ベンズアミド(20);N−シクロプロピル−5−(9−(2−(ジフルオロメトキシ)フェニル)−6−ヒドロキシ−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)ピコリンアミド(21);2−(4−(5−(9−(2−(ジフルオロメトキシ)フェニル)−6−ヒドロキシ−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)ピリミジン−2−イル)ピペラジン−1−イル)酢酸(22);(+/−)−trans−9−(4−フルオロ−2−メトキシフェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(23);(+/−)−trans−9−(2−エチルフェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(24);(+/−)−cis−9−(2−エチルフェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(25);2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−9−(2−(トリフルオロメトキシ)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(26);(+/−)−cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−イソブトキシフェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(27);(+/−)−trans−9−(5−クロロ−2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(28);(+/−)−cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシ−2−メチルプロポキシ)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(29);(+/−)−cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシ−2−メチルプロポキシ)−3−メトキシフェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(30);(+/−)−cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−エトキシフェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(31);(+/−)−cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−イソプロポキシフェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(32);(+/−)−cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−プロポキシフェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(33);(+/−)−cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−メトキシエトキシ)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(34);(+/−)−cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(1−エトキシエチル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(35);(+/−)−cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(1−ヒドロキシシクロプロピル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(36);(+/−)−cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−((2−メトキシベンジル)オキシ)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(37);(+/−)−trans−9−(4−フルオロ−2−メチルフェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(38);(+/−)−cis−9−(4−フルオロ−2−(トリフルオロメチル)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(39);(+/−)−cis−4−(9−(2−(ジフルオロメトキシ)フェニル)−6−ヒドロキシ−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)−N−メチルベンゼンスルホンアミド(40);(+/−)−cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(メチルスルホニル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(41);(+/−)−cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(ネオペンチルオキシ)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(42);(+/−)−cis−9−(4−フルオロ−2−メチルフェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(43);(+/−)−trans−9−(4−フルオロ−2−メチルフェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(44);(+/−)−cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−モルホリノフェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(45);(+/−)−cis−4−(9−(2−(ジフルオロメトキシ)フェニル)−6−ヒドロキシ−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)ベンゼンスルホンアミド(46);(+/−)−cis−(2−クロロ−4−(9−(2−(ジフルオロメトキシ)フェニル)−6−ヒドロキシ−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)フェニル)(モルホリノ)メタノン(47);(+/−)−cis−2−クロロ−4−(9−(2−(ジフルオロメトキシ)フェニル)−6−ヒドロキシ−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)ベンズアミド(48);(+/−)−cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(3−ヒドロキシペンタn−3−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(49);(+/−)−cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシブタン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(50);(+/−)−trans−9−(2−(ジフルオロメトキシ)フェニル)−2−(6−メトキシピリジン−3−イル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(51);(+/−)−trans−9−(2
−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシ−2−メチルプロポキシ)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(52);(+/−)−trans−9−(2,5−ジメチルフェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(53);(+/−)−cis−9−(5−クロロ−2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(54);(+/−)−trans−9−(5−クロロ−2−(トリフルオロメチル)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(55);(+/−)−trans−9−(5−クロロ−2−メトキシフェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,7,8,9−テトラヒドロピリド[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(56);rac−(6S,9S)−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−7,9−ジヒドロ−6H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(57);cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6,9−ジヒドロ−7H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(58);9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6−メチル−6,9−ジヒドロ−7H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(59);9−(2−(ジフルオロメトキシ)フェニル)−2−(4−(2−ヒドロキシプロパン−2−イル)フェニル)−6−(ピリジン−4−イル)−6,9−ジヒドロ−7H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(60);cis−9−(2−(ジフルオロメトキシ)フェニル)−2−(2−(2−ヒドロキシプロパン−2−イル)ピリミジン−5−イル)−6,9−ジヒドロ−7H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−6−オール(61);2−(4−(9−(2−(ジフルオロメトキシ)フェニル)−7,9−ジヒドロ−6H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)フェニル)プロパン−2−オール(62);2−(5−(9−(2−(ジフルオロメトキシ)フェニル)−7,9−ジヒドロ−6H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン−2−イル)ピリミジン−2−イル)プロパン−2−オール(63);または9−(2−(ジフルオロメトキシ)フェニル)−2−(1−メチル−1H−ピラゾール−4−イル)−7,9−ジヒドロ−6H−ピラノ[4’,3’:4,5]イミダゾ[1,2−b]ピリダジン(64)である、請求項1に記載の化合物またはその塩。 - 1以上の請求項1または2に記載の化合物またはその塩;および薬学的に許容される担体または希釈剤を含む、医薬組成物。
- 請求項1または2に記載の化合物またはその塩を含む、炎症性または自己免疫性疾患を処置するための医薬組成物。
- 疾患がクローン病、潰瘍性大腸炎、喘息、移植片対宿主病、同種移植片拒絶反応、慢性閉塞性肺疾患、グレーブス病、リウマチ性関節炎、全身性エリテマトーデス、ループス腎炎、皮膚ループス、乾癬、クリオピリン関連周期性症候群、TNF受容体関連周期熱症候群、家族性地中海熱、成人発症スチル病、全身発症若年性特発性関節炎、多発性硬化症、神経障害性疼痛、痛風および痛風関節炎から選択される、請求項4に記載の医薬組成物。
- 炎症性または自己免疫性疾患の処置用医薬の製造における、請求項1または2に記載の化合物またはその塩の使用。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562134779P | 2015-03-18 | 2015-03-18 | |
US62/134,779 | 2015-03-18 | ||
PCT/US2016/022738 WO2016149437A1 (en) | 2015-03-18 | 2016-03-17 | Tricyclic heterocyclic compounds useful as inhibitors of tnf |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2018508554A JP2018508554A (ja) | 2018-03-29 |
JP2018508554A5 JP2018508554A5 (ja) | 2019-04-25 |
JP6793658B2 true JP6793658B2 (ja) | 2020-12-02 |
Family
ID=55640933
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2017549093A Active JP6793658B2 (ja) | 2015-03-18 | 2016-03-17 | Tnf阻害剤として有用な三環式ヘテロ環式化合物 |
Country Status (14)
Country | Link |
---|---|
US (1) | US10308652B2 (ja) |
EP (1) | EP3271361B1 (ja) |
JP (1) | JP6793658B2 (ja) |
KR (1) | KR102630010B1 (ja) |
CN (1) | CN107635992B (ja) |
AU (1) | AU2016233289A1 (ja) |
BR (1) | BR112017019731A2 (ja) |
CA (1) | CA2982446A1 (ja) |
EA (1) | EA032314B1 (ja) |
ES (1) | ES2797685T3 (ja) |
IL (1) | IL254520A0 (ja) |
MX (1) | MX2017011433A (ja) |
SG (1) | SG11201707471RA (ja) |
WO (1) | WO2016149437A1 (ja) |
Families Citing this family (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EA032315B1 (ru) | 2015-03-18 | 2019-05-31 | Бристол-Маерс Сквибб Компани | Замещенные трициклические гетероциклические соединения |
JP6779899B2 (ja) | 2015-03-18 | 2020-11-04 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Tnf阻害剤として有用なヘテロ環式化合物 |
WO2016168638A1 (en) | 2015-04-17 | 2016-10-20 | Abbvie Inc. | Indazolones as modulators of tnf signaling |
UY36629A (es) | 2015-04-17 | 2016-11-30 | Abbvie Inc | Indazolonas como moduladores de la señalización de tnf |
EP3288939A1 (en) | 2015-04-17 | 2018-03-07 | AbbVie Inc. | Tricyclic modulators of tnf signaling |
GB201510758D0 (en) | 2015-06-18 | 2015-08-05 | Ucb Biopharma Sprl | Novel TNFa structure for use in therapy |
US10335392B2 (en) | 2015-08-03 | 2019-07-02 | Bristol-Myers Squibb Company | Cyclic compounds useful as modulators of TNF α |
GB201621907D0 (en) | 2016-12-21 | 2017-02-01 | Ucb Biopharma Sprl And Sanofi | Antibody epitope |
CA3055863A1 (en) | 2017-03-15 | 2018-09-20 | Ucb Biopharma Sprl | Fused pentacyclic imidazole derivatives as modulators of tnf activity |
Family Cites Families (33)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4391806A (en) * | 1982-07-12 | 1983-07-05 | The Dow Chemical Company | Substituted tetrahydropyridazino-(1,6-A)benzimidazoles and use as bronchodilators |
AU741772B2 (en) | 1997-02-25 | 2001-12-06 | Government Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services, The | Substituted benzimidazoles as non-nucleoside inhibitors of reverse transcriptase |
ATE311385T1 (de) * | 1999-10-27 | 2005-12-15 | Novartis Pharma Gmbh | Thiazol und imidazo(4,5-b)pyridin verbindungen und ihre verwendung als pharmazeutika |
WO2003064422A1 (fr) | 2002-01-31 | 2003-08-07 | Daiichi Pharmaceutical Co., Ltd. | Derive imidazo[1,2-a]pyridine |
WO2004050035A2 (en) | 2002-12-03 | 2004-06-17 | Isis Pharmaceuticals, Inc. | Benzimidazoles and analogs thereof as antivirals |
US20050124638A1 (en) | 2003-12-08 | 2005-06-09 | Swayze Eric E. | Benzimidazoles and analogs thereof as antivirals |
WO2009045174A1 (en) | 2007-10-05 | 2009-04-09 | S*Bio Pte Ltd | 2-morpholinylpurines as inhibitors of pi3k |
CN101717397B (zh) | 2008-10-09 | 2012-11-28 | 中国科学院上海药物研究所 | 一类取代吡啶并[2',1':2,3]咪唑并[4,5-c]异喹啉酮类化合物及其合成方法和用途,以及包含该类化合物的药物组合物 |
US8691187B2 (en) | 2009-03-23 | 2014-04-08 | Eli Lilly And Company | Imaging agents for detecting neurological disorders |
WO2012148550A1 (en) | 2011-02-25 | 2012-11-01 | Myrexis, Inc. | Prodrugs of therapeutic compounds |
EP2527344A1 (en) | 2011-05-25 | 2012-11-28 | Almirall, S.A. | Pyridin-2(1H)-one derivatives useful as medicaments for the treatment of myeloproliferative disorders, transplant rejection, immune-mediated and inflammatory diseases |
US9550737B2 (en) | 2012-06-11 | 2017-01-24 | Ucb Biopharma Sprl | TNF -α modulating benzimidazoles |
GB201212513D0 (en) | 2012-07-13 | 2012-08-29 | Ucb Pharma Sa | Therapeutic agents |
CN104619709B (zh) * | 2012-07-13 | 2016-11-09 | Ucb生物制药私人有限公司 | 作为tnf活性调节剂的咪唑并吡啶衍生物 |
MX2015005375A (es) * | 2012-11-07 | 2015-07-21 | Hoffmann La Roche | Compuestos de triazolo. |
ES2529865B8 (es) * | 2013-07-25 | 2016-01-22 | Fundación Para La Investigación Biomédica Del Hospital Universitario La Paz (Fibhulp) | USO DE COMPUESTOS DERIVADOS DE SALES DE PIRIDAZINO[1',6':1,2]PIRIDO[3,4-b]INDOLINIO COMO AGENTES ANTIINFLAMATORIOS |
GB201321746D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
RU2685234C1 (ru) | 2013-12-09 | 2019-04-17 | Юсб Байофарма Спрл | Конденсированные бициклические гетероароматические производные в качестве модуляторов активности tnf |
US9920052B2 (en) | 2013-12-09 | 2018-03-20 | Ucb Biopharma Sprl | Imidazopyridine derivatives as modulators of TNF activity |
GB201321745D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
GB201321744D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
GB201321741D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
GB201321735D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic Agents |
GB201321737D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic Agents |
GB201321738D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic Agents |
GB201321743D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
GB201321742D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
GB201321739D0 (en) | 2013-12-09 | 2014-01-22 | Ucb Pharma Sa | Therapeutic agents |
TW201629063A (zh) | 2014-10-06 | 2016-08-16 | 標誌製藥公司 | 經取代胺基嘌呤化合物、其組合物及用其之治療方法 |
EA032315B1 (ru) | 2015-03-18 | 2019-05-31 | Бристол-Маерс Сквибб Компани | Замещенные трициклические гетероциклические соединения |
JP6779899B2 (ja) | 2015-03-18 | 2020-11-04 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | Tnf阻害剤として有用なヘテロ環式化合物 |
EP3288939A1 (en) * | 2015-04-17 | 2018-03-07 | AbbVie Inc. | Tricyclic modulators of tnf signaling |
CA2980100A1 (en) * | 2015-05-04 | 2016-11-10 | Actelion Pharmaceuticals Ltd | Tricyclic piperidine compounds |
-
2016
- 2016-03-17 CA CA2982446A patent/CA2982446A1/en not_active Abandoned
- 2016-03-17 US US15/558,708 patent/US10308652B2/en active Active
- 2016-03-17 ES ES16712646T patent/ES2797685T3/es active Active
- 2016-03-17 KR KR1020177029450A patent/KR102630010B1/ko active IP Right Grant
- 2016-03-17 JP JP2017549093A patent/JP6793658B2/ja active Active
- 2016-03-17 MX MX2017011433A patent/MX2017011433A/es unknown
- 2016-03-17 EA EA201792025A patent/EA032314B1/ru not_active IP Right Cessation
- 2016-03-17 EP EP16712646.5A patent/EP3271361B1/en active Active
- 2016-03-17 BR BR112017019731-6A patent/BR112017019731A2/pt not_active Application Discontinuation
- 2016-03-17 SG SG11201707471RA patent/SG11201707471RA/en unknown
- 2016-03-17 AU AU2016233289A patent/AU2016233289A1/en not_active Abandoned
- 2016-03-17 WO PCT/US2016/022738 patent/WO2016149437A1/en active Application Filing
- 2016-03-17 CN CN201680025154.3A patent/CN107635992B/zh active Active
-
2017
- 2017-09-15 IL IL254520A patent/IL254520A0/en unknown
Also Published As
Publication number | Publication date |
---|---|
CN107635992B (zh) | 2020-05-22 |
BR112017019731A2 (pt) | 2018-05-22 |
AU2016233289A1 (en) | 2017-11-09 |
CA2982446A1 (en) | 2016-09-22 |
US20180111937A1 (en) | 2018-04-26 |
SG11201707471RA (en) | 2017-10-30 |
CN107635992A (zh) | 2018-01-26 |
MX2017011433A (es) | 2017-11-10 |
EA201792025A1 (ru) | 2018-01-31 |
IL254520A0 (en) | 2017-11-30 |
JP2018508554A (ja) | 2018-03-29 |
KR102630010B1 (ko) | 2024-01-25 |
EP3271361B1 (en) | 2020-04-22 |
ES2797685T3 (es) | 2020-12-03 |
WO2016149437A1 (en) | 2016-09-22 |
US10308652B2 (en) | 2019-06-04 |
EP3271361A1 (en) | 2018-01-24 |
EA032314B1 (ru) | 2019-05-31 |
KR20170129811A (ko) | 2017-11-27 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6793658B2 (ja) | Tnf阻害剤として有用な三環式ヘテロ環式化合物 | |
JP6982376B2 (ja) | Rorガンマ調節物質としての置換型テトラヒドロキノリン化合物 | |
JP6779899B2 (ja) | Tnf阻害剤として有用なヘテロ環式化合物 | |
JP6793657B2 (ja) | 置換三環式ヘテロ環式化合物 | |
KR20180073689A (ko) | Ret의 저해제 | |
JP2021193099A (ja) | 置換4−アザインドール及びglun2b受容体調節因子としてのそれらの使用 | |
CA3085561A1 (en) | Cyclohexyl acid triazole azines as lpa antagonists | |
JP6811233B2 (ja) | Tnfアルファの修飾因子として有用な環状化合物 | |
WO2007032466A1 (ja) | 複素環化合物、その製造方法並びに用途 | |
WO2021245427A1 (en) | N-phenylaminocarbonyl pyridino-, pyrimidino and benzo-tropanes as modulators of gpr65 | |
JP7299382B2 (ja) | Tnf活性のモジュレーターとしての縮合五環式イミダゾール誘導体 | |
JP2019512534A (ja) | Tnf活性のモジュレーターとしての縮合五環式イミダゾール誘導体 | |
WO2016063080A1 (en) | Indazole and indole derivatives as inhibitors of retinoic acid relates orphan receptor gamma (ror gamma) for the treatment of immune-related diseases | |
JP2021512049A (ja) | カルボン酸基を含む窒素含有ベンゾ複素環化合物、その調製方法及び使用 | |
CN117715898A (zh) | 六元芳基或杂芳基酰胺类化合物及其组合物和用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190315 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190315 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20200121 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200204 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200501 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20201013 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20201110 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6793658 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |