CN108503575A - 抗纤维化吡啶酮类 - Google Patents
抗纤维化吡啶酮类 Download PDFInfo
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- CN108503575A CN108503575A CN201810401768.8A CN201810401768A CN108503575A CN 108503575 A CN108503575 A CN 108503575A CN 201810401768 A CN201810401768 A CN 201810401768A CN 108503575 A CN108503575 A CN 108503575A
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- 230000002300 anti-fibrosis Effects 0.000 title description 3
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 596
- 229910052739 hydrogen Inorganic materials 0.000 claims description 299
- 239000001257 hydrogen Substances 0.000 claims description 299
- 238000006467 substitution reaction Methods 0.000 claims description 270
- 150000002431 hydrogen Chemical class 0.000 claims description 229
- 229910052736 halogen Inorganic materials 0.000 claims description 187
- 150000002367 halogens Chemical class 0.000 claims description 187
- 125000001072 heteroaryl group Chemical group 0.000 claims description 183
- 125000000623 heterocyclic group Chemical group 0.000 claims description 170
- -1 Phenyl Chemical group 0.000 claims description 131
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 103
- 239000007787 solid Substances 0.000 claims description 102
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 91
- 125000000217 alkyl group Chemical group 0.000 claims description 86
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 85
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 67
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 65
- 229910052760 oxygen Inorganic materials 0.000 claims description 54
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 52
- 239000001301 oxygen Substances 0.000 claims description 51
- 150000003839 salts Chemical class 0.000 claims description 51
- 125000006537 (C6-C10)-aryl alkyl group Chemical group 0.000 claims description 47
- 229910052757 nitrogen Inorganic materials 0.000 claims description 45
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 44
- 239000011737 fluorine Substances 0.000 claims description 38
- 229910052731 fluorine Inorganic materials 0.000 claims description 38
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 34
- 239000005864 Sulphur Substances 0.000 claims description 29
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 27
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 26
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 19
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 125000001425 triazolyl group Chemical group 0.000 claims description 4
- 125000004799 bromophenyl group Chemical group 0.000 claims description 3
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 46
- 201000010099 disease Diseases 0.000 abstract description 44
- 238000000034 method Methods 0.000 abstract description 41
- 230000003176 fibrotic effect Effects 0.000 abstract description 29
- 150000005299 pyridinones Chemical class 0.000 abstract 1
- 239000002585 base Substances 0.000 description 329
- 239000000203 mixture Substances 0.000 description 182
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 152
- 238000005160 1H NMR spectroscopy Methods 0.000 description 146
- 150000003254 radicals Chemical class 0.000 description 122
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 94
- 125000000304 alkynyl group Chemical group 0.000 description 89
- 125000004093 cyano group Chemical group *C#N 0.000 description 84
- 235000019439 ethyl acetate Nutrition 0.000 description 71
- 229910052799 carbon Inorganic materials 0.000 description 65
- 239000000243 solution Substances 0.000 description 64
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 64
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 56
- 238000006243 chemical reaction Methods 0.000 description 55
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 53
- 239000012267 brine Substances 0.000 description 52
- 150000001721 carbon Chemical group 0.000 description 52
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 52
- 239000007832 Na2SO4 Substances 0.000 description 51
- 229910052938 sodium sulfate Inorganic materials 0.000 description 51
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 48
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 48
- 125000004043 oxo group Chemical group O=* 0.000 description 48
- 239000012044 organic layer Substances 0.000 description 44
- 238000011282 treatment Methods 0.000 description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 41
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 40
- 239000004698 Polyethylene Substances 0.000 description 37
- 230000015572 biosynthetic process Effects 0.000 description 36
- 238000003786 synthesis reaction Methods 0.000 description 36
- 238000004809 thin layer chromatography Methods 0.000 description 36
- 239000000460 chlorine Substances 0.000 description 34
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 31
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 30
- 125000003118 aryl group Chemical group 0.000 description 28
- 238000001035 drying Methods 0.000 description 28
- 230000002969 morbid Effects 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 28
- 239000007864 aqueous solution Substances 0.000 description 27
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 26
- 229910052801 chlorine Inorganic materials 0.000 description 26
- 230000002829 reductive effect Effects 0.000 description 26
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 24
- 238000003756 stirring Methods 0.000 description 24
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 23
- 125000001118 alkylidene group Chemical group 0.000 description 23
- 239000003814 drug Substances 0.000 description 23
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 22
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 21
- 125000001424 substituent group Chemical group 0.000 description 21
- 125000004450 alkenylene group Chemical group 0.000 description 20
- 238000004440 column chromatography Methods 0.000 description 20
- 229940079593 drug Drugs 0.000 description 20
- 239000008194 pharmaceutical composition Substances 0.000 description 19
- 206010016654 Fibrosis Diseases 0.000 description 18
- 125000004432 carbon atom Chemical group C* 0.000 description 18
- 230000004761 fibrosis Effects 0.000 description 18
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 18
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- 208000032825 Ring chromosome 2 syndrome Diseases 0.000 description 16
- 239000003153 chemical reaction reagent Substances 0.000 description 16
- 239000002552 dosage form Substances 0.000 description 16
- 239000002904 solvent Substances 0.000 description 16
- 238000005406 washing Methods 0.000 description 16
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 15
- 125000004429 atom Chemical group 0.000 description 15
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 15
- 239000004327 boric acid Substances 0.000 description 15
- 229910052796 boron Inorganic materials 0.000 description 15
- 239000003208 petroleum Substances 0.000 description 15
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 15
- 208000005069 pulmonary fibrosis Diseases 0.000 description 15
- 239000000741 silica gel Substances 0.000 description 15
- 229910002027 silica gel Inorganic materials 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- 125000004122 cyclic group Chemical group 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 description 13
- 238000006069 Suzuki reaction reaction Methods 0.000 description 13
- 238000004458 analytical method Methods 0.000 description 13
- 238000001816 cooling Methods 0.000 description 13
- 238000003818 flash chromatography Methods 0.000 description 13
- 239000007788 liquid Substances 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- 239000000126 substance Substances 0.000 description 13
- 239000012043 crude product Substances 0.000 description 12
- 239000003937 drug carrier Substances 0.000 description 12
- 208000036971 interstitial lung disease 2 Diseases 0.000 description 12
- UYVXZUTYZGILQG-UHFFFAOYSA-N methoxyboronic acid Chemical compound COB(O)O UYVXZUTYZGILQG-UHFFFAOYSA-N 0.000 description 12
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 12
- 239000000546 pharmaceutical excipient Substances 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- UQFQONCQIQEYPJ-UHFFFAOYSA-N N-methylpyrazole Chemical compound CN1C=CC=N1 UQFQONCQIQEYPJ-UHFFFAOYSA-N 0.000 description 11
- 150000001335 aliphatic alkanes Chemical class 0.000 description 11
- 125000003342 alkenyl group Chemical group 0.000 description 11
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
- 230000008859 change Effects 0.000 description 11
- 238000011049 filling Methods 0.000 description 11
- 239000002609 medium Substances 0.000 description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 11
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical class [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 241000790917 Dioxys <bee> Species 0.000 description 9
- 206010023421 Kidney fibrosis Diseases 0.000 description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 125000003545 alkoxy group Chemical group 0.000 description 9
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 9
- 230000004663 cell proliferation Effects 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000010949 copper Substances 0.000 description 9
- 238000001514 detection method Methods 0.000 description 9
- 125000005842 heteroatom Chemical group 0.000 description 9
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- 238000007792 addition Methods 0.000 description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- 239000002808 molecular sieve Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 7
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 7
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 7
- 229910052794 bromium Inorganic materials 0.000 description 7
- 208000019425 cirrhosis of liver Diseases 0.000 description 7
- 229940127204 compound 29 Drugs 0.000 description 7
- 229940125936 compound 42 Drugs 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
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- 238000005859 coupling reaction Methods 0.000 description 7
- 230000034994 death Effects 0.000 description 7
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- 239000003085 diluting agent Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
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- 239000000796 flavoring agent Substances 0.000 description 7
- 235000013355 food flavoring agent Nutrition 0.000 description 7
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 7
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 7
- 239000003755 preservative agent Substances 0.000 description 7
- 230000002335 preservative effect Effects 0.000 description 7
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- YJLIKUSWRSEPSM-WGQQHEPDSA-N (2r,3r,4s,5r)-2-[6-amino-8-[(4-phenylphenyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound C=1C=C(C=2C=CC=CC=2)C=CC=1CNC1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O YJLIKUSWRSEPSM-WGQQHEPDSA-N 0.000 description 6
- 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 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Cs2CO3 Substances [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
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- 125000006239 protecting group Chemical group 0.000 description 6
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- 125000002098 pyridazinyl group Chemical group 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
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- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 5
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 5
- 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 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 125000000041 C6-C10 aryl group Chemical group 0.000 description 5
- 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 5
- 229930195725 Mannitol Natural products 0.000 description 5
- HHJYYZJLRNLUIF-UHFFFAOYSA-N [4-(trifluoromethoxy)phenoxy]boronic acid Chemical compound OB(O)OC1=CC=C(OC(F)(F)F)C=C1 HHJYYZJLRNLUIF-UHFFFAOYSA-N 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 description 5
- 229940125851 compound 27 Drugs 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 5
- 239000000835 fiber Substances 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 239000000594 mannitol Substances 0.000 description 5
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- 239000000463 material Substances 0.000 description 5
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- 230000002062 proliferating effect Effects 0.000 description 5
- 238000010926 purge Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
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- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- FSDYDBAXNANUQE-UHFFFAOYSA-N tris(2,4-dichlorophenyl) phosphate Chemical compound ClC1=CC(Cl)=CC=C1OP(=O)(OC=1C(=CC(Cl)=CC=1)Cl)OC1=CC=C(Cl)C=C1Cl FSDYDBAXNANUQE-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
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- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- Pyridine Compounds (AREA)
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- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Indole Compounds (AREA)
- Hydrogenated Pyridines (AREA)
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Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261709075P | 2012-10-02 | 2012-10-02 | |
| US61/709,075 | 2012-10-02 | ||
| US201361777499P | 2013-03-12 | 2013-03-12 | |
| US61/777,499 | 2013-03-12 | ||
| US201361872157P | 2013-08-30 | 2013-08-30 | |
| US61/872,157 | 2013-08-30 | ||
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