PL218749B1 - Pochodna pirydynonu oraz jej zastosowanie do wytwarzania leku - Google Patents
Pochodna pirydynonu oraz jej zastosowanie do wytwarzania lekuInfo
- Publication number
- PL218749B1 PL218749B1 PL371943A PL37194303A PL218749B1 PL 218749 B1 PL218749 B1 PL 218749B1 PL 371943 A PL371943 A PL 371943A PL 37194303 A PL37194303 A PL 37194303A PL 218749 B1 PL218749 B1 PL 218749B1
- Authority
- PL
- Poland
- Prior art keywords
- alkyl
- nmr
- mmol
- mhz
- pyridin
- Prior art date
Links
- 150000005299 pyridinones Chemical class 0.000 title claims description 6
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 title abstract description 27
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 title abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 25
- 238000011282 treatment Methods 0.000 claims abstract description 18
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 63
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 56
- -1 -O- (C1-C4) alkanoyl Chemical group 0.000 claims description 56
- 229910052736 halogen Inorganic materials 0.000 claims description 42
- 150000002367 halogens Chemical class 0.000 claims description 42
- 239000001257 hydrogen Substances 0.000 claims description 39
- 229910052739 hydrogen Inorganic materials 0.000 claims description 39
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 29
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 19
- 150000002431 hydrogen Chemical class 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 16
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 125000004193 piperazinyl group Chemical group 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 13
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 11
- 125000003386 piperidinyl group Chemical group 0.000 claims description 10
- 125000005862 (C1-C6)alkanoyl group Chemical group 0.000 claims description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 8
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 8
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 7
- 206010003246 arthritis Diseases 0.000 claims description 7
- 125000002757 morpholinyl group Chemical group 0.000 claims description 7
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 6
- KCAJXIDMCNPGHZ-UHFFFAOYSA-N PH 797804 Chemical compound CNC(=O)C1=CC=C(C)C(N2C(C(Br)=C(OCC=3C(=CC(F)=CC=3)F)C=C2C)=O)=C1 KCAJXIDMCNPGHZ-UHFFFAOYSA-N 0.000 claims description 6
- 208000006673 asthma Diseases 0.000 claims description 6
- 208000027866 inflammatory disease Diseases 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- 208000019693 Lung disease Diseases 0.000 claims description 4
- 125000004990 dihydroxyalkyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 4
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 4
- 208000002193 Pain Diseases 0.000 claims description 3
- 230000001684 chronic effect Effects 0.000 claims description 3
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 230000002685 pulmonary effect Effects 0.000 claims description 3
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 4
- 125000002252 acyl group Chemical group 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 213
- 238000000034 method Methods 0.000 abstract description 101
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 31
- 201000010099 disease Diseases 0.000 abstract description 20
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 399
- 238000005481 NMR spectroscopy Methods 0.000 description 329
- 239000011541 reaction mixture Substances 0.000 description 236
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 221
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 206
- 239000007787 solid Substances 0.000 description 190
- 239000000243 solution Substances 0.000 description 187
- 238000002360 preparation method Methods 0.000 description 171
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 163
- 235000019439 ethyl acetate Nutrition 0.000 description 157
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 154
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 143
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 118
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 116
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 115
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 110
- 239000000203 mixture Substances 0.000 description 108
- 238000006243 chemical reaction Methods 0.000 description 98
- 230000002829 reductive effect Effects 0.000 description 91
- 229910001868 water Inorganic materials 0.000 description 87
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 76
- 239000012267 brine Substances 0.000 description 72
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 72
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 64
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 58
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 56
- 229910052938 sodium sulfate Inorganic materials 0.000 description 56
- 235000011152 sodium sulphate Nutrition 0.000 description 56
- 239000007832 Na2SO4 Substances 0.000 description 54
- 239000003921 oil Substances 0.000 description 52
- 235000019198 oils Nutrition 0.000 description 52
- 239000002904 solvent Substances 0.000 description 51
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 50
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 49
- 239000000741 silica gel Substances 0.000 description 49
- 229910002027 silica gel Inorganic materials 0.000 description 49
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 48
- 239000000706 filtrate Substances 0.000 description 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 46
- 238000001914 filtration Methods 0.000 description 46
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
- 238000003818 flash chromatography Methods 0.000 description 43
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 39
- 239000000047 product Substances 0.000 description 35
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 34
- 238000000746 purification Methods 0.000 description 34
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 32
- 238000004587 chromatography analysis Methods 0.000 description 31
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 30
- 239000012044 organic layer Substances 0.000 description 30
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 29
- 235000019341 magnesium sulphate Nutrition 0.000 description 29
- 239000000377 silicon dioxide Substances 0.000 description 29
- 239000002244 precipitate Substances 0.000 description 27
- 229910000027 potassium carbonate Inorganic materials 0.000 description 25
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 24
- 239000000284 extract Substances 0.000 description 24
- 239000003480 eluent Substances 0.000 description 23
- 239000010410 layer Substances 0.000 description 23
- 238000003756 stirring Methods 0.000 description 23
- 239000011347 resin Substances 0.000 description 22
- 229920005989 resin Polymers 0.000 description 22
- 239000011550 stock solution Substances 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 238000004458 analytical method Methods 0.000 description 21
- 239000000725 suspension Substances 0.000 description 21
- 239000004480 active ingredient Substances 0.000 description 20
- 239000006227 byproduct Substances 0.000 description 20
- 238000004896 high resolution mass spectrometry Methods 0.000 description 20
- 238000010992 reflux Methods 0.000 description 20
- 235000002639 sodium chloride Nutrition 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 229960000583 acetic acid Drugs 0.000 description 17
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 16
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 16
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 16
- 239000012071 phase Substances 0.000 description 16
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 15
- 229910052786 argon Inorganic materials 0.000 description 15
- 125000003118 aryl group Chemical group 0.000 description 15
- 238000010511 deprotection reaction Methods 0.000 description 15
- 235000015320 potassium carbonate Nutrition 0.000 description 15
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 14
- 238000001816 cooling Methods 0.000 description 14
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 14
- 239000000546 pharmaceutical excipient Substances 0.000 description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 13
- 102000000589 Interleukin-1 Human genes 0.000 description 13
- 108010002352 Interleukin-1 Proteins 0.000 description 13
- 239000004793 Polystyrene Substances 0.000 description 13
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 13
- 229910052794 bromium Inorganic materials 0.000 description 13
- 230000036961 partial effect Effects 0.000 description 13
- 229920002223 polystyrene Polymers 0.000 description 13
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 12
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 12
- 229920000768 polyamine Polymers 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- IBLMYGXJKQIGSN-UHFFFAOYSA-N 1-(bromomethyl)-2,4-difluorobenzene Chemical compound FC1=CC=C(CBr)C(F)=C1 IBLMYGXJKQIGSN-UHFFFAOYSA-N 0.000 description 11
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 11
- 239000005388 borosilicate glass Substances 0.000 description 11
- 125000001246 bromo group Chemical group Br* 0.000 description 11
- 208000035475 disorder Diseases 0.000 description 11
- 125000001072 heteroaryl group Chemical group 0.000 description 11
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 10
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 10
- 235000011054 acetic acid Nutrition 0.000 description 10
- 238000007664 blowing Methods 0.000 description 10
- 238000001704 evaporation Methods 0.000 description 10
- 230000008020 evaporation Effects 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 10
- 239000000543 intermediate Substances 0.000 description 10
- OKKJLVBELUTLKV-VMNATFBRSA-N methanol-d1 Chemical compound [2H]OC OKKJLVBELUTLKV-VMNATFBRSA-N 0.000 description 10
- 235000011181 potassium carbonates Nutrition 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- NSYSSMYQPLSPOD-UHFFFAOYSA-N triacetate lactone Chemical compound CC1=CC(O)=CC(=O)O1 NSYSSMYQPLSPOD-UHFFFAOYSA-N 0.000 description 10
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 9
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 102000004127 Cytokines Human genes 0.000 description 9
- 108090000695 Cytokines Proteins 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
- 206010028980 Neoplasm Diseases 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 150000001718 carbodiimides Chemical class 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 239000002480 mineral oil Substances 0.000 description 9
- 229920000642 polymer Polymers 0.000 description 9
- 125000006507 2,4-difluorobenzyl group Chemical group [H]C1=C(F)C([H])=C(F)C(=C1[H])C([H])([H])* 0.000 description 8
- 208000030507 AIDS Diseases 0.000 description 8
- 206010040070 Septic Shock Diseases 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 238000001665 trituration Methods 0.000 description 8
- WJDXDEDMFQVYID-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]-4-hydroxypyridin-2-one Chemical compound O=C1C=C(O)C=CN1CC1=CC=CC(F)=C1 WJDXDEDMFQVYID-UHFFFAOYSA-N 0.000 description 7
- KWMLVJCBRJIQNB-UHFFFAOYSA-N 3-bromo-4-[(2,4-difluorophenyl)methoxy]-6-methyl-1h-pyridin-2-one Chemical compound O=C1NC(C)=CC(OCC=2C(=CC(F)=CC=2)F)=C1Br KWMLVJCBRJIQNB-UHFFFAOYSA-N 0.000 description 7
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 7
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 7
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 7
- 210000004027 cell Anatomy 0.000 description 7
- 239000003995 emulsifying agent Substances 0.000 description 7
- 239000012362 glacial acetic acid Substances 0.000 description 7
- 150000003840 hydrochlorides Chemical class 0.000 description 7
- 230000004054 inflammatory process Effects 0.000 description 7
- 235000010446 mineral oil Nutrition 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 6
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 6
- DOVNUEPFPBWTSV-UHFFFAOYSA-N 4-phenylmethoxy-1h-pyridin-2-one Chemical compound C1=CNC(=O)C=C1OCC1=CC=CC=C1 DOVNUEPFPBWTSV-UHFFFAOYSA-N 0.000 description 6
- 208000010412 Glaucoma Diseases 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 125000002029 aromatic hydrocarbon group Chemical group 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 229960005215 dichloroacetic acid Drugs 0.000 description 6
- 239000000839 emulsion Substances 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 239000000796 flavoring agent Substances 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- 231100000252 nontoxic Toxicity 0.000 description 6
- 230000003000 nontoxic effect Effects 0.000 description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 239000012312 sodium hydride Substances 0.000 description 6
- 229910000104 sodium hydride Inorganic materials 0.000 description 6
- 239000003765 sweetening agent Substances 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- ZGYIXVSQHOKQRZ-COIATFDQSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-[(3s)-oxolan-3-yl]oxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N#CC1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZGYIXVSQHOKQRZ-COIATFDQSA-N 0.000 description 5
- JQGXTJRUWYRVKB-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]-4-phenylmethoxypyridin-2-one Chemical compound FC1=CC=CC(CN2C(C=C(OCC=3C=CC=CC=3)C=C2)=O)=C1 JQGXTJRUWYRVKB-UHFFFAOYSA-N 0.000 description 5
- YYSFPMUFWPEKRE-UHFFFAOYSA-N 4-[(2,4-difluorophenyl)methoxy]-1-[(3-fluorophenyl)methyl]pyridin-2-one Chemical compound FC1=CC=CC(CN2C(C=C(OCC=3C(=CC(F)=CC=3)F)C=C2)=O)=C1 YYSFPMUFWPEKRE-UHFFFAOYSA-N 0.000 description 5
- 206010006895 Cachexia Diseases 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
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Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US35702902P | 2002-02-14 | 2002-02-14 | |
| US43691502P | 2002-12-30 | 2002-12-30 |
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| PL371943A1 PL371943A1 (en) | 2005-07-11 |
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