TW542831B - Novel pyrimidine derivatives and processes for the preparation thereof - Google Patents
Novel pyrimidine derivatives and processes for the preparation thereof Download PDFInfo
- Publication number
- TW542831B TW542831B TW087104605A TW87104605A TW542831B TW 542831 B TW542831 B TW 542831B TW 087104605 A TW087104605 A TW 087104605A TW 87104605 A TW87104605 A TW 87104605A TW 542831 B TW542831 B TW 542831B
- Authority
- TW
- Taiwan
- Prior art keywords
- methyl
- pyrimidine
- dimethyl
- fluoroaniline
- mmol
- Prior art date
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- 150000003230 pyrimidines Chemical class 0.000 title claims abstract description 24
- 238000000034 method Methods 0.000 title abstract description 63
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 title abstract description 4
- -1 3-trifluoromethylphenylmethyl Chemical group 0.000 claims abstract description 208
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 60
- 239000001257 hydrogen Substances 0.000 claims abstract description 59
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 43
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 34
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 17
- 229910052736 halogen Chemical group 0.000 claims abstract description 13
- 150000002367 halogens Chemical group 0.000 claims abstract description 13
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 10
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 6
- 125000004848 alkoxyethyl group Chemical group 0.000 claims abstract description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 5
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 4
- 125000004849 alkoxymethyl group Chemical group 0.000 claims abstract description 4
- 125000004372 methylthioethyl group Chemical group [H]C([H])([H])SC([H])([H])C([H])([H])* 0.000 claims abstract description 4
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract 11
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims abstract 2
- 125000006515 benzyloxy alkyl group Chemical group 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 189
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 claims description 145
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 124
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 239000002253 acid Substances 0.000 claims description 26
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 22
- 150000001412 amines Chemical class 0.000 claims description 21
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 150000003254 radicals Chemical class 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 235000013372 meat Nutrition 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 208000008469 Peptic Ulcer Diseases 0.000 claims description 3
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims description 3
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 229940079593 drug Drugs 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 208000011906 peptic ulcer disease Diseases 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 150000004032 porphyrins Chemical class 0.000 claims description 2
- RWSOTUBLDIXVET-UHFFFAOYSA-O sulfonium Chemical compound [SH3+] RWSOTUBLDIXVET-UHFFFAOYSA-O 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 13
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 4
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 3
- 229910052731 fluorine Inorganic materials 0.000 claims 3
- 239000011737 fluorine Substances 0.000 claims 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims 2
- 229960003677 chloroquine Drugs 0.000 claims 2
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 claims 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 claims 1
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical group COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 claims 1
- XWERKWVETTXNQX-UHFFFAOYSA-N 2,3-dimethyl-1,4-dioxine Chemical compound CC1=C(C)OC=CO1 XWERKWVETTXNQX-UHFFFAOYSA-N 0.000 claims 1
- VTSWSQGDJQFXHB-UHFFFAOYSA-N 2,4,6-trichloro-5-methylpyrimidine Chemical compound CC1=C(Cl)N=C(Cl)N=C1Cl VTSWSQGDJQFXHB-UHFFFAOYSA-N 0.000 claims 1
- AWBIJARKDOFDAN-UHFFFAOYSA-N 2,5-dimethyl-1,4-dioxane Chemical compound CC1COC(C)CO1 AWBIJARKDOFDAN-UHFFFAOYSA-N 0.000 claims 1
- JNGQZZUZGAWLRX-UHFFFAOYSA-N 2-(methoxymethoxy)benzaldehyde Chemical compound COCOC1=CC=CC=C1C=O JNGQZZUZGAWLRX-UHFFFAOYSA-N 0.000 claims 1
- FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 claims 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims 1
- KSSJBGNOJJETTC-UHFFFAOYSA-N COC1=C(C=CC=C1)N(C1=CC=2C3(C4=CC(=CC=C4C=2C=C1)N(C1=CC=C(C=C1)OC)C1=C(C=CC=C1)OC)C1=CC(=CC=C1C=1C=CC(=CC=13)N(C1=CC=C(C=C1)OC)C1=C(C=CC=C1)OC)N(C1=CC=C(C=C1)OC)C1=C(C=CC=C1)OC)C1=CC=C(C=C1)OC Chemical compound COC1=C(C=CC=C1)N(C1=CC=2C3(C4=CC(=CC=C4C=2C=C1)N(C1=CC=C(C=C1)OC)C1=C(C=CC=C1)OC)C1=CC(=CC=C1C=1C=CC(=CC=13)N(C1=CC=C(C=C1)OC)C1=C(C=CC=C1)OC)N(C1=CC=C(C=C1)OC)C1=C(C=CC=C1)OC)C1=CC=C(C=C1)OC KSSJBGNOJJETTC-UHFFFAOYSA-N 0.000 claims 1
- 241000252505 Characidae Species 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims 1
- PNKUSGQVOMIXLU-UHFFFAOYSA-N Formamidine Chemical compound NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 claims 1
- RQQDJYROSYLPPK-UHFFFAOYSA-N N1=CC=CC2=CC=CC=C21.N1=CC=CC2=CC=CC=C21 Chemical compound N1=CC=CC2=CC=CC=C21.N1=CC=CC2=CC=CC=C21 RQQDJYROSYLPPK-UHFFFAOYSA-N 0.000 claims 1
- 229910002651 NO3 Inorganic materials 0.000 claims 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims 1
- 125000005079 alkoxycarbonylmethyl group Chemical group 0.000 claims 1
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical class [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 claims 1
- 125000004104 aryloxy group Chemical group 0.000 claims 1
- HHHPKVLNNLPPKL-UHFFFAOYSA-N benzene;hydrofluoride Chemical compound F.C1=CC=CC=C1 HHHPKVLNNLPPKL-UHFFFAOYSA-N 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 claims 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- SRXOCFMDUSFFAK-UHFFFAOYSA-N dimethyl peroxide Chemical compound COOC SRXOCFMDUSFFAK-UHFFFAOYSA-N 0.000 claims 1
- 229910001882 dioxygen Inorganic materials 0.000 claims 1
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical compound C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 claims 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims 1
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims 1
- GASFVSRUEBGMDI-UHFFFAOYSA-N n-aminohydroxylamine Chemical compound NNO GASFVSRUEBGMDI-UHFFFAOYSA-N 0.000 claims 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims 1
- 125000003884 phenylalkyl group Chemical group 0.000 claims 1
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims 1
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims 1
- 239000013589 supplement Substances 0.000 claims 1
- IRFHMTUHTBSEBK-QGZVFWFLSA-N tert-butyl n-[(2s)-2-(2,5-difluorophenyl)-3-quinolin-3-ylpropyl]carbamate Chemical compound C1([C@H](CC=2C=C3C=CC=CC3=NC=2)CNC(=O)OC(C)(C)C)=CC(F)=CC=C1F IRFHMTUHTBSEBK-QGZVFWFLSA-N 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 abstract description 5
- 230000001262 anti-secretory effect Effects 0.000 abstract description 3
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 abstract description 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 abstract 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 abstract 1
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 229
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 228
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 121
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 110
- 239000000243 solution Substances 0.000 description 100
- 238000005481 NMR spectroscopy Methods 0.000 description 93
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 85
- 238000011049 filling Methods 0.000 description 80
- 229940086542 triethylamine Drugs 0.000 description 76
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 64
- 230000002079 cooperative effect Effects 0.000 description 56
- 238000006243 chemical reaction Methods 0.000 description 38
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- 229910052796 boron Inorganic materials 0.000 description 33
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 28
- 230000002829 reductive effect Effects 0.000 description 28
- 239000000203 mixture Substances 0.000 description 25
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 23
- 239000007787 solid Substances 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 21
- 239000002585 base Substances 0.000 description 18
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 18
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 15
- ZFCHNZDUMIOWFV-UHFFFAOYSA-N pyrimidine-2-carboxylic acid Chemical compound OC(=O)C1=NC=CC=N1 ZFCHNZDUMIOWFV-UHFFFAOYSA-N 0.000 description 15
- 238000010898 silica gel chromatography Methods 0.000 description 14
- 230000033228 biological regulation Effects 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-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
- 230000000694 effects Effects 0.000 description 10
- 238000012360 testing method Methods 0.000 description 9
- 230000000875 corresponding effect Effects 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- BYBCSHJGFWTWAB-UHFFFAOYSA-N pyrimidine-2-sulfonic acid Chemical compound OS(=O)(=O)C1=NC=CC=N1 BYBCSHJGFWTWAB-UHFFFAOYSA-N 0.000 description 8
- 230000002441 reversible effect Effects 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- BFXIDUSEHNCLTP-UHFFFAOYSA-N 2,4-dichloro-5,6-dimethylpyrimidine Chemical compound CC1=NC(Cl)=NC(Cl)=C1C BFXIDUSEHNCLTP-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 102100021904 Potassium-transporting ATPase alpha chain 1 Human genes 0.000 description 6
- 230000009858 acid secretion Effects 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000011777 magnesium Substances 0.000 description 6
- XOSPBPPBIYDMQE-UHFFFAOYSA-N pyrimidine sulfane Chemical compound N1=CN=CC=C1.S XOSPBPPBIYDMQE-UHFFFAOYSA-N 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- SCPUERXVEBRZMV-UHFFFAOYSA-N 2,4-dichloro-6-(methoxymethyl)-5-methylpyrimidine Chemical compound COCC1=NC(Cl)=NC(Cl)=C1C SCPUERXVEBRZMV-UHFFFAOYSA-N 0.000 description 5
- 108010083204 Proton Pumps Proteins 0.000 description 5
- XVEKWPFCSPBUFY-UHFFFAOYSA-N [N+]1(=CN=CC=C1)S(=O)(=O)[O-] Chemical compound [N+]1(=CN=CC=C1)S(=O)(=O)[O-] XVEKWPFCSPBUFY-UHFFFAOYSA-N 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 229940126409 proton pump inhibitor Drugs 0.000 description 5
- 239000000612 proton pump inhibitor Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- XQCZBXHVTFVIFE-UHFFFAOYSA-N 2-amino-4-hydroxypyrimidine Chemical compound NC1=NC=CC(O)=N1 XQCZBXHVTFVIFE-UHFFFAOYSA-N 0.000 description 4
- VVJKKWFAADXIJK-UHFFFAOYSA-N Allylamine Chemical compound NCC=C VVJKKWFAADXIJK-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 4
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 230000002496 gastric effect Effects 0.000 description 4
- 150000007857 hydrazones Chemical class 0.000 description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 4
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
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- 235000011164 potassium chloride Nutrition 0.000 description 1
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- GNFWGDKKNWGGJY-UHFFFAOYSA-N propanimidamide Chemical compound CCC(N)=N GNFWGDKKNWGGJY-UHFFFAOYSA-N 0.000 description 1
- 125000006308 propyl amino group Chemical group 0.000 description 1
- 210000001187 pylorus Anatomy 0.000 description 1
- GAPYKZAARZMMGP-UHFFFAOYSA-N pyridin-1-ium;acetate Chemical compound CC(O)=O.C1=CC=NC=C1 GAPYKZAARZMMGP-UHFFFAOYSA-N 0.000 description 1
- JYVYXDMNMUXYKD-UHFFFAOYSA-N pyrimidine pyrimidine-2-carboxylic acid Chemical compound N1=C(N=CC=C1)C(=O)O.N1=CN=CC=C1 JYVYXDMNMUXYKD-UHFFFAOYSA-N 0.000 description 1
- VZXWDGGSKPWCPO-UHFFFAOYSA-N pyrimidine;2h-triazole Chemical compound C1=CNN=N1.C1=CN=CN=C1 VZXWDGGSKPWCPO-UHFFFAOYSA-N 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- XIIOFHFUYBLOLW-UHFFFAOYSA-N selpercatinib Chemical compound OC(COC=1C=C(C=2N(C=1)N=CC=2C#N)C=1C=NC(=CC=1)N1CC2N(C(C1)C2)CC=1C=NC(=CC=1)OC)(C)C XIIOFHFUYBLOLW-UHFFFAOYSA-N 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- ZBJGUTPJDSWGDI-UHFFFAOYSA-N tert-butyl N-benzyl-N-propylcarbamate Chemical compound CC(C)(C)OC(=O)N(CCC)CC1=CC=CC=C1 ZBJGUTPJDSWGDI-UHFFFAOYSA-N 0.000 description 1
- LRZWWLVBFRBZNI-UHFFFAOYSA-N tert-butyl n-(3-phenylpropyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCC1=CC=CC=C1 LRZWWLVBFRBZNI-UHFFFAOYSA-N 0.000 description 1
- IPIGTJPBWJEROO-UHFFFAOYSA-B thorium(4+);tetraphosphate Chemical compound [Th+4].[Th+4].[Th+4].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O IPIGTJPBWJEROO-UHFFFAOYSA-B 0.000 description 1
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- 239000003440 toxic substance Substances 0.000 description 1
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- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR19970010863 | 1997-03-27 | ||
| KR19970010862 | 1997-03-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW542831B true TW542831B (en) | 2003-07-21 |
Family
ID=26632616
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW087104605A TW542831B (en) | 1997-03-27 | 1998-03-27 | Novel pyrimidine derivatives and processes for the preparation thereof |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US6352993B1 (enExample) |
| EP (1) | EP1015444B1 (enExample) |
| JP (1) | JP3176379B2 (enExample) |
| KR (1) | KR100278857B1 (enExample) |
| CN (1) | CN1118464C (enExample) |
| AR (1) | AR012181A1 (enExample) |
| AT (1) | ATE241613T1 (enExample) |
| AU (1) | AU720385B2 (enExample) |
| BR (1) | BR9808070A (enExample) |
| CA (1) | CA2284795C (enExample) |
| DE (1) | DE69815126T2 (enExample) |
| DK (1) | DK1015444T3 (enExample) |
| ES (1) | ES2200324T3 (enExample) |
| HU (1) | HUP0000851A3 (enExample) |
| IN (1) | IN188411B (enExample) |
| PT (1) | PT1015444E (enExample) |
| RU (1) | RU2203894C2 (enExample) |
| TR (1) | TR199902383T2 (enExample) |
| TW (1) | TW542831B (enExample) |
| UY (1) | UY24938A1 (enExample) |
| WO (1) | WO1998043968A1 (enExample) |
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| AU2004283751B2 (en) * | 2003-10-24 | 2011-05-19 | Exelixis, Inc. | p70S6 kinase modulators and method of use |
| CA2544325A1 (en) | 2003-11-03 | 2005-05-12 | Astrazeneca Ab | Imidazo [1,2-a] pyridine derivatives for the treatment of silent gastro-esophageal reflux |
| KR101122376B1 (ko) * | 2005-03-09 | 2012-03-26 | 주식회사유한양행 | 신규의 5,6-다이메틸피리미딘 유도체 및 그의 제조방법 |
| US20090124645A1 (en) * | 2005-10-14 | 2009-05-14 | Neurosearch A/S | Novel Pyrimidine-2,4-Diamine Derivatives and their Use as Modulators of Small-Conductance Calcium-Activated Potassium Channels |
| JP4946482B2 (ja) | 2007-02-08 | 2012-06-06 | 船井電機株式会社 | 緩衝用梱包材及びｔｖ受像機の緩衝用梱包材 |
| US8367684B2 (en) * | 2007-06-13 | 2013-02-05 | Valeant Pharmaceuticals International | Derivatives of 4-(N-azacycloalkyl) anilides as potassium channel modulators |
| MY153606A (en) | 2008-08-05 | 2015-02-27 | Daiichi Sankyo Co Ltd | Imidazopyridin-2-one derivatives |
| GB0908394D0 (en) | 2009-05-15 | 2009-06-24 | Univ Leuven Kath | Novel viral replication inhibitors |
| GB0913636D0 (en) | 2009-08-05 | 2009-09-16 | Univ Leuven Kath | Novel viral replication inhibitors |
| MX2013005478A (es) | 2010-11-15 | 2013-08-29 | Univ Leuven Kath | Compuestos heterociclicos condensados antivirales. |
| CA2827030C (en) | 2011-02-25 | 2019-01-08 | Yuhan Corporation | Diaminopyrimidine derivatives and processes for the preparation thereof |
| RU2014137448A (ru) * | 2012-02-17 | 2016-04-10 | Эббви Инк. | Диаминопиримидины, пригодные в качестве ингибиторов респираторно-синцитиального вируса человека (rsv) |
| KR102080782B1 (ko) | 2012-05-29 | 2020-02-27 | 모멘티브 퍼포먼스 머티리얼즈 게엠베하 | 이소시아네이토 실란의 제조 |
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| EP2970307B1 (en) | 2013-03-13 | 2020-03-11 | Genentech, Inc. | Pyrazolo compounds and uses thereof |
| WO2015030847A1 (en) * | 2013-08-30 | 2015-03-05 | Ptc Therapeutics, Inc. | Substituted pyrimidine bmi-1 inhibitors |
| ES2779152T3 (es) | 2013-10-07 | 2020-08-13 | Kadmon Corporation Llc | Derivados de (2-(5-isoindolin-2-il)pirimidin-4-il)-amina como inhibidores de Rho-quinasa para tratar enfermedades autoinmunes |
| US10584115B2 (en) | 2013-11-21 | 2020-03-10 | Ptc Therapeutics, Inc. | Substituted pyridine and pyrazine BMI-1 inhibitors |
| AU2015335980A1 (en) | 2014-10-22 | 2017-05-18 | Guangzhou Institutes Of Biomedicine And Health, Chinese Academy Of Sciences | Small-molecule inhibitors targeting discoidin domain receptor 1 and uses thereof |
| CN105669642B (zh) * | 2014-11-19 | 2020-06-09 | 江苏天士力帝益药业有限公司 | 一种盐酸洛氟普啶的制备方法 |
| WO2017118639A1 (en) * | 2016-01-04 | 2017-07-13 | ObsEva S.A. | Alpha-amino esters of hydroxypropylthiazolidine carboxamide derivative and salt form, crystal polymorph thereof |
| US11477982B2 (en) * | 2017-04-05 | 2022-10-25 | Bayer Cropscience Aktiengesellschaft | 2-amino-5-oxyalkyl-pyrimidine derivatives and their use for controlling undesired plant growth |
| AU2019340402B2 (en) | 2018-08-17 | 2025-04-03 | Ptc Therapeutics, Inc. | Method for treating pancreatic cancer |
| CN114685369B (zh) * | 2022-05-17 | 2024-02-02 | 河南省科学院高新技术研究中心 | 一种利用离子液体制备1-甲基-1,2,3,4-四氢异喹啉的方法 |
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| US4000138A (en) | 1966-03-31 | 1976-12-28 | Imperial Chemical Industries Limited | Organic compounds and compositions containing them |
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| US4044136A (en) | 1972-09-09 | 1977-08-23 | Pfizer Inc. | Aminoquinazoline therapeutic agents |
| GB1383409A (en) | 1972-09-09 | 1974-02-12 | Pfizer Ltd | Derivatives of 2-amino- and 4-amino-quinazoline and pharmaceutical compositions containing them |
| US3956495A (en) | 1973-10-30 | 1976-05-11 | Eli Lilly And Company | 2,4-Diaminoquinazolines as antithrombotic agents |
| US4755218A (en) | 1985-12-31 | 1988-07-05 | Monsanto Company | Haloacyl 1-substituted-1,2,3,4-tetrahydro-isoquinolines as herbicide antidotes |
| GB8621425D0 (en) * | 1986-09-05 | 1986-10-15 | Smith Kline French Lab | Compounds |
| IL88507A (en) * | 1987-12-03 | 1993-02-21 | Smithkline Beckman Intercredit | 2,4-diaminoquinazolines, process for their preparation and pharmaceutical compositions comprising them |
| US4966622A (en) | 1988-04-12 | 1990-10-30 | Ciba-Geigy Corporation | N-phenyl-N-pyrimidin-2-ylureas |
| HU206337B (en) * | 1988-12-29 | 1992-10-28 | Mitsui Petrochemical Ind | Process for producing pyrimidine derivatives and pharmaceutical compositions |
| DE3901448A1 (de) | 1989-01-19 | 1990-07-26 | Basf Ag | Emulsionscopolymerisate |
| TR25912A (tr) | 1989-03-22 | 1993-11-01 | Ciba Geigy Ag | 2-ANILIN-PRIMIDIN TüREVLERI BU MADDELERINELDE EDIL MELERI VE ZARARLILARA KARSI MüCADELEDE KULLANILMA- LARI |
| CA2015981A1 (en) * | 1989-05-10 | 1990-11-10 | Thomas H. Brown | Compounds |
| GB8910722D0 (en) | 1989-05-10 | 1989-06-28 | Smithkline Beckman Intercredit | Compounds |
| GB9012592D0 (en) | 1990-06-06 | 1990-07-25 | Smithkline Beecham Intercredit | Compounds |
| BR9107070A (pt) | 1990-11-06 | 1994-05-31 | Pfizer | Processo para a preparação de derivados de quinazolina uteis para melhorar a atividade antitumoral. |
| JPH0819121B2 (ja) | 1991-04-17 | 1996-02-28 | フアイザー・インコーポレイテツド | 抗腫瘍活性を増強するためのピリミジン誘導体 |
| US5276186A (en) | 1992-03-11 | 1994-01-04 | Ciba-Geigy Corporation | Process for the production of guanidine derivatives |
| KR0144833B1 (ko) | 1992-12-28 | 1998-07-15 | 김태훈 | 신규의 퀴나졸린 유도체 및 그의 제조방법 |
| CA2169280A1 (en) * | 1993-08-12 | 1995-02-23 | Robert James Gentile | Amidine derivatives with nitric oxide synthetase activities |
| DK0640599T3 (da) | 1993-08-26 | 1998-09-28 | Ono Pharmaceutical Co | 4-Aminopyrimidin-derivater |
| RU2153494C2 (ru) | 1993-10-12 | 2000-07-27 | Дзе Дюпон Мерк Фармасьютикал Компани | 1-n-алкил-n-арилпиримидинамины, способ лечения заболеваний, фармацевтическая композиция |
| CA2197298C (en) * | 1994-08-13 | 1999-10-19 | Jong Wook Lee | Novel pyrimidine derivatives and processes for the preparation thereof |
| JP3160297B2 (ja) | 1996-05-04 | 2001-04-25 | ユーハン・コーポレイション | ピリミジン誘導体の製造方法 |
-
1998
- 1998-03-23 IN IN724DE1998 patent/IN188411B/en unknown
- 1998-03-24 US US09/381,814 patent/US6352993B1/en not_active Expired - Fee Related
- 1998-03-24 EP EP98911242A patent/EP1015444B1/en not_active Expired - Lifetime
- 1998-03-24 JP JP54148798A patent/JP3176379B2/ja not_active Expired - Fee Related
- 1998-03-24 CA CA002284795A patent/CA2284795C/en not_active Expired - Fee Related
- 1998-03-24 WO PCT/KR1998/000058 patent/WO1998043968A1/en not_active Ceased
- 1998-03-24 ES ES98911242T patent/ES2200324T3/es not_active Expired - Lifetime
- 1998-03-24 PT PT98911242T patent/PT1015444E/pt unknown
- 1998-03-24 HU HU0000851A patent/HUP0000851A3/hu unknown
- 1998-03-24 DE DE69815126T patent/DE69815126T2/de not_active Expired - Fee Related
- 1998-03-24 AU AU65239/98A patent/AU720385B2/en not_active Ceased
- 1998-03-24 DK DK98911242T patent/DK1015444T3/da active
- 1998-03-24 CN CN98803765A patent/CN1118464C/zh not_active Expired - Fee Related
- 1998-03-24 RU RU99122603/04A patent/RU2203894C2/ru not_active IP Right Cessation
- 1998-03-24 BR BR9808070-9A patent/BR9808070A/pt not_active Application Discontinuation
- 1998-03-24 AT AT98911242T patent/ATE241613T1/de not_active IP Right Cessation
- 1998-03-24 TR TR1999/02383T patent/TR199902383T2/xx unknown
- 1998-03-26 UY UY24938A patent/UY24938A1/es not_active IP Right Cessation
- 1998-03-26 AR ARP980101380A patent/AR012181A1/es unknown
- 1998-03-27 KR KR1019980010754A patent/KR100278857B1/ko not_active Expired - Fee Related
- 1998-03-27 TW TW087104605A patent/TW542831B/zh not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK1015444T3 (da) | 2003-08-18 |
| JP2000513014A (ja) | 2000-10-03 |
| EP1015444B1 (en) | 2003-05-28 |
| CN1118464C (zh) | 2003-08-20 |
| WO1998043968A1 (en) | 1998-10-08 |
| US6352993B1 (en) | 2002-03-05 |
| IN188411B (enExample) | 2002-09-21 |
| DE69815126D1 (de) | 2003-07-03 |
| AR012181A1 (es) | 2000-09-27 |
| HK1026418A1 (en) | 2000-12-15 |
| PT1015444E (pt) | 2003-10-31 |
| RU2203894C2 (ru) | 2003-05-10 |
| EP1015444A1 (en) | 2000-07-05 |
| ATE241613T1 (de) | 2003-06-15 |
| HUP0000851A1 (hu) | 2001-04-28 |
| CA2284795A1 (en) | 1998-10-08 |
| KR100278857B1 (ko) | 2001-01-15 |
| TR199902383T2 (xx) | 2000-06-21 |
| CA2284795C (en) | 2004-01-20 |
| ES2200324T3 (es) | 2004-03-01 |
| AU6523998A (en) | 1998-10-22 |
| HUP0000851A3 (en) | 2002-04-29 |
| BR9808070A (pt) | 2000-03-08 |
| KR19980080789A (ko) | 1998-11-25 |
| DE69815126T2 (de) | 2004-04-08 |
| CN1251586A (zh) | 2000-04-26 |
| JP3176379B2 (ja) | 2001-06-18 |
| UY24938A1 (es) | 2001-01-31 |
| AU720385B2 (en) | 2000-06-01 |
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