KR20000076124A - 1,5-디히드로-피라졸로[3,4-ｄ]-피리미디논 유도체 - Google Patents
1,5-디히드로-피라졸로[3,4-ｄ]-피리미디논 유도체 Download PDFInfo
- Publication number
- KR20000076124A KR20000076124A KR1019997008213A KR19997008213A KR20000076124A KR 20000076124 A KR20000076124 A KR 20000076124A KR 1019997008213 A KR1019997008213 A KR 1019997008213A KR 19997008213 A KR19997008213 A KR 19997008213A KR 20000076124 A KR20000076124 A KR 20000076124A
- Authority
- KR
- South Korea
- Prior art keywords
- carbon atoms
- straight
- formula
- branched chain
- phenyl
- 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.)
- Ceased
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- RAEVFJQVGBSKJO-UHFFFAOYSA-N 1,2,4,7-tetrahydropyrazolo[3,4-d]pyrimidin-3-one Chemical class N1=CNCC2=C1NNC2=O RAEVFJQVGBSKJO-UHFFFAOYSA-N 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 62
- 239000003814 drug Substances 0.000 claims abstract description 10
- 208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 6
- 208000018262 Peripheral vascular disease Diseases 0.000 claims abstract description 5
- 208000025609 Urogenital disease Diseases 0.000 claims abstract description 4
- 208000026106 cerebrovascular disease Diseases 0.000 claims abstract description 4
- 230000002526 effect on cardiovascular system Effects 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 97
- 125000004432 carbon atom Chemical group C* 0.000 claims description 77
- -1 cyano, hydroxyl Chemical group 0.000 claims description 59
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- 239000000460 chlorine Substances 0.000 claims description 32
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
- 125000003545 alkoxy group Chemical group 0.000 claims description 25
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 25
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 22
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 125000005842 heteroatom Chemical group 0.000 claims description 15
- 239000001257 hydrogen Substances 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 13
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 13
- 125000002947 alkylene group Chemical group 0.000 claims description 13
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 13
- 229910052794 bromium Inorganic materials 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 239000011737 fluorine Substances 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 125000004076 pyridyl group Chemical group 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 125000002252 acyl group Chemical group 0.000 claims description 12
- 125000002541 furyl group Chemical group 0.000 claims description 12
- 239000012442 inert solvent Substances 0.000 claims description 11
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000001041 indolyl group Chemical group 0.000 claims description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 238000007363 ring formation reaction Methods 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 6
- 125000004450 alkenylene group Chemical group 0.000 claims description 6
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- 125000005605 benzo group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 238000009472 formulation Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000007800 oxidant agent Substances 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 235000009518 sodium iodide Nutrition 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 2
- 125000000524 functional group Chemical group 0.000 claims description 2
- 201000001881 impotence Diseases 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000004355 nitrogen functional group Chemical group 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 125000001725 pyrenyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- MIQLKTPRUZLHFE-UHFFFAOYSA-N 1,5,6,7a-tetrahydropyrano[2,3-c]pyrazol-3-amine Chemical class N1NC(C=2C1OCCC=2)=N MIQLKTPRUZLHFE-UHFFFAOYSA-N 0.000 claims 7
- 239000002671 adjuvant Substances 0.000 claims 1
- 201000010099 disease Diseases 0.000 claims 1
- 210000002229 urogenital system Anatomy 0.000 claims 1
- 239000013543 active substance Substances 0.000 abstract 1
- 150000003217 pyrazoles Chemical class 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 300
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 207
- 239000000243 solution Substances 0.000 description 126
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 121
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 106
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 73
- 239000002904 solvent Substances 0.000 description 71
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 57
- 239000012071 phase Substances 0.000 description 53
- 238000004587 chromatography analysis Methods 0.000 description 50
- 238000000746 purification Methods 0.000 description 44
- 239000007787 solid Substances 0.000 description 44
- 235000019439 ethyl acetate Nutrition 0.000 description 41
- 239000003921 oil Substances 0.000 description 41
- 229920006395 saturated elastomer Polymers 0.000 description 41
- 229940093499 ethyl acetate Drugs 0.000 description 39
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 38
- 239000011734 sodium Substances 0.000 description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 35
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 35
- 235000017557 sodium bicarbonate Nutrition 0.000 description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 239000012074 organic phase Substances 0.000 description 28
- 238000002844 melting Methods 0.000 description 24
- 230000008018 melting Effects 0.000 description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 19
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 18
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 16
- 239000003125 aqueous solvent Substances 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 15
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 14
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 150000003254 radicals Chemical class 0.000 description 14
- 229910052938 sodium sulfate Inorganic materials 0.000 description 14
- 235000011152 sodium sulphate Nutrition 0.000 description 14
- LKXHGCAQFYIOOO-UHFFFAOYSA-N 5-amino-1-(2-hydroxy-6-phenylhexan-3-yl)pyrazole-4-carboxamide Chemical compound N1=CC(C(N)=O)=C(N)N1C(C(O)C)CCCC1=CC=CC=C1 LKXHGCAQFYIOOO-UHFFFAOYSA-N 0.000 description 13
- SSVFMICWXDVRQN-UHFFFAOYSA-N ethanol;sodium Chemical compound [Na].CCO SSVFMICWXDVRQN-UHFFFAOYSA-N 0.000 description 13
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- HFEVEIJAYFFEBH-UHFFFAOYSA-N 5-amino-3-methyl-1-nonan-3-ylpyrazole-4-carboxamide Chemical compound CCCCCCC(CC)N1N=C(C)C(C(N)=O)=C1N HFEVEIJAYFFEBH-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 9
- 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 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- HEMYXNDMAAOTCK-UHFFFAOYSA-N methyl 2-(1,3-benzodioxol-5-yl)acetate Chemical compound COC(=O)CC1=CC=C2OCOC2=C1 HEMYXNDMAAOTCK-UHFFFAOYSA-N 0.000 description 9
- 229910052708 sodium Inorganic materials 0.000 description 9
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 8
- 238000009835 boiling Methods 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- LUQFHUKHDKTFNX-UHFFFAOYSA-N 5-amino-1-decan-4-yl-3-propylpyrazole-4-carboxamide Chemical compound CCCCCCC(CCC)N1N=C(CCC)C(C(N)=O)=C1N LUQFHUKHDKTFNX-UHFFFAOYSA-N 0.000 description 7
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 229910052786 argon Inorganic materials 0.000 description 7
- 235000015165 citric acid Nutrition 0.000 description 7
- 238000011194 good manufacturing practice Methods 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 235000019341 magnesium sulphate Nutrition 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 239000011591 potassium Substances 0.000 description 7
- 229910052700 potassium Inorganic materials 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 description 6
- BOSVWXDDFBSSIZ-UHFFFAOYSA-N 2-(1-ethoxyethylidene)propanedinitrile Chemical compound CCOC(C)=C(C#N)C#N BOSVWXDDFBSSIZ-UHFFFAOYSA-N 0.000 description 6
- DTRQOKJQNZVPMZ-UHFFFAOYSA-N 5-amino-1-(2-hydroxy-6-phenylhexan-3-yl)-3-methylpyrazole-4-carboxamide Chemical compound N1=C(C)C(C(N)=O)=C(N)N1C(C(O)C)CCCC1=CC=CC=C1 DTRQOKJQNZVPMZ-UHFFFAOYSA-N 0.000 description 6
- SAJMNAAPHDISPS-UHFFFAOYSA-N 5-amino-1-decan-4-yl-3-ethylpyrazole-4-carboxamide Chemical compound CCCCCCC(CCC)N1N=C(CC)C(C(N)=O)=C1N SAJMNAAPHDISPS-UHFFFAOYSA-N 0.000 description 6
- ICXAYWYCLCNIBP-UHFFFAOYSA-N 5-amino-1-decan-4-yl-3-methylpyrazole-4-carboxamide Chemical compound CCCCCCC(CCC)N1N=C(C)C(C(N)=O)=C1N ICXAYWYCLCNIBP-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- JDAADONCQPUNRY-UHFFFAOYSA-N tert-butyl n-(5-phenylpentan-2-ylideneamino)carbamate Chemical compound CC(C)(C)OC(=O)NN=C(C)CCCC1=CC=CC=C1 JDAADONCQPUNRY-UHFFFAOYSA-N 0.000 description 6
- GXMOSBIOUZALPM-UHFFFAOYSA-N 2-(1-ethoxypropylidene)propanedinitrile Chemical compound CCOC(CC)=C(C#N)C#N GXMOSBIOUZALPM-UHFFFAOYSA-N 0.000 description 5
- TYNSUEXNGLNQSS-UHFFFAOYSA-N 6-carbamoyl-5-hydroxy-4-methoxy-7,8-dihydro-3h-pyrrolo[3,2-e]indole-2-carboxylic acid Chemical compound C1=2C=C(C(O)=O)NC=2C(OC)=C(O)C2=C1CCN2C(N)=O TYNSUEXNGLNQSS-UHFFFAOYSA-N 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- DILOFCBIBDMHAY-UHFFFAOYSA-N methyl 2-(3,4-dimethoxyphenyl)acetate Chemical compound COC(=O)CC1=CC=C(OC)C(OC)=C1 DILOFCBIBDMHAY-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 229940086542 triethylamine Drugs 0.000 description 5
- GEDSOQMESIYDQX-UHFFFAOYSA-N 5-phenylpentan-2-ylhydrazine Chemical compound NNC(C)CCCC1=CC=CC=C1 GEDSOQMESIYDQX-UHFFFAOYSA-N 0.000 description 4
- TZYQTWHRLVDYPL-UHFFFAOYSA-N 5h-pyrimidin-4-one Chemical compound O=C1CC=NC=N1 TZYQTWHRLVDYPL-UHFFFAOYSA-N 0.000 description 4
- QAXDVKBGZRMSHF-UHFFFAOYSA-N 6-acetyl-5-hydroxy-4-methoxy-7,8-dihydro-3h-pyrrolo[3,2-e]indole-2-carboxylic acid Chemical compound C1=2C=C(C(O)=O)NC=2C(OC)=C(O)C2=C1CCN2C(C)=O QAXDVKBGZRMSHF-UHFFFAOYSA-N 0.000 description 4
- ZZNMARICFYRSPB-UHFFFAOYSA-N 6-benzyl-3-methoxy-1-(5-phenylpentan-2-yl)-5H-pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C1=2N=C(CC=3C=CC=CC=3)NC(=O)C=2C(OC)=NN1C(C)CCCC1=CC=CC=C1 ZZNMARICFYRSPB-UHFFFAOYSA-N 0.000 description 4
- 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 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 210000000709 aorta Anatomy 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- MWNQUUNHAXFIDV-UHFFFAOYSA-N decan-4-ylhydrazine Chemical compound CCCCCCC(NN)CCC MWNQUUNHAXFIDV-UHFFFAOYSA-N 0.000 description 4
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 description 4
- IGXAJUPIDFDTTR-UHFFFAOYSA-N methyl 2-(3,4,5-trimethoxyphenyl)acetate Chemical compound COC(=O)CC1=CC(OC)=C(OC)C(OC)=C1 IGXAJUPIDFDTTR-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 229960005235 piperonyl butoxide Drugs 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- VQVBNWUUKLBHGI-UHFFFAOYSA-N 2-(4-bromophenyl)acetyl chloride Chemical compound ClC(=O)CC1=CC=C(Br)C=C1 VQVBNWUUKLBHGI-UHFFFAOYSA-N 0.000 description 3
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- FQYDPCNJYNGRIZ-UHFFFAOYSA-N ethyl 3-(2-methoxy-2-oxoethyl)benzoate Chemical compound CCOC(=O)C1=CC=CC(CC(=O)OC)=C1 FQYDPCNJYNGRIZ-UHFFFAOYSA-N 0.000 description 1
- IVCGLVZNTOAJNU-UHFFFAOYSA-N ethyl 3-[(3-methyl-1-nonan-3-yl-4-oxo-5H-pyrazolo[3,4-d]pyrimidin-6-yl)methyl]benzoate Chemical compound CCCCCCC(CC)N1N=C(C)C(C(N2)=O)=C1N=C2CC1=CC=CC(C(=O)OCC)=C1 IVCGLVZNTOAJNU-UHFFFAOYSA-N 0.000 description 1
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- TVIVLENJTXGRAM-UHFFFAOYSA-N methyl 2-(4-aminophenyl)acetate Chemical compound COC(=O)CC1=CC=C(N)C=C1 TVIVLENJTXGRAM-UHFFFAOYSA-N 0.000 description 1
- NYZOHVGGRFFBEH-UHFFFAOYSA-N methyl 2-(4-morpholin-4-ylsulfonylphenyl)acetate Chemical compound C1=CC(CC(=O)OC)=CC=C1S(=O)(=O)N1CCOCC1 NYZOHVGGRFFBEH-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Urology & Nephrology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Vascular Medicine (AREA)
- Gynecology & Obstetrics (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19709877.0 | 1997-03-11 | ||
| DE19709877A DE19709877A1 (de) | 1997-03-11 | 1997-03-11 | 1,5-Dihydro-pyrazolo[3,4-d]-pyrimidinon-derivate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20000076124A true KR20000076124A (ko) | 2000-12-26 |
Family
ID=7822900
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019997008213A Ceased KR20000076124A (ko) | 1997-03-11 | 1998-02-26 | 1,5-디히드로-피라졸로[3,4-ｄ]-피리미디논 유도체 |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US6174884B1 (https=) |
| EP (1) | EP0973774B1 (https=) |
| JP (1) | JP2001514638A (https=) |
| KR (1) | KR20000076124A (https=) |
| CN (1) | CN1151155C (https=) |
| AT (1) | ATE231509T1 (https=) |
| AU (1) | AU727615B2 (https=) |
| BR (1) | BR9807995A (https=) |
| CA (1) | CA2283211A1 (https=) |
| DE (2) | DE19709877A1 (https=) |
| DK (1) | DK0973774T3 (https=) |
| ES (1) | ES2191294T3 (https=) |
| HU (1) | HUP0001805A3 (https=) |
| IL (1) | IL131450A0 (https=) |
| NZ (1) | NZ337724A (https=) |
| RU (1) | RU2219180C2 (https=) |
| WO (1) | WO1998040384A1 (https=) |
Families Citing this family (61)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9823103D0 (en) * | 1998-10-23 | 1998-12-16 | Pfizer Ltd | Pharmaceutically active compounds |
| WO2002009713A2 (de) * | 2000-08-01 | 2002-02-07 | Bayer Aktiengesellschaft | Selektive pde 2-inhibitoren als arzneimittel zur verbesserung der wahrnehmung |
| EP1343506A1 (de) * | 2000-12-19 | 2003-09-17 | MERCK PATENT GmbH | Pharmazeutische formulierung enthaltend pyrazolo 4,3-d]pyrimidine und antithrombotica, calcium-antagonisten, prostaglandine oder prostaglandinderivate |
| DE10064105A1 (de) | 2000-12-21 | 2002-06-27 | Bayer Ag | Neue Substituierte Imidazotriazinone |
| JP2004525890A (ja) * | 2001-02-02 | 2004-08-26 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング | ピラゾロ［４，３−ｄ］ピリミジンおよびエンドセリンレセプターアンタゴニストまたはチエノピリミジンおよびエンドセリンレセプターアンタゴニストを含む医薬製剤 |
| KR100393160B1 (ko) * | 2001-06-14 | 2003-07-31 | 한국과학기술연구원 | 신규한 피라졸로피리미딘티온 유도체, 그의 제법 및발기부전 치료제로서의 용도 |
| US6479493B1 (en) | 2001-08-23 | 2002-11-12 | Cell Pathways, Inc. | Methods for treatment of type I diabetes |
| AU2002366440A1 (en) * | 2001-09-27 | 2003-09-09 | Smithkline Beecham Corporation | Chemical compounds |
| FR2842809A1 (fr) * | 2002-07-26 | 2004-01-30 | Greenpharma Sas | NOUVELLES PYRAZOLO[1,5-a]-1,3,5-TRIAZINES SUBSTITUEES ET LEURS ANALOGUES, COMPOSITIONS PHARMACEUTIQUES LES CONTENANT, UTILISATION A TITRE DE MEDICAMENT ET PROCEDES POUR LEUR PREPARATION |
| DE10238722A1 (de) | 2002-08-23 | 2004-03-11 | Bayer Ag | Selektive Phosphodiesterase 9A-Inhibitoren als Arzneimittel zur Verbesserung kognitiver Prozesse |
| DE10238723A1 (de) * | 2002-08-23 | 2004-03-11 | Bayer Ag | Phenyl-substituierte Pyrazolyprimidine |
| DE10238724A1 (de) | 2002-08-23 | 2004-03-04 | Bayer Ag | Alkyl-substituierte Pyrazolpyrimidine |
| CN100397023C (zh) * | 2003-01-04 | 2008-06-25 | 胡云北 | 黄磷废渣载热量及反应尾气发热量的回收与综合利用方法 |
| EP1601675A1 (en) * | 2003-03-04 | 2005-12-07 | ALTANA Pharma AG | Purin-6-one-derivatives |
| DE102004004142A1 (de) | 2003-05-09 | 2004-11-25 | Bayer Healthcare Ag | 6-Cyclylmethyl- und 6-Alkylmethyl-substituierte Pyrazolopyrimidine |
| DE10320785A1 (de) * | 2003-05-09 | 2004-11-25 | Bayer Healthcare Ag | 6-Arylmethyl-substituierte Pyrazolopyrimidine |
| US8044060B2 (en) | 2003-05-09 | 2011-10-25 | Boehringer Ingelheim International Gmbh | 6-cyclylmethyl- and 6-alkylmethyl pyrazolo[3,4-D]pyrimidines, methods for their preparation and methods for their use to treat impairments of perception, concentration learning and/or memory |
| DE10328479A1 (de) | 2003-06-25 | 2005-01-13 | Bayer Ag | 6-Arylamino-5-cyano-4-pyrimidinone |
| AU2004268387A1 (en) * | 2003-08-28 | 2005-03-10 | Nycomed Gmbh | Composition comprising a pulmonary surfactant and a PDE2 inhibitor |
| DE102004001873A1 (de) * | 2004-01-14 | 2005-09-29 | Bayer Healthcare Ag | Cyanopyrimidinone |
| AU2005219517A1 (en) * | 2004-02-27 | 2005-09-15 | F.Hoffmann-La Roche Ag | Heteroaryl-fused pyrazolo derivatives |
| CN101397299B (zh) * | 2007-09-29 | 2011-11-16 | 温州大学 | 一种吡唑[3,4-d]嘧啶酮的合成方法 |
| JP5498392B2 (ja) | 2007-11-30 | 2014-05-21 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | １，５−ジヒドロ−ピラゾロ［３，４−ｄ］ピリミジン−４−オン誘導体及びｃｎｓ障害の治療のためのｐｄｅ９ａモジュレーターとしてのそれらの使用 |
| UA105362C2 (en) | 2008-04-02 | 2014-05-12 | Бьорингер Ингельхайм Интернациональ Гмбх | 1-heterocyclyl-1, 5-dihydro-pyrazolo [3, 4-d] pyrimidin-4-one derivatives and their use as pde9a modulators |
| JP5453431B2 (ja) | 2008-09-08 | 2014-03-26 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ピラゾロピリミジン及びｃｎｓ障害の治療のためのそれらの使用 |
| CA2756870A1 (en) | 2009-03-31 | 2010-10-07 | Arqule, Inc. | Substituted indolo-pyridinone compounds |
| PE20120505A1 (es) | 2009-03-31 | 2012-05-09 | Boehringer Ingelheim Int | Derivados de 1-heterociclil-1,5-dihidro-pirazolo[3,4-d]pirimidin-4-ona como moduladores de pde9a |
| AR077859A1 (es) * | 2009-08-12 | 2011-09-28 | Boehringer Ingelheim Int | Compuestos para el tratamiento de trastornos del snc |
| AP2012006631A0 (en) | 2010-08-12 | 2012-12-31 | Boehringer Ingelheim Int | 6-Cycloalkyl-1, 5-dihydro-pyrazolo[3,4-D] pyrimidin-4-one derivatives and their use as PDE9A inhibitors |
| US20130040971A1 (en) | 2011-02-14 | 2013-02-14 | Boehringer Ingelheim International Gmbh | 6-cycloalkyl-pyrazolopyrimidinones for the treatment of cns disorders |
| US8809345B2 (en) | 2011-02-15 | 2014-08-19 | Boehringer Ingelheim International Gmbh | 6-cycloalkyl-pyrazolopyrimidinones for the treatment of CNS disorders |
| EP2691393B1 (en) | 2011-03-31 | 2016-09-14 | Pfizer Inc | Novel bicyclic pyridinones |
| WO2012172449A1 (en) | 2011-06-13 | 2012-12-20 | Pfizer Inc. | Lactams as beta secretase inhibitors |
| ES2605565T3 (es) | 2011-08-31 | 2017-03-15 | Pfizer Inc | Compuestos de hexahidropirano [3,4-D][1,3]tiazin-2-amina |
| JO3407B1 (ar) | 2012-05-31 | 2019-10-20 | Eisai R&D Man Co Ltd | مركبات رباعي هيدرو بيرازولو بيريميدين |
| UA110688C2 (uk) | 2012-09-21 | 2016-01-25 | Пфайзер Інк. | Біциклічні піридинони |
| CN105121439A (zh) | 2013-02-19 | 2015-12-02 | 辉瑞公司 | 作为pde4亚型抑制剂用于治疗cns和其他病症的氮杂苯并咪唑化合物 |
| ES2742078T3 (es) | 2013-10-04 | 2020-02-13 | Pfizer | Piridonas bicíclicas novedosas como moduladores de gamma-secretasa |
| DK3126361T3 (da) | 2014-04-01 | 2020-01-02 | Pfizer | Chromen og 1,1a,2,7b-tetrahydrocyclopropa[c]chromen- pyridopyrazindioner som gamma-sekretase-modulatorer |
| WO2016012896A1 (en) | 2014-07-24 | 2016-01-28 | Pfizer Inc. | Pyrazolopyrimidine compounds |
| PL3177624T3 (pl) | 2014-08-06 | 2019-09-30 | Pfizer Inc. | Związki imidazopirydazynowe |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3165520A (en) * | 1965-01-12 | Certificate of correction | ||
| US3211732A (en) | 1965-10-12 | Pyrazolob:x-d]pyrlil/hdines | ||
| DE1153023B (de) | 1960-05-11 | 1963-08-22 | Ciba Geigy | Verfahren zur Herstellung von 4-Hydroxy-pyrazolo[3,4-d] pyrimidinen |
| CH398626A (de) * | 1960-05-11 | 1966-03-15 | Ciba Geigy | Verfahren zur Herstellung neuer Pyrazolopyrimidine |
| CH633297A5 (de) | 1977-09-16 | 1982-11-30 | Sandoz Ag | Verfahren zur herstellung von fluorenphosphoniten. |
| GB9121028D0 (en) | 1991-10-03 | 1991-11-13 | Pfizer Ltd | Therapeutic agents |
| US5294612A (en) * | 1992-03-30 | 1994-03-15 | Sterling Winthrop Inc. | 6-heterocyclyl pyrazolo [3,4-d]pyrimidin-4-ones and compositions and method of use thereof |
| CA2133346A1 (en) * | 1992-04-21 | 1993-10-28 | Shri Niwas | 7-disubstituted-methyl-4-oxo-3h,5h-pyrrolo[3,2-d]pyrimidine and pharmaceutical uses and compositions containing the same |
| US5656629A (en) * | 1995-03-10 | 1997-08-12 | Sanofi Winthrop, Inc. | 6-substituted pyrazolo (3,4-d)pyrimidin-4-ones and compositions and methods of use thereof |
| CZ280697A3 (cs) | 1995-03-10 | 1998-04-15 | Sanofi Pharmaceuticals, Inc. | 6 aryl-pyrazolo(3,4-d)pyrimidin-4-ony a kompozice je obsahující, a způsob jejich použití |
-
1997
- 1997-03-11 DE DE19709877A patent/DE19709877A1/de not_active Withdrawn
-
1998
- 1998-02-26 HU HU0001805A patent/HUP0001805A3/hu unknown
- 1998-02-26 IL IL13145098A patent/IL131450A0/xx not_active IP Right Cessation
- 1998-02-26 BR BR9807995-6A patent/BR9807995A/pt not_active IP Right Cessation
- 1998-02-26 RU RU99121518/04A patent/RU2219180C2/ru not_active IP Right Cessation
- 1998-02-26 US US09/367,538 patent/US6174884B1/en not_active Expired - Fee Related
- 1998-02-26 AT AT98913595T patent/ATE231509T1/de not_active IP Right Cessation
- 1998-02-26 DE DE59807011T patent/DE59807011D1/de not_active Expired - Fee Related
- 1998-02-26 JP JP53913598A patent/JP2001514638A/ja not_active Withdrawn
- 1998-02-26 KR KR1019997008213A patent/KR20000076124A/ko not_active Ceased
- 1998-02-26 WO PCT/EP1998/001086 patent/WO1998040384A1/de not_active Ceased
- 1998-02-26 CA CA002283211A patent/CA2283211A1/en not_active Abandoned
- 1998-02-26 DK DK98913595T patent/DK0973774T3/da active
- 1998-02-26 EP EP98913595A patent/EP0973774B1/de not_active Expired - Lifetime
- 1998-02-26 NZ NZ337724A patent/NZ337724A/xx unknown
- 1998-02-26 AU AU68240/98A patent/AU727615B2/en not_active Ceased
- 1998-02-26 ES ES98913595T patent/ES2191294T3/es not_active Expired - Lifetime
- 1998-02-26 CN CNB988049872A patent/CN1151155C/zh not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0001805A2 (hu) | 2000-11-28 |
| DK0973774T3 (da) | 2003-05-05 |
| NZ337724A (en) | 2000-08-25 |
| US6174884B1 (en) | 2001-01-16 |
| IL131450A0 (en) | 2001-01-28 |
| AU6824098A (en) | 1998-09-29 |
| BR9807995A (pt) | 2000-03-08 |
| ATE231509T1 (de) | 2003-02-15 |
| EP0973774B1 (de) | 2003-01-22 |
| CN1255133A (zh) | 2000-05-31 |
| HUP0001805A3 (en) | 2002-09-30 |
| CN1151155C (zh) | 2004-05-26 |
| DE59807011D1 (de) | 2003-02-27 |
| AU727615B2 (en) | 2000-12-14 |
| CA2283211A1 (en) | 1998-09-17 |
| JP2001514638A (ja) | 2001-09-11 |
| RU2219180C2 (ru) | 2003-12-20 |
| WO1998040384A1 (de) | 1998-09-17 |
| EP0973774A1 (de) | 2000-01-26 |
| HK1028035A1 (en) | 2001-02-02 |
| ES2191294T3 (es) | 2003-09-01 |
| DE19709877A1 (de) | 1998-09-17 |
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