NO323922B1 - Heterosykliske forbindelser og farmasoytisk middel omfattende samme - Google Patents
Heterosykliske forbindelser og farmasoytisk middel omfattende samme Download PDFInfo
- Publication number
- NO323922B1 NO323922B1 NO20022600A NO20022600A NO323922B1 NO 323922 B1 NO323922 B1 NO 323922B1 NO 20022600 A NO20022600 A NO 20022600A NO 20022600 A NO20022600 A NO 20022600A NO 323922 B1 NO323922 B1 NO 323922B1
- Authority
- NO
- Norway
- Prior art keywords
- tetrahydroisoquinoline
- methyl
- carboxylic acid
- ethoxy
- phenyloxasol
- Prior art date
Links
- 150000002391 heterocyclic compounds Chemical class 0.000 title claims description 60
- 239000008177 pharmaceutical agent Substances 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 202
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 106
- -1 2-methylpropenyl Chemical group 0.000 claims description 82
- 125000001424 substituent group Chemical group 0.000 claims description 56
- 150000003839 salts Chemical class 0.000 claims description 54
- 125000000217 alkyl group Chemical group 0.000 claims description 51
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 33
- 239000008103 glucose Substances 0.000 claims description 33
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 31
- 206010022489 Insulin Resistance Diseases 0.000 claims description 30
- 239000003795 chemical substances by application Substances 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 206010012601 diabetes mellitus Diseases 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 19
- 229940124597 therapeutic agent Drugs 0.000 claims description 19
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 17
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 16
- 238000011321 prophylaxis Methods 0.000 claims description 16
- 238000011282 treatment Methods 0.000 claims description 16
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 208000002249 Diabetes Complications Diseases 0.000 claims description 12
- 206010012655 Diabetic complications Diseases 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 12
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 11
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 claims description 11
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 claims description 11
- 239000003472 antidiabetic agent Substances 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- 239000003524 antilipemic agent Substances 0.000 claims description 9
- 229940126904 hypoglycaemic agent Drugs 0.000 claims description 9
- 230000001404 mediated effect Effects 0.000 claims description 9
- 208000011580 syndromic disease Diseases 0.000 claims description 9
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 7
- 230000000879 anti-atherosclerotic effect Effects 0.000 claims description 7
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 7
- 239000000883 anti-obesity agent Substances 0.000 claims description 7
- 229940125710 antiobesity agent Drugs 0.000 claims description 7
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 7
- 125000002971 oxazolyl group Chemical group 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 5
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 3
- 125000004973 1-butenyl group Chemical group C(=CCC)* 0.000 claims description 3
- 235000012149 noodles Nutrition 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 261
- 239000000203 mixture Substances 0.000 description 177
- 238000005160 1H NMR spectroscopy Methods 0.000 description 106
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 63
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 61
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
- 239000000243 solution Substances 0.000 description 50
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 48
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 47
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 44
- 238000006243 chemical reaction Methods 0.000 description 43
- 239000011734 sodium Substances 0.000 description 43
- 239000002904 solvent Substances 0.000 description 43
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 39
- 238000004519 manufacturing process Methods 0.000 description 38
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- 239000002253 acid Substances 0.000 description 30
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 26
- 238000001914 filtration Methods 0.000 description 25
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- 239000013078 crystal Substances 0.000 description 24
- 238000010898 silica gel chromatography Methods 0.000 description 23
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- 239000010410 layer Substances 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 239000011259 mixed solution Substances 0.000 description 18
- BSYVTEYKTMYBMK-UHFFFAOYSA-N tetrahydrofurfuryl alcohol Chemical compound OCC1CCCO1 BSYVTEYKTMYBMK-UHFFFAOYSA-N 0.000 description 18
- 238000012360 testing method Methods 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 15
- 241000699670 Mus sp. Species 0.000 description 14
- 238000001816 cooling Methods 0.000 description 14
- 239000008280 blood Substances 0.000 description 13
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- 230000000694 effects Effects 0.000 description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 description 13
- 235000011181 potassium carbonates Nutrition 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 12
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 12
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- 125000003342 alkenyl group Chemical group 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 10
- 230000002218 hypoglycaemic effect Effects 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- 238000006722 reduction reaction Methods 0.000 description 10
- 239000012312 sodium hydride Substances 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 125000004432 carbon atom Chemical group C* 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 235000020925 non fasting Nutrition 0.000 description 8
- 210000003462 vein Anatomy 0.000 description 8
- 229920000084 Gum arabic Polymers 0.000 description 7
- 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 7
- 241000978776 Senegalia senegal Species 0.000 description 7
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- 125000003118 aryl group Chemical group 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
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- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
- 230000035484 reaction time Effects 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 6
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- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- 102000004877 Insulin Human genes 0.000 description 6
- 108090001061 Insulin Proteins 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-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
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 125000003710 aryl alkyl group Chemical group 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 125000001309 chloro group Chemical group Cl* 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 125000001153 fluoro group Chemical group F* 0.000 description 6
- 125000005343 heterocyclic alkyl group Chemical group 0.000 description 6
- 201000001421 hyperglycemia Diseases 0.000 description 6
- 229940125396 insulin Drugs 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- 239000002609 medium Substances 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- PLUBXMRUUVWRLT-UHFFFAOYSA-N Ethyl methanesulfonate Chemical compound CCOS(C)(=O)=O PLUBXMRUUVWRLT-UHFFFAOYSA-N 0.000 description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
- 230000000055 hyoplipidemic effect Effects 0.000 description 5
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- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 4
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- 229910052783 alkali metal Inorganic materials 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- 230000002269 spontaneous effect Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 3
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 3
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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- 208000031226 Hyperlipidaemia Diseases 0.000 description 3
- 239000007832 Na2SO4 Substances 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 3
- 150000008041 alkali metal carbonates Chemical class 0.000 description 3
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- 125000002947 alkylene group Chemical group 0.000 description 3
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- 125000005279 aryl sulfonyloxy group Chemical group 0.000 description 3
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 150000007529 inorganic bases Chemical class 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 3
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 3
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 3
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 3
- 229910000105 potassium hydride Inorganic materials 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
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- 235000017550 sodium carbonate Nutrition 0.000 description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
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- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910000065 phosphene Inorganic materials 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229960005095 pioglitazone Drugs 0.000 description 1
- 125000001844 prenyl group Chemical group [H]C([*])([H])C([H])=C(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 125000005930 sec-butyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- QSUJAUYJBJRLKV-UHFFFAOYSA-M tetraethylazanium;fluoride Chemical compound [F-].CC[N+](CC)(CC)CC QSUJAUYJBJRLKV-UHFFFAOYSA-M 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 150000003548 thiazolidines Chemical class 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 229960001641 troglitazone Drugs 0.000 description 1
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Child & Adolescent Psychology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP34554399 | 1999-12-03 | ||
| JP2000295108 | 2000-09-27 | ||
| PCT/JP2000/008464 WO2001040192A1 (en) | 1999-12-03 | 2000-11-29 | Novel heterocyclic compounds and salts thereof and medicinal use of the same |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO20022600D0 NO20022600D0 (no) | 2002-05-31 |
| NO20022600L NO20022600L (no) | 2002-08-05 |
| NO323922B1 true NO323922B1 (no) | 2007-07-23 |
Family
ID=26578048
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20022600A NO323922B1 (no) | 1999-12-03 | 2002-05-31 | Heterosykliske forbindelser og farmasoytisk middel omfattende samme |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US6589963B2 (de) |
| EP (1) | EP1236719A4 (de) |
| KR (1) | KR100716525B1 (de) |
| CN (1) | CN1215059C (de) |
| AR (1) | AR033349A1 (de) |
| AU (1) | AU782631C (de) |
| BR (1) | BR0016064A (de) |
| CA (1) | CA2393265A1 (de) |
| CO (1) | CO5440230A1 (de) |
| CZ (1) | CZ20021911A3 (de) |
| HU (1) | HUP0203431A3 (de) |
| IL (2) | IL149883A0 (de) |
| MX (1) | MXPA02005528A (de) |
| NO (1) | NO323922B1 (de) |
| NZ (1) | NZ519592A (de) |
| PL (1) | PL356769A1 (de) |
| RU (1) | RU2256661C2 (de) |
| TW (1) | TWI286549B (de) |
| WO (1) | WO2001040192A1 (de) |
| YU (1) | YU50302A (de) |
Families Citing this family (37)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6455734B1 (en) * | 2000-08-09 | 2002-09-24 | Magnesium Diagnostics, Inc. | Antagonists of the magnesium binding defect as therapeutic agents and methods for treatment of abnormal physiological states |
| US6982251B2 (en) | 2000-12-20 | 2006-01-03 | Schering Corporation | Substituted 2-azetidinones useful as hypocholesterolemic agents |
| US7071181B2 (en) | 2001-01-26 | 2006-07-04 | Schering Corporation | Methods and therapeutic combinations for the treatment of diabetes using sterol absorption inhibitors |
| PT1355644E (pt) | 2001-01-26 | 2006-11-30 | Schering Corp | Utilização de compostos azetidinona substituídos para o tratamento de sitosterolemia |
| EP1911462A3 (de) | 2001-01-26 | 2011-11-30 | Schering Corporation | Zusammensetzungen enthaltend einen Sterolabsorptionshemmer |
| RS20100015A (sr) | 2001-01-26 | 2010-12-31 | Schering Corporation | Kombinacija aktivatora receptora aktiviranog peroksizom- proliferatorom (ppar) fenofibrata sa inhibitorom apsorpcije sterola ezetimibom za vaskularne indikacije |
| KR100874677B1 (ko) * | 2001-05-29 | 2008-12-18 | 교토 야쿠힝 고교 가부시키가이샤 | 신규 복소환 유도체 및 그 의약 용도 |
| WO2002096880A1 (en) | 2001-05-29 | 2002-12-05 | Kyoto Pharmaceutical Industries, Ltd. | Novel heterocyclic compound and medicinal use thereof |
| US7056906B2 (en) | 2001-09-21 | 2006-06-06 | Schering Corporation | Combinations of hormone replacement therapy composition(s) and sterol absorption inhibitor(s) and treatments for vascular conditions in post-menopausal women |
| US7053080B2 (en) | 2001-09-21 | 2006-05-30 | Schering Corporation | Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors |
| EP1429756B1 (de) | 2001-09-21 | 2006-11-22 | Schering Corporation | Behandlung von xanthom mittels azetidinon-derivate als hemmer der sterol absorption |
| WO2003059907A1 (en) * | 2002-01-17 | 2003-07-24 | Takeda Chemical Industries, Ltd. | Nitrogenous heterocyclic compounds, process for preparation of the same and use thereof |
| DE10222034A1 (de) * | 2002-05-17 | 2003-11-27 | Bayer Ag | Tetrahydroisochinolin-Derivate |
| JP2006508188A (ja) | 2002-11-06 | 2006-03-09 | シェーリング コーポレイション | 脱髄の処置のためのコレステロール吸収インヒビター |
| PA8594401A1 (es) * | 2003-02-21 | 2004-09-16 | Pfizer | Acidos carboxilicos de heteroarilo condensado como agonista del ppar |
| DE602004016123D1 (de) | 2003-03-07 | 2008-10-09 | Schering Corp | Substituierte azetidinon-derivate, deren pharmazeutische formulierungen und deren verwendung zur behandlung von hypercholesterolemia |
| CN1756756A (zh) | 2003-03-07 | 2006-04-05 | 先灵公司 | 取代的2－吖丁啶酮化合物、其制剂及其治疗高胆甾醇血症的用途 |
| CN1756755A (zh) | 2003-03-07 | 2006-04-05 | 先灵公司 | 取代的2－吖丁啶酮化合物、其制剂及其治疗高胆甾醇血症的用途 |
| US7459442B2 (en) | 2003-03-07 | 2008-12-02 | Schering Corporation | Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof |
| CN1300115C (zh) * | 2004-03-26 | 2007-02-14 | 厦门大学 | 一种合成1，2，3，4－四氢异喹啉衍生物的方法 |
| CA2585172C (en) | 2004-10-29 | 2014-08-12 | Kalypsys, Inc. | Sulfonyl-substituted bicyclic compounds as modulators of ppar |
| AU2006277742B2 (en) * | 2005-08-08 | 2010-08-26 | Pfizer Inc. | Salts and polymorphs of a VEGF-R inhibitor |
| AU2006287513A1 (en) * | 2005-09-07 | 2007-03-15 | Plexxikon, Inc. | 1, 3-disubstituted indole derivatives for use as PPAR modulators |
| US7790745B2 (en) | 2005-10-21 | 2010-09-07 | Bristol-Myers Squibb Company | Tetrahydroisoquinoline LXR Modulators |
| US7863276B2 (en) | 2005-10-25 | 2011-01-04 | Kalypsys, Inc | Salts of modulators of PPAR and methods of treating metabolic disorders |
| EP1790646A1 (de) * | 2005-11-24 | 2007-05-30 | Sanofi-Aventis | Isoquinolin- und Benzo[h]isoquinolinderivate, deren Herstellung und deren therapeutischen Verwendung als Antagonisten des Histamin-H3-Rezeptors . |
| US20080176861A1 (en) | 2007-01-23 | 2008-07-24 | Kalypsys, Inc. | Sulfonyl-substituted bicyclic compounds as ppar modulators for the treatment of non-alcoholic steatohepatitis |
| US20080186971A1 (en) * | 2007-02-02 | 2008-08-07 | Tarari, Inc. | Systems and methods for processing access control lists (acls) in network switches using regular expression matching logic |
| WO2009019598A2 (en) * | 2007-08-03 | 2009-02-12 | Dr. Reddy's Laboratories Ltd. | Inhalation therapy for respiratory disorders |
| KR101616737B1 (ko) * | 2008-03-07 | 2016-05-02 | 브이티브이 테라퓨틱스 엘엘씨 | 당뇨병 치료를 위한 옥사디아조안트라센 화합물 |
| AR080375A1 (es) | 2010-03-05 | 2012-04-04 | Sanofi Aventis | Procedimiento para la preparacion de 2-(cicloheximetil)-n-{2-[(2s)-1-metilpirrolidin-2-il] etil}-1,2,3,4-tetrahidroisoquinolina- 7-sulfonamida |
| US20130156720A1 (en) | 2010-08-27 | 2013-06-20 | Ironwood Pharmaceuticals, Inc. | Compositions and methods for treating or preventing metabolic syndrome and related diseases and disorders |
| WO2012033195A1 (ja) * | 2010-09-10 | 2012-03-15 | 京都薬品工業株式会社 | 複素環化合物 |
| CN102807526B (zh) * | 2011-06-21 | 2015-12-02 | 寿光富康制药有限公司 | 组蛋白去乙酰化酶抑制剂ZYJ-D08a及其差向异构体的制备方法与应用 |
| CN102702098A (zh) * | 2012-05-24 | 2012-10-03 | 盛世泰科生物医药技术(苏州)有限公司 | 6-甲氧基-1,2,3,4四氢喹啉-5羧酸甲酯的合成 |
| AR101196A1 (es) * | 2014-07-16 | 2016-11-30 | Gruenenthal Gmbh | Compuestos de pirimidina sustituidos |
| EP4265258A4 (de) * | 2020-12-18 | 2024-11-13 | ASKA Pharmaceutical Co., Ltd. | Feste formulierung |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6051189A (ja) | 1983-08-30 | 1985-03-22 | Sankyo Co Ltd | チアゾリジン誘導体およびその製造法 |
| AR240698A1 (es) | 1985-01-19 | 1990-09-28 | Takeda Chemical Industries Ltd | Procedimiento para preparar compuestos de 5-(4-(2-(5-etil-2-piridil)-etoxi)benzil)-2,4-tiazolidindiona y sus sales |
| ATE186724T1 (de) | 1987-09-04 | 1999-12-15 | Beecham Group Plc | Substituierte thiazolidindionderivate |
| US5246943A (en) * | 1992-05-19 | 1993-09-21 | Warner-Lambert Company | Substituted 1,2,3,4-tetahydroisoquinolines with angiotensin II receptor antagonist properties |
| GB9604242D0 (en) * | 1996-02-28 | 1996-05-01 | Glaxo Wellcome Inc | Chemical compounds |
| DE69731003D1 (de) * | 1996-07-01 | 2004-11-04 | Lilly Co Eli | Blutzuckersenkende und lipidsenkende verbindungen |
| IL121202A (en) * | 1996-07-01 | 2001-08-26 | Lilly Co Eli | Hypoglycemic and hypolipidemic compounds, process for their preparation, pharmaceutial compositions comprising same, and uses thereof |
-
2000
- 2000-11-29 CZ CZ20021911A patent/CZ20021911A3/cs unknown
- 2000-11-29 NZ NZ519592A patent/NZ519592A/en unknown
- 2000-11-29 EP EP00979026A patent/EP1236719A4/de not_active Withdrawn
- 2000-11-29 PL PL00356769A patent/PL356769A1/xx not_active Application Discontinuation
- 2000-11-29 BR BR0016064-4A patent/BR0016064A/pt not_active Application Discontinuation
- 2000-11-29 RU RU2002117450/04A patent/RU2256661C2/ru not_active IP Right Cessation
- 2000-11-29 YU YU50302A patent/YU50302A/sh unknown
- 2000-11-29 US US10/148,386 patent/US6589963B2/en not_active Expired - Fee Related
- 2000-11-29 CN CNB008165114A patent/CN1215059C/zh not_active Expired - Fee Related
- 2000-11-29 AU AU16495/01A patent/AU782631C/en not_active Ceased
- 2000-11-29 HU HU0203431A patent/HUP0203431A3/hu unknown
- 2000-11-29 MX MXPA02005528A patent/MXPA02005528A/es active IP Right Grant
- 2000-11-29 WO PCT/JP2000/008464 patent/WO2001040192A1/ja not_active Ceased
- 2000-11-29 IL IL14988300A patent/IL149883A0/xx active IP Right Grant
- 2000-11-29 KR KR1020027007113A patent/KR100716525B1/ko not_active Expired - Fee Related
- 2000-11-29 CA CA002393265A patent/CA2393265A1/en not_active Abandoned
- 2000-12-01 CO CO00091985A patent/CO5440230A1/es not_active Application Discontinuation
- 2000-12-01 TW TW089125558A patent/TWI286549B/zh not_active IP Right Cessation
- 2000-12-01 AR ARP000106345A patent/AR033349A1/es unknown
-
2002
- 2002-05-28 IL IL149883A patent/IL149883A/en not_active IP Right Cessation
- 2002-05-31 NO NO20022600A patent/NO323922B1/no unknown
Also Published As
| Publication number | Publication date |
|---|---|
| YU50302A (sh) | 2006-01-16 |
| WO2001040192A1 (en) | 2001-06-07 |
| CN1402712A (zh) | 2003-03-12 |
| TWI286549B (en) | 2007-09-11 |
| NO20022600D0 (no) | 2002-05-31 |
| PL356769A1 (en) | 2004-07-12 |
| US20030027836A1 (en) | 2003-02-06 |
| AR033349A1 (es) | 2003-12-17 |
| EP1236719A1 (de) | 2002-09-04 |
| RU2256661C2 (ru) | 2005-07-20 |
| CN1215059C (zh) | 2005-08-17 |
| HUP0203431A3 (en) | 2003-11-28 |
| HUP0203431A2 (hu) | 2003-02-28 |
| AU782631C (en) | 2006-08-17 |
| KR20020058079A (ko) | 2002-07-12 |
| CO5440230A1 (es) | 2004-09-30 |
| KR100716525B1 (ko) | 2007-05-10 |
| EP1236719A4 (de) | 2003-06-25 |
| IL149883A0 (en) | 2002-11-10 |
| US6589963B2 (en) | 2003-07-08 |
| NZ519592A (en) | 2003-11-28 |
| CA2393265A1 (en) | 2001-06-07 |
| HK1053657A1 (en) | 2003-10-31 |
| AU782631B2 (en) | 2005-08-18 |
| BR0016064A (pt) | 2004-07-27 |
| NO20022600L (no) | 2002-08-05 |
| AU1649501A (en) | 2001-06-12 |
| MXPA02005528A (es) | 2002-09-02 |
| IL149883A (en) | 2007-03-08 |
| CZ20021911A3 (cs) | 2002-10-16 |
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