ZA200300173B - Alpha-acyl and alpha-heteroatom-substituted benzene acetamide glucokinase activators. - Google Patents
Alpha-acyl and alpha-heteroatom-substituted benzene acetamide glucokinase activators. Download PDFInfo
- Publication number
- ZA200300173B ZA200300173B ZA200300173A ZA200300173A ZA200300173B ZA 200300173 B ZA200300173 B ZA 200300173B ZA 200300173 A ZA200300173 A ZA 200300173A ZA 200300173 A ZA200300173 A ZA 200300173A ZA 200300173 B ZA200300173 B ZA 200300173B
- Authority
- ZA
- South Africa
- Prior art keywords
- amide
- lower alkyl
- formula
- phenyl
- compound
- Prior art date
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- 102000030595 Glucokinase Human genes 0.000 title description 20
- 108010021582 Glucokinase Proteins 0.000 title description 20
- 239000012190 activator Substances 0.000 title description 4
- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical class NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 75
- 229910052760 oxygen Inorganic materials 0.000 claims description 40
- 229910052717 sulfur Chemical group 0.000 claims description 36
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 34
- 239000001301 oxygen Substances 0.000 claims description 34
- 150000001408 amides Chemical class 0.000 claims description 31
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 29
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 28
- 239000011593 sulfur Chemical group 0.000 claims description 28
- 125000000217 alkyl group Chemical group 0.000 claims description 27
- 229910052799 carbon Inorganic materials 0.000 claims description 27
- 125000005842 heteroatom Chemical group 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 125000004414 alkyl thio group Chemical group 0.000 claims description 19
- 125000005843 halogen group Chemical group 0.000 claims description 18
- -1 perfluoro Chemical group 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 125000004432 carbon atom Chemical group C* 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 229910052757 nitrogen Chemical group 0.000 claims description 14
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 12
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 10
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 10
- 125000000335 thiazolyl group Chemical group 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 9
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 7
- 125000003368 amide group Chemical group 0.000 claims description 6
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 241001465754 Metazoa Species 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 238000011321 prophylaxis Methods 0.000 claims description 5
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 4
- 150000003457 sulfones Chemical class 0.000 claims description 4
- XTDQXQIDBRVLFJ-UHFFFAOYSA-N 2-(3,4-dichlorophenyl)-2-(oxan-4-yloxy)-n-(1,3-thiazol-2-yl)acetamide Chemical compound C1=C(Cl)C(Cl)=CC=C1C(C(=O)NC=1SC=CN=1)OC1CCOCC1 XTDQXQIDBRVLFJ-UHFFFAOYSA-N 0.000 claims description 3
- CNNNBBYSLRJXCB-UHFFFAOYSA-N 2-(3-chloro-4-methylsulfonylphenyl)-2-cyclopentyloxy-n-(1,3-thiazol-2-yl)acetamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1SC=CN=1)OC1CCCC1 CNNNBBYSLRJXCB-UHFFFAOYSA-N 0.000 claims description 3
- GDLVELQZXTUWHH-UHFFFAOYSA-N 2-(3-chloro-4-methylsulfonylphenyl)-2-cyclopentyloxy-n-(methylcarbamoyl)acetamide Chemical compound C=1C=C(S(C)(=O)=O)C(Cl)=CC=1C(C(=O)NC(=O)NC)OC1CCCC1 GDLVELQZXTUWHH-UHFFFAOYSA-N 0.000 claims description 3
- OKVVHUTYWMKAMT-UHFFFAOYSA-N 2-cyclohex-2-en-1-yloxy-2-(3,4-dichlorophenyl)-n-(1,3-thiazol-2-yl)acetamide Chemical compound C1=C(Cl)C(Cl)=CC=C1C(C(=O)NC=1SC=CN=1)OC1C=CCCC1 OKVVHUTYWMKAMT-UHFFFAOYSA-N 0.000 claims description 3
- MMNSTTDMQWXPIG-UHFFFAOYSA-N 2-cyclohexyloxy-2-(3,4-dichlorophenyl)-n-(1,3-thiazol-2-yl)acetamide Chemical compound C1=C(Cl)C(Cl)=CC=C1C(C(=O)NC=1SC=CN=1)OC1CCCCC1 MMNSTTDMQWXPIG-UHFFFAOYSA-N 0.000 claims description 3
- POASZSTXBAHPDO-UHFFFAOYSA-N 2-cyclopentyloxy-2-(3,4-dichlorophenyl)-n-(1,3-thiazol-2-yl)acetamide Chemical compound C1=C(Cl)C(Cl)=CC=C1C(C(=O)NC=1SC=CN=1)OC1CCCC1 POASZSTXBAHPDO-UHFFFAOYSA-N 0.000 claims description 3
- AQFOGDIAJYVUPT-UHFFFAOYSA-N 2-cyclopentyloxy-2-(3,4-dichlorophenyl)-n-(methylcarbamoyl)acetamide Chemical compound C=1C=C(Cl)C(Cl)=CC=1C(C(=O)NC(=O)NC)OC1CCCC1 AQFOGDIAJYVUPT-UHFFFAOYSA-N 0.000 claims description 3
- VDMFSJBFMOBHGB-UHFFFAOYSA-N 2-cyclopentyloxy-2-(3,4-dichlorophenyl)-n-pyridin-2-ylacetamide Chemical compound C1=C(Cl)C(Cl)=CC=C1C(C(=O)NC=1N=CC=CC=1)OC1CCCC1 VDMFSJBFMOBHGB-UHFFFAOYSA-N 0.000 claims description 3
- KNDLNVKCYAIMBC-UHFFFAOYSA-N 2-cyclopentylsulfanyl-2-(3,4-dichlorophenyl)-n-(1,3-thiazol-2-yl)acetamide Chemical compound C1=C(Cl)C(Cl)=CC=C1C(C(=O)NC=1SC=CN=1)SC1CCCC1 KNDLNVKCYAIMBC-UHFFFAOYSA-N 0.000 claims description 3
- WAUWSYSGLFXHRD-UHFFFAOYSA-N 2-cyclopentylsulfonyl-2-(3,4-dichlorophenyl)-n-(1,3-thiazol-2-yl)acetamide Chemical compound C1=C(Cl)C(Cl)=CC=C1C(S(=O)(=O)C1CCCC1)C(=O)NC1=NC=CS1 WAUWSYSGLFXHRD-UHFFFAOYSA-N 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
- MIEVEFJYIVXWLB-UHFFFAOYSA-N 2-(3,4-dichlorophenyl)-n-(methylcarbamoyl)-2-(oxan-4-yloxy)acetamide Chemical compound C=1C=C(Cl)C(Cl)=CC=1C(C(=O)NC(=O)NC)OC1CCOCC1 MIEVEFJYIVXWLB-UHFFFAOYSA-N 0.000 claims description 2
- AKTVVVWFNHFFQE-UHFFFAOYSA-N 2-(3-chloro-4-methylsulfonylphenyl)-2-cyclohex-2-en-1-yloxy-n-(methylcarbamoyl)acetamide Chemical compound C=1C=C(S(C)(=O)=O)C(Cl)=CC=1C(C(=O)NC(=O)NC)OC1CCCC=C1 AKTVVVWFNHFFQE-UHFFFAOYSA-N 0.000 claims description 2
- GBRFVNIVLOASHK-UHFFFAOYSA-N 2-cyclohex-2-en-1-yloxy-2-(3,4-dichlorophenyl)-n-(methylcarbamoyl)acetamide Chemical compound C=1C=C(Cl)C(Cl)=CC=1C(C(=O)NC(=O)NC)OC1CCCC=C1 GBRFVNIVLOASHK-UHFFFAOYSA-N 0.000 claims description 2
- UMLQXVZOFOAQFB-UHFFFAOYSA-N 3-cyclopentyl-2-(3,4-dichlorophenyl)-3-oxo-n-(1,3-thiazol-2-yl)propanamide Chemical compound C1=C(Cl)C(Cl)=CC=C1C(C(=O)C1CCCC1)C(=O)NC1=NC=CS1 UMLQXVZOFOAQFB-UHFFFAOYSA-N 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 2
- 125000004306 triazinyl group Chemical group 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims 8
- 150000003568 thioethers Chemical class 0.000 claims 2
- 241000763212 Lype Species 0.000 claims 1
- 108010052300 RA X peptide Proteins 0.000 claims 1
- 229910052783 alkali metal Inorganic materials 0.000 claims 1
- 230000008878 coupling Effects 0.000 claims 1
- 238000010168 coupling process Methods 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 claims 1
- 230000005595 deprotonation Effects 0.000 claims 1
- 238000010537 deprotonation reaction Methods 0.000 claims 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- 239000012948 isocyanate Substances 0.000 claims 1
- 150000002513 isocyanates Chemical class 0.000 claims 1
- 229940037201 oris Drugs 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 150000001721 carbon Chemical group 0.000 description 12
- 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 description 9
- 239000002253 acid Substances 0.000 description 9
- 239000008103 glucose Substances 0.000 description 9
- 125000006239 protecting group Chemical group 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 238000007796 conventional method Methods 0.000 description 8
- 150000002148 esters Chemical class 0.000 description 8
- 150000001735 carboxylic acids Chemical class 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 5
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- 125000004149 thio group Chemical group *S* 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 4
- 125000005907 alkyl ester group Chemical group 0.000 description 4
- 230000032050 esterification Effects 0.000 description 4
- 238000005886 esterification reaction Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-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
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 102000005548 Hexokinase Human genes 0.000 description 3
- 108700040460 Hexokinases Proteins 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 150000001356 alkyl thiols Chemical class 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000001246 bromo group Chemical group Br* 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 210000003494 hepatocyte Anatomy 0.000 description 3
- 125000002346 iodo group Chemical group I* 0.000 description 3
- PZDFZWWTLUQGLV-UHFFFAOYSA-N 2-cyclohexyloxy-2-(3,4-dichlorophenyl)-n-(methylcarbamoyl)acetamide Chemical compound C=1C=C(Cl)C(Cl)=CC=1C(C(=O)NC(=O)NC)OC1CCCCC1 PZDFZWWTLUQGLV-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
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- 101150109586 Gk gene Proteins 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000035180 MODY Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
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- 125000005233 alkylalcohol group Chemical group 0.000 description 2
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000001033 ether group Chemical group 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
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- 125000001183 hydrocarbyl group Chemical group 0.000 description 2
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- NBSCHQHZLSJFNQ-GASJEMHNSA-N D-Glucose 6-phosphate Chemical compound OC1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H](O)[C@H]1O NBSCHQHZLSJFNQ-GASJEMHNSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- VFRROHXSMXFLSN-UHFFFAOYSA-N Glc6P Natural products OP(=O)(O)OCC(O)C(O)C(O)C(O)C=O VFRROHXSMXFLSN-UHFFFAOYSA-N 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
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- 241000124008 Mammalia Species 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000006392 alkylpyrimidinyl group Chemical group 0.000 description 1
- DEDGUGJNLNLJSR-UHFFFAOYSA-N alpha-hydroxycinnamic acid Natural products OC(=O)C(O)=CC1=CC=CC=C1 DEDGUGJNLNLJSR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- 125000001769 aryl amino group Chemical group 0.000 description 1
- 125000005002 aryl methyl group Chemical group 0.000 description 1
- 125000005164 aryl thioalkyl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 150000001559 benzoic acids Chemical class 0.000 description 1
- CHIHQLCVLOXUJW-UHFFFAOYSA-N benzoic anhydride Chemical compound C=1C=CC=CC=1C(=O)OC(=O)C1=CC=CC=C1 CHIHQLCVLOXUJW-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
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- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
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- 150000001649 bromium compounds Chemical class 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000007883 cyanide addition reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 1
- 238000011905 homologation Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 210000002660 insulin-secreting cell Anatomy 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004777 loss-of-function mutation Effects 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- 150000005217 methyl ethers Chemical class 0.000 description 1
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 210000004738 parenchymal cell Anatomy 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- LMKPPOCIIACDQU-UHFFFAOYSA-N phenyl 2-oxopropanoate Chemical class CC(=O)C(=O)OC1=CC=CC=C1 LMKPPOCIIACDQU-UHFFFAOYSA-N 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000029964 regulation of glucose metabolic process Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 150000003333 secondary alcohols Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229940014800 succinic anhydride Drugs 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/46—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylureas
- C07C275/48—Y being a hydrogen or a carbon atom
- C07C275/50—Y being a hydrogen or an acyclic carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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 ring carbon atoms
- C07D277/18—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- 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
- C07D417/02—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 two hetero rings
- C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Epidemiology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrane Compounds (AREA)
- Pyridine Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Enzymes And Modification Thereof (AREA)
Applications Claiming Priority (1)
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US21987200P | 2000-07-20 | 2000-07-20 |
Publications (1)
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ZA200300173B true ZA200300173B (en) | 2004-04-07 |
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ZA200300173A ZA200300173B (en) | 2000-07-20 | 2003-01-07 | Alpha-acyl and alpha-heteroatom-substituted benzene acetamide glucokinase activators. |
Country Status (21)
Country | Link |
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US (2) | US6486184B2 (zh) |
EP (1) | EP1305301B1 (zh) |
JP (1) | JP4138478B2 (zh) |
KR (1) | KR100556323B1 (zh) |
CN (1) | CN1184214C (zh) |
AR (1) | AR032626A1 (zh) |
AT (1) | ATE297907T1 (zh) |
AU (2) | AU8760001A (zh) |
BR (1) | BR0112658A (zh) |
CA (1) | CA2416229C (zh) |
DE (1) | DE60111534T2 (zh) |
DK (1) | DK1305301T3 (zh) |
ES (1) | ES2243547T3 (zh) |
GT (1) | GT200100146A (zh) |
MX (1) | MXPA03000365A (zh) |
PA (1) | PA8522701A1 (zh) |
PE (1) | PE20020335A1 (zh) |
PT (1) | PT1305301E (zh) |
UY (1) | UY26850A1 (zh) |
WO (1) | WO2002008209A1 (zh) |
ZA (1) | ZA200300173B (zh) |
Families Citing this family (70)
Publication number | Priority date | Publication date | Assignee | Title |
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SE0102299D0 (sv) | 2001-06-26 | 2001-06-26 | Astrazeneca Ab | Compounds |
SE0102764D0 (sv) | 2001-08-17 | 2001-08-17 | Astrazeneca Ab | Compounds |
EP1336607A1 (en) * | 2002-02-19 | 2003-08-20 | Novo Nordisk A/S | Amide derivatives as glucokinase activators |
CN100506807C (zh) | 2001-12-21 | 2009-07-01 | 诺沃挪第克公司 | 作为gk活化剂的酰胺衍生物 |
UA80427C2 (en) | 2002-04-26 | 2007-09-25 | Hoffmann La Roche | Substituted phenylacetamides and their use as glucokinase activators |
KR101124245B1 (ko) | 2002-06-27 | 2012-07-02 | 노보 노르디스크 에이/에스 | 치료제로서 아릴 카르보닐 유도체 |
AU2003243921B2 (en) | 2002-06-27 | 2009-05-07 | Novo Nordisk A/S | Aryl carbonyl derivatives as therapeutic agents |
BR0314864A (pt) | 2002-10-03 | 2005-08-02 | Novartis Ag | Compostos orgânicos |
GB0226931D0 (en) | 2002-11-19 | 2002-12-24 | Astrazeneca Ab | Chemical compounds |
US7132425B2 (en) | 2002-12-12 | 2006-11-07 | Hoffmann-La Roche Inc. | 5-substituted-six-membered heteroaromatic glucokinase activators |
AU2003294376A1 (en) * | 2003-01-06 | 2004-08-10 | Eli Lilly And Company | Heteroaryl compounds |
PL378117A1 (pl) | 2003-02-11 | 2006-03-06 | Prosidion Limited | Tricyklopodstawione związki amidowe |
CA2539596A1 (en) | 2003-09-30 | 2005-04-07 | Kilian Waldemar Conde-Frieboes | Melanocortin receptor agonists |
JP4865565B2 (ja) | 2003-12-09 | 2012-02-01 | ノヴォ ノルディスク アー/エス | Glp−1アゴニストを用いた食物選択の制御 |
WO2005066145A1 (en) | 2004-01-06 | 2005-07-21 | Novo Nordisk A/S | Heteroaryl-ureas and their use as glucokinase activators |
AU2005229415B2 (en) | 2004-04-02 | 2009-05-14 | Novartis Ag | Thiazolopyridine derivatives, pharmaceutical conditions containing them and methods of treating glucokinase mediated conditions |
CA2560689C (en) | 2004-04-02 | 2011-03-01 | Novartis Ag | Sulfonamide-thiazolpyridine derivatives as glucokinase activators useful in the treatment of type 2 diabetes |
MXPA06012008A (es) * | 2004-04-21 | 2007-01-25 | Prosidion Ltd | Compuestos de amida tri(ciclo) sustituidos. |
EP1758575A1 (en) | 2004-06-11 | 2007-03-07 | Novo Nordisk A/S | Counteracting drug-induced obesity using glp-1 agonists |
GB0418046D0 (en) * | 2004-08-12 | 2004-09-15 | Prosidion Ltd | Eantioselective process |
KR20080105180A (ko) * | 2004-08-12 | 2008-12-03 | 프로시디온 리미티드 | 치환된 페닐아세트아미드 및 글루코키나제 활성화제로서의 그의 용도 |
EP1904466A1 (en) * | 2005-07-08 | 2008-04-02 | Novo Nordisk A/S | Dicycloalkyl urea glucokinase activators |
ATE547396T1 (de) | 2005-07-08 | 2012-03-15 | Novo Nordisk As | Dicycloalkylcarbamoyl-harnstoffe als glucokinase- aktivatoren |
WO2007006814A1 (en) | 2005-07-14 | 2007-01-18 | Novo Nordisk A/S | Urea glucokinase activators |
WO2007015805A1 (en) | 2005-07-20 | 2007-02-08 | Eli Lilly And Company | 1-amino linked compounds |
US20090281142A1 (en) | 2005-08-31 | 2009-11-12 | Astellas Pharma Inc. | Thiazole derivative |
JP2007063225A (ja) | 2005-09-01 | 2007-03-15 | Takeda Chem Ind Ltd | イミダゾピリジン化合物 |
BRPI0617207A2 (pt) | 2005-09-29 | 2011-07-19 | Sanofi Aventis | derivados de fenil-1,2,4-oxadiazolona, processos para sua preparação e seu uso como produtos farmacêuticos |
GT200600429A (es) | 2005-09-30 | 2007-04-30 | Compuestos organicos | |
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2001
- 2001-07-11 MX MXPA03000365A patent/MXPA03000365A/es active IP Right Grant
- 2001-07-11 EP EP01967150A patent/EP1305301B1/en not_active Expired - Lifetime
- 2001-07-11 WO PCT/EP2001/007994 patent/WO2002008209A1/en active IP Right Grant
- 2001-07-11 DE DE60111534T patent/DE60111534T2/de not_active Expired - Lifetime
- 2001-07-11 JP JP2002514115A patent/JP4138478B2/ja not_active Expired - Fee Related
- 2001-07-11 PT PT01967150T patent/PT1305301E/pt unknown
- 2001-07-11 KR KR1020037000822A patent/KR100556323B1/ko not_active IP Right Cessation
- 2001-07-11 CA CA002416229A patent/CA2416229C/en not_active Expired - Fee Related
- 2001-07-11 DK DK01967150T patent/DK1305301T3/da active
- 2001-07-11 CN CNB01813050XA patent/CN1184214C/zh not_active Expired - Fee Related
- 2001-07-11 BR BR0112658-0A patent/BR0112658A/pt not_active IP Right Cessation
- 2001-07-11 AU AU8760001A patent/AU8760001A/xx active Pending
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- 2001-07-11 ES ES01967150T patent/ES2243547T3/es not_active Expired - Lifetime
- 2001-07-11 AU AU2001287600A patent/AU2001287600B2/en not_active Ceased
- 2001-07-13 US US09/905,152 patent/US6486184B2/en not_active Expired - Fee Related
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- 2001-07-19 PE PE2001000731A patent/PE20020335A1/es not_active Application Discontinuation
- 2001-07-19 UY UY26850A patent/UY26850A1/es not_active Application Discontinuation
- 2001-07-20 GT GT200100146A patent/GT200100146A/es unknown
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2002
- 2002-06-25 US US10/179,717 patent/US6608218B2/en not_active Expired - Fee Related
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DE60111534D1 (de) | 2005-07-21 |
US20020198200A1 (en) | 2002-12-26 |
CA2416229A1 (en) | 2002-01-31 |
DE60111534T2 (de) | 2006-05-11 |
WO2002008209A1 (en) | 2002-01-31 |
UY26850A1 (es) | 2002-01-31 |
EP1305301B1 (en) | 2005-06-15 |
KR100556323B1 (ko) | 2006-03-03 |
ATE297907T1 (de) | 2005-07-15 |
PA8522701A1 (es) | 2002-10-24 |
AU2001287600B2 (en) | 2006-07-13 |
KR20030016419A (ko) | 2003-02-26 |
AU8760001A (en) | 2002-02-05 |
JP2004504388A (ja) | 2004-02-12 |
US20020042512A1 (en) | 2002-04-11 |
DK1305301T3 (da) | 2005-10-17 |
CN1443177A (zh) | 2003-09-17 |
CN1184214C (zh) | 2005-01-12 |
PT1305301E (pt) | 2005-09-30 |
ES2243547T3 (es) | 2005-12-01 |
JP4138478B2 (ja) | 2008-08-27 |
EP1305301A1 (en) | 2003-05-02 |
AR032626A1 (es) | 2003-11-19 |
US6608218B2 (en) | 2003-08-19 |
GT200100146A (es) | 2002-07-04 |
MXPA03000365A (es) | 2003-05-27 |
US6486184B2 (en) | 2002-11-26 |
CA2416229C (en) | 2007-09-18 |
PE20020335A1 (es) | 2002-04-30 |
BR0112658A (pt) | 2003-06-24 |
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