DE60117059T2 - Kondensierte heteroaromatische glucokinaseaktivatoren - Google Patents
Kondensierte heteroaromatische glucokinaseaktivatoren Download PDFInfo
- Publication number
- DE60117059T2 DE60117059T2 DE60117059T DE60117059T DE60117059T2 DE 60117059 T2 DE60117059 T2 DE 60117059T2 DE 60117059 T DE60117059 T DE 60117059T DE 60117059 T DE60117059 T DE 60117059T DE 60117059 T2 DE60117059 T2 DE 60117059T2
- Authority
- DE
- Germany
- Prior art keywords
- cyclopentyl
- phenyl
- propionamide
- methanesulfonyl
- mmol
- 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.)
- Expired - Lifetime
Links
- 239000012190 activator Substances 0.000 title description 12
- 150000001875 compounds Chemical class 0.000 claims description 124
- 229910052736 halogen Inorganic materials 0.000 claims description 45
- 150000002367 halogens Chemical class 0.000 claims description 44
- 150000001408 amides Chemical class 0.000 claims description 43
- 125000004432 carbon atom Chemical group C* 0.000 claims description 37
- 239000000460 chlorine Substances 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 229910052799 carbon Inorganic materials 0.000 claims description 26
- -1 cyano-4-methanesulfonyl-phenyl Chemical group 0.000 claims description 23
- 150000002431 hydrogen Chemical class 0.000 claims description 23
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 22
- 150000003839 salts Chemical class 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 19
- 150000001721 carbon Chemical group 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 18
- 229910052801 chlorine Inorganic materials 0.000 claims description 16
- 229910052731 fluorine Inorganic materials 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 13
- 229940080818 propionamide Drugs 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- SOYSPEAIZRNEAT-UHFFFAOYSA-N 2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-quinolin-2-ylpropanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1N=C2C=CC=CC2=CC=1)CC1CCCC1 SOYSPEAIZRNEAT-UHFFFAOYSA-N 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 9
- 238000002360 preparation method Methods 0.000 claims description 9
- QZZFVLPXDBVTEZ-UHFFFAOYSA-N 2-(3-bromo-4-methylsulfonylphenyl)-3-cyclopentyl-n-quinolin-2-ylpropanamide Chemical compound C1=C(Br)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1N=C2C=CC=CC2=CC=1)CC1CCCC1 QZZFVLPXDBVTEZ-UHFFFAOYSA-N 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 8
- SOYSPEAIZRNEAT-LJQANCHMSA-N (2r)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentyl-n-quinolin-2-ylpropanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1N=C2C=CC=CC2=CC=1)CC1CCCC1 SOYSPEAIZRNEAT-LJQANCHMSA-N 0.000 claims description 7
- AWINNBCBCPJDHB-UHFFFAOYSA-N 2-(3-cyano-4-methylsulfonylphenyl)-3-cyclopentyl-n-quinolin-2-ylpropanamide Chemical compound C1=C(C#N)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1N=C2C=CC=CC2=CC=1)CC1CCCC1 AWINNBCBCPJDHB-UHFFFAOYSA-N 0.000 claims description 7
- NPIXKNXGHOZWPG-UHFFFAOYSA-N 3-cyclopentyl-2-(3,4-dichlorophenyl)-n-quinolin-2-ylpropanamide Chemical compound C1=C(Cl)C(Cl)=CC=C1C(C(=O)NC=1N=C2C=CC=CC2=CC=1)CC1CCCC1 NPIXKNXGHOZWPG-UHFFFAOYSA-N 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- QQZSSOYUTMZBTM-MRXNPFEDSA-N (2r)-n-(1,3-benzothiazol-2-yl)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentylpropanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1SC2=CC=CC=C2N=1)CC1CCCC1 QQZSSOYUTMZBTM-MRXNPFEDSA-N 0.000 claims description 6
- RBFUJKPDVLOKBZ-UHFFFAOYSA-N 3-cyclopentyl-2-(4-methylsulfonylphenyl)-n-quinolin-2-ylpropanamide Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C(C(=O)NC=1N=C2C=CC=CC2=CC=1)CC1CCCC1 RBFUJKPDVLOKBZ-UHFFFAOYSA-N 0.000 claims description 6
- CBSDSSJLVTWRIQ-UHFFFAOYSA-N n-(1,3-benzothiazol-2-yl)-2-(3-cyano-4-methylsulfonylphenyl)-3-cyclopentylpropanamide Chemical compound C1=C(C#N)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1SC2=CC=CC=C2N=1)CC1CCCC1 CBSDSSJLVTWRIQ-UHFFFAOYSA-N 0.000 claims description 6
- VXZQZJYMVXNSMK-UHFFFAOYSA-N n-(1h-benzimidazol-2-yl)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentylpropanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1NC2=CC=CC=C2N=1)CC1CCCC1 VXZQZJYMVXNSMK-UHFFFAOYSA-N 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- OBWANNDHEQDAJQ-OAHLLOKOSA-N (2r)-n-(1,3-benzothiazol-2-yl)-3-cyclopentyl-2-(3,4-dichlorophenyl)propanamide Chemical compound C1=C(Cl)C(Cl)=CC=C1[C@H](C(=O)NC=1SC2=CC=CC=C2N=1)CC1CCCC1 OBWANNDHEQDAJQ-OAHLLOKOSA-N 0.000 claims description 5
- AAQDRZIJUPVUDR-MRXNPFEDSA-N (2r)-n-(1,3-benzoxazol-2-yl)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentylpropanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1OC2=CC=CC=C2N=1)CC1CCCC1 AAQDRZIJUPVUDR-MRXNPFEDSA-N 0.000 claims description 5
- ACXDSKDJMZEDQU-OAHLLOKOSA-N (2r)-n-(1,3-benzoxazol-2-yl)-3-cyclopentyl-2-(3,4-dichlorophenyl)propanamide Chemical compound C1=C(Cl)C(Cl)=CC=C1[C@H](C(=O)NC=1OC2=CC=CC=C2N=1)CC1CCCC1 ACXDSKDJMZEDQU-OAHLLOKOSA-N 0.000 claims description 5
- HMOSAIJSNNENRZ-UHFFFAOYSA-N 3-cyclopentyl-2-(3,4-dichlorophenyl)-n-(6-fluoro-1,3-benzothiazol-2-yl)propanamide Chemical compound S1C2=CC(F)=CC=C2N=C1NC(=O)C(C=1C=C(Cl)C(Cl)=CC=1)CC1CCCC1 HMOSAIJSNNENRZ-UHFFFAOYSA-N 0.000 claims description 5
- CCEZAKRHOWJHQJ-UHFFFAOYSA-N 3-cyclopentyl-2-(3,4-dichlorophenyl)-n-(6-methylsulfonyl-1,3-benzothiazol-2-yl)propanamide Chemical compound S1C2=CC(S(=O)(=O)C)=CC=C2N=C1NC(=O)C(C=1C=C(Cl)C(Cl)=CC=1)CC1CCCC1 CCEZAKRHOWJHQJ-UHFFFAOYSA-N 0.000 claims description 5
- OBWANNDHEQDAJQ-UHFFFAOYSA-N n-(1,3-benzothiazol-2-yl)-3-cyclopentyl-2-(3,4-dichlorophenyl)propanamide Chemical compound C1=C(Cl)C(Cl)=CC=C1C(C(=O)NC=1SC2=CC=CC=C2N=1)CC1CCCC1 OBWANNDHEQDAJQ-UHFFFAOYSA-N 0.000 claims description 5
- SKOFSWUZPQBFAM-UHFFFAOYSA-N n-(1,3-benzothiazol-2-yl)-3-cyclopentyl-2-(4-methylsulfonyl-3-nitrophenyl)propanamide Chemical compound C1=C([N+]([O-])=O)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1SC2=CC=CC=C2N=1)CC1CCCC1 SKOFSWUZPQBFAM-UHFFFAOYSA-N 0.000 claims description 5
- KYRDLJWNZRNWSG-UHFFFAOYSA-N n-(1,3-benzothiazol-2-yl)-3-cyclopentyl-2-(4-methylsulfonylphenyl)propanamide Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C(C(=O)NC=1SC2=CC=CC=C2N=1)CC1CCCC1 KYRDLJWNZRNWSG-UHFFFAOYSA-N 0.000 claims description 5
- NDVQEFQAKFEDNT-UHFFFAOYSA-N n-(1,3-benzoxazol-2-yl)-3-cyclopentyl-2-(4-methylsulfonyl-3-nitrophenyl)propanamide Chemical compound C1=C([N+]([O-])=O)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1OC2=CC=CC=C2N=1)CC1CCCC1 NDVQEFQAKFEDNT-UHFFFAOYSA-N 0.000 claims description 5
- WVGDMEFWIHUPTL-UHFFFAOYSA-N n-(1h-benzimidazol-2-yl)-2-(3-bromo-4-methylsulfonylphenyl)-3-cyclopentylpropanamide Chemical compound C1=C(Br)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1NC2=CC=CC=C2N=1)CC1CCCC1 WVGDMEFWIHUPTL-UHFFFAOYSA-N 0.000 claims description 5
- CLTWWLUHQCWZQM-UHFFFAOYSA-N n-(1h-benzimidazol-2-yl)-3-cyclopentyl-2-(3,4-dichlorophenyl)propanamide Chemical compound C1=C(Cl)C(Cl)=CC=C1C(C(=O)NC=1NC2=CC=CC=C2N=1)CC1CCCC1 CLTWWLUHQCWZQM-UHFFFAOYSA-N 0.000 claims description 5
- 230000008569 process Effects 0.000 claims description 5
- NPIXKNXGHOZWPG-GOSISDBHSA-N (2r)-3-cyclopentyl-2-(3,4-dichlorophenyl)-n-quinolin-2-ylpropanamide Chemical compound C1=C(Cl)C(Cl)=CC=C1[C@H](C(=O)NC=1N=C2C=CC=CC2=CC=1)CC1CCCC1 NPIXKNXGHOZWPG-GOSISDBHSA-N 0.000 claims description 4
- VXZQZJYMVXNSMK-MRXNPFEDSA-N (2r)-n-(1h-benzimidazol-2-yl)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentylpropanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1NC2=CC=CC=C2N=1)CC1CCCC1 VXZQZJYMVXNSMK-MRXNPFEDSA-N 0.000 claims description 4
- DAFGCELMAUAKCZ-UHFFFAOYSA-N 3-cyclopentyl-2-(3,4-dichlorophenyl)-n-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)propanamide Chemical compound C1=C(Cl)C(Cl)=CC=C1C(C(=O)NC=1SC=2CCCCC=2N=1)CC1CCCC1 DAFGCELMAUAKCZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- RNCVQIUDLLDVEL-UHFFFAOYSA-N n-(1,3-benzothiazol-2-yl)-3-cyclopentyl-2-[4-methylsulfonyl-3-(trifluoromethyl)phenyl]propanamide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1SC2=CC=CC=C2N=1)CC1CCCC1 RNCVQIUDLLDVEL-UHFFFAOYSA-N 0.000 claims description 4
- AAQDRZIJUPVUDR-UHFFFAOYSA-N n-(1,3-benzoxazol-2-yl)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentylpropanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1OC2=CC=CC=C2N=1)CC1CCCC1 AAQDRZIJUPVUDR-UHFFFAOYSA-N 0.000 claims description 4
- ACXDSKDJMZEDQU-UHFFFAOYSA-N n-(1,3-benzoxazol-2-yl)-3-cyclopentyl-2-(3,4-dichlorophenyl)propanamide Chemical compound C1=C(Cl)C(Cl)=CC=C1C(C(=O)NC=1OC2=CC=CC=C2N=1)CC1CCCC1 ACXDSKDJMZEDQU-UHFFFAOYSA-N 0.000 claims description 4
- DZCJSSWRHOHJCP-UHFFFAOYSA-N n-(1,3-benzoxazol-2-yl)-3-cyclopentyl-2-(4-methylsulfonylphenyl)propanamide Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C(C(=O)NC=1OC2=CC=CC=C2N=1)CC1CCCC1 DZCJSSWRHOHJCP-UHFFFAOYSA-N 0.000 claims description 4
- AYXGRWBIQWQTFT-UHFFFAOYSA-N n-(1h-benzimidazol-2-yl)-3-cyclopentyl-2-[4-methylsulfonyl-3-(trifluoromethyl)phenyl]propanamide Chemical compound C1=C(C(F)(F)F)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1NC2=CC=CC=C2N=1)CC1CCCC1 AYXGRWBIQWQTFT-UHFFFAOYSA-N 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- KYRDLJWNZRNWSG-GOSISDBHSA-N (2r)-n-(1,3-benzothiazol-2-yl)-3-cyclopentyl-2-(4-methylsulfonylphenyl)propanamide Chemical compound C1=CC(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1SC2=CC=CC=C2N=1)CC1CCCC1 KYRDLJWNZRNWSG-GOSISDBHSA-N 0.000 claims description 3
- CLTWWLUHQCWZQM-OAHLLOKOSA-N (2r)-n-(1h-benzimidazol-2-yl)-3-cyclopentyl-2-(3,4-dichlorophenyl)propanamide Chemical compound C1=C(Cl)C(Cl)=CC=C1[C@H](C(=O)NC=1NC2=CC=CC=C2N=1)CC1CCCC1 CLTWWLUHQCWZQM-OAHLLOKOSA-N 0.000 claims description 3
- IEDAZVJYMUBPHE-GOSISDBHSA-N (2r)-n-(1h-benzimidazol-2-yl)-3-cyclopentyl-2-(4-methylsulfonylphenyl)propanamide Chemical compound C1=CC(S(=O)(=O)C)=CC=C1[C@H](C(=O)NC=1NC2=CC=CC=C2N=1)CC1CCCC1 IEDAZVJYMUBPHE-GOSISDBHSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- CDJWHCDZRBGAPD-UHFFFAOYSA-N n-(1,3-benzothiazol-2-yl)-2-(3-bromo-4-methylsulfonylphenyl)-3-cyclopentylpropanamide Chemical compound C1=C(Br)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1SC2=CC=CC=C2N=1)CC1CCCC1 CDJWHCDZRBGAPD-UHFFFAOYSA-N 0.000 claims description 3
- QQZSSOYUTMZBTM-UHFFFAOYSA-N n-(1,3-benzothiazol-2-yl)-2-(3-chloro-4-methylsulfonylphenyl)-3-cyclopentylpropanamide Chemical compound C1=C(Cl)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1SC2=CC=CC=C2N=1)CC1CCCC1 QQZSSOYUTMZBTM-UHFFFAOYSA-N 0.000 claims description 3
- IEDAZVJYMUBPHE-UHFFFAOYSA-N n-(1h-benzimidazol-2-yl)-3-cyclopentyl-2-(4-methylsulfonylphenyl)propanamide Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C(C(=O)NC=1NC2=CC=CC=C2N=1)CC1CCCC1 IEDAZVJYMUBPHE-UHFFFAOYSA-N 0.000 claims description 3
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 3
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 2
- XGRBXFPWATYYSK-UHFFFAOYSA-N n-(1,3-benzoxazol-2-yl)-2-(3-bromo-4-methylsulfonylphenyl)-3-cyclopentylpropanamide Chemical compound C1=C(Br)C(S(=O)(=O)C)=CC=C1C(C(=O)NC=1OC2=CC=CC=C2N=1)CC1CCCC1 XGRBXFPWATYYSK-UHFFFAOYSA-N 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 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 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 286
- 239000000243 solution Substances 0.000 description 221
- 239000011541 reaction mixture Substances 0.000 description 211
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 210
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 133
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 94
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 88
- 239000012044 organic layer Substances 0.000 description 75
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 74
- 238000006243 chemical reaction Methods 0.000 description 67
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 60
- 239000007787 solid Substances 0.000 description 58
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 57
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 51
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 51
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- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 21
- 125000004414 alkyl thio group Chemical group 0.000 description 21
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 21
- 235000019341 magnesium sulphate Nutrition 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
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- 238000003756 stirring Methods 0.000 description 20
- GCMNJUJAKQGROZ-UHFFFAOYSA-N 1,2-Dihydroquinolin-2-imine Chemical compound C1=CC=CC2=NC(N)=CC=C21 GCMNJUJAKQGROZ-UHFFFAOYSA-N 0.000 description 18
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- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
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- 238000009826 distribution Methods 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
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- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical class CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
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- 239000003205 fragrance Substances 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940124828 glucokinase activator Drugs 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
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- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 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
- 239000012456 homogeneous solution Substances 0.000 description 1
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- 230000007062 hydrolysis Effects 0.000 description 1
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- 238000012750 in vivo screening Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229960004903 invert sugar Drugs 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- AHCNXVCAVUYIOU-UHFFFAOYSA-M lithium hydroperoxide Chemical compound [Li+].[O-]O AHCNXVCAVUYIOU-UHFFFAOYSA-M 0.000 description 1
- 235000019359 magnesium stearate Nutrition 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
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- 235000012054 meals Nutrition 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- XGNSXUCZXQTRAU-UHFFFAOYSA-N methyl 3-cyclopentyl-2-(4-methylsulfonyl-3-nitrophenyl)propanoate Chemical compound C=1C=C(S(C)(=O)=O)C([N+]([O-])=O)=CC=1C(C(=O)OC)CC1CCCC1 XGNSXUCZXQTRAU-UHFFFAOYSA-N 0.000 description 1
- GGEWZWRPOFEHLH-UHFFFAOYSA-N methyl 3-cyclopentyl-2-[4-methylsulfonyl-3-(trifluoromethyl)phenyl]propanoate Chemical compound C=1C=C(S(C)(=O)=O)C(C(F)(F)F)=CC=1C(C(=O)OC)CC1CCCC1 GGEWZWRPOFEHLH-UHFFFAOYSA-N 0.000 description 1
- 150000002762 monocarboxylic acid derivatives Chemical class 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 description 1
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- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
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- 235000005985 organic acids Nutrition 0.000 description 1
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- 230000037361 pathway Effects 0.000 description 1
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- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003858 primary carboxamides Chemical class 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- KWGRBVOPPLSCSI-WCBMZHEXSA-N pseudoephedrine Chemical compound CN[C@@H](C)[C@@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WCBMZHEXSA-N 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
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- 238000012552 review Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
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- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- RMBAVIFYHOYIFM-UHFFFAOYSA-M sodium methanethiolate Chemical compound [Na+].[S-]C RMBAVIFYHOYIFM-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- GACTWZZMVMUKNG-ZXXMMSQZSA-N sorbitol 6-phosphate Chemical compound OC[C@@H](O)[C@H](O)[C@@H](O)[C@H](O)COP(O)(O)=O GACTWZZMVMUKNG-ZXXMMSQZSA-N 0.000 description 1
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- 239000005720 sucrose Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- HHVIBTZHLRERCL-UHFFFAOYSA-N sulfonyldimethane Chemical compound CS(C)(=O)=O HHVIBTZHLRERCL-UHFFFAOYSA-N 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
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- 125000004149 thio group Chemical group *S* 0.000 description 1
- 210000003371 toe Anatomy 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
- 125000003944 tolyl group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 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
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
- C07D215/38—Nitrogen atoms
-
- 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
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles 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 in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles 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 in position 2
- C07D277/82—Nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (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)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Endocrinology (AREA)
- Veterinary Medicine (AREA)
- Emergency Medicine (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Quinoline Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US25163700P | 2000-12-06 | 2000-12-06 | |
| US251637P | 2000-12-06 | ||
| PCT/EP2001/013870 WO2002046173A1 (en) | 2000-12-06 | 2001-11-28 | Fused heteroaromatic glucokinase activators |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE60117059D1 DE60117059D1 (de) | 2006-04-13 |
| DE60117059T2 true DE60117059T2 (de) | 2006-10-26 |
Family
ID=22952803
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE60117059T Expired - Lifetime DE60117059T2 (de) | 2000-12-06 | 2001-11-28 | Kondensierte heteroaromatische glucokinaseaktivatoren |
Country Status (21)
| Country | Link |
|---|---|
| US (3) | US6448399B1 (enExample) |
| EP (1) | EP1341774B1 (enExample) |
| JP (1) | JP4109111B2 (enExample) |
| KR (1) | KR100545431B1 (enExample) |
| CN (1) | CN1226294C (enExample) |
| AR (1) | AR031627A1 (enExample) |
| AT (1) | ATE316965T1 (enExample) |
| AU (2) | AU2190202A (enExample) |
| BR (1) | BR0115999A (enExample) |
| CA (1) | CA2429642C (enExample) |
| DE (1) | DE60117059T2 (enExample) |
| DK (1) | DK1341774T3 (enExample) |
| ES (1) | ES2256340T3 (enExample) |
| GT (1) | GT200100243A (enExample) |
| MX (1) | MXPA03005119A (enExample) |
| PA (1) | PA8534301A1 (enExample) |
| PE (1) | PE20020753A1 (enExample) |
| PT (1) | PT1341774E (enExample) |
| UY (1) | UY27055A1 (enExample) |
| WO (1) | WO2002046173A1 (enExample) |
| ZA (1) | ZA200303748B (enExample) |
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| SE0102764D0 (sv) | 2001-08-17 | 2001-08-17 | Astrazeneca Ab | Compounds |
| PL215132B1 (pl) | 2002-06-27 | 2013-10-31 | Novo Nordisk As | Pochodna arylokarbonylowa jako srodek terapeutyczny, jej zastosowanie i kompozycja farmaceutyczna ja zawierajaca |
| KR101124245B1 (ko) | 2002-06-27 | 2012-07-02 | 노보 노르디스크 에이/에스 | 치료제로서 아릴 카르보닐 유도체 |
| US6775812B2 (en) * | 2002-07-17 | 2004-08-10 | Hewlett-Packard Development Company, L.P. | Layout design process and system for providing bypass capacitance and compliant density in an integrated circuit |
| WO2004050645A1 (en) * | 2002-10-03 | 2004-06-17 | Novartis Ag | Substituted (thiazol-2-yl) -amide or sulfonamide as glycokinase activators useful in the treatment of type 2 diabetes |
| ES2293005T3 (es) | 2002-10-03 | 2008-03-16 | F. Hoffmann-La Roche Ag | Indol-3-carboxamidas como activadores de la glucocinasa. |
| GB0226930D0 (en) | 2002-11-19 | 2002-12-24 | Astrazeneca Ab | Chemical compounds |
| GB0226931D0 (en) * | 2002-11-19 | 2002-12-24 | Astrazeneca Ab | Chemical compounds |
| MY141521A (en) | 2002-12-12 | 2010-05-14 | Hoffmann La Roche | 5-substituted-six-membered heteroaromatic glucokinase activators |
| PL378117A1 (pl) | 2003-02-11 | 2006-03-06 | Prosidion Limited | Tricyklopodstawione związki amidowe |
| US7262196B2 (en) * | 2003-02-11 | 2007-08-28 | Prosidion Limited | Tri(cyclo) substituted amide glucokinase activator compounds |
| WO2005000301A1 (en) * | 2003-06-20 | 2005-01-06 | F. Hoffmann-La Roche Ag | 2-aminobenzothiazoles as cb1 receptor inverse agonists |
| MXPA06007667A (es) | 2004-01-06 | 2006-09-01 | Novo Nordisk As | Heteroaril-ureas y su uso como activadores de glucocinasa. |
| RU2392275C2 (ru) * | 2004-02-18 | 2010-06-20 | Астразенека Аб | Бензамидные производные и их применение в качестве активирующих глюкокиназу агентов |
| CA2554686A1 (en) * | 2004-02-18 | 2005-09-01 | Astrazeneca Ab | Compounds |
| EP1735322B1 (en) * | 2004-04-02 | 2011-09-14 | Novartis AG | Sulfonamide-thiazolpyridine derivatives as glucokinase activators useful for the treatment of type 2 diabetes |
| BRPI0509543A (pt) * | 2004-04-02 | 2007-09-18 | Novartis Ag | derivados de tiazolopiridina, condições farmacêuticas que contêm os mesmos e métodos para tratar condições mediadas por glucocinase |
| MXPA06012008A (es) * | 2004-04-21 | 2007-01-25 | Prosidion Ltd | Compuestos de amida tri(ciclo) sustituidos. |
| TW200600086A (en) * | 2004-06-05 | 2006-01-01 | Astrazeneca Ab | Chemical compound |
| CN101035767A (zh) | 2004-08-12 | 2007-09-12 | 普洛希典有限公司 | 被取代的苯乙酰胺及其作为葡糖激酶激活剂的用途 |
| MX2007004560A (es) | 2004-10-16 | 2007-06-08 | Astrazeneca Ab | Proceso para hacer compuestos de fenoxi benzamida. |
| GB0423043D0 (en) * | 2004-10-16 | 2004-11-17 | Astrazeneca Ab | Compounds |
| GB0423044D0 (en) * | 2004-10-16 | 2004-11-17 | Astrazeneca Ab | Compounds |
| US7932394B2 (en) * | 2004-11-02 | 2011-04-26 | Msd K.K. | Aryloxy-substituted benzimidazole derivatives |
| DE102005012872A1 (de) * | 2005-03-19 | 2006-09-28 | Sanofi-Aventis Deutschland Gmbh | Substituierte, bizyklische 8-Pyrrolidino-benzimidazole, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel |
| EP1891069A1 (en) * | 2005-05-24 | 2008-02-27 | AstraZeneca AB | 2-phenyl substituted imidazol [4,5b]pyridine/ pyrazine and purine derivatives as glucokinase modulators |
| TW200714597A (en) * | 2005-05-27 | 2007-04-16 | Astrazeneca Ab | Chemical compounds |
| US20110053910A1 (en) * | 2005-07-09 | 2011-03-03 | Mckerrecher Darren | 2 -heterocyclyloxybenzoyl amino heterocyclyl compounds as modulators of glucokinase for the treatment of type 2 diabetes |
| US20080234273A1 (en) * | 2005-07-09 | 2008-09-25 | Mckerrecher Darren | Heteroaryl Benzamide Derivatives for Use as Glk Activators in the Treatment of Diabetes |
| EP2301935A1 (en) * | 2005-07-09 | 2011-03-30 | AstraZeneca AB (Publ) | Heteroaryl benzamide derivatives for use as GLK activators in the treatment of diabetes |
| AU2006267338B2 (en) * | 2005-07-13 | 2012-08-16 | Msd K.K. | Heterocycle-substituted benzimidazole derivative |
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| US3840550A (en) * | 1971-05-24 | 1974-10-08 | Ciba Geigy Corp | Certain 6-isothiocyanobenzothiazoles |
| PT1169312E (pt) * | 1999-03-29 | 2005-01-31 | Hoffmann La Roche | Activadores de glicocinase |
| US6320050B1 (en) * | 1999-03-29 | 2001-11-20 | Hoffmann-La Roche Inc. | Heteroaromatic glucokinase activators |
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2001
- 2001-11-28 DK DK01999565T patent/DK1341774T3/da active
- 2001-11-28 PT PT01999565T patent/PT1341774E/pt unknown
- 2001-11-28 AT AT01999565T patent/ATE316965T1/de not_active IP Right Cessation
- 2001-11-28 CA CA002429642A patent/CA2429642C/en not_active Expired - Fee Related
- 2001-11-28 KR KR1020037007517A patent/KR100545431B1/ko not_active Expired - Fee Related
- 2001-11-28 BR BR0115999-2A patent/BR0115999A/pt not_active IP Right Cessation
- 2001-11-28 ES ES01999565T patent/ES2256340T3/es not_active Expired - Lifetime
- 2001-11-28 EP EP01999565A patent/EP1341774B1/en not_active Expired - Lifetime
- 2001-11-28 WO PCT/EP2001/013870 patent/WO2002046173A1/en not_active Ceased
- 2001-11-28 AU AU2190202A patent/AU2190202A/xx active Pending
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- 2001-12-04 US US10/007,091 patent/US6448399B1/en not_active Expired - Fee Related
- 2001-12-04 US US10/006,170 patent/US6545155B2/en not_active Expired - Fee Related
- 2001-12-04 AR ARP010105639A patent/AR031627A1/es unknown
- 2001-12-04 PE PE2001001217A patent/PE20020753A1/es not_active Application Discontinuation
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| EP1341774B1 (en) | 2006-02-01 |
| DE60117059D1 (de) | 2006-04-13 |
| CA2429642C (en) | 2007-11-20 |
| US20020107396A1 (en) | 2002-08-08 |
| EP1341774A1 (en) | 2003-09-10 |
| ES2256340T3 (es) | 2006-07-16 |
| US6545155B2 (en) | 2003-04-08 |
| CN1476438A (zh) | 2004-02-18 |
| PA8534301A1 (es) | 2002-08-26 |
| US6448399B1 (en) | 2002-09-10 |
| BR0115999A (pt) | 2003-09-30 |
| JP4109111B2 (ja) | 2008-07-02 |
| KR100545431B1 (ko) | 2006-01-24 |
| JP2004517087A (ja) | 2004-06-10 |
| MXPA03005119A (es) | 2004-10-15 |
| PT1341774E (pt) | 2006-05-31 |
| DK1341774T3 (da) | 2006-06-12 |
| PE20020753A1 (es) | 2002-08-27 |
| US6441184B1 (en) | 2002-08-27 |
| AU2002221902B2 (en) | 2006-11-23 |
| AR031627A1 (es) | 2003-09-24 |
| KR20030068555A (ko) | 2003-08-21 |
| AU2190202A (en) | 2002-06-18 |
| CA2429642A1 (en) | 2002-06-13 |
| US20020103241A1 (en) | 2002-08-01 |
| ZA200303748B (en) | 2004-08-16 |
| ATE316965T1 (de) | 2006-02-15 |
| US20020103199A1 (en) | 2002-08-01 |
| CN1226294C (zh) | 2005-11-09 |
| UY27055A1 (es) | 2002-07-31 |
| WO2002046173A1 (en) | 2002-06-13 |
| GT200100243A (es) | 2002-06-04 |
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