DE60316588T2 - Neue lactame und deren verwendungen - Google Patents
Neue lactame und deren verwendungen Download PDFInfo
- Publication number
- DE60316588T2 DE60316588T2 DE60316588T DE60316588T DE60316588T2 DE 60316588 T2 DE60316588 T2 DE 60316588T2 DE 60316588 T DE60316588 T DE 60316588T DE 60316588 T DE60316588 T DE 60316588T DE 60316588 T2 DE60316588 T2 DE 60316588T2
- Authority
- DE
- Germany
- Prior art keywords
- alkyl
- phenyl
- oxo
- nitrogen
- oxygen
- 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
- 150000001875 compounds Chemical class 0.000 claims description 209
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 188
- 125000000217 alkyl group Chemical group 0.000 claims description 102
- 229910052757 nitrogen Inorganic materials 0.000 claims description 95
- 125000000623 heterocyclic group Chemical group 0.000 claims description 66
- 229910052739 hydrogen Inorganic materials 0.000 claims description 64
- 125000004434 sulfur atom Chemical group 0.000 claims description 63
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 61
- 229910052799 carbon Inorganic materials 0.000 claims description 61
- 229910052760 oxygen Inorganic materials 0.000 claims description 51
- 125000003118 aryl group Chemical group 0.000 claims description 50
- 239000001301 oxygen Substances 0.000 claims description 50
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims description 41
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
- 229910052801 chlorine Inorganic materials 0.000 claims description 27
- 229910052731 fluorine Inorganic materials 0.000 claims description 27
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 27
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 24
- 229910052717 sulfur Inorganic materials 0.000 claims description 24
- 229910052794 bromium Inorganic materials 0.000 claims description 23
- 229910052740 iodine Inorganic materials 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 22
- 108010090849 Amyloid beta-Peptides Proteins 0.000 claims description 21
- 102000013455 Amyloid beta-Peptides Human genes 0.000 claims description 21
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 19
- 102000002659 Amyloid Precursor Protein Secretases Human genes 0.000 claims description 18
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 18
- 229910004013 NO 2 Inorganic materials 0.000 claims description 18
- 238000004519 manufacturing process Methods 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 108010043324 Amyloid Precursor Protein Secretases Proteins 0.000 claims description 17
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 15
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 14
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 claims description 13
- 238000011282 treatment Methods 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 11
- 150000003973 alkyl amines Chemical class 0.000 claims description 11
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims description 11
- 208000024827 Alzheimer disease Diseases 0.000 claims description 10
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 9
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 9
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 230000000694 effects Effects 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 201000010374 Down Syndrome Diseases 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- CEDUXAJHVPKNSP-CCDWMCETSA-N (2s)-2-[[2-(3,5-difluorophenyl)acetyl]amino]-n-[(6r,7r)-5-oxo-7-phenyl-1,4-thiazepan-6-yl]-2-phenylacetamide Chemical compound FC1=CC(F)=CC(CC(=O)N[C@H](C(=O)N[C@@H]2C(NCCS[C@@H]2C=2C=CC=CC=2)=O)C=2C=CC=CC=2)=C1 CEDUXAJHVPKNSP-CCDWMCETSA-N 0.000 claims description 4
- WMNYWACCTSYMMT-KKUQBAQOSA-N (2s)-2-[[2-(3,5-difluorophenyl)acetyl]amino]-n-[(6s,7r)-4-methyl-5-oxo-7-phenyl-1,4-oxazepan-6-yl]-2-phenylacetamide Chemical compound N([C@H](C(=O)N[C@H]1[C@H](OCCN(C1=O)C)C=1C=CC=CC=1)C=1C=CC=CC=1)C(=O)CC1=CC(F)=CC(F)=C1 WMNYWACCTSYMMT-KKUQBAQOSA-N 0.000 claims description 4
- 208000012902 Nervous system disease Diseases 0.000 claims description 4
- 208000025966 Neurological disease Diseases 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 238000011321 prophylaxis Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000000304 alkynyl group Chemical group 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- KIVOEKAYTUIUMB-BNAYGLTLSA-N (2s)-2-[[2-(3,5-difluorophenyl)acetyl]amino]-n-[(3r,6s,7r)-4-methyl-5-oxo-3,7-diphenyl-1,4-oxazepan-6-yl]-2-phenylacetamide Chemical compound N([C@H](C(=O)N[C@H]1[C@H](OC[C@H](N(C1=O)C)C=1C=CC=CC=1)C=1C=CC=CC=1)C=1C=CC=CC=1)C(=O)CC1=CC(F)=CC(F)=C1 KIVOEKAYTUIUMB-BNAYGLTLSA-N 0.000 claims description 2
- NSCCQTZXYYMJMD-YTCPBCGMSA-N (2s)-2-[[2-(3,5-difluorophenyl)acetyl]amino]-n-[(6r,7r)-7-naphthalen-1-yl-5-oxo-1,4-thiazepan-6-yl]-2-phenylacetamide Chemical compound FC1=CC(F)=CC(CC(=O)N[C@H](C(=O)N[C@@H]2C(NCCS[C@@H]2C=2C3=CC=CC=C3C=CC=2)=O)C=2C=CC=CC=2)=C1 NSCCQTZXYYMJMD-YTCPBCGMSA-N 0.000 claims description 2
- FDZXJPAKVPYJLA-XFCANUNOSA-N (2s)-2-[[2-(3,5-difluorophenyl)acetyl]amino]-n-[(6s,7r)-4-[(4-methoxyphenyl)methyl]-5-oxo-7-phenyl-1,4-oxazepan-6-yl]-2-phenylacetamide Chemical compound C1=CC(OC)=CC=C1CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)CC=2C=C(F)C=C(F)C=2)C=2C=CC=CC=2)[C@@H](C=2C=CC=CC=2)OCC1 FDZXJPAKVPYJLA-XFCANUNOSA-N 0.000 claims description 2
- VCZMUKMLFOBLCE-CWBXHPNXSA-N (2s)-2-hydroxy-4-methyl-n-[(1s)-2-[[(6s,7r)-4-methyl-5-oxo-7-phenyl-1,4-oxazepan-6-yl]amino]-2-oxo-1-phenylethyl]pentanamide Chemical compound C1([C@@H]2[C@@H](C(N(C)CCO2)=O)NC(=O)[C@@H](NC(=O)[C@@H](O)CC(C)C)C=2C=CC=CC=2)=CC=CC=C1 VCZMUKMLFOBLCE-CWBXHPNXSA-N 0.000 claims description 2
- UFJHZISQXFLCDQ-MYGLTJDJSA-N (2s)-2-hydroxy-4-methyl-n-[(1s)-2-oxo-2-[[(6r,7r)-5-oxo-7-phenyl-1,4-thiazepan-6-yl]amino]-1-phenylethyl]pentanamide Chemical compound C1([C@@H]2[C@@H](C(NCCS2)=O)NC(=O)[C@@H](NC(=O)[C@@H](O)CC(C)C)C=2C=CC=CC=2)=CC=CC=C1 UFJHZISQXFLCDQ-MYGLTJDJSA-N 0.000 claims description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical compound [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 11
- 229940079593 drug Drugs 0.000 claims 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 213
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 138
- 239000000243 solution Substances 0.000 description 108
- 239000000203 mixture Substances 0.000 description 95
- 239000007787 solid Substances 0.000 description 84
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 61
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 54
- 238000005160 1H NMR spectroscopy Methods 0.000 description 50
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 50
- -1 hydrocarbyl radical Chemical class 0.000 description 49
- 238000000034 method Methods 0.000 description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 42
- 150000001412 amines Chemical class 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- 239000002904 solvent Substances 0.000 description 30
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 26
- 238000003818 flash chromatography Methods 0.000 description 26
- 229920006395 saturated elastomer Polymers 0.000 description 26
- 239000012267 brine Substances 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 25
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 25
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 20
- 239000000460 chlorine Substances 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 20
- 235000017557 sodium bicarbonate Nutrition 0.000 description 20
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 20
- 239000003921 oil Substances 0.000 description 19
- 235000019198 oils Nutrition 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 18
- 238000004128 high performance liquid chromatography Methods 0.000 description 17
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 17
- 239000000741 silica gel Substances 0.000 description 15
- 229910002027 silica gel Inorganic materials 0.000 description 15
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 14
- 125000004432 carbon atom Chemical group C* 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 239000011734 sodium Substances 0.000 description 12
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
- IGGNSAVLXJKCNH-UHFFFAOYSA-N 2-(3,5-difluorophenyl)acetic acid Chemical compound OC(=O)CC1=CC(F)=CC(F)=C1 IGGNSAVLXJKCNH-UHFFFAOYSA-N 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- 125000001424 substituent group Chemical group 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 239000000284 extract Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- PJUPKRYGDFTMTM-UHFFFAOYSA-N 1-hydroxybenzotriazole;hydrate Chemical compound O.C1=CC=C2N(O)N=NC2=C1 PJUPKRYGDFTMTM-UHFFFAOYSA-N 0.000 description 9
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 9
- 125000004429 atom Chemical group 0.000 description 9
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 8
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 8
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 238000003556 assay Methods 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 239000000651 prodrug Substances 0.000 description 7
- 229940002612 prodrug Drugs 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- KEIOJOOWOYTXTN-NEWJYFPISA-N (2s)-2-amino-n-[(3r,6s,7r)-4-methyl-5-oxo-3,7-diphenyl-1,4-oxazepan-6-yl]-2-phenylacetamide Chemical compound C1([C@H](N)C(=O)N[C@H]2[C@H](OC[C@H](N(C2=O)C)C=2C=CC=CC=2)C=2C=CC=CC=2)=CC=CC=C1 KEIOJOOWOYTXTN-NEWJYFPISA-N 0.000 description 6
- IMVKLYOYDZONDB-JDFMPCBTSA-N (3r,6s,7r)-6-amino-4-methyl-3,7-diphenyl-1,4-oxazepan-5-one;hydrochloride Chemical compound Cl.C1([C@H]2OC[C@H](N(C([C@H]2N)=O)C)C=2C=CC=CC=2)=CC=CC=C1 IMVKLYOYDZONDB-JDFMPCBTSA-N 0.000 description 6
- 239000012591 Dulbecco’s Phosphate Buffered Saline Substances 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000003197 catalytic effect Effects 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- OZFAFGSSMRRTDW-UHFFFAOYSA-N (2,4-dichlorophenyl) benzenesulfonate Chemical compound ClC1=CC(Cl)=CC=C1OS(=O)(=O)C1=CC=CC=C1 OZFAFGSSMRRTDW-UHFFFAOYSA-N 0.000 description 5
- BSUXTQKBUZJNDX-NEWJYFPISA-N (2s)-2-amino-2-cyclohexyl-n-[(3r,6s,7r)-4-methyl-5-oxo-3,7-diphenyl-1,4-oxazepan-6-yl]acetamide Chemical compound C1([C@H](N)C(=O)N[C@H]2[C@H](OC[C@H](N(C2=O)C)C=2C=CC=CC=2)C=2C=CC=CC=2)CCCCC1 BSUXTQKBUZJNDX-NEWJYFPISA-N 0.000 description 5
- VXZFTVKOZHTXRO-GVDBMIGSSA-N (3r,6r,7r)-6-hydroxy-4-methyl-3,7-diphenyl-1,4-oxazepan-5-one Chemical compound C1([C@H]2OC[C@H](N(C([C@@H]2O)=O)C)C=2C=CC=CC=2)=CC=CC=C1 VXZFTVKOZHTXRO-GVDBMIGSSA-N 0.000 description 5
- BIXGFAGWWDYNMN-YESZJQIVSA-N (3r,6s,7r)-6-azido-4-methyl-3,7-diphenyl-1,4-oxazepan-5-one Chemical compound C1([C@H]2OC[C@H](N(C([C@H]2N=[N+]=[N-])=O)C)C=2C=CC=CC=2)=CC=CC=C1 BIXGFAGWWDYNMN-YESZJQIVSA-N 0.000 description 5
- LVRFTAZAXQPQHI-YFKPBYRVSA-N (S)-2-hydroxy-4-methylpentanoic acid Chemical compound CC(C)C[C@H](O)C(O)=O LVRFTAZAXQPQHI-YFKPBYRVSA-N 0.000 description 5
- DHSITKLSGYWHBD-UHFFFAOYSA-N 6-azido-4-methyl-2,7-diphenyl-1,4-oxazepan-5-one Chemical compound [N-]=[N+]=NC1C(=O)N(C)CC(C=2C=CC=CC=2)OC1C1=CC=CC=C1 DHSITKLSGYWHBD-UHFFFAOYSA-N 0.000 description 5
- SAIMPKHDTJKHNS-UHFFFAOYSA-N 6-hydroxy-4-methyl-2,7-diphenyl-1,4-oxazepan-5-one Chemical compound OC1C(=O)N(C)CC(C=2C=CC=CC=2)OC1C1=CC=CC=C1 SAIMPKHDTJKHNS-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 239000006260 foam Substances 0.000 description 5
- 238000011534 incubation Methods 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- GFVKPHGGHYOIQI-ZHZULCJRSA-N methyl (z)-3-naphthalen-1-yl-2-(phenylmethoxycarbonylamino)prop-2-enoate Chemical compound C=1C=CC2=CC=CC=C2C=1/C=C(C(=O)OC)\NC(=O)OCC1=CC=CC=C1 GFVKPHGGHYOIQI-ZHZULCJRSA-N 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- WMFFVAZKIWXNQV-LURJTMIESA-N (2s)-2-[[2-(3,5-difluorophenyl)acetyl]amino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)CC1=CC(F)=CC(F)=C1 WMFFVAZKIWXNQV-LURJTMIESA-N 0.000 description 4
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- 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
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/10—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/06—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D281/02—Seven-membered rings
- C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE0202929 | 2002-10-03 | ||
| SE0202929A SE0202929D0 (sv) | 2002-10-03 | 2002-10-03 | Novel benzothiazepines and uses thereof |
| SE0203829A SE0203829D0 (sv) | 2002-12-18 | 2002-12-18 | Novel lactams and uses thereof |
| SE0203829 | 2002-12-18 | ||
| PCT/SE2003/001534 WO2004031154A1 (en) | 2002-10-03 | 2003-10-02 | Novel lactams and uses thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE60316588D1 DE60316588D1 (de) | 2007-11-08 |
| DE60316588T2 true DE60316588T2 (de) | 2008-07-31 |
Family
ID=32072595
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE60316588T Expired - Lifetime DE60316588T2 (de) | 2002-10-03 | 2003-10-02 | Neue lactame und deren verwendungen |
Country Status (12)
| Country | Link |
|---|---|
| US (3) | US7294622B2 (https=) |
| EP (2) | EP1554250B1 (https=) |
| JP (2) | JP4637584B2 (https=) |
| AR (1) | AR041440A1 (https=) |
| AT (1) | ATE374187T1 (https=) |
| AU (1) | AU2003265202A1 (https=) |
| DE (1) | DE60316588T2 (https=) |
| DK (1) | DK1554250T3 (https=) |
| ES (1) | ES2291743T3 (https=) |
| PT (1) | PT1554250E (https=) |
| TW (1) | TW200502221A (https=) |
| WO (1) | WO2004031154A1 (https=) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004080983A1 (en) * | 2003-03-14 | 2004-09-23 | Astrazeneca Ab | Novel lactams and uses thereof |
| US7211573B2 (en) * | 2004-12-08 | 2007-05-01 | Hoffmann-La Roche Inc. | Malonamide derivatives |
| JP2008523141A (ja) * | 2004-12-14 | 2008-07-03 | アストラゼネカ・アクチエボラーグ | 新規の分子プローブ |
| GB2423085C (en) * | 2005-02-11 | 2011-11-09 | Cambridge Entpr Ltd | Ligands for G-protein coupled receptors |
| CA2628074C (en) | 2005-10-25 | 2014-01-14 | Shionogi & Co., Ltd. | Aminodihydrothiazine derivative |
| WO2007104933A1 (en) * | 2006-03-10 | 2007-09-20 | Astrazeneca Ab | Chemical compounds |
| ES2398531T3 (es) * | 2006-03-27 | 2013-03-20 | F. Hoffmann-La Roche Ag | Derivados de malonamida como inhibidores de gamma secretasa |
| CA2652669A1 (en) * | 2006-06-09 | 2007-12-21 | Merck & Co., Inc. | Benzazepinones as sodium channel blockers |
| US7919490B2 (en) * | 2006-10-04 | 2011-04-05 | Wyeth Llc | 6-substituted 2-(benzimidazolyl)purine and purinone derivatives for immunosuppression |
| JP5383484B2 (ja) | 2007-04-24 | 2014-01-08 | 塩野義製薬株式会社 | 環式基で置換されたアミノジヒドロチアジン誘導体 |
| US8653067B2 (en) | 2007-04-24 | 2014-02-18 | Shionogi & Co., Ltd. | Pharmaceutical composition for treating Alzheimer's disease |
| JP5385904B2 (ja) * | 2007-08-14 | 2014-01-08 | イーライ リリー アンド カンパニー | γ−セクレターゼ阻害剤 |
| KR101324426B1 (ko) | 2008-06-13 | 2013-10-31 | 시오노기세야쿠 가부시키가이샤 | β 세크레타제 저해 작용을 갖는 황 함유 복소환 유도체 |
| CN102186841A (zh) | 2008-10-22 | 2011-09-14 | 盐野义制药株式会社 | 具有bace1抑制活性的2-氨基嘧啶-4-酮及2-氨基吡啶衍生物 |
| CN101735211B (zh) * | 2008-11-04 | 2012-11-14 | 复旦大学 | 2,3-二氢[1,5]苯并噻氮杂*类化合物或其盐在制备GSK-3β抑制剂中的用途 |
| US9023767B2 (en) * | 2009-05-07 | 2015-05-05 | Memorial Sloan-Kettering Cancer Center | γ-Secretase substrates and methods of use |
| UY32799A (es) * | 2009-07-24 | 2011-02-28 | Novartis Ag | Derivados de oxazina y su uso en el tratamiento de trastornos neurológicos |
| MX2012006491A (es) | 2009-12-11 | 2012-07-03 | Shionogi & Co | Derivados de oxazina. |
| CN103502466A (zh) | 2010-09-07 | 2014-01-08 | 斯隆－凯特林纪念癌症中心 | 用于γ-分泌酶测定的方法和组合物 |
| JP2014001142A (ja) * | 2010-10-05 | 2014-01-09 | Astellas Pharma Inc | シクロアルカン化合物 |
| BR112013008420A2 (pt) * | 2010-10-07 | 2016-06-28 | Takeda Pharmaceutical | composto, medicamento, e, uso do composito |
| EP2634188A4 (en) | 2010-10-29 | 2014-05-07 | Shionogi & Co | FUSIONED AMINODIHYDROPYRIMIDINE DERIVATIVE |
| JP5816630B2 (ja) | 2010-10-29 | 2015-11-18 | 塩野義製薬株式会社 | ナフチリジン誘導体 |
| US8883779B2 (en) | 2011-04-26 | 2014-11-11 | Shinogi & Co., Ltd. | Oxazine derivatives and a pharmaceutical composition for inhibiting BACE1 containing them |
| BR112015001830A2 (pt) * | 2012-08-09 | 2017-07-04 | Hoffmann La Roche | composto, uso de um composto, método para o tratamento ou profilaxia de câncer e invenção |
| EP2912035A4 (en) | 2012-10-24 | 2016-06-15 | Shionogi & Co | DERIVATIVES OF DIHYDROOXAZINE OR OXAZEPINE HAVING BACE1 INHIBITING ACTIVITY |
Family Cites Families (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH04503073A (ja) | 1989-01-31 | 1992-06-04 | アボツト・ラボラトリーズ | アナフィラトキシン受容体リガンド |
| US5936065A (en) | 1993-12-06 | 1999-08-10 | Cytel Corporation | CS-1 peptidomimetics, compositions and methods of using the same |
| EP0900791A1 (en) | 1995-12-27 | 1999-03-10 | Ono Pharmaceutical Co., Ltd. | Tetrazole derivatives and drugs containing the same as the active ingredient |
| GB9621836D0 (en) | 1996-10-19 | 1996-12-11 | Zeneca Ltd | Peptide compounds |
| HUP0001232A3 (en) | 1996-12-23 | 2001-02-28 | Elan Pharmaceuticals Inc San F | Cycloalkyl, lactam, lactone derivatives and their thio analogues inhibiting betha-amyloid peptide release and/or its synthesis and pharmaceutical compositions containing the compounds |
| JP2002518481A (ja) * | 1998-06-22 | 2002-06-25 | エラン ファーマシューティカルズ，インコーポレイテッド | β−アミロイドペプチドの放出および／またはその合成を阻害するための化合物 |
| AU5204799A (en) * | 1998-06-22 | 2000-01-10 | Elan Pharmaceuticals, Inc. | Compounds for inhibiting beta-amyloid peptide release and/or its synthesis |
| WO1999067221A1 (en) | 1998-06-22 | 1999-12-29 | Elan Pharmaceuticals, Inc. | Compounds for inhibiting beta-amyloid peptide release and/or its synthesis |
| WO2000002903A1 (en) | 1998-07-10 | 2000-01-20 | Cytel Corporation | Cs-1 peptidomimetics, compositions and methods of using the same |
| HRP990246A2 (en) | 1998-08-07 | 2000-06-30 | Du Pont Pharm Co | Succinoylamino benzodiazepines as inhibitors of a beta protein production |
| EP1131634A2 (en) | 1998-09-30 | 2001-09-12 | Elan Pharmaceuticals, Inc. | Determining the mechanism of beta-amyloid peptide generation |
| WO2000038618A2 (en) * | 1998-12-24 | 2000-07-06 | Du Pont Pharmaceuticals Company | SUCCINOYLAMINO BENZODIAZEPINES AS INHIBITORS OF Aβ PROTEIN PRODUCTION |
| JP2001030342A (ja) | 1999-07-23 | 2001-02-06 | Japan Polychem Corp | ポリオレフィン製延伸ブロー成形用インモールドラベル及びそのラベルを熱融着させた成形体 |
| CA2377221A1 (en) * | 1999-09-13 | 2001-03-22 | Bristol-Myers Squibb Pharma Company | Hydroxyalkanoyl aminolactams and related structures as inhibitors of a.beta. protein production |
| AU2001243601A1 (en) | 2000-03-10 | 2001-09-24 | Ariad Pharmaceuticals, Inc. | Caprolactam derivatives and uses thereof |
| WO2001072324A1 (en) | 2000-03-28 | 2001-10-04 | Bristol-Myers Squibb Pharma Company | Lactams as inhibitors of a-beta protein production |
| WO2004080983A1 (en) | 2003-03-14 | 2004-09-23 | Astrazeneca Ab | Novel lactams and uses thereof |
| US7060698B2 (en) | 2003-05-19 | 2006-06-13 | Hoffmann-La Roche Inc. | Benzoxazepinone derivatives |
| JP2008523141A (ja) | 2004-12-14 | 2008-07-03 | アストラゼネカ・アクチエボラーグ | 新規の分子プローブ |
-
2003
- 2003-09-29 TW TW092126851A patent/TW200502221A/zh unknown
- 2003-09-30 AR ARP030103560A patent/AR041440A1/es not_active Application Discontinuation
- 2003-10-02 EP EP03799234A patent/EP1554250B1/en not_active Expired - Lifetime
- 2003-10-02 DE DE60316588T patent/DE60316588T2/de not_active Expired - Lifetime
- 2003-10-02 EP EP07012660A patent/EP1845089A1/en not_active Withdrawn
- 2003-10-02 WO PCT/SE2003/001534 patent/WO2004031154A1/en not_active Ceased
- 2003-10-02 ES ES03799234T patent/ES2291743T3/es not_active Expired - Lifetime
- 2003-10-02 DK DK03799234T patent/DK1554250T3/da active
- 2003-10-02 JP JP2004541383A patent/JP4637584B2/ja not_active Expired - Fee Related
- 2003-10-02 PT PT03799234T patent/PT1554250E/pt unknown
- 2003-10-02 AT AT03799234T patent/ATE374187T1/de not_active IP Right Cessation
- 2003-10-02 US US10/528,640 patent/US7294622B2/en not_active Expired - Fee Related
- 2003-10-02 AU AU2003265202A patent/AU2003265202A1/en not_active Abandoned
-
2007
- 2007-08-24 US US11/844,451 patent/US20080076752A1/en not_active Abandoned
-
2009
- 2009-01-26 US US12/359,465 patent/US7858776B2/en not_active Expired - Fee Related
-
2010
- 2010-06-15 JP JP2010136105A patent/JP2010248216A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AR041440A1 (es) | 2005-05-18 |
| JP2006503862A (ja) | 2006-02-02 |
| DK1554250T3 (da) | 2007-12-17 |
| PT1554250E (pt) | 2007-11-15 |
| US20080076752A1 (en) | 2008-03-27 |
| JP4637584B2 (ja) | 2011-02-23 |
| EP1554250B1 (en) | 2007-09-26 |
| EP1845089A1 (en) | 2007-10-17 |
| ES2291743T3 (es) | 2008-03-01 |
| DE60316588D1 (de) | 2007-11-08 |
| US7294622B2 (en) | 2007-11-13 |
| US20060089346A1 (en) | 2006-04-27 |
| TW200502221A (en) | 2005-01-16 |
| US20100160627A1 (en) | 2010-06-24 |
| ATE374187T1 (de) | 2007-10-15 |
| EP1554250A1 (en) | 2005-07-20 |
| WO2004031154A1 (en) | 2004-04-15 |
| US7858776B2 (en) | 2010-12-28 |
| JP2010248216A (ja) | 2010-11-04 |
| AU2003265202A1 (en) | 2004-04-23 |
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