ES2209122T3 - Compuestos de acido sulfonil alfa-hidroxi hidroxamico aromatico. - Google Patents
Compuestos de acido sulfonil alfa-hidroxi hidroxamico aromatico.Info
- Publication number
- ES2209122T3 ES2209122T3 ES98910177T ES98910177T ES2209122T3 ES 2209122 T3 ES2209122 T3 ES 2209122T3 ES 98910177 T ES98910177 T ES 98910177T ES 98910177 T ES98910177 T ES 98910177T ES 2209122 T3 ES2209122 T3 ES 2209122T3
- Authority
- ES
- Spain
- Prior art keywords
- carbon atoms
- hydrocarbyl
- group
- compound
- phenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 198
- 239000002253 acid Substances 0.000 title abstract description 63
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 title abstract description 14
- 125000003118 aryl group Chemical group 0.000 claims abstract description 50
- 238000000034 method Methods 0.000 claims abstract description 46
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 40
- 102000005741 Metalloproteases Human genes 0.000 claims abstract description 28
- 108010006035 Metalloproteases Proteins 0.000 claims abstract description 28
- 230000001575 pathological effect Effects 0.000 claims abstract description 18
- 230000008569 process Effects 0.000 claims abstract description 17
- 239000011159 matrix material Substances 0.000 claims abstract description 15
- -1 hydrocarbyloxy Chemical group 0.000 claims description 235
- 125000004432 carbon atom Chemical group C* 0.000 claims description 144
- 125000001424 substituent group Chemical group 0.000 claims description 93
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 75
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 65
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 55
- 125000004429 atom Chemical group 0.000 claims description 49
- 229910052799 carbon Inorganic materials 0.000 claims description 46
- 150000003839 salts Chemical class 0.000 claims description 44
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 42
- 125000000623 heterocyclic group Chemical group 0.000 claims description 41
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 38
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 claims description 28
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 claims description 26
- 238000002360 preparation method Methods 0.000 claims description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 150000002367 halogens Chemical group 0.000 claims description 20
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- 150000004678 hydrides Chemical class 0.000 claims description 12
- BJOBQJZONAZIHU-UHFFFAOYSA-N 2-benzamidopyridine-3-carboxamide Chemical compound NC(=O)C1=CC=CN=C1NC(=O)C1=CC=CC=C1 BJOBQJZONAZIHU-UHFFFAOYSA-N 0.000 claims description 10
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
- 125000002541 furyl group Chemical group 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 9
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000001204 arachidyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 5
- 125000005368 heteroarylthio group Chemical group 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 125000005085 alkoxycarbonylalkoxy group Chemical group 0.000 claims description 2
- 125000001769 aryl amino group Chemical group 0.000 claims description 2
- 125000004658 aryl carbonyl amino group Chemical group 0.000 claims description 2
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 2
- 125000005110 aryl thio group Chemical group 0.000 claims description 2
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 2
- 125000005224 heteroarylcarbonylamino group Chemical group 0.000 claims description 2
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 2
- 125000005419 heteroarylsulfonylamino group Chemical group 0.000 claims description 2
- 125000004476 heterocycloamino group Chemical group 0.000 claims description 2
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 5
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 3
- 125000005518 carboxamido group Chemical group 0.000 claims 3
- DZNDYNYYGOXWRI-UHFFFAOYSA-N 2-(phenylcarbamoylamino)-6-phenyldiazenylpyridine-3-carboxamide Chemical compound C1(=CC=CC=C1)N=NC1=NC(=C(C(=O)N)C=C1)NC(=O)NC1=CC=CC=C1 DZNDYNYYGOXWRI-UHFFFAOYSA-N 0.000 claims 2
- IJXCJGRIXKACLA-UHFFFAOYSA-N 4-anilino-2-benzamido-N-phenoxy-6-(phenylcarbamoylamino)-5-phenyldiazenyl-N-thiophen-2-yloxypyridine-3-carboxamide Chemical compound O(C1=CC=CC=C1)N(C(C1=C(N=C(C(=C1NC1=CC=CC=C1)N=NC1=CC=CC=C1)NC(=O)NC1=CC=CC=C1)NC(C1=CC=CC=C1)=O)=O)OC=1SC=CC=1 IJXCJGRIXKACLA-UHFFFAOYSA-N 0.000 claims 2
- PLWBSJWYLYHCHG-UHFFFAOYSA-N 2-anilino-6-benzamido-N-phenoxy-5-phenyldiazenyl-4-thiophen-2-yloxypyridine-3-carboxamide Chemical compound O(C1=CC=CC=C1)NC(C1=C(N=C(C(=C1OC=1SC=CC=1)N=NC1=CC=CC=C1)NC(C1=CC=CC=C1)=O)NC1=CC=CC=C1)=O PLWBSJWYLYHCHG-UHFFFAOYSA-N 0.000 claims 1
- IRZJMFLALCFHSF-UHFFFAOYSA-N 4-anilino-2-benzamido-N-phenoxy-6-phenyldiazenyl-5-thiophen-2-yloxypyridine-3-carboxamide Chemical compound O(C1=CC=CC=C1)NC(C1=C(N=C(C(=C1NC1=CC=CC=C1)OC=1SC=CC=1)N=NC1=CC=CC=C1)NC(C1=CC=CC=C1)=O)=O IRZJMFLALCFHSF-UHFFFAOYSA-N 0.000 claims 1
- 125000004470 heterocyclooxy group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 34
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 abstract description 25
- 102000002274 Matrix Metalloproteinases Human genes 0.000 abstract description 11
- 108010000684 Matrix Metalloproteinases Proteins 0.000 abstract description 11
- 230000002401 inhibitory effect Effects 0.000 abstract description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 408
- 239000000243 solution Substances 0.000 description 320
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 222
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 126
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 123
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 112
- 239000007787 solid Substances 0.000 description 102
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 82
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 72
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 70
- 239000000203 mixture Substances 0.000 description 69
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 62
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 57
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 54
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 51
- 239000012044 organic layer Substances 0.000 description 48
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 47
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 41
- 235000019341 magnesium sulphate Nutrition 0.000 description 41
- 239000002904 solvent Substances 0.000 description 41
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 38
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 36
- 238000004587 chromatography analysis Methods 0.000 description 34
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- 150000003457 sulfones Chemical class 0.000 description 33
- 230000005764 inhibitory process Effects 0.000 description 30
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 30
- 150000003254 radicals Chemical class 0.000 description 28
- 238000003756 stirring Methods 0.000 description 28
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 26
- 239000002585 base Substances 0.000 description 26
- 150000004702 methyl esters Chemical class 0.000 description 26
- 238000010992 reflux Methods 0.000 description 26
- 238000006243 chemical reaction Methods 0.000 description 25
- 239000010410 layer Substances 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 23
- 238000004128 high performance liquid chromatography Methods 0.000 description 23
- 239000001257 hydrogen Substances 0.000 description 23
- 229910052739 hydrogen Inorganic materials 0.000 description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- 239000000706 filtrate Substances 0.000 description 22
- 239000011734 sodium Substances 0.000 description 22
- 108050005238 Collagenase 3 Proteins 0.000 description 21
- 102100027995 Collagenase 3 Human genes 0.000 description 21
- 239000007832 Na2SO4 Substances 0.000 description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 21
- 229910052938 sodium sulfate Inorganic materials 0.000 description 21
- 235000011152 sodium sulphate Nutrition 0.000 description 21
- 102000004190 Enzymes Human genes 0.000 description 20
- 108090000790 Enzymes Proteins 0.000 description 20
- 239000003153 chemical reaction reagent Substances 0.000 description 20
- 229940088598 enzyme Drugs 0.000 description 20
- 102100026802 72 kDa type IV collagenase Human genes 0.000 description 19
- 229920006395 saturated elastomer Polymers 0.000 description 19
- 201000010099 disease Diseases 0.000 description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 18
- 239000003921 oil Substances 0.000 description 18
- 235000019198 oils Nutrition 0.000 description 18
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 17
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 17
- 150000001408 amides Chemical class 0.000 description 17
- 239000003112 inhibitor Substances 0.000 description 17
- 125000006239 protecting group Chemical group 0.000 description 17
- 150000002148 esters Chemical class 0.000 description 16
- 101710151806 72 kDa type IV collagenase Proteins 0.000 description 15
- 238000001953 recrystallisation Methods 0.000 description 15
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 14
- 235000015320 potassium carbonate Nutrition 0.000 description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 description 14
- 239000011780 sodium chloride Substances 0.000 description 14
- 125000000217 alkyl group Chemical group 0.000 description 13
- 230000015572 biosynthetic process Effects 0.000 description 13
- 150000002009 diols Chemical class 0.000 description 13
- 238000007254 oxidation reaction Methods 0.000 description 13
- 238000000746 purification Methods 0.000 description 13
- 238000001665 trituration Methods 0.000 description 13
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 230000003647 oxidation Effects 0.000 description 12
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
- 108010015302 Matrix metalloproteinase-9 Proteins 0.000 description 11
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 11
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- 150000002924 oxiranes Chemical class 0.000 description 11
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 11
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 10
- 239000012298 atmosphere Substances 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 9
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 9
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 9
- 150000001805 chlorine compounds Chemical class 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 102000003390 tumor necrosis factor Human genes 0.000 description 9
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 8
- 102000029816 Collagenase Human genes 0.000 description 8
- 108060005980 Collagenase Proteins 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 102100030412 Matrix metalloproteinase-9 Human genes 0.000 description 8
- 239000004202 carbamide Substances 0.000 description 8
- 210000002808 connective tissue Anatomy 0.000 description 8
- 210000004087 cornea Anatomy 0.000 description 8
- 239000008187 granular material Substances 0.000 description 8
- 150000004820 halides Chemical class 0.000 description 8
- 229910052744 lithium Inorganic materials 0.000 description 8
- 230000000269 nucleophilic effect Effects 0.000 description 8
- 150000003573 thiols Chemical class 0.000 description 8
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 7
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 7
- 241000124008 Mammalia Species 0.000 description 7
- 150000001204 N-oxides Chemical class 0.000 description 7
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 230000008901 benefit Effects 0.000 description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 7
- 229960002424 collagenase Drugs 0.000 description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 7
- 238000011068 loading method Methods 0.000 description 7
- 239000011777 magnesium Substances 0.000 description 7
- 229910052751 metal Inorganic materials 0.000 description 7
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- 239000012285 osmium tetroxide Substances 0.000 description 7
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 7
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- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 6
- YCOXTKKNXUZSKD-UHFFFAOYSA-N 3,4-xylenol Chemical compound CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 description 6
- VUFOTXYLUWEYFC-UHFFFAOYSA-N 4-phenoxybenzenethiol Chemical compound C1=CC(S)=CC=C1OC1=CC=CC=C1 VUFOTXYLUWEYFC-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical class C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- 102100030416 Stromelysin-1 Human genes 0.000 description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 6
- GNVMUORYQLCPJZ-UHFFFAOYSA-M Thiocarbamate Chemical compound NC([S-])=O GNVMUORYQLCPJZ-UHFFFAOYSA-M 0.000 description 6
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 6
- 125000002252 acyl group Chemical group 0.000 description 6
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
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- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 1
- 125000001010 sulfinic acid amide group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000375 suspending agent Substances 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
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000009967 tasteless effect Effects 0.000 description 1
- 210000002435 tendon Anatomy 0.000 description 1
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 1
- 150000003511 tertiary amides Chemical class 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 229940073455 tetraethylammonium hydroxide Drugs 0.000 description 1
- LRGJRHZIDJQFCL-UHFFFAOYSA-M tetraethylazanium;hydroxide Chemical compound [OH-].CC[N+](CC)(CC)CC LRGJRHZIDJQFCL-UHFFFAOYSA-M 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 210000000515 tooth Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000583 toxicological profile Toxicity 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000002827 triflate group Chemical class FC(S(=O)(=O)O*)(F)F 0.000 description 1
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 description 1
- BJAARRARQJZURR-UHFFFAOYSA-N trimethylazanium;hydroxide Chemical compound O.CN(C)C BJAARRARQJZURR-UHFFFAOYSA-N 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- ZDPHROOEEOARMN-UHFFFAOYSA-N undecanoic acid Chemical compound CCCCCCCCCCC(O)=O ZDPHROOEEOARMN-UHFFFAOYSA-N 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
Classifications
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- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
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- C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/64—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
- C07C323/65—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfone or sulfoxide groups bound to the carbon skeleton
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
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- Nutrition Science (AREA)
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- Pain & Pain Management (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US3518297P | 1997-03-04 | 1997-03-04 | |
| US35182P | 1997-03-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2209122T3 true ES2209122T3 (es) | 2004-06-16 |
Family
ID=21881145
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES98911481T Expired - Lifetime ES2206903T3 (es) | 1997-03-04 | 1998-03-04 | Compuestos sulfonilicos divalentes de acido aril o heteroaril-hidroxamco. |
| ES98910177T Expired - Lifetime ES2209122T3 (es) | 1997-03-04 | 1998-03-04 | Compuestos de acido sulfonil alfa-hidroxi hidroxamico aromatico. |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES98911481T Expired - Lifetime ES2206903T3 (es) | 1997-03-04 | 1998-03-04 | Compuestos sulfonilicos divalentes de acido aril o heteroaril-hidroxamco. |
Country Status (19)
| Country | Link |
|---|---|
| US (3) | US6380258B2 (enExample) |
| EP (4) | EP0973392B1 (enExample) |
| JP (4) | JP2001518081A (enExample) |
| KR (3) | KR20000075946A (enExample) |
| CN (3) | CN1254337A (enExample) |
| AT (1) | ATE254599T1 (enExample) |
| AU (2) | AU750130B2 (enExample) |
| BR (2) | BR9808214A (enExample) |
| CA (4) | CA2282318A1 (enExample) |
| DE (1) | DE69819878T2 (enExample) |
| DK (1) | DK0973392T3 (enExample) |
| EA (1) | EA199900792A1 (enExample) |
| ES (2) | ES2206903T3 (enExample) |
| IL (3) | IL131494A (enExample) |
| NO (1) | NO315647B1 (enExample) |
| NZ (1) | NZ337326A (enExample) |
| PL (1) | PL335732A1 (enExample) |
| PT (1) | PT973392E (enExample) |
| WO (1) | WO1998038859A1 (enExample) |
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-
1998
- 1998-03-04 CN CN98804628A patent/CN1254337A/zh active Pending
- 1998-03-04 KR KR1019997008028A patent/KR20000075946A/ko not_active Ceased
- 1998-03-04 DK DK98911481T patent/DK0973392T3/da active
- 1998-03-04 AT AT98911481T patent/ATE254599T1/de not_active IP Right Cessation
- 1998-03-04 EP EP98911481A patent/EP0973392B1/en not_active Expired - Lifetime
- 1998-03-04 EP EP98910177A patent/EP0984959B1/en not_active Expired - Lifetime
- 1998-03-04 AU AU65424/98A patent/AU750130B2/en not_active Ceased
- 1998-03-04 BR BR9808214-0A patent/BR9808214A/pt not_active IP Right Cessation
- 1998-03-04 JP JP53879998A patent/JP2001518081A/ja not_active Abandoned
- 1998-03-04 IL IL13149498A patent/IL131494A/xx not_active IP Right Cessation
- 1998-03-04 BR BR9808166-7A patent/BR9808166A/pt not_active Application Discontinuation
- 1998-03-04 CA CA002282318A patent/CA2282318A1/en not_active Abandoned
- 1998-03-04 EP EP98908949A patent/EP0983257A4/en not_active Withdrawn
- 1998-03-04 IL IL13149598A patent/IL131495A0/xx unknown
- 1998-03-04 ES ES98911481T patent/ES2206903T3/es not_active Expired - Lifetime
- 1998-03-04 DE DE69819878T patent/DE69819878T2/de not_active Expired - Fee Related
- 1998-03-04 WO PCT/US1998/004300 patent/WO1998038859A1/en not_active Ceased
- 1998-03-04 EA EA199900792A patent/EA199900792A1/ru unknown
- 1998-03-04 CN CN98804575A patent/CN1105114C/zh not_active Expired - Fee Related
- 1998-03-04 JP JP53798598A patent/JP2002515900A/ja not_active Abandoned
- 1998-03-04 PL PL98335732A patent/PL335732A1/xx unknown
- 1998-03-04 CN CN98804577A patent/CN1253474A/zh active Pending
- 1998-03-04 IL IL13149398A patent/IL131493A/en not_active IP Right Cessation
- 1998-03-04 NZ NZ337326A patent/NZ337326A/en unknown
- 1998-03-04 JP JP53878098A patent/JP2002515901A/ja not_active Abandoned
- 1998-03-04 ES ES98910177T patent/ES2209122T3/es not_active Expired - Lifetime
- 1998-03-04 KR KR1019997008036A patent/KR20000075954A/ko not_active Ceased
- 1998-03-04 KR KR1019997008037A patent/KR20000075955A/ko not_active Ceased
- 1998-03-04 CA CA002283145A patent/CA2283145A1/en not_active Abandoned
- 1998-03-04 PT PT98911481T patent/PT973392E/pt unknown
- 1998-03-04 EP EP98908964A patent/EP0983258A4/en not_active Withdrawn
- 1998-03-04 JP JP53879698A patent/JP2002513407A/ja not_active Abandoned
- 1998-03-04 CA CA002283272A patent/CA2283272A1/en not_active Abandoned
- 1998-03-04 CA CA002283275A patent/CA2283275A1/en not_active Abandoned
- 1998-03-04 AU AU66865/98A patent/AU750303B2/en not_active Ceased
- 1998-03-04 US US09/230,209 patent/US6380258B2/en not_active Expired - Fee Related
-
1999
- 1999-09-02 NO NO19994252A patent/NO315647B1/no unknown
-
2001
- 2001-11-29 US US09/997,552 patent/US6656954B2/en not_active Expired - Fee Related
-
2003
- 2003-10-27 US US10/695,278 patent/US20040097487A1/en not_active Abandoned
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