ZA200503995B - Pyridine N-oxide compounds as phosphodiesterase 4 inhibitors - Google Patents
Pyridine N-oxide compounds as phosphodiesterase 4 inhibitors Download PDFInfo
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- ZA200503995B ZA200503995B ZA200503995A ZA200503995A ZA200503995B ZA 200503995 B ZA200503995 B ZA 200503995B ZA 200503995 A ZA200503995 A ZA 200503995A ZA 200503995 A ZA200503995 A ZA 200503995A ZA 200503995 B ZA200503995 B ZA 200503995B
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- South Africa
- Prior art keywords
- alkyl
- substituted
- carbon atoms
- halogen
- unsubstituted
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- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 title description 6
- ILVXOBCQQYKLDS-UHFFFAOYSA-N pyridine N-oxide Chemical class [O-][N+]1=CC=CC=C1 ILVXOBCQQYKLDS-UHFFFAOYSA-N 0.000 title description 4
- -1 nitroxide compounds Chemical class 0.000 claims abstract description 591
- 150000001875 compounds Chemical class 0.000 claims abstract description 190
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical class C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 claims abstract description 114
- 101100296720 Dictyostelium discoideum Pde4 gene Proteins 0.000 claims abstract description 21
- 101100082610 Plasmodium falciparum (isolate 3D7) PDEdelta gene Proteins 0.000 claims abstract description 21
- 230000005764 inhibitory process Effects 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 470
- 125000004432 carbon atom Chemical group C* 0.000 claims description 405
- 229910052736 halogen Inorganic materials 0.000 claims description 370
- 150000002367 halogens Chemical class 0.000 claims description 347
- 125000003545 alkoxy group Chemical group 0.000 claims description 216
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 205
- 125000003118 aryl group Chemical group 0.000 claims description 164
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 158
- 125000004043 oxo group Chemical group O=* 0.000 claims description 132
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 130
- 125000006413 ring segment Chemical group 0.000 claims description 123
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 109
- 229920006395 saturated elastomer Polymers 0.000 claims description 108
- 125000000623 heterocyclic group Chemical group 0.000 claims description 91
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 90
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 81
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 76
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 71
- 229910052760 oxygen Inorganic materials 0.000 claims description 65
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 59
- 239000005711 Benzoic acid Substances 0.000 claims description 58
- 235000010233 benzoic acid Nutrition 0.000 claims description 58
- 239000002253 acid Substances 0.000 claims description 57
- 125000004414 alkyl thio group Chemical group 0.000 claims description 56
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 54
- 125000002252 acyl group Chemical group 0.000 claims description 50
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 49
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 49
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 49
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 48
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 48
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 48
- 125000004434 sulfur atom Chemical group 0.000 claims description 48
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 47
- 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 claims description 46
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 46
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 45
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 43
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 43
- 125000003282 alkyl amino group Chemical group 0.000 claims description 42
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 42
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 41
- 125000001072 heteroaryl group Chemical group 0.000 claims description 40
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 32
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 29
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 27
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 24
- 150000003839 salts Chemical class 0.000 claims description 24
- 229910052717 sulfur Inorganic materials 0.000 claims description 20
- 125000002837 carbocyclic group Chemical group 0.000 claims description 19
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 18
- 125000005389 trialkylsiloxy group Chemical group 0.000 claims description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 16
- YUCFVHQCAFKDQG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH] YUCFVHQCAFKDQG-UHFFFAOYSA-N 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 125000004076 pyridyl group Chemical group 0.000 claims description 15
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 14
- 102000004190 Enzymes Human genes 0.000 claims description 14
- 108090000790 Enzymes Proteins 0.000 claims description 14
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 14
- 230000000694 effects Effects 0.000 claims description 14
- 125000003342 alkenyl group Chemical group 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 12
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 125000002947 alkylene group Chemical group 0.000 claims description 10
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 10
- HFZZTHJMXZSGFP-UHFFFAOYSA-N 1-benzofuran-2-amine Chemical compound C1=CC=C2OC(N)=CC2=C1 HFZZTHJMXZSGFP-UHFFFAOYSA-N 0.000 claims description 9
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 9
- 206010027175 memory impairment Diseases 0.000 claims description 9
- 125000001624 naphthyl group Chemical group 0.000 claims description 9
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 9
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 9
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 8
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 8
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 7
- 125000002431 aminoalkoxy group Chemical group 0.000 claims description 7
- 125000004429 atom Chemical group 0.000 claims description 7
- 239000004305 biphenyl Substances 0.000 claims description 7
- 235000010290 biphenyl Nutrition 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- 229910021473 hassium Inorganic materials 0.000 claims description 7
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- 125000003944 tolyl group Chemical group 0.000 claims description 7
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000003678 cyclohexadienyl group Chemical group C1(=CC=CCC1)* 0.000 claims description 5
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims description 5
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 5
- 125000002883 imidazolyl group Chemical group 0.000 claims description 5
- 125000004130 indan-2-yl group Chemical group [H]C1=C([H])C([H])=C2C(=C1[H])C([H])([H])C([H])(*)C2([H])[H] 0.000 claims description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 230000019771 cognition Effects 0.000 claims description 4
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- 201000000980 schizophrenia Diseases 0.000 claims description 4
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
- YDTDKKULPWTHRV-UHFFFAOYSA-N 1H-indazol-3-amine Chemical compound C1=CC=C2C(N)=NNC2=C1 YDTDKKULPWTHRV-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
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- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
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- 125000004622 benzoxazinyl group Chemical group O1NC(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
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- 125000005843 halogen group Chemical group 0.000 claims 23
- WYLSGWZVDHQRNX-UHFFFAOYSA-N 2-(3,4-dimethoxy-n-(4-methylphenyl)sulfonylanilino)-n-(2,4-dimethylpentan-3-yl)acetamide Chemical compound C1=C(OC)C(OC)=CC=C1N(CC(=O)NC(C(C)C)C(C)C)S(=O)(=O)C1=CC=C(C)C=C1 WYLSGWZVDHQRNX-UHFFFAOYSA-N 0.000 claims 7
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- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
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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
- C07D213/89—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 with hetero atoms directly attached to the ring nitrogen atom
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- C07—ORGANIC CHEMISTRY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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- C07—ORGANIC CHEMISTRY
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- 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
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Landscapes
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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| US20030149052A1 (en) * | 2002-01-22 | 2003-08-07 | Memory Pharmaceuticals Corp. | Phosphodiesterase 4 inhibitors |
| MXPA05000827A (es) * | 2002-07-19 | 2005-08-29 | Memory Pharm Corp | Inhibidores de fosfodiesterasa 4, incluyendo analogos de anilina y difenilamina n-sustituidos. |
| CN101423497A (zh) * | 2002-07-19 | 2009-05-06 | 记忆药物公司 | 作为磷酸二酯酶4抑制剂的6-氨基-1h-吲唑和4-氨基苯并呋喃化合物 |
| MXPA05003477A (es) * | 2002-10-03 | 2005-07-22 | Targegen Inc | Agentes vasculo-estaticos y metodos de uso de los mismos. |
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| ES2211344B1 (es) * | 2002-12-26 | 2005-10-01 | Almirall Prodesfarma, S.A. | Nuevos derivados de piridazin-3(2h)-ona. |
| US20090048255A1 (en) * | 2003-07-21 | 2009-02-19 | Schumacher Richard A | Phosphodiesterase 4 inhibitors, including n-substituted aniline and diphenylamine analogs |
| MY141255A (en) * | 2003-12-11 | 2010-03-31 | Memory Pharm Corp | Phosphodiesterase 4 inhibitors, including n-substituted diarylamine analogs |
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| NZ588896A (en) | 2004-08-25 | 2012-05-25 | Targegen Inc | Heterocyclic compounds and methods of use |
| US20070049611A1 (en) * | 2005-06-10 | 2007-03-01 | Talamas Francisco X | Phosphodiesterase 4 inhibitors |
| EP2116523B1 (en) * | 2007-02-27 | 2015-05-06 | National University Corporation Okayama University | Rexinoid compound having alkoxy group |
| ES2320954B1 (es) * | 2007-03-02 | 2010-03-16 | Laboratorio Almirall S.A. | Nuevo procedimiento de preparacion de 3-metil-4-fenilisoxazolo (3,4-d)iridazin-7(6h)-ona. |
| US20090182035A1 (en) * | 2007-04-11 | 2009-07-16 | Alcon Research, Ltd. | Use of a combination of olopatadine and cilomilast to treat non-infectious rhinitis and allergic conjunctivitis |
| CA2682730A1 (en) * | 2007-04-11 | 2008-10-23 | Alcon Research, Ltd. | Use of an inhibitor of tnf.alpha. plus an antihistamine to treat allergic rhinitis and allergic conjunctivitis |
| WO2009067607A2 (en) * | 2007-11-20 | 2009-05-28 | Memory Pharmaceuticals Corporation | Combinations of pde4 inhibitors and antipsychotics for the treatment of psychotic disorders |
| EP2070913A1 (en) * | 2007-12-14 | 2009-06-17 | CHIESI FARMACEUTICI S.p.A. | Ester derivatives as phosphodiesterase inhibitors |
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| WO2010003084A2 (en) * | 2008-07-02 | 2010-01-07 | Memory Pharmaceuticals Corporation | Phosphodiesterase 4 inhibitors |
| JP5542059B2 (ja) * | 2008-10-09 | 2014-07-09 | 国立大学法人 岡山大学 | Ｒｘｒ作動性物質を有効成分とする抗アレルギー剤 |
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| WO2013106547A1 (en) | 2012-01-10 | 2013-07-18 | President And Fellows Of Harvard College | Beta-cell replication promoting compounds and methods of their use |
| AU2014241430B2 (en) | 2013-03-14 | 2018-04-26 | Dart Neuroscience (Cayman) Ltd. | Substituted pyridine and pyrazine compounds as PDE4 inhibitors |
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| CA2114114C (en) | 1992-06-15 | 2005-05-03 | Nigel Robert Arnold Beeley | Trisubstituted phenyl derivatives as selective phosphodiesterase iv inhibitors |
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| US5814651A (en) | 1992-12-02 | 1998-09-29 | Pfizer Inc. | Catechol diethers as selective PDEIV inhibitors |
| US5622977A (en) | 1992-12-23 | 1997-04-22 | Celltech Therapeutics Limited | Tri-substituted (aryl or heteroaryl) derivatives and pharmaceutical compositions containing the same |
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-
2003
- 2003-11-19 RU RU2005119627/04A patent/RU2356893C2/ru not_active IP Right Cessation
- 2003-11-19 DE DE60334243T patent/DE60334243D1/de not_active Expired - Lifetime
- 2003-11-19 WO PCT/US2003/036986 patent/WO2004046113A2/en not_active Ceased
- 2003-11-19 KR KR1020057008915A patent/KR20050075430A/ko not_active Ceased
- 2003-11-19 CN CNB2003801036392A patent/CN100513397C/zh not_active Expired - Fee Related
- 2003-11-19 JP JP2004553941A patent/JP2006508987A/ja not_active Ceased
- 2003-11-19 BR BR0315705-9A patent/BR0315705A/pt not_active Application Discontinuation
- 2003-11-19 NZ NZ540138A patent/NZ540138A/en not_active IP Right Cessation
- 2003-11-19 MX MXPA05005345A patent/MXPA05005345A/es active IP Right Grant
- 2003-11-19 CA CA002506297A patent/CA2506297A1/en not_active Abandoned
- 2003-11-19 US US10/715,819 patent/US7087625B2/en not_active Expired - Fee Related
- 2003-11-19 EP EP03786857A patent/EP1569908B1/en not_active Expired - Lifetime
- 2003-11-19 AT AT03786857T patent/ATE481387T1/de not_active IP Right Cessation
- 2003-11-19 AU AU2003295656A patent/AU2003295656B2/en not_active Expired - Fee Related
-
2005
- 2005-05-18 ZA ZA200503995A patent/ZA200503995B/en unknown
- 2005-06-17 NO NO20052976A patent/NO20052976L/no unknown
-
2006
- 2006-03-20 US US11/378,615 patent/US7700631B2/en not_active Expired - Fee Related
-
2010
- 2010-03-16 US US12/724,750 patent/US20100173942A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO2004046113A3 (en) | 2005-03-24 |
| US7087625B2 (en) | 2006-08-08 |
| NO20052976D0 (no) | 2005-06-17 |
| KR20050075430A (ko) | 2005-07-20 |
| DE60334243D1 (de) | 2010-10-28 |
| EP1569908A2 (en) | 2005-09-07 |
| US20100173942A1 (en) | 2010-07-08 |
| BR0315705A (pt) | 2005-09-06 |
| CA2506297A1 (en) | 2004-06-03 |
| US20040152902A1 (en) | 2004-08-05 |
| NZ540138A (en) | 2008-07-31 |
| US20060211865A1 (en) | 2006-09-21 |
| AU2003295656A1 (en) | 2004-06-15 |
| US7700631B2 (en) | 2010-04-20 |
| JP2006508987A (ja) | 2006-03-16 |
| MXPA05005345A (es) | 2005-08-26 |
| AU2003295656B2 (en) | 2010-11-11 |
| RU2005119627A (ru) | 2006-01-27 |
| NO20052976L (no) | 2005-08-18 |
| CN1714081A (zh) | 2005-12-28 |
| RU2356893C2 (ru) | 2009-05-27 |
| EP1569908B1 (en) | 2010-09-15 |
| AU2003295656A2 (en) | 2005-06-30 |
| CN100513397C (zh) | 2009-07-15 |
| ATE481387T1 (de) | 2010-10-15 |
| WO2004046113A2 (en) | 2004-06-03 |
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