ZA200503204B - Combination thereapy using 1-aminocyclohexane derivatives and acetylcholinesterase inhibitors - Google Patents
Combination thereapy using 1-aminocyclohexane derivatives and acetylcholinesterase inhibitors Download PDFInfo
- Publication number
- ZA200503204B ZA200503204B ZA200503204A ZA200503204A ZA200503204B ZA 200503204 B ZA200503204 B ZA 200503204B ZA 200503204 A ZA200503204 A ZA 200503204A ZA 200503204 A ZA200503204 A ZA 200503204A ZA 200503204 B ZA200503204 B ZA 200503204B
- Authority
- ZA
- South Africa
- Prior art keywords
- amino
- adamantane
- ethyl
- trans
- methyl
- Prior art date
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- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical class NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 title claims description 70
- 239000000544 cholinesterase inhibitor Substances 0.000 title claims description 67
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 claims description 250
- BUGYDGFZZOZRHP-UHFFFAOYSA-N memantine Chemical compound C1C(C2)CC3(C)CC1(C)CC2(N)C3 BUGYDGFZZOZRHP-UHFFFAOYSA-N 0.000 claims description 150
- 229960004640 memantine Drugs 0.000 claims description 145
- 239000000203 mixture Substances 0.000 claims description 120
- 229960003530 donepezil Drugs 0.000 claims description 116
- 208000024827 Alzheimer disease Diseases 0.000 claims description 96
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 88
- 238000000034 method Methods 0.000 claims description 74
- 239000003814 drug Substances 0.000 claims description 54
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 45
- 238000011282 treatment Methods 0.000 claims description 41
- 229940100578 Acetylcholinesterase inhibitor Drugs 0.000 claims description 37
- 206010012289 Dementia Diseases 0.000 claims description 36
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical group O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 claims description 33
- -1 ary} Chemical group 0.000 claims description 32
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 28
- OGZQTTHDGQBLBT-UHFFFAOYSA-N neramexane Chemical compound CC1(C)CC(C)(C)CC(C)(N)C1 OGZQTTHDGQBLBT-UHFFFAOYSA-N 0.000 claims description 24
- 150000001875 compounds Chemical class 0.000 claims description 23
- XSVMFMHYUFZWBK-NSHDSACASA-N Rivastigmine Chemical compound CCN(C)C(=O)OC1=CC=CC([C@H](C)N(C)C)=C1 XSVMFMHYUFZWBK-NSHDSACASA-N 0.000 claims description 20
- 229950004543 neramexane Drugs 0.000 claims description 19
- 125000002947 alkylene group Chemical group 0.000 claims description 18
- 229960004136 rivastigmine Drugs 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 18
- ORILYTVJVMAKLC-UHFFFAOYSA-N Adamantane Natural products C1C(C2)CC3CC1CC2C3 ORILYTVJVMAKLC-UHFFFAOYSA-N 0.000 claims description 17
- 229960003980 galantamine Drugs 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 claims description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 15
- 229960001685 tacrine Drugs 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 claims description 14
- 238000012360 testing method Methods 0.000 claims description 14
- 230000008859 change Effects 0.000 claims description 13
- 208000035475 disorder Diseases 0.000 claims description 13
- 210000003169 central nervous system Anatomy 0.000 claims description 12
- 230000006735 deficit Effects 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 12
- 230000002441 reversible effect Effects 0.000 claims description 12
- 125000000304 alkynyl group Chemical group 0.000 claims description 11
- 125000003118 aryl group Chemical group 0.000 claims description 11
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 239000003937 drug carrier Substances 0.000 claims description 9
- OVDULOGIHPNNKW-UHFFFAOYSA-N 1-(1,3,3,5,5-pentamethylcyclohexyl)pyrrolidine Chemical compound C1C(C)(C)CC(C)(C)CC1(C)N1CCCC1 OVDULOGIHPNNKW-UHFFFAOYSA-N 0.000 claims description 8
- 125000004450 alkenylene group Chemical group 0.000 claims description 7
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 7
- 238000009472 formulation Methods 0.000 claims description 7
- 125000003107 substituted aryl group Chemical group 0.000 claims description 7
- YKLPCZMZROZLJA-UHFFFAOYSA-N 1-ethyl-3,3,5,5-tetramethylcyclohexan-1-amine Chemical compound CCC1(N)CC(C)(C)CC(C)(C)C1 YKLPCZMZROZLJA-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- 201000010374 Down Syndrome Diseases 0.000 claims description 6
- 206010044688 Trisomy 21 Diseases 0.000 claims description 6
- 230000003287 optical effect Effects 0.000 claims description 6
- NBZGMQHFDNUNRQ-UHFFFAOYSA-N 3,3-diethyl-1,5,5-trimethylcyclohexan-1-amine Chemical compound CCC1(CC)CC(C)(C)CC(C)(N)C1 NBZGMQHFDNUNRQ-UHFFFAOYSA-N 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 150000004677 hydrates Chemical class 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- MEBONNVPKOBPEA-UHFFFAOYSA-N 1,1,2-trimethylcyclohexane Chemical compound CC1CCCCC1(C)C MEBONNVPKOBPEA-UHFFFAOYSA-N 0.000 claims description 4
- OMYKWZGACJRFAJ-UHFFFAOYSA-N 3,3,5,5-tetramethyl-1-propylcyclohexan-1-amine Chemical compound CCCC1(N)CC(C)(C)CC(C)(C)C1 OMYKWZGACJRFAJ-UHFFFAOYSA-N 0.000 claims description 4
- PMNUOTQOFZGNNQ-UHFFFAOYSA-N 1,3,5-trimethylcyclohexan-1-amine Chemical compound CC1CC(C)CC(C)(N)C1 PMNUOTQOFZGNNQ-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 150000003976 azacycloalkanes Chemical class 0.000 claims description 3
- 208000026106 cerebrovascular disease Diseases 0.000 claims description 3
- NEVCGYUBKUPZRL-UHFFFAOYSA-N (3,3,5,5-tetramethylcyclohexyl)methanamine Chemical compound CC1(C)CC(CN)CC(C)(C)C1 NEVCGYUBKUPZRL-UHFFFAOYSA-N 0.000 claims description 2
- QTXWDXKTMLBHIW-UHFFFAOYSA-N 1,3,3-trimethylcyclohexan-1-amine Chemical compound CC1(C)CCCC(C)(N)C1 QTXWDXKTMLBHIW-UHFFFAOYSA-N 0.000 claims description 2
- BADMBUCXLGEWNJ-UHFFFAOYSA-N 1,3-dimethyl-3-propylcyclohexan-1-amine Chemical compound CCCC1(C)CCCC(C)(N)C1 BADMBUCXLGEWNJ-UHFFFAOYSA-N 0.000 claims description 2
- QVEQDLBYFRYKKW-UHFFFAOYSA-N 1-(1,3,5-trimethylcyclohexyl)pyrrolidine Chemical compound C1C(C)CC(C)CC1(C)N1CCCC1 QVEQDLBYFRYKKW-UHFFFAOYSA-N 0.000 claims description 2
- LODZBBPOQRJCTJ-UHFFFAOYSA-N 1-(3,3,5,5-tetramethyl-1-propylcyclohexyl)pyrrolidine Chemical compound C1CCCN1C1(CCC)CC(C)(C)CC(C)(C)C1 LODZBBPOQRJCTJ-UHFFFAOYSA-N 0.000 claims description 2
- VZMMNFHWJMVOSI-UHFFFAOYSA-N 1-(3-ethyl-1,3,5,5-tetramethylcyclohexyl)pyrrolidine Chemical compound C1C(CC)(C)CC(C)(C)CC1(C)N1CCCC1 VZMMNFHWJMVOSI-UHFFFAOYSA-N 0.000 claims description 2
- XSOHXMFFSKTSIT-UHFFFAOYSA-N 1-adamantylmethanamine Chemical compound C1C(C2)CC3CC2CC1(CN)C3 XSOHXMFFSKTSIT-UHFFFAOYSA-N 0.000 claims description 2
- OIHULWBOFIEYPQ-UHFFFAOYSA-N 2-(3,3,5,5-tetramethylcyclohexyl)ethanamine Chemical compound CC1(C)CC(CCN)CC(C)(C)C1 OIHULWBOFIEYPQ-UHFFFAOYSA-N 0.000 claims description 2
- XOEUSMBMGXZZJL-UHFFFAOYSA-N 3,5,7-trimethyladamantan-1-amine Chemical compound C1C(C2)(C)CC3(C)CC1(C)CC2(N)C3 XOEUSMBMGXZZJL-UHFFFAOYSA-N 0.000 claims description 2
- ICJYJPOGTLSWBN-UHFFFAOYSA-N 3,5-di(propan-2-yl)adamantan-1-amine Chemical compound C1C(C2)CC3(N)CC1(C(C)C)CC2(C(C)C)C3 ICJYJPOGTLSWBN-UHFFFAOYSA-N 0.000 claims description 2
- KAQDREXRTIUTKK-UHFFFAOYSA-N 3,5-dibutyladamantan-1-amine Chemical compound C1C(C2)CC3(N)CC1(CCCC)CC2(CCCC)C3 KAQDREXRTIUTKK-UHFFFAOYSA-N 0.000 claims description 2
- SUVNEFNZAWETBP-UHFFFAOYSA-N 3,5-diethyladamantan-1-amine Chemical compound C1C(C2)CC3(N)CC1(CC)CC2(CC)C3 SUVNEFNZAWETBP-UHFFFAOYSA-N 0.000 claims description 2
- MAQDODRYDKZRSA-UHFFFAOYSA-N 3,5-dihexyladamantan-1-amine Chemical compound C1C(C2)CC3(N)CC1(CCCCCC)CC2(CCCCCC)C3 MAQDODRYDKZRSA-UHFFFAOYSA-N 0.000 claims description 2
- QWBQEEKAKVRBIF-UHFFFAOYSA-N 3,5-dipentyladamantan-1-amine Chemical compound C1C(C2)CC3(N)CC1(CCCCC)CC2(CCCCC)C3 QWBQEEKAKVRBIF-UHFFFAOYSA-N 0.000 claims description 2
- WPXLJHZRYJANCQ-UHFFFAOYSA-N 3,5-diphenyladamantan-1-amine Chemical compound C1C(N)(C2)CC(C3)CC1(C=1C=CC=CC=1)CC32C1=CC=CC=C1 WPXLJHZRYJANCQ-UHFFFAOYSA-N 0.000 claims description 2
- RBLRBILRVQBSIG-UHFFFAOYSA-N 3-butyl-5-cyclohexyladamantan-1-amine Chemical compound C1C(CCCC)(C2)CC(C3)CC1(N)CC32C1CCCCC1 RBLRBILRVQBSIG-UHFFFAOYSA-N 0.000 claims description 2
- DEIFIQCDTVHYOV-UHFFFAOYSA-N 3-butyl-5-ethyladamantan-1-amine Chemical compound C1C(C2)CC3(N)CC2(CC)CC1(CCCC)C3 DEIFIQCDTVHYOV-UHFFFAOYSA-N 0.000 claims description 2
- TXZQKDJQUVYBAV-UHFFFAOYSA-N 3-butyl-5-methyladamantan-1-amine Chemical compound C1C(C2)CC3(C)CC2(N)CC1(CCCC)C3 TXZQKDJQUVYBAV-UHFFFAOYSA-N 0.000 claims description 2
- DMYFHACLIMYSRB-UHFFFAOYSA-N 3-butyl-5-pentyladamantan-1-amine Chemical compound C1C(C2)CC3(N)CC2(CCCC)CC1(CCCCC)C3 DMYFHACLIMYSRB-UHFFFAOYSA-N 0.000 claims description 2
- HJFLKCNNMZSALM-UHFFFAOYSA-N 3-butyl-5-phenyladamantan-1-amine Chemical compound C1C(CCCC)(C2)CC(C3)CC1(N)CC32C1=CC=CC=C1 HJFLKCNNMZSALM-UHFFFAOYSA-N 0.000 claims description 2
- KUNFZDMYUIQERL-UHFFFAOYSA-N 3-butyladamantan-1-amine Chemical compound C1C(C2)CC3CC2(N)CC1(CCCC)C3 KUNFZDMYUIQERL-UHFFFAOYSA-N 0.000 claims description 2
- QPSPKNCPWYOZOQ-UHFFFAOYSA-N 3-cyclohexyl-5-ethyladamantan-1-amine Chemical compound C1C(CC)(C2)CC(C3)CC1(N)CC32C1CCCCC1 QPSPKNCPWYOZOQ-UHFFFAOYSA-N 0.000 claims description 2
- XWSMYWOEEAGQCR-UHFFFAOYSA-N 3-cyclohexyl-5-methyladamantan-1-amine Chemical compound C1C(C)(C2)CC(C3)CC1(N)CC32C1CCCCC1 XWSMYWOEEAGQCR-UHFFFAOYSA-N 0.000 claims description 2
- IFCVAKRZRKACNB-UHFFFAOYSA-N 3-cyclohexyl-5-pentyladamantan-1-amine Chemical compound C1C(CCCCC)(C2)CC(C3)CC1(N)CC32C1CCCCC1 IFCVAKRZRKACNB-UHFFFAOYSA-N 0.000 claims description 2
- BOBKSKBPCSEMON-UHFFFAOYSA-N 3-cyclohexyl-5-propyladamantan-1-amine Chemical compound C1C(CCC)(C2)CC(C3)CC1(N)CC32C1CCCCC1 BOBKSKBPCSEMON-UHFFFAOYSA-N 0.000 claims description 2
- WLPZAHQYMVQLHL-UHFFFAOYSA-N 3-cyclohexyladamantan-1-amine Chemical compound C1C(N)(C2)CC(C3)CC1CC32C1CCCCC1 WLPZAHQYMVQLHL-UHFFFAOYSA-N 0.000 claims description 2
- JINZKAFNDLFUEW-UHFFFAOYSA-N 3-ethyl-1,3,5,5-tetramethylcyclohexan-1-amine Chemical compound CCC1(C)CC(C)(C)CC(C)(N)C1 JINZKAFNDLFUEW-UHFFFAOYSA-N 0.000 claims description 2
- QJZCXHNEPQJAPJ-UHFFFAOYSA-N 3-ethyl-5,7-dimethyladamantan-1-amine Chemical compound C1C(C2)(C)CC3(C)CC2(N)CC1(CC)C3 QJZCXHNEPQJAPJ-UHFFFAOYSA-N 0.000 claims description 2
- WHQKNPQELALARV-UHFFFAOYSA-N 3-ethyl-5-hexyladamantan-1-amine Chemical compound C1C(C2)CC3(N)CC2(CC)CC1(CCCCCC)C3 WHQKNPQELALARV-UHFFFAOYSA-N 0.000 claims description 2
- ZWHAFHCGBIKBIF-UHFFFAOYSA-N 3-ethyl-5-methyladamantan-1-amine Chemical compound C1C(C2)CC3(C)CC2(N)CC1(CC)C3 ZWHAFHCGBIKBIF-UHFFFAOYSA-N 0.000 claims description 2
- GAWKCQRMGQRNML-UHFFFAOYSA-N 3-ethyl-5-pentyladamantan-1-amine Chemical compound C1C(C2)CC3(N)CC2(CC)CC1(CCCCC)C3 GAWKCQRMGQRNML-UHFFFAOYSA-N 0.000 claims description 2
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- LOPRUTAJASQIDA-UHFFFAOYSA-N 3-hexyl-5-methyladamantan-1-amine Chemical compound C1C(C2)CC3(C)CC2(N)CC1(CCCCCC)C3 LOPRUTAJASQIDA-UHFFFAOYSA-N 0.000 claims description 2
- URZNPFBAGSZRJP-UHFFFAOYSA-N 3-hexyl-5-pentyladamantan-1-amine Chemical compound C1C(C2)CC3(N)CC2(CCCCC)CC1(CCCCCC)C3 URZNPFBAGSZRJP-UHFFFAOYSA-N 0.000 claims description 2
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
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- A61K31/47—Quinolines; Isoquinolines
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
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ZA200503204A ZA200503204B (en) | 2002-10-24 | 2005-04-20 | Combination thereapy using 1-aminocyclohexane derivatives and acetylcholinesterase inhibitors |
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EP (2) | EP1556019A2 (de) |
JP (2) | JP2006506378A (de) |
KR (2) | KR100777904B1 (de) |
CN (1) | CN100339070C (de) |
AU (1) | AU2003274353B2 (de) |
CA (1) | CA2502432A1 (de) |
EA (1) | EA008863B1 (de) |
GE (1) | GEP20094759B (de) |
HK (1) | HK1085658A1 (de) |
MX (1) | MXPA04006900A (de) |
NO (1) | NO20052462L (de) |
PL (1) | PL376476A1 (de) |
TW (1) | TW200418446A (de) |
UA (1) | UA83645C2 (de) |
WO (1) | WO2004037234A2 (de) |
ZA (1) | ZA200503204B (de) |
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2003
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- 2003-10-23 CN CNB200380104613XA patent/CN100339070C/zh not_active Expired - Fee Related
- 2003-10-23 CA CA002502432A patent/CA2502432A1/en not_active Abandoned
- 2003-10-23 EP EP03758338A patent/EP1556019A2/de not_active Withdrawn
- 2003-10-23 EP EP10181505A patent/EP2260839A3/de not_active Withdrawn
- 2003-10-23 TW TW092129457A patent/TW200418446A/zh unknown
- 2003-10-23 WO PCT/GB2003/004549 patent/WO2004037234A2/en active IP Right Grant
- 2003-10-23 US US10/691,895 patent/US20040087658A1/en not_active Abandoned
- 2003-10-23 EA EA200500699A patent/EA008863B1/ru unknown
- 2003-10-23 MX MXPA04006900A patent/MXPA04006900A/es active IP Right Grant
- 2003-10-23 GE GEAP20038812A patent/GEP20094759B/en unknown
- 2003-10-23 UA UAA200504854A patent/UA83645C2/ru unknown
- 2003-10-23 PL PL03376476A patent/PL376476A1/xx not_active Application Discontinuation
- 2003-10-23 KR KR1020057007052A patent/KR100777904B1/ko not_active IP Right Cessation
- 2003-10-23 KR KR1020077016542A patent/KR100852834B1/ko not_active IP Right Cessation
- 2003-10-23 JP JP2004546158A patent/JP2006506378A/ja active Pending
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2005
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2010
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2014
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TW200418446A (en) | 2004-10-01 |
EA200500699A1 (ru) | 2005-10-27 |
US20140371260A1 (en) | 2014-12-18 |
EP1556019A2 (de) | 2005-07-27 |
US20100227852A1 (en) | 2010-09-09 |
US20160136144A1 (en) | 2016-05-19 |
EP2260839A2 (de) | 2010-12-15 |
WO2004037234A3 (en) | 2004-08-05 |
GEP20094759B (en) | 2009-08-25 |
CA2502432A1 (en) | 2004-05-06 |
EP2260839A3 (de) | 2012-05-02 |
JP2011246491A (ja) | 2011-12-08 |
AU2003274353A1 (en) | 2004-05-13 |
US20210169864A1 (en) | 2021-06-10 |
CN1720035A (zh) | 2006-01-11 |
KR100777904B1 (ko) | 2007-11-28 |
WO2004037234A2 (en) | 2004-05-06 |
AU2003274353B2 (en) | 2007-04-05 |
EA008863B1 (ru) | 2007-08-31 |
NO20052462D0 (no) | 2005-05-23 |
CN100339070C (zh) | 2007-09-26 |
JP2006506378A (ja) | 2006-02-23 |
US20090124659A1 (en) | 2009-05-14 |
US20040087658A1 (en) | 2004-05-06 |
HK1085658A1 (en) | 2006-09-01 |
MXPA04006900A (es) | 2004-10-15 |
KR100852834B1 (ko) | 2008-08-18 |
PL376476A1 (en) | 2005-12-27 |
KR20070087161A (ko) | 2007-08-27 |
NO20052462L (no) | 2005-07-20 |
KR20050072770A (ko) | 2005-07-12 |
UA83645C2 (ru) | 2008-08-11 |
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